Transition-Metal-Free Homologative Cross-Coupling of Aldehydes and Ketones with Geminal Bis(boron) Compounds

Article abstract of DOI:10.1021/acs.orglett.7b01474

We report a transition-metal-free coupling of aldehydes and ketones with geminal bis(boron) building blocks which provides the coupled, homologated carbonyl compound upon oxidation. This reaction not only extends an alkyl chain containing a carbonyl group, it also simultaneously introduces a new carbonyl substituent. We demonstrate that enantiopure aldehydes with an enolizable stereogenic center undergo this reaction with complete retention of stereochemistry.

Full text of DOI:10.1021/acs.orglett.7b01474

Letter
pubs.acs.org/OrgLett
Transition-Metal-Free Homologative Cross-Coupling of Aldehydes
and Ketones with Geminal Bis(boron) Compounds
Thomas C. Stephens and Graham Pattison*
Department of Chemistry, University of Warwick, Gibbet Hill Road, Coventry, CV4 7AL, U.K.
S
* Supporting Information
ABSTRACT: We report a transition-metal-free coupling of
aldehydes and ketones with geminal bis(boron) building blocks
which provides the coupled, homologated carbonyl compound
upon oxidation. This reaction not only extends an alkyl chain
containing a carbonyl group, it also simultaneously introduces a new
carbonyl substituent. We demonstrate that enantiopure aldehydes
with an enolizable stereogenic center undergo this reaction with
complete retention of stereochemistry.
range of coupling processes, both metal-catalyzed and
metal-free, are transforming the way chemists build
being found in a broad range of biologically active compounds
as well as being key substrates for the synthesis of many
alcohols, heterocycles, and enolate condensation products.
Homologation reactions of carbonyl compounds are
extremely useful, as they extend a chain by one carbon and
may convert a readily accessible carbonyl compound into its
much more valuable homologue. The homologation of
aldehydes and ketones to one-carbon-extended aldehydes is
well-known and is generally achieved by either Wittig reactions
with alkoxy-substituted phosphonium salts (via hydrolysis of
the enol ether formed), or epoxide formation with a sulfonium
ylid followed by acid-mediated Meinwald rearrangement to the
homologated aldehyde.15 However, a homologative cross-
coupling process in which an aldehyde or ketone not only
undergoes a one-carbon chain extension, but a new ketone
substituent is simultaneously introduced is not currently
available.
Here we present a versatile homologative coupling reaction
which allows the introduction of a new ketone substituent in
tandem with carbonyl chain extension. This process is formally
an umpolung coupling of two carbonyl compounds as the
geminal bis(boron) component can be readily derived from an
aldehyde via its tosylhydrazone.
This strategy can be used in iterative sequences, as the
homologated carbonyl products can then be subjected to
further boron-Wittig processes to add in an additional subunit
and extend the chain. In addition, the intermediate compounds
are amenable to the vast and well-established chemistry of vinyl
boronates and aldehydes and ketones which should allow the
rapid generation of a diverse range of functionalized products.
Conditions for the boron-Wittig reaction have been
optimized recently, including in particular the use of LiTMP
A
molecules. Transition-metal-free coupling processes1 are of
particular attraction due to very stringent requirements for low
ppm values of toxic transition metal residues in pharmaceutical
products. As a result, a series of such transition-metal-free
coupling processes are beginning to emerge, using in particular
readily available building blocks such as organoboron
compounds.2,3
One class of organoboron building block which is seeing
significant recent attention is geminal-bis(boronates). These are
air- and moisture-stable compounds of which diverse
substituted derivatives can be easily prepared. Bis[(pinacolato)-
boryl]methane, which can be used as a precursor for many
substituted geminal bis(boron) compounds by deprotonation
and alkylation,4 is now commercially available or can be
prepared easily in one step from dibromomethane.5 Several
other methods have been reported for the synthesis of these
compounds, including borylation of geminal dibromides,6
hydroboration of alkynes and vinylboronates,7 C−H boryla-
tion8 and the diborylation of N-tosylhydrazones, diazoalkanes,
and carbonyl compounds.9 The geminal bis(boronate) building
blocks have been used in several catalytic cross-coupling
processes including Suzuki−Miyaura cross-coupling,10 addi-
tions to carbonyl compounds,11 and allylic substitution
reactions12 among other transformations.13
One key reaction of interest regarding geminal bis-
(boronates) is the boron-Wittig reaction, which is the reaction
of a deprotonated geminal bis(boronate) with an aldehyde or
ketone to provide a vinyl boronate.14 These reactions often
proceed with a very high degree of stereocontrol over double
bond geometry.
The key to our general synthetic strategy was the realization
that oxidation of this vinyl boronate will afford a homologated
aldehyde or ketone. Carbonyl compounds have proven to be
some of the key mainstays of organic synthesis over the years,
Received: May 15, 2017
© XXXX American Chemical Society
A
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Letter
for the deprotonation of the geminal bis(boron) compound
without competing nucleophilic attack at boron.16 However,
conditions for the oxidation of alkenyl boronates to carbonyl
compounds were less clear, and examples of such oxidations are
surprisingly uncommon in the literature considering the
ubiquity of oxidation of aryl- and alkyl-boron species in
synthesis.14a−c,17 We also aimed to develop this as a one-pot
process, without need for isolation of the intermediate
alkenylboron compound.
which were not compatible with aqueous sodium perborate
(pH ≈ 14). For example, one-carbon extension of aromatic
aldehydes resulted in benzylic aldehydes which were susceptible
to self-aldol processes under the basic reaction conditions. Here
the use of oxone as oxidant (acidic) prevented the formation of
these byproducts, providing alternative conditions for the
successful homologation of both base- and acid-sensitive
substrates.20
We then looked to develop these optimized conditions into a
practical homologative coupling process using substituted
geminal bis(boron) compounds. We were pleased to discover
that our one-pot boron-Wittig/oxidation conditions could be
easily extended to the homologative coupling of both aldehydes
and ketones with substituted bis(boron) compounds (Scheme
2). A broad range of functional groups could be tolerated in this
process, including alkenes, aromatic rings bearing both
electron-withdrawing and electron-donating groups, hetero-
cyclic rings including pyridines and furans, amines, halogen
atoms, and an acetal. Oxidation of tetrasubstituted alkenes
arising from boron-Wittig reaction of ketones proceeded well,
although longer reaction times were required, along with the
addition of extra equivalents of oxidant. The reaction was also
effective to produce a ketone bearing a bulky tert-butyl group
2f.
We chose to optimize our oxidation on cyclohexyl vinyl
boronate 1, derived from cyclohexanone (Scheme 1). Of the
Scheme 1. Optimized One-Pot Homologation Conditions
range of oxidizing reagents studied we found aqueous sodium
perborate in acetone to give the most consistent and cleanest
results.18 It was important to find a solvent system in which
solubility of both the oxidant and vinyl boronate was
acceptable. Isolation and purification of the vinyl boronate
was not necessary, and the procedure could be performed in a
one-pot fashion with only a switch in solvent at the
intermediate stage.
Boron-Wittig/oxidation of menthone with 2-bromobenzyl
geminal bis(boronate) provided the homologated ketone 2j
with a high level of diastereoselectivity. Homologative coupling
to form ketone 2g was performed on a 3 mmol scale to
demonstrate the reliability of this process.
Impressively, a primary alkyl chloride 2l was also tolerated in
this reaction despite SN2-alkylation of lithiated geminal
bis(boron) compounds being a reliable procedure. In addition,
reaction of chloroacetone yielded enone 3 (eq 1), which was
formed by a boron-Wittig−oxidation−elimination sequence
under the basic oxidation conditions with no competing
After boron-Wittig reaction of the carbonyl compound and
lithiated geminal bis(boron) compound in THF was complete,
the THF could be removed and replaced with acetone,
followed by oxidation with aqueous sodium perborate.
It should be noted that on rare occasions alternative oxidants
were required to homologate certain base-sensitive substrates
Scheme 2. Homologative Cross-Coupling of Aldehydes and Ketones with Geminal Bis(boron) Compounds
a
dr >19:1. Also contains 18% unoxidized vinyl boronate.
B
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Letter
further chain extensions. This is an example of iterative
synthesis, in which a larger molecule is constructed stepwise by
the addition of one subunit in a sequential fashion.19 This
strategy mimics the way nature often builds complex molecules
and is particularly attractive to medicinal chemists and others
who require the synthesis of large numbers of diverse analogs
for testing. To demonstrate this concept we performed a 4-
carbon chain extension of benzaldehyde to which proceeded
efficiently with the introduction of an isopropyl group at a
defined point in the chain (Scheme 3a).
One key attraction of this approach is that the vinyl boronate
intermediates formed in the boron-Wittig reaction can be
readily transformed into either of the starting materials required
for boron-Wittig chemistry. While we have shown already that
oxidation yields a carbonyl derivative, it is also the case that
hydroboration will provide the geminal bis(boronate) compo-
nent. This will also allow components for cross-coupling to be
assembled separately, and then to be combined together in a
convergent fashion. To demonstrate this (Scheme 3b) we
performed boron-Wittig chain extensions of 3-(5-methyl-2-
furyl)butanal and hydrocinnamaldehyde, subjecting the former
to our standard oxidation conditions and the latter to
hydroboration conditions.7b This provided homologated
aldehyde 6 and geminal bis(boronate) 8 components that we
could then join together under our standard homologative
coupling conditions to yield ketone 9.
nucleophilic displacement of chlorine. It would seem that the
kinetics of addition of the deprotonated geminal bis(boron)
compound to a carbonyl compound are significantly faster than
in SN2 nucleophilic substitution of a primary alkyl chloride.
The use of a chiral enantiopure enolizable aldehyde in this
reaction provided the homologative coupling product 4 with
complete retention of stereochemistry (eq 2). That no
racemization was observed has important mechanistic implica-
tions. Our base optimization studies allow us to estimate the
pKa of geminal bis(boron) compounds to be between that of
HMDS and TMP (i.e., pKa between 26 and 36), which would
be sufficiently basic to lead to deprotonation of an enolizable
aldehyde. The fact that racemization is not observed would
suggest that nucleophilic addition into an aldehyde is
significantly kinetically favored over deprotonation. The
homologative coupling of readily prepared enantiopure α-
stereogenic aldehydes will allow the stereogenic center to be
moved to a position where it may be more difficult to introduce
with high enantioselectivity.
To conclude, we have developed a transition-metal-free
homologative cross-coupling reaction of aldehydes and ketones
via one-pot boron-Wittig reactions and oxidation of the
subsequent vinyl boronate. We have shown that a broad
range of functional groups can be tolerated in the carbonyl
component and demonstrated that enantiopure aldehydes
undergo this reaction without any racemization. Further work
on the application of this reaction to molecules of interest will
be reported in due course.
Of course, the product of all of these homologative coupling
reactions is another carbonyl compound which will also be
susceptible to boron-Wittig/oxidation sequences to undergo
Scheme 3. Iterative Homologative Couplings
C
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01474.
■
S
Experimental procedures, characterization data (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: graham.pattison@warwick.ac.uk.
ORCID
Graham Pattison: 0000-0003-0116-8457
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
G.P. is a Warwick IAS Global Research Fellow. The authors
would like to thank the University of Warwick and Royal
Society for Research Grants and the Warwick URSS scheme for
a summer bursary (T.C.S.). We thank Teena Rajan (Warwick)
for preparation of geminal bis(boron) substrates and Prof. Mike
Shipman (Warwick) for advice and useful suggestions.
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D
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