α,β-Unsaturated Nitriles: Stereoselective Conjugate Addition Reactions

Article abstract of DOI:10.1021/jo9619894

Dithiane anions undergo intramolecular conjugate additions with α,β-unsaturated nitriles when a dithiane anion is tethered to N-1 of the 3-cyano-1,4,5,6-tetrahydropyridine nucleus. 3-Cyano-1-[2-(1,3-dithianyl-2-yl)ethyl]-1,4,5,6-tetrahydropyridine (1a) and the one-carbon homologue 1b cyclize in the presence of 12-crown-4 to generate indolizidine 3 and quinolizidine 9, in which the nitrile group exhibits a strong, thermodynamic preference for the axial orientation. Oxidation of 1b provides dithiane S-oxide 10 that undergoes a highly stereoselective conjugate addition to provide crystalline quinolizidine 13. The X-ray structure of 13 is reported and corroborates our "peg-ina-pocket" principle for stereoselective conjugate additions with α,β-unsaturated nitriles.

Full text of DOI:10.1021/jo9619894

J . Org. Chem. 1997, 62, 1305-1309
1305
r,â-Un sa tu r a ted Nitr iles: Ster eoselective Con ju ga te Ad d ition
Rea ction s
Fraser F. Fleming,* Zahid Hussain, Douglas Weaver, and Richard E. Norman1
Department of Chemistry and Biochemistry, Duquesne University, Pittsburgh, Pennsylvania 15282
Received October 24, 1996X
Dithiane anions undergo intramolecular conjugate additions with R,â-unsaturated nitriles when a
dithiane anion is tethered to N-1 of the 3-cyano-1,4,5,6-tetrahydropyridine nucleus. 3-Cyano-1-
[2-(1,3-dithianyl-2-yl)ethyl]-1,4,5,6-tetrahydropyridine (1a ) and the one-carbon homologue 1b cyclize
in the presence of 12-crown-4 to generate indolizidine 3 and quinolizidine 9, in which the nitrile
group exhibits a strong, thermodynamic preference for the axial orientation. Oxidation of 1b
provides dithiane S-oxide 10 that undergoes a highly stereoselective conjugate addition to provide
crystalline quinolizidine 13. The X-ray structure of 13 is reported and corroborates our “peg-in-
a-pocket” principle for stereoselective conjugate additions with R,â-unsaturated nitriles.
Sch em e 1
In tr od u ction
Conjugate addition reactions are of central importance
for carbon-carbon bond formation.2 Numerous anionic
nucleophiles react conjugately with unsaturated carbonyl
derivatives, but many analogous reactions involving
unsaturated nitriles are problematic. Several organo-
copper3 and phenolic4 nucleophiles simply do not react
with many R,â-unsaturated nitriles. Other, more reac-
tive, organocopper reagents5 and alkaline peroxide6 afford
products resulting from both 1,2- and 1,4-addition.
The sparse number of conjugate additions to unsatur-
ated nitriles stimulated us to examine the key require-
ments for this reaction. From these initial studies7 we
developed highly efficient conjugate additions of sulfur
and selenium nucleophiles to various substituted R,â-
unsaturated nitriles. Our intention is to extend the
conjugate additions of unsaturated nitriles to carbon-
based nucleophiles, specifically with dithiane anions.
The reactions of dithiane anions are well established8
and include one report9 in which 2-lithio-1,3-dithiane
reacts conjugately with R,â-unsaturated nitriles. The
reaction is efficient provided that the R-carbon is conju-
gated to an aromatic substituent, but the yield is
significantly reduced with aliphatic substituents. This
report attracted us to dithiane anions, particularly since
recent advances in the formation10 and reactions of chiral
dithiane equivalents (dithiane S-oxides11 and dithiane
S,S-dioxides)12 indicated potential for a stereoselective
conjugate addition reaction.
by tethering a dithiane anion to an R,â-unsaturated
nitrile (Scheme 1). This strategy benefits from the
entropic advantage associated with constraining the two
reacting partners in close proximity but requires gener-
ating a dithiane anion with a base that will neither react
with the nitrile group nor cause deprotonation at other
sites in the molecule. These constraints have restricted
intramolecular cyclizations of dithiane anions to simple
alkyl halides and tosylates13 in all but a few14 cases.
Enamino nitrile 1a appeared to be an ideal substrate
for probing the intramolecular conjugate addition reac-
tion. Potential γ-deprotonation is avoided in 1a , and we
believed that the nitrile group would only slowly react
with n-butyllithium. The reaction of alkyllithiums and
Grignard reagents with nitriles is often sluggish15 and
would be further retarded since the nitrile is conjugated.
Enamino nitrile 1a had additional appeal since the
successful cyclization assembles indolizidine skeleton 3,
common to a number of natural products.16 In this paper
(10) (a) Bulman Page, P. C.; Wilkes, R. D.; Namwindwa, E. S.; Witty,
M. J . Tetrahedron 1996, 52, 2125. (b) Bulman Page, P. C.; Heer, J . P.;
Bethell, D.; Collington, E. W.; Andrews, D. M. Tetrahedron: Asymmetry
1995, 6, 2911. (c) Colonna, S.; Gaggero, N.; Bertinotti, A.; Carrea, G.;
Pasta, P.; Bernardi, A. J . Chem. Soc., Chem. Commun. 1995, 1123.
(d) Aggarwal, V. K.; Evans, G.; Moya, E.; Dowden, J . J . Org. Chem.
1992, 57, 6390. (e) Aggarwal, V. K.; Davies, I. W.; Franklin, R. J .;
Maddock, J .; Mahon, M.F.; Molloy, K. C. J . Chem. Soc., Perkin Trans.
I 1991, 662. (f) Bortolini, O.; Di Furia, F.; Licini, G.; Modena, G.; Rossi,
M. Tetrahedron Lett. 1986, 27, 6257.
Our strategy was to promote the conjugate addition
X Abstract published in Advance ACS Abstracts, February 1, 1997.
(1) Author to whom enquiries concerning the crystal structure
should be addressed.
(2) (a) Perlmutter, P. Conjugate addition reactions in organic
synthesis; Pergamon: New York, 1992. (b) Lipshutz, B. H.; Sengupta,
S. Org. React. 1992, 41, 135.
(3) (a) House, H. O.; Umen, M. J . J . Org. Chem. 1973, 38, 3893. (b)
Totleben, M. J .; Curran, D. P.; Wipf, P. J . Org. Chem. 1992, 57, 1740,
footnote 17. (c) Yamamoto, Y.; Yamamoto, S.; Yatagai, H.; Ishihara,
Y.; Maruyama, K. J . Org. Chem. 1982, 47, 119.
(4) Kawamine, K.; Takeuchi, R.; Miyashita, M.; Irie, H.; Shimamoto,
Ohfune, Y. Chem. Pharm. Bull. 1991, 39, 3170.
(5) (a) Alexakis, A.; Berlan, J .; Besace, Y. Tetrahedron Lett. 1986,
27, 1047. (b) Lipshutz, B. H.; Wilhelm, R. S.; Kozlowski, J . A. J . Org.
Chem. 1984, 49, 3938.
(6) Payne, G. B.; Deming, P. H.; Williams, P. H. J . Org. Chem. 1961,
26, 659. (b) Robert, A; Fouchaud, A. Bull. Chim. Soc. Fr. 1969, 4528.
(7) Fleming, F. F.; Pak, J . J . J . Org. Chem. 1995, 60, 4299.
(8) Gro¨bel, B.-T.; Seebach, D. Synthesis 1977, 357.
(9) Basha, F. Z.; DeBernardis, J . F.; Spanton, S. J . Org. Chem. 1985,
50, 4160.
(11) (a) Bulman Page, P. C.; Shuttleworth, S. J .; Schilling, M. B.;
Tapolczay, D. J . Tetrahedron Lett. 1993, 34, 6947. (b) Bulman Page,
P. C.; Allin, S. M.; Collington, E. W.; Carr, R. A. E. J . Org. Chem. 1993,
58, 6902.
(12) Aggarwal, V. K.; Franklin, R.; Maddock, J .; Evans, G. R.;
Thomas, A.; Mahon, M. F.; Molloy, K. C.; Rice, M. J . J . Org. Chem.
1995, 60, 2174.
(13) (a) Krohn, K.; Bo¨rner, G. J . Org. Chem. 1994, 59, 6063. (b) Sih,
J . C. J . Org. Chem. 1982, 47, 4311. (c) Seebach, D.; J ones, N. R.; Corey,
E. J . J . Org. Chem. 1968, 33, 300.
(14) (a) Grotjahn, D. B.; Andersen, N. H. J . Chem. Soc., Chem.
Commun. 1981, 306. (b) Davey, A. E.; Taylor, R. J . K. J . Chem. Soc.,
Chem. Commun. 1987, 25.
(15) Weiberth, F. J .; Hall, S. S. J . Org. Chem. 1987, 52, 3901.
(16) Michael, J . P. Nat. Prod. Rep. 1994, 11, 639.
S0022-3263(96)01989-5 CCC: $14.00 © 1997 American Chemical Society

1306 J . Org. Chem., Vol. 62, No. 5, 1997
Fleming et al.
Sch em e 2
Sch em e 3
we provide a full account of the first intramolecular
conjugate addition between a dithiane anion and an R,â-
unsaturated nitrile.
Sch em e 4
Resu lts a n d Discu ssion
Enamino nitrile 1a was readily prepared by coupling
the two requisite dithiane and nitrile fragments, 6 and
5. The latter is readily prepared by reduction of nicoti-
nonitrile (4),17 providing a fast, inexpensive method for
preparing large quantities of tetrahydropyridine 5. Ini-
tial attempts to alkylate 5 with the known13c dithianes
6a -c were based on similar alkylations with the corre-
sponding ester18 (5, CNdCO2Me). Typically the yields
of alkylated tetrahydropyridines 1a -c ranged between
50 and 60%, being comparable to alkylations with the
corresponding esters. We ultimately found that the
moderate yields resulted from hydroxide-promoted elimi-
nation and displacement reactions that were easily
avoided by scrupulously drying the rather hygroscopic
tetrahydropyridine 5. This simple precaution provided
the alkylated tetrahydropyridines 1a -c in 83-98% yield
(Scheme 2).
The rapid synthesis of 1a -c expediently provided
suitable precursors for examining the intramolecular
conjugate addition reaction. We were surprised to find
that the addition of butyllithium to a THF solution of 1a
afforded mainly unreacted material and only a trace of
the desired indolizidine, particularly since these condi-
tions were successful for the intermolecular reaction with
R-aryl unsaturated nitriles.9 A survey of different sol-
vents (Et2O, HMPA, TMEDA), additives (BF3‚OEt2, Et2-
AlCl, Ti(i-PrO)4, HMPA), and metal salts (LiCl, ZnBr2)
afforded varying amounts of the desired indolizidine
where the amount of indolizidine roughly correlated with
the solvation of the dithiane anion.
Solvent-separated ion pairs are known to promote
conjugate addition reactions,19 suggesting that sequester-
ing the counterion would facilitate the cyclization. The
cyclization did indeed proceed favorably when catalytic
12-crown-4 was added to the preformed anion, to provide
a 4:1 ratio20 of indolizidines 3a and 3b in 90% yield
(Scheme 3). The requirement for 12-crown-4 may reflect
the need for a free carbanion with an orbital that can
overlap with the π-system of the unsaturated nitrile, as
depicted in 7. The high yield of this reaction precludes
significant addition of butyllithium to the nitrile group,
and this was further confirmed by GCMS analysis21 of
the crude reaction mixture.
Stereochemical assignment of the indolizidine epimers
was achieved by X-ray crystallography. Surprisingly, the
major isomer 3a was found22 to have the nitrile group in
the axial orientation. The origin for this stereochemical
preference is unclear, but we note that a thermodynamic
preference for the axial isomer is conceivable given the
23
small A-value (0.2 kcal mol-1
)
for a nitrile group (vide
infra).
Having optimized the conjugate addition reaction for
indolizidine formation, we turned to the cyclization of
homologue 1b (Scheme 4). Deprotonation of 1b and
subsequent addition of 12-crown-4 smoothly afforded a
mixture of quinolizidines 9a and 9b (3:1 ratio,20 respec-
tively; 81% combined yield). Separation of the individual
epimers was more difficult than that for the indolizidines,
requiring a combination of chromatography and crystal-
lization, but these efforts were rewarded with a highly
crystalline sample of the major epimer. X-ray analysis
again demonstrated that the nitrile group was axial in
the major isomer24 and equatorial in the minor isomer.25
The unusual stereochemical preference for an axially
oriented nitrile prompted us to examine the origin of this
effect. Since both cyclizations occurred without signifi-
cant interference from butyllithium, we used catalytic
butyllithium to equilibrate a mixture of 9a and 9b to
underscore the low reactivity of the nitrile group toward
this nucleophilic base. Equilibration resulted in the
exclusive formation of 9a (Scheme 4). This equilibration
is in stark contrast to analogous reactions of quinolizidine
esters that result in the ester adopting an equatorial
orientation.26 We interpret the preference for an axial
nitrile substituent as arising from a very small nitrile-
proton syn-axial interaction rather than a less favorable
gauche interaction with the adjacent methylene in 9b.27
(22) Fleming, F. F.; Hussain, Z.; Mullaney, M.; Norman, R. E.;
Chang, S.-C. Acta Crystallogr. 1996, C52, 2849.
(23) Eliel, E. L.; Wilen, S. H. Mander, L. N. Stereochemistry of
Organic Compounds; Wiley: New York, 1994; p 697.
(24) Hussain, Z.; Fleming, F. F.; Norman, R. E.; Chang, S.-C. Acta
Crystallogr. 1996, C52, 1296.
(25) Fleming, F. F.; Hussain, Z.; Norman, R. E.; Chang, S.-C. Acta
Crystallogr. submitted.
(26) (a) Morley, C.; Knight, D. W.; Share, A. C. J . Chem. Soc., Perkin
Trans. I 1994, 2903. (b) Comins, D. L.; Brown, J . D. Tetrahedron Lett.
1986, 27, 2219. (c) Tufariello, J . J .; Tegeler, J . J . Tetrahedron Lett.
1976, 4037. (d) Goldberg, S. I.; Lipkin, A. H. J . Org. Chem. 1970, 35,
242.
(17) Kikugawa, Y.; Kuramoto, M.; Saito, I.; Yamada, S.-I. Chem.
Pharm. Bull. 1973, 21, 1914.
(18) Beckwith, A. L. J .; Westwood, S. W. Tetrahedron 1989, 45, 5269.
(19) (a) Cohen, T.; Abraham, W. D.; Meyers, M. J . Am. Chem. Soc.
1987, 109, 7923. (b) Reich, H. J .; Borst, J . P.; Dykstra, R. R.
Tetrahedron 1994, 50, 5869.
(20) Based on isolated yields.
(21) Only trace amounts of a material with a molecular weight
corresponding to the addition of butyllithum to the nitrile group was
detected by GCMS.

R,â-Unsaturated Nitriles
J . Org. Chem., Vol. 62, No. 5, 1997 1307
F igu r e 1.
Sch em e 5
F igu r e 2. ORTEP drawing of the cyclic dithiane di-S-oxide
13.
providing a single diastereomer in 79% yield. This
diastereomer was highly crystalline and subjected to
X-ray analysis to facilitate an otherwise difficult stere-
ochemical assignment. We were initially surprised to
find that the X-ray structure31 (Figure 2) contained an
additional S-oxide moiety. Di-S-oxide 13 contains a cis-
fused quinolizidine, unlike 3 and 9, which presumably
reflects the strong steric interactions that would other-
wise arise with the diaxial oxygen atoms. The quino-
lizidine ring is twisted slightly such that the axial nitrile
is positioned further away from the ring methylene
protons, effectively minimizing these 1,3-diaxial interac-
tions.
All attempts to extend this cyclization to formation of a
7-membered ring, with 1c, have been unsuccessful.
Asymmetric carbon-carbon bond formation is very
rare for nitrile-based methodology, mainly because of the
difficulty of associating a chiral auxiliary with the CN
unit. We reasoned that high stereoselectivity might be
achieved by exploiting the unique topology of R,â-
unsaturated nitriles. R,â-Unsaturated nitriles with one
trans â-substituent contain a pocket between the small
nitrile group and the proton that can act as a template
in reactions with chiral nucleophiles (Figure 1). We
envisaged that a dithiane S-oxide could provide a “peg”
capable of locating in the nitrile pocket with only one
matched “peg-in-a-pocket” conformation being accessible
for a dithiane S-oxide tethered to the â-carbon of an R,â-
unsaturated nitrile.
We have previously noted25 that dithiane-substituted
quinolizidines are easily oxidized, and on one occasion
oxidation occurred during crystallization from oxygen-
containing solvents. The cyclic dithiane S-oxide 12 seems
particularly susceptible to oxidation during purification,
1
and we have observed that the H NMR spectrum of the
crude cyclization product differs from that of 13, obtained
after chromatography. The cis relationship between the
S-oxide and the angular proton is established during
C-C bond formation, and severe steric interactions are
only avoided by positioning the S-oxide in the nitrile
pocket (11b). This cyclization leads directly to 12 with
the same conformation as that observed in the crystal
structure. A subsequent ring-flip to the trans-fused
quinolizidine is not expected since this would position the
oxygen atom close to the methine proton at C-1. Oxida-
tion of 12 from the cis conformer is likely directed29 by
the neighboring sulfoxide group leading to the observed
di-S-oxide 13.
We employed dithiane S-oxide 10 to test this “peg-in-
a-pocket” principle of stereocontrol. Periodate oxidation
of dithianes is known28 to generate trans-dithiane S-
oxides, and in this case treatment with sodium meta-
periodate furnished trans-S-oxide 10 (Scheme 5). 1H
NMR is particularly effective for assigning29 the stereo-
chemistry of the resultant S-oxide since the adjacent
equatorial proton appears between δ 3.2 and 3.6 for the
trans isomer and at higher fields for the cis isomer. The
stereochemical assignment of 10 is confirmed by the
diagnostic signal at δ 3.44, while the 13C NMR clearly
shows 13 distinct signals indicative of an unsymmetrical
dithiane ring.
The cyclization of 10 to 12 was remarkably stereo-
selective (Scheme 5). Deprotonation of 10 caused forma-
tion of a precipitate with no cyclization occurring until
the presumed anion was dissolved by the addition of
HMPA.30 Purification of the crude, cyclic, quinolizidine
again required both chromatography and crystallization,
Con clu sion
Functionalized indolizidine and quinolizidines are
rapidly assembled by an intramolecular conjugate addi-
tion between a dithiane-type anion and an R,â-unsatur-
ated nitrile. This cyclization is one of the few known
intramolecular conjugate additions involving an R,â-
(27) Molecular mechanics calculations (Chem-3D) indicate that the
equatorially oriented nitrile 9b is 0.2 kcal/mol more stable than 9a .
The X-ray structure24 of 9a shows that the quinolizidine ring is twisted
so that the nitrile and the syn-axial proton are splayed further away
from each other than in a true syn-axial relationship. In the X-ray
structure25 of the S-oxide derived from 9b, the nitrile group is bent
away from the dithiane ring and closer to the adjacent methylene unit,
thereby exacerbating the gauche interaction between the nitrile and
methylene groups.
(28) Cook, M. J .; Tonge, A. P. J . Chem. Soc., Perkin Trans. II 1974,
767.
(29) Carey, F. A.; Dailey, O. D., J r.; Hernandez, O.; Tucker, J . R. J .
Org. Chem. 1976, 41, 3975.
(30) The use of catalytic 12-crown-4 did not homogenize the colloidal
solution, and no cyclization was observed.
(31) Crystal data for C13H20N2O2S2, 13: M ) 300.43, orthorhombic
space group Pca21 (No. 29), a ) 11.103(2) Å, b ) 10.517(2) Å, c )
12.244(2) Å, V ) 1429.8(8) Å, Dc ) 1.40 g cm-3, Z ) 4, µ(Mo KR) ) 3.7
cm-1, l (Mo KR) ) 0.710 69 Å, R ) 0.032, Rw ) 0.027 for 1379 observed
reflections (I >3σ(I)). The authors have deposited atomic coordinates
for 13 with the Cambridge Crystallographic Data Center. The coordi-
nates can be obtained, on request, from the Director, Cambridge
Crystallographic Data Center, 12 Union Road, Cambridge, CB21EZ,
U.K.

1308 J . Org. Chem., Vol. 62, No. 5, 1997
Fleming et al.
hexane solution of n-butyllithium (1.36 M, 1.4 equiv) was
added by syringe to a THF solution (1 mL) of the 3-cyano-1-
[ω-(1, 3-dithian-2-yl)alkyl]-1,4,5,6-tetrahydropyridine (1 equiv)
at room temperature. The solution was stirred for 30 min and
then neat 12-crown-4 (0.1 equiv) was added. After 18 h
saturated, aqueous NH4Cl was added, and the aqueous phase
was separated and was then extracted with EtOAc (3 × 10
mL). The combined extracts were dried over anhydrous
sodium sulfate and concentrated under reduced pressure to
afford a crude material that was purified by radial chroma-
tography.
unsaturated nitrile and demonstrates the advantage of
using the nitrile group in dithiane-based cyclizations. The
method is unique in affording alkaloids with the nitrile
group in an axial orientation and opens numerous
possibilities for preparing axially-substituted indoliz-
idines and quinolizidines. We have demonstrated excel-
lent stereoselectivity in the first intramolecular conjugate
addition of a dithiane S-oxide and envisage several chiral
extensions using our “peg-in-a-pocket” principle.
(()-(8R,8a S)-In d olizid in e-1-sp ir o-2′-(1′,3′-d it h ia n e)-8-
ca r bon itr ile (3a ). The general procedure was used with
n-butyllithium (0.18 mL, 0.24 mmol), 3-cyano-1-[2-(1,3-dithian-
2-yl)ethyl]-1,4,5,6-tetrahydropyridine (44.9 mg, 0.18 mmol),
and 12-crown-4 (3.1 mg, 17.6 µmol). The crude product was
purified by radial chromatography (1 mm plate, 1:1 EtOAc:
hexane) to provide 32.5 mg (72%) of one diastereomer and 8.1
mg of another diastereomer (18%), both as white solids. The
major diastereomer was recrystallized (EtOAc/hexane) to
afford colorless crystals (mp 103-105 °C) of 3a : IR (KBr) 2934,
Exp er im en ta l Section
General experimental details can be found in ref 7. 1H NMR
spectra are recorded at 300 MHz while 13C NMR spectra are
recorded at 75 MHz. 3-Cyano-1,4,5,6-tetrahydropyridine was
prepared as previously described17 and dried by heating (75-
85 ˚C) under vacuum for 10 min. The (chloroalkyl)dithianes
6b and 6c were prepared by known methods13c while 6a was
prepared as described but using p-toluenesulfonic acid in place
of gaseous HCl.
N-Alk yla tion of 3-Cya n o-1,4,5,6-tetr a h yd r op yr id in e.
Freshly distilled DMF (5 mL) was added to dry, THF-washed
(3 × 1 mL), potassium hydride (35 wt %, 3 equiv) at room
temperature. Molten 3-cyano-1,4,5,6-tetrahydropyridine (1
equiv) was added in one portion, and then 2 mL of DMF was
used to wash the remaining material into the reaction flask.
The resultant solution was stirred for 30 min, and then neat
2-(ω-chloroalkyl)-1,3-dithiane (1 equiv) was added. After 2 h,
saturated aqueous NH4Cl was added, and the aqueous phase
was separated and then extracted with ether (3 × 20 mL). The
extracts were combined, dried over anhydrous sodium sulfate,
and concentrated under reduced pressure.
1
2806, 2250, 1041 cm-1; H NMR δ 1.54-1.71 (m, 3H), 2.02-
2.17 (m, 4H), 2.25-2.29 (m, 1H), 2.39 (br q, J ) 9 Hz, 1H),
2.54-2.73 (m, 2H), 2.81-3.18 (m, 7H); 13C NMR δ 23.8, 25.5,
26.9, 28.8, 29.5, 29.6, 43.1, 52.3, 52.5, 56.4, 74.9, 120.4; MS
254 (M+). The minor diastereomer was recrystallized from hot
hexane to give white crystalline (mp 96-99 °C) 3b: IR (KBr)
1
2943, 2252, 1039 cm-1; H NMR δ 1.55-1.66 (m, 2H), 1.87-
2.23 (m, 6H), 2.36-2.61 (m, 3H), 2.77 (br dt, J ) 15, 4 Hz,
1H), 2.88 (br dt, J ) 15, 4 Hz, 1H), 2.97 (br ddd, J ) 14, 10.5,
3.2 Hz, 1H), 3.08-3.26 (m, 4H); 13C NMR δ 21.3, 25.2, 27.6,
29.1, 29.9, 30.0, 42.0, 52.3, 53.2, 56.0, 77.3, 120.9; MS m/ e
255 (MH+).
(()-(9S,9a R)-1,3,4,6,7,8,9,9a -Octa h yd r o-2H-qu in olizin e-
1-sp ir o-2′-(1′,3′-d ith ia n e)-9-ca r bon itr ile (9a ). The general
procedure was employed with n-butyllithium (70 uL, 99.1
µmol), 3-cyano-1-[3-(1,3-dithian-2-yl)propyl]-1,4,5,6-tetrahy-
dropyridine (19.0 mg, 70.9 µmol) and 12-crown-4 (1.2 mg, 6.8
µmol). The crude reaction mixture was concentrated until all
but 0.5 mL of the solvent was removed, and the remaining
solvent was allowed to slowly evaporate. This procedure
afforded a solid that was recrystallized from hexane to afford
9.0 mg (47%) of 9a as a white, crystalline solid (mp 176-178
°C): IR (KBr) 2953, 2824, 2767, 2229, 1114, 913 cm-1; 1H NMR
δ 1.49-1.55 (m, 1H), 1.70-1.94 (m, 4H), 2.04-2.25 (m, 5H),
2.43 (d, J ) 6.1 Hz, 1H), 2.63 (dt, J ) 14.4, 3.8 Hz, 1H), 2.72-
2.94 (m, 5H), 3.03 (ddd, J ) 14.3, 11.2, 3.1 Hz, 2H), 3.55 (br q,
J ) 6 Hz, 1H); 13C NMR δ 20.2, 21.7, 25.3, 25.6, 26.4, 28.6,
30.3, 35.6, 53.9, 54.5, 57.5, 70.1, 122.1; MS m/ e 269 (MH+).
The remaining oil was purified by radial chromatography (1
mm plate, 3:7 EtOAc:hexane) to afford 4.0 mg (21%) of 9b as
a light brown solid (mp 175-177 °C): IR (KBr) 2942, 2809,
3-C y a n o -1-[2-(1,3-d it h ia n -2-y l)e t h y l]-1,4,5,6-t e t r a -
h yd r op yr id in e (1a ). The general procedure was employed
with potassium hydride (187.6 mg, 1.64 mmol), 3-cyano-1,4,5,6-
tetrahydropyridine (59.0 mg, 0.55 mmol), and 2-(2-chloroethyl)-
1,3-dithiane (99.7 mg, 0.55 mmol). The crude material was
purified by radial chromatography (3:7 EtOAc:hexanes) to
afford 120.1 mg (87%) of 1a as a viscous, light yellow liquid:
IR (film) 2931, 2181, 1623, 912 cm-1
;
1H NMR δ 1.72-1.79
(m, 3H), 1.84 (br q, J ) 7 Hz, 2H), 2.02-2.06 (m, 1H), 2.10 (br
t, J ) 6 Hz, 2H), 2.72-2.85 (m, 4 H), 3.00 (br t, J ) 5 Hz, 2H),
3.19 (t, J ) 6.6 Hz, 2H), 3.87 (t, J ) 7.0 Hz, 1 H), 6.73 (s, 1 H);
13C NMR δ 20.0 (t), 20.9 (t), 24.9 (t), 29.1 (t), 33.0 (t), 42.9 (d),
44.1 (t), 51.3 (t), 71.4 (s), 122.4 (s), 146.3 (d); MS m/ e 254 (M+).
3-Cya n o-1-[3-(1,3-d it h ia n -2-yl)p r op yl]-1,4,5,6-t e t r a -
h yd r op yr id in e (1b). The general procedure was employed
with potassium hydride (767.0 mg, 6.71 mmol), 3-cyano-1,4,5,6-
tetrahydropyridine (241.7 mg, 2.24 mmol), and 2-(3-chloro-
propyl)-1,3-dithiane (439.8 mg, 2.24 mmol). The crude mate-
rial was purified by radial chromatography (4 mm plate, 3:7
EtOAc:hexane) to afford 589.7 mg (98%) of 1b as a viscous,
1
2761, 2234, 1143 cm-1; H NMR δ 1.53-1.78 (m, 4H), 1.88-
yellow liquid: IR (film) 2931, 2178, 1621 cm-1 1H NMR δ
;
2.23 (m, 8H), 2.31 (br s, 1H), 2.63-2.91 (m, 5H), 3.00-3.18
(m, 3H), 3.55 (br s, 1H); 13C NMR δ 21.0, 22.2, 25.3, 25.6, 26.1,
26.4, 28.5, 37.0, 53.1, 56.2, 56.5, 71.3, 122.9; MS m/ e 269
(MH+). Several mixed fractions, containing predominantly 9a ,
were obtained providing 2.5 mg (13%) of a mixture of quino-
lizine isomers 9a and 9b.
1.63-1.87 (m, 7H), 2.04-2.10 (m, 1H), 2.14 (t, J ) 6.0 Hz, 2H),
2.74-2.89 (m, 4H), 3.01-3.05 (m, 4H), 3.99 (br t, J ) 6 Hz,
1H), 6.69 (s, 1H); 13C NMR δ 20.7 (t), 21.6 (t), 25.1 (t), 25.6 (t),
30.1 (t), 32.0 (t), 44.8 (t), 46.7 (d), 55.0 (t), 71.9 (s), 123.4 (s),
146.9 (d); MS m/ e 269 (MH+).
Equ ilibr a tion . A hexane solution of n-butyllithium (5 µL,
7 µmol) was added to a THF solution (1 mL) of a mixture of
quinolizidine epimers 9a and 9b (11.8 mg, 44.0 µmol), causing
the solution to become a light brown color. After 12 h
saturated, aqueous NH4Cl was added and the aqueous phase
was separated and was then extracted with CH2Cl2 (3 × 10
mL). The combined organic extracts were dried (Na2SO4) and
concentrated under reduced pressure to afford a crude material
that was purified by radial chromatography (1mm plate, 3:7
EtOAc:hexane) to give 9.2 mg (78%) of 9a , identical in all
respects to the material previously isolated.
3-Cyan o-1-[3-(tr a n s-1-oxo-1,3-dith ian -2-yl)pr opyl]-1,4,5,6-
tetr a h yd r op yr id in e (10). An aqueous solution (1 mL) of
sodium metaperiodate (20.2 mg, 0.09 mmol) was added,
dropwise, to a methanolic solution (2 mL) of 1b (23.1 mg, 0.09
mmol) at room temperature. After 1 h the mixture was
extracted with CH2Cl2 (3 × 10 mL) and the extracts were
3-C y a n o -1-[4-(1,3-d it h ia n -2-y l)b u t y l]-1,4,5,6-t e t r a -
h yd r op yr id in e (1c). The general procedure was used with
potassium hydride (1.63 g, 14.2 mmol), 3-cyano-1,4,5,6-tet-
rahydropyridine (512.4 mg, 4.74 mmol), and 2-(4-chlorobutyl)-
1,3-dithiane (998.9 mg, 4.74 mmol). The crude material was
purified by radial chromatography (4 mm plate, 3:7 EtOAc:
hexane) to afford 1.11 g (83%) of 1c as a white solid. A portion
was recrystallized from hot hexane to provide 1c as white
1
needles (mp 73-75 °C); IR (KBr) 2930, 2167, 1619 cm-1; H
NMR δ 1.43-1.58 (m, 4H), 1.71-1.92 (m, 5H), 2.05-2.08 (m,
1H), 2.09 (br t, J ) 3 Hz, 2H), 2.78-2.93 (m, 4 H), 3.02-3.07
(m, 4H), 4.03 (t, J ) 6.8 Hz, 1H), 6.73 (s, 1H); 13C NMR δ 20.7
(t), 21.6 (t), 23.4 (t), 25.7 (t), 27.8 (t), 30.2 (t), 34.8 (t), 45.0 (t),
47.0 (d), 55.3 (t), 71.6 (s), 123.5 (s), 147.0 (d); MS m/ e 283
(MH+).
Gen er a l P r oced u r e for th e Cycliza tion of 3-Cya n o-1-
[ω-(1,3-d ith ia n -2-yl)a lk yl]-1,4,5,6-tetr a h yd r op yr id in es. A

R,â-Unsaturated Nitriles
J . Org. Chem., Vol. 62, No. 5, 1997 1309
combined and then dried over anhydrous sodium sulfate. The
crude material was concentrated under reduced pressure and
purified by radial chromatography (1 mm plate, 1:6 EtOH:
EtOAc) to afford 20.3 mg (83%) of 10 as a light yellow oil: IR
of EtOAc and EtOH to afford 15.6 mg (79%) of 13 as a white,
crystalline solid (mp 194-196 °C): IR (film) 2996, 2916, 2250,
1047 cm-1; 1H NMR δ 1.25 (br s, 1H), 1.40-1.53 (m, 2H), 1.76-
2.38 (m, 6H), 2.53 (br td, J ) 14, 5.7 Hz, 1H), 2.63 (dd, J )
12.1, 4.2 Hz, 1H), 2.92-3.41 (m, 6H), 3.60 (br s, 1H), 3.84 (td,
J ) 12.1, 3.7 Hz, 1H), 4.16 (d, J ) 3.3 Hz, 1H); 13C NMR δ
3.9, 15.8, 20.4, 21.1, 22.1, 29.9, 41.9, 42.1, 44.0, 54.4, 55.0, 67.2,
123.6.
(film) 2933, 2854, 2178, 1621, 1018 cm-1 1H NMR δ 1.62-
;
1.91 (m, 5H), 2.17 (br t, J ) 6 Hz, 2H), 2.21-2.33 (m, 2H),
2.43-2.48 (m, 1H), 2.56-2.75 (m, 3H), 3.04-3.12 (m, 4H), 3.44
(br d, J ) 13 Hz, 1H), 3.56-3.60 (m, 1H), 6.72 (s, 1H); 13C
NMR δ 20.7 (t), 21.7 (t), 24.6 (t), 25.9 (t), 29.3 (t), 29.9 (t), 45.0
(t), 53.8 (t), 55.1 (t), 65.3 (d), 72.4 (s), 123.4 (s), 146.9 (d).
(()-(1′S,3′R,9S,9a R)-1,3,4,6,7,8,9,9a -Octa h yd r o-2H-qu in -
olizin e -1-sp ir o-2′-(1′,3′-d ioxo-1′,3′-d it h ia n e )-9-ca r b o-
n itr ile (13).31 A hexane solution of n-butyllithium (149.3 µL,
0.21 mmol) was added by syringe to a THF solution (1 mL) of
10 (19.8 mg, 69.7 µmol) at room temperature. After 30 min,
neat HMPA (120 µL) was added and the resultant solution
was allowed to stir for a further 6 h. Saturated, aqueous NH4-
Cl was then added the aqueous phase was separated and then
extracted with EtOAc (3 × 10 mL). The combined extracts
were dried over anhydrous sodium sulfate and concentrated
under reduced pressure to afford a light yellow liquid. The
crude product was purified by radial chromatography (2 mm
plate, 1:20 EtOH:CH2Cl2) and recrystallized from a mixture
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. Techni-
cal assistance from S.-C. Chang during the structure
determination is appreciated.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of all new compounds and a table of fractional atomic
coordinates (18 pages). This material is contained in libraries
on microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
J O9619894