Hypervalent iodine CF.SUB.2.CF.SUB.2.X reagents and their use

Abstract

Described herein are hypervalent iodine reagents.

Claims

1. A compound of formula (I) or formula (II), or a salt thereof, ##STR00138## wherein R is a nucleophile of formula III, -L.sup.1.sub.a-R.sup.1-L.sup.2.sub.c-R.sup.2.sub.d-L.sup.3.sub.e-E (III), wherein a is 0 or 1 and L.sup.1 is selected from O, S or C.sub.1-alkyl, R.sup.1 is selected from imidazole, pyrazole, benzimidazole, phenyl and pyridine, c is 0 or 1 and L.sup.2 is a C.sub.1-4-alkyl, d is 0 or 1 and R.sup.2 is selected from C(O)O, O(CO), N(R.sup.5), N(R.sup.5)C(O), C(O)N(R.sup.5) and N(R.sup.5)SO.sub.2, with R.sup.5 being selected from H, C.sub.1-4-alkyl, C.sub.2-4-alkene, C.sub.2-4-alkynyl, SO.sub.2F, CHO, C(O)O-tertbutyl (Boc), CCSi(CH.sub.3).sub.3, 3-Oxo-4,7,7-trimethyl-2-oxabicyclo[2.2.1]heptane-1-carbonyl (camphanic carbonyl), an affinity tag selected from the group consisting of a biotin tag and a Myc tag, or a fluorescent dye, e is 0 or 1 and L.sup.3 is selected from C.sub.1-8-alkyl-, -phenyl-, [(CH.sub.2).sub.1-4O].sub.1-5, [(CH.sub.2).sub.1-4O].sub.1-4(CH.sub.2).sub.1-4, and [(CH.sub.2).sub.1-4O].sub.1-4-triazole-[(CH.sub.2).sub.1-4O].sub.1-2(CH.sub.2).sub.1-2, and E is selected from H, C.sub.1-4-alkyl, C.sub.2-4-alkenyl, C.sub.2-4-alkynyl, NO.sub.2, halogen, NH.sub.2, OH, C.sub.1-3N.sub.3, N.sub.3, CN, SO.sub.2F, CHO, C(O)O-tertbutyl (Boc), Si(CH.sub.3).sub.3(TMS), Si(CH.sub.2CH.sub.3).sub.3, OSi(CH.sub.3).sub.3, OSi(CH.sub.2CH.sub.3).sub.3, CCSi(CH.sub.3).sub.3, 3-Oxo-4,7,7-trimethyl-2-oxabicyclo[2.2.1]heptane-1-carbonyl (camphanic carbonyl), pinalcolyl boronate, dioxolanyl, a bioorthogonal group, an affinity tag selected from the groups consisting of a biotin tag and a Myc tag, or a fluorescent dye, or R is a nucleophile of formula IV, -L.sup.4.sub.f-R.sup.6.sub.g-G (IV), wherein f is 0 or 1 and L.sup.4 is selected from C.sub.1-2-alkyl, g is 0 or 1 and R.sup.6 is selected from N(R.sup.8), C(O)N(R.sup.8), N(R.sup.8)C(O), with R.sup.8 being selected from H, C.sub.1-4-alkyl, C.sub.2-4-alkene, C.sub.2-4-alkynyl, C.sub.1-3N.sub.3, C(O)O-tertbutyl (Boc), an affinity tag selected from the group consisting of a biotin tag and a Myc tag, or a fluorescent dye, in case of f is 0 and g is 0, G is selected from C.sub.1-4-alkyl, C.sub.2-4-alkene, C.sub.2-4-alkynyl, C.sub.1-3N.sub.3, N.sub.3, C(O)O-tertbutyl (Boc), a bioorthogonal group, an affinity tag selected from the group consisting of a biotin tag and a Myc tag, or a fluorescent dye, in all other cases, G is selected from H, C.sub.1-4-alkyl, C.sub.2-4-alkene, C.sub.2-4-alkynyl, C.sub.1-3N.sub.3, N.sub.3, C(O)O-tertbutyl (Boc), a bioorthogonal group, an affinity tag selected from the group consisting of a biotin tag and a Myc tag, or a fluorescent dye.

2. The compound according to claim 1, wherein R is a nucleophile of formula III, -L.sup.1.sub.a-R.sup.1-L.sup.2.sub.c-R.sup.2.sub.d-L.sup.3.sub.e-E (III), wherein a is 0 or 1 and L.sup.1 is selected from O, or C.sub.1-alkyl, R.sup.1 is phenyl, c is 0 or 1 and L.sup.2 is a C.sub.1-4-alkyl, d is 0 or 1 and R.sup.2 is selected from C(O)O, N(R.sup.5), N(R.sup.5)C(O), and N(R.sup.5)SO.sub.2, with R.sup.5 being selected from H, C.sub.1-4-alkyl, C(O)O-tertbutyl (Boc), e is 0 or 1 and L.sup.3 is selected from C.sub.1-6-alkyl-, -phenyl-, [(CH.sub.2).sub.1-4O].sub.1-5, [(CH.sub.2).sub.1-2O].sub.1-4(CH.sub.2).sub.1-2, and [(CH.sub.2).sub.1-2O].sub.1-4-triazole-[(CH.sub.2).sub.1-2O].sub.1(CH.sub.2), and E is selected from H, C.sub.1-4-alkyl, C.sub.2-4-alkynyl, NO.sub.2, halogen, C.sub.1-3N.sub.3, N.sub.3, CN, SO.sub.2F, CHO, C(O)O-tertbutyl (Boc), CCSi(CH.sub.3).sub.3, 3-Oxo-4,7,7-trimethyl-2-oxabicyclo[2.2.1]heptane-1-carbonyl (camphanic carbonyl), an affinity tag selected from the group consisting of a biotin tag and a Myc tag, or a fluorescent dye, or R is a nucleophile of formula IV, -L.sup.4.sub.f-R.sup.6.sub.g-G (IV), wherein f is 0 or 1 and L.sup.4 is selected from C.sub.1-2-alkyl, g is 0 or 1 and R.sup.6 is selected from N(R.sup.8), C(O)N(R.sup.8), with R.sup.8 being selected from H, C.sub.1-4-alkyl, C.sub.2-4-alkenyl, C(O)O-tertbutyl (Boc), G is selected from H, C.sub.1-4-alkyl, C.sub.2-4-alkenyl, N.sub.3, C(O)O-tertbutyl (Boc).

3. The compound according to claim 1, wherein the bioorthogonal group is azide, pikolyl azide or fluoralkyl azide.

4. The compound according to claim 1, wherein the fluorescent dye is selected from coumarin type dyes, rhodamine type dyes, pyrene and fluoresceine.

5. The compound according to claim 1, wherein the fluorescent dye is selected from ##STR00139##

6. The compound according to claim 1, wherein L.sup.1 is selected from O or C.sub.1-alkyl.

7. The compound according to claim 1, wherein R.sup.1 is phenyl.

8. The compound according to claim 1, wherein L.sup.2 is C.sub.1-4-alkyl.

9. The compound according to claim 1, wherein R.sup.2 is selected from C(O)O, N(R.sup.5), N(R.sup.5)C(O) with R.sup.5 being C.sub.1-4-alkyl.

10. The compound according to claim 1, wherein L.sup.3 is C.sub.1-6-alkyl-.

11. The compound according to claim 1, wherein E is selected from H, C.sub.1-2-alkyl, N.sub.3, C(O)O-tertbutyl (Boc).

12. The compound according to claim 1, wherein R in formula I is a nucleophile of formula III, -L.sup.1.sub.a-R.sup.1-L.sup.2.sub.c-R.sup.2.sub.d-L.sup.3.sub.e-E (III), wherein a is 0 or 1 and L.sup.1 is selected from O, or C.sub.1-alkyl, R.sup.1 is selected from phenyl, and phenyl-dioxolane, c is 1 and L.sup.2 is a C.sub.1-4-alkyl, d is 1 and R.sup.2 is selected from C(O)O, N(R.sup.5), N(R.sup.5)C(O), and N(R.sup.5)SO.sub.2, with R.sup.5 being selected from H, C.sub.1-4-alkyl, C(O)O-tertbutyl (Boc), e is 0 or 1 and L.sup.3 is propyl, and E is selected from H, C.sub.1-4-alkyl, C.sub.2-4-alkynyl, NO.sub.2, halogen, C.sub.1-3N.sub.3, N.sub.3, CN, SO.sub.2F, CHO, C(O)O-tertbutyl (Boc), CCSi(CH.sub.3).sub.3, 3-Oxo-4,7,7-trimethyl-2-oxabicyclo[2.2.1]heptane-1-carbonyl (camphanic carbonyl), an affinity tag selected from the group consisting of a biotin tag and a Myc tag, or a fluorescent dye, or a is 0 or 1 and L.sup.1 is selected from O, or C.sub.1-alkyl, R.sup.1 is selected from phenyl, and phenyl-dioxolane, c is 1 and L.sup.2 is a C.sub.1-4-alkyl, d is 1 and R.sup.2 is selected from C(O)O, N(R.sup.5), N(R.sup.5)C(O), and N(R.sup.5)SO.sub.2, with R.sup.5 being selected from H, C.sub.1-4-alkyl, C(O)O-tertbutyl (Boc), e is 0 or 1 and L.sup.3 is selected from C.sub.1-6-alkyl-, -phenyl-, [(CH.sub.2).sub.1-4O].sub.1-5, [(CH.sub.2).sub.1-2O].sub.1-4(CH.sub.2).sub.1-2, and [(CH.sub.2).sub.1-2O].sub.1-4-triazole-[(CH.sub.2).sub.1-2O].sub.1(CH.sub.2), and E is N.sub.3.

13. The compound according to claim 1, wherein R in formula I or II, is of formula III, wherein a is 0 and L.sup.1 is selected from O, or C.sub.1-alkyl, R.sup.1 is selected from phenyl, and phenyl-dioxolane, c is 0 or 1 and L.sup.2 is a C.sub.1-4-alkyl, d is 0 or 1 and R.sup.2 is selected from C(O)O, N(R.sup.5), N(R.sup.5)C(O), and N(R.sup.5)SO.sub.2, with R.sup.5 being selected from H, C.sub.1-4-alkyl, C(O)O-tertbutyl (Boc), e is 0 or 1 and L.sup.3 is selected from C.sub.1-6-alkyl-, -phenyl-, [(CH.sub.2).sub.1-4O].sub.1-5, [(CH.sub.2).sub.1-2O].sub.1-4(CH.sub.2).sub.1-2, and [(CH.sub.2).sub.1-2O].sub.1-4-triazole-[(CH.sub.2).sub.1-2O].sub.1(CH.sub.2), and E is selected from H, C.sub.1-4-alkyl, C.sub.2-4-alkynyl, NO.sub.2, halogen, C.sub.1-3N.sub.3, N.sub.3, CN, SO.sub.2F, CHO, C(O)O-tertbutyl (Boc), CCSi(CH.sub.3).sub.3, 3-Oxo-4,7,7-trimethyl-2-oxabicyclo[2.2.1]heptane-1-carbonyl (camphanic carbonyl), an affinity tag selected from the group consisting of a biotin tag and a Myc tag, or a fluorescent dye.

14. The compound according to claim 1, wherein R in formula II is of formula III, wherein R is a nucleophile of formula III, -L.sup.1.sub.a-R.sup.1-L.sup.2.sub.c-R.sup.2.sub.d-L.sup.3.sub.e-E (III), wherein a is 0 or 1 and L.sup.1 is selected from O, or C.sub.1-alkyl, R.sup.1 is selected from phenyl, and phenyl-dioxolane, c is 1 and L.sup.2 is a C.sub.1-4-alkyl, d is 0 or 1 and R.sup.2 is selected from C(O)O, N(R.sup.5), N(R.sup.5)C(O), and N(R.sup.5)SO.sub.2, with R.sup.5 being selected from H, C.sub.1-4-alkyl, C(O)O-tertbutyl (Boc), e is 0 or 1 and L.sup.3 is selected from C.sub.1-6-alkyl-, -phenyl-, [(CH.sub.2).sub.1-4O].sub.1-5, [(CH.sub.2).sub.1-2O].sub.1-4(CH.sub.2).sub.1-2, and [(CH.sub.2).sub.1-2O].sub.1-4-triazole-[(CH.sub.2).sub.1-2O](CH.sub.2), and E is selected from H, C.sub.1-4-alkyl, C.sub.2-4-alkynyl, NO.sub.2, halogen, C.sub.1-3N.sub.3, N.sub.3, CN, SO.sub.2F, CHO, C(O)O-tertbutyl (Boc), CCSi(CH.sub.3).sub.3, 3-Oxo-4,7,7-trimethyl-2-oxabicyclo[2.2.1]heptane-1-carbonyl (camphanic carbonyl), an affinity tag selected from the group consisting of a biotin tag and a Myc tag, or a fluorescent dye, or R is a nucleophile of formula III, -L.sup.1.sub.a-R.sup.1-L.sup.2.sub.c-R.sup.2.sub.d-L.sup.3.sub.e-E (III), wherein a is 0 or 1 and L.sup.1 is selected from O, or C.sub.1-alkyl, R.sup.1 is selected from phenyl, and phenyl-dioxolane, c is 0 or 1 and L.sup.2 is a C14-alkyl, d is 0 or 1 and R.sup.2 is selected from C(O)O, N(R.sup.5), N(R.sup.5)C(O), and N(R.sup.5)SO.sub.2, with R.sup.5 being selected from H, C.sub.1-4-alkyl, C(O)O-tertbutyl (Boc), e is 0 or 1 and L.sup.3 is selected from C.sub.1-6-alkyl-, -phenyl-, [(CH.sub.2).sub.1-4O].sub.1-5, [(CH.sub.2).sub.1-2O].sub.1-4(CH.sub.2).sub.1-2, and [(CH.sub.2).sub.1-2O].sub.1-4-triazole-[(CH.sub.2).sub.1-2O](CH.sub.2), and E is selected from C.sub.1-4-alkyl, C.sub.2-4-alkynyl, NO.sub.2, halogen, C.sub.1-3N.sub.3, N.sub.3, CN, SO.sub.2F, CHO, C(O)O-tertbutyl (Boc), CCSi(CH.sub.3).sub.3, 3-Oxo-4,7,7-trimethyl-2-oxabicyclo[2.2.1]heptane-1-carbonyl (camphanic carbonyl), an affinity tag selected from the group consisting of a biotin tag and a Myc tag, or a fluorescent dye.

15. The compound according to claim 1, wherein R is a nucleophile of formula IV.

16. The compound according to claim 1, wherein R in formula I or II, is a nucleophile of formula IV, -L.sup.4.sub.f-R.sup.6.sub.g-G (IV), wherein f is 0 or 1, and L.sup.4 is C.sub.1-2-alkyl, g is 0 or 1 and R.sup.6 is selected from N(R.sup.8), C(O)N(R.sup.8), with R.sup.8 being selected from C.sub.1-4-alkyl, C(O)O-tertbutyl (Boc), G is selected from H, C.sub.1-4-alkyl, C.sub.2-alkenyl, N.sub.3, C(O)O-tertbutyl (Boc).

17. The salt according to claim 1, wherein the salt is an acid addition salt between a compound according to formula I or compound according to formula II and a Brnsted-Lowry acid, wherein the proton is bound to the oxygen in ortho position in the benzoiodoxol scaffold of formula I or II.

18. The compound according to claim 1, wherein the salt is an acid addition salt with the addition being selected from HCl or CF.sub.3COOH.

Description

BRIEF DESCRIPTION OF THE FIGURES

(1) FIG. 1 shows an ORTEP view of the X-ray structure of compound 9ak. Hydrogen atoms are omitted for clarity and thermal ellipsoids are drawn at the 50% probability level. Only one of the two independent molecules in the asymmetric unit is shown. Selected bond lengths [] and bond angles [1]: C16-C19 1.523(5), C16-C21 1.553(5), C16-C17 1.545(5), C16-C15 1.548(5),F8-C20 1.326(5), F6-C19 1.369(4); C19-C16-C21 110.8(3), C19-C16-C17112.2(3), C19-C16-C15 108.4(3), C17-C16-C21 113.6(3). CCDC 1442867.

(2) FIG. 2 shows tagging RA-CM with various fluorescent reagents[a] and testing the retro-aldol reaction of (:)-methodol.[b].

SUMMARY

(3) According to a first aspect of the invention, a compound of formula (I) or formula (II),

(4) ##STR00042##
is provided, wherein R is a nucleophile of formula III, -L.sup.1.sub.a-R.sup.1-L.sup.2.sub.c-R.sup.2.sub.d-L.sup.3.sub.e-E (III), wherein a is 0 or 1 and L.sup.1 is selected from O, S or C.sub.1-alkyl, R.sup.1 is selected from imidazole, pyrazole, benzimidazole, phenyl and pyridine, with R.sup.3 and R.sup.4 being independently from each other H or C.sub.1-4-alkyl, c is 0 or 1 and L.sup.2 is a C.sub.1-4-alkyl, d is 0 or 1 and R.sup.2 is selected from C(O)O, O(CO), N(R.sup.5), N(R.sup.5)C(O), C(O)N(R.sup.5) and N(R.sup.5)SO.sub.2, with R.sup.5 being selected from H, C.sub.1-4-alkyl, C.sub.2-4-alkene, C.sub.2-4-alkynyl, SO.sub.2F, CHO, C(O)O-tertbutyl (Boc), CCSi(CH.sub.3).sub.3, 3-Oxo-4,7,7-trimethyl-2-oxabicyclo[2.2.1]heptane-1-carbonyl (camphanic carbonyl), an affinity tag or a fluorescent dye, e is 0 or 1 and L.sup.3 is selected from C.sub.1-8-alkyl-, -phenyl-, [(CH.sub.2).sub.1-4O].sub.1-5, [(CH.sub.2).sub.1-4O].sub.1-4(CH.sub.2).sub.1-4, and [(CH.sub.2).sub.1-4O].sub.1-4-triazole-[(CH.sub.2).sub.1-4O].sub.1-2(CH.sub.2).sub.1-2, and E is selected from H, C.sub.1-4-alkyl, C.sub.2-4-alkenyl, C.sub.2-4-alkynyl, NO.sub.2, halogene, particularly I, NH.sub.2, OH, C.sub.1-3N.sub.3, N.sub.3, CN, SO.sub.2F, CHO, C(O)O-tertbutyl (Boc), Si(CH.sub.3).sub.3(TMS), Si(CH.sub.2CH.sub.3).sub.3, OSi(CH.sub.3).sub.3, OSi(CH.sub.2CH.sub.3).sub.3, CCSi(CH.sub.3).sub.3, 3-Oxo-4,7,7-trimethyl-2-oxabicyclo[2.2.1]heptane-1-carbonyl (camphanic carbonyl), pinalcolyl boronate, dioxolanyl, a bioorthogonal group, an affinity tag or a fluorescent dye, or R is a nucleophile of formula IV, -L.sup.4.sub.fR.sup.6.sub.g-G (IV), wherein f is 0 or 1 and L.sup.4 is selected from C.sub.1-2-alkyl, g is 0 or 1 and R.sup.6 is selected from N(R.sup.8), C(O)N(R.sup.8), N(R.sup.8)C(O), with R.sup.8 being selected from H, C.sub.1-4-alkyl, C.sub.2-4-alkene, C.sub.2-4-alkynyl, C.sub.1-3N.sub.3, C(O)O-tertbutyl (Boc), an affinity tag or a fluorescent dye, in case of f is 0 and g is 0, G is selected from C.sub.1-4-alkyl, C.sub.2-4-alkene, C.sub.2-4-alkynyl, C.sub.1-3N.sub.3, N.sub.3, C(O)O-tertbutyl (Boc), a bioorthogonal group, an affinity tag or a fluorescent dye, in all other cases, G is selected from H, C.sub.1-4-alkyl, C.sub.2-4-alkene, C.sub.2-4-alkynyl, C.sub.1-3N.sub.3, N.sub.3, C(O)O-tertbutyl (Boc), a bioorthogonal group, an affinity tag or a fluorescent dye.

(5) For a skilled person it is obvious that a bond between two heteroatoms (e.g. ON or NSi) will lead to an unstable compound. Thus, the moiety E may only be combined with a moiety R.sup.1, L.sup.2, R.sup.2 or L.sup.3 in such a way that a stable bond results. This means, the moieties NO.sub.2, NH.sub.2, N.sub.3, Si(CH.sub.3).sub.3 may be connected to a C-atom. The same applies for the moiety G.

(6) The double and triple bond of alkene or alkynyl moieties is preferably located at the distal end of the alkene or alkynyl moiety, i.e. the alkene or alkynyl moiety is connected to the parent moiety by a single bonded C atom, e.g. CH.sub.2CHCH.sub.2.

(7) In some embodiments, R is a nucleophile of formula III, -L.sup.1.sub.a-R.sup.1-L.sup.2.sub.c-R.sup.2.sub.d-L.sup.3.sub.e-E (III), wherein a is 0 or 1 and L.sup.1 is selected from O, or C.sub.1-alkyl, R.sup.1 is phenyl, c is 0 or 1 and L.sup.2 is a C.sub.1-4-alkyl, in particular C.sub.1-2-alkyl, d is 0 or 1 and R.sup.2 is selected from C(O)O, N(R.sup.5), N(R.sup.5)C(O), and N(R.sub.5)SO.sub.2, with R.sup.5 being selected from H, C.sub.1-4-alkyl, in particular C.sub.1-2-alkyl, C(O)O-tertbutyl (Boc), e is 0 or 1 and L.sup.3 is selected from C.sub.1-6-alkyl-, in particular C.sub.1-3-alkyl, -phenyl-, [(CH.sub.2).sub.1-4O].sub.1-5, [(CH.sub.2).sub.1-2O].sub.1-4(CH.sub.2).sub.1-2, and [(CH.sub.2).sub.1-2O].sub.1-4-triazole-[(CH.sub.2).sub.1-2O].sub.1(CH.sub.2), and E is selected from H, C.sub.1-4-alkyl, C.sub.2-4-alkynyl, NO.sub.2, halogene, particularly I, C.sub.1-3N.sub.3, N.sub.3, CN, SO.sub.2F, CHO, C(O)O-tertbutyl (Boc), CCSi(CH.sub.3).sub.3, 3-Oxo-4,7,7-trimethyl-2-oxabicyclo[2.2.1]heptane-1-carbonyl (camphanic carbonyl), an affinity tag or a fluorescent dye, or R is a nucleophile of formula IV, -L.sup.4.sub.f-R.sup.6.sub.g-G (IV), wherein f is 0 or 1 and L.sup.4 is selected from C.sub.1-2-alkyl, g is 0 or 1 and R.sup.6 is selected from N(R.sup.8), C(O)N(R.sup.8), with R.sup.8 being selected from H, C.sub.1-4-alkyl, in particular C.sub.1-2-alkyl, C.sub.2-4-alkenyl, in particular C.sub.2-alkenyl, C(O)O-tertbutyl (Boc), in case of f is 0 and g is 0, G is selected from C.sub.1-4-alkyl, in particular C.sub.1-2-alkyl, C.sub.2-4-alkenyl, in particular C.sub.2-alkenyl, N.sub.3, C(O)O-tertbutyl (Boc), in all other cases, G is selected from H, C.sub.1-4-alkyl, in particular C.sub.1-2-alkyl, C.sub.2-4-alkenyl, in particular C.sub.2-alkenyl, N.sub.3, C(O)O-tertbutyl (Boc).

(8) In some embodiments, the biorthogonal group is azide, pikolyl azide or fluoralkyl azide.

(9) Fluoralkyl azide is a moiety RCF.sub.2N.sub.3, wherein R is a C.sub.0-4-alkyl.

(10) In some embodiments, the affinity tag is selected from biotin tag or Myc tag.

(11) In some embodiments, the affinity tag is a biotin tag.

(12) In some embodiments, the fluorescent dye is selected from coumarin type dyes, rhodamine type dyes, pyrene and fluoresceine.

(13) In some embodiments, the fluorescent dye is selected from

(14) ##STR00043##

(15) In some embodiments, L.sup.1 is selected from O or C.sub.1-alkyl.

(16) In some embodiments, R.sup.1 is phenyl.

(17) In some embodiments, L.sup.2 is selected from C.sub.1-4-alkyl.

(18) In some embodiments, L.sup.2 is selected from C.sub.1-2-alkyl.

(19) In some embodiments, R.sup.2 is selected from C(O)O, N(R.sup.5), N(R.sup.5)C(O) with R.sup.5 being selected from C.sub.1-4-alkyl.

(20) In some embodiments, R.sup.2 is selected from C(O)O, N(R.sup.5), N(R.sup.5)C(O) with R.sup.5 being selected from C.sub.1-2-alkyl.

(21) In some embodiments, R.sup.2 is selected from C(O)O, N(R.sup.5), N(R.sup.5)C(O) with R.sup.5 being methyl.

(22) In some embodiments, L.sup.3 is selected from C.sub.1-6-alkyl.

(23) In some embodiments, L.sup.3 is selected from C.sub.1-3-alkyl.

(24) In some embodiments, L.sup.3 is propyl.

(25) In some embodiments, E is selected from H, C.sub.1-2-alkyl, N.sub.3, C(O)O-tertbutyl (Boc).

(26) In some embodiments, E is selected from C.sub.1-2-alkyl, N.sub.3, C(O)O-tertbutyl (Boc).

(27) In some embodiments, R in formula I is a nucleophile of formula Ill, -L.sup.1.sub.a-R.sup.1-L.sup.2.sub.c-R.sup.2.sub.d-L.sup.3.sub.e-E (Ill), wherein a is 0 or 1 and L.sup.1 is selected from O, or C.sub.1-alkyl, in particular O, R.sup.1 is selected from phenyl, and phenyl-dioxolane, in particular phenyl, c is 1 and L.sup.2 is a C.sub.1-4-alkyl, in particular C.sub.1-2-alkyl, d is 1 and R.sup.2 is selected from C(O)O, N(R.sup.5), N(R.sup.5)C(O), and N(R.sup.5)SO.sub.2, in particular N(R.sup.5), N(R.sup.5)C(O), more particularly N(R.sup.5)C(O), with R.sup.5 being selected from H, C.sub.1-4-alkyl, in particular C.sub.1-2-alkyl, C(O)O-tertbutyl (Boc), R.sup.5 being in particular C.sub.1-2 alkyl, more particularly methyl, e is 0 or 1 and L.sup.3 is propyl, and E is selected from H, C.sub.1-4-alkyl, C.sub.2-4-alkynyl, NO.sub.2, halogene, particularly I, C.sub.1-3N.sub.3, N.sub.3, CN, SO.sub.2F, CHO, C(O)O-tertbutyl (Boc), CCSi(CH.sub.3).sup.3, 3-Oxo-4,7,7-trimethyl-2-oxabicyclo[2.2.1]heptane-1-carbonyl (camphanic carbonyl), an affinity tag or a fluorescent dye,

(28) or a is 0 or 1 and L.sup.1 is selected from O, or C.sub.1-alkyl, in particular O, R.sup.1 is selected from phenyl, and phenyl-dioxolane, in particular phenyl, c is 1 and L.sup.2 is a C.sub.1-4-alkyl, in particular C.sub.1-2-alkyl, d is 1 and R.sup.2 is selected from C(O)O, N(R.sup.5), N(R.sup.5)C(O), and N(R.sup.5)SO.sub.2, in particular N(R.sup.5), N(R.sup.5)C(O), more particularly N(R.sup.5)C(O), with R.sup.5 being selected from H, C.sub.1-4-alkyl, in particular C.sub.1-2-alkyl, C(O)O-tertbutyl (Boc), R.sup.5 being in particular C.sub.1-2 alkyl, more particularly methyl, e is 0 or 1 and L.sup.3 is selected from C.sub.1-6-alkyl-, in particular C.sub.1-3-alkyl, -phenyl-, [(CH.sub.2).sub.1-4O].sub.1-5, [(CH.sub.2).sub.1-2O].sub.1-4(CH.sub.2).sub.1-2, and [(CH.sub.2).sub.1-2O].sub.1-4-triazole-[(CH.sub.2).sub.1-2O].sub.1(CH.sub.2), in particular C.sub.1-3 alkyl, and E is N.sub.3.

(29) In some embodiments, R in formula I is a nucleophile of formula III, -L.sup.1.sub.a-R.sup.1-L.sup.2.sub.c-R.sup.2.sub.d-L.sup.3.sub.e-E (III), wherein a is 0 or 1 and L.sup.1 is selected from O, or C.sub.1-alkyl, in particular O, R.sup.1 is selected from phenyl, and phenyl-dioxolane, in particular phenyl, c is 1 and L.sup.2 is a C.sub.1-4-alkyl, in particular C.sub.1-2-alkyl, d is 1 and R.sup.2 is selected from C(O)O, N(R.sup.5), N(R.sup.5)C(O), and N(R.sup.5)SO.sub.2, in particular N(R.sup.5), N(R.sup.5)C(O), more particularly N(R.sup.5)C(O), with R.sup.5 being selected from H, C.sub.1-4-alkyl, in particular C.sub.1-2-alkyl, C(O)O-tertbutyl (Boc), R.sup.5 being in particular C.sub.1-2 alkyl, more particularly methyl, e is 0 or 1 and L.sup.3 is propyl, and E is selected from H, C.sub.1-4-alkyl, C.sub.2-4-alkynyl, NO.sub.2, halogene, particularly I, C.sub.1-3N.sub.3, N.sub.3, CN, SO.sub.2F, CHO, C(O)O-tertbutyl (Boc), CCSi(CH.sub.3).sub.3, 3-Oxo-4,7,7-trimethyl-2-oxabicyclo[2.2.1]heptane-1-carbonyl (camphanic carbonyl), an affinity tag or a fluorescent dye.

(30) In some embodiments, R in formula I is a nucleophile of formula III, -L.sup.1.sub.a-R.sup.1-L.sup.2.sub.c-R.sup.2.sub.d-L.sup.3.sub.e-E (III), wherein a is 0 or 1 and L.sup.1 is selected from O, or C.sub.1-alkyl, in particular O, R.sup.1 is selected from phenyl, and phenyl-dioxolane, in particular phenyl, c is 1 and L.sup.2 is a C.sub.1-4-alkyl, in particular C.sub.1-2-alkyl, d is 1 and R.sup.2 is selected from C(O)O, N(R.sup.5), N(R.sup.5)C(O), and N(R.sup.5)SO.sub.2, in particular N(R.sup.5), N(R.sup.5)C(O), more particularly N(R.sup.5)C(O), with R.sup.5 being selected from H, C.sub.1-4-alkyl, in particular C.sub.1-2-alkyl, C(O)O-tertbutyl (Boc), R.sup.5 being in particular C.sub.1-2 alkyl, more particularly methyl, e is 0 or 1 and L.sup.3 is selected from C.sub.1-6-alkyl-, in particular C.sub.1-3-alkyl, -phenyl-, [(CH.sub.2).sub.1-4O].sub.1-5, [(CH.sub.2).sub.1-2O].sub.1-4(CH.sub.2).sub.1-2, and [(CH.sub.2).sub.1-2O].sub.1-4-triazole-[(CH.sub.2).sub.1-2O].sub.1(CH.sub.2), in particular C.sub.1-3 alkyl, and E is-N.sub.3.

(31) In some embodiments, R in formula I or II, in particular in formula I, is of formula III, wherein a is 0 and L.sup.1 is selected from O, or C.sub.1-alkyl, R.sup.1 is selected from phenyl, and phenyl-dioxolane, in particular phenyl, c is 0 or 1 and L.sup.2 is a C.sub.1-4-alkyl, in particular C.sub.1-2-alkyl, d is 0 or 1 and R.sup.2 is selected from C(O)O, N(R.sup.5), N(R.sup.5)C(O), and N(R.sup.5)SO.sub.2, with R.sup.5 being selected from H, C.sub.1-4-alkyl, in particular C.sub.1-2-alkyl, C(O)O-tertbutyl (Boc), e is 0 or 1 and L.sup.3 is selected from C.sub.1-6-alkyl-, in particular C.sub.1-3-alkyl, -phenyl-, [(CH.sub.2).sub.1-4O].sub.1-5, [(CH.sub.2).sub.1-2O].sub.1-4(CH.sub.2).sub.1-2, and [(CH.sub.2).sub.1-2O].sub.1-4-triazole-[(CH.sub.2).sub.1-2O].sub.1(CH.sub.2), and E is selected from H, C.sub.1-4-alkyl, C.sub.2-4-alkynyl, NO.sub.2, halogene, particularly I, C.sub.1-3N.sub.3, N.sub.3, CN, SO.sub.2F, CHO, C(O)O-tertbutyl (Boc), CCSi(CH.sub.3).sub.3, 3-Oxo-4,7,7-trimethyl-2-oxabicyclo[2.2.1]heptane-1-carbonyl (camphanic carbonyl), an affinity tag or a fluorescent dye.

(32) In some embodiments, R in formula II is of formula III, wherein R is a nucleophile of formula III, -L.sup.1.sub.a-R.sup.1-L.sup.2.sub.c-R.sup.2.sub.d-L.sup.3.sub.e-E (III), wherein a is 0 or 1 and L.sup.1 is selected from O, or C.sub.1-alkyl, R.sup.1 is selected from phenyl, and phenyl-dioxolane, in particular phenyl, c is 1 and L.sup.2 is a C.sub.1-4-alkyl, in particular C.sub.1-2-alkyl, d is 0 or 1 and R.sup.2 is selected from C(O)O, N(R.sup.5), N(R.sup.5)C(O), and N(R.sub.5)SO.sub.2, with R.sup.5 being selected from H, C.sub.1-4-alkyl, in particular C.sub.1-2-alkyl, C(O)O-tertbutyl (Boc), e is 0 or 1 and L.sup.3 is selected from C.sub.1-6-alkyl-, in particular C.sub.1-3-alkyl, -phenyl-, [(CH.sub.2).sub.1-4O].sub.1-5, [(CH.sub.2).sub.1-2O].sub.1-4(CH.sub.2).sub.1-2, and [(CH.sub.2).sub.1-2O].sub.1-4-triazole-[(CH.sub.2).sub.1-2O].sub.1(CH.sub.2), and E is selected from H, C.sub.1-4-alkyl, C.sub.2-4-alkynyl, NO.sub.2, halogene, particularly I, C.sub.1-3N.sub.3, N.sub.3, CN, SO.sub.2F, CHO, C(O)O-tertbutyl (Boc), CCSi(CH.sub.3).sub.3, 3-Oxo-4,7,7-trimethyl-2-oxabicyclo[2.2.1]heptane-1-carbonyl (camphanic carbonyl), an affinity tag or a fluorescent dye, or R is a nucleophile of formula III, -L.sup.1.sub.a-R.sup.1-L.sup.2.sub.c-R.sup.2.sub.d-L.sup.3.sub.e-E (III), wherein a is 0 or 1 and L.sup.1 is selected from O, or C.sub.1-alkyl, R.sup.1 is selected from phenyl, and phenyl-dioxolane, in particular phenyl, c is 0 or 1 and L.sup.2 is a C.sub.1-4-alkyl, in particular C.sub.1-2-alkyl, d is 0 or 1 and R.sup.2 is selected from C(O)O, N(R.sup.5), N(R.sup.5)C(O), and N(R.sub.5)SO.sub.2, with R.sup.5 being selected from H, C.sub.1-4-alkyl, in particular C.sub.1-2-alkyl, C(O)O-tertbutyl (Boc), e is 0 or 1 and L.sup.3 is selected from C.sub.1-6-alkyl-, in particular C.sub.1-3-alkyl, -phenyl-, [(CH.sub.2).sub.1-4O].sub.1-5, [(CH.sub.2).sub.1-2O].sub.1-4(CH.sub.2).sub.1-2, and [(CH.sub.2).sub.1-2O].sub.1-4-triazole-[(CH.sub.2).sub.1-2O].sub.1(CH.sub.2), and E is selected from C.sub.1-4-alkyl, C.sub.2-4-alkynyl, NO.sub.2, halogene, particularly I, C.sub.1-3N.sub.3, N.sub.3, CN, SO.sub.2F, CHO, C(O)O-tertbutyl (Boc), CCSi(CH.sub.3).sub.3, 3-Oxo-4,7,7-trimethyl-2-oxabicyclo[2.2.1]heptane-1-carbonyl (camphanic carbonyl), an affinity tag or a fluorescent dye.

(33) In some embodiments, R in formula II is of formula III, wherein R is a nucleophile of formula III, -L.sup.1.sub.a-R.sup.1-L.sup.2.sub.c-R.sup.2.sub.d-L.sup.3.sub.e-E (III), wherein a is 0 or 1 and L.sup.1 is selected from O, or C.sub.1-alkyl, R.sup.1 is selected from phenyl, and phenyl-dioxolane, in particular phenyl, c is 1 and L.sup.2 is a C.sub.1-4-alkyl, in particular C.sub.1-2-alkyl, d is 0 or 1 and R.sup.2 is selected from C(O)O, N(R.sup.5), N(R.sup.5)C(O), and N(R.sub.5)SO.sub.2, with R.sup.5 being selected from H, C.sub.1-4-alkyl, in particular C.sub.1-2-alkyl, C(O)O-tertbutyl (Boc), e is 0 or 1 and L.sup.3 is selected from C.sub.1-6-alkyl-, in particular C.sub.1-3-alkyl, -phenyl-, [(CH.sub.2).sub.1-4O].sub.1-5, [(CH.sub.2).sub.1-2O].sub.1-4(CH.sub.2).sub.1-2, and [(CH.sub.2).sub.1-2O].sub.1-4-triazole-[(CH.sub.2).sub.1-2O].sub.1(CH.sub.2), and E is selected from H, C.sub.1-4-alkyl, C.sub.2-4-alkynyl, NO.sub.2, halogene, particularly I, C.sub.1-3N.sub.3, N.sub.3, CN, SO.sub.2F, CHO, C(O)O-tertbutyl (Boc), CCSi(CH.sub.3).sub.3, 3-Oxo-4,7,7-trimethyl-2-oxabicyclo[2.2.1]heptane-1-carbonyl (camphanic carbonyl), an affinity tag or a fluorescent dye.

(34) In some embodiments, R in formula II is of formula III, wherein R is a nucleophile of formula III, -L.sup.1.sub.a-R.sup.1-L.sup.2.sub.c-R.sup.2.sub.d-L.sup.3.sub.e-E (III), wherein a is 0 or 1 and L.sup.1 is selected from O, or C.sub.1-alkyl, R.sup.1 is selected from phenyl, and phenyl-dioxolane, in particular phenyl, c is 0 or 1 and L.sup.2 is a C.sub.1-4-alkyl, in particular C.sub.1-2-alkyl, d is 0 or 1 and R.sup.2 is selected from C(O)O, N(R.sup.5), N(R.sup.5)C(O), and N(R.sub.5)SO.sub.2, with R.sup.5 being selected from H, C.sub.1-4-alkyl, in particular C.sub.1-2-alkyl, C(O)O-tertbutyl (Boc), e is 0 or 1 and L.sup.3 is selected from C.sub.1-6-alkyl-, in particular C.sub.1-3-alkyl, -phenyl-, [(CH.sub.2).sub.1-4O].sub.1-5, [(CH.sub.2).sub.1-2O].sub.1-4(CH.sub.2).sub.1-2, and [(CH.sub.2).sub.1-2O].sub.1-4-triazole-[(CH.sub.2).sub.1-2O].sub.1(CH.sub.2), and E is selected from C.sub.1-4-alkyl, C.sub.2-4-alkynyl, NO.sub.2, halogene, particularly I, C.sub.1-3N.sub.3, N.sub.3, CN, SO.sub.2F, CHO, C(O)O-tertbutyl (Boc), CCSi(CH.sub.3).sub.3, 3-Oxo-4,7,7-trimethyl-2-oxabicyclo[2.2.1]heptane-1-carbonyl (camphanic carbonyl), an affinity tag or a fluorescent dye.

(35) In some embodiments, R is a nucleophile of formula IV.

(36) In some embodiments, R in formula I or II, in particular I, is a nucleophile of formula IV, -L.sup.4.sub.f-R.sup.6.sub.g-G (IV), wherein f is 0 or 1, in particular 1, and L.sup.4 is selected from C.sub.1-2-alkyl, in particular C.sub.2-alkyl, g is 0 or 1 and R.sup.6 is selected from N(R.sup.8), C(O)N(R.sup.8), in particular N(R.sup.8) with R.sup.8 being selected from C.sub.1-4-alkyl, in particular C.sub.1-2-alkyl, C(O)O-tertbutyl (Boc), more particular methyl or Boc, in case of f is 0 and g is 0, G is selected from C.sub.1-4-alkyl, in particular C.sub.1-2-alkyl, C.sub.2-alkenyl, N.sub.3, C(O)O-tertbutyl (Boc), in all other cases, G is selected from H, C.sub.1-4-alkyl, in particular C.sub.1-2-alkyl, C.sub.2-alkenyl, N.sub.3, C(O)O-tertbutyl (Boc).

(37) In some embodiments, R in formula I, is a nucleophile of formula IV, -L.sup.4.sub.f-R.sup.6.sub.g-G (IV), wherein f is 0 or 1, in particular 1, and L.sup.4 is selected from C.sub.1-2-alkyl, in particular C.sub.2-alkyl, g is 0 or 1 and R.sup.6 is selected from N(R.sup.8), C(O)N(R.sup.8), in particular N(R.sup.8) with R.sup.8 being selected from C.sub.1-4-alkyl, in particular C.sub.1-2-alkyl, C(O)O-tertbutyl (Boc), more particular methyl or Boc, in case of f is 0 and g is 0, G is selected from C.sub.1-4-alkyl, in particular C.sub.1-2-alkyl, C.sub.2-alkenyl, N.sub.3, C(O)O-tertbutyl (Boc), in all other cases, G is selected from H, C.sub.1-4-alkyl, in particular C.sub.1-2-alkyl, C.sub.2-alkenyl, N.sub.3, C(O)O-tertbutyl (Boc).

(38) In some embodiments, R in formula I or II, in particular I, is a nucleophile of formula IV, -L.sup.4.sub.f-R.sup.6.sub.g-G (IV), wherein f is 1, and L.sup.4 is C.sub.2-alkyl, g is 0 or 1 and R.sup.6 is N(R.sup.8) with R.sup.8 being selected from C.sub.1-2-alkyl, C(O)O-tertbutyl (Boc), particular methyl or Boc, G is selected from H, C.sub.1-2-alkyl, C.sub.2-alkenyl, N.sub.3, C(O)O-tertbutyl (Boc).

(39) In some embodiments, the compound is a salt of the compound according to formula I or of the compound according to formula II, in particular an acid addition salt comprising HCl or CF.sub.3COOH.

(40) In some embodiments, the compound of formula I or II is selected from

(41) ##STR00044## ##STR00045## ##STR00046##
with R1 and R2 being unequal H, R1 and R2 preferably being alkyl,

(42) ##STR00047##
with R1 and R2 being unequal H, R1 and R2 preferably being alkyl,

(43) ##STR00048##
with R1 and R2 being unequal H, R1 and R2 preferably being alkyl

(44) ##STR00049## ##STR00050## ##STR00051##

(45) R.sub.f is selected from

(46) ##STR00052##

(47) In some embodiments, the compound of formula is selected from

(48) ##STR00053## ##STR00054##
with R1 and R2 being unequal H, R1 and R2 preferably being alkyl,

(49) ##STR00055##
with R1 and R2 being unequal H, R1 and R2 preferably being alkyl,

(50) ##STR00056##
with R1 and R2 being unequal H, R1 and R2 preferably being alkyl,

(51) ##STR00057## ##STR00058##

(52) In some embodiments, the compound is selected from

(53) ##STR00059##

(54) In some embodiments, the compound of formula II is selected from

(55) ##STR00060##
with R1 and R2 being unequal H, R1 and R2 preferably being alkyl,

(56) ##STR00061##
with R1 and R2 being unequal H, R1 and R2 preferably being alkyl,

(57) ##STR00062##
with R1 and R2 being unequal H, R1 and R2 preferably being alkyl,

(58) ##STR00063##

DETAILED DESCRIPTION AND EXAMPLES

Example 1. Synthesis of Reagent 7-Salt

(59) The synthesis of reagent 7-salt is described in Scheme 1. The phenolic oxygen of Boc-protected NMT (N-methyltyramine) was deprotonated with NaH and treated with BrCF.sub.2CF.sub.2Br (Halon 2402) giving the bromide 4, which was converted to corresponding fluoroalkylsilane 5. An Umpolung reaction of 5 with fluoroiodane 6 provided the protected fluoroalkylation reagent 7-Boc as a brown oil, which was found to be stable for at least for six months at 20 C. Eventually, 7-Boc was deprotected using excess trifluoroacetic acid and subsequent precipitation with diethyl ether afforded crystalline bis-trifluoroacetate salt (7-salt), which appeared stable even at room temperature . . . .sup.i Even though the deprotected reagent (7) could be isolated and characterized, it decomposed rapidly even when stored in a freezer. For that reason, it was generated in situ from 7-salt by addition of base in all subsequent syntheses.

(60) ##STR00064##

(61) In the present invention, 7 was derivatized via peptide coupling to form the corresponding amide reagents 8. 1-Pyrenecarboxylic acid was selected for optimization of the reaction conditions as an easy-to-handle fluorophore. Aiming for mild reaction conditions, the inventors started the investigations with the 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) coupling reagent. In an initial trial, product 8a was first obtained in 26% isolated yield, which was increased to 63% by further optimization. Addition of the activator 1-hydbroxybenzotriazole (HOBt) usually caused decomposition of the reagent. Along these lines, structurally related (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) (HATU) likewise induced reagent decomposition. Interestingly, acyl chloride (generated with oxalyl chloride and cat. DMF) afforded 8a in 78% yield at the first attempt and 89% under optimized conditions.

Example 2. Synthesis of Reagent 8-a-q

(62) In the present invention freshly generated acyl chlorides is employed, with only slight modifications such as using Hnig's base instead of triethylamine in some cases, reagents 8b-q were synthesized mostly in good to excellent yields (Scheme 2). The eight examples of benzoic acid derivatives (8b-i) revealed a remarkable scope of functional groups that can be used for further functionalization via coupling, cycloaddition, substitution, etc. Aside from two simple fluorophores (reagents based on coumarin 8j and fluorescein 8k), the rest of the scope comprises aliphatic carboxylic acids. The coupling of (1S)-()-camphanic acid (in 8l) implies the possibility of introducing a chiral building block, while reagent 8m is a viable candidate for thiol-selective biotinylations. Finally, the inventors synthesized reagents containing the tetra(ethylene glycol) chain that promotes water solubilitythese reagents featured groups suitable for click reactions (8n, 8o) and two examples of pyrene as a fluorophore (8p, 8q).

(63) ##STR00065## ##STR00066##

Example 3. Synthesis of Reagent 9-a-c

(64) The inventors further envisioned that the amine functionality present in 7 could be used for the preparation of sufonamide reagents 9 (Scheme 3). Indeed, three examples were synthesized, comprising 4-nitrophenyl (9a), dansyl (9b), and the highly fluorescent dye Lissamine Rhodamine B (9c).

(65) ##STR00067## ##STR00068##

Example 4. Synthesis of Reagent 10

(66) The synthesis of a reagent bearing a tertiary amine group was motivated by an expected increase in water solubility upon its protonation. To this end, a reaction of 7-salt with commercially available 6-(2-iodoacetamido)fluorescein was attempted. However, the iodide liberated by the S.sub.N.sup.2 reaction reduced the hypervalent iodine species and the desired product could not be isolated. This issue was resolved by starting from analogous 6-(2-bromoacetamido)fluorescein, which was coupled with 7-salt to give reagent 10a in 39% yield (Scheme 4). In a similar fashion, propargyl-functionalized amine reagent 10b was prepared in 56% yield.

(67) ##STR00069##

Example 5. Application of Hypervalent Iodine(III)-R.SUB.f .Reagents 1 and 2 in the Formation of a Quaternary Carbon Center

(68) All entries described in examples 5 to 9 refer to entries described in table 2.

(69) The inventors envisaged that the conversion of substrates to the corresponding ketene silyl amides (KSAs) might be beneficial to control the reactivity of these species towards hypervalent iodine-CF.sub.3 reagents. Hence, the inventors report herein a mild, operationally simple and highly efficient method for the a-trifluoromethylation and a perfluoroalkylation of lactamderived KSAs by the use of reagents 1 and 2a in the presence of catalytic amounts of TMSNTf2 (1 mol %) or even under catalyst free conditions. Additionally, the inventors describe a direct one-pot protocol enabling these transformations without the isolation of intermediate KSAs.

(70) ##STR00070##

Example 6: -Trifluoromethylation of KSAs and Direct, One-Pot a-Trifluoromethylation of Carbonyl Compounds: Lactam Scope.Trifluoromethylation of KSAs and Direct, One-Pot a-Trifluoromethylation of Carbonyl Compounds: Lactam Scope

(71) To probe the viability of this transformation, the inventors investigated the reaction between KSA 4a and reagents 1 and 2a under various conditions (Table 2). It turned out that the direct trifluoromethylation of 4a using either 1 or 2a in CH.sub.2Cl.sub.2 at low temperature (78 1C) gave after 19 h the corresponding product 8a in only moderate yields, whereby reagent 2a exhibited a slightly better reactivity (entries 1 and 2). Based on the experience with the activation of reagents 1 and 2a, various Lewis acids such as triflimides and metal complexes were tested as catalysts (entries 3-7 and 10-13). Among them, trimethylsilyl triflimide displayed excellent catalytic properties, leading to the desired product in 96% .sup.19F NMR yield (entry 6). Notably, 1 mol % of Mn and V catalysts with salen-type ligands also efficiently catalysed the reaction (entries 12 and 13). Surprisingly, however, catalyst loadings higher than 1 mol % significantly lowered product yields (entries 8 and 9).

(72) Having found an effective catalyst system for the trifluoromethylation of KSAs, the inventors next examined the reaction scope with various substituted KSAs, which were prepared by lithiation of the corresponding lactams followed by trapping with TMSCl. It is important to highlight that their synthesis was straightforward, as the isolated crude compounds were pure by elemental analysis and were directly used in the next trifluoromethylation step (ESI).

(73) As summarized in Scheme 6, a broad range of KSAs exhibiting diverse steric and electronic properties readily participate in this transformation. First experiments showed that lactamderived KSAs undergo trifluoromethylation with reagent 2a even without the TMSNTf.sub.2 catalyst giving the corresponding -trifluoromethylated products in moderate to good yields (8a,8e, 8f, 8g). the inventors believe that the level of efficiency observed under catalyst-free conditions is the result of both low steric requirements of the substrates and their high electron density. The addition of 1 mol % of the catalyst (TMSNTf.sub.2) considerably improved the reactivity as shown in Scheme 6. The reaction tolerates different N-protecting groups, albeit benzyl (Bn), benzyloxymethyl (BOM), and tert-butyloxycarbonyl (Boc) derivatives formed the corresponding products in lower yields relative to N-Me derivatives (8b-d). The ring size of KSAs had minimal impact on the yield of the corresponding products (8f-g). KSAs derived from -lactam with a variety of -substituents such as benzyl (4a), phenyl (4e), methoxyethyl (4h) and trimethysilyl (4j) featured excellent reactivity delivering the corresponding products in high yields. Functional -substituents such as allyl (4i) and 3-TMS-propargyl (4k) are fully compatible with this method as well. Notably, KSA 4l derived from substituted 3,4-dihydroquinolin-2-one was successfully trifluromethylated forming product 8l in 87% isolated yield. The latter substructure is present in many nitrogen heterocyclic compounds with a potential activity as plant disease control agents.

(74) The inventors further optimised the synthetic applicability of this method and devised a one-pot, two-step protocol for the direct a-trifluoromethylation of lactams (Scheme 6). Thus, the chosen KSA is first formed in situ, followed by the addition of reagent and catalyst to affect the targeted a-trifluoromethylation. This simple and straightforward procedure is applicable to various a-substituted lactams as shown in Scheme 6, affording the desired products with high overall efficiency. Interestingly, in the case of a-propargyl substituted NMP (3k) silylation of the terminal alkyne takes place in addition to a-trifluorormethylation.

(75) ##STR00071## ##STR00072##

Example 7: -Perfluoroalkylation of KSA

(76) The inventors recently developed a series of new hypervalent iodine(III)-Rf reagents based on the 1,3-dihydro-3,3-dimethyl-1,2-benziodoxole scaffold, able to transfer a functionalised tetrafluoroethyl unit. These reagents demonstrated very similar reactivity in a number of transformations compared to their established CF.sub.3 analogues 1 and 2a providing access to tetrafluoroethylated compounds. We therefore examined the applicability of previously developed (2b-d, 2f, 2h) and newly synthesised (2e, 2g, 2i-k) fluoroalkyl hypervalent iodine(III)-Rf reagents in the a-perfluoroalkylation of lactams. KSA 4a was chosen as a model substrate for these transformations, and the results are summarized in Scheme 7. The inventors were thus pleased to find that all tested reagents displayed excellent levels of reactivity towards KSA 4a giving the corresponding a fluoroalkylated products in moderate to high yields. The obtained products contain tetrafluoroethyl moieties bearing S-Ar (9ab), O-Ar (9ac-af), CH2-Ar (9ag), and N-heterocyclic (9ah) substituents and can be used for further functionalizations. Products 9ai and 9aj are particularly interesting due to the presence of a fluorescent moiety based on coumarin, which can serve for the labelling of biological targets.

Example 8: ORTEP View of the X-Ray Structure of -Perfluoroethyl Lactam

(77) Crystalline -perfluoroethyl lactam 9ak was obtained in high (95%) yield from reagent 2k and was characterised by X-ray analysis (FIG. 1). X-ray crystal structures of acyclic and cyclic all-carbon-substituted -perfluoroethyl carbonyl compounds have not been reported previously, as confirmed by a CCDC database search. In the solid state compound 9ak displays values of bond lengths and angles in the expected ranges.

Example 9: Synthesis of (Perfluoroethyl)Pyrrolidine 10 Via One-Pot, Multistep Transformation of Lactam 3a

(78) As shown in scheme 7, lactam 3a was successfully transformed to the corresponding 3-perfluoroethyl-substituted pyrrolidine 10 in overall 71% isolated yield via a straightforward three-step protocol including in situ silylation, a fluoroalkylation and reduction steps.

(79) ##STR00073##

(80) TABLE-US-00003 TABLE 2 Optimization reaction conditions for the catalytic trifluoro-methylation of KSA Entry.sup.a Reagent catalyst mol % Yield.sup.b (%) 1 1 42 2 2a 67 3 2a Zn(NTf.sub.2).sub.2 1 79 4 2a LiNTf.sub.2 1 68 5 2a AgNTf.sub.2 1 62 6 2a CuNTf.sub.2 1 71 7 2a TMSNTf.sub.2 1 96(94).sup.c 8 2a TMSNTf.sub.2 2.5 86 9 2a TMSNTf.sub.2 3 83 10 2a [V(acac).sub.2O] 1 74 11 2a 5 1 74 12 2a 6 1 91 13 2a 7 1 93 .sup.aReaction conditions: 4a (0.3 mmol, 0.5M in CH.sub.2Cl.sub.2), 1 or 2a (0.23 mmol), catalyst (1-3 mol %), Ar atmosphere, 19 h. .sup.bYields were determined by .sup.19F NMR using benzotrifluoride as in internal standard. .sup.cIsolated yield.

Example 10

General Information

(81) Reactions with air-sensitive materials were carried out under an argon atmosphere using standard Schlenk techniques. All solvents were dried by activated molecular sieves (3 ) and stored under argon. All commercially available chemicals were used as received unless stated otherwise. Flash column chromatography was performed using silica gel 60 (0.040-0.063 mm) supplied by Sigma-Aldrich. Automated flash column chromatography was performed on Teledyne ISCO CombiFlash Rf+ Lumen Automated Flash Chromatography System with UV/Vis and ELS detection using standard manufacturer's RediSep Rf columns. Unless stated otherwise, the TLC analyses were done using TLC silica gel 60 F254 aluminium sheets from Merck, which were visualized under UV (254/366 nm) or using the KMnO.sub.4 stain solution.

(82) The melting points are uncorrected. .sup.1H, .sup.13C and .sup.19F NMR spectra were measured on Bruker spectrometers (.sup.1H carrier frequency of 200, 300, 400 and 500 MHz) at ambient temperature using 5 mm diameter NMR tubes. The chemical shift values (6) are reported in ppm relative to residual solvents.sup.ii (for .sup.1H and .sup.13C spectra) and internal or external CFCl.sub.3 (=0 ppm for .sup.19F NMR). Coupling constants (J) are reported in Hertz. Multiplicity is described by abbreviations (d=doublet, t=triplet, dd=doublet of doublets, dm=doublet of multiplets, bs=broad singlet, bt=broad triplet, bm=broad multiplet, etc.). Structural elucidation was aided by additional acquisition of .sup.13C APT and/or various 2D spectra (.sup.1H-.sup.1H COSY, .sup.1H-.sup.13C HSQC, .sup.1H-.sup.13C HMBC, and .sup.19F-.sup.13C HMBC). High resolution MS spectra (HRMS) were recorded on an LTQ Orbitrap XL or Bruker maXis using electrospray ionization (ESI), Waters Micromass AutoSpec Ultima using electron impact (EI) ionization, Agilent 7890A GC coupled with Waters GCT Premier orthogonal acceleration time-of-flight detector using chemical ionization (CI), and on a Bruker solariX 94 ESI/MALDI-FT-ICR using dual ESI/MALDI ionization.

(83) Screening Peptide Coupling Conditions

(84) TABLE-US-00004 TABLE S1 Optimization of peptide coupling between 7-salt and 1-pyrenecarboxylic acid 0 Acid Time activation + Yield.sup.a Entry equiv Activator (equiv) Base (equiv) Solvent coupling (h) Temperature (%) 1.sup.b 1.0 EDC (1.1) Et.sub.3N (1.1) DCM 0.1 + 3 rt 26 2 1.2 EDC (1.4) Et.sub.3N (4) DCM 0.5 + 4 0 C. to rt 63 3 1.2 EDC (1.4) + HOBt (1.4) Et.sub.3N (4) DCM 1 + 2.5 rt 16 4.sup.b 1.0 HATU (1.5) (i-Pr).sub.2EtN DCM 0.25 + 2.5 rt 0 (2.5) 5 1.2 (COCl).sub.2 (1.5) + DMF Et.sub.3N (10) DCM 3 + 0.25 rt 78 (1.2) 6 1.2 (COCl).sub.2 (1.5) + DMF Et.sub.3N (10) DCM 3 + 2 25 C. to rt 89 (1.2) .sup.aIsolated yield. .sup.bFreshly prepared 7 was used instead of 7-salt.

Synthesis and Characterization of Compounds

Reagent # NMT and its Precursors

tert-Butyl (4-hydroxyphenethyl)(methyl)carbamate (#)JV083-4 [CAS 112196-70-0]

(85) ##STR00081##

(86) N-Methyltyramine hydrochloride (18.8 g, 100 mmol) was dissolved in a MeOH:H.sub.2O (2:1) mixture (350 mL). NaHCO.sub.3 (25.2 g, 300 mmol) and Boc.sub.2O (32.7 g, 150 mmol) were added, and the mixture was stirred for 4 h at rt. MeOH was removed under reduced pressure, the mixture was extracted with EtOAc (3200 mL) and the organic extracts were washed with 10% aqueous HCl (1200 mL), water (150 mL) and brine (150 mL), dried with Na.sub.2SO.sub.4, filtered, and concentrated under vacuum. The product was obtained as a dense brown oil of ca. 90% purity, which was used further without purification. Optionally, the compound could be purified by automated flash chromatography (gradient elution from hexane to EtOAc/hexane 1:1), yielding the product as colourless oil that crystallized as a white solid.

(87) Yield: 27.8 g at 90% purity (99%); R.sub.f=0.25 (EtOAc:hexane 1:4); m.p. 76-79 C.

(88) .sup.1H NMR (300.13 MHz, CDCl.sub.3): 1.40 (bs, 9H, C(10)H.sub.3), 2.73 (t, .sup.3J.sub.HH=7.2, 2H, C(5)H.sub.2), 2.80 (s, 3H, C(7)H.sub.3), 3.39 (t, .sup.3J.sub.HH=7.2, 2H, C(6)H.sub.2), 5.61 (bs, 1H, OH), 6.76 (d, .sup.3J.sub.HH=8.0, 2H, C(2)H), 7.03 (d, .sup.3J.sub.HH=8.0, 2H, C(3)H);

(89) .sup.13C {.sup.1H} NMR (125.80 MHz, CDCl.sub.3): 28.3 and 28.4 (s, C(10)H.sub.3), 33.1 and 33.5 (s, C(5)H.sub.2), and 34.7 (s, C(7)H.sub.3), 50.7 and 51.0 (s, C(6)H.sub.2), 79.8 (s, C(9)), 115.4 (s, C(2)H), 129.7 (s, C(3)H), 130.1 (s, C(4)), 154.9 and 155.1 (s, C(1)), 156.0 (s, C(8)).

(90) HRMS (m/z, ESI.sup.+): [M+Na].sup.+ calcd. for C.sub.14H.sub.21NNaO.sub.3, 274.1414; found, 274.1411.

tert-Butyl (4-(2-bromo-1,1,2,2-tetrafluoroethoxy)phenethyl)(methyl)carbamate (#) JV085-6

(91) NaH (60% in mineral oil; 4.0 g, 0.1 mol) was washed with dry pentane (220 mL) in an oven-dried three-necked flask. Anhydrous DMF (50 mL) was added, followed by a

(92) ##STR00082##
portionwise addition of a solution of BocNMT (14.0 g, 50.0 mmol, 90% purity) in DMF (60 mL) at 0 C. The mixture was stirred for 1 h 15 min. Tert-butylammonium iodide (185 mg, 0.50 mmol) was added, followed by a portionwise addition of BrCF.sub.2CF.sub.2Br (11.9 mL, 100 mmol), and the reaction mixture was stirred for 3 h at rt. The mixture was diluted with water (300 mL) and extracted with 1:1 ether/pentane mixture (3150 mL). The combined organic layers were washed with water (3100 mL) and brine (3100 mL), dried over Na.sub.2SO.sub.4, and concentrated to give the product as an orange-yellow liquid of ca. 85% purity, which was used further without purification. Optionally, the compound could be purified by automated flash chromatography (gradient elution from hexane to EtOAc/hexane 1:1), yielding the product as a yellow liquid.

(93) Yield: 18.6 g at 85% purity (74%); R.sub.f=0.60 (EtOAc:hexane 1:4);

(94) .sup.1H NMR (500.26 MHz, CDCl.sub.3): 1.36 and 1.42 (bs, 9H, C(10)H.sub.3), 2.79 (bs, 2H, C(5)H.sub.2), 2.83 (s, 3H, C(7)H.sub.3), 3.42 (bs, 2H, C(6)H.sub.2), 7.13 (d, .sup.3J.sub.HH=8.4, 2H, C(2)H), 7.19 (bs, 2H, C(3)H);

(95) .sup.19F NMR (282.38 MHz, CDCl.sub.3): 86.4 (bs, 2F, CF.sub.2), 68.4 (t, .sup.3J.sub.FF=4.9, 2F, CF.sub.2);

(96) .sup.13C {.sup.1H} NMR (125.80 MHz, CDCl.sub.3): 28.3 (s, C(10)H.sub.3), 33.4 and 33.8 (s, C(5)H.sub.2), 34.2 and 34.7 (s, C(7)H.sub.3), 50.1 and 50.5 (s, C(6)H.sub.2), 79.3 (s, C(9)), 113.6 (tt, .sup.1J.sub.CF=312, .sup.2J.sub.CF=44.9, CF.sub.2), 115.8 (tt, .sup.1J.sub.CF=275, .sup.2J.sub.CF=31.9, CF.sub.2), 121.6 (bm, C(2)H), 130.1 (s, C(3)H), 138.1 (s, C(4)), 147.2 (bm, C(1)), 155.5 (s, C(8));

(97) HRMS (m/z, ESI.sup.+): [M+Na].sup.+ calcd. for C.sub.16H.sub.20BrF.sub.4NNaO.sub.3, 452.0455, found, 452.0458.

tert-Butyl methyl(4-(1,1,2,2-tetrafluoro-2-(trimethylsilyl)ethoxy)phenethyl)carbamate (#) JV086-6

(98) ##STR00083##

(99) Bromide # (18.5 g, 36.6 mmol, 85% purity) was dissolved in anhydrous THF (150 mL) at 65 C. TMSCl (18.6 mL, 146 mmol) was added, followed by a portionwise addition of i-PrMgCl.LiCl (1.3 M solution in THF, 33.8 mL, 43.9 mmol) within 15 min, and the reaction mixture was stirred for 3 h at 65 C. to rt. The mixture was concentrated, water (200 mL) was added, and the product was extracted with an ether/hexane 1:1 mixture (3150 mL). The combined organic layers were washed with water (2100 mL) and brine (2100 mL), dried over Na.sub.2SO.sub.4, and concentrated to give the product as an orange-brown oil consisting of the target compound and the protodesilylated RCF.sub.2CF.sub.2H compound in a ratio of 89:11. The product of of ca. 80% purity was used further without purification. Optionally, the compound could be purified by automated flash chromatography (gradient elution from hexane to EtOAc/hexane 1:1), yielding the pure product as a yellow liquid that solidified.

(100) Yield: 17.3 g at 80% purity (89%); R.sub.f=0.40 (EtOAc:hexane 1:4); m.p. 32-33 C.;

(101) .sup.1H NMR (200.13 MHz, CDCl.sub.3): 0.30 (bs, 9H, Si(CH.sub.3).sub.3), 1.37 (bs, 9H, C(10)H.sub.3), 2.81 (bs, 5H, C(5)H.sub.2 and C(7)H.sub.3), 3.41 (t, .sup.3J.sub.HH=7.1, 2H, C(6)H.sub.2), 7.10 (d, .sup.3J.sub.HH=8.7, 2H, C(2)H), 7.16 (bs, 2H, C(3)H);

(102) .sup.19F NMR (188.29 MHz, CDCl.sub.3): 130.7 (t, .sup.3J.sub.FF=4.8, 2F, CF.sub.2), 85.5 (t, .sup.3J.sub.FF=4.8, 2F, CF.sub.2);

(103) .sup.13C {.sup.1H} NMR (50.33 MHz, CDCl.sub.3): 4.40 (tt, .sup.3J.sub.CF=2.3, .sup.4J.sub.CF=1.1, Si(CH.sub.3).sub.3), 28.3 (s, C(10)H.sub.3), 33.4 and 33.7 (s, C(5)H.sub.2), 34.2 and 34.5 (s, C(7)H.sub.3), 50.3 and 50.5 (s, C(6)H.sub.2), 79.3 (s, C(9)), 119.1 (tt, .sup.1J.sub.CF=275, .sup.2J.sub.CF=27.8, CF.sub.2), 120.5 (tt, .sup.1J.sub.CF=272, .sup.2J.sub.CF=38.2, CF.sub.2), 121.5 (s, C(2)H), 129.9 (s, C(3)H), 137.2 (s, C(4)), 147.6 (t, .sup.3J.sub.CF=1.9, C(1)), 155.5 (s, C(8)); HRMS (m/z, ESI.sup.+): [M+H].sup.+ calcd. for C.sub.19H.sub.30F.sub.4NO.sub.3Si, 424.1926, found, 424.1923.

tert-Butyl (4-(2-(3,3-dimethyl-1.SUP.3.-benzo[d][1,2]iodaoxol-1 (3H)-yl)-1,1,2,2-tetrafluoroethoxy)phenethyl)-(methyl)carbamate (#) JV087-7

(104) An oven-dried 3-necked round-bottom flask (1 L) equipped with an addition funnel (250 mL) and a massive magnetic stirring bar was charged with fluoroiodane (20.6 g, 73.6 mmol).

(105) Anhydrous CH.sub.3CN (250 mL) was added from a Schlenk via a PTFE cannula, and the solution was cooled down to 35 C. A solution of the silane (17.3 g, 32.7 mmol, 80% purity) in CH.sub.3CN (250 mL) was transferred to the addition funnel via a cannula. TBAT (0.40 g, 0.74 mmol) was added to the fluoroiodane solution as solid, and the silane solution was added dropwise at 35 C. to 15 C. over a period of 30 min. The orange mixture was stirred at 20 C. to rt for 3 h. The solvent was evaporated, the crude product was redissolved in an EtOAc/hexane mixture and anchored on Celite (25 g). The title product was isolated by column chromatography (1 kg of silica gel, column 950 cm; gradient elution from hexane to EtOAc), yielding a brown oil.

(106) Yield: 14.1 g (71%); R.sub.f=0.29 (EtOAc:hexane 1:1);

(107) .sup.1H NMR (500.26 MHz, CDCl.sub.3): 1.34-1.45 (bs, 9H, C(18)H.sub.3), 1.50 (s, 6H, C(2)H.sub.3), 2.72-2.87 (bs, 5H, C(13)H.sub.2 and C(15)H.sub.3), 3.42 (bs, 2H, C(14)H.sub.2), 7.12 (m, 2H, C(10)H or C(11)H), 7.14-7.24 (bs, 2H, C(10)H or C(11)H), 7.39 (m, 2H, C(4)Hand C(6)H), 7.50 (m, 1H, C(5)H), 7.74 (m, 1H, C(7)H);

(108) .sup.19F NMR (470.67 MHz, CDCl.sub.3): 97.5 (bs, 2F, CF.sub.2), 84.8 (bs, 2F, CF.sub.2);

(109) .sup.13C {.sup.1H} NMR (125.80 MHz, CDCl.sub.3): 28.3 (s, C(18)H.sub.3), 30.9 (s, C(2)H.sub.3), 33.4 and 33.9 (s, C(13)H.sub.2), 34.2 and 34.8 (s, C(15)H.sub.3), 50.2 and 50.6 (s, C(14)H.sub.2), 76.3 (s, C(1)), 79.4 (s, C(17)), 110.9 (m, C(8)), 111.5 (tt, .sup.1J.sub.CF=300, .sup.2J.sub.CF=38.1, CF.sub.2), 117.2 (tt, .sup.1J.sub.CF=276, .sup.2J.sub.CF=26.0, CF.sub.2), 121.7 (bs, C(10)H or C(11)H), 127.4 (s, C(4)H or C(6)H), 129.0 (tt, J.sub.CF=5.3, 1.3, C(7)), 129.4 (s, C(4)H or C(6)H), 130.1 (s, C(10)H or C(11)H), 130.3 (s, C(5)H), 138.0 (s, C(12)), 147.2 (m, C(9)), 149.9 (s, C(3)), 155.5 (s, C(16)); HRMS (m/z, ESI.sup.+): [M+H].sup.+ calcd. for C.sub.25H.sub.31F.sub.4INO.sub.4, 612.1228, found, 612.1228.

2-(4-(2-(3,3-Dimethyl-1.SUP.3.-benzo[d][1,2]iodaoxol-1 (3H)-yl)-1,1,2,2-tetrafluoroethoxy)phenyl)-N-methylethan-1-amine (#) JV090-12

(110) ##STR00084##

(111) Reagent N-BocNMT (193 mg, 0.30 mmol) was dissolved in DCM (5 mL) in a round-bottom flask. Trifluoroacetic acid (0.46 mL, 6.00 mmol) was added. The mixture was stirred for 2 h at rt. DCM was evaporated, 10% aqueous HCl (10 mL) was added, and the organic impurities were extracted to pentane (313 mL). The acidic aqueous phase was cooled down to 0 C., alkalized with cold 3M aqueous NaOH (40 mL), and extracted with DCM (330 mL). The organic phase was washed with water (230 mL), brine (230 mL), dried over Na.sub.2SO.sub.4 and concentrated, yielding a yellow oil.

(112) Yield: 110 mg (72%);

(113) .sup.1H NMR (500.13 MHz, CDCl.sub.3): 1.47 (s, 6H, C(2)H.sub.3), 2.46 (bs, 3H, C(15)H.sub.3), 2.86 (bs, 4H, C(13)H.sub.2 and C(14)H.sub.2), 3.69 (bs, 1H, NH), 7.10 (m, 2H, C(10)H), 7.20 (m, 2H, C(11)H), 7.36 (m, 2H, C(4)Hand C(6)H), 7.46 (m, 1H, C(5)H), 7.71 (m, 1H, C(7)H);

(114) .sup.19F NMR (470.55 MHz, CDCl.sub.3): 97.6 (bt, 2F, CF.sub.2), 84.8 (bt, 2F, CF.sub.2);

(115) .sup.13C {.sup.1H} NMR (125.77 MHz, CDCl.sub.3): 30.8 (s, C(2)H.sub.3), 34.6 (s, C(13)H.sub.2), 35.5 (s, C(15)H.sub.3), 52.4 (s, C(14)H.sub.2), 76.3 (s, C(1)), 110.9 (s, C(8)), 111.4 (tt, .sup.1J.sub.CF=337, .sup.2J.sub.CF=38.2, CF.sub.2), 117.2 (tt, .sup.1J.sub.CF=277, .sup.2J.sub.CF=25.8, CF.sub.2), 121.6 (s, C(10)H), 127.3 (s, C(4)H or C(6)H), 128.8 (t, J.sub.CF=5.2, C(7)), 129.3 (s, C(4)H or C(6)H), 129.8 (s, C(11)H), 130.2 (s, C(5)H), 137.9 (bm, C(12)), 147.2 (m, C(9)), 149.8 (s, C(3)); HRMS (m/z, ESI.sup.+): [M+H].sup.+ calcd. for C.sub.20H.sub.23F.sub.4INO.sub.2, 512.0704, found, 512.0691.

3,3-Dimethyl-1-(1,1,2,2-tetrafluoro-2-(4-(2-(methylammonio)ethyl)phenoxy)ethyl)-2,3-dihydro-1H-1.SUP.3.-benzo[d][1,2]iodaoxol-2-ium bis(trifluoroacetate) (#) JV1 17-5

(116) ##STR00085##

(117) Reagent N-BocNMT (4.38 g, 6.80 mmol) was dissolved in DCM (90 mL) in a round-bottom flask. Trifluoroacetic acid (10.4 mL, 136 mmol) was added. The mixture was stirred for 3 h at rt. DCM was evaporated giving yellow/orange oil. Diethyl ether was added slowly (70 mL in total), leading to the crystallization of a pale yellow solid. The solid was filtered off, washed with a small amount of ether and pentane, and dried in vacuum.

(118) Yield: 3.75 g (75%); m.p. 88-90 C. (dec.); .sup.1H NMR (300.13 MHz, CD.sub.2Cl.sub.2): 1.68 (s, 6H, C(2)H.sub.3), 2.68 (bs, 3H, C(15)H.sub.3), 3.06 (bm, 2H, C(13)H.sub.2), 3.17 (bm, 2H, C(14)H.sub.2), 7.32 (m, 2H, C(11)H), 7.35 (m, 2H, C(10)H), 7.53 (m, 2H, C(4)H and C(6)H), 7.64 (m, 1H, C(5)H), 7.78 (m, 1H, C(7)H), 8.18 (bs, 1H, OH.sup.+), 9.57 (bs, 2H, NH.sub.2Me.sup.+);

(119) .sup.19F NMR (282.38 MHz, CD.sub.2Cl.sub.2): 84.5 (t, .sup.3J.sub.FF=7.4, 2F, CF.sub.2), 83.2 (t, .sup.3J.sub.FF=7.4, 2F, CF.sub.2), 76.1 (s, 6F, CF.sub.3);

(120) .sup.13C {.sup.1H} NMR (100.62 MHz, CD.sub.2Cl.sub.2): 30.1 (s, C(2)H.sub.3), 32.2 (s, C(13)H.sub.2), 33.6 (s, C(15)H.sub.3), 50.8 (s, C(14)H.sub.2), 75.6 (s, C(1)), 108.3 (m, C(8)), 110.8 (tt, .sup.1J.sub.CF=337, .sup.2J.sub.CF=39.0, CF.sub.2), 117.0 (q, .sup.1J.sub.CF=292, CF.sub.3COO), 116.3 (tt, .sup.1J.sub.CF=278, .sup.2J.sub.CF=25.0, CF.sub.2), 122.9 (s, C(10)H), 129.7 (s, C(4)H or C(6)H), 130.9 (s, C(11)H), 131.0 (t, J.sub.CF=4.7, C(7)), 131.7 (s, C(4)H or C(6)H), 132.6 (s, C(5)H), 136.6 (s, C(12)), 147.7 (m, C(9)), 148.7 (bm, C(3)), 162.5 (q, .sup.2J.sub.CF=35.2, CF.sub.3COO);

(121) HRMS (m/z, ESI.sup.+): [M+H].sup.+ calcd. for C.sub.20H.sub.23F.sub.4INO.sub.2, 512.0704, found, 512.0699.

(122) Anal. calcd. for C.sub.24H.sub.24F.sub.10INO.sub.6 [C] 38.99%, [H] 3.27%, [N] 1.89%, [0] 12.98%, [F] 25.70%, [I]17.16%. Found: [C] 39.19%, [H] 3.27%, [N] 1.85%, [F] 25.52%.

Functionalized Carboxylic Acids and their Precursors

2-(2-(2-(2-Hydroxyethoxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (IK28_Tosylate) [CAS 77544-60-6]

(123) ##STR00086##

(124) Sodium hydroxide (640 mg, 16 mmol) in H.sub.2O (2.5 ml) was added to a solution of tetra(ethylene glycol) (17.3 mL, 0.1 mol) in THF (2.5 mL). The mixture was cooled down to 0 C. and p-toluenesulfonyl chloride (1.9 g, 10 mmol) in THF (7.5 mL) was slowly added. The mixture was stirred for 2 hours at 0 C., poured into water (40 mL), and the layers were separated. The aqueous phase was extracted with DCM (415 mL) and the combined organic portions were washed with water (315 mL) before being dried over MgSO.sub.4, filtered, and concentrated under reduced pressure to yield the product as a colorless oil, which was used directly in the next step without further purification.

(125) Yield: 3.2 g (91%);

(126) .sup.1H NMR (401.00 MHz, CDCl.sub.3): 2.31 (s, 1H, OH), 2.44 (s, 3H, C(1)H.sub.3), 3.55-3.72 (m, 14H, 7CH.sub.2), 4.15-4.17 (m, 2H, C(6)H.sub.2), 7.33 (dq, 2H, .sup.3J.sub.HH=7.9, .sup.4J.sub.HH=1.0, C(4)H), 7.78-7.80 (m, 2H, C(3)H);

(127) .sup.13C NMR (100.84 MHz, CDCl.sub.3): 21.6 (s, C(1)H.sub.3), 61.7 (s, CH.sub.2), 68.7 (s, CH.sub.2), 69.2 (s, C(6)H.sub.2), 70.3 (s, CH.sub.2), 70.4 (s, CH.sub.2), 70.6 (s, CH.sub.2), 70.7 (s, CH.sub.2), 72.4 (s, CH.sub.2) 127.9 (s, 2C(3)H), 129.8 (s, 2C(4)H), 132.9 (s, C(5)H), 144.8 (s, C(2)H). The data were consistent with those reported by Cubberley and Iverson.

2-(2-(2-(2-Azidoethoxy)ethoxy)ethoxy)ethan-1-ol (IK28_azide) [CAS 86770-67-4]

(128) ##STR00087##

(129) Sodium azide (975 mg, 15 mmol) was added to a solution of 2-(2-(2-(2-Hydroxyethoxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (3.18 g, 9.1 mmol) in CH.sub.3CN (25 mL). The mixture was heated to reflux and stirred for 8 h. The solution was allowed to cool down to rt and H.sub.2O (25 mL) was added. The aqueous phase was extracted with DCM (325 mL) and the combined organic portions were dried over MgSO.sub.4, filtered, and concentrated under reduced pressure to give the product as a pale yellow oil, which was used directly in the next step without further purification.

(130) Yield: 1.97 g (99%);

(131) .sup.1H NMR (401.00 MHz, CDCl.sub.3): 2.38 (s, 1H, OH), 3.39 (t, 2H, .sup.3J.sub.HH=5.1 Hz, C(1)H.sub.2), 3.60-3.74 (m, 14H, 7CH.sub.2);

(132) .sup.13C NMR (100.84 MHz, CDCl.sub.3): 50.6 (s, C(1)H.sub.2), 61.7 (s, CH.sub.2), 70.0 (s, CH.sub.2), 70.3 (s, CH.sub.2), 70.6 (s, CH.sub.2), 70.7 (m, 2CH.sub.2), 72.4 (s, CH.sub.2). The data were consistent with those reported by Cubberley and Iverson.

Ethyl 14-azido-3,6,9,12-tetraoxatetradecanoate (IK28_Ester) [CAS 256397-65-6]

(133) ##STR00088##

(134) Sodium hydride (341 mg, 13.5 mmol) was dispersed in dry THF (10 ml) under an argon atmosphere. The mixture was cooled to 0 C. and a solution of 2-(2-(2-(2-Azidoethoxy)ethoxy)ethoxy)ethan-1-ol (1.97 g, 9 mmol) in dry THF (10 mL) was added dropwise. The mixture was stirred for 1 h at rt and then cooled down to 0 C. Ethyl bromoacetate (1.53 mL, 13.5 mmol) was slowly added and the mixture was stirred for 1 h at rt and 16 h at 50 C. The reaction mixture was cooled down to rt and quenched with water (10 mL). THF was evaporated under reduced pressure and the residue was extracted with EtOAc (320 mL). Organic layers were dried over MgSO.sub.4, filtered and concentrated under reduced pressure to give crude orange oil. Purification by column chromatography (gradient elution from hexane:EtOAc 1:1 to 1:2) afforded the product as a yellow oil.

(135) Yield: 1.62 g (72%); R.sub.f=0.36 (EtOAc:hexane 1:1);

(136) .sup.1H NMR (401.00 MHz, CDCl.sub.3): 1.28 (t, 3H, .sup.3J.sub.HH=7.2 Hz, C(1)H.sub.3), 3.38 (t, 2H, .sup.3J.sub.HH=5.1 Hz, C(5)H.sub.2), 3.64-3.74 (m, 14H, 7CH.sub.2), 4.14 (s, 2H, C(4)H.sub.2), 4.21 (q, 2H, .sup.3J.sub.HH=7.2 Hz, C(2)H.sub.2);

(137) .sup.13C NMR (100.84 MHz, CDCl.sub.3): 14.1 (s, C(1)H.sub.3), 50.6 (s, C(5)H.sub.2), 60.7 (s, C(2)H.sub.2), 68.7 (s, C(4)H.sub.2), 70.0 (s, CH.sub.2), 70.5-70.6 (m, 5CH.sub.2), 70.8 (s, CH.sub.2) 170.4 (s, C(3)). The data were consistent with those reported by Shirude et al.

14-Azido-3,6,9,12-tetraoxatetradecanoic Acid (IK30) [CAS 201467-81-4]

(138) ##STR00089##

(139) Ethyl 14-azido-3,6,9,12-tetraoxatetradecanoate (173 mg, 0.57 mmol) was dissolved in 66% MeOH in water (2 mL), NaOH (79 mg, 1.98 mmol) was added, and the reaction mixture was stirred overnight. The mixture was concentrated under reduced pressure, the residue was acidified by 1M HCl to pH=2 and extracted with EtOAc (210 mL). The organic layers were dried over MgSO.sub.4, filtered, and concentrated under reduced pressure. The product was obtained as a yellow oil.

(140) Yield: 134 mg (85%);

(141) .sup.1H NMR (401.00 MHz, CDCl.sub.3): 3.31 (t, 2H, .sup.3J.sub.HH=5.0 Hz, C(3)H.sub.2), 3.58-3.63 (m, 12H, 6CH.sub.2), 3.66-3.68 (m, 2H, CH.sub.2), 4.10 (s, 2H, C(2)H.sub.2), 10.10 (br s, 1H, COOH);

(142) .sup.13C NMR (100.84 MHz, CDCl.sub.3): 50.3 (s, C(3)H.sub.2), 68.2 (s, C(2)H.sub.2), 69.7 (s, CH.sub.2), 70.1 (s, CH.sub.2), 70.2-70.3 (m, 4CH.sub.2), 70.8 (s, CH.sub.2) 173.3 (s, C(1)). The data were consistent with those reported by Bogdan et al.

Ethyl 3,6,9,12,15-pentaoxaoctadec-17-ynoate (IK72)

(143) ##STR00090##

(144) Sodium hydride (162 mg, 6.4 mmol) was dispersed in dry THF (12 mL) under an argon atmosphere. The mixture was cooled down to 0 C. and tetra(ethylene glycol) (3.5 ml, 20 mmol) was added dropwise. The mixture was stirred for 1 h at rt and then cooled down to 0 C. Propargyl bromide (80% in toluene, 0.43 mL, 4 mmol) was slowly added and the mixture was stirred overnight at rt. The reaction mixture was quenched with water (20 mL) and extracted with DCM (47 mL). The organic layers were washed with water (37 mL), dried over MgSO.sub.4, filtered and concentrated under reduced pressure to give crude 3,6,9,12-tetraoxapentadec-14-yn-1-ol (674 mg) as a yellow oil, which was used directly in the next step without further purification.

(145) Sodium hydride (73 mg, 2.9 mmol) was dispersed in dry THF (2.5 mL) under an argon atmosphere. The mixture was cooled to 0 C. and solution of 3,6,9,12-tetraoxapentadec-14-yn-1-ol (674 mg, 2.9 mmol) in dry THF (2.5 ml) was added dropwise. The mixture was stirred 1 h at rt and cooled to 0 C. Ethyl bromoacetate (0.39 mL, 3.5 mmol) was slowly added and the mixture was stirred at rt overnight. The reaction mixture was quenched with water (5 mL) and extracted with DCM (35 mL). Organic layers were dried over MgSO.sub.4, filtered and concentrated under reduced pressure to give the crude product. Purification by column chromatography (gradient elution from hexane:EtOAc 1:1 to 1:2) afforded the product as a pale yellow oil.

(146) Yield: 500 mg (39%); R.sub.f=0.31 (EtOAc:hexane 1:1);

(147) .sup.1H NMR (401.00 MHz, CDCl.sub.3): 1.28 (t, 3H, .sup.3J.sub.HH=7.2 Hz, C(1)H.sub.3), 2.42 (t, 1H, .sup.3J.sub.HH=2.4 Hz, C(7)H), 3.64-3.74 (m, 16H, 8CH.sub.2), 4.14 (s, 2H, C(4)H.sub.2),4.18-4.24 (m, 4H, C(5)H.sub.2, C(2)H.sub.2);

(148) .sup.13C NMR (100.84 MHz, CDCl.sub.3): 14.0 (s, C(1)H.sub.3), 58.1 (s, C(5)H.sub.2), 60.5 (s, C(2)H.sub.2), 68.5 (s, C(4)H.sub.2), 68.8 (s, CH.sub.2), 70.2 (s, CH.sub.2), 70.3-70.4 (m, 5CH.sub.2), 70.6 (s, CH.sub.2), 74.4 (s, C(7)H), 79.4 (s, C(6)), 170.2 (s, C(3)).

(149) HRMS (m/z, ESI.sup.+): [M+Na].sup.+ calcd. for C.sub.15H.sub.26NaO.sub.7, 341.1571; found, 341.1571.

3,6,9,12,15-Pentaoxaoctadec-17-ynoic Acid (IK73)

(150) ##STR00091##

(151) Ethyl 3,6,9,12,15-pentaoxaoctadec-17-ynoate (102 mg, 0.32 mmol) was dissolved in 66% MeOH in water (1 mL), NaOH (45 mg, 1.12 mmol) was added, and the mixture was stirred overnight. The mixture was concentrated under reduced pressure, the residue was acidified by 1M HCl to pH=2 and extracted with DCM (35 mL). The organic layers were dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The product was obtained as a pale yellow oil.

(152) Yield: 88 mg (95%);

(153) .sup.1H NMR (401.00 MHz, CDCl.sub.3): 2.41 (t, 1H, .sup.3J.sub.HH=2.4 Hz, C(5)H), 3.58-3.66 (m, 14H, 7CH.sub.2), 3.68-3.71 (m, 2H, CH.sub.2), 4.12 (s, 2H, C(2)H.sub.2), 4.15 (d, 2H, .sup.3J.sub.HH=2.4 Hz, C(3)H.sub.2), 9.65 (brs, 1H, OH);

(154) .sup.13C NMR (100.84 MHz, CDCl.sub.3): 58.2 (s, C(3)H.sub.2), 68.5 (s, C(2)H.sub.2), 68.8 (s, CH.sub.2), 70.1-70.4 (m, 6CH.sub.2), 71.0 (s, CH.sub.2), 74.5 (s, C(5)H), 79.4 (s, C(4)), 173.0 (s, C(1)).

(155) HRMS (m/z, ESI.sup.+): [M+Na].sup.+ calcd. for C.sub.13H.sub.22NaO.sub.7, 313.1258; found, 313.1258.

1-((Prop-2-yn-1-yloxy)methyl)pyrene (IK43)

(156) ##STR00092##

(157) 1-Pyrenemethanol (929 mg, 4 mmol) was dispersed in toluene (50 mL). The mixture was heated to 40 C. and PBr.sub.3 (0.5 mL, 4.9 mmol) was added. The flask was sealed and reaction mixture was heated to 80 C. After 2 hours, the reaction mixture was cooled down and quenched by saturated sodium carbonate solution (24 mL). An organic layer was separated, washed with water (220 mL) and brine (220 mL), dried over MgSO.sub.4, filtered, and concentrated under reduced pressure to give crude 4-(bromomethyl)pyrene (1.12 g) as yellow crystals, which was used directly in the next step without further purification.

(158) Sodium hydride (131 mg, 5.2 mmol) was dispersed in dry THF (10 mL) under an argon atmosphere. The mixture was cooled down to 0 C. and propargyl alcohol (0.48 mL, 8 mmol) was added dropwise. The mixture was stirred for 30 min at rt and then cooled down to 0 C. A solution of 4-(bromomethyl)pyrene (1.12 g, 4 mmol) in THF (15 mL) was slowly added and the mixture was stirred at rt overnight. The reaction mixture was quenched with saturated NH.sub.4Cl (20 mL). THF was evaporated under reduced pressure and the residue was extracted with DCM (410 mL). The organic layers were washed with brine (10 mL), dried (MgSO.sub.4), filtered and concentrated under reduced pressure to give the crude product. Purification by column chromatography (hexane:EtOAc 20:1) afforded the title compound as pale yellow crystals.

(159) Yield: 848 mg (72%); m.p. 84-85 C.; R.sub.f=0.35 (EtOAc:hexane 1:20);

(160) .sup.1H NMR (401.00 MHz, CDCl.sub.3): 2.59 (t, 1H, .sup.3J.sub.HH=2.4 Hz, C(1)H), 4.29 (d, 2H, .sup.3J.sub.HH=2.4 Hz, C(3)H.sub.2), 5.34 (s, 2H, C(4)H.sub.2), 7.98-8.10 (m, 4H, C.sub.ArH), 8.11-8.25 (m, 4H, C.sub.ArH), 8.41 (d, .sup.3J.sub.HH=9.2 Hz, 1H, C.sub.ArH);

(161) .sup.13C NMR (100.84 MHz, CDCl.sub.3): 57.1 (s, C(3)H.sub.2), 69.9 (s, C(4)H.sub.2), 74.9 (s, C(1)H), 79.8 (s, C(2)), 123.3 (s, C.sub.ArH), 124.4 (s, C.sub.ArH), 124.6 (s, C.sub.Ar), 124.9 (s, C.sub.Ar), 125.2-125.3 (s, 2C.sub.ArH), 125.9 (s, C.sub.ArH), 127.3 (s, C.sub.ArH), 127.4 (s, C.sub.ArH), 127.5 (s, C.sub.ArH), 127.8 (s, C.sub.ArH), 129.6 (s, C.sub.Ar), 130.2 (s, C.sub.Ar), 130.7 (s, C.sub.Ar), 131.2 (s, C.sub.Ar), 131.5 (s, C.sub.Ar).

(162) HRMS (m/z, Cl.sup.+): [M].sup.+ calcd. for C.sub.20H.sub.14O, 270.1045; found, 270.1046.

Ethyl 14-(4-((pyren-1-ylmethoxy)methyl)-1H-1,2,3-triazol-1-yl)-3,6,9,12-tetraoxatetradecanoate (IK15)

(163) ##STR00093##

(164) Ethyl 14-azido-3,6,9,12-tetraoxatetradecanoate (763 mg, 2.5 mmol) and 4-((prop-2-yn-1-yloxy)methyl)pyrene (541 mg, 2 mmol) were dissolved in THF (20 mL). 0.01 M aqueous solution of CuSO.sub.4.5H.sub.2O (10 mL) was added to the mixture while stirring, followed by 0.02 M solution of sodium L-ascorbate (10 mL). The pale yellow solution was stirred at rt for 2 h, then another portion (5 mL) of the sodium L-ascorbate solution was added, and the reaction mixture was stirred for 1 h. THF and water were evaporated on a rotary evaporator and the residue was extracted with EtOAc (315 mL), dried over MgSO.sub.4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (gradient elution from DCM:acetone 7:1 to 2:1), affording a pale yellow oil.

(165) Yield: 1.035 g (90%); R.sub.f=0.4 (DCM:acetone 7:1);

(166) .sup.1H NMR (400.13 MHz, CDCl.sub.3): 1.24 (t, 3H, .sup.3J.sub.HH=7.1 Hz, C(10)H.sub.3), 3.50-3.57 (m, 10H, CH.sub.2), 3.60-3.63 (m, 2H, CH.sub.2), 3.82 (t, 2H, .sup.3J.sub.HH=5.0 Hz, C(6)H.sub.2), 4.06 (s, 2H, C(7)H.sub.2), 4.17 (q, 2H, .sup.3J.sub.HH=7.1 Hz, C(9)H.sub.2), 4.51 (t, 2H, .sup.3J.sub.HH=5.0 Hz, C(5)H.sub.2), 4.82 (s, 2H, C(2)H.sub.2) 5.31 (s, 2H, C(1)H.sub.2), 7.74 (s, 1H, C(4)H), 7.98-8.05 (m, 4H, C.sub.ArH), 8.11-8.20 (m, 4H, C.sub.ArH), 8.34 (d, .sup.3J.sub.HH=9.3 Hz, 1H, C.sub.ArH);

(167) .sup.13C NMR (100.84 MHz, CDC.sub.3): 14.1 (s, C(10)H.sub.3), 50.2 (s, C(5)H.sub.2), 60.7 (s, C(9)H.sub.2), 63.7 (s, C(2)H.sub.2), 68.5 (s, C(7)H.sub.2), 69.4 (s, C(6)H.sub.2), 70.3-70.7 (m, 6CH.sub.2), 70.9 (s, C(1)H.sub.2), 123.4 (s, C.sub.ArH), 123.9 (s, C(4)H), 124.4 (s, C.sub.ArH), 124.6 (s, C.sub.Ar), 124.8 (s, C.sub.Ar), 125.2 (s, 2C.sub.ArH), 125.9 (s, C.sub.ArH), 127.2 (s, C.sub.ArH), 127.3 (s, C.sub.ArH), 127.4 (s, C.sub.ArH), 127.7 (s, C.sub.ArH), 129.3 (s, C.sub.Ar), 130.7 (s, C.sub.Ar), 131.0 (s, C.sub.Ar), 131.1 (s, C.sub.Ar), 131.3 (s, C.sub.Ar), 145.0 (s, C(3)), 170.3 (s, C(8)).

(168) HRMS (m/z, ESI.sup.+): [M+Na].sup.+ calcd. for C.sub.32H.sub.37N.sub.3NaO.sub.7, 598.2524; found, 598.2524.

14-(4-((pyren-1-ylmethoxy)methyl)-1H-1,2,3-triazol-1-yl)-3,6,9,12-tetraoxatetradecanoic Acid (IK75)

(169) ##STR00094##

(170) Ethyl 14-(4-((pyren-4-ylmethoxy)methyl)-1H-1,2,3-triazol-1-yl)-3,6,9,12-tetraoxatetradecanoate (830 mg, 1.44 mmol) was dissolved in 66% MeOH in water (6 mL) and NaOH (202 mg, 5.05 mmol) was added, and the mixture was stirred overnight. The mixture was concentrated under reduced pressure, the residue was acidified by 1M HCl to pH=2 and extracted with EtOAc (325 mL). The organic layers were dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The product was obtained as a pale yellow oil.

(171) Yield: 787 mg (99%);

(172) .sup.1H NMR (401.00 MHz, CDCl.sub.3): 3.42-3.49 (m, 10H, CH.sub.2), 3.54-3.56 (m, 2H, CH.sub.2), 3.76 (t, 2H, .sup.3J.sub.HH=5.0 Hz, C(6)H.sub.2), 4.05 (s, 2H, C(7)H.sub.2), 4.47 (t, 2H, .sup.3J.sub.HH=5.0 Hz, C(5)H.sub.2), 4.81 (s, 2H, C(2)H.sub.2) 5.26 (s, 2H, C(1)H.sub.2), 7.74 (s, 1H, C(4)H), 7.94-8.02 (m, 4H, C.sub.ArH), 8.06-8.16 (m, 4H, C.sub.ArH), 8.29 (d, .sup.3J.sub.HH=9.2 Hz, 1H, C.sub.ArH), 9.56 (br s, 1H, OH);

(173) .sup.13C NMR (100.84 MHz, CDCl.sub.3): 50.2 (s, C(5)H.sub.2), 63.4 (s, C(2)H.sub.2), 68.5 (s, C(7)H.sub.2), 69.1 (s, C(6)H.sub.2), 70.0-70.3 (m, 5CH.sub.2), 70.8 (m, CH.sub.2, C(1)H.sub.2), 123.3 (s, C.sub.ArH), 124.1 (s, C(4)H), 124.3 (s, C.sub.ArH), 124.5 (s, C.sub.Ar), 124.7 (s, C.sub.Ar), 125.1 (s, 2C.sub.ArH), 125.8 (s, C.sub.ArH), 127.1 (s, C.sub.ArH), 127.2 (s, C.sub.ArH), 127.3 (s, C.sub.ArH), 127.6 (s, C.sub.ArH), 129.2 (s, C.sub.Ar), 130.6 (s, C.sub.Ar), 130.8 (s, C.sub.Ar), 131.0 (s, C.sub.Ar), 131.2 (s, C.sub.Ar), 144.6 (s, C(3)), 172.4 (s, C(8)).

(174) HRMS (m/z, ESI.sup.+): [M+Na].sup.+ calcd. for C.sub.30H.sub.33N.sub.3NaO.sub.7, 570.2211; found, 570.2211.

2-Bromo-N-(3,6-dihydroxy-3-oxo-3H-spiro[isobenzofuran-1,9-xanthen]-6-yl)acetamide (#) AK10-9 [CAS 107142-62-1]

(175) ##STR00095##

(176) 6-Aminofluorescein (500 mg, 1.44 mmol) and NaHCO.sub.3 (363 mg, 4.32 mmol) were suspended in anhydrous THF (4.5 mL), and the mixture was stirred for 15 min at 0 C. A solution of bromoacetyl bromide (581 mg, 2.88 mmol) in anhydrous THF (1.5 mL) was added dropwise. After 15 min, the solvent was evaporated, followed by addition of HCl (5 mL, conc.?). The pH was adjusted to 4 using NaOH. The resulting precipitate was filtered off, the aqueous phase was extracted with EtOAc (35 mL), the extract was combined with the filter cake, and the mixture was concentrated to dryness. The crude product was purified by column chromatography (gradient elution from EtOAc:hexane 7:3 to EtOAc) to give an orange solid.

(177) Yield: 261 mg (39%); m.p. 230 C. (dec.); R.sub.f=0.7 (EtOAc);

(178) .sup.1H NMR (299.78 MHz, CD.sub.3OD): 3.90 (bs, 2H, C(1)H.sub.2), 6.53 (dd, .sup.3J.sub.HH=8.7, .sup.4J.sub.HH=2.4, 2H, C(15)H), 6.62 (d, .sup.3J.sub.HH=8.7, 2H, C(16)H), 6.68 (d, .sup.4J.sub.HH=2.4, 2H, C(13)H), 7.57 (dd, .sup.4J.sub.HH=1.8, .sup.5J.sub.HH=0.6, 1H, C(4)H), 7.76 (dd, .sup.3J.sub.HH=8.4, .sup.4J.sub.HH=1.8, 1H, C(8)H), 7.93 (dd, .sup.3J.sub.HH=8.4, .sup.5J.sub.HH=0.6, 1H, C(7)H);

(179) .sup.13C NMR (100.66 MHz, CD.sub.3OD): 29.5 (s, C(1)H.sub.2), 86.8 (bs, C(10)), 103.5 (s, C(13)H), 111.2 (s, C(11)), 113.6 (s, C(15)H), 115.1 (s, C(4)H), 122.1 (s, C(8)H), 123.3 (s, C(6)), 126.8 (s, C(7)H), 130.2 (s, C(16)H), 146.2 (s, C(3)), 153.9 (s, C(12) or C(14)), 155.8 (s, C(5)), 161.2 (s, C(12) or C(14)), 168.0 (s, C(2)), 171.1 (s, C(9));

(180) HRMS (m/z, ESI.sup.+): [M+H].sup.+ calcd. for C.sub.22H.sub.15BrNO.sub.6, 468.0077; found, 468.0073.

(181) Derivatives of # NMT

(182) General Procedure for the Synthesis of Amide Reagents #

(183) ##STR00096## ##STR00097##

(184) To a carboxylic acid (0.12 mmol, 1.2 equiv.) in an oven-dried Schlenk flask, anhydrous DCM (2 mL) was added at rt. (COCl).sub.2 (13 L, 0.15 mmol, 1.5 equiv.) and DMF (9 L, 0.12 mmol, 1.2 equiv.) were added, the mixture was stirred for 2 h at rt, and concentrated to dryness. The resulting acyl chloride was dissolved in DCM (2 mL).

(185) The NMT reagent (74 mg, 0.1 mmol, 1.0 equiv.) was dissolved in DCM (1 mL) in another Schlenk flask at 25 C., and a base (1 mmol, 10 equiv.) was added. The solution of acyl chloride was added dropwise, and the mixture was stirred at 25 C. to rt for a given period of time. In some cases, the reaction mixture was diluted with DCM (5 mL) and washed with pH 4 phosphate buffer (210 mL), aqueous NaHCO.sub.3 (210 mL), brine (210 mL), dried over Na.sub.2SO.sub.4, and concentrated onto Celite. The crude product was purified by automated flash chromatography.

N-(4-(2-(3,3-Dimethyl-1.SUP.3.-benzo[d][1,2]iodaoxol-1 (3H)-yl)-1,1,2,2-tetrafluoroethoxy)phenethyl)-N-methylpyrene-1-carboxamide (#) JV106 and JV131-4

(186) ##STR00098##

(187) The title compound was prepared according to the general procedure starting from 1-pyrenecarboxylic acid (0.06 mmol) using Et.sub.3N as the base. The reaction time was 2 h. The reaction mixture was directly concentrated on Celite, and the product was isolated by automated flash chromatography (12 g SiO.sub.2 column, gradient elution from hexane to EtOAc) as a colourless oil.

(188) Yield: 33 mg (89%); R.sub.f=0.34 (EtOAc);

(189) .sup.1H NMR (500.13 MHz, CDCl.sub.3): 1.50 and 1.52 (s, 6H, C(2)H.sub.3), 2.73 and 3.18 (bm, 2H, C(13)H.sub.2), 2.72 and 3.37 (s, 3H, C(15)H.sub.3), 3.34 and 4.04 (bm, 2H, C(14)H.sub.2), 6.73 and 7.44 (m, 2H, C(11)H), 6.95 and 7.26 (m, 2H, C(10)H), 7.38 (m, 2H, C(4)Hand C(6)H), 7.47 (m, 1H, C(5)H), 7.49 and 7.93 (m, 1H, C.sub.ArH), 7.73 and 7.79 (m, 1H, C(7)H), 7.81 (m, 1H, C.sub.ArH), 8.00-8.24 (m, 7H, C.sub.ArH);

(190) .sup.19F NMR (470.55 MHz, CDCl.sub.3): 97.3 (bs, 2F, CF.sub.2), 84.7 and 84.6 (bm, 2F, CF.sub.2);

(191) .sup.13C {.sup.1H} NMR (125.77 MHz, CDCl.sub.3): 30.9 (s, C(2)H.sub.3), 32.8 and 37.2 (s, C(15)H.sub.3), 32.9 and 34.0 (s, C(13)H.sub.2), 48.4 and 52.6 (s, C(14)H.sub.2), 76.3 (bs, C(1)), 110.9 (m, C(8)), 111.3 and 111.4 (tt, .sup.1J.sub.CF=337, .sup.2J.sub.CF=38.3, CF.sub.2), 117.2 and 117.3 (tt, .sup.1J.sub.CF=277, .sup.2J.sub.CF=25.9, CF.sub.2), 121.7 (s, C(10)H), 123.7 and 123.7 (s, C.sub.ArH), 123.7 and 123.8 (s, C.sub.ArH), 124.4 and 124.4 (s, C.sub.Ar), 124.5 (s, C.sub.ArH), 124.5 and 124.5 (s, C.sub.Ar), 124.7 (s, C.sub.ArH), 125.5 and 125.6 (s, C.sub.ArH), 125.7 and 125.7 (s, C.sub.ArH), 126.3 and 126.3 (s, C.sub.ArH), 127.1 (s, C.sub.Ar), 127.1 and 127.2 (s, C.sub.ArH), 127.4 (s, C(4)H or C(6)H), 128.1 and 128.1 (s, C.sub.ArH), 128.6 and 128.7 (s, C.sub.ArH), 129.1 (m, C(7)), 129.4 (s, C(4)H or C(6)H), 129.9 and 130.3 (s, C(11)H), 130.4 (s, C(5)H), 130.7 and 130.7 (s, C.sub.Ar), 131.0 and 131.5 (s, C(17)), 131.1 and 131.2 (s, C.sub.Ar), 131.5 and 131.5 (s, C.sub.Ar), 136.4 and 137.5 (s, C(12)), 147.3 and 147.5 (bm, C(9)), 149.8 (m, C(3)), 171.2 and 171.5 (s, C(16));

(192) HRMS (m/z, ESI.sup.+): [M+H].sup.+ calcd. for C.sub.37H.sub.31F.sub.4INO.sub.3, 740.1279, found, 740.1270.

N-(4-(2-(3,3-Dimethyl-1.SUP.3.-benzo[d][1,2]iodaoxol-1 (3H)-yl)-1,1,2,2-tetrafluoroethoxy)phenethyl)-4-iodo-N-methylbenzamide (#) JV136-1

(193) ##STR00099##

(194) The title compound was prepared according to the general procedure starting from 4-iodobenzoic acid (0.12 mmol) using Et.sub.3N as the base. The reaction time was 1 h. The reaction mixture was directly concentrated on Celite, and the product was isolated by automated flash chromatography (12 g SiO.sub.2 column, gradient elution from hexane to EtOAc) as a colourless oil.

(195) Yield: 60 mg (81%); R.sub.f=0.39 (EtOAc);

(196) .sup.1H NMR (400.13 MHz, CDCl.sub.3): 1.51 (s, 6H, C(2)H.sub.3), 2.79 and 2.99 (bs, 2H, C(13)H.sub.2), 2.82 and 3.13 (bs, 3H, C(15)H.sub.3), 3.48c and 3.74 (bs, 2H, C(14)H.sub.2), 6.70-7.20 (bm, 5H, C.sub.ArH), 7.29 (bm, 1H, C.sub.ArH), 7.40 (m, 2H, C(4)Hand C(6)H), 7.51 (m, 1H, C(5)H), 7.63 (bm, 1H, C.sub.ArH), 7.72 (bm, 1H, C.sub.ArH), 7.74 (m, 1H, C(7)H); .sup.19F NMR (376.46 MHz, CDCl.sub.3): 97.5 (bs, 2F, CF.sub.2), 84.8 and 84.7 (bs, 2F, CF.sub.2);

(197) .sup.13C {.sup.1H} NMR (100.62 MHz, CDCl.sub.3): 30.9 (s, C(2)H.sub.3), 32.6 and 33.8 (s, C(13)H.sub.2), 33.0 and 38.1 (s, C(15)H.sub.3), 49.1 and 52.6 (s, C(14)H.sub.2), 76.3 (s, C(1)), 95.3 and 95.6 (bs, C(20)), 111.0 (m, C(8)), 111.4 (tt, .sup.1J.sub.CF=338, .sup.2J.sub.CF=38.0, CF.sub.2), 117.2 (tt, .sup.1J.sub.CF=277, .sup.2J.sub.CF=26.0, CF.sub.2), 121.7 (bs, C.sub.ArH), 122.0 (bs, C.sub.ArH), 127.4 (s, C(4)H or C(6)H), 128.2 and 128.6 (bs, C.sub.ArH), 128.9 (t, J.sub.CF=5.3, C(7)), 129.4 (s, C(4)H or C(6)H), 130.1 (s, C.sub.ArH), 130.3 (s, C(5)H), 135.6 and 135.7 (bs, C.sub.Ar), 136.4 (bs, C.sub.Ar), 137.5 (bs, C.sub.ArH), 147.4 and 147.5 (m, C(9)), 149.9 (s, C(3)), 170.4 and 171.1 (s, C(16));

(198) HRMS (m/z, ESI.sup.+): [M+H].sup.+ calcd. for C.sub.27H.sub.26F.sub.4I.sub.2NO.sub.3, 741.9933, found, 741.9920.

4-Azido-N-(4-(2-(3,3-Dimethyl-1.SUP.3.-benzo[d][1,2]iodaoxol-1 (3H)-yl)-1,1,2,2-tetrafluoroethoxy)phenethyl)-N-methylbenzamide (#) JV137-1

(199) ##STR00100##

(200) The title compound was prepared according to the general procedure starting from 4-azidobenzoic acid (0.12 mmol) using Et.sub.3N as the base. The reaction time was 2 h. The reaction mixture was directly concentrated on Celite, and the product was isolated by automated flash chromatography (12 g SiO.sub.2 column, gradient elution from hexane to EtOAc) as a colourless oil.

(201) Yield: 45 mg (69%); R.sub.f=0.31 (EtOAc);

(202) .sup.1H NMR (400.13 MHz, CDCl.sub.3): 1.50 (s, 6H, C(2)H.sub.3), 2.80 and 2.98 (bs, 2H, C(13)H.sub.2), 2.85 and 3.12 (bs, 3H, C(15)H.sub.3), 3.51 and 3.74 (bs, 2H, C(14)H.sub.2), 6.88-7.36 (bm, 8H, C.sub.ArH), 7.39 (m, 2H, C(4)Hand C(6)H), 7.50 (m, 1H, C(5)H), 7.74 (m, 1H, C(7)H);

(203) .sup.19F NMR (376.46 MHz, CDCl.sub.3): 97.5 (bs, 2F, CF.sub.2), 84.7 (bs, 2F, CF.sub.2);

(204) .sup.13C {.sup.1H} NMR (100.62 MHz, CDCl.sub.3): 30.9 (s, C(2)H.sub.3), 32.7 and 33.8 (s, C(13)H.sub.2), 33.1 and 38.2 (s, C(15)H.sub.3), 49.3 and 52.7 (s, C(14)H.sub.2), 76.3 (bs, C(1)), 110.9 (m, C(8)), 111.4 (tt, .sup.1J.sub.CF=337, .sup.2J.sub.CF=38.5, CF.sub.2), 117.2 (tt, .sup.1J.sub.CF=276, .sup.2J.sub.CF=25.0, CF.sub.2), 118.8 (s, C.sub.ArH) 121.8 (bs, C.sub.ArH), 127.4 (s, C(4)H or C(6)H), 128.4 and 128.7 (bs, C.sub.ArH), 129.0 (t, J.sub.CF=5.2, C(7)), 129.4 (s, C(4)H or C(6)H), 130.1 (s, C.sub.ArH), 130.3 (s, C(5)H), 132.8 (s, C.sub.Ar), 136.6 and 137.5 (bs, C.sub.Ar), 141.3 (bs, C(20)), 147.4 (bm, C(9)), 149.8 (s, C(3)), 170.4 and 171.2 (s, C(16));

(205) HRMS (m/z, ESI.sup.+): [M+H].sup.+ calcd. for C.sub.27H.sub.26F.sub.4IN.sub.4O.sub.3, 657.0980, found, 657.0983.

N-(4-(2-(3,3-Dimethyl-1.SUP.3.-benzo[d][1,2]iodaoxol-1 (3H)-yl)-1,1,2,2-tetrafluoroethoxy)phenethyl)-N-methyl-4-(4,4,5,5-tetramethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (#) JV140-1

(206) ##STR00101##

(207) The title compound was prepared according to the general procedure starting from 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (0.12 mmol) using Et.sub.3N as the base. The reaction time was 2 h. The reaction mixture was directly concentrated on Celite, and the product was isolated by automated flash chromatography (12 g SiO.sub.2 column, gradient elution from hexane to EtOAc) as a colourless oil.

(208) Yield: 51 mg (69%); R.sub.f=0.44 (EtOAc);

(209) .sup.1H NMR (500.13 MHz, CDCl.sub.3): 1.34 (s, 12H, C(22)H.sub.3), 1.50 (s, 6H, C(2)H.sub.3), 2.78 and 2.99 (bs, 2H, C(13)H.sub.2), 2.80 and 3.12 (bs, 3H, C(15)H.sub.3), 3.45 and 3.75 (bs, 2H, C(14)H.sub.2), 6.90-7.20 (bm, 4H, C.sub.ArH), 7.29 (bm, 2H, C.sub.ArH), 7.39 (m, 2H, C(4)Hand C(6)H), 7.49 (m, 1H, C(5)H), 7.75 (m, 1H, C(7)H), 7.81 (bm, 2H, C.sub.ArH);

(210) .sup.19F NMR (470.55 MHz, CDCl.sub.3): 97.3 (bs, 2F, CF.sub.2), 84.7 and 84.6 (bs, 2F, CF.sub.2);

(211) .sup.13C {.sup.1H} NMR (125.77 MHz, CDCl.sub.3): 24:9 (s, C(22)H.sub.3), 30.9 (s, C(2)H.sub.3), 32.7 and 34.0 (s, C(13)H.sub.2), 33.0 and 38.1 (s, C(15)H.sub.3), 49.1 and 52.6 (s, C(14)H.sub.2), 76.3 (bs, C(1)), 84.0 (s, C(21)), 111.1 (m, C(8)), 111.5 (tt, .sup.1J.sub.CF=337, .sup.2J.sub.CF=38.0, CF.sub.2), 117.3 (tt, .sup.1J.sub.CF=277, .sup.2J.sub.CF=26.0, CF.sub.2), 121.7 and 121.8 (bs, C.sub.ArH), 127.4 (s, C(4)H or C(6)H), 125.6 and 125.9 (bs, C.sub.ArH), 129.2 (m, C(7)), 129.4 (s, C(4)H or C(6)H), 130.1 (bs, C.sub.ArH), 130.4 (s, C(5)H), 134.7 (bs, C.sub.ArH), 136.5 (bs, C.sub.Ar), 137.6 (bs, C.sub.Ar), 139.0 (bs, C.sub.Ar), 147.4 (bm, C(9)), 149.9 (s, C(3)), 171.2 and 171.9 (s, C(16));

(212) HRMS (m/z, ESI/MALDI): [M+H].sup.+ calcd. for C.sub.33H.sub.38BF.sub.4INO.sub.5, 724.1824, found, 724.1817.

N-(4-(2-(3,3-Dimethyl-1.SUP.3.-benzo[d][1,2]iodaoxol-1 (3H)-yl)-1,1,2,2-tetrafluoroethoxy)phenethyl)-4-formyl-N-methylbenzamide (#) JV151-1

(213) ##STR00102##

(214) The title compound was prepared according to the general procedure starting from 4-formylbenzoic acid (0.12 mmol) using (i-Pr).sub.2EtN as the base. The reaction time was 3 h. The reaction mixture was directly concentrated on Celite, and the product was isolated by automated flash chromatography (12 g SiO.sub.2 column, gradient elution from hexane to EtOAc) as a colourless oil.

(215) Yield: 47 mg (73%); R.sub.f=0.21 (EtOAc);

(216) .sup.1H NMR (500.13 MHz, CDCl.sub.3): 1.50 (s, 6H, C(2)H.sub.3), 2.79 and 3.01 (m, 2H, C(13)H.sub.2), 2.81 and 3.17 (s, 3H, C(15)H.sub.3), 3.46 and 3.79 (m, 2H, C(14)H.sub.2), 6.93 and 7.31 (d, .sup.3J.sub.HH=8.4, 2H, C(11)H), 7.09 and 7.18 (d, .sup.3J.sub.HH=8.4, 2H, C(10)H), 7.13 and 7.44 (d, .sup.3J.sub.HH=8.0, 2H, C(18)H), 7.39 (m, 2H, C(4)Hand C(6)H), 7.50 (m, 1H, C(5)H), 7.73 (m, 1H, C(7)H), 7.79 and 7.90 (d, .sup.3J.sub.HH=8.0, 2H, C(19)H), 10.0 and 10.03 (s, 1H, C(21)H);

(217) .sup.19F NMR (470.55 MHz, CDCl.sub.3): 97.4 and 97.3 (bs, 2F, CF.sub.2), 84.8 and 84.7 (bt, 2F, CF.sub.2);

(218) .sup.13C {.sup.1H} NMR (125.77 MHz, CDCl.sub.3): 30.9 (s, C(2)H.sub.3), 32.6 and 33.7 (s, C(13)H.sub.2), 32.9 and 37.9 (s, C(15)H.sub.3), 48.9 and 52.6 (s, C(14)H.sub.2), 76.2 (bs, C(1)), 110.8 (m, C(8)), 111.2 and 111.3 (tt, .sup.1J.sub.CF=337, .sup.2J.sub.CF=38.0, CF.sub.2), 117.2 (tt, .sup.1J.sub.CF=276, .sup.2J.sub.CF=27.0, CF.sub.2), 121.8 and 122.1 (s, C(10)H), 127.0 and 127.4 (s, C(18)H), 127.5 (s, C(4)H or C(6)H), 129.1 (bm, C(7)), 129.5 (s, C(4)H or C(6)H), 129.6 and 129.8 (s, C(19)H), 130.1 (s, C(11)H), 130.5 (s, C(5)H), 136.3 and 137.3 (s, C(12)), 136.5 and 136.7 (s, C(20)), 141.9 and 142.1 (s, C(17)), 147.4 and 147.6 (m, C(9)), 149.8 (s, C(3)), 170.0 and 170.6 (s, C(16)), 191.5 (s, C(21)H);

(219) HRMS (m/z, ESI.sup.+): [M+H].sup.+ calcd. for C.sub.28H.sub.27F.sub.4INO.sub.4, 644.0915, found, 644.0926.

4-Cyano-N-(4-(2-(3,3-dimethyl-1.SUP.3.-benzo[d][1,2]iodaoxol-1 (3H)-yl)-1,1,2,2-tetrafluoroethoxy)phenethyl)-N-methylbenzamide (#) JV153-2

(220) ##STR00103##

(221) The title compound was prepared according to the general procedure starting from 4-cyanobenzoic acid (0.12 mmol) using (i-Pr).sub.2EtN as the base. The reaction time was 1.5 h. The reaction mixture was washed with buffer, aqueous NaHCO.sub.3 and brine, concentrated on Celite, and the product was isolated by automated flash chromatography (12 g SiO.sub.2 column, gradient elution from hexane to EtOAc) as a colourless oil.

(222) Yield: 44 mg (69%); R.sub.f=0.24 (EtOAc);

(223) .sup.1H NMR (400.13 MHz, CDCl.sub.3): 1.50 (s, 6H, C(2)H.sub.3), 2.77 and 3.00 (m, 2H, C(13)H.sub.2), 2.79 and 3.16 (s, 3H, C(15)H.sub.3), 3.44 and 3.78 (m, 2H, C(14)H.sub.2), 6.94 and 7.29 (d, .sup.3J.sub.HH=8.1, 2H, C(11)H), 7.10 and 7.17 (d, .sup.3J.sub.HH=8.1, 2H, C(10)H), 7.01 and 7.37 (d, .sup.3J.sub.HH=7.6, 2H, C(18)H), 7.39 (m, 2H, C(4)Hand C(6)H), 7.50 (m, 1H, C(5)H), 7.73 (m, 1H, C(7)H), 7.53 and 7.67 (d, .sup.3J.sub.HH=7.6, 2H, C(19)-H);

(224) .sup.19F NMR (376.46 MHz, CDCl.sub.3): 97.7 and 97.6 (bs, 2F, CF.sub.2), 84.8 and 84.7 (bt, 2F, CF.sub.2);

(225) .sup.13C {.sup.1H} NMR (100.62 MHz, CDCl.sub.3): 30.9 (s, C(2)H.sub.3), 32.6 and 33.6 (s, C(13)H.sub.2), 32.9 and 37.9 (s, C(15)H.sub.3), 48.9 and 52.5 (s, C(14)H.sub.2), 76.4 (bs, C(1)), 110.9 (m, C(8)), 111.3 (m, CF.sub.2), 113.0 and 113.3 (s, C(20)), 117.3 (m, CF.sub.2), 118.0 (s, C(21)), 121.8 and 122.1 (s, C(10)H), 127.1 and 127.5 (s, C(18)H), 127.4 (s, C(4)H or C(6)H), 128.9 (bm, C(7)), 129.4 (s, C(4)H or C(6)H), 130.1 (s, C(11)H), 130.4 (s, C(5)H), 132.1 and 132.3 (s, C(19)H), 136.2 and 137.2 (s, C(12)), 140.5 and 140.7 (s, C(17)), 147.4 and 147.6 (m, C(9)), 149.8 (s, C(3)), 169.3 and 170.0 (s, C(16));

(226) HRMS (m/z, ESI.sup.+): [M+H].sup.+ calcd. for C.sub.28H.sub.26F.sub.4IN.sub.2O.sub.3, 641.0919, found, 641.0923.

4-((4-(2-(3,3-Dimethyl-1.SUP.3.-benzo[d][1,2]iodaoxol-1 (3H)-yl)-1,1,2,2-tetrafluoroethoxy)phenethyl)(methyl)carbamoyl)benzenesulfonyl fluoride (#) JV160-1

(227) ##STR00104##

(228) The title compound was prepared according to the general procedure starting from 4-(fluorosulfonyl)benzoic acid (0.12 mmol) using (i-Pr).sub.2EtN as the base. The reaction time was 1.5 h. The reaction mixture was directly concentrated on Celite, and the product was isolated by automated flash chromatography (12 g SiO.sub.2 column, gradient elution from hexane to EtOAc) as a pale yellow oil.

(229) Yield: 40 mg (57%); R.sub.f=0.25 (EtOAc);

(230) .sup.1H NMR (500.13 MHz, CDCl.sub.3): 1.50 (s, 6H, C(2)H.sub.3), 2.81 and 3.02 (m, 2H, C(13)H.sub.2), 2.81 and 3.18 (s, 3H, C(15)H.sub.3), 3.46 and 3.80 (m, 2H, C(14)H.sub.2), 6.95 and 7.30 (d, .sup.3J.sub.HH=8.4, 2H, C(11)H), 7.12 and 7.18 (d, .sup.3J.sub.HH=8.4, 2H, C(10)H), 7.12 and 7.51 (m, 2H, C(18)H), 7.40 (m, 2H, C(4)Hand C(6)H), 7.50 (m, 1H, C(5)H), 7.74 (m, 1H, C(7)H), 7.89 and 8.04 (d, .sup.3J.sub.HH=8.0, 2H, C(19)H);

(231) .sup.19F NMR (470.58 MHz, CDCl.sub.3): 97.7 and 97.6 (bs, 2F, CF.sub.2), 84.8 and 84.7 (bt, 2F, CF.sub.2), 65.5 and 65.5 (bs, 1F, SO.sub.2F);

(232) .sup.13C {.sup.1H} NMR (125.77 MHz, CDCl.sub.3): 30.8 (s, C(2)H.sub.3), 32.5 and 33.5 (s, C(13)H.sub.2), 32.9 and 37.8 (s, C(15)H.sub.3), 48.9 and 52.5 (s, C(14)H.sub.2), 76.4 (bm, C(1)), 110.8 (m, C(8)), 111.3 (m, CF.sub.2), 117.2 (m, CF.sub.2), 121.8 and 122.2 (s, C(10)H), 127.6 and 127.9 (s, C(18)H), 127.4 (bs, C(4)H or C(6)H), 128.9 (bm, C(7)), 129.5 (bs, C(4)H or C(6)H), 130.1 and 130.2 (s, C(11)H), 130.4 (bs, C(5)H), 128.5 and 128.8 (s, C(19)H), 133.5 and 133.7 (d, .sup.2J.sub.CF=25.3, C(20)), 136.1 and 137.0 (s, C(12)), 143.3 and 143.5 (s, C(17)), 147.4 and 147.7 (m, C(9)), 149.8 (bs, C(3)), 168.7 and 169.3 (s, C(16));

(233) HRMS (m/z, ESI.sup.+): [M+H].sup.+ calcd. for C.sub.27H.sub.26F.sub.5INO.sub.5S, 698.0491, found, 698.0473.

N-(4-(2-(3,3-Dimethyl-1.SUP.3.-benzo[d][1,2]iodaoxol-1 (3H)-yl)-1,1,2,2-tetrafluoroethoxy)phenethyl)-4-ethynyl-N-methylbenzamide (#) JV172-1

(234) ##STR00105##

(235) The title compound was prepared according to the general procedure starting from 4-ethynylbenzoic acid (0.12 mmol) using (i-Pr).sub.2EtN as the base. The reaction time was 2 h. The reaction mixture was washed with buffer, aqueous NaHCO.sub.3 and brine, concentrated on Celite, and the product was isolated by automated flash chromatography (12 g SiO.sub.2 column, gradient elution from hexane to EtOAc) as a yellow waxy oil.

(236) Yield: 47 mg (74%); R.sub.f=0.38 (EtOAc);

(237) .sup.1H NMR (500.13 MHz, CDCl.sub.3): 1.50 (s, 6H, C(2)H.sub.3), 2.78 and 3.00 (m, 2H, C(13)H.sub.2), 2.82 and 3.14 (s, 3H, C(15)H.sub.3), 3.13 (s, 1H, C(22)H), 3.47 and 3.75 (m, 2H, C(14)H.sub.2), 6.95 and 7.30 (bm, 2H, C(11)H), 6.98 and 7.27 (bm, 2H, C(18)H), 7.09 and 7.16 (bm, 2H, C(10)H), 7.39 (m, 2H, C(4)Hand C(6)H), 7.41 and 7.49 (bm, 2H, C(19)H), 7.50 (m, 1H, C(5)H), 7.74 (m, 1H, C(7)H);

(238) .sup.19F NMR (470.55 MHz, CDCl.sub.3): 97.6 (bs, 2F, CF.sub.2), 84.8 and 84.7 (bs, 2F, CF.sub.2);

(239) .sup.13C {.sup.1H} NMR (125.77 MHz, CDCl.sub.3): 30.9 (s, C(2)H.sub.3), 32.7 and 33.8 (s, C(13)H.sub.2), 33.0 and 38.1 (s, C(15)H.sub.3), 49.1 and 52.7 (s, C(14)H.sub.2), 76.3 (bs, C(1)), 78.5 (s, C(22)H), 82.8 (s, C(21)), 110.9 (bm, C(8)), 111.4 (m, CF.sub.2), 117.2 (m, CF.sub.2), 121.7 and 122.0 (s, C(10)H), 123.1 and 123.4 (s, C(20)), 126.4 and 126.9 (s, C(18)H), 127.4 (s, C(4)H or C(6)H), 128.9 (m, C(7)), 129.4 (s, C(4)H or C(6)H), 130.1 (s, C(11)H), 130.3 (s, C(5)H), 132.0 and 132.1 (s, C(19)H), 136.5 and 136.6 (s, C(17)), 136.5 and 137.5 (s, C(12)), 147.4 and 147.5 (m, C(9)), 149.8 (s, C(3)), 170.5 and 171.3 (s, C(16));

(240) HRMS (m/z, ESI.sup.+): [M+H].sup.+ calcd. for C.sub.29H.sub.27F.sub.4INO.sub.3, 640.0966, found, 640.0969.

N-(4-(2-(3,3-Dimethyl-1.SUP.3.-benzo[d][1,2]iodaoxol-1 (3H)-yl)-1,1,2,2-tetrafluoroethoxy)phenethyl)-N-methyl-4-((trimethylsilyl)ethynyl)benzamide (#) JV1 64-1

(241) ##STR00106##

(242) The title compound was prepared according to the general procedure starting from 4-[(Trimethylsilyl)ethynyl]benzoic acid (0.12 mmol) using (i-Pr).sub.2EtN as the base. The reaction time was 2 h. The reaction mixture was washed with buffer, aqueous NaHCO.sub.3 and brine, concentrated on Celite, and the product was isolated by automated flash chromatography (12 g SiO.sub.2 column, gradient elution from hexane to EtOAc) as a colourless oil.

(243) Yield: 60 mg (84%); R.sub.f=0.38 (EtOAc);

(244) .sup.1H NMR (500.13 MHz, CDCl.sub.3): 0.25 (s, 9H, Si(CH.sub.3).sub.3), 1.49 (s, 6H, C(2)H.sub.3), 2.77 and 2.98 (m, 2H, C(13)H.sub.2), 2.80 and 3.12 (s, 3H, C(15)H.sub.3), 3.45 and 3.74 (m, 2H, C(14)H.sub.2), 6.94 and 7.29 (bm, 2H, C(11)H), 6.97 and 7.24 (bm, 2H, C(18)H), 7.08 and 7.15 (bm, 2H, C(10)H), 7.38 and 7.46 (bm, 2H, C(19)H), 7.39 (m, 2H, C(4)Hand C(6)H), 7.49 (m, 1H, C(5)H), 7.73 (m, 1H, C(7)H);

(245) .sup.19F NMR (470.55 MHz, CDCl.sub.3): 97.6 (bs, 2F, CF.sub.2), 84.8 and 84.7 (bs, 2F, CF.sub.2);

(246) .sup.13C {.sup.1H} NMR (125.77 MHz, CDCl.sub.3): 0.2 (s, Si(CH.sub.3).sub.3), 30.9 (s, C(2)H.sub.3), 32.6 and 33.8 (s, C(13)H.sub.2), 32.9 and 38.1 (s, C(15)H.sub.3), 49.1 and 52.6 (s, C(14)H.sub.2), 76.3 (bs, C(1)), 95.8 (bs, C(22)), 104.1 (s, C(21)), 110.9 (bm, C(8)), 111.4 (tt, .sup.1J.sub.CF=338, .sup.2J.sub.CF=39.2, CF.sub.2), 117.2 (tt, .sup.1J.sub.CF=277, .sup.2J.sub.CF=26.0, CF.sub.2), 121.7 and 121.9 (s, C(10)H), 124.2 and 124.4 (s, C(20)), 126.4 and 126.8 (s, C(18)H), 127.4 (s, C(4)H or C(6)H), 128.9 (bm, C(7)), 129.4 (s, C(4)H or C(6)H), 130.1 (s, C(11)H), 130.3 (s, C(5)H), 131.8 (s, C(19)H), 136.1 (s, C(17)), 136.4 and 137.5 (s, C(12)), 147.3 and 147.5 (m, C(9)), 149.8 (s, C(3)), 170.6 and 171.4 (s, C(16));

(247) HRMS (m/z, ESI.sup.+): [M+H].sup.+ calcd. for C.sub.32H.sub.35F.sub.4INO.sub.3Si, 712.1362, found, 712.1351.

N-(4-(2-(3,3-Dimethyl-1.SUP.3.-benzo[d][1,2]iodaoxol-1 (3H)-yl)-1,1,2,2-tetrafluoroethoxy)phenethyl)-N-methyl-2-oxo-2H-chromene-3-carboxamide (#) JV144-1

(248) ##STR00107##

(249) The title compound was prepared according to the general procedure starting from coumarin-3-carboxylic acid (0.12 mmol) using Et.sub.3N as the base. The reaction time was 1 h. The reaction mixture was directly concentrated on Celite, and the product was isolated by automated flash chromatography (12 g SiO.sub.2 column, gradient elution from hexane to EtOAc) as a colourless oil.

(250) Yield: 57 mg (83%); R.sub.f=0.36 (EtOAc);

(251) .sup.1H NMR (400.13 MHz, CDCl.sub.3): 1.49 (s, 6H, C(2)H.sub.3), 2.89 and 2.98 (m, 2H, C(13)H.sub.2), 2.89 and 3.15 (s, 3H, C(15)H.sub.3), 3.49 and 3.73 (m, 2H, C(14)H.sub.2), 7.00 and 7.79 (s, 1H, C(18)H), 7.05 and 7.16 (m, 2H, C(10)H), 7.05 and 7.32 (m, 2H, C(11)H), 7.27 and 7.30 (m, 1H, C(21)H), 7.30 and 7.33 (m, 1H, C(23)H), 7.30 and 7.51 (m, 1H, C(20)H), 7.39 (m, 2H, C(4)H and C(6)H), 7.50 (m, 1H, C(5)-H), 7.53 and 7.57 (m, 1H, C(22)-H), 7.74 (m, 1H, C(7)H);

(252) .sup.19F NMR (376.46 MHz, CDCl.sub.3): 97.5 and 97.3 (bs, 2F, CF.sub.2), 84.7 and 84.6 (bt, 2F, CF.sub.2);

(253) .sup.13C {.sup.1H} NMR (100.62 MHz, CDCl.sub.3): 30.8 (s, C(2)H.sub.3), 32.7 and 33.4 (s, C(13)H.sub.2), 32.8 and 37.0 (s, C(15)H.sub.3), 49.5 and 52.2 (s, C(14)H.sub.2), 76.3 and 76.2 (bm, C(1)), 110.7 (m, C(8)), 111.2 and 111.3 (tt, .sup.1J.sub.CF=337, .sup.2J.sub.CF=37.8, CF.sub.2), 117.2 and 117.3 (tt, .sup.1J.sub.CF=277, .sup.2J.sub.CF=25.8, CF.sub.2), 116.6 and 116.7 (s, C(23)H), 118.1 and 118.2 (s, C(19)), 121.6 and 121.7 (s, C(10)H), 124.8 and 124.9 (s, C(21)), 125.1 and 125.8 (s, C(17)), 127.4 and 127.5 (bs, C(4)H or C(6)H), 128.4 and 128.5 (s, C(20)H), 129.0 (bm, C(7)), 129.5 (s, C(4)H or C(6)H), 130.2 and 130.3 (s, C(11)H), 130.4 (s, C(5)H), 132.6 and 132.7 (s, C(22)), 136.7 and 137.5 (s, C(12)), 142.5 (s, C(18)H), 147.3 and 147.5 (m, C(9)), 149.8 (s, C(3)), 153.7 and 154.0 (s, C(24)), 157.7 and 158.0 (s, C(25)), 164.9 and 165.0 (s, C(16)); HRMS (m/z, ESI.sup.+): [M+H].sup.+ calcd. for C.sub.30H.sub.27F.sub.4INO.sub.5, 684.0865, found, 684.0854.

N-(4-(2-(3,3-dimethyl-1.SUP.3.-benzo[d][1,2]iodaoxol-1 (3H)-yl)-1,1,2,2-tetrafluoroethoxy)phenethyl)-2-(6-methoxy-3-oxo-3H-xanthen-9-yl)-N-methylbenzamide (#) JV154-3

(254) ##STR00108##

(255) The title compound was prepared according to the general procedure starting from methylfluorescein (0.12 mmol) using (i-Pr).sub.2EtN as the base. The reaction time was 3.5 h. The reaction mixture was washed with buffer, aqueous NaHCO.sub.3 (2) and brine, concentrated on Celite, and the product was isolated by automated flash chromatography (12 g SiO.sub.2 column, gradient elution from DCM to MeOH) as an orange solid.

(256) Yield: 20 mg (24%); m.p. 88-90 C.; R.sub.f=0.24 (EtOAc:MeOH 10:1);

(257) .sup.1H NMR (500.13 MHz, CD.sub.3OD): 1.49 and 1.50 (s, 6H, C(2)H.sub.3), 2.46 and 2.81 (m, 2H, C(13)H.sub.2), 2.72 and 2.83 (s, 3H, C(15)H.sub.3), 3.20 and 3.43 (m, 2H, C(14)H.sub.2), 3.77 and 3.96 (s, 3H, C(19)H.sub.3), 6.45-8.00 (m, 10H, C.sub.ArH),.sup.1 7.09 and 7.16 (m, 2H, C(11)H), 7.09 and 7.22 (m, 2H, C(10)H), 7.49 (m, 1H, C(6)H), 7.54 (m, 1H, C(4)H), 7.59 (m, 1H, C(5)H), 7.78 (m, 1H, C(7)H); These signals could not be assigned due to extensive overlap and the presence of rotamers.

(258) .sup.19F NMR (470.55 MHz, CD.sub.3OD): 97.3 and 97.2 (bt, 2F, CF.sub.2), 85.4 and 85.3 (bt, 2F, CF.sub.2);

(259) .sup.13C NMR (125.77 MHz, CD.sub.3OD): 31.0 (s, C(2)H.sub.3), 32.9 and 34.2 (s, C(13)H.sub.2), 32.7 and 38.4 (s, C(15)H.sub.3), 49.6 and 54.1 (s, C(14)H.sub.2), 56.1 and 57.0 (s, C(19)H.sub.3), 77.5 (bm, C(1)), 101.4 (s, C.sub.ArH), 105.7 (s, C.sub.ArH) 111.2 (m, C(8)), 112.4 (m, CF.sub.2), 115.3 and 115.4 (s, C.sub.ArH), 115.9 (s, C.sub.Ar), 118.5 (s, C.sub.Ar), 118.6 and 118.8 (m, CF.sub.2), 122.7 and 123.1 and 123.2 (s, C(10)H), 128.6 and 128.7 (s, C.sub.ArH), 129.1 (s, C(4)H), 129.2 and 129.4 (s, C.sub.ArH), 130.2 (tm, J.sub.CF=4.5, 1H, C(7)H), 130.8 and 130.9 (s, C.sub.ArH), 131.0 (s, C(6)H), 131.2 and 131.9 (s, C(11)H), 131.6 (s, C.sub.ArH), 131.8 (s, C.sub.ArH), 131.9 (s, C.sub.ArH), 132.1 (s, C(5)H), 132.2 (s, C.sub.Ar), 133.3 and 133.3 (s, C.sub.ArH), 137.2 and 137.5 (s, C.sub.Ar), 138.8 and 139.0 (s, C(12)), 148.5 and 148.8 and 149.0 (s, C(9)), 151.1 and 151.1 (s, C(3)), 152.7 and 153.1 (s, C.sub.Ar), 156.4 (s, C.sub.Ar), 161.2 (s, C.sub.Ar), 167.2 (s, C(18)), 170.6 and 171.2 (s, C(16)), 187.2 and 187.3 (s, C(17));

(260) HRMS (m/z, ESI/MALDI): [M+H].sup.+ calcd. for C.sub.41H.sub.35F.sub.4INO.sub.6, 840.1440; found, 840.1438.

(1S)N-(4-(2-(3,3-Dimethyl-1.SUP.3.-benzo[d][1,2]iodaoxol-1(3H)-yl)-1,1,2,2-tetrafluoroethoxy)phenethyl)-N,4,7,7-tetramethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxamide (#) JV142-1

(261) ##STR00109##

(262) The title compound was prepared according to the general procedure starting from (1S)-()-camphanic acid (0.12 mmol) using Et.sub.3N as the base. The reaction time was 1.5 h. The reaction mixture was directly concentrated on Celite, and the product was isolated by automated flash chromatography (12 g SiO.sub.2 column, gradient elution from hexane to EtOAc) as a pale yellow oil.

(263) Yield: 49 mg (71%); R.sub.f=0.45 (EtOAc);

(264) .sup.1H NMR (400.13 MHz, CDCl.sub.3): 0.89 and 0.96 (s, 3H, C(23)H.sub.3 or C(24)H.sub.3), 1.07 and 1.09 (s, 3H, C(25)H.sub.3), 1.11 and 1.16 (s, 3H, C(23)H.sub.3 Or C(24)H.sub.3), 1.49 (s, 6H, C(2)H.sub.3), 1.60-1.70 and 1.78-2.04 and 2.26-2.37 (m, 4H, C(18)H.sub.2 and C(19)H.sub.2), 2.86 and 2.93 (m, 2H, C(13)H.sub.2), 3.00 and 3.14 (s, 3H, C(15)H.sub.3), 3.54 and 3.60 and 3.68 and 3.77 (m, 2H, C(14)H.sub.2),.sup.2 7.11 and 7.13 (m, 2H, C(10)H), 7.23 and 7.30 (m, 2H, C(11)H), 7.38 (m, 2H, C(4)Hand C(6)H), 7.49 (m, 1H, C(5)H), 7.73 (m, 1H, C(7)H);

(265) .sup.19F NMR (376.46 MHz, CDCl.sub.3): 97.5 (bs, 2F, CF.sub.2), 84.8 and 84.7 (bt, 2F, CF.sub.2);

(266) .sup.13C {.sup.1H} NMR (125.77 MHz, CDCl.sub.3): 9.6 (C(25)H.sub.3), 16.6 and 16.7 (s, C(23)H.sub.3 or C(24)H.sub.3), 17.6 and 17.8 (s, C(23)H.sub.3 or C(24)H.sub.3), 29.2 and 29.3 (s, C(18)H.sub.3 or C(19)H.sub.3), 30.8 (s, C(2)H.sub.3), 30.9 and 31.6 (s, C(18)H.sub.3 or C(19)H.sub.3), 32.5 and 35.1 (s, C(13)H.sub.2), 35.3 and 36.5 (s, C(15)H.sub.3), 50.8 and 52.0 (s, C(14)H.sub.2), 53.8 and 53.8 (s, C(22) or C(20)), 55.1 and 55.3 (s, C(22) or C(20)), 76.2 (bs, C(1)), 92.7 and 92.8 (s, C(17)), 110.7 (m, C(8)), 111.3 (tt, .sup.1J.sub.CF=337, .sup.2J.sub.CF=38.2, CF.sub.2), 117.1 (tt, .sup.1J.sub.CF=277, .sup.2J.sub.CF=26.2, CF.sub.2), 121.6 and 121.8 (s, C(10)H), 127.5 (s, C(4)H or C(6)H), 129.1 (t, J.sub.CF=5.3, C(7)), 129.5 (s, C(4)H or C(6)H), 130.1 and 130.4 (s, C(11)H), 130.4 (s, C(5)H), 137.0 and 137.4 (bs, C(12)), 147.3 and 147.4 (m, C(9)), 149.8 (s, C(3)), 166.7 and 167.2 (s, C(16)), 178.3 and 178.6 (s, C(21)); .sup.2 The signals are diastereomers of rotamers.

(267) HRMS (m/z, ESI.sup.+): [M+H].sup.+ calcd. for C.sub.30H.sub.35F.sub.4INO.sub.5, 692.1491, found, 692.1481.

N-(4-(2-(3,3-dimethyl-1.SUP.3.-benzo[d][1,2]iodaoxol-1 (3H)-yl)-1,1,2,2-tetrafluoroethoxy)phenethyl)-N-methyl-5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamide (#) JV132-7

(268) ##STR00110##

(269) The title compound was prepared according to the general procedure starting from biotin (0.11 mmol, only 1.1 equiv.) using (i-Pr).sub.2EtN as the base. The coupling reaction was carried out in DMF for 3 h. The reaction mixture was diluted with chloroform, washed with brine, concentrated on Celite, and the product was isolated by automated flash chromatography (12 g SiO.sub.2 column, gradient elution from DCM to DCM:MeOH 4:1) as a colourless waxy oil.

(270) Yield: 31 mg (42%); R.sub.f=0.46 (DCM:MeOH 9:1);

(271) .sup.1H NMR (500.26 MHz, CDCl.sub.3): 1.48 (s, 6H, C(2)H.sub.3), 1.30-1.77 (m, 6H, C(18)H.sub.2, C(19)H.sub.2, C(20)H.sub.2), 2.07 and 2.29 (m, 2H, C(17)H.sub.2), 2.72 and 2.87 (m, 2H, C(25)H.sub.2), 2.81 and 2.83 (m, 2H, C(13)H.sub.2), 2.87 and 2.92 (s, 3H, C(15)H.sub.3), 3.14 (m, 1H, C(21)H), 3.49 and 3.55 (m, 2H, C(14)H.sub.2), 4.28 (m, 1H, C(22)H), 4.47 (m, 1H, C(24)H), 5.61-6.07 (s, 2H, 2NHbiotin), 7.11 and 7.15 (m, 2H, C(10)H), 7.16 and 7.21 (m, 2H, C(11)H), 7.37 (m, 2H, C(4)Hand C(6)H), 7.49 (m, 1H, C(5)H), 7.72 (m, 1H, C(7)H);

(272) .sup.19F NMR (470.67 MHz, CDCl.sub.3): 97.5 (bs, 2F, CF.sub.2), 84.7 and 84.7 (bt, .sup.3J.sub.FF=4.4, 2F, CF.sub.2);

(273) .sup.13C {.sup.1H} NMR (125.80 MHz, CDCl.sub.3): 24.7-25.0 and 28.2-28.4 (s, C(18)H.sub.2, C(19)H.sub.2, C(20)H.sub.2), 30.9 (s, C(2)H.sub.3), 32.2 and 33.0 (s, C(17)H.sub.2), 33.0 and 34.2 (s, C(13)H.sub.3), 33.5 and 36.0 (s, C(15)H.sub.3), 40.4 and 40.5 (s, C(25)H.sub.2), 49.6 and 51.4 (s, C(14)H.sub.2), 55.4 (s, C(21)H), 60.1 (s, C(24)H), 61.8 and 61.8 (s, C(22)H), 76.3 (bs, C(1)), 110.9 (m, C(8)), 111.3 and 111.4 (tt, .sup.1J.sub.CF=338, .sup.2J.sub.CF=38.0, CF.sub.2), 117.2 (tt, .sup.1J.sub.CF=277, .sup.2J.sub.CF=27.0, CF.sub.2), 121.5 and 121.9 (s, C(10)H), 127.4 (bm, C(4) or C(6)), 129.0 (bm, C(7)), 129.4 (bm, C(4) or C(6)), 130.0 and 130.0 (s, C(11)H), 130.3 (bm, C(5)), 136.9 and 137.8 (s, C(12)), 147.2 and 147.5 (s, C(9)), 149.8 (m, C(3)), 163.7 (bs, C(23)), 172.8 and 172.8 (s, C(16));

(274) HRMS (m/z, ESI/MALDI): [M+H].sup.+ calcd. for C.sub.30H.sub.37F.sub.4IN.sub.3O.sub.4S, 738.1480, found, 738.1482.

14-Azido-N-(4-(2-(3,3-dimethyl-1.SUP.3.-benzo[d][1,2]iodaoxol-1 (3H)-yl)-1,1,2,2-tetrafluoroethoxy)phenethyl)-N-methyl-3,6,9,12-tetraoxatetradecanamide (#) JV128-5

(275) ##STR00111##

(276) The title compound was prepared according to the general procedure starting from N.sub.3-PEG acid (0.28 mmol) using (i-Pr).sub.2EtN as the base. The reaction time was 1.5 h. The reaction mixture was washed with buffer (2), aqueous NaHCO.sub.3 (2) and brine, concentrated on Celite, and the product was isolated by automated flash chromatography (24 g SiO.sub.2 column, gradient elution from hexane to EtOAc:MeOH 9:1) as a yellowish oil.

(277) Yield: 136 mg (77%); R.sub.f=0.13 (EtOAc:MeOH 10:1);

(278) .sup.1H NMR (500.13 MHz, CDCl.sub.3): 1.47 (s, 6H, C(2)H.sub.3), 2.84 and 2.86 (m, 2H, C(13)H.sub.2), 2.87 and 2.94 (s, 3H, C(15)H.sub.3), 3.35 (m, 2H, CH.sub.2), 3.51 and 3.55 (m, 2H, C(14)H.sub.2), 3.58-3.65 (m, 14H, 7CH.sub.2), 3.96 and 4.15 (s, 2H, C(17)H.sub.2), 7.10 and 7.12 (d, .sup.3J.sub.HH=8.5, 2H, C(10)H), 7.18 and 7.21 (d, .sup.3J.sub.HH=8.5, 2H, C(11)H), 7.37 (m, 2H, C(4)Hand C(6)H), 7.48 (m, 1H, C(5)H), 7.71 (m, 1H, C(7)H);

(279) .sup.19F NMR (470.55 MHz, CDCl.sub.3): 97.7 and 97.6 (bs, 2F, CF.sub.2), 84.8 and 84.8 (bt, 2F, CF.sub.2);

(280) .sup.13C {.sup.1H} NMR (125.77 MHz, CDCl.sub.3): 30.8 (s, C(2)H.sub.3), 32.8 and 34.0 (s, C(13)H.sub.2), 33.4 and 34.9 (s, C(15)H.sub.3), 49.6 and 50.7 (s, C(14)H.sub.2), 50.6 (s, CH.sub.2), 69.9 and 69.9 (s, CH.sub.2), 70.2 and 70.3 (s, C(17)H.sub.2), 70.4-70.6 (s, 6CH.sub.2), 76.3 (bs, C(1)), 110.9 (m, C(8)), 111.3 and 111.3 (tt, .sup.1J.sub.CF=337, .sup.2J.sub.CF=38.2, CF.sub.2), 117.2 (tt, .sup.1J.sub.CF=277, .sup.2J.sub.CF=26.0, CF.sub.2), 121.5 and 121.8 (s, C(10)H), 127.3 (s, C(4)H or C(6)H), 128.8 (bm, C(7)), 129.3 (s, C(4)H or C(6)H), 130.0 and 130.0 (s, C(11)H), 130.3 (s, C(5)H), 136.9 and 137.5 (s, C(12)), 147.2 and 147.4 (m, C(9)), 149.8 (s, C(3)), 169.0 and 169.1 (s, C(16));

(281) HRMS (m/z, ESI.sup.+): [M+H].sup.+ calcd. for C.sub.30H.sub.40F.sub.4IN.sub.4O.sub.7, 771.1872, found, 771.1862.

N-(4-(2-(3,3-dimethyl-1.SUP.3.-benzo[d][1,2]iodaoxol-1 (3H)-yl)-1,1,2,2-tetrafluoroethoxy)phenethyl)-N-methyl-3,6,9,12,15-pentaoxaoctadec-17-ynamide (#) JV171-1

(282) ##STR00112##

(283) The title compound was prepared according to the general procedure starting from propargyl-PEG acid (0.24 mmol) using (i-Pr).sub.2EtN as the base. The reaction time was 3 h. The reaction mixture was washed with buffer (2), aqueous NaHCO.sub.3 (2) and brine, concentrated on Celite, and the product was isolated by automated flash chromatography (24 g SiO.sub.2 column, gradient elution from hexane to EtOAc:MeOH 9:1) as a yellowish oil.

(284) Yield: 102 mg (65%); R.sub.f=0.07 (EtOAc:MeOH 10:1);

(285) .sup.1H NMR (500.13 MHz, CDCl.sub.3): 1.49 (s, 6H, C(2)H.sub.3), 2.42 (bt, 1H, C(20)H), 2.85 (m, 2H, C(13)H.sub.2), 2.89 and 2.95 (s, 3H, C(15)H.sub.3), 3.52 and 3.56 (m, 2H, C(14)H.sub.2), 3.58-3.68 (m, 16H, 8CH.sub.2), 3.98 and 4.17 (s, 2H, C(17)H.sub.2), 4.18 (t, J.sub.HH=2.5, 2H, C(18)H.sub.2), 7.12 and 7.14 (m, 2H, C(10)H), 7.19 and 7.23 (m, 2H, C(11)-H), 7.39 (m, 2H, C(4)Hand C(6)H), 7.50 (m, 1H, C(5)-H), 7.73 (m, 1H, C(7)H);

(286) .sup.19F NMR (470.55 MHz, CDCl.sub.3): 97.5 (bs, 2F, CF.sub.2), 84.8 and 84.8 (bt, 2F, CF.sub.2); .sup.13C {.sup.1H} NMR (125.77 MHz, CDCl.sub.3): 30.9 (s, C(2)H.sub.3), 32.8 and 34.1 (s, C(13)H.sub.2), 33.4 and 35.0 (s, C(15)H.sub.3), 49.7 and 50.7 (s, C(14)H.sub.2), 58.4 (s, C(18)H.sub.2), 69.1 (s, CH.sub.2), 70.3-70.6 (s, 8CH.sub.2), 74.5 (s, C(20)H), 76.3 (bs, C(1)), 79.6 (s, C(19)), 110.8 (m, C(8)), 111.4 (tt, .sup.1J.sub.CF=337, .sup.2J.sub.CF=38.0, CF.sub.2), 117.2 (tt, .sup.1J.sub.CF=277, .sup.2J.sub.CF=26.0, CF.sub.2), 121.6 and 121.9 (s, C(10)H), 127.4 (s, C(4)H or C(6)H), 129.0 (bm, C(7)), 129.4 (s, C(4)H or C(6)H), 130.0 and 130.1 (s, C(11)H), 130.4 (s, C(5)H), 137.0 and 137.6 (s, C(12)H), 147.2 and 147.5 (m, C(9)), 149.8 (s, C(3)), 169.0 and 169.2 (s, C(16));

(287) HRMS (m/z, ESI.sup.+): [M+H].sup.+ calcd. for C.sub.33H.sub.43F.sub.4INO.sub.8, 784.1964, found, 784.1956.

N-(4-(2-(3,3-Dimethyl-1.SUP.3.-benzo[d][1,2]iodaoxol-1 (3H)-yl)-1,1,2,2-tetrafluoroethoxy)phenethyl)-N-methyl-1-(pyren-1-yl)-2,5,8,11,14-pentaoxahexadecan-16-amide (#) JV124-4B

(288) ##STR00113##

(289) The title compound was prepared according to the general procedure starting from pyrene-PEG acid (0.12 mmol) using (i-Pr).sub.2EtN as the base. The reaction time was 4.5 h. The reaction mixture was washed with buffer, aqueous NaHCO.sub.3 and brine, concentrated on Celite, and the product was isolated by automated flash chromatography (12 g SiO.sub.2 column, gradient elution from DCM to MeOH) as a yellowish oil.

(290) Yield: 43 mg (48%); R.sub.f=0.58 (DCM:MeOH 9:1);

(291) .sup.1H NMR (400.13 MHz, CDCl.sub.3): 1.50 (s, 6H, C(2)H.sub.3), 2.77 and 2.79 (m, 2H, C(13)H.sub.2), 2.80 and 2.90 (s, 3H, C(15)H.sub.3), 3.43 and 3.51 (m, 2H, C(14)H.sub.2), 3.56-3.76 (m, 16H, 8CH.sub.2), 3.92 and 4.11 (s, 2H, C(17)H.sub.2), 5.27 (m, 2H, OCH.sub.2-pyrene), 7.10 (m, 2H, C(10)H), 7.11 and 7.18 (m, 2H, C(11)H), 7.37 (m, 2H, C(4)Hand C(6)H), 7.48 (m, 1H, C(5)H), 7.74 (m, 1H, C(7)H), 7.97-8.04 (m, 4H, C.sub.ArH), 8.11-8.19 (m, 4H, C.sub.ArH), 8.39 (m, 1H, C.sub.ArH);

(292) .sup.19F NMR (376.46 MHz, CDCl.sub.3): 97.3 (bs, 2F, CF.sub.2), 84.7 and 84.7 (bt, 2F, CF.sub.2);

(293) .sup.13C {.sup.1H} NMR (100.62 MHz, CDCl.sub.3): 30.9 (s, C(2)H.sub.3), 32.8 and 34.0 (s, C(13)H.sub.2), 33.4 and 34.8 (s, C(15)H.sub.3), 49.6 and 50.6 (s, C(14)H.sub.2), 69.5 (s, CH.sub.2), 70.2-70.7 (s, 8CH.sub.2), 71.8 (s, OCH.sub.2-pyrene), 76.2 and 76.3 (s, C(1)), 110.9 (m, C(8)), 111.3 and 111.4 (tt, .sup.1J.sub.CF=337, .sup.2J.sub.CF=37.0, CF.sub.2), 117.2 (tt, .sup.1J.sub.CF=277, .sup.2J.sub.CF=26.0, CF.sub.2), 121.6 and 121.8 (s, C(10)H), 123.5 (s, C.sub.ArH), 124.4 (s, C.sub.ArH), 124.6 (s, C.sub.Ar), 124.9 (s, C.sub.Ar), 125.1 (s, 2C.sub.ArH), 125.9 (s, C.sub.ArH), 127.0 (s, C.sub.ArH), 127.3 (s, 2C.sub.ArH), 127.4 (s, C(4)H or C(6)H), 127.6 (s, C.sub.ArH), 129.1 (bm, C(7)), 129.3 (s, C.sub.Ar), 129.4 (bs, C(4)H or C(6)H), 130.0 (s, C(11)H), 130.4 (bs, C(5)H), 130.8 (s, C.sub.Ar), 131.2 (s, 2C.sub.Ar), 131.4 (s, C.sub.Ar), 136.9 and 137.5 (s, C(12)), 147.2 and 147.4 (m, C(9)), 149.7 (s, C(3)), 169.0 and 169.1 (s, C(16));

(294) HRMS (m/z, ESI.sup.+): [M+H].sup.+ calcd. for C.sub.47H.sub.51F.sub.4INO.sub.8, 960.2590, found, 960.2578.

N-(4-(2-(3,3-dimethyl-1.SUP.3.-benzo[d][1,2]iodaoxol-1 (3H)-yl)-1,1,2,2-tetrafluoroethoxy)phenethyl)-N-methyl-14-(4-((pyren-4-ylmethoxy)methyl)-1H-1,2,3-triazol-1-yl)-3,6,9,12-tetraoxatetradecanamide (#) JV155-1

(295) ##STR00114##

(296) The title compound was prepared according to the general procedure starting from pyrene-triazole-PEG acid (0.12 mmol) using (i-Pr).sub.2EtN as the base. The reaction time was 2 h. The reaction mixture was washed with buffer, aqueous NaHCO.sub.3 and brine, concentrated on Celite, and the product was isolated by automated flash chromatography (12 g SiO.sub.2 column, gradient elution from DCM to MeOH) as a yellowish oil.

(297) Yield: 32 mg (31%); Rt=0.44 (DCM:MeOH 9:1);

(298) .sup.1H NMR (500.13 MHz, CDCl.sub.3): 1.49 (s, 6H, C(2)H.sub.3), 2.76 and 2.78 (m, 2H, C(13)H.sub.2), 2.76 and 2.89 (s, 3H, C(15)H.sub.3), 3.38 and 3.50 (m, 2H, C(14)H.sub.2), 3.48-3.55 (m, 12H, 6CH.sub.2), 3.82 (s, 2H, CH.sub.2), 3.88 and 4.06 (s, 2H, C(17)H.sub.2), 4.51 (m, 2H, CH.sub.2), 4.81 (m, 2H, OCH.sub.2-triazole), 5.31 (m, 2H, OCH.sub.2-pyrene), 7.10 (m, 2H, C(10)H), 7.10 and 7.18 (m, 2H, C(11)H), 7.38 (m, 2H, C(4)H and C(6)H), 7.49 (m, 1H, C(5)H), 7.72 (m, 1H, C(7)H), 7.74 (m, 1H, C.sub.triazoleH), 7.98-8.05 (m, 4H, C.sub.ArH), 8.13 (m, 2H, C.sub.ArH), 8.18 (m, 2H, C.sub.ArH), 8.34 (m, 1H, C.sub.ArH);

(299) .sup.19F NMR (470.55 MHz, CDCl.sub.3): 97.6 and 97.5 (bs, 2F, CF.sub.2), 84.8 and 84.8 (bt, 2F, CF.sub.2);

(300) .sup.13C {.sup.1H} NMR (125.77 MHz, CDCl.sub.3): 30.8 (bs, C(2)H.sub.3), 32.8 and 34.0 (s, C(13)H.sub.2), 33.4 and 34.8 (s, C(15)H.sub.3), 49.7 and 50.6 (s, C(14)H.sub.2), 50.2 (s, CH.sub.2), 63.7 (s, OCH.sub.2-triazole), 69.4 and 69.4 (s, CH.sub.2), 70.1 and 70.2 (s, C(17)H.sub.2), 70.3-70.5 (s, 6CH.sub.2), 70.9 (s, OCH.sub.2-pyrene), 76.3 (bs, C(1)), 110.6 (m, C(8)), 111.3 (m, CF.sub.2), 117.2 (m, CF.sub.2), 121.6 and 121.8 (s, C(10)H), 123.4 (s, C.sub.ArH), 123.9 (s, C.sub.triazoleH), 124.5 (s, C.sub.ArH), 124.7 (s, C.sub.Ar), 124.9 (s, C.sub.Ar), 125.2 (s, 2C.sub.ArH), 125.9 (s, C.sub.ArH), 127.2 (s, C.sub.ArH), 127.4 (s, 2C.sub.ArH), 127.5 (bs, C(4)H or C(6)H), 127.7 (s, C.sub.ArH), 128.9 (bm, C(7)), 129.4 (s, C.sub.Ar), 129.5 (bm, C(4)H or C(6)H), 130.0 (s, C(11)H), 130.5 (s, C(5)H), 130.8 (s, C.sub.Ar), 131.1 (s, C.sub.Ar), 131.2 (s, C.sub.Ar), 131.3 (s, C.sub.Ar), 136.9 and 137.6 (s, C(12)), 145.0 (s, C.sub.triazole), 147.2 and 147.4 (m, C(9)), 149.7 (s, C(3)), 168.9 and 169.0 (s, C(16));

(301) HRMS (m/z, ESI/MALDI): [M+Na].sup.+ calcd. for C.sub.50H.sub.53F.sub.4IN.sub.4NaO.sub.8, 1063.2736, found, 1063.2738.

N-(4-(2-(3,3-Dimethyl-1.SUP.3.-benzo[d][1,2]iodaoxol-1 (3H)-yl)-1,1,2,2-tetrafluoroethoxy)phenethyl)-N-methyl-4-nitrobenzenesulfonamide (#) JV1 50-1

(302) ##STR00115##

(303) The NMT reagent (74 mg, 0.1 mmol, 1.0 equiv.) was dissolved in anhydrous DCM (1 mL) in an oven-dried Schlenk flask at 25 C., and Et.sub.3N (140 L, 1 mmol, 10 equiv.) was added. A solution of 4-nitrobenzenesulfonyl chloride (24 mg, 0.11 mmol, 1.08 equiv.) in DCM (2 mL) was added dropwise, and the yellow solution was stirred at 25 C. to rt for 30 min. The reaction mixture was directly concentrated onto Celite and the product was isolated by automated flash chromatography (12 g SiO.sub.2 column, gradient elution from hexane to EtOAc) as a colourless oil.

(304) Yield: 59 mg (85%); R.sub.f=0.22 (EtOAc:hexane 1:1);

(305) .sup.1H NMR (400.13 MHz, CDCl.sub.3): 1.49 (s, 6H, C(2)H.sub.3), 2.80 (s, 3H, C(15)H.sub.3), 2.90 (t, .sup.3J.sub.HH=7.6, 2H, C(13)H.sub.2), 3.31 (t, .sup.3J.sub.HH=7.6, 2H, C(14)H.sub.2), 7.13 (d, .sup.3J.sub.HH=8.3, 2H, C(10)H), 7.20 (d, .sup.3J.sub.HH=8.3, 2H, C(11)H), 7.39 (m, 2H, C(4)H and C(6)H), 7.50 (m, 1H, C(5)H), 7.73 (m, 1H, C(7)H), 7.92 (d, .sup.3J.sub.HH=8.6, 2H, C(17)H), 8.33 (d, .sup.3J.sub.HH=8.6, 2H, C(18)H);

(306) .sup.19F NMR (376.46 MHz, CDCl.sub.3): 97.6 (bs, 2F, CF.sub.2), 84.8 (t, .sup.3J.sub.FF=4.0, 2F, CF.sub.2);

(307) .sup.13C {.sup.1H} NMR (100.62 MHz, CDCl.sub.3): 30.9 (s, C(2)H.sub.3), 34.2 (s, C(13)H.sub.2), 35.2 (s, C(15)H.sub.3), 51.6 (s, C(14)H.sub.2), 76.4 (s, C(1)), 111.0 (s, C(8)), 111.4 (tt, .sup.1J.sub.CF=337, .sup.2J.sub.CF=38.0, CF.sub.2), 117.2 (tt, .sup.1J.sub.CF=278, .sup.2J.sub.CF=26.0, CF.sub.2), 121.8 (s, C(10)H), 124.3 (s, C(18)H), 127.4 (s, C(4)H or C(6)H), 128.3 (s, C(17)H), 129.0 (t, J.sub.CF=5.1, C(7)H), 129.4 (s, C(4)H or C(6)H), 130.0 (s, C(11)H), 130.3 (s, 1H, C(5)H), 136.6 (s, C(12)), 143.8 (s, C(16)), 147.6 (t, .sup.3J.sub.CF=1.6, C(9)), 149.8 (s, C(3)), 150.0 (s, C(19));

(308) HRMS (m/z, ESI.sup.+): [M+H].sup.+ calcd. for C.sub.26H.sub.26F.sub.4IN.sub.2O.sub.6S, 697.0487, found, 697.0478.

1-(2-(4-(2-((5-(Dimethylammonio)-N-methylnaphthalene)-1-sulfonamido)ethyl)phenoxy)-1,1,2,2-tetrafluoroethyl)-3,3-dimethyl-2,3-dihydro-1H-1.SUP.3.-benzo[d][1,2]iodaoxol-2-ium chloride (#) IK2-46

(309) ##STR00116##

(310) The NMT reagent (74 mg, 0.1 mmol, 1.0 equiv.) was dissolved in anhydrous DCM (1 mL) in an oven-dried Schlenk flask at 25 C., and Et.sub.3N (140 L, 1 mmol, 10 equiv.) was added. A solution of dansyl chloride (29 mg, 0.11 mmol, 1.08 equiv.) in DCM (2 mL) was added dropwise, and the yellow solution was stirred at 25 C. to 5 C. for 2 h. The reaction mixture was directly concentrated on silica gel (evaporation at 20 C.) and the product was isolated by automated flash chromatography (12 g SiO.sub.2 column, gradient elution from cyclohexane to EtOAc) as a yellowish oil (70 mg). The oil was dissolved in diethyl ether (5 mL) at 5 C. and a 4M solution of HCl in dioxane (0.1 mL) was added, yielding a pale yellow solid.

(311) Yield: 74 mg (90%); m.p. 85 C. (dec.); R.sub.f=0.80 (EtOAc);

(312) .sup.1H NMR (400.13 MHz, CDCl.sub.3): 1.74 (s, 6H, C(2)H.sub.3), 2.87 (s, 3H, C(15)H.sub.3), 2.90 (m, 2H, C(13)H.sub.2), 3.40 (s, 6H, C(16)H.sub.3), 3.49 (m, 2H, C(14)H.sub.2), 7.07 (m, 2H, C(10)H), 7.13 (m, 2H, C(11)H), 7.31 (m, 1H, C(6)H), 7.61-7.68 (m, 3H, C(4)H, C(5)H, and C.sub.ArH), 7.83 (bm, 2H, C.sub.ArH), 8.17 (m, 1H, C(7)H), 8.26 (m, 1H, C.sub.ArH), 8.63 (m, 1H, C.sub.ArH), 9.31 (bm, 1H, C.sub.ArH);

(313) .sup.19F NMR (376.46 MHz, CDCl.sub.3): 84.5 (bt, .sup.3J.sub.FF=7.1, 2F, CF.sub.2), 84.4 (bt, .sup.3J.sub.FF=7.1, 2F, CF.sub.2);

(314) .sup.13C {.sup.1H} NMR (100.84 MHz, CDCl.sub.3):.sup.3 31.6 (s, C(2)H.sub.3), 33.4 (s, C(13)H.sub.2), 34.2 (s, C(15)H.sub.3), 47.3 (s, C(16)H.sub.3), 50.6 (s, C(14)H.sub.2), 74.2 (s, C(1)), 111.0 (tt, .sup.1J.sub.CF=341, .sup.2J.sub.CF=41.0, CF.sub.2), 112.9 (s, C(8)), 115.9 (tt, .sup.1J.sub.CF=278, .sup.2J.sub.CF=26.0, CF.sub.2), 121.5 (s, C(10)H), 126.2 (s, C.sub.Ar), 126.7 (s, C.sub.ArH), 127.1 (s, C.sub.ArH), 127.4 (s, C.sub.ArH), 128.0 (s, C.sub.ArH), 129.5 (s, C(4)H), 129.7 (s, C.sub.Ar), 130.0 (s, C(11)H), 130.2 (s, 1H, C(6)H), 130.8 (s, C.sub.ArH), 132.8 (s, 1H, C(5)H)), 134.8 (s, C.sub.Ar), 137.2 (s, C(12)), 138.5 (m, C(7)H), 139.2 (s, C.sub.Ar), 146.5 (s, C(9)), 147.2 (s, C(3));

(315) HRMS (m/z, ESI.sup.+): [MHCl.sub.2]+calcd. for C.sub.32H.sub.34F.sub.4IN.sub.2O.sub.4S, 745.1215, found, 745.1216. .sup.3 One C.sub.ArH signal of the naphthyl moiety was not observed, presumably due to an overlap.

2-(6-(Diethylamino)-3-(diethyliminio)-3H-xanthen-9-yl)-5-(N-(4-(2-(3,3-dimethyl-1.SUP.3.-benzo[d][1,2]iodaoxol-1 (3H)-yl)-1,1,2,2-tetrafluoroethoxy)phenethyl)-N-methylsulfamoyl)benzenesulfonate (#) JV174-6

(316) ##STR00117##

(317) Lissamine Rhodamine B sulfonyl chloride (29 mg, 0.05 mmol, 1 equiv.) was dissolved in anhydrous DCM (20 mL) in an oven-dried Schlenk flask at 0 C., and Et.sub.3N (70 L, 0.5 mmol, 10 equiv.) was added. The NMT reagent (37 mg, 0.05 mmol, 1.0 equiv.) was added as solid, and the intense red-purple solution was stirred at 0 C. to rt for 2 h. The reaction mixture was washed with brine (50 mL), dried over Na.sub.2SO.sub.4, and concentrated onto Celite. The product was isolated by automated flash chromatography (24 g SiO.sub.2 column, gradient elution from DCM to DCM:MeOH 4:1) deep purple solid.

(318) Yield: 23 mg (46%); R.sub.f=0.50 (DCM:MeOH 9:1);

(319) .sup.1H NMR (500.13 MHz, CD.sub.3OD): 1.29 (t, .sup.3J.sub.HH=7.2, 12H, C(30)H.sub.3), 1.49 (s, 6H, C(2)H.sub.3), 2.90 (s, 3H, C(15)H.sub.3), 2.96 (m, 2H, C(13)H.sub.2), 3.44 (m, 2H, C(14)H.sub.2), 3.66 (q, .sup.3J.sub.HH=7.2, 8H, C(29)H.sub.2), 6.93 (d, .sup.4J.sub.HH=2.5, 2H, C(25)H), 6.98 (dd, .sup.3J.sub.HH=9.5, .sup.4J.sub.HH=2.5, 2H, C(27)H), 7.09 (d, .sup.3J.sub.HH=9.5, 2H, C(28)H), 7.22 (d, .sup.3J.sub.HH=8.4, 1H, C(10)H), 7.38 (dm, .sup.3J.sub.HH=8.4, 2H, C(11)H), 7.50 (m, 2H, C(6)H), 7.51 (d, .sup.3J.sub.HH=8.0, 2H, C(20)H), 7.55 (m, 1H, C(4)H), 7.60 (m, 1H, C(5)H), 7.79 (m, 1H, C(7)H), 8.01 (dd, .sup.3J.sub.HH=8.0, .sup.4J.sub.HH=1.9, 1H, C(21)H), 8.58 (d, .sup.4J.sub.HH=1.9, 1H, C(17)H);

(320) .sup.19F NMR (470.55 MHz, CD.sub.3OD): 96.9 (bs, 2F, CF.sub.2), 85.4 and 85.3 (bt, 2F, CF.sub.2);

(321) .sup.13C {.sup.1H} NMR (150.93 MHz, CD.sub.3OD): 12.8 (s, C(30)H.sub.3), 31.0 (s, C(2)H.sub.3), 34.9 (s, C(13)H.sub.2), 35.6 (s, C(15)H.sub.3), 46.8 (s, C(29)H.sub.2), 52.8 (s, C(14)H.sub.2), 77.4 (s, C(1)), 97.0 (s, C(25)H), 111.1 (bm, C(8)), 112.3 (tt, .sup.1J.sub.CF=335, .sup.2J.sub.CF=39.0, CF.sub.2), 115.1 (s, C(27)H), 115.2 (s, C(23)), 118.4 (tt, .sup.1J.sub.CF=276, .sup.2J.sub.CF=26.0, CF.sub.2), 122.8 (s, C(10)H), 129.2 (s, C(4)H), 131.7 (s, C(11)H), 132.2 (s, 1H, C(5)H), 128.0 (s, C(17)H), 129.6 (s, C(21)H), 130.4 (m, C(7)H), 131.1 (bm, C(6)H), 132.7 (s, C(20)H), 133.6 (s, C(28)H), 135.8 (s, C(19)), 139.1 (s, C(12)), 141.2 (s, C(16) or C(18)), 147.3 (s, C(16) or C(18)), 148.7 (m, C(9)), 151.0 (s, C(3)), 157.2 (s, C(26)), 157.6 (s, C(22)), 159.4 (s, C(24));

(322) HRMS (m/z, ESI/MALDI): [M+H].sup.+ calcd. for C.sub.47H.sub.51F.sub.4IN.sub.3O.sub.8S.sub.2, 1052.2093, found, 1052.2095.

1-(2-(4-(2-((2-((3,6-Dihydroxy-3-oxo-3H-spiro[isobenzofuran-1,9-xanthen]-6-yl)amino)-2-oxoethyl)(methyl)ammonio)ethyl)phenoxy)-1,1,2,2-tetrafluoroethyl)-3,3-dimethyl-2,3-dihydro-1H-1.SUP.3.-benzo[d][1,2]iodaoxol-2-ium bis(trifluoroacetate) (#) AK10-15 and JV179-2

(323) ##STR00118##

(324) 6-(2-bromoacetamido)fluorescein (24 mg, 0.05 mmol, 0.5 equiv.) was dissolved in anhydrous DMF (350 L) at 0 C. K.sub.2CO.sub.3 (69 mg, 0.50 mmol, 5 equiv.) was added, followed by a solution of the NMT reagent (74 mg, 0.1 mmol, 1.0 equiv.) in DMF (400 L). The intense red reaction mixture was stirred at 0 C. to rt for 2 h. TFA (100 L) was added and the mixture turned intense yellow. The solution was diluted with chloroform (15 mL), washed with brine brine (110 mL), dried over Na.sub.2SO.sub.4, and concentrated onto Celite. The crude product was isolated by automated flash chromatography (24 g SiO.sub.2 column, gradient elution from DCM to DCM:MeOH 3:1) as a yellow solid.

(325) Yield: 22 mg (39%); m.p. 125-130 C. (dec.); R.sub.f=0.54 (DCM:MeOH 9:1);

(326) .sup.1H NMR (500.13 MHz, CD.sub.3OD): 1.69 (s, 6H, C(2)H.sub.3), 3.02 (s, 3H, C(15)H.sub.3), 3.12 (t, .sup.3J.sub.HH=8.3, 2H, C(13)H.sub.2), 3.46 (bm, 2H, C(14)H.sub.2), 4.20 (s, 2H, C(16)H.sub.2), 6.55 (dd, .sup.3J.sub.HH=8.6, .sup.4J.sub.HH=2.4, 2H, C(30)H), 6.63 (d, .sup.3J.sub.HH=8.6, 2H, C(31)H), 6.70 (d, .sup.4J.sub.HH=2.4, 2H, C(28)H), 7.27 (m, 2H, C(10)H), 7.41 (m, 2H, C(11)H), 7.58 (m, 1H, C(6)H), 7.66 (d, .sup.4J.sub.HH=1.8, 1H, C(19)H), 7.73 (m, 1H, C(5)H), 7.75 (dd, .sup.3J.sub.HH=8.5, .sup.4J.sub.HH=1.8, 1H, C(23)H), 7.77 (m, 1H, C(4)H), 7.98 (d, .sup.3J.sub.HH=8.5, 1H, C(22)H), 8.00 (m, 1H, C(7)H);

(327) .sup.19F NMR (470.55 MHz, CDCl.sub.3): 84.6 (bt, .sup.3J.sub.FF=5.5, 2F, CF.sub.2), 80.8 and 80.7 (bs, 2F, CF.sub.2), 77.1 and 77.1 (bm, 6F, CF.sub.3);

(328) .sup.13C {.sup.1H} NMR (125.77 MHz, CDCl.sub.3):.sup.4 30.2 (s, C(2)H.sub.3), 30.8 (s, C(13)H.sub.2), 42.4 (s, C(15)H.sub.3), 58.7 (s, C(16)H.sub.2), 58.9 (s, C(14)H.sub.2), 76.7 (s, C(1)), 103.5 (s, C(28)H), 110.3 (s, C(8)), 111.3 (s, C(26)), 113.7 (s, C(30)H), 110.5 (m, CF.sub.2), 117.1 (m, CF.sub.2), 115.4 (s, C(19)H), 117.8 (q, .sup.1J.sub.CF=292, CF.sub.3COO), 122.2 (s, C(23)H), 123.1 (s, C(10)H), 123.7 (s, C(21)), 127.1 (s, C(22)H), 130.2 (s, C(31)H), 130.7 (s, C(4)H), 131.8 (s, C(11)H), 132.4 (s, C(6)H), 133.8 (s, 1H, C(5)H), 134.2 (m, C(7)H), 137.3 (s, C(12)), 145.4 (s, C(18)), 148.7 (m, C(9)), 149.6 (s, C(3)), 154.1 (s, C(27) or C(29)), 156.0 (bs, C(20)), 161.5 (s, C(27) or C(29)), 162.3 (q, .sup.2J.sub.CF=35.5, CF.sub.3COO), 164.7 (s, C(17)), 170.9 (s, C(24));

(329) HRMS (m/z, ESI.sup.+): [M+H].sup.+ calcd. for C.sub.42H.sub.36F.sub.4IN.sub.2O.sub.8, 899.1447, found, 899.1441. .sup.4 The signal of C(25) was not observed, presumably due to significant broadening. The chemical shifts of CF.sub.2CF.sub.2 were determined from a .sup.19F-.sup.13C HMBC experiment.

Example 11

(330) ##STR00119## ##STR00120## ##STR00121## ##STR00122## ##STR00123##

Example 12

(331) TABLE-US-00005 Reaction code CFDM01_35 Date Jun. 19, 2018 Reaction scheme Compound w/% c/mol L.sup.1 M/g mol.sup.1 eq n/mmol /g mL.sup.1 m/g V/mL 306.055 2.00 23.62 7.23 CsF 151.904 0.100 1.181 0.179 423.524 1.02 12.05 5.10 597.345 1.00 11.81 7.06 633.803 1.00 11.81 7.49 Yield: 2.20 29.4% Literature Mat{hacek over (s)} Chvojka-BP Procedure Caesium fluoride (0.1 eq) was dried with a heat gun under vacuum and suspended together with acetoxyidodane (2.0 eq) in dry DMF (15 mL). The resulting mixture was cooled to 10 C. and solution of silane CFMA01_02 (1.0 eq) in dry DMF (10 mL) was gradually added over the course of 35 minutes. The resulting mixture was left to react while reaching the room temperature (95 min). Then it was diluted with water (600 mL) and stirred for 10 min. DCM (350 mL) was added, then biphasic mixture was thoroughly mixed and filtered. The organic phase was separated and the aqueous phase was extracted with additional DCM (200 mL). Combined organic phases were washed with dist. water (500 mL). The organic phase was dried over Na.sub.2SO.sub.4 and concentrated to near dryness. The residue was dissolved in EtOAc and extracted with dist water (250 mL). Organic layer was dried under anhydrous Na.sub.2SO.sub.4 and solvent evaporated. Yield yellow oil (~6 g). This was dissolved in dry Et.sub.2O (50 mL) and HCl in Et.sub.2O (3M, excess) was added to precipitate the HCl salt, which was filtered and washed with additional Et.sub.2O. Chemical NMR Melting analysis .sup.1H .sup.13C HRMS GC/HPLC point Other /1/19

Example 13

(332) TABLE-US-00006 Reaction code CFDM01_40 Date Jun. 25, 2018 Reaction scheme 0 c/mol M/g n/ /g Compound w/% L.sup.1 mol.sup.1 eq mmol mL.sup.1 m/g V/mL 633.803 1.00 9.309 5.90 HCl in Et2O 3.00 4.00 37.24 12.4 570.144 1.00 9.309 5.31 Yield: 3.20 60.3% Literature Mat{hacek over (s)} Chvojka-BP Procedure HCl salt (5.90 g, 9.31 mmol) was dissolved in dichloromethane (25 mL) and MeOH (10 mL). HCl in diethyl ether (3.0 M, 12 mL, 37.2 mmol) was added. The reaction mixture was stirred overnight at rt. Reaction mixture was checked by TLC. Volume of the solution was reduced by evaporation to half of its original volume. Solution was seeded with crystals of title compound and Et.sub.2O was added to start the precipitation. Suspension was stirred for several hours in ice bath to complete the precipitation. Suspension was filtered and solid washed with Et20 (2 20 mL). CFDM01_40_1 (3.2 g, off white fine powder). Addition of Et2O to filtrate led to separation of another layer with the rest of the product which did not want to crystallize as in the previous batch and was therefore discarded. Chemical NMR HRMS GC/HPLC Melting Other analysis .sup.1H .sup.13C point /1/19

Example 14

(333) ##STR00134##

Example 15

(334) ##STR00135##

(335) This compound was synthesized based on the corresponding reaction sequence and tested in protein.

(336) ##STR00136## ##STR00137##