A Versatile Route to Unstable Diazo Compounds via Oxadiazolines and their Use in Aryl–Alkyl Cross-Coupling Reactions

Article abstract of DOI:10.1002/anie.201710445

Coupling of readily available boronic acids and diazo compounds has emerged recently as a powerful metal-free carbon–carbon bond forming method. However, the difficulty in forming the unstable diazo compound partner in a mild fashion has hitherto limited their general use and the scope of the transformation. Here, we report the application of oxadiazolines as precursors for the generation of an unstable family of diazo compounds using flow UV photolysis and their first use in divergent protodeboronative and oxidative C(sp²)?C(sp³) cross-coupling processes, with excellent functional-group tolerance.

Full text of DOI:10.1002/anie.201710445

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Accepted Article
Title: A New Versatile Route to Unstable Diazo Compounds via
Oxadiazolines and Use In Aryl-Alkyl Cross-Coupling Reactions
Authors: Andreas Greb, Jian-Siang Poh, Stephanie Greed, Claudio
Battilocchio, Patrick Pasau, David C. Blakemore, and Steven
Victor Ley
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10.1002/anie.201710445
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A New Versatile Route to Unstable Diazo Compounds via
Oxadiazolines and Use In Aryl-Alkyl Cross-Coupling Reactions
Andreas Greba,†, Jian-Siang Poha,†, Stephanie Greeda, Claudio Battilocchioa, Patrick Pasaub, David C.
Blakemorec and Steven V. Leya,*
Abstract: Coupling of readily available boronic acids and diazo
compounds has emerged recently as a powerful metal-free carbon-
carbon bond forming method. However, the difficulty in forming the
unstable diazo compound partner in a mild fashion has hitherto limited
their general use and scope of the transformation. Here, we report the
application of oxadiazolines as precursors for the generation of an
unstable family of diazo compounds using flow UV photolysis and
their first use in divergent protodeboronative and oxidative C(sp2)-
C(sp3) cross-coupling processes, with excellent functional group
tolerance.
Scheme 1. Families of diazo compounds.
Diazo compounds represent a highly useful class of compounds
While a multitude of methods have been developed to access
in organic synthesis,1 for example in cyclopropanation,2
diazo compounds, few allow the generation of the non-stabilized
members of the family with sufficient generality. An interesting
report by Warkentin et al. in 1989 showed that UV photolysis of
1,3,4-oxadiazolines at ca. 300 nm formed diazoalkanes.8
heteroatom-H3 and C-H insertion4 reactions. In particular, the
reaction of diazo compounds with organoboron species has
attracted considerable interest over the past few years, for
example, in C(sp2)-C(sp3) cross coupling reactions.5
Surprisingly, this approach has been largely overlooked by
chemists as
a potential route to forming unstable diazo
Our previous studies on the flow oxidation of hydrazones,6
showed the effectiveness of utilizing mild conditions to generate
and react diazo compounds with boronic acid. In particular, this
allowed us to intercept the putative unstable boronic species and
thereby enable access to alcohols6 and powerful iterative bond
forming processes.7 Nevertheless, these studies were limited to
the generation of ‘semi-stabilized diazo compounds’, compounds
bearing either an adjacent aryl or vinyl group to the diazo moiety.
To truly generalize this concept would require expansion into the
elusive realm of ‘non-stabilized diazo compounds’, a class of
compounds notorious for their intrinsic instability, toxic/hazardous
nature and difficulty of preparation (Scheme 1).1b Within this class
of reactive intermediates, dialkyl substituted diazo compounds
pose a major challenge to both access and safely utilize these
reactive species. If a mild method to generate these non-
stabilized diazo compounds could therefore be realized, a more
general method to enable aryl-alkyl cross-couplings may become
possible, along with potential interception of the intermediate
boron species to afford new chemistries.
compounds, and has never before been engaged in the
development of new synthetic method. Oxadiazolines are
available by a two-step, one-pot procedure from readily available
ketones via condensation of acetic hydrazide and subsequent
PhI(OAc)2 mediated oxidation. In contrast to alternative diazo
precursors such as hydrazones and nitrosoamides, oxadiazolines
were found to be bench-stable over many months (also see SI for
differential scanning calorimetry data).
At the outset of our investigation, we decided to exploit enabling
flow technologies, to achieve more efficient irradiation compared
with a batch reactor,9 and to avoid the build-up of hazardous
quantities of any unstable diazo compounds.10-12 Initial studies
began with the generation of oxadiazoline 1, a potential precursor
for
the cyclic,
non-stabilized
diazo compound,
4-
diazotetrahydropyran (2) (Scheme 2). Passage of an ethereal
solution of 1 through a 10 mL reactor coil held at 10 °C and
irradiated at 310 nm by a 9 W UV lamp, at a 0.125 mL min-1 flow
rate (residence time = 80 min) led to the generation of a
distinctively red solution. In-line IR spectroscopic analysis
revealed two important features:
a
peak at 2040 cm-1
[a]
[b]
Dr. A. Greb, J.-S. Poh, S. Greed, Dr. C. Battilocchio and Prof. S. V.
Ley
Department of Chemistry, University of Cambridge, Lensfield Road,
Cambridge, CB2 1EW, UK
E-mail: svl1000@cam.ac.uk
Dr. P. Pasau
corresponding to the stretch of a diazo group confirmed the
presence of diazo compound 2; in addition, a peak at 1746 cm-1
corresponding to the C=O stretch of methyl acetate was observed,
a useful gauge of assessing photolytic conversion of the
oxadiazolines. Consequently, with this result we could now
efficiently access non-stabilized diazo compounds using a flow
protocol and then study their use in C(sp2)-C(sp3) cross-coupling
(see SI for optimization results). This procedure is divergent
depending upon the ‘workup’ conditions of the intermediate boron
species.
UCB Biopharma SPRL, Chemical Research R5, Chemin du Foriest,
B-1420 Braine-L'Alleud, Belgium
[c]
Dr. D. C. Blakemore
Medicine Design, Pfizer Inc., Eastern Point Road, Groton,
Connecticut 06340, United States.
These authors contributed equally to this work.
†
Supporting information for this article is given via a link at the end of
the document. Raw data are provided at
https://doi.org/10.17863/CAM.12635.
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10.1002/anie.201710445
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acid component, a variety of electron-deficient aromatic rings
harboring various functional groups were possible substrates,
including 4-bromo (3x), 4-trifluoromethyl (3y), 4-cyano (3z) and 4-
methoxycarbonyl (3aa) substituents. Electron-rich examples were
also tolerated, including 3-acetamide (3ab), 4-methoxy (3ac) and
o-methyl (3ad) substituents, although for the two latter cases, a
higher temperature was required to achieve protodeboronation.
While lower yielding, heterocyclic boronic acids could also be
employed in this protocol to provide useful amounts of desired
cross-coupled product, for example, 3-pyridyl (3ae) and 2-thienyl
(3af) substituents.
Table 1. Metal-free protodeboronative and oxidative C(sp2)-C(sp3) cross-
coupling.
Scheme 2. Oxadiazolines as diazo precursors and access to non-stabilized
diazo compound 2.
Using a number of oxadiazolines and readily available boronic
acids or boroxines,13 we were able to demonstrate a remarkably
broad reaction scope and unusually high functional group
compatibility (Table 1). With respect to the oxadiazoline
component, a variety of pharmaceutically relevant 4-, 5- and 6-
membered saturated heterocyclic examples were viable coupling
partners, including pyran (3a), tetrahydrofuran (3b),
tetrahydrothiopyran (3c), tetrahydrothiophene (3d), thietane (3e),
N-Boc piperidine (3f), N-Boc pyrrolidine (3g) and N-Boc azetidine
(3h) rings, providing moderate to excellent yields of the desired
C(sp2)-C(sp3) cross-coupling products. It is particularly notable
that the 4-membered rings were viable examples given the
instability of 4-membered cyclic diazo compounds,13 arising from
the relief of ring strain when moving from a sp2 to a sp3 carbon
center on reaction with electrophiles. Furthermore, tolerance of
the tetrahydrothiophene and thietane moieties highlights
examples where approaches using a tosylhydrazone route or
carbon-centred radical approaches would fail, due to the
tendency of these systems to undergo elimination/ring-opening. A
number of carbocyclic examples spanning cycloalkyl groups (3i-
3l) were also permissible substrates, along with the highly
hindered adamantane substituent (3m). Tolerance of
a
cyclopropyl group (3n) is not only indicative of a non-radical based
process for this C(sp2)-C(sp3) cross-coupling method, but also
further exemplifies the advantages of this procedure over
methods utilizing carbon-centered radicals (where cyclopropane
ring-opened products would be obtained instead). In terms of
functional group compatibility for the oxadiazoline component,
olefins (3o), alkynes (3p), acetals (3q), phosphonates (3r),
sulfones (3s), furans (3v) and pyrimidines (3w) were all viable
substrates. Remarkably, both an epoxide (3t) and an alkyl
bromide (3u) could participate in this coupling process, products
that would be intractable to access using metal-catalyzed
methods or harsh basic conditions. With respect to the boronic
Yields stated are of isolated product. Protodeboronation: using 0.5 mmol
of boronic acid, 1.0 mmol of oxadiazoline and 1.0 mmol of DIPEA, then
workup using TBAF (3 eq.) and stirred further at r.t. for 16 h;
*
protodeboronation was conducted at 75 °C for 16 h. Oxidation: using 0.5
mmol of boronic acid, 1.0 mmol of oxadiazoline and 1.0 mmol of DIPEA,
then workup by stirring further under air at r.t. for 16 h.
A simple switch in the workup procedure to stirring under air
provided the oxidized C(sp2)-C(sp3) cross-coupled products,
which exhibited a similar broad reaction scope and high functional
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10.1002/anie.201710445
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group compatibility (Table 1). Again, a variety of 4-, 5- and 6-
membered saturated heterocyclic oxadiazolines could be coupled
with 4-chlorophenylboronic acid to generate a variety of tertiary
alcohols (4a-4h) in generally similar yields to the
protodeboronative method. Similar yields were obtained for
carbocyclic examples (4i-4l, 4n), with the exception of
adamantane derivative 4m where oxidation appeared to be
extremely slow. For the functional group compatibility, olefins (4o),
alkynes (4p), acetals (4q), phosphonates (4r), sulfones (4s),
furans (4v) and pyrimidines (4w) all proceeded smoothly. A
particular highlight was the tolerance of highly reactive
functionalities such as an epoxide (4t) and alkyl bromide (4u).
Electron-poor boronic acids (4x, 4y) and electron-rich boronic
acids (4ab) were also viable coupling partners, although in the
case of 4aa, protodeboronation appeared to be facile and 30% of
the protodeboronative C(sp2)-C(sp3) cross-coupled product 3aa
was also obtained. This overall protocol is complementary to
conventional Grignard addition but in many cases afforded
products that are not compatible with organometallic species.
To illustrate the utility of our newly developed protocol, we first
turned to the trapping of the tertiary boronic acid derived from the
coupling of 4-chlorophenylboronic acid and the cyclobutane
oxadiazoline precursor, using excess pinacol as the final workup
quench, which provided the valuable Bpin product 5 in 74% yield
(Scheme 3a). General methods to access and assess the
reactivity of these tertiary alkylboron pinacol esters are vastly
underdeveloped, so this process serves as testament to enabling
a
versatile cross-coupling route to these highly valued
Scheme 3. Applications of the divergent C(sp2)-C(sp3) cross-coupling process.
organoboron intermediates. Utilization of 5 for the generation of
valuable and pharmaceutically relevant tertiary cyclobutylamines
was successfully demonstrated, providing the benzyl protected
derivative 6 in 70% yield over two steps.15 Furthermore, we were
also able to construct quaternary carbon centres using two
recently developed methodologies for C(sp2)-C(sp3) cross-
coupling of boronic esters: reaction of 5 with 2-lithiofuran and a
subsequent quench with N-bromosuccinimide (NBS) led to
cyclobutylated furan derivative 7 in 47% yield;16 whereas an
iridium-catalyzed photoredox flow process17 allowed us to couple
1-isoquinolinecarbonitrile to 5, leading to cyclobutylated
isoquinoline derivative 8 in 49% yield. Finally, we were further
able to apply this process to the short three-step synthesis of the
GABA receptor agonist drug, baclofen (10) (Scheme 3b).18
In summary, this work clearly demonstrates how oxadiazolines
may be used as efficient, bench-stable precursors for non-
stabilized diazo compounds. Indeed, with these improvements in
metal-free
complements
C(sp2)-C(sp3)
the well-established
cross-coupling,
this
process
and
organometallic
organohalide cross-coupling procedures. In combination with
readily available arylboronic acids, this newly developed flow
method allows a myriad of potent, divergent, metal-free C(sp2)-
C(sp3) cross-coupling processes exhibiting a very general
reaction scope and unparalleled functional group tolerance, as
well as access to new tertiary alkyl boronic pinacol ester
derivatives. Further applications of these unstable diazo
compounds are currently ongoing in our laboratories.
Acknowledgements
The authors are grateful to Pfizer (A.G. and D.C.B.), the
Cambridge Home and EU Scholarship Scheme (J.S.P.), UCB
Biopharma SPRL (J.S.P., S.G. and P.P.), the EPSRC (S.V.L.,
grant nos. EP/K009494/1, EP/K039520/1 and EP/M004120/1)
and ECH2020 (S.V.L., Future & Emerging Technologies (FET)
Sponsor Ref. – 206410) for financial support. We are also grateful
to David J. O’Rourke at UCB for conducting differential scanning
calorimetry analysis and Duncan Guthrie at Vapourtec for the
generous loan of a UV photoreactor.
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Entry for the Table of Contents (Please choose one layout)
Layout 2:
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Andreas Greb†, Jian-Siang Poh†,
Stephanie Greed, Claudio Battilocchio,
Patrick Pasau, David C. Blakemore and
Steven V. Ley*
Page No. – Page No.
A New Versatile Route to Unstable
Diazo Compounds via Oxadiazolines
and Use In Aryl-Alkyl Cross-Coupling
Reactions
Photo-finish: A mild versatile method for the generation of highly unstable diazo
compounds via photolysis of oxadiazolines and subsequent coupling with boronic
acids is described. Simple changes in workup conditions allows the divergent
generation of protodeboronated and oxidised products, along with boronic pinacol
esters, with excellent functional group tolerance.
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