Synthesis of 2,4-disubstituted piperidines via radical cyclization: Unexpected enhancement in diastereoselectivity with tris(trimethylsilyl)silane

Article abstract of DOI:10.1021/jo060495w

A novel approach to 2,4-disubstituted piperidines is reported, involving the radical cyclization of 7-substituted-6-aza-8-bromooct-2-enoates. Cyclization with tributyltin hydride affords the trans piperidines with trans/cis diastereomeric ratios ranging typically from 3:1 to 6:1. Cyclization with tris(trimethylsilyl)silane affords the same products with diastereomeric ratios of up to 99:1 in certain cases. The enhancement in diastereoselectivity results from the selective rearrangement of the minor stereoisomer through a cascade process involving radical cyclization to the piperidine radical, 1,5-radical translocation, and attack of the translocated radical onto the sulfonamide with extrusion of SO₂ in a Smiles-type rearrangement. Slower trapping of the piperidine radical by tris(trimethylsilyl)silane compared to tributyltin hydride accounts for the occurrence of the rearrangement cascade in the former case.

Full text of DOI:10.1021/jo060495w

Synthesis of 2,4-Disubstituted Piperidines via Radical Cyclization:
Unexpected Enhancement in Diastereoselectivity with
Tris(trimethylsilyl)silane
Lucile A. Gandon, Alexander G. Russell, Tatyana Gu¨veli, Angela E. Brodwolf,
Benson M. Kariuki, Neil Spencer, and John S. Snaith*
School of Chemistry, The UniVersity of Birmingham, Edgbaston, Birmingham, B15 2TT, U.K.
j.s.snaith@bham.ac.uk
ReceiVed March 7, 2006
A novel approach to 2,4-disubstituted piperidines is reported, involving the radical cyclization of
7-substituted-6-aza-8-bromooct-2-enoates. Cyclization with tributyltin hydride affords the trans piperidines
with trans/cis diastereomeric ratios ranging typically from 3:1 to 6:1. Cyclization with tris(trimethylsilyl)-
silane affords the same products with diastereomeric ratios of up to 99:1 in certain cases. The enhancement
in diastereoselectivity results from the selective rearrangement of the minor stereoisomer through a cascade
process involving radical cyclization to the piperidine radical, 1,5-radical translocation, and attack of the
translocated radical onto the sulfonamide with extrusion of SO2 in a Smiles-type rearrangement. Slower
trapping of the piperidine radical by tris(trimethylsilyl)silane compared to tributyltin hydride accounts
for the occurrence of the rearrangement cascade in the former case.
Introduction
are fewer reports of radical cyclizations leading to piperidines.8,9
We now report in full the results of our investigation into the
synthesis of 2,4-disubstituted piperidines by radical ring clo-
sure.10
The piperidine ring is an important structural motif present
in natural products1 and synthetic pharmaceuticals,2 and this
has led to the development of many synthetic approaches to
these heterocycles.3 Nevertheless, the variety of functionality
and substitution patterns found in piperidine targets continues
to drive the search for new methodologies.4
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(b) Brooks, C. A.; Comins, D. L. Tetrahedron Lett. 2000, 41, 3551-3553.
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1004-1005. (d) Shu, C.; Alcudia, A.; Yin, J.; Liebeskind, L. S. J. Am.
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Chem. 2003, 68, 4371-4381. (f) Legault, C.; Charette, A. B. J. Am. Chem.
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9525-9527. (h) Amat, M.; Escolano, C.; Lozano, O.; Llor, N.; Bosch, J.
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C. F.; Brookes, P. J. Chem. Soc., Perkin Trans. 1 2000, 1-14. (c) Bowman,
W. R.; Fletcher, A. J.; Potts, G. B. S. J. Chem. Soc., Perkin Trans. 1 2002,
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ReV. 1991, 91, 1237-1286. (b) Bar, G.; Parsons, A. F. Chem. Soc. ReV.
2003, 32, 251-263.
Free-radical cyclization processes occupy an important role
in the formation of heterocycles5 and have found many
applications in natural product synthesis.6 Radical cyclization
is well documented in the synthesis of pyrrolidines,7 but there
(1) (a) Findlay, J. A. In The Alkaloids; Brossi, A., Ed.; Academic Press:
London, 1985; Vol. 26, pp 89-183. (b) Pinder, A. R. Nat. Prod. Rep. 1986,
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(2) Between July 1988 and December 1998 over 12 000 piperidines were
mentioned in clinical and preclinical studies. See: Watson, P. S.; Jiang,
B.; Scott, B. Org. Lett. 2000, 2, 3679-3681.
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10.1021/jo060495w CCC: $33.50 © 2006 American Chemical Society
Published on Web 06/13/2006
5198
J. Org. Chem. 2006, 71, 5198-5207

Synthesis of 2,4-Disubstituted Piperidines
Slow addition of tributyltin hydride and AIBN (13 h via
syringe pump) to a solution of bromide 3 in refluxing benzene
(final concentration 0.01 M) afforded the expected 4-substituted
piperidine 4 in a near quantitative yield (90% isolated after
chromatography). Careful analysis of the reaction mixture using
NMR and GC-MS showed no sign of the acyclic reduction
product 5 or the 7-endo cyclization product 6 (Scheme 2).
Encouraged by the successful cyclization of the model system,
we set out to use similar methodology to construct analogous
cyclization precursors from a variety of 2-substituted amino
alcohols 7a-g (Scheme 3). N-Tosylation and O-silylation of
the amino alcohols to yield 8a-g was followed by conjugate
addition into methyl acrylate as before. Unfortunately, an
inseparable mixture of starting material and the desired product
was obtained in all cases. Attempts to optimize the reaction by
varying the temperature, solvent, and the acrylate ester (Me,
FIGURE 1. Retrosynthetic analysis.
We envisaged ring closure to the piperidine occurring by
formation of the C3-C4 bond (Figure 1) with the substituent
adjacent to nitrogen exerting stereocontrol over the forming
stereogenic center at C4. The C2 substituent of the piperidine
can be derived from the wide variety of commercially available
natural and unnatural amino acids. Since the relatively slow
6-exo-trig cyclization suffers from competing direct reduction
of the acyclic radical and poor exo/endo selectivity, the acceptor
double bond was activated as an R,â-unsaturated ester.11
t
Et, Bu) proved fruitless, and it appeared that the conjugate
addition was reversible with an equilibrium constant that did
not favor the product.
Instead, we switched to a route involving alkylation of 8a-g
with the dimethyl acetal of 3-iodopropanal, using Cs2CO3 as
base, to afford the acetals 9a-g (Scheme 4).
Results and Discussion
Before commencing on the synthesis of more complex
cyclization precursors, we first prepared a model system to
investigate the feasibility of using the 6-exo radical cyclization
to generate the C3-C4 bond of the piperidine ring (Scheme
1).
Acid-catalyzed acetal hydrolysis with concomitant TBDMS
removal gave the lactols 10a-g as a mixture of epimers at the
anomeric position. These were directly subjected to a Wittig
reaction with methyl- or tert-butyl(triphenylphosphoranylidene)-
acetate to give the corresponding R,â-unsaturated esters 11a-n
in good yield but with poor E/Z selectivity. Performing the
reactions at 90 °C in toluene with the inclusion of 20 mol %
benzoic acid under the modified conditions of Harcken and
Martin14 led to a significant improvement in the E/Z ratio.
Bromination of the methyl esters was straightforwardly
carried out using carbon tetrabromide and triphenylphosphine
to afford the bromides 12 in excellent yield. In the case of the
tert-butyl esters, bromination under these conditions gave a
mixture of the desired bromo ester and the bromo acid resulting
from the cleavage of the tert-butyl ester. Instead, the alcohols
were treated with methanesulfonyl chloride then lithium bromide
to give the tert-butyl bromides in excellent yield.
The E and Z esters proved separable at this stage, and so
residual Z ester was removed by chromatography. We wanted
to study the cyclization of the E and Z esters separately, since,
in earlier work on 6-exo-trig cyclizations by Hanessian et al.,11a
the geometry of the acceptor double bond was found to be an
important feature in controlling the stereoselectivity of the
cyclization. The Z ester experienced greater 1,3-diaxial interac-
tions when it adopted a pseudoaxial position, resulting in
preferential cyclization to the trans product (Figure 2).
To probe the effect of olefin geometry on the stereoselectivity
of the cyclization, the Z esters were prepared using the Still-
Gennari modified Horner-Wadsworth-Emmons reaction.15
Exposure of lactol 10a to methyl bis(trifluoroethyl)phosphono-
acetate in the presence of K2CO3 and 18-crown-6 in toluene
led to a quantitative recovery of N-tosyl alaninol, presumably
as a result of base-induced elimination of acrolein from aldehyde
13 (Scheme 5).
Conjugate addition of the diprotected amino ethanol 112 to
methyl acrylate, followed by reduction with diisobutylaluminum
hydride, afforded aldehyde 2. Wittig reaction gave the E-
configured R,â-unsaturated ester in 78% yield, along with 6%
of the Z-isomer, and one-pot desilylation-bromination13 by
dibromotriphenylphosphorane gave the desired E-bromide 3 in
84% yield.
(7) For examples see: (a) Tsuritani, T.; Shinokubo, H.; Oshima, K. J.
Org. Chem. 2003, 68, 3246-3250. (b) Besev, M.; Engman, L. Org. Lett.
2002, 4, 3023-3025. (c) Bustos, F.; Gorgojo, J. M.; Suero, R.;
Aurrecoechea, J. M. Tetrahedron 2002, 58, 6837-6842. (d) Jahn, U.;
Muller, M.; Aussieker, S. J. Am. Chem. Soc. 2000, 122, 5212-5213.
(8) (a) Katritzky, A. R.; Luo, Z.; Fang, Y.; Feng, D.; Ghiviriga, I. J.
Chem. Soc., Perkin Trans. 2 2000, 1375-1380. (b) Koreeda, M.; Wang,
Y.; Zhang, L. Org. Lett. 2002, 4, 3329-3332. (c) Yoo, S. E.; Yi, K. Y.;
Lee, S. H.; Jeong, N. Synlett 1990, 575-576. (d) Parsons, A. F.; Pettifer,
R. M. J. Chem. Soc., Perkin Trans. 1 1998, 651-660. (e) Ihara, M.; Setsu,
F.; Shoda, M.; Taniguchi, N.; Tokunaga, Y.; Fukumoto, K. J. Org. Chem.
1994, 59, 5317-5323. (f) Lee, E.; Kang, T. S.; Joo, B. J.; Tae, J. S.; Li, K.
S.; Chung, C. K. Tetrahedron Lett. 1995, 36, 417-420. (g) Lee, E.; Jeong,
E. J.; Min, S. J.; Hong, S.; Lim, J.; Kim, S. K.; Kim, H. J.; Choi, B. G.;
Koo, K. C. Org. Lett. 2000, 2, 2169-2171. (h) Prevost, N.; Shipman, M.
Org. Lett. 2001, 3, 2383-2385.
(9) For examples of formation of piperidines within polycyclic natural
products by radical ring-closure see: (a) Takayama, H.; Watanabe, F.;
Kitajima, M.; Aimi, N. Tetrahedron Lett. 1997, 38, 5307-5310. (b) Kaoudi,
T.; Miranda, L. D.; Zard, S. Z. Org. Lett. 2001, 3, 3125-3127. (c) Quirante,
J.; Escolano, C.; Bosch, J.; Bonjoch, J. J. Chem. Soc., Chem. Commun.
1995, 2141-2142. (d) Ishibashi, H.; Inomata, M.; Ohba, M.; Ikeda, M.
Tetrahedron Lett. 1999, 40, 1149-1152.
(10) For a preliminary account of this work see: Gandon, L. A.; Russell,
A. G.; Snaith, J. S. Org. Biomol. Chem. 2004, 2, 2270-2271.
(11) For earlier examples see: (a) Hanessian, S.; Dhanoa, D. S.; Beaulieu,
P. L. Can. J. Chem. 1987, 65, 1859-1866. (b) Anissa Yeung, B.-W.;
Contelles, J. L. M.; Fraser-Reid, B. J. Chem. Soc., Chem. Commun. 1989,
1160-1162. (c) Marco-Contelles, J.; Pozuelo, C.; Jimeno, M. L.; Martinez,
L.; Martinez-Grau, A. J. Org. Chem. 1992, 57, 2625-2631. (d) Marco-
Contelles, J.; Sanchez, B. J. Org. Chem. 1993, 58, 4293-4297. (e) Pedrosa,
R.; Andres, C.; Duque-Soladana, J. P.; Roson, C. D. Tetrahedron:
Asymmetry 2000, 11, 2809-2821. (f) Pedrosa, R.; Andres, C.; Iglesias, J.
M.; Obeso, M. A. Tetrahedron 2001, 57, 4005-4014. (g) Joshi, S. N.;
Puranik, V. G.; Deshmukh, A. R. A. S.; Bhawal, B. M. Tetrahedron:
Asymmetry 2001, 12, 3073-3076. (h) Zhang, X.; Guzi, T.; Pettus, L.;
Schultz, A. G. Tetrahedron Lett. 2002, 43, 7605-7608.
Happily, preforming the phosphonate anion by treatment with
KHMDS and 18-crown-6 in THF before adding the lactol
resulted in smooth olefination to give 14a in good yield and
with a Z/E ratio of 12:1. Both the methyl and tert-butyl
(12) Sato, Y.; Saito, N.; Mori, M. Tetrahedron 1998, 54, 1153-1168.
(13) Aizpurua, J. M.; Cossio, F. P.; Palomo, C. J. Org. Chem. 1986, 51,
4941-4943.
(14) Harcken, C.; Martin, S. F. Org. Lett. 2001, 3, 3591-3593.
(15) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405-4408.
J. Org. Chem, Vol. 71, No. 14, 2006 5199

Gandon et al.
SCHEME 1. Synthesis of the Model Cyclization Precursor
SCHEME 2. Cyclization of Bromide 3
SCHEME 3. Attempted Conjugate Additions of Protected Amino Alcohols
SCHEME 4. Preparation of Bromide Cyclization Precursors
Z-configured esters were prepared from a representative range
of lactols and brominated as before to afford 15a-f (Scheme
6). The Z esters were obtained free from any (E)-isomer after
chromatography.
With a range of suitable cyclization precursors in hand, radical
cyclizations were performed in refluxing benzene, or toluene
heated at 90 °C, with slow addition of tributyltin hydride and
AIBN, affording excellent yields of the diastereomeric piperi-
dines 16 and 17. With one exception (entry 10), the diastereo-
selectivities ranged from 3:1 to 6:1, increasing with the steric
bulk of the substituent adjacent to nitrogen (Table 1). Surpris-
ingly, and in contrast to the findings of Hanessian et al., results
for the E and Z esters were essentially identical.
Identification of the major and minor diastereomers was not
straightforward; separation of the diastereomers could only be
achieved by HPLC, and the 1H NMR data were too complex to
allow us to extract coupling constants. The major diastereomer
16 was assumed to have an axial 2-substituent and an equatorial
4-substituent, resulting from cyclization of the radical via
transition state 18 (Figure 3); in the chairlike transition state
5200 J. Org. Chem., Vol. 71, No. 14, 2006

Synthesis of 2,4-Disubstituted Piperidines
Piperidine 16d, also obtained by HPLC purification, was not
crystalline, but the brucine salt, prepared by acid-catalyzed
removal of the tert-butyl ester followed by treatment with
brucine dihydrate, yielded X-ray quality crystals from water.
Single-crystal X-ray analysis confirmed the structure.
Although the tendency for the 2-substituent of an N-
tosylpiperidine to lie in an axial position is usually very
marked,17 the fact that the axial/equatorial ratios are more
modest in this case is perhaps less surprising given the rather
early transition states for radical cyclization which distort the
transition state geometry from the idealized chair.18 This
distortion, with the forming bond being rather elongated, means
that factors such as the pseudo A1,3 strain which are important
in the product are of less importance in the transition state, and
other conformers are energetically accessible.
The toxicity of TBTH led us to explore the use of tris-
(trimethylsilyl)silane (TTMSS) in our cyclizations. As well as
lower toxicity, TTMSS also exhibits a lower rate constant than
TBTH for hydrogen atom donation as a result of the stronger
Si-H bond (79 kcal mol-1, compared with 74 kcal mol-1 for
the Sn-H bond of TBTH),19 a factor which can be beneficial
in radical cyclization reactions since products of direct reduction
of the uncyclized radical are minimized. Cyclization was carried
out by slow addition of solutions of TTMSS and AIBN to the
bromide in toluene at 90 °C (Table 2).
FIGURE 2. Improved selectivity for Z esters in Hanessian et al.’s
system.
the 2-substituent adopts the energetically more favorable
pseudoaxial disposition to minimize pseudo A1,3 strain with the
sulfonamide,16 while the acceptor double bond is in the
pseudoequatorial position to minimize 1,3-diaxial interactions.
The conformation of the transition state leading to the minor
diastereomer 17 was less clear-cut. In earlier work on 6-exo-
trig cyclizations by Hanessian et al., the major and minor
products resulted from cyclization onto pseudoequatorial and
pseudoaxial acceptor double bonds, respectively; Z-configured
esters gave reduced amounts of the minor product due to an
increase in 1,3-diaxial interactions. In our case, the essentially
identical results obtained for the E and Z esters suggested that
the minor product did not result from cyclization onto a
pseudoaxial double bond but was more likely to have both
substituents equatorial.
The identities of the diastereomers were tentatively confirmed
by NOE measurements, but crystallographic support was
hampered by the low crystallinity of the piperidines and the
fact that the diastereomers were often inseparable by flash
chromatography. Minor product 17k, purified by HPLC, did
yield X-ray quality crystals, and single-crystal X-ray analysis
confirmed the structure.
Cyclization yields were a little lower than those obtained with
TBTH, but the most striking feature was the improvement in
stereoselectivity in a number of cases, with, for example, the
product ratio for the cyclization of 12f increasing from 6:1
(TBTH) to 99:1 (TTMSS). The improvement was not ob-
served in all cases, and there was no correlation between the
size of the 2-substituent and the increased stereoselectivity with
TTMSS. There did, however, appear to be some correlation
between the increased selectivity and the nature of the
2-substituent, with secondary and benzylic substituents affording
the highest 16:17 ratios.
An enhancement in stereoselectivity on switching from TBTH
to TTMSS is remarkable and apparently without precedent.
Others have reported increased stereoselectivity in the reduction
of halides by TTMSS, a result attributed to the greater steric
SCHEME 5. Attempted Still-Gennari Olefination
SCHEME 6. Preparation of Z-Cyclization Precursors 15a-f
J. Org. Chem, Vol. 71, No. 14, 2006 5201

Gandon et al.
TABLE 1. Cyclizations with TBTHa
entry
bromide
R
R′
E or Z
16:17b
yield (%)c
1
2
3
4
5
6
7
8
12a
12b
12c
12d
12e
12f
12g
12h
12i
Me
Me
Bn
Me
tBu
Me
tBu
Me
tBu
Me
tBu
Me
tBu
Me
tBu
Me
tBu
Me
tBu
Me
tBu
Me
tBu
E
E
E
E
E
E
E
E
E
E
E
E
E
E
Z
Z
Z
Z
Z
Z
72:28
74:26
80:20
83:17
86:14
86:14
85:15
77:23
85:15
97:3
86:14
77:23
85:15
86:14
78:22
75:25
75:25
75:25
87:13
85:15
98
99
89
85
95
82
85
92
99
66
66
93
81
86
85
98
88
80
87
85
Bn
iPr
iPr
iBu
iBu
sec-Bu
sec-Bu
Ph
9
10
11
12
13
14
15
16
17
18
19
20
12j
12k
12l
Ph
12m
12n
15a
15b
15c
15d
15e
15f
tBu
tBu
Me
Me
Bn
Bn
iPr
iPr
a Reactions performed by syringe pump addition of benzene or toluene solutions of Bu3SnH and AIBN to a solution of the bromide in benzene or toluene
heated at 80-90 °C, final concentration typically 0.01-0.015 M. b Ratio determined by HPLC of the crude reaction mixture and/or 1H NMR after
chromatography to remove tin residues. c Isolated yields following chromatography.
decomposition of one diastereomer. This suggested that the
differences in selectivity achieved using the tin- and silicon-
based reagents were due to side reactions occurring at some
point in the radical chain process.
Smiles-type radical rearrangements have been observed for
certain aryl sulfonamides, and indeed the formation of biaryl-
FIGURE 3. Proposed transition state leading to the major diastereomer.
amines and sultams from aryl sulfonamides was first observed
demands of TTMSS leading to approach from the less hindered
(as unwanted side products in the Pschorr reaction) by Huppatz
face.20 However, this explanation cannot account for the
and Sasse in the 1960s.21 Later work from Ko¨hler and Speckamp
enhanced diastereoselectivities observed in our cyclizations.
showed that upon treatment with TBTH/AIBN, sulfonamide-
We suspected that the slightly lower yields obtained when
protected 2-halomethyl piperidines could undergo radical Smiles-
using TTMSS, coupled with the improved diastereoselectivities,
type rearrangement to yield the products of both ipso and ortho
resulted from selective loss of the minor stereoisomer. Pure
attack of the radical onto the aryl ring, as well as the direct
samples of both 16f and 17f were heated at reflux in benzene-
reduction product (Scheme 7).22 More recently, Tada et al.
d6 with TTMSS/AIBN and monitored by NMR. Even after
reported radical Smiles-type rearrangements in systems derived
1
prolonged heating (up to 48 h), no changes in the H NMR
from simple aliphatic amines,23 while Gheorghe et al. used the
spectra were observed, confirming that once the piperidines were
rearrangement to assemble a range of cyclization precursors for
formed, stereochemistry was fixed, and exposure to the cy-
piperidine synthesis.24
clization conditions did not result in isomerization or preferential
To see if such pathways could be competing during the
cyclization reactions, we returned to the cyclizations of 12f and
12i, since it was for these two substrates that we had observed
the greatest improvement in selectivity with TTMSS. If Smiles-
type rearrangements were occurring in our system, potential
products could include free amines which would form extremely
polar ammonium salts with the HBr formed from TTMSS-Br
on aqueous work up. Following each reaction the crude products
(16) The phenomenon of pseudo A1,3 strain in piperidines is reviewed
in: Johnson, F. Chem. ReV. 1968, 68, 375-413.
(17) For examples of the phenomenon in N-acyl, N-sulfonyl and related
piperidines see: (a) Beak, P.; Zajdel, W. J. J. Am. Chem. Soc. 1984, 106,
1010-1018. (b) Brown, J. D.; Foley, M. A.; Comins, D. L. J. Am. Chem.
Soc. 1988, 110, 7445-7447. (c) Heintzelman, G. R.; Weinreb, S. M.; Parvez,
M. J. Org. Chem. 1996, 61, 4594-4599. (d) Lemire, A.; Charette, A. B.
Org. Lett. 2005, 7, 2747-2750. (e) Cariou, C. A. M.; Snaith, J. S. Org.
Biomol. Chem. 2006, 4, 51-53.
(18) Curran, D. P.; Porter, N. A.; Giese, B. Stereochemistry of Radical
Reactions; VCH: Weinheim, Germany, 1996; pp 77-78.
(19) Kanabus-Kaminska, J. M.; Hawari, J. A.; Griller, D.; Chatgilialoglu,
C. J. Am. Chem. Soc. 1987, 109, 5267-5268.
(20) (a) Apeloig, Y.; Nakash, M. J. Am. Chem. Soc. 1994, 116, 10781-
10782. (b) Kawashima, E.; Uchida, S.; Miyahara, M.; Ishido, Y. Tetrahedron
Lett. 1997, 38, 7369-7372. (c) Mima, K.; Ishihara, T.; Kuwahata, S.; Konno,
T.; Yamanaka, H. Tetrahedron 2002, 58, 2369-2376.
(21) Huppatz, J. L.; Sasse, W. H. F. Aust. J. Chem. 1963, 16, 417-431.
(22) Ko¨hler, J. J.; Speckamp, W. N. Tetrahedron Lett. 1977, 18, 631-
634.
(23) Tada, M.; Shijima, H.; Nakamura, M. Org. Biomol. Chem. 2003,
1, 2499-2505.
(24) Gheorghe, A.; Quiclet-Sire, B.; Vila, X.; Zard, S. Z. Org. Lett. 2005,
7, 1653-1656.
5202 J. Org. Chem., Vol. 71, No. 14, 2006

Synthesis of 2,4-Disubstituted Piperidines
TABLE 2. Cyclizations with TTMSSa
entry
bromide
R
R′
E or Z
16:17b
yield (%)c
1
2
3
4
5
6
7
8
12a
12b
15b
12c
12d
12e
12f
12g
12h
12i
12j
12k
12l
12m
12n
Me
Me
tBu
tBu
Me
tBu
Me
tBu
Me
tBu
Me
tBu
Me
tBu
Me
tBu
E
E
Z
E
E
E
E
E
E
E
E
E
E
E
E
73:27
77:23
77:23
92:8
96:4
97:3
90
82
86
76
62
73
75
80
80
64
60
75
74
72
75
Me
Me
Bn
Bn
iPr
iPr
99:1
iBu
iBu
sec-Bu
sec-Bu
Ph
85:15
90:10
98:2
>99:1
79:21
78:22
86:14
88:12
9
10
11
12
13
14
15
Ph
tBu
tBu
a Reactions performed by syringe pump addition of toluene solutions of (Me3Si)3SiH and AIBN to a solution of the bromide in toluene heated at 90 °C,
final concentration typically 0.01-0.015 M. b Ratio determined by HPLC of the crude reaction mixture and 1H NMR after chromatography to remove
silicon residues. c Isolated yields following chromatography.
SCHEME 7. Smiles-Type Rearrangement in Aryl Sulfonamides
were purified by chromatography. After elution of the silicon-
containing byproducts (arising from TTMSS and TTMSSBr),
followed by the piperidines, the column was flushed with
CH2Cl2/MeOH (80:20), whereupon a small amount of highly
polar material was recovered in both cases.
Analytical HPLC of the material obtained from the cyclization
of 12f showed it to be a mixture of several compounds, but
with one major component, and purification by preparative
HPLC gave a small amount of a white solid. 2D NMR
experiments confirmed the structure as the ammonium ion 24f,
and NOE experiments showed a cis relationship between the
2- and 4-substituents, with both lying in equatorial positions.
The side product from the cyclization of 12i was similarly
purified by HPLC, affording a small amount of piperidinium
salt 24i as a 3:1 mixture of epimers at the stereocenter in the
2-substituent.
sion, this radical then undergoes a 1,5-radical translocation to
abstract the methine proton from the axial isopropyl or sec-
butyl group, giving a tertiary radical 20.25 Translocation is only
geometrically favorable for 2,4-cis piperidine radicals and,
further, depends on the formation of a stable translocated radical,
with the amount of rearranged product (and hence the stereo-
selectivity for the unrearranged trans product) being greatest
for tertiary and benzylic 2-substituents.
Another ring inversion occurs to restore the translocated
radical to an equatorial position. This can now attack the
aromatic ring in the ipso position resulting in the spiro-fused
radical 21, which then extrudes sulfur dioxide to give the
N-centered radical 22. Upon quenching with a hydrogen atom
from TTMSS, the piperidine 23 is formed.26 The rearranged
products are isolated as the piperidinium salts since the
piperidines react with the HBr arising from the hydrolysis of
the TTMSS-Br side product.
We propose that compounds 24f and 24i are formed as shown
in Scheme 8.
The initial primary alkyl radical 18 undergoes cyclization to
generate the secondary piperidine radical 19. After ring inver-
(25) For a review of radical translocations in synthesis see: Robertson,
J.; Pillai, J.; Lush, R. K. Chem. Soc. ReV. 2001, 30, 94-103.
J. Org. Chem, Vol. 71, No. 14, 2006 5203

Gandon et al.
SCHEME 8. Proposed Cascade of Rearrangements Leading to 24f and 24i
SCHEME 9. Deprotection of Piperidines
Slower hydrogen atom donation by TTMSS allows the
rearrangement cascade to compete with trapping of the piperi-
dine radical 19 to yield 17. With TBTH the rate of trapping of
19 is rapid, and so rearrangement is much less significant,
although a difference in stereoselectivity can still be observed
between slow and rapid addition of TBTH. Thus, cyclization
of bromide 12d by adding the TBTH in one portion afforded
the piperidines in a 70:30 trans/cis ratio (without any detectable
reduction product), while dropwise addition of TBTH over 12
h gave the products in an 83:17 diastereomeric ratio; longer
addition periods resulted in recovery of unreacted starting
materials due to breakdown of the chain process.
The more bulky tert-butyl esters reduce the rate of trapping
of the piperidine radical even further by sterically hindering
the approach of the bulky TTMSS. This was further emphasized
on moving to a more sterically demanding silane. Tris-
(phenyldimethylsilyl)silane was first prepared by Gilman et al.,27
but its use in radical reactions has not been reported. Employing
this bulky silane in the cyclization of 12c afforded the expected
piperidines with a diastereomeric ratio of 98:2 (59% yield),
compared with 92:8 (76%) with TTMSS and 80:20 (89%) with
TBTH.
the N-tosylpiperidines with phenol and HBr in acetic acid
(Scheme 9). Deprotection (performed on cis/trans mixtures)
proceeded cleanly with simultaneous ester hydrolysis to afford
essentially quantitative yields of the piperidine acids 25 with
unchanged cis/trans ratios.
Conclusion
In summary, we have demonstrated a diastereoselective
radical route to 2,4-disubstituted piperidines. Cyclization with
tributyltin hydride affords predominantly the trans piperidines
in excellent yield, with diastereomeric ratios typically ranging
from 3:1 to 6:1. Cyclization with tris(trimethylsilyl)silane leads
to an enhancement in diastereoselectivity in cases where the
2-substituent is secondary or benzylic, resulting from the
selective rearrangement of the minor stereoisomer through a
cascade process involving radical cyclization to the piperidine
radical, 1,5-radical translocation, and attack of the translocated
radical onto the sulfonamide with extrusion of SO2 in a Smiles-
Removal of the p-toluenesulfonyl protecting group was
carried out on a representative range of examples by stirring
(26) Work by Studer and Zard suggests that sulfur dioxide extrusion
from aminosulfonyl radicals is a slow process, so another possibility is that
21 undergoes C-S bond cleavage to give an aminosulfonyl radical which
is trapped by TTMSS before undergoing sulfur dioxide extrusion to afford
23. See ref 24 and also: Bossart, M.; Fassler, R.; Schoenberger, J.; Studer,
A. Eur. J. Org. Chem. 2002, 2742-2757.
(27) Gilman, H.; Atwell, W. H.; Sen, P. K.; Smith, C. L. J. Organomet.
Chem. 1965, 4, 163-167.
5204 J. Org. Chem., Vol. 71, No. 14, 2006

Synthesis of 2,4-Disubstituted Piperidines
The combined organic phases were washed with water and brine
and dried over MgSO4 before the solvents were removed in vacuo
to give the crude acetal as an oil. Purification by column
chromatography (hexane/Et2O, 9:1) provided 9c as a colorless oil
type rearrangement. Slow trapping of the piperidine radical by
tris(trimethylsilyl)silane accounts for the occurrence of the
rearrangement cascade with this reagent. The methodology
should find application to the synthesis of more complex
molecules.
(21.08 g, 91%): Rf ) 0.25; [R]24 ) -20.3° (c 1.0, CHCl3); IR
D
1
(film) 2956, 2929, 2882, 2857, 1598, 1494 cm-1; H NMR (300
MHz, CDCl3) δ -0.10 (s, 3H), -0.09 (s, 3H), 0.80 (s, 9H), 0.86
(d, J ) 6.6 Hz, 3H), 0.92 (d, J ) 6.6 Hz, 3H), 1.80-2.20 (m, 3H),
2.39 (s, 3H), 3.10-3.50 (m, 10H), 3.61 (dd, J ) 4.8, 11.4 Hz,
1H), 4.33 (t, J ) 5.5 Hz, 1H), 7.24 (d, J ) 8.3 Hz, 2H), 7.69 (d,
J ) 8.3 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ -5.8, -5.7, 18.2,
20.0, 20.8, 21.5, 25.9, 27.9, 34.0, 41.3, 52.8, 52.9, 63.4, 65.8, 102.9,
127.4, 129.6, 138.4, 142.9; MS (electrospray) m/z 496 (100%,
[M + Na]+). HRMS (electrospray) Calcd for C23H43NO5SSiNa:
496.2529. Found: 496.2524. Anal. Calcd for C23H43NO5SSi: C,
58.31; H, 9.15; N, 2.96. Found: C, 58.28; H, 9.29; N, 2.89.
Typical Procedure for the Hydrolysis of Acetals: (5S)-4-Aza-
1-hydroxy-5-isopropyl-6-oxa-4-(p-toluenesulfonyl)cyclohep-
tane (10c). To a solution of the acetal 9c (14.00 g, 29.6 mmol) in
THF/water (2:1, 80 mL) was added 2 M HCl (10 mL), and the
solution was stirred at room temperature for 36 h. THF was removed
in vacuo, and the aqueous residue was extracted with EtOAc. The
combined organic phases were washed with saturated NaHCO3
solution, water, and brine before being dried over MgSO4 and
concentrated in vacuo. Purification by column chromatography
(CH2Cl2/MeOH, 19:1) yielded the lactol 10c as a white solid (7.24
g, 78%): Rf ) 0.43; mp 104-106 °C (from EtOAc); IR (film)
3431, 3021, 2963, 2873, 1598, 1494 cm-1; MS (electrospray) m/z
368 (81%, [M + Na + MeOH]+), 336 (100%, [M + Na]+). HRMS
(electrospray) Calcd for C15H23NO4SNa: 336.1245. Found: 336.1237.
Anal. Calcd for C15H23NO4S: C, 57.48; H, 7.40; N, 4.47. Found:
Experimental Section
Typical Procedure for the Preparation of N-Tosyl O-Silyl
Amino Alcohols: (S)-O-(tert-Butyldimethylsilyl)-N-(p-toluene-
sulfonyl) Valinol (8c). Tosyl chloride (17.43 g, 91.4 mmol) in
CH2Cl2 (100 mL) was added dropwise over 2 h to a solution of
(S)-valinol (8.97 g, 87.1 mmol), DMAP (1.06 g, 8.7 mmol), and
Et3N (24.3 mL, 174.2 mmol) in CH2Cl2 (200 mL) at 0 °C. After
stirring overnight at room temperature, the reaction mixture was
poured into water and extracted with CH2Cl2. The combined organic
phases were washed with water and brine and dried over MgSO4
before the solvents were removed in vacuo to give the crude tosylate
as a white solid. Purification by column chromatography (CH2Cl2/
MeOH, 95:5) gave the N-(p-toluenesulfonyl)valinol as a white solid
(19.6 g, 88%): Rf ) 0.45; mp 87-89 °C (from hexane/EtOAc)
(lit.28 mp 86 °C, from Et2O); [R]18D ) -29.5° (c 1.0, CHCl3) (lit.26
[R]20D ) -27.4°, c 1.0, CHCl3); IR (film) 3493, 3282, 3026, 2962,
2874, 1598, 1494 cm-1; 1H NMR (300 MHz, CDCl3) δ 0.75 (d, J
) 6.6 Hz, 6H), 1.67-1.81 (m, 1H), 2.40 (s, 3H), 2.56 (br s, 1H),
2.96-3.05 (m, 1H), 3.47-3.61 (m, 2H), 5.35 (d, J ) 8.5 Hz, 1H),
7.27 (d, J ) 8.1 Hz, 2H), 7.77 (d, J ) 8.1 Hz, 2H); 13C NMR (75
MHz, CDCl3) δ 18.6, 19.2, 21.6, 29.5, 61.2, 63.0, 127.2, 129.7,
137.8, 143.5; MS (electrospray) m/z 280 (100%, [M + Na]+).
HRMS (electrospray) Calcd for C12H19NO3SNa: 280.0983.
Found: 280.0973. Anal. Calcd for C12H19NO3S: C, 56.00; H, 7.44;
N, 5.44. Found: C, 56.14; H, 7.41; N, 5.31.
1
C, 57.58; H, 7.58; N, 4.36. The H and 13C NMR spectra of the
sample were complex due to the presence of both anomers of the
lactol in solution along with a small amount of the open chain
aldehyde.
To a solution of the N-tosyl amino alcohol (15.00 g, 58.4 mmol)
in anhydrous DMF (50 mL) at 0 °C were added imidazole (7.94 g,
116.7 mmol) and TBDMSCl (10.56 g, 70.0 mmol). After stirring
overnight at room temperature, the reaction mixture was poured
into water and extracted with diethyl ether. The combined organic
phases were washed with water and brine and dried over MgSO4
before the solvents were removed in vacuo to give the crude silyl
ether as an oil. Purification by column chromatography (petrol/
Et2O, 9:1) gave 8c as a colorless solid (21.10 g, 97%): Rf ) 0.23;
mp 54-56 °C (from hexane/Et2O); [R]20D ) -22.1° (c 1.0, CHCl3);
Typical Procedure for Wittig Reactions: Methyl (S)-6-Aza-
8-hydroxy-7-isopropyl-6-(p-toluenesulfonyl)oct-2-enoate (11e).
To a solution of lactol 10c (1.50 g, 4.8 mmol) and benzoic acid
(0.12 g, 1.0 mmol) in toluene (40 mL) at 90 °C was added
methyltriphenylphosphoranylidene acetate (2.08 g, 6.2 mmol), and
the solution was stirred at 90 °C for 1 h. Toluene was removed in
vacuo, and the residue dissolved in ethyl acetate and extracted with
saturated NaHCO3 solution. The aqueous phase was further
extracted with EtOAc, and the combined organic phases were
washed with brine before being dried over MgSO4. The solvents
were removed in vacuo to yield the crude olefin as a pink oil.
Purification by column chromatography (hexane/EtOAc, 3:2)
yielded the ester 11e in an 8:1 (E)/(Z) ratio as a colorless oil (1.58
g, 89%). The stereoisomers were very difficult to separate by
column chromatography, so data were recorded on the mixture. In
the case of the NMR spectra, while some signals arising from the
minor isomer were observed, only those signals resulting from the
major (E)-isomer are reported: Rf ) 0.55; IR (film) 3526, 2961,
1723, 1656, 1598, 1494 cm-1; 1H NMR (300 MHz, CDCl3) δ 0.61
(d, J ) 6.6 Hz, 3H), 0.89 (d, J ) 6.3 Hz, 3H), 1.66-1.83 (m, 1H),
2.07 (t, J ) 5.1 Hz, 1H), 2.39 (s, 3H), 2.52-2.70 (m, 2H), 3.12-
3.45 (m, 3H), 3.49-3.60 (m, 1H), 3.68-3.80 (m, 4H), 5.81 (d, J
) 15.5 Hz, 1H), 6.83 (dt, J ) 7.3, 15.5 Hz, 1H), 7.27 (d, J ) 8.3
Hz, 2H), 7.70 (d, J ) 8.3 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ
20.2, 20.6, 21.6, 28.4, 33.7, 43.6, 51.6, 62.4, 66.5, 122.8, 127.5,
129.7, 137.9, 143.6, 145.4, 166.8; MS (electrospray) 392 (100%,
[M + Na]+). HRMS (electrospray) Calcd for C18H27NO5SNa:
392.1508. Found: 392.1503. Anal. Calcd for C18H27NO5S: C,
58.51; H, 7.37; N, 3.79. Found: C, 58.47; H, 7.38; N, 3.56.
Typical Procedure for Still-Gennari Modified Horner-
Wadsworth-Emmons Reactions: Methyl (S)-(Z)-6-Aza-8-hy-
droxy-7-methyl-6-(p-toluenesulfonyl)oct-2-enoate (14a). A mix-
ture of 18-crown-6 (3.40 g, 12.9 mmol), recrystallized from
acetonitrile, and bis(2,2,2-trifluoroethyl) methoxycarbonylmethyl
IR (film) 3285, 3027, 2957, 2929, 2882, 2857, 1599, 1495 cm-1
;
1H NMR (300 MHz, CDCl3) δ -0.10 (s, 3H), -0.07 (s, 3H), 0.80
(d, J ) 6.2 Hz, 3H), 0.81 (s, 9H), 0.86 (d, J ) 7.0 Hz, 3H), 1.75-
1.93 (m, 1H), 2.40 (s, 3H), 2.89-2.99 (m, 1H), 3.20 (dd, J ) 4.6,
10.2 Hz, 1H), 3.50 (dd, J ) 2.9, 10.2 Hz, 1H), 4.80 (d, J ) 8.8
Hz, 1H), 7.26 (d, J ) 8.1 Hz, 2H), 7.73 (d, J ) 8.1 Hz, 2H); 13C
NMR (75 MHz, CDCl3) δ -5.6, -5.5, 18.3, 18.7, 19.3, 21.6, 25.9,
29.5, 60.2, 62.0, 127.1, 129.7, 138.5, 143.2; MS (electrospray) m/z
394 (100%, [M + Na]+). HRMS (electrospray) Calcd for
C18H33NO3SSiNa: 394.1848. Found: 394.1840. Anal. Calcd for
C18H33NO3SSi: C, 58.18; H, 8.95; N, 3.77. Found: C, 57.93; H,
9.17; N, 3.78.
Typical Procedure for the Alkylation of Protected Amino
Alcohols: (S)-4-Aza-6-(tert-butyldimethylsilanyloxy)-5-isopro-
pyl-4-(p-toluenesulfonyl)hexanal Dimethyl Acetal (9c). To a
solution of the protected amino alcohol 8c (18.1 g, 48.8 mmol) in
anhydrous DMF (100 mL) was added Cs2CO3 (23.85 g, 73.2 mmol)
followed by 3-iodopropanal dimethyl acetal29 (16.83 g, 73.2 mmol).
The reaction mixture was stirred for 96 h at room temperature,
with further additions of Cs2CO3 (11.92 g, 36.6 mmol) and
iodoacetal (4.50 g, 36.6 mmol) at 24 h intervals. The reaction
mixture was poured into water and extracted with diethyl ether.
(28) Hoppe, I.; Hoffmann, H.; Gaertner, I.; Krettek, T.; Hoppe, D.
Synthesis 1991, 1157-1162.
(29) Clive, D. L. J.; Paul, C. C.; Wang, Z. J. Org. Chem. 1997, 62, 7028-
7032.
J. Org. Chem, Vol. 71, No. 14, 2006 5205

Gandon et al.
phosphonate (0.60 mL, 2.84 mmol) in THF (20 mL) was stirred at
-78 °C, and KHMDS (5.7 mL of a 0.5 M solution in toluene, 2.8
mmol) was added dropwise over 5 min. Stirring was continued for
1 h. Lactol 10a (0.73 g, 2.56 mmol) was then added portionwise
over 30 min, and the solution was stirred at -78 °C for 3 days.
The reaction mixture was quenched with saturated NH4Cl solution
and allowed to warm to room temperature before being extracted
with ethyl acetate. The combined organic layers were washed with
water and brine, dried over MgSO4, and concentrated in vacuo.
Purification by column chromatography (petrol/EtOAc, 6:4) pro-
vided a 12:1 (Z)/(E) mixture of isomers as a colorless oil (0.72 g,
82%). Repeated chromatography allowed the isolation of a sample
of pure 14a as a colorless oil. Data for the (Z)-isomer: Rf ) 0.34;
[R]19D ) +17.7 (c 1.11, CHCl3); IR (film) 3522, 2951, 2881, 1721,
1646, 1598, 1495 cm-1; 1H NMR (300 MHz, CDCl3) δ 0.93 (d, J
) 7.0 Hz, 3H), 2.41 (s, 3H), 2.88-3.10 (m, 2H), 3.13-3.26 (m,
1H), 3.30-3.44 (m, 1H), 3.53 (dd, J ) 5.0, 11.6 Hz, 1H), 3.61
(dd, J ) 8.3, 11.6 Hz, 1H), 3.70 (s, 3H), 3.85-4.00 (m, 1H), 5.87
(d, J ) 11.6 Hz, 1H), 6.30 (dt, J ) 7.7, 11.6 Hz, 1H), 7.28 (d, J
) 8.3 Hz, 2H), 7.72 (d, J ) 8.3 Hz, 2H); 13C NMR (75 MHz,
CDCl3) δ 14.2, 21.4, 30.7, 42.3, 51.2, 55.5, 64.7, 121.3, 127.0,
129.6, 137.5, 143.2, 145.7, 166.5; MS (electrospray) m/z 364 (100%,
[M + Na]+). HRMS (electrospray) Calcd for C16H23NO5SNa:
364.1195. Found: 364.1187. Anal. Calcd for C16H23NO5S: C,
56.29; H, 6.79; N, 4.10. Found: C, 56.26; H, 6.77; N, 4.06.
Typical Procedure for the Bromination of t-Butyl Esters: tert-
Butyl (S)-(E)-6-Aza-8-bromo-7-isopropyl-6-(p-toluenesulfonyl)-
oct-2-enoate (12f). Triethylamine (0.529 mL, 3.80 mmol) followed
by methane sulfonyl chloride (0.196 mL, 2.53 mmol) was added
to a stirred solution of the alcohol 11f (1.040 g, 2.53 mmol) in
CH2Cl2 (50 mL) at 0 °C. The solution was stirred for 1 h and then
poured into aqueous NH4Cl and extracted with CH2Cl2. The
combined organic layers were washed with brine and dried over
MgSO4, and the solvent was removed in vacuo to yield the mesylate
as a sticky oil. The crude mesylate was dissolved in THF (30 mL),
and anhydrous LiBr (0.880 g, 10.13 mmol) was added. The
suspension was heated at reflux for 48 h. THF was removed in
vacuo, and the residue dissolved in CH2Cl2/water, 1:1. The aqueous
layer was extracted with CH2Cl2, the combined organic layers dried
over MgSO4, and the solvent was removed in vacuo. Purification
by column chromatography (petrol/Et2O, 7:3) yielded 12f as a
colorless oil (1.009 g, 84%): Rf ) 0.53; [R]16 ) -10.3 ° (c 1.0,
D
CHCl3); IR (film) 2975, 2932, 1711, 1656, 1598, 1494 cm-1; H
1
NMR (300 MHz, CDCl3) δ 0.82 (d, J ) 6.6 Hz, 3H), 0.98 (d, J )
6.6 Hz, 3H), 1.47 (s, 9H), 1.88-2.01 (m, 1H), 2.41 (s, 3H), 2.53-
2.71 (m, 2H), 3.09-3.21 (m, 1H), 3.23-3.35 (m, 1H), 3.42 (dd, J
) 6.6, 11.4 Hz, 1H), 3.52 (dd, J ) 3.3, 11.4 Hz, 1H), 3.63-3.71
(m, 1H), 5.75 (d, J ) 15.8 Hz, 1H), 6.71 (dt, J ) 7.1, 15.8 Hz,
1H), 7.30 (d, J ) 8.3 Hz, 2H), 7.73 (d, J ) 8.3 Hz, 2H); 13C NMR
(75 MHz, CDCl3) δ 20.3, 20.5, 21.6, 28.3, 30.8, 33.7, 34.8, 43.7,
65.1, 80.5, 125.1, 127.7, 129.7, 137.6, 143.5, 143.6, 165.7; MS
(electrospray) m/z 498 (97%, [M(81Br) + Na]+), 496 (100%,
[M(79Br) + Na]+). HRMS (electrospray) Calcd for C21H32-
NO4S79BrNa: 496.1133. Found: 496.1138. Calcd for C21H32-
NO4S81BrNa: 498.1113. Found: 498.1113. Anal. Calcd for C21H32-
NO4SBr: C, 53.16; H, 6.80; N, 2.95. Found: C, 53.20; H, 6.92;
N, 2.81.
Data for the (E)-isomer: Rf ) 0.32. For further data see the
Supporting Information.
Typical Procedure for the Bromination of Methyl Esters:
Methyl (S)-(E)-6-Aza-8-bromo-7-isopropyl-6-(p-toluenesulfonyl)-
oct-2-enoate (12e). Triphenylphosphine (1.183 g, 4.51 mmol) and
carbon tetrabromide (1.497 g, 4.51 mmol) were added to a stirred
solution of an 8:1 (E)/(Z) mixture of alcohols 11e:14e (1.390 g,
3.76 mmol) in CH2Cl2 (100 mL) at 0 °C. The solution was allowed
to warm to room temperature and was stirred for 24 h after which
TLC showed some remaining starting material, so further portions
of PPh3 (0.493 g, 1.88 mmol) and CBr4 (0.623 g, 1.88 mmol) were
added, and the reaction mixture stirred a further 15 h. The crude
reaction mixture was adsorbed onto silica and purified by column
chromatography (petrol/Et2O, 7:3) to yield first 15e as a colorless
oil (0.144 g, 9%), followed by 12e as a colorless oil (1.249 g, 77%).
Typical Procedure for the Cyclization of Bromides Using
TTMSS: Preparation of (2R,4R)-4-(tert-Butoxycarbonylmethyl)-
2-isopropyl-1-(p-toluenesulfonyl)piperidine (16f), (2R,4S)-4-
(tert-Butoxycarbonylmethyl)-2-isopropyl-1-(p-toluenesulfonyl)-
piperidine (17f), and 4-tert-Butoxycarbonylmethyl-2-(1′-methyl-
1′-p-tolylethyl)piperidinium Bromide (24f). A solution of the
bromide (12f) (222 mg, 0.47 mmol) in toluene (10 mL) was
deoxygenated by bubbling argon through it for 30 min. The solution
was heated to 90 °C, and deoxygenated solutions of TTMSS (260
µL, 0.84 mmol) in toluene (10 mL) and AIBN (8 mg, 0.05 mmol)
in toluene (10 mL) were added simultaneously via syringe pump
over 12 h, followed by a further addition of TTMSS (144 µL, 0.47
mmol) in toluene (10 mL) and AIBN (8 mg, 0.05 mmol) in toluene
(10 mL) over another 12 h. After this addition was complete, the
reaction mixture was maintained at 90 °C for 15 h. Purification by
column chromatography (gradient, 100% hexane to 100% EtOAc)
yielded a 99:1 (determined by analytical HPLC on the crude reaction
mixture) trans/cis mixture of piperidines 16f and 17f (petrol/EtOAc,
4:1, Rf ) 0.45) as a colorless oil (139 mg, 75%). Data for trans
isomer 16f (recorded on trans/cis mixture): analytical HPLC (from
Overall yield: 86%. Data for the (Z)-isomer 15e: Rf ) 0.30; [R]19
D
) +22.0° (c 1.0, CHCl3); IR (film) 2965, 2875, 1720, 1644, 1598,
1
1494 cm-1; H NMR (300 MHz, CDCl3) δ 0.90 (d, J ) 7.0 Hz,
3H), 1.00 (d, J ) 6.2 Hz, 3H), 1.90-2.04 (m, 1H), 2.39 (s, 3H),
2.87-3.08 (m, 2H), 3.13-3.35 (m, 2H), 3.48 (dd, J ) 7.4, 11.4
Hz, 1H), 3.56 (dd, J ) 3.9, 11.4 Hz, 1H), 3.65-3.77 (m, 4H),
5.81 (d, J ) 11.4 Hz, 1H), 6.83 (dt, J ) 7.7, 11.4 Hz, 1H), 7.26 (d,
J ) 8.1 Hz, 2H), 7.75 (d, J ) 8.1 Hz, 2H); 13C NMR (75 MHz,
CDCl3) δ 20.6, 20.9, 21.6, 30.5, 31.4, 33.8, 43.6, 51.3, 65.8, 121.6,
127.8, 129.5, 137.9, 143.4, 145.5, 166.4; MS (electrospray) m/z
456 (100%, [M(81Br) + Na]+), 454 (85%, [M(79Br) + Na]+).
HRMS (electrospray) Calcd for C18H26NO4S79BrNa: 454.0664.
Found: 454.0674; Anal. Calcd for C18H26NO4SBr: C, 50.00; H,
6.06; N, 3.24. Found: C, 49.74; H, 6.03; N, 3.19.
100% water to 100% methanol over 60 min): tr ) 53.63 min; [R]18
D
) +34.9° (c 0.64, CHCl3); IR (film) 3024, 2973, 2933, 2874, 1726,
1
1599, 1494 cm-1; H NMR (300 MHz, CDCl3) δ 0.67-0.94 (m,
Data for the (E)-isomer 12e: Rf ) 0.21; [R]14D ) -12.0° (c 1.0,
1
CHCl3); IR (film) 2968, 1723, 1658, 1598, 1493 cm-1; H NMR
8H), 1.30-1.45 (m, 10H), 1.71 (d, J ) 12.1 Hz, 1H), 1.78-2.10
(m, 4H), 2.39 (s, 3H), 2.91-3.04 (m, 1H), 3.57 (dd, J ) 4.4, 10.7
Hz 1H), 3.80 (dd, J ) 4.1, 14.7 Hz, 1H), 7.24 (d, J ) 8.5 Hz, 2H),
7.68 (d, J ) 8.5 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 19.3,
19.6, 20.9, 26.0, 26.8, 27.4, 29.7, 30.9, 40.1, 42.0, 58.9, 79.8, 126.3,
128.9, 138.4, 142.1, 170.8; MS (electrospray) m/z 418 (100%, [M
+ Na]+). HRMS (electrospray) Calcd for C21H33NO4SNa: 418.2028.
Found: 418.2032. Anal. Calcd for C21H33NO4S: C, 63.76; H, 8.41;
N, 3.54. Found: C, 63.71; H, 8.46; N, 3.49.
Separation of the cis and trans isomers was possible by HPLC.
Data for the cis isomer 17f: Analytical HPLC (100% water to 100%
methanol over 60 min): tr ) 53.10 min; MS (electrospray) m/z
418 (100%, [M + Na]+). For further data vide infra.
(300 MHz, CDCl3) δ 0.81 (d, J ) 6.6 Hz, 3H), 0.98 (d, J ) 6.6
Hz, 3H), 1.88-2.01 (m, 1H), 2.41 (s, 3H), 2.57-2.75 (m, 2H),
3.10-3.21 (m, 1H), 3.25-3.35 (m, 1H), 3.43 (dd, J ) 6.6, 11.4
Hz, 1H), 3.52 (dd, J ) 3.3, 11.4 Hz, 1H), 3.61-3.70 (m, 1H),
3.71 (s, 3H), 5.84 (d, J ) 15.6 Hz, 1H), 6.83 (dt, J ) 7.2, 15.6 Hz,
1H), 7.28 (d, J ) 8.1 Hz, 2H), 7.72 (d, J ) 8.1 Hz, 2H); 13C NMR
(75 MHz, CDCl3) δ 20.2, 20.4, 21.6, 30.7, 33.9, 34.9, 43.6, 51.6,
65.0, 122.9, 127.6, 129.7, 137.5, 143.7, 145.1, 166.7; MS (electro-
spray) m/z 456 (96%, [M(81Br) + Na]+), 454 (100%, [M(79Br) +
Na]+). HRMS (electrospray) Calcd for C18H26NO4S79BrNa: 454.0664.
Found: 454.0666. Anal. Calcd for C18H26NO4SBr: C, 50.00; H,
6.06; N, 3.24. Found: C, 50.18; H, 6.13; N, 3.09.
5206 J. Org. Chem., Vol. 71, No. 14, 2006

Synthesis of 2,4-Disubstituted Piperidines
After elution from the column of the silane-derived byproducts,
followed by the piperidines, the column was flushed with CH2Cl2/
MeOH (4:1). Evaporation of the solvent in vacuo gave a yellow
solid (38 mg), a portion of which was purified by HPLC to afford
1H), 3.61 (ddd, J ) 2.7, 7.1, 15.0 Hz, 1H), 7.28 (d, J ) 8.1 Hz,
2H), 7.74 (d, J ) 8.1 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 17.8,
20.1, 21.6, 27.9, 28.1, 28.2, 28.3, 32.5, 40.0, 41.7, 60.7, 80.5, 127.3,
129.7, 138.4, 143.1, 171.6; MS (electrospray) m/z 418 (100%, [M
+ Na]+). HRMS (electrospray) Calcd for C21H33NO4SNa: 418.2028.
Found: 418.2033.
24f as a white solid: mp 186-189 °C (from CH2Cl2); [R]15
)
D
8.3° (c ) 0.3, CHCl3, l ) 0.25 dm); IR (film) 2921, 2764, 1782,
1579, 1516, 1477 cm-1; 1H NMR (500 MHz, CDCl3) δ 1.25-1.39
(m, 10H), 1.43-1.51 (m, 1H), 1.57 (s, 3H), 1.67 (s, 3H), 1.81-
1.93 (m, 3H), 2.06 (dd, J ) 5.8, 15.2 Hz, 1H), 2.16 (dd, J ) 5.8,
15.2 Hz, 1H), 2.31 (s, 3H), 2.91-2.99 (m, 1H), 3.16 (t, J ) 11.5
Hz, 1H), 3.81 (d, J ) 12.2 Hz, 1H), 7.15 (d, J ) 8.2 Hz, 2H), 7.21
(d, J ) 8.2 Hz, 2H), 8.33 (br s, 1H), 8.57 (br s, 1H); 13C NMR
(125 MHz, CDCl3) δ 20.8, 22.4, 27.9, 28.1, 28.2, 30.4, 32.3, 40.4,
41.7, 46.7, 67.5, 80.8, 125.8, 129.6, 136.8, 141.7, 170.8; MS
(electrospray) m/z 332 (100%, [ammonium ion]+). HRMS (electro-
spray) Calcd for C21H34NO2: 332.2590. Found: 332.2595.
Typical Procedure for the Deprotection with HBr: Prep-
aration of (2R,4R)-2-Benzyl-4-carboxymethylpiperidine (25b).
Piperidine 16d (as a 96:4 trans/cis mixture, 62 mg, 0.14 mmol)
was dissolved in 48% HBr in acetic acid (2 mL). Phenol (26 mg,
0.28 mmol) was added, and the solution was stirred at room
temperature for 4 days. Solvents were removed in vacuo to leave
a dark residue which was washed with diethyl ether (5 × 2 mL).
NMR showed the resulting gum (50 mg) to be essentially pure
piperidinium salt 25b. This was further purified by preparative
HPLC (99.95% water + 0.05% trifluoroacetic acid to 100%
acetonitrile over 40 min, flow rate 10 mL/min) to give 25b,
presumably with trifluoroacetate as the counterion, as a colorless
Typical Procedure for the Cyclization of Bromides Using
TBTH: Preparation of (2R,4R)-4-(tert-Butoxycarbonylmethyl)-
2-isopropyl-1-(p-toluenesulfonyl)piperidine (16f) and (2R,4S)-
4-(tert-Butoxycarbonylmethyl)-2-isopropyl-1-(p-toluenesulfonyl)-
piperidine (17f). A solution of the bromide 12f (188 mg, 0.40
mmol) in toluene (10 mL) was deoxygenated by bubbling argon
through it for 30 min. The solution was heated to 90 °C, and
deoxygenated solutions of TBTH (192 µL, 0.71 mmol) in toluene
(10 mL) and AIBN (7 mg, 0.04 mmol) in toluene (10 mL) were
added simultaneously via syringe pump over 12 h, followed by
heating at 90 °C for a further 6 h. Purification by column
chromatography gave an 86:14 (determined by analytical HPLC
on the crude reaction mixture) trans/cis mixture of piperidines 16f
and 17f (petrol/EtOAc, 4:1, Rf ) 0.45) as a colorless oil (129 mg,
82%). Further purification of a small sample of this material by
semipreparative HPLC (100% water to 100% methanol over 60
min) allowed separation of the diastereomers. Data for trans isomer
16f as before. Data for cis isomer 17f: Analytical HPLC (100%
1
film (39 mg, 80%). H NMR (300 MHz, D2O) δ 1.47-1.77 (m,
3H), 1.82-2.00 (m, 1H), 2.25-2.45 (m, 3H), 2.84-3.12 (m, 3H),
3.14-3.26 (m, 1H), 3.54-3.66 (m, 1H), 7.19-7.38 (m, 5H); 13C
NMR (100 MHz, D2O) δ 27.0, 27.7, 32.2, 37.9, 38.5, 40.7, 54.7,
129.3, 130.9, 131.2, 137.3, 178.7; MS (electrospray) m/z 234 (100%,
[M + H]+). HRMS (electrospray) Calcd for C14H20NO2: 234.1494.
Found: 234.1482.
Acknowledgment. We thank the Engineering and Physical
Sciences Research Council (Research Grant GR/M70964/01 and
studentships to A.G.R. and T.G.) and the University of
Birmingham for financial support.
Supporting Information Available: Experimental procedures,
NMR spectra, and full characterization for all compounds, as
well as CIF files and ORTEP diagrams for the X-ray structures.
This material is available free of charge via the Internet at
http://pubs.acs.org.
1
water to 100% methanol over 60 min): tr ) 53.10 min; H NMR
(300 MHz, CDCl3) δ 0.88-0.96 (m, 6H), 1.05-1.10 (m, 1H),
1.24-1.32 (m, 1H), 1.39 (s, 9H), 1.51-1.66 (m, 3H), 2.05-2.13
(m, 3H), 2.41 (s, 3H), 3.13-3.21 (m, 1H), 3.52 (q, J ) 7.4 Hz,
JO060495W
J. Org. Chem, Vol. 71, No. 14, 2006 5207