Exploring benzylicgem-C(sp3)-boron-silicon and boron-tin centers as a synthetic platform

Article abstract of DOI:10.1039/d1sc01741a

A stepwise build-up of multi-substituted C_sp3carbon centers is an attractive, conceptually simple, but often synthetically challenging type of disconnection. To this end, this report describes howgem-α,α-dimetalloid-substituted benzylic reagents bearing boron/silicon or boron/tin substituent sets are an excellent stepping stone towards diverse substitution patterns. Thesegem-dimetalloids were readily accessed, either by known carbenoid insertion into C-B bonds or by the newly developed scalable deprotonation/metallation approach. Highly chemoselective transformations of either the C-Si (or C-Sn) or the C-B bonds in the newly formedgem-C_sp3centers have been achieved through a set of approaches, with a particular focus on exploiting the synthetically versatile polarity reversal in organometalloids by λ³-aryliodanes. Of particular note is the metal-free arylation of the C-Si (or C-Sn) bonds in suchgem-dimetalloidsviathe iodane-guided C-H coupling approach. DFT calculations show that this transfer of the (α-Bpin)benzyl group proceedsviaunusual [5,5]-sigmatropic rearrangement and is driven by the high-energy iodine(iii) center. As a complementary tool, thegem-dimetalloid C-B bond is shown to undergo a potent and chemoselective Suzuki-Miyaura arylation with diverse Ar-Cl, thanks to the development of the reactivegem-α,α-silyl/BF₃K building blocks.

Full text of DOI:10.1039/d1sc01741a

Chemical
Science
View Article Online
View Journal | View Issue
EDGE ARTICLE
Exploring benzylic gem-C(sp3)–boron–silicon and
boron–tin centers as a synthetic platform†
Cite this: Chem. Sci., 2021, 12, 10514
ab
All publication charges for this article
have been paid for by the Royal Society
of Chemistry
Wei W. Chen,
Anton Cunillera,
Nahiane Pipaon Fernandez,a Marta Dıaz Baranda,ab
´
´
b
ab
b
*
Laura G. Rodrıguez,
Alexandr Shafir
´
a
*
and Ana B. Cuenca
3
A stepwise build-up of multi-substituted Csp carbon centers is an attractive, conceptually simple, but often
synthetically challenging type of disconnection. To this end, this report describes how gem-a,a-
dimetalloid-substituted benzylic reagents bearing boron/silicon or boron/tin substituent sets are an
excellent stepping stone towards diverse substitution patterns. These gem-dimetalloids were readily
accessed, either by known carbenoid insertion into C–B bonds or by the newly developed scalable
deprotonation/metallation approach. Highly chemoselective transformations of either the C–Si (or C–Sn)
3
or the C–B bonds in the newly formed gem-Csp centers have been achieved through a set of
approaches, with
a particular focus on exploiting the synthetically versatile polarity reversal in
organometalloids by l3-aryliodanes. Of particular note is the metal-free arylation of the C–Si (or C–Sn)
bonds in such gem-dimetalloids via the iodane-guided C–H coupling approach. DFT calculations show
that this transfer of the (a-Bpin)benzyl group proceeds via unusual [5,5]-sigmatropic rearrangement and
is driven by the high-energy iodine(III) center. As a complementary tool, the gem-dimetalloid C–B bond
is shown to undergo a potent and chemoselective Suzuki–Miyaura arylation with diverse Ar–Cl, thanks
to the development of the reactive gem-a,a-silyl/BF3K building blocks.
Received 27th March 2021
Accepted 28th June 2021
DOI: 10.1039/d1sc01741a
rsc.li/chemical-science
Along these lines, the prospect of selective introduction of
Background and motivation
two different substituents has also prompted interest in deriv-
atives bearing mutually distinct metalloids, either as chemically
differentiated boryl fragments5 or as a hetero-metalloid pair.
Inherent reactivity differences between the two carbon–metal-
loid bonds can then be leveraged to gain chemo-control in
modular C–C and/or C–heteroatom bond-forming sequences,
with 1,1-silyl-boranes constituting an obvious paradigm for
such a hetero-gem-dimetalloid platform.6 As part of our interest
in this area, some of us recently showed that 1,1-SiMe3/B(OR)2
disubstituted alkenes could be obtained by a novel boron-
Wittig-type olenation using the 1,1,1-B,B,Si-trimetalloid
2
In the context of diversity-oriented synthesis, reagents bearing
geminally disposed bis-metalloid units represent an attractive
class of building blocks. Expected to act as bis-nucleophilic
components in a variety of reactivity patterns, such molecules
may set the stage for densely 1,1-disubstituted carbon centers
through sequential reactions with two electrophilic partners,
including via catalytic cross-coupling. A potentially rewarding
3
aim is the use of the Csp -gem-dimetalloid group as a platform
for straightforward access to multi-substituted methanes.1 This
basic unit received a renewed spotlight as part of medicinal
chemistry's “escape from the atland” endeavor,2 and has been
the subject of important recent methodological breakthroughs.3
In terms of the substitution pattern, compounds featuring
a carbon center anchoring a gem-boron/boron pair have been
particularly popular, whereby a variety of methods have been
methane species,7 and that the newly formed olenic Csp
-
gem-Si,B group could be engaged in stereoselective access to
tetra-substituted olens. Encouraged by these earlier advances,
we set our sight on the gem-B/Si-benzylic scaffold of type 1
(Scheme 1). Creative recent approaches to 1 include a Suzuki–
Miyaura mono-arylation of the aforementioned 1,1,1-bis-(Bpin)-
trialkylsilyl methane 2,8 including its enantioselective desym-
metrization variant,8b or a homologation of an Ar–B bond using
the diazo-reagent Me3SiCHN2, 3 (Scheme 1A and B).9 However,
these advances in the preparation of 1 contrast with the scarcity
of methods that employ such gem-dimetalloids in the modular
3
developed to form such Csp -gem-diboronates and to selectively
transform one or both of their C–B sites.4
a
´
`
Department of Organic and Pharmaceutical Chemistry, Institut Quımic de Sarria,
´
URL, Vıa Augusta 390, Barcelona 08017, Spain. E-mail: anabelen.cuenca@iqs.url.edu
bDepartment of Biological Chemistry, Institute of Advanced Chemistry of Catalonia,
IQAC-CSIC, c/ Jordi Girona 20, Barcelona 08034, Spain. E-mail: alexandr.shar@
iqac.csic.es
3
build-up of poly-substituted Csp centers. For example, while the
C–Bpin bond in such species was recently shown to undergo
a Pd-catalyzed coupling with iodoarenes (Scheme 1C),9b the
† Electronic supplementary information (ESI) available. See DOI:
10.1039/d1sc01741a
10514 | Chem. Sci., 2021, 12, 10514–10521
© 2021 The Author(s). Published by the Royal Society of Chemistry

View Article Online
Edge Article
Chemical Science
Scheme 2 Complementary deprotonation/quench approaches to the
benzylic gem-Si/B core 1a. Approach A: (i) in hexane using 1.0 equiv. of
n-BuLi at rt; (ii): with 3 equiv. of B(OMe)3, ꢀ78 ꢁC to rt. Approach B: Li-
TMP generated at ꢀ40 ꢁC prior to addition of BnBpin at ꢀ78 ꢁC.
Approach C: lithiation of Me3SiCH2Cl with sec-BuLi/TMEDA followed
by addition of Ar–Bpin.
Scheme 1 (A and B) Recent approaches to the gem-Si/B compound
class 1, and (C) an example of Pd-catalyzed arylation of 1 with Ar–I; (D)
the outline of the gem-dimetalloid diversification strategy described
herein.
in reproducibly good yields on scales of up to 10–15 mmol.
chemistry at the C–Si bond has been largely limited to the more
established desilylative SN2 alkylations.9b In this report, we
describe a series of approaches to expand the arsenal of che-
moselective transformations of the gem-B/Si-benzylic scaffold 1.
In particular, our prior experience in polarity reversal and
rearrangement reactions of organosilanes induced by hyper-
valent iodine compounds has now been leveraged to achieve
a metal-free selective C–Si and C–Sn arylation, along with
a series of umpolung reactions (Scheme 1D). Among interesting
gem-dimetalloid targets, we also show that the triuoroborate
analogue of 1 can be prepared, allowing for the Suzuki–Miyaura
arylation (see Scheme 1D le) using bromo- and chloro-arenes.
3
Similarly, capping the Csp –B unit with dimethylpropane-1,3-
diol could be used to obtain the Bneop derivative 1a0 in 52%;
the diminished yield in the latter case is likely due to the
instability of the Bneop derivatives under column chromatog-
raphy on SiO2. A second approach was also developed starting
with a commercial benzylboronate core via deprotonation using
a hindered lithium 2,2,6,6-tetramethylpiperidide base (Li-TMP),
followed by the addition of a chlorosilane.10 This route was
convenient for producing derivatives with silyl groups other
than SiMe3, such as the gem-SiEt3 species 1b (84%, Scheme 2,
approach B) or the Si(tBu)Me2 analogue 1c (60%). Finally, when
a suitable B- or Si-benzylic precursor was not readily available,
a Matteson-type homologation9c of several Ar–Bpin species with
an in situ generated Me3Si(Cl)CH–Li reagent was found to
proceed smoothly. Following this route, the meta-halo gem
derivatives 1d and 1e were obtained in 82% and 85% yields,
respectively (Scheme 2, approach C).
Results and discussion
As was readily appreciated from the outset, the successful usage
of the gem-Si/B molecular platform such as 1 would be contin-
gent upon more ready access to this compound class. Our initial
approach to 1a involved the insertion of the carbenoid-type
fragment “SiMe3(H)C:” of the diazo species Me3SiCHN2, 3,
into the B–C bond of arylboroxines, as reported recently by Ley
and co-workers.9a Following this route (as in Scheme 1B), the
phenyl derivative 1a was obtained in good yields by heating
phenylboroxine, (PhBO)3, with 3 in toluene. Despite the success
of this approach on small scales (1–2 mmol), we continued our
search for a complementary method to access gram quantities
of the reagent. Aer some trials, it was found that 1a could be
conveniently prepared from commercial benzyl(trimethyl)
silane by deprotonation at the benzylic position, followed by
quenching the resulting benzyllithium species with an electro-
philic B(OR)3 reagent (Scheme 2, approach A). In our hands,
treating the a-B(OH)2 intermediate 4a with pinacol provided 1a
With gram quantities of the model gem-hetero-dimetalloid
1a now accessible, we turned our attention to a selective
transformation of its C–Si moiety. Although a Hiyama-type
metal-catalyzed C–Si arylation coupling would be a valuable
tool in this system, the applications of this reaction even to
simple benzylsilanes are scarce, and generally require an acti-
vated silicon group.11 As an alternative, we sought to engage 1a
in metal-free C–Si arylation with l3-ArI(OAc)2 species. This
possibility was based on our recent experience in the iodane-
guided C–H benzylation of iodoarene cores, a process re-
ported independently by the Hyatt and our laboratories.12 As
depicted in Scheme 3A for a benzylsilane model, this unusual
manifold would begin with the benzyl group transfer to the
iodine(III) center. While related to the iodane-guided ortho-C–H
coupling processes,13,14 the benzyl group in such case gave rise
© 2021 The Author(s). Published by the Royal Society of Chemistry
Chem. Sci., 2021, 12, 10514–10521 | 10515

View Article Online
Chemical Science
Edge Article
C–H site to one of the boronate O atoms (see TS2 in Scheme
4B).
A brief scope survey showed that the coupling efficiency may
benet from the presumably less encumbered Bneop substit-
uent, as seen in the formation of the Bneop analogue 60 in 65%
yield starting from 1a0 (Table 1). A similar moderate improve-
ment was also seen for the C–H benzylation at the 4-position of
l3-1-(diacetoxyiodo)-naphthalene, with a 43% yield obtained for
the a-Bpin derivative 7 and a 57% yield (NMR) for the Bneop
analogue 70. The reaction was also successful in providing the
para-(a-boryl)benzylated derivative of the protected 3-iodoani-
line (prod. 8, 67%), the meta-halo derivatives 9 and 10 (63% and
57%), and the iodoxylene coupling product 11 (85%). The
success of these reaction may partly be due to the presence of
electron-releasing substituents in most of the iodoarene cores.16
Indeed, the use of the non-activated simple PhI(OAc)2 initially
led to the target arylated species 12 in yields of ꢂ20%. Finally, as
we previously observed for l3-iodoanes blocked at the para
position,12b exposing 1a to the l3-iodane derived from iodome-
sitylene led to an efficient formation of the meta-CH–benzylated
species 13.17 The scope of this meta-substitution was then
extended to the m-xylyl derivative 14 and the bromo-target 15.
The method was also tolerant of a gem-Si/B reagent bearing
a second BPin substituent on the aromatic ring (Table 1, prod.
16).
Scheme 3 (A) A precedent in the iodane-guided C–Si arylation of
benzylsilanes with l3-iodanes (Hyatt et al. and Shafir et al.), 2018–19.
(B) Potential selectivity dilemma in the analogous arylation of 1a.
to a cationic head-to-tail p-stacked intermediate I, which
evolves via the C–C bond formation at the ArI para-C–H posi-
tion.12b We note that the Hyatt lab also showed the possibility of
similarly engaging benzylic triuoroborate nucleophiles.12a
Considering an application of such a manifold to 1a, an
interesting question arises as to which of the substrate's two
metalloid groups, i.e. Si or B, would be retained in the product
(Scheme 3B). Thus, the reactivity of 1a with the iodoanisole-
based l3-ArI(OAc)2 reagent 5 was probed at ꢀ78 ꢁC. While
no reaction took place between 1a and 5 in a CH3CN/CH2Cl2
mixture without an acid additive, enhancing the reactivity of
the l3-iodane with an acidic activator, either BF3$Et2O or
TMSOTf,15 led to the new benzylated species 6 in 55% yield,
with the new C–C created para to the iodine (Scheme 4). The
product retains the Bpin group, suggesting a more reactive
nature of the C–Si bond during the putative transmetallation
step, a feature that contrasts with C–B-specic Pd-catalyzed
coupling reactions (as in Scheme 1C). A DFT analysis was
used to understand how the process could play out for a gem-
B/Si-dimetalloid substrate. Calculations on the –B-glycolate
analogue of 1a (–Bgly, Scheme 4B) point to a cationic p-
stacked intermediate II with a head-to-tail alignment of the
two aromatic fragments. This species is analogous to the
adduct I, previously identied in a para-CH–benzylation
In view of the initially low yields in the coupling between 1a
and PhI(OAc)2, due to the formation of benzaldehyde and other
benzylic oxidation side products, we considered replacing the
SiMe3 fragment with a potentially more reactive SnBu3 group.
With that in mind, two new gem-Sn/B-dimetalloids 17 and 170
were synthesized from the benzylboronate 18 via benzylic
deprotonation followed by quenching with R3SnCl (Scheme 5).
(Scheme 3), and similarly evolves via
a
low-lying
Table 1 Chemoselective C–Si bond transformation in 1a and 1a0 via
iodane-guided para C–H couplinga
(ꢂ0.5 kcal molꢀ1) transition state to form a new carbon–
carbon bond para to iodine (Scheme 4B). The rearrangement
is expected to initially provide the ring protonated interme-
diate III. Although the nal aromatization may then take
place through proton transfer to an external base, the pres-
ence of the boronate group in III may also enable an inter-
esting low-barrier internal proton transfer from the acidic
a
b
Conditions analogous to those in Scheme 4A; ESI. Using a gem-Si/B
Scheme
4 (A) Para-selective C–H-(a-borylbenzylation) of the
precursor obtained by Suzuki–Miyaura borylation of the Ar–Cl 1d.
iodoanisole core. (B) DFT proposal for the C–C bond forming step.
10516 | Chem. Sci., 2021, 12, 10514–10521
© 2021 The Author(s). Published by the Royal Society of Chemistry

View Article Online
Edge Article
Chemical Science
Along with the transfer of an intact boryl substituent, an
important feature of the iodane-guided arylation reactions is
the retention of the synthetically versatile iodine handle. A
variety of downstream diversication routes could thus be
assayed, including Pd-catalyzed cross-coupling reactions, e.g.
Sonogashira alkynylation, Stille coupling or stanylation reac-
tions (Scheme 7, prods. 22–24).
Scheme 5 Formation of the gem-stannyl-boryl precursors 17 and 170.
While the pronounced para-C–H selectivity in the arylation
To our delight, a reaction between 17 and the l3-iodane of 1a and 17 is consistent with the iodane-guided rearrange-
PhI(OAc)2 led to the para-benzylated target 12 in 60% yield (65% ment mechanism outlined in Scheme 4, the outcome could in
by NMR), i.e. is ꢂ3 times higher than for the silyl analogue 1a principle be rationalized through a particularly selective Frie-
(Scheme 6A). This improvement may be tentatively explained by del–Cras type benzylation mechanism. Indeed, organosilanes
the enhanced ability of organo-stannanes to undergo trans- can undergo the umpolung of the C–Si unit in the presence of
metallation in iodane-guided C–H coupling reactions, a feature simple l3-iodane oxidants. In the case of the gem-dimetalloids 1
illustrated in the 1990's by the Ochiai group,13 and recently or 17, such a process might involve the benzyl iodonium
leveraged by Peng and co-workers in ortho-directed C–H cya- intermediate such as II, which would evolve by a dissociation
noalkylation.18 Similarly, while barely a trace amount of into the parent iodoarene and the a-boryl benzyl cation V. In
coupling took place between 1a and the 2-iodothiophene- such a sequence, the product would arise through an electro-
derived l3-iodane 19, switching to 17 led to the thienyl philic attack at the ArI para position (see Scheme 8A). To test for
product 20 in 50% yield (Scheme 6B). We note that although the the presence of free carbocationic species V, 17 was allowed to
2-iodothiophene core does not possess a para position per se react with PhI(OAc)2 in the presence of 1 equiv. of mesitylene,
with respect to I, the substrate's C(5)–H unit does correspond to 25. A concerted iodane-guided path would still favor the
a C–C coupling site predicted for a putative [5,5]-sigmatropic iodobenzene-derived 12, while any free V would be expected to
rearrangement path (see ESI†). Indeed, a DFT optimization of cause the functionalization of mesitylene. Here, the highly
the expected p-stacked intermediate IV (analogous to III in nucleophilic mesitylene was chosen so as to stack the odds in
Scheme 4) converges to a conformation with the benzylic favor of such a hypothetical Friedel–Cras process. Although
CH(BPin) group placed directly above the thiophene C(5)–H site the mesitylene-derived diarylmethane 26 was observed, this
(Scheme 6 bottom). Finally, the use of the Bu3Sn species 17 compound was present as a minor component, in a 1 : 5 ratio
allowed for the synthesis of the naphthyl-derived 7 to be with 12 (Scheme 8B, also see the ESI for Fig. S2†). This result
improved from the 43% reported in Table 1 using 1a to 65%. indicates that while the electrophilic aromatic substitution is
The use of 170 also allowed for the C–H coupling of an o-Br, m- possible, such a route does not represent the major path in the
OMe iodane precursor to give 21 in 51% yield.
formation of 12.
While these studies were underway, a parallel effort was
directed towards securing a complementary method for the
Scheme 7 Examples of downstream C–I diversification of 12.
Scheme 6 The C–H coupling reaction of the new gem-Sn–B benzylic
derivatives 17 and 170. The free energies in the mechanistic scheme are Scheme 8 Mechanistic assessment of the umpolung manifold in the
in kcal molꢀ1
.
oxidative coupling of 17 promoted by l3-iodanes.
© 2021 The Author(s). Published by the Royal Society of Chemistry
Chem. Sci., 2021, 12, 10514–10521 | 10517

View Article Online
Chemical Science
Edge Article
arylation of the C–B bond in gem-Si/B precursors, which we
As we hoped for, a switch from a Bpin to a BF3K gem-dime-
thought to be possible through a metal-catalyzed coupling talloid proved highly benecial for the Suzuki–Miyaura
approach. In fact, at the time when our early efforts were getting coupling with chloroarenes. While in our hands 1a failed to
underway (late 2018), there existed no literature reports on the undergo a C–B arylation with the p-Cl–methylbenzoate 28, the
coupling of a-silylated benzylboranes such as 1a. More recently, use of 27a led to very promising yields of the target diaryl-
however, Wang and co-workers described the arylation of 1 with methane 29 using a number of modern catalytic systems. In
iodoarenes using a Pd-catalyzed Ag-promoted coupling.9b,19 In particular, virtually quantitative conversions were achieved by
our case, the study centered on solving a more difficult coupling using the RuPhos/Pd(OAc)2 combination,21 or by applying the
of gem-silylborylated cores with bromo- and chloro-arenes, 3rd generation tBu3P–Pd palladacycle precatalyst (tBu3P–Pd G3),
which we hoped could be achieved using a series of newer Pd the latter as used by Biscoe and co-workers for the aliphatic
catalysts. Initial attempts to engage the Bpin precursor 1a in the secondary triuoroborate species (Scheme 10, gray inset).22 The
coupling with chloroarenes under a variety of catalytic condi- system was also suitable for bromoarenes, but gave unsatis-
tions led to unsatisfactory results. Reasoning that a more factory results with iodoarenes. This coupling efficiency is
reactive boryl substituent might prove benecial, we sought to remarkable, given that the challenging Ar–Cl electrophile is
access the triuoroborate derivative of 1a. Borrowing a page joined with the bulky a-SiMe3-substituted C(sp3) nucleophile
from the Molander group's synthesis of the methylene reagent without the loss of the potentially sensitive a-silyl substituent.
Me3Si–CH2BF3K,20 a treatment of 1a with KHF2 in an Et2O/H2O While the two catalyst systems showed similar performances,
mixture led to the precipitation of a white solid identied as the the scope of the arylation of 27a (Scheme 10) is mainly illus-
gem-silyl potassium triuoroborate 27a (Scheme 9, top path). trated using the Pd-G3 metallacycle. Hence, steric hindrance at
1
The NMR spectra of this species presented the benzylic H CH the Ar–X partner was found to be well tolerated, with nearly
signal at 1.26 ppm (broadened quartet, JH–F ¼ 7.1 Hz), and quantitative yields obtained with the ortho-bromotoluene (prod.
showed a displacement of the 11B-NMR resonance from 30, 98%), and a somewhat diminished yield for o,o-dimethyl
ꢂ33 ppm for the –Bpin group in 1a to ꢂ1 ppm for 27a. Note- bromoarene (31, 65%). Efficient coupling was also observed for
worthily, no uoro-desilylation of 27a was observed at this a series of substituted haloarenes to give diarylmethanes 32–35
stage. It was subsequently found that the lithiation/borylation in generally excellent yields. As a limitation, the coupling of the
approach, used earlier for the synthesis of 1a (i.e. as in strongly p-decient chloroquinoline was inefficient due to
Scheme 2), may be redirected toward 27a by intercepting the rampant product desilylation (prod. 36, <20%, observed by GC-
crude intermediate 4a (identied by GC-MS as two diastereo- MS). Nevertheless, the C–C coupling was also well-suited for
meric boroxine trimers, m/z ¼ 570, see the ESI†), with KHF2 naphthalene and thiophene-based haloarenes (see prods. 37–
(Scheme 9). This method circumvents the need for the isolation 39), with a somewhat lower yield in the isolation of 38 possibly
of 1a and allows for the ready synthesis of 27a on a gram scale. A due to mechanical losses during purication. The method is
small family of additional triuoroborate salts were also also suited for structure variations on the gem-Si-BF3K compo-
prepared, including 27-CF3 and 27-anis, as well the species 27b nent, including the successful formation of triuorotolyl and
and 27c, the latter with variations at the silyl group (Scheme 9), anisyl derivatives 40 and 41. Additionally, the method allowed
either from the corresponding –Bpin precursor or via for the ready formation of SiEt3 and tBuMe2Si analogues 42 and
deprotonation/silylation sequences. All were isolated as white 43, albeit with a somewhat lower yield for the latter. Our initial
or off-white powders.
venture into bio-active core functionalization involved the
coupling of the estrone moiety, which was possible starting with
the corresponding 3-Br derivative. Interestingly, the RuPhos-
based catalyst (but not the Pd-G3 system) also allowed for the
direct coupling of the more readily available 3-OTf form of the
precursor (prod. 44, 94%). The method was also applied to the
C–Cl moiety of the antihistaminic drug Loratadine, a polycyclic
N-containing bioactive chloroarene, providing the a-silyl-
benzylated core 45 in an excellent 94% yield. Likewise, the
reaction proved almost quantitative for the PPARa activator
Fenobrate as the Ar–Cl partner. Incidentally, the latter hyper-
lipidemic prodrug was recently considered for repurposing as
a SARS-CoV-2 infection inhibitor.23 Only mono-arylation was
observed in all cases, conrming the expected resistance of the
3
C
sp –SiMe3 group towards conventional cross-coupling. Inter-
estingly, although the two pre-catalysts were largely inter-
changeable, reactions conducted with the tBu3P–Pd G3 system
frequently showed a minor GC-MS peak with the same m/z value
as the target product (typically in a ꢂ25–30 : 1 area ratio). For
the –CN derivative 33, this minor isomer, 33inv, was isolated and
shown by NMR to correspond to the arylation at the para C–H
Scheme 9 A telescope synthesis of 27a from benzyl(trimethyl)silane.
(i) In hexane using 1.0 equiv. of n-BuLi at rt; (ii) with 3 equiv. of B(O-
iPr)3, ꢀ78 ꢁC to rt, and overnight; (iii) in Et2O/H2O 4 : 1. aPrepared from
the corresponding –Bpin precursors.
10518 | Chem. Sci., 2021, 12, 10514–10521
© 2021 The Author(s). Published by the Royal Society of Chemistry

View Article Online
Edge Article
Chemical Science
Scheme 10 Pd-catalyzed Suzuki–Miyaura coupling between benzyl-gem-silyl-trifluoroborates and chloro- or bromo-arenes. aMost examples
were carried out using the tBu3P–Pd G3 catalyst system: aryl halide (1 equiv.), gem-Si-BF3K precursor (2.0 equiv.), 2–10 mol% of Pd-G3 catalyst,
and K2CO3 (3.0 equiv.), in a toluene : H2O mixture; see the ESI† for details in each case. bEmploying a system composed of Pd(OAc)2 (2–3%) and
RuPhos (4–6%) and using the gem-Si-BF3K precursor (1.1–1.3 equiv.) and K2CO3 (3.0 equiv.).
position of the benzylic precursor (Scheme 10C). We note that further tests were conducted in CH2Cl2 using iodosobenzene,
while related Pd-catalyzed para-selective coupling in benzylic PhI]O, as an “acetate-free” l3-iodane oxidant. Under such
systems is known, it typically relies on the use of benzylic conditions, a reaction between 29 and mesitylene (10 equiv.)
electrophiles (e.g. benzyl chlorides), and not nucleophiles, as is afforded the differentially substituted triarylmethane 49 in an
the case in our system.24 While a number of mechanistic 82% yield, presumably via the intermediacy of the corre-
manifolds can be envisioned leading to such side-products, one sponding doubly benzylic carbocation VI (Scheme 11B). In
possibility is illustrated in the beige inset in Scheme 10C. a similar manner, a family of p-excessive arenes were also
Assuming a canonical oxidative addition/transmetallation path, engaged, including anisole, 2-iodothiophene and N-tosyl-5-
species 33inv could arise from the isomerization of the Pd(II)- iodoindole (see triarylmethanes 50–52, Scheme 11B, bottom).
benzyl fragment to one of its para-palladated forms prior to
reductive elimination. The bulky a-SiMe3 group appears to
inuence the process, as no such product was observed in the
control coupling using the simple benzyltriuoroborate
precursor (see the ESI†). In a few cases, e.g. for the Loratadine-
derived 46, the para-coupled species were formed in yields of up
to 10%. Gratifyingly, this side reaction is fully suppressed by
switching to the RuPhos-based catalyst system (i.e. the system
used to obtain the 94% yield of 46 as shown).
As a nal note, we envision that the retention of the C–Si
bond under Pd catalysis opens the door for the introduction of
a 3rd substituent at the central carbon. While this task was not
extensively pursued, some preliminary results shown below
attest to its viability. Specically, our experience with hyper-
valent iodine chemistry14a,b led us to seek the introduction of
a 3rd substituent via an umpolung transformation. It was found
that exposing the silylated diarylmethane 29 to PhI(OAc)2 and
BF3$Et2O in the standard CH2Cl2/CH3CN medium led to the
acetamide 47 as the main product (93%); in the absence of
acetonitrile, the O-acetate 48 was obtained instead (84%,
Scheme 11A). Seeking to suppress this C–O/N bond formation,
diaryl-a-silyl substrate 29.
Scheme 11 Iodane-promoted umpolung transformations of the gem-
© 2021 The Author(s). Published by the Royal Society of Chemistry
Chem. Sci., 2021, 12, 10514–10521 | 10519

View Article Online
Chemical Science
Edge Article
3 For the selected recent reviews on advances in
triarylmethane synthesis, see: (a) M. Nambo and
C. M. Crudden, ACS Catal., 2015, 5, 4734–4742; (b) X. Liu,
X. Wu, L. Zhang, X. Lin and D. Huang, Synthesis, 2020, 52,
2311–2329.
4 For reviews on the chemistry of gem-diborylalkanes, see: (a)
R. Nallagonda, K. Padala and A. Masarwa, Org. Biomol.
Chem., 2018, 16, 1050–1064; (b) N. Miralles, R. J. Maza and
Conclusions
In summary, this work expands the synthetic landscape of
versatile benzylic gem-boron–silicon and gem-boron–tin mole-
cules, going from the generation of these species to their C–M
reactivity applications. A new approach has been developed,
which complements prior routes and by which gram quantities
of benzylic gem-boron–silicon and gem-boron–tin reagents are
obtained via the straightforward electrophilic a-borylation of
the benzylsilane core. The products were isolated either as
–Bpin or novel gem-silylated triuoroborate salt derivatives. The
C–Si or C–Sn sites in these species undergo metal-free oxidative
arylation employing l3-bis(acetoxy)iodoarenes. The “iodane-
guided” mechanism leads to selective coupling at the Ar–I para
C–H site, with the molecule thus retaining both the C–I and the
C–B functional groups. In addition, a protocol was identied for
the Pd-catalyzed C–B arylation of hindered gem-SiMe3–BF3K
substrates with chloro- and bromo-arenes. We envisage that
these advances provide a strong foothold for further method
development directed towards the modular iterative construc-
tion of multi-substituted carbon centers, a task of great
importance in modern synthetic chemistry.
´
E. Fernandez, Adv. Synth. Catal., 2018, 360, 1306–1327; (c)
C. Wu and J. Wang, Tetrahedron Lett., 2018, 59, 2128–2140.
For Pd-catalyzed mono-arylation of gem-diboryl species,
including enantioselective variants, see (d) H.-Y. Sun,
K. Kubota and D. Hall, Chem.–Eur. J., 2015, 21, 19186–
19194; (e) C. Sun, B. Potter and J. Morken, J. Am. Chem.
Soc., 2014, 136, 6534–6537; (f) S. H. Cho and J. F. Hartwig,
Chem. Sci., 2014, 5, 694–698; (g) K. Endo, T. Ohkubo,
M. Hirokami and T. Shibata, J. Am. Chem. Soc., 2010, 132,
11033–11035. For additional selective functionalization of
3
C
sp -gem-diboryls, see: (h) C. E. Iacono, T. C. Stephens,
T. S. Rajan and G. Pattison, J. Am. Chem. Soc., 2018, 140,
2036–2040; (i) S. A. Murray, J. C. Green, S. B. Tailor and
S. J. Meek, Angew. Chem., Int. Ed., 2016, 55, 9065–9069.
5 (a) K. N. Babu, F. Massarwe, R. R. Reddy, N. Eghbarieh,
M. Jakob and A. Masarwa, Molecules, 2020, 25, 959–989; (b)
Data availability
´
´
´
A. B. Cuenca, J. Cid, D. Garcıa-Lopez, J. J. Carbo and
´
E. Fernandez, Org. Biomol. Chem., 2015, 13, 9659–9664.
Details of the experimental procedures, spectroscopic data and
the results of the DFT calculations are available in the ESI le.
6 W. Sun, Y. Hu, C. Xia and C. Liu, New J. Chem., 2021, DOI:
10.1039/d0nj01344g.
´
7 (a) E. La Cascia, A. B. Cuenca and E. Fernandez, Chem.–Eur.
Author contributions
J., 2016, 22, 18737–18741. For a recent tutorial review on
boron-Wittig olenation with gem-bis(boryl)alkanes, see: (b)
A. B. Cuenca and E. Fernandez, Chem. Soc. Rev., 2021, 50,
W. W. C., N. P. F., M. D. B., A. C. and L. G. R. contributed to the
experimental work; A. B. C. and A. S. contributed to ideation and
writing of the paper.
´
72–86.
8 (a) K. Endo, F. Kurosawa and Y. Ukaji, Chem. Lett., 2013, 42,
1363–1365; (b) J. Kim and S. H. Cho, ACS Catal., 2019, 9, 230–
235.
Conflicts of interest
9 (a) C. Bomio, M. A. Kabeshov, A. R. Lit, S. H. Lau, J. Ehlert,
C. Battilocchio and S. V. Ley, Chem. Sci., 2017, 8, 6071–
6075; (b) C. Wu, Z. Bao, X. Xua and J. Wang, Org. Biomol.
Chem., 2019, 17, 5714–5724. For the original Matteson C–
boron homologation: (c) D. J. S. Tsai and D. S. Matteson,
Organometallics, 1983, 2, 236–241. For an interesting gem-
silylborylation approach, see (d) L. Wang, T. Zhang,
W. Sun, Z. He, C. Xia, Y. Lan and C. Liu, J. Am. Chem. Soc.,
2017, 139, 5257–5264.
10 While this manuscript was in preparation, the formation of
analogous a-boryl carbanions was reported by Lee and
Chirik (in a different methodological context) via the
mono-deborylation of gem-bis-boryl precursors: B. Lee and
P. J. Chirik, J. Am. Chem. Soc., 2020, 142, 2429–2437.
11 For a notable example of a Hiyama-type benzylation, see:
K. Itami, M. Mineno, T. Kamei and J. I. Yoshida, Org. Lett.,
2002, 4, 3635–3638.
There are no conicts to declare.
Acknowledgements
This work was funded by MINECO (CTQ2017-86936-P), MICINN
(PID2020-113661GB-I00) and AGAUR (2017 SGR 01051 and 2017
SGR 00294), as well as nancial support from URL (2019-
URL_Proj-034), IQS-Obra Social La Caixa (2017-URL-Intermac-
010) and an entry-level grant from CSIC. IQS is also acknowl-
edged for a doctoral scholarship to W. W. C., and CSIC for the
JAE Intro scholarship for L. R. G.
Notes and references
1 For a specic review on CspI. Marek and J. F. Normant, Chem.
Rev., 1996, 96, 3241–3267-gem-dimetallated species, see:
2 (a) F. Lovering, J. Bikker and C. Humblet, J. Med. Chem., 12 (a) C. Mowdawalla, F. Ahmed, T. Li, K. Pham, L. Dave, G. Kim
¨
2009, 52, 6752–6756; (b) D. G. Brown and J. Bostrom, J.
and I. F. D. Hyatt, Beilstein J. Org. Chem., 2018, 14, 1039–
1045; (b) Y. Wu, S. Bouvet, S. Izquierdo and A. Shar,
Angew. Chem., Int. Ed., 2019, 58, 2617–2621.
Med. Chem., 2016, 59, 4443–4458; (c) T. T. Talele, J. Med.
Chem., 2020, 63, 13291–13315.
10520 | Chem. Sci., 2021, 12, 10514–10521
© 2021 The Author(s). Published by the Royal Society of Chemistry

View Article Online
Edge Article
Chemical Science
13 For one of the earliest forays into iodane-guided C–H 18 J. Tian, F. Luo, C. Zhang, X. Huang, Y. Zhang, L. Zhang,
coupling, see M. Ochiai, T. Ito, Y. Takaoka and Y. Masaki,
J. Am. Chem. Soc., 1991, 113, 1319–1323.
L. Kong, X. Hu, Z. X. Wang and B. Peng, Angew. Chem., Int.
Ed., 2018, 57, 9078–9082.
14 (a) For a recent overview on iodane-guided C–H coupling, 19 For the closely related precedent on the use of Ag2O, see: (a)
including a discussion on the unproductive Umpolung
phenomenon, see W. W. Chen, A. B. Cuenca and A. Shar,
Angew. Chem., Int. Ed., 2020, 59, 16294–16309. For related
review articles, see: (b) A. Bauer and N. Maulide, Chem.
Sci., 2021, 12, 853–864; (c) I. F. D. Hyatt, L. Dave, N. David,
D. Imao, B. W. Glasspoole, V. S. Laberge and C. M. Crudden,
J. Am. Chem. Soc., 2009, 131, 5024–5025. For the origin of the
acceleration of certain Suzuki–Miyaura coupling by Ag2O,
see: (b) J. Uenishi, J. M. Beau, R. W. Armstrong and
Y. Kishi, J. Am. Chem. Soc., 1987, 109, 4756–4758.
K. Kaur, M. Medard and C. Mowdawalla, Org. Biomol. 20 G. A. Molander, C. S. Yun, M. Ribagorda and B. Biolatto, J.
Chem., 2019, 17, 7822–7848. Org. Chem., 2003, 68, 5534–5539.
15 For the activation of ArI(OAc)2 reagents by acids such as 21 S. D. Dreher, S.-E. Lim, D. L. Sandrock and G. A. Molander, J.
HOTf and BF3$Et2O, see: S. Izquierdo, S. Essa, I. del Org. Chem., 2009, 74, 3626–3631.
Rosal, P. Vidossich, R. Pleixats, A. Vallribera, G. Ujaque, 22 (a) L. Li, S. Zhao, A. Joshi-Pangu, M. Diane and M. R. Biscoe,
´
A. Lledos and A. Shar, J. Am. Chem. Soc., 2016, 138,
J. Am. Chem. Soc., 2014, 136, 14027–14030; (b) N. C. Bruno,
M. T. Tudge and S. L. Buchwald, Chem. Sci., 2013, 4, 916–920.
12747–12750.
16 For earlier examples of improved performance of electron- 23 S. P. Davies, C. J. Mycro-West, I. Pagani, H. J. Hill,
rich l3-iodanes in related processes, see: (a) M. Ochiai,
M. Kida and T. Okuyama, Tetrahedron Lett., 1998, 39,
6207–6210; (b) H. R. Khatri and J. Zhu, Chem.–Eur. J., 2012,
18, 12232–12236.
Y.-H. Chen, R. Karlsson, I. Bagdonaite, S. E. Guimond,
Z. Stamataki, M. Andrade De Lima, J. E. Turnbull, Z. Yang,
E. Vicenzi, M. A. Skidmore, F. Khanim and A. Richardson,
bioRxiv, 2021, DOI: 10.1101/2021.01.10.426114.
17 The meta selectivity arises from the blocked aromatization 24 For a recent example of a related para C–H coupling in
for the initial cationic intermediate which forms
immediately aer the rearrangement step (species similar
to III). In such a case, the benzyl group in III may undergo
a [1,2] shi to the ring meta position prior to nal
aromatization.
a benzylic system, see: (a) F. de Azambuja, M.-H. Yang,
T. Feoktistova, M. Selvaraju, A. C. Brueckner, M. A. Grove,
S. Koley, P. H.-Y. Cheong and R. A. Altman, Nat. Chem.,
2020, 12, 489–496. For a review on the reactivity of Pd-
benzyl intermediates, see:(b) S. Zhang, Y. Yamamoto and
M. Bao, Adv. Synth. Catal., 2021, 363, 587–601.
© 2021 The Author(s). Published by the Royal Society of Chemistry
Chem. Sci., 2021, 12, 10514–10521 | 10521