1,4-Bis(arylsulfonyl)-1,2,3,4-tetrahydropyridines in synthesis. Regio- and stereoselective SN1 reactions

Article abstract of DOI:10.1016/S0040-4039(01)01771-3

1,4-Bis(4-tolylsulfonyl)-1,2,3,4-tetrahydropyridines undergo stereoselective S_N1 reactions with soft carbon nucleophiles in the presence of Lewis acids. Subsequent dihydroxylation of the double bond followed by esterification enables the stereoselective preparation of substituted piperidines.

Full text of DOI:10.1016/S0040-4039(01)01771-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8369–8372
1,4-Bis(arylsulfonyl)-1,2,3,4-tetrahydropyridines in synthesis.
Regio- and stereoselective SN1 reactions
Jean-Claude Adelbrecht, Donald Craig* and Serge Thorimbert†
Centre for Chemical Synthesis, Department of Chemistry, Imperial College of Science, Technology and Medicine,
London SW 7 2AY, UK
Received 8 August 2001; revised 11 September 2001; accepted 19 September 2001
Abstract—1,4-Bis(4-tolylsulfonyl)-1,2,3,4-tetrahydropyridines undergo stereoselective SN1 reactions with soft carbon nucleophiles
in the presence of Lewis acids. Subsequent dihydroxylation of the double bond followed by esterification enables the
stereoselective preparation of substituted piperidines. © 2001 Elsevier Science Ltd. All rights reserved.
Previous studies from this laboratory1 have demon-
strated that 1,4-bis(arylsulfonyl)-1,2,3,4-tetrahydro-
pyridines 3, readily made from sulfonyl acetal 1 and
N-tosylaziridines 2, undergo loss of the tolylsulfonyl
group in the presence of nucleophiles on treatment with
Lewis acid; depending on the nucleophile–Lewis acid
combination 1,2- or 1,4-substitution products were iso-
lated. Strikingly, intermolecular nucleophiles invariably
intercepted the putative conjugated iminium species in a
1,2-sense to give 4, arising from overall SN1% reaction,
whereas substrates with appended nucleophilic func-
tionality gave the SN1-type products 5 of intramolecu-
lar 1,4-attack (Scheme 1). We ascribed this change in
reactivity to the greater accessibility for the internal
nucleophiles of the required trajectory for interception
of the cations in the 1,4-sense.
ide functional group, which we had already shown to
be amenable to selective oxidation reactions, thereby
extending the utility of the methodology. The studies of
Husson2 and Lounasmaa3,4 nearly 20 years ago inde-
pendently established that soft nucleophiles such as
metal enolates or silyl enol ethers derived from b-dicar-
bonyl compounds react at the 4-position of 5,6-dihy-
dropyridinium ions generated in situ from
N-alkyl-2-cyanotetrahydropyridines. In view of these
precedents we anticipated that treatment of 3 with such
nucleophiles in the presence of a Lewis acid would
trigger SN1 reactions leading to the formation of 4-sub-
stituted-N-tosyl-1,2,3,4-tetrahydropyridines. This letter
reports the results of investigations, and describes fur-
ther cation-mediated transformations of the products
which take place with modified stereoselectivity com-
pared with the parent 1,4-bis(arylsulfonyl) compounds.
We became interested in identifying ways of modifying
the reactivity of tetrahydropyridines 3 such that inter-
molecular transformations would deliver the products
of 1,4-attack. Such compounds would retain the enam-
After initial experiments, in which use of the silyl
ketene acetal or sodium enolate derived from dimethyl
malonate as the nucleophilic coupling partner gave no
Scheme 1.
Keywords: alkylation; diastereoselectivity; Lewis acid; piperidines; SN1.
* Corresponding author. Fax: +44 20 7594 5868; e-mail: d.craig@ic.ac.uk
† Present address: Universite´ Pierre et Marie Curie, Laboratoire de Chimie Organique de Synthe`se, Tour 44-54, Place Jussieu, F-75252 Paris Cedex
05, France.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01771-3

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J.-C. Adelbrecht et al. / Tetrahedron Letters 42 (2001) 8369–8372
sterically less demanding 2-substituents the reactions
showed almost no selectivity (entries 1, 4 and 5). For
substrates 3b and 3e possessing bulkier R groups (i-Pr,
CH2OTBDPS) the anti product was the only stereoiso-
mer detectable by 1H NMR analysis of the crude
products (entries 2 and 6).8 It would appear from these
results that the b-face is sterically more accessible, and
that a-attack is significantly hindered. This explanation
is consistent with the likely axial disposition of the
2-substituent on the six-membered ring, and might also
indicate that the distal nature of the electrophilic 4-
position renders it less susceptible to steric hindrance
arising from the N-tosyl group. Mechanistically, it
seems plausible that initial tin(IV) chloride-mediated
heterolysis of the C4ꢀTs bond occurs with concomitant
generation of chloride ion, which then attacks BSA to
yield TMSCl and the conjugate base of N-(trimethylsi-
lyl)acetamide. Subsequent proton exchange with
dimethyl malonate generates the nucleophilic tin(IV)
enolate which intercepts the iminium species in a 1,4-
sense.
substitution product and the corresponding lithio-spe-
cies gave only moderate yields, we elected to generate
the nucleophilic species under non-basic conditions.
Titanium(IV) and tin(IV) enolates of mono- or diesters
have been employed extensively in CꢀC bond forming
transformations,5 and we envisaged that Lewis acidic
reagents such as SnCl4 or TiCl4 might simultaneously
activate the C-4 tosyl leaving group and effect forma-
tion of the nucleophilic enolate in situ. In practice,
treatment of a dichloromethane solution of tetra-
hydropyridine 3a (1 equiv.) with tin tetrachloride (3
equiv.) and dimethyl malonate (3 equiv.) was ineffec-
tive. However, inclusion of N,O-bis(trimethylsi-
lyl)acetamide (BSA)6 in the reaction mixture caused
complete consumption of the starting material to take
place during 4 h at ambient temperature; the product
6a was isolated in excellent yield as a mixture of C-4
epimers. This reaction procedure was extended to other
tetrahydropyridine substrates 3 (Scheme 2); the results
are collected in Table 1.7
These high-yielding substitution reactions were com-
pletely regioselective for the SN1 rather than the SN1%
products, in marked contrast to our earlier findings.1a
Replacing BSA with Hu¨nig’s base as the additive (entry
3) did not have a significant effect on the efficiency of
the reaction, provided an additional equivalent of SnCl4
was employed. It may be seen from the data in Table 1
that the stereoselectivity of the SN1 reactions is vari-
able. For tetrahydropyridines 3a, 3c and 3d bearing
The next phase of our study sought to evaluate alterna-
tive active methylene compounds as nucleophilic part-
ners in the SN1 reactions. In the event, reaction of
methyl acetoacetate with 3e under identical conditions
to those developed for dimethyl malonate gave 7, whilst
3e combined with ethyl nitroacetate to give 8; both
reactions were high-yielding. Again, the reactions
showed complete 2,4-trans-selectivity, with low stereo-
Scheme 2.
Table 1.
Entry
Substrate
R
Additive
Yield of 6
syn-6:anti-6
1
2
3
3a
3b
3b
3c
3d
3e
Me
BSA
BSA
i-Pr2NEt
BSA
BSA
100
100
90
45:55
\98:2
\98:2
50:50
45:55
\98:2
CH2OTBDPS
CH2OTBDPS
CH2OAc
CH2i-Pr
i-Pr
4
80
5a
6
65 (80)b
88
BSA
a Reaction performed over 4 h at rt.
b Yield in parentheses based on recovered starting material.
Scheme 3.

J.-C. Adelbrecht et al. / Tetrahedron Letters 42 (2001) 8369–8372
8371
Scheme 4.
control at the newly-formed exocyclic stereocentre
(Scheme 3). Other nucleophiles which were evaluated
either suffered degradation (a-cyanoesters, a-imi-
noesters) under the reaction conditions or were recov-
ered unchanged (a-sulfonylesters and -ketones).
sulfonyl)tetrahydropyridines under Lewis acidic condi-
tions. Dihydroxylation–esterification of two of the
malonate-containing products gives substrates for fur-
ther SN1 reactions, which proceed with complete
stereoselectivity and in a complementary sense to that
observed for the sulfonyl-substituted analogues.
The final part of this investigation focused on the effect
of the malonate substituent in 6 on the stereochemistry
of oxidation of the tetrahydropyridine double bond,
and on transformations of the dioxygenated products.
Dihydroxylation of 6c and 6e using OsO4–N-methyl-
morpholine-N-oxide (NMO)9 was carried out as previ-
ously described for tetrahydropyridines 3.10 Direct
diacetylation of the crude diol mixtures gave derivatives
9c and 9e as single diastereomers in, respectively, 50
and 64% yields over two steps. X-Ray diffraction anal-
ysis of a single-crystal of 9e provided unequivocal proof
of its stereochemistry.11 Next, compounds 9c and 9e
were separately subjected to the SN1 reaction conditions
used previously by us10 for the analogous 4-(tolylsul-
fonyl) substrates.12,13 Thus, SnCl4 was added to the
diacetates in cold (−60°C) dichloromethane solutions
containing the TBDMS enol ether of pinacolone. The
acetoxymethyl-substituted compound 10c was obtained
in 64% yield, in addition to a significant amount (36%)
of the product of selective hydrolysis of the C-2 ester.
Reaction of the analogous isopropyl-substituted sub-
strate 9e gave 10e in 83% isolated yield, without
detectable formation of the corresponding hydroxy
derivative. Both reactions were completely selective for
the products corresponding to nucleophilic attack on
the a-face of the iminium intermediate, syn with respect
to the 2-substituent; for isopropyl-substituted com-
pound 9e this is in marked contrast to the selectivity
observed for the analogous 4-(tolylsulfonyl) substrate
(Scheme 4).10
Acknowledgements
We thank the Department of Chemistry, Imperial Col-
lege and Roche Discovery Welwyn (Teaching Assis-
tantship to J.-C.A.), and the Universite´ Pierre et Marie
Curie, the CNRS and NATO (Fellowship to S.T.) for
financial support of this research.
References
1. (a) Craig, D.; McCague, R.; Potter, G. A.; Williams, M.
R. V. Synlett 1998, 55–57; (b) Craig, D.; McCague, R.;
Potter, G. A.; Williams, M. R. V. Synlett 1998, 58–60.
2. Grierson, D. S.; Harris, M.; Husson, H.-P. J. Am. Chem.
Soc. 1980, 102, 1064–1082.
3. Koskinen, A.; Lounasmaa, M. Tetrahedron Lett. 1983,
24, 1951–1952.
4. Lounasmaa, M.; Miettinen, J.; Hanhinen, P.; Jokela, R.
Tetrahedron Lett. 1997, 38, 1455–1458.
5. (a) Kitagawa, O.; Suzuki, T.; Fujiwara, H.; Taguchi, T.
Tetrahedron Lett. 1999, 40, 2549–2552; (b) Poli, G.;
Giambastiani, G.; Mordini, A. J. Org. Chem. 1999, 64,
2962–2965.
6. Trost, B. M.; Murphy, D. J. Organometallics 1985, 4,
1143–1145.
7. For the preparation of related structures by SN1% reactions,
see: Matsumura, Y.; Yoshimoto, Y.; Horikawa, C.;
Maki, T.; Watanabe, M. Tetrahedron Lett. 1996, 37,
5715–5718.
These results may be rationalised in terms of stabilisa-
tion of the iminium cation by a carbonyl oxygen atom
within the malonate function. Such internal coordina-
tion would render the b-face sterically more encum-
bered, forcing the nucleophile to attack the a-face.
Stable, isolable bicyclic products resulting from this
type of interaction have indeed been isolated from
reactions of 2-cyano-1,2,5,6-tetrahydropyridines, which
have been postulated to proceed via cationic intermedi-
ates closely related to those proposed here.2,3
8. All yields reported herein refer to isolated, pure materials
1
which had H and 13C NMR, IR and high-resolution MS
characteristics in accord with the proposed structures.
Preparation of 6e. To a solution of tetrahydropyridine 3e
(43 mg, 0.1 mmol), BSA (74 ml, 3 equiv.), and dimethyl
malonate (34 ml, 3 equiv.) in CH2Cl2 was added at −78°C
SnCl4 (300 ml of a 1 M solution in CH2Cl2, 0.3 mmol, 3
equiv.). The yellow mixture was stirred for 1 h at −78°C
then overnight at rt. The reaction was quenched by the
addition of saturated aqueous NaHCO3 and extracted
with ether (2×10 ml). The combined organic layers were
washed with brine (2×20 ml) and dried (Na2SO4). Con-
centration under reduced pressure followed by flash chro-
matography of the residue (5% ether–petrol) gave
In summary, we have demonstrated that soft nucleo-
philes derived from malonate and other active methyl-
ene species enter into completely regioselective and in
some cases stereoselective SN1 reactions with bis(aryl-

8372
J.-C. Adelbrecht et al. / Tetrahedron Letters 42 (2001) 8369–8372
tetrahydropyridine 6e (36 mg, 88%); [h]2D0 +191.7 (c 0.96,
13. Preparation of 10e. To a solution of diacetate 9e (10 mg,
1 equiv.) in CH2Cl2 (3 ml) at −60°C was added the
TBDMS enol ether of pinacolone (16 ml, 3 equiv.) fol-
lowed by SnCl4 (60 ml of a 1 M solution in CH2Cl2, 0.06
mmol, 3 equiv.) causing the colourless solution to become
yellow. The reaction was quenched after 3 h by the
addition of saturated aqueous NaHCO3 (10 ml) and the
mixture was extracted with EtOAc (3×10 ml). The com-
bined organic layers were washed with brine (10 ml),
dried (MgSO4) and concentrated under reduced pressure.
Flash chromatography of the residue (40% EtOAc–
petrol) gave 10e (9 mg, 83%) as a colourless oil; [h]D20
−35.0 (c 0.8, CH2Cl2); wmax (film) 2959, 2922, 1742, 1440,
1340, 1221, 1161 cm−1; lH (270 MHz) 7.80 (2H, d, J 8
Hz), 7.33 (2H, d, J 8 Hz), 5.06 (1H, dd, J 9, 6.5 Hz), 4.15
(1H, dd, J 12, 6 Hz), 3.66 (1H, m), 3.65 (3H, s), 3.48 (3H,
s), 3.30 (1H, d, J 5.5 Hz), 3.15 (1H, dd, J 18, 9.5 Hz),
2.67 (1H, dd, J 18, 1.5 Hz), 2.52, (1H, tdd, J 12, 6, 2
Hz), 2.41 (3H, s), 2.00 (1H, m), 1.80 (3H, s), 1.62 (1H,
m), 1.18 (3H, d, J 6.5 Hz), 1.13 (9H, s), 1.10 (1H, m),
1.01 (3H, d, J 6.5 Hz); lC (CDCl3, 67 MHz) 211.3, 168.9,
168.4, 167.6, 143.2, 137.9, 129.9, 127.0, 70.0, 59.3, 52.5,
52.2, 51.3, 48.4, 43.9, 38.1, 30.5, 29.7, 27.9, 26.5, 21.5,
21.0, 20.6, 20.4; m/z (CI) 585 [M+NH4]+, 568 [M+H]+,
414 (found: [M+H]+, 568.2580. C28H41NO9S requires [M+
H]+, 568.2583).
CH2Cl2); wmax (film) 2958, 2926, 1737, 1641, 1438, 1345,
1286, 1252, 1167 cm−1; lH (CDCl3, 270 MHz) 7.50 (2H,
d, J 8 Hz), 7.24 (2H, m), 6.57 (1H, dd, J 8, 1.5 Hz), 4.88
(1H, dt, J 8, 1.5 Hz), 3.65 (3H, s), 3.60 (3H, s), 3.47 (1H,
dt, J 10, 4 Hz), 2.93 (1H, d, J 9 Hz), 2.78 (1H, m), 2.40
(3H, s), 1.78 (2H, m), 1.07 (3H, d, J 7 Hz), 0.88 (3H, d,
J 7 Hz), 0.45 (1H, td, J 13, 4 Hz); lC (CDCl3, 67 MHz)
168.2, 168.1, 143.6, 135.6, 129.7, 125.5, 111.1, 59.4, 55.5,
52.6, 52.5, 28.9, 28.3, 25.5, 21.6, 20.6, 18.7; m/z (CI) 427
[M+NH4]+, 410 [M+H]+ (found: [M+NH4]+, 427.1903.
C20H27NO6S requires [M+NH4]+, 427.1894).
9. Schro¨der, M. Chem. Rev. 1980, 80, 187–213.
10. Adelbrecht, J.-C.; Craig, D.; Thorimbert, S. Synlett 2000,
467–470.
11. We thank Professor D. J. Williams and Dr. Andrew J. P.
White of this department for this determination. Crystal-
lographic data (excluding structure factors) for 9e have
been deposited with the Cambridge Crystallographic
Data Centre as supplementary data numbers CCDC
170601. Copies of the data may be obtained, free of
charge, on application to CCDC, 12 Union Road, Cam-
bridge CB2 1EZ [fax: +44(0)-1223-336033 or e-mail:
deposit@ccdc.cam.ac.uk].
12. (a) Weinreb, S. M. Top. Curr. Chem. 1997, 190, 131–184;
(b) Reider, P. J.; Rayford, R.; Grabowski, E. J. J. Tetra-
hedron Lett. 1982, 23, 379–382.