A convenient protocol for the alkylidenation of lactams

Article abstract of DOI:10.1055/s-2006-926390

A convenient two-step preparation of alkylidenepyrrolidines is reported. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-926390

1162
PAPER
A Convenient Protocol for the Alkylidenation of Lactams
A
lkylidenationof Lact
a
am
s
rk C. Elliott,* Stuart V. Wordingham
School of Chemistry, Cardiff University, Park Place, Cardiff CF10 3AT, UK
Fax +44(29)20874030; E-mail: elliottmc@cardiff.ac.uk
Received 22 September 2005; revised 15 November 2005
Dedicated to Dr. M. J. E. Hewlins on the occasion of his retirement
of compounds 4 and 5 as shown in Equation 2 (Table 1).
As expected, the b-keto esters existed solely in the keto
form, while the 1,3-diketones showed significant
(R2 = CH3) to total (R2 = Ph) enolisation. In all cases with
ketone and ester enolates, the reactions were clean and
high-yielding, and in many instances the crude products
were essentially pure.
Abstract: A convenient two-step preparation of alkylidenepyrro-
lidines is reported.
Key words: heterocycles, enamines, imides, enolates, aldol reac-
tions
Alkylidenepyrrolidines have long been used as synthetic
intermediates, particularly in the synthesis of pyrrolidines
and porphyrins.1 These compounds are generally prepared
by reaction of a thioamide with a a-bromocarbonyl com-
pound in a reaction commonly known as the Eschenmoser
sulfide contraction.2 The O-alkylation of lactams fol-
lowed by treatment with a malonate-type nucleophile also
gives the same compounds,3 although we have found this
method to be somewhat capricious. During the course of
studies directed towards the batzelladine alkaloids,4 we
required a broad range of alkylidenepyrrolidines, and
therefore sought a more convenient method for their prep-
aration. It is well known that imides and carbamates de-
rived from g-lactams can be selectively attacked at the
lactam carbonyl by a range of nucleophiles, including
Grignard reagents,5,6 other organometallics,7,8 hetero-
nucleophiles9 and stabilised anions10–13 (Equation 1). The
products of this reaction have been cyclised to the corre-
sponding pyrrolines and pyrrolidines in a number of in-
stances,6,8,12 but we are aware of only a single example of
the application of this general approach to alkylidenepyr-
rolidine synthesis, this being the preparation of sulfonyl
alkylidenepyrrolidines.14,15 We have therefore undertaken
a study of this approach, and now report an efficient and
convenient two-step preparation of alkylidenepyrroli-
dines which can be carried out on a multi-gram scale.
O
O
O
NBoc
NBoc
NBoc
OTBS
CO2Et
1
2
3
Figure 1 Lactams 1–3
O
O
O
CH3COR2
NHBoc
R2
NBoc
LDA, THF
R1
R1
1, R1 = H
4, R1 = H
5, R1 = CO2Et
2, R1 = CO2Et
a, R2 = OEt; b, R2 = OBn; c, R2 = O-(–)-menthyl;
d, R2 = CH3; e, R2 = Ph
Equation 2
Table 1 Compounds 4 and 5 Prepared
Compound
R1
R2
Yield (%)
4a
4b
4c
4d
4e
5a
5b
5c
5d
5e
H
OEt
88
68
84
74
75
78
67
71
72
74
H
OBn
H
O-(–)-menthyl
O
O
O
H
Nu
N
R
H
Me
Nu
N
R
O
H
Ph
R = alkoxy or bulky alkyl
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
OEt
Equation 1
OBn
Lactams 1,16 217 and 318 were prepared according to liter-
ature procedures. Compounds 1 and 2 underwent ready
reaction with ketone and ester enolates to provide a range
O-(–)-menthyl
Me
Ph
SYNTHESIS 2006, No. 7, pp 1162–1170
x
x
.
x
x
.2
0
0
6
Advanced online publication: 14.03.2006
DOI: 10.1055/s-2006-926390; Art ID: P15405SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Alkylidenation of Lactams
Table 2 Compounds 9 and 10 Prepared
1163
In reactions of compound 3, the desired products could
only be observed in the 1H NMR spectrum of the crude re-
action mixture, and upon standing overnight or rapid
chromatography on silica gel, only the cyclised com-
pounds 6 and 7 were isolated (Scheme 1). Compounds 4
and 5 underwent similar cyclisation, but at a much slower
rate (several days standing in CDCl3). Treatment of com-
pound 6 with trifluoroacetic acid in dichloromethane re-
moved both the nitrogen and oxygen protecting groups to
give compound 8 in excellent yield (Scheme 2). The dou-
ble-bond geometries of 6–8 seem likely, although these
are not trivial to determine (see below).
Compound
9a
R1
R2
Yield %)
78
H
OEt
9b
H
OBn
86
9c
H
O-(–)-menthyl
80
9d
H
Me
85
9e
H
Ph
74
10a
10b
10c
10d
10e
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
OEt
82
OBn
72
EtO2C
O
O-(–)-menthyl
75
LDA, EtOAc
NBoc
OTBS
NBoc
OTBS
THF, 63%
Me
Ph
55
44
3
6
H3COC
cemic menthyl acetate, and only one from optically pure
menthyl acetate in both compounds 5c and 10c. We would
therefore estimate the diastereomeric purity of com-
pounds 5c and 10c to be >95%, and see no reason why the
other compounds 10 should show any greater loss of ste-
reochemical integrity.
O
LDA, acetone
THF, 62%
NBoc
OTBS
NBoc
OTBS
3
7
Scheme 1
Formation of sulfone 12 was carried out under the present
reaction conditions (Scheme 3), and the overall yield for
the two steps was found to be comparable for the previous
formation of this compound.14
EtO2C
CO2Et
NH
TFA, CH2Cl2
87%
NBoc
OTBS
O
O
OH
PhSO2CH3
PhO2S
NHBoc
6
8
NBoc
BuLi, THF
96%
Scheme 2
1
11
TFA, CH2Cl2
67%
Cyclisation reactions of compounds 4 and 5 were investi-
gated next. These occurred smoothly under similar condi-
tions to the formation of compound 8 (Equation 3). The
results of these reactions are summarised in Table 2.
SO2Ph
NH
COR2
12
O
O
TFA
NHBoc
R2
NH
R1
Scheme 3
R1
The double-bond geometry in alkylidenepyrrolidines such
as 9 and 10 is not trivial to determine. Since both the NH
and alkene CH (enamine) protons are exchangeable, the
expected strong NOE enhancement between these protons
is observed, and should not be used as an indication of
double-bond geometry. During the course of the present
study, we have only observed small NOE enhancements
between the alkene CH and the allylic methylene group on
the ring which would support the expected Z double-bond
geometry.19 For steric reasons, compound 6 presumably
4, R1 = H
5, R1 = CO2Et
9, R1 = H
10, R1 = CO2Et
a, R2 = OEt; b, R2 = OBn; c, R2 = O-(–)-menthyl;
d, R2 = CH3; e, R2 = Ph
Equation 3
It has previously been reported that ring-opening reac-
tions of substrate 2 proceed without racemisation.10,11 We
were able to confirm that this is indeed the case by use of
racemic and optically pure menthyl acetates in the above
reaction. Comparison of the 13C NMR data clearly
showed the presence of two diastereoisomers from the ra-
1
possesses the E double-bond geometry shown. The H
NMR spectrum of this compound shows the 4-CH2 of the
pyrrolidine ring to be significantly deshielded compared
to compound 8, which we assume to have the Z-geometry.
Synthesis 2006, No. 7, 1162–1170 © Thieme Stuttgart · New York

1164
M. C. Elliott, S. V. Wordingham
PAPER
CH2Cl2 (3 × 50 mL). The combined organic layers were washed
with brine (2 × 50 mL), dried (MgSO4) and the solvent removed in
vacuo to give a yellow oil. Purification by flash column chromatog-
raphy (eluent: 5:1 hexane–EtOAc) gave the title compound (1.2 g,
68%) as a pale oil.
This chemical shift has been attributed to anisotropic ef-
fects,20 although since the only way to assure the E dou-
ble-bond geometry is to introduce a substitutent onto the
nitrogen atom, it is almost impossible to compare data for
both isomers of a single compound.21 The N–H stretches
in the infrared spectra of compounds 9 and 10 show that
the esters 9a–c and 10a–c are in the region of 3370 cm–1,
while the ketones 9d,e and 10d,e are all below 3300 cm–1.
The proton chemical shifts for the NH protons in this latter
group of compounds are significantly deshielded with re-
spect to the former.22 From this we can conclude that the
same Z double-bond geometry is formed in all cases.
IR (neat): 3402, 2976, 2925, 1739, 1714, 1519, 1167, 751, 698 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.36–7.26 (m, 5 Harom), 5.10 (s, 2
H, OCH2), 4.50 (br s, 1 H, NH), 3.42 (s, 2 H, COCH2CO), 3.01 (app
q, J = 6.4 Hz, CH2N), 2.50 (t, J = 7.1 Hz, 2 H, CH2CO), 1.68 (app
quintet, J = 6.8 Hz, 2 H, CH2CH2CH2), 1.37 [s, 9 H, C(CH3)3].
13C NMR (125 MHz, CDCl3): d = 202.7 (ketone C=O), 167.1 (ester
C=O), 156.1 (carbamate C=O), 135.2 (Carom), 128.7 (CHarom), 128.6
(CHarom), 128.5 (CHarom), 79.3 [(CH3)3CO], 67.2 (CH2O), 49.2
(CH2N), 45.0 (COCH2CO), 39.6 (COCH2), 28.4 [C(CH3)3], 23.8
(CH2CH2N).
Melting points were determined on a Gallenkamp melting point ap-
paratus and are uncorrected. IR spectra were recorded on a Perkin-
Elmer 1600 FTIR spectrophotometer. Mass spectra were recorded
on a Fisons VG Platform II spectrometer and on a Micromass Q-
TOF Micro spectrometer. NMR spectra were recorded on a Bruker
MS-ES: m/z (%) = 358 (M + Na, 62), 218 (100).
HRMS-ES: m/z [M + Na]+ calcd for C18H25NO5 + Na: 358.1630;
found: 358.1623.
1
DPX 400 spectrometer operating at 400 MHz for H and at 100
(–)-Menthyl 6-tert-Butoxycarbonylamino-3-oxohexanoate (4c)
A solution of lithium diisopropylamide (1.5 mL, 2 M in heptane,
3 mmol) in THF (10 mL) was cooled to –78 °C. (–)-Menthyl acetate
(595 mg, 3 mmol) in THF (3 mL) was added over 30 min. After stir-
ring for 30 min at –78 °C, N-tert-butoxycarbonylpyrrolidin-2-one
(1; 555 mg, 3 mmol) in THF (5 mL) was added over 30 min at –78 °C,
and the solution warmed to 25 °C and left to stir for 18 h. Sat. aq
NH4Cl (100 mL) was added and the mixture extracted with CH2Cl2
(3 × 50 mL). The combined organic layers were washed with brine
(2 × 50 mL), dried (MgSO4) and the solvent removed in vacuo to
give a yellow crystalline solid which was recrystallised from hex-
ane–Et2O to give the title compound (965 mg, 84%) as an off-white
crystalline solid; mp 88–89 °C.
MHz for 13C at 25 °C, or on a Bruker Avance 500 spectrometer op-
erating at 500 MHz for 1H and 125 MHz for 13C at 25 °C. All chem-
ical shifts are reported in ppm downfield from TMS. Coupling
constants (J) are reported in Hz. Multiplicity in 1H NMR is reported
as singlet (s), doublet (d), double doublet (dd), double triplet (dt),
double quartet (dq), triplet (t), and multiplet (m). Multiplicity in 13
C
NMR was obtained using the DEPT pulse sequence. Flash chroma-
tography was performed using Matrex silica 60 35–70 micron.
Ethyl 6-tert-Butoxycarbonylamino-3-oxohexanoate (4a)
A solution of lithium diisopropylamide (13.5 mL, 2 M in heptane,
27 mmol) in THF (100 mL) was cooled to –78 °C. EtOAc (2.58 mL,
27 mmol) in THF (3 mL) was added dropwise over 30 min, and the
solution allowed to stir for a further 30 min. N-tert-Butoxycarbon-
ylpyrrolidin-2-one (1; 5.0 g, 27 mmol) in THF (5 mL) was added
over 30 min at –78 °C, and the solution warmed to 25 °C and left to
stir for 18 h. Sat. aq NH4Cl solution (100 mL) was added and the
organic material extracted with CH2Cl2 (3 × 100 mL). The com-
bined organic layers were washed with brine (2 × 150 mL), dried
(MgSO4) and the solvent removed in vacuo. Purification by flash
column chromatography (eluent 2:1 hexane–EtOAc) gave the title
compound (6.46 g, 88%) as a pale-yellow oil.
IR (CHCl3): 3398, 2958, 1735, 1715, 1170 cm–1.
1H NMR (500 MHz, CDCl3): d = 4.65 (app dt, J = 4.4, 10.9 Hz, 1
H, menthyl 1-H), 4.59–4.52 (br s, 1 H, NH), 3.37 and 3.35 (AB
quartet, J = 15.5 Hz, 2 H, COCH2CO), 3.05 (app q, J = 6.3 Hz, 2 H,
CH2N), 2.52 (t, J = 7.1 Hz, 2 H, CH2CO), 1.98–1.92 (m, 1 H, men-
thyl 6-Heq), 1.82–1.75 [app doubled septet, J = 2.7, 7.0 Hz, 1 H,
CH(CH3)2], 1.72 (app quintet, J = 6.9 Hz, 2 H, CH2CH2CH2), 1.64–
1.58 (m, 2 H, menthyl 3-Heq and 4-Heq), 1.48–1.40 (m, 1 H, menthyl
5-Hax), 1.37 [s, 9 H, C(CH3)3], 1.35–1.27 (m, 1 H, menthyl 2-Hax),
1.03–0.96 (m, 1 H, menthyl 3-Hax), 0.92 (app q, J = 11.7 Hz, 1 H,
menthyl 4-Hax), 0.84 (d, J = 6.6 Hz, 3 H, CH3), 0.82 (d, J = 7.1 Hz,
3 H, CH3), 0.82–0.77 (m, 1 H, menthyl 4-Hax), 0.70 (d, J = 7.0 Hz,
3 H, CH3).
13C NMR (125 MHz, CDCl3): d = 202.5 (ketone C=O), 166.9 (ester
C=O), 156.1 (carbamate C=O), 79.2 (C–O), 75.5 (menthyl 1-CH),
49.6 (COCH2CO), 46.8 (menthyl 2-CH), 40.7 (menthyl 6-CH2),
40.0 (CH2), 39.7 (CH2), 34.1 (menthyl 4-CH2), 31.4 (menthyl 5-
CH), 28.4 [(CH3)3CO], 26.1 (CH), 23.8 (menthyl 3-CH2), 23.2
(CH2), 22.0 (CH3), 20.7 (CH3), 16.1 (CH3).
IR (neat): 3380, 2977, 2925, 1739, 1709, 1521 cm–1.
1H NMR (400 MHz, CDCl3): d = 4.60 (br s, 1 H, NH), 4.12 (q,
J = 7.1 Hz, 2 H, CH2O), 3.41 (s, 2 H, COCH2CO), 3.06 (app q,
J = 6.5 Hz, 2 H, CH2NHBoc), 2.53 (t, J = 7.1 Hz, 2 H, COCH2),
1.72 (app quintet, J = 6.9 Hz, 2 H, CH2CH2CH2), 1.37 [s, 9 H,
C(CH3)3], 1.21 (t, J = 7.1 Hz, 3 H, CH3CH2O).
13C NMR (100 MHz, CDCl3): d = 203.7 (C=O), 168.3 (C=O), 157.0
(C=O), 79.7 [OC(CH3)3], 61.8 (OCH2), 49.6 (NCH2), 40.2
(COCH2CO), 39.9 (COCH2CH2), 28.6 [C(CH3)3], 24.0
(CH2CH2N), 14.2 (OCH2CH3).
MS-ES: m/z (%) = 406 (M + Na, 100), 266 (73), 128 (32).
HRMS-ES: m/z [M + Na]+ calcd for C21H37NO5 + Na: 406.2569;
found: 406.2585.
MS-ES: m/z (%) = 296 (M + Na, 83), 240 (7), 156 (100), 128 (16).
HRMS-ES: m/z [M + Na]+ calcd for C13H23NO5 + Na: 296.1474;
found: 296.1473.
N-tert-Butoxycarbonyl-4,6-dioxoheptylamine (4d)
Benzyl 6-tert-Butoxycarbonylamino-3-oxohexanoate (4b)
A solution of lithium diisopropylamide (2.7 mL, 2 M in heptane, 5.4
mmol) in THF (40 mL) was cooled to –78 °C. Benzyl acetate (810
mg, 5.4 mmol) in THF (3 mL) was added over 30 min. After stirring
for 30 min at –78 °C, N-tert-butoxycarbonylpyrrolidin-2-one (1; 1.0
g, 5.4 mmol) in THF (8 mL) was added over 30 min at –78 °C, and
the solution allowed to warm to 25 °C and stirred for 18 h. Sat. aq
NH4Cl (100 mL) was added and the organic material extracted with
A solution of lithium diisopropylamide (1.5 mL, 2 M in heptane,
3 mmol) in THF (10 mL) was cooled to –78 °C. Acetone (174 mg,
3 mmol) in THF (3 mL) was added over 30 min. After stirring for
30 min at –78 °C, N-tert-butoxycarbonylpyrrolidin-2-one (1; 555
mg, 3 mmol) in THF (5 mL) was added over 30 min at –78 °C, and
the solution warmed to 25 °C and left to stir for 18 h. Sat. aq NH4Cl
(100 mL) was added and the solution extracted with CH2Cl2 (3 × 50
Synthesis 2006, No. 7, 1162–1170 © Thieme Stuttgart · New York

PAPER
Alkylidenation of Lactams
1165
mL). The combined organic layers were washed with brine (2 × 50
mL), dried (MgSO4) and the solvent removed in vacuo. The result-
ing yellow oil was purified by flash column chromatography (elu-
ent: 4:1 hexane–EtOAc) to give the title compound (535 mg, 74%)
as a colourless oil (5:1 mixture of enol and keto tautomers).
CH2CHN), 1.39 [s, 9 H, C(CH3)3], 1.21 (app t, J = 7.2 Hz, 6 H, 2
CH2CH3).
13C NMR (100 MHz, CDCl3): d = 201.7 (ketone C=O), 172.2 (ester
C=O), 167.1 (ester C=O), 155.5 (carbamate C=O), 80.0
[OC(CH3)3], 61.6 (OCH2), 61.5 (OCH2), 52.7 (CHNH), 49.3
(CH2NH), 38.8 (CH2CO), 28.3 [C(CH3)3], 26.5 (CH2) 14.2
(CH2CH3), 14.1 (CH2CH3).
IR (CH2Cl2): 3357, 2976, 1703, 1619, 1170 cm–1.
1H NMR (500 MHz, CDCl3): d (enol tautomer) = 5.44 (s, 1 H, enol
CH), 4.58 (br s, 1 H, NH), 3.09 (app q, J = 6.5 Hz, 2 H, CH2N), 2.25
(t, J = 7.3 Hz, COCH2), 1.98 (s, 3 H, CH3), 1.73 (app quintet, J = 7.5
Hz, 2 H, CH2), 1.37 [s, 9 H, C(CH3)3].
13C NMR (125 MHz, CDCl3): d (enol tautomer) = 194.0 (C=O),
190.7 (enol C–O), 156.0 (C=O), 100.0 (enol CH), 79.3 (C–O), 40.0
(CH2N), 35.7 (CH2), 28.4 [C(CH3)3], 25.9 (CH2), 24.8 (CH3).
MS-ES: m/z (%) = 384 (M + K, 34), 368 (M + Na, 100), 328 (17).
HRMS-ES: m/z [M + Na]+ calcd for C16H27NO7 + Na: 368.1685;
found: 368.1659.
(2S)-2-tert-Butoxycarbonylamino-5-oxoheptanedioic Acid
1-Ethyl Ester 7-Benzyl Ester (5b)
A solution of lithium diisopropylamide (5.93 mL, 2 M in heptane,
11.87 mmol) in THF (60 mL) was cooled to –78 °C. Benzyl acetate
(1.78 g, 11.87 mmol) in THF (10 mL) was added over 30 min. After
stirring for 30 min at –78 °C, compound 2 (3.05 g, 11.87 mmol) in
THF (10 mL) was added over 30 min at –78 °C. The solution was
allowed to warm to 25 °C and stirred for 18 h. Sat. aq NH4Cl (100
mL) was added and the organic material extracted into CH2Cl2
(3 × 100 mL). The combined organic layers were washed with brine
(2 × 100 mL), dried (MgSO4), and the solvent removed in vacuo to
give a yellow oil. Purification by flash column chromatography
(eluent: 6:1 hexane–EtOAc) gave the title compound (3.1 g, 67%)
as a pale oil.
MS-ES: m/z (%) = 266 (M + Na, 100), 127 (28).
HRMS-ES: m/z [M + Na]+ calcd for C12H21NO4 + Na: 266.1368;
found: 266.1355.
N-tert-Butoxycarbonyl-4,6-dioxo-6-phenylhexylamine (4e)
A solution of lithium diisopropylamide (2.8 mL, 2 M solution in
heptane, 5.6 mmol) in THF (10 mL) was cooled to –78 °C. Ace-
tophenone (0.67 mL, 5.6 mmol) in THF (2 mL) was added over 20
min. After stirring for 25 min at –78 °C, N-tert-butoxycarbonylpyr-
rolidin-2-one (1; 1.0 g, 5.4 mmol) in THF (5 mL) was added over
30 min at –78 °C and the solution warmed to 25 °C and left to stir
for 18 h. Sat. aq NH4Cl (100 mL) was added and the mixture ex-
tracted with CH2Cl2 (3 × 100 mL). The combined organic layers
were washed with brine (2 × 150 mL), dried (MgSO4) and the sol-
vent removed in vacuo to give an oily solid which was recrystallised
from EtOAc–hexane to give the title compound (1.23 g, 75%), as a
off-white crystalline solid existing exclusively as the enol tautomer;
mp 72–73 °C.
IR (neat): 3384, 2977, 1740, 1710, 1368 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.36–7.27 (m, 5 Harom), 5.12 (s, 2
H, OCH2), 5.05 (br d, J = 6.5 Hz, 1 H, NH), 4.22–4.09 (m, 3 H,
CHNH and CH2O), 3.45 (s, 2 H, COCH2CO), 2.67–2.50 (m, 2 H, m,
CH2CO), 2.18–2.06 (m, 1 H, one of CH2CHN), 1.90–1.78 (m, 1 H,
one of CH2CHN), 1.39 [s, 9 H, C(CH3)3], 1.22 (t, J = 7.1 Hz, 3 H,
CH2CH3).
13C NMR (125 MHz, CDCl3): d = 201.4 (ketone C=O), 172.2 (ester
C=O), 166.9 (ester C=O), 155.5 (carbamate C=O), 135.3 (Carom),
128.7 (CHarom), 128.5 (CHarom), 128.4 (CHarom), 80.0 [OC(CH3)3],
67.2 (OCH2), 61.6 (OCH2), 52.7 (CHNH), 49.2 (CH2NH), 38.9
(CH2CO), 28.3 [C(CH3)3], 26.5 (CH2) 14.2 (CH2CH3).
IR (CHCl3): 3360, 2975, 2929, 1702, 1601, 1169 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.81 (d, J = 7.3 Hz, 2 Harom), 7.43
(t, J = 7.3 Hz, 1 Harom), 7.34 (app t, J = 7.4 Hz, 2 Harom), 6.12 (s, 1
H, enol CH), 4.60 (br s, 1 H, NH), 3.11 (app q, J = 6.5 Hz, 2 H,
CH2N), 2.40 (t, J = 7.4 Hz, 2 H, CH2CO), 1.81 (app quintet, J = 7.2
Hz, 2 H, CH2CH2CH2), 1.35 [s, 9 H, C(CH3)3].
MS-ES: m/z (%) = 430 (M + Na, 18), 352 (40), 290 (100).
HRMS-ES: m/z [M + Na]+ calcd for C21H29NO7 + Na: 430.1842;
found: 430.1842.
13C NMR (125 MHz, CDCl3): d = 196.5 (ketone C=O), 182.9 (enol
C–O), 156.0 (carbamate C=O), 134.8 (Carom), 132.3 (CHarom), 128.6
(CHarom), 127.0 (CHarom), 96.2 (enol CH), 78.9 [(CH3)3CO], 40.1
(CH2N), 36.6 (CH2), 28.4 [C(CH3)3], 26.0 (CH2).
(2S)-2-tert-Butoxycarbonylamino-5-oxoheptanedioic Acid
1-Ethyl Ester 7-(–)-Menthyl Ester (5c)
MS-ES: m/z (%) = 328 (M + Na, 89), 188 (100).
HRMS-ES: m/z [M + Na]+ calcd for C17H23NO4 + Na: 328.1525;
found: 328.1499.
A solution of lithium diisopropylamide (1.5 mL, 2 M in heptane,
3 mmol) in THF (10 mL) was cooled to –78 °C. (–)-Menthyl acetate
(1.23 g, 6.2 mmol) in THF (3 mL) was added over 30 min. After
stirring for 30 min at –78 °C, compound 2 (1.6 g, 6.2 mmol) in THF
(5 mL) was added over 30 min at –78 °C, and the solution warmed
to 25 °C and allowed to stir for 18 h. Sat. aq NH4Cl (100 mL) was
added and the solution extracted with CH2Cl2 (3 × 100 mL). The
combined organic layers were washed with brine (2 × 150 mL),
dried (MgSO4) and the solvent removed in vacuo. The resulting yel-
low oil was purified by flash column chromatography (eluent: 4:1
hexane–EtOAc) to give the title compound (2.0 g, 71%) as an off-
white solid; mp 82–82.5 °C.
(2S)-2-tert-Butoxycarbonylamino-5-oxoheptanedioic Acid
Diethyl Ester (5a)11
A solution of lithium diisopropylamide (3.9 mL, 2 M solution in
heptane, 7.8 mmol) in THF (15 mL) was cooled to –78 °C. EtOAc
(0.76 mL, 7.8 mmol) in THF (4 mL) was added over 25 min. After
stirring for 20 min at –78 °C, compound 2 (2.0 g, 7.8 mmol) in THF
(5 mL) was added over 30 min at –78 °C. The solution was then al-
lowed to warm to 25 °C and left to stir for 18 h. Sat. aq NH4Cl
(100 mL) was added and the solution extracted with CH2Cl2
(3 × 100 mL). The combined organic layers were washed with brine
(2 × 150 mL), dried (MgSO4) and the solvent removed in vacuo.
Filtration through a short plug of silica gel, eluting with EtOAc,
gave the title compound (2.1 g, 78%), as a yellow oil.
IR (CHCl3): 3367, 2957, 1717 (v br), 1168 cm–1.
1H NMR (500 MHz, CDCl3): d = 5.03 (br d, J = 6.3 Hz, 1 H, NH),
4.65 (app dt, J = 4.4, 10.9 Hz, 1 H, menthyl 1 H), 4.22–4.14 (m, 1
H, CHN), 4.11 (q, J = 7.1 Hz, 2 H, CH2O), 3.38 and 3.35 (AB quar-
tet, J = 15.5 Hz, 2 H, COCH2CO), 2.65–2.50 (m, 2 H, CH2CO),
1.98–1.92 (m, 1 H, menthyl 6-Heq), 1.87–1.75 [m, 3 H, CH2CH2CO
and CH(CH3)2], 1.64–1.58 (m, 2 H, menthyl 3-Heq and 4-Heq), 1.47–
1.39 (m, 1 H, menthyl 5-Hax), 1.37 [s, 9 H, C(CH3)3], 1.34–1.26 (m,
IR (neat): 3368, 2979, 2934, 1741, 1713, 1512 cm–1.
1H NMR (400 MHz, CDCl3): d = 5.07 (br d, J = 7.6 Hz, 1 H, NH),
4.23–4.05 (m, 1 H, CHNH), 4.12 (app q, J = 7.2 Hz, 4 H, CH2O),
3.39 (s, 2 H, COCH2CO), 2.70–2.50 (m, 2 H, m, CH2CO), 2.16–
2.05 (m, 1 H, one of CH2CHN), 1.89–1.76 (m, 1 H, one of
Synthesis 2006, No. 7, 1162–1170 © Thieme Stuttgart · New York

1166
M. C. Elliott, S. V. Wordingham
PAPER
1 H, menthyl 2-Hax), 1.21 (t, J = 7.1 Hz, 3 H, CH3CH2), 1.03–0.93
(m, 1 H, menthyl 3-Hax), 0.92 (app q, J = 11.8 Hz, 1 H, menthyl 6-
Hax), 0.84 (d, J = 6.6 Hz, 3 H, CH3), 0.82 (d, J = 7.0 Hz, 3 H, CH3),
0.81–0.76 (m, 1 H, menthyl 4-Hax), 0.69 (d, J = 7.0 Hz, 3 H, CH3).
13C NMR (125 MHz, CDCl3): d = 201.7 (ketone C=O), 172.2 (ester
C=O), 166.7 (ester C=O), 155.5 (carbamate C=O), 80.0
[(CH3)3CO], 75.6 (menthyl 1-CH), 61.2 (CH2O), 52.8 (CHN), 49.6
(CH2), 46.9 (menthyl 2-CH), 40.7 (menthyl 6-CH2), 38.8 (CH2),
34.2 (menthyl 4-CH2), 31.4 (menthyl 5-CH), 28.3 [C(CH3)3], 26.6
(CH2), 26.2 (CH), 23.3 (menthyl 3-CH2), 22.0 (CH3), 20.7 (CH3),
16.2 (CH3), 14.2 (CH3).
2.41 (m, 2 H, CH2CH2), 2.19–2.10 (m, 1 H, one of CH2CHN), 1.99–
1.90 (m, 1 H, one of CH2CHN), 1.35 [s, 9 H, C(CH3)3], 1.21 (t,
J = 7.2 Hz, 3 H, CH2CH3).
13C NMR (125 MHz, CDCl3): d = 196.4 (PhC=O), 182.0 (enol ether
C–O), 172.3 (ester C=O), 155.5 (carbamate C=O), 134.4 (Carom),
132.5 (CHarom), 128.6 (CHarom), 126.9 (CHarom), 79.7 (Me3CO), 61.4
(OCH2), 53.1 (NCH), 35.4 (CH2COH), 28.2 [C(CH3)3], 28.0
(CH2CHN), 14.1 (CH3).
MS-ES: m/z (%) = 416 (M + K, 75), 400 (M + Na, 100), 378 (M+,
24).
HRMS-ES: m/z [M + Na]+ calcd for C20H27NO6 + Na: 400.1736;
found: 400.1729.
MS-ES: m/z (%) = 494 (M + K, 13), 478 (M + Na, 24), 338 (100).
HRMS-ES: m/z [M + Na]+ calcd for C24H41NO7 + Na: 478.2781;
found: 478.2795.
(2S)-2-(tert-Butyldimethylsilyloxymethyl)-5-[(E)-1-ethoxy-
carbonylmethylidene]pyrrolidine-1-carboxylic Acid tert-Butyl
Ester (6)23
Ethyl (2S)-2-tert-Butoxycarbonylamino-5,7-dioxooctanoate
(5d)
A solution of lithium diisopropylamide (0.25 mL, 2 M in heptane,
0.5 mmol) in THF (5 mL) was cooled to –78 °C. EtOAc (43 mg, 0.5
mmol) in THF (3 mL) was added over 20 min. After stirring for 25
min at –78 °C, compound 3 (164 mg, 0.5 mmol) in THF (2 mL) was
added over 20 min at –78 °C. The solution was allowed to warm to
25 °C and left to stir for 18 h. Sat. aq NH4Cl (20 mL) was added and
the solution extracted with CH2Cl2 (3 × 15 mL). The combined or-
ganic layers were washed with brine (2 × 15 mL), dried (MgSO4)
and the solvent removed in vacuo. The resulting yellow oil was pu-
rified by flash column chromatography (eluent: 4:1 hexane–EtOAc)
to give the title compound (123 mg, 63%) as a yellow oil.
A solution of lithium diisopropylamide (2.5 mL, 2 M solution in
heptane, 5 mmol) in THF (10 mL) was cooled to –78 °C. Acetone
(0.31 mL, 4.3 mmol) in THF (2 mL) was added over 20 min. After
stirring for 25 min at –78 °C, compound 2 (1.0 g, 3.9 mmol) in THF
(5 mL) was added over 30 min at –78 °C. The solution was then al-
lowed to warm to 25 °C and stirred for 18 h. Sat. aq NH4Cl
(100 mL) was added and the solution extracted with CH2Cl2
(3 × 100 mL). The combined organic layers were washed with brine
(2 × 150 mL), dried (MgSO4) and the solvent removed in vacuo.
The residue was purified by flash column chromatography (eluent:
4:1 hexane–Et2O) to give the title compound (900 mg, 72%) as a
yellow oil, existing as the enol tautomer.
IR (neat): 3368, 2955, 2857, 1739, 1709, 1501, 1471 cm–1.
1H NMR (500 MHz, CDCl3): d = 6.42 (br s, 1 H, C=CH), 4.19–4.15
(m, 1 H, CHN), 4.08 (q, J = 7.1 Hz, 2 H, CH2O), 3.68–3.62 (m, 2 H,
CH2OSi), 3.36 (app ddt, J = 18.4, 9.5, 1.5 Hz, 1 H, one of CH2C=C),
2.96 (dddd, J = 18.4, 11.3, 9.1, 2.3 Hz, 1 H, one of CH2C=C), 2.03–
1.85 (m, 2 H, CH2), 1.50 [s, 9 H, (CH3)3CO], 1.21 (t, J = 7.1 Hz, 3
H, CH3CH2), 0.83 [s, 9 H, (CH3)3CSi], 0.00 [s, 3 H, one of
(CH3)2Si], –0.02 [s, 3 H, one of (CH3)2Si].
13C NMR (125 MHz, CDCl3): d = 169.0 (ester C=O), 158.4 (car-
bamate C=O), 151.6 (C=CH), 96.1 (C=CH), 82.1 [(CH3)3CO], 63.7
(CH2OSi), 62.2 (CHN), 59.1 (CH2O), 31.0 (CH2), 28.3 [(CH3)3CO],
25.8 [(CH3)3CSi], 23.8 (CH2), 18.2 (CSi), 14.5 (CH3CH2), –5.4 [one
of (CH3)2Si], –5.5 [one of (CH3)2Si].
IR (CHCl3): 3372, 2979, 1712 (v br), 1164 cm–1.
1H NMR (400 MHz, CDCl3): d = 5.41 (s, 1 H, enol CH), 5.04 (br d,
J = 7.3 Hz, 1 H, NH), 4.23 (m, 1 H, CHNH), 4.13 (q, J = 7.1 Hz, 2
H, CH2O), 2.35–2.29 (m, 2 H, CH2CH2), 2.15–2.05 (m, 1 H, one
of CH2CHN), 1.97 (s, 3 H, CH3CO), 1.93–1.83 (m, 1 H, one
of CH2CHN), 1.37 [s, 9 H, C(CH3)3], 1.21 (t, J = 7.1 Hz, 3 H,
CH2CH3).
13C NMR (125 MHz, CDCl3): d = 194.0 (C=O), 189.7 (enol C–O),
172.3 (C=O), 155.4 (C=O), 100.0 (enol CH), 79.9 (C–O), 61.5
(CH2O), 53.1 (CHN), 34.5 (CH2), 28.3 [C(CH3)3], 28.0 (CH2), 24.4
(CH3), 14.1 (CH3).
MS-ES: m/z (%) = 354 (M + K, 62), 338 (100), 282 (21).
MS-ES: m/z (%) = 400 (MH+, 9), 300 (100).
HRMS-ES: m/z [M + Na]+ calcd for C15H25NO6 + Na: 338.1580;
HRMS-ES: m/z [M + H]+ calcd for C20H38NO5Si: 400.2519; found:
found: 338.1569.
400.2510.
Ethyl (2S)-2-tert-Butoxycarbonylamino-5,7-dioxo-7-phenyl-
heptanoate (5e)11
(2S)-2-(tert-Butyldimethylsilyloxymethyl)-5-[(E)-2-oxopropyl-
idene]pyrrolidine-1-carboxylic Acid tert-Butyl Ester (7)
A solution of lithium diisopropylamide (2.5 mL, 2 M solution in
heptane, 5 mmol) in THF (10 mL) was cooled to –78 °C. Acetophe-
none (0.53 mL, 4.3 mmol) in THF (2 mL) was added over 20 min.
After stirring for 25 min at –78 °C, compound 2 (1.0 g, 3.9 mmol)
in THF (5 mL) was added over 30 min at –78 °C. The solution was
then allowed to warm to 25 °C and left to stir for 18 h. Sat. aq NH4Cl
(100 mL) was added and the solution extracted with CH2Cl2
(3 × 100 mL). The combined organic layers were washed with brine
(2 × 150 mL), dried (MgSO4) and the solvent removed in vacuo to
give a orange oil which was purified by flash column chromatogra-
phy (eluent: 10:3 hexane–Et2O) to give the title compound (1.1 g,
74%) as a yellow crystalline solid; mp 63–64 °C.
A solution of lithium diisopropylamide (0.85 mL, 2 M in heptane,
1.7 mmol) in THF (10 mL) was cooled to –78 °C. Acetone (98 mg,
1.7 mmol) in THF (3 mL) was added over 30 min. After stirring for
30 min at –78 °C, compound 3 (555 mg, 1.7 mmol) in THF (6 mL)
was added over 25 min at –78 °C. The solution was allowed to warm
to 25 °C and left to stir for 18 h. Sat. aq NH4Cl (100 mL) was added
and the solution extracted with CH2Cl2 (3 × 50mL). The combined
organic layers were washed with brine (2 × 50 mL), dried (MgSO4)
and the solvent removed in vacuo. The resulting yellow oil was pu-
rified by flash column chromatography (eluent: 4:1 hexane–EtOAc)
to give the title compound (367 mg, 62%) as a pale-yellow oil.
IR (neat): 2928, 2845, 1718, 1578, 1144 cm–1.
IR (CHCl3): 3367, 2979, 1715 (v br), 1606, 1164 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.79 (app d, J = 7.2 Hz, 2 Harom),
7.40 (app tt, J = 7.4, 1.2 Hz, 1 Harom), 7.32 (app t, J = 7.6 Hz, 2
1H NMR (500 MHz, CDCl3): d = 6.92 (s, 1 H, C=CH), 4.20–4.13
(m, 1 H, CHN), 3.67 (dd, J = 10.2, 4.9 Hz, 1 H, one of CH2OSi),
3.64 (dd, J = 10.2, 3.4 Hz, 1 H, one of CH2OSi), 3.38 (app ddt,
J = 20.1, 9.6, 1.4 Hz, 1 H, one of CH2C=C), 2.95 (dddd, J = 20.1,
11.2, 9.3, 2.2 Hz, 1 H, one of CH2C=C), 2.15 (s, 3 H, CH3CO),
Harom), 6.10 (s, 1 H, CH=CCOH), 5.11 (br d, J = 8.3 Hz, 1 H, NH),
4.28–4.22 (m, 1 H, CHNH), 4.09 (q, J = 7.2 Hz, 2 H, CH2O), 2.52–
Synthesis 2006, No. 7, 1162–1170 © Thieme Stuttgart · New York

PAPER
Alkylidenation of Lactams
1167
2.02–1.87 (m, 2 H, CH2), 1.52 [s, 9 H, (CH3)3CO], 0.82 [s, 9 H,
(CH3)3CSi], 0.00 [s, 3 H, one of (CH3)2Si], –0.02 [s, 3 H, one of
(CH3)2Si].
13C NMR (125 MHz, CDCl3): d = 198.5 (ketone C=O), 158.6 (car-
bamate C=O), 151.5 (C=CH), 104.1 (C=CH), 82.3 [(CH3)3CO],
63.8 (CH2OSi), 62.1 (CHN), 32.0 (CH3CO), 31.7 (CH2), 28.3
[(CH3)3CO], 25.8 [(CH3)3CSi], 23.9 (CH2), 21.2 (CSi), –5.2 [one of
(CH3)2Si], –5.5 [one of (CH3)2Si].
per, and the organic material extracted into CH2Cl2 (3 × 80 mL).
The combined organic layers were dried (MgSO4) and the solvent
removed in vacuo. The resulting yellow oil was purified by flash
column chromatography (eluent: 4:1 hexane–EtOAc) to give the ti-
tle compound (1.5 g, 86%) as a waxy solid; mp 57–58 °C (Lit.25 mp
75–76 °C).
IR (neat): 3372, 2946, 1651, 1600, 1495, 1454, 1235, 1141, 740,
697 cm–1.
MS-ES: m/z (%) = 370 (MH+, 27), 270 (100).
HRMS-ES: m/z [M + H]+ calcd for C19H36NO4Si: 370.2414; found:
1H NMR (500 MHz, CDCl3): d = 7.85 (br s, 1 H, NH), 5.04 (s, 2 H,
CH2O), 4.54 (br s, 1 H, C=CH), 3.45 (t, J = 6.9 Hz, 2 H, CH2N),
2.52 (t, J = 7.8 Hz, 2 H, CH2CO), 1.90 (app quintet, J = 7.3 Hz, 2 H,
CH2CH2CH2).
370.2403.
(2S)-2-(Hydroxymethyl)-5-[(Z)-1-ethoxycarbonyl-
methylidene]pyrrolidine (8)
13C NMR (125 MHz, CDCl3): d = 170.4 (C=O), 167.0 (C=CH),
137.7 (Carom), 128.4 (CHarom), 127.8 (CHarom), 127.6 (CHarom), 76.3
(C=CH), 64.4 (CH2O), 47.1 (CH2N), 32.3 (CH2), 22.0 (CH2).
MS-ES: m/z (%) = 218 (MH+, 100), 91 (36).
HRMS-ES: m/z [M + H]+ calcd for C13H15NO2 + Na: 240.1000;
To a solution of compound 6 (200 mg, 0.50 mmol) in CH2Cl2 (3
mL) was added TFA (115 mg, 1.0 mmol) and the solution stirred for
3 h at 25 °C. Sat. aq Na2CO3 was added until neutral to pH paper,
and the organic material extracted into CH2Cl2 (3 × 20 mL). The or-
ganic layer was dried (MgSO4) and the solvent removed in vacuo to
give a yellow oil which was purified by flash column chromatogra-
phy (eluent: 5:1 hexane–EtOAc) to give the title compound (81 mg,
87%) as a colourless oil.
found: 240.0995.
(2Z)-Pyrrolidinylideneacetic Acid (–)-Menthyl Ester (9c)
(–)-Menthyl 6-tert-butoxycarbonylamino-3-oxohexanoate (4c; 900
mg, 2.3 mmol) was dissolved in TFA (0.35 mL, 4.6 mmol) and
stirred for 3 h at 25 °C. Sat. aq NaHCO3 was added until neutral to
pH paper, and the organic material was extracted into CH2Cl2
(3 × 20 mL). The combined organic layers were dried (MgSO4) and
the solvent removed in vacuo. The resulting yellow solid was puri-
fied by flash column chromatography (eluent: 4:1 hexane–EtOAc)
to give the title compound (485 mg, 80%) as a yellow oil.
IR (neat): 3402, 2955, 1714, 1689, 1171 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.00 (br s, 1 H, NH), 4.46 (s, 1 H,
C=CH), 4.01 (q, J = 7.1 Hz, 2 H, CH2CH3), 3.87 (app quintet,
J = 5.6 Hz, 1 H, CHNH), 3.62 (dd, J = 11.2, 3.9 Hz, 1 H, one of
CH2OH), 3.45 (dd, J = 11.2, 6.3 Hz, 1 H, one of CH2OH), 2.53 (m,
2 H, CH2C=C), 1.99 (m, 1 H, one of CH2CHN), 1.69 (m, 1 H, one
of CH2CHN), 1.19 (t, J = 7.1 Hz, 3 H, CH2CH3).
13C NMR (100 MHz, CDCl3): d = 171.9 (C=O), 167.3 (C=CH),
77.7 (C=CH), 65.9 (CH2O), 61.4 (CH), 59.0 (CH), 32.0 (CH2CO),
24.0 (CH2), 14.8 (CH3).
IR (CHCl3): 3365, 2951, 2868, 1651, 1603, 1236 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.82 (br s, 1 H, NH), 4.58 (app dt,
J = 4.2, 10.8 Hz, 1 H, menthyl 1-H), 4.50–4.35 (br s, 1 H, alkene
CH), 3.43 (t, J = 6.8 Hz, 2 H, CH2N), 2.50 (t, J = 7.6 Hz, 2 H,
MS-ES: m/z (%) = 186 (MH+, 100).
CH2C=C), 1.97–1.82 [m, 4 H, CH2CH2CH2 + menthyl 6-Heq +
CH(CH3)2], 1.63–1.55 (m, 2 H, menthyl 3-Heq + 4-Heq), 1.47–1.36
(m, 1 H, menthyl 5-Hax), 1.27 (app br t, J = 11.5 Hz, 1 H, menthyl
2-Hax), 0.99 (app dq, J = 2.7, 12.7 Hz, 1 H, menthyl 3-Hax), 0.88
(app q, J = 11.7 Hz, 1 H, menthyl 6-Hax), 0.87–0.76 (m, 1 H, men-
thyl 4-Hax), 0.81 (d, J = 6.5 Hz, 3 H, CH3), 0.80 (d, J = 7.0 Hz, 3 H,
CH3), 0.70 (d, J = 7.0 Hz, 3 H, CH3).
13C NMR (125 MHz, CDCl3): d = 170.5 (C=O), 166.4 (CN), 76.8
(C=CH), 71.7 (CHO), 47.3 (CH), 47.1 (CH2N), 41.6 (CH2), 34.5
(CH2), 32.2 (CH2), 31.5 (CH), 26.3 (CH), 23.7 (CH2), 22.1 (CH3),
22.0 (CH2), 20.8 (CH3), 16.6 (CH3).
HRMS-ES: m/z [M + H]+ calcd for C9H16NO3: 186.1130; found:
186.1125.
(Z)-Pyrrolidinylideneacetic Acid Ethyl Ester (9a)
Ethyl 6-tert-butoxycarbonylamino-3-oxohexanoate (4a; 0.5 g, 1.8
mmol) was dissolved in TFA (0.3 mL, 3.6 mmol) and the resulting
solution stirred for 3 h at 25 °C. Sat. aq NaHCO3 was added until
neutral to pH paper, and the organic materials extracted with
CH2Cl2 (3 × 20 mL). The combined organic layers were dried
(MgSO4) and the solvent removed in vacuo. The resulting yellow
solid was purified by flash column chromatography (eluent: 4:1
hexane–EtOAc) to give the title compound (0.22 g, 78%) as a yel-
low/orange crystalline solid; mp 62–62.5 °C (Lit.24 mp 60–62 °C).
MS-ES: m/z (%) = 266 (MH+, 100), 128 (39).
HRMS-ES: m/z [M + H]+ calcd for C16H28NO2: 266.2120; found:
266.2139.
IR (CH2Cl2): 3360, 2983, 1652, 1590, 1143 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.85 (br s, 1 H, NH), 4.49 (br s, 1
H, alkene CH), 4.05 (q, J = 7.1 Hz, 2 H, CH2O), 3.45 (t, J = 6.9 Hz,
2 H, CH2N), 2.51 (t, J = 7.8 Hz, 2 H, CH2CO), 1.91 (app quintet,
J = 7.3 Hz, 2 H CH2CH2CH2), 1.19 (q, J = 7.1 Hz, 3 H, CH3CH2).
13C NMR (125 MHz, CDCl3): d = 170.8 (C=O), 166.6 (C=CH),
76.5 (C=CH), 58.4 (CH2O), 47.1 (CH2N), 32.2 (CH2), 22.0 (CH2),
14.7 (CH3).
(Z)-1-Pyrrolidinylidenepropan-2-one (9d)26
N-tert-Butoxycarbonyl-4,6-dioxoheptylamine (4d; 530 mg, 2.2
mmol) was dissolved in TFA (0.34 mL, 4.4 mmol) and stirred for
3 h at 25 °C. Sat. aq NaHCO3 was added until neutral to pH paper,
and the organic material extracted into CH2Cl2 (3 × 50 mL). The
combined organic layers were dried (MgSO4) and the solvent re-
moved in vacuo. The resulting yellow solid was purified by recrys-
tallisation from hexane–Et2O to give the title compound (233 mg,
85%) as a yellow crystalline solid; mp 52–52.5 °C.
MS-ES: m/z (%) = 156 (MH+, 100), 128 (37).
HRMS-ES: m/z [M + Na]+ calcd for C8H14NO2 + Na: 156.1025;
IR (CHCl3): 3272, 1618, 1556, 1505, 1258 cm–1.
found: 156.1015.
1H NMR (500 MHz, CDCl3): d = 9.72 (br s, 1 H, NH), 5.04 (s, 1 H,
C=CH), 3.50 (t, J = 7.0 Hz, CH2N), 2.52 (t, J = 7.8 Hz, CH2), 1.96
(s, 3 H, CH3CO), 1.91 (app quintet, J = 7.4 Hz, CH2).
13C NMR (125 MHz, CDCl3): d = 195.0 (C=O), 167.4 (CN), 89.8
(C=CH), 47.5 (CH2N), 32.3 (CH2), 28.7 (CH3), 21.4 (CH2).
(Z)-Pyrrolidinylideneacetic Acid Benzyl Ester (9b)
Benzyl 6-tert-butoxycarbonylamino-3-oxohexanoate (4b; 2.0 g,
7.42 mmol) was dissolved in TFA (5.11 g, 44.5 mmol) and stirred
for 3 h at 25 °C. Sat. aq NaHCO3 was added until neutral to pH pa-
Synthesis 2006, No. 7, 1162–1170 © Thieme Stuttgart · New York

1168
M. C. Elliott, S. V. Wordingham
PAPER
MS-ES: m/z (%) = 126 (MH+, 100).
HRMS-ES: m/z [M + H]+ calcd for C7H12NO: 126.0919; found:
IR (neat): 3366, 2979, 2905, 1738, 1665, 1602, 1454, 1373, 1198,
1144, 1023, 739, 698 cm–1.
126.0917.
1H NMR (400 MHz, CDCl3): d = 8.08 (br s, 1 H, NH), 7.32–7.16
(m, 5 Harom), 5.07 and 5.02 (AB quartet, J = 12.6 Hz, 2 H, PhCH2O),
4.28 (dd, J = 8.3, 5.2 Hz, CHN), 4.16–4.09 (m, 2 H, CH2O), 2.68–
2.45 (m, 2 H, CH2C=C), 2.28–2.16 (m, 1 H, one of CH2), 2.10–1.97
(m, 1 H, one of CH2), 1.21 (3 H, t, J = 7.1 Hz, CH3).
13C NMR (100 MHz, CDCl3): d = 171.9 (C=O), 170.0 (C=O), 165.4
(C=CH), 135.2 (Carom), 128.5 (CHarom), 127.9 (CHarom), 127.7
(CHarom), 78.5 (C=CH), 64.6 (OCH2Ph), 61.5 (OCH2), 60.5 (CHN),
31.2 (CH2), 26.1 (CH2), 14.2 (CH3).
(Z)-1-Phenyl-2-pyrrolidinylideneethanone (9e)26
To a solution of 4e (200 mg, 0.65 mmol) in CH2Cl2 (5 mL) was add-
ed TFA (0.10 mL, 1.3 mmol) and the resulting solution stirred for 3
h at 25 °C. The volatiles were removed in vacuo and the resulting
oil dissolved in CH2Cl2 (2 mL). Sat. aq Na2CO3 was added until
neutral to pH paper, and the organic material extracted into CH2Cl2
(3 × 50 mL). The combined organic layers were dried (MgSO4) and
the solvent removed in vacuo. Purification by flash column chroma-
tography (eluent: 5:1 hexane–EtOAc) gave the title compound (90
mg, 74%) as a yellow solid; mp 108–109 °C (Lit.27 mp 108–
109 °C).
MS-ES: m/z = 290 (MH+, 100%).
HRMS-ES: m/z [M + H]+ calcd for C16H20NO4: 290.1392; found:
290.1382.
IR (CHCl3): 3278, 2956, 1700, 1610, 1521, 1260 cm–1.
(2S)-5-[(Z)-1-(–)-Menthyloxycarbonylmethylidene]pyrrolidine-
2-carboxylic Acid Ethyl Ester (10c)
1H NMR (400 MHz, CDCl3): d = 10.23 (br s, 1 H, NH), 7.80 (dd,
J = 7.6, 1.9 Hz, CHarom), 7.35–7.29 (m, 3 H, CHarom), 5.70 (s, 1 H,
C=CH), 3.56 (t, J = 7.0 Hz, 2 H, CH2NH), 2.65 (t, J = 7.9 Hz, 2 H,
CH2CCH), 1.95 (app quintet, J = 7.5 Hz, 2 H, CH2CH2CH2).
13C NMR (125 MHz, CDCl3): d = 188.1 (C=O), 169.4 (CN), 140.3
(Carom), 130.5 (CHarom), 128.2 (CHarom), 127.0 (CHarom), 86.6
(C=CH), 47.8 (CH2N), 33.0 (CH2), 21.4 (CH2).
TFA (0.23 mL, 3 mmol) was added to a solution of 5c (696 mg, 1.53
mmol) in CH2Cl2 (10 mL). After stirring for 3 h at 25 °C, the solu-
tion was neutralized with sat. aq Na2CO3 and extracted with CH2Cl2
(3 × 20 mL). The combined organic layers were dried (MgSO4) and
the solvent removed in vacuo. The resulting yellow oil was purified
by flash column chromatography (eluent: 10:1 CH2Cl2–MeOH) to
give the title compound (387 mg, 75%) as a white crystalline solid;
mp 72.0–72.5 °C.
MS-ES: m/z (%) = 188 (MH+, 100).
HRMS-ES: m/z [M + H]+ calcd for C12H14NO: 188.1075; found:
IR (Nujol): 3370, 1738, 1661, 1605, 1200 cm–1.
188.1062.
1H NMR (500 MHz, CDCl3): d = 8.05 (br s, 1 H, NH), 4.58 (app dt,
J = 4.3, 10.8 Hz, 1 H, menthyl 1-Hax), 4.52 (s, 1 H, C=CH), 4.28
(dd, J = 8.3, 5.4 Hz, 1 H, CHN), 4.17–4.09 (m, 2 H, OCH2), 2.63
(dddd, J = 16.6, 8.9, 6.8, 0.7 Hz, 1 H, one of CH2CO), 2.52 (dddd,
J = 16.6, 8.9, 6.3, 0.7 Hz, 1 H, one of CH2CO), 2.22 (app ddt,
J = 12.8, 6.9, 8.6 Hz, 1 H, one of CH2CH2CO), 2.09–2.01 (m, 1 H,
one of CH2CH2CO), 1.98–1.92 (m, 1 H, menthyl 6-Heq), 1.87 [app
doubled septet, J = 2.6, 7.0 Hz, 1 H, CH(CH3)2], 1.63–1.56 (m, 2 H,
menthyl 3-Heq + 4-Heq), 1.47–1.39 (m, 1 H, menthyl 5-Hax), 1.32–
1.25 (m, 1 H, menthyl 2-Hax), 1.21 (t, J = 7.1 Hz, 3 H, CH3CH2),
1.00 (app dq, J = 3.5, 13.0 Hz, 1 H, menthyl 3-Hax), 0.89 (app q,
J = 11.7 Hz, 1 H, menthyl 6-Hax), 0.82 (d, J = 6.5 Hz, 3 H, CH3),
0.81 (d, J = 7.0 Hz, 3 H, CH3), 0.80–0.75 (m, 1 H, menthyl 4-Hax),
0.70 (d, J = 7.0 Hz, 3 H, CH3).
13C NMR (125 MHz, CDCl3): d = 172.0 (ester C=O), 170.0 (ester
C=O), 164.7 (C=CH), 79.2 (C=CH), 72.1 (menthyl 1-CH), 61.5
(CH2O), 60.4 (CHN), 47.2 (menthyl 2-CH), 41.5 (menthyl 6-CH2),
34.4 (menthyl 4-CH2), 31.4 (menthyl 5-CH), 31.1 (CH2C=C), 26.2
[CH(CH3)2], 26.1 (CH2CH2CHN), 23.6 (menthyl 3-CH2), 22.1
(CH3), 20.8 (CH3), 16.5 (CH3), 14.2 (CH3).
(2S)-5-[(Z)-1-Ethoxycarbonylmethylidene]pyrrolidine-2-car-
boxylic Acid Ethyl Ester (10a)
A solution of 5a (4.9 g, 14.2 mmol) in TFA (2.1 mL, 28 mmol) was
stirred for 3 h at 25 °C. Excess TFA was removed in vacuo and the
resulting oil dissolved in CH2Cl2 (5 mL). Sat. aq Na2CO3 was added
until neutral to pH paper, and the organic material extracted into
CH2Cl2 (3 × 150 mL). The combined organic layers were dried
(MgSO4) and the solvent removed in vacuo. The resulting yellow
oil was purified by flash column chromatography (eluent: 4:1 hex-
ane–EtOAc) to give the title compound (2.6 g, 82%) as a pale-yel-
low oil.
IR (CHCl3): 3372, 2980, 1738, 1664, 1604, 1196 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.05 (br s, 1 H, NH), 4.53 (br s, 1
H, C=CH), 4.29 (dd, J = 8.3, 5.2 Hz, CHN), 4.16–4.11 (m, 2 H,
CH2O), 4.03 (q, J = 7.1 Hz, CH2O), 2.63 (ddd, J = 16.7, 8.1, 7.0 Hz,
1 H, one of CH2C=C), 2.57–2.50 (m, 1 H, one of CH2C=C), 2.23
(app ddt, J = 12.9, 7.1, 8.6 Hz, 1 H, one of CH2), 2.05 (app ddt,
J = 12.9, 9.0, 5.6 Hz, 1 H, one of CH2), 1.21 (t, J = 7.1 Hz, 3 H,
CH3), 1.19 (t, J = 7.1 Hz, 3 H, CH3).
13C NMR (125 MHz, CDCl3): d = 171.9 (C=O), 170.4 (C=O), 164.9
(CN), 78.8 (C=CH), 61.5 (OCH2), 60.5 (CHN), 58.7 (OCH2), 31.1
(CH2), 26.2 (CH2), 14.6 (CH3), 14.2 (CH3).
MS-ES: m/z (%) = 360 ([M + Na]+, 12), 339 (22), 338 (100).
HRMS-ES: m/z [M + Na]+ calcd for C19H31NO4 + Na: 360.2151;
found: 360.2155.
MS-ES: m/z (%) = 250 (M + Na, 34), 228 (MH+, 100), 182 (13).
HRMS-ES: m/z [M + H]+ calcd for C11H18NO2: 228.1236; found:
(2S)-5-[(Z)-2-Oxopropylidene]pyrrolidine-2-carboxylic Acid
Ethyl Ester (10d) 28
228.1239.
A solution of 5d (400 mg, 1.27 mmol) in CH2Cl2 (3 mL) and TFA
(0.16 mL, 2.4 mmol) was stirred for 3 h at 25 °C. After removal of
the volatiles in vacuo, the resulting oil was dissolved in CH2Cl2
(5 mL). Sat. aq Na2CO3 was added until neutral to pH paper and the
organic material was extracted into CH2Cl2 (3 × 50 mL). The com-
bined organic layers dried (MgSO4) and the solvent removed in vac-
uo. The resulting yellow oil was purified by flash column
chromatography (eluent: 4:1 hexane–EtOAc) to give the title com-
pound (138 mg, 55%) as a pale-yellow oil.
(2S)-5-[(Z)-1-(–)-Benzyloxycarbonylmethylidene]pyrrolidine-
2-carboxylic Acid Ethyl Ester (10b)
A solution of 5b (2.45 g, 6.01 mmol) in TFA (4.11 g, 36 mmol) was
stirred for 3 h at 25 °C. Sat. aq NaHCO3 was added until neutral to
pH paper, and the organic material extracted into CH2Cl2 (3 × 80
mL). The combined organic layers were dried (MgSO4) and the sol-
vent removed in vacuo. The resulting yellow oil was purified by
flash column chromatography (eluent: 4:1 hexane–EtOAc) to give
the title compound (1.26 g, 72%) as a yellow oil.
IR (neat): 3297, 2982, 1740, 1628, 1555, 1202 cm–1.
Synthesis 2006, No. 7, 1162–1170 © Thieme Stuttgart · New York

PAPER
Alkylidenation of Lactams
1169
1H NMR (500 MHz, CDCl3): d = 9.80 (br s, 1 H, NH) 5.10 (br s, 1
H, C=CH), 4.35 (dd, J = 8.5, 5.1 Hz, CHN), 4.18–4.10 (m, 2 H,
OCH2), 2.65 (ddd, J = 16.9, 8.9, 7.3 Hz, one of CH2C=C), 2.54
(ddd, J = 16.9, 9.1, 5.9 Hz, one of CH2C=C), 2.27–2.19 (m, 1 H, one
of CH2), 2.10–2.02 (m, 1 H, one of CH2), 1.98 (s, 3 H, CH3), 1.22
(t, J = 7.1 Hz, CH3CH2).
13C NMR (125 MHz, CDCl3): d = 196.0 (ketone C=O), 171.6 (ester
C=O), 165.8 (C=CH), 91.0 (C=CH), 61.6 (OCH2), 61.0 (CH), 31.3
(CH2), 28.9 (CH3), 25.6 (CH2) and 14.1 (CH3).
(Z)-2-Phenylsulfonylmethylylidenepyrrolidine (12)14
To a solution of 11 (1.4 g, 4.1 mmol) in CH2Cl2 (5 mL) was added
TFA (3.48 mL, 45 mmol) and the solution stirred for 18 h at 25 °C.
The volatiles were removed in vacuo and the resulting oil was dis-
solved in CH2Cl2 (5 mL). Sat. aq NaHCO3 was added until neutral
to pH paper, and the organic material was extracted into CH2Cl2
(3 × 50 mL). The combined organic layers were dried (MgSO4) and
the solvent removed in vacuo. The residual yellow oil was purified
by flash column chromatography (eluent: 4:1 hexane–EtOAc) to
give the title compound (620 mg, 67%) as a yellow oil.
1H NMR (400 MHz, CDCl3): d = 7.78 (d, J = 6.7 Hz, 2 Harom), 7.43–
7.34 (m, 3 Harom), 7.05 (br s, 1 H, NH), 4.58 (s, 1 H, CCH), 3.38 (t,
J = 6.9 Hz, 2 H, CH2N), 2.48 (t, J = 7.8 Hz, 2 H, CH2CO), 1.86 (app
quintet, J = 7.3 Hz, 2 H, CH2CH2CH2).
MS-ES: m/z = 198 (MH+, 100%).
HRMS-ES: m/z [M + H]+ calcd for C10H16NO3: 198.1130; found:
198.1131.
(2S)-5-[(Z)-2-Oxo-2-phenylethylidene]pyrrolidine-2-carboxylic
Acid Ethyl Ester (10e)
13C NMR (100 MHz, CDCl3): d = 161.9 (C=CH), 145.4 (Carom),
131.8 (CHarom), 128.1 (CHarom), 125.6 (CHarom), 80.8 (C=CH), 47.5
(CH2N), 33.2 (CH2C=C), 21.7 (CH2CH2N).
A solution of 5e (377 mg, 1.0 mmol) in CH2Cl2 (5 mL) and TFA
(0.13 mL, 2 mmol) was stirred for 3 h at 25 °C. After removal of the
volatiles in vacuo, the resulting oil was dissolved in CH2Cl2 (5 mL)
and sat. aq Na2CO3 was added until neutral to pH paper. The organic
material was extracted into CH2Cl2 (3 × 50 mL), the combined or-
ganic layers dried (MgSO4) and the solvent removed in vacuo. The
resulting yellow oil was purified by flash column chromatography
(eluent: 7:1 hexane–EtOAc) to give the title compound (114 mg,
44%) as a pale-yellow crystalline solid; mp 64–64.5 °C.
Acknowledgment
We thank the EPSRC for a studentship (S.V.W.) and to Mr. R. L.
Jenkins for technical assistance. We are grateful to Mr. J. L. Wood
for the preparation of compounds 5b and 9b.
IR (CHCl3): 3288, 2981, 1740 (v br), 1615, 1522, 1210 cm–1.
References
1H NMR (500 MHz, CDCl3): d = 10.32 (br s, 1 H, NH), 7.87–7.84
(m, 2 Harom), 7.42–7.35 (m, 3 Harom), 5.84 (s, 1 H, C=CH), 4.47 (dd,
J = 8.6, 5.4 Hz, 1 H, CHN), 4.24–4.16 (m, 2 H, OCH2), 2.84 (ddd,
J = 17.1, 9.1, 7.0 Hz, 1 H, one of CH2C=C), 2.73 (ddd, J = 17.1, 8.9,
5.8 Hz, 1 H, one of CH2C=C), 2.34 (dddd, J = 13.0, 8.9, 8.6, 7.0 Hz,
1 H, one of CH2), 2.18 (dddd, J = 13.0, 9.1, 5.8, 5.4 Hz, 1 H, one of
CH2), 1.27 (t, J = 7.1 Hz, 3 H, CH3).
13C NMR (125 MHz, CDCl3): d = 188.8 (ketone C=O), 171.4 (ester
C=O), 167.7 (C=CH), 139.9 (Carom), 130.8 (CHarom), 128.2 (CHarom),
127.2 (CHarom), 87.5 (C=CH), 61.7 (OCH2), 61.3 (CH), 31.9 (CH2),
25.6 (CH2), 14.2 (CH3).
(1) For a review, see: Elliott, M. C.; Wood, J. L.; Wordingham,
S. V. Trends Heterocycl. Chem. 2006, in press.
(2) Shiosaki, K. Compr. Org. Synth. 1991, 2, 865.
(3) Célérier, J.-P.; Deloisy, E.; Lhommet, G.; Maitte, P. J. Org.
Chem. 1979, 44, 3089.
(4) (a) Elliott, M. C.; Long, M. S. Tetrahedron Lett. 2002, 43,
9191. (b) Elliott, M. C.; Long, M. S. Org. Biomol. Chem.
2004, 2, 2003.
(5) (a) Moody, C. M.; Young, D. W. J. Chem. Soc., Perkin
Trans. 1 1997, 3519. (b) Williams, G. D.; Pike, R. A.;
Wade, C. E.; Wills, M. Org. Lett. 2003, 5, 4227.
(6) (a) Ohta, T.; Hosoi, A.; Nozoe, S. Tetrahedron Lett. 1988,
29, 329. (b) Ezquerra, J.; Pedregal, C.; Rubio, A.;
Valenciano, J.; García Navio, J. L.; Alvarez-Builla, J.;
Vaquero, J. J. Tetrahedron Lett. 1993, 34, 6317. (c) Yoda,
H.; Yamazaki, H.; Kawauchi, M.; Takabe, K. Tetrahedron:
Asymmetry 1995, 6, 2669. (d) v. Keyserlingk, N. G.;
Martens, J. Eur. J. Org. Chem. 2002, 301. (e) Mori, M.;
Tomita, T.; Kita, Y.; Kitamura, T. Tetrahedron Lett. 2004,
45, 4397. (f) Rudolph, A. C.; Machauer, R.; Martin, S. F.
Tetrahedron Lett. 2004, 45, 4895. (g) Brenneman, J. B.;
Machauer, R.; Martin, S. F. Tetrahedron 2004, 60, 7301.
(h) Arai, T.; Abe, H.; Aoyagi, S.; Kibayashi, C. Tetrahedron
Lett. 2004, 45, 5921.
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3243. (b) Farcas, S.; Namy, J.-L. Tetrahedron Lett. 2000, 41,
7299.
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Tourwé, D. Tetrahedron 1998, 54, 1753. (b)Momotake, A.;
Togo, H.; Yokoyama, M. J. Chem. Soc., Perkin Trans. 1
1999, 1193. (c) Yokoyama, M.; Ikenogami, T.; Togo, H. J.
Chem. Soc., Perkin Trans. 1 2000, 2067.
(9) (a) Molina, M. T.; del Valle, C.; Escribano, A. M.; Ezquerra,
J.; Pedregal, C. Tetrahedron 1993, 49, 3801. (b) de Blas, J.;
Dominguez, E.; Ezquerra, J. Tetrahedron Lett. 2000, 41,
4567.
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1988, 29, 4303.
MS-ES: m/z = 260 (MH+, 100%).
HRMS-ES: m/z [M + H]+ calcd for C15H18NO3: 260.1287; found:
260.1271.
N-tert-Butoxycarbonyl-4-oxo-5-phenylsulfonylpentylamine
(11)14
A solution of n-BuLi (2 mL, 2.5 M in hexanes, 5 mmol) in THF (10
mL) was cooled to –78 °C. Methyl phenyl sulfone (0.77 g, 5 mmol)
in THF (3 mL) was added over 30 min, after which the solution was
stirred for a further 30 min at –78 °C. N-tert-Butoxycarbonylpyrrol-
idin-2-one (1; 0.92 g, 5 mmol) in THF (5 mL) was added over 30
min at –78 °C, and the solution warmed to 25 °C and left to stir for
18 h. Sat. aq NH4Cl (100 mL) was added and the solution extracted
with CH2Cl2 (3 × 100 mL). The combined organic layers were
washed with brine (2 × 150 mL), dried (MgSO4) and the solvent re-
moved in vacuo to give the title compound (1.8 g, 96%) as an or-
ange oil which solidified upon standing to give a waxy solid.
1H NMR (400 MHz, CDCl3): d = 7.82 (d, J = 7.4 Hz, 2 Harom), 7.62
(t, J = 7.5 Hz, 1 Harom), 7.52 (app t, J = 7.7 Hz, 1 Harom), 4.62 (br s,
1 H, NH), 4.15 (s, 2 H, OCCH2CO), 3.03 (app q, J = 6.4 Hz, 2 H,
CH2NH), 2.70 (t, J = 6.8 Hz, 2 H, COCH2), 1.69 (app quintet,
J = 6.8 Hz, CH2CH2CH2), 1.36 [s, 9 H, C(CH3)3].
13C NMR (100 MHz, CDCl3): d = 197.8 (CH2COCH2), 156.1
(OCON), 138.7 (Carom), 134.4 (CHarom), 129.4 (CHarom), 128.3
(CHarom), 79.3 (OCCMe3), 67.0 (CH2O), 41.4 (CH2N), 39.3
(COCH2CO), 28.4 [C(CH3)3], 23.7 (CH2CH2N).
(11) Ezquerra, J.; de Mendoza, J.; Pedregal, C.; Ramírez, C.
Tetrahedron Lett. 1992, 33, 5589.
Synthesis 2006, No. 7, 1162–1170 © Thieme Stuttgart · New York

1170
M. C. Elliott, S. V. Wordingham
PAPER
(19) Roth, M.; Dubs, P.; Götschi, E.; Eschenmoser, A. Helv.
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(20) Célérier, J.-P.; Deloisy-Marchalant, E.; Lhommet, G. J.
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(21) A Chemical Abstracts search of compound 9a reveals 21
references to the Z-isomer and 6 to the E-isomer. However,
the reports of the E-isomer only mention this compound in
passing, and to the best of our knowledge full
characterisation data has never been reported for this double-
bond isomer. We are unaware of examples where full
characterisation data of both the E- and Z-isomers of a single
alkylidenepyrrolidine have been reported.
(22) Bachi, M. D.; Breiman, R.; Meshulam, H. J. Org. Chem.
1983, 48, 1439.
(23) The free alcohol corresponding to this compound is known:
Hussaini, S. R.; Moloney, M. G. Org. Biomol. Chem. 2003,
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keto esters prepared by other methods, see: (a) Lambert, P.
H.; Vaultier, M.; Carrié, R. J. Org. Chem. 1985, 50, 5352.
(b) Langer, P.; Freifeld, I. Chem. Commun. 2002, 2668.
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1985, 50, 4515. (d) Michael, J. P.; Hosken, G. D.; Howard,
A. S. Tetrahedron 1988, 44, 3025. (e) Calvet, S.; David, O.;
Vanucci-Bacqué, C.; Fargeau-Bellassoued, M.-C.;
Lhommet, G. Tetrahedron 2003, 59, 6333. (f) Wang, M.-
X.; Liu, Y.; Gao, H.-Y.; Zhang, Y.; Yu, C.-Y.; Huang, Z. T.;
Fleet, G. W. J. J. Org. Chem. 2003, 68, 3281.
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Chem. 2005, 505.
(25) Bartoli, G.; Cimarelli, C.; Dalpozzo, R.; Palmieri, G.
Tetrahedron 1995, 51, 8613.
(16) Pichon, M.; Figadere, B.; Cave, A. Tetrahedron Lett. 1996,
37, 7963.
(26) Delbecq, P.; Celerier, J.-P.; Lhommet, G. Tetrahedron Lett.
1990, 31, 4873.
(27) Couture, A.; Deniau, E.; Grandclaudon, P.; Lebrun, S.
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(18) Ikota, N. Chem. Pharm. Bull. 1992, 40, 1925.
(28) Honda, T.; Kimura, M. Org. Lett. 2000, 2, 3925.
Synthesis 2006, No. 7, 1162–1170 © Thieme Stuttgart · New York