The Versatile Reaction Chemistry of an Alpha-Boryl Diazo Compound

Article abstract of DOI:10.1021/jacs.1c06112

The first α-boryl diazo compound that is capable of engaging in classic synthetic organic diazo reaction chemistry is described. The diazomethyl-1,2-azaborine 1, which is a BN isostere of phenyldiazomethane, is significantly more stable than phenyldiazomethane; its reaction chemistry ranges from C-H activation, O-H activation, [3+2] cycloaddition, and halogenation, to Ru-catalyzed carbonyl olefination. The demonstrated broad range of reactivity of diazomethyl-1,2-azaborine 1 makes it an exceptionally versatile synthetic building block for the 1,2-azaborine heterocyclic motif.

Full text of DOI:10.1021/jacs.1c06112

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The Versatile Reaction Chemistry of an Alpha-Boryl Diazo
Compound
Yao Liu, Raimon Puig de la Bellacasa, Bo Li, Ana Belén Cuenca, and Shih-Yuan Liu*
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ABSTRACT: The first α-boryl diazo compound that is capable of engaging in classic synthetic organic diazo reaction chemistry is
described. The diazomethyl-1,2-azaborine 1, which is a BN isostere of phenyldiazomethane, is significantly more stable than
phenyldiazomethane; its reaction chemistry ranges from C−H activation, O−H activation, [3+2] cycloaddition, and halogenation, to
Ru-catalyzed carbonyl olefination. The demonstrated broad range of reactivity of diazomethyl-1,2-azaborine 1 makes it an
exceptionally versatile synthetic building block for the 1,2-azaborine heterocyclic motif.
Scheme 2. Synthesis and Comparative Characterization of
Diazomethyl-1,2-azaborine 1
ain group element substituted diazo compounds have
Mbeen well studied and utilized as versatile reagents in
organic synthesis. Illustrative examples include trimethylsilyl-
diazomethane (Si)1 and Ohira−Bestmann reagent2 (P). In
contrast, α-boryl diazo compounds are rare, with only about a
handful of examples reported to date (Scheme 1, top).3 Lewis
acidic boranes have been demonstrated to decompose diazo
compounds;4 thus all the reported α-boryl diazo compounds
either contain quaternized boron or involve trigonal planar
boron atoms attached to two π-donating heteroatoms (O, N)
to minimize boron’s Lewis acidity (see Scheme 1, top).
Despite the broad applicability of diazo compounds as versatile
reagents in synthetic organic applications,5 no instances of
organic reaction chemistry have been described for α-boryl
diazo compounds, presumably due to their perceived highly
a
a
Reported isolated yields are the average of two runs. TBS: tert-
Scheme 1. Novel α-Boryl Diazo Compound with Diverse
Reaction Chemistry
butyldimethylsilyl.
sensitive nature toward reaction conditions for organic
synthesis. We envisioned that when the boron atom of an α-
boryl diazo species is embedded in an aromatic scaffold such as
in diazomethyl-1,2-azaborine 16 (Scheme 1, bottom), sufficient
stability could still be achieved to enable diverse reaction
chemistry of the diazo functional group. In this communica-
tion, we demonstrate that diazomethyl-1,2-azaborine 1 is an
exceptional example of the α-boryl diazo family of compounds
that is remarkably stable and capable of engaging in a wide
range of diazo activation modes, in some cases with distinct
reaction selectivities, thus rendering 1 a powerful synthetic
building block for 1,2-azaborine chemistry.7 In view of
Received: June 13, 2021
https://doi.org/10.1021/jacs.1c06112
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A

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Scheme 3. Ru-Catalyzed Carbonyl Olefination with
Diazomethyl-1,2-azaborine 1 via Ru-α-borylalkylidine
Intermediate 3
Scheme 5. O-Alkylation of Carboxylic Acids with
Diazomethyl-1,2-azaborine
a
a
Reported isolated yields are the average of two runs.
Scheme 6. [3+2] Cycloaddition Reaction with Diazomethyl-
a
1,2-azaborine
a
Reported isolated yields are the average of two runs.
Scheme 7. Synthesis of Halomethyl 1,2-Azaborine Building
a
Blocks from 1
Scheme 4. Cu-Catalyzed C−H Activation of Terminal
a
Alkynes with Diazomethyl-1,2-azaborine
a
Reported isolated yields are the average of two runs.
emerging applications of BN heterocycles in materials
chemistry,8 biomedical research,9 and organic synthesis,10 the
development of new versatile 1,2-azaborine building blocks is a
significant objective.
Diazomethyl-1,2-azaborine 1 can be prepared in a two-step
procedure from commercially available starting materials.
Treatment of N-TBS-B-Cl-1,2-azaborine with AgOTf furnishes
the B-OTf adduct,11 which is more electrophilic toward
nucleophilic attack by TMSCHN2 to generate the target
compound 1 with concomitant release of TMSOTf (Scheme 2,
top). It is worth noting that the outcome of this process
contrasts with the reaction observed between TMSCHN2 and
other B−X-containing compounds, where insertion chemistry
with elimination of N2 and retention of the TMS group is
a
Yields are the average of two runs.
B
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Communication
the first isolated Ru-α-borylalkylidine complex.22,23 Not many
trans-bistriphenylphosphine dichlororuthenium alkylidene
complexes have been crystallographically characterized, and
we were unfortunately unable to obtain the structure of the
corresponding carbonaceous Ru-benzylidine complex for direct
comparison due to its facile decomposition in solution.24,25
Instead, we used the reported Cl2(PPh3)2Ru-vinylcarbene 4 as
the reference compound.26 While most structural parameters
are quite similar between 3 and 4, we note a few features for
the Ru-α-borylalkylidine 3 that are distinct from the reference
complex 4 (Scheme 3, table): (1) The two Ru−P bonds in 3
(2.484 Å, 2.326 Å; Δ = 0.158 Å) are significantly more
nonsymmetrical than the ones observed in 4 (2.400 Å, 2.372
Å; Δ = 0.028 Å). (2) The ∠Ru−C1−B angle (124.1°) in 3 is
smaller than the corresponding angle in 4 (131.2°). (3) The
Ru−C1−B plane in 3 is somewhat perpendicular to the plane
of the BN-heterocyclic ring (∠Ru−C1−B−N = 135.8(9)°).
This is in contrast to compound 4, where the alkenyl group is
more aligned to conjugate with the Ru alkylidine (∠Ru−C1−
C−C = −158.6(4)°).
Scheme 8. Bromomethyl 1,2-Azaborine 10 as a Versatile
Electrophilic Building Block
a
Next, we investigated the Cu-catalyzed C−H activation of
terminal alkynes in the presence of the α-boryl diazo
compound 1. Fu et al. reported a simple CuI-catalyzed
procedure that couples terminal alkynes with diazoesters and
diazoamides to furnish 3-alkynoates (Scheme 4, eq 4).27 In a
number of cases, the corresponding allene isomer was observed
as a minor byproduct. Fox and co-workers subsequently
optimized the conditions for allene formation for α-alkyl-α-
diazoesters with terminal alkynes and determined that the
initially formed alkynoate intermediates isomerize to the
allenoate products in the presence of the stoichiometrically
employed K2CO3 base (Scheme 4, eq 5).28 Thus, it appears
that the alkynoate species is the kinetically preferred product
under Cu catalysis that subsequently can isomerize to the
allenoates in the presence of a base. Surprisingly, when we
adapted the protocol developed by Fu and treated
diazomethyl-1,2-azaborine 1 with terminal alkynes in the
presence of catalytic amounts of CuI in MeCN, and in the
absence of any base, the corresponding allene 5 is formed
exclusively instead of the expected internal alkyne (Scheme 4,
eq 6).
a
Reported isolated yields are the average of two runs.
typically observed.12,13 Diazomethyl-1,2-azaborine 1 is the BN
isosteric analogue of phenyldiazomethane; thus comparisons
are warranted: (1) Stability: We determined that diazomethyl-
1,2-azaborine 1 is a stable oil. When stored at room
temperature as a neat compound, no decomposition of 1 has
been observed for over a month. In stark contrast, phenyl-
diazomethane is an unstable and potentially explosive liquid
that decomposes readily at room temperature.14 (2) IR: The
presence of the diazo functional group in 1 is indicated by an
intense band at ν = 2062 cm−1 for the asymmetric CN2
stretching vibration. In comparison, the CN2 vibration for
phenyldiazomethane15 is at 2053 cm−1.16 The higher CN2
vibrational frequency observed for 1 in comparison to
phenyldiazomethane is consistent with some additional
stabilization of the negative charge at the CN2 carbon
position.17
Undaunted by the lack of precedent of synthetic applications
of α-boryl diazo compounds, we investigated the reaction
chemistry of diazomethyl-1,2-azaborine 1 in the context of
diversity-oriented synthesis18,19 using 1 as a universal building
block. The first reaction we examined is the catalytic cross-
metathesis of a diazo compound and a carbonyl to form an
alkene.20 In the presence of Cl2Ru(PPh3)3 as the catalyst, diazo
compound 1 undergoes metathesis with benzaldehyde to
furnish BN stilbene derivative 2 with PPh3 as the
stoichiometric reductant (Scheme 3, eq 1).21 We were able
to isolate the corresponding Ru-α-borylalkylidine complex 3
(Scheme 3, eq 2) and demonstrate its chemical competency as
a catalyst for the transformation (Scheme 3, eq 3). Gratifyingly,
we are able to grow single crystals of complex 3 from a
pentane/dichloromethane solution that are suitable for X-ray
diffraction analysis. To the best of our knowledge, complex 3 is
The formation of allene 5 is indicated by the two
diastereotopic Si−Me signals of the N-tert-butyldimethylsilyl
1
(TBS) group in the H NMR, which is consistent with the
existence of an axially chiral stereogenic unit. The distinct
product selectivity of CuI-catalyzed alkyne−diazo coupling for
α-boryl diazo compound 1 again highlights its unique
electronic structure that is likely underlying the observed
selectivity.29
We also note that in the absence of a viable external C−H
source and in the presence of the Rh2OAc4 catalyst an
intramolecular C−H insertion occurs at the methyl or t-Bu
group (on the N-TBS moiety), respectively, yielding the
corresponding bicyclic 1,2-azaborine compounds 6a and 6b
with a strong preference for the formation of the five-
membered 6a (eq 7).30
In addition to C−H activation chemistry, diazo compounds are
known to engage in uncatalyzed O−H insertion chemistry.31
C
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This reactivity feature has been utilized in chemical biology
applications, where stabilized diazo compounds have been
developed to label proteins and nucleic acids via O-
alkylation.32 For an α-boryl diazo compound the high
oxophilicity of boron may present an additional challenge to
successfully O-alkylate suitable oxygen-based nucleophiles such
as carboxylic acids. Gratifyingly, we determined that
diazomethyl-1,2-azaborine 1 reacts quite rapidly at room
temperature with carboxylic acids to form esters in acetonitrile
in the absence of a catalyst. As can be seen from Scheme 5, aryl
and alkyl carboxylic acids are suitable substrates. An electro-
philic alkyl bromide functional group is also tolerated (Scheme
5, entry 7c).
To explore additional reactivity types that diazo compounds
can engage in, we investigated the [3+2] cycloaddition of
diazomethyl-1,2-azaborine 1 with alkenes. A diazo compound
is typically considered electron-rich and thus reacts as a
nucleophile in normal-electron-demand cycloadditions with
electron-deficient dipolarophiles.33 We are pleased to find that
diazomethyl-1,2-azaborine 1 undergoes regioselective [3+2]
cycloaddition reactions with α,β-unsaturated esters, ketones,
and nitriles in the presence of a Pd catalyst to presumably
initially form intermediates 8′, which then subsequently
undergoes a formal 1,3-boryl shift to furnish adducts 8
(Scheme 6). In contrast, phenyldiazomethane preferentially
forms cyclopropane compounds with elimination of N2 (see
Supporting Information for experimental details). As an
additional comparison, while phenyldiazomethane reacts
relatively cleanly with styrene to furnish 1,2-diphenylcyclopro-
pane in the presence of cobalt(II) tetraphenylporphyrin,34
diazomethyl-1,2-azaborine 1 remains mostly unreactive,
producing minor amounts of the intramolecular C−H
activation product 6a (see Supporting Information for
experimental details).
Finally, we envisioned that diazomethyl-1,2-azaborine 1 can
serve as a precursor to the halomethyl building blocks 9 and 10
(Scheme 7). Benzyl halides are versatile intermediates in
diversity-oriented synthesis in medicinal chemistry,35 and
compounds 9 and 10 represent the direct BN isosteres of
benzylic halides. While examples of halomethyl BN naph-
thalenes have been reported,36 to the best of our knowledge,
such a building block for the monocyclic 1,2-azaborine
heterocycle has not been prepared. Importantly, the annulation
method involving potassium chloromethyltrifluoroborate and
2-aminostyrene to yield the chloromethyl BN naphthalenes36
is not applicable to the monocyclic benzene-type BN
heterocycle. We envisioned that similar to how O-alkylation
proceeds with protonation of the α-boryl carbon followed by
nucleophilic attack of the oxygen nucleophile,31 treatment of 1
with a suitably matched proton/halide source should yield the
corresponding halomethyl 1,2-azaborines 9 and 10.37 After
screening a number of conditions, we determined that 1-
ethynyl-4-nitrobenzene as the proton source in combination
with CuI as the iodide nucleophile works well for the
iodination of diazomethyl-1,2-azaborine 1 (Scheme 7, eq 8).
Similarly, the combination of bromoacetic acid as the proton
source and cetrimonium (hexadecyltrimethylammonium) bro-
mide is suitable for converting 1 to the bromomethyl 1,2-
azaborine 10 (Scheme 7, eq 9).38
can engage in Suzuki−Miyaura cross-coupling reaction to
produce BN diarylmethanes 11. Compound 10 also reacts with
a number of nucleophiles such as thiocyanate, azide, amine,
and phthalimide anion to furnish the corresponding adducts
12−15 in moderate to good yields, further demonstrating the
diversity of compounds that can be accessed with diazomethyl-
1,2-azaborine 1 as the universal precursor.
In summary, we synthesized the first α-boryl diazo
compound that is capable of engaging in classic synthetic
organic diazo reaction chemistry, including C−H activation,
O−H activation, [3+2] cycloaddition, halogenation, and Ru-
catalyzed carbonyl olefination. Furthermore, we showed that
diazomethyl-1,2-azaborine 1, a BN isostere of phenyldiazo-
methane, is a stable compound and that its corresponding Ru
carbene complex 3 exhibits bonding features that are distinct
from an analogous Ru-alkylidine complex. Overall, we believe
that diazomethyl-1,2-azaborine 1 as a new member of the α-
boryldiazo compound family and as a remarkably versatile 1,2-
azaborine building block will advance both the basic science of
diazo chemistry and the multifaceted chemistry of 1,2-
azaborine heterocycles.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c06112.
■
sı
Experimental procedures, compound characterization
data, crystallographic information, and NMR spectra
for all new compounds (PDF)
Accession Codes
CCDC 2082462 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Shih-Yuan Liu − Department of Chemistry, Boston College,
Chestnut Hill, Massachusetts 02467-3860, United States;
orcid.org/0000-0003-3148-9147; Email: shihyuan.liu@
bc.edu
Authors
Yao Liu − Department of Chemistry, Boston College, Chestnut
Hill, Massachusetts 02467-3860, United States
Raimon Puig de la Bellacasa − Department of Organic and
̀
Pharmaceutical Chemistry, Institut Químic de Sarria,
Universitat Ramon Llull, E-08017 Barcelona, Spain
Bo Li − Department of Chemistry, Boston College, Chestnut
Hill, Massachusetts 02467-3860, United States
Ana Belén Cuenca − Department of Organic and
̀
Pharmaceutical Chemistry, Institut Químic de Sarria,
Universitat Ramon Llull, E-08017 Barcelona, Spain
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c06112
We chose bromomethyl 1,2-azaborine 10 to demonstrate the
ability of halomethyl 1,2-azaborines to serve as an electrophilic
building block in a variety of coupling and substitution
reactions.36,39 As can be seen from Scheme 8, compound 10
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
D
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Research reported in this publication was supported by the
National Institute of General Medical Sciences of the National
Institutes of Health under Award Number R01GM136920 and
by Boston College start-up funds. R.P. and A.B.C. thank the
Universitat Ramon Llull and “la Caixa” Foundation (2017-
URL-Internac-010 grant), the MICINN (PID2020-113661GB-
I00) grant, and the AGAUR SGR-00294 grant for support.
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