Thiophene diazotization

Electrocyclization reactions are often used to synthesize fused thiophenes. Diazotization of an aminoisoquinoline gave a mixture of products including a 6-thiaellipticine and a pyrazolo[3,4-A]isoquinoline in 34% and 41% yields, respectively (Eq. 30) <96CC2711>. A diazotization... 

Benzo[6]thiophene, 2-acetyl-3-hydroxy-synthesis, 4, 892 Benzo[6]thiophene, 2-acyl-synthesis, 4, 918 Benzo[6]thiophene, 3-acyl-synthesis, 4, 918- 19 Benzo[6]thiophene, acylamino-synthesis, 4, 815 Benzo[6]thiophene, alkenyl-synthesis, 4, 917 Benzo[6]thiophene, 2-alkoxy-synthesis, 4, 929 Benzo[6]thiophene, 3-alkoxy-synthesis, 4, 929 Benzo[6]thiophene, 4-alkoxy-synthesis, 4, 930 Benzo[6]thiophene, 2-alkyl-synthesis, 4, 877-878 Benzo[6]thiophene, 2-alkylthio-synthesis, 4, 931 Benzo[6]thiophene, 2-amino-diazotization, 4, 810 reactivity, 4, 797 stability, 4, 810 synthesis, 4, 869, 924-925 tautomerism, 4, 38 Benzo[6]thiophene, 3-amino-cycloaddition reactions, 4, 68 synthesis, 4, 109, 881, 925 Benzo[6]thiophene, 4-amino-synthesis, 4, 925 Benzo[6]thiophene, 5-amino-synthesis, 4, 925 Benzo[6]thiophene, 7-amino-synthesis, 4, 925 Benzo[6]thiophene, 3-t-amyl-synthesis, 4, 915 Benzo[6]thiophene, 2-aryl-synthesis, 4, 881... 

Thiophene-2-carboxamide, 3-amino-diazotization, 4, 810 Thiophene-2-carboxamide, 5-cyano-synthesis, 4, 898, 920... 

In —I—M-substituted aminothiophenes, the possibility of coupling during diazotization is eliminated. Thus ethyl 5-amino-2-thiophene-carboxylate and 5-amino-2-thiophenesulfonic acid and its amide- have been diazotized and coupled with various reagents. 

The diazotization of heteroaromatic amines is basically analogous to that of aromatic amines. Among the five-membered systems the amino-azoles (pyrroles, diazoles, triazoles, tetrazoles, oxazoles, isooxazoles, thia-, selena-, and dithiazoles) have all been diazotized. In general, diazotization in dilute mineral acid is possible, but diazotization in concentrated sulfuric acid (nitrosylsulfuric acid, see Sec. 2.2) or in organic solvents using an ester of nitrous acid (ethyl or isopentyl nitrite) is often preferable. Amino derivatives of aromatic heterocycles without ring nitrogen (furan and thiophene) can also be diazotized. 

When 2 -methoxy-2-biphenylamine is diazotized in fluoroboric acid, an 85% yield of solid 2 -methoxy-2-biphenylyldiazonium tetrafluoroborate is produced. On heating in dry benzene, this salt loses nitrogen and provides 0-methyldibenzofuranium tetrafluoroborate as an unstable solid. The latter salt, on account of the low basicity of dibenzofuran, reacts with a range of nucleophiles that undergo methylation with the release of dibenzofuran. Pyridine and pentachloropyridine are N-methylated, benzo[fc]thiophene is S-methylated, and tetrahydrofuran and phenetole are 0-methylated. ° Thus it is no surprise that diazotization of 2 -methoxy-2-biphenylamine, followed by boiling of the diazonium salt in acidic solution, provides dibenzofuran in 90% yield.The scope of this method of dibenzofuran synthesis (Scheme 18) has been little explored probably because of the difficulty of preparing the requisite biphenyls, which is usually accomplished by a crossed Ullmann reaction. A similar synthesis of xanthones from 2-amino-2 -methoxybenzophenones is known. ° ... 

Diazotization of aminothiophene and the Hurd-Mori reaction <1955JA5359> are two popular methods for synthesis of thieno[2,3- -l,2,3-thiadiazoles. Amine 128 gave only a poor yield of methyl thieno[2,3-/7]-l,2,3-thiadiazole-6-carbox-ylate 131a when subjected to acidic diazotization conditions (Scheme 14). The fully substituted thiophenes 129 and 126 underwent cyclization in much greater yields under similar conditions <1999M573>. Protected amines 127 and 130 also gave a better yield of the cyclized product than the unprotected amine 128 <1999JHC761>. 

As in the synthesis of thieno[2,3-,7]-l,2,3-thiadiazoles, thieno[3,2-.7 -l,2,3-thiadiazoles are made using diazotization of aminothio-substituted thiophenes and by Hurd-Mori reaction of hydrazones. Diazotization of compound 134 with NaN02 in AcOH/HCl at 0°C produced methyl thieno[3,2- / -l,2,3-thiadiazole-5-carboxylate 135 but in only low yield. Hydrazone tautomer 136 treated with excess SOCI2 in CH2CI2 at room temperature gave dimethyl thieno[3,2- / -l,2,3-thiadiazole-5,6-dicarboxylate 137 and dimethyl 5,6-dihydrothieno[3,2- / -l,2,3-thiadiazole-5,6-dicarboxylate 138 in a ratio of 3 2 (Equations 20 and 21) <1998H(48)259>. 

In competitive studies (73IJS295, 74AHC(16)123) using aprotic diazotization of aniline to generate phenyl radicals, it has been shown that the relative rates of phenylation for furan and thiophene compared to benzene are 11.5 and 2.6, respectively. The partial rate factors... 

Heteroaryl radicals, generated by aprotic diazotization of heteroarylamines, have been reacted with thiophene to form the heterylthiophenes in 20-50% yields (75JOC3183, 78HCA2941). The 2/3 isomer ratio was generally about 85 15. Other heterylthiophenes have been prepared by photolysis of the iodoheteroaromatic compound in a solution of thiophene in acetonitrile thus the 2-(5-pyrimidinyl)thiophene (224) was obtained in 58% yield (with 2% of the 3-isomer) (77JCS(Pl)62l) and 2-(3-pyridinyl)thiophene (225) in 42% yield (2/3 isomer ratio 7 1) (72CC594). 

Diazotization followed by cyclization has been used to prepare fused thiophene derivatives. Thus diazotization of 3-aminothiophene-2-carboxamides in cone. HC1 leads to thieno-1,2,3-triazines (Scheme 122) (75CRV241). A similar reaction was also observed with the 4-carboxamide derivatives. With 2,4-dicarboxamides as substrates the 3-diazo group preferred to cyclize with the 2-carboxamide group. 

There is considerable interest in the chemistry of triazines as some of these compounds show pronounced antimalarial, antimicrobial and antiviral activity (76JCS(Pl)252l). Therefore two types of thiophenes annelated with a triazine ring will be mentioned. Thieno[2,3-d]-1,2,3-triazines were synthesized by cyclization of diazotized 2-aminothiophene-3-carboxamides (equation 55) (73M1586). Treatment of 3-alkylthio-6-styryl-5-oxo-2,5-dihydro-l,2,4-triazines with phosphorus pentasulfide in pyridine yields thieno[2,3-e]-l,2,4-triazines (equation 56) (78CI(L)585). Probably a thiation with subsequent cycloaddition and elimination of a hydride ion is involved. 

The methods used for preparing cyanobenzo[6]thiophenes are merely summarized in the present section they are discussed in more detail elsewhere in this review. Cyanobenzo[6]thiophenes are most conveniently prepared by heating a halobenzo[6]thiophene with cuprous cyanide in a suitable solvent (Section VI, D, 2), or by means of a Sandmeyer reaction of the appropriate diazotized amine (Section VI, F, 4 and 5). Less commonly they are prepared from aldehydes or aldoximes, by methods described in Section VI, L, 1, or from carbox-... 

Arylthiophenes. Thiophene couples with the diazohydroxides 3 and with N-nitrosoacetylamines 1 to give phenylthiophenes and derivatives. The position taken by the aryl groups in the thiophene nucleus has not been determined in all instances. The product obtained from diazotized wj-cyanoaniline and thiophene 3 in 19% yield appears to be the a derivative (XV).13... 

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