Amides Activation: Transition Metal-Free Coupling Between C-N Activated Amides and Enolizable Amides

Article abstract of DOI:10.1002/bkcs.12371

Transition metal-free Claisen-type condensation between two different amides was developed. N-phenyl-N-tosylbenzamide derivatives reacted with enolizable amides such as N-methyl pyrrolidinone and N,N-dimethyl acetamide in the presence of NaHMDS to give th

Full text of DOI:10.1002/bkcs.12371

Communication
DOI: 10.1002/bkcs.12371
BULLETIN OF THE
D. Joseph et al.
KOREAN CHEMICAL SOCIETY
Amides Activation: Transition Metal-Free Coupling Between C N
Activated Amides and Enolizable Amides
*
Devaneyan Joseph, Min Seok Oh, Aravindan Jayaraman, and Sunwoo Lee
Department of Chemistry, Chonnam National University, Gwangju 61186, Republic of Korea.
*E-mail: sunwoo@chonnam.ac.kr
Received June 23, 2021, Accepted July 13, 2021
Transition metal-free Claisen-type condensation between two different amides was developed. N-phenyl-N-
tosylbenzamide derivatives reacted with enolizable amides such as N-methyl pyrrolidinone and N,N-dimethyl
acetamide in the presence of NaHMDS to give their corresponding β-ketoamides with moderate-to-good
yields.
Keywords: Amide, Metal-free, Coupling, Condensation, β-Ketoamide
Claisen condensation, which is known as the condensation
reaction between two esters, is one of the most useful tools
for the construction of carbon–carbon bond formations and
has been widely used for the synthesis of the beta keto
ester.1 As an analog reaction type, the condensation of the
ester and amide for the synthesis of β-ketoamide has also
been employed in organic synthesis (Scheme 1(a)).2 Com-
pared to these two ester reaction types, the condensation
between two amides has rarely been studied because the
C N bond of amide is known to be strong for the substitu-
tion reaction.
However, a variety of transformations using the C N
bond activation of an amide has been developed in the
recent 10 years by several groups. The C N bond of
amides was activated by transition metal catalysts and
substituted by nucleophiles such as amine,3 alcohol,4
and carbon moieties5 to give the corresponding amide,
ester, and ketone.
These reaction types were also developed under metal
catalyst-free conditions. Szostak group reported that
transition-metal-catalyst-free transamidation proceeded to
Table 1. Optimization of coupling reaction of 1a and 2aa.
entry
Base
Solvent
Yield (%)b
1
2
3
4
5
6
7
8
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
NaHMDS
KHMDS
LiOt-Bu
DMF
35
32
51
38
59
70
80
33
0
DMSO
Toluene
THF
1,4-Dioxane
Et2O
Et2O
Et2O
Et2O
9
10
11
12
NaOt-Bu
KOt-Bu
NaHMDS
Et2O
Et2O
THF
0
0
55
Scheme 1. Coupling reactions with amide. (a) Claisen condensa-
tion between ester and amide. (b) Ni-catalyzed amide and amide
coupling. (c) Metal-free amide and ketone (or ester) coupling.
(d) This work: Metal-free amide and amide coupling.
a Reaction conditions: 1a (0.3 mmol), 2a (1.5 mmol), and base
(0.75 mmol) were reacted at 25 ꢀC for 12 h.
b Isolated yield.
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Scheme 3. Condensation reaction between 1 and 2b (reaction con-
ditions: 1 [1.0 mmol], 2b [5.0 mmol], and NaHMDS [2.5 mmol]
were reacted in Et2O [5.0 mL] at 25 ꢀC for 12 h).
To find the optimal conditions, N-phenyl-N-tosyl-
benzamide and N-methyl pyrrolidinone were chosen as stan-
dard substrates and reacted under various reaction conditions.
The results are summarized in Table 1. First, a variety of sol-
vents was evaluated with LiHMDS. The reactions in polar
aprotic solvents such as DMF (N,N-Dimethylformamide) and
DMSO (Dimethysulfoxide) afforded 3a in low yields (entries
1 and 2). Toluene, THF, and 1,2-dioxane solvents provided
the desired product in 51%, 38%, and 59% yields, respec-
tively (entries 3–5). Utilizing Et2O as a solvent gave 3a in a
70% yield (entry 6). Next, various strong bases were
employed in Et2O solvent conditions. NaHMDS and
KHMDS provided 3a in 80% and 33% yields, respectively
(entries 7 and 8). However, alkoxide bases such as LiOt-Bu,
NaOt-Bu, and KOt-Bu did not provide the desired products
(entries 9–11). When the reaction was conducted with
NaHMDS in THF, 3a was formed in 55% yield (entry 12).
Based on these results, the optimized conditions were N-phe-
nyl-N-tosylbenzamide (1.0 equiv), N-methyl pyrrolidinone
(3 equiv), and NaHMDS (1.5 equiv) reacted in Et2O at room
temperature for 12 h.
With these optimized conditions, first, various N-phenyl-
N-tosylbenzamide derivatives were employed for reacting
with N-methyl pyrrolidinone (Scheme 1). Benzamides with
alkyl substituents such as methyl and tert-butyl afforded
their corresponding β-ketoamides 3b and 3c in good yields.
Benzamides having a methoxy group gave the desired cou-
pling products 3d, 3e, and 3f in moderate-to-good yields.
N,N-dimethylamino-substituted benzamides gave 3g and 3h
in 54% and 25% yields, respectively. Benzamides having a
fluoride group at the para- and meta-positions gave 3i and
3j in 52% and 26% yields, respectively. 2- and 3-Furamide
derivatives gave the desired products in moderate yields.
Scheme 2. Condensation reaction between 1 and 2a (reaction con-
ditions: 1 [1.0 mmol], 2a [5.0 mmol], and NaHMDS [2.5 mmol]
were reacted in Et2O [5.0 mL] at 25 ꢀC for 12 h).
give the desired amides in good yields when LiHMDS was
employed as the base.6
In 2020, we reported nickel-catalyzed Claisen-type con-
densation between two different amides and showed the
formation of the corresponding β-ketoamides (Scheme 1
(b)).7 However, this methodology required several chemical
additives and needed a higher reaction temperature. Very
recently, we found that activated amide coupled with the
alpha carbon of carbonyl compounds such as ketones and
esters in the presence of LiHMDS under transition metal-
free conditions produced 1,3-diketone and β-ketoester,
respectively (Scheme 1(c)).8 These results stimulated us to
develop metal-free conditions for the condensation reaction
of two different amides. Herein, we report the metal-free
condensation of two different amides for the synthesis of
β-ketoamides (Scheme 1(d)).
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Supporting Information. Additional supporting informa-
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