An efficient one-step method for the conversion of β-(dimethylamino) styrenes into arylacetonitriles

Article abstract of DOI:10.1055/s-2005-918405

A new simple and efficient one-step method for the preparation of arylacetonitriles by reaction of β-(dimethylamino)styrenes with hydroxylamine hydrochloride in formic acid solution is described. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-918405

2830
SHORT PAPER
An Efficient One-Step Method for the Conversion of b-(Dimethylamino)sty-
renes into Arylacetonitriles
Conversionof
b
-(D
l
imethy
e
lamino)sty
x
renes intoA
e
rylacetonitr
y
iles M. Starosotnikov,* Alexander V. Lobach, Svyatoslav A. Shevelev
N. D. Zelinsky Institute of Organic Chemistry, Leninsky pr. 47, Moscow 119991, Russia
Fax +7(095)135 5328; E-mail: ams@fromru.com
Received 20 January 2005; revised 31 May 2005
We have now found a new efficient one-step method for
Abstract: A new simple and efficient one-step method for the prep-
aration of arylacetonitriles by reaction of b-(dimethylamino)sty-
renes with hydroxylamine hydrochloride in formic acid solution is
described.
the synthesis of arylacetonitriles based on b-(N,N-dimeth-
ylamino)styrenes 1 containing electron-withdrawing sub-
stituents in the benzene ring (Scheme 1). Substrates 1 are
easily obtained by the reaction of the corresponding sub-
stituted toluenes with N,N-dimethylformamide dimethyl
acetal (DMA DMF) in DMF with heating (1a9 and 1b10)
or in toluene at 20 °C (1c11).
Key words: acetals, arylacetonitriles, b-(dimethylamino)styrenes,
hydrolyses, nitriles
Compound 1d was prepared analogously. Further trans-
formations of enamines 1 to nitriles 2 (Scheme 1) were
carried out in boiling formic acid solution in the presence
of 30% mol excess of NH2OH·HCl (Table 1). The system
NH2OH·HCl–HCO2H has already been used before for
the preparation of aromatic and aliphatic nitriles from the
corresponding aldehydes.12 The products 2a–d obtained
are listed in Table 1.
Arylacetic acid derivatives and in particular arylacetoni-
triles are widely used as useful precursors in the synthesis
of heterocyclic compounds because of the active methyl-
ene fragment (especially with electron-withdrawing sub-
stituents in the aromatic ring), as well as the cyano group
which is able to undergo reactions with nucleophiles1 and
dipolar cycloaddition reactions.2 One of the classical
methods for the synthesis of arylacetonitriles is the reac-
tion of (halomethyl)benzenes3,4 or benzyl tosylates4,5 with
the cyanide ion. A not less important method for the prep-
aration of arylacetonitriles is the dehydration of the corre-
sponding arylacetaldoximes3,4,6,7 or primary amides.3–5 In
addition, a one-step method for the conversion of b-(N,N-
dimethylamino)styrenes to arylacetonitriles is described,8
which involves treatment of initial enamines with hydrox-
ylamine-O-sulfonic acid (HASA) in aqueous media.
The most probable mechanism for the formation of 2 from
1 (Scheme 2) includes the hydrolysis of the enamine 1 to
form aldehyde 3 (formic acid containing 2–5% of water
was used), which reacts with hydroxylamine to the corre-
sponding oxime 4. Under the reaction conditions, 4 is then
converted to arylacetonitrile 2. The reaction time does not
depend on the enamine structure and the nature of its sub-
stituents.
CH3
a
NMe2
CN
b
EWG
EWG
EWG
1
2
EWG = 4-NO2 (a); 2,4-(NO2)2 (b); 2,4,6-(NO2)3 (c); 2,6-(NO2)2-4-CO2Me (d).
Scheme 1 Reagents and conditions: a) DMA DMF, DMF or toluene; b) NH2OH·HCl, HCO2H, 100 °C.
NOH
NMe2
H+
NH2OH⋅HCl
CHO
HCO2H
EWG
EWG
EWG
H2O
1
3
4
N
OCH
CN
D
EWG
EWG
– HCO2H
H
O
2
Scheme 2
SYNTHESIS 2005, No. 17, pp 2830–2832
x
x.
x
x
.
2
0
0
5
Advanced online publication: 23.09.2005
DOI: 10.1055/s-2005-918405; Art ID: Z02105SS
© Georg Thieme Verlag Stuttgart · New York

SHORT PAPER
Conversion of b-(Dimethylamino)styrenes into Arylacetonitriles
2831
Table 1 Nitriles 2 from Enamines 1
Product Yield (%) Mp (°C)
Found
1H NMR, d (J = Hz)
Enamine (1)
Nitrile (2)
Reported
NMe2
NMe2
2a
49
107–109 108–11317 4.2 (s, 2 H, CH2), 7.75 (d, 2 Harom
J = 9.3), 8.25 (d, 2 Harom-, J = 9.3)
,
CN
O2N
O2N
2b
57
85–86
8918
4.5 (s, 2 H, CH2), 8.05 (d, 1 Harom,
CN
NO2
J = 8.9), 8.6 (d, 1 Harom, J = 8.9),
8.85 (s, 1 Harom
)
O2N
NO2
O2N
2ca
2da
76
92
160–162
–
4.35 (s, 2 H, CH2), 9.1 (s, 2 Harom)
NO2
NO2
NMe2
CN
NO2
O2N
NO2
NO2
O2N
67–68
–
4.0 (s, 3 H, CH3), 4.3 (s, 2 H, CH2),
8.8 (s, 2 Harom
NO2
)
NMe2
CN
NO2
MeO2C
NO2
MeO2C
a Satisfactory microanalyses obtained: C 0.13, H 0.16.
The formation of arylacetonitriles 2 from the enamines 1 It should be noted that benzo[d]isoxazole-3-carbalde-
under the action of HASA was considered8 not to proceed hydes are usually unstable and undergo deformylation
via the corresponding aldehydes despite the fact that the with opening of the isoxazole ring.14,15 That is why the
process is carried out in water in the presence of a strong transformation of aldehyde derivatives 6 to nitrile 7 shows
acid (HASA) and the initial hydrolysis of the enamine can the possibility of further functionalization of ben-
not be excluded. However, we believe that aldehydes 3 zo[d]isoxazoles in position 3 without recourse to the prep-
serve as intermediates in our case (see Scheme 2). This as- aration of the intermediate aldehyde.
sumption is proved by the fact that the reaction conditions
In summary, a new general method for the synthesis of
are suitable not only for the conversion of b-(dimethyl-
arylacetonitriles from b-(dimethylamino)styrenes was de-
amino)styrenes to arylacetonitriles. We also found that
veloped. It was shown also that other derivatives of aro-
some other aldehyde derivatives (acetals, imines) form ni-
matic and arylacetic aldehydes such as acetals and imines
triles under these conditions as well. Thus 2-(2,4,6-trini-
form the corresponding nitriles under the applied reaction
conditions.
trophenyl)methyl-1,3-dioxolane (5)11 forms nitrile 2c
under the same conditions (Scheme 3).
Mps were measured on a Boetius apparatus and are uncorrected. 1H
NO2
NO2
NMR spectra were recorded on a Bruker AC-200 spectrometer in
DMSO–CCl4 (1:1) mixture as a solvent. Chemical shifts are report-
ed in ppm downfield from TMS using the d scale. All reactions were
monitored by TLC using Silufol plates which were visualized with
UV light. Organic solvents and reagents were purified by the stan-
dard literature procedures. For all new compounds satisfactory mi-
croanalyses were obtained. Compounds 1a,9 1b,10 1c,11 and 4-
methyl-3,5-dinitrobenzoic acid16 were prepared as described be-
fore.
O
NH2OH⋅HCl
CN
HCO2H, 100 °C
O
O2N
NO2
O2N
NO2
2c, yield 73%
5
Scheme 3
The heteroaromatic nitrile, 4,6-dinitrobenzo[d]isoxazole-
3-carbonitrile (7), can be obtained under these conditions
from O-methyloxime 6a as well as from the cyclic acetal
6b, which were synthesized before,13 without separation
of the corresponding aldehyde (Scheme 4).
Methyl 4-[(E)-2-(Dimethylamino)ethenyl]-3,5-dinitrobenzene-
carboxylate (1d)
A mixture of 4-methyl-3,5-dinitrobenzoic acid (0.70 g, 3.1 mmol),
DMA DMF (0.7 mL, 5.2 mmol) and toluene (10 mL) was refluxed
for 8 h and then allowed to cool to r.t. The solvent was removed un-
der reduced pressure and EtOH (10 mL) was added to the residue.
The resulting precipitate was collected by filtration and recrystal-
lized from EtOH to give 1d; yield: 0.65 g (71%); mp 128–130 °C
(EtOH).
NO2
NO2
R
CN
NH2OH⋅HCl
N
N
HCO2H, 100 °C
O
O
O2N
O2N
1H NMR: d = 2.95 (s, 6 H, 2 CH3), 3.9 (s, 3 H, OCH3), 5.45 (d, 1 H,
J = 13.1 Hz), 6.8 (d, 1 H, J = 13.1 Hz), 8.3 (s, 2 Harom).
7, yield 58% (from 6a)
yield 72% (from 6b)
6a, R = CH=NOCH3
6b, R = 1,3-dioxolan-2-yl
Anal. Calcd for C12H13N3O6: C, 48.82; H, 4.44. Found: C, 48.62; H,
4.59.
Scheme 4
Synthesis 2005, No. 17, 2830–2832 © Thieme Stuttgart · New York

2832
A. M. Starosotnikov et al.
SHORT PAPER
Arylacetonitriles 2 from b-(Dimethylamino)styrenes 1; General
Procedure
(2) (a) Lwowski, W. In 1,3-Dipolar Cycloaddition Chemistry,
Vol. 1; Padwa, A., Ed.; Wiley: New York, 1984. (b)Albert,
A. Adv. Heterocycl. Chem. 1986, 40, 129. (c) Bast, K.;
Christl, M.; Huisgen, R.; Mack, W. Chem. Ber. 1972, 102,
2825. (d) Koguro, K.; Oga, T.; Mitsui, S.; Orita, R. Synthesis
1998, 910. (e) Finnegan, W. G.; Henry, R. A.; Lofquist, R. J.
Am. Chem. Soc. 1958, 80, 3908. (f) L’abbe, G.; Beenaerts,
L. Tetrahedron 1989, 45, 749. (g) L’abbe, G.; Bruynseels,
M.; Beenaerts, L.; Vandendriessche, A.; Delbeke, P.;
Toppet, S. Bull. Soc. Chim. Belg. 1989, 98, 343.
(h) Moderhack, D.; Beissner, A. J. Prakt. Chem./Chem.-Ztg.
1997, 339, 582. (i) Preu, L.; Beissner, A.; Moderhack, D. J.
Chem. Soc., Perkin Trans. 2 1998, 785.
A solution of the corresponding enamine (2 mmol) and
NH2OH·HCl (181 mg, 2.6 mmol) in 95–98% formic acid (15 mL)
was refluxed for 3 h and then allowed to cool to r.t. The mixture was
diluted with ice-water (60 mL), the precipitate formed was collected
by filtration and dried in air to give pure (NMR) nitrile. In the case
of compound 2d, the aqueous solution was extracted with EtOAc
(3 × 25 mL), the combined organic layers were washed with brine
and dried (Na2SO4). The solvent was removed in vacuum and the
residue was purified by column chromatography (silica gel, CHCl3)
to give pure (NMR) product as yellow oil that solidified on standing
(Table 1).
(3) Smith, P. A. S. In Open Chain Nitrogen Compounds, Vol. 1;
Benjamin: New York, 1965, Chap. 5, 209–231.
(4) Friedrich, K.; Wallenfels, K. In The Chemistry of the Cyano
Group; Rappoport, Z., Ed.; Wiley-Interscience: New York,
1970, Chap. 2, 67–122.
(5) Harrison, I. T.; Harrison, S. Compendium of Organic
Synthetic Methods, Vol. 1; Wiley: Interscience New York,
1971, Chap. 13, 457–478.
2-(2,4,6-Trinitrophenyl)acetonitrile (2c) from Acetal (5)
A solution of compound 5 (0.60 g, 2 mmol) and NH2OH·HCl (0.20
g, 2.8 mmol) in 95–98% formic acid (15 mL) was refluxed for 2 h
and then allowed to cool to r.t. The mixture was diluted with ice-wa-
ter (60 mL), the precipitate formed was filtered off and dried in air
to give pure (NMR) nitrile 2c (0.37 g, 73%). Mp and spectral char-
acteristics of the product were identical to those listed in Table 1.
(6) Metzger, H. In Methoden der Organischen Chemie
(Houben–Weyl), Vol. 10; Müller, E., Ed.; Thieme: Stuttgart,
1968, Part 4, 217–282.
4,6-Dinitrobenzo[d]isoxazole-3-carbonitrile (7)
A solution of compound 6a or 6b (2 mmol) and NH2OH·HCl (0.2 g,
2.8 mmol) in 95–98% formic acid (15 mL) was refluxed for 15 h
and then worked up as described above to give pure (NMR) nitrile
7. The yields are shown in Scheme 4; mp 147–149 °C.
(7) Naumov, Y. A.; Grandberg, I. I. Russ. Chem. Rev. 1966, 35,
9.
(8) Biere, H.; Russe, R. Tetrahedron Lett. 1979, 16, 1361.
(9) Bredereck, H.; Simchen, G.; Wahl, R. Chem. Ber. 1968, 101,
4048.
(10) Dean Toste, F.; Steel, I. W. J. Org. Prep. Proced. Int. 1995,
27, 576.
IR (KBr): 3100, 3080, 2264, 1608, 1560, 1544, 1356, 1340, 1248,
1068, 1016, 964, 932, 800, 744, 742, 692, 640 cm–1.
1H NMR: d = 9.0 (s, 1 Harom), 9.5 (s, 1 Harom).
(11) Vinogradov, V. M.; Dalinger, I. L.; Starosotnikov, A. M.;
Shevelev, S. A. Mendeleev Commun. 2000, 140.
(12) Olah, G. A.; Keumi, T. Synthesis 1979, 112.
(13) Vinogradov, V. M.; Dalinger, I. L.; Starosotnikov, A. M.;
Shevelev, S. A. Russ. Chem. Bull. (Engl. Transl.) 2001, 50,
464.
Anal. Calcd for C8H2N4O5: C, 41.04; H, 0.86. Found: C, 41.02; H,
0.82.
References
(1) (a) Hall, J. H.; Gisler, M. J. Org. Chem. 1976, 41, 3769.
(b) Mayers, A. I.; Sircar, J. C. In The Chemistry of the Cyano
Group; Rappoport, Z., Ed.; Wiley: Interscience New York,
1970, Chap. 8, 341–421. (c) Brenner, S.; Bovete, M.
Tetrahedron 1975, 31, 153.
(14) Burlinson, N. E.; Sitzman, M. E.; Kaplan, L. A.; Kayser, E.
J. Org. Chem. 1979, 44, 3695.
(15) Wunsch, K.-H.; Boulton, A. J. Adv. Heterocycl. Chem. 1967,
8, 277.
(16) Brueckner, H. Ber. Dtsch. Chem. Ges. 1875, 8, 1678.
(17) van Leusen, A. M.; Oomkes, P. G. Synth. Commun. 1980,
10, 399.
(18) Fairbourne, A.; Fawson, H. R. J. Chem. Soc. 1927, 49.
Synthesis 2005, No. 17, 2830–2832 © Thieme Stuttgart · New York