Copper-catalyzed C-H cyanation of terminal alkynes with cyanogen iodide

Article abstract of DOI:10.1021/ol402863g

A copper-catalyzed reaction of terminal alkynes with cyanogen iodide (ICN) that produces alkynyl cyanides has been developed. The use of tetramethylpiperidine as a sterically congested base was successful in this reaction. Some control experiments revealed that the reaction involves the noncatalyzed formation of alkynyl iodides followed by copper-catalyzed cyanation of the iodides without the formation of copper(I) acetylide. This observation contrasts with what is normally observed in various copper-mediated reactions using terminal alkynes.

Full text of DOI:10.1021/ol402863g

ORGANIC
LETTERS
2013
Vol. 15, No. 22
5810–5813
Copper-Catalyzed CꢀH Cyanation of
Terminal Alkynes with Cyanogen Iodide
Kazuhiro Okamoto,* Masahito Watanabe, Naoki Sakata, Masahito Murai, and
Kouichi Ohe*
Department of Energy and Hydrocarbon Chemistry, Graduate School of Engineering,
Kyoto University, Katsura, Nishikyo-ku, Kyoto 615-8510, Japan
kokamoto@scl.kyoto-u.ac.jp; ohe@scl.kyoto-u.ac.jp
Received October 4, 2013
ABSTRACT
A copper-catalyzed reaction of terminal alkynes with cyanogen iodide (ICN) that produces alkynyl cyanides has been developed. The use of
tetramethylpiperidine as a sterically congested base was successful in this reaction. Some control experiments revealed that the reaction involves
the noncatalyzed formation of alkynyl iodides followed by copper-catalyzed cyanation of the iodides without the formation of copper(I) acetylide.
This observation contrasts with what is normally observed in various copper-mediated reactions using terminal alkynes.
Direct carbonꢀcarbon bond-forming transformation
of hydrocarbons is one of the ideal types of synthetic
reactions in terms of both availability and efficiency.1
Cyanation, the simplest and most traditional way of adding
C1 units, has also been applied to such reactions including
cyanofunctionalization of CꢀC multiple bonds,2ꢀ4
direct C(sp2)ꢀH cyanation,5ꢀ7 and direct conversion of
C(sp3)ꢀH bonds giving nitriles (Scheme 1).8 Among these,
the direct acetylenic C(sp)ꢀH cyanation, giving alkynyl
cyanides, appears to be simple and easy to achieve because
acetylenic CꢀH bonds are relatively acidic and therefore
readily deprotonated by strong bases. However, only
two methods that use a stoichiometric amount of metal
have been available for acetylenic cyanation until now
(Scheme 2). One is the reaction of preformed lithium or
copper acetylides with electrophilic cyanation agents,9
and the other is oxidative cyanation of terminal alkynes
mediated by a stoichiometric amount of copper(I)
(4) Heterocyanation; X = B: (a) Suginome, M.; Yamamoto, A.;
Murakami, M. J. Am. Chem. Soc. 2003, 125, 6358. (b) Suginome, M.;
Yamamoto, A.; Murakami, M. Angew. Chem., Int. Ed. 2005, 44, 2380.
(c) Suginome, M.; Yamamoto, A.; Murakami, M. J. Organomet. Chem.
2005, 690, 5300. X = Si: (d) Kusumoto, T.; Hiyama, T.; Ogata, K.
Tetrahedron Lett. 1986, 27, 4197. (e) Chatani, N.; Takeyasu, T.; Hanafusa,
T. Tetrahedron Lett. 1988, 29, 3979. (f) Chatani, N.; Takeyasu, T.;
Horiuchi, N.; Hanafusa, T. J. Org. Chem. 1988, 53, 3539. (g) Chatani,
N.; Hanafusa, T. J. Org. Chem. 1987, 52, 4408. (h) Suginome, M.;
Kinugasa, H.; Ito, Y. Tetrahedron Lett. 1994, 35, 8635. X = Ge: (i)
Chatani, N.; Horiuchi, N.; Hanafusa, T. J. Org. Chem. 1990, 55, 3393. (j)
Chatani, N.; Morimoto, T.; Muto, T.; Murai, S. J. Orgnomet. Chem. 1994,
473, 335. X = Sn: (k) Obora, Y.; Baleta, A. S.; Tokunaga, M.; Tsuji, Y.
J. Organomet. Chem. 2002, 660, 173. X = S: (l) Kamiya, I.; Kawakami, J.;
Yano, S.; Nomoto, A.; Ogawa, A. Organometallics 2006, 25, 3562. (m) Lee,
Y. T.; Choi, S. Y.; Chung, Y. K. Tetrahedron Lett. 2007, 48, 5673. (n)
Zheng, W.; Ariafard, A.; Lin, Z. Organometallics 2008, 27, 246. (o) Wang,
M.; Cheng, L.; Wu, Z. Dalton Trans. 2008, 3879. X = O: (p) Koester,
D. C.;Kobayashi, M.;Werz, D.B.;Nakao, Y.J. Am. Chem. Soc. 2012, 134,
6544. X = Br: (q) Murai, M.; Hatano, R.; Kitabata, S.; Ohe, K. Chem.
Commun. 2011, 47, 2375.
(1) (a) Dyker, G. Handbook of CꢀH Transformations; Wiley-VCH:
Weinheim, 2005. (b) Yu, J.-Q.; Shi, Z. CꢀH activation (Top. Curr. Chem.
Vol. 292); Springer: Berlin Heidelberg, 2010. (c) Shilov, A. E.; Shul'pin,
G. B. Chem. Rev. 1997, 97, 2879. (d) Jia, C.; Kitamura, T.; Fujiwara, Y.
ꢀ
Acc. Chem. Res. 2001, 34, 633. (e) Dıaz-Requejo, M. M.; Perez, P. J.
Chem. Rev. 2008, 108, 3379. (f) Davies, H. M. L.; Du Bois, J.; Yu, J.-Q.
Chem. Soc. Rev. 2011, 40, 1855 and references therein.
(2) For reviews on carbocyanation, see: (a) Nakao, Y.; Hiyama, T.
Pure Appl. Chem. 2008, 80, 1097. (b) Tobisu, M.; Chatani, N. Chem. Soc.
Rev. 2008, 37, 300.
(3) For recent examples of carbocyanation, see: (a) Nakao, Y.;
Hirata, Y.; Tanaka, M.; Hiyama, T. Angew. Chem., Int. Ed. 2008, 47,
385. (b) Nakao, Y.; Ebata, S.; Yada, A.; Hiyama, T.; Ikawa, M.; Ogoshi,
S. J. Am. Chem. Soc. 2008, 130, 12874. (c) Hirata, Y.; Tanaka, M.; Yada,
A.; Nakao, Y.; Hiyama, T. Tetrahedron 2009, 65, 5037. (d) Hirata, Y.;
Yukawa, T.; Kashihara, N.; Nakao, Y.; Hiyama, T. J. Am. Chem. Soc.
2009, 131, 10964. (e) Hirata, Y.; Inui, T.; Nakao, Y.; Hiyama, T. J. Am.
Chem. Soc. 2009, 131, 6624. (f) Nakao, Y.; Yada, A.; Hiyama, T. J. Am.
Chem. Soc. 2010, 132, 10024. (g) Hirata, Y.; Yada, A.; Morita, E.;
Nakao, Y.; Hiyama, T.; Ohashi, M.; Ogoshi, S. J. Am. Chem. Soc. 2010,
132, 10070. (h) Minami, Y.; Yoshiyasu, H.; Nakao, Y.; Hiyama, T.
Angew. Chem., Int. Ed. 2013, 52, 883.
(5) (a) Dohi, T.; Morimoto, K.; Kiyono, Y.; Tohma, H.; Kita, Y.
Org. Lett. 2005, 7, 537. (b) Yan, G.; Kuang, C.; Zhang, Y.; Wang, J. Org.
Lett. 2010, 12, 1052. (c) Ushijima, S.; Moriyama, K.; Togo, H. Tetra-
hedron 2012, 68, 4588.
r
10.1021/ol402863g
Published on Web 11/05/2013
2013 American Chemical Society

cyanide.10 Therefore, the development of a catalytic pro-
cess that leads to alkynyl cyanides directly from the simple
terminal alkynes is an important issue.
Table 1. Copper-Catalyzed Cyanation of 1-Dodecyne (1a) with
Cyanogen Iodidea
Scheme 1. Direct Cyanation of Hydrocarbons
conv (%)b
yield (%)b
entry
base
none
1a
2a
3a
4a
5a
1
2
3
5
5
6
7
8
9
0
0
0
0
0
Et3N
39
74
58
42
52
77
77
95
2
0
28
38
48
6
1
pyridine
K2CO3
DBU
2
1
16
1
Our research interest in this area has been focused on
the utilization of cyanogen halides, which serve as viable
electrophilic “CNþ” sources and are complementary to the
usual nucleophilic cyanation agents such as metal cyanides
or cyanohydrins.11 Herein, we report a copper-catalyzed
CꢀH cyanation of terminal alkynes that uses cyanogen
iodide (ICN) as the cyanation agent,12,13 for which the
reaction pathway has now been revealed by stoichiometric
reaction analysis and reaction monitoring.
3
1
15
17
45
50
78
13
0
0
iPr2NH
tBuNH2
PMP
28
21
12
2
2
1
2
8
5
TEMP
3
9
a Reaction conditions: 1-dodecyne 1a (0.40 mmol), cyanogen iodide
(1.0 mmol), base (0.60 mmol), copper catalyst (10 mol %) in THF
(1.6 mL). b The yields and conversions were determined by 1H NMR
using nitromethane as an internal standard.
(Table 1, entry 1). Because it is well-known that copper-
mediated cross-coupling of terminal acetylenes (e.g.,
SonogashiraꢀHagihara coupling) usually requires bases
to activate the copper acetylide formation, we employed
triethylamine, pyridine, and potassium carbonate as repre-
sentative bases (entries 2ꢀ4). A very small amount of the
expected alkynyl cyanide 2a together with alkynyl iodide
3a, diiodoalkene 4a, and triiodoalkene 5a were obtained
from the reaction mixture. The yield of 2a was increased by
using 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as a stron-
ger base or diisopropylamine as a secondary amine, but
only by ∼15% (entries 5 and 6). When tert-butyl amine was
used as a primary amine or 1,2,2,6,6-pentamethylpiperidine
(PMP) as a bulky tertiary amine, the yield of 2a was
increased to ∼50% (entries 7 and 8). Eventually, 2,2,6,6-
tetramethylpiperidine (TEMP) was shown to be the most
efficient base for the present reaction, the yield of 2a being
78% (entry 9). Under the optimized conditions, yields of
the side products 3aꢀ5a were less than 10%.14,15
Scheme 2. Acetylenic Cyanation Giving Alkynyl Cyanides
Our initial experiment was carried out with 1-dodecyne
(1a), ICN, and 10 mol % of copper(I) triflate complex
(CuOTf toluene) in THF at 60 °C for 17 h, but no reaction
occurred, and the starting alkyne was recovered intact
3
(6) (a) Chen, X.; Hao, X.-S.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem.
Soc. 2006, 128, 6790. (b) Jia, X.; Yang, D.; Zhang, S.; Cheng, J. Org.
Lett. 2009, 11, 4716. (c) Jia, X.; Yang, D.; Wang, W.; Luo, F.; Cheng, J.
J. Org. Chem. 2009, 74, 9470. (d) Do, H.-Q.; Daugulis, O. Org. Lett.
2010, 12, 2517. (e) Kim, J.; Chang, S. J. Am. Chem. Soc. 2010, 132, 10272.
(f) Zhang, G.; Ren, X.; Chen, J.; Hu, M.; Cheng, J. Org. Lett. 2011, 13,
5004. (g) Ding, S.; Jiao, N. J. Am. Chem. Soc. 2011, 133, 12374. (h) Gong,
T.-J.; Xiao, B.; Cheng, W.-M.; Su, W.; Xu, J.; Liu, Z.-J.; Liu, L.; Fu, Y.
J. Am. Chem. Soc. 2013, 135, 10630.
(7) Kim, J.; Kim, H. J.; Chang, S. Angew. Chem., Int. Ed. 2012, 51,
11948 and references therein.
The present acetylenic CꢀH cyanation reaction was
expanded to the synthesis of alkynyl cyanides having various
substituents (Scheme 3). Alkynes with primary, secondary,
and tertiary alkyl groups could all be used in this reaction,
with the corresponding alkynyl cyanides being obtained in
good yield (2aꢀ2c; 63ꢀ78%). Other than aliphatic alkynes,
various aromatic acetylenes bearing para-substituents
such as methoxy, fluoro, methoxycarbonyl, and Bpin also
€
(8) (a) Muller, E.; Huber, H. Chem. Ber. 1963, 96, 670. (b) Lemaire,
M.; Doussot, J.; Guy, A. Chem. Lett. 1988, 1581. (c) Zheng, Z.; Hill,
C. L. Chem. Commun. 1998, 2467. (d) Kamijo, S.; Hoshikawa, T.; Inoue,
M. Org. Lett. 2011, 13, 5928. (e) Hoshikawa, T.; Yoshioka, S.; Kamijo,
S.; Inoue, M. Synthesis 2013, 45, 874.
(9) (a) Compagnon, P.-L.; Grosjean, B. Synthesis 1976, 448. (b)
Murray, R. E.; Zweifel, G. Synthesis 1980, 150.
(10) (a) Casarini, A.; Dembech, P.; Reginato, G.; Ricci, A.; Seconi,
G. Tetrahedron Lett. 1991, 32, 2169. (b) Luo, F.-T.; Wang, R.-T.
Tetrahedron Lett. 1993, 34, 5911.
(11) Okamoto, K.; Watanabe, M.; Murai, M.; Hatano, R.; Ohe, K.
Chem. Commun. 2012, 48, 3127. See also ref 4q.
(14) Although some other copper(I) or copper(II) salts could serve as
catalysts for this reaction, the yields were generally lower than that
obtained by using CuOTf toluene as the catalyst.
(15) When the reaction temperature was raised up to 80 or 100 °C, the
yield markedly decreased because of thermal isomerization of alkynyl
cyanide into allenyl or propargyl cyanide. See: Wentrup, C.; Crow,
W. D. Tetrahedron 1971, 27, 361.
(12) ICN (mp 146ꢀ147 °C; volatility 130 Pa at 25.2 °C) is stable to air
and moisture and can be easily prepared from an aqueous solution of
NaCN and I2. See: Bak, B.; Hillebert, A. Org. Synth. 1952, 32, 29.
(13) Caution! All operations should be conducted in a well-ventilated
fume hood because of the potential hazard from the generation of HCN
in the catalytic conditions.
3
Org. Lett., Vol. 15, No. 22, 2013
5811

Scheme 3. Copper-Catalyzed CꢀH Cyanation of Terminal
Alkynes 1 with Cyanogen Iodidea,b
Figure 1. Copper-catalyzed cyanation of 1-dodecyne with cyano-
gen iodide in THF-d8. Monitoring of the yields of the recovered
reactant (1a) and the products (2a, 3a, and 5a) with time.
Therefore, we propose the reaction pathway described
in Scheme 4. First, the base-mediated reaction of terminal
acetylene 1 with ICN forms the alkynyl iodide 3 and
a Reaction conditions: alkyne 1 (0.40 mmol), cyanogen iodide (1.0
mmol), TEMP (0.60 mmol), and Cu(OTf) toluene (10 mol %) in THF
3
TEMP HCN (6) (Scheme 4a; step 1). Then, the copper
iodide complex 7 undergoes ligand exchange by the initi-
ally generated ammonium cyanide 6 to form the cyanide
(1.6 mL). b Isolated yields were shown. c Cu(OTf) toluene (20 mol %), at
3
3
d
e
80 °C for 36 h. At 80 °C. Cu(OTf) toluene (20 mol %), for 36 h.
3
f Cyanogen iodide (2.0 mmol), TEMP (1.2 mmol), and Cu(OTf) toluene
(20 mol %).
3
complex 8 (Scheme 4b; step 2) as well as TEMP HI (9).16
3
Alternatively, ICN can also react with complex 7 to give
the cyanide complex 8 and molecular iodine (Scheme 4b;
step 20). Finally, the iodide 3 reacts with the generated
copper(I) cyanide complex 8 to give the product cyanide 2,
regenerating the copper(I) iodide complex 7 (Scheme 4c;
step 3).17
To confirm the proposed reaction mechanism, we con-
ducted some control experiments using the preformed
alkynyl iodide 3a. First, the reaction of 3a with a stoichio-
metric amount of CuCN in THF at 60 °C did not proceed
at all; however, the addition of TEMP dramatically chan-
ged the reactivity and gave the cyanide in 45% yield
(Scheme 5a). This result supports the mechanism of step 3
in Scheme 4c, where the cyanation of alkynyl iodide is
caused by “CuCN” species and accelerated by TEMP.18ꢀ20
underwent the cyanation (2dꢀ2h; 66ꢀ73%). It should be
noted that the boronic pinacolester moiety was tolerated
under the reaction conditions, despite its transmetalation
activity, which enabled us to subject the product 2h to a
further transformation such as the SuzukiꢀMiyaura cou-
pling reaction. The reaction of 3-thienylacetylene also af-
forded the cyanide 2i in 58% yield. Aliphatic acetylenes
bearing various functional groups such as ether, chloro,
ester, and alkene moieties, as well as a silylacetylene, were
also tolerated in this reaction to afford the corresponding
cyanides with these functional groups intact (2jꢀ2o;
51ꢀ67%). Even cholesterol as a complex molecule was
tolerated (2n; 63%). Double cyanation of 1,6-heptadiyne
was also successfully achieved by using double the amounts
of the reagents (2p; 43%).
To gain insight into the reaction mechanism, we mon-
itored the catalytic reaction as a function of time using 1H
NMR. As shown in Figure 1, alkynyl iodide 3a was formed
initially, and the yield of 3a reached a maximum of 95% at
45 min with almost full conversion of starting alkyne 1a.
After this period, the alkynyl iodide 3a was gradually
converted into the target cyanide 2a with production of
a minor amount of triiodide 5a. The amount of diiodide
4a was only at a trace level throughout the reaction. In
addition to this result, alkynyl iodide 3a was also obtained
in high yield, even in the reaction without a copper salt
(eq 1).
(16) The advantage of TEMP compared with other organic bases is
due to its steric hindrance, which would maintain the cyanation activity
by weakening the affinity with ICN (eq 2).
(17) Copper species 7 and 8 would be initiated into the catalytic cycle
by the reaction of the copper catalyst precursor (CuOTf toluene) with
ICN.
3
(18) Formation of alkynyl cyanide from the reaction of alkynyl
bromide with CuCN has been reported. See: Sladkov, A. M.; Ukhin,
L. Y. Bull. Acad. Sci. USSR, Div. Chem. Sci. 1964, 13, 370.
(19) Very recently, the activation of alkynyl iodides with TEMP in a
silver-catalyzed reaction was reported. See: Zeng, Y.; Zhang, L.; Zhao,
Y.; Ni, C.; Zhao, J.; Hu, J. J. Am. Chem. Soc. 2013, 135, 2955.
5812
Org. Lett., Vol. 15, No. 22, 2013

Scheme 4. A Proposed Reaction Mechanism
Scheme 5. Copper-Mediated Cyanation Starting with Alkynyl
Iodide 3a
Second, the copper-catalyzed reaction of tetrabutylammo-
nium cyanide (Bu4NCN), a commercially available ammo-
nium cyanide, also afforded the cyanide 2a in 45% yield
(Scheme 5b). This result shows that the ammonium cyanide
serves as a cyanation agent in copper-catalyzed cyanation
of alkynyl iodides. Third, we investigated the possibility of
ICN as an alternative cyanation agent by performing the
catalytic cyanation of alkynyl iodide with ICN (Scheme 4b;
step 20). For this purpose, we performed the copper-
catalyzed reaction of alkynyl iodide 3a with ICN in the
standard conditions. However, cyanide 2a was obtained in
only 18% yield, and triiodide 5a was obtained in 53% yield
as the major product (Scheme 5c). This result indicates that
the ICN serves as only a minor cyanation agent and that
molecular iodine (I2) as a byproduct causes the undesirable
diiodination of alkynyl iodides.21 Moreover, the addition of
Bu4NCN in the above conditions markedly improved the
selectivity toward the cyanide 2a (44% yield), and only a
trace amount of triiodide 5a was observed. In the actual
catalytic cyanation reaction, diiodination of alkynyl iodide
3ais probably suppressed by the anion exchange reaction of
ammonium cyanide 6 with I2 (Scheme 4d).22
In conclusion, we have developed a copper-catalyzed
direct cyanation reaction of terminal alkynes with cyano-
gen iodide which leads to alkynyl cyanides. Although the
reaction appears to be simple, the actual mechanism
supported by several experiments is more complicated,
and every species generated in the reaction medium
plays a crucial role for the selective conversion of alkynes
to alkynyl cyanides. It is noteworthy that cyanogen
iodide (ICN) acts as an iodinating agent of the terminal
alkyne and that concomitantly produced ammonium cya-
nide (TEMP HCN) is diverted to a cyanation agent of the
3
alkynyl iodide. Although the undesirable formation of the
triiodoalkene occurred in the present system, ammonium
cyanide should also suppress this side reaction effectively
by consuming I2 in the equilibrium.
Further mechanistic investigations, as well as the appli-
cation of cyanation reactions through iodination as the
intermediary reaction, are in progress.
Acknowledgment. This work was supported financially
by a Grant-in-Aid for Scientific Research on Innovative
Areas “Reaction Integration”(No. 2105) from the MEXT,
Japan.
(20) In the current system, additional cyanide salts (KCN or NaCN)
greatly reduced the reactivity, which indicates that the neutral “CuCN”
(not cuprate) acts as the catalyst.
Supporting Information Available. Experimental Pro-
cedures and compound characterization data. This ma-
terial is available free of charge via the Internet at http://
pubs.acs.org.
(21) Alkynyl iodide 3a might undergo diiodination with molecular
iodine (I2) generated by comproportionation of ICN.
(22) In a related experiment, 13C NMR spectra (solvent: THF-d8) of a
mixture of Bu4NCN (original peak of CN carbon at 165.0 ppm) and I2 as
well as a mixture of Bu4NI and ICN (original peak at 44.0 ppm) both
showed the same peak at 64.2 ppm (assigned to CN carbon). In the case
of Scheme 4d, the two states will also be in a fast equilibrium.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 22, 2013
5813