Diazomethylation reagent and process for using it
10676427 · 2020-06-09
Assignee
Inventors
Cpc classification
C07C251/00
CHEMISTRY; METALLURGY
C07C271/26
CHEMISTRY; METALLURGY
C07D347/00
CHEMISTRY; METALLURGY
C07C245/18
CHEMISTRY; METALLURGY
International classification
C07C271/26
CHEMISTRY; METALLURGY
C07D347/00
CHEMISTRY; METALLURGY
C07C245/18
CHEMISTRY; METALLURGY
C07C251/00
CHEMISTRY; METALLURGY
Abstract
The present invention relates compounds useful as reagents for the diazomethylation reaction, their preparation and the use thereof as reagents in a method for the diazomethylation reaction of aromatic substrates. It relates in particular to a compound of formula (I) wherein E is an electron withdrawing group. ##STR00001##
Claims
1. A compound of formula (I) ##STR00100## wherein: the dotted line means that R.sub.1 is attached to the iodine atom through a bond selected from a covalent bond and a ionic bond, E is a radical selected from the group consisting of the radical of formula -G.sub.1, and the radical of formula -G.sub.2-G.sub.3 wherein: G.sub.1 and G.sub.3 are independently selected from the group consisting of (C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkyloxycarbonyl, benzyloxycarbonyl, a formyl group (CHO), (C.sub.1-C.sub.6)alkylcarbonyl, carboxyl (COOH), a radical of formula CONR.sub.aR.sub.b wherein R.sub.a and R.sub.b are each independently selected from the group consisting of hydrogen and (C.sub.1-C.sub.6)alkyl, halogen, nitro, (C.sub.1-C.sub.6)alkyloxysulfonyl, a radical of formula P(O)(O(C.sub.1-C.sub.6)alkyl).sub.2, nitrile and an aromatic ring system comprising from 1 to 2 6-membered aromatic rings, the members being selected from the group consisting of C, CH and N, being at least one member N, and the rings being further optionally substituted at any available position with one or more group selected from halogen, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkyloxy, (C.sub.1-C.sub.6)alkylcarbonyl, (C.sub.1-C.sub.6)alkylcarbonyloxy, (C.sub.1-C.sub.6)alkyloxycarbonyl, nitrile, a formyl group and nitro; and G.sub.2 is a diradical selected from the group consisting of vinyl (CHCH), carbonyl and an aromatic ring system comprising from 1 to 2 5- to 6-membered aromatic rings, the members being selected from the group consisting of C, CH, O, S and N, and where both the vinyl and the aromatic ring system are further optionally substituted at any available position with one or more groups selected from halogen, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkyloxy, (C.sub.1-C.sub.6)alkylcarbonyl, (C.sub.1-C.sub.6)alkylcarbonyloxy, (C.sub.1-C.sub.6)alkyloxycarbonyl, nitrile, a formyl group and nitro; R.sub.1 is selected from the group consisting of halo, (C.sub.1-C.sub.6)haloalkylsulfonyloxy, (C.sub.1-C.sub.6)alkylsulfonyloxy, phenylsulfonyloxy, tolylsulfonyloxy, (C.sub.1-C.sub.6)alkylcarbonyloxy, hexafluorophosphate, tetrafluoroborate, hexafluoroantimonate, and (C.sub.1-C.sub.6)haloalkylcarbonyloxy; R.sub.2 is a (C.sub.6-C.sub.20)aryl, optionally substituted at any available position with one or more radicals selected from the group consisting of (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkyloxy, (C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkylcarbonyl, (C.sub.1-C.sub.6)alkyloxycarbonyl, and a radical of formula XCH.sub.2-E wherein X is a diradical selected from the group consisting of the diradicals of formula COO, C((C.sub.1-C.sub.6)alkyl).sub.2O, SO.sub.2O, NRO, B(OR)O, SO, and P(O)(OR)O, wherein R is H or (C.sub.1-C.sub.6)alkyl; and E has the same meaning as E; or, alternatively, R.sub.1 and R.sub.2, together with the iodine atom to which they are attached form a ring in such a way that the compound of formula (I) is a compound of formula (II) ##STR00101## wherein: the dotted line means that X is attached to the iodine atom through a bond selected from a covalent bond and a ionic bond; X is a diradical selected from the group consisting of the diradicals of formula COO, C((C.sub.1-C.sub.6)alkyl).sub.2O, SO.sub.2O, NRO, B(OR)O, SO, and P(O)(OR)O, wherein R is H or (C.sub.1-C.sub.6)alkyl; and R.sub.3 and R.sub.4, together with the carbon atoms to which they are attached, form an aromatic ring system comprising from 1 to 2 rings, each ring comprising from 5 to 6 members, said members being selected from the group consisting of C, CH, N, NR, being R hydrogen or (C.sub.1-C.sub.6)alkyl, O and S; and the rings being further optionally substituted with one or more radicals selected from the group consisting of (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkyloxy, (C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkylcarbonyl, and (C.sub.1-C.sub.6)alkyloxycarbonyl; and provided that the compound of formula (I) is other than a compound of formula (Ia), or (Ib), or (Ic) ##STR00102## wherein in the compound of formula (Ia) R is ethyl or tert-butyl.
2. The compound of claim 1, wherein each of E and E is independently a group of formula -G.sub.1 selected from the group consisting of (C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkyloxycarbonyl, benzyloxycarbonyl, a radical of formula CONR.sub.aR.sub.b wherein R.sub.a and R.sub.b are each independently selected from the group consisting of hydrogen and (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkyloxysulfonyl and nitrile; or; alternatively, each of E and E is independently a group of formula -G.sub.2-G.sub.3, wherein: G.sub.3 is selected from the group consisting of (C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkyloxycarbonyl, benzyloxycarbonyl, a formyl group (CHO), (C.sub.1-C.sub.6)alkylcarbonyl, a radical of formula CONR.sub.aR.sub.b wherein R.sub.a and R.sub.b are each independently selected from the group consisting of hydrogen and (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkyloxysulfonyl, a radical of formula P(O)(O(C.sub.1-C.sub.6)alkyl).sub.2, phenyl and nitrile; and G.sub.2 is a carbonyl group.
3. The compound according to claim 2, wherein each of E and E is independently selected from the group consisting of trifluoromethyl, ethyloxycarbonyl, tert-butyloxycarbonyl, benzyloxycarbonyl, a radical of formula CON(C.sub.2H.sub.5).sub.2, ethyloxysulfonyl, phenylcarbonyl and nitrile.
4. The compound according to claim 1, wherein: R.sub.1 is selected from the group consisting of trifluoromethylsulfonyloxy, hexafluorophosphate and tetrafluoroborate; R.sub.2 is a phenyl optionally substituted at a carbon atom adjacent to the carbon atom of R.sub.2 attached to the iodine atom with a radical of formula XCH.sub.2-E; wherein X is a diradical selected from the group consisting of the diradicals of formula COO, C((C.sub.1-C.sub.6)alkyl).sub.2O and SO.sub.2O and E has the same meaning as E; or, alternatively; R.sub.1 and R.sub.2, together with the iodine atom to which they are attached form a ring in such a way that the compound of formula (I) is a compound of formula (II) wherein X is a diradical selected from the group consisting of the diradicals of formula COO, C((C.sub.1-C.sub.6)alkyl).sub.2O and SO.sub.2O; and R.sub.3 and R.sub.4, together with the carbon atoms to which they are attached, form a phenyl ring.
5. The compound according to claim 4 wherein: R.sub.1 is selected from the group consisting of trifluoromethanesulfonyloxy (CF.sub.3S(O).sub.2O), hexafluorophosphate and tetrafluoroborate; R.sub.2 is a phenyl optionally substituted at a carbon atom adjacent to the carbon atom of R.sub.2 attached to the iodine atom with a radical of formula XCH.sub.2-E wherein X is a diradical of formula COO; and E has the same meaning as E; or, alternatively; R.sub.1 and R.sub.2, together with the iodine atom to which they are attached form a ring in such a way that the compound of formula (I) is a compound of formula (II) wherein X is a diradical selected from the groups consisting of the diradicals of formula COO and C(CH.sub.3).sub.2O, and R.sub.3 and R.sub.4, together with the carbon atoms to which they are attached, form a phenyl ring.
6. The compound according to claim 1 that is selected from the compounds of formula (Id), (Ie), (If), (Ig), (Ih) and (Ii) ##STR00103##
7. The compound according to claim 1 that is selected from the group consisting of (IIa), (IIb), (IIc), (IId), (IIe), (IIf) and (IIg) ##STR00104## ##STR00105##
8. Use of the compound of formula (I) as defined in claim 1 or a compound of formula (Ia), (Ib) or (Ic) ##STR00106## wherein in the compound of formula (Ia) R is ethyl or tert-butyl; as a reagent for the transfer of a group of formula C(N.sub.2)(E) to a substrate comprising at least one aromatic or heteroaromatic ring system.
9. A process of preparing a compound comprising a moiety of formula (III) ##STR00107## comprising the step of contacting a compound comprising the moiety of formula (IV) ##STR00108## with a compound of formula (I) as defined in claim 1 or a compound selected from the compounds of formula (Ia), (Ib) and (Ic) ##STR00109## wherein in the compound of formula (Ia) R is ethyl or tert-butyl, in the presence of a suitable reducing agent and in the presence of a base, wherein, in the compounds comprising the moieties of formula (III) and (IV) C.sub.Ar represents a carbon atom comprised in an aromatic or heteroaromatic ring system and wherein the process transforms the moiety of formula (IV) into the moiety of formula (III).
10. The process according to claim 9, wherein the suitable reducing agent is a photoredox catalyst that is used in a catalytically effective amount, and the process is carried out under light irradiation.
11. The process according to claim 10, wherein the suitable reducing agent is a salt of of formula A-Y wherein A is a cation selected from the group consisting of tris-(2,2-bipyrimidine)ruthenium.sup.2+, tris-(2,2-bipyrazine)ruthenium.sup.2+, tris-(2,2-bipyridine)ruthenium.sup.2+, tris-(1,10-phenanthroline)ruthenium.sup.2+, bis-(2-(2,4-difluorophenyl)-5-trifluoromethylpyridine)(di-tert-butylbipyridine)iridium.sup.+, bis-(2-phenylpyridine)(di-tert-butylbipyridine)iridium.sup.+, and fac-(tris-(2,2-phenylpyridine))iridium.sup.+; and Y is an anion selected from the group consisting of tetrafluoroborate, hexafluorophosphate, chloride, and tetra(pentafluorophenyl)borate.
12. The process according to claim 11, wherein the suitable reducing agent is tris-(2,2-bipyrimidine)ruthenium.sup.2+ bis hexafluorophosphate that is used in a catalytically effective amount and the irradiation light is visible light.
13. The process according to claim 9, wherein the base is selected from the group consisting of alkaline bicarbonate salts, alkaline earth bicarbonate salts, and pyridine optionally substituted with one or more (C.sub.1-C.sub.6)alkyl groups.
14. The process according to claim 9 that is carried out in the presence of a polar aprotic solvent.
15. The process according to claim 9, further comprising the previous step of preparing a compound of formula (I), which comprises contacting a compound of formula (V) ##STR00110## wherein X.sup.2 is a diradical selected from the group consisting of the diradicals of formula COO, C((C.sub.1-C.sub.6)alkyl).sub.2O, SO.sub.2O, NRO, B(OR)O, SO, and P(O)(OR)O, wherein R is H or (C.sub.1-C.sub.6)alkyl, with a compound of formula ((C.sub.1-C.sub.6)alkyl).sub.3SiR.sub.1 (VI) and a compound of formula N.sub.2CH-E (VII) in the presence of a polar aprotic solvent; and optionally in the presence of a base, wherein: R.sub.5 is a (C.sub.1-C.sub.6)alkyl, R.sub.2 is a (C.sub.6-C.sub.20)aryl, optionally substituted at any available position with one or more radicals selected from the group consisting of (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkyloxy, (C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkylcarbonyl, and (C.sub.1-C.sub.6)alkyloxycarbonyl, or, alternatively, R.sub.5 and R.sub.2, together with the atoms to which they are attached, form an aromatic ring system comprising from 1 to 2 rings, each ring comprising from 5 to 6 members, said members being selected from the group consisting of C, CH, N, NR, being R hydrogen or (C.sub.1-C.sub.6)alkyl, O and S; and the rings being further optionally substituted with one or more radicals selected from the group consisting of (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkyloxy, (C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkylcarbonyl, and (C.sub.1-C.sub.6)alkyloxycarbonyl; or, alternatively, R.sub.5 and R.sub.2, together with the atoms to which they are attached, form a (C.sub.6-C.sub.20)aryl substituted at any available position with one or more radicals selected from the group consisting of (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkyloxy, (C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkylcarbonyl, and (C.sub.1-C.sub.6)alkyloxycarbonyl; R.sub.7 is a (C.sub.1-C.sub.6)alkyloxycarbonyl or a (C.sub.1-C.sub.6)alkyloxy; and wherein when in the compound of formula (I) R.sub.1 is selected from the group consisting of halo, (C.sub.1-C.sub.6)haloalkylsulfonyloxy, (C.sub.1-C.sub.6)alkylsulfonyloxy, phenylsulfonyloxy, tolylsulfonyloxy, (C.sub.1-C.sub.6)alkylcarbonyloxy, and (C.sub.1-C.sub.6)haloalkylcarbonyloxy; and R.sub.2 is a (C.sub.6-C.sub.20)aryl, optionally substituted at any available position with one or more radicals selected from the group consisting of (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkyloxy, (C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkylcarbonyl, and (C.sub.1-C.sub.6)alkyloxycarbonyl; then in the compound of formula (V), X.sup.2 is COO, R.sub.5 is a (C.sub.1-C.sub.6)alkyl, R.sub.2 is a (C.sub.6-C.sub.20)aryl, optionally substituted at any available position with one or more radicals selected from the group consisting of (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkyloxy, (C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkylcarbonyl, and (C.sub.1-C.sub.6)alkyloxycarbonyl, R.sub.7 is a (C.sub.1-C.sub.6)alkyloxycarbonyl; and the molar ratio of the compound of formula (VII) to the compound of formula (V) is comprised from 1:1 to 2:1.
16. The process according to claim 9, further comprising the previous step of preparing a compound of formula (I), which comprises contacting a compound of formula (V) ##STR00111## wherein X.sup.2 is a diradical selected from the group consisting of the diradicals of formula COO, C((C.sub.1-C.sub.6)alkyl).sub.2O, SO.sub.2O, NRO, B(OR)O, SO, and P(O)(OR)O, wherein R is H or (C.sub.1-C.sub.6)alkyl, with a compound of formula ((C.sub.1-C.sub.6)alkyl.sub.3SiR.sub.1 (VI) and a compound of formula N.sub.2CH-E (VII) in the presence of a polar aprotic solvent; and optionally in the presence of a base, wherein: R.sub.5 is a (C.sub.1-C.sub.6)alkyl, R.sub.2 is a (C.sub.6-C.sub.20)aryl, optionally substituted at any available position with one or more radicals selected from the group consisting of (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkyloxy, (C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkyl carbonyl, and (C.sub.1-C.sub.6)alkyloxycarbonyl, or, alternatively, R.sub.5 and R.sub.2, together with the atoms to which they are attached, form an aromatic ring system comprising from 1 to 2 rings, each ring comprising from 5 to 6 members, said members being selected from the group consisting of C, CH, N, NR, being R hydrogen or (C.sub.1-C.sub.6)alkyl, O and S; and the rings being further optionally substituted with one or more radicals selected from the group consisting of (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkyloxy, (C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkylcarbonyl, and (C.sub.1-C.sub.6)alkyloxycarbonyl; or, alternatively, R.sub.5 and R.sub.2, together with the atoms to which they are attached, form a (C.sub.6-C.sub.20)aryl substituted at any available position with one or more radicals selected from the group consisting of (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkyloxy, (C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkylcarbonyl, and (C.sub.1-C.sub.6)alkyloxycarbonyl; R.sub.7 is a (C.sub.1-C.sub.6)alkyloxycarbonyl or a (C.sub.1-C.sub.6)alkyloxy; and wherein when in the compound of formula (I) R.sub.1 is selected from the group consisting of halo, (C.sub.1-C.sub.6)haloalkylsulfonyloxy, (C.sub.1-C.sub.6)alkylsulfonyloxy, phenylsulfonyloxy, tolylsulfonyloxy, (C.sub.1-C.sub.6)alkylcarbonyloxy, and (C.sub.1-C.sub.6)haloalkylcarbonyloxy; and R.sub.2 is a (C.sub.6-C.sub.20)aryl substituted at any available position with one or more radicals selected from the group consisting of (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkyloxy, (C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkylcarbonyl, (C.sub.1-C.sub.6)alkyloxycarbonyl and the radicals of formula XCH.sub.2-E, said compound of formula (I) comprising at least one radical of formula XCH.sub.2-E, then in the compound of formula (V), R.sub.5 and R.sub.2, together with the atoms to which they are attached, form a (C.sub.6-C.sub.20)aryl substituted at any available position with one or more radicals selected from the group consisting of (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkyloxy, (C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkylcarbonyl, and (C.sub.1-C.sub.6)alkyloxycarbonyl; R.sub.7 is a (C.sub.1-C.sub.6)alkyloxy; and the molar ratio of the compound of formula (VII) to the compound of formula (V) is higher than 2:1.
17. The process according to claim 9, further comprising the previous step of preparing a compound of formula (I), which comprises contacting a compound of formula (V) ##STR00112## wherein X.sup.2 is a diradical selected from the group consisting of the diradicals of formula COO, C((C.sub.1-C.sub.6)alkyl).sub.2O, SO.sub.2O, NRO, B(OR)O, SO, and P(O)(OR)O, wherein R is H or (C.sub.1-C.sub.6)alkyl, with a compound of formula ((C.sub.1-C.sub.6)alkyl).sub.3SiR.sub.1 (VI) and a compound of formula N.sub.2CH-E (VII) in the presence of a polar aprotic solvent; and optionally in the presence of a base, wherein: R.sub.5 is a (C.sub.1-C.sub.6)alkyl, R.sub.2 is a (C.sub.6-C.sub.20)aryl, optionally substituted at any available position with one or more radicals selected from the group consisting of (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkyloxy, (C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkylcarbonyl, and (C.sub.1-C.sub.6)alkyloxycarbonyl, or, alternatively, R.sub.5 and R.sub.2, together with the atoms to which they are attached, form an aromatic ring system comprising from 1 to 2 rings, each ring comprising from 5 to 6 members, said members being selected from the group consisting of C, CH, N, NR, being R hydrogen or (C.sub.1-C.sub.6)alkyl, O and S; and the rings being further optionally substituted with one or more radicals selected from the group consisting of (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkyloxy, (C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkylcarbonyl, and (C.sub.1-C.sub.6)alkyloxycarbonyl; or, alternatively, R.sub.5 and R.sub.2, together with the atoms to which they are attached, form a (C.sub.6-C.sub.20)aryl substituted at any available position with one or more radicals selected from the group consisting of (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkyloxy, (C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkylcarbonyl, and (C.sub.1-C.sub.6)alkyloxycarbonyl; R.sub.7 is a (C.sub.1-C.sub.6)alkyloxycarbonyl or a (C.sub.1-C.sub.6)alkyloxy; and wherein when in the compound of formula (I) R.sub.1 and R.sub.2, together with the iodine atom to which they are attached form a ring in such a way that the compound of formula (I) is a compound of formula (II); then the process is carried out in the presence of a base, and in the compound of formula (V), R.sub.5 and R.sub.2, together with the atoms to which they are attached, form an aromatic ring system comprising from 1 to 2 rings, each ring comprising from 5 to 6 members, said members being selected from the group consisting of C, CH, N, NR, being R hydrogen or (C.sub.1-C.sub.6)alkyl, O and S; and the rings being further optionally substituted with one or more radicals selected from the group consisting of (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkyloxy, (C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkylcarbonyl, and (C.sub.1-C.sub.6)alkyloxycarbonyl; and R.sub.7 is a (C.sub.1-C.sub.6)alkyloxycarbonyl.
18. The process according to claim 9, further comprising the previous step of preparing a compound of formula (I), which comprises contacting a compound of formula (V) ##STR00113## wherein X.sup.2 is a diradical selected from the group consisting of the diradicals of formula COO, C((C.sub.1-C.sub.6)alkyl).sub.2O, SO.sub.2O, NRO, B(OR)O, SO, and P(O)(OR)O, wherein R is H or (C.sub.1-C.sub.6)alkyl, with a compound of formula ((C.sub.1-C.sub.6)alkyl).sub.3SiR.sub.1 (VI) and a compound of formula N.sub.2CH-E (VII) in the presence of a polar aprotic solvent; and optionally in the presence of a base, wherein: R.sub.5 is a (C.sub.1-C.sub.6)alkyl, R.sub.2 is a (C.sub.6-C.sub.20)aryl, optionally substituted at any available position with one or more radicals selected from the group consisting of (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkyloxy, (C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkylcarbonyl, and (C.sub.1-C.sub.6)alkyloxycarbonyl, or, alternatively, R.sub.5 and R.sub.2, together with the atoms to which they are attached, form an aromatic ring system comprising from 1 to 2 rings, each ring comprising from 5 to 6 members, said members being selected from the group consisting of C, CH, N, NR, being R hydrogen or (C.sub.1-C.sub.6)alkyl, O and S; and the rings being further optionally substituted with one or more radicals selected from the group consisting of (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkyloxy, (C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkylcarbonyl, and (C.sub.1-C.sub.6)alkyloxycarbonyl; or, alternatively, R.sub.5 and R.sub.2, together with the atoms to which they are attached, form a (C.sub.6-C.sub.20)aryl substituted at any available position with one or more radicals selected from the group consisting of (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkyloxy, (C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkylcarbonyl, and (C.sub.1-C.sub.6)alkyloxycarbonyl; R.sub.7 is a (C.sub.1-C.sub.6)alkyloxycarbonyl or a (C.sub.1-C.sub.6)alkyloxy; and wherein when in the compound of formula (I) R.sub.1 is selected from hexafluorophosphate, hexafluoroantimonate and tetrafluoroborate and R.sub.2 is a (C.sub.6-C.sub.20)aryl optionally substituted at any available position with one or more radicals selected from the group consisting of (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkyloxy, (C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkylcarbonyl, (C.sub.1-C.sub.6)alkyloxycarbonyl and the radicals of formula XCH.sub.2-E; then the product resulting from the processes described in the step (i) or in the step (ii) above is further contacted with an aqueous saturated solution of sodium hexafluorophosphate when R.sub.1 is hexafluorophosphate, an aqueous saturated solution of sodium hexafluoroantimonate when R.sub.1 is hexafluoroantimonate, or with an aqueous saturated solution of sodium tetrafluoroborate when R.sub.1 is tetrafluoroborate.
19. The process according to claim 9, wherein the base is selected from the group consisting of sodium hydrogen carbonate and 2,6-di-tert-butylpyridine.
20. The process according to claim 14 wherein the polar aprotic solvent is acetonitrile.
Description
DETAILED DESCRIPTION OF THE INVENTION
(1) All terms as used herein in this application, unless otherwise stated, shall be understood in their ordinary meaning as known in the art. Other more specific definitions for certain terms as used in the present application are as set forth below and are intended to apply uniformly through-out the specification and claims unless an otherwise expressly set out definition provides a broader definition.
(2) For the purposes of the invention, any ranges given include both the lower and the upper end-points of the range. Ranges given, such as temperatures, times, and the like, should be considered approximate, unless specifically stated.
(3) In the context of the invention, the term halo or halogen refers to an halogen radical, it thus refers to fluoro, chloro, bromo or iodo.
(4) In the context of the invention, the term alkyl refers to a saturated linear or branched hydrocarbon group having the number of carbon atoms indicated in the description or in the claims. Examples of alkyl groups include, but are not limited to: methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl, and hexyl.
(5) In the context of the invention, the term haloalkyl refers to a saturated linear or branched hydrocarbon group having the number of carbon atoms indicated in the description or in the claims wherein one or more, preferably one to five, and more preferably one to three of the hydrogen atoms are replaced by an halo group. In particular embodiments of the invention, the term haloakyl refers to a saturated linear or branched hydrocarbon group having the number of carbon atoms indicated in the description or in the claims wherein all the hydrogen atoms are replaced by a fluoro group (also called perfluoroalkyl). Examples of haloalkyl groups include, but are not limited to: chloromethyl, trifluoromethyl, bromomethyl, and pentafluoroethyl.
(6) In the context of the invention, the term alkyloxy refers to a saturated linear or branched hydrocarbon group having the number of carbon atoms indicated in the description or in the claims which is attached to the remainder of the formula through an ether group (O).
(7) In the context of the invention, the term alkylcarbonyl refers to a saturated linear or branched hydrocarbon group having the number of carbon atoms indicated in the description or in the claims which is attached to the remainder of the formula through a carbonyl group (CO).
(8) In the context of the invention, the term alkylcarbonyloxy refers to a saturated linear or branched hydrocarbon group having the number of carbon atoms indicated in the description or in the claims which is attached to the remainder of the formula through a carboxyl group (COO) and wherein the alkyl chain is attached to the carbon atom of the carboxyl group. Similarly, the term haloalkylcarbonyloxy refers to a haloalkyl group as defined above which is attached to the remainder of the formula through a carboxyl group (COO) and wherein the haloalkyl chain is attached to the carbon atom of the carboxyl group.
(9) In the context of the invention, the term alkyloxycarbonyl refers to a saturated linear or branched hydrocarbon group having the number of carbon atoms indicated in the description or in the claims which is attached to the remainder of the formula through a carboxyl group (OOC) and wherein the alkyl chain is attached to the oxygen atom of the carboxyl group and the C atom of the carboxyl group is attached to the remainder of the formula. Similarly, the term benzyloxycarbonyl refers to a benzyl group attached to the remainder of the formula through a carboxyl group (OOC) and wherein the benzyl is attached to the oxygen atom of the carboxyl group and the C atom of the carboxyl group is attached to the remainder of the formula.
(10) In the context of the invention, the term alkylsulfonyloxy refers to a saturated linear or branched hydrocarbon group having the number of carbon atoms indicated in the description or in the claims which is attached to the remainder of the formula through a sulfonate group (SO.sub.2O) and wherein the alkyl chain is attached to the sulphur atom of the sulfonate group. Similarly, the term phenylsulfonyloxy refers to a phenyl group attached to the remainder of the formula through a sulfonate group (SO.sub.2O) and wherein the phenyl is attached to the sulphur atom of the sulfonate group. Similarly, the term tolylsulfonyloxy refers to a tolyl group attached to the remainder of the formula through a sulfonate group (SO.sub.2O) and wherein the tolyl is attached to the sulphur atom of the sulfonate group. Similarly, the term haloalkylsulfonyloxy refers to a haloalkyl group as defined above attached to the remainder of the formula through a sulfonate group (SO.sub.2O) and wherein the haloalkyl is attached to the sulphur atom of the sulfonate group.
(11) In the context of the invention, the term alkyloxysulfonyl refers to a saturated linear or branched hydrocarbon group having the number of carbon atoms indicated in the description or in the claims which is attached to the remainder of the formula through a sulfonate group (OSO.sub.2) and wherein the alkyl chain is attached to the oxygen atom of the sulfonate group and the S atom of the sulfonyl group is attached to the remainder of the formula.
(12) In the context of the invention, the term electron withdrawing group (also called EWG) refers to a group or molecular fragment able to withdraw electron density from the atom to which the group is attached, thereby polarizing the bond between the aforementioned atom and the EWG. Particularly, in the context of the invention, suitable electron withdrawing groups E or E are independently selected from the group consisting of the radicals of formula -G.sub.1, and the radicals of formula -G.sub.2-G.sub.3 wherein: G.sub.1 and G.sub.3 are independently selected from the group consisting of (C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkyloxycarbonyl, benzyloxycarbonyl, a formyl group (CHO), (C.sub.1-C.sub.6)alkylcarbonyl, carboxyl (COOH), a radical of formula CONR.sub.aR.sub.b wherein R.sub.a and R.sub.b are each independently selected from the group consisting of hydrogen and (C.sub.1-C.sub.6)alkyl, halogen, nitro, (C.sub.1-C.sub.6)alkyloxysulfonyl, a radical of formula P(O)(O(C.sub.1-C.sub.6)alkyl).sub.2, nitrile and an aromatic ring system comprising from 1 to 2 6-membered aromatic rings, the members being selected from the group consisting of C, CH and N, being at least one member N, and the rings being further optionally substituted at any available position with one or more groups selected from halogen, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkyloxy, (C.sub.1-C.sub.6)alkylcarbonyl, (C.sub.1-C.sub.6)alkylcarbonyloxy, (C.sub.1-C.sub.6)alkyloxycarbonyl, nitrile, a formyl group and nitro; and G.sub.2 is a diradical selected from the group consisting of vinyl (CHCH), carbonyl and an aromatic ring system comprising from 1 to 2 5- to 6-membered aromatic rings, the members being selected from the group consisting of C, CH, O, S and N, and where both the vinyl and the aromatic ring system are further optionally substituted at any available position with a group selected from halogen, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkyloxy, (C.sub.1-C.sub.6)alkylcarbonyl, (C.sub.1-C.sub.6)alkylcarbonyloxy, (C.sub.1-C.sub.6)alkyloxycarbonyl, nitrile, a formyl group and nitro.
(13) In the context of the invention, the term base refers to a substance able to take protons from other substances.
(14) In the context of the invention, the term catalytically effective amount refers to the fact that the amount of reducing agent is much smaller than the stoichiometric amounts of either starting materials. The amount is expressed as percentage calculated as the ratio of the number of moles of reducing agent in relation to the number of molecules of the compound incorporating the moiety of formula (IV).
(15) In the context of the invention, the term aryl refers to an aromatic hydrocarbon ring system comprising the number of carbon atoms indicated in the description and claims and comprising 5 to 6-membered rings. Examples of aryl groups include, but are not limited to: phenyl, naphthyl, indenyl, anthracenyl and phenanthrenyl.
(16) In the context of the invention, the term suitable reducing agent refers to a compound or system able to reduce the compound of formula (I) to a radical of formula N.sub.2C.-E (i.e. carbyne equivalent) in the conditions of the method of the invention. Alternatively, the term suitable reducing agent may refer to a suitable electron source. Furthermore, the suitable reducing agent can be such that, in its oxidized form, it allows the oxidation of the reaction intermediate resulting from the attack of the radical of formula N.sub.2C.-E to the aromatic ring of the reaction substrate, in which case the reducing agent can be used in a catalytically effective amount, being regenerated in situ. Examples of suitable reducing agents include but are not limited to electrochemical cells, electrodes, photoelectrochemical means, photocatalysts, photosensitizers, or photoredox catalysts such as tris-(2,2-bipyrimidine)ruthenium.sup.2+, tris-(2,2-bipyrazine)ruthenium.sup.2+, tris-(2,2-bipyridine)ruthenium.sup.2+, tris-(1,10-phenanthroline)ruthenium.sup.2+, bis-(2-(2,4-difluorophenyl)-5-trifluoromethylpyridine)(di-tert-butylbipyridine)iridium.sup.+, bis-(2-phenylpyridine)(di-tert-butylbipyridine)iridium.sup.+, fac-(tris-(2,2-phenylpyridine))iridium, particularly those based on ruthenium (II) complexes (tris-(2,2-bipyrimidine)ruthenium.sup.2+, tris-(2,2-bipyrazine)ruthenium.sup.2+, tris-(2,2-bipyridine)ruthenium.sup.2+, tris-(1,10-phenanthroline)ruthenium.sup.2+).
(17) In the context of the invention, when in the compound of formula (I) the bond between R.sub.1 and the iodine atom is an ionic bond, then the compound of formula (I) may alternatively have the formula (I)
(18) ##STR00010##
(19) As it is mentioned above, the first aspect of the invention relates to a compound of formula (I) as defined above.
(20) In an embodiment of the first aspect of the invention, optionally in combination with one or more features of the various embodiments described below, in the compound of formula (I), each of E and E is independently selected from a group of formula -G.sub.1 and a group of formula -G.sub.2-G.sub.3, wherein: G.sub.1 and G.sub.3 are independently selected from the group consisting of (C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkyloxycarbonyl, benzyloxycarbonyl, a formyl group (CHO), (C.sub.1-C.sub.6)alkylcarbonyl, a radical of formula CONR.sub.aR.sub.b wherein R.sub.a and R.sub.b are each independently selected from the group consisting of hydrogen and (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkyloxysulfonyl, a radical of formula P(O)(O(C.sub.1-C.sub.6)alkyl).sub.2, nitrile, and phenyl; and G.sub.2 is a diradical selected from the group consisting of vinyl (CHCH), carbonyl and phenyl.
(21) In another embodiment of the first aspect of the invention, optionally in combination with one or more features of the various embodiments described above or below, in the compound of formula (I), each of E and E is independently a group of formula -G.sub.2-G.sub.3 wherein G.sub.3 is selected from the group consisting of (C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkyloxycarbonyl, benzyloxycarbonyl, a formyl group (CHO), (C.sub.1-C.sub.6)alkylcarbonyl, a radical of formula CONR.sub.aR.sub.b wherein R.sub.a and R.sub.b are each independently selected from the group consisting of hydrogen and (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkyloxysulfonyl, a radical of formula P(O)(O(C.sub.1-C.sub.6)alkyl).sub.2, phenyl and nitrile; and G.sub.2 is selected from vinyl and carbonyl.
(22) In another embodiment of the first aspect of the invention, optionally in combination with one or more features of the various embodiments described above or below, in the compound of formula (I), each of E and E is independently a group of formula -G.sub.2-G.sub.3 wherein G.sub.3 is selected from the group consisting of (C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkyloxycarbonyl, benzyloxycarbonyl, a formyl group (CHO), (C.sub.1-C.sub.6)alkylcarbonyl, a radical of formula CONR.sub.aR.sub.b wherein R.sub.a and R.sub.b are each independently selected from the group consisting of hydrogen and (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkyloxysulfonyl, a radical of formula P(O)(O(C.sub.1-C.sub.6)alkyl).sub.2, phenyl and nitrile; and G.sub.2 is a carbonyl group.
(23) In another embodiment of the first aspect of the invention, optionally in combination with one or more features of the various embodiments described above or below, in the compound of formula (I), each of E and E is independently a group of formula -G.sub.2-G.sub.3 wherein G.sub.3 is selected from the group consisting of (C.sub.1-C.sub.6)haloalkyl, and phenyl and G.sub.2 is a carbonyl group.
(24) In another embodiment of the first aspect of the invention, optionally in combination with one or more features of the various embodiments described above or below, in the compound of formula (I), each of E and E is independently a group of formula -G.sub.2-G.sub.3 wherein G.sub.3 is phenyl and G.sub.2 is a carbonyl group.
(25) In another embodiment of the first aspect of the invention, optionally in combination with one or more features of the various embodiments described above or below, in the compound of formula (I), each of E and E is independently a group of formula -G.sub.1 selected from the group consisting of (C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkyloxycarbonyl, benzyloxycarbonyl, a formyl group (CHO), (C.sub.1-C.sub.6)alkylcarbonyl, a radical of formula CONR.sub.aR.sub.b wherein R.sub.a and R.sub.b are each independently selected from the group consisting of hydrogen and (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkyloxysulfonyl, a radical of formula P(O)(O(C.sub.1-C.sub.6)alkyl).sub.2, and nitrile.
(26) In another embodiment of the first aspect of the invention, optionally in combination with one or more features of the various embodiments described above or below, in the compound of formula (I), each of E and E is independently a group of formula -G.sub.1 selected from the group consisting of (C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkyloxycarbonyl, benzyloxycarbonyl, a radical of formula CONR.sub.aR.sub.b wherein R.sub.a and R.sub.b are each independently selected from the group consisting of hydrogen and (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkyloxysulfonyl and nitrile.
(27) In another embodiment of the first aspect of the invention, in the compound of formula (I), each of E and E is independently a group of formula -G.sub.1 selected from the group consisting of (C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkyloxycarbonyl, benzyloxycarbonyl, a radical of formula CONR.sub.aR.sub.b wherein R.sub.a and R.sub.b are each independently selected from the group consisting of hydrogen and (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkyloxysulfonyl and nitrile;
(28) or; alternatively, each of E and E is independently a group of formula -G.sub.2-G.sub.3, wherein:
(29) G.sub.3 is selected from the group consisting of (C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkyloxycarbonyl, benzyloxycarbonyl, a formyl group (CHO), (C.sub.1-C.sub.6)alkylcarbonyl, a radical of formula CONR.sub.aR.sub.b wherein R.sub.a and R.sub.b are each independently selected from the group consisting of hydrogen and (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkyloxysulfonyl, a radical of formula P(O)(O(C.sub.1-C.sub.6)alkyl).sub.2, phenyl and nitrile; and G.sub.2 is a carbonyl group.
(30) In another embodiment of the first aspect of the invention, optionally in combination with one or more features of the various embodiments described above or below, in the compound of formula (I), each of E and E is independently selected from the group consisting of trifluoromethyl, ethyloxycarbonyl, tert-butyloxycarbonyl, benzyloxycarbonyl, a radical of formula CON(C.sub.2H.sub.5).sub.2, ethyloxysulfonyl, phenylcarbonyl and nitrile.
(31) In another embodiment of the first aspect of the invention, optionally in combination with one or more features of the various embodiments described above or below, in the compound of formula (I), R.sub.1 is selected from the group consisting of halo, (C.sub.1-C.sub.6)haloalkylsulfonyloxy, (C.sub.1-C.sub.6)alkylsulfonyloxy, phenylsulfonyloxy, tolylsulfonyloxy, (C.sub.1-C.sub.6)alkylcarbonyloxy, hexafluorophosphate, tetrafluoroborate, hexafluoroantimonate, and (C.sub.1-C.sub.6)haloalkylcarbonyloxy; and wherein the bond between R.sub.1 and the iodine atom is preferably ionic.
(32) In another embodiment of the first aspect of the invention, optionally in combination with one or more features of the various embodiments described above or below, in the compound of formula (I), R.sub.1 is selected from the group consisting trifluoromethylsulfonyloxy, hexafluorophosphate and tetrafluoroborate; and wherein the bond between R.sub.1 and the iodine atom is preferably ionic.
(33) In another embodiment of the first aspect of the invention, optionally in combination with one or more features of the various embodiments described above or below, in the compound of formula (I), R.sub.2 is a (C.sub.6-C.sub.20)aryl, optionally substituted at any available position with one or more radicals of formula XCH.sub.2-E wherein X and E are as previously defined.
(34) In another embodiment of the first aspect of the invention, optionally in combination with one or more features of the various embodiments described above or below, in the compound of formula (I), R.sub.2 is a (C.sub.6-C.sub.20)aryl, optionally substituted at the carbon atom adjacent to the carbon atom of R.sub.2 attached to the iodine atom with a radical of formula XCH.sub.2-E wherein X and E are as previously defined.
(35) In another embodiment of the first aspect of the invention, optionally in combination with one or more features of the various embodiments described above or below, in the compound of formula (I), R.sub.2 is a phenyl optionally substituted at the carbon atom adjacent to the carbon atom of R.sub.2 attached to the iodine atom with a radical of formula XCH.sub.2-E wherein X and E are as previously defined.
(36) In another embodiment of the first aspect of the invention, optionally in combination with one or more features of the various embodiments described above or below, in the compound of formula (I), R.sub.2 is a phenyl optionally substituted at the carbon atom adjacent to the carbon atom of R.sub.2 attached to the iodine atom with a radical of formula XCH.sub.2-E wherein X is a diradical selected from the group consisting of the diradicals of formula COO and C((C.sub.1-C.sub.6)alkyl).sub.2O; and E is as previously defined.
(37) In another embodiment of the first aspect of the invention, optionally in combination with one or more features of the various embodiments described above or below, in the compound of formula (I), R.sub.2 is a phenyl optionally substituted at a carbon atom adjacent to the carbon atom of R.sub.2 attached to the iodine atom with a radical of formula XCH.sub.2-E wherein X is a diradical of formula COO; and E is as previously defined.
(38) In another embodiment of the first aspect of the invention, optionally in combination with one or more features of the various embodiments described above or below, in the compound of formula (I), R.sub.2 is a phenyl optionally substituted at a carbon atom adjacent to the carbon atom of R.sub.2 attached to the iodine atom with a radical of formula XCH.sub.2-E wherein X is a diradical of formula COO; and E is selected from the group consisting of (C.sub.1-C.sub.6)alkyloxycarbonyl and benzyloxycarbonyl.
(39) In another embodiment of the first aspect of the invention, the compound of formula (I) is selected from the compounds of formula (Id), (Ie), (If), (Ig), (Ih) and (Ii):
(40) ##STR00011##
(41) In another embodiment of the first aspect of the invention, optionally in combination with one or more features of the various embodiments described above or below, in the compound of formula (I), R.sub.1 and R.sub.2, together with the iodine atom to which they are attached form a ring in such a way that the compound of formula (I) is a compound of formula (II) wherein X is a diradical selected from the group consisting of the diradicals of formula COO, C((C.sub.1-C.sub.6)alkyl).sub.2O and SO.sub.2O. Preferably, R.sub.1 and R.sub.2, together with the iodine atom to which they are attached form a ring in such a way that the compound of formula (I) is a compound of formula (II) wherein X is a diradical selected from the group consisting of the diradicals of formula COO, and C((C.sub.1-C.sub.6)alkyl).sub.2O. More preferably, R.sub.1 and R.sub.2, together with the iodine atom to which they are attached form a ring in such a way that the compound of formula (I) is a compound of formula (II) wherein X is a diradical selected from the group consisting of the diradicals of formula COO, and C((CH.sub.3).sub.2O. In the context of the invention, when R.sup.2 is a group substituted with a radical of formula XCH.sub.2-E, the meaning of X has to be read from left to right, i.e., if for example X is COO, it has to be understood that the C atom of the carboxyl group is attached to the group forming R.sub.2 and the O atom is attached to the CH.sub.2-E group. In another example, when X is NRO, it has to be understood that the N atom is attached to the group forming R.sub.2 and the O atom is attached to the CH.sub.2-E group. In another example, when X is NRO, it has to be understood that the N atom is attached to the cycle formed by R.sub.3 and R.sub.4 and the O atom is attached to the CH.sub.2 group.
(42) Similarly, in a compound of formula (II) and in a compound of formula (V) the meaning of X and X.sup.2 has also to be read from left to right. Thus, for example if X in a compound of formula (II) is COO, it has to be understood that the C atom of the carboxyl group is attached to a C atom comprised in the group R.sub.3 and the O atom is attached to the iodine atom. On the other hand, in a compound of formula (V) if X.sup.2 is COO, it has to be understood that the C atom of the carboxyl group is attached to a C atom comprised in the group R.sub.5 and the O atom is attached to the iodine atom.
(43) In another embodiment of the first aspect of the invention, optionally in combination with one or more features of the various embodiments described above or below, in the compound of formula (I), R.sub.1 and R.sub.2, together with the iodine atom to which they are attached form a ring in such a way that the compound of formula (I) is a compound of formula (II) wherein R.sub.3 and R.sub.4, together with the carbon atoms to which they are attached, form an aromatic ring system comprising from 1 to 2 rings, each ring comprising from 5 to 6 members, said members being selected from the group consisting of C and CH, and the rings being further optionally substituted with one or more radicals selected from the group consisting of (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkyloxy, (C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkylcarbonyl, and (C.sub.1-C.sub.6)alkyloxycarbonyl.
(44) In another embodiment of the first aspect of the invention, optionally in combination with one or more features of the various embodiments described above or below, in the compound of formula (I), R.sub.1 and R.sub.2, together with the iodine atom to which they are attached form a ring in such a way that the compound of formula (I) is a compound of formula (II) wherein R.sub.3 and R.sub.4, together with the carbon atoms to which they are attached, form an aromatic ring system comprising from 1 to 2 rings, each ring comprising from 5 to 6 members, said members being selected from the group consisting of C and CH.
(45) In another embodiment of the first aspect of the invention, optionally in combination with one or more features of the various embodiments described above or below, in the compound of formula (I), R.sub.1 and R.sub.2, together with the iodine atom to which they are attached form a ring in such a way that the compound of formula (I) is a compound of formula (II) wherein R.sub.3 and R.sub.4, together with the carbon atoms to which they are attached, form a phenyl ring.
(46) In another embodiment of the first aspect of the invention, optionally in combination with one or more features of the various embodiments described above or below, in the compound of formula (I), R.sub.1 is selected from the group consisting of trifluoromethylsulfonyloxy, hexafluorophosphate and tetrafluoroborate;
(47) R.sub.2 is a phenyl optionally substituted at a carbon atom adjacent to the carbon atom of R.sub.2 attached to the iodine atom with a radical of formula XCH.sub.2-E; wherein X is a diradical selected from the group consisting of the diradicals of formula COO, C((C.sub.1-C.sub.6)alkyl).sub.2O and SO.sub.2O and E has the same meaning as E;
(48) or, alternatively;
(49) R.sub.1 and R.sub.2, together with the iodine atom to which they are attached form a ring in such a way that the compound of formula (I) is a compound of formula (II) wherein X is a diradical selected from the group consisting of the diradicals of formula COO, C((C.sub.1-C.sub.6)alkyl).sub.2O and SO.sub.2O; and
(50) R.sub.3 and R.sub.4, together with the carbon atoms to which they are attached, form a phenyl ring.
(51) In another embodiment of the first aspect of the invention, optionally in combination with one or more features of the various embodiments described above or below, E and E are the same.
(52) In another embodiment of the first aspect of the invention, optionally in combination with one or more features of the various embodiments described above or below, in the compound of formula (I), R.sub.1 is selected from the group consisting of trifluoromethanesulfonyloxy (CF.sub.3S(O).sub.2O), hexafluorophosphate and tetrafluoroborate;
(53) R.sub.2 is a phenyl optionally substituted at a carbon atom adjacent to the carbon atom of R.sub.2 attached to the iodine atom with a radical of formula XCH.sub.2-E wherein X is a diradical of formula COO; and E has the same meaning as E;
(54) or, alternatively;
(55) R.sub.1 and R.sub.2, together with the iodine atom to which they are attached form a ring in such a way that the compound of formula (I) is a compound of formula (II) wherein X is a diradical selected from the groups consisting of the diradicals of formula COO and C(CH.sub.3).sub.2O, and
(56) R.sub.3 and R.sub.4, together with the carbon atoms to which they are attached, form a phenyl ring.
(57) In another embodiment of the first aspect of the invention, the compound of formula (I) is a compound of formula (II) selected from the group consisting of (IIa), (IIb), (IIc), (IId), (IIe), (IIf) and (IIg):
(58) ##STR00012## ##STR00013##
(59) The compounds of the invention are useful reagents for the transfer of a group of formula C(N.sub.2)-E onto a substrate bearing an aromatic or heteroaromatic moiety. As it mentioned above, the second aspect of the invention relates to the use of the compound of formula (I) as defined in the first aspect of the invention, or a compound of formula (Ia), (Ib) or (Ic)
(60) ##STR00014##
(61) wherein in the compound of formula (Ia) R is ethyl or tert-butyl; as a reagent for the transfer of a group of formula C(N.sub.2)(E) to a substrate comprising at least one aromatic or heteroaromatic ring system, being E as defined above.
(62) It is advantageous as the transfer of this group can be carried out in one step, under mild conditions and in the presence of a broad range of functional groups onto the reaction substrate.
(63) A third aspect of the invention relates to a process of preparing a compound comprising a moiety of formula (III) as defined above, comprising the step of contacting a compound comprising the moiety of formula (IV) with a compound of formula (I) or a compound selected from the formula (Ia), (Ib) and (Ic) as defined above.
(64) In an embodiment of the third aspect of the invention, the compound comprising a moiety of formula (IV) comprises at least one CH aromatic bond, wherein said carbon atom is a member of an aromatic or heteroaromatic ring system comprised in the molecule.
(65) In another embodiment of the third aspect of the invention, optionally in combination with one or more features of the various embodiments described above or below, the compound comprising a moiety of formula (IV) comprises at least a ring system comprising from one to two 5 to 6 membered rings, being at least one of said rings aromatic, the members of the rings being selected from the group consisting of C, CH, CH.sub.2, N, NH, O, S, and P, and the aromatic ring being further optionally substituted. In a preferred embodiment of the third aspect of the invention, optionally in combination with one or more features of the various embodiments described above or below, the compound comprising a moiety of formula (IV) comprises at least a ring system comprising from one to two 5 to 6 membered rings, being at least one of said rings aromatic, the members of the rings being selected from the group consisting of C, CH, CH.sub.2, N, NH, O, S, and P, and the aromatic ring being further optionally substituted with one or more radicals of formula Q selected from the group consisting of (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkyloxy, (C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkylcarbonyl, (C.sub.1-C.sub.6)alkyloxycarbonyl, (C.sub.1-C.sub.6)alkylcarbonyloxy, formyl (CHO), cyano, nitro, (C.sub.1-C.sub.6)alkylaminocarbonyl, (C.sub.1-C.sub.6)alkylcarbonylamino, (C.sub.1-C.sub.6)alkyloxycarbonylamino (such as a tert-butyloxycarbonylamino, or Boc group), halo, and [(C.sub.1-C.sub.6)alkyl].sub.2boronate, wherein in said Q radicals the (C.sub.1-C.sub.6)alkyl is further optionally substituted with one or more radicals of formula Q.
(66) In another embodiment of the third aspect of the invention, optionally in combination with one or more features of the various embodiments described above or below, the compound comprising a moiety of formula (IV) comprises at least a ring system comprising from one to two 5 to 6 membered rings, being at least one of said rings aromatic, the members of the rings being selected from the group consisting of C, CH, CH.sub.2, N, and O, and the aromatic ring being further optionally substituted with one or more radicals of formula Q selected from the group consisting of (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkyloxy, (C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkylcarbonyl, (C.sub.1-C.sub.6)alkyloxycarbonyl, (C.sub.1-C.sub.6)alkylcarbonyloxy, formyl (CHO), cyano, nitro, (C.sub.1-C.sub.6)alkylaminocarbonyl, (C.sub.1-C.sub.6)alkylcarbonylamino, (C.sub.1-C.sub.6)alkyloxycarbonylamino (such as a tert-butyloxycarbonylamino, or Boc group), halo, and [(C.sub.1-C.sub.6)alkyl].sub.2boronate.
(67) In another embodiment of the third aspect of the invention, optionally in combination with one or more features of the various embodiments described above or below, the compound comprising a moiety of formula (IV) is selected from the group consisting of a drug, a drug intermediate, a polymer, a biomolecule (proteins, enzymes, peptides, antibodies, nucleic acid sequences), an aminoacid derivative, a biologically active ingredient, a polyaromatic compound, a carbon nanotube, graphene, graphene oxide, fullerene and a small organic molecule.
(68) In another embodiment of the third aspect of the invention, optionally in combination with one or more features of the various embodiments described above or below, the compound comprising a moiety of formula (IV) is selected from the group consisting of benzene, toluene, xylene, anisol, N-Boc aniline, iodobenzene, phenyl acetate, methyl benzoate, 1-(tert-butyl)-4-methylbenzene, 1-(fluoro)-4-methylbenzene, 1-(trifluoromethyl)-4-methylbenzene, methyl 4-methylbenzoate, 1-(p-tolyl)ethanone, 4,4,5,5-tetramethyl-2-(p-tolyl)-1,3,2-dioxaborolane, naphthalene, 1-(4-methoxyphenyl)ethanone, mesitylene, methyl 2-((tert-butoxycarbonyl)amino)-3-phenylpropanoate, 3-hydroxy-13-methyl-7,8,9,11,12,13,15,16-octahydro-6H-cyclopenta[a]phenanthren-17(14H)-one, N-Boc duloxetine, N-Boc paroxetine, 2,6-di-tert-butyl pyridine, and 4-methyl-2,6-di-tert-butyl-pyridine.
(69) As illustrated in the Examples below, the process of the invention can be carried out on a wide range of reaction substrates bearing various functional groups. It is advantageous as this allows for the introduction of the diazomethyl group at a late-stage of the synthetic procedure, which can be useful for the diazomethylation of highly functionalized compounds such as biomolecules (peptides, nucleic acids, antibodies, enzymes, etc), pharmaceutical drugs and drug intermediates. The diazomethyl group is a carbene precursor and is therefore prompt to versatile reactivity, thereby allowing for instance to further modify the diazomethylated product and introduce new properties.
(70) In another embodiment of the third aspect of the invention, optionally in combination with one or more features of the various embodiments described above or below, the process is carried out in the presence of a compound of formula (I) as defined in any of the embodiments described above for the first aspect of the invention, or a compound of formula (Ia), (Ib) or (Ic) as defined above.
(71) In a preferred embodiment of the third aspect of the invention, optionally in combination with one or more features of the various embodiments described above or below, the process is carried out in the presence of a compound of formula (I) selected from the group consisting of the compounds of formulae (Id), (Ie), (Ih), (Ii), (IIa) and (IIb).
(72) In another embodiment of the third aspect of the invention, optionally in combination with one or more features of the various embodiments described above or below, the process is carried out in the presence of a suitable reducing agent selected from the group consisting of an electrode, a metal salt, a photoelectrochemical mean, a photocatalyst, a photosensitizer and a photoredox catalyst.
(73) In a preferred embodiment, optionally in combination with one or more features of the various embodiments described above or below, the third aspect of the invention relates to a process wherein the suitable reducing agent is a photoredox catalyst that is used in a catalytically effective amount.
(74) In a preferred embodiment of the third aspect of the invention, optionally in combination with one or more features of the various embodiments described above or below, the process is carried out in the presence of catalytically effective amount of a photoredox catalyst as suitable reducing agent wherein the photoredox catalyst is selected from the group consisting of the salts of tris-(2,2-bipyrimidine)ruthenium.sup.2+, tris-(2,2-bipyrazine)ruthenium.sup.2+, tris-(2,2-bipyridine)ruthenium.sup.2+, tris-(1,10-phenanthroline)ruthenium.sup.2+, bis-(2-(2,4-difluorophenyl)-5-trifluoromethylpyridine)(di-tert-butylbipyridine)iridium.sup.+, bis-(2-phenylpyridine)(di-tert-butylbipyridine)iridium.sup.+, fac-(tris-(2,2-phenylpyridine))iridium.
(75) In a more preferred embodiment of the third aspect of the invention, optionally in combination with one or more features of the various embodiments described above or below, the process is carried out in the presence of a catalytically effective amount of a photoredox catalyst as suitable reducing agent wherein the photoredox catalyst is selected from the group consisting of the salts of tris-(2,2-bipyrimidine)ruthenium.sup.2+, tris-(2,2-bipyrazine)ruthenium.sup.2+, tris-(2,2-bipyridine)ruthenium.sup.2+, and tris-(1,10-phenanthroline)ruthenium.sup.2+.
(76) In an even more preferred embodiment of the third aspect of the invention, optionally in combination with one or more features of the various embodiments described above or below, the process is carried out in the presence of a catalytically effective amount of a photoredox catalyst as suitable reducing agent wherein the photoredox catalyst is tris-(2,2-bipyridine)ruthenium.sup.2+ hexafluorophosphate.
(77) In another embodiment of the third aspect of the invention, optionally in combination with one or more features of the various embodiments described above or below, when the suitable reducing agent is selected from the group consisting of a photoelectrochemical mean, a photocatalyst, a photosensitizer and a photoredox catalyst, then the process is preferably carried out under light irradiation. In a more particular embodiment, optionally in combination with one or more features of the various embodiments described above or below, the suitable reducing agent is a photoredox catalyst that is used in a catalytically effective amount, and the process is carried out under light irradiation.
(78) In a particular embodiment of the third aspect of the invention, optionally in combination with one or more features of the various embodiments described above or below, the suitable reducing agent is a salt of formula A-Y wherein A is a cation selected from the group consisting of tris-(2,2-bipyrimidine)ruthenium.sup.2+, tris-(2,2-bipyrazine)ruthenium.sup.2+, tris-(2,2-bipyridine)ruthenium.sup.2+, tris-(1,10-phenanthroline)ruthenium.sup.2+, bis-(2-(2,4-difluorophenyl)-5-trifluoromethylpyridine)(di-tert-butylbipyridine)iridium.sup.+, bis-(2-phenylpyridine)(di-tert-butylbipyridine)iridium.sup.+, and fac-(tris-(2,2-phenylpyridine))iridium.sup.+;
(79) and Y is an anion selected from the group consisting of tetrafluoroborate, hexafluorophosphate, chloride, and tetra(pentafluorophenyl)borate.
(80) In a particular embodiment of the third aspect of the invention, optionally in combination with one or more features of the various embodiments described above or below, the suitable reducing agent is a tris-(2,2-bipyridine)ruthenium.sup.2+ bis hexafluorophosphate that is used in a catalytically effective amount, and the irradiation light is visible light.
(81) In another embodiment of the third aspect of the invention, optionally in combination with one or more features of the various embodiments described above or below, the process is carried out in the presence of a base selected from the group consisting of alkaline carbonate salts, alkaline earth carbonate salts, alkaline bicarbonate salts, alkaline earth bicarbonate salts, alkaline (C.sub.1-C.sub.6)alkyloxide salts, a compound of formula N[(C.sub.1-C.sub.6)alkyl].sub.3, N-methyl morpholine, and pyridine optionally substituted with one or more (C.sub.1-C.sub.6)alkyl groups.
(82) In a preferred embodiment of the third aspect of the invention, optionally in combination with one or more features of the various embodiments described above or below, the process is carried out in the presence of a base selected from the group consisting of alkaline bicarbonate salts, alkaline earth bicarbonate salts, and pyridine optionally substituted with one or more (C.sub.1-C.sub.6)alkyl groups.
(83) In a more preferred embodiment of the third aspect of the invention, optionally in combination with one or more features of the various embodiments described above or below, the process is carried out in the presence of a base selected from the group consisting of sodium hydrogen carbonate and 2,6-di-tert-butylpyridine. More preferably, the base is sodium hydrogen carbonate.
(84) In another embodiment of the third aspect of the invention, optionally in combination with one or more features of the various embodiments described above or below, the process is carried out in the presence of a polar aprotic solvent.
(85) In a preferred embodiment of the third aspect of the invention, optionally in combination with one or more features of the various embodiments described above or below, the polar aprotic solvent is selected from the group consisting of acetonitrile, acetone and dichloromethane. More preferably, optionally in combination with one or more features of the various embodiments described above or below, the polar aprotic solvent is acetonitrile.
(86) In another embodiment of the third aspect of the invention, optionally in combination with one or more features of the various embodiments described above or below, the process is carried out at room temperature.
(87) In another embodiment of the third aspect of the invention, optionally in combination with one or more features of the various embodiments described above or below, the process is carried out with a power of light irradiation comprised between 3 and 4 W.
(88) In another embodiment of the third aspect of the invention, optionally in combination with one or more features of the various embodiments described above or below, the molar ratio of the compound comprising the moiety of formula (IV) to the compound of formula (I), (Ia), (Ib) or (Ic) is comprised from 3:1 to 1:2. Preferably, the molar ratio of the compound comprising the moiety of formula (IV) to the compound of formula (I), (Ia), (Ib) or (Ic) is comprised from 2:1 to 1:1.5.
(89) In another embodiment of the third aspect of the invention, optionally in combination with one or more features of the various embodiments described above or below, the molar ratio of the compound comprising the moiety of formula (IV) to the base is comprised from 1:3 to 2:3.
(90) In another embodiment of the third aspect of the invention, optionally in combination with one or more features of the various embodiments described above or below, when the suitable reducing agent is a photoredox catalyst used in a catalytically effective amount, the molar ratio of the compound comprising the moiety of formula (IV) to the reducing agent is comprised from 1000:1 to 100:1.
(91) In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, the process of the third aspect further comprises the previous step of preparing a compound of formula (I), which comprises contacting a compound of formula (V)
(92) ##STR00015##
(93) wherein X.sup.2 is a diradical selected from the group consisting of the diradicals of formula COO, C((C.sub.1-C.sub.6)alkyl).sub.2O, SO.sub.2O, NRO, B(OR)O, SO, and P(O)(OR)O, wherein R is H or (C.sub.1-C.sub.6)alkyl,
(94) with a compound of formula ((C.sub.1-C.sub.6)alkyl).sub.3SiR.sub.1 (VI)
(95) and a compound of formula N.sub.2CH-E (VII) in the presence of a polar aprotic solvent; and optionally in the presence of a base wherein:
(96) R.sub.5 is a (C.sub.1-C.sub.6)alkyl,
(97) R.sub.2 is a (C.sub.6-C.sub.20)aryl, optionally substituted at any available position with one or more radicals selected from the group consisting of (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkyloxy, (C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkylcarbonyl, and (C.sub.1-C.sub.6)alkyloxycarbonyl,
(98) or, alternatively,
(99) R.sub.5 and R.sub.2, together with the atoms to which they are attached, form an aromatic ring system comprising from 1 to 2 rings, each ring comprising from 5 to 6 members, said members being selected from the group consisting of C, CH, N, NR, being R hydrogen or (C.sub.1-C.sub.6)alkyl, O and S; and the rings being further optionally substituted with one or more radicals selected from the group consisting of (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkyloxy, (C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkylcarbonyl, and (C.sub.1-C.sub.6)alkyloxycarbonyl; and
(100) R.sub.7 is a (C.sub.1-C.sub.6)alkyloxycarbonyl or a (C.sub.1-C.sub.6)alkyloxy.
(101) It also forms part of the invention a process for the preparation of a compound of formula (I), which comprises contacting a compound of formula (V)
(102) ##STR00016##
(103) as defined above, with a compound of formula ((C.sub.1-C.sub.6)alkyl).sub.3SiR.sub.1(VI) and a compound of formula N.sub.2CH-E (VII) as defined above in the presence of a polar aprotic solvent; and optionally in the presence of a base.
(104) In a particular embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the compound of formula (V), R.sub.5 and R.sub.2, together with the atoms to which they are attached, form a (C.sub.6-C.sub.20)aryl substituted at any available position with one or more radicals selected from the group consisting of (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkyloxy, (C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkylcarbonyl, and (C.sub.1-C.sub.6)alkyloxycarbonyl.
(105) In a preferred embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the compound of formula (V): X.sup.2 is a diradical of formula COO, R.sub.5 is a (C.sub.1-C.sub.6)alkyl, R.sub.2 is a phenyl ring, and R.sub.7 is a (C.sub.1-C.sub.6)alkyloxycarbonyl;
(106) or, alternatively, X.sup.2 is a diradical selected from the group consisting of the diradicals of formula COO and C((C.sub.1-C.sub.6)alkyl).sub.2O, R.sub.5 and R.sub.2, together with the atoms to which they are attached, form a phenyl ring; and R.sub.7 is a (C.sub.1-C.sub.6)alkyloxycarbonyl or a (C.sub.1-C.sub.6)alkyloxy.
(107) In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, the process of the third aspect further comprises the previous step of preparing a compound of formula (I), which comprises contacting a compound of formula (V)
(108) ##STR00017##
(109) wherein X.sup.2 is a diradical selected from the group consisting of the diradicals of formula COO, C((C.sub.1-C.sub.6)alkyl).sub.2O, SO.sub.2O, NRO, B(OR)O, SO, and P(O)(OR)O, wherein R is H or (C.sub.1-C.sub.6)alkyl,
(110) with a compound of formula ((C.sub.1-C.sub.6)alkyl).sub.3SiR.sub.1(VI)
(111) and a compound of formula N.sub.2CH-E (VII) in the presence of a polar aprotic solvent; and optionally in the presence of a base, wherein:
(112) R.sub.5 is a (C.sub.1-C.sub.6)alkyl,
(113) R.sub.2 is a (C.sub.6-C.sub.20)aryl, optionally substituted at any available position with one or more radicals selected from the group consisting of (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkyloxy, (C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkylcarbonyl, and (C.sub.1-C.sub.6)alkyloxycarbonyl,
(114) or, alternatively,
(115) R.sub.5 and R.sub.2, together with the atoms to which they are attached, form an aromatic ring system comprising from 1 to 2 rings, each ring comprising from 5 to 6 members, said members being selected from the group consisting of C, CH, N, NR, being R hydrogen or (C.sub.1-C.sub.6)alkyl, O and S; and the rings being further optionally substituted with one or more radicals selected from the group consisting of (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkyloxy, (C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkylcarbonyl, and (C.sub.1-C.sub.6)alkyloxycarbonyl; or, alternatively,
(116) R.sub.5 and R.sub.2, together with the atoms to which they are attached, form a (C.sub.6-C.sub.20)aryl substituted at any available position with one or more radicals selected from the group consisting of (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkyloxy, (C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkylcarbonyl, and (C.sub.1-C.sub.6)alkyloxycarbonyl;
(117) R.sub.7 is a (C.sub.1-C.sub.6)alkyloxycarbonyl or a (C.sub.1-C.sub.6)alkyloxy; and wherein:
(118) (i) when in the compound of formula (I) R.sub.1 is selected from the group consisting of halo, (C.sub.1-C.sub.6)haloalkylsulfonyloxy, (C.sub.1-C.sub.6)alkylsulfonyloxy, phenylsulfonyloxy, tolylsulfonyloxy, (C.sub.1-C.sub.6)alkylcarbonyloxy, and (C.sub.1-C.sub.6)haloalkylcarbonyloxy; and R.sub.2 is a (C.sub.6-C.sub.20)aryl, optionally substituted at any available position with one or more radicals selected from the group consisting of (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkyloxy, (C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkylcarbonyl, and (C.sub.1-C.sub.6)alkyloxycarbonyl; then in the compound of formula (V), X.sup.2 is COO, R.sub.5 is a (C.sub.1-C.sub.6)alkyl, R.sub.2 is a (C.sub.6-C.sub.20)aryl, optionally substituted at any available position with one or more radicals selected from the group consisting of (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkyloxy, (C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkylcarbonyl, and (C.sub.1-C.sub.6)alkyloxycarbonyl, and R.sub.7 is a (C.sub.1-C.sub.6)alkyloxycarbonyl; and the molar ratio of the compound of formula (VII) to the compound of formula (V) is preferably comprised from 1:1 to 2:1; or, alternatively,
(119) (ii) when in the compound of formula (I) R.sub.1 is selected from the group consisting of halo, (C.sub.1-C.sub.6)haloalkylsulfonyloxy, (C.sub.1-C.sub.6)alkylsulfonyloxy, phenylsulfonyloxy, tolylsulfonyloxy, (C.sub.1-C.sub.6)alkylcarbonyloxy, and (C.sub.1-C.sub.6)haloalkylcarbonyloxy; and R.sub.2 is a (C.sub.6-C.sub.20)aryl substituted at any available position with one or more radicals selected from the group consisting of (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkyloxy, (C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkylcarbonyl, (C.sub.1-C.sub.6)alkyloxycarbonyl and the radicals of formula XCH.sub.2-E, said compound of formula (I) comprising at least one radical of formula XCH.sub.2-E, then in the compound of formula (V), R.sub.5 and R.sub.2, together with the atoms to which they are attached, form a (C.sub.6-C.sub.20)aryl substituted at any available position with one or more radicals selected from the group consisting of (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkyloxy, (C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkylcarbonyl, and (C.sub.1-C.sub.6)alkyloxycarbonyl; and R.sub.7 is a (C.sub.1-C.sub.6)alkyloxy; and the molar ratio of the compound of formula (VII) to the compound of formula (V) is preferably higher than 2:1 or, alternatively,
(120) (iii) when in the compound of formula (I) R.sub.1 and R.sub.2, together with the iodine atom to which they are attached form a ring in such a way that the compound of formula (I) is a compound of formula (II); then the process is carried out in the presence of a base, and in the compound of formula (V), R.sub.5 and R.sub.2 form an aromatic ring system comprising from 1 to 2 rings, each ring comprising from 5 to 6 members, said members being selected from the group consisting of C, CH, N, NR, being R hydrogen or (C.sub.1-C.sub.6)alkyl, O and S; and the rings being further optionally substituted with one or more radicals selected from the group consisting of (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkyloxy, (C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkylcarbonyl, and (C.sub.1-C.sub.6)alkyloxycarbonyl; and R.sub.7 is a (C.sub.1-C.sub.6)alkyloxycarbonyl; or, alternatively,
(121) (iv) when in the compound of formula (I) R.sub.1 is selected from hexafluorophosphate, hexafluoroantimonate and tetrafluoroborate and R.sub.2 is a (C.sub.6-C.sub.20)aryl optionally substituted at any available position with one or more radicals selected from the group consisting of (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkyloxy, (C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkylcarbonyl, (C.sub.1-C.sub.6)alkyloxycarbonyl and the radicals of formula XCH.sub.2-E; then the product resulting from the processes described in the step (i) or in the step (ii) above is further contacted with an aqueous saturated solution of sodium hexafluorophosphate when R.sub.1 is hexafluorophosphate, an aqueous saturated solution of sodium hexafluoroantimonate when R.sub.1 is hexafluoroantimonate, or with an aqueous saturated solution of sodium tetrafluoroborate when R.sub.1 is tetrafluoroborate.
(122) Throughout the description and claims the word comprise and variations of the word, are not intended to exclude other technical features, additives, components, or steps. Additional objects, advantages and features of the invention will become apparent to those skilled in the art upon examination of the description or may be learned by practice of the invention. The following examples and drawings are provided by way of illustration, and they are not intended to be limiting of the present invention. Furthermore, the present invention covers all possible combinations of particular and preferred embodiments described herein.
EXAMPLES
(123) Compound (Ia) was prepared following the procedure reported in Weiss et al, Angew. Chem., Int. Ed. 1994, 33 (19), 1952-1953.
(124) ##STR00018##
Example 1: Preparation of (1-diazo-2-ethoxy-2-oxoethyl)(2-(2-ethoxy-2-oxoethoxy)carbonylphenyl)iodonium Trifluoromethanesulfonate
(125) ##STR00019##
(126) A solution of 1-methoxy-1,2-benziodoxol-3(1H)-one (180 mg, 0.65 mmol, 1.0 eq.) in dichloromethane (2.5 mL, 0.25 M) was treated with trimethylsilyl trifluoromethanesulfonate (0.12 mL, 0.65 mmol, 1.0 eq.) at room temperature. Then ethyl diazoacetate (0.15 mL, 1.43 mmol, 2.2 eq) was added dropwise and the reaction mixture was stirred for 1 hour at room temperature until a clear yellow solution was obtained. Solvent was removed under vacuum and the resulting solid was recrystallized from a mixture of diethyl ether/dichloromethane (5:1) during 12 hours at 30 C. The product was collected by filtration, washed with cold diethyl ether (200 mL), dried under high vacuum and stored at 30 C. as a yellow solid (572 mg, 96%).
(127) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.38 (dd, J=7.5, 1.9 Hz, 1H), 8.32 (dd, J=8.0, 1.2 Hz, 1H), 8.00 (td, J=7.7, 1.9 Hz, 1H), 7.95 (td, J=7.4, 1.3 Hz, 1H), 5.15 (s, 2H), 4.30-4.19 (m, 4H), 1.26-1.19 (m, 6H); .sup.13C NMR (101 MHz, DMSO-d.sub.6) 167.79, 167.15, 162.01, 138.10, 133.76, 133.08, 133.03, 126.70, 121.09 (q, J=324.21), 118.14, 64.09, 61.87, 14.51, 14.39. .sup.19F NMR (376 MHz, DMSO-d.sub.6): 77.87. Differential scanning calorimetry (DSC) analysis showed that IIa is stable up to 101.74 C.
Example 2: Preparation of 1-(1-diazo-2-ethoxy-2-oxoethyl)-1,2-benziodoxol-3(1H)-one (IIa)
(128) ##STR00020##
(129) A solution of 1-acetoxy-1,2-benziodoxol-3(1H)-one (200 mg, 0.65 mmol, 1.0 eq.) in dichloromethane 2.5 mL (0.25 M) was treated with trimethylsilyl trifluoromethanesulfonate (0.12 mL, 0.65 mmol, 1.0 eq.) at room temperature. After 10 min of stirring, a solution of pyridine (0.053 ml, 0.65 mmol, 1.0 eq) in dichloromethane (0.5 ml) was added. The resulted suspension was additionally stirred for 2 h at room temperature. Ethyl diazoacetate (0.08 mL, 0.76 mmol, 1.2 eq) was added and the mixture was stirred until a clear yellow solution was obtained. The solution was washed with distilled water and dried with anhydrous sodium sulfate. Solvent was removed under vacuum to afford a yellowish solid. The contained pyridine salt was removed by recrystallization (3 times) from dichloromethane during 12 hours at 30 C. The resulting filtrate was evaporated under vacuum and the product was collected as a yellow solid (63 mg, 27% yield), washed with cold diethyl ether (20 mL), dried under high vacuum and stored at 30 C.
(130) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.10 (dd, J=7.4, 1.7 Hz, 1H), 7.89 (d, J=8.2 Hz, 1H), 7.83 (ddd, J=8.3, 7.0, 1.7 Hz, 1H), 7.76 (td, J=7.2, 1.2 Hz, 1H), 4.24 (q, J=7.1 Hz, 2H), 1.21 (t, J=7.1 Hz, 3H); .sup.13C NMR (101 MHz, DMSO-d.sub.6) 167.42, 164.76, 135.59, 133.35, 132.47, 131.88, 128.19, 117.67, 63.47, 15.19. Differential scanning calorimetry (DSC) analysis showed that IIa is stable up to 91.28 C.
Example 3: Preparation of 1-(1-diazo-2-ethoxy-2-oxoethyl)-1,3-dihydro-3,3-dimethyl-1,2-benziodoxole (IIb)
(131) ##STR00021##
(132) A solution of the 3,3-dimethyl-1-acetoxy-1,2-benziodoxole (180 mg, 0.65 mmol, 1.0 eq.) in dichloromethane 2.5 mL (0.25 M) was treated with trimethylsilyl trifluoromethanesulfonate (0.12 mL, 0.65 mmol, 1.0 eq.) at room temperature. After 10 minutes of stirring, a solution of pyridine (0.053 ml, 0.65 mmol, 1.0 eq) in dichloromethane (0.5 ml) was added. The resulted suspension was additionally stirred for 2 hours at room temperature. Ethyl diazoacetate (0.08 mL, 0.76 mmol, 1.2 eq) was added and the mixture was stirred until a clear yellow solution was obtained. The solution was cautiously washed with distilled water and dried with anhydrous sodium sulfate. Solvents were removed under vacuum and the residue was purified by flash chromatography (EA:Hexane=1:1 as eluent) to afford a yellowish oil (96 mg, 40% yield). .sup.1H NMR (400 MHz, Chloroform-d) 7.51 (ddd, J=7.5, 6.4, 1.8 Hz, 1H), 7.45-7.38 (m, 2H), 7.37-7.31 (m, 1H), 4.22 (q, J=7.1 Hz, 2H), 1.48 (s, 6H), 1.25 (d, J=7.1 Hz, 3H); .sup.13C NMR (126 MHz, CDCl.sub.3) 177.30, 149.34, 130.38, 129.91, 129.87, 126.17, 115.68, 84.54, 60.86, 29.18, 21.45, 14.44.
Example 4: Preparation of (1-diazo-2,2,2-trifluoroethyl)(phenyl)iodonium Trifluoromethanesulfonate (Ie)
(133) ##STR00022##
(134) A solution of phenyliodoso diacetate (209 mg, 0.65 mmol, 1.0 eq.) in dichloromethane (2.5 mL, 0.25 M) was treated with trimethylsilyl trifluoromethanesulfonate (0.12 mL, 0.65 mmol, 1.0 eq.) at room temperature. Then trifluoromethyl diazomethane (0.35M, 4.0 mL, 1.43 mmol, 2.2 eq) was added dropwise and the reaction mixture was stirred for 1 hour at room temperature. Solvent was removed under vacuum and the crude was recrystallized from a mixture of diethyl ether/dichloromethane (5:1) during 12 hours at 30 C. The product was collected by filtration, washed with cold diethyl ether (200 mL), dried under high vacuum and stored at 30 C. Yellow solid (208 mg, 70%).
(135) .sup.1H NMR (400 MHz, Acetonitrile-d3) 8.21-8.14 (m, 2H), 7.84-7.80 (m, 1H), 7.68-7.61 (m, 2H); .sup.13C NMR (101 MHz, Acetonitrile-d3) 137.42, 135.30, 133.73, 132.42, 129.11 (q, J=280.78); .sup.19F NMR (376 MHz, CD.sub.3CN) 55.47, 79.43. Differential scanning calorimetry (DSC) analysis showed that IIa is stable up to 93.02 C.
Example 5: Preparation of 1-(1-diazo-2,2,2-trifluoroethyl)-1,2-Benziodoxol-
(136) ##STR00023##
3(1H)-one (IIc)
(137) A solution of 1-acetoxy-1,2-benziodoxol-3(1H)-one (200 mg, 0.65 mmol, 1.0 eq.) in dichloromethane 2.5 mL (0.25 M) was treated with trimethylsilyl trifluoromethanesulfonate (0.12 mL, 0.65 mmol, 1.0 eq.) at room temperature. After 10 min of stirring, a solution of pyridine (0.053 ml, 0.65 mmol, 1.0 eq) in dichloromethane (0.5 ml) was added. The resulted suspension was additionally stirred for 2 h at room temperature. trifluoromethyl diazomethane (0.35M, 2.2 mL, 1.78 mmol, 1.2 eq) was added and the mixture was stirred until a clear yellow solution was obtained. The solution was washed with distilled water (no vigorously shaking!) and dried with anhydrous sodium sulfate. Solvent were removed in a vacuum to afford a yellowish solid. The contained pyridine salt was removed by recrystallization (3 times) from dichloromethane during 12 hours at 30 C. Remove the solvent from the final filtrate and the product was collected as a yellow solid (46 mg, 20% yield), washed with cold diethyl ether (20 mL), dried under high vacuum and stored at 30 C.
(138) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.01 (dd, J=7.6, 1.5 Hz, 1H), 7.95 (ddd, J=8.7, 7.1, 1.6 Hz, 1H), 7.83 (d, J=8.0 Hz, 1H), 7.70 (t, J=7.5 Hz, 1H); .sup.13C NMR (126 MHz, DMSO) 168.51, 135.07, 131.73, 131.60, 130.91, 129.55 (q, J=226.80), 126.70, 120.81.
Example 6: Preparation of (1-diazo-2-benzyloxy-2-oxoethyl)(2-(2-benzyloxy-2-oxoethoxyl)carbonylphenyl)iodonium Trifluoromethanesulfonate (If)
(139) ##STR00024##
(140) A solution of 1-methoxy-1,2-benziodoxol-3(1H)-one (180 mg, 0.65 mmol, 1.0 eq.) in dichloromethane (2.5 mL, 0.25 M) was treated with trimethylsilyl trifluoromethanesulfonate (0.12 mL, 0.65 mmol, 1.0 eq.) at room temperature. Then benzyl diazoacetate (0.22 mL, 1.43 mmol, 2.2 eq) was added dropwise which accompanied by release of N.sub.2 and the reaction mixture was stirred for at room temperature until a clear yellow solution was obtained. Solvent was removed under vacuum and the crude was recrystallized from a mixture of diethyl ether/dichloromethane (5:1) during 12 hours at 30 C. The product was collected by filtration, washed with cold diethyl ether (200 mL), dried under high vacuum and stored at 30 C. Yellow solid (351 mg, 75%).
(141) .sup.1H NMR (400 MHz, Acetonitrile-d.sub.3) 8.41 (dd, J=7.6, 1.7 Hz, 1H), 8.03 (dd, J=8.4, 1.2 Hz, 1H), 7.97 (ddd, J=8.4, 7.1, 1.7 Hz, 1H), 7.90 (td, J=7.4, 1.2 Hz, 1H), 7.42-7.35 (m, 10H), 5.32 (s, 2H), 5.25 (s, 2H), 5.12 (s, 2H); .sup.13C NMR (101 MHz, Acetonitrile-d.sub.3); .sup.19F NMR (376 MHz, Acetonitrile-d.sub.3): 79.39.
Example 7: Preparation of (1-diazo-2-tert-butoxy-2-oxoethyl)(2-(2-tert-butoxy-2-oxoethoxyl)carbonylphenyl)iodonium Trifluoromethanesulfonate (Ig)
(142) ##STR00025##
(143) A solution of 1-methoxy-1,2-benziodoxol-3(1H)-one (180 mg, 0.65 mmol, 1.0 eq.) in dichloromethane (2.5 mL, 0.25 M) was treated with trimethylsilyl trifluoromethanesulfonate (0.12 mL, 0.65 mmol, 1.0 eq.) at room temperature. Then t-butyl diazoacetate (0.20 mL, 1.43 mmol, 2.2 eq) was added dropwise which accompanied by release of N.sub.2 and the reaction mixture was stirred for at room temperature until a clear yellow solution was obtained. Solvent was removed under vacuum and the crude was recrystallized from a mixture of diethyl ether/dichloromethane (5:1) during 12 hours at 30 C. The product was collected by filtration, washed with cold diethyl ether (200 mL), dried under high vacuum and stored at 30 C. Yellow solid (279 mg, 66%).
(144) .sup.1H NMR (400 MHz, Acetonitrile-d.sub.3) 8.43-8.39 (m, 1H), 8.02 (dd, J=3.6, 0.9 Hz, 2H), 7.91 (ddd, J=7.6, 4.7, 3.5 Hz, 1H), 4.95 (s, 2H), 1.49 (s, 9H), 1.48 (s, 9H); .sup.13C NMR (101 MHz, Acetonitrile-d.sub.3); .sup.19F NMR (376 MHz, Acetonitrile-d.sub.3): 79.39
Example 8: Preparation of (1-diazo-2-ethoxy-2-oxoethyl)(2-(2-ethoxy-2-oxoethoxy)carbonylphenyl)iodonium Hexafluorophosphate (Ih)
(145) ##STR00026##
(146) 2.0 mL solution of a saturated aqueous solution of NaPF.sub.6 was added to a solution of 1.0 mmol of the compound of formula (Id) in 2.0 mL DCM. The resulting biphasic mixture was stirred at room temperature for 16 h until the phases were separated and the aqueous layer extracted with a further three portions of DCM. The combined organic fractions were dried over anhydrous MgSO.sub.4 and concentrated in vacuo to give the corresponding PF.sub.6 salt as a yellow solid (456 mg, 77%).
(147) .sup.1H NMR (400 MHz, CDCl.sub.3) 8.39 (dd, J=7.7, 1.6 Hz, 1H), 8.03-7.97 (m, 1H), 7.88-7.78 (m, 2H), 5.02 (s, 2H), 4.39-4.22 (m, 4H), 1.33-1.27 (m, 6H); .sup.13C NMR (101 MHz, CDCl.sub.3) 169.52, 166.03, 161.14, 138.96, 133.85, 132.39, 128.37, 124.87, 114.93, 64.78, 64.08, 62.53, 14.24, 14.15; .sup.19F NMR (376 MHz, CDCl.sub.3): 71.83 (d, J=714.4); .sup.31P NMR (162 MHz, CDCl.sub.3) 141.43 (hept, J=712.8).
Example 9: Preparation of (1-diazo-2-ethoxy-2-oxoethyl)(2-(2-ethoxy-2-oxoethoxy)carbonylphenyl)iodonium Tetrafluoroborate (Ii)
(148) ##STR00027##
(149) 2.0 mL solution of a saturated aqueous solution of NaBF.sub.4 was added to a solution of 1.0 mmol of the compound of formula (Id) in 2.0 mL DCM. The resulting biphasic mixture was stirred at room temperature for 16 h until the phases were separated and the aqueous layer extracted with a further three portions of DCM. The combined organic fractions were dried over anhydrous MgSO.sub.4 and concentrated in vacuo to give the corresponding BF.sub.4 salt as a yellow solid (187 mg, 35%).
(150) .sup.1H NMR (400 MHz, CDCl.sub.3) 8.40 (dd, J=7.7, 1.6 Hz, 1H), 7.95 (dd, J=7.2, 1.6 Hz, 1H), 7.85 (dd, J=8.3, 0.8 Hz, 1H), 7.81 (td, J=7.6, 1.0 Hz, 1H), 5.04 (s, 2H), 4.39-4.25 (m, 4H), 1.37-1.28 (m, 6H); .sup.13C NMR (101 MHz, CDCl.sub.3) 169.41, 165.95, 161.30, 138.37, 133.71, 132.13, 128.75, 125.50, 115.82, 64.63, 64.01, 62.57, 14.37, 14.22; .sup.19F NMR (376 MHz, CDCl.sub.3) 149.84 (d, J=18.8); .sup.11B NMR (128 MHz, CDCl.sub.3) 1.22.
Example 10: Preparation of 1-(1-diazo-2-oxo-2-phenylethyl)-1,2-benziodoxol-3(1H)-one (IId)
(151) ##STR00028##
(152) A solution of 1-acetoxy-1,2-benziodoxol-3(1H)-one (200 mg, 0.65 mmol, 1.0 eq.) in dichloromethane 2.5 mL (0.25 M) was treated with trimethylsilyl trifluoromethanesulfonate (0.12 mL, 0.65 mmol, 1.0 eq.) at room temperature. After 10 min of stirring, a solution of pyridine (0.053 ml, 0.65 mmol, 1.0 eq) in dichloromethane (0.5 ml) was added. The resulted suspension was additionally stirred for 2 h at room temperature. -diazoacetophenone in 0.5 mL DCM solution (114 mg, 0.76 mmol, 1.2 eq) was added and the mixture was stirred until a clear yellow solution was obtained. The solution was washed with distilled water and dried with anhydrous sodium sulfate. Solvent was removed in a vacuum to afford a yellowish solid. The contained pyridine salt was removed by recrystallization (3 times) from dichloromethane during 12 hours at 30 C. Remove the solvent from the final filtrate and the product was collected as a yellow solid (73 mg, 29% yield), washed with cold diethyl ether (20 mL), dried under high vacuum and stored at 30 C.
(153) .sup.1H NMR (400 MHz, Chloroform-d) 8.43-8.37 (m, 1H), 7.74 (ddd, J=5.9, 3.5, 1.9 Hz, 4H), 7.66-7.59 (m, 2H), 7.53 (dd, J=8.3, 6.9 Hz, 2H); .sup.13C NMR (101 MHz, Chloroform-d) 185.69, 167.00, 134.89, 133.35, 133.22, 132.03, 131.50, 129.19, 127.67, 125.00.
Example 11: Preparation of 1-(1-diazo-2-oxo-2-(N,N-diethylamine)ethyl)-1,2-benziodoxol-3(1H)-one (IIe)
(154) ##STR00029##
(155) A solution of 1-acetoxy-1,2-benziodoxol-3(1H)-one (200 mg, 0.65 mmol, 1.0 eq.) in dichloromethane 2.5 mL (0.25 M) was treated with trimethylsilyl trifluoromethanesulfonate (0.12 mL, 0.65 mmol, 1.0 eq.) at room temperature. After 10 min of stirring, a solution of pyridine (0.053 ml, 0.65 mmol, 1.0 eq) in dichloromethane (0.5 ml) was added. The resulted suspension was additionally stirred for 2 h at room temperature. 2-diazo-N,N-diethylacetamide in 0.5 mL DCM solution (107 mg, 0.76 mmol, 1.2 eq) was added and the mixture was stirred until a clear yellow solution was obtained. The solution was washed with distilled water (no vigorously shaking!) and dried with anhydrous sodium sulfate. Solvent were removed in a vacuum to afford a yellowish solid. The contained pyridine salt was removed by recrystallization (3 times) from dichloromethane during 12 hours at 30 C. Remove the solvent from the final filtrate and the product was collected as a yellow solid (68 mg, 27% yield), washed with cold diethyl ether (20 mL), dried under high vacuum and stored at 30 C.
(156) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.09 (dd, J=7.4, 1.3 Hz, 1H), 7.87-7.79 (m, 2H), 7.74 (ddd, J=7.4, 6.4, 1.7 Hz, 1H), 3.39 (q, J=7.0 Hz, 4H), 1.11 (t, J=7.0 Hz, 6H); .sup.13C NMR (101 MHz, DMSO) 166.61, 160.86, 134.61, 132.74, 131.67, 130.98, 127.45, 116.62, 42.19, 13.40.
Example 12: Preparation of 1-(1-diazo-1-ethoxysulfonylmethyl)-1,2-benziodoxol-3(1H)-one (IIf)
(157) ##STR00030##
(158) A solution of 1-acetoxy-1,2-benziodoxol-3(1H)-one (200 mg, 0.65 mmol, 1.0 eq.) in dichloromethane 2.5 mL (0.25 M) was treated with trimethylsilyl trifluoromethanesulfonate (0.12 mL, 0.65 mmol, 1.0 eq.) at room temperature. After 10 min of stirring, a solution of pyridine (0.053 ml, 0.65 mmol, 1.0 eq) in dichloromethane (0.5 ml) was added. The resulted suspension was additionally stirred for 2 h at room temperature. Ethyl diazomethanesulfonate in 0.5 mL DCM solution (114 mg, 0.76 mmol, 1.2 eq) was added and the mixture was stirred until a clear yellow solution was obtained. The solution was washed with distilled water (no vigorously shaking!) and dried with anhydrous sodium sulfate. Solvent were removed in a vacuum to afford a yellowish solid. The contained pyridine salt was removed by recrystallization (3 times) from dichloromethane during 12 hours at 30 C. Remove the solvent from the final filtrate and the product was collected as a yellow solid (79 mg, 31% yield), washed with cold diethyl ether (20 mL), dried under high vacuum and stored at 30 C.
(159) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.10 (dd, J=7.5, 1.5 Hz, 1H), 7.98-7.90 (m, 2H), 7.83-7.79 (m, 1H), 4.41 (q, J=7.0 Hz, 2H), 1.32 (t, J=7.0 Hz, 3H); .sup.13C NMR (101 MHz, DMSO) 167.42, 140.93, 135.12, 131.62, 130.94, 127.85, 126.69, 69.79, 14.89.
Example 13: Preparation of 1-(1-diazo-1-cianylmethyl)-1,3-dihydro-3,3-dimethyl-1,2-benziodoxole (IIg)
(160) ##STR00031##
(161) A solution of 1-acetoxy-1,2-benziodoxol-3(1H)-one (180 mg, 0.65 mmol, 1.0 eq.) in dichloromethane 2.5 mL (0.25 M) was treated with trimethylsilyl trifluoromethanesulfonate (0.12 mL, 0.65 mmol, 1.0 eq.) at room temperature. After 10 min of stirring, a solution of pyridine (0.053 ml, 0.65 mmol, 1.0 eq) in dichloromethane (0.5 ml) was added. The resulted suspension was additionally stirred for 2 h at room temperature. 2-Diazoacetonitrile in DCM solution (3.0 mL, 0.76 mmol, 1.2 eq) was added and the mixture was stirred until a clear yellow solution was obtained. The solution was washed with distilled water (no vigorously shaking!) and dried with anhydrous sodium sulfate. Solvent were removed in a vacuum and the residue was purified by flash chromatography (DCM:EA=5:1 as eluent) to afford a yellowish oil (38 mg, 18% yield). The product was not stable at room temperature and should be stored at 30 C.
(162) .sup.1H NMR (300 MHz, Chloroform-d) 7.65-7.51 (m, 3H), 7.37-7.30 (m, 1H), 1.50 (s, 6H); .sup.13C NMR (75 MHz, Chloroform-d) 149.06, 131.13, 130.35, 127.57, 126.39, 113.45, 111.65, 79.33, 30.68.
Example 14: Diazomethylation Reactions
(163) General Procedure A:
(164) To an oven-dried 8.0 ml tube equipped with a magnetic stir bar was added the compound of formula (I) or of formula (II) as described in Table 1 below (0.13 mmol, 1.3 equiv.), NaHCO.sub.3 (25.2 mg, 0.3 mmol, 3.0 equiv.) and Ru(bpy).sub.3(PF.sub.6).sub.2 (0.8 mg, 0.001 mmol, 0.01 equiv.). The tube was sealed with septum and degassed 3 times with Argon. The substrate of the reaction incorporating an aromatic moiety (as described in Table 1) (0.1 mmol, 1.0 equiv.) was dissolved in 0.5 ml degassed MeCN and added via a syringe, the resulting mixture was stirred under irradiation of white LED for 2 h. The reaction mixture was diluted with 3.0 ml DCM, followed by addition of 3.0 g silica gel. The solvent was removed under vacuum and the resulting solid was purified by flash chromatography (FC) on silica gel column to afford the product indicated in Table 1 below.
(165) TABLE-US-00001 TABLE 1 Compound of Yield Entry Substrate formula (I) or (II) Product (%) 1 2.sup.1 3.sup.1 p-xylene p-xylene p-xylene (Id) (IIa) (IIb)
(166) General Procedure B:
(167) To an oven-dried 8.0 ml tube equipped with a magnetic stir bar was added compound (Id) (119.2 mg, 0.2 mmol, 1.0 equiv.), NaHCO.sub.3 (50.4 mg, 0.6 mmol, 3.0 equiv.) and Ru(bpy).sub.3(PF.sub.6).sub.2 (1.6 mg, 0.002 mmol, 0.01 equiv.). The tube was sealed with septum and degassed 3 times with Argon. The substrate of the reaction incorporating an aromatic moiety (as described in Table 2) (0.4 mmol, 2.0 equiv.) was dissolved in 2.0 ml degassed acetonitrile and added via a syringe, the resulting mixture was stirred at room temperature adjacent to a 3.45 W white LED. After complete conversion of the diazomethylator reagent (usually 2 h), the reaction mixture was passed through a short plug of silica gel, washed with ethyl acetate. The solvent was removed under vacuum and the residue was purified by column chromatography to afford the product indicated in Table 2 below.
(168) TABLE-US-00002 Yield Entry Substrate Product (%) 1.sup.1
(169) General Procedure C:
(170) ##STR00099##
(171) To an oven-dried 8.0 ml tube equipped with a magnetic stir bar was added compound the compound of formula (I) as indicated in the Table 3, the base as indicated in Table 3 below and Ru(bpy).sub.3(PF.sub.6).sub.2 (1 mol %). The tube was sealed with septum and degassed 3 times with Argon. p-xylene (amount indicated in Table 3) was dissolved in 1.0 ml degassed solvent (see Table 3) and added via a syringe, the resulting mixture was stirred at room temperature adjacent to a LED. After a certain amount of time, the reaction mixture was evaporated and analyzed by .sup.1H NMR. Table 3 shows the conditions and NMR-measured yields for the diazomethylated p-xylene product.
(172) TABLE-US-00003 TABLE 3 Com- Amount Amount pound of of of Reaction formula p-xylene (I) LED time Yield (I) (equiv.) (equiv.) colour (h) Solvent Base (%) (Ih) 1 1.5 White 2 MeCN NaHCO.sub.3 46 (Ih) 1 1.5 White 2 MeCN 2,6-tBu- 41 Pyridine (Ih) 1 1.5 White 2 CH.sub.2Cl.sub.2 NaHCO.sub.3 Trace (Ih) 1 1.5 White 2 acetone NaHCO.sub.3 38 (Ih) 1 1.5 Blue 1 MeCN NaHCO.sub.3 35 (Ii) 1 1.5 White 2 MeCN NaHCO.sub.3 40 (Ih) 2 1 White 2 MeCN NaHCO.sub.3 65
PRIOR ART DISCLOSED IN THE APPLICATION
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