One-pot borylation/Suzuki-Miyaura sp2-sp3 cross-coupling

Article abstract of DOI:10.1039/c7cc05037b

We describe the first one-pot borylation/Suzuki-Miyaura sp²-sp³ cross-coupling between readily available aryl (pseudo)halides and activated alkyl chlorides. This method streamlines the synthesis of diaryl methanes, α-aryl carbonyls and allyl aryl compounds, substructures that are commonly found in life changing drug molecules.

Full text of DOI:10.1039/c7cc05037b

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One-pot borylation/Suzuki-Miyaura sp2–sp3 cross-coupling
Luke Whitaker,a,b Hassan Y. Harb,a,* and Alexander P. Pulisb,*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
We describe the first one-pot borylation/Suzuki-Miyaura sp2–sp3 molecules. For example, diaryl methanes, allyl aryls and α-
cross-coupling between readily available aryl (pseudo)halides and arylated carbonyls are commonly found in major
activated alkyl chlorides. This method streamlines the synthesis of pharmaceutical compounds, such as elvitegravir, mycophenolic
diaryl methanes, α-aryl carbonyls and allyl aryl compounds, acid, repaglinide and indomethacin (Scheme 1A and ESI for
substructures that are commonly found in life changing drug additional examples).18
molecules.
Herein we report the first one-pot borylation/SM sp2–sp3
cross-coupling for the efficient construction of diaryl methanes,
allyl aryls and α-arylated carbonyls (Scheme 1B). We utilise aryl
(pseudo)halides and the most economical diborane reagent,
tetrakis(dimethylamino)diboron [B2(NMe2)4], and propylene
The Suzuki-Miyaura (SM) cross-coupling1 is a powerful method
for the construction of organic molecules2 and as a result has
become a staple carbon-carbon bond forming reaction in
chemical synthesis, particularly in pharmaceutical discovery.3
The classic SM reaction is the palladium catalysed union of an
aryl boron and an aryl halide (or pseudo-halide) to form biaryl
compounds,2 and still receives significant attention from the
scientific community.4 However, there remains a number of
drawbacks associated with the preparation of the required
boron based coupling partner. Isolation and storage of the more
reactive organoborane building blocks is often non trivial and
the addition of an extra discrete synthetic step reduces overall
process efficiency.5, 6
glycol in
a palladium catalysed borylation event and
subsequently couple the in situ generated aryl borons with
activated alkyl chlorides, such as benzyl chlorides, α-chloro
carbonyls, and allyl chlorides, in a one-pot procedure. This
efficient method is operationally simple and is broadly
applicable to a range of substrates.
The Miyaura borylation,7-11 where aryl boronic esters are
formed from aryl (pseudo)halides and diboranes under
palladium catalysis,12,13 has opened the door for the
development of efficient processes where isolation of the aryl
boron coupling partner is avoided. Miyaura,14 Giroux15 and
others16 subsequently reported the efficient one-pot
borylation/SM sp2–sp2 cross-coupling for the stepwise, one-pot
synthesis of biaryls from aryl (pseudo)halides, which
encompasses impressive scope in both sp2 coupling partners.
SM coupling processes are not limited to the formation of
sp2–sp2 carbon bonds.17 However, the more efficient one-pot
borylation/SM cross-coupling strategy has not been previously
applied to the union of sp2 and sp3 carbon atoms despite the
prevalence of such linkages in natural products and bioactive
Scheme 1. The prevalence of sp2–sp3 linkages in pharmaceuticals (A) and this work
describing efficient one-pot borylation/Suzuki-Miyaura sp2–sp3 cross-coupling (B).
a.Concept Life Sciences, Frith Knoll Road, Chapel-en-le-Frith, High Peak, SK23 0PG,
UK.
b.School of Chemistry, University of Manchester, Oxford Rd, Manchester, M13 9PL,
UK. Email: hassan.harb@conceptlifesciences.com;
alexander.pulis@manchester.ac.uk.
Electronic Supplementary Information (ESI) available: See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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We began our investigation by using the previously reported
one-pot borylation/SM sp2–sp2 cross-coupling conditions, that
use atom efficient borylating agents, to the desired sp2–sp3
couplings.9 We discovered that these conditions were not
transferrable to sp3 coupling partners since poor yields were
obtained and significant homocoupling was observed: using 1-
bromonaphthylene 1a, B2(OH)4, benzyl chloride 2a, XPhos-Pd-
G2 precatalyst,19 and ethanol as the solvent, diaryl methane 3a
was obtained in only 29% yield along with homocoupled
product 1,1'-binaphthalene in 60% yield.20 We were also keen
to avoid limiting the scope of the reaction by eliminating
ethanol, since we anticipated alkylation of the solvent by the
activated alkyl chloride coupling partners and palladium
catalysed hydride reduction of functional groups such as nitro
and keto which was previously observed under these borylation
conditions.9b Based on work by Molander10 and Schmidt-
Leithoff,11 we decided on the use of the most atom economical
diboron reagent, B2(NMe2)4. Indeed, commercially available
B2(NMe2)4 is the synthetic precursor to other more common
diboranes such as B2(pin)2 and B2(OH)4,21 but has not been
previously utilised in any one-pot borylation/SM cross-coupling
processes. After extensive optimisation, we arrived at the use
of Buchwald’s XPhos-Pd-G2 precatalyst,19 the environmentally
friendly solvent 2-methyltetrahydrofuran22 and propylene
gylcol for the in situ esterification of B2(NMe2)4. Under these
conditions, we were able to efficiently borylate 1-
bromonaphthylene 1a and subsequently, in the same pot,
couple the in situ generated boronic ester with benzyl chloride
2a23 to afford the sp2–sp3 SM cross-coupling product, diaryl
methane 3a, in 70% isolated yield (84% average yield for each
stage of the reaction, Scheme 2). Crucially, no trace of
homocoupled products were observed in this or subsequent
examples.
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DOI: 10.1039/C7CC05037B
Scheme 2. Scope of the aryl halide in the one-pot borylation/SM sp2–sp3 cross-coupling.
a X = Br; b X = Cl; c X = OTf; d Internal standard NMR yield. Conditions: B2(NMe2)4 (3 equiv.),
potassium acetate (3 equiv.), XPhos-Pd-G2 (1 mol%), XPhos (2 mol%), propylene glycol
(6 equiv.), 2-Me-THF, 1 (1 equiv.), 80 °C; then K2CO3(aq), 2 (1.2 equiv.), 80 °C.
We then examined the sp3 coupling partner in the one-pot
borylation/SM sp2–sp3 cross-coupling reaction. We decided
upon the use of activated alkyl chlorides since they are readily
accessible, often commercially available, and more stable than
other activated alkyl halides. Whilst secondary alkyl chlorides,
such as 2-chloropropanoate did not yield the desired cross-
coupled product, pleasingly we found that a variety of primary
alkyl chlorides could be employed and allowed the efficient
generation of diaryl methanes, α-aryl esters, α-aryl amides and
allyl aryl compounds (Scheme 3). Thus, benzylic chlorides with
ortho substitution (3q), electron withdrawing groups such as
ester (3r), trifluoromethyl (3s), fluoro (3t), and dinitro (3u), as
The method is operationally simple24 as all reagents are
used as received and addition of more pre-catalyst is not
required after the initial reaction set up.
In exploring the scope of the sp2 unit in the one-pot
borylation/SM sp2–sp3 cross-coupling, we found that the
reaction was broadly amenable to
a range of aryl
(pseudo)halides with different steric and electronic parameters
as well as bearing a variety of functional groups (Scheme 2).
well as heterocycles such as pyridines (3v,x) and thiazole (3y)
were successfully coupled to 1-bromonapthalene 1a to deliver
a variety of diaryl methanes. The use of para-methoxy benzyl
chloride failed to yield the desired cross-coupled product.
As other functional groups are often attached to the sp3
carbon of the sp2–sp3 linkage of biologically important
compounds (cf. Scheme 1A) we examined other readily
available classes of activated alkyl chloride coupling partners.
We found that allyl chlorides, such as cinnamyl chloride and 2-
(trimethylsilylmethyl)allyl chloride, gave the desired cross-
coupled product 1,3-diaryl propene 4a and versatile allyl silane
4b, without isomerisation or migration of the double bond.
Electron deficient (3c
successfully coupled with benzyl chloride, as were
heteroaromatic halides including pyridine (3k ), quinoline (3m),
-f) and electron rich aryl halides (3g-j) were
,l
indole (3n) and benzofuran (3o). The reaction displayed
excellent functional group tolerance and substrates bearing
functional groups such as phenyl (3b), ester (3d
,e,k,n), ketone
(
3c ), nitrile (3f), methyl ether (3g ), and unprotected
,
l
,
p
,h
hydroxy (3i) and amino (3j) were effective sp2 units in the
coupling reaction. In addition, aryl bromides, chlorides and
triflates reacted with similar efficiency (cf. entries for 3c and 3g),
with the latter allowing for the functionalisation of estrone (3p).
2 | J. Name., 2012, 00, 1-3
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Scheme 4. Proposed mechanism of the one-pot borylation/SM sp2–sp3 cross-coupling.
In summary, we found that the conditions used in the
previously reported one-pot borylation/SM sp2-sp2 cross
couplings afforded low yields and significant homocoupling in
the sp2-sp3 reaction.20 However, under our conditions, yields
are higher and homocoupling is completely avoided. This has
led to the development of the first one-pot borylation/SM sp2–
sp3 cross-coupling for the operationally simple, efficient
construction of diaryl methanes, α-aryl carbonyls and allyl aryl
compounds. We employ readily available aryl (pseudo)halides
and the most economical diborane, B2(NMe2)4, with
a
commercially available palladium pre-catalyst, to generate
boronic esters in situ, saving the need for isolation after a
discrete synthetic step. The in situ generated boronic esters
undergo SM sp2–sp3 cross-coupling, catalysed by the same Pd(0)
that mediates the borylation stage, with readily accessible
activated alkyl chlorides, such as benzyl chlorides, α-chloro
esters, α-chloro amides and allyl chlorides, to deliver diaryl
methanes, α-aryl esters, α-aryl amides and allyl aryl
compounds. In addition, we use the same general and simple
procedure across all of the investigated classes of sp2 and sp3
coupling partners, making the procedure particularly relevant
to the straightforward generation of diverse molecular libraries.
We are currently investigating the use of this efficient synthetic
strategy for the coupling of sp3 partners bearing β-hydrogens.
The present study has significantly streamlined the synthesis of
important substructures found in validated pharmaceuticals
and we anticipate the methodology will be of particular interest
to medicinal chemists.
Scheme 3. Scope of the alkyl chloride in the one-pot borylation/SM sp2–sp3 cross-
coupling. a Internal standard NMR yield; b the corresponding hydrochoride salt of 2 was
used directly in reaction. Using 3 equiv. of 2-(chloromethyl)allyl-trimethylsilane.
c
Conditions: as in Scheme 2.
In addition, α-chloro amides and α-chloro esters, which have
only previously been employed in the SM coupling with aryl
trifluoroborate salts,25 were successfully utilised in the efficient
one-pot borylation/SM sp2–sp3 cross-coupling and delivered α-
aryl amide 5a, and α-aryl esters 5b and 5c. The triflate derived
from estrone (1b) was also coupled to tert-butyl chloroacetate
2b to give 5d in high yield. Pleasingly, homocoupling of the
in situ generated boronic ester was not observed despite being
a common and significant side-reaction in SM couplings with α-
halo carbonyl coupling partners.26,20 It is worth noting that these
sp2-sp3 cross couplings operate under the same reaction
conditions, regardless of the nature of the coupling partners
involved.
We thank Concept Life Sciences, RSC (Enterprise Plus
placement to L.W.), and the University of Manchester
(Lectureship to A.P.P.). In addition, we are grateful to Dr.
Daniele Leonori and Prof. David J. Procter for their support and
many helpful discussions.
The mechanism of the one-pot borylation/SM sp2–sp3 cross-
coupling is proposed to begin with the in situ esterification of
B2(NMe2)4 with propylene gylcol to form diborane
4).11a Subsequently, Miyaura borylation of aryl (pseudo)halide
with diborane , catalysed by Pd(0) generated in situ from
Buchwald’s XPhos-Pd-G2 precatalyst,19 yields aryl boronic ester
. Borylation was not observed in the absence of the diol. Upon
6 (Scheme
1
6
Notes and references
7
1
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addition of aqueous K2CO3, any remaining diborane is
destroyed, preventing deleterious side reactions of the
2
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G. C. Lloyd-Jones, Chem. Soc. Rev., 2014, 43, 412; (b) J. W. B.
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Thynne, D. C. Blakemore, D. C. Prydeb and A. C. Spivey, Chem.
diborane and alkyl chloride.10 Addition of alkyl chloride
2
then
allows the SM sp2–sp3 cross-coupling with the in situ generated
aryl boronic ester , catalysed by the same Pd(0) that mediated
the borylation stage, yielding diaryl methanes , allyl aryls
and α-aryl carbonyl compounds
7
3
4,
5
.
Sci., 2017, 8, 40-62.
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This journal is © The Royal Society of Chemistry 20xx
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equiv), B2(OH)4 (3 equiv.), XPhos-Pd-G2 (1 mol%), XPhos (2
mol%), propylene glycol (6 equiv.), KOAc, EtOH, 4 h, 80 °C;
then benzyl chloride 2a (1.2 equiv.), K2CO3 (aq), 80 °C, gave 3a
(29%) and 1,1'-binaphthalene (60%). Using ethyl
chloroacetate instead of benzyl chloride, gave 5b (37%) and
1,1'-binaphthalene (24%). In both cases, under our conditions,
the yields of the desired products are higher and
homocoupling was not observed. See SI for scheme. Note that
borylation with B2(OH)4 is limited in the absence of the diol
(see ref. 9d).
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halide
and heated at 80 °C until the aryl halide was consumed (0.5-
4 h). K2CO3(aq) and alkyl chloride (1.2 equiv.) were added
and heating continued until conversion of the intermediate
aryl boron was complete (1-16 h).
1 (1 equiv.) was added to a nitrogen flushed vessel
2
7
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10978.
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16 For select examples of one-pot borylation/SM coupling
reactions in biaryl synthesis, see references 8, 9, 14, 15 and:
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