Copper-catalyzed selective benzylic C-O cyclization of N-o-tolylbenzamides: Synthesis of 4 H-3,1-benzoxazines

Article abstract of DOI:10.1021/ol301492d

A novel Selectfluor-mediated copper-catalyzed highly selective benzylic C-O cyclization for the synthesis 4H-3,1-benzoxazines is reported. The predominant selectivity for a benzylic C(sp³)-H over an aromatic C(sp ²)-H bond in N-o-tolylbenzamides is achieved.

Full text of DOI:10.1021/ol301492d

ORGANIC
LETTERS
2012
Vol. 14, No. 13
3522–3525
Copper-Catalyzed Selective Benzylic
CꢀO Cyclization of N-o-Tolylbenzamides:
Synthesis of 4H-3,1-Benzoxazines
Yan Li,†,‡ Zhongshu Li,‡ Tao Xiong,† Qian Zhang,*,† and Xiangyang Zhang*,‡
Department of Chemistry, Northeast Normal University, 130024 Changchun, China, and
Laboratory of Organic Chemistry, ETH Zurich, 8093 Zurich, Switzerland
xiangyang.zhang@org.chem.ethz.ch; zhangq651@nenu.edu.cn
Received May 31, 2012
ABSTRACT
A novel Selectfluor-mediated copper-catalyzed highly selective benzylic CꢀO cyclization for the synthesis 4H-3,1-benzoxazines is reported. The
predominant selectivity for a benzylic C(sp3)ꢀH over an aromatic C(sp2)ꢀH bond in N-o-tolylbenzamides is achieved.
Selective direct CꢀH bond functionalization is emerging
as a valuable tool in organic synthesis.1 A particularly
appealing aspect of this chemistry is the potential to
introduce a new functional group at precise locations,
especially in multisite reactive substrates (for example,
arenes with multiple aromatic CꢀH and benzylic CꢀH
bonds). Current paradigms have greatly been achieved in
the transition metal catalyzed selective activation of aro-
matic CꢀH bonds ortho, meta, or para to the directing
group,2 whereas the proximal benzylic methyl CꢀH bonds
remain inert. Therefore, it is a great challenge to develop
transition metal catalyst systems which selectively activate
benzylic CꢀH bonds over the normally “favored” aro-
matic CꢀH bonds in the ligand directed CꢀH functionali-
zation of arenes. Copper catalysts are particularly attractive
in transition metal catalyzed direct CꢀH functionalization
reactions because of their low cost and low toxicity.2b,3ꢀ5
Since Yu et al. first reported copper-catalyzed pyridyl group
directed aromatic CꢀH bond functionalizations,4 several
related reactions have been well explored.2b,5 And, copper-
catalyzed dehydrogenative functionalizations of benzylic
CꢀH bonds with various nucleophiles have also been
(3) For a review on copper-catalyzed aromatic CꢀH bond functio-
nalizations, see: (a) Zhang, M. Appl. Organomet. Chem. 2010, 24, 269.
For selected examples of copper-catalyzed CꢀH activation, see: (b) Do,
H.-Q.; Daugulis, O. J. Am. Chem. Soc. 2007, 129, 12404. (c) Li, Z.; Li,
C.-J. J. Am. Chem. Soc. 2005, 127, 6968. (d) Do, H.-Q.; Daugulis, O.
J. Am. Chem. Soc. 2008, 130, 1128. (e) Ban, I.; Sudo, T.; Taniguchi, T.;
Itami, K. Org. Lett. 2008, 10, 3607. (f) Lee, J. M.; Park, E. J.; Cho, S. H.;
Chang, S. J. Am. Chem. Soc. 2008, 130, 7824. (g) Do, H.-Q.; Khan,
R. M. K.; Daugulis, O. J. Am. Chem. Soc. 2008, 130, 15185. (h) Li, Z.; Li,
C.-J. J. Am. Chem. Soc. 2006, 128, 56. (i) Usui, S.; Hashimoto, Y.;
Morey, J. V.; Wheatley, A. E. H.; Uchiyama, M. J. Am. Chem. Soc. 2007,
129, 15102. (j) Hamada, T.; Ye, X.; Stahl, S. S. J. Am. Chem. Soc. 2008,
130, 833. (k) Richter, J. M.; Whitefield, B. W.; Maimone, T. J.; Lin,
D. W.; Castroviejo, M. P.; Baran, P. S. J. Am. Chem. Soc. 2007, 129,
12857. (l) Wang, Q.; Schreiber, S. L. Org. Lett. 2009, 11, 5178.
(m) Yotphan, S.; Bergman, R. G.; Ellman, J. A. Org. Lett. 2009, 11,
1511.
† Northeast Normal University.
‡ ETH Zurich.
(4) Chen, X.; Hao, X.-S.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem.
Soc. 2006, 128, 6790.
(1) For selected reviews, see: (a) Labinger, J. A.; Bercaw, J. E. Nature
2002, 417, 507. (b) Godula, K.; Sames, D. Science 2006, 312, 67.
(c) Simmons, E. M.; Hartwig, J. F. Nature 2012, 483, 70.
(2) For a review on the activation of an aromatic CꢀH bond ortho to
the directing group, see: (a) Lyons, T. W.; Sanford, M. S. Chem. Rev.
2010, 110, 1147. For activation of an aromatic CꢀH bond meta to the
directing group, see: (b) Phipps, R. J.; Gaunt, M. J. Science 2009, 323,
1593. (c) Zhang, Y.-H.; Shi, B.-F.; Yu, J.-Q. J. Am. Chem. Soc. 2009,
131, 5072. For activationof an aromatic CꢀH bond para to the directing
group, see: (d) Sun, K.; Li, Y.; Xiong, T.; Zhang, J.; Zhang, Q. J. Am.
Chem. Soc. 2011, 133, 1694.
(5) (a) Ciana, C.-L.; Phipps, R. J.; Brandt, J. R.; Meyer, F.-M.;
Gaunt, M. J. Angew. Chem., Int. Ed. 2011, 50, 458. (b) Duong, H. A.;
Gilligan, R. E.; Cooke, M. L.; Phipps, R. J.; Gaunt, M. J. Angew. Chem.,
Int. Ed. 2011, 50, 463. (c) Brashe, G.; Buchwald, S. L. Angew. Chem., Int.
Ed. 2008, 47, 1932. (d) Ueda, S.; Nagasawa, H. Angew. Chem., Int. Ed.
2008, 47, 6411. (e) Ueda, S.; Nagasawa, H. J. Org. Chem. 2009, 74, 4272.
(f) Xiong, T.; Li, Y.; Bi, X.; Lv, Y; Zhang, Q. Angew. Chem., Int. Ed.
2011, 50, 7140. (g) Wang, W.; Luo, F.; Zhang, S.; Cheng, J. J. Org. Chem.
2010, 75, 2415. (h) Bernini, R.; Fabrizi, G.; Sferrazza, A.; Cacchi, S.
Angew. Chem., Int. Ed. 2009, 48, 8078.
r
10.1021/ol301492d
Published on Web 06/22/2012
2012 American Chemical Society

developed in recent years.6,7 However, to our knowledge,
copper-catalyzed directing group assisted C(sp3)ꢀH bond
functionalization is rare, with the only relevant example
using imine derivatives to direct benzylic oxidation being
reported by Chiba et al.7
Initially, N-(4-chloro-2-methylphenyl)benzamide (1a)
was used as a substrate to explore this intramolecular
cyclization reaction. The purpose for chloro occupation
of the position para to the directing group is to avoid
any complication due to competitive CꢀH bonds. In a
typical procedure, a mixture of 1a (0.4 mmol), Cu(OTf)2
(0.04 mmol, 0.1 equiv), Selectfluor (0.8 mmol, 2.0 equiv),
and HNTf2 (0.4 mmol, 1.0 equiv) was added to 1,2-
dichloroethane (DCE) and heated in a sealed tube under
an air atmosphere (eq 1).
Recently, Nagasawa et al. reported a copper-catalyzed
intramolecular CꢀO cyclization reaction of benzanilides
(Scheme 1, path a).5d,e In our previous communication, a
copper-catalyzed intermolecular CꢀH dehydrogenative
cross-coupling reaction followed by an intramolecular
CꢀO cyclization reaction was described.5f In both of the
above reactions, aromatic CꢀH bonds were efficiently
activated, but the benzylic methyl groups ortho to the
amide group stayed intact. By employing palladium cata-
lysts, Fagnou et al. achieved a selective arylation of the
corresponding aromatic CꢀH and benzylic CꢀH bonds in
azine and diazine N-oxide substrates via different activa-
tion approaches.8 Taking the possible copper-mediated
single electron trcansfer (SET) mechanism for CꢀH
functionalizaton9 intoaccount, we postulated thatbenzylic
CꢀH rather than aromatic CꢀH bonds could be selec-
tively functionalized when an appropriate copper catalytic
system is applied. Herein, we report a straightforward and
versatile method to obtain 4H-3,1-benzoxazines10 by cop-
per-catalyzed intramolecular highly selective benzylic
CꢀO bond formation from readily available ortho-methyl
benzanilides (Scheme 1, path b).
When the reaction was performed at 130 °C for 4 h, the
desired benzylic CꢀO cyclization benzoxazine 2a was
obtained in 34% yield, along with benzoxazole 3 (12%)
and aldehyde 4 (41%). The “Nagasawa” product 3 and
oxidation product 4 clearly showed the influence of oxygen
and led us to optimize the benzylic CꢀO cyclization
reaction under a N2 atmosphere. Expectantly, the reaction
became very clean and benzoxazine 2a was isolated in 71%
yield. No aromatic CꢀH (ortho to the directing group)
activation product was detected.
To further confirm the inertness of aromatic CꢀH
bonds, the substrate 1b was used instead. Benzoxazine 2b
was obtained in 81% yield without complication from
other aromatic CꢀH activation products. Therefore, sub-
strate 1b was used as a model substrate for general
optimization (Table 1, entry 1). It should be noted that
this is one of the most direct and simplest routes to
synthesize benzoxazines 2.11 No reaction was observed
when the copper catalyst, oxidant, or additive was absent
(Table 1, entries 2ꢀ4). When the oxidant or additive was
reduced by half, the yields also dropped accordingly down
to 36% or 41% (Table 1, entries 5 and 6). When other acids
such as acetic acid and trifluoroacetic acid were used, only
a trace amountof2bwasdetected(Table1, entries7 and 8).
In the presence of trifluoromethanesulfonic acid, 2b was
obtained in 43% yield (Table 1, entry 9). With N-fluoro-
2,4,6-trimethylpyridinium tetrafluoroborate or triflate as
the oxidant, 2b was obtained in 72% and 49% yield,
respectively (Table 1, entries 10 and 11). However, a widely
used oxidant tert-butyl hydroperoxide (TBHP) was not
effective in the reaction (Table 1, entry 12). Next, we
attempted to reduce the loading amount of the copper
catalyst (Table 1, entries 13ꢀ15). Surprisingly, a decrease
Scheme 1. Copper-Catalyzed Benzylic CꢀO Cyclization
(6) For a review on the general catalytic dehydrogenative cross-
couplingꢀformation of CꢀC bonds by oxidizing two CꢀH bonds, see:
(a) Yeung, C. S.; Dong, V. M. Chem. Rev 2011, 111, 1215. For more
specific work on copper-catalyzed dehydrogenative functionalization of
a benzylic CꢀH bond, see: (b) Li, C.-J. Acc. Chem. Res. 2009, 42, 335.
(c) Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2005, 127, 6968. (d) Li, Z.; Li, C.-J.
Org. Lett. 2004, 6, 4997. (e) Pelletier, G.; Powell, D. A. Org. Lett. 2006, 8,
6031. (f) Powell, D. A.; Fan, H. J. Org. Chem. 2010, 75, 2726.
(g) Borduas, N.; Powell, D. A. J. Org. Chem. 2008, 73, 7822. To our
knowledge, there are two examples of platinum- and palladium-
catalyzed carboxyl group directed intramolecular benzylic CꢀO cyclization;
ꢀ
see: (h) Lee, J. M.; Chang, S. Tetrahedron Lett. 2006, 47, 1375. (i) Novak, P.;
Correa, A.; Gallardo-Donaire, J.; Martin, R. Angew. Chem., Int. Ed. 2011,
50, 12236.
(7) To our knowledge, the only example of copper-catalyzed imine
assisted benzylic CꢀH oxygenation can be found in: Zhang, L.; Ang,
G. Y.; Chiba, S. Org. Lett. 2011, 13, 1622.
(8) Campeau, L.-C.; Schipper, D. J.; Fagnou, K. J. Am. Chem. Soc.
2008, 130, 3266.
(9) For reviews on CꢀH oxidation initiated by a single-electron tran-
sfer process, see: (a) Part 2 of the review Wendlandt, A. E.; Suess, A. M.;
Stahl, S. S. Angew. Chem., Int. Ed. 2011, 50, 11062 and references cited
therein. (b) Zhang, C.; Tang, C.; Jiao, N. Chem. Soc. Rev. 2012, 41, 3464.
(10) The 4H-3,1-benzoxazine ring system displays important biological
activities, see: (a) Dias, N.; Goosens, J. F.; Baldeyrou, B.; Lansiaux, A.;
Colson, P.; Salvo, D.; Bernal, J.; Turnbull, A.; Mincher, D.; Bailly, C.
Bioconjugate Chem. 2005, 16, 949. (b) Hays, S. J.; Caprathe, B. W.;
Gilmore, J. L.; Amin, N.; Emmerling, M. R.; Michael, W.; Nadimpalli,
R.; Nath, R.; Raser, K. J.; Stafford, D.; Watson, D.; Wang, K.; Jaen, J. C.
J. Med. Chem. 1998, 41, 1060. (c) Sugiyama, H.; Hosoda, K.; Kumagai,Y.;
Takeuchi, M.; Okada, M. U.S. Patent 4.596.801, 1986.
(11) In most cases ortho-aminobenzyl alcohols or ortho-aminobenzyl
halides or acylamino alcohols and also ortho-isocyanophenylethanones
are used as starting materials for the synthesis of 4H-3,1-benzoxazines.
These methods require prefunctionalization steps. For selected exam-
ples, see: (a) Kobayashi, K.; Okamura, Y.; Konishi, H. Synthesis 2009,
9, 1494. (b) Besson, T.; Guillaumet, G.; Lamazzi, C.; Rees, C. W. Synlett
1997, 704. (c) Nishio, I.; Kurokawa, Y.; Narasaki, Y.; Tokunaga, K.
Heterocycles 2006, 67, 247.
Org. Lett., Vol. 14, No. 13, 2012
3523

in the catalyst loading from 0.1 to 0.02 equiv had no
influence on the yield of 2b (Table 1, entries 1, 13, and
14). While decreasing catalyst loading to 0.005 equiv, no
reaction was observed (Table 1, entry 15). Other copper
using this new protocol. As described in Table 2, substrates
with electron-donating or -withdrawing groups on the
phenyl ring behaved similarly (Table 2, 2aꢀ2g). Reactions
of substrates with the second methyl group on the phenyl
ring (for example, 1c, 1d, and 1e) provided the exclusively
regioselective (only the CꢀH bond of ortho-methyl is
activated) intramolecular CꢀO cyclization product 2c,
2d, and 2e, respectively. Interestingly, no intermolecular
CꢀH dehydrogenative cross-coupling/intramolecular
CꢀO cyclization product was isolated from the substrate
1d.5f Products containing the halogen atom (Table 2, 2a
and 2g), which offer an opportunity for further cross-
coupling, could be obtained in good yields. Replacing the
methyl group ortho to the directing group by an ethyl or
isopropyl group, we found that the reaction time was
significantly reduced and the yield was accordingly in-
creased (Table 2, 2b, 2h, and 2i, from 80% to 84% and
89%), with the reactivity order of C(sp3)ꢀH bonds as
follows: tertiary CꢀH > secondary CꢀH > primary
CꢀH bond. When 1j was used as the substrate, a mixture
of 2j and 2j0 with the ratio of 2j to 2j0 (94:6) was obtained in
83% yield. These results further confirmed that the sec-
ondary C(sp3)ꢀH bond was much more reactive than the
primary C(sp3)ꢀH bond. No obvious electronic effect on
the phenyl ring of the directing group was observed (2b
salts such as CuCl2, Cu(OTf) C6H6, and CuCl were less
3
active and gave 2b in 69%, 52%, and 61% yield, respec-
tively (Table 1, entries 16ꢀ18).
Table 1. Copper-Catalyzed Benzylic CꢀO Cyclization Reaction
of 1ba,b
entry
catalyst
Cu(OTf)2
oxidant
additive
2b (%)
1
Selectfluor
Selectfluor
0
HNTf2
HNTf2
HNTf2
0
81
2
0
(100)c
(100)c
(100)c
36(40)c
41(38)c
Trace
Trace
43(30)
72(10)c
49(30)c
(100)c
80
3
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
Cu(OTf)2
Cu(OTf)2
4
Selectfluor
Selectfluord
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Fþf
5
HNTf2
e
6
HNTf2
7
HOAc
8
TFA
9
CF3SO3H
HNTf2
HNTf2
HNTf2
HNTf2
HNTf2
HNTf2
HNTf2
HNTf2
HNTf2
10
11
12
13
14
15
16
17
18
Fþg
TBHP
h
Table 2. Copper-Catalyzed Benzylic CꢀO Cyclization of
1aꢀ1na,b
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
i
Cu(OTf)2
80
(100)c
69
j
Cu(OTf)2
CuCl2
Cu(OTf) C6H6
52(33)c
3
CuCl
61
a Reactions were carried out with 1b (0.4 mmol), catalyst (0.1 equiv),
oxidant (2.0 equiv), and additive (1.0 equiv) in 1,2-dichloroethane
(DCE) (1.5 mL) under a nitrogen atmosphere at 130 °C for 4 h, unless
otherwise noted. b Yield of the isolated product. c In the parentheses,
recovery of the substrate 1b. d 1.0 equiv of Selectfluor was used.
e 0.5 equiv of HNTf2 was used. f 2.0 equiv of 1-fluoro-2,4,6-trimethyl-
pyridinium tetrafluoroborate were used. g 2.0 equiv of 1-fluoro-2,4,6-
trimethylpyridinium triflate were used. h 0.05 equiv of Cu(OTf)2 was
used. i 0.02 equiv of Cu(OTf)2 was used. j 0.005 equiv of Cu(OTf)2 was
used.
Under the optimized reaction conditions (Table 1, entry
14), various 4H-3,1-benzoxazines were synthesized by
(12) (a) Xiong, T.; Li, Y.; Lv, Y.; Zhang, Q. Chem. Commun. 2010, 46,
6831. (b) Ni, Z.; Zhang, Q.; Xiong, T.; Zheng, Y.; Li, Y.; Zhang, H.;
Zhang, J.; Liu, Q. Angew. Chem., Int. Ed. 2012, 51, 1244.
(13) Vincent, S. P.; Burkart, M. D.; Tsai, C.-Y.; Zhang, Z.; Wong,
C.-H. J. Org. Chem. 1999, 64, 5264.
(14) The active Cu(I) species can be initially formed through either
the reduction of Cu(II) by the nucleophile or the disproportionation of
Cu(II). For reduction, see: (a) Phipps, R. J.; Grimster, N. P.; Gaunt,
M. J. J. Am. Chem. Soc. 2008, 130, 8172. (b) Ley, S. V.; Thomas, A. W.
Angew. Chem., Int. Ed. 2003, 42, 5400. For disproportionation, see:
(c) Ribas, X.; Jackson, D. A; Donnadieu, B.; Mahıa, J.; Parella, T.;
´
Xifra, R.; Hedman, B.; Hodgson, K. O.; Llobet, A.; Stack, T. D. P.
Angew. Chem., Int. Ed. 2002, 41, 2991. (d) Yao, B.; Wang, D.-X.; Huang,
Z.-T.; Wang, M.-X. Chem. Commun. 2009, 2899. (e) Ribas, X.; Calle, C.;
Poater, A.; Casitas, A.; Gomez, L.; Xifra, R.; Parella, T.; Benet-
ꢁ
Buchholz, J.; Schweiger, A.; Mitrikas, G.; Sola, M.; Llobet, A.; Stack,
a Reactions were carried out with 1 (0.4 mmol), Cu(OTf)2
(0.02 equiv), Selectfluor (2.0 equiv) and HNTf2 (1.0 equiv) in 1,2-
dichloroethane (DCE) 1.5 mL under a nitrogen atmosphere at 130 °C.
unless specially mentioned. b Yield of the isolated product.
ꢀ
T. D. P. J. Am. Chem. Soc. 2010, 132, 12299.
3524
Org. Lett., Vol. 14, No. 13, 2012

Cu(I) intermediate I.14 Then, the Selectfluor-mediated
oxidative addition15 of Cu(I) provided a Cu(III) species
II2b,i,16 in the presence of HNTf2 or CF3SO3H. Next, a
hydrogen atom abstraction (HAA) of a benzylic methyl
group by the Cu(III) center formed a benzyl radical III
with a Cu(II) center.12b Finally, an intramolecular oxida-
tive coupling of intermediate III gave the benzeoxazine 2b,
leaving Cu(I) for the next catalytic cycle.
Scheme 2. Proposed Mechanism for the Formation of 2b
In conclusion, we have developed a copper-catalyzed
intramolecular benzylic CꢀO cyclization of N-o-tolylben-
zamide using Selectfluor as an oxidant for the efficient
synthesis of 4H-3,1-benzoxazines. The exclusive selectivity
for benzylic CꢀH over aromatic CꢀH bonds is realized.
The detailed mechanistic studies and the application of this
methodology for selectively benzylic CꢀH functionaliza-
tion are ongoing in our laboratory.
Acknowledgment. Financial support from the ETH
80%, 2k 76%, and 2l 79%). 2mꢀn were obtained in
excellent yields (90% and 93%) when the directing group
was replaced by the tert-butyl group, indicating the tert-
butyl group is a better promotor.
€
Zurich and Swiss National Foundation is gratefully ac-
knowledged. The authors are also thankful for additional
financial support by the NCET (08-0756), NNSFC
(21172033), and Fundamental Research Funds for the
Central Universities (09ZDQD07) from China.
Combined with our previous work,5f,12 a radical-
involved catalytic cycle was suggested for the transfor-
mation from N-o-tolylbenzamides to 4H-3,1-benzoxazines
(Scheme 2). A radical scavenger 2,6-di-tert-butyl-4-methyl-
phenol (BHT)13 (2.0 equiv) was added to the reaction under
the optimal condition (Table 1, entry 14). As a result, no
reaction was observed. This radical-involved mechanism
was also confirmed by the fact that the reaction was much
slower under an air atmosphere. The diradical-like dioxy-
gen molecule plays a role as a radical scavenger to some
extent. The suggested initial step was the formation of the
Supporting Information Available. Experimental pro-
cedures and full spectroscopic data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(16) For discussions of mechanisms involving Cu(III) intermediates,
see the following selected examples: (a) King, A. E.; Huffman, L. M.;
Casitas, A.; Costas, M.; Ribas, X.; Stahl, S. S. J. Am. Chem. Soc. 2010,
132, 12068. (b) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003,
42, 5400. (c) Phipps, R. J.; Grimster, N. P.; Gaunt, M. J. J. Am. Chem.
Soc. 2008, 130, 8172. (d) Matsumoto, T.; Ohkubo, K.; Honda, K.;
Yazawa, A.; Furutachi, H.; Fujinami, S.; Fukuzumi, S.; Suzuki, M. J.
Am. Chem. Soc. 2009, 131, 9258. In our previous work, the Cu(III)
intermediate was detected via the ESI-MS analysis; see ref 5f.
(15) The bystanding oxidant Fþ could effectively oxidize metal but
not get involved in the reductive elimination due to the metalꢀF bond
strength. For a review on Fþ oxidant mediated formation of high-valent
metal species, see: Engle, K. M.; Mei, T.-S.; Wang, X.; Yu, J.-Q. Angew.
Chem., Int. Ed. 2011, 50, 1478 and references cited therein.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 13, 2012
3525