A convenient new procedure for converting primary amides into nitriles

Article abstract of DOI:10.1039/b614061k

An operationally simple and high-yielding procedure has been developed for the conversion of primary amides to the corresponding nitriles, using ethyl dichlorophosphate/DBU as the mild dehydrating agent. The Royal Society of Chemistry.

Full text of DOI:10.1039/b614061k

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A convenient new procedure for converting primary amides into nitriles
Chun-Wei Kuo,ab Jia-Liang Zhu,c Jen-Dar Wu,a Cheng-Ming Chu,ab Ching-Fa Yao*b and Kak-Shan Shia*a
Received (in Cambridge, UK) 28th September 2006, Accepted 18th October 2006
First published as an Advance Article on the web 27th October 2006
DOI: 10.1039/b614061k
active phosphorus center compared to other coupling reagents
examined. Thus, the system (EtOPOCl2/DBU) indicated in Entry 3
is considered the method of choice, and the typical procedure is
illustrated as follows. Benzamide (1) (0.121 g, 1.0 mmol) was
treated with 3 equivalents of DBU (0.457 g, 3.0 mmol) in
dichloromethane (5 mL) at room temperature for 10 min, at which
time 2 equivalents of ethyl dichlorophosphate (0.326 g, 2.0 mmol)
was then added, and the reaction was continued at the same
temperature for additional 50 min. Addition of aqueous NH4Cl
followed by dichloromethane extraction and flash chromatogra-
phy (silica gel, 10% ethyl acetate in n-hexane) afforded the
corresponding nitrile 2{ (0.101 g, 98%) as a colorless oil. Its
An operationally simple and high-yielding procedure has been
developed for the conversion of primary amides to the
corresponding nitriles, using ethyl dichlorophosphate/DBU as
the mild dehydrating agent.
The conversion of the primary carboxamido functionality into the
cyano group is an important process which has extensive utility in
organic synthesis.1,2 Herein, we wish to report a convenient new
protocol for this operation. The new dehydration process is
facilitated by the ease of primary amides to undergo coupling with
ethyl dichlorophosphate (EtOPOCl2) or phenyl dichlorophosphate
(C6H5OPOCl2) followed by rapid elimination with 1,8-diazabicy-
clo[5.4.0]undec-7-ene (DBU) to form the corresponding nitriles.
While a wealth of dehydrating agents are available to effect this
transformation,3–17 the mild reagent, either EtOPOCl2 or
C6H5OPOCl2, applied in this newly developed methodology, to
our knowledge, are unprecedented. Compiled in Table 1 are results
for the initial model study by the use of benzamide (1) as a
substrate under treatment with each hitherto unexplored dehy-
drating agents, including ethyl dichlorophosphate (EtOPOCl2),{
phenyl dichlorophosphate (C6H5OPOCl2),{ N,N-dimethyl-
phosphoramidic dichloride [(CH3)2NPOCl2],{ and N,N-dimethyl-
phosphoramidous dichloride [(CH3)2NPCl2]{ in the presence of
different bases to afford benzonitrile (2). Accordingly, when
accompanied with DBU as a base, ethyl dichlorophosphate is
considered the reagent of choice to facilitate the dehydration
reaction in terms of conversion rate and reaction time (Entry 3).
As well, DBU was found to be more effective than other
commonly used bases such as triethylamine and pyridine among
the dehydration systems investigated (Entries 1, 2 and 3). The
underlying cause of this remarkable base effect is still not fully
understood. Other structure-related dehydrating agents such as
C6H5OPOCl2, (CH3)2NPOCl2, and (CH3)2NPCl2 were also
examined. As shown in Table 1 (Entries 3 and 4), both
EtOPOCl2 and C6H5OPOCl2 are equally effective for the
transformation of carboxamide 1 into nitrile 2 in virtually
quantitative yield (y98%). However, similar reaction conditions
with (CH3)2NPOCl2 or (CH3)2NPCl2 as the coupling reagent
merely gave rise to the desired product in 64% and 40%,
respectively (Entries 5 and 6). In the case with (CH3)2NPCl2, a
low yield was obtained even after the reaction time was extended
under refluxing conditions (Entry 7), presumably due to the less
1
structure was verified by spectroscopy with spectral data (IR, H
NMR and 13C NMR) identical to those of the authentic sample
available from Aldrich. When the reaction was repeated with
phenyl dichlorophosphate in place of ethyl dichlorophosphate,
97% yield of the pure product was isolated.
Table 1 Conversion of benzamide into benzonitrile with various
dehydrating agents and bases
Dehydrating
agent
Yield
(%)b
Entry
1
Base
Time/h
3
Temp./uC
NEt3
rt
63
50
98
97
64
2
3
4
5
Pyridine
DBU
3
rt
rt
rt
rt
1
DBU
1.5
5
DBU
6
7
a
DBU
DBU
3
8
rt
40c
54c
reflux
aDivision of Biotechnology and Pharmaceutical Research, National
Health Research Institutes, Miaoli County, 350, Taiwan, R.O.C.
E-mail: ksshia@nhri.org.tw
All reactions were performed using amide 1 (1 equiv.), dehydrating
b
agent (2 equiv.), and base (3 equiv.) in dichloromethane. Yields are
bDepartment of Chemistry, National Taiwan Normal University, Taipei,
116, Taiwan, R.O.C. E-mail: cheyaocf@scc.ntnu.edu.tw
cDepartment of Chemistry, National Dong-Hwa University, Hualien,
974, Taiwan, R.O.C.
c
for isolated, chromatographically pure products. Starting material
was recovered intact in less than 10% along with an unidentified side
product.
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Chem. Commun., 2007, 301–303 | 301

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Table 2 Conversion of primary amides into nitriles with ethyl
dichlorophosphate and DBU as base
EtOPOCl2 ð2 equiv:Þ, DBU ð3 equiv:Þ
RCONH2 DCDCDCDCDCDCDCCA RCN
CH2Cl2, rt
Yield
Time/h (%)b
Entry Substratea
1
Product
2
85
Scheme 1
Under similar conditions, dehydration of several functionally
diverse primary amides was further performed. The generality of
the method is apparently demonstrated by results outlined in
Table 2. Comparison of Entries 1 and 2 reveals that the labile
stereogenic center adjacent to the carboxamido group remains
intact, as evidenced by obtaining individual enantiomeric nitrile
product in optically pure form,§ potentially rendering this mild
dehydration system a great synthetic utility. Additional examples
of substituted benzamides were also subjected to the transforma-
tion (Entries 3–7) and all resulted in excellent yields (91–95%)
within 3 h, indicating that the reaction rate appears to be little
affected by the stereoelectronic nature of the substitution. More
intriguingly, N-containing heteroaromatic carboxamides including
those containing a pyrrolic N-hydrogen (Entries 8–12) are readily
converted into the corresponding nitriles in good to high yields.
Especially, when nicotinamide (Entry 8) was employed as a
starting substrate, a substantially high yield of the corresponding
3-cyanopyridine (90%) was obtained compared to other reported
methods such as trichloromethyl chloroformate (0%),17 trichloro-
acetyl chloride/triethylamine (77%),15 and titanium tetrachloride/
triethylamine (78%).5 Alkyl or arakyl carboxamides bearing
various functionalities are also allowed to provide the correspond-
ing nitriles in high yields (80–92%) under this newly developed
protocol (Entries 13–16). In addition, it is noteworthy that
carboxamide 5 (Entry 17), under treatment with the titled method
(EtOPOCl2 (2 equiv.)/DBU (3 equiv.)), cleanly afforded the desired
nitrile 6 in 92% yield; however, for comparison, when the same
reaction was carried out using a classical system, trifluoroacetic
anhydride (2 equiv.)/pyridine (3 equiv.),10 nitrile 6 was formed in
only 64% yield along with an over-acylated side product 7 in 23%
yield (Scheme 1). The aforementioned example, again, demon-
strates the usefulness and versatility of this new synthetic method.
A mechanistic rationale of the dehydration reaction is depicted
in Scheme 2 by taking the conversion of benzamide into
2
2
86
3
4
5
3
3
2
92
94
91
6
7
3
2
95
93
8
1
90
9
1
3
1
1
88
73
78
81
10
11
12
13
14
2
3
92
92
15
16
2
3
88
80
17
2
92
a
All substrates are commercially available and used without further
purification. Yields are for isolated, chromatographically pure
products.
b
Scheme 2
302 | Chem. Commun., 2007, 301–303
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126.9, 129.3, 129.4, 133.4, 154.2; EIMS: m/z 255 (M + 23); mp 120.5–
121.3 uC; [a]2D4 + 1.83 (c = 1.09, CHCl3).
benzonitrile as a typical pathway. It is highly conceivable that the
carboxamido group is initially coupled with ethyl dichloropho-
sphate to form an active intermediate which in turn undergoes
elimination rapidly with DBU to give the corresponding cyano
group.
1 L. N. Mander and M. M. McLachlan, J. Am. Chem. Soc., 2003, 125,
2400.
2 B. R. Lahue, S. M. Lo, Z. K. Wan, G. H. C. Woo and J. K. Snyder,
J. Org. Chem., 2004, 69, 7171.
3 (a) A. V. Narsaiah and K. Nagaiah, Adv. Synth. Catal., 2004, 346, 1271;
(b) D. S. Bose and A. V. Narsaiah, Synthesis, 2001, 373; (c) K. Ishihara,
Y. Furuya and H. Yamamoto, Angew. Chem., Int. Ed., 2002, 41, 2983;
(d) D. S. Bose and P. R. Goud, Tetrahedron Lett., 1999, 40, 747; (e)
D. S. Bose and B. Jayalakshmi, J. Org. Chem., 1999, 64, 1713; (f)
S. V. Ley, A. G. Leach and R. I. Storer, J. Chem. Soc., Perkin Trans. 1,
2001, 358; (g) E. C. Wang, K. S. Huang, H. M. Chen, C. C. Wu and
G. J. Lin, J. Chin. Chem. Soc., 2004, 51, 619.
As described above, the EtOPOCl2/DBU system presents itself
as a mild, highly effective dehydrating agent for the conversion of
primary amides to the corresponding nitriles. In addition to high
yields, enhanced reaction rates and operational simplicity, this
newly developed process is expected to have broad synthetic utility,
particularly for the preparation of thermodynamically labile
nitriles.
4 E. Yamto and S. Sugasawa, Tetrahedron Lett., 1970, 4383.
5 W. Lehnert, Tetrahedron Lett., 1971, 1501.
6 C. Ressler, G. R. Nagarajan, M. Kirisawa and D. V. Kashelikar, J. Org.
Chem., 1971, 36, 3960.
We are grateful to the National Health Research Institutes and
National Science Council of the Republic of China for financial
support.
7 T. Sodeyama, M. Kodomari and K. Itabashi, Chem. Lett., 1973, 577.
8 T. Saraie, T. Ishiguro, K. Kawashima and K. Morita, Tetrahedron Lett.,
1973, 2121.
Notes and references
9 J. B. Hendrickson and S. M. Schwartzman, Tetrahedron Lett., 1975,
277.
10 F. Campagna, A. Carotti and G. Casini, Tetrahedron Lett., 1977,
1813.
11 D. Cooper and S. Trippett, Tetrahedron Lett., 1979, 1725.
12 G. A. Olah, S. C. Narang, A. P. Fung and B. G. B. Gupta, Synthesis,
1980, 657.
13 T. M. Bargar and C. M. Riley, Synth. Commun., 1980, 10, 479.
14 T. Imamoto, T. Takaoka and M. Yokoyama, Synthesis, 1983, 142.
15 A. Saednya, Synthesis, 1985, 184.
{ EtOPOCl2, C6H5OPOCl2, (CH3)2NPOCl2 and (CH3)2NPCl2 were
obtained from Aldrich or Acros and used without further purification.
{ Satisfactory spectral and elemental or LC-MS analytical data were
obtained for all new compounds; all known nitriles showed physical and
spectral properties identical to those reported in the literature.
§ (R)-2-N-tert-butoxycabonylamino-2-phenylethanenitrile (3): 1H NMR
(400 MHz, CDCl3): d 1.47 (s, 9H), 5.23 (br s, 1H), 5.78 (br s, 1H), 7.41–
7.48 (m, 5H, ArH); 13C NMR (100 MHz, CDCl3): d 28.2, 46.0, 81.5, 177.7,
126.8, 129.2, 129.4, 133.5, 154.2; EIMS: m/z 255 (M + 23); mp 119.5–
120.2 uC; [a]2D4 21.82 (c = 1.1, CHCl3) {Lit.18 [a]D22 21.9 (c = 1.1, CHCl3)}.
(S)-2-N-tert-butoxycabonylamino-2-phenylethanenitrile (4): 1H NMR
(400 MHz, CDCl3): d 1.46 (s, 9H), 5.21 (br s, 1H), 5.77 (br s, 1H), 7.41–
7.48 (m, 5H, ArH); 13C NMR (100 MHz, CDCl3): d 28.2, 46.1, 81.5, 177.6,
16 D. M. Ketcha and G. W. Gribble, J. Org. Chem., 1985, 50, 5451.
17 K. Mai and G. Patil, Tetrahedron Lett., 1986, 27, 2203.
18 N. Noriyuki, S. Miho and U. Makoto, Tetrahedron, 2002, 58, 3561.
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Chem. Commun., 2007, 301–303 | 303