Alfa-diazo-beta-oksoaldehitlerden triazol türevlerinin sentezi

Abstract

Bu çalışmada on adet a-diazo-P-oksoaldehit bileşiği, değişik kombinasyonlar ile anilin, amonyak, hidroksilamin ve semikarbazid ile kondenzasyon reaksiyonuna sokul muş ve 18 adet lH-l,2,3-triazol bileşiği sentez edilmiştir. Bunlardan 14 tanesi yeni bileşikler olup aşağıda listelenmiştir: 4-Asetil-l-fenil-lH-l,2,3-triazol, 4-(2-Metilpropanoil)-l-fenil-lH-l,2,3-triazol, 4-(3-Metilbutanoil)-l-fenil-lH-l,2,3-triazol, 4-(l-naftoü)-l-ferıil-lH-l,2,3-tria- zol, 4-(4-Klorobenzoil)-l-fenil-lH-l,2,3-triazol, 4-(3,4-diklorobenzoil)-l-fenil- lH-l,2,3-triazol, 4-(2,4-Diklorobenzoil)-l-fenil-lH-l,2,3-triazol, 4-(2,4-Dibro- mobenzoil)- 1-fenil- İH- 1,2,3-triazol, 4-(2,4,6-Trimetilbenzoil)-l-fenil- İH- 1,2,3- triazol, 4-Karbetoksi- İH- 1,2,3-triazol, 4-Asetil-lH-l,2,3-triazol, 4-(2,4-Diklo- robenzoil) -lH-l,2,3-triazol, 4-(2,4-Dibromobenzoil) -lH-l,2,3-triazol, 4-Karb- etoksi-l-hidroksi-lH-l,2,3-triazol, 4-Asetil-l-hidroksi-lH-l,2,3-triazol oksim, 4-(2,4-Dibromobenzoil)-l-hidroksi-lH-l,2,3-triazol oksim, 4-Karbetoksi- 1- üreido-lH-l,2,3-triazol, 4-Asetil-l-üreido-lH-l,2,3-triazol semikarbazon. Sentezlenen bileşikler kromatografik yöntemlerle ayrılıp, spektral yöntemlerle (İR, lH- ve 13C-NMR, El- ve CI-MS) tanımlanmışlardır. Çalışmada kullanılan 10 adet a-diazo-P-oksoaldehit çıkış bileşiğinin sentezi için önce metü ketonların formik esterler ile Claisen kondenzasyonu uygulanıp yüksek verimlerle (3-oksoaldehit sodyum enolatlan elde edilmiştir. Ardından bu P-oksoaldehit- lerin 2-azido-l-etilpiridinyum floroborat ile diazo transferi reaksiyonları sonucunda a-diazo-P-oksoaldehitler elde edilmiştir. Bu diazo transfer reaksiyonu yakın geçmişte çalışma grubumuz tarafından geliştirilmiştir ve kısmen deformilasyonsuz gerçekleşmesi nedeniyle amaç diazo bileşiklerinin sentezi için önem taşımaktadır. Aminler ile kondenzasyon reaksiyonu orta-yüksek verimlerle gerçekleşmektedir. Literatürde yer alanlara kıyasla uygulanan yöntemin kestirme oluşu ve benzer/üstün verimleri yamnda regiospesifik olması da üstünlük kazandırmaktadır: Kondenzasyon sonucunda olası iki regioizomerden 5-R-l-R>lH-l,2,3-triazol-4-karbaldehitler oluş- mamakta, yalnızca 4-açil-l-Rl-lH-l,2,3-triazoller oluşmaktadır.

Triazoles constitue a large class of heterocycles, many of which are biologically active. Numerous examples of their synthesis and also their uses as starting materials for several natural products can be found in the literature. The vast majority of the synthetic methods leading to lH-l,2,3-triazoles are based on dipolar cycloaddition of azides to multiple bonds. Another method uses the condensation of amine derivatives with ct-diazo-l,3-dicarbonyl compounds. With this procedure, several triazol- containing antibiotics were prepared in patented works. a-Diazo-|3-oxoaldehydes remained having only three examples until 1994, when Sezer and Anaç found that 2-azido-l-ethylpyridinium fluoroborate diazotizes 0- oxoaldehydes partially without deformylation in the presence of sodium acetate. This reaction can be used as an alternative synthetic method for these diazoaldehydes (Scheme- 1). s^S* m «* R-C-CH=N, (T n - NaOAc ii 2 R-C-CH2-CH=0 + [ I BF4 *- o SN' I '"3 Et N, + R-C-C-CHO II II O N2 Scheme-1: The reaction of (3-oxoaldehydes with 2-azido-l-ethylpyridinium BF4. In our study, ten different a-diazo-P-oxoaldehydes were condensed with amin derivatives, namely with aniline, ammonia, hydroxylamine and semicarbazide. (Scheme-2) CH R- C- Ç- Ç- H + R1- NH2 *. R- CO- C* NN-R' II II II \ / o n2 o k=N Scheme 2: Reaction of a-diazo-P-oxoaldehydes with amin derivatives. The reaction mechanism for this condensation is given in Scheme-3. The reaction yields and the melting points of the products are presented in Table- 1. vu 8 § R- CD- C- CHO -«-*. R- CD- C- CHO ?*-*. R- CO- C- CHO II I I N2 fflN !N N Nffi R1- NH, 8 II 2-». R-CO- C- CHO - R- CO- CH- C- H / ^ / f 'N jr Ov H HO H > y -». R- CO-CH ^NHR1 ^ «. R- CO-CH" SN- R1 \ /. \ / N=N N=N CH ». R- CD C* VN- R1 - H2° N=N Scheme-3. Formation mechanism of l-substituted-4-acyl-lH-l,2,3-triazoles The advantage of this method is that it yields only one of the two possible regioisomers of the products. The condensation takes place regiospesifically with the highly electrophilic formyl group, not with the less electrophilic and sterically demanding acyl group. Most of the reactions were very clear and no difficulty was experienced in the purification steps. The condensations with hydroxylamine and semicarbazide went further and the ketone functions were converted to oximes and semicarbazones respectively. The ester groups remained intact as expected (Equations 1-4). The diazomethyl ketones, which forms besides the diazooxoaldehydes in the diazotization reaction, do not interfere this condensation (Equation-5). Therefore the diazooxoaldehydes may be safely employed as mixtures with diazomethyl ketones. The high crystallinities of the triazole products simplify the purification process. In the worst cases the products were purified by preparative TLC very easily. The widely used azide + acylacetylene method is regioselective but not regio- spesific. It usually gives the normal addition product with respect to the polarization of the acetylene, but the inverse adducts sometimes appear in varying amounts (Equations 6-7). In this manner our method is more advantageous. vm CH R-CO- C-CHO + 2NH2OH * R-C-C* "N-OH II II \ / (1) N, N N=N I OH CH R- CO- C- CHO + 2NH2NHCONH2 *? R- C- C NN- NH N2 N N=N CO NH NH2 CO I NH2 R-CO-C-H + R'- NH2 *? No Reaction N2 R- CO- C=C- H CH «xt Sr # *" R- CO- C* VN- R1 N 9 N=N Normal Addition N< Inverse Addition (2) C2H50-CO-C-CHO + NH2OH * C2H50-CO-C "N-OH ns II \ / (3) No N=N CH C,H50- CO- C- CHO + NH2NHCONH, - *-C2H50- CO- C* XN- NH //1N z 5 n 2 2 \ / l (4) N2 N=N CO I NH, (5) (6) R_co- C=C- H CH, -q ". *- R- CO- C* NN Rl-.< Jl@ \ // (7) v^ N-N IX Table - 1. Structures, yields and melting points of the synthesized triazoles. Yield (%)a'b Formula mp. (°C) CBj-C-^N-Ph O N=N 73 107-8 CH3-CH-C- f "N-Ph J I II \ / CH3 O N=N 19 (52) 100-100.5 CH3-CH-CH2-C- ^N-Ph CH, CD N=N 17 (65) 107-8 II \ ' O N=N N-Ph 10 (26) 118-9 CI N-Ph O N=N 28 (53) 183-4 N-Ph O N=N 58 (78) 205-6 CI D N-Ph O N=N a 75 (87) 135-136.5 Br-(0>-Ç-f ;N"Ph O N=N Br 75 (80) 151-2 CH CH3 N - { O N=N CH, 27 (29) 102-102.5 Table - 1. (Cont). Structures, yields and melting points of the synthesized triazoles. Formula Yield (%) ^b mp. (°C) C^HgO-C- f^^N-H Ö N=N 50 111-2 CH3-C- ^ N-H 0 N=N 24 131 C! D N-H O N=N a 20 153 Br N-H O N=N Br 26 162.5-166 cy-lgO-C- ^Nj-OH Ö N=N 161-2 CH3-C- ^N-OH N N=N * OH 12 168-170 ( N N=N Br OH 15 186' o,d CjHgO-C- ^N-NH-CO-NH2 O N=N 35 I9r CH3-C-^Nj-NH-CO-NH2 N N=N NH-CO-NH2 64 239.5C XI Table - 1. (Cont). Structures, yields and melting points of the synthesized triazoles. a All diazooxQaldehydes were employed without separation from their by-standing diazo- methyl ketones, except tor 2-diazo-3-oxobutanal (R=Me) and 2-diazo-3-oxopropanoic acid ethyl ester (ROEt). Yields after pure isolation, based on the starting P-oxoaldehydes. The values in parant- heses are the yields based on the oc-diazo-p-oxoaldehydes, calculated by the diazoaldeyde content of the diazo mixture. 0 Decomposition. d Softens around 150°.