Synthesis of 5,6-bis(alkyn-1-yl)pyrimidines and related nucleosides

Article abstract of DOI:10.1016/S0040-4039(00)01566-5

Sonogashira coupling of 5-iodo-1-methyluracil or 5'-O-TBDMS-5-iodo-2',3'-O-isopropylideneuridine with alkynes gave 5-(alkyn-1-yl) derivatives that underwent 6-lithiation/iodination to give 5-(alkyn-1-yl)-6-iodo-(1-methyluracil or uridine) intermediates (57-80%). Coupling of the 5-(alkyn-1-yl)-6-iodo intermediates gave 5,6-bis(alkyn-1-yl)pyrimidines and protected nucleosides (51-79%). Two of the 5,6-bis(ethynyl)-1,3-dimethyluracil derivatives underwent Bergman cycloaromatization at 130°C with half-lives of 2-8 h. (C) 2000 Published by Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01566-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8741–8745
Synthesis of 5,6-bis(alkyn-1-yl)pyrimidines and related
nucleosides
E. Sathyajith Kumarasinghe, Matt A. Peterson* and Morris J. Robins*
Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT 84602-5700, USA
Received 10 August 2000; accepted 28 August 2000
Abstract
Sonogashira coupling of 5-iodo-1-methyluracil or 5%-O-TBDMS-5-iodo-2%,3%-O-isopropylideneuridine
with alkynes gave 5-(alkyn-1-yl) derivatives that underwent 6-lithiation/iodination to give 5-(alkyn-1-yl)-6-
iodo-(1-methyluracil or uridine) intermediates (57–80%). Coupling of the 5-(alkyn-1-yl)-6-iodo intermedi-
ates gave 5,6-bis(alkyn-1-yl)pyrimidines and protected nucleosides (51–79%). Two of the
5,6-bis(ethynyl)-1,3-dimethyluracil derivatives underwent Bergman cycloaromatization at 130°C with
half-lives of 2–8 h. © 2000 Published by Elsevier Science Ltd.
The Bergman1 cycloaromatization reaction is of interest both from a mechanistic point of
view and because of its relevance to the mode of action of enediyne antibiotics including the
esperamicins, calicheamicins, dynemicins, and kedarcidin. These DNA-cleaving molecules are
among the most cytotoxic compounds known,2 and considerable efforts have been focused on
the synthesis of analogs with enhanced properties for chemotherapeutic applications.3 Unfortu-
nately, most cytotoxic enediynes exhibit limited selectivity for tumor cells, and this has been a
major obstacle to their development as anticancer drugs.2 We reasoned that enediyne moieties
elaborated at the 5,6-bond of pyrimidines might provide a scaffold for directed delivery of aryl
diradical precursors for the cleavage of nucleic acids. The enhanced uptake of base and
nucleoside analogs by certain rapidly dividing tumor cells might provide some selectivity.
Progression from bases to nucleosides to oligonucleotides containing strategically incorporated
pyrimidine-based enediynes should generate enhanced selectivity for nucleic acid target
structures.
During the course of our studies, Russell and co-workers reported the synthesis and Bergman
cycloaromatization of three 5,6-bis(alkyn-1-yl)pyrimidine derivatives.4 Their synthesis started
with 6-chloro-2,4-dimethoxypyrimidine and was not oriented to the preparation of nucleosides.
We now report efficient syntheses of 5,6-bis(ethynyl)uracil derivatives and related nucleosides
from uracil or uridine.5a
* Corresponding authors. Fax: (801) 378-5474; e-mail: matt peterson@byu.edu; morris robins@byu.edu
–
–
0040-4039/00/$ - see front matter © 2000 Published by Elsevier Science Ltd.
PII: S0040-4039(00)01566-5

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The respective 5-iodo-1-methyluracil (1a) or 5%-O-(tert-butyldimethylsilyl)-5-iodo-2%,3%-O-iso-
propylideneuridine (1b) derivatives were readily obtained in 2–3 steps from uracil or uridine
(Scheme 1).5 Sonogashira coupling5,6 of 1a,b with TMS-ethyne or 1-hexyne proceeded smoothly
to give 5-alkynyl derivatives 2a–3b (79–96%). C6-lithiation,7 followed by treatment with iodine
gave 5-(alkyn-1-yl)-6-iodo analogs 4a–5b in good yields. Coupling of 4a with 1-hexyne afforded
minor amounts of 5,6-bis(hexyn-1-yl) derivative 10a, but the major product of this reaction was
bicyclic compound 14 (Fig. 1). Furano[2,3-d]pyrimidin-2-ones related to 14 are known byprod-
ucts of Sonogashira couplings with 5-iodouracil substrates,5,8 and variable amounts (10–15%) of
the corresponding bicyclic pyrimidine-2-ones were observed when 2a,b were prepared from 1a,b.
In the case of 2a,b, cyclization was minimized with optimized reaction conditions, but coupling
of the 6-iodo derivatives 4a,b was considerably slower. The longer reaction times invariably gave
furano[2,3-d]pyrimidin-2-ones as major products. This furan cyclization was circumvented by
Scheme 1. Reagents: (a) HCꢀCR/Pd(0), Cu(I). (b) (i) LDA, −78°C; (ii) I2. (c) BzCl/(iPr)2NEt. (d) NH3/MeOH. (e)
CH2N2/Et2O. (f) NH4F/BTAC/THF. (g) NH4F/MeoH16
Figure 1.

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N3-benzoylation of 4a,b. The resulting 6a,b underwent coupling to give 8a,b without
accompanying addition of O4 to the C5-alkynyl triple bond. Compound 5a was N3-benzoylated
to give 7a, but 5a,b underwent coupling without formation of furano[2,3-d]pyrimidin-2-one
byproducts. Thus, 9a,b were prepared from 5a or 5b by direct coupling with (trimethyl-
silyl)acetylene. The N3-benzoyl group was removed under standard conditions, and treatment of
8a with NH3/MeOH gave 10a (75%).
Attempts9 to bis-desilylate 9a gave intractable mixtures. Remarkably, N3-methylation over-
came this problem and 13 was obtained in 91% yield upon treatment of 11 with NH4F/MeOH.
The C6-ethynyl TMS group was selectively cleaved10 to give 12 (77%) with NH4F/benzyltriethyl-
ammonium chloride (BTAC)/THF.
Enediynes 12 and 13 underwent thermal Bergman cycloaromatization in 1,4-cyclohexadiene at
130°C with half-lives of 8 and 2 h, respectively (Scheme 2).11 Compound 11 did not undergo
Bergman cyclization under these conditions, and higher temperatures resulted in significant
decomposition. Isolated yields of 15 and 16 were approximately 20%, and decomposition of
starting material (prolonged reaction time with 12, low solubility in 1,4-cyclohexadiene with 13)
contributed to the modest yields.
Scheme 2.
Activation energies for Bergman cycloaromatizations have been correlated with the a,b-dis-
tance between the two terminal alkynyl carbon atoms.12 Acyclic enediynes with a,b-distances
,
>3.5 A were unreactive at 25°C and required heating to effect cyclization. In compounds 11–13,
13
,
the a,b-distance is calculated to be approximately 4.1 A. Terminally substituted acyclic
enediynes exhibit increased activation barriers due to unfavorable steric interactions and
entropic effects,14 and the relative reactivities of 11–13 are consistent with these observations.
In summary, we have prepared 5,6-bis(alkyn-1-yl)-1-methyluracil derivatives and protected
nucleosides via successive Sonogashira couplings of 5- and 6-iodo(uracil or uridine) analogs 1a,b
and 5a–6b. Coupling of the 6-iodo derivatives was sluggish and required longer reaction times
or higher temperatures than couplings with the 5-iodo compounds. Extended reaction times
resulted in increased formation of furano[2,3-d]pyrimidin-2-one byproducts from 5-(hexyn-1-yl)
derivatives 4a,b, but they were not observed with 5-(TMS-ethyn-1-yl) intermediates 3a,b or 5a,b.
The 5,6-bis(ethynyl) derivatives underwent Bergman cycloaromatization at elevated tempera-
tures to give quinazoline-2,4-dione derivatives 15 and 16.15 Connection of the two ethynyl
substituents to form fused bicyclic uracil-based enediynes should significantly lower activation
barriers to Bergman cycloaromatization. We are actively pursuing such studies and biological
testing of nucleoside enediynes.

8744
Acknowledgements
We thank the BYU Cancer Center and BYU for partial support of this work.
References
1. (a) Bergman, R. G. Acc. Chem. Res. 1973, 6, 25–31. (b) Jones, R. R.; Bergman, R. G. J. Am. Chem. Soc. 1972,
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Science 1992, 256, 1172–1178.
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Eur. J. 2000, 6, 1555–1558.
5. (a) Kumarasinghe, E. S. Masters Thesis, Brigham Young University, 2000. (b) Robins, M. J.; Barr, P. J.
Tetrahedron Lett. 1981, 22, 421–424. (c) Robins, M. J.; Barr, P. J. J. Org. Chem. 1983, 48, 1854–1862. (d) De
Clercq, E.; Descamps, J.; Balzarini, J.; Giziewicz, J.; Barr, P. J.; Robins, M. J. J. Med. Chem. 1983, 26, 661–666.
(e) Robins, M. J.; Vinayak, R. S.; Wood, S. G. Tetrahedron Lett. 1990, 31, 3731–3734.
6. Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 4467–4470.
7. (a) Tanaka, H.; Hayakawa, H.; Shibata, S.; Haraguchi, K.; Miyasaka, T. Nucleosides Nucleotides 1992, 11,
319–328. (b) Tanaka, H.; Hayakawa, H.; Iijima, S.; Haraguchi, K.; Miyasaka, T. Tetrahedron 1985, 41, 861–866.
8. McGuigan, C.; Yarnold, C. J.; Jones, G.; Vela´zquez, S.; Barucki, H.; Brancale, A.; Andrei, G.; Snoeck, R.; De
Clercq, E.; Balzarini, J. J. Med. Chem. 1999, 42, 4479–4484.
9. Protective Groups in Organic Synthesis, 3rd ed.; Greene, T. W.; Wuts, P. G. M., Eds.; John Wiley & Sons: New
York, 1999; pp. 654–656.
10. Determined by HMBC NMR experiments.
1
11. Half-lives were determined by H NMR.
12. Nicolaou, K. C.; Zuccarello, G.; Ogawa, Y.; Schweiger, E. J.; Kumazawa, T. J. Am. Chem. Soc. 1988, 110,
4866–4868.
13. Determined by semi-empirical (AM-1) calculations.
14. (a) Chen, W.-C.; Chang, N.-Y.; Yu, C.-H. J. Phys. Chem. A 1998, 102, 2584–2593. (b) Schreiner, P. R. J. Am.
Chem. Soc. 1998, 120, 4184–4190.
15. Compound 16 was identical to an authentic sample of 1,3-dimethyl-(1H,3H)-quinazoline-2,4-dione.4b
1
16. Yields shown are for isolated compounds. All new compounds were characterized by H and 13C NMR and had
HRMS values within 10 ppm of theory.5a Spectral data for representative compounds are: Compound 4a: UV
1
(MeOH) max 230, 309 nm, min 260 nm; H NMR (CDCl3, 300 MHz) l 8.43 (s, 1H), 3.73 (s, 3H), 2.49 (t, J=6.6
Hz, 2H), 1.68–1.54 (m, 2H), 1.53–1.44 (m, 2H), 0.94 (t, J=7.2 Hz, 3H); 13C NMR (CDCl3, 50 MHz) l 159.5,
148.7, 122.2, 111.8, 99.1, 42.7, 30.5, 22.2, 19.7, 13.8; MS (FAB) m/z 333.0092 (MH+ [C11H14IN2O2]=333.0100).
1
Compound 6a: UV (MeOH) max 248, 316 nm, min 274 nm; H NMR (CDCl3, 200 MHz) l 7.93 (dd, J=12.5,
2.3 Hz, 2H), 7.64–7.60 (m, 1H), 7.53–7.50 (m, 2H), 3.78 (s, 3H), 2.48 (t, J=6.8 Hz, 2H), 1.62–1.40 (m, 4H), 0.93
(t, J=7.1 Hz, 3H); 13C NMR (CDCl3, 75 MHz) l 167.6, 158.3, 147.4, 135.4, 131.2, 130.7, 129.3, 121.8, 111.8,
1
99.8, 77.3, 42.9, 30.4, 22.2, 19.7, 13.8; MS (CI) m/z 436.0294 (M+ [C18H17IN2O
]
3 =436.0284). Compound 8a: H
NMR (CDCl3, 200 MHz) l 7.91 (dd, J=12.6, 2.4 Hz, 2H), 7.63–7.55 (m, 1H), 7.51–7.47 (m, 2H), 3.54 (s, 3H),
2.61 (t, J=7.0 Hz, 2H), 2.46 (t, J=6.8 Hz, 2H), 1.62–1.40 (m, 8H), 0.98 (t, J=7.2 Hz, 3H), 0.91 (t, J=7.2 Hz,
3H); 13C NMR (CDCl3, 75 MHz) l 168.2, 149.3, 135.2, 131.6, 130.8, 129.4, 129.3, 100.2, 34.2, 30.8, 30.1, 29.9,
22.3, 22.1, 20.1, 19.9, 13.9, 13.8; MS (CI) m/z 391.2017 (MH+ [C24H27N2O3]=391.2022). Compound 10a: UV
1
(MeOH) max 231, 333 nm, min 266 nm; H NMR (CDCl3, 300 MHz) l 8.38 (s, 1H), 3.50 (s, 3H), 2.58 (t, J=7.1
Hz, 2H), 2.48 (t, J=6.8 Hz, 2H), 1.68–1.44 (m, 8H), 0.97 (t, J=7.2 Hz, 3H), 0.94 (t, J=7.2 Hz, 3H); 13C NMR
(CDCl3, 75 MHz) l 161.3, 149.9, 140.6, 109.9, 99.2, 73.1, 72.67, 34.0, 30.9, 30.2, 29.9, 22.25, 22.18, 19.92, 19.88,
13.9, 13.8; MS (CI) m/z 287.1742 (MH+ [C17H23N2O2]=287.1760). Compound 11: UV (MeOH) max 234, 340
1
nm, min 276 nm; H NMR (CDCl3, 500 MHz) l 3.57 (s, 3H), 3.36 (s, 3H), 0.32 (s, 9H), 0.26 (s, 9H); 13C NMR

8745
(CDCl3, 125 MHz) l 161.1, 150.9, 138.8, 115.1, 104.0, 103.6, 96.7, 94.4, 34.9, 28.7, −0.1, −0.5; MS (EI)
1
m/z 332.1370 (M+ [C16H24N2O2Si2]=332.1376). Compound 13: UV (MeOH) max 223, 325 nm, min 266 nm; H
NMR (CDCl3, 500 MHz) l 4.05 (s, 1H), 3.61 (s, 3H), 3.46 (s, 1H), 3.39 (s, 3H); 13C NMR (CDCl3, 125 MHz)
l 160.9, 150.7, 138.9, 103.9, 94.5, 85.8, 75.7, 74.1, 35.1, 28.9; MS (CI) m/z 189.0653 (MH+ [C10H9N2O2]=
189.0664).
.