The electrophilic iodine-triggered cyclization of ortho substituted arylalkynes is one of the prominent methods for the synthesis of iodine containing fused heterocyclic derivatives.9 A wide variety of fused heterocycles including 5-iodopyrrolo[1,2-a]quinolines, fused benzimidazoles, iodoisoquinoline-fused benzimidazoles, iodofuro[2,3-b]chromones, iodo-indoloazepinones, 2-iodo-spiro[indene-1,10-isobenzofuran]-30-ones, dihydrocyclopenta[b]indole, furo[2,3-b]quinoline, iodopyrano[4,3-b]quinolines and pyrralopyridines ...etc. were constructed using iodocyclization strategy.10
Scheme II.B.3.1 Plausible pathway for the formation of products
On the other hand, 2-alkynylbenzaldehyde is a handy and an interesting structural motif for the generation of functionalized polycyclic compounds and is also very good electrophilic species for iodocyclization.11 Our group have been interested in exploring the iodine mediated transformations for long time.12 In this context, we found that the reaction of aldehyde with various indoles in the presence catalytic amount of iodine produced corresponding bisindole in high yields. On the other hand, recently, Verma and his co-workers have reported the synthesis of indolo[1,2-a]quinolines via (6-endo-dig) iodocyclization using molecular iodine.10d Moreover, recently, Enders and co-workers observed the formation of seven membered (7-endo-dig) fused tetracyclic azulene derivatives using gold catalyst.7 Based on these two observations, we envisioned that the reaction of 2-(phenylethynyl)benzaldehyde and indole in the presence of iodine could initially produce corresponding bisindole which further can undergoes iodocyclization to produce either indole fused azulene compound 3a or benzofusedcarbazole derivative 4a (Scheme 1).
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To investigate our assumption, we choose 2-(phenylethynyl)benzaldehyde and indole as model substrates. In our initial reaction, we treated 2-(phenylethynyl)benzaldehdye (1 equiv) and indole (2 equiv) in the presence of 2 equiv of iodine (I2) in dichloromethane at 0oC to room temperature (Table II.B.3.1, entry 1). Under these conditions, the reaction produced bisindole derivative (i) as a sole product. However, when 2 equiv of sodium bicarbonate was used as base (entry 2), two products were formed. Among the two products, the major product was bisindole and the 1H NMR, 13C NMR, LRMS, HRMS, single crystal X-ray diffraction revealed that the minor product was indole fused azulene compound 3a (Figure II.B.3.1). Interestingly, indole fused azulene derivatives exhibit anti-cancer and anti-neoplastic properties.2 In fact, the synthesis of few indole fused tetracyclic azulene derivatives have reported in the literature using various metal catalysts.4 However, to our knowledge, there is no efficient, non-metallic protocol is available for the construction of indole fused azulene tetracyclic derivatives. This fact prompted us to investigate iodocyclization reaction in more details.
Figure II.B.3.1 ORTEP Diagram of Single X-ray Diffraction Structure of 3a.15
To determine the best conditions for the formation of indole fused azulene (3a), we screened various reaction conditions. In this regard, we first evaluate the efficiency of iodine reagent by the reaction of 2-(phenylethynyl)benzaldehdye (1 equiv), indole (2 equiv) and sodium bicarbonate (2 equiv) in dichloromethane at 0oC. The reaction results indicate that the use of molecular iodine below 3 equiv produces desired indole fused azulene 3a along with bisindole as a minor product. However, the reaction with 3.2 equiv iodine and 2 equiv NaHCO3 resulted in 66% of compound 3a as a single product (entry 4).
Next, we screened the reaction with different solvents such as acetonitrile, 1,4-dioxane,
113 Table II.B.3.1 Optimization of reaction condition
a Reactions were performed on 0.25 mmol scale. b Yields refer to isolated and purified compound. Parentheses correspond to the NMR yield using CH2Br2 as an internal standard.
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THF and diethyl ether. The reaction worked in most of the solvents but not produce high yields, however, chloroform produced the best yield of the desired product (entry 9).
After solvent screening, we screened different bases such as K2CO3, Cs2CO3 and t-BuOK.
The desired product was obtained in poor yields (entries 11, 12 and 14). However, the reactions furnished good yields of the expected product, when the mild bases such as Na2CO3 and K3PO4 were used in the reaction (entries 10 and 13). Moreover, we screened the reaction in the presence of organic bases. When the reaction was carried out in the presence of strong organic bases such as DIPEA (N,N-Diisopropylethylamine), DBU (1,8-Diazabicycloundec-7-ene) and weak base such as DABCO (1,4-diazabicyclo[2.2.2]octane), the desired product obtained in moderate yields (entries 16, 17 and 18). To our delight, in the presence of TEA (Triethylamine) the reaction gave the best result with 84% isolated yield (100% NMR yield) of the desired product in 9 hours (entry 15). Further, we also screened different iodine sources for this reaction. NIS (N-Iodosuccinimide) and ICl (Iodine monochloride) gave the desired product in poor yields (entries 19 and 20). Molecular iodine was found to be the best choice for this reaction.
The reaction was also tested on varied quantities of Iodine with TEA as a base (entries 21-23). However, in the presence of iodine less than 3.2 equiv, the reactions were incomplete and resulted in poor yield of the desired product.
To compare the stepwise and one pot reactions, the intermediate bisindole (i) was prepared by the reaction of 1 equiv of aldehyde (1a) and 2 equiv of indole (2a) in the presence of catalytic amount of iodine. Then, bisindole was treated with 2.2 equiv of iodine and 2 equiv of triethylamine. The reaction resulted in 100% NMR yield and 88%
isolated yield of the desired product in 8 hours. The stepwise and one pot reaction produced almost similar results. Hence, the scope of reaction was examined with one pot reaction conditions.
After the optimization of reaction conditions, the scope and limitations of this one-pot tandem iodocyclization of the indole fused tetracyclic azulene was further investigated by using various 2-(phenyethynyl)benzaldehyde and substituted indole derivatives. The reaction of 1a with unsubstituted indole under the optimized reaction conditions, gave the corresponding product 3a in excellent yield (Table II.B.3.2, entry 1). However, moderate electron withdrawing groups such as chloro and bromo on indoles produces corresponding compounds 3b and 3c in good yields in shorter reaction time (entries 2 and 3). Indoles with moderate electron donating groups (methyl and ethyl) also provided the desired product 3d and 3e in good yields with longer reaction time (entries 4 and 5). On
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the other hand, the reaction of 1a with indole bearing strong electron donating group such as methoxy gave the desired product 3f in moderate yield (entry 6). It is worth noting that reactions of indole possessing electron donating groups took longer reaction time compared to indoles with electron withdrawing groups. Furthermore, under the standard reaction conditions, the indole derivatives possessing strong electron withdrawing groups like nitro, cyano furnishes only trace of intermediate bisindole derivatives. However, when the reactions were carried out at 60oC, the reactions produced corresponding tetracyclic derivatives 3g and 3h in good yields. The need of higher temperature is may be due to the less nucleophilic nature of the indoles.
Next, we investigated the tandem iodocyclization of various substituted 2-(phenethynyl)benzaldehydes and substituted indoles. As depicted in Table II.B.3.3, the reactions of both electron donating (OMe) and electron withdrawing (NO2) substitutions on 2-(phenylethynyl)benzaldehyde with indole delivered the desired products 3i and 3j in good yields (entries 1 and 2). However, nitro aldehyde forms corresponding compound faster than methoxy aldehyde. Moreover, the aldehydes possessing strong electron donating groups such as 1d and 1e gave the expected products 3k and 3l in moderate yields, with longer reaction time (entries 3 and 4). On the other hand, the reactions of methyl indole (2d) with aldehyde 1b and 1c furnished the desired products 3m and 3n in good yields but nitro aldehyde 1c took longer time. Similar trend were observed, when ethyl indole (2e) was used as indole component (entries 7 and 8) to obtain corresponding products 3o and 3p. The reactions of indoles containing moderate electron withdrawing groups such as chloro and bromo gave the desired products in good yields with 5-methoxy-2-(phenylethynyl)benzaldehyde (1b) and 5-nitro-2-(phenylethynyl)benzaldehyde (1c) (entries 9-12). Furthermore, the scope of the reaction was examined with mild and strong electron donating substitution at aromatic alkynes.
The moderate electron donating methyl substituted alkyne aldehyde 1f produced the compound 3v in better yield in shorter reaction time than compound 3w when strong electron donating methyleneoxy alkyne aldehyde was used as a substrate (entries 14 and 15). This protocol failed to produce corresponding product with aliphatic 2-(hex-1-yn-1-yl)benzaldehyde Probably the bulky long chain alkyl group may prevent the attack of indole on intermediate iodonium ion to form corresponding tetracyclic compound. This may leads to decomposition or formation of several other products. (entry 16).
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Table II.B.3.2. Iodine mediated tandem cyclization of 2-(phenylethynyl)benzaldehyde and various indole derivatives
a All reactions were performed on 0.25 mmol of aldehyde 1a and 0.5 mmol of indole 2a-2h. b Iodine (3.2 equiv) and triethylamine (2.0 equiv) in CHCl3. c Yields refer to isolated and purified compound. d The reactions were carried out at 60oC.
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Table II.B.3.3. Iodine mediated tandem cyclization of 2-(phenylethynyl)benzaldehyde and various indole derivatives
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a All reactions were performed on 0.25 mmol of aldehyde 1a-1h and 0.5 mmol of indole 2a-2f. b Iodine (3.2 equiv) and triethylamine (2.0 equiv) in CHCl3. c Yields refer to isolated and purified compound. d Inseparable mixture of products.
In order to extend the scope of our protocol, we synthesized N-((1H-indol-3-yl)((phenylethynyl)phenyl)methyl)-N-methylaniline (5a) using N-methylaniline (2 equiv), 2-(phenylethynyl)benzaldehyde (1 equiv) and indole (1 equiv) in ethanol with Bromodimethylsulfonium bromide (BDMS, 20 mol%) to obtain crude compound 5a.13 Further, the crude compound (5a) was treated with iodine (2 equiv) and triethylamine (2 equiv) to yield compound (6a) in 65% and 10% unreacted starting material (Scheme
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II.B.3.2). The unreacted starting material was not consumed even after the addition of extra iodine to the reaction mixture.