Zr-Mediated hydroboration: Stereoselective synthesis of vinyl boronic esters

Article abstract of DOI:10.1016/j.tetlet.2005.10.031

An improved process for the preparation of (E)-vinylboronic esters via a Zr-mediated hydroboration of alkynes, especially oxygen-containing alkynes, is described.

Full text of DOI:10.1016/j.tetlet.2005.10.031

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 8777–8780
Zr-Mediated hydroboration: stereoselective synthesis
of vinyl boronic esters
Yanong D. Wang,a,* Gregory Kimball,b Amar S. Prashada and Yan Wanga
aChemical and Screening Sciences, Wyeth Research, 401 N. Middletown Road, Pearl River, NY 10965, USA
bDepartment of Chemistry, Columbia University, 3000 Broadway, New York, NY 10027, USA
Received 8 September 2005; accepted 11 October 2005
Abstract—An improved process for the preparation of (E)-vinylboronic esters via a Zr-mediated hydroboration of alkynes, espe-
cially oxygen-containing alkynes, is described.
Ó 2005 Published by Elsevier Ltd.
The formation of new asymmetric carbon–carbon bonds
can be accomplished readily using a wide range of palla-
dium-catalyzed cross coupling reactions1–3 that have
also been utilized extensively in the construction of
biologically active molecules.4 One of these processes
involves the cross coupling reaction of an organometallic
derivative with an alkyl or aryl halide, with organo-
borane derivatives being especially useful.5,6 As one type
of frequently used synthetic building block, vinylboronic
esters can be prepared by several methods,7–10 particu-
larly by hydroboration of alkynes using catechol-
borane,11,12 which often requires harsh reaction
conditions. In 1992, Knochel and co-workers13 reported
the preparation of pinacolborane. It was also shown
that pinacolborane is an efficient hydroboration reagent,
which offers advantages of mild reaction conditions,
high functional group tolerance, and excellent stability
over catecholborane.
We present here a modified protocol of Zr-mediated
hydroboration, which offers (E)-vinylboronic esters in
high yield as well as excellent stereoselectivity and
regioselectivity.
In general, hydroboration of hydrocarbon alkynes all
proceeded smoothly at ambient temperature, in the
absence of solvent (Table 1). Formation of the (Z)-
isomer was observed for alkynes substituted by less
bulky groups in negligible quantities.
Hydroboration of oxygen-containing alkynes (Table 2)
was rather sluggish compared to the hydrocarbon alky-
nes. The E/Z ratio of the hydroboration products dra-
matically decreased, especially for the alkynes with
longer linkers between the alkyne and oxygen atom.
Zr-Mediated hydroboration of alkynes is believed to
operate by a pathway involving alkyne insertion, r-bond
The transition metal complex catalyzed hydroboration
of alkynes has been investigated considerably, including
development of new methodologies and mechanistic
studies.14–18 Pereira and Srebnik reported15 that the Sch-
wartz reagent (Cp2ZrHCl) catalyzes hydroboration of
alkynes with pinacolborane at room temperature. In
the process high selectivity of syn addition and regiose-
lectivity were observed. However, the hydroboration of
some less reactive alkynes can be sluggish, and the stereo-
selectivity toward E-vinylboronic esters is unsatis-
factory, especially for oxygen-containing alkynes.
Table 1.
Cp2ZrHCl
O
B
O
O
(0.1 eq)
R
+
+
O
O
B
B
R
O
room temp.
H
R
E
Z
R
Yield (%)
E
Z
n-Butyl
Cyclohexyl
Phenyl
90
86
96
58
97
98
98
3
2
2
0
*
Corresponding author. Tel.: +1 845 6025523; fax: +1 845 602
5561; e-mail: wangd@wyeth.com
tert-Butyl
100
0040-4039/$ - see front matter Ó 2005 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2005.10.031

8778
Y. D. Wang et al. / Tetrahedron Letters 46(2005) 8777–8780
Table 2.
It is speculated that the intramolecular interaction
between the 16-electron bis(cyclopentadienyl)-zirconium
center and oxygen favors the formation of a pseudo-
(Z) intermediate, which in turn leads to the formation
of (Z)-vinylboronic esters, as shown in Figure 1. The
longer the linker between the alkyne and oxygen atom
is, the more likely the formation of the pseudo-(Z)
intermediate.
O
B
OTBS
O
Cp2ZrHCl
(0.1 eq)
n
OTBS
(E)
+
O
H
+
O
B
20oC
OTBS
n
O
n
B
O
(Z)
This prompted us to investigate practical modifications
to disrupt this hypothesized intramolecular O–Zr inter-
action in order to improve the stereoselectivity and yield
toward (E)-vinylboronic esters. Therefore, a Lewis acid
n
Yield (%)
79
E
Z
1
262
3
4
9
95
5
90
10
63
66
37
79
62
54
2
38
46
1
and base, targeting either the oxygen or zirconium
site, respectively, were examined. While a Lewis acid
(BF3–Et2O) had limited impact on the outcome of hyd-
roboration, the base Et3N improved the stereoselectivity
considerably (Table 3). A catalytic amount of Et3N
appeared to work better than a stoichiometric amount
on both yield and stereoselectivity (Et3N > DMAP >
pyridine), though it gave a lower yield of vinylboronic
metathesis, and vinyl–hydride exchange, similar to the
mechanism of lanthanide-catalyzed hydroboration of
alkenes,17,18 as shown in Figure 1.
R
H
TBS
O
H
Cl
H
n
H
Zr
Zr
Cl
Zr
Cl
O
TBS
O
H
n
H
O
B
H
H
R
Pseudo-E
Pseudo-Z
(E)
H
Cl
H
O
B
Zr
O
O
R
H
R
(Z)
B
H
O
H
Figure 1.
Table 3.
O
O
O
O
+
O
H
B
OTBS
n
+
B
B
OTBS
n
O
Cp2ZrHCl (0.1 eq)
OTBS
n
(Z)
(E)
n
Additive
None
Reaction time (h)
Reaction temperature
rt
Yield (%)
E
Z
4
20
rt
66
10
62
38
2None
0
2
62
90
4
4
4
4
4
1.0 equiv BF3–Et2O
1.0 equiv Et3N
0.1 equiv pyridine
0.1 equiv DMAP
0.1 equiv Et3N
2
2
20
20
2
0
rt
<5
74
2
0
0
rt
rt
19
41
82
93
rt
rt
45
10
54
79
46
21
4
None
16
60 °C
°C
94
93
96
95
4
5
2None
16
60
4
0.1 equiv Et3N
16
16
60 °C
60 °C
94
96
98
98
2
2
20.1 equiv Et
3N

Y. D. Wang et al. / Tetrahedron Letters 46(2005) 8777–8780
8779
Et
Acknowledgments
TBS
Et
Et
N
O
heat or Et3N
H
n
Si
We thank the Chemical Technologies group at Wyeth
Research, Pearl River, NY for spectral and combustion
analyses. We also thank Drs. Diane H. Boschelli, Den-
nis Powell and Tarek Mansour for their support of this
work.
Zr
Cl
Zr
Cl
O
n
H
H
H
Pseudo-Z
Pseudo-E
Figure 2.
ester than hydroboration without amine. We then
looked at the possibility of a thermal intervention of
the intramolecular Zr–O interaction. We found that
hydroboration at an elevated temperature indeed affor-
ded (E)-vinylboronic esters with better stereoselectivity
and yield than reaction at ambient temperature. Fur-
thermore, hydroboration at an elevated temperature in
the presence of a catalytic amount of Et3N resulted in
an optimal outcome in both stereoselectivity and yield
(Fig. 2).
References and notes
1. Tsuji, T. Palladium Reagents and Catalysts: Innovation in
Organic Chemistry; John Wiley & Sons: Chichester, 1995.
2. Malleron, J. L.; Fiaud, J. C.; Legros, J. Y. Handbook of
Palladium Catalyzed Organic Reactions: Synthetic Aspects
and Catalytic Cycles; Academic Press, 1997; p 1.
3. Suzuki, A. In Metal-catalyzed Cross-coupling Reactions;
Diederich, F., Stang, P. J., Eds.; Wiley-VCH: Weinheim,
1998; p 49.
4. Larsen, R. D. Curr. Opin. Drug Discovery Dev. 1999, 2,
651.
5. Suzuki, A. Pure Appl. Chem. 1991, 63, 419.
6. Sato, M.; Miyaura, N.; Suzuki, A. Chem. Lett. 1989, 8,
1405.
We carried out the hydroborations of alkynes substi-
tuted by various functional groups using this protocol
(Table 4).19 They all proceeded smoothly to afford the
corresponding (E)-vinylboronic esters in both good yield
and stereoselectivity.
7. Matteson, D. S. Chem. Rev. 1989, 89, 1535.
8. Roush, W. R.; Palkowitz, A. D.; Ando, K. J. Am. Chem.
Soc. 1990, 112, 6348.
9. Hoffmann, R. W.; Dresely, S. Synthesis 1988, 2, 103.
10. Brown, H. C.; Rucherla, U. S.; Pellechia, P. J. J. Org.
Chem. 1990, 55, 1868.
11. Brown, H. C.; Gupta, S. K. J. Am. Chem. Soc. 1971, 93,
1816.
12. Lane, C. F.; Kabalka, G. W. Tetrahedron 1976, 32,
981.
13. Tucker, C. E.; Davidson, J.; Knochel, P. J. Org. Chem.
1992, 57, 3482.
In summary, a robust and mild reaction protocol was
developed for the hydroboration of alkynes to give
E-vinylboronic esters in good to excellent yield (59–
99%). High stereoselectivity (E/Z > 95:5) and regioselec-
tivity were achieved. This new protocol showed high
tolerance for various functional groups on the alkynes.
An intramolecular interaction between the 16-electron
zirconium center and oxygen atom was proposed based
on the experimental results observed in the Zr-mediated
hydroboration reaction of oxygen-containing alkynes.
14. He, X.; Hartwig, J. F. J. Am. Chem. Soc. 1996, 118, 1696.
15. Pereira, S.; Srebnik, M. Organometallics 1995, 14, 3127.
Table 4.
Cp2ZrHCl (0.1 eq),
Et3N (0.1 eq)
O
O
B
O
R
+
+
B
R
O
O
B
60oC
R
O
H
(Z)
(E)
Entry
R
Yield (%)
E
Z
2
1
2
3
4
5
90
98
98
OTHP
96
2
OTBS
OTBS
OTBS
9296
94
4
98
99
2
1
93
SEt
6
7
8
99
76
59
100
96
0
4
3
OTs
3-MeO–phenyl
97
CN
9
95
90
100
100
0
0
Cl
OTBS
10
N
11
99
98
2
N
Et

8780
Y. D. Wang et al. / Tetrahedron Letters 46(2005) 8777–8780
16. Hartwig, J. F.; Muhoro, C. N.; He, X.; Eisenstein, O.;
Booque, R.; Maseras, F. J. Am. Chem. Soc. 1996, 118,
10936.
17. Pereira, S.; Srebnik, M. Tetrahedron Lett. 1996, 37, 3283.
18. Harrison, K. N.; Marks, T. J. J. Org. Chem. 1992, 114,
9220.
19. General procedure: To a mixture of tert-butyl-but-3-
ynyloxy-dimethylsilane (1.0 g, 7.14 mmol)20 and 4,4,5,5-
tetramethyl-[1,3,2]dioxaborolane (958 mg, 7.49 mmol) was
added bis(cyclopentadienyl)zirconium chloride hydride
(183 mg, 0.714 mmol) and triethylamine (72mg,
0.714 mmol). The resulting mixture was heated at 60 °C
for 16 h and diluted with hexanes. The precipitate was
removed by filtering over a short pad of silica gel and
washed with hexanes. The filtrate was concentrated and
dried in vacuum to give 1.76 g (93% yield) of tert-
butyl(dimethyl){[(5E)-6-(4,4,5,5-tetramethyl-1,3,2-dioxa-
borolan-2-yl)hex-5-en-1-yl]oxy}silane as a colorless liquid.
20. Pereira, R.; Iglesias, B.; de Lera, A. R. Tetrahedron 2001,
57, 7871.