Development of a [3+3] cycloaddition strategy toward functionalized piperidines

Article abstract of DOI:10.1021/jo030002c

This paper describes a novel route to functionalized piperidines via a formal [3+3] cycloaddition reaction of activated aziridines and palladium-trimethylenemethane (Pd-TMM) complexes. The cycloaddition reaction generally proceeds enantiospecifically with

Full text of DOI:10.1021/jo030002c

Develop m en t of a [3+3] Cycloa d d ition Str a tegy tow a r d
F u n ction a lized P ip er id in es
Simon J . Hedley,† Wesley J . Moran,† David A. Price,‡ and J oseph P. A. Harrity*,†
Department of Chemistry, University of Sheffield, Sheffield, S3 7HF, United Kingdom, and Discovery
Chemistry, Pfizer Central Research, Ramsgate Road, Sandwich, Kent, CT13 9NJ , United Kingdom
j.harrity@sheffield.ac.uk
Received J anuary 3, 2003
This paper describes a novel route to functionalized piperidines via a formal [3+3] cycloaddition
reaction of activated aziridines and palladium-trimethylenemethane (Pd-TMM) complexes. The
cycloaddition reaction generally proceeds enantiospecifically with ring opening at the least hindered
site of the aziridine. Therefore, readily available enantiomerically pure 2-substituted aziridines
can be utilized to prepare enantiomerically pure 2-substituted piperidines in good to excellent yield.
The N-substituent on the aziridine proved to be crucial to the success of this reaction with only
4-toluenesulfonyl (Ts) and 4-methoxybenzenesulfonyl (PMBS) aziridines permitting smooth cy-
cloaddition to take place. Additionally, spirocyclic aziridines have been found to participate in the
[3+3] cycloaddition reaction, whereas 2,3-disubstituted aziridines can be applied to provide fused
bicyclic piperidines, albeit in low yield.
CHART 1
In tr od u ction
The piperidine ring system is one of the most common
structural subunits in natural products and synthetic
compounds of biological significance.1 Indeed, it has been
stated recently that a substructure search of the piperi-
dine ring using the electronic version of the Drug Data
Report (J uly 1988 through to December 1998) revealed
over 12 000 discrete piperidine entities that have been
mentioned in clinical or preclinical studies.2 In the
context of naturally occurring piperidines, a variety of
structural features surround the heterocyclic core. No-
table examples include (-)-coniine 1, a Conium macu-
latum hemlock alkaloid;3 (-)-histrionicotoxin 2, isolated
from the skin extracts of the “poison dart” frog Dendro-
bates histrionicus,4 which has shown the ability to act
as a noncompetitive inhibitor of nicotinic acetylcholine
receptors;5 and (-)-pumiliotoxin C 3, also isolated from
dendrobatic frogs,6 which has been shown to be a revers-
ible blocker of the nicotinic acetylcholine receptor channel
(Chart 1).7
From a synthetic viewpoint, we wished to develop a
new strategy to obtain the piperidine ring system.
Additionally, we considered the following to be important
factors in our approach: (1) The piperidine moiety should
be assembled efficiently and with scope for stereocontrol.
(2) The products should be endowed with functionality,
which would allow them to be transformed to specific
target compounds. (3) The technique should exhibit
sufficient flexibility so as to allow the assembly of a wide
number of skeletal types. In this context, cycloaddition
reactions are among the most effective methods for the
rapid synthesis of functionalized cyclic systems in a
stereocontrolled manner. With regard to six-membered-
ring formation, the Diels-Alder reaction holds a uniquely
prominent position and formally comprises a [4+2]
assembly strategy.8 In contrast, the employment of a
[3+3] cycloaddition approach has been much less widely
studied.9 Nonetheless, the employment of Pd-catalysis
has led to techniques for the assembly of pyran deriva-
tives10 whereas piperidine systems have been prepared
† University of Sheffield.
‡ Pfizer Central Research.
(1) (a) Bailey, P. D.; Millwood, P. A.; Smith, P. D. Chem Commun
1998, 633. (b) Laschat, S.; Dickner, T. Synthesis 2000, 1781.
(2) Watson, P. S.; J iang, B.; Scott, B. Org. Lett. 2000, 2, 3679.
(3) Fodor, G. B.; Colasanti, B. In Alkaloids: Chemical and Biological
Perspectives; Pelletier, S. W., Ed.; Wiley: New York, 1985; Vol. 3, pp
1-90.
(4) Daly, J . W.; Karle, I.; Myers, C. W.; Tokuyama, T.; Waters, J .
A.; Witkop, B. Proc. Natl. Acad. Sci. U.S.A. 1971, 68, 1870.
(5) Takahashi, K.; Witkop, B.; Brossi, A.; Malque, M. A.; Alburqu-
erque, E. X. Helv. Chim. Acta 1982, 65, 252.
(8) For a review on [4+2] cycloaddition processes see: Oppolzer, W.
In Comprehesive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, UK, 1991; Vol. 5, p 315.
(6) Daly, J . W.; Tokuyama, T.; Habermehl, G.; Karle, I. L.; Witkop,
B. Liebigs Ann. Chem. 1969, 729, 198.
(7) (a) Warnick, J . E.; J essup, P. J .; Overman, L. E.; Eldefrawi, M.
E.; Nimit, Y.; Daly, J . W.; Alburquerque, E. X. Mol. Pharmacol. 1982,
22, 565. (b) Daly, J . W.; Nishizawa, Y.; Padgett, W. L.; Tokuyama, T.;
McCloskey, P. J .; Waykole, L.; Schultz, A. G.; Aronstam, R. S.
Neurochem. Res. 1991, 16, 1207.
(9) (a) Lautens, M.; Klute, W.; Tam, W. Chem. Rev. 1996, 96, 49.
(b) Fru¨hauf, H.-W. Chem. Rev. 1997, 97, 523.
(10) (a) Huang, Y.; Lu, X. Tetrahedron Lett. 1987, 28, 6219. (b) van
der Louw, J .; van der Baan, J . L.; Out, G. J . J .; de Kanter, F. J . J .;
Bickelhaupt, F.; Klumpp, G. W. Tetrahedron 1992, 48, 9901.
10.1021/jo030002c CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/22/2003
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J . Org. Chem. 2003, 68, 4286-4292

[3+3] Cycloaddition Strategy to Functionalized Piperidines
TABLE 1. Op tim iza tion of th e [3+3] Cycloa d d ition
SCHEME 1
Rea ction a
yield,
%
entry
catalyst system
10% Pd(PPh3)4
solvent
1
2
3
4
5
6
7
8
9
THF
THF
THF
THF
THF
17
49
59
82
43
53
24
52
28
47
10% Pd(OAc)2, 40% PPh3, 20% nBuLi
10% Pd(OAc)2, 40% P(OiPr)3, 20% nBuLi
10% Pd(OAc)2, 60% P(OiPr)3, 20% nBuLi
10% Pd(OAc)2, 80% P(OiPr)3, 20% nBuLi
10% Pd(OAc)2, 60% P(OiPr)3, 20% 1-hexene THF
10% Pd(OAc)2, 60% P(OiPr)3
THF
10% Pd(OAc)2, 60% P(OiPr)3, 20% nBuLi
10% Pd(OAc)2, 60% P(OiPr)3, 20% nBuLi
10% Pd(OAc)2, 60% P(OiPr)3, 20% nBuLi
toluene
dioxan
benzene
10
SCHEME 2
a
Reactions carried out in 0.1 M refluxing solvent with 1.5 equiv
of 7.
Resu lts a n d Discu ssion
At the outset of our investigations, only a single ex-
ample of the cycloaddition reaction of Pd-TMM complexes
with aziridines was present in the literature.19 Addition-
ally, the employment of enantiomerically enriched aziri-
dines had not received any attention and therefore the
potential of this reaction to furnish piperidine products
in a stereocontrolled fashion was unknown. With these
issues in mind, we set out to establish the scope of the
Pd-catalyzed [3+3] cycloaddition reaction for the stereo-
controlled synthesis of functionalized piperidines.
Cycloaddition Reaction s of Mon osu bstitu ted Azir -
id in es. To act as effective electrophiles, aziridines re-
quire either an electron-withdrawing activating group
attached to nitrogen or catalysis by Lewis or protic
acids.20 We decided to utilize p-toluenesulfonyl (Ts) as
the N-substituent as N-tosylaziridines readily undergo
nucleophilic ring cleavage with a range of nucleophiles,
and also reacts chemospecifically due to the poor elec-
trophilicity of the sulfonyl group.21 Enantiomerically pure
monosubstituted N-tosylaziridines were convieniently
prepared in three steps by the method of Craig.22 With
the requisite substrates in hand, we began our studies
by investigating the effects of the catalyst system on the
efficiency of the [3+3] cycloaddition reaction of 5 and
(S)-N-tosyl-2-methyl-aziridine 7; the results are outlined
in Table 1. The use of Pd(PPh3)4 (freshly prepared or
generated in situ) proved ineffective in promoting pip-
eridine formation, with the desired product 8 only
isolated in low to moderate yield (Entries 1 and 2).
Inspired by Trost’s Pd-TMM [3+2] cycloaddition stud-
ies,14 we opted to investigate the use of phosphite ligands.
Indeed, the cycloaddition reaction proved to be more
efficient and reproducible with this ligand system. In the
event, the use of six catalyst equivalents of P(OiPr)3 with
by a formal [3+3] cycloaddition reaction of 1,3-cyclic
sulfates with C,N-dianions,11 vinylogous amides with R,â-
unsaturated iminiums,12 and R,R′-dimethoxylated amides
with allyltrimethylsilane.13 We envisaged that an effec-
tive [3+3] cycloaddition approach to piperidines that
would encompass our objectives stated would be highly
desirable, and anticipated that it would complement
existing [4+2] approaches. More specifically, we opted
to study the cycloaddition reaction of palladium-tri-
methylenemethane (Pd-TMM) complexes 4 with aziri-
dines with a view to accessing common piperidine-
containing structural types, such as those exhibited in
the natural products shown in Chart 1 (vide supra). This
general strategy is summarized in Scheme 1.
Trost has carried out extensive studies on the utiliza-
tion of Pd-TMM complexes in the synthesis of five-
membered rings via a [3+2] cycloaddition reaction with
electron-deficient alkenes.14 Crucial to the development
of this methodology was the observation that Pd-TMM
complexes 4 can be generated in situ as fleeting reactive
intermediates by heating 2-[(trimethylsilyl)methyl]-2-
prop-1-enyl acetate 5 in the presence of a palladium
catalyst (Scheme 2).15 Pd-TMM complexes have also been
reported to undergo [3+2] cycloaddition reactions with
aldehydes to provide methylenetetrahydrofurans16 and
imines to provide methylenepyrrolidines,17 and under-
go a [4+3] cycloaddition reaction with pyrones.18 Thus,
Pd-TMM complexes such as 4 have been shown to be
powerful and versatile synthetic tools.
(11) Eskici, M.; Gallagher, T. Synlett 2000, 1360.
(12) (a) Sklenicka, H. M.; Hsung, R. P.; Wei, L.-L.; McLaughlin, M.
J .; Gerasyuto, A. I.; Degen, S. J . Org. Lett. 2000, 2, 1161. (b) Slkenicka,
H. M.; Hsung, R. P.; McLaughlin, M. J .; Wei, L.-I.; Gerasyuto, A. I.;
Brennessel, W. B. J . Am. Chem. Soc. 2002, 124, 10435.
(13) Shono, T.; Matsumura, Y.; Uchida, K.; Kobayashi, H. J . Org.
Chem. 1985, 50, 3243.
(14) Trost, B. M. Angew. Chem., Int. Ed. Engl. 1986, 25, 1 and
references therein.
(15) Trost, B. M.; Chan, D. M. T. J . Am. Chem. Soc. 1979, 101, 6429.
(16) Trost, B. M.; King, S. A. J . Am. Chem. Soc. 1990, 112, 408.
(17) Trost, B. M.; Bonk, P. J . J . Am. Chem. Soc. 1985, 107, 1778.
(18) Trost, B. M.; Schneider, S. Angew. Chem., Int. Ed. Engl. 1989,
28, 213.
(19) Bambal, R. B.; Kemmitt, R. D. W. J . Organomet. Chem. 1989,
362, C18.
(20) Pearson, W. H.; Lian, B. W.; Bergmeier, S. C. In Comprehensive
Heterocyclic Chemistry II; Padwa, A., Ed.; Pergamon Press: Oxford,
UK, 1996; Vol. 1A, pp 1-60.
(21) (a) Stamm, H.; Weiss, R. Synthesis 1986, 392, 395. (b) Baldwin,
J . E.; Adlington, R. M.; Robinson, N. G. Chem. Commun. 1987, 153.
(22) Berry, M. B.; Craig, D. Synlett 1992, 41.
J . Org. Chem, Vol. 68, No. 11, 2003 4287

Hedley et al.
TABLE 2. Exp lor in g th e Scop e of th e [3+3]
Cycloa d d ition Rea ction
SCHEME 3
SCHEME 4
pleased to find that more useful functionality could be
incorporated into the piperidine products: silyl protected
alcohols (Entry 6) and allyl groups (Entry 7) were both
well tolerated in the reaction.
To date we have been unable to successfully employ
aziridines which do not have an arylsulfonamide activat-
ing group.27 Nonetheless, we have found that N-p-
methoxy-benzenesulfonyl (PMBS) aziridines 21 and 23
smoothly undergo [3+3] cycloaddition reaction to provide
22 and 24 respectively, in good yield (Scheme 3). Notably,
24 was used further in the stereoselective synthesis of
(-)-pseudoconhydrine.24
a
Reaction carried out on racemic aziridine.
nBuLi as a reductant provided the best balance of
reactivity and catalyst stability23 (Entries 3-7) while
THF was found to be the solvent of choice (Entries 4 and
8-10).
This study demonstrates the need for a strongly
activating group to be present on the aziridine substrate.
Indeed, we have found further evidence for the sluggish
nature of this process from a control experiment, which
is outlined in Scheme 4. The addition of 1 equiv of 5 to a
mixture containing equimolar quantities of methyl acry-
late 25 (a typical substrate used in [3+2] cycloaddition
reactions)28 and 9 results in a selective cycloaddition at
25 to produce 26 in good yield with complete recovery of
the aziridine. This result suggests that the development
of promoter systems to facilitate the reaction with aziri-
dines would be highly beneficial, and studies toward this
end are currently under investigation in our laboratories.
Cycloaddition Reaction s of 2,2-Disu bstitu ted Azir -
id in es. We next turned our attention to the synthesis of
more substituted piperidine products. We postulated that
the spiropiperidine core of naturally occurring and bio-
logically active targets such as 2 could be accessed by
our methodology and therefore decided to examine the
potential of the [3+3] cycloaddition reaction toward this
end. A rapid route to aziridines has been achieved by
Having uncovered conditions which gave consistently
high yields of cycloadduct 8, we turned our attention to
the investigation of the scope of the [3+3] cycloaddition
process with a range of monosubstituted N-tosylaziri-
dines, our results are outlined in Table 2.24
In all cases the [3+3] cycloaddition reaction proceeded
to furnish the desired piperidines in good to excellent
yield. Notably, these aziridines underwent regioselective
addition at the less hindered site and furnished the
products in enantiomerically pure form, confirming that
the cycloaddition process did not cause unwanted epimer-
ization at the remote stereogenic center.25 One exception
to this trend was observed when N-tosyl-2-phenylaziri-
dine 15 (Entry 5) was employed, in which case an almost
equal mixture of regioisomeric products 16a and 16b was
observed. This result is unsurprising as the tendency for
a phenyl substituent to promote aziridine cleavage at the
benzylic site is well documented.26 Finally, we were
(23) Good yields of piperidine product could be obtained by using
40 mol % P(OPr-i)3; however, the reaction was capricious due to
problems associated with precipitation of Pd-metal.
(24) For a preliminary report of this work see: Hedley, S. J .; Moran,
W. J .; Prenzel, A. H. G. P.; Price, D. A.; Harrity, J . P. A. Synlett 2001,
1596.
(25) As judged by chiral HPLC analysis of 10 and 14. The enantio-
meric purity of compounds 8, 12, and 18 was inferred from these data.
(26) For a recent example see: Wu, J .; Hou, X.-L.; Dai, L.-X. J . Org.
Chem. 2000, 65, 1344.
(27) Aziridines bearing SES, Boc, Cbz, and Dpp N-substituents do
not undergo cycloaddition and are recovered from the reaction mixture
unchanged. In contrast, the more highly activated Ns-protected
aziridines furnish a complex mixture of products possibly because of
competing addition of the Pd-TMM complex to the aromatic ring:
Holzapfel, C. W.; van der Merwe, T. Tetrahedron Lett. 1996, 37, 2307.
(28) Trost, B. M.; Chan, D. M. T. J . Am. Chem. Soc. 1983, 105, 2315.
4288 J . Org. Chem., Vol. 68, No. 11, 2003

[3+3] Cycloaddition Strategy to Functionalized Piperidines
SCHEME 5
SCHEME 9 a
SCHEME 6
a
Reagents and conditions: (a) DMDO, DCM, 25 °C, 16 h; 91%
(2.8:1). (b) PhIO, TsNH2, Cu(MeCN)4PF6 (10 mol %), MeCN, 4Å
MS, 25 °C, 16 h; 34% (100:0). (c) 10% Pd/C, 1 atm of H2, MeOH,
16 h; 88% (9:1). (d) (i) 9-BBN, 3 h. (ii) H2O2, NaOH(aq), 20 min;
85% (2:1).
reactions were very sluggish but we were pleased to find
that compounds 38 and 39 could be isolated, albeit in
low yield. However, no piperidine product 40 was ob-
served from reaction of 37 and starting material was
recovered in quantitative yield from the reaction mixture.
Cycloa d d ition Rea ction s of 2,2,3-Tr isu bstitu ted
Azir id in es. Despite the low reactivity of 2,3-disubsti-
tuted aziridines, we were interested in whether 2,2,3-
trisubstituted aziridines would participate in the [3+3]
cycloaddition process. With this in mind, we prepared 41
and 42 via the copper-catalyzed aziridination. In the case
SCHEME 7
SCHEME 8
of 42, we hoped that benzylic activation would promote
nucleophilic ring-opening. However, on subjecting these
aziridines to the established reaction conditions, no
piperidine products were isolated, and the starting aziri-
dines were recovered quantitatively.
Evans via a copper-catalyzed nitrene transfer to alkenes
using [N-(4-toluenesulfonyl)imino]phenyliodinane.29 There-
fore, we reasoned that spirocyclic aziridines 27-30 could
be prepared by this method in a one-step process from
the corresponding exo-methylene carbocycles (Scheme 5).
The optimum conditions for the [3+3] cycloaddition
reactions of monosubstituted aziridines were employed
directly for substrates 27-30 (Scheme 6), and we were
pleased to find that the cycloaddition reaction proceeded
smoothly in all cases to furnish the corresponding
spiropiperidines 31-34 in good yield. The employment
of this strategy toward the synthesis of analogues of 2 is
currently underway and will be reported in due course.
Cycloaddition Reaction s of 2,3-Disu bstitu ted Azir -
id in es. As described in Table 2, ring opening of aziridines
generally proceeds via nucleophilic attack at the least
hindered site. We decided to examine the possibility of
Pd-TMM addition at tertiary centers by utilizing 2,3-
disubstituted aziridines. Additionally, this methodology
would provide an expedient route to bicyclic piperidines.
Once again, we applied the copper-catalyzed aziridination
protocol to rapidly generate bicyclic aziridines 35-37
from the corresponding cycloalkenes (Scheme 7).
Finally, we have carried out some representative
alkene functionalization reactions to uncover the poten-
tial of the piperidine intermediates for further diaster-
eselective elaboration. Accordingly, piperidine 14 was
subjected to standard epoxidation, hydroboration, aziri-
dination, and hydrogenation reactions. As outlined in
Scheme 9, the levels of diastereoselectivity were found
to vary considerably, with epoxidation and hydroboration
processes providing the corresponding products 43 and
46 in high yield but with modest levels of stereoselectiv-
ity. In contrast, the aziridination and hydrogenation
reactions provided 44 and 45 respectively with excellent
levels of stereocontrol. Interestingly, the major diaster-
eomers isolated in products 43-45 all result from reagent
addition across the Si-face of the alkene.30 We have
(30) Only the major diastereomer is shown in each case in Scheme
7. The stereochemical assignment of cis- and trans-46 was not carried
out due to the poor levels of selectivity observed in this case. The major
epoxide diastereomer 43a was assigned based on the characteristic
long-range coupling observed with one of the epoxide CH2 protons and
a ring methylene proton (J ) 1.5 Hz): Vedejs, E.; Dent, W. H., III;
Kendall, J . T.; Oliver, P. A. J . Am. Chem. Soc. 1996, 118, 3556.
Assignment of 44 is based on 2D ROESY, which is provided in the
Supporting Information. Assignment of the major diastereomer of 45
is based on the coupling constants of the protons at C-5 and C-6, see
Supporting Information for more details.
The results of our attempted cycloaddition to bicyclic
aziridines 35-37 are shown in Scheme 8. In general, the
(29) (a) Evans, D. A.; Faul, M. M.; Bilodeau, M. T. J . Org. Chem.
1991, 56, 6744. (b) Evans, D. A.; Faul, M. M.; Bilodeau, M. T. J . Am.
Chem. Soc. 1994, 116, 2742.
J . Org. Chem, Vol. 68, No. 11, 2003 4289

Hedley et al.
m), 1.57-1.73 (1H, m), 1.89 (1H, dt, J ) 14.0, 3.5 Hz), 2.16
(1H, m), 2.34 (3H, s), 3.58 (1H, d, J ) 15.5 Hz), 3.80-3.90
(1H, m), 4.17 (1H, d, J ) 15.5 Hz), 4.58 (1H, br), 4.68 (1H, br),
7.19 (2H, d, J ) 8.5 Hz), 7.64 (2H, d, J ) 8.5 Hz). 13C NMR
(62.9 MHz, CDCl3): δ 13.9, 19.5, 21.5, 27.3, 28.0, 32.3, 46.5,
52.5, 110.3, 127.3, 129.4, 138.2, 141.2, 142.8. FTIR (CH2Cl2):
previously invoked the importance of the Ts-group for
controlling stereochemistry in related functionalization
reactions at this position;24 however, factors which are
important in determining the level of selectivity are still
unclear and are currently the subject of further studies.
3055 (m), 2962 (w), 1336 (m), 1270 (s), 1162 (s), 1094 (m) cm-1
.
m/z (TOF ES): 294 (MH+, 100%). HRMS (TOF ES) Calcd for
Con clu sion s
C
16H24NO2S (MH+): 294.1528. Found: 294.1519.
In conclusion, we have developed a rapid and effective
approach to enantiomerically pure 2-substituted pip-
eridines from the corresponding enantiomerically pure
aziridines and Pd-TMM complex 4. Additionally, the
piperidine products are furnished with an exocyclic
methylene group, which provides the opportunity for
further functionalization. We have also demonstrated the
use of this methodology in the synthesis of spirocyclic and
fused bicyclic piperidines although the latter substrates
are found to exhibit diminished reactivity, likely because
of increased steric hindrance at the electrophilic site.
Finally, we have examined some common alkene func-
tionalization reactions and found these to proceed ef-
ficiently but with variable levels of diastereoselectivity.
(R)-2-Ben zyl-5-m eth ylen e-1-(tolu en e-4-su lfon yl)-p ip e-
r id in e (14). Following the representative procedure, 14 was
isolated as a white solid (79%), mp 85-86 °C. [R]25 -15.56 (c
D
1
0.90, CH2Cl2). H NMR (250 MHz, CDCl3): δ 1.12-1.46 (2H,
m), 1.99 (1H, dt, J ) 14.5, 4.0 Hz), 2.07-2.23 (1H, m), 2.44
(3H, s), 2.95 (2H, d, J ) 7.5 Hz), 3.74 (1H, d, J ) 15.0 Hz),
4.09-4.21 (1H, m), 4.26 (1H, d, J ) 15.0 Hz), 4.71 (1H, br),
4.82 (1H, br), 7.23-7.34 (7H, m), 7.63 (2H, d, J ) 8.0 Hz). 13C
NMR (62.9 MHz, CDCl3): δ 21.5, 26.4, 27.1, 36.9, 46.8, 54.3,
110.6, 126.5, 127.3, 128.6, 129.2, 129.5, 137.7, 138.2, 141.1,
143.0. FTIR (CH2Cl2): 2952 (w), 1599 (w), 1339 (m), 1272 (s),
1160 (s) cm-1. m/z (FAB): 342 (MH+, 68%), 250 (100%), 186
(19%), 155 (39%). Anal. Calcd for C20H23NO2S: C, 70.35; H,
6.79; N, 4.10. Found: C, 70.26; H, 6.68; N, 4.04.
2-P h en yl-5-m et h ylen e-1-(t olu en e-4-su lfon yl)-p ip er i-
d in e (16a ). Following the representative procedure, 16a was
1
isolated as an impure mixture with 16b. H NMR (250 MHz,
Exp er im en ta l Section
CDCl3): δ 1.45-1.65 (1H, m), 1.45-1.55 (1H, m), 2.00-2.20
(1H, m), 2.28-2.36 (1H, m), 2.44 (3H, s), 3.67 (1H, d, J ) 15.5
Hz), 4.32 (2H, d, J ) 15.5 Hz), 4.65 (1H, br), 4.76 (1H, br),
5.04-5.12 (1H, m), 7.13-7.45 (7H, m), 7.72 (2H, d, J ) 8.0
Hz). 13C NMR (62.9 MHz, CDCl3): δ 21.5, 27.7, 47.6, 55.2, 66.8,
110.3, 127.1, 127.4, 127.9, 128.6, 129.5, 137.8, 138.7, 141.0,
143.1.
General experimental methods and literature references to
known compounds are reported in the Supporting Information.
Rep r esen ta tive P r oced u r e for [3+3] Cycloa d d ition
R ea ct ion ssSyn t h esis of (S)-2-Met h yl-5-m et h ylen e-1-
(tolu en e-4-su lfon yl)-p ip er id in e (8): P r ep a r a tion of 0.14
M P a lla d iu m Ca ta lyst. To a suspension of Pd(OAc)2 (50 mg,
0.22 mmol, 1 equiv) in THF (1.6 mL) was added P(OiPr)3 (0.33
mg, 1.34 mmol, 6 equiv) then nBuLi (2.5 M in hexanes, 0.18
mL, 0.45 mmol, 2 equiv), and the resultant yellow solution
was stirred for 15 min before use.
3-P h en yl-5-m et h ylen e-1-(t olu en e-4-su lfon yl)-p ip er i-
d in e (16b). Following the representative procedure, 16b was
isolated as a white solid from recrystallization of the mixture
1
of 16a and 16b, mp 142-143 °C. H NMR (250 MHz, CDCl3):
δ 2.12-2.24 (1H, m), 2.44 (3H, s), 2.53 (1H, m), 2.87 (1H, tt, J
) 13.5, 2.0 Hz), 2.98 (1H, d, J ) 12.5 Hz), 3.90 (1H, m), 4.23
(1H, d, J ) 12.5 Hz), 4.91 (1H, br), 5.00 (1H, br), 7.16 (2H, d,
J ) 8.0 Hz), 7.2-7.4 (5H, m), 7.65 (2H, d, J ) 8.0 Hz). 13C
NMR (62.9 MHz, CDCl3): δ 21.6, 39.0, 42.6, 51.9, 52.2, 112.6,
127.1, 127.2, 127.8, 128.7, 129.7, 133.2, 139.8, 141.6, 143.6.
FTIR (CH2Cl2): 3068 (w), 3032 (w), 2951 (m), 1599 (m), 1496
(m), 1450 (m), 1341 (s), 1163 (s), 1095 (s). HRMS (CI) calcd
for C19H22NO2S (MH+) 328.1371, found 328.1382.
A solution of 7 (150 mg, 0.71 mmol, 1.5 equiv) in THF (3
mL) was treated with freshly prepared 0.14 M palladium
catalyst solution (0.34 mL, 0.05 mmol, 10 mol %) and 5 (0.10
mL, 0.47 mmol, 1 equiv) and the reaction mixture was heated
at reflux for 16 h. Solvent was removed in vacuo and the
residue purified by flash chromatography to yield 8 as a
white solid (102 mg, 82%), mp 68-69 °C. [R]25D -10.10 (c 1.19,
1
CH2Cl2). H NMR (250 MHz, CDCl3): δ 1.23 (3H, d, J ) 7.0
Hz), 1.35-1.62 (2H, m), 2.05 (1H, dt, J ) 13.0, 4.5 Hz), 2.22-
2.31 (1H, m), 2.44 (3H, s), 3.72 (1H, d, J ) 14.5 Hz), 4.02-
4.19 (2H, m), 4.74 (1H, br), 4.83 (1H, br), 7.29 (2H, d, J ) 8.0
Hz), 7.72 (2H, d, J ) 8.0 Hz). 13C NMR (100.6 MHz, CDCl3):
δ 16.2, 21.4, 27.0, 30.5, 46.2, 48.3, 110.4, 127.2, 129.5, 137.8,
141.3, 142.9. FTIR (CH2Cl2): 2944 (w), 1598 (w), 1338 (m),
1268 (s), 1162 (s) cm-1. m/z (CI) 266 (MH+, 60%), 250 (100%),
155 (32%), 110 (43%), 91 (63%). Anal. Calcd for C14H19NO2S:
C, 63.36; H, 7.22; N, 5.28. Found: C, 63.36; H, 7.32; N, 5.09.
(R)-2-Isop r op yl-5-m eth ylen e-1-(tolu en e-4-su lfon yl)-p i-
p er id in e (10). Following the representative procedure, 10 was
(R)-2-(ter t-Bu tyl-d im eth yl-sila n oxym eth yl)-5-m eth yl-
en e-1-(tolu en e-4-su lfon yl)-p ip er id in e (18). Following the
representative procedure, 18 was isolated as a white solid, mp
74-76 °C. [R]25 +8.3 (c 0.61, CH2Cl2). 1H NMR (250 MHz,
D
CDCl3): δ 0.05 (3Η, s), 0.06 (3H, s), 0.88 (9H, s), 1.31-1.48
(2H, m), 1.76-1.92 (2H, m), 2.17-2.34 (1H, m), 2.41 (3H, m),
3.69-3.88 (4H, m), 4.24 (1H, d, J ) 15.5 Hz), 4.68 (1H, br),
4.77 (1H, br), 7.25 (2H, d, J ) 8.0 Hz), 7.70 (2H, d, J ) 8.0
Hz). 13C NMR (62.9 MHz, CDCl3): δ -5.5, -5.4, 21.5, 24.4,
25.9, 27.2, 47.8, 53.6, 62.9, 110.1, 127.3, 129.4, 137.6, 141.4,
143.0. FTIR (CH2Cl2): 2956 (m), 2931 (m), 2858 (m), 1472 (w),
1340 (m), 1263 (s), 1160 (s), 1103 (m) cm-1. Anal. Calcd for
isolated as a white solid, mp 83-84 °C. [R]25 -45.09 (c 1.12,
D
1
CH2Cl2). H NMR (250 MHz, CDCl3): δ 0.87 (3H, d, J ) 6.5
C
20H33NO3SSi: C, 60.72; H, 8.41; N, 3.54. Found: C, 60.69;
Hz), 0.94 (3H, d, J ) 6.5 Hz), 1.02-1.27 (1H, m), 1.52-1.70
(1H, m), 1.74-2.25 (3H, m), 2.33 (3H, s), 3.31-3.47 (1H, m),
3.58 (1H, d, J ) 16.0 Hz), 4.23 (1H, d, J ) 16.0 Hz), 4.55 (1H,
br), 4.66 (1H, br), 7.17 (2H, d, J ) 8.0 Hz), 7.63 (2H, d, J )
8.0 Hz). 13C NMR (100.6 MHz, CDCl3): δ 19.6, 20.0, 21.5, 25.0,
26.6, 27.2, 47.0, 59.1, 110.2, 127.4, 129.3, 138.3, 141.0, 142.7.
FTIR (CH2Cl2): 2964 (m), 2874 (w), 1598 (w), 1337 (s), 1269
(s), 1160 (s) cm-1. m/z (CI) 294 (MH+, 100%), 250 (75%), 155
(9%). Anal. Calcd for C16H23NO2S: C, 65.49; H, 7.90; N, 4.77.
Found: C, 65.49; H, 7.84; N; 4.77.
H, 8.52; N, 3.46.
2-Ally l-5-m e t h y le n e -1-(t o lu e n e -4-su lfon y l)-p ip e r i-
d in e (20). Following the representative procedure, 20 was
isolated as a white solid, mp 77-78 °C. 1H NMR (250 MHz,
CDCl3): δ 1.21-1.42 (1H, m), 1.47-1.73 (1H, m), 1.94 (1H,
dt, J ) 14.5, 4.0 Hz), 2.10-2.48 (3H, m), 2.38 (3H, s), 3.65
(1H, d, J ) 15.5 Hz), 3.92-4.05 (1H, m), 4.22 (1H, d, J ) 15.5
Hz), 4.65 (1H, br), 4.75 (1H, br), 4.99-5.11 (2H, m), 5.73 (1H,
ddt, J ) 17.0, 10.0, 7.0 Hz), 7.22 (2H, d, J ) 8.0 Hz), 7.66 (2H,
d, J ) 8.0 Hz). 13C NMR (62.9 MHz, CDCl3): δ 21.5, 27.0, 27.1,
34.9, 46.7, 52.3, 110.5, 117.4, 127.3, 129.4, 134.6, 138.0, 141.0,
142.9. FTIR (CH2Cl2): 3075 (w), 2926 (w), 2854 (w), 1642 (w),
1598 (w), 1445 (w), 1340 (m), 1159 (s), 1092 (m) cm-1. m/z (TOF
(R)-2-P r op yl-5-m eth ylen e-1-(tolu en e-4-su lfon yl)-p ip e-
r id in e (12). Following the representative procedure, 12 was
isolated as a colorless oil, [R]25D 23.80 (c 0.90, CH2Cl2). 1H NMR
(250 MHz, CDCl3): δ 0.86 (3H, t, J ) 7.0 Hz), 1.15-1.47 (5H,
4290 J . Org. Chem., Vol. 68, No. 11, 2003

[3+3] Cycloaddition Strategy to Functionalized Piperidines
ES): 292 (MH+, 100%), 250 (38%). Anal. Calcd for C16H21
NO2S: C, 65.95; H, 7.26; N, 4.81. Found: C, 65.71; H, 7.44;
N, 4.77.
-
34 was isolated as a white solid, mp 185-187 °C. 1H NMR
(250 MHz, CDCl3): δ 1.55 (2H, t, J ) 6.5 Hz), 1.80-1.91 (2H,
m), 2.21 (2H, t, J ) 6.5 Hz), 2.29-2.39 (2H, m), 2.42 (3H, s),
2.46 (3H, s), 2.60-2.73 (2H, m), 3.37 (2H, dt, J ) 12.0, 4.5
Hz), 4.12 (2H, s), 4.80 (1H, br), 4.89 (1H, br), 7.23 (2H, d, J )
8.0 Hz), 7.33 (2H, d, J ) 8.0 Hz), 7.62 (4H, d, J ) 8.0 Hz). 13C
NMR (62.9 MHz, CDCl3): δ 21.5, 21.6, 27.3, 31.6, 33.1, 42.5,
48.6, 58.9, 111.1, 127.1, 127.7, 129.6, 129.7, 133.1, 140.2, 140.9,
143.1, 143.6. FTIR (CH2Cl2): 2925 (m), 2854 (m), 1596 (w),
1456 (w), 1330 (m), 1166 (s), 1091 (m) cm-1. m/z (FAB): 475
(MH+, 12%), 155 (34%). HRMS (FAB) calcd for C24H31N2O4S2
475.1725, found 475.1746.
3-Meth ylen e-1-(tolu en e-4-su lfon yl)-octa h yd r o-[1]p yr i-
d in e (38). Following the representative procedure, 38 was
isolated as a white solid, mp 127-129 °C. 1H NMR (250 MHz,
CDCl3): δ 0.80-2.25(8H, m), 2.20-2.31 (1H, m), 2.39-2.52
(1H, m), 2.45 (3H, s), 2.87 (1H, d, J ) 12.0 Hz), 4.27 (1H, d, J
) 12.0 Hz), 4.86 (1H, br), 4.96 (1H, br), 7.34 (2H, d, J ) 8.0
Hz), 7.67 (2H, d, J ) 8.0 Hz). 13C NMR (62.9 MHz, CDCl3): δ
20.5, 21.5, 27.4, 38.0, 46.1, 54.7, 64.2, 112.3, 128.0, 129.6, 132.9,
141.1, 143.5. FTIR (CH2Cl2): 2952 (m), 1600 (w), 1494 (w),
1454 (w), 1351 (s), 1168 (s), 1094 (m) cm-1. m/z (EI): 291 (M+,
82%), 262 (65%), 155 (33%), 136 (74%), 91 (100%). HRMS (EI)
calcd for C16H21NO2S (M+) 291.1293, found 291.1295.
3-Met h ylen e-1-(t olu en e-4-su lfon yl)-d eca h yd r oq u in o-
lin e (39). Following the representative procedure, 39 was
isolated as a white solid, mp 92-93 °C. 1H NMR (250 MHz,
CDCl3): δ 0.82-1.01 (1H, m), 1.09-1.77 (8H, m), 2.03-2.20
(1H, m), 2.20-2.31 (1H, m), 2.38 (3H, s), 2.78 (1H, td, J )
10.5, 3.5 Hz), 3.94 (1H, d, J ) 16.0 Hz), 4.10 (1H, d, J ) 16.0
Hz), 4.77 (1H, br), 4.77 (1H, br), 7.25 (2H, d, J ) 8.0 Hz), 7.66
(2H, d, J ) 8.0 Hz). 13C NMR (62.9 MHz, CDCl3): δ 21.5, 25.6,
25.7, 33.0, 33.4, 36.4, 39.5, 49.1, 62.9, 109.8, 127.6, 129.3, 142.3,
143.0. FTIR (CH2Cl2): 3055 (m), 2930 (m), 1737 (w), 1450 (m),
1422 (m), 1339 (m), 1272 (s), 1161 (s), 1091 (m) cm-1. m/z
(EI): 305 (M+, 65%), 262 (98%), 155 (32%), 150 (37%), 91
(100%). Anal. Calcd for C17H23NO2S: C, 66.85; H, 7.59; N, 4.59.
Found: C, 66.86; H, 7.65; N, 4.54.
6-Ben zyl-5-(tolu en e-4-su lfon yl)-1-oxa -5-a za -sp ir o[2.5]-
octa n e (43). A 0.062 M solution of dimethyldioxirane in
acetone (11.77 mL, 0.73 mmol, 5 equiv) was added to a solution
of 14 (50 mg, 0.15 mmol, 1 equiv) in CH2Cl2 (15 mL) at 0 °C
via syringe. The reaction was stirred at 0 °C for 1 h and then
allowed to warm to room temperature overnight. The reaction
mixture was then concentrated in vacuo and purification by
flash chromatography providing epoxides 43a (35 mg, 67%)
and 43b (12 mg, 24%) as colorless oils.
(R )-2-I s o p r o p y l-1-(4-m e t h o x y -b e n ze n e s u lfo n y l)-5-
m eth ylen e-p ip er id in e (22). Following the representative
procedure, 22 was isolated as a white solid, mp 115-117 °C.
1
[R]25 -43.33 (c 0.60, CH2Cl2). H NMR (250 MHz, CDCl3): δ
D
0.87 (3H, d, J ) 6.5 Hz), 0.96 (3H, d, J ) 6.5 Hz), 1.05-1.26
(1H, m), 1.55-1.74 (1H, m), 1.82-2.24 (3H, m), 3.35-3.49 (1H,
m), 3.58 (1H, d, J ) 16.0), 3.80 (3H, s), 4.22 (1H, d, J ) 16.0),
4.56 (1H, br), 4.66 (1H, br), 6.84 (2H, d, J ) 9.0 Hz), 7.67 (2H,
d, J ) 9.0 Hz). 13C NMR (100.6 MHz, CDCl3): δ 19.6, 20.1,
25.0, 26.7, 27.3, 47.0, 55.5, 59.1, 110.2, 113.8, 129.4, 133.0,
141.2, 162.4. FTIR (CH2Cl2): 3052 (w), 2929 (w), 1598 (w), 1499
(w), 1421 (w), 1336 (w), 1260 (s), 1158 (w), 1094 (w) cm-1. m/z
(FAB): 310 (MH+), 266 (60%), 171 (100%), 138 (25%), 123
(61%). Anal. Calcd for C16H23NO3S: C, 62.11; H, 7.49; N, 4.53.
Found: C, 61.84; H, 7.66; N, 4.33.
(R)-2-P r op yl-5-m eth ylen e-1-(4-m eth oxy-ben zen esu lfo-
n yl)-p ip er id in e (24). Following the representative procedure,
24 was isolated as a white solid, mp 112-113 °C. [R]25 39.52
D
1
(c 0.99, CH2Cl2). H NMR (250 MHz, CDCl3): δ 0.94 (3H, t, J
) 7.5 Hz), 1.19-1.52 (5H, m), 1.62-1.76 (1H, m), 1.97 (1H,
dt, J ) 14.0, 4.0 Hz), 2.05-2.26 (1H, m), 3.68 (1H, d, J ) 15.5
Hz), 3.81-3.99 (1H, m), 3.86 (3H, s), 4.20 (1H, d, J ) 15.5
Hz), 4.66 (1H, br), 4.75 (1H, br), 6.93 (2H, d, J ) 9.0 Hz), 7.73
(d, 2H, J ) 9.0 Hz). 13C NMR (62.9 MHz, CDCl3): δ 13.9, 19.5,
27.3, 28.0, 32.3, 46.5, 52.4, 55.5, 110.3, 113.9, 129.4, 132.9,
141.3, 162.4. FTIR (CH2Cl2): 3077 (w), 2960 (w), 2874 (w), 1598
(m), 1498 (m), 1338 (m), 1265 (s), 1157 (s), 1094 (m) cm-1. m/z
(EI): 309 (M+, 4%), 266 (100%), 171 (39%), 107 (12%). HRMS
(EI) calcd for C16H23NO3S (M+) 309.1399, found 309.1388.
7-Met h ylen e-5-(t olu en e-4-su lfon yl)-5-a za -sp ir o[3.5]-
n on a n e (31). Following the representative procedure, 31 was
isolated as a white solid, mp 109-110 °C. 1H NMR (250 MHz,
CDCl3): δ 1.55-1.72 (2H, m), 1.69 (2H, t, J ) 6.5 Hz), 1.90-
2.03 (2H, m), 2.27 (2H, t, J ) 6.5 Hz), 2.40 (3H, s), 2.44 (2H,
ddd, J ) 20.5, 10.0, 3.0 Hz), 3.90 (2H, s), 4.75(1H, br), 4.88
(1H, br), 7.23 (2H, d, J ) 8.5 Hz), 7.68 (2H, d, J ) 8.5 Hz). 13
C
NMR (62.9 MHz, CDCl3): δ 14.6, 21.5, 29.2, 31.6, 33.6, 49.5,
60.3, 110.8, 127.3, 129.4, 140.2, 141.1, 142.7. FTIR (CH2Cl2):
2940 (m), 1598 (w), 1443 (w), 1337 (s), 1156 (s), 1091 (m) cm-1
.
m/z (EI): 291 (M+, 4%), 198 (91%), 155 (5%), 136 (17%). Anal.
Calcd for C16H21NO2S: C, 65.95; H, 7.26; N, 4.81. Found: C,
65.90; H, 7.42; N, 4.82.
8-Met h ylen e-6-(t olu en e-4-su lfon yl)-6-a za -sp ir o[4.5]-
d eca n e (32). Following the representative procedure, 32 was
isolated as a white solid, mp 95-97 °C. 1H NMR (250 MHz,
CDCl3): δ 1.43-1.87 (8H, m), 1.94-2.20 (2H, m), 2.34 (2H, t,
J ) 6.5 Hz), 2.41 (3H, s, ArCH3), 4.19 (2H, s, C7-H), 4.83 (1H,
br, CdCHH), 4.94 (1H, br, CdCHH), 7.24 (2H, d, J ) 8.0 Hz,
ArH), 7.70 (2H, d, J ) 8.0 Hz, ArH). 13C NMR (62.9 MHz,
CDCl3): δ 21.5, 22.6, 29.4, 34.7, 36.0, 51.2, 68.0, 110.6, 127.2,
129.3, 140.7, 142.1, 142.5. FTIR (CH2Cl2): 2951 (m), 1598 (w),
1450 (w), 1328 (s), 1156 (s), 1091 (s) cm-1. m/z (EI): 305 (M+,
(2R,6S)-6-Ben zyl-5-(t olu en e-4-su lfon yl)-1-oxa -5-a za -
sp ir o[2.5]octa n e (43a ): [R]25 -31.79 (c 0.98, CH2Cl2). 1H
D
NMR (250 MHz, CDCl3): δ 1.26-1.38 (1H, m), 1.67-1.92 (2H,
m), 2.23 (1H, td, J ) 13.0, 5.0 Hz), 2.43 (3H, s), 2.63 (1H, dd,
J ) 4.5, 1.5 Hz), 2.74-2.81 (1H, m), 2.74-2.79 (2H, m), 2.82-
2.96 (2H, m), 3.33 (1H, d, J ) 14.0 Hz), 3.49 (1H, app dd, J )
14.0, 1.5 Hz), 4.30-4.41 (1H, m), 7.16 (2H, d, J ) 8.0 Hz),
7.21-7.32 (5H, m), 7.56 (2H, d, J ) 8.0 Hz). 13C NMR (62.9
MHz, CDCl3): δ 21.5, 26.4, 26.5, 35.7, 45.8, 53.7, 55.7, 118.8,
126.6, 127.1, 128.7, 129.1, 129.7, 137.4, 137.9, 143.3. FTIR
(CH2Cl2): 3024 (w), 2948 (w), 2862 (w), 1599 (w), 1495 (w),
1453 (w), 1338 (m), 1158 (s), 1095 (m), 966 (m) cm-1. m/z (TOF
ES): 358 (100%, MH+). HRMS (TOF ES) calcd for C20H24NO3S
(MH+) 358.1477, found 358.1480.
1%), 198 (79%), 155 (100%), 150 (58%). HRMS calcd for C17H23
-
NO2SNa (MNa+) 328.1336, found 328.1341.
3-Met h ylen e-1-(t olu en e-4-su lfon yl)-1-a za -sp ir o[5.5]-
u n d eca n e (33). Following the representative procedure, 33
was isolated as a white solid, mp 98-100 °C. 1H NMR (250
MHz, CDCl3): δ 1.16-1.39 (2H, m), 1.53-1.65 (4H, m), 1.70-
1.86 (4H, m), 2.02-2.17 (2H, m), 2.25 (2H, t, J ) 6.0 Hz), 2.41
(3H, s), 4.20 (2H, s), 4.81 (1H, br), 4.89 (1H, br), 7.24 (2H, d,
J ) 8.0 Hz), 7.69 (2H, d, J ) 8.0 Hz). 13C NMR (62.9 MHz,
CDCl3): δ 21.5, 22.8, 25.2, 27.2, 31.2, 33.5, 48.2, 62.2, 109.7,
126.8, 129.3, 141.4, 142.3, 142.8. FTIR (CH2Cl2): 2933 (m),
1599 (w), 1452 (w), 1317 (m), 1152 (s), 1091 (m) cm-1. m/z
(CI): 320 (MH+, 9%), 199 (21%), 164 (25%), 149 (100%). Anal.
Calcd for C18H25NO2S: C, 67.67; H, 7.89; N, 4.38. Found: C,
67.80; H, 7.99; N, 4.42.
(2S,6S)-6-Be n zyl-5-(t olu e n e -4-su lfon yl)-1-oxa -5-a za -
sp ir o[2.5]octa n e (43b): [R]25D -2.55 (c 0.98, CH2Cl2). 1H NMR
(250 MHz, CDCl3): δ 1.04-1.17 (1H, m), 1.36-1.60 (2H, m),
2.25 (1H, td, J ) 13.5, 5.0 Hz), 2.38 (3H, s), 2.67 (1H, d, J )
4.5 Hz), 2.75 (1H, d, J ) 4.5 Hz), 2.98 (2H, d, J ) 8.0 Hz),
3.48 (1H, d, J ) 14.5 Hz), 3.73 (1H, d, J ) 14.5 Hz), 4.06-
4.19 (1H, m), 7.14-7.34 (7H, m), 7.78 (2H, d, J ) 8.0 Hz). 13C
NMR (62.9 MHz, CDCl3): δ 21.6, 22.8, 25.4, 36.1, 47.1, 51.7,
53.7, 55.3, 126.7, 127.5, 128.7, 129.2, 129.5, 137.7, 138.1, 143.1.
FTIR (CH2Cl2): 3028 (w), 2951 (w), 2862 (w), 1599 (w), 1496
(w), 1454 (w), 1335 (m), 1159 (s), 1097 (m), 964 (m) cm-1. m/z
3-Meth ylen e-1,9-bis(tolu en e-4-su lfon yl)-1,9-diaza-spir o-
[5.5]u n d eca n e (34). Following the representative procedure,
J . Org. Chem, Vol. 68, No. 11, 2003 4291

Hedley et al.
(EI): 357 (M+, 4%), 266 (100%), 155 (19%), 91 (38%). HRMS
(EI) calcd for C20H23NO3S (M+) 357.1399, found 357.1403.
(2R,6S)-6-Ben zyl-1,5-bis(tolu en e-4-su lfon yl)-1,5-d ia za -
sp ir o[2.5]octa n e (44). To a solution of Cu(MeCN)4PF6 (55 mg,
0.15 mmol, 0.1 equiv), 14 (500 mg, 1.45 mmol, 1 equiv), and
4-toluenesulfonamide (351 mg, 2.03 mmol, 1.4 equiv) in MeCN
(5.0 mL) in the presence of 1.00 g of activated 4Å molecular
sieves was added, at 0 °C under nitrogen, iodosylbenzene (451
mg, 2.03 mmol, 1.4 equiv). The reaction mixture was stirred
at 0 °C for a further 2 h and then at room temperature
overnight. The solution was diluted with EtOAc and filtered
through Celite. The volatiles were removed in vacuo and the
resultant residue purified by flash chromatography on silica
gel to give aziridine 44 as a white solid (250 mg, 34%), mp
175-176 °C. [R]25D -7.50 (c 1.00, CH2Cl2). 1H NMR (400 MHz,
CDCl3): δ 1.75-1.96 (3H, m), 2.39 (3H, s), 2.44 (3H, s), 2.48
(1H, app s), 2.53 (1H, app s), 2.60 (1H, m), 2.80 (1H, dd, J )
13.5, 7.0 Hz), 2.87 (1H, dd, J ) 13.5, 9.0 Hz), 3.43 (1H, d, J )
14.0 Hz), 3.64 (1H, d, J ) 14.0 Hz), 4.39 (1H, m), 7.11 (2H, d,
J ) 8.0 Hz), 7.18 (2H, d, J ) 8.0 Hz), 7.22-7.27 (3H, m), 7.35
(2H, d, J ) 8.0 Hz), 7.46 (2H, d, J ) 8.0 Hz), 7.86 (2H, d, J )
8.0 Hz). 13C NMR (62.9 MHz, CDCl3): δ 21.5, 21.6, 24.8, 27.0,
35.3, 41.7, 45.9, 48.9, 53.8, 126.6, 127.1, 127.4, 128.7, 129.1,
129.7, 137.2, 137.3, 137.9, 143.3, 144.3. FTIR (CH2Cl2): 2924
(w), 1598 (w), 1454 (w), 1321 (m), 1157 (s), 1092 (m) cm-1. m/z
(EI): 510 (M+, 5%), 419 (100%), 355 (6%), 155 (52%). HRMS
(TOF ES) calcd for C27H30N2O4S2 (MH+) 511.1720, found
511.1708.
2-Ben zyl-5-m eth yl-1-(tolu en e-4-su lfon yl)-piper idin e (45).
To a solution of 14 (89 mg, 0.26 mmol, 1 equiv) in MeOH (1.5
mL) under nitrogen was added 10% Pd/C (27 mg, 0.026 mmol,
0.1 equiv). A balloon filled with H2 gas was attached to the
flask and the nitrogen atmosphere was purged through a
needle. The reaction mixture was left to stir for 16 h at room
temperature. The volatiles were removed in vacuo and the
resulting residue was purified by flash chromatography to give
45, an inseparable mixture of diastereomers, as a colorless oil
(86 mg, 88%). Spectroscopic data for the major diastereomer:
1H NMR (400 MHz, CDCl3) δ 0.94 (3H, d, J ) 7.0 Hz), 1.23-
1.32 (2H, m), 1.59-1.69 (1H, m), 1.81-1.99 (2H, m), 2.39 (3H,
s), 2.60 (1H, dd, J ) 13.0, 4.0 Hz), 2.86 (1H, dd, J ) 13.0, 11.5
Hz), 3.22 (1H, dd, J ) 13.0, 3.5 Hz), 3.45 (1H, d, J ) 13.0 Hz),
4.11-4.17 (1H, m), 7.10 (2H, d, J ) 7.0 Hz), 7.19 (1H, d, J )
7.5 Hz), 7.24 (2H, d, J ) 7.0 Hz), 7.26 (2H, d, J ) 7.5 Hz),
7.71 (2H, d, J ) 8.5 Hz). 13C NMR (62.9 MHz, CDCl3) δ 16.8,
20.7, 21.5, 24.2, 27.4, 35.0, 46.2, 54.8, 126.3, 127.0, 128.5, 129.2,
129.6, 138.3, 138.7, 142.9. FTIR (CH2Cl2) 3055 (s), 2987 (s),
2306 (m), 1422 (s), 1261 (s), 1164 (m) cm-1. HRMS (TOF ES)
calcd for C20H26NO2S (MH+) 344.1684, found 344.1696.
[6-Ben zyl-1-(tolu en e-4-su lfon yl)-p ip er id in -3-yl]-m eth a -
n ol (46). To a stirred solution of 14 (60 mg, 0.18 mmol, 1 equiv)
in THF (0.5 mL) at 0 °C under nitrogen was added 0.5 M
9-BBN (0.35 mL, 0.18 mmol, 1 equiv). After 3 h, aqueous 1 M
NaOH solution (0.35 mL, 0.35 mmol, 2 equiv) and 30% H2O2
solution (0.04 mL, 0.35 mmol, 2 equiv) were added and stirring
continued for 20 min. The resulting mixture was extracted
with ethyl acetate and dried over MgSO4, and the volatiles
were removed in vacuo. Purification by flash chromatography
provided 46, an inseparable mixture of diastereomers, as a
colorless oil (53 mg, 85%). Spectroscopic data for the major
diastereomer: 1H NMR (250 MHz, CDCl3) δ 1.15-1.91 (5H,
m), 2.32 (3H, s), 2.66-2.82 (2H, m), 3.40 (1H, dd, J ) 10.5,
5.0 Hz), 3.40 (1H, dd, J ) 10.5, 7.0 Hz), 3.72-3.89 (2H, m),
4.17-4.31 (1H, m), 6.95-8.24 (7H, m), 7.52 (2H, m, J ) 8.0
Hz). 13C NMR (62.9 MHz, CDCl3) δ 21.5, 22.3, 35.5, 38.2, 43.3,
54.1, 65.6, 126.4, 126.7, 127.0, 128.6, 129.2, 129.6, 138.5, 142.9.
FTIR (CH2Cl2) 3618 (m), 3537 (br), 3065 (m), 3030 (m), 2938
(s), 2869 (s), 1600 (s), 1496 (s), 1456 (s), 1336 (s), 1153 (s), 1091
(s) 1032 (s) cm-1. HRMS (TOF ES) calcd for C20H26NO3S (MH+)
360.1633, found 360.1617
Ack n ow led gm en t. We are grateful to the EPSRC
for studentships (S.J .H. and W.J .M.), Pfizer for a CASE
award (S.J .H.), and the University of Sheffield.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
1
cedures for the synthesis of aziridines and H and 13C spectra
for select piperidine compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
J O030002C
4292 J . Org. Chem., Vol. 68, No. 11, 2003