Continuous flow enables metallaphotoredox catalysis in a medicinal chemistry setting: Accelerated optimization and library execution of a reductive coupling between benzylic chlorides and aryl bromides

Article abstract of DOI:10.1021/acs.orglett.9b04117

Continuous flow has been used widely in process chemistry and academic settings for various applications. However, initial reaction discovery has generally remained "batch-exclusive" despite the existence of efficient, reproducible flow systems. We hereby disclose a workflow to bridge the gap between early medicinal chemistry efforts and process-scale development, showcased by the discovery and optimization of a metallaphotoredox-catalyzed cross-coupling between benzylic chlorides and aryl bromides, followed by two library syntheses of complex drug-like compounds.

Full text of DOI:10.1021/acs.orglett.9b04117

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Continuous Flow Enables Metallaphotoredox Catalysis in a
Medicinal Chemistry Setting: Accelerated Optimization and Library
Execution of a Reductive Coupling between Benzylic Chlorides and
Aryl Bromides
Zachary G. Brill,* Casey B. Ritts,‡,† Umar Faruk Mansoor, and Nunzio Sciammetta
,‡
Department of Discovery Chemistry, MRL, Merck & Co., Inc., Boston, Massachusetts 02115, United States
*
S Supporting Information
ABSTRACT: Continuous flow has been used widely in process chemistry and academic settings for various applications.
However, initial reaction discovery has generally remained “batch-exclusive” despite the existence of efficient, reproducible flow
systems. We hereby disclose a workflow to bridge the gap between early medicinal chemistry efforts and process-scale
development, showcased by the discovery and optimization of a metallaphotoredox-catalyzed cross-coupling between benzylic
chlorides and aryl bromides, followed by two library syntheses of complex drug-like compounds.
rganic chemistry in continuous flow displays several
O
advantages over classical batch reactions, including the
ability to form and immediately use reactive intermediates in
situ, tight control of temperature, increased surface area to
volume ratio, and the ability to scale out reactions under
1
identical conditions. These advantages are well recognized in
process chemistry, wherein tight control of reaction parameters
2
during optimization and scale-up can be invaluable. Medicinal
chemists have not widely incorporated flow chemistry into
their own projects because they often employ synthetic routes
that are not compatible with flow reactors, so they tend to use
batch reactors for microscale singleton reactions. Recently,
however, a number of applications toward parallel synthesis of
3
libraries have been disclosed. We propose that utilization of
the workflow shown in Figure 1 to perform reaction/substrate
development in flow can be a primary option for medicinal
chemists when higher throughput experimentation and syn-
Figure 1. Medicinal chemistry workflow: continuous flow optimiza-
tion and library synthesis.
4
thesis is challenging. If a key reaction for Structure−Activity
Relationship (SAR) exploration is identified but difficult to
optimize in batch, limited effort can be used to generate
homogeneous reaction conditions. These conditions are then
translated to continuous flow, and after validation of product
formation, a full optimization effort with a number of
parameters is performed. The optimized conditions, once
identified, are leveraged to execute libraries with a collection of
coupling partners.
regularly to the field have developed bespoke systems for
screening reactions to ensure homogeneous, consistent light
6
penetration and temperature control. Scientists at our
company frequently use an integrated photoreactor, developed
in collaboration with MacMillan and co-workers, which
achieves consistency between reactions but only allows for
7
single reaction setups. Continuous flow, meanwhile, allows for
sustained light penetration, temperature control and monitor-
Reactions featuring photoredox catalysis are particularly
suited to the workflow in Figure 1. Photoredox catalysis
facilitates a variety of new bond formations under surprisingly
Received: November 18, 2019
5
mild conditions. However, most laboratories which contribute
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b04117
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
ing, and shorter reaction times due to a high surface area to
8
,9
volume ratio.
To support a discovery chemistry project, we pursued an
efficient route to access a range of di(hetero)arylmethanes, a
chemotype also present in a variety of marketed drugs (Figure
2
3
2
). One strategy that maximizes convergence is an sp −sp
Figure 2. Examples of di(hetero)arylmethanes in pharmaceuticals.
coupling of suitably functionalized benzylic and aryl partners.
Figure 3A showcases a number of methods achieving this bond
connection, but many contain limitations that hinder
10
application to a diverse array of products to explore SAR.
Palladium-catalyzed cross-coupling of benzylic halides and
hetero)aryl nucleophiles sometimes requires toxic and
2
Figure 3. Formation of di(hetero)arylmethanes through sp −
(
3
sp coupling.
noncommercial (hetero)aryl stannanes when the boronic
ester is either not available or unreactive in the transmetalation
1
1
step. Formation of benzylzinc halides and subsequent
disclose a modified protocol to couple benzylic chlorides with
aryl bromides (Figure 3C) and the use of continuous flow to
optimize this reaction and execute multiple libraries with
diverse pharmaceutically relevant coupling partners.
At the outset of our investigations, we were encouraged by
the mild conditions reported by MacMillan to access highly
Negishi coupling can be operationally difficult and requires
12
rigorously anhydrous conditions. Oxidative copper-catalyzed
coupling of arylboronic acids/esters and benzylic C−H bonds
1
3
2
3
is limited to a select subset of substrates. Csp −Csp
reductive coupling circumvents many of these problems,
allowing use of readily available coupling partners. While
most such reported reductive couplings use alkyl halides as the
19
functionalized di(hetero)arylmethanes, but we recognized
that some modifications would be necessary. First, the
substrate scope in MacMillan’s work did not include benzylic
bromides, and internal efforts to reproduce the reaction with
benzylic bromides were unsuccessful. Second, for our purposes
we viewed the benzylic halide component as the limiting
reagent, as opposed to the aryl bromide. Finally, we intended
to use this reaction to run libraries in a short period of time.
For these reasons, we decided to use the workflow described in
Figure 1 to discover and optimize a reductive metal-
laphotoredox transformation to access di(hetero)arylmethanes.
As described in Figure 1, we first needed to establish a
reaction in batch that produced product and then modify the
conditions to maintain homogeneity throughout the course of
the reaction. After some experimentation, we discovered that
benzylic chlorides could be coupled with heteroaryl bromides
3
14
sp component, conditions with benzylic halides have also
1
5
been reported. Weix and co-workers disclosed a nickel-
catalyzed reductive coupling of benzylic mesylates and aryl
halides using stoichiometric cobalt, and Reisman and co-
workers reported an enantioselective nickel-catalyzed coupling
16,17
of secondary benzylic chlorides and aryl iodides.
Photo-
redox catalysis obviates the need for stoichiometric metals and
has been shown to operate under mild conditions in related
systems (Figure 3B). For example, Molander and co-workers
demonstrated the coupling of aryl bromides and benzylic
trifluoroborate salts, but we were concerned about the lack of
diverse, commercially available benzylic BF K salts to access
3
18
complex diheteroarylmethanes via this method. Meanwhile,
MacMillan and co-workers recently developed a metal-
laphotoredox reductive coupling of alkyl bromides and aryl
under slightly modified conditions (1 mol % {Ir[dF(CF )-
3
19
20
bromides using (TMS) SiH as a mild reductant. Herein, we
ppy] (dtbbpy)}PF , 5 mol % [Ni(dtbbpy)Cl ](H O) ,
3
2
6
2
2
4
B
DOI: 10.1021/acs.orglett.9b04117
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Reaction Optimization in Continuous Flow
b
c
entry
temperature
photocatalyst
{Ir[dF(CF )ppy] (dtbbpy)}PF
base
reductant
yield
3a:4a
e
e
e
e
e
e
,
,
,
,
f
f
f
f
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
30 °C
40 °C
50 °C
60 °C
40 °C
40 °C
40 °C
40 °C
40 °C
40 °C
40 °C
40 °C
40 °C
40 °C
40 °C
40 °C
40 °C
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
Bu N
Et N
2,6-Lutidine
NMM
Et N
(TMS) SiH
17%
23%
28%
32%
3.7:1
3.5:1
2.0:1
1.3:1
4.7:1
2.1:1
2.6:1
1.2:1
6.5:1
8.6:1
19:1
25:1
23:1
17:1
4.8:1
23:1
23:1
3
2
6
6
6
6
6
6
6
6
3
{Ir[dF(CF )ppy] (dtbbpy)}PF
(TMS) SiH
3
2
3
{Ir[dF(CF )ppy] (dtbbpy)}PF
(TMS) SiH
3
2
3
{Ir[dF(CF )ppy] (dtbbpy)}PF
(TMS) SiH
3
2
3
d
d
d
d
{Ir[dF(CF )ppy] (dtbbpy)}PF
(TMS) SiH
20%
24%
32%
30%
37%
41%
47%
61%
49%
42%
22%
54%
81%
3
2
3
,
g
{Ir[dF(CF )ppy] (dtbbpy)}PF
(TMS) SiH
3
2
3
{Ir[dF(CF )ppy] (dtbbpy)}PF
(TMS) SiH
3
2
3
h
{Ir[dF(CF )ppy] (dtbbpy)}PF
(TMS) SiH
3
2
3
Ir(ppy) (dtbbpy)(PF )
(TMS) SiH
2
6
3
d
d
d
d
d
d
d
0
1
2
3
4
5
6
7
4-DPA-IPN
(TMS) SiH
3
4-DPA-IPN
4-DPA-IPN
4-DPA-IPN
4-DPA-IPN
4-DPA-IPN
4-DPA-IPN
4-DPA-IPN
(TMS) SiOH
3
(TMS) SiOH
3
3
(TMS) SiOH
3
3
(TMS) SiOH
3
(TMS) SiOH
3
i
i
(TMS) SiOH
3
3
d
d
Bu N
(TMS) SiOH
3
3
a
Unless otherwise noted, reactions were carried out with 0.05 mmol of 1a (0.025 M), 0.125 mmol of 2a, 2 mol % photocatalyst, 5 mol %
Ni(dtbbpy)(H O) ]Cl , 0.075 mmol of reductant and 0.15 mmol of base in 2 mL of DMA at the temperature indicated with a flow residence time
[
2
4
2
b
c
of 30 min. Determined by LCMS peak integration versus a calibrated internal standard. Ratio of LCMS peak area (UV signal, 254 nm); it does
not determine yield of 4a but can be used for head-to-head comparisons of reactions. Average of two runs of the reaction. Reaction run with 10
mol % [Ni] and 0.5 mol % photocatalyst. Reaction run at 0.05 M in 1a (0.1 mmol of 1a, 0.25 mmol of 2a, 0.15 mmol of reductant, and 0.3 mmol
of base in 2 mL of DMA). Reaction run at 0.1 M in 1a. (0.2 mmol of 1a, 0.5 mmol of 2a, 0.3 mmol of reductant, 0.6 mmol of base in 2 mL of
DMA). Reaction run with 5 mol % [Ni] and 5 mol % photocatalyst. Reaction run with a flow residence time of 60 min. dtbbpy = di-tert-butyl-
bipyridine, DMA = dimethylacetamide, ppy = 2-phenylpyridinato, DIPEA = N,N-diisopropylethylamine, TMS = trimethylsilyl, NMM = N-
methylmorpholine.
d
e
f
g
h
i
lithium hydroxide, (TMS) SiH, dimethoxyethane [DME]).
observed at temperatures greater than 40 °C. Selecting 40 °C
as our optimal temperature, we then evaluated the effect of
concentration and discovered that dilution to 0.025 M helped
mitigate formation of 4a, relative to 0.05 M or higher
3
These conditions were heterogeneous, required long reaction
times (8−10 h), and provided undesired side reactions of the
benzylic component, including hydrodehalogenation, dimeri-
zation, and a solvent adduct with DME. To generate a set of
homogeneous conditions, we experimented with the reaction
solvent and base. Lithium hydroxide was substituted with the
soluble organic base 2,6-lutidine. Eight solvents were screened,
but only with dimethylacetamide (DMA) was product
observed and the reaction homogeneous throughout. Further
screening in batch identified that diisopropylethylamine
23
concentrations [entries 5−6].
We next explored the ratio of the two catalysts. With
experimentation, we identified a 2.5:1 ratio of nickel
precatalyst to photocatalyst as ideal, and 5 mol % nickel
precatalyst/2 mol % photocatalyst seemed to provide the most
24
efficient conversion relative to cost [entries 7−8]. It is worth
noting the difference between this ratio (5:2) and the 1:2 ratio
19
(
DIPEA) provided superior yield to 2,6-lutidine.
With fully homogeneous conditions in hand, we sought to
used by MacMillan, which may result from our use of a
reactive benzylic halide as the limiting reagent instead of a
limiting aryl halide in combination with nonactivated alkyl
bromides. We then explored a small selection of photocatalysts
and identified that the organophotocatalyst 4-DPA-IPN was
further optimize the reaction between 1a and 2a using a
Vaportec R-Series flow reactor equipped with a UV-150
photoreactor. We quickly discovered that a 30 min residence
time in flow gave results comparable to our batch reactions,
and this allowed us to set up 20−24 reactions in a single day
25
optimal for this reaction [entries 9−10]. Finally we re-
examined the reducing agent and the base. We hypothesized
21
using autosampler technology. Table 1 shows the results of
our optimization efforts, with LCMS yields of 3a being
calculated relative to a calibrated internal standard and the
that (TMS) SiOH, recently reported by MacMillan as an
3
26
alternative to (TMS) SiH, could reduce formation of 4a due
3
to its inability to serve as a hydrogen atom donor, and to our
22
ratio of 3a to 4a being calculated from UV peak intensity. We
first tested temperature and concentration parameters. Clear
and opposite trends were observed for reactivity and selectivity
when adjusting reaction temperature [entries 1−4]. While
increasing temperature improved reaction conversion, sub-
stantial formation of the hydrodehalogenation product 4a was
delight we did see an improved ratio of 3a vs 4a while still
27
providing acceptable conversion of 1a [entry 11]. After
screening additional organic bases, we identified that tributyl-
2
8
amine was preferred for the reaction [entries 12−15].
Finally, we explored extending the reaction time to 60 min
[entries 16−17]. While we did observe an increase in yield
C
DOI: 10.1021/acs.orglett.9b04117
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
,
a b
from 61% [entry 12] to 81% [entry 16] with tributylamine as
the base, we concluded that library synthesis and scale out
would be more efficiently executed with the 30 min setup.
Scheme 1. Library Showcasing Scope of Aryl Bromide
29
The optimized reaction was scaled out to 1 mmol in 57% yield
and returned to a batch setup providing 82% yield (compared
to the original heterogeneous conditions in batch, which
provided 13% yield of 3a; see Supporting Information).
Control experiments in the absence of (TMS) SiOH suggested
3
that the trialkylamine base can serve as a reductant in this
30
reaction (see Supporting Information), but it was unclear if
this silanol-free mechanism would proceed efficiently with a
wider range of substrates, so library efforts were performed
31
using the conditions of entry 12.
Having discovered optimized conditions for this trans-
formation, we proceeded to evaluate the substrate scope.
Schemes 1 and 2 show the results of two libraries, varying the
aryl bromide and the benzylic chloride, respectively. Execution
of the libraries was operationally simple (see Supporting
Information), and use of the Vaportec autosampler feature
facilitated the completion of a library of 20 compounds in only
1
9 h. The goals for these libraries differed from traditional
substrate scope explorations. Typically, simplistic coupling
partners are used to test specific hypotheses about functional
group, steric, or electronic effects. We mostly chose complex,
multifunctional building blocks one would see in a medicinal
chemistry setting. While the highest possible yields were
desired, we defined success to be the ability of these 0.05 mmol
scale reactions to deliver enough material for profiling in key in
vitro pharmacological assays (>1−2 mg). All products shown
in Schemes 1 and 2 met this standard except where indicated.
We argue that despite moderate yields in many cases, the high
“hit rate” for both libraries suggests substantial functional
group tolerance and scope in a number of settings.
We first varied the aryl bromide coupling partner 2 (Scheme
). Sixteen out of 20 reactions formed product, with 14 targets
1
isolated in sufficient quantity for testing. In addition to
nitrogen-, oxygen-, and sulfur-containing heteroaromatics, aryl
chlorides (3n), amides (3m), sulfones (3o), ketones (3p),
unprotected alcohols (3r), nitriles (3j, 3t), and ethers (3u)
were tolerated. An aryl triflate was tolerated albeit in low yield
(
3
3c), but unprotected amines appeared to be problematic (3e,
i, 3k, 3l). In general, six-membered (heteroaryl)bromides
without amino groups were well tolerated across steric and
electronic environments (see simple arenes 3q, 3u, and 3t).
Five-membered heteroaryl bromides were less efficient but still
produced some product (see 3b, 3h, 3j, 3o).
Our second library explored the scope of benzylic chlorides
in combination with heteroaryl bromide 2a (Scheme 2). In
1
this experiment, 11 of 14 reactions formed product, and nine
products were isolated with enough material for testing. A wide
variety of functional groups were tolerated on the benzylic
chloride, including (hetero)aryl chlorides (5b, 5k), sulfona-
32
mides (5h), esters (5n), and even free amino groups (5c).
Benzylic chlorides adjacent to both five- and six-membered
heterocycles were suitable for the transformation, and
competent heterocycles included quinolines (5b), thiazoles
a
Reactions were carried out with 0.05 mmol 1a, 0.125 mmol 2b−u, 2
mol % 4-DPA-IPN, 5 mol % [Ni(dtbbpy)(H O) ]Cl , 0.075 mmol
2
4
2
(
TMS) SiOH and 0.15 mmol Bu N in 2 mL of DMA at 40 °C with a
3 3
b
(
(
5d), imidazoles (5e, 5f, 5h, 5k), pyrimidines (5c), and furans
5n). Interestingly, oxadiazole- (5g, 5i) and benzoxazole- (5a,
flow residence time of 30 min. Isolated yield after HPLC indicated.
c
Insufficient material produced for use in in vitro pharmacological
5
j) based chlorides provided little to no product. A
d
assays. Product isolated from HPLC purification at lower purity level
nonheteroaromatic naphthalene-derived product (5l) was
isolated in low yield. It is worth noting the complementary
reactivity of the coupling partners in this reaction; products
derived from nonheteroaromatic aryl bromides (i.e., 3s) were
e
(
70−95%). Product was unstable during first characterization but
similar yield observed in batch reaction, albeit at lower purity level.
dtbbpy = di-tert-butyl-bipyridine, DMA = dimethylacetamide, TMS =
trimethylsilyl.
D
DOI: 10.1021/acs.orglett.9b04117
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Library Showcasing Scope of Benzylic
Chloride
Ongoing work is focused on increasing the scope of the
transformation. To this end, we discovered that the reaction of
allylic chloride 6 with bromide 2a furnished the desired
coupling product 7, albeit in low yield (Scheme 3).
Furthermore, the aryl bromide component can be replaced
with vinyl bromide 8, providing 9. Further expansion of the
reaction scope will be reported in due course.
,
a b
,
a b
Scheme 3. Extension to Additional Substrate Classes
a
Reactions were carried out with 0.05 mmol of 6 or 1a, 0.125 mmol
of 2a or 8, 2 mol % 4-DPA-IPN, 5 mol % [Ni(dtbbpy)(H O) ]Cl ,
2
4
2
0
.075 mmol of (TMS) SiOH, and 0.15 mmol of Bu N in 2 mL of
3 3
b
DMA at 40 °C with a flow residence time of 30 min. Isolated yield
shown after HPLC purification. Compound isolated at lower purity
c
level after HPLC purification (70−95%). dtbbpy = di-tert-butyl-
bipyridine, DMA = dimethylacetamide, TMS = trimethylsilyl.
In summary, we have developed a rapid, efficient, and
selective coupling reaction under metallaphotoredox condi-
tions between benzylic chlorides and (hetero)aryl bromides
using continuous flow. We leveraged the Vapourtec R-Series
flow reactor to optimize this transformation in flow and then
executed multiple libraries with complex, functionalized
medicinal chemistry building blocks. We believe that the
general strategy of using continuous flow to optimize reactions
and execute libraries for photochemical reactions will be of
continued value to our company and the medicinal chemistry
community, and efforts with additional reaction types are
currently under exploration in our laboratory.
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04117.
a
Reactions were carried out with 0.05 mmol of 1b−o, 0.125 mmol of
a, 2 mol % 4-DPA-IPN, 5 mol % [Ni(dtbbpy)(H O) ]Cl , 0.075
2
2
4
2
Experimental procedures, additional control experi-
ments, and spectroscopic data for all new compounds
(PDF)
mmol of (TMS) SiOH and 0.15 mmol of Bu N in 2 mL of DMA at
4
after HPLC purification. Insufficient material produced for use in in
vitro pharmacological assays. Compound isolated at lower purity
level after HPLC purification (70−95%). dtbbpy = di-tert-butyl-
bipyridine, DMA = dimethylacetamide, TMS = trimethylsilyl.
3
3
b
0 °C with a flow residence time of 30 min. Isolated yield shown
c
d
AUTHOR INFORMATION
Corresponding Author
■
*
E-mail: zachary.brill@merck.com.
ORCID
isolated in higher yields than those from benzylic chlorides
such as 5l; meanwhile, benzylic chlorides adjacent to five-
membered heteroarenes generated higher yields than five-
membered aryl bromides. This can be taken into account if
using the reaction to retrosynthetically disconnect a diheter-
oarylmethane target of interest.
Zachary G. Brill: 0000-0003-2652-4673
Casey B. Ritts: 0000-0002-1734-3128
Present Address
†
Department of Chemistry, University of Minnesota, Minne-
apolis, Minnesota, 55455, USA.
E
DOI: 10.1021/acs.orglett.9b04117
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Author Contributions
‡Z.G.B. and C.B.R. contributed equally to this work.
Development of a Large-Scale Asymmetric Process for tert-
Butanesulfinamide. Org. Process Res. Dev. 2019, 23, 263−268.
(
f) Levesque, F.; Rogus, N. J.; Spencer, G.; Grigorov, P.;
́
Notes
McMullen, J. P.; Thaisrivongs, D. A.; Davies, I. W.; Naber, J. R.
Advancing Flow Chemistry Portability: A Simplified Approach to
Scaling Up Flow Chemistry. Org. Process Res. Dev. 2018, 22, 1015−
The authors declare no competing financial interest.
1021.
ACKNOWLEDGMENTS
■
(3) Selected articles on library synthesis in flow: (a) Gioiello, A.;
Rosatelli, E.; Teofrasti, M.; Filipponi, P.; Pellicciari, R. Building a
Sulfonamide Library by Eco-Friendly Flow Synthesis. ACS Comb. Sci.
We thank the 2018 MSD Future Talent Program for its
support of C.B.R.’s internship at our company. We thank Dr.
Brandon Vara, Dr. Andrew Musacchio, and Dr. Emily
Corcoran for helpful discussions and suggestions, and for
reviewing this paper. We greatly acknowledge Dr. Yuan Jiang
for running HRMS analysis to confirm all compounds
disclosed herein. We acknowledge Dr. Yuan Jiang, Taylor
Johnson, Adam Beard, and Xiaochen Zuo for LCMS support
and thank Adam Beard and Xiaochen Zuo for creating a new
method that allowed for determination of LCMS yield during
optimization. We also thank Miroslawa Darlak, Dr. Spencer
McMinn, Dr. Lisa Nogle, Mark Pietrafitta, David Smith, Adam
Beard, and Sharon Wilhelm for HPLC purification of coupling
products. Finally, we acknowledge Dr. Eugene Kwan, Dr.
2013, 15, 235−239. (b) Riesco-Domínguez, A.; Blanco-Ania, D.;
Rutjes, F. P. J. T. Continuous Flow Synthesis of Urea-Containing
Compound Libraries Based on the Piperidin-4-one Scaffold. Eur. J.
Org. Chem. 2018, 1312−1320. (c) Yavorskyy, A.; Shvydkiv, O.;
Hoffmann, N.; Nolan, K.; Oelgemoller, M. Parallel Microflow
̈
Photochemistry: Process Optimization, Scale-up, and Library Syn-
thesis. Org. Lett. 2012, 14, 4342−4345. (d) Thompson, C. M.; Poole,
J. L.; Cross, J. L.; Akritopoulou-Zanze, I.; Djuric, S. W. Small
Molecule Library Synthesis Using Segmented Flow. Molecules 2011,
16, 9161−9177. (e) Lange, P. P.; James, K. Rapid Access to
Compound Libraries through Flow Technology: Fully Automated
Synthesis of a 3-Aminoindolizine Library via Orthogonal Diversifica-
tion. ACS Comb. Sci. 2012, 14, 570−578.
Donovon Adpressa, and Dr. Josep Saurı
́
for help with NMR
(4) A variety of advanced, fully-automated versions of similar
workflows have been developed and custom-built, though these are
not widely accessible to medicinal chemists. Selected example:
characterization of final compounds. All acknowledged
individuals were affiliated with MRL, Merck & Co., Inc.,
Boston, MA, USA, at the time of their contributions.
Bedard, A.-C.; Adamo, A.; Aroh, K. C.; Russell, M. G.; Bedermann,
́
A. A.; Torosian, J.; Yue, B.; Jensen, K. F.; Jamison, T. F.
Reconfigurable system for automated optimization of diverse
chemical reactions. Science 2018, 361, 1220−1225.
REFERENCES
■
(
1) See reviews and references within: (a) Gutmann, B.; Cantillo,
(5) See selected reviews on applications of photoredox catalysis and
references therein: (a) Prier, C. K.; Rankic, D. A.; MacMillan, D. W.
C. Visible Light Photoredox Catalysis with Transition Metal
Complexes: Applications in Organic Synthesis. Chem. Rev. 2013,
D.; Kappe, C. O. Continuous-Flow Technology−A Tool for the Safe
Manufacturing of Active Pharmaceutical Ingredients. Angew. Chem.,
Int. Ed. 2015, 54, 6688−6728. (b) Wiles, C.; Watts, P. Continuous
flow reactors: a perspective. Green Chem. 2012, 14, 38−54.
1
13, 5322−5363. (b) Douglas, J. J.; Nguyen, J. D.; Cole, K. P.;
(
c) Cambie,
Noel, T. Applications of Continuous-Flow Photochemistry in Organic
Synthesis, Material Science, and Water Treatment. Chem. Rev. 2016,
́
D.; Bottecchia, C.; Straathof, N. J. W.; Hessel, V.;
Stephenson, C. R. J. Enabling novel photoredox reactivity via
̈
photocatalyst selection. Aldrichimica Acta 2014, 47, 15−25.
(c) Twilton, J.; Le, C.; Zhang, P.; Shaw, M. H.; Evans, R. W.;
1
16, 10276−10341. (d) Webb, D.; Jamison, T. F. Continuous flow
MacMillan, D. W. C. The merger of transition metal and
photocatalysis. Nat. Rev. Chem. 2017, 1, No. 0052. (d) Milligan, J.
A.; Phelan, J. P.; Badir, S. O.; Molander, G. A. Alkyl Carbon-Carbon
Bond Formation by Nickel/Photoredox Cross-Coupling. Angew.
Chem., Int. Ed. 2019, 58, 6152−6163.
multi-step organic synthesis. Chem. Sci. 2010, 1, 675−680. (e) Seo,
H.; Nguyen, L. V.; Jamison, T. F. Using Carbon Dioxide as a Building
Block in Continuous Flow Synthesis. Adv. Synth. Catal. 2019, 361,
2
47−264. (f) Tucker, J. W.; Zhang, Y.; Jamison, T. F.; Stephenson, C.
R. J. Visible-Light Photoredox Catalysis in Flow. Angew. Chem., Int.
Ed. 2012, 51, 4144−4147. (g) Plutschack, M. B.; Pieber, B.; Gilmore,
K.; Seeberger, P. H. The Hitchhiker’s Guide to Flow Chemistry.
Chem. Rev. 2017, 117, 11796−11893. (h) Porta, R.; Benaglia, M.;
Puglisi, A. Flow Chemistry: Recent Developments in the Synthesis of
Pharmaceutical Products. Org. Process Res. Dev. 2016, 20, 2−25.
(
6) McAtee, R. C.; McClain, E. J.; Stephenson, C. R. J. Illuminating
Photoredox Catalysis. Trends in Chemistry 2019, 1, 111−125.
7) (a) Le, C.; Wismer, M. K.; Shi, Z.-C.; Zhang, R.; Conway, D. V.;
(
Li, G.; Vachal, P.; Davies, I. W.; MacMillan, D. W. C. A General
Small-Scale Reactor to Enable Standardization and Acceleration of
Photocatalytic Reactions. ACS Cent. Sci. 2017, 3, 647−653.
(
i) Mak, X. Y.; Laurino, P.; Seeberger, P. H. Asymmetric reactions in
(
b) Zhang, R.; Li, G.; Wismer, M.; Vachal, P.; Colletti, S. L.; Shi,
continuous flow. Beilstein J. Org. Chem. 2009, 5, No. 19. (j) Garlets, Z.
J.; Nguyen, J. D.; Stephenson, C. R. J. The Development of Visible-
Light Photoredox Catalysis in Flow. Isr. J. Chem. 2014, 54, 351−360.
3
2
Z.-C. Profiling and Application of Photoredox C(sp )-C(sp ) Cross-
Coupling in Medicinal Chemistry. ACS Med. Chem. Lett. 2018, 9,
7
(
73−777.
(
2) (a) Adeyemi, A.; Bergman, J.; Brånalt, J.; Savmarker, J.; Larhed,
̈
8) The value of flow in photochemical reactions has been
M. Continuous Flow Synthesis under High-Temperature/High-
Pressure Conditions Using a Resistively Heated Flow Reactor. Org.
Process Res. Dev. 2017, 21, 947−955. (b) Marre, S.; Adamo, A.; Basak,
S.; Aymonier, C.; Jensen, K. F. Design and Packaging of Microreactors
for High Pressure and High Temperature Applications. Ind. Eng.
Chem. Res. 2010, 49, 11310−11320. (c) Thaisrivongs, D. A.; Naber, J.
R.; Rogus, N. J.; Spencer, G. Development of an Organometallic Flow
Chemistry Reaction at Pilot-Plant Scale for the Manufacture of
Verubecestat. Org. Process Res. Dev. 2018, 22, 403−408. (d) Yayla, H.
G.; Peng, F.; Mangion, I. K.; McLaughlin, M.; Campeau, L.-C.;
Davies, I. W.; DiRocco, D. A.; Knowles, R. R. Discovery and
mechanistic study of a photocatalytic indoline dehydrogenation for
the synthesis of elbasvir. Chem. Sci. 2016, 7, 2066−2073. (e) DeCroos,
P.; Han, Z. S.; Sidhu, K.; Lorenz, J.; Nummy, L.; Byrne, D.; Qu, B.;
Xu, Y.; Wu, L.; Lee, H.; Roschangar, F.; Song, J. J.; Senanayake, C. H.
demonstrated in both academic and industrial settings. Selected
examples in photoredox catalysis: (a) Beatty, J. W.; Douglas, J. J.;
Miller, R.; McAtee, R. C.; Cole, K. P.; Stephenson, C. R. J.
Photochemical Perfluoroalkylation with Pyridine N-Oxides: Mecha-
nistic Insights and Performance on a Kilogram Scale. Chem. 2016, 1,
4
56−472. (b) Seo, H.; Liu, A.; Jamison, T. F. Direct β-Selective
Hydrocarboxylation of Styrenes with CO Enabled by Continuous
2
Flow Photoredox Catalysis. J. Am. Chem. Soc. 2017, 139, 13969−
13972. (c) Beatty, J. W.; Stephenson, C. R. J. Synthesis of
(−)-Pseudotabersonine, (−)-Pseudovincadifformine, and (+)-Coro-
naridine Enabled by Photoredox Catalysis in Flow. J. Am. Chem. Soc.
̈
2014, 136, 10270−10273. Straathof, N. J. W.; Noel, T. In Visible light
photocatalysis in organic chemistry, Stephenson, C. R. J., Yoon, T.,
MacMillan, D. W. C., Eds.; Wiley-VCH: Berlin, 2018; pp 389−413.
F
DOI: 10.1021/acs.orglett.9b04117
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(
9) Additional examples of photochemistry in continuous flow:
Solvents. Chem. - Eur. J. 2016, 22, 11564−11567. (b) Zhang, J.; Lu,
G.; Xu, J.; Sun, H.; Shen, Q. Nickel-Catalyzed Reductive Cross-
Coupling of Benzyl Chlorides with Aryl Chlorides/Fluorides: A One-
Pot Synthesis of Diarylmethanes. Org. Lett. 2016, 18, 2860−2863.
(16) Ackerman, L. K. G.; Anka-Lufford, L. L.; Naodovic, M.; Weix,
D. J. Cobalt co-catalysis for cross-electrophile coupling: diaryl-
methanes from benzyl mesylates and aryl halides. Chem. Sci. 2015, 6,
1115−1119.
(
a) Blanco-Ania, D.; Gawade, S. A.; Zwinkels, L. J. L.; Maartense, L.;
Bolster, M. G.; Benningshof, J. C. J.; Rutjes, F. P. J. T. Rapid and
Scalable Access into Strained Scaffolds through Continuous Flow
Photochemistry. Org. Process Res. Dev. 2016, 20, 409−413. (b) Elliott,
L. D.; Berry, M.; Harji, B.; Klauber, D.; Leonard, J.; Booker-Milburn,
K. I. A Small-Footprint, High-Capacity Flow Reactor for UV
Photochemical Synthesis on the Kilogram Scale. Org. Process Res.
Dev. 2016, 20, 1806−1811. (c) Liang, Y.-F.; Steinbock, R.; Yang, L.;
Ackermann, L. Continuous Visible-Light Photoflow Approach for a
Manganese-Catalyzed (Het)Arene C-H Arylation. Angew. Chem., Int.
́
Ed. 2018, 57, 10625−10629. (d) Corcoran, E. B.; Levesque, F.;
McMullen, J. P.; Naber, J. R. Studies Toward the Scaling of Gas-
Liquid Photocycloadditions. ChemPhotoChem. 2018, 2, 931−937.
́
e) Schultz, D. M.; Levesque, F.; DiRocco, D. A.; Reibarkh, M.; Ji, Y.;
(17) Poremba, K. E.; Kadunce, N. T.; Suzuki, N.; Cherney, A. H.;
Reisman, S. E. Nickel-Catalyzed Asymmetric Reductive Cross-
Coupling To Access 1,1-Diarylalkanes. J. Am. Chem. Soc. 2017, 139,
5684−5687.
(18) Tellis, J. C.; Primer, D. N.; Molander, G. A. Single-electron
transmetalation in organoboron cross-coupling by photoredox/nickel
dual catalysis. Science 2014, 345, 433−436.
(
Joyce, L. A.; Dropinski, J. F.; Sheng, H.; Sherry, B. D.; Davies, I. W.
Oxyfunctionalization of the Remote C-H Bonds of Aliphatic Amines
by Decatungstate Photocatalysis. Angew. Chem., Int. Ed. 2017, 56,
(19) Zhang, P.; Le, C.; MacMillan, D. W. C. Silyl Radical Activation
of Alkyl Halides in Metallaphotoredox Catalysis: A Unique Pathway
for Cross-Electrophile Coupling. J. Am. Chem. Soc. 2016, 138, 8084−
8
(
087.
́
20) Gutierrez-Bonet, A.; Tellis, J. C.; Matsui, J. K.; Vara, B. A.;
́
1
(
5274−15278.
10) For additional selected examples of diarylmethane synthesis
2
3
Molander, G. A. 1,4-Dihydropyridines as Alkyl Radical Precursors:
Introducing the Aldehyde Feedstock to Nickel/Photoredox Dual
Catalysis. ACS Catal. 2016, 6, 8004−8008.
through sp −sp coupling, see: (a) Vara, B. A.; Patel, N. R.; Molander,
G. A. O-Benzyl Xanthate Esters under Ni/Photoredox Dual Catalysis:
3
2
Selective Radical Generation and Csp -Csp Cross-Coupling. ACS
Catal. 2017, 7, 3955−3959. (b) Sha, S.-C.; Tcyrulnikov, S.; Li, M.;
Hu, B.; Fu, Y.; Kozlowski, M. C.; Walsh, P. J. Cation-π Interactions in
the Benzylic Arylation of Toluenes with Bimetallic Catalysts. J. Am.
Chem. Soc. 2018, 140, 12415−12423. (c) Bolliger, J. L.; Frech, C. M.
Dichloro-Bis(aminophosphine) Complexes of Palladium: Highly
Convenient, Reliable and Extremely Active Suzuki-Miyaura Catalysts
with Excellent Functional Group Tolerance. Chem. - Eur. J. 2010, 16,
(21) Reaction solutions were kept in amber vials in order to block
out ambient light.
(22) See Supporting Information (p 19) of the following: Hansen, E.
C.; Pedro, D. J.; Wotal, A. C.; Gower, N. J.; Nelson, J. D.; Caron, S.;
Weix, D. J. New ligands for nickel catalysis from diverse
pharmaceutical heterocycle libraries. Nat. Chem. 2016, 8, 1126−1130.
(23) Concentrations of 0.05 M and above can still be used to
process more material when necessary, albeit with some erosion of
selectivity.
4
075−4081. (d) Li, G.; Arisawa, M.; Yamaguchi, M. Rhodium-
catalyzed synthesis of unsymmetrical di(aryl/heteroaryl)methanes
using aryl/heteroarylmethyl ketones via CO-C bond cleavage. Chem.
Commun. 2014, 50, 4328−4330. (e) Burns, M. J.; Fairlamb, I. J. S.;
Kapdi, A. R.; Sehnal, P.; Taylor, R. J. K. Simple Palladium(II)
Precatalyst for Suzuki-Miyaura Couplings: Efficient Reactions of
Benzylic, Aryl, Heteroaryl, and Vinyl Coupling Partners. Org. Lett.
(
24) Reduced catalyst loadings are still competent and can be
explored on larger scales if catalyst expense becomes a limiting factor.
25) Investigation on the development of new nickel precatalysts is
currently ongoing in our laboratories.
26) (a) Le, C.; Chen, T. Q.; Liang, T.; Zhang, P.; MacMillan, D. W.
(
(
C. A radical approach to the copper oxidative addition problem:
2
007, 9, 5397−5400. (f) Chen, X.; Zhou, L.; Li, Y.; Xie, T.; Zhou, S.
Trifluoromethylation of bromoarenes. Science 2018, 360, 1010−1014.
Synthesis of Heteroaryl Compounds through Cross-Coupling
Reaction of Aryl Bromides or Benzyl Halides with Thienyl and
Pyridyl Aluminum Reagents. J. Org. Chem. 2014, 79, 230−239.
(
b) Smith, R. T.; Zhang, X.; Rincon, J. A.; Agejas, J.; Mateos, C.;
́
Barberis, M.; García-Cerrada, S.; de Frutos, O.; MacMillan, D. W. C.
Metallaphotoredox-Catalyzed Cross-Electrophile Csp -Csp Coupling
3
3
(
11) (a) Burton, P. M.; Morris, J. A. Palladium-Catalyzed Benzylic
of Aliphatic Bromides. J. Am. Chem. Soc. 2018, 140, 17433−17438.
Arylation of 2-Methyl Azaarenes. Org. Lett. 2010, 12, 5359−5361.
b) WO 2017001924 A1.
12) (a) WO 2000031067 A1. (b) Metzger, A.; Schade, M. A.;
(
27) Early experiments with (TMS) SiOH in batch led to low
3
(
conversion of starting material.
(
(28) Though not necessary for our purposes, tributylamine has also
Knochel, P. LiCl-Mediated Preparation of Highly Functionalized
Benzylic Zinc Chlorides. Org. Lett. 2008, 10, 1107−1110.
(
Pharmacophores: Cu-Catalyzed Oxidative Arylation of Inexpensive
Alkylarenes Enabling Direct Access to Diarylalkanes. J. Am. Chem. Soc.
been shown to be a more soluble lipophilic base for flow applications
than triethylamine. See: Yasukouchi, H.; Nishiyama, A.; Mitsuda, M.
Safe and Efficient Phosgenation Reactions in a Continuous Flow
Reactor. Org. Process Res. Dev. 2018, 22, 247−251.
13) (a) Vasilopoulos, A.; Zultanski, S. L.; Stahl, S. S. Feedstocks to
(
29) The 60 min reaction time could still find use when yield is of
primary importance.
30) For previous studies invoking alkylamine base as a reductant in
2
017, 139, 7705−7708. (b) Zhang, W.; Chen, P.; Liu, G. Copper-
Catalyzed Arylation of Benzylic C-H bonds with Alkylarenes as the
(
Limiting Reagnets. J. Am. Chem. Soc. 2017, 139, 7709−7712.
(
Shrestha, R.; Weix, D. J. Nickel-Catalyzed Reductive Cross-Coupling
metallaphotoredox couplings, see: (a) Duan, Z.; Li, W.; Lei, A.
Nickel-Catalyzed Reductive Cross-Coupling of Aryl Bromides with
14) Selected examples from the Weix group: (a) Everson, D. A.;
Alkyl Bromides: Et N as the Terminal Reductant. Org. Lett. 2016, 18,
3
of Aryl Halides with Alkyl Halides. J. Am. Chem. Soc. 2010, 132, 920−
4
012−4015. (b) Paul, A.; Smith, M. D.; Vannucci, A. K. Photoredox-
9
21. (b) Biswas, S.; Weix, D. J. Mechanism and Selectivity in Nickel-
Assisted Reductive Cross-Coupling: Mechanistic Insight into
Catalyzed Cross-Electrophile Coupling of Aryl Halides with Alkyl
Halides. J. Am. Chem. Soc. 2013, 135, 16192−16197. (c) Weix, D. J.
Methods and Mechanisms for Cross-Electrophile Coupling of Csp
Catalytic Aryl-Alkyl Cross-Couplings. J. Org. Chem. 2017, 82,
1
(
996−2003.
2
31) A control experiment in the absence of 4-DPA-IPN did provide
Halides with Alkyl Electrophiles. Acc. Chem. Res. 2015, 48, 1767−
a small amount of 3a; see Supporting Information for discussion of
this result.
1
775. (d) Hansen, E. C.; Li, C.; Yang, S.; Pedro, D.; Weix, D. J.
Coupling of Challenging Heteroaryl Halides with Alkyl Halides via
Nickel-Catalyzed Cross-Electrophile Coupling. J. Org. Chem. 2017,
(32) It remains unclear if the successful synthesis of amine-
containing 5c indicates complementary reactivity of the coupling
partners or something particular about this building block (perhaps
hydrogen bonding to a neighbouring ester group).
8
(
2, 7085−7092.
15) Additional selected examples of diarylmethane synthesis
through reductive coupling: (a) Anka-Lufford, L. L.; Huihui, K. M.
M.; Gower, N. J.; Ackerman, L. K. G.; Weix, D. J. Nickel-Catalyzed
Cross-Electrophile Coupling with Organic Reductants in Non-Amide
G
DOI: 10.1021/acs.orglett.9b04117
Org. Lett. XXXX, XXX, XXX−XXX