5-Endo-Dig Electrophilic Cyclization of

r-Alkynyl Carbonyl Compounds: Synthesis

of Novel Bicyclic 5-Iodo- and
5-Bromofuranopyrimidine Nucleosides

Meneni Srinivasa Rao, Noor Esho, Craig Sergeant, and

Roman Dembinski*
Department of Chemistry, Oakland University,
2200 N. Squirrel Road, Rochester, Michigan 48309-4477

FIGURE 1. Structure of furanopyrimidine nucleoside 2.

dembinsk@oakland.edu

Received April 30, 2003 nism involving a cationic intermediate.8,11 Although

reactions of o-alkynyl phenols,7 acetoxy- or benzyloxypy-
ridines,8 and thiophenols12 have been investigated, the
Abstract: 5-Endo-dig electrophilic cyclization of 5-alkynyl-
2′-deoxyuridines with N-iodosuccinimide or N-bromosuccin- electrophilic halocyclization of R-alkynyl carbonyl com-
imide in acetone at room temperature gives 3-(2′-deoxy-β- pounds has not been synthetically explored.6,13
D-ribofuranosyl)-5-halo-2,3-dihydrofuro[2,3-d]pyrimidin-2- Elucidation of biological properties for 5-alkynyl uridines
ones that usually precipitate from the reaction mixture (86- (1) has resulted in detailed synthetic studies.14,15 When
74%). synthesis of 1 via palladium-catalyzed coupling is carried
out at a higher temperature in the presence of a base,
formation of bicyclic furanopyrimidine (2, Figure 1) is
Construction of the furan ring, which is found in many
observed.14c,d,16 The recent discovery of selective inhibi-
natural and biologically important molecules,1-3 is at-
tion of varicella-zoster virus (VZV) replication17,18 has
tracting considerable attention.4 Heteroannulation proc-
revitalized interest in bicyclic structure 2. In particular,
esses for the synthesis of substituted furans have been
the activity of furanopyrimidines substituted at C-6 with
vigorously applied, in particular palladium-catalyzed
the 4-(n-alkyl)phenyl group surpasses ca. 104 times the
annulation of alkynes,5,6 which is also suited for com-
activity of acyclovir or (E)-5-(2-bromovinyl)-2′-deoxy-
binatorial synthesis.3 Electrophilic cyclization of unsat-
uridine (BVDU).18a It is likely that 2 will be further
urated compounds has also proven to be an efficient
pursued for clinical development.17a,b
method for one-step construction and functionalization
The synthetic methodology leading to bicyclic furano-
of the furan unit.7-10 This reaction is generally believed
pyrimidine nucleosides 2 includes palladium- or copper-
to proceed through an intramolecular, stepwise mecha-
catalyzed 5-endo-dig cyclization of alkynyluridines 1,14c,18
involving the C-4 pyrimidine oxygen and acetylenic bond.
(1) (a) König, B. Furan. In Hetarenes and Related Ring Systems;
Science of Synthesis; Maas, G., Ed.; George Thieme Verlag: Stuttgart,
2001; Category 2, Vol. 9, pp 183-285. (b) Dell, C. P. Benzo[b]furans. (11) Ren, X.-F.; Turos, E. Tetrahedron Lett. 1993, 34, 1575-1578.
In Hetarenes and Related Ring Systems; Science of Synthesis; Thomas, (12) (a) Yue, D.; Larock, R. C. J. Org. Chem. 2002, 67, 1905-1909.
E. J., Ed.; George Thieme Verlag: Stuttgart, 2000; Category 2, Vol. (b) Larock, R. C.; Yue, D. Tetrahedron Lett. 2001, 42, 6011-6013.
10, pp 11-86. (c) Eberbach, W. Furan. In Houben-Weyl; George Thieme (13) Lee, C.-F.; Yang, L.-M.; Hwu, T.-Y.; Feng, A.-S.; Tseng, J.-C.;
Verlag: Stuttgart, 1994; E6a, Teil I, pp 16-185d. (d) Hou, X. L.; Luh, T.-Y. J. Am. Chem. Soc. 2000, 122, 4992-4993.
Cheung, H. Y.; Hon, T. Y.; Kwan, P. L.; Lo, T. H.; Tong, S. Y.; Wong, (14) (a) Robins, M. J.; Vinayak, R. S.; Wood, S. G. Tetrahedron Lett.
H. N. C. Tetrahedron 1998, 54, 1955-2020. 1990, 31, 3731-3734. (b) Cruickshank, K. A.; Stockwell, D. L.
(2) Mendez-Andino, J.; Paquette, L. A. Org. Lett. 2000, 2, 4095- Tetrahedron Lett. 1988, 29, 5221-5224. (c) Robins, M. J.; Barr, P. J.
4097 and references therein. J. Org. Chem. 1983, 48, 1854-1862. (d) Robins, M. J.; Barr, P. J.
(3) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003, Tetrahedron Lett. 1981, 22, 421-424. (e) Crisp, G. T.; Flynn, B. L. J.
103, 893-930. Org. Chem. 1993, 58, 6614-6619.
(4) (a) Gilchrist, T. L. J. Perkin 1 2001, 2491-2515. (b) Gilchrist, (15) Review: Korshun, V. A.; Manasova, E. V.; Berlin, Yu. A.
T. L. J. Chem. Soc., Perkin Trans. 1 1999, 2849-2866. Bioorganicheskaya Khimia 1997, 23, 324-387 (in Russian).
(5) (a) Larock, R. C. Palladium-Catalyzed Annulation. In Perspec- (16) Yu, C. J.; Yowanto, H.; Wan, Y.; Meade, T. J.; Chong, Y.; Strong,
tives in Organopalladium Chemistry for the XXI Century; Tsuji, J., Ed.; M.; Donilon, L. H.; Kayyem, J. F.; Gozin, M.; Blackburn, G. F. J. Am.
Elsevier Press: Lausanne, Switzerland, 1999; pp 111-124. (b) Larock, Chem. Soc. 2000, 122, 6767-6768.
R. C. Pure Appl. Chem. 1999, 71, 1435-1442. (c) Larock, R. C. J. (17) Reviews: (a) De Clercq, E. D. Med. Res. Rev. 2003, 23, 253-
Organomet. Chem. 1999, 576, 111-124. (d) Larock, R. C.; Yum, E. K.; 274. (b) Balzarini, J.; McGuigan, C. Biochim. Biophys. Acta 2002, 1587,
Doty, M. J.; Sham, K. K. C. J. Org. Chem. 1995, 60, 3270-3271. 287-295. (c) Balzarini, J.; McGuigan, C. J. Antimicrob. Chemother.
(6) Kel’in, A. V.; Gevorgyan, V. J. Org. Chem. 2002, 67, 95-98. 2002, 50, 5-9. (d) McGuigan, C.; Brancale, A.; Barucki, H.; Srinivasan,
(7) Arcadi, A.; Cacchi, S.; Fabrizi, G.; Marinelli, F.; Moro, L. Synlett S.; Jones, G.; Pathirana, R.; Carangio, A.; Blewett, S.; Luoni, G.; Bidet,
1999, 1432-1434. O.; Jukes, A.; Jarvis, C.; Andrei, G.; Snoeck, R.; De Clercq. E.;
(8) Arcadi, A.; Cacchi, S.; Di Giuseppe, S.; Fabrizi, G.; Marinelli, F. Balzarini, J. Antiviral Chem. Chemother. 2001, 12, 77-89. (e) McGuigan,
Org. Lett. 2002, 4, 2409-2412. C.; Brancale, A.; Barucki, H.; Srinivasan, S.; Jones, G.; Pathirana, R.;
(9) (a) El-Taeb, G. M. M.; Evans, A. B.; Jones, S.; Knight, D. W. Blewett, S.; Alvarez, R.; Yarnold, C. J.; Carangio, A.; Velázquez, S.;
Tetrahedron Lett. 2001, 42, 5945-5948. (b) Bew, S. P.; Barks, J. M.; Andrei, G.; Snoeck, R.; De Clercq, E.; Balzarini, J. Drugs Future 2000,
Knight, D. W.; Middleton, R. J. Tetrahedron Lett. 2000, 41, 4447- 25, 1151-1161.
4451. (c) Bew, S. P.; Knight, D. W. Chem. Commun. 1996, 1007-1008. (18) (a) McGuigan, C.; Barucki, H.; Blewett, S.; Carangio, A.;
(d) Nichols, C. J.; Parks, J. J. J. Undergrad. Chem. Res. 2002, 1, 27- Erichsen, J. T.; Andrei, G.; Snoeck, R.; De Clercq, E.; Balzarini, J. J.
32. (e) See also: Knight, D. W.; Redfern, A. L.; Gilmore, J. J. Perkin 1 Med. Chem. 2000, 43, 4993-4997. (b) Brancale, A.; McGuigan, C.;
2002, 622-628. Andrei, G.; Snoeck, R.; De Clercq, E.; Balzarini, J. Bioorg. Med. Chem.
(10) Anionic process (n-BuLi/I2) leads also to iodofuran derivatives: Lett. 2000, 10, 1215-1217. (c) McGuigan, C.; Yarnold, C. J.; Jones,
Buckle, D. R.; Rockell, C. J. M. J. Chem. Soc., Perkin Trans. 1 1985, G.; Velázquez, S.; Barucki, H.; Brancale, A.; Andrei, G.; Snoeck, R.;
2443-2446. De Clercq, E.; Balzarini, J. J. Med. Chem. 1999, 42, 4479-4484.

10.1021/jo0345648 CCC: $25.00 © xxxx American Chemical Society

Published on Web 00/00/0000 PAGE EST: 2.8 J. Org. Chem. XXXX, XX, A
SCHEME 1. Synthesis of Bicyclic Halofuranopyrimidine Nucleosides 3 and 4

This approach introduces hydrogen at C-5 of the furano chromatography in 80% yield. The results are sum-
pyrimidine (IUPAC nomenclature numbering of the marized in Table 1.
bicyclic ring, Figure 1), limiting access to nucleoside A p-tolyl derivative 1a was treated with N-bromo-
analogues with different substitutents at this position.19 succinimide (NBS) (1.9 equiv) in a similar manner to
Here we report a type of new chemistry that opens a access a bromoderivative 4 and compare reactivity of an
valuable route to a new series of iodo- and bromofurano- analogous reagent. Reaction time was prolonged com-
pyrimidine nucleosides (3, 4), with a potential for biologi- pared to iodination; full conversion and precipitation
cal activity.20 We have synthesized the halo-functional- occurred after 5 h. Although it is known that substituted
ized bicyclic structures for the following reasons: (i) vinyl furans undergo oxidative ring opening with NBS in
halides 3 and 4 are key synthons; palladium-catalyzed acetone,29 bicyclic 5-bromofuranopyrimidine 4a was iso-
reactions will allow for introduction of a variety of lated, after workup, in 79% yield. However, the bromo-
substituents at C-5 of the furanopyrimidine, thus provid- cyclization is sensitive to the quality of the reagents.
ing access to a wide range of functionalized 5,6-disubsti- Sometimes cleavage of the N-glycosidic bond was ob-
tuted furano nucleosides;7,21 (ii) nucleosides 3 or 4 served in repeated experiments, especially when acetone
combine halovinyl- and furanopyrimidine fragments,22 was not of high purity. In that case the bromocyclized
both with well-documented high activity.17,18,23 nucleoside base was isolated, as determined by 1H and
13C NMR.
Halogens were introduced via electrophilic 5-endo-dig
cyclization of 5-alkynyluridines. 4-Alkylphenyls17,18a and
cyclopropyl24 were selected as model R substituents. (19) Conversion of alkynyl uridines to 5-aryl substituted furano
Iodination using elemental iodine was approached; a base pyrimidines has been reported: Carangio, A.; McGuigan, C.; Andrei,
G.; Snoeck, R.; De Clercq, E.; Balzarini, J. Antiviral Chem. Chemother.
was not included as it may affect the N-glycosidic bond. 2001, 12, 187-197. Also carbonylative annulation allows for function-
Although successful I2 electrophilic cyclizations have been alization of benzofurans at analogous position: Liao, Y.; Reitman, M.;
described,7-9 attempts to effect iodocyclization of homo- Zhang, Y.; Fathi, R.; Yang, Z. Org. Lett. 2002, 4, 2607-2609. Chaplin,
J. H.; Flynn, B. L. Chem. Commun. 2001, 1594-1595.
propargylic alcohols have led to vinyl diiodides.9e How- (20) In a preliminary studies, the iodonucleoside 3a was tested using
ever, a cyclization reaction was observed when cyclo- cytotoxicity assay and exhibited activity comparable to 5-fluorouracil.
propyl-substituted ethynyluridine (1c, R ) c-C3H5) was We are indebt to Prof. Rasul Chaudry for this experiment.
(21) 3a was successfully coupled with p-(CH3)3CC6H4CtCH in Sono-
treated with I2 in CH2Cl2. Two products were isolated in gashira conditions. We thank Ms. Bo Bezeau for this observation.
poor yield; the structures were assigned as the iodo- (22) Synthesis of 6-bromofurano pyrimidine (2, R ) Br): Eger, K.;
cyclized nucleoside 3c and its base. Therefore, we have Jalalian, M.; Schmidt, M. J. Heterocycl. Chem. 1995, 32, 211-218.
(23) (a) De Clercq, E. Antiviral activity of nucleoside analogues: the
turned our attention to N-halosuccinimides, which have BVDU connection. In Recent Advances in Nucleosides: Chemistry and
precedence in the synthesis of bromobenzo[b]thio- Chemotherapy; Chu, C. K., Ed.; Elsevier Science: New York, 2002; pp
433-454. (b) Walker, R. T.; De Clercq, E. Pharmacol. Ther. 1984, 26,
phene.11,25,26 1-44. (c) De Clercq, E.; Descamps, J.; De Sommer, P.; Barr, P. J.;
5-Alkynyluridines 1b,c were prepared by Sonogashira Jones, A. S.; Walker, R. T. Proc. Natl. Acad. Sci. U.S.A. 1979, 76, 2947-
2951. (d) See also: Guenther, S.; Balzarini, J.; De Clercq, E.; Nair, V.
coupling at room temperature,14c,27 similar to 1a.28 5-Iodo- J. Med. Chem. 2002, 45, 5426-5429.
2′-deoxyuridine (5) (1.0 equiv) was combined with ter- (24) (a) Zemlicka, J. Unusual analogues of nucleosides: chemistry
minal alkyne HCtCR (R ) C6H4-p-C(CH3)3, c-C3H5) (1.8- and biological activity. In Recent Advances in Nucleosides: Chemistry
and Chemotherapy; Chu, C. K., Ed.; Elsevier Science: New York, 2002;
2.0 equiv) in the presence of Pd(PPh3)4 (0.11 equiv), CuI pp 327-357. (b) De Clercq E. Biochim. Biophys. Acta 2002, 1587, 258-
(0.3-1.0 equiv), Ph3P (1.0 equiv), n-Bu4NI (1.0 equiv), and 275. (c) Pietruszka, J. Chem. Rev. 2003, 103, 1051-1070.
Et3N (2.0 equiv) in DMF (Scheme 1). Alkynyl nucleosides (25) For application of NBS in relevant nucleoside chemistry see:
Kumar, R.; Nath, M.; Tyrrell, D. L. J. J. Med. Chem. 2002, 45, 2032-
1b/c were obtained in 84/76% yield. The isolated nucleo- 2040.
sides 1a-c were treated with N-iodosuccinimide (NIS) (26) For NBS bromination of furan ring, see: (a) Grubenmann, W.;
(1.5 equiv) in acetone at room temperature, as visualized Erlenmeyer, H. Helv. Chim. Acta 1948, 31, 78-83. (b) Lukevics, E.;
Ignatovich, L.; Goldberg, Yu.; Polyak, F.; Gaukhman, A.; Rozite, S.;
in Scheme 1. Formation of precipitate was observed after Popelis, J. J. Organomet. Chem. 1988, 348, 11-23.
2 h or more for aryl-substituted compounds 1a,b. The (27) (a) Sonogashira, K. Cross-coupling Reactions to sp Carbon
Atoms. In Metal catalyzed Cross-coupling Reactions; Diederich, F.,
solid was isolated by filtration, giving usually analytically Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1998; pp 203-230. (b)
pure bicyclic 5-iodofuranopyrimidines 3a/b in 86/74% Nakamura, K.; Okubo, H.; Yamaguchi, M. Synlett 1999, 549-550.
yield. Short column silica gel chromatography was ap- (28) Esho, N.; Davies, B.; Lee, J.; Dembinski, R. Chem. Commun.
2002, 332-333.
plied as needed. The cyclopropyl derivative 3c is more (29) Kobayashi, Y.; Nakano, M.; Kumar, G. B.; Kishihara, K. J. Org.
soluble in acetone; therefore, it was isolated by column Chem. 1998, 63, 7505-7515.

B J. Org. Chem.
TABLE 1. Preparation of Halofuranopyrimidines 3 and
4 via Cyclization of 1

The bicyclic nucleosides were characterized by 1H and

13C NMR, IR, MS, UV-vis, and fluorescence spectros-
FIGURE 2. UV-vis (s) and fluorescence (λex ) 340) (- - -)
copy. The 1H and 13C NMR spectra supported the struc- spectra for 3a (methanol).
tural assignment for 3a-c and 4a. First, the furano-
pyrimidine H-4 signal exhibited a downfield shift by
emissions do not vary much, and are between 430 and
comparison to its alkynyl precursor (9.00-8.63 vs 8.35-
450 nm, slightly shifted to the red by comparison to the
8.11 (H-6) ppm, DMSO-d6). Second, the furan CdC
alkynyl precursor 1a.28 A representative emission curve
signals showed a chemical shift (157.8-154.2 and 59.0-
for 3a is shown in Figure 2. All iodobicyclic nucleosides
58.4 (I), 90.3 (Br) ppm, DMSO-d6) characteristic for
3 gave the correct elemental analyses.
O-vinyl and I/Br-vinyl carbons.8 Distinctive changes occur
as compared to the parent alkynes 1a-c (96.9-91.8 and In summary, we have demonstrated that electrophilic
82.1-68.6 ppm, DMSO-d6) or nonhalogenated bicyclic cyclization of R-alkynyl carbonyl compounds leads to
furano pyrimidines 2 (100.2-99.5 (C-5) ppm, DMSO- halofurans in mild conditions, and we have synthesized
d6).18a Third, the 13C NMR coupled (gated decoupling) a new class of modified nucleosides containing biologically
experiment showed an absence of hydrogen at C-5 for 3a. active substructures. The resulting bicyclic nucleoside
In addition, this experiment allowed assignment of the iodides or bromides should be particularly useful as
13C signals based upon the 1J
C-H coupling constants
substrates in a variety of palladium-catalyzed reactions
pattern, which was extrapolated for other analogues. such as Heck, Suzuki, Sonogashira, or amination, and
Mass spectra of 3a-c and 4a exhibited intense molec- should thus provide material for a broad range of
ular ions. The IR νCO values clustered in a narrow range modified nucleosides for drug discovery. Corresponding
(1663-1670 cm-1). The representative UV-vis spectrum synthetic studies are currently underway in our labora-
for 3a is shown in Figure 2. As expected, absorptions shift tory. Our protocol also offers a potential for iodine isotope
to longer wavelengths for the fused cyclic system, as labeling.
compared to the parent alkynyl uridines 1a-c. The first
two bands usually appear at 248-257 and 282-285 nm Acknowledgment. We thank the Oakland Univer-
for aryl-substituted compounds, but a single band was sity, Research Excellence Program in Biotechnology, for
observed at 248 nm for the cyclopropyl derivative 3c. The support of this research, and Profs. J. A. Gladysz, M.
position of the last well-pronounced band (longest wave- A. Ubeda, and J. Zemlicka for helpful discussions.
length), shifts slightly from cyclopropyl substituted 3c
(341 nm) to the aryl derivatives 3a,b and 4a (357/356/ Supporting Information Available: Synthetic proce-
356 nm) and does not depend on the halogen. The molar dures and analytical and spectral characterization data for all
absorptivities reach nearly to 18 000 M-1 cm-1. new compounds, and 1H and 13C NMR and MS spectra for 1b,c,
Both iodo- and bromofurano pyrimidines 3 and 4 3a-c, and 4a. This material is available free of charge via
the Internet at http://pubs.acs.org.
exhibited a strong purple luminescence on TLC plates
under a UV lamp (254 nm); more detailed characteriza- JO0345648
tion was also undertaken as fluorescent nucleosides find
practical applications.30 We found optimal excitations (30) See, for example: Okamoto, A.; Tainaka, K.; Saito, I. J. Am.
between 320 and 350 nm. Wavelengths of the observed Chem. Soc. 2003, 125, 4972-4973.

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