Trichlorophenyl formate: Highly reactive and easily accessible crystalline CO surrogate for palladium-catalyzed carbonylation of aryl/alkenyl halides and triflates

Article abstract of DOI:10.1021/ol302593z

The high utility of 2,4,6-trichlorophenyl formate, a highly reactive and easily accessible crystalline CO surrogate, is demonstrated. The decarbonylation with NEt₃ to generate CO proceeded rapidly at rt, thereby allowing external-CO-free Pd-catalyzed carbonylation of aryl/alkenyl halides and triflates. The high reactivity of the CO surrogate enabled carbonylation at rt and significantly reduced the quantities of formate to near-stoichiometric levels. The obtained trichlorophenyl esters can be readily converted to a variety of carboxylic acid derivatives in high yields.

Full text of DOI:10.1021/ol302593z

ORGANIC
LETTERS
2012
Vol. 14, No. 20
5370–5373
Trichlorophenyl Formate: Highly Reactive
and Easily Accessible Crystalline CO
Surrogate for Palladium-Catalyzed
Carbonylation of Aryl/Alkenyl Halides
and Triflates
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 September 20, 2012
ABSTRACT
The high utility of 2,4,6-trichlorophenyl formate, a highly reactive and easily accessible crystalline CO surrogate, is demonstrated. The
decarbonylation with NEt3 to generate CO proceeded rapidly at rt, thereby allowing external-CO-free Pd-catalyzed carbonylation of aryl/alkenyl
halides and triflates. The high reactivity of the CO surrogate enabled carbonylation at rt and significantly reduced the quantities of formate to near-
stoichiometric levels. The obtained trichlorophenyl esters can be readily converted to a variety of carboxylic acid derivatives in high yields.
Because of its versatility for the regioselective synthesis
of carbonyl-containing compounds, Pd-catalyzed carbo-
nylation of aryl halides and related compounds employing
CO has generated considerable interest in organic synthe-
sis since the pioneering work of Heck et al. in 1974.1
Continuous improvement of this class of transformations
as a synthetic tool has so far enabled the efficient syntheses
of numerous carbonyl compounds2 and large-scale appli-
cation in industry. However, this methodology possesses
major problems such as its highly toxic nature and use of
the colorless gaseous form of CO leading to problematic
handling at both laboratory and multikilogram produc-
tion scales. Additional safety measurements such as a CO
detector and special waste treatment protocols are often
required, thereby reducing the overall utility of this reac-
tion. Therefore, there is significant interest in developing
alternative methods without CO gas.3 In this sense, various
compounds such as formic acid derivatives4 and metal
(3) For a review on carbonylation without CO gas, see: Morimoto,
T.; Kakiuchi, F. Angew. Chem., Int. Ed. 2004, 43, 5580.
(4) Cacchi et al. reported on the Pd-catalyzed hydroxycarbonylation
with lithium formate. See: (a) Cacchi, S.; Fabrizi, G.; Goggiamani, A.
Org. Lett. 2003, 5, 4269. For examples of Pd-catalyzed carbonylation
with alkyl formate, see: (b) Schareina, T.; Zapf, A.; Cotte, A.; Gotta, M.;
Beller, M. Adv. Synth. Catal. 2010, 352, 1205. (c) Ko, S.; Lee, C.; Choi,
M. G.; Na, Y.; Chang, S. J. Org. Chem. 2003, 68, 1607. (d) Carpentier,
J. F.; Castanet, Y.; Brocard, J.; Mortreux, A.; Petit, F. Tetrahedron Lett.
1991, 32, 4705.
† University of Shizuoka.
‡ Daiichi Sankyo Co., Ltd.
(1) (a) Schoenberg, A.; Bartoletti, I.; Heck, R. F. J. Org. Chem. 1974,
39, 3318. For a review on Pd-catalyzed carbonylation of aryl halides and
related compounds, see: (b) Brennfuhrer, A.; Neumann, H.; Beller, M.
€
Angew. Chem., Int. Ed. 2009, 48, 4114.
(2) For recent examples of Pd-catalyzed carbonylations, see: (a)
GØgsig, T. M.; Nielsen, D. U.; Lindhardt, A. T.; Skrydstrup, T. Org.
Lett. 2012, 14, 2536. (b) Wu, X.; Neumann, H.; Beller, M. Chem.;Eur.
J. 2012, 18, 3831.
(5) (a) Wieckowska, A.; Fransson, R.; Odell, L. R.; Larhed, M.
J. Org. Chem. 2011, 76, 978. (b) Wannberg, J.; Larhed, M. In Modern
Carbonylation Methods; Kollar, L., Ed.; Wiley-VCH: Weinheim, Germany,
2008; pp 93À114.
ꢀ
r
10.1021/ol302593z
Published on Web 09/28/2012
2012 American Chemical Society

carbonyl compounds5 have already been developed as
alternatives. However, most of them require either a very
high temperature or strong bases to release CO gas.
Recently, Skrydstrup et al. reported on several Pd-
catalyzed carbonylation reactions by using silacarboxylic
acids or tertiary acid chlorides operating crystalline CO
surrogates.6 Their method allowed strict control of the
amount of CO released for the carbonylation reactions by
using two-chamber equipment. However, the necessity of
such special equipment would reduce the utility of the
reaction leading to difficult scale-up. Furthermore, fluo-
ride reagents, strong bases, or an extra Pd catalyst is still
required to release CO.
balloon) as compared to existing methodologies. Further-
more, the obtained trichlorophenyl esters can be readily
transformed to various carboxylic acid derivatives.
For the initial experiment, several phenyl formates hav-
ing electron-withdrawing groups at ortho- and/or para-
positions were synthesized from the corresponding phe-
nolsby using HCOOH, Ac2O, and AcONa (Table 1). After
the reaction, simple extraction with toluene and subse-
quent concentration provided quite pure products without
column chromatography. Among the seven types of prod-
ucts synthesized, 4-phenylphenyl formate (1b) and 2,4,6-
trichlorophenyl formate (1f)9 were confirmed to be highly
crystalline compounds.
In the course of our investigation of practical methodol-
ogies for the synthesis of biologically active compounds,
we recently developed the practical external-CO-free Pd-
catalyzed carbonylation of aryl, alkenyl, and allyl halides,
and alkenyl tosylates with phenyl formate.7 In this ap-
proach, decarbonylation of phenyl formate with a mild
base (e.g., NEt3) generates phenol and CO, which is sub-
sequently used for the Pd-catalyzed carbonylation of elec-
trophiles to afford the corresponding phenyl esters. To
elaborate this process, we hypothesized that the installation
of electron-withdrawing groups at the ortho- or para-posi-
tions of the phenyl formate would enhance its reactivity as a
CO surrogate,8 thereby developing more efficient carbony-
lation reactions (Scheme 1). In addition, if the formate is
crystalline, it would be stable and easy to handle. Further-
more, carbonylation products can be regarded as highly
reactive carboxylic acid derivatives to nucleophiles and they
would be readily converted to various compounds.
Subsequently, the rt decarbonylation of the as-prepared
phenyl formates to generate CO and phenols with NEt3
was examined (Table 1). Remarkably, the presence of
electron-withdrawing groups significantly accelerated the
decarbonylation. In particular, crystalline 1f proved to be
the most reactive among the phenyl formates prepared,
and the decarbonylation was almost completed within
30 min. 1f can be stored at rt for 1 month with no signs
of degradation. Furthermore, 2,4,6-trichlorophenol, the
raw material used to prepare 1f, is inexpensive and readily
available.
Table 1. Synthesis of Phenyl Formates and Their Decarbony-
lationa with NEt3
Scheme 1. A Working Hypothesis
formate
(R)
yield
(%)
decarbonylation
conversion (%)b
entry
appearance
1
1a (H)
71
96
66
95
91
98
oil
16
2
1b (4-Ph)
1c (4-F)
crystal
oil
11
3
11
4
1d (4-Cl)
oil
24
5
1e (4-CF3)
1f (2,4,6-Cl3)
oil
69
6.0
crystal
92 (10 min)
98 (30 min)
100 (24 h)
46 (30 min)
100 (24 h)
In this communication, we demonstrate the high utility
of 2,4,6-trichlorophenyl formate as a highly reactive and
easily accessible crystalline CO surrogate for Pd-catalyzed
carbonylation reactions under considerably milder and
more practical conditions (i.e., rt, near-stoichiometric quan-
tities of formate, a simple flask equipped with an Ar
7
1g (2,6-F2)
53
oil
a Concentration: 0.5 M. b Determined by 1H NMR.
The obtained phenyl formates were subsequently applied
to the rt carbonylation of iodobenzene (2a) and alkenyl
triflate 2b under the presence of a PdÀxantphos7,10 catalyst
system (Table 2). As found in previous studies,7 alkyl for-
mates such as 1h and 1i did not react at all (entries 1 and 2).
Phenyl formate (1a) was not effective in rt carbonyla-
tion, affording products in poor yields (entries 3 and 4).
(6) (a) Friis, S. D.; Taaning, R. H.; Lindhardt, A. T.; Skrydstrup, T.
J. Am. Chem. Soc. 2011, 133, 18114. (b) Hermange, P.; Lindhardt, A. T.;
Taaning, R. H.; Bjerglund, K.; Lupp, D.; Skrydstrup, T. J. Am. Chem.
Soc. 2011, 133, 6061.
(7) (a) Ueda, T.; Konishi, H.; Manabe, K. Org. Lett. 2012, 14, 3100.
(b) Ueda, T.; Konishi, H.; Manabe, K. Tetrahedron. Lett. 2012, 53, 5171.
(c) Tsuji et al. also reported the Pd-catalyzed esterification of aryl halides
using aryl formates. See: Fujihara, T.; Hosoki, T.; Katafuchi, Y.; Iwai,
T.; Terao, J.; Tsuji, Y. Chem. Commun. 2012, 48, 8012.
(9) van Es, A.; Stevens, W. Recl. Trav. Chim. Pays-Bas 1965, 84,
1247.
(10) Martinelli, J. R.; Watson, D. A.; Freckmann, D. M. M.; Barder,
T. E.; Buchwald, S. L. J. Org. Chem. 2008, 73, 7102.
(8) Tsuji et al. reported that electron-withdrawing substituents ac-
celerated the Pd-catalyzed decarbonylation of phenyl formates; see:
Katafuchi, Y.; Fujihara, T.; Iwai, T.; Terao, J.; Tsuji, Y. Adv. Synth.
Catal. 2011, 353, 475.
Org. Lett., Vol. 14, No. 20, 2012
5371

Table 2. Pd-Catalyzed Carbonylation of 2a and 2ba
Table 4. Substrate Scope of the Pd-Catalyzed Carbonylation
with Formate 1fa
entry
electrophile
formate (R1)
product
yield (%)
1
2a
2a
2a
2b
2a
2b
2a
2b
2a
2b
2a
2b
2a
2b
2a
2b
1h
4
0
2
1i
5
0
3
1a (H)
6
10
30
5
4
1a (H)
7
5
1b (4-Ph)
1b (4-Ph)
1c (4-F)
1c (4-F)
1d (4-Cl)
1d (4-Cl)
1e (4-CF3)
1e (4-CF3)
1f (2,4,6-Cl3)
1f (2,4,6-Cl3)
1g (2,6-F2)
1g (2,6-F2)
8
6
9
17
30
35
81
87
94
91
>99
>99
99
94
7
10
11
12
13
14
15
3a
3b
16
17
8
9
10
11
12
13
14
15
16
a Reactions were conducted with 0.36À0.49 mmol of electrophile.
Table 3. Pd-Catalyzed Carbonylation of 2c with 1fa
temp
1f
yield
(%)c
entry
methodb
(°C)
ligand
(equiv)
1
2
3
4
5
6d
7
8
9
A
A
B
B
B
B
B
B
B
45
xantphos
xantphos
xantphos
xantphos
xantphos
xantphos
PPh3
2.0
2.0
2.0
2.0
1.2
1.2
1.2
1.2
1.2
25
45
68
95
90
89
28
17
43
80
80
100
100
100
100
100
100
dppf
a Reactions were conducted with 100 mg of electrophiles. b Method A:
The reactions were conducted in a test tube at rt for 10À21 h. 0.5 mL of
PhCF3 and 2.0 equiv of 1f and NEt3 were used. Method B: The reactions
were conducted in a 10-mL flask equipped with an Ar balloon. A degassed
solution of 1.2 equiv of 1f in 0.9 mL of toluene was added dropwise for 3 h to
a degassed solution of containing the electrophile, NBu3, Pd(OAc)2, and
xantphos in 0.6 mL of toluene at 100 °C. Then, the mixture was stirred for 1
h. c Isolated yields. d At 45 °C. e 5 mol % of Pd(OAc)2, 10 mol % of
xantphos, and 3.0 equiv of 1f and NEt3 were used. f 5 mol % of Pd(OAc)2,
10 mol % of xantphos, 2.5 equiv of 1f, and 4.0 equiv of NBu3 were used.
P(t-Bu)3
a Reactions were conducted with 0.48 mmol of 2c. b Method A: The
reactions were conducted in a test tube for 12À19 h. NEt3 was used.
Method B: The reactions were conducted in a 10-mL flask equipped with an
Ar balloon. A degassed solution of 1f in toluene was added dropwise for 3 h
to a solution containing 2c, NBu3, Pd(OAc)2, and the ligand in toluene.
Then, the mixture was stirred for 1 h. c Isolated yield. d 4.8 mmol of 2c.
Formates showing higher decarbonylation reactivities
such as 1e, 1f, and 1g (Table 1) gave higher yields of the
carbonylated products (entries 11À16). Trichlorophenyl
formate (1f) was found to show the highest reactivity,
affording the corresponding trichlorophenyl esters 3a and
5372
Org. Lett., Vol. 14, No. 20, 2012

3b in quantitative yields. These observations highlight the
importance of the rapid decarbonylation of the formates
for the Pd-catalyzed carbonylation reaction.
Scheme 2. Transformations of 3a
Having identified the most suitable crystalline CO sur-
rogate, we next tried to apply this methodology to the
carbonylation of arylbromide2c(Table 3). Unfortunately,
the reaction of 2c with 1f resulted in low yields at both 45
and 80 °C (entries 1 and 2). We hypothesized that an excess
amount of CO rapidly generated from 1f retarded the
oxidative addition of 2c to the Pd center because of the
π-acidic nature of CO as a ligand. We thus decided to
explorean experimentalprocedure that could minimize the
effects of CO. Consistent with this reasoning, a slow addi-
tion (3 h) of 1f to a solution containing 2c, the Pd catalyst,
and NBu3 significantly improved the yield of 3c (entries
3À4). Surprisingly, high yields (90%) were also obtained
even under near-stoichiometric quantities of 1f in a simple
flask equipped with an Ar balloon (entry 5). Other ligands
such as PPh3, dppf, and P(t-Bu)3 were ineffective in this
carbonylation (entries 7À9).
To determine the scope of this process, a variety of
electrophiles were employed as substrates (Table 4). The
experimental method (A or B) was chosen to suit the
relative ease of the oxidative addition of the RÀX bond.
A variety of functional groups (e.g., ester, cyano, ketone,
and aldehylde) were found to be tolerated, and both
electron-donating and -withdrawing groups at the 4-
position did not affect the reaction (entries 1À8). Un-
fortunately, ortho-substituted substrate 2m and 2n were
found to be recalcitrant substrates at rt. However, by
slightly raising the reaction temperature to 45 °C, the
yields were significantly improved (entries 11 and 12).
Aryl bromide 2k also reacted with 1f in good yields by
following method B (entry 9). Double carbonylation of 2o
and 2oa proceeded smoothly to afford 3o (entries 12 and 13).
This reaction is also applicable to heteroaromatic substrates.
The reactions of N- and S-containing heteroaromatic halides
proceeded well to afford 3qÀ3x in high yields (entries
15À24). The rt carbonylation of alkenyl bromide 2y and
triflate 2z also afforded the products in good yields (entries
25 and 26).
a 3 equiv of 0.5 M NH3/dioxane were used in place of NEt3, DMAP.
reacted with a small excess of nucleophiles under mild
conditions to afford the corresponding carboxylic acid
derivatives in high yields.
In summary, we have found that 2,4,6-trichlorophenyl
formate (1f) could serve as a highly reactive and easily
accessible crystalline CO surrogate. The decarbonylation to
generate CO proceeded smoothly at rt, and it was success-
fully applied to the external-CO-free Pd-catalyzed carbony-
lation of aryl/alkenyl halides and triflates. The high reac-
tivity of 1f as a CO surrogate allowed the carbonylation to
be achieved at rt or with a significantly reduced amount of
formate (i.e., near-stoichimetric quantities). Furthermore,
the obtained trichlorophenyl ester can be readily trans-
formed to alkyl esters, amides, thioesters, and carboxylic
acids in high yields. Further investigations concerning the
application of this methodology to other CO-free Pd-
catalyzed reactions will be carried out in due course.
Finally, we examined the transformation of 2,4,6-tri-
chlorophenyl ester (3a) by using various nucleophiles
(Scheme 2). Surprisingly, in contrast to the simple struc-
tures of trichlorophenyl esters, there are a few reports on
these kinds of transformations.11 As expected, the trichloro-
phenyl ester proved to be a highly reactive compound, and it
Acknowledgment. This work was partly supported by
Daiichi-Sankyo Co., Ltd.
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.
(11) (a) Chakraborti, A. K.; Rudrawar, S.; Kaur, G.; Sharma, L.
Synlett. 2004, 9, 1533. (b) Edmont, D.; Rocher, R.; Plisson, C.; Chenault,
J. Bioorg. Med. Chem. Lett. 2000, 10, 1831.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 20, 2012
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