Pd-catalyzed ortho-C-H acylation/cross coupling of aryl ketone O-methyl oximes with aldehydes using tert-butyl hydroperoxide as oxidant

Article abstract of DOI:10.1021/ol101618u

A Pd-catalyzed protocol for direct C-H bond acylation by cross coupling of aryl ketone oximes and aldehydes using tert-butyl hydroperoxide (TBHP) as oxidant was developed. With oximes as a directing group for the C-H activation, the coupling with aldehydes was achieved with remarkable regioselectivity. The acylation reactions exhibit excellent functional group tolerance, and both aliphatic and heteroaromatic aldehydes can be effectively coupled to the oximes.

Full text of DOI:10.1021/ol101618u

ORGANIC
LETTERS
2010
Vol. 12, No. 17
3926-3929
Pd-Catalyzed Ortho-C-H Acylation/
Cross Coupling of Aryl Ketone O-Methyl
Oximes with Aldehydes Using tert-Butyl
Hydroperoxide as Oxidant
Chun-Wo Chan, Zhongyuan Zhou, Albert S. C. Chan, and Wing-Yiu Yu*
State Key Laboratory of Chirosciences and the Open Laboratory of Chirotechnology of
the Institute of Molecular Technology for Drug DiscoVery and Synthesis, Department
of Applied Biology and Chemical Technology, The Hong Kong Polytechnic UniVersity,
Hung Hom, Kowloon, Hong Kong
bcwyyu@inet.polyu.edu.hk
Received July 13, 2010
ABSTRACT
A Pd-catalyzed protocol for direct C-H bond acylation by cross coupling of aryl ketone oximes and aldehydes using tert-butyl hydroperoxide
(TBHP) as oxidant was developed. With oximes as a directing group for the C-H activation, the coupling with aldehydes was achieved with
remarkable regioselectivity. The acylation reactions exhibit excellent functional group tolerance, and both aliphatic and heteroaromatic aldehydes
can be effectively coupled to the oximes.
Aryl ketones are important motifs in some bioactive and
functional materials.1 Apart from the classical Friedel-Crafts
acylation reactions,2 which often suffer from poor regioselec-
tivity and the use of a stoichiometric amount of reactive acyl
halide reagents, transition metal catalyzed cross coupling
reactions of aldehydes with arylboronic acids or aryl halides
have emerged as an appealing alternative to Friedel-Crafts
chemistry.3 Hartwig and co-workers also reported a convenient
synthesis of aryl ketones by Pd-catalyzed coupling of aryl
bromides with N-tert-butylhydrazones as an acyl anion equiva-
lent.4 Other Pd-catalyzed cross coupling reactions of aryl halides
under carbonylative5 and decarbonylative6 conditions are also
developed. Despite the apparent success of the cross coupling
strategy, catalytic reactions that transform unactivated C-H
bonds to aryl ketones are sparse in the literature.
Significant progress has been achieved in the Pd-catalyzed
regioselective C-H bond arylations and vinylations.7 How-
(4) Takemiya, A.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128, 14800.
(5) Neumann, H.; Brennführer, A.; Beller, M. Chem.sEur. J. 2008, 14,
3645. For a review, see Brunet, J.-J.; Chauvin, R. Chem. Soc. ReV. 1995,
24, 89.
(1) (a) Romines, 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. (b) Masson, P. J.; Coup, D.; Millet, J.; Brown, N. L. J. Biol.
Chem. 1995, 270, 2662.
(6) Goossen, L. J.; Rudolphi, F.; Oppel, C.; Rodriguez, N. Angew. Chem.,
Int. Ed. 2008, 47, 3043.
(2) Olah, G. A. Friedel-Crafts Chemistry; Wiley: New York, 1973.
(3) (a) Ko, S.; Kang, B.; Chang, S. Angew. Chem., Int. Ed. 2005, 44,
455. (b) Pucheault, M.; Darses, S.; Genet, J.-P. J. Am. Chem. Soc. 2004,
126, 15356. (c) Huang, Y.-C.; Majumdar, K. K.; Cheng, C.-H. J. Org. Chem.
2002, 67, 1682. (d) Ishiyama, T.; Hartwig, J. F. J. Am. Chem. Soc. 2000,
122, 12043. (e) Satoh, T.; Itaya, T.; Miura, M.; Nomura, M. Chem. Lett.
1996, 823. (f) Hirao, T.; Misu, D.; Agawa, T. J. Am. Chem. Soc. 1985,
107, 7179.
(7) For recent reviews on C-H activations, see: (a) Lyon, T. W.; Sanford,
M. S. Chem. ReV. 2010, 110, 1147. (b) Colby, D. A.; Bergman, R. G.;
Ellman, J. A. Chem. ReV. 2010, 110, 624. (c) Ackermann, L.; Vicente, R.;
Kapdi, A. R. Angew. Chem., Int. Ed. 2009, 48, 9792. (d) Daugulis, O.; Do,
H.-Q.; Shabashov, D. Acc. Chem. Res. 2009, 42, 1074. (e) Chen, X.; Engle,
K. M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094. (f)
Li, C.-J. Acc. Chem. Res. 2009, 42, 335. (g) Kakiuchi, F.; Kochi, T. Synthesis
2008, 3013.
10.1021/ol101618u  2010 American Chemical Society
Published on Web 08/12/2010

ever, examples of direct arene C-H bond coupling reactions
with aldehydes to aryl ketones are less established. Notably,
Cheng and co-workers pioneered in developing a Pd-
catalyzed coupling of 2-arylpyridines with benzaldehydes to
give aromatic ketones using dioxygen as oxidant.8 During
the course of our investigation, Li and co-workers recently
reported the oxidative coupling of 2-arylpyridines with
aliphatic aldehydes by TBHP.9 Motivated by Cheng’s work
and our earlier studies10 on the Pd-catalyzed ortho-selective
C-H ethoxycarbonylation of 2-arylpyridines with diethyl
azodicarboxylate (DEAD),10c we considered that the analo-
gous C-H bond coupling of aryl ketone oxime ethers with
aldehydes would be a versatile route to 1,2-diacylbenzenes
after the oxime deprotection. 1,2-Diacylbenzenes are useful
precursors to isoindoles, isoquinolines, N-arylphthalimidines,
and phthalazines, which are scaffolds for compounds of
biological or pharmaceutical interest.11 While a general
synthetic method is lacking, 1,2-diacylbenzenes can be
prepared from 2-hydroxylarylaldehyde/ketone acylhydra-
zones with Pb(OAc)4 or PhI(OAc)2 as reagent.12 However,
this reaction would be limited by the requirement of
prefunctionalized starting materials and use of highly toxic
lead compounds.
Our previous investigation implicated that the reaction of
organopalladium(II) complexes with carboradicals such as
•CO2Et and Ar• radicals would be a key step for the direct
ethoxycarbonylations10c and arylations.10a Thus, we hypoth-
esized that the analogous coupling of organopalladium(II)
with acyl [•C(O)R] radicals would lead to aryl ketone
formation.13 In this regard, hydrogen atom abstraction from
aldehydes by reactive oxygen radicals (e.g., tBuO•) is known
to be the cleanest way to generate acyl radicals.14 Herein
we describe a convenient synthesis of 1,2-diacylbenzene
oximes via Pd-catalyzed oxidative arene C-H bond coupling
with aldehydes using TBHP as oxidant. Good to excellent
yields of the coupled ketones were obtained from aliphatic
and heteroaromatic aldehydes.
Table 1. Reaction Optimizationa
aldehyde
entry
Pd
Pd(OAc)2
(equiv)
solvent
toluene
% yieldb
1c
2
3
3
3
3
3
6
6
6
6
6
6
47
58
Pd(OAc)2
toluene
toluene
toluene
toluene
toluene
toluene
DCE
dioxane
acetonitrile 18
DMF 11
d
3
4
5
6
Pd(CH3CN)2(OTs)2
PdCl2(PhCN)2
PdCl2(PPh3)2
Pd(OAc)2
-
53
63
76
73 (71)f
56
7e
8e
9e
10e
11e
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
51
Pd(OAc)2
a Conditions: 1a (0.25 mol), 4-Cl-C6H4CHO, Pd catalyst (5 mol %),
TBHP (2 equiv), solvent (1 mL) with AcOH (0.5 equiv) as additive, 100
°C, 12 h. b Yield determined by GC-FID. c 0.5 mL of AcOH was used.
d No detectable product formation. e Reaction run for 2 h. f Isolated yield
in parentheses.
mixture (2:1 v/v) at 100 °C for 12 h. We were gratified that
2a was obtained in 47% yield (Table 1, entry 1). A slightly
better yield of 2a (58%) resulted with the use of 0.5 equiv
of AcOH as additives (entry 2). The molecular structure of
2a has been established by X-ray crystallography (see
Supporting Information). Presumably, the TBHP serves as
a source of reactive oxygen radicals (e.g., tBuO•), which
would act upon the benzaldehyde to generate acyl radicals
in situ. As expected, the 2a formation was suppressed in the
presence of a radical scavenger such as ascorbic acid (see
Supporting Information).15 Employing proprionic acid or
benzoic acid as additives produced comparable results; other
oxidants such as di-tert-butyl peroxide, hydrogen peroxide,
and benzoyl peroxide are less effective for the acylaton
reaction (see Supporting Information). The catalytic activities
of other palladium compounds (5 mol %) have been
evaluated; only Pd(PPh3)2Cl2 (63%) and Pd(OAc)2 (58%)
exhibited significant activities (entries 3-5). After several
trials, 2a was isolated in 71% yield within 2 h by utilizing
6 equiv of benzaldehyde (entry 7). Toluene was found to be
the solvent of choice; other solvents such as dioxane,
acetonitrile, and DMF failed to yield better results (entries
8-11).
To begin, acetophenone O-methyl oxime (1a, 0.25 mmol)
and 4-chlorobenzaldehyde (0.75 mmol) were treated with
TBHP(0.5mmol)andPd(OAc)2 (5mol%)inatoluene-AcOH
(8) Jia, X.; Zhang, S.; Wang, W.; Luo, F.; Cheng, J. Org. Lett. 2009,
11, 3120.
(9) Basle, O.; Bidange, J.; Shuai, Q.; Li, C.-J. AdV. Synth. Catal. 2010,
352, 1145.
(10) (a) Yu, W.-Y.; Sit, W. N.; Zhou, Z.; Chan, A. S.-C. Org. Lett.
2009, 11, 3174. (b) Yu, W.-Y.; Tai, Y.-T.; Zhou, Z.; Chan, A. S. C. Org.
Lett. 2009, 11, 469. (c) Yu, W.-Y.; Sit, W. N.; Lai, K.-M.; Zhou, Z.; Chan,
A. S. C. J. Am. Chem. Soc. 2008, 130, 3304. (d) Thu, H.-Y.; Yu, W.-Y.;
Che, C.-M. J. Am. Chem. Soc. 2006, 128, 9048. (e) Choi, M. K.-W.; Yu,
W.-Y.; Che, C.-M. Org. Lett. 2005, 7, 1081. (f) Cheung, W.-H.; Zheng,
S.-L.; Yu, W.-Y.; Zhou, G.-C.; Che, C.-M. Org. Lett. 2003, 5, 2535.
(11) Kotali, A.; Harris, P. A. Org. Prep. Proc. Int. 2003, 35, 583.
(12) (a) Kotali, A.; Lafazanis, I. S.; Harris, P. A. Synthesis 2009, 5,
836. (b) Kotali, A.; Harris, P. A. Org. Prep. Proc. Int. 1994, 26, 159.
(13) For a review, see: (a) Chatgilialoglu, C.; Crich, D.; Komatsu, M.;
Ryu, I. Chem. ReV. 1999, 99, 1991. For selected examples of the
Pd-catalyzed radical carbonylation reactions involving acyl radicals, see:
(b) Ryu, I.; Kreimerman, S.; Araki, F.; Nishitani, S.; Oderaotoshi, S.;
Minakata, S.; Komatsu, M. J. Am. Chem. Soc. 2002, 124, 3812. (c)
Fukuyama, T.; Nishitani, S.; Inouye, T.; Morimoto, K.; Ryu, I. Org. Lett.
2006, 8, 1383. (d) Fusano, A.; Fukuyama, T.; Nishitani, T.; Inouye, T.;
Ryu, I. Org. Lett. 2010, 12, 2410.
Scheme 1 summarizes the results of the substrate scope
studies. With 4-chlorobezaldehyde as reagent, the substituted
acetophenone oximes were transformed to the corresponding
ketones 2b, c, and g in 50-88% yields. In general, electron-
withdrawing (F, Cl, Br, MeSO2) and -donating groups (OMe,
amide) are tolerated (see for 2a-2f). For 2e, the aldehyde
coupling was selectively directed to the ortho-position of the
(14) (a) Chatgilialoglu, C.; Lunazzi, L.; Macciantelli, D.; Placucci, G.
J. Am. Chem. Soc. 1984, 106, 5252. (b) Walling, C.; Mintz, M. J. J. Am.
Chem. Soc. 1967, 89, 1515.
(15) For a recent study on ascorbic acid as radical scavenger, see:
Warren, J. J.; Mayer, J. M. J. Am. Chem. Soc. 2010, 132, 7784.
Org. Lett., Vol. 12, No. 17, 2010
3927

Oximes with a bicyclic scafford would also undergo facile
C-H acylation reactions. For instance, 4-chromanone O-
methyl oxime would react with 4-chlorobenzaldehyde (6
equiv) under the Pd-catalyzed conditions to furnish ketone
2g in 88% yield. Likewise, effective transformations of the
tetralone analogues to 2h (75%) and 2i (87%) were also
accomplished with piperonal and 2-naphthaldehyde as the
coupling partners. Analogous to a recent report by Li and
co-workers,9 aliphatic aldehydes such as 3-phenylpropanal,
1-hexanal, and cyclohexylcarboxyaldehyde can be coupled
to the oximes under our experimental conditions to afford
ketones 2j (90%), 2k (87%), and 2l (77%), respectively.
Heteroaromatic rings such as indoles are important
scaffolds for many pharmaceutically active compounds,18
1-aryoylindoles can be readily prepared by direct acylation
of the N-H free indole precursors. Other regioisomers
were prepared from the indolecarboxyaldehydes by Grig-
nard addition, followed by PDC oxidation.19 In this work,
when the tetralone O-methyl oxime was treated with ethyl
5-formyl-1H-indole-1-carboxylate under the Pd-catalyzed
conditions, ketone 2p was exclusively isolated in 60%
yield, and C3-functionalized products were not detected.
Similarly, effective couplings with furfural and 5-chloro-
2-thiophenecarboxyaldehyde were also accomplished in
55 and 95% yields. As expected, the catalytic coupling
of 4-chromanone oxime with 2-benzofurancarboxyalde-
hyde gave ketone 2m in 72% yield. In all cases, no
significant oxidation to the heterocycles was observed
under our experimental conditions.
Scheme 1
.
Pd-Catalyzed Oxidative C-H Bond Coupling with
Aldehydesa
In this work, the direct acylation of the sp3 C-H bond
was also pursued. Treatment of 8-methylquinoline with
4-chlorobenzaldehyde using the Pd-catalyzed protocol
afforded ketone 2q in 42% yield. 8-Quinolyl benzil was
obtained as a side product (22%) due to overoxida-
tion.
According to Sanford and co-workers, O-acetyl oximes
were effective directing groups for the Pd-catalyzed C-H
acetoxylations, and they can be removed more readily than
the oxime ether groups.20 Despite this apparent advantage,
our Pd-catalyzed protocol failed to give ketone products
when acetophenone O-acetyl oxime was employed as
substrate. NMR analysis of the reaction mixture revealed
substantial decomposition of the starting oximes.
Having established a catalytic direct acylation reaction,
we turned to develop a straightforward synthesis of phthala-
zines. It is known that phthalazines and derivatives would
exhibit interesting luminescent21 and anticancer22 activities.
In this work, the oxime deprotection for 2a and 2c was
a Isolated yields. b DCE as solvent.
oxime group, rather than the amide group. This result reflects
the stronger donor ability of the nitrogen than the oxygen
atom.16 Consistent with many related studies,17 the Pd-
catalyzed C-H acylation of meta-substituted arenes was
favored at the less hindered site of the aromatic ring (for 2c
and 2f).
(16) Desai, L. V.; Stowers, K. J.; Sanford, M. S. J. Am. Chem. Soc.
2008, 130, 13285.
(18) (a) Sundberg, R. J. Indoles; Academic Press: London, 1996. (b)
Sundberg, R. J. The Chemistry of Indoles; Academic Press: New York,
1970.
(17) For selected examples, see:(a) Yang, S.; Li, B.; Wan, X.; Shi, Z.
J. Am. Chem. Soc. 2007, 129, 6066. (b) Chiong, H. A.; Pham, Q.-N.;
Daugulis, O. J. Am. Chem. Soc. 2007, 129, 9879. (c) Giri, R.; Maugel, N.;
Li, J.-J.; Wang, D.-H.; Breazzano, S. P.; Saunders, L. B.; Yu, J.-Q. J. Am.
Chem. Soc. 2007, 129, 3510. (d) Chen, X.; Li, J.-J.; Hao, X.-S.; Goodhue,
C. E.; Yu, J.-Q. J. Am. Chem. Soc. 2006, 128, 78. (e) Chen, X.; Goodhue,
C. E.; Yu, J.-Q. J. Am. Chem. Soc. 2006, 128, 12634. (f) Lazareva, A.;
Daugulis, O. Org. Lett. 2006, 8, 5211. (g) Kalyani, D.; Dick, A. R.; Anani,
W. Q.; Sanford, M. S. Org. Lett. 2006, 8, 2523. (h) Zaitev, V. G.; Shabashov,
D.; Daugulis, O. J. Am. Chem. Soc. 2005, 127, 13154. (i) Kalyani, D.;
Deprez, N. R.; Desai, L. V.; Sanford, M. S. J. Am. Chem. Soc. 2005, 127,
7330. (j) Kalyani, D.; Sanford, M. Org. Lett. 2005, 7, 4149.
(19) Liou, J. P.; Wu, C.-W.; Hsieh, H.-P.; Chang, C.-Y.; Chen, C.-M.;
Kuo, C.-C.; Chang, J.-Y. J. Med. Chem. 2007, 50, 4548.
(20) Neufeldt, S. R.; Sanford, M. S. Org. Lett. 2010, 12, 532.
(21) Mi, B. X.; Pang, P. F.; Gao, Z. Q.; Lee, C. S.; Lee, S. T.; Hong,
H. L.; Chen, X. M.; Wong, M. S.; Xia, P. F.; Cheah, K. W.; Chen, C. H.;
Huang, W. AdV. Mater. 2009, 21, 339.
(22) (a) Austin, R. J.; Kaizerman, J.; Lucas, B.; McMinn, D. L.; Powers,
J. PCT Int. App. WO 2009002469, 2008. (b) Tasker, A.; Zhang, D.; Pettus,
L. H.; Rzasa, R. M.; Sham, K. K. C.; Xu, S.; Chakrabarti, P. P. PCT Int.
App. WO 2008030466, 2008.
3928
Org. Lett., Vol. 12, No. 17, 2010

Scheme 2
.
Phthalazine Synthesis
Scheme 3. Plausible Catalytic Cycle
performed in HCl/dioxane (Scheme 2). After hydrazine
condensation, 4a and 4c were obtained in ca. 45% overall
yield.23 Yet, treatment of 2o with HCl/dioxane produced a
complicated mixture. However, successful oxime deprotec-
tion for 2o was achieved in the presence of copper powder,
and subsequent hydrazine condensation afforded 4o in 40%
overall yield.
A plausible mechanism of the catalytic C-H acylation is
depicted in Scheme 3. The reaction is probably initiated by
oxime-assisted ortho-selective cyclometalation on the arene
ring by Pd(OAc)2. The palladacycle would react with the
acyl radicals, which were generated in situ by hydrogen atom
abstraction of the aldehydes, to afford the product ketones
via either reactive Pd(IV)24 or dimeric Pd(III)25 intermediates.
Direct reaction of the cyclopalladated oximes with aldehydes
can be ruled out since stoichiometric reaction of a related
palladium complex of 2-phenylpyridine with 4-chloroben-
zaldehyde did not produce any acylation products in the
absence of TBHP. Consistent with the involvement of radical
intermediates, the catalytic C-H acylation was suppressed
by raical scavengers such as ascorbic acid in a dose-
dependent manner.26
In conclusion, we developed a Pd-catalyzed protocol for
an ortho-selective C-H acylation reaction of aromatic
oximes by oxidative coupling with aldehydes. This protocol
constitutes a versatile route to a diverse library of diaryl
ketones, which are difficult to obtain by the classical
Friedel-Crafts acylation. Simple deprotection of the oxime
group would afford 1,2-diacylbenzenes, which can be de-
rivatized to phthalazines and other useful compounds for
potential application.
Acknowledgment. We thank the financial support from
The Hong Kong Research Grants Council (PolyU 5031/09P,
SEG_PolyU01) and The Areas of Excellence Scheme (AoE/
P-10-01) administered by the University Research Grants
Council (HKSAR, China).
Supporting Information Available: Details of experi-
mental procedures and characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
(23) During the acid deprotection, the reaction mixture developed an
intense blue color in several minutes, and TLC analyses revealed formation
of some unidentified byproducts.
OL101618U
(24) (a) Deprez, N. R.; Sanford, M. S. J. Am. Chem. Soc. 2009, 131,
11234. (b) Racowski, J. M.; Dick, A. R.; Sanford, M. S. J. Am. Chem. Soc.
2009, 131, 10974.
(26) With privaldehyde as the coupling partner, no coupled ketone was
obatined with spontaneous palladium black formation. Probably, the tert-
butylacyl radical was rapidly decarbonylated to form the tert-butyl radical,
which undergoes ꢀ-hydrogen elimination. We thank one of the reviewers
for this comment and suggestion.
(25) (a) Powers, D. C.; Geibel, M. A. L.; Klein, J. E. M. N.; Ritter, T.
J. Am. Chem. Soc. 2009, 131, 17050. (b) Powers, D. C.; Ritter, T. Nat.
Chem. 2009, 1, 302.
Org. Lett., Vol. 12, No. 17, 2010
3929