Reductive Arylation of Amides via a Nickel-Catalyzed Suzuki–Miyaura-Coupling and Transfer-Hydrogenation Cascade

Article abstract of DOI:10.1002/anie.202012048

We report a means to achieve the addition of two disparate nucleophiles to the amide carbonyl carbon in a single operational step. Our method takes advantage of non-precious-metal catalysis and allows for the facile conversion of amides to chiral alcohols via a one-pot Suzuki–Miyaura cross-coupling/transfer-hydrogenation process. This study is anticipated to promote the development of new transformations that allow for the conversion of carboxylic acid derivatives to functional groups bearing stereogenic centers via cascade processes.

Full text of DOI:10.1002/anie.202012048

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
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Accepted Article
Title: Reductive Arylation of Amides via a Nickel-Catalyzed Suzuki–
Miyaura Coupling and Transfer Hydrogenation Cascade
Authors: Timothy Boit, Milauni Mehta, Junyong Kim, Emma Baker, and
Neil K. Garg
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of the final Version of Record (VoR). This work is currently citable by
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202012048
Link to VoR: https://doi.org/10.1002/anie.202012048

10.1002/anie.202012048
Angewandte Chemie International Edition
COMMUNICATION
Reductive Arylation of Amides via a Nickel-Catalyzed Suzuki–
Miyaura Coupling and Transfer Hydrogenation Cascade
Timothy B. Boit,† Milauni M. Mehta,† Junyong Kim, Emma L. Baker, and Neil K. Garg*
Abstract: We report a means to achieve the addition of two
disparate nucleophiles to the amide carbonyl carbon in a single
operational step. Our method takes advantage of non-precious metal
catalysis and allows for the facile conversion of amides to chiral
alcohols via a one-pot Suzuki–Miyaura cross-coupling / transfer
hydrogenation process. This study is anticipated to promote the
development of new transformations that allow for the conversion of
carboxylic acid derivatives to functional groups bearing stereogenic
centers via cascade processes.
couplings, methods to leverage this platform for the addition of
disparate nucleophiles to carboxylic acid derivatives remain
underexplored.[7] We envisioned that amides could provide a
viable entry to address this challenge, given their recent
popularization as cross-coupling handles.[4j–o,8,9] Amides have
been shown to undergo a variety of couplings through the
intermediacy of acyl-metal species using either non-precious or
precious metal catalysis (e.g., Ni or Pd). Additionally, we viewed
them as ideal substrates for one-pot cascade reactions, as their
stability under non-metal catalyzed conditions could allow for the
orchestration of orthogonal bond-forming events.[10] Dixon has
reported an elegant intramolecular reductive cyclization of a
tertiary lactam substrate mediated by Vaska’s Ir complex,[11 ]
however, no examples exist for the intermolecular addition of
two distinct nucleophiles to amides using catalysis in a single
operation.[ 12 , 13 ] Indeed, a reductive alkylation of aryl pyridyl
esters reported by Chen and coworkers in 2019 represents the
only known example of a carboxylic acid derivative undergoing
direct catalytic addition of two nucleophiles through a cross-
The synthetic manipulation of carboxylic acid derivatives
has become central to organic chemistry after more than a
century of methodological development.[1] Though the field has a
rich history, strategies for nucleophilic addition to carboxylic acid
derivatives may be largely characterized by two primary
mechanisms (Figure 1a). The first involves an addition-
elimination sequence to produce carbonyl derivatives via a
tetrahedral intermediate.[2] Notably, this traditional strategy has
limitations in the context of organometallic nucleophiles, as the
ketone products resulting from initial acyl substitution are
susceptible to further nucleophilic attack to give achiral alcohol
products. Specialized acyl derivatives such as N-methyl-N-
methoxy amides, or “Weinreb amides,” are often required to
avoid such undesired reactivity and necessitate two-step
protocols.[2, 3 ] A complementary approach employs transition
metal catalysis,[4 ] where mild substrate activation affords an
acyl-metal intermediate and allows for cross-coupling with a
14
]
coupling approach (Figure 1b).[
Though mechanistically
distinct and not involving acyl metal species, two additional
relevant methodologies should be highlighted. Buchwald and
coworkers have reported a copper-catalyzed reductive alkylation
of symmetric anhydrides to afford enantioenriched secondary
alcohols,[15] and more recently the Hoveyda group reported a
copper-catalyzed asymmetric reductive allylation of nitriles to
access enantioenriched homoallylic amines (Figure 1b).[ 16 ]
Together, these examples illustrate some of the potential
advantages of cascade reactions that add disparate
nucleophiles to a single reactive center of an achiral substrate
and uncover synergistic reactivity beyond the capabilities of one
reaction manifold.[17]
5
]
variety of nucleophiles.[4a,
This alternative pathway
differentiates the reactivity of the substrate from the product
carbonyl to overcome the selectivity challenges mentioned
above. An exciting opportunity offered by the latter strategy is
the addition of
a
second, different nucleophile to the
a. Strategies for nucleophilic addition to carboxylic acid derivatives
intermediate resulting from the initial cross-coupling reaction to
generate chiral products. Cascade reactions of this type would
provide efficient access to important chiral products in racemic
or enantioenriched form from achiral starting materials.[6]
Transition metal
Nu–
Nu–
O
O
catalyst
via tetrahedral
intermediate
via acyl-metal
intermediate
Nu–
Nu–
Nu–
R
R
O
Nu–
Challenging
Well-established
R
X
Despite the widely recognized importance of cross-
Carboxylic acid
derivative
OH
OH
Nu–
Nu–
Nu–
Achiral products
from over-addition
Chiral products
from controlled cascade
R
R
Timothy B. Boit,† Milauni M. Mehta,† Dr. Junyong Kim, Dr. Emma L.
Baker, and Prof. Dr. Neil K. Garg
Department of Chemistry and Biochemistry
University of California, Los Angeles
Nu–
b. Direct catalytic approaches to chiral alcohols / amines from carboxylic acid derivatives
Chen, 2019
Buchwald, 2016
O
Los Angeles, CA 90095 (USA)
E-mail: neilgarg@chem.ucla.edu
Homepage: https://garg.chem.ucla.edu
Reductive alkylation
R
OR'
Esters
O
R'
O
O
R
N
X
Reductive
arylation
R''
R
O
R
Supporting information for this article is given via a link at the end of
the document.
Nu–
R
Amides
Anhydrides
Nu–
This study
• Precursor to acyl-
metal species
Chiral alcohols
or amines
N
• Pronounced
stability
R
Hoveyda, 2019
Reductive allylation
Nitriles
Achiral starting materials
Privileged chiral products
Controlled cascade reactions
This article is protected by copyright. All rights reserved.

10.1002/anie.202012048
Angewandte Chemie International Edition
COMMUNICATION
Ni(cod)2, 2
Phenyl boronate
Reductant
Figure 1. (a) Common reaction pathways for nucleophilic additions
to carboxylic acid derivatives. (b) Direct catalytic approaches to
chiral amines or alcohols from carboxylic acid derivatives.
O
O
OH
Bn
+
Ph
N
Ph
Ph
K3PO4, H2O
solvent, 120 ºC
Ph
Ph
Boc
In this manuscript, we describe a synthetic method for
1
3
4
achieving the addition of two different nucleophiles to
a
Yielda Yielda
Ni(cod)2
(mol%)
2
(mol%)
Boronate
(equiv)
Reductant
(equiv)
carboxylic acid derivative using nickel catalysis.[18] The overall
transformation relies on a Suzuki–Miyaura cross-coupling /
transfer hydrogenation cascade reaction of amide starting
materials to form a C–C and C–H bond,[19,20] consecutively, and
ultimately furnish alcohol products (Figure 2).[ 21 ] The results
presented herein not only reinforce the notion that amides are
versatile building blocks for transition-metal catalyzed reactions,
but also validate their utility as synthons for directly generating
sp3 carbon centers from the amide carbonyl.
Entry
Solvent
3
4
5 (2.5)
5 (2.5)
5 (4.0)
5 (4.0)
5 (4.0)
5 (4.0)
6 (4.0)
1
2
3
4
5
6
7
5
10
10
20
20
20
20
20
PhMe
i-PrOH
–
98%
0%
0%
18%
3%
0%
0%
0%
solvent
solvent
i-PrOH (2.5)
7 (2.5)
5
14%
21%
32%
51%
78%
82%
i-PrOH
10
10
10
10
10
PhMe
PhMe
7 (2.5)
1,4-dioxane
1,4-dioxane
7 (2.5)
Me
Me
Me
Me
Me
OH
This study: Direct conversion of amides to alcohols via a reductive arylation
Me
O
O
B
O
HO
H
Me
B
Ni-catalyzed
Suzuki–Miyaura coupling
N
N
O
O
Cy
Cy
Bn
N
(Het)
Alk
NMe2
(Het)
Alk
Ar
Cl
Benz-ICy•HCl (2)
Cy = cyclohexyl
& Transfer hydrogenation
Boc
Ph–B(pin) (5)
Ph–B(nep) (6)
DMPE (7)
Addition of 2 different Nu–
Alkyl–Aryl Alcohols
Amides
Figure 3. Evaluation of reaction conditions for the nickel-catalyzed
Suzuki–Miyaura coupling / transfer hydrogenation cascade of amide
1 with phenyl boronates and reductants. Standard conditions unless
otherwise noted: amide substrate (0.20 mmol, 1.0 equiv); phenyl
boronate (0.50–0.80 mmol, 2.5–4.0 equiv); reductant (0.50 equiv,
2.5 equiv); K3PO4 (0.80 mmol, 4.0 equiv); H2O (0.40 mmol, 2.0
equiv); Ni(cod)2 (0.010–0.020 mmol, 5–10 mol%); 2 (0.020–0.040
mmol, 10–20 mol%); solvent (1.0 M); 120 °C; 16 h in a sealed vial.
[a] Yield determined by 1H NMR analysis using 1,3,5-
trimethoxybenzene as an external standard.
Transfer
hydrogenation
O
Ni-catalysis
(Het)
Ar
HO
R'
H
(RO)2B Ar
Alk
R''
Figure 2. Overview of current study involving the conversion of
aliphatic amides to alkyl–aryl alcohols via a Suzuki–Miyaura coupling
/ transfer hydrogenation cascade.
We initiated our study by examining the Ni-catalyzed
Suzuki–Miyaura
coupling
and
in
situ
reduction
of
With optimized conditions in hand, we evaluated the scope
of the reaction with respect to the aliphatic amide[33] coupling
partner using phenyl boronate 6, which afforded a range of
alkyl–aryl alcohol products (Figure 4). Beginning with the parent
dihydrocinnamic acid-derived amide substrate used in
optimization studies (i.e., 1), the reductive arylation furnished
alcohol 4 in 76% isolated yield. Additionally, the use of an
unbranched amide derived from decanoic acid provided alcohol
8 in 82% yield. Carrying out the reaction at 130 °C allowed for
the reductive arylation of sterically encumbered substrates, as
demonstrated by the formation of alcohol 9 in 61% yield. The
compatibility of carbocyclic amides with boronate 6 was explored
as well and gave alcohols 10–14 in good yields. We also
evaluated an amide substrate bearing an epimerizable
stereocenter α to the amide carbonyl. As shown by the formation
of alcohol 15 from the corresponding trans amide substrate,
minimal erosion of stereochemistry was observed.[34] Of note,
the ester moiety was not disturbed, demonstrating both the
preferential cleavage of the amide C–N bond over the ester C–O
bond and the mildness of the reducing conditions. 35 The
tolerance of the methodology toward heterocycles was also
determined. Notably, tetrahydropyrans, pyrrolidines, and
piperidines, all of which are valuable in medicinal chemistry,36
could be employed as evidenced by the synthesis of alcohols
16–20, respectively.
dihydrocinnamic acid-derived amide 1 as shown in Figure 3.[19b]
In the absence of a reducing agent, the Suzuki–Miyaura
coupling with boronate
5 delivered ketone 3 in nearly
quantitative yield (entry 1).[22,23,,24] With the aim of developing the
reductive variant, we questioned whether the use of a secondary
alcohol reductant could effect the in situ transfer hydrogenation
of ketone 3 to deliver alcohol 4. In this regard, we attempted the
use of i-PrOH as solvent, reminiscent of common Meerwein–
Ponndorf–Verley (MPV) reduction conditions.[25 ,26] Unfortunately,
this change resulted in low yields of 4 (entries 2 and 3).[27] By
shifting to the use of i-PrOH as an additive while using toluene
as solvent, we obtained the desired product 4 in a slightly
improved yield of 32%, with 18% of ketone 3 remaining (entry 4).
Given
our
lab’s
recent
success
in
using
1-4-
(dimethylamino)phenyl)-1-ethanol (DMPE, 7) in base-catalyzed
MPV reductions,[28] we also tested this benzylic alcohol in our
system.[29] By simply replacing i-PrOH with 7, alcohol 4 was
obtained in 51% yield (entry 5). Finally, switching the solvent to
1,4-dioxane (entry 6) and using boronate 6 in place of boronate
5 (entry 7) led to further improvements, delivering alcohol 4 in
82% yield.[30,31,32]
It is worth noting that these optimized conditions satisfy a
challenging balance of reactivity required for the success of the
amide to alcohol conversion. Specifically, reducing agent 7 does
not significantly impede the nickel-catalyzed cross-coupling step,
yet is reactive enough to efficiently reduce ketone 3.
Furthermore, as will be shown, other carbonyl functional groups
are tolerated by the methodology’s mild reducing conditions.
With the aim of further improving the synthetic utility of the
reductive arylation, we performed a robustness screen to assess
the compatibility of the reaction with various functional groups
and heterocycles (Figure 4).[37] Results indicated the tolerance of
functional groups including tertiary alcohols, secondary anilines,
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10.1002/anie.202012048
Angewandte Chemie International Edition
COMMUNICATION
and secondary amides, as demonstrated by moderate to good
yields of alcohol 20 and appreciable recoveries of additives 22–
24, respectively. Additionally, heterocycles such as quinoline
(25), dibenzofuran (26), and N-methyl indole (27) were found to
be stable under our standard reductive arylation conditions with
the formation of alcohols 28–30 in synthetically useful yields. We
also evaluated aryl boronic ester nucleophiles bearing either a
trimethylsilyl or trifluoromethyl group, which furnished alcohols
31 and 32, respectively, in good yields. Additionally, a naphthyl
boronate ester underwent the reductive arylation to afford
alcohol 33 in 58% yield. We also tested several boronates that
possess functional groups that have been demonstrated to be
reactive to nickel catalysis. To our delight, an aryl ester,[35] an
ether,[40] and a dimethyl amine were tolerated,[41] thus giving rise
to alcohols 34–36, respectively. Furthermore, a boronic ester
containing a morpholinopyridine motif was employed to furnish
alcohol 37, showing the reaction’s tolerance of this heteroatom-
rich unit.[42]
38
]
minimal to no inhibition of reactivity.[
These results
complement those presented in the scope of the reaction and
further demonstrate the methodology’s robustness toward
several heteroatom-containing functional groups.
Ni(cod)2,
2
O
OH
(nep)B
7
Bn
+
N
(Het)
Alk
(Het)
Alk
K3PO4, H2O
1,4-dioxane, 120 ºC
Boc
6
Ni(cod)2,
2
OH
OH
7
OH
O
OH
7
Me
Me
Bn
+
(pin)B (Het)Ar
Me
N
(Het)Ar
(Het)
Alk
(Het)
Alk
K3PO4, H2O
1,4-dioxane, 120 ºC
Me
Boc
9
4
8
82% yielda
61% yieldb
76% yield
OH
OH
OH
OH
OH
OH
R
N
O
O
Boc
CF3
SiMe3
28 55% yield (R = o-Me)
29 59% yield (R = m-Me)
30 62% yield (R = p-Me)
n
32
53% yield
31
63% yield
11 76% yielda (n = 1)
12 74% yielda (n = 2)
10
66% yield
14
81% yielda
64% yielda (n = 3)
13
OH
OH
OH
OH
Oi-Pr
H
OH
OH
O
Ot-Bu
N
O
Boc
MeO
O
O
33
58% yield
34
61% yield
35
72% yield
O
O
15
16
17
70% yield
84% yield
73% yield (1:1 d.r.)
OH
OH
OH
OH
OH
NMe2
Boc
N
N
N
N
O
N
36
52% yielda
37
Boc
Boc
44% yielda
18
19
20
74% yield (1:1 d.r.)
75% yield (1:1 d.r.)
84% yield
Figure 5. Scope of the reductive arylation of aliphatic amides and
aryl boronates. Standard conditions unless otherwise noted: amide
substrate (0.20 mmol, 1.0 equiv); aryl boronate (0.80–1.2 mmol, 4.0–
6.0 equiv); 7 (0.50 mmol, 2.5 equiv); K3PO4 (0.80 mmol, 4.0 equiv);
H2O (0.40 mmol, 2.0 equiv); Ni(cod)2 (0.020–0.040 mmol, 10–20
mol%); 2 (0.040–0.080 mmol, 20–40 mol%); solvent (1.0 M); 120 °C;
16–24 h. Unless otherwise noted, yields reflect the average of two
isolation experiments. [a] Yield determined by 1H NMR analysis
using 1,3,5-trimethoxybenzene as an external standard.
Robustness Screen
O
OH
H
N
Substrate
O
NHMe
Ph
n-Bu
Bn
N
22
23
24
N
Boc
89% yielda
>99% recovery
of additive
83% yielda
>99% recovery
of additive
58% yielda
88% recovery
of additive
Boc
21
Me
N
O
N
The utility of this methodology was evaluated in the
synthesis of known intermediates toward two bioactive
compounds (Figure 6). In the first example (Figure 6a), amide 38
underwent reductive arylation with boronate 39, despite the
notable electron deficiency of this nucleophile. This delivered
alcohol 40, a precursor to a known γ-secretase modulator.[43] We
also targeted the interception of a known route to fluoxetine,[44]
the active ingredient in the blockbuster drug Prozac®. Toward
this end, amide 42, derived from the corresponding
commercially available carboxylic acid, was coupled with
boronate 6. This transformation furnished alcohol 43 in 69%
yield, providing facile access to a known intermediate in the
synthesis of 44 from commercially available materials.[44] These
results not only further demonstrate the viability of leveraging a
cross-coupling approach to add two disparate nucleophiles into
an amide carbonyl carbon, but also showcase the practical utility
25
88% yielda
98% recovery
of additive
26
27
78% yielda
80% recovery
of additive
68% yielda
94% recovery
of additive
Figure 4. Scope of the reductive arylation of aliphatic amides and
boronate 6. Standard conditions unless otherwise noted: amide
substrate (0.20 mmol, 1.0 equiv); phenyl boronate 6 (0.80 mmol, 4.0
equiv); 7 (0.50 mmol, 2.5 equiv); K3PO4 (0.80 mmol, 4.0 equiv); H2O
(0.40 mmol, 2.0 equiv); Ni(cod)2 (0.020 mmol, 10 mol%); 2 (0.040
mmol, 20 mol%); solvent (1.0 M); 120 °C; 16 h. Unless otherwise
noted, yields reflect the average of two isolation experiments. [a]
Yield determined by 1H NMR analysis using 1,3,5-
trimethoxybenzene as an external standard. [b] Reaction ran at
130 °C.
The scope of the aryl boronate component was also
examined by coupling pinacol boronates with various amides
(Figure 5).[31,39] Methyl substitution at the ortho, meta, or para
positions of the aryl boronate was tolerated, as demonstrated by
This article is protected by copyright. All rights reserved.

10.1002/anie.202012048
Angewandte Chemie International Edition
COMMUNICATION
instrumentation grants from the NSF (CHE-1048804) and the
National Center for Research Resources (S10RR025631).
of this reductive arylation protocol in the synthesis of complex
chiral molecules.
a.
(pin)B
CF3
O
Keywords: base metal catalysis • amides • Suzuki–Miyaura
coupling • transfer hydrogenation • cascade reaction
Me
Bn
N
+
N
O
Boc
N
CF3
39
O
[1] Larock, R. C. Comprehensive Organic Transformations: A Guide to
Functional Group Preparation; 2nd Ed. John Wiley & Sons: New York,
1997.
38
(4.0 equiv)
N
Ni(cod)2, 2
7
K3PO4, H2O
O
N
[2] For the classic Weinreb amide synthesis of ketones from amides via a
tetrahedral intermediate, see: S. Nahm, S. M. Weinreb, Tetrahedron Lett.
1981, 22, 3815–3818.
1,4-dioxane, 130 ºC
CF3
O
OH
[3] For a related synthetic method that allows for the addition of two
nucleophiles to substituted ureas, thus affording ketone products, see: S. T.
Heller, J. N. Newton, T. Fu, R. Sarpong, Angew. Chem., Int. Ed. 2015, 54,
9839–9843.
CF3
41
CF3
O
ɣ-Secretase Modulator
0.5 µM IC50 in amyloidic
Aβ42 peptide assay
40
40% yield
CF3
[4] For representative reviews and publications on the non-decarbonylative
transition metal-catalyzed cross-coupling of carboxylic acid derivatives,
see: (a) L. S. Liebeskind, J. Srogl, J. Am. Chem. Soc. 2000, 122, 45, 11260–
11261; (b) H.-G. Cheng, H. Chen, Y. Liu, Z. Qianghui, Asian J. Org.
Chem. 2008, 7, 490–508; (c) J. B. Johnson, T. Rovis, Acc. Chem. Res.
2008, 41, 327–338; (d) L. J. Gooßen, N. Rodriguez, K. Gooßen, Angew.
Chem. Int. Ed. 2008, 47, 3100–3120; Angew. Chem. 2008, 120, 3144–3164;
(e) G. Albano, L. A. Aronica, Catalysts 2020, 10, 25–61; (f) M. Blangetti,
H. Rosso, C. Prandi, A. Deagostino, P. Venturello, Molecules 2013, 18,
1188–1213; (g) V. Hirschbeck, P. H. Gehrtz, I. Fleischer, Chem. Eur. J.
2018, 24, 7092–7107; (h) Y. Ogiwara, N. Sakai, Angew. Chem. Int. Ed.
2020, 59, 574–594; Angew. Chem. 2020, 132, 584–605; (i) L. J. Gooßen, K.
Gooßen, N. Rodriguez, M. Blanchot, C. Linder, B. Zimmermann, Pure
Appl. Chem. 2008, 80, 1725–1733; (j) G. Meng, S. Shi, M. Szostak,
Synlett 2016, 27, 2530–2540; (k) C. Liu, M. Szostak, Chem. Eur. J. 2017,
23, 7157–7173; (l) J. E. Dander, N. K. Garg, ACS Catal. 2017, 7, 1413–
1423; (m) R. Takise, K. Muto, J. Yamaguchi, Chem. Soc. Rev. 2017, 46,
5864–5888; (n) G. Meng, M. Szostak, Eur. J. Org. Chem. 2018, 2352–
2365; (o) J. Buchspies, M. Szostak, Catalysts 2019, 9, 53–75.
b.
CF3
Boc
Me
N
O
Me
Cl
Bn
H2N
O
N
Ni(cod)2, 2
Boc
Boc
Me
42
7
N
OH
Ph
+
K3PO4, H2O
1,4-dioxane, 120 ºC
Prozacꊾ (44, fluoxetine)
Selective seratonin
(nep)B
Ph
43
69% yield
6
(6.0 equiv)
reuptake inhibitor
Figure 6. (a) Synthesis of alcohol 40, an intermediate in the
synthesis of γ-secretase modulator 41. (b) Synthesis of alcohol 43,
intercepting a known synthetic route toward Prozac® (44, fluoxetine).
See Supporting Information for details.
In summary, we have developed the first catalytic method
for the direct intermolecular addition of two distinct nucleophiles
to the amide carbonyl carbon. This transformation takes
advantage of non-precious metal catalysis and allows for the
facile conversion of amides to chiral alcohols via a cascade
[5] J. Hu, Y. Zhao, J. Liu, Y. Zhang, Z. Shi, Angew. Chem. Int. Ed. 2016,
55, 8718–8722; Angew. Chem. 2016, 128, 8860–8864.
[6] These cascade reactions could involve either one or two catalytic steps.
For discussion on the definitions of cascade and tandem processes, see: (a)
D. E. Fogg, E. N. dos Santos, Coord. Chem. Rev. 2004, 248, 2365–2379;
(b) Y. Hayashi, Chem. Sci. 2016, 7, 866–880.
reaction
involving
Suzuki–Miyaura
cross-coupling and
subsequent transfer hydrogenation. The methodology has a
broad scope with respect to both the amide and boronate cross-
coupling partners. Additionally, it shows tolerance toward
epimerizable stereocenters, select functional groups (i.e.,
alcohols, amines, esters, ethers, and secondary amides,) and a
range of heterocycles. Moreover, the methodology can be used
to access scaffolds of value to medicinal chemistry, as shown by
the syntheses of 40 and 43. This study validates the use of a
cross-coupling approach to construct sp3 carbon centers from
the amide carbonyl carbon in a single operational step. We hope
this study will prompt the development of additional processes
that allow for the direct conversion of carboxylic acid derivatives
to functional groups bearing stereogenic centers[45] via catalytic
cascade processes.
[7] For representative examples of one-pot, sequential protocols for the
reductive functionalization of amides, see: (a) A. Meyers, D. Comins,
Tetrahedron Lett. 1978, 19, 5179–5182; (b) Y. Oda, T. Sato, N. Chida,
Org. Lett. 2012, 14, 950–953; (c) X. Zheng, J. Liu, C.-X. Ye, A. Wang, A.-
E. Wang, P.-Q. Huang, J. Org. Chem. 2015, 80, 1034–1041; (d) J. E.
Dander, M. Giroud, S. Racine, E. R. Darzi, O. Alvizo, D. Entwistle, N. K.
Garg, Commun. Chem. 2019, 2, 82; (e) D. Y. Ong, D. Fan, D. J. Dixon, S.
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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 National Science Foundation GRFP
(DGE-1650604 to M.M.M. and DGE-1144087 for E.L.B.), the
Trueblood Family (N.K.G.), the Graduate Division of UCLA (J.
K.), and the University of California, Los Angeles, for financial
support. These studies were supported by shared
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neopentyl glycol. However, the superior commercial availability of
boronates derived from pinacol can sometimes be advantageous.
[32] Notably, the reductive arylation of amide 1 could be performed on the
benchtop by employing either (a) a paraffin wax capsule charged with the
precatalyst/ligand combination, Ni(cod)2/Benz-ICy•HCl, or (b) the air-
stable Ni(II) precatalyst [(TMEDA)Ni(o-tolyl)Cl]. See Supporting
Information for details.
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catalytic reductive alkylation and reductive allylation methods shown in
Figure 1b.
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reaction. See Supporting Information for details.
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[ 42 ] When boronates bearing para electron-donating groups were
employed, a significant amount of the ketone intermediate was observed.
For example, the coupling of amide 1 with p-NMe2Ph–B(pin) under our
standard reaction conditions gave the corresponding ketone and alcohol in
17% and 42% yields, respectively.
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[45] An exciting opportunity lies in catalytic asymmetric variants of our
strategy. In an encouraging preliminary result, we have found that the use
of a chiral NHC ligand allows for the synthesis of 4 in 36% yield and 20%
ee. See Supporting Information for details.
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Entry for the Table of Contents
COMMUNICATION
The first catalytic intermolecular addition of two disparate
nucleophiles to the amide carbonyl carbon in a single
operational step is reported. The method relies on nickel
catalysis and enables the conversion of amides to chiral
alcohols via a Suzuki–Miyaura cross-coupling / transfer
hydrogenation cascade process.
Timothy B. Boit,† Milauni M.
Mehta,† Dr. Junyong Kim, Dr.
Emma L. Baker, and Prof. Dr.
Neil K. Garg*
Page No. – Page No.
Reductive Arylation of Amides
via a Nickel-Catalyzed
Suzuki–Miyaura Coupling and
Transfer Hydrogenation
Cascade
O
HO
H
Ni-catalyzed
Suzuki–Miyaura coupling
Bn
N
(Het)
Alk
(Het)
Alk
Ar
& Transfer hydrogenation
Boc
Alkyl–Aryl Alcohols
Amides
Addition of 2 different nucleophiles
O
CF3
Me
O
N
Me
N
Cl
H2N
O
N
N
O
F3C
ɣ-Secretase
Modulator
Prozacꊾ(fluoxetine)
CF3
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