KOtBu-Promoted Transition-Metal-Free Transamidation of Primary and Tertiary Amides with Amines

Article abstract of DOI:10.1021/acs.orglett.9b02306

This work discloses transamidation of primary and tertiary amides with a range of aryl, heteroaryl, and aliphatic amines using potassium tert-butoxide. The reaction proceeds at room temperature under transition-metal-free conditions providing secondary amides in high yields. Moreover, reaction of cyclopropyl amine with tertiary amides proceeds with ring-opening to provide a rapid access to enamides.

Full text of DOI:10.1021/acs.orglett.9b02306

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
KOtBu-Promoted Transition-Metal-Free Transamidation of Primary
and Tertiary Amides with Amines
Tridev Ghosh, Snehasish Jana, and Jyotirmayee Dash*
School of Chemical Sciences, Indian Association for the Cultivation of Science, 2A and 2B Raja S. C. Mullick Road, Jadavpur,
Kolkata-700032, India
S
* Supporting Information
ABSTRACT: This work discloses transamidation of primary and tertiary amides with a range of aryl, heteroaryl, and aliphatic
amines using potassium tert-butoxide. The reaction proceeds at room temperature under transition-metal-free conditions
providing secondary amides in high yields. Moreover, reaction of cyclopropyl amine with tertiary amides proceeds with ring-
opening to provide a rapid access to enamides.
mide groups are ubiquitously found in many drugs
(Figure 1), fine chemicals, and synthetic and biological
catalysts work mostly in organic solvents and only limited
examples of transamidation are reported under solvent-free
conditions. Therefore, development of an operationally simple,
straightforward, and high-yielding transition-metal-free green
and sustainable synthetic method for transamidation has
remained a challenging task over the past two decades.
A
In view of the above perceptions, organocatalyzed trans-
amidations have been described as alternative green method-
ologies (Scheme 1). In this context, L-proline14 was envisioned
as a useful alternative. Subsequently, various groups reported
Scheme 1. Synthetic Approaches for Transamidation
Figure 1. Amide frameworks in bioactive substances.
polymers.1 Amides also serve as potential synthetic precursors
for the preparation of natural products,2 pharmaceuticals,3
pesticides,4 and polymers.5 Amides are conventionally
prepared by cross-coupling of aromatic or aliphatic amines
with activated carboxylic acids.6 Subsequently, nontraditional
methods to synthesize amide bonds have been developed.
Most of these processes require a stoichiometric amount of the
reagents, high temperature to avoid unreactive carboxylate-
ammonium salts formation, and, moreover, substrate engineer-
ing of C(acyl)−O or C(acyl)−N bonds.
In the past few years, the transamidation has emerged as a
convenient, economical, and straightforward alternative for the
amide bond formation.7 Transamidation has been reported
using metal catalysts8 such as AlCl3, Sc(OTf)3, Ti(NMe2)4,9
polymer-bound HfCl4,10 etc. Lanthanide catalysts (Ce,11 Zr,12
Nb13) have also been reported to promote transamidation.
Metal-catalyzed reactions are cost-ineffective, and they produce
toxic metal wastes that should be avoided for pharmaceutical
processes as well as for environmental safety. In addition, these
Received: July 4, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02306
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
the use of ammonium salts,15 N,N-dialkyl formamide dimethyl
15). In the next set of experiments, we optimized the amount
of base required for the transformation (Table 1, entries 12−
15). It was observed that the yield of 3a was decreased by
decreasing the amount of KOtBu from 200 mol % to 100 mol
% (Table 1, entry 12).
However, when the amount of base was increased from 200
mol % to 300 mol %, no significant impact on the yield was
observed (Table 1, entry 13). Gratifyingly, when the reaction
was conducted with 150% KOtBu at room temperature, the
product 3a was obtained in 97% yield within 2 h (Table 1,
entry 15). Further, when the transamidation was carried out
with 1−4 equiv of DMF as the formylating reagent using
toluene and THF as the solvents, the amide 3a was obtained in
good yield (Table S1, Supporting Information).
We then explored the generality of the transamidation using
the optimal reaction conditions (Table 1, entry 15). As listed
in Scheme 2, the KOtBu mediated transamidation of DMF
with a variety of amines produced the expected products in
moderate to excellent yields. Anilines containing electron-
donating groups (Me, Et, OMe) in the aryl ring reacted to
provide the corresponding transamidation products 3a−d in
excellent yields (Scheme 2). Aryl amines with electron-
acetals,16 boric acid derivatives,17 chitosan,18 an imidazole
21
derivatives,19 hypervalent iodine,20 and NEt3 as well as
microwave irradiation processes22 for transamidation. Re-
cently, the Szostak group reported LiHMDS23 promoted
chemoselective transamidation of amides by N−C(acyl)
cleavage at room temperature. In most reactions, DMF and
DMAC have been used as amide electrophiles.24
Although these metal-free protocols offer several advantages,
these protocols use a stoichiometric or substoichiometric
amount catalysts. Furthermore, the metal-free methods are
restricted to the reaction of active primary amides with
aliphatic amines. Therefore, it is a worthy goal to develop a
facile approach for the transamidation of amides with weakly
nucleophilic aromatic amines under catalyst-free as well as
solvent-free conditions. With these key points in mind, herein
we demonstrate the remarkable efficiency of potassium tert-
butoxide in promoting transamidation of amides with different
amines to provide a diverse range of carboxamides in the
absence of solvent.
We initially studied the formylation of p-anisidine 1a with
dimethyl formamide (DMF) 2a as the formyl source. In order
to optimize the reaction conditions, a series of experiments
were performed by varying reaction time, temperature, and
base. In the absence of any base, a very high temperature and
prolonged reaction time were required for the formylation of
1a, providing a poor yield of the transamidation product 3a.25
Subsequently, various commercially available bases such as
KOH, K2CO3, Cs2CO3, KOtBu, DBU, and NaOH (Table 1,
Scheme 2. Scope of the Transamidation of Dimethyl
formamide with Amines
a
Table 1. Optimization of Reaction Conditions
entry
base (%mol)
solvent
temp
time (h)
yield (%)
1.
2.
3.
4.
5.
6.
7.
8.
KOH (100)
K2CO3 (100)
Cs2CO3(100)
KOtBu (100)
NaOH (100)
DBU (100)
KOtBu (100)
KOtBu (100)
KOtBu (100)
KOtBu (100)
KOtBu (100)
KOtBu (100)
KOtBu (300)
KOtBu (200)
KOtBu (150)
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
rt
rt
rt
rt
rt
rt
rt
80
rt
rt
rt
rt
rt
rt
rt
12
12
12
12
12
12
12
12
8
4
2
2
2
NR
NR
NR
85
NR
NR
85
85
85
80
75
9.
10.
11.
12.
13.
14.
15.
75
95
95
97
2
2
a
Conditions: aniline 2 (0.5 mmol), DMF (10 mmol), KOtBu (0.75
mmol) rt, 2 h. Isolated yields were reported.
entries 1−6) were tested. Among the bases, KOtBu was found
to be efficient in promoting the formylation of 1a to afford the
product 3a in 85% yield at room temperature for 12 h (Table
1, entry 4). By increasing the reaction temperature (80 °C), no
appreciable improvement in the yield of 3a was achieved
(Table 1, entry 8). We were delighted to find that the desired
product was obtained in 97% yield at room temperature by
decreasing the reaction time from 12 to 2 h (Table 1, entry
B
DOI: 10.1021/acs.orglett.9b02306
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
withdrawing substituents (Br, F, CN, CF3 etc.) required a
relatively longer reaction time (4−6 h) to provide the
corresponding transamidation products in high yields (Scheme
2). These results suggest that no significant electronic effect of
substituents on reactivity was observed. However, no reaction
took place with 2,6-dimethyl aniline, which may be attributed
to the steric hindrance at the ortho-positions. The p-nitro
aniline was also less reactive under the optimized conditions,
providing the product 3t in moderate yield (>50%). Trans-
amidation with 1,2-diammino benzenes provided bis-formy-
lated products (3u and 3v) in good yields. The reaction with o-
amino phenols afforded the corresponding products in good
yields (3f−g). Heteroaromatic amines were efficiently trans-
formed to the corresponding amides (3w−x) in high yields.
The reaction was successful with primary amines, providing the
corresponding products (3y−z) in good yields.
Scheme 4. Transamidation with Cyclopropyl Amine
Scheme 5. Transamidation of Amides with Amines
To further ascertain the scope, we examined the reactivity of
acetamide 2b with a diverse range of amines (Scheme 3). The
Scheme 3. Scope of the Transamidation of Acetamide with
Amines
as the carbonyl source, no product formation was observed
(7c, <10%), probably due to insolubility of the substrate. The
product 7c was obtained in high yield (85%) by using N,N-
dimethyl benzamide 2c.
To elucidate the mechanism, the reaction of 1a with DMF
(2a) in the presence of KOtBu was monitored using TEMPO
as a radical trap. It was found that the yield of formylated
product 3a was suppressed by increasing the amount of
TEMPO (Scheme 6). The reaction was completely inhibited
Scheme 6. Transamidation of p-Anisidine in the Presence of
Radical Scavengers
corresponding transamidation products (5a−x) were obtained
in good to excellent yields. Heteroaromatic amines such as 4-
amino pyridine, and 8-amino quinolone also gave the desired
products in good to excellent yields (5w−x).
Under the reaction conditions, cyclopropyl amine 1a′
reacted with acetamide 2b to provide the corresponding N-
acetylated product in poor yield (30%). Interestingly, amine
1a′ was transformed into enamide 6a in high yield at elevated
temperature (80 °C). Similarly, transamidation with benza-
mide 2c provided the ring opening product propenyl amide
6b′ in high yield (Scheme 4). This protocol provides a simple
and new synthetic route to enamides, an important class of
compounds that are widely used as synthetic intermediates in
organic synthesis.26
by using galvainoxyl (2 equiv) as a radical scavenger. These
experiments reveal the formation of radical intermediates in
the transamidation process.27
Electron paramagnetic resonance (EPR) studies of the
reaction mixture containing p-anisidine (1 mmol) and KOtBu
(1.5 mmol) in DMF (0.8 mL) after stirring for 1 h showed the
formation of strong hyperfine EPR signals for the amine radical
(Figure S1, Supporting Information (SI)). This indicates that
the reaction proceeds via electron-transfer processes. These
observations suggest that a radical pathway is involved for the
transamidation (Scheme 7). A Lewis basic amine can
coordinate with the potassium cation to form complex A,
which instantaneously forms anion B by proton abstraction.
Subsequently, a single electron transfer (SET) from B provides
the amine radical C,28 which undergoes another SET with the
Next, we explored other carbonyl sources for the N-acylation
of amines (Scheme 5). Trifluoroacetamide could be success-
fully used as an acyl source, affording the desired products (7a,
7b) in excellent yields (>85%). However, by using benzamide
C
DOI: 10.1021/acs.orglett.9b02306
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
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ASSOCIATED CONTENT
* Supporting Information
■
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AUTHOR INFORMATION
(13) Ghosh, S. C.; Li, C. C.; Zeng, H. C.; Ngiam, J. S. Y.; Seayad, A.
M.; Chen, A. Adv. Synth. Catal. 2014, 356, 475−484.
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1496−1499.
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■
Corresponding Author
*E-mail: ocjd@iacs.res.in.
ORCID
Jyotirmayee Dash: 0000-0003-4130-2841
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
The authors thank Professor Hiriyakkanavar Ila on the
occasion of her 75th birthday. J.D. thanks DST-India for a
SwarnaJayanti fellowship (DST/SJF/CSA-01/2015-16). This
work was supported by DST and CSIR-India for funding. T.G.
and S.J. thank CSIR, India for a research fellowship.
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