Remarkable improvement achieved by imidazole derivatives in ruthenium-catalyzed hydroesterification of alkenes using formates

Article abstract of DOI:10.1021/ol301850y

Imidazole derivatives are revealed to be effective ligands in the Ru-catalyzed hydroesterification of alkenes using formates, affording one-carbonelongated esters in high yields. Further, intramolecular hydroesterification was successfully performed to give lactones for the first time. Imidazole derivatives can contribute to promote the reaction as well as to suppress the undesired decarbonylation of formate. Toxic CO gas, a directing group, and large excess alkenes are not required.

Full text of DOI:10.1021/ol301850y

ORGANIC
LETTERS
2012
Vol. 14, No. 18
4722–4725
Remarkable Improvement Achieved
by Imidazole Derivatives in
Ruthenium-Catalyzed Hydroesterification
of Alkenes Using Formates
Hideyuki Konishi,† Tsuyoshi Ueda,‡ Takashi Muto,† 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 July 6, 2012
ABSTRACT
Imidazole derivatives are revealed to be effective ligands in the Ru-catalyzed hydroesterification of alkenes using formates, affording one-carbon-
elongated esters in high yields. Further, intramolecular hydroesterification was successfully performed to give lactones for the first time.
Imidazole derivatives can contribute to promote the reaction as well as to suppress the undesired decarbonylation of formate. Toxic CO gas,
a directing group, and large excess alkenes are not required.
Catalytic hydroesterification of alkenes is an important
process in synthetic organic chemistry, and hence, con-
siderable efforts are devoted toward enhancing the effi-
ciency of this process.1 Transition-metal-catalyzed Reppe
carbonylation of alkenes by CO gas and alcohols has been
commercially used to produce esters with high synthetic
versatility.2 However, the toxicity of CO gas makes han-
dling difficult. Therefore, there is significant interest in the
development of alternative processes that do not require
CO.3 Over the past few decades, hydroesterification of
alkenes with alkyl or aryl formates has been identified
to be a popular one-step route to esters with one-carbon
elongation.4 Formates are considered inexpensive C1
building blocks.5 They are less toxic and can be handled
much more easily than CO. Moreover, the hydroesterifica-
tion reaction proceeds with complete atom economy.6
Previously, hydroesterification with formates was re-
stricted to a few special substrates such as ethylene and
(4) (a) Isnard, P.; Denise, B.; Sneeden, R. P. A. J. Organomet. Chem.
1983, 256, 135–139. (b) Mlekuz, M.; Joo, F.; Alper, H. Organometallics
1987, 6, 1591–1593. (c) Ueda, W.; Yokoyama, T.; Morikawa, Y.;
Moro-oka, Y.; Ikawa, T. J. Mol. Catal. 1988, 44, 197–200. (d) Kondo,
T.; Yoshii, S.; Tsuji, Y.; Watanabe, Y. J. Mol. Catal. 1989, 50, 31–38. (e)
Keim, W.; Becker, J. J. Mol. Catal. 1989, 54, 95–101. (f) Lin, I. J. B.;
Alper, H. J. Chem. Soc., Chem. Commun. 1989, 248–249. (g) Nahmed,
ꢀ
E. M.; Jenner, G. J. Mol. Catal. 1990, 59, L15–L19. (h) Grevin, J.; Kalck,
P. J. Organomet. Chem. 1994, 476, C23–C24. (i) Legrand, C.; Castanet,
Y.; Mortreux, A.; Petit, F. J. Chem. Soc., Chem. Commun. 1994, 1173–
1174. (j) Suzuki, Y.; Katoh, H.; Ishii, Y.; Hidai, M. J. Mol. Catal. A
† University of Shizuoka.
ꢀ
1995, 95, 129–133. (k) Lugan, N.; Lavigne, G.; Soulie, J. M.; Fabre, S.;
‡ Daiichi Sankyo Co., Ltd.
Kalck, P.; Saillard, J. Y.; Halet, J. F. Organometallics 1995, 14, 1712–
1731. (l) Fabre, S.; Kalck, P.; Lavigne, G. Angew. Chem., Int. Ed. 1997,
36, 1092–1095. (m) Kondo, T.; Okada, T.; Mitsudo, T. Organometallics
1999, 18, 4123–4127.
(5) For use of methyl formate, see review: (a) Jenner, G. Appl. Catal.,
A 1995, 121, 25–44. For a recent example, see: (b) Lee, H. W.; Chan,
A. S. C.; Kwong, F. Y. Chem. Commun. 2007, 2633–2635.
(6) (a) Trost, B. M. Science 1991, 254, 1471–147. (b) Trost, B. M. Acc.
Chem. Res. 2002, 35, 695–705.
(1) (a) El Ali, B.; Alper, H. Hydrocarboxylation and hydroesterifica-
tion reactions catalyzed by transition metal complexes. In Transition
Metals for Organic Synthesis, 2nd ed.; Beller, M., Bolm, C., Eds.; Wiley-
VCH: Weinheim, 2004; pp 113ꢀ132. (b) Brennfuehrer, A.; Neumann, H.;
Beller, M. ChemCatChem 2009, 1, 28–41.
(2) Kiss, G. Chem. Rev. 2001, 101, 3435–3456.
(3) (a) Morimoto, T.; Kakiuchi, K. Angew. Chem., Int. Ed. 2004, 43,
5580–5588. (b) Keim, W. Pure Appl. Chem. 1986, 58, 825–832.
r
10.1021/ol301850y
Published on Web 08/30/2012
2012 American Chemical Society

methyl formate.4a,c Moreover, high reaction temperatures
that exceeded the boiling points of the solvents and the
substrates were required, which mandated the use of
pressure-resistant apparatus.4c,j Further, undesirable side
reactions such as decarbonylation of the formates to
alcohols resulted in serious complications.7 In some cases,
high-pressure CO gas had to be reluctantly used to sup-
press the decarbonylation pathway.8 Recently, significant
improvements were reported in the hydroesterification
reactions by using either 2-pyridylmethyl formate as a
chelating substrate in the presence of Ru catalysts9 or
phenyl formate in the presence of Pd catalysts.10 However,
the limitations of formates have persisted and need to
be addressed more effectively. Furthermore, the alkenes
or formates must be used in large excess (3ꢀ4 equiv) to
achieve high yields.
In the course of our investigation of practical methodol-
ogies for the synthesis of biologically active compounds,
we hypothesized that the use of an appropriate ligand
that forms a catalytically active metal complex similar to
that formed by Ru and a chelating substrate would aid in
efficient hydroesterification with a wider range of sub-
strates. Extensive investigations showed that imidazole
derivatives not only accelerate these reactions but also
suppress undesired decarbonylation pathways, thereby
significantly improving the reaction efficiency. In this
paper, we report a general catalytic hydroesterification of
alkenes with various alkyl and aryl formates remarkably
improved by a novel Ruꢀimidazole system (Scheme 1).
Since the addition of an imidazole derivative could
expel the use of either directing groups or any external
CO that was previously essential, the reaction is expected
to be more economical and practical than those reported
previously.
Scheme 1. Hydroesterification Catalyzed by RuꢀImidazole
oftheligand 3awasconfirmedby acontrol experiment. No
reaction occurred when the reaction was conducted with-
out 3a (entry 2).
Further, we screened various ligands (Table 1). PPh3
and 1,2-bis(diphenylphosphino)ethane (DPPE) resulted in
significant decarbonylation of 1a, which was consistent
with a precedent literature12 noting the decarbonylation
of formate in the presence of phosphines (entries 3 and 4).
N,N,N0,N0-Tetramethylethylenediamine (TMEDA) also
led to decarbonylation of 1a, affording no product at all
(entry 5). Several nitrogen heterocycles such as pyridine,
pyrazole, oxazole, and imidazole were tested. While most
of them gave the desired ester in 30ꢀ40% yield, a promis-
ing result was obtained with imidazole 3d, with yields up to
55% (entries 6ꢀ9). This result prompted us to investigate
imidazole derivatives in detail. While other N-alkyl imida-
zoles 3e were only moderately effective (entry 10), the
highly substituted imidazole 3h and 2-hydroxymethyl imi-
dazole 3i gave better results(entries11 and12, respectively).
The length of the carbon chain attached to the hydroxy
group seemed to influence the reaction (entries 12 and 13).
Further, substitution by a long-chain alkyl group at the
N1 position of the imidazole ring contributed to an im-
provement in the yield (entry 14). However, methyl ether
substitution at the C2 position resulted in slightly reduced
yield (entry 15). It is worth mentioning that the regioselec-
tivity of the product was reversed only when 2-hydroxy-
methyl imidazoles 3g and 3i were used (entries 12 and 14).
Furthermore, through the analysis of catalysts, solvents,
and the equivalence of reagents (see Supporting Informa-
tion for details), we established that the best yield was
obtained when using 3i and a slight excess of 2a under neat
conditions (entry 16). Importantly, complete suppression
of decarbonylation was also observed in this case. Thus, we
discovered efficient conditions for the Ru-catalyzed hydro-
esterification of alkenes using formate; an imidazole ligand
could contribute to promote thereactionaswell as tosuppress
undesired decarbonylation of a formate. A thorough under-
standing of the reaction mechanism requires further exam-
ination. While we assume that the imidazole would
facilitate ligand exchange with CO to generate catalytically
active triruthenium species, we cannot exclude the possibi-
lity that a monomeric Ru species forms in the presence of
the ligand.
On the basis of the reported hydroesterification using
2-pyridylmethyl formate,9,11 we hypothesized that a Lewis
basic moiety can act as a ligand to alter the catalytic
activity. Further, we screened ligands that would coordi-
nate to the metal. Ru3(CO)12-catalyzedhydroesterification
of 4-methoxystyrene (2a) with benzyl formate (1a) in the
presence of a catalytic amount of 2-pyridylmethanol (3a)
as the ligand afforded the desired ester products, linear
4aa and branched 4ab, in moderate yields. Benzyl alcohol
was observed, which was derived as a byproduct from the
decarbonylation of 1a (Table 1, entry 1). The significance
(7) Both decarbonylation and decarboxylation of alkyl formates
have been reported: (a) Kondo, T.; Tantayanon, S.; Tsuji, Y.;
Watanabe, Y. Tetrahedron Lett. 1989, 30, 4137–4140. (b) Jenner, G.;
Nahmed, E. M.; Leismann, H. Tetrahedron Lett. 1989, 30, 6501–6502.
ꢀ
(c) Vega, F. R.; Clement, J.-C.; des Abbayes, H. Tetrahedron Lett. 1993,
34, 8117–8118.
(8) (a) Mlekuz, M.; Joo, F.; Alper, H. Organometallics 1987, 7, 1591–
1593. (b) Kondo, T.; Yoshii, S.; Tsuji, Y.; Watanabe, Y. J. Mol. Catal.
1989, 50, 31–38. (c) Lin, I. J. B.; Alper, H. J. Chem. Soc., Chem. Commun.
1989, 248–249. (d) Suzuki, Y.; Katoh, H.; Ishii, Y.; Hidai, M. J. Mol.
Catal. A 1995, 95, 129–133.
(9) (a) Ko, S.; Na, Y.; Chang, S. J. Am. Chem. Soc. 2002, 124, 750–
751. (b) Na, Y.; Ko, S.; Hwang, L. K.; Chang, S. Tetrahedron Lett. 2003,
44, 4475–4478.
Having identified the optimal conditions, we investi-
gated the substrate scope of the hydroesterification and
found that the reaction was applicable to a wide range of
(10) Katafuchi, Y.; Fujihara, T.; Iwai, T.; Terao, J.; Tsuji, Y. Adv.
Synth. Catal. 2011, 353, 475–482.
(11) Wang, L.; Floreancig, P. E. Org. Lett. 2004, 6, 4207–4210.
(12) Jenner, G.; Nahmed, E. M.; Leismann, H. J. Organomet. Chem.
1990, 387, 315–321.
Org. Lett., Vol. 14, No. 18, 2012
4723

Table 1. Screening of Ligandsa
Table 2. Scope of Formatesa
yield of
4 (%)b
yield of
BnOH (%)d
entry
ligand
3a
4aa:4abc
1
43
0
73:27
ꢀ
7
2
ꢀ
30
88
150
104
48
36
74
57
5
3
PPh3
DPPE
TMEDA
pyridine
3b
22
0
66:34
ꢀ
4
5
trace
35
32
30
55
61
72
68
34
80
56
89f
ꢀ
6
75:25
76:24
69:31
68:32
69:31
72:28
35:65
78:22
38:62
76:24
54:46
7
8
3c
9
3d
a Reactions run with 1 (1.0 equiv), 2a (1.5 equiv), Ru3(CO)12
(5 mol %), and 3i (15 mol %) under neat conditions at 135 °C for
24 h. Ar = 4-methoxyphenyl. b Isolated yield. The ratio of isomers,
determined by 1H NMR analysis of the isolated mixture of products, is
shown in parentheses.
10
11
12
13
14
15
16e
3e
3f
42
6
3g
3h
43
40
14
<1
3i
3j
3i
of which 4nc seemed to be attributed to CdC bond
isomerization13 to form allylbenzene and following hydro-
esterification (entry 6).
a Reactions run with 1a (1.5 equiv), 2a (1.0 equiv), Ru3(CO)12
(5 mol %), and ligand (15 mol %) in mesitylene (2.0 M) at 135 °C for
24 h. Ar = 4-methoxyphenyl. b Isolated yield. c Determined by 1H NMR
analysis of the isolated mixture of 4aa and 4ab. d Determined by crude
1H NMR analysis, based on 1a. e 1a (1.0 equiv) and 2a (1.5 equiv) were
used under neat conditions. f Based on 1a.
Furthermore, the potential of intramolecular hydroes-
terification for the direct synthesis of lactones was inves-
tigated. Intramolecular hydroesterification with substrates
bearing both alkenyl and formyl groups revealed that this
is an efficient method to synthesize various lactones in
high yields (Table 4). Again, the importance of imidazole
derivatives was confirmed, since no product formation
was observed when imidazole 3e was omitted (entry 1).
Unlike in the case of the intermolecular version, the use of
mesitylene as the solvent and 3e or 3f as the ligand con-
tributed to an improvement in the product yield. Terminal
alkenes, geminally disubstituted alkenes, and sterically
congested trisubstituted alkenes were shown to react in-
tramolecularly with the formyl group. Interestingly, the
same products were obtained from different substrates
because isomerization of the alkene preceded the hydro-
esterification under the present reaction conditions
(entries 7 and 8). Moreover, spirocycles could be accessed
from cyclic alkenes (entries 13 and 14). Thus, these results
in Table 4 reveal that our catalytic Ruꢀimidazole hydro-
esterification system can be efficiently applied to the direct
formates, including various benzyl, naphthylmethyl, and
aryl formates (1bꢀ1f) (Table 2, entries 1ꢀ5). Formates
bearing analkyl group (1g) ora stericallybulky benzhydryl
group (1h) were also well tolerated to afford the desired
esters (entries 6 and 7). The wide applicability of forma-
tes in our Ruꢀimidazole system appeared to be highly
contrastive to the previous reports that limited usage to
only special formates, indicating that a catalytic Ruꢀ3i
system was unambiguously more versatile for the hydro-
esterification.
We then investigated the substrate scope of the hydro-
esterification using a variety of alkenes (Table 3). Styrene
2b was converted to the desired product in quantitative
yield (entry 1). Alkyl-substituted terminal alkene 2c, gem-
inally disubstituted alkene 2d, and cyclic alkenes 2e and
2f were all found to be suited for the reaction (entries 2ꢀ5).
In the case of 2d, only a linear product was obtained, sug-
gesting that steric interaction played an important role
in determining the regioselectivity (entry 3). Further, the
reaction with β-methylstyrene 2g yielded three products,
(13) (a) Dallmann, K.; Buffon, R. J. Mol. Catal. A 2001, 172, 81–87.
^
(b) Ammar, H. B.; Notre, J. L.; Salem, M.; Kaddachi, M. T.; Toupet, L.;
Renaud, J.-L.; Bruneau, C.; Dixneuf, P. H. Eur. J. Inorg. Chem. 2003,
4055–4064.
4724
Org. Lett., Vol. 14, No. 18, 2012

Table 3. Scope of Alkenesa
Table 4. Intramolecular Hydroesterificationa
a Reactions run with 1a (1.0 equiv), 2 (1.5 equiv), Ru3(CO)12
(5 mol %), and 3i (15 mol %) under neat conditions at 135 °C for 24 h.
b Isolated yield. The ratio of isomers, determined by 1H NMR analysis of
the isolated mixture of products, is shown in parentheses.
synthesis of structurally diverted lactones. It is noted that
these are the first examples of the intramolecular hydro-
esterification to afford lactones.14
In conclusion, imidazole derivatives were discovered to
drastically improve the efficiency of the Ru-catalyzed hydro-
esterification of alkenes with formates. The Ru3(CO)12ꢀ3i
system is the best catalyst for intermolecular reactions,
while Ru3(CO)12ꢀ3e or Ru3(CO)12ꢀ3f would be suitable
for intramolecular reactions. The reaction can be adapted
to include a variety of alkenes and formates, which in-
dicates the first achievement of wide substrate generality.
Moreover, imidazoles contribute to make the reaction
proceed without the use of a directing group, toxic CO
gas, or a large excess alkene. As such, the reaction system is
safer and more economical than those reported previously.
Importantly, the present catalytic system has been applied
for the first time and very efficintly to the synthesis of
lactones. Investigation of the reaction mechanism, the
application of this reaction for the synthesis of biologically
active compounds, and development of novel synthetic
reactions concerning catalytic Ruꢀimidazole will be un-
dertaken in due course.
a Reaction run with 5, Ru3(CO)12 (5 mol %), and 3e (15 mol %) in
mesitylene (1.0ꢀ2.0 M) at 135 °C for 12ꢀ24 h. b Isolated yield. The ratio
of isomers, determined by 1H NMR analysis of the isolated mixture of
products, is shown in parentheses. c 3e was not used. d 3i (15 mol %) was
used instead of 3e. e 3f (15 mol %) was used instead of 3e. f Ratio of
diastereomers (shown in brackets) determined by 13C NMR analysis
of the isolated mixture of diastereomers. Relative configuration was not
determined.
Acknowledgment. This research was partly supported
by Daiichi Sankyo Co., Ltd. and by the Uehara Memorial
Foundation.
Supporting Information Available. Experimental proce-
dures, copies of 1H and 13C NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
(14) Floreancig et al. reported lactone formation via intermolecular
hydroesterification, followed by intramolecular attack of the hydroxy
group to the ester carbonyl. See ref 11.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 18, 2012
4725