Synthesis and reactivity of 1-pyrroline-5-carboxylate ester 1-oxides

Article abstract of DOI:10.1016/S0040-4020(00)00094-6

Some C5 mono- and diester-substituted 1-pyrroline-1-oxides have been prepared via reductive cyclisation of the corresponding γ-nitro carbonyl compounds. Ethyl 2-phenyl-1-pyrroline-1-oxide-5-carboxylate 5c was regioselectively alkylated at C5. Acylation of this molecule occurs exclusively on the nitrone oxygen and leads to C3 substituted pyrrolines as the result of a hetero-Cope rearrangement. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00094-6

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 1889–1897
Synthesis and Reactivity of 1-Pyrroline-5-carboxylate
Ester 1-Oxides
*
David StC. Black, Gavin L. Edwards, Richard H. Evans, Paul A. Keller and Sean M. Laaman
School of Chemistry, The University of New South Wales, Sydney 2052, Australia
Received 21 October 1999; revised 10 January 2000; accepted 27 January 2000
Abstract—Some C5 mono- and diester-substituted 1-pyrroline-1-oxides have been prepared via reductive cyclisation of the corresponding
g-nitro carbonyl compounds. Ethyl 2-phenyl-1-pyrroline-1-oxide-5-carboxylate 5c was regioselectively alkylated at C5. Acylation of this
molecule occurs exclusively on the nitrone oxygen and leads to C3 substituted pyrrolines as the result of a hetero-Cope rearrangement.
᭧ 2000 Elsevier Science Ltd. All rights reserved.
The cyclic nature of the 1-pyrroline-1-oxide unit imparts
stability towards hydrolysis of the nitrone system.1 The
majority of experimentation on such compounds has been
performed with gem-dimethyl substitution at C5 of the ring.
Whilst this pattern of substitution provides further stability,
facile chemical elaboration is disallowed at this position.
We envisaged that incorporation of a single ester function
at C5 would provide a means by which carbanion chemistry
could be performed at this position via basic removal of the
acidic proton. The synthesis of such novel nitrones and the
reactivity of a representative example will be described
herein.
Although new synthetic routes to cyclic nitrones continue to
emerge,2–4 the reductive cyclisation of g-nitro carbonyl
compounds is most commonly used and was our chosen
strategy. The synthetic approach to the C5 monoester substi-
tuted nitrones was initially planned to proceed via overall
dealkoxycarbonylation of the malonate derivatives 5a and
5b. To this end, requisite precursors 3a and 3b were
Scheme 1.
Keywords: nitrones; pyrrolines/pyrrolinones; rearrangements; cyclisation.
* Corresponding author. Tel.: ϩ61-2-9385-4657; fax: ϩ61-2-9385-6141; e-mail: d.black@unsw.edu.au
0040–4020/00/$ - see front matter ᭧ 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00094-6

1890
D. StC. Black et al. / Tetrahedron 56 (2000) 1889–1897
Scheme 2.
prepared by reacting diethyl nitromalonate 2a with the
Mannich bases 1a and 1b, respectively, in refluxing toluene.
Subsequent treatment of these compounds with cold
aqueous ammonium chloride and zinc dust produced the
nitrones 5a and 5b without isolation of the intermediate
hydroxylamines 4a and 4b. Development of the monoester
derivative 5c from the malonate compound 5a was
attempted and proved to be problematic using both
Krapcho5 and standard hydrolysis-decarboxylation-esterifi-
cation methodology. This problem was circumvented by
replacing malonate 2a with ethyl nitroacetate 2b in reaction
Scheme 1. It was found that compound 2b could be reacted
with either amino ketone 1a or 1b to give the g-nitro
carbonyl compounds 3c and 3d. Reductive cyclisation of
these latter derivatives gave the target C5 monoester
nitrones 5c and 5d in 70% and 46% yield, respectively.
The attempted reduction of pyrroline 7 using sodium boro-
hydride was unsuccessful, so catalytic hydrogenation was
employed. Reduction at 1 atm gave the desired pyrrolidine 8
together with the amino ester 9. Hydrogenation at 20 psi
gave an 89% yield of compound 9. Oxidation of the pyrro-
lidine 8 using urea hydrogen peroxide (UHP)6 and sodium
tungstate7 gave a mixture of the two isomeric nitrones 5c
and 10 in a ratio of 3.8:1 (Scheme 2). The product ratio
suggests that the nitrone is better stabilised when conjugated
to the phenyl group as opposed to the ester function. This
result is not surprising when considering that the nitrone
carbon is somewhat cationic in nature and can be relatively
destabilised by electron withdrawing groups.
The reactivity of nitrone 5c was examined, initially with
respect to removal of the acidic proton at C5. Treatment
with sodium hydride followed by quenching with methyl
iodide produced compound 11 exclusively, with no
evidence for the formation of the isomeric compound 12
(Scheme 3), which would be formed by methylation of the
alternative carbanion. This finding is consistent with the
result of oxidation of pyrrolidine 8 with UHP and sodium
tungstate.
An interesting by-product, identified as hydroxylamine 6
(Scheme 1), was isolated in small yield on recrystallisation
of 5c from ethanol, and is believed to arise via trapping of
the intermediate hydroxylamine 4c by contaminant phenyl
vinyl ketone.
During the reductive cyclisation of 3c it was found that an
elevated temperature of 10ЊC gave the corresponding
pyrroline 7 in 92% yield. This subtle change in methodology
produced superior results for ring formation and was not as
sensitive to changes in zinc quality as was the nitrone
synthesis. An alternative route to the desired nitrone system
followed reduction of compound 7 to the pyrrolidine 8 and
subsequent oxidation of the secondary amine to give the
target molecule 5c.
It was found that nitrone 5c could also be regioselectively
alkylated at C5 with allyl bromide to give compound 13,
which on heating in refluxing toluene gave a single product
15 resulting from 1,3-dipolar cycloaddition. When
compared with an earlier example of this type,8 formation
of the isomeric nitrone 14 (Scheme 4) could be expected
via 3,3-Cope rearrangement of allyl nitrone 13. Although
both allylated nitrones 13 and 14 should give the same
Scheme 3.

D. StC. Black et al. / Tetrahedron 56 (2000) 1889–1897
1891
Scheme 4.
cycloaddition product 15, monitoring of the reaction by 1H
NMR spectroscopy revealed that nitrone 14 was not formed
at any stage.
To test the generality of the route to 7-azabicyclo[2.2.1]hep-
tane skeletons such as compound 17, addition of the
a,b-unsaturated carbonyl compounds chalcone and ethyl
crotonate to the C5 carbanion of 5c was carried out.
However, no bicyclic compounds were isolated under
these conditions and only the products 18 and 19 of Michael
addition were observed. It appears that the intermediate
carbanions a- to the carbonyl functions located on the
acceptor during the Michael reaction are too stable, relative
to that in the nitrile analogue, and do not attack the nitrone
system. Indeed, treatment of compounds 18 and 19 with one
molar equivalent of sodium hydride followed by aqueous
workup resulted in only near quantitative recovery of
starting material.
The attempted alkylation of nitrone 5c with b-bromopropio-
nitrile as alkylating agent gave unexpected results.
Treatment with 1 equiv. of sodium hydride followed by
addition of the b-halo nitrile gave quantitative recovery of
5c. Failure of this reaction was attributed to quenching of
the C5 carbanion via proton exchange with the position a-
to the nitrile of the alkylating agent. When repeated with
2 equiv. of base the reaction not only gave the C5 alkylated
product 16 but also the bicyclic compound 17 (Scheme 5). It
is proposed that compound 17 arises through net loss of
hydrogen bromide from 3-bromopropionitrile to give acrylo-
nitrile, followed by Michael addition of the C5 carbanion of
nitrone 5c and subsequent trapping of the intermediate anion
a- to the nitrile. Inferential evidence in support of this
mechanism was found when treatment of nitrone 5c with
1 equiv. of base followed by acrylonitrile gave an improved
yield of hydroxylamine 17 together with some C5 alkylated
compound 16.
The above results argue against a [3ϩ2] concerted cyclo-
addition mechanism in the formation of compound 17 from
nitrone 5c and acrylonitrile. The a,b-unsaturation in the
carbonyl bearing examples is more activated and
would be expected to give bicyclic compounds, at
least to some extent, if a concerted process was in
operation.
Scheme 5.
Scheme 6.

1892
D. StC. Black et al. / Tetrahedron 56 (2000) 1889–1897
Preparation of g-nitro ketones 3a–d
A solution containing either diethyl nitromalonate 1a18 or
ethyl nitroacetate 1b19 and an equimolar amount of
1-diethylaminopropiophenone 2a20 or 1-diethylamino-3-
butanone 2b21 in dry toluene was gently refluxed in a nitro-
gen flow until diethylamine ceased to be evolved (2–6 h).
The solvent was removed and the residue was purified by
flash chromatography (5% methanol/chloroform) to give the
pure g-nitro ketone 3.
Acylation of the C5 carbanion derived from nitrone 5c was
attempted with a variety of acid chlorides. However, elec-
trophilic attack occurred exclusively at oxygen and not at
C5 to give compounds 20a–e via hetero-Cope rearrange-
ment. These products readily lose carboxylic acid and
undergo aromatisation to the pyrrole 21 (Scheme 6). This
result was not entirely unexpected as it has been shown that
nitrones, when treated with benzoyl chloride9–14 or benzoic
anhydride,14 produce O-benzoyl imine derivatives. In a few
of these previous examples small amounts of 2H-pyrroles
have also been obtained. More recently a reliable route to
these pyrroles from 1-pyrroline-1-oxides has been
described.15
Diethyl 1-nitro-4-oxo-4-phenylbutane-1,1-dicarboxylate
3a. The above procedure using malonate 1a18 (10.0 g,
49.0 mmol) and amino ketone 2a20 (10.3 g, 49.0 mmol)
gave nitro ketone 3a as a light yellow oil (16.4 g, 100%).
IR nmax 1770, 1690, 1570, 1450, 1375, 1090, 355, 740,
655 cmϪ1. dH (300 MHz, CDCl3) 1.31 (6H, t, Jˆ7.1 Hz,
Me), 2.91 (2H, m, H3), 3.31 (2H, m, H2), 4.35 (4H, q,
Jˆ7.1 Hz, OCH2), 7.46 (2H, m, ArH), 7.57 (1H, m, ArH),
7.93 (2H, m, ArH); dC (75.5 MHz, CDCl3) 13.5, 25.1, 34.0,
63.6, 76.9, 127.5, 128.4, 133.2, 137.3, 162.3, 197.3; m/z
338 (Mϩ1, 62%), 292 (57), 173 (29), 133 (48), 105 (100).
The 2,4-dinitrophenylhydrazone formed as a yellow
solid, mp 156–157ЊC. (Found: C, 51.4; H, 4.2; N, 13.1.
C22H23N5O10 requires C, 51.1; H, 4.5; N, 13.5%).
The acylation of nitrone 5c generated both possible isomers
of the compounds 20a–e. The C3 ester exists both cis and
trans to the C5 ethyl carboxylate and there appears to be no
particular preference for the formation of either isomer. The
two isomeric forms were distinguished by the observation of
a 1.5 Hz ‘W’ type coupling between the C3 and C5 protons
Diethyl 1-nitro-4-oxopentane-1,1-dicarboxylate 3b. The
above procedure using malonate 1a18 (25.0 g, 0.12 mol)
and amino ketone 2b21 (19.2 g, 0.12 mol) gave nitro ketone
3b as a pale yellow oil (23.5 g, 70%): bp 160ЊC/2.5 mmHg.
(Found: C, 48.4; H, 6.3; N, 5.4. C11H17NO7 requires C, 48.0;
H, 6.2; N, 5.1%). IR nmax 1760, 1730, 1570, 1370, 1090,
1010 cmϪ1. dH (300 MHz, CDCl3) 1.29 (6H, t, Jˆ7.1 Hz,
CH2Me), 2.14 (3H, s, COMe), 2.71 (4H, m, H2 and H3),
4.31 (4H, q, Jˆ7.1 Hz, OCH2); dC (75.5 MHz, CDCl3)
13.55, 27.52, 29.71, 37.84, 63.65, 96.89, 162.31, 205.25;
m/z 276 (Mϩ1, 9%), 230 (66), 184 (100), 173 (95), 160
(40), 141 (30), 127 (23), 111 (17).
1
in the H NMR spectrum of the cis compounds.
In summary, some 1-pyrroline-1-oxide-5-carboxylic esters
have been synthesised by the reductive cyclisation of g-nitro
ketoesters. The carbanion of the nitrone monoester 5c reacts
with alkylating agents and Michael acceptors but not with
acyl chlorides in which cases attack on the nitrone oxygen
atom occurs. In connection with this work, pendant alkenyl
chains have been introduced at C5 of compound 5c and the
intramolecular 3ϩ2 cycloaddition chemistry of the resulting
nitrones examined.16 These nitrones have also been
converted into the corresponding oxaziridines and their
radical cyclisation chemistry investigated.17
Ethyl 2-nitro-5-oxo-5-phenylpentanoate 3c. The above
procedure using acetate 1b19 (4.92 g, 37.0 mmol) and
amino ketone 2a20 (7.59 g, 37.0 mmol) gave nitro ketone
3c as a light brown oil (9.81 g, 100%). bp 250ЊC/
110 mmHg. (Found: C, 58.6; H, 5.9; N, 5.0. C13H15NO5
requires C, 58.9; H, 5.6; N, 5.2%). IR nmax 1750, 1990,
Experimental
1565, 1450, 1375, 1020, 860, 750, 695 cmϪ1
. dH
General information
(300 MHz, CDCl3) 1.30 (3H, t, Jˆ6.0 Hz, Me), 2.70 (2H,
m, H3), 3.14 (2H, m, H4), 4.30 (2H, q, Jˆ7.1 Hz, OCH2),
5.37 (1H, t, Jˆ8.3 Hz, H2), 7.92 (5H, m, ArH); dC
(75.5 MHz, CDCl3) 13.73, 24.38, 33.52, 62.98, 86.88,
127.84, 128.62, 133.44, 136.06, 164.27, 197.36; m/z 265
(M, 15%), 264 (100), 105 (10), 52 (14).
Melting points and boiling points are uncorrected. Infrared
spectra were recorded on a Hitachi model EPI-G instrument
and refer to thin films of liquids between KBr plates or
paraffin mulls of solids. H and 13C NMR spectra were
1
recorded using a Bruker CXP 300 instrument (300 MHz).
The chemical shifts are reported in parts per million (d) with
chloroform as an internal standard. Electron ionisation mass
spectra were measured at 70 eV ionising voltage using an
AEI MS12 instrument with an 8000 V accelerating voltage
and an ion source temperature of 200ЊC. Chemical ioni-
sation mass spectra were recorded on a MEI MS902
instrument using a 450 V ionising voltage and a source
temperature of 200ЊC at 8000 V accelerating voltage.
Flash column chromatography employed Kieselgel 60 silica
gel and the solvents used as eluent are quoted in the text.
Ethyl 2-nitro-5-oxohexanoate 3d. The above procedure
using acetate 1b19 (4.65 g, 34.9 mmol) and amino ketone
2b21 (5.00 g, 34.9 mmol) gave nitro ketone 3d as a waxy
white solid 22 (4.28 g, 60%). bp 218ЊC/760 mmHg. (Found:
C, 47.2; H, 6.5; N, 6.7. C8H13NO5 requires C, 47.3; H, 6.40;
N, 6.9%). IR nmax 1755, 1720, 1540, 1365, 1000, 800 cmϪ1
.
dH (300 MHz, CDCl3) 1.27 (3H, t, Jˆ7.1 Hz, CH2Me), 2.14
(3H, s, COMe), 2.41 (2H, m, H3), 2.58 (2H, m, H4), 4.25
(2H, q, Jˆ7.1 Hz, OCH2), 5.21 (1H, m, H2); m/z 203 (M,
11%), 188 (24), 157 (22), 130 (58), 84 (22).

D. StC. Black et al. / Tetrahedron 56 (2000) 1889–1897
1893
Preparation of 1-pyrroline-1-oxides 5a–d
Attempted recrystallisation of nitrone 5c (0.10 g,
0.43 mmol) gave some ethyl 2-benzoyl-1-hydroxy-4-hydroxyl-
amino-1-phenylcyclohexane-4-carboxylate 6 as colourless
crystals (11.0 mg, 7.0%). mp 93ЊC. (Found: C, 68.7; H, 6.9;
N, 3.4. C22H25NO5 requires C, 68.9; H, 6.6; N, 3.7%). IR nmax
3405, 2950, 1740, 1660, 1600, 1450, 1380, 1265, 1225, 1160,
1090, 1070, 1050, 960, 920, 850, 765, 750, 705, 690 cmϪ1. dH
(300 MHz, CDCl3) 1.28 (3H, t, Jˆ6.93 Hz, Me), 1.73 (2H, m,
H6), 2.16 (2H, m, H5), 2.50 (2H, m, H3), 4.23 (2H, q,
Jˆ7.2 Hz, OCH2), 4.59 (1H, dd, Jˆ13.0, 3.6 Hz, H2), 7.11
(1H, t, Jˆ7.2 Hz, ArH), 7.22 (2H, t, Jˆ7.2 Hz, ArH), 7.54
(3H, m, ArH), 7.88 (2H, dd, Jˆ8.7, 1.5 Hz, ArH); dC
(75.5 MHz, CDCl3) 14.06, 26.29, 29.08, 35.37, 44.90, 61.61,
64.47, 74.05, 124.45, 128.20, 128.71, 135.75, 147.34, 174.45,
205.29; m/z 384 (Mϩ1, 8%), 366 (100), 348 (12), 338 (10),
234 (24).
A cold solution of ammonium chloride in water was added
to the g-nitro ketone 3 in tetrahydrofuran. The mixture was
cooled to 0ЊC before adding zinc powder at such a rate that
the temperature was not allowed to exceed 5ЊC and stirring
was continued for 3–5 h. The solution was filtered, evapo-
rated under reduced pressure and the aqueous residue
extracted with chloroform. The combined organic extracts
were dried (MgSO4) and the solvent removed under reduced
pressure to leave the crude product.
Diethyl 2-phenyl-1-pyrroline-5,5-dicarboxylate 1-oxide
5a. The reduction of nitro ketone 3a (7.00 g, 20.0 mmol)
in tetrahydrofuran (60 ml) used ammonium chloride
(2.00 g, 37.0 mmol) in water (50 ml) and zinc powder
(8.50 g). The crude product was recrystallised from 95%
ethanol to give nitrone 5a as white needles (3.50 g, 55%).
mp 118–120ЊC. (Found: C, 63.0; H, 6.2; N, 4.6. C16H19NO5
requires C, 63.0; H, 6.20; N, 4.6%). IR nmax 1760, 1740,
1580, 1570, 1460, 1390, 1310, 1300, 1280, 1260, 1220,
1180, 1120, 1040, 760, 690, 560 cmϪ1. dH (300 MHz,
CDCl3) 1.34 (6H, t, Jˆ7.1 Hz, Me), 2.36 (2H, m, H4),
3.18 (2H, m, H3), 4.37 (4H, m, OCH2), 7.36 (3H, m,
ArH), 8.4 (2H, m, ArH); dC (75.5 MHz, CDCl3) 13.86,
27.27, 29.31, 62.45, 77.90, 127.48, 129.45, 130.10, 131.00,
150.30, 167.31; m/z 305 (M, 16%), 233 (17), 232 (57), 217
(28), 216 (100), 215 (15), 171 (19), 160 (25), 156 (10), 144
(35), 143 (39), 125 (18), 105 (41), 103 (13), 77 (23).
Ethyl 2-methyl-1-pyrroline-5-carboxylate 1-oxide 5d.
The reduction of nitro ketone 3d (3.50 g, 17.3 mmol) in
tetrahydrofuran (90 ml) used ammonium chloride (2.75 g,
51.5 mmol) in water (70 ml) and zinc powder (17.0 g). The
crude product was purified via flash chromatography with
5% methanol/chloroform as eluent to give nitrone 5d as a
viscous yellow oil (1.40 g, 46%). bp 165ЊC (dec.). (Found:
C, 56.2; H, 7.3; N, 8.0. C8H13NO3 requires C, 56.1; H, 7.6;
N, 8.2%). IR nmax 2995, 1750, 1730, 1550, 1460, 1300,
1250, 1205, 1150, 780 cmϪ1. dH (300 MHz, CDCl3) 1.28
(3H, t, Jˆ7.1 Hz, CH2Me), 2.07 (3H, s, 2-Me), 2.16 (1H,
m, H4), 2.37 (1H, m, H4), 2.72 (1H, m, H3), 2.85 (1H, m,
H3), 4.25 (2H, m, OCH2), 4.64 (1H, m, H5); m/z 171 (M,
8%), 155 (28), 154 (34), 141 (43), 109 (56).
Diethyl 2-methyl-1-pyrroline-5,5-dicarboxylate 1-oxide
5b. The reduction of nitro ketone 3b (8.52 g, 30.9 mmol)
in tetrahydrofuran (80 ml) used ammonium chloride
(3.00 g, 56.0 mmol) in water (50 ml) and zinc powder
(10.0 g). The crude product was distilled to give nitrone
5b as a bright yellow oil (5.80 g, 77%). bp 165ЊC/
3.5 mmHg. (Found: C, 54.5; H, 7.2; N, 5.4. C11H17NO5
requires C, 54.3; H, 7.0; N, 5.8%). IR nmax 1740, 1645,
1370, 1270, 1150, 1090, 1020, 860 cmϪ1. dH (300 MHz,
CDCl3) 1.23 (6H, t, Jˆ7.1 Hz, CH2Me), 2.10 (3H, s,
2-Me), 2.51 (2H, t, Jˆ7.3 Hz, H4), 3.34 (2H, t, Jˆ7.3 Hz,
H3), 4.15 (4H, m, OCH2); dC (75.5 MHz, CDCl3) 14.01,
24.55, 28.89, 35.99, 63.71, 97.01, 150.01, 164.50; m/z 243
(M, 21%), 171 (21), 170 (100), 142 (26), 125 (13), 124 (50),
99 (47).
Ethyl 2-phenyl-1-pyrroline-5-carboxylate 7. This com-
pound was prepared as for compounds 5a–d using nitro
ketone 3c (7.50 g, 28.3 mmol) in tetrahydrofuran (140 ml),
ammonium chloride (4.52 g, 84.5 mmol) in water (140 ml)
and zinc powder (28.1 g) with a temperature increase to
10ЊC during and after the zinc addition. The resulting
product was purified via flash chromatography to give
imine 7 as a yellow oil23 (5.70 g, 92%). bp 214ЊC (dec.).
(Found: C, 70.3; H, 7.1; N, 6.3. C13H15NO2 requires C, 71.9;
H, 6.9; N, 6.5%). IR nmax 2910, 1735, 1575, 1445, 1370,
1340, 1260, 1185, 1035, 755, 690 cmϪ1. dH (300 MHz,
CDCl3) 1.26 (3H, t, Jˆ7.1 Hz, Me), 2.24 (2H, m, H4),
3.02 (2H, m, H3), 4.19 (2H, q, Jˆ7.1 Hz, OCH2), 4.85
(1H, m, H5), 7.36 (3H, m, ArH), 7.83 (2H, m, ArH); dC
(75.5 MHz, CDCl3) 14.11, 26.33, 35.34, 60.98, 74.56,
127.93, 128.29, 130.81, 133.75, 172.84, 175.92; m/z 217
(M, 10%), 146 (5), 145 (20), 144 (100), 117 (10), 115
(22), 91 (25), 41 (5).
Ethyl 2-phenyl-1-pyrroline-5-carboxylate 1-oxide 5c.
The reduction of nitro ketone 3c (1.60 g, 6.03 mmol) in
tetrahydrofuran (30 ml) used ammonium chloride (1.00 g,
18.0 mmol) in water (30 ml) and zinc powder (6.00 g). The
crude product was a yellow oil which crystallised on stan-
ding to give nitrone 5c as white needles (1.00 g, 70%). mp
140ЊC (dec.). (Found: C, 66.9; H, 6.5; N, 5.9. C13H15NO3
requires C, 66.9; H, 6.5; N, 6.0%). IR nmax 1746, 1570,
1550, 1450, 1392, 1375, 1348, 1295, 1255, 1235, 1210,
1200, 1180, 1155, 1045, 1020, 760 cmϪ1. dH (300 MHz,
CDCl3) 1.33 (3H, t, Jˆ7.1 Hz, Me), 2.33 (1H, m, H4),
2.50 (1H, m, H4), 3.20 (1H, m, H3), 3.31 (1H, m, H3),
4.30 (2H, m, OCH2), 4.90 (1H, dd, Jˆ4.9, 1.3 Hz, H5),
7.45 (3H, m, ArH), 8.35 (2H, m, ArH; dC (75.5 MHz,
CDCl3) 14.11, 19.62, 30.17, 61.69, 68.13, 127.50, 128.50,
130.79, 135.80, 149.23, 169.02; m/z 233 (M, 43%), 161
(17), 105 (18), 102 (20), 91 (10), 77 (20).
Catalytic hydrogenation of 1-pyrroline 7
(i) Ethyl 2-phenyl-1-pyrroline-5-carboxylate 7 (0.25 g,
1.15 mmol) was hydrogenated in absolute ethanol (10 ml)
over palladium-charcoal (0.2 g of 10%) in the Parr appa-
ratus at 20 psi for 12 h. The reaction mixture was passed
through a plug of Celite which was washed with dichloro-
methane and the filtrate and washings were combined. The
solvent was evaporated under reduced pressure to leave a
crude tan oil. The oil was purified using preparative TLC
with ether/light petroleum as eluent to give ethyl 2-amino-
5-phenylpentanoate 9 as a tan oil (227 mg, 89%). (Found:

1894
D. StC. Black et al. / Tetrahedron 56 (2000) 1889–1897
C, 70.0; H, 9.2; N, 6.0. C13H19NO2 requires C, 70.6; H, 8.6;
N, 6.3%). dH (300 MHz, CDCl3) 1.35 (3H, t, Jˆ7.2 Hz,
Me), 1.78 (4H, m, H2, H3), 2.72 (2H, m, H4), 3.53 (1H,
m, H1), 4.25 (2H, q, Jˆ7.2 Hz, OCH2), 7.27 (3H, m, ArH),
7.36 (2H, m, ArH); dC (75.5 MHz, CDCl3) 14.14, 27.28,
34.34, 35.46, 54.22, 60.70, 125.70, 128.22, 128.27,
141.83, 175.86; m/z 221 (M, 4%), 193 (14), 149 (12), 148
(62), 131 (100), 103 (39), 91 (89), 77 (26), 74 (27), 65 (22),
56 (35), 44 (19).
residue, which was extracted with chloroform (3×15 ml)
and the combined organic extracts were dried (MgSO4),
concentrated under reduced pressure and flash chroma-
tographed using ether/light petroleum as eluent to give
ethyl 5-methyl-2-phenyl-1-pyrroline-5-carboxylate 1-oxide
11 as a yellow oil (400 mg, 76%): bp 285ЊC. (Found: C,
68.0; H, 6.9; N, 5.7. C14H17NO3 requires C, 68.0; H, 6.9; N,
5.7%). IR nmax 1640, 1535, 1460, 1370, 1310, 1290, 1210,
1040, 900, 720 cmϪ1. dH (300 MHz, CDCl3) 1.15 (3H, t,
Jˆ7.2 Hz, CH2Me), 1.69 (3H, s, 5-Me), 2.02 (2H, m, H4),
3.06 (2H, m, H3), 4.13 (2H, m, OCH2), 7.34 (3H, m, ArH),
8.27 (2H, m, ArH); dC (75.5 MHz, CDCl3) 13.85, 21.19,
28.06, 29.76, 61.19, 81.08, 127.24, 128.25, 129.05,
130.36, 140.63, 170.35; m/z 247 (M, 23%), 175 (18), 174
(100), 159 (9), 158 (54), 156 (30), 143 (11), 130 (13), 129
(18), 128 (38), 115 (72), 105 (64), 103 (58), 91 (42), 89
(16), 79 (6), 78 (20), 77 (97), 65 (17), 63 (22), 51 (42),
41 (40).
(ii) Ethyl 2-phenyl-1-pyrroline-5-carboxylate 7 (0.25 g,
1.15 mmol) was hydrogenated in absolute ethanol (10 ml)
over palladium-charcoal (0.02 g of 10%) at 1 atm for 6 h.
The reaction mixture was passed through a plug of Celite
which was washed with dichloromethane and the filtrate and
washings were combined. The solvent was evaporated
under reduced pressure to leave a crude tan oil. The oil
was purified using preparative TLC with ether/light petro-
leum as eluent to give a-amino ester 9 as a tan oil in 20%
yield with identical spectral characteristics to those above
and ethyl 5-phenylpyrrolidine-2-carboxylate 8 as a pale
yellow oil23 (136 mg, 54%). (Found: C, 70.9; H, 8.0; N,
7.0. C13H17NO2 requires C, 71.2; H, 7.8; N, 6.4%). dH
(300 MHz, CDCl3) 1.29 (3H, t, Jˆ6.7 Hz, Me), 1.72 (1H,
m, H4), 2.15 (3H, m, H4, H3), 2.52 (1H, bs, NH), 3.91 (1H,
m, H2), 4.18 (1H, m, H5), 4.22 (2H, q, Jˆ6.7 Hz, OCH2),
7.23 (1H, m, ArH), 7.31 (2H, m, ArH), 7.44 (2H, m, ArH);
dC (75.5 MHz, CDCl3) 14.34, 30.59, 34.09, 60.04, 60.95,
63.53, 126.68, 127.12, 128.37, 143.12, 175.03; m/z 219 (M,
1%), 218 (10), 217 (40), 145 (16), 144 (82), 143 (29), 129
(13), 117 (31), 115 (71), 105 (52), 104 (41), 103 (26), 91
(68), 89 (42), 77 (100), 76 (24), 63 (33), 57 (30), 51 (71).
Ethyl 5-allyl-2-phenyl-1-pyrroline-5-carboxylate 1-oxide
13. The reaction was performed as described for the
synthesis of 1-pyrroline 11 above, replacing methyl iodide
with allyl chloride (165 mg, 2.15 mmol) to give ethyl 5-
allyl-2-phenyl-1-pyrroline-5-carboxylate 1-oxide 13 as a
waxy yellow solid (390 mg, 66%): mp 46ЊC. (Found: C,
70.1; H, 7.1; N, 5.1. C16H19NO3 requires C, 70.3; H, 7.0;
N, 5.1%). IR nmax 1735, 1680, 1570, 1543, 1465, 1375,
1360, 1305, 1275, 1250, 1205, 1175, 1120, 1068, 1025,
910, 760 cmϪ1. dH (300 MHz, CDCl3) 1.23 (3H, t,
Jˆ6.9 Hz, Me), 2.28 (2H, m, H4), 2.74 (1H, m, H3), 3.08
(3H, m, H10, H3), 4.22 (2H, d, Jˆ6.9 Hz, OCH2), 5.16 (2H,
m, H30), 5.64 (1H, m, H20), 7.42 (3H, m, ArH), 8.32 (2H, m,
ArH); dC (75.5 MHz, CDCl3) 13.79, 25.21, 37.40, 61.93,
84.12, 120.45, 127.22, 128.19, 129.10, 130.30, 131.29,
162.25, 169.98; m/z 273 (M, 28%), 256 (10), 233 (11),
232 (51), 216 (12), 201 (17), 200 (100), 184 (24), 182
(51), 170 (21), 156 (36), 143 (22), 142 914), 128 912),
115 938), 103 (40), 91 (19), 80 (32), 77 (64).
Oxidation of ethyl 5-phenylpyrrolidine-2-carboxylate 8
To a solution of ethyl 5-phenylpyrrolidine-2-carboxylate 8
(75.0 mg, 0.34 mmol) in methanol (5 ml) was added sodium
tungstate (5.6 mg, 0.02 mmol) and urea hydrogen peroxide
(125 mg, 1.37 mmol). The reaction mixture was stirred for
3 h and the solvent evaporated under reduced pressure. The
remaining residue was dissolved in dichloromethane (5 ml),
filtered and the solvent evaporated under reduced pressure
Ethyl 6-phenyl-8-oxa-7-azatricyclo[4.2.1.03,7]nonane-3-
carboxylate 15. A solution of ethyl 5-allyl-2-phenyl-1-
pyrroline-5-carboxylate 1-oxide 13 (0.30 g, 1.09 mmol) in
dry, degassed toluene (50 ml) was heated at reflux for 7
days. The solvent was evaporated under reduced pressure
to leave a red–brown residue. The crude residue was
chromatographed using dichloromethane as eluent to
give ethyl 6-phenyl-8-oxa-7-azatricyclo[4.2.1.03,7]nonane-
3-carboxylate 15 as colourless crystals (237 mg, 79%): mp
98ЊC. (Found: C, 70.2; H, 7.2; N, 5.1. C16H19NO3 requires
C, 70.3; H, 7.0; N, 5.1%). IR nmax 2800, 2750, 2555, 2300,
1
to leave an oil. A H NMR spectrum of the crude reaction
mixture showed only two products to be present. One of
these had identical spectroscopic characteristics to 1-pyrro-
line-1-oxide 5c above and the other product appeared to fit
the expected 1H NMR spectrum for ethyl 5-phenyl-1-pyrro-
line-1-oxide-2-carboxylate 10. The latter product rapidly
decomposed on attempted purification via chromatography
and could not be further characterised. However, inte-
gration and comparison of both C5 proton peaks for
nitrones 5c and 10 showed that these products were in
the ratio of 3.8:1.
2110, 1720, 1595, 1415, 1250, 1115, 1010, 975, 885 cmϪ1
.
dH (300 MHz, CDCl3) 1.30 (3H, t, Jˆ7.2 Hz, Me), 1.72
(1H, d, Jˆ12.3 Hz, H9), 1.94 (1H, d, Jˆ12.0 Hz, H2),
2.18 (2H, m, H4, H5), 2.43 (3H, m, H2, H4, H5), 2.68
(1H, m, H9), 4.24 (2H, q, Jˆ7.2 Hz, OCH2), 4.88 (1H, t,
Jˆ4.9 Hz, H1), 7.17 (1H, m, ArH), 7.29 (2H, m, ArH), 7.51
(2H, m, ArH); dC (75.5 MHz, CDCl3) 14.08, 30.14, 34.97,
47.23, 50.21, 62.22, 74.92, 76.32, 81.25, 125.14, 126.24,
128.24, 147.19, 173.31; m/z 273 (M, 48%), 256 (12), 233
(12), 232 (60), 210 (10), 201 (20), 200 (100), 184 (21),
182 (28), 170 (24), 156 (30), 144 (32), 143 (21), 129
(25), 115 (48), 103 (50), 91 (65), 80 (18), 77(35), 69
(11), 57 (12).
Ethyl 5-methyl-2-phenyl-1-pyrroline-5-carboxylate 1-oxide
11. Ethyl 2-phenyl-1-pyrroline-5-carboxylate 1-oxide 5c
(0.50 g, 2.15 mmol) was dissolved with stirring in dry tetra-
hydrofuran (10 ml). Sodium hydride (70 mg of an 80%
dispersion in oil, 2.36 mmol) was added, followed after
5 min by dimethylformamide (0.5 ml). After a further
5 min methyl iodide (0.30 g, 2.15 mmol) was added slowly
over 10 min. After 24 h water (1 ml) was added and the
solvent evaporated under reduced pressure to leave an oily

D. StC. Black et al. / Tetrahedron 56 (2000) 1889–1897
1895
Attempted C5 alkylation of 1-pyrroline-1-oxide 5c with
3-bromopropionitrile
m, H4), 2.36 (2H, m, H20), 2.80 (1H, m, H4), 3.78 (3H, m,
H3, H10), 4.32 (2H, m, OCH2), 7.04–7.15 (3H, m, ArH),
7.37–7.52 (8H, m, ArH), 7.92–7.99 (2H, m, ArH), 8.27–
8.32 (2H, m, ArH); dC (75.5 MHz, CDCl3) 13.98, 27.59,
28.16, 42.16,45.62, 62.42, 86.67, 127.40, 128.01, 128.35,
128.49, 129.11, 129.25, 129.87, 130.50, 132.81, 136.84,
138.31, 143.20, 170.07, 191.80; m/z 441 (M, 10%), 423
(13), 397 (11), 396 (28), 380 (15), 353 (18), 352 (54), 349
(74), 348 (37), 338 (32), 336 (100), 334 (32), 320 (45), 307
(45), 304 (39), 290 (30), 279 (24).
To a solution of ethyl 2-phenyl-1-pyrroline-5-carboxylate
1-oxide 5c (0.25 g, 1.07 mmol) in dry tetrahydrofuran
(5 ml) was added sodium hydride (33 mg of an 80% disper-
sion in oil, 1.12 mmol) followed after 30 min by 3-bromo-
propionitrile (143 mg, 1.07 mmol). Sodium hydride (33 mg
of an 80% dispersion in oil, 1.12 mmol) was again added
and stirring was continued for 2 h before quenching with
water (1 ml). The solvent was evaporated under reduced
pressure and the resulting aqueous residue was extracted
with dichloromethane (3×5 ml). The combined organic
extracts were dried (MgSO4) and the solvent evaporated
under reduced pressure to leave a viscous brown oil. The
oil was flash chromatographed using 30% ether/light petro-
leum as eluent to give: (i) ethyl 5-cyanoethyl-2-phenyl-1-
pyrroline-5-carboxylate 1-oxide 16 as a yellow oil (74 mg,
24%). Due to instability of this compound, a satisfactory
microanalysis could not be obtained. IR nmax 2350, 1745,
1560, 1375, 1360, 1330, 1300, 1280, 1250, 1215, 1180,
1050, 1020, 910, 780, 720, 650 cmϪ1. dH (300 MHz,
CDCl3) 1.27 (3H, t, Jˆ7.2 Hz, Me), 2.51 (6H, m, H10,
H20, H4), 3.21 (2H, m, H3), 4.24 (2H, q, Jˆ7.2 Hz,
OCH2), 7.45 (3H, m, ArH), 8.34 (2H, m, ArH); dC
(75.5 MHz, CDCl3) 12.6, 14.34, 27.17, 28.76, 30.66,
63.02, 82.79, 119.55, 127.88, 128.04, 128.93, 131.41,
142.63, 169.58; m/z 287 (Mϩ1, 6%), 286 (18), 234 (14),
233 (88), 216 (100), 213 (64), 197 (34), 195 (22), 188 (16),
172 (49), 156 (48), 144 (52), 128 (19), 115 (38), 105 (42),
103 (34), 77 (63), 76 (19), 51 (17) and (ii) ethyl 3-cyano-7-
hydroxy-4-phenyl-7-azabicyclo[2.2.1]heptane-1-carboxy-
late 17 as a white solid (88 mg, 29%): mp 92ЊC. (Found: C,
65.7; H, 6.6; N, 8.7. C16H18N2O3.1/2H2O requires C, 65.1;
H, 6.4; N, 9.5%). IR nmax 3390, 2950, 2150, 1745, 1445,
1235, 1090, 1010, 810, 700, 690 cmϪ1. dH (300 MHz,
CDCl3) 1.29 (3H, t, Jˆ7.2 Hz, Me), 2.04 (2H, m, H5,
H6), 2.20 (1H, m, H5), 2.33 (1H, dd, Jˆ12.6, 5.1 Hz, H2),
2.48 (1H, m, H6), 3.02 (1H, td, Jˆ12.3, 3.1 Hz, H3), 4.23
(2H, q, Jˆ7.2 Hz, OCH2), 7.35 (3H, m, ArH), 7.64 (2H, m,
ArH); dC (75.5 MHz, CDCl3) 14.07, 29.79, 31.16, 33.06,
36.80, 61.43, 74.80, 77.20, 121.02, 126.59, 127.63,
130.52, 137.90, 171.02; m/z 216 (12), 160 (15), 144 (22),
143 (25), 128 (24), 116 (30), 115 (100), 103 (47), 91 (49), 77
(98), 65 (35), 51 (52).
Ethyl 5-[2-(ethoxycarbonyl)-1-methylethyl]-2-phenyl-1-
pyrroline-5-carboxylate 1-oxide 19. The C5 carbanion of
1-pyrroline-1-oxide 5c was generated as above on a
1.07 mmol scale then treated with an equimolar amount of
ethyl 2-butenoate. Following workup in the usual way a
white solid was produced. The crude material was partially
purified via flash chromatography using 30% ether/light
petroleum as eluent to give ethyl 5-[2-(ethoxycarbonyl)-1-
methylethyl]-2-phenyl-1-pyrroline-5-carboxylate 1-oxide
19 as an orange oil (301 mg, 81%). IR nmax 1740, 1730,
1575, 1540, 1460, 1375, 1200, 1090, 1060, 1025, 850,
760, 690 cmϪ1. dH (300 MHz, CDCl3) 1.13 (3H, d,
Jˆ3.2 Hz, CHMe), 1.18 (3H, t, Jˆ7.2 Hz, CH2Me), 1.23
(3H, t, Jˆ7.2 Hz, CH2Me), 2.17 (2H, m, H4), 2.50 (2H,
m, H20), 3.18 (3H, m, H10, H3), 4.08 (2H, q, Jˆ7.2 Hz,
OCH2), 4.22 (2H, q, Jˆ7.2 Hz, OCH2), 7.39 (3H, m,
ArH), 8.32 (2H, m, ArH); dC (75.5 MHz, CDCl3) 13.81,
13.99, 14.23, 23.07, 28.27, 32.66, 36.05, 60.23, 62.02,
86.76, 127.27, 128.24, 128.81, 130.42, 141.39, 169.18,
171.95; m/z 347 (M, 5%), 318 (25), 274 (65).
Reaction of 1-pyrroline-1-oxide 5c with acyl chlorides
The C5 carbanion of 1-pyrroline-1-oxide 5c (4.3 mmol) was
generated as above before adding the desired acyl chloride
(4.3 mmol) and stirring the reaction mixture for 4–8 h. The
reaction was quenched with water (1 ml) and the solvent
evaporated under reduced pressure to leave a residue
which was extracted with dichloromethane (3×5 ml).
The combined organic extracts were dried (MgSO4) and
the solvent evaporated under reduced pressure to leave the
crude product mixture. The products were separated rapidly
using preparative TLC with ether/light petroleum as eluent.
Satisfactory analytical data could not be obtained for the
pyrrolines 20 because of trace contamination by the pyrrole
21.
The reaction was performed as for the synthesis of 11 above
using acrylonitrile as alkylating agent to give compounds 16
and 17 in 27 and 59% yields, respectively.
Reaction of 1-pyrroline-1-oxide 5c with acetyl chloride
Ethyl 5-(1,3-diphenyl-3-oxoprop-1-yl)-2-phenyl-1-pyrro-
line-5-carboxylate 1-oxide 18. The C5 carbanion of
1-pyrroline-1-oxide 5c was generated as above on a
1.07 mmol scale then treated with an equimolar amount of
chalcone. Following workup in the usual way a white solid
was produced. The crude material was purified via flash
chromatography using 30% ether/light petroleum as eluent
to give ethyl 5-(1,3-diphenyl-3-oxoprop-1-yl)-2-phenyl-1-
pyrroline-5-carboxylate 1-oxide 18 as a white powder
(350 mg, 74%): mp 115–116ЊC. (Found: C, 73.3; H, 6.5;
N, 2.8. C28H27NO4.H2O requires C, 73.2; H, 6.3; N, 3.0%).
IR nmax 2950, 1735, 1680, 1550, 1250, 1040 cmϪ1. dH
(300 MHz, CDCl3) 1.26 (3H, t, Jˆ7.2 Hz, Me), 2.01 (1H,
The reaction was performed as described above to give: (i)
cis ethyl 3-acetoxy-2-phenyl-1-pyrroline-5-carboxylate
20a as a waxy yellow solid (28 mg, 24%): mp 42ЊC. dH
(300 MHz, CDCl3) 1.31 (3H, t, Jˆ7.2 Hz, CH2Me), 2.06
(3H, s, COMe), 2.27 (1H, m, H4), 2.66 (1H, m, H4), 4.25
(2H, q, Jˆ7.2 Hz, OCH2), 5.08 (1H, ddd, Jˆ8.2, 5.1,
1.5 Hz, H5), 6.32 (1H, ddd, Jˆ7.9, 4.2, 1.5 Hz, H3), 7.46
(3H, m, ArH), 7.86 (2H, m, ArH); dC (75.5 MHz, CDCl3)
14.15, 20.93, 34.08, 34.78, 61.53, 72.84, 128.35, 128.66,
130.56, 131.44, 171.74, 174.85; m/z 275 (M, 5%), 274 (10),
260 (30), 246 (44), 142 (100), (ii) trans ethyl 3-acetoxy-2-
phenyl-1-pyrroline-5-carboxylate 20a as a yellow oil
(23 mg, 20%). dH (300 MHz, CDCl3) 1.33 (3H, t,

1896
D. StC. Black et al. / Tetrahedron 56 (2000) 1889–1897
Jˆ7.2 Hz, CH2Me), 2.06 (3H, s, COMe), 2.20 (1H, m, H4),
2.86 (1H, m, H4), 4.27 (2H, q, Jˆ7.2 Hz, OCH2), 4.89 (1H,
dd, Jˆ7.9, 4.3 Hz, H5), 6.27 (1H, dd, Jˆ7.6, 5.6 Hz, H3),
7.44 (3H, m, ArH), 7.84 (2H, m, ArH); dC (75.5 MHz,
CDCl3) 14.19, 20.91, 34.07, 35.01, 61.52, 71.70, 128.36,
128.64, 130.10, 131.52, 170.21, 171.35, 174.61; m/z 275
(M, 3%), 274 (15), 261 (42), 244 (16), 142 (96), 77 (100),
(iii) ethyl 5-phenylpyrrole-2-carboxylate 21 as a white
crystalline solid24–26 (37 mg, 41%): mp 116ЊC (lit.24,25 mp
121–122ЊC; lit.26 mp 115–116ЊC).
172.79; m/z 310, 308 (5%), 233 (5), 216 (12), 215 (92),
189 (64), 169 (82), 161 (47), 143 (47), 142 (70), 115
(100), 105 (64), 104 (47), 89 (28), (ii) trans ethyl 2-phenyl-
3-(40-bromobutanoyloxy)-1-pyrroline-5-carboxylate 20d as
a yellow oil (35 mg, 22%). (Found: C, 53.6; H, 5.3; N, 3.4.
C17H20BrNO4 requires C, 53.4; H, 5.2; N, 3.7%). dH
(300 MHz, CDCl3) 1.33 (3H, t, Jˆ6.8 Hz, Me), 2.19 (3H,
m, H4), 2.49 (2H, t, Jˆ7.3 Hz, H20), 2.84 (1H, m, H4), 3.38
(2H, t, Jˆ8.7 Hz, H40), 4.25 (2H, q, Jˆ6.8 Hz, OCH2), 4.87
(1H, dd, Jˆ8.2, 5.6 Hz, H5), 6.28 (1H, dd, Jˆ8.2, 5.1 Hz,
H3), 7.44 (3H, m, ArH), 7.82 (2H, m, ArH); dC (75.5 MHz,
CDCl3) 14.09, 27.00, 32.18, 32.42, 33.99, 61.50, 71.77,
72.84, 127.64, 128.25, 128.92, 131.44, 171.62, 172.75,
173.48; m/z 310, 308 (10%), 233 (11), 216 (12), 215 (86),
189 (100), 169 (16), 161 (76), 151 (55), 143 (74), 142 (91),
115 (70), 105 (84), 104 (52), 77 (23), 73 (13) and (iii) ethyl
5-phenylpyrrole-2-carboxylate 21 as a white crystalline
solid (35 mg, 39%) with identical spectroscopic character-
istics to the sample above.
Reaction of 1-pyrroline-1-oxide 5c with propanoyl
chloride
The reaction was performed as described above to give: (i)
cis ethyl 2-phenyl-3-propanoyl-1-pyrroline-5-carboxylate
20b as a yellow oil (27 mg, 22%): bp 180ЊC (dec.). dH
(300 MHz, CDCl3) 1.11 (3H, t, Jˆ7.0 Hz, COCH2Me),
1.29 (3H, t, Jˆ7.1 Hz, OCH2Me), 2.26 (3H, m, H4,
COCH2; 2.66 (1H, m, H4), 4.26 (2H, q, Jˆ7.1 Hz, OCH2,
5.04 (1H, ddd, Jˆ7.6, 4.1, 1.5 Hz, H5, 6.42 (1H, ddd, Jˆ7.8,
4.1, 1.5 Hz, H3). 7.40 (3H, m, ArH), 7.85 (2H, m, ArH); dC
(75.5 MHz, CDCl3) 14.15, 20.93, 25.19, 34.59, 48.95,
61.52, 72.84, 128.36, 128.60, 128.66, 131.44, 152.55,
171.98, 174.52; m/z 290 (Mϩ1, 9%), 289 (4), 261 (14),
233 (48), 216 (65), 77 (100), (ii) trans ethyl 2-phenyl-3-
propanoyl-1-pyrroline-5-carboxylate 20b as a yellow oil
(23 mg, 19%). dH (300 MHz, CDCl3)(1.11 (3H, t, Jˆ
6.7 Hz, OCH2Me), 1.33 (3H, t, Jˆ7.7 Hz, COCH2Me),
2.18(1H, m, H4), 2.31 (2H, q, Jˆ7.7 Hz, COCH2; 2.86
(1H, m, H4), 4.27 (2H, q, Jˆ6.7 Hz, OCH2), 4.86 (1H, dd,
Jˆ6.2, 4.1 Hz, H5), 6.28 (1H, dd, Jˆ8.2, 4.6 Hz, H3), 7.41
(3H, m, ArH), 7.82 (2H, m, ArH); dC (75.5 MHz, CDCl3)
8.96, 14.18, 25.07, 27.55, 61.46, 71.74, 76.69, 128.29,
128.87, 131.36, 131.61, 171.45, 172.93, 173.69; m/z 290
(Mϩ1, 6%), 289 (7), 260 (19), 233 (64), 216 (68), 143
(86), 77 (100) and (iii) ethyl 5-phenylpyrrole-2-carboxylate
21 as a white crystalline solid (30 mg, 33%) with identical
spectroscopic characteristics to the sample above.
Reaction of 1-pyrroline-1-oxide 5c with benzoyl chloride
The reaction was performed as described above to give:
(i) cis ethyl 2-phenyl-3-benzoyl-1-pyrroline-5-carboxylate
20e as a brown oil (50 mg, 35%): bp 206ЊC (dec.). (Found:
C, 70.2; H, 5.8; N, 3.9. C20H19NO4 requires C, 71.2; H, 5.6;
N, 4.2%). dH (300 MHz, CDCl3) 1.32 (3H, t, Jˆ7.2 Hz,
Me), 2.39 (1H, m, H4), 2.78 (1H, m, H4), 4.26 (2H, q,
Jˆ7.2 Hz, OCH2), 5.13 (1H, ddd, Jˆ7.7, 5.6, 1.5 Hz, H5),
6.60 (1H, ddd, Jˆ7.7, 3.1, 1.5 Hz, H3), 7.49 (6H, m, ArH),
7.95 (4H, m, ArH); m/z 338 (Mϩ1, 16%), 265 (14), 164
(62), 233 (8), 232 (54), 215 (100), 142 (92), 89 (71), 73 (48),
(ii) trans ethyl 2-phenyl-3-benzoyl-1-pyrroline-5-carboxy-
late 20e as a brown oil (44 mg, 31%). (Found: C, 68.7; H,
5.7; N, 4.4. C20H19NO4 requires C, 71.2; H, 5.6; N, 4.2%).
dH (300 MHz, CDCl3) 1.32 (3H, t, Jˆ7.2 Hz, Me), 2.32
(1H, m, H4), 2.98 (1H, m, H4), 4.27 (2H, q, Jˆ7.2 Hz,
OCH2), 4.95 (1H, dd, Jˆ8.2, 5.6 Hz, H5), 6.49 (1H, dd,
Jˆ8.5, 5.6 Hz, H3), 7.46 (6H, m, ArH), 7.97 (4H, m,
ArH); m/z 337 (M, 2%), 336 (21), 290 (18), 232 (12), 215
(68), 189 (33), 169 (41), 115 (69), 105 (100), 104 (37), 77
(89), 51 (50) and (iii) ethyl 2-phenylpyrrole-5-carboxylate
21 as a white crystalline solid (35 mg, 39%) with identical
spectroscopic characteristics to the sample above.
Reaction of 1-pyrroline-1-oxide 5c with 3-bromo-
propanoyl chloride
The reaction was performed as described above to give ethyl
5-phenylpyrrole-2-carboxylate 21 as a white crystalline
solid (84 mg, 92%) with identical spectroscopic charac-
teristics to the sample above.
Acknowledgements
Reaction of 1-pyrroline-1-oxide 5c with 4-bromo-
butanoyl chloride
We thank the Australian Research Council for an Australian
Postgraduate Award (to S. M. L).
The reaction was performed as described above to give: (i)
cis ethyl 2-phenyl-3-(40-bromobutanoyloxy)-1-pyrroline-5-
carboxylate 20d as a tan oil (40 mg, 25%): bp 146ЊC (dec.).
(Found: C, 53.8; H, 5.2; N, 3.4. C17H20BrNO4 requires C,
53.4; H, 5.2; N, 3.7%). dH (300 MHz, CDCl3) 1.30 (3H, t,
Jˆ7.2 Hz, Me), 2.13 (2H, quin., Jˆ6.7 Hz, H30), 2.25 (1H,
m, H4), 2.48 (2H, t, Jˆ7.2 Hz, H20), 3.38 (2H, t, Jˆ6.2 Hz,
H40), 4.24 (2H, q, Jˆ7.2 Hz, OCH2), 5.04 (1H, ddd, Jˆ7.7,
6.2, 1.5 Hz, H5), 6.42 (1H, ddd, Jˆ7.7, 3.1, 1.5 Hz, H3),
7.43 (3H, m, ArH), 7.82 (2H, m, ArH); dC (75.5 MHz,
CDCl3) 14.13, 27.43, 32.25, 32.41, 34.70, 61.52, 72.98,
77.25, 128.26, 128.64, 131.49, 131.53, 171.66, 171.74,
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