Palladium-catalyzed carbonylation of aryl, alkenyl, and allyl halides with phenyl formate

Article abstract of DOI:10.1021/ol301192s

Highly efficient palladium-catalyzed carbonylation of aryl, alkenyl, and allyl halides with phenyl formate is reported. This procedure does not use carbon monoxide and affords one-carbon-elongated carboxylic acid phenyl esters in excellent yields. The reaction proceeds smoothly under mild conditions and tolerates a wide range of functional groups including aldehyde, ether, ketone, ester, and cyano groups. Furthermore, a variety of heteroaromatic bromides can be converted to the corresponding phenyl esters in high yields.

Full text of DOI:10.1021/ol301192s

ORGANIC
LETTERS
2012
Vol. 14, No. 12
3100–3103
Palladium-Catalyzed Carbonylation of
Aryl, Alkenyl, and Allyl Halides with
Phenyl Formate
Tsuyoshi Ueda,†,‡ Hideyuki Konishi,† and Kei Manabe*,†
School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku,
Shizuoka 422-8526, Japan, and Process Technology Research Laboratories,
Pharmaceutical Technology Division, Daiichi Sankyo Co., Ltd., 1-12-1 Shinomiya,
Hiratsuka, Kanagawa 254-0014, Japan
manabe@u-shizuoka-ken.ac.jp
Received May 1, 2012
ABSTRACT
Highly efficient palladium-catalyzed carbonylation of aryl, alkenyl, and allyl halides with phenyl formate is reported. This procedure does not use
carbon monoxide and affords one-carbon-elongated carboxylic acid phenyl esters in excellent yields. The reaction proceeds smoothly under mild
conditions and tolerates a wide range of functional groups including aldehyde, ether, ketone, ester, and cyano groups. Furthermore, a variety of
heteroaromatic bromides can be converted to the corresponding phenyl esters in high yields.
The synthesis of carboxylic acid esters from aryl halides
is one of the most important transformations in organic
chemistry. The conventional strategy for this conversion
involves halogenꢀmetal exchange by alkyllithium or
Grignard reagents and subsequent addition to carbon
dioxide to afford carboxylic acids that can be condensed
with alcohols to give the desired carboxylic acid esters. In
this procedure, the reaction needs stoichiometric amounts
of metal reagents, the strong basicity of which limits the
tolerated functional groups. An efficient and complemen-
tary methodology is the palladium-catalyzed carbonyla-
tion of aryl halides with alcohols employing CO gas. This
method has found broad applications in the synthesis of a
variety of ester compounds.1 However, it also has a major
problem: CO gas is highly toxic and difficult to utilize in
reactions on a laboratory scale, which reduces the overall
utility of the reaction. Therefore, there is significant inter-
est in developing alternative methods that avoid the use of
CO gas.2
In this respect, formates are considered to be especially
promising alternatives because of their ease of handling
compared to toxic CO gas. In fact, much effort has already
been expended on realizing carbonylation utilizing for-
mates without CO gas.3 However, so far carbonylation
methods employing formates have suffered from low
efficiency because of the necessity of directing groups for
formates, of an Ru cocatalyst,3b and of strong bases,3c
limited substrate scope and unsatisfactory yields,3aꢀc very
high required temperatures (135ꢀ140 °C for aryl
bromides)3a,b,4 and pressure (15 bar of N2),3c and the
necessity of large excess amounts of formate.3a
(2) For review on carbonylations without CO gas, see: Morimoto, T.;
Kakiuchi, K. Angew. Chem., Int. Ed. 2004, 43, 5580.
† University of Shizuoka.
‡ Daiichi Sankyo Co., Ltd.
(3) (a) Schareina, T.; Zapf, A.; Cotte, A.; Gotta, M.; Beller, M. Adv.
Synth. Catal. 2010, 352, 1205. (b) Ko, S.; Lee, C.; Choi, M. G.; Na, Y.;
Chang, S. J. Org. Chem. 2003, 68, 1607. (c) Carpentier, J. F.; Castanet,
Y.; Brocard, J.; Mortreux, A.; Petit, F. Tetrahedron Lett. 1991, 32, 4705.
(4) Cacchi et al. reported Pd-catalyzed hydroxycarbonylation of aryl
bromides with lithium formate at 80 °C with a reaction time of 64 h. See:
(a) Cacchi, S.; Fabrizi, G.; Goggiamani, A. Org. Lett. 2003, 5, 4269. (b)
Berger, P.; Bessmernykh, A.; Caille, J.-C.; Mignonac, S. Synthesis 2006,
3106.
€
(1) Review: (a) Brennfuhrer, A.; Neumann, H.; Beller, M. Angew.
Chem., Int. Ed. 2009, 48, 4114. For recent examples of Pd-catalyzed
carbonylations, see: (b) Wu, X.; Neumann, H.; Beller, M. Chem.;Eur.
J. 2012, 18, 3831. (c) Akpinar, G. E.; Kus, M.; Cuncu, M. U.; Karakus,
E.; Artok, L. Org. Lett. 2011, 13, 748. (d) Mercadante, M. A.; Leadbeater,
N. E. Org. Biomol. Chem. 2011, 9, 6575. (e) Reeves, D. C.; Rodriquez, S.;
Lee, H.; Haddad, N.; Krishnamurthy, D.; Senanayake, C. H. Org. Lett.
2011, 13, 2495.
r
10.1021/ol301192s
Published on Web 05/30/2012
2012 American Chemical Society

In the course of our search for practical methodologies
for the synthesis of bioactive compounds, we hypothesized
that the use of an appropriate ligand, formate ester, and
base would lead to a more efficient carbonylation reaction
with wide substrate generality. Herein, we now report the
carbonylation of aryl, alkenyl, and allyl halides with
phenyl formate in the presence of a PdꢀP(t-Bu)3 or
Pdꢀxantphos catalyst system to give one-carbon-elon-
gated phenyl esters. The reaction proceeds smoothly with
small excess amounts of phenyl formate (1.5ꢀ2.0 equiv)
under milder conditions (80 °C, NEt3 is used as the base)
than those found in previous examples. Moreover, a
variety of heteroaromatic bromides can be converted to
the corresponding phenyl esters in satisfactory yields.
At the beginning of our investigation, we tested the
carbonylation of bromobenzene (1a) with 2 equiv of phe-
nyl formate5,6 and NaHCO3 under a PdꢀPPh3/Ru bime-
tallic catalyst system at 100 °C (Table 1, entry 1).3b,7 As we
expected, the desired phenyl ester 3a was obtained in 23%
yield. To confirm the effect of the Ru catalyst, the reaction
was attempted in the absence of Ru3(CO)12. Surprisingly,
the yield was dramatically improved to afford 3a in 64%
(entry 2). In addition, NEt3 is found to be a very effective
base for this reaction that affords the product in 97%
(entry 3). Evidently, the P/Pd ratio affected the catalytic
activity, because the yield decreased to 68% at P/Pd = 2
(entry 4). Alkyl formates such as benzyl formate (2b) and
ethyl formate (2c) did not give the corresponding alkyl
esters (3b,c) at all (entries 5 and 6).
When Pd2(dba)3 was used with no ligand, no product was
obtained at all (entry 1). Bidentate phosphines with larger
Table 2. Screening of Ligands for Carbonylationa
entry
ligand
temp (°C)
yieldb (%)
1c
2
none
PPh3
PCy3
dppe
dppp
dppbz
dppf
100
100
100
100
100
100
100
100
100
100
80
0
97
7
3
4
5
5
71
3
6
7
96
96
99
11
88d
89d
90d
93d
34d
8
xantphos
9
P(t-Bu)3 HBF4
3
10
11
12
13
14
15
P(c-pentyl)3 HBF4
3
PPh3
dppf
80
xantphos
80
P(t-Bu)3 HBF4
80
3
3
P(t-Bu)3 HBF4
60
a Reactions were conducted on a 0.637 mmol scale in bromobenzene
(1a) and anhydrous mesitylene (1 mL) using 1 equiv of 1a, 2 equiv of 2a,
and 2 equiv of NEt3 in the presence of 3 mol % of Pd(OAc)2 and 6 or 12
mol % of phosphine (P/Pd = 4/1). The reaction time was 13ꢀ21 h.
b Isolated yields of 3a. c 3 mol % of Pd2(dba)3 was used. d HPLC yields.
bite angles such as dppf and xantphos8 showed excellent
catalytic activities and afforded 3a in 96% yield (entries 7
and 8). The best activity was found for P(t-Bu)3 HBF4,
3
which gave a 99% yield of 3a (entry 9). High yield was also
realized at 80 °C (entry 14), but at 60 °C the yield
dramatically decreased to 34% (entry 15).
Table 1. Pd-Catalyzed Carbonylation of 1a with Formatea
In the next stage, we examined the effect of the solvent
on the reaction (Table 3). CH3CN is the solvent of choice,
although the type of solvent had no significant effect on the
yield of 3a (63%ꢀ99%, entries 1ꢀ10). A further series of
experiments showed that the yields of the reaction re-
mained high (91%ꢀ95%) even when a reduced amount
of phenyl formate (1.5 equiv) or catalyst (1.5 mol %) was
used (entries 11 and 12).
entry
R
Ru3(CO)12
base
yieldb (%)
c
1
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Bn (2b)
Et (2c)
þ
NaHCO3
NaHCO3
NEt3
23
64
97
68
0
2
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
The best conditions found above for bromobenzene (1a)
(1 equiv of aryl halide, 2 equiv of phenyl formate (2a), 2
equiv of NEt3 in the presence of 3 mol % Pd(OAc)2 and
3d
4e
5
NEt3
NEt3
12 mol % P(t-Bu)3 HBF4 in CH3CN at 80 °C) were
6
NEt3
0
3
employed to test the generality of our catalyst system for
a variety of aryl halides and phenyl triflate (Table 4).
Iodobenzene (1b) smoothly reacted with 2a to afford 3a
in excellent yield (entry 2). Unlike for 1a and 1b, the use of
toluene as solvent and xantphos as ligand was favorable
for triflate 1c to give 3a in 99% yield (entry 3).
a Reactions were conducted on a 0.637 mmol scale in bromobenzene
(1a) and anhydrous mesitylene (1 mL) at 100 °C using 1 equiv of 1a, 2
equiv of 2aꢀc, and 2 equiv of base in the presence of 3 mol % of
Pd(OAc)2 and 12 mol % of PPh3. The reaction time was 44 h. b Isolated
yields. c 3 mol % of Ru3(CO)12 was used. d The reaction time was 13 h.
e 6 mol % of PPh3 was used.
A variety of functional groups (ester, cyano, ketone, and
aldehyde groups) is tolerated in this reaction. Neither
electron-donating nor electron-withdrawing groups at
the 4- and 2-positions affected the reaction (entries 4ꢀ13),
except for the 2-NO2 group (entry 14). Steric bulkiness
We then tested several ligands in the carbonylation of
bromobenzene (1a) with phenyl formate (2a) (Table 2).
(5) Tsuji et al. reported Pd-catalyzed hydroesterification of alkynes
with phenyl formate. See: Katafuchi, Y.; Fujihara, T.; Iwai, T.; Terao, J.;
Tsuji, Y. Adv. Synth. Catal. 2011, 353, 475.
(6) Phenyl formate was easily prepared from phenol by using acetic
anhydride, formic acid, and AcONa without silica gel column chroma-
tography, and the obtained product can be used for this reaction.
(7) Jenner, G.; Bentaleb, A. J. Organomet. Chem. 1994, 470, 257.
(8) Buchwald et al. used Pd-xantphos for carbonylation of aryl
bromides under CO atmosphere. See: Martinelli, J. R.; Watson, D. A.;
Freckmann, D. M. M.; Barder, T. E.; Buchwald, S. L. J. Org. Chem.
2008, 73, 7102.
Org. Lett., Vol. 14, No. 12, 2012
3101

Table 3. Solvent Study for Carbonylationa
Table 4. Carbonylation of Various Aryl, Alkenyl, and Allyl
Halides and Phenyl Triflate (1aꢀu)a
entry
solvent
yield of 3ab (%)
1
mesitylene
toluene
PhCF3
DCE
93
2
95
3
63
4
63
5
THF
92
6
DME
92
7
CPME
DMF
87
8
82
9
NMP
89
10
11c
12d
CH3CN
CH3CN
CH3CN
95 (97)e
95
91
a Reactions were conducted on a 0.637 mmol scale in bromobenzene
(1a) and anhydrous solvent (1 mL) at 80 °C using 1 equiv of 1a, 2 equiv of
2a, and 2 equiv of NEt3 in the presence of 3 mol % of Pd(OAc)2 and 12
mol % of P(t-Bu)3 HBF4. The reaction time was 17 h. b HPLC yields.
3
c 1.5 equiv of 2a and NEt3 were used. d 1.5 mol % of Pd(OAc)2 was used.
e Isolated yields of 3a.
around the bromine atom did not affect the yield signifi-
cantly (entry 15). Double carbonylation of p-dibromoben-
zene (1p) proceeded to give 3p in 94% yield (entry 16).
Alkenyl bromides also coupled with 2a, and conjugated esters
3s and 3t were obtained in good yields (entries 19 and 20).
In addition, allyl bromide was another good coupling
partner to afford 3u (entry 21).
This reaction is also applicable to heteroaromatic sys-
tems, as shown in Table 5. Bromopyridines 1vꢀx were
coupled with 2a to afford the corresponding phenyl esters
in good yields (entries 1ꢀ3). Other N-containing aromatic
bromides also gave the corresponding phenyl esters in
good yields (entries 4ꢀ7). The reactions of S- and O-con-
taining heteroaromatic bromides proceeded well to afford
3acꢀae in high yields (entries 8ꢀ10).
The reaction profile9 of carbonylation of 1d with phenyl
formate (2a) is shown in Figure 1a. As the 2aconcentration
decreased, the 3d concentration increased at a compatible
rate. From this fact, we suppose that decarbonylation of
2a to form phenol and CO is the rate-determining
step. Therefore, this step was examined in detail with
2a, as shown in Figure 1b. The conversion of 2a at 80 °C
in the presence of 1 equiv of NEt3 showed a first-
order dependence on the concentration of 2a (k = 9.5 ꢁ
10ꢀ3 minꢀ1).10 The addition of PdꢀP(t-Bu)3 did not
affect the reaction rate.11 Without NEt3, 2a did not react
at all. These results indicate that decarbonylation is a
NEt3-catalyzed reaction.12
a Reactions were conducted on a 100 mg scale in aryl, alkenyl, and
allyl halides and phenyl triflate (1aꢀu) in anhydrous CH3CN (1 mL) at
80 °C using 1 equiv of 1aꢀu, 2 equiv of 2a, and 2 equiv of NEt3 in the
presence of 3 mol % of Pd(OAc)2 and 12 mol % of P(t-Bu)3 HBF4. The
3
reaction time was 15ꢀ20 h. b Isolated yields. c 6 mol % of xantphos was
used in place of P(t-Bu)3 HBF4. The reaction solvent was toluene.
3
(9) The reaction was monitored by HPLC by using ethyl benzoate as
the internal standard.
d 4 equiv of 2a and 4 equiv of NEt3 were used in the presence of 5 mol %
of Pd(OAc)2 and 20 mol % of P(t-Bu)3 HBF4. Two milliliters of CH3CN
was used.
3
(10) v = ꢀd[2a]/dt = k[2a].
(11) Tsuji et al. reported that Pd-catalyzed decarbonylation of 2a
without a base showed zero-order dependence on the concentration of
2a. See ref 5.
(12) Alkyl formates are known to undergo base-catalyzed decom-
position to CO and alcohols. For example, see: Ma, F. Q.; Lu, D. S.;
Guo, Z. Y. J. Mol. Catal. 1993, 78, 309.
A plausible catalytic cycle is shown in Scheme 1. Phenyl
formate is converted to phenol and CO by NEt3. Insertion
3102
Org. Lett., Vol. 14, No. 12, 2012

Table 5. Carbonylation of Various Heteroaromatic Bromides
(1vꢀz and 1aaꢀae)a
Figure 1. (a) Reaction profile of carbonylation: 0, yield of 3d; 2,
residual ratio of 2a. (b) Decarbonylation of 2a: (, 1 equiv of
NEt3; 0, 1 equiv of NEt3, 3 mol % Pd(OAc)2, and 12 mol %
P(t-Bu)3 HBF4; ꢁ,without NEt3 and Pd cat.
3
Scheme 1. Plausible Reaction Mechanism
a Reactions were conducted on a 100 mg scale in aryl halides and
anhydrous CH3CN (1 mL) at 80 °C using 1 equiv of substrate, 2 equiv of
2a, and 2 equiv of NEt3 in the presence of 3 mol % of Pd(OAc)2 and 12 mol %
of P(t-Bu)3 HBF4. The reaction time was 15ꢀ20 h. b Isolated yields. c 4 equiv
3
of 2a and 4 equiv of NEt3 were used in the presence of 5 mol % of Pd(OAc)2
and 20 mol % of P(t-Bu)3 HBF4. Two milliliters of CH3CN was used.
cocatalyst, toxic CO gas, or large excess amounts of
formate. Further investigation concerning the reaction’s
application to synthesis of biologically active compounds
is being carried out in due course.
3
of CO in arylpalladium species B generates the acylpalla-
dium species C that reacts with phenol and NEt3 to form
phenoxy(acyl)palladium species D. The reductive elimina-
tion provides the carbonylation product 3a and the active
palladium species A.
Acknowledgment. This work was partly supported by
Daiichi-Sankyo.
In conclusion, we have found that carbonylation of aryl,
alkenyl, and allyl halides with phenyl formate was pro-
moted under the PdꢀP(t-Bu)3 system. Various halides
can be used in the reaction to afford the corresponding
phenyl esters in high yields under mild conditions. The
reaction can proceed without the use of a directing group,
Supporting Information Available. Experimental pro-
cedures and characterization data of new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 12, 2012
3103