In this reaction, the cyanide functionality was shifted to the benzylic position and a six membered pyran ring was rearranged to a five membered furan ring. As the reaction was occurred only at high temperature, we first assumed a thermal reaction. Hence, our initial assumption was a thermal cleavage of the pyran ring, followed by the 1, 2-shift of the cyano functionality and cyclization to produce intermediate c (Pathway A, Scheme
23 Table I.B.3.1.Effect of different bases
a All reactions were carried out on 0.5 mmol scale. b Base (1.2 equiv) in DMSO at mentioned temp. c Yields refers to isolated and purified compound.
I.B.3.2). Aromatization of the intermediate c produces the final product. However, when we performed a reaction in the absence of sodium azide, no product was formed and the starting material was recovered. This experimental observation rules out the possibility, which is described in pathway A. Then we assumed a nucleophilic attack by azide anion to form intermediate e (Pathway B), which is followed by the ring opening via the cleavage of C-O bond in SN2 manner to form intermediate f. A base mediated E2 reaction on intermediate f, may produce intermediate b, which would be converted into final product as described earlier. To clarify this assumption, we screened the reaction with
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bases, like DIPA, NaOMe and N,N-diethylethane-1,2-diamine as they may act as nucleophile as well as base (Table I.B.3.1). However, the reactions were either failed (entries 6 and 13) or produced the desired product in poor yields (entry 12). On the other hand, bases like DBU, K2CO3, Na2CO3 and Cs2CO3 produced better yields of the desired product. Among the different bases, K2CO3 produced better yields than the others. This fact tells more about a base mediated mechanism, which happened via the abstraction of a proton by a base at high temperature to produce the unstable anion g. This anion undergoes ring cleavage to produce the intermediate h. The 1,2-shift of the cyano functionality was occurred either via pathway D or E to produce the intermediate k (allene intermediate). Intermediate k undergoes cyclization and followed by the aromatization to produce the desired product. It is not clear whether the reaction was occurred via pathway D or E. However, in the crude 1H NMR, we did not observe the formation of product m under air and moisture. We prefer the pathway D as the most favorable route for the formation of the product d. From our studies with different bases, we found that a base of moderate strength, such as sodium azide, was more suitable than other strong or weak bases. Hence, we evaluated the scope of our methodology by using sodium azide in DMSO (entry 2)
After determining the best conditions for the conversion, we utilized different cyanochromene derivatives, to evaluate the scope of this methodology (Table I.B.3.2).
With unsubstituted cyanochromene, the reaction produced the expected benzofuran derivative in good yield (entry 1). A comparable result was observed with 6-methyl-3-cyanochromene (entry 2). However, the yields of the desired products were decreased in the case of methoxy substituted cyanochromenes (entries 3-4). The yield of the product was further decreased when the dimethoxy substituted cyanochromene derivative was used as substrate (entry 5). Moreover, the desired products were obtained in moderate yields from the 6-halo cyanochromene derivatives (entries 6, 7). However, the yield of the desired product was poor in case of 6-iododerivative (entry 8). Interestingly, when the benzene ring of the cyanochromene was replaced with naphthalene moiety (entry 9) the reaction furnished the corresponding product in good yield. On the other hand, the reaction of 6-acetyl-2H-chromene-3-carbonitrile in the present reaction conditions compounds resulted in the formation of an inseparable mixture of products even at lower temperature (entry 10). The crude 1H NMR did not show a trace amount of the desired product, although, all the starting materials were consumed. The present reaction conditions were found to be suitable even for the preparation of benzothiophene
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Table I.B.3.2.Synthesis of benzofuran and benzothiophene derivatives
Continue…………..
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a All reactions were carried out on 0.5 mmol scale. b NaN3 (1.2 equiv.) in DMSO at 160oC.
c Yields refer to isolated and purified compounds. d Inseparable mixture. e NR: Reaction was not occurred and only starting material was recovered.
derivative (entry 11). However, in this case, the desired product was obtained in poor yield. The protocol failed to form corresponding compound, when the stable aromatic heterocycle, such as 2-amino-3-cyanoquinoline (entry 12), was treated with sodium azide under catalyst free.
On the other hand, the result was completely different when the reaction of sodium azide and cyanochromene (1) was carried out in the presence of catalytic amount of CuI with DMSO as a solvent (Table I.B.3.3, entry 1). In this case, the reaction was occurred at lower temperature and the resulting product was chromenotetrazole (1a, Table 3), which was confirmed by 1H NMR, 13C NMR, LRMS, HRMS and single crystal X-ray analysis data (Figure I.B.3.2). With this exciting experimental outcome in hand, we focused our attention towards exploring the most favorable conditions for the reaction as depicted in Table I.B.3.3. During the reaction with DMSO, we faced difficulty in separation of compounds but when the reaction was carried out in DMF as a solvent, excellent yield of
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compound 1b was obtained in 4h (entry 2). Next, we screened different copper catalysts such as Cu2O, CuSO4, Cu(OAc)2 in both DMF and DMSO but fail to improve the reaction yield and reduce the reaction time (entries 3 to 8). To find a better alternative of CuI, other Lewis acids such as TiCl4, AlCl3 and ZnBr2 was screened but produced the desired product in lower yields (entries 9 to 11). Iodine was found to be ineffective for the conversion (entry 12). Hence, DMF as solvent and CuI as catalyst at 120oC was found to be optimal reaction condition for evaluating the scopes of this protocol.
Figure I.B.3.2. X-Ray Crystal structure of 1b (ORTEP diagram) Table I.B.3.3. Solvent and reagent screening
a All reactions were carried out on 0.5 mmol scale. b Yields refers to isolated and purified compounds.
28 Table I.B.3.4. Synthesis of chromenotetrazoles
29 Continue…………..
a All reactions were carried out on 0.5 mmol scale. b NaN3 (1.2 equiv)/ CuI (20 mol %) in DMF at 120oC. c Yields refers to isolated and purified compounds.
Under the present reaction conditions, several cyanochromenes underwent cycloaddition to form chromenotetrazoles as shown in Table I.B.3.4. The use of unsubstituted and methyl substituted cyanochromenes resulted in excellent yields of the product (entries 1 and 2). Moreover, comparable yields were obtained with methoxy substituted cyanochromenes (entries 3, 4, 11 and 12). The expected tetrazoles were obtained in excellent yields from cyanochromenes with electron withdrawing groups (entries 5, 6 and 8). Interestingly, the cyanobenzochromene (entry 9) is also produced the expected tetrazole in excellent yield under the present reaction conditions. From the Table I.B.3.4, it is evident that the reaction of cyanochromen possessing an electron donating group took longer time compared with unsubstituted cyanochromene and a cyanochromene with an electron withdrawing substituent to form their corresponding tetrazoles. It is worthy to note that the present reaction conditions were utilized for the nitrogen and sulphur
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analogues of cyanochromenes like cyanothiochromene (11) and cyanoquinoline (12).
Under these conditions the reaction furnished their corresponding products i.e.
thiochromenotetrazole (11b) and 2-aminoquinolinotetrazole (12b) in moderate and excellent yields respectively
The most notable point is that under these reaction conditions the chromene ring remained unaffected and the product formation was occurred via selective transformation of the cyano functionality into tetrazoles. The plausible mechanism is similar to the Zn2+
catalyzed transformation of nitriles into tetrazole, which was proposed earlier by Sharpless (Scheme I.B.3.3).12 We assume a similar type of activation of nitrile functionality by the coordination of Cu(I) with the nitrogen (intermediate x, Scheme I.B.3.3) and hence, the azide anion attacked at the nitrile functionality. To the best of our knowledge, these chromenotetrazole derivatives are new in the literature.