Sulfoximine directed intermolecular o-C-H amidation of arenes with sulfonyl azides

Article abstract of DOI:10.1021/ol400411v

The Ru(II)-catalyzed intermolecular o-C-H amidation of arenes in N-benzoylated sulfoximine with sulfonyl azides is demonstrated. The reaction proceeds with broad substrate scope and tolerates various functional groups. Base hydrolysis of the amidation product provides the anthranilic acid derivatives and methylphenyl sulfoximine (MPS) directing group. This method is successfully employed for the synthesis of HMR 1766.

Full text of DOI:10.1021/ol400411v

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Sulfoximine Directed Intermolecular o‑CꢀH
Amidation of Arenes with Sulfonyl Azides
M. Ramu Yadav, Raja K. Rit, and Akhila K. Sahoo*
School of Chemistry, University of Hyderabad, Hyderabad, India
akhilchemistry12@gmail.com
Received February 12, 2013
ABSTRACT
The Ru(II)-catalyzed intermolecular o-CꢀH amidation of arenes in N-benzoylated sulfoximine with sulfonyl azides is demonstrated. The reaction
proceeds with broad substrate scope and tolerates various functional groups. Base hydrolysis of the amidation product provides the anthranilic
acid derivatives and methylphenyl sulfoximine (MPS) directing group. This method is successfully employed for the synthesis of HMR 1766.
Anthranilic acid derivatives are found in numerous
natural products and biologically active compounds of
pharmaceutical importance (Figure 1).1 The transition-
metal-catalyzed o-CꢀH amination of benzoic acid deriva-
tives enables the synthesis of structurally diverse anthra-
nilic acids in a straightforward manner. Among the
strategies developed for CꢀN bond formations on arenes,
the BuchwaldꢀHartwig amination protocol is highly
useful.2 This process requires the prefunctionalized arenes
in general, employs Pd and/or Cu catalysts in combination
with appropriate ligands and bases, and generates the salts
of HX and base byproducts.
The direct CꢀN bond formation through amination of
CꢀH bond appears appealing, as this process does not
need the prefunctionalized arenes.3 For example: the CꢀH
bond of azoles, perfluorobenzenes, and other directing
groups containing arenes were successfully aminated with
the aid of Pd/Cu/Rh catalyst and oxidant.4,5
(1) (a) Michael, J. P. Nat. Prod. Rep. 2008, 25, 166. (b) Doungsoongnuen,
S.; Worachartcheewan, A.; Pingaew, R.; Suksrichavalit, T.; Prachayasittikul,
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Figure 1. Biologically active molecules containing anthranilic
acid derivative.
€
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Stokes, B. J.; Driver, T. G. Eur. J. Org. Chem. 2011, 4071.
Recently, the Yu group demonstrated the Pd(II)-cata-
lyzed o-CꢀH amination of benzamides with O-benzoyl
hydroxyl amines in the presence of AgOAc oxidant.5e
(4) (a) Monguchi, D.; Fujiwara, T.; Furukawa, H.; Mori, A. Org.
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Angew. Chem., Int. Ed. 2010, 49, 9899. (e) Kawano, T.; Hirano, K.;
Satoh, T.; Miura, M. J. Am. Chem. Soc. 2010, 132, 6900. (f) Zhao, H.;
Wang, M.; Su, W.; Hong, M. Adv. Synth. Catal. 2010, 352, 1301. (g)
Miyasaka, M.; Hirano, K.; Satoh, T.; Kowalczyk, R.; Bolm, C.; Miura,
M. Org. Lett. 2011, 13, 359. (h) Liu, X.-Y.; Gao, P.; Shen, Y.-W.; Liang,
Y.-M. Org. Lett. 2011, 13, 4196. (i) Li, Y.; Liu, J.; Xie, Y.; Zhang, R.; Jin,
K.; Wang, X.; Duan, C. Org. Biomol. Chem. 2012, 10, 3715.
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r
10.1021/ol400411v
XXXX American Chemical Society

The electrophilic aminating reagents have been used for
the CꢀN bond formation in the absence of external
oxidants. The o-CꢀH bonds of benzamides/aryl oximes
were aminated at an ambient temperature with the aid of
N-chloroamines (Scheme 1, eq 1).5f,g An elegant approach
Rh(III)-catalyzed pyridyl- and/or oxime-directed amida-
tion of arene CꢀH bonds with sulfonyl azides6,7 has
recently been reported by the Chang group;7a this process
produces the benign N2 gas byproduct.
chemo- and regioselective o-CꢀH amidation of arenes in
N-benzoylated methylphenyl sulfoximine (MPS) with
sulfonyl azide amino source (Scheme 1, eq 2). The MPS-
DG can be cleaved from the product and recovered. This
method is successfully employed herein, enabling the
synthesis of HMR 1766.
Table 1. Screening of o-CꢀH Amidation with Tosyl Azidea
Scheme 1. Amide-Directed o-CꢀN Bond Formation
additive
base
solvent
yield
(%)b
entry
(40 mol %)
(0.1 mmol)
(1.0 mL)
1c
AgSbF6
AgSbF6
AgBF4
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
CH2Cl2
<5
41
2
3
32
4
AgPF6
<5
<5
37
5
KPF6
6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
A survey of these reports reveal that the o-CꢀH amina-
tion on arenes has been achieved with the assistance of
modifiable directing groups (DGs),5,7 while the identical
reaction with the aid of a reusable DG has yet to be
investigated. Furthermore, the Ru-catalyzed intermolecu-
lar o-CꢀH amination is rare.7ꢀ9 The use of reusable
sulfoximine10 DGs for the development of novel CꢀH
functionalizations led us to disclose our preliminary
studies on the Ru(II)-catalyzed intermolecular direct
7
CHCl3
38
8
9d
toluene
9
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
56e
60e
76e
81e
59e
78e
56g
69h
10d
11d
12d
13d
14d,f
15b,d
16b,d
Cu(OAc)2.H2O
NaOAc
KOAc
AgOAc
KOAc
KOAc
KOAc
a Reaction conditions: 2a (0.1 mmol), 3a (0.2 mmol), [RuCl2(p-
cymene)]2 (5 mol %). b Crude 1H NMR conversion based on the ratio
of starting material to product. c [RhCp*Cl2]2 (5 mol %). d [RuCl2(p-
cymene)]2 (10 mol %). e 2a (0.5 mmol), ClCH2CH2Cl (2.0 mL), isolated
yields. f KOAc (0.25 mmol). g 80 °C. h 100 °C.
(6) For informations on organic azides, see: (a) Katsuki, T. Chem.
Lett. 2005, 34, 1304. (b) Cenini, S.; Gallo, E.; Caselli, A.; Ragaini, F.;
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Driver, T. G. Org. Biomol. Chem. 2010, 8, 3831.
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Kim, J. Y.; Chang, S. Angew. Chem., Int. Ed. 2012, 51, 9904. (c) Shi, J.;
Zhou, B.; Yang, Y.; Li, Y. Org. Biomol. Chem. 2012, 10, 8953.
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Hu, J.; Chen, S.; Sun, Y.; Yang, J.; Rao, Y. Org. Lett. 2012, 14, 5030. (c)
Leung, S. K.-Y.; Tsui, W.-M.; Huang, J.-S.; Che, C.-M.; Liang, J.-L.;
Zhu, N. J. Am. Chem. Soc. 2005, 127, 16629. (d) Liang, J.-L.; Yuan,
S.-X.; Huang, J.-S.; Yu, W.-Y.; Che, C.-M. Angew. Chem., Int. Ed. 2002,
41, 3465. (e) He, L.; Chan, P.W.H.; Tsui, W.-M.; Yu, W.-Y; Che, C.-M.
Org. Lett. 2004, 6, 2405. (f) Harvey, M. E.; Musaev, D. G.; Du Bois, J.
J. Am. Chem. Soc. 2011, 133, 17207. (g) Milczek, E.; Boudet, N.; Blakey, S.
Angew. Chem., Int. Ed. 2008, 47, 6825.
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Pure Appl. Chem. 2010, 82, 1403. (e) Ackermann, L.; Vicente, R. Top.
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2012, 14, 764. (g) Ackermann, L.; Wang, L.; Lygin, A. V. Chem. Sci.
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(i) Hashimoto, Y.; Hirano, K.; Satoh, T.; Kakiuchi, F.; Miura, M. Org.
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B. Org. Lett. 2012, 14, 736. (l) Li, B.; Feng, H.; Wang, N.; Ma, J.; Song,
H.; Xu, S.; Wang, B. Chem.;Eur. J. 2012, 18, 12873. (m) Flegeau, E. F.;
Bruneau, C.; Dixneuf, P. H.; Jutand, A. J. Am. Chem. Soc. 2011, 133,
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3724.
To find the general reaction conditions for the o-CꢀH
amidation of arenes, compound N-[m-methylbenzoyl]-
MPS (2a) was subjected to the known reaction condi-
tions (RhCp*Cl2)2 (5 mol %)/AgSbF6 (0.4 equiv) in
ClCH2CH2Cl (DCE) with tosyl azide at 120 °C] reported
by Chang.7a We were pleased to notice a trace amount of
the desired product 4a (entry 1, Table 1). Interestingly, the
o-CꢀH amidation product 4a was observed in 41% yield
by NMR, when [RuCl2(p-cymene)]2 was employed in
combination with AgSbF6 (entry 2). Among the two
different arenes of 2a, the less hindered o-CꢀH bonds of
the N-benzoylated aryl ring has been exclusively function-
alized, demonstrating chemo- as well as regioselective
CꢀH amidation of arenes. Screening of other Ag/K salts
did not show satisfactory results (entries 3ꢀ5). Among
various solvents examined, DCE was found to be the best
compared with CH2Cl2, CHCl3, and toluene (entries 6ꢀ8).
The enhanced catalyst loading resulted in improved yield
of 4a (entry 9). Base plays an important role in the case of
CꢀH functionalizations;8,9 thus, exploration of different
bases isinvestigated. AmongAgOAc, NaOAc, KOAc, and
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 2. Scope of Para-Substituted N-Benzoylated Sulfoximinesa,b
Scheme 2. Scope of N-Benzoylated Sulfoximinesa,b
entry
1
R
TsN3 (equiv) yield of 4 (%) yield of 40 (%)
Me (2n)
4n
30c
43c
49
14
10
16c
4o
55
<5
4p
49
12
4q
50
48
4r
37
20
4n0
22c
28c
32
1.0
1.5
2.0
2.5
3.0
4.0
66
73
59c
4o0
28
2
3
4
5
OMe (2o)
F (2p)
2.0
3.0
71
4p0
2.0
3.0
40
68
4q0
CF3 (2q)
H (2r)
a Reaction conditions: 2 (0.5 mmol), azide (1.0 mmol), [RuCl2(p-
cymene)]2 (10 mol %), AgSbF6 (40 mol %), KOAc (0.25 mmol),
2.0
3.0
25
30
4r0
ClCH2CH2Cl (2.0 mL). b Isolated yields. c Cu(OAc)2 H2O (1.0 mmol)
was used instead of KOAc.
3
2.0
3.0
28
52
Cu(OAc)2 H2O screened, KOAc was found to be effec-
3
a Reaction conditions: 2 (0.5 mmol), [RuCl2(p-cymene)]2 (10 mol %),
AgSbF6 (40 mol %), KOAc (0.25 mmol), ClCH2CH2Cl (2.0 mL).
b Isolated yields. c Crude 1H NMR conversion based on the ratio of
starting material to product.
tive and afforded 4a in 81% yield (entries 10ꢀ13). The
use of KOAc (0.25 mmol) did not affect the product
yield (entry 14). A moderate amount of 4a was obtained
when the reaction conducted at lower temperature
(entries 15 and 16). Thus, the optimized conditions in
entry 14, Table 1 [[RuCl2(p-cymene)]2 (10 mol %),
AgSbF6 (40 mol %) and KOAc (50 mol %) in DCE at
120 οC for 24 h] have been chosen for the o-CꢀH
amidation of arenes.
respectively, when the reaction was performed in the pres-
ence of Cu(OAc)2. The β-naphthyl derivative 2l under the
catalytic conditions gave 4l in 81% yield. Gratifyingly,
reaction of 2-thienyl-substituted 2m with 3a afforded 4m
albeit in poor yield.
We then studied the scope and generality of the CꢀH
amidation reaction by exposing various N-benzoylated-
MPS with tosyl azide (3a) under the optimized conditions
(Scheme 2). The steric and electronic nature of the ortho-
substituted arenes was probed first. The amidation of
N-(o-methylbenzoyl)-MPS (2b) gave the desired 4b in
88% yield. Similarly, 4c was obtained in good yield
from 2,4-dimethyl-substituted 2c. Importantly, the halo-
substituted arenes successfully underwent the CꢀH ami-
dation reaction, and the corresponding 4dꢀf were isolated
in 80%, 65%, and 43% yields, respectively. Interestingly,
the electron-deficient fluoro group on arene did not affect
the reaction efficiency. However, the sterically demanding
o-phenyl group in 2g hindered the reaction and afforded4g
in moderate yield. Reaction of R-naphthyl derivative 2h
with 3a produced 4h in good yield. The meta-substituted
substrates regioselectively underwent amidation in the
sterically less hindered position. The chloro- and methyl-
substituted products 4i and 4a were obtained in moderate
to good yields. The electron-withdrawing ester and nitro
groups did not affect the efficiency, and the corresponding
products 4j and 4k were isolated in 74% and 62% yields,
The reaction of para-substituted N-benzoylated-MPS
with TsN3 (3a) provided the mono- and diamidation
products (Table 2). At first, the p-Me-substituted N-ben-
zoylated-MPS (2n) was exposed to different amounts of
TsN3 (3a) under the optimized conditions.11 However, the
use of 3a (2.0 equiv) was found to be optimum affording 4n
(major) and 4n0 (minor) in 49% and 32% yields, respec-
tively (entry 1). Interestingly, an excess amount of 3a
(2.5/3.0/4.0 equiv) led to 4n0 as major product; in particu-
lar, the reaction of 2n with 3.0 equiv of 3a resulted 4n0 in
73% yield (entry 1). These modified conditions were then
applied to various para-substituted N-benzoylated-MPS
compounds (2oꢀr). The reaction of electron-rich p-OMe-
substituted 2o with 3a (2.0 equiv) gave 55% of 4o as major
product, while diamidation product 4o0 (71%) was isolated
when 3a (3.0 equiv) was employed (entry 2).11 The mono-
and diamidation products 4p and 4p0 were obtained in
49% and 40% yields, respectively, from the reaction of the
F-group bearing electron-deficient 2p with 3a (2.0 equiv),
whereas 3.0 equiv of TsN3 yielded 4p0 in 68% yield (entry 3).
(11) For more details, see the Supporting Information.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 3. Scope of Azidesa,b
Scheme 5. Synthesis of HMR 1766
Following the same conditions, 4n was successfully hydro-
lyzed and the MPS moiety was recovered in 78% yield.
Next, we envisioned the synthesis of HMR 1766 (9)
involving the reusable MPS-directed CꢀH amidation
protocol as a key step. HMR 1766, named ataciguat, is a
class of sGC activators useful in targeting deficient NO
signaling in hypertension, peripheral, and coronary artery
disease, heart failure, etc.12 The campaign for the synthesis
of 9 commenced by inserting the Cl-thienyl-sulfonyl amido
group at the less hindered o-CꢀH bond on 2i (Scheme 5);
the desired product 5g was produced in 41% yield. Hydro-
lysis of 5g delivered the corresponding acid 7 in 90% yield.
Finally, coupling of 7 with amine 811 resulted in HMR
1766 (9) in 60% yield. X-ray crystallographic analysis
unambiguously confirms the structure of 9.11
In summary, we have developed a Ru-catalyzed, sulfox-
imine-directed, chemo- and regioselective o-CꢀN bond
formation of arenes with broad substrate scope. The reac-
tion of para-substituted N-benzoylated-MPS with an ex-
cess amount of tosyl azide delivered major amount of
ortho-diamidation product. Anthranilic acid derivatives
and recovery of MPS-DG are realized through the base
hydrolysis of amidation products. The utility of this meth-
od is demonstrated in the synthesis of HMR 1766. Efforts
to unravel milder reaction conditions for sp2 and sp3 CꢀH
amination and diastereoselective CꢀH aminations are
currently underway.
a Reaction conditions: 2 (0.5 mmol), azide (1.0 mmol), [RuCl2-
(p-cymene)]2 (10 mol %), AgSbF6 (40 mol %), KOAc (0.25 mmol),
ClCH2CH2Cl (2.0 mL). b Isolated yields.
Surprisingly, the use of an enhanced amount of TsN3 did
not affect the reactivity of p-CF3-susbstituted 2q, produc-
ing the monoamidation 4q as the major product (entry 4).
The electron-neutral N-benzoylsulfoximine 2r gave a mod-
erate amount of 4r/4r0 inthe presence of 2.0/3.0 equivof3a.
We next examined the scope of different sulfonyl azides
with 2 (Scheme 3). Electron-withdrawing substituted ar-
ylsulfonyl azides 3b, 3c, and 3d effectively participated; the
corresponding o-CꢀH amidation products 5aꢀc were
obtained in good yields. Similarly, amidation of N-(3,4-
dimethoxybenzoyl)-MPS (2s) with 3e yielded 48% of 5d.
Pleasingly, the reaction of aliphatic sulfonyl azides 3f/3g
with 2a produced a moderate amount of the desired
amidation products 5e and 5f.
Scheme 4. Recovery of the Sulfoximine Directing Group
Acknowledgment. This manuscript is dedicated to the
memory of Professor A. Srikrishna, Indian Institute of
Science, Bangalore, India. We thank DST (SR/S1/OC-34/
2009), UoH, and ACRHEM for the support. M.R.Y. and
R.K.R. thank CSIR, India, for fellowship. We thank Mr.
N. Rajesh Goud and Dr. P. Raghavaiah, University of
Hyderabad, for X-ray crystallographic analysis.
Cleavage of the MPS-directing group from the product
would broaden the synthetic versatility of the method. To
our delight, 4a was hydrolyzed under the base hydrolysis
conditions (NaOH in MeOH/H2O at 60 οC in 6 h),
providing the corresponding anthranilic acid 6a and
MPS in 89% and 74% yield, respectively (Scheme 4).
Supporting Information Available. Detailed experimen-
tal procedures, spectra, and X-ray data (CIF). This
material is available free of charge via the Internet at
http://pubs.acs.org.
€
€
(12) Schindler, U.; Strobel, H.; Schonafinger, K.; Linz, W.; Lohn,
M.; Martorana, P. A.; Rutten, H.; Schindler, P. W.; Busch, A. E.; Sohn,
€
€
€
M.; Topfer, A.; Pistorius, A.; Jannek, C.; Mulsch, A. Mol. Pharmacol.
2006, 69, 1260.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX