Clean six-step synthesis of a piperidino-thiomorpholine library using polymer-supported reagents

Article abstract of DOI:10.1039/a805997g

Polymer-supported reagents and other solid sequestering agents may be used to generate a library of piperidino-thiomorpholine derivatives without any chromatographic purification steps.

Full text of DOI:10.1039/a805997g

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Clean six-step synthesis of a piperidino-thiomorpholine library
using polymer-supported reagents
Jörg Habermann, Steven V. Ley* and James S. Scott
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge,
UK CB2 1EW
Received (in Cambridge) 30th July 1998, Accepted 24th August 1998
Polymer-supported reagents and other solid sequestering
agents may be used to generate a library of piperidino-
thiomorpholine derivatives without any chromatographic
purification steps.
Thiomorpholine analogues have found applications in
medicine and agriculture.6 Therefore, development of
simple, fast and flexible method to generate libraries of such
compounds was desirable. Consequently we have designed a
route to piperidino-thiomorpholines as potentially interesting
a
The growing speed of biological evaluation of potential drug
substances during the past years has imposed the need to
develop new methods for the fast and efficient generation of
new chemical entities. In general, chemical libraries containing
large numbers of compounds may be prepared either on poly-
mer supports or in solution.1a The use of supported reagents
combines the advantages of polymer supported reactions (e.g.
allowing the application of a large excess of the reagent without
the need for additional purification steps) with the benefits
of solution phase chemistry (e.g. the ease of monitoring
the progress of the reaction by simply applying LC-MS or
TLC techniques). While, many solid-supported reagents have
been described,1a–d only a few have been used in combinatorial
chemistry.2a–e Furthermore, multi-step reaction sequences using
polymer supported reagents are rare,3 although there is a grow-
ing interest in sequestering agents on solid supports.2e,4 Recent
work in our group has focussed on the development of orches-
trated multi-step methods using polymer supported reagents for
the preparation of chemical compound libraries.5 In this com-
munication we wish to report a further example using various
supported reagents for the efficient construction of heterocyclic
derivatives.
chemical scaffolds using a series of polymer-supported
reagents.
Starting from commercially available 4-piperidone hydro-
chloride hydrate 1 (Schemes 1 and 2) the nitrogen was deriv-
atised with a range of commercially available sulfonyl chlorides
to give the corresponding sulfonamides 2a–2d in high yields
and purities (reaction 1). This reaction was carried out using
carefully dried polymer supported (dimethylamino)pyridine in
dichloromethane5c with excess of amine being removed by
addition of acidic Amberlyst 15 as a sequestering agent.
This was followed by a bromination α to the keto-function
using polymer supported pyridinium bromide perbromide7 in
toluene at 10 ЊC (reaction 2). This process needed careful con-
trol of the reaction temperature, as higher temperatures
resulted in the formation of a substantial amount of the
undesired dibromination product. Similar bromination using
amberlyst resins has also been described.8
The α-bromo ketones 3a–3d were then reacted with N-Boc-
protected aliphatic 1-amino-2-thiols in tetrahydrofuran using
Amberlyst A21 as base to effect the coupling (reaction 3).
Cleavage of the Boc-group using trifluoroacetic acid in dichloro-
methane yielded the corresponding imine directly which could
Table 1 Summary of polymer supported reactions
Yield (%)13
LC-Purity (%)
90
>95
>95
90
85
90
85
90
>98
>90
>92
>97
>95
>85
>97
>95
>97
>98
>95
>98
>95
>98
>96
>85
>92
>50
ES-MS14
Yield (%)13
LC-Purity (%)
>90
ES-MS14
2a
2b
2c
2d
3a
3b
3c
3d
4a
4b
4c
4d
4e
4f
94
32
87
66
84
85
42
78
268.12
—
306.13
—
6l
80
552.66
466.25
504.26
436.30
504.44
448.17
494.43
534.08
464.23
533.09
523.99
486.90
523.76
455.94
518.33
586.24
548.34
586.16
498.24
538.34
467.09
523.99
403.18
421.12
433.19
6m
6n
6o
6p
7
Quant.
Quant.
Quant.
Quant.15
76
>97
>98
>98
>98
>98
>96
>98
>97
>98
>98
>97
>98
>98
>95
>95
>95
>95
>98
>98
>98
>98
—
331.99
339.90
401.94
352.09
313.07
305.05
367.15
317.05
399.17
341.19
361.12
462.45
502.35
432.28
501.30
492.36
454.15
492.32
424.21
486.15
554.49
516.63
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
8m
8n
8o
8p
9a
9b
9c
Quant.
Quant.
Quant.
Quant.
Quant.
Quant.
Quant.
Quant.
Quant.
Quant.
Quant.
Quant.
Quant.
Quant.
Quant.
Quant.
~6017
Quant.16
Quant.
Quant.
Quant.
90
Quant.
80
Quant.
Quant.
Quant.
92
50
62
Quant.
Quant.
39
51
49
5
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
~6017
—
—
~6017
J. Chem. Soc., Perkin Trans. 1, 1998, 3127–3130
3127

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6
8
OMe
OMe
O
O
8
S
S
HN
N
N
HN
a
O
O
O
N
N
O
O S
O
S
Cl
Cl
Cl
Cl
O
O
8
8
8
4a
S
O
S
O
7
HN
N
HN
N
b
c
d
O
7
N
O
O
O
N
O
O
O
S
O
S
O
6
N
HN
O
S
S
S
O S
O
N
NH
N
S
7
S
S
O
O
S
O
7
S
O
N
HN
N
HN
7
N
N
5
O S
O
O
S
O
O
O
S
O
S
O
N
O
CF3
N
HN
CF3
N
HN
S
H
N
Boc
N
N
O S
O
3
O
S
O
O
S
O
O
S
O
O
S
O
4
3
5
3a
N
NH
N
O
N
NH
N
O
R"
S
S
Br
H
S
N
5
Boc
R"
R": COOMe, H 4e, f
2
O
S
O
N
O
2a
1: a) R-SO2Cl
b) Amberlyst 15
Toluene
DMAP Dichloromethane
SO3H
1
2:
Br2
O
3: N-Boc-2-Mercaptoamine, Amberlyst A21
Tetrahydrofuran
NMe2
4: a) 2-Aminothiophenol,
NMe3 CNBH3
Methanol
•HCl
N
H
b) Amberlite IRA-420
5: a) Trifluoroacetic acid, Dichloromethane
b) NMe3 CNBH3 Methanol
6: a) Phenyl-NCS
NH2
NMe3 OH
1
1
NEt2 Dichloromethane
O
S
O
N
O
2b
3b
b)
c) Amberlyst 15
S
SO3H
2
7: a) R'-NCO Dichloromethane
b)
c) Amberlyst 15
NH2
O
S
O
SO3H
N
O
S
8: Dimethyldioxirane Acetone
Br
3
6
8
O
S
N
O
S
8
O
O
O
S
S
O
S
S
S
H
N
Boc
S
CF3
N
HN
N
HN
CF3
O
e
O
O
N
N
O
O
O S
O
S
S
5
OMe
OMe
8
8
O
O
7
S
S
S
S
S
O
S
O
N
HN
N
HN
O
O
7
N
NH
f
N
N
S
O S
O
S
7
Cl
Cl
Cl
Cl
7
O
O
4b
S
S
S
O
S
N
N
HN
HN
O
g
h
N
O
O
N
O
O
S
S
O S
O
O
8
O
S
S
N
HN
N
HN
O
O
N
N
O S
O
Scheme 1
be reduced with polymer supported cyano borohydride in
methanol5c,9 to give the corresponding thiomorpholine deriv-
atives 4a–4f (reaction 5). Alternatively, the Boc-group could be
cleaved by shaking a solution of the compound with Amberlyst
15 in dichloromethane.10 The reduction of the imines resulted in
the formation of two diastereomers (cis and trans about the ring
junction, where the trans-product predominates in ≈2:1 ratio).
It was also demonstrated that aromatic 2-aminothiophenols
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J. Chem. Soc., Perkin Trans. 1, 1998, 3127–3130

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6
8
CF3
CF3
O
O
8
S
S
N
HN
N
HN
O
i
O
O
N
N
O
O
S
S
CF3
CF3
Cl
Cl
O
Cl
Cl
O
O
8
8
8
4c
S
S
S
S
O
7
HN
N
HN
N
O
j
7
O
O
O
N
O
O
O
N
O
S
O
CF3
S
S
S
O S
O
CF3
N
NH
OMe
OMe
7
F3C
S
O
O
S
O
7
N
HN
N
HN
O
k
l
N
N
5
CF3
O S
O
CF3
CF3
CF3
O
S
O
O
O
S
O
N
O
HN
N
HN
N
O
F3C
S
H
N
Boc
N
N
O
S
O
3
O
S
3c
N
O
O
F3C
Br
2
O
S
O
N
O
2c
F3C
1
O
•HCl
N
H
1
1
O
S
O
F
N
O
2d
3d
2
O
S
O
F
N
O
Br
3
6
8
O
S
O
F
N
O
F
F
F
F
OMe
8
OMe
O
O
H
S
S
S
N
Boc
N
HN
N
HN
O
O
m
O
N
N
O
O S
O
S
5
Cl
Cl
F
F
Cl
Cl
8
8
O
O
7
S
S
O
O
S
O
N
HN
N
HN
O
7
n
o
p
F
N
NH
O
O
N
N
O
O
O S
O
S
S
7
O
7
O
4d
S
S
HN
N
N
HN
O
O
N
N
O S
O
S
S
F
F
8
O
O
S
O
S
CF3
N
HN
N
HN
CF3
O
O
N
N
O
O S
O
Scheme 2 (For reagents see Scheme 1).
were compatible with the reductive amination conditions to
give the thiomorpholine derivatives (e.g. 5). In the example
attempted (reaction 4), the excess of the 2-aminothiophenol
was removed by treatment of the reaction mixture with Amber-
lite IRA-420 to act as a sequestering agent which could be
removed by filtration.
The amino function of the thiomorpholine unit could be
further elaborated with a range of commercially available
J. Chem. Soc., Perkin Trans. 1, 1998, 3127–3130
3129

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isocyanates (reaction 7) and isothiocyanates (reaction 6) to
furnish ureas 6a–6p and thioureas (e.g. 7), respectively. The
reaction of the isothiocyanate required the presence of diethyl-
aminomethyl polystyrene11 as basic catalyst. The excess quan-
tities of the isocyanates and isothiocyanates were scavenged
with aminomethyl polystyrene. This was followed by a brief
treatment of the reaction solution with Amberlyst 15 and
resulted in pure products being isolated. If desired, the
diastereomeric mixture could be separated by classical methods
to aid 1H NMR spectroscopic determination of the products.
The resultant thiomorpholine derivatives could be treated
with a solution of dimethyldioxirane in acetone to give the
corresponding sulfones 8a–8p also in a clean reaction process
(reaction 8).12 After complete conversion the dimethyldioxirane
was evaporated together with the solvent to afford the pure
products.
Acknowledgements
We gratefully acknowledge financial support from the Stiftung
Stipendien-Fonds des Verbandes der Chemischen Industrie
(Germany, Post Doctoral Fellowship to J. H.), the Ramsay
Trust (Post Doctoral Fellowship to J. S. S.), the BP endowment
and the Novartis Research Fellowship (to S. V. L.).
Notes and references
1 (a) L. A. Thompson and J. A. Ellman, Chem. Rev., 1996, 96, 555;
(b) A. Akelah and D. C. Sherrington, Chem. Rev., 1981, 81, 557;
(c) S. J. Shuttleworth, S. M. Allin and P. K. Sharma, Synthesis, 1997,
1217; (d) S. W. Kaldor and M. G. Siegel, Curr. Opin. Chem. Biol.,
1997, 1, 101.
2 (a) M. J. Suto, L. M. Gayo-Fung, M. S. S. Palanki and R. Sullivan,
Tetrahedron, 1998, 54, 4141; (b) L. M. Gayo and M. J. Suto, Tetra-
hedron Lett., 1997, 38, 513; (c) J. J. Parlow, Tetrahedron Lett., 1996,
37, 5257; (d) S. W. Kaldor, M. G. Siegel, J. E. Fritz, B. A. Dressman
and P. J. Hahn, Tetrahedron Lett., 1996, 37, 7193; (e) D. L. Flynn,
R. V. Devraj and J. J. Parlow, Curr. Opin. Drug Discovery Dev., 1998,
1, 41.
An attempt to alkylate the amino function in 4a reductively
with a range of aromatic aldehydes using the cyano boro-
hydride methodology showed gradual, clean conversion to
the products 9a–9c, but was not synthetically useful because the
reaction could not be driven to completion in these cases with-
out requiring excessive reagent sequestration (Scheme 3).
3 M. Bessodes and K. Antonakis, Tetrahedron Lett., 1985, 26, 1305;
J. J. Parlow, Tetrahedron Lett., 1995, 36, 1395; G. Cainelli,
M. Contento, F. Manescalchi and R. Regnol, J. Chem. Soc., Perkin
Trans. 1, 1980, 2516.
O
4 D. L. Flynn, J. Z. Crich, R. V. Devraj, S. L. Hockerman, J. J. Parlow,
M. S. South and S. Woodward, J. Am. Chem. Soc., 1997, 119, 4874;
M. W. Creswell, G. L. Bolton, J. C. Hodges and M. Meppen, Tetra-
hedron, 1998, 54, 3983.
S
N
NH
O
S
5 (a) B. Hinzen and S. V. Ley, J. Chem. Soc., Perkin Trans. 1, 1998,
1; (b) F. Haunert, M. H. Bolli, B. Hinzen and S. V. Ley, J. Chem.
Soc., Perkin Trans. 1, 1998, 2235; (c) S. V. Ley, M. H. Bolli,
B. Hinzen, A.-G. Gervois and B. J. Hall, J. Chem. Soc., Perkin Trans.
1, 1998, 2239; (d) M. H. Bolli and S. V. Ley, J. Chem. Soc., Perkin
Trans. 1, 1998, 2243.
4a
R
CHO
NMe3 CNBH3
6 See for example: M. R. Barbachyn, D. K. Hutchinson, S. J.
Brickner, M. H. Cynamon, J. O. Kilburn, S. P. Klemens, S. E.
Glickman, K. C. Grega, S. K. Hendges, D. S. Toops, C. W. Ford
and G. E. Zurenko, J. Med. Chem., 1996, 39, 680.
7 M. J. Frechet, M. J. Farrel and L. J. Nuyens, J. Macromol. Sci.
Chem., 1977, 11, 507.
8 A. Bongini, G. Cainelli, M. Contento and F. Manescalchi, Syn-
thesis, 1980, 143.
9 R. O. Hutchins, N. R. Natale and I. M. Taffer, J. Chem. Soc., Chem.
Commun., 1978, 1088.
O
S
R
N
N
O
S
10 Y.-S. Liu, C. Zhao, D. E. Bergbreiter and D. Romo, J. Org. Chem.,
1998, 63, 3471.
R: H, F, OMe
9a–c
11 Diethylaminomethyl polystyrene was prepared by heating a suspen-
sion of chloromethylpolystyrene in N,N-dimethylformamide with
diethylamine in the presence of a catalytic amount of tetra-N-
butylammonium iodide at 75 ЊC for 20 h.
Scheme 3
In conclusion we have developed a new clean multi-step prep-
aration of piperidino-thiomorpholines 6 and their correspond-
ing sulfones 8 starting from 4-piperidone 1 by a process which
is suitable for automated synthesis. Although we have only
generated a library of 32 ureas (6a–p, 8a–p) to demonstrate the
versatility of sequentially applying polymer supported reagents
and sequestering agents in synthetic sequences, many further
analogues could, in principle, be prepared by this route. Due to
the high yielding nature of all reactions this could be carried
out without the need for any chromatographic purification.
All intermediates were essentially pure according to LC-MS
and could be isolated by intercepting part of the reaction
streams. Yields and purities of the various products are given in
Table 1.
12 R. W. Murray and R. Jeyaraman, J. Org. Chem., 1985, 50, 2847;
W. Adam, Y.-Y. Chan, D. Cremer, J. Gauss, D. Scheutzow and
M. Schindler, J. Org. Chem., 1987, 52, 2800; R. W. Murray, Chem.
Rev., 1989, 89, 1187.
13 Yield for reaction from precursor compound.
14 Masses given are obtained in positive mode and are M ϩ H or in
some cases M ϩ NH4. No mass ions were observed for compounds
2b and 2d under ES-MS conditions.
15 cis:trans ratio by separation was determined to be ~1:2.
16 Quantitative on 40 mg scale, 74% on 200 mg scale.
17 About 60% conversion after 2 days, but reaction does not go to
completion on extended reaction time.
Communication 8/05997G
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J. Chem. Soc., Perkin Trans. 1, 1998, 3127–3130