Photoredox-Mediated Reaction of gem-Diborylalkenes: Reactivity Toward Diverse 1,1-Bisborylalkanes

Article abstract of DOI:10.1002/chem.202000603

The use of gem-diborylalkenes as radical-reactive groups is explored for the first time. These reactions provide an efficient and general method for the photochemical conversion of gem-diborylalkenes to rapidly access 1,1-bisborylalkanes. This method expl

Full text of DOI:10.1002/chem.202000603

A Journal of
Accepted Article
Title: Photoredox Mediated of gem-Diborylalkenes: A New Reactivity
Toward Diverse 1,1-Bisborylalkanes
Authors: Ahmad Masarwa, Nivesh Kumar, Nadim Eghbarieh, Tamar
Stein, and Alexander Shames
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Photoredox Mediated of gem-Diborylalkenes: A New Reactivity
Toward Diverse 1,1-Bisborylalkanes
Nivesh Kumar, Nadim Eghbarieh, Tamar Stein, Alexander I. Shames, and Ahmad Masarwa*
Abstract: The use of gem-diborylalkenes as radical-reactive groups
is explored for the first time. These reactions provide an efficient and
general method for the photochemical conversion of gem-
diborylalkenes to rapidly access 1,1-bisborylalkanes. This method
exploits a novel photoredox decarboxylative radical addition to gem-
diborylalkenes to afford α-gemdiboryl carbon-centered radicals, which
benefit from additional stability by virtue of an interaction with the
empty p-orbitals on borons. The reaction offers a highly modular and
regioselective approach to γ-amino gem-diborylalkanes. Furthermore,
EPR spectroscopy and DFT calculations have provided insight into
the radical mechanism underlying the photochemistry reaction and
the stability of the bis-metalated radicals, respectively.
center, e.g., (II’) is conceptually new, and it has not yet been
thoroughly explored. The resulting radical intermediates II are
expected to be highly stabilized,[7] since they are flanked by two
boronate groups, respectively, each providing one empty p-orbital
(Scheme 1C).[6, 8] According to our theoretical calculations[9] of
their radical stabilization energy (RSE),[7-8, 10] one boronate group,
e.g., in 3 and 3’ is expected to stabilize an adjacent radical by at
least 6.7 kcal/mol (Scheme 1D). However gemboron radical
intermediates (II) are expected to be more stable by 1.1-3.4
kcal/mol (4, 4’) via a conjugation (or hyperconjugation-like
[11]
interaction as highlighted in blue in Scheme1C); therefore,
their generation should be possible. Note that the oxygen’s lone
pairs reduce the radical stabilization (3 vs 3’, 4 vs 4’; Scheme 1D).
gem-Bisboronate species (1 and 2) are a bisnucleophilic
geminated-organometallic equivalent, which is considered to be
one of the most valuable reagents in modern organic synthesis,
providing rapid access to a wide array of transformations including
constructing C–C and C–heteroatom bonds (Schemes 1A).[1]
Moreover, they have recently served as an end point late-stage
diversification and as a site for subsequent functionalization of
simple organic molecules, natural compounds, and bioactive
molecules.[2] In all of these cases, they act as a nucleophilic
counterpart (e.g., I, Scheme 1B) that also includes various
electrophilic counterparts that participate in alkylation[3] and cross-
coupling reactions using super stoichiometric amounts of strong
bases, metals, or transition metal catalysts.[4-5] However, their
radical chemistry (e.g., II)[6] has rarely been explored,[7] and it can
indeed be used to overcome these limitations (Scheme 1B-C).
The novel reactivity of these species toward the radical scenario
will create a new class of transformations, leading to a wider
diversity of organoborones that could operate under mild and
benign conditions, where research is still beginning to develop.
The key step to address these aims can be found in the stability
of gemdiboryl-radical Type-II.[7-8] This radical is considered as the
equivalent of the proposed gem-metalated radical Type-II’
(Scheme 1C). It is worth emphasizing that the concept of having
a radical and an organo-bismetallic species on the same carbon
Scheme 1. Overview of the gem-Bisboronate species and their proposed
reactivity toward the photochemistry.
[*]
Dr. N. Kumar, N. Eghbarieh, Asst. Prof. Dr. A. Masarwa
Institute of Chemistry, The Hebrew University of Jerusalem
Edmond J. Safra Campus, Jerusalem 9190401 (Israel)
E-mail: Ahmad.Masarwa1@mail.huji.ac.il
Asst. Prof. Dr. T. Stein; Fritz Haber Center for Molecular Dynamics
Research Institute of Chemistry, The Hebrew University Jerusalem
Jerusalem 91904 (Israel).
Dr. A. I. Shames; Physics Department, Ben-Gurion University of the
Negev, 8410501 Be’er Sheva, Israel.
We posit that one efficient way to form gemdiboryl radical (II) can
be achieved by adding carbon-centered radicals to gem-
diborylalkenes[2a, 12] 2 as described in Scheme 1F. An analogous
alkylation via generating α-monoboryl carbon-centered
radicals[13] [6, 14] IV using vinyl-boron species III by adding a variety
’
Supporting information for this article is given via a link at the end of
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of carbon-centered radicals to vinyl-borons III has been reported
by Aggarwal,[15] Zard,[13] Morken,[16] Studer,[17] Shi[2d], Molander,[18]
and others (See Scheme 1E).[6, 19] Considering the fact that gem-
diboryalkenes (2) are more electron deficient than vinyl-borons III
are, they (2) are expected to be suitable candidates for this type
of radical addition scenario.
Importantly, our results show that we obtained a desired coupling
γ-Amino
gem-diborylated
product,
6a,
using
Tris[2-
phenylpyridinato-C2,N]iridium(III) A as a photoredox catalyst and
427 nm Blue-LED, along with CsF, which was used as a base
(Entry 7, Table 1). Remarkably, we found that the base plays a
critical role in this reaction, since using other bases such as
Cs2CO3 (used previously for the Aggarwal reaction condition),
only resulted in the competing formation of the protodeboronation
side product 7 (Entry 1).[2a] Even with organic photocatalyst E =
4CzIPN, the reaction worked smoothly with an 81% yield (Entry
5). Using other photocatalyst B = Ir(ppy)2(dtbbpy)PF6 afforded the
desired product in a 82% yield (entry 2); however, using
photocatalysts such as C = Ir(bpy)3, D = Ru(bpy)3Cl2 6H2O, F =
Acr-Mes BF4 (see entries 3, 4, and 6) were completely ineffective.
Changing the solvent to DCE (entry 8) lowered the yield of 6a;
however, switching the wavelength of the light source to 450nm
(entry 9) did not give the products ( for details, see the SI).
Subsequently, we investigated the scope of this photoredox
coupling reaction of readily available gem-diborylalkenes 2 with
respect to carboxylic acid substrates (5) by testing various
aliphatic and benzylic compounds and α-heteroatom substituents
(Scheme 2). Generally, the products (6a-ai) were isolated in good
yields under the established optimal conditions. We tested a
broad range of primary (see 6b, Scheme 2B), secondary, and
tertiary aliphatic carboxylic acids 5a-ak (Scheme 2B).
Phenylacetic acids 5f-g were also tested under our optimized
reaction conditions, which afforded the desired products in
moderate yields (6f-g). Both 6-membered, and 7-membered ring
cyclic-carboxylic acids were very compatible, leading to gem-
diborylated products (6c-e, 6h, 6j). A cyclic α-oxy group
containing carboxylic acid 5K was photo-decarboxylated to
generate an α-oxy radical and was added to gem-diborylalkene
(2). The reaction proceeded smoothly, leading to the desired gem-
diboryl product (6k) in synthetically acceptable yields (Scheme
2B). Coming back to the α-amino photo-decarboxylation reaction,
we found that aliphatic (primary and secondary) amines and
protected amino acids; having the NH group free did not
compromise the yield and afforded the product (6s-sz), in good
yields (Schemes 2C-D). Six-membered N-Boc piperidine-2-
carboxylic acid also performed perfectly with 80% isolated yield
(6p). Testing the functional group tolerance revealed that under
our reaction conditions thioether, ethers, esters, carbamates, and
completely free amide were tolerated (6i-6ai). In addition,
(iso)dipeptides were investigated using our protocol, and the
products 6ad, 6ae and 6af were observed in good yields of 63-
75% (Scheme 2F). Furthermore, the tertiary cyclic, acyclic, fused
ring, and complex acids were also reacted to test the viability of
the transformation, and in the all cases, good efficiency was
observed (6c-6ai). Moreover, we found that the reaction also
works well with tri-substituted alkenes (of 2) to afford the desired
products 6aa-ac in high regioselectivity (Scheme 2E).
While we can propose an array of radical generation strategies by
adding an R-radical to the double bond of II (Scheme 1F),[6, 19b]
we envisioned that the photoredox chemistry of carboxylic acids
may offer a unique reactivity to create a wider diversity of
gemdiboryl compounds (6)[20] that could operate under more
benign conditions (Scheme 1F). One more advantage of this
method over the other processes is that carboxylic acids are
abundant and can be found in natural products, drugs, and
bioactive organic molecules. Thus, carboxylic acids can easily be
linked to gemdiboryl units; therefore, this method could serve as
a powerful tool for late-stage diversification.[2b, 2d] In this regard,
in 2014, MacMillan reported a related cross reaction with RCOOH
and acrylates.[21] Furthermore, Aggarwal and co-workers have
recently shown that RCOOH can be cross-coupled with vinyl
boronic esters III under visible light-mediated radical addition
conditions (Scheme 1E).[22] These elegant reports are the source
of our inspiration and support our proposed scheme (as
designated in Scheme 1F).
In this work, we tested whether gem-diborylalkenes[23] (2) could
be used as photolabile intermediates for photoredox chemistry to
access α-polyboronate radicals[7] (II) and then selectively be
added to electrophiles (Scheme 1F). To investigate our idea,
gem-diborylalkene (2), along with 5a, was subjected to
photoredox reaction conditions. Accordingly, the optimization
screening includes visible light, photoredox catalysts, solvents,
and additives as shown in Table 1.
Table 1. Optimization of the reaction conditions[a-b]
Entry
[PC] (mol%)
A (10 mol%)
B (10 mol%)
C (10 mol%)
D (10 mol%)
E (10 mol%)
F (10 mol%)
A (2 mol%)
A (2 mol%)
A (2 mol%)
Base
Cs2CO3
CsF
Solvent
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DCE
Yield% [6a/7]
0/71
1
2
3
4
5
6
7
8
9c
82/00
00/00
CsF
00/00
CsF
81/00
CsF
00/00
CsF
84/00
CsF
Importantly, selected functionalized natural products, including a
tartaric acid derivative (5ag), a drug (Bezafibrat-5ai), the
analogue of Vitamin E (5ah) were photo-decarboxylated in good
yields to afford the gemdiborylalkane products 6ag, 6ai, and 6ah
respectively (Scheme 2G).[2]
The proposed mechanism for this decarboxylative conjugate
addition reaction is discussed in Scheme 2H. The initial SET
(single-electron transfer) between the photoexcited photo-
53/traces
00/00
CsF
DMA
CsF
aReactions were carried out with 0.20 mmol of N-boc-L-proline, 0.22 mmol of 2,
0.20 mmol of base, 2 mL of solvent, c40W blue LED (427nm) and the mol% of
photocatalyst PC at room temperature. bIsolated yields. c40W blue LED (450nm)
was used. A = Ir[dF(CF3)-ppy]2 (dtbbpy)PF6, B = Ir(ppy)2(dtbbpy)PF6, C =
Ir(bpy)3, D = Ru(bpy)3Cl2 6H2O, E = 4CzIPN, F = Acr-Mes BF4, DMA = N,N-
dimethylacetamide, DCE = 1,2-dichloroethane.
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Scheme 2. Scope of the synthesis of gem-diborylalkanes, the proposed mechanism and a deuterium-labelling study.
catalyst PC* and carboxylate 5-Cs undergoes decarboxylation to
form the radical 5-R. The conjugate addition to 2 generates the
Electron paramagnetic resonance (EPR)[24] studies have been
performed in situ under different reaction conditions (see the SI
for more details).[25] Surprisingly, when EPR was taken in the
reaction using 4CzIPN as PC,[26] two types of signals were
observed (Scheme 3A). Most likely, the signals of both types
could be related to some 4CzIPN-originating radical species that
appear during the UV-driven excitation of the 4CzIPN molecule.
Here, an UV-excited 4CzIPN molecule acts as a spin-trap,
resulting in the evolution of some short-lived radical species
created in the reaction.[25] The signal of the first type, which could
be [4CzIPN]*, was observed under irradiation in the absence of
both substrates 5a and 2. The signal of the second type, which
stabilized gemdiborylmethane radical 6-II, which then undergoes
.
SET with the reduced photocatalyst PC , yielding the
gemdiborylanion anion 6-I; then protonation of 6-I affords the
gemdiborylalkane product 6. When the reaction of
gemdiborylethene 2 was carried out with 5a in the presence of
D2O, the desired product 6a-D was obtained with 70% D-
incorporation at the geminated carbon, thus confirming the
formation of gemdiborylanion 6-I (Scheme 2I). The results of
these deuterium labelling studies may support the proposed
single-electron reduction of 6-II to 6-I (Scheme 2H-I).[22a] Of note,
a control experiment of the reaction of 6a with D2O under the
reaction conditions did not gave 6a-D.
.
could be [4CzIPN] , appears under the reaction conditions only
after 60 min under UV (blue LED) irradiation, upon the complete
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disappearance of the first one [4CzIPN]*. These obvious changes
in the EPR traces (see scheme 3A) clearly support the SET steps
and the radical pathway of the reaction (see the SI for details).
observed as the sole product in 41% yield (Scheme 3B).
Interestingly, the decarboxylative addition reaction of proline
reacts in a regioselective manner when reacted with E-1,2-
bisboraneyl-1-silane[27] (7ak), yielding a rapid access to the γ-
amino 1,2-bisboryl-1-silane product (6ak), which passes through
a 1,1-boron-silicon-radical intermediate[28] (III-ak) (Scheme 3C).
This radical III-ak has an about the same SRE value of II-a 13.01
and 13.74 kcal/mol respectively.
Finally, with these valuable gem-diborylalkanes (6) in hand, we
sought to demonstrate their synthetic utility by converting them
(e.g. 6K) to the unsymmetrical gem-diborylalkanes 8[20] and 9[29]
(Scheme 3D).
In summary, we have shown a new visible light-triggered
decarboxylative carbon-radical addition reaction to gem-
diborylalkenes, leading to various ranges of 1,1 gem-
bisborylalkanes. Remarkably, this method creates equivalents of
a gem-bismetalated carbon-centered radical, i.e., II, and III. Given
the abundance of carboxylic acids in natural and bioactive
compounds, which can be utilized in the reaction, this efficient
gemdiborylalkylation method holds promise as a powerful and
reliable strategy for late stage diversification. Studies to achieve
new transformations of (unsymmetrical) gem-diborylalkanes-
radicals (II) are currently under investigation in our research group.
Acknowledgments ((optional))
This research was supported by grants from the Azrieli
Foundation, and The Hebrew University.
Keywords: gem-bisboronates • α-boryl-radical • decarboxylation
• organoborones • photochemistry
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Entry for the Table of Contents
The use of gem-bis-metalated-alkenes, i.e., vinyl gemdiboron-compound, as radical-labile substrates is explored. The knowledge
gained provided us with an in-depth understanding of the reactivity of the radical intermediates of geminal-metalated ethane. This
methodology can serve as the late-stage diversification of bioactive molecules and simple organic molecules in which it drives the
synthesis of gemdiborylalkanes.
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