A General C(sp3)-C(sp3) Cross-Coupling of Benzyl Sulfonylhydrazones with Alkyl Boronic Acids

Article abstract of DOI:10.1021/acs.orglett.0c00471

A general transition-metal-free cross-coupling between benzylic sulfonylhydrazones and 1°, 2°, or 3° alkyl boronic acids is reported. The base-promoted reaction is operationally simple and exhibits a broad substrate scope to forge a variety of alkyl-alkyl bonds, including between sterically encumbered secondary and tertiary sp³-carbons. The ability of this method to simplify retrosynthetic analysis is exemplified by the improved synthesis of multiple medicinally relevant scaffolds.

Full text of DOI:10.1021/acs.orglett.0c00471

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Letter
A General C(sp3)−C(sp3) Cross-Coupling of Benzyl
Sulfonylhydrazones with Alkyl Boronic Acids
Rohan R. Merchant* and Jovan A. Lopez
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ABSTRACT: A general transition-metal-free cross-coupling between benzylic sulfonylhydrazones and 1°, 2°, or 3° alkyl boronic
acids is reported. The base-promoted reaction is operationally simple and exhibits a broad substrate scope to forge a variety of alkyl−
alkyl bonds, including between sterically encumbered secondary and tertiary sp3-carbons. The ability of this method to simplify
retrosynthetic analysis is exemplified by the improved synthesis of multiple medicinally relevant scaffolds.
here has been growing interest in the pharmaceutical
industry to increase the sp3-character of small molecules.1
its practicality.8,9 However, to the best of our knowledge, these
reports have focused on cross-coupling of benzylic sulfonylhy-
drazones with aryl and heteroaryl boronic acids 610,11 and a
general protocol for coupling alkyl boronic acids 7 to construct
sp3−sp3 C−C bonds remains elusive.
In this communication, we report a general and operation-
ally facile method for the cross-coupling between benzylic
sulfonylhydrazones and widely available alkyl boronic acids.
Starting from 1°, 2°, or 3° alkyl boronic acids, this method
provides a straightforward solution for generating a variety of
C(sp3)−C(sp3) bonds.
Figure 1C presents an abbreviated picture of the
optimization conducted on bromopyridine tosylhydrazone 8
and cyclopentyl boronic acid 9, culminating in an 82% isolated
yield. To establish the optimal conditions, a broad evaluation
of sulfonylhydrazones (entries 1−3), bases (entries 4−6),
solvents (entries 7−8), and temperatures (entry 9) was
undertaken, with the optimal conditions requiring tosylhy-
drazone 8 (1 equiv), boronic acid 9 (1.5 equiv), and Cs2CO3
(1.5 equiv) in 1,4-dioxane (0.25 M) at 110 °C (see Supporting
Information (SI) for full optimization table). Here, we
benefited from the pioneering studies preceding ours,6,8
which had showcased the importance of modulating the
electron density of the sulfonylhydrazone moiety, and the
identity of the base on the efficiency of reductive cross-
T
Alkyl bioisosteres (e.g., bicyclo[1.1.1]pentane) have been
shown to possess improved physiochemical properties
compared to their aromatic counterparts,2 resulting in a need
to access both aromatic and alkyl analogs during a medicinal
chemistry campaign. Therefore, new retrosynthetic strategies
that forge C(sp3)−C(sp2) and C(sp3)−C(sp3) bonds in a
divergent and efficient manner are required. For example, the
hypothetical medicinal chemistry building blocks 1 and 2
(Figure 1A) contain the same heterocyclic core with aryl or
alkyl substituents appended. An ideal medicinal chemistry
strategy would involve a robust late-stage cross-coupling,
allowing for diversification of a bench-stable common
intermediate (e.g., tosylhydrazone 3) with a wide range of
commercially available alkyl and aryl building blocks (e.g.,
boronic acids 4).3 A synthetic approach that could enable this
type of strategy would notably expedite structure−activity
relationship (SAR) studies in medicinal chemistry.
In recent years, there have been significant advances in the
area of alkyl−alkyl transition-metal catalyzed cross-coupling
reactions.4,5 However, due to substantial challenges (such as β-
hydride elimination, protonation of electrophile, or need for
unstable organometallic nucleophile) new approaches to access
these alkyl−alkyl bonds are still desired.5 In 2009, Barluenga
́
and Valdes reported a transition-metal-free, reductive cross-
coupling between alkyl tosylhydrazones 5 and boronic acids
(Figure 1B) to forge C−C bonds without the need for precious
metal catalysts or ligands.6 The transformation utilizes boronic
acids, a widely available building block, and alkyl sulfonylhy-
drazones, bench-stable solids that are readily prepared from
aldehydes or ketones.7 Since the original report, the method
has been widely adopted by industry chemists, demonstrating
Received: February 6, 2020
https://dx.doi.org/10.1021/acs.orglett.0c00471
© XXXX American Chemical Society
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demonstrate that the conditions to install the sulfonylhy-
drazone and the cross-coupling are mild enough to tolerate
activated 2-chloropyridines, which could then be further
functionalized via SNAr. It is worth noting that each aldehyde
and ketone was commercially available and the corresponding
sulfonylhydrazones were prepared as bench-stable solids and
purified by filtration without column chromatography. In
contrast, substantially fewer benzylic halides are available and,
in some cases, such as electron-rich benzylic halides, they are
unstable (e.g., for substrate 11, 12). This points again to the
operational convenience of this reaction.
Figure 2B outlines the cross-coupling with various 1° and 2°
alkyl boronic acids. The reaction was compatible with both
primary and secondary acyclic (21−24), cyclic (25−27),
heterocyclic (28, 30), benzylic (29), and α-heterocyclic (31)
alkyl boronic acids. A variety of functional groups including
terminal olefin (22), alkyl bromide (23), protected amines (N-
Boc 31 and N-Bn 28), and cyclic ethers (30) were tolerated
under the reaction conditions. Substrates 25 and 26 are
striking, as cyclopropanes are privileged scaffolds in medicinal
chemistry12 and this method provides an alternative approach
for their installation. The reaction could also be run easily on a
gram scale without modification of the optimized conditions to
provide 26 without any erosion of relative stereochemistry.
This result also highlights the stereoretentive nature of this
reaction, wherein the stereochemistry of the alkyl group is
transferred with complete fidelity from the corresponding alkyl
boronic acid.
Tertiary alkyl boronic acids (Figure 2C, 32−37) also
smoothly participated in the cross-coupling, generating all
alkyl quaternary centers. It is noteworthy that even extremely
sterically hindered C−C bonds between secondary and tertiary
sp3-carbons (substrate 37) can be forged with ease under this
reaction scaffold. Tertiary alkyl substituents continue to remain
one of the most challenging groups to install via transition-
metal catalysis (e.g., tBu has 9 β-Hs), and this method provides
for a simple and practical route for their installation.
Bicyclo[1.1.1]pentane boronic acids could also be cross-
coupled in a straightforward manner to access substrates 35
and 36. Bicyclo[1.1.1]pentanes are emerging as a powerful
saturated mimic of para-substituted benzene,13 making this a
useful method for their installation on a variety of medicinal
chemistry projects. Although several alkyl boronic acids are
commercial, there were some instances where the alkyl Bpin
was easier to access (commercial or synthesized using
decarboxylative cross-coupling methodologies14). In such
scenarios, alkyl BPins were subjected to deprotection and the
crude alkyl boronic acid utilized in the cross-coupling to
furnish the desired alkyl−alkyl coupling products (30 and 33−
36; see SI for experimental details).
The feasibility of directly employing the carbonyl substrate
using an in situ protocol was demonstrated with substrate 38
(Figure 2D). Tosylhydrazone 8 was generated in situ and
subjected to the cross-coupling without any purification or
solvent removal to obtain the desired product 10 in
comparable yield (85% one pot vs 90% from tosylhydrazone).
Owing to the ubiquity and commercial availability of the
benzylic aldehydes and ketones, the one-pot procedure can
expedite and assist medicinal chemistry efforts by rapid
diversification of benzylic heterocycles.
Figure 1. (A and B) Inspiration for developing alkyl−alkyl cross-
coupling between alkyl sulfonylhydrazones and alkyl boronic acids
and (C) optimization of alkyl−alkyl cross-coupling. a0.1 mmol. bYield
1
determined by H NMR with 1,3,5-trimethoxybenzene as an internal
c
standard. Isolated yield.
coupling between alkyl sulfonylhydrazones and aryl boronic
acids. Gratifyingly, when the reaction was performed without
any precautions, under air and with an open bottle of 1,4-
dioxane (dump and stir), the desired coupling product was still
obtained in 64% yield, thus demonstrating the robustness of
the method (entry 10).
With an optimized set of conditions in hand, the scope of
this reaction was systematically evaluated, as shown in Figure
2. First, a range of alkyl tosylhydrazones (Figure 2A) were
coupled with cyclopentyl boronic acid 9. Tosylhydrazones
derived from the corresponding aldehydes of electron-rich (11,
12) and electron-poor (13) aromatics, and that of various
heterocycles relevant to medicinal chemistrysuch as
pyridines (10, 17, 19), unprotected indazole (16), thiazole
(15), and quinoline (18)were well tolerated. Notably,
sulfonylhydrazones derived from both cyclic (19) and linear
(20) ketones underwent facile cross-coupling to generate a
C(sp3)−C(sp3) bond between two sterically hindered
secondary carbon centers. Historically, under transition-metal
catalysis, such hindered alkyl−alkyl bonds are difficult to
generate due to the ease of β-hydride elimination.5 Under the
reaction conditions, aryl bromides (10, 15, 16, 17, and 20) and
chlorides (17, 19) go untouched, allowing for subsequent
functionalization using transition-metal catalysis in an
orthogonal manner. In addition, examples 17 and 19
We believe the mechanism for this reaction is analogous to
the cross-coupling with aryl boronic acids.6 The base
(Cs2CO3) promotes the formation of diazo compound in situ
B
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Figure 2. Initial scope for alkyl−alkyl cross-coupling between benzylic sulfonylhydrazones and alkyl boronic acids. Standard reaction conditions:
a
tosylhydrazone (1.0 equiv), boronic acid (1.5 equiv), Cs2CO3 (1.5 equiv), 1,4-dioxane (0.25 M), 110 °C, 12 h. With sulfonylhydrazone derived
from PMPSO2NHNH2 (1.0 equiv) and alkylB(OH)2 (3.0 equiv). bWith alkylB(OH)2 (3.0 equiv). cQuenched after 4 h. d1,4-dioxanes (0.17 M). Ts
= tosyl, Ms = mesityl, Ph = phenyl, Bn = benzyl, Boc = tert-butyloxycarbonyl, [1.1.1]BCP = bicyclo[1.1.1]pentane, PMP = para-methoxyphenyl.
See SI for details.
which then reacts with the alkyl boronic acid to form a
tetracoordinate boronate. Subsequent 1,2-migration generates
the C−C bond with concomitant loss of N2 followed by
protodeboration of benzylic boronic acid to give the desired
product.15 Alternatively, the intermediate diazo compound
could lose N2 first to form benzylic carbene which could then
engage with the boronic acid to form the tetracoordinate
boronate. A final sequence involving 1,2-migration and
protodeboration then gives the desired product.
The retrosynthetic simplification enabled by this cross-
coupling is further demonstrated with application to three
reported medicinal chemistry case studies from the patent
literature (Figure 3). In one instance (Figure 3A), GSK
scientists targeted building blocks differing only in the
substituent appended to the triazole core (3-fluorophenyl
and cyclopentyl, among others).16 To access each of these
simple structures, a linear de novo approach was devised with
the point of diversification occurring as the first step in a
synthetic sequence that requires condensation at 200 °C to
prepare the triazole core. By leveraging the wide commercial
availability of boronic acids (aryl and alkyl), in contrast, the
tosylhydrazone 39 could instead be directly coupled with 3-
fluorophenyl boronic acid, cyclopentyl boronic acid, or CF3-
bicyclo[1.1.1]pentane boronic acid to deliver 40 and 41 and a
new analog 42 at a later stage and in a much more divergent
fashion.
The second and third case studies (Figure 3B), drawn
respectively from medicinal chemistry campaigns at Yale
University and Eli Lilly, highlight the functional group
compatibility of this method.17,18 Previous approaches to the
targets, 43 (Yale)17 and 44 (Eli Lilly),18 were plagued by the
chemoselectivity issues surrounding the Wittig, Grignard, and
C
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Figure 3. (A and B) Applications of alkyl−alkyl cross-coupling between alkyl sulfonylhydrazones and alkyl boronic acids to the synthesis of
pharmaceutically relevant building blocks. (B) Cross-couplings were performed with in situ activation of the aldehyde. See SI for details.
hydrogenation reactions. This resulted in both reports starting
from the protected phenol 45 for the Wittig or Grignard
reaction, followed by hydrogenation prior to late-stage
installation of iodine. In contrast, using the method disclosed
here, commercial iodophenol aldehyde 46 was subjected to in
situ coupling with either isopropyl boronic acid or tert-butyl
boronic acid to obtain 43 and 44, respectively, in a single step,
obviating the need for any protecting group manipulations.
Overall, this approach also provides a milder alternative to the
traditional Wittig/hydrogenation sequence for appending an
alkyl group to an aldehyde or ketone.
In summary, we have reported a general protocol for
C(sp3)−C(sp3) coupling between benzylic sulfonylhydrazones
and 1°, 2°, or 3° alkyl boronic acids. By leveraging the ubiquity
of alkyl boronic acids, this operationally simple, scalable, and
chemoselective approach extends the ability to diversify
sulfonylhydrazones with a diverse range of alkyl substituents.
This method has already proven to be invaluable on several
internal medicinal chemistry programs, and as such, we
anticipate that it will have meaningful impacts within drug
discovery and synthetic chemistry.
https://pubs.acs.org/10.1021/acs.orglett.0c00471
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to W. Michael Seganish, Jonathan Hughes,
Donna Hayes, and Phillip Sharp (all from Merck & Co., Inc.,
Kenilworth, NJ, USA (MSD)) for feedback on our manuscript.
We would like to thank Jonathan Hughes (MSD), and Patrick
Fier (MSD) for assistance in preparing the triazole
tosylhydrazone, Melissa Lin (MSD) for assistance with NMR
spectroscopy, and Wilfred Pinto (MSD) for assistance with
HRMS.
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AUTHOR INFORMATION
Corresponding Author
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Rohan R. Merchant − Department of Discovery Chemistry,
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Email: rohan.merchant@merck.com
́
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Complete contact information is available at:
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