Synthesis and substitution reactions of N-protected 2-(phenylselenonylmethyl)pyrrolidines

Article abstract of DOI:10.1071/C96148

Alkyl phenyl selenides derived from the benzeneselenenyl chloride induced cyclization of N-protected pent-4-enylamines can be converted in good yield into the corresponding 2-hydroxymethyl- or 2-alkoxymethyl-substituted pyrrolidines by oxidation to the corresponding selenone, followed by reaction with water (or hydroxide) or with the corresponding alcohol. Details of the reactions and possible mechanisms for the substitution are discussed.

Full text of DOI:10.1071/C96148

C S I R O P U B L I S H I N G
Australian Journal
of Chemistry
Volume 50, 1997
© CSIRO Australia 1997
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Aust. J. Chem., 1997, 50, 181–187
.
Synthesis and Substitution Reactions of
N -Protected 2-(Phenylselenonylmethyl)pyrrolidines
Matthew A. Cooper A and A. David Ward A,B
A
Department of Chemistry, The University of Adelaide, Adelaide, S.A. 5005.
Author to whom correspondence should be addressed.
B
Alkyl phenyl selenides derived from the benzeneselenenyl chloride induced cyclization of N -protected
pent-4-enylamines can be converted in good yield into the corresponding 2-hydroxymethyl- or 2-
alkoxymethyl-substituted pyrrolidines by oxidation to the corresponding selenone, followed by reaction
with water (or hydroxide) or with the corresponding alcohol. Details of the reactions and possible
mechanisms for the substitution are discussed.
The discovery of the selenoxide syn elimination
as a mild and eꢀcient method for the formation of
double bonds has generated a substantial increase in
organoselenium chemistry.1ꢀ3 The versatility of the
phenylseleno moiety lies in its ability to be introduced
to a molecule as either a nucleophile, an electrophile, or
as an adjunct to cyclization, by using mild conditions.
Subsequent removal of this group, however, is generally
only accomplished by elimination of the corresponding
selenoxide,4ꢀ6 or by reduction.7ꢀ9 Few examples of
substitution reactions of alkyl phenyl selenides have
been reported. Selenides have been converted into
halides via the intermediacy of selenonium halides,10ꢀ16
or into ethers via the intermediacy of selenones.17,18
As part of our studies19,20 on the synthesis of poly-
hydroxylated pyrrolidines and piperidines we required
a method to convert the alkyl phenyl selenide (1)
into the diol (2) (Scheme 1). To our knowledge only
one example of the conversion of an alkyl phenyl
selenide into an alcohol has been reported17 in the
literature and the general applicability of this reaction
has not been investigated. The results presented
herein describe an investigation of the formation and
substitution reactions of a heterocycle-containing alkyl
phenyl selenone.
(3), which was deprotected with hydrazine hydrate,22
and the ethereal extracts containing the amine were
reacted directly with ethyl chloroformate and base
to give the carbamate (4) which was cyclized23 with
benzeneselenenyl chloride to aꢁord (5).
PhthK
Br
Phth
dmf, ∆
(3)
NH2NH2
O
H2N
N
Phth =
ClCO2Et/NaOH
O
PhSeCl
CH2Cl2
SePh
NH
CO2Et
(4)
N
CO2Et
(5)
Scheme 2
Initial attempts to form the alcohol (8) via the
selenone (7) by using m-chloroperbenzoic acid and
potassium hydroxide or tetrabutylammonium hydrox-
ide in reꢂuxing tetrahydrofuran gave a mixture of (8),
the alkene (9) and the ketone (10); these last two
compounds result from elimination of the selenoxide
(6) (Scheme 3).
As the yield of (8) was dependent upon the yield of
the selenone (7), the rates of formation of (7) with a
variety of reaction conditions were examined by using
timed 77Se n.m.r. spectroscopy. By using tetrahydro-
furan as solvent and m-chloroperbenzoic acid as the
oxidizing agent the starting selenide, whose 77Se n.m.r.
signal appeared at 267 ppm, oxidized rapidly to the
OH
OH
Boc = ButOCO
SePh
OH
N
N
Boc
Boc
Scheme 1
(1)
(2)
Results and Discussion
Synthesis of the selenide (5) was accomplished as
outlined in Scheme 2. Reaction of 5-bromopent-1-ene
with potassium phthalimide21 gave a good yield of
Manuscript received 19 August 1996
0004-9425/97/030181$05.00
10.1071/CH96148

182
M. A. Cooper and A. D. Ward
O
O
O
SePh
SePh
m-chloroperbenzoic acid
KOH, ∆
SePh
N
N
N
CO2Et (5)
(6)
(7)
CO2Et
CO2Et
H2O
OH
NH
CO2Et
N
O
N
CO2Et
CO2Et
(9)
Scheme 3
(10)
(8)
selenoxide, at 850 ppm, which then slowly oxidized
to the selenone, at 988 ppm. These resonances were
assigned by comparison with literature values24ꢀ27 and
from the 77Se n.m.r. spectra of the isolated compounds.
The type of solvent employed in the oxidations had
a marked eꢁect upon the rate of formation of the
selenone. Generally the rate was much slower in
aprotic solvents compared to protic solvents. When
the logarithm of the time taken for the complete
conversion of the selenide into the selenone was plotted
against the dielectric constant of the solvent an almost
linear relationship was seen for the alcohol solvents
(Fig. 1).
excess m-chloroperbenzoic acid in methanol or ethanol
at room temperature for 90 min aꢁorded the ethers
(11) and (12) respectively in high yield.
It is possible that this replacement of the selenone
is being eꢁected by anchimeric assistance of the
neighbouring ethoxycarbonyl group (Scheme 4). Alter-
natively, it has been proposed18 that m-chlorobenzoic
acid or m-chloroperbenzoic acid itself catalyses the
formation of an intermediate selenonyl ester in which
the phenylseleninium group acts as a much better
leaving group than the phenylselenonyl group, due to
the formation of an electron-withdrawing aryl ester
(Scheme 5). This latter mechanism is in accordance
with the observation of Krief et al.17 that decyl phenyl
selenone reacts with methanol to give decyl methyl
ether only upon the addition of m-chloroperbenzoic
acid to the reaction medium, and the observation
that (13) was also converted cleanly into a methyl
ether (14) upon treatment with m-chloroperbenzoic
acid in methanol (Scheme 6). The sulfonamide group
would not be expected to participate in anchimeric
assistance due to its unfavourable geometry and low
nucleophilicity.29
O
O
SePh
SePh
m-chloroperbenzoic acid
ROH
N
N
CO2Et
••
EtO
(5)
O
HOR
••
OR
+
PhSeO2H
Fig. 1. Plot of log tmin against dielectric constant (ꢀ0) for the
formation of (7) from (5) by using m-chloroperbenzoic acid in
various solvents.
N
N
O
EtO
O
EtO
+
(11) R = Me
(12) R = Et
When the oxidation was carried out with an alcohol
as the solvent, a peak at 1215 ppm corresponding25,28
to benzeneseleninic acid also appeared. This resonance
appeared most rapidly with methanol or ethanol,
slowly with isopropyl alcohol or t-butyl alcohol, and
did not appear at all with non-nucleophilic solvents.
Examination of the products formed from the reactions
with alcoholic solvents revealed that substitution of
the selenonyl moiety with the alcohols was occurring
to aꢁord alkyl ethers. Reaction of the selenide and
Scheme 4
The optimum conditions for the oxidation of an
alkyl phenyl selenide to the selenone were found to
be reaction with 3 equiv. of m-chloroperbenzoic acid
in isopropyl alcohol or dimethylformamide for 1–2 h
at room temperature. Attempted formation of (7) by
using OXONER in ethanol/water, or hydrogen peroxide

N -Protected 2-(Phenylselenonylmethyl)pyrrolidines
183
in a variety of solvents, gave only the selenoxide (6).
These conditions would thus be appropriate if the
selenoxide was the desired product. The alcohol (8)
could be obtained in 78% yield from the reaction of
(5) with m-chloroperbenzoic acid for 1 h, followed by
treatment with aqueous sodium hydroxide for 4 h at
room temperature. If the base and m-chloroperbenzoic
acid were added simultaneously, lower yields of (8)
were accompanied by the formation of (9) and (10),
these last two compounds resulting from elimination
of the intermediate selenoxide. The alcohol (8) could
also be formed in good yield by reaction with m-
chloroperbenzoic acid in dimethylformamide at room
temperature for 2 h, then heating the mixture with
water at 80ꢁ for 2 h. When the oxidation was carried
out in acetic acid a mixture of the starting selenide
(5) and the alcohol (8) was recovered but the corre-
sponding acetate was not observed. It is possible that
the benzeneseleninic acid formed in the reaction eꢁects
reduction30 of the selenone to the selenide under acidic
conditions.
extended reaction times were employed (Scheme 7).
It is not clear if (8) arises from direct attack of
adventitious water on the selenonyl group or if a
selenone–seleninate rearrangement takes place. Com-
mercial m-chloroperbenzoic acid contains 3–5% water,33
however, yields of (8) of up to 32% were obtained by
using recrystallized m-chloroperbenzoic acid and anhy-
drous dimethylformamide in the presence of 4 A sieves
under argon. This suggests that the rearrangement
process is more likely.
ꢄ
SePh
N
CO2Et
(5)
m-chloroperbenzoic acid
dmf, 3 days
O
C
(7)
+
(8)
+
Cl
N
CO2Et
O
(15)
O
O
m-chloroperbenzoic
Scheme 7
R
SePh
Se
Ph
acid
R
The optically active selenide (17), formed by
reaction34 of the S-(+)-alcohol (16) with N -(phenyl-
seleno)phthalimide and tributylphosphine, was con-
verted cleanly back into (14) by using m-chloroperben-
zoic acid and aqueous potassium hydroxide in isopropyl
alcohol without any loss of optical activity (Scheme
8). In a similar manner the selenide (1) was converted
into the cis diol (2) in good yield by reaction with
m-chloroperbenzoic acid and sodium hydroxide. The
diol35 (2) is a useful template for the synthesis of
a variety of alkaloids and other biologically active
molecules. It can be elaborated to ꢀ-hydroxyproline,36
(ꢁ)-detoxinine,37 and 3-hydroxyglutamic acid.38 We
are currently investigating other methods for the inter-
and intra-molecular displacement of selenones.
m-chloroperbenzoic
acid
R′OH
O
••
O
CAr
R
OR′
Se
Ph
R
O
Scheme 5
TsCl, py
SePh
SePh
N
N
H
(13)
Ts
m-chloroperbenzoic acid
MeOH
OMe
ClCO2Et
OH
OH
NaOH
N
N
N
H
Ts (14)
Scheme 6
CO2Et
(16)
m-chloroperbenzoic acid
PhthSePh
Bu3P
The selenone (7) was isolated as crystalline material
PriOH, NaOH
suitable for X-ray analysis.31 The diastereotopic exo-
cyclic methylene protons of (7) appeared as doublets
of doublets at 4ꢀ10 and 3ꢀ69 ppm in the 1H n.m.r.
spectrum, compared to 2ꢀ88 and 2ꢀ73 ppm for the
same protons of the selenide (5) and 3ꢀ21 and 3ꢀ03 ppm
for those of the selenoxide (6). Characteristic Se=O
absorptions32 at 910 and 890 cmꢀ1 were seen in the
infrared spectrum of (7). The selenone (7) gave a
molecular ion and a fragmentation corresponding to loss
of PhSeO2 under conditions of fast-atom bombardment.
Formation of (7) was accompanied by signiꢃcant
amounts of the alcohol (8), and the ester (15) if
SePh
N
Scheme 8
CO2Et
(17)
Experimental
Infrared spectra were recorded on a Jasco A-102 spectrometer
as Nujol mulls or liquid ꢀlms, or as solutions where indicated. 1H
and 13C n.m.r. spectra were obtained at 300 MHz on a Bruker
ACP-300 spectrometer. 77Se n.m.r. spectra were obtained at

184
M. A. Cooper and A. D. Ward
300 MHz on a Bruker CXP-300 spectrometer. All 1H n.m.r.
spectra were recorded as solutions in (D)chloroform, by using
tetramethylsilane as an internal standard. Electron-impact
mass spectra and accurate mass measurements were recorded
at 70 eV on an AEI 3074 mass spectrometer, or by the School
of Chemistry, the University of Melbourne. Fast-atom bom-
bardment mass spectra and CA-MIKES spectra were recorded
on a V.G. ZAB 2HF mass spectrometer. Optical rotations
were carried out in ethanol with a 5-cm cell by using a Perkin
Elmer 141 spectropolarimeter. Melting points were recorded on
a Koꢁer hot-stage apparatus equipped with a Reichert micro-
scope, and are uncorrected. Microanalyses were performed by
the Australian Microanalytical Service, Melbourne, and the
Chemistry Department, University of Otago.
Preparative chromatography was performed with Merck
Kieselgel PF254 by using, unless otherwise stated, a Chro-
matotron 7924T (Harrison Research, Palo Alto/TC Research,
California), eluting with a gradient of ethyl acetate/light
petroleum. Flash chromatography was performed with Merck
Kieselgel 60 (230–400 mesh), eluting with a gradient of light
petroleum/ethyl acetate. All solvents were puriꢀed by distilla-
tion and dried by standard laboratory procedures.33 All organic
extracts were dried over anhydrous sodium sulfate unless oth-
erwise speciꢀed. Light petroleum refers to the fraction with a
boiling range of 66–69ꢀ. Benzeneselenenyl chloride was obtained
from AldrichR Australia and was used without further puriꢀca-
tion. N -(Phenylseleno)phthalimide was synthesized according
to the method of Nicolaou.34,39 m-Chloroperbenzoic acid was
85% pure after recrystallization from dichloromethane/light
petroleum. ‘Block’ distillation refers to a short-path microdis-
tillation with a sublimation block.
H 2; 3ꢀ50, m, H 5a; 3ꢀ32, m, H 5b; 3ꢀ19, dd, J 12ꢀ3, 3ꢀ2 Hz,
CHaSe; 2ꢀ85, br s, OH; 2ꢀ51, dd, J 12ꢀ3, 11ꢀ6 Hz, CHbSe;
1ꢀ95, m, H 4a; 1ꢀ76, m, H 4b; 1ꢀ37, s, 9H. 13C n.m.r. (CDCl3,
50ꢀ) ꢂ 154ꢀ4, C=O; 132ꢀ9, 131ꢀ9, 129ꢀ0, 127ꢀ1, Ar; 87ꢀ8,
CMe3; 75ꢀ1, C 3; 44ꢀ6, CH2Se; 30ꢀ9, C 2; 30ꢀ2, C 5; 29ꢀ6, C 4;
28ꢀ5, CH3. Mass spectrum: m/z 355 (M), 138 (M ꢁ SePh),
124 (M ꢁ CH2SePh).
t-Butyl (2Rꢂ,3Rꢂ)-3-Hydroxy-2-(hydroxymethyl)pyrrolidine-
1-carboxylate (2)
To the cis selenide (1) (178 mg, 0ꢀ5 mmol) in isopropyl
alcohol (40 ml) was added m-chloroperbenzoic acid (407 mg,
2 mmol) and the mixture stirred at room temperature for 1 h.
Sodium hydroxide (5 ml, 10%) was then added and the mixture
stirred at room temperature for a further 4 h. The solution
was diluted with saturated sodium bicarbonate (10 ml) and
extracted with chloroform (2ꢂ20 ml). The combined organic
extracts were washed with saturated sodium chloride (10 ml),
dried, the solvent was removed under reduced pressure and the
residue chromatographed to give the diol35 (2) as a light yellow
oil (64 mg, 59%). ꢁmax 3400, 1695, 1670 cmꢁ1
.
1H n.m.r. ꢂ
3ꢀ85, br s, 1H; 3ꢀ75, br s, 1H; 3ꢀ6–3ꢀ4, m, 3H; 3ꢀ29, m, 1H;
3ꢀ05, br s, 1H; 1ꢀ95, m, 1H; 1ꢀ63, m, 1H; 1ꢀ46, s, 9H. 13C
n.m.r. ꢂ 156ꢀ3, C=O; 80ꢀ3, OCMe3; 72ꢀ6, C 3; 67ꢀ9, CH2OH;
63ꢀ8, C 2; 44ꢀ9, C 5; 31ꢀ5, C 4; 28ꢀ3, CH3. Mass spectrum
(f.a.b.): m/z 219 (M+2H), 217 (M), 186 (M ꢁ CH2OH), 162
(M+H2 ꢁ But), 144 (M ꢁ ButO).
Ethyl 2-(Phenylselenomethyl)pyrrolidine-1-carboxylate (5)
To a stirred mixture of the carbamate (4) [prepared23 from
the phthalimide41 (3)] (1ꢀ57 g, 10 mmol), dry silica gel (1 g), and
anhydrous potassium carbonate (0ꢀ5 g) in dry dichloromethane
(20 ml) at ꢁ78ꢀ under nitrogen was added dropwise over 5 min
a solution of benzeneselenenyl chloride (2ꢀ1 g, 1ꢀ1 mmol) in
dry dichloromethane (5 ml). The mixture was stirred at ꢁ78ꢀ
for 10 min then at room temperature for 40 h. The solution
was ꢀltered, the solvent removed under reduced pressure and
the residue chromatographed to give the selenide23 (5) as a
t-Butyl (3-Hydroxypent-4-enyl)carbamate
This compound was obtained as a colourless oil by using
literature procedures,35,40 b.p. 108ꢀ/0ꢀ01 mm (block) (Found:
C, 59ꢀ4; H, 9ꢀ6; N, 6ꢀ8. C10H19NO3 requires C, 59ꢀ7; H, 9ꢀ5;
N, 7ꢀ0%). ꢁmax 3340, 1685, 1520 cmꢁ1
.
1H n.m.r. ꢂ 5ꢀ87,
ddd, J 17ꢀ1, 10ꢀ6, 6ꢀ6 Hz, CH=CH2; 5ꢀ42, br s, NH; 5ꢀ24,
dd, J 1ꢀ8, 17ꢀ1 Hz, CHaHb=CH; 5ꢀ08, dd, J 1ꢀ8, 10ꢀ6 Hz,
CHaHb=CH; 4ꢀ18, m, CHOH; 4ꢀ03, s, OH; 3ꢀ32, m, CHaN;
3ꢀ15, m, CHbN; 1ꢀ64, m, CH2; 1ꢀ44, s, 9H. Mass spectrum:
m/z 202 (M+H), 145 (M ꢁ But), 101 (M ꢁ CO2But).
light yellow oil (2ꢀ44 g, 78%). ꢁmax 1685, 1405, 1105 cmꢁ1
.
1H n.m.r. ꢂ 7ꢀ54, m, 2H; 7ꢀ23, m, 3H; 4ꢀ07, q, J 6ꢀ9 Hz,
CH2; 4ꢀ01, m, CHN; 3ꢀ50–3ꢀ29, m, CH2N; 2ꢀ88, dd, J 6ꢀ8,
7ꢀ2 Hz, CHaSe; 2ꢀ73, dd, J 6ꢀ8, 7ꢀ2 Hz, CHbSe; 2ꢀ02–1ꢀ75,
m, 4H; 1ꢀ22, t, J 6ꢀ9 Hz, CH3. Mass spectrum: m/z 313 (M),
157 (M ꢁ SePh), 143 (M ꢁ CH2SePh).
t-Butyl (2Rꢂ,3Rꢂ)-3-Hydroxy-2-(phenylselenomethyl)-
pyrrolidine-1-carboxylate (1) and t-Butyl (2Sꢂ,3Rꢂ)-3-
Hydroxy-2-(phenylselenomethyl)pyrrolidine-1-carboxylate
Reactions of the Selenide (5)
To a solution of the above carbamate (201 mg, 1 mmol), dry
silica (250 mg), and anhydrous potassium carbonate (250 mg)
in dry chloroform (10 ml) under nitrogen at 0ꢀ was added
dropwise over 5 min a solution of benzeneselenenyl chloride
(230 mg, 1ꢀ2 mmol) in dry chloroform (3 ml). The mixture was
stirred at 0ꢀ for 10 min, then at room temperature for 30 min.
The mixture was ꢀltered through Celite, the Celite washed with
ethyl acetate, the ꢀltrate concentrated under reduced pressure
and the residue was chromatographed to give the cis pyrroli-
dine (1) as translucent needles (219 mg, 62%), m.p. 101–103ꢀ
(Found: C, 54ꢀ0; H, 6ꢀ8; N, 4ꢀ1. C16H23NO3Se requires C,
(A) With OXONE R. To a vigorously stirred mixture of the
selenide (5) (105 mg, 0ꢀ33 mmol) at 0ꢀ in dry ethanol (10 ml)
was added a solution of OXONE (1ꢀ02 g, 1ꢀ66 mmol) in water
(5 ml). The mixture was warmed to room temperature, stirred
for a further 5 days, then diluted with water (10 ml) and extracted
with chloroform (2ꢂ10 ml). The combined organic extracts
were dried, the solvent was removed under reduced pressure and
the residue chromatographed to give the alcohol (8) (2 mg, 3%).
Further elution gave ethyl 2-(phenylseleninylmethyl)pyrrolidine-
1-carboxylate (6) as a pale yellow oil (111 mg, 97%) (Found:
M+ꢃ, 329ꢀ0532. C14H19NO3Se requires M+ꢃ, 329ꢀ0529). ꢁmax
53ꢀ9; H, 6ꢀ5; N, 3ꢀ9%). ꢁmax 3410, 1660, 1460 cmꢁ1
.
1H
1700, 1580, 1420, 1260, 830 cmꢁ1
.
1H n.m.r. ꢂ 7ꢀ99, d, J
n.m.r. (CDCl3, 50ꢀ) ꢂ 7ꢀ63, m, 2H; 7ꢀ10, m, 3H; 4ꢀ49, m,
H 3; 3ꢀ96, m, H 2; 3ꢀ51, m, H 5a,5b; 3ꢀ38, dd, J 12ꢀ3, 3ꢀ6
Hz, CHaSe; 3ꢀ02, dd, J 12ꢀ3, 11ꢀ8 Hz, CHbSe; 2ꢀ09, br s,
OH; 1ꢀ88, m, H 4a,4b; 1ꢀ36, s, 9H. 13C n.m.r. (CDCl3, 50ꢀ)
ꢂ 154ꢀ6, C=O; 133ꢀ1, 131ꢀ5, 129ꢀ2, 127ꢀ5, Ar; 88ꢀ1, CMe3;
74ꢀ0, C 3; 43ꢀ3, CH2Se; 32ꢀ4, C 2; 30ꢀ6, C 5; 28ꢀ7, C 4; 28ꢀ4,
CH3. Mass spectrum: m/z 355 (M), 138 (M ꢁ SePh), 124
(M ꢁ CH2SePh).
8ꢀ0 Hz, 2H; 7ꢀ67, m, 3H; 4ꢀ17, m, H 2; 3ꢀ68, q, J 7ꢀ0 Hz,
CH2O; 3ꢀ42, m, H 5a,5b; 3ꢀ21, dd, J 12ꢀ0, 9ꢀ0 Hz, CHaSe;
3ꢀ03, dd, J 12ꢀ0, 2ꢀ6 Hz, CHbSe; 2ꢀ0–1ꢀ7, m, 4H; 1ꢀ21,
t, J 7ꢀ0 Hz, CH3. 77Se n.m.r. ꢂ 865ꢀ9. Mass spectrum:
m/z 329 (weak M), 313 (M ꢁ O), 156 (M ꢁ Se(O)Ph), 142
(M ꢁ CH2Se(O)Ph).
(B) With m-chloroperbenzoic acid in Pr iOH. A mixture
of the selenide (5) (313 mg, 1 mmol) and m-chloroperbenzoic
acid (608 mg, 3 mmol) in isopropyl alcohol (10 ml) was stirred
at room temperature for 4 h. The solvent was removed under
reduced pressure and the residue redissolved in ethyl acetate
Further elution gave the trans pyrrolidine as a light yellow
oil (39 mg, 8%). ꢁmax 3400, 1660, 1460 cmꢁ1
.
1H n.m.r.
(CDCl3, 50ꢀ) ꢂ 7ꢀ63, 2H; 7ꢀ14, m, 3H; 4ꢀ31, m, H 3; 3ꢀ73, m,

N -Protected 2-(Phenylselenonylmethyl)pyrrolidines
185
(10 ml). The solution was washed with saturated sodium bicar-
bonate (2ꢂ10 ml), dried, the solvent removed under reduced
pressure and the residue chromatographed to give ethyl 2-(3 0-
chlorobenzoyloxymethyl)pyrrolidine-1-carboxylate (15) (12 mg,
4%) as a yellow oil (Found: M+ꢃ, 311ꢀ0925. C15H18ClNO4
1H n.m.r. ꢂ 8ꢀ09, t, J 1ꢀ8 Hz, H 20; 8ꢀ01, dt, J 7ꢀ7, 1ꢀ3 Hz,
H 60; 7ꢀ53, ddd, J 7ꢀ7, 1ꢀ8, 1ꢀ3 Hz, H 40; 7ꢀ42, t, J 7ꢀ7 Hz,
H 50; 4ꢀ95, m, CH2O; 4ꢀ21, m, H 2; 4ꢀ16, q, J 7ꢀ0 Hz,
CH2O; 3ꢀ6–3ꢀ4, m, H 5a,5b; 2ꢀ0–1ꢀ8, m, H 4a,4b; 1ꢀ26, t,
J 7ꢀ0 Hz, CH3. 13C n.m.r. ꢂ 170ꢀ6, OC=O; 160ꢀ3, NC=O;
134ꢀ4, 133ꢀ8, 130ꢀ2, 129ꢀ8, 128ꢀ3, 123ꢀ7, Ar; 67ꢀ7, CH2O;
47ꢀ2, C 2; 43ꢀ9, C 5; 29ꢀ0, C 3; 14ꢀ6, C 4. Mass spectrum:
m/z 311/313 (M), 266/268 (M ꢁ EtO), 238/240 (M ꢁ CO2Et),
155 (M ꢁ C6H4ClCO2H), 111/113 (C6H4Cl). Further elution
gave the alcohol (8) (35 mg, 20%) as a yellow oil, followed by
ethyl 2-(phenylselenonylmethyl)pyrrolidine-1-carboxylate31 (7)
as translucent crystals (220 mg, 64%), m.p. 103–104ꢀ. ꢁmax
(F) With m-chloroperbenzoic acid in acetic acid. A mixture
of the selenide (5) (62 mg, 0ꢀ2 mmol) and m-chloroperbenzoic
acid (103 mg, 0ꢀ6 mmol) in acetic acid (2 ml) was stirred at room
temperature for 24 h. The solvent was removed under reduced
pressure and the residue redissolved in dichloromethane (5 ml).
The solution was washed with saturated sodium bicarbonate
(5 ml), dried, the solvent removed under reduced pressure and
the residue chromatographed to give the selenide (5) (15 mg,
24%). Further elution gave the alcohol (8) (12 mg, 34%).
(G) With m-chloroperbenzoic acid in methanol. A mixture of
the selenide (5) (105 mg, 0ꢀ33 mmol) and m-chloroperbenzoic
acid (174 mg, 1 mmol) in methanol (10 ml) was stirred at
room temperature for 90 min. The mixture was diluted
with chloroform (20 ml) and washed with saturated sodium
bicarbonate (10 ml). The organic phase was separated, dried,
the solvent removed under reduced pressure and the residue
chromatographed to give ethyl 2-(methoxymethyl)pyrrolidine-
1-carboxylate (11) (50 mg, 87%) as a colourless oil (Found: C,
57ꢀ3; H, 9ꢀ2; N, 7ꢀ0. C9H17NO3 requires C, 57ꢀ7; H, 9ꢀ2;
requires M+ꢃ, 311ꢀ0924). ꢁmax 1725, 1705, 1560, 1175 cmꢁ1
.
1710, 1255, 910, 890 cmꢁ1
.
1H n.m.r. ꢂ 8ꢀ00, d, J 8ꢀ2 Hz, 2H;
7ꢀ69, m, 3H; 4ꢀ30, m, H 2; 4ꢀ10, dd, J 12ꢀ2, 2ꢀ3 Hz, CHaSe;
3ꢀ95, m, H 5a,5b; 3ꢀ69, dd, J 12ꢀ2, 9ꢀ6 Hz, CHbSe; 3ꢀ39, q, J
6ꢀ8 Hz, CH2; 2ꢀ44, m, 1H; 2ꢀ22, m, 1H; 1ꢀ93, m, 2H; 1ꢀ29, t,
J 6ꢀ8 Hz, CH3. 77Se n.m.r. ꢂ 1000ꢀ6. Mass spectrum (f.a.b.):
m/z 345 (M), 156 (M ꢁ SeO2Ph).
N, 7ꢀ5%). ꢁmax 1735, 1475, 940 cmꢁ1
.
1H n.m.r. ꢂ 4ꢀ13,
m, CHaOMe; 4ꢀ13, q, J 6ꢀ9 Hz, CH2; 3ꢀ78, m, CHbOMe;
3ꢀ57, m, H 2; 3ꢀ38, s, OCH3; 3ꢀ19, m, H 5a,5b; 1ꢀ90, m,
H 3a; 1ꢀ74, m, H 3b; 1ꢀ17, m, H 4a,4b; 1ꢀ26, t, J 6ꢀ9 Hz,
CH3. Mass spectrum: m/z 187 (M), 155 (M ꢁ MeOH), 142
(M ꢁ CH2OMe).
(C) With m-chloroperbenzoic acid and NaOH in Pr iOH. To
a solution of the selenide (5) (313 mg, 1 mmol) in isopropyl
alcohol (10 ml) was added m-chloroperbenzoic acid (608 mg,
3 mmol) and the mixture stirred at room temperature for 1 h.
Sodium hydroxide (5 ml, 10%) was then added and the mixture
stirred for a further 4 h. The solvent was removed under reduced
pressure and the residue redissolved in ethyl acetate (10 ml).
This solution was washed with saturated sodium bicarbonate
(2ꢂ10 ml), dried, the solvent removed under reduced pressure
and the residue chromatographed to give the alcohol (8) as a
colourless oil (135 mg, 78%), with spectroscopic data identical
to those of the enantiomer42 (16).
(H) With m-chloroperbenzoic acid in ethanol. A mixture
of the selenide (5) (313 mg, 1 mmol) and m-chloroperbenzoic
acid (608 mg, 3 mmol) in dry ethanol (10 ml) was stirred at
room temperature for 2 h. The solvent was removed under
reduced pressure and the residue redissolved in ethyl acetate
(20 ml). The solution was washed with saturated sodium
bicarbonate solution (10 ml), dried, the solvent removed under
reduced pressure and the residue chromatographed to give ethyl
2-(ethoxymethyl)pyrrolidine-1-carboxylate (12) (161 mg, 80%)
as a colourless oil, b.p. 65ꢀ/0ꢀ01 mm block (Found: M+ꢃ
,
201ꢀ1358. C10H19NO3 requires M+ꢃ, 201ꢀ1365). ꢁmax 1730,
(D) With m-chloroperbenzoic acid and H2O in dmf. To
a solution of the selenide (5) (313 mg, 1 mmol) in isopropyl
alcohol (10 ml) was added m-chloroperbenzoic acid (608 mg,
3 mmol) and the mixture stirred at room temperature for
1 h. The solvent was removed under reduced pressure and
the residue redissolved in ethyl acetate (10 ml). This solution
was washed with saturated sodium bicarbonate (2ꢂ10 ml), the
solvent removed under reduced pressure, the residue redissolved
in dimethylformamide (4 ml) and water (1 ml), and the mixture
heated at 80ꢀ for 2 h. The cooled mixture was diluted with ether
(10 ml), washed with saturated sodium chloride (5 ml), satu-
rated sodium bicarbonate (5 ml), then with saturated sodium
chloride again (5 ml). The organic phase was separated, dried,
the solvent removed under reduced pressure and the residue
chromatographed to give the alcohol (8) (125 mg, 72%).
(E) With m-chloroperbenzoic acid in water/tetrahydrofuran.
A mixture of the selenide (5) (195 mg, 0ꢀ33 mmol) and m-
chloroperbenzoic acid (288 mg, 1ꢀ66 mmol) in tetrahydrofuran
(5 ml) and water (1 ml) was stirred at room temperature for
6 h. The mixture was diluted with saturated sodium chloride
(5 ml), the organic phase separated, washed with saturated
sodium bicarbonate (5 ml), dried, the solvent removed under
reduced pressure and the residue chromatographed to give ethyl
2-methylidenepyrrolidine-1-carboxylate (9) as an unstable light
1460 cmꢁ1
.
1H n.m.r. ꢂ 4ꢀ37, q, J 7ꢀ0 Hz, CH2O; 4ꢀ20,
m, CHaOEt; 4ꢀ14, q, J 6ꢀ9 Hz, CH2O; 4ꢀ07, m, CHbOEt;
3ꢀ8–3ꢀ3, m, 3H; 1ꢀ9–1ꢀ5, m, 4H; 1ꢀ25, t, J 6ꢀ9 Hz, CH3;
1ꢀ19, t, J 7ꢀ0 Hz, CH3. Mass spectrum: m/z 201 (M), 155
(M ꢁ EtOH), 142 (M ꢁ CH2OEt).
Ethyl (2 S)-2-(Hydroxymethyl)pyrrolidine-1-carboxylate (16)
(A) From (S)-(+)-pyrrolidin-2-ylmethanol. To an emulsiꢀed
mixture of (S)-(+)-pyrrolidin-2-ylmethanol (5ꢀ05 g, 50 mmol)
in water (100 ml) at 0ꢀ was added ethyl chloroformate (3ꢀ29 g,
30 mmol). The mixture was stirred at this temperature for
5 min and then a second portion of ethyl chloroformate (3ꢀ29 g,
30 mmol) was added, followed immediately by a solution of
sodium hydroxide (2ꢀ4 g, 60 mmol) in water (5 ml). The
mixture was stirred at 0ꢀ for a further 4 h, then washed
with hydrochloric acid (10 ml, 1 M), and sodium bicarbonate
(10 ml, 10%). The organic phase was separated, dried, the
solvent removed under reduced pressure and the residue chro-
matographed to give the carbamate42 (16) (7ꢀ51 g, 87%) as a
light yellow oil, [ꢃ]2D5 ꢁ17ꢀ8ꢀ. ꢁmax 3385, 1680, 1430, 1385,
1085 cmꢁ1
.
1H n.m.r. ꢂ 4ꢀ58, m, CHaOH; 4ꢀ15, q, J 7ꢀ0 Hz,
CH2; 4ꢀ00, m, CHbOH; 3ꢀ64, m, H 2; 3ꢀ61, s, OH; 3ꢀ51, m,
H 5a; 3ꢀ34, m, H 5b; 2ꢀ04, m, 1H; 1ꢀ85, m, 2H; 1ꢀ58, m, 1H;
1ꢀ28, t, J 7ꢀ0 Hz, CH3. Mass spectrum: m/z 173 (M), 155
(M ꢁ H2O), 142 (M ꢁ CH2OH).
yellow oil (10 mg, 20%). ꢁmax 1710, 1640, 1530 cmꢁ1
.
1H
n.m.r. ꢂ 5ꢀ65, s, =CHa; 5ꢀ63, s, =CHb; 4ꢀ11, q, J 6ꢀ9 Hz, CH2;
3ꢀ37, m, CH2N; 2ꢀ0–1ꢀ67, m, 4H; 1ꢀ25, t, J 6ꢀ9 Hz, CH3.
Mass spectrum: m/z 155 (M). Further elution gave a light
yellow oil (20 mg, 34%) whose spectroscopic properties were
consistent with it containing mainly ethyl 4-oxopentylcarbamate
(B)From the selenide (17). To a solution of the selenide
(17) (313 mg, 1 mmol) in isopropyl alcohol (10 ml) was added
m-chloroperbenzoic acid (608 mg, 3 mmol) and the mixture
stirred at room temperature for 1 h. Sodium hydroxide (10%,
5 ml) was then added and the mixture stirred for a further
4 h. The solvent was removed under reduced pressure and the
residue redissolved in ethyl acetate (10 ml). This solution was
washed with saturated sodium bicarbonate (2ꢂ10 ml), dried,
(10). ꢁmax 3380, 1715, 1530 cmꢁ1
.
1H n.m.r. ꢂ 4ꢀ78, s, NH;
4ꢀ11, q, J 6ꢀ9 Hz, CH2; 3ꢀ16, m, CH2N; 2ꢀ50, t, J 7ꢀ0 Hz,
CH2CO; 2ꢀ15, s, CH3; 1ꢀ77, m, 2H; 1ꢀ23, t, J 6ꢀ9 Hz, CH3.
Mass spectrum: m/z 173 (M), 119 (M ꢁ CH2COCH3).

186
M. A. Cooper and A. D. Ward
4
the solvent removed under reduced pressure and the residue
chromatographed (ethyl acetate/light petroleum) to give the
alcohol (16) as a colourless oil (130 mg, 75%), [ꢃ]D25 ꢁ17ꢀ2ꢀ.
Other spectroscopic data were identical to those reported in
(A) above.
Sharpless, K. B., Gordon, K. M., Laurer, R. F., Patrick,
D. W., Singer, S. P., and Young, M. W., Chem. Scr., 1975,
8A, 9.
Reich, H. J., Reich, I. L., and Renga, J. M., J. Am. Chem.
Soc., 1973, 95, 5813.
5
6
7
Hori, T., and Sharpless, K. B., J. Org. Chem., 1978, 43,
1689.
Ethyl (2 S)-2-(Phenylselenomethyl)pyrrolidine-1-carboxylate
(17)
Clive, D. L. J., Chittattu, G. J., Farina, V., Kiel, W. A.,
Menchen, S. M., Russell, C. G., Singh, A., Wong, C. K.,
and Curtis, N. J., J. Am. Chem. Soc., 1980, 102, 4438.
Corey, E. J., Pearce, H. L., Szekely, I., and Ishiguro, M.,
Tetrahedron Lett., 1978, 1023.
Back, T. G., Birss, V. I., Edwards, M., and Krishna, M.
V., J. Org. Chem., 1988, 53, 3815.
Krief, A., Tetrahedron, 1980, 36, 2531.
Sevrin, M., and Krief, A., J. Chem. Soc., Chem. Commun.,
1980, 656.
To a stirred mixture of the alcohol (16) (3ꢀ46 g, 20 mmol)
and tributylphosphine (6ꢀ07 g, 30 mmol) in dry thf (100 ml) at
0ꢀ was added N -(phenylseleno)phthalimide (9ꢀ06 g, 30 mmol).
The mixture was stirred at this temperature for 2 h, the
solvent removed under reduced pressure and the residue chro-
matographed to give the selenide (17) as a yellow oil (5ꢀ84 g,
93%), [ꢃ]D25 ꢁ5ꢀ6ꢀ, with spectroscopic data identical to those
of the racemic material (5).
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
Sevrin, M., Dumont, W., Hevesi, L., and Krief, A., Tetra-
hedron Lett., 1976, 2647.
Lawson, D. D., and Schmid, G. H., Can. J. Chem., 1974,
53, 1922.
Morella, A. M., and Ward, A. D., Tetrahedron Lett., 1984,
25, 1197.
Morella, A. M., and Ward, A. D., Tetrahedron Lett., 1985,
26, 2899.
Morella, A. M., and Ward, A. D., Aust. J. Chem., 1995,
48, 445.
Krief, A., Dumont, W., and Denis, J., J. Chem. Soc., Chem.
Commun., 1985, 571.
Uemura, S., and Fukuzawa, S., J. Chem. Soc., Perkin
Trans. 1, 1985, 471.
Cooper, M. A., and Ward, A. D., Tetrahedron Lett., 1992,
33, 5999.
2-(Phenylselenomethyl)-1-(p-tolylsulfonyl)pyrrolidine (13)
A mixture of 2-(phenylselenomethyl)pyrrolidine (239 mg,
1 mmol; prepared34 from pyrrolidin-2-ylmethanol, N -(phenyl-
seleno)phthalimide and tributylphoshine) and p-toluenesulfonyl
chloride (290 mg, 1ꢀ5 mmol) in pyridine (10 ml) was stirred
at room temperature for 4 h. The mixture was diluted with
ethyl acetate (20 ml), washed with hydrochloric acid (10 ml,
10%) and sodium bicarbonate (10 ml, 10%), and dried. The
solvent was removed under reduced pressure and the residue
distilled to give the sulfonamide (13) as a yellow oil (316 mg,
80%), b.p. 210ꢀ/0ꢀ04 mm (block) (Found: C, 55ꢀ4; H, 5ꢀ5; N,
3ꢀ6. C18H21NO2SSe requires C, 54ꢀ7; H, 5ꢀ4; N, 3ꢀ6%). ꢁmax
1600, 1580, 1500, 1480, 1345, 1200, 1150, 1090, 810, 735 cmꢁ1
.
1H n.m.r. ꢂ 7ꢀ58, m, 2H; 7ꢀ49, d, J 8ꢀ0 Hz, 2H; 7ꢀ31, m,
3H; 7ꢀ21, d, J 8ꢀ0 Hz, 2H; 3ꢀ60, m, 2H; 3ꢀ46, m, 1H; 3ꢀ10,
dt, J 10ꢀ1, 6ꢀ7 Hz, 1H; 2ꢀ82, dd, J 11ꢀ4, 13ꢀ0 Hz, 1H; 2ꢀ38,
s, CH3; 1ꢀ8–1ꢀ4, m, 4H. Mass spectrum: m/z 395 (M), 238
(M ꢁ SePh), 224 (M ꢁ CH2SePh).
Cooper, M. A., and Ward, A. D., Tetrahedron Lett., 1994,
35, 5065.
Salzberg, P. L., and Supniewski, J. V., Org. Synth., 1941,
Collect. Vol. 1, 119.
Sheehan, J. C., and Bolhofer, W. A., J. Am. Chem. Soc.,
1950, 72, 2786.
2-(Methoxymethyl)-1-(p-tolylsulfonyl)pyrrolidine (14)
Clive, D. L. J., Farina, V., Singh, A., Wong, C. K., Kiel,
W., and Menchen, S., J. Org. Chem., 1980, 45, 2120.
McFarlane, H. C. E., and McFarlane, W., in ‘NMR of
Newly Accessible Nuclei’ (Ed. P. Laszlo) Vol. 2 (Academic:
New York 1983).
Paulmier, C., ‘Selenium Reagents and Intermediates in
Organic Synthesis’ (Pergamon: Oxford 1986).
Lardon, M., in ‘Organic Selenium Compounds: their Chem-
istry and Biology’ (Eds D. L. Klayman and W. H. H.
Gunther) (Wiley–Interscience: New York 1973).
Duddeck, H., Wagner, P., and Biallass, A., Magn. Reson.
Chem., 1991, 29, 248.
Reich, H. J., Hoeger, C. A., and Willis, W. W., Tetrahedron,
1985, 41, 4771.
Hart, D. J., and Kanai, K., J. Org. Chem., 1982, 47, 1555.
Clark, R. D., and Heathcock, C. H., J. Org. Chem., 1976,
41, 1396.
Cooper, M. A., Tiekink, E. R. T., and Ward, A. D., Z.
Kristallogr., 1996, 211, 751.
Paetzold, R., and Bochman, G., Spectrochim. Acta, 1970,
26A, 391.
Perrin, D. D., and Armarego, W. L. F., ‘Puriꢀcation of
Laboratory Chemicals’ 3rd Edn (Pergamon: Oxford 1988).
Nicolaou, K. C., Petasis, N. A., and Claremon, D. A.,
Tetrahedron, 1985, 41, 4835.
Takahata, H., Banba, Y., Mayumi, T., and Momose, T.,
J. Org. Chem., 1991, 56, 240.
To a stirred mixture of the selenide (13) (200 mg, 0ꢀ5 mmol)
in methanol (20 ml) was added m-chloroperbenzoic acid (540 mg,
2ꢀ5 mmol) and the mixture stirred at room temperature for
1 h. The solvent was removed under reduced pressure, the
residue redissolved in dichloromethane (10 ml), washed with
sodium hydroxide (10 ml, 10%), dried, the solvent removed
under reduced pressure and the residue chromatographed to
give the ether (14) as a colourless oil (80 mg, 60%) (Found:
C, 58ꢀ3; H, 7ꢀ2; N, 5ꢀ5. C13H19NO3S requires C, 57ꢀ9; H,
25
26
7ꢀ1; N, 5ꢀ2%). ꢁmax 1600, 1500, 1340, 1160, 910 cmꢁ1
.
1H
27
28
n.m.r. ꢂ 7ꢀ64, d, J 8ꢀ2 Hz, 2H; 7ꢀ31, d, J 8ꢀ2 Hz, 2H; 3ꢀ61,
m, CHaOMe; 3ꢀ37, s, OMe; 3ꢀ35, m, CHbOMe; 3ꢀ33, m, H 2;
2ꢀ45, m, H 5a; 2ꢀ43, s, ArCH3; 2ꢀ36, m, H 5b; 1ꢀ8–1ꢀ2, m,
4H. Mass spectrum (f.a.b.): m/z 270 (M+H), 238 (M ꢁ OMe),
155 (CH3C6H4SO2), 91 (C6H4CH2).
29
30
Acknowledgments
31
32
33
34
35
36
37
We thank John Papageorgiou, Jo Pratt and Ilse
Scharfbillig for some assistance with technical aspects
of this work. M.A.C. thanks the Commonwealth
Government for an Australian Postgraduate Research
Award (priority).
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Trahanovsky) Vol. 5, Part C (Academic: New York 1978).
Clive, D. L. J., Tetrahedron, 1978, 34, 1049.
Reich, H. J., Acc. Chem. Res., 1979, 12, 22.
2
3

N -Protected 2-(Phenylselenonylmethyl)pyrrolidines
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