A highly stereocontrolled intramolecular cycloaddition reaction of azomethine ylide activated by a pyrimidine ring: Access to novel tricyclic hexahydro-1H-pyrrolo[2′,3′:4,5]pyrido[2,3-d]pyrimidines

Article abstract of DOI:10.1055/s-0031-1290333

A pyrimidine ring was discovered to aid formation of an azomethine ylide undergoing intramolecular cycloaddition reactions. This method enabled efficient synthesis of a novel tricyclic pyrimidine-piperidine-pyrrolidine scaffold from various pyri-midinemethyl amines and aldehydes in complete stereocontrol and could be rationalized by an S-shaped azomethine ylide intermediate. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290333

LETTER
585
A Highly Stereocontrolled Intramolecular Cycloaddition Reaction of
Azomethine Ylide Activated by a Pyrimidine Ring: Access to Novel Tricyclic
Hexahydro-1H-pyrrolo[2¢,3¢:4,5]pyrido[2,3-d]pyrimidines
Cycloaddition of
P
o
yrimidine-A
n
ctivated
A
zo
g
methine
Y
lid
x
e
s
iang Xie, Jinbao Xiang, Qun Dang,* Xu Bai*
The Center for Combinatorial Chemistry and Drug Discovery, The College of Chemistry and The School of Pharmaceutical Sciences,
Jilin University, 1266 Fujin Road, Changchun, Jilin 130021, P. R. of China
Fax +86(431)85188900; E-mail: xbai@jlu.edu.cn; E-mail: qdang@jlu.edu.cn
Received 26 October 2011
thine ylide and enable the subsequent productive 1,3-di-
Abstract: A pyrimidine ring was discovered to aid formation of an
polar cycloaddition reactions.7 In this case, the pyrimidine
ring acts both as a linker between the eventually formed
azomethine ylide and the dienophile, and as the activating
azomethine ylide undergoing intramolecular cycloaddition reac-
tions. This method enabled efficient synthesis of a novel tricyclic
pyrimidine–piperidine–pyrrolidine scaffold from various pyri-
midinemethyl amines and aldehydes in complete stereocontrol and group without metal coordination through a nitrogen atom
as reported.8 This reaction should produce tricyclic com-
could be rationalized by an S-shaped azomethine ylide intermedi-
ate.
pounds with several stereogenic centers in highly con-
Key words: azomethine ylide, intramolecular cycloaddition, 1,3-
dipolar cycloaddition, pyrimidine, pyrrolidine
trolled manners. Herein, the preliminary results of the
investigation are reported.
R5
R1
R1
1,3-Dipolar cycloaddition of azomethine ylide is one of
the most efficient approaches to prepare pyrrolidine deriv-
atives and has been extensively used in the synthesis of
natural products and biologically active molecules.1 In-
tramolecular azomethine ylide reactions can provide di-
rect access to polycyclic scaffolds of considerable
complexity with high to complete stereocontrol.2 Azome-
thine ylides are often generated from a secondary amine
and an aldehyde,2a however the amine usually must con-
tain an electron-withdrawing group1,2a,3 which serves dual
purposes: increasing the acidity of the a-proton to pro-
mote formation of the azomethine ylide and stabilizing the
resulting negatively charged carbon. Thus far, only a cou-
ple of cases of azomethine ylide reactions involving cyclic
amines with an aromatic ring that may serve as the direct
facilitating group have been reported.4
R4
R3
R2
R5
Cl
N
N
Cl
N
N
[3+2]
R4
N
N
N
R3
N
R2
Me
Me
R5CHO
Cl
N
R1
N
N
R4
H
N
R3
Me
R2
Scheme 1 Strategy for the synthesis of novel tricyclic compounds
A series of pyrimidines 4–10 were prepared in a four-step
sequence in 30–64% overall yields as depicted in
Scheme 2. For detailed reactions conditions please con-
sult the Supporting Information.
Pyrimidine is a well-known electron-deficient heterocycle
and has been widely utilized in the design of biologically
active agents,5 while pyrrolidine is frequently present
among natural products and pharmacologically active
molecules.6 Therefore, development of methodologies for
the synthesis of novel polycyclic scaffolds containing
both pyrimidine and pyrrolidine moieties should be of in-
terest to synthetic and medicinal chemists. In this context,
we envisaged a synthetic strategy to create novel tricyclic
pyrimidine–piperidine–pyrrolidine system via an in-
tramolecular 1,3-dipolar cycloaddition of azomethine
ylides (Scheme 1). In the outlined strategy, the pyrimidine
ring could play the dual roles of electron withdrawing and
charge delocalization to facilitate the formation of azome-
Treatment of 4 with benzaldehyde (1.2 equiv) for four
hours in refluxing toluene with removal of water using a
Dean–Stark trap yielded the desired product 11a in 89%
yield (entry 1, Table 1).9 Product 11a was characterized as
configured with phenyl and the two bridgehead hydrogen
atoms on the same side of the newly formed pyrrolidine
ring based on 1H NMR spectrum (J3a,9b = 3.6 Hz) and X-
ray analysis.10 Pyrimidine 4 (R1 = n-Bu) reacted with var-
ious aldehydes to produce exclusively analogously con-
figured products 11 as determined by comparison of their
1H NMR spectra (Table 1).
In general, aromatic aldehydes (including heterocyclic
and a,b-unsaturated aldehydes) participated in the current
reaction effectively to produce the desired products in
good to excellent yields (entries 1–13, Table 1). Both
SYNLETT 2012, 23, 585–588
Advanced online publication: 06.02.2012
DOI: 10.1055/s-0031-1290333; Art ID: W59611ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.
2
0
1
1

586
H. Xie et al.
LETTER
R4
Table 1 Cycloadditions of 4 via Pyrimidine-Stabilized Azomethine
Ylide
Cl
N
Cl
N
CHO
N
R4
HN
R3
N
CHO
R5
N
Me
R2
n-Bu
H
R3
Cl
N
Cl
N
N
Et3N, CHCl3,
0–5 °C, 30 min
H
Cl
Me
2a–d
R2
9b
n-Bu
R5CHO
N
N
N
H
1
3a
H
toluene, N2,
reflux (– H2O)
N
N
NaBH3CN,
AcOH, EtOH
Me
11a–p
Me
4
Cl
Cl
N
Entry
1
R5
Ph
Time (h) 11
Yield (%)
89
R1
R2
1) SOCl2,
CH2Cl2
N
N
R4
N
OH R4
H
4
11a
N
N
R3
N
R3
2) R1NH2
2
4-O2NC6H4
4-ClC6H4
3-ClC6H4
2-ClC6H4
4-MeC6H4
3-MeC6H4
2-MeC6H4
4-MeOC6H4
2-MeOC6H4
2-furanyl
4
11b
11c
11d
11e
11f
95
Me
Me
R2
3a–d
4–10
3
6.5
1
86
Scheme 2 Synthesis of substrates 4–10
4
93
5
4
97
electron-rich and electron-deficient aldehydes gave excel-
lent yields, suggesting that the current reaction is less sen-
sitive to electronic factors on the aromatic aldehydes. On
the other hand, 2-methoxybenzaldehyde gave lower yield
(entry 10, Table 1) compared to other benzaldehydes, sug-
gesting potential steric hindrance. In contrast, aliphatic
aldehydes failed in the current reaction with only cyclo-
hexanecarbaldehyde producing the desired product 11p in
51% yield (entry 16, Table 1). Ready enamine formation
for butyraldehyde might explain its failure to produce any
desired product,2a while pivalaldehyde might be just too
hindered sterically for the cycloaddition.
6
4
85
7
4
11g
11h
11i
97
8
7
97
9
5.5
83
10
11
12
13
36
11j
66
5
4
11k
11l
88
2-thienyl
83
(E)-2-phenylethenyl
3
11m
11n
11o
11p
95
This new intramolecular [3+2]-cycloaddition reaction
was further explored by varying the substituents in the 14
substrates (Table 2). Both aliphatic and aromatic groups
n-Pr
12
9
0a
15
t-Bu
0a
R3
R4
R5
R2
H
16
c-Hex
48
51
Cl
N
Cl
N
a Starting material 4 was recovered.
R1
R2
R5CHO
N
N
H
R4
N
N
R1
were suitable as R1 for the cycloaddition (entries 1–3,
Table 2). However, the reaction proceeded very slowly
when R1 was an aromatic group (entry 3, Table 2). This
was very likely due to the difficulty in forming the imini-
um ion between a secondary aromatic amine and an alde-
hyde. The reaction seemed very sensitive to R3 since no
product 11t was formed when R3 was a methyl group (en-
try 4, Table 2), while product 11u was obtained in a 46%
yield when R3 was a phenyl group (entry 5, Table 2). It is
interesting that the Baylis–Hillman adduct 10 could also
react with benzaldehyde to give the desired product 11v in
41% yield (entry 6, Table 2), which indicated that the ori-
entation of R3 group in substrate dictated the one of R3 in
product 11. The product structures of 11q and 11v were
unambiguously determined by X-ray crystal structure
analysis10 and the rest by 1H NMR spectra in comparison.
N
R3
N
Me
Me
4–10
12
R5
R1
H
Cl
N
R4
R3
H
N
R2
N
N
Me
11
H
H
H
H
H
Cl
Cl
H
H
H
H
N
N
N
N
N
N
N
N
Me
Me
The stereoselectivity of products 11 suggested that the
cycloaddition reaction proceeded exclusively via an S-
shaped azomethine ylide 12 as depicted in Scheme 3. The
12t
12u
Scheme 3 Possible reaction mechanism for the intramolecular
cycloaddition
Synlett 2012, 23, 585–588
© Thieme Stuttgart · New York

LETTER
Cycloaddition of Pyrimidine-Activated Azomethine Ylides
587
Table 2 Azomethine Ylide Cycloadditions of Pyrimidines 5–10
Ph
R1
H
Cl
N
Cl
N
N
R4
R3
H
R1
N
PhCHO
N
R4
N
H
R2
toluene, N2,
reflux (– H2O)
N
R3
N
Me
R2
Me
11q–v
5–10
Entry
5–10
R1
R2
H
H
H
H
H
R3
H
R4
H
Time (h)
11
Yield (%)
1
2
3
4
5
6
5
6
Me
i-Pr
Ph
1
23
60
1
11q
11r
11s
11t
11u
11v
75
59
32a
0b
H
H
7
H
H
8
Me
Me
Me
Me
Ph
H
H
9
H
1.5
1.5
46
41
10
CO2Me
Ph
a Starting material 7 (43%) was recovered.
b Starting material 8 decomposed.
results of entries 4 and 5 in Table 2 could be easily ex-
plained by the transition states shown in Scheme 3.
References and Notes
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© Thieme Stuttgart · New York
Synlett 2012, 23, 585–588

588
H. Xie et al.
LETTER
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data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Synlett 2012, 23, 585–588
© Thieme Stuttgart · New York

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