Stereospecific Rearrangements during the Synthesis of Pyrrolidines and Related Heterocycles from Cyclizations of Amino Alcohols with Vinyl Sulfones

Article abstract of DOI:10.1021/jo0350864

Conjugate additions of amino alcohols derived from α-amino acids to vinyl sulfones, followed by N-benzylation, chlorination, and intramolecular alkylation, provide a convenient route to substituted pyrrolidines. The process is accompanied by the stereospe

Full text of DOI:10.1021/jo0350864

Ster eosp ecific Rea r r a n gem en ts d u r in g th e Syn th esis of
P yr r olid in es a n d Rela ted Heter ocycles fr om Cycliza tion s of Am in o
Alcoh ols w ith Vin yl Su lfon es
Thomas G. Back,* Masood Parvez,† and Huimin Zhai
Department of Chemistry, University of Calgary, Calgary, AB, Canada T2N 1N4
tgback@ucalgary.ca
Received J uly 25, 2003
Conjugate additions of amino alcohols derived from R-amino acids to vinyl sulfones, followed by
N-benzylation, chlorination, and intramolecular alkylation, provide a convenient route to substituted
pyrrolidines. The process is accompanied by the stereospecific rearrangement of substituents from
the R-position of the amine to the â-position of the product and takes place via the corresponding
aziridinium ion intermediates. Another type of rearrangement was observed during the reaction
of (2-piperidine)methanol or 2-(2-piperidine)ethanol with phenyl trans-1-propenyl sulfone, in which
the methyl group appears to migrate from the â- to the R-position of the sulfone moiety. This process
involves the isomerization of phenyl trans-1-propenyl sulfone to phenyl 2-propenyl sulfone by the
addition-elimination of catalytic benzenesulfinate anion to the former vinyl sulfone, followed by
conjugate addition of the amino group to the latter sulfone. Chlorination and intramolecular
alkylation then afford the corresponding rearranged indolizidine and quinolizidine derivatives,
respectively.
SCHEME 1
Unsaturated sulfones have proven to be versatile
synthetic reagents.1 For example, the activating and
electron-withdrawing effects of the sulfone moiety enable
these compounds to undergo conjugate additions and
cycloadditions, as well as deprotonation and alkylation
of the corresponding R-anions. Moreover, the sulfone
group can be removed at the end of a synthetic sequence
by a variety of reductive, alkylative, or oxidative methods,
where the sulfonyl moiety is replaced by hydrogen, an
alkyl group from a suitable organometallic cross-coupling
reagent, or an oxygen function, respectively.2 We recently
reported the syntheses of various types of nitrogen
heterocycles by conjugate additions of cyclic or acyclic
amines bearing â- or γ-chloro substituents to acetylenic
sulfones, followed by intramolecular alkylation.3 The
products included variously substituted pyrrolizidines,
indolizidines, quinolizidines, and piperidines (e.g., see
Scheme 1). These ring systems are found in myriad
natural and synthetic products possessing diverse types
of bioactivity.
Alternatively, ring-closure has been achieved via in-
tramolecular acylation by incorporating ester instead of
chloro substituents in the amine. Since many of the
amines can be derived from natural amino acids, enan-
tioselective syntheses of the target compounds are pos-
sible. When followed by desulfonylation and other func-
tional group transformations, these cyclization protocols
provided concise enantioselective routes to (-)-pumil-
iotoxin C,4 indolizidines (-)-167B, (-)-209D, (-)-209B,
and (-)-207A,3b as well as to (-)-lasubine II5 (for example,
see Scheme 2) and certain quinolone alkaloids found in
the medicinal herb Ruta chalepensis.6
The success of the above cyclizations with use of
acetylenic sulfones prompted us to investigate their
extension to vinyl sulfones.7 We now report that similar
cyclizations with the latter compounds are indeed pos-
sible, but in some cases are accompanied by two types of
* Address general correspondence to this author.Phone: (403) 220-
6256. Fax: (403) 289-9488.
† Address correspondence regarding X-ray structures to this author.
Phone: (403) 220-5348. Fax: (403) 289-9488.
(1) For general reviews of sulfone chemistry, see: (a) Simpkins, N.
S. Sulphones in Organic Synthesis; Pergamon Press: Oxford, UK, 1993.
(b) Patai, S.; Rappoport, Z.; Stirling, C. J . M., Eds. The Chemistry of
Sulphones and Sulphoxides; Wiley: Chichester, UK, 1988. For reviews
of acetylenic and allenic sulfones, see: (c) Back, T. G. Tetrahedron
2001, 57, 5263. For vinyl sulfones, see: (d) Simpkins, N. S. Tetrahedron
1990, 46, 6951. For dienyl sulfones, see: (e) Ba¨ckvall, J . E.; Chinchilla,
R.; Na´jera, C.; Yus, M. Chem. Rev. 1998, 98, 2291.
(4) Back, T. G.; Nakajima, K. J . Org. Chem. 1998, 63, 6566.
(5) Back, T. G.; Hamilton, M. D. Org. Lett. 2002, 4, 1779.
(6) Back, T. G.; Parvez, M.; Wulff, J . E. J . Org. Chem. 2003, 68,
2223.
(2) Na´jera, C.; Yus, M. Tetrahedron 1999, 55, 10547.
(3) (a) Back, T. G.; Nakajima, K. Org. Lett. 1999, 1, 261. (b) Back,
T. G.; Nakajima, K. J . Org. Chem. 2000, 65, 4543.
10.1021/jo0350864 CCC: $25.00 © 2003 American Chemical Society
Published on Web 11/06/2003
J . Org. Chem. 2003, 68, 9389-9393
9389

Back et al.
SCHEME 2
confirmed by an NOE experiment (see the Experimental
Section). In addition, reductive desulfonylation of 6a with
sodium amalgam10 afforded the known compound (R)-N-
benzyl-3-methylpyrrolidine.11a,b This method therefore
permits the stereospecific transposition of substituents
from the R-positions of the starting amines, which are
readily available from the corresponding amino acids, to
the less accessible â-positions in the pyrrolidine products.
In contrast, 8 afforded two diastereomeric products 9
and 10, neither of which had undergone rearrangement
of the C-methyl group under similar conditions. The
structure of the major product 9 was confirmed by X-ray
crystallography, while that of 10 was based on NMR
evidence. Moreover, reductive desulfonylation10 of 9 and
10 furnished the known11c compounds trans- and cis-N,2-
dimethyl-3-phenylpyrrolidine, respectively. The similar
cyclization of adducts 12a and 12b afforded the corre-
sponding indolizidine 14a and quinolizidine 14b, respec-
tively. Product 14a was obtained as a 54:46 mixture of
separable diastereomers, while 14b was obtained as a
single diastereomer. Unambiguous assignment of respec-
tive stereochemistry was not possible for 14a and 14b.12
The above rearrangements leading to 6a -c can be
rationalized by invoking the formation of aziridinium ion
intermediates 15a -c during the chlorination of 4a -c
with thionyl chloride (Scheme 4). The neighboring group
effects of nitrogen mustards and related species are well-
known to involve such intermediates.13 Moreover, the
regiochemistry of ring-opening of aziridinium species is
determined by a combination of steric and electronic
factors, and there is precedent for preferential reaction
at the more substituted carbon atom by chloride ion.14
Thus, attack by chloride ion at the tertiary carbon atoms
of 15a -c with inversion of configuration affords the
rearranged products 5a -c, and ultimately 6a -c, respec-
tively, after a second inversion during intramolecular
alkylation of the corresponding sulfone-stabilized anion.
The absence of rearranged products from (-)-ephedrine,
along with the observed epimerization of the phenyl-
substituted carbon atom, suggests the formation of
carbocation 16 rather than aziridinium ion 17 during the
chlorination step (Scheme 4).15 Similarly, the formation
of 14a instead of the rearranged product 18 (Scheme 4)
from 11a indicates that either aziridinium ion formation
rearrangements of substituents that originate from the
R-position of the amino group or â-position of the vinyl
sulfone in the starting materials.
The amino alcohols 2a , 2b, and 2c were readily
obtained from (L)-alanine, (L)-phenylalanine, and (L)-
valine, respectively,8 while phenyl vinyl sulfone (1a )9a and
phenyl trans-1-propenyl sulfone (1b) were obtained by
literature methods.9b Compounds 2a -c, as well as (-)-
ephedrine (7) and the homologous racemic amino alcohols
11a and 11b, all reacted with sulfone 1a by conjugate
addition in refluxing 2-propanol or xylenes to afford the
adducts 3a -c, 8, and 12a ,b, respectively (Scheme 3). To
permit easier handling in subsequent steps, products
3a -c were N-benzylated to give 4a -c prior to chlorina-
tion with thionyl chloride. Alternatively, when N-benzy-
lated amino alcohols were employed in the initial conju-
gate addition step, a more sluggish reaction was observed,
leading to diminished yields of the corresponding ad-
ducts. Products 4a -c were treated with thionyl chloride,
followed by workup with aqueous potassium hydroxide
solution. We observed that a facile rearrangement oc-
curred during this process, leading to the stereospecific
formation of the corresponding chlorides 5a -c. Cycliza-
tion of the latter compounds with LDA then afforded the
pyrrolidine derivatives 6a -c, respectively (Scheme 3).
Evidence for the rearranged structures was based on
NMR evidence, including the observation of relatively
1
downfield H and 13C NMR signals consistent with the
(10) Desulfonylation was effected via the method of Trost et al.:
Trost, B. M.; Arndt, H. C.; Strege, P. E.; Vehoeven, T. R. Tetrahedron
Lett. 1976, 3477.
(11) (a) Coldham, I.; Hufton, R. Tetrahedron 1996, 52, 12541. (b)
Di Cesare, P.; Bouzard, D.; Essiz, M.; J acquet, J . P.; Ledoussal, B.;
Kiechel, J . R.; Remuzon, P.; Kessler, R. E.; Fung-Tomc, J .; Desiderio,
J . J . Med. Chem. 1992, 35, 4205. (c) Chelucci, G.; Saba, A. Angew.
Chem., Int. Ed. Engl. 1995, 34, 78.
(12) Compound 14b with unspecified stereochemistry has been
reported previously: Padwa, A.; Kline, D. N.; Murphree, S. S.; Yeske,
P. E. J . Org. Chem. 1992, 57, 298.
(13) (a) Miller, B. Advanced Organic Chemistry-Reactions and
Mechanisms; Prentice Hall: Upper Saddle River, NJ , 1998; pp 177-
181. (b) Crist, D. R.; Leonard, N. J . Angew. Chem., Int. Ed. Engl. 1969,
8, 962.
(14) (a) Fuson, R. C.; Zirkle, C. L. J . Am. Chem. Soc. 1948, 70, 2760.
(b) Kerwin, J . F.; Ullyot, G. E.; Fuson, R. C.; Zirkle, C. L. J . Am. Chem.
Soc. 1947, 69, 2961. (c) Schultz, E. M.; Sprague, J . M. J . Am. Chem.
Soc. 1948, 70, 48.
(15) Alternatively, the epimerization could result from competing
SNi and SN2 reactions of the presumed chlorosulfite intermediate. For
the regio- and stereoselectivity of other reactions of ephedrine and
pseudoephedrine with nucleophiles via aziridinium ion intermediates,
see: Dieter, R. K.; Deo, N.; Lagu, B.; Dieter, J . W. J . Org. Chem. 1992,
57, 1663.
presence of three CH2N groups. The trans orientation of
the methyl and benzenesulfonyl substituents in 6a was
(7) For examples of other types of synthetic applications involving
conjugate additions of amines to vinyl sulfones, see: (a) Caldwell, J .
J .; Craig, D.; East, S. P. Synlett 2001, 1602. (b) Berry, M. B.; Craig,
D.; J ones, P. S.; Rowlands, G. J . J . Chem. Soc., Chem. Commun. 1997,
2141. (c) Toyooka, N.; Yotsui, Y.; Yoshida, Y.; Momose, T.; Nemoto, H.
Tetrahedron 1999, 55, 15209. (d) Iradier, F.; Arraya´s, R. G. Org. Lett.
2001, 3, 2957. (e) de Vicente, J .; Arraya´s, R. G.; Can˜ada, J .; Carretero,
J . C. Synlett 2000, 53. (f) Carretero, J . C.; Arraya´s, R. G. Synlett 1999,
49. (g) Zhou, F.; Rosen, J .; Zebrowski-Young, J . M.; Freihammer, P.
M.; Detty, M. R.; Lachicotte, R. J . J . Org. Chem. 1998, 63, 5403 and
references therein.
(8) Amino alcohols 2a -c were prepared by the same method as
reported for 2a : Hsiao, Y.; Hegedus, L. S. J . Org. Chem. 1997, 62,
3586.
(9) For the preparation of 1a , see: (a) Brace, N. O. J . Org. Chem.
1993, 58, 4506. (b) Sulfone 1b was prepared by the same procedure as
1a , using 1,2-dibromopropane as the starting material. (c) Sulfone 1c
was obtained by the method of Reich and Peake: Reich, H. J .; Peake,
S. L. J . Am. Chem. Soc. 1978, 100, 4888.
9390 J . Org. Chem., Vol. 68, No. 24, 2003

Synthesis of Pyrrolidines and Related Heterocycles
SCHEME 3
SCHEME 4
SCHEME 5
drine (7) to 1b was also attempted, but gave very poor
yields even after prolonged reaction times, presumably
reflecting the greater steric hindrance associated with a
secondary amino group and a â-substituted vinyl sulfone.
Finally, we attempted the same sequence of reactions
with the cyclic amines 11a and 11b, and sulfone 1b. To
our surprise, the product 24a , obtained from 11a as a
mixture of separable epimers, contained methyl groups
that had rearranged from the â- to the R-position of the
sulfone moiety in each isomer (Scheme 6). This was
clearly evident from their 1H NMR spectra, where the
methyl signals appeared as singlets instead of doublets.
A similar rearrangement was observed with 11b, which
afforded a single epimer 24b, whose structure was
unequivocally determined by X-ray crystallography. In
both cases, the initial conjugate addition step was slug-
gish and afforded a poor yield of the corresponding
adducts 22a and 22b. Further scrutiny of the crude
reaction product of 11a with 1b revealed the presence of
small amounts of the isomeric sulfones 1c and 1d . We
therefore postulate that, under the prolonged reaction
conditions required for the additions of 11a or 11b to 1b,
a small amount of the starting vinyl sulfone 1b or the
does not occur during the chlorination of 12a or that
chloride attack occurs at the less substituted aziridinium
carbon atom, in contrast to the outcome with 15a -c.16
The substituted vinyl sulfone 1b was also investigated.
The same sequence of conjugate addition, N-benzylation,
chlorination with thionyl chloride, and cyclization with
LDA was applied to amino alcohol 2a (Scheme 5). The
structures of the two main products 20 and 21 were
confirmed by X-ray crystallography, which clearly indi-
cated that rearrangement of the methyl group in 2a had
again taken place. The conjugate addition of (-)-ephe-
(16) For a precedent where the ring-opening of an aziridinium ion
that is fused to a six-membered ring occurs at the less substituted site
with chloride ion and other nucleophiles, see: Evans, D. A.; Mitch, C.
H. Tetrahedron Lett. 1982, 23, 285.
J . Org. Chem, Vol. 68, No. 24, 2003 9391

Back et al.
SCHEME 6
SCHEME 7
to 1b at an appreciable rate, thus providing the op-
portunity for the competing isomerization of 1b to the
more reactive isomer 1c (and the inert 1d ) to take place
via Scheme 7, followed by conjugate addition to 1c.
In conclusion, the conjugate additions of amino alcohols
derived from R-amino acids to vinyl sulfones, followed by
N-benzylation, chlorination, and intramolecular alkyla-
tion, provide a convenient route to substituted pyrro-
lidines. The process is accompanied by the stereospecific
rearrangement of substituents from the R-position of the
original amine moiety to the â-position of the product. A
second type of rearrangement was discovered with pip-
eridine-based amino alcohols 11a and 11b and the
â-substituted vinyl sulfone 1b, resulting in the migration
of the â-substituent to the R-position of the sulfone.
corresponding conjugate addition products first undergo
elimination of benzenesulfinate anion. The latter anion
then catalyzes the conversion of 1b to 1c and 1d by a
sequence of addition-elimination reactions proceeding
via the bis-sulfone 25 (Scheme 7).17 Although the unac-
tivated allyl sulfone 1d cannot undergo conjugate addi-
tion, the 2-propenyl isomer 1c reacts preferentially with
the amino alcohols 11a or 11b to give the observed
products 22a and 22b, ultimately leading to 24a and 24b,
respectively.18 Several control experiments were per-
formed to test this hypothesis. First, the treatment of
vinyl sulfone 1b with sodium benzenesulfinate in the
absence of 11a , under the same conditions as used for
the conjugate additions, resulted in the formation of 1c
and 1d , thus lending support for the proposed addition-
elimination steps in Scheme 7. In a separate experiment,
the reaction of 11a was performed with authentic 1c,9c
followed by the usual cyclization protocol, to afford the
same product 24a that had been obtained from 1b. Third,
a crossover experiment was conducted in which amino
alcohol 11a and sulfone 1b were allowed to react in the
presence of added sodium p-toluenesulfinate, resulting
in a mixture of adduct 22a and its p-toluenesulfonyl
analogue. These results are all consistent with the
mechanism in Scheme 7. The failure to observe a similar
rearrangement during the reaction of 2a with 1b in
Scheme 5 is attributed to the fact that 2a is a primary
amine that undergoes a far more facile direct conjugate
addition to 1b than the more hindered secondary amines
11a and 11b in Scheme 6.19 The latter amines fail to add
Exp er im en ta l Section
NMR spectra were recorded in CDCl3 unless otherwise
noted. 13C NMR signals were identified as CH3, CH2, CH, or
C by DEPT experiments. Mass spectra were obtained by EI
unless otherwise noted. Chromatography refers to flash chro-
matography over silica gel.
Typ ica l P r oced u r e for Cycliza tion s Sta r tin g w ith
Vin yl Su lfon e 1a : (3R,4S)-3-(Ben zen esu lfon yl)-N-ben zyl-
4-m eth ylp yr r olid in e (6a ). A solution of (S)-2-amino-1-pro-
panol (2a ) (846 mg, 11.3 mmol) and sulfone 1a (1.895 g, 11.3
mmol) was refluxed for 2 days in 40 mL of 2-propanol and
concentrated in vacuo. The residue was chromatographed
(hexanes-ethyl acetate-methanol, 4:1:0.5) to afford 2.604 g
(95%) of 3a as a colorless oil, which solidified upon standing:
1
mp 47.5-49.5 °C; IR (film) 3305, 1303, 1148 cm-1; H NMR
(200 MHz) δ 7.82-7.93 (m, 2 H), 7.66-7.47 (m, 3 H), 3.49 (dd,
J ) 10.8, 3.9 Hz, 1 H), 3.30-3.16 (m, 3 H), 3.15-2.99 (m, 1
H), 2.97-2.83 (m, 1 H), 2.77-2.61 (m, 1 H), 2.59-2.29 (br s 2
H), 0.95 (d, J ) 6.5 Hz, 3 H); 13C NMR (50 MHz) δ 139.1 (C),
133.7 (CH), 129.2 (CH), 127.7 (CH), 65.4 (CH2), 56.2 (CH2),
54.2 (CH), 40.3 (CH2), 16.7 (CH3); MS (m/z, %) 212 (10.5), 141
(33), 125 (27), 77 (51), 70 (100); HRMS calcd for C10H14NO2S
(M+ - CH2OH) 212.0745, found 212.0748.
The amino alcohol 3a (723 mg, 2.98 mmol), ethyldiisopro-
pylamine (577 mg, 4.47 mmol), and benzyl bromide (612 mg,
3.58 mmol) were refluxed for 4 h in 15 mL of anhydrous
acetonitrile. The mixture was concentrated in vacuo and
chromatographed (50% ethyl acetate-hexanes) to give 781 mg
(79%) of 4a as a colorless oil, which solidified upon standing:
mp 40-42 °C; IR (film) 3483, 1448, 1299, 1145, 1083 cm-1; 1H
NMR (200 MHz) δ 7.86-7.72 (m, 2 H), 7.70-7.45 (m, 3 H),
7.35-7.15 (m, 5 H), 3.74 (d, J ) 13.5 Hz, 1 H), 3.38 (d, J )
13.5 Hz, 1 H), 3.35 (m, 2 H), 3.15-2.74 (m, 6 H), 0.91 (d, J )
6.7 Hz, 3 H); 13C NMR (50 MHz) δ 138.9 (C), 138.4 (C), 133.3
(CH), 128.9 (CH), 128.4 (CH), 128.1 (CH), 127.3 (CH), 126.9
(CH), 62.8 (CH2), 56.9 (CH), 54.4 (CH2), 53.8 (CH2), 43.1 (CH2),
9.4 (CH3); MS (m/z, %) 332 (M+ - 1, 1), 302 (26), 160 (29), 132
(24), 91 (100); HRMS calcd for C17H19NO2S (M+ - CH3OH)
301.1137, found 301.1134.
(17) For some earlier studies of elimination-addition reactions of
bis-sulfones similar to 25, see: Kader, A. T.; Stirling, C. J . M. J . Chem.
Soc. 1962, 3686.
(18) The rate of addition of piperidine to sulfone 1b is greater than
that to 1c; see: McDowell, S. T.; Stirling, C. J . M. J . Chem. Soc. B
1967, 351. However, these relative rates may be reversed with
substituted piperidines such as 11a and 11b because of the additional
steric interaction between the piperidine substituent and the â-methyl
group of 1b.
(19) We note that the additions of amines 11a and 11b to 1b
provided yields of only 29% and 26% of the rearranged adducts 22a
and 22b, even after 3 and 4 days, respectively, in refluxing xylenes.
Extensive decomposition of the amine starting materials was observed
during this time, along with the gradual appearance of 1c and 1d . On
the other hand, the direct addition of 2a to 1b was considerably more
facile and proceeded even in the lower boiling solvent 2-propanol to
afford 50% of 19 after refluxing for only 1 day. When refluxed in
xylenes, the reaction was largely complete in less than 1 day and
proceeded cleanly to form 19 in 91% yield after 2 days.
Product 4a (2.054 g, 6.17 mmol) and thionyl chloride (1.102
g, 9.26 mmol) were refluxed for 2 h in 30 mL of chloroform.
9392 J . Org. Chem., Vol. 68, No. 24, 2003

Synthesis of Pyrrolidines and Related Heterocycles
The solution was washed with 1 M aqueous KOH solution,
water, and brine. The organic layer was dried, concentrated,
and chromatographed (20% ethyl acetate-hexanes) to afford
2.038 g (94%) of 5a as a light yellow oil: IR (film) 1444, 1308,
3.00 (m, 2 H), 3.01-2.70 (m, 1 H), 2.70-2.07 (m, 3 H), 2.07-
1.75 (m, 1 H), 1.29 (d, J ) 6.8 Hz, 3 H) superimposed on 1.68-
1.16 (m, 7 H); 13C NMR (50 MHz), major diastereomer, δ 137.7
(C), 133.5 (CH), 129.0 (CH), 128.6 (CH), 62.0 (CH2), 59.3 (CH),
58.6 (CH), 52.9 (CH2), 50.0 (CH2), 31.5 (CH2), 26.4 (CH2), 22.2
(CH2), 21.0 (CH2), 12.8 (CH3); 3C NMR (50 MHz), minor
diastereomer, δ 137.7 (C), 133.5 (CH), 129.0 (CH), 128.6 (CH),
61.6 (CH2), 60.1 (CH), 58.8 (CH), 52.7 (CH2), 48.6 (CH2), 31.7
(CH2), 27.5 (CH2), 22.4 (CH2), 21.5 (CH2), 12.6 (CH3); MS (m/
z, %) 311 (M+, 0.12), 266 (3), 124 (100), 82 (17); HRMS calcd
for C14H20NO2S (M+ - C2H4OH) 266.1215, found 266.1204.
A solution containing 199 mg (0.640 mmol) of 22b and
thionyl chloride (0.11 mL, 1.50 mmol) in 10 mL of chloroform
was refluxed for 3 h and then concentrated in vacuo. The
residue of crude 23b was dissolved in 4 mL of THF and added
to a solution of excess LDA (1.00 mmol) in 8 mL of THF at
-78 °C. The mixture was stirred at -78 °C for 2 h and at room
temperature for 6 h, and was then quenched by filtration
through neutral alumina. The filtrate was concentrated in
vacuo, and the residue was chromatographed (15% ethyl
acetate-hexanes) to afford 140 mg (75%) of 24b as a single
diastereomer. Crystallization from ethyl acetate-hexanes gave
light yellow crystals: mp 127-129 °C; IR (film) 1443, 1297,
1
1145, 1079 cm-1; H NMR (200 MHz) δ 7.93-7.79 (m, 2 H),
7.69-7.49 (m 3 H), 7.32-7.16 (m, 5 H), 3.93 (sextet, J ) 6.5
Hz, 1 H), 3.64 (d, J ) 13.7 Hz, 1 H), 3.56 (d, J ) 13.7 Hz, 1 H),
3.37-3.17 (m, 2 H), 3.05-2.92 (m, 2 H), 2.67 (m, 2 H), 1.42 (d,
J ) 6.7 Hz, 3 H); 13C NMR (50 MHz) δ 139.3 (C), 137.9 (C),
133.6 (CH), 129.2 (CH), 128.8 (CH), 128.3 (CH), 127.8 (CH),
127.3 (CH), 62.5 (CH2), 59.1 (CH2), 55.4 (CH), 53.5 (CH2), 47.8
(CH2), 22.9 CH3); MS (m/z, %) 351 (M+, 1), 314 (3), 208 (14),
144 (27), 91 (100); HRMS calcd for C18H22ClNO2S 351.1060,
found 351.1042.
The chloroamine 5a (503 mg, 1.43 mmol) was dissolved in
5 mL of THF and added to 2.0 mmol of LDA in 5 mL of THF
at -78 °C. The mixture was stirred at -78 °C for 2 h and was
then quenched by filtration through neutral alumina. The
filtrate was concentrated in vacuo, and the residue was
chromatographed (15% ethyl acetate-hexanes) to afford 361
mg (80%) of 6a as a light yellow oil: IR (film) 1447, 1304, 1146,
1
1089 cm-1; H NMR (200 MHz) δ 7.96-7.83 (m, 2 H), 7.72-
7.50 (m, 3 H), 7.33-7.15 (m, 5 H), 3.62 (d, J ) 13.2 Hz, 1 H),
3.48 (d, J ) 13.2 Hz, 1 H), 3.34-3.20 (m, 1 H), 3.02 (dd, J )
10.4, 5.6 Hz, 1 H), 2.87-2.62 (m, 3 H), 2.23 (dd, J ) 8.2, 5.3
Hz, 1 H), 1.03 (d, J ) 6.8 Hz, 3 H); all 1H and 13C NMR signals
were assigned by COSY, DEPT, and HMQC spectra and
irradiation of the CH3CH signal at δ 1.03 enhanced the CHSO2
signal at δ 3.3 by 3%, while irradiation of the latter signal
enhanced that of the CH3 group by 9%; 13C NMR (50 MHz) δ
138.4 (C), 138.2 (C), 133.5 (CH), 129.1 (CH), 128.6 (CH), 128.4
(CH), 128.1 (CH), 127.0 (CH), 70.1 (CH), 61.3 (CH2), 59.3 (CH2),
54.2 (CH2), 34.5 (CH), 19.8 (CH3); MS (m/z, %) 315 (M+, 1),
1
1147 cm-1; H NMR (200 MHz) δ 7.93-7.80 (m, 2 H), 7.72-
7.49 (m, 3 H), 2.80-2.56 (m, 2 H), 2.44 (d, J ) 10.6 Hz, 1 H),
2.11-1.86 (m, 2 H), 1.46 (s, 3 H) superimposed on 1.72-1.10
(m, 10 H); 13C NMR (50 MHz) δ 135.4 (C), 133.6 (CH), 130.4
(CH), 128.7 (CH), 62.7 (C), 62.0 (CH), 58.4 (CH2), 56.6 (CH2),
32.6 (CH2), 28.8 (CH2), 28.7 (CH2), 25.7 (CH2), 24.3 (CH2), 17.6
(CH3); MS (m/z, %) 292 (M+ - 1, 1.2), 150 (100), 136 (48), 94
(40); HRMS calcd for C16H23NO2S: 293.1450, found 293.1452.
Anal. Calcd for C16H23NO2S: C, 65.49; H, 7.90; N, 4.77.
Found: C, 65.12; H, 8.03; N, 4.71. The structure was confirmed
by X-ray crystallography.
173 (27), 158 (100), 145 (27), 91 (64); HRMS calcd for C18H21
NO2S 315.1293, found 315.1312.
-
Typ ica l P r oced u r e for Cycliza tion s Sta r tin g w ith
Vin yl Su lfon e 1b: (()-3-cis-(Ben zen esu lfon yl)-3-tr a n s-
m eth ylqu in olizid in e (24b). 2-(2-Piperidine)ethanol (11b)
(808 mg, 6.26 mmol) and 1.140 g (6.26 mmol) of vinyl sulfone
1b were refluxed in 25 mL of xylenes for 4 days. After removal
of solvent in vacuo, chromatography (hexanes-ethyl acetate-
methanol ) 4:1:0.5) afforded 506 mg (26%) of 22b. The product
was a light yellow oil that consisted of two diastereomers
formed in the ratio of ca. 55:45 (NMR): IR (film) 3530, 1443,
Ack n ow led gm en t. We thank the Natural Sciences
and Engineering Research Council of Canada (NSERC)
for financial support.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and characterization data for products; 1H and 13C
NMR spectra of new compounds and X-ray data for 9, 20, 21,
and 24b. This material is available free of charge via the
Internet at http://pubs.acs.org.
1
1305, 1145, 1080 cm-1; H NMR (200 MHz, mixture) δ 7.96-
7.81 (m, 2 H), 7.70-7.48 (m, 3 H), 3.85-3.50 (m, 3 H), 3.42-
J O0350864
J . Org. Chem, Vol. 68, No. 24, 2003 9393