Letter pubs.acs.org/OrgLett
Selective Synthesis of (E)- and (Z)‑Allyl Nitriles via Decarboxylative Reactions of Alkynyl Carboxylic Acids with Azobis(alkylcarbonitriles) Francis Mariaraj Irudayanathan and Sunwoo Lee* Department of Chemistry, Chonnam National University, Gwangju 61186, Republic of Korea S Supporting Information *
ABSTRACT: Allyl nitriles were synthesized from the reactions of arylpropiolic acids with azobis(alkylcarbonitriles) (AIBN or ACCN). In the presence of Cu(OAc)2 as a catalyst and pyridine as the solvent, the (E)-stereoisomer was formed as the major product. This transformation shows good tolerance toward alkoxy, halogen, alcohol, amine, ester, and ketone functional groups. When the reaction was conducted with the sterically bulky amine, ethyldiisopropylamine, in the absence of a copper catalyst, the corresponding (Z)-stereoisomers were formed preferentially.
T
Scheme 1. Synthesis of Allyl Nitriles
he nitrile group is one of the most important functional groups in organic synthesis. It is found in natural products and has been introduced into functional materials, pharmaceuticals, and other bioactive compounds. Moreover, it plays a key role in the synthesis of functional organic compounds because it is readily converted to other useful functional groups such as amines,1 amides,2 and carboxylic acids.3 In particular, the allyl nitrile (or allylcyano) group has been found in bioactive compounds such as the vitamin D receptor, pesticides, and antifungal agents, as shown in Figure 1.4
Mao reported the synthesis of isobutyronitrile amides from the reactions of carboxylic acids with AIBN.13 These results inspired us to develop decarboxylative coupling reactions of alkynyl carboxylic acids with AIBN. We have, over many years, studied decarboxylative reactions with the aim of furnishing useful building blocks for the synthesis of functional materials.14 In particular, we have widely used arylpropiolic acid derivatives as starting materials because they are readily prepared through the one-pot reactions of aryl halides with propiolic acid and they can be purified by simple acid−base workup procedures.15 Although Mao and Xu reported that they failed to obtain the desired allyl nitrile from the attempted decarboxylative coupling reaction of 4-bromophenylpropiolic acid under argon,11 we found that the corresponding allyl nitrile is formed under aerobic conditions. Furthermore, we found that (Z)-allyl nitriles are selectively formed under copper-free conditions. Herein, we report the efficient and selective synthesis of (E)and (Z)-allyl nitriles from arylpropiolic acid derivatives.
Figure 1. Bioactive compounds bearing an allyl nitrile.
A number of synthetic methods for the preparation of allyl nitriles have been developed (Scheme 1). In the more classical methods, allyl substrates bearing leaving groups, such as halide,5 acetate,6 alcohol,7 phosphate,8 or carbonate,9 are reacted with a metal cyanide or trimethylsilyl nitrile. However, these methods require harsh reaction conditions or expensive catalysts. As an alternative method, the Huang group reported the decarboxylative coupling reactions of cinnamic acids and 1,1′-azobis(cyclohexane-1-carbonitrile) (ACCN) to provide β,γ-unsaturated nitriles in moderate yields.10 Mao and Xu similarly employed azobis(isobutyronitrile) (AIBN) as a nitrile source for reactions with terminal alkynes.11 They found that terminal alkynes were converted into allyl nitriles under argon; however, alkynyl nitriles were obtained under aerobic conditions. Azobis(alkylcarbonitriles) such as AIBN (2a) and ACCN (2b) have mostly been used as radical initiators and have rarely been employed in organic synthesis as reagents for the preparation of nitrile-containing compounds.12 Zhang and © 2017 American Chemical Society
Received: March 22, 2017 Published: April 19, 2017 2318
DOI: 10.1021/acs.orglett.7b00860 Org. Lett. 2017, 19, 2318−2321
Letter
Organic Letters To identify the optimum conditions for these transformations, phenylpropiolic acid and AIBN were reacted under the reaction conditions listed in Table 1. A number of
Scheme 2. Synthesis of (E)-Allyl Nitriles by CopperCatalyzed Decarboxylationa
Table 1. Optimization of Reaction Conditions for the Synthesis of Allyl Nitrilesa
entry
copper
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(acac)2 Cu(OTf)2 Cu(NO3)2 Cu(CO3)2 CuF2 CuCl2 CuBr2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2
additive
solvent
yield (%)
pyridineb Et3N DBU
toluene CH3CN dioxane DMSO DMF EtOH pyridine pyridine pyridine pyridine pyridine pyridine pyridine pyridine CH3CN CH3CN CH3CN
1 34 20 14 19 15 67 14 1 2 18 37 24 12 38 37 22 (1:1)c
a
Reaction conditions: 1 (2.0 mmol), AIBN or ACCN (4.0 mmol), and Cu (0.2 mmol) were reacted in pyridine (5.0 mL) at 80 °C for 12 h, air.
afforded a slightly lower yield of (E)-3h. Bromo-, chloro-, fluoro-, and trifluoromethyl-substituted phenylpropiolic acids gave the corresponding products, (E)-3i, (E)-3j, (E)-3k, and (E)-3l in 60%, 57%, 44%, and 41% yield, respectively. 3-(6Methoxynaphthalen-2-yl)propiolic acid provided (E)-3m in 61% yield. Alcohol, ester, ketone, and amine substituents on the benzene ring afforded the corresponding allyl nitriles (E)-3n, (E)-3o, (E)-3p, and (E)-3q in 47%, 65%, 52%, and 39% yield, respectively. 3-(Thiophene-2-yl)propiolic acid gave (E)-3r with 60% yield. However, none of the desired product, (E)-3s, was obtained from the attempted reaction of 4-cyanophenylpropiolic acid. Alkyl-substituted alkynyl carboxylic acids, such as 1octynoic acid, also provided no product. Except for 3b, 3l, 3o, and 3p, which were formed as 12.5:1, 11:1, 4.5:1, and 3:1 mixtures of (E)- and (Z)-isomers, respectively, it is noteworthy that (E)-configured nitriles were exclusively formed in these reactions. Instead of AIBN, ACCN was also employed as a nitrile source. Phenylpropiolic acid afforded the desired product (E)-3t with 50% yield. 4-Methyl-, 4-methoxy-, 4-chloro-, 4fluoro-substituted phenylpropiolic acids provided the corresponding allyl nitriles with moderate yields. Entry 17 in Table 1 reveals that the addition of DBU to the reaction also resulted in a mixture of (E)-3a and (Z)-3a. This observation prompted us to develop a stereoselective synthesis of the corresponding (Z)-isomers. We chose solvents bearing an amine group and performed the reaction in the absence of copper. The results of this study are summarized in Table 2. Trace amounts of the desired allyl nitrile were detected in the reaction mixture when the reaction was conducted in pyridine (entry 1). Surprisingly, the desired allyl nitrile was formed predominantly as the (Z)-isomer when the reaction was carried out in DBU (entry 2). The use of the more sterically bulky amine, ethyldiisopropylamine ((i-Pr)2EtN), provided (Z)-3a as the major product in an 11:1 (Z)/(E) ratio (entry 3). However, the reaction with the chelating diamine, TMEDA, afforded the desired product in low yield and with low selectivity (entry 4).
a
Reaction conditions: 1a (0.3 mmol), AIBN (0.6 mmol) and Cu (0.06 mmol) were reacted in solvent (1.2 mL) at 80 °C for 12 h, air. b0.9 mmol was used. cBoth (E)-3a and (Z)-3a were formed in a 1:1 ratio.
solvents were tested for the reaction with Cu(OAc)2. Toluene provided a trace amount of the desired product (E)-3a (entry 1). Reactions in CH3CN, 1,4-dioxane, DMSO, DMF, and EtOH provided low yields of 3a (entries 2−6); however, when the reaction carried out in pyridine, the desired product was formed in 67% yield (entry 7). With pyridine identified as the solvent of choice, a variety of copper catalysts were tested; however, all of the Cu(II) catalysts listed in entries 8−14 provided unsatisfactory results. When the reaction was conducted with 3 equiv of pyridine in CH3CN, the yield of (E)-3a decreased to 38% (entry 15). Other bases, such as Et3N and DBU, gave the desired product in 37% and 22% yield, respectively (entries 16 and 17). It is noteworthy that the (E)stereoisomer is formed as the major product in most cases. However, the reaction in the presence of DBU afforded a 1:1 mixture of (E)-3a and (Z)-3a (entry 17). To obtain the desired allyl nitrile, (E)-3, from the corresponding alkynyl carboxylic acid, the optimized conditions were found to involve reacting the aryl alkynyl carboxylic acid (1.0 equiv), AIBN (2.0 equiv), and Cu(OAc)2 (20 mol %), in pyridine, at 80 °C for 12 h. With these optimized conditions in hand, we evaluated the scope of this reaction for the general synthesis of allyl nitriles from aryl alkynyl carboxylic acids. The results of this study are summarized in Scheme 2. As expected, phenylpropiolic acid acid provided (E)-3a in 67% yield. 2-Methyl-, 4-methyl-, and 4-ethyl-substituted phenylpropiolic acids were transformed to the corresponding allyl nitriles (E)-3b, (E)-3c, and (E)-3d in 46%, 65%, and 71% yield, respectively. Mono-, di-, and trimethoxy-substituted substrates gave the corresponding desired products in a range of yields (49−64%); however, 4-ethoxyphenylpropiolic acid 2319
DOI: 10.1021/acs.orglett.7b00860 Org. Lett. 2017, 19, 2318−2321
Letter
Organic Letters Table 2. Copper-Free Reactions in Amine Solventsa
entry
1
solvent
yieldb (%)
1 2 3 4 5
1a 1a 1a 1a 1b
pyridine DBU (i-Pr)2EtN TMEDA (i-Pr)2EtN
trace 62 56 15 0
Scheme 4. Copper-Free Reaction in a Non-amine Solvent
ratio of (E)-3a/(Z)-3ac
Based on previous reports,11 and our results, we propose the reaction pathways depicted in Scheme 5 to rationalize our observations.
1:4 1:11 1:2
Scheme 5. Proposed Reaction Pathways
a
Reaction conditions: 1 (1.0 mmol) and AIBN (2.0 mmol) were reacted in solvent (5 mL) at 80 °C for 12 h, air. bIsolated yield. c Determined by 1H NMR analysis.
Interesting, no allyl nitrile 3 was formed in the reaction of phenylacetylene, AIBN, and (i-Pr)2EtN in the absence of copper catalyst. With these copper-free conditions identified, a variety of arylpropiolic acids were employed for the selective syntheses of (Z)-allyl nitriles. As shown in Scheme 3, (Z)-allyl nitriles were Scheme 3. Synthesis of (Z)-Allyl Nitriles by Copper-Free Decarboxylationa
First, the 2-cyano-2-propyl radical is generated from the thermal decomposition of AIBN. This radical then reacts with the arylpropiolic acid salt A, formed through an acid/base reaction, to provide the intermediate copper complex B, through path I. Protonation then takes place at both the vinyl copper and decarboxylation sites to give (E)-3.16 Intermediate C is formed in the absence of copper, following path II. The stereochemistry of the vinyl radical center in intermediate C is most likely determined by steric interactions between the aryl group, the sterically bulky amine, and the carboxylate. Finally, vinyl radical C abstracts a hydrogen atom which is delivered from the bulky amine trans to isobutyronitrile to give (Z)-3. In the absence of copper in a nonamine solvent, the 2-cyano-2propyl radical is converted into intermediate D, which then reacts with the carboxylic acid, following path III, to give the isobutyronitrile amide 4. However, in no case was the alkynyl nitrile observed, which may be formed through path IV, even though the reaction was conducted in air. Mao and Xu obtained an alkynyl nitrile from the reaction of a terminal alkyne with AIBN in air. We believe that our results are different because the reactivity of an alkynyl carboxylic acid toward the 2-cyano2-propyl radical is greater than that of a terminal alkyne. In summary, we have developed decarboxylative reactions for the synthesis of allyl nitriles. The reactions of arylpropiolic acids with AIBN (or ACCN), in the presence of pyridine and a copper catalyst afford the desired allyl nitriles in moderate to good yields. This reaction shows tolerance toward alkoxy, halogen, alcohol, amine, ester, and ketone functional groups. However, 4-cyanophenylpropiolic acid and 1-octynoic acid failed to produce the corresponding allyl nitrile. We also developed a selective synthesis of (Z)-3 and found that a
a
Reaction conditions: 1 (2.0 mmol) and AIBN (or ACCN) (4.0 mmol) were reacted in (i-Pr)2EtN (7.0 mL) at 80 °C for 12 h, air.
formed as the major isomer in all cases. 2-Methyl-, 4-methyl-, and 4-methoxy-substituted phenylpropiolic acids gave (Z)-3b, (Z)-3c, and (Z)-3e in 39%, 39%, and 44% yield, respectively, and each exhibited a 12.5:1 (Z)/(E) ratio. The 4-bromo- and 4chloro-substituted analogues provided (Z)-3i and (Z)-3j in 37% and 40% yield, respectively; the (Z)/(E) ratio was 11:1 in each case. (Z)-3o and (Z)-3p were obtained in 45% and 42%, yield, respectively, with (Z)/(E) ratios of 14:1. 3-(Thiophene2-yl)propiolic acid showed the highest stereoselectivity with a (Z)/(E) ratio of 33.3:1. The reactions with ACCN also provided the desired products with 30−46% yields. They all gave (Z)-allyl nitriles as major. We found that stereoselectivity seems to be largely unaffected by substituents on the aryl group. When these reactions were conducted under copper-free and amine-free conditions, N-(2-cyanopropan-2-yl)-N-isobutyryl-3phenylpropiolamide (4a) was formed instead of the allyl nitriles (3), as shown in Scheme 4. The propiolamide 4a was formed from the reaction of phenylpropiolic acid with a rearranged fragment of AIBN. This type reaction has been reported previously by Zhang and Mao;13 however, they obtained a secondary amide because the high-temperature reaction conditions in ClCH2CH2Cl gave rise to the hydrolysis of 4a. 2320
DOI: 10.1021/acs.orglett.7b00860 Org. Lett. 2017, 19, 2318−2321
Letter
Organic Letters
(5) (a) Munemori, D.; Tsuji, H.; Uchida, K.; Suzuki, T.; Isa, K.; Minakawa, M.; Kawatsura, M. Synthesis 2014, 46, 2747−2750. (b) Fleming, F. F.; Liu, W.; Ghosh, S.; Steward, O. W. Angew. Chem., Int. Ed. 2007, 46, 7098−7100. (6) (a) Tsuji, Y.; Kusui, T.; Kojima, T.; Sugiura, Y.; Yamada, N.; Tanaka, S.; Ebihara, M.; Kawamura, T. Organometallics 1998, 17, 4835−4841. (b) Grenning, A. J.; Tunge, J. A. J. Am. Chem. Soc. 2011, 133, 14785−14794. (7) Soltani Rad, M. N.; Khalafi-Nezhad, A.; Behrouz, S.; Faghihi, M. A. Tetrahedron Lett. 2007, 48, 6779−6784. (8) Yoneda, S. H.; Kurihara, T. J. Org. Chem. 1991, 56, 1827−1832. (9) Tsuji, Y.; Yamada, N.; Tanaka, S. J. Org. Chem. 1993, 58, 16−17. (10) Gao, B.; Xie, Y.; Yang, L.; Huang, H. Org. Biomol. Chem. 2016, 14, 2399−2402. (11) Rong, G.; Mao, J.; Zheng, Y.; Yao, R.; Xu, X. Chem. Commun. 2015, 51, 13822−13825. (12) (a) De Vleeschouwer, F.; Van Speybroeck, V. V.; Waroquier, M.; Geerlings, P.; De Proft, F. D. Org. Lett. 2007, 9, 2721−2724. (b) Xie, Y.; Guo, S.; Wu, L.; Xia, C.; Huang, H. Angew. Chem., Int. Ed. 2015, 54, 5900−5904. (c) Gao, B.; Xie, Y.; Shen, Z.; Yang, L.; Huang, H. Org. Lett. 2015, 17, 4968−4971. (d) Xu, H.; Liu, P.-T.; Li, Y.-H.; Han, F.-S. Org. Lett. 2013, 15, 3354−3357. (e) Teng, F.; Yu, J.-T.; Yang, H.; Jiang, Y.; Cheng, J. Chem. Commun. 2014, 50, 12139−12141. (f) Wei, W.; Wen, J.; Yang, D.; Guo, M.; Tian, L.; You, J.; Wang, H. RSC Adv. 2014, 4, 48535−48538. (g) Wang, R.; Bao, W. RSC Adv. 2015, 5, 57469−57471. (h) Teng, F.; Yu, J.-T.; Zhou, Z.; Chu, H.; Cheng, J. J. Org. Chem. 2015, 80, 2822−2826. (13) Rong, G.; Liu, D.; Yan, H.; Chen, J.; Zheng, Y.; Zhang, G.; Mao, J. Adv. Synth. Catal. 2015, 357, 71−76. (14) (a) Moon, J.; Jeong, M.; Nam, H.; Ju, J.; Moon, J. H.; Jung, H. M.; Lee, S. Org. Lett. 2008, 10, 945−948. (b) Moon, J.; Jang, M.; Lee, S. J. Org. Chem. 2009, 74, 1403−1406. (c) Park, K.; Bae, G.; Moon, J.; Choe, J.; Song, K. H.; Lee, S. J. Org. Chem. 2010, 75, 6244−6251. (d) Park, K.; Lee, S. RSC Adv. 2013, 3, 14165−14182. (e) Hwang, J.; Park, K.; Choe, J.; Min, H.; Song, K. H.; Lee, S. J. J. Org. Chem. 2014, 79, 3267−3271. (f) Min, H.; Palani, T.; Park, K.; Hwang, J.; Lee, S. J. J. Org. Chem. 2014, 79, 6279−6285. (15) Park, K.; Palani, T.; Pyo, A.; Lee, S. Tetrahedron Lett. 2012, 53, 733−737. (b) Park, K.; You, J.-M.; Jeon, S.; Lee, S. Eur. J. Org. Chem. 2013, 2013, 1973−1978. (16) When the reaction was carried out in the presence of D2O (5.0 equiv), deuterium incorporation was observed at the vinyl group. See the Supporting Information for more details.
sterically bulky amine solvent was the key to achieving selectivity. Compared with previous methods, this method has several advantages: arylpropiolic acids are more easily prepared than terminal arylalkynes; there is no requirement to use excess amounts of the aryl propiolic acid to obtain the allyl nitrile; the reaction does not require an argon atmosphere, and can be performed without the requirement of inert conditions; and the (E)-3 and (Z)-3 stereoisomers are obtained with high selectively. Further mechanistic studies are ongoing in our laboratory.
■
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b00860. Experimental procedures and spectral data for the products (PDF)
■
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Sunwoo Lee: 0000-0001-5079-3860 Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS This research was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIP) (NRF-2015R1A4A1041036, NRF2014R1A2A1A11050018). The spectral data were obtained from the Korea Basic Science Institute, Gwangju branch.
■ ■
DEDICATION This paper is dedicated to Professor Jaiwook Park (POSTECH) on the occasion of his 60th birthday. REFERENCES
(1) (a) Mukherjee, A.; Srimani, D.; Chakraborty, S.; Ben-David, Y.; Milstein, D. J. Am. Chem. Soc. 2015, 137, 8888−8891. (b) Adam, R.; Alberico, E.; Baumann, W.; Drexler, H.-J.; Jackstell, R.; Junge, H.; Beller, M. Chem. - Eur. J. 2016, 22, 4991−5002. (c) Bornschein, C.; Werkmeister, S.; Junge, K.; Beller, M. New J. Chem. 2013, 37, 2061− 2065. (d) Haddenham, D.; Pasumansky, L.; DeSoto, J.; Eagon, S.; Singaram, B. J. Org. Chem. 2009, 74, 1964−1970. (e) Kukula, P.; Studer, M.; Blaser, H.-U. Adv. Synth. Catal. 2004, 346, 1487−1493. (2) (a) García-Á lvarez, R.; Zablocka, M.; Crochet, P.; Duhayon, C.; Majoral, J. P.; Cadierno, V. Green Chem. 2013, 15, 2447−2456. (b) Nambo, M.; Yar, M.; Smith, J. D.; Crudden, C. M. Org. Lett. 2015, 17, 50−53. (c) Vervisch, K.; D’hooghe, M.; Rutjes, F. P. J. T.; De Kimpe, N. Org. Lett. 2012, 14, 106−109. (d) Midya, G. C.; Kapat, A.; Maiti, S.; Dash, J. J. Org. Chem. 2015, 80, 4148−4151. (e) Battilocchio, C.; Hawkins, J. M.; Ley, S. V. Org. Lett. 2014, 16, 1060−1063. (3) (a) Li, X.-J.; Qiao, J.-B.; Sun, J.; Li, X.-Q.; Gu, P. Org. Lett. 2014, 16, 2865−2867. (b) Zhou, F.; Cheng, G.-J.; Yang, W.; Long, Y.; Zhang, S.; Wu, Y.-D.; Zhang, X.; Cai, Q. Angew. Chem., Int. Ed. 2014, 53, 9555−9559. (c) Black, G. W.; Brown, N. L.; Perry, J. J. B.; Randall, P. D.; Turnbull, G.; Zhang, M. Chem. Commun. 2015, 51, 2660−2662. (4) Otaka, K.; Oohira, D.; Okada, S. PCT Int. Appl. WO 2002090320 A2, 2002. 2321
DOI: 10.1021/acs.orglett.7b00860 Org. Lett. 2017, 19, 2318−2321
