Microwave-assisted palladium-catalysed carbonylations of aryl and heteroaryl halides with sulfamide nucleophiles utilising a solid CO source

Article abstract of DOI:10.1016/j.tetlet.2010.08.009

Mo(CO)₆ acts as a source of carbon monoxide for the palladium-catalysed, microwave-assisted, carbonylative coupling of aryl or heteroaryl halides with sulfamide nucleophiles to yield aryl and heteroaryl acyl sulfamides.

Full text of DOI:10.1016/j.tetlet.2010.08.009

Tetrahedron Letters 51 (2010) 5341–5343
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Microwave-assisted palladium-catalysed carbonylations of aryl and
heteroaryl halides with sulfamide nucleophiles utilising a solid CO source
*
David Liptrot, Lilian Alcaraz, Bryan Roberts
Department of Chemistry, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leics, LE11 5RH, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history:
Mo(CO)6 acts as a source of carbon monoxide for the palladium-catalysed, microwave-assisted, carbony-
lative coupling of aryl or heteroaryl halides with sulfamide nucleophiles to yield aryl and heteroaryl acyl
sulfamides.
Received 18 July 2010
Accepted 3 August 2010
Available online 9 August 2010
Crown Copyright Ó 2010 Published by Elsevier Ltd. All rights reserved.
Keywords:
Carbonylation
Palladium
Homogeneous catalysis
Microwave chemistry
Sulfamides
Acyl sulfamides
The acyl sulfamide functional group (Fig. 1) is a useful func-
tional group in the field of medicinal chemistry. When R3 = H, the
acyl sulfamide is acidic and can serve as a suitable bioisostere for
phenols, carboxylic acids, sulfonic acids and acyl sulfonamides.1
Recently acyl sulfamide structures have been reported as HCV pro-
tease inhibitors,2 CXCR2 antagonists3 and aryl acyl sulfamide
structures have been disclosed in a number of pharmaceutical pat-
ents as potential therapeutic agents with wide ranging biological
activities.4
To date, methods for the preparation of aryl acyl sulfamides in-
volve activation of a precursor carboxylic acid with a suitable cou-
pling agent and reaction with an appropriately substituted
sulfamide.5 The yields of product obtained using these methods
are dependent on the choice of coupling agent and substituted
sulfamide used. The scope of these transformations is often limited
by the availability of the precursor carboxylic acids, which can in
some cases be difficult to handle and isolate, or are prone to rapid
decarboxylation. To address this issue we recently reported a new
route to aryl and heteroaryl acyl sulfamides via palladium-cata-
lysed carbonylation of aryl and heteroaryl halides with sulfamides
utilising microwave irradiation and vials pre-pressurised with car-
bon monoxide gas.6 This method is simple and efficient with wide
substrate scope but does require the use of specialised carbonyl-
ation equipment which is not available in all laboratories. Further-
more the method is not easily adaptable to parallel synthesis and
automation, often required in modern medicinal chemistry labora-
O
S
O
R1
N
N
R4
O
R2 R3
Figure 1. The acyl sulfamide functional group.
tories. The palladium-catalysed Mo(CO)6-mediated carbonylative
coupling of aryl and heteroaryl halides with a variety of nucleo-
philes under microwave-assisted conditions is now well estab-
lished in the literature and ideally suited to small scale
laboratory reactions, parallel synthesis and semi-automation.7
Herein we report the first synthesis of aryl and heteroaryl acyl sul-
famides via palladium-catalysed carbonylation using Mo(CO)6 as
the CO source. We began by examining the reaction shown in Table
1. Using iodobenzene as a model aryl halide, for reactions with
sulfamide 1a, DBU as base, 1,4-dioxane, Mo(CO)6 and Pd(OAc)2,
an optimisation of the reaction was performed in the microwave
with respect to time and temperature. Unfortunately, at tempera-
tures below 140 °C poor conversion to product was observed even
with extended reaction times (5 h). At temperatures above 140 °C
isolated yields of product were low due to competing pyrrolidine
amide formation, resulting from decomposition of the sulfamide
under basic conditions to yield the more nucleophilic amine
(Scheme 1).8
After screening several phosphine ligands it was found that
addition of PtBu3[HBF4], a temperature of 100 °C and a reaction
time of 2 h gave complete conversion of iodobenzene and afforded
the desired acyl sulfamide in 87% yield (Table 1, entry 1). The
* Corresponding author. Tel.: +44 12509 644 542; fax: +44 1509 645 571.
E-mail address: bryan.roberts@astrazeneca.com (B. Roberts).
0040-4039/$ - see front matter Crown Copyright Ó 2010 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.08.009

5342
D. Liptrot et al. / Tetrahedron Letters 51 (2010) 5341–5343
Table 1
Using bromobenzene as a model aryl halide, for reactions with
Reaction between aryl iodides and sulfamide 1aa
sulfamide 1a, DBU, 1,4-dioxane, Mo(CO)6, [Pd(OAc)(P(o-tolyl)3)]2
and PtBu3[HBF4] as the ligand, an optimisation of the reaction
was performed in the microwave with respect to time and temper-
ature. A reaction time of 2.5 h and a temperature of 100 °C gave
complete conversion of bromobenzene and afforded the desired
acyl sulfamide in 78% yield (Table 2, entry 1). The reaction condi-
tions were then applied to a range of aryl bromides. (Table 2). A
wide range of meta- and para-substituted aryl bromides performed
well in the reaction giving moderate to excellent yields (Table 2,
entries 2–12). It is also worth noting the complete chemoselectiv-
ity for bromine over chlorine in the reaction (Table 2, entries 2 and
O
S
O
O
Pd(OAc)2
PtBu3[HBF4]
S
N
N
H
Ar
+ Ar-I
NH2
N
O
O
DBU
Mo(CO)6
Microwaves
1a
2
Entry
Ar-I
Acyl sulfamide
Yieldb (%)
1
2
3
4
5
C6H5-I
2a
2b
2c
2d
2e
87
92
93
94
94
3-Cl-C6H4-I
4-MeO-C6H4-I
4-NC-C6H4-I
3-Thienyl-I
a
Reaction conditions: aryl iodide (1 mmol), sulfamide 1a (2 mmol), Pd(OAc)2
Table 3
(0.1 mmol), PtBu3[HBF4] (0.2 mmol), DBU (3 mmol), Mo(CO)6 (1 mmol) in 1,4-
Reaction between heteroaryl bromides and sulfamide 1aa
dioxane (3 mL), microwave heated in a sealed tube to 100 °C for 2 h.
b
[Pd(OAc)(P(o-tolyl)3)]2
Isolated and purified.
O
S
O
O
S
PtBu3[HBF4]
N
N
H
Het
+
N
NH2 Het-Br
O
O
DBU
O
Mo(CO)6
Microwaves
1a
O
S
2
S
Base
Heat
N
NH2
NH
Entry
1
Het-X
Acyl sulfamide
Yieldb (%)
84
O
O
NH
Br
Scheme 1. The formation of amines from sulfamides under basic conditions at
elevated temperatures.
2s
2e
O
Br
reaction conditions were then applied to a small set of aryl iodides
(Table 1). Electron-donating and electron-withdrawing groups on
the aryl ring (Table 1, entries 2–4) and heteroaromatic iodides (Ta-
ble 1, entry 5) all gave excellent yields. Attempts to apply this
method to aryl bromides were unsuccessful. Thus we sought con-
ditions for the more widely available aryl bromides. Guided by lit-
erature precedent,9 we examined the reaction shown in Table 2.
2
51
S
3
4
2t
58
74
Br
S
Br
2u
N
Table 2
Br
N
Reaction between aryl bromides and sulfamide 1aa
5
6
2v
46c
[Pd(OAc)(P(o-tolyl)3)]2
O
S
O
O
S
PtBu3[HBF4]
N
N
H
Ar
+ Ar-Br
NH2
N
Br
O
O
DBU
Mo(CO)6
Microwaves
2w
76c
1a
2
N
Entry
Ar-Br
Acyl sulfamide
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
C6H5-Br
3-Cl-C6H4-Br
2a
2b
2f
2g
2h
2i
78
90
88
68
74
72
77
88
73
86
50
53
Br
O
3-MeO-C6H4-Br
3-F3C-C6H4-Br
3-NC-C6H4-Br
3-Me-C6H4-Br
4-Cl-C6H4-Br
4-MeO-C6H4-Br
4-F3C-C6H4-Br
4-Me2NC(O)-C6H4-Br
4-NC-C6H4-Br
4-tBu-C6H4-Br
2-Naphthyl-Br
2-Cl-C6H4-Br
7
8
9
2x
2y
2z
52c
2j
Br
2c
2k
2l
2d
2m
2n
2o
2p
2q
2r
S
87
70
Br
S
20 (56c)
78
2-F-C6H4-Br
2-MeO-C6H4-Br
2-Me-C6H4-Br
55
0d (68c)
0d (60c)
a
Reaction conditions: aryl bromide (1 mmol), sulfamide 1a (2 mmol),
a
[Pd(OAc)(P(o-tolyl)3)]2 (0.1 mmol), PtBu3[HBF4] (0.2 mmol), DBU (3 mmol),
Mo(CO)6 (1 mmol) in 1,4-dioxane (3 mL), microwave heated in a sealed tube to
100 °C for 2.5 h.
Reaction conditions: heteroaryl bromide (1 mmol), sulfamide 1a (2 mmol),
[Pd(OAc)(P(o-tolyl)3)]2 (0.1 mmol), PtBu3[HBF4] (0.2 mmol), DBU (3 mmol),
Mo(CO)6 (1 mmol) in 1,4-dioxane (3 mL), microwave heated in a sealed tube to
100 °C for 2.5 h.
b
Isolated and purified.
DMAP (1 mmol) added.
10–20% product in reaction mixtures by HPLC/MS—reactions not progressed.
b
c
Isolated and purified.
Workup modified to tolerate basic N atom.
c
d

D. Liptrot et al. / Tetrahedron Letters 51 (2010) 5341–5343
5343
Table 4
is once again due to steric effects around the intermediate aryl acyl
palladium species.
Reaction between bromobenzene and substituted sulfamidesa
In summary, we have developed a new, practical and efficient
route to aryl and heteroaryl acyl sulfamides via palladium-
catalysed Mo(CO)6-mediated carbonylative coupling of readily
available aryl and heteroaryl halides in the presence of sulfamides.
The protocol should find broad application for the synthesis of a
wider variety of aryl and heteroaryl acyl sulfamides than currently
accessible through the known methodologies. We also believe that
this reaction complements our recently disclosed report of using
CO gas for this reaction, in that no specialised gas handling carbon-
ylation equipment is required thus enabling the reactions to be
carried out in parallel or in a semi-automated manner.
[Pd(OAc)(P(o-tolyl)3)]2
O
S
O
O
PtBu3[HBF4]
S
R
R
N
H
N
H
Ph
+
Ph-Br
NH2
N
H
O
O
DBU
Mo(CO)6
Microwaves
3
Entry
1
Sulfamide
Acyl sulfamide
Yieldb (%)
91
O
S
O
3a
N
H
NH2
O
S
O
2
3
3b
3c
72
59
Ph
Acknowledgements
N
NH2
H
O
S
We are grateful to Sara Griffiths and Richard Evans both of
AstraZeneca Charnwood Chemistry Department for their expert
assistance with MS studies and microwave equipment,
respectively.
N
H
NH2
Ph
O
a
Reaction conditions: bromobenzene (1 mmol), substituted sulfamide (2 mmol),
[Pd(OAc)(P(o-tolyl)3)]2 (0.1 mmol), PtBu3[HBF4] (0.2 mmol), DBU (3 mmol),
Mo(CO)6 (1 mmol) in 1,4-dioxane (3 mL), microwave heated in a sealed tube to
100 °C for 2.5 h.
Supplementary data
b
Isolated and purified.
Supplementary data (further experimental procedures and full
characterisation for all newly synthesised compounds. Caution:
Mo(CO)6 is toxic and the heating of sealed vessels should only be
performed using the appropriate equipment) associated with this
article can be found, in the online version, at doi:10.1016/
j.tetlet.2010.08.009.
7). Fused aryls also performed well in the reaction (Table 2, entry
13). It should be noted that ortho-substituted aryl bromides gave
poor yields with substituents any larger than fluorine. We believe
that this is due to steric effects around the intermediate acyl palla-
dium species. Based on precedent from the literature,10 and our
previous experience of using DMAP as an acyl transfer reagent,
we found that addition of DMAP to these reactions improved the
yields (Table 2, entries 14, 16 and 17). Attempts to apply these
methods to both electron-rich and electron-poor aryl chlorides,
even with extended reaction times and increased temperatures
met with no success. This is not too surprising since there are
few literature reports for using aryl chlorides in the palladium-
catalysed Mo(CO)6-mediated carbonylative coupling. Larhed and
Lagerlund11 have reported the formation of benzamides from aryl
chlorides via palladium-catalysed Mo(CO)6-mediated carbonyla-
tive coupling but this method required temperatures of 170 °C
which in our reactions leads to sulfamide decomposition.
Having had success with a wide range of aryl bromides we
turned our attention to heteroaryl bromides. Gratifyingly the con-
ditions optimised for aryl bromides gave moderate to good isolated
yields of heteroaryl acyl sulfamides without further optimisation
(Table 3). This methodology is applicable to a wide range of hetero-
cycles such as five-membered furans and thiophenes (Table 3,
entries 1–3), six-membered pyridines (Table 3, entries 4 and 5),
and fused five- and six-membered heterocycles (Table 3, entries
6–9). It should be noted that basic heterocycles required moder-
ately different workup conditions to non-basic as described in
the Supplementary data.
References and notes
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Ed., 2nd ed.; Academic Press: London, 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.
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8. During the course of our work with sulfamides we have observed that they can
undergo base catalysed thermal decomposition to release the corresponding
amine. Alcaraz, L.; Bennion, C.; Morris, J.; Meghani, P.; Thom, S. M. Org. Lett.
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Finally, a small set of sulfamides was synthesised12 and utilised
in the coupling with bromobenzene without any further optimisa-
tion (Table 4). Good to excellent isolated yields of acyl sulfamides
were obtained with a range of substituted sulfamides; alkyl-, phe-
nyl- and benzyl-substituted sulfamides all performed well in the
reaction (Table 4, entries 1–3). It is worth noting that in all these
cases complete regioselectivity was observed with the reaction
taking place on the least substituted nitrogen. This, we speculate,
12. Winum, J.-Y.; Toupet, L.; Barragan, V.; Dewynter, G.; Montero, J. L. Org. Lett.
2001, 3, 2241.