Synthesis of novel aryl and heteroaryl acyl sulfonimidamides via Pd-catalyzed carbonylation using a nongaseous precursor

Article abstract of DOI:10.1021/ol400049m

Hitherto unexplored aryl and heteroaryl acyl sulfonimidamides have been prepared through the development of a new Pd-catalyzed carbonylation protocol. This novel methodology, employing sulfonimidamides as nucleophiles and CO gas ex situ released from solid Mo(CO)₆ in a sealed two-chamber system, yields a wide range of carbamate protected acyl sulfonimidamides in good to excellent yields.

Full text of DOI:10.1021/ol400049m

ORGANIC
LETTERS
2013
Vol. 15, No. 5
1056–1059
Synthesis of Novel Aryl and
Heteroaryl Acyl Sulfonimidamides
via Pd-Catalyzed Carbonylation
Using a Nongaseous Precursor
€
Sanjay R. Borhade, Anja Sandstrom,* and Per I. Arvidsson*
Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry BMC,
Uppsala University, Box 574, SE-751 23, Uppsala, Sweden
Per.Arvidsson@orgfarm.uu.se; Anja.Sandstrom@orgfarm.uu.se
Received January 8, 2013
ABSTRACT
Hitherto unexplored aryl and heteroaryl acyl sulfonimidamides have been prepared through the development of a new Pd-catalyzed carbonylation
protocol. This novel methodology, employing sulfonimidamides as nucleophiles and CO gas ex situ released from solid Mo(CO)6 in a sealed two-
chamber system, yields a wide range of carbamate protected acyl sulfonimidamides in good to excellent yields.
Sulfonimidamides, i.e. chiral analogues of sulfonamides
in which one of the sulfonamide O-atom has been replaced
by a N-atom, have received modest attention in the litera-
ture.1 Since the pioneering report on sulfonimidamides
fromthe Levchenko group intheearly1960s, the chemistry
of these hexavalent sulfur derivatives has long been over-
shadowed.2 Yet, in the past decade the Malacria and Dodd
groups have investigated the reactivity and applications
of sulfonimidamides in organic synthesis, mainly as a
N-source for metal-catalyzed nitrene transfer reactions,
for imination of sulfides using chiral nitrenes derived from
sulfonimidamides, and for CÀH insertion applications.3
Moreover, Bolm et al. explored sulfonimidamides as ligands
for transition-metal-catalyzed asymmetric synthesis and as
chiral organocatalysts.4 Also, a few reports, including pat-
ent applications, have revealed the usefulness of the sulfo-
nimidamide functional group in bioactive molecules. These
include synthesis of sulfonimidamide analogues of oncolytic
sulfonylureas, sodium channel antagonists, pesticidal agents,
and as transition state analogue inhibitors of aspartic acid
metalloproteases.5 Additionally, our group recently ratio-
nally explored sulfonimidamides as potential bioisosteres of
(4) (a) Worch, C.; Bolm, C. Synlett 2009, 2425. (b) Steurer, M.; Bolm,
C. J. Org. Chem. 2010, 75, 3301.
(5) (a) Toth, J. E.; Grindey, G. B.; Ehlhardt, W. J.; Ray, J. E.; Boder,
G. B.; Bewley, J. R.; Klinggerman, K. K.; Gates, S. B.; Rinzel, S. M.;
Schultz, R. M; Weir, L. C.; Worzalla, J. F. J. Med. Chem. 1997, 40, 1018.
(b) Gnamm, C.; Jeanguenat, A.; Dutton, A. C.; Grimm, C.; Kloer, D. P.;
Crossthwaite, J. Bioorg. Med. Chem. Lett. 2012, 22, 3800. (c) Kleemann,
H.-W.; Brendel, J.; Schwark, J. R.; Weichert, A.; Lang, H. J.; Albus, U.;
Scholz, W. EP0771788 A2, 1997 (Hoechst AG, Frankfurt am Main,
Germany), and Kleemann, H.-W.; Lang, H. J.; Schwark, J. R.; Weichert,
A.; Scholz, W.; Albus, U. US6057322 A, 2000 (Hoechst AG, Frankfurt am
Main, Germany). (d) Paulini, R.; Breuninger, D.; von Deyn, D.; Bastiaans,
H. M. M.; Beyer, C.; Anspaugh, D. D.; Oloumi-Sadeghi, H. (BASF SE,
Ludwigshafen, Germany), WO 2009/156336 A1, 2009 and Paulini, R.;
Breuninger, D.; von Deyn, D.; Bastiaans, H. M. M.; Beyer, C. WO 2011/
069955 A1, 2011 (BASF SE, Ludwigshafen,Germany).
(1) (a) Robak, M. T.; Herbage, M. A.; Ellman, J. A. Chem. Rev. 2010,
110, 3600. (b) Zhou, P.; Chen, B. C.; Davis, F. A. Tetrahedron 2004, 60,
8003. (c) Paitoon, R.; Harmata, M. Chemtracts 2006, 19, 143. (d) Collet,
F.; Dodd, R. H.; Dauban, P. Chem. Commun. 2009, 34, 5061. (e)
Carreno, M. C.; Hernandez-Torres, G.; Ribagorda, M.; Urbano, A.
Chem. Commun. 2009, 41, 6129.
(2) (a) Levchenko, E. S.; Sheinkman, I. E.; Kirsanov, A. V. Zh.
Obshch. Khim. 1960, 30, 1941. (b) Levchenko, E. S.; Derkach, N. Y.;
Kirsanov, A. V. Zh. Obshch. Khim. 1962, 32, 1208.
(3) (a) Leca, D.; Toussaint, A.; Mareau, C.; Fensterbank, L.; Lacote,
E.; Malacria, M. Org. Lett. 2004, 6, 3573. (b) Azzaro, S.; Desage-El
Murr, M.; Fensterbank, L.; Lacote, E.; Malacria, M. Synlett 2011, 849.
(c) Di Chenna, P. H.; Robert-Peillard, F.; Dauban, P.; Dodd, R. H. Org.
Lett. 2004, 6, 4503. (d) Liang, C.; Robert-Peillard, F.; Fruit, C.; Muller,
P.; Dodd, R. H.; Dauban, P. Angew. Chem., Int. Ed. 2006, 45, 4641.
(6) (a) Sehgelmeble, F.; Janson, J.; Ray, C.; Rosqvist, S.; Gustavsson,
S.; Nilsson, L. I.; Minidis, A.; Holenz, J.; Rotticci, D.; Lundkvist, J.;
Arvidsson, P. I. ChemMedChem 2012, 7, 396. (b) Maldonado, M. F.;
Sehgelmeble, F.; Bjarnemark, F.; Svensson, M.; Ahman, J.; Arvidsson,
P. I. Tetrahedron 2012, 68, 7456.
r
10.1021/ol400049m
Published on Web 02/08/2013
2013 American Chemical Society

sulfonamides in medicinal chemistry.6 We observed in-
creased solubility, decreased lipophilicity, and decreased
plasma protein binding with the sulfonimidamide containing
inhibitor, as compared to the corresponding sulfonamide.
As part of our current medicinal chemistry program,
aiming to develop novel HCV NS3 protease inhibitors, we
have had a long-standing interest in carboxylic acid bio-
isosteres.7 Among several explored groups, the acyl sulfo-
namide group was proven to yield the most potent inhibi-
tors for this target, a conclusion reflected in several of the
clinical candidates encompassing the acyl sulfonamide
group.8 Our most recent inhibitors encompass aryl based
acyl sulfonamides which allows for novel optimization
possibilities.9 Given the recent interest in sulfonimida-
mides as bioisosteres for sulfonamides, we became inter-
ested in exploring related acyl sulfonimidamides as car-
boxylic acid isosteres in our medicinal chemistry program.
We envisioned that attachment of an acyl group to the
sulfonimidamide should increase the acidity and thereby
qualify this functionality as a potential carboxylic acid re-
placement. Besides, the stereogenic tetrahedral sulfur center
and the additional points of diversity (i.e., the N-atom and
S-atoms), offer additional means to tune potency and
other properties of importance for drug design. Altera-
tion of the stereochemistry at the chiral sulfur atom might
also allow optimization to minimize off-target interactions,
thus achieving greater selectivity toward drug targets. Alto-
gether, these structural features offer unique optimization
possibilities related to this functionality that are not feasible
with other commonly used carboxylic acid bioisosteres, such
as tetrazole and isoxazolone. Indeed, Pemberton et al.
showed that the related cyclic analogue to the acyl sulfoni-
midamide possessed promising physicochemical properties
including a slightly acidic proton.10 In this respect we
became interested in studying linear acyl sulfonimidamides.
While evaluating methods for the preparation of this rather
unexplored functional group through a methodology that
would allow convenient access to a range of derivatives,
we concluded that such derivatives might be available
through a novel Pd-catalyzed carbonylation protocol
utilizing a protected sulfonimidamide function as a hitherto
unexplored nucleophile in this reaction.
We herein report, for the first time, the synthesis of carba-
mate protected aryl and heteroaryl acyl sulfonimidamides
(compounds of pharmaceutical interest) through a Pd-cata-
lyzed carbonylation process using ex situ generation of CO from
Mo(CO)6 as a solid source in a sealed two-chamber system.
Initially we screened reaction conditions on 4-iodo
anisole as a model aryl halide, N-Boc protected sulfonimi-
damide 1 as the nucleophile, and 1,8-diazabicycloundec-7-
ene (DBU)/triethylamine (TEA) as the base with 10 mol %
of palladium acetate in 1,4-dioxane solvent. A quick
screening of the effect of different CO reactants on the
yield of N-Boc protected aryl acyl sulfonimidamides 2 and
3 was performed, and the results are summarized in Table 1.
Gaseous CO at 75 psi in a pressure reactor afforded 51%
yield at 80 °C (Table 1, entry 1). However, the problems
associated with the invisible and odorless CO gas, such
as high toxicity and high flammability, limit its use in
modern carbonylative couplings.11 As an alternative,
CO-gas-free protocols that rely on solid or liquid reagents
with the ability to release CO in situ have been developed
as a safer, more convenient procedure.12 In this regard, we
also performed the amidocarbonylation of a sulfonimi-
damide nucleophile with molybdenum hexacarbonyl
(Mo(CO)6) as a solid CO source using microwave heat-
ing. However, the reaction was sluggish, possibly due to
degradation of the formed product, which resulted in very
poor yields of the isolated product after purification
(Table 1, entries 2À3). Recently, Skrydstrup et al. devel-
oped a user-friendly two-compartment reaction setup for
the Pd-catalyzed aminocarbonylation of aryl halides using
ex situ generation of CO gas from a CO releasing source.13
Successively, Larhed et al. used Mo(CO)6 as the CO releas-
ing source in a similar sealed two-chamber system.14 We
attempted this protocol for our amidocarbonylation of
sulfonimidamide using the base triethylamine (TEA) in
chamber A and 1,8-diazabicycloundec-7-ene (DBU) in
chamber B. To our delight, product 2 was successfully
isolated in 76% yield (Table 1, entry 5). It should be noted
that the difference in yield reported between entry 1 and
entries 4À5 (Table 1) was most probably related to the
€
€
(7) (a) Bergstrom, C. A. S.; Bolin, S.; Artursson, P.; Ronn, R.;
€
€
Sandstrom, A. Eur. J. Pharm. Sci. 2009, 38, 556. (b) Ronn, R.; Gossas,
˚
T.; Sabnis, Y. A.; Daoud, H.; Akerblom, E.; Danielson, U. H.;
€
Sandstrom, A. Biorg. Med. Chem. 2007, 15, 4057. (c) Johansson, A.;
˚
Poliakov, A.; Akerblom, E.; Wiklund, K.; Lindeberg, G.; Winiwarter,
S.; Danielson, U. H.; Samuelsson, B.; Hallberg, A. Biorg. Med. Chem.
2003, 11, 2551.
(8) (a) Raboisson, P.; Kock, H. D.; Rosenquist, A.; Nilsson, M.;
˚
€
Salvador-Oden, L.; Lin, T.-I.; Roue, N.; Ivanov, V.; Wahling, H.;
Wickstrom, K.; Hamelink, E.; Edlund, M.; Vrang, L.; Vendeville, S.;
€
Vreken, W. V. D.; McGowan, D.; Tahri, A.; Hu, L.; Boutton, C.; Lenz,
O.; Delouvroy, F.; Pille, G.; Surleraux, D.; Wigerinck, P.; Samuelsson,
B.; Simmen, K. Bioorg. Med. Chem. Lett. 2008, 18, 4853. (b) Condroski,
K. R. Z. H.; Seiwert, S. D.; Ballard, J. A.; Bernat, B. A.; Brandhuber,
B. J.; Andrews, S. W.; Josey, J. A.; Blatt, L. M. Digestive Disease Week,
May 20À25, Los Angeles, 2006, Poster #T1794. (c) Liverton, N. J.;
Carroll, S. S.; DiMuzio, J.; Fandozzi, C.; Graham, D. J.; Hazuda, D.;
Holloway, M. K.; Ludmerer, S. W.; McCauley, J. A.; McIntyre, C. J.;
Olsen, D. B.; Rudd, M. T.; Stahlhut, M.; Vacca, J. P. Antimicrob. Agents
Chemother. 2010, 54, 305. (d) Manns, M. P.; Bourliere, M.; Benhamou,
Y.; Pol, S.; Bonacini, M.; Trepo, C.; Wright, D.; Berg, T.; Calleja, J. L.;
White, P. W.; Stern, J. O.; Steinmann, G.; Yong, C. L.; Kukolj, G.;
Scherer, J.; Boecher, W. O. J. Hepatol. 2011, 54, 1114.
(11) (a) Beller, M.; Cornils, B.; Frohning, C. D.; Kohlpaintner, C. W.
J. Mol. Catal. A: Chem. 1995, 104, 17. (b) Skolda-Foldes, R.; Kollar, L.
Curr. Org. Chem. 2002, 6, 1097. (c) Barnard, C. F. J. Organometallics
ꢀ
2008, 27, 5402. (d) Modern Carbonylation Methods; Kollar, L., Ed.;
Wiley-VCH: Weinheim, 2008. (e) Brennf€uhrer, A.; Neumann, H.; Beller, M.
Angew. Chem., Int. Ed. 2009, 48, 4114. (f) Grigg, R.; Mutton, S. P.
Tetrahedron 2010, 66, 5515. (g) Wu, X.- F.; Neumann, H.; Beller, M.
Chem. Soc. Rev. 2011, 40, 4986.
(12) (a) Roy, S.; Roy, S.; Gribble, G. W. Tetrahedron 2012, 68, 9867.
(b) Odell, L. R.; Russo, F.; Larhed, M. Synlett 2012, 685. (c) Morimoto,
T.; Kakiuchi, K. Angew. Chem., Int. Ed. 2004, 43, 5580.
(13) (a) Friis, S.; Taaning, R.; Lindhardt, A.; Skrydstrup, T. J. Am.
Chem. Soc. 2011, 133, 18114. (b) Hermange, P.; Gogsig, T.; Lindhardt,
A.; Taaning, R.; Skrydstrup, T. Org. Lett. 2011, 13, 2444. (c) Hermange,
P.; Lindhardt, A. T.; Taaning, R. H.; Bjerglund, K.; Lupp, D.; Skrydstrup,
T. J. Am. Chem. Soc. 2011, 133, 6061.
˚
€
(9) Ronn, R.; Lampa, A.; Peterson, T.; Gossas, T.; Akerblom, E.;
ꢀ
€
Danielson, U. H.; Karlen, A.; Sandstrom, A. Biorg. Med. Chem. 2008,
16, 2955.
€
(10) Pemberton, N.; Graden, H.; Evertsson, E.; Bratt, E.; Lepisto,
M.; Johannesson, P.; Svensson, P. H. ACS Med. Chem. Lett. 2012, 3,
574.
(14) Nordeman, P.; Odell, L. R; Larhed, M. J. Org. Chem. 2012, 77,
11393.
Org. Lett., Vol. 15, No. 5, 2013
1057

Table 1. Evaluation of Different CO Sources for the
Pd-Catalyzed Carbonylation Reaction between
Sulfonimidamides and 4-Iodoanisolea
Table 2. Optimization of the Amidocarbonylation between
Sulfonimidamides and 4-Iodoanisolea
entry
solvent
base
TEA
TEA
TEA
TEA
TEA
TEA
TEA
Pd-catalyst
yield (%)d
CO
time
1
1,4-dioxane
1,4-dioxane
1,4-dioxane
THF
CH3CN
DMF
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(PPh3)4
Pd/C
76
54
63
73
59
68
43
53
46
57
26
39
13
72
48
entry
PG
Boc
source
product
(min)
yield (%)d
2b
3c
4
1a
2b
3b
4c
5c
CO (75 psi)
Mo(CO)6
Mo(CO)6
Mo(CO)6
Mo(CO)6
2
2
3
2
2
45
45
45
60
120
51
19
29
69
76
Boc
5
6
7
8
CO2Et
Boc
toluene
DCE
Boc
TEA
a Reaction conditions: sulfonimidamide (0.393 mmol, 1.0 equiv),
4-iodoanisole (0.984 mmol, 2.5 equiv), Pd(OAc)2 (10 mol %, 0.1 equiv),
DBU (0.984 mmol, 2.5 equiv), 1,4-dioxane (3.0 mL). b Mo(CO)6 (0.589
mmol, 1.5 equiv) was used as a CO-releasing reagent, and the reaction
mixture was heated by microwave irradiation. c Ex situ generation of CO
gas from Mo(CO)6 in a sealed two-chamber system (maximum expected
CO pressure in the system is 20À30 psi).14 Chamber A: sulfonimidamide
(0.393 mmol, 1.0 equiv), 4-iodoanisole (0.984 mmol, 2.5 equiv), triethyl-
amine (0.984 mmol, 2.5 equiv), Pd(OAc)2 (10 mol %, 0.1 equiv) in
dioxane (2.5 mL). Chamber B: Mo(CO)6 (0.589 mmol, 1.5 equiv), DBU
(0.984 mmol, 2.5 equiv) in dioxane (2.5 mL). d Isolated yields.
9
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
DIPEA
DBU
NaOAc
Cs2CO3
NaHCO3
TEA
10
11
12
13
14
15
TEA
a Reaction conditions: Chamber A: sulfonimidamide (0.393 mmol,
1.0 equiv), 4-iodoanisole (0.984 mmol, 2.5 equiv), trietylamine (0.984 mmol,
2.5 equiv), Pd(OAc)2 (10 mol %, 0.1 equiv) in dioxane (2.5 mL). Chamber B:
Mo(CO)6 (0.589 mmol, 1.5 equiv), DBU (0.984 mmol, 2.5 equiv) in
dioxane (2.5 mL). b Reaction performed at 60 °C. c 5.0 mol % of Pd(OAc)2
was used. d Isolated yields.
actual bases used. In entry 1, DBU was used as the base, in
a single vial. In entries 4À5, using the two-compartment
system, TEA was used as the base to regenerate Pd(0)
species in chamber A and DBU to release CO gas in
chamber B. Indeed, a similar yield (57%) was observed
when we used DBU as the base in both chambers (vide
infra, Table 2, entry 10), supporting the effect from bases
on the yield. Using the two-chamber protocol, workup
was simplified due to the absence of Mo-containing
complexes formed during the reaction, and we did not
observe any problems with product purification or with
degradation under conventional heating. Furthermore,
compounds containing aromatic nitro groups, which
normally undergo reduction in the presence of Mo(CO)6
in a single vial,15 are now possible substrates for carbo-
nylation reactions. Thus, we decided to perform the Pd-
catalyzed carbonylation reactions in the two-chamber
system for all aryl and heteroaryl acyl sulfonimidamides
prepared throughout this work.
Next, the influence of various reaction parameters such
as temperature, time, Pd-source, Pd-concentration, effects
of solvents, and bases was examined using a two-chamber
sealed vessel (Table 2). The optimization study concluded
that the best yields (76%) were obtained with 1,4-dioxane
as the solvent and triethylamine as the base over 10 mol %
ofPd(OAc)2 at 80 °C for 2 h. Reactions carried out at60°C
or with reduced Pd-concentration to 5 mol % lowered the
yields (Table 2, entries 2À3). Among the solvents studied,
1,4-dioxane, tetrahydrofuran, and dimethylformamide
gave the best yields (entries 1, 4, 6). The use of a nonpolar
solvent (i.e., toluene) resulted in lower yields (43%, entry 7).
Organic bases were superior to inorganic bases, possibly
due to the partial inhomogeneity of inorganic bases in
the reaction mixture (entries 1, 9À10 vs 11À13). There
was no further advantage in changing the Pd-source to
Pd(PPh3)4, since a similar yield of product was provided
as compared to using Pd(OAc)2 (entries 1, 14). However,
Pd loaded onto the carbon support (Pd/C) was less successful
(48% yield, entry 15).
To establish the scope of amidocarbonylation, the opti-
mized reaction conditions were then applied to a wide
range of aryl iodides and bromides and various aryl sulfo-
nimidamide nucleophiles to deliver corresponding pro-
tected acyl sulfonimidamides (Table 3). The effect of differ-
ent N-protecting groups on the sulfonimidamide was studied,
and no significant difference was observed when changing the
protecting group from N-Boc 2 (76%) to N-Bz 4 (81%).
However, the yield was reduced marginally when N-CO2Et 3
(62%) was used as the protecting group on sulfonimidamide.
Because of its comparatively easy removal N-Boc was se-
lected in the forthcoming experiments.
Amidocarbonylation of N-Boc protected sulfonimi-
damides with aryl iodides proceeded with 10 mol % of
Pd(OAc)2 for 2 h. In contrast, aryl bromides required the
use of 10 mol % Pd(dppf)Cl2/DCM catalyst and a 4 h
reaction duration to offer comparable yields to aryl
iodides.16 Different N-Boc protected sulfonimidamides
were carbonylated with 4-iodoanisole, providing products in
(15) Spencer, J.; Anjum, N.; Patel, H.; Rathnam, R. P.; Verma, J.
Synlett 2007, 2557.
1058
Org. Lett., Vol. 15, No. 5, 2013

Table 3. Synthesis of Aryl Acyl Sulfonimidamidesa
Scheme 1. Synthesis of Heteroaryl Acyl Sulfonimidamidea
prod.
R
R1
Boc
Boc
CO2Et
COPh
R2
R3
X
yield (%)b
2a
2b
3
4
5
6
7
8
9
10
11a
11b
12
13a
13b
14
15
16
17
18
19
20
21
22c
23
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
4-Br
4-Cl
2-Cl, 4-Cl
H
H
4-Me
4-CN
4-CN
4-F
4-CF3
4-Ac
2-NO2
3-NO2
4-NO2
4-CO2Et
4-Ph
I
Br
I
I
I
I
I
I
I
I
I
Br
I
I
Br
Br
Br
I
I
I
76
73
62
81
74
67
61
75
78
59
72
69
71
78
74
82
78
63
53
87
78
76
79
66
13
4-Me Boc
4-Cl Boc
4-CF3 Boc
H
Boc
4-Cl Boc
4-Cl Boc
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
a Reaction conditions: Chamber A: sulfonimidamide (1.0 equiv), aryl
halide (2.5 equiv), triethylamine (2.5 equiv), Pd(dppf)Cl2 DCM (10 mol %)
3
I
Br
Br
in dioxane (2.5 mL). Chamber B: Mo(CO)6 (1.5 equiv), 1,8-diazabicycloun-
dec-7-ene (2.5 equiv) in dioxane (2.5 mL).
3f4(ÀCO(CH2)2CH2À) Br
Me 4-OMe
I
sulfonimidamide without further optimization. Scheme 1
depicts that the methodology is applicable to a wide range of
heterocycles such as five-membered furan and thiophene,
six-membered pyridine and pyrimidine, and fused systems
(26, 28À29).
a Reaction conditions:Chamber A: sulfonimidamide (1.0 equiv), aryl
halide (2.5 equiv), triethylamine (2.5 equiv), Pd(OAc)2 (10 mol %) in
dioxane (2.5 mL). Chamber B: Mo(CO)6 (1.5 equiv), DBU (2.5 equiv) in
dioxane (2.5 mL). For aryl bromides: Pd(dppf)Cl2.DCM (10 mol %) was
used as the catalyst, and reaction duration was 4 h. b Isolated yields.
c 7-Bromo-3,4-dihydronapthalen-1(2H)-one used as aryl halide.
In summary, we report a novel synthesis of linear and
protected acyl sulfonimidamides, a rarely explored chemi-
cal group in organic/medicinal chemistry, by means of Pd-
catalyzed carbonylations of aryl and heteroaryl iodides
and bromides with sulfonimidamides as nucleophiles. The
reaction shows high functional group tolerance and pro-
vides good to excellent yields of carbamate protected acyl
sulfonimidamides. We anticipate great potential for this
novel functional group as a unique carboxylic acid bioisos-
tere. Next, we plan to explore the physicochemical properties
of linear acyl sulfonimidamides and their deprotected ana-
logues, as well as their pharmacological qualities.
moderate to good yields (5À7). In general, a variety of
functional groups were tolerated, and the reaction proceeded
efficiently with meta- and para-substituted aryl halides.
However, ortho-substitution on the aryl halide ring lowered
the yield [10 (59%) and 17 (53%)]. It is also worth noting
that complete chemoselectivity for iodine over bromine and
chlorine was achieved in the reactions (8À10). Furthermore,
products derived from o-, m-, and p-iodonitrobenzenes
(17À19) were isolated in excellent yields, which further
demonstrate the advantage of using the two-chamber sealed
system where CO gas is generated ex situ from Mo(CO)6.
Although the optimized protocol was high-yielding with all
of the investigated aryl iodides and bromides, there seems to
be a limitation using secondary sulfonimidamides since
N-methylated 23 was isolated in only 13% yield.
Acknowledgment. Weare grateful toProf. MatsLarhed
Department of Medicinal Chemistry, Uppsala University,
for helpful discussions and review of this manuscript. S.R.B.
is thankful to the Erasmus-Mumdus EXPERTS Foun-
dation for providing financial support.
Having established an excellent scope with aryl iodides
and bromides, the usefulness of the protocol with
heteroaryl halides as substrates was addressed (Scheme 1).
Gratifyingly, the conditions optimized for aryl bro-
mides provided moderate to good yields of heteroaryl acyl
Supporting Information Available. Experimental pro-
cedures and full characterization data with copies of
spectra for all the compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
(16) Aryl bromides gave a very poor yield (11%) when we used
10 mol% Pd(OAc)2 catalyst.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 5, 2013
1059