1,2-Cyclic sulfamidates as versatile precursors to thiomorpholines and piperazines

Article abstract of DOI:10.1021/ol027418h

(Matrix presented) 1,2-Cyclic sulfamidates undergo regiospecific nucleophilic displacement with either methyl thioglycolate or α-amino esters, followed by lactamization (thermal, base-mediated, or cyanide-catalyzed), to give thiomorpholin-3-ones and piper

Full text of DOI:10.1021/ol027418h

ORGANIC
LETTERS
2003
Vol. 5, No. 6
811-814
1,2-Cyclic Sulfamidates as Versatile
Precursors to Thiomorpholines and
Piperazines
Andrew J. Williams,† Suda Chakthong,†,‡ Diane Gray,† Ron M. Lawrence,§ and
,†
Timothy Gallagher*
School of Chemistry, UniVersity of Bristol, Bristol, BS8 1TS, UK, and
Chemical DeVelopment, GlaxoSmithKline, Medicines Research Centre,
SteVenage, SG1 2NY, UK
t.gallagher@bristol.ac.uk
Received December 6, 2002
ABSTRACT
1,2-Cyclic sulfamidates undergo regiospecific nucleophilic displacement with either methyl thioglycolate or r-amino esters, followed by
lactamization (thermal, base-mediated, or cyanide-catalyzed), to give thiomorpholin-3-ones and piperazin-2-ones.
Cyclic sulfates and cyclic sulfamidates represent a versatile
class of functionalized and enantiomerically pure electro-
philes. As a result, these reactive alkylating agents are finding
increasing synthetic applications across a range of areas.1
We previously reported the use of 1,3-cyclic sulfates as
components of a [3 + 3] annulation approach to piperidines.2
C,N-Bis nucleophiles, e.g., enolate 1, enable a stepwise,
double displacement of a cyclic 1,3-cyclic sulfate 2 to be
achieved in a regio- and stereocontrolled manner, providing
functionalized piperidines (Scheme 1).
† University of Bristol.
‡ On leave from Chulabhorn Research Institute, Bangkok, and Department
of Chemistry, Mahidol University, Bangkok, Thailand.
§ GlaxoSmithKline.
Scheme 1. Functionalized Piperidines via 1,3-Cyclic Sulfates
(1) Byun, H.-S.; He, L.; Bittman, R. Tetrahedron 2000, 56, 7051-7091.
Lohray, B. B.; Bhushan, V. AdV. Heterocycl. Chem. 1997, 68, 89-180.
For recent methods of synthesis of cyclic sulfamidates, see: Lowe, G.; Reed,
M. A. Tetrahedron: Asymmetry 1990, 1, 885-894. Espino, C. G.; Wehn,
P. M.; Chow, J.; Du Bois, J. J. Am. Chem. Soc. 2001, 123, 6935-6936.
Nicolaou, K. C.; Huang, X.; Snyder, S. A.; Rao, P. B.; Bella, M.; Reddy,
M. V. Angew. Chem., Int. Ed. 2002, 41, 834-838. Posakony, J. J.; Grierson,
J. R.; Tewson, T. J. J. Org. Chem. 2002, 67, 5164-5169. Duran, F.; Leman,
L.; Ghini, A.; Burton, G.; Dauban, P.; Dodd, R. H. Org. Lett. 2002, 4,
2481-2483.
(2) Littler, B. J.; Gallagher, T.; Boddy, I. K.; Riordan, P. D. Synlett 1997,
22-26. Eskici, M.; Gallagher, T. Synlett 2000, 1360-1362.
(3) Step b (Scheme 1) can be achieved by direct thermal displacement
of a secondary O-sulfate, or by hydrolysis and subsequent Mitsunobu
reaction. Thermal cyclization did lead to some loss of stereochemical
integrity (up to 10% ee), the extent of which depended on the substrate
involved. The chemistry in Scheme 1 has also been applied to the synthesis
of substituted pyrrolidines using enolate 1 and enantiomerically pure 1,2-
cyclic sulfates.
However, there are issues with the second (intramolecular)
displacement (step b, Scheme 1), such as the ease of reaction
and the degree of enantiospecificity observed.3
10.1021/ol027418h CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/22/2003

1,2-Cyclic sulfamidates 34 provide an attractive alternative
entry to N-heterocycles by allowing the key C-N bond
stereochemistry to be defined at the outset and retained. Our
approach is outlined in Scheme 2, using 4 as the other
Scheme 3. Synthesis of Substituted Thiomorpholin-3-onesa
Scheme 2
component, where a heteroatom nucleophile is adjacent to
an acetate moiety. This combination would allow a regio-
selective nucleophilic displacement to occur on 3 (C-O bond
cleavage always being favored over C-N bond cleavage),
followed by lactamization (involving the adjacent acetate
fragment) to give a six-ring N-heterocycle.
This chemistry has been explored using both methyl
thioglycolate 4a and a range of R-amino esters (cf 4b), which
leads to thiomorpholine and piperazine derivatives, respec-
tively. The synthesis of thiomorpholin-3-ones 5 is outlined
in Scheme 3.5 Base-mediated reaction of methyl thioglycolate
4a with cyclic sulfamidate 3a6 gave the thiomorpholin-3-
one 5a in 97% yield. The optimized procedure used either
NaHCO3 or Cs2CO3 as a base, and after initial nucleophilic
a Reagents and conditions: (a) NaHCO3, 1:1 THF/H2O or
Cs2CO3, THF; (b) 5 M HCl, rt, then NaHCO3; (c) PhMe, reflux, 3
h.
displacement, acidic hydrolysis (of the intermediate N-
sulfate) was followed by neutralization and thermolysis to
achieve lactamization.
Similarly, the ephedrine-derived sulfamidate 3b7 gave the
trans 5,6-disubstituted thiomorpholin-3-one 5b8 in 85% yield,
the structure of which was confirmed by X-ray crystal-
lographic analysis (Figure 1). We were also interested in the
ability of a 3-substituted cyclic sulfamidate 3c (the regio-
isomer of 3a) to participate in this process. In the event, the
(4) For general nucleophilic displacements of 1,2- and 1,3-cyclic
sulfamidates, see: (a) Meunier, N.; Veith, U.; Ja¨ger, V. Chem. Commun.
1996, 331-332. (b) Pound, M. K.; Davies, D. L.; Pilkington, M.; Sousa,
M.; Wallis, J. D. Tetrahedron Lett. 2002, 43, 1915-1918. Synthesis of
fluoroamines: (c) Posakony, J. J.; Tewson, T. J. Synthesis 2002, 766-
770. (d) Posakony, J. J.; Tewson, T. J. Synthesis 2002, 859-864. (e) Ok,
D.; Fisher, M. H.; Wyvratt, M. J.; Meinke, P. T. Tetrahedron Lett. 1999,
40, 3831-3834. (f) Lyle, T. A.; Magill, C. A.; Pitzenberger, S. M. J. Am.
Chem. Soc. 1987, 109, 7890-7891. (g) Thompson, W. J.; Anderson, P. S.;
Britcher, S. F.; Lyle, T. A.; Thies, J. E.; Magill, C. A.; Varga, S. L.;
Schwering, J. E.; Lyle, P. A.; Christy, M. E.; Evans, B. E.; Colton, C. D.;
Holloway, M. K.; Springer, J. P.; Hirshfield, J. M.; Ball, R. G.; Amato, J.
S.; Larsen, R. D.; Wong, E. H. F.; Kemp, J. A.; Tricklebank, M. D.; Singh,
L.; Oles, R.; Priestly, T.; Marshall, G. R.; Knight, A. R.; Middlemiss, D.
N.; Woodruff, G. N.; Iversen, L. L. J. Med. Chem. 1990, 33, 789-808. (h)
Van Dort, M. E.; Jung, Y.-W.; Sherman, P. S.; Kilbourn, M. R.; Wieland,
D. M. J. Med. Chem. 1995, 38, 810-815. Synthesis of chiral ether
ligands: (i) Okuda, M.; Tomioka, K. Tetrahedron Lett. 1994, 35, 4585-
4586. In manipulating carbohydrates: (j) Aguilera, B.; Ferna´ndez-Mayoralas,
A. Chem. Commun. 1996, 127-128. (k) Aguilera, B.; Ferna´ndez-Mayoralas,
A.; Jaramillo, C. Tetrahedron 1997, 53, 5863-5876. (l) Aguilera, B.;
Fernandez-Mayoralas, A. J. Org. Chem. 1998, 63, 2719-2723. Manipulation
of R-amino acids, including serine derivatives: (m) Baldwin, J. E.; Spivey,
A. C.; Schofield, C. J. Tetrahedron: Asymmetry 1990, 1, 881-884. (n)
Boulton, L. T.; Stock, H. T.; Raphy, J.; Horwell, D. C. J. Chem. Soc., Perkin
Trans. 1 1999, 1421-1429. (o) Wei, L.; Lubell, W. D. Org. Lett. 2000, 2,
2595-2598. (p) Wei, L.; Lubell, W. D. Can. J. Chem. 2001, 79, 94-104.
(q) Atfani, M.; Wei, L.; Lubell, W. D. Org. Lett. 2001, 3, 2965-2968. (r)
Cohen, S. B.; Halcomb, R. L. Org. Lett. 2001, 3, 405-407. (s) Cohen, S.
B.; Halcomb, R. L. J. Am. Chem. Soc. 2002, 124, 2534-2543. Synthesis
of 2-substituted pyrrolidines: (t) Cooper, G. F.; McCarthy, K. E.; Martin,
M. G. Tetrahedron Lett. 1992, 33, 5895-5896.
(5) Thiomorpholin-3-ones, including 5d, have also been prepared ef-
ficiently by reaction of oxazolinidin-2-ones with ethyl thioglycolate.
Ishibashi, H.; Uegaki, M.; Sakai, M. Synlett 1997, 915-916. Ishibashi, H.;
Uegaki, M.; Sakai, M.; Takeda, Y. Tetrahedron 2001, 57, 2115-2120.
(6) Sulfamidate 3a was prepared from the corresponding (S)-amino
alcohol using a modification4q of the procedure reported by Garst (White,
G. J.; Garst, M. E. J. Org. Chem. 1991, 56, 3177-3178).
Figure 1. Structure of 5b.
812
Org. Lett., Vol. 5, No. 6, 2003

racemic 6-substituted thiomorpholin-3-one 5c, which is the
regioisomer of 5a, was isolated in excellent yield.
Scheme 4. Synthesis of Substituted Piperazin-2-onesa
The method is also applicable to bicyclic sulfamidates,
such as 3d, which provided the corresponding bicyclic
thiomorpholinone 5d in 35% yield. The synthesis of 5d was
problematic because hydrolysis of the initially formed
N-sulfate was very slow under our standard reaction condi-
tions, and extended reactions times may have contributed to
the lower yield observed in this case.
R-Amino esters are also reactive toward 1,2-cyclic sulf-
amidates, and this provides a flexible entry to piperazine
derivatives9 (Scheme 4). Use of the (S)-phenylalanine-derived
1,2-sulfamidate 3a as a prototype in reaction with N-tosyl
glycine ethyl ester 6a gave the differentially protected
piperazin-2-one 7a in 84% yield.
It was important to validate the ability of a base-sensitive
stereocenter to withstand the conditions used in this chem-
istry. This was established using amino esters 6b and 6c
derived from (R)- and (S)-alanine, respectively. Reaction of
each amino ester with 3a gave the corresponding trans- and
cis-3,6-disubstituted piperazin-2-ones 7b and 7c, respectively.
In neither case was the other diastereomer detected, thus
demonstrating the stability of these epimerizable substrates
to the particular conditions used (however, see below).
A more hindered variant, such as 6d, gave piperazinone
7d, and in this case, lactamization was successfully carried
out under both thermal and base-mediated conditions in 50
and 78% yields, respectively. The ephedrine-derived sulf-
amidate 3b, which now requires the amino ester to displace
at a secondary center, did react with 6a to give the
5,6-disubstituted piperazin-2-one 7e in 25% yield.10 While
azide ion is known to react well with secondary cyclic
sulfamidates, amine nucleophiles do require significantly
more forcing conditions.11
a Reagents and conditions: (a) NaH or Cs2CO3, DMF; (b) 5 M
HCl, rt, then NaHCO3; (c) PhMe, reflux, 18 h; (d) NaOEt, EtOH,
reflux. bYield using thermal lactamization. cYield under base-
mediated lactamization conditions.
An important issue associated with this approach to the
synthesis of substituted piperazines became apparent with
(7) Sulfamidates 3b,4h 3c, and 3d were prepared from the corresponding
amino alcohols using essentially the same procedures as those used for 3a.
In the case of 3c, racemic amino alcohol was used.
(8) The cis and trans morpholine analogues of 5b are known (Spassov,
S. L.; Stefanovsky, J. N.; Kurtev B. J.; Fodor, G. Chem. Ber. 1972, 105,
2467-2475), but the coupling constants associated with H(5) and H(6) that
were reported did not correlate well to those observed for 5b. For this reason,
the relative configuration of 5b was established by X-ray crystallographic
analysis.
(9) For the synthesis of C-substituted piperazines and piperazinones,
see: Jung, M. E.; Rohloff, J. C. J. Org. Chem. 1985, 50, 4909-4913. Shono,
T.; Kise, N.; Shirakawa, E.; Matsumoto, H.; Okazaki, E. J. Org. Chem.
1991, 56, 3063-3067. Schanen, V.; Riche, C.; Chiaroni, A.; Quirion, J.-
C.; Husson, H.-P. Tetrahedron Lett. 1994, 35, 2533-2536. Mickelson, J.
W.; Belonga, K. L.; Jacobsen, E. J. J. Org. Chem. 1995, 60, 4177-4183.
Schanen, V.; Cherrier, M. P.; de Melo, S. J.; Quirion, J.-C.; Husson, H.-P.
Synthesis 1996, 833-837. Nefzi, A.; Giulianotti, M. A.; Houghten, R. A.
Tetrahedron Lett. 1999, 40, 8539-8542. Dinsmore, C. J.; Zartman, C. B.
Tetrahedron Lett. 2000, 41, 6309-6312. Rubsam, F.; Mazitschek, R.;
Giannis, A. Tetrahedron 2000, 56, 8481-8487. Gonza´lez-Go´mez, J. C.;
Uriarte-Villares, E.; Figueroa-Pe´rez, S. Synlett 2002, 1085-1088. Viso, A.;
de la Pradilla, R. F.; Lo´pez-Rodr´ıguez, M. L.; Garc´ıa, A.; Tortosa, M. Synlett
2002, 755-758. Beshore, D. C.; Dinsmore, C. J. Org. Lett. 2002, 4, 1201-
1204.
(S)-proline ethyl ester 6e and ethyl (S)-pyroglutamate 6f.
Reaction of 3a with 6e gave, after hydrolysis, the initial
adduct 8. Thermal lactamization (xylene, reflux) was slow
and very inefficient, but 7f was isolated without epimeriza-
tion at C(8a) being detected. More rapid (and essentially
quantitative) lactamization of 8 was achieved using NaOMe
(in MeOH); however, under these conditions, 7f was obtained
as a 1:1 mixture of diastereomers, epimeric at C(8a) (Scheme
5).
These problems (slow lactamization vs facile epimeriza-
tion) were overcome by using catalytic sodium cyanide12 to
promote the final ring-closure step (of 8), which gave 7f as
a single diastereomer in 50% yield.
Analogous problems were encountered when ethyl (S)-
pyroglutamate 6f was employed and were also solved using
catalytic cyanide to achieve lactamization, and under these
(10) The stereochemistry of 7e is based on comparison with 5b, the
structure of which was unambiguously assigned (see Figure 1).
(11) Azide displacement: Li, G.; Chang, H. T.; Sharpless, K. B. Angew.
Chem., Int. Ed. Engl. 1996, 35, 451-454. Amine nucleophiles require 125
°C in a steel bomb: Zubovics, Z.; Toldy, L.; Varro, A.; Rabloczky, G.;
Kurthy, M.; Dvortsak, P.; Jerkovich, G.; Tomori, E. Eur. J. Med. Chem.
1986, 21, 370-378.
(12) Mori, K.; Tominaga, M.; Takigawa, T.; Matsui, M. Synthesis 1973,
790-791. Ho¨gberg, T.; Stro¨m, P.; Ebner, M.; Ra¨msby, S. J. Org. Chem.
1987, 52, 2033-2036.
Org. Lett., Vol. 5, No. 6, 2003
813

Scheme 5. Synthesis of Bicyclic Piperazinones. Base vs
Scheme 6. Use of Primary Amino Ester Nucleophilesa
Thermal vs Cyanide-Mediated Lactamizationa
a Reagents and conditions: (a) DIPEA, EtOH, rt; (b) 5 M HCl,
rt, then NaHCO3.
In summary, 1,2-cyclic sulfamidates, which are easily
prepared from the corresponding 1,2-amino alcohols, provide
a flexible and generally efficient entry to a range of
N-heterocycles based on thiomorpholines and piperazines,
the scope of which is reflected by the range of sulfamidates
used. It is important to appreciate the advantages that 1,2-
cyclic sulfamidates offer over related electrophiles such as
aziridines. Sulfamidates readily undergo a regiospecific
displacement (compare 3a and 3c, Scheme 3), and application
of this chemistry to provide other classes of N-heterocycles
is currently underway.
a Reagents and conditions: (a) NaH, DMF, rt; (b) 5 M HCl, rt,
then NaHCO3; (c) xylene, reflux, >24 h (<10%); (d) NaOMe,
MeOH; (e) NaCN (5-10 mol %), MeOH, reflux; (f) NaCN (5-10
mol %), EtOH, 50 °C.
Acknowledgment. We thank EPSRC and GSK Research
and Development for the provision of a CASE award (to
A.J.W.), and S.C. thanks the Thailand Research Fund for
the award of a Royal Golden Jubilee Scholarship through
Professor Somsak Ruchirawat.
conditions, the bicyclic adduct 7g was isolated as a single
diastereomer in 63% overall yield.13
The use of primary amino ester 6g failed to react with 3a
to give the desired piperazine product 9. In this case, a facile
double N-alkylation of 6g occurred, which could not be
suppressed. This led to the 2:1 adduct 10 in 60% yield (based
on 3a) (Scheme 6). In this case, formation of oxazolidinone
11 (11%) was observed, which arises from the use of
NaHCO3.14
Supporting Information Available: Experimental details
and characterization data for all new compounds, including
crystallographic details for 5b. This material is available free
of charge via the Internet at http://pubs.acs.org.
(13) In the case of 7f, NaCN in MeOH at reflux was more efficient than
use of EtOH at 50 °C. Formation of 7g via thermal lactamization (xylene,
5 days, reflux) proceeded in 48% yield, and no stereochemical scrambling
at C(8a) was observed. Piperazine 7g was also isolated in 50% yield using
NaCN (10 mol %) in MeOH at reflux. Cyanide may mediate lactamization
via transesterification when MeOH is used as a solvent, but 7g was formed
efficiently using EtOH as a solvent.
OL027418H
(14) This is a known process,4c but attempts to prevent production of 11
(a major byproduct under our standard conditions) using NaOH led to low
mass recovery. Also, lactamization to give 10 occurred directly following
neutralization.
814
Org. Lett., Vol. 5, No. 6, 2003