Synthesis and reaction of secondary and primary diorganozinc reagents using a boron-zinc exchange reaction. A useful method for the stereo- and regioselective formation of new carbon-carbon bonds

Article abstract of DOI:10.1016/S0022-328X(03)00237-7

Applications of the boron-zinc exchange reaction to make new carbon-carbon bonds are reviewed. Functionalized chiral secondary alkylzinc reagents can be prepared by this exchange reaction and allows to perform formal enantioselective Michael-additions wit

Full text of DOI:10.1016/S0022-328X(03)00237-7

Journal of Organometallic Chemistry 680 (2003) 136Á142
/
www.elsevier.com/locate/jorganchem
Synthesis and reaction of secondary and primary diorganozinc
reagents using a boronÁzinc exchange reaction
A useful method for the stereo- and regioselective formation of new
carbonÃcarbon bonds
/
/
Eike Hupe, M. Isabel Calaza, Paul Knochel *
Department Chemie, Ludwig-Maximilians-Universitat Munchen, Butenandtstrasse 5-13, D-81377 Munchen, Germany
¨ ¨ ¨
Received 13 February 2003; received in revised form 14 March 2003; accepted 14 March 2003
Abstract
Applications of the boronÁ
/
zinc exchange reaction to make new carbonÃ/carbon bonds are reviewed. Functionalized chiral
secondary alkylzinc reagents can be prepared by this exchange reaction and allows to perform formal enantioselective Michael-
additions with umpolung of reactivity. The scope of substrate controlled diastereoselective hydroborations can be considerably
enhanced by this methodology. A chemoselective approach to difunctionalized arylsilanes is also described.
# 2003 Elsevier Science B.V. All rights reserved.
Keywords: Diastereoselective synthesis; Hydroboration; Transmetallation; Zinc organometallics; CÁC coupling
/
1. Introduction
a trisubstituted olefin such as 1, hydroboration with
diethylborane leads to the triorganoborane 2, which can
be easily converted into the corresponding zinc reagent 3
by addition of iPr2Zn. This diorganozinc reagent can
then be trapped, after transmetallation to Cu(I) or by
Pd(0) catalysis [6d], with a broad range of electrophiles,
giving the desired products of type 4 in satisfactory
overall yields and excellent stereochemical control. All
reaction steps in this sequence proceed with retention of
stereochemistry (Scheme 1) [7].
Organometallic reagents are useful intermediates for
the formation of new carbonÃ
/
carbon bonds [1]. The
stereoselective formation of new carbonÃ
/carbon bonds
implies the availability of Csp3-hybridized organome-
tallic compounds having a defined configuration [2].
Whereas chiral organolithium or organomagnesium
compounds require chelating heteroatoms in an alpha-
position or low temperature to ensure a configurational
stability [3,4], chiral diorganozinc compounds have
shown to be configurationally stable over a wide
temperature range without the need of any stabilizing
heteroatoms [5]. Furthermore, these chiral diorganozinc
reagents have shown to be highly compatible with
various functional groups [5]. This high configurational
This sequence can also be applied for the synthesis of
optically active diorganozinc reagents. Thus, starting
from 1-phenylcyclopentene (5), an asymmetric hydro-
boration with (ꢀ
/
)- isopinocampheylborane ((ꢀ)-
/
IpcBH2) [8] leads to the intermediate organoborane 6
in 94% ee. Further treatment with Et2BH [9] and iPr2Zn
provides the optically active diorganozinc reagent 7.
After transmetallation to the corresponding copper
stability is due to the covalent nature of the CÃ
/
Zn bond.
Chiral diorganozinc reagents can be easily obtained by a
one-pot sequence of hydroboration and subsequent
reagent with CuCN×/2LiCl [10], it was reacted with allyl
boronÁzinc exchange reaction [6]. Thus, starting from
/
bromide with retention of stereochemistry. The allylated
product 8 was obtained in 94% ee and an overall yield of
44% as a 98:2 mixture of trans and cis isomers, showing
the configurational stability of the intermediate diorga-
nozinc reagent 7 (Scheme 2) [6e].
* Corresponding author. Tel.: ꢁ
218077680.
E-mail address: paul.knochel@cup.uni-muenchen.de (P. Knochel).
/
49-89-218077681; fax: ꢁ49-89-
/
0022-328X/03/$ - see front matter # 2003 Elsevier Science B.V. All rights reserved.
doi:10.1016/S0022-328X(03)00237-7

E. Hupe et al. / Journal of Organometallic Chemistry 680 (2003) 136Á
/
142
137
To demonstrate the validity of the umpolung proce-
dure, the functionalized alkyne 12a was deprotected by
treatment with dilute aqueous HCl furnishing the free
trans-aldehyde 14 as one diastereoisomer in 88% ee and
93% yield (42% overall yield starting from the unsatu-
rated acetal 9) (Scheme 4).
An extension to open chain systems was also possible.
Thus, the protected exo-alkylidene enone 15 was
Scheme 1.
hydroborated with (ꢀ)-IpcBH2 affording, after further
/
treatment with Et2BH and iPr2Zn, the optically active
secondary alkylzinc reagent 16 in 76% ee. After a
transmetallation with Cu(I) and allylation, the desired
2. Using the boron zinc exchange reaction for a formal
enantioselective 1,4-addition with umpolung of the
reactivity
/
Á
products 17aÁ
/
b were obtained in excellent diastereos-
electivities (]94:6) (Scheme 5) [15].
/
The conjugate addition of nucleophiles to a,b-unsa-
turated carbonyl compounds has been extensively stu-
died over the last years [11]. Especially, its
enantioselective version has received much attention
[12]. Although many excellent methods for conjugate
additions have been described, the enantioselectivity of
Michael-addition is very much dependent on the nature
of the nucleophile used. Furthermore, several classes of
nucleophiles, such as alkynyl [13], allenyl or allylic
organometallics, still cannot be generally added enan-
3. Substrate controlled diastereoselective synthesis of
chiral diorganozinc reagents
Substrate controlled hydroboration is a useful reac-
tion for performing diastereoselective syntheses [16].
One major drawback of these reactions is that the
resulting chiral organoboranes are usually not reactive
tioselectively. The hydroboration/boronÁzinc exchange
/
enough to participate in new carbonÃ
/
carbon bond
sequence, allows to perform conjugate additions with an
umpolung [14] of the classical 1,4-addition. Whereas the
usual reactivity pattern of an a,b-unsaturated carbonyl
compound requires a reaction with a nucleophile, we
envisioned a reaction of a protected Michael-acceptor
with an electrophile [15]. Thus, the unsaturated acetal 9
formations. The boronÁzinc exchange allows to convert
/
usually unreactive organoboranes to more reactive
organozinc reagents, which in the presence of appro-
priate catalysts are efficiently used for the formation of
new carbonÃ
/
carbon bonds. Thus, the trisubstituted
olefin 20, obtained after diastereoselective Luche reduc-
tion [17] and protection of 18 [18], is diastereoselectively
was hydroborated with (ꢀ)-IpcBH2 and converted by
/
the addition of iPr2Zn into the optically active diorga-
nozinc reagent 10 (91% ee). Its reaction, after transme-
tallation to the corresponding copper reagent, with a
variety of different electrophiles afforded the desired
hydroborated (d.r. (1, 2)ꢂ97:3) by using CH2Cl2 as a
co-solvent. Further conversion to the corresponding
diorganozinc reagent and Cu(I) mediated reaction with
/
propionyl chloride (d.r. (2, 3)ꢂ94:6) leads to the desired
/
products 11Á
overall yields (Scheme 3) [15].
The zinc reagent 10 shows a high configurational
stability after transmetallation, in the reaction with
various alkynyl bromides. Reaction with allyl bromides
/
13 in excellent selectivities and 46Á52%
/
product 22 which was obtained in 59% overall yield. It
was possible to generate a chiral diorganozinc reagent
with the control of four stereogenic centers (Scheme 6)
[19].
Most literature procedures for substrate controlled
diastereoselective hydroborations use sterically hindered
hydroborating reagents. Fleming et al. have reported
excellent diastereoselectivities for the hydroboration of
or propargyl bromide leads to small amounts (3Á
the undesired cis product, but the alkynylated products
12aÁb were obtained in selectivities of ]99:1 and
acceptable overall yields.
/6%) of
/
/
the chiral allylic silane 23 using 9-BBNÃ/H [20]. The
Scheme 2.

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E. Hupe et al. / Journal of Organometallic Chemistry 680 (2003) 136Á
/
142
Scheme 3.
Scheme 4.
hydroboration of 23 under Fleming’s conditions fol-
lowed by a boronÁzinc exchange affords the corre-
sponding zinc reagent 24, which readily reacted with a
/
variety of different electrophiles. The desired products
25Á27 were obtained in good yields and in excellent
/
Scheme 6.
diastereoselectivities (Scheme 7) [21,22].
Similarly, Burgess et al. have shown that protected
chiral allylic amines such as 28 can be hydroborated
lead to a triorganoborane that was then converted to the
corresponding zinc organometallic 29, which by the
reaction with different electrophiles provided the desired
with 9-BBNÃ
corresponding amino alcohol in a selectivity of ꢀ
4 [23]. Hydroboration of 28 under Burgess’s conditions
/
H yielding, after oxidative workup, the
/
96:B
/
Scheme 5.

E. Hupe et al. / Journal of Organometallic Chemistry 680 (2003) 136Á
/
142
139
Scheme 7.
This example demonstrates that the scope of substrate
controlled diastereoselective hydroborations can be
considerably enhanced by performing a BÃZn exchange
sequence.
/
4. One-pot chemoselective difunctionalization of
arylsilanes using a boron zinc exchange reaction
/
Á
synthesis of allylzincs was described by Thiele et al. [25].
The use of the boronÁ/zinc exchange reaction for the
Oppolzer and Srebnik have used the boronÁzinc ex-
/
change reaction for the synthesis of vinylic organozinc
reagents starting from vinylic organoboranes [26]. To
complement the scope of the boronÁzinc exchange
/
reaction, we turned our attention to the synthesis of
arylzinc reagents starting from arylboranes [27].
Arylboranes of the type ArBCl2 are easily available by
a siliconÁboron exchange of arylsilanes with BCl3 [28].
/
Scheme 8.
Thus, starting from the aromatic 1,4-disilane 37, the
arylborane 38 was obtained by adding BCl3. Transme-
tallation of 38 to the corresponding zinc reagent 39 with
iPr2Zn was quantitative after 2 h at 25 8C. Further
transmetallation of 39 with Cu(I) and subsequent
reaction with propargyl bromide or propionyl chloride
lead to the desired aromatic products 40 and 41 in 73
and 72% yield by a one-pot procedure (Scheme 10) [29].
It was possible to treat the disilane 37 with BCl3
functionalized amines 30Á
/
32 in good overall yields and
excellent diastereoselectivities (Scheme 8) [22].
A boronÁzinc exchange reaction was possible after
/
rhodium-catalyzed hydroborations with catecholborane
[21,22]. The protected exo-methylidene cyclohexanol
derivative 33 was hydroborated with catecholborane
and catalytic amounts of Rh(PPh3)3Cl according to a
procedure described by Evans et al. [24]. Treatment with
iPr2Zn leads to the diorganozinc compound 34, which
could then be allylated to yield 35aÁb in 52 and 46%
overall yield or trapped with bromopentyne yielding the
alkyne 36 in 49% overall yield (Scheme 9). The
yielding the mixed BÃ/Si-aryl derivative 38. Its treatment
in a one-pot procedure with ICl allows the regio- and
chemoselective exchange of the second Si-functionality
to iodine furnishing the iodoarylboron derivative 42,
which was then transmetalated, via a chemoselective
/
boronÁzinc exchange to the zinc reagent 43. The
/
diastereoselectivities obtained in the products 35aÁb
/
arylzinc reagent 43 was, after transmetalation to Cu(I),
trapped with a variety of different electrophiles to
and 36 are the same as described by Evans for the
corresponding alcohol obtained after oxidative workup
of the intermediate boronic ester [24].
provide the desired products 44Á
/
45 in acceptable overall
yields (Scheme 11) [29].

140
E. Hupe et al. / Journal of Organometallic Chemistry 680 (2003) 136Á
/
142
Scheme 9.
The aromatic disilane 46 was similarly functionalized
twice by a double SiÃB exchange yielding the aromatic
/
diborane 47, that was easily transfered into the corre-
sponding bis-diorganozinc reagent 48 by addition of
iPr2Zn. After Cu(I) mediated reaction with 1-bromo-2-
trimethylsilylacetylene, the desired product 49 was
obtained in good overall yield (68%, one-pot procedure)
(Scheme 12) [29].
5. Summary
In summary, we have shown that the boronÁ
exchange reaction is an useful method for the formation
of new carbonÃcarbon bonds. An asymmetric hydro-
boration and subsequent boronÁzinc exchange reaction
/
zinc
/
/
on protected a,b-unsaturated ketones or aldehydes lead
to products of a formal enantioselective Michael-addi-
tion with umpolung of the reactivity. Furthermore, we
have shown that chiral triorganoboranes, obtained after
substrate controlled diastereoselective hydroborations
on chiral, protected allylic alcohols, leads to chiral
diorganozinc reagents that can be trapped with different
electrophiles. The scope of substrate controlled diaster-
Scheme 11.
eoselective hydroborations can be considerably en-
hanced by the method presented herein. Finally, we
Scheme 10.

E. Hupe et al. / Journal of Organometallic Chemistry 680 (2003) 136Á
/
142
141
Scheme 12.
[5] (a) P. Knochel, N. Millot, A.L. Rodriguez, C.E. Tucker, Org.
React., vol. 58, 2001, p. 417;
have shown that arylsilanes can be easily difunctiona-
lized by the boronÁzinc exchange reaction on arylbor-
anes, leading to functionalized aromatic systems in good
/
(b) R. Duddu, M. Eckhardt, M. Furlong, H.P. Knoess, S. Berger,
P. Knochel, Tetrahedron 50 (1994) 2415.
overall yields.
[6] (a) L. Micouin, M. Oestreich, P. Knochel, Angew. Chem. Int. Ed.
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(b) C. Darcel, F. Flachsmann, P. Knochel, J. Chem. Soc. Chem.
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Acknowledgements
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We thank the DFG (Leibniz-Program) for financial
support. E.H. thanks the Fonds der Chemischen Indus-
trie for a Kekule´-fellowship. M.I.C. thanks the Eur-
opean Community for a Marie Curie fellowship
(HPMF-CT-2000-01024). We thank also the BASF
AG, Bayer AG, Chemetall GmbH and Degussa AG
for the generous gift of chemicals.
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