Transition-Metal-Free Reductive Functionalization of Tertiary Carboxamides and Lactams for α-Branched Amine Synthesis

Article abstract of DOI:10.1002/anie.202004272

A new method for the synthesis of α-branched amines by reductive functionalization of tertiary carboxamides and lactams is described. The process relies on the efficient and controlled reduction of tertiary amides by a sodium hydride/sodium iodide composite, in situ treatment of the resulting anionic hemiaminal with trimethylsilyl chloride and subsequent coupling with nucleophilic reagents including Grignard reagents and tetrabutylammonium cyanide. The new method exhibits broad functional-group compatibility, operates under transition-metal-free reaction conditions, and is suitable for various synthetic applications on both sub-millimole and on multigram scales.

Full text of DOI:10.1002/anie.202004272

A Journal of the Gesellschaft Deutscher Chemiker
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Chemie
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Accepted Article
Title: Transition-metal free reductive functionalization of tertiary
carboxamides and lactams for α-branched amine synthesis
Authors: Derek Yiren Ong, Dongyang Fan, Darren J. Dixon, and
Shunsuke Chiba
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202004272
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10.1002/anie.202004272
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COMMUNICATION
Transition-metal free reductive functionalization of tertiary
carboxamides and lactams for α-branched amine synthesis
Derek Yiren Ong,[a] Dongyang Fan,[a] Darren J. Dixon,*[b] and Shunsuke Chiba*[a]
[a]
D. Y. Ong, Dr. D. Fan, Prof. Dr. S. Chiba
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences
Nanyang Technological University
Singapore 637371 (Singapore)
E-mail: shunsuke@ntu.edu.sg
[b]
Prof. Dr. D. J. Dixon
Department of Chemistry, Chemistry Research Laboratory
University of Oxford
Mansfield Road, Oxford OX1 3TA, UK
E-mail: darren.dixon@chem.ox.ac.uk
Supporting information for this article is given via a link at the end of the document.((Please delete this text if not appropriate))
Abstract: A new protocol for the synthesis of α-branched amines by
reductive functionalization of tertiary carboxamides and lactams is
described. The process relies on the efficient and controlled
reduction of tertiary amides by sodium hydride-sodium iodide
composite, in situ treatment of the resulting anionic hemiaminal with
trimethylsilyl chloride and subsequent coupling with nucleophilic
reagents including Grignard reagents and tetrabutylammonium
this approach requires the use of strong organometallic bases
for the initial deprotonation.[2] Recently, the α-C-H
arylation/alkylation of amines by photoredox catalysis has
enabled the synthesis of such constructs under much milder
reaction conditions.[3]
Another promising approach to access α-branched amines is via
reductive functionalization of readily available and bench-stable
carboxamides.[4,5] In this context, several protocols have been
developed by taking advantage of electrophilic activation or
controlled hydride reduction (including transition-metal-catalyzed
hydrosilylation) as the initiation process to enable subsequent
selective functionalization whilst minimizing over-reduction. As
for the initiation by electrophilic activation of amides, triflic
anhydride (Tf2O)[6] and phosphoryl chloride (POCl3)[7] have been
cyanide.
The new protocol exhibits broad functional group
compatibility, operates under transition-metal free reaction
conditions, and is suitable for various synthetic applications on both
sub-millimole and on multi-gram scales.
α-Branched amines and their derivatives are found as key
structural and functional units in various pharmaceutical
compounds and natural products (Scheme 1). Accordingly,
significant efforts have been made over the years to develop
new and effective methods for their construction.
utilized.
For example, Huang has demonstrated that
electrophilic activation of carboxamides by Tf2O results in
formation of nitrilium ion intermediates, which could be
subsequently functionalized by the sequential addition of metal
hydride and Grignard reagents for the α-functionalization
(Scheme 2A).[6] Reductive activation by use of stoichiometric
hydride reagents could be implemented by reduction of N-alkoxy
amides[8] with DIBAL-H or the Schwartz’s reagent (Cp2ZrHCl) as
well as that of tertiary/secondary amides with Cp2ZrHCl.[9] The
corresponding metallated hemi-aminal intermediates were
treated with acids and carbon nucleophiles to deliver α-branched
Ph
Ph
N
O
N
N
Ph
N
O
Ph
Cinnarizine
Me
Vesicare
amines (Scheme 2B).
Metal-catalyzed hydrosilylation of
carboxamides with silane reagents has also been found useful
to initiate their reductive functionalization. In this context,
N
H
Cl
CO2Me
N
Nagashima’s
Ir-catalyzed
hydrosilylation
of
tertiary
S
carboxamides and lactams with 1,1,3,3-tetramethyldisiloxane
(TMDS)[10] has been developed and applied by Dixon[11]
Chida/Sato,[12] and Huang,[13] in which the O-silylated hemi-
aminal intermediates were utilized for subsequent α-carbon-
carbon bond forming processes with various nucleophiles
Sensipar
CF3
Plavix
Scheme 1. Selected α-branched amines currently used in the clinic
(Scheme 2C).
Recently, Adolfsson reported the use of
For the synthesis of acyclic α-branched amines, multicomponent
approaches such as Mannich, Petasis and Strecker reactions
are classical yet powerful protocols of choice.[1] Construction of
cyclic derivatives commonly relies on directed lithiation at the α-
carbon of cyclic amines having an unreactive Lewis basic
directing group on the nitrogen atom (such as tert-
butyloxycarbonyl) and subsequent reaction of the resulting
carbanion with reactive carbon electrophiles. Although effective,
molybdenum(VI) hexacarbonyl as a catalyst with TMDS to
perform the reductive Strecker reaction on tertiary carboxamides
(Scheme 2C).[14]
Recently, the Chiba group disclosed
a controlled hydride
reduction of tertiary carboxamides for the synthesis of
aldehydes using a combination of NaH and NaI in THF.[15] Key
to the success of this chemistry was the stability (prior to
aqueous work up) of the anionic hemi-aminal intermediates
1
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10.1002/anie.202004272
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COMMUNICATION
formed via single hydride transfer from the activated NaH to the
carboxamides.[16] Building on this discovery, we were keen to
leverage further synthetic value from these intermediates in
particular for the synthesis of α-branched amines. Accordingly,
we sought to identify a suitable reagent that could react with the
anionic hemi-aminal intermediate and facilitate its substitution
with carbon-centered nucleophiles. We hypothesized that
chlorosilane reagents could indeed possess the necessary
oxophilicity to both trap and activate the intermediates towards
downstream carbon-carbon bond formation and thus enable
their conversion to α-branched amines, and herein we wish to
describe our findings (Scheme 2D).
the intermediacy of the O-trimethylsilyl hemiaminal B was
implied.[17] Elimination of trimethylsiloxide, presumably assisted
by MgBr2 present in the Schlenk equilibrium, generates reactive
iminium ion C that is subsequently attacked by PhMgBr to
provide product 2a. Not only was this protocol simple to perform,
it was also found to be easily up-scaled to 30 mmol of substrate
and was applicable for the synthesis of N,N-diethylamine 2b as
well as pyrrolidine (2c), piperidine (2d), and morpholine (2e)
(Scheme 3B).
A. Optimized reaction conditions
O
NaH (3 equiv)
NaI (1 equiv)
TMSCl (2.5 equiv)
PhMgBr (2 equiv)
Ph
NMe2
NMe2
1a (0.5 mmol)[a]
NaH-NaI
previous work
Ar
THF
60 °C, 5 h
0 to 24 °C, 2 h
A. Electrophilic activation by Tf2O
2a 86% (76%)[b]
R-Li
CeCl3
Tf2O
2-F-Py
O
R
Ph
TfO–
Me
Me
PhMgBr
N
Ph
N
H
Ph
N
H
Me
then
NaBH4
TMSCl
PhMgBr
H
O–
Na+
NMe2
H
OSiMe3
NMe2
H
–OSiMe3
B. Reduction by stoichiometric hydride reagents
Ar
Ar
Ar
NMe2
SnBu3
Sc(OTf)3
[Al]
O
A
B
C
O
H
DIBAL-H
OMe
OMe
(Ar = 2-naphthyl)
OMe
R
N
N
R
N
R
B. Scope of substituents on the amide nitrogen[a]
Ph
Me
Me
Me
Ph
Ph
Ph
NEt2
2b 89%
SnBu3
CF3CO2H
[Zr]
O
Ar
N
Ar
N
O
Ar
N
Cp2ZrHCl
Ar
R’
O
R’
R’
R
N
R
N
R
N
H
R’
2c 85%
2d 86%
2e 83%
R”
R’
C. Catalytic hydrosilylation
Scheme 3. Reductive functionalization of 2-naphthamides
1
using
cat. IrCl(CO)(PPh3)2
or
phenylmagnesium bromide. [a] Unless otherwise stated, the reactions were
conducted using 0.5 mmol of 2-naphthamides. [b] The reaction was carried
out on 30 mmol scale (see the SI for details).
[Nu]
conditions
O
[Si]
Nu
O
H
cat. Mo(CO)6
R’
R’
R
N
R’
R
N
R
N
R”
R’’
Si O Si
R”
H
H
(TMDS)
We next investigated the scope of the reaction with respect to
the Grignard reagent using 2-naphthamide substrates (Scheme
4). The method was found to be compatible with use of both
electron-rich and electron-deficient aryl Grignard reagents as
well as sterically hindered 2,6-dimethylphenylmagnesium
bromide, providing the corresponding amines 3-5 in good yields
(Scheme 4A). Installation of heteroaryl moieties such as 2-
thienyl (for 6) and pyridyl motifs (for 7 and 8)[18] could be
implemented efficiently. Similarly, the protocol allowed the
introduction of vinyl and acetylenic moieties, providing allylamine
9 and propargylamine 10, respectively, in good yields. As for
alkyl Grignard reagents (Scheme 4B), our method was suitable
for installing methyl (for 11 and 12) as well as primary alkyl
groups including allyl and benzyl (for 13-15). More sterically
demanding secondary alkyl groups such as isopropyl and
cyclopropyl (for 16 and 17) could be introduced efficiently, and,
impressively, use of 1-adamantylmagnesium bromide resulted in
formation of the corresponding amine 18 albeit in slightly
reduced yield (38%). Notably, the method was also compatible
with the use of phenyldimethylsilyllithium in the presence of
MgBr2, affording α-silylamine 19 in good yield.
this work
D. NaH-NaI composite-based reductive functionalization
R’
or
Na+
O
R
NMe2
O
H
TMSCl
NaH-NaI
R
NMe2
R’-MgBr
or Bu4NCN
R
NMe2
CN
NMe2
R
transition-metal free reductive functionalization
applicable to tertiary carboxamides and lactams
readily up-scaled (0.5 - 30 mmol)
Scheme 2. Synthesis of α-branched amines by reductive functionalization of
carboxamides.
We targeted the reductive functionalization of N,N-dimethyl-2-
naphthamide (1a) with phenylmagnesium bromide as the model
reaction (Scheme 3A). A brief survey of various reaction
parameters allowed us to identify trimethylsilylchloride (TMSCl)
as the preferred silylating reagent, as well as efficient and
general reaction conditions. These comprised treatment of 1a
(0.5 mmol) with NaH (3 equiv) and NaI (1 equiv) in THF at 60 °C
to form the anionic hemi-aminal A, followed by sequential
addition of TMSCl (2.5 equiv) and phenylmagnesium bromide (2
equiv) at 0 °C and further stirring of the reaction mixture for 2 h
at 25 °C before work up afforded the α-branched amine 2a in
86% yield. As 2a was not formed if the TMSCl was not added,
2
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10.1002/anie.202004272
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COMMUNICATION
NaH (3 equiv)
NaI (1 equiv)
NaH (3 equiv)
NaI (1 equiv)
TMSCl (2.5 equiv)
PhMgBr (2 equiv)
TMSCl (2.5 equiv)
R’–MgX (2 equiv)
O
Ph
O
R’
R
NR’2
R
NR’2
Ar
NR2
Ar
NR2
THF
40-60 °C
THF
60 °C, 5 h
0 to 24 °C, 2 h
0 to 24 °C, 2 h
(X = Br or Cl)
(0.5 mmol)[a]
(0.5 mmol)[a]
(Ar = 2-naphthyl)
A. Aryl/alkenyl amides
A. Aryl/alkenyl/alkynyl Grignard reagents
OMe
Ph
Ph
Me Ph
NMe2
CF3
NMe2
NMe2
S
Ph
MeO
20 62%
OMe Ph
21 71%
22 65%
Ar
Ar
NMe2
5 67%
Ar
NMe2
Ar
NMe2
Ar
NMe2
4 63%
Ph
Ph
3 60%
6 74%
O
O
N
NMe2
NMe2
Br
N
R
N
25 (R = CF3): 83%
26 (R = Br): 49%
23 76%
24 75%
NMe2
9 80%
Ar
NMe2
Ar
NMe2
7 67%
Ar
NMe2
8 64%
Ph
Ph
10 79%
Ph
NMe2
B. Alkyl Grignard reagents
NMe2
Fe
NMe2
N
N
Me
Me
Ph
Ph
Me
Bn
28 77%
Ph
Ar
N
Ar
N
27 66%
29 84%
Ar
NMe2
11 81%
Ar
NMe2
14 74%
Ar
NMe2
Ph
12 84%
13 80%
15 85%
Ph
Ph
NMe2
NMe2
S
N
Ph
NMe2
SiMe2Ph
Ar NMe2
Ar
N
Ar
NMe2
17 84%
Ar
NMe2
32 48%
30 59%
31 89%
16 83%
18 38%
19 64%
B. Aliphatic amides
Ph
NMe2
Me
Scheme 4. Scope with respect to the Grignard reagents. [a] The reactions
were conducted using 0.5 mmol of carboxamides.
Ph
NMe2
Ph
Me
O
3
NMe2
33 66%
34 85%
Ph
35 64%
We also examined the compatibility of various carboxamides in
the present protocol, using phenylmagnesium bromide as the
coupling reagent (Scheme 5). As for aromatic amides, the
process was not detrimentally influenced by the presence of
biaryl and sterically demanding 2-tolyl groups (for 20 and 21)
and tolerated substituents with differing electronic properties
such as electron-donating groups (for 22-24) and electron-
withdrawing groups including a bromine atom (for 25 and 26)
(Scheme 5A). Amides based on electron-rich 5-membered
(hetero)aromatic rings such as ferrocene 27, pyrrole 28, indole
29, and benzothiophene 30 as well as electron-deficient 6-
membered ring quinoline 31 were also compatible. Reductive
phenylation of α,β-unsaturated amide gave α-branched
allylamine 32 in 48% yield. We then surveyed a range of
aliphatic amides for the reductive functionalization (Scheme 5B).
Sterically congested α-quaternary amides could be smoothly
converted to the corresponding amines 33 and 34 in good yields.
The reactions of carboxamides having enolizable α-protons
proceeded well to afford the corresponding amines 35-39 in
good yields, however, for 40 derived from a linear primary alkyl
carboxamide the yield was slightly diminished (48%). It is
worthy of note that synthesis of amines 38 and 39 by the
functionalization of N,N-diethyl-2-(1-naphthyloxy)propanamide
(known as napropamide used as a herbicide)[19] and (1R*,2R*)-
N,N-dimethyl-2-phenylcyclopropane-1-carboxamide,
Ph
Ph
O
NMe2
N
NMe2
BnN
O
38 81 %
(d.r. = 4.6:1)
36 85%
37 91%
Ph
H
Ph
NMe2
NMe2
Ph
Ph
H
40 48%
39 71%
(d.r. = 4.9:1)
Scheme 5. Scope with respect to the carboxamides. [a] The reactions were
conducted using 0.5 mmol of carboxamides (see the SI for details).
Significantly, the present protocol was amenable to transform
lactams to C2-functionalized saturated nitrogen-containing
heterocycles, which are mainstream in small molecule libraries
for drug discovery programs (Scheme 6).[20] Treatment of N-
benzyl-2-piperidinone with NaH-NaI followed by TMSCl and
Grignard reagents allowed for installation of (hetero)aryl (for 41-
45), vinyl (for 46), alkynyl (for 47), and alkyl (for 48-51) motifs
onto the piperidine core in good yields. Again, the scalable
nature of this protocol was confirmed by demonstrating
synthesis of 41 on 30 mmol scale. Synthesis of functionalized
pyrrolidines 52 and 53 as well as tetrahydroisoquinoline and
azepane derivatives 54 and 55 could also be readily achieved
using our method.
respectively,
proceeded
with
moderate
to
good
diastereoselectivity.
3
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10.1002/anie.202004272
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COMMUNICATION
NaH (3 equiv)
NaI (1 equiv)
TMSCl (3.5 equiv)
Bu4NCN (2 equiv)
NaH (3 equiv)
NaI (1 equiv)
TMSCl (2.5 equiv)
R–MgX (2 equiv)
O
CN
NR’2
n
n
R
NR’2
R
THF
40-60 °C
24 °C, 4 h
THF
40 °C
0 to 24 °C, 2 h
(X = Br or Cl)
(0.5 mmol)[a]
N
R
N
O
Bn
Bn
(0.5 mmol)[a]
CN
CN
CN
NMe2
NMe2
NMe2
41 (Ar = Ph): 78% (77%)[b]
42 (Ar = 4-MeOC6H4): 74%
43 (Ar = 4-CF3C6H4): 81%
Ph
MeO
S
N
N
N
N
Ar
Bn
Bn
56 86%
57 82%
58 77%
Bn
OMe CN
CN
CN
NMe2
44 82%
45 72%
MeO
BnO
NMe2
NMe2
F3C
N
N
N
N
Me
N
Ph
Bn
Bn
Bn
Bn
Bn
59 69%
CN
NMe2
60 71%
61 57%
46 68%
47 78%
48 54%
49 91%
50 83%
CN
CN
NMe2
NMe2
Fe
Ph
N
N
Ph
N
N
N
N
Me
Ph
Bn
Bn
Bn
Bn
Bn
55 87%
N
Ph
Bn
54 88%
62 49%
CN
NMe2
63 76%
64 51%
51 62%
52 67%
53 76%
CN
Me
Ph
CN
NMe2
Scheme 6. Reductive functionalization of lactams. [a] Unless otherwise stated,
the reactions were conducted using 0.5 mmol of lactam substrates (see the SI
for details). [b] The reaction was carried out on 30 mmol scale.
NMe2
N
Me
O
3
65 60%
66 72%
67 71%
Finally, as an extension of the protocol to generate α-amino
nitriles, we sought to explore the reductive Strecker reaction of
carboxamides under the transition-metal free protocol (Scheme
7). Following preliminary scouting studies, we identified that use
of tetrabutylammonium cyanide in place of Grignard reagents
enabled the synthesis of structurally varied α-aminonitriles 56-70
from both tertiary carboxamides and lactams in yields ranging
from 48-91%.
CN
NMe2
N
CN
O
Bn
N
CN
Bn
68 48%
69 64%
70 91%
Scheme 7. Reductive Strecker reactions. [a] The reactions were conducted
using 0.5 mmol of carboxamides (see the SI for details).
The key enabling advance in the present method takes
advantage of the unique hydridic reactivity of NaH in the
presence of NaI for controlled reduction of tertiary carboxamides
including lactams. Subsequent treatment of the resulting anionic
hemi-aminal intermediates with TMSCl and Grignard reagents or
tetrabutylammonium cyanide allows for deoxygenative
installation of the carbon functionality to afford α-branched
amines. Thus, the present protocol operates under transition-
metal free reaction conditions, circumventing the requirement for
stoichiometric use of expensive metal hydride reagents or
transition-metal catalysts. Efforts are currently underway to
extend the new protocol to new reactions and to explore its
applicability to the synthesis of more complex molecules.
Acknowledgements
This work was supported by funding from Nanyang
Technological University (NTU) (for S.C.), the Singapore
Ministry of Education (Academic Research Fund Tier 2:
MOE2017-T2-1-064 for S.C.).
Keywords: amines • amides • lactams • sodium hydride •
Grignard reagents
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NMR and proton-coupled 13C NMR analyses of the intermediate
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10.1002/anie.202004272
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
A practical, scaleable, and transition-metal free protocol for the synthesis of α-branched amines from tertiary carboxamides and
lactams with carbon-centered nucleophiles has been developed. The process relies on the controlled reduction of tertiary amides by
sodium hydride-sodium iodide composite, in situ treatment of the resulting anionic hemiaminal with trimethylsilyl chloride and
subsequent coupling with nucleophilic reagents including Grignard reagents and tetrabutylammonium cyanide.
6
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