Letter pubs.acs.org/OrgLett
(3 + 2)-Annulation of p‑Quinamine and Aryne: A Strategy To Construct the Multisubstituted Hydrocarbazoles Dengyu Xu,† Yulong Zhao,† Dengpeng Song,† Zhuliang Zhong,† Shangbiao Feng,† Xingang Xie,† Xiaolei Wang,† and Xuegong She*,†,‡ †
State Key Laboratory of Applied Organic Chemistry, Department of Chemistry, Lanzhou University, Lanzhou 730000, People’s Republic of China ‡ Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300071, People’s Republic of China S Supporting Information *
ABSTRACT: A strategy for the synthesis of multisubstituted hydrocarbazoles has been developed through (3 + 2)-annulation of p-quinamines and arynes. In this way, new analogs of hydrocarbazoles with quaternary carbon center can be synthesized in satisfactory yield under mild conditions. Furthermore, this (3 + 2)-annulation can be easily scaled-up, and the products can be modified through simple transformation.
H
Scheme 1. Previous Methods and Our Strategy for Constructing Hydrocarbazoles
ydrocarbazoles, possessing a heterotricyclic ring system, are a significant class of organic compounds. This motif also exists in many natural alkaloids, such as strychnine, kopsane, minfiensine, and aspidospermidine (Figure 1).1 Some
Figure 1. Selected examples of natural indole alkaloids that contain the hydrocarbazole core.
Akai through benzynes and γ-amion-α,β-unsaturated esters or nitriles.9 Inspired by the previous research, the development of a general, efficient, and new means for the synthesis of structurally diverse hydrocarbazoles still remains desirable. Herein we describe a fluorion promoted formal (3 + 2) cycloaddition of p-quinamines and arynes to construct the multisubsitituted hydrocarbazoles (Scheme 1c). Arynes have historically received much attention from physical organic chemists, and they are frequently used in organic chemistry in recent years.10 The fluorion-induced elimination of ortho-silyl
terpene-indole alkaloids have high-profile activities and are used as clinical drugs.2 The potential activity of indole-fused hydrocarbazole as therapeautic agents has attracted the attention of synthetic and medicinal chemists. To date, the common approach for constructing the tricyclic core is the cycloaddition of indole or indole derivatives (Scheme 1a, 1b).3 Using different dienes and dienophiles, various tricyclic hydrocarbazoles can be synthesized through Diels−Alder reaction.4−7 Using chiral catalysts, stereoselective construction of the hydrocarbazoles has developed rapidly in recent years.8 Some methods were successfully used in the total synthesis of natural products.8c,d Moreover, another efficient method to synthesize indolines was developed by Sudalai and © 2017 American Chemical Society
Received: May 25, 2017 Published: June 28, 2017 3600
DOI: 10.1021/acs.orglett.7b01578 Org. Lett. 2017, 19, 3600−3603
Letter
Organic Letters
aryltriflate solution to the reaction system slowly to avoid the polymerization of aryne; however, the yield was the same as that for entry 1 (Table 1, entry 5). The yield slightly decreased when we switched the solvent from CH3CN to THF or removed the 4 Å MS additive. Surprisingly, when we chose the KF and 18-crown-6 system, the yield increased dramatically (Table 1, entries 8−10). Finally we established the standard conditions: employing p-quinamine 1a and ortho-silyl aryltriflate 2a in the presence of KF (4.0 equiv), 18-crown-6 (4.0 equiv), and 4 Å MS in THF at room temperature under an argon atmosphere (Table 1, entry 10). To examine the substrate scope and limitations of this approach, various p-quinamines were prepared and reacted with 2a under the optimized reaction conditions (Scheme 2). This
aryltriflates described a mild method for the in situ preparation of benzynes at moderate temperature.11 And p-quinamines were also used as a novel synthon in many recent publications for constructing the hydroindole motifs.12 Based on these ideas, we designed this new approach as Scheme 1c. At the outset of this investigation, we employed p-quinamine 1a and ortho-silyl aryltriflate 2a in the presence of CsF (4.0 equiv) in CH3CN at room temperature for 18 h (Table 1, entry Table 1. Optimization of the Reaction Conditionsa
entry
F− source (4.0 equiv)
1 2 3 4 5c 6 7 8 9
CsF CsF CsF CsF CsF CsF CsF KF KF
10
KF
additive 4 Å MS 4 Å MS 4 Å MS 4 Å MS 4 Å MS 4 Å MS none 18-crown-6 4 Å MS 18-crown-6 4 Å MS 18-crown-6
time (h)
temp (°C)
solvent
yieldb (%)
18 36 6 48 10 18 18 10 10
25 25 60 0 25 25 25 25 25
CH3CN CH3CN CH3CN CH3CN CH3CN THF CH3CN THF CH3CN
25 23 22 15 25 15 17 62 78
10
25
THF
86
Scheme 2. Reaction Scope of p-Quinaminesa
a
Reaction conditions: p-quinamine (1a, 0.2 mmol, 1.0 euqiv), orthosilyl aryltriflate (2a, 0.6 mmol, 3.0 equiv), fluoride source (4.0 equiv), solvent (6.0 mL) under argon. bIsolated yields. cUsing syringe pump to add the ortho-silyl aryltriflate.
1). 4 Å Molecular sieve (4 Å MS) was used as an additive to guarantee the anhydrous condition (Table 1, entry 7). To our delight, the desired product 3aa was obtained in 25% yield. The relative configuration of 3aa was determined by X-ray single crystal diffraction (Figure 2).13 When we prolonged the reaction time or elevated the temperature, the yield slightly dropped (Table 1, entries 2 and 3). When we reduced the temperature to 0 °C and maintained this reaction at this temperature for 48 h, the yield was still very low (Table 1, entry 4). We also used a syringe pump to add the ortho-silyl
a
Reaction conditions: 1a−1l (0.2 mmol, 1.0 equiv), 2a (0.6 mmol, 3.0 equiv), KF (4.0 equiv), 18-crown-6 (4.0 equiv), THF (6.0 mL), at ambient temperature under argon for 10−18 h. bIsolated yields.
reaction was successfully amenable to a wide range of pquinamines; the R 1 group can be Me, n-Bu, Ph, or multisubstituted phenyl rings, generating the corresponding hydrocarbazoles (3aa−3la) in moderate to excellent yields (52−94%). Apparently, when the R 1 was an aryl group, the corresponding product was obtained in higher yield (3aa− 3ia) than in the case where R1 was an alkyl group (3ja−3ka). Especially when there were electron-donating groups on the aryl, the yields were good (3ba−3fa). This reaction was also tolerant of other functional groups (Cl, Br, and CF3), and the desired products (3ga−3ia) were gained in good yields. The R1 group can also be the alkynyl group, and the desired product (3la) was gained in moderate yield. In order to probe the effect of aryne substitution on reactivity, a variety of functionalized ortho-silyl aryltriflates were tested under the optimized reaction conditions (Scheme 3). To our delight, all the ortho-silyl aryltriflates performed well in the reaction and provided functionalized hydrocarbazoles (3aa− 3ae) with satisfactory yields. To investigate the synthetic utility of this reaction, a gramscale version of the reaction using substrates 1a and 2a was
Figure 2. X-ray crystallographic structure of product 3aa (CCDC 1551379). 3601
DOI: 10.1021/acs.orglett.7b01578 Org. Lett. 2017, 19, 3600−3603
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Scheme 3. Reaction Scope of ortho-Silyl Aryltriflatesa
Letter
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b01578. Crystallographic data (CIF) Detailed experimental procedures and full spectroscopic data for all new compounds (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Xuegong She: 0000-0002-3002-2433 Notes
a
Reaction conditions: 1a (0.2 mmol, 1.0 equiv), 2a−2e (0.6 mmol, 3.0 equiv), KF (4.0 equiv), 18-crown-6 (4.0 equiv), THF (6.0 mL), at ambient temperature under argon for 10−18 h. bIsolated yields.
The authors declare no competing financial interest.
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Scheme 4. Scale-up and Transformation of Hydrocarbazoles 3aa and 3ja
ACKNOWLEDGMENTS This work was supported by the National Science Foundation of China (21125207, 21372103, 21472079, and 21572088), SRFDP (20130211110018), PCSIRT (IRT_15R28), and the Fundamental Research Funds for the Central Universities (lzujbky-2016-ct02).
conducted using product 3aa and 3ja. Upon treatment of 3aa with NaBH4 in MeOH, reduction product 4 was generated in 88% yield with 15:1 diastereoselectivity. Moreover, product 5 could also be obtained from 3aa via a Knoevenagel reaction in 83% yield. When another product 3ja was treated with Pd/C in MeOH under a H2 atmosphere, the hydrogenation product 6 can be formed in 95% yield. Product 7 can be obtained from 3ja via an Eschenmoser methenylation in 30% yield in two steps. In conclusion, a simple (3 + 2)-annulation reaction between p-quinamines and arynes has been developed, which can provide indole-fused hydrocarbazoles in good yield. The synthetic method described in this manuscript provides an alternative preparation of indole-fused hydrocarbazoles and might be used in the construction of molecules with interesting biological properties.
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carried out, and desired product 3aa was obtained in 81% yield on 1.2 g scale (Scheme 4). And some transformations were
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