Silver-Mediated Direct C-H Cyanation of Terminal Alkynes with N-Isocyanoiminotriphenylphosphorane

Article abstract of DOI:10.1021/acs.orglett.7b02743

A direct cyanation of terminal alkynes for the synthesis of propionitrile derivatives, with the aid of silver salt using water additive, has been achieved. The cyano source used is N-isocyanoiminotriphenylphosphorane, which is nontoxic, safe, and easy to handle. This protocol is characterized by its operational simplicity, high efficiency with excellent yields, broad substrate scope, and greater functional group tolerance.

Full text of DOI:10.1021/acs.orglett.7b02743

Letter
pubs.acs.org/OrgLett
Silver-Mediated Direct C−H Cyanation of Terminal Alkynes with
N‑Isocyanoiminotriphenylphosphorane
Hannan Wang,†,∥ Pengbing Mi,†,∥ Wanjun Zhao,† Ravi Kumar,§ and Xihe Bi*,†,‡
†Jilin Province Key Laboratory of Organic Functional Molecular Design & Synthesis, Department of Chemistry, Northeast Normal
University, Changchun 130024, China
‡State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China
§Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow 226031, India
S
* Supporting Information
ABSTRACT: A direct cyanation of terminal alkynes for the synthesis of
propionitrile derivatives, with the aid of silver salt using water additive, has
been achieved. The cyano source used is N-isocyanoiminotriphenylphos-
phorane, which is nontoxic, safe, and easy to handle. This protocol is characterized by its operational simplicity, high efficiency
with excellent yields, broad substrate scope, and greater functional group tolerance.
or harsh conditions. Therefore, safe, moisture stable, convenient
itrile functionality represents one of the most promising
Nactive units, which is not only present in natural products approaches to propiolonitriles from simple starting materials is of
great interest in modern organic synthesis.
from plant/animal sources but is also present in a large number of
clinically used drugs and polymers and serves as a valuable
synthetic precursor in organic chemistry.1 One of the most
important nitrile compounds is propiolonitrile, which is
characterized by assembly of two important functionalities,
alkyne and nitrile, and has been identified as a versatile building
block for decades.2 Molecules obtained from derivatizing these
two functional units possess great importance both in chemical
and biological aspects.3 Therefore, the development of practical
methods for its preparation is of great importance. In this line,
few groups have converted propargylic systems to propionitrile
under metal or metal-free conditions.4 Direct cyanation5 of
terminal alkynes, however, opens a new avenue to approach
propionitrile using both organic and inorganic cynating reagents
(Scheme 1). The methodologies, however, suffer from the
limitations to use toxic cyanide salts, moisture sensitive reagents,
Over the past few decades isocyanide has shown spectacular
rise in its application as reactive intermediate in organic synthesis
because of its ability to act as one carbon unit in the insertion
reaction and as the coupling partner.6 Among innumerable
applications of isocyanide, the most striking feature is to acts as
“cyano” source and have advantages over others being nontoxic,
commercially available, easy to handle, and environmentally
benign. Accordingly, a plethora of examples has been reported
for the introduction of nitrile unit using isocyanides into
heteroarenes,7 imines,8 aldehydes,9 alkyl halogens,10 and N N-
dimethyl-2-alkynylaniline.11 One of the bench stable isocyanides,
N-isocyanoiminotriphenylphosphorane (NIITP), was reported
by Fehlhammer and Weinberger in 1980, which opened the door
for extensive use of isocyanides as these are bench-stable, safe,
easy-to-handle, and odorless solids.12 Since its inception, the
synthetic potency has been extensively explored, but they are
restricted to act as a “CNN” building block in base-mediated
heterocyclic synthesis.13 However, from the first application of
NIITP for converting acid chloride to α-diazoketone, NIITP is
still a great choice due to safety and ease of handling.14 As our
journey is to explore the silver-catalyzed σ-activation of
isocyanides15 and alkynes,16 herein we reported a silver-
promoted intermolecular direct cyanation of terminal alkynes
with NIITP via cleavage of its N−NC bond, thereby providing a
safe, moisture-stable, and convenient method for the synthesis of
propiolonitriles.
Scheme 1. Preparation of Propiolonitriles
We started our investigations by studying the reaction of 1-
ethynyl-4-methoxybenzene (1a) with NIITP (2) in the presence
of a quantitative amount of silver carbonate (Table 1). To our
delight we get our desired 3-(4-methoxyphenyl)propiolonitrile
(3a) in 24% yield using MeCN as solvent (entry 1). A solvent
Received: September 3, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02743
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a,
b
a,b
Table 1. Optimization of the Reaction Conditions
Scheme 2. Substrate Scope of Alkyne
b
entry
[M] cat.
additive
solvent
temp
yield (%)
1
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
AgOTf
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
CH3CN
PhCl
DCE
THF
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
100
60
24
17
12
6
2
3
4
5
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
26
76
18
25
50
0
6
7
AgNO2
Ag3PO4
AgNO3
Sc(OTf)3
Bi(OTf)3
Ga(OTf)3
AgOTf
8
9
10
11
12
24
35
16
np
67
58
67
c
13
14
15
16
17
AgOTf
AgOTf
CH3OH
H2O
AgOTf
AgOTf
H2O
a
Reaction conditions: 1a (0.5 mmol), 2 (1.0 mmol), and additive (10
b
c
equiv) for 6 h, under Ar. Isolated yield. AgOTf (30 mol %).
a
Reaction conditions: 1 (0.5 mmol), 2 (1.0 mmol), and AgOTf (0.5
mmol) and H2O (5 mmol) in DMF (5 mL) at 80 °C for 6 h, under Ar.
b
screening then conducted to improve the yield; accordingly,
PhCl, DCE, and THF, were tested and found unsuitable for the
conversion (entries 2−4). Switching to DMF as solvent
marginally raised the yield of 3a to 26% (entry 5). Interestingly
use of AgOTf was particularly propitious affording 3a in 76%
yield (entry 6). Other silver salts were soon tested for further
improvement of the product outcome. Likewise AgNO2,
Ag3PO4, and AgNO3 were chosen and found ineffective in the
title conversion and afforded 3a in 18−50% yield (entries 7−9).
We next turned our attention to use Lewis acids as promoter of
the reaction. In this context, Sc(OTf)3 totally halted the reaction
(entry 10); however, Bi(OTf)3 and Ga(OTf)3 were less effective
in direct cyanation process and yielded 3a in 24% and 35%,
respectively (entries 11−12). Interestingly, product yield was
totally diminished when silver loading was dropped to 30%,
which showed that silver is necessary in stoichiometric amount
(entry 13). Either removal of water as additive or replacement
with methanol totally resisted the reaction or afforded 3a in lower
yield (entries 14−15). We also probe to test the fate of the
reaction temperature by carrying out reaction at 100 or 60 °C,
which did not lead to the improvement of the yield (entries 16−
17).
Isolated yield.
effective for product formation 3j−l but in moderate reactivity
(49−55%). Similarly 3- and 2-substituted aryl acetylenes did not
resist the reaction and gave propionitrile derivative 3m−p in high
yield (65−83%). Reactivity of disubstituted acetylene was
equally potent and delivered 3r and 3q in 75% yields. Substrate
scope was then extended to naphthalene (1s) and fluorene (1t)
derivatives, which afforded corresponding propionitrile deriva-
tives in moderate yields. We were also curious to check the
feasibility of reaction on some heterocyclic (1u) and olefinic (1v)
alkynes, which furnished 3u−v in good yield. In addition, we also
tested some aliphatic alkynes, which indeed converted into
corresponding propionitrile derivatives, but in moderate to good
reactivity, and afforded 4a−f in 34−59% yields.
Gram-scale synthesis of 3c was achieved in 75% yield
demonstrating the practicability of the transformation. Further,
we investigated the follow-up chemistry using propiolonitrile 3c
as a substrate (Scheme 3). The synthetic utility of 3c was
demonstrated by preparation of a series of heterocycles, such as
1,2,3-triazole (5), pyrrole (6), and benzofuran (7), in good to
high yields. Additionally, acrylonitriles (8−9) were efficiently
synthesized from 3c upon treatment with phenol or 1-
methylimidazole under mild conditions.
We therefore proceeded with the best condition involving
stoichiometric the use of AgOTf with 10 equiv of water as
additive in DMF solvent. We investigate the scope and limitation
of the reaction on aryl acetylenes containing both electron-
donating/withdrawing substituents (Scheme 2). Likewise 4-
On the basis of previous results,15b,d and our experimental
observations, we have proposed a plausible mechanism shown in
Scheme 4. Initially, the alkyne 1b reacts with AgOTf to generate
the silver acetylide I. In the next step, insertion of isonitrile 2
(NIITP) into the silver−carbon bond of I produced an acetylinic
imido complex II. Finally, the complex II give the target
compound 2b with the release of AgOH and triphenylphosphine
azaylide.
t
substituted Me (1c) and Bu (1d) aryl acetylene smoothly
converted to corresponding propionitrile derivatives (3c−d) in
84% and 66% yield, respectively. Halogen-containing acetylenes
(1e−g) were suitable feedstock for the direct cyanation process
but afforded halogen-containing propionitrile derivatives 3e−g
in somewhat lower yields (48−63%). Next electron withdrawing
groups like −CF3 and −CN were tested for title conversion,
which afforded 3h and 3i in good yields. Sensitive functional
groups like ester (1j), keto (1k), and aldehyde (1l) were well
In summary, we have developed a safe, efficient approach for
the synthesis of propiolonitriles derivatives starting from simple
terminal alkynes via a direct C−H cyanation process. In the
B
DOI: 10.1021/acs.orglett.7b02743
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Scheme 3. Gram-Scale Synthesis and Applications
REFERENCES
■
(1) (a) Kleemann, J. E.; Kutscher, B.; Reichert, D. Pharmaceutical
Substance: Synthesis, Patents, Applications, 4th ed.; Georg Thieme:
Stuttgart, 2001. (b) Miller, J. S.; Manson, J. L. Acc. Chem. Res. 2001, 34,
563. (c) Fleming, F. F.; Wang, Q. Chem. Rev. 2003, 103, 2035.
(2) (a) Xu, Y.; Zhao, J.; Chen, H.; Wu, W.; Jiang, H. Chem. Commun.
2014, 50, 2488. (b) Sahner, J. H.; Groh, M.; Negri, M.; Haupenthal, J.;
Hartmann, R. W. Eur. J. Med. Chem. 2013, 65, 223. (c) Chen, Y. R.;
Duan, W. L. J. Am. Chem. Soc. 2013, 135, 16754. (d) Duckert, H.;
Khedkar, V.; Waldmann, H.; Kumar, K. Chem. - Eur. J. 2011, 17, 5130.
(e) Shi, Z.; Zhang, C.; Li, S.; Pan, D.; Ding, S.; Cui, Y.; Jiao, N. Angew.
Chem., Int. Ed. 2009, 48, 4572. (f) Kirsch, G.; Thomae, D.; Seck, P.
Synthesis 2008, 2008, 1600. (g) Romagnoli, R. P.; Remusat, G.; Carrion,
V. M.; Cara, D.; Preti, C. L.; Baraldi, D.; Fruttarolo, F.; Pavani, M. G.;
Tabrizi, M. A.; Tolomeo, M.; Grimaudo, S.; Balzarini, J.; Jordan, M. A.;
Hamel, E. J. Med. Chem. 2006, 49, 6425. (h) Wender, P. A.; Paxton, T. J.;
Williams, T. J. J. Am. Chem. Soc. 2006, 128, 14814. (i) Kamijo, S.;
Kanazawa, C.; Yamamoto, Y. J. Am. Chem. Soc. 2005, 127, 9260.
(j) Kamijo, S.; Jin, T.; Huo, Z.; Yamamoto, Y. Tetrahedron Lett. 2002, 43,
9707. (k) McCauley, J. A.; Theberge, C. R.; Liverton, N. J. Org. Lett.
2000, 2, 3389. (l) Norman, M. H.; Chen, N.; Chen, Z.; Fotsch, C.; Hale,
C.; Han, N.; Hurt, R.; Jenkins, T.; Kincaid, J.; Liu, L.; Lu, Y.; Moreno, O.;
Santora, V. J.; Sonnenberg, J. D.; Karbon, W. J. Med. Chem. 2000, 43,
4288. (m) Liu, Y.; Shen, B.; Kotora, M.; Takahashi, T. Angew. Chem., Int.
Ed. 1999, 38, 949. (n) Ren, W. Y.; Rao, K. V. B.; Klein, R. S. J. Heterocycl.
Chem. 1986, 23, 1757. (o) Hartmann, H.; Liebscher, J. Synthesis 1984,
1984, 275.
Scheme 4. Plausible Mechanism
(3) (a) Iwai, I.; Nakamura, N. Chem. Pharm. Bull. 1966, 14, 1277.
(b) Cheng, Z. Y.; Li, W. J.; He, F.; Zhou, J. M.; Zhu, X. F. Bioorg. Med.
Chem. 2007, 15, 1533. (c) Lazennec, M. Bull. Soc. Chim. Fr. 1906, 3, 526.
(d) Heard, N. E.; Turner, J. J. Org. Chem. 1995, 60, 4302. (e) Rama Rao,
V. V. V. N. S.; Lingaiah, B. P. V.; Ezikiel, G.; Yadla, R.; Rao, P. S.
Heterocycl. Commun. 2006, 12, 275.
(4) For selected examples, see: (a) Wang, T.; Yin, H.; Jiao, N. Adv.
Synth. Catal. 2013, 355, 1207. (b) Sharma, P. K.; Ram, S.; Chandak, N.
Adv. Synth. Catal. 2016, 358, 894. (c) Murray, R. E.; Zweifel, G. Synthesis
1980, 1980, 150. (d) Merah, B.; Texier, F. Bull. Soc. Chim. Fr. 1980, 552.
(e) Beccalli, E. M.; Manfredi, A.; Marchesini, A. J. Org. Chem. 1985, 50,
2372. (f) Wu, Y.-Q.; Limburg, D. C.; Wilkinson, D. E.; Hamilton, G. S.
Org. Lett. 2000, 2, 795.
(5) (a) Zhang, G.; Chen, S.; Fei, H.; Cheng, J.; Chen, F. Synlett 2012,
23, 2247. (b) Wen, Q.; Jin, J.; Hu, B.; Lu, P.; Wang, Y. RSC Adv. 2012, 2,
6167. (c) Luo, F.-H.; Chu, C.-I.; Cheng, C.-H. Organometallics 1998, 17,
1025. (d) Kim, J.; Chang, S. J. Am. Chem. Soc. 2010, 132, 10272. (e) Xu,
H.; Liu, P.-T.; Li, Y.-H.; Han, F.-S. Org. Lett. 2013, 15, 3354. (f) Teng, F.;
Yu, J.-T.; Yang, H.; Cheng, J. Chem. Commun. 2014, 50, 12139.
(g) Teng, F.; Yu, J.-T.; Zhou, Z.; Chu, H.; Cheng, J. J. Org. Chem. 2015,
80, 2822. (h) Xu, W.; Xu, Q.; Li, J. Org. Chem. Front. 2015, 2, 231.
(i) Pan, C.; Jin, H.; Xu, P.; Liu, X.; Cheng, Y.; Zhu, C. J. Org. Chem. 2013,
78, 9494. (j) Lin, S.; Wei, Y.; Liang, F. Chem. Commun. 2012, 48, 9879.
(k) Zhang, Y.; Peng, H.; Zhang, M.; Cheng, Y.; Zhu, C. Chem. Commun.
2011, 47, 2354. (l) Zhu, C.; Xia, J.-B.; Chen, C. Org. Lett. 2014, 16, 247.
(m) Powell, K. J.; Han, L.-C.; Sharma, P.; Moses, J. E. Org. Lett. 2014, 16,
2158. (n) Shu, Z.; Ji, W.; Wang, X.; Zhou, Y.; Zhang, Y.; Wang, J. Angew.
Chem., Int. Ed. 2014, 53, 2186. (o) Li, J.; Ackermann, L. Angew. Chem.,
Int. Ed. 2015, 54, 3635. (p) Yang, Y.; Liu, P. ACS Catal. 2015, 5, 2944.
(q) Martin Castro, M.-C. Chem. Rev. 2004, 104, 2939. (r) Rehbein, J.;
Hiersemann, M. Synthesis 2013, 45, 1121.
(6) (a) Ugi, I. Isonitrile Chemistry; Academic Press: New York, 1971.
(b) Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168.
(c) Domling, A. Chem. Rev. 2006, 106, 17. (d) Lygin, A. V.; de Meijere,
A. Angew. Chem., Int. Ed. 2010, 49, 9094. (e) Gulevich, A. V.; Zhdanko,
A. G.; Orru, R. V. A.; Nenajdenko, V. G. Chem. Rev. 2010, 110, 5235. (f)
Nenajdenko, V. G. Isocyanide Chemistry; Wiley-VCH: Weinheim, 2012.
(7) (a) Xu, S.; Huang, X.; Hong, X.; Xu, B. Org. Lett. 2012, 14, 4614.
(b) Peng, J.; Zhao, J.; Hu, Z.; Liang, D.; Huang, J.; Zhu, Q. Org. Lett.
2012, 14, 4966. (c) Hong, X.; Wang, H.; Qian, G.; Tan, Q.; Xu, B. J. Org.
Chem. 2014, 79, 3228. (d) Chen, Z.-B.; Zhang, Y.; Yuan, Q.; Zhang, F.-
L.; Zhu, Y.-M.; Shen, J.-K. J. Org. Chem. 2016, 81, 1610.
reaction, NIITP served as a nontoxic, facile “CN” source. The
synthetic value of this compound was evaluated by utilizing them
in various organic transformations. Further studies on the
utilization of NIITP are ongoing in our group.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b02743.
Experimental procedures and spectra copies (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: bixh507@nenu.edu.cn.
ORCID
Xihe Bi: 0000-0002-6694-6742
Author Contributions
∥These authors contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by the NSFC (21522202, 21372038).
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Letter
(8) Cioc, R. C.; Preschel, H. D.; van der Heijden, G.; Ruijter, E.; Orru,
R. V. A. Chem. - Eur. J. 2016, 22, 7837.
(9) Cioc, R. C.; Schuckman, P.; Preschel, H. D.; Vlaar, T.; Ruijter, E.;
Orru, R. V. A. Org. Lett. 2016, 18, 3562.
(10) (a) Jiang, X.; Wang, J.-M.; Zhang, Y.; Chen, Z.; Zhu, Y.-M.; Ji, S.-J.
Tetrahedron 2015, 71, 4883. (b) Coppola, A.; Sanchez-Alonso, P.;
́
Sucunza, D.; Burgos, C.; Alajarín, R.; Alvarez-Builla, J.; Mosquera, M. E.
G.; Vaquero, J. J. Org. Lett. 2013, 15, 3388.
(11) Qiu, G.; Qiu, X.; Liu, J.; Wu, J. Adv. Synth. Catal. 2013, 355, 2441.
(12) Weinberger, B.; Fehlhammer, W. P. Angew. Chem., Int. Ed. Engl.
1980, 19, 6.
(13) (a) Giustiniano, M.; Basso, A.; Mercalli, V.; Massarotti, A.;
Novellino, E.; Tron, G. C.; Zhu, J. Chem. Soc. Rev. 2017, 46, 1295.
(b) Aller, E.; Molina, P.; Lorenzo, A. Synlett 2000, 526. (c) Bio, M. M.;
Javadi, G.; Song, Z. J. Synthesis 2005, 2005, 19. (d) Souldozi, A.;
Ramazani, A. Tetrahedron Lett. 2007, 48, 1549. (e) Souldozi, A.;
Ramazani, A.; Bouslimani, N.; Welter, R. Tetrahedron Lett. 2007, 48,
2617. (f) Adib, M.; Kesheh, M.; Ansari, S.; Bijanzadeh, H. Synlett 2009,
2009, 1575. (g) Adib, M.; Ansari, S.; Fatemi, S.; Bijanzadeh, H. R.; Zhu,
L. G. Tetrahedron 2010, 66, 2723. (h) Ramazani, A.; Rezaei, A. Org. Lett.
2010, 12, 2852. (i) Adib, M.; Ansari, S.; Feizi, S.; Bijanzadeh, H. R.
Synlett 2010, 2010, 921. (j) Adib, M.; Sheikhi, E.; Kavoosi, A.;
Bijanzadeh, H. R. Synthesis 2010, 2010, 4082. (k) Cui, L.; Liu, Q.; Yu, N.
C.; Yu, H. Tetrahedron Lett. 2011, 52, 5530. (l) Nasrabadi, F. Z.;
Ramazani, A.; Ahmadi, Y. Mol. Diversity 2011, 15, 791. (m) Brockmeyer,
F.; van Gerven, D.; Saak, W.; Martens, J. Synthesis 2014, 46, 1603.
(n) Rouhani, M.; Ramazani, A.; Joo, S. W. Ultrason. Sonochem. 2014, 21,
262. (o) Adib, M.; Ansari, S.; Bijanzadeh, H. R. Synlett 2011, 2011, 619.
(p) Adib, M.; Ansari, S.; Zhu, L.-G.; Rahimi-Nasrabadi, M. Helv. Chim.
Acta 2013, 96, 675.
(14) (a) Aller, E.; Molina, P.; Lorenzo, A. Synlett 2000, 526. (b) Bio, M.
M.; Javadi, G.; Song, Z. J. Synthesis 2005, 2005, 19.
(15) For examples, see: (a) Fang, G.; Bi, X. Chem. Soc. Rev. 2015, 44,
8124. (b) Liu, J.; Fang, Z.; Zhang, Q.; Liu, Q.; Bi, X. Angew. Chem., Int.
Ed. 2013, 52, 6953. (c) Liu, J.; Liu, Z.; Liao, P.; Zhang, L.; Tu, T.; Bi, X.
Angew. Chem., Int. Ed. 2015, 54, 10618. (d) Liu, J.; Liu, Z.; Wu, N.; Liao,
P.; Bi, X. Chem. - Eur. J. 2014, 20, 2154.
(16) For examples, see: (a) Liu, Z.; Liu, J.; Zhang, L.; Liao, P.; Song, J.;
Bi, X. Angew. Chem., Int. Ed. 2014, 53, 5305. (b) Liu, Z.; Liao, P.; Bi, X.
Org. Lett. 2014, 16, 3668. (c) Ning, Y.; Ji, Q.; Liao, P.; Anderson, E. A.;
Bi, X. Angew. Chem., Int. Ed. 2017, DOI: 10.1002/anie.201705122.
D
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