Highly selective β-hydride elimination in Pd-catalyzed decarboxylative heck-type reaction

Article abstract of DOI:10.1021/ol400818v

A variety of β-aryl ketones and aldehydes were facilely synthesized via a Pd(II)/Ag₂CO₃-mediated decarboxylative Heck type reaction between readily available benzoic acid derivatives and allylic alcohols under mild conditions. The control experiments indicated that this transformation may proceed via a hydrogen migration process.

Full text of DOI:10.1021/ol400818v

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Highly Selective β‑Hydride Elimination in
Pd-Catalyzed Decarboxylative Heck-Type
Reaction
Liangbin Huang,† Ji Qi,† Xia Wu, Kefan Huang, and Huanfeng Jiang*
School of Chemistry and Chemical Engineering, South China University of Technology,
Guangzhou 510640, P. R. China
jianghf@scut.edu.cn
Received February 6, 2013
ABSTRACT
A variety of β-aryl ketones and aldehydes were facilely synthesized via a Pd(II)/Ag2CO3-mediated decarboxylative Heck type reaction between
readily available benzoic acid derivatives and allylic alcohols under mild conditions. The control experiments indicated that this transformation
may proceed via a hydrogen migration process.
Recently, the oxidative cross-coupling reaction has at-
tracted increasing interest,1 especially the oxidative Heck-
type reaction.2ꢀ5 Due to the instability of traditional
carbon nucleophiles (CNs) originating from organometal-
lic reagents,6 the discovery of new and efficient carbon
nucleophiles (CNs) for oxidative cross coupling reactions
is of significant importance. Among those, the CꢀH
activation step has been the most direct and atom-economic
strategy to form CNs.7 A variety of aromatic compounds
can be employed as arene nucleophiles, and high levels of
site selectivity are possible for the substrates containing
directing groups.8 Despite the above illustrated advances,
the substrates scope of CꢀH activation for simple aromatics
that do not contain directing groups remains primarily
limited to electron-rich derivatives. The electron-deficient
(4) Examples for olefination of vinylic CꢀH bonds: (a) Xu, Y.-H.;
Lu, J.; Lop, T.-P. J. Am. Chem. Soc. 2009, 131, 1372. (b) Hatamoto, Y.;
Sakaguchi, S.; Ishii, Y. Org. Lett. 2004, 6, 4623. (c) Yu, H.; Jin, W.; Sun,
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Gillaizeau, I. Org. Lett. 2012, 14, 3304. (f) Xu, Y.-H.; Chok, Y. K.; Lop,
T.-P. Chem. Sci. 2011, 2, 1822. (g) Moon, Y.; Kwon, D.; Hong, S.
Angew. Chem., Int. Ed. 2012, 51, 11333. (h) Bai, Y.; Zeng, J.; Cai, S.; Liu,
X.-W. Org. Lett. 2011, 13, 4394. (i) Zhang, Y.; Li, Z.; Liu, Z.-Q. Org.
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2008, 130, 11270. (b) Werner, E. W.; Sigman, M. S. J. Am. Chem. Soc.
2011, 133, 9692. (c) Zheng, C.; Wang, D.; Stahl, S. S. J. Am. Chem. Soc.
2012, 134, 16496. (d) Nishimura, T.; Araki, H.; Maeda, Y.; Uemura, S.
Org. Lett. 2003, 5, 2997. (e) Hadi, V.; Yoo, K.; Jeong, M.; Jung, K. W.
Tetrahedron Lett. 2009, 50, 2370.
† L.H. and J.Q. contributed equally to this work.
(1) For selected reviews on oxidative cross-coupling reactions: (a) Li,
C.-J. Acc. Chem. Res. 2009, 42, 335. (b) Li, B.-J.; Shi, Z.-J. Chem. Soc.
Rev. 2012, 41, 5588. (c) Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111,
1215. (d) Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem. Rev. 2002, 102, 1731.
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Rev. 2007, 107, 5318. (f) Bras, J. L.; Muzart, J. Chem. Rev. 2011, 111,
1170.
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Wang, D.-H; Engle, K. M.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 5916.
(b) Engle, K. M.; Wang, D.-H.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132,
14137. (c) Zhang, Y.-H.; Shi, B.-F.; Yu, J.-Q. J. Am. Chem. Soc. 2009,
131, 5072. (d) Shi, B.-F.; Zhang, Y.-H.; Lam, J. K.; Wang, D.-H.; Yu,
J.-Q. J. Am. Chem. Soc. 2010, 132, 460. (e) Kubota, A.; Emmert, M. H.;
Sanford, M. S. Org. Lett. 2012, 14, 1760. (f) Wang, D.-H.; Engle, K. M.;
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r
10.1021/ol400818v
XXXX American Chemical Society

arenes exhibit sluggish reactivity of CꢀH activation.
Decarboxylation provids a complementary approach
to obtain carbon nucleophiles (CNs).9,10 Carboxylates
and a series of variants are cheap and easy to obtain sub-
strates for cross-coupling reactions.
Gratifyingly, when the reaction of 1a with 1.2 equiv of 2a
wasconductedina DMSO/toluene (1:20) solvent systemat
100 °C in the presence of 5 mol % of Pd(OAc)2 and 1 equiv
of Ag2CO3, the yield of the desired product 3a was 83%
(entry 1).10d,e Pd(TFA)2 (5 mol %) could slightly increase
the yield of the product (entry 2). Further investigation of
the oxidants led to the discovery that Ag2CO3 was the best
oxidant for this transformation (entries 3ꢀ5). In contrast
to DMSO/toluene (1:20) solvent system, the use of more
polar solvents, such as DMSO/DMF (1:20) and dioxane,
resulted in a decreased yield of 3a with amount of the
protodecarboxylation byproduct formed (entries 6 and 7).
It might be because decarboxylation was too fast in polar
solvent. The reactivity decreased if the reaction tempera-
ture was elevated or decreased (see the Supporting Infor-
mation for details), and the oxidative dehydration of 3a
couldbedetectedwhen2equivofAg2CO3 wasusedorwhen
this reaction went through under air (entries 8 and 9).12
In 2002, Myers reported the first example of the de-
carboxylative Heck-type reaction. However, the alkenes
were limited to the active olefins such as R,β-unsaturated
olefins and styrene (eq 1).10a In 2009, Su reported a
decarboxylative Heck-type reaction using the electroni-
cally nonbiased olefins as the substrates (eq 2).10d,e Herein,
we directly utilized allylic alcohols as coupling partners
with benzoic acids as the carbon nucleophils to obtain
β-aryl ketones and aldehydes (eq 3).11
The inspection of the coupling reaction between 2,6-
dimethoxybenzoic acid (1a) and allyl alcohol (2a) was
chosen as a model reaction for the optimization studies
(Table 1). Initially, we examined the feasibility of this
model reaction using the reaction conditions, which were
previously established for the decarboxylative Heck reaction.
Table 1. Impact of Reaction Parametersa
entry catalyst
oxidant
solvent v/v
yieldb (%)
1
Pd(OAc)2 Ag2CO3
Pd(TFA)2 Ag2CO3
Pd(TFA)2 Ag2O
Pd(TFA)2 AgOAc
DMSO/toluene =1:20
DMSO/toluene =1:20
DMSO/toluene =1:20
DMSO/toluene =1:20
83
2
85 (81)
61
3
4
76
5
Pd(TFA)2 O2 (1 atm) DMSO/toluene =1:20
NR
46
6
Pd(TFA)2 Ag2CO3
Pd(TFA)2 Ag2CO3
Pd(TFA)2 Ag2CO3
Pd(TFA)2 Ag2CO3
DMSO/DMF = 1:20
DMSO/dioxane =1:20
DMSO/toluene =1:20
DMSO/toluene =1:20
7
37
(8) (a) Kuhl, N.; Hopkinson, M. N.; Wencel-Delord, J.; Glorius, F.
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9d
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80(75)
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a Reactions were carried out under N2, with 1a (0.5 mmol), 2a (1.2
equiv), Ag2CO3 (0.5 mmol), Pd(II) (0.025 mmol), solvent (3 mL), 100 °C.
b Determined by GC using dodecane as the internal standard. The yield
of isolated product is shown in parentheses. c Ag2CO3 (1 mmol) was
used. d Under air.
With the optimized conditions in hand, we started
employing other substrates to this Pd-catalyzed Heck-type
reaction. First, various aryl-substituted allylic alcohols
were employed to couple with 2,6-dimethoxybenzoic acid
(Scheme 1). A series of para-substituted 1-phenylprop-2-
en-1-ols, including some with electron-donating groups
(R0 = Me, OMe) and some with electron-withdrawing
groups (R0 = F, Cl, CF3), were converted into the corre-
sponding β-aryl ketones in moderate yields (Scheme 1,
3bꢀg). Other substituted 1-phenylprop-2-en-1-ols were
also suitable substrates for this transformation to afford
the corresponding products 3hꢀj in good yields. To our
delight, the furan-substituted allyl alcohol was tolerated in
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B
Org. Lett., Vol. XX, No. XX, XXXX

this transformation (Scheme 1, 3k). And R0-unsaturated
β-aryl ketones were facilely obtained when 2,6-dimethoxy-
benzoic acid coupled with the allyilc alcohols which were
synthesized from cinnamaldehyde derivatives (Scheme 1,
3mꢀo). The alkyl-substituted allyl alcohols were similarly
found to be suitable substrates for this transformation and
gave the desired products in good yields (Scheme 1, 3pꢀt).
The sole chemical selectivity could be obtained when the
substrate containing more than one CꢀC double bonds
(Scheme 1, 3u).
the significant limitation for decarboxylative coupling reac-
tion.9,10 In addition, the benzoic acid containing electron-
withdrawing group could convert to the corresponding
product and dehydrogen product (5:1) in 120 °C
(Scheme 2, 3ea). To our delight, this transformation
was also suitable for the heterocyclic acids (Scheme 2,
3faꢀga).
Scheme 2. Scope of Benzoic Acidsaꢀc
Scheme 1. Scope of Allyl Alcoholsa,b
a Reactions were carried out under N2 with 1 (0.5 mmol), 2 (1.2
equiv), Ag2CO3 (0.5 mmol), Pd(TFA)2 (0.025 mmol), DMSO/toluene =
1:20 (3 mL), 100 °C. b Isolated yield. c 120 °C.
Encouraged by these promising results, we further per-
formed D-labeled experiments. 2, 6-Dimethoxybenzoic
acid was employed to couple with D-1-phenylprop-2-en-
1-ol under the standard conditions (eq 4). It was as
expected that R-D-β-aryl ketone was the sole product and
3b could not be detected (for details, see the Supporting
Information).11a Subsequently, no D-labeled product
could be detected when 0.2 mL of D2O was added under
a Reactions were carried out under N2 with 1a (0.5 mmol), 2 (1.2
equiv), Ag2CO3 (0.5 mmol), Pd(TFA)2 (0.025 mmol), DMSO/toluene =
1:20 (3 mL), 100 °C. b Isolated yield.
Then some other o-OMe-substituted benzoic acids pro-
ceeded well, coupling with allyl alcohol to give the corre-
sponding β-aryl aldehydes (Scheme 2, 3baꢀca). This
transformation was compatible with alkenes that contained
Br-substituted aryl rings, which could undergo a Heck-type
reaction with themselves under Pd catalysis, but in this case
did not (Scheme 2, 3ca). And 2-methylprop-2-en-1-ol could
be also transformed to the desired R-methyl-β-aryl aldehyde
(Scheme 2, 3da) Unfortunately, 2-methoxybenzoic acid was
not a suitable substrate for this reaction, possibly because
of electronic and steric effects, which was consistent with
(13) Examples for quenching the CꢀPdII bond by protonolysis: (a)
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Org. Lett., Vol. XX, No. XX, XXXX
C

the standard conditions (eq 5). It indicated that 3b was not
formed via the protonolysis of intermediate D by D2O.13
Scheme 3. Plausible Reaction Mechanism
On the basis of the above results, a tentative mechanism
for the Pd-cataylzed oxidative Heck-type reaction of ben-
zoic acids with allylic alcohols to synthesize β-aryl ketones
and aldehydes was proposed (Scheme 3). When benzoic
acids were used as the substrates, the arylpalladium species
I was formed through the loss of carbon dioxide from
intermediate A. And then it inserted into the allylic alcohol
to afford intermediate II. The selective β-H elimination
from intermediate II generated Pd(II) species III, followed
by HPdX species inserting into the enol to generate the
critical intermediateIV. This process realized the hydrogen
transfer, just like the oxidative Wacker process.11a,14,15
And then the desired products would be obtained through
two controversial approaches: β-H elimination from
R-OH groups or the anion-mediated reductive elimination.16
Finally, PdII active species was regenerated by the oxidation
of Ag2CO3.
were found to be suitable substrates for this transforma-
tion. This work opens up a new approach to realize the
selective β-H elimination in Pd-catalyzed oxidative Heck
reactions. Tentative mechanistic studies indicated that the
hydrogen transfer might go through the Wacker oxidative
process, and it would be a significant model for the
mechanism study of Wacker oxidation. Further studies
into the use of arylꢀH as the source of aryl nucleophile, as
well as more mechanistic investigations, are underway in
our laboratory.
Acknowledgment. We thank the National Natural
Science Foundation of China (21172076 and 20932002), the
National Basic Research Program of China (973 Program)
(2011CB808600), the Changjiang Scholars and Innovation
Team Project of Ministry of Education, the Guangdong
Natural Science Foundation (10351064101000000), and the
Fundamental Research Funds for the Central Universities
(2012ZP0003) for financial support.
In conclusion, we have developed a simple and efficient
method for the Pd-catalyzed oxidative Heck reaction of
benzoic acids with allylic alcohols to construct β-aryl
ketones and aldehydes through hydrogen migration. Sev-
eralsubstituted benzoicacids and a seriesofallylic alcohols
(15) Examples for reversible palladium hydride elimination: (a)
Huang, Q.; Larock, R. C. J. Org. Chem. 2003, 68, 7342. (b) Huang,
Q.; Larock, R. C. Org. Lett. 2002, 4, 2505. (c) Jiang, H.; Qiao, C.; Liu, W.
Chem.;Eur. J. 2010, 16, 10968.
(16) Another possible mechanism for this transformation can not be
excluded completely, that is the isomerization of PhCHdCHCH(OH)R
to PhCH2CH2C(dO)R in the presence of palladium catalyst. Thanks to
one reviewer proposing it for us. And the controlled experiment was
conducted in the Supporting Information.
Supporting Information Available. Experimental pro-
cedure and characterization of compounds 3aꢀga. This
material is available free of charge via the Internet at
http://pubs.acs.org
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX