Copper-catalyzed dehydrogenative cross-coupling reactions of N-para-tolylamides through successive C-H activation: Synthesis of 4H-3,1-benzoxazines

Article abstract of DOI:10.1002/anie.201101391

A novel annulation reaction of readily available tolylamides was catalyzed by Cu(OTf)₂ in the presence of Selectfluor and water through successive intermolecular C-H activated dehydrogenative cross-coupling reactions of benzylic methyl C(sp³)-H and aromatic C(sp²)-H bonds, and subsequent intramolecular C-O bond formation (see scheme). Copyright

Full text of DOI:10.1002/anie.201101391

Communications
DOI: 10.1002/anie.201101391
À
C H Activation
Copper-Catalyzed Dehydrogenative Cross-Coupling Reactions of
À
N-para-Tolylamides through Successive C H Activation: Synthesis of
4H-3,1-Benzoxazines**
Tao Xiong, Yan Li, Xihe Bi,* Yunhe Lv, and Qian Zhang*
Carbon–carbon bond-formation reactions are among the
most important processes in chemistry because they enable
key steps in building more complex molecules from simple
precursors. A transition-metal-catalyzed dehydrogenative
À
Scheme 1. Design for DCC reactions of benzylic methyl C(sp3)-H and
cross-coupling (DCC) reaction from two C H bonds will
avoid the installation of functional groups and thus make
synthetic routes shorter and more efficient. Some excellent
pioneering progress had been achieved on this subject.[1]
However, important limitations in regioselectivity and unde-
sired homocoupling pathways still exist. A remarkable
method for suppressing homocoupling relies on achieving
2
À
À
ligand directed aromatic C(sp ) H bonds through C H activation
catalyzed by a transition-metal hydroxo complex. L=ligand.
À
and ArCH2 M bond, will lead to a DCC product C by
reductive elimination. So far, to the best of our knowledge,
À
two successive palladium-catalyzed C H activations of two
there is no example of DCC reactions through transition-
2
À
arene substrates (for example, indole and benzene) utilizing
mechanistic duality.[2] Considering both regioselectivity and
the elimination of homocoupling, the development of
directed metalation[3] of a metal catalyst with potential
dichotomous behavior for highly regioselective activation of
metal-catalyzed activation of both aromatic C(sp ) H and
3
[1a,6,7]
À
benzylic methyl C(sp ) H bonds.
Copper catalysts are particularly attractive in transition-
À
metal-catalyzed direct C H functionalization reactions
because of their low cost and low toxicity.[8] Recently, a
À
À
two kinds of C H bonds in a successive manner, might
become a promising strategy for efficient DCC reactions.
From the mechanistic point of view, most of the ligand-
copper-catalyzed intramolecular oxidative C O coupling of
benzanilides was developed, in which the para-methyl group
was unreactive (Scheme 2, path a).[8d,e] Herein, we report a
directed transition metals (such as Pd, Ru,
2
À
Rh, and Pt) catalyzed aromatic C(sp ) H
bonds functionalizations through cyclome-
talated intermediates. The cyclometalated
intermediates such as cyclopalladium spe-
cies were known to be reluctant to undergo
homocoupling reaction under Pd0/II condi-
tions.[3] On the other hand, benzylic methyl
II
À
Scheme 2. Copper-catalyzed C H functionalization. Tf=trifluoromethanesulfonyl.
À
C H bonds could be activated by Ru
hydroxo complexes[4] through possible
[5]
À
ambiphilic or nucleophilic C H activation. Therefore, we
hypothesized that by choosing a suitable metal hydroxo
novel annulation of N-para-tolylamides catalyzed by Cu-
(OTf)2 and with Selectfluor as the oxidant, for the synthesis of
complex catalyst A (Scheme 1), a successive C H activation
4H-3,1-benzoxazines[9] through successive intermolecular C
À
À
2
À
À
involving ligand directed ortho-arene C(sp ) H bond and
H activated DCC reaction of aromatic C H and benzylic
3
À
À
À
benzylic methyl C(sp ) H bond might take place. As a result,
the formation of intermediate B, which contains Ar M bond
methyl C H bonds, and subsequent intramolecular C O
bond formation (Scheme 2, path b). During this reaction a
catalytic amount of water might play an important role for
in situ generation of the key copper hydroxo complex
catalyst.
À
[*] T. Xiong, Y. Li, Prof. Dr. X.-H. Bi, Y.-H. Lv, Prof. Dr. Q. Zhang
Department of Chemistry, Northeast Normal University
Changchun, 130024 (China)
Based on our recent studies on the palladium-catalyzed
amide-directed benzylic C H[10a] and aromatic ortho- or para-
À
C H
Fax: (+86)431-509-9759
À
E-mail: bixh507@nenu.edu.cn
[10b]
amination with N-fluorobenzenesulfonimide (F+ as
zhangq651@nenu.edu.cn
oxidant), we sought to use Selectfluor as an oxidant to
perform an amide-directed DCC reaction. Therefore, our
initial testing was carried out in the presence of Selectfluor
(1.0 equiv) and HNTf2 (1.0 equiv), Cu(OTf)2 (0.1 equiv)
catalyzed the reaction of N-para-tolylpivalamide (1a;
Table 1). When the reaction was performed at 1208C for
[**] Financial support of this research by the NCET-08-0756, NNSFC
(20902010), JLSDP (20080547), and the Fundamental Research
Funds for the Central Universities (09ZDQD07) is gratefully
acknowledged.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201101391.
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ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 7140 –7143

Table 1: Copper-catalyzed DCC reactions of 1a.
this new method. As described in Table 2, substrates with
electron-withdrawing or electron-donating groups on the
benzene ring worked well (Table 2, entries 1–12). Reactions
Table 2: Copper-catalyzed DCC reactions of 1b–q.[a]
Entry
1
R1
R2
t [h] Yield [%][b]
Entry Catalyst
Solvent
H2O [equiv] t [h] Yield of
2a (3a) [%][a]
1
2
3
4
5
6
7
8
1b
1c
1d
1e
1 f
1g
1h
1i
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
3-Me
2-Me
3-F
3-Cl
3-Br
3-Ph
2-Ph
2-(4-MeC6H4)
2-(4-ClC6H4)
2-(3-CF3C6H4)
2-C6H3-5-Me
1.5
3.0
2.0
1.8
3.0
1.1
1.5
1.3
2.0
2.0
2.0
76
54
67
62
61
79
87
82
84
73
76
80
84
80
91
62
1
2
3
4
5
6
7
8
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
DCE
DCE
DCE
DCE
DCE
DCE
–
6.0
0
1.0
0.05
0.1
0.2
0.5
2.5 63 (12)
2.0 81
1.5 88
3.5 74
3.0 67 (6)
2.0 78
Cl2CHCHCl2 0.1
C6H5NO2
DCE
9
1j
1k
1l
0.1
0.1
0.1
0.1
0.1
0.1
2.0 74
2.0 80
9[b]
10
11
12
13
10
11
12
13
14
15
16[c]
Cu(OAc)2 DCE
12.0
12.0
0
0
1m tBu
2-(4-MeC6H4)-5-Me 1.4
CuCl2
CuF2
CuI
DCE
DCE
DCE
12.0 43[c]
12.0 27[d]
1n
1o
1p
1q
Ph
Ph
Ph
3-Me
3-Cl
H
1.8
1.2
2.0
2.5
[a] Yield of the isolated product. [b] N-Fluoro-2,4,6-trimethylpyridinium
tetrafluoroborate was used instead of Selectfluor. [c] 38% of 1a was
recovered. [d] 59% of 1a was recovered. Also, the same result was
obtained by adding 0.1 equiv of 1,10-phenanthroline and without HNTf2.
=
CH CHCH3
H
[a] Reactions were carried out with 1 (0.3 mmol), Cu(OTf)2 (0.1 equiv),
H2O (0.1 equiv), Selectfluor (2.0 equiv), and HNTf2 (1.0 equiv) in
anhydrous DCE (2 mL) at 1208C. [b] Yield of the isolated product.
[c] With N-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate as the
oxidant.
6.0 hours with anhydrous 1,2-dichloroethane (DCE) as the
solvent, no reaction occurred (Table 1, entry 1). Surprisingly,
when 1.0 equivalent of H2O was added to the above reaction,
an intermolecular annulation product 4H-3,1-benzoxazine 2a
was generated in 63% yield, along with 12% of 3a (Table 1,
entry 2). When 0.05, 0.1, 0.2 or 0.5 equivalents of H2O were
added, 2a was obtained in 81%, 88%, 74%, and 67% yield,
respectively (Table 1, entries 3–6). These results showed that
during the transformation from 1a into 2a, a catalytic amount
of H2O played an important role. Therefore, 0.1 equivalent of
H2O (Table 1, entry 4) was used for further optimization of
the reaction condition. When the reactions were performed
with Cl2CHCHCl2 and C6H5NO2 as solvents, 2a were
obtained in 78% and 74% yield, respectively, along with
some unidentified by-products (Table 1, entries 7 and 8). With
N-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate as the
oxidant, 2a could also be obtained in 80% yield (Table 1,
entry 9). Other copper salts such as Cu(OAc)2 and CuCl2 were
not effective, and most of the 1a was recovered (Table 1,
entries 10 and 11). Copper salts CuF2 and CuI were less
effective, and gave 2a in 43% and 27% yield, respectively
(Table 1, entries 12 and 13). No reaction was observed in the
absence of the copper salts. Interestingly, during the trans-
of substrates with ortho- and meta-methyl groups on the
benzene ring (for example, 1b and 1c), provided the highly
regioselective para-methyl-substituted annulation products.
Products containing fluoride 2d, chlorides 2e, 2j, and 2o as
well as bromide 2 f could be obtained in good to high yields.
The tolerance for chlorides and bromide on the aromatic ring
in this transformation offers an opportunity for further cross-
À
coupling. When meta-substituted substrates were used, C C
coupling occurred exclusively at the less-hinder site (Table 2,
entries 1, 3–6, 13, and 14). We also found that 2n–q could be
obtained by changing the acyl directing groups (Table 2,
entries 13–16), in which benzamido was identified as the best
directing group in the transformation from 1 into 2 (Table 2,
entries 13–15). However, no reaction occurred with substrate
N-para-tolylacetamide,
3-methyl-N-para-tolylbutanamide,
and 2-phenyl-N-para-tolylacetamide, which may result from
their lack of directing ability when using Cu(OTf)2 in the
transformation.[11] In addition, starting from substrate N-(4-
ethylphenyl)benzamide with an ethyl group para to the direct
amide group, no reaction occurred.
À
formation from 1a into 2a, no intramolecular C O coupling
benzoxazole product (Scheme 2, path a) and homocoupling
by-products were detected.
To help ascertain the character of the key copper complex
catalyst that is generated in situ, the corresponding 19F NMR
and ESI/MS experiments were performed.[12] The Cu F bond
À
Under the optimized reaction conditions (Table 1,
entry 4), various 4H-3,1-benzoxazines were generated with
region of 19F NMR spectra of a mixture of CuI (1.0 equiv),
1,10-phenanthroline (1.0 equiv), and N-fluoro-2,4,6-trime-
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7141

Communications
[2] D. R. Stuart, K. Fagnou, Science 2007, 316, 1172 – 1175.
[3] Selected reviews for directed metalation: a) K. Godula, D.
Sames, Science 2006, 312, 67 – 72; b) T. W. Lyons, M. S. Sanford,
Chem. Rev. 2010, 110, 1147 – 1169; selected examples for
thylpyridinium tetrafluoroborate (3.0 equiv) showed a single
signal at d = À256 ppm. The results of ESI/MS experiment
under the above conditions indicates the formation of the
in situ generated CuIIIFOH complex catalyst.[12] Moreover,
when the reaction of 1a was performed under the conditions
described in Table 1, entry 9, but with 1.0 equivalent of
suppressing homocoupling through the use of
a directing
group: c) K. L. Hull, M. S. Sanford, J. Am. Chem. Soc. 2007,
129, 11904 – 11905; d) J. B. Xia, S. L. You, Organometallics 2007,
26, 4869 – 4871; e) B. J. Li, S. L. Tian, Z. Fang, Z. J. Shi, Angew.
Chem. 2008, 120, 1131 – 1134; Angew. Chem. Int. Ed. 2008, 47,
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Soc. 2006, 128, 12634 – 12635; g) C. S. Yeung, X. Zhao, N.
Borduas, V. M. Dong, Chem. Sci. 2010, 1, 331 – 336.
À
Cu(OTf)2, after 20 minutes, the Cu F bond region exhibited
a single signal at d = À227 ppm as shown in the 19F NMR
spectra.[12] In our experiment, the formation of C C coupling/
À
oxidation product 3a (Table 1) might indicate that during the
À
formation of 2, C C bond coupling occurred before the
À
[4] We are aware of two examples for benzylic methyl C H
À
coupling of the C O bond. Therefore, the transformation
activation mediated by a RuII hydroxo complex: a) Y. Feng, M.
Lail, K. A. Barakat, T. R. Cundari, T. B. Gunnoe, J. L. Petersen,
J. Am. Chem. Soc. 2005, 127, 14174 – 14175; b) B. G. Hashiguchi,
K. J. H. Young, M. Yousufuddin, W. A. Goddard III, R. A.
Periana, J. Am. Chem. Soc. 2010, 132, 12542 – 12544.
from 1 into 2 might begin with the successive activation of
À
both benzylic methyl and aromatic C H bonds by the
CuIIIFOH complex catalyst that is generated in situ to provide
À
the intermolecular C C bond-coupling intermediate as de-
À
À
scribed in Scheme 1. The next intramolecular C O coupling
[5] It was suggested that the variously named C H activation
reactions can be broadly classified on a continuum of electro-
philic, ambiphilic, or nucleophilic character depending on the
reactions give the final annulation products 2. Further
investigation of the mechanism of this transformation is
under way.[13–15]
À
net direction of charge transfer between the C H bond and the
À
metal fragment in the transition state for C H cleavage, see:
In conclusion, we have reported a novel Cu(OTf)2-
catalyzed annulation for the construction of benzoxazine
derivatives from readily available N-para-tolylamides in the
presence of Selectfluor and water through the first intermo-
D. H. Ess, R. J. Nielsen, W. A. Goddard III, R. A. Periana, J.
Am. Chem. Soc. 2009, 131, 11686 – 11688.
2
À
[6] Examples for cross-coupling of aromatic C(sp ) H and benzylic
3
À
C(sp ) H, see: a) Z. Li, D. S. Bohle, C. J. Li, Proc. Natl. Acad.
À
lecular C H activated dehydrogenative cross-coupling reac-
Sci. USA 2006, 103, 8928 – 8933; b) Z. Li, C. J. Li, J. Am. Chem.
Soc. 2005, 127, 6968 – 6969; c) Y.-Z. Li, B. J. Li, X. Y. Lu, S. Lin,
Z. J. Shi, Angew. Chem. 2009, 121, 3875 – 3878; Angew. Chem.
3
2
À
À
tion of benzylic methyl C(sp ) H and aromatic C(sp ) H
À
bonds, and subsequent intramolecular C O bond formation.
This strategy might inspire the development of additional new
catalyst for DCC reaction between two different kinds of
Int. Ed. 2009, 48, 3817 – 3820.
[7] For a recent review on transition-metal-mediated C(sp ) H
3
À
functionalization reactions, see: R. Jazzar, J. Hitce, A. Renaudat,
J. Sofack-Kreutzer, O. Baudoin, Chem. Eur. J. 2010, 16, 2654 –
2672.
À
unactivated C H bonds. Studies are ongoing to apply this
DCC cascade for the synthesis of other heterocycles.
À
[8] a) A recent review on copper-catalyzed aromatic C H function-
alization: M. Zhang, Appl. Organomet. Chem. 2010, 24, 269 –
284; b) X. Chen, X. S. Hao, C. E. Goodhue, J. Q. Yu, J. Am.
Chem. Soc. 2006, 128, 6790 – 6791; c) G. Brasche, S. L. Buchwald,
Angew. Chem. 2008, 120, 1958 – 1960; Angew. Chem. Int. Ed.
2008, 47, 1932 – 1934; d) S. Ueda, H. Nagasawa, Angew. Chem.
2008, 120, 6511 – 6513; Angew. Chem. Int. Ed. 2008, 47, 6411 –
6413; e) S. Ueda, H. Nagasawa, J. Org. Chem. 2009, 74, 4272 –
4277; f) Y. Wei, H. Zhao, J. Kan, W. Su, M. Hong, J. Am. Chem.
Soc. 2010, 132, 2522 – 2523; g) F. Bellina, R. Rossi, Adv. Synth.
Catal. 2010, 352, 1223 – 1276.
Experimental Section
N-para-tolylpivalamide 1a (57.3 mg, 0.3 mmol), Cu(OTf)2 (10.8 mg,
0.03 mmol), Selectfluor (212.6 mg, 0.6 mmol), and HNTf2 (84 mg,
0.3 mmol) were added to an over-dried screw-cap test tube equipped
with a magnetic stir bar while in a glovebox. The test tube was then
sealed off with a screw-cap and taken out of the glovebox. Then
solvent (2.0 mL; from a mixture of 10 mL DCE and 2.7 mL H2O) was
added, the vessel was evacuated and backfilled with nitrogen (this
process was repeated a total of three times). The reaction mixture was
stirred at 1208C for the 1.3 h. After cooling to RT, the mixture was
poured on ice-water and extracted with dichloromethane (3 ꢀ 15 mL).
The combined organic layers were dried (Na2SO4), filtered over
Celite, and evaporated in vacuo. The residue was purified by column
chromatography on silica gel with a gradient eluent of n-hexane and
ethyl acetate to afford the product 2a (49.9 mg, 88%).
[9] 4H-3,1-benzoxazine ring system displays important biological
activities: a) N. Dias, J. F. Goosens, B. Baldeyrou, A. Lansiaux, P.
Colson, D. Salvo, J. Bernal, A. Turnbull, D. Mincher, C. Bailly,
Bioconjugate Chem. 2005, 16, 949 – 958; b) S. J. Hays, B. W.
Caprathe, J. L. Gilmore, N. Amin, M. R. Emmerling, W.
Michael, R. Nadimpalli, R. Nath, K. J. Raser, D. Stafford, D.
Watson, K. Wang, J. C. Jaen, J. Med. Chem. 1998, 41, 1060 – 1067;
c) H. Sugiyama, K. Hosoda, Y. Kumagai, M. Takeuchi, M.
Okada, U.S. Patent 4.596.801, 1986.
Received: February 24, 2011
Revised: May 20, 2011
Published online: June 10, 2011
[10] a) T. Xiong, Y. Li, Y. Lv, Q. Zhang, Chem. Commun. 2010, 46,
6831 – 6833; b) K. Sun, Y. Li, T. Xiong, J. Zhang, Q. Zhang, J.
À
Keywords: benzoxazines · C H activation · copper ·
Am. Chem. Soc. 2011, 133, 1694 – 1697.
[11] Selected examples for amide-directed C(sp ) H functionaliza-
.
2
À
cross-coupling · Selectfluor
tion: a) O. Daugulis, V. G. Zaitsev, Angew. Chem. 2005, 117,
4114 – 4116; Angew. Chem. Int. Ed. 2005, 44, 4046 – 4048;
b) W. C. P. Tsang, N. Zheng, S. L. Buchwald, J. Am. Chem. Soc.
2005, 127, 14560 – 14561; also see Ref. [3e].
[1] For recent reviews of dehydrogenative cross-coupling reactions,
see: a) C. J. Li, Acc. Chem. Res. 2009, 42, 335 – 344; b) J. A.
Ashenhurst, Chem. Soc. Rev. 2010, 39, 540 – 548; c) C. Jia, T.
Kitamura, Y. Fujiwara, Acc. Chem. Res. 2001, 34, 633 – 639.
[12] For details of 19F NMR and ESI/MS spectra, see the Supporting
Information.
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Angew. Chem. Int. Ed. 2011, 50, 7140 –7143

[13] There is no obvious effect on the annulation reactions by
addition of 2,2,6,6-tetramethyl-piperidine-1-oxyl (TEMPO), and
thus suggests no radical mechanism.
Costas, X. Ribas, S. S. Stahl, J. Am. Chem. Soc. 2010, 132, 12068 –
12073; b) S. V. Ley, A. W. Thomas, Angew. Chem. 2003, 115,
5558 – 5607; Angew. Chem. Int. Ed. 2003, 42, 5400 – 5449; c) R. J.
Phipps, M. J. Gaunt, Science 2009, 323, 1593 – 1597; d) R. J.
Phipps, N. P. Grimster, M. J. Gaunt, J. Am. Chem. Soc. 2008, 130,
[14] Under the optimal reaction conditions described in Table 1,
entry 4, the reaction between 1a and 1b provided an inseparable
mixture.
8172 – 8174; AuIII F bond was proven to exist, see: e) N. P.
À
[15] For discussions of mechanisms involving CuIII intermediates, see
selected examples: a) A. E. King, L. M. Huffman, A. Casitas, M.
Mankad, F. D. Toste, J. Am. Chem. Soc. 2010, 132, 12859 – 12861.
Angew. Chem. Int. Ed. 2011, 50, 7140 –7143
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