Copper(I)-catalyzed formal carboboration of alkynes: Synthesis of tri- and tetrasubstituted vinylboronates

Article abstract of DOI:10.1021/ja307670k

The first copper-catalyzed formal carboboration of alkynes, in which a C-B bond and a C-C bond are created in a single catalytic cycle, is presented. The reaction proceeds with high regioselectivity and syn-stereoselectivity to form tri- and tetrasubstituted vinylboronic esters from commercially available bis(pinacolato)diboron. A subsequent cross-coupling reaction gives access to highly substituted alkenes.

Full text of DOI:10.1021/ja307670k

Communication
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Copper(I)-Catalyzed Formal Carboboration of Alkynes: Synthesis of
Tri- and Tetrasubstituted Vinylboronates
Ricardo Alfaro,† Alejandro Parra,† Jose Aleman, Jose Luis García Ruano, and Mariola Tortosa*
́
́
́
́ ́ ́
Departamento de Química Organica (modulo 01), Universidad Autonoma de Madrid, Cantoblanco, 28049 Madrid, Spain
S
* Supporting Information
is hampered by the use of highly sensitive boryllithium
intermediates and stoichiometric amounts of copper. Addition-
ally, the diisopropylbenzene (Dip) diamino group had to be
transformed into a pinacolate group for further functionaliza-
tion.9 Hoveyda,10 Yun,11 Ito,12 and more recently Carretero
ABSTRACT: The first copper-catalyzed formal carbobo-
ration of alkynes, in which a C−B bond and a C−C bond
are created in a single catalytic cycle, is presented. The
reaction proceeds with high regioselectivity and syn-
stereoselectivity to form tri- and tetrasubstituted vinyl-
boronic esters from commercially available bis-
(pinacolato)diboron. A subsequent cross-coupling reaction
gives access to highly substituted alkenes.
́ ́
and Gom have reported the related Cu-catalyzed
ez-Arrayas13
hydroboration of alkynes (Scheme 1, eq 2).14,15 Although
vinylcopper species are proposed as intermediates, their further
reaction with an alkyl halide has never been reported. Herein,
we describe the first Cu-catalyzed formal syn carboboration of
simple alkynes (Scheme 1, eq 3). The reaction proceeds
without directing groups to create both a C−B and a C−C
bond, in a single catalytic cycle, using commercially available
bis(pinacolato)diboron.
To start our carboboration studies we first focused on cis-
branched methyl vinylboronates. These boronic esters are
direct precursors of cis-branched methylalkenes, widely found
in natural products16 and also prominent in drugs and
biologically active compounds (Figure 1).17 However, stereo-
inylboronates play an important role in organic synthesis.1
VTheir utility as partners in the Suzuki−Miyaura coupling
reaction2 and their ability to undergo Rh-catalyzed3 and metal-
free4 conjugate additions make them highly versatile
intermediates in the synthesis of complex molecules. Several
approaches have been developed for the synthesis of
disubstituted vinylboronic esters.1 However, methods to
synthesize tri-5 and tetrasubstituted6 vinylboronates are
significantly more limited. Among them, metal-catalyzed
carboboration reactions are the most direct way to access
these highly substituted vinylboronic esters. An excellent work
by Suginome described the palladium- and nickel-catalyzed
carboboration reactions of alkynes.7 However, despite the
importance of these transformations, they usually require an
alkyne functionalized with a hydroxyl group to promote an
intramolecular boron addition and/or the use of boron sources
which are difficult to handle.8 Consequently, it would be
desirable to find carboboration conditions that required less
expensive metals, nonfunctionalized alkynes and commercially
available boron sources. Recently, the copper-mediated
carboboration of propiolates has been developed (Scheme 1,
eq 1). Unfortunately, the synthetic application of this reaction
Figure 1. Biologically active methyl-branched alkenes.
selective methods to synthesize cis-branched methyl alkenyl-
boronates are still limited,18 especially those in which a C−B
and a C−Me bond are created in a single catalytic cycle.19
Therefore, a Cu-catalyzed methylboration of alkynes would be
an interesting approach to this class of boronic esters.
Scheme 1. Cu-Catalyzed Carboboration of Alkynes
Based on the proposed catalytic cycle for the Cu-catalyzed
hydroboration (blue in Scheme 2), we reasoned that a
methylboration (red in Scheme 2) would require the presence
of an electrophile (MeI instead of MeOH) and the use of at
least 1 equiv of NaOt-Bu (instead of the 0.2 equiv usually
required for hydroboration). The CuI formed by reaction of the
vinylcopper intermediate with MeI would be transformed into
the catalytically active CuOt-Bu. Under these conditions, the
Received: April 24, 2012
© XXXX American Chemical Society
A
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Journal of the American Chemical Society
Communication
Scheme 2. Comparison of the Catalytic Cycles of the Cu-
Catalyzed Hydroboration and Carboboration (Present
Work)
Table 2. Cu(I)-Catalyzed Methylboration of Aryl-Substituted
Alkynes
d
entry
R1
R2
product
yield (%)
a
1
C6H5, 2a
H
3a
3b
3c
3d
3e
3f
74
68
83
75
76
80
72
72
66
_
a
2
p-MeC6H4, 2b
H
a
3
p-t-BuC6H, 2c
H
4
a
4
m-MeC6H4, 2d
H
b
5
p-MeOC6H4, 2e
o-MeOC6H4, 2f
p-FC6H4, 2g
H
b
6
H
a
7
H
3g
3h
3i
a
8
p-BrC6H4, 2h
H
a
9
m-FC6H4, 2i
H
a
10
3,5-(CF3)2-C6H3, 2j
p-(CH3CO2CH2)C6H4, 2k
2,4,5-(CH3)3-C6H2, 2l
2-thienyl, 2m
H
3j
a
11
H
3k
3l
70
81
83
50
50
70
b
12
H
b
13
H
3m
3n
3o
3p
c
carboboration of alkynes would be possible if the vinyl cuprate
intermediate were reactive enough to interact with MeI and if
the catalyst or excess of NaOt-Bu did not interfere with the
electrophile.20
We began by examining the methylboration of phenyl-
acetylene 2a with bis(pinacolato)diboron 1 and methyl iodide
in the presence of catalytic amounts of a ligand (10 mol%),
CuCl (10 mol%), and NaOt-Bu (Table 1). The use of xantphos
14
C6H , 2n
Me
C6H5
Me
5
c
15
C6H5, 2o
c
16
3,5-(CF3)2-C6H3, 2p
a
b
Conditions: xantphos, 0.1 M in THF, 16 h, rt. Conditions: xantphos,
c
0.6 M in THF, 24 h, rt. Conditions: P(p-tolyl)3, 0.6 M toluene, 24 h,
60 °C. Yield of isolated 3.
d
We observed that strong electron-donating groups at the para
and ortho positions (2e and 2f) diminished the rate of
methylboration, needing higher concentrations and longer
reaction times (entries 5 and 6). Halogen-containing alkynes
2g−i selectively gave the methylboration products in good
yields (entries 7−9).21 Unfortunately, the 3,5-bis-
(trifluoromethyl)phenyl derivative 2j did not react, probably
due to deprotonation of the alkyne in the presence of the
alkoxide (entry 10). Base-sensitive functional groups such as
acetates were compatible with the methylboration conditions
(entry 11). Alkyne 2l, with a trisubstituted aryl ring, and thienyl
substituted 2m also underwent the methylboration reaction in
excellent yields (entries 12 and 13). Poor yields were obtained
from nonterminal alkynes 2n,o using xantphos as ligand.
However, after searching for different conditions (see
Supporting Information for details), we were able to improve
the results by heating the reaction to 65 °C with trip-
tolylphosphine (entries 14−16). The best result was obtained
with alkyne 2p (entry 16) bearing two electron withdrawing
groups on the aromatic ring. One stereoisomer was exclusively
formed in all cases, resulting from the syn addition of the
methyl and boron groups.
We then explored the methylboration of alkyl-substituted
alkynes. While simple alkyl terminal alkynes did not react under
the conditions described above, those bearing an ether moiety
at the propargylic position gave good results (Scheme 3).
Propargylic ether 2q afforded vinylboronate 3q as a single
regio- and stereoisomer. Importantly, the methylboration
conditions did not promote the formation of di- or triborylated
compounds by β-oxygen elimination from vinylcopper
species.14 Acetals were also compatible with the methylboration
conditions and alkyne 2r gave protected aldehyde 3r, which is a
very versatile synthetic intermediate. Additionally, we were
pleased to find that tertiary ether 2s also gave the
methylboration product in good yield as a single compound.
Table 1. Cu(I)-Catalyzed Methylboration of Alkyne 2a
c
NaOt-Bu
(equiv)
MeI
(equiv)
yield
(%)
a
b
d
entry
ligand
3:4
1
2
3
4
5
1.1
0.6
1.1
1.1
1.1
1.1
xantphos
xantphos
PPh3
2.0
2.0
2.0
2.0
4.0
4.0
68
26
60
30
74
72
92:8
92:8
90:10
80:20
>98:2
>98:2
dppe
xantphos
xantphos
e
6
a
b
Conditions: 0.1 M in THF, 16 h, rt. Abbreviations: xantphos = 4,5-
bis(diphenylphosphino)-9,9-dimethylxanthene; dppe = 1,2-bis-
c
d
(diphenylphosphino)ethane. Yield of isolated 3a. Determined by
e
1H NMR analysis. 5 mol% CuCl and 5 mol% xantphos were used.
and 1.1 equiv of NaOt-Bu at room temperature gave the
desired product 3a, along with a small amount of the
hydroboration product 4a (entry 1). The yield decreased
using 0.6 equiv of the alkoxide, verifying our initial hypothesis
(entry 2). Triphenylphosphine (entry 3) or a diphosphine with
a smaller bite angle (entry 4) did not improve the result.
Finally, we found that by adding 4 equiv of the electrophile we
could suppress the formation of 4a and 3a was obtained in
good yield as a single regio- and stereoisomer. Additionally, the
catalyst loading could be reduced to 5% without affecting the
yield (entry 6).
Next, we applied the optimized conditions to different aryl-
substituted terminal (entries 1−13) and nonterminal (entries
14−16) alkynes (Table 2). Alkynes 2b−d, with alkyl groups at
the para and meta positions, afforded (E) trisubstituted
vinylboronates 3b−d as single regioisomers (entries 1−4).
B
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Journal of the American Chemical Society
Communication
place in good yield but very poor regioselectivity. The result
observed for 9b is in contrast with that found for the Cu-
catalyzed hydroboration of similar alkynes.12 Under hydro-
boration conditions, only the regioisomer related to 10 was
obtained with PPh3, while complete hydroboration of the
double bond of the enyne was observed with xantphos.
Interestingly, 2-substituted and 1,2-disubstituted enynes 9c (R1,
R2, R4 = H, R3 = Me) and 9d (R1, R4 = H, R2, R3 = −(CH2)4−)
afforded the methylboration products 10c−d as single
compounds. Additionally, nonterminal enyne 9e (R1, R2 = H,
R3 = Me, R4 = Et) gave tetrasubstituted vinylboronate 10e
along with a small amount of the regioisomer 11e.25 Together,
these data and those in Scheme 4 would suggest that the
carboboration reaction mechanism differs significantly from the
generally accepted Cu-catalyzed hydroboration mechanism.
The vinylboronates obtained in this study are useful synthetic
intermediates for the synthesis of trisubstituted alkenes
(Scheme 6). The coupling of thienyl derivative 3m with ethyl
Scheme 3. Cu(I)-Catalyzed Methylboration of Propargylic-
Functionalized Alkynes
The introduction of other electrophiles was then addressed
(Scheme 4). Surprisingly, the reaction of 2a with allyl bromide
Scheme 4. Cu(I)-Catalyzed Carboboration of Alkynes
Scheme 6. Synthetic Applications of Vinylboronic Esters
gave only allylation at the terminal position of the alkyne.22
Hoping to avoid this problem, we then explored the reaction of
a nonterminal alkyne, 2o, with allyl iodide and benzyl bromide.
Gratifyingly, we obtained the desired compounds 6o and 7o in
moderate to good yields. Reaction of benzyl bromide with the
nonsymmetrical alkyne 2n also gave the benzylated carbobora-
tion product but as a mixture of regioisomers 7n and 8n.23 This
result is in contrast with those obtained with 2n under
hydroboration11 and methylboration (Table 2, entry 14)
conditions in which only one regioisomer was obtained and
suggests that the electrophile is playing a role in the control of
the regiochemistry of the reaction. Importantly, we did not
observe borylation of the benzyl bromide in any case.20,24
These results provide the first evidence that intermediates in
the Cu-catalyzed hydroboration reactions can be trapped by
different electrophiles.
4-iodobenzoate, with concomitant hydrolysis of the methyl
ester, afforded namirotene derivative 12 in good yield.
Additionally, alkenes 13a and 13g were prepared in good
overall yield through a one-pot methylboration-Suzuki coupling
sequence from commercially available alkynes, allowing an easy
entry to trisubstituted alkenes.
In summary, we have developed the first copper-catalyzed
formal carboboration of alkynes. Through this process, highly
functionalized vinyl pinacol boronic esters can be obtained
from readily available starting materials. Additionally, the one-
pot methylboration-Suzuki coupling sequence allows rapid
access to highly functionalized alkenes, which are fundamental
building blocks in organic synthesis. Some of the results
disclosed in this paper suggest significant differences between
the hydro- and the carboboration reactions. Mechanistic studies
to understand these discrepancies are underway.
Finally, we explored the methylboration of the more
challenging 1,3-enynes (Scheme 5). With enynes 9a (R1, R3,
R4 = H, R2 = C6H13) and 9b (R1, R3 = H, R2 = C6H13, R4 = Bu),
and using either PPh3 or xantphos, the methylboration took
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and spectral data for new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Scheme 5. Cu(I)-Catalyzed Methylboration of 1,3-Enynes
■
S
AUTHOR INFORMATION
Corresponding Author
mariola.tortosa@uam.es
■
Author Contributions
†R.A. and A.P. contributed equally to this work.
Notes
The authors declare no competing financial interest.
C
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Journal of the American Chemical Society
Communication
(17) The following are selected examples of branched methyl-
containing natural products with important biological activity. (a)
ACKNOWLEDGMENTS
■
Financial support from Spanish Government (CTQ-2009-
12168) and CAM (“programa AVANCAT CS2009/PPQ-
1634”) is gratefully acknowledged. J.A. and M.T. thank the
MICINN for “Ramon y Cajal” contracts, and R.A. thanks the
“Consejo Nacional de Ciencia y Tecnologia de Mex
Epothilone A: Hofle, G.; Bedorf, N.; Steinmetz, H.; Schomburg, D.;
̈
Gerth, K.; Reichenbach, H. Angew. Chem., Int. Ed. 1996, 35, 1567. (b)
́
Rapamycin: Vezina, C.; Kudelski, A.; Sehgal, S. N. J. Antibiot. 1975, 28,
721. (c) Calyculin A: Suganuma, M.; Fujiki, H.; Furaya-Suguri, H.;
Yoshizawa, S.; Yasumoto, S.; Kato, Y.; Fusetani, N.; Sugimura, T.
Cancer Res. 1990, 50, 3521.
́
́
ico” for a
postdoctoral fellowship.
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