Cyclic sulfamidates as vehicles for the synthesis of poly- and diversely substituted benzosultams via unusual S(O)2-O bond cleavage

Article abstract of DOI:10.1021/ol100288k

"Chemical Equation Presented" 1,2-Cycllc sulfamidates undergo novel, efficient, and regiospecific Intramolecular nucleophilic cleavage with aryllithiated species to provide an entry to poly-, diversely, and enantiopure N-substituted benzosultams.

Full text of DOI:10.1021/ol100288k

ORGANIC
LETTERS
2010
Vol. 12, No. 6
1356-1359
Cyclic Sulfamidates as Vehicles for the
Synthesis of Poly- and Diversely
Substituted Benzosultams via Unusual
S(O)2-O Bond Cleavage
Magali Lorion, Vangelis Agouridas, Axel Couture,* Eric Deniau, and
Pierre Grandclaudon
UniV Lille Nord de France, F-59000 Lille, France, USTL, Laboratoire de Chimie
Organique Physique, Baˆtiment C3(2), F-59655 VilleneuVe d’Ascq, France, and CNRS,
UMR 8009 “COM”, F-59655 VilleneuVe d’Ascq, France, CNRS, UMR 8181 “UCCS”,
F-59655 VilleneuVe d’Ascq, France
axel.couture@uniV-lille1.fr
Received February 5, 2010
ABSTRACT
1,2-Cyclic sulfamidates undergo novel, efficient, and regiospecific intramolecular nucleophilic cleavage with aryllithiated species to provide an
entry to poly-, diversely, and enantiopure N-substituted benzosultams.
Five-membered cyclic sulfamidates play an important role
in organic synthesis, and their reactivity and synthetic
importance have been widely harnessed and profusely
described in the literature.1 These heterocyclic compounds,
which are readily available in enantiomerically pure form,
represent a readily accessible and versatile set of ꢀ-amino
alcohol derived electrophiles that undergo facile nucleophilic
cleavage.1a The nucleophilic attack which proceeds by a SN2
pathway occurs selectively at the O-bearing carbon center
(Figure 1) in a highly stereospecific manner, and this
nucleophilic displacement with carbon (cyanide and orga-
nometallic reagents), [18 and 19]F-, nitrogen (e.g., azide, thio-
cyanate, amines and pyrazole), oxygen (e.g., MeO-, AcO-
and ArO-), and RS- nucleophiles has been widely ex-
plored.1,2 The regiospecific ring-opening then results in the
formation of a N-sulfate which can be readily hydrolyzed
under mildly acid conditions to final chiral amines equipped
with heteroatomic functional groups.1 Alternatively, the ring-
opening operation can be accompanied with a number of
annulation processes to provide a flexible entry to a range
of substituted and enantiomerically pure heterocyclic scaf-
folds,1d,e,3 including benzo-fused systems.4
The key feature of these reactions is then the high
reactivity exhibited by the C-O bond toward nucleophiles
and the activation of the carbon center for exclusive
intermolecular nucleophilic displacement. Bearing these facts
in mind, we were then intrigued by the chemical outcome
of a carbanionic process involving an aryl-based nucleophile,
e.g., an aryllithiated species, carrying an adjacent benzylic
sulfamidate moiety. In this regard, we surmised that intramo-
10.1021/ol100288k  2010 American Chemical Society
Published on Web 02/24/2010

corresponding ꢀ-amino alcohols 2-6 using a modification
of literature conditions6 (Scheme 1). In the first instance, a
reductive amination process involving a variety of 2-bro-
mobenzaldehyde derivatives 7-10 and an array of (enan-
tio)pure amino alcohols 2-6 delivered a high yield of the
bromobenzylated amino alcohols 11a-f. Subsequent treat-
ment with thionyl chloride proceeded smoothly to afford the
cyclic sulfamidites 12a-f in very satisfactory yield. In most
cases, these preliminary annulated compounds were obtained
as diastereoisomeric mixtures, but stereochemical consider-
ations at this stage were not crucial since conversion into
the achiral dioxides 1 was envisaged in the sequel. The
literature protocols for the oxidation into the desired sulfa-
midates using catalytic RuCl3 with NaIO4 as reoxidant clearly
indicate that the chemoselectivity of the oxidation step can
be tailored via judicious choice of the reaction solvent.3d We
observed that efficiency of this process was slightly better
in biphasic media (H2O-ethyl acetate; e.g., 87% for 1a)3a,7
than in the more commonly used H2O-MeCN solvent
system (e.g., 78% for 1a) presumably due to competing
oxidation of the polyalkoxylated bromobenzyl substituent,
a precedented phenomenom.3d These operation are known
to spare the stereochemistry at the carbon centers embedded
in the sulfamidate framework and allowed for the assembly
of the constitutionally diverse models 1a-f, candidates for
the planned Parham-type cyclization process.
Figure 1. Sites for inter- and/or intranucleophilic attacks.
lecular N-S(O2)-O bridge scission (Figure 1a) could be
forced and strongly favored over well-established intermo-
lecular nucleophilic displacement at the carbon center
neighboring the oxygen atom (Figure 1b), the latter process
being highly unlikely in the intramolecular version (Figure
1c). This unexpected and unusual ring-opening/ring-closing
reaction sequence would notably enrich the repertoire of the
Parham-type anionic cyclization process5 and would also
provide the basis of a flexible entry to a range of new
heterocyclic scaffolds.
We then embarked on the synthesis of a structurally
representative set of cyclic sulfamidates 1a-f. These com-
pounds were readily and efficiently synthesized from the
The protocol developed by Parham which cursorily hinges
upon aromatic lithiation and subsequent capture with an
internal electrophile occupies a place of choice in the arsenal
of synthetic tactics for the elaboration of carbo- and
heterocyclic systems,5 but applications of this concept to
build up five-membered heterocyclic systems are rather
scarce.8 To ensure the optimal formation of the mandatory
lithiated species, variation of the ethereal solvent (THF or
Et2O), base (n-BuLi or t-BuLi), temperature profile (-90,
-78, 0 °C, rt), course of the addition process (normal or
reverse), and inclusion of anion modifiers (TMEDA, crown-
ether) were all screened in order to facilitate halogen/metal
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Org. Lett., Vol. 12, No. 6, 2010
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Scheme 1. Synthesis and Nucleophilic Opening of Sulfamidates 1a-f
Table 1. Sulfamidates 1a-f and Benzosultams 13a-f Synthesized
starting materials
yield (%)
amino alcohol
sulfimidite
12a-f
sulfamidate
benzosultam
R1
R2
R3
R4
R5
R6
7-10
2-6
11a-f
1a-f
13a-f
a
b
c
d
e
f
H
OMe
OMe
OMe
H
OCH2O
OCH2O
OMe
OMe
OMe
OMe
H
H
H
OMe
H
H
Ph
H
H
i-Pr
Ph
H
H
Me
Me
H
7
8
8
9
10
10
2
3
4
4
5
6
87
90
91
93
92
47
89
94
93
91
91
92
87
87
90
90
84
87
95
76
82
81
73
90
OMe
OMe
H
H
H
H
Ph
conversion while sparing the sulfamidate moiety. After
considerable experimentation, we found that adding n-BuLi
(1.1 equiv) to a degassed solution of 1a-f (1 equiv) and
TMEDA (1.1 equiv) in THF at -90 °C for 30 min (normal
addition) led to the complete consumption of the starting
material. The intramolecular ring closure was highly efficient
as demonstrated by isolation solely of the hydroxyalkyl chain
tethered benzosultams 13a-f. A representative series of
annulated compounds which have been prepared by this
method are presented in Table 1, where it can be seen that
this simple procedure afford excellent yields of these new
highly functionalized models. One can reasonably assume
that the nucleophilic attack by the preliminary formed
aryllithiated species 14 triggers scission of the N-S-O
bridge, and ring opening is accompanied by a simultaneous
new ring-forming reaction to generate the sultam unit.
Benzosultams, which can be regarded as conformationally
constrained cyclic counterpart of sulfonamides, have emerged
as privileged structures in drug discovery9 and have served
as key functional groups in the development of nonsteroidal
anti-inflammatory agents and as agonists of 5HT1A recep-
tors.10 They have been also reported to exhibit broad
inhibitory properties against of a variety enzymes, including
COX-2,11 HIV integrase,12 lipoxygenase,13 calpain I,14 and
MMP-2.15 Beyond their significance in the treatment of
diseases, the sultam compounds are an important class of
(9) Levy, I. Drugs Future 1992, 17, 451–454.
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references cited therein.
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563. (b) Inagaki, M.; Tsuri, T.; Jyoyama, H.; Ono, T.; Yamada, K.;
Kobayashi, M.; Hori, Y.; Arimura, A.; Yasui, K.; Ohno, K.; Kakudo, S.;
Koizumi, K.; Suzuki, R.; Kato, Kawai, S.; M.; Matsumoto, S. J. Med. Chem.
2000, 43, 2040–2048.
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Lett. 2006, 16, 5298–5302.
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2001, 44, 3488–3503.
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Covington, M. B.; Qian, M.; Wasserman, Z. R.; Christ, D. D.; Trzaskos,
J. M.; Newton, R. C.; Decicco, C. P. J. Med. Chem. 2004, 47, 2981–2983.
1358
Org. Lett., Vol. 12, No. 6, 2010

chiral auxiliaries which have been successfully applied to a
number of asymmetric reactions16 and of chemical reagents
employed with considerable success in contemporary organic
reactions. Interestingly, the anionic cyclization process
applied to 1a-f provokes the concomitant creation of a tailor-
made hydroxyalkyl appendage, possibly equipped with
stereocontrolled carbon centers, which may serve as a handle
for further synthetic manipulations, in particular, installation
of tethered functionalities liable to act on the biological
profile of targeted models. The method is tolerant to a wide
variety of structurally different sulfamidates and provide a
flexible entry to a collection of poly and diversely alkoxylated
models, one of the most challenging tasks in the elaboration
of these benzo-fused sultams.17
representative cyclic 1,2-sulfamidates and undergo regiose-
lective intramolecular S(O)2-O bond cleavage to provide
the basis of a new and efficient entry to substituted
benzosultams. These readily available building blocks pro-
vide the functionalized title compounds with the capacity to
incorporate additional substituents/functionalities at a later
stage. High yields, one-pot ring-opening/ring-closing reac-
tion, procedural simplicity, and easy isolation of the products
are the key feature of this new methodology. This methodol-
ogy represents an important advance that significantly
underpins the utility of cyclic 1,2-sulfamidates as effective,
synthetically useful electrophiles.
Acknowledgment. This research was supported by the
Centre National de la Recherche Scientifique, MENESR
(grant to M.L.) and by the Programme PRIM (Re´gion Nord-
Pas-de-Calais).
In summary, we have demonstrated that aryllithiated
species are effective nucleophiles toward a set of structurally
(16) (a) Oppolzer, W.; Wills, M.; Kelly, M. J.; Signer, M.; Blagg, J.
Tetrahedron Lett. 1990, 31, 5015–5018. (b) Oppolzer, W.; Rodriguez, I.;
Starkemann, C.; Walther, E. Tetrahedron Lett. 1990, 31, 5019–5022. (c)
Ahn, K. H.; Kim, S.-K.; Ham, C. Tetrahedron Lett. 1998, 39, 6321–6322.
(d) Oppolzer, W.; Wills, M.; Starkemann, C.; Bernardinelli, G. Tetrahedron
Lett. 1990, 31, 4117–4120. (e) Ahn, K. H.; Ham, C.; Kim, S.-K.; Cho,
C.-W. J. Org. Chem. 1997, 62, 7047–7048.
Supporting Information Available: Experimental pro-
cedures, spectroscopic data, and copies of 1H and 13C NMR
spectra for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
(17) (a) Liu, Z.; Takeuchi, Y. Heterocycles 2009, 78, 1387–1412. (b)
Rayabarapu, D. K.; Zhou, A.; Jeon, K. O.; Samarakoon, T.; Rolfe, A.;
Siddiqui, H.; Hanson, P. R. Tetrahedron 2009, 65, 3180–3188.
OL100288K
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