Sequential Phosphine-Catalyzed [4+ 2] Annulation of β′-Acetoxy

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

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Sequential Phosphine-Catalyzed [4 + 2] Annulation of β′-Acetoxy Allenoates: Enantioselective Synthesis of 3‑Ethynyl-Substituted Tetrahydroquinolines Qinglong Zhang,† Hongxing Jin,† Jiaxu Feng,† Yannan Zhu,† Penghao Jia,† Chengzhou Wu,† and You Huang*,†,‡

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†

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: The first enantioselective sequential phosphine-catalyzed (SPC as abbreviation) mode for the formation of tetrahydroquinolines with an ethynyl-substituted all-carbon quaternary stereogenic center is reported. In this SPC process, a novel [4 + 2] annulation process was devised employing α-substituted allenoates as C2 synthons (α−β′, 1,2dipole) for the first time. 3-Ethynyl-substituted tetrahydroquinolines were readily prepared in good yields and high enantioselectivities.

O

activated alkenes was also completed (Scheme 1, eq 2).5 In 2013, Huang and Marinetti independently reported the utilization of γ-substituted allenoates in phosphine-catalyzed [4 + 2] annulation reactions with activated olefins to construct spirocyclic structures, and allenoates were used as C4 synthons (α−δ, 1,4-dipole) in those studies (Scheme 1, eq 3).6 Subsequently, cyclization reactions involving substituted allenoate compounds as diverse dipoles have been reported (Scheme 1).7 In 2010, Tong8 and co-workers disclosed a novel [4 + 1] annulation of β′-acetoxy allenoates; it is noteworthy that allenoates were used as C4 synthons by the 1,4biselectrophile intermediates (Scheme 1, eq 2). Next, enantioselective [4 + 1] annulation of β′-acetoxy allenoates was also reported by the groups of Lu and Fu.9 To the best of our knowledge, besides the two reaction mechanisms based on the (1,n)-zwitterion intermediate and the 1,4-bis-electrophile intermediates of phosphine-catalyzed reactions, no other reaction mechanism has been reported. We report herein a novel sequential phosphine-catalyzed mode for the highly enantioselective formation of tetrahydroquinolines by [4 + 2] annulation reaction with α-substituted allenoates (Scheme 1, eq 4). Substituted tetrahydroquinolines are widespread in many natural products and medically synthetic molecules and exhibit a wide spectrum of significant biological activities, which have attracted considerable attention from organic and medicinal chemists.10 There are some examples of these ring systems contributing to biological activities (Figure 1a).11 Meanwhile, terminal alkynyl linking in a quaternary stereogenic center as a key structural element in numerous natural alkaloids and

ver the past decades, nucleophilic phosphine catalysis has been intensely investigated as a powerful tool for preparing structurally divergent molecules or chiral molecules.1 From the angle of mechanism, nucleophilic addition of a nucleophilic phosphine to activated alkenes, allenes, or alkynes to form a zwitterion intermediate, which is then trapped by an electrophile, is involved. Since the pioneering report of Lu’s [3 + 2] cycloaddition,2 the research paradigm of the phosphinecatalyzed cycloadditions of activated allenes has been well established in which allenoates were used as C3 synthons (Scheme 1, eq 1). Subsequently, [3 + 2] annulations have been a powerful tool to construct five-membered carbocyclic and heterocyclic compounds.3 In 2003, Kwon4 reported a novel [4 + 2] annulation of α-substituted allenoates with Nsulfonylimines, in which allenoates first act as C4 synthons (β′-γ, 1,4-dipole). Later, [4 + 2] annulation of allenoates with Scheme 1. Previous Works and This Work

Received: January 11, 2019

© XXXX American Chemical Society

A

DOI: 10.1021/acs.orglett.9b00130 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Table 1. Substrate Scope for the Synthesis of Tetrahydroquinolines 3a

entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19

Figure 1. Examples of biologically active compounds.

bioactive molecules has led to a great demand for the efficient construction of this skeleton (Figure 1b).12 Although numerous methods have thus been developed to access tetrahydroquinoline ring skeletons, the development of new effective methods, which tolerate special functional groups, is still very important. To the best of our knowledge, there are no reports on the synthesis of chiral alkynylsubstituted tetrahydroquinoline skeletons via asymmetric phosphine catalysis. Recently, 2-aminochalcones were used to construct tetrahydroquinolines and indolines.13 On the basis of our continuous interest in exploring phosphine-catalyzed domino reactions and asymmetric phosphine catalysis,14 we envisioned that α-substituted allenoates containing a leaving group could be transferred to enyne intermediates to promote [4 + 2] annulation of 2-aminochalcones with enynes to construct 3-alkynyl-substituted tetrahydroquinoline skeletons by a sequential phosphine-catalyzed process (Scheme 1, eq 4). In this SPC process, α-substituted allenoates, for the first time, act as C2 synthons of α and β′ sites. Herein, we document a novel [4 + 2] annulation reaction between 2-aminochalcones and α-substituted allenoates involving a SPC process, leading to highly enantioselective construction of 3-alkynyl-substituted tetrahydroquinoline architectures. We initiated our investigation by examining the reaction between 2-aminochalcone 1a and allenoate 2a using PPh3 (20 mol %) in CHCl3 (1.0 mL) at 25 °C (see the Supporting Information for details). To our delight, the reaction proceeded smoothly and afforded the desired product 3aa in 70% yield (Table S1, entry 1). For further optimization study, various solvents such as THF, acetone, hexane, and toluene were scanned (Table S1, entries 2−6); when THF was used, 3aa was obtained in 75% yield (Table S1, entry 2). No base could improve the yields (Table S1, entries 7−10). For the screening of nucleophilic phosphine catalysis (Table S1, entries 11−17), PhPEt2 could improve the reaction and 3aa was obtained in 82% yield (Table S1, entry 15). If a tosyl group was used instead of the Mts (mesityl-λ5-sulfanedione) group, the yield of 3aa decreased. With the optimized reaction conditions in hand, the established reaction conditions were applicable to a variety of substituted 2-aminochalcones and gave the corresponding products in moderate to high yields (Table 1). Increasing the steric bulk of the aryl groups led to a lower reactivity (Table 1, entries 1−3). It was noted that the electron-deficient aryl groups led to a higher reactivity than the electron-rich aryl groups (Table 1, entries 4−10). Unfortunately, alkyl group substituted 2-aminochalcones could not give the corresponding products because of low reactivity (Table 1, entry 11). Screening revealed that the 2-aminochalcone 1l with a 2-furyl group could also smoothly convert into the corresponding 3la in good yield (81%) (Table 1, entry 11). Several substituents

R1 4-BrC6H4 3-BrC6H4 2-BrC6H4 4-ClC6H4 4-FC6H4 4-MeC6H4 4-NO2C6H4 4-PhC6H4 2,4-Cl2C6H3 Ph Me 2-furyl 4-BrC6H4 4-ClC6H4 4-BrC6H4 4-BrC6H4 4-BrC6H4 4-BrC6H4 4-ClC6H4

R2 H H H H H H H H H H H H 5-Cl 5-Br 5-Me H H H H

R3 c

Mts Mts Mts Mts Mts Mts Mts Mts Mts Mts Mts Mts Mts Mts Mts Mts Mts Ms Ms

R4

3

yieldb (%)

Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn Me Et Bn Bn

3aa 3ba 3ca 3da 3ea 3fa 3ga 3ha 3ia 3ja 3ka 3la 3ma 3na 3oa 3ab 3ac 3pa 3qa

82 59 41 83 79 42 78 76 58 66 NR 81 70 73 66 85 84 88 77

a

Unless otherwise specified, all reactions were carried out with 1a(0.1 mmol), 2a (0.15 mmol), PhPEt2 (20 mol %), Cs2CO3 (0.12 mmol), and 1.0 mL of THF at 25 °C. bIsolated yield. cMts = mesityl-λ5sulfanedione.

(R2), namely 5′-Br, 5′-Cl, and 5′-Me, on the aromatic ring of the aniline moiety were well-tolerated and led to a high reactivity (Table 1, entries 12−15). For α-substituted allenoates, when R3 was a variety of ester groups, the reactions converted into the corresponding 3ab and 3ac in high yields (Table 1, entries 16 and 17). Use of an Ms group instead of an Mts group also led to the corresponding tetrahydroquinolines in high yields (Table1, entries 18 and 19). After establishing a practical and highly efficient method for the synthesis of 3-alkynyl-substituted tetrahydroquinoline adducts, we next focused on the development of an enantioselective organocatalytic version. For this purpose, several catalysts, additives, and solvent combinations were evaluated with 1r and 2d as model substrates (see the Supporting Information for details, Table S2 and Table S3). To our delight, the bifunctional catalyst F in toluene delivered the desired products in high enantiomeric excesses and yields. The substituent steric effects of α-substituted allenoates were screened, and the isopropyl group led to the best result (er = 95:5). All of the 2-tosylaminochalcones generated the respective products consistently with moderate to high enantioselectivities and yields (Table 2, entries 1−13). The absolute stereochemistry of 3rd was determined by X-ray diffraction analysis. The substituent steric effect of 2-tosylaminochalcones obviously influenced the enantioselectivities (Table 2, entries 1−3). Unfortunately, alkyl group substituted 2-aminochalcones could not give the corresponding products because of low reactivity (Table 2, entry 8). B

DOI: 10.1021/acs.orglett.9b00130 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Table 2. Substrate Scope for the Enantioselective Synthesis of Tetrahydroquinolines 3a

entry 1 2 3 4 5 6 7 8 9 10 11 12 13

R1 4-BrC6H4 3-BrC6H4 2-BrC6H4 4-ClC6H4 4-FC6H4 4-PhC6H4 Ph Me 2-Furyl 4-BrC6H4 4-BrC6H4 4-BrC6H4 4-BrC6H4

R2 H H H H H H H H H 5-Br 5-Me H H

R3 i

Pr Pr i Pr i Pr i Pr i Pr i Pr i Pr i Pr i Pr i Pr Bn Et i

time (d)

3

yieldb (%)

4 4 4 4 5 5 5 10 4 4 4 4 4

3rd 3sd 3td 3ud 3vd 3wd 3xd 3yd 3zd 3aad 3bbd 3ra 3rc

67 59 trace 73 65 60 43 NR 53 42 53 80 72

Scheme 2. Gram-Scale Synthesis of 3aa and 3rd and Further Transformation from 3aaa

erc 95:5 74:26 91:9 83:17 93:7 91:9 86:14 91:9 93:7 92:8 93:7

a

Conditions: (a) PdCl2(PPh3)2 (5 mol %), CuI (10 mol %), Et3N (2.5 equiv), THF, rt, 2 h, 85% yield; (b) copper(I) thiophene-2carboxylate (10 mol %), TsN3 (1.5 equiv), DCM (0.1 M), rt, 99.2% yield; (c) PdCl2(PPh3)2 (5 mol %), CuI (10 mol %), Et3N (2.5 equiv), PhI (2.0 equiv) THF, rt, 2 h, 54% yield.

a

Unless otherwise specified, all reactions were carried out with 1 (0.1 mmol), 2 (0.15 mmol), Cat. F (20 mol %), Cs2CO3 (0.12 mmol), and 1.0 mL of toluene at 25 °C bIsolated yield. cDetermined by chiralphase HPLC.

Scheme 3. Control Experiments

To demonstrate the further synthetic utility of this protocol, we carried out the reaction on gram scale using 1a with 2a as the representative substrate to provide 3aa in 81% yield. Similarly, 3rd was obtained in 78% yield and high enantioselectivity (er = 90:10). The reduction of the ee value is probably due to the reaction being too long. It was noted that 3rd (> 99% ee) could be obtained by recrystallization. Self-coupling and click reaction of 3aa were achieved in good yields (Scheme 2). Meanwhile, internal alkynyl-substituted tetrahydroquinoline (5c) could be produced by metal-catalyzed cross-coupling of 3-ethynyl-substituted tetrahydroquinolines that were not directly constructed using this SPC process (see the Supporting Information for details). Control experiments (Scheme 3, eq 1) showed that 4a was obtained in 50% isolated yield from 2a using PEt2Ph (20 mol %) and Cs2CO3 (1.2 equiv) in CHCl3. The separation yield of 4a is low due to the instability of the intermediate 4a. Then the reaction of 4a and 1a under the standard conditions did not provide the desired product (Scheme 3, eq 2), but 3aa was obtained in 55% yield without Cs2CO3 (Scheme 3, eq 3). It proved that the reaction was achieved via the intermediate 4a by a SPC process. Meanwhile, the base played a role in the first catalytic cycle, and a negative result for the second catalytic cycle was found when an excess of base was used. According to the control experimental results and previous studies, a possible mechanism, involving a SPC process, was proposed to account for the formation of 3-ethynyl-substituted tetrahydroquinoline derivatives (Scheme 4). Initially, the Lee− Tong intermediate II was produced by a phosphine catalyst from α-substituted allenoates 2 via an addition and elimination reaction.8,15 Then the key intermediate 4a was obtained by the elimination of the phosphine catalyst from Int II under the

Scheme 4. Proposed Reaction Mechanism Involving a Sequential Phosphine-Catalyzed Process

base to accomplish the first catalytic cycle (Scheme 3). Subsequently, in a recatalytic process, nucleophilic attack of C

DOI: 10.1021/acs.orglett.9b00130 Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

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PR3 to 4a generated intermediate III. Then, nucleophilic addition of Int III to 2-aminochalcones 1 generated Int IV. Sequential proton shift and nucleophilic addition process led to the desired tetrahydroquinoline 2 after the release of catalyst PR3, accomplishing the second catalytic cycle. It is worth mentioning that the results of deuterium-labeling experiments also supported the proposed mechanism (see the Supporting Information for details). The key hydrogen-bonding interactions between the NH group of the ester are crucial for the stereochemical outcome of the reaction (see the transition state depicted in Scheme 4, b). In summary, we have unraveled a novel enantioselective SPC mode of asymmetric [4 + 2] annulation reaction between α-substituted allenes and 2-aminochalcones. In this SPC process, α-substituted allenoates were used as C2 synthons (α−β′, 1,2-dipole) for the first time. Notably, it is proven that this reaction involves a phosphine sequential catalytic process via the isolation of the intermediate 4a in the mechanistic study. It provides a new method for construction of 3-ethynylsubstituted tetrahydroquinolines in moderate to high yields and high enantioselectivities, and only one isomer was isolated in all reactions. Further diversity transformations of the products were also carried out. Further development of new annulation reactions by the SPC mode is ongoing in our laboratory.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b00130. Experimental procedures and spectroscopic data (PDF) Accession Codes

CCDC 1491301 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Author

*Email:[email protected]. ORCID

Hongxing Jin: 0000-0001-6024-3600 You Huang: 0000-0002-9430-4034 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was financially supported by the National Natural Science Foundation of China (21672109, 21871148, and 21472097) and the Natural Science Foundation of Tianjin (15JCYBJC20000).

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DEDICATION Dedicated to the 100th anniversary of Nankai University and the 100th anniversary of the birth of Academician Ruyu Chen. D

DOI: 10.1021/acs.orglett.9b00130 Org. Lett. XXXX, XXX, XXX−XXX

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DOI: 10.1021/acs.orglett.9b00130 Org. Lett. XXXX, XXX, XXX−XXX