Generation and tandem reactions of 1-alkenyl-1,1-heterobimetallics: Practical and versatile reagents for organic synthesis

Article abstract of DOI:10.1021/ja077664u

A practical and straightforward method for generation of versatile 1-alkenyl-1,1-heterobimetallic intermediates and their application to construction of functionalized building blocks are disclosed. Beginning with readily available air-stable 1-alkynyl-1-boronate esters, hydroboration with dicyclohexylborane generates 1-alkenyl-1,1-diboro species. In situ transmetallation with dialkylzinc reagents furnishes 1-alkenyl-1,1- heterobimetallic intermediates. Direct treatment with aldehydes followed by workup allows isolation of B(pin)-substituted allylic alcohols in 70-95% yield. The B(pin)-substituted allylic alcohols react with NBS to afford (E)-α,β-unsaturated aldehydes in 51-77% yield via a semipinacol-type rearrangement. In situ treatment of 1-alkenyl-1,1-heterobimetallic intermediates with aldehydes followed by TBHP oxidation enables the preparation of α-hydroxy ketones. Under optimized conditions, addition of 1-alkenyl-1,1-heterobimetallic intermediates to a variety of protected α- and β-hydroxy aldehydes proceeds with good to excellent control over diastereoselectivity to furnish differentially protected dihydroxy ketones. The 1-alkenyl-1,1-heterobimetallic intermediates have also been employed in tandem aldehyde addition/Suzuki cross-coupling reactions to provide densely functionalized allylic alcohols in good to excellent yields.

Full text of DOI:10.1021/ja077664u

Published on Web 02/27/2008
Generation and Tandem Reactions of
1-Alkenyl-1,1-Heterobimetallics: Practical and Versatile
Reagents for Organic Synthesis
Hongmei Li, Patrick J. Carroll, and Patrick J. Walsh*
P. Roy and Diana T. Vagelos Laboratories, UniVersity of PennsylVania, Department of
Chemistry, 231 South 34th Street, Philadelphia, PennsylVania, 19104-6323
Received October 4, 2007; E-mail: pwalsh@sas.upenn.edu
Abstract: A practical and straightforward method for generation of versatile 1-alkenyl-1,1-heterobimetallic
intermediates and their application to construction of functionalized building blocks are disclosed. Beginning
with readily available air-stable 1-alkynyl-1-boronate esters, hydroboration with dicyclohexylborane generates
1-alkenyl-1,1-diboro species. In situ transmetallation with dialkylzinc reagents furnishes 1-alkenyl-1,1-
heterobimetallic intermediates. Direct treatment with aldehydes followed by workup allows isolation of B(pin)-
substituted allylic alcohols in 70-95% yield. The B(pin)-substituted allylic alcohols react with NBS to afford
(E)-R,â-unsaturated aldehydes in 51-77% yield via a semipinacol-type rearrangement. In situ treatment
of 1-alkenyl-1,1-heterobimetallic intermediates with aldehydes followed by TBHP oxidation enables the
preparation of R-hydroxy ketones. Under optimized conditions, addition of 1-alkenyl-1,1-heterobimetallic
intermediates to a variety of protected R- and â-hydroxy aldehydes proceeds with good to excellent control
over diastereoselectivity to furnish differentially protected dihydroxy ketones. The 1-alkenyl-1,1-heterobi-
metallic intermediates have also been employed in tandem aldehyde addition/Suzuki cross-coupling reactions
to provide densely functionalized allylic alcohols in good to excellent yields.
workers,15 hydroboration of 1-iodoalkynes with HBBr2‚SMe2
(Scheme 1) generated vinylboranes that were then hydrolyzed
to boronic acids. Subsequent treatment with pinacol and
purification by column chromatography gave pinacol boronate
esters in 50-80% isolated yields. The 1-iodoalkenyl boronate
esters were then exposed to zinc dust in DMA to generate (Z)-
1-alkenyl-1,1-heterobimetallic compounds. Unfortunately, inser-
tion of zinc into the C-I bond did not proceed with stereo-
chemical fidelity but provided a mixture of double bond isomers
(E:Z ) 82:12), limiting the utility of these 1,1-bimetallic
reagents. Reaction of the resulting 1-alkenyl-1,1-zinc boron
bimetallics with CuCN resulted in formation of 1,1-copper boron
derivatives, which were subjected to a variety of electrophiles.
For example, reaction of the 1,1-copper boron bimetallic with
aldehydes in the presence of BF3‚OEt2 provided the vinyl
boronate ester addition products. After standard workup, the
resulting E:Z mixture of vinyl boronate esters was treated with
30% H2O2 to provide the R-hydroxy ketones in 74-87% yield
(50-58% yield from the 1-iodoalkynes, Scheme 1).15
1. Introduction
The ever-increasing complexity of organic target molecules
necessitates the introduction of new methods for the efficient
assembly of functionalized intermediates from simple precur-
sors.1,2 An appealing strategy toward this end is the development
of novel tandem reactions whereby sequential transformations
canbeperformedwithoutisolationorpurificationofintermediates.3-5
Our approach to this goal entails generation of functionalized
1-alkenyl-1,1-heterobimetallic intermediates, wherein each metal
exhibits distinct reactivity that can be selectivity exploited in
C-C bond-forming reactions or for installation of functional
groups.
The generation and reactivity of 1-alkenyl-1,1-bimetallics has
been of interest for several years; however, relatively few
practical applications to stereoselective organic transformations
have been reported.6-14 In pioneering work by Knochel and co-
(1) Hudlicky, T.; Natchus, M. G. In Organic Synthesis: Theory and Applica-
tions; JAI Press: London, 1993; Vol. 2, p 1.
(2) Trost, B. M.; Fleming, I. ComprehensiVe Organic Synthesis: SelectiVity
Strategy and Efficiency in Modern Organic Chemistry; Pergamon Press:
Elmsford, NY, 1991; Vol. 9.
(3) Parsons, P. J.; Penkett, C. S.; Shell, A. J. Chem. ReV. 1996, 96, 195.
(4) Schmalz, H.-G.; Geis, O. In Handbook of Organopalladium Chemistry for
Organic Synthesis; Negishi, E.-I., Ed.; Wiley: New York, 2002; Vol. 2, p
2377.
In related work, Srebnik and co-workers examined the
hydrozirconation of alkynyldioxaborolanes with Schwartz re-
agent to generate 1-alkenyl-1,1-heterobimetallic intermediates
(5) Nicolaou, K. C.; Montagnon, T.; Snyder, S. A. Chem. Commun. 2003, 551.
(6) Marek, I. Chem. ReV. 2000, 100, 2887.
(11) Shimizu, M.; Nakamaki, C.; Shimono, K.; Schelper, M.; Kurahashi, T.;
Hiyama, T. J. Am. Chem. Soc. 2005, 127, 12506.
(7) Marek, I. Actualite Chimique 2003, 15.
(8) Ben-Valid, S.; Quntar, A. A. A.; Srebnik, M. J. Org. Chem. 2005, 70,
3554.
(12) Ali, H. A.; Al Quntar, A. E. A.; Goldberg, I.; Srebnik, M. Organometallics
2002, 21, 4533.
(9) Dembitsky, V. M.; Ali, H. A.; Srebnik, M. Appl. Organomet. Chem. 2003,
17, 327.
(13) Kurahashi, T.; Hata, T.; Masai, H.; Kitagawa, H.; Shimizu, M.; Hiyama,
T. Tetrahedron 2002, 58, 6381.
(14) Creton, I.; Marek, I.; Normant, J. F. Synthesis 1996, 1499.
(15) Waas, J. R.; Sidduri, A.; Knochel, P. Tetrahedron Lett. 1992, 33, 3717.
(10) Zheng, B.; Deloux, L.; Perieira, S.; Skrzypczak-Jankun, E.; Chessmann,
B. V.; Sabat, M.; Srebnik, M. Appl. Organomet. Chem. 1996, 10, 267.
9
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J. AM. CHEM. SOC. 2008, 130, 3521-3531
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A R T I C L E S
Li et al.
Scheme 1. Knochel’s Synthesis of R-Hydroxy Ketones via
1,1-Bimetallic Reagents
Scheme 3. Application of 1-Alkenyl-1,1-heterobimetallic
Intermediates to the Synthesis of Boronate-Substituted Allylic
Alcohols, R-Hydroxy Ketones, Dienols, and R,â-Unsaturated
Aldehydes
Scheme 2. Srebnik’s Preparation of Dienes by Negishi and
Suzuki Coupling Reactions
Scheme 4. One-Pot Generation of B(pin)-Substituted Allylic
Alcohols
1,1-heterobimetallics can be generated, using our method, from
air-stable B(pin)-substituted alkynyl boronate esters and can be
employed in further applications without isolation of intermedi-
ates.
2. Results and Discussion
(Scheme 2).16-18 Transmetallation of the Zr-C bond allowed
selective coupling reactions to be performed with retention of
the stereochemistry of the alkenyl group. For example, reaction
of the 1,1-boron zirconium bimetallic with ZnCl2 generated the
1,1-boron zinc bimetallic. In the presence of 5 mol % Pd(PPh3)4
and a vinyl bromide, a Negishi coupling ensued with formation
of the dienyl boronate ester in 62% isolated yield. In the next
step, treatment of dienyl boronate ester with PhI, EtONa, and
fresh Pd(PPh3)4 (5 mol %) provided the Suzuki coupling product
in 84% yield.16
Our interest in the application of 1-alkenyl-1,1-heterobime-
tallics to organic synthesis stems from their potential to serve
as versatile multifunctional intermediates in sequential bond-
forming reactions. With the goal of developing simple and
practical methods employing such heterobimetallics, the fol-
lowing criteria were deemed important. The 1-alkenyl-1,1-
heterobimetallics must be easily generated using standard
organic laboratory techniques and used without isolation or
purification of air-sensitive intermediates.
2.1. Generation and Reactions of 1-Alkenyl-1,1-Hetero-
bimetallic Reagents. With the above guidelines in mind, we
generated 1-alkenyl-1,1-heterobimetallic reagents via hydrobo-
ration of air-stable B(pin)-substituted alkynes with dicyclohexyl-
borane (Scheme 4).19-24 The resulting 1,1-diboro species
exhibited resonances at 30 and 80 ppm in the 11B NMR
spectrum, consistent with the proposed structure.25 Only one
regioisomer was observed in the hydroboration reaction, and
no isomerization of the double bond was detected by 1H NMR
spectroscopy.
Although both B-C bonds of the 1-alkenyl-1,1-diboro
compounds in Scheme 4 are similarly unreactive toward most
organic electrophiles, we hypothesized that they would display
significantly different rates of transmetallation with organozinc
reagents. This hypothesis was based on the ease of transmet-
allation of dialkyl vinylboranes (R2BCHdCHR′) versus aryl
boronate esters and acids. Srebnik26 and Oppolzer27 demon-
Although both of these studies represent important advances
in the chemistry of 1,1-heterobimetallics, each has drawbacks
in its applications to organic synthesis. The multistep synthesis
and the need for isolation of the 1-iodoalkenyl boronate esters
in Scheme 1 diminish the synthetic efficiency and attractiveness
of these reagents. Furthermore, the loss of stereochemistry in
the zinc insertion step gives rise to isomeric mixtures of (E)-
and (Z)-products, limiting their synthetic utility. The application
of Schwartz reagent, Cp2ZrHCl, on large scale is impractical
and prohibitively expensive. We speculate that these limitations
have discouraged the adoption of 1-alkenyl-1,1-heterobimetallic
reagents by the organic community.
In this report, we outline the generation of practical and
synthetically useful 1-alkenyl-1,1-heterobimetallic intermediates
that undergo a variety of transformations to provide boronate-
substituted allylic alcohols, R-hydroxy ketones, dienols, and R,â-
unsaturated aldehydes (Scheme 3). We have also studied
additions of 1-alkenyl-1,1-heterobimetallic reagents to chiral
aldehydes to furnish syn and anti protected R,â-dihydroxy
ketones with high diastereoselectivity. Importantly, 1-alkenyl-
(19) Brown, H. C.; Bhat, N. G.; Srebnik, M. Tetrahedron Lett. 1988, 29, 2631.
(20) Blanchard, C.; Framery, E.; Vaultier, M. Synthesis 1996, 45.
(21) Brown, H. C.; Roy, C. D.; Soundararajan, R. Tetrahedron Lett. 1997, 38,
765.
(22) Kim, M.; Lee, D. Org. Lett. 2005, 7, 1865.
(16) Deloux, L.; Skrzypczak-Jankun, E.; Cheesman, B. V.; Srebnik, M.; Sabat,
M. J. Am. Chem. Soc. 1994, 116, 10302.
(17) Deloux, L.; Srebnik, M. J. Org. Chem. 1994, 59, 6871.
(18) Deloux, L.; Srebnik, M.; Sabat, M. J. Org. Chem. 1995, 60, 3276.
(23) Renaud, J.; Graf, C.-D.; Oberer, L. Angew. Chem., Int. Ed. 2000, 39, 3101.
(24) Chong, J. M.; Shen, L.; Taylor, N. J. J. Am. Chem. Soc. 2000, 122, 1822.
(25) Yamamoto, Y.; Moritani, I. J. Org. Chem. 1975, 40, 3434.
(26) Srebnik, M. Tetrahedron Lett. 1991, 32, 2449.
9
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1-Alkenyl-1,1-Heterobimetallics
A R T I C L E S
Table 1. Preparation of B(pin)-Substituted Allylic Alcohols from
Scheme 4
Scheme 5. NBS Promoted Rearrangement of B(pin)-Substituted
Allylic Alcohols
Table 2. Stereospecific Synthesis of (E)-Trisubstituted
R,â-Unsaturated Aldehydes from Scheme 5
strated that dialkyl vinylboranes undergo rapid transmetallation
with dialkylzinc reagents at low temperature. In contrast, Bolm
reported that B(pin)-substituted aryl groups undergo transmet-
allation with dialkylzinc reagents only on prolonged heating.28
Thus, by selective transmetallation of the more reactive alkenyl
dicyclohexylborane with dimethylzinc, we believed it would be
possible to generate reactive zinc boron heterobimetallic species.
We were pleased to find that the Cy2B group underwent
transmetallation with dimethylzinc much faster than the (pin)B
and that the resulting boron/zinc heterobimetallic reagent readily
added to aldehydes to provide B(pin)-substituted (E)-allylic
alcohols in high yields (Scheme 4). We propose that the origin
of this reactivity difference stems from the availability of the p
orbitals on the borons. Through resonance, the B(pin) oxygens
donate electron density to boron, reducing its Lewis acidity. In
contrast, the cyclohexyl groups donate electron density through
the sigma bonds, leaving the boron p orbital more available to
participate in the alkyl/vinyl exchange and lowering the barrier
for the transmetallation process at BCy2. No product derived
from methyl addition to the aldehyde was observed.
Table 1 presents representative examples of the synthesis and
isolation of B(pin)-substituted allylic alcohols (70-95% isolated
yield). Benzaldehyde derivatives with ortho or para substituents
and benzaldehyde itself were very good substrates for the vinyl
addition reaction (entries 1-6). Furthermore, the aliphatic
aldehyde in entry 7 gave 95% yield. Other saturated aldehydes
have been used successfully in tandem reactions and are outlined
in subsequent sections. A variety of B(pin)-substituted alkynes
were employed, including those with small substituents (n-Bu)
and bulky groups (t-Bu). In entry 6, the boron alkyne contains
a conjugated vinyl group whereas the substrates in entries 3-5
possess chlorides. Importantly, only one isomer of the allylic
alcohol was observed in each case, indicating that isomerization
a Stereochemistry determined by nOe. See the Supporting Information
for details.
of the double bond does not occur under the transmetallation,
addition, or workup conditions. This is particularly impressive
in the case of cis t-Bu and B(pin) groups in entries 2 and 7.
B(pin)-substituted allylic alcohols are potentially suitable sub-
strates for Suzuki cross-coupling reactions, a topic addressed
in Section 2.5.
2.2. Stereospecific Generation of (E)-Trisubstituted r,â-
Unsaturated Aldehydes. With the B(pin)-substituted allylic
alcohols in hand, we desired to examine their reactivity toward
oxidants such as N-bromosuccinimide (NBS). It is known that
vinyl borane derivatives react with electrophilic halide sources
to give halodeborylation products with inversion of the double
bond stereochemistry.29,30 In contrast to the reaction of vinyl
boranes with halogenating reagents, combination of our B(pin)-
substituted benzylic allylic alcohols with NBS resulted in an
interesting skeletal rearrangement with formation of (E)-
trisubstituted enals (Scheme 5). The (E)-stereochemistry was
assigned on the basis of NOE experiments with the enals in
entries 1 and 2. Although substrates with aryl carbinols
underwent migration to form (E)-trisubstituted enals (Scheme
5), alkyl derivatives resulted in complex mixtures of products
under the conditions examined. This observation is most likely
related to the greater migratory aptitude of aryl groups.31 The
products of these oxidative rearrangements are listed in
Table 2.
(29) Brown, H. C.; Subrahmanyam, C.; Hamaoka, T.; Ravindran, N.; Bowman,
D. H.; Misumi, S.; Unni, M. K.; Somayaji, V.; Bhat, N. G. J. Org. Chem.
1989, 54, 6068.
(30) Brown, H. C.; Hamaoka, T.; Ravindran, N.; Subrahmanyam, C.; Somayaji,
V.; Bhat, N. G. J. Org. Chem. 1989, 54, 6075.
(31) Nakamura, K.; Osamura, Y. J. Am. Chem. Soc. 1993, 115, 9112.
(27) Oppolzer, W.; Radinov, R. N. HelV. Chim. Acta 1992, 75, 170.
(28) Rudolph, J.; Schmidt, F.; Bolm, C. Synthesis 2005, 840.
9
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A R T I C L E S
Li et al.
Scheme 7. Enolization/Oxidation Strategy for the Synthesis of
Scheme 6. Proposed Reaction Pathway for the Stereospecific
Formation of R,â-Unsaturated Aldehydes
R-Hydroxy Ketones
Scheme 8. One-Pot Procedure for the Synthesis of R-Hydroxy
Ketones
A possible reaction pathway for the formation of the enals is
illustrated in Scheme 6. Attack of the NBS on the C-C double
bond forms a bromonium intermediate. A semipinacol-type
rearrangement ensues with migration of the carbinol Ar group,
opening of the bromonium ion, and generation of the aldehyde
after deprotonation. Finally, after bond rotation, we propose a
syn elimination of the boronate ester and the bromide to give
the (E)-enal product. The stereoselective synthesis of R,â-
unsaturated aldehydes represents a challenge due to the ease of
isomerization of the double bond by nucleophiles. As such, these
enals would be difficult to prepare with high selectivity by other
methods.
Table 3. One-Pot Preparation of R-Hydroxy Ketones from
Scheme 8
2.3. One-Pot Synthesis of r-Hydroxy Ketones. The high
isolated yields in the synthesis of B(pin)-substituted allylic
alcohols (Table 1) imply that formation of the 1,1-heterobime-
tallic intermediates and carbonyl additions occur smoothly and
that the intermediates in this process might be suitable for further
elaboration. We were initially attracted to the preparation of
R-hydroxy ketones, which are important intermediates in the
synthesis of natural and non-natural products. The synthesis of
R-hydroxy ketones has been studied,15,33-46 with most methods
based on the oxidation of enolates or their derivatives.35,36,47-51
This approach relies on a regio- and stereoselective enolization,
which may be difficult to achieve (Scheme 7). Moreover, if the
substrate contains pre-existing stereocenters, the facial selectivity
of the oxidation becomes crucial. Alternative approaches entail
the catalytic asymmetric benzoin52-56 and the cross silyl benzoin
condensations.57-59 These reactions are elegant and suitable for
aromatic substrates but give low yields with aliphatic derivatives.
a Five equiv of TBHP as oxidant. b One and one-tenth equiv of BF3‚OEt2
were added at -78 °C, 10 equiv of TBHP were used as oxidant.
We envisioned a one-pot synthesis of R-hydroxy ketones
beginning with hydroboration of B(pin)-substituted alkynes with
dicyclohexylborane, transmetallation to zinc to furnish 1-alkenyl-
1,1-heterobimetallics, and addition to aldehydes (Scheme 8).
The resulting B(pin)-substituted allylic alkoxides are then
subjected to in situ oxidation with tert-butylhydroperoxide
(TBHP) to provide the R-hydroxy ketones. As illustrated in
Table 3, this one-pot procedure was successful. Most substrates
gave higher yields when BF3‚OEt2 was used during the carbonyl
addition (entries 2-6). After optimization, B(pin) alkynes were
converted into R-hydroxy ketones in good yields for the one-
pot 4-step transformation.
(32) Kim, J.-H.; Kulawiec, R. J. J. Org. Chem. 1996, 61, 7656.
(33) Miller, K. M.; Huang, W.-S.; Jamison, T. F. J. Am. Chem. Soc. 2003, 125,
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1109.
Aromatic aldehydes substituted at the 2- or 4-positions
successfully underwent the addition/oxidation procedure to
afford R-hydroxy ketones in 65-83% yield (entries 1-4).
Aliphatic aldehydes, as found in entry 5 and further described
below, were also good substrates for the tandem reaction. In
entry 6, the enyne addition product isomerized under the reaction
and work up conditions to give the conjugated R-hydroxy enone
in lower yield (40%).
(38) Plietker, B.; Niggemann, M. Org. Biomol. Chem. 2004, 2, 2403.
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Ed. 2006, 45, 3492.
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Asymmetry 2004, 15, 2599.
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2005, 7, 61.
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46, 5317.
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Yanagisawa, A. Chem. Lett. 2005, 34, 1590.
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1-Alkenyl-1,1-Heterobimetallics
A R T I C L E S
Scheme 9. Enolization and Oxidation of Benzyl Isopentyl Ketone
11, P ) protecting group) in good yields (77-84%), but with
modest dr (1:3-5, entries 2 and 3, Table 4). Increasing the size
of the protecting group to TBDPS and TIPS gave high dr’s of
1:11 and 1:14, respectively, favoring the expected Felkin
addition products (entries 4 and 5). The stereochemical assign-
ments were based on either X-ray analysis of the major
diastereomer or on 1H NMR studies using the modified Mosher
method62 (see Table footnotes and Supporting Information).
To prepare the diastereomer, enantioenriched R-hydroxy
aldehydes protected with benzyl and PMB groups were exam-
ined. Addition of 1,1-heterobimetallics to benzyl and PMB
protected R-hydroxy aldehydes gave the expected anti-Felkin
or Cram products via chelation control with high dr g 15:1. A
variety of B(pin) alkynes were employed resulting in formation
of R,â-dioxygenated ketones with yields between 70-87%
(entries 6-10). Thus, as outlined in Table 4, our method enables
synthesis of both diastereomeric R,â-dioxygenated ketones with
excellent control over diastereoselectivity (up to 1:14 favoring
Felkin and 20:1 favoring anti-Felkin addition).
Early in our reaction optimization efforts outlined in Table 4
(entry 2), we had occasion to examine the effect of several Lewis
acids on the addition of 1,1-heterobimetallics to silyl protected
R-hydroxy propanals. Surprisingly, addition of the Lewis acid
BF3‚OEt2 resulted in a reversal of the diastereoselectivity (Table
5). In the absence of Lewis acids, addition to the TBS protected
aldehyde provided the Felkin addition product (Table 5, entry
1). In contrast, in toluene or dichloromethane with 1.1-2.5 equiv
of BF3‚OEt2 the anti-Felkin addition products were formed with
6:1 to 20:1 dr (entries 2-5).63 Although diastereoselectivities
were better in dichloromethane, yields were higher in toluene
and with less BF3‚OEt2. In the case of the TBDPS-protected
aldehyde, the dr went from 1:11 favoring Felkin addition in
the absence of BF3‚OEt2 to 1:1 in its presence. The highest dr
in the absence of Lewis acids was with the TIPS derivative,
which furnished product with 1:14 dr favoring Felkin addition
(entry 9). When the addition with the TIPS protected aldehyde
was conducted in the presence of BF3‚OEt2, the anti-Felkin
product was obtained with 8:1 to 20:1 dr (entries 10-13). Thus,
use of the TIPS protected R-hydroxy aldehydes with and without
BF3‚OEt2 enabled synthesis of R,â-dihydroxyketones with dr’s
between 16:1 and 1:14. Such high levels of diastereocontrol
with the same substrate increase the flexibility and attractiveness
of these methods.
Scheme 10. One-Pot Synthesis of sattabacin
The R-hydroxy ketone in Scheme 9, called sattabacin, was
isolated from soil and found to exhibit antiviral properties.60
The generation of this product from benzyl isopentyl ketone
by oxidation would be difficult (Scheme 9) because the
increased acidity of the benzylic hydrogens and the higher
thermodynamic stability of the resulting enolate favors the
formation of the isomeric product. Using our 1,1-heterobime-
tallics, sattabacin was obtained with high yield (84%) in a one-
pot procedure (Scheme 10).
Overall, our procedure for the synthesis of R-hydroxy ketones
represents a significant improvement over previous methods,
because it is not necessary to isolate or purify the intermediates
and the entire procedure can be conveniently conducted in a
single reaction vessel. These promising results inspired us to
develop methods for the addition of 1,1-heterobimetallic reagents
to chiral aldehydes to prepare highly oxygenated enantioenriched
building blocks that would be of value in natural product
synthesis.
2.4. Diastereoselective Additions of 1-Alkenyl-1,1-hetero-
bimetallic Reagents to Chiral Aldehydes. Diastereoselective
C-C bond-forming reactions are crucial to the successful
elaboration of intermediates in natural product synthesis. Toward
our goal of developing synthetically useful 1,1-heterobimetallic
reagents, we next focused on stereoselective additions of
1-alkenyl-1,1-heterobimetallic reagents to chiral aldehydes bear-
ing protected R- or â-hydroxy groups that permit chelation, such
as benzyl, or that traditionally disfavor chelation, such as
trialkylsilyl.
2.4.1. Diastereoselective Additions to Chiral Propanals.
Treatment of racemic 2-phenyl-propionaldehyde with our boron/
zinc 1,1-heterobimetallic reagent followed by oxidation with
TBHP resulted in formation of the R-hydroxy ketone in 72%
yield with 1:6 dr (Scheme 8 above, Table 4, entry 1). In this
case, the stereochemistry has not been determined, but the
reaction is assumed to proceed by Felkin addition to give the
predicted product.61
The unexpected diastereofacial selectivities in Table 5 are
not consistent with current models used to predict diastereose-
lectivity in additions to silyl-protected R-hydroxy aldehydes.
First, monodentate Lewis acids, such as BF3‚OEt2, are expected
to increase the proportion of Felkin addition product, exactly
the opposite of our observations (Table 5). Furthermore,
although there are some examples of silyl-protected R-hydroxy
aldehydes that do undergo chelation controlled addition reac-
tions,64,65 the silyl groups in these reports are significantly
smaller than TIPS, such as TMS and TBS. Chelation controlled
addition to these substrates, however, is observed with Lewis
acids possessing two open coordination sites.
Chiral aldehydes with R- or â-hydroxy groups are among
the most useful substrates for the synthesis of polyhydroxylated
products. The enantioenriched TBS protected R-hydroxy alde-
hyde gave syn-products derived from Felkin addition (Scheme
(62) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc.
1991, 113, 4092.
(63) Jeon, S.-J.; Fisher, E. L.; Carroll, P. J.; Walsh, P. J. J. Am. Chem. Soc.
2006, 128, 9618.
(64) Chen, X.; Hortelano, E. R.; Eliel, E. L. J. Am. Chem. Soc. 1990, 112, 6130.
(65) Chen, X.; Hortelano, E. R.; Eliel, E. L.; Frye, S. V. J. Am. Chem. Soc.
1992, 114, 1778.
(60) Lampis, G.; Deidda, D.; Maullu, C.; Madeddu, M. A.; Pompei, R.; Delle
Monache, F.; Satta, G. J. Antibiot. 1995, 48, 967.
(61) Spino, C.; Granger, M.-C.; Tremblay, M.-C. Org. Lett. 2002, 4, 4735.
9
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A R T I C L E S
Li et al.
Table 4. Diastereoselective Addition of 1,1-Heterobimetallic Complexes to Chiral Aldehydes from Scheme 11
a Absolute configurations of products were determined by X-ray crystallography. b Absolute configurations of products were determined by analysis of
1
the Mosher esters. c Anti-Felkin:Felkin; determined by H NMR. d Isolated yield.
Scheme 11. Diastereoselective Additions of 1,1-Heterobimetallics
to Protected R-Hydroxy Propanals
observed in Table 5. Studies to shed light on the origin of
stereoselectivity in these reactions are ongoing in our laboratory.
2.4.2. Diastereoselective Additions to Protected â-Hydroxy
Propanals. Chiral protected â-hydroxy aldehydes are useful
precursors in synthesis because the product 1,3-diol is a common
structural motif in natural products. Chelation-controlled addi-
tions to these substrates are more challenging, because the
additional carbon separating the carbonyl and protected hydroxyl
makes chelation less favorable. The similarity in size of the
R-substituents also reduces diastereoselectivity in Felkin addi-
tions. The most difficult substrates in this class, however, are
those that are protected with bulky silyl groups, which disfavor
chelation due to the reduced propensity of such silyl ethers to
bind to Lewis acids.
Our initial efforts focused on addition of 1,1-heterobimetallics
to benzyl protected â-hydroxy aldehydes (Scheme 13) with the
goal of controlling diastereoselectivity through chelation. In the
absence of additional Lewis acids, the dr of the R-hydroxy
ketone product was very low (1.5:1, entry 1, Table 6) favoring
anti-Felkin addition. Lewis acids with the potential to chelate,
such as ZnBr2, MgBr2, and AlMe2Cl, resulted in formation of
Examples of chelation-controlled additions have been reported
by Evans and co-workers employing AlMe2Cl and AlMeCl2,
which have a single open coordination site but can undergo
chloride abstraction to generate a chelating cationic Lewis acid
(Scheme 12).66 Similar behavior was not observed with BF3‚
OEt2 under the Evans conditions, however. A halide abstraction
mechanism analogous to the aluminum system has been
proposed by Crimmins with TiCl4 and a tridentate substrate.67,68
At this time, we do not have sufficient experimental evidence
to introduce a model to explain the unexpected Lewis acid effect
(66) Evans, D. A.; Allison, B. D.; Yang, M. G.; Masse, C. E. J. Am. Chem.
Soc. 2001, 123, 10840.
(67) Crimmins, M. T.; King, B. W.; Tabet, E. A. J. Am. Chem. Soc. 1997, 119,
7883.
(68) Crimmins, M. T.; McDougall, P. J. Org. Lett. 2003, 5, 591.
9
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1-Alkenyl-1,1-Heterobimetallics
A R T I C L E S
Table 5. Examination of the Effect of BF3‚OEt2 on the Diastereomeric Ratio in the Addition of 1,1-Heterobimetallics to Silyl Protected
R-Hydroxy Propanals
a Anti-Felkin:Felkin.
Scheme 12. Chelation-Controlled Addition Model Proposed by Evans and Co-workers
Scheme 13. Diastereoselective Addition of 1,1-Bimetallics to
Protected â-Hydroxy Aldehydes
We next examined the challenging chiral TBS-protected
â-hydroxy aldehydes. Employing B(pin) alkynes, unacceptably
low dr’s (∼1:2) were obtained in the absence of Lewis acids
and in the presence of ZnBr2 or BF3•OEt2 (entries 1-3, Table
7). We next examined the size of the boron-containing group
on the alkyne (BX2 in Table 7), because it is known that
changing the size of the nucleophile impacts diastereoselectivity.
Thus, we examined the use of boron alkynes based on
1,3-propane diol, 9-BBN, and isopropoxide. In this study, it was
the chelation-controlled addition products with dr’s as high as
found that the bulky diisopropoxy boronate ester exhibited high
dr (11:1) favoring the anti-Felkin addition product (entry 10).
6:1 (entries 2-4, Table 6). We were again surprised and gratified
to find that addition of BF3‚OEt2 resulted in excellent control
of the diastereoselectivity, with the anti-Felkin product formed
in 93% yield with a dr of 20:1 (entry 5). Similar dr’s were
obtained with other B(pin) alkynes (entries 6 and 7).
The high diastereofacial selectivities observed with both
benzyl and TBS protected â-hydroxy aldehydes in the presence
of BF3‚OEt2 are surprising because BF3‚OEt2 is considered to
9
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A R T I C L E S
Li et al.
Table 6. Optimization of 1,1-Heterobimetallic Addition to Benzyl Protected â-Hydroxy Aldehydes
1
a Absolute configurations of products were determined by X-ray crystallography. b Anti-Felkin:Felkin; determined based on H NMR analysis. c Yields
not determined in reactions that gave low dr. Yields listed are isolated.
Table 7. Optimization of 1,1-Heterobimetallic Addition to
TBS-Protected â-Hydroxy Aldehydes
aldehyde carbonyl group. When the dipole interactions are
greater than the cost of attack of the nucleophile over the
medium size group on the R-carbon (methyl), anti-Felkin
addition products are obtained. This model, however, cannot
be used to explain our results, because there is no â-stereocenter
on our substrates. Thus, the dipole interactions can be minimized
in conformations leading to both the Felkin and anti-Felkin
addition pathways using the Evans model (Scheme 14).
One speculative reaction pathway to rationalize the highly
diastereoselective formation of anti-Felkin addition products in
Table 7 involves binding of BF3 to the carbonyl followed by
removal of one of the fluorides by a second molecule of BF3 to
give a chelating boron species, as outlined in Scheme 15.71-73
As mentioned earlier, a somewhat related mechanism has been
proposed by Crimmins in the diastereoselective aldol reaction
67,68
in the presence of excess TiCl4
and by Evans in the aldol
and allyl additions to â-alkoxy aldehydes promoted by dim-
ethylaluminum chloride and methylaluminum dichloride.66,74,75
We do not currently have experimental evidence for or against
this model but note that it does serve to predict the observed
stereochemistry in Table 7.
The high diastereoselectivities obtained with both R- and
â-hydroxy aldehydes in Tables 4-7 indicate that the 1-alkenyl-
1,1-heterobimetallic intermediates outlined herein have signifi-
cant potential utility in the stereoselective formation of C-C
bonds.
a Anti-Felkin:Felkin. b Yields not determined in reactions that gave low
dr. Yields listed are isolated.
2.5. One-Pot Tandem Carbonyl Additions/Cross-Coupling
Reactions. Vinyl boronate esters are useful substrates for a
variety of transformations, most notably Suzuki cross-coupling
reactions.18,76,77 With this in mind, we explored the possibility
be a monodentate Lewis acid. Excellent models have been
proposed by Evans to rationalize the observation of anti-Felkin
addition products with protected R,â-disubstituted â-hydroxy
aldehydes.69,70 In these cases, the conformation of the aldehyde
is controlled by the dipole interactions between the Lewis acid-
bound carbonyl group and the protected â-hydroxy group
(Scheme 14). The larger R group of the â-stereocenter is situated
in the least sterically hindered position, oriented away from the
(71) Reetz, M. T.; Kesseler, K.; Jung, A. Tetrahedron Lett. 1984, 25, 729.
(72) Reetz, M. T.; Sauerwald, M. J. Org. Chem. 1984, 49, 2292.
(73) Reetz, M. T. Angew. Chem., Int. Ed. 1984, 23, 556.
(74) Evans, D. A.; Allison, B. D.; Yang, M. G. Tetrahedron Lett. 1999, 40,
4457.
(75) Evans, D. A.; Halstead, D. P.; Allison, B. D. Tetrahedron Lett. 1999, 40,
4461.
(69) Evans, D. A.; Dart, M. J.; Duffy, J. L.; Yang, M. G. J. Am. Chem. Soc.
1996, 118, 4322.
(70) Evans, D. A.; Duffy, J. L.; Dart, M. J. Tetrahedron Lett. 1994, 35, 8537.
(76) Miyaura, N.; Yamada, K.; Suginome, H.; Suzuki, A. J. Am. Chem. Soc.
1985, 107, 972.
(77) Miyaura, N.; Satoh, M.; Suzuki, A. Tetrahedron Lett. 1986, 27, 3745.
9
3528 J. AM. CHEM. SOC. VOL. 130, NO. 11, 2008

1-Alkenyl-1,1-Heterobimetallics
A R T I C L E S
Scheme 14. Evans Model for Additions to R,â-Disubstituted â-Hydroxy Aldehydes (Above) and Application of This Model to the Results in
Table 7 (Below)
Scheme 15. Possible Reaction Pathway to Rationalize the
Observed anti-Felkin Addition Products in Table 7
Table 8. Tandem Addition/Cross-Coupling Reaction of
1-Alkenyl-1,1-heterobimetallics to Generate Functionalized Allylic
Alcohols from Scheme 16
Scheme 16. One-Pot Addition/Cross-Coupling Reaction to
Generate Functionalized Allylic Alcohols (Table 8)
of tandem reactions involving initial carbonyl addition of the
Zn-C bond, followed by subsequent palladium-mediated cross-
coupling of the B-C bond.
formation of the enyne product in 65% yield in the one-pot
procedure. The enone 2-iodo-2-cyclohexenone underwent cou-
pling to give the dienone product with 66% yield (entry 5). The
results in Table 8 indicate that the 1-alkenyl-1,1-heterobimetallic
species generated in the carbonyl additions can be easily
employed in further C-C bond-forming reactions.
As outlined in Scheme 16, steps 1-3 are identical to the
synthesis of B(pin) allylic alcohols (Scheme 4). After completion
of the carbonyl addition step, Pd(OAc)2 (5 mol %), PPh3 (10
mol %), Cs2CO3 (3 equiv), and the coupling partner were added.
The reactions were heated to reflux and the progress followed
by TLC. When product formation ceased, the reactions were
quenched and subjected to column chromatography on silica
gel. The results are presented in Table 8.
The intermediate allylic alkoxy boronate esters were found
to undergo coupling with a variety of vinyl and aryl halides.
For example, coupling with 2-bromopropene resulted in forma-
tion of the dienol product with 82% yield (entry 1). Iodobenzene
also proved to be a successful coupling partner for vinyl and
dienyl boronate esters, generating allylic alcohol and dienol
products in 90 and 84% yield, respectively (entries 2 and 3).
Use of 1-bromohexyne in the Suzuki reaction resulted in
3. Summary and Outlook
We have introduced a straightforward and reliable method
for the generation of 1-alkenyl-1,1-heterobimetallic species
based on hydroboration of readily available B(pin)-substituted
alkynes with dicyclohexylborane. The resulting 1-alkenyl-1,1-
diboro intermediates are used in situ. The B-vinyl bond of the
dicyclohexyl alkenyl borane undergoes rapid and chemoselective
transmetallation with the dialkylzinc reagents to generate 1,1-
heterobimetallic complexes. These boron/zinc heterobimetallics
undergo addition of the more reactive Zn-C bonds to aldehydes
to generate the key B(pin)-substituted alkoxide intermediates.
Simple protonation furnishes B(pin)-substituted allylic alcohols
9
J. AM. CHEM. SOC. VOL. 130, NO. 11, 2008 3529

A R T I C L E S
Li et al.
dioxaborolane (0.60 mmol), and the reaction mixture was stirred for
30 min at rt, after which it was homogeneous. The reaction mixture
was cooled to -78 °C and treated with Me2Zn (0.30 mL, 2.0 M in
toluene, 0.60 mmol) for 30 min. The solution was then warmed to -10
°C, and an aldehyde (0.50 mmol) was added. The reaction mixture
was stirred at -10 °C until TLC showed complete consumption of the
aldehyde. The reaction mixture was diluted with EtOAc (4 mL),
quenched with H2O (2 mL), extracted with EtOAc (3 × 40 mL), dried
over MgSO4, and concentrated. The residue was purified by flash
chromatography on silica gel.
Preparation of 1-Phenyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaboro-
lan-2-yl)-hept-2-en-1-ol (entry 1, Table 1). The product was prepared
by General Procedure A using benzaldehyde (51 µL, 0.5 mmol), 2-hex-
1-ynyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (125 mg, 0.6 mmol).
The crude product was purified by flash column chromatograghy on
silica gel (hexanes/EtOAc, 96:4) as an oil (81% yield). 1H NMR (CDCl3,
500 MHz) δ 0.86 (t, J ) 7.2 Hz, 3H), 1.03 (s, 6H), 1.09 (s, 6H), 1.29-
1.37 (m, 4H), 2.32-2.36 (m, 2H), 3.02 (s, 1H), 5.11 (br, 1H), 6.22 (t,
J ) 7.5 Hz, 1H), 7.12-7.15 (m, 1H), 7.21-7.24 (m, 2H), 7.29-7.31
(m, 2H) ppm; 13C{1H} NMR (CDCl3, 125 MHz) δ 14.1, 22.5, 24.5,
25.0, 30.9, 32.1, 79.1, 83.5, 126.4, 126.9, 128.1, 144.8, 148.2 ppm;
11B NMR (CDCl3, 128 MHz) 27.7 ppm; IR (neat) 1449, 1603, 1635,
2859, 3029, 3454 cm-1; HRMS m/z 299.2172 [(M-OH)+; calcd for
C19H28BO2: 299.2183].
in high isolated yield. Treatment of isolated B(pin)-substituted
allylic alcohols with NBS induces a novel semipinacol-type
rearrangement to form (E)-trisubstituted R,â-unsaturated alde-
hydes with excellent control over the stereochemistry of the
double bond. The aldehyde products prepared by this procedure
would be challenging to synthesize by other methods.
The B(pin)-substituted allylic alkoxides formed in situ can
be treated with TBHP to afford R-hydroxy ketones in high
yields. When enantioenriched protected R- or â-hydroxy alde-
hydes are employed, the diastereoselectivity can be controlled
by the proper choice of protecting group and by addition of
Lewis acids. For example, with TIPS protected 2-hydroxypro-
panal, the Felkin addition product can be obtained with 14:1
dr. Addition of BF3‚OEt2, however, results in a reversal of
diastereoselectivity with the anti-Felkin product formed in 16:1
dr. As expected, benzyl protected R-hydroxy aldehydes provide
the anti-Felkin products via chelation control in 70-87% yield
with >15:1 dr. Benzyl-protected â-hydroxy aldehydes also lead
to anti-Felkin products with excellent dr (>20:1) in the presence
of BF3‚OEt2. Thus, with protected R- or â-hydroxy aldehydes,
three of the four possible diastereomers have been prepared with
good to excellent control over the diastereoselectivity.
General Procedure B: Synthesis of (E)-Trisubstituted r,â-
Unsaturated Aldehydes. To the solution of B(pin)-substituted allylic
alcohol in 2 mL of CH3CN/1 mL of H2O was added slowly NBS
(N-bromosuccinimide) in 2 mL CH3CN at rt. The reaction mixture was
stirred for 10 h, or until TLC showed complete consumption of starting
material. The volatile materials were evaporated under reduced pressure.
Next, water was added (4 mL), the solution was extracted with EtOAc
(3 × 40 mL), and the combined organic layer was dried over MgSO4
and concentrated. The residue was purified by flash chromatography
on silica gel.
Finally, we have advanced a one-pot procedure wherein
B(pin)-substituted allylic alkoxides formed in situ can be directly
employed in Suzuki cross-coupling reactions with vinyl, phenyl,
and alkynyl halides to provide functionalized allylic alcohols
and dienols with good yields. Our tandem reaction allows rapid
construction of a variety of densely functionalized synthetic
intermediates from readily available precursors. These products
would be difficult to prepare in an efficient manner using other
methods. We anticipate that the ease of generation, the versatil-
ity, and the mild nature of our 1,1-heterobimetallic species will
make them useful in the synthesis of a wide range of natural
and unnatural products.
Preparation of (E)-2-Phenyl-hept-2-enal (Entry 2, Table 2). The
product was prepared by General Procedure B using 1-phenyl-2-
(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-hept-2-en-1-ol (84 mg,
0.265 mmol) and NBS (47 mg, 0.265 mmol). The crude product was
purified by flash column chromatograghy on regular silica gel (hexanes/
Experimental Section
1
EtOAc, 97:3) as an oil (74% yield). H NMR (CDCl3, 500 MHz) δ
General Methods. All reactions were carried out under a nitrogen
atmosphere with oven-dried glassware. All manipulations involving
dicyclohexylborane and dimethylzinc were carried out under an inert
atmosphere in a Vacuum Atmospheres drybox with an attached MO-
40 Dritrain or by using standard Schlenk or vacuum line techniques.
All chemicals were obtained from Aldrich, Acros, or GFS Chemicals
unless otherwise specified. All solvents were purchased from Fischer
Scientific. Toluene, dichloromethane, diethyl ether, and hexanes were
dried through activated alumina columns. All liquid substrates were
distilled prior to use. Dimethylzinc (1.0 or 2.0 M in toluene) was
prepared and stored in a Vacuum Atmospheres drybox. NMR spectra
were obtained on a Bru¨ker 300, 400, or 500 MHz Fourier transform
spectrometer at the University of Pennsylvania NMR facility. 13C{1H}
NMR spectra were referenced to residual solvent. 11B NMR spectra
were referenced to BF3‚OEt2. The infrared spectra were obtained using
a Perkin-Elmer 1600 series spectrometer. Thin-layer chromatography
was performed on Whatman precoated silica gel 60 F-254 plates and
visualized by ultraviolet light or by staining with cerric ammonium
molybdate or phosphomolybdic acid solutions. Silica gel (230-400
mesh, Silicycle) was used for air-flashed chromatography.
0.90 (t, J ) 7.3 Hz, 3H), 1.32-1.39 (m, 2H), 1.49-1.54 (m, 2H), 2.35-
2.42 (td, J ) 7.5, 7.5 Hz, 2H), 6.75 (t, J ) 7.5 Hz, 1H), 7.16-7.20
(m, 2H), 7.36-7.42 (m, 3H), 9.64 (s, 1H) ppm; 13C{1H} NMR (CDCl3,
125 MHz) δ 14.2, 22.8, 29.9, 31.3, 128.3, 128.6, 129.8, 144.4, 156.9,
194.1 ppm; NOE NMR (CDCl3, 500 MHz); IR (neat) 1450, 1600, 1694,
2872, 2960, 3060 cm-1; HRMS-CI m/z 188.1196 [M+; calcd for
C13H16O: 188.1201].
General Procedure C: Synthesis of r-Hydroxy Ketones in One-
Pot. To a suspension of HBCy2 (155 mg, 0.60 mmol) in toluene (2.0
mL) under N2 was added alkyne-4,4,5,5-tetramethyl-[1,3,2]dioxaboro-
lane (0.60 mmol) and the reaction mixture was stirred for 30 min at rt,
after which it was homogeneous. The reaction mixture was cooled to
-78 °C and treated with Me2Zn (0.30 mL, 2.0 M in toluene, 0.60 mmol)
for 30 min. The solution was then warmed to -10 °C, and an aldehyde
(0.50 mmol) was added. The reaction mixture was stirred at -10 °C
until TLC showed complete consumption of the aldehyde. TBHP
(0.27-0.45 mL, 5.5 M in octane, 1.5-2.5 mmol) was added slowly
into the reaction solution. The reaction was stirred at 0 °C for 20-40
h. The reaction mixture was diluted with EtOAc (4 mL), quenched
with H2O (2 mL), extracted with EtOAc (3 × 40 mL), dried over
B(pin)-substituted alkynes19,22,23,78 and chiral aldehydes were prepared
by literature methods.79-83
(79) Takai, K.; Heathcock, C. H. J. Org. Chem. 1985, 50, 3247.
(80) Ireland, R. E.; Thaisrivongs, S.; Dussault, P. H. J. Am. Chem. Soc. 1988,
110, 5678.
(81) Roush, W. R.; Palkowitz, A. D.; Ando, K. J. Am. Chem. Soc. 1990, 112,
6348.
(82) Yu, W.; Zhang, Y.; Jin, Z. Org. Lett. 2001, 3, 1447.
(83) Kelly, T. R.; Kaul, P. N. J. Org. Chem. 1983, 48, 2775.
General Procedure A: Preparation of B(pin)-Substituted Allylic
Alcohols. To a suspension of HBCy2 (107 mg, 0.60 mmol) in toluene
(2.0 mL) under N2 was added alkyne-4,4,5,5-tetramethyl-[1,3,2]-
(78) Brown, H. C.; Sinclair, J. A. J. Organomet. Chem. 1977, 131, 163.
9
3530 J. AM. CHEM. SOC. VOL. 130, NO. 11, 2008

1-Alkenyl-1,1-Heterobimetallics
A R T I C L E S
MgSO4, and concentrated. The residue was purified by flash chroma-
tography on deactivated silica gel (Et3N/SiO2 ) 2.5% V/V).
reaction mixture was stirred at -10 °C until TLC showed complete
consumption of the aldehyde. The volatile materials were evaporated
under reduced pressure followed by the addition of 2 mL of THF/H2O
(10:1) at 0 °C. The resulting solution was stirred for 5 min, and Pd-
(OAc)2 (4.5 mg, 5 mol %), PPh3 (11 mg, 10 mol %), RX (2.0 equiv,
0.8 mmol), and Cs2CO3 (391 mg, 1.2 mmol, 3 equiv) were added. The
reaction mixture was then refluxed at 75 °C for 10 h. The resulting
solution was diluted with water (2 mL) and extracted with EtOAc (3
× 40 mL). The combined organic layer was washed with brine, dried
over MgSO4, and concentrated under reduced pressure. The remaining
residue was purified by flash chromatography on silica gel.
Preparation of 2-Isopropenyl-1-phenyl-hept-2-en-1-ol (Entry 3,
Table 8). The product was prepared by General Procedure F using
benzaldehyde (51 µL, 0.5 mmol), 2-hex-1-ynyl-4,4,5,5-tetramethyl-
[1,3,2]dioxaborolane (125 mg, 0.60 mmol), and 2-bromopropene (89
µL, 1.0 mmol). The crude product was purified by flash column
chromatography on silica gel (hexanes/EtOAc, 97:3) to give the title
compound as an oil (84% yield). 1H NMR (CDCl3, 500 MHz) δ 0.82-
0.85 (t, J ) 6.9 Hz, 3H), 1.21-1.32 (m, 4H), 1.55 (s, 3H), 1.97-2.04
(m, 2H+1OH), 4.54 (s, 1H), 4.94 (s, 1H), 5.16 (s, 1H), 5.44-5.47 (t,
J ) 7.3 Hz, 1H), 7.17-7.20 (m, 1H), 7.24-7.30 (m, 4H) ppm; 13C-
{1H} NMR (CDCl3, 125 MHz) δ 14.2, 22.6, 23.9, 28.6, 32.3, 77.0,
115.9, 126.8, 127.5, 127.8, 128.3, 142.6, 142.8, 144.8 ppm; IR (neat)
1452, 1494, 1628, 2856, 2926, 2958, 3029, 3400 cm-1; HRMS-CI m/z
212.1562 [(M-H2O)+; calcd for C16H20: 212.1566].
General Procedure D: Synthesis of r-Hydroxy Ketones with
BF3‚OEt2. To a suspension of HBCy2 (64 mg, 0.36 mmol) in toluene
(2.0 mL) under N2 was added alkyne-4,4,5,5-tetramethyl-[1,3,2]-
dioxaborolane (0.36 mmol), and the reaction mixture was stirred for
30 min at rt, after which it was homogeneous. The reaction mixture
was cooled to -78 °C and treated with Me2Zn (0.18 mL, 2.0 M in
toluene, 0.36 mmol) for 30 min. BF3‚OEt2 (1.1 or 2.5 equiv) was then
added to the reaction mixture at -78 °C, followed by the aldehyde
(0.30 mmol). The reaction mixture was warmed to -40 °C and stirred
between -40 and -20 °C until TLC showed complete consumption
of the aldehyde. TBHP (0.54 mL, 5.5 M in octane, 3.0 mmol) was
added into the reaction mixture. The solution was stirred at 0 °C for
20-40 h. Workup is the same as in General Procedure C.
General Procedure E: Synthesis of r-Hydroxy Ketones with BF3‚
OEt2. To a suspension of HBCy2 (64 mg, 0.36 mmol) in toluene (2.0
mL) under N2 was added alkyne-4,4,5,5-tetramethyl-[1,3,2] dioxaboro-
lane (0.36 mmol), and the reaction mixture was stirred for 30 min at
rt, after which it was homogeneous. The reaction mixture was cooled
to -78 °C and treated with Me2Zn (0.18 mL, 2.0 M in toluene, 0.36
mmol) for 30 min. In a separate flask, the aldehyde (0.30 mmol) and
BF3‚OEt2 (1.1 or 2.5 equiv) were premixed at -78 °C and for 2 min
in 1 mL toluene, then transferred to the Schlenk flask that contained
vinylzinc at -78 °C. The reaction mixture was warmed to -40 °C
and stirred between -40 and -20 °C until TLC showed complete
consumption of the aldehyde. TBHP (0.54 mL, 5.5 M in octane, 3.0
mmol) was added into the reaction solution. The reaction was stirred
at 0 °C for 20-40 h. Workup is the same as in General Procedure C.
General Procedure F: Synthesis of Trisubstituted Allylic Alco-
hols in One-Pot. To a suspension of HBCy2 (86 mg, 0.48 mmol) in
toluene (2.0 mL) under N2 was added 2-hex-1-ynyl-4,4,5,5-tetramethyl-
[1,3,2]dioxaborolane (100 mg, 0.48 mmol), and the reaction mixture
was stirred for 30 min at rt, after which it was homogeneous. The
reaction mixture was cooled to -78 °C and treated with Me2Zn (0.30
mL, 2.0 M in toluene, 0.60 mmol) for 30 min. The solution was then
warmed to -10 °C, and the aldehyde (0.50 mmol) was added. The
Acknowledgment. We thank the NIH (National Institute of
General Medical Sciences, GM58101) and NSF (CHE-065210)
for support of this work. We are also grateful to Akzo Nobel
Polymer Chemicals for a gift of dialkylzinc reagents.
Supporting Information Available: Procedures and full
characterization, stereochemical assignments, and X-ray deter-
minations of new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
JA077664U
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J. AM. CHEM. SOC. VOL. 130, NO. 11, 2008 3531