Dual Catalytic Platform for Enabling sp3 α C-H Arylation and Alkylation of Benzamides

Article abstract of DOI:10.1021/acscatal.0c01318

A dual catalytic sp³ α C-H arylation and alkylation of benzamides with organic halides is described. This protocol exhibits an exquisite site selectivity, chemoselectivity, and enantioselectivity pattern, offering a complementary reactivity mode to existing sp³ arylation or alkylations via transition metal catalysis or photoredox events.

Full text of DOI:10.1021/acscatal.0c01318

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Letter
A Dual Catalytic Platform for Enabling sp3
a C–H Arylation & Alkylation of Benzamides
Alexander W. Rand, Hongfei Yin, Liang Xu, Jessica Giacoboni, Raul
Martin-Montero, Ciro Romano, John Montgomery, and Ruben Martin
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.0c01318 • Publication Date (Web): 27 Mar 2020
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A Dual Catalytic Platform for Enabling sp3  C–H Arylation &
Alkylation of Benzamides
Alexander W. Rand, Hongfei Yin,† Liang Xu,† Jessica Giacoboni,† Raul Martin-Montero,† Ciro
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Romano,† John Montgomery* and Ruben Martin†§*
†Institute of Chemical Research of Catalonia (ICIQ), The Barcelona Institute of Science and Technology, Av. Països
Catalans 16, 43007 Tarragona, Spain
§ ICREA, Passeig Lluís Companys, 23, 08010 Barcelona, Spain
 Department of Chemistry, University of Michigan, Ann Arbor, MI 48109-1055, USA
Supporting Information Placeholder
diversity.4 In this vein, photoredox catalysis has recently
offered new tactics for the  sp3 C–H functionalization of
ABSTRACT: A dual catalytic sp3  C–H arylation &
alkylation of benzamides with organic halides is
described. This protocol exhibits an exquisite site-,
aliphatic tertiary amines via single-electron transfer (SET)
or hydrogen-atom transfer (HAT) pathways due to their
favorable redox profile.4,5Although the higher reduction
potential of tertiary amide congeners makes the
functionalization of this substrate class more difficult,
elegant solutions have been described with more
oxidizing catalysts or conditions.6 In contrast, the sp3 C–
H functionalization of aliphatic secondary amides have
received much less attention. Independent work
developed by Rovis7 and Knowles8 established a new
rationale for enabling  sp3 C–H alkylation with activated
Michael acceptors through [1,5]-HAT processes via
amidyl radical species (Scheme 1, path a).9 Although a
site-selectivity switch has recently been obtained with
specific amide patterns (path b),10 this technology
remains confined to activated electron-deficient olefins
and stoichiometric HAT-mediators.6,11 In view of the
foregoing, the design of a catalytic protocol aimed at
expanding the boundaries of sp3 -functionalization of
aliphatic secondary amides with broadly applicable
counterparts might provide an opportunity to explore
inaccessible chemical space while offering new strategic
bond-forming reactions. Herein, we describe the
successful realization of this goal via dual catalysis
(Scheme 1, bottom).12,13 Our protocol is distinguished by
its mild reaction conditions, broad substrate scope and
exquisite site-, chemo- and enantioselective pattern.
chemo- and enantioselectivity pattern, offering
a
complementary reactivity mode to existing sp3 arylation
or alkylation events via transition metal catalysis or
photoredox events.
Keywords: sp3 C–H activation, Photocatalysis, Nickel,
enantioselectivity, metallaphotoredox.
Catalytic C–H functionalization reactions have
streamlined the synthesis of valuable molecules by
avoiding functional group manipulations while offering a
reliable solution to forge C–C bonds from simple
precursors.1 However, the ability to rationally and
predictably switch the site-selectivity pattern in these
endeavors still remains a problematic, yet highly
rewarding, scenario.2
Scheme 1. Site-Selective sp3 Functionalization of Amides.
Scheme 2. sp3  C–H Arylation of Aliphatic Benzamides.
The prevalence of aliphatic amines in a myriad of
molecules displaying biological activities3 has prompted
chemists to develop mild, non-invasive site-selective sp3
C–H functionalizations as a platform for structural
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We started our investigations by studying the sp3 -
arylation of 1a and 1k with 4-trifluoromethyl
bromobenzene (Scheme 2). After systematic evaluation
of all reaction parameters,14 we found that a protocol
based on PC1/L1 or PC2/L2 provided the best results
under Blue-LED irradiation, affording 2a and 2k in 70%
and 53% yield. As expected, the nature of the ligand,
nickel precatalyst and photocatalyst had a non-negligible
impact on reactivity. Equally important was the nature of
the base and solvent; indeed, inferior results were found
for K2HPO4 and Cs2CO3 or solvents other than dioxane
and EtOAc, thus showing the subtleties of our
protocol.15,16
Table 1. sp3 -Arylation of Benzamides.a
a Isolated yields, average of two independent runs. b 1 (0.40
mmol), (Het)ArBr (0.20 mmol), NiBr2·diglyme (10 mol%),
L1 (15 mol%), PC1 (1 mol%), K3PO4 (0.30 mmol), dioxane
(1.0 mL) at rt for 20 h. c 1 (3 equiv) were used. d 1 (0.20
mmol), (Het)ArBr (1.50 mmol), NiCl2·glyme (5 mol%), L2
(5 mol%), PC2 (2 mol%), K3PO4 (0.4 mmol), EtOAc (1.0
mL) at rt for 20 h.
Next, we turned our attention to investigating the
generality of our dual catalytic sp3 -arylation. As shown
in Table 1, compounds bearing esters (2d, 2j), nitriles (2s),
sulfonamides (2i), ketones (2f, 2g, 2t) or amides (2j)
could all be well-accommodated. Similar results were
found independently whether substituents were located at
the ortho, meta or para position. Importantly, however,
electron-deficient arenes generally provided better yields
of the targeted sp3 -arylated products. The method
shows a strong preference for aryl bromides, as the
corresponding aryl chlorides (2r), aryl fluorides (2c, 2p,
2s) or boronic esters (2n) remained inert, thus providing
ample room for further derivatization via conventional
cross-coupling reactions. Albeit in slightly lower yields,
the method was shown to be compatible with heteroaryl
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bromides (2u-2w). The exclusive formation of 2j bearing
Therefore, at the outset of our investigations it was
unclear whether it would be possible to promote a sp3–sp3
bond-formation adjacent to the amide function with
unactivated alkyl halides. Gratifyingly, we found that the
sp3 -alkylation was within reach by using a Ni/L3
regime under otherwise identical reaction conditions to
those shown in the sp3 -arylation event (Table 2). As
shown in Table 3, a host of unactivated alkyl halides
possessing -hydrogens promoted the targeted
transformation with similar ease. In addition, the presence
of nitriles (3d), free alcohols (3f), alkyl chlorides (3g),
amides (3h), ketones or esters (3i) did not hinder the
reaction.
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two seemingly similar benzamides is particularly
noteworthy; no traces of sp3 C–H functionalization
adjacent to the ester motif were found in the crude
mixtures. Although tentative, this result is consistent with
C–C bond-formation occurring at the more hydridic sp3
C–H bond that is more susceptible to HAT by
electrophilic radical species.4,5 Notably, similar results
were found for benzamides possessing different
electronic environments (2ac, 2ad) or with heteroaryl-
substituted motifs (2ae) regardless of the length of the
alkyl side-chain (2x, 2y), even in the presence of free
alcohols (2z), acetates (2aa) or alkyl chlorides (2ab).
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Table 2. sp3 -Alkylation of Benzamides.a,b
Table 3. Enantioselective sp3 -Arylation of Benzamides.a,b
a 1 (0.20 mmol), ArBr (1.50 mmol), NiCl2·glyme (5 mol%),
iPrBiOx (5 mol%), PC1 (2 mol%), K3PO4 (0.40 mmol),
EtOAc (1.0 mL) at –15 ºC. b Isolated yields.
A close inspection into the literature data reveals that an
asymmetric sp3 C–H arylation initiated via photoinduced
HAT processes remains an elusive endeavour within the
metallaphotoredox arena.13,18 To address this gap, we
focused on developing an enantioselective sp3  C–H
functionalization of aliphatic secondary amides with aryl
halides. Gratifyingly, we found that a protocol based on
iPrBiOx (L3) was particularly suited for our purposes
(Table 3). Although preliminary, the corresponding -
arylated products could be obtained in high levels of
enantioselectivity with comparable yields to those shown
in Table 2 regardless of the substitution pattern at both the
aryl halide and the aliphatic amide backbone (4a-4c), thus
constituting a complementary, yet powerful, platform to
elegant protocols recently described by Doyle and Yu.18,19
a 1 (0.60 mmol), (Het)ArBr (0.20 mmol), NiBr2·diglyme (10
mol%), L3 (bipyridine; 15 mol%), PC1 (1 mol%), K3PO4
(0.30 mmol), dioxane (1.0 mL) at rt. Isolated yields,
b
average of at least two independent runs.
Encouraged by these results, we wondered whether our
method would be robust enough to forge related sp3–sp3
linkages by using unactivated alkyl halides as
counterparts. The successful implementation of such a
protocol, however, might not be particularly
straightforward. Indeed, the available sp3 -alkylation
portfolio of aliphatic secondary amides largely remains
confined to the use of particularly activated -
unsaturated carbonyls as coupling partners,9a although
some developments from MacMillan have described
alkylations on substrate classes other than secondary
aliphatic amides.9b In addition, -hydride elimination and
the low propensity for sp3–sp3 C–C reductive elimination
represent important drawbacks to be overcome.17
Prompted by the PCET work of Rovis6,8 and Knowles7 on
the  sp3 C–H alkylation of aliphatic secondary amides
with electron-deficient olefins,20 we anticipated that our
protocol might serve as an orthogonal gateway to forge
sp3 C–C bonds in aliphatic amides at either - or -
positions. As shown in Scheme 3, this turned out to be the
case and regiodivergent C–C bond-formation could be
accessed by using 5 as substrate. As expected, -
alkylation with an activated -unsaturated compound
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to PC-3 and
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was obtained by subjecting
5
illustrative, arguing against a scenario based on 1,5-HAT
followed by recombination with Ni-I and a chain-walking
manifold prior to C–C bond-formation at the -position
(bottom).23 Whether the key transient radical species
adjacent to the amide function are obtained via
intermolecular HAT processes or invoke other
mechanistic considerations is the subject of ongoing
studies.24
NBu4OP(O)(OBu)2 under Blue-LED irradiation,7
whereas exclusive sp3 -arylation (7a, 7b) was obtained
under the Ni(L1)/PC1 or Ni(L2)/PC2 couple. Notably, 8
could be prepared from 6b and 7b following the same
rationale, demonstrating the orthogonality of our sp3 C–
H functionalization approach for forging C–C bonds at
either  or -positions. At present, we don´t have an
explanation for the low yields obtained. Taken together,
the results in Tables 1-3 and Scheme 3 illustrate the
prospective impact of our dual catalytic platform for
forging sp3 C–C linkages adjacent to benzamide motifs in
a site-selective manner.
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Scheme 4. Preliminary Mechanistic Experiments.
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Scheme 3. Orthogonality with 1,5-HAT processes.
Next, we decided to gather indirect evidence about the
mechanism by deuterium-labelling (Scheme 4, top). As
shown, a primary kinetic isotope effect (KIE) was
observed by exposing a 1:1 mixture of 1a and 1a-D2
under a PC1/L1 regime, suggesting that sp3 C–H bond-
cleavage might be involved in the rate-determining step
of the reaction. Similar results were found using a 1:1
ratio of 1k:1k-D2 with PC2/L2. Aimed at shedding light
on the subsequent C–C bond-forming event, we turned
our attention to study the reactivity of the putative
oxidative addition species Ni-I, readily obtained by
reacting 4-trifluoromethyl bromobenzene to Ni(COD)2
and L1 in THF (middle).14 As expected, Ni-I was found
to be catalytically competent, affording 2a in 32% yield.21
Although speculative, the lower yields of 2a employing
Ni-I when compared to an in situ protocol based on
NiBr2·diglyme/L1 can tentatively be ascribed to its
inherent instability in the absence of aryl bromide and its
strong absorption in the visible light region.22 In addition,
the preparation of 2x, 2y, 2aa and 2ab is particularly
In summary, we have documented a dual catalytic
strategy that enables an sp3 -arylation and sp3 -
alkylation of benzamides, offering a complementary
activation mode to existing metal-catalyzed or
photoinduced processes. The protocol is characterized by
its mild conditions, wide scope and exquisite site-,
chemo- and enantioselectivity. Further studies to unravel
the mechanistic intricacies of the reaction and the
extension to other C–C bond-forming scenarios are
currently ongoing.
AUTHOR INFORMATION
Corresponding Author
* rmartinromo@iciq.es; jmontg@umich.edu
Author contributions
¥ These authors contributed equally.
Funding Sources
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(5) For an excellent review on the topic: He, C.; Whitehurst, W.
No competing financial interests have been declared.
1
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G.; Gaunt, M. J. Palladium-catalyzed C(sp3)–H bond
functionalization of aliphatic amines. Chem 2019, 5, 1031-
1058.
ASSOCIATED CONTENT
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Supporting Information. Experimental procedures,
crystallographic data and spectral data. This material is
available free of charge via the Internet at
http://pubs.acs.org.
(6) For related C–C bond-forming strategies using tertiary rather
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(g) Rohe, S.; Morris, A. O.; McCallum, T.; Barriault, L.
Hydrogen atom transfer reactions via photoredox catalyzed
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ACKNOWLEDGMENT
R. Martin thank ICIQ and FEDER/MCI –AEI/PGC2018-
096839-B-I00 for financial support. L.X thank China
Scholarship Council (CSC) for a postdoctoral fellowship and
H. Y. thanks European Union’ s Horizon 2020 under the
Marie Sklodowska-Curie grant agreement (844854). J.
Montgomery thank National Science Foundation under the
CCI Center for Selective C–H Functionalization (CHE-
1205646). We also thank Cole Cruz for helpful discussions
and assistance with mechanistic investigations, the
Stephenson group for helpful discussions and Cameron
Nobile for his help in designing a chilled photoreactor block.
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in
ChemRxiv
&
(https://doi.org/10.26434/chemrxiv.10003277.v1
https://doi.org/10.26434/chemrxiv.9978824.v1), and are now
merged into a joint publication
(13) For reviews on dual catalysis in photochemical events: (a)
Twilton, J.; Le, C.; Zhang, P.; Shaw, M. H.; Evans, R. W.;
MacMillan, D. W. C. The merger of transition metal and
photocatalysis. Nat. Rev. Chem. 2017, 1, 0052. (b) Kärkäs,
M. D.; Porco, J. A.; Stephenson, C. R. J. Photochemical
approaches to complex chemotypes: applications in natural
product synthesis. Chem. Rev. 2016, 116, 9683-9747. (c)
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, 113,
5322-5363. (d) Levin, M. D.; Kim, S.; Toste, F. D.
Photoredox catalysis unlocks single-electron elementary
steps in transition metal catalyzed cross-coupling. ACS Cent.
Sci. 2016, 2, 293-301. (e) Skubi, K. L.; Blum, T. R.; Yoon,
T. P. Dual catalysis strategies in photochemical synthesis.
Chem. Rev. 2016, 116, 10035-10074.
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(24) Based on our available data, several possibilities might come
into play for the generation of the key -carbon radical
intermediates. If we take PC1 into consideration, we could
consider the following: (a) triplet-triplet energy transfer
occurring from PC1* to Ni-I (see ref. 21) followed by
arylNi(II)–Br homolysis, generating bromine radicals that
enable an intermolecular HAT at the  sp3 C–H bond (a close
look at the triplet energies of PC-1 (61.8 kcal/mol) vs fac-
Ir(ppy)3PF6 (58.1 kcal/mol) or Ir(ppy)2(dtbpy)PF6 (49.2
kcal/mol) is particularly illustrative (see Supporting
information for details). For a leading reference, see: Shields,
B.; Doyle, A. G. Direct C(sp3)–H cross coupling enabled by
catalytic generation of chlorine radicals. J. Am. Chem. Soc.
2016, 138, 12719-12722; (b) PCET followed by [1,2]-HAT
assisted by the K3PO4 (see Morton, C. M.; Zhu, Q.;
Ripberger, H.; Troian-Gautier, Z. S.; Toa, D.; Knowles, R.
R.; Alexanian, E. J. C–H Alkylation via Multisite-Proton-
Coupled Electron Transfer of an Aliphatic C–H Bond. J. Am.
Chem. Soc. 2019, 141, 13253-13260 and Wakaki, T.; Sakai,
K.; Enomoto, T.; Kondo, M.; Masaoka, S.; Oisaki, K.; Kanai,
M. C(sp3)−H Cyanation Promoted by Visible ‐ Light
Photoredox/Phosphate Hybrid Catalysis. Chem. –Eur. J.
2018, 24, 8051-8055 or (c) SET oxidation of PC1* to K3PO4
followed by intermolecular HAT (see Margrey, K. A.;
Czaplyski, W. L.; Nicewicz, D. A.; Alexanian, E. J. A
General Strategy for Aliphatic C–H Functionalization
Enabled by Organic Photoredox Catalysis. J. Am. Chem. Soc.
2018, 140, 4213-4217).
(14) For more details, see Supporting information.
(15) Significant amounts of sp3 C–H arylation of THF (27%),
DME (26%) and DMA (75%) were observed in the crude
mixtures, suggesting competitive intermolecular HAT to the
solvent. This is consistent with the lower bond-dissociation
energies of the corresponding methylene sp3 C–H bonds
adjacent to the oxygen atom in THF and DME or nitrogen
atom in DMA when compared to sp3 C–H bonds in dioxane:
Blanksby, S. J.; Ellison, G. B. Acc. Chem. Res. 2003, 36, 255-
263.
(16) The mass balance accounts for recovered starting material,
homocoupling/reduction of the aryl bromide and trace
amounts of sp3 C–H arylation of the solvent employed.
(17) For selected reviews on cross-coupling reactions of sp3
hybridized electrophiles, see: (a) Molander, G.; Milligan, J.
A.; Phelan, J. P.; Badir, S. O. Recent advances in alkyl
carbon-carbon bond formation by Nickel/Photoredox
crosscoupling. Angew. Chem. Int. Ed. 2019, 58, 6152-6163.
(b) Choi, F.; Fu, G. C. Transition metal-catalyzed alkyl-alkyl
bond formation: Another dimension in cross-coupling
chemistry. Science 2017, 356, 152. (c) Kambe, N.; Iwasaki,
T.; Terao, J. Pd-catalyzed cross-coupling reactions of alkyl
halides. Chem. Soc. Rev. 2011, 40, 4937-4947. (d) Jana, R.;
Pathak, T. P.; Sigman, M. S. Advances in transition metal
(Pd, Ni, Fe)-catalyzed cross-coupling reaction using alkyl-
organometallics as reaction patterns. Chem. Rev. 2011, 111,
1417-1492. (e) Hu, X. Nickel-catalyzed cross-coupling of
non-activated alkyl halides: a mechanistic perspective.
Chem. Sci. 2011, 2, 1867-1886.
(18) Ahneman, D. T.; Doyle, A. G. C–H functionalization of
amines with aryl halides by nickel-photoredox catalysis.
Chem. Sci. 2016, 7, 7002-7006.
(19) (a) Spangler, J. E.; Kobayashi, Y.; Verma, P.; Wang, D.-H.;
Yu, J.-Q.; -Arylation of saturated azacycles and N-
methylamines via palladium(II)-catalyzed C(sp3)–H
coupling. J. Am. Chem. Soc. 2015, 137, 11876-11879. (b)
Jain, P.; Verma, P.; Xia, G.; Yu, J.-Q. Enantioselective amine
-functionalization via palladium-catalyzed C–H arylation
of thioamides. Nat. Chem. 2017, 9, 140-144.
(20) Gentry, E. C.; Knowles, R. R. Synthetic applications of
proton-coupled electron transfer. Acc. Chem. Res. 2016, 49,
1546-1556.
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