Palladium-catalyzed oxidative carbonylation of the alkenyl C-H bonds of enamides: Synthesis of 1,3-oxazin-6-ones

Article abstract of DOI:10.1002/anie.201307942

Palladium and CO.: The title reaction proceeds in the presence of CO, thus providing a synthesis for 1,3-oxazin-6-ones (see scheme; DABCO=1,4- diazabicyclo[2.2.2]octane, DMF=N,N-dimethylformamide). The reaction tolerates a variety of functional groups on both the aryl ring and the amide of the substrate. Initial mechanistic studies suggest the activation of the alkenyl C-H bond to be a key step. Copyright

Full text of DOI:10.1002/anie.201307942

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Angewandte
Communications
DOI: 10.1002/anie.201307942
CÀH Activation
À
Palladium-Catalyzed Oxidative Carbonylation of the Alkenyl C H
Bonds of Enamides: Synthesis of 1,3-Oxazin-6-ones**
Ming Chen, Zhi-Hui Ren, Yao-Yu Wang, and Zheng-Hui Guan*
Carbonylation reactions with CO have been and continue to
be a very active area of research. Transition-metal-catalyzed
bond carbonylation for the synthesis of 1,3-oxazin-6-ones
under mild reaction conditions.
[
1]
[
2]
carbonylation of organic halides,
hydroformylation of
We began our study with the palladium-catalyzed carbon-
ylation of the enamide 1a with CO and ethanol. The
carbonylation product, the 1,3-oxazin-6-one 2a, was formed
in 12% yield instead of the ethoxycarbonylation product 2aa
[Eq. (1); DMF = N,N-dimethylformamide]. Importantly, the
[
3]
alkenes, and carbonylations for acetic acid and acetic
[4]
anhydride processes have been demonstrated as powerful
and practical methods to synthesize various of carbonyl
compounds. In recent decades, much progress has been made
in transition-metal-catalyzed CÀH bond activation and func-
[5]
tionalization. Ruthenium-catalyzed carbonylation of CÀH
bonds with CO and olefins has been developed for the
synthesis of aryl alkyl ketones by Murai, Chatani, and co-
[
6]
workers. Recently, palladium- and rhodium-catalyzed car-
bonylation of aromatic CÀH bonds for atom-economical
construction of aromatic carbonyl compounds have been
[
7]
developed by several groups, including ours. However,
transition-metal-catalyzed alkenyl CÀH bond activation and
carbonylation with CO for the direct synthesis of a,b-
carbonylation of the alkenyl CÀH bond of enamide was
observed. 1,3-Oxazin-6-ones are a class of important six-
membered heterocyclic compounds. Present methods for the
synthesis of 1,3-oxazin-6-ones involve the ring enlargement of
[8]
unsaturated carbonyl compounds has not yet been realized.
Enamides and their derivatives are versatile building
[
9]
blocks in organic synthesis. Asymmetric hydrogenation of
enamides and 1,2-nucleophilic addition of enamides to active
electrophiles have been developed for the synthesis of
[13]
isoxazol-5-ones or thermolysis of 1,3-dioxane-4,6-diones.
The CÀH carbonylation of enamides for the synthesis of 1,3-
oxazin-6-ones would be an ideal and environmentally friendly
approach to this structure.
[
10]
pharmaceutical chiral amines. Recently, transition-metal-
catalyzed cross-coupling of the CÀH bonds of enamides with
alkynes or organometallic regents for the construction of aza-
Therefore, the carbonylation reaction conditions were
optimized (Table 1). KI which has been shown to improve the
efficiency of palladium-catalyzed carbonylations was used in
[
11]
heterocycles have received significant attention.
In con-
[
7a,b]
nection with our interest in the CÀH bond carbonylation,
[7a,14]
we hypothesized that palladium-catalyzed oxidative carbon-
the reaction as an additive.
The yield of 2a was improved
ylation of the CÀH bond of an enamide may be achieved
to 25% (Table 1, entry 2). By screening various solvents, such
under a CO atmosphere. However, the execution of this
carbonylation reaction faces a formidable challenge: palla-
dium-catalyzed CÀH carbonylation preferentially proceeds
as CH CN, toluene, and THF, we found that DMF was still is
3
the most effective solvent (Table 1, entries 3–5). Increasing
the loading of KI resulted in a 35% yield of 2a. However,
further increasing the loading of KI resulted in no improve-
ment (Table 1, entry 6). Next, acetic anhydride, which may
inhibit the possible reduction of the active palladium(II)
catalyst intermediate to inactive palladium(0) by CO, was
under acidic conditions, thus generating highly electrophilic
[
7c,d]
cationic palladium(II) species
and inhibiting the possible
II
0
[7b–c,12]
reduction of Pd to Pd by CO,
tolerated under acidic conditions.
but enamides cannot be
Herein, we describe the
[
10,11]
[
7b–c,12]
development of a palladium-catalyzed oxidative alkenyl CÀH
added to the reaction,
5% (Table 1, entry 7). To further improve the reaction
and the yield 2a was improved to
4
outcome, various bases were screened. Among of various
inorganic bases and organic bases, DABCO (1,4-diazabicyclo-
[2.2.2]octane) was found to be the most effective for this
carbonylation reaction, thus giving 2a in 84% yield (Table 1,
entries 8–12).
[
*] M. Chen, Z.-H. Ren, Prof. Y.-Y. Wang, Prof. Dr. Z.-H. Guan
Key Laboratory of Synthetic and Natural Functional Molecule
Chemistry of Ministry of Education, Department of Chemistry &
Materials Science, Northwest University
Xi’an, 710069 (P. R. China)
With the optimized reaction conditions established, the
scope of the reaction was investigated (Table 2). This new
carbonylation reaction displayed high functional-group toler-
ance and proved to be a quite general methodology. Aryl
enamides with methyl, phenyl, methoxyl, [1,3]dioxole, amino,
fluoro, and sensitive functional groups such as chloro and
bromo groups on the aromatic rings all gave the correspond-
E-mail: guanzhh@nwu.edu.cn
Homepage: http://chem.nwu.edu.cn/teacher.php?id=189
[
**] This work was supported by generous grants from the National
Natural Science Foundation of China (NSFC-21272183, 21002077),
and the Fund of the Rising Stars of Shanxi Province (2012KJXX-26).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201307942.
1
4196
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Chemie
Table 1: Reaction optimization for the palladium-catalyzed carbonylation
of the alkenyl CÀH bond of enamide.
Table 2: (Continued)
Entry Substrate
[
a]
Product
Yield
[
b]
[
%]
6
89
73
78
[
b]
Entry
Additive
Base
Solvent
Yield [%]
1
2
3
4
5
–
–
–
–
–
–
–
–
DMF
DMF
12
25
9
KI
KI
KI
KI
KI
7
8
9
CH CN
3
toluene
THF
8
18
35
45
56
38
48
50
84
[
[
[
[
c]
6
7
8
9
1
1
1
DMF
DMF
DMF
DMF
DMF
DMF
DMF
c,d]
c,d]
c,d]
KI, Ac O
KI, Ac O
KI, Ac O
KI, Ac O
KI, Ac O
KI, Ac O
2
KOAc
K2CO3
tBuOK
NEt3
2
2
[
[
[
c,d]
0
1
2
2
c,d]
c,d]
2
DABCO
2
81
74
88
79
70
40
83
[
a] Reaction conditions: enamide 1a (0.2 mmol), Pd(OAc) (5 mol%),
2
Cu(OAc) (1.0 equiv), KI (0.2 equiv), base (1.5 equiv), solvent (2 mL),
CO (balloon pressure), at 808C. [b] Yield of isolated product. [c] KI
(
2
2
1.0 equiv). [d] Ac O (3.0 equiv). THF=tetrahydrofruan.
1
0
Table 2: Palladium-catalyzed carbonylation of the alkenyl CÀH bond of
[
a]
11
enamides for the synthesis of 1,3-oxazin-6-ones.
1
1
1
1
2
3
4
5
Entry
1
Substrate
Product
Yield
[
b]
[%]
84
86
2
3
4
80
95
[
a] Reaction conditions: enamide 1 (0.2 mmol), Pd(OAc) (5 mol%),
2
Cu(OAc) (1.0 equiv), KI (1.0 equiv), Ac O (3.0 equiv), DABCO
(
isolated product. Boc=tert-butoxycaarbonyl.
2
2
1.5 equiv), DMF (2 mL), CO (balloon pressure), 808C. [b] Yield of
ing substituted 1,3-oxazin-6-ones in high to excellent yields.
Electron-neutral substituents, such as methyl, alkyl, phenyl,
on the aromatic ring of the enamides give the best results with
up to 95% yield of the 1,3-oxazin-6-one product under the
standard conditions (Table 2, entries 1–5). Enamides substi-
tuted with electron-donating groups, such as methoxyl,
5
86
[
1,3]dioxole, and amino, or electron-withdrawing groups
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such as chloro and bromo, reacted smoothly and resulted in
the carbonylation products 2 f–m in 70–89% yields, thus
implying that the electronic nature of the substrates has little
influence on the carbonylation reaction (Table 2, entries 6–
were unable to induce the carbonylation reaction, for
example, N-(3,4-dihydronaphthalen-1-yl)acetamide (1u)
gave only trace amounts of the desired product 2u, and 1u
was mostly recovered (Table 3, entry 6).
1
3). However, the strong electron-poor nitro-substituted 2n
To gain more insight into the mechanism of the reaction,
1a was reacted with a stoichiometric amount of palladium
was only obtained in 40% yield, with 52% recovery of the
enamide 1n (Table 2, entry 14). In addition, the b-naphthyl-
substituted enamide 1o shows reactivity similar to that of the
aryl-substituted enamides and afforded the corresponding 2o
in 83% yield (Table 2, entry 15).
Furthermore, N-propionyl and N-benzoyl enamides (1p–
t) were investigated to explore the reaction scope (Table 3).
The carbonylation reactions proceeded smoothly to give the
corresponding 2-ethyl and 2-phenyl 1,3-oxazin-6-ones 2p–t in
good yields. These results indicated that a variety of 2-
substituted 1,3-oxazin-6-ones could be prepared by this
carbonylation reaction. However, b-substituted enamides
acetate in [D ]DMSO. A palladium complex, whose structure
6
1
is consistent with A by H NMR and high-resolution mass
spectrometry analysis, was obtained in nearly quantitative
yield [Eq. (2); DMSO = dimethylsulfoxide; S in structure A
[
15]
stands for solvent].
Loh and co-workers had recently
characterized the same six-membered vinylpalladium com-
[
8b]
plex. Our data is in agreement with the results reported by
Loh and co-workers.
Table 3: Palladium-catalyzed carbonylation of the alkenyl CÀH bond of
[
a]
enamides for the synthesis of 1,3-oxazin-6-ones.
Then, the stoichiometric reaction was performed in DMF
which was optimized solvent for the carbonylation reaction
[
15]
[
Eq. (3)].
Treating the vinylpalladium complex A with
Entry
1
Substrate
Product
Yield
[
b]
[%]
61
83
87
66
85
DABCO in the presence of KI in DMF under a CO
atmosphere gave the 2a in 70% yield. Therefore, the
vinylpalladium complex A, which was generated from alkenyl
CÀH bond cleavage, should be a key intermediate in the
2
carbonylation reaction.
On the basis of the above results and previous studies,
a tentative mechanism for this carbonylation is proposed in
3
4
5
6
Scheme 1. Alkenyl CÀH activation by Pd(OAc) forms the
2
<5
[
a] Reaction conditions: enamide 1 (0.2 mmol), Pd(OAc) (5 mol%),
2
Cu(OAc) (1.0 equiv), KI (1.0 equiv), Ac O (3.0 equiv), DABCO
2
2
(
1.5 equiv), DMF (2 mL), CO (balloon pressure), 808C. [b] Yield of
Scheme 1. A plausible mechanism for palladium-catalyzed carbonyla-
isolated product.
tion of enamides.
1
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Chemie
[
8a–b,16]
vinylpalladium intermediate A.
Coordination and inser-
Sanford, Chem. Rev. 2010, 110, 1147; f) A. E. Shilov, G. B.
Shulꢂpin, Chem. Rev. 1997, 97, 2879.
tion of CO into A affords the acylpalladium intermediate B.
Then, B is transformed into C assisted by DABCO. Reductive
elimination of C gives the carbonylation product 1,3-oxazin-6-
one 2 and Pd . Finally, Pd is reoxidized by Cu(OAc) to
regenerate the Pd(OAc) catalyst.
[
6] a) N. Chatani, T. Fukuyama, F. Kakiuchi, S. Murai, J. Am. Chem.
Soc. 1996, 118, 493; b) T. Fukuyama, N. Chatani, J. Tatsumi, F.
Kakiuchi, S. Murai, J. Am. Chem. Soc. 1998, 120, 11522; c) N.
Chatani, T. Asaumi, T. Ikeda, S. Yorimitsu, Y. Ishii, F. Kakiuchi,
S. Murai, J. Am. Chem. Soc. 2000, 122, 12882; d) S. Inoue, H.
Shiota, Y. Fukumoto, N. Chatani, J. Am. Chem. Soc. 2009, 131,
6898; e) N. Hasegawa, V. Charra, S. Inoue, Y. Fukumoto, N.
Chatani, J. Am. Chem. Soc. 2011, 133, 8070.
0
0
2
2
In summary, we have developed the first palladium-
catalyzed carbonylation of alkenyl CÀH bonds of enamides
with CO for the synthesis of 1,3-oxazin-6-ones. The reaction
[
7] a) Z.-H. Guan, M. Chen, Z.-H. Ren, J. Am. Chem. Soc. 2012,
employs KI and Ac O as additives and proceeds under mild
2
134, 17490; b) Z.-H. Guan, Z.-H. Ren, S. M. Spinella, S. Yu, Y.-
basic conditions. This novel palladium-catalyzed carbonyla-
tion reaction tolerates a wide range of functional groups and
is a reliable method for the rapid elaboration of readily
available enamides into a variety of substituted 1,3-oxazin-6-
ones under atomospheric pressure of CO. Further studies on
substrate scope and mechanism of the reaction are underway
in our laboratory and will be reported in due course.
M. Liang, X. Zhang, J. Am. Chem. Soc. 2009, 131, 729; c) R. Giri,
J. K. Lam, J.-Q. Yu, J. Am. Chem. Soc. 2010, 132, 686; d) C. E.
Houlden, M. Hutchby, C. D. Bailey, J. G. Ford, S. N. G. Tyler,
M. R. Gagne, G. C. Lloyd-Jones, K. I. Booker-Milburn, Angew.
Chem. 2009, 121, 1862; Angew. Chem. Int. Ed. 2009, 48, 1830;
e) Y. Lu, D. Leow, X. Wang, K. M. Engle, J.-Q. Yu, Chem. Sci.
2011, 2, 967; f) R. Giri, J.-Q. Yu, J. Am. Chem. Soc. 2008, 130,
14082; g) B. Haffemayer, M. Guliasa, M. J. Gaunt, Chem. Sci.
2011, 2, 312; h) H. Zhang, R. Shi, P. Gan, C. Liu, A. Ding, Q.
Wang, A. Lei, Angew. Chem. 2012, 124, 5294; Angew. Chem. Int.
Ed. 2012, 51, 5204; i) K. Orito, A. Horibata, T. Nakamura, H.
Ushito, H. Nagasaki, M. Yuguchi, S. Yamashita, M. Tokuda, J.
Am. Chem. Soc. 2004, 126, 14342; j) P. Xie, Y. Xie, B. Qian, H.
Zhou, C. Xia, H. Huang, J. Am. Chem. Soc. 2012, 134, 9902; k) S.
Luo, F.-X. Luo, X.-S. Zhang, Z.-J. Shi, Angew. Chem. 2013, 125,
10792; Angew. Chem. Int. Ed. 2013, 52, 10598; l) D. Liang, Z. Hu,
J. Peng, J. Huang, Q. Zhu, Chem. Commun. 2013, 49, 173; m) Q.
Xing, L. Shi, R. Lang, C. Xia, F. Li, Chem. Commun. 2012, 48,
11023.
Experimental Section
Enamides 1 (0.2 mmol), Pd(OAc)2 (5 mol%, 2.2 mg), Cu(OAc)2
(0.2 mmol, 36.3 mg), KI (0.2 mmol, 33.2 mg), Ac O (0.6 mmol,
2
6
1.2 mg), DABCO (0.3 mmol, 33.6 mg), and DMF (2 mL) was
charged in a 10 mL round-bottom flask. The flask was then, evacuated
and back-filled with CO (3-times, balloon) and stirred at 808C. When
the reaction was completed (detected by TLC), the mixture was
cooled to room temperature and vented to discharge the excess CO.
The reaction was quenched with H O (10 mL) and extracted with
2
EtOAc (3 ꢀ 10 mL). The combined organic layers were dried over
anhydrous Na SO and then evaporated in vacuo. The residue was
purified by column chromatography on silica gel to afford the
corresponding 1,3-oxazin-6-one 2 with hexanes/ethyl acetate as the
eluent.
[8] a) K. Sasano, J. Takaya, N. Iwasawa, J. Am. Chem. Soc. 2013, 135,
10954; b) Y.-H. Xu, Y. K. Chok, T.-P. Loh, Chem. Sci. 2011, 2,
1822; c) C. Feng, T.-P. Loh, Chem. Sci. 2012, 3, 3458; d) H. Chen,
C. Cai, X. Liu, X. Li, H. Jiang, Chem. Commun. 2011, 47, 12224.
[9] For the synthesis of enamides, see: Z.-H. Guan, Z.-Y. Zhang, Z.-
H. Ren, Y.-Y. Wang, X. Zhang, J. Org. Chem. 2011, 76, 339.
[10] a) J.-H. Xie, S.-F. Zhu, Q.-L. Zhou, Chem. Rev. 2011, 111, 1713;
b) K. Gopalaiah, H. B. Kagan, Chem. Rev. 2011, 111, 4599; c) R.
Matsubara, S. Kobayashi, Acc. Chem. Res. 2008, 41, 292; d) W.
Zhang, Y. Chi, X. Zhang, Acc. Chem. Res. 2007, 40, 1278.
2
4
Received: September 10, 2013
Published online: November 7, 2013
Keywords: CÀH activation · carbonylation · heterocycles ·
.
[11] a) S. Pankajakshan, Y.-H. Xu, J. K. Cheng, M. T. Low, T.-P. Loh,
Angew. Chem. 2012, 124, 5799; Angew. Chem. Int. Ed. 2012, 51,
heterogeneous catalysis · palladium
5701; b) H. Zhou, Y.-H. Xu, W.-J. Chung, T.-P. Loh, Angew.
Chem. 2009, 121, 5459; Angew. Chem. Int. Ed. 2009, 48, 5355;
c) H. Zhou, W.-J. Chung, Y.-H. Xu, T.-P. Loh, Chem. Commun.
[
1] a) X.-F. Wu, H. Neumann, M. Beller, Chem. Rev. 2013, 113, 1;
b) Q. Liu, H. Zhang, A. Lei, Angew. Chem. 2011, 123, 10978;
Angew. Chem. Int. Ed. 2011, 50, 10788.
2009, 3472; d) K. D. Hesp, R. G. Bergman, J. A. Ellman, J. Am.
Chem. Soc. 2011, 133, 11430; e) D. R. Stuart, P. Alsabeh, M.
Kuhn, K. Fagnou, J. Am. Chem. Soc. 2010, 132, 18326; f) L.
Wang, L. Ackermann, Org. Lett. 2013, 15, 176; g) M.-N. Zhao,
Z.-H. Ren, Y.-Y. Wang, Z.-H. Guan, Chem. Commun. 2012, 48,
[
2] a) X.-F. Wu, H. Neumann, M. Beller, Chem. Soc. Rev. 2011, 40,
4986; b) A. Brennfꢁhrer, H. Neumann, M. Beller, Angew. Chem.
2009, 121, 4176; Angew. Chem. Int. Ed. 2009, 48, 4114; c) X.-F.
Wu, P. Anbarasan, H. Neumann, M. Beller, Angew. Chem. 2010,
22, 7474; Angew. Chem. Int. Ed. 2010, 49, 7316; d) H. Zhang, R.
Shi, A. Ding, L. Lu, B. Chen, A. Lei, Angew. Chem. 2012, 124,
2710; Angew. Chem. Int. Ed. 2012, 51, 12542.
8
105.
12] a) J. Dupont, C. S. Consorti, J. Spenser, Chem. Rev. 2005, 105,
527; b) A. D. Ryabov, Synthesis 1985, 233; c) H. Horino, N.
1
[
[
[
2
1
Inoue, J. Org. Chem. 1981, 46, 4416.
[
3] a) R. Franke, D. Selent, A. Bçrner, Chem. Rev. 2012, 112, 5675;
b) F. Hebrard, P. Kalck, Chem. Rev. 2009, 109, 4272.
13] a) F. Risitano, G. Grassi, F. Foti, F. Caruso, G. L. Vecchio, J.
Chem. Soc. Perkin Trans. 1 1979, 1522; b) Y. Yamamoto, Y.
Morita, K. Minami, Chem. Pharm. Bull. 1986, 34, 1980.
14] a) Z.-H. Guan, H. Lei, M. Chen, Z.-H. Ren, Y. Bai, Y.-Y. Wang,
Adv. Synth. Catal. 2012, 354, 489; b) S. Fukuoka, M. Chono, M.
Kohno, J. Org. Chem. 1984, 49, 1458; c) V. L. K. Valli, H. Alper,
Organometallics 1995, 14, 80.
[
4] a) J. R. Zoeller, V. H. Agreda, S. L. Cook, N. L. Lafferty, S. W.
Polichnowski, D. M. Pond, Catal. Today 1992, 13, 73; b) J. F.
Roth, J. H. Craddock, A. Hershman, F. E. Paulik, Chem. Tech.
1
971, 1, 600.
5] a) K. M. Engle, T.-S. Mei, M. Wasa, J.-Q. Yu, Acc. Chem. Res.
012, 45, 788; b) S. H. Cho, J. Y. Kim, J. Kwak, S. Chang, Chem.
[
2
[
[
15] See the Supporting Information for details.
16] G. R. Newkome, K. J. Theriot, B. K. Cheskin, D. W. Evans, G. R.
Baker, Organometallics 1990, 9, 1375.
Soc. Rev. 2011, 40, 5068; c) C.-L. Sun, B.-J. Li, Z.-J. Shi, Chem.
Rev. 2011, 111, 1293; d) D. A. Colby, R. G. Bergman, J. A.
Ellman, Chem. Rev. 2010, 110, 624; e) T. W. Lyons, M. S.
Angew. Chem. Int. Ed. 2013, 52, 14196 –14199
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