Copper-catalyzed C-N cross-coupling of sulfondiimines with boronic acids

Article abstract of DOI:10.1021/ol401642n

The copper-catalyzed C-N cross-coupling of sulfondiimines with boronic acids has been developed. The reaction proceeds at room temperature in good to excellent yields and provides access to a variety of N,N′-disubstituted sulfondiimines, including N-(hetero)aryl sulfondiimines and the first reported N-alkenylated sulfondiimine.

Full text of DOI:10.1021/ol401642n

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Copper-Catalyzed CꢀN Cross-Coupling of
Sulfondiimines with Boronic Acids
Rebekka Anna Bohmann and Carsten Bolm*
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1,
D-52074 Aachen, Germany
carsten.bolm@oc.rwth-aachen.de
Received June 11, 2013
ABSTRACT
The copper-catalyzed CꢀN cross-coupling of sulfondiimines with boronic acids has been developed. The reaction proceeds at room temperature
in good to excellent yields and provides access to a variety of N,N0-disubstituted sulfondiimines, including N-(hetero)aryl sulfondiimines and the
first reported N-alkenylated sulfondiimine.
In the past decades, sulfoximines have attracted signifi-
cant attention due to their biological activity. In particular,
N-(hetero)aryl sulfoximines have been investigated as
anticancer agents1 or agrochemicals.2 Replacement of the
sulfoximine oxygen by nitrogen leads to a surprisingly
unexplored class of tetracoordinated diaza analogues,
namely the sulfondiimines. Despite possessing numerous
intriguing properties, since their discovery in 19643 these
high-valent sulfur compounds have been underrepresented
in chemical literature, and to date, only a few applications
exist.4ꢀ6 Since our group reported the NCS-mediated
oxidative imination of sulfiliminium salts,7 a broad variety
of NH-sulfondiimines are readily accessible, and further
derivatization appeared desirable. In this context, we
recently described the N-arylation of NH-sulfondiimines
by palladium-catalyzed cross-coupling with aryl bro-
mides.8 Although this method provided access to a series
of N,N0-disubstituted products, it suffered from several
disadvantages, such as harsh reaction conditions including
high reaction temperatures and the requirement of expen-
sive palladium catalysts. Furthermore, the use of a glove-
box was crucial, and the product scope was limited. As
such, the development of a more experimentally simple
and cost-efficient method for the synthesis of a more
diverse library of sulfondiimines, in particular toward
N-(hetero)aryl sulfondiimines, appeared desirable. We
herein report an advancement in this area with the devel-
opment of a copper-catalyzed CꢀN cross-coupling of
sulfondiimines with boronic acids.
Inspired by a method previously developed in our group
for the N-arylation of NH-sulfoximines,9 the ChanꢀLam
type cross-coupling reaction of sulfondiimine 1a with phenyl-
boronic acid (2a) was initially investigated.10,11 Early
attempts were performed using 10 mol % of Cu(OAc)2 in
dry MeOH at room temperature with 2.3 equiv of the
(1) For N-(hetero)aryl sulfoximines showing anticancer activity, see:
(a) Shetty, S. J.; Patel, G. D.; Lohray, B. B.; Lohray, V. B.; Chakrabarti,
G.; Chatterjee, A.; Jain, M. R.; Patel, P. R. WO Patent 077574 (A2),
2007. (b) L€ucking, U.; Siemeister, G.; Jautelat, R. WO Patent 099974 (A1),
2006.
(2) For N-(hetero)aryl sulfoximines as agrochemicals, see: Kajita, S.;
Miyashita, Y.; Shibayama, K.; Tamai, T.; Tsukuda, K.; Yamada, S.;
Yamaguchi, M. WO Patent 035737 (A1), 2008.
(3) Cogliano, J. A.; Braude, G. L. J. Org. Chem. 1964, 29, 1397.
(4) For sulfondiimines in heterocyclic chemistry, see: (a) Ried, W.;
Jacobi, M. A. Chem. Ber. 1988, 121, 383. (b) Diederich, W. E.; Haake,
M. J. Org. Chem. 2003, 68, 3817.
(8) Candy, M.; Bohmann, R. A.; Bolm, C. Adv. Synth. Catal. 2012,
354, 2928.
(5) For sulfondiimines in pseudopeptides, see: Dehli, J. R.; Bolm, C.
Synthesis 2005, 1058.
(9) Moessner, C.; Bolm, C. Org. Lett. 2005, 7, 2667.
(10) For other ChanꢀLam reactions and the proposed mechanism,
see: (a) Qiao, J. X.; Lam, P. Y. S. Synthesis 2011, 829 and references
therein. (b) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42,
5400 and references therein.
(6) For sulfondiimines in methods development, see: (a) Georg, G. I.;
Pfeifer, S. A.; Haake, M. Tetrahedron Lett. 1985, 26, 2739. (b)
Yoshimura, T.; Fujie, T.; Fujii, T. Tetrahedron Lett. 2007, 48, 427.
(7) Candy, M.; Guyon, C.; Mersmann, S.; Chen, J.-R.; Bolm, C.
Angew. Chem., Int. Ed. 2012, 51, 4440.
(11) For more details on the synthesis of the starting materials,
see ref 7.
r
10.1021/ol401642n
XXXX American Chemical Society

phenylboronic acid affording the N-phenylated product
3a in 85% yield (Table 1, entry 1).
and trifluoromethylboronic acid afforded products 3d and
3e in yields of 90% and 89% (Table 2, entries 2ꢀ5). In
addition, 4-biphenyl- and 2-naphthylboronic acid reacted
well affording the products3fand 3gin84% and94%yield
(Table 2, entries 6 and 7).
To further explore this reaction process, alternate cop-
per salts [both Cu(I) and Cu(II)] and solvents were eval-
uated. Results showed that copper salts other than
anhydrous Cu(OAc)2 and solvents other than anhydrous
methanol led to lower yields and reactivity. As reported for
literature-known reactions,10 the amount of oxygen and
water present in the reaction flask proved to have a
significant impact on the transformation. While incom-
plete conversions and low yields were observed in an argon
atmosphere (64%; Table 1, entry 2), exclusion of moisture
by a CaCl2-drying tube afforded sulfondiimine 3a in the
best yield (85%; Table 1, entry 1). Other reactions per-
formed in an oxygen atmosphere or with the addition of
molecular sieves led to lower yields of the desired product
3a (both 82%; Table 1, entries 3ꢀ4).
Table 2. Cross-Coupling of Sulfondiimine 1a with Boronic
Acids 2aꢀq
product, yield
entry
R1-, boronic acid 2
C6H5- (2a)
(%)a
Table 1. Optimization of the Reaction Conditions
1
3a, 85
3b, 72
3c, 67
3d, 90
3e, 89
3f, 84
3g, 94
3h, 94
3i, 85
3j, 87
3k, 85
3l, 51
ꢀ
2
4-MeO-C6H4- (2b)
4-MeS-C6H4- (2c)
4-Ac-C6H4- (2d)
3
4
5
3-F3C-C6H4- (2e)
4-biphenyl- (2f)
6
7
2-naphthyl- (2g)
2-Br-C6H4- (2h)
8
9
2-Cl-C6H4- (2i)
10
11
12
13
14
15
16
17
4-Me-C6H4- (2j)
Cu(OAc)2
(mol %)
3a, yielda
3-Me-C6H4- (2k)
2-Me-C6H4- (2l)
entry
2 (equiv)
(%)
2,4,6-Me3-C6H4- (2m)
6-Cl-pyridin-3-yl- (2n)
thiophen-3-yl- (2o)
5-indolyl- (2p)
1
2
3
4
5
6
7
8
10
10
10
10
10
10
5
2a (2.3)
2a (2.3)
2a (2.3)
2a (2.3)
2a (1.0)
2a (2.0)
2a (2.3)
2ab (2.3)
85
64b
82c
82d
50
3n, 84
3o, 82
3p, 61b
3q, 41b
benzo[b]thien-3-yl- (2q)
79
a After column chromatography, moisture excluded by CaCl2-drying
tube. b Reaction performed for 40 h.
79
37e
10
a Yields after column chromatography; moisture excluded by CaCl2-
drying tube. b Under argon atmosphere. c Under oxygen atmosphere.
d Addition of molecular sieves. e Reaction performed for 40 h at 40 °C.
Notably, in contrast to the previously reported pro-
cedure,8 this method facilitated the preparation of bromo-
and chloro-substituted products 3h and 3i (94% and 85%,
respectively; Table 2, entries 8 and 9). Of particular inter-
est, the carbonꢀhalogen bond was preserved during the
reaction process and remains amenable to further trans-
formation by classical cross-coupling reactions. Steric
factors notably affected the reactivity, as illustrated in
the case of methylphenylboronic acid: while para- and
meta-substituted derivatives 2j and 2k reacted well (87%
and 85% yield, respectively), the corresponding ortho-
substituted boronic acid 2l (51% yield) resulted in a
significant decrease in yield, and the sterically hindered
2,4,6-trimethylphenyl derivative 2m did not react at all
(Table 2, entries 10ꢀ13). Of note, the cross-coupling
reaction of sulfondiimine 1a with heteroaromatic sub-
strates was also successful (Table 2, entries 14ꢀ17). To
this end, chloro-pyridinyl and thiophenyl derivatives
3n and 3o were synthesized in good yields (84% and
82%, respectively) and indolyl (3p, 61% yield) and
Reducing the amount of boronic acid or the catalyst
loading resulted in lower yields and incomplete conversion
to the product 3a (Table 1, entries 5ꢀ7). Additional
investigations indicated that the use of potassium trifluoro-
borate salts was also possible, but resulted in lower yields of
3a (37%; Table 1, entry 8) than when the boronic acid was
employed.
With optimal conditions in hand, further investigations
into the substrate scope of this reaction process were
performed. Sulfondiimine 1a was coupled with a variety
of commercially available boronic acids to afford the
corresponding N,N0-disubstituted sulfondiimines 3 in
good to excellent yields (Table 2). Both electron-donating
and -withdrawing groups on the aromatic ring of the
arylboronic acid were well-tolerated. To this end, meth-
oxy- and thiomethyl-substituted products 3b and 3c were
synthesized (72% and 67% yield, respectively), and acetyl-
B
Org. Lett., Vol. XX, No. XX, XXXX

To further extend the application of this reaction pro-
cess, use of an alkenyl-substituted boronic acid was in-
vestigated. The cross-coupling of sulfondiimine 1a with
(E)-styrylboronic acid (2x) afforded (E)-N-alkenylated
product 3x in 78% yield (Scheme 1). This transforma-
tion represents, to the best of our knowledge, the first
N-alkenylation of a sulfondiimine.13 This result presents
significant potential for the preparation of an entirely new
class of N,N0-disubstituted sulfondiimines.
Scheme 1. The First N-Alkenylation of a Sulfondiimine
Figure 1. Various NH-sulfondiimines stemming from reactions
with phenylboronic acid (2a).
In conclusion, we have developed a new synthetic path-
way towardN,N0-disubstituted sulfondiimines through the
copper-catalyzed CꢀN cross-coupling with boronic acids.
The reaction proceeds under mild and base-free conditions
at room temperature using a simple copper catalyst and
takes advantage of the umpolung reactivity of a variety
of commercially available boronic acids. This protocol
allows the preparation of several previously unreported
N,N0-disubstituted sulfondiimines, including N-(hetero)-
arylsulfondiimines, ingoodtoexcellent yields. Inaddition,
the synthesis of a previously unknown N-alkenylated sul-
fondiimine is presented.
benzo[b]thienyl (3q, 41% yield) derivatives were acces-
sible,12 while the NꢀH moiety of indole remains available
for further transformation.
The previously optimized reaction conditions proved
applicable to alternatively substituted NH-sulfondiimines
(Figure 1). In general, S-aryl-S-alkyl sulfondiimines reacted
readily with phenylboronic acid affording N-phenylated
products 3r (87%), 3s (84%), and cyclopropyl derivative
3t (57%) in good yields. Interestingly, the alternate syn-
thetic pathway toward sulfondiimine 3b by phenylation of
a
N-(4-methoxyphenyl)-substituted NH-sulfondiimine
gave the product in a significantly higher yield (90%) than
the previously mentioned transformation of sulfondiimine
1a with 4-methoxyphenylboronic acid (72%; Table 2,
entry 2). Unfortunately, sulfondiimines with an electron-
withdrawing group on the nitrogen (here: N-tosyl), a
S-benzyl substituent, or two aliphatic groups (here: tetrahy-
drothiophene) led to degradation of the NH-sulfondiimine,
and products 3uꢀw could not be obtained.
Acknowledgment. We thank the Deutsche Forschungs-
gemeinschaft (IRTG 1628, SeleCa) for financial sup-
port and Dr. Mathieu Candy as well as Dr. Daniel L.
Priebbenow (both RWTH Aachen University) for helpful
discussions.
Supporting Information Available. Experimental pro-
cedures, full characterization of new products, and copies
1
of H, 13C, and 19F NMR spectra can be found in the
(12) The cross-coupling of sulfondiimine 1a with furan-3-yl- or
pyridin-3-ylboronic acid proved unsuccessful.
(13) Column chromatography with basic alumina was crucial. Use of
silica gel led to partial hydrolysis. For an analogous behavior observed
for N-alkynylated sulfoximines, see: Wang, L.; Huang, H.; Priebbenow,
D. L.; Pan, F.-F.; Bolm, C. Angew. Chem., Int. Ed. 2013, 52, 3478.
Supporting Information. This material is available free of
charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. XX, No. XX, XXXX
C