Highly efficient Pd-catalyzed synthesis of nitriles from aldoximes

Article abstract of DOI:10.1016/j.tetlet.2009.01.150

An expedient method of Pd-catalyzed conversion of aldoxime into nitrile was developed. The reaction was carried out under the influence of Pd(OAc)₂/PPh₃ in refluxing CH₃CN to provide good to high yields. The use of Cs₂CO₃ (0.1-0.5 equiv) was crucial in some cases.

Full text of DOI:10.1016/j.tetlet.2009.01.150

Tetrahedron Letters 50 (2009) 1717–1719
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Highly efficient Pd-catalyzed synthesis of nitriles from aldoximes
*
Hoo Sook Kim, Sung Hwan Kim, Jae Nyoung Kim
Department of Chemistry and Institute of Basic Science, Chonnam National University, Gwangju 500-757, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
An expedient method of Pd-catalyzed conversion of aldoxime into nitrile was developed. The reaction
was carried out under the influence of Pd(OAc)2/PPh3 in refluxing CH3CN to provide good to high yields.
The use of Cs2CO3 (0.1–0.5 equiv) was crucial in some cases.
Received 26 December 2008
Revised 22 January 2009
Accepted 25 January 2009
Available online 5 February 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Palladium
Nitriles
Aldoximes
Palladium-catalyzed reactions of oxime derivatives can be classi-
fied into a few categories.1–5 Allylationof oximecan be carried out by
bond of 1 to Pd(0) to form the p-allylpalladium complex (I), (ii)
deprotection to oxime by trace water in the reaction mixture,2,8
(iii) oxidative addition of N–O bond of oxime to Pd(0),3 and (iv)
the following typical b-H elimination pathway to form nitrile 2a.
Actually, the reaction of p-nitrobenzaldoxime ethyl ether did not
produce any trace amounts of 2a under the same conditions. The
results state that Pd-catalyzed deprotection of allyl ether and the
following Pd-catalyzed dehydration to nitrile could be the plausi-
ble mechanism.
the reaction with p
-allylpalladium complex.1 Deprotection of allyl
oxime to oxime can also be catalyzed by Pd under Et3N/HCOOH con-
ditions.2 Recently, Heck-type cyclizations of oxime ether have been
reported.3 Various Pd-catalyzed ortho-functionalizations via C–H
activation have been studied recently.4 However, conversion of
oxime or its derivatives into nitrile with the aid of Pd catalyst has
not been reported, to the best of our knowledge.6 Although many
methods for the conversion of oxime or its derivative into nitrile
has been reported,7 the synthesis of nitrile using transition metal
catalyst is somewhat limited. The use of PtCl4(EtCN)2,6 [RuCl2(p-cym-
The interesting results made us to investigate Pd-catalyzed gen-
eration of nitrile from aldoxime (Scheme 2), and we wish to report
herein the preliminary successful results. We examined the reac-
tion of p-nitrobenzaldehyde oxime (5a) and obtained p-nitro-
benzonitrile (2a) in moderate yield (67%) under the influence of
Pd(OAc)2 (10 mol %)/PPh3 (20 mol %) in toluene at refluxing tem-
perature for 24 h (entry 1 in Table 1). Fortunately, the yield was in-
creased to 90% when we replace the solvent to CH3CN within short
time (3 h), as shown in Scheme 2 and in Table 1 (entry 2).11 The
conversion was completely ineffective without Pd catalyst (entry
3). The use of other Pd catalysts including PdCl2 (entry 4) and
Pd(PPh3)4 (entry 5), other phosphine ligands such as P(o-tolyl)3
(entry 6) or PBu3 (entry 7) did not improve the yield of 2a. The
reaction mechanism could be regarded as shown in Scheme 2,
which involve the intermediate (IV). As in the Pd-catalyzed b-car-
bon elimination of cyclobutanone O-benzyloximes,5b b-H elimina-
tion can explain the formation of nitrile.12 As given in Table 1, the
best yield was observed under the conditions comprising
Pd(OAc)2/PPh3 in refluxing CH3CN (Conditions A, entry 2). This is
the first successful results on Pd-catalyzed dehydration of ben-
zaldoxime into nitrile.
7f
ene)]2,7a,b (HO)ReO3,7c Ga(OTf)3,7d W–Sn hydroxide7e, and Cu(OAc)2
has been reported.
During our recent studies on the Pd-catalyzed decarboxylative
protonation reaction,8 we imagined the possibility of allyl group
migration from oxygen to carbon as shown in Scheme 1. We chose
p-nitrobenzaldoxime allyl ether (1) as the model substrate based
on the fact that p-nitro group can stabilize the Pd-intermediates
as in recent papers of Tunge and co-workers.9 Initially formed
p-
allylpalladium complex (I) could be changed to (II), which might
be converted into nitroso compound (III) and produced eventually
allyl oxime 4. However, we did not observe the formation of 4 at
all. Instead, we isolated p-nitrobenzonitrile (2a, 26%) and cinnamyl
derivative 3 (8%),10 together with recovered starting material 1
(30%).
The mechanism for the formation of 2a from 1 could be postu-
lated as depicted in Scheme 1: (i) an oxidative addition of O-allyl
Encouraged by the results we examined various arylaldoxime
* Corresponding author. Tel.: +82 62 530 3381; fax: +82 62 530 3389.
E-mail address: kimjn@chonnam.ac.kr (J.N. Kim).
derivatives 5b–j and cinnamyl oxime 5k.11 When the aromatic nu-
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.01.150

1718
H. S. Kim et al. / Tetrahedron Letters 50 (2009) 1717–1719
H
H
OH
Pd
Pd(0)
(I)
OH
Ar
N
Ar
Ar is 4-nitrophenyl
N
- H2O, - Pd(0)
Pd(0)
H
H
Pd(OAc)2 (10 mol%)
PPh3 (20 mol%)
CN
O
O
Ph
N
N
1 (30%)
+
+
O
toluene, reflux, 24 h
O2N
N
O
O2N
3 (8%)
2a (26%)
1
Pd(0)
H
H
H
NO
OH
N
O
N
O
N
Pd
- Pd(0)
O
Pd O
N
O
N
O
N
O
O2N
O
(III)
(I)
(II)
4 (not formed)
Scheme 1.
H
H
OH
Pd
Pd(OAc)2 (10 mol%)
PPh3 (20 mol%)
CN
OH
β-H elimination
N
N
CH3CN, reflux, 3 h
O2N
- Pd(0), - H2O
O2N
O2N
5a
2a (90%)
(IV)
Scheme 2.
Table 1
Optimization of conditions for the conversion of 5a to 2a and 5e to 2e
Entry
Compound
Conditions
Yield (%)
1
5a
5a
5a
5a
5a
5a
5a
5a
5e
5e
Pd(OAc)2 (10 mol %), PPh3 (20 mol %), toluene, reflux, 24 h
Pd(OAc)2 (10 mol %), PPh3 (20 mol %), CH3CN, reflux, 3 h
no Pd catalyst, PPh3 (20 mol %), CH3CN, reflux, 24 h
PdCl2 (10 mol %), PPh3 (20 mol %), CH3CN, reflux, 24 h
Pd(PPh3)4 (10 mol %), PPh3 (20 mol %), CH3CN, reflux, 16 h
Pd(OAc)2 (10 mol %), P(o-tol)3 (20 mol %), CH3CN, reflux, 3 h
Pd(OAc)2 (10 mol %), PBu3 (20 mol %), CH3CN, reflux, 18 h
Pd(OAc)2 (10 mol %), PPh3 (20 mol %), Cs2CO3 (0.1 equiv), CH3CN, 80 °C, 1 h
Pd(OAc)2 (10 mol %), PPh3 (20 mol %), CH3CN, reflux, 4 h
Pd(OAc)2 (10 mol %), PPh3 (20 mol %), Cs2CO3 (0.1 equiv), CH3CN, reflux, 1 h
67
90
0
85
86
83
82
87
49
83
2a,b
3
4
5
6
7
8
9
10c
a
Conditions A.
b
c
Without PPh3 the reaction required longer time (8 h, 84%).
Conditions B.
cleus has a strong electron-withdrawing substituent, the yield of
oxime was good to high (entries 1–4 in Table 2). However, 2,6-dic-
hlorobenzaldoxime (5e) showed sluggish reactivity under the con-
ditions (entry 9 in Table 1). Thus, we used Cs2CO3 (0.1 equiv) as in
entry 10 in Table 1 (vide supra) and could improve the yield
(Conditions B) although the role of Cs2CO3 is not clear at this
stage. Thus, we used variable amounts of Cs2CO3 (0.1–0.5 equiv)
for the substrates which showed sluggish reactivity under the
conditions A such as 5e–h, and E-5j. The results are summarized
in Table 2.
The reaction of 5g required long reaction time for the comple-
tion (entry 7). The reaction of cinnamyl oxime (5k) also showed
same reactivity to produce 2k in high yield (entry 12). It is interest-
ing to note that both reactions of E- and Z-form of 2,4,6-trim-
ethylbenzaldoxime (5j) produced nitrile 2j in similar yields
(entries 10 and 11). From the results, we have to reconsider our
proposed mechanism (vide supra, Scheme 2) in part. The possibil-
ity involving the Pd-catalyzed H2O transfer from oxime to nitrile,
as shown in Scheme 3, could not be excluded at this stage. This
type of mechanism was suggested by Maffioli et al. very recently
in their PdCl2-catalyzed reversible dehydration of amides.13 Thus,
the clarification of the final mechanism deserved further stud-
ies.14–16
In summary, we disclosed the first successful Pd-catalyzed
dehydration of aldoximes into nitriles. The plausible mechanism
involved an oxidative addition of N–O bond to Pd(0) and the fol-
lowing typical b-H elimination pathway for most of the E-oximes.
Irrespective of the mechanism as well as the configuration of
oxime, Pd-catalyzed dehydration of aldoximes occurred very easily
under mild conditions.

H. S. Kim et al. / Tetrahedron Letters 50 (2009) 1717–1719
1719
Table 2
References and notes
Pd-catalyzed dehydration of aldoximes.
1. For the Pd-assisted allylation of oximes, see: (a) Miyabe, H.; Yoshida, K.; Reddy,
V. K.; Matsumura, A.; Takemoto, Y. J. Org. Chem. 2005, 70, 5630–5635; (b)
Miyabe, H.; Matsumura, A.; Yoshida, K.; Yamauchi, M.; Takemoto, Y. Synlett
2004, 2123–2126.
2. For deprotection of allyl group, see: Yamada, T.; Goto, K.; Mitsuda, Y.; Tsuji, J.
Tetrahedron Lett. 1987, 28, 4557–4560.
Entry
1
Aldoximea
Conditions
A(3 h)
Nitrileb (%)
CH=NOH
.
2a (90)
O2N
O2N
5a
3. For Heck type cyclizations, see: (a) Ichikawa, J.; Nadano, R.; Ito, N. Chem.
Commun. 2006, 4425–4427; (b) Ohno, H.; Aso, A.; Kadoh, Y.; Fujii, N.; Tanaka, T.
Angew. Chem., Int. Ed. 2007, 46, 6325–6328; (c) Zhu, J.-L.; Chan, Y.-H. Synlett
2008, 1250–1254; For the Pd-catalyzed amino-Heck reactions of oxime
derivatives, see: (d) Narasaka, K. Pure Appl. Chem. 2003, 75, 19–28; (e)
Kitamura, M.; Zaman, S.; Narasaka, K. Synlett 2001, 974–976; (f) Kitamura, M.;
Narasaka, K. Chem. Rec. 2002, 2, 268–277. and further references cited therein.
4. For C–H activations, see: (a) Desai, L. V.; Hull, K. L.; Sanford, M. S. J. Am. Chem.
Soc. 2004, 126, 9542–9543; (b) Thu, H.-Y.; Yu, W.-Y.; Che, C.-M. J. Am. Chem. Soc.
2006, 128, 9048–9049; (c) Desai, L. V.; Malik, H. A.; Sanford, M. S. Org. Lett.
2006, 8, 1141–1144; (d) Thirunavukkarasu, V. S.; Parthasarathy, K.; Cheng, C.-
H. Angew. Chem., Int. Ed. 2008, 47, 9462–9466.
5. For the miscellaneous reactions of oximes, see: (a) Jiang, D.; Peng, J.; Chen, Y.
Org. Lett. 2008, 10, 1695–1698; (b) Nishimura, T.; Nishiguchi, Y.; Maeda, Y.;
Uemura, S. J. Org. Chem. 2004, 69, 5342–5347; (c) Grigg, R.; Markandu, J.
Tetrahedron Lett. 1991, 32, 279–282; (d) Suzuki, O.; Hashiguchi, Y.; Inoue, S.;
Sato, K. Chem. Lett. 1988, 291–294; (e) Miyabe, H.; Yamaoka, Y.; Naito, T.;
Takemoto, Y. J. Org. Chem. 2004, 69, 1415–1418.
CH=NOH
2
3
4
5
A(3 h)
A(2 h)
A(1 h)
B (1 h)c
2b (81)
2c (87)
2d (92)
2e (83)
5b
NO2
CH=NOH
5c
CH=NOH
O2N
Cl
Cl
Cl
5d
CH=NOH
Cl
5e
CH=NOH
6
B (8 h)d
B (80 h)d
B (8 h)d
A(7 h)
2f (88)
2g (90)
2h (88)
2i (87)
2j (87)
[6]. For ligand-mediated dehydration of aldoxime with nitrile complex trans-
[PtCl4(EtCN)2], see: Makarycheva-Mikhailova, A. V.; Bokach, N. A.; Haukka,
M.; Kukushkin, V. Y. Inorg. Chim. Acta 2003, 356, 382–386.
MeO
5f
CH=NOH
7. For examples, on the synthesis of nitriles from oximes, see: (a) Yang, S. H.;
Chang, S. Org. Lett. 2001, 3, 4209–4211; (b) Choi, E.; Lee, C.; Na, Y.; Chang, S. Org.
Lett. 2002, 4, 2369–2371; (c) Ishihara, K.; Furuya, Y.; Yamamoto, H. Angew.
Chem., Int. Ed. 2002, 41, 2983–2986; (d) Yan, P.; Batamack, P.; Prakash, G. K. S.;
Olah, G. A. Catal. Lett. 2005, 101, 141–143; (e) Yamaguchi, K.; Fujiwara, H.;
Ogasawara, Y.; Kotani, M.; Mizuno, N. Angew. Chem., Int. Ed. 2007, 46, 3922–
3925; (f) Attanasi, O.; Palma, P.; Serra-Zanetti, F. Synthesis 1983, 741–742; (g)
Maeyama, K.; Kobayashi, M.; Kato, H.; Yonezawa, N. Synth. Commun. 2002, 32,
2519–2525; (h) Konwar, D.; Boruah, R. C.; Sandhu, J. S. Tetrahedron Lett. 1990,
31, 1063–1064; (i) Hart-Davis, J.; Battioni, P.; Boucher, J.-L.; Mansuy, D. J. Am.
Chem. Soc. 1998, 120, 12524–12530; (j) Supsana, P.; Liaskopoulos, T.; Tsoungas,
P. G.; Varvounis, G. Synlett 2007, 2671–2674. and further references cited
therein.
7
5g
CH=NOH
8
Ph
N
5h
CH=NOH
9
5i
H
OH
B(12 h)c
N
10
8. For our recent contribution on Pd-mediated decarboxylative protonation and
allylation, see: Gowrisankar, S.; Kim, K. H.; Kim, S. H.; Kim, J. N. Tetrahedron Lett.
2008, 49, 6241–6244. and further references on Pd-mediated protonation and
allylation reactions were cited therein.
E-5j
H
9. For the Pd-mediated decarboxylative allylation and related reactions involving
nitro arene or pyridine moiety, see: (a) Waetzig, S. R.; Tunge, J. A. J. Am. Chem.
Soc. 2007, 129, 14860–14861; (b) Waetzig, S. R.; Tunge, J. A. J. Am. Chem. Soc.
2007, 129, 4138–4139.
10. Formation of cinnamyl compound 3 was very unusual. The result in CH3CN was
almost similar to that of the reaction in toluene. The phenyl moiety must be
derived from PPh3; however, detailed mechanism and scope of this novel
finding needs further study. For the use of tetraarylphosphonium halides as
arylating reagents in Pd-catalyzed Heck and cross-coupling reactions, see:
Hwang, L. K.; Na, Y.; Lee, J.; Do, Y.; Chang, S. Angew. Chem., Int. Ed. 2005, 44,
6166–6169.
N
OH
Z-5j
11
A(1 h)
A(3 h)
2j (83)
2k (91)
CH=NOH
12
5k
a
The configuration of oximes 5a–k is E-form (>95%) except Z-5j (entry 11).
Isolated yield.
Cs2CO3 (0.1 equiv) was used.
b
c
d
Cs2CO3 (0.5 equiv) was used.
11. Typical procedure for the conversion of p-nitrobenzaldoxime (5a) into p-
nitrobenzonitrile (2a):
A stirred mixture of p-nitrobenzaldoxime (83 mg,
0.5 mmol), Pd(OAc)2 (11 mg, 10 mol %), and PPh3 (26 mg, 20 mol %) in CH3CN
(1.5 mL) was heated to reflux for 3 h. The reaction mixture was filtered through
a Celite pad, washed with EtOAc, and the solvent was removed. After column
chromatographic purification process (hexanes/EtOAc, 8:1), analytically pure
p-nitrobenzonitrile was isolated, 67 mg (90%) as a white solid.
H
Ar
H
Ar
NH2
Me
N
"Pd"
??
N
+
12. For the reactions involving L–Pd–OH intermediate, see: (a) Hosokawa, T.;
Sugafuji, T.; Yamanaka, T.; Murahashi, S.-I. J. Organomet. Chem. 1994, 470, 253–
255; (b) Kim, S. H.; Lee, H. S.; Kim, S. H.; Kim, J. N. Tetrahedron Lett. 2008, 49,
5863–5866.
13. For the reversible dehydration of primary amides with PdCl2 in aqueous
acetonitrile, see: Maffioli, S. I.; Marzorati, E.; Marazzi, A. Org. Lett. 2005, 7,
5237–5239.
N
N
O
HO
Me
Me
OH
Scheme 3.
14. For the possibility of anti-b-hydride elimination, see: Schwarz, I.; Braun, M.
Chem. Eur. J. 1999, 5, 2300–2305. and further references cited therein.
15. The reaction of acetophenone oxime under the same reaction conditions
(CH3CN, 0.1 equiv of Cs2CO3, reflux, 36 h) showed no reaction.
16. During the evaluation process of this Letter, we carried out the reaction of
phenylacetaldehyde oxime (E/Z = 5:4 mixture), a typical aliphatic oxime, and
obtained benzyl cyanide in 56% under the same conditions given in Table 2
(conditions B with 0.5 equiv of Cs2CO3, 3 h).
Acknowledgments
This work was supported by the Korea Research Foundation
Grant funded by the Korean Government (MOEHRD, KRF-2008-
313-C00487). Spectroscopic data was obtained from the Korea Ba-
sic Science Institute, Gwangju branch.