N-benzyl-5-hydroxy-3-pyrrolidin-2-one by hydrogen peroxide oxidation of N-benzyl-3-phenylseleno-2-pyrrolidinone

Article abstract of DOI:10.1080/00397910601133615

Using the known peroxide oxidation of N-benzyl-3-phenylseleno-2- pyrrolidinone with 30% hydrogen peroxide at -5°C after 3.5 h, we prepared the expected N-benzyl-3-pyrrolin-2-one. However, reaction with 30% hydrogen peroxide for 12 h (-5°C→ambient) gave the unexpected product N-benzyl-5-hydroxy-3-pyrrolidin-2-one in 84% isolated yield. This procedure is a new synthetic route to N-benzyl-5-hydroxy-3-pyrrolidin-2-one. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910601133615

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N‐Benzyl‐5‐hydroxy‐3‐pyrrolidin‐2‐one
by Hydrogen Peroxide Oxidation of
N‐Benzyl‐3‐phenylseleno‐2‐pyrrolidinone
JiYoung Mun a & Michael B. Smith a
a Department of Chemistry , University of Connecticut , Storrs, CT, USA
Published online: 10 Mar 2007.
To cite this article: JiYoung Mun & Michael B. Smith (2007) N‐Benzyl‐5‐hydroxy‐3‐pyrrolidin‐2‐one by
Hydrogen Peroxide Oxidation of N‐Benzyl‐3‐phenylseleno‐2‐pyrrolidinone, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 37:5, 813-819, DOI:
10.1080/00397910601133615
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Synthetic Communicationsw, 37: 813–819, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910601133615
N-Benzyl-5-hydroxy-3-pyrrolidin-2-one
by Hydrogen Peroxide Oxidation
of N-Benzyl-3-phenylseleno-2-pyrrolidinone
JiYoung Mun and Michael B. Smith
Department of Chemistry, University of Connecticut, Storrs, CT, USA
Abstract: Using the known peroxide oxidation of N-benzyl-3-phenylseleno-2-pyrroli-
dinone with 30% hydrogen peroxide at 258C after 3.5 h, we prepared the expected
N-benzyl-3-pyrrolin-2-one. However, reaction with 30% hydrogen peroxide for 12 h
(258C ! ambient) gave the unexpected product N-benzyl-5-hydroxy-3-pyrrolidin-
2-one in 84% isolated yield. This procedure is a new synthetic route to N-benzyl-5-
hydroxy-3-pyrrolidin-2-one.
Keywords: elimination, lactam, peroxide, pyrrolidin-2-one, rearrangement,
selenoxide
While pursuing a new approach to the synthesis of ceramides, we required
N-benzyl-3-pyrrolin-2-one (3). This lactam has been reported in the litera-
ture,[1] relying on a straightforward procedure that involved syn-elimination
of selenoxide 2,[2] prepared by oxidation of N-benzyl-3-phenylseleno-2-
pyrrolidinone, 1. Such selenoxide elimination reactions are commonplace.[2]
N-Benzyl-2-pyrrolidinone is readily prepared from 2-pyrrolidinone and
benzyl bromide[3] or benzyl chloride.[4] The preparation of conjugated
lactams is also well known, via reaction of the lactam enolate anion with
PhSeBr, followed by oxidation and syn elimination of the selenoxide.[5]
Received in the USA July 26, 2006
Address correspondence to Michael B. Smith, Department of Chemistry, University
of Connecticut, 55 North Eagleville Road, Storrs, CT 06269-3060, USA. E-mail:
michael.smith@uconn.edu
813

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J. Mun and M. B. Smith
In this work, we prepared 1 in 52% yield by reaction of N-benzyl-2-pyrrolidi-
none with lithium diisopropylamide (LDA), tetrahydrofuran (THF), 2788C
and with PhSeBr, THF, 2788C.[2–5] The literature procedure to prepare 3
by oxidation of 1 was repeated several times, using 30% aqueous hydrogen
peroxide at 258C, for 3.5 h. Under these conditions, we obtained 3 in 87%
yield with few by-products. During the course of one oxidation with 30%
hydrogen peroxide at 258C, the solution was allowed to stir for 12 h. During
this time period, the reaction mixture warmed to ambient temperatures. Upon
workup, we discovered that the major product was not 3 but rather 4.[6] This
was unexpected, and such a hydroxylation reaction had not been reported pre-
viously from selenoxide elimination reactions with lactams. Lactam 4 is a
known compound, however, prepared by the cerium chloride/sodium borohy-
dride reduction of N-benzyl maleimide,[7] which can be prepared by reaction
of maleic anhydride and benzylamine.[8]
Formation of 4 was unusual, given that the preparation of conjugated lactams by
this method had been reported many times, and we repeated the reaction to
confirm the transformation. Indeed, lactam 4 was formed in 84% isolated
yield under these conditions, making this process a synthetically viable alterna-
tive to the previously reported synthesis.[7] Perhaps more important, the
synthetic community should be aware of this anomalous reaction when
preparing conjugated lactam compounds and also be aware of the sensitivity
of the reaction to temperature and time.
The mechanism of the hydroxylation is unknown at this time, but allylic
oxidation of 3, or rearrangement from an intermediate that is as yet undefined,
are possibilities. However, mechanistic analogies suggested by literature
precedent do not adequately explain this transformation. One possibility is
the Evans–Mislow rearrangement of allylic sulfides,[9] which involves a
[2,3]-sigmatropic rearrangement. Reich and Yelm reported a similar [2,3]-
sigmatropic rearrangement of selenoxides,[10] which they stated was facile
at temperatures hotter than 2508C. Sharpless and Lauer showed that
oxidation of allylic selenides gave rearrangement to alcohols via a [2,3]-
sigmatropic rearrangement.[11] To invoke such a mechanism, however,
requires initial formation of an allylic selenide, which seems unlikely in this

N-Benzyl-5-hydroxy-3-pyrrolidin-2-one
815
case. Benzeneselenic acid is a by-product of the selenoxide elimination and
can add to alkenes as reported by Sharpless, who showed that cyclooctene
reacted with benzeneselenic acid to give the hydroxy-selenide.[12] Subsequent
oxidation with tert-butylhydroperoxide gave cyclooct-2-en-1-ol. Such an
addition–elimination sequence involving 3 would not lead to 4 directly but
may lead to an intermediate that rearranges to 4. This is, of course, speculative.
The allylic oxidation of alkenes with selenium dioxide[13] involving an initial
ene reaction followed by a [2,3]-sigmatropic rearrangement[14] is another
possible analogy. There is no evidence of selenium dioxide in the reaction of
1, but reaction of the S55O unit of the PhSeOH by-product with 3 may be
possible. If so, rearrangement and conversion to 4 in the aqueous medium is
possible. All of this is speculative, of course, and a detailed mechanistic
study is required. Such speculation has some value in that it points to a
working hypothesis that formation of 4 may involve initial formation of 3
followed by a reaction with PhSeOH in the presence of the aqueous
hydrogen peroxide.
Apart from the mechanistic speculation, the reaction of 1 with aqueous
hydrogen peroxide under these conditions is a synthetically useful route to
hydroxy-lactam 4. From a practical standpoint, formation of 4shouldbe considered
a competitive sidereaction for the preparation of conjugated lactams by selenoxide
elimination that is dependent upon temperature control and reaction time.
EXPERIMENTAL
All glassware was flame-dried under nitrogen, and all reactions were
performed under nitrogen. All chemicals were purchased from the Aldrich
Chemical Co. and used without further purification. The tetrahydrofuran
was dried over sodium–benzophenone and distilled immediately prior to its
use. The 1H NMR (400 MHz) and the 13C NMR (100.65 MHz) were
recorded on a Bru¨cker DRX-400 instrument, in CDCl3, and all chemical
shifts are reported in d, relative to tetramethylsilane (TMS) as an internal
standard. Infrared spectra were recorded on a Jasco FT/IR-410 instrument
and are reported in centimeters21. Mass spectra were recorded on a Hewlet-
Packard 5970 GC/MS instrument.
Preparation of N-Benzyl-2-pyrrolidinone
Addition of benzyl bromide (18 mL, 151 mmol) and 2-pyrrolidinone (12.75 g,
150 mmol) to a mixture of pulverized KOH (8.30 g, 149 mmol) and

816
J. Mun and M. B. Smith
tetrabutylammonium bromide (TBAB, 7.09 g, 22 mmol) in 100 mL of THF,
in a 500-mL, three-neck, round-bottom flask fitted with an overhead mechan-
ical stirrer, was followed by stirring of the reaction mixture for 1 h at ambient
temperature. During the addition and subsequent reaction, the reaction flask
was immersed in a Bransonic 220 ultrasonic bath. Filtration of the precipitate
and concentration of the reaction mixture in vacuo led to an oil, which was
treated with 100 mL of diethyl ether. The precipitated TBAB was filtered,
the organic layer dried with MgSO4, and the solution filtered and concentrated
in vacuo. Purification by silica-gel chromatography (ether/hexane) gave
1
15.0 g of N-benzyl-2-pyrrolidinone[3] (86.0 mmol, 57%). H NMR: d 7.27–
7.19 (m, 5H), 4.40 (s, 2H), 3.17 (t, 2H), 2.33 (t, 2H), and 1.94 ppm
(m, 2H); 13C NMR: d 174.5 (S), 136.7 (s), 128.4 (d), 128.3 (d), 128.1 (d),
127.8 (d), 127.5 (d), 46.4 (t), 46.3 (t), 30.8 (t), and 17.6 ppm (t); IR (neat):
3030, 2915, 1687, 1429, 1286, and 702 cm21; MS (m/z, rel. int.), 176 (67,
P), 146 (44), 118 (19), 104 (38), 91 (100, B), 65 (35), and 51 (15).
Preparation of N-Benzyl-3-phenylseleno-2-pyrrolidinone
A 250-mL, three-neck, round bottom flask was charged with 2.63 mL of dii-
sopropylamine (18.8 mmol) dissolved in 20 mL of dry THF, at room tempera-
ture. The reaction flask was immersed in a dry-ice bath, and the solution was
stirred for 5 min at 2788C). Addition of 15.85 mL of butyllithium in hexane
(1.2 M, 19.3 mmol) to the diisopropylamine solution was accomplished via
cannula. The reaction mixture was stirred for 15 min at 2788C, and
2.74 mL of 1-benzyl-2-pyrrolidinone (16.8 mmol) dissolved in 20 mL of
THF was transferred to the reaction mixture via cannula. The reaction
mixture was stirred for 1 h at 2788C, and 4.638 g of phenylselenenyl
bromide (19.3 mmol) dissolved in 20 mL of THF was transferred to the
reaction mixture. The reaction mixture was stirred for 30 min at 2788C,
and 10 mL of saturated aqueous ammonium chloride was added. The
reaction mixture was stirred while the reaction mixture warmed to ambient
temperature, and 100 mL of ethyl acetate and 50 mL of distilled water were
added to the reaction. After separation of the organic phase, it was washed
with brine, dried with magnesium sulfate, and concentrated in vacuo. The
crude product was purified with silica column chromatography using 25%
ethyl acetate in hexane to give 2.94 g of 3-phenylselenopyrrolidin-2-one[3,5]
(10.0 mmol, yield 51.9%).

N-Benzyl-5-hydroxy-3-pyrrolidin-2-one
817
1
GC/MS (m/z): 51, 65, 91 (b), 157, 174, 250, 331 (Mþ), H NMR: d
2.05–2.13 (1H, m), 2.44–2.54 (1H, m), 2.93–2.99 (1H, m), 3.06–3.11 (1H,
m), 3.94–3.98 (1H, dd, J 8.83 Hz, J 4.37 Hz), 4.34–4.43 (2H, dd, J
21.8 Hz, J 16.7 Hz), and 7.15–7.68 ppm (10H, m).
Preparation of N-Benzyl-3-pyrrolin-2-one
A 25-mL, three-neck, flask containing 525 mg of 3-phenylseleno-2-pyrrolidi-
none (1.59 mmol) dissolved in 5 mL of ethyl acetate was immersed in a salt-
ice bath and stirred for 5 min at 2108C. Slow addition of 0.9 mL of 30%
aqueous hydrogen peroxide was followed by stirring at 258C until the 3-phe-
nylseleno-2-pyrrolidinone disappeared, as monitored by thin-layer chromato-
graphy (TLC) (about 4 h). After the completion of the reaction, the ice bath
was removed, and 10 mL of ethyl acetate and 5 mL of brine were added to
the reaction mixture. Extraction was followed by separation of the organic
layer. The organic layer was washed with 5 mL of saturated aqueous
sodium bicarbonate solution and then 5 mL of brine. Drying of the organic
layer with MgSO4 was followed by filtration and concentration in vacuo.
The crude product was purified with silica column chromatography (50%
ethyl acetate in hexane) to give 238 mg of 1-benzyl-3-pyrrolin-2-one[3,5]
(1.38 mmol, 87%).
GC/MS (m/z): 51, 65, 91 (B), 144, and 173 (Mþ); 1H NMR: d 3.80 (2H,
s, 5H), 4.57 (2H, s), 6.15–6.17 (1H, dt, J 6.0 Hz, J 1.8 Hz), 6.97–6.99 (1H, dt,
J 6.0 Hz, J 1.6 Hz, 3H), and 7.16–7.28 ppm (5H, m); 13C: d 45.97, 52.27,
127.58, 127.94, 128.00, 128.76, 137.30, 142.83, and 171.36 ppm; IR (neat):
3082, 1703, and 1677 cm21
.
Preparation of N-Benzyl-5-hydroxy-3-pyrrolin-2-one
A 25-mL, three-neck flask was charged with 525 mg of N-benzyl-3-phenylse-
leno-2-pyrrolidinone (1.59 mmol) dissolved in 5 mL of ethyl acetate and

818
J. Mun and M. B. Smith
immersed in a salt-ice bath. After stirring for 5 min at 2108C, 0.9 mL of 30%
aqueous hydrogen peroxide solution was slowly added to the solution. The
reaction mixture was stirred at 258C until the N-benzyl-3-phenylseleno-2-
pyrrolidinone disappeared as monitored by TLC (about 4 h). The reaction
mixture was stirred overnight with slow elevation of temperature from
258C to room temperature. At this time, 10 mL of ethyl acetate and 5 mL
of brine were added to the reaction mixture, and the organic layer was
separated. The organic layer was washed with 5 mL of saturated aqueous
sodium bicarbonate solution and then 5 mL of brine, dried with MgSO4,
and concentrated in vacuo. The crude product was purified with silica
column chromatography (100% ethyl acetate) to give 254 mg of N-benzyl-
5-hydroxy-3-pyrrolin-2-one[7] (1.34 mmol, 84%).
GC/MS (m/z): 55, 65, 79, 91, 106 (B), 189 (Mþ); 1H NMR (400 MHz): d
3.56–3.59 (1H, d, J 10.9 Hz), 4.14–4.18 (1H, d, J 14.9 Hz), 4.81–4.85 (1H, d,
J 14.9 Hz), 5.16–5.19 (1H, d, J 10.9 Hz), 6.03–6.05 (1H, d, J 5.9 Hz), 6.84–
6.86 (1H, d, J 5.9 Hz), and 7.18–7.25 ppm (5H, m); 13C NMR (100.65 MHz):
d 43.1, 83.1, 128.1 (2C), 128.7 (2C), 129.2 (2C), 137.5, 146.5, and 170.0 ppm;
IR (KBr): 3178, 2963, 1662, 1591 cm21
.
ACKNOWLEDGMENT
We thank the R&C Patterson Trust for partial funding of this work. We thank
Martha Morton, coordinator of the NMR facility, and Marvin Thompson,
coordinator of the mass spectrometer facility, for their generous help in this
work.
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