Highly regioselective copper-catalyzed benzylic C-H amination by N-fluorobenzenesulfonimide

Article abstract of DOI:10.1002/anie.201107427

Primary target: A practical and effective copper-catalyzed amination strategy for synthesizing various benzylic amines from benzylic hydrocarbons is described (see scheme; DCE=1,2-dichloroethane). Xylene substrates can undergo diamination reactions using this method. The remarkable preference for primary over secondary benzylic C-H bonds has been observed for the first time. Copyright

Full text of DOI:10.1002/anie.201107427

.
Angewandte
Communications
DOI: 10.1002/anie.201107427
Synthetic Methods
À
Highly Regioselective Copper-Catalyzed Benzylic C H Amination by
N-Fluorobenzenesulfonimide**
Zhikun Ni, Qian Zhang,* Tao Xiong, Yiying Zheng, Yan Li, Hongwei Zhang, Jingping Zhang,*
and Qun Liu*
Amines are ubiquitous in both naturally occurring and man-
made compounds which demonstrate high levels of biological
reactions of toluene, a large excess of toluene (15–500 equiv)
is usually necessary.[10,13–15]
activity.[1,2] Direct construction of a C N bond through C H
amination is one of the most exciting and challenging fields in
The selective activation of benzylic C H bonds in toluene
À
À
À
is particularly important since the catalytic functionalization
of toluene can yield industrially important chemicals such as
benzyl alcohols, benzaldehydes, and benzoic acids. However,
amine chemistry.[3,4] Direct aliphatic C H amination has led
À
to significant results arising from the discovery of metal
nitrenoids,[5–8] but highly active free nitrene is unselective and
it is more difficult to achieve the benzylic C H bond
À
uncontrollable. Recently, highly regioselective aliphatic C H
activation[16–18] because of the existence of four different C
À
À
amination was realized by employing N-triflylimino-l3-bro-
H bonds (ortho, meta, para, and benzylic). Generally, metal-
À
mane as the nitrogen source, and the selectivity for tertiary
catalyzed C H activating systems exhibit preferences for
[9]
À
À
À
over secondary C H bonds was observed. Therefore, a
aromatic C H bond activation over the benzylic C H
delicate balance between reactivity and selectivity for direct
bond;[16–18] even the amination with nitrene as the nitrogen
À
À
C H amination is very important, especially with regard to
source (AuCl3 as catalyst) provided aromatic C H amination
the choice of the nitrogen source.[9,10] Toluene and xylenes are
among the basic organic raw materials and it is highly
desirable to develop a general method for direct amination of
products.[19] Herein, highly selective copper-catalyzed ben-
À
zylic C H mono- and diamination reactions of a sterically
hindered non-nitrene nitrogen source, N-fluorobenzenesulfo-
nimide (NFSI), were efficiently realized. These reactions
possess the advantage of avoiding the use of a large excess of
benzylic substrates and the remarkable selectivity of primary
À
their benzylic C H bonds. However, because of the favored
electronic effect of the secondary C H bond (for example, the
major product of path a in Scheme 1), the selective amination
À
À
over second C H bonds (for example, the major product of
path b in Scheme 1).
[20,21]
silylation,[22]
À
Recently, benzylic C H bond arylation,
and fluorination,[23] directed by N-oxide, pyridine, and
quinoline, respectively, were realized. However, specific
directing groups on the substrates are required to facilitate
À
a C H activation process, thus diminishing the general
applicability of the methods. Our findings of the highly
À
selective amide-directed, palladium-catalyzed C H amina-
tion (para position) of N-phenylacetamides[24] and benzylic
[25]
À
C H amination of N-p-tolylacetamides by commercially
À
Scheme 1. Regioselectivity in benzylic C H amination reactions.
available NFSI enabled us to find a general method for
À
directing-group-free benzylic C H amination reaction
À
of primary C H bonds, for example in 1-ethyl-4-methylben-
through a suitable choice in the catalyst system. After careful
screening (see the Supporting Information), we were pleased
to find that N-benzyl-N-(phenylsulfonyl)benzenesulfonamide
(2a) could be obtained in 80% yield from the reaction of
toluene (1a, 1.0 mmol) with NFSI (1.1 equiv) in 1,2-dichloro-
ethane (DCE, 3 mL) in the presence of CuCl (10 mol%) and
1,10-phenanthroline (phen; 5 mol%) at 1108C in open air for
3.0 hours (Scheme 2). Similarly, 2a was obtained in 80% yield
zene, remains a great challenge.[11,12] In addition, to our
knowledge, no efficient method exists for direct diamination
of the two methyl groups in xylene. Even for the amination
[*] Z.-K. Ni, Prof. Dr. Q. Zhang, T. Xiong, Y.-Y. Zheng, Y. Li, H.-W. Zhang,
Prof. Dr. J.-P. Zhang, Prof. Dr. Q. Liu
Department of Chemistry, Northeast Normal University
Changchun, 130024 (China)
À
under a nitrogen atmosphere. Interestingly, no aromatic Csp2
H functionalization product was observed as obtained in
NFSI-promoted carboamination reactions of an alkene with
toluene.[26] Notably, the above synthesis of benzylamine by
using stoichiometric amounts of toluene and an aminating
agent are rare.[27,28]
The generality of the C H amination reaction was next
examined. As described in Scheme 2, a broad range of
toluene derivatives are compatible with this operationally
E-mail: zhangq651@nenu.edu.cn
zhangjp162@nenu.edu.cn
liuqun@nenu.edu.cn
[**] This work was supported by the NCET (08-0756), the NSFC
(21172033), and the Fundamental Research Funds for the Central
Universities (09ZDQD07) for financial support of this research.
À
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201107427.
1244
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1244 –1247

Angewandte
Chemie
In addition, 1-phenylethanamine (2w), and 4-(1-aminoethyl)-
phenyl pivalate (2x) were also obtained in good yields from
ethylbenzene and 4-ethylphenyl pivalate, respectively.
The CuCl/phen catalytic system could also be applied to
the amination of the o-, m-, and p-xylene (3a–c), mesitylene
(3d), and hexamethylbenzene (3e). By using the general
reaction conditions described in Scheme 2, the corresponding
monoamination products 4a–e were synthesized in high yields
(Scheme 3). The above results show that 3e having six methyl
Scheme 3. Scope of the copper-catalyzed amination reaction using 3a–
e with NFSI. [a] Used 5.0 equiv of NFSI for 4bb–dd.
groups on the benzene ring reacted at the fastest rate to
deliver 4e. In addition, it was found that the reaction of 3b–d
also gave the corresponding diamines 4bb–dd in moderate
yields under the optimal reaction conditions (Scheme 3)
albeit it with 5.0 equivalents of NFSI. The successful diami-
nation of xylene provides the simplest access to benzylic
diamines, which are the important units in polyamides and
molecular cages.[29,30]
Scheme 2. Scope of the copper-catalyzed amination reaction using the
toluene derivatives 1a–x with NFSI. Unless otherwise noted, the
reaction conditions are as follows: 1 (1.0 mmol), NFSI (1.1 equiv), and
1,2-dichloroethane (DCE, 3 mL) in the presence of CuCl (10 mol%)
and phen (5 mol%) at 1108C in open air.
The above results clearly show the efficiency and general-
ity of this amination method (Schemes 2 and 3). Next, the
selectivity of the reaction was studied (Scheme 4). Under
À
simple copper-catalyzed C H amination reaction. Substrates
with various electron-donating and electron-withdrawing
functional groups at the para position of the benzene ring
can give the corresponding benzylamines 2b–m in good to
high yields. Remarkably, the reaction can tolerate toluene
substrates bearing electron-withdrawing groups on the ben-
zene ring (see products 2g, 2i–l). In the case of toluene
bearing a variety of typical functional groups at the meta po-
sition, the corresponding benzylamines 2o–q were also be
obtained in good yields. Under the general reaction con-
ditions described above, benzylamines 2r and 2s were
produced in good yield from 2-methylnaphthalene o-tolyl
pivalate and 1-chloro-2-methylbenzene, respectively. The
generality of the reaction was additionally demonstrated by
its application to the synthesis of 2-phenylglycine (2t), 2-
amino-2-phenylacetonitrile (2u), and 2-amino-1,2-diphenyl-
À
ethanone (2v) through Csp3 H amination adjacent to either a
carbonyl or cyano group of the active methylene compounds.
Scheme 4. Selectivity in the copper-catalyzed amination reactions of
5a and 5b using NFSI.
Angew. Chem. Int. Ed. 2012, 51, 1244 –1247
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
1245

.
Angewandte
Communications
identical reaction conditions as those described in Scheme 2,
N-(4-ethylbenzyl)-N-(phenylsulfonyl)benzenesulfonamide
(6a) and N-(phenylsulfonyl)-N-(1-p-tolylethyl)benzene-
sulfonamide (6a’) were obtained after 1.5 hours in 77%
total yield in a ratio of 10:1 from 1-ethyl-4-methylbenzene
(5a). Moreover, similar selectivity was also observed from
reaction of ethyl 2-p-tolylacetate (5b; giving 6b and 6b’ in
73% total yield with 3:1 ratio). The results shown in Scheme 4
(6a/6a’ and 6b/6b’) indicate the remarkable preference for
hindered CuIII complex. The remarkable preference for
À
primary over second C H bonds is realized for the first
time. Although the mild N-benzenesulfonate removal strat-
egy for this nitrogen source needs to be additionally explored,
we anticipate that the general copper-catalyzed, directing-
À
group-free benzylic C H amination reaction will have an
À
impact on C H amination pathways and should prompt the
À
investigation of metal complex catalysts for benzylic C H
functionalization such as C C and C O cross-coupling
reactions.
À
À
À
primary over second C H bonds in the amination reaction;
this preference is in sharp contrast to the previous
reports.[11,12]
Although the mechanistic details of this transformation Experimental Section
In a 25 mL round-bottomed flask, toluene 1a (0.106 mL, 1 mmol),
are not clear at the moment, we presently favor the catalytic
cycle involving CuI, CuII, and CuIII species (Scheme 5). In the
CuCl (9.90 mg, 0.10 mmol), NFSI (346.5 mg, 1.10 mmol), and 1,10-
phenanthroline (9.90 mg, 0.05 mmol) were dissolved in 3.0 mL DCE.
The reaction mixture was stirred at 1108C for 3 h (monitored by
TLC). After the reaction was quenched by water, the mixture was
extracted with CH2Cl2 (5.0 mL ꢀ 3), and the combined extracts were
washed with NaHCO3 (aq) (5.0 mL) and brine (5.0 mL). The organic
layer was dried over Na2SO4 and concentrated in vacuo. The residue
was purified by flash column chromatography on silica gel (eluent:
EtOAc/hexanes 1:1) to give compound 2a (309 mg, 80%) as a white
solid.
Received: October 21, 2011
Published online: December 15, 2011
À
Keywords: amination · arenes · C H activation · copper ·
synthetic methods
.
À
Scheme 5. A putative mechanism of benzylic C H amination.
L=ligand.
[1] R. Hili, A. K. Yudin, Nat. Chem. Biol. 2006, 2, 284 – 287.
[2] T. Henkel, R. M. Brunne, H. Mꢁller, F. Reichel, Angew. Chem.
1999, 111, 688 – 691; Angew. Chem. Int. Ed. 1999, 38, 643 – 647.
[3] J. A. Labinger, J. E. Bercaw, Nature 2002, 417, 507 – 514.
[4] K. Godula, D. Sames, Science 2006, 312, 67 – 72.
[5] R. Breslow, S. H. Gellman, J. Chem. Soc. Chem. Commun. 1982,
1400 – 1401.
presence of ligands, the oxidation of CuCl with NFSI provides
the CuIII complex A, which abstracts a benzylic hydrogen
atom[14,31] from substrate 1 to give the benzylic radical
intermediate B and the CuII species C. The subsequent
oxidation of the benzylic radical by the CuII species C leads to
the formation of the amination product 2 along with CuCl for
the next catalytic cycle.[32] The remarkable amination selec-
[6] F. Collet, C. Lescot, P. Dauban, Chem. Soc. Rev. 2011, 40, 1926 –
1936.
[7] F. Collet, R. H. Dodd, P. Dauban, Chem. Commun. 2009, 5061 –
5074.
[8] H. M. L. Davies, J. R. Manning, Nature 2008, 451, 417 – 424.
[9] M. Ochiai, K. Miyamoto, T. Kaneaki, S. Hayashi, W. Nakanishi,
Science 2011, 332, 448 – 451.
[10] H. J. Kim, J. Kim, S. H. Cho, S. Chang, J. Am. Chem. Soc. 2011,
133, 16382 – 16385.
[11] S. K. Y. Leung, W. M. Tsui, J. S. Huang, C. M. Che, J. L. Liang, N.
Zhu, J. Am. Chem. Soc. 2005, 127, 16629 – 16640.
[12] M. R. Fructos, S. Trofimenko, M. M. Dꢂaz-Requejo, P. J. Pꢃrez, J.
Am. Chem. Soc. 2006, 128, 11784 – 11791.
[13] K. Huard, H. Lebel, Chem. Eur. J. 2008, 14, 6222 – 6230.
[14] S. Wiese, Y. M. Badiei, R. T. Gephart, S. Mossin, M. S. Varonka,
M. M. Melzer, K. Meyer, T. R. Cundari, T. H. Warren, Angew.
Chem. 2010, 122, 9034 – 9039; Angew. Chem. Int. Ed. 2010, 49,
8850 – 8855.
À
tivity favoring the benzylic methyl C H bond could originate
from the last amination step involving the key sterically
hindered nitrogen source. Considering the steric effect, we
also performed the amination reaction of cumene, and an
unidentified mixture of products was obtained. Furthermore,
the isotope effect (kH/kD = 4.0; Scheme 6, the reaction was
performed under the optimal reaction conditions) implies the
benzylic hydrogen abstraction might be involved in the rate-
limiting step.
À
Herein, we have described a highly selective benzylic C
H amination reaction by using an in situ generated sterically
[15] D. A. Powell, H. Fan, J. Org. Chem. 2010, 75, 2726 – 2729.
[16] H. A. Zhong, J. A. Labinger, J. E. Bercaw, J. Am. Chem. Soc.
2002, 124, 1378 – 1399.
[17] L. Johansson, O. B. Ryan, C. Romming, M. Tilset, J. Am. Chem.
Soc. 2001, 123, 6579 – 6590.
Scheme 6. The kinetic deuterium isotope effect for reactions between
toluene and NFSI.
[18] A. F. Heyduk, T. G. Driver, J. A. Labinger, J. E. Bercaw, J. Am.
Chem. Soc. 2004, 126, 15034 – 15035.
1246
www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1244 –1247

Angewandte
Chemie
[19] Z. Li, D. A. Capretto, R. O. Rahaman, C. He, J. Am. Chem. Soc.
2007, 129, 12058 – 12059.
[26] C. F. Rosewall, P. A. Sibbald, D. V. Liskin, F. E. Michael, J. Am.
Chem. Soc. 2009, 131, 9488 – 9489.
[20] L. C. Campeau, D. J. Schipper, K. Fagnou, J. Am. Chem. Soc.
2008, 130, 3266 – 3267.
[21] D. Kalyani, N. R. Deprez, L. V. Desai, M. S. Sanford, J. Am.
Chem. Soc. 2005, 127, 7330 – 7331.
[22] F. Kakiuchi, K. Tsuchiya, M. Matsumoto, E. Mizushima, N.
Chatani, J. Am. Chem. Soc. 2004, 126, 12792 – 12793.
[23] K. L. Hull, W. Q. Anani, M. S. Sanford, J. Am. Chem. Soc. 2006,
128, 7134 – 7135.
[24] K. Sun, Y. Li, T. Xiong, J. Zhang, Q. Zhang, J. Am. Chem. Soc.
2011, 133, 1694 – 1697.
[27] R. Bhuyan, K. M. Nicholas, Org. Lett. 2007, 9, 3957 – 3959.
[28] C. Liang, F. Collet, F. Robert-Peillard, P. Mꢁller, R. H. Dodd, P.
Dauban, J. Am. Chem. Soc. 2008, 130, 343 – 350.
[29] H. Zeng, Z. Guan, J. Am. Chem. Soc. 2011, 133, 1159 – 1161.
[30] A. Granzhan, C. Schouwey, T. Riis-Johannessen, R. Scopelliti,
K. Severin, J. Am. Chem. Soc. 2011, 133, 7106 – 7115.
[31] H. R. Lucas, L. Li, A. A. N. Sarjeant, M. A. Vance, E. I. Solo-
mon, K. D. Karlin, J. Am. Chem. Soc. 2009, 131, 3230 – 3245.
[32] To gain additional evidence for the proposed mechanism,
ESI(+)(À)-MS experiments were performed: see the Support-
ing Information.
[25] T. Xiong, Y. Li, Y. Lv, Q. Zhang, Chem. Commun. 2010, 46,
6831 – 6833.
Angew. Chem. Int. Ed. 2012, 51, 1244 –1247
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
1247