Pd-catalyzed three-component reaction of 3-(Pinacolatoboryl)ally acetates, aldehydes, and organoboranes: A new entry to stereoselective synthesis of (Z)- anti -homoallylic alcohols

Article abstract of DOI:10.1021/acs.orglett.5b01244

The Pd-catalyzed three-component reaction of 3-(pinacolatoboryl)allyl acetates, aldehydes, and organoboranes is described. The reaction is initiated by the formation of an allylic gem-palladium/boryl intermediate, which then undergoes allylation of aldehydes by allylboronates followed by a coupling reaction of in situ generated (Z)-vinylpalladium acetates with organoboranes to provide the (Z)-anti-homoallylic alcohols with high levels of diastereoselectivity and alkene stereocontrol.

Full text of DOI:10.1021/acs.orglett.5b01244

Letter
pubs.acs.org/OrgLett
Pd-Catalyzed Three-Component Reaction of 3‑(Pinacolatoboryl)ally
Acetates, Aldehydes, and Organoboranes: A New Entry to
Stereoselective Synthesis of (Z)-anti-Homoallylic Alcohols
Yoshikazu Horino,* Ataru Aimono, and Hitoshi Abe
Department of Applied Chemistry, Graduate School of Science and Engineering, University of Toyama, Gofuku, Toyama 930-8555,
Japan
S
* Supporting Information
ABSTRACT: The Pd-catalyzed three-component reaction of 3-(pinacolatoboryl)allyl acetates, aldehydes, and organoboranes is
described. The reaction is initiated by the formation of an allylic gem-palladium/boryl intermediate, which then undergoes
allylation of aldehydes by allylboronates followed by a coupling reaction of in situ generated (Z)-vinylpalladium acetates with
organoboranes to provide the (Z)-anti-homoallylic alcohols with high levels of diastereoselectivity and alkene stereocontrol.
rgano-gem-sp3-heterobimetallic reagents have appeared to
Scheme 1. Utilization of Allylic gem-Palladium/Metalloid
Intermediates
Oenhance the synthetic application of C−C bond forming
reactions and opened the facile synthetic route to many
molecular constructions in single-step reactions.1 In general,
these methods require more than the stoichiometric amount of
metal reagents and additional steps to install two different types
of metal at geminal positions in advance. Moreover, most of the
C−C bond-forming reactions are limited to nucleophilic
reaction. Recently, Fillion et al. demonstrated the unique
reactivities of organo-gem-sp3-transition metal/main-group
metal intermediates for the C−C bond-forming reactions.2
They pioneered the cyclopropanation of strained alkenes and
dimerization reactions starting from organostannatranes, and
1,2-alkyl migration from organoalanes. In addition to these
advancements, however, synthetic applications of organo-gem-
sp3-transition metal/metalloid intermediates utilizing two differ-
ent types of C−C bond forming reactions in a single synthetic-
step operation have rarely been exploited. In our recent studies,
tolerant of functional groups.6 Moreover, this method provides
we demonstrated the distinct reactivities of allylic gem-
(Z)-anti-homoallylic alcohols, with high stereoselectivity, that
cannot be easily accessed by known catalytic conditions.7,8
To demonstrate our hypothesis, we initially examined the
reaction of 1-phenyl-3-(pinacolatoboryl)allyl acetate (1a) and
benzaldehyde (2a) in the presence of catalytic amounts of
Pd(OAc)2 and Ph3P (Scheme 2). As we expected, 4-acetoxy
homoallylic alcohol 3 was obtained in 42% yield as a mixture of
(Z)-anti-3 and (E)-anti-3 (Z/E = 11/1). Encouraged by this
result, we selected triethylborane as a coupling partner and
performed the reaction under similar reaction conditions.
The three-component reaction proceeded as designed, and the
corresponding (Z)-anti-homoallylic alcohol 4aa was obtained in
good yield along with 5aa. Notably, allylation of aldehydes with
palladium/metalloid intermediates that could serve as C3 units
in reactions other than allylation reactions. For example, we have
reported the stereoselective cyclopropanation of strained alkenes
by the Pd-catalyzed reaction of 1 (Scheme 1).3 Furthermore, a
Pd-stabilized vinylcarbene intermediate B was formed from A,
and it can be used in the carbene dimerization.4 We envisaged
that an allylboronate generated during the formation of an allylic
gem-palladium/boryl intermediate C would initially undergo
nucleophilic allylation toward an electrophile if an appropriate
electrophile is present,5 possibly resulting in the formation of a
(Z)-vinylpalladium acetate intermediate D that potentially
undergoes further coupling reaction. Herein, we report the Pd-
catalyzed three-component reaction of 3-(pinacolatoboryl)allyl
acetates, aldehydes, and organoboranes; this reaction involves
Suzuki−Miyaura-type vinyl−alkyl and vinyl−aryl coupling
reactions under neutral conditions that make it even more
Received: April 28, 2015
Published: May 21, 2015
© 2015 American Chemical Society
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Letter
Scheme 2. Initial Studies for Palladium-Catalyzed Three-
Component Reaction
Scheme 4. Palladium-Catalyzed Three-Component Reaction
of 1a, Cinnamaldehydes, and Triethylborane
a
Scheme 5. Substrate Screening
a
Scheme 3. Reaction Scope of Aldehydes
a
The ratio of compounds 4 and 5 was determined by NMR analysis of
the crude mixtures.
Furthermore, not only aromatic aldehydes but also aliphatic
aldehydes participated in the present reaction to afford the
corresponding products 4aq−4as in good yields. A beneficial
effect on the chemical yield of 4ar was observed when AcOK was
added. However, this effect was limited to product 4ar.10
Moreover, the reaction of (E)-2t also proceeded smoothly to
provide 4at in good yield with modest diastereoselectivity
(Scheme 4). On the other hand, when (Z)-2t was subjected to
the reaction, the reaction time required to achieve full conversion
was longer than that required by (E)-2t and provided 4at in good
yield. This reaction probably proceeded after isomerization of
(Z)-2t to (E)-2t because (Z)-2t was recovered as (E)-2t after the
reaction.
To demonstrate the scope of the present reactions,
substituents at the C1 position of 1 were surveyed under
optimized reaction conditions (Scheme 5). It was found that the
reaction proceeded smoothly irrespective of the electronic nature
of the substituent on the aromatic ring to give 4ba−4ja in good
yields with high diastereoselectivity and complete alkene
stereocontrol. With respect to the isopropyl-substituted
substrate 1k, the reaction proceeded smoothly to provide 4ka
in moderate yield; a mixture of a stereoisomer of alkene geometry
and the β-hydride elimination product of 1k was obtained in 25%
yield. We subsequently reacted 1 with benzaldehyde (2a) and
various organoboranes to demonstrate the generality of the
coupling reaction (Scheme 6). The scope with respect to the tri-
n-alkylboranes was demonstrated to be fairly broad. For example,
tri-n-alkylboranes prepared from styrene, 4-methoxystyrene,
allylbenzene, and 1-hexene with the BH3·SMe2 complex nicely
participated in the coupling reaction to give 6a−6d, respectively,
in good yields with excellent stereoselectivity. In addition, a
commercially available tri-n-butylborane also underwent a cross-
coupling reaction to afford 6e in 55% yield. Although trace
a
Reaction conditions: 1 (0.5 mmol), 2a (1.2 mmol), (R3)3B (1.2
mmol), Pd(OAc)2 (5 mol %), and CyPh2P (10 mol %) in THF at 50
°C. The ratio of compounds 4 and 5 was determined by NMR analysis
of the crude mixtures. 3.6 equiv of Et3B were used. Pd2(dba)3CHCl3
(2.5 mol %), (o-tol)3P (10 mol %), AcOK (2.4 equiv), and toluene as a
solvent were used.
b
c
α-substituted allyl/crotylboronates often gives low E/Z
selectivity.8,9
Under optimized reaction conditions,10 the scope of various
aldehydes was examined (Scheme 3). The reaction of 1a and
triethylborane with electron-rich and -deficient aromatic
aldehydes gave 4ab−4ag and 4aj, respectively, in good to high
yields with high levels of diastereoselectivity and complete alkene
stereocontrol. In addition, bromo-substituted benzaldehydes
were also suitable electrophiles for the reaction, affording 4ah
and 4ai in good yields. Notably, 3- and 4-hydroxybenzaldehydes
were utilized without prior protection of the hydroxyl group,
although 3.6 equiv of Et3B were required to achieve satisfactory
reaction progress. Furthermore, the present reaction was also
effective for the heterocyclic aldehydes, such as pyridyl-, furyl-,
and thienyl-substituted heterocyclic aldehydes, giving 4am−4ap
in good yields. In this case, poor diastereoselectivity was
observed when the 4-pyridinecarboxaldehyde was employed.
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a
Scheme 6. Reaction Scope of Organoboranes
Scheme 8. A Plausible Reaction Mechanism
mediated transformations. In addition, alkenylboronate 1m that
introduced stereogenic centers onto the boronic ester moiety
also enables a chirality transfer reaction.15 Consequently,
chirality transfer into the product was observed in 45% ee.
Based on the results described above, a preliminary reaction
mechanism is described in Scheme 5. First, oxidative addition of
1 to a palladium complex should lead to an η3-allylpalladium
intermediate E. To rationalize the stereochemical outcome of the
reaction as shown in Scheme 8, the palladium atom in η1-
allylpalladium intermediate E′ (depicted in another η1-allyl form
for simplicity) instead of the boron atom in an allylboronate
moiety would coordinate to an aldehyde to form a putative cis-
decalin-like transition state F.16 Accordingly, the transition state
is cyclic for an η1-allylpalladium moiety and is open-chain for an
allylboronate moiety. Because the oxygen atom of an acetoxy
group can coordinate intramolecularly to the boron atom, this
would mask the Lewis acidity of the boron atom and instead
consequently enhance the ability of that of the palladium atom in
E′. Furthermore, due to the formation of E′, racemization of the
substrate would be restrained. Thus, the nucleophilic allylation of
an aldehyde by an allylboronate takes place to form a (Z)-
vinylpalladium acetate intermediate G. This reasonably can
explain the observed chirality transfer. Finally, the trans-
metalation of G with an organoborane followed by reductive
elimination from a vinylpalladium intermediate H gives the
desired product 4.
Yet, β-hydride elimination from H followed by reductive
elimination of the resulting palladium hydride intermediate leads
to product 5. The present reaction mechanism via a formation of
F is not a common path, however, other plausible reaction paths
involving a closed transition state controlled by allylboronates do
not match the observed chirality transfer.17 For example, if E′
reacts with an aldehyde in a fashion similar to Hoffman’s reaction
of aldehydes with α,γ-substituted crotylborane reagents, the
overall transformation would lead to an opposite stereo-
isomer.8a,b Another interesting mechanistic feature of this
reaction is that the C−Pd bond is maintained during the two
processes because Pd-catalyzed tandem reactions usually
proceed with breaking of the initially formed C−Pd bond to
form the next C−Pd bond.18
a
Reaction conditions: 1 (0.5 mmol), 2a (1.2 mmol), (R3)3B (1.5
mmol), Pd(OAc)2 (5 mol %), and CyPh2P (10 mol %) in THF at 50
°C.
Scheme 7. Chirality Transfer Reactions
amounts of protodepalladation products 5 were observed by
NMR analysis of the crude mixtures in all cases, 5 could not be
isolated. On the other hand, the present reaction did not proceed
with tri-sec-alkylboranes such as tricyclohexylborane and tri-sec-
butylborane; however, the use of Ph3B provided the desired
product 6h in high yield as a mixture of (E)- and (Z)-isomers.11
Another attempt to use B-alkyl-9-BBN and alkyl boronate esters
did not result in any conversion. To further expand the scope of
the reaction from a synthetic viewpoint, we conducted a chirality
transfer experiment using (R)-1a under optimized reaction
conditions (Scheme 7). Intriguingly, to our delight, an efficient
chirality transfer was observed, and the inversion product 4aa
was obtained in 76% yield. The absolute stereochemistry of 4aa
was determined to be (1S, 2R) by transformation into known
diols.10 To address the racemization process, (R)-1a was treated
with a catalytic amount of Pd(OAc)2 (5 mol %) and CyPh2P (10
mol %) in THF at 50 °C for 3 h. In fact, (R)-1a was recovered in
56% yield without significant loss in optical purity (97% ee).10 To
gain additional insights into the reaction mechanism, (R)-1l was
also applied to a chirality transfer experiment under the same
reaction conditions since allylic alcohols can be used directly for
the generation of η3-allylpalladium intermediates in the presence
of organoboranes.14 As a consequence, unexpectedly, a chirality
transfer was not observed (0% ee, 52% yield). A similar efficient
chirality transfer experiment was reported in a Tsuji−Trost allylic
alkylation.12,13 However, these results show that leaving groups
affect the chirality transfer in boryl-substituted η3-allylpalladium-
In summary, we have developed a Pd-catalyzed three-
component coupling reaction that provides access to a wide
variety of (Z)-anti-homoallylic alcohols from easily accessible
and stable 3-(pinacolatoboryl)allyl acetates, aldehydes, and
organoboranes. Interestingly, the palladium complex and
allylboronates function cooperatively in this process. This
outstanding reactivity of allylic gem-palladium/boryl intermedi-
ates promises to serve as a powerful strategy for the development
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Letter
of η3-allylpalladium-mediated transformations. Further inves-
tigations along these lines are currently underway in our
laboratories.
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, NMR spectra, and HRMS for all new
compounds. The Supporting Information is available free of
charge on the ACS Publications website at DOI: 10.1021/
acs.orglett.5b01244.
AUTHOR INFORMATION
Corresponding Author
■
(10) See Supporting Information for details.
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*E-mail: horino@eng.u-toyama.ac.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Mr. Yu Takahashi (University of Toyama) for
checking some reactions for reproducibility. This work was
financially supported by a Grant-in-Aid for Scientific Research
(C) (No. 24550115) from the Japan Society for the Promotion
of Science.
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NOTE ADDED AFTER ASAP PUBLICATION
Scheme 8 has been updated. The revised version was posted on
June 5, 2015.
■
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