Letter Cite This: Org. Lett. 2019, 21, 444−447
pubs.acs.org/OrgLett
Metal-Free Radical [2 + 2 + 1] Cyclization of orthoCyanoarylacrylamides with Alkyl Nitriles: Synthesis of Pyrrolo[3,2‑c]quinolines Tao Yang,† Wen-Jin Xia,† Jia-Qi Shang,† Yi Li,† Xiang-Xiang Wang,† Meng Sun,‡ and Ya-Min Li*,† †
Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, China Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, Department of Chemistry & Materials Science, Northwest University, Xi’an 710127, China
‡
Org. Lett. 2019.21:444-447. Downloaded from pubs.acs.org by IOWA STATE UNIV on 01/18/19. For personal use only.
S Supporting Information *
ABSTRACT: A novel radical [2 + 2 + 1] cyclization of orthocyanoarylacrylamides with dual α-C−H bonds in alkyl nitriles has been developed. The reaction provides new facile and straightforward access to cyano-substituted pyrrolo[3,2-c]quinolines, which are important nitrogen-containing polyheterocycles. A possible mechanism for the transformation is proposed.
P
linked 1,n-enynes with the dual C−H bonds on the identical carbon atom.6 The annulation of 1,n-enynes with α-carbonyl alkyl bromides, aliphatic aldehydes, alkyl carboxylic acids, and dichloromethane as a one-carbon unit has also been developed (Scheme 1a).7 Heinrich and co-workers described a radical [2 +
yrrolo[3,2-c]quinolines are an important class of nitrogencontaining polyheterocycles which widely exist in many natural products and biologically active compounds (Figure 1).1
Scheme 1. Radical-Mediated [2 + 2 + 1] Cyclization
Figure 1. Selected bioactive pyrrolo[3,2-c]quinoline derivatives.
For example, natural product martinelline was found to possess antibacterial activity as well as affinity for muscarinic, adrenergic, and bradykinin receptors.1a Pyrrolo[3,2-c]quinoline II is a 5HT6R antagonist.1e Compound III is a potassium-competitive inhibitor of gastric (H+/K+)-ATPase.1g Because of their structural importance, great synthetic efforts have been exerted to develop efficient methods for the synthesis of such nitrogencontaining polyheterocycles.1,2 However, multiple synthetic steps or complex substrates are always involved in these approaches. Therefore, new and efficient methods to construct pyrrolo[3,2-c]quinolines are needed. The [2 + 2 + 1] cyclization of both unsaturated moieties and a one-carbon unit is one of the powerful methods for the construction of five-membered rings due to its high efficiency and atom economy.3 However, in this context, the majority focus on the use of CO as a one-carbon unit (the Pauson− Khand-type reaction).4 Recently, the radical-mediated [2 + 2 + 1] cyclization of unsaturated moieties with other carbon units has received increased attention.5−8 The Jiang et al. and Li et al. reported the radical-mediated [2 + 2 + 1] cyclization of benzene© 2018 American Chemical Society
2 + 1] spirocyclization leading to ortho-spirocyclohexadienones via a highly diastereoselective cascade reaction with alkynes featuring three consecutive carbon−carbon bond formations (Scheme 1b).8 Despite these advances, only alkenes and alkynes were used as unsaturated moieties in these examples, and the radical [2 + 2 + 1] cyclization in which the nitrile group served as Received: November 14, 2018 Published: December 27, 2018 444
DOI: 10.1021/acs.orglett.8b03638 Org. Lett. 2019, 21, 444−447
Letter
Organic Letters
yield (Table 1, entry 18). The structure of the major isomer of 3a was identified by X-ray crystallographic analysis (Figure 2).
an unsaturated moiety has not been well-developed until now.9,10 On the basis of our continuing interest in developing new radical cascade reactions,11 herein, we report a novel radical [2 + 2 + 1] cyclization of ortho-cyanoarylacrylamides with dual α-C−H bonds in alkyl nitriles (Scheme 1c). The reaction generated one C−N bond, two C−C bonds, and two new rings through an α,α-C(sp3)−H difunctionalization and annulation sequence to afford cyano-substituted pyrrolo[3,2-c]quinolines. At the outset of our investigation, N-(2-cyanophenyl)-Nmethylmethacrylamide (1a) was chosen as the model substrate for the cyclization. When ortho-cyanoarylacrylamide 1a was treated with MeCN (both as reactant and as solvent) and tertbutyl peroxybenzoate (TBPB) at 100 °C for 12 h under an argon atmosphere, the reaction proceeded smoothly and afforded the desired product 3a in 28% yield with 2.0:1 dr (Table 1, entry 1).
Figure 2. X-ray structure of the major isomer of pyrrolo[3,2c]quinoline 3a.
Table 1. Reaction Conditions’ Screeninga
entry
oxidant (equiv)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16c 17d 18e
TBPB (2.0) TBPB (3.0) TBPB (4.0) DTBP (2.0) DCP (3.0) K2S2O8 (3.0) TBPB (3.0) TBPB (3.0) TBPB (3.0) TBPB (3.0) TBPB (3.0) TBPB (3.0) TBPB (3.0) TBPB (3.0) TBPB (3.0) TBPB (3.0) TBPB (3.0) TBPB (3.0)
additive (equiv)
CH3CN (mL)
yield (%)b
DBU (0.2) K2CO3 (0.2) AcOK (0.2) AcONa (0.2) HCO2Na (0.2) AcONa (0.1) AcONa (0.3) AcONa (0.2) AcONa (0.2) AcONa (0.2)
3 3 3 3 3 3 4.5 6 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5
28 58 53 0 0 0 64 60 21 19 38 75 53 59 68 49 65 61
With the optimized reaction conditions, a variety of orthocyanoarylacrylamides were subjected to the optimized conditions to evaluate the scope of the [2 + 2 + 1] cyclization, and the results are summarized in Scheme 2. The N-methyl- and Nbenzyl-substituted acrylamides reacted well with MeCN, and the expected products, 3a and 3b, were obtained in 75 and 65% yields, respectively, but the N-acetyl-substituted substrate failed to give the desired product. It was found that N-unprotected phenylmethacrylamide was compatible with this system. For aromatic units, the electronic properties of the substituents had no apparent effect on the efficiency of the reaction. The substrates with both electron-withdrawing and electrondonating groups at the phenyl ring underwent the reaction smoothly, affording products 3e−3q in moderate to good yields. Halogen groups such as Cl and Br also could be well-tolerated in the transformation, which provided opportunities for further functionalization. Steric hindrance in the ortho-substituted acrylamides did not have a considerable influence on the reaction, and satisfactory yields were provided in all cases. The effect of the substituents on olefins was next evaluated, and it was found that substrates with different functional groups such as phenyl, benzyl, ester, and phthalimide at the α-position of the olefins were suitable for the reaction (3r−3u). Heterocyclic substrate pyridineacrylamide was also compatible with this reaction, giving the corresponding pyrrolo[3,2-c]quinoline 3v in 75% yield. With respect to the nitriles employed, 4chlorobutyronitrile, 2-methoxyacetonitrile, malononitrile, and 2-(pyridin-2-yl)acetonitrile also reacted well with acrylamide, leading to products 3w−3z in moderate to good yields. A gram-scale reaction was carried out to show the potential applications of this protocol. As shown in Scheme 3, the reaction of 9.0 mmol of acrylamide 1a with MeCN under the standard reaction conditions gave 1.53 g of the desired product 3a in 71% yield. The result indicate that the [2 + 2 + 1] cyclization could be readily scaled up with similar efficiency. To probe the reaction mechanism, several control experiments were carried out (Scheme 4). Initially, when radical inhibitors such as 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) and 2,6-di-tert-butyl-4-methylphenol (BHT) were added to the standard reaction conditions, the cyclization process was remarkably suppressed, and TEMPO−CH2CN and BHT−CH2CN could be detected by HRMS. These results indicate that the reaction should proceed through a radical pathway. In addition, a large KIE (kH/kD = 11.5) was obtained when the reaction was carried out in a 1:1 mixture of CH3CN/ CD3CN as the solvent, thus implying that the cleavage of the
a Reaction conditions: 1a (0.30 mmol), oxidant, and additive in CH3CN at 100 °C for 12 h under Ar. bIsolated yield of 3a. The dr value is about 1.5−2.3:1 as determined by 1H NMR analysis of the crude products. cAt 90 °C. dAt 110 °C. eUnder an air atmosphere.
When the amount of TBPB was increased to 3.0 equiv, the yield of 3a was increased to 58%. Further increases in the amount of the oxidant resulted in a lower yield (Table 1, entries 2 and 3). Notably, the reaction was sensitive to the oxidant, and TBPB was proven to be the best choice. No reaction occurred when other oxidants such as di-tert-butyl peroxide (DTBP), dicumyl peroxide (DCP), and K2S2O8 were used (Table 1, entries 4− 6). Subsequently, the cage effect of solvent was investigated, and the results indicate that 4.5 mL of acetonitrile was preferred (Table 1, entries 7 and 8). A satisfactory yield of 75% was achieved when AcONa was employed as additive, and the appropriate amount of it was 20 mol % (Table 1, entries 9−15) (see the Supporting Information). Different reaction temperatures were also investigated, and the best result was obtained at 100 °C (Table 1, entries 16 and 17). When the reaction was carried out in an atmosphere of air, 3a could be obtained in 61% 445
DOI: 10.1021/acs.orglett.8b03638 Org. Lett. 2019, 21, 444−447
Letter
Organic Letters Scheme 2. Substrate Scopea−c
Scheme 4. Control Experiments
Scheme 5. Proposed Mechanism
Intermediate B readily undergoes a 1,5-H shift with the α-C−H bond of nitrile to produce the new alkyl radical intermediate C, followed by a radical cyclization with imine to afford intermediate D. Intermediate D then reacts with TBPB, thus leading to the cation intermediate E. Finally, deprotonation of E by base delivers the product 3a. Product 3a can also be directly generated from intermediate D through hydrogen abstraction on amine by the tert-butoxy radical if the tert-butoxy radical or radical D is long-lived and accumulates in solution.13 The mechanism involving radical anion species cannot also be ruled out.14 In conclusion, we have developed a novel radical-mediated [2 + 2 + 1] cyclization of ortho-cyanoarylacrylamides with dual αC−H bonds in alkyl nitriles. This transformation is characterized by high atom economy, utilization of readily available reagents, and good functional group tolerance, thus providing an efficient and straightforward way for the construction of cyanosubstituted pyrrolo[3,2-c]quinolines. Further studies for the applications of this reaction are underway.
a
Reaction conditions: 1a (0.30 mmol), TBPB (3.0 equiv), and AcONa (0.2 equiv) in alkyl nitrile (4.5 mL) at 100 °C for 12 h under Ar. bIsolated yield. cThe dr value is given in parentheses and was determined by 1H NMR spectroscopic analysis of the crude products. d Reaction conditions: 1a (0.30 mmol), malononitrile (10.0 equiv), TBPB (3.0 equiv), and AcONa (0.2 equiv) in PhCl (4.5 mL) at 100 °C for 12 h under Ar.
Scheme 3. Gram-Scale Reaction
C(sp3)−H bond of acetonitrile contributed to the ratedetermining step. Based on the above results and literature,6,11a−d,12 a plausible mechanism for the [2 + 2 + 1] cyclization was proposed in Scheme 5. Initially, the thermal hemolytic cleavage of TBPB generates the tert-butoxy radical and benzoate radical. Cyanomethyl radical is formed by hydrogen abstraction reaction of MeCN with benzoate or a tert-butoxy radical. Subsequently, the cyanomethyl radical attacks the carbon−carbon double bond of 1a, giving the alkyl radical intermediate A, which can sequentially react with the nitrile to generate the imine radical B.
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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.8b03638. Experimental procedures, characterization data of all new compounds, 1H and 13C NMR spectra (PDF) 446
DOI: 10.1021/acs.orglett.8b03638 Org. Lett. 2019, 21, 444−447
Letter
Organic Letters Accession Codes
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CCDC 1876624 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 data_
[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
*E-mail:
[email protected]. ORCID
Meng Sun: 0000-0003-0257-4174 Ya-Min Li: 0000-0003-4233-5274 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We are grateful for financial support from the National Natural Science Foundation of China (Nos. 21871114 and 21662021) and the Applied Basic Research Foundation of Yunnan Province (2017FB016).
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REFERENCES
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DOI: 10.1021/acs.orglett.8b03638 Org. Lett. 2019, 21, 444−447
