DOI:
10.1039/C5RA01107H
(Paper)
RSC Adv., 2015,
5, 38075-38084
Lewis acid catalyzed C-3 alkylidenecyclopentenylation of indoles: an easy access to functionalized indoles and bisindoles†
Received
19th January 2015
, Accepted 16th March 2015
First published on 16th March 2015
Abstract
A Lewis acid catalyzed C-3 alkylidenecylopentenylation of indoles through the ring opening of pentafulvene derived diazabicyclic olefins has been developed. The present protocol offers an efficient route toward the synthesis of indole and bisindole derivatives. The role of the hydrazine group, as a reaction carrier in the strategy has also been demonstrated by the stepwise synthesis of functionalized bisindole.
Indole, an important nitrogen containing heterocyclic scaffold, is one of the primary building blocks of many natural products, biologically active molecules and functional materials.1 Moreover, indole is the key component in many pharmaceutical agents such as triptan and its derivatives, a class of psychoactive drugs used in the treatment of 5HT receptor related disorders (Fig. 1).2 Owing to the great prevalence of the indole nucleus, enormous research effort has been devoted towards the synthesis and functionalization, especially at the C-3 position, of this privileged core.3 Various synthetic methodologies, involving Lewis and Brønsted acids, organocatalysts or transition metal catalysts, have been developed by different research groups for the selective C-3 functionalization of indoles.4 In 2001, Kobayashi et al. achieved the C-3 cyclopentenylation of indoles through a Lewis acid/surfactant catalyzed Friedel–Crafts type conjugate addition in aqueous medium.5 Later, King and coworkers explored the Lewis acid catalyzed Michael addition of indoles to cyclopent-2-enone for the preparation of 3-cis-(3-aminocyclopentenyl)indoles as potent inhibitors of hSERT.6 Among indole derivatives, bisindole moieties are present in several natural alkaloids7 and many of these compounds show promising medicinal properties (Fig. 1).8 So the design and development of new atom economic methods for construction of bisindole derivatives remains as a highly demanding strategy in organic synthesis. Herein, we disclose a Lewis acid catalyzed ring-opening of pentafulvene derived bicyclic olefins with N-alkyl as well as free (NH) indoles toward the efficient synthesis of mono and bisindolyl functionalized alkylidenecyclopentenes.
![image file: c5ra01107h-f1.tif](/image/article/2015/RA/c5ra01107h/c5ra01107h-f1.gif) |
| Fig. 1 Bioactive compounds with indole or bisindole scaffolds. | |
In various cycloaddition reactions, pentafulvenes, a cyclic cross conjugated system, have been well explored as a 2π, 4π or 6π component for the construction of numerous biologically relevant molecules.9 Additionally, desymmetrization of diazabicyclic olefins under transition metal catalysis or acid catalysis has been developed as an efficient protocol by several research groups,10 including our laboratory for the synthesis of highly functionalized cyclopentene derivatives.11
As part of our continuous interest in the chemistry of strained norbornene derivatives, we have utilized diazabicyclic olefins derived from different pentafulvenes as a simple precursor for the synthesis of substituted alkylidenecyclopentenes and complex heterocyclic scaffolds in the presence of a palladium catalyst or Lewis acid. In our previous report we have demonstrated a Lewis acid catalyzed ring-opening of pentafulvene derived diazabicyclic olefins using various ortho-functionalized aryl iodides such as 2-iodoanilines, 2-iodophenols and 2-iodobenzene thiols and aliphatic alcohols to access a variety of trans-3,4-disubstituted alkylidenecyclopentenes.12 In the same report, a palladium/Lewis acid mediated transformation of pentafulvene derived diazabicyclic olefins has also been described for the synthesis of novel spiropentacyclic motifs with indoline/dihydrobenzothiophene and pyrazolidine fused to the cyclopentene core. As a perpetuation of our ongoing investigations in the area of strained bicyclic olefins, we have decided to undertake the Lewis acid catalyzed desymmetrization of pentafulvene derived diazabicyclic olefins by employing biologically significant indoles as nucleophiles. The developed method successfully leads to the C-3 functionalization of indoles with alkylidenecyclopentenes, along with the formation of bisindole derivatives.
We initiated our investigation by the treatment of pentafulvene derived diazabicyclic olefin 1a (1.2 equiv.) with N-methylindole 2b (1 equiv.) in the presence of Sc(OTf)3 (2 mol%) in toluene at room temperature (Scheme 1). After 4 h, the reaction afforded the desired trans-3,4-disubstituted alkylidene cyclopentene derivative 3ab in 44% yield. The structure of 3ab was established by the usual spectroscopic techniques and also based on comparison with our previous report.12 Furthermore, the structure and stereochemistry of the product was confirmed by single crystal X-ray analysis of a similar derivative 3eb (see ESI†).
![image file: c5ra01107h-s1.tif](/image/article/2015/RA/c5ra01107h/c5ra01107h-s1.gif) |
| Scheme 1 Lewis acid catalyzed C-3 functionalization of N-methylindole 2b with diazabicyclic olefin 1a. | |
Further screening of solvents such as DMF, THF, 1,2-dichloroethane, DCM and CH3CN revealed that CH3CN was the most favorable medium for the transformation. Astonishingly, when CH3CN was employed as the solvent, the bisindolyl functionalized alkylidene cyclopentene 4ab was observed along with the expected 3,4-disubstituted alkylidene cyclopentene 3ab (Scheme 2). Various Lewis acids were also tested for the ring-opening of 1a with 2b in acetonitrile. Among them, Sn(OTf)2 and Fe(OTf)3 provided the product 3ab in comparable yields. During optimization studies, we perceived that the change in equivalents of starting materials 1a or 2b played a crucial role in the outcome of the reaction. Use of 2 equiv. of N-methylindole 2b resulted in the formation of bisindole product 4ab (58% yield) in excess over 3ab (31% yield) (entry 16). Under optimal conditions (2 mol% Sc(OTf)3 in CH3CN), the reaction could be finely tuned towards the formation of alkylidenecyclopentenyl derivative of indole 3ab or bisindole 4ab by simply altering the equivalents of starting materials 1a or 2b.
![image file: c5ra01107h-s2.tif](/image/article/2015/RA/c5ra01107h/c5ra01107h-s2.gif) |
| Scheme 2 Sc(OTf)3 catalyzed C-3 functionalization of N-methylindole 2b with diazabicyclic olefin 1a in acetonitrile. | |
Under the optimized catalytic conditions for the preparation of alkylidenecyclopentenyl derivative of indole (Table 1, entry 6) and bisindole (Table 1, entry 16), we examined the scope of different olefins and indoles (Table 2). Diazabicyclic alkenes 1a–d easily underwent ring opening with 1H-indole 2a and gave the corresponding indole derivatives 3aa–da and bisindole 4aa in good to moderate yields (entries 1–4). To demonstrate the generality of the reaction, several C-1, C-2 and C-5 substituted indoles 2b–f were subjected to C-3 alkylidenecyclopentenylation. Reaction was found to be compatible to a variety of indoles having substituents such as –F, –OH, –NO2 etc. and yielded the C-3 functionalized indoles and bisindoles (entries 5–9).
Table 1 Screening of the reactivity of various Lewis acids in different solventsa
Entry |
Lewis acid |
Solvent |
Yield (%) |
3ab |
4ab |
Reaction conditions: alkene (1.2 equiv.), N-methylindole (1 equiv.), catalyst (2 mol%), solvent (2 mL), at rt. for 4 h. Reaction in the presence of 1.0 equiv. of alkene and 2 equiv. of N-methylindole. |
1 |
Sc(OTf)3 |
Toluene |
44 |
— |
2 |
Sc(OTf)3 |
DMF |
38 |
— |
3 |
Sc(OTf)3 |
THF |
30 |
— |
4 |
Sc(OTf)3 |
DCE |
65 |
5 |
5 |
Sc(OTf)3 |
DCM |
58 |
Trace |
6 |
Sc(OTf)3 |
CH3CN |
75 |
14 |
7 |
Yb(OTf)3 |
CH3CN |
37 |
— |
8 |
Zn(OTf)2 |
CH3CN |
Trace |
— |
9 |
La(OTf)3 |
CH3CN |
35 |
— |
10 |
Cu(OTf)2 |
CH3CN |
46 |
— |
11 |
Sn(OTf)2 |
CH3CN |
70 |
8 |
12 |
Fe(OTf)3 |
CH3CN |
62 |
6 |
13 |
AgOTf |
CH3CN |
Trace |
— |
14 |
AlCl3 |
CH3CN |
53 |
Trace |
15 |
BF3OEt2 |
CH3CN |
36 |
— |
16b |
Sc(OTf)3 |
CH3CN |
31 |
58 |
Table 2 Substrate scope of indoles with various 6,6-pentamethylene fulvene derived diazabicyclic olefinsa
Entry |
Bicyclic olefin |
Indole |
Product 3 |
Product 4 |
Yield (%) |
3 |
4 |
Reaction conditons: alkene (1.2 equiv.), indole (1 equiv.), catalyst (2 mol%), solvent (2 mL), at rt. for 4 h. Reaction in presence of 1 equiv. of alkene and 2 equiv. of indole. |
1 |
1a |
2a |
![image file: c5ra01107h-u1.tif](/image/article/2015/RA/c5ra01107h/c5ra01107h-u1.gif) |
![image file: c5ra01107h-u2.tif](/image/article/2015/RA/c5ra01107h/c5ra01107h-u2.gif) |
73 |
16 |
27b |
64b |
2 |
1b |
2a |
![image file: c5ra01107h-u3.tif](/image/article/2015/RA/c5ra01107h/c5ra01107h-u3.gif) |
4aa |
72 |
16 |
14b |
72b |
3 |
1c |
2a |
![image file: c5ra01107h-u4.tif](/image/article/2015/RA/c5ra01107h/c5ra01107h-u4.gif) |
4aa |
42 |
14 |
27b |
28b |
4 |
1d |
2a |
![image file: c5ra01107h-u5.tif](/image/article/2015/RA/c5ra01107h/c5ra01107h-u5.gif) |
4aa |
39 |
12 |
17b |
33b |
5 |
1a |
2b |
![image file: c5ra01107h-u6.tif](/image/article/2015/RA/c5ra01107h/c5ra01107h-u6.gif) |
![image file: c5ra01107h-u7.tif](/image/article/2015/RA/c5ra01107h/c5ra01107h-u7.gif) |
75 |
14 |
31b |
58b |
6 |
1a |
2c |
![image file: c5ra01107h-u8.tif](/image/article/2015/RA/c5ra01107h/c5ra01107h-u8.gif) |
![image file: c5ra01107h-u9.tif](/image/article/2015/RA/c5ra01107h/c5ra01107h-u9.gif) |
78 |
11 |
32b |
54b |
7 |
1a |
2d |
![image file: c5ra01107h-u10.tif](/image/article/2015/RA/c5ra01107h/c5ra01107h-u10.gif) |
![image file: c5ra01107h-u11.tif](/image/article/2015/RA/c5ra01107h/c5ra01107h-u11.gif) |
61 |
14 |
24b |
52b |
8 |
1a |
2e |
![image file: c5ra01107h-u12.tif](/image/article/2015/RA/c5ra01107h/c5ra01107h-u12.gif) |
![image file: c5ra01107h-u13.tif](/image/article/2015/RA/c5ra01107h/c5ra01107h-u13.gif) |
59 |
12 |
26b |
48b |
9 |
1a |
2f |
![image file: c5ra01107h-u14.tif](/image/article/2015/RA/c5ra01107h/c5ra01107h-u14.gif) |
![image file: c5ra01107h-u15.tif](/image/article/2015/RA/c5ra01107h/c5ra01107h-u15.gif) |
56 |
8 |
28b |
39b |
Next, we turned our attention to explore the scope of C-3 functionalization of indoles with diazabicyclic olefins derived from different pentafulvenes (Table 3). Alkylidenecyclopentenylation of indoles proceeds efficiently through the ring opening of diazabicyclic alkenes 1e–h to provide the desired indole and bisindole derivatives. In the case of diphenylfulvene derived bicyclic olefin 1h with indoles 2a and 2b, corresponding bisindole derivatives were formed in 84% and 81% yield respectively (entries 7 and 8). Furthermore, the stereochemistry of the bisindole product 4 was unambiguously confirmed by the single crystal X-ray analysis of compound 4ha (Fig. 2, ESI†).
Table 3 Substrate scope of various pentafulvene derived diazabicyclic olefins for the C-3 functionalization of indolea
Entry |
Bicyclic olefin |
Indole |
Product 3 |
Product 4 |
Yield (%) |
3 |
4 |
Reaction conditons: alkene (1.2 equiv.), indole (1 equiv.), catalyst (2 mol%), solvent (2 mL), at rt. for 4 h. Reaction in presence of 1 equiv. of alkene and 2 equiv. of indole. |
1 |
1e |
2a |
![image file: c5ra01107h-u16.tif](/image/article/2015/RA/c5ra01107h/c5ra01107h-u16.gif) |
![image file: c5ra01107h-u17.tif](/image/article/2015/RA/c5ra01107h/c5ra01107h-u17.gif) |
69 |
18 |
24b |
64b |
2 |
1e |
2b |
![image file: c5ra01107h-u18.tif](/image/article/2015/RA/c5ra01107h/c5ra01107h-u18.gif) |
![image file: c5ra01107h-u19.tif](/image/article/2015/RA/c5ra01107h/c5ra01107h-u19.gif) |
65 |
15 |
27b |
56b |
3 |
1f |
2a |
![image file: c5ra01107h-u20.tif](/image/article/2015/RA/c5ra01107h/c5ra01107h-u20.gif) |
![image file: c5ra01107h-u21.tif](/image/article/2015/RA/c5ra01107h/c5ra01107h-u21.gif) |
70 |
9 |
25b |
53b |
4 |
1g |
2a |
![image file: c5ra01107h-u22.tif](/image/article/2015/RA/c5ra01107h/c5ra01107h-u22.gif) |
![image file: c5ra01107h-u23.tif](/image/article/2015/RA/c5ra01107h/c5ra01107h-u23.gif) |
66 |
24 |
30b |
58b |
5 |
1g |
2b |
![image file: c5ra01107h-u24.tif](/image/article/2015/RA/c5ra01107h/c5ra01107h-u24.gif) |
![image file: c5ra01107h-u25.tif](/image/article/2015/RA/c5ra01107h/c5ra01107h-u25.gif) |
70 |
16 |
32b |
55b |
6 |
1g |
2c |
![image file: c5ra01107h-u26.tif](/image/article/2015/RA/c5ra01107h/c5ra01107h-u26.gif) |
![image file: c5ra01107h-u27.tif](/image/article/2015/RA/c5ra01107h/c5ra01107h-u27.gif) |
66 |
14 |
13b |
74b |
7 |
1h |
2a |
![image file: c5ra01107h-u28.tif](/image/article/2015/RA/c5ra01107h/c5ra01107h-u28.gif) |
![image file: c5ra01107h-u29.tif](/image/article/2015/RA/c5ra01107h/c5ra01107h-u29.gif) |
62 |
28 |
8b |
84b |
8 |
1h |
2b |
![image file: c5ra01107h-u30.tif](/image/article/2015/RA/c5ra01107h/c5ra01107h-u30.gif) |
![image file: c5ra01107h-u31.tif](/image/article/2015/RA/c5ra01107h/c5ra01107h-u31.gif) |
68 |
24 |
10b |
81b |
![image file: c5ra01107h-f2.tif](/image/article/2015/RA/c5ra01107h/c5ra01107h-f2.gif) |
| Fig. 2 Single crystal X-ray structure of compound 4ha. | |
Based on these results we propose a plausible mechanism as shown in Scheme 3. As similar to our previous reports,12 the catalytic cycle is initiated by coordination of the Lewis acid with the carbonyl oxygen of one of the carbamate groups of diazabicyclic olefin 1 and subsequent cleavage of the C–N bond leads to the generation of a transient allylic cation species A. Regioselective nucleophilic attack of indole from the opposite side with respect to the hydrazine moiety of intermediate A delivers trans-3,4-disubstituted alkylidene cyclopentene 3. In the next step, the Lewis acid coordinates with the carbonyl group of the hydrazine moiety, followed by the elimination of the hydrazine group through C–N bond cleavage, resulting in the formation of intermediate D. Attack of the second molecule of indole to intermediate D furnishes the bisindole product 4. Furthermore, ESI-MS studies provided strong supporting evidence for the formation of intermediates C and D (see ESI†).
![image file: c5ra01107h-s3.tif](/image/article/2015/RA/c5ra01107h/c5ra01107h-s3.gif) |
| Scheme 3 Plausible mechanism. | |
To confirm the Lewis acid catalyzed generation of an intermediate from 3 by the elimination of hydrazine moiety, we have carried out a reaction with 1 equiv. of 3,4-disubstituted alkylidene cyclopentene 3ha and 1.2 equiv. of indole 2a (Scheme 4). As expected, bisindole product 4ha was obtained in 62% yield, supporting the role of 3,4-disubstituted alkylidene cyclopentene as an intermediate in the course of reaction. It is to be noted that the hydrazine group acts as a key functional moiety in the present atom economic strategy toward the synthesis of functionalized bisindoles. In addition, oxidation of the generated hydrazine could provide the corresponding dialkyl diazene-1,2-dicarboxylates, which can be reused in the cycloaddition reactions.
![image file: c5ra01107h-s4.tif](/image/article/2015/RA/c5ra01107h/c5ra01107h-s4.gif) |
| Scheme 4 Lewis acid catalyzed synthesis of bisindole derivative catalyzed synthesis of bisindole derivative. | |
In summary, we have developed a Lewis acid catalyzed C-3 alkylideneclopentenylation of indoles through the ring opening of pentafulvene derived diazabicyclic olefins. The developed method provides an efficient synthetic route to furnish pharmaceutically valuable indole and bisindole derivatives of alkylidenecyclopentenes from easily accessible starting materials. While multiple steps are involved in conventional synthetic strategies, this protocol offers a one-pot access to cyclopentene–bisindole hybrids. Moreover, the present strategy is compatible with both N-alkyl and free (NH) indoles. Further investigations to elaborate the scope of the reaction on other N-heterocycles and also to explore the biological applications of synthesized molecules are currently underway.
Experimental section
General methods
All chemicals were of the best grade commercially available and are used without further purification. All solvents were purified according to standard procedure; dry solvents were obtained according to the literature methods and stored over molecular sieves. Analytical thin layer chromatography was performed on glass plates coated with silica gel containing calcium sulfate binder. Gravity column chromatography was performed using 60–120 or 100–200 mesh silica gel and mixtures of hexane/ethyl acetate were used for elution.
Melting points were determined on a Buchi melting point apparatus and are uncorrected. Proton nuclear magnetic resonance spectra (1H NMR) were recorded on a Bruker AMX 500 spectrophotometer (CDCl3 as solvent). Chemical shifts for 1H NMR spectra are reported as δ in units of parts per million (ppm) downfield from SiMe4 (δ 0.0) and relative to the signal of chloroform-d (δ 7.25, singlet). Multiplicities were given as: s (singlet); d (doublet); t (triplet); q (quadret); dd (double doublet); m (multiplet). Coupling constants are reported as J value in Hz. Carbon nuclear magnetic resonance spectra (13C NMR) are reported as δ in units of parts per million (ppm) downfield from SiMe4 (δ 0.0) and relative to the signal of chloroform-d (δ 77.03, triplet). Mass spectra were recorded under EI/HRMS at 60
000 resolution using Thermo Scientific Exactive mass spectrometer. IR spectra were recorded on Bruker FT-IR spectrometer.
General procedure for the Lewis acid catalyzed reaction of pentafulvene derived bicyclic hydrazines towards the synthesis of 3. A mixture of pentafulvene derived bicyclic hydrazine (1.2 eqiuv.), indole (1.0 equiv.) and Sc(OTf)3 (2 mol%) were weighed in a Schlenk tube and degassed for 10 minutes. Dry CH3CN (2 mL) was added and the reaction mixture was purged with argon and allowed to stir at room temperature for 4 hours. The solvent was evaporated in vacuo and the residue on silica gel (100–200 mesh) column chromatography yielded trans-3,4-disubstituted alkylidene cyclopentene (3) along with minor amount of trans-3,4-disubstituted bisindolyl product (4).
General procedure for the Lewis acid catalyzed reaction of pentafulvene derived bicyclic hydrazines towards the synthesis of 4. A mixture of pentafulvene derived bicyclic hydrazine (1.0 eqiuv.), indole (2.0 equiv.) and Sc(OTf)3 (2 mol%) were weighed in a Schlenk tube and degassed for 10 minutes. Dry CH3CN (2 mL) was added and the reaction mixture was purged with argon and allowed to stir at room temperature for 4 hours. The solvent was evaporated in vacuo and the residue on silica gel (100–200 mesh) column chromatography yielded trans-3,4-disubstituted bisindolyl product (4) along with minor amount of trans-3,4-disubstituted alkylidene cyclopentene (3).
Diethyl 1-(2-cyclohexylidene-5-(1H-indol-3-yl)cyclopent-3-enyl)hydrazine-1,2-dicarboxylate (3aa). Yield: 73%; pale yellow solid; M. p. 122–124 °C; Rf: 0.31 (hexane/ethyl acetate = 3
:
1). IR (Neat) νmax: 3334, 3054, 2976, 2920, 2853, 1709, 1586, 1458, 1410, 1330, 1220, 1120, 1052, 920, 745 cm−1. 1H NMR (500 MHz, CDCl3, TMS): δ 8.10 (brs, 1H), 7.68 (brs, .03) (m, 1H), 6.84 (s, 1H), 6.53 (d, J = 6 Hz, 1H), 6.26 (brs, 1H), 6.04 (brs, 1H), 5.34–5.12 (m, 1H), 4.50–4.40 (m, 1H), 4.24–4.17 (m, 4H), 2.39–2.33 (m, 2H), 2.08–2.07 (m, 2H), 1.66–1.53 (m, 6H), 1.30–1.29 (m, 5H), 1.02 (brs, 1H). 13C NMR (125 MHz, CDCl3, TMS): δ 156.6, 155.1, 136.7, 136.2, 134.0, 129.7, 126.6, 121.9, 120.0, 119.2, 118.1, 110.0, 65.4, 64.1, 62.4, 61.9, 47.4, 32.0, 31.0, 28.4, 28.1, 26.6, 14.5, 14.2. HRMS (ESI): calcd for C25H31N3O4Na: 460.22123; found: 460.22171.
Diethyl 1-(2-cyclohexylidene-5-(1-methyl-1H-indol-3-yl)cyclopent-3-enyl)hydrazine-1,2-dicarboxylate (3ab). Yield: 75%; pale yellow solid; M. p. 120–122 °C, Rf: 0.33 (hexane/ethyl acetate = 3
:
1). IR (Neat) νmax: 3323, 3055, 2981, 2932, 2855, 1710, 1619, 1583, 1513, 1458, 1415, 1339, 1302, 1227, 1096, 1061, 920, 743 cm−1. 1H NMR (500 MHz, CDCl3, TMS): δ 7.68 (brs, 1H), 7.25–7.23 (m, 2H), 7.05 (t, J = 7 Hz, 1H), 6.73 (s, 1H), 6.53 (d, J = 5.5, 1H), 6.23 (brs, 1H), 6.04 (s, 1H), 5.31–5.09 (m, 1H), 4.49–4.39 (m, 1H), 4.24–4.18 (m, 4H), 3.72 (s, 3H), 2.38–2.34 (m, 2H), 2.07–2.03 (m, 2H), 1.61–1.53 (m, 6H), 1.31–1.26 (m, 5H), 1.05–1.04 (brs, 1H). 13C NMR (125 MHz, CDCl3, TMS): δ 156.4, 155.1, 137.4, 133.7, 129.6, 127.0, 125.7, 121.5, 120.1, 118.7, 109.1, 108.8, 65.5, 62.3, 61.8, 47.5, 32.5, 31.9, 28.3, 28.0, 26.5, 14.5. HRMS (ESI): calcd for C26H33N3O4Na: 474.23688; found: 474.23764.
Diethyl 1-(2-cyclohexylidene-5-(2-phenyl-1H-indol-3-yl)cyclopent-3-enyl)hydrazine-1,2-dicarboxylate (3ac). Yield: 78%; yellow viscous liquid; Rf: 0.36 (hexane/ethyl acetate = 3
:
1). IR (Neat) νmax: 3324, 2980, 2930, 2854, 1701, 1519, 1472, 1420, 1382, 1332, 1261, 1233, 1097, 1060 cm−1. 1H NMR (500 MHz, CDCl3, TMS): δ 8.16 (brs, 1H), 7.60–7.25 (m, 6H), 7.19–7.03 (m, 2H), 7.03 (d, J = 7 Hz, 1H), 6.55 (brs, 1H), 6.20–6.03 (m, 1H), 5.91 (brs, 1H), 5.59–5.45 (m, 1H), 4.68–4.53 (m, 1H), 4.16–4.12 (m, 4H), 2.58 (brs, 1H), 2.39–2.12 (m, 3H), 1.75–1.59 (m, 6H), 1.29–0.88 (m, 6H). 13C NMR (125 MHz, CDCl3, TMS): δ 156.2, 155.4, 137.7, 136.3, 134.7, 132.8, 129.0, 128.6, 128.2, 127.6, 125.3, 121.9, 120.3, 119.4, 110.9, 62.4, 61.7, 60.3, 48.3, 34.6, 32.1, 26.9, 26.7, 21.5, 14.5, 14.2. HRMS (ESI): calcd for C31H35N3O4Na: 536.25253; found: 536.25289.
Diethyl 1-(2-cyclohexylidene-5-(5-fluoro-1H-indol-3-yl)cyclopent-3-enyl)hydrazine-1,2-dicarboxylate (3ad). Yield: 61%; colourless viscous liquid; Rf: 0.26 (hexane/ethyl acetate = 3
:
1). IR (Neat) νmax: 3363, 3277, 3054, 2984, 2931, 2854, 1711, 1582, 1500, 1149, 1411, 1330, 1120, 1050, 1010, 919, 744 cm−1. 1H NMR (500 MHz, CDCl3, TMS): δ 8.26 (s, 1H), 7.34 (brs, 1H), 7.27–7.22 (m, 1H), 6.96–6.92 (brs, 1H), 6.65–6.56 (m, 2H), 6.40–6.31 (m, 1H), 6.02 (d, J = 3.5 Hz, 1H), 5.32–5.11 (m, 1H), 4.46–4.18 (m, 5H), 2.41–2.33 (m, 2H), 2.07–2.05 (m, 2H), 1.62–1.45 (m, 6H), 1.35–1.07 (m, 6H). 13C NMR (125 MHz, CDCl3, TMS): δ 158.5, 156.8, 155.3, 136.9, 133.3, 130.0, 126.9, 123.1, 118.1, 111.5, 110.3, 104.9, 65.4, 62.6, 62.3, 47.5, 32.0, 31.1, 28.3, 28.0, 26.5, 14.4. HRMS (ESI): calcd for C25H30FN3O4Na: 478.21180; found: 478.21223.
Diethyl 1-(-2-cyclohexylidene-5-(5-nitro-1H-indol-3-yl)cyclopent-3-enyl)hydrazine-1,2-dicarboxylate (3ae). Yield: 59%; pale yellow solid; M. p. 132–134 °C; Rf: 0.22 (hexane/ethyl acetate = 3
:
1). IR (Neat) νmax: 3365, 3071, 2960, 2852, 1712, 1623, 1582, 1469, 1410, 1380, 1318, 1245, 1173, 1115, 1058, 743 cm−1. 1H NMR (500 MHz, CDCl3, TMS): δ 9.22 (brs, 1H), 8.56 (s, 1H), 7.92 (brs, 1H), 7.17–7.13 (m, 1H), 6.92–6.82 (m, 1H), 6.61 (d, 1H, J = 4.5 Hz), 6.34 (brs, 1H), 5.98 (brs, 1H), 5.39–5.17 (m, 1H), 4.49–4.23 (m, 5H), 2.56–2.06 (m, 4H), 1.76–1.22 (m, 12H). 13C NMR (125 MHz, CDCl3, TMS): δ 156.3, 155.6, 141.3, 139.8, 137.7, 130.1, 129.0, 128.2, 125.5, 125.3, 124.2, 117.6, 117.2, 111.0, 64.3, 62.9, 62.2, 47.5, 32.1, 31.3, 28.2, 26.6, 21.5, 14.5, 14.2. HRMS (ESI): calcd for C25H30N4O6Na: 505.20630; found: 505.20668.
Diethyl 1-(2-cyclohexylidene-5-(5-hydroxy-1H-indol-3-yl)cyclopent-3-enyl)hydrazine-1,2-dicarboxylate (3af). Yield: 56%; pale yellow viscous liquid; Rf: 0.17 (hexane/ethyl acetate = 3
:
1). IR (Neat) νmax: 3380, 3280, 3054, 2976, 2928, 2853, 1709, 1586, 1499, 1149, 1410, 1330, 1220, 1120, 1052, 1011, 920, 745 cm−1. 1H NMR (500 MHz, CDCl3, TMS): δ 7.89 (brs, 1H), 7.23–7.15 (m, 2H), 6.79–6.77 (m, 1H), 6.56–6.28 (m, 2H), 6.05 (brs, 1H), 5.32–5.09 (m, 1H), 4.45–4.11 (m, 5H), 2.37–2.33 (m, 2H), 2.07–2.06 (m, 2H), 1.60–1.38 (m, 6H), 1.29–1.13 (m, 5H), 0.99 (brs, 1H). 13C NMR (125 MHz, CDCl3, TMS): δ 155.2, 154.5, 147.5, 135.8, 135.0, 134.3, 127.2, 126.8, 125.3, 111.9, 111.8, 108.5, 104.5, 64.9, 62.8, 62.2, 41.9, 32.0, 28.2, 26.5, 19.4, 19.2, 14.5. HRMS (ESI): calcd for C25H31N3O5Na: 476.21614; found: 476.21658.
Diisopropyl 1-(2-cyclohexylidene-5-(1H-indol-3-yl)cyclopent-3-enyl)hydrazine-1,2-dicarboxylate (3ba). Yield: 72%; pale yellow viscous liquid; Rf: 0.33 (hexane/ethyl acetate = 3
:
1). IR (Neat) νmax: 3331, 3068, 2981, 2932, 2857, 1688, 1621, 1583, 1514, 1462, 1380, 1304, 1238, 1108, 1042, 957, 931, 743 cm−1. 1H NMR (500 MHz, CDCl3, TMS): δ 8.16 (brs, 1H), 7.75–7.71 (m, 1H), 7.31–7.23 (m, 1H), 7.18–7.05 (m, 2H), 6.88 (brs, 1H), 6.56–6.27 (m, 2H), 6.07 (brs, 1H), 5.34–5.14 (m, 1H), 5.00–4.95 (m, 2H), 4.53–4.43 (m, 1H), 2.36 (brs, 2H), 2.09–1.81 (m, 2H), 1.61–1.51 (m, 6H), 1.44–1.22 (m, 12H). 13C NMR (125 MHz, CDCl3, TMS): δ 156.5, 154.7, 136.8, 133.8, 129.8, 129.0, 128.2, 126.7, 125.3, 121.7, 119.1, 110.9, 69.9, 69.5, 63.9, 47.2, 31.6, 30.8, 29.7, 28.3, 26.9, 22.7, 22.4, 22.1. HRMS (ESI): calcd for C27H35N3O5Na: 488.25253; found: 488.25286.
Di-tert-butyl 1-(2-cyclohexylidene-5-(1H-indol-3-yl)cyclopent-3-enyl)hydrazine-1,2-dicarboxylate (3ca). Yield: 42%; pale yellow viscous liquid; Rf: 0.40 (hexane/ethyl acetate = 3
:
1). IR (Neat) νmax: 3375, 3078, 2992, 2943, 2836, 1690, 1610, 1583, 1565, 1468, 1462, 1400, 1316, 1238, 1152, 1123, 969, 938, 746 cm−1. 1H NMR (500 MHz, CDCl3, TMS): δ 8.00 (d, J = 11 Hz, 1H), 7.99–7.79 (m, 1H), 7.32–7.28 (m, 1H), 7.20–7.06 (m, 2H), 6.87 (s, 1H), 6.55 (d, J = 5.5 Hz, 1H), 6.15–6.00 (m, 2H), 5.30–5.08 (m, 1H), 4.54–4.44 (m, 1H), 2.37 (brs, 2H), 2.12 (brs, 2H), 1.63–1.53 (m, 24H). 13C NMR (125 MHz, CDCl3, TMS): δ 155.7, 154.0, 136.7, 136.5, 126.7, 122.1, 121.8, 119.2, 118.2, 111.1, 110.9, 110.7, 81.3, 80.7, 65.5, 44.3, 32.0, 31.1, 28.3, 28.2, 28.0, 26.6. HRMS (ESI): calcd for C29H39N3O4Na: 516.28383; found: 516.28414.
Dibenzyl 1-(2-cyclohexylidene-5-(1H-indol-3-yl)cyclopent-3-enyl)hydrazine-1,2-dicarboxylate (3da). Yield: 39%; yellow viscous liquid; Rf: 0.31 (hexane/ethyl acetate = 3
:
1). IR (Neat) νmax: 3358, 3059, 3027, 2920, 2858, 1702, 1580, 1489, 1449, 1400, 1311, 1281, 1050, 1000, 743 cm−1. 1H NMR (500 MHz, CDCl3, TMS): δ 8.28 (brs, 1H), 7.66 (brs, 1H), 7.39–6.90 (m, 13H), 6.75 (brs, 2H), 6.46 (s, 1H), 5.98–5.86 (m, 1H), 5.36–5.05 (m, 5H), 4.52–4.29 (m, 1H), 2.36–2.32 (m, 2H), 2.02–1.94 (m, 2H), 1.56–1.26 (m, 6H). 13C NMR (125 MHz, CDCl3, TMS): δ 156.4, 154.8, 136.7, 135.8, 133.4, 128.6, 128.5, 128.3, 128.2, 127.9, 126.6, 122.0, 121.2, 119.9, 119.4, 117.5, 110.9, 68.1, 67.6, 47.5, 32.0, 31.0, 28.3, 28.0, 26.5. HRMS (ESI): calcd for C35H35N3O4Na: 584.25253; found: 584.25288.
Diethyl 1-(2-(1H-indol-3-yl)-5-(propan-2-ylidene)cyclopent-3-enyl)hydrazine-1,2-dicarboxylate (3ea). Yield: 69%; colourless viscous liquid; Rf: 0.29 (hexane/ethyl acetate = 3
:
1). IR (Neat) νmax: 3317, 3056, 2982, 2931, 1719, 1620, 1582, 1512, 1415, 1382, 1229, 1096, 1062, 744 cm−1. 1H NMR (500 MHz, CDCl3, TMS): δ 8.30 (s, 1H), 7.71 (brs, 1H), 7.34–7.27 (m, 1H), 7.19–7.08 (m, 2H), 6.86–6.78 (m, 2H), 6.52 (d, 1H, J = 5 Hz), 6.05 (s, 1H), 5.35–5.14 (m, 1H), 4.53–4.18 (m, 5H), 1.89 (s, 3H), 1.67 (brs, 3H), 1.29–1.26 (m, 6H). 13C NMR (125 MHz, CDCl3, TMS): δ 156.9, 155.8, 136.8, 136.6, 135.5, 129.0, 126.7, 125.3, 121.7, 119.9, 119.1, 119.0, 117.9, 111.3, 66.0, 62.6, 62.2, 47.6, 21.5, 14.4. HRMS (ESI): calcd for C22H27N3O4Na: 420.18993; found: 420.18866.
Diethyl 1-(2-(1-methyl-1H-indol-3-yl)-5-(propan-2-ylidene)cyclopent-3-enyl)hydrazine-1,2-dicarboxylate (3eb). Yield: 65%; colourless solid; M. p. 124–126 °C, Rf: 0.33 (hexane/ethyl acetate = 3
:
1). IR (Neat) νmax: 3385, 3055, 2981, 2924, 1707, 1611, 1474, 1413, 1379, 1321, 1265, 1219, 1163, 1122, 1061, 1021, 933, 739 cm−1. 1H NMR (500 MHz, CDCl3, TMS): δ 7.73 (s, 1H), 7.29–7.23 (m, 2H), 7.10 (t, J = 7 Hz, 1H), 6.77 (brs, 1H), 6.53 (d, J = 5 Hz, 1H), 6.39 (brs, 1H), 6.07 (s, 1H), 5.36–5.14 (m, 1H), 4.53–4.20 (m, 5H), 3.73 (s, 3H), 1.90 (s, 3H), 1.69 (s, 3H), 1.31–1.05 (m, 6H). 13C NMR (125 MHz, CDCl3, TMS): δ 156.7, 155.6, 137.5, 136.7, 135.6, 130.5, 128.3, 127.1, 125.9, 121.6, 120.1, 118.8, 116.7, 109.0, 66.2, 62.5, 61.9, 47.5, 32.6, 21.5, 13.8. HRMS (ESI): calcd for C23H29N3O4Na: 434.20588; found: 434.20615.
Diethyl 1-(2-cycloheptylidene-5-(1H-indol-3-yl)cyclopent-3-enyl)hydrazine-1,2-dicarboxylate (3fa). Yield: 70%; colourless viscous liquid; Rf: 0.31 (hexane/ethyl acetate = 3
:
1). IR (Neat) νmax: 3348, 3056, 2924, 2853, 1708, 1617, 1458, 1414, 1380, 1226, 1177, 1121, 1061, 741 cm−1. 1H NMR (500 MHz, CDCl3, TMS): δ 8.09 (brs, 1H), 7.66 (brs, 1H), 7.28 (brs, 1H), 7.16–7.04 (m 2H), 6.84 (brs, 1H), 6.51 (d, J = 5.5 Hz, 1H), 6.25–6.21 (m, 1H), 6.04 (brs, 1H), 5.33–5.11 (m, 1H), 4.50–4.18 (m, 5H), 2.50–2.41 (m, 2H), 2.20–2.16 (brs, 2H), 1.71–1.03 (m, 14H). 13C NMR (125 MHz, CDCl3, TMS): δ 156.3, 155.5, 136.8, 129.0, 128.2, 126.6, 125.3, 121.7, 119.0, 119.0, 111.1, 62.4, 61.9, 47.6, 32.7, 32.3, 29.1, 28.2, 27.6, 14.5, 14.2. HRMS (ESI): calcd for C26H33N3O4Na: 474.23688; found: 474.23714.
Compound 3ga. Yield: 66%; colourless viscous liquid; Rf: 0.33 (hexane/ethyl acetate = 3
:
1). IR (Neat) νmax: 3323, 3057, 2920, 2848, 1713, 1620, 1475, 1413, 1381, 1305, 1294, 1216, 1116, 1085, 1065, 1025, 742 cm−1. 1H NMR (500 MHz, CDCl3, TMS): δ 8.21 (brs, 1H), 7.70 (brs, 1H), 7.32–7.25 (m, 2H), 7.20–7.05 (m, 3H), 6.86 (brs, 1H), 6.56 (d, J = 5.5 Hz, 1H), 6.29 (brs, 1H), 6.05 (brs, 1H), 5.39–5.16 (m, 1H), 4.53–4.41 (m, 1H), 4.30–4.13 (m, 4H), 3.06 (brs, 1H), 2.59 (brs, 1H), 2.08–1.64 (m, 12H), 1.35–1.08 (m, 6H). 13C NMR (125 MHz, CDCl3, TMS): δ 156.7, 155.2, 144.4, 136.5, 130.2, 129.0, 128.3, 126.6, 125.3, 121.4, 121.1, 119.9, 119.0, 117.1, 111.1, 63.8, 62.5, 62.0, 47.6, 39.9, 39.5, 39.1, 37.0, 35.1, 34.4, 28.1, 28.0, 21.5, 14.6. HRMS (ESI): calcd for C29H35N3O4: 512.25253; found: 515.25290.
Compound 3gb. Yield: 70%; pale yellow viscous liquid; Rf: 0.36 (hexane/ethyl acetate = 3
:
1). IR (Neat) νmax: 3315, 3054, 2910, 2852, 1711, 1612, 1472, 1413, 1379, 1305, 1221, 1124, 1061, 1019, 740 cm−1. 1H NMR (500 MHz, CDCl3, TMS): δ 7.71 (brs, 1H), 7.7–7.21 (m, 2H), 7.07 (t, J = 7 Hz, 1H), 6.80 (brs, 1H), 6.55 (d, J = 5.5 Hz, 1H), 6.25 (brs, 1H), 6.05 (s, 1H), 5.35–5.12 (m, 1H), 4.53–4.28 (m, 1H), 4.23–4.13 (m, 4H), 3.75 (s, 3H), 3.05 (s, 1H), 2.58 (brs, 1H), 2.02–1.63 (m, 12H), 1.37–1.09 (m, 6H). 13C NMR (125 MHz, CDCl3, TMS): δ 156.6, 154.9, 137.4, 130.2, 127.1, 125.8, 121.5, 120.2, 118.7, 108.9, 62.3, 61.9, 47.2, 39.6, 37.0, 35.1, 34.7, 32.6, 28.1, 26.9, 25.3, 22.9, 20.8, 14.9. HRMS (ESI): calcd for C30H37N3O4Na: 526.26818; found: 526.26862.
Compound 3gc. Yield: 66%; pale yellow viscous liquid; Rf: 0.38 (hexane/ethyl acetate = 3
:
1). IR (Neat) νmax: 3378, 3058, 2978, 2908, 2848, 1756, 1704, 1467, 1445, 1409, 1379, 1364, 1338, 1308, 1277, 1248, 1218, 1172, 1157, 1097, 1062, 1022 cm−1. 1H NMR (500 MHz, CDCl3, TMS): δ 7.58–7.44 (m, 6H), 7.33–7.19 (m, 3H), 7.04 (brs, 1H), 6.50–6.42 (m, 1H), 6.12–5.81 (m, 2H), 5.45 (brs, 1H), 4.25–4.15 (m, 4H), 3.58 (s, 3H), 3.06 (brs, 1H), 2.65–2.61 (m, 1H), 2.03–1.85 (m, 10H), 1.59–1.25 (m, 2H), 1.01–0.87 (m, 6H). 13C NMR (125 MHz, CDCl3, TMS): δ 156.4, 155.3, 137.4, 131.3, 130.6, 128.1, 128.0, 121.5, 120.2, 119.0, 113.5, 109.3, 65.9, 62.3, 61.7, 47.8, 39.5, 39.4, 37.0, 35.1, 34.6, 30.8, 28.2, 28.1, 14.7. HRMS (ESI): calcd for C36H41N3O4Na: 602.29948; found: 602.29977.
Diethyl 1-(2-(diphenylmethylene)-5-(1-methyl-1H-indol-3-yl)cyclopent-3-enyl)hydrazine-1,2-dicarboxylate (3ha). Yield: 62%; pale yellow solid, M. p. 182–184 °C; Rf: 0.24 (hexane/ethyl acetate = 3
:
1). IR (Neat) νmax: 3362, 3051, 2968, 2911, 2852, 1736, 1710, 1552, 1514, 1467, 1454, 1411, 1384, 1364, 1308, 1287, 1243, 1231, 1168, 1157, 1069, 1063, 1022, 742 cm−1. 1H NMR (500 MHz, CDCl3, TMS): δ 7.85–7.79 (m, 1H), 7.42–7.03 (m, 12H), 6.90–6.59 (m, 3H), 6.32–6.22 (brs, 1H), 6.04–5.91 (m, 2H), 5.08 (brs, 1H), 4.23–4.13 (m, 4H), 3.92–3.73 (m, 1H), 1.35–1.01 (m, 6H). 13C NMR (125 MHz, CDCl3, TMS): δ 156.0, 154.7, 142.5, 142.4, 141.3, 140.8, 137.4, 130.0, 129.9, 128.6, 128.2, 127.7, 127.4, 126.8, 121.6, 120.2, 119.1, 116.9, 115.5, 110.2, 65.6, 62.0, 61.8, 47.9, 14.8. HRMS (ESI): calcd for C32H31N3O4Na: 544.22123; found: 544.22151.
Diethyl 1-(2-(diphenylmethylene)-5-(1-methyl-1H-indol-3-yl)cyclopent-3-enyl)hydrazine-1,2-dicarboxylate (3hb). Yield: 68%; yellow viscous liquid; Rf: 0.29 (hexane/ethyl acetate = 3
:
1). IR (Neat) νmax: 3340, 3068, 2981, 2932, 2857, 1688, 1621, 1602, 1583, 1555, 1514, 1462, 1380, 1315, 1238, 1108, 1042, 931, 743 cm−1. 1H NMR (500 MHz, CDCl3, TMS): δ 7.79 (brs, 1H), 7.34–7.19 (m, 14H), 7.09–6.97 (m, 2H), 6.61–6.55 (m, 1H), 6.32 (brs, 1H), 5.82–5.56 (m, 2H), 4.70–4.65 (m, 1H), 4.25–4.15 (m, 4H), 3.76 (brs, 3H), 1.32–1.29 (m, 4H), 1.03 (brs, 1H), 0.69 (brs, 1H). 13C NMR (125 MHz, CDCl3, TMS): δ 156.9, 154.9, 142.6, 142.3, 141.3, 140.7, 137.4, 130.0, 129.9, 128.5, 128.1, 127.4, 127.3, 127.1, 126.6, 121.4, 120.2, 118.8, 116.0, 115.3, 108.9, 65.5, 62.0, 61.8, 47.6, 32.6, 14.5, 13.8. HRMS (ESI): calcd for C33H33N3O4Na: 558.23688; found: 558.23721.
3,3′-(5-Cyclohexylidenecyclopent-3-ene-1,2-diyl)bis(1H-indole) (4aa). Yield: 64%; pale yellow coloured solid, M. p. 152–156 °C; Rf: 0.43 (hexane/ethyl acetate = 3
:
1). IR (Neat) νmax: 3405, 2922, 2851, 2362, 2349, 1590, 1459, 1421, 1364, 1120, 1033 cm−1. 1H NMR (500 MHz, CDCl3, TMS): δ 7.93 (s, 1H), 7.85 (s, 1H), 7.61–7.57 (m, 2H), 7.38–7.34 (m, 2H), 7.22–7.17 (m, 2H), 7.09–6.94 (m, 4H), 6.78 (d, J = 5.5 Hz, 1H), 6.04 (dd, J1 = 5.5 Hz, J2 = 2.5 Hz, 1H), 4.32 (brs, 1H), 4.19 (brs, 1H), 2.46 (t, J = 6 Hz, 2H), 2.04–1.97 (m, 2H), 1.67–1.29 (m, 6H). 13C NMR (125 MHz, CDCl3, TMS): δ 139.1, 136.9, 135.9, 133.0, 129.9, 129.1, 128.3, 126.7, 126.6, 125.4, 121.9, 121.8, 121.0, 120.9, 120.2, 120.1, 119.6, 118.9, 111.2, 111.0, 52.3, 45.8, 32.1, 31.8, 28.6, 27.7, 26.9. HRMS (ESI): calcd for C27H26N2Na: 401.19937; found: 401.19968.
3,3′-(5-Cyclohexylidenecyclopent-3-ene-1,2-diyl)bis(1-methyl-1H-indole) (4ab). Yield: 58%; pale yellow viscous liquid; Rf: 0.48 (hexane/ethyl acetate = 3
:
1). IR (Neat) νmax: 2935, 2855, 2358, 2353, 1680, 1595, 1449, 1431, 1358, 1156, 1120, 1033 cm−1. 1H NMR (500 MHz, CDCl3, TMS): δ 7.56–7.52 (m, 2H), 7.28–7.16 (m, 4H), 7.14–6.99 (m, 2H), 6.83 (s, 1H), 6.75 (s, 1H), 6.71 (dd, J1 = 5.5 Hz, J2 = 1 Hz, 1H), 5.97 (dd, J1 = 5.5 Hz, J2 = 2.5 Hz, 1H), 4.26 (s, 1H), 4.11 (s, 1H), 3.77 (s, 3H), 3.74 (s, 3H), 2.45–2.41 (m, 2H), 2.02–2.00 (m, 1H), 1.94–1.92 (m, 1H), 1.63–1.45 (m, 4H), 1.34–1.31 (m, 1H), 1.18–1.17 (m, 1H). 13C NMR (125 MHz, CDCl3, TMS): δ 139.2, 137.5, 137.4, 136.1, 132.8, 129.6, 129.0, 128.2, 127.1, 126.9, 125.6, 125.3, 121.5, 121.3, 120.4, 120.3, 120.2, 118.8, 118.6, 118.3, 109.1, 108.9, 52.3, 45.7, 32.6, 32.5, 32.0, 31.9, 28.6, 27.7, 26.9. HRMS (ESI): calcd for C29H30N2Na: 429.23067; found: 429.23102.
3,3′-(5-Cyclohexylidenecyclopent-3-ene-1,2-diyl)bis(2-phenyl-1H-indole) (4ac). Yield: 54%; pale yellow solid, M. p. 160–164 °C; Rf: 0.52 (hexane/ethyl acetate = 3
:
1). IR (Neat) νmax: 3342, 3075, 2953, 2912, 2857, 1695, 1611, 1514, 1462, 1380, 1238, 1100, 1030, 931, 740 cm−1. 1H NMR (500 MHz, CDCl3, TMS): δ 7.98 (s, 1H), 7.88 (s, 1H), 7.68 (d, J = 8 Hz, 1H), 7.59 (d, J = 8 Hz, 1H), 7.42–7.37 (m, 4H), 7.28–6.80 (m, 13H), 6.14 (m, 1H), 4.76 (brs, 1H), 4.71 (brs, 1H), 2.51–2.49 (m, 1H), 2.38–2.18 (m, 1H), 1.83–1.07 (m, 8H). 13C NMR (125 MHz, CDCl3, TMS): δ 138.4, 136.5, 136.4, 136.3, 135.1, 134.5, 133.4, 132.6, 132.5, 130.5, 128.4, 128.3, 128.2, 127.9, 127.8, 127.4, 127.3, 122.3, 122.2, 121.3, 120.9, 119.6, 119.2, 117.3, 114.7, 110.5, 110.3, 50.6, 44.8, 32.5, 30.8, 28.6, 27.1, 26.8. HRMS (ESI): calcd for C39H34N2Na: 553.26197; found: 553.26233.
3,3′-(5-Cyclohexylidenecyclopent-3-ene-1,2-diyl)bis(5-fluoro-1H-indole) (4ad). Yield: 52%; pale yellow viscous liquid; Rf: 0.40 (hexane/ethyl acetate = 3
:
1). IR (Neat) νmax: 3356, 3052, 2978, 2939, 2849, 1689, 1619, 1583, 1514, 1462, 1415, 1402, 1380, 1304, 1238, 1111, 1047, 942, 740 cm−1. 1H NMR (500 MHz, CDCl3, TMS): δ 8.03 (s, 1H), 7.94 (s, 1H), 7.31–7.20 (m, 4H), 7.07 (s, 1H), 7.00–6.77 (m, 4H), 6.00 (t, 1H, J = 3 Hz), 4.22 (s, 1H), 4.09 (s, 1H), 2.46–2.42 (m, 2H), 2.06–2.04 (m, 1H), 1.96–1.94 (m, 1H), 1.67–1.44 (m, 6H). 13C NMR (125 MHz, CDCl3, TMS): δ 158.5, 156.7, 138.5, 135.3, 133.8, 133.5, 130.3, 126.9, 122.9, 122.7, 121.9, 120.3, 111.7, 111.6, 110.5, 110.3, 110.2, 105.2, 105.0, 45.6, 32.0, 31.8, 28.5, 27.6, 26.8. HRMS (ESI): calcd for C27H24F2N2Na: 437.18052; found: 437.18088.
3,3′-(5-Cyclohexylidenecyclopent-3-ene-1,2-diyl)bis(5-nitro-1H-indole) (4ae). Yield: 48%; orange red viscous liquid; Rf: 0.40 (hexane/ethyl acetate = 3
:
1). IR (Neat) νmax: 3326, 3056, 2955, 2932, 2850, 1675, 1629, 1583, 1457, 1385, 1300, 1238, 1100, 1040, 931, 7445 cm−1. 1H NMR (500 MHz, CDCl3, TMS): δ 8.91 (s, 1H), 8.74 (s, 1H), 8.53–8.52 (m, 2H), 8.12–8.09 (m, 2H), 7.45–7.41 (m, 2H), 7.26 (d, J = 10.5 Hz, 1H), 7.14 (s, 1H), 6.86 (d, J = 5.5 Hz, 1H), 5.99 (d, J = 4.5 Hz, 1H), 4.33 (s, 1H), 4.22 (brs, 1H), 2.61–2.58 (m, 1H), 2.44–2.42 (m, 1H), 2.07–2.04 (m, 1H), 1.93–1.90 (m, 1H), 1.89–1.37 (m, 6H). 13C NMR (125 MHz, CDCl3, TMS): δ 141.4, 141.2, 140.1, 140.0, 137.6, 135.1, 134.6, 130.9, 125.9, 125.7, 124.1, 124.0, 123.8, 122.2, 117.7, 117.6, 117.5, 112.9, 111.3, 52.3, 45.7, 32.1, 32.0, 28.2, 27.7, 26.7. HRMS (ESI): calcd for C27H24N2O4Na: 491.16952; found: 491.16993.
3,3′-(5-Cyclohexylidenecyclopent-3-ene-1,2-diyl)bis(1H-indol-5-ol) (4af). Yield: 39%; pale yellow viscous liquid; Rf: 0.19 (hexane/ethyl acetate = 3
:
1). IR (Neat) νmax: 3339, 3061, 2990, 2940, 2842, 1680, 1623, 1580, 1514, 1380, 1302, 1240, 1110, 1042, 931, 740 cm−1. 1H NMR (500 MHz, CDCl3, TMS): δ 7.87 (brs, 1H), 7.78 (brs, 1H), 7.27–7.22 (m, 2H), 7.03–6.98 (m, 3H), 6.92 (d J = 2 Hz, 1H), 6.81–6.74 (m 3H), 6.01–6.00 (dd, J1 = 6 Hz, J2 = 3 Hz, 1H), 4.82 (d, J = 6.5 Hz, 2H), 4.16 (s, 1H), 4.07 (s, 1H), 2.45–2.39 (m, 2H), 1.99–1.94 (m, 2H), 1.50–1.44 (m 3H), 1.33–0.87 (m 5H). 13C NMR (125 MHz, CDCl3, TMS): δ 149.1, 148.9, 138.8, 135.6, 133.1, 132.1, 130.0, 127.3, 122.2, 121.3, 119.8, 111.8, 111.7, 111.6, 111.6, 104.8, 104.7, 51.7, 45.8, 32.0, 31.8, 28.6, 27.6, 26.8. HRMS (ESI): calcd for C27H26N2O2Na: 433.18920; found: 433.18954.
3,3′-(5-(Propan-2-ylidene)cyclopent-3-ene-1,2-diyl)bis(1H-indole) (4ea). Yield: 64%; colourless viscous liquid; Rf: 0.45 (hexane/ethyl acetate = 3
:
1). IR (Neat) νmax: 3315, 2920, 2857, 2377, 1648, 1590, 1520, 1468, 1367, 1160, 1119, 1037 cm−1. 1H NMR (500 MHz, CDCl3, TMS): δ 7.99 (s, 1H), 7.92 (s, 1H), 7.60–7.56 (m, 2H), 7.40–7.37 (m, 2H), 7.23–7.18 (m, 3H), 7.09–7.05 (m, 3H), 7.00 (s, 1H), 6.94 (s, 1H), 6.74 (dd, 1H, J1 = 5.5 Hz, J2 = 2 Hz), 6.05 (dd, 1H, J1 = 5.5 Hz, J2 = 2.5 Hz), 4.28 (s, 1H), 4.22 (s, 1H), 1.93 (s, 3H), 1.61 (s, 3H). 13C NMR (125 MHz, CDCl3, TMS): δ 141.9, 137.1, 136.9, 135.8, 130.4, 127.3, 126.8, 125.8, 125.7, 124.4, 121.5, 121.3, 120.5, 120.3, 120.0, 118.4, 118.2, 117.9, 110.8, 110.7, 52.4, 46.4, 21.3. HRMS (ESI): calcd for C24H22N2Na: 361.16807; found: 361.16848.
3,3′-(5-(Propan-2-ylidene)cyclopent-3-ene-1,2-diyl)bis(1-methyl-1H-indole) (4eb). Yield: 56%; pale yellow solid, M. p. 162–164 °C; Rf: 0.50 (hexane/ethyl acetate = 3
:
1). IR (Neat) νmax: 2925, 2852, 2371, 1649, 1586, 1523, 1465, 1364, 1254, 1167, 1122, 1042 cm−1. 1H NMR (500 MHz, CDCl3, TMS): δ 7.66–7.61 (m, 2H), 7.38–7.31 (m, 2H), 7.29–7.27 (m, 2H), 7.14–7.09 (m, 2H), 6.90 (s, 1H), 6.83 (s, 1H), 6.78 (dd, 1H, J1 = 5.5 Hz, J2 = 2 Hz), 6.09 (dd, H, J1 = 5.5 Hz, J2 = 2.5 Hz), 4.32 (s, 1H), 4.25 (s, 1H), 3.81 (s, 3H), 3.79 (s, 3H), 1.99 (s, 3H), 1.60 (s, 3H). 13C NMR (125 MHz, CDCl3, TMS): δ 142.2, 137.6, 137.5, 135.9, 130.5, 127.1, 127.0, 125.9, 125.7, 124.4, 121.5, 121.3, 120.3, 120.2, 119.9, 118.8, 118.7, 118.4, 109.2, 109.1, 52.6, 46.6, 31.7, 21.4. HRMS (ESI): calcd for C26H26N2Na: 389.19937; found: 389.19969.
3,3′-(5-Cycloheptylidenecyclopent-3-ene-1,2-diyl)bis(1H-indole) (4fa). Yield: 53%; colourless viscous liquid; Rf: 0.43 (hexane/ethyl acetate = 3
:
1). IR (Neat) νmax: 3408, 3056, 2923, 2853, 1703, 1619, 1583, 1517, 1485, 1455, 1338, 1227, 1095, 1012, 741 cm−1. 1H NMR (500 MHz, CDCl3, TMS): δ 7.97 (s, 1H), 7.89 (s, 1H), 7.59–7.57 (d, J = 8 Hz, 2H), 7.37–7.34 (m, 2H), 7.21–7.16 (m, 2H), 7.07–7.05 (m, 2H), 6.98–6.93 (m, 2H), 6.76 (dd, J1 = 5.5 Hz, J2 = 2.5 Hz, 1H), 6.04 (dd, J1 = 5.5 Hz, J2 = 3 Hz, 1H), 4.27 (s, 1H), 4.18 (brs, 1H), 2.57–2.51 (m, 2H), 2.25–2.19 (m, 1H), 2.07–2.06 (m, 1H), 1.72–1.29 (m, 8H). 13C NMR (125 MHz, CDCl3, TMS): δ 142.1, 136.9, 136.7, 135.9, 134.3, 130.4, 129.0, 128.2, 126.7, 126.6, 121.9, 121.5, 120.8, 120.7, 120.2, 120.1, 119.2, 119.0, 111.0, 110.9, 52.5, 46.1, 32.8, 32.5, 29.8, 28.8, 27.2, 26.9. HRMS (ESI): calcd for C28H28N2Na: 415.21502; found: 415.21538.
Compound 4ga. Yield: 58%; colourless viscous liquid; Rf: 0.43 (hexane/ethyl acetate = 3
:
1). IR (Neat) νmax: 3289, 3066, 2931, 2857, 1668, 1620, 1582, 1520, 1455, 1304, 1238, 933, 744 cm−1. 1H NMR (500 MHz, CDCl3, TMS): δ 7.88 (s, 1H), 7.79 (s, 1H), 7.62 (d, J = 8 Hz, 1H), 7.55 (d, J = 8 Hz, 1H), 7.54–7.21 (m, 2H), 7.19–7.13 (m, 2H), 7.05–6.93 (m, 4H), 6.72–6.71 (m, 1H), 5.94 (dd, J1 = 5.5 Hz, J2 = 3 Hz, 1H), 4.30 (s, 1H), 4.11 (brs, 1H), 3.12 (brs, 1H), 2.49 (brs, 1H), 2.04–1.68 (m, 9H), 1.53–1.43 (m, 2H), 0.88–0.84 (m, 1H). 13C NMR (125 MHz, CDCl3, TMS): δ 140.8, 137.8, 137.0, 136.9, 135.4, 135.2, 129.5, 129.1, 128.3, 126.8, 126.5, 125.4, 122.0, 121.8, 120.9, 120.4, 119.2, 118.9, 111.2, 111.1, 52.4, 45.2, 39.8, 39.4, 38.2, 37.3, 35.1, 34.8, 28.4, 21.6. HRMS (ESI): calcd for C31H30N2Na: 453.23067; found: 453.23101.
Compound 4gb. Yield: 55%; colourless viscous liquid; Rf: 0.48 (hexane/ethyl acetate = 3
:
1). IR (Neat) νmax: 3090, 2950, 2932, 2857, 1688, 1621, 1583, 1514, 1462, 1380, 1304, 1238, 1108, 1042, 957, 931, 743 cm−1. 1H NMR (500 MHz, CDCl3, TMS): δ 7.65 (d, J = 8 Hz, 1H), 7.58 (d, J = 8 Hz, 1H), 7.33–7.20 (m, 6H), 7.08–7.02 (m, 2H), 6.89 (s, 1H), 6.83 (s, 1H), 6.73 (d, J = 5.5 Hz, 1H), 5.95 (t, J = 2.5 Hz, 1H), 4.32 (s, 1H), 4.13 (s, 1H), 3.81 (s, 3H), 3.77 (s, 3H), 3.17 (s, 1H), 2.53 (s, 1H), 2.01–1.58 (m, 12H). 13C NMR (125 MHz, CDCl3, TMS): δ 140.6, 137.6, 135.6, 135.2, 129.2, 127.2, 127.0, 125.6, 125.5, 121.5, 120.5, 120.3, 118.8, 118.8, 118.6, 109.1, 108.9, 52.5, 45.2, 39.8, 39.3, 38.2, 37.3, 35.0, 34.4, 32.6, 32.5, 28.4, 28.3. HRMS (ESI): calcd for C33H34N2Na: 481.26197; found: 481.26141.
Compound 4gc. Yield: 74%; colourless viscous liquid; Rf: 0.55 (hexane/ethyl acetate = 3
:
1). IR (Neat) νmax: 2981, 2915, 2833, 1671, 1621, 1586, 1542, 1380, 1300, 1238, 1042, 957, 931, 743 cm−1. 1H NMR (500 MHz, CDCl3, TMS): δ 7.62–7.47 (m, 6H), 7.38–6.96 (m, 12H), 6.66 (dd, J1 = 5.5 Hz, J2 = 2.5 Hz, 1H), 6.04 (dd, J1 = 5.5 Hz, J2 = 2.5 Hz, 1H), 4.41 (brs, 1H), 4.22 (brs, 1H), 3.61 (s, 3H), 3.57 (s, 3H), 2.98 (brs, 1H), 2.32 (brs, 1H), 1.83–1.50 (m, 12H). 13C NMR (125 MHz, CDCl3, TMS): δ 140.2, 137.9, 137.4, 136.2, 135.8, 134.6, 133.9, 133.4, 131.3, 130.5, 129.7, 128.7, 128.2, 127.7, 127.5, 126.6, 125.3, 122.3, 121.4, 120.3, 119.5, 119.1, 119.0, 117.5, 115.2, 108.9, 108.7, 51.0, 45.3, 39.3, 38.9, 37.8, 37.4, 34.9, 33.1, 30.9, 28.1. HRMS (ESI): calcd for C45H42N2Na: 633.32457; found: 633.32486.
3,3′-(5-(Diphenylmethylene)cyclopent-3-ene-1,2-diyl)bis(1H-indole) (4ha). Yield: 84%; pale yellow solid, M. p. 154–156 °C; Rf: 0.43 (hexane/ethyl acetate = 3
:
1). IR (Neat) νmax: 3294, 2857, 2366, 2335, 1647, 1590, 1369, 1120, 1037, 702 cm−1. 1H NMR (500 MHz, CDCl3, TMS): δ 7.90 (s, 1H), 7.67–7.51 (m, 3H), 7.37–7.06 (m, 9H), 6.98–6.78 (m, 9H), 6.40 (d, J = 4 Hz, 1H), 6.24 (brs, 1H), 4.51–4.49 (m, 2H). 13C NMR (125 MHz, CDCl3, TMS): δ 148.1, 143.2, 142.6, 140.4, 136.8, 136.5, 135.0, 133.1, 129.8, 129.3, 127.9, 127.4, 126.7, 126.5, 126.2, 125.9, 122.0, 121.5, 120.8, 120.1, 119.8, 119.5, 119.3, 119.0, 118.9, 111.1, 110.9, 57.7, 48.5. HRMS (ESI): calcd for C34H26N2Na: 485.19937; found: 485.19969.
3,3′-(5-(Diphenylmethylene)cyclopent-3-ene-1,2-diyl)bis(1-methyl-1H-indole) (4hb). Yield: 81%; yellow solid, M. p. 160–162 °C; Rf: 0.48 (hexane/ethyl acetate = 3
:
1). IR (Neat) νmax: 3053, 2927, 1709, 1688, 1613, 1513, 1469, 1427, 1372, 1328, 1242, 1156, 1130, 1013, 740 cm−1. 1H NMR (500 MHz, CDCl3, TMS): δ 7.78–7.76 (m, 2H), 7.72–7.30 (m, 9H), 7.20–6.99 (m, 6H), 6.87 (brs, 3H), 6.52 (t, J = 3 Hz, 1H), 6.09 (dd, J1 = 4 Hz, J2 = 2.5 Hz, 1H), 4.66 (brs, 1H), 4.57–4.54 (m, 1H), 3.81 (s, 3H), 3.58 (s, 3H). 13C NMR (125 MHz, CDCl3, TMS): δ 148.8, 143.3, 143.0, 140.8, 137.6, 137.3, 134.9, 132.9, 129.9, 129.3, 129.2, 128.4, 128.0, 127.4, 127.2, 127.2, 126.8, 126.5, 125.8, 125.7, 121.7, 121.1, 120.3, 120.0, 118.9, 118.4, 118.1, 117.6, 109.3, 109.1, 51.8, 48.9, 32.6, 32.2. MS (ESI): calcd for C36H30N2Na: 513.23067; found: 513.23098.
Acknowledgements
SCS, PS and PP thank UGC for a research fellowship. Financial assistance from Department of Science and Technology (DST no.: SB/S1/OC-24/2014), Indo-French Centre for Promotion of Advanced Research (IFCPAR/CEFIPRA (Project 4505-1)), and Council of Scientific and Industrial Research (12th FYP project, ORIGIN-CSC-0108), New Delhi are greatly acknowledged. Thanks are due to Dr K. M. Sureshan and Mr Alex Andrews of IISER Trivandrum, for single crystal X-ray analysis. The authors also thank Mrs Saumini Mathew, Mrs S. Viji and Mr Saran P. Raveendran of CSIR-NIIST and Mr B. Adarsh of IISER Trivandrum for recording NMR and mass spectra.
Notes and references
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Footnote |
† Electronic supplementary information (ESI) available: 1H and 13C NMR spectra of all new compounds. CCDC 1034718 and 989506. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5ra01107h |
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