Synthesis of Functionalized Thieno[2,3-b]indoles via One-Pot Reaction of Indoline-2-thiones with Morita–Baylis–Hillman and Rauhut–Currier Adducts of Nitroalkenes

Abstract

A straightforward protocol for the synthesis of functionalized thieno[2,3-b]indoles by base-mediated [3 + 2]-annulation of indoline-2-thione with Morita–Baylis–Hillman and Rauhut–Currier adducts of nitroalkenes is described. Complete regioselectivity, broad substrate scope, and mild reaction conditions make this strategy very valuable. Moreover, the thieno[2,3-b]indoles comprising functional groups such as hydrazine and ketoalkyl moieties are amenable for further synthetic elaboration.

Introduction

Organosulfur compounds exhibit drug-like properties and thus they have been widely exploited for medicinal chemistry applications.¹ Thiophene and their fused analogues stand out among various sulfur-containing compounds because of their excellent medicinal properties.² The indole-annulated thiophene, particularly, thieno[2,3-b]indole, constitutes a privileged structural motif and has gained considerable attention among synthetic and medicinal chemists.³ Structures of some of the bioactive indole-annulated thiophene derivatives are listed in Figure 1. The core structure, thieno[2,3-b]indole A exhibits antifungal activity⁴ and the substituted thieno[2,3-b]indoles have potential medicinal applications for the treatment of neurological diseases such as epilepsy, senile dementia, Parkinson’s disease, and deficiencies of mental and motoric performance observed after conditions of brain ischemia.⁵ Also, the natural product thienodolin B has the same structural framework which displays plant growth-promoting and -inhibiting activities in rice seedlings.^3,6 In addition to their pronounced pharmacological properties, some of these scaffolds (D–G) are also employed in organic electronics as electroluminescent materials⁷ and in the field of conducting polymers (H, Figure 1).⁸

Figure 1.

Bioactive (A–C) and functional materials (D–H) containing the thieno[2,3-b]indole skeleton.

Owing to their wide range of biological and electronic material applications, various synthetic methods have been developed for the synthesis of thieno[2,3-b]indole skeletons.⁹ The prominent strategies include deoxygenative or palladium-catalyzed reductive cyclization of 3-(2-nitrophenyl)thiophenes,¹⁰ electrophilic cyclization of 2-alkyl-5-(2-isothiocyanoaryl)furans in the presence of AlCl₃,¹¹ oxidative cycloamination of benzothiophenes,¹² radical or palladium-catalyzed cyclization of 3-(2-bromoindol-3-yl)acrylonitriles,¹³ Paal–Knorr cyclization of oxindoles in the presence of Lawesson’s reagent,¹⁴ and so forth. Recently, Deng et al. demonstrated efficient methods for the regioselective synthesis of thieno[2,3-b]indoles by Brønsted acid-promoted multicomponent reactions.¹⁵

Indoline-2-thione has been recognized as a suitable binucleophilic synthon for the synthesis of various indole-annulated heterocycles,¹⁶ and few reports are also available for the synthesis of thieno[2,3-b]indoles starting from indoline-2-thione.¹⁷ Although many elegant methods are documented in the literature, the development of novel and efficient diversity-oriented strategies for the construction of functionalized indole-annulated thiophenes are still desirable considering their synthetic and biological significance.

Our group has long-term interest in the Morita–Baylis–Hillman (MBH)¹⁸ and Rauhut–Currier (RC)¹⁹ reactions of nitroalkenes and their applications toward the synthesis of several carbo- and heterocycles.²⁰ Specifically, α-hydrazinonitroalkenes prepared via MBH reaction of nitroalkenes with azodicarboxylates²¹ and an RC adduct of nitroalkene with MVK²² are well utilized as synthons for the preparation of several functionalized carbo- and heterocycles.^23,24 These are excellent Michael acceptors which participate in cascade Michael addition–cyclization sequences.²²⁻²⁶ There is also the possibility of further exploitation of the reactivity of hydrazino and ketoalkyl moieties that are retained in the products. α-Hydrazinonitroalkenes were employed as substrates for the synthesis of functionalized triazoles and arenofurans,²³ whereas pyrazoles, furans, decalins, cycloalkanones, spirocycles, and a bridged heterobicyclic compound epibatidine were efficiently synthesized from RC-adducts.^22,24,25 Very recently, we reported an effective strategy for the synthesis of aminophenanthrenes and benzoquinolines from RC-adducts of nitroalkenes using Hauser–Kraus reaction of sulfonyl phthalide as the key step.²⁶ As part of our ongoing program to synthesize functionalized heterocycles, herein, we report a novel approach for the construction of indole-annulated thiophenes from MBH/RC-adducts of nitroalkenes and indoline-2-thione.

Results and Discussion

Our investigation commenced with a model reaction between N-methylated indoline-2-thione 1a and hydrazinated nitroalkene 2a in the presence of a mild base such as KOAc at room temperature (Table 1, entry 1). The desired product, fused thienoindole 4a, was formed in 75% yield after 4 days of stirring. The role of inorganic and organic bases was studied to improve the yield in short reaction time. When the reaction was carried out in the presence of inorganic bases such as K₂CO₃, Cs₂CO₃, and NaOH, instead of the expected aromatized fused thienoindole, the dihydrothienoindole 3a was formed in 58, 27 and 62% yields, respectively, in a relatively short reaction period (Table 1, entries 2–4). Subsequently, the role of an organic base was evaluated by performing the reaction in the presence of Et₃N. In this case also the reaction exclusively furnished the dihydrothienoindole 3a in 62% yield (Table 1, entry 5). Among several bases screened, only KOAc delivered the desired product. After successful screening of bases, we have investigated the effect of solvents by using the optimized base KOAc. A brief evaluation of solvents was then performed by conducting the reaction in tetrahydrofuran (THF), methanol, and toluene (entries 6–8). Among the solvents screened, THF and methanol provided the desired product 4a after 8 d of reaction, but the yield was inferior as compared to that in CH₃CN (entry 1). When the reaction was carried out in the presence of 1 mol % acid additive, viz, acetic acid, the yield improved to 78% and the reaction was completed in 4 days. These reaction conditions were the best for this transformation (Table 1, entry 9).

Table 1. Optimization Studies^a.

				% yieldb
entry	base	solvent	time	3ac	4a
1	KOAc	CH3CN	4 d		75
2	K2CO3	CH3CN	30 min	58
3	Cs2CO3	CH3CN	30 min	27
4	NaOH	CH3CN	25 min	62
5	Et3N	CH3CN	25 min	62
6	KOAc	THF	8 d		60
7	KOAc	MeOH	8 d		63
8	KOAc	toluene	8 d
9	KOAc	CH3CN	4 d		78d

^aReaction scale: 1a (0.25 mmol, 1.0 equiv), 2a (0.25 mmol, 1.0 equiv), base (0.25 mmol, 1.0 equiv), and solvent (3 mL) at RT.

^bAfter silica gel column chromatography.

^cSlowly gets converted to 4a during purification and upon storage; prolonging the reaction time beyond the indicated time or heating to 60–80 °C in the case of entries 2–5 led to complex mixtures.

^dAcetic acid as the additive (1 mol %).

After establishing the best reaction conditions for this transformation, we have investigated the generality of the reaction (Table 2). Various N-substituted indoline-2-thiones 1 and different hydrazinonitroalkenes 2 were well tolerated, and the thienoindole derivatives 4 were formed in moderate to good yields. The electronic nature of groups present on the aryl ring of hydrazinonitroalkenes 2 did not influence the product yield. The hydrazinonitroalkenes 2a and 2c bearing an isopropyl ester moiety and weakly and strongly electron-donating para-substituted aryl groups on reaction with 1a afforded the corresponding products 4a and 4c in 78 and 66% yield (entries 1 and 3), respectively. Likewise, the hydrazinonitroalkene 2e having a weakly electron-withdrawing aryl substituent also produced the product 4e in 66% yield (entry 5). Comparable to those bearing electron-donating and electron-withdrawing aryl groups, a lower yield (58%) was obtained in the case of the electron-neutral substrate 2b (entry 2). The methodology was further generalized with the heterocycle-substituted hydrazinonitroalkene 2f, which also reacted smoothly with 1a to provide the desired fused thienoindole derivative 4f in 40% yield (entry 6). Additionally, the bulky tert-butyl dicarboxylate-containing hydrazinonitroalkene 2d is also compatible for this transformation and delivered 4d in 75% yield (entry 4).

Table 2. Synthesis of Thienoindole 4 by Cascade Reaction of Indoline-2-thione 1 with Hydrazinonitroalkene 2^a.

entry	1, R	2, Ar	R1	3 or 4	time	% yieldb
1	1a, Me	2a, 4-MeC6H4	iPr	4a	4 d	78
2	1a, Me	2b, C6H5	iPr	4b	4 d	58
3	1a, Me	2c, 4-OMeC6H4	iPr	4c	2 d	66
4	1a, Me	2d, 4-OMeC6H4	tBu	4d	3 d	75
5	1a, Me	2e, 4-ClC6H4	iPr	4e	3 d	66
6	1a, Me	2f, 2-thienyl	iPr	4f	3 d	40c
7	1b, Et	2a, 4-MeC6H4	iPr	4g	8 d	43c
8	1c, nPr	2a, 4-MeC6H4	iPr	4h	7 d	65
9	1d, Bn	2a, 4-MeC6H4	iPr	4i	8 d	64
10	1a, Me	2a, 4-MeC6H4	iPr	3a	3 h	46d
11	1a, Me	2g, Cy	iPr	4j	1 d	e

^aReaction scale: 1 (0.7 mmol, 1.0 equiv), 2 (0.7 mmol, 1.0 equiv), KOAc (0.7 mmol, 1.0 equiv), and acetic acid (0.4 μL, 1 mol %) in CH₃CN (3 mL) at RT.

^bAfter silica gel column chromatography.

^c10–20% of 1 and 2 was recovered; prolonged reaction led to a complex mixture.

^dShort reaction time allows isolation of the product before aromatization in this case.

^eComplex mixture.

Next, the substrate scope with regard to N-substituted indoline-2-thione was studied. It was found that various N-protected thioindoles 1b–d, including ethyl, n-propyl, and benzyl, reacted efficiently and provided the desired products in decent to good yields (43–64%) (Table 2, entries 7–9). It is worth to stress that the synthesis of desired aromatized thienoindoles requires a prolonged reaction time (2–8 days), but it is impressive by considering the outcome of the reaction. When the reaction was allowed to proceed for short  time, for instance, the reaction of N-methylated indoline-2-thione 1a with hydrazinonitroalkene 2a under the optimized reaction conditions provided dihydrothienoindole 3a in 46% yield after 3 h (Table 2, entry 10). Unfortunately, hydrazinonitroalkenes bearing an alkyl group such as cyclohexyl as in 2g was not suitable for our reaction (Table 2, entry 11).

The synthesized indole-annulated thiophene derivatives 4a–i were characterized by usual spectroscopic analyses. In most cases, these compounds showed signal broadening in the NMR spectrum because of the presence of rotamers. The partial double bond character of carbamate in the hydrazine moiety is responsible for the existence of rotamers, and additionally, the quadrupolar effect of N-atoms present in the hydrazine moiety complicates the NMR spectra (Scheme 1). To study this dynamic NMR phenomenon, variable-temperature ¹H NMR experiments were conducted by taking 4g as the representative compound (Figure 2). The spectra were recorded in the range of 296–328 K, but only marginal changes were observed in the spectral pattern. Although the signals for most of the aromatic and N–Et protons were reasonably well resolved and methyl protons of the isopropyl group remained unresolved at all of the temperatures studied, gradual resolution of one of the isopropyl methine protons resonating at 4.98–5.08 ppm was discernible upon increasing the temperature. A similar resolution was observed for two of the aromatic protons resonating at ∼7.50 ppm. The two broad signals appearing at ∼7.00 and 6.85 ppm in approximately 2:1 ratio, assigned for the N–H of two rotamers, in the spectrum recorded at 296 K coalesce at 313 K and become sharper at higher temperature. Overall, the sharper signals observed for the protons upon increasing the temperature are attributed to faster rotation about the C–N bond. Furthermore, the structure and regiochemistry of both indole-fused thiophenes and dihydrothienoindole were established by single-crystal X-ray analysis of compounds 4h and 3a (Figure 3).

Scheme 1. Possible Isomers of 4g.

Figure 2.

Variable-temperature ¹H NMR spectra of 4g recorded at different temperatures in the range 296–328 K.

Figure 3.

ORTEP representation of compounds 3a and 4h.

On the basis of the results obtained and the literature precedents,^16,17 a logical mechanism for the formation of indole-annulated thiophene 4 is proposed in Scheme 2. The anion, generated from indoline-2-thione 1 by abstraction of a proton from C-3 position, adds in a Michael fashion to hydrazinonitroalkene 2, which is activated by AcOH via H-bonding, leading to the formation of intermediate I. The lone pair of electrons on the nitrogen atom of the hydrazine moiety participates in the elimination of the nitro group in intermediate I and generates a transient acyliminium-type intermediate II. Subsequently, the intramolecular cyclization of II occurs in a 5-exo-trig fashion, resulting in the formation of dihydrothienoindole 3 which on air oxidation gives the desired aromatized thienoindole 4. Alternatively, the reaction can proceed in another pathway starting from intermediate I. Thio-enolization of I followed by intramolecular 5-exo-tet cyclization and subsequent air oxidation results in the formation of thieno[2,3-b]indole 4 (Scheme 2).

Scheme 2. Mechanism of Formation of Thienoindole 4 from Hydrazinonitroalkene 2 and Indoline-2-thione 1.

To further demonstrate the scope of the developed method for the synthesis of diversely functionalized fused thienoindoles, we employed the RC adduct of nitroalkene 5 with MVK 5 as the reaction partner with indoline-2-thione 1. The initial reaction was performed by treating 1a with the RC adduct 5a under the established reaction conditions (Table 3, entry 1). As expected, the indole-annulated thiophene 6a was formed, but the yield was quite low (20%) after 19 h stirring at room temperature. To improve the yield of the reaction, optimization studies were conducted by varying the bases, solvents, and additives by choosing 1a and 5a as the model substrates. Initially, we screened several organic and inorganic bases in acetonitrile medium. When the reaction was carried out in the presence of an organic base, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), the yield slightly improved to 44% in 1 h (Table 3, entry 2). Subsequent screening of milder inorganic bases such as K₂CO₃ and Cs₂CO₃ and stronger inorganic bases such as NaOH and KO^tBu revealed that the milder base K₂CO₃ promoted the reaction efficiently and delivered the product in 71% yield in 15 h (entries 3–6). Different solvents were then screened by selecting K₂CO₃ as the optimal base (entries 7–9). A considerable decline in yield was observed when the reaction was performed in other solvents such as THF, CHCl₃, and toluene, and the initially employed medium CH₃CN was found to be suitable for this transformation. Further, the loading of the base was varied which resulted in the formation of the product in reduced yield upon decreasing or increasing the amount of K₂CO₃ from 1 equiv (entries 10 and 11). Few additional experiments were performed by employing the additives such as LiCl and H₂O (entries 12 and 13). The additive, LiCl was found to be inefficient for improving the yield (entry 12). The reaction was complete in 8 h and the yield improved (76%) when H₂O was used as an additive (entry 13). When the reaction was performed under microwave irradiation at 40 °C, the reaction was complete in 15 min, but a substantial drop in yield (43%) was observed (entry 14). Finally, in terms of chemical yield and reaction time, entry 14 has been considered as optimal for this transformation. It may be noted that unlike in the reaction of thienoindole 1 with hydrazinonitroalkene 2, the aromatized fused thienoindole 6a was isolated in all of the cases when RC-adducts of nitroalkene 5a was employed.

Table 3. Optimization Studies^a.

entry	base (equiv)	time (h)	solvent	% yieldb
1	KOAc (1.0)	19	CH3CN	20
2	DBU (1.0)	1	CH3CN	44
3	K2CO3 (1.0)	15	CH3CN	71
4	Cs2CO3 (1.0)	15	CH3CN	57
5	NaOH (1.0)	4	CH3CN	50
6	KOtBu (1.0)	4	CH3CN	52
7	K2CO3 (1.0)	17	THF	45
8	K2CO3 (1.0)	18	CHCl3	35
9	K2CO3 (1.0)	26	toluene	30
10	K2CO3 (0.5)	23	CH3CN	47
11	K2CO3 (2.0)	12	CH3CN	55
12	K2CO3 (1.0) (LiCl)c	15	CH3CN	44
13	K2CO3(1.0) (H2O)d	8	CH3CN	76e
14	K2CO3 (1.0)	15 min	CH3CN	43f

^aReaction scale: 1a (0.23 mmol, 1.0 equiv), 5a (0.23 mmol, 1.0 equiv), and solvent (3 mL) at RT until complete consumption of at least one of the starting materials.

^bAfter column chromatography.

^cLiCl (0.23 mmol, 1.0 equiv).

^dCH₃CN/H₂O (97:3 v/v).

^e59% yield at 60 °C for 6 h.

^fUnder microwave at 40 °C.

With the optimal reaction conditions in hand, the scope of the reaction was investigated with different substituted RC-adducts of nitroalkenes 5 and indoline-2-thiones 1. Initially, we focused on studying the reactivity of various substituted RC-adducts of nitroalkenes 5b–l, taking thienoindole 1a as the representative reaction partner, and the results are summarized in Table 4. In general, the electron-donating substituents on the aryl group of RC-adducts of nitroalkenes 5 afforded the thieno[2,3-b]indole derivatives 6 in low to moderate yields (28–51%, entries 2, 3, 5, and 6). In some cases, fairly good yields (59 and 70%) were obtained when multiple electron-donating groups were placed at different positions (entries 4 and 7). RC-adducts of nitroalkenes bearing weakly electron-withdrawing groups (5h–j) were also subjected to the reaction. While high yield (63%) was observed in the case of 4-chloro-substituted RC-adduct 5i, modest yields were obtained from RC-adducts 5h and 5j containing bromo- and fluoro substituents (entries 8–10). The RC-adduct of nitroalkene 5k containing bulky 1-naphthyl group also participated in the reaction and furnished the corresponding fused thienoindole derivative 6k in comparable yield. Notably, the heteroaryl-derived RC-adduct of nitroalkene 5l also reacted with 1a and delivered the product, though in low yield (31%).

Table 4. Synthesis of Thienoindoles (6a–l) from Indoline-2-thione 1a and Various Aryl-Substituted RC Adducts 5^a.

entry	5, R	6	time (h)	% yieldb
1	5a, C6H5	6a	8	76
2	5b, 4-MeC6H4	6b	9	37c
3	5c, 4-OMeC6H4	6c	5	35c
4	5d, 3,4-(OMe)2C6H3	6d	9	59
5	5e, 3-OMeC6H4	6e	7	28c
6	5f, 3-(PhCH2O)C6H4	6f	7	51
7	5g, 2,5-(OMe)2C6H3	6g	9	70
8	5h, 4-BrC6H4	6h	7	46c
9	5i, 4-ClC6H4	6i	12	63
10	5j, 4-FC6H4	6j	7	48c
11	5k, 1-naphthyl	6k	7	56
12	5l, 2-thienyl	6l	8	31c

^aReaction scale: 1a (0.75 mmol, 1.0 equiv), 5 (0.75 mmol, 1.0 equiv), K₂CO₃ (0.75 mmol, 1.0 equiv) in CH₃CN and H₂O (97:3 v/v, 3 mL) at RT.

^bAfter silica gel column chromatography.

^c10–20% 1a and 5 was recovered; prolonged reaction led to a complex mixture.

Subsequently, the scope of indoline-2-thione 1 was explored by reacting a representative RC-adduct 5a with different N-substituted and aryl-substituted thienoindoles 1 under the optimized conditions (Table 5). Various N-protecting groups such as ethyl, n-propyl, and benzyl were tested. Among these, N-ethyl- and N-benzyl-protected indoline-2-thiones 1b and 1d afforded the product in excellent yields (87 and 94%, respectively, entries 1 and 3), whereas the N-propyl derivative 1c provided the corresponding product in much lower yield (entry 2). Indoline-2-thione 1e having chlorine on the aryl group (located at C-5 position) was subjected to reaction with 1a, and the expected product was isolated in moderate yield (44%, entry 4). It is noteworthy that the unprotected indoline-2-thione 1f is also compatible for this transformation and furnished the desired product in 44% yield (entry 5). Finally, the structures of thienoindoles 6a–q synthesized from RC-adducts 5a–l were characterized by analysis of their spectral data and further unambiguously confirmed by single-crystal X-ray analysis of a representative compound 6e (Figure 4). (Table 5

Table 5. Synthesis of Thienoindoles (6m–q) from RC Adduct 5a and Differently Substituted Indoline-2-thiones 1^a.

entry	1, R	X	6	time (h)	% yieldb
1	1b, Et	H	6m	12	87
2	1c, nPr	H	6n	12	55
3	1d, Bn	H	6o	13	94
4	1e, Me	Cl	6p	5	44
5	1f, H	H	6q	7	44

^aReaction scale: 1a (0.75 mmol, 1.0 equiv), 5 (0.75 mmol, 1.0 equiv), K₂CO₃ (0.75 mmol, 1.0 equiv) in CH₃CN, and H₂O (97:3 v/v, 3 mL) at RT.

^bAfter silica-gel column chromatography.

Figure 4.

ORTEP representation of compound 6e.

A plausible mechanism for the one-pot synthesis of thiophene-annulated indole derivatives 6 from RC-adducts is outlined in Scheme 3. The base-mediated Michael addition of indoline-2-thione 1 to the RC-adduct 5 generates intermediate I. Subsequently, an intramolecular thio-Mannich-type reaction occurs in a 5-exo-trig manner resulting in the intermediate II which undergoes elimination of HNO and H₂O to afford the aromatized product 6.

Scheme 3. Mechanism of Formation of Thienoindole 6 from RC-Adduct 5 and Indoline-2-thione 1.

Because the thieno[2,3-b]indole frameworks prepared from hydrazinonitroalkene 2 and RC-adducts 5 consist of functional moieties such as hydrazine and ketone, there exist enormous possibilities for further synthetic manipulation. The synthetic potential of these compounds was then highlighted by exemplifying a specific one-pot transformation of thieno[2,3-b]indole 4d containing a hydrazine ester moiety to pyrazole-tethered thieno[2,3-b]indole 8 (Scheme 4). Acid hydrolysis of 4d followed by decarboxylation generated the corresponding hydrazine derivative which on reaction in situ with acetyl acetone (Knorr-pyrazole synthesis) provided 8, though in moderate yield (48%).

Scheme 4. Synthesis of Pyrazole-Tethered Thieno[2,3-b]indole.

Conclusions

In summary, we have developed a convenient one-pot strategy for the synthesis of diverse functionalized thieno[2,3-b]indoles from easily accessible starting materials. The base-mediated [3 + 2] annulation of indoline-2-thione and α-hydrazinonitroalkenes derived from the MBH-reaction of nitroalkenes and azodicarboxylates provided the functionalized indole-annulated thiophene motifs in moderate to excellent yields. In a similar fashion, the RC-adducts of nitroalkenes underwent cascade cyclization when reacted with indoline-2-thione and afforded corresponding indole-fused thiophenes in moderate to good yields. Although a prolonged reaction time was required for the construction of thieno[2,3-b]indoles bearing a hydrazine moiety (2–8 d), the mild and metal-free reaction conditions make this protocol quite attractive. Moreover, the hydrazine moiety on the thieno[2,3-b]indole skeleton could be transformed to pyrazole, which further broadens the synthetic applicability of the developed strategy. Studies to further extend the scope of the developed method for synthesizing novel heterocycle-fused indoles by employing various indolines and functionalized nitroalkenes are currently underway in our laboratory.

Experimental Section

General Information

The melting points recorded are uncorrected. NMR spectra (¹H, ¹H decoupled ¹³C, ¹⁹F, APT, ¹H–¹H COSY) were recorded with tetramethylsilane as the internal standard. The coupling constants (J values) are given in Hz. IR spectra were recorded on a Fourier transform infrared spectrometer, and the values are expressed in cm^–1. High-resolution mass spectra were recorded under ESI Q-TOF conditions. X-ray data were collected on a diffractometer equipped with graphite monochromated Mo Kα radiation. The structure was solved by direct methods shelxs97 and refined by full matrix least squares against F2 using shelxl97 software. The starting materials indoline-2-thiones,²⁷ MBH-adducts,²¹ and RC-adducts²² were prepared by literature methods.

General Procedure for the Synthesis of Thienoindole (4)

To a stirred solution of indoline-2-thione 1 (0.7 mmol, 1 equiv), KOAc (104 mg, 0.7 mmol, 1 equiv), and AcOH (0.4 μL, 1 mol %) in CH₃CN (3 mL) at room temperature was added the MBH adduct 2 (0.7 mmol, 1 equiv). After the completion of the reaction [monitored by thin-layer chromatography (TLC)], the reaction mixture was concentrated in vacuo and the crude product was purified by silica gel (60–120 mesh) column chromatography by gradient elution with ethyl acetate/pet ether (10–25%).

Diisopropyl 1-(8-Methyl-3-(p-tolyl)-3,8-dihydro-2H-thieno[2,3-b]indol-2-yl)hydrazine-1,2-dicarboxylate (3a)

White solid; yield 155 mg, 46%; mp 158–160 °C; IR (KBr, cm^–1): 3292 (br m), 2980 (m), 1720 (vs), 1384 (m), 1107 (s); ¹H NMR (CDCl₃, 500 MHz): δ 1.10–1.40 (br poorly resolved, 12H), 2.32 (s, 3H), 3.68 (s, 3H), 4.90–5.10 (br unresolved, 3H), 6.60 (br s, 1H), 6.72 (br unresolved d, 1H), 6.95 (br d, J = 7.3 Hz, 2H), 7.06 (t, J = 8.1 Hz, 1H), 7.11 (d, J = 7.3 Hz, 2H), 7.21 (d, J = 8.1 Hz, 1H), 7.24 (br unresolved, 2H); ¹³C NMR (CDCl₃, 125 MHz): δ 21.2, 22.0, 22.1, 32.1, 50.8, 70.3, 71.6, 83.9, 109.0, 117.3, 117.5, 119.7, 119.8, 125.1, 127.5, 127.8, 129.5, 136.9, 138.0, 141.0, 154.5, 156.0; MS (ES+, Ar) m/z (rel intensity): 520 (MK⁺, 30), 504 (100), 482 (MH⁺, 40); HRMS (ES⁺): calcd for C₂₆H₃₁N₃O₄SNa (MNa⁺, 100), 504.1927; found, 504.1925.

Diisopropyl 1-(8-Methyl-3-(p-tolyl)-8H-thieno[2,3-b]indol-2-yl)hydrazine-1,2-dicarboxylate (4a)

White solid; yield 261 mg, 78%; mp 192–194 °C; IR (KBr, cm^–1): 3289 (br m), 2980 (m), 1725 (vs), 1483 (m), 1469 (m), 1372 (m), 1306 (m), 1241 (m), 1180 (m), 1106 (s), 1038 (m), 742 (s); ¹H NMR (CDCl₃, 500 MHz): δ 1.14 (br unresolved d, 6H), 1.25–1.40 (br unresolved, 6H), 2.45 (s, 3H), 3.84 (s, 3H), 4.90–5.00 (br unresolved m, 1H), 5.00–5.10 (br unresolved m, 1H), 6.90 (br s, 1H), 7.07 (t, J = 8.0 Hz, 1H), 7.27 (t, J = 8.0 Hz, 1H), 7.31 (d, J = 7.7 Hz, 2H), 7.37 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 7.7 Hz, 2H), 7.58 (d, J = 8.0 Hz, 1H); ¹³C NMR (CDCl₃, 125 MHz): δ 21.5, 21.8, 22.1, 32.2, 70.4, 71.6, 109.1, 117.8, 119.2, 119.4, 122.2, 122.9, 128.7, 129.5, 131.5, 133.2, 133.8, 137.8, 141.5, 142.0, 155.7, 156.0; MS (ES⁺, Ar) m/z (rel intensity): 518 (MK⁺, 85), 502 (MNa⁺, 100), 480 (MH⁺, 6), 377 (18); HRMS (ES⁺): calcd for C₂₆H₂₉N₃O₄SNa (MNa⁺, 100), 502.1771; found, 502.1778.

Diisopropyl 1-(8-Methyl-3-phenyl-8H-thieno[2,3-b]indol-2-yl)hydrazine-1,2-dicarboxylate (4b)

White solid; yield 189 mg, 58%; mp 179–172 °C; IR (KBr, cm^–1): 3291 (br w), 2980 (m), 1724 (s), 1482 (s), 1466 (s), 1374 (m), 1304 (m), 1244 (s), 1106 (s), 740 (m); ¹H NMR (CDCl₃, 500 MHz): δ 1.11 (br unresolved d, 6H), 1.25–1.40 (br unresolved, 6H), 3.84 (s, 3H), 4.90–5.00 (br unresolved m, 1H), 5.00–5.10 (br unresolved m, 1H), 7.01 (br s), 7.08 (t, J = 8.0 Hz, 1H), 7.28 (t, J = 8.0 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.43 (t, J = 7.6 Hz, 1H), 7.52 (t, J = 7.6 Hz, 2H), 7.57 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 7.6 Hz, 2H); ¹³C NMR (CDCl₃, 125 MHz): δ 21.8, 22.1, 32.2, 70.4, 71.6, 109.1, 117.7, 119.1, 119.4, 122.2, 122.8, 128.0, 128.8, 128.9, 129.2, 133.1, 134.5, 141.5, 142.0, 155.6, 156.1; MS (ES⁺, Ar) m/z (rel intensity): 504 (MK⁺, 100); HRMS (ES⁺): calcd for C₂₅H₂₇N₃O₄SK (MK⁺, 100), 504.1354; found, 504.1355.

Diisopropyl 1-(3-(4-Methoxyphenyl)-8-methyl-8H-thieno[2,3-b]indol-2-yl)hydrazine-1,2-dicarboxylate (4c)

White solid; yield 229 mg, 66%; mp 96–98 °C; IR (KBr, cm^–1): 3304 (br m), 2980 (m), 1726 (s), 1726 (vs), 1486 (m), 1246 (s), 1107 (m); ¹H NMR (CDCl₃, 500 MHz): δ 1.13 (br unresolved, 6H), 1.27 (d, J = 6.2 Hz, 6H), 3.84 (s, 3H), 3.89 (s, 3H), 4.90–5.08 (unresolved m, 2H), 6.85 (br s, 1H), 7.02 (d, J = 8.6 Hz, 2H), 7.06 (t, J = 7.5 Hz, 1H), 7.26 (t, J = 7.5 Hz, 1H), 7.37 (d, J = 8.6 Hz, 2H), 7.51 (d, J = 7.5 Hz, 1H), 7.56 (d, J = 7.5 Hz, 1H); ¹³C NMR (CDCl₃, 125 MHz): δ 21.9, 22.1, 32.2, 55.5, 70.1, 71.6, 109.1, 114.3, 117.9, 119.1, 119.4, 122.2, 122.9, 126.8, 128.6, 130.1, 132.9, 141.5, 142.0, 155.8, 156.0, 159.4; MS (ES⁺, Ar) m/z (rel intensity): 534 (MK⁺, 32), 518 (MNa⁺, 30) 496 (100); HRMS (ES⁺): calcd for C₂₆H₃₀N₃O₅S (MH⁺, 100), 496.1901; found, 496.1911.

Diisobutyl 1-(3-(4-Methoxyphenyl)-8-methyl-8H-thieno[2,3-b]indol-2-yl)hydrazine-1,2-dicarboxylate (4d)

White solid; yield 275 mg, 75%; mp 201–203 °C; IR (KBr, cm^–1): 3302 (br w), 2979 (m), 1725 (s), 1482 (s), 1247 (s), 1159 (vs); ¹H NMR (CDCl₃, 500 MHz): δ 1.30, 1.53 (s, 18H), 3.84 (s, 3H), 3.89 (s, 3H), 6.90 (br s, 1H), 7.03–7.12 (br unresolved, 3H), 7.25–7.31 (br unresolved, 1H), 7.35–7.40 (br unresolved, 1H), 7.54–7.66 (br unresolved, 3H); ¹³C NMR (CDCl₃, 125 MHz): δ 28.0, 28.3, 32.2, 55.4, 81.9, 82.5, 109.1, 114.2, 117.7, 119.1, 119.3, 122.0, 122.9, 127.0, 129.5, 130.0, 132.2, 141.4, 141.9, 154.6, 155.5, 159.3; MS (ES⁺, Ar) m/z (rel intensity): 562 (MK⁺, 100); HRMS (ES⁺): calcd for C₂₈H₃₃N₃O₅SK (MK⁺, 100), 562.1773; found, 562.1769.

Diisopropyl 1-(3-(4-Chlorophenyl)-8-methyl-8H-thieno[2,3-b]indol-2-yl)hydrazine-1,2-dicarboxylate (4e)

White solid; yield 231 mg, 66%; mp 164–166 °C; IR (KBr, cm^–1): 3284 (br w), 2980 (w), 1725 (vs), 1481 (m), 1466 (m), 1374 (m), 1306 (m), 1245 (m), 1105 (s), 741 (m); ¹H NMR (CDCl₃, 500 MHz): δ 1.12 (br unresolved d, 6H), 1.20–1.40 (br unresolved, 6H), 3.85 (s, 3H), 4.90–5.00 (br unresolved m, 1H), 5.00–5.10 (br unresolved m, 1H), 6.91 (br s, 1H), 7.07 (t, J = 7.9 Hz, 1H), 7.28 (t, J = 7.9 Hz, 1H), 7.37 (d, J = 7.9 Hz, 1H), 7.48 (d, J = 8.2 Hz, 2H), 7.51 (d, J = 8.2 Hz, 2H), 7.53–7.57 (br unresolved, 1H); ¹³C NMR (CDCl₃, 125 MHz): δ 21.9, 22.2, 32.3, 70.6, 71.8, 109.3, 117.6, 119.0, 119.6, 122.4, 122.7, 129.1, 129.7, 130.3, 132.0, 133.0, 134.0, 141.6, 142.2, 155.6, 156.2; MS (ES⁺, Ar) m/z (rel intensity): 524 ([MNa+2]⁺, 11), 526 (MNa⁺, 40), 502 ([MH+2]⁺, 35), 500 (MH⁺, 100); HRMS (ES⁺): calcd for C₂₅H₂₇N₃O₄SCl (MH⁺, 100), 500.1405; found, 500.1404.

Diisopropyl 1-(8-Methyl-3-(thiophen-2-yl)-8H-thieno[2,3-b]indol-2-yl)hydrazine-1,2-dicarboxylate (4f)

White solid; yield 132 mg, 40%; mp 145–147 °C; IR (KBr, cm^–1): 3299 (br w), 2980 (w), 1728 (vs), 1599 (w), 1480 (m), 1237 (m), 1105 (m); ¹H NMR (CDCl₃, 500 MHz): δ 1.13 (br d, J = 5.3 Hz, 6H), 1.35–1.45 (br unresolved, 6H), 3.83 (s, 3H), 4.95–5.00 (br m, 1H), 5.02–5.12 (br unresolved m, 1H), 7.06 (br s, 1H), 7.15 (t, J = 7.9 Hz, 1H), 7.21 (dd, J = 4.7, 4.2 Hz, 1H), 7.31 (t, J = 7.9 Hz, 1H), 7.38 (d, J = 7.9 Hz, 1H), 7.42 (d, J = 4.7 Hz, 1H), 7.50 (br unresolved, 1H), 7.92 (d, J = 7.9 Hz, 1H); ¹³C NMR (CDCl₃, 125 MHz): δ 21.8, 22.1, 32.2, 70.5, 71.8, 109.2, 117.1, 119.4, 119.5, 122.4, 122.6, 126.0, 126.1, 127.2, 127.4, 129.3, 134.8, 141.5, 142.0, 155.5, 156.0; MS (ES⁺, Ar) m/z (rel intensity): 510 (MK⁺, 100); HRMS (ES⁺): calcd for C₂₃H₂₅N₃O₄S₂K (MK⁺, 100), 510.0918; found, 510.0919.

Diisopropyl 1-(8-Ethyl-3-(p-tolyl)-8H-thieno[2,3-b]indol-2-yl)hydrazine-1,2-dicarboxylate (4g)

White solid; yield 148 mg, 43%; mp 184–186 °C; IR (KBr, cm^–1): 3289 (br m), 2980 (s), 1726 (vs), 1479 (s), 1466 (s), 1374 (m), 1302 (m), 1242 (s), 1181 (m), 1106 (s), 1038 (m), 740 (m); ¹H NMR (CDCl₃, 500 MHz): δ 1.11 (br unresolved d, 6H), 1.20–1.40 (br resolved, 6H), 1.51 (t, J = 7.2 Hz, 3H), 2.43 (s, 3H), 4.26 (q, J = 7.2 Hz, 2H), 4.88–4.95 (br unresolved m, 1H), 4.98–5.08 (br unresolved, 1H), 6.84 (br s, 1H), 7.03 (t, J = 8.1 Hz, 1H), 7.24 (t, J = 8.1 Hz, 1H), 7.28 (d, J = 7.2 Hz, 2H), 7.37 (d, J = 8.1 Hz, 1H), 7.46 (br d, J = 7.2 Hz, 2H), 7.55 (d, J = 8.1 Hz, 1H), no appreciable change in the pattern even at 328 K, see VT NMR spectra; ¹³C NMR (CDCl₃, 125 MHz): δ 13.9, 21.4, 21.8, 22.0, 40.8, 70.3, 71.5, 109.1, 118.1, 119.2, 122.0, 122.9, 128.7, 129.4, 131.4, 133.1, 133.6, 137.7, 140.4, 155.6, 156.0; MS (ES⁺, Ar) m/z (rel intensity): 532 (MK⁺, 100), 516 (MNa⁺, 65), 494 (35); HRMS (ES⁺): calcd for C₂₇H₃₁N₃O₄SK (MK⁺, 100), 532.1667; found, 532.1665.

Diisopropyl 1-(8-Propyl-3-(p-tolyl)-8H-thieno[2,3-b]indol-2-yl)hydrazine-1,2-dicarboxylate (4h)

White solid; yield 230 mg, 65%; mp 169–171 °C; IR (KBr, cm^–1): 3290 (br w), 2979 (m), 1726 (vs), 1478 (m), 1244 (m), 1107 (s); ¹H NMR (CDCl₃, 500 MHz): δ 1.03 (t, J = 7.2 Hz, 3H), 1.14 (br unresolved d, 6H), 1.25–1.40 (br unresolved, 6H), 1.99 (sextet, J = 7.2 Hz, 2H), 2.46 (s, 3H), 4.18 (t, J = 7.2 Hz, 2H), 4.92–4.98 (br unresolved m, 1H), 5.02–5.10 (br unresolved m, 1H), 6.95 (br s, 1H), 7.06 (t, J = 8.0 Hz, 1H), 7.26 (t, J = 8.0 Hz, 1H), 7.32 (d, J = 7.1 Hz, 2H), 7.40 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 7.1 Hz, 2H), 7.60 (d, J = 8.0 Hz, 1H); ¹³C NMR (CDCl₃, 125 MHz): δ 11.8, 21.5, 21.8, 22.1, 22.3, 47.9, 70.4, 71.5, 109.3, 118.0, 118.1, 119.2, 122.0, 122.9, 128.7, 129.5, 131.5, 133.1, 133.6, 137.7, 141.0, 141.2, 155.7, 156.1; MS (ES⁺, Ar) m/z (rel intensity): (MK⁺, 100); HRMS (ES⁺): calcd for C₂₈H₃₃N₃O₄SK (MK⁺, 100), 546.1823; found, 546.1821.

Diisopropyl 1-(8-Benzyl-3-(p-tolyl)-8H-thieno[2,3-b]indol-2-yl)hydrazine-1,2-dicarboxylate (4i)

White solid; yield 249 mg, 64%; mp 166–168 °C; IR (KBr, cm^–1): 3278 (br m), 2980 (m), 1720 (vs), 1454 (m), 1373 (m), 1303 (s), 1244 (s), 1106 (s), 1037 (m), 738 (m); ¹H NMR (CDCl₃, 500 MHz): δ 1.13 (br unresolved d, 6H), 1.22–1.35 (br unresolved, 6H), 2.46 (s, 3H), 4.90–5.00 (br unresolved m, 1H), 5.00–5.08 (br unresolved m, 1H), 5.38 (s, 2H), 6.92 (br s, 1H), 7.08 (t, J = 7.5 Hz, 1H), 7.23–7.43 (m, 7H), 7.32 (d, J = 7.8 Hz, 2H), 7.51 (br d, J = 7.8 Hz, 2H), 7.62 (d, J = 7.5 Hz, 1H); ¹³C NMR (CDCl₃, 125 MHz): δ 21.5, 21.9, 22.1, 50.0, 70.4, 71.5, 109.6, 118.5, 119.3, 119.6, 122.3, 123.1, 127.5, 127.8, 128.1, 128.8, 129.0, 129.4, 129.5, 131.4, 133.0, 135.9, 137.8, 141.2, 155.7, 155.9; MS (ES⁺, Ar) m/z (rel intensity): 612 ([MK + H₂O]⁺, 25), 594 (MK⁺, 100), 578 (MNa⁺, 45); HRMS (ES⁺): calcd for C₃₂H₃₃N₃O₄SK (MK⁺, 100), 594.1823; found, 594.1825.

General Procedure for the Synthesis of Thienoindoles (6)

To a stirred solution of indoline-2-thione 1 (0.75 mmol, 1 equiv) and K₂CO₃ (104 mg, 0.75 mmol, 1 equiv) in CH₃CN/H₂O (97:3, 3 mL) at room temperature was added the RC adduct 5 (0.75 mmol, 1 equiv). After the completion of the reaction (monitored by TLC), the reaction mixture was concentrated in vacuo and the crude residue was purified by silica gel column chromatography by gradient elution with ethyl acetate/pet ether (10–25%).

4-(8-Methyl-2-phenyl-8H-thieno[2,3-b]indol-3-yl)butan-2-one (6a)

White solid; yield 189 mg, 76%; mp 129–131 °C; IR (KBr, cm^–1): 3052 (w), 2922 (m), 1715 (vs), 1590 (m), 1360 (m), 1330 (s), 1163 (m), 743 (s); ¹H NMR (CDCl₃, 500 MHz): δ 2.10 (s, 3H), 2.76 (t, J = 7.4 Hz, 2H), 3.15 (t, J = 7.4 Hz, 2H), 3.80 (s, 3H), 6.99 (t, J = 8.2 Hz, 1H), 7.21 (t, J = 8.2 Hz 1H), 7.30 (d, J = 8.2 Hz, 1H), 7.41–7.45 (m, 2H), 7.50 (t, J = 7.4 Hz, 2H), 7.55 (t, J = 7.4 Hz, 2H); ¹³C NMR (CDCl₃, 125 MHz): δ 23.1, 30.1, 32.2, 45.9, 109.0, 118.9, 119.1, 121.7, 122.1, 122.4, 127.5, 128.7, 129.6, 130.2, 131.7, 136.1, 141.4, 142.0, 207.6; MS (ES⁺, Ar) m/z (rel intensity): 379 (M2Na⁺, 100), 372 (MK⁺, 70), 356 (MNa⁺, 80); HRMS (ES⁺): calcd for C₂₁H₁₉NOSK (MK⁺), 372.0819; found, 372.0825.

4-(8-Methyl-2-(p-tolyl)-8H-thieno[2,3-b]indol-3-yl)butan-2-one (6b)

White solid; yield 95 mg, 37%; mp 122–124 °C; IR (KBr, cm^–1): 3050 (w), 2925 (m), 1715 (s), 1484 (m), 1465 (m), 1266 (m), 1162 (m), 822 (m), 740 (vs), 705 (m); ¹H NMR (CDCl₃, 500 MHz): δ 2.12 (s, 3H), 2.47 (s, 3H), 2.78 (t, J = 4.0 Hz, 2H), 3.15 (t, J = 4.0 Hz, 2H), 3.83 (s, 3H), 7.02 (t, J = 7.5 Hz, 1H), 7.23 (t, J = 7.5 Hz, 1H), 7.31–7.34 (m, 3H), 7.43–7.47 (m, 3H); ¹³C NMR (CDCl₃, 125 MHz): δ 21.5, 23.2, 30.2, 32.2, 46.0, 109.0, 119.0, 119.1, 121.7, 122.3 (×2), 129.4, 129.5, 129.9, 131.7, 133.0, 137.2, 141.4, 142.0, 207.7; MS (ES⁺, Ar) m/z (rel intensity): 386 (MK⁺, 30), 370 (MNa⁺, 100); HRMS (ES⁺): calcd for C₂₂H₂₁NOSNa (MNa⁺), 370.1236; found, 370.1240.

4-(2-(4-Methoxyphenyl)-8-methyl-8H-thieno[2,3-b]indol-3-yl)butan-2-one (6c)

White solid; yield 95 mg, 35%; mp 132–134 °C; IR (KBr, cm^–1): 3053 (w), 2930 (m), 1715 (s), 1610 (m), 1502 (s), 1490 (s), 1465 (s), 1245 (vs), 1174 (s), 1030 (s), 742 (vs); ¹H NMR (CDCl₃, 500 MHz): δ 2.13 (s, 3H), 2.78 (t, J = 7.4 Hz, 2H), 3.16 (t, J = 7.4 Hz, 2H), 3.83 (s, 3H), 3.91 (s, 3H), 7.03 (t, J = 8.1 Hz, 1H), 7.06 (d, J = 8.6 Hz, 2H), 7.24 (t, J = 8.1 Hz, 1H), 7.33 (d, J = 8.1 Hz, 1H), 7.45 (d, J = 8.1 Hz, 1H), 7.49 (d, J = 8.6 Hz, 2H); ¹³C NMR (CDCl₃, 125 MHz): δ 23.2, 30.2, 32.2, 46.0, 55.5, 109.0, 114.1, 118.9, 119.1, 121.7, 122.2, 122.4, 128.3, 129.7, 130.7, 131.4, 141.3, 142.0, 159.1, 207.7; MS (ES⁺, Ar) m/z (rel intensity): 402 (MK⁺, 25), 386 (100), 364 (MH⁺, 20); HRMS (ES⁺): calcd for C₂₂H₂₁NO₂SNa (MNa⁺), 386.1185; found, 386.1178.

4-(2-(3,4-Dimethoxyphenyl)-8-methyl-8H-thieno[2,3-b]indol-3-yl)butan-2-one (6d)

Brown sticky solid; yield 174 mg, 59%; IR (KBr, cm^–1): 3054 (w), 2931 (m), 1714 (s), 1507 (s), 1487 (s), 1465 (s), 1260 (s), 1245 (s), 1026 (s), 742 (vs); ¹H NMR (CDCl₃, 500 MHz): δ 2.13 (s, 3H), 2.78 (t, J = 7.3 Hz, 2H), 3.19 (t, J = 7.3 Hz, 2H), 3.81 (s, 3H), 3.91 (s, 3H), 3.98 (s, 3H), 7.01 (t, J = 8.2 Hz, 1H), 7.04 (d, J = 7.3 Hz, 1H), 7.09 (dd, J = 7.3, 1.3 Hz, 1H), 7.14 (d, J = 1.3 Hz, 1H), 7.24 (t, J = 8.2 Hz, 1H), 7.33 (d, J = 8.2 Hz, 1H), 7.40 (d, J = 8.2 Hz, 1H); ¹³C NMR (CDCl₃, 125 MHz): δ 23.1, 30.2, 32.2, 45.8, 56.0 (×2), 109.0, 111.2, 112.7, 118.8, 119.0, 121.7, 121.8, 122.1, 122.2, 128.5, 129.7, 131.3, 141.2, 141.9, 148.4, 148.9, 207.6; MS (ES⁺, Ar) m/z (rel intensity): 432 (MK⁺, 25), 416 (MNa⁺, 100); HRMS (ES⁺): calcd for C₂₃H₂₃NO₃SNa (MNa⁺), 416.1291; found, 416.1298.

4-(2-(3-Methoxyphenyl)-8-methyl-8H-thieno[2,3-b]indol-3-yl)butan-2-one (6e)

White solid; yield 76 mg, 28%; mp 97–99 °C; IR (KBr, cm^–1): 3052 (w), 2933 (m), 1714 (s), 1599 (m), 1578 (m), 1491 (s), 1465 (s), 1223 (m), 740 (vs); ¹H NMR (CDCl₃, 500 MHz): δ 2.14 (s, 3H), 3.80 (t, J = 7.3 Hz, 2H), 3.20 (t, J = 7.3 Hz, 2H), 3.83 (s, 3H), 3.88 (s, 3H), 7.00 (d, J = 7.8 Hz, 1H), 7.05 (t, J = 8.2 Hz, 1H), 7.15 (d, J = 7.8 Hz, 1H), 7.17 (s, 1H), 7.25 (t, J = 8.2 Hz, 1H), 7.34 (d, J = 8.2 Hz, 1H), 7.44 (t, J = 7.8 Hz, 1H), 7.49 (d, J = 8.2 Hz, 1H); ¹³C NMR (CDCl₃, 125 MHz): δ 23.2, 30.2, 32.3, 46.0, 55.5, 109.1, 113.4, 115.0, 119.1, 119.2, 121.8, 122.1, 122.2, 129.7, 130.3, 131.6, 137.4, 141.4, 142.1, 159.9, 207.6; MS (ES⁺, Ar) m/z (rel intensity): 402 (MK⁺, 50), 386 (MNa⁺, 100), 364 (MH⁺, 5), 306 (5); HRMS (ES⁺): calcd for C₂₂H₂₁NO₂SNa (MNa⁺), 386.1185; found, 386.1182.

4-(2-(3-(Benzyloxy)phenyl)-8-methyl-8H-thieno[2,3-b]indol-3-yl)butan-2-one (6f)

Brown sticky solid; yield 167 mg, 51%; IR (KBr, cm^–1): 2928 (w), 1715 (s), 1713 (s), 1491 (m), 1465 (m), 1264 (m), 738 (vs); ¹H NMR (CDCl₃, 500 MHz): δ 2.14 (s, 3H), 2.77 (t, J = 7.3 Hz, 2H), 3.18 (t, J = 7.3 Hz, 2H), 3.83 (s, 3H), 5.16 (s, 2H), 7.06 (t, J = 7.0 Hz, 1H), 7.09 (dd, J = 7.5 Hz, J = 1.8 Hz, 1H), 7.21 (d, J = 7.5 Hz, 1H), 7.23 (t, J = 7.0 Hz, 1H), 7.26 (t, J = 7.5 Hz, 1H), 7.34–7.38 (m, 2H), 7.41 (t, J = 8.2 Hz, 2H), 7.46 (d, J = 7.0 Hz, 1H), 7.47–7.51 (m, 3H); ¹³C NMR (CDCl₃, 125 MHz): δ 23.1, 30.1, 32.2, 45.9, 70.1, 109.0, 114.4, 115.8, 119.0, 119.1, 121.7, 122.0, 122.1, 122.3, 127.6, 128.1, 128.7, 129.7, 130.3, 131.4, 137.1, 137.4, 141.4, 142.0, 159.0, 207.6; MS (ES⁺, Ar) m/z (rel intensity): 478 (MK⁺, 50), 462 (MNa⁺, 100); HRMS (ES⁺): calcd for C₂₈H₂₅NO₂SNa (MNa⁺), 462.1498; found, 462.1504.

4-(2-(2,5-Dimethoxyphenyl)-8-methyl-8H-thieno[2,3-b]indol-3-yl)butan-2-one (6g)

White solid; yield 205 mg, 70%; mp 131–133 °C; IR (KBr, cm^–1): 2935 (m), 1714 (s), 1493 (m), 1465 (m), 1268 (m), 1218 (s), 1047 (s), 1024 (m), 738 (vs); ¹H NMR (CDCl₃, 500 MHz): δ 2.14 (s, 3H), 2.80 (t, J = 7.3 Hz, 2H), 3.08 (t, J = 7.3 Hz, 2H), 3.71 (s, 3H), 3.81 (s, 3H), 3.82 (s, 3H), 6.96–7.01 (m, 2H), 7.01–7.04 (m, 2H), 7.22 (t, J = 7.8 Hz, 1H), 7.30 (ABq collapsed to t, J = 9.0 Hz, 2H); ¹³C NMR (CDCl₃, 125 MHz): δ 23.7, 30.1, 32.2, 45.6, 55.9, 56.3, 108.9, 112.7, 114.2, 117.1, 118.9, 119.0, 121.5, 122.4, 122.6, 125.6, 127.2, 131.2, 141.2, 141.9, 151.6, 153.7, 207.9; MS (ES⁺, Ar) m/z (rel intensity): 432 (MK⁺, 20), 416 (MNa⁺, 80), 394 (MH⁺, 35), 390 (100); HRMS (ES⁺): calcd for C₂₃H₂₃NO₃SNa (MNa⁺), 416.1291; found, 416.1291.

4-(2-(4-Bromophenyl)-8-methyl-8H-thieno[2,3-b]indol-3-yl)butan-2-one (6h)

White solid; yield 142 mg, 46%; mp 122–124 °C; IR (KBr, cm^–1): 3049 (w), 2925 (m), 1715 (vs), 1479 (s), 1465 (s), 1332 (m), 1162 (m), 827 (m), 741 (vs); ¹H NMR (CDCl₃, 500 MHz): δ 2.15 (s, 3H), 2.79 (t, J = 7.3 Hz, 2H), 3.15 (t, J = 7.3 Hz, 2H), 3.84 (s, 3H), 7.05 (t, J = 8.0 Hz, 1H), 7.26 (t, J = 8.0 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 8.2 Hz, 2H), 7.66 (d, J = 8.2 Hz, 2H); ¹³C NMR (CDCl₃, 125 MHz): δ 23.0, 30.2, 32.3, 45.8, 109.2, 118.8, 119.3, 121.6, 121.8, 121.9, 130.4, 130.6, 131.3, 131.9, 135.0, 141.5, 142.0, 207.4; MS (ES⁺, Ar) m/z (rel intensity): 452 ([MK+2]⁺, 15), 450 (MK⁺, 14), 436 [MNa+2]⁺, 100), 434 (MNa⁺, 98); (HRMS (ES⁺): calcd for C₂₁H₁₈NOSBrNa (MNa⁺), 434.0185; found, 434.0183.

4-(2-(4-Chlorophenyl)-8-methyl-8H-thieno[2,3-b]indol-3-yl)butan-2-one (6i)

White solid; yield 175 mg, 63%; mp 95–97 °C; IR (KBr, cm^–1): 3051 (w), 2927 (m), 1715 (vs), 1481 (s), 1465 (s), 1332 (m), 1162 (m), 1088 (m), 829 (m), 740 (vs); ¹H NMR (CDCl₃, 500 MHz): δ 2.16 (s, 3H), 2.80 (t, J = 7.3 Hz, 2H), 3.17 (t, J = 7.3 Hz, 2H), 3.83 (s, 3H), 7.07 (t, J = 8.0 Hz, 1H), 7.28 (t, J = 8.0 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.52–7.54 (unresolved m, 4H); ¹³C NMR (CDCl₃, 125 MHz): δ 23.0, 30.1, 32.2, 45.7, 109.1, 118.7, 119.2, 121.8, 121.9, 128.9, 130.3, 130.6, 130.9, 133.4, 134.5, 141.4, 142.0, 207.3; MS (ES⁺, Ar) m/z (rel intensity): 408 ([MK+2]⁺, 20), 406 (MK⁺, 60), 392 ([MNa+2]⁺, 33), 390 (MNa⁺, 100); HRMS (ES⁺): calcd for C₂₁H₁₈ClNOSNa (MNa⁺), 390.0690; found, 390.0692.

4-(2-(4-Fluorophenyl)-8-methyl-8H-thieno[2,3-b]indol-3-yl)butan-2-one (6j)

White solid; yield 125 mg, 48%; mp 79–81 °C; IR (KBr, cm^–1): 2928 (w), 1715 (vs), 1500 (s), 1465 (m), 1221 (s), 1158 (m), 742 (vs); ¹H NMR (CDCl₃, 500 MHz): δ 2.16 (s, 3H), 2.81 (t, J = 7.3 Hz, 2H), 3.17 (t, J = 7.3 Hz, 2H), 3.84 (s, 3H), 7.07 (t, J = 8.2 Hz, 1H), 7.24 (t, J = 8.2 Hz, 1H), 7.27 (dd, J = 7.7 Hz, J = 3.5 Hz, 2H), 7.36 (d, J = 8.2 Hz, 1H), 7.43 (d, J = 8.2 Hz, 1H), 7.56 (dd, J = 7.7, 5.6 Hz, 2H); ¹³C NMR (CDCl₃, 125 MHz): δ 23.0, 30.1, 32.2, 45.8, 109.1, 115.7 (d, J = 21.3 Hz), 118.7, 119.2, 121.8, 122.0, 122.1, 130.3, 130.5, 131.2 (d, J = 8.8 Hz), 132.0 (d, J = 3.8 Hz), 141.3, 142.0, 162.3 (d, J = 245.0 Hz), 207.5; ¹⁹F NMR (CDCl₃, 470 MHz): δ 114.7; MS (ES⁺, Ar) m/z (rel intensity): 390 (MK⁺, 55), 374 (MNa⁺, 100), 352 (MH⁺, 8), 294 (17); HRMS (ES⁺): calcd for C₂₁H₁₈FNOSNa (MNa⁺), 374.0985; found, 374.0989.

4-(8-Methyl-2-(naphthalen-1-yl)-8H-thieno[2,3-b]indol-3-yl)butan-2-one (6k)

White solid; yield 160 mg, 56%; mp 99–100 °C; IR (KBr, cm^–1): 3054 (m), 2928 (m), 1715 (s), 1489 (m), 1464 (m), 1331 (m), 1265 (m), 1163 (m), 803 (m), 782 (s), 740 (vs), 703 (m); ¹H NMR (CDCl₃, 500 MHz): δ 2.0 (s, 3H), 2.68, 2.72 (ABqdd, J = 17.7, 7.1, 6.6 Hz, 2H), 3.00 (ddd, J = 15.1, 7.1, 6.6 Hz, 1H), 3.09 (ddd, J = 15.1, 7.1, 6.6 Hz, 1H), 3.88 (s, 3H), 6.68 (d, J = 7.9 Hz, 1H), 6.83 (t, J = 7.9 Hz, 1H), 7.18 (t, J = 7.9 Hz, 1H), 7.33 (d, J = 7.9 Hz, 1H), 7.36 (t, J = 7.2 Hz, 1H), 7.53 (t, J = 7.2 Hz, 1H), 7.59 (d, J = 7.1 Hz, 1H), 7.63 (t, J = 7.1 Hz, 1H), 7.78 (d, J = 7.2 Hz, 1H), 7.98 (d, J = 7.2 Hz, 1H), 7.99 (d, J = 7.1 Hz, 1H); ¹³C NMR (CDCl₃, 125 MHz): δ 23.4, 30.0, 32.3, 45.8, 108.9, 119.0, 119.1, 121.6, 122.1, 123.5, 125.7, 126.1, 126.3, 126.4, 127.7, 128.3, 128.4, 129.6, 131.4, 132.4, 133.8, 133.9, 141.2, 141.9, 207.6; MS (ES⁺, Ar) m/z (rel intensity): 422 (MK⁺, 100), 406 (MNa⁺, 50); HRMS (ES⁺): calcd for C₂₅H₂₁NOSK (MK⁺), 422.0975; found, 422.0995. Confirmed by ¹H–¹H COSY experiments.

4-(8-Methyl-2-(thiophen-2-yl)-8H-thieno[2,3-b]indol-3-yl)butan-2-one (6l)

Brown sticky solid; yield 80 mg, 31%; IR (KBr, cm^–1): 3050 (vw), 2924 (w), 1714 (vs), 1491 (m), 1464 (m), 1332 (m), 1162 (m), 742 (vs), 702 (s); ¹H NMR (CDCl₃, 500 MHz): δ 2.16 (s, 3H), 2.83 (t, J = 7.4 Hz, 2H), 3.25 (t, J = 7.4 Hz, 2H), 3.83 (s, 3H), 7.08 (td, J = 8.2, 0.8 Hz, 1H), 7.21 (dd, J = 3.5, 1.6 Hz, 1H), 7.26 (td, J = 8.2, 0.8 Hz, 1H), 7.27 (d, J = 1.6 Hz, 1H), 7.34 (br d, J = 8.2 Hz, 1H), 7.45 (dd, J = 5.2, 3.5 Hz, 1H), 7.67 (br d, J = 8.2 Hz, 1H); ¹³C NMR (CDCl₃, 125 MHz): δ 23.4, 30.2, 32.2, 46.0, 109.1, 119.1, 119.2, 121.9, 122.0, 122.2, 124.0, 125.7, 127.3, 127.4, 132.0, 136.5, 141.2, 142.0, 207.7; MS (ES⁺, Ar) m/z (rel intensity): 362 (MNa⁺, 95), 340 (MH⁺, 100); HRMS (ES⁺): calcd for C₁₉H₁₈NOS₂ (MH⁺), 340.0824; found, 340.0825.

4-(8-Ethyl-2-phenyl-8H-thieno[2,3-b]indol-3-yl)butan-2-one (6m)

White solid; yield 225 mg, 87%; mp 79–87 °C; IR (KBr, cm^–1): 3052 (w), 2976 (m), 2931 (w), 1715 (vs), 1485 (s), 1467 (m), 1452 (m), 1336 (m), 1163 (m), 742 (vs); ¹H NMR (CDCl₃, 500 MHz): δ 1.52 (t, J = 7.2 Hz, 3H), 2.13 (s, 3H), 2.79 (t, J = 7.4 Hz, 2H), 3.16 (t, J = 7.4 Hz, 2H), 4.26 (q, J = 7.2 Hz, 2H), 7.00 (t, J = 8.2 Hz, 1H), 7.22 (t, J = 8.2 Hz, 1H), 7.35 (d, J = 8.2 Hz, 1H), 7.41 (d, J = 8.2 Hz, 1H), 7.43 (overlapped t, J = 7.4 Hz, 1H), 7.51 (t, J = 7.4 Hz, 2H), 7.56 (d, J = 7.4 Hz, 2H); ¹³C NMR (CDCl₃, 125 MHz): δ 14.1, 23.1, 30.2, 40.8, 46.0, 109.1, 118.9, 119.0, 121.7, 122.2, 122.5, 127.5, 128.7, 129.6, 130.2, 131.6, 136.0, 139.9, 141.0, 207.7; MS (ES⁺, Ar) m/z (rel intensity): 386 (MK⁺, 20), 370 (MNa⁺, 55), 348 (MH⁺, 100); HRMS (ES⁺): calcd for C₂₂H₂₂NOS (MH⁺), 348.1417; found, 348.1411.

4-(2-Phenyl-8-propyl-8H-thieno[2,3-b]indol-3-yl)butan-2-one (6n)

Brown sticky solid; yield 150 mg, 55%; IR (KBr, cm^–1): 2964 (w), 1714 (s), 1646 (s), 1484 (m), 1460 (m), 740 (vs), 703 (m); ¹H NMR (CDCl₃, 500 MHz): δ 1.03 (t, J = 7.2 Hz, 3H), 1.99 (sextet, J = 7.2 Hz, 2H), 2.14 (s, 3H), 2.81 (t, J = 7.4 Hz, 2H), 3.19 (t, J = 7.4 Hz, 2H), 4.18 (t, J = 7.2 Hz, 2H), 7.03 (t, J = 7.5 Hz, 1H), 7.24 (t, J = 7.5 Hz, 1H), 7.37 (d, J = 7.5 Hz), 7.45 (d, J = 7.5 Hz, 1H), 7.46 (overlapped t, J = 7.6 Hz, 1H), 7.54 (t, J = 7.6 Hz, 2H), (d, J = 7.6 Hz, 2H); ¹³C NMR (CDCl₃, 125 MHz): δ 11.9, 22.5, 23.0, 30.1, 45.9, 47.8, 109.2, 118.9, 119.0, 121.6, 122.1, 122.3, 127.5, 128.7, 129.6, 130.1, 131.5, 136.0, 140.5, 141.5, 207.7; MS (ES⁺, Ar) m/z (rel intensity): 400 (MK⁺, 20), 384 (MNa⁺, 50), 378 (55), 360 ([M – 1]⁺, 100); HRMS (ES⁺): calcd for C₂₃H₂₃NOSNa (MNa⁺), 384.1393; found, 384.1394.

4-(8-Benzyl-2-phenyl-8H-thieno[2,3-b]indol-3-yl)butan-2-one (6o)

White solid; yield 287 mg, 94%; mp 100–102 °C; IR (KBr, cm^–1): 3055 (m), 2919 (w), 1714 (vs), 1481 (s), 1456 (s), 1359 (m), 1336 (m), 1162 (m), 781 (m), 736 (vs), 703 (vs); ¹H NMR (CDCl₃, 500 MHz): δ 2.11 (s, 3H), 2.76 (t, J = 7.5 Hz, 2H), 3.15 (t, J = 7.5 Hz, 2H), 5.37 (s, 2H), 7.06 (t, J = 7.6 Hz, 1H), 7.24 (t, J = 7.6 Hz, 1H), 7.29–7.32 (m, 2H), 7.33–7.41 (m, 4H), 7.44–7.51 (m, 2H), 7.55 (t, J = 7.9 Hz, 2H), 7.60 (d, J = 7.9 Hz, 2H); ¹³C NMR (CDCl₃, 125 MHz): δ 23.0, 30.1, 45.9, 49.8, 109.5, 119.0, 119.3, 121.9, 122.4, 122.9, 127.5, 127.6, 128.1, 128.7, 129.0, 129.6, 130.7, 131.4, 135.9, 136.0, 140.5, 141.7, 207.6; MS (ES⁺, Ar) m/z (rel intensity): 448 (MK⁺, 45), 432 (MNa⁺, 100); HRMS (ES⁺): calcd for C₂₇H₂₃NOSNa (MNa⁺), 432.1393; found, 432.1396.

4-(5-Chloro-8-methyl-2-phenyl-8H-thieno[2,3-b]indol-3-yl)butan-2-one (6p)

Brown sticky solid; yield 122 mg, 44%; IR (KBr, cm^–1): 3055 (w), 2924 (m), 1715 (vs), 1488 (s), 1474 (s), 1362 (m), 1309 (m), 1163 (m), 924 (m), 793 (s), 739 (m); ¹H NMR (CDCl₃, 500 MHz): δ 2.12 (s, 3H), 2.77 (t, J = 7.4 Hz, 2H), 3.15 (t, J = 7.4 Hz, 2H), 3.79 (s, 3H), 7.16, 7.21 (ABq, J = 7.5 Hz, 2H), 7.35 (s, 1H), 7.43–7.46 (unresolved m, 1H), 7.51–7.54 (m, 4H); ¹³C NMR (CDCl₃, 125 MHz): δ 23.1, 30.2, 32.4, 45.9, 109.9, 118.5, 121.5, 121.8, 122.9, 124.8, 127.8, 128.9, 129.4, 130.8, 131.5, 135.6, 140.4, 142.6, 207.5; MS (ES⁺, Ar) m/z (rel intensity): 408 ([MK+2]⁺, 5), 406 (MK⁺, 15), 392 (MNa+2]⁺, 33), 390 (MNa⁺, 100); HRMS (ES⁺): calcd for C₂₁H₁₈NOSClNa (MNa⁺), 390.0690; found, 390.0690.

4-(3-Phenyl-8H-thieno[2,3-b]indol-2-yl)butan-2-one (6q)

White solid; yield 105 mg, 44%; mp 144–146 °C; IR (KBr, cm^–1): 3390 (br vs), 2962 (s), 2931 (m), 1728 (vs), 1619 (vs), 1506 (m), 1440 (m), 1286 (m), 1246 (vs), 1027 (m), 820 (m), 765 (m); ¹H NMR (CDCl₃, 400 MHz): δ 2.13 (s, 3H), 2.79 (t, J = 7.4 Hz, 2H), 3.19 (t, J = 7.4 Hz, 2H), 7.05 (t, J = 8.1 Hz, 1H), 7.20 (t, J = 8.1 Hz, 1H), 7.34 (d, J = 8.1 Hz, 1H), 7.45 (t, J = 7.3 Hz, 1H), 7.47 (d, J = 8.1 Hz, 1H), 7.54 (t, J = 7.3 Hz, 2H), 7.59 (d, J = 7.3 Hz, 2H), 8.56 (br s, 1H); ¹³C NMR (CDCl₃, 100 MHz): δ 23.0, 30.1, 45.9, 111.4, 118.8, 119.5, 122.1, 122.3, 124.4, 127.5, 128.7, 129.6, 130.7, 131.1, 135.9, 138.1, 141.8, 208.3; MS (ES⁺, Ar) m/z (rel intensity): 342 (MNa⁺, 100); HRMS (ES⁺): calcd for C₂₀H₁₇NOSNa (MNa⁺), 342.0923; found, 342.0928.

Procedure for the Synthesis of Pyrazole-Containing Thieno[2,3-b]indole (8)

To a stirred solution of hydrazinothienoindole 4d (54 mg, 0.103 mmol, 1 equiv) in MeOH (1.5 mL) was added 4N HCl in dioxane (0.77 mL, 3.093 mmol, 30 equiv) at room temperature. The reaction mixture was stirred for 10 min, and then, acetyl acetone 7 (21 mg, 0.206 mmol, 2 equiv) was added and the mixture was stirred at room temperature for 12 h. After completion of the reaction (monitored by TLC), the solvent was removed in vacuo and the crude product was partitioned between EtOAc (10 mL) and sat aq NaHCO₃ (10 mL). The organic phase was separated, washed with brine (10 mL), dried over anhydrous sodium sulphate, and concentrated in vacuo. The crude product was purified by silica gel column chromatography by gradient elution with ethyl acetate-pet ether (15–20%).

2-(3,5-Dimethyl-1H-pyrazol-1-yl)-3-(4-methoxyphenyl)-8-methyl-8H-thieno[2,3-b]indole (8)

Brown solid; yield 19 mg, 48%; mp 175–177 °C; IR (KBr, cm^–1): 1647 (s), 1612 (s), 1248 (m), 1029 (m), 739 (vs); ¹H NMR (CDCl₃, 500 MHz): 1.77 (s, 3H), 2.33 (s, 3H), 3.84 (s, 3H), 3.87 (s, 3H), 5.82 (s, 1H), 6.92 (d, J = 8.5 Hz, 2H), 7.11 (t, J = 7.5 Hz, 1H), 7.31 (t, J = 7.5 Hz, 1H), 7.40 (d, J = 8.5 Hz, 2H and d, J = 7.5 Hz, 1H overlapped), 7.75 (d, J = 7.5 Hz, 1H); ¹³C NMR (CDCl₃, 125 MHz): δ 11.4, 13.9, 32.4, 55.4, 106.0, 109.3, 114.2, 118.3, 119.5, 119.6, 122.5, 122.9, 124.7, 126.3, 132.9, 141.1, 141.7, 143.5 (×2), 149.8, 159.4; MS (ES⁺, Ar) m/z (rel intensity): 410 (MNa⁺, 5), 388 (MH⁺, 100), HRMS (ES⁺): calcd for C₂₃H₂₂N₃OS (MH⁺), 388.1478; found, 388.1475.

Supporting Information Available

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsomega.8b02147.

• Crystal data and structure refinement for compounds 3a, 4h, and 6e and NMR spectra of compounds 3a, 4a–i, 6a–q, and 8 (PDF)

• Single-crystal X-ray data of compound 3a: CCDC 1862743 (CIF)

• Single-crystal X-ray data of compound 4h: CCDC 1862744 (CIF)

• Single crystal X-ray data of compound 6e: CCDC 1862745 (CIF)

Author Present Address

^† Service de Chimie Bioorganique et de Marquage (SCBM), CEA, Université Paris-Saclay, 91191 Gif-sur-Yvette, France.

The authors declare no competing financial interest.