,
2003, 13(6), 260–261
2
,4,4,6-Tetrabromocyclohexa-2,5-dienone in the presence of triphenylphosphine
as a specific reagent for nucleophilic substitution in cyanohydrins
Elena D. Matveeva,* Tatyana A. Podrugina, Elena V. Tishkovskaya and Nikolai S. Zefirov
Department of Chemistry M. V. Lomonosov Moscow State University, 119992 Moscow, Russian Federation.
1
0.1070/MC2003v013n06ABEH001830
A convenient method for the synthesis of α-bromonitriles from aliphatic cyanohydrins using the 2,4,4,6-tetrabromocyclohexa-2,5-
dienone complex with triphenylphosphine was developed.
Halonitriles can serve as starting materials for the synthesis of
heterocyclic systems and biologically active compounds.1
Published methods for the synthesis of halonitriles are based on
radical processes often leading to mixtures of isomers.3 The
methods based on nucleophilic substitution for the hydroxyl
group give low yields, or they are time-consuming multistage
processes.6
crotonic aldehyde cyanohydrin 3 occurs under mild conditions
at 5 °C in an inert atmosphere and completes in 1.5 h leading
to 4-bromopentene-2-nitrile with 82% yield. Analysis of the
H and C NMR spectra shows that the reaction product is a
mixture of cis-4a and trans-4b isomers in a 1:1 ratio (deter-
mined by GLC).
,2
–5
1
13
§
,7
OH
CN
Br
CN
Br
Previously, we found that 2,4,4,6-tetrabromocyclohexa-2,5-
dienone 1 in the presence of triphenylphosphine can be success-
fully used for the regio- and stereospecific substitution of bromine
Me
Me
Me
CN
3
4a
4b
8
for hydroxyl in alcohols. The above reagent can be employed
1
for the nucleophilic substitution of bromine for hydroxyl in
cyanohydrins in accordance with the following reaction scheme:
The H NMR spectra exhibited the signals of the vinyl protons
of 4-bromopentene-2-nitrile with the constant of spin–spin inter-
action J 10.81 Hz corresponding to a cis-configuration and the
signals with the constant J 16.21 Hz corresponding to a trans-
configuration (the ratio between the integrated intensities of
O
OH
Br
Br
RHC
+
Ph P +
cis:trans protons is 1:1). The C NMR signals with chemical
13
3
CN
shifts of 153 and 100 ppm correspond to the carbon atoms of a
double bond conjugated with the cyano group instead of the
Br Br
1
Table 1 Reaction times and yields of α-bromonitriles.
OH
Br
Br
Br
Br
Yields of
bp/°C
(Torr)
Compound
R
Time/h α-bromo-
Reference
RHC
+ Ph PO +
3
nitriles (%)
CN
2
2b
a
Me
Et
1
1
3
24
2
24
24
24
55
60
45
65
65
60
70
90
45
52 (60)
60 (27)
64 (20)
64 (20)
64 (11)
oil
mp 162
mp 79–80
oil
9
10
11
11
12
2
a–h
i
2c
2c
2d
2e
2f
Pr
It was found that an optimum ratio between the reagents
hydroxynitrile : tetrabromide 1 : triphenylphosphine) is 1:1.5:1.5.
The substitution for aliphatic cyanohydrins occurs regiospecifi-
cally with the formation of the only product, α-bromonitrile,
under mild conditions (0 °C, methylene chloride as a solvent).
The product structures were confirmed by H and C NMR
spectroscopy. The times of the reactions, the yields of α-bromo-
nitriles and some constants of the products are presented in
Table 1.
It follows from the above data that an increase of steric
hindrances at the α-carbon atom of cyanohydrins increases the
reaction time, but it has no influence on the yield of α-bromo-
nitriles.
Under similar conditions, the cyanohydrins of aromatic
aldehydes also interact with the complex of triphenylphosphine
and bromide 1 to form corresponding α-bromoarylacetonitriles
Table 1). In this case, the substitution reaction fully occurs
only for 24 h at room temperature. The yields of the products
depend on substituents in a benzene ring.
i
Pr
(
Pr
Ph
3-NO C H
4-BrC H
4-Me NC H 24
2
6
4
†
2g
2h
6 4
1
13
2 6 4
‡
‡
Selected spectral data.
1
For 2a: H NMR (400 MHz, CDCl3) d: 1.9 (d, 3H, Me), 4.3 (q, 1H,
1
3
CH). C NMR, d: 20.93 (Me), 23.84 (CH), 118.03 (CN).
1
For 2b: H NMR, d: 1.1 (t, 3H, Me), 2.1 (dt, 2H, CH ), 4.3 (t, 1H,
2
1
3
CH). C NMR, d: 11.28 (Me), 28.84 (CH ), 30.05 (CH), 117.10 (CN).
2
For 2c: 1H NMR, d: 1.15 (dd, 6H, 2Me), 2.2 (m, 1H, CH), 4.25
1
3
(d, 1H, CHBr). C NMR, d: 18.95 (Me), 19.45 (CH), 35.61 (CHBr),
1
16.42 (CN).
1
For 2d: H NMR, d: 1.0 (t, 3H, Me), 1.6 (dq, 2H, MeCH ), 2.1 (m,
2
13
2
2
H, CH ), 4.3 (t, 1H, CHCN). C NMR, d: 12.76 (Me), 20.19 (CH2),
2
†
(
6.85 (CH ), 38.18 (CH), 117.31 (CN).
2
For 2f: 1H NMR, d: 6.95 (s, 1H, CH), 7.08 (m, 3H, Ar), 7.8 (m, 1H, Ar).
1
13
For 2g: H NMR, d: 5.4 (s, 1H, CH), 7.39, 7.42, 7.46, 7.49 (Ar).
C
Substitution for the hydroxyl group in α,β-conjugated hydroxy-
nitriles is accompanied by allylic isomerisation. The reaction of
NMR, d: 26.56 (CH), 115.79 (CN), 124.77, 129.28, 132.47, 132.74 (Ar).
1
For 2h: H NMR, d: 2.91 (s, 1H, CH), 3.14 (s, 6H, 2Me), 6.68 (d, 2H,
Ar), 7.95 (d, 2H, Ar).
For 4a: H NMR (CDCl ) d: 1.84 (d, 3H, Me, J 6.67 Hz), 5.02 (m,
†
§
1
3
Synthesis of 2-alkylnitriles: 6.15 g (15 mmol) of compound 1 in 5 ml
of dichloromethane were added to 3.93 g (15 mmol) of PPh on cooling
in an inert atmosphere. After 10 min, 1 mmol of 2-hydroxyalkylnitrile
was added. At the end of reaction, the solvent was evaporated and the
residue was distilled.
Synthesis of 2-arylnitriles: 6.15 g (15 mmol) of compound 1 in 5 ml of
dichloromethane were added to 3.93 g (15 mmol) of PPh on cooling in
an inert atmosphere. After 10 min, 1 mmol of 2-hydroxyarylnitrile was
added. At the end of reaction, the solvent was evaporated and the residue
was purified by column chromatography.
3
2
3
3
4
4
1H, H , J
2
H ,H3
10.81 Hz, J 6.67 Hz, J
2
H ,H4
0.56 Hz), 5.29 (dd, 1H, H ,
0.56 Hz), 6.60 (t, 1H, H ,
3
3
4
3
3
3
J
3
H ,H4
10.81 Hz,
J
H ,H2
4
J = J
3
2
3
4
H ,H
H ,H
1
3
1
2
3
10.81 Hz). C NMR (CDCl ) d: 24.99 (C ), 42.39 (C ), 98.54 (C ),
153.20 (C ), 114.31 (C ).
3
4
5
1
3
For 4b: H NMR (CDCl ) d: 1.83 (d, 3H, Me, J 6.78 Hz), 4.65 (m,
3
4
2
3
3
3
4
1H, H ,
16.21 Hz, J
J
2
H ,H3
7.70 Hz,
J
2
H ,H4
1.15 Hz), 6.80 (dd, 1H, H ,
J
3
4
3
H ,H
3
4 3
3
H ,H2
7.81 Hz), 5.54 (dd, 1H, H , J
H4,H3
16.21 Hz, J
4
2
H ,H
1
3
1
2
3
1.15 Hz). C NMR (CDCl ) d: 24.10 (C ), 43.84 (C ), 100.27 (C ),
153.69 (C ), 116.14 (C ).
3
4
5
–
260 –
Matveeva, Elena D.
