1,4-Bis(arylsulfonyl)-1,2,3,4-tetrahydropyridines in synthesis. Intramolecular alkylation reactions and stereoselective synthesis of anti-2,6-disubstituted piperidines

Article abstract of DOI:10.1055/s-1998-1567

1,4-Bis(arylsulfonyl)-1,2,3,4-tetrahydropyridines 1 having R¹ containing aromatic groups undergo intramolecular electrophilic aromatic substitution reactions to give benzo-fused bicyclo[3.3.1] systems with chemoselectivities which depend on the nature of the acidic reagent used. Cationic hydrogenation of the C-5-C-6 double bond in substrates 1 substituted at C-6 provides an entry to anti-2,6-disubstituted piperidines upon desulfonylation.

Full text of DOI:10.1055/s-1998-1567

58
LETTERS
SYNLETT
1,4-Bis(arylsulfonyl)-1,2,3,4-tetrahydropyridines in Synthesis. Intramolecular Alkylation
Reactions and Stereoselective Synthesis of Anti-2,6-Disubstituted Piperidines
a
b
b
a
Donald Craig *, Raymond McCague , Gerard A. Potter and Meredith R. V. Williams
a
Department of Chemistry, Imperial College of Science, Technology and Medicine, London SW7 2AY, U.K.
b
Chiroscience Limited, Science Park, Milton Road, Cambridge CB4 4WF
fax: +44 171-594 5804; e-mail: dcraig@ic.ac.uk
Received 23 September 1997
Abstract: 1,4-Bis(arylsulfonyl)-1,2,3,4-tetrahydropyridines 1 having
methine signals characteristic of the enamide double bond. Both 7a and
7b were reduced by the action of triethylsilane and trifluoroacetic acid
1
3
R
containing aromatic groups undergo intramolecular electrophilic
aromatic substitution reactions to give benzo-fused bicyclo[3.3.1]
systems with chemoselectivities which depend on the nature of the
acidic reagent used. Cationic hydrogenation of the C-5–C-6 double
bond in substrates 1 substituted at C-6 provides an entry to anti-2,6-
disubstituted piperidines upon desulfonylation.
to give tricycles 8a and 8b; 8a was further elaborated by sequential
4
desulfonylation and two-step methylation to give 2-methyl-6,7-
5
benzomorphan 9 (Scheme 2).
1
In the preceding communication we described the Lewis acid-assisted
S 1'
reactions
of
2-alkyl
1,4-bis(4-tolylsulfonyl)-1,2,3,4-
N
tetrahydropyridines 1, which give syn-2,6-disubstituted 1,2,5,6-
tetrahydropyridines 2 in excellent yields and with complete regio- and
stereoselectivity. As a natural development of this study, we became
interested in the intramolecular reactions of the analogous compounds 3
1
possessing nucleophilic R groups. It was anticipated that ionisation of
3 would immediately be followed by cyclisation to give bicyclic
products. Compounds 3 may in principle form two distinct cationic
species
4 5
and by loss of tolylsulfinate ion and protonation
respectively, and we wished to assess the extent to which these
competing pathways could be controlled (Scheme 1). This Letter reports
the results of these investigations, and describes new chemistry for the
synthesis of anti-2,6-disubstituted piperidines.
We next looked at the Brønsted acid-catalysed cyclisation reactions of
3. Exposure of 3a and 3b to catalytic sulfuric acid in dichloromethane
effected rapid, clean cyclisation to the tropane analogues 10a and 10b
respectively. Tropane 10a was cleanly desulfonylated using the standard
Na(Hg) conditions. The facility with which the acid-mediated
cyclisations occurred was such that during the formation of 3b from its
acyclic precursor 12, compound 10b was formed to a significant extent
if larger quantities of acid and/or longer reaction times were employed.
This tandem cyclisation was also observed when the tryptophan-derived
compound 13 was treated with TMS-I according to one of the two
standard tetrahydropyridine-forming methods described in the
preceding paper; compound 14 was formed as a single diastereomer in
6
moderate yield. The acid-mediated cyclisation reactions of
tetrahydropyridines 3a and 3b, and of the acyclic substrates 12 and 13
are depicted in Scheme 3.
The last part of this phase of our study was directed towards the
development of a route to anti-2,6-disubstituted piperidines using the
Brønsted acid-catalysed reactions described above. We reasoned that
intermolecular interception of iminium ions such as 5 (Scheme 1) with a
hydride source would take place on the α-face of C-6 along an axial
trajectory, such that any substituent at C-6 in the substrate would be
oriented β in the product piperidine. Substrate 16, bearing a methyl
group at C-6 was readily assembled using the method used previously.
Scheme 1
Compounds
tolylsulfonyl)propane
tolylsulfonyl)aziridine and (S)-2-[(4-methoxyphenyl)methyl]-1-(4-
tolylsulfonyl)aziridine in two steps as described in the preceding
3a,b
were
and
made
respectively
from
1,1-dimethoxy-3-(4-
(S)-2-benzyl-1-(4-
2
7
communication. Treatment of 3a with SnCl in dichloromethane gave
Thus, reaction of the lithio-anion of sulfonylacetal 15 with (S)-1-(4-
4
tolylsulfonyl)-2-benzylaziridine, and brief treatment of the product with
exclusively and in good yield the tricycle 7a, the product of interception
of the putative cation 6 at the 4-position. The analogous substrate 3b (X
= OMe) similarly gave 7b in high yield. The identities of 7a,b were
catalytic sulfuric acid in dichloromethane gave 16 essentially as a single
8
stereoisomer. Treatment of 16 with triethylsilane in the presence of
1
trifluoroacetic acid in dichloromethane gave piperidine 17 as a single,
firmly established by the appearance in their H nmr spectra of the

January 1998
SYNLETT
59
Figure: X-Ray structure of 17
Acknowledgements
We thank Chiroscience Ltd, DTI and EPSRC (LINK Studentship to M.
R. V. W.) for financial support of this research.
References and Notes
1.
Craig, D.; McCague, R.; Potter, G. A.; Williams, M. R. V. Synlett,
1998, 55.
2.
(S)-2-[(4-Methoxyphenyl)methyl]-1-(4-tolylsulfonyl)aziridine
was prepared from O-methyltyrosine (Aldrich Chemical Co.) by
reduction to O-methyltyrosinol followed by one-pot N,O-
ditosylation and cyclisation. All yields cited herein are of isolated,
purified materials which gave satisfactory H, C nmr and ir
spectra, and which showed low-resolution ms and either elemental
combustion analysis or high-resolution ms characteristics in
accord with the assigned structures.
1
13
2,6-anti diastereomer, as evidenced by X-ray crystallographic analysis
9
(Figure). Similarly, exposure of cyclisation substrate 3a to the same
reagents gave the piperidine 18. Both 18 and 17 were cleanly
desulfonylated using Na(Hg), giving respectively piperidines 19 and 20
10
(Scheme 4).
3.
4.
5.
For a review of ionic hydrogenation, see: Kursanov, D. N.;
Parnes, Z. N.; Loim, N. M. Synthesis 1974, 633-651.
Trost, B. M.; Arndt, H. C.; Strege, P. E.; Verhoeven, T. R.
Tetrahedron Lett. 1976, 3477-3478.
For other syntheses, see: Takeda, M.; Jacobson, A. E.;
Kanematsu, K.; May, E. L. J. Org. Chem. 1969, 34, 4154-4157;
Stella, L.; Raynier, B.; Surzur, J. M. Tetrahedron 1981, 37, 2843-
2854.
6.
Compound 14 contains four of the five rings present in the
naturally occurring indole alkaloid alstonerine. See: Peterson, A.
C.; Cook, J. M. J. Org. Chem. 1995, 60, 120-129, and references
cited therein.
7.
8.
Bonete, P.; Nájera, C. Tetrahedron 1995, 51, 2763-2776.
We speculate that under the acidic conditions used for the
cyclisation reaction to form 16, the minor diastereomer undergoes
epimerisation via an ionisation–recombination mechanism.
9.
We thank Professor David J. Williams and Dr Andrew J. P. White
of this department for these determinations.
Crystal data for 17: C
H NO S , M = 497.7, monoclinic, space
27 31 4 2
group P2 (no. 4), a = 11.124(1), b = 8.649(1), c = 13.236(1) Å, β
1
3
-3
= 90.40(1)°, V = 1273.5(2) Å , Z = 2, D = 1.298 g cm , µ(Cu-
K ) = 2.16 mm , F(000) = 528, T = 293 K. A clear hexagonal
c
-1
In summary, we have shown that 1,4-bis(4-tolylsulfonyl)-1,2,3,4-
tetrahydropyridines containing aryl side-chains are useful intermediates
both for the enantiospecific synthesis of 2-substituted and anti-2,6-
disubstituted piperidines, and for the efficient assembly of structurally
more complex, polycyclic frameworks with high stereoselectivities.
Future contributions from this laboratory will describe the applications
of these and related reactions to the synthesis of naturally occurring
alkaloids.
α
blocky needle of dimensions 0.40 x 0.23 x 0.13 mm was used.
2266 Independent reflections were measured on a Siemens P4/PC
diffractometer with Cu-K radiation (graphite monochromator)
α
using ω-scans. The structure was solved by direct methods and all
the non-hydrogen atoms were refined anisotropically by full-
2
matrix least squares based on F to give R = 0.040, wR = 0.097
1
2
for 2080 independent observed absorption corrected reflections

60
LETTERS
SYNLETT
[|F | > 4σ(|F |), 2θ ≤ 128°] and 296 parameters. The absolute
H-2 and H-6 of Ts), 7.33 (2H, d, J 8 Hz, H-3 and H-5 of Ts), 7.01
(2H, d, J 8 Hz, H-3 and H-5 of Ts), 6.67 (1H, d, J 8.5 Hz, aromatic
o
o
chirality was determined unambiguously by use of the Flack
parameter which refined to a value of –0.06(6). Computations
were carried out using the SHELXTL PC program system version
5.03.10.
CHC(OCH )CHCH), 6.63 (1H, dd, J 8.5, 2.5 Hz, aromatic
3
CHC(OCH )CHCH), 6.48 (1H, d,
J
2.5 Hz, aromatic
3
CHC(OCH )CHCH), 5.13 (1H, br s, H-5), 4.44 (1H, m, H-1),
3
3.76 (3H, s, OCH ), 3.04 (1H, tt, J 13, 4.0 Hz, H-3), 2.74 (1H, dd,
10. Experimental procedure for preparation of 7a.
To a solution of 3a (45.9 mg, 0.095 mmol) in dry CH Cl (3 ml)
3
J 17.5, 8.0 Hz, H-8), 2.46 (3H, s, CH of Ts), 2.34 (1H, d, J 17.5
3
2
2
Hz, H-8), 2.29 (3H, s, CH of Ts), 2.12 (1H, br d, J 12.5 Hz) and
at -78°C was added SnCl (210 µl of a 1M solution in CH Cl ,
3
4
2
2
2.02-1.87 (3H, m, H-2 and H-4); δ (100 MHz) 158.1, 145.2,
0.21 mmol, 2.2 eq) and the mixture allowed to warm to rt. After 1
C
143.3, 136.6, 134.8, 132.7, 129.9, 129.3, 129.2, 129.2, 127.0,
124.8, 113.9, 110.8, 60.4, 55.3, 55.3, 52.1, 47.2, 32.7, 29.8, 21.7,
h the reaction was quenched with satd. aq. NaHCO (3 ml), the
layers separated and the aqueous layer extracted with ether (3 x 10
ml). The combined organic layers were washed with brine (5 ml)
3
+
+
21.4; m/z (CI) 529 [M+NH ] , 512 [M+H] , 358, 202 (Found:
4
+
+
[M+H] , 512.1580. C
H NO S requires [M+H] , 512.1565).
27 29 5 2
and dried (MgSO ). Chromatography (SiO , 70% ether–petrol)
4
2
Experimental procedure for preparation of 18.
To a solution of 3a (84 mg, 0.17 mmol) in dry CH Cl (3 ml) was
yielded 7a (21 mg, 68%) as a colourless solid, mp 104-106°C;
26
[α]
+401.9 (c 1.1, CHCl ); ν (film) 2928, 1642, 1597,
max
2
2
D
3
added triethylsilane (31 µl, 0.19 mmol, 1.1 eq) and trifluoroacetic
acid (27 µl, 0.35 mmol, 2 eq). The reaction mixture was stirred at
1498, 1451, 1398, 1362, 1341, 1253, 1163, 1110, 1099, 1022,
-1
938, 892, 745, 717, 684 cm ; δ (500 MHz) 7.72 (2H, d, J 8.5 Hz,
H
rt for 30 min and then quenched with satd. aq. NaHCO (3 ml).
H-2 and H-6 of Ts), 7.32 (2H, d, J 8.5 Hz, H-3 and H-5 of Ts),
7.25-7.23 (3H, m, Ph), 7.10-7.07 (3H, m, Ar), 7.05-7.03 (1H, m,
Ar), 6.71 (1H, d, J 8 Hz, H-3), 5.27 (1H, td, J 7, 1.5 Hz, H-4),
4.52-4.50 (1H, m, H-1), 3.27 (1H, dd, J 18.5, 6 Hz, H-8), 3.30-
3
The layers were separated and the aqueous layer extracted with
ether (3 x 10 ml). The combined organic layers were washed with
satd. aq. NaHCO (5 ml), brine (5 ml) and dried (MgSO ).
3
4
Chromatography (SiO , 80→90% ether–petrol) yielded a mixture
of diastereomers of 18 (84 mg, 99%) as a colourless solid, mp
3.24 (1H, m, H-5), 3.12 (1H, d, J 18.5 Hz, H-8), 2.44 (3H, s, CH
2
3
of Ts), 1.81 (1H, ddd, J 12.5, 4, 2.5 Hz, CHCH CH), 1.43 (1H, br
2
179-190°C; ν
(film) 2951, 2925, 2855, 1597, 1455, 1315,
d, J 12.5 Hz, CHCH CH); δ (75 MHz) 142.6, 140.5, 136.4,
max
2
C
-1
1145, 1098, 938, 670, 603 cm ; δ (300 MHz, major isomer)
132.9, 129.8, 129.6, 127.3, 126.8, 126.1, 125.9, 123.0, 112.3,
H
+
7.65 (2H, d, J 8 Hz, H-2 and H-6 of Ts), 7.55 (2H, d, J 8.5 Hz, H-
2 and H-6 of Ts), 7.33 (2H, d, J 8 Hz, H-3 and H-5 of Ts), 7.21
(2H, d, J 8 Hz, H-3 and H-5 of Ts), 7.16-7.11 (3H, m, Ph), 6.91-
6.88 (2H, m, Ph), 4.39-4.32 (1H, m, H-2), 3.93 (1H, dd with
additional fine splitting, J 14, 2.5 Hz, H-6), 3.25 (1H, tt, 12.5, 3
Hz, H-4), 3.08 (1H, td, J 13.5, 2 Hz, H-6), 2.75-2.60 (2H, m,
48.3, 37.9, 31.4, 30.3, 29.7, 25.9, 21.6; m/z (CI) 326 [M+H] , 172
+
+
(Found: [M+H] , 326.1197. C
H NO S requires [M+H] ,
19 19 2
326.1215).
Experimental procedure for preparation of 10b.
To a solution of 3b (69.5 mg, 0.1358 mmol) in dry CH Cl (3 ml)
2
2
were added 2 drops of conc. H SO giving a yellow-brown
2
4
CH Ph), 2.45 (3H, s, CH of Ts), 2.39 (3H, s, CH of Ts), 2.10
solution. After 30 min at rt the reaction was quenched with satd.
aq. NaHCO (3 ml), and diluted with water and CH Cl . The
2
3
3
(1H, br d, J 13 Hz, equatorial H-3 or equatorial H-5), 1.77 (1H, br
d, J 12 Hz, equatorial H-5 or equatorial H-3), 1.68-1.45 (2H, m,
3
2
2
aqueous phase was separated and extracted with CH Cl . The
2
2
axial H-3 and axial H-5); δ (75 MHz) 145.1, 143.5, 137.5, 137.1,
combined organics were washed with brine and dried (MgSO ).
C
4
133.2, 129.9, 129.8, 129.1, 128.9, 128.7, 126.9, 126.7, 57.2, 53.6,
Chromatography (20→30% EtOAc–petrol) yielded a mixture of
+
39.5, 36.1, 26.2, 24.2, 21.7, 21.5; m/z (CI) 501 [M+NH ] , 484
diastereomers of 10b (68.1 mg, 98%) as a colourless solid; υ
4
max
+
+
[M+H] , 392 [M-C H ] , 330, 238, 172, 108, 82 (Found: C,
(film) 2958, 2926, 1613, 1592, 1504, 1446, 1341, 1319, 1270,
7 7
-1
64.34; H, 5.79; N, 2.83. C
N, 2.90%).
H NO S requires C, 64.57; H, 6.04;
26 29 4 2
1240, 1160, 1050, 813, 674 cm ; δ (400 MHz, major isomer)
H
7.61 (2H, d, J 8.5 Hz, H-2 and H-6 of Ts), 7.44 (2H, d, J 8.5 Hz,