Highly efficient asymmetric construction of novel indolines and tetrahydroquinoline derivatives via aza-Barbier/C–N coupling reaction

Abstract

Highly stereoselective syntheses of chiral indolines and tetrahydroquinolines are achieved by combining the asymmetric Zn-mediated allylation of chiral N-tert-butanesulfinyl imines with efficient intramolecular C–N cross-coupling. Herein, the advantages of such a synthetic strategy are illustrated by the synthesis of indolines and tetrahydroquinolines with quaternary stereocenters and multi-substituted 1-oxo-1,2,3,4-tetrahydroisoquinolines.

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Heterocyclic compounds are very important structural units primarily due to their widespread use as crucial intermediates for the synthesis of pharmaceutical compounds, as well as their occurrence in a number of biologically active compounds.¹ Among the heterocyclic compounds, indolines and tetrahydroquinolines attract the most attention, because they exhibit an extensive range of important bio-activities, serving as antibiotics, antitumor agents, cholinesterase inhibitors, antineoplastic agents, etc. (Fig. 1).² Owing to the enormous benefits of these compounds, organic and medicinal chemists are stimulated to develop new strategies for synthesizing such compounds.³

Fig. 1 Examples of biologically active chiral indolines and tetrahydroquinoline derivatives.

Hence, a variety of methodologies have been developed for this purpose, such as asymmetric hydrogenation of indoles and quinolines,⁴ transition metal-catalysed cyclization of amine, amide, enamine, or carbamate,⁵ direct functionalization of C–H bonds of arenes or alkyl chains and [3 + 2]/[4 + 2]-cycloaddition reactions.⁶ Although these strategies brought significant improvements, some drawbacks still limit the application of these preparative strategies. For example, these methods mainly result in cis-multisubstituted indolines and tetrahydroquinolines.⁷ Furthermore, most of the synthetic approaches induced asymmetric construction to the molecules that lacked quaternary carbon stereocenters.⁸ Therefore, the development of a new, straightforward and efficient method to provide trans-multisubstituted indolines and tetrahydroquinolines with quaternary centers still remains a great challenge for fine chemical synthesis.

Previously, Ellman and Foubelo reported on the diastereoselective addition of allylmagnesium and allylindium to different N-tert-butanesulfinyl imines to yield chiral homoallylic amines.⁹ According to their well-established methods, Sun reported a successful development for the synthesis of chiral homoallylic amines of the opposite configuration with both up to 98% de and good yields by simply changing the solvent from THF to the polar aprotic solvent HMPA.¹⁰ In the THF system, a six-membered transition-state chair model was engaged, while an open-chair form was preferred in amide solvents (DMF or HMPA). Recently, Liu and Shen found that the use of DMF as the solvent and LiCl as the additive can also lead to a similar stereoselectivity (up to 99% ee, 98% de) as that using the harmful HMPA solvent, which allows one to avoid the latter.¹¹ Subsequently, we succeeded in developing a convenient method for the asymmetric synthesis of chiral quaternary carbon-containing homoallylic and homopropargylic amines with high diastereoselectivities.¹² The next rational step in our research was to envisage the asymmetric construction of trans-multisubstituted indolines 4 and tetrahydroquinolines 5via the intramolecular C–N cross-coupling of chiral homoallylic amines 3, which could be readily obtained through the Zn-mediated allylation of chiral N-tert-butanesulfinyl imines 1 (Scheme 1).

Scheme 1 Proposed reaction routes for the asymmetric construction of indolines and tetrahydroquinolines.

We firstly investigated the reaction between (R)-N-tert-butanesulfinyl imine 1a and 1-bromo-2-(3-bromoprop-1-enyl)benzene 2a in DMF at room temperature and using zinc dust (2 equiv.) as the catalyst. Without any additive, the reaction led to the homoallylic amine 3a/3a′ with a 96% yield and dr = 45 : 55 (Table 1, entry 1). The diastereoselectivity of the reaction improved greatly (dr = 10 : 90) when 2 equiv. of LiCl was used as the additive, but at the expense of the yield that decreased slightly (Table 1, entry 2). By replacing the solvent with HMPA, a diastereomeric ratio of 6 : 94 was observed, but with a significant decrease in the yield (Table 1, entry 3). A really great improvement was noticed when THF was used as the solvent. Under such conditions, the reaction was mainly directed towards the formation of the stereoisomer 3a (dr = 96 : 4) with a 96% yield (Table 1, entry 4). On the basis of such an encouraging result, we tried to enhance the yield and diastereoselectivity even more by changing the additive. Therefore, the addition of 4 Å MS to the reaction mixture led to the best result. Thus, a diastereomeric ratio of 97 : 3 with a 96% yield was obtained with this additive (Table 1, entry 8). It is worth mentioning that the E/Z ratio of the 2a compound did not have a significant contribution to the reaction yield and diastereoselectivity (Table 1, entry 7).

Table 1 Optimization of reaction conditions^a

Entry	Solvent	Additive (equiv.)	Yield^b [%]	3a : 3a′ ^c
a The reaction was performed with 1a (0.25 mmol), Zn/2a (0.5 mmol), the additive in dry solvent (5 mL) at rt for 12 h, and an 82 : 18 E/Z ratio for 2a. b Isolated yield. c Determined by ^1H NMR of the crude product. d Pure E isomer of 2a was used.
1	DMF	—	96	45 : 55
2	DMF	LiCl (2)	84	10 : 90
3	HMPA	—	48	6 : 94
4	THF	—	96	96 : 4
5	THF	H2O (1)	94	97 : 3
6	THF	H2O (2)	93	95 : 5
7^d	THF	4 Å MS (2)	96	96 : 4
8	THF	4 Å MS (2)	96	97 : 3

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Once the reaction conditions were optimized, we focused on Cu-catalyzed intramolecular C–N coupling.¹³ Initially, the cyclization reaction was examined without the removal of the sulfinyl auxiliary; however, no reaction took place. Then, 2 M HCl-dioxane (0.5 mL) was used to remove the sulfinyl auxiliary. After the evaporation of the solution, Cs₂CO₃ (0.5 mmol, 2 equiv.), CuI (0.038 mmol, 0.15 equiv.), L-proline (0.075 mmol, 0.3 equiv.) and 2 mL of dry DMF were added, followed by stirring at 70 °C for 3 h, leading to the corresponding indoline 4a with a 71% yield after three steps (Table 2, entry 1). Different amino acids, bases and solvents were screened for this reaction. Among them, L-proline, Cs₂CO₃, and DMF were found to provide the optimum conditions for ensuring the best result. A series of multi-substituted indolines were synthesized by this means. As summarized in Table 2, all the reactions proceeded well to give the desired products with excellent diastereoselectivity (dr > 20 : 1 in all cases) and enantioselectivity (up to >99% ee) (Table 2, entries 1–13). Satisfactory yields were observed for the aromatic and heterocyclic substrates. The relatively lower yields noticed for the aliphatic substrates (Table 2, entries 8 and 9) could be rationalized by their decreased stability when compared to the aromatic substrates, in addition to the larger steric hindrance.

Table 2 Diastereoselective synthesis of indolines^a

Entry	R^1	2	4	Yield^b [%]	ee^c [%]
a E/Z ratios: 82 : 18 for 2a, 88 : 12 for 2b, 91 : 9 for 2c, 96 : 4 for 2d were used. b Overall yields after three steps. c Determined by chiral HPLC.
1	Phenyl	2a	4a	71	94
2	4-ClC6H4	2a	4b	76	95
3	4-MeC6H4	2a	4c	79	98
4	4-MeOC6H4	2a	4d	71	96
5	4-FC6H4	2a	4e	73	94
6	α-Naphthyl	2a	4f	80	95
7	2-Thiehyl	2a	4g	78	97
8	Isopropyl	2a	4h	61	97
9	Cyclohexyl	2a	4i	53	97
10	Styryl	2a	4j	76	92
11	4-MeC6H4	2b	4k	71	>99
12	4-MeOC6H4	2c	4l	66	>99
13	Styryl	2d	4m	75	90

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The outstanding results obtained for the multi-substituted indolines encouraged us to switch to the synthesis of tetrahydroquinolines. Unfortunately, when pure THF and DMF were used as solvents, the generated outcomes were not the expected ones (Table 3, entries 1–3). However, LiCl added to the reaction carried out in DMF had a remarkable impact on stereocontrol, the diastereoselectivity increasing greatly to over 98 : 2 (Table 3, entry 4). Interestingly, concentrating the substrate by reducing the volume of the solvent, for instance, from 5 to 2 mL of DMF, and increasing the amounts of Zn and allyl bromide 2e from 2 to 3 equiv. resulted in excellent yields and diastereoselectivities (Table 3, entries 4–7). However, the best result was obtained when 2 equiv. of LiCl and a Zn/2e ratio of 3/3 were used (94% yield, >98 : 2 dr) (Table 3, entry 6). It should be noted that the addition of water had a negative impact on the reaction yield; a value of 78% being obtained in this case (Table 3, entry 8).

Table 3 Optimization of reaction conditions^a

Entry	Solvent	Additive/(eq.)	Time (h)	Zn (eq.)/2e (eq.)	Yield^b	3n : 3n′ ^c
a The reaction was performed with 0.25 mmol of 1a, Zn/2e and the additive in dry THF (5 mL) or DMF (2 mL) at rt. b Isolated yield. c Determined by ^1H NMR of the crude product.
1	THF	—	10	2/2	98	10 : 90
2	THF	H2O/2	10	2/2	81	20 : 80
3	DMF	—	10	2/2	90	83 : 17
4	DMF	LiCl/2	2	2/2	81	>98 : 2
5	DMF	LiCl/2	5	2/2	84	>98 : 2
6	DMF	LiCl/2	5	3/3	94	>98 : 2
7	DMF	LiCl/4	5	3/3	89	>98 : 2
8	DMF	H2O/1	5	3/3	78	>98 : 2
		LiCl/2

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C–N coupling reaction was also used to synthesize a set of multi-substituted tetrahydroquinolines. Notably, it was found that the reaction is not only highly efficient, but it has a general character, as well. Hence, good yields and enantioselectivities were obtained for aromatic, heterocyclic and aliphatic substrates (Table 4, entries 1–11). It seems that both electron-donating and electron-withdrawing groups attached to the phenyl ring of imines do not significantly affect the yield or stereoselectivity. The effect of the functional groups (i.e., methyl and ethyl) on the R⁴ position of the substrate was further explored. trans-Multisubstituted tetrahydroquinolines in a moderate to good yield with excellent enantioselectivity (up to 99% ee) and diastereoselectivity (up to trans : cis > 20 : 1) were generated (Table 4, entries 12–17).

Table 4 Diastereoselective synthesis of tetrahydroquinolines^a

Entry	R^1	2	5	Yield^b [%]	trans : cis^c	ee^d [%]
a Single E isomer was used for 2f and 2g. b Overall yields after three steps. c Determined by ^1H NMR of the product. d Determined by chiral HPLC.
1	Phenyl	2e	5a	70	—	99
2	4-MeC6H4	2e	5b	70	—	97
3	4-FC6H4	2e	5c	74	—	96
4	4-ClC6H4	2e	5d	71	—	97
5	4-MeOC6H4	2e	5e	74	—	>99
6	α-Naphthyl	2e	5f	55	—	97
7	2-Thiehyl	2e	5g	59	—	97
8	2-Furanyl	2e	5h	71	—	98
9	Cyclohexyl	2e	5i	66	—	92
10	Isopropyl	2e	5j	68	—	>99
11	Styryl	2e	5k	68	—	98
12	4-MeOC6H4	2f	5l	67	92 : 8	97
13	4-ClC6H4	2f	5m	66	88 : 12	96
14	4-MeC6H4	2f	5n	55	>20 : 1	94
15	α-Naphthyl	2f	5o	62	>20 : 1	98
16	4-MeOC6H4	2g	5p	75	94 : 6	99
17	4-MeC6H4	2g	5q	67	>20 : 1	98

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The absolute configuration of the cyclization products was established through the X-ray crystallographic analysis of the 4-bromobenzoyl derivatives, 6a and 6b, of the products 4d and 5l, respectively (Fig. 2).

Fig. 2 X-ray crystal structure of the enantiomerically pure 4-bromobenzoyl derivatives 6a and 6b.¹⁴

To underline that our synthetic strategy is attractive and straightforward and allows very flexible access to more complicated molecules, we applied it for the construction of indolines and tetrahydroquinolines with quaternary stereocenters. It was extremely interesting to note that this synthetic approach generated excellent results not only for aromatic methyl ketimines but also for alkyl methyl ketimines (Scheme 2). More importantly, the reaction between imines and ketone bromide reagent 2h allowed the formation of quaternary carbons at C-3 in indolines 4n and 4o. The generation of quaternary stereocenters with a high stereoselectivity is still one of the most challenging tasks in organic synthesis due to the inherent steric repulsion of the four substituents.¹⁵ Therefore this new method is significant as it allows access to quaternary carbon-containing indolines and tetrahydroquinolines.

Scheme 2 Preparation of indolines and tetrahydroquinolines with quaternary stereocenters.

After the successful synthesis of various indolines and tetrahydroquinolines, we further focused on building up more valuable molecular structures. After the N-sulfinyl cleavage of the obtained homoallylic amine 3a, the heterocyclic compound 7 was easy to prepare through the aminocarbonylation reaction with carbon monoxide by using Pd(PPh₃)₂Cl₂ as the catalyst.¹⁶ The reaction was carried out under optimal conditions (20 bar, 100 °C) and using 3 mol% of a palladium catalyst (Scheme 3). Under these conditions, a yield of 40% was obtained for compound 7.

Scheme 3 Aminocarbonylation reaction of 3a.

Conclusions

In summary, we report a new, effective, straightforward, and promising synthetic route for the development of bioactive compounds as trans-multisubstituted indolines and tetrahydroquinolines, with excellent yields and stereoselectivities under mild reaction conditions. Moreover, the construction of indolines and tetrahydroquinolines with quaternary stereocenters from N-tert-butanesulfinyl imines was clearly demonstrated. The absolute stereochemistry of the obtained products was confirmed unambiguously by X-ray analysis. We are confident that by using this new method, the synthesis of fine chemicals will be enriched, especially in the field of complex biologically active compounds, thus opening up new avenues in the design and development of new and efficient pharmaceuticals.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

Financial support from the National Natural Science Foundation of China (21472019), the Open Project of Grain & Corn Engineering Technology Research Center in State Administration of Grain (No. 24400042), the Colleges and Universities Key Research Program Foundation of Henan Province (No. 17A150006), the Science and Technology Foundation of Henan Province (No. 172102310621) and the Fundamental Research Funds for the Henan Provincial Colleges and Universities in Henan University of Technology (No. 2015QNJH08) is greatly appreciated. The authors are also thankful to Dr Xiao-di Yang for assistance with X-ray crystallography.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: CCDC 1573458, 1573459 and 1573547. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c7ob02891a

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