Alternating Radical Stabilities: A Convergent Route to Terminal and Internal Boronates

Article abstract of DOI:10.1002/anie.201906497

Pinacolato boronates (Bpin) with an empty p-orbital on boron stabilize an adjacent carbon radical, in contrast to diethanolamino boronates [B(DEA)] where the boron is sp³-hybridized. By alternately placing a pinacol or diethanolamine moiety on the boron atom, thus stabilizing or not stabilizing the corresponding adjacent radical, it is possible to control the behavior of α-boronyl xanthates and construct a large variety of terminal or internal boronates in a modular fashion. The remarkable tolerance of polar groups and the ability to introduce quaternary centers are particularly noteworthy features of this process.

Full text of DOI:10.1002/anie.201906497

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Alternating Radical Stabilities. Convergent Route to Terminal
and Internal Boronates Qi Huang, Jean Michalland, and Samir Z.
Zard*
Authors: Samir Z. Zard, Qi Huang, and Jean Michalland
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201906497
Angew. Chem. 10.1002/ange.201906497
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10.1002/anie.201906497
Angewandte Chemie International Edition
RESEARCH ARTICLE
Alternating Radical Stabilities: Convergent Route to Terminal and
Internal Boronates
Qi Huang, Jean Michalland, and Samir Z. Zard*
This article is dedicated with respect to the memory of Professor Koji Nakanishi (Columbia University).
Abstract: Pinacolato boronates (Bpin) with an empty p-orbital on
onychomycosis[4a] and Bortezomib (Velcade®) 3 for the treatment
of patients with refractory multiple myeloma.[4b] Boronic acid 4 is
boron stabilize an adjacent carbon radical, in contrast to
diethanolamino boronates [B(DEA)] where the boron is sp3 hybridized. a potent inhibitor of human arginases I and II destined for treating
By alternately placing a pinacol or diethanolamine around the boron
atom, thus stabilizing or not stabilizing the corresponding adjacent
radical, it is possible to control the behavior of α-boronyl xanthates
and construct in a modular fashion a large variety of terminal or
internal boronates. The remarkable tolerance for polar groups and the
ability to introduce quaternary centers are particularly noteworthy.
myocardial reperfusion injury,[4c] while GSK5852 5 is effective
against hepatitis C virus,[4d] and Vaborbactam 6, approved in 2017,
is a cyclic boronic acid possessing a broad spectrum β-lactamase
inhibitor activity and effective for the treatment of multidrug
resistant Gram-negative bacteria.[4e] Finally, organoboron
derivatives have found extensive applications in material sciences,
ranging from self-healing polymers to hydrogels to lithium
batteries to fluoride and carbohydrate sensors to controlled drug
release, and even to wood preservatives.[5]
Introduction
The importance of organoboron chemistry can hardly be
overestimated.[1] Organoboranes are involved in numerous
transformations including functional group inter-conversions and,
especially, C—C bond formation. Many of these reactions can be
made enantioselective. Boron is also increasingly appearing in
natural products and in synthetic drugs with important biological
activities.[2] Examples of the former are the antibiotics boromycin,
borophycin, aplasmomycin, and tartolon B, where the boron is
present as a borate complex. The antibacterial activity of these
natural products is probably related to the discovery that small
molecule borate complexes, such as AI-2 1 (AutoInducer-2;
Results and Discussion
Most of the approaches to organoboron compounds have relied
hitherto on traditional ionic and organometallic reactions. In recent
times, however, radical based processes have found increasing
use, especially for the synthesis of aliphatic organoboron
derivatives.[6,7] We have ourselves produced highly decorated
boronates by exploiting the remarkable ability of xanthates to add
to a variety of boron substituted alkenes.[8] We have now been
able to expand this strategy considerably by altering the
Figure 1), are used by many microorganisms as “Quorum Sensing” substitution pattern around the boron atom and modulating thus
or QS signals in cell-to-cell communication to modulate biofilm
formation and pathogenicity.[3]
the relative stability of the intermediate radicals. The correct
choice of the reacting partners, guided by considerations of
radical stabilities (thermodynamic factors) and polar effects
(kinetic factors), is crucial to mastering the xanthate transfer
process and to avoiding the unwanted formation of oligomers.
The xanthate addition-transfer proceeds by the simplified
mechanism outlined in Scheme 1.[9] The initial radical 8 is not
consumed by addition to its xanthate precursor 7, since the
formation of adduct 9 is fast but reversible. The effective lifetime
of this initial radical 8 is therefore considerably increased, allowing
it to add to alkene 10. The resulting adduct radical 11 is in turn
reversibly captured by xanthate 7, and reversible fragmentation
leads to addition product 13 and regenerates initial radical 8. For
this sequence to operate efficiently, it is necessary for the
equilibrium, via intermediate 12, between radical 11 and 8 to favor
the latter, so as to drive the process forward. In other words, and
neglecting to a first approximation polar effects, substituent Y has
to stabilize radical 8 more than substituent Z stabilizes radical 11.
Failure to conform to this condition encourages accumulation of
adduct radical 11 and the formation of oligomers by uncontrolled
further additions to alkene 10.
Figure 1. Examples of biologically active organoboron compounds.
Examples of pharmacologically significant boron containing drugs
include Tavaborole (AN2690; Kerydin®) 2 for the treatment of
[*]
Dr. Qi Huang, J. Michalland, Prof. Dr. S. Z. Zard
Laboratoire de Synthèse Organique, CNRS UMR 7652
Ecole polytechnique
Route de Saclay, 91128 Palaiseau Cedex, France
E-mail : samir.zard@polytechnique.edu
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This constraint is seldom obeyed in the case of additions to vinyl
pinacolato boronate 14, since the corresponding adduct radical
15 is stabilized by delocalization into the empty orbital on the
boron atom and this radical is in many cases more stable than
initial radical 8.[10] Indeed, additions to vinylBpin 14 are capricious
and often low-yielding.[8d,e] In contrast, radicals 17 from addition
to vinylB(MIDA) 16 cannot benefit from such stabilization and are
in general less stable than initial radical 8. This results in highly
effective additions with a broad range of functional xanthates.[8b]
reason for this behavior is not clear. We initially ascribed it to the
stabilization of α-boryl radical 19 to an extent that its reactivity is
Scheme 2. Two α-boronyl xanthate based routes to boronates.
significantly impacted, in a manner analogous to benzylic radicals,
which do not react well with unactivated alkenes (see discussion
below).[13] After some experimentation, we found that conducting
the reaction at lower temperature to slow down the flux of radicals
from the initiator to be beneficial. This can be seen in the reaction
of xanthate 18 with alkene 27 where a yield of 51% of adduct 28
was obtained, even if a substantial amount of starting xanthate
remained. Increasing the temperature to 100 °C to speed up the
addition step, without solvent, proved to be somewhat more
efficient and was adopted for most of our study. Under these
conditions, boronate 28 was obtained in 57% yield after 3 hours,
with no starting xanthate 18 remaining. Other examples are
displayed in Scheme 3. All were prepared without solvent or with
just the minimum of DCE when the alkene did not dissolve
completely in the liquid xanthate 18. While the yields were
generally below our expectations, these additions nevertheless
Scheme 1. Xanthate transfer and radical stabilization by an adjacent boron
atom.
In the light of these observations, we considered the two
alternative approaches depicted in Scheme 2, hinging on the use
of a pinacolato boronate to stabilize the initial radical. In the first
case, A, addition of boryl xanthate 18 would proceed via stabilized
initial radical 19 to give adduct 20, where the boron is at the
"beginning" of the structure, in contrast to addition to alkenes 14
and 16, where the boronate finds itself at the "end". In the second,
B, generic xanthate 7 is added first to vinyl diethanolamino
boronate 21, noted hereafter vinylB(DEA), to give adduct 23 via
unstabilized intermediate radical 22. Replacement of the
diethanolamino with a pinacolato motif would now provide
boronate 24 which, being the precursor of stabilized radical 15,
can now act as the starting point for a second addition to give
compound 25, where the boronate is located in the "middle" of the
structure. Like MIDA boronates, B(DEA) boronates have an sp3
hybridized boron and do not therefore stabilize an adjacent
carbon radical but are much easier to cleave, as reported by
Santos and co-workers.[11] The robustness of MIDA boronates[12]
is not an advantage in the present context.
Xanthate 18 was prepared trivially by reacting commercial
bromomethylboronate 26 with potassium O-ethyl xanthate
(Scheme 3). Unfortunately, its addition to alkenes proved less
efficient than expected and a substantial optimization effort had to
be invested, and, even then, with mixed success. In refluxing
dichloroethane (DCE), with dilauroyl peroxide (DLP) as initiator,
the desired product 28 was formed in a modest 49% yield. The
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expediently furnish boronates that would not be readily accessible
otherwise.
characterization. Thus, the first yield corresponds to the addition
step and the second to the reduction.
Scheme 3. Synthesis of terminal boronates. [a] Reaction run at 60°C for 24h;
ratio of product to starting material 5:1. At 100°C, the yield dropped to about
28%.
Scheme 4. A second route to terminal boronates.
Fortunately, the situation improved markedly when we examined
access to more complex boronates by approach B. VinylB(DEA)
37 was prepared by treating vinyl boronic acid 36 with
diethanolamine and crystallizing the product (Scheme 4).[14] The
addition of phthalimide derived xanthate 38 (PhthN = phthalimide)
proceeded under normal conditions to give the corresponding
adduct 39, which was isolated by simple filtration in 61% yield.
Pleasingly, hydrolysis with 1N HCl and treatment with pinacol in
dichloromethane (DCM) furnished the desired pinacolato
boronate 40 in 88% yield without affecting the xanthate group.
This sequence could be easily scaled up to provide > 2 g of
product (picture in Scheme 4). A number of other geminal xanthyl
boronates 41-49 were similarly prepared. The two yields given for
each substance correspond to the radical addition for the first and
to the exchange of the diethanolamino for a pinacolato group for
the second. The facile creation of quaternary centers, illustrated
by adducts 47-49, is one of the strengths of xanthate chemistry.[15]
With a series of geminal boronyl xanthates in hand, the feasibility
of the second radical addition could be tested. Initially, we
examined the reactions of xanthate 40 with various alkenes
(Scheme 5). The addition was again found to proceed best at a
slightly higher temperature (100 °C), neat or in the minimum
amount of solvent. Inspection of examples 52-66 compiled in
Scheme 5 gives an idea of the range of boronates that can be
accessed. The adducts, essentially all 1:1 mixtures of
diastereoisomers, were reductively dexanthylated with
tris(trimethylsilyl)silane[16]
to
simplify
spectroscopic
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Scheme 5. Synthesis of protected α-aminoboronic acids. [a] Reaction run at
Scheme 6. Modular synthesis of internal boronates. [a] Reaction run in refluxing
reflux in DCE; [b] Reaction run at 60°C. AIBN
=
2,2’-Azobis(2-
DCE; [b] 2 h reaction; [c] 3 h reaction.
methylpropionitrile).
Even more complex boronates can be constructed by combining
three different alkenes in succession. Two examples are depicted
in Scheme 7. In the first, xanthate 81, made by reaction of S-
cyanomethyl-O-ethyl xanthate to N-vinyl phthalimide,[17] is first
added to vinyl boronate 37 to give 82 and the B(DEA) group then
replaced by a radical stabilizing Bpin unit. A second addition to
allyl acetate is now possible leading to compound 85 after
reductive removal of the xanthate group from adduct 84. Three
new carbon-carbon bonds have thus been created in the process.
In the second example, the starting xanthate 86 is prepared by
addition of S-malonyl xanthate to 1,3-diacetyl-1-imidazolone,[18]
and a similar sequence furnishes highly decorated boronate 90
via intermediates 87-89.
The synthesis of trialkoxysilane 58, an interesting compound for
material sciences, and di-boronates 63 and 64, and tri-boronate
65, as well as protected amino acid 66 are noteworthy.
Furthermore, all these adducts derived from xanthate 40 can be
viewed as masked γ-aminoboronic acids, or boron analogues of
γ-aminobutyric acid (GABA), which could prove to be of medicinal
significance.
Extension of the second addition to a few of the boronyl xanthates
displayed in Scheme 4 was equally successful and gave adducts
67-77 (Scheme 6). The yield in adducts 75-77 was, however,
unexpectedly low. The source of the complication was revealed
in the case of addition of xanthate 42 to allyl trimethysilane, which
gave compound 77 in 35% yield after a 2 h reaction time and 24%
after 3 h, pointing to a gradual degradation of the product under
the reaction conditions. A more careful examination of the crude
mixture showed the presence of double addition product 80 (16%)
as a mixture of 4 diastereoisomers. A 1,5-hydrogen translocation
has clearly taken place on radical 78 to give the more stable
regioisomeric radical 79, which then adds to allyl trimethysilane
and transfers the xanthate group from the starting xanthate 42. It
is quite probable that this unwanted internal hydrogen atom
transfer is occurring with some of the other examples and causing
a lowering of the yield. The presence of three uncontrolled
asymmetric centers in such side-products obviously complicates
a superficial analysis.
Scheme 7. Modular synthesis of complex boronates.
The observation that the yield of the additions of xanthates
derived from substituted pinacolato boronates were generally
significantly higher than those for the parent boronate 18 was
puzzling. One simple explanation was the greater hydrolytic
stability of the more hindered substituted boronates and the
corresponding lesser formation of side-products, which not only
lower the yield but could even act as chain inhibitors. To test this
hypothesis, we prepared bromomethyl benzopinacolato boronate
91 by a modification of the literature procedure[19] and converted
it into corresponding xanthate 92. This nicely crystalline and easy
to purify compound was prepared on a 10 mmol scale and tested
on a number of alkenes.
As can be seen from the results assembled in Scheme 8, the
yields of the addition reactions are comparable to those of the
simpler xanthate 18 pictured in Scheme 3, with the notable
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RESEARCH ARTICLE
exception of 101, which was produced in a significantly higher
yield (60%) as compared to pinacolato analogue 35 (36%).
Clearly, the use of the less readily available benzopinacolato
boronate 98 does not offer significant advantages, apart from the
crystallinity of reagent and the greater stability of the adducts to
chromatography on normal silica gel. The possible partial
hydrolysis of the pinacolato boronates is also obviously not the
cause of the moderate yields in the case of the additions of
xanthate 18. The reason must therefore lie elsewhere, perhaps in
the increased stability of the more substituted initial α-boronyl
radical.
Scheme 9. Synthesis of a methyl substituted benzopinacolato boronate.
comparable to that of a boronate (6-7 kcal/mol).[10] The methyl
group contributes an extra 2-3 kcal/mol of stabilization energy.
The relative difference in stabilization energy between ester
substituted radicals 109 and 110 on one hand and α-boryl radicals
111 (or 19) and 112 on the other is therefore comparable. To
explain the disparity in yield between additions of primary and
secondary α-boryl xanthates, one must assume that either the
calculated stabilization energy for α-borylmethyl radicals has
been overestimated or there are unusually important polar factors
at play, or possibly both. In the present instance, it is not obvious
how a simple methyl group could exert such a significant polar
effect on the course of the addition.
Scheme 8. Synthesis of benzopinacolato boronates.
Scheme 10. Comparison of radical stabilities.
To test this second working hypothesis, we prepared the methyl
substituted homologue, benzopinacolato boronyl xanthate 104,
from the corresponding bromide 103, itself obtained from
dibromide 102 by a Matteson reaction with methyl Grignard
reagent according to the literature procedure,[20] as outlined in
Scheme 9. The addition of xanthate 104 to N-allyl phthalimide
proceeded smoothly to furnish adduct 105 in 81% yield, as a
nearly 1:1 mixture of diastereoisomers. To simplify the
characterization, the xanthate group was reductively removed to
give compound 106.
We finally explored the possibility of controlling the
stereochemistry in the addition step. To this end, we enlisted the
bulky C2 symmetrical diol 113 derived from tartaric acid, a chiral
auxiliary extensively studied by Pietruszka and co-workers.[22]
Heating with vinyl boronic acid in the presence of molecular
sieves furnished the corresponding boronate 114, to which
addition of xanthate 38 afforded adduct 115 in 60% yield, with
essentially no stereoselectivity. This is not surprising since the
transfer of the xanthate group is fast and reversible, and the
reaction is under thermodynamic control. This example belongs
to the cases where the addition of the xanthate can be
accomplished with adequate efficiency directly on a pinacolato-
type boronate, without the need for passage by a MIDA or
diethanolamino-type boronate.
Thus, the presence of a simple methyl substituent is sufficient to
cause a dramatic difference in the yield (81% vs 49% for 105 and
94). We have not previously observed such an important
difference in the yield of the xanthate addition upon the insertion
of a methyl substituent, for example between acetate and
propionate derived xanthates 107 and 108, yet the calculated
stabilization of a radical by an ester group (5-6 kcal/mol)[21] is
Addition of xanthate 115 to allyl trimethylsilane and reductive
removal of the xanthate group from adduct 116 provided
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compound 117 as a mixture of diastereoisomers, with dr = 80:20.
The radical addition to the olefin is an irreversible step and now
the process is under kinetic control, allowing in this case an
honorable control of the stereoselectivity. Repetition of this
experiment at 0 °C, using Et3B / air as the initiator, furnished
directly the dexanthylated product 117 in modest yield (28%) and
with no improvement on the stereoselectivity (ca 73:27). Much
further work will be necessary to attain diastereoselectivities
comparable to those observed with ionic and organometallic
reactions, where steric effects have a more pronounced influence.
boronic acid substituted azepines. Studies along these lines are
underway.
Acknowledgements
We thank Ecole Polytechnique for a scholarship to Q. H. and J.
M., and Mr Piotr Roest (University of Toronto) for a few
preliminary experiments performed within the framework of a brief
internship at Ecole Polytechnique, and Mrs Sophie Bourcier and
Mr Vincent Jactel (both at Ecole Polytechnique) for HRMS
measurements.
Keywords: radical addition • radical stabilities • xanthates•
boronates • aminoboronic acids
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Conclusion
In summary, the present study demonstrates the possibility of
constructing highly functional and otherwise inaccessible
boronates. The boron group can be placed at the beginning, at
the end, or in the middle of the structures by switching the
hybridization of boron from a non-stabilizing sp3 to a stabilizing
sp2 mode and thus modulating the stability of the intermediate
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become possible. Moreover, the use of bulky chiral boronate
esters could allow the enantioselective synthesis of complex
organoboron compounds. Finally, the variety of accessible
associations of functional groups opens up numerous
opportunities for post-modification using all the armamentarium of
the synthetic organic chemist. For example, compound 59 is a
protected 1,6-aminoaldehyde; it could act as a building block for
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10.1002/anie.201906497
Angewandte Chemie International Edition
RESEARCH ARTICLE
Entry for the Table of Contents
RESEARCH ARTICLE
Text for Table of Contents: To
stabilize or not to stabilize.
Qi Huang, Jean Michalland, Samir Z.
Zard*
Alternating the relative stabilities of
the intermediate radicals, by switching
the hybridization of the adjacent boron
atom from sp2 to sp3 and vice-versa,
allows a convenient control of
successive intermolecular radical
additions leading to complex, highly
functional boronates.
Page No. – Page No.
Alternating Radical Stabilities.
Convergent Route to Terminal and
Internal Boronates
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