CAN mediated decarboxylative hydroxylation/alkoxylation of N-aryl-γ-lactam-carboxylic acids at room temperature: an easy access to N-aryl-α-hydroxy/alkoxy-γ-lactams

Article abstract of DOI:10.1016/j.tetlet.2008.03.147

An efficient and mild protocol for one-pot decarboxylative hydroxylation/alkoxylation of 1,3-diaryl-5-oxo-pyrrolidine-2-carboxylic acids to trans-5-hydroxy-1,4-diarylpyrrolidin-2-ones and 5-alkoxy-1,4-diaryl-1,5-dihydropyrrol-2-ones at room temperature us

Full text of DOI:10.1016/j.tetlet.2008.03.147

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 3659–3662
CAN mediated decarboxylative hydroxylation/alkoxylation
of N-aryl-c-lactam-carboxylic acids at room temperature:
an easy access to N-aryl-a-hydroxy/alkoxy-c-lactams
Pranab Haldar, Jayanta K. Ray *
Department of Chemistry, Indian Institute of Technology, Kharagpur 721 302, India
Received 18 February 2008; revised 26 March 2008; accepted 28 March 2008
Available online 8 April 2008
Abstract
An efficient and mild protocol for one-pot decarboxylative hydroxylation/alkoxylation of 1,3-diaryl-5-oxo-pyrrolidine-2-carboxylic
acids to trans-5-hydroxy-1,4-diarylpyrrolidin-2-ones and 5-alkoxy-1,4-diaryl-1,5-dihydropyrrol-2-ones at room temperature using
CAN in organo-aqueous solvent has been developed.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Decarboxylative hydroxylation; c-Lactam-carboxylic acid; Ceric ammonium nitrate; 1,5-Dihydropyrrol-2-one
1. Introduction
a-Hydroxy-c-lactams are of particular interest to chem-
ists due to their versatile applications, for example, as the
core structure of the neuritogenic agent epolactaene,3a in
the synthesis of a number of heterocyclic compounds3b,c
and also as precursors for the highly reactive cyclic a-acyli-
minium ion.3d N-Methyl-a-hydroxy-c-lactam is an impor-
tant intermediate for the synthesis of (ꢀ)ecgoninic acid,3e
whereas the alkaloid isolongistrobine contains an N-aryl-
a-hydroxy-c-lactam unit as a key structural feature.3f N-
Alkyl-a-hydroxy-c-lactams are usually prepared as the
major product by anodic oxidation of N-alkyl-c-lactams,4a
NaBH4/HCl mediated regioselective reduction of substi-
tuted succinimides,4b osmium tetroxide–sodium metaperio-
date (Lemieux–Johnson reagent)4c mediated oxidation of
cis- or trans-4-octen-1,8-dicarboxamides4d or via an elec-
trochemical method.4e
Although radical-induced decarboxylation of amino
acids5 is of great significance for biological systems consid-
ering the many well-established enzymatic or metabolic
pathways for radical generation in vivo,6 to date there
are no reports on the one-pot decarboxylative hydroxyl-
ation/alkoxylation of c-lactam-carboxylic acids at room
temperature. In continuation of our ongoing interest to
develop simple methodologies7 for various functional
The carboxylic acid functionality is present in many
classes of synthetic as well as natural bioactive aza-hetero-
cycles. The possibility of manipulating this ubiquitous
functional group under mild conditions should open up
new vistas in terms of partial syntheses and improved bio-
logical activity profiles. A number of high valent metals,1
for examples, Pb(IV), Mn(III) and Tl(III) have been used
as oxidative decarboxylating agents, but all of these
reagents suffer from the disadvantages of toxicity. Due to
the lack of a convenient oxidizing agent, the room temper-
ature decarboxylative hydroxylation/alkoxylation of c-lac-
tam-carboxylic acids in a single-step is a complex problem
in synthetic organic chemistry. This one-pot transforma-
tion would be very useful for the synthesis of a variety of
bioactive hydroxy/alkoxy-c-lactam derivatives which con-
stitute attractive synthetic targets for promising biological
applications including antimicrobial,2a a-glucosidase inhi-
biting2b and as neuritogenic agents.2c,d
*
Corresponding author. Tel.: +91 3222 283326; fax: +91 3222 282252.
E-mail address: jkray@chem.iitkgp.ernet.in (J. K. Ray).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.03.147

3660
P. Haldar, J. K. Ray / Tetrahedron Letters 49 (2008) 3659–3662
group transformations of N-aryl-c-lactam derivatives,
herein we report our study on a reagent system that pro-
vides a simple, one-step method for the conversion of
1,3-diaryl-5-oxo-pyrrolidine-2-carboxylic acids (1,3-diaryl-
c-lactam-2-carboxylic acids) to trans-5-hydroxy-1,4-diaryl-
pyrrolidin-2-ones (trans-1,4-diaryl-a-hydroxy-c-lactams)
and 5-alkoxy/azido-1,4-diaryl-1,5-dihydropyrrol-2-ones at
room temperature.
O
Ce(IV)
Ar
CO2H
Ar'
Ar
Ar
.
N
O
H
CAN
N
N
-CO2
CH3CN-H2O
Ar'
Ce(III)
O
O
Ar'
O
1
-
-e
Ce(IV)
..
Ar
..
N
OH
Ar'
Ar
Ar
+
N
+
H2O
N
Ar'
O
Ar'
O
O
The advantages of good solubility in water (1.41 g/mL
at 25 °C and 2.27 g/mL at 80 °C), low cost, low toxicity,
commercial availability, ease of handling and the profound
reactivity endowed in the reduction potential of +1.6 V
compared to NHE (normal hydrogen electrode) have con-
tributed to the general acceptance of ceric ammonium
nitrate (CAN) as a versatile one-electron oxidant for car-
bon–heteroatom bond formation reactions8 and give rise
to the possibility of the development of more practical
reactions in organo-aqueous medium at room temperature.
In view of the above usefulness of CAN as a single
electron oxidant, we became interested in exploring its
reactivity towards the decarboxylative hydroxylation/
alkoxylation of 1,3-diaryl-5-oxo-pyrrolidin-2-carboxylic
acids (1,3-diaryl-c-lactam-2-carboxylic acids) at room
temperature in organo-aqueous solvent.
The starting materials for this study, 1,3-diaryl-5-oxo-
pyrrolidin-2-carboxylic acids 1, were synthesized following
the general method7,9 developed in our laboratory. Decarb-
oxylative hydroxylation10 of 1 with CAN in acetonitrile–
water (1:1, v/v) at room temperature furnished exclusively
trans-5-hydroxy-1,4-diarylpyrrolidin-2-ones 2 (Scheme 1)
in high yields (Table 1).
2
Scheme 2.
it can be speculated that the reaction proceeds (Scheme
2) through an N-acyliminium intermediate. The mechanism
involving a complex intermediate as evidence for a complex
in the Ce(IV) oxidation of acetic acid has been obtained.13
This complex is generated through loss of CO2 leading to
an alkyl radical a to nitrogen, which is easily oxidized by
excess CAN to a cation, and the resulting iminium ion is
converted to the a-hydroxy-c-lactam (trans-5-hydroxy-
1,4-diarylpyrrolidin-2-one) via nucleophilic attack of
water.
The pleasing outcome of the above reaction prompted
us to extend this method to include other nucleophilic sol-
vents. Instead of water, we performed the same reaction
using alcohols with acetonitrile (1:1, v/v). However, in this
case, dehydrogenation14 along with decarboxylative alk-
oxylation (Scheme 3) occurred to give 5-alkoxy-1,4-di-
aryl-1,5-dihydropyrrol-2-ones 3 in good yields (Table 2).
To further test the generality of this reaction we next
investigated the reaction of trans-1-(3,4-dichlorophenyl)-
3-phenyl-5-oxo-pyrrolidin-2-carboxylic acid 1c (1 mmol)
with sodium azide (1.1 mmol) as the nucleophilic agent in
acetonitrile (15 mL) at room temperature. After stirring
for 5 h, we obtained 5-azido-1-(3,4-dichlorophenyl)-4-
phenyl-1,5-dihydropyrrol-2-one 4 in 77% yield (Scheme 4).
Though we are able to speculate a possible mechanistic
pathway for the decarboxylative hydroxylation (Scheme 2),
we are unable to put forward a plausible mechanism for the
dehydrogenation to give compounds 3 and 4.
The trans arrangement of the C-4 and C-5 substituents
of 2 was confirmed from the coupling constant values
between C-4H and C-5H (ꢁ2–2.4 Hz).11
Although the mechanism of the reaction is uncertain, as
might be expected of a very powerful one-electron oxidant,
the chemistry of Ce(IV) oxidation of organic molecules is
dominated by radical cation chemistry and by analogy12
In summary, we have developed a mild and efficient
method for the synthesis of a-hydroxy/alkoxy/azido-c-
Ar
O
OH
Ar'
Ar
O
CO2H
Ar'
N
N
CAN
CH3CN-H2O
rt
2
1
Ar
O
OR
Ar'
Ar
O
CO2H
Ar'
Scheme 1.
N
N
CAN
CH3CN-ROH
1
3
Table 1
Synthesis of trans-5-hydroxy-1,4-diarylpyrrolidin-2-ones
diaryl-5-oxo-pyrrolidin-2-carboxylic acids 1
2
from 1,3-
Yield (%)
Scheme 3.
Substrate
Ar
Ar0
Product
Table 2
1a
1b
1c
1d
1e
1f
Ph
Ph
Ph
Ph
Ph
2-Thienyl
Ph
2a
2b
2c
2d
2e
2f
90
88
87
88
82
91
Synthesis of 5-alkoxy-1,4-diaryl-1,5-dihydropyrrol-2-ones 3 from 1,3-
diaryl-5-oxo-pyrrolidine-2-carboxylic acids 1
4-ClC6H4
3,4-Cl2C6H3
3-Cl,4-FC6H3
3-Cl,4-FC6H3
4-FC6H4
Substrate
Ar
Ar0
R
Product
Yield (%)
1a
1f
Ph
4-FC6H4
Ph
Ph
Et
Me
3a
3b
84
93

P. Haldar, J. K. Ray / Tetrahedron Letters 49 (2008) 3659–3662
3661
3.2. 1-(4-Fluorophenyl)-5-methoxy-4-phenyl-1,5-
dihydropyrrol-2-one ð3bÞ
Ar
O
N3
Ar'
Ar
O
CO2H
Ar'
N
N
CAN
CH3CN-NaN3
1c
4
Colourless solid; mp 136–139 °C; IR (KBr) m
1688,
max
1
1509 cmꢀ1; H NMR (200 MHz; CDCl3): d 2.99 (s, 3H),
6.40 (s, 1H), 6.61 (s, 1H), 7.06–7.15 (m, 2H), 7.45–7.49
(m, 3H), 7.70–7.78 (m, 4H). 13C NMR (50 MHz; CDCl3):
d 48.7, 88.4, 115.8 (d, J ꢁ 22.4 Hz), 122.3, 122.4, 122.6,
126.9, 129.1, 130.1, 130.9, 133.2, 152.9, 159.8 (d,
J ꢁ 242.7 Hz), 168.7. Anal. Calcd for C17H14FNO2: C,
72.07; H, 4.98; N, 4.94. Found: C, 71.98; H, 5.01; N,
4.92. ESI-MS: for C17H14FNO2 [M], [M+H] + = 284.09.
Scheme 4.
lactam derivatives via CAN mediated one-pot decarboxyl-
ative hydroxylation/alkoxylation/azidination of 1,3-diaryl-
5-oxo-pyrrolidin-2-carboxylic acids at room temperature.
The 5-alkoxy/azido-dihydropyrrol-2-one derivatives may
serve as dienophiles in Diels–Alder reactions.15 The lactam
carbonyl could be further reduced7a,d,e using sodium boro-
hydride–iodine in dry THF to synthesize differently substi-
tuted hydroxy-pyrrolidine derivatives, which have often
been found to show versatile biological activities.16a–c The
operational simplicity and the mild conditions of this
one-pot process open up new prospects in this area and it
is anticipated that this method will lead to broader applica-
tions in the synthesis of bioactive hydroxy-pyrrolidine
derivatives.
3.3. 5-Azido-1-(3,4-dichlorophenyl)-4-phenylpyrrolidin-2-
one ð4Þ
1
Off-white solid; yield 77%; mp 224–226 °C; H NMR
(200 MHz; CDCl3 + DMSO-d6): d 6.13 (s, 1H), 6.24 (s,
1H), 7.20–7.26 (m, 4H), 7.54–7.61 (m, 3H), 7.88 (d, 1H,
J ꢁ 2.5 Hz). 13C NMR (50 MHz; CDCl3 + DMSO-d6): d
82.6, 118.9, 119.2, 120.9, 125.8, 127.1, 128.4, 129.7, 130.0,
130.1, 131.5, 137.1, 156.4, 167.7. Anal. Calcd for
C16H10Cl2N4O: C, 55.67; H, 2.92; N, 16.23. Found: C,
55.78; H, 2.90; N, 16.19.
2. General procedure for the synthesis of trans-5-hydroxy-
1,4-diarylpyrrolidin-2-ones (2) from 1,3-diaryl-5-oxo-
pyrrolidine-2-carboxylic acids (1)
Acknowledgements
To a stirred solution of 1,3-diaryl-5-oxo-pyrrolidine-2-
carboxylic acid 1 (1 mmol) in acetonitrile (10 mL) in an
open-necked round bottom flask, an aqueous solution of
ceric ammonium nitrate (2.2 mmol in 10 mL of water)
was added and stirring was continued at room temperature
(25–30 °C) for 3–4 h. After completion of the reaction
(monitored by TLC), acetonitrile was removed under vac-
uum and the residue was dissolved in ether. The solution
was washed with saturated sodium bicarbonate solution
and then with brine solution and dried over anhydrous
Na2SO4. Removal of the solvent furnished the crude prod-
uct, which was purified by crystallization from ether–petro-
leum ether (6:1) mixture.
Financial support from DST and CSIR (New Delhi) is
gratefully acknowledged.
References and notes
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3. Spectral data of representative compounds
3.1. 1-(3,4-Dichlorophenyl)-5-hydroxy-4-phenylpyrrolidin-
2-one ð2cÞ
White solid; mp 164–166 °C; 1H NMR (200 MHz;
CDCl3): d 2.67 (dd, 1H, J ꢁ 4.3 Hz and 17.5 Hz), 3.22
(dd, 1H, J ꢁ 8.9 Hz and 17.5 Hz), 3.41–3.47 (m, 1H),
5.49 (d, 1H, J ꢁ 2.1 Hz), 7.19–7.24 (m, 3H), 7.29–7.37
(m, 3H), 7.41–7.44 (m, 1H), 7.70 (d, 1H, J ꢁ 2.8 Hz). 13C
NMR (50 MHz; CDCl3 + DMSO-d6): d 36.9, 45.0, 89.6,
121.1, 123.3, 126.0, 127.5, 128.2, 129.5, 131.4, 136.7,
140.5, 172.4. ESI-MS: for C16H13Cl2NO2 [M],
[M+H]+ = 322.03 (35Cl), 324.03 (35Cl and 37Cl). Anal.
Calcd for C16H13Cl2NO2: C, 59.65; H, 4.07; N, 4.35.
Found: C, 59.57; H, 4.04; N, 4.30.

3662
P. Haldar, J. K. Ray / Tetrahedron Letters 49 (2008) 3659–3662
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