Cu-catalyzed stereoselective conjugate addition of arylboronic acids to alkynoates

Article abstract of DOI:10.1039/b802231c

The CuOAc-catalyzed reaction of internal alkynoates with arylboronic acids proceeded under mild conditions to yield trisubstituted cinnamates stereoselectively. The Royal Society of Chemistry.

Full text of DOI:10.1039/b802231c

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Cu-catalyzed stereoselective conjugate addition of arylboronic acids to
alkynoatesw
Yoshihiko Yamamoto,* Naohiro Kirai and Yu Harada
Received (in Cambridge, UK) 8th February 2008, Accepted 5th March 2008
First published as an Advance Article on the web 25th March 2008
DOI: 10.1039/b802231c
The CuOAc-catalyzed reaction of internal alkynoates with
arylboronic acids proceeded under mild conditions to yield
trisubstituted cinnamates stereoselectively.
Initially, various transition-metal (TM) salts bearing oxygen
ligands were screened as catalyst precursors, because they
possibly facilitate the transmetalation with organoboron com-
pounds by donating their ligand to the highly oxophilic boron
center.6 Among the TM salts examined [Fe(OAc)2, Fe(acac)3,
Co(OAc)2ꢀ4H2O, Ni(OAc)2ꢀ4H2O, and AgOAc], copper acet-
ates proved to be effective. Thus, the exploratory reaction of
methyl 2-octynoate (1a) and 3 equiv. of phenylboronic acid (2a)
was carried out with 10 mol% Cu(OAc)2 in MeOH (0.5 M) at a
temperature of 28 1C (Scheme 1 and Table 1). TLC analysis
indicated that 1a was consumed within 2.5 h, and the chromato-
graphic purification afforded the desired conjugate-addition
product 3aa in 96% yield (run 1). It should be noted that 3aa
was exclusively obtained as an E-isomer as confirmed from a
The conjugate addition of organometallic reagents to alkyno-
ates is one of the most efficient methods to obtain synthetically
valuable multiply substituted acrylates. For this purpose,
organocopper reagents have been typically used,1 since the
first report of Corey’s group2a and others.2b,c Organocopper-
based methods, however, have several limitations: (a) they
usually require stoichiometric amounts of the copper source,
(b) the stereochemistry of the resulting alkene depends on both
the reaction conditions and nature of the organocopper re-
agents,1 and (c) they are incompatible with highly reactive
functional groups such as aldehydes. Therefore, other methods
using catalytic amounts of transition-metal complexes as
promoters were developed. Hayashi and co-workers have
reported the rhodium-catalyzed hydroarylation of alkynes.3
In their study, they obtained conjugate addition products from
two internal alkynoates with phenylboronic acid in high yields.
Later, Oh and co-workers also carried out the palladium-
catalyzed conjugate addition of arylboronic acids to alkyno-
ates with a good substrate scope.4 Although these catalytic
protocols enable the use of commercially available bench-top
stable boronic acids and yield trisubstituted a,b-unsaturated
esters with moderate to excellent regio- and stereoselectivity,
the development of a new method using an inexpensive non-
precious metal catalyst would be beneficial. In this regard, the
copper-catalyzed addition of Grignard reagents to alkynoates
has been reported by Jennings and co-workers.5 It should be
noted that they have succeeded in obtaining both syn- and
anti-hydroarylation products with moderate to good stereo-
selectivities by selecting appropriate trialkylsilyl mediators and
quenching methods. However, substrate scope in terms of
both the organometallic reagent and alkynoate has not been
addressed in this copper-catalyzed method. In this commu-
nication, we report the copper-catalyzed conjugate addition of
differently functionalized arylboronic acids to alkynoates that
proceeds under mild reaction conditions to yield syn-hydro-
arylation products in good yields.
1
comparison of its H NMR data with those for known com-
pounds (see ESIw). The methanol solvent is essential for efficient
catalytic turnover. The use of ethanol or THF resulted in much
lower conversion of 1a, giving 3aa in less than 20% yields. No
product was detected when the reaction was carried out in 1,2-
dichloroethane for 24 h. When a lower concentration of the
substrate (0.25 M) was used, the reaction was complete in 10 h
and the yield of 3aa decreased to 84%. Moreover, a trace
amount of methyl 2,3-diphenyl-2-octenoate (4) was also detected
in the 1H NMR spectra of the crude reaction mixture. The
decrease in the amount of 2a (2 equiv.) also decreased the yield
(71%, 10 h). A similar high yield was achieved with a lower
catalyst loading of 1 mol%; however, the reaction was only
complete after a long time (run 2). The reaction with CuOAc
proceeded faster to give 3aa in a similar yield (run 3). In this
case, a trace amount of 4 was observed in the crude reaction
mixture. A similar yield was achieved with even lower loadings
of the catalyst (1 mol%) and 2a (1.5 equiv.) (runs 4 and 5).
Encouraged by these results, we examined other copper salts,
but none of them were superior to the acetates. CuCl and CuBr
gave the desired product in comparable yields (runs 6 and 7),
although their reactions were only complete after a long time. In
contrast, CuI, CuCl2, and CuBr2 hardly exhibited any catalytic
activity. Electron-donating ligands such as 2,20-bipyridine (bipy)
and N-heterocyclic carbenes [1,3-bis(2,6-diisopropylphenyl)imi-
dazolin-2-ylidene: SIiPr; or 1,3-dimesitylimidazol-2-ylidene:
Department of Applied Chemistry, Graduate School of Science and
Engineering, Tokyo Institute of Technology, Ookayama, Meguro-ku,
Tokyo 152-8552, Japan. E-mail: omyy@apc.titech.ac.jp; Fax: 81 3
5734 3339; Tel: 81 3 5734 3339
w Electronic supplementary information (ESI) available: Experimental
details and spectral data. See DOI: 10.1039/b802231c
Scheme 1 Cu-catalyzed reaction of 1a and 2a.
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Table 1 Cu-catalyzed reaction of 1a and 2a
Run
Cu salt, mol%
Time/h
Yield (%)
1
2
3
4
5
6
7
8
9
10
Cu(OAc)2, 10 mol%
Cu(OAc)2, 1 mol%
CuOAc, 10 mol%
CuOAc, 1 mol%
2.5
8
1
5
6
14
9
2
24
24
96
95
95a
94a
95a
93
CuOAc, 1 mol%b
CuCl, 10 mol%
CuBr, 10 mol%
Fig. 1 Reagents which failed to give conjugate addition products.
92a
95a
80a
61a
Cu(OAc)2(bipy), 5 mol%
CuCl(SIiPr), 5 mol%
CuCl(IMes), 5 mol%
heteroaryl-, ferrocenyl-, 2-(p-chlorophenyl)ethenyl-, and
n-pentylboronic acids did not undergo conjugate addition to
alkynoate 1a under the optimal reaction conditions (Fig. 1).
Then, we examined the catalytic conjugate addition of aryl-
boronic acids to various alkynoates 1b–1g (Scheme 2 and
Table 3). Alkynoates 1b,c whose alkyl chains have methoxy or
chloro substituents were allowed to react with phenylboronic
acid (2a), affording the corresponding cinnamates 3ba and 3ca in
excellent yields (runs 1 and 2). It is noteworthy that protection-
free propargyl alcohol derivative 1d can be directly used in our
Cu-catalyzed conjugate addition. In this case, the conjugate
addition of 2a was followed by in situ lactonization to yield
the known 3-phenylbutenolide 5, albeit in a moderate yield of
61% (run 3). We then focused on the synthesis of 3,3-diaryla-
crylates that are difficult to prepare with precise control of
stereochemistry via the conventional Horner–Wittig and Wads-
worth–Emmons methods. In the presence of 1–3 mol% CuOAc,
phenylboronic acids bearing methyl, chloro, and methoxy sub-
stituents at the para-position were allowed to react with ethyl
phenylpropiolate 1e, affording the corresponding diarylacrylates
3eb, 3eg, and 3en in high yields as single stereoisomers (runs
4–6). It is noteworthy that electron-rich 2n reacted with 1e
uneventfully to yield (E)-3en in 91% yield. On the other hand,
its stereoisomer (Z)-3fa was selectively obtained by the addition
of phenylboronic acid to (p-methoxyphenyl)propiolate 1f (run
7). The present method enabled the stereoselective preparation
of 3gn possessing o- and p-methoxyphenyl groups (run 8).
Trace amounts of 4 were detected in 1H NMR spectra of crude
a
b
samples. 1.5 equiv. of 2a was used.
IMes]7 did not show any positive effect (runs 8–10). Accordingly,
CuOAc was employed for further study.
The scope and limitations of the arylboronic acid are
summarised in Table 2.8 To ensure complete consumption of
the alkynoates, 3 equiv. of arylboronic acid were employed. In
the presence of 1–3 mol% CuOAc, o-, m-, and p-tolylboronic
acids, 3,5-xylylboronic acid, and 2-naphthylboronic acid gave
the corresponding adducts 3ab–3af in high yields (runs 1–5).
Similarly, p-halophenylboronic acids 2g–i can be used without
the loss of the reactive C(sp2)–halogen bonds that are useful
synthetic handles for carrying out further functionalization
(runs 6–8). Moreover, carbonyl groups reactive towards
Grignard or organolithium reagents are compatible with the
present Cu-catalyzed conjugate addition of arylboronic acids
(runs 9–11). Consequently, (E)-cinnamates 3aj–3al, whose
phenyl rings have a formyl, acetyl, or ethoxycarbonyl group,
were obtained in 82–93% yields. Although a catalyst loading
of 10 mol% was required, m-nitro derivative 3am was also
obtained in 94% yield (run 12). However, the use of electron-
rich p-methoxyphenylboronic acid 2n was problematic, lead-
ing to an inseparable mixture of the desired compound 3an,
4,40-dimethoxybiphenyl, and 1,4-dimethoxybenzene (run 13).
The latter side products were formed probably by the Cu-
catalyzed homo coupling of 2n and its Ullmann-type coupling
with the methanol solvent. In contrast to phenylboronic acids,
Table 2 CuOAc-catalyzed addition of various arylboronic acids 2
to 1aa
Run
2, Ar
Cu (mol%)
Time/h
3, yield (%)
Scheme 2 Reaction of various alkynoates 1b–1g.
1
2
3
4
5
6
7
8
9
2b, p-MeC6H4
2c, m-MeC6H4
2d, o-MeC6H4
2e, 3,5-Me2C6H3
2f, 2-naphthyl
2g, p-ClC6H4
1
1
3
3
1
3
5
5
3
3
3
10
1
4
10
6
2
24
4
24
3
10
5
24
5
24
3ab, 94
3ac, 94
3ad, 91
3ae, 88
3af, 90
3ag, 94
3ah, 94
3ai, 91
3aj, 88
3ak, 93
3al, 82
3am, 94
3an, 60b
Table 3 Conjugate addition of arylboronic acids to alkynoates 1b–1g
3, yield
Run 1, R1/R2
2, Ar
Conditionsa
(%)
2h, p-BrC6H4
2i, p-IC6H4
1
2
3
4
5
6
7
8
1b, MeO(CH2)3/Me 2a, Ph
2 mol%, 3 h 3ba, 92
1 mol%, 2 h 3ca, 97
2 mol%, 2 h 5, 61
1 mol%, 4 h 3eb, 90
3 mol%, 12 h 3eg, 89
2j, p-OHCC6H4
2k, p-AcC6H4
2l, p-EtO2CC6H4
2m, m-O2NC6H4
2n, p-MeOC6H4
1c, Cl(CH2)3/Me
1d, HOCH2/Me
1e, Ph/Et
2a, Ph
2a, Ph
2b, p-MeC6H4
2g, p-ClC6H4
10
11
12
13
a
1e, Ph/Et
1e, Ph/Et
2n, p-MeOC6H4 1 mol%, 4 h 3en (E), 91
1 mol%, 24 h 3fa (Z), 97
1g, o-MeOC6H4/Me 2n, p-MeOC6H4 3 mol%, 1 h 3gn, 88
1f, p-MeOC6H4/Et 2a, C6H5
Methyl 2-octynoate (1a) was reacted with 3 equiv. of the arylboronic
acid in MeOH (0.5 M) at 28 1C. Yield determined by 1H NMR analysis
of a mixture with 4,40-dimethoxybiphenyl and 1,4-dimethoxybenzene.
b
a
All reactions were carried out with CuOAc in 0.5 M MeOH solution at 28 1C.
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oxide (or acetate) proceeds via a four-centered transition state
to yield reactive arylcopper species.6 Subsequent carbocupra-
tion of the alkynoates produces vinylcopper intermediates,
which then undergo protonolysis by methanol to yield the final
cinnamates with the concomitant restoration of copper meth-
oxide. In previous cuprate-based methods, a low reaction
temperature was required to prevent the isomerization of the
initially formed syn-carbocupration adducts to anti-isomers
via allenolate intermediates.1,5,9 Because our protocol employs
methanol as a solvent, the vinylcopper intermediates undergo
facile protonolysis before isomerization, resulting in the
stereoselective formation of the syn-hydroarylation products
even at ambient temperature.
Scheme 3 Cu-catalyzed conjugate addition of 2a to alkynyl ketone 6.
In conclusion, we succeeded in carrying out the catalytic
conjugate addition of arylboronates to alkynoates.10 The
reaction proceeded in MeOH under mild conditions to yield
trisubstituted cinnamates with precise syn-selectivity. This
protocol is compatible with phenylboronic acids bearing car-
bon–halogen bonds as well as carbonyl functional groups.
This research was partially supported by the Ministry of
Education, Science, Sports and Culture, Grant-in-Aid for
Young Scientists (A), 17685008, and the Global COE program
(Tokyo Instituted of Technology). We thank Prof. H. Suzuki
(Tokyo Institute of Technology) for use of the GC mass
spectrometer, and Prof. K. Tomooka (Kyushu University)
for use of the NMR spectrometer.
Scheme 4 Reactions in MeOD.
Notes and references
1 K. Nilsson, T. Andersson, C. Ullenius, A. Gerold and N. Krause,
Chem.–Eur. J., 1998, 4, 2051, and references cited; G. Li, H.-X. Wei, B.
R. Whittlesey and N. N. Batrice, J. Org. Chem., 1999, 64, 1061; M. C.
P. Yeh and P. Knochel, Tetrahedron Lett., 1989, 30, 4799; Y. Yama-
moto, H. Yatagai and K. Maruyama, J. Org. Chem., 1979, 44, 1744.
2 (a) E. J. Corey and J. A. Katzenellenbogen, J. Am. Chem. Soc.,
1969, 91, 1851; (b) J. B. Siddall, M. Biskup and J. H. Fried, J. Am.
Chem. Soc., 1969, 91, 1853; (c) J. Klein and R. M. Turkel, J. Am.
Chem. Soc., 1969, 91, 6186.
Scheme 5 Proposed mechanism.
Similar to other alkynyl ester substrates, methyl propiolate
and its trimethylsilyl and bromo analogues were also tested,
but none of them gave the desired product (Fig. 1). This result
is in contrast to that of alkynyl ketone 6 that underwent
conjugate addition to yield the corresponding adduct 7 in a
high yield with a moderate stereoselectivity of E : Z = 86 : 14
(Scheme 3). The minor stereoisomer (Z)-7 was considered to
be formed due to the isomerization of the initially formed
vinylcopper species (E)-8 to (Z)-8 via transient allenolate 9, as
previously reported for the related conjugate additions of
organocopper reagents to alkynoates.1,5,9
3 T. Hayashi, K. Inoue, N. Taniguchi and M. Ogasawara, J. Am.
Chem. Soc., 2001, 123, 9918.
4 C. H. Oh and J. H. Ryu, Bull. Korean Chem. Soc., 2003, 24, 1563; C. H.
Oh, H. H. Jung, K. S. Kim and N. Kim, Angew. Chem., Int. Ed., 2003,
42, 805; A. K. Gupta, K. S. Kim and C. H. Oh, Synlett, 2005, 457.
5 A. J. Mueller and M. P. Jennings, Org. Lett., 2007, 9, 5327; M. P.
Jennings and K. B. Sawant, Eur. J. Org. Chem., 2004, 3201.
6 T. Hayashi, M. Takahashi, Y. Takaya and M. Ogasawara, J. Am.
Chem. Soc., 2002, 124, 5052; T. Nishikawa, Y. Yamamoto and N.
Miyaura, Organometallics, 2004, 23, 4317.
7 S. Okamoto, S. Tominaga, N. Saino, K. Kase and K. Shimoda, J.
Organomet. Chem., 2005, 690, 6001; V. Lillo, M. R. Fructos, J.
Ramirez, A. A. C. Braga, F. Maseras, M. M. Diaz-Requejo, P. J.
To obtain further insight into the reaction mechanism, we
carried out the reaction of 1a and 2a (1.5 equiv.) in MeOD
(Scheme 4). As a result, mono-deuterated (E)-3aa-d was
obtained with 74% D content, indicating that the hydroxy
group of methanol behaved as a proton donor. Insufficient
deuteration might be attributed to the H–D exchange between
MeOD and 2a or direct proton transfer from 2a to an
alkenylcopper intermediate (see below). Thus, the use of 2-
phenyl-5,5-dimethyl-1,3,2-dioxaborinane 10 instead of 2a gave
(E)-3aa-d with a D content of more than 98%.
Perez and E. Fernandez, Chem.–Eur. J., 2007, 13, 2614.
´ ´
8 Most of the arylboronic acids were purchased and used as received.
These boronic acids usually contain varying amounts of the correspond-
ing anhydrides, including triarylboroxins. We hence examined the
reaction of alkynoate 1a with triphenylboroxin (1 equivalent) otherwise
under the same conditions. The reaction reached completion within 10 h
to furnish (E)-3aa in 94% yield. This result shows that the amount of
anhydride might influence only the reaction rate.
9 J. Klein and R. Levene, J. Chem. Soc., Perkin Trans. 2, 1973, 1971;
J. P. Marino and R. J. Linderman, J. Org. Chem., 1983, 48, 4621;
M. Ahlquist, T. E. Nielsen, S. Le Quement, D. Tanner and P.-O.
Norrby, Chem.–Eur. J., 2006, 12, 2866.
10 During the preparation of this manuscript, the Cu-catalyzed syn-
selective conjugate addition of diboron reagents to alkynoates was
reported, see: J.-E. Lee, J. Kwon and J. Yun, Chem. Commun.,
2008, 733.
Scheme 5 outlines a plausible mechanism of the Cu-cata-
lyzed conjugate addition of arylboronic acids to alkynoates.
Transmetallation from the arylboronic acids to copper meth-
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2012 | Chem. Commun., 2008, 2010–2012