Hydroxylated α,β-unsaturated nitriles: Stereoselective synthesis

Full text of DOI:10.1021/jo005692o

J . Org. Chem. 2001, 66, 2171-2174
2171
Sch em e 1
Hyd r oxyla ted r,â-Un sa tu r a ted Nitr iles:
Ster eoselective Syn th esis
Fraser F. Fleming,* Qunzhao Wang, and
Omar W. Steward
Department of Chemistry and Biochemistry, Duquesne
University, Pittsburgh, Pennsylvania 15282-1530
saturated nitriles syntheses, there is no one method for
synthesizing unsaturated nitriles with hydroxylation at
carbons successively removed from the unsaturated
nitrile moiety.13 Gram quantities of a range of hydroxy-
lated unsaturated nitriles were required from readily
available precursors, for expanding a key chelation-
controlled conjugate addition-alkylation reaction (Scheme
1).14
Numerous â,γ-unsaturated nitriles are commercially
available suggesting an expedient synthesis of hydroxy
unsaturated nitriles by sequential epoxidation and base-
induced ring opening. The strategy is based on the
pioneering ring opening of 4a (eq 1)15 and a related ring
opening of epoxy nitriles generated in situ from the
corresponding chloroketones.11 The intention was to
synthesize γ-hydroxynitriles from commercially available
â,γ-unsaturated nitriles, complementing the substitution
available via chloroketones, and to generalize the concept
to the ring opening of tetrahydrofuranyl- and tetrahy-
dropyranyl- acetonitriles.
flemingf@duq.edu
Received October 20, 2000
R,â-Unsaturated nitriles are versatile synthetic inter-
mediates1 that are readily transformed into an array of
carbocycles2 and heterocycles.3 R,â-Unsaturated nitriles
are particularly valuable as precursors to substituted
nitriles by conjugate additions4 and have featured as
intermediates in several natural product syntheses.5
Usually the R,â-unsaturated nitrile acts as a key precur-
sor of an unsaturated carbonyl compound although the
increasing isolation of bioactive nitrile-containing natural
products6 has recently reversed this trend.
R,â-Unsaturated nitriles can be synthesized from a
variety of precursors7 although fewer methods exist for
accessing hydroxylated unsaturated nitriles. γ-Hydroxy
unsaturated nitriles have been synthesized by cyanide
or acetonitrile additions to vinyl iodides,8 aldehydes,9
ketones,10 or chloroketones11 and in some instances from
nitrile precursors.12 In contrast to these γ-hydroxy un-
(1) Fatiadi, A. J . In The Chemistry of Functional Groups, Supple-
ment C.; Patai, S., Rappoport, Z., Eds.; Wiley: New York, NY, 1983;
Ch 26.
(2) (a) Fleming, F. F.; Shook, B. C.; J iang, T.; Steward, O. W. Org.
Lett. 1999, 1, 1547. (b) Zoretic, P. A.; Fang, H.; Ribeiro, A. A. J . Org.
Chem. 1998, 63, 7213. (c) Kametani, T.; Kondoh, H.; Tsubuki, M.;
Honda, T. J . Chem. Soc., Perkin Trans. 1 1990, 5. (d) Osborn, M. E.;
Pegues, J . F.; Paquette, L. A. J . Org. Chem. 1980, 45, 167. (e)
Kametani, T.; Tsubuki, M.; Nemoto, H.; Fukumoto, K. Chem. Pharm.
Bull. 1979, 27, 152. (f) Brattesani, D. N.; Heathcock, C. H. J . Org.
Chem. 1975, 40, 2165. (g) White, D. R. J . Chem. Soc. Chem. Commun.
1975, 95.
(3) Sharanin, Y. A.; Goncharenko, M. P.; Litvinov, V. P. Russ. Chem.
Rev. 1998, 67, 442.
(4) (a) Fleming, F. F.; Pu, Y.; Tercek, F. J . Org. Chem. 1997, 62,
4883. (b) Fleming, F. F.; Hussain, Z.; Weaver, D.; Norman, R. E. J .
Org. Chem. 1997, 62, 1305. (c) Fleming, F. F.; Pak, J . J . J . Org. Chem.
1995, 60, 4299.
Optimizing the synthesis of 1a provided critical insight
for preparing an array of hydroxylated unsaturated
nitriles. Nitrile 1a is highly water soluble and prone to
both E:Z isomerization and polymerization. Ring opening
of the epoxide is extremely facile, producing exclusively
the E-nitrile in less than 5 min at -78 °C while prolonged
exposure of 1a to the reaction conditions causes consider-
able polymerization. Prompt addition of acetic acid (4
equiv) circumvents polymerization and allows a non-
aqueous workup of water-soluble 1a . However, the excess
acetic acid must be removed prior to concentrating the
crude product since extensive E:Z isomerization other-
wise occurs. The most effective workup is to dilute the
reaction mixture with EtOAc immediately after adding
acetic acid, followed by a small volume of saturated,
aqueous NaCl. Filtration of the resulting precipitate
through silica gel, removal of the solvent, and chroma-
tography provides gram-quantities of 1a as a single
stereoisomer.
(5) For recent examples see: (a) Ho, T.-L.; Su, C.-Y. J . Org. Chem.
2000, 65, 3566. (b) Williams, G. M.; Roughley, S. D.; Davies, J . E.;
Holmes, A. B. J . Am. Chem. Soc. 1999, 121, 4900. (c) Carless, H. A. J .;
Dove, Y. Tetrahedron Asym. 1996, 7, 649.
(6) Fleming, F. F. Nat. Prod. Rep. 1999, 16, 597.
(7) Kiefel, M. J . In Comprehensive Organic Functional Group
Transformations; Katritzky, A. R., Meth-Cohn, O., Rees, C. W., Eds.;
Pergamon: Cambridge, U.K., 1995; 3, 641-676.
(8) Kitano, Y.; Matsumoto, T.; Wakasawa, T.; Okamoto, S.; Shi-
mazaki, T.; Kobayashi, Y.; Sato, F.; Miyaji, K.; Arai, K. Tetrahedron
Lett. 1987, 28, 6351.
The optimized ring-opening efficiently provides an
array of hydroxylated R,â-unsaturated nitriles from the
corresponding nitriles (Table 1). The nitrile precursors
were synthesized in high yield by epoxidation of com-
mercially available nitriles with m-CPBA, while the
(9) (a) Abe, H.; Nitta, H.; Mori, A.; Inoue, S. Chem. Lett. 1992, 2443.
(b) Nudelman, A.; Keinan, E. Synthesis 1982, 687. (c) Mandai, T.;
Hashio, S.; Kawada, M.; Goto, J . Tetrahedron Lett. 1981, 22, 2187.
(10) (a) Kurihara, T.; Miki, M.; Yoneda, R.; Harusawa, S. Chem.
Pharm. Bull. 1986, 34, 2747. (b) Nokami, J .; Mandai, T.; Nishimura,
A.; Takeda, T.; Wakabayashi, S.; Kunieda, N. Tetrahedron Lett. 1986,
27, 5109. (c) Nokami, J .; Mandai, T.; Imakura, Y.; Nishiuchi, K.;
Kawada, M.; Wakabayashi, S. Tetrahedron Lett. 1981, 22, 4489.
(11) Larcheveque, M.; Perriot, P.; Petit, Y. Synthesis 1983, 297.
(12) (a) Sarrazin, L.; Mauze´, B. Synth. Commun. 1996, 26, 3179.
(b) Aiai, M.; Baudy-Floc’h, M.; Robert, A.; Le Grel, P. Synthesis 1996,
403. (c) Tiecco, M.; Testaferri, L.; Tingoli, M.; Bagnoli, L.; Santi, C. J .
Chem. Soc., Chem. Commun. 1993, 637. (d) Kang, S.-K.; Lee, D.-H.;
Kim, Y.-S.; Kang, S.-C. Synth. Commun. 1992, 22, 1109. (e) Imagawa,
T.; Uemura, K.; Magai, Z.; Kawanisi, M. Synth. Commun. 1984, 14,
1267. (f) Sato, Y.; Hitomi, K. J . Chem. Soc. Chem. Commun. 1983, 170.
(13) For an isolated synthesis of an γ-hydroxy unsaturated nitriles
see: Crombie, L.; Rainbow, L. J . J . Chem. Soc., Perkin Trans. 1 1994,
673.
(14) Fleming, F. F.; Wang, Q.; Steward, O. W. Org. Lett. 2000, 2,
1477.
(15) Burrows, C. J .; Carpenter, B. K. J . Am. Chem. Soc. 1981, 103,
6983. (b) Burrows, C. J . Ph.D. Dissertation, Cornell University, Ithaca,
NY, 1982.
10.1021/jo005692o CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/27/2001

2172 J . Org. Chem., Vol. 66, No. 6, 2001
Notes
Ta ble 1. Syn th esis of Hyd r oxyla ted r,â-Un sa tu r a ted
Sch em e 2
Nitr iles
formation of the unsaturated nitrile is favored even when
the ring-opening is not facilitated by the relief of ring
strain.
Particularly significant is the exclusive formation of
E-unsaturated nitriles. The stereoselectivity is readily
assigned from diagnostic coupling and chemical shift
signatures19 while the stereochemical assignment for 1d
was secured through an X-ray analysis20 of the corre-
sponding p-nitrobenzoate. Mechanistically the E-stereo-
selectivity results from complexation between the lithium
amide base and the epoxide oxygen that triggers a syn-
elimination from a cyclic, six-membered transition state
(Scheme 2).21 The exclusive formation of 1d likely reflects
a preferential syn-elimination from transition state 6′′
where the nitrile π-electrons are aligned for delocalization
into the developing π-bond. Comparative ring-opening of
4d with LiHMDS generates a 1:1 ratio of cis:trans
isomers, confirming that chelation, and not dipole inter-
actions, control the stereoselectivity. The influence of
chelation is further evident in the rapid ring opening of
4f (<5 min at -78 °C, Table 1, entry 6) compared with
the slower ring opening of 4g (30 min at -78 °C, Table
1, entry 7) where intramolecular chelation is geometri-
cally precluded.22
Performing the ring-opening with a lithium amide base
at low temperatures is critical for the success of the
reaction. The lithium alkoxide intermediates are suf-
ficiently covalent to suppress inter- and intramolecular
additions to the unsaturated nitrile moiety that would
otherwise trigger polymerization. Intermediates 7h and
7i are particularly prone to cyclize,23 generating a
relatively free anion (8) that initiates polymerization
(Scheme 3). Performing the ring opening at high dilution
circumvents polymerization and results in the rapid
formation of unsaturated nitriles 1h and 1i (5 min at -78
°C) with hydroxylation 3- and 4-carbons removed from
the double bond.
Hydroxy R,â-unsaturated nitriles are readily synthe-
sized by the chelation-controlled ring opening of epoxy,
tetrahydrofuranyl, and tetrahydropyranyl acetonitriles.
The precursor acetonitriles are readily synthesized by
epoxidation of the corresponding â,γ-unsaturated nitriles
or by cyanide displacement of tetrahydrofuran- or tet-
rahydropyranmethanol. The ring-opening is highly ste-
tetrahydrofuranyl and tetrahydropyranyl nitriles 4h 16
and 4i were synthesized from the corresponding alcohols
by conversion to the tosylate and displacement with
NaCN. The presence of molecular sieves was found to be
particularly beneficial for the large-scale cyanide dis-
placement,17 possibly through cyanide absorption,18 pro-
viding a very reliable synthesis of 4h and 4i. Ring
opening of substituted epoxides is equally efficient for
synthesizing di- and trisubstituted unsaturated nitriles
(Table 1, entries 1-2 and 8-9, and 3-7, respectively)
from both acyclic and cyclic nitriles (Table 1, entries 1-3
and 4-9, respectively). Efficient opening of the furan 4h
and the pyran 4i (Table 1, entries 8-9) demonstrates that
(19) Ronayne, J .; Williams, D. H. J . Chem. Soc. (C) 1967, 2642.
(20) The authors have deposited atomic coordinates with the
Cambridge Crystallographic Data Center. The coordinates can be
obtained, on request, from the Director, Cambridge Crystallographic
Data Center, 12 Union Road, Cambridge, CB2 1EZ, U.K.
(21) Crandall, J . K.; Apparu, M. Org. React. 1983, 29, 345.
(22) The slower ring-opening rate for 4g with LDA, and the lack of
stereocontrol exhibited with LiHMDS and 4d , suggest that these
reactions proceed through an E1CB-type transition state.
(23) Passarotti, C. M.; Valenti, M.; Ceriani, R.; Grianti, M. Boll.
Chim. Farm. 1993, 132, 150.
(16) 4h has been synthesized directly from the corresponding alcohol
although we obtained only trace quantities of the desired nitriles using
this procedure: Davis, R.; Untch, K. G. J . Org. Chem. 1981, 46, 2985.
(17) Shimizu, T.; Ohzeki, T.; Hiramoto, K.; Hori, N.; Nakata, T.
Synthesis 1999, 1373.
(18) Clark, J . H.; Duke, C. V. A. J . Org. Chem. 1985, 50, 1330.

Notes
J . Org. Chem., Vol. 66, No. 6, 2001 2173
cyclohex-2-enecarbonitrile28 (212 mg), followed by radial chro-
matography (1:4 EtOAc:hexanes), to provide 104 mg of 4f and
54 mg of 4g (65% total) that were spectrally identical to material
previously synthesized.29
Sch em e 3
(()-2-Oxola n -2-yleth a n en itr ile (4h ). An absolute ethanol
solution of the tosylate30 (3.33 g), KCN (2.0 g), and molecular
seives (2 g) was vigorously refluxed for 3 days. The resulting
mixture was filtered through silical gel and carefully concen-
trated in a rotorary evaporator, maintaining the water bath at
30 °C to prevent decomposition. Radial chromatography (CH2-
Cl2) of the crude nitrile afforded 0.93 g (64%) of 4h that was
spectrally identical to material previously synthesized.30
(()-2-P er h yd r o-2H-p yr a n -2-yleth a n en itr ile (4i). Standard
treatment31 of tetrahydropyran-2-methanol (1.57 g) with p-TsCl
(3.87 g) and NaOH (1.08 g) provided 3.57 g (98%) of the desired
tosylate as a solid: 1H NMR (CDCl3) δ 1.18-1.84 (m, 6H), 2.43
(s, 3H), 3.30-59 (m, 2H), 3.89-4.00 (m, 1H), 3.93 (d, J ) 5.0
Hz, 2H), 7.32 (d, J ) 8.2 Hz, 2H), 7.78 (d, J ) 8.2 Hz, 2H); 13C
NMR (CDCl3) δ 21.5, 22.6, 25.4, 27.5, 68.2, 72.5, 74.8, 127.9,
129.7, 133.0, 144.7. An absolute ethanol solution of the tosylate
(1.9 g) KCN (1.8 g), and molecular seives (0.5 g) was vigorously
refluxed for 3 days. The resulting mixture was filtered through
silical gel, and carefully concentrated in a rotorary evaporator,
maintaining the water bath at 30 °C to prevent decomposition.
Radial chromatography (CH2Cl2) of the crude nitrile provided
reoselective providing an efficient two-step synthesis of
trans-R,â-unsaturated nitriles with hydroxylation on
carbons successively removed from the double bond.
Exp er im en ta l Section 24
Gen er a l Ep oxid a tion P r oced u r e. Solid m-CPBA (1.5 equiv)
was added to a room temperature, CH2Cl2 solution (0.1-0.5 M)
of the 3-alkenenitrile. The resultant solution was stirred over-
night, and then saturated, aqueous NaHSO3 was added to reduce
the excess m-CPBA. The organic phase was separated, washed
with saturated aqueous NaHCO3 (3 × 50 mL/mmol alkeneni-
trile), and then dried over anhydrous Na2SO4 or MgSO4. The
dry solution was concentrated under reduced pressure to afford
analytically pure epoxynitrile.
0.618 g (70%) of 4i as an oil: IR (film) 2238 cm-1 1H NMR
;
(CDCl3) δ 1.41-1.89 (m, 6H), 2.49 (d, J ) 6.0 Hz, 2H), 3.45 (dt,
J ) 11, 3 Hz, 1H), 3.50-3.60 (m, 1H), 3.97-4.01 (m, 1H); 13C
NMR (CDCl3) δ 22.8, 24.9, 25.2, 31.0, 68.7, 72.8, 117.3.
Gen er a l Rin g-Op en in g P r oced u r e. A THF solution of the
epoxynitrile was added, by syringe, to a cold (-78 °C), THF
solution (0.5-1 M) of LDA [2 equiv, prepared by the addition of
a hexanes solution of BuLi (2 equiv) to a THF solution of i-Pr2-
NH (2 equiv) at -78 °C]. [For reactions performed with more
than 2 g of an epoxynitrile the precooled (-78 °C), THF solutions
were added by cannula.] After 5 min, 4 equiv of neat HOAc was
added, followed by EtOAc (2-3 times the volume of THF), and
then the solution was gently warmed to room temperature in a
stream of hot air. The crude product was filtered through a short
column of silica gel (2-5 cm pad), concentrated, and then
purified by chromatography.
(()-2-Oxir a n -2-yleth a n en itr ile (4a ). The general procedure
was employed with 3-butenenitrile (5.0 g), adding 1/8 of the
m-CPBA each day for a total of 8 days to provide 4.78 g (77%) of
4a as an oil: IR (film) 2248 cm-1 13C NMR (CDCl3) δ 21.1, 46.1,
;
46.6, 115.4; MS m/e 84 (M + H). The 1H NMR was identical to
that previously reported.15b
(()-2-(3-Meth yloxir a n -2-yl)eth a n en itr ile (4b). The general
procedure was employed with 3-pentenenitrile (5.0 g) to provide
5.3 g (89%) of 4b: IR (film) 2252 cm-1; 1H NMR (CDCl3) δ 1.35
(d, J ) 5.2 Hz, 3H), 2.70 (t, J ) 4 Hz, 2H), 2.93 (dt, J ) 4.6, 2
Hz, 1H), 3.01 (dq, J ) 5.2, 2 Hz, 1H); 13C NMR (CDCl3) δ 16.7,
20.6, 53.1, 54.0, 115.9; 13C NMR (CDCl3) δ 16.7, 20.6, 53.1, 54.0,
115.7; MS m/e 98 (M + H).
(2E)-4-Hyd r oxybu t-2-en en itr ile (1a ). The general proce-
dure was employed with 4a (3.0 g in 30 mL of THF) followed by
radial chromatography (1:1 EtOAc:hexanes) to provide 2.5 g of
1a (83%) as an oil: 13C NMR (CDCl3) δ 61.4, 98.3, 117.4, 153.9.
The 1H NMR was identical to that previously reported.9b,15b
(2E)-4-Hyd r oxyp en t-2-en en itr ile (1b). The general proce-
dure was employed with 4b (5.3 g in 50 mL of THF) followed by
radial chromatography (1:0.8 EtOAc:hexanes) to provide 4.2 g
of 1b (79%) as an oil: 13C NMR (CDCl3) δ 21.8, 66.4, 97.4, 117.2,
(()-2-(2-Meth yloxir a n -2-yl)eth a n en itr ile (4c). The general
procedure was employed with 3-methyl 3-butenenitrile25 (1.05
1
g) to provide 0.77 g (61%) of 4c: IR (film) 2252 cm-1; H NMR
(CDCl3) δ 1.48 (s, 3H), 2.65-2.67 (m, 2H), 2.78 (ABq, ∆ν ) 37
Hz, J ) 4.2 Hz, 2H); 13C NMR (CDCl3) δ 20.5, 25.8, 52.8, 52.9,
115.9; MS m/e 98 (M + H).
(()-2-(6-Oxa bicyclo[3.1.0]h exyl)eth a n en itr ile (4d ). The
general procedure was employed with 1-cyclopenteneacetonitrile
(2.00 g) to provide 1.88 g (82%) of 4d :26 IR (film) 2251 cm-1; 1H
NMR (CS2) δ 1.67-2.03 (m, 4H), 2.14-2.30 (m, 2H), 3.08 (ABq,
∆ν ) 22 Hz, J ) 17 Hz, 2H), 3.64 (s, 1H); 13C NMR (CS2) δ 21.5,
22.2, 28.8, 30.6, 63.2, 63.3, 116.6.
1
158.2. The H NMR was identical to that previously reported.9b
(2E)-4-Hyd r oxy-3-m eth ylbu t-2-en en itr ile (1c). The gen-
eral procedure was employed with 4c (437.8 mg, 4.51 mmol in
5 mL of THF) followed by radial chromatography (2:3 EtOAc:
hexanes) to provide 320.2 mg of 1c (73%) as an oil: 13C NMR
(CDCl3) δ 17.4, 64.9, 93.1, 117.1, 163.9. The 1H NMR was
identical to that previously reported.11
(()-2-(7-Oxa bicyclo[4.1.0]h ep tyl)eth a n en itr ile (4e). The
general procedure was employed with 1-cyclohexeneacetonitrile
1
(1.21 g) to provide 1.28 g (93%) of 4e:27 IR (film) 2249 cm-1; H
2-(2-Hyd r oxycyclop en tylid en e)eth a n en itr ile (1d ). The
general procedure was employed with 4d (117.3 mg in 1 mL of
THF) followed by radial chromatography (2:3 EtOAc:hexanes)
to provide 70.7 mg (60%) of 1d 32 as an oil: IR (film) 2253, 3383
NMR (CDCl3) δ 1.17-1.55 (m, 4H), 1.79-2.06 (m, 4H), 2.65
(ABq, ∆ν ) 24.8 Hz, J ) 17.1 Hz, 2H), 3.20 (br s, 1H); 13C NMR
(CDCl3) δ 19.1, 19.6, 24.1, 26.6, 27.7, 55.8, 58.0, 116.1; MS m/e
138 (M + H).
(()-(6S,1R,2R)-7-Oxa b icyclo[4.1.0]h ep t a n e-2-ca r b on i-
tr ile (4f) and (()-(2S,6S,1R)-7-Oxa bicyclo[4.1.0]h ep ta n e-2-
ca r bon itr ile (4g). The general procedure was employed with
cm-1 1H NMR (CS2) δ 1.83-2.10 (m, 2H), 2.21-2.31 (m, 1H),
;
2.37-2.46 (m, 2H), 2.92-3.00 (m, 2H), 4.74-4.78 (m, 1H), 5.70
(q, J ) 2 Hz, 1H); 13C NMR (CS2) δ 22.2, 31.4, 36.5, 76.3, 93.9,
117.1, 173.2; MS m/e 124 (M + H). A hexanes solution of
butyllithium (1.1 equiv, 1.45 M in hexanes) was added to a cold
(24) For general experimental procedures, see: Fleming, F. F.;
Hussain, Z.; Weaver, D.; Norman, R. E. J . Org. Chem. 1997, 62, 1305.
(25) Prepared from 3-choloro-2-methylpropene and NaCN: Shiraka-
wa, H.; Hayashibara, T.; Nakamura, A. J apanese Patent 91-32525
19910131, 1992. Chem. Abstr. 1993, 118, 38471.
(26) Epoxide 4d has been previously prepared although no spectral
data has been reported: Arias, L. A.; Adkins, S.; Nagel, C. J .; Bach,
R. D. J . Org. Chem. 1983, 48, 888.
(28) Davies, S. G.; Whitham, G. H. J . Chem. Soc., Perkin Trans. 1
1976, 2279.
(29) Murray, W. R.; Singh, M.; Williams, B. L.; Moncrieff, H. M. J .
Org. Chem. 1996, 61, 1830.
(30) Laxmi, Y. R. S.; Iyengar, D. S. Synthesis 1996, 594.
(31) Barger, G.; Robinson, R.; Smith, L. H. J . Chem. Soc. 1937, 718.
(32) Nitrile 1d of unspecified stereochemistry was previously syn-
thesized and partial 1H NMR data reported: Annunziata, R.; Cinquini,
M.; Cozzi, F.; Raimondi, L.; Restelli, A. Gazz. Chim. Ital. 1985, 115,
637.
(27) Epoxide 4e has been previously prepared although no spectral
data has been reported: Suh, Y.-G.; Koo, B.-A.; Ko, J .-A.; Cho, Y.-S.
Chem. Lett. 1993, 1907.

2174 J . Org. Chem., Vol. 66, No. 6, 2001
Notes
(-78 °C), THF solution (2 mL) of 1d (80.7 mg), followed after
10 min., by neat p-nitrobenzoyl chloride (134 mg). The resulting
solution was allowed to warm to room temperature, stirred for
1 h, water was added, and the crude product was then extracted
with EtOAc (3 × 10 mL) and dried (MgSO4). Concentration and
radial chromatography (1:4 EtOAc:hexanes) provided 101.0 mg
solution was allowed to react for 30 min at -78 °C. Conventional
workup, followed by radial chromatography (3:2 EtOAc:hexanes),
provided 14.0 mg of 1f (88%) as an oil.
(2E)-6-Hyd r oxyh ex-2-en en itr ile (1h ). The general proce-
dure was employed with 4h (22.2 mg in 10 mL of THF) and 3
equiv of LDA (prepared in 100 mL of THF) to provide, after
radial chromatography (3:2 EtOAc:hexanes), 14.9 mg (67%) of
1h as an oil spectrally identical to material previously synthe-
sized.13
(2E)-7-Hyd r oxyh ep t-2-en en itr ile (1i). The general proce-
dure was employed with 4i (25.4 mg, 0.190 mmol in 10 mL of
THF) and 4 equiv of LDA (prepared in 100 mL of THF) to
provide, after radial chromatography (3:2 EtOAc:hexanes), 19.4
mg (76%) of 1i as an oil spectrally identical to material
previously synthesized.35
(57%) of the p-nitrobenzoate as
a crystalline solid whose
structure was solved by X-ray diffraction (see Supporting
Information): IR (KBr) 1725, 2216, 2366 cm-1; 1H NMR (CDCl3)
δ1.81-2.15 (m, 3H), 2.28 (sextet, J ) 6 Hz, 1H), 2.66-2.89 (m,
2H), 5.59 (dd, J ) 4.5, 2.7 Hz, 1H), 5.77-5.82 (m, 1H), 8.19 (d,
J ) 8.7 Hz, 1H), 8.30 (d, J ) 8.7 Hz, 1H); 13C NMR (C6D6) δ
21.8, 31.0, 32.6, 77.2, 96.3, 116.6, 123.9, 131.0, 135.0, 151.2,
164.2, 167.1; MS m/e 272 (M).
2-(2-Hydr oxycycloh exyliden e)eth an en itr ile (1e). The gen-
eral procedure was employed with 4e (1.19 g in 20 mL of THF)
followed by radial chromatography (2:3 EtOAc:hexanes) to
provide 1.11 g of 1e (94%) as an oil that was spectrally identical
to material previously synthesized.33
Ack n ow led gm en t. Financial support from NIH is
gratefully acknowledged. We are particularly grateful
to Dr. Carpenter for providing experimental details from
ref 15b.
3-Hyd r oxycycloh ex-1-en eca r bon itr ile (1f). The general
procedure was employed with 4f (103.6 mg in 2 mL of THF)
followed by radial chromatography (2:3 EtOAc:hexanes) to
provide 93.5 mg of 1f (90%) as an oil: 13C NMR (CDCl3) δ 18.6,
Su p p or t in g In for m a t ion Ava ila b le: 1H NMR and 13C
NMR spectra for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
1
26.5, 30.2, 64.7, 114.3, 118.7, 146.1. The H NMR was identical
to that previously reported.34 The general procedure was em-
J O005692O
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