Unsaturated nitriles: Precursors for a domino ozonolysis-aldol synthesis of oxonitriles

Article abstract of DOI:10.1021/jo9822885

Cyclic five-, six-, and seven-membered oxonitriles are prepared by a tandem ozonolysis-aldol sequence. Cyclopentenylacetonitrile (4) and cyclohexenylacetonitrile (12) afford the ring-expanded oxonitriles 3 (98%) and 17 (58%), respectively, in highly effic

Full text of DOI:10.1021/jo9822885

2830
J . Org. Chem. 1999, 64, 2830-2834
Un sa tu r a ted Nitr iles: P r ecu r sor s for a Dom in o Ozon olysis-Ald ol
Syn th esis of 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 November 18, 1998
Cyclic five-, six-, and seven-membered oxonitriles are prepared by a tandem ozonolysis-aldol
sequence. Cyclopentenylacetonitrile (4) and cyclohexenylacetonitrile (12) afford the ring-expanded
oxonitriles 3 (98%) and 17 (58%), respectively, in highly efficient one-pot syntheses. Homologous
five-membered oxonitriles 22a -c are prepared by analogous ozonolysis-aldol cyclizations employing
ω-alkenyl â-ketonitriles. The method tolerates various substitution patterns and allows for the
synthesis of â,â-disubstituted oxonitriles (22c). The reaction conditions are essentially neutral
providing the â-hydroxyoxonitriles 22d and 22e with only trace amounts of the aromatic dehydration
product.
Doubly activated alkenes bearing two electron-with-
drawing groups on the same carbon are exceptionally
reactive electrophiles.1 The highly polarized π-bond al-
lows Michael reactions2 and Diels-Alder cycloadditions3
that are otherwise unsuccessful with comparable mono-
activated alkenes. Several syntheses have exploited this
reactivity, both to assemble sterically demanding inter-
mediates4 and to successfully complete reactions in
otherwise unreactive substrates.2,3
The extensive use of doubly activated alkenes has
stimulated a number of excellent syntheses, particularly
of cycloalkenones containing an additional electron-
withdrawing group on the R-carbon.5 Historically, many
doubly activated alkenes have been prepared by
Knoevanagel condensations,6 although some products are
incompatible with the reaction conditions. For example,
1 and 2 rapidly decompose7 and are frequently prepared
by selenation-selenoxide elimination1b sequences. The
resultant crude alkene is often used without purification
since decomposition commonly occurs during silica gel
chromatography.8
Unsaturated oxonitriles, such as 3, represent an ideal
compromise between stability and high reactivity. Most
unsaturated oxonitriles are relatively stable to chroma-
tography and storage and are ideal intermediates for
carbocyclic9 and heterocyclic syntheses.10,11 Importantly,
unsaturated oxonitriles maintain an exceptional reactiv-
ity in Diels-Alder reactions12 and photochemical cyclo-
additions.13 Michael reactions of unsaturated oxonitriles
exhibit a similar heightened reactivity, giving conjugate
addition products with Grignard reagents,14 allyl si-
lanes,15 and radicals.11 Biological nucleophiles, particu-
larly sulfides present at enzymatic active sites, react
conjugately with unsaturated oxonitriles, making these
Michael acceptors potential irreversible enzyme inhibi-
tors.16
The exceptional reactivity of unsaturated oxonitriles
stimulated us to develop a rapid and general synthesis
of this class of compounds. We previously reported our
successful synthesis of several substituted unsaturated
oxonitriles17 and fully describe the scope of this method
in this paper.
(1) (a) Gololobov, Y. G.; Gruber, W. Russ. Chem. Rev. 1997, 66, 953.
For doubly activated alkenes prepared by selenoxide elimination, see:
(b) Reich, H. J .; Wollowitz, S. Org. React. 1993, 44, 1-296 and Table
11 (pp 254-272) in particular. (c) Liu, H.-J .; Yeh, W.-L.; Browne, E.
N. C. Can. J . Chem. 1995, 73, 1135.
(2) (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. (c) Boring, D. L.; Sindelar, R. D. J . Org. Chem. 1988, 53,
3617.
(3) (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.
(4) (a) Bouchard, H.; Lallemand, J . Y. Tetrahedron Lett. 1990, 31,
5151. (b) Sasaki, M.; Murae, T.; Matsuo, H.; Konosu, T.; Tanaka, N.;
Yagi, K.; Usuki, Y.; Takahshi, T. Bull. Chem. Soc. J pn. 1988, 61, 3587.
(c) Crimmins, M. T.; Gould, L. D. J . Am. Chem. Soc. 1987, 109, 6199.
(d) Funk, R. L.; Abelman, M. M. J . Org. Chem. 1986, 51, 3247. (e)
Heathcock, C. H.; Mahaim, C.; Schlecht, M. F.; Utawanit, T. J . Org.
Chem. 1984, 49, 3264.
(5) (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) Taber, D. F.; Amedio, J . C.; Sherrill, R. G. J . Org. Chem.
1986, 51, 3382. (e) Posner, G. H.; Mallamo, J . P.; Hulce, M.; Frye, L.
L. J . Am. Chem. Soc. 1982, 104, 4180.
(8) Marx, J . N.; Cox, J . H.; Norman, L. R. J . Org. Chem. 1972, 37,
4489.
(9) Kuehne, M. E.; Nelson, J . A. J . Org. Chem. 1970, 35, 161.
(10) (a) Ivanyuk, T. V.; Kadushkin, A. V.; Solov’eva, N. P.; Granik,
V. V. Mendeleev Commun. 1993, 160. (b) Elnagdi, M. H.; Fahmy, S.
M.; Hafez, E. A. A.; Elmoghayar, M. R. A.; Amer, S. A. R. J . Heterocycl.
Chem. 1979, 16, 1109.
(11) Kotake, Y.; Iijima, A.; Yoshimatsu, K.; Tamai, N.; Ozawa, Y.;
Koyanagi, N.; Kitoh, K.; Nomura, H. J . Med. Chem. 1994, 37, 1616.
(12) (a) Hsung, R. P. J . Org. Chem. 1997, 62, 7904. (b) Bogdanowicz-
Szwed, K.; Palasz, A. Monatsh. 1995, 126, 1341. (c) Lee, I.; Han, E. S.
Hsksurwon Nonmunjip, Cha’yon Kwahak P’yon 1983, 22, 43; Chem.
Abstr. 1984 101, #109891.
(13) Andresen, S.; Margaretha, P. J . Chin. Chem. Soc. 1995, 42, 991.
(14) Fleming, F. F.; Pu, Y.; Tercek, F. J . Org. Chem. 1997, 62, 4883.
(15) Pan, L.-R.; Tokoroyama, T. Chem. Lett. 1990, 1999.
(16) Brillon, D.; Sauve, G. J . Org. Chem. 1992, 57, 1838.
(17) Fleming, F. F.; Huang, A.; Sharief, V. A.; Pu, Y. J . Org. Chem.
1997, 62, 3036.
(6) J ones, G. Org. React. 1967, 15, 204.
(7) Liu, H.; Ngooi, T.; Browne, E. N. C. Can. J . Chem. 1988, 66,
3143.
10.1021/jo9822885 CCC: $18.00 © 1999 American Chemical Society
Published on Web 03/20/1999

Ozonolysis-Aldol Synthesis of Oxonitriles
J . Org. Chem., Vol. 64, No. 8, 1999 2831
Sch em e 1
Sch em e 3
Sch em e 2
The successful reduction-cyclization of 9 implied that
a more efficient one-pot synthesis of the oxonitrile 3
should be possible. In fact, ozonolysis of a dichloro-
methane solution of cyclopenteneacetonitrile (4) followed
by the removal of excess ozone and addition of dimethyl
sulfide affords the oxonitrile 3 in 98% yield after chro-
matography. This reaction has been performed numerous
times on a 1-5 g scale24 and consistently affords the
oxonitrile 3 in yields greater than 90%. Oxonitrile 3 is
remarkably stable to storage with only trace decomposi-
tion being observed after several weeks at -4 °C.
Resu lts a n d Discu ssion
Our strategy for assembling cyclic 2-oxocycloalkene-
carbonitriles was based on an attractive domino ozonoly-
sis-aldol sequence18 (4 f 3). Cyclopenteneacetonitrile (4)
represented an ideal substrate to test this sequence since
4 is readily available and relatively inexpensive.19 The
resultant oxonitrile 3 is particularly valuable both as a
substitute for the less stable ester 1 and for uncatalyzed
conjugate addition reactions with Grignard reagents.14
Formation of the analogous seven-membered ring
oxonitrile is readily achieved from commercially available
cyclohexeneacetonitrile (12). Ozonolysis of an acetone
solution of 12 affords an intermediate ozonide that is
redissolved in CH2Cl2 and reduced with Me2S providing
the intermediate 16 (Scheme 3). Cyclization is induced
by treating 16 with a catalytic amount of TsOH in CH2Cl2
to provide the desired oxonitrile 17 in 58% overall yield.
The ozonolysis of 12 must be performed in acetone in
order to efficiently intercept the trans-carbonyl oxide 14
in an intermolecular cycloaddition. The trans geometry
of the carbonyl oxide is determined by fragmentation
from an exocyclic conformation of the primary ozonide
13.21 Unlike the homologous cis-carbonyl oxide 7, the
trans-carbonyl oxide 14 is unable to achieve a conforma-
tion for intramolecular cycloaddition and polymerizes in
the absence of a suitable 2π reactant. Cleavage of the
intermediate ozonide 13 must position the electron-
deficient carbonyl oxide on the electron-releasing termi-
nal carbon21 since the terminal acetal 18 is obtained (80%
yield) when the ozonolysis is performed in methanol.
Exposure of the acetal to TsOH induces cyclization of the
resultant aldehyde and provides 17, although the yield
is modest because of the instability of 17 to the prolonged
acid exposure required to cleave the acetal.
Ozonolysis of cyclopenteneacetonitrile generates a
surprisingly stable ozonide 9 (Scheme 1). Careful dis-
placement of excess ozone and solvent removal provides
the pure ozonide 9 (71% yield) as a highly crystalline
solid, whose structure was determined by X-ray analy-
sis.20 Formation of 9 involves several complex stereo-
selective reactions that directly impinge on the efficiency
of the reaction. The cycloaddition reaction affords a
primary ozonide 6 that is predicted21 to adopt a confor-
mation with the trioxo bridge in an endo fold. Fragmen-
tation from this conformation dictates the formation of
the cis-carbonyl oxide 7. Intramolecular cycloaddition
proceeds smoothly since the cis-carbonyl oxide readily
achieves a conformation (8) where there is effective
orbital overlap between the 4π and 2π components.
Dimethyl sulfide reduction of the ozonide 9 triggers a
cascade of reactions that generates the oxonitrile 3 in
91% yield (Scheme 2). Formation of 3 is surprisingly easy
given the number of proton transfers involved in the
conversion of the initial intermediate 5 to the oxonitrile
3. Enolization of oxonitriles is usually quite facile22 and,
in the case of 5, provides the intermediate enol 10 that
is ideally poised for the ensuing aldol condensation.
Spontaneous dehydration of the resultant aldol is par-
ticularly facile since 11 is both an aldol and a â-hydroxy
nitrile, functionalities that are particularly prone to
dehydration.23
The synthesis of oxonitriles more substituted than 3
or 17 is readily achieved from the corresponding ω-al-
kenyl esters (Table 1), many of which are commercially
available. The classical procedure25 for converting esters
(18) Kretchmer, R. A.; Thompson, W. J . J . Am. Chem. Soc. 1976,
98, 3379.
(19) Oakwood Products supplies cyclopenteneacetonitrile at $1.21/g
for 100 g quantities.
(20) Tzou, J .-R.; Huang, A.; Fleming, F. F.; Norman, R. E.; Chang,
S.-C. Acta Crystallogr. Sect. C. 1996, C52, 1012.
(21) Bunnelle, W. H. Adv. Cycloaddit. 1993, 3, 67.
(22) Elnagdi, M. H.; Elmoghayar, M. R. H.; Elgemeie, G. E. H.
Synthesis 1984, 1.
(23) DiBiase, S. A.; Lipisko, B. A., Haag, A.; Wolak, R. A.; Gokel, G.
W. J . Org. Chem. 1979, 44, 4640.
(24) 1H NMR spectra of concentrated solutions of 3 (165 mg/mL)
exhibit significant spectral shifts (∆ν ) 0.5 ppm for the olefinic proton)
relative to more dilute spectra (∼10 mg/mL), which suggests the
presence of dimeric aggregates: Ilich, P.; Mishra, P. K.; Macura, S.;
Burghardt, T. P. Spectrochim. Acta A 1996, 52, 1323.
(25) Eby, C. J .; Hauser, C. R. J . Am. Chem. Soc. 1957, 79, 723.

2832 J . Org. Chem., Vol. 64, No. 8, 1999
Fleming et al.
Ta ble 1. Ta n d em Ozon olysis-Ald ol Cycliza tion of
separated by chromatography. Reduction of 23 in neat
dimethyl sulfide provides the cyclic oxonitrile 22e in 62%
yield, although the preparative formation of 22e is best
achieved using the more efficient one-pot procedure
(Table 1, entry 5).
Un sa tu r a ted Keton itr iles
The six-membered oxonitriles cyclize more easily than
the five- and seven-membered ring oxonitriles. Monitor-
ing the reactions after the dimethyl sulfide addition
reveals that the six-membered oxonitriles are formed
with only a small accumulation of the intermediate
aldehydes. For the five-membered ring precursors 20a
and 20b the dimethyl sulfide reduction affords primarily
the aldehyde intermediates that cyclize during radial
silica gel chromatography.16 Cyclization of 20c is even
more difficult with chromatography providing the corre-
sponding ketone. The most effective method for obtaining
the oxonitrile 22c is to treat the intermediate ketone with
calcium hydride followed by stirring with ammonium
chloride to eliminate the presumed aldol intermediate.
Geometric constraints retard the cyclization rate of the
five- and seven-membered aldehydes 21. Cyclization of
20a -c through the enol 24 requires a rather difficult
orbital alignment since the double bond rigidifies the
carbon framework. A further impediment is the 120°
angle of the enol that results in a difficult alignment for
the aldehyde and enolic carbons. Presumably, the use of
silica gel or CaH2 generates more reactive oxonium or
enolate intermediates capable of overcoming these steric
constraints. Cyclization of the keto ester 2529 is even
slower (8 days, p-TsOH, rt), possibly as a consequence of
the slower enolization of keto esters compared to keto
nitriles.9 The cyclization of 25 affords the desired keto
ester 2, but the instability of this material to silica gel
chromatography8 prevents this from being a viable
preparative procedure.
a
b
Prepared by silylation of 19d . The intermediate aldehydes
cyclize during silica gel chromatography. c The intermediate ke-
tone is cyclized by sequential treatment with CaH2 and aqueous
NH4Cl.
to oxonitriles employs sodium amide to deprotonate
acetonitrile, but in our experience, this procedure is
sometimes unpredictable. Cleaner, more reliable de-
protonation is achieved with butyllithium,26 which con-
sistently affords good yields of the corresponding oxo-
nitriles and is particularly effective for labile systems.
The advantage of using LiCH2CN is seen in the formation
of 20d (Table 1, entry 4) where a significantly lower yield
is obtained with NaCH2CN (70% and 46%, respectively).27
Ozonolysis of the â-ketonitriles 20a -c occurs readily
in CH2Cl2 at -78 °C to provide the corresponding
ozonides. Excess ozone is removed by purging the solution
with N2, followed by the addition of Me2S. Careful 1H
NMR monitoring of the ozonide reduction indicates that
the reaction is initially quite rapid, affording several
unidentified side products when performed at room
temperature. We assume that the reduction of the
ozonide is exothermic and therefore add the dimethyl
sulfide slowly at -78 °C.
Collectively, the examples in Table 1 show that the
method is quite general for assembling substituted
oxonitriles. The method tolerates various substitution
patterns and allows for the synthesis of â,â-disubstituted
systems (entry 3). The cyclization conditions are es-
sentially neutral, allowing the synthesis of the rather
sensitive nitriles 22d and 22e with only trace amounts
of the aromatic dehydration product. Preparation of gram
quantities of 22d revealed a sensitivity of this material
to dehydration on silica gel. Consequently, trace impuri-
ties were removed by rapid radial chromatography,
allowing for the preparation of 22d in slightly greater
than 50% yield, although on one occasion the yield was
as high as 98%.
The ozonides from 20d and 20e were significantly more
difficult to reduce. Steric crowding has a profound effect
on the stability of ozonides,28 and in our case, the
diastereomeric ozonides 23 are sufficiently stable to be
(26) Arseniyadis, S.; Kyler, K. S.; Watt, D. S. Org. React. 1984, 31,
1.
(27) The reaction of NaCH2CN with 19e affords only trace amounts
(8%) of 20e. The main component is tentatively assigned as the
conjugated enoate resulting from elimination of trimethylsiloxide. For
a related example, see: Martin, V. A.; Murray, D. H.; Pratt, N. E.;
Zhao, Y.-B.; Albizati, K. F. J . Am. Chem. Soc. 1990, 112, 6965.
(28) Mayr, H.; Baran, J .; Will, E.; Yanakoshi, H.; Teshima, K.;
Nojima, M. J . Org. Chem. 1994, 59, 5055.
(29) Prepared by ozonolysis of commercially available methyl 3-oxo-
6-octenoate.

Ozonolysis-Aldol Synthesis of Oxonitriles
J . Org. Chem., Vol. 64, No. 8, 1999 2833
(br s, 1H), 4.15 (q, J ) 7.1 Hz, 2H), 5.02-5.11 (m, 2H), 5.75-
5.90 (m, 1H); 13C NMR δ 14.1, 26.7, 44.3, 46.4, 60.5, 70.6, 118.4,
133.6, 172.8; MS m/e 173 (MH+).
Con clu sion
The tandem ozonolysis-aldol reaction of unsaturated
nitriles is an efficient method for preparing cyclic five-,
six-, and seven-membered oxonitriles. In the case of
cyclopentene- and cyclohexeneacetonitrile (3 and 17,
respectively) the sequence represents a new method for
ring expansion that converts â,γ-unsaturated nitriles into
highly reactive oxonitriles. The conditions are extremely
mild, allowing for the synthesis of a diverse range of
oxonitriles.
Standard silylation (TMSCl, 1.5 equiv; Et3N, 2.5 equiv;
CH2Cl2) of 19d afforded 19e in 58% yield as an oil: IR (film)
1
3078, 2960, 1737, 1641 cm-1; H NMR δ 0.12 (s, 9H), 1.25 (t,
J ) 7.1 Hz, 3H), 1.35 (s, 3H), 2.33-2.37 (m, 2H), 2.43 (ABq,
∆ν ) 16.9, J ) 13 Hz, 2H), 4.11 (q, J ) 7.1 Hz, 2H), 5.03-5.06
(m, 1H), 5.09 (s, 1H), 5.76-5.90 (m, 1H); 13C NMR δ 2.42, 14.2,
27.6, 46.8, 47.3, 60.0, 74.6, 117.9, 134.4, 171.0; MS m/e 229
(M - CH3+).
Formation of 20d was achieved using the general procedure
with acetonitrile (2.92 mL, 56 mmol), n-butyllithium (56
mmol), and 19d (2.756 g, 16 mmol). Radial chromatography
of the crude product (4 mm silica gel plate, 1:3 EtOAc/hexanes)
gave 1.88 g (70%) of the nitrile 20d as a yellow oil: IR (film)
3455, 3078, 2978, 2920, 2260, 2210, 1726, 1641 cm-1; 1H NMR
δ 1.26 (s, 3H), 2.26-2.34 (m, 3H), 2.68 (ABq, ∆ν ) 44.2, J )
15.3 Hz, 2H), 3.61 (ABq, ∆ν ) 23.6, J ) 19.7 Hz, 2H), 5.08-
5.19 (m, 2H), 5.74-5.88 (m, 1H); 13C NMR δ 27.0, 33.8, 46.7,
51.6, 71.6, 113.7, 119.7, 132.8, 198.2; MS m/e 168 (MH+).
5-Meth yl-5-tr im eth ylsilyloxy-3-oxo-7-octen en itr ile (20e).
Neat triethylamine (67 µL, 0.48 mmol) and trimethylsilyl
chloride (37 µL, 0.29 mmol) were sequentially added to a
dichloromethane solution (1 mL) of ethyl 3-hydroxy-3-methyl-
5-hexenoate (19d ) at room temperature. After 21 h, saturated,
aqueous NaHCO3 was added, the phases were separated, and
the organic phase was extracted with EtOAc (3 × 10 mL). The
combined extracts were dried (MgSO4), concentrated, and then
purified by radial chromatography (1:9 then 1:5 EtOAc/
hexanes) to provide 26.8 mg (58%) of 20e as an oil: IR (film)
Exp er im en ta l Section 30
Gen er a l P r oced u r e for P r ep a r in g 3-Oxon itr iles (20a -
d ). Neat acetonitrile (2.0 equiv) was added to a cold (-78 °C),
stirred, THF solution (0.1 M) of n-butyllithium (∼1 M in
hexanes, 2.0 equiv). A white suspension formed that was
stirred for 1 h before the slow addition (5-10 min) of a THF
solution (0.1 M) of the alkenylester (1.0 equiv). The resultant
yellow mixture was warmed to -45 °C and stirred for 2 h, and
then aqueous hydrochloric acid (2 M) was added until the
solution was neutral to pH paper. The organic phase was
separated, washed with brine, dried over Na2SO4, and con-
centrated under reduced pressure. Radial chromatography of
the crude product (2:8 EtOAc/hexanes) provided the corre-
sponding 3-oxonitrile.
4-Meth yl-3-oxo-6-h ep ten en itr ile (20a ). The general pro-
cedure was employed with acetonitrile (28.1 mmol, 1.47 mL),
n-butyllithium (28.1 mmol, 1.43 M), and ethyl 2-methyl-4-
pentenoate (14.1 mmol, 2.29 mL). Radial chromatography of
the crude product (4 mm silica gel plate, 2:8 EtOAc/hexanes)
provided 1.57 g (81%) of the nitrile 20a as a yellow oil: IR
(film) 3079, 2261, 1732, 1641 cm-1; 1H NMR δ 1.15 (d, J ) 6.9
Hz, 3H), 2.12-2.22 (m, 1H), 2.35-2.46 (m, 1H), 2.79 (sextet,
J ) 6.9 Hz, 1H), 3.51 (s, 2H), 5.04-5.11 (m, 2H), 5.71 (ddt, J
) 17.3, 9.8, 7.1 Hz, 1H); 13C NMR δ: 15.6 (q), 31.0 (t), 36.6 (t),
45.5 (d), 113.7 (s), 117.9 (t), 134.2 (d), 200.6 (s).
1
3079, 2958, 2259, 2213, 1731, 1641 cm-1; H NMR δ 0.16 (s,
9H), 1.33 (s, 3H) 2.25 (dd, J ) 13.7, 7.9 Hz, 1H), 2.39 (dd, J )
13.7, 6.9 Hz, 1H), 2.58 (ABq, ∆ν ) 84.3, J ) 12.5 Hz, 2H),
3.58 (ABq, ∆ν ) 27.9, J ) 19.5 Hz, 2H), 5.07-5.15 (m, 2H),
5.70-5.84 (m, 1H); 13C NMR δ 2.4, 27.6, 34.2, 47.6, 52.9, 75.9,
114.0, 119.1, 133.3, 197.4; MS m/e 224 (M - CH3+).
Gen er a l Ozon olysis P r oced u r e. A stream of ozone was
bubbled through a cold (-78 °C), dichloromethane solution of
the unsaturated nitrile until the distinctive blue color of ozone
was clearly observed. Ozonolysis was then terminated, and
excess ozone was displaced by passing a stream of nitrogen
through the solution for 5-10 min. The solution was allowed
to warm to room temperature, and then neat dimethyl sulfide
was added.
5,5-Dim eth yl-3-oxo-6-h ep ten en itr ile (20b). The general
procedure was employed with acetonitrile (14.0 mmol, 0.73
mL), n-butyllithium (14.0 mmol, 1.36 M), and methyl 3,3-
dimethyl-4-pentenoate (7.02 mmol, 1.11 mL). Radial chroma-
tography of the crude product (4 mm silica gel plate, 2:8 EtOAc/
hexanes) gave 770 mg (73%).
1-Cya n om eth yl-6,7,8-tr ioxa bicyclo[3.2.1]octa n e. Ozo-
nolysis of a dichloromethane (5 mL) solution of 4 (112.3 mg,
1.05 mmol) was performed according to the general procedure
except that the solution was concentrated after purging with
nitrogen. Crystallization occurred during concentration to
provide 115.4 mg (71%) of the ozonide 9 as colorless crystals
6-Meth yl-3-oxo-6-h ep ten en itr ile (20c). The general pro-
cedure was employed with acetonitrile (14.0 mmol, 0.73 mL),
n-butyllithium (14.0 mmol, 1.15 M), and ethyl 4-methyl-4-
pentenoate (6.95 mmol, 1.11 mL). Radial chromatography of
the crude product (4 mm silica gel plate, 2:8 EtOAc/hexanes)
gave 683 mg (71%).
1
(mp 50-51 °C): IR (KBr) 2259, 1105 cm-1; H NMR δ 1.71-
5-Hyd r oxy-5-m eth yl-3-oxo-7-octen en itr ile (20d ). This
oxonitrile was prepared from ethyl 3-hydroxy-3-methyl-5-
hexenoate (19d ), which was prepared by a modification of the
literature procedure:31 Dry ethyl acetoacetate (110 µL, 0.86
mmol) and allyl bromide (407.1 mg, 3.37 mmol) were added,
sequentially, to a stirred, THF suspension (1 mL) of grannular
zinc (236.9 mg, 3.62 mmol). The resultant mixture was heated
to reflux for 0.5 h, allowed to cool to room temperature, and
then filtered through a plug of cotton wool. The filtrate was
diluted with EtOAc (20 mL) and vigorously stirred, and then
aqueous HCl (1%, 20 mL) was added. After 5 min, the mixture
was filtered through a plug of Celite, extracted with EtOAc (3
× 10 mL), dried, and concentrated. Radial chromatography of
the crude product (1 mm plate, 1:9 then 1:5 EtOAc/hexane),
followed by concentration of the appropriate fractions, provided
104.1 mg (58%) of 19d whose spectral data have not previously
2.04 (m, 5H), 2.18-2.32 (m, 1H), 2.90 (s, 2H), 5.89 (s, 1H). 13
C
NMR δ 15.5 (t), 24.9 (t), 28.5 (t), 31.8 (t), 103.7 (d), 105.2 (s),
114.1 (s).
2-Oxo-6-cycloh exen eca r bon itr ile (3). (a ) F r om Ozo-
n id e 9. Neat Me2S (0.2 mL) was added to a dichloromethane
solution (4 mL) of the ozonide 9 (91.9 mg, 0.592 mmol) at room
temperature. The resultant solution was stirred at room
temperature for 35 h, and then the solvent was removed under
reduced pressure. Chromatography of the crude product (1 mm
plate, elution with EtOAc/hexane 4:6) followed by concentra-
tion of the appropriate fractions gave 65.1 mg (91%) of 3 as a
1
yellow oil: IR (film) 2233, 1698, 1615 cm-1; H NMR δ 2.10
(br quintet, J ) 6 Hz, 2H), 2.53-2.61 (m, 4H), 7.75 (t, J ) 4.2
Hz, 1H): 13C NMR δ 21.2 (t), 26.3 (t), 36.9 (t), 114.0 (s), 117.3
(s), 163.4 (d), 192.0 (s). MS m/e 122 (M + H+).
been published: IR (film) 3454, 3079, 2979, 1714, 1641 cm-1
;
(b) F r om 4 w ith ou t Isola tion of th e Ozon id e 9. Ozo-
nolysis of a dichloromethane (5 mL) solution of 4 (128.4 mg,
1.20 mmol) was performed according to the general procedure
using 0.2 mL of dimethyl sulfide. The resultant mixture was
stirred at room temperature for 30 h, and then the solvent
was removed under reduced pressure. Radial chromatography
of the crude product (1 mm silica gel plate) with rapid elution
(3:2 EtOAc/hexane, 4 mm solvent delivery tip), and concentra-
1H NMR δ: 1.22 (s, 3H), 1.25 (t, J ) 7.1 Hz, 3H), 2.27 (br d,
J ) 7 Hz, 2H), 2.43 (ABq, ∆ν ) 30.6, J ) 15.6 Hz, 2H), 3.61
(30) For general experimental procedures, see: Fleming, F. F.;
Hussain, Z.; Weaver, D.; Norman, R. E. J . Org. Chem. 1997, 62, 1305.
(31) Wilson, W. K.; Baca, S. B.; Barber, Y. J .; Scallen, T. J .; Morrow,
C. J . J . Org. Chem. 1983, 48, 3960.

2834 J . Org. Chem., Vol. 64, No. 8, 1999
Fleming et al.
tion of the appropriate fractions under reduced pressure gave
142.3 mg (98%) of 3.
trated and redissolved in dimethyl sulfide (1 mL). The result-
ant solution was stirred for 12 h, and then the solvent was
removed under reduced pressure. The crude ketone was
dissolved in THF (5 mL), and solid calcium hydride (35.5 mg,
0.84 mmol) was added. After 3 h, saturated aqueous am-
monium chloride (3.0 mL) was cautiously added and stirring
continued for 1 h. The organic phase was separated, dried over
MgSO4, and concentrated under reduced pressure. Radial
chromatography of the crude product (1 mm silica gel plate,
EtOAc) afforded 64.0 mg (81%) of 22c as a colorless oil: IR
2-Oxo-6-cycloh ep ten eca r bon itr ile (17). (a ) F r om 12.
Ozonolysis of an acetone (5 mL) solution of 12 (504.0 mg, 4.16
mmol) was performed according to the general procedure using
0.6 mL of dimethyl sulfide. The resultant mixture was stirred
overnight and was then concentrated. The resultant material
was dissolved in dry CH2Cl2 (5 mL), TsOH (44.1 mg, 0.23
mmol) was added, and the solution was then stirred overnight.
The solvent was removed under reduced pressure, and the
crude product was purified by radial chromatography (1 mm
silica gel plate, 6:4 EtOAc/hexane) to provide 326.7 mg (58%)
of 17 as a yellow oil: IR (film) 2229, 1684, 1616 cm-1; 1H NMR
δ 1.81-1.86 (m, 4H), 2.64-2.72 (m, 4H), 7.49 (t, J ) 6.0 Hz,
1H); 13C NMR δ 20.9 (t), 24.9 (t), 30.1 (t), 42.7 (t), 115.9 (s),
120.9 (s), 160.0 (d), 196.7 (s); MS m/e 136 (MH+).
(b) F r om 18. TsOH (13.0 mg, 68.3 µmol) was added to a
dichloromethane solution (5 mL) of 18 (135.8 mg, 0.68 mmol),
and the resultant solution was stirred for 30 h at room
temperature. Concentration of the resultant crude product
followed by chromatography on silica gel (CH2Cl2) gave 36.8
mg (40%) of 17 as a yellow oil.
8,8-Dim eth oxy-3-oxoocta n en itr ile (18). Ozonolysis of a
dichloromethane-methanol solution (5 mL, 4:1, v/v) of 12 (103.2
mg, 0.85 mmol) was performed according to the general
procedure using 0.2 mL of dimethyl sulfide. The resultant
mixture was stirred for 30 h, and then the solvent was removed
under reduced pressure. Radial chromatography of the crude
product with rapid elution (1 mm silica plate, elution with
EtOAc/hexane 4:6, 4 mm solvent delivery tip), and concentra-
tion of the appropriate fractions gave 135.8 mg (80%) of 18 as
a colorless oil: IR (film) 2208, 1732 cm-1; 1H NMR δ 1.33-
1.42 (m, 2H), 1.57-1.70 (m, 4H), 2.62 (t, J ) 7.2 Hz, 2H), 3.31
(s, 6H), 3.45 (s, 2H), 4.34 (t, J ) 5.6 Hz, 1H); 13C NMR δ 23.0,
23.7, 31.9, 32.1 41.9, 52.8, 104.2, 113.8, 197.4.
3-Meth yl-2-oxo-5-cyclop en ten eca r bon itr ile (22a ). Ozo-
nolysis of a dichloromethane (6 mL) solution of 20a (102.4 mg,
0.75 mmol) was performed according to the general procedure,
terminating the ozonolysis immediately upon observation of
the distinctive blue color of ozone. Neat dimethyl sulfide (2.5
mL) was then added, dropwise, at -78 °C. The resultant
mixture was allowed to warm to room temperature and stirred
for 4 h, and then the solvent was removed under reduced
pressure. Chromatography of the crude product (1 mm silica
gel plate, 3:2 EtOAc/hexanes) and concentration of the ap-
propriate fractions under reduced pressure gave 75.0 mg (83%)
of 22a as a colorless oil: IR (film) 3074, 2974, 2936, 2234, 1729,
1647 cm-1; 1H NMR δ 1.23 (d, J ) 7.5 Hz, 3H), 2.43-2.61 (m,
2H), 3.14 (br ddd, J ) 21, 7, 3 Hz, 1H), 8.28 (t, J ) 3 Hz, 1H);
13C NMR δ 15.7, 37.3, 39.5, 111.9, 120.4, 172.8, 203.9; MS m/e
121 (M+).
(film) 2919, 2229, 1719, 1633 cm-1 1H NMR δ 2.41 (s, 3H),
;
2.57 (br t, J ) 5 Hz, 2 H), 2.78-2.82 (m, 2H); 13C NMR δ 19.6,
33.0, 34.8, 111.8, 118.0, 189.3, 201.0; GC/MS m/e 122 (M + 1).
4-H y d r o x y -4-m e t h y l-2-o x o -6-c y c lo h e x e n e c a r b o -
n itr ile (22d ). Ozonolysis of a dichloromethane (2 mL) solution
of 20d (45.4 mg, 0.27 mmol) was performed according to the
general procedure. The solvent was removed, and the resultant
material was dissolved in dimethyl sulfide (1 mL) with the
aid of sonication. The solution was allowed to stir for 15 h and
was then concentrated and purified by radial chromatography
(1 mm plate, 3:2 EtOAc/hexanes) to afford 21.9 mg (53%) of
22d as an oil: IR (film) 3473, 2972, 2929, 2235, 1698, 1616
1
cm-1; H NMR δ 1.43 (s, 3H); 2.68 (ABq, ∆ν ) 37.9, J ) 16.4
Hz, 2H), 2.72-2.84 (m, 2H), 7.64 (dd, J ) 4.9, 3.4 Hz, 1H); 13
C
NMR δ 29.5, 40.5, 51.0, 71.4, 113.9, 117.3, 159.1, 191.4; MS
m/e 134 (M - OH+).
4-Meth yl-2-oxo-4-tr im eth ylsilyloxy-6-cycloh exen eca r -
bon itr ile (22e). Ozonolysis of a dichloromethane (1 mL)
solution of 20e (25.6 mg, 0.11 mmol) was performed according
to the general procedure. The solvent was removed, and the
resultant material was dissolved in dimethyl sulfide (1 mL)
with the aid of sonication. The solution was allowed to stir for
15 h and was then concentrated and purified by radial
chromatography (1 mm plate, 1:4 EtOAc/hexanes) to afford
13.7 mg (57%) of 22e as an oil: IR (film) 2976, 2234, 1703,
1619 cm-1; 1H NMR δ 0.09 (s, 9H), 1.42 (s, 3H), 2.36-2.80 (m,
4H), 7.56 (dd, J ) 5.0, 3.3 Hz, 1H); 13C NMR δ 2.2, 29.1, 42.0,
52.1, 74.1, 114.0, 117.4, 158.6, 191.2.
5-Meth yl-5-tr im eth ylsilyloxy-6-(2,3,5-tr ioxa cyclop en -
tyl)-3-oxoh exan en itr ile (23). Ozonolysis of a dichloromethane
(1 mL) solution of 20e (17.3 mg, 72.4 µmol) was performed
according to the general procedure. The solvent was removed,
and the resultant material was purified by radial chromatog-
raphy (1 mm plate, 1:4 EtOAc/hexanes) to afford 2.3 mg (11%)
of a fast eluting diastereomer 23a as an oil: IR (film) 2960,
2260, 1732 cm-1 1H NMR δ 0.16 (s, 9H), 1.45 (s, 3H), 1.97
;
(dd, J ) 14.8, 6.8 Hz, 1H), 2.08 (dd, J ) 14.8, 3.3 Hz, 1H),
2.76 (ABq, J ) 14.7, ∆νAB ) 34.0 Hz, 2H), 3.55 (ABq, J ) 19.3,
∆νAB ) 26.8 Hz, 2H), 5.08 (d, J ) 18.9, 2H), 5.33 (dd, J ) 6.8,
3.3 Hz, 1H); 13C NMR δ 2.4, 28.7, 33.9, 43.6, 53.1, 73.4, 93.7,
101.2, 113.7, 196.2; MS m/e 286 (M - H+). Chromatography
also afforded 3.0 mg (14%) of a slow-eluting diastereomer 23b
as an oil: IR (film) 2959, 2260, 1732 cm-1; 1H NMR δ 0.16 (s,
9H), 1.47 (s, 3H), 1.95-2.04 (m, 2H), 2.81 (ABq, J ) 15.0, ∆νAB
) 27.7 Hz, 2H), 3.53 (ABq, J ) 19.4, ∆νAB ) 24.2 Hz, 2H),
5.00 (s, 1H), 5.19 (s, 1H), 5.29 (t, J ) 4.9 Hz, 1H); 13C NMR δ
2.4, 28.8, 33.7, 42.9, 53.2, 73.4, 93.9, 101.1, 113.7, 196.1; MS
m/e 286 (M - H+).
4,4-Dim eth yl-2-oxo-5-cyclop en ten eca r bon itr ile (22b).
Ozonolysis of a dichloromethane (6 mL) solution of 20b (102.0
mg, 0.67 mmol) was performed according to the general
procedure, terminating the ozonolysis immediately upon ob-
servation of the distinctive blue color of ozone. Neat dimethyl
sulfide (2.5 mL) was then added, dropwise, at -78 °C. The
resultant mixture was allowed to warm to room temperature
and stirred for 22 h, and then the solvent was removed under
reduced pressure. Chromatography of the crude product (1 mm
silica gel plate, 1:1 EtOAc/hexanes) and concentration of the
appropriate fractions under reduced pressure gave 83.0 mg
(91%) of 22b as a colorless oil: IR (film) 3056, 2974, 2236, 1702,
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. Sugges-
tions from Drs. Terry Collins and William Bunnelle for
optimizing the ozonolyses are much appreciated.
1
1654 cm-1; H NMR δ 1.31 (s, 6H), 2.40 (s, 2H), 8.04 (s, 1H);
13C NMR δ 27.3, 41.5, 49.1, 111.5, 118.4, 181.8, 200.5; GC/MS
m/e 136 (MH).
5-Meth yl-2-oxo-5-cyclop en ten eca r bon itr ile (22c). Ozo-
nolysis of a dichloromethane solution (2.5 mL) of 20c (89.0 mg,
0.65 mmol) was performed according to the general procedure,
terminating the ozonolysis immediately upon observation of
the distinctive blue color of ozone. The solution was concen-
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. This material is available
free of charge via the Internet at http://pubs.acs.org.
J O9822885