Palladium-catalyzed Csp2-H carbonylation of aromatic oximes: Selective access to benzo[d][1,2]oxazin-1-ones and 3-methyleneisoindolin-1-ones

Article abstract of DOI:10.1039/c5cc01661d

A highly selective palladium-catalyzed carbonylation of Csp²-H bonds with aromatic oximes for the synthesis of benzo[d][1,2]oxazin-1-ones and 3-methyleneisoindolin-1-ones has been developed. Interestingly, we found that the N-OH group of the oximes could be used as a directing group and/or an internal oxidant under different conditions. This transformation is supposed to proceed through a hydroxyl-directed ortho-Csp²-H carbonylation or activation of vinyl Csp²-H bond/ortho-Csp²-H carbonylation process. The uses of readily available starting materials, atmospheric pressure of carbon monoxide, as well as operational simplicity make this practical and atom-economical method particularly attractive. This journal is

Full text of DOI:10.1039/c5cc01661d

ChemComm
View Article Online
View Journal
COMMUNICATION
Palladium-catalyzed Csp2–H carbonylation
of aromatic oximes: selective access
to benzo[d][1,2]oxazin-1-ones and
3-methyleneisoindolin-1-ones†
Cite this:DOI: 10.1039/c5cc01661d
Received 25th February 2015,
Accepted 11th March 2015
Yanli Xu, Weigao Hu, Xiaodong Tang, Jinwu Zhao, Wanqing Wu and
Huanfeng Jiang*
DOI: 10.1039/c5cc01661d
www.rsc.org/chemcomm
A highly selective palladium-catalyzed carbonylation of Csp2–H bonds
with aromatic oximes for the synthesis of benzo[d][1,2]oxazin-1-ones
and 3-methyleneisoindolin-1-ones has been developed. Interestingly, we
found that the N–OH group of the oximes could be used as a directing
group and/or an internal oxidant under different conditions. This
transformation is supposed to proceed through a hydroxyl-directed
ortho-Csp2–H carbonylation or activation of vinyl Csp2–H bond/
ortho-Csp2–H carbonylation process. The uses of readily available
starting materials, atmospheric pressure of carbon monoxide, as well
as operational simplicity make this practical and atom-economical
method particularly attractive.
The carbonylation reaction is an attractive synthetic method since
it utilizes carbon monoxide (CO) as a carbon-atom source for the
addition of a carbonyl group to organic molecules.1 Particularly,
palladium-catalyzed carbonylation for the construction of carbonyl
compounds has received considerable attention.2 There is no
doubt that Pd(0)-catalyzed Heck carbonylation of aryl halides,
triflates, and tosylates provides an expedient access to carboxylic acid
derivatives;3 however, regioselective introduction of the halide group
Scheme 1 C(sp2)–H carbonylation.
is not always straightforward, sometimes requiring several additional to the ubiquity and robustness of C–H bonds. Therefore, how to
steps. Besides, the generation of environmentally unfriendly waste design reactions that are compatible with readily available
also makes the development of alternative approaches highly starting materials where the inherent functionality of the
desirable. In order to achieve green and atom-economical molecule can be used to chelate with the metal and facilitate
synthesis, carbonylation of C–H bonds is undoubtedly an ideal selective C–H activation is a great issue. A practical solution is to use
strategy to introduce carbonyl functional units into molecules. a directing group which allows the selective C–H bond activation by
Pd(II)-catalyzed C–H carbonylation of aromatic compounds, the localized transition-metal catalyst. In recent years, a variety of
which was first discovered by Fujiwara and co-workers,4 continues functional groups including carboxylic acids,5 hydroxyl groups,6
to attract considerable attention by virtue of its atom economy and amines,7 amides,8 amidines,9 and N-containing heterocycles10 have
high efficiency. However, the chemo- and regioselective activation been reported to direct C–H bond carbonylation (Scheme 1), and the
of a specific C–H bond is still a big challenge, which should be due choice of oxidant is also very important in these cases.
Oximes are easily prepared from aldehydes and ketones and are
School of Chemistry and Chemical Engineering, South China University of Technology,
Guangzhou 510640, China. E-mail: jianghf@scut.edu.cn; Fax: +86-20-87112906;
Tel: +86-20-87112906
useful precursors for the synthesis of N-heterocycles.11 Moreover,
they can also serve as internal oxidants and have been used as
substrates for transition-metal catalyzed C–H activation.12 To the
best of our knowledge, there are no reported examples dedicated to
oximes as substrates for direct C–H bond carbonylation. Inspired
by our previous research on palladium-catalyzed carbonylation
† Electronic supplementary information (ESI) available: Experimental section,
characterization of all compounds, copies of 1H and 13C NMR spectra for selected
compounds. CCDC 1012731. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c5cc01661d
This journal is ©The Royal Society of Chemistry 2015
Chem. Commun.

View Article Online
Communication
ChemComm
reactions,13 and oxime esters as substrates,14 herein, we would provided the corresponding benzoxazinone products 2b–2f in
like to disclose a palladium-catalyzed carbonylation of Csp2–H good to excellent yields. The para-substituted acetophenone
bonds with aromatic oximes for the selective synthesis of oximes with electron-donating groups could be converted into
benzo[d][1,2]oxazin-1-ones and 3-methyleneisoindolin-1-ones the corresponding 1H-benzo[d][1,2]oxazin-1-ones (2g–2l) in good
(Scheme 1). In this reaction, we found that the N–OH group to excellent yields. However, strong electron-withdrawing groups
of the oximes could be used as a directing group or as an such as CF3 on the aromatic ring did not show a positive effect to
internal oxidant under different conditions.
this transformation, and the desired product 2m was just formed
At first, propiophenone oxime (1a) was attached with a CO in very low GC yield. The acetophenone oxime substrates with
balloon in the presence of 10 mol% PdCl2 in 2 mL mixed substituents at the meta position reacted exclusively at the less
solvent C3H7COOH/(C3H7CO)2O (v/v = 20 : 1) at 100 1C, and the sterically hindered position, leading to the formation of single
desired product 4-ethyl-1H-benzo[d][1,2]oxazin-1-one (2a) was regioisomers (2n and 2o). Moreover, the ortho-substituted aceto-
obtained in 74% yield (see the ESI† for details). It was reported that phenone oxime (R1 = F) was also a suitable substrate for this
this skeleton is an important class of heterocycle exhibiting potential transformation, and the reaction afforded 2p in 66% yield. In
biological activities. For example, the tetrahydronaphthalene– addition, the substrates 30,40-dimethylacetophenone, 1-(benzo[d]-
benzoxazine glucocorticoid receptor (GR) partial agonists (I, II) were [1,3]dioxol-5-yl)-ethanone oximes also gave good yields of the
optimized to produce potent, full agonists of GR, and compound ZK desired products 2q and 2r. Heteroaromatic substrates such as
21634832 was also reported as a GR agonist demonstrating dissocia- thiophene oxime also participated well in this process and gave
tion between transrepression and transactivation activities.15
2s in 68% yield. More sterically hindered substrates such as
Considering the importance of this skeleton, we then studied 1-(naphthalen-2-yl)ethanone oxime could be converted to the
the scope of the substrates, and the results are summarized in corresponding product 2t in 84% yield. It should be noted that
Table 1. Both phenyl alkyl ketone oximes and phenyl aryl ketone benzaldehyde oximes (3-methoxybenzaldehyde oxime and 4-methyl-
oximes were successfully subjected to this reaction system, and benzaldehyde oxime) were also good substrates for this trans-
formation, and provided the desired products 2u and 2v in 77
and 46% yields, respectively.
Table 1 Synthesis of benzoxazinones from a range of aromatic oximesa
Pleasingly, another useful product 3a was detected when a
reaction with the mixture of propiophenone oxime (1a) and 10 mol%
PdCl2 in C3H7COOH with a CO balloon was carried out at 120 1C. We
speculated that the formation of 3a might be firstly through the vinyl
Csp2–H bond activation followed by ortho-Csp2–H carbonylation.16
To our delight, a single crystal of product 3a, obtained by slow
crystallization from a mixture of petroleum ether and ethyl acetate,
illustrated its structure was (Z)-3-ethylideneisoindolin-1-one,17 which
is an important structural motif in a number of naturally occurring
compounds and designed pharmaceutical molecules.18 It is also
a useful intermediate in the synthesis of alkaloids including
lennoxamine, aristocularines and aristolactams.19 In addition,
numerous methods for their preparation have been developed;20
however, these methods often suffer from poor regioselectivity of
the product, tedious and expensive substrate preparation or
harsh reaction conditions.
Further optimization showed that the best conditions for
the synthesis of 3a included 10 mol% PdCl2, 50 mol% K2CO3 in
C3H7COOH with a CO balloon at 120 1C (for details see the
ESI†). With the optimal reaction conditions in hand, we next
evaluated the substrate scope of this transformation, and the
results are shown in Table 2. The reactions of 1-phenylbutan-1-
one and 1-phenylpentan-1-one oximes proceeded smoothly and
gave the desired products 3b and 3c in 79 and 75% yields,
respectively. Different para-substituted propiophenone oximes
including some with electron-donating groups (R0 = OMe, Me,
t-Bu, OTs) and some with electron-withdrawing groups (R0 = F,
CF3) could be converted into the corresponding products in
good to excellent yields (3d–3i), and electron-donating groups
showed a positive effect on this reaction. In the case of meta-
substituted propiophenone oximes, excellent selectivity to the
a
Reaction conditions: aromatic oximes 1 (0.5 mmol), PdCl2 (0.05 mmol),
AgOAc (1.0 mmol), CO (balloon), C3H7COOH/(C3H7CO)2O (2 mL, v/v =
20: 1), 100 1C. Yield is that of the isolated product.
C–H bond with less steric hindrance was observed, regardless
Chem. Commun.
This journal is ©The Royal Society of Chemistry 2015

View Article Online
ChemComm
Communication
Table 2 Synthesis of 3-methyleneisoindolin-1-ones from a variety of
aromatic oximesa
Scheme 3 Plausible mechanism.
from the seven-membered palladocycle B led to the desired
product 2 and concurrent formation of a Pd(0) species, which is
oxidized to Pd(II) by AgOAc and air to complete the catalytic
cycle.6a For the right pathway, oxidative addition of 1 afforded
intermediate 10, which could undergo tautomerization to generate
the enamine-derived amido-PdII species C. A molecule of CO then
bound to C and led to the formation of complex D. And C–H bond
cleavage resulted in the formation of palladacyclic complex E.
Subsequent reductive elimination afforded the 3-methyleneiso-
indolin-1-one product 3 and regenerated the active Pd(0)
catalyst.11c,22
In summary, a new and convenient palladium-catalyzed
carbonylation of Csp2–H bonds with aromatic oximes for the pre-
paration of benzo[d][1,2]oxazin-1-ones and 3-methyleneisoindolin-
1-ones has been developed. There are two pathways including a
hydroxyl-directed ortho-Csp2–H carbonylation and activation of vinyl
Csp2–H bond/ortho-Csp2–H carbonylation. The use of readily
available starting materials, atmospheric pressure of carbon
monoxide, as well as operational simplicity make this practical
and atom-economical method particularly attractive. Further
investigation toward extending this transformation to the synth-
esis of biologically active compounds is currently ongoing in our
laboratory.
We thank the National Basic Research Program of China
(973 Program) (2011CB808600), the National Natural Science
Foundation of China (21172076 and 21420102003), Guangdong
Natural Science Foundation (10351064101000000) and the
Fundamental Research Funds for the Central Universities
(2014ZP0004).
a
Reaction conditions:
1 (0.5 mmol), PdCl2 (0.05 mmol), K2CO3
(0.25 mmol), CO balloon, n-C3H7COOH (2 mL), 120 1C. Yield is that
of the isolated product.
of the electronic character of the substituents in the meta position
(3j–3k). Besides, the transformation of 1-(2-fluorophenyl)propan-1-
one oxime could also proceed smoothly, and provided the desired
product 3l in 72% yield. These results indicated that this chemical
process was tolerant towards the electronic and steric effects of the
aromatic ring.
Moreover, the free NH group in the product of 3-methylene-
isoindolin-1-ones makes it an attractive and versatile synthetic
building block in the chemical transformations. Thus, to further
highlight the application of this strategy, we next found that
compound 3a could be converted to the desired product 4, a
good bioactivity indicator receptor antagonist, in 93% yield in
the presence of 20 mol% CuI, 3 equiv. K2CO3 in DMF at 150 1C
under a N2 atmosphere (Scheme 2).
A tentative mechanism for the selectivity in Pd-catalyzed
carbon monoxide insertion to oximes is proposed in Scheme 3.
The left pathway21 is an oxime hydroxyl directing ortho-C–H
bond cleavage by Pd(II) to form the key six-membered palladacycle
intermediate A. 1,1-migratory insertion of CO into the Pd–C
bond then occurred to forge the new C–C bond, generating a
seven-membered cyclic intermediate B. Reductive elimination
Notes and references
1 For selected examples, see (a) R. Long, J. Huang, W. Shao, S. Liu,
Y. Lan, J. Gong and Z. Yang, Nat. Commun., 2014, 5, 5707;
(b) S. Sumino, A. Fusano, T. Fukuyama and I. Ryu, Acc. Chem. Res.,
2014, 47, 1563; (c) Z. Guan, Z. Ren, S. M. Spinella, S. Yu, Y. Liang and
X. Zhang, J. Am. Chem. Soc., 2009, 131, 729; (d) T. Asaumi, T. Matsuo,
T. Fukuyama, Y. Ie, F. Kakiuchi and N. Chatani, J. Org. Chem., 2004,
69, 4433; (e) N. Chatani, T. Asaumi, T. Ikeda, S. Yorimitsu, Y. Ishii,
F. Kakiuchi and S. Murai, J. Am. Chem. Soc., 2000, 122, 12882;
( f ) S. Inoue, H. Shiota, Y. Fukumoto and N. Chatani, J. Am. Chem.
Soc., 2009, 131, 6898; (g) N. Hasegawa, V. Charra, S. Inoue,
Y. Fukumoto and N. Chatani, J. Am. Chem. Soc., 2011, 133, 8070.
2 (a) L. Wu, X. Fang, Q. Liu, R. Jackstell, M. Beller and X. Wu, ACS
Catal., 2014, 4, 2977; (b) X. Wu, H. Neumann and M. Beller, Chem.
Rev., 2013, 113, 1; (c) C. E. Houlden, M. Hutchby, C. D. Bailey, J. G.
´
Ford, S. N. G. Tyler, M. R. Gagne, G. C. Lloyd-Jones and K. I. Booker-
Milburn, Angew. Chem., Int. Ed., 2009, 48, 1830; (d) R. Giri, J. K. Lam
and J. Yu, J. Am. Chem. Soc., 2010, 132, 686; (e) N. Hasegawa,
Scheme 2 Synthesis of bioactivity indicator receptor antagonist 4.
This journal is ©The Royal Society of Chemistry 2015
Chem. Commun.

View Article Online
Communication
ChemComm
V. Charra, S. Inoue, Y. Fukumoto and N. Chatani, J. Am. Chem. Soc.,
2011, 133, 8070.
Commun., 2014, 50, 2488; (d) H. Chen, C. Cai, X. Liu, X. Li and
H. Jiang, Chem. Commun., 2011, 47, 12224; (e) L. Jia, H. Jiang and
J. Li, Green Chem., 1999, 4, 91; ( f ) J. Li, H. Jiang and M. Chen, Green
Chem., 2001, 3, 137; (g) J. Li, H. Jiang, A. Feng and L. Jia, J. Org.
Chem., 1999, 64, 5984.
3 (a) A. Schoenberg, I. Bartoletti and R. F. Heck, J. Org. Chem., 1974,
39, 3318; (b) R. H. Munday, J. R. Martinelli and S. L. Buchwald, J. Am.
Chem. Soc., 2008, 130, 2754; (c) A. Brennfu¨hrer, H. Neumann and
M. Beller, Angew. Chem., Int. Ed., 2009, 48, 4114.
4 Y. Fujiwara, T. Kawauchi and H. Taniguchi, J. Chem. Soc., Chem.
Commun., 1980, 220.
5 R. Giri and J. Yu, J. Am. Chem. Soc., 2008, 130, 14082.
6 (a) Y. Lu, D. Leow, X. Wang, K. E. Engle and J. Yu, Chem. Sci., 2011,
2, 967; (b) S. Luo, F. Luo, X. Zhang and Z. Shi, Angew. Chem., Int. Ed.,
2013, 52, 10598.
14 (a) H. Huang, X. Ji, W. Wu and H. Jiang, Chem. Soc. Rev., 2015,
44, 1155; (b) X. Tang, L. Huang, J. Yang, Y. Xu, W. Wu and H. Jiang,
Chem. Commun., 2014, 50, 14793; (c) X. Tang, L. Huang, C. Qi,
W. Wu and H. Jiang, Chem. Commun., 2013, 49, 9597; (d) H. Huang,
X. Ji, X. Tang, M. Zhang, X. Li and H. Jiang, Org. Lett., 2013, 15, 6254;
(e) X. Tang, H. Gao, J. Yang, W. Wu and H. Jiang, Org. Chem. Front.,
2014, 1, 1295.
7 (a) Z. Guan, M. Chen and Z. Ren, J. Am. Chem. Soc., 2012, 134, 17490; 15 (a) M. Barker, M. Clackers, R. Copley, D. A. Demaine, D. Humphreys,
(b) D. Liang, Z. Hu, J. Peng, J. Huang and Q. Zhu, Chem. Commun., 2013,
G. G. A. Inglis, M. J. Johnston, H. T. Jones, M. V. Haase, D. House,
R. Loiseau, L. Nisbet, F. Pacquet, P. A. Skone, S. E. Shanahan, D. Tape,
V. M. Vinader, M. Washington, I. Uings, R. Upton, I. M. McLay and
S. J. F. Macdonald, J. Med. Chem., 2006, 49, 4216; (b) M. Barker,
M. Clackers, D. A. Demaine, D. Humphreys, M. J. Johnston,
H. T. Jones, F. Pacquet, J. M. Pritchard, M. Salter, S. E. Shanahan,
P. A. Skone, V. M. Vinader, I. Uings, I. M. McLay and S. J. F. Macdonald,
J. Med. Chem., 2005, 48, 4507; (c) H. Schacke, A. Schottelius, W. D. Docke,
P. Strehlke, S. Jaroch, N. Schmees, H. Rehwinkel, H. Hennekes and
K. Asadullah, Proc. Natl. Acad. Sci. U. S. A., 2004, 101, 227.
´
49, 173; (c) B. Lopez, A. Rodriguez, D. Santos, J. Albert, X. Ariza, J. Garcia
and J. Granell, Chem. Commun., 2011, 47, 1054; (d) B. Haffemayer,
M. Gulias and M. J. Gaunt, Chem. Sci., 2011, 2, 312; (e) K. Orito,
A. Horibata, T. Nakamura, H. Ushito, H. Nagasaki, M. Yuguchi,
S. Yamashita and M. Tokuda, J. Am. Chem. Soc., 2004, 126, 14342;
( f ) H. Li, G. Cai and Z. Shi, Dalton Trans., 2010, 39, 10442.
8 (a) C. E. Houlden, M. Hutchby, C. D. Bailey, J. G. Ford, S. N. G. Tyler,
´
M. R. Gagne, G. C. Lloyd-Jones and K. I. Booker-Milburn, Angew.
Chem., Int. Ed., 2009, 48, 1830; (b) E. J. Yoo, M. Wasa and J. Yu, J. Am.
Chem. Soc., 2010, 132, 17378; (c) R. Giri, J. K. Lam and J. Yu, J. Am. 16 X. Tang, L. Huang, Y. Xu, J. Yang, W. Wu and H. Jiang, Angew.
Chem. Soc., 2010, 132, 686; (d) N. Hasegawa, V. Charra, S. Inoue, Chem., Int. Ed., 2014, 53, 4205.
Y. Fukumoto and N. Chatani, J. Am. Chem. Soc., 2011, 133, 8070; 17 CCDC 1012731 (3a). A single crystal of product 3a is in ESI†.
(e) J. W. Wrigglesworth, B. Cox, G. C. Lloyd-Jones and K. I. Booker- 18 (a) E. Valencia, V. Fajardo, A. J. Freyer and M. Shamma, Tetrahedron
Milburn, Org. Lett., 2011, 13, 5326.
9 B. Ma, Y. Wang, J. Peng and Q. Zhu, J. Org. Chem., 2011, 76, 6362.
Lett., 1985, 26, 993; (b) G. Blasko, D. J. Gula and M. Shamma, J. Nat.
Prod., 1982, 45, 105.
10 (a) D. Liang, Y. He and Q. Zhu, Org. Lett., 2014, 16, 2748; (b) T. Asaumi, 19 (a) A. Couture, E. Deniau, P. Grandclaudon and C. Hoarau,
N. Chatani, T. Matsuo, F. Kakiuchi and S. Murai, J. Org. Chem., 2003,
68, 7538; (c) Y. Ie, N. Chatani, T. Ogo, D. R. Marshall, T. Fukuyama,
F. Kakiuchi and S. Murai, J. Org. Chem., 2000, 65, 1475.
Tetrahedron, 2000, 56, 1491; (b) S. Couty, B. Liegault, C. Meyer and
J. Cossy, Tetrahedron, 2006, 62, 3882; (c) A. Moreau, A. Couture,
E. Deniau and P. Grandclaudon, J. Org. Chem., 2004, 69, 4527;
(d) V. Rys, A. Couture, E. Deniau, S. Lebrun and P. Grandclaudon,
Tetrahedron, 2005, 61, 665; (e) C. Hoarau, A. Couture, H. Cornet,
E. Deniau and P. Grandclaudon, J. Org. Chem., 2001, 66, 8064.
11 (a) Y. Wei and N. Yoshikai, J. Am. Chem. Soc., 2013, 135, 3756; (b) W. Du,
M. Zhao, Z. Ren, Y. Wang and Z. Guan, Chem. Commun., 2014, 50, 7437;
(c) Y. Tan and J. F. Hartwig, J. Am. Chem. Soc., 2010, 132, 3676.
12 (a) R. K. Chinnagolla, S. Pimparkar and M. Jeganmohan, Chem. 20 For selected examples, see (a) H. Cao, L. McNamee and H. Alper,
Commun., 2013, 49, 3703; (b) P. C. Too, Y. Wang and S. Chiba, Org.
Lett., 2010, 12, 5688; (c) R. K. Chinnagolla, S. Pimparkar and
M. Jeganmohan, Org. Lett., 2012, 14, 3032; (d) C. Kornhaaß, J. Li
and L. Ackermann, J. Org. Chem., 2012, 77, 9190; (e) Y. Yoshida,
T. Kurahashi and S. Matsubara, Chem. Lett., 2012, 41, 1498;
( f ) L. Zheng, J. Ju, Y. Bin and R. Hua, J. Org. Chem., 2012, 77, 5794;
Org. Lett., 2008, 10, 5281; (b) B. Zhou, W. Hou, Y. Yang and Y. Li,
Chem. – Eur. J., 2013, 19, 4701; (c) S. Couty, B. Liegault, C. Meyer and
J. Cossy, Org. Lett., 2004, 6, 2511; (d) Y. Uozumi, N. Kawasaki,
E. Mori, M. Mori and M. Shibasaki, J. Am. Chem. Soc., 1989,
111, 3725; (e) R. Mancuso, I. Ziccarelli, D. Armentano, N. Marino,
`
S. V. Giofre and B. Gabriele, J. Org. Chem., 2014, 79, 3506.
(g) J. Ju, C. Qi, L. Zheng and R. Hua, Tetrahedron Lett., 2013, 54, 5159. 21 The KIE for the synthesis of 1H-benzo[d][1,2]oxazin-1-ones is 3 (for
13 (a) F. Ji, X. Li, W. Wu and H. Jiang, J. Org. Chem., 2014, 79, 11246; details see ESI†).
(b) J. Li, S. Yang, W. Wu and H. Jiang, Chem. Commun., 2014, 22 W. P. Hong, A. V. Iosub and S. S. Stahl, J. Am. Chem. Soc., 2013,
50, 1381; (c) Y. Xu, J. Zhao, H. Chen, W. Wu and H. Jiang, Chem.
135, 13664.
Chem. Commun.
This journal is ©The Royal Society of Chemistry 2015