Palladium-catalyzed synthesis of aryl ketones by coupling of aryl bromides with an acyl anion equivalent

Article abstract of DOI:10.1021/ja064782t

Palladium-catalyzed couplings of aryl bromides with N-tert-butylhydrazones as acyl anion equivalents to form aryl ketones are reported. The coupling process occurs at the C-position of hydrazones to form N-tert-butyl azo compounds. Isomerization of these azo compounds to the corresponding hydrazones, followed by hydrolysis, gave the desired mixed alkyl aryl ketones. The selectivity of C- versus N-arylation was strongly influenced by the substituent on nitrogen. Arylation at carbon occurred with N-tert-butylhydrazones, whereas N-arylation occurred with N-arylhydrazones. The arylation of hydrazones containing primary and secondary alkyl groups, as well as aryl groups, gave the desired ketones in good yields after hydrolysis. Functional groups on the aromatic ring, such as alkoxy, cyano, trifluoromethyl, carboalkoxy, carbamoyl, and keto groups, were tolerated. This reaction likely occurs by C-C bond-forming reductive elimination from an intermediate containing an η1-diazaallyl ligand. Copyright

Full text of DOI:10.1021/ja064782t

Published on Web 11/02/2006
Palladium-Catalyzed Synthesis of Aryl Ketones by Coupling of Aryl Bromides
with an Acyl Anion Equivalent
Akihiro Takemiya and John F. Hartwig*
Department of Chemistry, Yale UniVersity, P.O. Box 208107, New HaVen, Connecticut 06520-8107
Received July 5, 2006; E-mail: john.hartwig@yale.edu
Palladium-catalyzed coupling reactions1,2 to form carbon-carbon
Table 1. Palladium-Catalyzed Coupling of Bromobenzene with
N-tert-Butylhydrazone
bonds have recently been expanded to include the coupling of aryl
halides with carbonyl compounds to form R-aryl ketones,3,4 esters,5
and amides.6,7 We envisioned a related reaction between an aryl
halide and an acyl anion equivalent to form the acyl aryl carbon-
carbon bond in aryl ketones by combining methods to couple aryl
halides with substrates containing acidic C-H bonds and methods
to convert electrophilic aldehydes into nucleophiles. Compared to
conversion
of PhBra (%)
yield of
ketonea (%)
the conventional preparation of aryl ketones from aldehydes by
addition of Grignard reagents, followed by oxidation, the coupling
of an acyl anion equivalent would avoid the conversion of the
organic halide to a Grignard reagent, would alleviate the relative
intolerance of organomagnesium reagents toward functional groups,
and would eliminate the need for redox processes. There are only
a few reports of direct coupling reactions between aryl halides and
aldehydes to form ketones,8,9 and they form alkyl aryl ketones in
low yield or require a metal-binding group on the aldehyde.
Several acyl anion equivalents could be envisioned to undergo
cross-coupling. Dithianes10 and cyanohydrins11 are often used in
purely organic transformations, and an acyl anion equivalent is
generated during the Stetter reaction.12 However, the acyl anion
equivalents based on hydrazones developed by Baldwin13-15 seemed
more amenable to cross-coupling (eq 1) because their acidity is
closer to that of the carbonyl compounds that undergo palladium-
catalyzed arylation in the presence of alkoxide base. As shown in
eq 1, if the N-tert-butylhydrazones underwent coupling at the carbon
of the diazaallyl unit, isomerization of the initial azo product to
the corresponding hydrazone, followed by hydrolysis, would yield
the arylketone.14 The direct reaction of N-tert-butylhydrazones with
organic electrophiles is known,16,17 but the use of hydrazones as
acyl anion equivalents in metal-catalyzed reactions is not. Moreover,
the addition of the deprotonated hydrazone to a metal center would
be likely to form a diazaallyl intermediate, and the chemistry of
such compounds is unexplored. We report the development of a
palladium-catalyzed coupling of aryl bromides with N-tert-butyl-
hydrazones to form alkyl aryl ketones or diaryl ketones from aryl
halides and alkyl or aryl aldehydes (eq 1). These reactions occur
in the presence of a number of electrophilic functional groups, and
preliminary data imply that they occur through η1-diazaallyl
intermediates.
entry
phosphine
1
2
3
4
5
6
7
8
DPEphosb
100
100
91
54
59
77
100
100
99
93
61
trace
28
7
Xantphosc
BINAPd
DPPFe
DPPBf
PPh3 (10 mol %)
PtBu3
56
37
Q-phos
a Determined by GC with an internal standard. b Bis(2-diphenylphos-
phinophenyl)ether. c 9,9-Dimethyl-4,5-bis(diphenylphoshino)xanthene. d 2,2′-
Bis(diphenylphosphino)-1,1′-binaphthyl. e 1,1′-Bis(diphenylphosphino)fer-
rocene. f 1,4-Bis(diphenylphosphino)butane.
solvent and were heated for 24 h at 80 °C. The results of reactions
conducted with several ligands are shown in Table 1.
The reaction with Pd2(dba)3 and DPEphos as catalyst occurred
to form the desired butyrophenone in nearly quantitative yield after
hydrolysis (entry 1). Reactions conducted with Pd2(dba)3 and
Xantphos also gave the desired ketone in good yield (entry 2). The
similarity of the results of these two reactions is consistent with
the comparable bite angle of DPEphos and Xantphos. Reactions
conducted with bidentate phosphines containing smaller bite angles
than DPEphos resulted in lower conversions (entries 3-5). The
reactions catalyzed by Pd2(dba)3 and a monodentate arylphosphine
formed complex mixtures (entry 6), and reactions conducted with
sterically hindered monodentate ligands formed both C- and
N-arylation products and ultimately a moderate yield of the desired
ketone (entries 7 and 8). No reaction was observed in the presence
of Cs2CO3 as base, and the yield of desired ketone was lower (87%)
when the reactions with Pd2(dba)3 and DPEphos as catalyst were
conducted in toluene.
We also tested reactions of several hydrazones containing
different substituents on nitrogen. As summarized in Table 2, this
group strongly influenced the extent of reaction and the selectivity
for C- versus N-arylation. The reaction of bromobenzene with
N-tert-butylhydrazone gave the desired C-arylated product selec-
tively in good yield (entry 1). In contrast, the N-Boc and
N-benzoylhydrazone, which have more acidic N-H protons and
less nucleophilic conjugate bases, did not react (entries 2 and 3).
Although the N-phenylhydrazone did react with PhBr, it formed
the product from N-arylation (entry 4). Only trace amounts of the
product of C-arylation were formed.
To develop the coupling of aryl halides with the N-tert-
butylhydrazones of aldehydes, we studied the reactions of bromo-
benzene with the N-tert-butylhydrazone of butyraldehyde in the
presence of NaO-tBu as base and Pd2(dba)3 and several phosphines
as catalyst precursors. The reactions were conducted in dioxane
The scope of the coupling of different aliphatic and aromatic
N-tert-butylhydrazones with a variety of bromoarenes is summarized
9
14800
J. AM. CHEM. SOC. 2006, 128, 14800-14801
10.1021/ja064782t CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Palladium-Catalyzed Coupling of Bromobenzene with
Various Hydrazones
the reactions of the three hydrazones occurred with 4-bromo-
benzophenone. The reaction also occurred in the presence of a tert-
butyl ester (entries 17 and 18) and in the presence of a morpholine
amide (entries 19-21). Aryl bromides containing TBS-protected
alcohols also reacted to form the ketone. In this case, the free alcohol
was obtained after hydrolysis (entries 22 and 23). In addition, the
reaction occurred with some heteroaryl halides (entries 24-26).
Likewise, reactions of vinyl triflates with the acyl anion equivalent
formed R,â-unsaturated ketones (entry 27). However, 4-bromo-
acetophenone, which contains enolizable hydrogens, did not react
to give the desired ketone (entry 28).
entry
R
yielda (%)
1
2
3
4
tBu
Bocc
Bzd
Ph
98 (C-arylation)b
no reaction
no reaction
91 (N-arylation)
The most likely mechanism for this process would parallel the
mechanism for coupling of aryl halides with amines and ketones.
After oxidative addition to form an arylpalladium halide complex,
a diazaallyl intermediate would form by reaction of this complex
with the combination of hydrazone and base. The diazaallyl ligand
in this complex could be bound in an η1 mode through carbon or
nitrogen, or it could be bound in an η3 mode through the acyl carbon
and the two nitrogen atoms. Although more detailed mechanistic
studies are needed to define the binding mode of this ligand, the
C-C bond-forming reductive elimination appears to occur from
an η1-diazaallyl complex because the reaction occurred faster with
catalysts containing bidentate ligands that would enforce an η1
binding mode of the allyl ligand than with catalysts containing
monodentate ligands that would accommodate an η3 binding mode.
In summary, we have developed an efficient cross-coupling
reaction of aryl bromides using N-tert-butylhydrazones as acyl anion
equivalent. These hydrazones are readily accessible from aldehydes
and N-tert-butylhydrazine, and the coupling occurred under mild
conditions at the C-position of the diazaallyl group when the
hydrazone contained a tert-butyl group on nitrogen. Studies of the
mechanism of this coupling reaction, including efforts to observe
a diazaallyl intermediate, will be the focus of future work.
a Isolated yield. b Yield of corresponding ketone after hydrolysis. c tert-
Butoxycarbonyl. d Benzoyl.
Table 3. Palladium-Catalyzed Coupling of Aryl Bromides with
N-tert-Butylhydrazones
entry
Ar
R
T (°
C)
yield (%)a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
Ph
Ph
Ph
Ph
n-propyl
cyclohexyl
benzyl
80
80
80
80
80
80
80
80
70
70
70
70
70
70
70
70
70
70
50
50
50
50
50
70
70
70
70
50
98
81
96
85
94
79
91
70
46
73
90
66
80
87
52
95
75
91
83
60
88
78b
97b
98
85
71
52
N.D.
Ph
4-OMeC6H4
4-OMeC6H4
4-OMeC6H4
4-CNC6H4
4-CNC6H4
4-CNC6H4
4-CF3C6H4
4-CF3C6H4
n-propyl
cyclohexyl
benzyl
n-propyl
cyclohexyl
benzyl
n-propyl
cyclohexyl
benzyl
n-propyl
cyclohexyl
benzyl
n-propyl
benzyl
n-propyl
cyclohexyl
benzyl
n-propyl
benzyl
n-propyl
cyclohexyl
benzyl
4-CF3C6H4
4-PhCOC6H4
4-PhCOC6H4
4-PhCOC6H4
4-tBuO2CC6H4
4-tBuO2CC6H4
4-morpholino-COC6H4
4-morpholino-COC6H4
4-morpholino-COC6H4
4-TBSO(CH2)2C6H4
4-TBSO(CH2)2C6H4
3-pyridyl
Acknowledgment. We thank the NIH (NIGMS GM-58108) for
support of this work. A.T. thanks Mitsubishi Pharma Corporation
for financial support.
Supporting Information Available: Reaction procedures and
characterization of reaction products. This material is available free of
charge via the Internet at http://pubs.acs.org.
References
(1) Negishi, E.-i. Handbook of organopalladium chemistry for organic
synthesis; Wiley-Interscience: New York, 2002.
3-pyridyl
(2) Astruc, D. Modern arene chemistry; Wiley-VCH: Weinheim, Germany,
3-pyridyl
2002.
1-cyclohexenylOTfc
4-MeCOC6H4
benzyl
n-propyl
(3) Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 1999, 121, 1473-1478.
(4) Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res. 2003, 36, 234-245.
(5) Jorgensen, M.; Lee, S.; Liu, X. X.; Wolkowski, J. P.; Hartwig, J. F. J.
Am. Chem. Soc. 2002, 124, 12557-12565.
a Isolated yield. b Free alcohol was obtained as product. c 1-Cyclohexenyl
trifluoromethanesulfonate was used as a substrate instead of aryl bromide.
TBS ) tert-butyldimethylsilyl. N.D. ) not detected.
(6) Hama, T.; Liu, X. X.; Culkin, D. A.; Hartwig, J. F. J. Am. Chem. Soc.
2003, 125, 11176-11177.
(7) Hama, T.; Culkin, D. A.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128,
4976-4985.
in Table 3.18 These reactions were conducted under the optimized
conditions of entry 1 in Table 2. The reactions of hydrazones
containing primary and secondary alkyl groups gave the desired
ketones in good yield after hydrolysis (entries 1 and 2). Even the
reaction of the hydrazone containing acidic benzylic hydrogens
underwent reaction as an acyl anion to form the corresponding
benzyl ketone in high yield (entry 3). In addition to hydrazones
from alkyl aldehydes, the hydrazone from benzaldehyde reacted,
in this case to form a diaryl ketone (entry 4).
The reaction also occurred with aryl bromides containing various
substituents. Both electron-rich (entries 5-7) and electron-poor
(entries 8-21) aryl bromides gave the desired ketones in high yield
after hydrolysis. Further, the reaction occurred in the presence of
several classes of functional groups. As shown in entries 14-16,
(8) Huang, Y. C.; Majumdar, K. K.; Cheng, C. H. J. Org. Chem. 2002, 67,
1682-1684.
(9) Ko, S.; Kang, B.; Chang, S. Angew. Chem., Int. Ed. 2005, 44, 455-457.
(10) Smith, A. B.; Adams, C. M. Acc. Chem. Res. 2004, 37, 365-377.
(11) Stork, G.; Maldonad, L. J. Am. Chem. Soc. 1971, 93, 5286-5287.
(12) Stetter, H. Angew. Chem., Int. Ed. Engl. 1976, 15, 639-647.
(13) Baldwin, J. E.; Adlington, R. M.; Newington, I. M. J. Chem. Soc., Chem.
Commun. 1986, 176-178.
(14) Baldwin, J. E.; Adlington, R. M.; Bottaro, J. C.; Kolhe, J. N.; Perry, M.
W. D.; Jain, A. U. Tetrahedron 1986, 42, 4223-4234.
(15) Baldwin, J. E.; Adlington, R. M.; Bottaro, J. C.; Jain, A. U.; Kolhe, J. N.;
Perry, M. W. D.; Newington, I. M. J. Chem. Soc., Chem. Commun. 1984,
1095-1096.
(16) Wang, S. F.; Warkentin, J. Can. J. Chem. 1988, 66, 2256-2258.
(17) Alexander, C. W.; Lin, S. Y.; Dieter, R. K. J. Organomet. Chem. 1995,
503, 213-220.
(18) Studies on the reactions of chloroarenes will be reported in due course.
JA064782T
9
J. AM. CHEM. SOC. VOL. 128, NO. 46, 2006 14801