Cytosine analogues from substituted acetonitriles via Thorpe condensation

Article abstract of DOI:10.1021/ol035223j

(Matrix presented) A Thorpe condensation is the key bond construction in a rapid and efficient synthesis of substituted cytosine derivatives from readily available starting materials.

Full text of DOI:10.1021/ol035223j

ORGANIC
LETTERS
2003
Vol. 5, No. 18
3333-3335
Cytosine Analogues from Substituted
Acetonitriles via Thorpe Condensation
Julia L. Barkin, Marcus D. Faust Jr., and William C. Trenkle*
Department of Chemistry, Brown UniVersity, ProVidence, Rhode Island 02912
trenkle@brown.edu
Received July 2, 2003
ABSTRACT
A Thorpe condensation is the key bond construction in a rapid and efficient synthesis of substituted cytosine derivatives from readily available
starting materials.
Uracil and cytosine ring systems have received increasing
attention due to the efficacy of anti-cancer drugs such as
5-fluorouracil and capecitabine, as well as anti-viral agents
such as azidothymidine (AZT, Figure 1).1,2 As part of our
with stoichiometric amounts of a potassium alkoxide base
lead to high yields of a new product. Examination of the
spectral data revealed that the product was an oxygenated
â-enaminonitrile (general structure 2) arising via a Thorpe
condensation (see Table 1).4 The facile intermolecular
dimerization of cyanomethyl aryl ethers at low temperature
was surprising, as Thorpe condensations of alkyl nitriles
require elevated temperatures and prolonged reaction times.5,6
The literature provides few examples of the Thorpe conden-
sation of cyanomethyl ethers, and these are primarily
examples of undesired side products that were isolated in
poor yield.7,8 Recognizing that â-enaminonitriles 2 could
function as a scaffold for the construction of highly func-
tionalized cytosine derivatives, we subjected a range of
Figure 1. Representative pharmaceuticals.
(3) Aryl ethers 1 were obtained in 87-99% yield from commercially
available aryl alcohols (aryl alcohol, K2CO3, acetone, ClCH2CN, reflux):
(a) Benarab, A.; Boye´, S.; Savelon, L.; Guillaumet, G. Tetrahedron Lett.
1993, 34, 7567-7568. (b) Rooney, C. S.; Stuart, R. S.; Wasson, B. K.;
Williams, H. W. R. Can. J. Chem. 1975, 53, 2279-2292.
(4) (a) Schaefer, J. P.; Bloomfield, J. J. Org. React. (N. Y.) 1967, 15,
1-203. (b) Davis, B. R.; Garratt, P. J. Compr. Org. Synth. 1991, 2, 848-
852.
(5) Yoshizawa, K.; Toyota, S.; Toda, F. Green Chem. 2002, 4, 68-70.
(6) Cross coupling between the anion of an alkyl nitrile and a R-branched
cyanomethyl ether at low temperature has been reported: Kobayashi, K.;
Hiyama, T. Tetrahedron Lett. 1983, 24, 3509-3512.
(7) (a) Makosza, M.; Ziobrowski, T.; Serebriakov, M.; Kwast, A.
Tetrahedron 1997, 53, 4739-4750. (b) Kova´cs, L. Molecules 2000, 5, 127-
131.
ongoing interest in heterocyclic structures, we have devel-
oped a rapid synthesis of 5-aryloxy-6-methylaryloxy-cy-
tosines from cyanomethyl ethers via three high-yielding
transformations. This report showcases the ability of the
Thorpe condensation to provide an efficient route to â-
enaminonitriles for the synthesis of cytosine analogues.
During the course of our research, we noted that the
treatment of a cyanomethyl aryl ether (general structure 1)3
(1) For an overview of nucleosides with anti-cancer activity, see: Cole,
C.; Foster, A. J.; Freeman, S.; Jaffar, M.; Murray, P. E.; Stratford, I. J.
Anti-Cancer Drug Des. 1999, 14, 383-392.
(2) For a review of nucleosides with anti-viral activity, see: Gumina,
G.; Song, G.-Y.; Chu, C. K. FEMS Microbiol. Lett. 2001, 202, 9-15.
(8) For additions of alkylmetals to cyanomethyl ethers, see: (a) Charette,
A. B.; Gagnon, A. Tetrahedron: Asymmetry 1999, 10, 1961-1968. (b)
Charette, A. B.; Gagnon, A.; Janes, M.; Mellon, C. Tetrahedron Lett. 1998,
39, 5147-5150. (c) Kuwahara, Y.; Yen, L. T. M.; Tominaga, Y.;
Matsumoto, K.; Wada, Y. Agric. Biol. Chem. 1982, 46, 2283-2291.
10.1021/ol035223j CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/05/2003

Table 1. Thorpe Condensation of Aryl Ethers
Table 2. Acylation with Benzoyl Isocyanate
entry
substrate
yield
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
2g
2h
2i
92%
99%
99%
99%
91%
97%
86%
94%
98%
induced cyclization to provide the desired cytosine analogues
4 in good to excellent yield (Table 3).12 Although the
reactions were clean and proceeded to completion, isolated
yields of some analogues suffered from difficulties associated
with their poor solubility. In particular, bis-ortho-methyl
derivative 4e is exceptionally insoluble in most solvents,
which lead to a reduced isolated yield.
Table 3. Cyclization to Form Pyrimidines
entry
substrate
yield
70%
92%
94%
83%
40%a
75%
69% (76%)b
98%
1
a Olefin isomer ratios determined by H NMR. The structure of (Z)-2d
was unambiguously assigned by fractional crystallization and single-crystal
X-ray diffraction.9 Stereochemical assignments of 2a-c,e-i are provision-
ally assigned on the basis of analogy to 2d.
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3f
3g
3h
3i
R-aryloxyacetontriles to our reaction conditions (Table 1).
These condensations afford excellent yields for a wide range
of aryl ethers, including sterically hindered cases such as
ortho-substituted aryl ethers 1b,d-f.
78%
The selective N-acylation of enamines 2 proved to be
difficult, as mixtures of products from C and N acylation
were obtained under many conditions.10 Ultimately, treatment
of enamines 2 with benzoyl isocyanate and pyridine in
CH2Cl2 provided exclusively the desired benzoyl ureas 3
(Table 2).11 This reaction proceeded cleanly and furnished
excellent yields (88-99%).
a Although the NMR spectrum of the unpurified reaction showed clean
and complete conversion of 3e, isolation of 4e was hindered by solubility
problems. b Overall isolated yield of 4g from 2g without intermediate
purification of 3g.
An intramolecular variant of our procedure utilizing the
bis-cyanomethyl ether 5 furnished cyclic enaminonitrile 6
(74% yield),3b,4,13 which was transformed into benzodiox-
epine fused tricyclic pyrimidine 8 in good yield (67% yield
for two steps, Scheme 1).
Treatment of benzoyl ureas 3 with sodium ethoxide in
refluxing ethanol cleanly removed the benzoyl group and
(9) Crystallographic data for this compound has been deposited with the
Cambridge Crystallographic Data Centre. The coordinates can be obtained
on request from the Director, Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge, CB2 1EZ, U.K.
(10) Variables screened include: base (NaH, pyridine, and R3N), solvent
(THF, DMF, Et2O, and CH2Cl2), and isocyanate (ClSO2NCO, BnNCO,
CF3C(O)NCO, TMSNCO, and TsNCO).
Addition of base to bromo- and chloroacetonitrile results
in uncharacterizable polymeric products, while fluoroaceto-
(12) Enamines 3 must undergo Z/E isomerization to cyclize. This
isomerization presumably occurs through a base-catalyzed enamine-imine
tautomerization.
(11) Isomer ratios of ureas 3 were unchanged from the corresponding
enaminonitrile starting material.
(13) For a review of the intramolecular Thorpe-Ziegler cyclization,
see: Fleming, F. F.; Shook, B. C. Tetrahedron 2002, 58, 1-23.
3334
Org. Lett., Vol. 5, No. 18, 2003

In conclusion, we have developed an efficient synthesis
of 5,6-disubstituted cytosine analogues using the Thorpe
condensation as a key transformation. This method allows
the synthesis of cytosine derivatives that are unreported in
the literature and difficult to access using alternative methods.
The efficiency and mild conditions of the Thorpe condensa-
tion of aryl ethers is noteworthy. Further work is underway
to examine the scope and versatility of this approach for the
preparation of cytosine analogues as well as to elucidate the
biological activity of these interesting new analogues.
Scheme 1
nitrile (9) undergoes clean dimerization to provide difluoro-
enamine 10,14 which can be converted with the aforemen-
tioned procedure into 5-fluoro-6-fluoromethylcytosine (12)
in good yield (61% overall from 9, Scheme 2). This is the
Acknowledgment. We are grateful to Brown University
for research support; Dr. Tun-Li Shen for assistance with
mass spectral analyses; and Dr. Joe Ziller, of the University
of California, Irvine, for expert assistance with single-crystal
X-ray diffraction.
Scheme 2
Supporting Information Available: Experimental pro-
cedures and characterization for the preparation of 1a-i, 2a-
i, 3a-i, 4a-i, and 5-12. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL035223J
first reported synthesis of 5-fluoro-6-fluoromethylcytosine,
although the synthesis of 5-fluoro-6-fluoromethyl-uracil has
been reported in poor yields using fluorine gas.15 In contrast
to the haloacetonitriles, cyanomethyl benzenesulfonate and
alkyl nitriles failed to produce any dimer with our conditions
and resulted in complete recovery of the starting nitrile.
(14) It was found that dimer 10 codistills with many common organic
solvents, including diethyl ether, hexanes, and ethyl acetate. Better yields
of the corresponding urea were obtained when 10 was acylated directly
without purification.
(15) Cech, D.; Herrmann, G.; Holy, A. Nucleic Acids Res. 1977, 4, 3259-
3266.
Org. Lett., Vol. 5, No. 18, 2003
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