C(sp3)-C(sp2) cross-coupling of alkylsilicates with borylated aryl bromides-an iterative platform to alkylated aryl- and heteroaryl boronates

Article abstract of DOI:10.1039/c6sc03236b

The attractive field of iterative cross-coupling has seen numerous advances, although almost exclusively in the union of sp²-hybridized partners. Conspicuously absent from this useful synthetic manifold is the inclusion of sp³-hybridized pronucleophiles that can undergo transmetalation under mild conditions. Described here is the use of primary and secondary ammonium alkylsilicates, which undergo facile C(sp³)-C(sp²) cross-coupling with borylated aryl bromide partners under photoredox/nickel dual catalysis conditions. This operationally simple procedure allows the production of alkylated small molecules possessing boronate ester (BPin, Bneopentyl, BMIDA) functional handles. Because of the extremely mild reaction conditions and the innocuous byproduct generated upon fragmentative oxidation of silicates, the corresponding borylated compounds were isolated in good to excellent yields. Aryl bromides bearing unprotected boronic acids are also generally tolerated for the first time and prove useful in multistep syntheses. Unlike many previously reported photoredox/Ni dual cross-couplings, the C(sp³)-C(sp²) bonds were forged using a transition metal-free photocatalyst, allowing a substantial increase in sustainability as well as a cost reduction. Because the developed Ni-catalyzed cross-coupling does not require discrete boron speciation control, as in many popular orthogonal Pd-based methods, this protocol represents a significant advance in atom- and step-economy.

Full text of DOI:10.1039/c6sc03236b

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C(sp3)–C(sp2) cross-coupling of alkylsilicates with
borylated aryl bromides – an iterative platform to
alkylated aryl- and heteroaryl boronates†
Cite this: DOI: 10.1039/c6sc03236b
*
Brandon A. Vara,‡ Matthieu Jouffroy‡ and Gary A. Molander
The attractive field of iterative cross-coupling has seen numerous advances, although almost exclusively in
the union of sp2-hybridized partners. Conspicuously absent from this useful synthetic manifold is the
inclusion of sp3-hybridized pronucleophiles that can undergo transmetalation under mild conditions.
Described here is the use of primary and secondary ammonium alkylsilicates, which undergo facile
C(sp3)–C(sp2) cross-coupling with borylated aryl bromide partners under photoredox/nickel dual
catalysis conditions. This operationally simple procedure allows the production of alkylated small
molecules possessing boronate ester (BPin, Bneopentyl, BMIDA) functional handles. Because of the
extremely mild reaction conditions and the innocuous byproduct generated upon fragmentative
oxidation of silicates, the corresponding borylated compounds were isolated in good to excellent yields.
Aryl bromides bearing unprotected boronic acids are also generally tolerated for the first time and prove
useful in multistep syntheses. Unlike many previously reported photoredox/Ni dual cross-couplings, the
C(sp3)–C(sp2) bonds were forged using a transition metal-free photocatalyst, allowing a substantial
increase in sustainability as well as a cost reduction. Because the developed Ni-catalyzed cross-coupling
does not require discrete boron speciation control, as in many popular orthogonal Pd-based methods,
this protocol represents a significant advance in atom- and step-economy.
Received 21st July 2016
Accepted 3rd September 2016
DOI: 10.1039/c6sc03236b
www.rsc.org/chemicalscience
iterative cross-coupling, unmasking the latent functional group
through solvent swaps/hydrolysis sequences to unveil the reactive
boronic acid or ester ([B1]). Burke has been instrumental in
Introduction
Iterative cross-coupling strategies in the presence of reactive
handles for the rapid assembly of multifunctionalized small
molecules have seen numerous advances in recent years,1
capitalizing on decades of increasingly reliable C(sp2)–C(sp2)
cross-coupling approaches. Arenes and heteroarenes constitute
the core structural feature in many materials (pharmaceuticals
or agrochemicals), and polysubstituted arenes allow multidi-
rectional syntheses, greatly extending accessible chemical
space. Although signicant improvements have been realized,
primarily in the context of iterative Suzuki–Miyaura cross-
coupling reactions,2 other traditional C–C cross-coupling
methods have been associated with various constraints, such as
high temperatures, long reaction times, and the need for strong
bases and/or protecting groups.
employing MIDA boronate esters in an iterative and recently
automated context.6 However, boronic acids and pinacol boronates
remain the most widely employed and versatile partners because
of their high and predictable reactivity using transition metal
catalysis, even though protection/functionalization from these
commercially available species is oen non-ideal in terms of atom-
and step economy.7
In a separate vein, the general union of C(sp3) pronucleo-
philes with C(sp2) partners [aryl- or alkenyl(pseudo)halides] in
N-Methyliminodiacetic boronates (BMIDA),3 1,8-diaminonaph-
thalenes (BDAN),4 and triuoroborates (BF3K)5 are the most
popular modes of boron protection ([B2], Scheme 1) in Pd-based
Roy and Diana Vagelos Laboratories, Department of Chemistry, University of
Pennsylvania, 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323, USA.
E-mail: gmolandr@sas.upenn.edu
† Electronic supplementary information (ESI) available: Experimental details and
spectral data. See DOI: 10.1039/c6sc03236b
Scheme
1 Comparison between traditional orthogonal cross-
coupling reactions and this work. ICC ¼ iterative cross-coupling.
‡ These authors contributed equally.
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the presence of reactive handles (e.g., boronic acids or boro- strategies. Successful execution would be a welcomed advance
nates) has been a longstanding challenge under traditional Pd- to the eld by accelerating the modular synthesis of complex
based catalysis and still represents a formidable transformation small molecules.16
for which a direct solution remains elusive.8 A powerful
synthetic paradigm was recently unveiled by several groups,
Results and discussion
including our own, combining mild photoredox catalysis with
transition metal cross-coupling, granting access to new C(sp3)–
We began by gauging the reactivity and tolerability of cyclo-
hexylsilicate 1 with a borylated bromoarene, 4-bromophenyl
C(sp2) bond-forming reactions of alkyl radicals.9 This process
takes advantage of a facile single electron transmetalation step,
circumventing the high-energy and difficult two-electron
transmetalation required by traditional alkyl pronucleophiles
(e.g., alkylboron reagents).
pinacolboronate (2). The combination of photocatalyst
[Ru(bpy)3](PF6)2, (2 mol%), alongside [NiCl2(dme)]/dtbbpy
(5 mol% of each; dtbbpy ¼ 4,40-di-tert-butyl-2,20-bipyridine) in
the presence of blue LEDs was previously shown to be suitable
for cross-coupling and was attempted rst.10a Aer 16 h we
observed full conversion (99%, entry 1, Table 1) to the desired
C(sp3)–C(sp2) coupled pinacol ester 3 by HPLC analysis, without
any byproducts (e.g., protodeboronation or oxidation) tradi-
tionally associated with Pd-catalysis or more harsh coupling
conditions.
To verify that the proposed mechanistic events are tran-
spiring as hypothesized, control experiments in the absence of
blue LEDs, photocatalyst, and nickel (entries 2–4, Table 1,
respectively) afforded none of the desired coupled product, only
starting material (2). Fortunately, the organic photocatalyst
4CzIPN17 4 provided 3 in comparable yield to the ruthenium
photocatalyst (entry 6, Table 1), as did the more strongly
oxidizing iridium photocatalyst (entry 5, Table 1). Additionally,
organic photocatalyst 4 was compatible with a standard 26 W
compact uorescent lightbulb (CFL) and white LEDs (95% and
94% yield, entries 9 and 10, respectively).
Most recently, we reported the use of ammonium alkylsili-
cates that smoothly react with aryl bromides, generating new
sp3–sp2 C–C bonds.10 Under this photoredox/Ni dual cross-
coupling protocol, a variety of unactivated ammonium alkylsi-
licates were cross-coupled with various (hetero)aryl and alkenyl
halides10e or sulfonates in high yields. In comparison to
previous reports using potassium alkyltriuoroborates9b,11,14
and carboxylic acid derivatives9e,12 in photoredox/nickel-medi-
ated C(sp3)–C(sp2) cross-couplings, reactions involving ammo-
nium alkylsilicate radical precursors do not require any
additives or additional base, allowing exceptional functional
group tolerance, especially for protic functional groups. The
relatively low oxidation potential of the ammonium silicates
(E0 ¼ +0.75 V vs. SCE for 1ꢀ alkylsilicates, on average)13 allows
the use of the less expensive and readily available [Ru(bpy)3]-
(PF6)2 photocatalyst. Collectively, the extremely mild reaction
parameters used for alkylsilicates and the virtually barrierless
nature of alkyl-to-nickel transfer should allow the general
inclusion of diverse, reactive handles under this odd-electron
manifold.
With suitable reaction conditions in hand for the photo-
redox/Ni dual-catalyzed cross-coupling of 4-bromophenyl
We recently unveiled the rst general and mechanistically
orthogonal union of alkyl-BF3K nucleophiles with borylated
bromoarenes.14 This departure from strictly C(sp2) coupling
partners in an iterative fashion offers a potentially powerful tool
to access structurally more elaborate molecules in short order.
Unlike conventional, orthogonal Suzuki reactions between sp2-
hybridized bromides and sp2-hybridized boronic acids, where
orthogonality is based solely on boron speciation (Scheme 1),15
the applicability of mildly-generated sp3-carbon nucleophiles is
a feature that not only complements Pd-based iterative cross-
coupling protocols, but one that is mechanistically distinct
from preexisting cross-coupling methods, suggesting broad
impact.
Table 1 Reaction optimization
Entry
Variation from standard
% yield (HPLC)
1
2
3
4
5
No variation
No light
No [Ru(bpy)3](PF6)2
No [NiCl2(dme)]
[Ir{dF(CF3)2ppy}2(bpy)]PF6
instead of [Ru]
99
2
0
0
96
Though successful in C(sp3)–C(sp2)/C(sp2)–C(sp2) cross-
couplings, alkyl-BF3Ks possess several drawbacks, notably the
release of BF3 upon oxidative fragmentation. This byproduct is
corrosive and can inhibit reaction progression. Additionally,
BF3 can be problematic for the tolerance of some functional
groups, and its generation requires the addition of exogenous
base. In the presence of boronate esters, these inherent limi-
tations prevented the straightforward isolation of the interme-
diate boron-containing compounds.14 Therefore, we envisioned
a mild C(sp3)–C(sp2) dual catalytic cross-coupling of alkylsili-
cates with borylated aryl bromides, complementing the paucity
of Pd- and Ni-based C(sp3)–C(sp2) orthogonal Suzuki–Miyaura
6
7
8
4CzIPN (4) instead of [Ru]
[Ni(COD)2] instead of [NiCl2(dme)]
+3 equiv. HTMP
98
90
76
95
94
9
10
4CzIPN (4) with CFL
4CzIPN (4) with white LEDs
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Table 3 Examination of various boron protecting groupsa
pinacolboronate (2), we set out to determine the generality of
the developed protocol using a library of ammonium alkylsili-
cates. A range of ammonium alkylsilicates were well tolerated,
and various 2ꢀ and even 1ꢀ alkylsilicates were effectively cross-
coupled in good to excellent yields without compromising the
integrity of the boronate ester (Table 2). Brønsted and Lewis
basic 3-pyridyl (6) and aniline (12) adducts can be generated and
isolated from the corresponding silicates without issue. As the
developed protocol requires no additives or base, protic amide 7
and urea 13 can be suitably cross-coupled with 2. To our
knowledge, these oen problematic moieties have never been
cross-coupled in the presence of pinacolboronates, notably
expanding the alkyl partners and functional groups that can be
integrated under this C(sp3)–C(sp2) cross-coupling manifold. To
demonstrate the scalability of this photocatalyzed reaction,
1.0 g of 4-bromophenyl pinacolboronate 2 was coupled in
a simple round bottom ask (see ESI†) and also afforded adduct
3 in excellent yield (96%, Table 2), moreover with reduced
catalyst loading {1.5 mol% 4CzIPN, 3 mol% [NiCl2(dme)] and
[dtbbpy]}. It is also worth noting that the crude reaction proles
in nearly all cases are exceptionally clean following a simple
basic workup and extraction.18
a
Isolated yields. [NiCl2(dme)] was complexed with dtbbpy ligand prior
to reaction setup, see ESI. Reactions run on 0.5 mmol of aryl bromide.
Satised with the functional group tolerance of primary and
secondary ammonium alkylsilicates, we next explored other
common boronate esters (Table 3). Although this mild C(sp3)–
C(sp2) cross-coupling is tolerant of relatively reactive pina-
colboronate esters and does not necessitate the use of more
robust boron protecting groups as required in other iterative
methods using Pd,15 diverse masked boronate esters are none-
theless useful reagents in cross-coupling chemistry. Having
established the effectiveness of the 4CzIPN organic photo-
catalyst (4), we decided to use the latter because it is free of
costly transition metals (i.e., Ir or Ru), and therefore inherently
more sustainable and cost efficient (Table 3).19 Pinacolboro-
nates 9 and 12 and the neopentyl boronate ester adducts
(14 and 15) were isolated in good yields following standard
column chromatography.
Interestingly, yields obtained for 9 and 12 while using
4CzIPN (Table 3) are in the same range as those obtained using
[Ru(bpy)3](PF6)2 (Table 2), proving the efficiency of the organic
photocatalyst under this reaction manifold. The reactions
employing BMIDA aryl bromide proceeded to nearly full, clean
conversion, although yields of 16 and 17 were moderate
(16 isolated via crystallization) because of difficulties in puri-
cation. Nevertheless, the prepared BMIDA boronate esters can
be useful intermediates in the automated, iterative assembly of
complex molecules.6 The 1,8-diaminonaphthalene (BDan)
adducts (18 and 19) uniformly provided trace desired product.
The attractiveness of a simplied assembly of alkylated are-
nes bearing reactive, borylated handles may perhaps be most
relevant in pharmaceutical discovery chemistry. Although
successive, bidirectional reactions at both boron and the
halogen are attractive processes, we were initially interested in
isolating the alkylated BPin intermediates, as we surmised
these may serve as more useful synthetic intermediates toward
discretionary tandem reactions.15d From this viewpoint, we set
out to demonstrate the breadth of structural diversity by
examining three distinct ammonium alkylsilicates (Table 4)
with various bromo-substituted aryl- and heteroaryl pinacol
boronates. To our knowledge, heteroaromatic BPins, which are
known to be particularly sensitive because of their reactivity,
have never been successfully alkylated under a transition metal-
mediated process. The bicycloheptylsilicate (35) coupled
Table 2 Examination of various primary and secondary ammonium
alkylsilicates with borylated bromoarene 2a
a
Isolated yields. Ar ¼ 4-phenyl pinacol boronate. [NiCl2(dme)] was
complexed with dtbbpy prior to reaction setup, although pre-
complexation was shown to not always be necessary, see ESI.
Reactions run on 0.5 mmol of bromide 2 for the allotted time. 1.00
b
gram (3.5 mmol) of 2, dtbbpy (3 mol%), [NiCl2(dme)] (3 mol%) and
4CzIPN (1.5 mol%).
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Table 4 Combinatorial examination of silicate and borylated aryl
pure in a modest 46% yield. Protic and even mildly Brønsted
acidic substrates are traditionally incompatible under basic
Suzuki cross-coupling conditions, and in this context, the
aniline-derived silicate (3rd box, Table 4) together with various
borylated aryl bromides was next examined. Collectively, alkyl-
ation of various bromoarenes proceeded in generally high
yields, including the electron-rich 2-methoxypyridyl BPin 31
and the electron-poor 2-triuoromethylpyridyl BPin 33. 5-Bro-
mopyridyl-3-pinacol boronate 32 was not compatible with this
particular silicate. Observing clean crude reaction proles from
the C(sp3)–C(sp2) cross-coupling, we surmised purication
limitations (i.e., for compounds 22 and 27, Table 4) could be
overcome by directly reacting the crude cross-coupled BPin in
a following transformation. Alkylated pyridyl BPin 22 expressed
uncharacteristic instability on silica gel and thus provided an
opportunity to investigate this notion. Silicate 35 and bromo-
pyridyl BPin 36 were subjected to the standard reaction condi-
tions using 4CzIPN (4), and following a basic aqueous workup
and isolation, the alkylated crude material (22) was next sub-
jected to standard Suzuki conditions with 3-bromoacetophe-
none (Scheme 2, eqn (1)). The reaction proceeded smoothly
(even in the presence of trace residual catechol and 4CzIPN),
and difunctionalized pyridine 37 was isolated in 72% yield over
2 steps. In direct comparison to other orthogonal cross-
coupling reactions, it is evident that this iterative C(sp3)–C(sp2),
C(sp2)–C(sp2) coupling does not require boron speciation con-
trol,1b,15a activation, deprotection, or neighboring group control3
of any kind, streamlining accessibility to multifunctionalized
molecules.
bromide coupling partnersa
a
Isolated yields. [NiCl2(dme)] was complexed with dtbbpy ligand prior
to reaction setup, see ESI. Reactions run on 0.5 mmol of aryl bromide
b
c
for the allotted time. Yield without purication on silica. Yield
aer purication on silica.
smoothly with hindered benzene-derived bromo BPins to afford
20 and 24 (Table 4), as well as several heteroarenes (21–23) for
the rst time. Boronate esters adjacent to heteroatoms as in 21
are notoriously challenging to couple under Pd-catalysis (owing
to competitive protodeboronation),20 but prove to be robust
under these Ni-catalyzed conditions. 3-Bromopyridyl BPin
(precursor to 22) was an intriguing case, as the crude reaction
mixture contained only 22 and residual catechol, yet 22 largely
decomposed upon purication attempts (90% crude yield, see
ESI†). We conjectured 22 could be carried on crude though
subsequent transformations (vide infra).
The 3-acetoxypropylsilicate was found to be a suitable
substrate when paired with various borylated aryl- and hetero-
aryl bromides. The more structurally complex bromo piper-
azinylarene and 2-bromophenylbenzamide BPins afforded 25
and 26, respectively, in acceptable yields (82% and 52%; Table
4). The dialkylated pyridine 27 suffered from higher than
normal instability on silica, yet in this case could be isolated
Scheme 2 Example of iterative C(sp3)–C(sp2)/Suzuki cross-coupling
and the compatibility of bromoarylboronic acids. Isolated yields. (a)
Pinacol (2 equiv.), THF, 40 ꢀC, 90 min (70%, 2 steps); (b) 3-bromoa-
cetophenone, [Pd(PPh3)4], Cs2CO3, dioxane/H2O, 90 ꢀC (72%, 2 steps);
(c) 30% H2O2, 1 M NaOH, THF, rt, 1 h (80%, 2 steps).
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We next questioned whether these mild and base-free reaction
Chemical Science
2 (a) N. Miyaura, Bull. Chem. Soc. Jpn., 2008, 81, 1535; (b)
A. Suzuki, Angew. Chem., Int. Ed., 2011, 50, 6722.
conditions were tolerant of bromoarylboronic acids. Arylboronic
acids arguably represent the most accessible and convenient
modular building blocks in cross-coupling chemistry, yet noto-
riously require protection in multistep syntheses because of their
high reactivity under various modes of catalysis. Bicyclo-
heptylsilicate 35 was subjected to a standard C(sp3)–C(sp2) cross-
coupling with 4-bromophenyl-boronic acid 38 using 4 as the
photocatalyst (Scheme 2, eqn (2)). Full conversion was accom-
plished aer 14 h, but esterication of the boronic acid had
occurred, generating the catechol boronate ester (39, Scheme 2).
Even though catecholboronate esters are among the most
sensitive of all the boronate functional groups, 39 nonetheless
proved synthetically useful if promptly reacted. Thus, catechol
39 was subsequently transformed in several different ways.
Alkylation and subsequent protection with pinacol afforded
BPin 8 in good yield (70%, 2 steps; Scheme 2, eqn (3)). Subjec-
tion of 39 to Suzuki–Miyaura conditions afforded arylated 40 in
72% yield over two steps, and straightforward oxidation of 39
also proceeded smoothly, generating phenol 41 in 80% yield
over 2 steps. To our knowledge, these tandem 2-step syntheses
beginning from unadulterated arylboronic acids are the rst
examples of C(sp3)–C(sp2) cross-coupling with such general
tolerance of these abundant building blocks. Collectively,
reactions using bromoboronic acids are comparable in yield
and setup to those employing more robust bromoaryl BPins.
3 For examples of the use of BMIDA protecting groups: (a)
E. P. Gillis and M. D. Burke, J. Am. Chem. Soc., 2007, 129,
6716; (b) S. J. Lee, K. C. Gray, J. S. Paek and M. D. Burke, J.
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4 For examples of the use of BDan protecting groups: (a)
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S. R. Neufeldt and M. S. Sanford, J. Am. Chem. Soc., 2011,
133, 18566; (b) Y. Ye and M. S. Sanford, J. Am. Chem. Soc.,
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J. C. Tellis, D. N. Primer and G. A. Molander, Science, 2014,
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Conclusions
In summary, secondary and primary ammonium alkylsilicates
were found to be exceptional alkylating agents in the presence
of various brominated aryl- and heteroaryl boronate esters, and
for the rst time, ubiquitous boronic acids prove to be generally
tolerable substrates to more elaborate compounds. Indeed,
because of the extremely mild reaction conditions and single-
electron regime used for the cross-coupling of ammonium
alkylbis(catecholato)silicates with (hetero)aryl bromides, 10 (a) M. Jouffroy, D. N. Primer and G. A. Molander, J. Am.
´
various boronate ester functional groups were largely allowable
while forging C(sp3)–C(sp2) bonds. Moreover, unlike most of the
methods reported so far, the versatile, alkylated (hetero)aryl
boronates can be isolated in high yields or carried through in
crude form. Under this photoredox/Ni dual-catalysis manifold,
the implementation of readily available Ni(II), light, and a cost-
effective organic photocatalyst in place of late transition metal-
Chem. Soc., 2016, 138, 475; (b) V. Corce, L.-M. Chamoreau,
E. Derat, J.-P. Goddard, C. Ollivier and L. Fensterbank,
Angew. Chem., Int. Ed., 2015, 54, 11414; (c) M. Jouffroy,
C. B. Kelly and G. A. Molander, Org. Lett., 2016, 18, 876; (d)
M. Jouffroy, G. H. M. Davies and G. A. Molander, Org. Lett.,
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toward multifunctionalized, alkylated arenes.
Chem.–Eur. J., 2016, 22, 120; (b) M. El Khatib,
R. A. M. Seram and G. A. Molander, Angew. Chem., Int.
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I. Karakaya, J. C. Tellis and G. A. Molander, J. Am. Chem.
Soc., 2015, 137, 2195.
Acknowledgements
We thank Kingson Lin (University of Pennsylvania) for the
preparation of alkylsilicates. We thank NIGMS (RO1 GM-
113878) for nancial support of this research.
12 (a) L. L. Chu, J. M. Lipshultz and D. W. C. MacMillan, Angew.
Chem., Int. Ed., 2015, 54, 7929; (b) C. C. Nawrat,
C. R. Jamison, Y. Slutskyy, D. W. C. MacMillan and
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