L -Proline-Catalyzed Cyclization of 6-Aminopyrimidine-4(3 H)-ones with Nitroolefins: Synthesis of Polysubstituted 5-Arylpyrrolo[2,3- d ]pyrimidin-4-ones

Article abstract of DOI:10.1055/s-0036-1588757

A simple and efficient one-pot procedure for the synthesis of new pyrrolo[2,3- d ]pyrimidine derivatives has been established through an l -proline-catalyzed cyclization of 6-aminopyrimidine-4(3 H)-one with nitroolefins in water. The reaction at 80 °C in water gives various highly substituted pyrrolo[2,3- d ]pyrimidines in good to excellent yields. This procedure has the advantages of environmental friendliness, good yields, and convenient operation.

Full text of DOI:10.1055/s-0036-1588757

SYNLETT
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2
1
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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–F
letter
A
C. Li, F. Zhang
Letter
Synlett
L-Proline-Catalyzed Cyclization of 6-Aminopyrimidine-4(3H)-ones
with Nitroolefins: Synthesis of Polysubstituted 5-Arylpyrrolo[2,3-
d]pyrimidin-4-ones
Chunmei Li
O
O
Ar
Furen Zhang*
HN
HN
NO2
R
L-proline (10 mol%)
H2O, 80 °C
Ar
School of Chemistry and Chemical Engineering, Zhejiang Key
Laboratory of Alternative Technologies for Fine Chemicals
Process, Shaoxing University, Shaoxing, Zhejiang Province
312000, P. R. of China
N
H
H2N
N
NH2
H2N
N
R
Ar = phenyl bearing various H, F, Cl, Br,
Me, OMe, NO2 groups and 2-thienyl
R = Me, Et
frzhang@usx.edu.cn
10 examples prepared, up to 90% yield
NH2
Received: 04.01.2017
Accepted after revision: 26.02.2017
Published online: 13.03.2017
O
COOH
NC
H
N
H
N
HN
COOH
DOI: 10.1055/s-0036-1588757; Art ID: st-2017-w0009-l
O
O
N
N
H
HO
N
H2N
N
Abstract A simple and efficient one-pot procedure for the synthesis of
new pyrrolo[2,3-d]pyrimidine derivatives has been established through
an L-proline-catalyzed cyclization of 6-aminopyrimidine-4(3H)-one with
nitroolefins in water. The reaction at 80 °C in water gives various highly
substituted pyrrolo[2,3-d]pyrimidines in good to excellent yields. This
procedure has the advantages of environmental friendliness, good
yields, and convenient operation.
HO
OH
Type I Pemetrexed (Pmx)
Type II Toyocamycin
NH2
Cl
HN
COOH
H
N
H
N
N
O
N
H
H2N
N
OMe
COOH
N
O
Key words proline, nitroalkenes, organocatalysis, cyclization, pyrrolo-
HN
pyrimidinones, Michael addition
N
N
N
O
Me
Pyrrolo[2,3-d]pyrimidines, as an important class of het-
erocyclic compounds, have attracted increased attention in
both the organic chemistry and pharmaceutical communi-
ties, due to the presence of these moieties in numerous nat-
urally occurring products,1 synthetic drugs,2 and industrial
materials.3 A survey of the literature revealed the presence
of a pyrrolo[2,3-d]pyrimidine core in many promising phar-
maceuticals that exhibit a broad spectrum of biological ac-
tivities, such as antiviral,4 antiinflammatory,5 antifolate,6
antitumor,7 antibacterial,8 antifungal,9 or receptor tyrosine
kinase-inhibitory activities.10 Representative examples
(Figure 1) include pemetrexed (Pmx; Alimta), a unique anti-
folate used in the treatment of hematological malignancies
and solid tumors (Type I);11 toyocamycin, a naturally occur-
ring nucleoside antibiotic (Type II);12 TNP-351, a strong in-
hibitor of dihydrofolate reductase that has been applied
clinically as an anticancer agent (Type III);13 and PF-
06459988, which functions as a third-generation epidermal
growth factor receptor inhibitor (Type IV).14
Type III TNP-351
Type IV PF-06459988
Figure 1 Structures of biologically active pyrrolo[2,3-d]pyrimidine de-
rivatives
efficient synthetic methods or improving existing synthetic
routes to these substances, as well as to the introduction of
various substituents onto the core.15 Among these methods,
the Sonogashira reaction, followed by tandem cyclization in
a one- or two-pot manner, is the conventional approach to
constructing the pyrrolo[2,3-d]pyrimidine scaffold.2b–d,16
Some other strategies have also been developed for the syn-
thesis of these heterocycles. For example, Taylor and Liu re-
ported the synthesis of derivatives of 5-arylpyrrolo[2,3-
d]pyrimidine by a four-step process in modest yields.17 Re-
cently, Thakur and co-workers reported the synthesis of 5-
arylpyrrolo[2,3-d]pyrimidines in a one-pot two-step man-
ner from an aminopyrimidine and nitrostyrenes.18 Despite
these advances, most of these approaches suffer from one
or more drawbacks such as the need for a transition-metal
catalyst, the use of a strong base or acid, the use of hazard-
ous or expensive reagents, multistep sequences, or the need
In view of their interesting properties, the chemistry of
pyrrolopyrimidines has been developed significantly, and
considerable efforts have been devoted to developing more
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

B
C. Li, F. Zhang
Letter
Synlett
Table 1 (continued)
for special apparatus, which are not compatible with some
biological applications, are uneconomical, or are not eco-
friendly. Consequently, there still remains a necessity to de-
velop a new environmentally friendly method to realize the
preparation of polysubstituted pyrrolo[2,3-d]pyrimidines.
L-Proline, as a versatile organocatalyst, has been effec-
tively used for C–C bond formation in various organic trans-
formations.19 In a continuation of our efforts to develop
new methods for the synthesis of useful heterocyclic blocks
from common starting materials,20 we recently reported
the synthesis of tetrahydro-4H-indol-4-one derivatives
through an L-proline-catalyzed domino approach.20a Here,
we wish to report a cyclization for the synthesis of new pyr-
rolo[2,3-d]pyrimidine derivatives by using L-proline as a
catalyst in water. To the best of our knowledge, this conve-
nient and efficient procedure has not been reported before.
Initially, we examined the reaction of 2,6-diaminopy-
Entry
Solvent
Catalyst (mol%)
Temp (°C) Yieldb (%)
7
8c
H2O
pyridine (10)
K2CO3 (10)
80
80
<10
–
H2O
9
H2O
L-proline (20)
L-proline (5)
L-proline (10)
L-proline (10)
L-proline (10)
L-proline (10)
L-proline (10)
L-proline (10)
L-proline (10)
L-proline (10)
L-proline (10)
L-proline (10)
80
84
56
62
71
80
40
33
41
37
17
44
84
10
11
12
13
14
15
16
17
18
19c
20
H2O
80
MeOH
EtOH
reflux
reflux
80
HO(CH2)2OH
chloroform
THF
reflux
reflux
80
DMF
MeCN
toluene
H2O
reflux
80
60
rimidin-4(3H)-one
with
[(1E)-(2-nitroprop-1-en-1-
H2O
100
yl)]benzene as a model reaction for optimization of the
conditions. As is well known, the selection of an appropri-
ate catalyst is of critical importance for the synthesis of het-
erocyclic compounds. First, the model substrates were
mixed in water in the absence of any catalyst; unfortunate-
ly, the desired product was not obtained, even after 24
hours at 80 °C (Table 1, entry 1). However, when L-proline
(10 mol%) was added as a catalyst, 2-amino-6-methyl-5-
phenyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one
(3a) was obtained in 82% yield after two hours (entry 2).
Subsequently, various other catalysts (DL-alanine, triethyl-
amine, 4-dimethylaminopyridine, N-methylmorpholine,
pyridine, and potassium carbonate) were tested for the re-
action in water (entries 3–8). However, none of these cata-
lysts showed a better catalytic activity than L-proline under
the same experimental conditions. Screening of the
amount of catalyst showed that 10 mol% of L-proline was
sufficient to push the reaction forward successfully (entries
2, 9 and 10).
a Reaction conditions: 1 (0.5 mmol), 2a (0.5 mmol), solvent (2.5 mL), 2 h.
b Isolated yield.
c Reaction time: 24 h.
Next, we repeated the model reaction in various sol-
vents (Table 1, entries 11–18), and we found that reactions
in protic solvents gave higher yields than did those in non-
protic solvents and that the reaction in water gave the high-
est yield (entry 2). The same model reaction was then car-
ried out at temperatures of 60, 80, and 100 °C for two hours.
The yield of product 3a rose from 44% to 82% when the
temperature was increased from 60 to 80 °C (entries 2 and
19), but then almost leveled off when the temperature was
increased further to 100 °C (entry 20); 80 °C is therefore a
suitable temperature, and a higher temperature is not nec-
essary.
The generality of the protocol was explored by using the
optimized conditions (Scheme 1).21 A range of nitroolefins
bearing various substituents, including electron-deficient
and electron-rich groups on the aromatic ring, were sub-
jected to the reaction to examine the efficiency and appli-
cability of the method. The reaction was found to be com-
patible with various nitroolefin substrates with either elec-
tron-withdrawing groups (such as halide or nitro) or
electron-donating groups (such as methyl or methoxy).22
We also noted that nitroolefins bearing electron-withdraw-
ing groups gave higher yields than did those bearing elec-
tron-donating groups. We attributed the high activities of
nitroolefins bearing electron-deficient groups to the low
electronic cloud density at their α-carbon atoms. Particu-
larly noteworthy was the fact that the heterocyclic nitroole-
fin [(1E)-2-(2-nitroprop-1-en-1-yl)]thiophene tolerated
this procedure and gave the corresponding product in 80%
yield. Additionally, the substrate [(1E)-1-chloro-4-(2-nitro-
but-1-en-1-yl)]benzene gave the corresponding product, 2-
Table 1 Optimization of the Conditions for the Model Reactiona
O
O
HN
NO2
HN
+
H2N
N
NH2
N
H
H2N
N
1
2a
3a
Entry
Solvent
Catalyst (mol%)
Temp (°C) Yieldb (%)
1c
2
3
4
5
6
H2O
H2O
H2O
H2O
H2O
H2O
–
80
80
80
80
80
80
–
L-proline (10)
DL-alanine (10)
Et3N (10)
DMAP (10)
NMM (10)
82
52
33
21
<10
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

C
C. Li, F. Zhang
Letter
Synlett
O
O
N
Ar
HN
NO2
HN
L-proline (10 mol%)
H2O, 80 °C
Ar
R
+
H2N
N
NH2
N
H
R
H2N
1
2
3
F
Cl
Br
O
O
N
O
O
O
HN
HN
HN
HN
HN
N
H
H2N
N
N
H
H2N
N
H
N
H
N
H
H2N
N
H2N
N
H2N
N
3a, 82%
3b, 90%
3c, 83%
3d, 80%
3e, 79%
Cl
OMe
Cl
NO2
O
N
S
O
O
O
O
Cl
HN
HN
HN
HN
HN
N
H
H2N
N
H
N
H
H2N
N
N
H
H2N
N
N
H
H2N
N
H2N
N
3f, 77%
3g, 83%
3h, 79%
3i, 80%
3j, 76%
Scheme 1 Synthesis of products 3. Reagents and conditions: 1 (0.5 mmol), 2 (0.5 mmol), L-proline (10 mol%), H2O (2.5 mL), 80 °C, 2 h.
amino-5-(4-chlorophenyl)-6-ethyl-3,7-dihydro-4H-pyrro-
lo[2,3-d]pyrimidin-4-one (3j), in 76% yield, which high-
lighted the wide scope of this condensation.
However, the reaction of optionally substituted [(E)-(2-
nitrovinyl])benzenes 4a–c with 2,6-diaminopyrimidin-
4(3H)-one (1) under the same conditions did not give the
With acceptable results in hand, we proceeded to probe
the substrate diversity of the reactions of 6-aminopyrimi-
dine-2,4(1H,3H)-dione (7a; X = O) or 6-amino-2-thioxo-
2,3-dihydropyrimidin-4(1H)-one (7b; X = S) with various
nitroolefins 2. To our delight, the reactions proceeded
smoothly and afforded the desired products in good yields
(Scheme 3). The reactions of 6-aminopyrimidine-
2,4(1H,3H)-dione (7a) with substituted nitroolefins bearing
electron-withdrawing groups such as fluoro, chloro, or bro-
mo worked well, and gave the corresponding products 8a–c
in 61–71% yields. 6-Amino-2-thioxo-2,3-dihydropyrimidin-
4(1H)-one (7b) reacted with a variety of substituted ni-
troolefins bearing either an electron-deficient group such
as fluoro or an electron-rich group such as methyl to give
the desired products 8d–f. The difference in bond strength
between C=O and C=S bonds might affect the activity of the
pyrimidine substrate. In addition, to further expand the
substrate scope, we examined the reaction of [(1E)-(2-ni-
troprop-1-ene-1,3-diyl)]dibenzene with 2,6-diaminopy-
rimidin-4(3H)-one (1); unfortunately, no target product
was obtained under the optimized conditions, probably as a
result of steric hindrance in the nitroolefin substrate.
expected
2-amino-5-aryl-3,7-dihydro-4H-pyrrolo[2,3-
d]pyrimidin-4-ones 5; instead, the corresponding 2,6-di-
amino-5-(2-nitro-1-arylethyl)pyrimidin-4(3H)-ones 6a–c
were obtained in 70–75% yield (Scheme 2). The active pro-
ton-bearing nitro group probably destabilized the cyclic in-
termediate, indirectly impeding the elimination of the nitro
group.
O
Ar
HN
O
N
H
H2N
N
L-proline
(10 mol%)
5
HN
O
Ar
NO2
+
Ar
H2O, 80 °C
H2N
N
NH2
NO2
HN
1
4
H2N
N
NH2
Ar = Ph, 6a (70%)
Ar = 4-MeC6H4, 6b (72%)
Ar = 4-MeOC6H4, 6c (75%)
Scheme 2 The synthesis of unexpected 2,6-diamino-5-(1-aryl-2-nitro-
ethyl)pyrimidin-4(3H)-ones
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

D
C. Li, F. Zhang
Letter
Synlett
and smoothly obtained in good yields by controlling the re-
action process. The structures of all products and interme-
O
O
Ar
L-proline
(10 mol%)
HN
1
diates were determined by H and 13C NMR spectroscopy
HN
NO2
+
Ar
H2O, 80 °C
X
N
H
NH2
N
H
and high-resolution mass spectrometry.
X
N
H
7
2
8
O
N
Ph
O
Br
Cl
F
NO2
NO2 L-proline (10 mol%)
H2O, 80 °C, 0.5 h
HN
HN
Ph
+
H2N
NH2
H2N
N
NH2
O
O
O
1
2a
9 (67%)
HN
HN
HN
Scheme 4 Control experiment with 2,6-diaminopyrimidin-4(3H)-one
N
H
N
H
N
H
O
N
H
O
N
H
O
N
H
O
Ar
O
8a (71%)
8b (65%)
8c (61%)
NO2
HN
NO2 L-proline (10 mol%)
H2O, 80 °C, 0.5 h
HN
+
Ar
F
O
N
H
NH2
O
N
H
NH2
O
O
Ar = Ph, 10a (70%)
Ar = 2-thienyl, 10b (58%)
2
O
7a
HN
HN
HN
Scheme 5 Control experiment with 6-aminopyrimidine-2,4(1H,3H)-di-
one
N
N
N
N
S
S
N
H
H
H
S
N
H
H
H
8d (71%)
8e (73%)
8f (54%)
On the basis of the above experimental results and a re-
port in the literature,23 a mechanism for the reaction is pro-
posed as shown in Scheme 6. 2,6-Diaminopyrimidin-4(3H)-
one (1) first condenses with the nitroolefin 2 to generate
intermediate A; this reaction is catalyzed by L-proline as an
acid catalyst. Subsequently, electron transfer yields the
enamine intermediate B. This undergoes further transfor-
mation into intermediate 11, which can be separated in a
good yield (Schemes 1 and 4). Intramolecular nucleophilic
addition of B then gives adduct C; in this reaction, the ami-
no group is activated by L-proline, which facilitates nucleo-
philic attack. Finally, aromatization of intermediate C oc-
curs with elimination of H2O and HNO to give the target
product 3.
Scheme 3 Expanding the scope of the pyrimidine substrate
Generally, the reactions proceeded rapidly to comple-
tion within two hours at 80 °C. In most cases, the desired
products were obtained in good yields after workup of the
mixture with water and ethanol. However, we also noted
that lower reaction temperatures or shorter reaction times
could lead to the generation of Michael addition products.
Ring-opening product 9 were obtained when the time for
the reaction of diamine 1 with nitroolefin 2a was reduced
to 30 minutes (Scheme 4), and the same products, with dif-
ferent yields, were also obtained when the reaction tem-
perature was reduced to 50 °C for two hours. The corre-
sponding reaction of the amino dione 7a with nitroolefins 2
(R = Ph, 2-thienyl) at 80 °C for 30 minutes similarly gave the
corresponding Michael addition products 10a and 10b
(Scheme 5). Products 9 and 10 can therefore be separately
In summary, we have established novel protocols for
rapid access to 2-amino-5-aryl-6-alkyl-3,7-dihydro-4H-
pyrrolo[2,3-d]pyrimidin-4-ones 3, 6-methyl-5-aryl-1,7-di-
hydro-2H-pyrrolo[2,3-d]pyrimidine-2,4(3H)-diones 8a–c,
O
N
Ar
OH
NO2
O
O
N
Ar
N
OH
N
Ar
N
HN
O
R
HN
HN
O
2
R
R
H2N
NH2
H2N
N
NH2
H2N
COO
H
N
H
COO
H
B
A
N
H2
1
O
N
O
O
Ar
Ar
Ar
H
R
NO2
HN
HN
HN
R
OH
R
N
N
H
– H2O
– HNO
N
H
H2N
H2N
N
H2N
N
NH2
OH
11
C
3
Scheme 6 Proposed mechanism for the formation of pyrrolo[2,3-d]pyrimidin-4-ones 3
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

E
C. Li, F. Zhang
Letter
Synlett
and 6-methyl-5-aryl-2-thioxo-1,2,3,7-tetrahydro-4H-pyr-
rolo[2,3-d]pyrimidin-4-ones 8d–f. The reactions are easy to
perform under concise conventional heating conditions. A
plausible reaction mechanism for such reaction was pro-
posed and partially confirmed by control experiments. This
approach has a broad substrate scope and excellent func-
tional-group tolerance, permitting the rapid construction
of highly functionalized products from readily available
starting materials. Undoubtedly, this strategy provides a
straightforward pathway to construct biologically and
pharmacologically interesting target molecules in an effec-
tive manner.
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Acknowledgment
We are grateful for financial support from the Foundation of Educa-
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

F
C. Li, F. Zhang
Letter
Synlett
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(21) 2-Amino-5-aryl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-
ones 3; General Procedure
A mixture of 2,6-diaminopyrimidin-4(3H)-one (1, 0.5 mmol),
the appropriate nitroolefin 2 (0.5 mmol), and L-proline (10
mol%) in H2O (2.5 mL) was heated at 80 °C for the appropriate
time then cooled to r.t. The mixture was diluted with cold H2O
(30 mL), and the solid was collected by filtration, washed with
H2O and 95% EtOH, dried, and crystallized from 95% EtOH to
give the pure product 3.
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2016, 26, 992.
(22) 2-Amino-5-(4-methoxyphenyl)-6-methyl-3,7-dihydro-4H-
pyrrolo[2,3-d]pyrimidin-4-one (3f)
Prepared by following the general procedure from 2,6-diamino-
pyrimidin-4(3H)-one (1, 0.5 mmol) and 1-methoxy-4-[(1E)-2-
nitroprop-1-en-1-yl]benzene (0.5 mmol) as a pale-yellow solid;
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Synthesis 2006, 3238. (d) He, Y.-H.; Cao, J.-F.; Li, R.; Xiang, Y.;
Yang, D.-C.; Guan, Z. Tetrahedron 2015, 71, 9299.
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Liang, X.; Zhang, F.; Qi, C. Catal. Commun. 2015, 62, 6. (c) Zhang,
F.; Li, C.; Wang, C.; Qi, C. Org. Biomol. Chem. 2015, 13, 5022.
(d) Chen, Z.; Shi, Y.; Shen, Q.; Xu, H.; Zhang, F. Tetrahedron Lett.
2015, 56, 4749; highlighted in Synfacts 2015, 11, 1118. (e) Li, C.;
Zhang, F.; Yang, Z.; Qi, C. Tetrahedron Lett. 2014, 55, 5430. (f) Li,
C.; Zhang, F. RSC Adv. 2016, 6, 75359. (g) Li, C.; Zhang, F.; Qi, C.
RSC Adv. 2016, 6, 102924.
1
yield: 104.5 mg (77%); mp >300 °C. H NMR (400 MHz, DMSO-
d6): δ = 10.94 (s, 1 H, NH), 10.16 (s, 1 H, NH), 7.33 (d, J = 8.0 Hz, 2
H, ArH), 6.88 (d, J = 8.4 Hz, 2 H, ArH), 6.00 (br s, 2 H, NH2), 3.76
(s, 3 H, OMe), 2.17 (s, 3 H, CH3). 13C NMR (100 MHz, DMSO-d6):
δ = 158.9, 157.4, 152.3, 151.1, 131.3, 127.6, 123.0, 113.2, 98.0,
+
55.4, 12.1. HRMS (ESI): m/z [M + H]+ calcd for C14H15N4O2
:
271.1190; found: 271.1194.
(23) (a) Xie, M.-S.; Chu, Z.-L.; Niu, H.-Y.; Qu, G.-R.; Guo, H.-M. J. Org.
Chem. 2014, 79, 1093. (b) Maiti, S.; Biswas, S.; Jana, U. J. Org.
Chem. 2010, 75, 1674. (c) Guan, Z.-H.; Li, L.; Ren, Z. H.; Li, J.;
Zhao, M.-N. Green Chem. 2011, 13, 1664.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F