Synthesis of 2,3-dihydropyrrolizines from Weinreb 3-(pyrrolidin-2-ylidene)propionamides or Weinreb N-vinylprolinamides

Article abstract of DOI:10.1055/s-2002-35220

Weinreb 3-(pyrrolidin-2-ylidene)propionamides and Weinreb N-vinylprolinamides were used for the synthesis of 2,3-dihydropyrrolizines. The selective reaction of the carboxamide group with organometallic compounds allowed us to obtain a great variety of carbonyl intermediates, analogous to the Hantzsch and Knorr pyrrole synthesis, which were thermally cyclized.

Full text of DOI:10.1055/s-2002-35220

2450
PAPER
Synthesis of 2,3-Dihydropyrrolizines from Weinreb 3-(Pyrrolidin-2-
ylidene)propionamides or Weinreb N-Vinylprolinamides
2
, 3-Dihydropyr
u
rolizines from
i
3-(Py
s
rrolidin-2-ylide
C
ne)propionamide
a
s or
N
-
V
iny
l
lprolin
v
a
mides o, Alfonso González-Ortega,* M. Carmen Sañudo
Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Valladolid, 47005, Spain
Fax +34(983)423013; E-mail: algon@qo.uva.es
Received 2 July 2002; revised 2 August 2002
OMe
N
Abstract: Weinreb 3-(pyrrolidin-2-ylidene)propionamides and
Weinreb N-vinylprolinamides were used for the synthesis of 2,3-di-
hydropyrrolizines. The selective reaction of the carboxamide group
with organometallic compounds allowed us to obtain a great variety
of carbonyl intermediates, analogous to the Hantzsch and Knorr
pyrrole synthesis, which were thermally cyclized.
W
O
R
W
W
O
N
Z
1. RM
Me
RM
2. H2O
N
H
1 : 1
N
H
- H2O
W = CN, COR1, CO2Et
Z = CON(OMe)Me
W
R
Key words: Weinreb amides, cyclizations, amines, pyrroles, bicy-
clic pyrrolizines
N
H
Scheme 2
-Functionalized enamines have been widely used with
great success in the synthesis of a great variety of hetero-
cycles.1,2 However, there are few procedures in which one
of the key stages is based on the use of these substrates as
deactivated and inert systems towards determinate re-
agents. For example, the tetronic acid was prepared start-
ing from diethyl aminomaleate by selective reduction of
only one of the two ester groups present in the molecule3
(Scheme 1). More recently, we have described a modified
Knorr synthesis starting from Weinreb -enamino carbox-
amides (Scheme 2) in which organometallic reagents se-
lectively attack the carboxamide group, and the W
function (ketone, ester or nitrile) remains untransformed.4
In both schemes, the intermediate anion deactivates the
conjugated W function with the enamine and, if an excess
of the organometallic compound is used, this allows the
selective reaction of other Z functions present in the mol-
ecule.
oped two complementary procedures for the synthesis of
2,3-dihydro-1H-pyrrolizines starting from type A or B
structures. In both, we started from pyrrolidine derivatives
and the processes were completed with the formation of
C6–N7 or C4–C5 bonds (Scheme 3). They are, respec-
tively, variations of the Hantzsch and Knorr pyrrole syn-
thesis in which the versatile Weinreb amides were
precursors of the traditional carbonyl intermediates. Our
objective with this type of key synthon was not to obtain
entirely new synthetic designs, but rather to modify some
of the procedural stages already described with the aim of
increasing their potential with simple chemical processes.
W
W
W
Z
Z
N
H
N
Z
N
H
H
O
W
Z
CO2Et
CO2Et
CO2Et
OH
Type C
Type A
Type B
LiAlH4
1 : 1
LiAlH4
O
H2N
HN
H2N
Figure 1
HO
W = Z = CO2Et
Type B
Type A
Scheme 1
Me
N
W
OMe
N
N
The characteristics of the final heterocycles will depend,
among other factors, on the nature and position of the
chain which links the Z function with the enamine. In
Figure 1 we show three general synthons of which one
type C was used for the formation of the tetronic acid and
one type B in the synthesis of pyrroles. Among the multi-
ple possibilities of the above, in this paper we have devel-
H
O
O
R2
N
OMe
W
Me
R1
W
N
N
Synthesis 2002, No. 16, Print: 14 11 2002.
Art Id.1437-210X,E;2002,0,16,2450,2456,ftx,en;Z10002SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881
R2
R1
W
Scheme 3

PAPER
2,3-Dihydropyrrolizines from Weinreb 3-(Pyrrolidin-2-ylidene)propionamides
2451
Their partial or total cyclization to 14–16 took place spon-
Method A
taneously and, consequently, no attempt was made to iso-
This procedure (Scheme 4) is referable to those described late 11–13 from the reaction mixture and the process was
by other authors for the synthesis of pyrrolizinones start- continued at reflux in chloroform in the presence of silica
ing from ethyl pyrrolidin-2-ylideneacetate (3) and ethyl gel in order to obtain a complete transformation to pyr-
bromoacetate.5 In our case N-methoxy-N-methyl- -bro- rolizines 14–16 (Table 2).
moacetamide (4) was used, which, in THF–LDA, chiefly
produced C-alkylation in the enamine derivatives 1–3 to
give the key intermediates 5–7 (55–70%, Table 1). In the
said intermediates, which are secondary enamines, the de-
Although substrates analogous to 1–3 have been de-
scribed in which W is a carbonyl group,6 we have not used
them as starting products for the synthesis of 7-acyl-2,3-
dihydropyrrolizine derivatives 17–18. These were pre-
activation of the W function (8–10) was complete in the
pared by reaction of their analogous cyano derivatives 14
presence of organometallic compounds (R1MgX, R1Li,
with organolithium reagents (Scheme 5). The adequate
DIBAL) and the Weinreb amide reacted selectively to
selection of the two stages in which organometallic com-
give the carbonyl compounds 11–13 without limitations
pounds are used, potentially gives great versatility to this
simple synthetic sequence.
in the nature of the incorporated substituent (R1 = H,
alkyl, ethenyl, ethynyl, aryl or masked function). Normal-
ly, a strict control of the temperature and proportion of re-
agents is unnecessary and it is advisable to use
tetrahydrofuran as the solvent.
Method B
The ketonic intermediates 11–13 were obtained as a mix- The second procedure (Scheme 6) is an extension of our
ture of Z/E isomer olefins in a push–pull equilibrium. own method developed from -functionalized enamines
Table 1 Preparation and Physical Data of Enaminesa 5–7, 25–29
Start
1 + 4
Conditions
Product (% Yield) Mp (°C)
IR (KBr) (cm–1)
1H NMR or 13C NMR (CDCl3), , J (Hz)
LDA–THF
–78 0 °C
5 (70)
6 (77)
90
67
2181,1668,
1622
1H NMR: 2.03 (m, 2 H, J = 7.4), 2.77 (t, 2 H, J = 7.4), 3.17 (s,
2 H), 3.19 (s, 3 H), 3.49 (t, 2 H, J = 7.4), 3.81 (s, 3 H), 6.61 (br
s, 1 H, NH)
2 + 4
3 + 4
LDA–THF
–78 0 °C
1659, 1596
1662, 1590
1H NMR: 1.95 (m, 2 H, J = 7.5), 2.59 (t, 2 H, J = 7.5), 3.15 (s,
3 H), 3.27 (s, 2 H), 3.51 (t, 2 H, J = 7.5), 3.60 (s, 3 H), 3.69 (s,
3 H), 8.21 (br s, 1 H, NH)
LDA–THF
–78 0 °C
7 (65)
87
1H NMR: 1.23 (t, 3 H, J = 7.1), 1.99 (m, 2 H, J = 7.4), 2.64 (t,
2 H, J = 7.4), 3.19 (s, 3 H), 3.30 (s, 2 H), 3.54 (t, 2 H, J = 7.4),
3.73 (s, 3 H), 4.09 (q, 2 H, J = 7.1), 8.25 (br s, 1 H, NH)
19 + 24 MeOH, re-
25 (31)
26 (82)
27 (52)
62
2194,1670,
1621
13C NMR: 23.4 (CH3), 30.0 (CH2), 32.3 (CH3), 48.1 (br, CH2),
61.0 (br, CH), 61.4 (CH3), 62.0 (CH), 121.7 (C), 149.9 (CH),
171.9 (C)
flux, 36 h
20 + 24 MeOH, re-
75
2178,1680,
1572
13C NMR: 18.9 (CH3), 23.2 (CH2), 30.5 (CH2), 32.6 (CH3),
49.1 (CH2), 58.8 (CH), 61.6 (CH3), 62.3 (CH), 122.4 (C), 159.2
(C), 172.8 (C)
flux, 7 h
21 + 24 MeOH, re-
133
1666,1538
1222, 759,
711
13C NMR:c 17.6 (CH3), 22.7 and 23.2 (CH2), 30.0 (CH2), 32.5
(CH3), 48.9 and 49.2 (CH2), 58.7 (CH), 61.4 (CH3), 93.2 and
93.9 (CH), 127.1 (2 CH), 127.8 (2 CH), 130.1 (CH), 142.7 (C),
160.7 (C), 172.7 (C)
flux, 48 h
22 + 24 MeOH, re-
28 (51)
oil
89
1680,1610,
1143b
13C NMR: 13.9 (CH3), 22.8 (CH2), 29.4 (br, CH2), 31.6 (CH3),
46.6 (br, CH2), 57.9 (CH2), 60.8 (CH3), 61.0 (br, CH), 147.4
(CH), 168.4 (C), 171.7 (br, C)
flux, 40 h
23 + 24 Et3N–CH2Cl2 29 (48)
1695,1646,
1541
13C NMR: 20.0 (CH3), 22.9 (CH2), 29.9 and 30.1 (CH2), 32.2
(CH3), 48.1 and 48.4 (CH2), 58.1 (CH), 61.4 (CH3), 81.5 and
82.1 (CH), 96.3 and 97.0 (CH), 155.7 (C), 161.4 (C), 164.6 (C),
171.5 and 172.4 (C)
r.t., 24 h
a Satisfactory microanalyses were obtained: C 0.30, H 0.30, N 0.30.
b Film.
c Undetected C=O.
Synthesis 2002, No. 16, 2450–2456 ISSN 0039-7881 © Thieme Stuttgart · New York

2452
L. Calvo et al.
PAPER
Table 2 Preparation of 2,3-Dihydropyrrolizines (14–16, 35–39) from 5–7, 19–23
Reaction with organometallic compounds
Cyclization
Start
R1M
Ratio
Temp
(°C)
Time
(min)
Solvent
reflux
Time
(min)
W
R1
R2
Pyrrolizine
(% Yield)a
c
5
5
5
5
5
5
DIBALH
MeLi
1:2.5
1:2.5
1:3
–40
–40
15
-
–
CN
CN
CN
CN
CN
CN
H
–
–
–
–
–
–
14a (50)
14b (83)
14c (40)
14f (60)
14g (56)
14i (49)
15
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
45
45
45
120
45
Me
Et
EtBrMg
PhC CLi
PhLi
0
20
60b
30
1:2.5
1:2.5
1:3
0
PhC C
Ph
–40
0
15
20
60b
O
O
O
O
MgBr
5
1:2.5
–40
15
CHCl3
45
CN
–
14j (99)
S
S
Li
S
S
6
6
6
CH2=CHLi
BuC CLi
1:2.5
1:3
–30
–40
–40
30
30
30
CHCl3
CHCl3
CHCl3
45
45
45
CO2Me
CO2Me
CO2Me
CH2=CH
–
–
–
15d (44)
15e (75)
15h (80)
BuC C
1:2.5
Li
S
S
c
7
7
DIBALH
MeLi
1:2.5
1:2.5
1:2.5
1:1.5
1:2.5
1:1.5
1:3
–40
–40
–40
–40
0
15
15
10
25
90
30
40
80
60
60
20
90
15
-
–
CO2Et
CO2Et
CO2Et
CN
H
–
16a (53)
16b (74)
16g (67)
35b (92)
35f (65)
36b (81)
36e (95)
36f (72)
36k (87)
37b (67)
38b (61)
38f (53)
39b (79)
c
-
–
Me
–
7
PhLi
CHCl3
Toluene
Toluene
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
Toluene
Toluene
Xylene
90
60
60
60
60
60
60
30
60
60
60
Ph
–
19
19
20
20
20
20
21
22
22
23
MeLi
Me
H
PhC CLi
MeLi
CN
PhC C
Me
H
–40
0
CN
Me
Me
Me
Me
Me
H
BuC CLi
PhC CLi
HC CLi
MeLi
CN
BuC C
PhC C
HC Cb
Me
1:2.5
1:3
0
CN
r.t.
–40
–40
0
CN
1:3
COPh
CO2Et
CO2Et
MeLi
1:1.5
1:2.5
1:1.5
Me
PhC CLi
MeLi
PhC C
H
–40
O
Me
O
N
Me
a Yield from 5–7, 19–23.
b Ultrasonic bath.
c Spontaneous cyclization.
and Weinreb -amino amides4 (Scheme 2). The principal (e.g. MeLi and RC CLi) allowed us to prepare the ke-
difference is that the key intermediates 25–29 are tertiary tones 30–34. The rest of the organolithium (PhLi, BuLi)
enamines and that the deactivation of the W group toward or dialkylmagnesium compounds (Bu2Mg) led to complex
the organometallic reagents is only partial (compare struc- reaction mixtures in which the transposition of the meth-
tures 8–10 in Scheme 4 with 25 –29 in Scheme 6). As a oxy group occurred in a high proportion.4 Moreover, nei-
consequence, control of the selective reaction of the ther were the results of the alkylmagnesium halides
Weinreb amide group with organometallic reagents was effective, given that at low temperatures no evolution of
less satisfactory than with the secondary enamines 5–7. 25–29 was observed and at high temperatures the process
Only the less basic organolithium compounds at –40 °C could not be controlled.
Synthesis 2002, No. 16, 2450–2456 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
2,3-Dihydropyrrolizines from Weinreb 3-(Pyrrolidin-2-ylidene)propionamides
2453
conformation for cyclization is favoured. On the other
hand, the pyrrolizine 39, fused to a pyranone, was only
obtained at high temperatures by means of xylene reflux.
OMe
N
Me
W
THF, LDA
N
OMe
+
Br
Me
O
-78 → 0ºC
N
H
O
4
1 W = CN
2 W = CO2Me
3 W = CO2Et
N
W
OMe
N
L
OMe
N
H
5 W = CN,
70%
+
R2
Me
6 W = CO2Me, 77%
7 W = CO2Et, 65%
Me
N
N
H2
O
W
O
Br
R2
19-23
24
R1M
25-29
W
R1
19, 21 L= N(CH2)4
20, 22 L= NH2
23 L= Br
W
1. R1M
2. H2O
O
W
N
N
H
OMe
N
O
N
N
R1
W
H
R1
R1M
O
δ
N
Me
N
OMe
O
- H2O
O
11-13(a-j)
R2
Me
R2
25´-29´
a R1 = H
b R1 = Me
c R1 = Et
d R1 = CH=CH2
e R1 = C≡CBu
f R1 = C≡CPh
g R1 = Ph
30-34(a-d)
W
δ
8-10
W
W
N
11, 14 W = CN
- H2O
R1M
OMe
h =
12, 15 W = CO2Me
13, 16 W = CO2Et
S
R1
O
R1
W
i =
j =
14-16(a-j)
O
N
CONHMe
N
S
S
R2
40 W = CN
R2
W
35-39(a-d)
Scheme 4
19, 25, 30, 35 W= CN, R2= H
20, 26, 31, 36 W= CN, R2= Me
21, 27, 32, 37 W= COPh, R2= Me
22, 28, 33, 38 W= CO2Et, R2= H
b R1= Me
O
R1M
1. R2Li
2. H3O+
e R1= C≡CBu
f R1= C≡CPh
k R1= C≡CH
CN
1
R2
N
N
23, 29, 34, 39 W-R2= CO2CMe=CH
R1
R1
Scheme 6
14b
14g
17 R1 = Me, R2 = Bu; 75%
18 R1 = Ph, R2 = Me; 81%
In short, Method B presented greater limitations than
Method A in the incorporation of the R1 group via organo-
metallic reagents. However, the advantage was that enam-
ines 19–23 were more accessible and varied than the 2-
methylidenepyrrolidines 1–3, in which the nitrogenated
exchange to 25–28 occurred easily in refluxing methanol.
In the 4-amino-6-methyl-2H-pyran-2-one the amino sub-
stituent was an inefficient leaving group. Consequently,
the 4-bromo derivative 23 was used and its reaction with
the -aminocarboxamide 24 was carried out at 20 °C in
dichloromethane–triethylamine to give 29.
Scheme 5
As in the Method A the ketonic intermediates 30–34 were
not isolated from the reaction mixture. Their cyclization
conditions to pyrrolizines 35–39 not only depended on the
reactivity of the carbonyl group (COMe > COCCR), but
also on the nature of R2. The structures with R2 = H re-
quired more vigorous cyclization conditions (reflux of tol-
uene in the presence of silica gel) than their analogues
with R2 = Me (reflux of chloroform in the presence silica-
gel). A simple explanation for this phenomenon can be
found in the conformational stability with regard to theen-
amine bond C–N: as the size of R2 increases, the adequate
Table 3 Physical Dataa for Pyrrolizines 14–18, 35–39 and Enamino Nitrile 40b
Product Mp or bp IR (KBr) (cm–1)
(°C)
1H NMR (CDCl3), , J (Hz)
13C NMR (CDCl3),
14a
62
2217, 1550, 1300
2.55 (m, 2 H, J = 7.3), 2.93 (t, 2 H, J = 7.3), 24.1 (CH2), 27.0 (CH2), 47.2 (CH2), 83.7 (C),
3.97 (t, 2 H, J = 7.3), 6.36 (d, 1 H, J = 2.8), 115.1 (CH), 115.2 (CH), 117.2 (C), 145.1 (C)
6.53 (d, 1 H, J = 2.8)
14b
73
2208, 1532, 1428, 1303 2.16 (s, 3 H), 2.55 (m, 2 H, J = 7.4), 2.96 (t, 11.6 (CH3), 24.6 (CH2), 27.0 (CH2), 45.2
2 H, J = 7.4), 3.86 (t, 2 H, J = 7.4), 6.07 (s, (CH2), 82.9 (C), 111.8 (CH), 117.7 (C),
1 H)
124.6 (C), 143.9 (C)
Synthesis 2002, No. 16, 2450–2456 ISSN 0039-7881 © Thieme Stuttgart · New York

2454
L. Calvo et al.
PAPER
Table 3 Physical Dataa for Pyrrolizines 14–18, 35–39 and Enamino Nitrile 40b (continued)
Product Mp or bp IR (KBr) (cm–1)
(°C)
1H NMR (CDCl3), , J (Hz)
13C NMR (CDCl3),
14c
84
2206, 1529, 1305
1.20 (t, 3 H, J = 7.5), 2.50 (q, 2 H, J = 7.5), 12.7 (CH3), 19.6 (CH2), 24.4 (CH2), 27.0
2.56 (m, 2 H, J = 7.2), 2.96 (t, 2 H, J = 7.2), (CH2), 45.3 (CH2), 82.9 (C), 110.4 (CH),
3.88 (t, 2 H, J = 7.2), 6.08 (s, 1 H)
117.7 (C), 131.0 (C), 143.9 (C)
14f
112
2219, 1474, 1144, 755, 2.61 (m, 2 H, J = 7.2), 3.04 (t, 2 H, J = 7.2), 25.0 (CH2), 26.6 (CH2), 46.5 (CH2), 78.0 (C),
691
4.09 (t, 2 H, J = 7.2), 6.67 (s, 1 H), 7.34–
7.41 (m, 5 H, Ar)
84.8 (C), 92.3 (C), 110.9 (C), 116.3 (C),
120.2 (CH), 122.3 (C), 128.3 (2 CH), 128.4
(CH), 131.1 (2 CH), 145.0 (C)
14g
14i
102
101
186
oil
2221, 1601, 1488, 1153, 2.59 (m, 2 H, J = 7.5), 3.03 (t, 2 H, J = 7.5), 24.3 (CH2), 27.2 (CH2), 47.7 (CH2), 84.8 (C),
757, 692
4.15 (t, 2 H, J = 7.5), 6.55 (s, 1 H), 7.26–
7.43 (m, 5 H, Ar)
112.8 (CH), 117.1 (C), 126.0 (2 CH), 127.1
(CH), 128.8 (2 CH), 130.0 (C), 131.4 (C),
146.3 (C)
2207, 1530, 1396, 1142, 1.93 (m, 2 H), 2.55 (m, 2 H, J = 7.4), 2.61 20.6 (CH2), 24.5 (CH2), 27.0 (CH2), 32.6
1031
(m, 2 H), 2.96 (t, 2 H, J = 7.4), 3.82–4.01
(m, 4 H, AA BB ), 3.88 (t, 2 H, J = 7.4),
4.90 (t, 1 H, J = 4.5), 6.10 (s, 1 H)
(CH2), 45.4 (CH2), 64.9 (2CH2), 83.1 (C),
103.2 (CH), 111.2 (CH), 117.6 (C), 128.4
(C), 144.1 (C)
14j
15d
15e
15h
16a
16b
16g
17
2214, 1420, 1300, 767
1.82–2.20 (m, 2 H), 2.55 (m, 2 H, J = 7.3), 24.4 (CH2), 24.9 (CH2), 26.9 (CH2), 31.3 (2
2.86–3.05 (m, 4 H), 2.96 (t, 2 H, J = 7.3), CH2), 42.0 (CH), 47.1 (CH2), 84.2 (C), 114.4
4.15 (t, 2 H, J = 7.4), 5.18 (s, 1 H), 6.44 (s, (CH), 116.9 (C), 125.6 (C), 146.1 (C)
1 H)
1701, 1228, 1085, 774c 2.52 (m, 2 H, J = 7.4), 3.04 (t, 2 H, J = 7.4), 25.2 (CH2), 26.6 (CH2), 46.4 (CH2), 50.7
3.77 (s, 3 H), 4.01 (t, 2 H, J = 7.4), 5.00 (d, (CH3), 107.1 (C), 109.9 (CH2), 111.9 (CH),
1 H, J = 11.5), 5.37 (d, 1 H, J = 17.8), 6.43 126.1 (CH), 127.3 (C), 144.8 (C), 165.3 (C)
(dd, 1 H, J = 11.5, 17.8), 6.62 (s, 1 H)
185/0.1
mmHg
1711, 1229, 1087, 722 c 0.94 (t, 3 H, J = 7.2), 1.47 (m, 2 H), 1.54
13.6 (CH3), 19.2 (CH2), 21.9 (CH2), 26.3
(m, 2 H), 2.41 (t, 2 H, J = 7.0), 2.52 (m, 2 (CH2), 26.6 (CH2), 30.7 (CH2), 46.0 (CH2),
H, J = 7.3), 3.07 (t, 2 H, J = 7.3), 3.77 (s, 3 50.9 (CH3), 71.3 (C), 92.9 (C), 106.8 (C),
H), 3.96 (t, 2 H, J = 7.3), 6.68 (s, 1 H)
110.8 (C), 117.4 (CH), 144.0 (C), 165.1 (C)
143
27
1686, 1206, 1093, 767
1699, 1246, 1122, 714
1697, 1210, 1081, 767
2.59 (m, 2 H, J = 7.3), 3.13 (t, 2 H, J = 7.3), 25.6 (CH2), 26.9 (CH2), 47.1 (CH2), 50.9
3.81 (s, 3 H), 4.16 (t, 2 H, J = 7.3), 6.78 (s, (CH3), 107.5 (C), 111.5 (CH), 122.4 (CH),
1 H), 7.01–7.27 (m, 3 H, Ar)
123.3 (C), 123.4 (CH), 127.5 (CH), 134.8
(C), 144.9 (C), 165.4 (C)
1.32 (t, 3 H, J = 7.1), 2.51 (m, 2 H, J = 7.4), 14.4 (CH3), 25.4 (CH2), 26.9 (CH2), 46.7
3.04 (t, 2 H, J = 7.4), 3.94 (t, 2 H, J = 7.4), (CH2), 59.1 (CH2), 106.9 (C), 113.3 (CH),
4.24 (q, 2 H, J = 7.1), 6.52 (d, 1 H, J = 2.9), 114.5 (CH), 143.8 (C), 165.1 (C)
6.58 (d, 1 H, J = 2.9)
58
1.31 (t, 3 H, J = 7.1), 2.16 (s, 3 H), 2.50 (m, 11.6 (CH3), 14.5 (CH3), 25.8 (CH2), 26.8
2 H, J = 7.3), 3.05 (t, 2 H, J = 7.3), 3.83 (t, (CH2), 44.8 (CH2), 59.0 (CH2), 106.1 (C),
2 H, J = 7.3), 4.22 (q, 2 H, J = 7.1), 6.26 (s, 109.9 (CH), 123.9 (C), 142.5 (C), 165.3 (C)
1 H)
94
1693, 1248, 1184, 1090, 1.34 (t, 3 H, J = 7.1), 2.52 (m, 2 H, J = 7.4), 14.5 (CH3), 25.5 (CH2), 27.1 (CH2), 47.4
761, 697
3.11 (t, 2 H, J = 7.4), 4.12 (t, 2 H, J = 7.4), (CH2), 59.3 (CH2), 107.7 (C), 111.3 (CH),
4.27 (q, 2 H, J = 7.1), 6.79 (s, 1 H), 7.21– 125.8 (2 CH), 126.4 (CH), 128.6 (2 CH),
7.46 (m, 5 H, Ar)
129.3 (C), 132.4 (C), 145.2 (C), 165.1 (C)
195/1
1645, 1523, 1428c
0.91 (t, 3 H, J = 7.3), 1.36 (m, 2 H, J = 7.3 11.5 (CH3), 13.9 (CH3), 22.5 (CH2), 26.5
mmHg
and J = 7.4), 1.64 (m, 2 H, J = 7.4 and
J = 7.5), 2.16 (s, 3 H), 2.52 (m, 2 H,
(CH2), 26.8 (CH2), 27.0 (CH2), 39.4 (CH2),
44.6 (CH2), 109.5 (CH), 116.5 (C), 124.2
J = 7.4), 2.62 (t, 2 H, J = 7.5), 3.08 (t, 2 H, (C), 141.8 (C), 196.0 (C)
J = 7.4), 3.82 (t, 2 H, J = 7.4), 6.26 (s, 1 H)
18
109
1643, 763, 694
2.42 (s, 3 H), 2.60 (m, 2 H, J = 7.3), 3.19 (t, 26.2 (CH2), 27.2 (CH2), 27.7 (CH3), 47.2
2 H, J = 7.3), 4.17 (t, 2 H, J = 7.3), 6.77 (s, (CH2), 111.1 (C), 118.0 (C), 126.0 (2 CH),
1 H), 7.25–7.49 (m, 5 H, Ar)
126.8 (CH), 128.8 (2 CH), 129.6 (C), 132.3
(C), 144.7 (C), 193.4 (C)
Synthesis 2002, No. 16, 2450–2456 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
2,3-Dihydropyrrolizines from Weinreb 3-(Pyrrolidin-2-ylidene)propionamides
2455
Table 3 Physical Dataa for Pyrrolizines 14–18, 35–39 and Enamino Nitrile 40b (continued)
Product Mp or bp IR (KBr) (cm–1)
(°C)
1H NMR (CDCl3), , J (Hz)
13C NMR (CDCl3),
35b
67
2210, 1718, 1504, 770
2.08 (s, 3 H), 2.50 (m, 2 H, J = 7.2), 2.73 (t, 9.8 (CH3), 22.6 (CH2), 27.6 (CH2), 46.8
2 H, J = 7.2), 3.94 (t, 2 H, J = 7.2), 6.99 (s, (CH2), 96.2 (C), 112.6 (C), 117.0 (C), 120.3
1 H) (CH), 135.0 (C)
35f
86
2218, 1689, 751, 689
2.56 (m, 2 H, J = 7.3), 2.95 (t, 2 H, J = 7.3), 23.8 (CH2), 27.1 (CH2), 47.5 (CH2), 80.9 (C),
4.01 (t, 2 H, J = 7.3), 7.04 (s, 1 H), 7.30–
7.52 (m, 5 H, Ar)
91.9 (C), 98.6 (C), 99.5 (C), 115.5 (C), 121.4
(CH), 123.2 (C), 127.8 (CH), 128.1 (2 CH),
131.2 (2 CH), 141.9 (C)
36b
36e
88
98
2202, 1428
2211, 1423
2.04 (s, 3 H), 2.28 (s, 3 H), 2.48 (m, 2 H,
J = 7.1), 2.72 (t, 2 H, J = 7.1), 3.79 (t, 2 H, (CH2), 44.7 (CH2), 94.2 (C), 111.2 (C), 117.4
J = 7.1)
9.9 (CH3), 11.2 (CH3), 22.9 (CH2), 27.5
(C), 131.3 (C), 132.5 (C)
0.94 (t, 3 H, J = 7.2), 1.48 (m, 2 H), 1.58
(m, 2 H), 2.29 (s, 3 H), 2.40 (t, 2 H,
11.2 (CH3), 13.7 (CH3), 19.3 (CH2), 21.9
(CH2), 24.0 (CH2), 27.1 (CH2), 31.0 (CH2),
J = 7.0), 2.51 (m, 2 H, J = 7.1), 2.86 (t, 2 H, 45.4 (CH2), 72.0 (C), 92.4 (C), 96.1 (C), 98.9
J = 7.1), 3.83 (t, 2 H, J = 7.1) (C), 116.3 (C), 132.0 (C), 139.2 (C)
36f
120
2213, 1489, 758, 692
2.28 (s, 3 H), 2.51 (m, 2 H, J = 7.3), 2.90 (t, 11.2 (CH3), 24.1 (CH2), 26.9 (CH2), 45.4
2 H, J = 7.3), 3.84 (t, 2 H, J = 7.3), 7.27–
7.49 (m, 5 H, Ar)
(CH2), 81.4 (C), 91.6 (C), 96.0 (C), 97.9 (C),
116.0 (C), 123.4 (C), 127.7 (CH), 128.1 (2
CH), 131.1 (2 CH), 132.6 (C), 140.1 (C)
36k
37b
149
109
3253, 2209, 2101, 1405, 2.31 (s, 3 H), 2.54 (m, 2 H, J = 7.3), 2.90 (t, 11.2 (CH3), 24.0 (CH2), 26.9 (CH2), 45.5
615
2 H, J = 7.3), 3.14 (s, 1 H), 3.87 (t, 2 H,
J = 7.3)
(CH2), 75.7 (CH), 79.6 (C), 96.5 (C), 96.9
(C), 115.7 (C), 132.5 (C), 141.1 (C)
1623, 1421, 1375, 730, 1.93 (s, 3 H), 2.09 (s, 3 H), 2.45 (m, 2 H,
11.6 (CH3), 12.6 (CH3), 22.7 (CH2), 27.1
699
J = 7.2), 2.74 (t, 2 H, J = 7.2), 3.79 (t, 2 H, (CH2), 44.3 (CH2), 106.3 (C), 123.8 (C),
J = 7.2), 7.36–7.69 (m, 5 H, Ar)
128.0 (2 CH), 128.8 (2 CH), 129.7 (C), 130.9
(CH), 133.2 (C), 141.8 (C), 193.9 (C)
38b
38f
175/0.4
mmHgd
1703, 1233, 1079c
1.31 (t, 3 H, J = 7.1), 2.19 (s, 3 H), 2.41 (m, 10.7 (CH3), 14.0 (CH3), 22.1 (CH2), 27.1
2 H, J = 7.2), 2.69 (t, 2 H, J = 7.2), 3.86 (t, (CH2), 46.0 (CH2), 58.6 (CH2), 110.8 (C),
2 H, J = 7.2), 4.21 (q, 2 H, J = 7.1), 7.16 (s, 117.2 (C), 119.0 (CH), 135.0 (C), 165.3 (C)
1 H)
86
3135, 2213, 1694, 1212 1.36 (t, 3 H, J = 7.1), 2.51 (m, 2 H, J = 7.3), 14.4 (CH3), 24.0 (CH2), 27.1 (CH2), 47.2
2.95 (t, 2 H, J = 7.3), 3.98 (t, 2 H, J = 7.3), (CH2), 59.7 (CH2), 83.7 (C), 90.8 (C), 96.8
4.30 (q, 2 H, J = 7.1), 7.22 (s, 1 H), 7.23– (C), 120.0 (CH), 120.2 (C), 124.4 (C), 127.3
7.53 (m, 5 H, Ar)
(CH), 128.1 (2CH), 131.2 (2 CH), 143.0 (C),
164.2 (C)
39b
40
168
oil
1703, 1630, 1485, 1312 2.24 (s, 3 H), 2.28 (s, 3 H), 2.54 (m, 2 H,
10.0 (CH3), 19.8 (CH3), 22.2 (CH2), 27.6
J = 7.2), 2.80 (t, 2 H, J = 7.2), 3.90 (t, 2 H, (CH2), 44.0 (CH2), 94.0 (CH), 108.4 (C),
J = 7.2), 6.08 (s, 1 H)
109.3 (C), 134.6 (C), 137.2 (C), 154.2 (C),
161.2 (C)
3353, 2194, 1680, 1582, 2.04 (m, 2 H), 2.14 (s, 3 H), 2.24 (m, 2 H), 18.0 (br, CH3), 21.9 (CH2), 25.8 (CH3), 35.8
1539 c
2.84 (d, 3 H, J = 4.8), 3.25 (s, 3 H), 3.50
(m, 2 H), 4.07 (s, 1 H), 7.01 (q, 1 H, NH,
J = 4.8)
(CH2), 49.5 (CH3), 51.1 (CH2), 66.6 (CH),
95.2 (C), 121.1 (C), 159.1 (C), 171.5 (C).
a Satisfactory microanalyses were obtained: C 0.30, H 0.30, N 0.30.
b Compound selected from series 40.
c Film.
d With decomposition.
The NMR spectra of the 25–29 series presented broad sig- brium between the two pseudo-planar conformations of
nals with a low magnetic response and, on occasions, du- the enamine group (C=CNR2) plays an important role in
plicated. The Z/E push–pull equilibrium appears to be the number and type of NMR signals. Only the chemical
insufficient for the explanation of this phenomenon, given behaviour of the enamines 25–29, capable of transforming
that this was also observed in the cyclic compound 29, to 35–39 via 30–34, allowed us to confirm their structure
with a single configuration. This suggests that the equili- and to overcome the ambiguity and difficulty of the spec-
Synthesis 2002, No. 16, 2450–2456 ISSN 0039-7881 © Thieme Stuttgart · New York

2456
L. Calvo et al.
PAPER
11.6 mmol) and Et3N (3.08 mL, 22.2 mmol) in anhyd CH2Cl2 (40
mL) was stirred at r.t. for 24 h. H2O (40 mL) was added, then de-
canted, and the aq layer was extracted with CH2Cl2 (2 50 mL).
The combined organic layer was dried (Na2SO4) and evaporated to
dryness. The residue was chromatographed (silica gel; CH2Cl2–
THF, 5:1) to give 29.
troscopic assignment. For this reason, in the characteriza-
tion of the compounds 25–29 (Table 1) only the 13C NMR
spectra are included which are simpler and better defined
than the 1H NMR spectra.
Mps were measured on a Reichert–Jung Thermo Galen and are un-
corrected. IR spectra were obtained on a Perkin–Elmer 1720 X
spectrometer. NMR spectra were recorded on a Bruker AC300
spectrometer, and chemical shifts are given downfield from SiMe4
as an internal standard; 13C NMR spectra were carried out with
Yield: 1.35 g (5.1 mmol, 48%).
2,3-Dihydropyrrolizines 14–16(a–j) from 5–7 or 35–39(b–k)
from 25–29; General Procedure
To a magnetically stirred solution of amides 5–7, 25–29 (2.22
mmol) in anhyd THF (35 mL) was added dropwise the organome-
tallic compound under nitrogen (see Table 2). At the end of the re-
action (monitored by TLC), the mixture was hydrolyzed. The
organic layer was decanted, washed with water, dried (Na2SO4) and
evaporated. The carbonyl intermediates 11–13(a–j) or 30–34(b–k)
were not isolated and the concentrate underwent cyclization treat-
ment.
1
complete H decoupling and the assignments were made by addi-
tional DEPT experiments.
The starting compounds were purchased from the usual suppliers
(20) or prepared by literature procedures. Pyrrolidin-2-ylideneace-
tonitrile (1) was synthesized from 5-ethoxy-3,4-dihydro-2H-pyrrole
and methyl cyanoacetate;7 methyl pyrrolidin-2-ylideneacetate (2)
from 5-ethoxy-3,4-dihydro-2H-pyrrole and Meldrum’s acid,7,8 and
ethyl pyrrolidin-2-ylideneacetate (3) from pyrrolidine-2-thione and
ethyl bromoacetate.5The preparation of enamines 19, 21, 22 in-
volves the condensation of ammonia or pyrrolidine with corre-
sponding -keto nitriles, -keto esters or -diketones.2 The
halogenation of 4-hydroxy-6-methyl-2H-pyran-2-one with phos-
phorus tribromide gives 4-bromo-6-methyl-2H-pyran-2-one (23).9
The N-methoxy-N-methylprolinamide (hydrobromide derivative)
(24) was obtained from their Cbz-derivative10 by deprotection with
HBr in HOAc (33%) and precipitation in anhyd Et2O.11
The previously mentioned reaction mixtures of 11–13(a–j) or 30–
34(b–k) (ca. 2.2 mmol) and silica gel (5 w/w) in appropriate sol-
vent (50 mL) were heated in a rotary evaporator, slowly distilling
the solvent (see Table 2). The silica gel was filtered off and washed
thoroughly with hot acetone. The solvent was removed in vacuo,
and the concentrate was recrystallized from hexane–toluene (36e,
36f, 36k, 39b) or chromatographed [silica gel; CH2Cl2 (35b, 35f,
38b, 38f); or CH2Cl2–Et2O (10:1) (36b, 37b)].
4-Acyl-3,4-dihydropyrrolizines (17–18) from 14b,g
N-Methoxy-N-methyl-3-(pyrrolidin-2-ylidene)propionamides
5–7 from 1–3; General Procedure
To a magnetically stirred solution of 14 (5.5 mmol) in anhyd THF
(100 mL) was added dropwise (30 min) the organolithium com-
pound (11 mmol) under nitrogen. At the end of the reaction (30–60
min, monitored by TLC), aq HCl (10%; 5 mL) was added, and the
mixture was stirred rapidly at r.t. overnight. Then it was extracted
with CH2Cl2 (2 50 mL), dried (Na2SO4) and evaporated to dry-
ness. The residue was chromatographed (silica gel using; CH2Cl2–
Et2O, 15:1).
To a solution at –78 °C of pyrrolidine derivative 1–3 (7.10 mmol)
in THF (7 mL) was added dropwise LDA (10.65 mmol) in THF (10
mL) over a 40 min period followed by a 30 min stirring period. Then
N-methoxy-N-methylbromoacetamide (4) (2.20 g, 12.07 mmol, in
10 mL of THF) was added slowly and stirring was continued for 2
h at –78 °C. The reaction mixture was allowed to warm to 0 °C,
stirred for another 6 h, hydrolyzed with aq HCl (5%), and neutra-
lized with solid NaHCO3. The THF was removed with a rotary
evaporator and the residue was extracted with CH2Cl2 (3 70 mL).
The combined CH2Cl2 layers were washed twice with brine, dried
(Na2SO4) and concentrated. The residue was chromatographed (sil-
ica gel; CH2Cl2–Et2O, 5: 1).
References
(1) Kuckländer, U. The Chemistry of Enamines, In The
Chemistry of Functional Groups, Part 1; Rappoport, Z., Ed.;
Wiley: New York, 1994, 523–636.
(2) Lue, P.; Greenhill, J. V. Adv. Heterocycl. Chem. 1997, 67,
207.
(3) Greenhill, J. V.; Ramli, M.; Tamassini, T. J. Chem. Soc.,
Perkin Trans. 1 1975, 588.
(4) Alberola, A.; González, A.; Sádaba, M. L.; Sañudo, C.
Tetrahedron 1999, 55, 6555.
(5) Pinick, H. W.; Chang, Y. J. Org. Chem. 1978, 43, 4662.
(6) Roth, M.; Dubs, P.; Götschi, E.; Eschenmoser, A. Helv.
Chim. Acta 1971, 54, 710.
(7) Fasseur, D.; Cauliez, P.; Couturier, D. J. Heterocycl. Chem.
1994, 31, 829.
(8) Fasseur, D.; Rigo, B.; Leduc, C.; Cauliez, P.; Couturier, D.
J. Heterocycl. Chem. 1992, 29, 1285.
Weinreb N-Vinylprolinamides 25–28 from 19–22; General Pro-
cedure
A mixture of enamine 19–22 (10.5 mmol) and N-methoxy-N-meth-
ylprolinamide (hydrobromide derivative) (24) (2.51 g, 10.5 mmol)
in MeOH (25 mL) was stirred at 40 °C for the times given in
Table 1. At the end of the reaction, monitored by TLC, the solution
was concentrated in vacuo, and the residue was dissolved in
CH2Cl2–H2O (1:1; 100 mL). The aq layer was extracted with
CH2Cl2 (2 50 mL) and the combined organic layer was dried
(Na2SO4) and evaporated to dryness. The residue was chromato-
graphed (silica gel; CH2Cl2–Et2O; 10:1 for 25, 26 and 28; 1:1 for
27).
(9) Cervera, M.; Moreno-Mañas, M.; Pleixats, R. Tetrahedron
1990, 46, 7885.
(10) Fahrentz, J. A.; Castro, B. Synthesis 1983, 676.
(11) Ben-Ishai, D. J. Org. Chem. 1954, 18, 62.
N-(6-Methyl-2-oxo-2H-pyran-4-yl)proline N -Methoxy-N -me-
thylamide (29)
A mixture of 4-bromo-2H-pyran-2-one (2 g, 10.6 mmol), N-meth-
oxy-N-methylprolinamide (hydrobromide derivative) (24) (2.77 g,
Synthesis 2002, No. 16, 2450–2456 ISSN 0039-7881 © Thieme Stuttgart · New York