Scaling out by microwave-assisted, continuous flow organic synthesis (MACOS): Multi-gram synthesis of bromo- and fluoro-benzofused Sultams Benzthiaoxazepine-1,1-dioxides

Article abstract of DOI:10.1002/chem.201001651

(Figure Presented). Go with the flow! Using a combination of continuous-flow techniques and microwave irradiation, a 19-member collection of 5-10 gram quantities of benzthiaoxazepine-1,1-dioxides has been produced (see scheme). The elimination of intermediate- and largescale process optimization by invoking the concept of scale-out (rather than scale up) has significantly reduced the time necessary to prepare these compounds.

Full text of DOI:10.1002/chem.201001651

COMMUNICATION
DOI: 10.1002/chem.201001651
Scaling Out by Microwave-Assisted, Continuous Flow Organic Synthesis
(MACOS): Multi-Gram Synthesis of Bromo- and Fluoro-benzofused Sultams
Benzthiaoxazepine-1,1-dioxides
Farman Ullah,[a] Thiwanka Samarakoon,[b] Alan Rolfe,[b] Ryan D. Kurtz,[b]
Paul R. Hanson,*[b] and Michael G. Organ*[a]
Sultams (cyclic sulfonamides) are an important class of
molecules that exhibit widespread biological activity against
a variety of biological targets.[1] In particular, the benzoxaze-
pine-1,1-dioxide motif has exhibited activity towards a varie-
ty of targets including: histone deacetylase inhibition (for
treatment of cognitive disorders such as Alzheimerꢀs dis-
ease),[2] glucokinase activation,[3] serotonin 5-HT2C activa-
tion,[4] modulation of the histamine H3 receptor,[5] inhibition
of MDM2-p53,[6] inhibition of sodium–proton exchange, bra-
dykinin B1 receptor antagonism (for treating Alzheimerꢀs
disease),[7] AMPA receptor agonism,[8] and inhibition of met-
alloproteinase.[9] As a consequence, there is interest in the
development of general strategies for the synthesis of organ-
ized collections (libraries) of these compounds to serve as
probes for biological pathways and as potential therapeutic
agents.
ties in this regard.[12] The desire to utilize benzofused sultam
cores for DOS approaches has prompted the investigation
of strategies that would allow facile access to these scaffolds.
In this regard a-fluorobenzenesulfonyl chlorides represent a
versatile building block synthon. The electron-withdrawing
SO2 moiety imparts enhanced electrophilicity at the b-
carbon atom, and a-fluorobenzenesulfonyl chlorides may
therefore be viewed as bis-electrophiles. Pairing of these
bis-electrophilic synthons with amino alcohols (bis-nucleo-
philes) in a complementary fashion would allow access to
benzofused sultams bearing a secondary sulfonamide in a
highly efficient manner. The reaction potential of this versa-
tile functionality can be harnessed for functionalization,
while placement of halides on the aromatic ring allows
either SNAr or metal-catalyzed cross-coupling pathways of
diversification; stereochemical and skeletal diversity can be
achieved by utilizing a variety of chiral amino alcohols
(Figure 1). Additionally, the ability to functionalize around
the periphery of the molecule along with access to stereo-
chemical diversity allows maximal interactions with macro-
molecules within biological systems.
The use of an intramolecular SNAr O-arylation route to
benzothiazepine-1,1-dioxides containing a secondary sulfo-
namide was explored. Investigations commenced with the
nucleophilic substitution of the sulfonyl chloride (first Click
reaction) by a variety of 1,2-amino alcohols by employing
modified Schotten–Bauman conditions. Accordingly, addi-
tion of a-fluorobenzenesulfonyl chloride to a vigorously stir-
ring CH2Cl2/H2O biphasic system of 1,2-amino alcohols in
the presence of NaHCO3 furnished the b-hydroxy a-fluoro-
benzene sulfonamides in excellent yields. These products
were thereafter subjected to microwave irradiation at 1408C
for 30 min in DMF in the presence of Cs2CO3 to produce a
variety of chiral benzothiaoxazepine-1,1-dioxides in excel-
lent yields (Table 1).
Diversity-oriented synthesis (DOS)[10,11] has emerged as
an effective strategy to synthesize structurally varied com-
pound collections. The development of strategies that allow
the production of versatile core scaffolds in a highly efficient
manner is crucial for DOS-based strategies. The advent of
rational DOS whereby ꢁprivileged structuresꢀ are utilized as
core scaffolds in DOS approaches has presented opportuni-
[a] Dr. F. Ullah, Prof. M. G. Organ
Department of Chemistry, York University
4700 Keele Street, Toronto, ON, M3J 1P3 (Canada)
Fax : (+1)416-736-5936
E-mail: organ@yorku.ca
[b] Dr. T. Samarakoon, Dr. A. Rolfe, R. D. Kurtz, Prof. P. R. Hanson
Department of Chemistry, University of Kansas
Malott Hall 4027, 1251 Wescoe Hall Drive, Lawrence, KS 66045-7582
The Center for Chemical Methodologies and Library Development at
the University of Kansas (KU-CMLD)
2034 Becker Drive, Del Shankel Structural Biology Center
Lawrence, KS 66047 (USA)
E-mail: phanson@ku.edu
With a successful two-step protocol in hand, we next
turned our attention to the quantity of final core structure
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201001651.
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10959

contact with the final product,
which, as a result, minimizes
side reactions that reduce yield
and complicate purification.
This means that flowed synthe-
sis is controllable both in terms
of space and time. Keeping re-
actants separate, providing that
they are stable in their reservoir
(e.g., in a syringe pump or in a
larger tank) for extended peri-
Figure 1. Pairing strategy to benzofused sultams.
ods of time, means that the
same level of conversion is sus-
Table 1. Click–cyclize protocol to diverse benzothiaoxazepine-1,1-diox-
ides.
tainable, in principle, indefinitely. This means that only a
single drop of product mixture is necessary to ascertain how
a given set of reaction conditions are going to perform, dra-
matically reducing the time and waste associated with pro-
cess optimization. Once a desired set of conditions has been
realized, then all that is necessary is to simply collect the ef-
fluent from the reaction tube for as long as is necessary to
accrue the desired quantity of product. This approach to
raising larger amounts of product is termed ꢁscaling outꢀ,
rather than the conventional ꢁscaling upꢀ process chemistry
that has historically dominated the production of fine chem-
icals. Of course, this is only useful if the reaction proceeds
to a high level of conversion; to meet these criteria, micro-
wave irradiation can be applied to the flowing reactant
stream to help drive the reaction to completion during the
time that any plug of reactant spends flowing through the
reactor.
Entry
R1
R2
R3
Sulfonamide
(yield [%])[a]
Sultam
ACHTUNGTRENNUNG
(yield [%])[a]
U
1
2
3
4
5
6
7
8
4-Br
4-Br
4-Br
4-Br
4-Br
6-F
Ph
H
H
H
H
Ph
H
Ph
H
3a (93)
3b (96)
3c (97)
3d (89)
3e (92)
3 f (93)
3g (94)
3h (95)
4a (89)
4b (87)
4c (94)
4d (83)
4e (95)
4 f (88)
4g (92)
4h (93)
iPr
iBu
Bn
Me
iBu
Me
iBu
6-F
4-F
[a] Yields of isolated product after column chromatography.
We next sought to optimize the MACOS process for the
multi-gram preparation of 4 keeping in mind the brief resi-
dence time in the flow tube, while addressing the heteroge-
neous reaction conditions in Table 1 that are not ideal for
flow. To begin, we examined the cyclization of homogeneous
mixtures in batches, where the reaction was heated for 60 s
to simulate the approximate time that any single plug of
moving reaction stream would be receiving microwave irra-
diation during flow (Table 2).
that could be produced. As the building blocks still have to
undergo two further diversification steps, it would be neces-
sary to produce these scaffolds on (at least) a 5-gram scale
to allow larger library synthesis. The cyclization step worked
best (cleanest and highest yielding) when performed under
microwave heating while keeping the concentration of 3 at
0.1m. Given the vessel size limitation imposed by the Biot-
age Initiator Microwave Synthesizer, and the relatively
dilute reaction conditions, the only way to obtain the desired
quantity of 4 would be to run the reaction repeatedly on
small scale in batches and pool the product. Not only is this
undesirable, but it dramatically increases the handling and
consumables required (e.g., high-pressure reaction tubes)
and occupies the microwave synthesizer for prolonged peri-
ods (days) of time just to obtain one single scaffold. Move-
ment of the cyclization step (at least) to a flow platform
would remove the limitations imposed by scale up. With this
goal in mind, we set out to employ a microwave-assisted,
continuous flow organic synthesis (MACOS) platform for
the scale-up synthesis of sultam 4.
Table 2. Optimization of base using batch microwave.[a]
Entry
Base
Conversion [%]
1
2
3
4
5
Et3N
2,6-lutidine
Cs2CO3
decomposition
no reaction
80[b]
87
AHCTUNGTRENNUNG
100
[a] Reaction of 3 to 4 (R1 =4-Br, R2 =Ph, R3 =H) was performed as out-
lined in Table 1 using DMF at 608C. [b] Solvent was DMF–H2O, 3:1.
While amine-derived bases proved ineffective (entries 1
and 2, Table 2),[15] Cs2CO3 solubilized in DMF/water provid-
ed reasonable conversion to 4 (entry 3). Potassium silanox-
ide (entry 4) worked nicely and full conversion was achieved
with tBuOK (entry 5); both bases were fully soluble in
DMF. This proved that cyclization was a very efficient trans-
Conducting chemical synthesis in a moveable (flowing)
platform offers several significant advantages that make its
implementation desirable from a strategic point of view.[13,14]
The compartmentalization of starting materials, reagents,
and/or catalysts from the site of reaction minimizes their
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Chem. Eur. J. 2010, 16, 10959 – 10962

Bromo- and Fluoro-benzofused Sultams Benzthiaoxazepine-1,1-dioxides
COMMUNICATION
Table 3. Final solvent optimization for MACOS preparation of sultam (4) sublibrary.
Acknowledgements
This investigation was generously sup-
ported by funds provided by the NIH
Center for Chemical Methodologies
and Library Development at the Uni-
versity of Kansas (P50 GM069663),
and NIGMS Pilot-Scale Libraries Pro-
gram (NIH P41 GM076302).
Entry
R2
X
Solvent
Time of
run (min)
Conversion
[%]
Yield
[%][a]
Product
(grams produced)
1
2
3
4
5
6
7
8
Me
Me
Me
Me
Me
Me
Ph
iBu
iBu
Bn
4-Br
4-Br
4-Br
4-Br
4-Br
4-Br
4-Br
4-Br
4-Br
4-Br
4-Br
6-F
6-F
6-F
6-F
6-F
6-F
4-F
4-F
4-F
DMF
DMA
NMP
25
25
25
25
100
100
100
100
–
–
–
–
–
–
–
–
–
–
–
–
–
53
52
49
78
80
75
73
80
93
86
85
84
84
92
89
79
87
79
76
91
96
72
72
4i (R) (0.1)
4i (R) (0.1)
Keywords: benzthiaoxazepine-
1,1-dioxides · flow chemistry ·
4i (R) (0.09)
4i (R) (0.15)
4i (R) (6.65)
4i (S) (4.21)
4a (R) (2.07)
4c (R) (8.53)
4c (S) (9.48)
4d (R) (9.83)
4d (S) (10.1)
4j (R) (7.72)
4j (S) (7.5)
4 f (R) (9.9)
4 f (S) (9.5)
4k (R) (8.4)
4k (S) (10.57)
4l (R) (8.45)
4l (S) (7.1)
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
heterocycles
·
microwave
chemistry · synthetic methods
9
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Bn
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iBu
iBu
Bn
Bn
Me
Me
iBu
iBu
Bn
–
–
–
–
–
–
4h (R) (10.37)
4h (S) (10.89)
4m (R) (6.05)
4m (S) (7.55)
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Bn
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Under the conditions given in Table 3, the above solvent
and base indeed led to excellent conversion to product using
MACOS (entry 1, Table 3). However, while the crude mass
was as expected and the crude NMR spectra showed the
presence of what appeared to be only product, recovery of
4i was disappointing. With this knowledge, we explored a
variety of other solvents (entries 2–4, Table 3) to improve
recovery and DMSO provided consistently the best mass
balance of product. Moving forward with these conditions, a
collection of 19 sultam building blocks was obtained in 5–10
gram quantities each.
In summary, an effective microwave-assisted flow synthe-
sis protocol for the preparation of multi-gram quantities of
benzofused sultams has been developed. The production
runs to generate each sultam took approximately 2.5 h.
Thus, all compounds were obtained in approximately two
weeks, including the time required to optimize the flow pro-
cess. The preparation of the same number and gram quanti-
ty of these compounds using a robotically fed batch micro-
wave would have taken more time and consumables. The
bulk sultams thus produced will be elaborated into approxi-
mately 1000 compounds using a combination of alkylation
and substitution or cross-coupling chemistry. This work is
ongoing and will be reported in due course.
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pylethylamine, quinuclidine, and 1-methylimidazole. DBU (3 equiv)
did show limited promise at 1808C providing 69% conversion.
[15] In addition to Et3N and lutidine, the following amine bases also
showed no conversion to product at 1208C for 3 min: N,N-diisopro-
Received: June 10, 2010
Published online: August 16, 2010
10962
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Chem. Eur. J. 2010, 16, 10959 – 10962