Pd-Catalyzed Regiodivergent Hydroesterification of Aryl Olefins with Phenyl Formate

Article abstract of DOI:10.1021/acs.orglett.5b01630

An effective Pd-catalyzed regiodivergent hydroesterification of aryl olefins with phenyl formate is described. Either linear or branched phenyl arylpropanoates can be obtained in good yields with high regioselectivities by the judicious choice of ligand without the use of toxic CO gas.

Full text of DOI:10.1021/acs.orglett.5b01630

Letter
pubs.acs.org/OrgLett
Pd-Catalyzed Regiodivergent Hydroesterification of Aryl Olefins with
Phenyl Formate
Wenlong Ren,† Wenju Chang,† Yang Wang,† Jingfu Li,† and Yian Shi*,†,‡,§
†State Key Laboratory of Coordination Chemistry, Collaborative Innovation Center of Chemistry for Life Sciences, Center for
Multimolecular Organic Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093, China
‡Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Molecular Recognition and Function, Institute of
Chemistry, Chinese Academy of Sciences, Beijing 10090, China
§Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523, United States
S
* Supporting Information
ABSTRACT: An effective Pd-catalyzed regiodivergent hydroesterification of aryl olefins with phenyl formate is described. Either
linear or branched phenyl arylpropanoates can be obtained in good yields with high regioselectivities by the judicious choice of
ligand without the use of toxic CO gas.
Scheme 1. Regiodivergent Hydroesterification of Olefins
arboxylic esters are an important class of compounds in
organic chemistry and play an important role in
C
pharmaceuticals and fine chemicals. Hydroesterfication of
olefins presents an attractive approach to this class of
compound. Transition-metal catalyzed hydroesterification
with CO has been intensively studied and provides a useful
method for the synthesis of esters.1,2 Nevertheless, CO is highly
toxic and difficult to handle. Moreover, traditional processes are
frequently carried out under high pressure and temperature.
These drawbacks hamper the study and application of the
hydroesterification in the laboratory. In the past, efforts have
been made to use formates as CO surrogates to overcome the
aforementioned disadvantages.3,4 Regioselective hydroesterifi-
cation of aryl olefins provides a straightforward approach to
linear or branched arylpropanoates, which are useful
intermediates for medicinally important compounds, such as
nonsteroidal anti-inflammatory agents (Figure 1).5 A number of
examples have been reported with formates in the presence of a
Ru4j,l,n or Pd4i,k catalyst. Generally, a mixture of linear or
branched arylpropanoates have been obtained. Hydroester-
ification of aryl olefins with high regioselectivity still remains
very challenging.3c During our ongoing studies on Pd-catalyzed
CO-free hydrocarbonylation of olefins,6 we have found that
either linear or branched phenyl arylpropanoates can be
regioselectively formed from aryl olefins by the choice of
ligand (Scheme 1). Herein, we wish to report our preliminary
results on this subject.
Styrene (1a) was used as the test substrate for the
hydroesterification. Various phosphine ligands were initially
examined with 5 mol % Pd(OAc)2 and 3.0 equiv of
HCOOPh4i,j in toluene at 90 °C for 24 h. It was found that
the ligand has a profound effect on the reaction efficiency and
regioselectivity. The common bidentate ligands, such as dppe,
dppp, dppb, and dppf, generally favored linear ester 2a with up
to 4:1 l/b ratio (Table 1, entries 1−4). When the phenyl group
in dppf was replaced by a cyclohexyl group (L17), compound
2a was much more favored (with an 18:1 l/b ratio) (Table 1,
entry 5). No regioselectivity was observed with Xantphos (L2)
(Table 1, entry 6). No product was obtained with a cyclohexyl
analogue of Xantphos (L3) (Table 1, entry 7). In contrast, the
regioselectivity was reversed with PPh3, favoring compound 3a
with a 1:3 l/b ratio (Table 1, entry 8). A slightly lower
Received: June 3, 2015
Figure 1. Examples of anti-inflammatory agents.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01630
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Studies of the Reaction Conditions
Scheme 3. Proposed Catalytic Cycle for Regioselective
Hydroesterification
b
entry
ligand
dppe
additive
yield (%) (2a:3a)
1
64 (2:1)
95 (4:1)
88 (4:1)
92 (2:1)
88 (18:1)
93 (1:1)
0
2
dppp
dppb
dppf
L1
3
4
5
6
L2
7
L3
8
PPh3
L4
89 (1:3)
89 (1:2)
45 (<1:20)
0
9
10
11
12
13
14
15
L5
P(o-tolyl)3
L6
trace
L1
MeSO3H
HCOOH
CH3COOH
CH3COOH
CH3COOH
HCOOH
HCOOH
HCOOH
HCOOH
HCOOH
HCOOH
HCOOH
28 (>20:1)
89 (>20:1)
92 (>20:1)
83 (>20:1)
53 (<1:20)
67 (<1:20)
92 (<1:20)
82 (<1:20)
0
L1
L1
c
16
L1
17
18
L5
L5
d
19
L5
c,d
5). However, in the case of L5,8 the yield increased from 45 to
67% with 10 mol % HCOOH (Table 1, entry 18 vs entry 10).
The exact role of the acid is not currently clear; the acid could
facilitate the reaction by activating HCOOPh. Studies showed
that the yield was further increased to 92% with more ligand
added (Table 1, entry 19). The yield was decreased when the
amount of HCOOPh was reduced (Table 1, entries 16 and 20).
Control experiments showed that no ester products were
observed when HCOOnBu was used instead of HCOOPh
(Table 1, entries 21 and 22). When the reaction was carried out
with 3.0 equiv of HCOOH in the absence of HCOOPh, the
reduction product (ethylbenzene) was mainly formed (Table 1,
entries 21−24).
The regiodivergent hydroesterification can be extended to a
wide variety of aryl olefins. Either linear or branched phenyl
arylpropanoates can be obtained in 54−98% yields with high
regioselectivities with ligand L1 or L5 (Table 2, entries 1−16).
Substituted styrenes were effective substrates. The phenyl rings
can have various substituents, including OMe, alkyl, phenyl, Cl,
and CF3 groups (Table 2, entries 1−11). The hydro-
esterification also worked well for olefins with other aromatics,
such as naphthalene and thiophene (Table 2, entries 12−16).
For alkyl terminal olefins, linear esters were formed
predominately under both conditions (methods A and B)
(Table 2, entries 17 and 18). Further studies showed that the
regioselectivity for the linear ester with 1-hexene (1q) was
increased to >20:1 when 1,1′-bis(di-tert-butylphosphino)-
ferrocene was used as ligand (Table 2, entry 17, method C).
For β-methylstyrene (cis and trans mixture), a mixture of
phenyl 4-phenylbutanoate (11), phenyl 2-methyl-3-phenyl-
propanoate (12), and phenyl 2-phenylbutanoate (13) was
isolated in 50% yield with a ratio of 100:7:1 when the reaction
was carried out with method A. When method B was used, a
mixture of phenyl 4-phenylbutanoate (11) and phenyl 2-
phenylbutanoate (13) (1:45) was obtained in 21% yield.
The branched esters from 1-isobutyl-4-vinylbenzene and 2-
methoxy-6-vinylnaphthalene (Table 2, entries 3 and 13) are
20
21
22
23
24
L5
e
e
f
L1
L5
0
L1
0
f
L5
0
a
The reactions were carried out with 1a (0.50 mmol), HCOOPh (1.50
mmol), Pd(OAc)2 (0.025 mmol), ligand (0.050 or 0.10 mmol, P/Pd =
4:1), and additive (0.050 mmol) in toluene (0.10 mL) at 90 °C for 24
b
h unless otherwise stated. Isolated yield. The ratio of 2a:3a was
determined by 1H NMR analysis of the crude reaction mixture.
c
d
e
HCOOPh at 1.00 mmol. Ligand at 0.15 mmol. The reaction was
f
carried out with 3.0 equiv of HCOOnBu instead of HCOOPh. The
reaction was carried out with 3.0 equiv HCOOH in the absence of
HCOOPh.
Scheme 2. Synthetic Transformations
selectivity was obtained with 2-(diphenylphosphino)biphenyl
(L4) (Table 1, entry 9). Again, compound 3a was greatly
favored (with a <1:20 l/b ratio) with a cyclohexyl analogue of
ligand L4, and a relatively lower yield was obtained (Table 1,
entry 10). Little product was detected with P(o-tolyl)3 and L6
(Table 1, entries 11 and 12). Similar yield and regioselectivity
were obtained for the reaction with L1 by addition of 10 mol %
HCOOH or CH3COOH (Table 1, entries 14 and 15 vs entry
B
DOI: 10.1021/acs.orglett.5b01630
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 2. Pd-Catalyzed Regiodivergent Hydroesterification of Olefins
a
Method A: The reactions were carried out with 1 (0.50 mmol), HCOOPh (1.50 mmol), Pd(OAc)2 (0.025 mmol), L1 (0.050 mmol), and
CH3COOH (0.050 mmol) in toluene (0.10 mL) at 90 °C for 24 h unless otherwise stated. Method B: The reactions were carried out with 1 (0.50
mmol), HCOOPh (1.50 mmol), Pd(OAc)2 (0.025 mmol), L5 (0.150 mmol), and HCOOH (0.050 mmol) in toluene (0.10 mL) at 90 °C for 24 h
unless otherwise stated. Method C: The reaction was carried out with 1q (0.50 mmol), HCOOPh (1.50 mmol), Pd(OAc)2 (0.025 mmol), 1,1′-
b
bis(di-tert-butylphosphino)ferrocene (0.050 mmol), and HCOOH (0.050 mmol) in toluene (0.10 mL) at 90 °C for 24 h. Isolated yield and the
c
1
ratio of two regioisomers was determined by H NMR analysis of the crude reaction mixture. The reaction mixture was stirred at 90 °C for 48 h.
Scheme 4. Deuterium-Labeling Experiments
Scheme 5. Palladium η1−η3 Benzyl Complexes
A precise reaction mechanism is not clear at this moment
and requires further study. One plausible catalytic cycle is
proposed in Scheme 3. The oxidative addition of Pd(0) to
HCOOPh led to palladium hydride complex 4, which
rearranged to palladium carbonyl complex 5. The olefin
substrate was subsequently hydropalladated to form complexes
6 and 7, which gave acylpalladium complexes 8 and 9 upon a
migratory insertion. The reduction elimination of complexes 8
and 9 led to esters 2 and 3 with regeneration of the Pd catalyst.
closely related to ibuprofen and naproxen (Figure 1). Phenyl
esters are reactive intermediates. The corresponding acid,
methyl ester, and amide can be readily obtained by direct
addition of KOH-H2O, MeOH, and n-butylamine to the
reaction mixture at the end of hydroesterification (Scheme 2).
C
DOI: 10.1021/acs.orglett.5b01630
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(2) For leading references on regioselective hydroesterification of
olefin with CO gas, see: (a) Fuchikami, T.; Ohishi, K.; Ojima, I. J. Org.
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deuterium-labeled styrene 1a-d2 to the hydroesterification
reaction conditions (Scheme 4). With bidentate ligand L1,
the resulting linear ester has 50% H at the α-carbon to the ester
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regiodivergent hydroesterification of aryl olefins with phenyl
formate under mild reaction conditions by a judicious choice of
ligand. A wide variety of linear or branched phenyl
arylpropanoates have been obtained with high yields and
excellent regoselectivities. The reaction process is potentially
useful for organic synthesis and operationally simple, requiring
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ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, characterization data, NMR spectra,
and CIF information. The Supporting Information is available
free of charge on the ACS Publications website at DOI:
10.1021/acs.orglett.5b01630.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: Yian.Shi@colostate.edu.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We gratefully acknowledge the National Natural Science
Foundation of China (0205131566) and Nanjing University
for financial support.
Shaughnessy, K. H. J. Organomet. Chem. 2005, 690, 3620. (c) Munoz,
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B. K.; Garcia, E. S.; Godard, C.; Zangrando, E.; Bo, C.; Ruiz, A.;
Claver, C. Eur. J. Inorg. Chem. 2008, 2008, 4625.
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DOI: 10.1021/acs.orglett.5b01630
Org. Lett. XXXX, XXX, XXX−XXX