A Ligand-Directed Catalytic Regioselective Hydrocarboxylation of Aryl Olefins with Pd and Formic Acid

Article abstract of DOI:10.1021/acs.orglett.7b00507

An effective Pd-catalyzed hydrocarboxylation of aryl olefins with Ac₂O and formic acid is described. A variety of 2- and 3-arylpropanoic acids can be regioselectively formed by the judicious choice of ligand without the use of toxic CO gas.

Full text of DOI:10.1021/acs.orglett.7b00507

Letter
pubs.acs.org/OrgLett
A Ligand-Directed Catalytic Regioselective Hydrocarboxylation of
Aryl Olefins with Pd and Formic Acid
Wei Liu,† Wenlong Ren,† Jingfu Li,† Yuan Shi,† Wenju Chang,† 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
‡Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523, United States
S
* Supporting Information
ABSTRACT: An effective Pd-catalyzed hydrocarboxylation of aryl olefins with Ac2O and formic acid is described. A variety of 2-
and 3-arylpropanoic acids can be regioselectively formed by the judicious choice of ligand without the use of toxic CO gas.
arboxylic acids are a class of organic compounds of great
importance in pharmaceuticals and fine chemicals. For
example, a number of 2-arylpropanoic acids are effective
nonsteroidal anti-inflammatory agents including ibuprofen,
naproxen, and loxoprofen (Figure 1).1 Regioselective hydro-
tigated. The ligand was found to be highly crucial to the
regioselectivity. Either 2-arylpropanoic or 3-arylpropanoic acids
can be obtained regioselectively by the judicious choice of ligand
(Scheme 1). Herein, we report our preliminary results on this
subject.
C
Scheme 1. Pd-Catalyzed Regioselective Hydrocarboxylation
without CO
Figure 1. Medicinally important 2-arylpropanoic acids.
carboxylation of olefins provides a straightforward approach to
carboxylic acids. Traditionally, this process involves the use of
toxic and flammable CO under high pressure and/or high
temperature,2,3 which may limit its use in laboratories. Thus, it
would be highly desirable to develop effective, mild, and
operationally simple hydrocarboxylation processes with non-
gaseous CO surrogates.4 However, prior to our studies,5 only
limited examples of such reaction were reported primarily with
formic acid or esters as a CO source and Ir or Rh as a catalyst at
high temperature (>100 °C).6 As part of our efforts in developing
CO-free hydrocarbonylation reactions, we have recently found
that carboxylic acids can be formed by direct addition of
HCOOH to olefins with a Pd catalyst in the presence of
HCOOPh5a,c,e or Ac2O.5b In this reaction process, HCOOPh
and Ac2O can also be used in catalytic amounts.5a−c,7 The
hydrocaboxylation of styrene was also investigated with our
previous conditions. The corresponding carboxylic acids were
isolated in 96% yield, but only with a 1:2 b/l ratio.5b For this class
of olefins, it is clear that the regioselectivity obtained is not
synthetically useful and remains to be solved. To address this
issue, various reaction parameters were subsequently inves-
Styrene (1a) was used as the test substrate for initial studies.
Various ligands were investigated with 2.0 equiv of HCOOH and
1.0 equiv of Ac2O in the presence of 5 mol % Pd(OAc)2 in
toluene at 80 °C (Table 1, entries 1−18). The ligand was found
to be an important factor for both reactivity and regioselectivity.
Among the ligands examined, the highest regioselectivity for the
branched acid (2a) (15:1 b/l ratio) was obtained with tris[4-
(trifluoromethyl)phenyl]phosphine (L3) (Table 1, entry 4).
Among the solvents tested, toluene was found to be the best
solvent in terms of the b/l ratio (Table 1, entry 4 vs entries 19−
23). A higher yield and selectivity were obtained when the
amount of HCOOH was increased to 3.0 equiv (Table 1, entry
24 vs entry 4). The yield was slightly increased when the amount
of Ac2O was reduced to 20 mol % (Table 1, entry 25 vs entry 24).
The yield was further increased with a lower reaction
temperature (65 °C) (Table 1, entry 26) and prolonged reaction
Received: February 20, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00507
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
were examined. The best result was obtained with L8. Linear acid
3a was formed in 75% yield with a 1:10 b/l ratio when the
reaction was carried out with 5 mol % Pd(OAc)2, 20 mol % L8,
2.0 equiv of HCOOH, and 20 mol % Ac2O in toluene at 80 °C for
36 h (Table 1, entry 29).
Table 1. Studies on Reaction Conditions
The generality for the reaction process was subsequently
investigated. As shown in Table 2, the regioselective hydro-
carboxylation with tris[4-(trifluoromethyl)phenyl]phosphine
(L3) can be extended to a wide variety of aryl olefins, giving 2-
arylpropanoic acids in 45−91% yields with generally high b/l
ratios (Table 2, entries 1−16). The aromatic groups can have
various substituents including alkyl, phenyl, OR, and Cl groups.
Ibuprofen (2c) and naproxen (2p) can be readily obtained with
high yields and regioselectivities (Table 2, entries 3 and 16). A
lower reactivity and regioselectivity obtained for o-methylstyrene
were likely due to the steric hindrance of the ortho methyl group
(Table 2, entry 11).
As shown in Table 3, the regioselective hydrocarboxylation
with tris(2-methoxyphenyl)phosphine (L8) can also be applied
to various aryl olefins, giving the corresponding 3-arylpropanoic
acids in 53−78% yields with b/l ratios ranging from 1:8 to <1:20
(Table 3, entries 1−14) depending upon the substituents on the
phenyl groups. The steric hindrance of ortho substituents
generally led to higher regioselectivities (Table 3, entries 8−12
and 14). A low reactivity and regioselectivity were obtained with
alkyl olefins such as 1-octene (1w) under the current reaction
conditions (Table 3, entry 15).
A precise reaction mechanism is not clear at this moment and
awaits further study. One plausiable catalytic cycle is outlined in
Scheme 2.5b,d HCOOAc (4) was in situ generated from
HCOOH and Ac2O. The oxidative addition of Pd(0) to 4 gave
palladium complex 5a or 5b, which rearranged to complex 6. The
olefin was subsequently hydropalladated by 6 to form complexes
7 and 8, which were converted to acyl Pd complexes 9 and 10
upon migratory insertion. The reductive elimination of 9 and 10
led to anhydride 11 or 12 with the Pd(0) catalyst being
regenerated. Anhydrides 11 and 12 reacted with HCOOH to
give carboxylic acids 2 and 3 with reformation of HCOOAc (4).
In order to further probe the reaction mechanism, deuterium
studies were carried out with 1-methyl-4-vinylbenzene (1b) and
1-methyl-2-vinylbenzene (1k) under the reaction conditions for
regioselective formation of the branched acid (Table 2) and
linear acid (Table 3), respectively (Scheme 3). In the case of
substrate 1b with L3, the corresponding branched acid (2b-d)
has 45% D (vs 33% D theoretically) at the methyl group,
indicating that there is some deuterium−hydrogen exchange at
this carbon. In the case of substrate 1k with L8, the
corresponding linear acid (3k-d) has about 40% D at both
methylene groups, indicating deuterium was incorporated into
both carbons. These results suggest that the hydropalladation
process is likely reversible, and the regioselectivity is probably
determined in the subsequent migratory insertion step.
b
c
entry
ligand
PPh3
solvent
yield (%) (2a:3a)
1
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
hexane
DCM
100 (3:1)
100 (2:1)
100 (3:1)
47 (15:1)
0
2
L1
3
L2
4
L3
5
L4
6
P(m-tolyl)3
P(o-tolyl)3
L5
87 (7:1)
0
7
8
57 (4:1)
34 (10:1)
10 (1:1)
82 (1:3)
13 (2:1)
35 (1:6)
83 (1:3)
100 (1:1)
72 (1:2)
100 (1:1)
21 (3:1)
75 (5:1)
89 (2:1)
66 (2:1)
9 (8:1)
9
L6
10
11
12
13
14
15
16
17
18
19
20
21
22
23
L7
L8
dppe
dppp
dppb
dppf
L9
L10
L11
L3
L3
L3
dioxane
EtOAc
THF
L3
L3
trace
d
24
L3
toluene
toluene
toluene
toluene
toluene
toluene
61 (>20:1)
67 (>20:1)
74 (>20:1)
96 (>20:1)
55 (1:10)
75 (1:10)
e
25
L3
ef
,
26
27
28
29
L3
eg
,
L3
h
i
L8
L8
a
The reactions were carried out with 1a (0.50 mmol), Pd(OAc)2
(0.025 mmol), ligand (0.050 or 0.10 mmol, P/Pd = 4:1), HCOOH
(1.0 mmol), and Ac2O (0.50 mmol) in toluene (0.50 mL) at 80 °C for
b
24 h unless otherwise stated. The yield was determined from the
crude reaction mixture by 1H NMR with BnOMe as an internal
c
standard. The ratio of 2a:3a was determined by the 1H NMR analysis
d
of the crude reaction mixture. With HCOOH (1.5 mmol) and Ac2O
(0.50 mmol). With HCOOH (1.5 mmol) and Ac2O (0.10 mmol). At
65 °C for 24 h. At 65 °C for 48 h. With HCOOH (1.0 mmol) and
Ac2O (0.10 mmol) at 80 °C for 24 h. With HCOOH (1.0 mmol) and
e
f
g
h
i
Ac2O (0.10 mmol) at 80 °C for 36 h.
The regioselectivity was found to be highly influenced by the
ligand used. As shown in Table 1 (entries 1−9), the branched
acid (2a) was mainly formed with mostly monodentate
ligands.3j,8 The regioselectivity was particularly favored with
electron-deficient ligand L3.3r,9 The phenyl group could stabilize
palladium intermediate 7 via delocalization to form the η3-benzyl
complex. Ligand L3 appeared to be highly favorable to such
stabilization, thus facilitating the formation of 7 and/or the
subsequent migratory insertion process to predominately give
branched acid 2. In contrast, ligand L8 appeared to favor linear
palladium intermediate 8 likely due to the steric hindrance of the
time (Table 1, entry 27). The branched acid (2a) was formed in
96% yield with a >20:1 b/l ratio in the presence of 5 mol %
Pd(OAc)2, 20 mol % L3, 3.0 equiv of HCOOH, and 20 mol %
Ac2O in toluene at 65 °C for 48 h (Table 1, entry 27). With the
optimized reaction conditions in hand for the branched acid,
studies were also carried out to increase the regioselectivity for
the linear acid (3a). Among the ligands examined, tris(2-
methoxyphenyl)phosphine (L8), dppp, and dppb appeared to be
the most promising ligands for the linear acid (Table 1, entries
11, 13, and 14). With these ligands, various reaction conditions
B
DOI: 10.1021/acs.orglett.7b00507
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 2. Hydrocarboxylation of Olefins for Branched
Carboxylic Acids
Table 3. Hydrocarboxylation of Olefins for Linear Carboxylic
Acids
a
a
a
The reactions were carried out with 1 (0.50 mmol), Pd(OAc)2 (0.025
mmol), L8 (0.10 mmol), HCOOH (1.0 mmol), and Ac2O (0.10
b
mmol) in toluene (0.50 mL) at 80 °C for 36 h. Isolated yield of two
c
regioisomers. The ratio of 2:3 was determined by the 1H NMR
analysis of the crude reaction mixture.
o-MeO group and/or the coordination of the o-MeO group to
the palladium, consequently facilitating the formation of linear
acid 3.3j,8
a
The reactions were carried out with 1 (0.50 mmol), Pd(OAc)2 (0.025
In summary, we have developed an efficient Pd-catalyzed
regioselective hydrocarboxylation of aryl olefins under mild
reaction conditions. A variety of 2- and 3-arylpropanoic acids
have been obtained in good yields with generally high
regioselectivities by the judicious choice of ligand. The reaction
process requires no handling of toxic CO gas and is operationally
simple. The observation of the profound ligand effect on the
regioselectivity provides new insights for the reaction process.
mmol), L3 (0.10 mmol), HCOOH (1.50 mmol), and Ac2O (0.10
b
mmol) in toluene (0.50 mL) at 65 °C for 48 h. Isolated yield of two
c
regioisomers. The ratio of 2:3 was determined by the 1H NMR
analysis of the crude reaction mixture.
C
DOI: 10.1021/acs.orglett.7b00507
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Proposed Catalytic Cycle for Hydrocarboxylation
REFERENCES
■
(1) For leading references on nonsteroidal anti-inflammatory agents,
see: (a) Hart, F. D. Drugs 1975, 9, 321. (b) Kantor, T. G.
Pharmacotherapy 1986, 6, 93. (c) Rieu, J.-P.; Boucherle, A.; Cousse,
H.; Mouzin, G. Tetrahedron 1986, 42, 4095. (d) Harrington, P. J.;
Lodewijk, E. Org. Process Res. Dev. 1997, 1, 72.
(2) For leading reviews on metal-catalyzed hydrocarboxylation, see:
(a) Kiss, G. Chem. Rev. 2001, 101, 3435. (b) del Río, I.; Claver, C.; van
Leeuwen, P. W. N. M. Eur. J. Inorg. Chem. 2001, 2001, 2719. (c) Ali, B.
E.; Alper, H. In Handbook of Organopalladium Chemistry for Organic
Synthesis; Negishi, E., Ed.; John Wiley & Sons, Inc.: New York, 2002; pp
2333−2349. (d) Brennfuhrer, A.; Neumann, H.; Beller, M.
̈
ChemCatChem 2009, 1, 28.
(3) For leading references on metal-catalyzed regioselective hydro-
carboxylation of olefins with CO gas, see: (a) Fuchikami, T.; Ohishi, K.;
Ojima, I. J. Org. Chem. 1983, 48, 3803. (b) Alper, H.; Woell, J. B.;
Despeyroux, B.; Smith, D. J. H. J. Chem. Soc., Chem. Commun. 1983,
1270. (c) Alper, H.; Hamel, N. J. Am. Chem. Soc. 1990, 112, 2803. (d) El
Ali, B.; Alper, H. J. Org. Chem. 1993, 58, 3595. (e) El Ali, B. E.; Vasapollo,
G.; Alper, H. J. Org. Chem. 1993, 58, 4739. (f) Brunet, J.-J.; Neibecker,
D.; Srivastava, R. S. Tetrahedron Lett. 1993, 34, 2759. (g) Papadogianakis,
G.; Verspui, G.; Maat, L.; Sheldon, R. A. Catal. Lett. 1997, 47, 43.
́ ́
(h) Miquel-Serrano, M. D.; Aghmiz, A.; Dieguez, M.; Masdeu-Bulto, A.
M.; Claver, C.; Sinou, D. Tetrahedron: Asymmetry 1999, 10, 4463.
(i) Seayad, A.; Jayasree, S.; Chaudhari, R. V. Org. Lett. 1999, 1, 459.
(j) del Río, I.; Ruiz, N.; Claver, C.; van der Veen, L. A.; van Leeuwen, P.
W. N. M. J. Mol. Catal. A: Chem. 2000, 161, 39. (k) Verspui, G.;
Besenyei, G.; Sheldon, R. A. Can. J. Chem. 2001, 79, 688. (l) Ali, B. E.;
Fettouhi, M. J. Mol. Catal. A: Chem. 2002, 182-183, 195.
(m) Mukhopadhyay, K.; Sarkar, B. R.; Chaudhari, R. V. J. Am. Chem.
Scheme 3. Deuterium-Labeling Experiments
Soc. 2002, 124, 9692. (n) Tortosa-Estorach, C.; Ruiz, N.; Masdeu-Bulto,
́
A. M. Chem. Commun. 2006, 2789. (o) Neumann, H.; Brennfuhrer, A.;
̈
Beller, M. Adv. Synth. Catal. 2008, 350, 2437. (p) Frew, J. J. R.; Clarke,
M. L.; Mayer, U.; Van Rensburg, H. V.; Tooze, R. P. Dalton Trans. 2008,
1976. (q) Frew, J. J. R.; Damian, K.; Van Rensburg, H. V.; Slawin, A. M.
Z.; Tooze, R. P.; Clarke, M. L. Chem. - Eur. J. 2009, 15, 10504.
(r) Konrad, T. M.; Durrani, J. T.; Cobley, C. J.; Clarke, M. L. Chem.
Commun. 2013, 49, 3306. (s) He, Z.; Hou, Z.; Zhang, Y.; Wang, T.;
Dilixiati, Y.; Eli, W. Catal. Today 2015, 247, 147.
(4) For leading reviews on carbonylations with CO surrogates, see:
(a) Morimoto, T.; Kakiuchi, K. Angew. Chem., Int. Ed. 2004, 43, 5580.
(b) Leung, J. C.; Krische, M. J. Chem. Sci. 2012, 3, 2202. (c) Konishi, H.;
Manabe, K. Synlett 2014, 25, 1971. (d) Wu, L.; Liu, Q.; Jackstell, R.;
Beller, M. Angew. Chem., Int. Ed. 2014, 53, 6310. (e) Liu, B.; Hu, F.; Shi,
B.-F. ACS Catal. 2015, 5, 1863.
Further efforts will be devoted to understanding the reaction
mechanism, expanding the substrate scope, and developing an
asymmetric hydrocarboxylation process.
(5) (a) Wang, Y.; Ren, W.; Li, J.; Wang, H.; Shi, Y. Org. Lett. 2014, 16,
5960. (b) Wang, Y.; Ren, W.; Shi, Y. Org. Biomol. Chem. 2015, 13, 8416.
(c) Dai, J.; Ren, W.; Wang, H.; Shi, Y. Org. Biomol. Chem. 2015, 13, 8429.
(d) Wang, Y.; Zeng, Y.; Yang, B.; Shi, Y. Org. Chem. Front. 2016, 3, 1131.
(e) Dai, J.; Ren, W.; Chang, W.; Zhang, P.; Shi, Y. Org. Chem. Front.
2017, 4, 297.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b00507.
■
S
Experimental procedures, characterization data, NMR
spectra (PDF)
(6) (a) Drury, D. J.; Williams, P. S. (BP Chemicals) EP 106656, 1983.
(b) Pruett, R. L.; Burke, P. L. (EXXON) EP 0092350, 1983.
Crystallographic information (CIF, CIF)
(c) Simonato, J.-P.; Walter, T.; Metivier, P. J. Mol. Catal. A: Chem.
́
2001, 171, 91. (d) Simonato, J.-P. J. Mol. Catal. A: Chem. 2003, 197, 61.
(7) For leading references on Pd- and Ni-catalyzed hydrocarboxylation
of alkynes with HCOOH/Ac2O, see: (a) Hou, J.; Xie, J.-H.; Zhou, Q.-L.
Angew. Chem., Int. Ed. 2015, 54, 6302. (b) Hou, J.; Yuan, M.-L.; Xie, J.-
H.; Zhou, Q.-L. Green Chem. 2016, 18, 2981. (c) Fu, M.-C.; Shang, R.;
Cheng, W.-M.; Fu, Y. ACS Catal. 2016, 6, 2501.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: Yian.Shi@colostate.edu.
ORCID
(8) Ren, W.; Chang, W.; Wang, Y.; Li, J.; Shi, Y. Org. Lett. 2015, 17,
Wei Liu: 0000-0003-3294-9360
Notes
3544.
(9) Guiu, E.; Caporali, M.; Munoz, B.; Muller, C.; Lutz, M.; Spek, A. L.;
Claver, C.; van Leeuwen, P. W. N. M. Organometallics 2006, 25, 3102.
̃
̈
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We gratefully acknowledge the National Natural Science
Foundation of China (21632005, 21472083).
■
D
DOI: 10.1021/acs.orglett.7b00507
Org. Lett. XXXX, XXX, XXX−XXX