Unsaturated Nitriles: A Domino Ozonolysis-Aldol Synthesis of Highly Reactive Oxonitriles

Full text of DOI:10.1021/jo9703818

3036
J . Org. Chem. 1997, 62, 3036-3037
Sch em e 1
Un sa tu r a ted Nitr iles: A Dom in o
Ozon olysis-Ald ol Syn th esis of High ly
Rea ctive Oxon itr iles
Fraser F. Fleming,* Adrian Huang,
Vaqar A. Sharief, and Yifang Pu
Department of Chemistry and Biochemistry,
Duquesne University, Pittsburgh, Pennsylvania 15282
Received February 28, 1997
Cycloalkenones have been valued as synthetic precur-
sors almost since the birth of natural product synthesis.1
The importance of cyclohexenones and cyclopentenones2
as Michael acceptors is illustrated in a recent review3 of
organocopper reagents employed in natural product
syntheses. Over half of the conjugate additions surveyed
involve the reaction of an organocopper reagent with a
cyclohexenone or a cyclopentenone.3
The demand for highly reactive cycloalkenones has led
several groups4 to prepare cycloalkenones that contain
an additional electron-withdrawing group on the R-car-
bon. These doubly activated alkenes5 are extremely
reactive and have been employed in Diels-Alder6 and
Michael7 reactions that are otherwise unsuccessful. For
example,8 in the synthesis of a forskolin analog, 1a
gave no conjugate addition products when treated
with a variety of organocopper reagents, whereas 1b
smoothly reacted to afford the conjugate addition product
2 (eq 1).
2-carbonitrile12 (8, 98% yield) upon exposure to dimethyl
sulfide.13 The reaction proceeds under remarkably mild
conditions, simply upon stirring the intermediate ozonide
at room temperature in dichloromethane with no added
acid or base. The high efficiency and mild conditions of
this domino ozonolysis-aldol sequence reflects the facile
enolization14 of ketonitriles and the rapid dehydration of
cyano-aldols.15
Direct extension of this domino ozonolysis-aldol se-
quence to the analogous seven-membered ring is opera-
tionally simple but inefficient. Ozonolysis of 9 (CH2Cl2,
-78 °C) and reduction of the intermediate ozonide cleanly
affords the desired nitrile 11 (13% yield), but the main
product from this reaction is an insoluble polymeric
material that is presumably an oligomeric peroxide.
Bunnelle has performed several clever experiments16 to
show that oligomers form during cyclohexene ozonolyses
when the intermediate carbonyl oxide is geometrically
constrained from an intramolecular [3 + 2] cycloaddition
with the ketone group. We minimized the polymerization
by performing the ozonolysis of 9 in acetone that ef-
fectively intercepts the carbonyl oxide in an intermolecu-
lar cycloaddition (Scheme 2). Reduction of the resultant
ozonide 10 and exposure to p-toluenesulfonic acid pro-
vides 1-oxo-2-cycloheptenyl-2-carbonitrile (11) in 58%
yield.
(1)
The importance of highly activated Michael acceptors
stimulated us to synthesize cyclic 1-oxo-2-cycloalkenyl-
2-carbonitriles as potent electrophiles for nitrile-based
conjugate addition reactions.9 We envisaged a domino
ozonolysis-aldol sequence10 to unmask a â-ketonitrile
and allow for a subsequent intramolecular aldol conden-
sation followed by dehydration of the resultant aldol
(Scheme 1). Execution of this sequence by ozonolysis of
3 in dichloromethane provides an intermediate ozonide
411 that directly affords the desired 1-oxo-2-cyclohexenyl-
We have generalized this domino ozonolysis-aldol
sequence to synthesize substituted 5- and 6-membered
oxonitriles. The precursors to these substituted oxoni-
triles are the ω-alkenyl â-ketonitriles 13 that are readily
(11) Direct cyclization of the intermediate carbonyl oxide with the
ketonitrile is precluded since the intermediate ozonide 4 has been
isolated and characterized: Tzou, J .-R.; Huang, A.; Fleming, F. F.;
Norman, R. E.; Chang, S.-C. Acta Crystallogr. 1996, C52, 1012.
Dimethyl sulfide reduction of 4 affords 8 in comparable yield.
(12) We prefer to name these compounds as nitriles in accordance
with IUPAC nomenclature since the trivial name “R-cyanocyclohex-
enone” de-emphasizes the profound effect of the nitrile group on the
reactivity of this compound: Fleming, F. F.; Pu, Y.; Tercek, F. J . Org.
Chem., submitted.
(13) Gen er a l P r oced u r e. A stream of ozone is passed through a
cold (-78 °C), dichloromethane solution of the unsaturated nitrile until
the distinctive blue color of ozone is observed. Ozonolysis is then
terminated, and the excess ozone is displaced by passing a stream of
nitrogen through the solution for 5-10 min. The solution is allowed
to warm to room temperature, neat dimethyl sulfide is added, and the
solution is then allowed to stir at room temperature for 5-30 h.
Concentration of the crude product, followed by radial chromatography,
provides the nitriles 14a -d . The syntheses of 14a and 14b require
terminating the ozonolysis immediately upon observation of excess
ozone, purging with nitrogen, and then the dropwise addition of
dimethyl sulfide at -78 °C. Caution: Care must be taken to prevent
contact with these oxonitriles since minute quantities of these com-
pounds, particularly 14a and 14b, cause headaches.
(1) Rapson, W. S.; Robinson, R. J . Chem. Soc. 1935, 1285.
(2) Ramaiah, M. Synthesis 1984, 529.
(3) Lipshutz, B. H.; Sengupta, S. Org. React. 1992, 41, 135.
(4) (a) Crimmins, M. T.; Huang, S.; Guise, L. E.; Lacy, D. B.
Tetrahedron Lett. 1995, 36, 7061. (b) Funk, R. L.; Fitzgerald, J . F.;
Olmstead, T. A.; Para, K. S.; Wos, J . A. J . Am. Chem. Soc. 1993, 115,
8849. (c) Schultz, A. G.; Harrington, R. E. J . Am. Chem. Soc. 1991,
113, 4926. (d) Posner, G. H.; Mallamo, J . P.; Hulce, M.; Frye, L. L. J .
Am. Chem. Soc. 1982, 104, 4180.
(5) For doubly activated alkenes prepared by selenoxide elimination
see: (a) Reich, H. J .; Wollowitz, S. Org. React. 1993, 44, 1 and Table
XI 254-272 in particular. (b) Liu, H.-J .; Yeh, W.-L.; Browne, E. N. C.
Can. J . Chem. 1995, 73, 1135.
(6) (a) Liu, H.-J .; Browne, E. N. C. Can. J . Chem. 1987, 65, 1262.
(b) Caine, D.; Harrison, C. R.; VanDerveer, D. G. Tetrahedron Lett.
1983, 24, 1353.
(7) (a) Lane, S.; Taylor, R. J . K. Tetrahedron Lett. 1985, 26, 2821.
(b) Levison, B. S.; Miller, D. B.; Salomon, R. G. Tetrahedron Lett. 1984,
25, 4633.
(8) Boring, D. L.; Sindelar, R. D. J . Org. Chem. 1988, 53, 3617.
(9) (a) Fleming, F. F.; Pak, J . J . J . Org. Chem. 1995, 60, 4299. (b)
Fleming, F. F.; Hussain, Z.; Weaver, D.; Norman, R. E. J . Org. Chem.
1997, 62, 1305.
(10) Kretchmer, R. A.; Thompson, W. J . J . Am. Chem. Soc. 1976,
98, 3379.
(14) Elnagdi, M. H.; Elmoghayar, M. R. H.; Elgemeie, G. E. H.
Synthesis 1984, 1.
(15) DiBiase, S. A.; Lipisko, B. A., Haag, A.; Wolak, R. A.; Gokel, G.
W. J . Org. Chem. 1979, 44, 4640.
(16) Bunnelle, W. H. Adv. Cycloaddit. 1993, 3, 67.
S0022-3263(97)00381-2 CCC: $14.00 © 1997 American Chemical Society

Communications
J . Org. Chem., Vol. 62, No. 10, 1997 3037
Ta ble 1. Ta n d em Ozon olysis-Ald ol Cycliza tion of
Sch em e 2
Un sa tu r a ted Keton itr iles
prepared17 from the corresponding ω-alkenyl esters18 12
by treatment with excess sodioacetonitrile (eq 2).
(2)
Ozonolysis of the â-ketonitriles 13a -d proceeds cleanly
and efficiently to provide the corresponding oxonitriles
14a -d (Table 1). The cyclization of the intermediate
aldehydes varies significantly with 13c and 13d cyclizing
upon reduction with dimethyl sulfide. In contrast, the
aldehydes from 13a and 13b cyclize much more slowly,
and complete cyclization only occurs during silica gel
chromatography. Silica gel is known to catalyze a related
intermolecular Knoevenagel condensation.19
The domino ozonolysis-aldol sequence is effective with
substituted ketonitriles and is even effective when the
aldehyde intermediate is flanked by a gem-dimethyl
group (entry 2, Table 1). The domino ozonolysis-aldol
reaction of 13c demonstrates that this domino reaction
sequence tolerates labile functionality, since no dehydra-
tion occurs with any intermediates or the product. The
high yield obtained with 13c establishes that dehydration
to aromatic phenols does not complicate these reactions.
The domino ozonolysis-aldol cyclization is a rapid and
efficient method for preparing cyclic five-, six-, and seven-
membered oxonitriles with various substitution patterns.
Having developed a one-pot synthesis of cyclic oxonitriles,
we are currently exploiting the unique reactivity of these
highly activated alkenes.
Ack n ow led gm en t. Financial support from the J a-
cob and Frieda Hunkele Charitable Foundation and the
Kresge Foundation is gratefully acknowledged.
(17) Eby, C. J .; Hauser, C. R. J . Am. Chem. Soc. 1957, 79, 723.
(18) Ethyl 2-methyl-4-pentenoate and ethyl 3,3-dimethyl-4-pen-
tenoate are commercially available. Ethyl 3-hydroxy-3-methyl-5-hex-
enoate was prepared by a modification of the literature method:
Wilson, W. K.; Baca, S. B.; Barber, Y. J .; Scallen, T. J .; Morrow, C. J .
J . Org. Chem. 1983, 48, 3960. 5-Methyl-5-[(trimethylsilyl)oxy]-3-oxo-
7-octenenitrile (13d ) was prepared by silylation of 13c.
Su p p or t in g In for m a t ion Ava ila b le: 1H NMR and 13C
NMR spectra of all new compounds and experimental proce-
dures (24 pages).
(19) Brillon, D.; Sauve´, G. J . Org. Chem. 1992, 57, 1838.
J O9703818