A simple method for the electrophilic cyanation of secondary amines

Article abstract of DOI:10.1021/ol403245r

Bleach oxidizes trimethylsilyl cyanide to generate an electrophilic cyanating reagent that readily reacts with an amine nucleophile. This oxidative N-cyanation reaction allows for the preparation of disubstituted cyanamides from amines without using highly toxic cyanogen halides.

Full text of DOI:10.1021/ol403245r

Letter
pubs.acs.org/OrgLett
A Simple Method for the Electrophilic Cyanation of Secondary
Amines
Chen Zhu, Ji-Bao Xia, and Chuo Chen*
University of Texas Southwestern Medical Center, Department of Biochemistry, 5323 Harry Hines Boulevard, Dallas, Texas 75390,
United States
S
* Supporting Information
ABSTRACT: Bleach oxidizes trimethylsilyl cyanide to generate an electrophilic cyanating
reagent that readily reacts with an amine nucleophile. This oxidative N-cyanation reaction
allows for the preparation of disubstituted cyanamides from amines without using highly
toxic cyanogen halides.
Table 1. Development of the Oxidative N-Cyanation
Reaction
yanamide is a valuable functional group in medicinal and
a
1
Ccoordination chemistry. It is frequently used for urea,
thiourea, and guanidine synthesis.2 It can also be transformed
easily into heterocycles such as 2-aminoxazole, 2-heteroimida-
zole, 5-aminotetrazole, and 2-aminopyridine.3 The most
straightforward method for cyanamide synthesis is the electro-
philic cyanation of amines using cyanogen halides.4 Cyanogen
chloride, produced by reacting sodium cyanide with chlorine
gas,5 is a poisonous gas (bp 13 °C and mp −7 °C).6 Cyanogen
bromide is a solid and therefore a safer N-cyanating reagent.7
However, it has high vapor pressure (126 Torr) and low melting
and boiling points (mp 52 °C and bp 62 °C). This reagent should
therefore be handled very carefully.
entry
oxidant
TBHP
CN source
yield
1
TMSCN
TMSCN
TMSCN
TMSCN
TMSCN
TMSCN
TMSCN
TMSCN
TMSCN
NaCN
0%
0%
2
H2O2
3
Oxone
0%
4
mCPBA
O2
<5%
0%
We have been interested in developing new oxidation
reactions8 and synthesizing highly nitrogenated natural prod-
ucts.9 During the development of a vanadium catalyst system
for the oxidative Strecker reactions,8b we found that secondary
amines can be cyanated at either the α-C- or N-position depend-
ing on the oxidant used. We studied the origin of this selectivity
and found a convenient way to generate an electrophilic cyanat-
ing reagent in situ. This new oxidative method allows for the
preparation of cyanamides from amines without using highly
toxic cyanogen halides.
5
6
PhIO
0%
7
NaBrO3
NaClO2
NaClO(aq)
NaClO(aq)
0%
8
0%
9
70%
0%
10
a
Reaction conditions: 1 (0.1 mmol), oxidant (0.15 mmol), TMSCN
(0.12 mmol), 1 mL solvent.
We examined the ability of a variety of oxidants in promoting
the N-cyanation of N-(4-methoxyphenyl)benzylamine (1) (Table 1).
We used trimethylsilyl cyanide (TMSCN) as the cyanide source
and acetonitrile as the solvent. While most of the oxidants we
examined gave little or no cyanamide 2 (entries 1−8), NaClO
(household bleach, 10−15% NaClO in water) promoted a
smooth N-cyanation (entry 9). However, no reaction occurred
when we used sodium cyanide (NaCN) as the cyanide source
(entry 10). Using water as a cosolvent did not improve the
N-cyanation of 1 for entries 7, 8, and 10.
The generality of this N-cyanation reaction is shown in
Figure 1. This method is useful for preparing both arylalkyl-
cyanamides (2−14) and dialkylcyanamides (15−17). A range of
functional groups can be tolerated, including the methoxyl (3),
halogen (F, Cl, Br) (4−6), tert-butyloxycarbonyl (Boc) (10), and
trimethylsilyloxyl (TMSO) (17) groups. The reactive naphthyl,
furyl, and thiophenyl groups were also compatible (7−9).
While our initial studies focused on the cyanation of the more
nucleophilic PMP-alkylamines (2−13), the 4-methoxyl group
was not needed for the reactivity. Cyanation of N-phenylbenzyl-
amine gave 14 smoothly. However, the reaction was slower and
an increased amount of the reagents and extended reaction time
were required. This reaction could also be used to functionalize
dialkylamines. Cyanation of dialkylamines proceeded smoothly,
giving cyanamides 15−17 in high yields. We have also obtained a
single crystal of 5 and used X-ray analysis to confirm its structure
(Figure 2).
We believe that NaClO oxidized TMSCN instead of the
amines4c in this N-cyanation reaction. We found that NaClO
reacted with TMSCN but not 1 according to 13C NMR
Received: November 11, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ol403245r | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Figure 1. Scope of the N-cyanation reaction. aReaction conditions: 3.0 equiv of NaClO (aq), 2.0 equiv of TMSCN, 24 h.
Figure 2. Crystal structure of 5.
Figure 3. 13C NMR spectrum of the reaction of TMSCN and NaClO in
CDCl3 after 5 min.
analyses (Figure 3).10 The reaction between NaClO and
TMSCN was rapid and exothermic. It was accompanied by gas
evolution and a change of solution pH to 11. The silyl group of
TMSCN may activate NaClO for the oxidation of CN because
replacing TMSCN with NaCN resulted in no reaction. We
suspect that mixing NaClO with TMSCN gave cyanogen
chloride (ClCN), which reacted with amines to give
cyanamides (Figure 4).
In summary, we have developed an operationally simple
method for generating an electrophilic cyanating reagent in situ
from TMSCN and NaClO. It is useful for synthesizing a wide
range of cyanamides from amines. We are exploring further
synthetic utilities of this CN-umpolung reaction.
Figure 4. Proposed mechanism for the N-cyanation reaction.
B
dx.doi.org/10.1021/ol403245r | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(7) For safety information, see the Hazardous Substances Data Bank
on the Toxicology Data Network of the U.S. National Library of
Medicine, National Institutes of Health: http://toxnet.nlm.nih.gov/cgi-
bin/sis/search/r?dbs+hsdb:@term+@DOCNO+708.
(8) (a) Xia, J.-B.; Cormier, K. W.; Chen, C. Chem. Sci. 2012, 3, 2240−
2245. (b) Zhu, C.; Xia, J.-B.; Chen, C. Tetrahedron Lett., in press,
DOI:10.1016/j.tetlet.2013.11.012. (c) Xia, J.-B.; Zhu, C.; Chen, C. J.
Am. Chem. Soc. 2013, 135, 17494−17500.
(9) (a) Lu, J.; Tan, X.; Chen, C. J. Am. Chem. Soc. 2007, 129, 7768−
7769. (b) Ma, Z.; Lu, J.; Wang, X.; Chen, C. Chem. Commun. 2011, 47,
427−429. (c) Wang, X.; Lu, Z. M. J.; Tan, X.; Chen, C. J. Am. Chem. Soc.
2011, 133, 15350−15353. (d) Wang, X.; Wang, X.; Tan, X.; Lu, J.;
Cormier, K. W.; Ma, Z.; Chen, C. J. Am. Chem. Soc. 2012, 134, 18834−
18842.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: Chuo.Chen@UTSouthwestern.edu.
Notes
The authors declare no competing financial interest.
(10) (a) Hamada, T.; Manabe, K.; Kobayashi, S. Chem.Eur. J. 2006,
12, 1205−1215. (b) Liu, X.; Qin, B.; Zhou, X.; He, B.; Feng, X. J. Am.
Chem. Soc. 2005, 127, 12224−12225.
ACKNOWLEDGMENTS
■
Financial support was provided by NIH/NIGMS (R01-
GM079554) and the Welch Foundation (I-1596). We thank
Dr. Vincent Lynch (University of Texas at Austin) for
performing the X-ray analysis of 5.
REFERENCES
■
(1) (a) Nekrasov, D. D. Russ. J. Org. Chem. 2004, 40, 1387−1402.
(b) Larraufie, M.-H.; Maestri, G.; Malacria, M.; Ollivier, C.;
̂
Fensterbank, L.; Lacote, E. Synthesis 2012, 44, 1279−1292.
(2) (a) Kim, S. H.; Park, B. R.; Kim, J. N. Bull. Korean Chem. Soc. 2011,
32, 716−718. (b) Hua, G.; Zhang, Q.; Li, Y.; Slawin, A. M. Z.; Woollins,
J. D. Tetrahedron 2009, 65, 6074−6082. (c) Katritzky, A. R.; Rogovoy, B.
́
V. ARKIVOC 2005, 49−87. (d) Simig, G.; Lempert, K.; Tamas, J.; Czira,
G. Tetrahedron 1975, 31, 1195−1200. (e) Reddy, N. L.; Hu, L.-Y.;
Cotter, R. E.; Fischer, J. B.; Wong, W. J.; McBurney, R. N.; Weber, E.;
Holmes, D. L.; Wong, S. T.; Prasad, R.; Keanal, J. F. W. J. Med. Chem.
1994, 37, 260−267. (f) Zahariev, S.; Guarnaccia, C.; Lamba, D.;
̌
Cemazar, M.; Pongor, S. Tetrahedron Lett. 2004, 45, 9423−9426.
̌
̂
(g) Larraufie, M.-H.; Ollivier, C.; Fensterbank, L.; Malacria, M.; Lacote,
E. Angew. Chem., Int. Ed. 2010, 49, 2178−2181. (h) Looper, R. E.;
Haussener, T. J.; Mack, J. B. C. J. Org. Chem. 2011, 76, 6967−6971.
(i) Zhou, L.; Chen, J.; Zhou, J.; Yeung, Y.-Y. Org. Lett. 2011, 13, 5804−
5807.
(3) (a) Ross, W. J.; Harrison, R. G.; Jolley, M. R. J.; Neville, M. C.;
Todd, A.; Verge, J. P.; Dawson, W.; Sweatman, W. J. F. J. Med. Chem.
1979, 22, 412−417. (b) Knapp, S.; Kukkola, P. J. J. Org. Chem. 1990, 55,
1632−1636. (c) Devan, B.; Rajagopalan, K. Tetrahedron Lett. 1994, 35,
1585−1586. (d) Giles, R. L.; Sullivan, J. D.; Steiner, A. M.; Looper, R. E.
Angew. Chem., Int. Ed. 2009, 48, 3116−3120. (e) Giles, R. L.; Nkansah,
R. A.; Looper, R. E. J. Org. Chem. 2010, 75, 261−264. (f) Demko, Z. P.;
Sharpless, K. B. Org. Lett. 2001, 3, 4091−4094. (g) Duan, M.; Aquino,
C.; Ferris, R.; Kazmierski, W. M.; Kenakin, T.; Koble, C.; Wheelan, P.;
Watson, C.; Youngman, M. Bioorg. Med. Chem. Lett. 2009, 19, 1610−
1613. (h) Stolley, R. M.; Maczka, M. T.; Louie, J. Eur. J. Org. Chem. 2011,
3815−3824.
(4) (a) van Leusen, A. M.; Jagt, J. C. Tetrahedron Lett. 1970, 11, 967−
970. (b) Cockerill, A. F.; Deacon, A.; Osborne, R. G. H. D. J.; Prime, D.
M.; Ross, W. J.; Todd, A.; Verge, J. P. Synthesis 1976, 591−593.
́
(c) Troyanskii, E. I.; Ioffe, V. A.; Mizintsev, V. V.; Nikishin, G. I. Bull.
Acad. Sci. USSR Div. Chem. Sci. 1984, 33, 1661−1667. (d) Kaupp, G.;
Schmeyers, J.; Boy, J. Chem.Eur. J. 1998, 4, 2467−2474. (e) Kamijo,
S.; Jin, T.; Yamamoto, Y. Angew. Chem., Int. Ed. 2002, 41, 1780−1782.
(f) Wong, F. F.; Chen, C.-Y.; Yeh, M.-Y. Synlett 2006, 559−562.
(g) Ghosh, H.; Yella, R.; Ali, A. R.; Sahoo, S. K.; Patel, B. K. Tetrahedron
Lett. 2009, 50, 2407−2410. (h) Ramana, T.; Saha, P.; Das, M.;
Punniyamurthy, T. Org. Lett. 2010, 12, 84−87.
(5) Coleman, G. H.; Leeper, R. W.; Schulze, C. C. Inorg. Synth. 1946, 2,
90−94.
(6) For safety information, see the Emergency Response Safety and
Health Database published by the National Institute for Occupational
Safety and Health, Centers for Disease Control and Prevention: http://
www.cdc.gov/niosh/ershdb/EmergencyResponseCard_29750039.
html.
C
dx.doi.org/10.1021/ol403245r | Org. Lett. XXXX, XXX, XXX−XXX