Preparation of 3-oxocyclohex-1-ene-1-carbonitrile

Article abstract of DOI:10.1055/s-2005-872177

Chromium trioxide oxidation of cyclohexenecarbonitrile efficiently provides analytically pure 3-oxocyclohex-1-ene-1-carbonitrile. The procedure is described in detail, providing a very reliable, one-step synthesis of a highly versatile oxonitrile. Georg T

Full text of DOI:10.1055/s-2005-872177

PRACTICAL SYNTHETIC PROCEDURES
3179
Preparation of 3-Oxocyclohex-1-ene-1-carbonitrile
P
F
reparation of
r
3-Oxoc
y
a
clohex-1-e
s
ne-1-carb
e
onitrile r F. Fleming,* Zhiyu Zhang, Guoqing Wei
Department of Chemistry and Biochemistry, Duquesne University, Pittsburgh, PA 15282, USA
Fax +1(412)3965683; E-mail: flemingf@duq.edu
Received 3 May 2005; revised 13 June 2005
PSP
No59
Abstract: Chromium trioxide oxidation of cyclohexenecarbonitrile efficiently provides analytically pure 3-oxocyclohex-1-ene-1-carboni-
trile. The procedure is described in detail, providing a very reliable, one-step synthesis of a highly versatile oxonitrile.
Key words: oxonitrile, nitrile, oxidation, synthesis
CN
CN
CrO3,
HN
N
–10 °C to –12 °C, CH2Cl2
1
O
2
Scheme 1 Allylic oxidation route to 3-oxocyclohex-1-ene-1-carbonitrile
3
-Oxoalkenenitriles are exceptional electrophiles. The More recently 3-oxocyclohex-1-ene-1-carbonitrile (2) has
synergistic influence of two strong electron-withdrawing featured in a multicomponent 1,2-1,4-Grignard addition-
groups generates an electron deficient alkene with excel- alkylation providing rapid access to cyclic nitriles of high
4
lent reactivity in numerous addition reactions (Scheme 2). molecular complexity. Sequential addition of two differ-
The exceptional electrophilicity is evident in the facile ent Grignard reagents triggers carbonyl addition followed
5
[
2+2] cycloaddition of 3-oxocyclohex-1-ene-1-carboni- by chelation-controlled conjugate addition, to generate a
1
2
trile (2) with alkenes and alkynes to give functionalized C-magnesiated nitrile containing three chiral centers
4.2.0]cyclooctanes (2 → 4 and 2 → 5), and in Diels–Al- (Scheme 2, 2 → 6). Intercepting the C-magnesiated nitrile
der cycloadditions which assemble functionalized cis- 6 with diverse electrophiles reveals a remarkable electro-
[
3
fused decalins (2 → 3).
phile-dependent stereoselectivity, with stereochemical re-
tention at the C–Mg bond for alkyl halides (6 → 8) and
stereochemical inversion for acyl cyanides (6 → 7). Re-
markably, the alkylation stereochemistry for alkyl halides
can be reversed through the sequential addition of butyl-
CN
CN
R3
lithium and alkyl halide to 6 which triggers alkylation
CN
CN
R2
HO
R1
through the corresponding N-lithiated nitrile.6
9
O
3
2
The versatility of 3-oxocyclohex-1-ene-1-carbonitrile (2)
has stimulated several syntheses of this valuable electro-
phile. Cyanide addition to the monoethylene ketal of cy-
clohexane-1,3-dione is reportedly capricious with better
reproducibility, and improved yields, being obtained from
the addition of diethylaluminum cyanide to 3-methoxycy-
clohexenone. Notwithstanding cost and safety issues,
the conjugate cyanation of Et AlCN to 3-methoxycyclo-
hexenone, or cyclohexenone followed by periodinane ox-
idation, currently provide the most effective routes to 3-
R = (CH2)4Cl
HO R1
hν,H2C=CH2
3
R X
O
4
8
CN
7
Mg
1
hν,
HC=CH
R MgX;
O
2CN
4
2
R X
R MgX
R
CN
R4
8
9
10
O
2
R1
6
CN
R2
2
1
1
R1
HO
7
O
5
oxocyclohex-1-ene-1-carbonitrile (2).
Scheme 2 Synthetic applications of 3-oxocyclohex-1-ene-1-carbo-
nitrile
A single-step, robust synthesis of 3-oxocyclohexene-1-
carbonitrile (2) is achieved by allylic oxidation of cyclo-
1
2
hexenecarbonitrile (1) (Scheme 1). Chromium trioxide-
1
3
3
,5-dimethylpyrazole complex is by far the best oxidant.
14
For comparison, selenium dioxide oxidation affords
35% of 3-hydroxy-1-cyclohexene-1-carbonitrile which
requires further oxidation15 to afford 2. Similarly, at-
tempted oxidation with palladium hydroxide and tert-bu-
SYNTHESIS 2005, No. 18, pp 3179–3180
x
x.
x
x
.
2
0
0
5
16
Advanced online publication: 17.08.2005
DOI: 10.1055/s-2005-872177; Art ID: Z09105SS
Georg Thieme Verlag Stuttgart · New York
©

3
180
F. F. Fleming et al.
PRACTICAL SYNTHETIC PROCEDURES
tylhydrogen peroxide,17 or with chromium hexacarbonyl Acknowledgment
1
8
and hydrogen peroxide, were ineffective despite being
effective with related cyclic 5- and 6-membered alkenes.
Financial support from the National Institutes of Health is gratefully
acknowledged.
The oxidation efficiency directly correlates with the qual-
ity of the chromium trioxide. Commercial chromium tri-
oxide is supplied as large flakes which must be ground to
a fine powder, to maximize the surface exposure, and then
thoroughly dried under vacuum (<5 mm/Hg) in a desicca-
tor containing phosphorous pentoxide (>16 h). The 3,5-
dimethylpyrazole, supplied as a white powder, is dried in
the same fashion. Once the oxidation is initiated the reac-
tion requires efficient stirring at –10 to –12 °C since oth-
erwise the reduced chromium species aggregates,
irreversibly trapping the organic material in an intractable
chromium matrix.
References
(
(
(
1) (a) Cantrell, T. S. Tetrahedron 1971, 27, 1227. (b) Agosta,
W. C.; Lowrance, W. W. Jr. Tetrahedron Lett. 1969, 3053.
2) Serebryakov, E. P.; Kulomzina-Pletneva, S. D.; Margaryan,
A. K. Tetrahedron 1979, 35, 77.
3) Yang, W. Q.; Chen, S. Z.; Huang, L. Chin. Chem. Lett. 1998,
9, 233; Chem. Abstr. 1999, 131, 736759.
(4) Fleming, F. F.; Zhang, Z.; Wang, Q.; Steward, O. W. Angew.
Chem. Int. Ed. 2004, 43, 1126.
(
(
5) Fleming, F. F.; Wang, Q.; Steward, O. W. J. Org. Chem.
003, 68, 4235.
2
6) Fleming, F. F.; Zhang, Z.; Wei, G.; Steward, O. W. Org.
Lett. 2005, 7, 447.
Pursuing several workup variations identified an unusual
means for efficiently removing the reduced chromium
species. Addition of sodium hydroxide and maintaining
the reaction temperature at 0 °C for one hour is followed
by allowing the mixture to stand, without stirring, at
(7) (a) Wang, Y.; Doering, W. V. E.; Staples, R. J. J. Chem.
Crystallogr. 1999, 29, 977. (b) Cronyn, M. W.; Goodrich, J.
E. J. Am. Chem. Soc. 1952, 74, 3331.
(
8) Agosta, W. C.; Lowrance, W. W. J. Org. Chem. 1970, 35,
851.
9) Available from Organometallics Inc.
3
–
10 °C. After 12–16 hours two phases separate, allowing
(
relatively facile extraction of oxonitrile 2 and trace quan-
(
10) Nakai, T.; Tomooka, K. In Encyclopedia of Reagents for
Organic Synthesis, Vol. 3; Paquette, L. A., Ed.; Wiley:
Chichester, 1995, 1779.
tities of cyclohexenecarbonitrile (1), which is readily sep-
1
9
arated by silica gel chromatography.
(11) Nicolaou, K. C.; Gray, D. L. F.; Montagnon, T.; Harrison, S.
Effectively, the chromium trioxide-3,5-dimethylpyrrazole
oxidation of cyclohexenecarbonitrile (1) provides a robust
synthesis of gram quantities of 3-oxocyclohex-1-ene-1-
carbonitrile (2). The procedure is technically simple and
readily provides 3-oxocyclohex-1-ene-1-carbonitrile (2)
for a variety of synthetic applications.
T. Angew. Chem. Int. Ed. 2002, 41, 996.
12) Zimmerman, H. E.; Pasteris, R. J. J. Org. Chem. 1980, 45,
4864.
(
(13) (a) Johnson, J. N. In Encyclopedia of Reagents for Organic
Synthesis, Vol. 2; Paquette, L. A., Ed.; Wiley: Chichester,
1995, 1275–1277. (b) Lee, T. V. In Comprehensive Organic
Synthesis, Vol. 7; Fleming, I.; Trost, B. M., Eds.; Pergamon:
Oxford, 1991, 291–303. (c) Salmond, W. G.; Barta, M. A.;
Havens, J. L. J. Org. Chem. 1978, 43, 2057.
3
-Oxocyclohex-1-ene-1-carbonitrile (2)
(14) Mousseron, M.; Jacquier, R.; Fontaine, A.; Zagdoun, R.
Bull. Soc. Chim. Fr. 1954, 1247.
Two individual watch glasses having a thin (<3mm) layer of pow-
dered CrO (0.30 mol, 30 g) or 3,5-dimethylpyrazole (0.30 mol, 29
(15) Kurihara, T.; Miki, M.; Yoneda, R.; Harusawa, S. Chem.
3
g) were dried overnight (>16 h) in a vacuum desiccator (<5 mm Hg)
containing P O . Dry 3,5-dimethylpyrazole was added to a magnet-
Pharm. Bull. 1986, 34, 2747.
(16) Attempts to optimize the selenium dioxide oxidation of 1
afforded low yields of 2 despite excellent results with related
unsaturated esters: Bestmann, H. J.; Schobert, R. Angew.
Chem., Int. Ed. Engl. 1985, 24, 791.
(17) Yu, J.-Q.; Wu, H.-C.; Corey, E. J. Org. Lett. 2005, 7, 1415.
(18) (a) Attempted oxidation with hydrogen peroxide and
chromium hexacarbonyl is ineffective: Pearson, A. J.; Chen,
Y.-S.; Han, G. R.; Hsu, S.-Y.; Ray, T. J. Chem. Soc., Perkin
Trans. 1 1985, 267. (b) The lack of oxidation may be due to
competitive metal ligation of the nitrile as occurs with
dirhodium(II) caprolactamate: Doyle M. P. personal
communication. (c) For a related oxidation see: Catino, A.
J.; Forslund, R. E.; Doyle, M. P. J. Am. Chem. Soc. 2004,
126, 13622.
2
5
ically stirred CH Cl solution (250 mL) of dry CrO in a 500 mL, 3-
2
2
3
necked flask at –20 °C. After stirring at –20 °C for 15 min, neat ni-
trile 1 (2.7 g, 0.025 mol) was added. The mixture was stirred be-
tween –10 °C to –12 °C for 6 h and then the temperature was raised
to 0 °C. Aq NaOH (5 M, 125 mL) was then added and stirring con-
tinued at 0 °C for 1 h. The crude mixture was then refrigerated (4
°C) overnight causing the aqueous phase to freeze and the organic
phase to be removed by decanting. The aqueous phase was further
extracted with CH Cl (2 × 200 mL), the organic extracts were then
2
2
combined, and the resulting organic material was then washed se-
quentially with HCl (250 mL, 3 M), H O (200 mL) and brine (200
2
mL). The organic extract was dried (Na SO ) and then concentrated
2
4
to give a dark yellow oil, which after radial chromatography
CH Cl –hexanes, 1.5:1) afforded 1.97 g (65%) of oxonitrile 2 as a
(
(19) Assaying several different solvent mixtures identified
2
2
very light yellow oil.
CH Cl –hexanes (1.5:1) as optimal, although a stepped
2 2
–
1
EtOAc–hexanes gradient (3:17, 1:4, 1:3) permitted isolation
of 2.30 g of 2 in 64% yield.
IR (film): 2225, 1700, 1605 cm .
1
H NMR (300 MHz, CDCl ): d = 2.08–2.19 (m, 2 H), 2.51 (t, J =
.4 Hz, 2 H), 2.56 (t, J = 5.9 Hz, 2 H), 6.52 (s, 1 H).
3
7
1
3
C NMR (75 MHz, CDCl ): d = 21.8, 27.3, 37.0, 116.8, 130.8,
3
1
38.3, 196.2.
Synthesis 2005, No. 18, 3179–3180 © Thieme Stuttgart · New York