Palladium(II)-mediated nucleophilic cyanation of 4-substituted quinoline 1-oxide in tue presence of trimethylsilyl cyanide and an oxidant

Article abstract of DOI:10.3987/COM-04-10228

Reaction of 4-substituted (electron-releasing group) quinoline 1-oxides (1) with trimethylsilyl cyanide in the presence of palladium(II) acetate and DDQ gave 2-cyano-4-substituted quinoline 1-oxides (2) in THF in moderate yields. It was reasoned that this

Full text of DOI:10.3987/COM-04-10228

HETEROCYCLES, Vol. 63, No. 12, 2004, pp. 2859 - 2862
Received, 13th September, 2004, Accepted, 28th October, 2004, Published online, 29th October, 2004
PALLADIUM(II)-MEDIATED NUCLEOPHILIC CYANATION OF
4-SUBSTITUTED QUINOLINE 1-OXIDE IN THE PRESENCE OF
TRIMETHYLSILYL CYANIDE AND AN OXIDANT
Yoshinobu Tagawa,a* Yoshitaka Higuchi,a Kenji Yamagata,a Kazuhiko Shibata,b
and Daisuke Teshimac
aFaculty of Pharmaceutical Sciences, Fukuoka University, Nanakuma 8-19-1,
Jonan-ku, Fukuoka 814-0180, Japan
bDepartment of Hospital Pharmacy, Okayama University Hospital, Okayama,
Japan
cDepartment of Clinical Pharmacy, School of Pharmacy, Shujitsu University,
Okayama, Japan
Abstract- Reaction of 4-substituted (electron-releasing group) quinoline 1-oxides
(1) with trimethylsilyl cyanide in the presence of palladium(II) acetate and DDQ
gave 2-cyano-4-substituted quinoline 1-oxides (2) in THF in moderate yields.
It was reasoned that this reaction proceeds through palladium-catalyzed
dehydrosilylation.
Cyanation is one of the most useful synthetic methods for the formation of a carbon-carbon bond.
Two convenient procedures for introducing a cyano group into a heteroaromatic ring involve the
reaction of the cyanide ion with an N-oxide in the presence of an acylating agent (Reissert-type
reaction), or with an N-oxide quaternary salt, and the cyanation usually occurs in an α-position,
accompanied by deoxygenation of the N-oxide group.1 If it is possible for the N-oxide group to be left
intact after cyanation, the resulted α- or γ-cyanoheteroaromatic N-oxides will become much more
versatile for further chemical transformation than the corresponding deoxygenated products due to the
various reactivities of the N-oxide function. However, N-reoxygenation by peracids incurs some
difficulties in that hydrolysis, oxidation or rearrangement1b may possibly occur if the compounds have
substituents vulnerable to peracids. Therefore, exploring the reaction of heteroaromatic N-oxides with
nucleophile, not accompanied by deoxygenation of the N-oxide group, is desirable and theoretically
interesting.
However, reports on such cyanation not accompanied by deoxygenation of
heteroaromatic N-oxides are almost unavailable with the exception of the reaction of bi- and tricyclic
aromatic N-oxides with KCN in the presence of K3Fe(CN)6 to afford the corresponding α-
cyanoaromatic N-oxide in moderate yields.2 It has been recently reported that palladium(II) acetate
catalyzes dehydrosilylation of silyl enol ether in the presence of p-benzoquinone to giveα,β-
unsaturated carbonyl compounds,3 which reaction led us to embark upon the reaction of the

trimethylsilyloxy adduct of heteroaromatic N-oxide with palladium(II) acetate in the presence of an
oxidant.
In this report, we would like to present the reaction of 4-substituted quinoline 1-oxide (1) with
trimethylsilyl cyanide in the presence of palladium(II) acetate and 2,3-dichloro-5,6-dicyano- 1,4-
benzoquinone (DDQ) as an oxidant in THF to give 2-cyano-4-substituted quinoline 1-oxides (2). The
general procedure of the present reaction is as follows: 1 (1.5 mmol) was stirred with trimethylsilyl
cyanide (3 mmol) in THF at room temperature for 1 h under N2, followed by the addition of
palladium(II) acetate (0.15 mmol) and stirring for 1 h and successively the addition of DDQ (0.75
mmol) and then the mixture was further stirred at room temperature for 1 day. Usual work-up of
chloroform extraction and SiO2-purification gave 2 in the yields shown in Table 1.
Table 1 Reaction of 4-substituted quinoline 1-oxides (1) with Me3SiCN
in the presence of Pd(OAc)2 and DDQ
R
R
1) Me3SiCN, THF, rt, 1 h
2) Pd(OAc)2, DDQ, rt, 1 day
N
O
N
O
CN
2
1
Temp. (℃)
R
H
Time (h) Equiv. of Pd(OAc)2
Yield (%)
Product No.
8
354
9
0
rt
rt
24
2a
24
0.1
rt
rt
24
24
0
2b
2c
455
Me
0.1
rt
rt
40
66
46b)
51b)
24
24
0
OMe6
NMe2
0.1
rt
rt
24
24
0
7
2d
2e
0.1
24
24
0c)
0
0.1
rt
rt
EWGa)
0c)
a) EWG = electron-withdrawing group, NO28 and CHO9 groups
b) The yields include also that of the deoxygenated product (2f) in this case.
Formation ratio, N-oxide : deoxygenated product = 1 : 4 ~ 1 : 5
c) starting material recovery
As can be seen from Table 1, the reaction of 1 having an electron-releasing group at the 4-position of
the quinoline nuclei in the presence of a catalytic amount of palladium(II) acetate (0.1 eq.) provided the
corresponding 2-cyanoquinoline 1-oxides in better yields than the reaction in the absence of
palladium(II) acetate, however, the reaction of 1 having electron-withdrawing groups at the 4-position
and that of pyridine 1-oxide did not proceed at all. It is conceivable as a reaction mechanism that in
the reaction without palladium(II) acetate, the cyano anion attacks the carbon atom at the 2-position
which is activated by both the electron-releasing group at the 4-position and the trimethylsilyloxy
group, and then dehydrosilylation takes place by oxidant (DDQ) to give the products. On the other
hand, in the reaction using palladium(II) acetate more efficient dehydrosilylation would proceed
through metal exchange reaction between the trimethylsilyloxy group and palladium(II) acetate and

finally the resulted Pd(0) is reoxidized by DDQ to regenerate the active palladium(II) species (Scheme
1).3
R
R
R
Me3SiOAc
Pd(OAc)2
Me3SiCN
CN
CN
N
O
N
N
H
H
OSiMe3
O-PdOAc
DDQ
R
DDQ
+ Pd(0)
+
AcOH
N
O
CN
Scheme 1
EXPERIMENTAL
Melting points were measured on a Yanagimoto micro melting points apparatus and are uncorrected.
Spectral data were recorded in the following spectrometers: IR spectra, JASCO FT/IR-470Plus;
1H-NMR spectra, JEOL GX-400 (400MHz) and JEOL A-500 (500MHz); 13C-NMR spectra, JEOL
GX-400 (100MHz) and JEOL A-500 (125MHz); MS spectra, Shimadzu GC-MS QP5050 for EI-MS and
JMS-HX100 for FAB-MS. The H-COSY, DEPT and HMQC experiments were also used for the
assignments of the structures. The chemical shifts are given in the δscale. Elemental analyses were
performed on a Yanaco CHN CORDER MT-6 instrument. Medium-pressure liquid chromatography
(MPLC) was carried out with Yamazen 540 FMI-C pump and Wakogel FC-40 (20-40 μm, Wako).
Column chromatography was carried out with Kieselgel 60 (70-230 mesh, Merck). High-performance
thin layer chromatography (HPTLC) for the yields shown Table 1 was conducted on Shimadzu high
speed thin layer chromatoscanner (CS-9300PC) with the detector set at uv 254nm.
General procedure for reaction 4-substituted quinoline 1-oxides (1) with Me3SiCN in the presence
of Pd(OAc)2 and DDQ----- 1 (1.5 mmol) was stirred with trimethylsilyl cyanide (3 mmol) in THF at rt
for 1 h under N2, followed by the addition of palladium(II) acetate (0.15 mmol) and stirring for 1 h and
successively the addition of DDQ (0.75 mmol) and then the mixture was further stirred at rt for 1 day.
The catalyst was removed by filtration and the solvent was evaporated off. The residue was extracted
with CHCl3 and after removal of the solvent the residue was respectively post-treated in the manner as
shown below.
2-Cyano-4-methoxyquinoline 1-oxide (2c)
The residue was purified by medium-pressure liquid chromatography (AcOEt) to afford 2c (0.2 g, 66%
yield). mp 236-238 ℃(from benzene), Anal. Calcd for C11H8N2O2 : C, 66.00; H, 4.03; N, 13.99.
Found: C, 65.98; H, 4.07; N, 13.85. 1H-NMR(CDCl3): δ 4.09(3H, s, CH3), 6.81(1H, s, H-3),
7.76(1H, dd, J=7.9 and 7.9Hz, H-6), 7.86(1H, dd, J=7.6 and 7.6Hz, H-7), 8.24(1H, d, J= 8.2Hz, H-5),
8.70(1H, d, J= 9.2Hz, H-8). 13C-NMR(CDCl3): δ56.7(q, CH3), 101.5(d, C-3), 113.0(s, Ar), 120.3(d,

C-8), 123.1(d, C-5), 123.8(s, Ar), 130.3(d, C-6), 131.9(d, C-7), 141.6(s, Ar), 152.7(s, Ar). MS(FAB+):
201(M++H).
2-Cyano-4-dimethylaminoquinoline 1-oxide (2d) and 2-Cyano-4-dimethylaminoquinoline (2f)
The residue was purified by medium-pressure liquid chromatography to afford 2d (n-hexane:AcOEt =
5:1) and 2f (n-hexane:AcOEt = 10:1), 0.03g (10% yield) and 0.12g (41% yield), respectively.
Compound (2d): mp 145-146 ℃(from Et2O, yellow-green prisms). Anal. Calcd for C12H11N3O : C,
67.59; H, 5.20; N, 19.71. Found: C, 67.57; H, 5.29; N, 19.67. 1H-NMR(CDCl3): δ 3.03(6H, s, CH3
×2), 6.88(1H, s, H-3), 7.71(1H, dd, J=7.8 and 7.6Hz, H-6), 7.80(1H, dd, J=7.9 and 7.6Hz, H-7),
8.13(1H, d, J= 9.2Hz, H-5), 8.74(1H, d, J= 8.9Hz, H-8). 13C-NMR(CDCl3): δ44.2(q, CH3×2),
109.5(d, C-3), 113.2(s, Ar), 121.0(d, C-8), 125.3(d, C-5), 125.7(s, Ar), 129.4(d, C-6), 131.1(d, C-7),
142.0(s, Ar), 148.4(s, Ar). MS(FAB+): 214(M++H).
Compound (2f): mp 88-89 ℃(from petr.ether-Et2O, pale yellow prisms). Anal. Calcd for C12H11N3 : C,
73.02; H, 5.62; N, 21.30. Found: C, 73.16; H, 5.71; N, 21.30. 1H-NMR(CDCl3): δ 3.13(6H, s, CH3
×2), 6.98(1H, s, H-3), 7.54(1H, dd, J=7.8 and 7.6Hz, H-6), 7.71(1H, dd, J=7.9 and 7.5Hz, H-7),
8.04-8.07(2H, m, H-5 and H-8). 13C-NMR(CDCl3): δ43.7(q, CH3×2), 109.2(d, C-3), 118.1(s, Ar),
122.8(s, Ar), 124.6(d, C-8), 126.7(d, C-6), 130.2(d, C-7), 130.5(d, C-5), 149.8(s, Ar), 158.1(s, Ar).
MS(FAB+): 198(M++H).
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