A formal [4 + 4] complementary ambiphile pairing reaction: A new cyclization pathway for ortho-quinone methides

Article abstract of DOI:10.1021/ol100495w

A formal, one-pot [4 + 4] cyclization pathway for the generation of eight-membered sultams via in situ generation of an ortho-quinone methide (o-QM) is reported. The pairing of ambiphilic synthons in a complementary fashion is examined whereby o-fluorobenzenesulfonamides are merged with in situ generated o-QM in a formal [4 + 4] cyclization pathway to afford 5,2,1- dibenzooxathiazocine-2,2-dioxide scaffolds under microwave (mW) conditions. The method reported represents the first use of an o-QM in a formal hetero [4 + 4] cyclization.

Full text of DOI:10.1021/ol100495w

ORGANIC
LETTERS
2010
Vol. 12, No. 10
2182-2185
A Formal [4 + 4] Complementary
Ambiphile Pairing Reaction: A New
Cyclization Pathway for ortho-Quinone
Methides
Thiwanka B. Samarakoon, Moon Y. Hur, Ryan D. Kurtz, and Paul R. Hanson*
Department of Chemistry, UniVersity of Kansas, 1251 Wescoe Hall DriVe,
Lawrence, Kansas 66045-7582, and the Center for Chemical Methodologies and
Library DeVelopment at the UniVersity of Kansas (KU-CMLD), 2121 Simons DriVe,
Lawrence, Kansas 66047
phanson@ku.edu
Received February 26, 2010
ABSTRACT
A formal, one-pot [4 + 4] cyclization pathway for the generation of eight-membered sultams via in situ generation of an ortho-quinone methide
(o-QM) is reported. The pairing of ambiphilic synthons in a complementary fashion is examined whereby o-fluorobenzenesulfonamides are
merged with in situ generated o-QM in a formal [4 + 4] cyclization pathway to afford 5,2,1-dibenzooxathiazocine-2,2-dioxide scaffolds under
microwave (mW) conditions. The method reported represents the first use of an o-QM in a formal hetero [4 + 4] cyclization.
The development of chemical methodologies allowing ready
access to novel heterocyclic scaffolds in a minimal number
of steps is a key facet of drug discovery. Single-pot,
multicomponent reaction (MCR) strategies in particular have
gained high value in this regard.1 The great majority of these
reactions involve the combination of reactive partners
possessing single nucleophile-electrophile interactions, fol-
lowed by subsequent merging in domino, cascade, or tandem
pathways to produce heterocyclic moieties. In comparison,
synthons containing both electrophilic and nucleophilic sites
(ambiphilic synthons)2-4 have great potential in developing
new reaction pathways with high step economy5 but remain
underdeveloped. Interest in the development of chemical
methodologies for the production of diverse sultam libraries
has led to the exploration of complementary ambiphile
pairing (CAP) pathways as part of a general strategy for the
(2) (a) Bontemps, S.; Gornitzka, H.; Bouhadir, G.; Miqueu, K.;
Bourissou, D. Angew. Chem., Int. Ed. 2006, 45, 1611–1614. (b) Bontemps,
S.; Bouhadir, G.; Miqueu, K.; Bourissou, D. J. Am. Chem. Soc. 2006, 128,
12056–12057. (c) Bontemps, S.; Bouhadir, G.; Dyer, P. W; Miqueu, K.;
Bourissou, D. Inorg. Chem. 2007, 46, 5149–5151.
(3) Molecules containing both electrophilic and nucleophilic nodes have
also been also defined as amphiphilic molecules, see: (a) Nakamura, H.;
Shim, J.-G.; Yamamoto, Y. J. Am. Chem. Soc. 1997, 119, 8113–8114. (b)
Nakamura, H.; Aoyagi, K.; Shim, J.-G.; Yamamoto, Y. J. Am. Chem. Soc.
2001, 123, 372–377. (c) Kimura, M.; Tamaki, T.; Nakata, M.; Tohyama,
K.; Tamaru, Y. Angew. Chem., Int. Ed. 2008, 120, 5887–5889.
(4) Molecules containing both electrophilic and nucleophilic nodes have
been also defined as amphoteric molecules by Yudin, see: (a) Yudin, A.;
Hili, R. J. Am. Chem. Soc. 2009, 131, 16404–16406. (b) Yudin, A.; Hili,
R. Angew. Chem., Int. Ed. 2008, 120, 4188–4191.
(1) (a) Zhu, J.; Bienayme, H.; Multicomponent Reactions; Wiley-VCH
Verlag GmbH & Co. KGaA: Weinheim, 2005. (b) Toure, B. B.; Hall, D. G.
Chem. ReV. 2009, 109, 4439–4486. (c) Sunderhaus, J. D.; Martin, S. F.
Chem.sEur. J. 2009, 15, 1300–1308.
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Res. 2008, 41, 40–49.
10.1021/ol100495w  2010 American Chemical Society
Published on Web 04/15/2010

production of benzofused sultams in a facile manner (Figure
1).
The aforementioned dibenzooxathiazocine ring system
represents a new subclass within sultams that have not been
reported to date. Sultams are a class of non-natural hetero-
cycles that have gained prominence in recent years due to
their activity against a wide spectrum of biological tar-
gets.12,13 Their acyclic precursors, sulfonamides, are highly
versatile synthons due to the tunability of the SO2NH pKa.14
In this regard, o-fluorobenzenesulfonamides are particularly
attractive due to the highly electron-withdrawing nature of
the SO2 functionality, in conjunction with the o-fluoro
substituent, which imparts enhanced electrophilicity at the
ortho-carbon as well as attenuated acidity/nucleophilicity of
the sulfonamide NH (Scheme 1). The ability of o-fluoroben-
Figure 1. Pairing strategies for benzofused sultam synthesis.
At the heart of the titled method is the complementary
pairing of two ambiphilic synthons, o-fluorobenzenesulfona-
mides and ortho-quinone methide (o-QM) in a formal, one-
pot [4 + 4] approach to afford the novel 5,2,1-dibenzoox-
athiazocine-2,2-dioxide ring system. This route augments a
recently reported [4 + 3] epoxide cascade strategy developed
in our laboratory and others using the ambiphilic character
of o-fluorobenzenesulfonamides for the synthesis of benzo-
fused sultams.6
Scheme 1
.
Pairing o-Fluorobenzenesulfonamides and o-QMs in
a Formal [4 + 4] Reaction
Quinone methides are reactive intermediates that have been
known for more than 50 years7 and are extensively utilized
in biological processes.8 In addition to their use in nature,
they also have great synthetic potential. In particular, o-QMs
are highly versatile intermediates as they can serve as
Michael acceptors or dienes in cycloaddition reactions. A
number of natural products as well as biologically active
heterocycles have been accessed utilizing in situ generated
o-QMs.9 The overwhelming majority of cases involves the
utilization of o-QMs as dienes in hetero Diels-Alder
reactions. Recently, elegant use of acyl-anion Michael
additions into o-QMs has been reported for the generation
of R-aryl ketones.10 However, in spite of numerous reports
of aza-Michael reactions of o-QMs in biological systems,
the exploitation of these pathways in the synthesis of
heterocycles is limited to reports of the dimerization of
orthoquinone methides (o-QMs).11 In contrast, the utilization
of o-QMs as ambiphiles in hetero [4 + 4] cyclizations has
not been reported in the literature.
zenesulfonamides to undergo facile nucleophilic aromatic
substitution (SNAr) reactions6,15 at the ortho-carbon allows
for their potential pairing with o-QMs in CAP strategies for
production of benzofused sultams. This pairing entails an
aza-Michael addition at the exo methylene o-QM carbon and
subsequent interception of the nucleophilic phenoxy by
o-fluorobenzenesulfonamides via an SNAr reaction in a
formal [4 + 4] cyclization pathway (Scheme 1).
Investigations commenced with the production of an
array of 2° o-fluorobenzenesulfonamides under modified
Schotten-Baumann conditions. o-QMs can be formed in situ
from 2-hydroxybenzyl alcohol derivatives under basic condi-
tions.7 Accordingly, a mixture of 2-fluorobenzenesulfona-
mide 1c was mixed with 2-hydroxy benzyl alcohol in the
presence of anhydrous K2CO3 (3.0 equiv) in DMF and was
subjected to microwave irradiation (mW) at 140 °C for 30
min (Scheme 2). The sulfonamide starting material was
completely consumed to afford a compound that was highly
visible on TLC under UV irradiation. Characterization of
the product revealed the novel tricyclic sultam 2c containing
the dibenzooxathiazocine ring system. However, the overall
yield of the reaction was modest possibly due to inefficient
(6) (a) Rolfe, A.; Samarakoon, T. B.; Hanson, P. R. Org. Lett. 2010,
12, 1216–1219. (b) Cleator, E.; Baxter, C. A.; O’Hagan, M.; O’Riordan,
T. J. C.; Sheen, F. J.; Stewart, G. W. Tetrahedron Lett. 2010, 1079–1082.
(7) For a comprehensive review on o-QM see: (a) Rokita, S. E. Quinone
Methides. Wiley Series of ReactiVe Intermediates in Chemistry and Biology;
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R. W.; Pettus, T. R. R. Tetrahedron 2002, 58, 5367–5404. (c) Pettus,
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J. K. J. Am. Chem. Soc. 2009, 131, 11350–11352. (b) Lumb, J.-P.; Choong,
K. C.; Trauner, D. J. Am. Chem. Soc. 2008, 130, 9230–9231. (d) Selenski,
C.; Pettus, T. R. R. J. Org. Chem. 2004, 69, 9196–9203.
(12) (a) Drews, J. Science 2000, 287, 1960–1964. (b) Scozzafava, A.;
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925–953
.
(10) Mattson, A. E.; Scheidt, K. A. J. Am. Chem. Soc. 2007, 129, 4508–
4509.
(13) Jime´nez-Hopkins, M.; Hanson, P. R. Org. Lett. 2008, 10, 2223–
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(11) (a) Pisova, N.; Soucek, M. Collect. Czech. Chem. Commun. 1982,
47, 838–842. (b) Wang, P.; Wang, Y.; Hu, W.; Liang, X. Eur. J. Org. Chem.
2009, 13, 2055–2058. (c) Rosenau, T.; Bo¨mdorfer, S. In Quinone Methides.
Wiley Series of ReactiVe Intermediates in Chemistry and Biology; John
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Org. Lett., Vol. 12, No. 10, 2010
2183

Scheme 2
.
Formal [4 + 4] Heterocyclization Reaction Utilizing
o-QM under mW Irradiation
Scheme 3
.
Mechanism for Formal [4 + 4] CAP Utilizing
o-Silyloxybenzyl Acetate
generation of the o-QM intermediate as well as potential
dimerzation/trimerization of the o-QM.16
were found to proceed smoothly to afford the desired sultam
in excellent yields (Table 1). The optimized reaction protocol
was found to tolerate a range of substituents on the N atom
including alkyl, propargyl, and benzyl functionalities. Pleas-
ingly, the reaction protocol was found to tolerate Cl and Br
atoms on the aromatic ring. Halide substitution was impor-
tant, as this would allow for functionalization of these
scaffolds for library production via transition metal-catalyzed
coupling reactions.
To the best of our knowledge, the ring system produced
has not been reported in the literature. The structure of these
unique heterocycles was confirmed via X-ray crystallography
(Figure 2). The method reported herein represents the first
Investigations were then focused on alternate methods of
o-QM generation. Interestingly, exposure of 1c to the
o-acetoxybenzyl acetate of o-hydroxybenzyl alcohol afforded
the desired product in increased yields. Attention was then
turned to the conditions reported by Rokita and co-workers.7a
Accordingly, microwave irradiation of the sulfonamide in
the presence of TBAF and o-silyloxy benzyl acetate in THF
at 100 °C for 30 min furnished the desired product in 90%
yield (Table 1, entry 3). In this latter result, the fluoride anion
Table 1. Substrate Scope of o-QM Mediated [4 + 4] Reaction
entry
pdt
R1
R2
yield (%)a
1
2
3
4
5
6
7
8
9
10
11
12
13
2a
2b
2c
2d
2e
2f
2g
2h
2i
H
H
2-OMe Bn
2,3-Cl CH2Ph
nBu
71
73
90
91
82
81
94
94
71
93
87
93
77
4-Br
4-Br
4-Br
4-Br
4-Br
5-Cl
5-Cl
5-Cl
5-Cl
4-Br
4-Br
iBu
PMB
cyclopropyl
propargyl
allyl
PMB
3-F Bn
2-OMe Bn
(iPr)CHCO2Me
(iBu)CHCO2Me
Figure 2. ORTEP diagram of 2f.
2j
2k
2l
instance of the use of an o-QM in a formal hetero [4 + 4]
cyclization pathway to generate a heterocycle.
2m
a Isolated yield after column chromatography.
To expand the method, application of the o-QM-mediated
[4 + 4] CAP strategy was investigated with amino ester-
derived o-fluorobenzenesulfonamides. Treatment of both and
valine- and leucine-derived substrates, 2l and 2m, under the
above conditions gratifyingly afforded the desired product
in excellent yields (Table 1, entries 12 and 13). These results
enhance the scope of the method and allow for further
elaboration of the scaffolds in library efforts. X-ray data also
serves to desilylate the silyl-protected phenol functionality
thus generating the phenoxy anion, which further continues
on the cascade pathway to produce the pivotal o-QM
intermediate. In addition, it also serves as the base to produce
the sulfonylamide intermediate required for the desired
reaction to take place (Scheme 3).
1
confirmed the source of the unique upfield H NMR shifts
The substrate scope was next investigated. A variety of
sulfonamides were subjected to the above conditions and
of the MeO group in entries 12 and 13 which were found to
be at 2.28 and 2.40 ppm, respectively, most likely due to
shielding from the aromatic ring system in these conforma-
tionally rigid systems (Figure 3).
(16) Heating at 110 °C in DMF for 12 h under reflux resulted in poor
conversion and low product yields.
2184
Org. Lett., Vol. 12, No. 10, 2010

above). In contrast, the 1H NMR shifts for the diastereotopic
gem-dimethyl groups in the 2l-minor rotamer are at 0.75 and
0.02 ppm due to shielding by the aromatic ring system (as
opposed to 1.10 and 0.98 ppm in the 2l-major rotamer).
In conclusion, a one-pot, complementary ambiphile-
pairing (CAP) reaction has been developed to produce
5,2,1-dibenzooxathiazocine-2,2-dioxides in a formal [4 +
4] cyclization pathway under mW conditions. This report
represents the first instance of the generation of 5,2,1-
dibenzooxathiazocine-2,2-dioxide scaffolds and the first
reported method utilizing in situ generated o-QM in a formal
hetero [4 + 4] cyclization process. This method is suitable
to library production and diversity-oriented synthesis. Efforts
along these lines and additional applications of CAP strate-
gies are currently in order and will be reported in due course.
Figure 3. ORTEP diagram of 2l.
Acknowledgment. This investigation was generously
supported by funds provided by the National Institute of
General Medical Sciences [Pilot-Scale Libraries Program
(P41 GM076302) and The University of Kansas Center for
Chemical Methodologies and Library Development (KU-
CMLD) (P50 GM069663)].
In the last two entries (12 and 13), a 6:1 and a 3.7:1
mixture of inseparable products are seen in the H NMR
1
spectra, which have been tentatively assigned as N-C14
1
rotamers. Evidence of this lies in the fact that the H, 13C,
1
1H/1H COSY, H/13C HSQC, and DEPT all showed the
existence of a set of peaks that was almost identical to that
of the major product albeit with a change in chemical shift
values and matching the expected structure of the product.
The 1H NMR shifts for the MeO group in 2l-minor and 2m-
minor are 3.52 and 3.72 ppm, respectively (compared with
2.28 and 2.40 in the major isomers, respectively, as stated
Supporting Information Available: Experimental details
and spectral charactization for all compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL100495W
Org. Lett., Vol. 12, No. 10, 2010
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