Continuous Flow-Enabled Synthesis of Bench-Stable Bicyclo[1.1.1]pentane Trifluoroborate Salts and Their Utilization in Metallaphotoredox Cross-Couplings

Article abstract of DOI:10.1021/acs.orglett.0c00242

Bicyclo[1.1.1]pentane motifs have gained increasing popularity in medicinal chemistry as bioisosteres because of their ability to impact key physicochemical properties. However, reports of direct C(sp²)-C(sp³) cross-coupling of these

Full text of DOI:10.1021/acs.orglett.0c00242

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Letter
Continuous Flow-Enabled Synthesis of Bench-Stable
Bicyclo[1.1.1]pentane Trifluoroborate Salts and Their Utilization in
Metallaphotoredox Cross-Couplings
Michael D. VanHeyst,* Ji Qi,* Anthony J. Roecker, Jonathan M. E. Hughes, Lili Cheng, Zheyu Zhao,
and Jingjun Yin
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ABSTRACT: Bicyclo[1.1.1]pentane motifs have gained increasing popularity in medicinal chemistry as bioisosteres because of their
ability to impact key physicochemical properties. However, reports of direct C(sp2)−C(sp3) cross-coupling of these fragments to
afford biaryl isosteres have been scarce. Herein we describe the development of continuous flow-enabled synthesis of bench-stable
bicyclo[1.1.1]pentane trifluoroborate salts. Furthermore, we demonstrate the use of metallaphotoredox conditions to enable cross-
coupling of these building blocks with complex aryl halide substrates.
aromatic character has yielded successful drugs, it has become
desirable in many cases to replace these motifs using isosteric
strategies.2 Since the landmark publication by Stepan et al.
detailed the use of bicyclo[1.1.1]pentanes (BCPs) as isosteric
replacements for para-substituted phenyl motifs and high-
lighted the resulting beneficial effects (increased solubility,
permeability, and sp3 character with decreased lipophilicity),
the field has seen a dramatic surge in the development of new
methods to access these important building blocks (Figure
1B).3
edicinal chemistry is replete with syntheses of biaryl
Mrings because of their ease of preparation, following the
advent of metal-mediated cross-coupling reactions.1 This is
evident in the wide variety of biaryl drugs on the market and
drug candidates proceeding through various stages of develop-
ment (Figure 1A). While the incorporation of additional
While many elegant methods have recently been developed
to enable efficient access to high-value BCP-containing
molecules, carbon−carbon cross-couplings that directly in-
corporate BCPs into structures of interest are relatively
underdeveloped. In the last two decades, Szeimies (1999),
de Meijere (2000), and Knochel (2017) have each
independently contributed to the area of carbon−carbon
coupling strategies based on the addition of organometallic
reagents to solutions of [1.1.1]propellane followed by Negishi
or Kumada coupling of the resultant BCP metalates (Figure
2A).4 While the yields were generally good, the protocol
mandated either long duration (3−7 days) or temperatures
Received: January 16, 2020
Figure 1. Impact of replacing biaryl motifs with BCPs.
https://dx.doi.org/10.1021/acs.orglett.0c00242
© XXXX American Chemical Society
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A

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Metallaphotoredox catalysis has been demonstrated as a
powerful and convenient approach to cross-couple aryl halides
with a variety of bench-stable coupling partners. Among these
coupling partners, carboxylic acids and potassium trifluor-
oborate salts have found extensive application because of their
widespread availability, ease of preparation, and robust
reactivity. However, despite these advantages, the cross-
coupling of an aryl halide with either a BCP carboxylic acid
or a BCP trifluoroborate salt has not been thoroughly
explored.9−11 Given the well-precedented advantages that
these two substrate classes exhibit in terms of stability and
reactivity, we decided to explore their potential utility as
precursors to valuable aryl-bound BCP products.
We began our investigations by screening metallaphotoredox
conditions to cross-couple BCP carboxylic acid 5 with pyridine
4 to yield BCP pyridine 7 (Table 1). Initially we employed a
Table 1. Optimization of Metallaphotoredox Cross-
Coupling Conditions for BCP Carboxylic Acid and
Trifluoroborate
Figure 2. Cross-coupling methods to access aryl-BCPs.
exceeding the boiling point of their solvent in a sealed tube.
These methods also required organometallic reagents, which
ultimately limited the functional group compatibility of the
transformations. Baran and co-workers included a BCP
substrate in their iron-catalyzed cross-coupling of activated
esters and obtained a moderate yield of coupled product (37%;
Figure 2B).5 However, the scope of this reaction utilizing this
motif was not fully explored. Kanazawa, Uchiyama, and co-
workers recently developed a Pd-catalyzed Suzuki−Miyaura
cross-coupling of a silaborated BCP, but this protocol required
preactivation of the BCP pinacolboronate ester (Bpin) with
stoichiometric amounts of tert-butyllithium.6,7 In addition,
BCP carboxylic acids and BCP pinacolboronates have been
reported to engage directly in cross-coupling reactions with
aryl halides, although the details surrounding the development
and scope of these reactions remain limited.8 Collectively,
these reports represent significant advances for the con-
struction of aryl−BCP bonds. Importantly, however, the
established literature methods require the synthesis and use
of organometallic reagents (either the aryl component or the
BCP component), which are not typically stable over extended
periods of time and also restrict the functional group
compatibility. Thus, the development of new bench-stable
BCP building blocks that can be effectively and broadly
engaged in cross-coupling reactions would be highly valuable
to those seeking to incorporate a BCP moiety into a molecule
of interest. Herein we describe the development of a scalable
route to prepare several BCP trifluoroborate salts that was
enabled by the use of a continuous flow decarboxylative
borylation. Furthermore, we established these BCP building
blocks as convenient precursors to biaryl isosteres via
metallaphotoredox-mediated cross-coupling with aryl halides.
photocatalyst
(loading)
Ni/ligand
loading
entry
R
base
DBU
DBU
DBU
DBU
Na2CO3
Na2CO3
Na2CO3
yield
b
1
2
3
4
5
6
7
CO2H
CO2H
CO2H
CO2H
CO2H
BF3K
1 (1 mol %)
3 (2 mol %)
3 (2 mol %)
3 (10 mol %)
2 (10 mol %)
2 (1 mol %)
2 (10 mol %)
10 mol %
10 mol %
20 mol %
20 mol %
15 mol %
10 mol %
15 mol %
trace
b
14%
26%
23%
13%
25%
81%
b
BF3K
a
450 nm wavelength, 100% light intensity, 5200 rpm fan speed, 1000
rpm stir speed. NMR yield.
b
modified version of conditions published by Doyle and
MacMillan11 using the [Ni(dtbbpy)(H2O)4]Cl2 precatalyst
developed by the Molander group.12 A screen of common
organic and inorganic bases revealed that the use of DBU led
to trace quantities of product 7 via this catalytic paradigm
(entry 1). Next, a brief screen of photocatalysts led us to
identify 4CzIPN (3) as the most effective catalyst for this
system, providing 7 in a modest 14% yield (entry 2). Further
evaluation of the catalyst loading enabled us to increase the
yield of 7 to 26% by employing 2 mol % photocatalyst 3 and
20 mol % Ni (entry 3). However, even after extensive
optimization, we were unable to further increase the yield of
the cross-coupled product when employing BCP acid 5 as the
starting material.13 As a result, we turned our attention to the
use of potassium BCP trifluoroborate 6 as a coupling partner,
which was conveniently prepared from the corresponding
B
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requisite pinacolboronate used to prepare 6 can be purchased,
it is only available on a small scale and is prohibitively
expensive for large-scale work.14 Furthermore, only a handful
of other BCP boronates are commercially available, and each is
equally expensive. As such, we recognized the need to develop
a reliable and scalable route to access these valuable building
blocks.
Scheme 1. Scalable Synthesis of BCP Trifluoroborate Salts
To access the BCP BF3K salts in a rapid fashion, we chose to
employ the photoinduced decarboxylative borylation of NHP
esters 8a−e (accessible in one step from the corresponding
carboxylic acids 5a−e), which was recently reported by the
Aggarwal group.15,16 We began the evaluation of this method
on BCP methyl ester substrate 8b and were delighted to
observe similar yields (mg scale) as those reported in the
original article.15a Hoping to develop a robust and scalable
procedure, we turned our attention to continuous flow-enabled
technologies, often an optimal setting for photoredox
reactivity.9e During the course of optimization we focused on
variations of the light source, reaction temperature, residence
time, and reagent equivalency. After screening, high-yielding
(78% assay yield and 65% isolated yield) and scalable
continuous flow conditions for the synthesis of BCP Bpin 9b
were identified with a 100 W 460−465 nm blue LED light
source and a residence time of 30 min at 90 °C (Scheme 1).
Subsequent treatment of 9b with KHF2 led to the formation of
BCP BF3K 6b in good yield. Improvements in the workup and
crystallization conditions of both boronic ester 9b and
trifluoroborate salt 6b enabled a 200 g scale borylation
reaction (51% yield over two steps) utilizing a readily self-
assembled photo flow setup.17 To further understand the scope
and generality of the continuous flow photoborylation method,
we evaluated several additional BCP acid substrates with varied
substituents at the 3-position (8a, 8c, 8d, and 8e). Notably,
moderate to high yields were obtained for both borylation and
trifluoroborate salt formation in almost every case.
Bpin.14 With BCP 6 in hand, we evaluated conditions for its
cross-coupling and were pleased to find that those reported by
the Molander group provided 7 in a modest but promising
25% yield (entry 6).10a Finally, additional experimentation
revealed that increasing the catalyst loading allowed aryl-BCP
7 to be isolated in an excellent 81% yield (entry 7). Notably,
when these higher photocatalyst loadings were applied to the
reaction of BCP acid 5, we did not see an increase in the
isolated yield of 7 (entries 4 and 5).
After having identified conditions to enable effective cross-
coupling of BCP BF3K 6, we focused our efforts on the
development of a scalable route to access useful quantities of 6
and several other BCP BF3K building blocks. While the
With an efficient route in hand to synthesize BCP BF3K
salts, we began to explore the utility and scope of the arylation
Figure 3. Evaluation of optimized reaction conditions for late-stage functionalization of drug-like molecules. Teal structures = product formed. Red
structures = no product formed.
C
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reaction of 6 on a series of complex aryl halides. Accordingly,
we surveyed the metallaphotoredox-mediated cross-coupling of
6 with a set of drug-like aryl halide “informers” using
microscale high-throughput experimentation (HTE).18 This
informer set has been benchmarked in a variety of chemistries
and was used here to inform on the versatility of these reaction
conditions.19
seen in trace quantities by LC−MS. We attributed this lack of
reactivity to the seemingly slow oxidative addition of the nickel
complex into the aryl chloride bond. Notably, attempts to
access 10-X2 and 10-X15 from BCP acid 5 (under the
conditions shown in Table 1, entry 3) led to products in
significantly diminished yields.23 These results reinforce the
advantage of using BCP BF3K 6 as a building block to form
aryl−BCP bonds under metallaphotoredox conditions and
further highlights its utility in medicinal chemistry for late-
stage incorporation of the BCP motif.
In addition to BCP BF3K 6, we also demonstrated that the
corresponding methyl ester BCP 6b can be effectively installed
onto aryl frameworks under slightly modified conditions
(Scheme 3).24 Again, several important functional groups
We surveyed the reactivity of these substrates under our
reaction conditions using a parallel HTE format to ensure
unity of reaction conditions.20 Gratifyingly, we observed the
formation of the desired cross-coupled product in 13 out of 18
wells (72%), which demonstrated the generality of this method
for the late-stage functionalization of complex aryl substrates
(Figure 3). Notably, a variety of important functional groups
and N-containing heterocycles were tolerated under the
reaction conditions, including esters, amides, ketones, sulfones,
sulfonamides, unprotected alcohols and amines, imidazoles,
indoles, pyrimidines, and quinolines, among others. It is worth
noting that some of the failures in this screen were expected.
For instance, X7 and X9 both contain primary carboxylic acids,
which are known to be oxidized under these conditions. In
addition, efavirenz (X17), an antiretroviral to treat HIV/AIDS,
is known to undergo rearrangement under basic conditions.21
Given the promising results of our high-throughput screen,
we selected a subset of informers to scale up utilizing the
PennOC photoreactor (Scheme 2).22 Markedly, the reactions
proved to be scalable, and the corresponding products were
obtained in modest to excellent yields. The sole exception
occurred with an attempt to access 10-X18, which was only
Scheme 3. Survey of BCP Ester BF3K Cross-Coupling Scope
Scheme 2. Isolated Yields of Select Informer Set Substrates
were tolerated, including the BCP ester. For instance, aryl-BCP
analogues possessing amides (11-X2), nitriles (14), and
sulfonamides (15) were all delivered in synthetically useful
yields. Moreover, pharmaceutically relevant heteroaromatics
such as imidazoles (11-X2), pyridines (12), and quinolines
(16) were also tolerated in the cross-coupling reaction, making
this an attractive method for late-stage BCP incorporation in
drug discovery.
In summary, we have developed a concise and reliable route
to generate bench-stable BCP BF3K salts that leverages a
continuous flow-enabled decarboxylative borylation. Further-
more, we have demonstrated the utility of these BCP building
blocks for direct arylation under metallaphotoredox cross-
coupling conditions. A set of complex drug-like aryl halides
were shown to effectively cross-couple under these conditions
to deliver the corresponding BCP-bound products. The broad
functional group compatibility and the diverse range of N-
heterocycles that are tolerated in these cross-coupling reactions
underscores the utility of this approach as a tool for late-stage
BCP installation for drug discovery.
D
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A. F.; Subramanyam, C.; Efremov, I. V.; Dutra, J. K.; O’Sullivan, T. J.;
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00242.
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Experimental procedures and characterization data for
new compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Michael D. VanHeyst − Discovery Chemistry, Merck & Co.,
Inc., West Point, Pennsylvania 19486, United States;
orcid.org/0000-0003-3299-3329;
Email: michael.vanheyst@merck.com
Ji Qi − Department of Process Research and Development, Merck
& Co., Inc., Rahway, New Jersey 07065, United States; Process
Research and Development, MSD R&D (China) Co., Ltd.,
Beijing 100012, China; orcid.org/0000-0003-4585-6534;
Email: ji_qi@merck.com
Authors
Anthony J. Roecker − Discovery Chemistry, Merck & Co., Inc.,
West Point, Pennsylvania 19486, United States
Jonathan M. E. Hughes − Department of Process Research and
Development, Merck & Co., Inc., Rahway, New Jersey 07065,
United States
Lili Cheng − Chemistry Service Unit, WuXi AppTec (Tianjin),
Tianjin 300457, China
Zheyu Zhao − Chemistry Service Unit, WuXi AppTec (Tianjin),
Tianjin 300457, China
Jingjun Yin − Department of Process Research and Development,
Merck & Co., Inc., Rahway, New Jersey 07065, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00242
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank and acknowledge the following people for
their contributions: James Perkins (Merck & Co., Inc., West
Point, PA, USA) for aiding in kit screening setup and analysis,
Spencer Dreher (Merck & Co., Inc., Kenilworth, NJ, USA) for
coordinating shipment of the informer set, and Meng Chen
(WuXi AppTec, Tianjin, China) for experimental help. We are
grateful to L.C. Campeau (Merck & Co., Inc., Rahway, NJ,
USA), Jeffrey Hale (Merck & Co., Inc., West Point, PA, USA),
Ben Sherry (Merck & Co., Inc., Rahway, NJ, USA), Abdellatif
El Marrouni (Merck & Co., Inc., West Point, PA, USA), and
Dani Schultz (Merck & Co., Inc., Rahway, NJ, USA) for
helpful discussions.
(4) (a) Makarov, I. S.; Brocklehurst, C. E.; Karaghiosoff, K.; Koch,
G.; Knochel, P. Synthesis of Bicyclo[1.1.1]pentane Bioisosteres of
Internal Alkynes and para-Disubstituted Benzenes from [1.1.1]-
Propellane. Angew. Chem., Int. Ed. 2017, 56, 12774−12777.
(b) Messner, M.; Kozhushkov, S. I.; De Meijere, A. Nickel- and
Palladium-Catalyzed Cross-Coupling Reactions at the Bridgehead of
Bicyclo[1.1.1]pentane Derivatives − A Convenient Access to Liquid
Crystalline Compounds Containing Bicyclo[1.1.1]pentane Moieties.
Eur. J. Org. Chem. 2000, 2000, 1137−1155. (c) Rehm, J. D. D.;
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Bicyclo[1.1.1]pentanes Involving Palladium-Catalyzed Cross-Cou-
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ligands described on p S5 in the Supporting Information for ref 10a.
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ligand for nickel.
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(16) A related decarboxylative borylation has also been reported but
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(17) See the Supporting Information for details and pictures of the
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standard pyridine substrate 4 to this plate and observed a 24% LC
area percent, compared with an 81% isolated yield when an optimal
PennOC photoreactor was used.
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(23) These reactions lead to mixtures of starting material,
protodehalogenated starting material, and DMA-coupled starting
material. See the Supporting Information for experimental details and
yields.
(24) We did not see productive coupling of BF3Ks 6c−e, and work is
ongoing to identify conditions to effectively cross-couple these
building blocks. For bridgehead−bridgehead electronic interactions in
BCP systems that may cause the oxidation potential to be out of range
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Elsey, G. M.; Head, N. H.; Krstic, A. R.; Levin, M. D.; Michl, J.;
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