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TETRAHEDRON LETTERS Pergamon
Tetrahedron Letters 40 (1999) 7553-755 6

Novel Route to b-Fused Thiazoles Starting from a 2-Chloro-1-Phenacylpyridinium Salt and KSCN. Crystal Structure s of Thiazolo- and Oxazolo[3,2-a]pyridinium Thiocyanates

Eugene V. Babaev,* Alexander A. Bush, Irina A. Orlova, Viktor B. Rybakov, Sergey G. Zhukov
Chemistry Department, Moscow State University, 119899, Moscow, Russia E-mail: babaev@org.chem.msu.su

Received 9 June 1999; accepted 24 August 1999

Abstract. Reaction of 2-chloro-l-phenacylpyridinium bromide la with KSCN led to 2-aminothiazolo[3,2-a]pyridinium salts 4a,b thus opening a novel route to fused thiazoles. In reaction with KSCN oxazolo[3,2-a]pyridinium perchlorate 2a was converted to thiocyanate 2b. Crystal structures of thiocyanates 2b and 4b were determined. © 1999 Elsevier Science Ltd. All rights reserved.

In many reactions with nucleophiles 2-halogen-N-phenacylpyridinium pyridinium salts 2 yield the same products.1-3 The origin of this similarit intermediates 3 which may undergo further cyclizations (as in the case of X with NaSH both types of the salts led to the same pyridinethione 3 (X = S),3,4 Scheme 1.

salts 1 and 2-aryloxazolo[3,2-a]y lies in formation of the same = NH, NR). In a simple reaction see Scheme 1:

Attempts to involve the salts 1 and 2 in reactions with RS-nucleophiles (e.g., PhCH2SH) under various conditions led only to disulfides and complex mixtures of products.5 No other reactions with sulfur-containing nucleophiles have been reported for the salts 1 and 2. We found that during reaction with KSCN the salts 1 and 2 behave in different ways. Pyridinium bromide l a (Hal = Cl, Ar = p-NO2Ph) readily and quantitatively gave previously unknown aminothiazole derivative 4 (isolated as perchlorate 4a and thiocyanate 4b), 6 whereas oxazolopyridinium perchlorate 2a (Ar = p-NO22Ph) underwent simple ionic exchange to the stable thiocyanate 2b 7 (see Scheme 2). Scheme 2. KSCN MeO H or MeCN , A Ar KSCN 2b - KC1O, 2, 4: a - perchlorates, b - thiocyanates
0040-4039/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved. PII: S0040-4039(99)01601-9

S-

c
Cl"(Br")

-NR , COA r X" 4 a (100%) , 4 b (55%)

Ar la Br"

1
1, 2, 4: Ar = p-NO2Ph\

2a


7554

1H NM R spectra of the oxazolopyridinium salts 2a and 2b showed no significant differences.8 The crystal structure of 2b was determined,9 and X-ray data confirmed the presense of thiocyanate as the counterion in this salt (Fig. 1). The bond lengths in the molecule 2b were the same as in the previously reported X-ray structure of 2-(p-nitrophenyl)oxazolo[3,2-a]pyridinium bromide.10 Clear alternation of the bond lengths along the six-membered fragment (and around the whole perimeter of the bicycle) was observed in the case of 2b. This confirms the earlier hypothesis " about the "pyridone-like" structure of bridgehead oxazolopyridines.

NO

CO

SO
02 2

02 1

Fig. 1. Crystal structure and atoms numbering in the salt 2b. The conversion of l a to thiazolopyridine 4b occurred easily either in solution (MeOH:H2O 1:1, 80°C) or under heterogeneous conditions (MeCN, 80cC). Initially formed light-yellow thiocyanate 4b (poorly soluble in most common solvents) was converted to the dark-yellow perchlorate 4a by dissolving it in H2SO4 and addition of HClO4. All signals in 1H NMR spectra of cations 4a,b12 were clearly resolved and located exclusively in the aromatic region, thus indicating the presence of an unchanged p-nitrobenzoyl group and four pyridine protons. However, instead of a singlet for the CH2-group, initially present in the spectrum of the salt la , a new singlet of the NH2-group appeared at 8.2 -- 8.5 ppm in the spectra of products 4. This signal disappeared when D2O was added to the solution of 4b in DMSO, thus confirming the acidic character of NH2-group. IR spectra clearly supported the presence of a new NH2-group and benzoyl fragment in the salts 4. According to X-ray data,13 the counter-ion in the initally formed salt 4 b was thiocyanate (Fig. 2). The angle between the carbonyl group and the plane of thiazolopyridinium bicycle was 23°, whereas such an angle for the p-nitrophenyl group was 42°. Slight alternation of single and double bond lengths around the pyridine ring (analogous to that in 2b) was also observed in the molecule 4. The length of the CS bond adjacent to the bridgehead carbon atom is slightly shorter than that of another CS bond, thus confirming bond alternation around the whole perimeter of the heterocycle 4. The cyclization of 1 into 4 opens a novel route to the previously unknown class of 2-aminoderivatives of thiazolo[3,2-a]pyridinium cations. One would expect formation of mesoionic (munchnone-like) derivatives by deprotonation of NH2-group in the salts 4 (see, e.g. review1 ). Although the salts 4 are soluble in alkali, our attempts to obtain a crystalline mesoionic compound have so far failed. The cyclization discovered corresponds to the novel disconnection scheme CNC + CS for the thiazole ring. Although thiocyanate ion is the standard reagent for SCN + CC synthetic strategy, it has never been used as the source of CS fragment in the chemistry of thiazoles.15,16 The structural design of this reaction has some similarity with the known cyclocondensation of salts 1 with b-dicarbonyl compounds leading to indolizines17 (with the disconnection scheme CNC + CC). In both cases displacement of halogen is followed by intramolecular cyclization, where the electrophilic component arises from an external reagent (CO group of CH-acid or CN-fragment of SCN anion), and the CH2-group in the salt 1 serves as the nucleophilic center.


7555

C16a C6a C7a

051a 052a

C7b
O11b 052b «\)N 15b C14b
Fig. 2. Crystal structure and atoms numbering in the salt 4b. Supplementary Materials: the list of refined coordinates and e.s.d. for 2 b and 4b ; all materials are deposited in the Cambridge Crystal Database. Acknowledgement We thank Russian Foundation of Basic Research (RFBR, grant 99-03-33076a) and Nippon Soda Co. Ltd. for generous support of this work. We also thank RFBR for covering the licence fee for use of the Cambridge Structural Database (project 96-07-89187). References and notes 1. 2. 3. 4. 5. 6. (a) Bradsher, C. K.; Brandau, R. D.; Boilek, J. E.; Hough, T. L., J. Org. Chem. 1969, 34, 2129. (b) Hand, E. S.; Paudler, W. W., J. Org. Chem. 1978, 43, 658. Babaev, E. V.; Tsisevich, A. A., J. Chem. Soc, Perkin Trans. 1 1999, 4, 399. (a) Blank, B.; DiTullio, N. W.; Krog, A. J.; Saunders, H. L., J. Med. Chem. 1978, 21, 489. (b) Pauls, H.; Krohnke, F., Chem. Ber. 1976, 109, 3653. Babaev, E. V.; Maiboroda, D. A.; Pasichnichenko, K. Yu., Khim. Geterotsikl. Soedin. 1997, 3, 397. Babaev, E. V.; Tsisevich, A. A.; unpublished results. Typical procedure for 4b : A suspension of the salt l a (0.358 g, 1 mmol) and KSCN (0.194 g, 2 mmols) in 10 ml of MeCN was refluxed for 5 h. The mixture was filtered off, and the yellow precipitate was washed with water giving the thiocyanate 4b in quantitative yield. To obtain a single crystal (mp 295297°C) for X-ray analysis the compound 4b was dissolved in solution of NaOH in 50% MeOH followed by neutralization with HOAc and addition of CHC13. Perchlorate 4a (mp 245-247°C, 55%) was prepared by dissolving the salt 4b (1.68 mmol) in 2 ml of H2SO4 followed by addition 1 ml of HC1O4. Thiocyanate 2 b was obtained by heating suspension of perchlorate 2a (0.15 g, 0.44 mmol) and KSCN (0.15 g, 1.55 mmol) in 5 ml of MeCN for 5 h. The resulting solid contained a white powder (inorganic products) and large yellow crystals (mp 205-207°C) of 2b ; the crystals were separated and used for Xray analysis (the yield was not optimized). Data for 2b : 1H NMR (in (CD3)SO, 400 MHz): d (ppm) 9.01 (H3, s, 1H); 8.73 (H5, d, 1H, J56=7,3 Hz); 8.06 (m, H7 and H8, 2H, J78=5.2 Hz); 7.99 and 7.80 (Ar, m, 4H); 7.48 (H6, dd, 1H, J56=7.3, J67=6.9 Hz).

C5b

^O C6b

7.

8.


7556

9.

10. 11. 12.

13.

For spectral data of perchlorate 2a see Ref. 23 . X-Ray structure determination and refinement. The intensitity data were collected on an Enraf-Nonius CAD-4 diffractometer18 with graphite monochromated Mo radiation. The reference reflections showed no lost of intensity. Data were corrected for Lorentz and porarization effects using WinGX.19 An absorption correction was not applied. The crystal structures were solved by SHELXS-97.20 Refinement was performed by full-matrix least squares with the SHELXL-97 21 system of programs using F2-values. The positions of the H-atoms were located by difference Fourier maps. Scattering factors were those included in SHELXL-97.20 The ORTEP plots were prepared by PLATON-9721 program. Crystal structure of 2b . (a) Crystal data: molecular formula C13H9N2O3XNCS, Mr=299.30. Cell parameters a=l2.370(3) A; b=8.925(4) A; c=24.425(5) A; a=90.0°; p=90.0°; y=90.0°. V=2696(2) A3. Dc=1.475 gxcm"3. Z=8. Space group orthorhombic Pbca. Crystal size 0.5x0.5x0.5 mm. )X Mo Ka=0.254 mm"1, (b) Data collection: temperature 293K, 9max =27.96°. Reflections measured 2609. (c) Refinement: independent reflections observed with I>2a(I) 2264. No. parameters in LS 227. Rl=0.0587 , wR2=0.1445. Residual electron density (Ap)max 0.239, (Ap)min -0.240. Babaev, E. V.; Rybakov, V. B.; Zhukov, S. G.; Orlova, I. A., Khim. Geterotsikl. Soedin. 1999, 4, 542. Babaev, E. V.; Bozhenko, S. V.; Maiboroda, D. A.; Rybakov, V. B.; Zhukov, S. G., Bull. Soc. Chim. Belg. 1997,106,631. Data for 4a. IR (KBr) v (cm-1) 3310 and 3445 (NH), 1612 and 1720 (CO). ' H NMR (in (CD3)SO, 400 MHz): 8 (ppm) 9.30 (H5> d, 1H, J56 = 6.6 Hz); 8.57 (H8, d, 1H, J78=8.6 Hz); 8.36 and 8.03 (Ar, m, 4H); 8.17 (NH2, s, 2H); 8.14 (H7, d, 1H, J67=7.1 Hz); 7.78 (H6, dd, 1H, J56=6.6, J67=7.1 Hz). Data for 4b . IR (KBr) v (cm"1) 3350 and 3420 (NH), 1610 and 1720 (CO). ' H NMR (in (CD3)SO, 400 MHz): 5 (ppm) 9.24 (H5, d, 1H, J56 = 6.7 Hz); 8.63 (H8, d, 1H, J78=8 Hz); 8.38 and 8.02 (Ar, m, 4H); 8.56 (NH2, s, 2H); 8.15 (H7, d, 1H, J67=7.5 Hz); 7.78 (H6, dd, 1H, J56=6.7, J67=7.5 Hz). Crystal structure of 4b . The compound contained a crystalline water molecule, (a) Crystal data: molecular formula C14H10N3O3SxNCS x 0.5H2O, Mr=365.39. Cell parameters a=5.975(7) A; b=13.624(l)A;c=20.17(2)A;a=91.55(7)°;P=90.11(ll) o ;y=102.66(8)° . V=1601(3)A 3 . Dc=1.516 gxcm"1. Z=4. Space group triclinic P(-l) . Crystal size 0.5x0.5x0.5 mm. (i Mo Ka 0.357 mm"1, (b) Data collection: temperature 293K, 6 max = 24.97 0 . Reflections measured 5174. (c) Refinement: independent reflections observed with I>2a(I) 5174. No. of parameters in LS 523. R 1=0.0643, wR2=0.1481. Residual electron density (Ap)max 0.399, (Ap)mm -0.329. Newton, C. G.; Ramsden, C. A., Tetrahedron 1982, 38, 2965. Vernin, G. Thiazole and Its Derivatives, Part 1 (The Chemistry of Heterocyclic Compounds, vol.34. Ed. Metzger, J. V.), New York: Interscience, 1979, p . 165. Comprehensive Heterocyclic Chemistry. Eds. Katritzky, A. R.; Rees, C. W., Oxford: Pergamon, 1984. Vol. 6, p. 305. Nugent, R. A.; Murphy, M., J. Org. Chem. 1987, 52, 2206. Enraf-Nonius CAD-4 Software, version 5.0. Enraf-Nonius, Delft, The Netherlands, 1989. Farrugia, L. J., WinGX-96. X-Ray Crystallographic Programs for Windows, version 1.5a. University of Glasgow, UK, 1996. Sheldrick, G. M., SHELXS-97. Program for Solution of Crystal Structures. University of Gottingen, Germany, 1997. Sheldrick, G. M., SHELXL-97. Program for Refinement of Crystal Structures. University of Gottingen, Germany, 1997. Spek, A. L., PLATON-97. Molecular Geometry Program, version 1997. University of Utrecht, The Netherlands, 1997. Babaev, E. V.; Efimov, A. V.; Maiboroda, D. A.; Jug K., Europ. J. Org. Chem. 1998, 1, 193.

14. 15. 16. 17. 18. 19. 20. 21 . 22. 23.