Rhodium-catalyzed oxidative ortho -acylation of benzamides with aldehydes: Direct functionalization of the sp2 C-H bond

Article abstract of DOI:10.1021/ol201729w

A rhodium-catalyzed oxidative acylation of benzamides with aryl aldehydes via direct sp² C-H bond cleavage is described. In the presence of [Cp*RhCl₂]₂, AgSbF₆, and silver carbonate as an oxidant, N,N-diethyl be

Full text of DOI:10.1021/ol201729w

ORGANIC
LETTERS
2011
Vol. 13, No. 16
4390–4393
Rhodium-Catalyzed Oxidative ortho-
Acylation of Benzamides with Aldehydes:
Direct Functionalization of the sp2
CÀH Bond
Jihye Park,† Eonjeong Park,† Aejin Kim,† Youngil Lee,† Ki-Whan Chi,†
Jong Hwan Kwak,‡ Young Hoon Jung,‡ and In Su Kim*,†
Department of Chemistry, University of Ulsan, Ulsan, 680-749, Republic of Korea, and
School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea
insukim@ulsan.ac.kr
Received June 27, 2011
ABSTRACT
A rhodium-catalyzed oxidative acylation of benzamides with aryl aldehydes via direct sp2 CÀH bond cleavage is described. In the presence of
[Cp*RhCl2]2, AgSbF6, and silver carbonate as an oxidant, N,N-diethyl benzamides can be effectively carbonylated to yield ortho-acyl benzamides.
Transition-metal-catalyzed direct transformation of in-
active C;H bonds has emerged as a powerful tool for the
facile production of structurally diverse organic mole-
cules.1 Since the pioneering efforts of Murai,2 great pro-
gress has been made in transition-metal-catalyzed C;H
bond functionalization upon trapping with appropriate
electrophiles or nucleophiles under oxidative or basic
conditions, respectively.3 In particular, reactions involving
the activation of C;H bonds by a neighboring directing
(4) For recent selected examples, see: (a) Lu, Y.; Wang, D.-H.; Engle,
K. M.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 5916. (b) Schiffner, J. A.;
€
Woste, T. H.; Oestreich, M. Eur. J. Org. Chem. 2010, 174. (c) Xiao, B.;
Fu, Y.; Xu, J.; Gong, T.-J.; Dai, J.-J.; Yi, J.; Liu, L. J. Am. Chem. Soc.
2010, 132, 468. (d) Patureau, F. W.; Glorius, F. J. Am. Chem. Soc. 2010,
132, 9982. (e) Wang, D.-H.; Engle, K. M.; Shi, B.-F.; Yu, J.-Q. Science
2010, 327, 315. (f) Wasa, M.; Engle, K. M.; Yu, J.-Q. J. Am. Chem. Soc.
2010, 132, 3680. (g) Wang, F.; Song, G.; Li, X. Org. Lett. 2010, 12, 5430.
(h) Zhang, Y.-H.; Shi, B.-F.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131,
† University of Ulsan.
‡ Sungkyunkwan University.
(1) (a) Dyker, G. Handbook of CÀH Transformations: Application in
Organic Synthesis; Wiley-VCH: Weinheim, 2005. (b) Yu, J. Q.; Shi, Z. J.
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5072. (i) Garcıa-Rubia, A.; Arrayas, R. G.; Carretero, J. C. Angew.
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Sonoda, M.; Chatani, N. Nature 1993, 366, 529.
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(5) For recent selected examples, see: (a) Muralirajan, K.; Parthasarathy,
K.; Cheng, C.-H. Angew. Chem., Int. Ed. 2011, 50, 4169. (b) Rakshit,
S.; Patureau, F. W.; Glorius, F. J. Am. Chem. Soc. 2010, 132, 9585. (c)
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6908. (d) Morimoto, K.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett.
2010, 12, 2068. (e) Mochida, S.; Hirano, K.; Satoh, T.; Miura, M. J. Org.
Chem. 2009, 74, 6295. (f) Guimond, N.; Fagnou, K. J. Am. Chem. Soc.
2009, 131, 12050. (g) Li, L.; Brennessel, W. W.; Jones, W. D. J. Am.
Chem. Soc. 2008, 130, 12414. (h) Umeda, N.; Tsurugi, H.; Satoh, T.;
Miura, M. Angew. Chem., Int. Ed. 2008, 47, 4019. (i) Stuart, D. R.;
Bertrand-Laperle, M.; Burgess, K. M. N.; Fagnou, K. J. Am. Chem. Soc.
2008, 130, 16474.
(3) For recent reviews on CÀH bond functionalization, see: (a)
Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147. (b) Mkhalid,
I. A. I.; Barnard, J. H.; Marder, T. B.; Murphy, J. M.; Hartwig, J. F.
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Chem. Rev. 2010, 110, 890. (c) Coperet, C. Chem. Rev. 2010, 110, 656. (d)
Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010, 110, 624.
(e) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Commun. 2010, 46, 677. (f)
Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed.
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Res. 2008, 41, 222. (j) Diaz-Requejo, M. M.; Perez, P. J. Chem. Rev.
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r
10.1021/ol201729w
Published on Web 07/27/2011
2011 American Chemical Society

group have been extensively investigated. As a result, the
combination of transition metals and directing groups
provides efficient conversion of C;H bonds to C;C,4,5
C;X,6 C;O,7 and C;N bonds.8 Although car-
bonÀcarbon bond formation reactions using CdC4 or
CtC5 bonds as the coupling partners have been well
established, the reactions between C;H bonds and C;
heteroatom unsaturated bonds (e.g., CdO and CdN
bonds) remain relatively unexplored. In 2009, Cheng
reported a palladium-catalyzed coupling reaction between
arene compounds containing a pyridine-directing group
and aryl aldehydes to afford aryl ketones.9 Li and co-
workers described the palladium-catalyzed oxidative sp2
C;H bond acylation of 2-phenylpyridine or benzo-
[h]quinoline with aliphatic aldehydes in the presence of
Pd(OAc)2 with tert-butyl hydroperoxide as an oxidant.10
Deng and Li also demonstrated a palladium-catalyzed
sp2Àsp2 coupling reaction of 2-arylpyridines and benzylic
or aliphatic alcohols from the alcohol oxidation level.11 Ge
developed palladium-catalyzed decarboxylative C;H
bond acylation of arylpyridines or acetanilides using R-
oxocarboxylic acids as the acyl surrogates to yield ortho-
acyl arylpyridine12 or ortho-acyl acetanilides,13 respec-
tively. Also, Li and Kwong reported palladium-catalyzed
oxidative coupling of acetanilides and aldehydes to pro-
vide ortho-acyl acetanilides.14 Recently, the Ellman15 and
Shi groups16 described very similar results, which included
rhodium-catalyzed direct addition of the C;H bond of
arylpyridines to the CdN bond of N-sulfonyl aldimines or
N-Boc aldimines providing the corresponding amine com-
pounds. However, from a synthetic point of view, the
introduction of a pyridine-directing group9À12,15,16 can
pose additional barriers to their use due to the difficulty
of further manipulations to the desired functional groups.
Aryl ketones are crucial structural motifs in biologically
active compounds and functional materials.17 Traditional
methods for the preparation of aryl ketones rely primarily
on FriedelÀCrafts acylation18 or the reaction of activated
carboxylic acid derivatives, (e.g., Weinreb amides), with
organometallic reagents prepared by halogenÀmetal ex-
change reactions of aryl halides.19 However, these appro-
aches present intrinsic drawbacks, namely, the deficiency
of regioselectivity and the need for prefunctionalization of
both coupling partners. Therefore, it is highly desirable to
develop more efficient methodologies for synthesizing aryl
ketones with fewer synthetic steps that avoid waste for-
mation.
As part of an ongoing research program directed toward
the development of transition-metal-catalyzed carbonÀ
carbon bond formation reactions,20 we became interested
in developing an efficient route to synthesize ortho-acyl
benzamides from benzamides via CÀH bond activation.
Herein, we report the rhodium-catalyzed regioselective
acylation of sp2 CÀH bonds using aldehydes as the acyl
sources in the presence of silver carbonate as an oxidant,
affording aryl ketones in moderate to good yields.
Our initial investigation focused on the coupling of N,
N-diethyl benzamide (1a) with benzaldehyde (2a); selected
results are summarized in Table 1. To our delight, the
cationic rhodium complex, derived from [Cp*RhCl2]2 and
AgSbF6, was found to catalyze the coupling of benzamide
1a and aldehyde 2a to produce the desired adduct 3a in
23% yield (Table 1, entry 1). Neutral rhodium complexes
did not promote the coupling reaction. Our study focused
on the use of oxidants such as Ag2CO3, benzoquinone, O2
gas, (NH4)2S2O8, and CuCO3 (Table 1, entries 5À9). Since
aldehydes are sensitive to some oxidants, the choice of
oxidants is crucial for this transformation. The use of
Ag2CO3 as the oxidant resulted in the acylation of a sp2
CÀH bond in N,N-diethyl benzamide (1a) to afford the
desired product 3a as a single regioisomer in 41% yield, as
shown in entry 5. However, the combination of isolable
catalyst, [Cp*Rh(CH3CN)3][SbF6]2, and Ag2CO3 was re-
latively ineffective. Solvent screening showed that an im-
proved chemical yield could be obtained using THF as a
solvent, providing the ortho-acylation product 3a in 58%
yield (Table 1, entry 14), whereas the use of other solvents
such as chlorobenzene, toluene, and 1,4-dioxane was less
effective (Table 1, entries 11À13). After further optimiza-
tion, the best results were obtained using a treatment of 5
mol % of [Cp*RhCl2]2 and 20 mol % of AgSbF6, in the
presence of 200 mol % of Ag2CO3 in THF solvent at
110 °C for 20 h, affording the desired aryl ketone 3a in high
yield (70%), as shown in entry 15.
(7) For recent selected examples, see: (a) Wang, X.; Lu, Y.; Dai,
H.-X.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 12203. (b) Zhang, Y.-H.;
Yu, J.-Q. J. Am. Chem. Soc. 2009, 131, 14654. (c) Powers, D. C.; Geibel,
M. A. L.; Klein, J. E. M. N.; Ritter, T. J. Am. Chem. Soc. 2009, 131,
17050. (d) Desai, L. V.; Stowers, K. J.; Sanford, M. S. J. Am. Chem. Soc.
2008, 130, 13285.
(8) For recent selected examples, see: (a) Ackermann, L.; Lygin,
A. V.; Hofmann, N. Org. Lett. 2011, 13, 3278. (b) Cho, S. H.; Yoon,
J.; Chang, S. J. Am. Chem. Soc. 2011, 133, 5996. (c) Shuai, Q.; Deng, G.;
Chua, J.; Bohle, D. S.; Li, C.-J. Adv. Synth. Catal. 2010, 352, 632. (d)
Mei, T.-S.; Wang, X.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131, 10806. (e)
Wang, Q.; Schreiber, S. L. Org. Lett. 2009, 11, 5178. (f) Monguchi, D.;
Fujiwara, T.; Furukawa, H.; Mori, A. Org. Lett. 2009, 11, 1607.
(9) Jia, X.; Zhang, S.; Wang, W.; Luo, F.; Cheng, J. Org. Lett. 2009,
11, 3120.
ꢀ
(10) Basle, O.; Bidange, J.; Shuai, Q.; Li, C.-J. Adv. Synth. Catal.
2010, 352, 1145.
(11) Xiao, F.; Shuai, Q.; Zhao, F.; Basle, O.; Deng, G.; Li, C.-J. Org.
ꢀ
Lett. 2011, 13, 1614.
(12) Li, M.; Ge, H. Org. Lett. 2010, 12, 3464.
(13) Fang, P.; Li, M.; Ge, H. J. Am. Chem. Soc. 2010, 132, 11898.
(14) Wu, Y.; Li, B.; Mao, F.; Li, X.; Kwong, F. Y. Org. Lett. 2011, 13,
3258.
(15) Tsai, A. S.; Tauchert, M. E.; Bergman, R. G.; Ellman, J. A. J.
Am. Chem. Soc. 2011, 133, 1248.
(16) Li, Y.; Li, B.-J.; Wang, W.-H.; Huang, W.-P.; Zhang, X.-S.;
Chen, K.; Shi, Z.-J. Angew. Chem., Int. Ed. 2011, 50, 2115.
(17) (a) Surburg, H.; Panten, J. Common Fragrance and Flavor
Materials, 5th ed.; Wiley-VCH: Weinheim, Germany, 2006. (b) Deng, Y.;
Chin, Y.-W.; Chai, H.; Keller, W. J.; Kinghorn, A. D. J. Nat. Prod. 2007, 70,
2049. (c) Romins, K. R.; Freeman, G. A.; Schaller, L. T.; Cowan, J. R.;
Gonzales, S. S.; Tidwell, J. H.; Andrews, C. W.; Stammers, D. K.;
Hazen, R. J.; Ferris, R. G.; Short, S. A.; Chan, J. H.; Boone, L. R. J.
Med. Chem. 2006, 49, 727. (d) Masson, P. J.; Coup, D.; Millet, J.; Brown,
N. L. J. Biol. Chem. 1994, 270, 2662.
Apart from the N,N-diethylamide moiety as a direct-
ing group, the influence of other directing groups was
(18) Sartori, G.; Maggi, R. Advances in FriedelÀCrafts Acylation
Reactions; CRC Press: Boca Raton, FL, 2010.
(19) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.
(20) Park, J.; Park, E.; Kim, A.; Park, S.-A.; Lee, Y.; Chi, K.-W.;
Jung, Y. H.; Kim, I. S. J. Org. Chem. 2011, 76, 2214.
Org. Lett., Vol. 13, No. 16, 2011
4391

Table 1. Selected Optimization for Reaction Conditionsa
Table 2. Screening of Directing Groupsa
yield
(%)b
yield
(%)b
entry
ligand
AgSbF6
oxidant
solvent
entry
R
product
1
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
23
1
2
3
4
5
6
N(Et)2
1a
1b
1c
1d
1e
1f
3a
3b
3c
3d
3e
3f
70
0
2
AgOTf
trace
4
NHMe
3
AgBF4
N(Me)2
64
6
4
AgPF6
7
N(Bn)2
5
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
[Cp*Rh(CH3CN)3]-
[SbF6]2
Ag2CO3
41
pyrrolidine
morpholine
52
8
6
benzoquinone
O2
trace
7
7
a Reaction conditions: 1aÀf (0.3 mmol), 2a (0.6 mmol), 110 °C for
20 h under N2 in 13 Â 100 mm2 pressure tubes. b Yield isolated by column
chromatography.
8
(NH4)2S2O8
CuCO3
trace
8
9
10c
Ag2CO3
38
11
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
PhCl
27
13
32
58
70
12
13
14
15d
toluene
dioxane
THF
Scheme 1. Scope of Aldehydes in the Oxidative ortho-Acylationa
THF
a Reaction conditions: 1a (0.3 mmol), 2a (0.6 mmol), [Cp*RhCl2]2
(2.5 mol %), ligand (10 mol %), oxidant (0.6 mmol), solvent (1 mL) at
110 °C for 20 h under N2 in 13 Â 100 mm2 pressure tubes. b Yield isolated
by column chromatography. c [Cp*Rh(CH3CN)3][SbF6]2 (5 mol %)
was used as a catalyst. d [Cp*RhCl2]2 (5 mol %) and AgSbF6 (20 mol %)
were used.
examined, as outlined in Table 2. Primary amide 1b did not
yield the desired product (Table 2, entry 2). Dimethyla-
mide 1c and amide 1e derived from pyrrolidine were
compatible with the reaction conditions (Table 2, entries
3 and 5), whereas sterically hindered dibenzylamide 1d and
less Lewis basic amide 1f were far more ineffective in this
coupling (Table 2, entries 4 and 6).
To explore the substrate scope and limitaions of this
process, theestablishedreactionconditions wereappliedto
aromatic aldehydes 2a and 2gÀ2p, as shown in Scheme 1.
2-Naphthylaldehyde (2g) underwent the sp2Àsp2 cou-
pling reaction to afford a good yield of the ortho-arylated
product 3g. The coupling of benzamide 1a and aldehydes
2h and 2i with para-substituted electron-donating groups
(Me and OMe) gave the corresponding products 3h and 3i
in high yields. Electron-rich meta-anisaldehyde 2j and
piperonal 2k were also converted to the corresponding
products 3j and 3k, respectively. Moreover, halogen-sub-
stituted aldehydes 2l and 2m were compatible under op-
timal reaction conditions. In particular, the bromo moiety
of 3m remained intact during the course of the reaction,
allowing for further cross-coupling reactions to be per-
formed on the products. In contrast, electron-deficient
m-nitrobenzaldehyde (2n) was less reactive under these
reaction conditions. Finally, the heterocyclic aldehydes 2o
and 2p also participated in the oxidative coupling to
furnish 3o and 3p in slightly decreased yields. It should
a Reaction conditions: 1a (0.3 mmol), aldehyde (0.6 mmol), 110 °C for
20 h under N2 in 13 Â 100 mm2 pressure tubes. bYield isolated by column
chromatography.
be noted that the reaction exclusively afforded the mono-
acylated products in all cases, and no bis-acylation pro-
ducts were observed by 1H NMR or GC-MS analysis.
To further evaluate the scope of this process, the cou-
pling of a variety of benzamides 1gÀq and p-anisaldehyde
(2h) under identical reaction conditions was examined
(Scheme 2). Electron-neutral and electron-richbenzamides
1gÀl were found to be favored in the reaction, whereas
substrates with electron-withdrawing groups (e.g., NO2
4392
Org. Lett., Vol. 13, No. 16, 2011

2-naphthamide 1q selectively afforded the corresponding
product 4q in 55% yield. Interestingly, no C-1 acylation
adduct was obtained since the CÀH bond in the C-8
position of the naphthalene moiety may interfere with
the approach of the aldehyde to the C-1 position.
Scheme 2. Scope of N,N-Diethyl Benzamides in the Oxidative
ortho-Acylationa
Scheme 3. Oxidative ortho-Acylation of Dicarboxamide
Finally, we examined the reaction of dicarboxamide 1r
and p-anisaldehyde (2h) under optimal reaction condi-
tions. As expected, dicarboxamide 1r was converted to
the monoacylated product 5a and the bis-acylated product
5b with an excellent regioselectivity in 23% and 52% yield,
respectively (Scheme 3).
Inconclusion, wehavedevelopedanefficient method for
Rh-catalyzed oxidative carbonylation of benzamides with
aldehydes via CÀH bond activation. The cationic rhodium
complex, derived from [Cp*RhCl2]2 and AgSbF6, cata-
lyzes the coupling of N,N-diethyl benzamides and aryl
aldehydes in the presence of Ag2CO3 to yield ortho-mono-
acylated N,N-diethyl benzamides. Mechanistic studies and
applications for the synthesis of biologically active com-
pounds are currently underway, and the results will be
reported in due course.
a Reaction conditions: 1gÀq (0.3 mmol), 2h (0.6 mmol), 110 °C for 20
h under N2 in 13 Â 100 mm2 pressure tubes. bYield isolated by column
chromatography.
and CO2Et) in para- or meta-positions failed to deliver the
acylation products under these conditions (data not shown).
This observation is consistent with the previous results that
monoacylated adducts with an electron-withdrawing acyl
moiety did not participate in the bis-acylation process.
Benzamides 1mÀo with halogen functional groups (F, Cl,
and Br) were well converted to the corresponding products
4mÀo, respectively. However, ortho-methoxy substituted
benzamide 1p gave a low yield, presumably due to the
increased steric effect preventing the formation of a copla-
nar conformation between the aromatic ring and the
ketonemoiety in the N,N-diethylamide group. Inaddition,
Acknowledgment. This work was supported by Na-
tional Research Foundation of Korea (Nos. 2010-0002465
and 2011-0005400) and the Priority Research Centers Pro-
gram (No. 2009-0093818) through the National Research
Foundation of Korea funded by the Ministry of Educa-
tion, Science and Technology.
Supporting Information Available. Spectroscopic data
for all compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 16, 2011
4393