The tertiary sulfonamide as a latent directed-metalation group: Ni 0-catalyzed reductive cleavage and cross-coupling reactions of aryl sulfonamides with Grignard reagents

Article abstract of DOI:10.1002/anie.200352633

A mild method for the Ni⁰-catalyzed hydrodesulfamoylation (see scheme, B) of aryl sulfonamides (1→2) with iPr₂Mg or iPrMgCl as β-hydride transfer sources can be linked with directed ortho metalation (A and C) to give meta-substituted aromatics 2. Cross-coupling process with alkyl and aryl Grignard reagents furnish disubstituted benzenes and bi- and teraryl compounds.

Full text of DOI:10.1002/anie.200352633

Communications
Cross-Coupling Reactions
The Tertiary Sulfonamide as a Latent Directed-
Metalation Group: Ni0-Catalyzed Reductive
Cleavage and Cross-Coupling Reactions of Aryl
Sulfonamides with Grignard Reagents
Robert R. Milburn and Victor Snieckus*
In the rich portfolio of transition-metal-catalyzed cross-
coupling reactions that have been added to the synthetic
chemist's repertoire during the last thirty years,[1] sulfur-based
leaving groups of the organometallic coupling partners have
been underdeveloped. Thus application of sulfur groups in
modern cross-coupling chemistry has been largely neglected
in favor of the highly successful and readily available halo,[2]
triflate,[3] and, to some extent, O-carbamate[4] leaving groups
in combination with various aryl metal partners. Exception-
ally, Wenkert et al.[5] demonstrated coupling of sulfur deriv-
atives in several oxidation states with RMgX reagents (1!2),
our group[6,7] and Julia and co-workers[8] married the directed
ortho metalation strategy with the Corriu–Kumada–Tamao
reaction to allow access to 1,3-di- and 1,2,3-trisubstituted
benzenes, (e.g., 3!4), and Takei and co-workers[9] explored
the cross-coupling of vinyl sulfones, and the coupling of aryl
sulfonates (5!6) was recently reported (Scheme 1).[10]
Herein we report that tertiary aryl sulfonamides undergo
Ni0-catalyzed reductive cleavage with b-hydride donors
(iPr2Mg or iPrMgCl)[11] under especially mild conditions,
[*] R. R. Milburn, Prof. V. Snieckus
Department of Chemistry, Queens University
Kingston, Ontario, K7L 3N6 (Canada)
Fax : (+1)613-533-6089
E-mail: snieckus@chem.queensu.ca
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
888
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DOI: 10.1002/anie.200352633
Angew. Chem. Int. Ed. 2004, 43, 888 –888

Angewandte
Chemie
Table 1: Ni0-catalyzed reduction of monosubstituted aryl sulfonamides.
Entry
7
G
8
Yield [%][a]
1
2
3
4
5
6
7
8
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
H
2-Me
3-Me
4-Me
2-CONEt2
4-CONEt2
2-N(Me)Ph
4-N(Me)Ph
2-OMe
2-OCH2Ph
2-Oi-Pr
3-OMe
4-OMe
2-TMS
4-TMS
2-(p-MeO-C6H4)
4-(p-MeO-C6H4)
a
b
b
b
c
c
d
d
e
f
g
e
e
h
h
i
(74)
(74)
(94)
(56)
60(64)
58(67
53
18
(97)
68
9
10
11
12
13
14
15
16
17
59
(91)
(18)
(48)
(76)
90
Scheme 1. Application of sulfur leaving groups in modern cross-cou-
pling chemistry. acac=acetylacetonate; dppf=1,1’-bis(diphenylphos-
phanyl)ferrocene.
i
85
[a] Values in parenthesis indicate yields determined by GC analysis.
TMS=trimethylsilyl.
(Tables 1 and 2) and cross-coupling with Grignard reagents
(Table 3), thus presenting a new directed ortho metalation—
connected methodology for the construction of polysubsti-
tuted aromatic and biaryl compounds. The hydrodesulfamoyl-
ation reaction establishes a latent quality to the powerful
sulfonamide directed-metalation group[12] and thereby allows
the construction of 1,3-disubstituted aromatic compounds
(Table 2), which are unavailable by traditional electrophilic
aromatic substitution protocols. The increasing prominence
of aryl sulfonamides as commercial entities or lead-drug
candidates[13] constitutes an appropriate backdrop in which
this new chemistry may find application and extension.
Table 1 summarizes the initial results of the Ni-catalyzed
hydrodesulfamoylation reaction of substituted tertiary aryl
sulfonamides, 7!8.[14] Several qualitative trends in the
screened aryl sulfonamides deserve attention. The reaction
is very sensitive to both steric and electronic effects. Large
ortho substituents (Table 1, entries 7, 11, 14) and para-
substituted electron-donating groups (Table 1, entries 8, 13)
promote lower yields. Groups ortho to the sulfonamide that
are capable of metal coordination[15] (Table 1, entry 9) appear
to enhance the yield significantly, which may also be used to
overcome inhibitory effects of electron-donating substituents
(compare Table 1, entries 8 and 13with Table 2, entries 4 and
2, respectively).
Scheme 2. Heteroaryl sulfonamides and sultams for the hydrodesulfa-
moylation reaction.
To develop a new combined directed ortho metalation–
hydrodesulfamoylation route to meta-substituted aromatic
compounds that overrides the standard electrophilic substi-
tution approach, a selected group of aryl sulfonamides,
readily available from inexpensive commercial entities, was
tested (13!14, Table 2). Thus, prototypes of 1,3-dioxygen-
ated (Table 2, entries 2, 8, 9) and 3-aminoanisole (Table 2,
entry 4) were obtained in modest to good yields. Additional
synthetic advantage is gained by the availability of products
that originate from Negishi cross-coupling[17] (Table 2,
[18]
ꢀ
entry 7) and Buchwald–Hartwig C N coupling
entry 4) regimens.
(Table 2,
As a further test of scope, cyclic and other aryl and
heteroaryl sulfonamides were subjected to the representative
hydrodesulfamoylation conditions (Scheme 2). Thus N,N-
diethyl-1-naphthalenesulfonamide (9) furnished naphthalene
in moderate yield (59%) while the N-methyl-1,8-naphthalene
sultam (10) afforded the reductive SO2 extrusion product, N-
methyl-1-naphthylamine in 43% yield.[16] N,N-Diethylpyridi-
nesulfonamide (11) gave pyridine in 29% yield (complete
consumption of starting material) while the corresponding 2-
thiophenesulfonamide (12) was quantitatively recovered.
To take advantage of the mechanistic implications of the
above results, the cross-coupling of aryl sulfonamides with
Grignard reagents was studied (7!15, Table 3). Screening of
catalysts led to optimization using the [Ni(acac)2]–bidentate
phosphane ligand (dppp) combination, although higher
temperatures were required to achieve efficient coupling.[19]
Electronic effects appear to have little influence on the yields
of products (Table 3, entries 3, 7, and 9) while comparison of
ortho and para substituents shows consistently lower yields
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Communications
Table 2: Ni0-catalyzed reduction of di- and trisubstituted aryl sulfon-
amides.
ortho metalation potential of 7p,q followed by the above
modular coupling approach may be envisaged.
[20]
ꢀ
The established oxidative addition into the C S bond
for most oxidation states of sulfur, including sulfonates[5,8,9]
suggest a similar mechanistic path for the aryl sulfonamide–
Grignard desulfamoylation and cross-coupling reactions.
Reduction of N,N-diethyl-2,6-dimethoxy-4-trimethylsilyl-
benzenesulfonamide (Table 2, entry 9) with [D7]iPrMgBr
afforded 1,3-dimethoxy-5-trimethylsilylbenzene (85%[D] by
Entry
13
G
14
Yield [%][a]
1
2
3
4
5
6
7
8
9
a
b
c
d
e
f
g
h
i
4-TMS
4-OMe
4-Me
4-N(Me)Ph
4-NBn2
a
b
c
d
e
f
g
h
i
91
(87)
(80)
77
10
63
89
(54)
53(60)
1
2
GC–MS, H- and H NMR) supports the proposed mecha-
nism. These results, in combination with regiospecific cross-
coupling of aryl sulfonamides with aryl Grignard reagents
(Table 3), suggest that the aryl sulfonamide cross-coupling
reaction proceeds predominantly through the catalytic cycle
proposed for the Corriu–Kumada–Tamao reaction.[11]
4-Cl
6-(p-MeO-C6H4)
6-OMe
6-OMe, 4-TMS
In conclusion, a new Ni0-catalyzed aryl sulfonamide–
Grignard reagent reaction has been developed, which pro-
vides reductive desulfamoylation (Et2O, room temperature)
and cross-coupling (toluene/reflux)[21] processes of synthetic
interest. The former reaction, paralleling the work of Julia
and co-workers[8] on aryl-tert-butyl sulfones, allows the
powerful sulfonamide directed-metalation group to act in a
latent capacity, thus providing a route to aromatic compounds
with 1,3-substitution patterns (Table 2) which are in opposi-
tion to those available, usually as mixtures, by classical
electrophilic aromatic substitution chemistry. The cross-
coupling process represents a new variant of the Corriu–
Kumada–Tamao protocol but enjoys the advantage of the
directed ortho metalation connection (Table 3).[22] Although
the sensitivity of the reaction to both electronic and steric
effects somewhat constrains functional-group flexibility, the
enhancing, unprecedented ortho coordination group effect
bodes well for further synthetic utility.[23]
[a] Values in parenthesis indicate yields determined by GC analysis.
Table 3: Ni0-catalyzed cross-coupling of aryl sulfonamides.
Entry
7
G
R
15
Yield [%][a]
1
2
3
4
5
6
7
8
9
i
i
2-OMe
2-OMe
4-OMe
2-(p-MeO-C6H4)
4-(p-MeO-C6H4)
2-Me
4-Me
2-TMS
Me
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
a
b
i
c
d
e
f
(60)
52
79
65
72
(69)
(80)
(73)
(84)
m
p
q
b
d
n
o
g
h
4-TMS
[a] Values in parenthesis indicate yields determined by GC analysis.
Experimental Section
for the former with the exception of the OMe group (Table 3,
entries 2 vs. 3, 6 vs. 7, 8 vs. 9).
Representative Procedure for Desulfamoylation: iPr2Mg (5.4 mL,
0.65m in tBuOMe, 3.6 mmol) was added to a solution of 7q (510 mg,
1.6 mmol) and [Ni(acac)2] (20.0 mg, 0.08 mmol) in a mixture of Et2O
(20 mL) and tBuOMe (15 mL) at room temperature, and the reaction
mixture was stirred for 8 h. The reaction mixture was cooled in an ice
bath and quenched with saturated aqueous NH4Cl solution, parti-
tioned between Et2O and H2O, and the organic layer was extracted
twice with Et2O. The combined organic layer was washed twice with
saturated aqueous NH4Cl solution, and then once with H2O, and once
with brine. The solution was dried (Na2SO4), and the solvent was
removed in vacuo to give 8i[24] (249 mg, 85%) as a colorless solid after
column chromatography (20:1 hexane/EtOAc). M.p. 82–838C
To demonstrate the iterative cross-coupling potential,
haloaryl sulfonamides (Scheme 3, 16a,b) were subjected to
Negishi cross-coupling to afford biaryl compounds 7p,q
which, upon sulfonamide–PhMgBr coupling, furnished ter-
aryls 15c,d in good overall yields. Further regioselective
polyaryl construction by taking advantage of the directed
1
(hexane); H NMR (200 MHz): d = 7.58–7.22 (m, 6H), 6.97 (d, 2H,
J = 8.9 Hz), 3.84 ppm (s, 3H); 13C NMR (50.3MHz): d = 159.2, 140.8,
133.8, 128.7, 128.1, 126.7, 126.6, 114.2, 55.3 ppm; LRMS (EI): m/z
(%): 184 [M+] (100), 169 [M ꢀ 15] (60), 141 (61), 115 (37).
Representative Procedure for Cross-Coupling: PhMgBr
(1.33 mL, 3.0m in Et2O, 4.0 mmol) was added to a solution of 7p
(319 mg, 1.0 mmol), [Ni(acac)2] (13.0 mg, 0.05 mmol), and dppp
(13.0 mg, 0.10 mmol) in toluene (10 mL), and the reaction mixture
was heated at reflux for 6 h. The reaction mixture was cooled in an ice
bath, quenched with saturated aqueous NH4Cl solution, partitioned
between EtOAc and H2O, and the organic components were
extracted twice with EtOAc. The combined organic layer was
washed twice with saturated aqueous NH4Cl solution, once with
H2O, and once with brine. The solution was dried (Na2SO4), and the
Scheme 3. Iterative Negishi/Kumada cross-coupling of haloaryl sulfon-
amides to furnish teraryls. dppp=propane-l,3-diylbis(diphenylphos-
phane).
890
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Angewandte
Chemie
solvent was removed in vacuo to give 15c[25] (168 mg, 65%) as a
colorless oil after chromatography (50:1 hexane/Et2O). 1H NMR
(200 MHz): d = 7.62–7.50 (m, 4H), 7.45–7.30 (m, 4H), 7.21 (d, 2H, J =
8.9 Hz), 6.90 (d, 2H, J = 8.9 Hz), 3.89 ppm (s, 3H); 13C NMR
(50.3MHz): d = 159.0, 142.4, 141.1, 140.8, 134.6, 131.6, 131.3, 131.2,
130.5, 129.4, 128.5, 128.1, 127.7, 127.4, 127.0, 114.0, 55.7 ppm.
Chem. 2003, 11, 1371; N. Murugesan, Z. Gu, S. Spergel, M.
Young, P. Chen, A. Mathur, L. Leith, M. Hermsmeier, E. C.-K.
Liu, R. Zhang, E. Bird, T. Waldron, A. Marino, B. Koplowitz,
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Received: August 12, 2003 [Z52633]
Keywords: arenes · cross-coupling · magnesium · nickel ·
.
[14] Excess Grignard reagent was necessary. [Ni(cod)] (cod = cyclo-
octa-1,5-diene), NiCl2, and Ni(OAc)2 gave negligible reduction.
[NiCp2] was found to be an effective catalyst. The control
experiment without catalyst gave no reaction. Catalyst loadings
of 1 mol% gave slightly lower yields. Use of THFand hexanes as
solvents and the addition of phosphane ligands gave poor yields.
The nature of the amine portion of the sulfonamide (e.g.
sterically demanding or aromatic) had a negligible influence on
the yield. Secondary amines were inert to the reaction con-
ditions, possibly due to the insolubility of their magnesium salts.
[15] M. Alami, C. Amatore, S. Bensalem, A. Choukchou-Brahim, A.
Jutand, Eur. J. Inorg. Chem. 2001, 2675.
[16] Other cyclic sulfonamides gave synthetically unproductive
results: 2-methyl-3,3-diphenyl-2,3-dihydro-benzo[d]isothiazole
1,1-dioxide was inert while 2-methyl-1,1-dioxo-1,2-dihydro-D6-
benzo[d]isothiazol-3-one (N-methyl saccharin) gave N-methyl-
benzamide in 15% yield.
[17] For Suzuki cross-coupling chemistry of aryl sulfonamides, see:
S. L. MacNeil, O. B. Familoni, V. Snieckus, J. Org. Chem. 2001,
66, 3662.
[18] H Tomori, J. M. Fox, S. L. Buchwald, J. Org. Chem. 2000, 65,
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[19] Use of Pd(OAc)2, [Pd(PPh3)4] and [Pd(dppp)]Cl2 resulted in
complex mixtures. The [NiCl2]–dppp combination was an
ineffective catalyst, while under [Ni(acac)2] alone, cross-cou-
pling products were obtained in low yields.
[20] E. Wenkert, M. E. Shepard, A. T. McPhail, J. Chem. Soc. Chem.
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[21] Recently, the conversion of 7i!15b (Table 3) was effected at
room temperature in 54% yield in the presence of catalytic
[CpNi(IMes)Cl]: C. D. Abernethy, A. H. Cowley, R. A. Jones, J.
Organomet. Chem. 2000, 596, 3; R. R. Milburn, A. Pla, V.
Snieckus, unpublished results (Mes = mesityl = 2,4,6-trimethyl-
phenyl).
[22] For other directed ortho metalation–cross-coupling links, see: J.-
G. Anctil, V. Snieckus, J. Organomet. Chem. 2002, 653, 150.
[23] For the use of reductive chemistry in the development of a new
amine-protecting group, see subsequent communication in this
issue: R. R. Milburn, V. Snieckus, Angew. Chem. 2004, 116, 910;
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Angew. Chem. Int. Ed. 2004, 43, 888 –891
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