Nickel-catalyzed 1,4-addition of trialkylboranes to α,β- unsaturated esters: Dramatic enhancement by addition of methanol

Article abstract of DOI:10.1021/ol070288y

Equation presented Nickel catalyst systems for 1,4-addition of trialkylboranes to α,β-unsaturated esters have been developed. Addition of methanol was found to be essential for the alkylation reaction with 9-alkyl-9-BBNs.

Full text of DOI:10.1021/ol070288y

ORGANIC
LETTERS
2007
Vol. 9, No. 8
1541-1544
Nickel-Catalyzed 1,4-Addition of
Trialkylboranes to -Unsaturated
Esters: Dramatic Enhancement by
Addition of Methanol
r,â
Koji Hirano, Hideki Yorimitsu,* and Koichiro Oshima*
Department of Material Chemistry, Graduate School of Engineering, Kyoto UniVersity,
Kyoto-daigaku Katsura, Nishikyo-ku, Kyoto 615-8510, Japan
oshima@orgrxn.mbox.media.kyoto-u.ac.jp; yori@orgrxn.mbox.media.kyoto-u.ac.jp
Received February 5, 2007
ABSTRACT
Nickel catalyst systems for 1,4-addition of trialkylboranes to
be essential for the alkylation reaction with 9-alkyl-9-BBNs.
r,
â
-unsaturated esters have been developed. Addition of methanol was found to
Transition metal-catalyzed 1,4-addition of alkylmetal reagents
to R,â-unsaturated carbonyl compounds is one of the most
powerful and promising carbon-carbon bond formations in
organic synthesis. In particular, 1,4-addition of alkylmag-
nesium halides, dialkylzincs, and trialkylaluminums in the
presence of copper catalysts has been developed and achieved
alkylation of various unsaturated molecules involving the
asymmetric version.1 On the other hand, 1,4-addition of
trialkylboranes to R,â-unsaturated carbonyl compounds has
been much less explored. 1,4-Addition of trialkylboranes to
R,â-unsaturated aldehydes and ketones is a well-established
process under radical conditions initiated by molecular
oxygen.2 However, the radical conditions mentioned above
could not be applicable to the reactions of R,â-unsaturated
esters due to rapid radical polymerization.3 Only photo-4 and
electrochemical5 conditions achieved these transformations
while 1,4-addition of aryl- and alkenylboronic acid deriva-
tives to various unsaturated compounds including R,â-
unsaturated esters became available in the presence of
transition metal catalysts such as rhodium,6 palladium,7 and
nickel.8
(2) Brown, H. C.; Kabalka, G. W. J. Am. Chem. Soc. 1970, 92, 714-
716.
(3) Miyaura and Suzuki reported the conjugate additions of cuprous
tetraalkylborates prepared from trialkylboranes, methyllithium, and copper
bromide to acrylonitrile. However, the reaction with ethyl acrylate gave
the desired adduct in only 44% yield with contamination by the dimerization
product. See: Miyaura, N.; Itoh, M.; Suzuki, A. Tetrahedron Lett. 1976,
17, 255-258.
(4) Polykarpov, A. Y.; Neckers, D. C. Tetrahedron Lett. 1995, 36, 5483-
5486.
(1) (a) Alexakis, A.; Benhaim, C. Eur. J. Org. Chem. 2002, 3221-3236.
(b) Perlmutter, P. Conjugate Addition Reaction in Organic Synthesis;
Tetrahedron Organic Chemistry, Ser. 9; Pergamon: Oxford, UK, 1992. (c)
Rossiter, B. E.; Swingle, N. M. Chem. ReV. 1992, 92, 771-806. (d)
Woodward, S. Angew. Chem., Int. Ed. 2005, 44, 5560-5562. Recent
advances in this field: (e) d’Augustin, M.; Palais, L.; Alexakis, A. Angew.
Chem., Int. Ed. 2005, 44, 1376-1378. (f) Lee, K.; Brown, M. K.; Hird, A.
W.; Hoveyda, A. H. J. Am. Chem. Soc. 2006, 128, 7182-7184. (g) Martin,
D.; Kehrli, S.; d’Augustin, M.; Clavier, H.; Mauduit, M.; Alexakis, A. J.
Am. Chem. Soc. 2006, 128, 8416-8417. (h) Harutyunyan, S. R.; Lo´pez,
F.; Browne, W. R.; Correa, A.; Pen˜a, D.; Badorrey, R.; Meetsma, A.;
Minnaard, A. J.; Feringa, B. L. J. Am. Chem. Soc. 2006, 128, 9103-9118.
(i) Wang, S.-Y.; Ji, S.-J.; Loh, T.-P. J. Am. Chem. Soc. 2007, 129, 276-
277.
(5) Takahashi, Y.; Yuasa, K.; Tokuda, M.; Itoh, M.; Suzuki, A. Bull.
Chem. Soc. Jpn. 1978, 51, 339-340.
(6) Reviews: (a) Fagnou, K.; Lautens, M. Chem. ReV. 2003, 103, 169-
196. (b) Hayashi, T.; Yamasaki, K. Chem. ReV. 2003, 103, 2829-2844.
(7) (a) Cho, C.-S.; Motofusa, S.; Ohe, K.; Uemura, S. J. Org. Chem.
1995, 60, 883-888. (b) Nishikata, T.; Yamamoto, Y.; Miyaura, N. Angew.
Chem., Int. Ed. 2003, 42, 2768-2770. (c) Nishikata, T.; Yamamoto, Y.;
Miyaura, N. Organometallics 2004, 23, 4317-4324. (d) Lu, X.; Lin, S. J.
Org. Chem. 2005, 70, 9651-9653. (e) Gini, F.; Hessen, B.; Minnaard, A.
J. Org. Lett. 2005, 7, 5309-5312. (f) Yamamoto, T.; Iizuka, M.; Ohta, T.;
Itoh, Y. Chem. Lett. 2006, 35, 198-199. (g) He, P.; Lu, Y.; Dong, C.-G.;
Hu, Q.-S. Org. Lett. 2007, 9, 343-346.
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10.1021/ol070288y CCC: $37.00
© 2007 American Chemical Society
Published on Web 03/16/2007

During our recent studies on the reactivity of trialkyl-
boranes with carbonyl compounds, we found the nickel-
catalyzed 1,2-addition of trialkylboranes to aldehydes.9
Herein, we wish to report effective nickel catalyst systems
for 1,4-addition of trialkylboranes to R,â-unsaturated esters.
Moreover, the dramatic effect of addition of methanol in the
nickel-catalyzed 1,4-addition is also described.10
Table 1. Nickel-Catalyzed 1,4-Addition of Triethylborane (2a)
and Tributylborane (2b) to R,â-Unsaturated Esters 1a
Treatment of benzyl (E)-crotonate (1a) with triethylborane
(2a) in the presence of 8 mol % of Ni(cod)2 and 19.2 mol %
of P(t-Bu)3 in toluene at room temperature, which are the
optimized conditions in our previous work,9 for 17 h afforded
the 1,4-adduct, benzyl 3-methylpentanoate (3a), in 26% yield
(Scheme 1).11 Half of the 1a remained untouched. According
Scheme 1
to our previous observation,9 a stoichiometric (to triethyl-
borane) amount of cesium carbonate was added to the
reaction mixture as an activator for triethylborane. To our
delight, the reaction was completed in 17 h and the desired
product was obtained in 88% yield.
With the optimized conditions in hand, we examined 1,4-
addition of triethylborane to a variety of R,â-unsaturated
esters (Table 1). Triethylborane reacted with 1b smoothly
to furnish 3b in 94% yield. The conceivable Suzuki-Miyaura
cross-coupling product was not obtained (entry 2). Not only
crotonic acid esters but unsaturated esters having a larger
alkyl group at the â position participated in the reaction.
Phenylethyl- and cyclohexyl-substituted esters 1c and 1d
were converted to 3c and 3d in 74% and 81% yields,
respectively (entries 3 and 4). In contrast, the reaction of
cinnamic acid ester 1e resulted in low conversion and yielded
a trace amount of the desired product (entry 5). Interestingly,
the substitution of an electron-donating methoxy group on
the aromatic ring improved the yield to 57% (entry 6).
Tributylborane (2b) as well as triethylborane was a suitable
alkylation agent. Crotonate ester 1a underwent the butylation
to provide 3g in 87% yield while the reaction of 1b afforded
a A mixture of 1 (0.5 mmol), 2 (3.0 equiv), Ni(cod)2 (8 mol %), P(t-
Bu)3 (19.2 mol %), and Cs2CO3 (3.0 equiv) was stirred in toluene (5 mL)
for 17-24 h at room temperature. b Isolated yield. c 1H NMR yield.
d Reduced product, ethyl 3-(4-methoxyphenyl)propanoate was also obtained
in 10% yield. e Reduced product, ethyl 3-cyclohexylpropanoate was also
obtained in 5% yield.
3h in 35% yield (entries 7 and 8). The butylations of 1c and
1d led to moderate conversions and yields probably due to
the steric factors (entries 9 and 10).
Next, we performed 1,4-addition of triethylborane (2a) to
benzyl acrylate (4) (Scheme 2, eq 1), which is a challenging
substrate since 4 can undergo polymerization much more
readily. Under similar conditions for the reaction of â-sub-
Scheme 2
(9) (a) Hirano, K.; Yorimitsu, H.; Oshima, K. Org. Lett. 2005, 7, 4689-
4691. (b) Hirano, K.; Yorimitsu, H.; Oshima, K. AdV. Synth. Catal. 2006,
348, 1543-1546.
(10) Nickel-catalyzed 1,4-additions of dialkylzincs and trialkylindiums
were reported. For zinc: (a) Soai, K.; Hayasaka, T.; Ugajin, S. J. Chem.
Soc., Chem. Commun. 1989, 516-517. (b) Bolm, C.; Ewald, M. Tetrahedron
Lett. 1990, 31, 5011-5012. (c) Jansen, J. F. G. A.; Feringa, B. L.
Tetrahedron: Asymmetry 1992, 3, 581-582. (d) Corma, A.; Iglesias, M.;
Mart´ın, M. V.; Rubio, J.; Sa´nchez, F. Tetrahedron: Asymmetry 1992, 3,
845-848. (e) Yin, Y.; Li, X.; Lee, D.-S.; Yang, T.-K. Tetrahedron:
Asymmetry 2000, 11, 3329-3333. (f) Wakimoto, I.; Tomioka, Y.; Kawan-
ami, Y. Tetrahedron 2002, 58, 8095-8097. For indium: (g) Pe´rez, I.;
Sestelo, J. P.; Maestro, M. A.; Mourin˜o, A.; Sarandeses, L. A. J. Org. Chem.
1998, 63, 10074-10076.
(11) NiCl2 and Ni(acac)2 did not catalyze the reaction. Other ligands
such as PPh3, P(n-Bu)3, and P(c-C6H11)3 were ineffective.
1542
Org. Lett., Vol. 9, No. 8, 2007

stituted R,â-unsaturated esters 1, 1,4-adduct 5a was obtained
in 59% yield.12 About half of 4 underwent the undesired
polymerization. The addition of the initially formed boryl
enolate to 4 would cause the side reaction. Given that the
smooth protonolysis of the intermediate was essential, we
conducted the reaction in an aqueous/organic biphasic
system.13 Gratifyingly, the desired product 5a was obtained
in 94% yield under water/Et2O biphasic conditions. Unfor-
tunately, in 1,4-addition of tributylborane (2b) to 4, the
polymerization was not completely suppressed (eq 2).
Alkylboranes are easily prepared from hydroboranes and
alkenes via hydroboration. Taking advantage of the facile
access to alkylboranes, we tested one-pot hydroboration/1,4-
addition. Terminal olefin having a benzyl ether moiety 6a,
9-borabicyclo[3.3.1]nonane (9-BBN), and benzyl (E)-croto-
nate (1a) were chosen as model substrates. Alkylborane 7a
was prepared from 6a and 9-BBN in advance and transferred
to a mixture of the nickel catalyst and cesium carbonate in
toluene. Finally, 1a was added dropwise. However, to our
surprise, 1,4-adduct 8a was not detected (Table 2, entry 1).
Fortunately, an addition of 4.0 equiv of methanol dramati-
cally enhanced the reaction to provide 8a in 96% yield (entry
4). As observed in the case of the addition of water, a large
amount of methanol prevented the reaction (entry 5). Other
alcohols such as tert-butyl alcohol and phenol gave no effect
on yield (entries 6 and 7). The use of N,N-dimethylacetamide
(DMA), which is known to catalyze hydroboration of alkenes
with catecholborane,14 also led to the improvement of the
yield, although the yield was lower than that in the presence
of methanol (entry 8 vs entry 4). A much stronger Lewis
base, pyridine, did not work to promote the reaction (entry
9).
By using the optimal methanol-promoted conditions, we
conducted 1,4-addition of an array of 9-alkyl-9-BBN to
benzyl (E)-crotonate (1a) (Table 3). The 1,4-addition of
Table 3. Nickel-Catalyzed One-Pot
Hydroboration/1,4-Additiona
Table 2. Nickel-Catalyzed One-Pot Hydroboration/
1,4-Addition: The Effect of an Additivea
entry
additive
8a, yield (%)b
1
2
3
4
5
6
7
8
9
none
H2O (4.0 equiv)
H2O (1.0 mL)
MeOH (4.0 equiv)
MeOH (1.0 mL)
t-BuOH (4.0 equiv)
phenol (4.0 equiv)
DMA (4.0 equiv)
pyridine (4.0 equiv)
0
24
0
96
0
0
0
65
0
a A mixture of 1a (0.5 mmol), 7a (3.0 equiv) prepared in advance from
6a and 9-BBN, additive, Ni(cod)2 (8 mol %), P(t-Bu)3 (19.2 mol %), and
Cs2CO3 (3.0 equiv) was stirred in toluene (5 mL) for 8.5 h at room
temperature. b Isolated yield.
a A mixture of 1 (0.5 mmol), 7 (3.0 equiv) prepared in advance from 6
and 9-BBN, MeOH (4.0 equiv), Ni(cod)2 (8 mol %), P(t-Bu)3 (19.2 mol
%), and Cs2CO3 (3.0 equiv) was stirred in toluene (5 mL) for 6.5-10 h at
room temperature. b Isolated yield. c Reaction time was 15 h. d Reaction time
was 17 h.
The starting material was completely recovered. Thus, further
optimization studies were performed to achieve the reaction
with 9-alkyl-9-BBN. An addition of water was found to
improve the yield of the desired product to 24% (entry 2).
Interestingly, a large excess of water completely suppressed
the reaction (entry 3). The oxygen atom of water seemed to
coordinate to the boron center as a Lewis base and to activate
alkylborane 7a. Hence, various Lewis bases were screened.
9-hexyl-9-BBN (7b) and 9-(4-phenylbutyl)-9-BBN (7c) to
1a proceeded to produce 8b and 8c in 90% and 85% yields,
respectively. Alkylborane 7d prepared from â,â-disubstituted
olefin 6d took part in the reaction without any difficulties
(entry 4) while bulky substitution at the â position on
alkylborane decreased the yield (entry 5). The reaction of
(12) In these cases, the use of Na2CO3 instead of Cs2CO3 gave better
results.
(13) Kinoshita, H.; Shinokubo, H.; Oshima, K. J. Am. Chem. Soc. 2003,
125, 7784-7785.
(14) Garrett, C. E.; Fu, G. C. J. Org. Chem. 1996, 61, 3224-3225.
Org. Lett., Vol. 9, No. 8, 2007
1543

6f provided 8f in good yield, leaving the silyl moiety
untouched (entry 6). Silyl ether and ester functionalities were
tolerated under the reaction conditions (entries 7 and 8). It
should be noted that alkylborane 7i having an sp3 C-Br
bond, which the corresponding alkylmagnesium halide and
dialkylzinc are difficult to prepare, underwent 1,4-addition
in spite of conceivable oxidative addition of the sp3 C-Br
bond to the zerovalent nickel (entry 9).
enhance the transmetalation step through their coordination
to the boron center of 12. Moreover, methanol can be a good
proton source for the intermediate 14.
In conclusion, we have developed 1,4-addition of trialkyl-
boranes to R,â-unsaturated esters under nickel catalysis.
Moreover, addition of methanol was found to dramatically
enhance the nickel-catalyzed reactions of R,â-unsaturated
esters with 9-alkyl-9-BBNs. The catalyst system allows
trialkylboranes to serve as the promising alkyl sources to
R,â-unsaturated esters.
We are tempted to assume the mechanism of the reaction
with 9-alkyl-9-BBN as follows (Scheme 3). A nickel(0)
Acknowledgment. This work was supported by Grants-
in-Aid for Scientific Research and COE Research from the
Ministry of Education, Culture, Sports, Science, and Tech-
nology, Japan. K.H. acknowledges JSPS for financial sup-
port.
Scheme 3
Supporting Information Available: Detailed experi-
mental procedures and characterization data of compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL070288Y
(15) The fact that the electron-rich substrate 1f was more reactive than
1e is highly suggestive of the existence and importance of the coordination
(Table 1, entry 5 vs. entry 6). Namely, the more electron-rich carbonyl
group of nickel-coordinated 1f would have stronger interaction with
alkylborane, which efficiently activates the carbonyl group of 1f.
(16) Ogoshi and Kurosawa reported that the η2-coordinated palladium
complexes with cinnamaldehyde were converted to η3-coordinated ones in
the presence of BF3 with the aid of the Lewis acidity of boron (see the
following equation)
species 9 initially reacts with 1a to generate η2-coordinated
complex 10. The coordination of the carbonyl moiety of 10
to the alkylborane gives the intermediate 11.15 The Lewis
acidity of the alkylborane promotes the formation of η3-
coordinated complex 12 followed by transmetalation to
furnish the alkylnickel species 13.16,17 Finally, reductive
elimination from 13 affords 14 and regenerates 9. Proto-
nolysis of 14 would provide 8. The exact roles of cesium
carbonate and methanol are not clear at this stage. They can
and proposed the palladium-catalyzed 1,4-addition of trimethylaluminum
to benzalacetone would proceed through a similar intermediate. (a) Ogoshi,
S.; Yoshida, T.; Nishida, T.; Morita, M.; Kurosawa, H. J. Am. Chem. Soc.
2001, 123, 1944-1950. Also see: (b) Marshall, J. A.; Herold, M.; Eidam,
H. S.; Eidam, P. Org. Lett. 2006, 8, 5505-5508.
(17) Chlorotrialkylsilane was known to promote transformation of η2-
coordinated nickel complexes with R,â-unsaturated aldehydes and ketones
to the corresponding η3-fashion. (a) Grisso, B. A.; Johson, J. R.; Mackenzie,
P. B. J. Am. Chem. Soc. 1992, 114, 5160-5165. (b) Ikeda, S.-i.; Sato, Y.
J. Am. Chem. Soc. 1994, 116, 5975-5976.
1544
Org. Lett., Vol. 9, No. 8, 2007