Preparation of α,β-unsaturated esters and amides via external-CO-free palladium-catalyzed carbonylation of alkenyl tosylates

Article abstract of DOI:10.1016/j.tetlet.2012.07.057

Palladium-catalyzed carbonylation of tosylates with phenyl formate is described. This procedure needs neither external carbon monoxide nor any pressure-resistant apparatus. A variety of cyclic and acyclic alkenyl tosylates can be converted into the corresponding phenyl esters in good yields. Furthermore, this method is effective for the one-pot synthesis of α,β-unsaturated amides.

Full text of DOI:10.1016/j.tetlet.2012.07.057

Tetrahedron Letters 53 (2012) 5171–5175
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Preparation of
a,b-unsaturated esters and amides via external-CO-free
palladium-catalyzed carbonylation of alkenyl tosylates
Tsuyoshi Ueda a,b, Hideyuki Konishi a, Kei Manabe a,
⇑
a School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan
b Process Technology Research Laboratories, Pharmaceutical Technology Division, Daiichi Sankyo Co., Ltd., 1-12-1 Shinomiya, Hiratsuka, Kanagawa 254-0014, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Palladium-catalyzed carbonylation of tosylates with phenyl formate is described. This procedure needs
neither external carbon monoxide nor any pressure-resistant apparatus. A variety of cyclic and acyclic
alkenyl tosylates can be converted into the corresponding phenyl esters in good yields. Furthermore, this
Received 14 June 2012
Revised 9 July 2012
Accepted 13 July 2012
Available online 20 July 2012
method is effective for the one-pot synthesis of
a,b-unsaturated amides.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Carbonylation
Alkenyl tosylates
Phenyl formate
Palladium
Introduction
carbonylation of alkenyl tosylates. Recently, Reeves et al., reported
the palladium-catalyzed carbonylation of alkenyl tosylates using
enantiopure skewphos as the ligand at a CO pressure of 100 psi.3
CO-free carbonylation chemistry has been the focus of exten-
sive research in organic synthesis for the last three decades.8 Var-
ious compounds such as formic acid derivatives and metal
carbonyl compounds have already been developed as alternatives
to toxic CO gas. Among them, formate is the most attractive due
to their low price and the ease of preparation. However, the past
reported carbonylation of aryl and alkenyl halides and aryl triflates
employing formates has suffered from low efficiency such as the
necessity of the harsh reaction conditions, the limited substrate
scope, and the unsatisfactory yields.9 Moreover, to the best of
our knowledge, there is no precedent for the carbonylation of alke-
nyl tosylates with a formate.
In the course of our research on practical methodologies for the
synthesis of bioactive compounds, we recently developed the prac-
tical carbonylation of aryl, alkenyl, and allyl halides with phenyl
formate in the presence of a PdÀP(t-Bu)3 catalyst system.10 This
method needs neither toxic CO gas nor any high-pressure equip-
ment and affords one-carbon-elongated phenyl esters. Herein, we
describe the external-CO-free carbonylation of alkenyl tosylates
with phenyl formate in the presence of a Pd-xantphos catalyst sys-
tem. Using the proposed method, a variety of cyclic and acyclic
alkenyl tosylates can be converted into the corresponding phenyl
esters in good yields under mild conditions (Scheme 1). Further-
a,b-Unsaturated carboxylic acid derivatives are valuable syn-
thetic intermediates in asymmetric reactions such as Michael,
Diels–Alder, and hydrogenation reactions, since they provide effi-
cient synthetic routes to various chiral key intermediates for phar-
maceutical compounds. Among several strategies for producing
a,b-unsaturated carboxylic acid derivatives, Horner–Wadsworth–
Emmons reaction is the most reliable and well-established
transformation that affords two-carbon-elongated esters from
aldehyldes.1 Alternatively, the palladium-catalyzed carbonylation
employing CO gas is a complementary and useful method for the
preparation of one-carbon-elongated
a,b-unsaturated carboxylic
acid derivatives from alkenyl electrophiles.2 In particular, the
carbonylation of alkenyl tosylates3 is more attractive than the reac-
tion of conventional alkenyl electrophiles such as alkenyl halides4
and triflates.5,6 This is because alkenyl tosylates can be prepared
easily from ketone or aldehyde precursors in one step, and their
high stability and crystallinity simplify isolation and handling. In
addition, tosylating agents are cheaper and more readily available
than N-phenyl triflimide, the reagent used to prepare alkenyl
triflates.7
While many methods for the carbonylation of alkenyl halides
and triflates have been reported, there is only one report on the
more, this method is effective for the one-pot synthesis of
unsaturated amides.
a,b-
⇑
Corresponding author. Tel./fax: +81 54 264 5754.
E-mail address: manabe@u-shizuoka-ken.ac.jp (K. Manabe).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.07.057

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T. Ueda et al. / Tetrahedron Letters 53 (2012) 5171–5175
CO2Ph
R3
OTs
O
Pd-xantphos
R1
R1
Ts2O, base
R1
phenyl formate
R3
R3
R2
R2
R2
aldehydes or ketones
NEt3, PhCF3
one-carbon-elongated esters
a,b-unsaturated phenyl esters via palladium-catalyzed carbonylation with phenyl formate.
Scheme 1. Synthesis of
Table 1
Screening of ligands for carbonylationa
O
Pd(OAc)2 (3 mol%)
ligand (P/Pd = 4 : 1)
OTs
+
O
OPh
H
OPh
NEt3 (2.0 equiv)
toluene
100 °C, 18 h
1a
2
3a
2.0 equiv
Entry
Ligand
Yieldb (%)
1
2
3
P(t-Bu)3ÁHBF4
PPh3
dppm
0
16
8
4
5
6
7
8
9
10
dppe
dppp
dppb
dppf
rac-Binap
xantphos
DPEphos
90
67
17
40
42
78
6
a
Reactions were conducted on a 0.333 mmol scale in tosylate 1a and anhydrous toluene (1 mL) at 100 °C using
2 equiv of 2 and 2 equiv of NEt3 in the presence of 3 mol % Pd(OAc)2 and 6 or 12 mol % phosphine (P/Pd = 4). The
reaction time was 18 h.
b
HPLC yields of 3a.
Table 2
Optimization of carbonylationa
Pd(OAc)2 (3 mol%)
dppe or xantphos (6 mol%)
O
O
OTs
n
+
H
OPh
n
OPh
NEt3 (2.0 equiv)
solvent
100 °C, 13–21 h
2
1a
1b
3a (n = 2)
(n = 2)
(n = 1)
2.0 equiv
3b
(n = 1)
Entry
n
Ligand
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
2
2
2
2
2
2
2
2
2
2
2
1
1
1
1
1
1
dppe
xantphos
dppe
dppe
dppe
dppe
dppe
dppe
dppe
dppe
xantphos
dppe
xantphos
xantphos
xantphos
xantphos
xantphos
Toluene
Toluene
THF
DME
CPME
DMF
NMP
CH3CN
DCE
PhCF3
PhCF3
PhCF3
PhCF3
Toluene
CH3CN
PhCF3
PhCF3
90
78
61
70
29
73
54
88
9
83
10
11d
12d
13d
14d
15d
16d,e
17d,e,f
92 (86)c
87 (89)c
42c
84c
73c
34c
89c
34c
a
Reactions were conducted on a 0.333À0.349 mmol scale in tosylate 1a or 1b and anhydrous solvent (1 mL) at 100 °C using
2 equiv of 2 and 2 equiv of NEt3 in the presence of 3 mol % Pd(OAc)2 and 6 mol % dppe or xantphos. The reaction time was
13À21 h.
b
HPLC yields.
Isolated yields.
0.5 mL of solvent was used.
2.5 equiv of phenyl formate (2) and NEt3 were used.
c
d
e
f
Reaction temperature was 80 °C.

T. Ueda et al. / Tetrahedron Letters 53 (2012) 5171–5175
5173
xantphos (110°), but the former two do not show good catalytic
activity (entries 7 and 10). Under the same conditions as in entry
9, alkyl formates and formamide such as benzyl formate, heptyl
formate, and dimethylformamide did not react at all and the corre-
sponding esters and amide could not be obtained. These results
highlight the importance of the rapid decarbonylation of phenyl
formate (2) with NEt3.10
Next, we examined the effect of solvent on the carbonylation of
1a using dppe as the ligand (Table 2). The type of solvent had a sig-
nificant effect on the yield of 3a. Ether- and amide-type solvents
such as THF, DME, CPME, DMF, and NMP were not suited for this
reaction (29À73%; entries 3–7). When using CH3CN and PhCF3, sat-
isfactory yields were obtained (92% and 88%, respectively; entries 8
and 10). In particular, in the case of Pd-xantphos catalyst system,
PhCF3 afforded 3a in significantly improved yield (87%, entry 11).
Next, we tried the carbonylation of 1b using dppe and xantphos
as ligands (entries 12 and 13). While dppe gave a poor yield of
3b (42%), xantphos showed good catalytic activity and afforded
3b in 84% yield. When using toluene and CH3CN, the yields of 3b
decreased significantly compared to the result of PhCF3 (entries
14 and 15 vs entry 13), which might be explained by the high sol-
Results and discussion
Optimization
We began our investigation, by testing several ligands in the
carbonylation of tosylate 1a with 2.0 equiv of phenyl formate (2)
and NEt3 in the presence of 3 mol % Pd(OAc)2 at 100 °C (Table 1).
In contrast to the carbonylation of aryl halides which we reported
recently,10 PdÀP(t-Bu)3 catalyst system was totally ineffective in
the carbonylation of 1a (entry 1). Dppe, which has a two-carbon
tether, showed excellent catalytic activity and afforded 3a in 90%
yield (entry 4). Bidentate ligands having longer or shorter carbon
tethers, such as dppm, dppp, and dppb, were not effective for this
carbonylation (entries 3, 5, and 6). This efficiency trend of the li-
gands is different from that in the previously reported carbonyl-
ation of alkenyl tosylates in CO atmosphere;3 the suitable ligands
in that case were bidentate phosphines having three-carbon teth-
ers, such as dppp, skewphos, and dcpp. In addition to dppe, xant-
phos10–12 proved to be an efficient ligand, affording 3a in 78%
yield (entry 9). This result is worth noting because the bite an-
gle13,14 of dppf15 (106°) and DPEphos (108°) is similar to that of
Table 3
Carbonylation of various alkenyl tosylatesa
Pd(OAc)2 ( 3 mol%)
xantphos ( 6 mol%)
R3
R3
O
R1
R1
+
CO2Ph
OTs
H
OPh
NEt3, PhCF3
100 °C
R2
3c-m
R2
1c-m
2
Entry
1
Substrate
Product
Yieldb (%)
90
OTs
CO2Ph
3c
1c
OTs
Ph
CO2Ph
Ph
1d
2
3
89 (E/Z = 10/90)
3d
Ph
OTs
Ph
1e
Ph
CO2Ph
Ph
3e
81
Ph
Ph
Ph
Ph
Ph
1f
3f
OTs
CO2Ph
4
5
95 (E/Z = 97/3)
(E/Z = 91/9)
Ph
1g
3g
47
OTs
OTs
CO2Ph
CO2Ph
1h
3h
6
86
Ph
Ph
7
8
9
80
79
74
OTs
R = H (1i)
CO2Ph
R = H (3i)
= CO2Et (3j)
= t-Bu (3k)
R
R
= CO2Et (1j)
= t-Bu (1k)
10
CO2Ph
CO2Ph
72
73
OTs
OTs
3l
1l
11c
3m
1m
CO2Et
CO2Et
OTs
CO2Ph
1n
12
58
3n
BocN
BocN
a
Reactions were conducted on a 100 mg scale in alkenyl tosylate 1c–m and PhCF3 (0.5 mL) at 100 °C using 2.5 equiv of 2 and 2.5 equiv of NEt3 in the presence of 3 mol %
Pd(OAc)2 and 6 mol % xantphos. The reaction time was 11À18 h.
b
Isolated yields.
c
4.0 equiv of 2 and 4.0 equiv of NEt3 in the presence of 5 mol % Pd(OAc)2 and 10 mol % xantphos.

5174
T. Ueda et al. / Tetrahedron Letters 53 (2012) 5171–5175
ubility of the catalyst and 3b in PhCF3. The yield improved slightly
(89%) when an increased amount of phenyl formate (2.5 equiv)
was used (entry 16 vs entry 13). At 80 °C, the yield dramatically de-
creased to 34% (entry 17).
of NEt3 in the presence of 3 mol % Pd(OAc)2 and 6 mol % xantphos in
PhCF3 at 100 °C) were employed to test the generality of our catalyst
system for a variety of alkenyl tosylates 1c–m (Table 3). Cyclic and
acyclic tosylates containing an aryl group at the b-position were
found to be competent substrates for this reaction (entries 2, 3, 4,
Scope of substrates
and 6). An aryl group at the a-position of the enol tosylate 1c did
not affect the reaction (entry 1), but the geminally disubstituted
alkenyl tosylate 1g gave the product in lower yield (entry 5). This
reaction was tolerant of steric hindrance in the alkenyl tosylates,
The aforementioned optimum conditions for tosylates 1a and 1b
(1 equiv of alkenyl tosylate, 2.5 equiv of phenylformate (2), 2.5 equiv
Table 4
One-pot synthesis of amide via carbonylationa
Pd(OAc)2 (3 mol%)
R3
R3 R4
dppe or xantphos
R4R5NH
R1
R1
N
phenyl formate (2)
OTs
R5
R2
R2
O
NEt3, PhCF3
80–100°C
80–100°C
Entry
1c
Substrate
Product
Yieldb (%)
89
OTs
O
O
O
O
1a
4aa
4ab
4ac
NHBn
2c
1a
1a
1a
81
82
N
N
3c
O
4c,d
4ad
4b
81
75
NH2
O
1b
OTs
5e
NHBn
OTs
Ph
O
NHBn
6e
83
70
80
68
1c
4c
OTs
O
NHBn
Ph
1e
1h
7e,f
8e,f
9e
4e
Ph
Ph
OTs
Ph
O
4h
NHBn
Ph
OTs
O
1i
N
4ia
EtO2C
O
EtO2C
EtO2C
O
Bn
10e
1i
70
N
H
4ib
a
Reactions were conducted on 100 mg scale in alkenyl tosylate and PhCF3 (0.5 mL) at 80À100 °C using 2.0À2.5 equiv of 2 and 2.0À2.5 equiv of NEt3 in the presence of
3 mol % Pd(OAc)2 and 6 mol % xantphos or dppe. The carbonylation reaction time was 10À18 h. After carbonylation, 3.0À5.0 equiv of amine was added and stirred for
12À48 h.
b
Isolated yields.
c
Dppe was used as the ligand. 2.0 equiv of phenyl formate and NEt3 were used. The reaction temperature was 80 °C.
5 equiv of 0.5 M NH3/dioxane solution was used. The amidation temperature was 100 °C.
Xantphos was used as the ligand. 2.5 equiv of phenyl formate and NEt3 were used. The carbonylation reaction temperature was 100 °C.
5 equiv of amine was used. The amidation temperature was 100 °C.
d
e
f

T. Ueda et al. / Tetrahedron Letters 53 (2012) 5171–5175
5175
thus allowing for the preparation of tetrasubstituted
a
,b-unsatu-
General procedure for the one-pot synthesis of amides via
carbonylation
rated phenyl esters 3e, 3h, and 3m (entries 3, 6, and 11). Cyclic tosy-
lates without conjugation of an aryl group also reacted with phenyl
formate (2) to afford the corresponding phenyl esters in good yields
(entries 7À10). The reaction of the b-ketoester enol tosylate 1m re-
quired increased amounts of the palladium catalyst and 2 for com-
plete consumption of the tosylate (entry 11). The functionalized N-
Boc piperidine substrate 1n could also be coupled with 2 to give
3n in moderate yield (entry 12). 3n is the backbone of isoguvacine,
Pd(OAc)2 (3.0 mol %) and xantphos or dppe (6.0 mol %) were
added to a 10-mL test tube. The test tube was evacuated and back-
filled with argon three times, and then, a degassed solution of phe-
nyl formate (2, 2.5 equiv), alkenyl tosylate (100 mg, 1.0 equiv), and
triethylamine (2.5 equiv) in PhCF3 (0.5 mL) was added to the test
tube under flowing argon. The test tube was sealed by a plastic
screw cap, and the mixture was warmed to 80À100 °C (bath tem-
perature) and stirred for 11À18 h. Then, the reaction mixture was
cooled to rt. Amine (3.0À5.0 equiv) was added, and the test tube
was re-sealed, warmed to 80À100 °C (bath temperature), and stir-
red for 12À48 h. The mixture was diluted with toluene, washed
with 10% aq. NaOH and H2O, dried over Na2SO4, filtered, and con-
centrated. The obtained residue was purified by PTLC (SiO2, CHCl3)
to afford the desired amide product.
which is a potent
c
-amino butyric acid (GABA) agonist.16,17
,b-unsaturated
Finally, we examined the one-pot synthesis of
a
amides via the carbonylation of alkenyl tosylates by adding
3.0À5.0 equiv of amine after the carbonylation (Table 4). Both pri-
mary and secondary amines reacted smoothly with the phenyl es-
ters to afford the corresponding amides in good yields (entries
1À3, 5, and 6). In addition, ammonia could be employed to give a
primary amide 4ad (entry 4). This one-pot amidation could also
be applied to synthesize tetrasubstituted
a,b-unsaturated amides
4e and 4h (entries 7 and 8). Furthermore, this reaction tolerated al-
kyl ester groups to give the desired amides containing ethyl ester
(entries 9 and 10).
Acknowledgments
This research was supported in part by Daiichi-Sankyo Co., Ltd.
Conclusion
Supplementary data
We have found that carbonylation of alkenyl tosylates with
phenyl formate can be promoted using a Pd-xantphos catalyst sys-
tem. This procedure requires neither external carbon monoxide
nor any pressure-resistant apparatus. A variety of cyclic and acyclic
alkenyl tosylates can be converted into the corresponding phenyl
esters in good yields. This method is also effective for the one-
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.07.057.
References and notes
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pot synthesis of
a,b-unsaturated amides. Further investigation
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Experimental
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Synthesis of phenyl formate (2)
Formic acid (19 mL, 500 mmol, 5.0 equiv) was added to acetic
anhydride (38 mL, 400 mmol, 4.0 equiv) at rt. The mixture was stir-
red at 60 °C for 1 h and cooled to rt. The resulting solution was
poured into a flask containing phenol (9.4 g, 100 mmol) and AcONa
(4.1 g, 50 mmol, 0.5 equiv). The mixture was stirred for 4 h in a
water bath and then diluted with toluene (150 mL), washed with
H2O (100 mL) three times, dried over MgSO4, filtered, and concen-
trated to afford the desired product 2 (8.7 g, 71 mmol, 71%) as a
colorless oil. This product was used for the subsequent carbonyl-
ation reactions without further purification.
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2.4 Hz), 7.25 (tt, 1H, J = 7.8, 1.9 Hz), 7.10 (ddd, 2H, J = 8.3, 2.4, 1.9 Hz);
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General procedure for the carbonylation of alkenyl tosylates
Pd(OAc)2 (3.0 mol %) and xantphos (6.0 mol%) were added to a
10-mL test tube. The test tube was evacuated and backfilled with
argon three times, and then, a degassed solution of phenyl formate
(2, 2.5 equiv), alkenyl tosylate (100 mg, 1.0 equiv), and triethyl-
amine (2.5 equiv) in PhCF3 (0.5 mL) was added to the test tube un-
der flowing argon. The test tube was sealed by a plastic screw cap,
the mixture was warmed to 100 °C (bath temperature) and stirred
for 11À18 h. Then, the reaction mixture was cooled to rt, diluted
with EtOAc, washed with H2O, dried over Na2SO4, filtered, and con-
centrated. The obtained residue was purified by PTLC (SiO2, hex-
ane/EtOAc 10/1À1/1) to afford the desired phenyl ester product.
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aryl and alkenyl bromides with lithium formate. See Ref.
16. Falch, E.; Krogsgarrd-Larsen, P. J. Med. Chem. 1981, 24, 285.
17. Reeves et al. reported a three-step synthesis of isoguvacine via palladium-
3
catalyzed carbonylation employing CO gas. See Ref.