On the nucleophilic tele-substitution of dichloropyrazines by metallated dithianes

Article abstract of DOI:10.1016/j.tetlet.2005.10.146

The reaction of dichloropyrazines with a dithiane anion gave isomers of the expected formylated chloropyrazines after deprotection with methyl iodide. A tele-substitution mechanism accounts for these observations and is supported by deuterium labelling studies.

Full text of DOI:10.1016/j.tetlet.2005.10.146

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 31–34
On the nucleophilic tele-substitution of dichloropyrazines by
metallated dithianes
Jane E. Torr,a Jonathan M. Large,a Peter N. Horton,b Michael B. Hursthouseb and
Edward McDonalda,*
aMedicinal Chemistry Team, The Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research,
15 Cotswold Road, Belmont, Surrey SM2 5NG, UK
bEPSRC National Crystallography Service, School of Chemistry, University of Southampton, Highfield, Southampton SO17 1BJ, UK
Received 8 September 2005; revised 10 October 2005; accepted 25 October 2005
Available online 16 November 2005
Abstract—The reaction of dichloropyrazines with a dithiane anion gave isomers of the expected formylated chloropyrazines after
deprotection with methyl iodide. A tele-substitution mechanism accounts for these observations and is supported by deuterium
labelling studies.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Aromatic heterocycles are commonly observed motifs in
a wide variety of drugs, due in part to their involvement
in binding and physicochemical properties.1 In addition,
the development of contemporary synthetic method-
ology for the preparation of substituted heteroaromatic
compounds continues to be an important and produc-
tive area of research.2,3 Among the diazines, the pyra-
zine ring system is important, and substituted pyrazine
motifs are often to be found in compounds with applica-
tions as anti-cancer agents, including currently marketed
drugs4 and those recently reported.5
We first attempted to prepare the formylated chloropyr-
azine 2 by metallation and quenching of 1,6 as shown in
Scheme 1. After one successful outcome (72% yield), in
our hands the reaction could not be reliably repeated,
despite brief attempts to optimise the reaction condi-
tions and the formyl source.8
One indirect alternative to this approach would involve
nucleophilic substitution of dichloropyrazines with a
dithiane-based anion,9 followed by conversion to the
corresponding aldehyde.10 To the best of our knowl-
edge, pyrazines bearing a formyl substituent have not
previously been prepared by such a method.11 Surpris-
ingly, on treatment of commercially available 3 with 2-
lithio-1,3-dithiane, only the 2,3-disubstituted product 4
was obtained in 69% yield after column chromatogra-
phy (Scheme 2).9,12,13 This unexpected structure was
suggested by the appearance of two doublets in the aro-
matic region, each with a coupling constant of 2.4 Hz
In the context of a medicinal chemistry project, we
required synthetic access to a set of pyrazine templates
bearing formyl and halogen substituents. The metalla-
tion and quenching of halopyrazines seemed an attrac-
tive approach.6 We report here some of our initial
observations in this area, which resulted in the develop-
ment of an alternative method for the preparation of
this type of compound, and which subsequently uncov-
ered some interesting examples of a nucleophilic tele-
substitution mechanism.7
Keywords: Pyrazines; Dithianes; tele-Substitution; Metallation.
*
Corresponding author. Tel.: +44 (0) 20 8722 4294; fax: +44 (0) 20
8722 4205; e-mail: ted.mcdonald@icr.ac.uk
Scheme 1.
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.10.146

32
J. E. Torr et al. / Tetrahedron Letters 47 (2006) 31–34
Scheme 2. Reagents and conditions: (i) nBuLi, 1,3-dithiane, THF, À70 ꢁC, 1 h; (ii) MeI, CaCO3, MeCN, H2O, 60 ꢁC, 24 h.
Figure 1. ORTEP drawings of compounds 4 and 6.
1
(representing H-5 and H-6) in the H NMR spectrum,
and subsequently confirmed by X-ray crystallography
(see Fig. 1).14 Treatment of 4 with iodomethane and
aqueous calcium carbonate in acetonitrile15 gave a
68% yield of aldehyde 2, whose spectroscopic data
matched those previously reported.6
Figure 2. Products of D2O quench.
Similarly, reaction of 2,3-dichloropyrazine 5 under the
same conditions provided the corresponding 2,6-prod-
uct 6 in good yield—none of the expected 2,3-compound
This indicates that the deuterium atoms in 8 and 9
was observed in the crude reaction mixture. The identity
of 6 was again established by H NMR spectroscopy
originate from the quenching agent and not from the
solvent.
1
(the two pyrazine protons showed no discernible cou-
pling) and by X-ray crystallography. Pyrazine 6 could
be converted to aldehyde 7 using the procedure
described above. The substitution products 4 and 6
can be prepared in large quantities and are stable under
ambient conditions; both can be conveniently trans-
formed into the (potentially unstable) aldehydes6 as
required.
A plausible mechanistic explanation for these observa-
tions is shown in Scheme 3, for the case of 2,6-dichloro-
pyrazine 3.17 Nucleophilic addition of the lithiated
dithiane on 3 must lead to intermediate 10, which can-
not aromatise directly prior to quenching. Protonation
of 10 is followed by 1,4-elimination of HCl to give 4.
None of isomer 11, the product of 1,2-elimination is
formed. A similar mechanism explains the formation
of 6 as the only product from dichloropyrazine 5.
We probed these findings further by undertaking reac-
tions with D2O as the quenching electrophile. These
experiments afforded deuterated products 8 and 9,
respectively (Fig. 2, from reaction of 3 and 5). Analysis
by NMR spectroscopy revealed that the level of deute-
rium incorporation in 8 and 9 was 90% and 73%, respec-
tively. When the same procedure was carried out using
deuterated THF as solvent and H2O as the quenc-
hing agent, no deuterium incorporation was observed.16
Conversely, the reactions of 3 and 5 with morpholine as
the nucleophile under non-anionic conditions afforded
the previously reported products 1218 and 1319 respec-
1
tively (Scheme 4). Structural assignment by H NMR
spectroscopy was unambiguous, showing that these
products were formed by straightforward nucleophilic
aromatic substitution.

J. E. Torr et al. / Tetrahedron Letters 47 (2006) 31–34
33
Scheme 3.
´
2. (a) Mongin, F.; Queguiner, G. Tetrahedron 2001, 57,
´
´
4059–4090; (b) Turck, A.; Ple, N.; Mongin, F.; Queguiner,
G. Tetrahedron 2001, 57, 4489–4505.
3. Knochel, P.; Dohle, W.; Gommermann, N.; Kniesel, F. F.;
Kopp, F.; Korn, T.; Sapountzis, I.; Vu, V. A. Angew.
Chem., Int. Ed. 2003, 42, 4302–4320.
4. Baker, D. C.; Hand, E. S.; Plowman, J.; Rampal, J. B.;
Safavy, A.; Haugwitz, R. D.; Narayanan, V. L. Anticancer
Drug Des. 1987, 2, 297–309.
5. For a recent example, see: Burns, C. J.; Wilks, A. F.; Bu,
X. Worldwide Patent WO2005054230, 2005; Burns, C. J.;
Wilks, A. F.; Bu, X. Chem. Abstr. 2005, 143, 60004.
´
6. Turck, A.; Mojovic, L.; Queguiner, G. Synthesis 1988,
881–884.
7. For a recent review, see: Suwinski, J.; Swierczek, K.
Tetrahedron 2001, 57, 1639–1662.
Scheme 4. Reagents and conditions: (i) 6 equiv morpholine, CH2Cl2,
50 ꢁC, 3 h.
8. Other electrophiles such as N-formylmorpholine and ethyl
formate were employed. THF was distilled from calcium
hydride, or alternatively purchased with water content
60.005% (Acros Organics, UK).
In summary, we have explored a novel route to formyl-
ated chloropyrazines utilising dithiane-derived nucleo-
philes and, in so doing, uncovered an interesting tele-
substitution mechanism. This work represents a useful
and practical alternative to currently existing methodol-
ogy for the preparation of compounds of this type.
9. Allway, P. A.; Sutherland, J. K.; Joule, J. A. Tetrahedron
Lett. 1990, 31, 4781–4782.
10. For a recent review of methodology and applications, see:
Yus, M.; Najera, C.; Foubelo, F. Tetrahedron 2003, 59,
6147–6212, and references cited therein.
11. Sato, N. In Comprehensive Heterocyclic Chemistry II;
Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.;
Pergamon, 1996; Vol. 6, pp 233–278.
12. Baarschers, W. H.; Loh, T. L. Tetrahedron Lett. 1971, 37,
3483–3484.
Acknowledgements
13. Preparation of 4: nBuLi (9.00 ml, 2.5 M in hexanes,
22.50 mmol) was added dropwise to a cooled (À78 ꢁC),
nitrogen flushed, solution of 1,3-dithiane (2.65 g,
22.04 mmol, 1.1 equiv) in anhydrous THF (10 ml) and
left for 30 min. 2,6-Dichloropyrazine (3.01 g, 20.20 mmol,
1 equiv) in THF (2 ml) was added. TLC indicated the
complete consumption of the starting material after
10 min. The reaction mixture was poured into water
(10 ml) and the organic components were extracted (ethyl
acetate), rinsed (brine) and dried (sodium sulfate) and the
solvent evaporated in vacuo to give an orange solid
(4.49 g). Purification by flash chromatography (silica, 20 g,
hexane–ethyl acetate 20:1) gave the title compound
(3.33 g, 69%) as a white solid; mp 120–122 ꢁC; Rf 0.36
(hexane–ethyl acetate, 5:1); dH (CDCl3, 250 MHz) 8.52
This work was supported by Cancer Research UK
[CUK] programme Grant number C309/A2187. The
provision of a Ph.D. studentship (to J.E.T.) by the Insti-
tute of Cancer Research is gratefully acknowledged. We
also thank Dr. Amin Mirza and Mr. Meirion Richards,
for their assistance with NMR and mass spectrometry.
References and notes
1. Fuhrhop, J. H.; Corey, E. J.; Li, G.; Penzler, G. Organic
Synthesis, Concepts and Methods; John Wiley and Sons,
2003.

34
J. E. Torr et al. / Tetrahedron Letters 47 (2006) 31–34
(1H, d, J = 2.4, H5), 8.32 (1H, d, J = 2.4, H6), 5.55 (1H, s,
16. The reaction of 2-lithio-1,3-dithiane and 2,6-dichloropyr-
azine was carried out in d8-THF and worked up with
water as previously described. The only product observed
was identical to 4.
CH), 3.07 (4H, m, 2 · SCH2), 2.14 (2H, m, CH2); dC
(CDCl3, 70 MHz) 153.1 (C3), 147.0 (C2), 142.9 (C6), 142.2
(C5), 46.7 (CH), 29.9 (SCH2), 25.3 (CH2); GC–MS (+ve
CI) tR 4.20 min, m/z 233 (35M+), 235 (42%, 37M+).
17. For a related example, see: Bradacˇ, J.; Furek, Z.; Janezˇicˇ,
D.; Molan, S.; Smerkolj, I.; Stanovnik, B.; Tisˇler, M.;
Vercˇek, B. J. Org. Chem. 1977, 42, 4197–4201.
18. Bamford, M. J.; Dean, D. K.; Sehmi, S. S.; Wilson, D. M.;
Witherington, J. Worldwide Patent WO2004056369, 2004;
Bamford, M. J.; Dean, D. K.; Sehmi, S. S.; Wilson, D. M.;
Witherington, J. Chem. Abstr. 2005, 141, 106391.
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German Patent DE2406930, 1974; Frei, J.; Jaeggi, K. A.;
Ostermayer, F.; Schroeter, H. Chem. Abstr. 1977, 86,
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14. For further details see crystallographic data (excluding
structure factors) for compounds 4 and 6 that have been
deposited with the Cambridge Crystallographic Data
Centre as supplementary publication numbers CCDC
280191 and CCDC 280192. Copies of the data can be
obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK [fax +44 (0)1223
336033 or e-mail: deposit@ccdc.cam.ac.uk].
15. Cardani, S.; Bernardi, A.; Colombo, L.; Gennari, C.;
Scolastico, C.; Venturini, I. Tetrahedron 1988, 44, 5563–
5572.