N -bromosuccinimide-promoted cyclization of -carboxymethyl enamino esters; Synthesis of functionalized 4-amino-2(5 H)-furanones

Article abstract of DOI:10.1055/s-0030-1260132

An easy, two-step approach to various 5-carboxymethyl-2(5H)-furanones is described. A detailed study of the reaction of -carboxymethyl enamino esters with N-bromosuccinimide is presented. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1260132

PAPER
2781
N-Bromosuccinimide-Promoted Cyclization of b-Carboxymethyl Enamino
Esters; Synthesis of Functionalized 4-Amino-2(5H)-Furanones
Valérie Toum, Catherine Kadouri-Puchot,* Louis Hamon, Gérard Lhommet, Virginie Mouriès-Mansuy,
Corinne Vanucci-Bacqué, Luc Dechoux*
Université Pierre et Marie Curie-Paris 6, Institut Parisien de Chimie Moléculaire, UMR 7201, 4 place Jussieu, case courrier 47, 75005 Paris,
France
Fax +33(1)44275097; E-mail: luc.dechoux@upmc.fr
Received 6 April 2011; revised 9 June 2011
yield solely as the E-diastereoisomer (see Scheme 3 be-
Abstract: An easy, two-step approach to various 5-carboxymethyl-
low).
2(5H)-furanones is described. A detailed study of the reaction of b-
carboxymethyl enamino esters with N-bromosuccinimide is pre-
The crude mixture of Z- and E-enamino esters 2a was
sented.
used in an oxidative step using one equivalent of N-bro-
Key words: tetronamides, 4-amino-2(5H)-furanones, bromocy- mosuccinimide (NBS) in ethyl acetate. After 24 hours,
clization, alkylation, decarborxylation
evaporation of the solvent followed by chromatography
on silica gel furnished the tetronamides 3a and 4a, respec-
tively, in 39 and 18% yields (entry 1, Table 1) along with
starting material 2a (Scheme 2). The desired products
could be isolated by chromatography without aqueous
workup. In contrast, when the reaction was quenched with
an aqueous solution of sodium sulfite, compound 4a was
reduced to 3a and the latter compound was isolated after
chromatography in 66% yield (Table 1, entry 2). Various
reaction conditions were investigated to optimize the re-
action; the results are listed in Table 1.
4-Amino-2(5H)-furanones, which are commonly named
tetronamides, are important intermediates in the synthesis
of natural products,1 and are also an interesting class of
pharmaceutical and agrochemical compounds.2 Many
methods have been reported for the preparation of tetron-
amides. Most generally, the sequence of amino-addition
to acetylenecarboxylates followed by intramolecular cy-
clization affords 5-unsubstituted primary or secondary 4-
amino-2(5H)-furanones.3 A sequence involving conden-
sation between primary or secondary amines with tetronic
acids followed by alkylation or aldolization using, most
generally, tert-butyllithium as a base furnished 5-substi-
tuted tetronamides.4 Nucleophilic halogen substitution on
4-bromofuranones is described as a method for the intro-
duction of an alkylamino-group.5 Tetronamides have been
also used in aza-annulation processes with acrolein deriv-
atives, and have even been used in asymmetric organocat-
alytic approaches for the synthesis of chiral piperidines.6
Other synthetic routes involve the [2,3]-Wittig rearrange-
ment of g-allyloxy-b-enamino esters leading to g-hy-
droxy-b-enamino esters, which can subsequently be
lactonized to 5-substituted tetronamides.7 Here, we would
like to report an easy route to various 5-carboxymethyl
substituted tetronamides 3–6 starting from enamino esters
2, using N-bromosuccinimide (NBS) as reagent. The con-
densation of acetonedimethyldicarboxylate with different
primary amines 1 allowed the formation of the two Z- and
E-enamino esters 2 with the Z-diastereoisomers predomi-
nating (Scheme 1).8 We observed that the chemical shift
of the NH proton for the major Z stereoisomers was found
downfield (d = 8.5–9 ppm) from those of the E stereoiso-
mers (d = 5–5.5 ppm). Starting from the secondary amine,
pyrrolidine compound 2d was formed in quantitative
MeO2C
O
MeOH, r.t., 24 h
100%
R
NH2
+
HN
Ph
MeO2C
CO2Me
CO2Me
R
Ph
1a R = H
1b R = Me
2
1c R = CH2OTBS
Scheme 1
CO2Me
O
CO2Me
O
MeO2C
H
Br
NBS (1 equiv)
EtOAc, r.t.
O
O
+
HN
Bn
HN
HN
CO2Me
Bn
Bn
2a
3a 39%
4a 18%
Scheme 2
Solvents such as deuterochloroform and tetrahydrofuran
were tested but they had no significant effect on the reac-
tion outcome (entries 3 and 4). We also tried the reaction
with more than one equivalent of N-bromosuccinimide in
ethyl acetate. We expected to observe an enhancement in
the yield of product 4a, however, using 1.5 equivalents of
N-bromosuccinimide led to the formation of compound
4a in 44% yield (entry 5). Furthermore 3a was obtained in
good yield by quenching the reaction with an aqueous so-
lution of sodium sulfite (entry 6). When three equivalents
of N-bromosuccinimide were used, product 5a was exclu-
SYNTHESIS 2011, No. 17, pp 2781–2788
x
x.
x
x
.
2
0
1
1
Advanced online publication: 21.07.2011
DOI: 10.1055/s-0030-1260132; Art ID: Z36011SS
© Georg Thieme Verlag Stuttgart · New York

2782
V. Toum et al.
PAPER
Table 1 Optimization of the Reaction
CO2Me
O
CO2Me
O
CO2Me
O
CO2Me
O
MeO2C
H
Br
Br
H
NBS, solvent
O
O
O
O
+
+
+
HN
R
HN
HN
HN
HN
Br
Br
CO2Me
Ph
R
Ph
R
Ph
R
Ph
R
Ph
2
3
4
5
6
Entry
2
R
NBS (equiv)
Solvent
Yield (%)a
3
4
5
6
1
2
2a
H
H
H
H
H
H
H
H
H
1
EtOAc
EtOAc
CDCl3
THF
39
66
54c
64c
29
69
–
18
–
–
–
–
–
–
–
40
–
–
–
–
–
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
1b
–
3
1
46c
36c
44
–
–
4
1
–
5
1.5
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
–
6
1.5b
–
7
3
–
–
8
3b
–
–
35
71
–
9
2 × 1.5b
–
–
10
11
Me
CH2OTBS
1
1
43
33
22
20
–
a Yield of isolated compound.
b The reactions were quenched with an aqueous solution of Na2SO3.
c Ratio determined by 1H NMR analysis of the crude reaction mixture.
sively formed (entry 7), and when the reaction was fol- starting material;14 the results are presented in Table 2.
lowed by an aqueous sodium sulfite workup, tetronamide Five minutes after addition of 1.5 equivalents of N-bro-
6a was isolated in 35% yield (entry 8). By slightly modi- mosuccinimide, the 1H NMR spectrum showed that 8% of
fying the procedure (addition of 1.5 equiv of NBS 12 h af- the starting material was still present in the medium and
ter the first addition, entry 9), the yield of compound 6a that no N-bromosuccinimide remained. We also observed
reached 71%. To our knowledge, the synthesis of 4-ami- the formation of enamino ester 8a (36%) and dibrominat-
no-5-halogeno-2(5H)-furanones such as 4a and 5a, has ed enamino ester 9a (56%). Compounds 8a and 9a, which
seldom been described.9 Previously, the halogenation of were too unstable to be isolated, were characterized by 1H
4-amino-2(5H)-furanones with N-bromosuccinimide,10 NMR analysis. We observed that the chemical shift of the
13
bromine,11 iodine,12 or I(py)2BF4 were reported to give allylic proton for the major Z stereoisomers resonated
3-halogenated products. Both substrates 2b and 2c gave downfield in compound 8a (d = 4.95 ppm) from those of
the desired tetronamides 3b, 4b, 3c, and 4c, respectively, the starting product 2a (d = 3.11 ppm), and was absent in
as a 50:50 mixture of diastereoisomers (entries 10–11).
9a. It is likely that these signals arose from a brominated
N-Chlorosuccinimide furnished the expected product 3a
only in trace amounts after 24 hours, and gave a complex
mixture of inseparable mono- and di-chloroenamino es-
ters. N-Iodosuccinimide did not give the desired tetron-
amide 3a, and only a-keto ester 7 could be isolated in 18%
yield (Scheme 3).
MeO2C
MeO2C
O
NIS (1 equiv), EtOAc, r.t.
18%
I
HN
HN
Bn
2a
CO2Me
Bn
CO2Me
7
It is noteworthy that the enamino ester 2d, derived from
the secondary amine pyrrolidine, gave the (E)-bromo-
enamino ester 8d, which was unreactive under the given
conditions (Scheme 3).
MeO2C
MeO2C
Br
NBS (1 equiv), EtOAc, r.t.
100%
CO2Me
N
N
CO2Me
We then turned our attention to the mechanism of this
transformation. To this end, we monitored the reaction by
1H NMR spectroscopy in deuterochloroform using 2a as
2d
8d
Scheme 3
Synthesis 2011, No. 17, 2781–2788 © Thieme Stuttgart · New York

PAPER
Cyclization of b-Carboxymethyl Enamino Esters
2783
CO2Me
O
Br
MeO2C
MeO2C
iminium species. This latter may then afford the isomeric
vinylic bromide 10a through deprotonation of the most
acidic proton, which is alpha to the bromine atom. After
3.5 hours, the percentage of the brominated enamino es-
ters 8a and 9a fell, while those of tetronamides 3a and 4a,
respectively, increased. After seven hours, only traces of
uncyclized enamines 8a and 9a remained, and the amount
of 3a had increased. Finally, after 24 hours, equilibrium
was reached and the tetronamides 3a and 4a were formed
in almost the same proportions.
Br
NBS, CDCl3
k1
HN
HN
HN
OMe
Bn
CO2Me
Bn
CO2Me
Bn
2a
8a
k3
10a
k2
NBS
Br
MeO2C
HN
Br
MeO2C
O
O
H
N
Me
An examination of the frontier orbital interactions indicat-
ed that the vinylic bromide 10a, which is in equilibrium
with 8a, has a HOMO much higher (–8.844 eV) than that
of the allylic bromine 8a (–9.128 eV), explaining the high
level of formation of 9a. The gem-dibromination should
also be kinetically favored because the HOMO of 2a is
even lower (–8.868 eV), explaining why k2 is higher than
k1 (Scheme 4).15
Bn
CO2Me
Bn
Br
11a
9a
k4
MeBr
MeBr
CO2Me
O
CO2Me
CO2Me
O
H
H
Br
O
NBS, CH2Cl2
O
O
O
HN
HN
HN
The mechanism of the cyclization from either 8a or 9a in-
volves intramolecular nucleophilic substitution of bro-
mine by the ester function. Further attack of a bromide
anion on the methyl of iminium 11a gives rise to the
tetronamide 3a and methyl bromide. Such a mechanism
has already been outlined in the case of b-chloroenamino
esters.16 In respect to the cyclization, the gem-dibromo-
enamino ester 9a is more reactive than the bromoenamino
ester 8a. Indeed the LUMO (s* of the breaking C–Br
bond) of 9a is lower (–0.853 eV) than the LUMO of 8a
(–0.646 eV), which is consistent with the observation that
k4 is higher than k3.
Br
6a
Bn
Bn
Bn
3a
4a
Scheme 4
Because compounds 3–6 are expected to be very useful
synthons, we studied the regio- and stereoselective intro-
duction of substituents at C-5. For example, product 3a
was regioselectively alkylated using lithium hexamethyl-
disilazide, sodium hexamethyldisilazide, or potassium
carbonate as bases; the results are presented in Table 3.
The first reaction was performed with potassium carbon-
ate as base and benzyl bromide as electrophile in dichlo-
romethane. After 48 hours, the reaction mixture was
filtered and evaporated to furnish the expected regioiso-
mer 12a in 65% yield (entry 1). The yield of 12a was
enhanced by using the more basic lithium hexamethyl-
disilazide at room temperature (entry 2). Similar results
All attempts to isolate and purify intermediates 8a and 9a
by chromatography on silica gel were unsuccessful. It is
also noteworthy that bromination of purified 3a with N-
bromosuccinimide led to the formation of 6a, suggesting
that 4a arises from 9a (Scheme 4).
Table 2 Analysis of Product Formation over Time
CO2Me
MeO2C
Br
H
O
O
HN
HN
Bn
8a
CO2Me
Bn
MeO2C
HN
3a
NBS (1.5 equiv), CDCl3, r.t.
Br
CO2Me
Bn
CO2Me
Br
O
MeO2C
HN
Br
O
2a
HN
Bn
9a
CO2Me
Bn
4a
Time
5 min
3.5 h
7 h
2a (%)
8
8a (%)
9a (%)
3a (%)
0
4a (%)
0
36
16
5
56
8
13
21
42
16
2
32
45
24 h
16
0
0
41
43
Synthesis 2011, No. 17, 2781–2788 © Thieme Stuttgart · New York

2784
V. Toum et al.
PAPER
tion, gives easy access to 5-substituted tetronamides,
which are important intermediates in the synthesis of
many natural products. Applications of this methodology
for the synthesis of 5-methylidene substituted tetron-
amides are in progress.
Table 3 Regio- and Stereoselective Introduction of Substituents at
C-5
CO2Me
O
MeO2C
R
O
1) base, THF
2) RX, THF
O
O
HN
Bn
HN
3a
12
Bn
IR spectra were recorded with samples dissolved in chloroform. 1H
NMR spectra were measured at 250 MHz, in CDCl3 or DMSO, us-
ing TMS as internal standard. 13C NMR spectra were measured at
62.5 MHz in CDCl3. The chemical shifts of 13C NMR signals were
recorded relative to the central resonance of CDCl3 (d = 77.3 ppm).
HRMS were measured with a LTQ-Orbitrap instrument, using elec-
trospray ionization.
Entry RX
Base (equiv)
Product Yield
(%)
65
96
84
98
24
97
95
89
1
2
3
4
5
6
7
8
BnBr
BnBr
K2CO3 (2.5)a
LiHMDS (1)
K2CO3 (2.5)a
LiHMDS (1)
K2CO3 (2.5)a
LiHMDS (1)
12a
12a
12b
12b
12c
12c
12d
12e
allyl bromide
allyl bromide
MeI
Dimethyl 3-Benzylaminopent-2-enedioate (2a)
To a solution of 1,3-dimethyl acetonedicarboxylate (6.6 mL, 45.7
mmol) in MeOH (40 mL), was added benzylamine (5.0 mL, 45.8
mmol) and the reaction mixture was stirred at r.t. for 24 h. The mix-
ture was evaporated to afford compound 2a (quantitative) as a mix-
ture of two diastereoisomers (65:35), which was used in the next
step without purification.
MeI
methyl bromoacetate NaHMDS (1)
bromoacetonitrile NaHMDS (1)
Z-Isomer
1H NMR (250 MHz, CDCl3): d = 3.11 (s, 2 H, CCH2), 3.50 (s, 3 H,
CH3), 3.53 (s, 3 H, CH3), 4.32 (d, J = 6.4 Hz, 2 H, NCH2), 4.54 (s,
1 H, CH), 7.09–7.26 (m, 5 H, PhH), 8.86 (t, J = 6.4 Hz, 1 H, NH).
a K2CO3 in CH2Cl2.
13C NMR (62.5 MHz, CDCl3): d = 38.0, 46.5, 49.7, 51.9, 84.6,
were obtained when allyl bromide (entries 3 and 4) or
methyl iodide (entries 5 and 6) were used as electrophiles
to give compounds 12b and 12c, respectively. a-Bromo
ester and a-bromo nitrile were also found to be successful
reagents for this reaction (entries 7 and 8). We then turned
our attention to the decarboxylation of compounds 3a and
12 (Scheme 5). The reactions were performed by adding
one equivalent of aqueous sodium hydroxide to a solution
of esters 3a and 12c–e in tetrahydrofuran at reflux. After
30 minutes, the reaction was quenched with 10% aqueous
hydrochloric acid solution. The results are summarized in
Scheme 5.
126.4, 127.1, 128.3, 138.0, 156.6, 168.7, 170.3.
E-Isomer
IR (NaCl): 3322, 1739, 1674 cm–1.
1H NMR (250 MHz, CDCl3): d = 3.45 (s, 3 H, CH3), 3.57 (s, 3 H,
CH3), 3.80 (s, 2 H, CCH2), 4.11 (d, J = 5.3 Hz, 2 H, NCH2), 4.66 (s,
1 H, CH), 5.64 (t, J = 5.3 Hz, 1 H, NH), 7.09–7.26 (m, 5 H, PhH).
13C NMR (62.5 MHz, CDCl3): d = 36.9, 47.0, 49.7, 51.6, 84.2,
126.4, 127.1, 128.4, 136.7, 154.4, 168.6, 170.2.
Dimethyl 3-[(1R)-Phenylethylamino]pent-2-enedioate (2b)
To a solution of 1,3-dimethyl acetonedicarboxylate (3.0 mL, 23.3
mmol) in MeOH (20 mL), was added (1R)-phenylmethylamine
(3.36 mL, 23.3 mmol) and the reaction mixture was stirred at r.t. for
24 h. The mixture was evaporated to afford compound 2b (quanti-
tative) as a mixture of Z and E diastereoisomers (80:20), which was
used in the next step without purification.
R
R
MeO2C
1) NaOH (1 equiv), THF
2) HCl (10%), H2O
H
O
O
O
O
HN
HN
Bn
Bn
Z-Isomer
1H NMR (250 MHz, CDCl3): d = 1.72 (d, J = 6.8 Hz, 3 H, CH3),
3.27 (d, J = 15.7 Hz, 1 H, CCH2), 3.14 (d, J = 15.7 Hz, 1 H, CCH2),
3.67 (s, 3 H, CH3), 3.76 (s, 3 H, CH3), 4.69 (s, 1 H,CH), 4.71–4.85
(br s, 1 H, NCH), 7.31–7.48 (m, 5 H, PhH), 9.21 (d, J = 8.0 Hz, 1 H,
NH).
3a R = H
12c R = Bn
12d R = CH2CO2Me
12e R = CH2CN
13 65%
13c 74%
13d 99%
13e 22%
Scheme 5
13C NMR (62.5 MHz, CDCl3): d = 24.8, 38.4, 49.9, 52.0, 52.7, 84.9,
125.2, 127.0, 128.6, 144.3, 156.2, 168.8, 170.6.
In all cases, product 13 was formed as the major product.
It is noteworthy that the second ester function in com-
pound 12d was stable under these conditions. This result
would indicate that the high reactivity of the ester in com-
pounds 3a and 12c–e towards saponification is due to con-
comitant decarboxylation.
E-Isomer
1H NMR (250 MHz, CDCl3): d = 1.67 (d, J = 6.8 Hz, 3 H, CH3),
3.60 (s, 3 H, CH3), 3.81 (s, 3 H, CH3), 4.06 (d, J = 16.6 Hz, 1 H,
CCHH), 4.22 (d, J = 16.6 Hz, 1 H, CCHH), 4.51–4.60 (m, 1 H,
NCH), 4.66 (s, 1 H, CH), 5.74 (d, J = 5.9 Hz, 1 H, NH), 7.31–7.48
(m, 5 H, PhH).
In summary, the bromocyclization–regioselective alkyla-
tion sequence, in some cases followed by decarboxyla-
13C NMR (62.5 MHz, CDCl3): d = 23.5, 36.8, 49.9, 52.0, 52.7, 85.8,
125.4, 127.0, 128.2, 142.7, 153.2, 168.8, 170.6.
Synthesis 2011, No. 17, 2781–2788 © Thieme Stuttgart · New York

PAPER
Cyclization of b-Carboxymethyl Enamino Esters
2785
Dimethyl 3-[2-(tert-Butyldimethylsilanyloxy)-(1S)-phenylethyl-
amino]pent-2-enedioate (2c)
5.27 (s, 1 H, OCH), 6.11–6.16 (br s, 1 H, NH), 7.14–7.32 (m, 5 H,
PhH).
1,3-Dimethyl acetonedicarboxylate (1.15 mL, 8.0 mmol) was added
to a solution of 2-(tert-butyldimethylsilanyloxy)-(1S)-phenylethyl-
amine (2 g, 8.0 mmol) in toluene (40 mL), and the reaction mixture
was stirred at r.t. for 48 h. The solvent was evaporated to afford
compound 2c (quantitative) as a mixture of two diastereoisomers
(74:26), which was used in the next step without purification.
13C NMR (62.5 MHz, CDCl3): d = 23.1, 53.2, 55.3, 75.5, 82.3,
125.5, 127.7, 128.8, 141.9, 163.2, 167.4, 173.6.
HRMS: m/z [M + Na]+ calcd for C14H15NO4: 284.0899; found:
284.0893.
Second Diastereoisomer 3b
1H NMR (250 MHz, CDCl3): d = 1.52 (d, J = 3.0 Hz, 3 H, CH3),
3.79 (s, 3 H, CH3), 4.28–4.41 (m, 1 H, NCH), 4.43 (s, 1 H, CH),
5.22 (s, OCH, H-2), 6.11–6.16 (m, 1 H, NH), 7.14–7.32 (m, 5 H,
PhH).
Z-Isomer
1H NMR (250 MHz, CDCl3): d = 0.09 (s, 6 H, OTBS), 1.01 (s, 9 H,
OTBS), 3.22 (d, J = 15.5 Hz, 1 H, CHHC), 3.38 (d, J = 15.5 Hz,
1 H, CHHC), 3.72 (s, 3 H, CH3), 3.82 (s, 3 H, CH3), 3.86–3.93 (m,
1 H, CHHO), 4.00–4.06 (m, 1 H, CHHO), 4.74 (s, 1 H, CH), 4.78–
4.82 (m, 1 H, CHPh), 7.39–7.53 (m, 5 H, PhH), 9.34 (d, J = 8.8 Hz,
1 H, NH).
13C NMR (62.5 MHz, CDCl3): d = 23.1, 53.3, 55.5, 75.4, 82.3,
125.8, 127.8, 128.8, 141.7, 163.1, 167.5, 173.6.
13C NMR (62.5 MHz, CDCl3): d = –5.6, 18.3, 25.9, 39.3, 50.3–52.4,
First Diastereoisomer 4b
1H NMR (250 MHz, CDCl3): d = 1.62 (d, J = 6.6 Hz, 3 H, CH3),
3.94 (s, 3 H, CH3), 4.41–4.51 (m, 1 H, NCH), 4.53 (s, 1 H, CH),
5.95–6.03 (m, 1 H, NH), 7.20–7.42 (m, 5 H, PhH).
59.2, 68.0, 85.4, 126.8–127.7–128.7, 140.1, 156.5, 169.3, 170.6.
Dimethyl 3-Pyrrolidin-1-yl-pent-2-enedioate (2d)
13C NMR (62.5 MHz, CDCl3): d = 23.7, 54.6, 55.5, 79.3, 82.6,
125.8, 128.2, 129.2, 141.1, 165.4, 165.9, 168.1.
A solution containing 1,3-dimethyl acetonedicarboxylate (5.0 mL,
34.7 mmol) and pyrrolidine (2.9 mL, 34.7 mmol) in MeOH (30 mL)
was stirred at r.t. overnight. Evaporation of the solvent afforded
compound 2d (quantitative) as a single diastereoisomer.
1H NMR (250 MHz, CDCl3): d = 1.75–1.82 (m, 4 H, 2 × CH2),
3.02–3.23 (m, 4 H, 2 × NCH2), 3.39 (s, 3 H, CH3), 3.53 (s, 3 H,
CH3), 3.96 (s, 2 H, CH2), 4.39 (s, 1 H, CH).
Second Diastereoisomer 4b
1H NMR (250 MHz, CDCl3): d = 1.62 (d, J = 6.6 Hz, 3 H, CH3),
3.93 (s, 3 H, CH3), 4.41–4.51 (m, 1 H, NCH), 4.59 (s, 1 H, CH),
5.95–6.03 (m, 1 H, NH), 7.20–7.42 (m, 5 H, PhH).
13C NMR (62.5 MHz, CDCl3): d = 23.4, 54.6, 55.9, 79.5, 82.5,
125.7, 128.2, 129.2, 141.4, 165.5, 165.9, 168.1.
13C NMR (62.5 MHz, CDCl3): d = 24.8, 35.2, 47.7, 49.7, 51.8, 84.5,
154.3, 168.9, 169.8.
Methyl 3-[2-(tert-Butyldimethylsilanyloxy)-(1S)-phenylethyl-
amino]-5-oxo-2,5-dihydrofuran-2-carboxylate (3c) and Methyl
2-Bromo-3-[2-(tert-butyldimethylsilanyloxy)-(1S)-phenylethyl-
amino]-5-oxo-2,5-dihydrofuran-2-carboxylate (4c)
To a solution of 2c (0.58 g, 1.4 mmol) in EtOAc (13 mL), was added
NBS (0.25 g, 1.4 mmol) and the mixture was stirred for 24 h. The
solution was extracted with EtOAc (3 × 50 mL) and the organic lay-
er was washed with H2O (50 mL), dried over anhydrous MgSO4,
and evaporated. The residue was purified by chromatography
(Et2O–PE, 50:50) to afford 3c (33% yield) as a mixture of two dias-
tereoisomers (50:50) and 4c (20% yield) as a mixture of two diaste-
reoisomers (50:50).
Methyl 3-Benzylamino-5-oxo-2,5-dihydrofuran-2-carboxylate
(3a)
To a solution of 2a (1.06 g; 4.0 mmol) in EtOAc (40 mL), was add-
ed NBS (1.07 g, 6.0 mmol) and the mixture was stirred at r.t. for
24 h. A saturated aqueous solution of Na2SO3 (100 mL) was added
and, 5 min later, the solution was extracted with EtOAc (3 × 100
mL). The organic layer was washed with H2O (100 mL), dried over
anhydrous MgSO4 and evaporated. The residue was purified by
chromatography (Et2O–PE, 70:30) to afford 3a.
Yield: 69%.
IR (NaCl): 3355, 1761, 1732, 1623 cm–1.
1H NMR (250 MHz, CDCl3): d = 3.84 (s, 3 H, CH3), 4.31 (d,
J = 5.5 Hz, 2 H, CH2), 4.71 (s, 1 H, CH), 5.25 (s, 1 H, OCH), 5.73–
5.80 (br s, 1 H, NH), 7.22–7.42 (m, 5 H, PhH).
13C NMR (62.5 MHz, CDCl3): d = 49.2, 53.4, 75.5, 81.5, 127.3,
128.1, 128.8, 136.1, 164.2, 167.4, 173.7.
HRMS: m/z [M + Na]+ calcd for C13H13NO4: 270.0742; found:
270.0737.
First Diastereoisomer 3c
1H NMR (250 MHz, CDCl3): d = 0.03 (s, 3 H, OTBS), 0.05 (s, 3 H,
OTBS), 0.90 (s, 9 H, OTBS), 3.68–3.78 (m, 1 H, CHHO), 3.86 (s,
3 H, CH3), 4.00 (dd, J = 4.1, 10.5 Hz, 1 H, CHHO), 4.30–4.40 (br s,
1 H, NCH), 4.36 (s, 1 H, CH), 5.30 (s, 1 H, OCH), 6.32–6.37 (m,
1 H, NH), 7.14–7.38 (m, 5 H, PhH).
13C NMR (62.5 MHz, CDCl3): d = –5.5, 18.1, 25.7, 53.3, 61.4, 66.6,
75.4, 83.5, 126.8, 128.3, 128.8, 137.1, 163.2, 167.5, 173.3.
Methyl 5-Oxo-3-[(1R)-phenylethylamino]-2,5-dihydrofuran-2-
carboxylate (3b) and Methyl 2-Bromo-5-oxo-3-[(1R)-phenyleth-
ylamino]-2,5-dihydrofuran-2-carboxylate (4b)
Second Diastereoisomer 3c
1H NMR (250 MHz, CDCl3): d = –0.08 (s, 3 H, OTBS), –0.01 (s,
3 H, OTBS), 0.88 (s, 9 H, OTBS), 3.68–3.78 (m, 2 H, CH2O), 3.88
(s, 3 H, CH3), 4.30–4.40 (m, 1 H, NCH), 4.40 (s, 1 H, CH), 5.30 (s,
1 H, OCH), 6.32–6.37 (m, 1 H, NH), 7.14–7.38 (m, 5 H, PhH).
To a solution of 2b (0.81 g, 2.9 mmol) in EtOAc (30 mL), was add-
ed NBS (0.52 g, 2.9 mmol) and the mixture was stirred for 24 h. The
solution was extracted with EtOAc (3 × 100 mL) and the organic
layer was washed with H2O (100 mL), dried over anhydrous
MgSO4, and evaporated. The residue was purified by chromatogra-
phy (Et2O–PE, 60:40) to afford 3b (43% yield) as a mixture of two
diastereoisomers (50:50) and 4b (22% yield) as a mixture of two
diastereoisomers (50:50).
13C NMR (62.5 MHz, CDCl3): d = –5.5, 18.1, 25.7, 53.3, 60.6, 66.4,
75.5, 83.1, 126.5, 128.1, 128.6, 137.7, 162.9, 167.4, 173.3.
First Diastereoisomer 4c
1H NMR (250 MHz, CDCl3): d = 0.04 (s, 3 H, OTBS), 0.06 (s, 3 H,
OTBS), 0.91 (s, 9 H, OTBS), 3.68–3.78 (m, 1 H, CHHO), 3.93 (s,
3 H, CH3), 3.97–4.04 (m, 1 H, CHHO), 4.37 (s, 1 H, CH), 4.37–
4.44 (m, 1 H, NCH), 6.68–6.70 (br s, 1 H, NH), 7.19–7.38 (m, 5 H,
PhH).
First Diastereoisomer 3b
1H NMR (250 MHz, CDCl3): d = 1.49 (d, J = 3.3 Hz, 3 H, CH3),
3.74 (s, 3 H, CH3), 4.28–4.41 (m, 1 H, NCH), 4.43 (s, 1 H, CH),
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2786
V. Toum et al.
PAPER
13C NMR (62.5 MHz, CDCl3): d = –5.5, 18.2, 25.8, 54.5, 61.0, 66.7,
NH), 7.26–7.43 (m, 5 H, PhH).
13C NMR (62.5 MHz, CDCl3): d = 47.4, 53.5, 75.5, 93.5, 127.1,
128.0, 128.9, 137.1, 158.0, 166.3, 169.3.
HRMS: m/z [M + Na]+ calcd for C13H12BrNO4: 347.9847,
349.9827; found: 347.9842, 349.9822.
79.4, 83.0, 126.9, 128.5, 129.2, 136.7, 165.5, 165.8, 168.1.
Second Diastereoisomer 4c
1H NMR (250 MHz, CDCl3): d = –0.02 (s, 3 H, OTBS), 0.00 (s, 3 H,
OTBS), 0.91 (s, 9 H, OTBS), 3.68–3.78 (m, 1 H, CHHO), 3.95 (s,
3 H, CH3), 3.97–4.04 (m, 1 H, CHHO), 4.37–4.44 (br s, 1 H, NCH),
4.44 (s, 1 H, CH), 6.52–6.54 (m, 1 H, NH), 7.19–7.38 (m, 5 H,
PhH).
Dimethyl 3-Benzylamino-2-iodo-4-oxopent-2-enedioate (7)
To a solution of 2a (0.30 g, 1.15 mmol) in EtOAc (10 mL), was add-
ed NIS (0.26 g, 1.15 mmol) and the mixture was stirred for 24 h.
The mixture was concentrated and the residue was purified by silica
gel column chromatography (Et2O–PE, 20:80) to afford the iodo de-
rivative 7
13C NMR (62.5 MHz, CDCl3): d = –5.5, 18.2, 25.8, 54.5, 61.3, 66.4,
79.8, 82.6, 126.9, 128.5, 129.2, 137.2, 165.4, 165.7, 168.2.
Methyl 3-Benzylamino-2-bromo-5-oxo-2,5-dihydrofuran-2-
carboxylate (4a)
Yield: 18%.
1H NMR (250 MHz, CDCl3): d = 3.67 (s, 3 H, CH3), 3.77 (s, 3 H,
CH3), 4.31 (d, J = 5.9 Hz, 2 H, NCH2), 5.66–5.71 (br s, 1 H, NH),
7.25–7.37 (m, 5 H, PhH).
13C NMR (62.5 MHz, CDCl3): d = 48.6, 53.4, 53.6, 55.2, 128.1,
128.2, 128.9, 136.5, 158.5, 159.1, 166.9, 180.4.
HRMS: m/z [M + Na]+ calcd for C14H14INO5: 425.9814; found:
425.9809.
To a solution of 2a (9.7 mmol) in EtOAc (60 mL), was added NBS
(2.60 g, 14.6 mmol) and the mixture was stirred at r.t. for 24 h. The
solution was washed with H2O (100 mL), extracted with EtOAc
(3 × 100 mL), and the organic layer was washed with H2O (100
mL), dried over anhydrous MgSO4, and evaporated. The residue
was purified by chromatography (Et2O–PE, 10:90) to afford 3a
(29% yield) as described above, and the bromo derivative 4a as a
mixture of two diastereoisomers (50:50).
Yield: 44%.
Dimethyl 4-Bromo-3-pyrrolidin-1-ylpent-2-enedioate (8d)
To a solution of 2d (0.09 g, 0.40 mmol) in CH2Cl2 (4 mL), was add-
ed NBS (0.07 g, 0.40 mmol) and the mixture was stirred for 24 h.
The mixture was washed with H2O (10 mL) and the aqueous layer
was extracted with CH2Cl2 (3 × 30 mL). The organic layer was
dried over anhydrous MgSO4 and concentrated to afford 8d.
1H NMR (250 MHz, CDCl3): d = 3.93 (s, 3 H, CH3), 4.42 (d,
J = 5.7 Hz, 2 H, NCH2), 4.80 (s, 1 H, CH), 6.05–6.12 (m, 1 H, NH),
7.30–7.43 (m, 5 H, PhH).
13C NMR (62.5 MHz, CDCl3): d = 49.1, 54.5, 79.4, 81.1, 127.2,
128.1, 129.0, 135.6, 165.3, 166.6, 168.3.
HRMS: m/z [M + Na]+ calcd for C13H12BrNO4: 347.9847 and
Yield: 55%.
1H NMR (250 MHz, CDCl3): d = 1.80–1.91 (m, 4 H, 2 × CH2),
2.95–3.10 (m, 2 H, NCH2), 3.40–3.55 (m, 2 H, NCH2), 3.60 (s, 3 H,
CH3), 3.75 (s, 3 H, CH3), 4.52 (s, 1 H, CH), 7.90 (s, 1 H, CHBr).
13C NMR (62.5 MHz, CDCl3): d = 25.2, 39.6, 48.5, 50.7, 54.0, 85.7,
154.4, 167.6, 169.1.
HRMS: m/z [M + Na]+ calcd for C11H16BrNO4: 328.0160,
330.0140; found: 328.0155, 330.0135.
349.9827; found: 347.9842 and 349.9822
Methyl 3-Benzylamino-2,4-dibromo-5-oxo-2,5-dihydrofuran-2-
carboxylate (5a)
To a solution of 2a (0.50 g, 1.9 mmol) in EtOAc (18 mL), was added
NBS (0.51 g, 2.8 mmol) and the mixture was stirred at r.t. for 24 h.
Further NBS (0.51 g, 2.8 mmol) was added and, 15 min later, the so-
lution was washed with H2O (50 mL) and extracted with EtOAc
(3 × 50 mL). The organic layer was dried over anhydrous MgSO4
and evaporated. The residue was purified by silica gel column chro-
matography (Et2O–PE, 10:90) to afford the dibromo derivative 5a.
Alkylation of 3a; General Procedure
To a solution of 3a (0.36 g, 1.5 mmol) in THF (15 mL), was added
LiHMDS (1 M in THF, 1.60 mL, 1.7 mmol) at 0 °C, and the mixture
was stirred at r.t. for 30 min. The electrophile (benzyl bromide, allyl
bromide, or methyl iodide; 1.5 mmol) was added and the solution
was allowed to reach r.t. and stirred for 24 h. The solution was
poured into saturated aq NH4Cl (50 mL) and extracted with CH2Cl2
(3 × 50 mL). The organic layer was dried over anhydrous MgSO4
and evaporated to afford the corresponding alkylated compound.
Yield: 40%.
IR (NaCl): 3363, 1773, 1743, 1705, 1636 cm–1.
1H NMR (250 MHz, CDCl3): d = 3.91 (s, 3 H, CH3), 4.95 (dd,
J = 15.1, 6.3 Hz, 2 H, NCH2), 4.98 (dd, J = 15.1, 6.4 Hz, 2 H,
NCH2), 5.90–5.96 (br s, 1 H, NH), 7.32–7.45 (m, 5 H, PhH).
13C NMR (62.5 MHz, CDCl3): d = 47.4, 54.9, 72.1, 80.0, 127.2,
128.2, 129.0, 136.9, 159.0, 164.7, 164.9.
HRMS: m/z [M + Na]+ calcd for C13H11Br2NO4: 425.8952,
Methyl 2-Benzyl-3-benzylamino-5-oxo-2,5-dihydrofuran-2-
carboxylate (12a)
427.8932, 429.8912; found: 425.8947, 427.8927, 429.8906.
Yield: 96%.
1H NMR (250 MHz, CDCl3): d = 3.25 (d, J = 14.1 Hz, 1 H, CHH-
Ph), 3.47 (d, J = 14.1 Hz, 1 H, CHHPh), 3.73 (s, 3 H, CH3), 4.27 (d,
J = 5.6 Hz, 2 H, NCH2), 4.56 (s, 1 H, CH), 6.25 (t, J = 5.6 Hz, 1 H,
NH), 7.24–7.45 (m, 5 H, PhH).
13C NMR (62.5 MHz, CDCl3): d = 42.6, 49.2, 53.3, 83.0, 84.7,
127.6, 128.0, 128.3, 128.8, 128.9, 130.3, 132.7, 136.2, 166.1, 169.7,
172.4.
Methyl 3-Benzylamino-4-bromo-5-oxo-2,5-dihydrofuran-2-
carboxylate (6a)
To a solution of 2a (0.43 g, 1.6 mmol) in EtOAc (16 mL), was added
NBS (0.44 g, 2.4 mmol) and the mixture was stirred at r.t. for 12 h.
Further NBS (0.44 g, 2.4 mmol) was added and, 15 min later, satu-
rated aq Na2SO3 (50 mL) was added. After 5 min, the solution was
extracted with EtOAc (3 × 50 mL) and the organic layer was
washed with H2O (50 mL), dried over anhydrous MgSO4, and evap-
orated. The residue was purified by chromatography on silica gel
(Et2O–PE, 50:50) to afford 6a.
HRMS: m/z [M + Na]+ calcd for C20H19NO4: 360.1212; found:
360.1206.
Methyl 2-Allyl-3-benzylamino-5-oxo-2,5-dihydrofuran-2-car-
boxylate (12b)
Yield: 98%.
Yield: 71%.
1H NMR (250 MHz, CDCl3): d = 3.70 (s, 3 H, CH3), 4.76 (d,
J = 6.2 Hz, 2 H, NCH2), 5.25 (s, 1 H, OCH), 5.45–5.55 (br s, 1 H,
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Cyclization of b-Carboxymethyl Enamino Esters
2787
1H NMR (250 MHz, CDCl3): d = 2.60 (dd, J = 14.3, 6.7 Hz, 1 H,
CHH), 2.80 (dd, J = 14.3, 7.4 Hz, 1 H, CHH), 3.70 (s, 3 H, CH3),
4.22 (d, J = 5.6 Hz, 2 H, NCH2), 4.58 (s, 1 H, CH), 5.10 (m, 2 H,
=CH2), 5.60 (ddt, J = 16.7, 9.7, 7.1 Hz, 1 H, =CH), 5.92 (t,
J = 5.6 Hz, 1 H, NH), 7.16–7.31 (m, 5 H, PhH).
ing extracted with CH2Cl2 (3 × 30 mL). The organic layer was dried
over MgSO4, filtered, and evaporated to afford the corresponding
decarboxylated compound after chromatography.
4-Benzylamino-5H-furan-2-one (13)
Yield: 65%.
13C NMR (62.5 MHz, CDCl3): d = 41.0, 49.2, 53.4, 82.6, 84.2,
121.0, 127.4, 128.1, 128.9, 129.1, 136.2, 166.4, 169.6, 172.6.
1H NMR (250 MHz, CDCl3): d = 4.19 (d, J = 4.5 Hz, 2 H, NCH2),
4.59 (br s, 3 H, OCH2 and CH), 5.99 (br s, 1 H, NH), 7.17–7.29 (m,
5 H, PhH).
13C NMR (62.5 MHz, CDCl3): d = 49.3, 68.1, 81.8, 127.7, 128.2,
129.1, 136.4, 168.7, 177.3.
HRMS: m/z [M + Na]+ calcd for C16H17NO4: 310.1055; found:
310.1050.
Methyl 3-Benzylamino-2-methyl-5-oxo-2,5-dihydrofuran-2-
carboxylate (12c)
Yield: 97%.
5-Benzyl-4-benzylamino-5H-furan-2-one (13c)
Yield: 74%.
1H NMR (250 MHz, CDCl3): d = 1.72 (s, 3 H, CH3), 3.75 (s, 3 H,
CH3), 4.29 (d, J = 5.7 Hz, 2 H, CHa), 4.59 (s, 1 H, CH), 6.01–6.05
(br s, 1 H, NH), 7.20–7.36 (m, 5 H, PhH).
13C NMR (62.5 MHz, CDCl3): d = 23.5, 49.1, 53.4, 81.4, 82.0,
127.2, 128.0, 128.9, 136.2, 168.3, 170.0, 172.8.
HRMS: m/z [M + Na]+ calcd for C14H15NO4: 284.0899; found:
284.0893.
1H NMR (250 MHz, CDCl3): d = 3.00 (dd, J = 14.1, 6.8 Hz, 1 H,
CHHPh), 3.20 (dd, J = 14.1, 6.1 Hz, 1 H, CHHPh), 4.17 (d, J =
5.3 Hz, 2 H, NCH2), 4.58–4.62 (m, 1 H, NH), 4.65 (s, 1 H, CH),
4.98 (t, J = 6.5 Hz, 1 H, OCH), 7.15–7.35 (m, 5 H, PhH).
13C NMR (62.5 MHz, CDCl3): d = 39.7, 49.4, 78.4, 83.0, 127.5,
127.7, 128.2, 128.9, 129.0, 129.7, 134.8, 136.3, 169.4, 174.4.
HRMS: m/z [M + Na]+ calcd for C18H17NO2: 302.1157; found:
Methyl 3-Benzylamino-2-methoxycarbonylmethyl-5-oxo-2,5-
dihydrofuran-2-carboxylate (12d)
302.1152.
NaHMDS (1 M in THF, 6.10 mL, 6.08 mmol) was added to a solu-
tion of 3a (1.50 g, 6.08 mmol) in THF (60 mL) at 0 °C. After
30 min, methyl bromoacetate (0.60 mL, 6.08 mmol) was added and
the mixture was stirred for 2 h. The mixture was poured into satu-
rated aq NH4Cl (150 mL) and extracted with CH2Cl2 (3 × 150 mL).
The organic layer was dried over anhydrous MgSO4 and concentrat-
ed to afford 12d.
Methyl (3-Benzylamino-5-oxo-2,5-dihydrofuran-2-yl)acetate
(13d)
Yield: 99%.
1H NMR (250 MHz, CDCl3): d = 2.75 (dd, J = 18.1, 9.7 Hz, 1 H,
CHH), 3.16 (dd, J = 18.1, 3.7 Hz, 1 H, CHH), 3.74 (s, 3 H, CH3),
4.29 (d, J = 5.4 Hz, 2 H, NCH2), 4.67 (s, 1 H, CH), 5.12 (dd, J = 9.7,
3.7 Hz, 1 H, OCH), 6.45–6.50 (br s, 1 H, NH), 7.24–7.40 (m, 5 H,
PhH).
Yield: 95%.
IR (NaCl): 3331, 1735, 1627 cm–1.
13C NMR (62.5 MHz, CDCl3): d = 38.1, 48.8, 52.2, 74.3, 80.8,
127.2, 127.7, 128.7, 136.4, 170.4, 171.0, 175.0.
1H NMR (250 MHz, CDCl3): d = 2.86 (d, J = 16.7 Hz, 1 H, CHH),
3.11 (d, J = 16.7 Hz, 1 H, CHH), 3.57 (s, 3 H, CH3), 3.69 (s, 3 H,
CH3), 4.17 (d, J = 5.6 Hz, 2 H, NCH2), 4.54 (s, 1 H, CH), 6.13 (t,
J = 5.6 Hz, 1 H, NH), 7.08–7.25 (m, 5 H, PhH).
13C NMR (62.5 MHz, CDCl3): d = 41.5, 49.2, 52.6, 53.8, 81.6, 82.3,
127.3, 128.1, 129.0, 136.0, 166.6, 168.9, 169.7, 172.1.
(3-Benzylamino-5-oxo-2,5-dihydrofuran-2-yl)acetonitrile (13e)
Yield: 22%.
IR (NaCl): 3222, 2259, 1705, 1599 cm–1.
1H NMR (250 MHz, DMSO): d = 3.12 (dd, J = 17.4, 5.1 Hz, 1 H,
CHH), 3.34 (dd, J = 17.4, 4.0 Hz, 1 H, CHH), 4.32 (d, J = 5.7 Hz,
2 H, NCH2), 4.74 (s, 1 H, CH), 5.12 (t, J = 4.5 Hz, 1 H, OCH),
7.27–7.41 (m, 5 H, PhH), 7.98 (t, J = 5.7 Hz, 1 H, NH).
Methyl 3-Benzylamino-2-cyanomethyl-5-oxo-2,5-dihydrofu-
ran-2-carboxylate (12e)
NaHMDS (1 M in THF, 7.62 mL, 7.60 mmol) was added to a solu-
tion of 3a (1.88 g; 7.60 mmol) in THF (70 mL) at 0 °C. After
30 min, bromoacetonitrile (0.48 mL, 6.84 mmol) was added and the
mixture was stirred for 2 h. The mixture was poured into saturated
aq NH4Cl (150 mL) and extracted with CH2Cl2 (3 × 150 mL). The
organic layer was dried over anhydrous MgSO4 and concentrated to
afford 12e.
13C NMR (62.5 MHz, DMSO): d = 21.9, 48.0, 72.3, 80.5, 116.4,
127.4, 127.5, 128.5, 137.4, 168.3, 172.6.
References
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118, 3301. (b) Clark, J. S.; Marlin, F.; Nay, B.; Wilson, C.
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(2) For some example, see: Wang, J.; Jiang, X.; Chen, M.; Ge,
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Yield: 89%.
IR (NaCl): 3305, 2228, 1721, 1607 cm–1.
1H NMR (250 MHz, CDCl3): d = 3.16 (s, 2 H, CH2), 3.88 (s, 3 H,
CH3), 4.34 (d, J = 5.4 Hz, 2 H, CH2Ph), 4.86 (s, 1 H, CH), 5.50–
5.54 (br s, 1 H, NH), 7.26–7.39 (m, 5 H, PhH).
HRMS: m/z [M + Na]+ calcd for C15H14N2O4: 309.0851; found:
309.0846.
(4) (a) Nishide, K.; Aramata, A.; Kamanaka, T.; Inoue, T.;
Node, M. Tetrahedron 1994, 50, 8337. (b) Dankwardt, S.
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Decarboxylation of 3a and 12c–e; General Procedure
A solution of 3a (or 12c–e; 1.22 mmol) in THF (12 mL) was heated
at reflux and a solution of NaOH (0.05 g, 1.22 mmol) in H2O (3 mL)
was added. The mixture was stirred at reflux for 30 min, then al-
lowed to reach r.t. and 10% HCl (2 mL) was added. The mixture
was stirred under reflux for 1 h, then allowed to reach r.t. before be-
Synthesis 2011, No. 17, 2781–2788 © Thieme Stuttgart · New York

2788
V. Toum et al.
PAPER
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(14) Data were obtained from reactions with less than 5%
deviation
(15) An initial approximation of the structure leads to a geometry
that was first improved using molecular mechanics
techniques (MM2) implemented in Chem3D 5.0, and the
resulting structure was optimized by the semiempirical
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Synthesis 2011, No. 17, 2781–2788 © Thieme Stuttgart · New York