Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Mn(III)-Mediated Cascade Cyclization of 3‑Isocyano-[1,1′-biphenyl]2-carbonitrile with Arylboronic Acid: Construction of Pyrrolopyridine Derivatives Pei Xu, Yi-Ming Zhu, Fei Wang, Shun-Yi Wang,* and Shun-Jun Ji* Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science & Collaborative Innovation Center of Suzhou Nano Science and Technology, Soochow University, Suzhou 215123, China Org. Lett. Downloaded from pubs.acs.org by EASTERN KENTUCKY UNIV on 01/13/19. For personal use only.
S Supporting Information *
ABSTRACT: A Mn(III) mediated cascade cyclization of new designed multifunctionalized 3-isocyano-[1,1′-biphenyl]-2-carbonitrile with arylboronic acid to construct pyrrolopyridine derivatives is developed. A series of pyrroloporidine compounds have been constructed through the formation of two new C−C bonds and one C−N bond via a radical pathway.
I
undergoes processes to terminate the reaction which can be generally classified into three types: (1) hydrolysis to provide a carbonyl group;10 (2) intramolecular cyano migration to introduce new compounds;11 (3) cyclization to construct Nheterocylic compounds.12 During the past decade, our group has focused on the reactions of isocyanides.13 In addition, we reported the synthesis of phenanthridine by the reaction of 2isocyano-1,1′-biphenyls with different radical donors.14 In continuation of our ongoing interest in the reaction of functionalized isocyanides, we designed multifunctionalized 3-isocyano-[1,1′-biphenyl]-2-carbonitriles as radical acceptors. Herein, we describe a Mn(III) mediated cascade cyclization of 3-isocyano-[1,1′-biphenyl]-2-carbonitrile with phenylboronic acid15 to construct pyrrolopyridine derivatives (Scheme 1). This reaction provides a new method for the construction of new fused heterocyclic compounds based on the multifunctionalized isocyanides. We initiated the studies by the design and synthesis of 3isocyano-[1,1′-biphenyl]-2-carbonitrile 1a. Next, we investigated the cascade reactions of multifunctionalized isocyanide 1a with phenylboronic acid 2a in the presence of 2 equiv of Mn(OAc)3·2H2O in toluene. To our delight, the desired product 5-phenylpyrrolo[4,3,2-gh]phenanthridine (3aa) was formed in 56% GC-yield after 12 h. A screening of other manganese catalysts revealed that Mn(acac)3 and Mn(OAc)2· 4H2O could not afford the desired product (Table 1, entries 2−3). Notably, decreasing the loading of Mn(OAc)3·2H2O resulted in a lower yield (Table 1, entry 4). Increasing the loading of Mn(OAc)3·2H2O resulted in higher yields (Table 1, entries 5−6). Other solvents such as dioxane, THF, CH3CN, DMSO, and DMF also proved to be successful in this reaction. However, no improvement in yields of 3aa were obtained (Table 1, entries 7−11). Screening different concentrations in the reaction revealed that 2 mL of toluene were the ideal
socyanides are highly active compounds that have served as extraordinarily valuable building blocks in organic chemistry. Isocyanides can participate in a variety of reaction types, such as multicomponent,1 transition-metal-catalyzed,2 and radical reactions.3 Recently, the radical cascade reactions utilizing arylisocyanides as radical acceptors have received increasing attention from researchers. All of the arylisocyanides with an ortho substituent, specifically, alkenyl,4 alkynyl,5 aryl,6 isonitrile,7 azide,8 and thioether groups,9 have been successfully developed. The reactions of these isocyanides could construct indole, quinolone, phenanthridine, quinoxaline, benzimidazole, and benzothiazole derivatives, respectively (Scheme 1). Therefore, it is more desirable to develop tandem reactions of new developed functionalized isocyanides. Scheme 1. Arylisocyanides React with Radical
However, the above arylisocyanides have a single functional group, which limits the diversity of the product. To the best of our knowledge, the multisubstitued functional isocyanides have not been studied. Very recently, radical reactions involving cyano group have been well studied. A nitrogen-centered radical generates when the radical addition to the cyano group © XXXX American Chemical Society
Received: December 4, 2018
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DOI: 10.1021/acs.orglett.8b03868 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters Table 1. Optimization of the Reaction of 1a with 2aa
entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
cat. (equiv) Mn(OAc)3·2H2O Mn(acac)3 (2) Mn(OAc)2·4H2O Mn(OAc)3·2H2O Mn(OAc)3·2H2O Mn(OAc)3·2H2O Mn(OAc)3·2H2O Mn(OAc)3·2H2O Mn(OAc)3·2H2O Mn(OAc)3·2H2O Mn(OAc)3·2H2O Mn(OAc)3·2H2O Mn(OAc)3·2H2O Mn(OAc)3·2H2O Mn(OAc)3·2H2O Mn(OAc)3·2H2O
(2) (2) (1) (3) (4) (3) (3) (3) (3) (3) (3) (3) (3) (3) (3)
t (°C)
solvent
yield (%)b
80 80 80 80 80 80 80 80 80 80 80 80 80 80 60 100
toluene toluene toluene toluene toluene toluene dioxane THF CH3CN DMSO DMF toluenec toluened toluenee toluened toluened
56 messy 0 22 59 58 25 20 14 11 29 49 76 (73) 75 29 63
Scheme 2. Substrate Scope of Boronic Acida,b
a
Reaction conditions: 1a (0.1 mmol, 1.0 equiv), 2a (0.2 mmol, 2.0 equiv), manganese catalyst, solvent (1.5 mL), Schlenk tube, argon atmosphere, 80 °C, 12 h. bThe yields were determined by GC analysis using biphenyl as the internal standard, and the isolated yields were given in parentheses. cThe toluene was 1 mL. dThe toluene was 2 mL. e The toluene was 2.5 mL.
Reaction conditions: 1a (0.1 mmol), 2 (0.2 mmol), Mn(OAc)3· 2H2O (0.3 mmol), toluene (2 mL), 80 °C, 12 h, argon atmosphere. b Isolated yield. a
Scheme 3. Substrate Scope of Isocyanidesa,b
amount (Table 1, entries 12−14). Further optimization study indicated that the temperature had a great impact on the reaction (Table 1, entries 15−16). Therefore, the optimized reaction conditions included the following: multifunctionalized isocyanide 1a (0.1 mmol) with phenylboronic acid 2a (0.2 mmol) in the presence of 3 equiv of Mn(OAc)3·2H2O (0.3 mmol) in 2.0 mL of toluene. With the optimal conditions in hand, we first investigated the substrate scope of boronic acid 2 (Scheme 2). Explicitly, the reaction tolerated electron-donating substituents on the boronic acid, including methyl (3ab) and methoxy (3ac) groups. Moreover, the halogen group (F, Cl, Br) substituted ary boronic acid proceeded smoothly to furnish the corresponding products 3ad−af in 63% to 73% yields. It should be noted that aryl boronic acid bearing an electronwithdrawing group (acetyl) led to the desired product 3ah in 47% yield. It is worth mentioning that steric effects have a great impact on the reaction. When the methyl group shifted to the ortho position of the aryl ring, the reaction failed to give the desired product 3ai. A similar result was observed when the (2,6-dimethylphenyl)boronic acid 1j was applied to the reaction with 1a. The reactions of 3-methyl-, 3,5-dimethyl-, or 3,5-bis(trifluoromethyl)-substituted phenylboronic acid with 1a could also result in the desired products 3ak, 3al, and 3am in 54% to 65% yields. Unfortunately, heterocycle boronic acids and alkyl boronic acids failed to furnish the desired products 3an−p under the standard reaction conditions. To expand the scope of this method, different substituted isocyanides were synthesized and examined, and most of the tested substrates proceeded smoothly to afford the desired products under the optimal conditions (Scheme 3). To our delight, different substrates with electron-rich (Me, OMe) or
Reaction conditions: 1a (0.1 mmol), 2 (0.2 mmol), Mn(OAc)3· 2H2O (0.3 mmol), toluene (2 mL), 80 °C, 12 h, argon atmosphere. b Isolated yield. a
electron-deficient (F, Cl) groups at the para-position of the aryl ring could proceed well, giving the desired products 3ba, 3ca, 3da, and 3ea in 60% to 73% yields. The reaction of 2a with 3-isocyano-[1,1′:4′,1′′-terphenyl]-2-carbonitrile 1f afforded the target product 3fa in 60% yield. It should be noted that dimethyl functionalized 3-isocyano-3′,5′-dimethyl[1,1′-biphenyl]-2-carbonitrile 1g reacted well with 2a to give 3ga in 86% yield. The reaction of 3-isocyano-3′,5′-bis(trifluoromethyl)-[1,1′-biphenyl]-2-carbonitrile 1h with 2a gave 3ha in 47% yield. Unfortunately, when a more bulky B
DOI: 10.1021/acs.orglett.8b03868 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters
the loading of TEMPO to 4 equiv yielded only trace amounts of product. At the same time, a TEMPO adduct phenyl radical can be detected by LC-MS. These results indicate that this reaction might proceed through a radical pathway. Based on the experiment results and previous reports,12,15 a plausible reaction mechanism is proposed (Scheme 6).
substrate such as 3-isocyano-2′-methyl-[1,1′-biphenyl]-2-carbonitrile was applied to the reaction with 2a, no desired products were obtained due to the steric effect. It should be noted that the reaction of 3-isocyano-3′-methyl-[1,1′-biphenyl]-2-carbonitrile 1j with 2a proceeded smoothly to result in a mixture of 3ja and 3ja′ (1:3) in total 80% yield. In this reaction, the two isomers were obtained due to the presence of two cyclization sites. It is worth noting that the reaction of 3isocyano-2′,5′-dimethoxy-[1,1′-biphenyl]-2-carbonitrile 1k with 2a successfully led to the desired product 3ka in 67% yield. The methyl group exhibits a certain flexibility due to the oxygen atom which reduces steric hinderence. The pyrrolopyridine is the skeleton of Plakinidines A and B which indicated in vitro activity against Nippostrongylus brastiliensis.16 To show the potential applications of our method, we attempted to amplify the model reaction to a 0.5 g scale and further functionalized the pyrrolopyridine derivatives. The reaction of 1a with 2a in 3 mmol scale under the standard reaction conditions (Scheme 4), to our delight, afforded 3aa in 53% yield. The cross-coupling reaction of 3af and 2q proceeded smoothly to afford pyrrolopyridine derivative 4a in 71% yield.
Scheme 6. Plausible Mechanism
Initially, the aryl radical is generated in situ from arylboronic acid in the presence of Mn(III). The aryl radical reacts with 1a through intermolecular addition to give imdoyl radical A. Subsequently, the radical A undergoes an intramolecular cyclization with the cyano group to give the radical intermediate B. The following intramolecular addition of the iminyl radical B on the pendant aromatic ring provides the radical C. The cationic intermediate D is formed through single-electron oxidation of C by Mn(III). Finally, product 3aa is afforded by hydrogen abstraction from intermediate D. In summary, we have developed a Mn(III)-mediated cascade reaction of new multifunctionalized isocyanides with arylboronic acid for the synthesis of pyrroloporidine compounds. This reaction not only constructs a new class of fused heterocyclic compounds but also expands the reactions of multifunctionalized isocyanides.
Scheme 4. Scale-up Synthesisa and Transformations of 3afb
a Reaction conditions: 1a (3.0 mmol), 2 (6.0 mmol), Mn(OAc)3· 2H2O (9.0 mmol), toluene (50 mL), 80 °C, 12 h, argon atmosphere. The yield is isolated yield. bReaction conditions: 3af (0.1 mmol), 2q (0.12 mmol), PdCl 2 (PPh 3 ) 2 (10 mol %), Cs 2 CO 3 (0.2 mmol),CH3CN/H2O (2 mL/0.05 mL), 80 °C, 12 h, argon atmosphere. The yield is isolated yield.
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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.8b03868. Detailed experimental procedures; characterization data (PDF)
To explore the possible mechanism of the reaction, a series of controlled experiments were carried out, as shown in (Scheme 5). When 2 equiv of radical scavenger 2,2,6,6tetramethyl-1-piperidinyloxy (TEMPO) was added to the reaction mixture under the standard reaction conditions, the desired product 3aa was only obtained in 20% yield. Increasing
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AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected].
Scheme 5. Controlled Experimentsa,b
ORCID
Shun-Yi Wang: 0000-0002-8985-8753 Shun-Jun Ji: 0000-0002-4299-3528 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We gratefully acknowledge the National Natural Science Foundation of China (21772137, 21542015, and 21672157), PAPD, the Project of Scientific and Technologic Infrastructure of Suzhou (SZS201708), the Major Basic Research Project of the Natural Science Foundation of the Jiangsu Higher
a Reaction conditions: 1a (0.1 mmol), 2a (0.2 mmol), Mn(OAc)3· 2H2O (0.3 mmol), TEMPO (2 or 4 equiv), toluene (2 mL), 80 °C, 12 h, argon atmosphere. bIsolated yield.
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DOI: 10.1021/acs.orglett.8b03868 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters
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Education Institutions (No. 16KJA150002), Soochow University, and State and Local Joint Engineering Laboratory for Novel Functional Polymeric Materials for financial support. We thank Tian Jiang in this group for reproducing the result of 3ab, 3af, 3ga, and 4a.
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DOI: 10.1021/acs.orglett.8b03868 Org. Lett. XXXX, XXX, XXX−XXX
