Iridium-Catalyzed Reductive Nucleophilic Addition to Secondary Amides

Article abstract of DOI:10.1021/acs.orglett.8b02421

An iridium-catalyzed reductive nucleophilic addition to secondary amides is reported. After the iridium-catalyzed reduction, the resulting imines can undergo the Strecker reaction, the Mannich reaction, allylation, and [3 + 2]-cycloaddition. The method sh

Full text of DOI:10.1021/acs.orglett.8b02421

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Iridium-Catalyzed Reductive Nucleophilic Addition to Secondary
Amides
Yoshito Takahashi, Risa Yoshii, Takaaki Sato,* and Noritaka Chida*
Department of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1, Hiyoshi, Kohoku-ku, Yokohama
223-8522, Japan
S
* Supporting Information
ABSTRACT: An iridium-catalyzed reductive nucleophilic addi-
tion to secondary amides is reported. After the iridium-catalyzed
reduction, the resulting imines can undergo the Strecker reaction,
the Mannich reaction, allylation, and [3 + 2]-cycloaddition. The
method shows high chemoselectivity in the presence of other
functional groups such as methyl ester.
Scheme 1. Nucleophilic Addition to Secondary Amides
ucleophilic addition to amides is a promising synthetic
Ntool to prepare biologically active alkaloids and
pharmaceuticals because multisubstituted amines can be
prepared from easily available amides in a one-step process.1
However, this reaction has been overlooked for a long time
due to the poor electrophilicity of the amide carbonyl. To
overcome this problem, a number of synthetic chemists have
been exploring their original nucleophilic additions, and
significant progress has been made in this field over the past
ten years.2−5 A current hot topic is the development of a late-
stage nucleophilic addition6 and enables amides to serve as
stable surrogates of multisubstituted amines toward concise
syntheses of complex alkaloids and pharmaceuti-
cals.1j,2e,3e−g,k,l,p However, most successful examples focus on
nucleophilic addition to N-methoxyamides2 and tertiary
amides.3 The case of secondary amides still remains an
unsolved issue despite their large abundance (Scheme 1A).4 In
this communication, we report an iridium-catalyzed reductive
nucleophilic addition to secondary amides with a wide
substrate scope in the presence of a variety of functional
groups.
The general scheme of nucleophilic addition to secondary
amide 1 is depicted in Scheme 1A. The reaction starts with
deprotonation of amide 1, followed by addition of the first
organometallic reagent R1 M to metalated amide 2. The
resulting N,O-acetal 3 is then transformed to imine 4, which
undergoes the second nucleophilic addition with R2 M to
provide secondary amine 5. The nucleophilic addition to
secondary amides is more challenging than that to tertiary
amides due to the poor electrophilicities of both metalated
amide 2 and imine 4. Huang and co-workers achieved the
nucleophilic addition to secondary amides via an in situ
activation method with Tf2O.4c,f,h,j−l The groups of Ganem,4a
Sato/Chida,3d,h and Stecko/Furman4e reported reductive
nucleophilic addition with the Schwartz reagent [Cp2ZrHCl].7
Recently, Tokuyama and co-workers accomplished the total
synthesis of histrionicotoxin, whose key step was the reductive
allylation of a secondary lactam by the modified Buchwald
reduction [(Ti(Oi-Pr)4 and Et2SiH2].4i Unfortunately, most
successful examples of nucleophilic addition to secondary
amides have relied on the use of equimolar amounts of
reducing agents.8 To solve this problem, we planned to use
iridium-catalyzed dehydrosilylation and hydrosilylation
(Scheme 1B). First, secondary amide 1 would be converted
to N-silylamide 2a through dehydrosilylation. The resulting
neutral intermediate 2a would undergo hydrosilylation of the
Received: July 30, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02421
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Optimization of Transition-Metal-Catalyzed
Reduction
Table 2. Combination of Two Iridium Catalysts for
Reductive Nucleophilic Addition to the γ-Lactam
a
a
b
yields (%)
entry
1
reduction conditions
6a
1a
reduction conditions
b
Cp2ZrHCl (2.4 equiv), CH2Cl2
−40 °C to rt
76
0
[Ir]-1 (1 mol %), [Si−H]-1
[Ir]-2 (1 mol %), [Si−H]-2
yields (%)
entry
1
6j
1j
2
3
IrCl(CO)(PPh3)2 (1 mol %)
(Me2SiH)2O (2 equiv), toluene, rt
[Ir(COE)2Cl]2 (0.5 mol %)
Et2SiH2 (2 equiv), toluene, rt
[Ir(COE)2Cl]2 (0.5 mol %)
Et2SiH2 (2 equiv), toluene, rt
[Ir(COD)OMe]2 (0.5 mol %)
Et2SiH2 (2 equiv), toluene, rt
23
84
80
82
72
0
[Ir(COE)2Cl]2, Et2SiH2 (2 equiv)
none
IrCl(CO)(PPh3)2, (Me2SiH)2O (2 equiv)
none
IrCl(CO)(PPh3)2, (Me2SiH)2O (1 equiv)
[Ir(COE)2Cl]2, Et2SiH2 (1 equiv)
[Ir(COE)2Cl]2, Et2SiH2 (1 equiv)
IrCl(CO)(PPh3)2, (Me2SiH)2O (1 equiv)
0
100
c
2
3
4
56
78
0
0
0
c
4
0
d
5
0
100
a
Conditions: secondary amide 1a (200 μmol), reductant, solvent (0.2
a
Conditions: lactam 1j, [Ir]-1 (1 mol %), [Si−H]-1, toluene (0.2 M),
M); then TMSCN (2 equiv), Yb(OTf)3 (10 mol %), MeCN (0.2 M),
b
rt, 15 min; [Ir]-2 (1 mol %), [Si−H]-2, rt, 30 min; then TMSCN (2
rt. Yield of isolated product after purification by column
b
c
equiv), Y(OTf)3 (10 mol %), rt, 1 h. Yield of isolated product after
chromatography on silica gel. The reaction was performed with 1a
(1 mmol).
c
purification by column chromatography on silica gel. 6jα:6jβ = 1.6:1.
d
6jα:6jβ = 1.6:1.
Scheme 2. Reductive Strecker Reaction of Secondary
Amides
a,b
Scheme 3. Reductive Nucleophilic Addition to Secondary
Amides
a
Conditions: secondary amide 1, [Ir(COE)2CI]2 (0.5 mol %),
Et2SiH2 (2 equiv), toluene (0.2 M), rt, 15 min; then TMSCN (2
b
equiv), Yb(OTf)3 (10 mol %), MeCN (0.2 M), rt, 1 h. Yield of
metallic reagent R2 M′ to imine 4a would provide substituted
secondary amine 5a.
isolated product after purification by column chromatography on
c
d
silica gel. THF (0.2 M) was used instead of toluene. Y(OTf)3 (10
mol %) was used instead of Yb(OTf)3 (10 mol %) without MeCN.
To test our hypothesis, we investigated the iridium-catalyzed
reductive Strecker reaction of N-benzylbenzamide 1a (Table
1). After the reduction of amide 1a, the resulting imine was
treated with TMSCN in the presence of Yb(OTf)3 (10 mol
%).9 As a control experiment, the reduction using the Schwartz
reagent [Cp2ZrHCl] was conducted to afford aminonitrile 6a
in 76% yield (Table 1, entry 1). The group of Dixon reported
e
[Ir(COE)2CI]2 (0.1 mol %) was used for reduction, and Yb(OTf)3
(20 mol %) without MeCN at −20 °C was used for nucleophilic
addition.
amide carbonyl and subsequent elimination to generate the
transient imine 4a. Finally, addition of the second organo-
B
DOI: 10.1021/acs.orglett.8b02421
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Organic Letters
Letter
seminal contributions to the iridium-catalyzed reductive
Strecker reaction to tertiary amides3m using Nagashima’s
conditions [IrCl(CO)(PPh3)2 (1 mol %) and (Me2SiH)2O].10
However, reduction of secondary amide 1a with IrCl(CO)-
(PPh3)2 (1 mol %) and (Me2SiH)2O gave aminonitrile 6a in
23% yield, along with the recovery of 1a in 72% yield (Table 1,
entry 2). The best results were obtained when employing the
Brookhart reduction with [Ir(COE)2Cl)]2 (0.5 mol %) and
the iridium-catalyzed reduction of 1a, addition of the silyl
ketene acetal in the presence of Yb(OTf)3 provided secondary
amine 7 in 65% yield (Scheme 3A). The reductive allylation
was possible with allylstannane in the presence of SnCl2,3d,h
giving 8 in 80% yield (Scheme 3B). The conspicuous
application of our method was demonstrated through [3 +
2]-cycloaddition of an azomethine ylide (Scheme 3C).13,14
The amide-selective reduction of 1k generated the imine in the
presence of the methyl ester, which was crucial for subsequent
formation of azomethine ylide 9. [3 + 2]-Cycloaddition then
took place with dimethyl fumarate, giving pyrrolidines 10 in
73% combined yield in a one-pot process (α:β = 1.3:1).
In conclusion, we developed an iridium-catalyzed reductive
nucleophilic addition to secondary amides. The reaction
showed high amide selectivity in the presence of a variety of
functional groups such as a methyl ester. The developed
conditions were applicable to the reductive Strecker reaction,
the Mannich reaction, allylation, and [3 + 2]-cycloaddition of
the azomethine ylide. We believe that the developed method
will facilitate the concise synthesis of complex alkaloids and
pharmaceuticals.
11
Et2SiH2 to afford 6a in 84% yield (Table 1, entry 3). The
conditions were scalable on a 1 mmol scale to give aminonitrile
6a in 80% yield (Table 1, entry 4). We also found that the use
of [Ir(COD)OMe]2 (0.5 mol %) and Et2SiH2, which were
developed for arene C−H functionalization by Hartwig,12
yielded results comparable to Brookhart’s conditions (Table 1,
entry 5, 6a: 82%). Both iridium-catalyzed reductions exhibited
promising results, but further investigation was conducted with
[Ir(COE)2Cl2] (0.5 mol %) due to its ease of handling.
The scope of the iridium-catalyzed reductive Strecker
reaction demonstrated good functional group tolerance
(Scheme 2). The reaction of secondary amide 1b took place
without affecting the more electrophilic methyl ester (6b:
95%). Substituents with either an electron-rich or electron-
deficient group on the carbonyl side did not disturb the
reaction (6c: 85%; 6d: 87%). Hydrosilylation of a double bond
did not compete with reduction of the amide carbonyls (6e:
87%). An aromatic bromide was well tolerated under the
developed conditions (6f: 86%). A carbamate is one of the
most challenging functional groups to differentiate from
amides due to its similar electrophilicity, but the reaction
took place with high chemoselectivity (6g: 70%). One of the
limitations in this method was inhibition of the reduction by
Lewis basic functional groups such as a nitrile group (6h: 0%).
The reaction of aliphatic secondary amides took place at a
lower catalyst loading (0.1 mol %), giving 6i in 84% yield.
We next turned our attention to the reductive Strecker
reaction of five-membered lactam 1j (Table 2). To our
surprise, the iridium-catalyzed reduction of 1j did not take
place with [Ir(COE)2Cl]2 (0.5 mol %) and Et2SiH2 (2 equiv),
resulting in the recovery of lactam 1j (Table 2, entry 1).
However, use of Nagashima conditions [IrCl(CO)(PPh3)2 (1
mol %) and (Me2SiH)2O] provided pyrrolidines 6j in 56%
combined yields (Table 2, entry 2). We then investigated the
use of a combination of two iridium catalysts on the
assumption that the best catalytic system might be different
in the dehydrosilylation of lactam 1j and hydrosilylation of the
resulting silylated lactam. Gratifyingly, treatment of 1j with
IrCl(CO)(PPh3)2 (1 mol %) and (Me2SiH)2O (1 equiv),
followed by addition of [Ir(COE)2Cl]2 (0.5 mol %) and
Et2SiH2 (1 equiv), smoothly promoted the reduction of the
lactam (Table 2, Entry 3). The resulting cyclic imine
underwent the Strecker reaction to afford pyrrolidines 6j in
78% combined yield (α:β = 1.6:1). As a control experiment,
addition of [Ir(COE)2Cl]2 and Et2SiH2 (1 equiv), followed by
IrCl(CO)(PPh3)2 and (Me2SiH)2O (1 equiv), did not induce
the reduction of the lactam carbonyl. Thus, although we did
not observe any direct evidence, we revealed that the
dehydrosilylation might require the use of IrCl(CO)(PPh3)2
and (Me2SiH)2O, and the subsequent hydrosilylation would
prefer [Ir(COE)2Cl]2 (0.5 mol %) and Et2SiH2 in the case of
the γ-lactam.
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.8b02421.
Experimental details and compound characterization
(PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: takaakis@applc.keio.ac.jp.
*E-mail: chida@applc.keio.ac.jp.
ORCID
Takaaki Sato: 0000-0001-5769-3408
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by a Grant-in-Aid for Scientific
Research (C) from MEXT (18K05127) and the Tobe Maki
Foundation.
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