Mild, Metal-Free and Protection-Free Transamidation of N-Acyl-2-piperidones to Amino Acids, Amino Alcohols and Aliphatic Amines and Esterification of N-Acyl-2-piperidones

Article abstract of DOI:10.1002/ejoc.201900517

Amides are indispensable building blocks of biological systems, pharmaceuticals, and materials. We report a highly selective method for the synthesis of amides via transamidation process. Transamidation of N-acyl-2-piperidones with a broad range of amines is demonstrated under exceedingly mild and metal-free reaction condition that relies on the amide bond twist to weaken the amidic resonance. Transamidation proceeds under the neat condition at room temperature, in short reaction times (30–90 min) with good yields. Considerable variation is tolerated with both amine and imide substrates. Of note, amines bearing carboxylic acids (glycine and serine) and hydroxyl groups (dopamine, tyramine, etc.) are well tolerated which are otherwise problematic under the metal-catalyzed protocol. Our current method is applicable for transamidation of both alkyl and aryl-N-acyl-2-piperidones. The practical value of the method is highlighted by the synthesis of four natural product amide alkaloids in high yields under mild reaction conditions. In the absence of nucleophilic amines, N-acyl-2-piperidones undergoes esterification with EtOH at elevated temperature. Single crystal X-ray analysis of an N-acyl-2-piperidone shows amide bond twist, τ = –20.39° and pyramidalization, χ_N = –11.73°. This weakens the amidic conjugation and might be the factor controlling the reactivity and selectivity of these imides. We envision that the N-acyl-2-piperidone scaffold would be useful in the synthesis of pharmaceuticals and materials.

Full text of DOI:10.1002/ejoc.201900517

A Journal of
Accepted Article
Title: Mild, Metal-Free and Protection-Free Transamidation of N-Acyl-2-
piperidones to Amino acids, Amino alcohols and Aliphatic Amines
and Esterification of N-Acyl-2-piperidones
Authors: Muthuraman Subramani and Saravanakumar Rajendran
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900517
Link to VoR: http://dx.doi.org/10.1002/ejoc.201900517
Supported by

10.1002/ejoc.201900517
European Journal of Organic Chemistry
Mild, Metal-Free and Protection-Free Transamidation of N-Acyl-2-piperidones to Amino
acids, Amino alcohols and Aliphatic Amines and Esterification of N-Acyl-2-piperidones
Muthuraman Subramani, Saravana Kumar Rajendran*
*Dr. R. Saravanakumar Rajendran, Mr. Muthuraman Subramani
Chemistry Division, School of Advanced Sciences,
Vellore Institute of Technology, Chennai,
Chennai – 600127. Tamilnadu, India.
E-mail: sar.org@gmail.com & saravanakumar.r@vit.ac.in
Supporting information for this article is given separately
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900517
European Journal of Organic Chemistry
Abstract
Amides are indispensable building blocks of biological systems, pharmaceuticals, and materials.
We report a highly selective method for the synthesis amides via transamidation process.
Transamidation of N-acyl-2-piperidones with a broad range of amines is demonstrated under
exceedingly mild and metal-free reaction condition that relies on the amide bond twist to weaken
the amidic resonance. Transamidation proceeds under the neat condition at room temperature, in
short reaction times (30-90 min) with good yields. Considerable variation is tolerated with both
amine and imide substrates. Of note, amines bearing carboxylic acids (glycine and serine) and
hydroxyl groups (dopamine and tyramine) are well tolerated which are otherwise problematic
under the metal-catalyzed protocol. Our current method is applicable for transamidation of both
alkyl and aryl-N-acyl-2-piperidones. The practical value of the method is highlighted by the
synthesis of four natural product amide alkaloids in high yields under mild reaction conditions. In
the absence of nucleophilic amines, N-acyl-2-piperidones undergoes esterification with aliphatic
alcohols at elevated temperature. Single crystal X-ray analysis of an N-acyl-2-piperidone shows
amide bond twist, τ = -20.39° and pyramidalization, χN = -11.73°. This weakens the amidic
conjugation and might be the factor controlling the reactivity and selectivity of these imides. We
envision that the N-acyl-2-piperidone scaffold would be useful in the synthesis of pharmaceuticals
and materials.
Introduction
Amides are essential constituents of life and building blocks of many drugs, pharmaceutical
molecules, agrochemicals, and natural products. It is estimated that 55% of pharmaceutical drugs
and 25% of the registered pharmaceuticals contain the amide motif. [1] A recent survey estimates
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900517
European Journal of Organic Chemistry
that the formation of the amide bond is one of the most prevalent chemical transformations
conducted by industrial organic chemists. Thus the development of new methods for amides will
have a major impact on chemical and biological sciences.[1] Typically, amides are prepared by the
reaction of amines with activated carboxylic acids, esters, aldehydes, alcohols, hydration of
nitriles, hydroamination of alkynes and aminocarbonylation.[2] Alternately, amides can be
prepared by transamidation, in which an amine is exchanged with a constituent of amides.[2] The
high stability of amide linkages arising out of amidic resonance and comparable energetics of
starting materials and products render transamidation a challenging task. Due to this,
transamidation requires harsh reaction conditions, high temperature, prolonged reaction times[1]
and activating agents in stoichiometric/catalytic amounts.[3] For the past two decades, great efforts
have been made in this area to conduct transamidation at relatively milder reaction conditions.[1,4]
Though great headway has been achieved with primary amides,[4d,5] it is still elusive with
secondary amides[6]. A general strategy that was widely followed is the functionalization of amide
nitrogen with electron-withdrawing functional groups typically tert-butoxycarbonyl[4a,7] acetyl,
benzoyl[8] and lactams[9] to weaken the amidic resonance and enhance the electrophilicity of the
amide carbonyl. Also, to create an imbalance in the thermoneutrality of the reactants and the
products (by-products will be carbamates or amides rather than competitive amines). In 2016, a
breakthrough study was reported by Garg and co-workers[6d] in addition to the above activation
strategy, a non-precious metal catalyst was used for the transamidation of secondary amides under
mild reaction conditions. The N-tert-butoxycarbonyl (N-BoC) functionalization weakens the
amidic resonance thereby facilitating the N-C metal insertion/transamidation process. Significant
progress has been made in the development of this method for amide bond cross-coupling[10] and
transamidation.[11] Recently (2018), Szostak et al[4a,b] and Chandrasekaran et al[12] followed the
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900517
European Journal of Organic Chemistry
above N-selective amide bond activation/destabilization strategy i.e N-BoC or N-tosyl
functionalization, to achieve transamidation of secondary amides under mild and metal-free
conditions. Interestingly, the amide bond in these amides was shown to twisted up to 50-60°.[13]
More recently (2018), Szostak and co-workers[14a,b] utilized amide bond twist of N-acyl-
glutaraimide and achieved transamidation under mild and metal-free conditions (Scheme 1). N-
Acyl-glutaraimide was established to possess high amide bond (85.7°) twist and most reactive
amide substrate in transition-metal catalyzed amide N-C bond activation. This amide bond twist
weakens the amidic resonance and facilitated nucleophilic addition. Further, the leaving group
ability and lower nucleophilicity of glutaraimide are the factors controlling the reactivity of the
process. The same group in a recent study reported the most twisted acyclic amides described to
date. Benzamide nitrogen was coupled with tosyl and acetyl/Boc groups to achieve the near
perpendicularity. They established that these amides readily undergo transamidation and Suzuki
coupling.[14c] In 1994, Bertrand and co-workers reported transamidation of acyclic imides
promoted by AlCl3.[8] Gowri et al in 2015[15] have shown transamidation of piperlongumine, an
imide substrate, with various alkyl amines catalyzed by magnesium bromide etherate at room
temperature (Scheme 1). Herein, we exploited amide bond twist associated with N-acyl-2-
piperidones to achieve highly selective transamidation with a broad range of amines under mild
and metal-free conditions (Scheme 2). Single crystal X-ray analysis shows amide bond twist, τ =
-20.39 ° and pyramidalization, χN = -11.73. As cited earlier, it is believed that the amide bond twist
though less than N-acyl-glutaraimide, might weaken the amidic conjugation and facilitated the
nucleophilic addition (amines) selectively to N-acyl carbonyl carbon (Scheme 2). Further, this was
supported by C-N bond metrics (Figure 1). The transamidation proceeds at room temperature,
under neat condition (when at least one of the reactant is a liquid. Otherwise ethanol was used as
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900517
European Journal of Organic Chemistry
a solvent), no additional base in short reaction times of 30-90 min. The broad applicability of the
process was demonstrated with amines bearing carboxylic acids, esters, and hydroxyl groups and
alkyl and aryl-N-acyl moieties. A competitive transamidation of primary Vs secondary amine was
conducted to reveal the selectivity pattern. Further, the scope of the methodology was validated
with a synthesis of four natural product amide alkaloids under mild condition. Esterification was
observed in the absence of primary/secondary amines with aliphatic alcohols ethanol and benzyl
alcohol at elevated temperature (85 °C).
Scheme 1. Transamidation protocols reported earlier and present work
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900517
European Journal of Organic Chemistry
Scheme 2. Amidic conjugation of N-acyl-2-piperidones biased towards lactam carbonyl carbon
Results and Discussion
During the course of our investigation for the synthesis of piperlongumine derivatives, we
serendipitously obtained transamidation product of piperlongumine. Piperlongumine is a primary
constituent of long pepper (Piper Longum). It is an amide alkaloid, structured with 3,4,5-
trimethoxyl cinnamoyl moiety bonded to 5,6-dihydro-2(1H)-pyridinone (Scheme 3).[16] It is a
bioactive compound with a broad spectrum of therapeutic activities with a major focus on
anticancer activity.[16] Recent studies show piperlongumine selectively kills cancer cells leaving
the normal cells unaffected in vitro and in vivo.[17] This attracts wide interest for piperlongumine
and its derivatives for the treatment of various malignancies. The high activity of piperlongumine
and our continued interest in pepper based compounds draws our interest in the synthesis of
piperlongumine derivatives. We sought to prepare 5,6-dihydro-2(1H)-pyridinone ring for the
synthesis of piperlongumine derivatives. Synthetic routes known for the preparation of 5,6-
dihydro-2(1H)-pyridinone ring is either lengthy or uses expensive metal catalysts[18]. Hence, we
decided to synthesize 5,6-dihydro-2(1H)-pyridinone under metal-free conditions. Among the
various methods attempted, we were trying to hydrolyze piperlongumine (isolated from long
pepper) with 70% ethylamine to obtain 5,6-dihydro-2(1H)-pyridinone. In one of the earlier reports,
70% ethylamine was used for the deprotection of 5,6-dihydro-2(1H)-pyridinone type molecule.[19]
When piperlongumine was reacted with 70% ethylamine at room temperature, it was consumed
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900517
European Journal of Organic Chemistry
within 1.5 hours (Scheme 3). Analysis of 1H NMR spectrum of the crude reaction mixture shows
no sign of 5,6-dihydro-2(1H)-pyridinone or its ring-opened product. Instead, the formation of
transamidation product of piperlongumine with ethylamine, i.e N-(3,4,5-trimethoxycinnamoyl)-
benzylamine was observed. Several attempts to isolate/find the status of the 5,6-dihydro-2(1H)-
pyridinone ring left us clueless. Referring to the literature, we found very few reports for
transamidation of imides.[8,14,15] Moreover, these methods require a metal catalyst, activating
agents in stoichiometric quantity or excess, long reaction times and used chlorinated solvents,
whereas our reaction conditions are exceedingly mild and metal-free. Transamidation proceeds at
room temperature, under neat condition (when at least one of the reactant is liquid. Otherwise
ethanol was used as a solvent), with no additional base in short reaction time, 30-90 min. These
simple conditions imply that there is great potential to develop this method as a valuable synthetic
tool for amide synthesis.
Scheme 3. Transamidation of piperlongumine with ethylamine
Solvent optimization studies
Effect of solvents on this reaction was evaluated with solvents outlined in table 1. Benzylamine
was taken as the standard amine substrate. Yields and reactions time revealed that neat conditions
(Table 1, entry 5) are the best if at least one of the reactant is liquid. Otherwise, ethanol was found
to be the most optimal solvent (Table 1, entry 1).
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900517
European Journal of Organic Chemistry
Table 1. Solvent optimization studies
S. No
1a
Solvent
EtOH
DCM
DMSO
DMF
Time (h)
1.5
Yield (%)
74
63
67
65
76
2 a
3 a
4 a
5b
24
1.5
1.5
Neat
45 min
aPiperlongumine (50 mg, 1 equiv.), amine (3 equiv.). bPiperlongumine (50 mg, 1 equiv.), amine (5
equiv.).
Transamidation of piperlongumine with various amines
Under the optimized reaction condition, the scope of our initial finding was expanded to a broad
range of amines outlined in table 2. Transamidation proceeds smoothly with ethyl and allylamine
and now, the time required for completion is just half of the reaction time of ethanol condition
(compare Table 2, entry 1 and Scheme 3) and almost same yield was observed, 76%. We were
pleased to find that even amines bearing a hydroxyl group(s) such as ethanolamine, dopamine, and
tyramine were well suited for the transamidation process. Of note, only the amine group
participated in the nucleophilic addition. The hydroxyl groups remained unaffected and did not
interfere with the transamidation process (Table 2, entry 2, 4 and 5). The corresponding amides
were formed in moderate yields of 71, 62 and 54% respectively (Table 2, entry 2, 4 & 5). The
dopamine coupled amide was evaluated as an efflux pump inhibitor.[20] Tyramine and dopamine
were commercially available as hydrochloride salts they were neutralized with trimethylamine
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900517
European Journal of Organic Chemistry
prior to use. Transamidation of tyramine and dopamine was conducted in ethanol, trace amount
(~5%) of formation of ethyl ester of piperlongumine was observed as a by-product in both cases.
The obtained results show that the process is highly selective for N-nucleophile than O-
nucleophile. Transamidation proceeds smoothly with ethyl glycinate, and the secondary amine,
piperidine. The reaction completed within 45 min and the corresponding amides were formed in
good yields of 78 and 71% respectively (Table 2, entry 6 and 9). Glycine ethyl ester is
commercially available as the hydrochloride salt. It was neutralized with trimethylamine prior to
use. Transamidation of sterically demanding amine, isopropylamine was found to be a little slower,
it takes 1.5 hours for the completion of the reaction (Table 2, entry 8). We then examined the
challenging amine substrate, free amino acid, glycine. The zwitterionic glycine was initially
neutralized with trimethylamine and then reacted with piperlongumine in trimethylamine/ethanol
solvent. We were delighted to find that in both cases, glycine underwent transamidation. However,
it required longer reaction times. It requires 6 h stirring at 40 °C with trimethylamine and with
ethanol it took 16 h at 40 °C for the completion of the reaction (Table 2, entry 7). The
corresponding transamidated product formed in good yields of 70 and 62% respectively. The
reaction that uses ethanol solvent, lead to the formation of minor amount (~10%) of ethyl ester of
piperlongumine as a by-product. To the best of our knowledge, this is the first report of
transamidation of free amino acid. We determined that sterically hindered di-isopropyl amine was
unreactive under the reaction conditions (Table 2, entry 10). Extending the reaction time up to 24
hours at room temperature or heating at 85 °C for 24 hours was also not fruitful. Only the starting
materials were recovered. We envisaged that increasing the bulkiness around amines would
decrease the reactivity which can be exploited for selective transamidation of less sterically-
hindered amine in the presence of sterically-demanding amines. Similarly, aromatic amine, aniline
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900517
European Journal of Organic Chemistry
was also found to be unreactive under the reaction conditions (Table 2, entry 11). Only the starting
materials were recovered. This inactivity can be exploited for selective transamidation of
alkylamine in the presence of an aromatic amine.
Table 2. Transamidation of piperlongumine with various amines
S.No
Amine
Product
Yield (%)
1a
76
2a
71
76
3a
4b
62
54
5b
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900517
European Journal of Organic Chemistry
6b
78
62, 70
69
7c,d
8e
9a
71
10a
No reaction
11a
No reaction
b
aPiperlongumine (50 mg, 1 equiv.), amine (5 equiv.), 45 min. (i)hydrochloride salt of amine (3
equiv.), EtOH (0.8 mL), Et3N (3 equiv.), 30 min, RT, (ii) piperlongumine (50 mg, 1 equiv), 1.5 h,
RT. c(i) Zwitterionic glycine (3 equiv.), H2O (22 µL), EtOH (0.8 mL), Et3N (3 equiv.), 30 min, RT
d
(ii) piperlongumine (50 mg, 1 equiv.), 40 °C, 16 h. Piperlongumine (50 mg, 1 equiv.), zwitterionic
glycine (3 equiv.), Et3N (10 equiv.), H2O (22 µL), 40 °C, 6 h. ePiperlongumine (50 mg, 1 equiv.),
amine (5 equiv.), 1.5 h, RT.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900517
European Journal of Organic Chemistry
Transamidation of hydroxyl piperlongumine
Another important observation of the reaction scope is that the hydroxyl group on the imide
substrate was also well tolerated. p-Hydroxy piperlongumine was found to undergo transamidation
with ethylamine at room temperature. The transamidation completed within 25 min. The phenolic
-OH did not interfere with the transamidation process. The corresponding amide formed in a good
yield of 79% (Scheme 4). This finding corroborated that the process is highly selective for the
N-nucleophile than the O-nucleophile. p-Hydroxy piperlongumine was synthesized from
piperlongumine (ESI) by monodemethylation.
Scheme 4. Transamidation of p-hydroxy piperlongumine with ethylamine
Transamidation of saturated piperlongumine (SPL) with various amines
To expand the substrate scope, we evaluated the applicability of piperlongumine with the saturated
2-piperidone ring as the imide substrate. Accordingly, we synthesized piperlongumine with
saturated piperidone ring[21] (SPL, Scheme 5) and subjected to the transamidation process. The
molecular structure of saturated piperlongumine (SPL) was unambiguously established by single
crystal X-ray analysis (Figure 1). The two carbonyl groups were almost anti-periplanar and their
torsion angle was found to be 153.80° (O5-N1-C9-O4). The bond distance between the amide
nitrogen and the carbonyl carbons (N1-C9 = 1.413 Å, N1-C10= 1.386 Å, N1-C14 = 1.48 Å, C10-
O5 = 1.213 Å, C9-O4 = 1.215 Å) indicates that amidic resonance is more prominent towards ring
carbonyl carbon (Figure 1). The amide bond twist (τ) and pyramidalization (χN) were calculated
to, -20.39° and = -11.73° respectively.[22]
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900517
European Journal of Organic Chemistry
In the initial study, we examined the transamidation of saturated piperlongumine (SPL) with
benzylamine under neat conditions at room temperature. We were delighted to find that
transamidation proceeded smoothly and even faster than piperlongumine. The transamidation
completed with 30 min and the corresponding amide product formed in 76% yield (Table 3, entry
1). We were able to isolate the by-product, 2-piperidone in 38% yield. To examine the scope,
saturated piperlongumine (SPL) was reacted with a broad range of amines to afford
pharmaceutically valuable amides in good yields. Transamidation accommodates simple alky
amines, ethyl, and allylamine, amines bearing hydroxyl group like ethanolamine, sterically
demanding isopropylamine and the secondary amine, piperidine. The reaction completed within
30 min with primary amines and 45 min with sterically demanding isopropylamine and piperidine.
The corresponding transamidation products were formed in good yields of 70%, 74%, 71%, 69%
and 74% respectively (Table 3, entry 2-6). We then evaluated the challenging amine substrates,
amino acids such as glycine, and serine. Notably, the transamidation was carried out keeping
carboxylic acid groups and hydroxyl groups remain unprotected. We were pleased to find that
transamidation proceeds smoothly with both the amino acids and yielded the corresponding amides
in good yields 70 and 60% respectively (Table 3, entry 7 and 8). Glycine/serine was initially
neutralized with trimethylamine prior to transamidation process. To the amino acid, SPL in
triethylamine was added and stirred for 6 h at 40 °C for glycine and 60 °C for serine. The
corresponding amide products were formed in good yields (Table 3, entry 7 and 8). Since these
amide products are previously not known, they could be evaluated as piperlongumine derivatives
for biological applications. Similarly, transamidation proceeded smoothly with a neuromodulator,
tyramine, and neurotransmitter, dopamine (Table 3, entry 9 and 10 ). Yielded the corresponding
amides in good to moderate yield, 64 and 54% respectively. Di-isopropylamine and aniline were
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900517
European Journal of Organic Chemistry
ineffective under our reaction conditions (Table 3, entry 11 and 12). Only the starting materials
were recovered, which should prove useful in selective transamidation of this class of imides with
aliphatic amines in the presence of less nucleophilic aromatic and sterically demanding amines.
Scheme 5. Synthesis and transamidation of saturated piperlongumine (SPL)
Single crystal X-ray structure of saturated piperlongumine (SPL)
Figure 1. ORTEP diagram of piperlongumine with saturated 2-piperidone ring. Bond distance:
N1-C9 = 1.413 Å, N1-C10= 1.386 Å, N1-C14 = 1.48 Å, C10-O5 = 1.213 Å, C9-O4 = 1.215 Å
Torsion angle (O5-N1-C9-O4) = 153.80°, amide bond twist, τ = -20.39° and pyramidalization, χN
= -11.73°, τ+ χN = 32.12 °.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900517
European Journal of Organic Chemistry
Table 3. Transamidation of saturated piperlongumine with various amines
S.No Amine
Product
Yield (%)
1a
76
2a
3a
4a
5b
6b
7c
70
74
71
69
74
70
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900517
European Journal of Organic Chemistry
8d
60
9e
64
54
10e
No
reaction
11a
12a
No
reaction
b
aSaturated piperlongumine (100 mg, 1 equiv.), amine (5 equiv.), 30 min, RT. Saturated
piperlongumine (100 mg, 1 equiv.), amine (5 equiv.), 45 min, RT. cSaturated piperlongumine (100
d
mg, 1 equiv.), glycine (3 equiv.), Et3N (10 equiv., 0.4 mL), H2O (44 µL), 40 °C, 6 h. Saturated
piperlongumine (100 mg, 1 equiv.), glycine (3 equiv.), Et3N (10 equiv., 0.4 mL), H2O (44 µL), 60
°C, 6 h. e(i) hydrochloride salt of amine (3 equiv.), EtOH (1.6 mL), Et3N (3 equiv.), 30 min, RT,
(ii) Saturated piperlongumine (100 mg, 1 equiv.), 1.5 h, RT.
Transamidation of different N-acyl-2-piperidones with benzylamines
We next focused on the scope of N-acyl-2-piperidones that can participate in this protocol.
Accordingly, N-acetyl, N-benzoyl, N-cinnamoyl, and N-piperoyl-2-piperidone (Table 4) were
synthesized[21] and evaluated for transamidation. N-Acyl-2-piperidones and benzylamine were
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900517
European Journal of Organic Chemistry
reacted at room temperature under neat conditions. We determined that both alkyl and aryl N-acyl-
2-piperidones underwent transamidation smoothly and the reaction completed within 30-45 min
(Table 4, entry 1-6). The corresponding amides were formed in good yields. Notably, fluorine
substituent often encountered as a medicinally relevant scaffold, and electrophilic nitro substituent
posed no difficulty (Table 4, entry 4, 5). In fact, the higher yield was observed with electrophilic
substituents (-F and -NO2) (Table 4, entry 4, 5). The most probable reason is that these substituents
increase the electrophilicity of the acyl carbonyl carbon. Interestingly, transamidation proceeds
faster with N-piperoyl-2-piperidone (Table 4, entry 6), the reaction completed within 30 min. This
is the first report of transamidation of di-conjugated amides. Yields and reaction times (Table 4,
compare entry 2, 3 and 6) suggest that increasing the conjugation to N-acyl-2-piperidone may be
beneficial for the transamidation process. The enhanced reactivity may be due to reduced steric
hindrance around the acyl carbonyl carbon.
Table 4. Transamidation of various imides with benzylamine
Time
(min)
S.No
R
Product
Yield (%)
1a
45
79
2a
45
69
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900517
European Journal of Organic Chemistry
3a
45
45
72
81
4a
5a
45
82
77
6a
30
aN-Acyl-2-piperidone (100 mg, 1 equiv.), benzylamine (5 equiv.), 45 min.
The selectivity of transamidation process: Primary Vs Secondary amines
To establish selectivity of the transamidation process for primary and secondary amine, SPL was
reacted with a mixture of an equal amount of benzylamine and piperidine (Scheme 6).
Interestingly, benzylamine underwent faster transamidation than piperidine, yielding the
benzylamide as the major product at 75% yield and piperidine exchanged amide as the minor
product in 5% yield. This is contrary to the consideration of the relative basicity of primary and
secondary amines.[14] This reversal of reactivity is attributed to higher steric hindrance associated
with secondary amines.[6b] The above factor should be advantageous for selective transamidation
of this class of imides with sterically less demanding primary amines in the presence of a sterically
hindered secondary amines.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900517
European Journal of Organic Chemistry
Scheme 6. Selectivity study of transamidation protocol: Primary Vs secondary amines.
Synthesis of natural product amide alkaloids
The practical value of the method was highlighted by the synthesis of four pharmaceutically
important natural product amides, (i) Antiepilepsirine an antiepileptic drug[23] and TRPV1
agonist;[24] (ii) Piperlonguminine an anti-tumor and anti-inflammatory agent;[25] (iii) Piperyline an
antifungal[26a] and antibacterial agent;[26b] and (iv) Fagaramide which is an antidepressant[27] and
antifungal agent,[26a] in high yields at mild reaction conditions. These amides were prepared at
room temperature, under solvent-free condition, in short reaction times of 30-45 min, no additional
base and needed no purification by column chromatography. The N-piperoyl-2-piperidone was
reacted with isobutylamine/pyrrolidine to obtain Piperlonguminine/Piperyline in good yields of
74% and 73% respectively (Scheme 7). Similarly, N-(3,4-methylenedioxy cinnamoyl)-2-
piperidone was reacted with isobutylamine/piperidine to obtain Fagaramide/Antiepilepsirine in
good yields of 72% and 71% respectively (Scheme 7).
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900517
European Journal of Organic Chemistry
Scheme 7. Synthesis of natural product amide alkaloids via present transamidation protocol
Esterification of different imides with aliphatic alcohols
Recently, Szostak and co-works recently (2018) demonstrated esterification of transient N-BoC
activated amide with aromatic and aliphatic alcohols. Also, they have showcased thioesterification
reaction under the same reaction conditions.[28] To expand the scope of our methodology for the
synthesis of esters, N-acyl-2-piperidone was reacted with O-nucleophile in the absence of
nucleophilic amines. Our studies commenced by surveying the reaction of SPL with ethanol in the
presence of trimethylamine at room temperature. There was no reaction, hence, the reaction
mixture was heated to reflux for 6 h, starting materials were completely consumed. Analysis of
the reaction products shows the formation of expected ester, 3,4,5-trimethoxy ethyl cinnamate in
good yield, 72% (Scheme 8). Similarly, the other N-acyl-2-piperidones outlined in Table 5 were
reacted with ethanol/benzyl alcohol. All the N-acyl-2-piperidones underwent esterification and
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900517
European Journal of Organic Chemistry
yielded the corresponding esters in good yields, 67-77% (Table 5). It is noticed that reactivity for
esterification increased with increasing the number of alkene double bond (compare time and yield
of benzoyl, cinnamoyl and piperoyl imides). As mentioned earlier, the increased reactivity could
be due to decreased steric hindrance around the acyl carbonyl carbon. This highlights the broad
scope of the present methodology for the synthesis of both amides and esters from this class of
imides by simply changing the reaction conditions.
Scheme 8. Esterification of saturated piperlongumine
Table 5. Esterification of different imides with ethanol.
S.No
R
Time (h)
Product
Yield (%)
1a
8
69
2a
8
70
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900517
European Journal of Organic Chemistry
3a
4.5
67
4a
6
8
67
70
5a
8
7
8
74
77
71
6a
7a
8a
aN-Acyl-2-piperidone (100 mg, 1 equiv.), Ethanol or benzyl alcohol (1.5-2.5 mL), Et3N (3 equiv.).
Esterification of different imides with phenol
Attempts to esterify N-acyl-2-piperidones, SPL and piperlongumine with aromatic alcohol, phenol
under the aforementioned conditions were not fruitful (Scheme 9). SPL/PL was reacted with
phenol in the presence of triethylamine at room temperature, at 85 °C and at 110 °C. There was no
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900517
European Journal of Organic Chemistry
reaction, only the starting materials were retrieved. The same observation was noticed when the
reaction was conducted in acetonitrile at reflux conditions for 8 h.
Scheme 9. Attempted esterification of piperlongumine and saturated piperlongumine with phenol
Determination of stability of piperlongumine and saturated piperlongumine under the
hydrolytic condition
We next evaluated the stability of the imides, piperlongumine, and SPL under hydrolytic
conditions. An aqueous solution of piperlongumine/SPL was heated under reflux in the presence
of trimethylamine for 8 h. There was no noticeable hydrolytic cleavage observed in both cases.
Only the starting material was recovered (Scheme 10). These results indicate that the imides are
robust and that they can be prepared in large quantities for further chemical transformations.
Scheme 10. Hydrolysis of piperlongumine and saturated piperlongumine.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900517
European Journal of Organic Chemistry
In essence, our results support the applicability of aliphatic N-nucleophilic and O-nucleophilic
addition to the weakened amide bond, arising out of the amide twist, however under selective
reaction conditions viz N-nucleophilic addition at room temperature and O-nucleophilic addition
at a higher temperature in the absence of nucleophilic amines.
Conclusions
A simple protocol for the synthesis of amides is developed based on the transamidation process.
Transamidation of N-acyl-2-piperidones with amines is achieved under mild and metal-free
conditions. Transamidation proceeds at room temperature, under neat condition (in the case of
solid reactants, EtOH was used as solvent), in short reaction time of 30-90 min, no additional base
with good to moderate yields. Amide bond twist associated with N-acyl-2-piperidones was
exploited for the transamidation of amines. Considerable variation is tolerated with regard to both
imide and amine substitutions. Of note, amines bearing carboxylic acid, ester and hydroxyl groups
that would be problematic under metal-catalyzed protocols, are tolerated under the reaction
condition. Transamidation of both alkyl and aryl N-acyl-2-piperidones was demonstrated.
Transamidation was found to be ineffective with less nucleophilic amines, anilines and biased
towards less sterically demanding alkyl amines, which should be useful for selective
transamidation in the presence of aromatic and sterically demanding alkyl amines. The practical
value of the methodology was highlighted by the synthesis of four pharmaceutically important
amide alkaloids, antiepilepsirine, piperlonguminine, piperyline and fagaramide in good yields
under mild reaction conditions, in short reaction time, 30-45 min and no purification by column
chromatography. In the absence of nucleophilic amines, N-acyl-2-piperidones underwent
esterification with aliphatic alcohols at elevated temperature (85 °C). Furthermore, N-acyl-2-
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900517
European Journal of Organic Chemistry
piperidones are easier to synthesize and robust under the reaction conditions and they could be
prepared in large quantities for general applications in metal-free transformations. Thus, the
transamidation protocol developed herein for the synthesis of amides have broad substrate scope,
yet involves simple reaction conditions, will be of great interest in organic synthesis, polymers,
natural products, pharmaceuticals, and material sciences.
Experimental Section
The full experimental data related to this article are given in the supplementary file. It includes
1
synthetic procedure, H NMR, and 13C NMR spectra of transamidation products and their
precursors. CIF data of SPL was deposited in Cambridge Crystallographic Data Centre (CCDC)
and its CCDC numbers: 1899117. The data is available free of charge at
http://www.ccdc.cam.ac.uk
Acknowledgments
S.M and R.S.K thanks, Chemistry Division and VIT Chennai, for providing infrastructure facility,
instrumentation facility (CHN analysis, GC-MS, FT-IR) and financial support for characterization
and fellowship for S.M. SAIF, VIT Vellore is gratefully acknowledged for recording 1H and 13C
NMR.
Keywords: Transamidation, Piperlongumine, Piperidones, Amide alkaloid, Amide bond twist.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900517
European Journal of Organic Chemistry
References
[1]
[2]
[3]
P. Acosta-Guzman, A. Mateus-Gomez, D. Gamba-Sanchez, Molecules, 2018, 23, 2382.
S. N. Rao, D. C. Mohan, S. Adimurthy, Org. Lett. 2013, 15, 1496.
a) S. E. Eldred, D. A. Stone, S. H. Gellman, S. S. Stahl, J. Am. Chem. Soc. 2003, 125, 3422;
b) J. M. Hoerter, K. M. Otte, S. H. Gellman, S. S. Stahl, J. Am. Chem. Soc. 2006, 128,
5177; c) J. M. Hoerter, K. M. Otte, S. H. Gellman, Q. Cui, S. S. Stahl, J. Am. Chem. Soc.
2008, 130, 647; d) N. A. Stephenson, J. Zhu, S. H. Gellman, S. S. Stahl, J. Am. Chem. Soc.
2009, 131, 10003.
[4]
a) Y. Liu, S. Shi, M. Achtenhagen, R. Liu, M. Szostak, Org. Lett. 2017, 19, 1614; b) G. Li,
Michal Szostak, Nat. Commun. 2018, 9, 4165; c) S. Shi, S. P. Nolan, M. Szostak, Acc.
Chem. Res. 2018, 51, 51, 2589; d) W. Guo, J. Huang, H. Wu, T. Liu, Z. Luo, J. Jian, Z.
Zeng, Org. Chem. Front., 2018, 5, 2950.
[5]
[6]
a) T. B. Nguyen, J. Sorres, M. Q. Tran, L. Ermolenko, A. Al-Mourabit, Org. Lett. 2012,
14, 3202; b) J. Yin, J. Zhang, C. Cai, G-J. Deng, H. Gong, Org. Lett., 2019, 21, 387; c)
S. N. Rao, D. C. Mohan, S. Adimurthy, Green Chem., 2014, 16, 4122.
a) W. Guo, J. Huang, H. Wu, T. Liu, Z. Luo, J. Jian, Z. Zeng, Org. Chem. Front. 2018, 5,
2950; b) J. E. Dander, E. L. Baker, N. K. Garg, Chem. Sci. 2017, 8, 6433; c) C. W. Cheung,
M. L. Ploeger, X. Hu, ACS Catal. 2017, 7, 7092; d) E. L. Baker, M. M. Yamano, Y. Zhou,
S. M. Anthony, N. K. Garg, Nat. Commun. 2016, 7, 11554.
[7]
[8]
a) S. K. Davidsen, P. D. May, J. B. Summers, J. Org. Chem. 1991, 56, 5482; b) 55) Y.
Liu, R. Liu, M. Szostak, Org. Biomol. Chem. 2017, 15, 1780.
E. Bon, D. C. H. Bigg, Guy Bertrand, J. Org. Chem. 1994, 59, 4035.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900517
European Journal of Organic Chemistry
[9]
a) E. Bon, D. C. H. Bigg, G. Bertrand, Synlett. 1992, 747; b) C. A. Goodman, J. B.
Eagles, L. Rudahindwa, C. G. Hamaker, S. R. Hitchcock, Syn. Commun. 2013, 43, 2155;
c) Y. Liu, G. Meng, R. Liuband, M. Szostak, Chem. Commun. 2016, 52, 6841.
[10] a) C. Liu, M. Szostak, Org. Biomol. Chem., 2018, 16, 7998; b) G. Meng, S. Shi, M. Szostak,
Synlett. 2016, 27, 2530; c) G. Meng, M. Szostak, Org. Lett. 2015, 17, 4364; d) G. Meng,
M. Szostak, Org. Biomol. Chem. 2016, 14, 5690; e) P. Lei, G. Meng, M. Szostak, ACS
Catal. 2017, 7, 1960; f) S. Shi, M. Szostak, Chem. Eur. J. 2016, 22, 10420; g) G. Meng,
M. Szostak, Eur. J. Org. Chem. 2018, 20-21, 2352; h) Md. M. Rahman, J. Buchspies, M.
Szostak, Catalysts, 2019, 9, 129.
[11] a) G. Meng, P. Lei, M. Szostak, Org. Lett. 2017, 19, 2158; b) S. Shi, M. Szostak, Chem.
Commun. 2017, 53, 10584.
[12] R. Ramkumar, S. Chandrasekaran, Synthesis, 2019, 51, 921.
13]
R. Szostak, S. Shi, G. Meng, R. Lalancette, M. Szostak, J. Org. Chem., 2016, 81,
8091.
[14] a) Y. Liu, M. Achtenhagen, R. Liu, M. Szostak, Org. Biomol. Chem. 2018, 16, 1322; b) R.
Szostak, M. Szostak, Org. Lett. 2018, 20, 1342; c) C. Liu, S. Shi, Y. Liu, R. Liu, R.
Lalancette, R. Szostak, M. Szostak, Org. Lett., 2018, 20, 7771.
[15] P. M. Gowri, S. V. S. Radhakrishnan; V. R. S. Rao, A. Madnu, A. Hymavathi, J. M. Rao,
Curr. Sci. 2015, 109, 1775.
[16] a) D. P. Bezerra, C. Pessoa, M. O. de Moraes, N. Saker-Neto, E. R. Silveira, L. V. Costa-
Lotufo, Eur. J. Pharm.Sci. 2013, 48, 453; b) W. Harshbarger, S. Gondi, S. B. Ficarro, J.
Hunter, D. Udayakumar, D. Gurbani, W. Singer, Y. Liu, L. Li, J. A. Marto, K. D. Westover,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900517
European Journal of Organic Chemistry
J. Biol. Chem. 2017, 292, 112; c) S. Shrivastava, P. Kulkarni, D. Thummuri, M. K. Jeengar,
V. G. M. Naidu, M. Alvala, G. B. Reddy, S. Ramakrishna, Apoptosis, 2014, 19, 1148.
[17] a) D. J. Adams, M. Dai, G. Pellegrino, B. K. Wagner, A. M. Sterna, A. F. Shamjia, S. L.
Schreiber, Proc. Natl. Acad. Sci. 2012, 109, 15115; b) L. Raj, T. Ide, A. U. Gurkar, M.
Foley, M. Schenone, X. Li, N. J. Tolliday, T. R. Golub, S. A. Carr, A. F. Shamji, A. M.
Stern, A. Mandinova, S. L. Schreiber, S. W. Lee, Nature, 2011, 475, 231.
[18] a) Z. V. Boskovic, M. M. Hussain, D. J. Adams, M. Dai, S. L. Schreiber, Tetrahedron,
2013, 69, 7559; b) L. Simon, F. M. Muniz, S. Saez, C. Raposo, F. Sanz, J. R. Moran, Helv.
Chim. Acta, 2005, 88, 1682; c) L. Han, P. A. Stanley, P. J. Wood, P. Sharma, A. I. Kuruppu,
T. D. Bradshaw, J. E. Moses, Org. Biomol. Chem. 2016, 14, 7585; d) V. R. Rao, P.
Muthenna, G. Shankaraiah, C. Akileshwari, K. H. Babu, G. Suresh, K. S. Babu, R. S. C.
Kumar, K. R. Prasad, P. A. Yadav, J. M. Petrash, G. B. Reddy, J. M. Rao, Eur. J. Med.
Chem. 2012, 57, 344.
[19] V. N. Divvela, S. Rao, G. N. Trinadhachari, K. J. Prabahar, R. Dandala, M. Sivakumaran,
Andra Naidu, J. Heterocyclic Chem. 2007, 44, 663.
[20] S. Michalet, G. Cartier, B. David, A. Mariotte, M. Dijoux-franca, G. W. Kaatz, M. Stavrid,
Simon Gibbons, Bioorg. Med. Chem. Lett. 2007, 17, 1755.
[21] Y. H. Seo, J. K. Kim, J. G. Jun, Bioorg. Med. Chem. Lett. 2014, 24, 5727.
[22] a) R. Szostak, J. Aube, M. Szostak, Chem. Commun. 2015, 51, 6395; b) R. Szostak, J.
Aube, M. Szostak, J. Org. Chem. 2015, 80, 7905.
[23] L. Wang, R. Vieth, R. C. Landes, Y. Suzuki, P. D. Walson, Epilepsy Res. 1993, 15, 1.
[24] E. A. Correa, E. D. Hogestatt, O. Sterner, F. Echeverri, P. M. Zygmunt, Bioorg. Med.
Chem. 2010, 18, 3299.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900517
European Journal of Organic Chemistry
[25] M. Song, J. Y. Hwang, M. Y. Lee, J. Jee, Y. M. Lee, J. Bae, J. Ah. Kim, S. H. Lee, Sangkyu
Lee, Arch. Pharm. Res. 2014, 37, 1063.
[26] a) R. V. da Silva, H. M. D. Navickiene, M. J. Kato, V. S. Bolzani, C. I. Meda, M. C. M.
Young, Maysa Furlan, Phytochemistry, 2002, 59, 521; b) K. M. Meepagala1, K. K. Schrader,
C. L. Burandt, J. Agric. Chem. Environ. 2013, 2, 90.
[27]
M. Han, X. Ma, Y. Jin, W. Zhou, J. Cao, Y. W. Shuiping Zhou, G. Wang, Y. Zhu, Bioorg.
Med. Chem. Lett. 2014, 24, 5284.
[28] G. Li, P. Lei, M. Szostak, Org. Lett., 2018, 20, 5622.
This article is protected by copyright. All rights reserved.