1,4-Bis(arylsulfonyl)-1,2,3,4-tetrahydropyridines in synthesis. Highly regio- and stereoselective SN1′ and alkylation reactions

Article abstract of DOI:10.1055/s-1998-1566

Reaction of lithiated β-sulfonyl acetals with amino acid-derived N-tosylaziridines followed by acid-catalysed cyclisation gives enantiomerically pure 2-alkyl 1,4-bis(arylsulfonyl)-1,2,3,4-tetrahydropyridines 3 in good yields. These heterocyclic substrates react efficiently and highly stereoselectively with a range of carbon nucleophiles under Lewis acidic conditions to give the 1,2,5,6-tetrahydropyridine products of S_N1′ reaction, and undergo lithiation followed by completely stereoselective reaction at the 4-position with haloalkanes.

Full text of DOI:10.1055/s-1998-1566

January 1998
SYNLETT
55
1,4-Bis(arylsulfonyl)-1,2,3,4-tetrahydropyridines in Synthesis. Highly Regio- and
Stereoselective S 1' and Alkylation Reactions
N
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: Reaction of lithiated β-sulfonyl acetals with amino acid-
derived N-tosylaziridines followed by acid-catalysed cyclisation gives
enantiomerically
tetrahydropyridines 3 in good yields. These heterocyclic substrates react
efficiently and highly stereoselectively with range of carbon
nucleophiles under Lewis acidic conditions to give the 1,2,5,6-
pure
2-alkyl
1,4-bis(arylsulfonyl)-1,2,3,4-
a
tetrahydropyridine products of S 1' reaction, and undergo lithiation
N
followed by completely stereoselective reaction at the 4-position with
haloalkanes.
As part of our ongoing programme investigating the utility of sulfone-
1
containing intermediates in heterocyclic synthesis, we have been
looking at the synthesis and reactions of 1,4-bis(arylsulfonyl)-1,2,3,4-
tetrahydropyridines 3. It occurred to us that these would serve as useful,
stereodefined templates for C−C bond forming reactions on account of
the diverse reactivity of the sulfonyl group. Specifically, we envisaged
two main types of reactivity. Firstly, it was anticipated that 3 would
undergo ionisation on treatment with Lewis acids, giving conjugated
Scheme 2. (i) n-BuLi (1.1 eq), THF−TMEDA (4:1, 0,2M), -78°C, add
2 (1 eq), -78°C→rt, then AcOH−THF (1 eq); (ii) TMSCl (6 eq), MeCN
(0.1M), rt, 20 min (method A), or conc. H SO (cat.), CH Cl (0.2M),
2
4
2
2
2
iminium species which would react with carbon nucleophiles.
rt, 15 min (method B); (iii) t-BuOK (0.1 eq), t-BuOH (10 eq), THF
Secondly, we considered that lithiation and alkylation would take place
3
at the 4-position to give more substituted analogues of 3. We reasoned
Reaction of 3 with diethylaluminium chloride similarly gave the ethyl
analogues 5e-h as single, syn diastereomers. Allylation could be
that 3 would be readily available in enantiomerically pure form from the
simple sulfonylacetal 1 and N-tosylaziridines 2 (Scheme 1).
effected by addition of SnCl to dichloromethane solutions of 3 and
4
10
allyltrimethylsilane at low temperature, and a single example of an
aldol-like transformation was carried out using the tert-
butyldimethylsilyl (TBS) enol ether derived from pinacolone as the
nucleophile in conjunction with SnCl , in a fashion analogous to the
4
allyltrimethylsilane reactions. As with the products 5a-h of the
organometallic-mediated processes, compounds 5i-l were formed
exclusively as the 2,6-syn isomers. The Lewis acid-mediated reactions
11
of 3 are summarised in Scheme 3 and Table 2.
Scheme 1
4
Compound 1 was easily made according to the literature procedure, or
5
by a three-step sequence from acrolein and thiocresol. Lithiation of 1
6
and reaction with 2 gave the expected adducts 4 as diastereomeric
mixtures. These were converted into 3 upon treatment with TMSI in
MeCN (method A), or by brief exposure to a catalytic amount of
concentrated sulfuric acid in CH Cl (method B), although the former
2
2
method generally gave higher yields. Tetrahydropyridines 3 prepared in
this way were isolated typically as ca. 2:1 mixtures of 4S and 4R
diastereomers; treatment with potassium tert-butoxide in t-BuOH−THF
effected complete, quantitative conversion into the 4S compounds. The
syntheses of 3 are shown in Scheme 2 and Table 1.
That the reactions proceeded via an S 1' mechanism was shown by the
N
complete stereoselectivity of the transformations, irrespective of the
configuration at C-4 in 3. Presumably, initial Lewis acid-assisted
ionisation of 3 takes place to generate the conjugated iminium species 6,
which are intercepted exclusively from the α-face to give 2,6-syn 5.
That nucleophilic attack at the iminium centre takes place along the
ostensibly more hindered axial, α-trajectory is striking, and may be a
consequence of a stereoelectronic preference for a more chair-like
7
We initially investigated reactions of
3
with Lewis acidic
organometallic reagents possessing nucleophilic alkyl groups.
Treatment of toluene solutions of 3 with trimethylaluminium at room
temperature over 0.5-2 h gave in mostly excellent yields the products
12
9
transition-state. Also, the X-ray crystal structure of 3a (Figure 2)
5a-d of S ' reactions as single diastereomers. The 2,6-syn nature of
N
8
shows the N-tosyl group oriented so as to minimise repulsive
interactions with the axial C-2 substituent, and an analogous solution
these products was unambiguously established by n.O.e. studies, and
by X-ray crystallographic analysis; Figure 1 shows the structure of 5b.
9

56
LETTERS
SYNLETT
The final part of this study was devoted to the identification of reaction
conditions for the reduction of the C3−C4 double bond, and for removal
of the N-tosyl group. After extensive experimentation, it was found that
5a could be hydrogenated under one atmosphere of H in the presence
2
14
of Wilkinson's catalyst, giving 9 in high yield. Several reagent
systems, including H −Pd(C) and diimide failed to effect this
2
transformation. We speculate that the low reactivity of the double bond
is a consequence of its doubly-hindered nature, with the β-face
encumbered by the N-tosyl group, and the α-face blocked by the axial
C-6 substituent. Piperidine 9 was efficiently desulfonylated in high yield
15
to give 10 by treatment with excess Na(Hg) in boiling THF−MeOH
(Scheme 6).
conformation for intermediate 6 would render the α-face of C-6
sterically less encumbered (Scheme 4). Similar phenomena have been
13
described for related, more highly oxygenated nitrogen heterocycles.
In summary, we have discovered that a new class of readily available,
enantiomerically pure tetrahydropyridines enter into efficient and highly
selective reactions with nucleophiles and electrophiles under Lewis
16
acidic and basic conditions respectively.
The following paper
describes the extension of this chemistry to the intramolecular mode,
and shows that the novel cyclisation reactions uncovered have
17
significant potential in the assembly of natural product skeletons.
Acknowledgements
We thank Chiroscience Ltd, DTI and EPSRC (LINK Studentship to M.
R. V. W.) for financial support of this research.
The second part of our investigation was concerned with the generation
and synthetic potential of nucleophilic species derived from 3.
Treatment of a THF solution of 3a or 3b with n-butyllithium at low
temperature effected formation of an orange-red lithio-anion, which
combined smoothly with iodomethane or 1-bromo-2-propene to give the
References and Notes
1.
Craig, D.; Ikin, N. J.; Mathews, N.; Smith, A. M. Tetrahedron
Lett. 1995, 36, 7531-7534; Craig, D.; Tierney, J. P.; Williamson,
C. Tetrahedron Lett. 1997, 38, 4153-4156.
3
products 7a-c of exclusive 4-alkylation, α- to the sulfone group. These
2.
Allylic and tertiary sulfones may be cleaved by oxaphilic Lewis
acids: Trost, B. M.; Reza Ghadiri, M. J. Am. Chem. Soc. 1986,
108, 1098-1100, and references therein.
reactions were completely selective for the 2,4-anti diastereomers, as
shown by X-ray crystallographic analysis of 7b (Scheme 5, Figure 3).
Like the parent compounds 3, substrate 7a reacted efficiently with
diethylaluminium chloride in toluene, and gave the expected
trialkyltetrahydropyridine 8 in almost quantitative yield.
9
3.
4.
Simpkins, N. S. Sulphones in Organic Synthesis; Pergamon:
Oxford, 1993, pp 115-117.
Bonete, P.; Nájera, C. Tetrahedron 1995, 51, 2763-2776. All
yields cited herein are of isolated, purified materials which gave
1
13
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.
5.
Triethylamine-catalysed conjugate addition of thiocresol to
acrolein was followed by acetalisation (trimethyl orthoformate, K-
10 clay, CCl ) and oxidation (CH CO H).
4
3
3
6.
7.
Berry, M. B.; Craig, D. Synlett 1992, 41-44.
Treatment of 3a with one equivalent of t-BuOK resulted in the
high-yielding formation of 2-benzylpyridine. We are currently
investigating the scope and limitations of this novel pyridine-
forming reaction.
8.
9.
We thank Mr Dick Sheppard and Mr Paul Hammerton of this
department for these determinations.
We thank Professor David J. Williams and Dr Andrew J. P. White
of this department for these determinations.

January 1998
SYNLETT
57
Crystal data for 3a: C
H
NO S , M = 481.6, monoclinic, space
(487 mg, 1.69 mmol, 1 eq) in THF (2 ml) was added via cannula.
The reaction mixture was allowed to warm to rt, and after 30 min
AcOH (1.85 ml of a 1M solution in THF, 1.85 mmol, 1.1 eq) was
added. Simple extractive work-up (ether) and concentration under
reduced pressure gave a pale yellow solid. Chromatography
26 27
4 2
group P2 (no. 4), a = 12.744(3), b = 6.351(1), c = 15.802(3) Å β
1
3
-3
= 105.94(2)°, V = 1229.8(4) Å , Z = 2, D = 1.301 g cm , µ(Cu-
c
-1
K ) = 2.23 mm , F(000) = 508. A clear platy needle of
α
dimensions 0.30 x 0.22 x 0.05 mm was used. 2198 Independent
reflections were measured on a Siemens P4/PC diffractometer
(SiO , 70% ether−petrol) yielded an isomeric mixture of (5S)-3-
2
with Cu-K radiation (graphite monochromator) using ω-scans.
The structure was solved by direct methods and all the non-
(4-tolylsulfonyl)-5-[(4-tolylsulfonyl)-amino]-1,1-dimethoxy-6-
phenylhexane 4a (0.85 g, 1.56 mmol, 93%) as a colourless solid.
To a solution of 4a (204 mg, 0.374 mmol) and NaI (168 mg, 1.12
mmol, 3 eq) in MeCN (3.8 ml) at rt was added TMSCl (142 µl,
1.12 mmol, 3 eq). After 20 min the reaction was quenched with
α
hydrogen atoms were refined anisotropically by full-matrix least
2
squares based on F to give R = 0.043, wR = 0.106 for 1918
1
2
independent observed reflections [|F | > 4σ(|F |), 2θ ≤ 124°] and
o
o
287 parameters. The absolute chirality was determined
unambiguously by use of the Flack parameter which refined to a
value of -0.01(3).
satd. aq. NaHCO (2 ml) and diluted with water (2 ml). Simple
3
extractive work-up (ether) including washing with aq Na S O ,
2
2 3
and concentration under reduced pressure followed by
Crystal data for 5b: C
H
NO S, M = 293.4, monoclinic, space
chromatography of the residue (SiO , 80% ether−petrol) yielded a
16 23
2
2
group P2 (no. 4), a = 8.159(2), b = 13.565(3), c = 8.286(2) Å β =
2:1 mixture of S)-1,4-bis(4-tolylsulfonyl)-2-benzyl-1,2,3,4-
tetrahydropyridine 3a (173 mg, 96%) as a colourless solid.
To a stirred solution of 3a (112 mg, 0.23 mmol) in PhMe (3 ml)
1
3
-3
115.27(2)°, V = 829.4(3) Å , Z = 2, D = 1.175 g cm , µ(Cu-K )
c
α
-1
= 1.74 mm , F(000) = 316. A clear plate of dimensions 0.50 x
0.40 x 0.20 mm was used. 1417 Independent reflections were
under N at rt was added Me Al (232 µl of a 2M solution in
2 3
measured on a Siemens P4/PC diffractometer with Cu-K
hexanes, 0.46 mmol, 2 eq). After 30 min the reaction was
α
radiation (graphite monochromator) using ω-scans. The structure
quenched with satd. aq. NaHCO (3 ml). Simple extractive work-
3
was solved by direct methods and all the non-hydrogen atoms
up (ether) and removal of solvents under reduced pressure
were refined anisotropically by full-matrix least squares based on
followed by chromatography (SiO , 70% ether−petrol) yielded
(2R,6R)-2-methyl-6-benzyl-1-(4-tolylsulfonyl)-1,2,5,6-tetrahy-
2
2
F to give R = 0.035, wR = 0.092 for 1385 independent observed
1
2
reflections [|F | > 4σ(|F |), 2θ ≤ 126°] and 182 parameters. The
absolute chirality was determined unambiguously by use of the
Flack parameter which refined to a value of 0.09(4).
dropyridine 5a (66 mg, 84%) as a colourless, oily solid; R 0.63
o
o
f
(70% ether−petrol); [α]D26 +2.7 (c 1.3, CH Cl ); ν
(film) 3028,
max
2
2
2957, 2929, 2852, 1598, 1494, 1454, 1389, 1330, 1289, 1234,
-1
Crystal data for 7b: C
H
NO S , M = 447.6, orthorhombic,
1163, 1131, 1101, 982, 726, 702, 653 cm ; δ (300 MHz) 7.68
23 29
4
2
H
space group P2 2 2 (no. 19), a = 8.699(2), b = 13.156(2), c =
(2H, d, J 8.5 Hz, H-2 and H-6 of Ts), 7.28 (2H, d, J 8.5 Hz, H-3
and H-5 of Ts), 7.25-7.23 (3H, m, Ph), 7.20 (2H, t, J 7.5 Hz, Ph),
5.68-5.61 (2H, m, H-3 and H-4), 4.46-4.44 (1H, m, H-2 or H-6),
4.21-4.17 (1H, m, H-6 or H-2), 2.99 (1H, dd, J 13.0 and 3.5 Hz,
1
1 1
3
-3
20.317(3) Å, V = 2325.1(7) Å , Z = 4, D = 1.279 g cm , µ(Cu-
c
-1
K ) = 2.31 mm , F(000) = 952. A clear columnal needle of
α
dimensions 0.93 x 0.18 x 0.10 mm was used. 2157 Independent
reflections were measured on a Siemens P4/PC diffractometer
CH Ph), 2.86 (1H, dd, J 13.0 and 11.5 Hz, CH Ph), 2.39 (3H, s,
2
2
with Cu-K radiation (graphite monochromator) using ω-scans.
CH of Ts), 1.76 (1H, dd, J 17.5 and 6.0 Hz, H-5), 1.64-1.60 (1H,
3
α
The structure was solved by direct methods and all the non-
m, H-5), 1.49 (3H, d, J 7.0 Hz, C-2 CH ); δ (75 MHz) 143.0,
3 C
hydrogen atoms were refined anisotropically by full-matrix least
139.2, 138.3, 134.8, 129.7, 129.3, 128.6, 126.8, 126.5, 121.5,
2
+
squares based on F to give R = 0.051, wR = 0.127 for 1699
52.3, 49.1, 41.8, 24.1, 24.0, 19.1; m/z (CI) 359 [M+NH ] , 342
1
2
4
+
+
+
independent observed reflections [|F | > 4σ(|F |), 2θ ≤ 126°] and
[M+H] , 274, 250 [M-C H ] , 188, 96 (Found: [M+H] ,
7 7
o
o
+
272 parameters. The absolute chirality was determined
unambiguously by use of the Flack parameter which refined to a
value of 0.04(5).
All computations were carried out using the SHELXTL PC
program system version 5.03. Atomic coordinates, bond lengths
and angles, and thermal parameters for 3a, 5b and 7a have been
deposited at the Cambridge Crystallographic Data Centre.
342.1515. C H NO S requires [M+H] , 342.1528).
20 23 2
12. Toromanoff, E. Tetrahedron 1980, 36, 2809-2931.
13. Hopman, J. C. P.; van den Berg, E.; Ollero Ollero, L.; Hiemstra,
H.; Speckamp, W. N. Tetrahedron Lett. 1995, 36, 4315-4318.
14. For leading references, see: Takaya, H.; Noyori, R. In
Comprehensive Organic Synthesis; Trost, B. M., Ed.; Pergamon:
Oxford, 1991; Vol. 8, pp 443-444.
10. For a review of electrophilic substitution reactions of allylsilanes,
see: Chan, T. H.; Fleming, I. Synthesis 1979, 761-786; see also:
Sakurai, H.; Sasaki, K.; Hosomi, A. Tetrahedron Lett. 1981, 22,
745-748.
15. Trost, B. M.; Arndt, H. C.; Strege, P. E.; Verhoeven, T. R.
Tetrahedron Lett. 1976, 3477-3478.
16. We thank Dr Christopher J. Etheridge (Imperial College) for some
exploratory experiments.
11. Experimental procedure for preparation of 5a.
17. 2,3-Dihydro-4-pyridones have emerged as versatile intermediates
for the enantiocontrolled synthesis of nitrogen heterocycles. See:
Comins, D. L.; Joseph, S. P.; Hong, H.; Alawar, R. S.; Foti, C. J.;
Zhang, Y. M.; Chen, X. H.; La Munyon, D. H.; Guerra-Weltzien,
M. Pure Appl. Chem. 1997, 69, 477-481, and references therein.
To a stirred solution of 1,1-dimethoxy-3-(4-tolylsulfonyl)propane
1 (435 mg, 1.68 mmol, 1 eq) in THF (6.8 ml) and TMEDA (1.7
ml) at -78°C under N was added n-BuLi (742 µl of a 2.5 M
2
solution in hexanes, 1.85 mmol, 1.1 eq). After stirring for 20 min a
solution of (S)-2-(phenylmethyl)-1-(4-tolylsulfonyl)aziridine 2a