Novel aryl and heteroaryl acyl sulfamide synthesis via microwave-assisted palladium-catalyzed carbonylation

Article abstract of DOI:10.1021/ol100083w

Chemical Equation Presented A novel, simple synthesis of aryl and heteroaryl acyl sulfamides has been developed via palladium-catalyzed carbonylation of aryl or heteroaryl halides In the presence of sulfamide nucleophiles. A range of reactions illustrating the wide scope of this reaction was carried out under microwave irradiation In a vessel equipped with a gas inlet adapter and proceeded in good to excellent yields.

Full text of DOI:10.1021/ol100083w

ORGANIC
LETTERS
2010
Vol. 12, No. 6
1264-1267
Novel Aryl and Heteroaryl Acyl Sulfamide
Synthesis via Microwave-Assisted
Palladium-Catalyzed Carbonylation
Bryan Roberts,* David Liptrot, and Lilian Alcaraz
Department of Medicinal Chemistry, AstraZeneca R&D Charnwood, Bakewell Road,
Loughborough, Leics, LE11 5RH, United Kingdom
bryan.roberts@astrazeneca.com
Received January 20, 2010
ABSTRACT
A novel, simple synthesis of aryl and heteroaryl acyl sulfamides has been developed via palladium-catalyzed carbonylation of aryl or heteroaryl
halides in the presence of sulfamide nucleophiles. A range of reactions illustrating the wide scope of this reaction was carried out under
microwave irradiation in a vessel equipped with a gas inlet adapter and proceeded in good to excellent yields.
The sulfamide functional group 1 is not as widely represented
in the area of medicinal chemistry as either the urea or
sulfonamide functional groups (Figure 1). However, over the
past decade, it has found use in many applications in the
field of medicinal chemistry.1,2 The sulfamide group can act
as a useful bioisosteric replacement for sulfamate, sulfon-
amide, carbamate, amide, and phenol functionalities.3 At-
tachment of an acyl group to the sulfamide group gives the
more acidic acyl sulfamides 2, which can serve as bioisosteric
replacements for carboxylic acids, sulfonic acids, and phe-
nols.3 Over the past few years an increasing number of
patents have disclosed aryl acyl sulfamide structures as
potential therapeutic agents with diverse biological activities.4
To date, the only available methods for the preparation of
aryl acyl sulfamides involve activation of a precursor
carboxylic acid with a suitable coupling agent and reaction
with an appropriately substituted sulfamide.5 The scope of
(1) For selected examples from recent literature see: (a) Avalle, P.; Foley,
J. R.; Mullens, P.; Wang, Y.; Yehl, P. Chem. Abstr. 2009, 151, 173453;
US-2009182002, 2009. (b) Harrison, R. J.; Major, J.; Middlesmiss, D.;
Ramsden, N.; Kruse, U.; Drewes, G. Chem. Abstr. 2009, 151, 10194; WO-
2009080638, 2009. (c) Shibata, T.; Iwataru, H.; Kiga, M.; Shimazaki, N.;
Echigo, Y.; Fujiwara, K.; Tanzawa, F. Chem. Abstr. 2006, 144, 331427;
JP-2006083133, 2006. (d) Zhong, J.; Gan, X. Bioorg. Med. Chem. 2004,
12, 589–593. (e) Collins, I. J.; Cooper, L. C. Chem. Abstr. 2003, 139,
381492; WO-2003093264, 2003. (f) Kadow, J. F.; Regueiro-Ren, A.; Xue,
Q. M. Chem. Abstr. 2003, 140, 59662; WO-2004000210, 2003. (g) Cherney,
R. J.; King, B. W. Chem. Abstr. 2002, 136, 309923; WO-2002028846, 2002.
(h) Schaal, W.; Karlsson, A.; Ahlse´n, G.; Lindberg, J.; Andersson, H. O.;
Danielson, U. H.; Classon, B.; Unge, T.; Samuelsson, B.; Hulte´n, J.;
Hallberg, A.; Karle´n, A. J. Med. Chem. 2001, 44, 155–169. (i) Groutas,
W. C.; He, S.; Kuang, R.; Ruan, S.; Tu, J.; Chan, H.-K. Bioorg. Med. Chem.
(3) (a) On Medicinal Chemistry, 1sr ed.; Stocks, M., Alcaraz, L., Griffen,
E., Eds.; Sci.Ink: Oxford, UK, 2007. (b) The Practice of Medicinal
Chemistry, 2nd ed.; Wermuth, C. G., Ed.; Academic Press: London, UK,
2003. (c) Albright, J. D.; DeVries, V. G.; Du, M. T.; Largis, E. E.; Miner,
T. G.; Reich, M. F.; Shepherd, R. G. J. Med. Chem. 1983, 26, 1393–1411.
(4) Reitz, A. B.; Smith, G. R.; Parker, M. H. Expert Opin. Ther. Pat.
2009, 19, 1449–1452.
(5) For selected examples from recent literature see: (a) Gentles, R. G.;
Ding, M.; Hewawasam, P. Chem. Abstr. 2007, 148, 11085; US-2007275930,
2007. (b) Schmidt, T.; Gebhardt, J.; Loehr, S.; Keil, M.; Wevers, J. H.;
Rack, M.; Mayer, G.; Pleschke, A. Chem. Abstr. 2007, 147, 52713; WO-
2007063028, 2007. (c) Ravindranadh, V.; Somu,; Boshoff, H.; Qiao, C.;
Bennett, E. M.; Clifton, E.; Barry, C. E., III; Aldrich, C. C. J. Med. Chem.
2006, 49, 31–34.
2001, 9, 1543–1548
(2) Bolli, M.; Boss, C.; Fischli, W.; Clozel, M.; Weller, T. Chem. Abstr.
2002, 137, 93766; WO-2002053557, 2002
.
.
10.1021/ol100083w  2010 American Chemical Society
Published on Web 02/11/2010

these transformations is limited by the availibility of the
required precursor acids which can, in some cases, be difficult
to handle and isolate. With the increasing use of aryl acyl
sulfamides in medicinal chemistry, we decided to investigate
the development of alternative methodologies for their
synthesis.
of microwave heating without the need for using gaseous
carbon monoxide have also been reported. These alternative
methods rely on the in situ generation of carbon monoxide
from molybdenum hexacarbonyl or DMF and formamide.12
Our results on in situ carbon monoxide generation for this
reaction will be published in due course.
We focused our initial investigation on using bromoben-
zene as a model aryl halide for reactions with sulfamide 1a,
triethylamine as base, 1,4-dioxane as solvent, and
PdCl2(dppf)·CH2Cl2 as the palladium source. Carbon mon-
oxide pressure was fixed at 65 psi and an optimization of
the reaction was carried out in the microwave with respect
to time and temperature. A temperature of 100 °C and
reaction time of 4 h were found to give complete conversion
of bromobenzene and afforded an isolated yield of 92% of
the desired acylsulfamide (Table 1, entry 1). We also
performed an identical control reaction using conventional
oil bath heating. Analysis of the crude HPLC/MS data for
the conventional oil bath heating and microwave irradiation
reactions indicated comparable results although the micro-
wave reaction did show a cleaner impurity profile. For
convenience in our laboratory we chose to use microwave
irradiation. To establish the scope of this transformation,
these reaction conditions were then applied to a range of
aryl halides. The results are summarized in Table 1. A variety
of functional groups were tolerated and both electron-
donating and electron-withdrawing groups give good isolated
yields. It is interesting to note that iodobenzene gave a
reduced isolated yield compared with bromobenzene (entries
1 versus 2). Ortho-substituted aryl bromides are well tolerated
in the reaction (entries 3-6). However, the more challenging
2-cyclohexylbromobenzene only gave a modest 36% yield
(entry 7). Para- (entries 8-12) and meta- (entries 13-16)
substitutued systems also performed well in the reaction. In
the preceding examples the complete chemoselectivity
observed for bromo over chloro is worth noting (entries 5,
11, and 15). Activated aryl chloride did provide a modest
isolated yield of product albeit with a longer reaction time
(entry 17). However, unactivated 3-methoxychlorobenzene
gave unreacted starting material (entry 18). This is not too
suprising since carbonylation of aryl chlorides usually
requires more forcing conditions, and or alternative palladium
catalysts.13
Figure 1. Sulfamide 1 and acyl sulfamide 2 functional groups
In 1974, Heck and co-workers reported the first use of a
palladium-catalyzed reaction of carbon monoxide, aryl
halides, and alcohols or amines as nucleophiles to give the
respective benzoate and benzamide products.6 Since then the
scope of the palladium-catalyzed carbonylation reaction has
been developed such that a wide range of nucleophiles can
now be used, enabling the efficient synthesis of numerous
carbonyl derivatives.7,8
To the best of our knowledge the synthesis of aryl and
heteroaryl acyl sulfamides via palladium-catalyzed carbo-
nylation is unprecedented in the literature. We hereby report
the first palladium-catalyzed carbonylation process under
microwave irradiation using gaseous carbon monoxide for
the synthesis of these compounds of pharmaceutical interest.
Microwave-assisted organic synthesis is an increasingly
popular field. The advantages of using microwave irradiation
over conventional heating are often a reduction in reaction
times and cleaner reactions leading to improved yields.9
Recently we acquired a gas inlet adapter allowing us to
charge microwave vials with gaseous reagents and heat these
prepressurized reaction vessels safely in the microwave.10
There are few reports in the literature of using prepressurized
reaction vials in the microwave. Of interest to us was the
work of Kormos and Leadbeater who reported the formation
of esters and acids via carbonylation of aryl iodides using
carbon monoxide gas in prepressurized reaction vials.11
Procedures for performing carbonylation reactions with use
Having established a good scope with aryl bromides,
application of the method to heteroaryl halides was per-
formed. The results are summarized in Table 2. Gratifyingly
the conditions optimized for aryl bromides provided moderate
to good isolated yields of heteroaryl acyl sulfamides without
further optimization. As shown in Table 2 the methodology
is applicable to a wide range of heterocyles such as
5-membered (entries 1-3), 6-membered (entries 4-7), and
fused systems (entries 8 and 9). However, once again
(6) (a) Schoenberg, A.; Bartoletti, I.; Heck, R. F. J. Org. Chem. 1974,
39, 3318–3326. (b) Schoenberg, A.; Heck, R. F. J. Org. Chem. 1974, 39,
3327–3331.
(7) Martinelli, J. R.; Donald, A.; Watson, D. M.; Martinelli, J. R.;
Watson, D. A.; Freckmann, D. M. M.; Barder, T. E.; Buckwald, S. L. J.
Org. Chem. 2008, 73, 7102–7107, and references cited within.
(8) For a general review on carbonylation reactions see: Barnard, C. F. J.
Organometallics 2008, 5402–5422
.
(9) For reviews on microwave chemistry see: (a) MicrowaVe Assisted
Organic Synthesis; Tierney, J. P., Lidstrom, P. Eds.; Blackwell Publishing:
Oxford, UK, 2005. (b) Kappe, C. O.; Stadler, A. MicrowaVes in Organic
and Medicinal Chemistry; Wiley-VCH: Weinheim, Germany, 2005. (c)
Kappe, C. O. Controlled Microwave Heating in Modern Organic Synthesis.
Angew. Chem., Int. Ed. 2004, 43, 6250–6284.
(11) (a) Kormos, C. M.; Leadbeater, N. E. Synlett 2006, 11, 1663–1666.
(b) Kormos, C. M.; Leadbeater, N. E. Org. Biomol. Chem. 2007, 5, 65–68.
(12) For selected examples see: (a) Wan., Y.; Alterman, M.; Larhed,
M.; Hallberg, A. J. Org. Chem. 2002, 67, 6232–6235. (b) Kaiser, N. F. K.;
Hallberg, A.; Larhed, M. J. Comb. Chem. 2002, 4, 109–111. (c) Wannberg,
J.; Larhed, M. J. Org. Chem. 2003, 68, 5750–5753.
(10) Experimental setup: All reactions were performed with a CEM
Discover single mode microwave reactor equipped with a 300 W source.
A 10 mL fiber optic accessory was equipped with a gas inlet to allow
introduction of carbon monoxide gas to the reaction vessel and each of the
reactions was performed in a CEM 10 mL microwave reaction vial. All
temperature measurements were performed with a fiber optic probe.
(13) Watson, D. A.; Fan, X.; Buckwald, S. L. J. Org. Chem. 2008, 73,
7096–7101, and references cited within.
Org. Lett., Vol. 12, No. 6, 2010
1265

Table 1. Pd-Catalyzed Carbonylation of Sulfamide 1a with Aryl
Halides 2a-r15
Table 2. Pd-Catalyzed Carbonylation of Sulfamide 1a with
Heteroaryl Halides15
acyl
sulfamide 3
yield
(%)a
entry
Ar-X 2
C6H5-Br
1
2
3
4
5
2a
2b
2c
2d
2e
2f
3a
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3l
92
80
83
73
61
76
36
70
83
82
76
78
80
80
90
75
54b
0
C6H5-I
2-Me-C6H4-Br
2-MeO-C6H4-Br
2-Cl-C6H4-Br
2-F-C6H4-Br
6
7
8
9
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
2r
2-Cy-C6H4-Br
3-MeO2C-C6H4-Br
3-Me-C6H4-Br
3-MeO-C6H4-Br
3-Cl-C6H4-Br
3-NC-C6H4-Br
4-NC-C6H4-Br
4-MeO-C6H4-Br
4-Cl-C6H4-Br
4-Me-C6H4-Br
4-NC-C6H4-Cl
3-MeO-C6H4-Cl
10
11
12
13
14
15
16
17
18
3j
a Yields quoted are isolated yields. b 20 h.
activated heteroaryl chlorides required a longer reaction time
to achieve only a modest isolated yield (entry 10).
Turning our attention to the sulfamide partner in these
carbonylation reactions, we synthesized a number of sub-
stituted sulfamides using known literature methods.14 Good
isolated yields of product were obtained with a range of
substituted sulfamides as can be seen in Table 3. Variations
of the dialkylated portion of the sulfamide did not signifi-
cantly affect the outcome of the reaction (entries 1-4).
Utilization of sulfamide produced a moderate yield of the
desired product (entry 5), whereas a range of monosubstituted
alkyl (entries 6-9) and benzyl (entries 10-12) substrates
performed well in the reaction. It is worth noting that in all
these cases complete regioselectivity was observed with
reaction taking place on the least substituted nitrogen.
Analysis of these crude reaction mixtures by HPLC/MS
revealed no evidence of the presence of the other regioiso-
mers. This regioselectivity is possibly due to steric effects
around the intermediate acyl palladium species.
a Yields quoted are isolated yields. b 20 h.
Exploring this effect further, the reaction of trisubstituted
sulfamide 8a with 4-cyanobromobenzene was performed and
gave only a 20% isolated yield of product representing a
limitation with these reactions conditions (Table 4, entry 1).
Other products isolated were the dimethylamide resulting
from breakdown of the sulfamide under basic conditions and
benzonitrile via unwanted reduction of the aryl bromide.16
Some reports in the literature suggests that DMAP can act
as an acyl transfer reagent reacting readily with the acyl
palladium species, to give a sterically less demanding acyl-
DMAP derivative, which then reacts with the nucleophile.17
It was satisfying to note that the addition of DMAP did
provide the desired product with a significant increase in
(14) (a) McManus, J. M.; McFarland, J. W.; Gerber, C. F.; McLamore,
W. M.; Laubach, G. D. J. Med. Chem. 1965, 8, 766–776. (b) Aeberli, P.;
Gogerty, J.; Houlihan, W. J. J. Med. Chem. 1967, 10, 636–642. (c) Abdaoui,
M.; Dewynter, G.; Aouf, N.; Favre, G.; Morere, A.; Montero, J.-L. Bioorg.
Med. Chem. 1996, 4, 1227–1235. (d) Kavalek, J.; Kralikova, U.; Machacek,
V.; Sedlak, M.; Sterba, V. Collect. Czech. Chem. Commun. 1990, 55, 203–
222. (e) Winum, J.-Y.; Toupet, L.; Barragan, V.; Dewynter, G.; Montero,
J.-L. Org. Lett. 2001, 3, 2241–2243.
(15) General reaction conditions: sulfamide 1a (2 equiv), aryl halide
(1 equiv), PdCl2(dppf)·CH2Cl2 10 mol %, triethylamine (3 equiv), 0.3 M
dioxane, 4 h, 100 °C, 65 psi CO.
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Org. Lett., Vol. 12, No. 6, 2010

Table 3. Pd-Catalyzed Carbonylation of Sulfamides 6a-i with
Aryl Bromides 2a, 2m, and 2n15
Table 4. Pd-Catalyzed Carbonylation of Sulfamides 7a-d with
Aryl Halide 2m18
acyl
sulfamide 9
yield
(%)a
entry
sulfamide R 8
1
2
3
4
8a
8a
8b
8c
CH3
CH3
CH3CH2
C6H5CH2
9a
9a
9b
9c
(20)15
68
47
0
a Yields quoted are isolated yields.
no reaction at all (entry 4). Although we hypothesize that
this may be due to steric effects, this could equally be due
to a decrease in stability of the trisubstituted sulfamides and/
or products under our reaction conditions.
In summary, we have developed a novel, simple, and
efficient route to aryl and heteroaryl acyl sulfamides via a
palladium-catalyzed carbonylation of readily available aryl
or heteroaryl bromides in the presence of sulfamides. The
reaction tolerates a wide range of substituted sulfamides and
substituted aryl or heteroaryl halides. We anticipate that this
new method will find broad application for the synthesis of
a wider variety of aryl and heteroaryl acyl sulfamides than
currently accessible through the known methodologies.
Acknowledgment. We are grateful to Sarah Griffiths and
Richard Evans both of the Astrazeneca Charnwood Chem-
istry Department for their expert assistance with MS studies
and microwave equipment respectively.
Supporting Information Available: Experimental pro-
cedures and full characterization (1H and 13C NMR data and
spectra, and HRMS analysis) for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL100083W
a Yields quoted are isolated yields. b 0.3 M DMF used as solvent instead
of dioxane and 3 equiv of sulfamide used.
(16) During the course of our work with sulfamides we have observed
that they can undergo base-catalyzed thermal decomposition to release the
corresponding amine. Alcaraz, L.; Bennion, C.; Morris, J.; Meghani, P.;
Thom, S. M. Org. Lett. 2004, 6, 2705–2708. This has also previously been
reported in the literature: Kavalek, J.; Kralikova, U.; Machacek, V.; Seldlak,
M.; Sterba, V. Collect. Czech. Chem. Commun. 1990, 55, 202–222.
(17) Odell, L. R.; Sa¨vmarker, J.; Larhed, M. Tetrahedron Lett. 2008,
49, 6115–6118, and references cited within.
yield (Table 4, entry 2).18 Inspired by this result we extended
this procedure to a set of trisubstituted sulfamides. As can
been seen from the results summarized in Table 4, an
increase in the size of the group on the reacting sulfamide
nitrogen leads to a proportional decrease in the yield of
isolated product (entry 3) with the benzyl substituent giving
(18) General reaction conditions: sulfamide 1a (2 equiv), aryl halide
(1 equiv), PdCl2(dppf)·CH2Cl2 10 mol %, triethylamine (3 equiv), DMAP
(1 equiv), 0.3 M dioxane, 4 h, 100 °C, 65 psi CO.
Org. Lett., Vol. 12, No. 6, 2010
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