Ni-Catalyzed Suzuki-Miyaura Cross-Coupling of Aliphatic Amides on the Benchtop

Article abstract of DOI:10.1021/acs.orglett.9b03434

Suzuki-Miyaura cross-couplings of amides offer an approach to the synthesis of ketones that avoids the use of basic or pyrophoric nucleophiles. However, these reactions require glovebox manipulations, thus limiting their practicality. We report a benchtop

Full text of DOI:10.1021/acs.orglett.9b03434

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Ni-Catalyzed Suzuki−Miyaura Cross-Coupling of Aliphatic Amides
on the Benchtop
Milauni M. Mehta,† Timothy B. Boit,† Jacob E. Dander,† and Neil K. Garg*
Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095-1569, United States
S
* Supporting Information
ABSTRACT: Suzuki−Miyaura cross-couplings of amides
offer an approach to the synthesis of ketones that avoids the
use of basic or pyrophoric nucleophiles. However, these
reactions require glovebox manipulations, thus limiting their
practicality. We report a benchtop protocol for Suzuki−
Miyaura cross-couplings of aliphatic amides that utilizes a
paraffin capsule containing a Ni(0) precatalyst and NHC
ligand. This methodology is broad in scope, is scalable, and
provides a user-friendly approach to convert aliphatic amides
to alkyl−aryl ketones.
he conversion of carboxylic acid derivatives to ketones is
a fundamental transformation in synthetic chemistry
We recently reported a Ni-catalyzed Suzuki−Miyaura
coupling of aliphatic amides to generate alkyl−aryl ketones
(Figure 1, e.g. 1 + 2 → 3).10,11 This methodology is broad in
scope, but requires the use of a glovebox, thus limiting its
practical utility.12 We questioned if a paraffin-encapsulation
strategy, analogous to that pioneered by Buchwald, could
prove useful.13 In this approach, air-sensitive reagents are
stored in paraffin capsules, ultimately providing a user-friendly
means to perform air-sensitive transition-metal-catalyzed
reactions. Previously, we showed the promise of this strategy
for the Suzuki−Miyaura cross-coupling of a single benzamide-
derived substrate utilizing paraffin−Ni(cod)2/SIPr capsules.14
However, this precatalyst and ligand combination is ineffective
in the coupling of amides derived from aliphatic carboxylic
acids.10 Moreover, only a single example of a glovebox free
arylation of an aliphatic amide derivative has been reported,
which uses a bench-stable Pd(II) precatalyst.15 We report the
realization of a paraffin encapsulation strategy to achieve the
nickel-catalyzed Suzuki−Miyaura coupling of aliphatic amides
on the benchtop.
Our studies were initiated by preparing the desired paraffin
capsules, using a molding process analogous to one we had
previously reported (Figure 2).14 These capsules were charged
with Ni(cod)2 and Benz-ICy·HCl, as this precatalyst/ligand
combination had proven effective in our original studies on the
Suzuki−Miyaura coupling of aliphatic amides using a glove-
box.10 Next, we assessed the utility of these capsules in the
benchtop Suzuki−Miyaura coupling of amide 4 with N-
methylpyrrole-2-boronic acid pinacol ester (5), using 5 mol%
Ni. Unfortunately, the use of our literature conditions resulted
in a poor yield of ketone 6.16 Specifically, the coupling of 4 and
5 employing paraffin-encapsulated Ni(cod)2/Benz-ICy·HCl,
T
(Figure 1).1 A common strategy to achieve this conversion is
Figure 1. Methods for the conversion of amides to ketones, prior
studies of Ni-catalyzed Suzuki−Miyaura couplings that utilize a
glovebox, and paraffin encapsulation strategy for benchtop delivery
(present study).
the Weinreb ketone synthesis, in which a N-methoxy-N-methyl
amide undergoes net substitution with an organometallic
nucleophile.2 An alternative strategy lies in the development of
transition-metal-catalyzed cross-couplings of acyl electro-
philes,1c,3 which avoid the use of strongly basic and pyrophoric
organometallic reagents. Our laboratory and others have
shown that amides, which are well suited for multistep
synthesis due to their pronounced stability, are particularly
useful in this context.4 Specifically, Ni-5,6 and Pd-catalysis7
have enabled the mild activation of the amide C−N bond for
cross-coupling with boronic acids and esters,8 as well as
organozinc reagents.9
Received: September 27, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03434
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
ology was found to be tolerant of medicinally privileged N-
heterocyclic aryl boronates,19 as evidenced by the formation of
ketones 6−8, in good to excellent yields. Additionally,
electron-poor p-CF3 and sterically encumbered o-CH3
substituted phenyl boronate esters could be employed in the
coupling, providing ketones 9 and 10 in 53% and 74% yields,
respectively. Boronate esters featuring extended aromatic ring
systems were also competent nucleophiles in the methodology,
as demonstrated by the formation of naphthyl ketone 11 in
71% yield. Of note, in all cases, benchtop yields of the desired
ketone products were comparable to those obtained when
using literature conditions requiring a glovebox (yields using
the glovebox protocol are shown in parentheses in Figures 3
and 4).10
Figure 2. Preparation of Ni(cod)2/Benz-ICy·HCl−paraffin capsules
and their use in the benchtop Suzuki−Miyaura coupling of piperidinyl
amide 4 and pyrrole boronic ester 5 under optimized conditions.
Yield was determined by 1H NMR analysis using 1,3,5-trimethox-
ybenzene as an external standard.
2.5 equiv of 5, toluene as the reaction solvent, and a stir rate of
1
400 rpm for 16 h at 120 °C provided ketone 9 in 28% H
NMR yield.17 After extensive experimentation, it was found
that employing higher equivalents of 5 (2.5 to 5.0), utilizing
1,4-dioxane as the reaction solvent, and extending the reaction
time to 24 h proved beneficial. This provided ketone 6 in 91%
yield on the benchtop. Additionally, these capsules displayed
long-term air and moisture stability when stored outside of a
glovebox. After two months of storage, a benchtop coupling of
4 and 5 generated 6 in comparable yield.16 These capsules are
currently undergoing commercialization to enable their
widespread use.18
Having validated our encapsulation approach and arrived at
optimized reaction conditions, we evaluated the scope of this
transformation with respect to the boronate ester coupling
partner. A variety of aryl boronate esters were assessed in
couplings with piperidinyl amide 4 (Figure 3). The method-
Figure 4. Scope of the amide substrate. General conditions unless
otherwise stated: amide substrate (1.0 equiv, 0.4 mmol), K3PO4 (4.0
equiv), boronic ester 5 (5.0 equiv), Ni(cod)2 (5 mol%), Benz-ICy·
HCl (10 mol%), and 1,4-dioxane (1.0 M) heated at 120 °C for 24 h
in a sealed vial under an atmosphere of N2. Unless otherwise noted,
yields reflect the average of two isolation experiments. Yields in
parentheses were obtained by carrying out the reaction in a glovebox
utilizing literature conditions without encapsulating Ni(cod)2 and
Benz-ICy·HCl in paraffin. a Yield was determined by 1H NMR
analysis using 1,3,5-trimethoxybenzene as an external standard.
We next surveyed a range of amide substrates in the Suzuki−
Miyaura coupling with pyrroloboronate 5 (Figure 4).20 An
additional piperidine-derived amide substrate could be used in
the coupling to furnish 12 in excellent yield. Furthermore,
amides derived from isomeric 3- and 4-tetrahydropyran-
carboxylic acids were competent substrates, giving rise to
ketones 13 and 14 in 79% and 84% yields, respectively. We
also evaluated the coupling of non-heterocyclic amides. Linear
and carbocyclic amides underwent the reaction smoothly, as
demonstrated by the formation of 15 and 16 in 83% and 89%
yield, respectively. Notably, steric bulk adjacent to the amide
carbonyl did not hinder the Suzuki−Miyaura coupling, as the
use of a pivalamide substrate gave ketone 17 in 90% yield.
Finally, we assessed the Suzuki−Miyaura coupling of
piperidine amide 1 with N-methylindole-2-boronic ester 18
on gram-scale as shown in Figure 5. Using 5 mol% Ni, the
coupling proceeded smoothly to deliver ketone 19 in 73%
yield. We view this result as promising in the context of the
scalable construction of biologically relevant bis-heterocyclic
ketones19 where the enolizable alkyl−aryl ketone provides a
valuable synthetic handle for further manipulation.
Figure 3. Scope of the boronic ester coupling partners. General
conditions unless otherwise stated: substrate 4 (1.0 equiv, 0.4 mmol),
K3PO4 (4.0 equiv), boronic ester (5.0 equiv), Ni(cod)2 (5 mol%),
Benz-ICy·HCl (10 mol%), and 1,4-dioxane (1.0 M) heated at 120 °C
for 24 h in a sealed vial under an atmosphere of N2. Unless otherwise
noted, yields reflect the average of two isolation experiments. Yields in
parentheses were obtained by carrying out the reaction in a glovebox
utilizing literature conditions without encapsulating Ni(cod)2 and
Benz-ICy·HCl in paraffin. a Yield was determined by 1H NMR
analysis using 1,3,5-trimethoxybenzene as an external standard.
B
DOI: 10.1021/acs.orglett.9b03434
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REFERENCES
■
(1) (a) Larock, R. C. Comprehensive Organic Transformations: A
Guide to Functional Group Preparations; VCH: New York, 1989; pp
685−702. (b) Nicholson, J. W.; Wilson, A. D. The conversion of
carboxylic acids to ketones: a repeated discovery. J. Chem. Educ. 2004,
81, 1362−1366. (c) Amani, J.; Molander, G. A. Direct conversion of
carboxylic acids to alkyl ketones. Org. Lett. 2017, 19, 3612−3615.
(2) (a) Nahm, S.; Weinreb, S. M. N-Methoxy-N-methylamides as
effective acylating agents. Tetrahedron Lett. 1981, 22, 3815−3818.
(b) Balasubramaniam, S.; Aidhen, I. S. The growing synthetic utility
of the Weinreb amide. Synthesis 2008, 3707−3738.
Figure 5. Gram-scale Suzuki−Miyaura coupling of amide 1 with
boronate ester 18 to generate ketone 19.
(3) For couplings of acyl halides, anhydrides, esters, and thioesters,
see: (a) Labadie, J. W.; Tueting, D.; Stille, J. K. Synthetic utility of the
palladium-catalyzed coupling reaction of acid chlorides with organo-
tins. J. Org. Chem. 1983, 48, 4634−4642. (b) Stille, J. K. The
palladium-catalyzed cross-coupling reactions of organotin reagents
with organic electrophiles. Angew. Chem., Int. Ed. 1986, 25, 508−524.
(c) Stephan, M. S.; Teunissen, A. J. J. M.; de Vries, J. G. Heck
reactions without salt formation: aromatic carboxylic anhydrides as
arylating agents. Angew. Chem., Int. Ed. 1998, 37, 662−664.
(d) Gooßen, L. J.; Ghosh, K. Palladium-catalyzed synthesis of aryl
ketones from boronic acids and carboxylic acids or anhydrides. Angew.
Chem., Int. Ed. 2001, 40, 3458−3460. (e) Kakino, R.; Narahashi, H.;
Shimizu, I.; Yamamoto, A. Palladium-catalyzed direct conversion of
carboxylic acids into ketones with organoboronic acids promoted by
anhydride activators. Bull. Chem. Soc. Jpn. 2002, 75, 1333−1345.
(f) Bykov, V. V.; Korolev, D. N.; Bumagin, N. A. Palladium-catalyzed
reactions of organoboron compounds with acyl chlorides. Russ. Chem.
Bull. 1997, 46, 1631−1632. (g) Zhang, L.; Wu, J.; Shi, L.; Xia, C.; Li,
F. Ionically tagged benzimidazole palladium(II) complex: preparation
and catalytic application in cross-coupling reactions. Tetrahedron Lett.
2011, 52, 3897−3901. (h) Kakino, R.; Shimizu, I.; Yamamoto, A.
Synthesis of trifluoromethyl ketones by palladium-catalyzed cross-
coupling reaction of phenyl trifluoroacetate with organoboron
compounds. Bull. Chem. Soc. Jpn. 2001, 74, 371−376. (i) Cherney,
A. H.; Reisman, S. E. Pd-catalyzed Fukuyama cross-coupling of
secondary organozinc reagents for the direct synthesis of unsym-
metrical ketones. Tetrahedron 2014, 70, 3259−3265. (j) Harada, T.;
Kotani, Y.; Katsuhira, T.; Oku, A. Novel method for generation of
secondary organozinc reagent: application to tandem carbon-carbon
bond formation reaction of 1,1-dibromoalkane. Tetrahedron Lett.
1991, 32, 1573−1576. (k) Negishi, E.-I.; Bagheri, V.; Chatterjee, S.;
Luo, F.-T.; Miller, J. A.; Stoll, A. T. Palladium-catalyzed acylation of
organozincs and other organometallics as a convenient route to
ketones. Tetrahedron Lett. 1983, 24, 5181−5184. (l) Iwai, T.; Nakai,
T.; Mihara, M.; Ito, T.; Mizuno, T.; Ohno, T. Pd-catalyzed cross-
coupling reactions of pyridine carboxylic acid chlorides with alkylzinc
reagents. Synlett 2009, 1091−1094. (m) Grey, R. A. A palladium-
catalyzed synthesis of ketones from acid chlorides and organozinc
compounds. J. Org. Chem. 1984, 49, 2288−2289. (n) Bercot, E. A.;
Rovis, T. A mild and efficient catalytic alkylative monofunctionaliza-
tion of cyclic anhydrides. J. Am. Chem. Soc. 2002, 124, 174−175.
(o) Bercot, E. A.; Rovis, T. A palladium-catalyzed enantioselective
alkylative desymmetrization of meso-succinic anhydrides. J. Am. Chem.
Soc. 2004, 126, 10248−10249. (p) Johnson, J. B.; Yu, R. T.; Fink, P.;
Bercot, E. A.; Rovis, T. Selective substituent transfer from mixed zinc
reagents in Ni-catalyzed anhydride alkylation. Org. Lett. 2006, 8,
4307−4310. (q) Tokuyama, H.; Yokoshima, S.; Yamashita, T.;
Fukuyama, T. A novel ketone synthesis by a palladium-catalyzed
reaction of thiol esters and organozinc reagents. Tetrahedron Lett.
1998, 39, 3189−3192. (r) Mori, Y.; Seki, M. A novel procedure for
the synthesis of multifunctional ketones through the Fukuyama
coupling reaction employing dialkylzincs. Tetrahedron Lett. 2004, 45,
7343−7345. (s) Miyazaki, T.; Han-ya, Y.; Tokuyama, H.; Fukuyama,
T. New odorless protocols for the synthesis of aldehydes and ketones
from thiol esters. Synlett 2004, 3, 477−480. (t) Dieter, R. K. Reaction
of acyl chlorides with organometallic reagents: a banquet table of
metals for ketone synthesis. Tetrahedron 1999, 55, 4177−4236.
(u) Shi, S.; Nolan, S. P.; Szostak, M. Well-defined palladium(II)-
We have developed a benchtop protocol for the Suzuki−
Miyaura cross-coupling of aliphatic amides to access alkyl−aryl
ketones. Our strategy leverages mild Ni-catalyzed C−N bond
activation to avoid the use of strongly basic and pyrophoric
reagents typically employed in amide to ketone conversions.
Additionally, the Ni(cod)2/Benz-ICy·HCl−paraffin capsules,
which are currently undergoing commercialization,18 obviate
the need to set up the reactions in a glovebox. Notably, this
methodology enables the coupling of heterocyclic and aliphatic
amides with a variety of aryl boronic esters for the formation of
C−C bonds. Moreover, this transformation is scalable and,
further, provides a valuable approach to the synthesis of alkyl−
aryl ketones from amides, which benefits further from the use
of base-metal catalysis and commercially available boronic
ester nucleophiles. Thus, we hope these studies promote the
use of Ni-mediated Suzuki−Miyaura couplings of aliphatic
amides as a complement to traditional synthetic strategies.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03434.
Experimental details and compound characterization
data (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: neilgarg@chem.ucla.edu.
ORCID
Milauni M. Mehta: 0000-0002-4597-2829
Neil K. Garg: 0000-0002-7793-2629
Author Contributions
†M.M.M. and T.B.B., and J.E.D. contributed equally to this
work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the NIH-NIGMS (R01-GM117016 to
N.K.G.), the California Tobacco-Related Disease Research
Program (28DT-0006 to T.B.B.), the NSF (DGE-1144087 to
J.E.D.), the Trueblood Family (N.K.G.), the Foote Family
(J.E.D.), and the University of California, Los Angeles for
financial support. Hui-Qi Ni (Scripps Research Institute) and
Angel Mendoza (University of California, Los Angeles) are
acknowledged for experimental assistance. These studies were
supported by shared instrumentation grants from the NSF
(CHE-1048804) and the NIH-NCRR (S10RR025631).
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NHC precatalysts for cross-coupling reactions of amides and esters by
selective N−C/O−C cleavage. Acc. Chem. Res. 2018, 51, 2589−2599.
(v) Ben Halima, T.; Zhang, W.; Yalaoui, T.; Hong, X.; Yang, Y.-F.;
Houk, K. N.; Newman, S. G. Palladium-catalyzed Suzuki−Miyaura
coupling of aryl esters. J. Am. Chem. Soc. 2017, 139, 1311−1318.
(4) For recent reviews, see: (a) Dander, J. E.; Garg, N. K. Breaking
amides using nickel catalysis. ACS Catal. 2017, 7, 1413−1423.
(b) Meng, G.; Shi, S.; Szostak, M. Cross-coupling of amides by N−C
bond activation. Synlett 2016, 2530−2540. (c) Takise, R.; Muto, K.;
Yamaguchi, J. Cross-coupling of aromatic esters and amides. Chem.
Soc. Rev. 2017, 46, 5864−5888. (d) Kaiser, D.; Bauer, A.; Lemmerer,
M.; Maulide, N. Chem. Soc. Rev. 2018, 47, 7899−7925.
3094. (d) Liu, C.; Szostak, M. Decarbonylative phosphorylation of
amides by palladium and nickel catalysis: the Hirao cross-coupling of
amide derivatives. Angew. Chem., Int. Ed. 2017, 56, 12718−12722.
(e) Yue, H.; Guo, L.; Liao, H.-H.; Cai, Y.; Zhu, C.; Rueping, M.
Catalytic ester and amide to amine interconversion: nickel-catalyzed
decarbonylative amination of esters and amides by C−O and C−C
bond activation. Angew. Chem., Int. Ed. 2017, 56, 4282−4285.
(f) Chatupheeraphat, A.; Liao, H.-H.; Lee, S.-C.; Rueping, M. Nickel-
catalyzed C−CN bond formation via decarbonylative cyanation of
esters, amides, and intramolecular recombination fragment coupling
of acyl cyanides. Org. Lett. 2017, 19, 4255−4258. (g) Yue, H.; Guo,
L.; Lee, S.-C.; Liu, X.; Rueping, M. Selective reductive removal of
ester and amide groups from arenes and heteroarenes through nickel-
catalyzed C−O and C−N bond activation. Angew. Chem., Int. Ed.
2017, 56, 3972−3976. (h) Lee, S.-C.; Guo, L.; Yue, H.; Liao, H.-H.;
Rueping, M. Nickel-catalyzed decarbonylative silylation, borylation,
and amination of arylamides via a deamidative reaction pathway.
Synlett 2017, 2594−2598.
(5) For nickel-catalyzed reactions proceeding with cleavage of the
amide C−N bond, see: (a) Hie, L.; Fine Nathel, N. F.; Shah, T. K.;
Baker, E. L.; Hong, X.; Yang, Y.-F.; Liu, P.; Houk, K. N.; Garg, N. K.
Conversion of amides to esters by the nickel-catalysed activation of
amide C−N bonds. Nature 2015, 524, 79−83. (b) Weires, N. A.;
Baker, E. L.; Garg, N. K. Nickel-catalysed Suzuki−Miyaura coupling
of amides. Nat. Chem. 2016, 8, 75−79. (c) Baker, E. L.; Yamano, M.
M.; Zhou, Y.; Anthony, S. M.; Garg, N. K. A two-step approach to
achieve secondary amide transamidation enabled by nickel catalysis.
Nat. Commun. 2016, 7, 11554. (d) Simmons, B. J.; Weires, N. A.;
Dander, J. E.; Garg, N. K. Nickel-catalyzed alkylation of amide
derivatives. ACS Catal. 2016, 6, 3176−3179. (e) Shi, S.; Szostak, M.
Nickel-catalyzed diaryl ketone synthesis by N−C bond cleavage:
direct Negishi cross-coupling of primary amides by site-selective N,N-
di-Boc activation. Org. Lett. 2016, 18, 5872−5875. (f) Shi, S.; Szostak,
M. Efficient synthesis of diaryl ketones by nickel-catalyzed Negishi
cross-coupling of amides via carbon−nitrogen bond cleavage at room
temperature accelerated by solvent effect. Chem. Eur. J. 2016, 22,
10420−10424. (g) Hie, L.; Baker, E. L.; Anthony, S. M.; Desrosiers,
J.-N.; Senanayake, C.; Garg, N. K. Nickel-catalyzed esterification of
aliphatic amides. Angew. Chem., Int. Ed. 2016, 55, 15129−15132.
(h) Dey, A.; Sasmal, S.; Seth, K.; Lahiri, G. K.; Maiti, D. Nickel-
catalyzed deamidative step-down reduction of amides to aromatic
hydrocarbons. ACS Catal. 2017, 7, 433−437. (i) Ni, S.; Zhang, W.;
Mei, H.; Han, J.; Pan, Y. Ni-catalyzed reductive cross-coupling of
amides with aryl iodide electrophiles via C−N bond activation. Org.
Lett. 2017, 19, 2536−2539. (j) Medina, J. M.; Moreno, J.; Racine, S.;
Du, S.; Garg, N. K. Mizoroki−Heck cyclizations of amide derivatives
for the introduction of quaternary centers. Angew. Chem., Int. Ed.
2017, 56, 6567−6571. (k) Hu, J.; Wang, M.; Pu, X.; Shi, Z. Nickel-
catalysed retro-hydroamidocarbonylation of aliphatic amides to
olefins. Nat. Commun. 2017, 8, 14993. (l) Weires, N. A.; Caspi, D.
D.; Garg, N. K. Kinetic modeling of the nickel-catalyzed esterification
of amides. ACS Catal. 2017, 7, 4381−4385. (m) Shi, S.; Szostak, M.
Nickel-catalyzed Negishi cross-coupling of N-acylsuccinimides: stable,
amide-based, twist-controlled acyl transfer reagents via N−C
activation. Synthesis 2017, 3602−3608. (n) Dander, J. E.; Baker, E.
L.; Garg, N. K. Nickel-catalyzed transamidation of aliphatic amide
derivatives. Chem. Sci. 2017, 8, 6433−6438. (o) Huang, P.-Q.; Chen,
H. Ni-catalyzed cross-coupling reactions of N-acylpyrrole-type amides
with organoboron reagents. Chem. Commun. 2017, 53, 12584−12587.
(p) Deguchi, T.; Xin, H.-L.; Morimoto, H.; Ohshima, T. Direct
catalytic alcoholysis of unactivated 8-aminoquinoline amides. ACS
Catal. 2017, 7, 3157−3161. (q) Dander, J. E.; Giroud, M.; Racine, S.;
Darzi, E. R.; Alvizo, O.; Entwistle, D.; Garg, N. K. Chemoenzymatic
conversion of amides to enantioenriched alcohols in aqueous medium.
Commun. Chem. 2019, 2, 82.
(7) For Pd-catalyzed amide C−N bond activations, see: (a) Li, X.;
Zou, G. Acylative Suzuki coupling of amides: acyl-nitrogen activation
via synergy of independently modifiable activating groups. Chem.
Commun. 2015, 51, 5089−5092. (b) Yada, A.; Okajima, S.;
Murakami, M. Palladium-catalyzed intramolecular insertion of alkenes
into the carbon−nitrogen bond of β-lactams. J. Am. Chem. Soc. 2015,
137, 8708−8711. (c) Meng, G.; Szostak, M. Palladium-catalyzed
Suzuki−Miayura coupling of amides by carbon−nitrogen cleavage:
general strategy for amide N−C bond activation. Org. Biomol. Chem.
2016, 14, 5690−5705. (d) Meng, G.; Szostak, M. General olefin
synthesis by the palladium-catalyzed Heck reaction of amides:
sterically-controlled chemoselective N−C activation. Angew. Chem.,
Int. Ed. 2015, 54, 14518−14522. (e) Meng, G.; Szostak, M. Sterically-
controlled Pd-catalyzed chemoselective ketone synthesis via N−C
cleavage in twisted amides. Org. Lett. 2015, 17, 4364−4367. (f) Liu,
C.; Meng, G.; Liu, Y.; Liu, R.; Lalancette, R.; Szostak, R.; Szostak, M.
N-Acylsaccharins: stable electrophilic amide-based acyl transfer
reagents in Pd-catalyzed Suzuki−Miyaura coupling via N−C cleavage.
Org. Lett. 2016, 18, 4194−4197. (g) Lei, P.; Meng, G.; Szostak, M.
General method for the Suzuki−Miyaura cross-coupling of amides
using commercially available, air- and moisture-stable palladium/
NHC (NHC = N-heterocyclic carbene) complexes. ACS Catal. 2017,
7, 1960−1965. (h) Liu, C.; Liu, Y.; Liu, R.; Lalancette, R.; Szostak, R.;
Szostak, M. Palladium-catalyzed Suzuki−Miyaura cross-coupling of N-
mesyl amides by N−C cleavage: electronic effect of the mesyl group.
Org. Lett. 2017, 19, 1434−1437. (i) Liu, C.; Meng, G.; Szostak, M. N-
Acylsaccharins as amide-based arylating reagents via chemoselective
N−C cleavage: Pd-catalyzed decarbonylative Heck reaction. J. Org.
Chem. 2016, 81, 12023−12030. (j) Meng, G.; Shi, S.; Szostak, M.
Palladium-catalyzed Suzuki−Miyaura cross-coupling of amides via
site-selective N−C bond cleavage by cooperative catalysis. ACS Catal.
2016, 6, 7335−7339. (k) Cui, M.; Wu, H.; Jian, J.; Wang, H.; Liu, C.;
Stelck, D.; Zeng, Z. Palladium-catalyzed Sonogashira coupling of
amides: access to ynones via C−N bond cleavage. Chem. Commun.
2016, 52, 12076−12079. (l) Wu, H.; Li, Y.; Cui, M.; Jian, J.; Zeng, Z.
Suzuki coupling of amides via palladium-catalyzed C−N cleavage of
N-acylsaccharins. Adv. Synth. Catal. 2016, 358, 3876−3880. (m) Shi,
S.; Szostak, M. Decarbonylative cyanation of amides by palladium
catalysis. Org. Lett. 2017, 19, 3095−3098. (n) Lei, P.; Meng, G.; Ling,
Y.; An, J.; Szostak, M. Pd-PEPPSI: Pd-NHC precatalyst for Suzuki−
Miyaura cross-coupling reactions of amides. J. Org. Chem. 2017, 82,
6638−6646. (o) Meng, G.; Szostak, R.; Szostak, M. Suzuki−Miyaura
cross-coupling of N-acylpyrroles and pyrazoles: planar, electronically
activated amides in catalytic N−C cleavage. Org. Lett. 2017, 19,
3596−3599. (p) Meng, G.; Lalancette, R.; Szostak, R.; Szostak, M. N-
Methylamino pyrimidyl amides (MAPA): highly reactive, electroni-
cally-activated amides in catalytic N−C(O) cleavage. Org. Lett. 2017,
19, 4656−4659. (q) Osumi, Y.; Szostak, M. N-Acylsuccinimides:
twist-controlled, acyl transfer reagents in Suzuki−Miyaura cross-
coupling by N−C amide bond activation. Org. Biomol. Chem. 2017,
15, 8867−8871. (r) Lei, P.; Meng, G.; Ling, Y.; An, J.; Nolan, S. P.;
(6) For nickel-catalyzed decarbonylative coupling reactions of
amides, see: (a) Shi, S.; Meng, G.; Szostak, M. Synthesis of biaryls
via nickel-catalyzed Suzuki−Miyaura coupling of amides by carbon−-
nitrogen cleavage. Angew. Chem., Int. Ed. 2016, 55, 6959−6963.
(b) Hu, J.; Zhao, Y.; Liu, J.; Zhang, Y.; Shi, Z. Nickel-catalyzed
decarbonylative borylation of amides: evidence for acyl C−N bond
activation. Angew. Chem., Int. Ed. 2016, 55, 8718−8722. (c) Srimon-
tree, W.; Chatupheeraphat, A.; Liao, H.-H.; Rueping, M. Amide to
alkyne interconversion via a nickel/copper-catalyzed deamidative
cross-coupling of aryl and alkenyl amides. Org. Lett. 2017, 19, 3091−
D
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Organic Letters
Letter
Szostak, M. General method for the Suzuki−Miyaura cross-coupling
of primary amide-derived electrophiles enabled by [Pd(NHC)(cin)-
Cl] at room temperature. Org. Lett. 2017, 19, 6510−6513. (s) Li, X.;
Zou, G. Palladium-catalyzed acylative cross-coupling of amides with
diarylboronic acids and sodium tetraarylborates. J. Organomet. Chem.
2015, 794, 136−145. (t) Liu, C.; Li, G.; Shi, S.; Meng, G.; Lalancette,
R.; Szostak, R.; Szostak, M. Acyl and decarbonylative Suzuki coupling
of N-acetyl amides: Electronic tuning of twisted, acyclic amides in
catalytic carbon−nitrogen bond cleavage. ACS Catal. 2018, 8, 9131−
9139. (u) Meng, G.; Szostak, M. Palladium/NHC (NHC = N-
heterocyclic carbene)-catalyzed B-alkyl Suzuki cross-coupling of
amides by selective N−C bond cleavage. Org. Lett. 2018, 20,
6789−6793. (v) Shi, S.; Szostak, M. Decarbonylative borylation of
amides by palladium catalysis. ACS Omega 2019, 4, 4901−4907.
(w) Zhou, T.; Li, G.; Nolan, S. P.; Szostak, M. [Pd(NHC)(acac)Cl]:
well-defined, air-stable, and readily available precatalysts for Suzuki
and Buchwald−Hartwig cross-coupling (transamidation) of amides
and esters by N−C/O−C activation. Org. Lett. 2019, 21, 3304−3309.
(8) For Ni- and Pd-catalyzed cross-couplings of amides with aryl
boronic esters or acids, see refs 5b, o, q, 6a, b, 7a, c, f−h, j, n, o, q−u,
w.
(18) TCI Chemicals is commercializing the capsules containing
Ni(cod)2 and Benz-ICy·HCl.
(19) (a) Vitaku, E.; Smith, D. T.; Njardarson, J. T. Analysis of the
structural diversity, substitution patterns, and frequency of nitrogen
heterocycles among U.S. FDA approved pharmaceuticals. J. Med.
Chem. 2014, 57, 10257−10274. (b) Hirata, T.; Funatsu, T.; Keto, Y.;
Nakata, M.; Sasamata, M. Pharmacological profile of ramosetron, a
novel therapeutic agent for IBS. Inflammopharmacology 2007, 15, 5−
9.
(20) Amide derivatives featuring various N-substituents have been
employed successfully in cross-coupling reactions (see ref 4). N-Bn-N-
Boc derivatives were selected for the present study due to their utility
in the glovebox methodology (see ref 10) and ease of preparation.
(9) For Ni- and Pd-catalyzed cross-couplings of amides with alkyl
zinc reagents, see refs 5d−f, m.
(10) Boit, T. B.; Weires, N. A.; Kim, J.; Garg, N. K. Nickel-catalyzed
Suzuki−Miyaura coupling of aliphatic amides. ACS Catal. 2018, 8,
1003−1008.
(11) The Molander group has reported a dual-metal photoredox
approach to the synthesis of alkyl−alkyl ketones using alkyltrifluor-
oborate salts and aliphatic acyl succinimides; see: Amani, J.; Alam, R.;
Badir, S.; Molander, G. A. Synergistic visible-light photoredox/nickel-
catalyzed synthesis of aliphatic ketones via N−C cleavage of imides.
Org. Lett. 2017, 19, 2426−2429.
(12) The use of air-stable Ni(II) precatalysts represents a
complementary strategy for avoiding glovebox manipulations; see:
(a) Shields, J. D.; Gray, E. E.; Doyle, A. G. A modular, air-stable nickel
precatalyst. Org. Lett. 2015, 17, 2166−2169. (b) Magano, J.;
Monfette, S. Development of an air-stable, broadly applicable nickel
source for nickel-catalyzed cross-coupling. ACS Catal. 2015, 5, 3120−
3123. (c) Standley, E. A.; Jamison, T. F. Simplifying nickel(0)
catalysis: an air-stable nickel precatalyst for the internally selective
benzylation of terminal alkenes. J. Am. Chem. Soc. 2013, 135, 1585−
1592. (d) Park, N. H.; Teverovskiy, G.; Buchwald, S. L. Development
of an air-stable nickel precatalyst for the amination of aryl chlorides,
sulfamates, mesylates, and triflates. Org. Lett. 2014, 16, 220−223.
(e) Ge, S.; Hartwig, J. F. Highly reactive, single-component nickel
catalyst precursor for Suzuki−Miyaura cross-coupling of heteroaryl
boronic acids with heteroaryl halides. Angew. Chem., Int. Ed. 2012, 51,
12837−12841.
(13) (a) Sather, A. C.; Lee, H. G.; Colombe, J. R.; Zhang, A.;
Buchwald, S. L. Dosage delivery of sensitive reagents enables glove-
box free synthesis. Nature 2015, 524, 208−211. (b) Fang, Y.; Liu, Y.;
Ke, Y.; Guo, C.; Zhu, N.; Mi, X.; Ma, Z.; Hu, Y. A new chromium-
based catalyst coated with paraffin for ethylene oligomerization and
the effect of chromium state on oligomerization selectivity. Appl.
Catal., A 2002, 235, 33−38. (c) Taber, D. F.; Frankowski, K. J.
Grubbs’ catalyst in paraffin: an air-stable preparation for alkene
metathesis. J. Org. Chem. 2003, 68, 6047−6048.
(14) (a) Dander, J. E.; Weires, N. A.; Garg, N. K. Benchtop delivery
of Ni(cod)2 using paraffin capsules. Org. Lett. 2016, 18, 3934−3936.
(b) Dander, J. E.; Morrill, L. A.; Nguyen, M. M.; Chen, S.; Garg, N. K.
Breaking amide C−N bonds in an undergraduate organic chemistry
laboratory. J. Chem. Educ. 2019, 96, 776−780.
(15) Lei, P.; Meng, G.; Shi, S.; Ling, Y.; An, J.; Szostak, R.; Szostak,
M. Suzuki−Miyaura cross-coupling of amides and esters at room
temperature: correlation with barriers to rotation around C−N and
C−O bonds. Chem. Sci. 2017, 8, 6525−6530.
(16) See the Supporting Information (SI) for details.
(17) See the Supporting Information for full optimization details.
E
DOI: 10.1021/acs.orglett.9b03434
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