ChemBead Enabled High-Throughput Cross-Electrophile Coupling Reveals a New Complementary Ligand

Article abstract of DOI:10.1002/chem.202102347

High-throughput experimentation (HTE) methods are central to modern medicinal chemistry. While many HTE approaches to C?N and Csp²?Csp² bonds are available, options for Csp²?Csp³ bonds are limited. We report here how the adaptation of nickel-catalyzed cross-electrophile coupling of aryl bromides with alkyl halides to HTE is enabled by AbbVie ChemBeads technology. By using this approach, we were able to quickly map out the reactivity space at a global level with a challenging array of 3×222 micromolar reactions. The observed hit rate (56 %) is competitive with other often-used HTE reactions and the results are scalable. A key to this level of success was the finding that bipyridine 6-carboxamidine (BpyCam), a ligand that had not previously been shown to be optimal in any reaction, is as general as the best-known ligands with complementary reactivity. Such “cryptic” catalysts may be common and modern HTE methods should facilitate the process of finding these catalysts.

Full text of DOI:10.1002/chem.202102347

Communication
doi.org/10.1002/chem.202102347
Chemistry—A European Journal
ChemBead Enabled High-Throughput Cross-Electrophile
Coupling Reveals a New Complementary Ligand
Ana L. Aguirre,[a] Nathan L. Loud,[b] Keywan A. Johnson,[b] Daniel J. Weix,*[b] and Ying Wang*[a]
Dedicated to the memory of Donald C. Batesky, who first proposed the use of the BpyCam class of ligands.
Abstract: High-throughput experimentation (HTE) methods
are central to modern medicinal chemistry. While many HTE
approaches to CÀ N and Csp2À Csp2 bonds are available,
options for Csp2À Csp3 bonds are limited. We report here
how the adaptation of nickel-catalyzed cross-electrophile
coupling of aryl bromides with alkyl halides to HTE is
enabled by AbbVie ChemBeads technology. By using this
approach, we were able to quickly map out the reactivity
space at a global level with a challenging array of 3×222
micromolar reactions. The observed hit rate (56%) is
competitive with other often-used HTE reactions and the
results are scalable. A key to this level of success was the
finding that bipyridine 6-carboxamidine (BpyCam), a ligand
that had not previously been shown to be optimal in any
reaction, is as general as the best-known ligands with
complementary reactivity. Such “cryptic” catalysts may be
common and modern HTE methods should facilitate the
process of finding these catalysts.
Figure 1. ChemBeads-enabled high-throughput cross-electrophile coupling.
High-throughput experimentation (HTE) methods have become
a key component of drug development,[1] facilitating the rapid
exploration of structure-activity relationships (SAR) in medicinal
chemistry and the rapid optimization of reactions in process
development.[2] In industrial and academic labs, HTE methods
are increasingly used in reaction optimization,[3] reaction
discovery,[4] and the discovery of new ligands.[5] Translation of
methods from academic labs to medicinal chemistry can be
accelerated by HTE assessments using arrays of representative
substrates tested against arrays of the best available catalysts
and conditions.[6] To date, most of the methods adapted to HTE
at AbbVie for medicinal chemistry have been CÀ N, CÀ O, and
Csp2À Csp2 bond-forming reactions (Figure 1).[7] HTE methods to
explore SAR while increasing Csp3 character in molecules would
be valuable because increased saturation generally improves
parameters important to drug discovery.[8]
Nickel-catalyzed cross-electrophile coupling of alkyl electro-
philes with aryl electrophiles[9] has become an increasingly used
approach to the formation of Csp2À Csp3 bonds in the past
decade[10,11] because it is compatible with many functional
groups and the pool of available substrates is large (Figure 1).[12]
The stability and availability of organic electrophiles is especially
attractive for HTE in medicinal chemistry, where many analogs
must be generated quickly. A recently published survey of
available methods for Csp3À Csp2 cross-coupling in medicinal
chemistry demonstrated the potential of cross-electrophile
coupling in library synthesis and its complementarity to other
approaches.[13] In that study, however, the scope of the survey
was limited by the format – standard parallel library synthesis in
4 mL vials at 0.1 mmol scale. HTE library generation is generally
conducted on orders of magnitude smaller scale (micromole to
nanomole) because only small amounts of material are needed
for initial screening and, in early stages of a project, available
starting materials may be limited.
[a] A. L. Aguirre, Dr. Y. Wang
Advanced Chemistry Technologies Group, AbbVie
1 N Waukegan Road, North Chicago, IL 60064 (USA)
E-mail: wang.ying@abbvie.com
[b] N. L. Loud, Dr. K. A. Johnson, Prof. D. J. Weix
Department of Chemistry, University of Wisconsin-Madison
1101 University Ave, Madison, WI 53706 (USA)
E-mail: dweix@wisc.edu
The primary challenge to implementing cross-electrophile
coupling chemistry in an HTE format suitable for medicinal
chemistry applications at AbbVie was the heterogeneous nature
of these reactions – dispensing the solid metal reductants (Zn
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/chem.202102347
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Communication
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Chemistry—A European Journal
or Mn powders) in parallel at micromolar scale[14] and efficiently
stirring the reactions in multi-well plates.[15,16] The challenges of
heterogeneity have motivated the development of homoge-
neous conditions that employ organic terminal reductants,[17]
plates.[13] We report here the successful application of the
AbbVie ChemBeads HTE platform[20] to cross-electrophile cou-
pling, providing a general solution to Csp2À Csp3 bond forma-
tion and facilitating the discovery of a new, general ligand
(Scheme 1).
To overcome the challenges associated with weighing solids
and stirring heterogeneous reactions, we turned to our AbbVie
ChemBeads technology. While we had not previously coated
beads with malleable metals,[21] we found that Zn coats on glass
sometimes
using
photoredox
co-catalysis[13,18]
or
electrochemistry[19] to help drive the reaction. While avoiding
some of the challenges of dispensing and stirring, these
approaches often have different scope than metal-reductant
conditions and some could be a challenge to adapt to parallel
Scheme 1. Results of HTE library survey of 222 different products utilizing ChemBeads and three different cross-electrophile coupling catalysts (L1, L10, L13).
Green denotes molecular ion for product observed by LC-MS at 10 μmol scale and verified by isolation at 100 μmol scale; Yellow denotes molecular ion
observed at 10 μmol scale, but isolation at 100 μmol scale did not provide >95% pure product; Red denotes no ion observed. Yields reported are isolated
yields after isolation by mass-directed HPLC. Ligands only noted if a large difference was noted or if the product was isolated. No noted ligand means that all
three ligands worked well. See Supporting Information for experimental details.
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beads well (4.8 mass%, “Zn@ChemBeads”), as long as activated
Zn powder is used. While an acoustic mixer is generally required
for reliable coating, Zn coated well even using a simple
vortexer. In addition, we found that shaking plates on a
modified orbital shaker (Torrey Pines SC20) with glass beads is a
general replacement for the use of specialized stirrers and micro
stir bars (Scheme 2A). Pre-coated ChemBeads are still advanta-
geous because they simplify working on μmol scale and with
solid-handling robots or calibrated scoops.
In order to examine the suitability of nickel-catalyzed
coupling of aryl halides with alkyl halides for medicinal
chemistry applications, an array of 222 different products was
chosen to represent the diversity of aryl and alkyl coupling
partners of interest to medicinal chemistry: 6 aryl halides × 37
alkyl halides (Scheme 1). While a wide array of heteroaryl
halides have been explored recently in cross-electrophile
coupling,[22] alkyl halides have been more limited: even in our
recent study,[13] 40% of the 20 alkyl bromides tested were
simple hydrocarbons. In this study, we emphasized alkyl
bromides of interest to medicinal chemistry that we expected
to be particularly challenging, including: neopentyl
substrates,[23] tertiary alkyl substrates,[24] substrates with β-
leaving groups,[25] substrates prone to methylcyclobutane
radical rearrangement,[26] reactive heteroarylmethyl chlorides,[27]
basic tertiary amines,[28] and precursors to valuable four-
membered rings.[29] For the HTE experiments run at AbbVie,
catalysts and additives were coated onto beads, substrates
were dispensed as solutions, and plates were set up using a
robotic solid handling system (Chemspeed Technologies). Even
without a robot, Zn@ChemBeads simplify small-scale reaction
setup in parallel because a calibrated scoop can be used in
place of individual weighing or inaccurate zinc slurries. Initially,
we chose our published optimal conditions for the coupling of
aryl bromides with alkyl bromides (L=4,4'-di-tert-butyl-2,2'-
bipyridine, dtbbpy, L10)[9] and heteroaryl bromides with alkyl
bromides (L=2,6-bis(N-cyanocarboxamidine)pyridine, PyB-
CamCN, L1).[22b] Preliminary examination of optimal ligands from
published reports (phenanthrolines, bipyridines, pyridine car-
boxamidines, terpyridines) and exchanging Mn for Zn did not
provide substantial improvements in the observed hit rate
Scheme 2. Analysis of HTE library results. A. comparison of Zn powder vs. Zn@ChemBeads. Yields are GC corrected against a 1,3,5-trimethoxybenzene internal
standard. B. Library coverage by ligand class. C. Library coverage by aryl bromide core. D. New chemical space accessible with L13. Yields are isolated from
scaled up reactions after observing a hit on HTE screens.[a] Isolated yield on 0.1 mmol scale using ChemBeads.[b] Isolated on 0.5 mmol scale using Zn powder
and stir bars.
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beyond 46%. A major breakthrough was achieved when we
examined non-optimal ligands derived from our Pfizer
collaboration.[5a] We found that the ligand bipyridine-6-carbox-
amidine (BpyCam, L13) proved to be general and, in some
cases, complementary to dtbbpy and PyBCamCN (Scheme 2B
and D).
The success of L13 was surprising because, while pyridine
carboxamidines and pyridine bis(carboxamidine) ligands have
proven to be useful in several cross-coupling reactions,[5a,10d,22b]
the value of (BpyCam)NiCl2 was only evident when tested against
a diverse, challenging library. In analogy to similar situations in
biology, we term this a “cryptic” catalyst.[30]
The overall hit rate for the 222-member μmol-scale library
with the addition of L13 rose from 46% to 56% (124/222
product ions detected) (Schemes 1 and 2B). This hit rate is
higher than what we had found previously using micro stir bars
and a less diverse substrate set,[13] suggesting that some of the
improvement is due to better mixing/activation with Chem-
Beads. This number is also impressive when considered in
context: even methods considered reliable can give moderate
hit rates in diverse medicinal chemistry libraries. For example,
Merck noted only 45% of metal-catalyzed CÀ N bond forming
reactions on complex, polar substrates succeeded.[1b] Similarly,
internal AbbVie data for Pd-catalyzed amine arylation[31] gave a
55% hit rate.
Examination of the array reveals the differences and
similarities between the three catalysts. For example, reactions
conducted with each ligand had a similar level of success:
79/222 (36%) for PyBCamCN (L1), 61/222 (27%) for dtbbpy (L10),
62/222 (28%) for BpyCam (L13) (Scheme 2B). There was also
considerable heterogeneity in what substrate combinations
were successful with each ligand. For example, reactions of
Core 2 did not work at all with L1, but L13 had a reasonable hit
rate. On the other hand, L13 was a poor choice for Core 6, but
reactions with L1 worked well. Finally, we note that the hit rate
of this approach could be further improved by the use of
obtain a global overview of currently accessible scope, we did
not focus on reaction optimization. In our study, the reactions
were carried out in parallel, with fixed concentration, temper-
ature and reaction time, and purification was optimized for
purity and speed over yield. Further optimization would
presumably improve on these yields, as would the inclusion of
additional conditions for specialized substrates.
These results demonstrate the power of using μmol scale
high throughput experimentation to quickly identify workable
conditions and map out the reactivity space of the substrates of
interest. The sensitivity of the analysis tool (UPLC-MS) ensured
even a trace amount of product peak signal could be detected,
thus greatly eliminating the possibility for false negative
findings on the micromole scale. This workflow, which is
accessible with a minimal investment, allows researchers to get a
global understanding of gaps in scope while using minimal
amounts of material (for 666 reactions, 1.11 mmol of each core,
0.36 mmol of each alkyl halide, and 0.16 mmol of each ligand)
and time (the screens were conducted over about two weeks).
We anticipate that the use of Zn@ChemBeads for cross-
electrophile coupling will be broadly useful in HTE. Indeed,
based on this study and the promising results we obtained, this
methodology has become one of the few methods we use in
screening aryl-alkyl coupling conditions for complex med-chem
substrates. In addition, this study suggests that HTE libraries
could be used to find catalysts that are general, but whose
value is not evident with relatively simple substrate pairs. A
corollary to this suggestion is that collections of ligands should
be focused on diversity as much as performance in one or two
test reactions. Ligands that might appear to be poor choices,
and are thus not routinely screened, might in fact be just as
useful as optimal ligands. These “cryptic catalysts” only show
their value when challenged with the correct prompts, a task
that is now possible with modern HTE.
additional modified conditions to accommodate the alkyl Acknowledgements
bromides in this study that provided no product (e.g., for
adamantyl
bromide,[24,32]
2,2,2-trifluoroethyl
bromide,[33]
This work was supported by the NIH (R01GM097243) and
AbbVie. We thank Dr. Phil Cox (AbbVie) for assistance with data
analysis, Dr. Gashaw Goshu (AbbVie) for assistance with
monitoring and assembling plates, and Dr. Noah Tu (AbbVie)
for assistance with ChemBeads and instrument programming.
MOMÀ Br,[34] and 1-(2-bromoethyl)-2-methylpyrrolidine[35]). These
alkyl coupling partners accounted for 24% of the reactions that
failed to show any product in HTE screening. The use of even
ten different sets of conditions is routine and not a barrier in
HTE approaches.
Cross-couplings conducted at 10 μmol scale translated to
larger scale (10× and 50× scale) as well as a normal vial/stir bar Conflict of Interest
format. A subset of these reactions were performed at 100 μmol
scale followed by mass-directed purification resulted in the
isolation of 72/124 products with >95% purity and an addi-
tional 14 products with <95% purity. The other 37 products
were not isolated because the reactions had low conversion
and/or isolation was hindered by overlapping peaks. We further
scaled three reactions to 500 μM scale using standard lab
techniques (4 mL vials with stirbars, isolations by standard flash
chromatography (19, 130, 139)). Of the 87 isolated products, 27
products were fully characterized (see Supporting Information
for additional details). As the main purpose of this study was to
The authors declare no conflict of interest.
Keywords: nickel cross-electrophile coupling
·
·
high-
throughput experimentation · medicinal chemistry · carbon-
carbon bond formation
[1] a) T. W. J. Cooper, I. B. Campbell, S. J. F. Macdonald, Angew. Chem. Int.
Ed. 2010, 49, 8082–8091; Angew. Chem. 2010, 122, 8258–8267; b) D.
Perera, J. W. Tucker, S. Brahmbhatt, C. J. Helal, A. Chong, W. Farrell, P.
Richardson, N. W. Sach, Science 2018, 359, 429; c) A. Buitrago Santanilla,
Chem. Eur. J. 2021, 27, 1–7
www.chemeurj.org
4
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

Communication
doi.org/10.1002/chem.202102347
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E. L. Regalado, T. Pereira, M. Shevlin, K. Bateman, L.-C. Campeau, J.
Schneeweis, S. Berritt, Z.-C. Shi, P. Nantermet, Y. Liu, R. Helmy, C. J.
Welch, P. Vachal, I. W. Davies, T. Cernak, S. D. Dreher, Science 2015, 347,
49–53.
[15] Stir rate and method have been shown to be important in the cross-
electrophile coupling of aryl halides with alkyl halides. See: D. A.
Everson, D. T. George, D. J. Weix, J. F. Buergler, J. L. Wood, Org. Synth.
2013, 90, 200–214.
[16] There are reports of success from Merck[10c,d] with syringing slurries of
zinc powder on 2.5–50 μmol scale, but we found that careful
optimization of the apparatus is required, reproducibility can be a
challenge, and reproducibility across a large plate can be challenging.
[17] a) L. L. Anka-Lufford, K. M. M. Huihui, N. J. Gower, L. K. G. Ackerman, D. J.
Weix, Chem. Eur. J. 2016, 22, 11564–11567; b) N. Suzuki, J. L. Hofstra,
K. E. Poremba, S. E. Reisman, Org. Lett. 2017, 19, 2150–2153; c) A. García-
Domínguez, Z. Li, C. Nevado, J. Am. Chem. Soc. 2017, 139, 6835–6838;
d) D. T. Flood, S. Asai, X. Zhang, J. Wang, L. Yoon, Z. C. Adams, B. C.
Dillingham, B. B. Sanchez, J. C. Vantourout, M. E. Flanagan, D. W.
Piotrowski, P. Richardson, S. A. Green, R. A. Shenvi, J. S. Chen, P. S. Baran,
P. E. Dawson, J. Am. Chem. Soc. 2019, 141, 9998–10006; e) D. J.
Charboneau, E. L. Barth, N. Hazari, M. R. Uehling, S. L. Zultanski, ACS
Catal. 2020, 10, 12642–12656.
[2] a) S. W. Krska, D. A. DiRocco, S. D. Dreher, M. Shevlin, Acc. Chem. Res.
2017, 50, 2976–2985; b) S. M. Mennen, C. Alhambra, C. L. Allen, M.
Barberis, S. Berritt, T. A. Brandt, A. D. Campbell, J. Castañón, A. H.
Cherney, M. Christensen, D. B. Damon, J. Eugenio de Diego, S. García-
Cerrada, P. García-Losada, R. Haro, J. Janey, D. C. Leitch, L. Li, F. Liu, P. C.
Lobben, D. W. C. MacMillan, J. Magano, E. McInturff, S. Monfette, R. J.
Post, D. Schultz, B. J. Sitter, J. M. Stevens, I. I. Strambeanu, J. Twilton, K.
Wang, M. A. Zajac, Org. Process Res. Dev. 2019, 23, 1213–1242.
[3] a) M. Shevlin, ACS Med. Chem. Lett. 2017, 8, 601–607; b) A.-C. Bédard, A.
Adamo, K. C. Aroh, M. G. Russell, A. A. Bedermann, J. Torosian, B. Yue,
K. F. Jensen, T. F. Jamison, Science 2018, 361, 1220.
[4] a) M. W. Kanan, M. M. Rozenman, K. Sakurai, T. M. Snyder, D. R. Liu,
Nature 2004, 431, 545–549; b) A. McNally, C. K. Prier, D. W. C. MacMillan,
Science 2011, 334, 1114–1117; c) D. W. Robbins, J. F. Hartwig, Science
2011, 333, 1423–1427.
[5] a) E. C. Hansen, D. J. Pedro, A. C. Wotal, N. J. Gower, J. D. Nelson, S.
Caron, D. J. Weix, Nat. Chem. 2016, 8, 1126–1130; b) V. S. Chan, S. W.
Krabbe, C. Li, L. Sun, Y. Liu, A. J. Nett, ChemCatChem 2019, 11, 5748–
5753; c) A. Modak, A. J. Nett, E. C. Swift, M. C. Haibach, V. S. Chan, T. S.
Franczyk, S. Shekhar, S. P. Cook, ACS Catal. 2020, 10, 10495–10499; d) S.
Biswas, B. Qu, J.-N. Desrosiers, Y. Choi, N. Haddad, N. K. Yee, J. J. Song,
C. H. Senanayake, J. Org. Chem. 2020, 85, 8214–8220.
[6] a) A. Nadin, C. Hattotuwagama, I. Churcher, Angew. Chem. Int. Ed. 2012,
51, 1114–1122; Angew. Chem. 2012, 124, 1140–1149; b) P. S. Kutchukian,
J. F. Dropinski, K. D. Dykstra, B. Li, D. A. DiRocco, E. C. Streckfuss, L.-C.
Campeau, T. Cernak, P. Vachal, I. W. Davies, S. W. Krska, S. D. Dreher,
Chem. Sci. 2016, 7, 2604–2613.
[7] a) S. D. Roughley, A. M. Jordan, J. Med. Chem. 2011, 54, 3451–3479; b) J.
Boström, D. G. Brown, R. J. Young, G. M. Keserü, Nat. Rev. Drug Discovery
2018, 17, 709–727.
[8] a) M. Ishikawa, Y. Hashimoto, J. Med. Chem. 2011, 54, 1539–1554; b) F.
Lovering, J. Bikker, C. Humblet, J. Med. Chem. 2009, 52, 6752–6756; c) F.
Lovering, MedChemComm 2013, 4, 515–519; d) Y. Yang, O. Engkvist, A.
Llinàs, H. Chen, J. Med. Chem. 2012, 55, 3667–3677; e) P. D. Leeson, S. A.
St-Gallay, M. C. Wenlock, MedChemComm 2011, 2, 91–105; f) N. A.
Meanwell, Chem. Res. Toxicol. 2016, 29, 564–616.
[9] a) M. J. Goldfogel, L. Huang, D. J. Weix, in: Nickel Catalysis in Organic
Synthesis (Ed.: S. Ogoshi), Wiley-VCH, Weinheim, 2020, pp. 183–222;
b) D. A. Everson, R. Shrestha, D. J. Weix, J. Am. Chem. Soc. 2010, 132,
920–921; c) D. A. Everson, B. A. Jones, D. J. Weix, J. Am. Chem. Soc. 2012,
134, 6146–6159.
[10] Medicinal Chemistry analog synthesis. a) L. Fakhouri, C. D. Cook, M. H.
Al-Huniti, L. M. Console-Bram, D. P. Hurst, M. B. S. Spano, D. J. Nasrallah,
M. G. Caron, L. S. Barak, P. H. Reggio, M. E. Abood, M. P. Croatt, Bioorg.
Med. Chem. 2017, 25, 4355–4367; b) A. Dumas, J.-B. Garsi, G. Poissonnet,
S. Hanessian, ACS Omega 2020, 5, 27591–27606; c) K. M. Mennie, B. A.
Vara, S. M. Levi, Org. Lett. 2020, 22, 556–559; d) J. M. E. Hughes, P. S.
Fier, Org. Lett. 2019, 21, 5650–5654.
[11] Total Synthesis: a) R. K. Boeckman, J. M. Niziol, K. F. Biegasiewicz, Org.
Lett. 2018, 20, 5062–5065; b) Y. Fegheh-Hassanpour, T. Arif, H. O. Sintim,
H. H. Al Mamari, D. M. Hodgson, Org. Lett. 2017, 19, 3540–3543; c) M.
Menger, D. Lentz, M. Christmann, J. Org. Chem. 2018, 83, 6793–6797;
d) Z. C. Girvin, M. K. Andrews, X. Liu, S. H. Gellman, Science 2019, 366,
1528; e) H.-G. Cheng, Z. Yang, R. Chen, L. Cao, W.-Y. Tong, Q. Wei, Q.
Wang, C. Wu, S. Qu, Q. Zhou, Angew. Chem. Int. Ed. 2021, 60, 5141–
5146; Angew. Chem. 2021, 133, 5201–5206.
[12] While there are only hundreds of readily available alkylzinc reagents,
thousands of alkyl halides are readily commercially available. Numbers
from eMolecules: 443 alkylzinc reagents vs. 200760 alkyl bromides
(April, 2019). In general, the stringent storage requirement and lack of
diverse functional groups of the alkylzinc reagents also render them
much less desirable than alkyl halides.
[13] A. W. Dombrowski, N. J. Gesmundo, A. L. Aguirre, K. A. Sarris, J. M.
Young, A. R. Bogdan, M. C. Martin, S. Gedeon, Y. Wang, ACS Med. Chem.
Lett. 2020, 11, 597–604.
[18] a) Z. Duan, W. Li, A. Lei, Org. Lett. 2016, 18, 4012–4015; b) P. Zhang, C. C.
Le, D. W. C. MacMillan, J. Am. Chem. Soc. 2016, 138, 8084–8087; c) A.
Paul, M. D. Smith, A. K. Vannucci, J. Org. Chem. 2017, 82, 1996–2003;
d) S. O. Badir, J. Sim, K. Billings, A. Csakai, X. Zhang, W. Dong, G. A.
Molander, Org. Lett. 2020, 22, 1046–1051.
[19] a) R. J. Perkins, D. J. Pedro, E. C. Hansen, Org. Lett. 2017, 19, 3755–3758;
b) H. Li, C. P. Breen, H. Seo, T. F. Jamison, Y.-Q. Fang, M. M. Bio, Org. Lett.
2018, 20, 1338–1341; c) T. Koyanagi, A. Herath, A. Chong, M. Ratnikov,
A. Valiere, J. Chang, V. Molteni, J. Loren, Org. Lett. 2019, 21, 816–820;
d) R. J. Perkins, A. J. Hughes, D. J. Weix, E. C. Hansen, Org. Process Res.
Dev. 2019, 23, 1746–1751; e) B. L. Truesdell, T. B. Hamby, C. S. Sevov, J.
Am. Chem. Soc. 2020, 142, 5884–5893.
[20] N. P. Tu, A. W. Dombrowski, G. M. Goshu, A. Vasudevan, S. W. Djuric, Y.
Wang, Angew. Chem. Int. Ed. 2019, 58, 7987–7991; Angew. Chem. 2019,
131, 8071–8075.
[21] Although most reagents coated well, some metal salts coated glass
beads poorly.[20] In general, an acoustic mixer (Resodyn) is required for
consistent coating.
[22] a) N. T. Kadunce, S. E. Reisman, J. Am. Chem. Soc. 2015, 137, 10480–
10483; b) E. C. Hansen, C. Li, S. Yang, D. Pedro, D. J. Weix, J. Org. Chem.
2017, 82, 7085–7092.
[23] Neopentyl substrates usually require modified conditions for high
yields.[5d]
.
[24] Tertiary alkyl halides have been coupled successfully, but generally
have required different conditions and have been less explored with
heteroaryl halides. a) X. Wang, S. Wang, W. Xue, H. Gong, J. Am. Chem.
Soc. 2015, 137, 11562–11565; b) X. Wang, G. Ma, Y. Peng, C. E. Pitsch,
B. J. Moll, T. D. Ly, X. Wang, H. Gong, J. Am. Chem. Soc. 2018, 140,
14490–14497.
[25] Generally, β-leaving groups have been tolerated, but at somewhat
lower yield. This has not been explored systematically with variation of
the geometry and leaving group ability.[9].
[26] Methylcyclopropyl radical (krearrangement ~6.7×107 sÀ 1
) has repeatedly
been shown to rearrange faster than the coupling reaction, leading to
homoallylation instead of cyclopropylmethylation. The slower 5-hexenyl
radical (krearrangement ~2.3×105 sÀ 1) tends to give mixtures of products.
Methylcyclobutane radicals rearrange more slowly (krearrangement ~5×
103 sÀ 1) and could possibly work reliably in cross-electrophile coupling.
M. Newcomb, in: Radicals in Organic Synthesis, Vol. 1, 1st ed. (Eds.: P.
Renaud, M. P. Sibi), Wiley-VCH, Weinheim, 2001, pp. 317–336.
[27] While coupling of benzylic chlorides and benzylic mesylates has been
reported, only one example of a heteroaryl iodide (5-iodopyrimidine)
and no examples of heteroarylmethyl chloride/mesylate substrates had
been reported before last year. a) L. K. G. Ackerman, L. L. Anka-Lufford,
M. Naodovic, D. J. Weix, Chem. Sci. 2015, 6, 1115–1119; b) L. L. Anka-
Lufford, K. M. M. Huihui, N. J. Gower, L. K. G. Ackerman, D. J. Weix, Chem.
Eur. J. 2016, 22, 11564–11567; c) Z. G. Brill, C. B. Ritts, U. F. Mansoor, N.
Sciammetta, Org. Lett. 2020, 22, 410–416.
[28] Tertiary amines can coordinate to metals and are easily oxidized,
making them challenging in many cross-coupling reactions. See
reference 13.
[29] Radicals in strained rings can be more difficult to form and react
differently than unstrained secondary radicals. Success in cross-electro-
phile and metallaphotoredox coupling has been mixed, with simple
oxetanes and azetidines generally working well.[22] a) K. Kolahdouzan, R.
Khalaf, J. M. Grandner, Y. Chen, J. A. Terrett, M. P. Huestis, ACS Catal.
2020, 10, 405–411.
[14] The low MW of Zn and Mn mean that sub-milligram quantities are often
required and handling of solids in parallel remains a challenge. See:
a) M. Shevlin, ACS Med. Chem. Lett. 2017, 8, 601–607; b) M. N. Bahr, D. B.
Damon, S. D. Yates, A. S. Chin, J. D. Christopher, S. Cromer, N. Perrotto, J.
Quiroz, V. Rosso, Org. Process Res. Dev. 2018, 22, 1500–1508.
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Chemistry—A European Journal
[30] Cryptic binding, gene clusters, and natural products are only found
when challenged with the correct stimulus. In the absence of the
correct environment, they appear to have no useful function. We
propose the term cryptic catalysts for catalysts that appear to have little
value until challenged with the right conditions (types of substrates,
additives). a) D. Beglov, D. R. Hall, A. E. Wakefield, L. Luo, K. N. Allen, D.
Kozakov, A. Whitty, S. Vajda, Proc. Natl. Acad. Sci. USA 2018, 115, E3416;
b) K. Scherlach, C. Hertweck, Org. Biomol. Chem. 2009, 7, 1753–1760.
[31] a) R. Dorel, C. P. Grugel, A. M. Haydl, Angew. Chem. Int. Ed. 2019, 58,
17118–17129; Angew. Chem. 2019, 131, 17276–17287; b) P. A. Forero-
Cortés, A. M. Haydl, Org. Process Res. Dev. 2019, 23, 1478–1483; c) P.
Ruiz-Castillo, S. L. Buchwald, Chem. Rev. 2016, 116, 12564–12649; d) K.
Okano, H. Tokuyama, T. Fukuyama, Chem. Commun. 2014, 50, 13650–
13663; e) S. Bhunia, G. G. Pawar, S. V. Kumar, Y. Jiang, D. Ma, Angew.
Chem. Int. Ed. 2017, 56, 16136–16179; Angew. Chem. 2017, 129, 16352–
16397.
[32] Other approaches to adamantyl coupling with aryl halides. a) P. Zhang,
C. C. Le, D. W. C. MacMillan, J. Am. Chem. Soc. 2016, 138, 8084–8087;
b) Y. Sato, K. Nakamura, Y. Sumida, D. Hashizume, T. Hosoya, H. Ohmiya,
J. Am. Chem. Soc. 2020, 142, 9938–9943.
[33] H. Li, J. Sheng, G.-X. Liao, B.-B. Wu, H.-Q. Ni, Y. Li, X.-S. Wang, Adv. Synth.
Catal. 2020, 362, 5363–5367.
[34] Best current approach is using MOM-BF3 K. G. A. Molander, B. Canturk,
Org. Lett. 2008, 10, 2135–2138.
[35] A search of the Beilstein database via REAXYS turned up only a few
examples of nucleophilic substitution and no transition-metal catalyzed
coupling reactions of 1-(2-bromoethyl)-2-methypyrrolidine .
Manuscript received: June 30, 2021
Accepted manuscript online: July 7, 2021
Version of record online: ■■■, ■■■■
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COMMUNICATION
A. L. Aguirre, N. L. Loud, Dr. K. A.
Johnson, Prof. D. J. Weix*, Dr. Y. Wang*
1 – 7
ChemBead Enabled High-Through-
put Cross-Electrophile Coupling
Reveals a New Complementary
Ligand
Shaken, not stirred: Coating reduc-
tants onto glass beads simplifies
μmol-scale cross-electrophile
coupling, enabling the rapid survey of
222 different reactions and the
discovery of a new, useful catalyst.
Although the reactions are heteroge-
neous, the glass beads enable the use
of shakers instead of complex micro
stirrers.