Letter pubs.acs.org/OrgLett
Sequential [1 + 4]- and [2 + 3]-Annulation of Prop-2-ynylsulfonium Salts: Access to Hexahydropyrrolo[3,2‑b]indoles Penghao Jia,† Qinglong Zhang,† Qima Ou,† and You Huang*,†,‡ †
State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300071, China
‡
S Supporting Information *
ABSTRACT: A powerful sequential [1 + 4]- and [2 + 3]-annulation has been developed using prop-2-ynylsulfonium salts and sulfonyl-protected o-amino aromatic aldimines, affording a series of hexahydropyrrolo[3,2-b]indoles in high yields. Prop-2ynylsulfonium salts act as C2 synthons in the reaction, and fused rings containing two five-membered azaheterocycles can be constructed in a single operation with readily accessible starting materials.
N
group to generate intermediate II. The subsequent intramolecular substitution reaction and elimination of Me2S lead to the construction of the fused-ring skeleton. In the past few years, the groups of Aggarwal, Xiao, and others have made great advances in the field of sulfur ylide chemistry using vinylsulfonium salts as C2 synthons (Scheme 2). Upon reaction with active methylene compounds bearing electron-withdrawing groups, a [2 + 1]-cycloaddition took place, and substituted cyclopropane derivatives were obtained.8
itrogen-containing heterocyclic compounds, because of their prevalence in natural products and pharmaceuticals, have received much attention in recent years.1 Specifically, indole and indoline skeletons are privileged structural subunits present in many biologically active natural and synthetic compounds.2 Among these structures, fused indolines have attracted considerable synthetic interest.3 Therefore, a new synthetic approach to this class of useful molecules is of great value. Sulfur ylides, a kind of efficient methylene-transfer reagents, are widely used in the synthesis of three-membered rings.4 With the development of sulfur ylide chemistry,5 sulfur ylides are also viewed as potential dipole reagents because of the leaving ability of the charged sulfur atom and the nucleophilicity of the α-carbon atom.6 On the basis of the in-depth understanding of sulfur ylides, new working models of diverse sulfur ylides can be proposed. Different from a traditional sulfur ylide, a prop-2ynylsulfonium salt7 can transform into an allenic sulfonium salt and be attacked by a nucleophile at the β-carbon atom first (Scheme 1). The obtained intermediate I can undergo a second nucleophilic addition at the carbon atom α to the electrophilic
Scheme 2. Reactions of Sulfonium Salts Acting as C2 Synthons
Scheme 1. Proposed Working Model of Prop-2ynylsulfonium Salts
Received: July 26, 2017 Published: August 22, 2017 © 2017 American Chemical Society
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DOI: 10.1021/acs.orglett.7b02298 Org. Lett. 2017, 19, 4664−4667
Letter
Organic Letters Sequential [1 + 2]- and [2 + n]-annulations were realized by reaction with α-, β-, and γ-amino aldehydes, hydroxy aldehydes, or similar olefins or imines, and the reactions generated a series of three-membered-ring-fused heterocycles.9 On the basis of the proposed working model of prop-2-ynylsulfonium salts and our previous work,10 we report here a novel sequential [1 + 4]and [2 + 3]-annulation of prop-2-ynylsulfonium salts and sulfonyl-protected o-amino aromatic aldimines11 that provides facile access to hexahydropyrrolo[3,2-b]indoles. In the reaction, the prop-2-ynylsulfonium salt acts as a C2 synthon, and the sequential [1 + 4]- and [2 + 3]-sequence introduces two fivemembered azaheterocycles into the fused-ring skeleton, which further broadens the application of sulfur ylides. We commenced our study using phenylsulfonyl-protected oamino aromatic aldimine 2a as a model substrate, which was stirred in the presence of 2 equiv of prop-2-ynylsulfonium salt 1a and 2 equiv of Cs2CO3 as a base in CH3CN at 20 °C (Table 1, entry 1). We were pleased to observe the formation of the
With the optimized reaction conditions in hand, we then investigated the substrate scope with respect to the protecting group of the o-amino aromatic aldimine (Scheme 3). To probe Scheme 3. Scope with Respect to the Protecting Group of the o-Amino Aromatic Aldiminea,b
Table 1. Screening of the Reaction Conditionsa
entry
solvent
base
1a/2a/base
temp (°C)
t (h)
yield (%)b
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Cs2CO3 DBU Et3N NaOH t-BuOK Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3
CH3CN CH3CN CH3CN CH3CN CH3CN DCM CHCl3 THF CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN
2:1:2 2:1:2 2:1:2 2:1:2 2:1:2 2:1:2 2:1:2 2:1:2 1:1.5:1.5 1:1.2:1.5 1:1.2:1.5 1:1.2:1.5 1:1.2:1.5 1:1.2:1.5 1:1.2:1.5
20 20 20 20 20 20 20 20 20 20 30 40 50 60 70
5 5 5 5 5 8 8 12 5 5 5 3 2 2 2
31 25 30 25 27 18 14 trace 47 48 48 58 88 91 91
a Reactions of 1a (0.20 mmol) and 2 (0.24 mmol) were carried out in the presence of Cs2CO3 (0.30 mmol) in 2 mL of CH3CN at 60 °C. b Isolated yields are shown.
the generality of the current reaction, a variety of substituted phenylsulfonyl groups were tested. Studies with parasubstituted benzene rings showed that electronic effects did not have a significant effect on this reaction, as substrates with either electron-donating groups (3ab, 3ac) or electronwithdrawing groups (3ad−af) provided comparable yields, among which 4-methoxyphenylsulfonyl-protected o-amino aromatic aldimine 2c gave the highest yield of 94%. Further investigation demonstrated that aldimines 2 with 2-methyl- and 2,4,6-trimethyl-substituted phenylsulfonyl groups were also well-tolerated, generating the sequential annulation products in good yields (3ag and 3ah), which indicated that steric hindrance did not influence the reaction. Changing the protecting group to a methylsulfonyl group produced the corresponding product 3ai in a lower yield of 57%. Substrates bearing protecting groups like benzoyl or t-butoxycarbonyl groups resulted in a mixture of reactions, and the desired products could not be detected. The structure and stereochemistry of 3ah were unambiguously assigned by single-crystal X-ray analysis (Figure 1).12 We then moved on to investigate the suitability of various substituted phenylsulfonyl-protected o-amino aromatic aldimines (Scheme 4). Aldimines 2 with different substituents at different positions of the arene all participated smoothly in the reaction. Substrates with electron-donating groups (Me) and electron-withdrawing groups (F, Cl, Br) at the 4-, 5-, and 6-
a
Unless otherwise noted, the reaction was carried out on a 0.2 mmol scale in 2 mL of the solvent. bIsolated yields.
sequential annulation product 3aa in 31% yield. Further screening of bases (DBU, Et3N, NaOH, and t-BuOK) and solvents (DCM, CHCl3, and THF) did not give a better yield (Table 1, entries 2−8). During the reaction process, the decomposition of 2a was observed, and 4a was formed, which encouraged us to optimize the molar ratio of the substrates (Table 1, entries 9 and 10). The results demonstrated that 1.2 equiv of 2a and 1.5 equiv of Cs2CO3 gave the product 3aa in an increased yield of 48%. Subsequent screening of temperature showed that raising the temperature was beneficial to the reaction (Table 1, entries 11−15), and product 3aa was obtained in 91% yield at 60 °C (Table 1, entry 14). Accordingly, the optimal reaction conditions were established as 1a/2a/Cs2CO3 (1:1.2:1.5) in CH3CN at 60 °C. 4665
DOI: 10.1021/acs.orglett.7b02298 Org. Lett. 2017, 19, 4664−4667
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Organic Letters
Scheme 5. Scope of Sulfonium Salts and X-ray Crystal Structure of 3caa,b
Figure 1. X-ray crystal structure of 3ah.
Scheme 4. Scope of Substituted Phenylsulfonyl-Protected oAmino Aromatic Aldiminea,b
a Reactions of 1 (0.20 mmol) and 2a (0.24 mmol) were carried out in the presence of Cs2CO3 (0.30 mmol) in 2 mL of CH3CN at 60 °C. b Isolated yields are shown.
Scheme 6. Gram-Scale Synthesis and Further Transformation of 3ao
a
Reactions of 1a (0.20 mmol) and 2 (0.24 mmol) were carried out in the presence of Cs2CO3 (0.30 mmol) in 2 mL of CH3CN at 60 °C. b Isolated yields are shown.
position of the arene produced the desired products in good to high yields (3aj−aq). An aldimine containing a naphthalene ring was also suitable substrate, affording the corresponding product 3ar in 97% yield. To further broaden the scope of the reaction, different sulfonium salts were employed in the reaction (Scheme 5). Treatment of tetrahydrothiophene sulfonium salt 1b under the standard reaction conditions gave 3aa in 77% yield. Phenylsubstituted sulfonium salt 1c could also be transformed into the corresponding product 3ca in 85% yield. However, when nbutyl-substituted sulfonium salt 1d was subjected to the reaction, a complex reaction mixture was obtained. The structure and stereochemistry of 3ca were determined by single-crystal X-ray analysis.13 To demonstrate the synthetic utility, this method was assessed on a larger scale using substrates 1a and 2o. Pleasingly, compound 3ao was obtained in 98% yield (Scheme 6). Some transformations were conducted using product 3ao. Suzuki cross-coupling product 5 was obtained from 3ao and
benzo[b]thiophen-2-ylboronic acid in 79% yield. Upon treatment of 3ao with MeLi, an intramolecular C−N acyl transfer reaction produced 6 in 86% yield with a 2.5:1 diastereomeric ratio.14 In summary, we have developed a sequential annulation reaction of prop-2-ynylsulfonium salts and sulfonyl-protected oamino aromatic aldimines involving a sulfonium salt-based sequential [1 + 4]- and [2 + 3]-annulation. This reaction provides facile access to hexahydropyrrolo[3,2-b]indoles in high yields with a wide range of substrates. Consistent with our proposed working model, the prop-2-ynylsulfonium salt acts as a C2 synthon and is incorporated into the construction of a fused five-membered azaheterocycle beyond the traditional three-membered-ring structure. Further efforts toward the 4666
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practical syntheses of high-value bioactive compounds are also underway.
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ASSOCIATED CONTENT
* Supporting Information S
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b02298. Experimental details, characterization data for new compounds, copies of NMR spectra, and X-ray crystal structures of 3ah and 3ca (PDF) Crystallographic data for 3ah (CIF) Crystallographic data for 3ca (CIF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
You Huang: 0000-0002-9430-4034 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank the National Natural Science Foundation of China (21472097, 21672109, and 21421062) and the Natural Science Foundation of Tianjin (15JCYBJC20000).
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REFERENCES
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