meta-C?H Arylation and Alkylation of Benzylsulfonamide Enabled by a Palladium(II)/Isoquinoline Catalyst

Article abstract of DOI:10.1002/anie.201704411

Palladium(II)-catalyzed meta-C?H arylation and alkylation of benzylsulfonamide using 2-carbomethoxynorbornene (NBE-CO₂Me) as a transient mediator are realized by using a newly developed electron-deficient directing group and isoquinoline as a ligand. This protocol features broad substrate scope and excellent functional-group tolerance. The meta-substituted benyzlsulfonamides can be readily transformed into sodium sulfonates, sulfonate esters, and sulfonamides, as well as styrenes by Julia-type olefination. The unique impact of the isoquinoline ligand underscores the importance of subtle matching between ligands and the directing groups.

Full text of DOI:10.1002/anie.201704411

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Accepted Article
Title: Meta-C‒H Arylation and Alkylation of Benzylsulfonamide Enabled
by a Pd(II)/Isoquinoline Catalyst
Authors: Jin-Quan Yu, Guolin Cheng, and Peng Wang
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10.1002/anie.201704411
Angewandte Chemie International Edition
DOI: 10.1002/anie.201((will be filled in by the editorial staff))
C–H Activation
Meta-C‒H Arylation and Alkylation of Benzylsulfonamide Enabled by a
Pd(II)/Isoquinoline Catalyst
Guolin Cheng,+ Peng Wang,+ and Jin-Quan Yu*
Abstract: Palladium(II)-catalyzed meta-C‒H arylation and
alkylation of benzylsulfonamide using 2-carbomethoxynorbornene
(NBE-CO2Me) as a transient mediator are realized using a newly
developed electron-deficient directing group and isoquinoline as a
ligand. This protocol features broad substrate scope and excellent
functional group tolerance. The meta-substituted benyzlsulfonamide
can be readily transformed to sodium sulfonate, sulfonate ester,
sulfonamide, as well as styrenes via Julia-type olefination. The
unique impact of the isoquinoline ligand underscores the importance
of subtle matching between ligands and the directing groups.
S
ulfonamide functional group is one of the most important
pharmacophores for many agents possessing antibacterial, anti-
carbonic anhydrase, diuretic, hypoglycemic, antithyroid, and
antitumor activity.1 Currently, over hundred marketed drugs contain
sulfonamide derived core structures, notably in sumatriptan, and
giripladib et al (Scheme 1a).2 In addition, the alkyl sulfonamide
functional group is a useful synthon that can be readily converted to
alkene in the presence of aldehyde or ketone via a Julia-type
olefination (Scheme 1b). Therefore selective C–H functionalization
of sulfonamide substrates or sulfonamide containing drug molecules
is highly valuable. Though directed ortho-C–H functionalization of
aryl sulfonamide and benzylsulfonamide has been demonstrated,3
diverse meta-functionalizations of those substrates remain scarce.
Successful meta-functionalization of sulfonamide containing
molecules will find broad utility in drug discovery and styrene
synthesis.
Scheme 1. Meta-C‒H arylation and alkylation of benzylsulfonamide.
strategy could open a new avenue for meta-C–H functionalization of
sulfonamide containing substrates. Herein, we report an isoquinoline
enabled Pd(II)-catalyzed meta-C‒H arylation and alkylation of
benzylsulfonamide using 2-carbomethoxynorbornene as a transient
mediator with broad substrate scope and functional group tolerance
(Scheme 1c). This protocol represents an efficient method to acess the
meta-arylated or alkyated benzylsulfonamide. Moreover, further
Julia-type olefination of the meta-functionalized benzylsulfomamides
affords a novel class of styrenes.
Over the past decade, while substantial progress has been made
in the transition-metal-catalyzed meta-C‒H activations,4-7 many of
the established approaches are still limited in efficiency and scope.4-7
For instance, although the devolopment of various U-shaped
templates allows selective C–H functionalization of a wide range of
substrates at the remote position,4 these transformations are limited to
olefinaiton,4a acetoxylation,4b arylation,4c and iodination reactions.4d
Given our continued interest on the direct C–H functionalization
of sulfonamide containing drugs and substrates,3a we chose
benzylsulfonamide as the model substrate to examine the feasiblity of
norbornene-mediated meta-functionalization. After systematic
evaluation of different sulfonamide directing groups, the 3,5-
bis(trifluoromethyl)aniline was found as the most efficient one,
giving the desired meta-arylated products in 50% combined yield
(mono/di = 2.1/1.0, see Supporting Information for more information)
in the presence of Pd(OAc)2 (10 mol%), pyridine (20 mol%), AgOAc
(3.0 equiv.), NBE-CO2Me (1.5 equiv.) in DCE at 100 oC. It is
noteworthy that the pyridine ligand is crucial for this transformation
as only trace products was observed in the absence of ligand. Next,
we systematically evaluated the pyridine- and quinoline-type ligands
employing 1a as substrate and p-iodotoluene as coupling partner.
While simple pyridine L1 gave the desired meta-arylated product in
42% yield, 2-picoline dramatically increased the yield to 69%. 3- or
4-Picoline provided lower yield compared to the 2-picoline (L3 or L4
vs L2). Following this finding, other substituents at the 2-position of
pyridine were investigated (L5-8). Unfortunately, both electron
donating and electron withdrawing groups reduced the yields. 2,6-
Lutidine (L9) and 2,3-lutidine (L10) were also evaluated, giving the
desired product in 32% and 60% yields, respectively. Although the
5,6,7,8-tetrahydroquinoline (L11) resulted in 38% yield, quinoline
(L12) significantly increased the yield to 85%. Other quinoline
Very recently, our group7a and others7b have developed
a
Pd(II)/norbornene relay approach to realize the meta-C–H arylation
and alkylation reaction by combining the directed ortho-C–H
activation and the Catellani’s norbornene process.8 Taking advantage
of this new approach, serval unprecedented transformations such as
meta-amination,7f alkynylation,7f and chlorination7g have been
realized by developing a modified norbornene (NBE-CO2Me, 2-
carbomethoxynorbornene)7c and new ligand scaffolds.7e,h This new
[*]
Prof. Dr. G. Cheng,[+] Dr. P. Wang,[+] Prof. Dr. J.-Q. Yu
Department of Chemistry, The Scripps Research Institute
(TSRI)
10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
E-mail: yu200@scripps.edu
These authors contributed equally to this work.
[+]
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201xxxxxx.
1
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10.1002/anie.201704411
Angewandte Chemie International Edition
derivatives led to lower yields (43-74%, L13-17). Notably,
isoquinoline (L18) was found as the most efficient ligand to promote
this meta-C–H arylation reaction, affording 94% yield (see
Supporting Information for more ligand screening). 1-
methylisoquinoline decreased the yield to 75% (L19). Moreover,
control experiments revealed that 2-carbomethoxynorbornene (NBE-
CO2Me) is crucial for this ligand-enabled meta-C–H
functionalization of benzysulfonamide as 2-norbornene only gave 31%
yield under the optimal conditions.
standard conditions to afford the di-arylated product in 90% yield. 4-
Fluorobenzylsulfonamide is also suitable substrate giving the di-
arylated product 94% yield (5l).
Table 2. Scope of aryl iodides.[a,b]
Table 1. Ligand evaluation for meta-C–H arylation of benzylsulfonamide.[a,b]
[a] Reaction conditions: 1a (0.1 mmol), p-iodotoluene 2a (3.0 equiv), Pd(OAc)2 (10 mol
%), Ligand (20 mol %), AgOAc (3.0 equiv), NBE-CO2Me (1.5 equiv), DCE (1.0 mL),
100 oC, 24 h. [b] The yield was determined by 1H NMR using CH2Br2 as the internal
standard. [c] 2-Norbornene was used instead of 2-carbomethoxynorbornene.
[a] Reaction conditions: 1a (0.1 mmol), Aryl iodide 2 (3.0 equiv), Pd(OAc)2 (10 mol %),
Isoquinoline (20 mol%), NBE-CO2Me (1.5 equiv), AgOAc (3.0 equiv), DCE (1.0 mL),
100 oC, 24 h. [b] Isolated yield.
Under the optimal conditions, the scope of aryl iodide coupling
partners were examined first by employing 3-methyl
benzylsulfonamide 1a as the model substrate (Table 2). Various aryl
iodides are compatible with this procedure affording the desired
meta-arylated benzylsulfonamide in moderate to excellent yield.
Functional groups, including Me, Ph, MeO, CF3O, F, Cl, Br, I, CF3,
CO2Me, Ac, and NO2, are all tolerated (3a-m). 3-substituted aryl
iodides (3n-p) and 2-substituted aryl iodides (3q and 5a) are also
suitable coupling partners. 2-Iodonaphthalene (3r) resulted in 90%
yield, while 3,5-Disubstituted and 3,4-disubstituted aryl iodide (3s
and 3t) afforded the desired product in 90% and 88% yields,
respectively.
Table 3. Meta-arylation of benzylsulfonamides.[a,b]
Notably, the heterocyclic aryl iodides are highly reactive under
those conditions (Table 2). A series of heterocylic aryl iodides
containing pyridine, thiophene, furan, benzothiophene, and indole
scaffold are tolerated in this procedure affording the desired products
in 43-83% yields (4a-h). The compatiablity of heterocylic aryl
iodides is noteworthy, and highlights the effectiveness of the
isoquinoline ligand.
[a] Reaction conditions: 1 (0.1 mmol), 2u (3.0 equiv), Pd(OAc)2 (10 mol %), Isoquinoline
(20 mol%), NBE-CO2Me (1.5 equiv), AgOAc (3.0 equiv), DCE (1.0 mL), 100 oC, 24 h.
[b] Isolated yield.
Next, the scope of benzylsulfonamide was evaluated using
methyl 2-iodobenzoate as the coupling partner (Table 3). Substrates
containing either electron-withdrawing or electron-donating
substituents at the 3-position of the phenyl ring were arylated at the
The
generality
of
this
ligand-enabled
meta-C–H
functionalization approach for benzylsulfonamide was further
demonstrated by the development of meta-C–H alkylation reaction
(Table 4). A variety of alkyl iodides are suitable coupling partner
under the optimized conditions. The functional groups including
phenyl (7d), TBS-protected alcohol (7e), benzylic ether (7f), ester
meta-position
in
excellent
yields
(5a-f).
2-substituted
benzylsulfonamides are also tolerated, albeit with a slight lower
yields (5g-j). Simple benzylsulfonamide 1k was subjected to the
2
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10.1002/anie.201704411
Angewandte Chemie International Edition
group (7g) are tolerated in this protocol, giving the desired meta-
alkylated products in moderate to high yields. A benzylsulfonamide
derivative 1i was also evaluated providing the alkylated product 7h
in 60% yield.
In summary, meta-C‒H arylation and alkylation of
benzylsulfonamide are realized using 2-carbomethoxynorbornene as
the transient mediator and isoquinoline as the ligand. This protocol
features borad substrates sope and functional group tolerance. The
compatiabilty of heterocylic aryl idodies and alkyl idodides is an
important advantage over other meta-C‒H functionalization
protocols . Meta-substituted sulfonate esters, sulfonamides, as well as
styrene derivatives can be obtained via this approach.
Table 4. Meta-alkylation of benzylsulfonamides.[a,b]
Received: ((will be filled in by the editorial staff))
Published online on ((will be filled in by the editorial staff))
Acknowledgement
We gratefully acknowledge The Scripps Research Institute and the NIH
(NIGMS, 2R01 GM102265) for financial support.
Keywords: meta-C–H arylation · alkylation · isoquinoline · palladium ·
[a] Reaction conditions: 1a or 1i (0.1 mmol), 6 (3.0 equiv), Pd(OAc)2 (10 mol%),
Isoquinoline (20 mol%), NBE-CO2Me (1.5 equiv), AgOAc (3.0 equiv), DCE (1.0 mL),
100 oC, 24 h. [b] Isolated yields.
sulfonamide
[1]
a) J. Drews, Science 2000, 287, 1960. b) A. Scozzafava, T. Owa, A.
Mastrolorenzo, T. C. Supuran, Curr. Med. Chem. 2003, 10, 925. c) L. Levy,
Drugs Future 1992, 17, 451. d) A. Kalgutkar, R. Jones, A. Sawant, In
Metabolism Pharmacokinetics and Toxicity of Functional Groups, RSC
Drug Discovery Series No. 1, (D. A. Smith, Ed.), RSC: Cambridge, U.K.,
2010; Chapter 5. e) C. Hansch, P. G. Sammes, J. B. Taylor, in
Comprehensive Medicinal Chemistry, Vol. 2; Pergamon Press, Oxford, UK,
1990, Chapter 7.1.
a) F. D. King, A. M. Brown, L. M. Gaster, A. J. Kaumann, A. D. Medhurst,
S. G. Parker, A. A. Parsons, T. L. Patch, P. Raval, J. Med. Chem. 1993, 36,
1918. b) G. Kokotos, A. J. Feuerherm, E. Barbayianni, I. Shah, M. Saether,
V. Magrioti, T. Nguyen, V. Constantinou-Kokotou, E. A. Dennis, B.
Johansen, J. Med. Chem. 2014, 57, 7523. c) F. Sielaffa, E. Böttcher-
Friebertshäuserb, D. Meyera, S. M. Saupea, I. M. Volka, W. Gartenb, T.
Steinmetzer, Bioorg. Med. Chem. Lett. 2011, 21, 4860.
For selected examples of directed ortho-C–H functionalization of
sulfonamides, see: a) H.-X. Dai, A. F. Stepan, M. S. Plummer, Y.-H. Zhang,
J.-Q. Yu, J. Am. Chem. Soc. 2011, 133, 7222. b) M. V. Pham, B. Ye, N.
Cramer, Angew. Chem. Int. Ed. 2012, 51, 10610. c) W. Ma, R. Mei, G.
Tenti, L. Ackermann, Chem. Eur. J. 2014, 20, 15248. d) W. Xie, J. Yang, B.
Wang, B. Li, J. Org. Chem. 2014, 79, 8278. e) W. J. Kerr, M. Reid, T. Tuttle,
ACS Catal. 2015, 5, 402. f) D. Kalsi, B. Sundararaju, Org. Lett. 2015, 17,
6118.
The scalability of this meta-C–H reaction was demonstrated by
the meta-arylation reaction. Employing 1k as model substrate in the
presence of 5 mol% Pd(OAc)2, 10 mol% isoquinoline, and 1.0
equivalent of NBE-CO2Me, the di-arylated product (8di) was obtained
in 91% yield, along with the mono-arylated product (8mono) in 5%
yield (Scheme 2a). Boc-Protection of the meta-arylated product with
(Boc)2O afforded intermediate 9 in 99% yield. Subsequent hydrolysis
gave the corresponding sodium sulfonate 11 in 85% yield. It is
noteworthy that the Boc-protected 3,5-bistrifluoromethyl aniline
(directing group) can also be recovered in 91% yield. Furthermore,
the intermediate 9 can be readily transformed to other sulfonamides
(13), sulfonate ester (14) in excellent yields (Scheme 2b). These
transformations indicate the versatility of this reaction for
diversifying the benzylsulfonamide containing drug molecules. An
important synthetic application is also demonstrated by the coupling
of 9 with aldehyde under Julia olefination conditions to give the
trans-alkenes 10 in 86% yield, thus providing a new avenue for
making a novel class of meta-substituted styrenes.
[2]
[3]
[4]
For selected examples of template directed meta-C–H functionalization, see:
a) D. Leow, G. Li, T.-S. Mei, J.-Q. Yu, Nature 2012, 486, 518. b) R. Tang,
G. Li, J.-Q. Yu, Nature 2014, 507, 215. c) L.Wan, N. Dastbaravardeh, G. Li,
J.-Q. Yu, J. Am. Chem. Soc. 2013, 135, 18056. d) L. Chu, M. Shang, K.
Tanaka, Q. Chen, N. Pissarnitski, E. Streckfuss, J.-Q. Yu, ACS Cent. Sci.
2015, 1, 394. e) Y. Kuninobu, H. Ida, M. Nishi, M. Kanai, Nat. Chem. 2015,
7, 712. f) H. J. Davis, M. T. Mihai, R. J. Phipps, J. Am. Chem. Soc. 2016,
138, 12759. g) M. Bera, A. Maji, S.K. Sahoo, D. Maiti, Angew. Chem. Int.
Ed. 2015, 54, 8515. h) A. Maji, B. Bhaskararao, S. Singha, R. B. Sunoj, D.
Maiti, Chem. Sci. 2016, 7, 3147. i) Z. Zhang, K. Tanaka, J.-Q. Yu, Nature
2017, 543, 538.
[5] For examples of Ru(II) catalyzed meta-C–H functionalization via ortho-
cyclometallation, see: a) O. Saidi, J. Marafie, A. E. W. Ledger, P. M. Liu,
M. F. Mahon, G. Kociok-Köhn, M. K. Whittlesey, C. G. Frost, J. Am. Chem.
Soc. 2011, 133, 19298. b) N. Hofmann, L. Ackermann, J. Am. Chem. Soc.
2013, 135, 5877. c) C. J. Teskey, A. Y. W. Lui, M. F. Greaney, Angew. Chem.
Int. Ed. 2015, 54, 11677. d) Z. Fan, J. Ni, A. Zhang, J. Am. Chem. Soc. 2016,
138, 8470.
[6] For other examples of meta-C–H functionalizations through steric or the
electronic influence: a) T. Ishiyama, J. Takagi, K. Ishida, N. Miyaura, N. R.
Anastasi, J. F. Hartwig, J. Am. Chem. Soc. 2002, 124, 390. b) J.-Y. Cho, M.
K. Tse, D. Holmes, R. E. Maleczka Jr., M. R. Smith III, Science 2002, 295,
305. c) R. Bisht, B. Chattopadhyay, J. Am. Chem. Soc. 2016, 138, 84. d) R.
Scheme 2. Gram-scale reaction and deprotection. Conditions: a) MeONa (2.2 equiv),
MeOH, rt, 24 h; b) Morpholine (2.0 equiv), n-BuLi (2.4 equiv), THF , rt, 5 h; c) PhONa
(2.0 equiv), DMF, rt, 24 h.
3
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10.1002/anie.201704411
Angewandte Chemie International Edition
J. Phipps, M. J. Gaunt, Science 2009, 323, 1593. e) Y.-H. Zhang, B.-F. Shi,
J.-Q. Yu, J. Am. Chem. Soc. 2009, 131, 5072. For an example using a
traceless directing group relay strategy: f) J. Luo, S. Preciado, I. Larrosa, J.
Am. Chem. Soc. 2013, 136, 4109.
Farmer, J. He, P.-X. Shen, J.-Q. Yu, J. Am. Chem. Soc. 2016, 138, 14092. g)
H. Shi, P. Wang, S. Suzuki, M. E. Farmer, J.-Q. Yu, J. Am. Chem. Soc. 2016,
138, 14876. h) P. Wang, M. E. Farmer, J.-Q. Yu, Angew. Chem. Int. Ed.
2017, 56, 5125.
[7] For selected examples using Pd/norbornene relay process to achieve meta-
C–H arylation, see: a) X.-C. Wang, W. Gong, L.-Z. Fang, R.-Y. Zhu, S. Li,
K. M. Engle, J.-Q. Yu, Nature 2015, 519, 334. b) Z. Dong, J. Wang, G. Dong,
J. Am. Chem. Soc. 2015, 137, 5887. c) P.-X. Shen, X.-C. Wang, P. Wang,
R.-Y. Zhu, J.-Q. Yu, J. Am. Chem. Soc. 2015, 137, 11574. d) J. Han, L.
Zhang, Y. Zhu, Y. Zheng, X. Chen, Z.-B. Huang, D.-Q. Shi, Y. Zhao, Chem.
Comm. 2016, 52, 6903. e) P. Wang, M. E. Farmer, X. Huo, P. Jain; P.-X.
Shen, M. Ishoey, J. E. Bradner, S. R. Wisniewski, M. E. Eastgate, J.-Q. Yu,
J. Am. Chem. Soc. 2016, 138, 9269. f) P. Wang, G.-C. Li, P. Jain, M. E.
[8] For reviews on norbornene mediated ortho-C–H functionalizations, see: a)
M. Catellani, Top. Organomet. Chem. 2005, 14, 21. b) A. Martins, B.
Mariampillai, M. Lautens, Top. Curr. Chem. 2010, 292, 1. c) N. Della Ca’,
M. Fontana, E. Motti, M. Catellani, Acc. Chem. Res. 2016, 49, 1389. For
indole C-2 C–H functionalizations using norbornene as a transient mediator:
d) L. Jiao, T. Bach, J. Am. Chem. Soc. 2011, 133, 12990. e) L. Jiao, E.
Herdtweck, T. Bach, J. Am. Chem. Soc. 2012, 134, 14563.
4
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10.1002/anie.201704411
Angewandte Chemie International Edition
C–H Activation
G. Cheng, P. Wang, J.-Q. Yu*
__________ Page – Page
Meta-C‒H Arylation and Alkylation of
Benzylsulfonamide Enabled by
Pd(II)/Isoquinoline Catalyst
Palladium(II)-catalyzed meta-C‒H arylation and alkylation of benzylsulfonamide
using 2-carbomethoxynorbornene (NBE-CO2Me) as a transient mediator are realized
using isoquinoline as a ligand. This protocol features broad substrate scope and
excellent functional group tolerance. The meta-substituted benyzlsulfonamide can be
readily transformed to sodium sulfonate, sulfonate ester, sulfonamide, as well as
styrenes via Julia-type olefination.
5
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