Metal-free transamidation of benzoylpyrrolidin-2-one and amines under aqueous conditions

Article abstract of DOI:10.1039/d1ob00967b

N-Acyl lactam amides, such as benzoylpyrrolidin-2-one, benzoylpiperidin-2-one, and benzoylazepan-2-one reacted with amines in the presence of DTBP and TBAI to afford the transamidated products in good yields. The reactions were conducted under aqueous conditions and good functional group tolerance was achieved. Both aliphatic and aromatic primary amines displayed good activity under metal-free conditions. A radical reaction pathway is proposed.

Full text of DOI:10.1039/d1ob00967b

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Metal-free transamidation of benzoylpyrrolidin-2-
one and amines under aqueous conditions†
Cite this: Org. Biomol. Chem., 2021,
19, 6227
Devaneyan Joseph, Myeong Seong Park and Sunwoo Lee
*
Received 19th May 2021,
Accepted 29th June 2021
DOI: 10.1039/d1ob00967b
rsc.li/obc
N-Acyl lactam amides, such as benzoylpyrrolidin-2-one, benzoyl- be employed as counterparts for the reaction with amides in
piperidin-2-one, and benzoylazepan-2-one reacted with amines in the presence of LiHMDS to provide the corresponding 1,3-dike-
the presence of DTBP and TBAI to afford the transamidated pro- tones and beta-ketoesters in good yields.6 The use of LiHMDS
ducts in good yields. The reactions were conducted under for the activation of amides provided transition-metal-free con-
aqueous conditions and good functional group tolerance was ditions; however, the strong basicity of LiHMDS limited the
achieved. Both aliphatic and aromatic primary amines displayed substrate scope. Moreover, this system cannot operate using
good activity under metal-free conditions.
A
radical reaction environmentally benign polar aprotic solvents, such as alcohol
and water (Scheme 1a). Therefore, the development of trans-
amidation methods that involve aqueous or environmentally
benign solvent systems is in high demand.
pathway is proposed.
Non-organic solvent systems had been reported, however,
they have some drawbacks. Srivastava group reported the trans-
amidation of N-Boc-N-phenyl amides under neat conditions
Introduction
Transamidation, the transformation of one amide to another,
has been extensively studied since the first report of amide C–
N bond activation and subsequent substitution by other
nucleophiles.1 The Stahl group reported the transformation of
secondary amides to other amides when reacted with amines
in the presence of Lewis acids, such as Al, Zr, and Sc. However,
this reaction provided equilibrium mixtures of two amides.2
Numerous research groups have developed direct transami-
dation methodologies to obtain a single amide product. The
use of palladium or nickel catalysts for activating the C–N
bond of amides gave the desired amides as major products. A
variety of amide structures bearing activating groups, such as
glutarimide, succimide, saccharine, pyrazoles, N-Tos, and
N-Boc have been used in the transformation of amides to
afford other amides, as well as carbonyl compounds, such as
ketones and esters.3 In addition, transition-metal-catalyst-free
conditions have also been developed.4 Szostak group demon-
strated that transition-metal-catalyst-free transamidation pro-
ceeded smoothly when LiHMDS was employed as the base in
the reaction of both activated and unactivated amides.5
Recently, we reported that enolizable ketones or esters could
Department of Chemistry, Chonnam National University, Gwangju, 61186, Republic
of Korea. E-mail: sunwoo@chonnam.ac.kr
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
d1ob00967b
Scheme 1 Transamidation of tertiary amides.
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Table 1 Optimization of the transamidation of 1a with 2a a
and generated a variety of examples in good yields.7 However,
the release of N-Boc-N-phenyl amine as the leaving group is a
drawback in terms of atom economy. Rajendran group devel-
oped the transamidation of N-acyl-2-piperidones under mild
conditions; only reactions of active primary amines, such as
aliphatic and benzyl amines, were reported, while aniline
derivatives failed to react.8
Entry
Deviation from the standard conditions
Yieldb (%)
The use of water as a reaction solvent has received consider-
able attention because it is safe, inexpensive, and eco-friendly.
However, reports of transamidation under aqueous conditions
are rare, even though both amides and amines are generally
highly soluble in water. Moreover, in most cases, primary
amides were used under metal-free aqueous conditions.9
Chandrasekaran group reported the transamidation of N-tosyl-
N-benzyl amide using water as the solvent, and achieved
several transformations with alkylamines; however, only one
aniline example was described. In addition, the atom economy
of this approach is unsatisfactory, as N-tosyl-N-benzyl amine is
produced as the leaving group (Scheme 1b).10 Herein, we
report metal-free transamidation of tertiary amides and
amines under aqueous conditions (Scheme 1c).
1
2
3
4
5
6
7
8
None
95
65
15
32
17
74
54
55
0
15
50
0
0
0
DTBP (2.0 equiv.) was used
TBHP instead of DTBP
Cu(OAc)2 instead of DTBP
Mn(OAc)2 instead of DTBP
TBABr instead of TBAI
TBACl instead of TBAI
TBAF instead of TBAI
In the absence of TBAI
EtOH instead of H2O
CH3CN instead of H2O
DMF instead of H2O
DMSO instead of H2O
EtOAc instead of H2O
DCM instead of H2O
Reaction temperature at 50 °C
Reaction time for 6 h
9
10
11
12
13
14
15
16
17
0
45
55
To address the narrow substrate scope, we focused on devel-
oping a metal-catalyst-free protocol under aqueous conditions
for the transamidation of amides using a variety of aniline 80 °C for 16 h. b Isolation by using column chromatography.
derivatives. We also considered the atom economy of the
amide living group and found that benzoylpyrrolidin-2-one
was a suitable substrate.
a Reaction conditions: 1a (0.33 mmol), 2a (0.30 mmol), DTBP
(0.9 mmol) and TBAI (0.03 mmol) were reacted in H2O (1.5 mL) at
are shown in Table 2. As expected, aniline successfully pro-
vided 3aa in 95% isolated yield. 4-Methyl-, 4-methoxy-,
4-phenoxy-, and 4-methylthio-substituted anilines gave the
Results and discussion
corresponding transamidated products 3ab, 3ac, 3ad, and 3ae,
To determine the optimal conditions, benzoylpyrrolidin-2-one respectively, in excellent yields. 2,4,6-Trimethylaniline and
and aniline were chosen as the standard substrates and 2-phenoxyaniline, in which the substituents are located near
reacted under various conditions. After numerous attempts, it the reaction site, provided 3af and 3ag in 61% and 78% yield,
was found that when di-tert-butylperoxide (DTBP) (3.0 equiv.) respectively. In the reaction with N-phenylbenzene-1,2-
and tetra-n-butylammonium iodide (TBAI) (10 mol%) were diamine, it was found that the primary amine selectively
employed as the oxidant and additive, respectively, the highest reacted with 1a to give 3ah in 81% yield. Aniline derivatives
product yield was obtained (entry 1) (Table 1). Decreasing the bearing halide groups, such as fluoride, iodide, bromide, and
amount of DTBP to 2.0 equiv. resulted in a 65% yield of 3aa chloride afforded the desired products in good yields. It is
(entry 2). When tert-butylhydroperoxide (TBHP) was employed, noteworthy that all halides were tolerated without hydrode-
the desired product was obtained in 15% yield (entry 3). halogenation. 1-Amino- and 2-aminonaphthalene provided
Employing other oxidants, such as Cu(OAc)2 and Mn(OAc)2, 3ap and 3aq in 69% and 91% yield, respectively. 1,1′-Biphenyl-
did not provide satisfactory results (entries 4 and 5). When the 2-amine and 4-aminobenzonitrile gave 3ar and 3as in 80% and
reactions were conducted in the presence of TBABr, TBACl, or 69% yield, respectively. Benzylamine derivatives provided 3at,
TBAF, 3aa was obtained in 74%, 54%, and 55% yield, respect- 3au and 3av in 95%, 65% and 48% yields, respectively. In
ively (entries 6–8). Interestingly, no product was obtained addition, n-hexylamine, and cyclohexylamine gave the desired
when the reaction was performed in the absence of TBAI products in good yields. However, when secondary and tertiary
(entry 9). Reactions in EtOH and CH3CN resulted in 15% and amines such as dicyclohexylamine and trimethylamine were
50% yield, respectively (entries 10 and 11). However, the use of employed in the reaction with 1a under the standard con-
DMF, DMSO, EtOAc and CH2Cl2 did not result in product for- ditions, no expected 3ay and 3az were formed. In addition, we
mation (entries 12–15). Decreasing the reaction temperature to failed to obtain the transamidated product 3a-1 and 3a-2 from
50 °C and reducing the reaction time to 6 h resulted in lower the reaction with 1a and amino acids.
yields than those obtained under standard conditions (entries
16 and 17).
Next, we explored various benzoylpyrrolidin-2-ones bearing
substituents on the phenyl ring in the reaction with aniline
Under these optimized conditions, a variety of aniline under the standard reaction conditions (Table 3). Alkyl-substi-
derivatives were explored in the reaction with 1a. The results tuted benzoylpyrrolidin-2-ones, such as 1b, 1c, and 1d gave the
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Table 2 Transamidation of 1a with aromatic and aliphatic aminesa
pryrrolidin-2-one. Alkyl-substituted carbonylpyrrolidin-2-ones,
including 1r, 1s, 1t, and 1u, reacted with aniline or 4-methyl-
aniline to give the corresponding products 3ra, 3sb, 3tb, and
3ub in good yields. 2-Phenylacetylpyrrolidin-2-one reacted with
4-methylaniline
to
afford
3vb
in
91%
yield.
4-Methoxybenzoylpyrrolidin-2-one reacted with 2-methoxyben-
zylamine to deliver 3wz in 88% yield.
We attempted to extend the amide substrate scope for the
reaction with aniline under standard conditions. The results
are shown in Scheme 2. When benzoylpiperidin-2-one and
benzoylazepan-2-one were reacted with aniline, 3aa was
obtained in 90% and 86% yield, respectively. However,
N-benzoyl succinimide and benzoyl glutarimide did not
produce the desired product.
To study the effect of the substituents, we conducted com-
petitive reactions, as shown in Scheme 3. When equal
amounts of 2b and 2q were allowed to react with 1a under
standard reaction conditions, the corresponding products 3ab
and 3aq were formed in 62% and 32% yield, respectively
Table 3 Transamidation of substituted acylpyrrolidin-2-ones with
aminesa
a Reaction conditions: 1a (1.1 mmol), 2 (1.0 mmol), DTBP (3.0 mmol)
and TBAI (0.1 mmol) were reacted in H2O (5.0 mL) at 80 °C for 16 h.
corresponding products 3ba, 3ca, and 3da in 93%, 91%, and
94% yield, respectively. However, 2-methyl benzoylpyrrolidin-2-
one provided a slightly lower product yield (66%) owing to the
steric effect of the substituent. The 4-methoxy-substituted
derivative afforded 3fa in 95% yield. 4-Fluoro-, 2-fluoro-, and
4-trifluoromethyl-substituted compounds provided 3ga, 3ha,
and 3ia in 92%, 76%, and 82% yield, respectively.
2-Naphthoyl- and 1,1′-biphenyl-4-carbonyl-pyrrolidin-2-ones
reacted with aniline to give the corresponding products 3ja
and 3ka in 88% and 86% yield, respectively. When 4-fluoro-
benzoylpyrrolidin-2-one and 4-tert-butylaniline reacted, 3ly was
obtained in 84% yield. 2,4,6-Trichlorobenzoypyrrolidin-2-one
also provided the desired product 3ma in 67% yield.
Benzoylpyrrolidin-2-ones bearing cyano, nitro and N,N-di-
propylsulfamoyl groups produced the corresponding products
3na, 3oa and 3pa in good yields. However, we failed to obtain
3qa which has an ester group at the phenyl ring of benzoyl-
a Reaction conditions: 1 (1.1 mmol), 2 (1.0 mmol), DTBP (3.0 mmol)
and TBAI (0.1 mmol) were reacted in H2O (5.0 mL) at 80 °C for 16 h.
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bearing an electron-withdrawing group is higher reactive than
that bearing an electron-donating group.
Several control experiments were performed to elucidate
the reaction pathway (Scheme 4). When 2a was reacted in the
presence of the radical scavenger BHT under standard con-
ditions, the adduct 8, which was formed from the reaction of
BHT and aniline, was obtained in 68% yield (Scheme 4a). The
structure of 8 was confirmed by HRMS and NMR analysis11
(see ESI†). When 1a was treated with 1,1-diphenylethylene (9)
in the absence of 2a under standard conditions, 9 was formed
in 66% yield (Scheme 4b). These results support the hypoth-
esis that the reaction proceeds via a radical mechanism; the
aniline radical and acyl radical might be intermediates. In
addition, mechanistic studies on kinetic isotope effects (KIE)
Scheme 2 Transamidation of benzylamide derivatives with aniline.
Scheme 4 Control experiments.
Scheme 3 Competitive reactions.
(Scheme 3a). This result signifies that anilines bearing elec-
tron-donating groups are more reactive than those bearing
electron-withdrawing groups. In the competitive reaction of 1a
with aniline (2a) and benzylamine (2q), 3aa and 3ar were
formed in 42% and 39% yields, respectively (Scheme 3b). This
result suggests that both aromatic and benzyl amines exhibi-
ted similar reactivity under the standard reaction conditions.
When the competitive reaction between 1a and 1l was con-
ducted with 2a, 3aa and 3la were formed in 55% and 24%
yields, respectively (Scheme 3c). This result implies that aryl-
substituted 1a displayed higher reactivity than its alkyl-substi-
tuted counterpart. In addition, when the competitive reaction
of 1f and 1n was conducted under standard conditions, 3fa
and 3na were obtained in 34% and 58% yields, respectively
(Scheme 3d). This result supports that benzoylpyrrolidin-2-one Scheme 5 Proposed mechanism.
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were also conducted (Scheme 4c). In parallel experiments with
H2NPh and D2NPh from initial rate, a KIE of kH/kD = 1.7 was
obtained. From this result, the abstract of hydrogen radical of
aniline might be the rate-limiting step.
Notes and references
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On the basis of these results, we propose the reaction
pathway depicted in Scheme 5. Di-tert-butyl peroxide reacts
with TBAI to give tert-butoxyl radical and tert-butoxide.12 The
reaction of tert-butoxide and DTBP generates tert-butyl peroxy
radical by iodine. These two radical species react with aniline
via single-electron transfer to generate aniline cation radical
species A. Cation radical species A reacts with benzoylpyrroli-
din-2-one, which provides B through a radical pathway, and
the subsequent radical dissociation releases the pyrrolidin-2-
one radical as a leaving group to give transamidated cation C.
Finally, hydroxide or tert-butoxide abstracts a proton from C to
provide the final product.
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In summary, we developed a metal-free transamidation proto-
col conducted under aqueous conditions. Both aromatic and
aliphatic amines reacted with N-acylpyrrolidin-2-one in the
presence of DTBP and TBAI to give the corresponding trans-
amidated products in good yields. This reaction system
involves the use of water as an environmentally benign solvent,
and exhibits a broad substrate scope. In particular, halide-
substituted aniline derivatives were well tolerated. It was found
that benzoylpiperidin-2-one and benzoylazepan-2-one also
showed good activity under the standard conditions. To the
best of our knowledge, this is the first report of transamidation
of N-acyl lactam amides, exemplified by the reactions of 1, 4,
and 5. Based on the results of the control experiments, we
propose a radical reaction pathway proceeding through the
reaction of aniline radical and acyl radical intermediates.
Author contributions
Devaneyan Joseph: conceptualization, methodology, investi-
gation. Myeong Seong Park: methodology, investigation.
Sunwoo Lee: conceptualization, writing – review & editing,
supervision, project administration, and funding acquistition.
4 (a) C. L. Allen, B. N. Atkinson and J. M. Williams, Angew.
Chem., Int. Ed., 2012, 51, 1383–1386; (b) Y. Liu, S. Shi,
M. Achtenhagen, R. Liu and M. Szostak, Org. Lett., 2017,
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Conflicts of interest
5 (a) G. Li and M. Szostak, Nat. Commun., 2018, 9, 4165;
(b) G. Li, C. L. Ji, X. Hong and M. Szostak, J. Am. Chem.
Soc., 2019, 141, 11161–11172.
There are no conflicts to declare.
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2931–2937; (b) J. Chen, D. Joseph, Y. Xia and S. Lee, J. Org.
Chem., 2021, 86, 5943–5953.
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V. Srivastava, Asian J. Org. Chem., 2019, 8, 853–857.
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Acknowledgements
This research was supported by the National Research
Foundation of Korea (NRF) grant funded by the Korea
Government (MSIT) (NRF-2021R1A2C1005169). The spectral
and HRMS data were obtained from the Korea Basic Science
Institute, Gwangju center and Daegu center.
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