Processes for the preparation of heterocyclic scaffolds from alpha enaminones
11091438 · 2021-08-17
Assignee
Inventors
Cpc classification
C07D215/06
CHEMISTRY; METALLURGY
C07D413/06
CHEMISTRY; METALLURGY
C07F7/1892
CHEMISTRY; METALLURGY
C07C225/20
CHEMISTRY; METALLURGY
C07D409/06
CHEMISTRY; METALLURGY
International classification
C07D215/06
CHEMISTRY; METALLURGY
C07D409/06
CHEMISTRY; METALLURGY
C07D413/06
CHEMISTRY; METALLURGY
C07C225/20
CHEMISTRY; METALLURGY
Abstract
The present invention provides processes for the preparation of diverse heterocyclic scaffolds from alpha-enaminone building bloc of formula (I). ##STR00001##
Claims
1. A process for the preparation of a heterocyclic compound comprising the step of: ##STR00098## Wherein X is a halogen; is a single or double bond; R1-R4 are each independently selected from H, straight or branched C.sub.1-C.sub.15 alkyl, straight or branched C.sub.2-C.sub.15 alkenyl, straight or branched C.sub.2-C.sub.15 alkynyl, C.sub.5-C.sub.12 aryl, C.sub.5-C.sub.12 heteroaryl; each optionally substituted by at least one OH, amine, amide, halide, straight or branched C.sub.1-C.sub.15 alkyl, straight or branched C.sub.2-C.sub.15 alkenyl, straight or branched C.sub.2-C.sub.15 alkynyl, —O(C.sub.1-C.sub.8 akyl), —OC(═O)(C.sub.1-C.sub.8 alkyl), —C(═O)(C.sub.1-C.sub.8 alkyl), —C(═O)O(C.sub.1-C.sub.8 alkyl); C.sub.5-C.sub.12 aryl, C.sub.5-C.sub.12 heteroaryl, C.sub.3-C.sub.12 cycloalkyl, C.sub.3-C.sub.12 heterocycloalkyl; or R.sub.3 and R.sub.4 together with the atoms they are attached to form a 5 to 15 saturated, unsaturated or aromatic ring; L is H; n is an integer between 1 to 10; And wherein TABLE-US-00008 Main Product When R.sub.2 is And n is produces is/are H Greater than 1 Compound (VI) straight or branched C.sub.1-C.sub.15 alkyl, Greater than 1 Compound (IV) and straight or branched C.sub.2-C.sub.15 alkenyl, Compound (V) straight or branched C.sub.2-C.sub.15 alkynyl, 1 Compound (II) optionally substituted as above C.sub.5-C.sub.12 aryl, C.sub.5-C.sub.12 heteroaryl; Greater than 1 Compound (III) and optionally substituted as above Compound (IV) 1 Compound (II).
2. A process according to claim 1, wherein ##STR00099## Wherein R2 is H and n is greater than 1.
3. A process according to claim 1, wherein ##STR00100## Wherein R2 is straight or branched C.sub.1-C.sub.15 alkyl, straight or branched C.sub.2-C.sub.15 alkenyl, straight or branched C.sub.2-C.sub.15 alkynyl, optionally substituted as defined above and n is greater than 1.
4. A process according to claim 1, wherein ##STR00101## Wherein R.sub.2 is C.sub.5-C.sub.12 aryl, C.sub.5-C.sub.12 heteroaryl; optionally substituted as above and n is greater than 1.
5. A process according to claim 1, wherein ##STR00102## Wherein R2 is straight or branched C.sub.1-C.sub.15 alkyl, straight or branched C.sub.2-C.sub.15 alkenyl, straight or branched C.sub.2-C.sub.15 alkynyl, C.sub.5-C.sub.12 aryl, C.sub.5-C.sub.12 heteroaryl; each optionally substituted by at least one OH, amine, amide, halide, straight or branched C.sub.1-C.sub.15 alkyl, straight or branched C.sub.2-C.sub.15 alkenyl, straight or branched C.sub.2-C.sub.15 alkynyl, —O(C.sub.1-C.sub.8 akyl), —OC(═O)(C.sub.1-C.sub.8 alkyl), —C(═O)(C.sub.1-C.sub.8 alkyl), —C(═O)O(C.sub.1-C.sub.8 alkyl); C.sub.5-C.sub.12 aryl, C.sub.5-C.sub.12 heteroaryl, C.sub.3-C.sub.12 cycloalkyl, C.sub.3-C.sub.12 heterocycloalkyl; and n is 1.
6. A process according to claim 1, wherein ##STR00103## Wherein X is a halogen; is a single or double bond; R1-R4 are each independently selected from H, straight or branched C.sub.1-C.sub.15 alkyl, straight or branched C.sub.2-C.sub.15 alkenyl, straight or branched C.sub.2-C.sub.15 alkynyl, C.sub.5-C.sub.12 aryl, C.sub.5-C.sub.12 heteroaryl; each optionally substituted by at least one OH, amine, amide, halide, straight or branched C.sub.1-C.sub.15 alkyl, straight or branched C.sub.2-C.sub.15 alkenyl, straight or branched C.sub.2-C.sub.15 alkynyl, —O(C.sub.1-C.sub.8 akyl), —OC(═O)(C.sub.1-C.sub.8 alkyl), —C(═O)(C.sub.1-C.sub.8 alkyl), —C(═O)O(C.sub.1-C.sub.8 alkyl); C.sub.5-C.sub.12 aryl, C.sub.5-C.sub.12 heteroaryl, C.sub.3-C.sub.12 cycloalkyl, C.sub.3-C.sub.12 heterocycloalkyl; or R.sub.3 and R.sub.4 together with the atoms they are attached to form a 5 to 15 saturated, unsaturated or aromatic ring; L is H; n is an integer between 1 to 10; And wherein TABLE-US-00009 Main Product When R.sub.2 is And n is produces is/are H Greater than 1 Compound (XII) straight or branched C.sub.1-C.sub.15 alkyl, Greater than 1 Compound (XI) and straight or branched C.sub.2-C.sub.15 alkenyl, Compound (X) straight or branched C.sub.2-C.sub.15 alkynyl, 1 Compound (VIII) optionally substituted as above C.sub.5-C.sub.12 aryl, C.sub.5-C.sub.12 heteroaryl; Greater than 1 Compound (IX) and optionally substituted as above Compound (X) 1 Compound (VIII).
7. A process according to claim 1, wherein ##STR00104## Wherein R2 is H and n is greater than 1.
8. A process according to claim 1, wherein ##STR00105## Wherein R2 is straight or branched C.sub.1-C.sub.15 alkyl, straight or branched C.sub.2-C.sub.15 alkenyl, straight or branched C.sub.2-C.sub.15 alkynyl, optionally substituted as defined above and n is greater than 1.
9. A process according to claim 1, wherein ##STR00106## Wherein R2 is C.sub.5-C.sub.12 aryl, C.sub.5-C.sub.12 heteroaryl; optionally substituted as above and n is greater than 1.
10. A process according to claim 1, wherein ##STR00107## Wherein R2 is straight or branched C.sub.1-C.sub.15 alkyl, straight or branched C.sub.2-C.sub.15 alkenyl, straight or branched C.sub.2-C.sub.15 alkynyl, C.sub.5-C.sub.12 aryl, C.sub.5-C.sub.12 heteroaryl; each optionally substituted by at least one OH, amine, amide, halide, straight or branched C.sub.1-C.sub.15 alkyl, straight or branched C.sub.2-C.sub.15 alkenyl, straight or branched C.sub.2-C.sub.15 alkynyl, —O(C.sub.1-C.sub.8 akyl), —OC(═O)(C.sub.1-C.sub.8 alkyl), —C(═O)(C.sub.1-C.sub.8 alkyl), —C(═O)O(C.sub.1-C.sub.8 alkyl); C.sub.5-C.sub.12 aryl, C.sub.5-C.sub.12 heteroaryl, C.sub.3-C.sub.12 cycloalkyl, C.sub.3-C.sub.12 heterocycloalkyl; and n is 1.
Description
DETAILED DESCRIPTION OF EMBODIMENTS
(1) A simple building block of Type-2 was prepared (Table 1; R.sup.1=Et; see SI) and selected as the model precursor. α-Enaminone 4 was obtained by reacting 2 with 1,3-dibromopropane in the presence of K.sub.3PO.sub.4 (1.sup.st equivalent of base). Surprisingly, an unexpected direct cyclization was observed. During the preparation of 4, the alkylation of 2 with dibromopropane led to the isolation of stable bicyclic quinolinone system 3 rather than the anticipated α-enaminone. It was assumed that subsequent fast cyclization of 4 yields compound 3 as exclusive single product. Presumably, an equilibrium between 5 and 4 is established due to prevailing enamine-type
(2) TABLE-US-00003 TABLE 1 Rapid composition of Quinolinones: 1,4-addition
(3) Subsequent nucleophilic attack leads to favorable 6-membered ring 6. In the presence of a second equivalent of base, the deprotonation of 6 occurs, generating product 3. No hydrolysis of 6 was detected, and only 3 was observed, which suggests that a very fast deprotonation may have occurred. This deprotonation allows the formation of the thermodynamically favorable product while preserving its α,β-unsaturated functionality. An efficient system for the desired transformation involves a combination of 2 with 10 equivalents of 1,3-dibromopropane, 0.5 equivalents of TBAB, and 2 equivalents of K.sub.3PO.sub.4 at 100 éC in toluene (entry 10, Table 1). Control experiments were performed and demonstrated that no cyclization occurred in the absence of base. Additional experiments were conducted with various α-enaminone precursors bearing different R.sup.1 groups (Table 1) under the optimized cyclization conditions. Exclusive 1,4-selectivity was detected, which led to the generation of quinolinone scaffolds 7-10..sup.[12]
(4) An unexpected cyclization caught our attention when precursor 11 (R.sup.2≠H) was subjected to 1,2-di bromoethane (Table 2). During the preparation of α-enaminone 13, the rapid cyclization led to the unforeseen isolation of stable oxazine-12 (general structure). Surprisingly, 13 delivers two different outcomes (i.e., 12a-methylene-oxazine or 12b-benzoxazine) depending on the nature of the R.sup.2 substituent. The best system for C—O bond formation involves a combination of 11 with 2 equivalents of 1,2-dibromoethane, 0.2 equivalents of TBAB and 2 equivalents of base at 100 éC. Table 2 lists the conditions evaluated for α-enaminone integrated with the aliphatic R.sup.2 group (with DIE A as optimal base; entry 6). Then, the same set of variables was applied to the starting material, bearing an aromatic R.sup.2 residue. For this setting, K.sub.2CO.sub.3 has been determined to be the best base. It was believed that in the presence of base, the deprotonation of 13 is established (two variants are possible depending on the R.sup.2 substituent; Scheme 2). The subsequent nucleophilic attack of the oxygen, which was driven by the enone transient attitude, leads further to more favorable 6-membered ring scaffolds that bear a conjugated double bond system (i.e., 12a) or fully aromatized oxazine (i.e., 12b). Representative examples of methylene- and benzoxazines, that were synthesized through C—O bond formation, shown in the Table 2. For this transformation, compounds with a variety of R.sup.1— and R.sup.2— substituted Type-11 cores were prepared (see SI section) and subjected to the optimized conditions. It is also imperative to mention the exclusive E-selectivity was observed for cyclization products 16-19. The critical stereochemical assignment of the bicyclic targets has been confirmed by NM R analysis (see SI)..sup.[13]
(5) As shown in Table 2, the isolated yields of compounds 20-21 were significantly lower than of those of 16-19. The apparent difference between these two groups was attributed to the nature of their R.sup.2 residue. As proposed in the Table, an aromatic R.sup.2 (in the presence of base) enables formation of a stable resonance form (23) of starting precursor 22, which dramatically slows down the alkylation step towards α-enaminone 24. This result is confirmed by our ability to recover a vast amount of unreacted starting materials. In contrast, the compounds integrated with aliphatic R.sup.2 groups did not transform into the resonance form, and most likely undergo the desired alkylations to generate bicyclic products.
(6) TABLE-US-00004 TABLE 2 Annulation of α-enaminone via C—O bond formation: Synthesis of methylene- and benzoxazines.
(7) ##STR00023##
(8) With suitable access to quinolinones and oxazines in hand, the next experiment was directed to other cyclizations. The reaction scope was extended to the synthesis of more challenging heterocycles using the same precursor (11) as a starting material (Table 3A). An interesting result was observed when 11 (R.sup.2≠H) was subjected to 1,3-dibromopropane rather than 1,2-dibromo-ethane (as in the previously discussed transformation). In contrast to α-enaminones 4 (Table 1) and 13 (Table 2), the type-27 enaminones were stable (for various R.sup.1 and R.sup.2). Following the exposure of enaminone 27 to basic conditions (the optimized reaction protocol is provided in Table 4, entry 12), another unexpected and novel cyclization was detected. 1,3-addition was observed, and formation of aza-spirones (Table 3B). The derivatives of 27 were then synthesized and further subjected to the optimized cyclization conditions to generate products 32-39 (Tables 3C and 3D). Interestingly, of the two intermediates (28 and 30; Table 3B), deprotonation primarily occurs at 28 regardless of the nature of R.sup.2 group (aliphatic CH.sub.2R or Aromatic). The endo-terminated cyclizations (29) were consistently observed as the dominant products for this transformation. It was postulated that the formation of 31 (minor outcome) is suppressed due to the steric intramolecular hindrance from the R-group, and the alkylbromide chain (30; Table 3B). Enaminone 27a (integrated with the Me group as R.sup.2) was prepared and subjected to the optimized cyclization conditions (Table 3E). The ratio of endo and exo products inverts with exo 40b being a major product, which further strengthens our core assumption. Additionally, the effect of the temperature on selectivity of this reaction (1,3-addition) was investigated. Therefore, enaminone 27a (with R.sup.1 and R.sup.2 being Et groups; Scheme 2) was subjected to cyclization conditions at a lower temperature of 50 éC, utilizing NaOt-Bu as a base..sup.[14] A similar ratio for products 36a and 36b (67:18) was detected. Notwithstanding the lack of selectivity, the successful construction of azaspirones via the 1,3-cyclization of enaminone is remarkable. All pairs of exo- and endo-products were successfully separated, providing access to two conceptually different heterocycles. It should be also mentioned, that the exclusive E-selectivity observed for all exo-terminated products 35b, 36b, 37b, 38b and 39b. The critical stereochemical assignment was confirmed by NMR analysis..sup.[13]
(9) TABLE-US-00005 TABLE 3 Synthesis of Azaspirones via 1,3-addition: plausible mechanism, and the substrate scope.sup.a) A
(10) TABLE-US-00006 TABLE 4 Conditions evaluation for 1,3-addition R.sup.1 = Ph, R.sup.2 = Et (compound 17) Yield (%) # Base Solvent 12:11.sup.a) 1 K.sub.2CO.sub.3 Acetone 62:25 2 Na.sub.2CO.sub.3 Acetone 67:5 3 Cs.sub.2CO.sub.3 Acetone 17:51 4 K.sub.3PO.sub.4 Acetone 55:9 5 DIEA Acetone 74:3 6 DIEA THF 85:0 7 DIEA Toluene 76:9 8 DIEA DMF 13:0 9 DIEA 1,4-Dioxane 64:18 10 DIEA Pyridine nr 11 DIEA MeCN 43:8 .sup.a)GC yields: 0.2 mmol scale
(11) ##STR00038##
(12) To complete the picture, the inventors have executed additional cyclizations to investigate the final 1,2-addition of the α-enaminone system. The protocols designed for the radical cyclization of classical enones were followed..sup.[15] The attempts were carried out using the SmI.sub.2/HMPA system..sup.[16] Here, type-41 α-enaminones (see SI for preparation) were subjected to radical cyclization conditions to provide bicyclic quinolinols 42 or quinoline 43, however, both were obtained in low yields (Table 5). The two transformations were confirmed to undergo the desired termination, even though reduction and other side products were detected in the reaction mixtures (quinoline was obtained if R.sup.2=aromatic). Despite our goal of enhancing the outcome of this transformation by varying the temperature, solvent, concentration, amount of SmI.sub.2 or HMPA alternation, and order of reagent addition, our efforts were not successful. Nevertheless, radical reactions of 41 afforded the desired products. To the best of our knowledge, these results represent the first examples of intramolecular cyclizations that incorporate quinolinols and quinolines from a simple enaminone. In these less effective cyclizations, the formation of 42 and 43 required 4 equivalents of the Sm reagent, 10 equivalents of HMPA, and 10 equivalents of tert-butyl alcohol. Regardless of the mentioned drawbacks, the successful construction of the reported heterocycles via this type of transformation is unprecedented and unique.
(13) TABLE-US-00007 TABLE 5 Radical 1,2-cyclization: direct access to Quinolines and Quinolinols.
(14) The inventors report the unprecedented reactivity of α,β-unsaturated enaminones driven by their “dual electronic attitude”, introducing novel, stable α-enaminone synthones and discovered the unusual and novel functionalities of these building blocks. Readily available α-enaminone precursors undergo facile cyclizations under basic conditions to afford a broad spectrum of heterocycles, such as azaspirones, quinolinones, quinolines, quinolinols and oxazines. Accurate design of the starting material allows for specific and selective functionalization reactions across the unsaturated scaffold, enabling the preparation of diverse products.
(15) Experimental Section
(16) General
(17) Unless otherwise noted, all reagents were purchased from commercial suppliers and used without further purification. Solvents used in the reactions were distilled from appropriate drying agents prior to use.
(18) Reactions were monitored by thin-layer chromatography (TLC) on silica gel 60 F.sub.254 aluminium plates (Merck) and/or gas chromatography-mass spectrometry (GCMS). Visualization of compounds on TLC was accomplished by irradiation with UV light at 254 nm, iodine or vanillin stain. GCMS Analysis was performed with ‘Agilent 7820A’ gas chromatograph equipped with ‘Agilent 5975’ quadrupole mass selective detector, using Agilent HP-5MS capillary column (30 m, 0.25 mm, 0.25 μm film).
(19) Column chromatography was performed using silica gel 60 (particle size 0.040-0.063 mm) purchased from Sigma-Aldrich or aluminium oxide 90 active basic (particle size 0.063-0.200 mm) purchased from Merck.
(20) Proton and carbon NM R spectra were recorded on Varian Mercury 300 MHz or Varian Mercury 500 MHz spectrometer in deuterated solvent. Proton chemical shifts are reported in ppm (δ) relative to tetramethylsilane with the solvent resonance employed as the internal standard (CDCl.sub.3, δ 7.26 ppm). .sup.13C chemical shifts are reported in ppm from tetramethylsilane with the solvent resonance as the internal standard (CDCl.sub.3, δ 77.0 ppm). Data are reported as follows: chemical shift, multiplicity (s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet), integration and coupling constants (Hz). High resolution mass spectra were determined on a Thermo Scientific LTQ Orbitrap XL (FTMS).
(21) Infrared spectra (IR) were recorded on a Thermo Fischer Scientific NICOLET iS10 spectrometer.
(22) Unless otherwise noted, the diastereomeric ratios were calculated from GCMS analysis of the crude reaction mixture.
(23) 2. General Procedure A: Synthesis of Quinolinones (1,4-Addition)
(24) ##STR00041##
(25) To a flame-dried 15.0 mL reaction tube flushed with nitrogen, fitted with a magnetic stirring bar and rubber septum, were added imminone (1.0 equiv.), K.sub.3PO.sub.4 (2.0 equiv.), dibromopropane (10.0 equiv.), TBAB (0.5 equiv.) and molecular sieves (4{acute over (Å)}, 500 mg, 1.0 mmol) in dry toluene (0.1 M) at room temperature. The reaction mixture was refluxed at 100 éC for 16 h. The mixture was then concentrated in vacuo, and the crude mixture was purified by flash chromatography to yield the desired product.
(26) ##STR00042##
(27) 7: 1-Propyl-1,3,4,5,6,7-hexahydroquinolin-8(2H)-one General procedure A was applied. α-Iminone (1) (77 mg, 0.5 mmol) prepared according to General Procedure E, K.sub.3PO.sub.4 (212 mg, 1.0 mmol), dibromopropane (1.01 g, 5.0 mmol), TBAB (83 mg, 0.25 mmol) and molecular sieves (4 {acute over (Å)}, 250 mg) were mixed in dry toluene (5.0 mL) at room temperature. The reaction mixture was refluxed at 100 éC for 16 h. The mixture was then concentrated in vacuo and the crude product was purified by flash chromatography (Silica gel, 4/96% MeOH/DCM) to yield 7 in 78% yield (75 mg) as yellow liquid. .sup.1H NMR (300 MHz, CDCl.sub.3): δ 2.93-2.87 (m, 2H), 2.72-2.63 (m, 2H), 2.46-2.35 (m, 2H), 2.27 (t, J=6.2 Hz, 2H), 2.11 (t, J=6.6 Hz, 2H), 1.89 (p, J=6.3 Hz, 2H), 1.71-1.52 (m, 4H), 0.85 (t, J=7.4 Hz, 3H). .sup.13C NMR (75 MHz, CDCl.sub.3): δ 196.20, 141.09, 139.17, 54.61, 47.59, 39.29, 31.10, 29.74, 22.51, 21.96, 18.54, 11.49. IR (neat): 2930, 2868, 2824, 1671, 1603, 1184 cm.sup.1. HRMS (m/z) calcd. for C.sub.12H.sub.19NONa ([M+Na]+): 216.1359; found: 216.1356.
(28) ##STR00043##
(29) 8: 1-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-1,3,4,5,6,7-hexahydroquinolin-8(2H)-one General procedure A was applied. α-Iminone (2) (135 mg, 0.5 mmol) prepared according to General Procedure E, K.sub.3PO.sub.4 (212 mg, 1.0 mmol), dibromopropane (1.01 g, 5.0 mmol), TBAB (83 mg, 0.25 mmol) and molecular sieves (4 {acute over (Å)}, 250 mg) were mixed in dry toluene (5.0 mL) at room temperature. The reaction mixture was refluxed at 100 éC for 16 h. The mixture was then concentrated in vacuo and the crude product was purified by flash chromatography (Silica gel, 5/95% ether/hexane) to yield 8 in 58% yield (90 mg) as yellow liquid. .sup.1H NMR (300 MHz, CDCl.sub.3): δ 3.82 (t, J=6.7 Hz, 2H), 3.00-2.93 (m, 2H), 2.87 (t, J=6.7 Hz, 2H), 2.44-2.36 (m, 2H), 2.26 (t, J=6.2 Hz, 2H), 2.11 (t, J=6.6 Hz, 2H), 1.89 (p, J=6.3 Hz, 2H), 1.67 (p, J=6.3 Hz, 2H), 0.87 (s, 9H), 0.05 (s, 6H). .sup.13C NMR (75 MHz, CDCl.sub.3): δ 196.23, 140.74, 138.84, 62.87, 54.83, 49.31, 39.21, 31.04, 29.62, 25.94, 22.49, 18.90, −5.33. IR (neat): 2927, 2855, 1673, 1251, 1099, 832, 774 cm.sup.−1. HRMS (m/z) calcd. for C.sub.17H.sub.31NO.sub.2Si ([M+Na].sup.+): 332.2016; found: 322.2019.
(30) ##STR00044##
(31) 9: 1-Isobutyl-1,3,4,5,6,7-hexahydroquinolin-8(2H)-one General procedure A was applied. α-Iminone (3) (84 mg, 0.5 mmol) prepared according to General Procedure E, K.sub.3PO.sub.4 (212 mg, 1.0 mmol), dibromopropane (1.01 g, 5.0 mmol), TBAB (83 mg, 0.25 mmol) and molecular sieves (4{acute over (Å)}, 250 mg) were mixes in dry toluene (5 mL) at room temperature. The reaction mixture was refluxed at 100 éC for 16 h. The mixture was then concentrated in vacuo and the crude product was purified by flash chromatography (Silica gel, 20/80% ethyacetate/hexane) to yield 9 in 57% yield (59 mg) as yellow liquid. .sup.1H NM R (300 MHz, CDCl.sub.3): δ 2.95-2.86 (m, 2H), 2.56 (d, J=7.3 Hz, 2H), 2.40 (t, J=7.4 Hz, 2H), 2.27 (t, J=6.2 Hz, 2H), 2.12 (t, J=6.6 Hz, 2H), 2.02-1.84 (m, 3H), 1.73-161 (m, 2H), 0.93 (d, J=6.7 Hz, 6H). .sup.13C NMR (75 MHz, CDCl.sub.3): δ 196.14, 141.47, 138.70, 59.80, 47.64, 39.54, 31.23, 29.82, 27.69, 22.44, 20.63, 18.31. IR (neat): 2951, 2866, 2822, 1671, 1602, 1435, 1184, 1121, 978 cm.sup.−1. HRMS (m/z) calcd. for C.sub.13H.sub.21NO ([M+Na].sup.+): 230.1515; found: 230.1519.
(32) ##STR00045##
(33) 10: 1-Benzyl-1,3,4,5,6,7-hexahydroquinolin-8(2H)-one General procedure A was applied. α-Iminone (4) (101 mg, 0.5 mmol) prepared according to General Procedure E, K.sub.3PO.sub.4 (212 mg, 1.0 mmol), dibromopropane (1.01 g, 5.0 mmol), TBAB (83 mg, 0.25 mmol) and molecular sieves (4{acute over (Å)}, 250 mg) were mixed in dry toluene (5 mL) at room temperature. The reaction mixture was refluxed at 100 éC for 16 h. The mixture was then concentrated in vacuo and the crude product was purified by flash chromatography (Silica gel, 20/80% ether/hexane) to yield 10 in 54% yield (66 mg) as pale yellow solid (M.p. 86-89 éC). .sup.1H NMR (300 MHz, CDCl.sub.3): δ 7.48-7.43 (m, 2H), 7.34-7.19 (m, 3H), 3.93 (s, 2H), 2.80-2.76 (m, 2H), 2.50-2.44 (m, 2H), 2.31 (t, J=6.2 Hz, 2H), 2.12 (t, J=6.5 Hz, 2H), 1.95 (p, J=6.3 Hz, 2H), 1.67-1.57 (m, 2H). .sup.13C NMR (75 MHz, CDCl.sub.3): δ 196.13, 140.72, 140.52, 139.79, 129.05, 128.10, 126.88, 55.71, 46.54, 39.44, 31.15, 29.85, 22.51, 17.83. IR (neat): 2943, 2928, 2864, 1661, 1611, 1161, 946, 746, 702 cm.sup.−1. HRMS (m/z) calcd. for C.sub.16H.sub.19NO ([M+H].sup.+): 242.1539; found: 242.1538.
(34) 3. General Procedure B: Synthesis of Oxazines (C—O Formation)
(35) ##STR00046##
(36) To a flame-dried 15 mL reaction tube, fitted with a magnetic stirring bar and a rubber septum connected to a nitrogen source, □-iminone (1.0 equiv.), base (2.0 equiv.), TBAB (0.2 equiv.), dibromoethane (2.0 equiv.) were mixed in dry THF (0.5M) at room temperature. The reaction mixture was refluxed at 100 éC for 16 h. The mixture was then concentrated in vacuo and the crude mixture was purified by flash chromatography to yield the desired product.
(37) ##STR00047##
(38) 16: 5-Ethylidene-4-propyl-3,4,5,6,7,8-hexahydro-2H-benzo[b][1,4]oxazine General procedure B was applied. α-Iminone (5) (91 mg, 0.5 mmol) prepared according to General Procedure E, Hunig's base (130 mg, 1.0 mmol), TBAB (33 mg, 0.1 mmol) and dibromoethane (188 mg, 1.0 mmol) were mixed in dry THF (1.0 mL) at room temperature. The reaction mixture was refluxed at 100 éC for 16 h. The mixture was then concentrated in vacuo and the crude mixture was purified by flash chromatography (basic alumina, 5/95% ether/hexane) to yield 16 in 80% yield 84 mg) as yellow liquid. .sup.1H NMR (300 MHz, CDCl.sub.3): δ 5.48 (q, J=7.1 Hz, 1H), 3.97-3.90 (m, 2H), 2.94 (t, J=4.3 Hz, 2H), 2.56-2.47 (m, 2H), 2.22 (q, J=6.6 Hz, 4H), 1.62-1.74 (m, 5H), 1.54 (h, J=7.4 Hz, 2H), 0.88 (t, J=7.4 Hz, 3H). .sup.13C NMR (75 MHz, CDCl.sub.3): δ 140.03, 132.48, 122.04, 112.02, 59.48, 54.99, 45.68, 27.93, 25.28, 22.43, 21.78, 13.21, 11.49. IR (neat): 2958, 2929, 2869, 1624, 1455, 1353, 1143, 700 cm.sup.−1. HRMS (m/z) calcd. for C.sub.13H.sub.21NO ([M+H].sup.+): 208.1696; found: 208.1690.
(39) ##STR00048##
(40) 17: 4-Benzyl-5-ethylidene-3,4,5,6,7,8-hexahydro-2H benzo[b][1,4]oxazine General procedure B was applied, α-Iminone (6) (115 mg, 0.5 mmol) prepared according to General Procedure E, Hunig's base (130 mg, 1 mmol), TBAB (33 mg, 0.1 mmol) and di bromoethane (188 mg, 1.0 mmol) were mixed in dry THF (1.0 mL) at room temperature. The reaction mixture was refluxed at 100 éC for 16 h. The mixture was then concentrated in vacuo and the crude product was purified by flash chromatography (basic alumina, 5/95% ether/hexane) to yield 17 in 75% yield (95 mg) as yellow liquid. .sup.1H NMR (300 MHz, CDCl3): δ 7.43 (d, J=7.6 Hz, 2H), 7.35 (t, J=7.4 Hz, 2H), 7.31-7.23 (m, 1H), 5.70 (q, J=7.2 Hz, 1H), 3.99-3.95 (m, 2H), 3.93 (s, 2H), 2.90 (t, J=4.4 Hz, 2H), 2.30 (q, J=6.7 Hz, 4H), 1.77 (q, J=6.4 Hz, 2H), 1.69 (d, J=6.9 Hz, 3H). .sup.13C NMR (75 MHz, CDCl3): δ 140.97, 139.40, 132.24, 128.44, 127.81, 126.86, 121.35, 112.00, 59.44, 56.40, 45.75, 27.98, 25.35, 22.49, 13.30. IR (neat): 2957, 2928, 2864, 1642, 1624, 1194, 1146, 731, 696 cm.sup.−1. HRMS (m/z) calcd. for C.sub.17H.sub.21NO ([M+H].sup.+): 256.1696; found: 256.1693.
(41) ##STR00049##
(42) 18: 5-Ethylidene-4-propyl-3,4,5,6,7,8-hexahydro-2H-benzo[b][1,4]oxazine General procedure B was applied. α-Iminone (7) (149 mg, 0.5 mmol) prepared according to General Procedure E, Hunig's base (130 mg, 1.0 mmol), TBAB (33 mg, 0.1 mmol) and dibromoethane (188 mg, 1.0 mmol) were mixed in dry THF (1.0 mL) at room temperature. The reaction mixture was refluxed at 100 éC for 16 h. The mixture was then concentrated in vacuo and the crude mixture was purified by flash chromatography (basic alumina, 5/95% ether/hexane) to yield 18 in 71% yield 95 mg) as yellow liquid. .sup.1H NM R (300 MHz, CDCl3): δ 5.54 (q, J=7.2 Hz, 1H), 3.96 (t, J=4.4 Hz, 2H), 3.76 (t, J=6.3 Hz, 2H), 3.03 (t, J=4.4 Hz, 2H), 2.73 (t, J=6.4 Hz, 2H), 2.23 (q, J=6.2 Hz, 4H), 1.63-1.75 (m, 5H), 0.90 (s, 9H), 0.07 (s, 6H). .sup.13C NMR (75 MHz, CDCl3): δ 140.12, 132.35, 121.74, 112.35, 62.63, 59.67, 55.15, 47.12, 27.93, 25.94, 25.27, 22.39, 18.33, 13.21, −5.35. IR (neat): 2957, 2930, 2859, 1456, 1249, v1098, 837, 770 cm.sup.−1. HRMS (m/z) calcd. for C.sub.18H.sub.33NO.sub.2Si ([M+H].sup.+): 324.2353; found: 324.2354.
(43) ##STR00050##
(44) 19: 5-Ethylidene-4-(thiophen-2-yl methyl)-3,4,5,6,7,8-hexahydro-2H-benzo[b][1,4]oxazine General procedure B was applied. α-Iminone (8) (118 mg, 0.5 mmol) prepared according to General Procedure E, Hunig's base (130 mg, 1.0 mmol), TBAB (33 mg, 0.1 mmol) and dibromoethane (188 mg, 1.0 mmol) were mixed in dry THF (1.0 mL) at room temperature. The reaction mixture was refluxed at 100 éC for 16 h. The mixture was then concentrated in vacuo and the crude product was purified by flash chromatography (basic alumina, 5/95% ether/hexane) to yield 19 in 71% yield (93 mg) as yellow liquid. .sup.1H NM R (300 MHz, CDCl.sub.3): δ 7.27-7.22 (m, 1H), 6.99-6.91 (m, 2H), 5.77 (q, J=7.1 Hz, 1H), 4.01 (s, 2H), 3.95 (t, J=4.4 Hz, 2H), 3.00-2.92 (m, 2H), 2.36-2.23 (m, 4H), 1.82-1.67 (m, 5H). .sup.13C NMR (75 MHz, CDCl.sub.3): δ 143.73, 141.06, 132.01, 126.52, 124.84, 124.58, 120.87, 112.27, 59.56, 51.79, 45.68, 27.89, 25.30, 22.40, 13.30. IR (neat): 2955, 2928, 2858, 1455, 1246, 1094, 830, 771 cm.sup.1. HRMS (m/z) calcd. for C.sub.15H.sub.19NOS ([M+H].sup.+): 262.1260; found: 262.1251.
(45) ##STR00051##
(46) 20: 5-Phenyl-4-propyl-3,4,5,6,7,8-hexahydro-2H-benzo[b][1,4]oxazine General procedure B was applied. α-Iminone (9) (115 mg, 0.5 mmol) prepared according to General Procedure E, K.sub.2CO.sub.3 (138 mg, 1.0 mmol), TBAB (33 mg, 0.1 mmol) and dibromoethane (188 mg, 1.0 mmol) were mixed in dry THF (1.0 mL) at room temperature. The reaction mixture was refluxed at 100 éC for 16 h. The mixture was then concentrated in vacuo and the crude product was purified by flash chromatography (Silica gel, 2/98% ether/hexane) to yield 20 in 26% yield (32 mg) as yellow liquid. .sup.1H NMR (300 MHz, CDCl.sub.3): δ 7.57-7.52 (m, 2H), 7.41 (dd, J=8.2, 6.6 Hz, 2H), 7.36-7.31 (m, 1H), 6.98-6.86 (m, 2H), 6.82 (dd, J=7.1, 2.0 Hz, 1H), 4.13 (t, J=4.4 Hz, 2H), 3.17 (t, J=4.5 Hz, 2H), 2.54-2.46 (m, 2H), 1.26-1.07 (m, 1H), 0.47 (t, J=7.4 Hz, 3H). .sup.13C NMR (75 MHz, CDCl.sub.3): δ 147.71, 141.07, 136.01, 134.23, 129.09, 128.13, 126.69, 123.59, 121.90, 116.37, 60.33, 57.75, 45.65, 20.70, 11.09. IR (neat): 2964, 2860, 1580, 1461, 1433, 1240, 1006, 871, 775, 702 cm.sup.−1. HRMS (m/z) calcd. for C.sub.17H.sub.19NO ([M+H].sup.+): 276.1357; found: 276.1360.
(47) ##STR00052##
(48) 21: 5-(4-Chlorophenyl)-4-propyl-3,4,5,6,7,8-hexahydro-2H-benzo[b][1,4]oxazine General procedure B was applied. α-Iminone (10) (132 mg, 0.5 mmol) prepared according to General Procedure E, K.sub.2CO.sub.3 (138 mg, 1.0 mmol), TBAB (33 mg, 0.1 mmol) and dibromoethane (188 mg, 1.0 mmol) were mixed in dry THF (1.0 mL) at room temperature. The reaction mixture was refluxed at 100 éC for 16 h. The mixture was then concentrated in vacuo and the crude product was purified by flash chromatography (Silica gel, 2/98% Ether/hexane) to yield 21 in 17% yield (49 mg) as yellow liquid. .sup.1H NMR (300 MHz, CDCl.sub.3): δ 7.50-7.45 (m, 2H), 7.38-7.33 (m, 2H), 6.96-6.83 (m, 2H), 6.74 (dd, J=7.2, 1.9 Hz, 1H), 4.10 (t, J=4.5 Hz, 2H), 3.14 (t, J=4.5 Hz, 2H), 2.50-2.42 (m, 2H), 1.23-1.10 (m, 2H), 0.49 (t, J=7.4 Hz, 3H). .sup.13C NMR (75 MHz, CDCl.sub.3): δ 139.42, 132.50, 130.40, 128.27, 123.36, 122.13, 116.69, 60.21, 57.71, 45.40, 20.69, 11.14. IR (neat): 2964, 2930, 2860, 1580, 1461, 1433, 1240, 1134, 1006, 871, 763, 702 cm.sup.1. HRMS (m/z) calcd. for C.sub.17H.sub.18ClNO ([M+H].sup.+): 288.1150; found: 288.1152.
(49) 4. General Procedure C: Synthesis of Azaspiro-Decanones (1,3 Addition)
(50) ##STR00053##
(51) ##STR00054##
(52) To a flame-dried 15 mL reaction tube flushed with nitrogen, fitted with a magnetic stirring bar and rubber septum, were added α-enaminone (1.0 equiv., 0.5 mmol) and NaOMe (2.0 equiv., 1 mmol) in dry MeCN (1M) at o room temperature. The reaction mixture was refluxed at 100 éC for 1 h. The mixture was then concentrated in vacuo and the crude product was purified by flash chromatography to yield the desired product.
(53) ##STR00055##
(54) 32: 10-(4-Chlorophenyl)-1-propyl-1-azaspiro[4.5]dec-9-en-6-one General procedure C was applied. α-Enaminone (1) (192 mg, 0.5 mmol) prepared according to General Procedure F and NaOMe (54 mg, 1.0 mmol) were mixed in dry MeCN (0.5 mL) at room temperature. The reaction mixture was refluxed at 100 éC for 1 h. The mixture was then concentrated in vacuo and the crude product was purified by flash chromatography (Silica gel, 5/95% ether/hexane) to yield 32 in 73% yield (111 mg) as pale yellow oil. .sup.1H NM R (300 MHz, CDCl.sub.3): δ 7.52 (dd, J=6.6, 3.0 Hz, 2H), 7.27 (dd, J=4.9, 1.9 Hz, 3H), 6.13 (t, J=4.2 Hz, 1H), 3.12-3.26 (m, 1H), 2.79 (q, J=8.2 Hz, 1H), 2.56-2.57 (m, 2H), 2.56-2.36 (m, 4H), 1.88-1.77 (m, 3H), 1.69-1.39 (m, 2H), 0.84 (t, J=7.4 Hz, 3H). .sup.13C NMR (75 MHz, CDCl.sub.3): δ 213.43, 143.13, 140.98, 130.28, 129.26, 127.38, 126.86, 73.08, 51.17, 50.33, 39.51, 34.37, 24.38, 22.62, 22.50, 12.08. IR (neat): 2958, 2931, 2871, 2846, 1704, 1486, 1174, 1089, 1015, 822 cm.sup.−1. HRMS (m/z) calcd. for C.sub.18H.sub.22ClNO ([M+H].sup.+): 304.1463; found: 304.1467.
(55) ##STR00056##
(56) 33: 10-Phenyl-1-propyl-1-azaspiro[4.5]dec-9-en-6-one General procedure C was applied. α-Enaminone (2) (175 mg, 0.5 mmol) prepared o according to General Procedure F and NaOMe (54 mg, 1.0 mmol) were mixed in dry MeCN (0.5 mL) at room temperature. The reaction mixture was refluxed at 100 éC for 1 h. The mixture was then concentrated in vacuo and the crude product was purified by flash chromatography (Silica gel, 5/95% ether/hexane) to yield 33 in 72% yield (97 mg) as pale yellow oil. .sup.1H NM R (300 MHz, CDCl.sub.3): δ 7.48 (d, J=8.2 Hz, 2H), 7.23 (d, J=8.1 Hz, 2H), 6.12 (t, J=4.2 Hz, 1H), 3.18 (td, J=8.1, 2.7 Hz, 1H), 2.78 (q, J=7.4 Hz, 1H), 2.67-2.35 (m, 6H), 1.90-1.69 (m, 3H), 1.66-1.49 (m, 2H), 1.33-1.47 (m, 1H), 0.83 (t, J=7.4 Hz, 3H). .sup.13C NMR (75 MHz, CDCl.sub.3): δ 213.06, 142.08, 139.32, 132.80, 130.66, 130.55, 127.51, 72.95, 51.10, 50.32, 39.45, 34.43, 24.31, 22.59, 22.48, 12.09. IR (neat): 2957, 2930, 2846, 1704, 1442, 1174, 1075, 759, 698 cm.sup.−1. HRMS (m/z) calcd. for C.sub.18H.sub.23NO ([M+H].sup.+): 270.18524; found: 270.18506.
(57) 34: 10-Phenyl-1-(thiophen-2-yl methyl)-1-azaspiro[4.5]dec-9-en-6-one General procedure C was applied. α-Enaminone (3) (202 mg, 0.5 mmol) prepared according to General Procedure F, Cs.sub.2CO.sub.3 (326 mg, 1.0 mmol) were mixed in dry MeCN (0.5 mL) at room temperature. The reaction mixture was refluxed at 100 éC for 20 h. The mixture was then concentrated in vacuo and the crude product was purified by flash chromatography (Silica gel, 5/95% ether/hexane) to yield 34 in 75% yield (122 mg) as yellow oil. .sup.1H NMR (300 MHz, CDCl.sub.3): δ 7.62-7.54 (m, 2H), 7.40-7.28 (m, 3H), 7.16 (d, J=5.1, 1.3 Hz, 1H), 6.93-6.86 (m, 1H), 6.81 (d, J=3.4 Hz, 1H), 6.20 (t, J=4.3 Hz, 1H), 4.05-3.86 (m, 2H), 3.10-2.99 (m, 1H), 2.89 (q, J=8.0 Hz, 1H), 2.80-2.68 (m, 1H), 2.60-2.46 (m, 3H), 2.14-2.01 (m, 1H), 2.01-1.78 (m, 2H), 1.77-1.56 (m, 1H). .sup.13C NMR (75 MHz, CDCl.sub.3): δ 212.87, 144.18, 143.11, 140.60, 130.78, 129.36, 127.60, 127.06, 126.11, 125.16, 124.55, 73.17, 50.69, 48.05, 39.06, 35.21, 24.51, 22.46. IR (neat): 2958, 2845, 1704, 1444, 1169, 758, cm.sup.−1. HRMS (m/z) calcd. for C.sub.20H.sub.21NOS ([M+Na].sup.+): 346.1236; found: 346.1236.
(58) 35a (endo) and 35b (exo): General procedure C was applied. α-Enaminone (4) (178 mg, 0.5 mmol) prepared according to General Procedure F and NaOMe (54 mg, 1.0 mmol), were mixes in dry MeCN (0.5 mL) at room temperature. The reaction mixture was refluxed at 100 éC for 1 h. The mixture was then concentrated in vacuo and the crude product was purified by flash chromatography (Silica gel, 5/95% ether/hexane) to yield 54% of 35a and 5% of 35b (65 mg and 7 mg respectively).
(59) ##STR00057##
(60) 35a: 10-Ethyl-1-(thiophen-2-yl methyl)-1-azaspiro[4.5]dec-9-en-6-one pale yellow solid (M.p. 49-51 éC). .sup.1H NM R (300 MHz, CDCl.sub.3): δ 7.17 (d, J=5.0, 1.3 Hz, 1H), 6.92-6.84 (m, 2H), 5.88-5.79 (m, 1H), 3.96 (d, J=14.1 Hz, 1H), 3.72 (d, J=14.0 Hz, 1H), 3.17-3.07 (m, 1H), 2.92 (q, J=7.8 Hz, 1H), 2.72-2.58 (m, 1H), 2.44-2.30 (m, 4H), 2.24-2.11 (m, 1H), 2.06-1.94 (m, 1H), 1.90-1.78 (m, 3H), 1.12 (t, J=7.4 Hz, 3H). .sup.13C NMR (75 MHz, CDCl.sub.3): δ 213.58, 145.58, 143.87, 126.25, 124.13, 123.73, 74.04, 50.67, 47.90, 38.69, 35.37, 24.88, 22.64, 22.06, 13.25. IR (neat): 2957, 2924, 2848, 1703, 1177, 722 cm.sup.−1. HRMS (m/z) calcd. for C.sub.16H.sub.21NOS ([M+Na].sup.+): 298.1236; found: 298.1237.
(61) ##STR00058##
(62) 35b: 10-Ethylidene-1-(thiophen-2-yl methyl)-1-azaspiro[4.5]decan-6-one pale yellow solid (M.p. 53-55 éC). .sup.1H NMR (300 MHz, CDCl.sub.3): δ 7.19 (dd, J=4.8, 1.6 Hz, 1H), 6.93 (d, J=5.2 Hz, 2H), 6.07 (q, J=7.0 Hz, 1H), 4.14 (d, J=14.5 Hz, 1H), 3.72 (d, J=14.5 Hz, 1H), 3.22-3.10 (m, 1H), 2.95-2.84 (m, 1H), 2.79-2.68 (m, 1H), 2.54-2.47 (m, 2H), 2.27-2.10 (m, 2H), 1.97-1.71 (m, 3H), 1.70-1.56 (m, 5H). .sup.13C NMR (75 MHz, CDCl.sub.3): δ 213.77, 145.85, 139.23, 126.30, 124.15, 123.88, 118.49, 79.54, 50.86, 48.59, 39.93, 38.08, 25.91, 22.90, 21.66, 13.27. IR (neat): 2926, 2841, 1702, 1454, 1134, 851, 696 cm.sup.−1. HRMS (m/z) calcd. for C.sub.16H.sub.21NOS ([M+Na].sup.+): 298.1236; found: 298.1236.
(63) 36a (endo) and 36b (exo): General procedure C was applied. α-Enaminone (5) (151 mg, 0.5 mmol) prepared according to General Procedure F and NaOMe (54 mg, 1.0 mmol) were mixed in dry MeCN (0.5 mL) at room temperature. The reaction mixture was refluxed at 100 éC for 1 h. The mixture was then concentrated in vacuo and the crude product was purified by flash chromatography (Silica gel, 5/95% ether/hexane) to yield 71% of 36a and 16% of 36b (78 mg and 18 mg respectively) as pale yellow oils.
(64) ##STR00059##
(65) 36a: 10-Ethyl-1-propyl-1-azaspiro[4.5]dec-9-en-6-one 1H NMR (300 MHz, CDCl.sub.3): δ 5.81-5.72 (m, 1H), 3.20-3.08 (m, 1H), 2.84-2.73 (m, 1H), 2.60-2.46 (m, 1H), 2.45-1.91 (m, 7H), 1.90-1.69 (m, 4H), 1.54-1.19 (m, 2H), 1.03 (t, J=7.5 Hz, 3H), 0.81 (t, J=7.4 Hz, 3H). .sup.13C NMR (75 MHz, CDCl.sub.3): δ 214.52, 144.22, 123.10, 73.64, 50.66, 50.38, 39.27, 34.74, 24.35, 22.71, 22.58, 21.91, 13.18, 11.85. IR (neat): 2958, 2931, 2872, 2847, 1712, 1458, 1180, 1085 cm.sup.−1. HRMS (m/z) calcd. for C.sub.14H.sub.23NO ([M+Na].sup.+): 244.1672; found: 244.1679.
(66) ##STR00060##
(67) 36b: 10-Ethylidene-1-propyl-1-azaspiro[4.5]decan-6-one 1H NMR (300 MHz, CDCl.sub.3): δ 5.81-5.70 (m, 1H), 3.25-3.17 (m, 1H), 2.93-2.83 (m, 1H), 2.75-2.55 (m, 21H), 2.47-2.38 (m, 2H), 2.33-2.25 (m, 1H), 2.18-2.03 (m, 2H), 1.89-1.82 (m, 1H), 1.76-1.70 (m, 3H), 1.64 (d, J=6.9 Hz, 3H), 1.57-1.39 (m, 3H), 0.86 (t, J=7.4 Hz, 3H). .sup.13C NMR (75 MHz, CDCl.sub.3): δ 214.43, 139.65, 117.77, 51.71, 51.05, 40.11, 38.07, 29.69, 25.76, 22.87, 22.69, 21.61, 13.21, Me 11.97. IR (neat): 2956, 2928, 2668, 1707, 1456, 1197, 1153, 1096 cm.sup.−1. HRMS (m/z) calcd. for C.sub.14H.sub.23NO ([M+H].sup.+): 222.1852; found: 222.1855.
(68) 37a (endo) and 37b (exo): General procedure C was applied. α-Enaminone (6) (175 mg, 0.5 mmol) prepared according to General Procedure F and NaOMe (54 mg, 1.0 mmol) were mixed in dry MeCN (0.5 mL) at room temperature. The reaction mixture was refluxed at 100 éC for 1 h. The mixture was then concentrated in vacuo and the crude product was purified by flash chromatography (Silica gel, 5/95% ether/hexane) to yield 63% of 37a and 15% of 37b (85 mg and 20 mg respectively).
(69) ##STR00061##
(70) 37a: 1-Benzyl-10-ethyl-1-azaspiro[4.5]dec-9-en-6-one pale yellow solid (M.p. 52-55 éC). .sup.1H NM R (300 MHz, CDCl.sub.3): δ 7.34-7.16 (m, 5H), 5.90-5.82 (m, 1H), 3.76-3.51 (m, 2H), 3.04-2.93 (m, 1H), 2.85 (h, J=6.5 Hz, 1H), 2.73-2.57 (m, 1H), 2.49-2.28 (m, 4H), 2.25-2.14 (m, 1H), 2.05-1.76 (m, 4H), 1.11 (t, J=7.5 Hz, 3H). .sup.13C NMR (75 MHz, CDCl.sub.3): δ 213.99, 143.86, 140.54, 128.14, 128.02, 126.48, 123.77, 73.88, 52.80, 50.51, 39.03, 35.02, 24.68, 22.77, 22.09, Me 13.28. IR (neat): 2961, 2847, 1709, 1494, 1452, 1153, 733, 697 cm.sup.1. HRMS (m/z) calcd. for C.sub.18H.sub.23NO ([M+H].sup.+): 270.1852; found: 270.1857.
(71) ##STR00062##
(72) 37b: 1-Benzyl-10-ethylidene-1-azaspiro[4.5]decan-6-one pale yellow solid (M.p. 57-58 éC). .sup.1H NMR (300 MHz, CDCl.sub.3): δ 7.38 (d, J=7.0 Hz, 2H), 7.32 (t, J=7.5 Hz, 2H), 7.26-7.17 (m, 1H), 5.97 (q, J=7.0 Hz, 1H), 3.88 (d, J=14.4 Hz, 1H), 3.65 (d, J=14.6 Hz, 1H), 3.11-3.02 (m, 1H), 2.90-2.79 (m, 1H), 2.77-2.67 (m, 1H), 2.57-2.48 (m, 2H), 2.30-2.13 (m, 2H), 1.97-1.68 (m, 4H), 1.67-1.59 (m, 4H). .sup.13C NMR (75 MHz, CDCl.sub.3): δ 214.07, 140.89, 139.55, 128.14, 127.98, 126.33, 118.28, 79.69, 53.15, 50.72, 39.99, 37.69, 25.94, 22.93, 21.67, 13.28. IR (neat): 2926, 2849, 1703, 1492, 1453, 1209, 1152, 1136, 735, 697 cm.sup.−1. HRMS (m/z) calcd. for C.sub.18H.sub.23NO ([M+Na].sup.+): 292.1672; found: 292.1676.
(73) 38a (endo) and 38b (exo): General procedure C was applied. α-Enaminone (7) (209 mg, 0.5 mmol) prepared according to General Procedure F and NaOMe (54 mg, 1.0 mmol) were mixed in dry MeCN (0.5 mL) at room temperature. The reaction mixture was refluxed at 100 éC for 1 h. The mixture was then concentrated in vacuo and the crude product was purified by flash chromatography (Silica gel, 5/95% ether/hexane) to yield 60% of 38a and 3% of 38b (101 mg and 5 mg respectively) as pale yellow oils.
(74) ##STR00063##
(75) 38a: 1-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-10-ethyl-1-azaspiro[4.5]dec-9-en-6-one .sup.1H NMR (300 MHz, CDCl.sub.3): δ 5.78-5.72 (m, 1H), 3.65-3.51 (m, 2H), 3.22-3.13 (m, 1H), 2.99-2.88 (m, 1H), 2.70-2.47 (m, 3H), 2.42-2.11 (m, 4H), 2.05-1.91 (m, 1H), 1.90-1.64 (m, 4H), 1.03 (t, J=7.4 Hz, 3H), 0.87 (s, 9H), 0.02 (s, 6H). .sup.13C NMR (75 MHz, CDCl.sub.3): δ 214.05, 144.07, 123.18, 74.22, 62.67, 51.63, 51.48, 38.80, 34.77, 25.96, 24.68, 22.98, 21.89, 18.39, 12.92, −5.34. IR (neat): 2956, 2928, 2845, 1714, 1253, 1103, 832, 774 cm.sup.−1. HRMS (m/z) calcd. for C.sub.19H.sub.35NO.sub.2Si ([M+H].sup.+): 360.2329; found: 360.2329.
(76) ##STR00064##
(77) 38b: 1-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-10-ethylidene-1-azaspiro[4.5]decan-6-one .sup.1H NMR (300 MHz, CDCl.sub.3): δ 5.81 (q, J=6.4 Hz, 1H), 3.77-3.65 (m, 2H), 3.26-3.18 (m, 1H), 3.00-2.78 (m, 2H), 2.76-2.65 (m, 1H), 2.58-2.47 (m, 1H), 2.45-2.38 (m, 2H), 2.20-2.01 (m, 2H), 1.94-1.66 (m, 3H), 1.68-1.45 (m, 5H), 0.89 (s, 9H), 0.05 (s, 6H). .sup.13C NMR (75 MHz, CDCl.sub.3): δ 214.01, 139.45, 118.18, 80.14, 62.78, 52.35, 51.90, 39.98, 37.75, 25.99, 25.82, 22.94, 21.83, 18.42, 13.22, −5.27, −5.31. IR (neat): 2954, 2928, 2856, 1709, 1254, 1104, 834, 775 cm.sup.−1. HRMS (m/z) calcd. for C.sub.19H.sub.35NO.sub.2Si ([M+H].sup.+): 360.2329; found: 360.2327.
(78) 40a (exo) and 40b (endo): General procedure C was applied. α-Enaminone (8) (144 mg, 0.5 mmol) prepared according to General Procedure F and NaOMe (54 mg, 1.0 mmol) were mixed in dry MeCN (0.5 mL) at room temperature. The reaction mixture was refluxed at 100 éC for 1 h. The mixture was then concentrated in vacuo and the crude product was purified by flash chromatography (Silica gel, 5/95% ether/hexane) to yield 17% of 40a and 46% of 40b (18 mg and 48 mg respectively) as pale yellow oils.
(79) ##STR00065##
(80) 40a: 10-Methyl-1-propyl-1-azaspiro[4.5]dec-9-en-6-one 1H NM R (300 MHz, CDCl.sub.3): δ 5.82-5.71 (m, 1H), 3.21-3.09 (m, 1H), 2.88-2.78 (m, 1H), 2.61-2.50 (m, 1H), 2.48-2.37 (m, 1H), 2.38-2.21 (m, 4H), 1.99-1.72 (m, 4H), 1.71 (s, 3H), 1.55-1.28 (m, 2H), 0.84 (t, J=7.4 Hz, 3H). .sup.13C NMR (75 MHz, CDCl.sub.3): δ 214.27, 138.85, 125.69, 73.34, 50.55, 50.36, 39.34, 34.43, 24.41, 22.66, 22.59, Me 17.71, 11.90. IR (neat): 2957, 2930, 2848, 1711, 1448, 1184, 1083, 807 cm.sup.−1. HRMS (m/z) calcd. for C.sub.13H.sub.21NO ([M+H].sup.+): 208.1696; found: 208.1697.
(81) ##STR00066##
(82) 40b: 10-M ethylene-1-propyl-1-azaspiro[4.5]decan-6-one 1H NM R (300 MHz, CDCl.sub.3): δ 5.19-5.13 (m, 1H), 4.89-4.84 (m, 1H), 3.32-3.22 (m, 1H), 3.00-2.89 (m, 1H), 2.72-2.62 (m, 1H), 2.55 (dt, J=14.0, 4.3 Hz, 1H), 2.48-2.29 (m, 4H), 2.17-2.03 (m, 1H), 1.95-1.72 (m, 4H), 1.64-1.50 (m, 2H), 1.46-1.36 (m, 1H), 0.86 (t, J=7.4 Hz, 3H). .sup.13C NMR (75 MHz, CDCl.sub.3): δ 213.51, 150.10, 109.41, 79.72, 51.78, 51.22, 40.46, 38.75, 33.61, 23.56, 22.90, 21.70, 11.92. IR (neat): 2955, 2934, 2870, 2843, 1708, 1457, 1100, 1082, 905 cm.sup.−1. HRMS (m/z) calcd. for C.sub.13H.sub.21NO ([M+H].sup.+): 208.1696; found: 208.1696.
(83) 5. General procedure D: Synthesis of Quinolines and Quinolinols (1,2-addition)
(84) ##STR00067##
In a flame-dried 100 mL reaction flask flushed with nitrogen, fitted with a magnetic stirring bar and rubber septum a solution of SmI.sub.2 in THF (0.1 M, 4.0 equiv.) was added dropwise (1 mL/min) to a solution of α-enaminone (1.0 equiv, 0.5 mmol), HMPA (10.0 equiv., 5.0 mmol) and t-BuOH (10.0 equiv., 5.0 mmol) in dry TH F (0.05 M) at 0 éC. The reaction mixture was then stirred under inert atmosphere for 1 h at room temperature and quenched with aqueous saturated NH.sub.4Cl. The mixture was extracted with EtOAc, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude mixture was purified by flash chromatography to yield the desired product.
(85) ##STR00068##
(86) 44: 1-Benzyl-8-ethyl-1,3,4,5,6,7-hexahydroquinolin-4a(2H)-ol General procedure D was applied. A solution of SmI.sub.2 in THF (20.0 mL, 0.1 M, 2.0 mmol) was added dropwise to a solution of α-enaminone (9) prepared according to General Procedure G, (199 mg, 0.5 mmol), HMPA (895 mg, 5.0 mmol), and t-BuOH (370 mg, 5.0 mmol) in dry THF (10.0 mL) at 0 éC. The reaction mixture was stirred under inert atmosphere for 1 h at room temperature and quenched with aqueous saturated NH.sub.4Cl. The mixture was then dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (Silica gel, 10/90% EtOAc/hexane) to yield 44 in 43% yield (58 mg) as mixture of 2 diastereomers as yellow liquid. .sup.1H NMR (300 MHz, CDCl.sub.3): δ 7.42-7.29 (m, 4H), 7.28-7.21 (m, 1H), 4.39 (d, J=14.5 Hz, 1H), 3.83 (d, J=14.3 Hz, 1H), 2.79-2.90 (m, 1H), 2.60 (t, J=12.8, 2.9 Hz, 1H), 2.28 (q, J=7.5 Hz, 2H), 2.17-2.02 (m, 2H), 2.01-1.79 (m, 2H), 1.79-1.71 (m, 1H), 1.59-1.70 (m, 2H), 1.56-1.38 (m, 2H), 1.29-1.14 (m, 1H), 0.99 (t, J=7.6 Hz, 3H). .sup.13C NMR (75 MHz, CDCl.sub.3): δ 142.41, 140.98, 130.13, 128.28, 128.08, 126.70, 69.37, 60.26, 48.13, 39.37, 39.33, 29.28, 24.84, 18.39, 18.07, 12.79. IR (neat): 2930, 2872, 1710, 1459, 942, 734, 697 cm.sup.1. HRMS (m/z) calcd. for C.sub.18H.sub.25NONa ([M+Na].sup.+): 294.1828; found: 294.1824.
(87) ##STR00069##
(88) 45: 8-Ethyl-1-propyl-1,3,4,5,6,7-hexahydroquinolin-4a(2H)-ol: General procedure D was applied. A solution of SmI.sub.2 in THF (20 mL, 0.1 HO M, 2.0 mmol) was added dropwise to a solution of α-enaminone (10) prepared according to General Procedure G, (175 mg, 0.5 mmol), HMPA (895 mg, 5.0 mmol), and t-BuOH (370 mg, 5.0 mmol) in dry THF (10.0 mL) at 0 éC. The reaction mixture was stirred under inert atmosphere for 1 h at room temperature and quenched with aqueous saturated NH.sub.4Cl. The mixture was then dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (Basic alumina, 5/95% EtOAc/hexane) to yield 45 in 37% yield (41 mg) as mixture of 2 diastereomers as yellow liquid. .sup.1H NMR (300 MHz, CDCl.sub.3): Mixture of diastereomers: δ 3.09-2.92 (m, 2H), 2.70-2.58 (m, 2H), 2.16-2.06 (m, 3H), 2.04-1.95 (m, 2H), 1.86-1.71 (m, 2H), 1.61-1.53 (m, 2H), 1.52-1.38 (m, 4H), 1.34-1.24 (m, 2H), 0.95 (t, J=7.6 Hz, 3H), 0.87 (t, J=7.4 Hz, 3H). .sup.13C NMR (75 MHz, CDCl.sub.3): Major diastereomer: δ 142.78, 127.72, 69.31, 58.40, 49.22, 39.66, 38.90, 29.50, 25.13, 22.97, 19.59, 18.68, 12.97, 11.63. Minor diastereomer, characteristic signals: δ 79.90, 57.91, 53.66, 42.41, 34.71, 34.05, 23.57, 20.99, 19.44, 18.98, 12.12, 6.71. IR (neat): 3486, 2956, 2925, 2870, 1709, 1670, 1457, 1376, 1088 cm.sup.−1. HRMS (m/z) calcd. for C.sub.14H.sub.25NO ([M+H].sup.+): 224.2009; found: 224.2014.
(89) ##STR00070##
(90) 46: 8-(4-Chlorophenyl)-1-propyl-1,2,3,4-tetrahydroquinoline: General procedure D was applied. A solution of SmI.sub.2 in THF (20.0 mL, 0.1 M, 2.0 mmol) was added dropwise to a solution of α-enaminone (11) prepared according to General Procedure G, (216 mg, 0.5 mmol), HMPA (895 mg, 5.0 mmol), and t-BuOH (370 mg, 5.0 mmol) in dry THF (10.0 mL) at 0 éC. The reaction mixture was stirred under inert atmosphere for 1 h at room temperature and quenched with aqueous saturated NH.sub.4Cl. The mixture was then dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (Silica gel, 1/99% EtOAc/hexane) to yield 46 in 30% yield (48 mg) as yellow oil. .sup.1H NMR (300 MHz, CDCl.sub.3): δ 7.42-7.32 (m, 2H), 7.25 (d, J=8.4 Hz, 2H), 7.15-7.01 (m, 1H), 6.67-6.53 (m, 1H), 6.47 (d, J=7.5, 1.2 Hz, 1H), 3.39-3.17 (m, 4H), 2.57 (t, J=6.3 Hz, 2H), 1.84 (p, J=6.5 Hz, 1H), 1.67 (h, J=7.4 Hz, 2H), 0.97 (t, J=7.4 Hz, 3H). .sup.13C NMR (75 MHz, CDCl.sub.3): δ 145.98, 145.52, 140.93, 132.44, 130.51, 128.02, 126.58, 119.47, 116.92, 109.89, 53.71, 49.41, 26.64, 22.19, 19.54, 11.60, 1.04. IR (neat): 2951, 2925, 2870, 1714, 1582, 1484, 1459, 1199, 1085, 1017, 831, 774, 719 cm.sup.−1. HRMS (m/z) calcd. for C.sub.18H.sub.20ClN ([M+H].sup.+): 286.1357; found: 286.1365.
(91) 6. General Procedure E: Preparation of α-Iminones
(92) ##STR00071##
(93) ##STR00072##
(94) α-Iminone 1: 2-(propylamino)cyclohex-2-en-1-one General procedure E was applied. The corresponding epoxide precursor 7-oxabicyclo[4.1.0]heptan-2-one (1.0 g, 9.0 mmol) and propylamine (800 mg, 13.5 mmol) were mixed in 9.0 mL of methanol, and 3.0 mL of water. The mixture was then refluxed for 4 h. After cooling, the solvent was removed and the residue was diluted with saturated brine solution, extracted with EtOAc, dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography (Silica gel, 10/90% EtOAc/hexane) to yield the desired product in 63% yield (865 mg) as yellow liquid. .sup.1H NMR (300 MHz, CDCl.sub.3): δ 5.32 (t, J=4.7 Hz, 1H), 4.15-3.90 (m, 1H), 2.71 (t, J=7.0 Hz, 2H), 2.42-2.32 (m, 2H), 2.28 (q, J=5.6 Hz, 2H), 1.50 (h, J=7.3 Hz, 2H), 0.87 (t, J=7.4 Hz, 3H). .sup.13C NMR (75 MHz, CDCl3): δ 195.71, 140.61, 110.56, 44.93, 37.87, 24.47, 23.48, 22.08, 11.69. IR (neat): 3399, 2958, 2931, 2872, 1671, 1626, 1488, 1167, 867 cm.sup.−1. HRMS (m/z) calcd. for C.sub.9H.sub.15NO ([M+H].sup.+): 154.1226; found: 154.1228.
(95) ##STR00073##
(96) α-Iminone 2: 2-((2-((tert-butyldimethylsilyl)oxy)ethyl)amino)cyclohex-2-en-1-one General procedure E was applied. The corresponding epoxide precursor 7-oxabicyclo[4.1.0]heptan-2-one (1.0 g, 9 mmol) and 2-((tert-butyl-dimethylsilyl)oxy)ethan-1-amine (1.9 g, 10.8 mmol) were mixed in 9.0 mL of methanol, and 3.0 mL of water. The mixture was then refluxed for 4 h. After cooling, the solvent was removed and the residue was diluted with brine solution, extracted with EtOAc, dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography (Silica gel, 20/80% EtOAc/hexane) to yield the desired product in 44% yield (1.1 g) as yellow liquid. .sup.1H NM R (300 MHz, CDCl3): δ 5.43 (t, J=4.7 Hz, 1H), 4.44 (s, 1H), 3.73 (t, J=5.5 Hz, 2H), 2.92 (t, J=5.5 Hz, 2H), 2.49-2.38 (m, 2H), 2.33 (q, J=5.6 Hz, 2H), 1.91 (p, J=6.1 Hz, 2H), 0.86 (s, 9H), 0.02 (s, 6H). .sup.13C NM R (75 MHz, CDCl3): δ 195.63, 145.98, 140.64, 111.26, 61.29, 45.14, 37.92, 25.86, 24.50, 23.46, 18.26, −5.39. IR (neat): 2928, 2856, 1675, 1629, 1472, 1629, 1472, 1252, 1101, 830, 775 cm.sup.−1. HRMS (m/z) calcd. for C.sub.14H.sub.27NO.sub.2 ([M+H].sup.+): 270.1884; found: 270.1887.
(97) ##STR00074##
(98) α-Iminone 3: 2-(isobutylamino)cyclohex-2-en-1-one General procedure E was applied. The corresponding epoxide precursor 7-oxabicyclo[4.1.0]heptan-2-one (1.0 g, 9.0 mmol) and 2-methylpropan-1-amine (988 mg, 13.5 mmol) were mixed in 9.0 mL of methanol, and 3.0 mL of water. The mixture was then refluxed for 4 h. After cooling, the solvent was removed and the residue was diluted with brine solution, extracted with EtOAc, dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography (Silica gel, 8/92% ether/hexane) to yield the desired product in 74% yield (1.1 g) as light brown liquid. .sup.1H NMR (300 MHz, CDCl3): δ 5.35 (t, J=4.7 Hz, 1H), 4.15 (s, 1H), 2.64-2.55 (m, 2H), 2.46-2.37 (m, 2H), 2.32 (q, J=5.6 Hz, 2H), 1.89 (p, J=6.1 Hz, 2H), 1.81-1.72 (m, 1H), 0.89 (d, J=6.7, 6H). .sup.13C NMR (75 MHz, CDCl.sub.3): δ 195.83, 140.68, 110.49, 51.09, 37.92, 27.60, 24.50, 23.48, 20.59. IR (neat): 3403, 2953,2868, 2827, 1671, 1626, 1488, 1333, 1201, 1167, 1126, 866 cm.sup.−1. HRMS (m/z) calcd. for C.sub.10H.sub.17NO ([M+H].sup.+): 168.1383; found: 168.1388.
(99) ##STR00075##
(100) α-Iminone 4: 2-(benzylamino)cyclohex-2-en-1-one General procedure E was applied. The corresponding epoxide precursor 7-oxabicyclo[4.1.0]heptan-2-one (900 mg, 8.0 mmol) and benzylamine (1.71 g, 16.0 mmol) were mixed in 8.0 mL of methanol, and 2.3 mL of water. The mixture was then refluxed for 4 h. After cooling, the solvent was removed and the residue was diluted with saturated brine solution, extracted with EtOAc, dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography (Silica gel, 20/80% EtOAc/hexane) to yield the desired product in 32% yield (1.02 g) as pale green solid (M.p. 56-59 éC). .sup.1H NMR (300 MHz, CDCl.sub.3): δ 7.20-7.36 (m, 5H), 5.42 (t, J=4.7 Hz, 1H), 4.60 (s, 1H), 4.08 (d, J=4.3 Hz, 2H), 2.59-2.41 (m, 2H), 2.33 (q, J=5.6 Hz, 2H), 1.94 (p, J=6.3 Hz, 2H). .sup.13C NMR (75 MHz, CDCl3): δ 195.83, 140.35, 139.00, 128.50, 127.38, 127.08, 111.76, 47.55, 37.91, 24.48, 23.47. IR (neat): 3407, 2928, 1659, 1619, 1488, 1361, 1208, 742, 700 cm.sup.−1. HRMS (m/z) calcd. for C.sub.13H.sub.15NO ([M+H].sup.+): 202.1226; found: 202.1224.
(101) ##STR00076##
(102) α-Iminone 5: 3-ethyl-2-(propylamino)cyclohex-2-en-1-one General procedure E was applied. The corresponding epoxide precursor 6-Ethyl-7-oxabicyclo[4.1.0]heptan-2-one (1.42 g, 10.1 mmol) and propylamine (0.89 g, 15.2 mmol) were mixed in 10.0 mL of methanol, and 3.3 mL of water. The mixture was then refluxed for 4 h. After cooling, the solvent was removed and the residue was diluted with saturated brine solution, extracted with EtOAc, dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography (Silica gel, 10/90% EtOAc/hexane) to yield the desired product in 48% yield (880 mg) as yellow liquid. .sup.1H NMR (300 MHz, CDCl.sub.3): δ 3.69 (s, 1H), 2.64 (t, J=7.1 Hz, 2H), 2.38-2.15 (m, 6H), 1.87-1.69 (m, 2H), 1.39 (q, J=7.3 Hz, 2H), 1.01 (t, J=7.6 Hz, 3H), 0.82 (t, J=7.4 Hz, 3H). .sup.13C NMR (75 MHz, CDCl.sub.3): δ 196.63, 143.41, 139.51, 51.27, 37.09, 28.93, 26.19, 23.56, 22.11, 11.59, 11.48. IR (neat): 3337, 2960, 2874, 1662, 1625, 1486, 1168 cm.sup.−1. HRMS (m/z) calcd. for C.sub.11H.sub.19NO ([M+H].sup.+): 182.1539; found: 182.1539.
(103) ##STR00077##
(104) α-Iminone 6: 2-(benzylamino)-3-ethylcyclohex-2-en-1-one General procedure E was applied. The corresponding epoxide precursor 6-Ethyl-7-oxabicyclo[4.1.0]heptan-2-one (2.1 g, 15.0 mmol) and of benzylamine (2.4 g, 22.5 mmol) were mixed in 15.0 mL of methanol, and 5.0 mL of water. The mixture was then refluxed for 4 h. After cooling, the solvent was removed and the residue was diluted with saturated brine solution, extracted with EtOAc, dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography (Silica gel, 10/90% EtOAc/hexane) to yield the desired product in 58% yield (1.99 g) as yellow liquid. .sup.1H NMR (300 MHz, CDCl.sub.3): δ 7.30 (d, J=4.3 Hz, 4H), 7.27-7.19 (m, 1H), 4.14 (s, 1H), 3.95 (s, 2H), 2.29-2.45 (m, 7H), 1.96-1.76 (m, 2H), 1.11 (t, J=7.5 Hz, 3H). .sup.13C NMR (75 MHz, CDCl.sub.3): δ 196.96, 140.98, 138.80, 128.91, 128.10, 128.03, 127.09, 48.34, 37.20, 32.04, 23.02, 22.34, 11.28. IR (neat): 2965, 2935, 2875, 1660, 1624, 1453, 1184, 1161, 734, 697 cm.sup.−1. HRMS (m/z) calcd. for C.sub.15H.sub.19NO ([M+H].sup.+): 252.1364; found: 252.1357.
(105) ##STR00078##
(106) α-Iminone 7: 2-((2-((tert-butyldimethylsilyl)oxy)ethyl)amino)-3-ethylcyclohex-2-en-1-one General procedure E was applied. The corresponding epoxide precursor 6-ethyl-7-oxabicyclo[4.1.0]heptan-2-one (1.3 g, 9.4 mmol) and 2-((tert-butyldimethylsilyl)oxy)ethan-1-amine (2.46 g, 14.1 mmol) were mixed in 9.0 mL of methanol, and 3.0 mL of water. The mixture was then refluxed for 4 h. After cooling, the solvent was removed and the residue was diluted with saturated brine solution, extracted with EtOAc, dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography (Silica gel, 1:1 DCM/hexane) to yield the desired product in 41% yield (1.17 g) as yellow oil. .sup.1H NMR (300 MHz, CDCl.sub.3): δ 3.68 (t, J=5.6 Hz, 2H), 2.91 (t, J=5.6 Hz, 2H), 2.48-2.24 (m, 6H), 1.91 (q, J=6.3 Hz, 2H), 1.10 (t, J=7.5 Hz, 3H), 0.91 (d, J=2.2 Hz, 9H), 0.06 (d, J=2.1 Hz, 6H). 13C NMR (75 MHz, CDCl.sub.3): δ 196.41, 143.40, 139.35, 62.49, 51.01, 37.35, 29.10, 26.16, 25.89, 22.20, 18.28, 11.70, −5.36. IR (neat): 2952, 2928, 2856, 1666, 1627, 1462, 1253, 1103, 830, 774 cm.sup.−1. HRMS (m/z) calcd. for C.sub.16H.sub.31NO.sub.2Si ([M+H].sup.+): 298.2197; found: 298.2196.
(107) ##STR00079##
(108) α-Iminone 8: 3-ethyl-2-((thiophen-2-ylmethyl)amino)cyclohex-2-en-1-one General procedure E was applied. The corresponding epoxide precursor 6-ethyl-7-oxabicyclo[4.1.0]heptan-2-one (1.4 g, 10.0 mmol) and thiophen-2-ylmethanamine (1.7 g 15.0 mmol) were mixed in 10.0 mL of methanol, and 3.3 mL of water. The mixture was then refluxed for 4 h. After cooling, the solvent was removed and the residue was diluted with saturated brine solution, extracted with EtOAc, dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography (Silica gel, 60/40% DCM/hexane) to yield the desired product in 48% yield (1.13 g) as yellow liquid. .sup.1H NMR (300 MHz, CDCl.sub.3): δ 7.15 (dd, J=4.9, 1.5 Hz, 1H), 6.97-6.80 (m, 2H), 4.18 (s, 1H), 4.12 (s, 2H), 2.39 (q, J=7.0 Hz, 6H), 1.87 (p, J=6.3 Hz, 2H), 1.11 (t, J=7.6 Hz, 3H). .sup.13C NMR (75 MHz, CDCl.sub.3): δ 196.45, 145.79, 143.37, 138.63, 126.58, 124.86, 124.34, 47.72, 37.18, 29.00, 26.27, 22.07, 11.63. IR (neat): 3319, 2930, 2872, 1656, 1619, 1464, 1160, 697 cm.sup.−1. HRMS (m/z) calcd. for C.sub.13H.sub.17NOS ([M+Na].sup.+): 258.0923; found: 258.0923.
(109) ##STR00080##
(110) α-Iminone 9: 2-(propylamino)-5,6-dihydro-[1,1′-biphenyl]-3(4H)-one General procedure E was applied. The corresponding epoxide precursor 6-Phenyl-7-oxabicyclo[4.1.0]heptan-2-one (1.2 g, 6.3 mmol) and propylamine (560 mg, 9.5 mmol) were mixed in 6.0 mL of methanol, and 2.0 mL of water. The mixture was then refluxed for 4 h. After cooling, the solvent was removed and the residue was diluted with saturated brine solution, extracted with EtOAc, dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography (Silica gel, 10/90% EtOAc/hexane) to yield the desired product in 48% yield (630 mg) as yellow liquid. .sup.1H NMR (300 MHz, CDCl.sub.3): δ 7.44-7.39 (m, 2H), 7.33 (t, J=7.7 Hz, 2H), 7.26-7.19 (m, 1H), 4.27 (s, 1H), 2.67 (t, J=6.0 Hz, 2H), 2.58-2.46 (m, 2H), 2.32 (t, J=7.0 Hz, 2H), 2.03 (q, J=6.4 Hz, 2H), 1.27 (h, J=7.2 Hz, 2H), 0.69 (t, J=7.4 Hz, 3H). .sup.13C NMR (75 MHz, CDCl.sub.3): δ 196.96, 140.97, 138.80, 128.89, 128.12, 128.04, 127.10, 48.34, 37.20, 32.04, 23.02, 22.34, 11.31. IR (neat): 3341, 2956, 2920, 2859, 1660, 1468, 1328, 1187, 1128, 765, 670 cm.sup.−1. HRMS (m/z) calcd. for C.sub.15H.sub.19NO ([M+H].sup.+): 230.1538; found: 230.1539.
(111) ##STR00081##
(112) α-Iminone 10: 4′-chloro-2-(propylamino)-5,6-dihydro-[1,1′-biphenyl]-3(4H)-one General procedure E was applied. The corresponding epoxide precursor 6-(4-chlorophenyl)-7-oxabicyclo[4.1.0]heptan-2-one (1.59 g, 7.15 mmol) and propylamine (610 mg, 10.7 mmol) in 7.5 mL of methanol, and 2.5 mL of water. The mixture was then refluxed for 4 h. After cooling, the solvent was removed and the residue was diluted with saturated brine solution, extracted with EtOAc, dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography (Silica gel, 10/90% EtOAc/hexane) to yield the desired product in 66% yield (1.24 g) as orange paste. .sup.1H NMR (300 MHz, CDCl.sub.3): δ 7.37 (d, J=8.6 Hz, 2H), 7.33-7.25 (m, 2H), 4.28 (s, 1H), 2.64 (t, J=6.0 Hz, 2H), 2.57-2.44 (m, 2H), 2.32 (t, J=6.9 Hz, 2H), 2.01 (p, J=6.4 Hz, 2H), 1.28 (h, J=7.1 Hz, 2H), 0.71 (t, J=7.4 Hz, 3H). .sup.13C NMR (75 MHz, CDCl.sub.3): δ 196.76, 139.35, 139.10, 132.58, 129.50, 128.26, 126.75, 48.54, 37.06, 31.69, 23.05, 22.16, 11.32. IR (neat): 3351, 2956, 2927, 2873, 1662, 1608, 1488, 1191, 1091, 1016, 217, 691 cm.sup.−1. HRMS (m/z) calcd. for C.sub.15H.sub.18ClNO ([M+Na].sup.+): 286.0969; found: 286.0981.
(113) ##STR00082##
(114) α-Iminone 11: 2-(cyclopropylamino)cyclohex-2-en-1-one General procedure E was applied. The corresponding epoxide precursor 7-oxabicyclo[4.1.0]heptan-2-one (1.12 g, 10.0 mmol) and propylamine (885 mg, 15.0 mmol) were mixed in 10.0 mL of methanol, and 3.3 mL of water. The mixture was then refluxed for 4 h. After cooling, the solvent was removed and the residue was diluted with brine solution, extracted with EtOAc, dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography (Silica gel, 5/95% EtOAc/hexane) to yield 2-(cyclopropylamino)cyclohex-2-en-1-one in 80% yield (1.2 g) as yellow liquid. .sup.1H NMR (300 MHz, CDCl.sub.3): δ 5.83 (t, J=4.7 Hz, 1H), 4.46 (s, 1H), 2.46-2.32 (m, 4H), 2.12-2.03 (m, 1H), 1.92 (p, J=6.2 Hz, 2H), 0.61-0.52 (m, 2H), 0.40-0.31 (m, 2H). .sup.13C NMR (75 MHz, CDCl.sub.3): δ 195.83, 140.97, 113.19, 37.86, 24.54, 24.27, 23.52, 6.53. IR (neat): 3394, 2940, 2839, 1672, 1630, 1481, 1379 cm.sup.−1. HRMS (m/z) calcd. for C.sub.9H.sub.13NO ([M+H].sup.+): 152.1070; found: 152.1070.
(115) 7. General Procedure F: Synthesis of Stable α-Enaminones
(116) ##STR00083##
(117) ##STR00084##
(118) α-Enaminone 1: 2-((3-bromopropyl)(propyl)amino)-4′-chloro-5,6-dihydro-[1,1′-biphenyl]-3(4H)-one General procedure F was applied. α-Iminone (10) (1.0 g, 3.8 mmol) prepared according to General Procedure E, anhydrous K.sub.2CO.sub.3 (1.05 g, 7.6 mmol), dibromopropane (7.6 g, 38.0 mmol) were mixed in THF (4.0 mL). The resultant mixture was refluxed for 16 h. After cooling, the reaction mixture was filtered and concentrated in vacuo. The crude mixture was purified by flash chromatography (Silica gel, 8/92% EtOAc/hexane) to yield the desired product in 54% yield (800 mg) as yellow liquid .sup.1H NMR (300 MHz, CDCl.sub.3): δ 7.33 (d, J=8.3 Hz, 2H), 7.24 (d, J=8.3 Hz, 2H), 3.11 (t, J=6.6 Hz, 2H), 2.80 (t, J=6.7 Hz, 2H), 2.61-2.73 (m, 4H), 2.51 (t, 2H), 2.04 (p, J=6.5 Hz, 2H), 1.72 (p, J=6.7 Hz, 2H), 1.35-1.14 (m, 2H), 0.72 (t, J=7.4 Hz, 3H). .sup.13C NM R (75 MHz, CDCl3): δ 199.29, 151.65, 142.34, 139.11, 133.49, 129.10, 128.12, 55.47, 51.27, 39.63, 32.69, 32.06, 31.84, 22.39, 21.75, 11.60. IR (neat): 2956, 2930, 2869, 1670, 1489, 1091, 1016, 823, 699 cm.sup.−1. HRMS (m/z) calcd. for C.sub.18H.sub.23BrClNO ([M+Na].sup.+): 408.0524; found: 408.0523.
(119) ##STR00085##
(120) α-Enaminone 2: 2-((3-bromopropyl)(propyl)amino)-5,6-dihydro-[1,1′-biphenyl]-3(4H)-one General procedure F was applied. α-Iminone (9) (600 mg, 2.62 mmol) prepared according to General Procedure E, anhydrous K.sub.2CO.sub.3 (725 mg, 5.24 mmol), dibromopropane (5.3 g, 26.0 mmol) were mixed in THF (2.6 mL). The resultant mixture was refluxed for 16 h. After cooling, the reaction mixture was filtered and concentrated in vacuo. The crude mixture was purified by flash chromatography (Silica gel, 20/80% Ether/hexane) to yield the desired product in 81% yield (730 mg) as yellow oil. .sup.1H NM R (300 MHz, CDCl.sub.3): δ 7.43-7.17 (m, 5H), 3.01 (t, J=6.6 Hz, 2H), 2.78 (t, J=6.6 Hz, 2H), 2.69 (td, J=6.8, 6.1, 3.9 Hz, 4H), 2.50 (dd, J=7.5, 5.9 Hz, 2H), 2.08-1.98 (m, 2H), 1.69 (p, J=6.6 Hz, 2H), 1.30-1.23 (m, 2H), 0.71 (t, J=7.3 Hz, 3H). .sup.13C NMR (75 MHz, CDCl.sub.3): δ 199.51, 153.62, 142.02, 140.75, 127.88, 127.59, 55.66, 51.18, 39.69, 32.97, 32.21, 31.95, 22.49, 21.76, 11.61. IR (neat): 2955, 2927, 2869, 1667, 1449, 1180, 1116, 753, 697 cm.sup.−1. HRMS (m/z) calcd. for C.sub.18H.sub.24BrNO ([M+Na].sup.+): 372.0933; found: 372.0931.
(121) ##STR00086##
(122) α-Enaminone 13: 2-((3-bromopropyl)(thiophen-2-ylmethyl)amino)-5,6-dihydro-[1,1′-biphenyl]-3(4H)-one General procedure F was applied. The corresponding α-iminone 2-((thiophen-2-ylmethyl)amino)-5,6-dihydro-[1,1′-biphenyl]-3(4H)-one (982 mg, 3.47 mmol), anhydrous K.sub.2CO.sub.3 (994 mg, 6.94 mmol), dibromopropane (7 g, 34.7 mmol) were mixed in THF (3.5 mL). The resultant mixture was refluxed for 16 h. After cooling, the reaction mixture was filtered and concentrated in vacuo. The crude mixture was purified by flash chromatography (Silica gel, 1:1 DCM/hexane) to yield the desired product in 16% yield (218 mg) as pale yellow solid (M.p. 72-75 éC). .sup.1H NM R (300 MHz, CDCl.sub.3): δ 7.43-7.29 (m, 3H), 7.22-7.12 (m, 3H), 6.90-6.82 (m, 1H), 6.81-6.76 (m, 1H), 4.24 (s, 2H), 2.90 (t, J=6.9 Hz, 2H), 2.79 (t, J=6.5 Hz, 2H), 2.71 (t, J=6.0 Hz, 2H), 2.59-2.51 (m, 2H), 2.06 (p, J=6.2 Hz, 2H), 1.64 (p, J=6.8 Hz, 3H). .sup.13C NMR (75 MHz, CDCl.sub.3): δ 199.27, 155.96, 143.19, 141.11, 140.27, 128.14, 127.93, 127.47, 126.15, 124.95, 53.01, 50.10, 39.66, 33.20, 32.05, 31.86, 22.41. IR (neat): 2951, 2926, 2850, 1662, 1610, 1211, 755, 698 cm.sup.−1.
(123) ##STR00087##
(124) α-Enaminone 4: 2-((3-bromopropyl)(thiophen-2-ylmethyl)amino)-3-ethylcyclohex-2-en-1-one General procedure F was applied. α-Iminone (8) (705 mg, 3.0 mmol) prepared according to General Procedure E, anhydrous K.sub.2CO.sub.3 (830 mg, 6.0 mmol), dibromopropane (6.1 g, 30.0 mmol) were mixed in THF (3.0 mL). The resultant mixture was refluxed for 16 h. After cooling, the reaction mixture was filtered and concentrated in vacuo. The crude mixture was purified by flash chromatography (Silica gel, 10/90% EtOAc/hexane) to yield the desired product in 50% yield (543 mg) as yellow oil. .sup.1H NM R (300 MHz, CDCl.sub.3): δ 7.17 (dd, J=5.1, 1.3 Hz, 1H), 6.85-6.91 (m, 1H), 6.91-6.80 (m, 1H), 4.19 (s, 2H), 3.35 (t, J=6.9 Hz, 2H), 3.01 (t, J=7.0 Hz, 2H), 2.51 (q, J=9.5, 8.6 Hz, 2H), 2.36 (dt, J=8.9, 6.4 Hz, 4H), 1.86 (dp, J=13.9, 6.7 Hz, 4H), 0.97 (t, J=7.6 Hz, 3H). .sup.13C NMR (75 MHz, CDCl.sub.3): δ 198.33, 164.15, 144.40, 140.48, 126.29, 125.57, 124.64, 53.63, 51.27, 39.63, 32.43, 31.81, 29.33, 26.44, 22.33, 11.96. IR (neat): 2924, 2861, 1667, 1129, 910, 729, 702 cm.sup.−1. HRMS (m/z) calcd. for C.sub.16H.sub.22BrNOS ([M+Na].sup.+): 378.0498; found: 378.0495.
(125) ##STR00088##
(126) α-Enaminone 5: 2-((3-bromopropyl)(propyl)amino)-3-ethylcyclohex-2-en-1-one General procedure F was applied. α-Iminone (5) (740 mg, 4.0 mmol) prepared according to General Procedure E, anhydrous K.sub.2CO.sub.3 (1.1 g, 8.0 mmol), dibromopropane (8.28 g, 40.0 mmol) were mixed in T H F (4.0 mL). The resultant mixture was refluxed for 16 h. After cooling, the reaction mixture was filtered and concentrated in vacuo. The crude mixture was purified by flash chromatography (Silica gel, 10/90% ether/hexane) to yield the desired product in 69% yield (857 mg) as yellow oil. .sup.1H NM R (300 MHz, CDCl.sub.3): δ 3.39 (t, J=6.8 Hz, 2H), 2.94 (t, J=6.9 Hz, 2H), 2.79-2.67 (m, 2H), 2.49 (q, J=7.6 Hz, 2H), 2.29-2.40 (m, 4H), 1.85 (dp, J=13.6, 6.5 Hz, 4H), 1.28 (dq, J=15.4, 7.7 Hz, 2H), 1.01 (t, J=7.6 Hz, 3H), 0.80 (t, J=7.3 Hz, 3H). .sup.13C NMR (75 MHz, CDCl.sub.3): δ 198.37, 162.82, 141.08, 56.40, 52.25, 39.79, 32.62, 32.09, 29.24, 26.19, 22.44, 22.41, 11.95, 11.79. IR (neat): 2957, 2933, 2870, 1667, 1611, 1457, 1218, 1117, 776 cm.sup.−1. HRMS (m/z) calcd. for C.sub.14H.sub.24BrNO ([M+H].sup.+): 302.1114; found: 302.1113.
(127) ##STR00089##
(128) α-Enaminone 6: 2-(benzyl(3-bromopropyl)amino)-3-ethylcyclohex-2-en-1-one General procedure F was applied. α-Iminone (6) (1.2 g, 5.24 mmol) prepared according to General Procedure E, o anhydrous K.sub.2CO.sub.3 (1.45 g, 10.48 mmol), dibromopropane (10.6 g, 52.0 mmol) were mixed in THF (5.0 mL). The resultant mixture was refluxed for 16 h. After cooling, the reaction mixture was filtered and concentrated in vacuo. The crude mixture was purified by flash chromatography (Silica gel, 15/85% ether/hexane) to yield enaminone in 70% yield (1.26 g) as yellow oil. .sup.1H NMR (300 MHz, CDCl.sub.3): δ 7.36-7.13 (m, 5H), 4.00 (s, 2H), 3.35 (t, J=6.9 Hz, 2H), 3.01 (t, J=7.0 Hz, 2H), 2.32-2.45 (m, 4H), 2.27 (t, J=6.1 Hz, 2H), 1.92-1.77 (m, 4H), 0.85 (t, J=7.6 Hz, 3H). .sup.13C NMR (75 MHz, CDCl.sub.3): δ 198.50, 163.57, 140.47, 139.93, 129.12, 128.01, 126.77, 58.64, 51.81, 39.73, 32.46, 31.81, 29.19, 26.22, 22.31, 11.66. IR (neat): 2959, 2935, 2863, 1664, 1610, 1453, 1130, 728, 699 cm.sup.−1. HRMS (m/z) calcd. for C.sub.18H.sub.24BrNO ([M+Na].sup.+): 372.0934; found: 372.0940.
(129) ##STR00090##
(130) α-Enaminone 7: 2-((3-bromopropyl)(2-((tert-butyldimethylsilyl)oxy)ethyl)amino)-3-ethyl-cyclohex-2-en-1-one General procedure F was applied. α-Iminone (7) (1.17 g, 3.84 mmol) prepared according to General Procedure E, anhydrous K.sub.2CO.sub.3 (1.06 g, 7.7 mmol), dibromopropane (7.95 g, 38.4 mmol) and THF (4.0 mL). The resultant mixture was refluxed for 16 h. After cooling, the reaction mixture was filtered and concentrated in vacuo. The crude mixture was purified by flash chromatography (Silica gel, 10/90% ether/hexane) to yield enaminone in 83% yield (946 mg) as pale yellow liquid. .sup.1H NMR (300 MHz, CDCl.sub.3): δ 3.52 (t, J=6.4 Hz, 2H), 3.45 (t, J=6.7 Hz, 2H), 2.96 (dt, J=19.0, 6.6 Hz, 4H), 2.54 (q, J=7.7 Hz, 2H), 2.38 (t, J=6.4 Hz, 4H), 1.88 (dp, J=13.7, 6.6 Hz, 4H), 1.04 (t, J=7.6 Hz, 3H), 0.87 (s, 9H), 0.03 (s, 6H). .sup.13C NMR (75 MHz, CDCl.sub.3): δ 198.14, 162.96, 141.38, 62.27, 56.84, 52.64, 39.68, 32.77, 32.07, 29.22, 26.13, 25.92, 22.40, 18.29, 11.99, −5.31. IR (neat): 2952, 2928, 2855, 1670, 1462, 1255, 1099, 939, 832, 774 cm.sup.−1. HRMS (m/z) calcd. for C.sub.19H.sub.36BrNO.sub.2SiNa ([M+Na].sup.+): 252.1466; found: 252.1357.
(131) ##STR00091##
(132) α-Enaminone 8: 2-((3-bromopropyl)(propyl)amino)-4′-chloro-5,6-dihydro-[1,1′-biphenyl]-3(4H)-one General procedure F was applied. The corresponding α-iminone 3-methyl-2-(propylamino)cyclohex-2-en-1-one (330 mg, 1.98 mmol), anhydrous K.sub.2CO.sub.3 (545 mg, 3.96 mmol), dibromopropane (3.87, 19.8 mmol) were mixed in T H F (2.0 mL). The resultant mixture was refluxed for 16 h. After cooling, the reaction mixture was filtered and concentrated in vacuo. The crude product was purified by flash chromatography (Silica gel, 10/90% EtOAc/hexane) to yield enaminone in 79% yield (448 mg) as yellow oil. .sup.1H NM R (300 MHz, CDCl.sub.3): δ 3.42 (t, J=6.8 Hz, 2H), 2.97 (t, J=6.8 Hz, 2H), 2.76 (t, J=7.6 Hz, 2H), 2.44-2.34 (m, 4H), 1.99 (s, 3H), 1.92-179 (m, 4H), 1.30 (h, J=7.8 Hz, 2H), 0.81 (t, J=7.4 Hz, 3H). .sup.13C NMR (75 MHz, CDCl.sub.3): δ 198.11, 157.72, 141.68, 56.19, 52.02, 39.76, 32.46, 32.37, 32.19, 22.29, 22.21, 20.51, 11.84. IR (neat): 2930, 2869, 1667, 1429, 1252, 1219, 1121 cm.sup.−1. HRMS (m/z) calcd. for C.sub.13H.sub.22BrNO ([M+Na].sup.+): 310.0777; found: 310.0776.
(133) 8. General Procedure G:
(134) ##STR00092##
(135) ##STR00093##
(136) α-Enaminone 9: 2-(benzyl(3-iodopropyl)amino)-3-ethylcyclohex-2-en-1-one General procedure G was applied. α-Enaminone (6) (1.05 g, 3.0 mmol) prepared according to General Procedure F and NaI (2.25 g, 15.0 mmol) were dissolved in acetone (6.0 mL). The solution was stirred for 3 h at room temperature. The suspension was filtered and the filtrate was concentrated in vacuo. The crude mixture was purified by flash chromatography (Silica gel, 15/85% ether/hexane) to yield iodo-enaminone in 89% yield (1.06 g) as yellow liquid .sup.1H NMR (300 MHz, CDCl.sub.3): δ 7.31-7.13 (m, 5H), 4.00 (s, 2H), 3.12 (t, J=7.1 Hz, 2H), 2.97 (t, J=7.0 Hz, 2H), 2.39 (dt, J=16.5, 7.3 Hz, 4H), 2.28 (t, J=6.1 Hz, 2H), 1.93-1.72 (m, 4H), 0.86 (t, J=7.7 Hz, 3H). .sup.13C NMR δ 198.49, 163.55, 140.50, 139.94, 129.14, 128.03, 126.79, 58.71, 53.82, 39.74, 33.31, 29.20, 26.24, 22.33, 11.72, 4.55. IR (neat): 2935, 2863, 1664, 1453, 1193, 1131, 728, 699 cm.sup.−1. HRMS (m/z) calcd. for C.sub.18H.sub.24INO ([M+Na].sup.+): 420.0795; found: 420.0794.
(137) ##STR00094##
(138) α-Enaminone 10: 2-((3-iodopropyl)(propyl)amino)-3-ethylcyclohex-2-en-1-one General procedure G was applied, α-Enaminone (5) (602 mg, 2.0 mmol) prepared according to General Procedure F and NaI (1.50 g, 10.0 mmol) were dissolved in acetone (4.0 mL). The solution was stirred for 3 h at room temperature. The suspension was filtered and the filtrate was concentrated in vacuo. The crude mixture was purified by flash chromatography (Silica gel, 10/90% ether/hexane) to yield iodo-enaminone in 94% yield (660 mg) as yellow liquid. .sup.1H NMR (300 MHz, CDCl.sub.3): δ 3.15 (t, J=7.0 Hz, 2H), 2.88 (t, J=6.9 Hz, 2H), 2.73 (t, J=8.7, 6.7 Hz, 2H), 2.49 (q, J=7.6 Hz, 2H), 2.38-2.30 (m, 4H), 1.93-1.75 (m, 4H), 1.28 (h, J=7.8 Hz, 2H), 1.01 (t, J=7.6 Hz, 3H), 0.79 (t, J=7.3 Hz, 3H). .sup.13C NM R (75 MHz, CDCl.sub.3): δ 198.36, 162.76, 141.11, 56.50, 54.29, 39.78, 33.43, 29.24, 26.20, 22.46, 22.42, 12.00, 11.80, 4.99. IR (neat): 2956, 2932, 2870, 1667, 1456, 1200, 1172, 1115 cm.sup.−1. HRMS (m/z) calcd. for C.sub.14H.sub.24INONa ([M+Na].sup.+): 372.0794; found: 372.0795.
(139) ##STR00095##
(140) α-Enaminone 11: 2-((3-iodopropyl)(propyl)amino)-4′-chloro-5,6-dihydro-[1,1′-biphenyl]-3(4H)-one General procedure G was applied. α-Enaminone (1) (260 mg, 0.67 mmol) prepared according to General Procedure F and NaI (500 mg, 3.35 mmol) were dissolved in acetone (1.4 mL). The solution was stirred for 3 h at room temperature. The suspension was filtered and the filtrate was concentrated in vacuo. The crude mixture was purified by flash chromatography (Silica gel, 5/95% ether/hexane) to yield 2-((3-iodopropyl)(propyl)amino)-4′-chloro-5,6-dihydro-[1,1′-biphenyl]-3(4H)-one in 93% yield (269 mg) as yellow oil. .sup.1H NMR (300 MHz, CDCl.sub.3): δ 7.35 (d, J=8.7 Hz, 2H), 7.29-7.22 (m, 2H), 2.90 (t, J=6.8 Hz, 2H), 2.78-2.63 (m, 5H), 2.55-2.49 (m, 2H), 2.05 (p, J=6.3 Hz, 2H), 1.70 (p, J=6.8 Hz, 2H), 1.37-1.21 (m, 3H), 0.73 (t, J=7.4 Hz, 3H). .sup.13C NMR (75 MHz, CDCl.sub.3): δ 199.30, 151.34, 142.39, 139.11, 133.50, 129.10, 128.16, 55.49, 53.33, 39.63, 32.67, 22.39, 21.80, 11.61, 5.14. IR (neat): 2955, 2929, 2666, 1670, 1489, 1201, 1090, 822, 731 cm.sup.−1. HRMS (m/z) calcd. for C.sub.18H.sub.23ClNO ([M+Na].sup.+): 454.0405; found: 454.0407.
(141) Dimerization of α-Enaminone Precursor: Access to Carbazoledione
(142) ##STR00096##
9-propyl-3,4,5,6,7,9-hexahydro-1H-carbazole-1,8-(2H)-dione
(143) 2-(propylamino)cyclohex-2-en-1-one 1 (0.9 g, 5.9 mmol, 1 equiv.) and Cs.sub.2CO.sub.3 (0.59 g, 1.8 mmol, 2 equiv.) were mixed in 10.0 mL of dry methanol. The mixture was then refluxed at 80° C. for 24 h. After cooling, the solvent was removed and the residue was diluted with saturated brine solution, extracted with EtOAc, dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography (Silica gel, 10% ether/hexane) to yield 2 in 30% yield (220 mg) as colorless crystals. .sup.1H NM R (300 MHz, Chloroform-d) δ 4.76-4.64 (m, 1H), 2.63 (t, J=6.1 Hz, 2H), 2.59-2.48 (m, 2H), 2.07 (h, J=6.3, 5.8 Hz, 2H), 1.77-1.58 (m, 1H), 0.88 (t, J=7.4 Hz, 1H). .sup.13C NMR (75 MHz, cdcl3) δ 191.41, 131.56, 129.79, 47.97, 40.44, 24.72, 24.25, 21.77, 10.89.
(144) Direct Synthesis of Dibenzoazepines from α-Enaminones
(145) ##STR00097##
(146) Starting enaminone 1 (70 mg, 0.2 mmol, 1 equiv.) and K.sub.2CO.sub.3 (80 mg, 0.6 mmol, 3 equiv.) were mixed in 0.5 mL of dry THF. The mixture was then refluxed at 80° C. for 18 h. After cooling, the solvent was removed and the residue was purified by flash chromatography (Silica gel, 10% ether/hexane) to yield 2. .sup.1H NMR (300 MHz, Chloroform-d) δ 8.15 (d, J=10.9 Hz, 1H), 7.94 (s, 1H), 7.40 (d, J=8.4 Hz, 1H), 5.71 (s, 1H), 5.27 (s, 1H), 4.20 (s, 2H), 2.70 (t, J=6.2 Hz, 2H), 2.63-2.56 (m, 2H), 2.51-2.44 (m, 2H), 1.99 (p, J=6.4 Hz, 2H), 1.55 (h, J=7.4 Hz, 2H), 0.80 (t, J=7.4 Hz, 3H).