Synthesis of 2-chloro-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one

Article abstract of DOI:10.1016/S0040-4039(00)02219-X

1,3-Dihydro-2H-indol-2-ones (oxindoles) and 1,3-dihydro-2H-pyrrolopyridin-2-ones (azaoxindoles) are useful scaffolds that have been explored for various pharmaceutical uses. Herein we report the synthesis of 2-chloro-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin

Full text of DOI:10.1016/S0040-4039(00)02219-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 999–1001
Synthesis of
2-chloro-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
Mui Cheung,* Philip A. Harris and Karen E. Lackey
Glaxo Wellcome, Inc., Five Moore Drive, Research Triangle Park, NC 27709, USA
Received 6 November 2000; accepted 29 November 2000
Abstract—1,3-Dihydro-2H-indol-2-ones (oxindoles) and 1,3-dihydro-2H-pyrrolopyridin-2-ones (azaoxindoles) are useful scaffolds
that have been explored for various pharmaceutical uses. Herein we report the synthesis of 2-chloro-5,7-dihydro-6H-pyrrolo[2,3-
d]pyrimidin-6-one (5) and its derivatives, and the application of 5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-ones (diazaoxindoles)
as novel scaffold to kinase research areas. © 2001 Elsevier Science Ltd. All rights reserved.
Substituted oxindoles and azaoxindoles have attracted
considerable interest in the pharmaceutical industry
because of their wide range of biological activities in
areas such as inflammation, analgesia, and cancer.1,2 In
an effort to discover novel kinase inhibitors,3 we
explored diazaoxindole as a potential novel template
for kinase inhibition. Numerous synthetic efforts on
substituted oxindoles and azaoxindoles were reported;4
however, reports on the synthesis of diazaoxindole have
been very limited. In addition, all reports required the
construction of 2-substituted-4-chloro-pyrimidine-5-
acetate as an intermediate for the synthesis of diazaox-
indole, and this limited the substitution modification at
the 2-position.5 In this letter, we report the synthesis of
2-chloro-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
(5) via its indole precursor 3, derivatization of 5 to
introduce diverse substitution at the 2-chloro position,
and application of diazaoxindole as useful scaffold to
kinase research areas. We believe that diazaoxindole
will be of use to many research programs that have
focused on creating biologically useful molecules from
oxindoles and azaoxindoles.
As shown in Scheme 1,6 4-amino-5-bromo-2-chloropy-
rimidine (1) was obtained in 98% yield by bubbling
ammonia gas into a solution of commercially available
5-bromo-2,4-dichloropyrimidine in tetrahydrofuran at
room temperature for 1 h. Stille coupling of 1 with
(Z)-1-ethoxy-2-(tributylstannyl)ethene7 using a catalytic
amount of tetrakis(triphenylphosphine)palladium(0) in
refluxing toluene for 16 h afforded a mixture of the (Z)-
and (E)-isomers of alkenylpyrimidine 2 in 51% yield.8
By using Yamanaka’s conditions,9 alkenylpyrimidine 2
was readily cyclised in the presence of hydrochloric acid
in methanol under reflux to give 2-chloro-7H-
pyrrolo[2,3-d]pyrimidine (3) in 70% yield.10 Treatment
Scheme 1.
* Corresponding author. Tel.: +1-919-483-2303; fax: +1-919-483-6053; e-mail: mc72785@glaxowellcome.com
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)02219-X

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M. Cheung et al. / Tetrahedron Letters 42 (2001) 999–1001
Scheme 2.
Scheme 3.
In conclusion, we have prepared diazaoxindole 5 that
not only allows diverse substitution at the 2-chloro
position but also is an attractive intermediate for phar-
maceutical research areas.
of compound 3 under Marfat’s procedure of using
pyridinium tribromide in tert-butanol at room tempera-
ture provided dibromo derivative 4 in 98% yield.4e
Dibromo diazaoxindole 4 underwent facile reduction in
the presence of excess zinc dust in saturated ammonium
chloride and tetrahydrofuran solution at room temper-
ature for 30 min provided 2-chloro-5,7-dihydro-6H-
pyrrolo[2,3-d]pyrimidin-6-one (5) in 80% yield.11
Acknowledgements
We thank O. Bradley McDonald and Edgar Wood for
providing c-Raf1 biological activity of compounds 9a
and 9b. We also acknowledge Lee Kuyper and Stephen
Frye for providing helpful discussion.
Compound 5 can be further manipulated in several
ways. Highlighted in Scheme 2 are three examples of
introducing substitution at the 2-chloro position of
compound 5. Dechlorination of 5 can be easily
achieved by standard hydrogenation conditions [H2 (50
psi), Pd/C, EtOH] at room temperature to give 5,7-di-
hydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (6). Palladium-
catalysed Stille coupling reaction of 5 with tetravinyltin
in the presence of Pd(PPh3)2Cl2 (0.05 equiv.) and tetra-
ethylammonium chloride (3 equiv.) in acetonitrile under
reflux yielded 7 in 40% yield. Treatment of 5 with neat
n-propylamine at 95°C in a sealed tube afforded amino
derivative 8 in 60% yield.
References
1. (a) Marfat, A.; Robinson, R. P. U.S. Patent 005811432A,
1998; (b) Robinson, R. P.; Donahue, K. M.; Son, P. S.;
Wagy, S. D. J. Heterocyclic Chem. 1996, 33, 287; (c)
Walsh, D. A.; Shamblee, D. A.; Welstead, Jr., W. J.;
Sancilio, L. F. J. Med. Chem. 1982, 25, 446.
2. (a) Shiraishi, T.; Domoto, T.; Imai, N.; Shimada, Y.;
Watanabe, K. Biochem. Biophys. Res. Commun. 1987,
147, 322; (b) Sun, L.; Tran, N.; Tang, F.; Harald, A.;
Hirth, P.; McMahon, G.; Tang, C. J. Med Chem. 1998,
41, 2588.
3. (a) Lackey, K. E.; McNutt, R. W., Jr.; Jung, D. K.;
Harris, P. A.; Hunter, R. N., III; Veal, J. M.; Dickerson,
S.; Peel, M. R. PCT Int. Appl., WO 9910325, 1999; (b)
Lackey, K. E.; Cory, M.; Davis, R.; Frye, S. V.; Harris,
P. A.; Hunter, R. N.; Jung, D. K.; McDonald, B.;
McNutt, R. W.; Peel, M. R.; Rutkowske, R. D.; Veal, J.
M.; Wood, E. R. Bioorg. Med. Chem. Lett. 2000, 10, 223.
Benzylidine oxindoles and azaoxindoles are known
kinase inhibitors.3,12 In order to examine the biological
activity of the diazaoxindoles, we converted 5 and 6
into the corresponding benzylidine derivatives 9a and
9b in 50% yield by treatment with 3,5-dibromo-4-
hydroxybenzaldehyde in 1:4 ratio of 12N hydrocholoric
acid and acetic acid at room temperature (Scheme 3).13
To our delight, both 9a and 9b were potent c-Raf1
kinase inhibitors with IC50’s of 24 nM and 14 nM,
respectively.14

M. Cheung et al. / Tetrahedron Letters 42 (2001) 999–1001
1001
1
4. (a) For synthesis of oxindole, see: Gassman, P. G.;
Bergen, T. J. van. J. Am. Chem. Soc. 1974, 96, 5508; (b)
For synthesis of 4-azaoxindole, see: Finch, N.; Robison,
M. M.; Valerio, M. P. J. Org. Chem. 1972, 37, 51; (c) For
synthesis of 4- and 6-azaoxindole, see: Daisley, R. W.;
Hanbali, J. R. Synthetic Communications, 1981, 11, 743;
(d) For synthesis of 5-azaoxindole, see: Robinson, R. P.;
Donahue, K. M. J. Org. Chem. 1991, 56, 4805; (e) For
synthesis of 7-azaoxindole, see: Marfat, A.; Carta, M. P.
Tetrahedron Lett. 1987, 28, 4027.
5. (a) Awaya, A.; Nakano, T.; Kobayashi, H.; Tan, K.;
Horikomi, K.; Sasaki, T.; Yokoyama, K.; Ohno, H.;
Kato, K.; Kitahara, T.; Tomino, I.; Isayama, S. U.S.
Patent 4 959368, 1987; Chem. Abstr. 1988, 109, 73472j;
(b) Hennequin, L. F. A.; Ple, P.; Lohmann, J.-J. M.;
Thomas, A. P. PCT Int. Appl., WO 9910349, 1999.
6. 1H NMR (300 or 400 MHz) and mass spectrometry
(APCI or ES) were used to identify all reaction products.
7. Sakamoto, T.; Kondo, Y.; Yasuhara, Y.; Yamanaka, H.
Heterocycles 1990, 31, 219.
2H); MS (+ve APCI) m/z (209, M+H). E isomer of 2: H
NMR (300 MHz, CDCl3): l 7.97 (s, 1H), 6.78 (d, J=12.7
Hz, 1H), 5.44 (d, J=12.7 Hz, 1H), 5.41 (bs, 2H), 3.96 (q,
J=7.1 Hz, 2H), 1.39 (t, J=7.1 Hz, 3H); MS (+ve APCI)
m/z (200, M+H). Z isomer of 2: 1H NMR (300 MHz,
CDCl3): l 8.22 (s, 1H), 6.28 (d, J=7.1 Hz, 1H), 5.60 (bs,
2H), 4.93 (d, J=7.1 Hz, 1H), 4.00 (q, J=7.1 Hz, 2H),
1.31 (t, J=7.1 Hz, 3H); MS (+ve APCI) m/z (200, M+H).
1
3: H NMR (400 MHz, CDCl3): l 10.87 (s, 1H), 8.88 (s,
1H), 7.40 (m, 1H), 6.63 (m, 1H); MS (+ve APCI) m/z
1
(154, M+H). 3a: H NMR (300 MHz, CDCl3): l 7.94 (s,
1H), 5.78 (bs, 2H), 4.48 (t, J=4.8 Hz, 1H), 3.46 (s, 6H),
1
2.79 (d, J=4.8 Hz, 2H). 4: H NMR (300 MHz, CDCl3):
l 8.57 (s, 1H); MS (-ve APCI) m/z (326, M-H). 5: 1H
NMR (400 MHz, DMSO-d6): l 11.71 (s, 1H), 8.20 (s,
1
1H), 3.57 (s, 2H); MS (-ve APCI) m/z (168, M-H). 7: H
NMR (300 MHz, CDCl3): l 8.35 (s, 1H), 6.81 (m, 1H),
6.58 (d, J=17.9 Hz, 1H), 5.76 (d, J=10 Hz, 1H), 3.63 (s,
1
2H); MS (+ve APCI) m/z (162, M-H). 8: H NMR (300
MHz, CDCl3): l 7.88 (s, 1H), 6.41 (bs, 1H), 3.34 (s, 2H),
8. Sakamoto, T.; Satoh, C.; Kondo, Y.; Yamanaka, H.
3.21 (q, J=6.7 Hz, 2H), 1.54 (m, 2H), 0.93 (t, J=7.5 Hz,
Heterocycles 1992, 34, 2379.
1
3H); MS (-ve APCI) m/z (191, M-H). 9a: H NMR (400
9. (a) Yamanaka, H.; Sakamoto, T.; Satoh, C.; Niitsuma, S.
JP. Patent 05025175, 1993; (b) Sakamoto, T.; Satoh, C.;
Kondo, Y.; Yamanaka, H. Chem. Pharm. Bull. 1993, 41,
81.
10. Compound 3a was also isolated from the reaction mix-
ture. It can be converted by 3 by repeating the same
cyclization conditions (HCl in MeOH under reflux).
MHz, DMSO-d6): l 12.04 (s, 1H), 8.66 (s, 2H), 8.64 (s,
1
1H), 7.93 (s, 1H); MS (-ve APCI) m/z (430, M-H). 9b: H
NMR (400 MHz, DMSO-d6): l 11.64 (s, 1H), 8.15 (s,
1H), 7.95 (s, 1H), 7.91 (s, 1H), 7.21 (s, 1H), 7.09 (s, 1H),
6.96 (s, 1H); MS (-ve APCI) m/z (396, M-H).
12. Cheung, M.; Glennon, K. C.; Lackey, K. E.; Peel, M. R.
PCT int. Appl., WO 9921859, 1999.
13. Both E and Z isomers were observed in the 1H NMR
spectra with Z isomer as major product. This trend was
observed in previously published benzylidine oxindole
series (see Ref. 3b).
14. McDonald, O. B.; Chen, W. J.; Ellis, B.; Hoffman, C.;
Overton, L.; Rink, M.; Smith, A.; Marshall, C. J.; Wood,
E. R. Analytical Biochem. 1999, 268, 318.
11. Spectroscopicdata for selected compounds are provided.
1
1: H NMR (400 MHz, CDCl3): l 8.22 (s, 1H), 5.71(bs,
.