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Article

Dialkylation of Indoles with Trichloroacetimidates to Access 3,3-Disubstituted Indolenines

by
Tamie Suzuki
,
Nilamber A. Mate
,
Arijit A. Adhikari
and
John D. Chisholm
*
Department of Chemistry, Syracuse University, 1-014 Center for Science and Technology, Syracuse, NY 13244-4100, USA
*
Author to whom correspondence should be addressed.
Molecules 2019, 24(22), 4143; https://doi.org/10.3390/molecules24224143
Submission received: 30 October 2019 / Revised: 11 November 2019 / Accepted: 13 November 2019 / Published: 15 November 2019
(This article belongs to the Special Issue Development of New Methods of Synthesis of Heterocycles)
Browse Figures
Versions Notes

Abstract

:
2-Substituted indoles may be directly transformed to 3,3-dialkyl indolenines with trichloroacetimidate electrophiles and the Lewis acid TMSOTf. These reactions provide rapid access to complex indolenines which are present in a variety of complex natural products and medicinally relevant small molecule structures. This method provides an alternative to the use of transition metal catalysis. The indolenines are readily transformed into spiroindoline systems which are privileged scaffolds in medicinal chemistry.

Graphical Abstract

1. Introduction

3,3-Dialkyl indolenines are common substructures found in many complex alkaloids like strictamine 1 [1] and tubifoline 2 [2] (Figure 1). A number of other alkaloids appear to derive from the intramolecular addition of heteroatom nucleophiles to the indolenine. This includes complex alkaloids such as echiboline 3 [3], aspidophylline A 4 [4], and perophoramidine 5 [5] (Figure 1). 3,3-Dialkyl indolenines have also been utilized as platforms in medicinal chemistry studies [6,7], as a means to move towards more three-dimensional structures with a greater proportion of sp3 hybridized carbons, which is desirable in order to create molecules which interact with more complex pharmaceutical target receptors [8,9,10,11]. Structurally related spiropiperidine-indanes have also been referred to as “privileged scaffolds” [12,13,14] for the design of medicinally relevant small molecules, including the ghrelin receptor agonists MK-0677 6 [15] and 7 [16], the Akt inhibitor 8 [17] and the P2Y1 antagonist 9 [18]. Besides their presence in natural products, similar indolines are also utilized as precursors to indolenine dyes [19], which have applications in biological imaging [20,21,22,23], sensors [24,25], and in solar cells [26,27].
Given the common nature of 3,3-dialkyl indolenines and related structures, researchers have been active in investigating efficient methods to access similar architectures [28,29,30,31]. These include intramolecular condensation of an aniline [32,33,34], the interrupted Fischer indole synthesis [35,36,37], and the addition of organometallic reagents to benzylic nitriles [38,39,40]. One popular method is the dearomatization of indoles [41,42,43,44] with an electrophilic alkylating agent. Many of these reactions are complicated by competing N-alkylation of the indole. In spite of this issue, a number of acid promoted [45,46,47], base promoted [48,49,50,51,52,53,54], and transition metal catalyzed [55,56,57,58,59,60,61,62,63,64] transformations have been described to access indolenines from 3-substituted indoles.
In a recent study on the alkylation of indoles utilizing trichloroacetimidate electrophiles [65], we observed a small amount of the dialkylated indolenine 13 as a side product from the TMSOTf catalyzed C3-alkylation of 2-methyl-5-nitroindole 10 with allyl imidate 11 in dichloromethane (DCM) (Scheme 1). While the formation of indolenines from 2,3-disubstituted indoles with imidates has been reported [66], the direct dialkylation of indoles could provide a rapid entry to 3,3-dialkyl indolenine intermediates from less substituted (and therefore less expensive) indole starting materials. This would provide an efficient alternative approach for the direct C3-dialkylation of indoles that does not rely on costly transition metal catalysts. The use of trichloroacetimidate electrophiles as the alkylating agent is attractive because they can be easily formed from readily available alcohols under mild conditions [67]. Intrigued by the potential of this dialkylation reaction, we began optimization studies to explore the scope of this Lewis acid promoted dearomatization reaction.

2. Results & Discussion

Our recent studies on promoter free substitution reactions with trichloroacetimidate electrophiles [68,69,70,71,72,73,74] led us to speculate that imidates may be reactive enough to participate in indole dialkylation without the need for a Lewis acid catalyst. Heating 2-methyl indole 14 and allyl trichloroacetimidate 11 in refluxing 1,2-dichloroethane (DCE) for 24 h showed no trace of alkylation product, however, so the use of TMSOTf as the Lewis acid was then investigated (Table 1). Previous investigations with indoles and trichloroacetimidates have demonstrated that TMSOTf is especially effective in these systems [65,66], and encouraging results were immediately obtained. Use of 20 mol% TMSOTf led to the formation of indolenine 15 with a 27% yield (Table 1, Entry 2). Increasing reaction time, temperature and using excess imidate were then evaluated, but these changes only led to modest increases in yield (Entries 3–5). Given that a more basic reaction media is being formed after the second alkylation (the imine on 15 is a functional base), it was considered that perhaps product inhibition was occurring, with the imine scavenging the Lewis acid and halting the reaction. An increase in the TMSOTf loading would therefore be necessary to obtain higher conversions. Increasing the amount of TMSOTf provided a 61% yield of 15 when a stoichiometric amount of the Lewis acid was employed (Entry 7). Further increasing the amount of TMSOTf did not significantly improve the yield, nor did heating the reaction. Little indole starting material 14 was isolated from the reaction, with the rest of the mass balance being a mixture of overalkylation products (alkylation can also occur at C5 and C7 of the indole ring).
The indole dialkylation was then evaluated with regard to the indole nucleophile. The addition of either electron donating or electron withdrawing groups to the 5-position of the indole was tolerated, with yields in the 40%–70% range being observed (Table 2). Interestingly, the 5-nitro-2-methyl indole 10 provided the diallylation product 13, which is not accessible using palladium catalysis, as N-alkylation is favored when this indole is employed [6]. Changing the alkyl group at the 2-position of the indole was also explored. Use of indole (Entry 7) provided only a complex mixture of products, and this substrate was not pursued further. A more moderate yield was obtained with 2-phenylindole, likely due to steric effects from the larger group at the indole 2-position. Indole 2-carboxylic acid methyl ester 14h was not reactive under these conditions, returning the starting indole and decomposed imidate from the reaction mixture. While many of these yields are moderate, it is important to realize that two reactions are actually occurring in sequence during the dialkylation, so the yield may perhaps be best thought of in terms of a sequence of two separate steps proceeding a ~75% yield where isolation and purification of the intermediate 3-alkylindole is avoided.
The efficacy of these conditions was then evaluated using a number of allylic and benzylic imidates (Table 3). More highly substituted allylic imidates gave lower yields, this may be due to the electrophile being more highly stabilized and therefore less reactive. Improved yields could be achieved by performing many of the reactions in refluxing DCE. Similar results were obtained with propargyl imidate 18, which was less reactive (only providing trace product at room temperature) but would participate when the reaction was heated to reflux, albeit in a moderate yield. Benzylic trichloroacetimidates were also evaluated. The highly reactive 4-methoxybenzyl imidate 19 gave a complex mixture of products due to polyalkylation. Better results were obtained with the less reactive benzyl imidate 20, which gave a 30% yield of the dialkylation product 15m (38% when the reaction was performed under reflux). Benzylic imidates decorated with electron withdrawing groups (21–23) were also less reactive and provided only trace amounts of the dialkylation products at rt, with C3-monoalkylation being the major product [65]. Heating the reaction to reflux provided the desired dialkylation products in much improved overall yields, however.
With ready access to 3,3-diallyl indolenines via imidate alkylation, we turned our attention to the functionalization of these systems to three-dimensional scaffolds like those used in medicinal chemistry studies. Initially a spirocycle formation was explored utilizing the Grubbs metathesis catalyst. This led to the formation of spirocycle 24 (Scheme 2). The indolenine 15a was also transformed into a spiropiperidine-indane that is similar to that found in the ghrelin receptor agonists MK-0677 6 and 7. This involved initial reduction of the indolenine 15a to the indoline 25 with lithium aluminum hydride. The sulfonamide 26 was then formed with TsCl and triethylamine. Oxidative cleavage of the alkenes to the corresponding aldehyde was executed via ozonolysis. Purification of this dialdehyde proved difficult when triphenylphosphine was used to reduce the ozonide, but the use of 1,3-bis(diphenylphosphino)propane (dppp) as the reductant made the purification easier as the bisphosphine oxide was more polar and easier to separate from the product. The dialdehyde proved to be unstable and readily self-condensed, so it was immediately subjected to a reductive amination with benzylamine and NaBH(OAc)3, which provided the desired spiropiperidine-indane 27 with a 35% yield over two steps.
Oddly, the spiropiperidine 27 showed a multiplet in the 1H NMR at 0.28 ppm that integrated for a single hydrogen resonance. A proton with this chemical shift was not congruent with the proposed structure, so some additional studies were performed. A COSY experiment verified that the upfield proton was part of the piperidine ring. Some molecular modeling studies indicated that this unusual chemical shift is likely to be attributed to diamagnetic anisotropy from the aromatic ring of the toluenesulfonamide, which prefers to reside on the opposite face of the pyrroline ring as the methyl group due to steric effects. This holds the -system of the sulfonamide in a position to shield one of the protons on the piperidine ring (Ha, Figure 2). The molecular modeling predicts that in the lowest energy conformation Ha is only ~2.8 Å from the center of the aromatic ring. This upfield chemical shift is consistent with literature reports of similar spiropiperidine-indanes [75]. In further support of this rationale, in structures where the C2 position of the pyrroline is unsubstituted [76], or there is no aromatic sulfonamide [77], no similar upfield shifts are observed in the 1H NMR.

3. Materials and Methods

3.1. General Experimental Information

All anhydrous reactions were run under a positive pressure of argon. Dichloromethane (DCM) was dried by passage through an alumina column. 1,2-Dichloroethane (DCE) was freshly distilled from calcium hydride before use. Silica gel column chromatography was performed using 60 Å silica gel (230−400 mesh). Melting points are uncorrected. The indoles used in this study were purchased from commercial sources.

3.2. Preparation of Trichloroacetimidates

Allyl-2,2,2-trichloroacetimidate 11 [78], 1-(1-imino-2,2,2-trichloroethoxy)-3-phenyl-2(E)-propene 17 [79], propargyl-2,2,2-trichloroacetimidate 18 [70], (4-methoxyphenyl)methyl-2,2,2-trichloroacetimidate 19 [69], benzyl-2,2,2-trichloroacetimidate 20 [78], (4-chloro)methyl-2,2,2-trichloroacetimidate 21 [80], (4-trifluoromethyl)methyl-2,2,2-trichloroacetimidate 22 [66], and (4-nitrophenyl)methyl-2,2,2-trichloroacetimidate 23 [81] were synthesized as previously reported.
2-Methyl-2-propenyl trichloroacetimidate (16). A flame dried flask was charged with 2-methyl-2-propen-1-ol (7.0 mmol, 0.589 mL) and placed under argon. Dry DCM (35 mL) was then added, and the flask was cooled to 0 °C. 1,8-Diazabicyclo [5.4.0]undec-7-ene (0.7 mmol, 0.108 mL) was added to the solution, followed by trichloroacetonitrile (8.4 mmol, 0.843 mL). After ~22 h the reaction mixture was concentrated and the residue purified by silica gel column chromatography (10% EA/3% Et3N/87% hexanes). Clear oil (1.502 g, 99%). TLC Rf = 0.42 (60% DCM/40% hexanes); IR (thin film) 3365, 3072, 2975, 2904, 1637, 1607, 1482, 912 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.31 (bs, 1H), 5.11 (s, 1H), 4.99 (s, 1H), 4.71 (s, 2H), 1.83 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 162.6, 139.4, 113.3, 91.5, 72.3, 19.4.; HRMS (ESI+) calcd for C6H8Cl3NONa+ [M + Na]+: 237.9563. Found: 237.9564.

3.3. Synthesis of 3,3′-Disubstituted Indolenines

General procedure for C3-dialkylation of indoles. In a flame dried flask, the imidate (2.5 equiv) was dissolved in anhydrous DCE (0.3 M) followed by the addition of the indole (1.0 equiv). To this solution freshly distilled TMSOTf (1.0 equiv) was added and the resulting mixture was stirred at room temp. or heated to reflux for 3 h. After cooling to room temperature, the reaction mixture was quenched with 10 mL 1 M NaOH. The organic layer was separated and the aqueous layer was extracted with DCM (3 × 5 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography using the listed solvent system.
3,3-Diallyl-2-methyl-3H-indole (15a). Synthesized by the general procedure from 2-methylindole 14a and imidate 11 [78], purified using silica gel chromatography (3% EA/97% DCM). This compound has been previously reported [58]. Orange oil (0.14 g, 59%); TLC Rf = 0.35 (5% EA/95% DCM); 1H NMR (300 MHz, CDCl3) δ 7.52 (d, J = 7.6 Hz, 1H), 7.34–7.28 (m, 2H), 7.22–1.17 (m, 1H), 5.18–5.05 (m, 2H), 4.95 (d, J = 17.0 Hz, 2H), 4.85 (d, J = 10.9 Hz, 2H), 2.69 (dd, J = 13.9, 6.1 Hz, 2H), 2.45 (dd, J = 13.9, 7.7 Hz, 2H), 2.25 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 185.2, 154.8, 141.2, 132.1, 127.9, 125.0, 122.2, 119.8, 118.1, 61.8, 40.3, 16.5.
3,3-Diallyl-5-methoxy-2-methyl-3H-indole (15b). Synthesized by general procedure from 5-methoxy-2-methyl-1H-indole 14b and imidate 11 [78], purified using silica gel chromatography (5% EA/95% DCM). This compound has been previously reported [6]. Brown solid (0.18 g, 61%); mp = 45–46 °C; TLC Rf = 0.33 (10% EA/90% DCM); IR (ATR) 3077, 3000, 1640, 1591, 1576, 908 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.44 (d, J = 9.0 Hz, 1H), 6.85–6.83 (m, 2H), 5.20–5.06 (m, 2H), 4.96 (d, J = 16.2 Hz, 2H), 4.87 (d, J = 9.8 Hz, 2H), 3.83 (s, 3H), 2.66 (dd, J = 13.8, 5.8 Hz, 2H), 2.45 (dd, J = 13.9, 7.7 Hz, 2H), 2.25 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 182.9, 157.8, 142.9, 132.1, 119.9, 118.1, 117.5, 112.2, 109.2, 61.9, 55.7, 40.4, 16.4.
3,3-Diallyl-2,5-dimethyl-3H-indole (15c). Synthesized by general procedure from 2,5-dimethyl-1H-indole 14c and imidate 11 [78], purified using silica gel chromatography (20% EA/80% hexanes). Brown solid (0.13 g, 41%); mp = 38–40 °C; TLC Rf = 0.38 (40% EA/60% hexanes); IR (ATR) 3081, 3002, 1638, 1574, 820 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.38 (d, J = 7.8 Hz, 1H), 7.11 (d, J = 7.8 Hz, 1H), 7.07 (s, 1H), 5.16–5.06 (m, 2H), 4.95 (d, J = 17.0 Hz, 2H), 4.85 (d, J = 9.9 Hz, 2H), 2.66 (dd, J = 13.9, 6.0 Hz, 2H), 2.43 (dd, J = 13.9, 7.8 Hz, 2H), 2.39 (s, 3H), 2.22 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 184.0, 152.7, 141.3, 134.7, 132.3, 128.5, 122.9, 119.3, 118.0, 61.5, 40.4, 21.5, 16.5; HRMS (ESI+) m/z calcd for C16H19NNa+ [M + Na]+: 248.1409, found: 248.1409.
3,3-Diallyl-5-chloro-2-methyl-3H-indole (15d). Synthesized by general procedure from 5-chloro-2-methyl-1H-indole 14d and imidate 11 [78], purified using silica gel chromatography (10% EA/90% hexanes). Yellow oil (0.10 g, 45%); TLC Rf = 0.42 (30% EA/70% hexanes); IR (ATR) 3076, 1728, 1577, 1451, 920, 825 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.44 (d, J = 8.4 Hz, 1H), 7.31–7.26 (m, 2H), 5.18–5.08 (m, 2H), 4.99 (d, J = 16.8 Hz, 2H), 4.91 (d, J = 10.4 Hz, 2H), 2.68 (dd, J = 13.6, 6.0 Hz, 2H), 2.47 (dd, J = 14.0, 7.6 Hz, 2H), 2.26 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 185.7, 153.4, 143.1, 131.5, 130.9, 128.1, 122.7, 120.6, 118.6, 62.3, 40.1, 16.5; HRMS (ESI+) m/z calcd for C15H16ClNNa+ [M + Na]+: 268.0863, found: 268.0864.
3,3-Diallyl-5-fluoro-2-methyl-3H-indole (15e). Synthesized by general procedure from 5-chloro-2-methyl-1H-indole 14e and imidate 11 [78], purified using silica gel chromatography (10% EA/90% hexanes). Purple oil (0.16 g, 68%); TLC Rf = 0.37 (30% EA/70% hexanes); IR (ATR) 3077, 1727, 1581, 1462, 918, 821 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.41 (dd, J = 8.2, 4.7 Hz, 1H), 7.00–6.94 (m, 2H), 5.15–5.04 (m, 2H), 4.94 (d, J = 16.8 Hz, 2H), 4.85 (d, J = 10.0 Hz, 2H), 2.63 (dd, J = 13.9, 6.3 Hz, 2H), 2.43 (dd, J = 13.6, 7.7 Hz, 2H), 2.21 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 184.8 (d, J = 3.5 Hz), 161.0 (d, J = 242.1 Hz), 150.8 (d, J = 1.8 Hz), 143.2 (d, J = 8.5 Hz), 131.6, 120.3 (d, J = 8.8 Hz), 118.5, 114.6 (d, J = 23.4 Hz), 109.9 (d, J = 23.3 Hz), 62.3 (d, J = 2.0 Hz), 40.2, 16.4; HRMS (ESI+) m/z calcd for C15H16FNNa+ [M + Na]+: 252.1159, found: 252.1158.
3,3-Diallyl-5-nitro-2-methyl-3H-indole (13). Synthesized by the general procedure from 2-methyl-5-nitro-1H-indole 10 and imidate 11 [78], purified using silica gel chromatography (5% EA/95% DCM). Brown oil (0.21 g, 71%); TLC Rf = 0.47 (10% EA/90% DCM); IR (ATR) 3007, 1703, 1571, 1518, 1338 cm−1; 1H NMR (300 MHz, CDCl3) δ 8.28 (dd, J = 8.5, 2.3 Hz, 1H), 8.16 (d, J = 2.0 Hz, 1H), 7.62 (d, J = 8.5 Hz, 1H), 5.17–5.04 (m, 2H), 5.03–4.88 (m, 4H), 2.77 (dd, J = 14.0, 6.1 Hz, 2H), 2.53 (dd, J = 14.0, 7.1 Hz, 2H), 2.35 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 191.6, 159.6, 145.6, 142.4, 130.7, 124.9, 119.9, 119.4, 117.9, 62.9, 40.0, 17.0; HRMS (ESI+) m/z calcd for C15H16N2O2Na+ [M + Na]+: 279.1104, found: 279.1103.
3,3-Diallyl-2-phenyl-3H-indole (15g). Synthesized by general procedure from the known indole 14g and imidate 11 [78], purified using silica gel chromatography (5% EA/95% hexanes). This compound has been previously reported [6]. Yellow oil (0.09 g, 34%); TLC Rf = 0.52 (5% EA/95% DCM); 1H NMR (300 MHz, CDCl3) δ 8.14–8.10 (m, 2H), 7.67 (d, J = 7.5 Hz, 1H), 7.49–7.47 (m, 3H), 7.40–7.26 (m, 3H), 5.18–5.05 (m, 2H), 4.79–4.71 (m, 4H), 2.90 (d, J = 6.9 Hz, 4H); 13C NMR (100 MHz, CDCl3) δ 180.3, 154.4, 142.9, 133.9, 131.8, 130.6, 128.6, 128.1, 128.0, 125.7, 121.7, 120.7, 118.3, 62.4, 41.8.
2-Methyl-3,3-bis(2-methyl-2-propenyl)-3H-indole (15i). Synthesized by general procedure from 2-methylindole 14a and imidate 16, purified using silica gel chromatography (10% EA/90% hexanes). Yellow oil (0.13 g, 46%); TLC Rf = 0.52 (5% EA/95% DCM); IR (ATR) 3074, 2967, 2918, 1642, 1575,1447, 765 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.42 (d, J = 8.0 Hz, 1H), 7.25–7.21 (m, 2H), 7.12–7.09 (m, 1H), 4.48–4.47 (m, 2H), 4.40 (s, 2H), 2.63 (d, J = 13.6 Hz, 2H), 2.53 (d, J = 14.0 Hz, 2H), 2.26 (s, 3H), 1.06 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 185.8, 155.2, 141.7, 140.9, 127.8, 124.6, 122.9, 120.0, 114.2, 62.3, 45.5, 23.4, 17.2; HRMS (ESI+) m/z calcd for C17H21NNa+ [M + Na]+: 262.1566, found: 262.1566.
3,3-Bis[(E)-3-phenyl-2-propenyl]-2-methyl-3H-indole (15j). Synthesized by the general procedure from 2-methylindole 14a and imidate 17 [79], purified using silica gel chromatography (100% DCM). Yellow oil (0.055 g, 20%); TLC Rf = 0.26 (100% DCM); IR (ATR) 3024, 2919, 1576, 1447, 906, 730 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 7.6 Hz, 1H), 7.35–7.31 (m, 3H), 7.26–7.12 (m, 10H), 6.35 (d, J = 15.7 Hz, 2H), 5.60–5.52 (m, 2H), 2.89 (dd, J = 14.0, 6.7 Hz, 2H), 2.63 (dd, J = 13.9, 8.0 Hz, 2H), 2.33 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 185.0, 154.8, 141.2, 136.9, 133.3, 128.5, 128.4, 128.1, 127.3, 126.1, 125.1, 123.7, 122.3, 120, 62.1, 39.4, 16.7; HRMS (ESI+) m/z calcd for C27H25NNa+ [M + Na]+: 386.1879, found: 386.1878.
2-Methyl-3,3-di(prop-2-yn-1-yl)-3H-indole (15k). Synthesized by the general procedure from 2-methylindole 14a and imidate 18 [70], purified using silica gel chromatography (3% EA/97% DCM). Yellow oil (0.06 g, 24%); TLC Rf = 0.55 (10% EA/90% DCM); IR (ATR) 3285, 2924, 2119, 1579, 1468, 770, 624 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.53 (t, J = 7.7 Hz, 2H), 7.36 (dt, J = 7.6, 1.2 Hz, 1H), 7.22 (t, J = 7.4 Hz, 1H), 2.76 (dd, J = 16.7, 2.6 Hz, 2H), 2.60 (dd, J = 16.8, 2.6 Hz, 2H), 2.37 (s, 3H), 1.98 (t, J = 2.6 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 183.1, 154.4, 140.0, 128.7, 125.4, 122.4, 120.0, 78.6, 71.5, 57.6, 24.4, 16.7; HRMS (ESI+) m/z calcd for C15H13NNa+ [M + Na]+: 230.0940, found: 230.0939.
3,3-Dibenzyl-2-methyl-3H-indole (15m). Synthesized by the general procedure from 2-methylindole 14a the imidate 20 [78], purified using silica gel chromatography (1% EA/99% DCM). This compound has been previously reported [58]. Brown oil (0.10 g, 30%); TLC Rf = 0.49 (5% EA/95% DCM); 1H NMR (400 MHz, CDCl3) δ 7.18–7.14 (m, 2H), 7.06 (td, J = 7.2, 1.6 Hz, 1H), 7.02–6.95 (m, 7H), 6.68 (dd, J = 7.2, 1.2 Hz, 4H), 3.28 (d, J = 13.6 Hz, 2H), 2.99 (d, J = 13.6 Hz, 2H), 2.32 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 184.1, 155.1, 140.5, 135.7, 129.4, 127.9, 127.8, 126.7, 124.4, 23.7, 119.8, 64.0, 42.3, 17.3.
3,3-Bis[(p-chlorophenyl)methyl]-2-methyl-3H-indole (15n). Synthesized by the general procedure from 2-methylindole 14a and imidate 21 [80], purified using silica gel chromatography (3% EA/97% DCM). Yellow oil (0.08 g, 18%); TLC Rf = 0.24 (30% EA/70% hexanes); IR (ATR) 3046, 2918, 2848, 1595, 1491, 1013, 837 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.32–7.17 (m, 3H), 7.11 (d, J = 6.9 Hz, 1H), 7.02 (d, J = 8.4 Hz, 4H), 6.66 (d, J = 8.4 Hz, 4H), 3.32 (d, J = 13.7 Hz, 2H), 3.04 (d, J = 13.6 Hz, 2H), 2.42 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 183.3, 155.1, 139.8, 133.9, 132.7, 130.5, 128.3, 128.0, 124.6, 123.3, 120.2, 63.8, 41.5, 17.3; HRMS (ESI+) m/z calcd for C23H19Cl2NNa+ [M + Na]+: 402.0787, found: 402.0785.
2-Methyl-3,3-bis{[p-(trifluoromethyl)phenyl]methyl}-3H-indole (15o). Synthesized by the general procedure from the known indole 14a and imidate 22 [66], purified using silica gel chromatography (2% EA/98% DCM). Yellow oil (0.23 g, 45%); TLC Rf = 0.51 (5% EA/95% DCM); IR (ATR) 3049, 2924, 1919, 1726, 1616, 1319, 1100 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.30 (d, J = 8.4 Hz, 4H), 7.26–7.19 (m, 3H), 7.15 (d, J = 7.2 Hz, 1H), 6.84 (d, J = 8.0 Hz, 4H), 3.42 (d, J = 13.6 Hz, 2H), 3.15 (d, J = 13.6 Hz, 2H), 2.40 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 182.8, 154.9, 139.4, 129.5, 129.4 (q, J = 32.3 Hz), 128.6, 124.8 (q, J = 3.7 Hz), 124.0 (q, J = 270.3 Hz), 123.2, 120.3, 63.6, 42.0, 17.2; HRMS (ESI+) m/z calcd for C25H19F6NNa+ [M + Na]+: 470.1314, found: 470.1311.
2-Methyl-3,3-bis[(p-nitrophenyl)methyl]-3H-indole (15p). Synthesized by general procedure from 2-methylindole 14a and imidate 23 [81], purified using silica gel chromatography (50% EA/50% hexanes). Yellow oil (0.29 g, 63%); TLC Rf = 0.50 (10% EA/90% DCM); IR (ATR) 3076, 1728, 1577, 1451, 920, 825 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 8.8 Hz, 4H), 7.31–7.20 (m, 4H), 6.88 (d, J = 8.4 Hz, 4H), 3.48 (d, J = 13.6 Hz, 2H), 3.26 (d, J = 13.6 Hz, 2H), 2.44 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 182.0, 154.9, 147.0, 142.6, 138.7, 129.9, 129.0, 125.3, 123.1, 123.0, 120.6, 63.6, 41.9, 17.2; HRMS (ESI+) m/z calcd for C23H19N3O4 [M + H]+: 402.1448, found: 402.1451.

3.4. Elaboration of the 3,3′-Disubstituted Indolenines

2’-Methylspiro[3-cyclopentene-1,3’-indole] (24). The diallyl indoline 15a (0.236 mmol, 50 mg) was dissolved in 2 mL of DCM. In a round bottom flask, Grubbs II catalyst (0.024 mmol, 21 mg) was taken in DCM (4 mL) and flushed with argon. The indoline in DCM was then added dropwise to the flask and stirred for 6 h at rt. Evaporated the solvent, purified using silica gel chromatography (5% EA/95% DCM). This compound has been previously prepared [7]. Yellow oil (21 mg, 46%); TLC Rf = 0.43 (10% EA/90% DCM); 1H NMR (400 MHz, CDCl3) δ 7.52 (d, J = 7.6 Hz, 1H), 7.34 (d, J = 7.6 Hz, 1H), 7.29 (dt, J = 7.6, 0.8 Hz, 1H), 7.18 (t, J = 7.6 Hz, 1H), 5.92 (s, 2H), 2.68 (s, 4H), 2.27 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 186.9, 153.7, 146.4, 129.8, 127.6, 125.5. 121.0, 119.5, 61.4, 41.4, 15.6.
3,3-Diallyl-2-methylindoline (25). The diallyl indoline 15a (2.37 mmol, 0.50 g) was dissolved in 10 mL THF and cooled to 0 °C using an ice bath. LiAlH4 solution (1 M in THF, 8.3 mmol, 8.3 mL) was then slowly added. After 5 min the reaction mixture was allowed to warm to room temperature. After 30 min the reaction mixture was recooled to 0 °C and quenched by dropwise addition of 15 mL solution of saturated aqueous Rochelle’s salt (potassium sodium tartrate). The reaction was poured into another 15 mL solution of saturated aqueous Rochelle’s salt and extracted to with EA (3 × 20 mL). The organic layers were combined and washed with saturated aqueous sodium chloride (50 mL), dried over sodium sulfate, filtered and concentrated. Purification using silica gel chromatography (60% DCM/40% hexanes) provided indoline 25. Colorless oil (0.35 g, 70%); TLC Rf = 0.42 (60% DCM/40% hexanes); IR (ATR) 3365, 3072, 2975, 2904, 1637, 1607, 1482, 912 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.04 (dt, J = 7.6, 1.2 Hz, 1H), 6.99 (d, J = 7.4 Hz, 1H), 6.74 (dt, J = 7.4, 0.8 Hz, 1H), 6.65 (d, J = 7.8 Hz, 1H), 5.80–5.68 (m, 2H), 5.06–4.97 (m, 4H), 3.78 (q, J = 6.6 Hz, 1H), 2.53 (dd, J = 14.2, 6.6 Hz, 1H), 2.39 (dd, J = 14.0, 7.9 Hz, 2H), 2.16 (dd, J = 13.8, 7.8 Hz, 1H), 1.24 (d, J = 6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 149.5, 134.92, 134.91, 134.6, 127.5, 124.4, 118.6, 117.7, 117.5, 109.7, 62.5, 49.3, 40.5, 37.5, 15.3. HRMS (ESI+) calcd for C15H19NH+ [M + H]+: 214.1590, found: 214.1594.
3,3-Diallyl-2-methyl-1-(p-tolylsulfonyl)indoline (26). The diallyl indole 25 (5.02 mmol, 1.07 g) was dissolved in 20 mL of DCM and p-toluene sulfonyl chloride (8.78 mmol, 1.67 g) was added followed by triethylamine (10.97 mmol, 1.52 mL). After 16 h the reaction was quenched with 1M aq. HCl (50 mL) and extracted with DCM (3 × 50 mL). The combined organic extracts were washed with sat. aq. NaCl (50 mL), dried over Na2SO4, filtered and concentrated. Purification using silica gel chromatography (70% DCM/30% hexanes) provided sulfonamide 26. Colorless oil (1.49 g, 81%); TLC Rf = 0.48 (80% DCM/20% hexanes); IR (ATR) 3073, 2979, 1637, 1457,1351, 1163, 915 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.70–7.67 (m, 3H), 7.25–7.19 (m, 3H), 6.98–6.96 (m, 2H), 5.80–5.66 (m, 1H), 5.41–5.27 (m, 1H), 5.11 (s, 1H), 5.07 (d, J = 7.6 Hz, 1H), 4.83 (d, J = 13.6 Hz, 1H), 4.59 (d, J = 16.8 Hz, 1H), 3.99 (q, J = 6.6 Hz, 1H), 2.49 (dd, J = 14.9, 7.7 Hz, 1H), 2.35 (s, 3H), 2.30 (dd, J = 14.8, 6.3 Hz, 1H), 1.92 (dd, J = 13.9, 7.2 Hz, 1H) 1.46–1.39 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 143.9, 140.2, 136.5, 135.6, 133.9, 132.7, 129.5, 128.2, 127.0, 124.6, 123.2, 118.7, 118.6, 115.5, 67.4, 49.6, 42.8, 36.3, 21.5, 17.5. HRMS (ESI+) calcd for C22H25NO2SNa+ [M + Na]+: 390.1498, found: 390.1495.
1’-Benzyl-2-methyl-1-(p-tolylsulfonyl)spiro[indoline-3,4’-piperidine] (27). The diallyl indole 26 (0.517 mmol, 0.190 g) was dissolved in 5 mL DCM and cooled to −100 °C (dry ice/ethyl ether bath). Ozone was then bubbled through the solution for about 2 min until the color changed to blue. The reaction mixture was then purged with argon until the blur color dissipated. 1,3-Bis(diphenylphosphino)propane (0.517 mmol, 0.213 g) was then added and reaction mixture was allowed to warm to room temp. The reaction mixture was then stirred for 1.5 h and then the solvent was evaporated. The resulting residue was purified by silica gel chromatography (75%EA/25%DCM) to provide the corresponding crude dialdehyde. The dialdehyde was dissolved in DCE (5.3 mL) and benzylamine (0.269 mmol, 0.029 mL) was added. After 5 min, sodium triacetoxyborohydride (1.07 mmol, 0.227 g) was added. After 16 h, the reaction was quenched with addition of water (5 mL) and extracted with DCM (3 × 10 mL). The combined organic extracts were washed with sat. aq. NaCl (20 mL), dried over sodium sulfate and concentrated. Purification of the residue using silica gel chromatography (20% EA/80% DCM) provided piperidine 27. Off-white powder (0.08 g, 35% over 2 steps); TLC Rf = 0.47 (80% DCM/20%EA); IR (ATR) 2927, 2802, 2757, 2359, 2341, 1598, 1493, 1348, 1132 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 8.2 Hz, 2H), 7.64 (d, J = 8.0 Hz, 1H), 7.33–7.28 (m, 5H), 7.23–7.17 (m, 3H), 7.06–6.99 (m, 2H), 4.30 (q, J = 6.6 Hz, 1H), 3.51–3.43 (m, 2H), 2.88 (d, J = 9.1 Hz, 1H), 2.44 (d, J = 11.7 Hz, 1H), 2.32 (s, 3H), 2.07–1.94 (m, 3H), 1.76 (d, J = 11.8 Hz, 1H), 1.34 (d, J = 6.6 Hz, 3H), 1.14 (t, J = 11.1 Hz, 1H), 0.28 (d, J = 13.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 143.8, 139.3, 136.3, 129.6, 129.1, 128.3, 128.2, 127.1, 126.6, 124.0, 123.0, 115.7, 64.5, 63.4, 51.4, 50.1, 45.7, 38.6, 28.9, 21.5, 17.6; HRMS (ESI+) calcd for C27H31N2O2S+ [M + H]+: 447.2101. Found: 447.2108.

4. Conclusions

A new method for the synthesis of 3,3-dialkyl indolenines has been developed utilizing the Lewis acid promoted alkylation of indoles with trichloroacetimidates. This method is differentiated from past methods in that it does not depend on transition metal mediated alkylation or the use of strong base, instead a Lewis acid and a trichloroacetimidate leaving group are utilized to perform the alkylation. Notably even electron poor indoles undergo the dialkylation, which are difficult substrates for other alkylation reactions. The indolenines generated from this reaction provide ready access to spirocyclic structures which are useful platforms for the development of three dimensional architectures that may interact with more complex biological receptors of interest to the medicinal chemistry community.

Supplementary Materials

Copies of 1H and 13C spectra are available at https://www.mdpi.com/1420-3049/24/22/4143/s1.

Author Contributions

Conceptualization, J.D.C., T.S., N.A.M. and A.A.A.; investigation, T.S., N.A.M., and A.A.A.; formal analysis, J.D.C., T.S. and N.A.M.; writing—original draft preparation, J.D.C., T.S. and N.A.M.; writing—review and editing, J.D.C., T.S. and N.A.M.; supervision, J.D.C.

Funding

Acknowledgement is also made to the Donors of the American Chemical Society Petroleum Research Fund for a New Directions award in support of this research (54823-ND1). The National Institute of General Medical Sciences (R15-GM116054) also provided partial financial support.

Conflicts of Interest

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

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Sample Availability: Samples of the compounds are not available from the authors.
Molecules 24 04143 g001 550
Figure 1. Natural products containing the 3,3-dialkyl indolenine motif and related spiroindoline structures.
Figure 1. Natural products containing the 3,3-dialkyl indolenine motif and related spiroindoline structures.
Molecules 24 04143 g001
Molecules 24 04143 sch001 550
Scheme 1. Detection of the dialkylation product 13 during alkylation of 5-nitro-2-methyl-indole 10.
Scheme 1. Detection of the dialkylation product 13 during alkylation of 5-nitro-2-methyl-indole 10.
Molecules 24 04143 sch001
Molecules 24 04143 sch002 550
Scheme 2. Elaboration of the 3,3-Diallyl indolenine 15a to spiro-polycyclic systems.
Scheme 2. Elaboration of the 3,3-Diallyl indolenine 15a to spiro-polycyclic systems.
Molecules 24 04143 sch002
Molecules 24 04143 g002 550
Figure 2. Upfield Shift of Ha in the 1H NMR of Spiropiperidine 27 due to Diamagnetic Anisotropy from the Sulfonamide -System.
Figure 2. Upfield Shift of Ha in the 1H NMR of Spiropiperidine 27 due to Diamagnetic Anisotropy from the Sulfonamide -System.
Molecules 24 04143 g002
Table
Table 1. Optimization of the diallylation reaction.
Table 1. Optimization of the diallylation reaction.
Molecules 24 04143 i001
EntryEquiv
Imidate 11		Equiv
TMSOTf		Temp. (°C)Reaction
Time		Yield (%)
12.208424 h0
22.20.2rt3 h27
32.20.2rt6 h20
42.20.2843 h41
53.00.2rt3 h31
62.50.5rt3 h39
72.51.0rt3 h61
82.51.5rt3 h59
92.51.0843 h59
Conditions: 1,2-Dichloroethane (DCE), TMSOTf, rt or reflux.
Table
Table 2. C3-Dialkylation of functionalized indoles with allyl imidate.
Table 2. C3-Dialkylation of functionalized indoles with allyl imidate.
Molecules 24 04143 i002
EntryIndoleProductYield (%)
1 Molecules 24 04143 i00314a Molecules 24 04143 i00415a61
2 Molecules 24 04143 i00514b Molecules 24 04143 i00615b61
3 Molecules 24 04143 i00714c Molecules 24 04143 i00815c41
4 Molecules 24 04143 i00914d Molecules 24 04143 i01015d45
5 Molecules 24 04143 i01114e Molecules 24 04143 i01215e68
6 Molecules 24 04143 i01310 Molecules 24 04143 i0141370
7 Molecules 24 04143 i01514f Molecules 24 04143 i01615f0 a
8 Molecules 24 04143 i01714g Molecules 24 04143 i01815g34
9 Molecules 24 04143 i01914h Molecules 24 04143 i02015h0 b
a A complex mixture resulted. b Starting material was recovered.
Table
Table 3. Direct C3-dialkylation of 2-methyl indole 14a with trichloroacetimidates.
Table 3. Direct C3-dialkylation of 2-methyl indole 14a with trichloroacetimidates.
Molecules 24 04143 i021
EntryImidateProductYield (%)
1 Molecules 24 04143 i02211 Molecules 24 04143 i02315a61 (59 a)
2 Molecules 24 04143 i02416 Molecules 24 04143 i02515i40 (46 a)
3 Molecules 24 04143 i02617 Molecules 24 04143 i02715j12 (20 a)
4 Molecules 24 04143 i02818 Molecules 24 04143 i02915ktrace (24 a)
5 Molecules 24 04143 i03019 Molecules 24 04143 i03115l0 b
6 Molecules 24 04143 i03220 Molecules 24 04143 i03315m30 (38 a)
7 Molecules 24 04143 i03421 Molecules 24 04143 i03515ntrace (52 a)
8 Molecules 24 04143 i03622 Molecules 24 04143 i03715otrace (45 a)
9 Molecules 24 04143 i03823 Molecules 24 04143 i03915ptrace (63 a)
a Yield when the reaction was performed at reflux. b A complex mixture resulted.

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MDPI and ACS Style

Suzuki, T.; Mate, N.A.; Adhikari, A.A.; Chisholm, J.D. Dialkylation of Indoles with Trichloroacetimidates to Access 3,3-Disubstituted Indolenines. Molecules 2019, 24, 4143. https://doi.org/10.3390/molecules24224143

AMA Style

Suzuki T, Mate NA, Adhikari AA, Chisholm JD. Dialkylation of Indoles with Trichloroacetimidates to Access 3,3-Disubstituted Indolenines. Molecules. 2019; 24(22):4143. https://doi.org/10.3390/molecules24224143

Chicago/Turabian Style

Suzuki, Tamie, Nilamber A. Mate, Arijit A. Adhikari, and John D. Chisholm. 2019. "Dialkylation of Indoles with Trichloroacetimidates to Access 3,3-Disubstituted Indolenines" Molecules 24, no. 22: 4143. https://doi.org/10.3390/molecules24224143

APA Style

Suzuki, T., Mate, N. A., Adhikari, A. A., & Chisholm, J. D. (2019). Dialkylation of Indoles with Trichloroacetimidates to Access 3,3-Disubstituted Indolenines. Molecules, 24(22), 4143. https://doi.org/10.3390/molecules24224143

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