RESEARCH
| REPORT
In addition, the amine-substituted hydroxyl
benzoxaborin (5d), a known cross-linker for
constructing saccharide-based hydrogels, was
recently prepared in seven steps (23); for com-
parison, subjection of commercially avail-
able 6-bromo-2,3-dihydrobenzofuran to this
boron-insertion condition, followed by one-
pot aminolysis of the B−Mes bond and a Ni-
catalyzed C−N bond formation using lithium
bis(trimethylsilyl)amide (LiHMDS) as the
amine source (27), provided the cyclic boro-
nate product 5d in 48% yield in two steps.
As expected, the boron moiety in the in-
sertion products could be conveniently con-
verted to various other functional groups (Fig.
together with the one-carbon ring expansion
strategy, was demonstrated in a streamlined
formal enantioselective synthesis of the anti-
hypertensive drug nebivolol (Fig. 3E). The key
chiral chromane intermediate (15) was previ-
ously prepared, either in 37% yield with 82%
enantiomeric excess (ee) in five steps using
a chiral auxiliary approach (35) or 30% yield
with 80% ee in 10 steps using chiral catalysis
(36). Here, from the commercially available
5-fluoro-2,3-dihydrobenzofuran, the same com-
pound (15) was accessed in just three steps,
with a 50% overall yield and 97% ee, through a
sequence of boron-insertion, one-carbon ring
expansion, and an Ir-catalyzed asymmetric
allylic alkylation (37).
form product 3a (fig. S11) and rapid buildup
of intermediate 4a during this period. This
observation is consistent with the hypothesis
of an initial transformation of 1a to 4a and
also implies that the subsequent Ni-catalyzed
C−Br/B−Br coupling step is rate-determining
(for more details, see supplementary materials,
section 6).
To gain deeper understanding of the reac-
tion mechanism, density functional theory
(DFT) calculations were carried out with cyclic
ether 1a as the model substrate. The most
favorable pathway from the calculations sup-
ported the cleavage-then-rebound mechanism
via Zn/Ni tandem catalysis (Fig. 4D). First,
3
B). For example, treatment of the crude
MesBBr
2
binds to the ether oxygen assisted by
product 3a with hydrogen peroxide and base
afforded 1,2-tyrosol (6a) in excellent yield. The
Suzuki−Miyaura coupling of 3a with bromo-
benzene efficiently provided o-phenethylphenol
To gain some insights into the reaction
mechanism, control experiments were first
carried out (Fig. 4). In the absence of the Ni
catalyst and Zn, no reaction occurred be-
the in situ generated 1a·ZnBr
form complex IM2, which then undergoes
facile Zn-promoted bromide anion abstrac-
tion (TS1) with an activation free energy (DG )
2
dimer (IM1) to
‡
(
7a). The 2H-benzoxaborin product could be
tween MesBBr
standard conditions; however, upon addi-
tion of a catalytic amount of ZnBr , the ring-
2
and substrate 1a under the
of 11.4 kcal/mol to form an ion pair IM3,
easily transformed to the potassium trifluoro-
borate (Molander salt) 8a, which could serve as
a precursor of a carbon radical or nucleophile
N
followed by an S 2-type C–O cleavage (TS2,
‡
2
DG = 16.2 kcal/mol) (40). The low barriers in
this ring-opening process are consistent with
the facile formation of alkyl bromide 4a ob-
served experimentally. Several mechanistic
pathways are possible in the subsequent Ni-
catalyzed C–Br/B–Br coupling with interme-
diate 4a (41). Among these, a radical chain
reaction and a double oxidative addition would
both be consistent with the radical clock ex-
periment. Our DFT calculations suggest that
the most favorable pathway involves the fac-
ile B–Br bond oxidative addition of 4a with
opening product 4a was formed in 89% yield
(Fig. 4A). The alkylbromide 4a could be effi-
ciently transformed to the 2H-benzoxaborin
product (3a) under the standard conditions,
which suggests the intermediacy of 4a. This
result also suggests that zinc not only serves
as the reductant but also plays a critical role
in the C−O bond cleavage, which is also con-
sistent with the fact that other reductants (Mn
or Mg) were not effective (see below and table
S1). The intermediacy of the alkyl bromide was
further supported by a competition experiment
with a linear ether, where an added alkyl bro-
mide could also be borylated (see supplementary
materials). In addition, 2,2-dimethylcoumaran
competently underwent the C−O borylation
(
3
28). Treatment of 8a with BnN converted
the C−B bond to a C−N bond (9a). In addition,
an O-to-N editing strategy was conveniently
achieved when using less-bulky PhBBr as the
2
reagent for the boron insertion (Fig. 3C) (29).
The resulting methanolysis intermediates could
be first transformed to the Molander salts,
followed by amination of the C−B bonds and
in situ dehydration, to afford the correspond-
ing pyrrolidines and piperidines (10a to 10k)
from tetrahydrofurans and tetrahydropyrans,
respectively. The drug molecule (−)-ambroxide
that contains a trisubstituted tetrahydrofuran
moiety was also a suitable substrate (10l).
This method also enables efficient one-carbon
ring expansion reactions (Fig. 3D). Type I ring
expansion involves direct homologation of the
(
0)
‡
2
Ni (L1) [TS3, DG = 3.0 kcal/mol with re-
spect to the 4a·Ni(0) complex IM4] (42) to
generate a Ni(II) boryl species IM5 (43). Sin-
gle electron reduction of IM5 by zinc powder
forms a Ni(I) boryl complex IM6. From IM6,
the C–Br bond cleavage may occur via either
2
reaction using less-bulky PhBBr as the re-
agent (see supplementary materials), implying
that the mechanism for the C−O bond cleav-
N
the S 2-type C–Br oxidative addition (TS4,
‡
boron-insertion product with LiCH
2
Cl (30, 31)
DG = 18.2 kcal/mol) (44) or the bromine atom
‡
followed by an intramolecular Mitsunobu reac-
tion, which converts 2,3-dihydrobenzofuran to
chromane 12. Type II expansion capitalizes on
the boronate intermediate after the methanolysis,
which can initiate a boron-based homologation
N
age may not be limited to a S 2 pathway and
could be substrate-dependent.
transfer (TS5, DG = 19.5 kcal/mol) to form
an alkyl radical IM7 (27, 28), which then re-
combines intramolecularly with the Ni(II)
center. The comparable barriers of these tran-
sition states suggest that either pathway may
operate depending on the steric environment
of the alkyl bromide intermediate (e.g., primary
versus secondary). For example, the reaction
with the a-substituted ether (S-1z) favors the
bromine-atom-transfer pathway by 4.2 kcal/mol
(fig. S37), consistent with the complete prod-
uct racemization observed in experiment.
Both C–Br bond cleavage pathways lead to tran-
sient Ni(III) species (IM8 and IM9), which
then undergo fast reductive elimination to
form the cyclic boron-insertion product 3a.
The resulting Ni(I)Br intermediate could be
The nature of the alkyl group in the cou-
pling reaction and the role of the Ni catalyst
were key to understanding the subsequent
C−B bond formation step. First, the use of a
cyclopropyl-substituted ether as substrate
led only to the ring-opening product (3as),
suggesting the possibility of radical inter-
mediates (Fig. 4B). In addition, a substrate
(S-1z) containing an a-stereocenter initially
enriched to 98% ee was observed to racemize
completely in both the oxaborinane and the
alcohol products (Fig. 4C). In contrast, the
ring-opening intermediate (the secondary
alkyl bromide) retained high enantiopurity
(90% ee), which further supports the gener-
with LiCHCl
2 2
followed by a ZnCl -mediated
(32) intramolecular chloride displacement (33)
to provide a boron-retentive ring expansion.
Although not explicitly shown here, the re-
sulting B(pin)-substituted chromane (13a to
1
3d) could potentially undergo various boron-
mediated downstream transformations. Type III
expansion takes advantage of the carbon sub-
stituent on the borylation reagent (RBBr
Double 1,2-migration (34) with the resulting
cyclic borinate took place when the LiCHCl
ZnCl combination was used. Upon oxidation
2
).
2
/
2
3
of the C−B bond, the subsequent Mitsunobu
reaction delivered the ring-expansion products
ation of sp carbon radicals in the C−B bond
2
reduced by Zn(0) to form ZnBr and regener-
formation, probably via single electron trans-
ate the Ni(0) catalyst.
3
(14a to 14 g) containing the carbon substituent
fer between active Ni species and the C(sp )-Br
As ethers are readily available and robust
substrates, this boron-insertion method could
be used to streamline synthesis of complex
from the boron reagent in good overall yield.
Finally, the utility of the ether editing method,
moiety (38, 39). Finally, kinetic studies were
performed, showing an induction period to
Lyu et al., Science 372, 175–182 (2021)
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