Practical one-pot protocol for the syntheses of 2-chloro-pyrrolo[3,2-d] pyrimidines

Article abstract of DOI:10.1016/j.tet.2011.01.089

A novel one-pot protocol for the syntheses of 2-chloro-pyrrolo[3,2-d] pyrimidines was described. A series of 2-chloro-pyrrolo[3,2-d]pyrimidines were prepared from readily available starting materials in moderate to good yields using this methodology.

Full text of DOI:10.1016/j.tet.2011.01.089

Tetrahedron 67 (2011) 2803e2806
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Practical one-pot protocol for the syntheses of 2-chloro-pyrrolo[3,2-d]pyrimidines
,b,
Liwen Zhao a, Kemei Tao a, Haitian Li a, Jiancun Zhang a
*
a Guangzhou Institutes of Biomedicine and Health, CAS, 190 Kaiyuan Avenue, Science Park, Guangzhou 510530, China
b State Key Laboratory of Respiratory Diseases, Guangzhou Medical College, Guangzhou 510120, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel one-pot protocol for the syntheses of 2-chloro-pyrrolo[3,2-d]pyrimidines was described. A series
of 2-chloro-pyrrolo[3,2-d]pyrimidines were prepared from readily available starting materials in mod-
erate to good yields using this methodology.
Received 29 November 2010
Received in revised form 21 January 2011
Accepted 28 January 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Available online 3 February 2011
Keywords:
Pyrrolo[3,2-d]pyrimidines
2,4-Dichloro-5-nitropyrimidine
b
-Ketoesters
1,3-Dicarbonyl compounds
Suzuki coupling
1. Introduction
an enamine to a chloropyrimidine intermediate (route E).7,20 How-
ever, these methods suffered from either multiple steps, harsh re-
Construction of privileged chemical structures is an important
strategy in medicinal chemistry. Pyrimidine nucleus fused with
another heterocycle has shown diverse biological activities.1,2 In
1964, Imai reported preparation of pyrrolo[3,2-d]pyrimidines and
their activities against bacteria and protozoa.3,4 Recently, pyrrolo
[3,2-d]pyrimidines have attracted considerable interest due to their
remarkable pharmacological properties.5e11 However, there are
only a few reported literature examples for the synthesis of pyrrolo
[3,2-d]pyrimidines.12,13 Among these reports, Imai and Sokolova
published a series of papers describing the syntheses of pyrrolo
[3,2-d]pyrimidines by employing the Madelung cyclization as a key
step in the synthesis (Scheme 1, route A).3,7,14,15 The general method
involving the use of 3-amino-2-carboxylpyrroles proved to be very
useful and provided synthetic entries into several pyrrolopyr-
imidine analogues with various substitution patterns (route B).7,16
The pyrrolo[3,2-d]pyrimidine ring system was also prepared via
a Sonogashira reaction followed by a copper (I) iodide catalyzed
cyclization (route C).7,17 The fourth method developed for the syn-
theses of pyrrolo[3,2-d]pyrimidine derivatives by Otmar, used benzyl
as the arylmethyl substituent, which was introduced by prior alkyl-
ation of the 5-nitro-4(6)-(cyanomethyl)pyrimidines followed by re-
ductive cyclization (route D).11,18,19 The last method is based on the
work of Montgomery, wherein the key step involved the addition of
actionconditions, expensivereagents, ortedious workup procedures,
and thus there is a need to develop a more simple and direct method.
R2
Ο
O
O
NH
NH2
NH
N
OEt
+
R1
Route A
N
R1
N
OH
H2N
R1
N
+
Route B
Route C
EtO2C
N
R2
NH2
N
H
H
N
NH2
N
N
R2
R2
+
R1
N
R1
N
R1
N
N
Cl
R3
R2
NO2
CN
NO2
N
Route D
Route E
R1
R3
N
R1
N
R3
Cl
NO2
NO2
N
N
N
R2
+
R1
N
Cl
R1
N
R2
Scheme 1. Reported routes for the syntheses of pyrrolo[3,2-d]pyrimidines.
Herein, we report a new method for the syntheses of 2-chloro-
pyrrolo[3,2-d]pyrimidines from readily available 2,4-dichloro-5-
nitropyrimidine.21 These compounds can be further converted to
2-amino-pyrrolo[3,2-d]pyrimidines or 2-aryl-pyrrolo[3,2-d] py-
rimidines as depicted in Scheme 2.
* Corresponding author. Tel./fax: þ86 20 301532; e-mail address: zhang_jiancun@
gibh.ac.cn (J. Zhang).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.01.089

2804
L. Zhao et al. / Tetrahedron 67 (2011) 2803e2806
entries 1e9). This protocol can be extended to the 1,3-dicarbonyl
compounds as well (Table 2, entries 10 and 11).
Table 2
Preparation of 2-chloro-pyrrolo[3,2-d]pyrimidines
Entry
Substrate
Product
Yield (%)
61
1
Scheme 2. Our route for the syntheses of pyrrolo[3,2-d]pyrimidine derivatives.
2. Results and discussion
2
3
4
5
6
7
46
41
46
35
52
49
Initially, 2,4-dichloro-5-nitropyrimidine (1) and ethyl benzoy-
lacetate (2a) were chosen as the model substrates to survey the
reaction conditions of nucleophilic substitution including bases,
solvents, and reaction temperatures (Scheme 3). When a weak
base, such as potassium carbonate or Et3N, was used, the nucleo-
philic substitution did not complete overnight at rt in THF or eth-
anol. If the reaction conducted at the elevated temperatures at
50 ꢀC, the reaction system became complicated perhaps due to the
instability of 2,4-dichloro-5-nitropyrimidine. In contrast, when
NaH was used as the base, the reaction was completed in about 3 h
at ꢁ50 ꢀC in dry THF in 81% yield. Under this condition, the sub-
stitution reaction was region-selective to react mainly at the 4-
chloro position and only minor 2-subtituted product was formed.
HPLC analysis indicated that the ratio of isomers was 10:1, but the
desired major regio-isomer was not readily isolated by the column
chromatography. Without further purification, the compound 3
was converted into the 2-chloro-pyrrolo[3,2-d]pyrimidine through
a reductive cyclization process. A few reaction conditions including
SnCl2/HCl, Fe/HCl, Fe/NH4Cl, and Fe/AcOH were explored, and iron
powder in AcOH was found to be the optimal reductive cyclization
condition at 70 ꢀC, with up to 83% yield, as shown in Table 1.
8
9
63
53
Scheme 3.
Table 1
Reductive cyclization of nitropyrimide 3a
Entry
Reductive cyclization conditions
Yield of 5a (%)
1
2
3
4
5
SnCl2/HCl/rt/12 h
Fe/HCl/EtOH/rt/12 h
Fe/NH4Cl/EtOH/rt/12 h
Fe/AcOH/rt/12 h
11
68
35
75
83
10
11
55
58
Fe/AcOH/70 ꢀC/3 h
Under the optimized condition (1.1 equiv of NaH as the base,
3.0 equiv of FeeAcOH as the reductive cyclization reagents), the
scope of this one-pot protocol for the synthesis of 2-chloro-pyrrolo
[3,2-d]pyrimidines was investigated. As shown in Table 2, most of
the b-ketoesters examined afforded moderate to good yields (Table 2,

L. Zhao et al. / Tetrahedron 67 (2011) 2803e2806
2805
This one-pot reaction sequence is presumably involved first the
selective nucleophilic aromatic substitution at 4-Cl of the pyrimi-
dines, followed by reduction of nitro group by Fe/AcOH, and further
cyclization of the resulting amino group with the ketone group.
To test the reactivity of the 2-Cl group in 2-chloro-pyrrolo[3,2-d]
pyrimidines, a nucleophilic substitution was performed by an
amine as shown in Scheme 4. The desired amine-substituted
product 6f was obtained in a good yield (83%). A Suzuki coupling
reaction was also feasible for C-functionalization of pyrrolo[3,2-d]-
pyrimidine scaffold in position 2 (Scheme 5). These further modi-
fications allow the ready access of various important frameworks
with diverse substitutions.
(26 mg, 1.1 mmol), after stirring of the mixture for 15 min at rt, the
mixture was cooled down to ꢁ50 ꢀC. Then 2,4-dichloro-5-nitro-
pyrimidine (194 mg,1 mmol) in 1 mL of THF was added. The mixture
was stirred at ꢁ50 ꢀC for 3 h (TLC determination), then when
warmed to rt, Fe powder (3.0 equiv) and 3 mL of AcOH were added.
The mixture reacted for 3 h at 70 ꢀC. The resulting mixture was
cooled to rt and filtered. The solid was washed with methanol two
times (2ꢂ3 mL), and the combined filtrate was concentrated on the
rotary evaporator, and the residue was purified by column chro-
matography on silica gel using petroleum ether/ethyl acetate (3:1, v/
v)as the eluent to give the desired product 5a (pale yellow solid,
184 mg, 61%). Mp 176e177 ꢀC; 1H NMR (400 MHz, DMSO-d6):
d
13.04 (s,1H), 8.84 (s,1H), 7.68e7.70 (m, 2H), 7.52e7.56 (m, 3H), 4.19
(q, 2H, J¼7.2 Hz), 1.14 (t, 3H, J¼7.2 Hz); 13C NMR (100 MHz, DMSO-
d6): d 163.0, 153.2, 151.8, 151.4, 143.2, 130.7, 130.6, 130.0, 128.7, 126.8,
104.1, 60.3, 14.3; ESI-MS: m/z¼302.1 (MþHþ); HRMS: m/z 302.0693
(MþHþ, C15H13ClN3Oþ2 requires 302.0691), m/z 324.0507(MþNaþ,
C15H12ClN3NaOþ2 requires 324.0510).
4.2.2. Ethyl 2-chloro-6-(furan-2-yl)-5H-pyrrolo[3,2-d]pyramidine-
7-carboxylate (5b). Following the general procedure, the reaction
was performed with 1b (182 mg, 1.0 mmol) to afford 5b as a brown
solid (134 mg, 46%). Mp 204e205 ꢀC; 1H NMR (400 MHz, DMSO-
Scheme 4.
d6):
d
13.10 (s, 1H), 8.78 (s, 1H), 8.09 (d, 1H, J¼1.2 Hz), 7.81 (d, 1H,
J¼3.2 Hz), 6.82 (dd, 1H, J¼1.2, 3.2 Hz), 4.37 (q, 2H, J¼7.2 Hz), 1.34 (t,
3H, J¼7.2 Hz); 13C NMR (100 MHz, DMSO-d6):
d 163.1, 153.5, 151.3,
146.4, 144.4, 143.1, 139.6, 126.8, 117.7, 113.6, 102.2, 60.5, 14.8; ESI-
MS: m/z¼292.1 (MþHþ); HRMS: m/z 292.0487 (MþHþ,
C13H11ClN3Oþ3 requires 292.0483).
4.2.3. Ethyl 2-chloro-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carbox-
ylate (5c). Following the general procedure, the reaction was per-
formed with 1c (130 mg, 1.0 mmol) to afford 5c as a brown solid
(98 mg, 41%). Mp 142e143 ꢀC; 1H NMR (400 MHz, DMSO-d6):
Scheme 5.
3. Conclusions
d
12.55 (s, 1H, broad), 8.89 (1H, s), 4.30 (q, 2H, J¼3.2 Hz), 2.73 (s, 3H),
1.31 (t, 3H, J¼3.2 Hz); 13C NMR (125 MHz, DMSO-d6):
d 162.9, 153.7,
In summary, we have developed a novel one-pot procedure for
the syntheses of 2-chloro-pyrrolo[3,2-d]pyrimidines starting from
readily available 2,4-dichloro-5-nitropyrimidine. The resulting
2-chloro-pyrrolo[3,2-d]pyrimidines can be subjected to further
nucleophilic substitution or metal catalyzed cross-coupling to
provide chemical structures with more diversity. This strategy
provides an efficient method to access a library of compounds
based on pharmacologically privileged substructures.
150.0, 146.0, 140.4, 124.3, 99.9, 60.0, 14.8, 11.3; ESI-MS: m/z¼240.1
(MþHþ); HRMS: m/z 240.0536 (MþHþ, C10H11ClN3Oþ2 requires
240.0534).
4.2.4. Isopropyl 2-chloro-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-
carboxylate (5d). Following the general procedure, the reaction
was performed with 1d (144 mg, 1.0 mmol) to afford 5d as a yel-
low solid (117 mg, 46%). Mp 155e156 ꢀC; 1H NMR (400 MHz,
DMSO-d6):
d 12.46 (s, 1H, br), 8.97 (1H, s), 5.12 (m, 1H), 2.72 (s,
3H), 1.33 (d, 6H, J¼6 Hz); 13C NMR (125 MHz, DMSO-d6):
d 161.8,
4. Experimental
4.1. General
153.1, 149.2, 145.6, 140.0, 123.8, 99.5, 66.9, 21.9, 11.0; ESI-MS: m/
z¼254.1 (MþHþ); HRMS: m/z 254.0694 (MþHþ, C11H13ClN3O2þ
requires 254.0691).
All reagents were commercially available and used without
any further purification. Anhydrous tetrahydrofuran used was
freshly distilled from sodium benzophenone. Melting points were
uncorrected. NMR spectra were recorded on a Bruker AV400 or
Bruker AV500 instrument. Low resolution mass spectra were
recorded on an Agilent1200/MSD LCeMS spectrometer. High-
resolution mass spectra were performed on Kompact Axima-CFR
MALDI mass spectrometers. The reactions were monitored by
TLC, and visualized with UV light. All yields refer to isolated
products.
4.2.5. tert-Butyl 2-chloro-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-
carboxylate (5e). Following the general procedure, the reaction was
performed with 1e (158 mg, 1.0 mmol) to afford 5e as a brown solid
(94 mg, 35%). Mp 202e203 ꢀC; 1H NMR (400 MHz, methanol-d4):
d
8.61 (s, 1H), 2.76 (s, 3H), 1.63 (s, 9H); 13C NMR (100 MHz, meth-
anol-d4):
d 164.3, 154.5, 153.4, 141.8, 127.1, 106.5, 82.2, 28.8, 15.3;
ESI-MS: m/z¼268.0 (MþHþ); HRMS: m/z 268.0848 (MþHþ,
C12H15ClN3Oþ2 requires 268.0847).
4.2.6. Ethyl 2-chloro-6-propyl-5H-pyrrolo[3,2-d]pyrimidine-7-carbox-
ylate (5f). Following the general procedure, the reaction was per-
formed with 1f (158 mg, 1.0 mmol) to afford 5f as a deep brown
solid (139 mg, 52%). Mp 182e183 ꢀC; 1H NMR (400 MHz, DMSO-d6):
4.2. Typical procedure for the preparation of 2-chloro-
pyrrolo[3,2-d]pyrimidines 5
4.2.1. Ethyl 2-chloro-6-phenyl-5H-pyrrolo[3,2-d]pyrimidine-7-carbox-
ylate (5a). A 10 mL round-bottom flask was charged with a magnetic
stirrer, THF (2 mL), ethyl benzoylacetate (192 mg, 1 mmol), and NaH
d
12.48 (s, 1H, br), 8.92 (s, 1H), 4.30 (q, 2H, J¼7.2 Hz), 3.15 (t, 2H,
J¼7.6 Hz), 1.70 (m, 2H), 1.32 (t, 3H, J¼7.2 Hz), 0.96 (t, 3H, J¼7.2 Hz);
13C NMR (125 MHz, DMSO-d6):
162.7, 153.7, 153.2, 146.1, 140.7,
d

2806
L. Zhao et al. / Tetrahedron 67 (2011) 2803e2806
124.3, 99.6, 60.0, 26.5, 21.9, 14.8, 14.2; ESI-MS: m/z¼268.1 (MþHþ);
HRMS: m/z 268.0849 (MþHþ, C12H15ClN3O2þ requires 268.0847).
59.8, 45.0, 30.6, 22.3,14.4,13.8; ESI-MS: m/z¼319.1 (MþHþ); HRMS:
m/z 319.1768 (MþHþ, C16H23N4Oþ3 requires: 319.1765).
4.2.7. Ethyl 2-chloro-6-(trifluoromethyl)-5H-pyrrolo[3,2-d]pyrimidine-
7-carboxylate(5g). Following the general procedure, the reaction was
performed with 1g (184 mg, 1.0 mmol) to afford 5g as a brown solid
(144 mg, 49%). Mp 164e165 ꢀC; 1H NMR (400 MHz, methanol-d4):
4.4. Procedure for the preparation of ethyl 2,6-diphenyl-5H-
pyrrolo[3,2-d]pyrimidine-7-carboxylate (7a)
A mixture of compound 6a (61 mg, 0.20 mmol), phenyl-boronic
acid (99 mg, 0.80 mmol), potassium carbonate (112 mg, 0.80 mmol),
and Pd(PPh3)4 (46 mg, 0.04 mmol) in toluene (5 mL) was heated to
100 ꢀC under argon for 5 h, then was taken into ethyl acetate,
washed with water, and evaporated. Chromatography on a silica gel
column (petroleum ether/ethyl acetate, 3:1) afforded compound 7a
(51 mg, 73%) as a white solid. Mp 205e206 ꢀC; 1H NMR (400 MHz,
d
8.96 (s, 1H), 4.41 (q, 2H, J¼7.2 Hz), 1.40 (t, 3H, J¼7.2 Hz); 13C NMR
(125 MHz, methanol-d4):
d 162.2, 155.9, 150.6, 146.8, 137.2 (d,
2JCF¼40 Hz),126.9,121.1 (d, 1JCF¼271 Hz), 108.2, 62.3, 14.4; ESI-MS: m/
z¼294.1 (MþHþ); HRMS: m/z 294.0256 (MþHþ, C10H8ClF3N3Oþ2 re-
quires: 294.0252).
4.2.8. Ethyl 2-chloro-6-(2-ethoxy-2-oxoethyl)-5H-pyrrolo[3,2-d]pyrim-
idine-7-carboxylate (5h). Following the general procedure, the re-
action was performed with 1h (202 mg, 1.0 mmol) to afford 5h as
a deep brown solid (196 mg, 63%). Mp 89e90 ꢀC; 1H NMR (400 MHz,
CDCl3):
d
9.58 (s, br, 1H), 8.85 (s, 1H), 8.51 (d, 2H, J¼6.4 Hz), 7.63 (d,
2H, J¼6.4 Hz), 7.42e7.45 (m, 6H), 4.37(q, 2H, J¼7.2 Hz), 1.37 (t, 3H,
J¼7.2 Hz); 13C NMR (125 MHz, CDCl3):
d 163.8, 159.1, 150.4, 150.1,
140.1, 138.6, 130.7, 130.2, 129.7, 129.4, 128.4, 128.3, 128.1, 125.7, 105.5,
60.4, 14.2; ESI-MS: m/z¼344.1 (MþHþ); HRMS: m/z 344.1396
(MþHþ, C21H18N3O2þ requires: 344.1394).
DMSO-d6): d 12.91 (s, 1H, br), 8.91 (s, 1H), 4.25e4.30 (m, 4H), 4.14 (q,
2H, J¼7.2 Hz), 1.29 (t, 3H, J¼7.2 Hz), 1.19 (t, 3H, J¼7.2 Hz); 13C NMR
(100 MHz, DMSO-d6):
d 168.6, 162.9, 153.5, 150.7, 148.8, 143.3, 126.2,
104.8, 61.4, 60.1, 34.6, 14.7, 14.4; ESI-MS: m/z¼312.1 (MþHþ); HRMS:
Acknowledgements
m/z 312.0751 (MþHþ, C13H15ClN3Oþ4 requires: 312.0746).
We are grateful for financial support from Knowledge In-
novation Project of The Chinese Academy of Sciences (KSCX1-YW-
10), Guangzhou Science and Technology Plan Item (2006Z2-E5011),
andGuangdong Natural Science Foundation (Grant No. 06200872).
4.2.9. Ethyl 6-benzyl-2-chloro-5H-pyrrolo[3,2-d]pyrimidine-7-carbox-
ylate (5i). Following the general procedure, the reaction was per-
formed with 1i (206 mg, 1.0 mmol) to afford 5i as a brown solid
(167 mg, 53%). Mp 115e117 ꢀC; 1H NMR (400 MHz, DMSO-d6):
d
12.68 (s,1H, br), 8.93 (s, 1H), 7.19e7.31 (m, 5H), 4.59 (s, 2H), 4.30 (q,
Supplementary data
2H, J¼7.2 Hz), 1.27 (t, 3H, J¼7.2 Hz); 13C NMR (125 MHz, DMSO-d6):
Copies of 1H NMR, 13C NMR spectra of 5aek, 6f, and 7a are
provided. Supplementary data associated with this article can be
found in online version, at doi:10.1016/j.tet.2010.01.089. These data
include MOL files and InChiKeys of the most important compounds
described in this article.
d
162.3, 153.3, 150.3, 145.3, 140.8, 136.7, 128.5, 128.5, 126.6, 123.8,
99.3, 59.7, 29.7, 14.3; ESI-MS: m/z¼316.0 (MþHþ); HRMS: m/z
316.0850 (MþHþ, C16H15ClN3Oþ2 requires: 316.0847).
4.2.10. 1-(2-Chloro-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-yl)
ethanone (5j). Following the general procedure, the reaction was
performed with 1j (100 mg, 1.0 mmol) to afford 5j as a brown solid
(115 mg, 55%). Mp 110e111 ꢀC; 1H NMR (400 MHz, methanol-d4):
References and notes
8.73(s, 1H), 2.78 (s, 3H), 2.77 (s, 3H); 13C NMR (100 MHz, meth-
1. Brown, D. J. Pyrimidines and their Benzo Derivatives. In Comprehensive Het-
erocyclic Chemistry; Katritzky, A. R., Rees, C. W., Eds.; Pergamon: Oxford, 1984;
Vol. 3, p 443.
2. Roth, B.; Cheng, C. In Progress in Medicinal Chemistry; Ellis, G. P., West, G. B.,
Eds.; Elsevier Biomedical: New York, NY, 1982; Vol. 19, p 267.
3. Tanaka, K.; Sugawa, T.; Nakamori, R.; Sanno, Y.; Ando, Y.; Imai, K. Chem. Pharm.
Bull. 1964, 12, 1024.
d
anol-d4):
d 194.5, 153.5, 150.4, 146.7, 138.9, 123.9, 108.3, 29.7, 9.9;
ESI-MS: m/z¼210.1 (MþHþ); HRMS: m/z 210.0430 (MþHþ,
C9H9ClN3Oþ requires: 210.0429).
4.2.11. (2-Chloro-6-phenyl-5H-pyrrolo[3,2-d]pyrimidine-7-yl)(phe-
nyl)methanone (5k). Following the general procedure, the reaction
was performed with 1k (224 mg, 1.0 mmol) to afford 5 k as a brown
solid (193 mg, 58%). Mp 147e148 ꢀC; 1H NMR (400 MHz, DMSO-
4. Imai, K. Chem. Pharm. Bull. 1964, 12, 1030.
5. McGuire, J. J.; Bergoltz, V. V.; Heitzman, K. J.; Haile, W. H.; Russell, C. A.; Bola-
nowska, W. E.; Kotake, Y.; Haneda, T.; Nomura, H. Cancer Res. 1994, 54, 2673.
6. Norman, M. H.; Chen, N.; Chen, Z. D.; Fotsch, C.; Hale, C.; Han, N. H.; Hurt, R.;
Jenkins, T.; Kincaid, J.; Liu, L. B.; Lu, Y. L.; Moreno, O.; Santora, V. J.; Sonnenberg,
J. D.; Karbon, W. J. Med. Chem. 2000, 43, 4288.
7. Trejo, A.; Arzeno, H.; Browner, M.; Chanda, S.; Cheng, S.; Comer, D. D.; Dalrymple,
S. A.; Dunten, P.; Lafargue, J.; Lovejoy, B.; Freire-Moar, J.; Lim, J.; Mcintosh, J.;
Miller, J.; Papp, E.; Reuter, D.; Roberts, R.; Sanpablo, F.; Saunders, J.; Song, K.;
Villasenor, A.; Warren, S. D.; Welch, M.; Weller, P.; Whiteley, P. E.; Zeng, L.;
Goldstein, D. M. J. Med. Chem. 2003, 46, 4702.
d6):
d
12.12 (s, 1H, br), 8.93 (s, 1H), 7.76e7.78 (m, 2H), 7.57e7.60 (m,
190.7,
3H), 7.40e7.45 (m, 5H); 13C NMR (125 MHz, DMSO-d6):
d
152.2, 151.0, 149.2, 142.9, 138.0, 133.2, 130.2, 129.8, 129.8, 129.1,
128.8, 128.4, 126.2, 111.8; ESI-MS: m/z¼334.1 (MþHþ); HRMS: m/z
334.0744 (MþHþ, C19H13ClN3Oþ requires: 334.0742).
8. Evans, G. B.; Furneaux, R. H.; Hausler, H.; Larsen, J. S.; Tyler, P. C. J. Org. Chem.
2004, 69, 2217.
4.3. Procedure for the preparation of ethyl 2-morpholino-6-
propyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (6f)
9. Gomtsyan, A.; Didomenico, S.; Lee, C.; Stewart, A. O.; Bhagwat, S. S.; Kowaluk,
E. A.; Jarvis, M. F. Bioorg. Med. Chem. Lett. 2004, 14, 4165.
10. Otmar, M.; Masojídkova, M.; Votruba, I.; Holy, A. Bioorg. Med. Chem. 2004,12, 3187.
11. Bambuch, V.; Otmar, M.; Pohl, R.; Masojídkova, M.; Holy, A. Tetrahedron 2007,
63, 1589.
12. Amarnath, V.; Madhav, R. Synthesis 1974, 837.
13. Glushkov, R. G.; Sizova, O. S. Pharm. Chem. J. (Eng. Ed.) 1986, 20, 415.
14. Sokolova, V. N.; Modnikova, G. A.; Novitskii, K.; Shcherbakova, L. I.; Pershchin,
G. N.; Zykova, T. N. Pharm. Chem. J. (Eng. Ed.) 1974, 8, 13.
ꢀ
ꢀ
ꢀ
ꢀ
Ethyl 2-chloro-6-propyl-5H-pyrrolo[3,2-d]pyrimidine-7-carb-
oxylate 5f (98 mg, 0.37 mmol) was dissolved in ethanol (5 mL),
morpholine (70 mg, 2.2 mmol) and three drops of HCl (concd) was
added at rt. After being stirred for 6 h at reflux, the reaction mixture
was concentrated in vacuo and purified by flash chromatography
with petroleum/EtOAc (1:1, v/v) as the eluent to afford 97 mg (83%)
of 6f as a pale yellow solid. Mp 186e187 ꢀC; 1H NMR (400 MHz,
15. Modnikova, G. A.; Titkova, R. M.; Glushkov, R. G.; Sokolova, A. S.; Silin, V. A.;
Chernov, V. A. Pharm. Chem. J. (Eng. Ed.) 1988, 22, 135.
16. Lim, M. I.; Ren, W. Y.; Otter, B. A.; Klein, R. S. J. Org. Chem. 1983, 48, 780.
17. Xu, L.; Lewis, I. R.; Davidson, S. K.; Summers, J. B. Tetrahedron Lett. 1998, 39, 5159.
18. Otmar, M.; Masojídkova, M.; Holy, A. Tetrahedron 1997, 53, 391.
19. Otmar, M.; Masojídkova, M.; Budesínsky, M.; Holy, A. Tetrahedron 1998, 54,
ꢀ
ꢀ
CDCl3):
d
9.59 (s, br, 1H). 8.31 (s, 1H), 4.37(q, 2H, J¼7.2 Hz), 3.79 (d,
ꢀ
ꢁꢁ
ꢀ
ꢀ
4H, J¼4.0 Hz), 3.74 (d, 4H, J¼4.0 Hz), 3.06 (t, 2H, J¼7.6 Hz),1.71 (q, 2H,
2931.
J¼7.6 Hz), 1.41 (t, 3H, J¼7.2 Hz), 0.93 (t, 3H, J¼7.6 Hz); 13C NMR
20. Montgomery, J. A.; Laseter, A. G. J. Heterocycl. Chem. 1972, 9, 1077.
21. Whittaker, N.; Jones, T. S. G. J. Chem. Soc. 1951, 1565.
(125 MHz, CDCl3): d 164.6,159.2,154.2,151.6,140.0,121.3,103.0, 67.0,