Cascade cyclization intermolecular dipolar cycloaddition by multi-component couplings-synthesis of indolizidines and pyrrolizidines

Article abstract of DOI:10.1016/j.tetlet.2008.07.010

A three-component coupling reaction of a primary amine (an amino-acid or amino-ester or hydroxylamine), an alkene or alkyne dipolarophile and an aldehyde bearing a halide as a leaving group has been developed. Condensation of the amine with the aldehyde and cyclization (intramolecular N-alkylation) provides, after decarboxylation or deprotonation, a cyclic azomethine ylide (or nitrone) that undergoes intermolecular dipolar cycloaddition with the dipolarophile. This sets up, in a single step, the bicyclic indolizidine or pyrrolizidine ring system, depending on the length of the tether between the aldehyde and the halide. The reaction is successful with stabilized and non-stabilized azomethine ylides that result from using primary amino-esters or amino-acids, respectively.

Full text of DOI:10.1016/j.tetlet.2008.07.010

Tetrahedron Letters 49 (2008) 5408–5410
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Cascade cyclization intermolecular dipolar cycloaddition by multi-component
couplings—synthesis of indolizidines and pyrrolizidines
a,*
a
a
b
Iain Coldham , Samaresh Jana , Luke Watson , Christopher D. Pilgram
a
Department of Chemistry, University of Sheffield, Brook Hill, Sheffield S3 7HF, UK
AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK
b
a r t i c l e i n f o
a b s t r a c t
Article history:
A three-component coupling reaction of a primary amine (an amino-acid or amino-ester or hydroxyl-
amine), an alkene or alkyne dipolarophile and an aldehyde bearing a halide as a leaving group has been
developed. Condensation of the amine with the aldehyde and cyclization (intramolecular N-alkylation)
provides, after decarboxylation or deprotonation, a cyclic azomethine ylide (or nitrone) that undergoes
intermolecular dipolar cycloaddition with the dipolarophile. This sets up, in a single step, the bicyclic ind-
olizidine or pyrrolizidine ring system, depending on the length of the tether between the aldehyde and
the halide. The reaction is successful with stabilized and non-stabilized azomethine ylides that result
from using primary amino-esters or amino-acids, respectively.
Received 10 June 2008
Accepted 1 July 2008
Available online 4 July 2008
Ó 2008 Elsevier Ltd. All rights reserved.
The dipolar cycloaddition reaction of azomethine ylides pro-
vides a convenient method to access substituted pyrrolidines,
dihydropyrroles and pyrroles.1 Various methods can be used to
generate the azomethine ylide, and many intermolecular examples
using activated dipolarophiles (typically alkenes or alkynes bearing
electron-withdrawing groups) have been reported. The chemistry
can be applied to bicyclic products using intramolecular cycloaddi-
tions, in which the dipolarophile is tethered to the azomethine
CHO
110—136 °C
–6
N
MR3
n
n
Cl
Cl
1
2
Z
Z
N
N
7
–24
n
n
ylide.
An alternative way to access bicyclic products was
3
4
reported by Pearson and co-workers, in which a cyclization gener-
ates the azomethine ylide that undergoes intermolecular cyclo-
addition with a dipolarophile.25 In this chemistry, the aldehydes
Scheme 1. Pearson’s cyclization–cycloaddition chemistry.3 n = 1–3; MR
SiMe ; Z = electron-withdrawing group.
3
3
= SnBu or
3
1
were treated with (tributylstannyl)methylamine or (trimethyl-
silyl)methylamine to give the imines 2 (Scheme 1). Heating with
the dipolarophile promoted cyclization and demetalation to give
the azomethine ylides 3, which undergo cycloaddition to the bicy-
clic amines 4.
would be amenable to using amino-acids or esters. We report here
the successful demonstration of this chemistry.
The aldehyde 1 (n = 1) was prepared by a method that was
25
slightly different from that used by Pearson and co-workers. In
Recently, we used this type of chemistry in an intramolecular
cycloaddition to give three rings in a single transformation and
our case, we alkylated the commercially available isobutyronitrile
with LDA and 1-bromo-3-chloropropane and then reduced the
nitrile 5, n = 1, with DIBAL-H (Scheme 2). This method was unsuit-
able for the analogue 1, n = 0 and it was better to alkylate
isobutyronitrile with 2-bromoethyl-trimethylsilyl ether followed
by desilylation with HCl to give the intermediate alcohol that
was converted to the chloride 5 (n = 0) with N-chlorosuccinimide
2
6
applied it to the total synthesis of several Aspidosperma alkaloids.
In this work, we found that simple amino-acids or amino-esters
could be used in place of the stannyl- or silyl-methylamines. This
has advantages as it avoids the use of the metal species and allows
ready access to different substituted products by using readily
available amino-acid starting materials. We therefore considered
whether the cyclization—intermolecular cycloaddition chemistry
(
1
NCS) and PPh
, n = 0.
Heating the aldehyde 1, n = 1, with glycine and a selection of
3
. Reduction with DIBAL-H then gave the aldehyde
dipolarophiles in toluene for 24 h resulted in the formation of
*
Corresponding author. Tel.: +44 (0) 114 222 9428; fax: +44 (0) 114 222 9346.
E-mail address: i.coldham@sheffield.ac.uk (I. Coldham).
the desired cycloadducts 6–10 (Scheme 3, Table 1, Fig. 1). The best
0
040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.07.010

I. Coldham et al. / Tetrahedron Letters 49 (2008) 5408–5410
5409
Z
Z
i
CN
ii
CHO
CHO
CN
N
n
n
Cl
H2N
CO2H
Cl
Cl
PhMe, heat
1
(n=0)
11—12
5
1
Scheme 4. Cyclization/cycloaddition of 1, n = 0 with glycine.
Scheme 2. Preparation of the aldehyde 1; Reagents and condition: (i) For n = 1:
LDA, THF, À78 °C, then ClCH CH CH Br, 86%; or for n = 0: LDA, THF, À78 °C, then
TMSOCH CH Br, 98%, then HCl, room temperature, 86%, then NCS, PPh , THF, 81%;
ii) DIBAL-H, CH
2
2
2
2
2
3
(
Cl
2 2
, n = 1: 88%, n = 0: 56%.
We next attempted cycloadditions with alanine (Scheme 5).
Suprafacial cycloaddition onto cis-disubstituted dipolarophiles (di-
methyl maleate and N-methylmaleimide) could give rise to four
possible stereoisomeric products. However, only two stereoiso-
mers were obtained in each case. Previously, the reactions with
glycine (Scheme 3) gave two stereoisomers; it is likely therefore
Z
Z
CHO
N
H N
CO H
2
2
that the methyl substituent
a- to the nitrogen atom prefers one
PhMe, heat
Cl
1
(n=1)
6—10
of the two configurations (i.e., cycloaddition through the S- or
1
W-shaped azomethine ylide). Using H NMR COSY and NOESY
Scheme 3. Cyclization/cycloaddition of 1, n = 1, with glycine.
(
plus coupling constants), we were able to determine that the
cycloadducts from reaction with N-methylmaleimide had the
structures 14a and 14b. These arise from cycloaddition through
the S-shaped azomethine ylide. The stereochemistry of the
cycloadducts 13a and 13b is assumed, based on the expected
preference for cycloaddition through the S-shaped ylide.
Table 1
Yields for reaction of aldehydes 1 with glycine
1, n
Dipolarophile CH
2
@CHZ
Producta
Yield
dr
Heating the aldehydes 1 (n = 1 or 0) with glycine ethyl ester and
various dipolarophiles in the multi-component cyclization/cyclo-
addition for 18–24 h provided the expected bicyclic and tricyclic
amine products 15–20 (Scheme 6, Table 2, Fig. 2). Of the four
possible stereoisomeric products 15, only three stereoisomers
1
1
1
1
1
0
0
N-Methylmaleimide
N-Phenylmaleimide
Dimethyl maleate
Phenyl vinyl sulfone
Methyl acrylate
6
7
8
70
63
63
53
66
48
52
1:1
1:1
1:1
1.5:1:1:1
2:1.5:1:1
1:1
9
10
11
12
N-Methylmaleimide
Dimethyl maleate
1:1
a
See Figure 1.
CO Me
CO Me
2
H
2
H
H N
CO H
2
CHO
(n=1)
2
+
CO Me
CO Me
2
2
PhMe, heat
N
N
O
CO Me
R
O
CO Me
2
Me
O
Me
2
Cl
1
H
N
H
N
13a
13b
N
CO Me
2
CO Me
O
2
Me
O
Me
Me
N
H
H
O
N
N
6
R=Me
R=Ph
8
+
7
O
O
N
N
O
Me
Me
Me
14a
14b
SO Ph
H
2
H
H
N
N
+
SO Ph
Scheme 5. Cyclization/cycloaddition with alanine; for dimethyl maleate, 51%, dr
.2:1; for N-methylmaleimide, 52%, dr 1.3:1 (14a:14b).
2
O
N
N
1
9
a
H
N
9b
11
CO Me
CO2Me
CO Me
2
H
H
Z
Z
+
CO Me
CHO
2
2
N
N
N
n
Cl•H N
CO Et
PhMe, Pr NEt, heat
n
3
2
10a
10b
12
i
CO Et
2
Cl
2
1
n=1 15—18
Figure 1. Structures of cycloadducts 6–12.
n=0 19—20
Scheme 6. Cyclization/cycloaddition with glycine ethyl ester.
yields were obtained using an excess (4 M equiv) of glycine and a
slight excess (1.5 M equiv) of the dipolarophile. No products were
isolated when heating using a microwave or using THF or water
as the solvent. With symmetrical dipolarophiles, a mixture of
two stereoisomers of the indolizidine ring products (6–8) was
formed without any selectivity. With unsymmetrical dipolaro-
philes, a mixture of regio- and stereoisomers was obtained (9
and 10).
Table 2
Yields for reaction of aldehydes 1 with glycine ethyl ester
1, n
Dipolarophile
Producta
Yield
dr
1
1
1
1
0
0
N-Methylmaleimide
Dimethyl maleate
Methyl acrylate
DMAD
N-Methylmaleimide
Dimethyl maleate
15
16
17
18
19
20
94
74
77
2.2:2:1
2.5:1:1
3.4:2.4:1
1:0
7:2:1
15:2:1
Cyclization/cycloaddition of the aldehyde 1, n = 0, was also
attempted with glycine and various dipolarophiles and resulted
in the formation of the pyrrolizidine ring products 11 and 12
b
45
73
62
(Scheme 4, Table 1, Fig. 1). As before, a mixture of isomeric prod-
a
See Figure 2.
Cycloaddition at room temperature.
b
ucts was formed.

5
410
I. Coldham et al. / Tetrahedron Letters 49 (2008) 5408–5410
O
CO2Me
CO2Me
NH OH·HCl
2
H
N
H
N
2
Me
O
CO Me
2
iPr NEt, PhMe
H
N
CHO
+
CO Me
CO2Me
CO2Me
2
heat, 24 h
CO Me
O
O
2
N
N
N
CO Me
2
Cl
1 (n=1)
2
1a
21b
CO Et
CO Et
CO Et
CO2Me
2
2
2
15
16
17
O
N
Scheme 7. Cyclization/cycloaddition with hydroxylamine; 77%, dr 1.6:1.
Me
O
CO Me
2
CO Me
H
N
2
H
CO Me
CO Me
2
2
N
N
In summary, we have demonstrated that various amines can be
added to the aldehydes 1 (n = 1 or 0) to generate cyclic 1,3-dipoles
that undergo intermolecular cycloaddition with activated dipol-
arophiles. The amines glycine, alanine, glycine ethyl ester and
hydroxylamine all reacted successfully. The chemistry provides
an efficient multi-component synthesis of substituted indolizi-
dines and pyrrolizidines. Further examples, including other types
of aldehyde substrates, are currently under investigation and will
be reported in due course.
CO2Et
CO2Et
CO2Et
18
19
20a
Figure 2. Structures of cycloadducts 15–20.
C9
C8
C12
C7
Acknowledgements
C10
C13
C6
N2
O2
C4
O4
We thank the Royal Society for an International Incoming
Fellowship (IIF-2007/R1), the EPSRC and AstraZeneca for support
of this work. We are grateful to Brian Taylor for NMR spectra
including NOESY experiments and Harry Adams for X-ray crystal
structure analysis (CCDC- 690593).
C3
H
O
O
C16
N
C15
C14 O3
C5
N
CO2Et
C2
Me
N1
C1
C11
15
O1
Figure 3. X-ray crystal structure of the major isomer of compound 15.
References and notes
1.
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(
separable) were obtained. The major stereoisomer was crystalline,
and X-ray crystal structure analysis revealed that the product was
the stereoisomer shown in Figure 3. This is the endo adduct from
the S-shaped ylide, although two other stereoisomers were formed
in similar amounts.
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1
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1
1
1
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acetylene dicarboxylate (DMAD) was best carried out by heating
the aldehyde 1, n = 1, with glycine ethyl ester at 60 °C for 2 h then
cooling to room temperature and addition of DMAD. This gave the
dihydropyrrole product 18 as a single stereoisomer (determined by
13. Warner, D. L.; Hibberd, A. M.; Kalman, M.; Klapars, A.; Vedejs, E. J. Org. Chem.
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2
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H NMR NOESY). Cycloadditions to give the pyrrolizidine ring sys-
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stereoisomer (Table 2, n = 0). In line with the previous examples,
the major isomer for compound 20 was found (by H NMR NOESY)
7
2, 4135.
1
1
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2
0a). Separation of the isomers was possible by column chroma-
2
tography, and compound 20a was isolated in 52% yield.
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In addition to the above, we have carried out the cyclization/
cycloaddition sequence using hydroxylamine. This gives the inter-
mediate oxime and, after cyclization, the nitrone. Intermolecular
dipolar cycloaddition of 1 (n = 1) with dimethyl maleate gave the
cycloadducts 21 (Scheme 7). The stereoisomers were separable,
2
2
2. Coldham, I.; Pih, S. M.; Rabot, R. Synlett 2005, 1743.
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1
and H NMR NOESY indicated that the major stereoisomer was
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