An efficient new procedure for the one-pot conversion of aldehydes into the corresponding nitriles

Article abstract of DOI:10.1055/s-2007-980338

A new and efficient procedure for the one-pot conversion of various aldehydes into the corresponding nitriles under mild reaction conditions has been developed. The ethyl dichlorophosphate/DBU-mediated dehydration of aldoxime intermediates was utilized as a key operation to effect the transformation. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-980338

LETTER
1317
An Efficient New Procedure for the One-Pot Conversion of Aldehydes into the
Corresponding Nitriles
One-Pot
C
i
onvers
a
ion of
A
lde
-
hydes in
L
to the Correspo
inding a
itriles ng Zhu,*a Fa-Yen Lee,a Jen-Dar Wu,b Chun-Wei Kuo,b Kak-Shan Shia*b
a
Department of Chemistry, National Dong-Hwa University, Hualien 974, Taiwan, R.O.C.
Fax +886(38)633570; E-mail: jlzhu@mail.ndhu.edu.tw
b
Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli 350, Taiwan, R.O.C.
Fax +886(37)586456; E-mail: ksshia@nhri.org.tw
Received 30 January 2007
aldehydes into nitriles to occur smoothly at ambient tem-
perature and, consequently, is endowed with a broad
application scope.
Abstract: A new and efficient procedure for the one-pot conversion
of various aldehydes into the corresponding nitriles under mild re-
action conditions has been developed. The ethyl dichlorophosphate/
DBU-mediated dehydration of aldoxime intermediates was utilized
as a key operation to effect the transformation.
Under different combinations, several bases (DBU, pyri-
dine, Et3N) and phosphorus-containing activating re-
agents, including EtOPOCl2, diethyl cholorophosphate
[(EtO)2POCl] and N,N-dimethylphosphoramidous dichlo-
ride [(CH3)2NPCl2], were initially investigated by using
benzaldehyde (1) as a substrate (Table 1). We observed
that on the treatment with NH2OH·HCl and DBU, fol-
lowed by EtOPOCl2 at room temperature in CH2Cl2, 1
could be converted into benzonitrile (2) in good yield
(85%, Table 1, entry 1). However, switching EtOPOCl2 to
either (EtO)2POCl (entry 2) or Me2NPCl2 (entry 3) under
similar reaction conditions caused the decreased yields of
2, together with the notable isolation of O-diethylphos-
phinyloxime [PhCH=NOPO(OEt)2] (entry 2, 22%) and
aldoxime (PhCH=NOH; entry 3, 45%).8 These results in-
dicate that EtOPOCl2 is far more effective than the other
two attested reagents in promoting the dehydration pro-
cess. A mechanistic study for disclosing the reason(s) of
their divergent reactivity is currently under investigation.
Key words: aldehydes, nitriles, ethyl dichlorophosphate, DBU,
dehydration
The conversion of aldehydes into the corresponding ni-
triles is an important functional group transformation due
to the extensive utilities of nitrile compounds in synthetic
chemistry.1 Among numerous methods developed for this
purpose,2–6 those based on the dehydration of aldoximes
generated from the condensation of aldehydes with hy-
droxylamine are the most widely employed ones. Accord-
ing to the literature reports,6 many aldehydes can be
directly converted into nitriles without the isolation of
aldoxime intermediates upon the one-pot treatment with
hydroxylamine hydrochloride (NH2OH·HCl) in the pres-
ence of various dehydrating agents, such as N-methyl-2-
pyrrolidinone,6d alumina/MeSO2Cl,6e silica chloride,6g
NaI,6h etc. However, these literature precedents often
require drastic refluxing6a,d,e,h,i or microwave heating6b,c,f,g
conditions to effect such one-pot transformation, and
therefore practically may not be compatible with thermal-
ly unstable molecules. In addition, some of these methods
have shown to be less efficient when applied to enolizable
aliphatic aldehydes in giving unsatisfactory yields of ali-
phatic nitriles. With respect to these limitations, herein we
report a novel protocol for the one-pot synthesis of a wide
range of nitriles from the corresponding aldehydes by em-
ploying ethyl dichlorophosphate (EtOPOCl2) combined
with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)7 as a
mild dehydrating system. In such an approach, the de-
hydration of aldoximes generated in situ can be greatly
facilitated, conceivably via a process involving a coupling
reaction of aldoximes with EtOPOCl2 to form active inter-
mediates, followed by a rapid DBU-promoted elimination
to give the corresponding nitriles. In contrast to the
previous requirement for heating conditions, this newly
developed protocol permits the one-pot conversion of
Table 1 Optimization of the Reaction Conditionsa
O
CN
H
NH2OH·HCl, reagents
CH2Cl2, r.t., 15 h
1
2
Entry
Reagentsb
Yield (%)c
1
2
3
4
5
6
EtOPOCl2, DBU
85
53
25
15
5
(EtO)2POCl, DBU
Me2NPCl2, DBU
EtOPOCl2, pyridine
EtOPOCl2, Et3N
DBU, EtOPOCl2, MS 3 Å
96
a All reactions were performed using benzaldehyde (1 equiv),
NH2OH·HCl (1.2 equiv), phosphorus-activating reagent (1.5 equiv)
and base (5 equiv).
SYNLETT 2007, No. 8, pp 1317–1319
1
6.
0
5.
2
0
0
7
b All reagents were purchased from Fluka and Aldrich and used
directly without further purification.
Advanced online publication: 08.05.2007
DOI: 10.1055/s-2007-980338; Art ID: W02107ST
© Georg Thieme Verlag Stuttgart · New York
c Isolated yield of the purified product.

1318
J.-L. Zhu et al.
LETTER
O
P
In addition, the replacement of DBU in entry 1 with pyri-
dine (entry 4) or triethylamine (entry 5) also led to poor
conversion even after reaction time was extended to a few
days.
OEt
O
H
O
P
N
Cl
NOH
H
EtO
Cl
Cl
The recovery of intact 1 in both cases (entry 4, 67%; entry
5, 80%) implies that DBU may also play an essential role
in the condensation reaction between 1 and NH2OH·HCl.
Moreover, based on the conditions of entry 1, it was found
that significant improvement (85% to 96%) could be fur-
ther achieved by the addition of a certain amount of 3 Å
molecular sieves (MS)9 to the reaction mixture (entry 6),
resulting in the formation of 2 in almost quantitative yield
(96%). Therefore, as an optimal choice, the reagent com-
bination indicated in entry 6 (EtOPOCl2, DBU, 3 Å MS)
was subsequently applied into our general procedure.
DBU
8
7
O
CN
N
EtO
P
O–
+
+
Cl
N
H+
2
Scheme 1 Proposed mechanism of the dehydration of aldoximes
Table 2 One-Pot Conversion of Various Aldehydes into Nitriles
Having established the optimized conditions of the meth-
od, we turned to investigate its generality by probing an
array of structurally diverse aldehydes. As outlined in
Table 2, on the subjection to similar treatment, a broad
range of substrates, including aromatic (Table 2, entries
1–4), heteroaromatic (entry 5 and 6), a,b-unsaturated (en-
try 7), cyclic (entry 8) and aliphatic (entry 9) aldehydes,
were all uniformly transferred into the corresponding
nitriles10 in high to quantitative yields (83–98%). The
yields of these nitrile products obtained from our studies
are shown to be comparable or better than those of related
literature methods. Additionally, this newly developed
protocol was also applied to (S)-2-(tert-butoxycarbonyl-
amino)propanal (3)11 and (S)-2-(tert-butoxycarbonylami-
no)-3-phenylpropanal (5), the molecules bearing the
labile stereogenic centers and N-tert-butoxycarbonyl ami-
no protecting group. In both cases, 3 and 5 underwent
ready conversion into the corresponding nitriles 4 (entry
10, 87%) and 6 (entry 11, 80%) with the maintenance of
the steric integrity, demonstrating that the current proce-
dure, in consistency with its mild reaction conditions, ap-
pears to be an attractive approach for the preparation of
labile nitrile compounds that are otherwise difficult to ob-
tain through related methods involving refluxing condi-
tions. The N-Boc-protected amino nitriles 4 and 6 are the
useful building blocks for synthesizing biologically inter-
esting peptidomimetic compounds.12,13 Their identities
were unambiguously confirmed by the comparison of
spectral data13,14 and [a] values14,15 with those previously
described in the literature.16
O
NH2OH·HCl (1.2 equiv), DBU (5 equiv), MS 3 Å
R
CN
R
H
CH2Cl2, r.t.,10 h, then EtOPOCl2 (1.5 equiv), r.t., 5 h
Entry
Substratea
Product
Yield (%)b
90
CHO
CN
1
2
3
Me
Me
CHO
CN
98
87
MeO
O2N
MeO
O2N
CN
CN
CHO
CHO
4
5
6
7
85
83
90
98
CN
CN
CHO
N
N
CHO
N
N
CHO
CN
CHO
CN
8
9
92
98
n-C7H15 CHO
n-C7H15 CN
By taking the case of converting benzaldehyde (1) into
benzonitrile (2) as an example, a proposed mechanism of
the crucial EtOPOCl2/DBU-mediated aldoxime dehydra-
tion process is illustrated in Scheme 1. At first, the in situ
generated aldoxime 7 couples with EtOPOCl2 to form an
active intermediate 8. Following this, 8 can undergo a
rapid elimination reaction promoted by DBU to afford the
corresponding nitrile 2.
87
80
10
11
BocHN
CN
BocHN
CHO
3
4
CH2Ph
CHO
CH2Ph
CN
BocHN
BocHN
5
6
a All substrates are commercially available except for that in
In conclusion, we have described a novel and efficient
procedure for the one-pot conversion of aldehydes into the
corresponding nitriles, using ethyl dichlorophosphate/
DBU as a highly effective agent for the dehydration of
entry 10.11
b Isolated yield of purified product.
Synlett 2007, No. 8, 1317–1319 © Thieme Stuttgart · New York

LETTER
One-Pot Conversion of Aldehydes into the Corresponding Nitriles
(10) Satisfactory spectral and LC-MS analytical data were
1319
aldoxime intermediates. The mild reaction conditions of
this method enabled us to prepare a large variety of nitriles
from readily available aldehydes in high to excellent
yields. As a supplement to those existing one-pot proto-
cols, the current procedure appears to be particularly
valuable for synthesizing the nitriles bearing labile func-
tionalities.16
obtained for all products; all known nitriles showed physical
and spectral properties identical to those reported in the
literature.
(11) For the preparation of compound 3, see: Falorni, M.;
Giacomelli, G.; Porcheddu, A.; Teddei, M. J. Org. Chem.
1999, 64, 8962.
(12) Monica, C. D.; Randazzo, A.; Bifulco, G.; Cimino, P.;
Aquino, M.; Izzo, I.; Riccardis, F. De; Luigi, G. P.
Tetrahedron Lett. 2002, 43, 5707.
(13) Costello, G. F.; James, R.; Shaw, J. S.; Slater, A. M.;
Stutchbury, N. C. J. J. Med. Chem. 1991, 34, 181.
(14) Liskamp R. M. J., Boiejen A.; Eur. J. Org. Chem.; 1999,
2127.
Acknowledgment
We are grateful to the National Science Council of Republic of
China, National Dong-Hwa University and National Health Re-
search Institutes for financial support.
(15) Kohrt A., Hartke K.; Liebigs Ann. Chem.; 1992, 6: 595.
(16) A representative experimental procedure is described for the
preparation of benzonitrile (2). To a solution of
benzaldehyde (1, 0.2 g, 1.88 mmol) in CH2Cl2 (8 mL),
powdered 3 Å MS (120 mg), 1.2 equiv of NH2OH·HCl
(0.157 g, 2.26 mmol) and 5 equiv of DBU (1.43 g, 9.42
mmol) were successively added in one portion. The reaction
mixture was stirred at r.t. for 10 h, cooled in an ice-water
bath to 5 °C, and 1.5 equiv of EtOPOCl2 (0.46 g, 2.83 mmol)
were added. Then, stirring at r.t. was continued for an
additional 5 h. The mixture was then quenched with aq
NH4Cl, extracted with CH2Cl2 and subjected to
chromatographic purification on silica gel (15% EtOAc in
hexane) to afford 2 in 96% yield (0.186 g), whose spectral
data (IR, 1H NMR and 13C NMR) were identical to those of
the authentic sample.
References and Notes
(1) Friedrich, K.; Wallensfels, K. The Chemistry of the Cyano
Group; Rappoport, Z., Ed.; Wiley-Interscience: New York,
1970.
(2) Coskun, N.; Arikan, N. Tetrahedron 1999, 55, 11943.
(3) Boruah, M.; Knowar, D. J. Org. Chem. 2002, 67, 7138.
(4) (a) Erman, M. B.; Snow, J. W.; Williams, M. J. Tetrahedron
Lett. 2000, 41, 6749. (b) Talukar, S.; Hsu, J. L.; Chou, T. C.;
Fang, J. M. Tetrahedron Lett. 2001, 42, 1103.
(5) Foley, P. J. J. Org. Chem. 1969, 34, 2805.
(6) For examples, see: (a) Sandnya, A. Synthesis 1982, 190.
(b) Feng, J. C.; Lin, G.; Dia, L.; Bian, N. S. Synth. Commun.
1998, 28, 3765. (c) Das, B.; Madhusudhan, P.; Venkataiah,
B. Synlett 1999, 1569. (d) Kumar, H. M. S.; Reddy, B. V. S.;
Deddy, P. T.; Yadav, J. S. Synthesis 1999, 586. (e) Sharghi,
H.; Sarvari, M. H. Tetrahedron 2002, 58, 10323.
(f) Koshima, H.; Hamada, M.; Tani, M.; Iwasaki, S.; Sato, F.
Heterocycles 2002, 57, 2145. (g) Srinivas, K. V. N. S.;
Mahender, I.; Das, B. Chem. Lett. 2003, 32, 738.
(h) Ballini, R.; Fiorini, D.; Palmieri, A. Synlett 2003, 1841.
(i) Sharghi, H.; Sarvari, M. H. Synthesis 2003, 243; and
references cited therein.
(7) Kuo, C. W.; Zhu, J. L.; Wu, J. D.; Chu, C. M.; Yao, C. F.;
Shia, K. S. Chem. Commun. 2007, 301.
(8) Both PhCH=NOPO(OEt)2 and PhCH=NOH were obtained
as the single stereoisomers. The stereochemistry remains to
be determined.
(9) An optimized amount of 3 Å MS was used. It was found that
at least 120 mg of 3 Å MS was required for a quantitative
conversion of 1.50 mmol of benzaldehyde (1) into
benzonitrile (2).
Benzonitrile(2): IR (KBr): 2228, 1701, 1597, 1583, 1489,
1447 cm–1. 1H NMR (300 MHz, CDCl3): d = 7.56–7.46 (m,
3 H), 7.43–7.32 (tm, J = 7.5 Hz, 2 H). 13C NMR (75 MHz,
CDCl3): d = 132.8, 132.0, 129.1, 118.8, 112.2. GC-MS:
m/z = 103.5 [M]+.
(S)-2-(tert-Butoxycarbonylamino)propanenitrile (4): IR
(KBr): 3317, 2979, 2260, 1680 cm–1. 1H NMR (400 MHz,
CDCl3): d = 1.46 (s, 9 H), 1.53 (d, J = 7.2 Hz, 3 H), 4.61 (br
s, 1 H), 4.99 (m, 1 H). 13C NMR (100 MHz, CDCl3): d =
19.6, 28.2, 37.6, 81.2, 119.6, 154.1. LC-MS (ES): m/z = 193
[M + 23]+; mp 105–106 °C; [a]D25 –24.5 (c 2.5, CHCl3)
{Lit.15 [a]D20 –24.6 (c 2.5, CHCl3)}.
(S)-2-(tert-Butoxycarbonylamino)-3-phenylpropanenitrile
(6): IR (KBr): 3353, 3065, 2248, 1691 cm–1. 1H NMR (400
MHz, CDCl3): d = 1.45 (s, 9 H), 3.08 (m, 2 H), 4.84 (m, 1 H),
4.95 (m, 1 H), 7.25–7.40 (m, 5 H). 13C NMR (100 MHz,
CDCl3): d = 28.2, 39.2, 43.4, 81.3, 118.4, 127.9, 129.0,
129.5, 133.9, 154.1. LC-MS (ES): m/z 246 [M]+; mp 114–
115 °C; [a]D25 –16.4 (c 0.98, dioxane) {Lit.14 [a]D25 –16.4 (c
0.98, dioxane)}.
Synlett 2007, No. 8, 1317–1319 © Thieme Stuttgart · New York

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