Gold-catalyzed formation of pyrrolo- and indolo-oxazin-1-one derivatives: The key structure of some marine natural products

Various N-propargylpyrrole and indolecarboxylic acids were efficiently converted into 3,4-dihydropyrrolo- and indolo-oxazin-1-one derivatives by a gold(III)-catalyzed cyclization reaction. Some of the products underwent TFA-catalyzed double bond isomerization and some did not. Cyclization reactions in the presence of alcohol catalyzed by Au(I) resulted in the formation of hemiacetals after cascade reactions.

The design and synthesis of pharmaceutically relevant building blocks has always been a significant goal in organic synthesis. Moreover, modification of natural products is also an important approach to identify promising anticancer agents. Especially due to the bioactivity of lukianols, many groups accomplished the synthesis of these marine products and their analogues [21][22][23][24][25][26]. Despite the general and widespread interest in these struc- tures, the core structure, 1H-pyrrolo[2,1-c] [1,4]oxazin-1-one (5), is not described in the literature. However, there are relatively few synthetic routes leading to the substituted core structure 6 ( Figure 2), which was generated by treatment of methyl 2-pyrrole-carboxylate with chloroacetone [2,[27][28][29][30]. This core structure is also a very important intermediate for the synthesis of pyrrolo-pyrazinones as well as for pyrrolo-pyrazines [31]. Recently, Wang et al. reported the base-catalyzed intramolecular cyclization of alkynyl alcohols at high temperatures to give 1,4-oxaza heterocycles [32]. In this manuscript we envisaged a synthetic strategy leading to the core skeleton of marine products 6 and 7 ( Figure 2) or their analogues with short reaction times and an atom-economic process using a gold-catalyzed alkyne cyclization reaction as the key step.

Results and Discussion
The starting compound 11 was synthesized via a slightly modified route by acetylation of pyrrole with trichloroacetyl chloride in 99% yield [42,43]. The propargyl ester 13 [44][45][46] was obtained in high yield from the reaction of 12 with propargyl bromide in the presence of NaH as a base (Scheme 2). Gold catalysis is an excellent method for constructing complex chemical architectures in a mild manner that would be difficult to achieve using other reactions [41,[47][48][49][50][51][52][53]. Reaction of propargyl ester 13 with AuCl 3 resulted in the formation of 14, which is an H 2 O (present in the reaction media) addition product to alkyne units. It has been proposed that a gold-activated water intermediate can easily be added to alkynes. The addition of water to alkyne has been reported by several research groups [54,55]. The expected cyclization product having the structure 6 or 7 was not formed. Scheme 2: Synthesis of 13 and its reaction with AuCl 3 .

Scheme 3: Synthesis of 6.
After failure of the cyclization reaction of 13 with AuCl 3 , even in water-free solvents, we turned our attention to the construction of the pyrrolo-oxazin-1-one skeleton with the corresponding acid 15. For this purpose, the propargyl ester 13 was first hydrolyzed with K 2 CO 3 to acid 15 (Scheme 3) [56]. The acid 15 was reacted with various metal catalysts in chloroform at different temperatures and for different reaction times. Five different catalysts were tried (Table 1). Surprisingly, no reaction was observed when the reaction was conducted with the N-heterocyclic carbene (NHC) complex of Au(I) in chloroform ( Table 1, entry 5). Reactions with InCl 3 and PtCl 2 (PPh 3 ) 3 as catalysts gave very poor yields of exo-dig cyclization product 7 after 24 h (entries 3 and 4). AgOTf and AuCl 3 were also screened and AuCl 3 was identified as the optimal choice due to the shorter reaction time, high yield, and easy isolation of the product 7 (entries 1 and 2, Table 1). We next investigated the isomerization of the double bond in 7, which was treated with trifluoroacetic acid (TFA) in chloroform at room temperature to give 3-methyl-1H-pyrrolo[2,1-c] [1,4]oxazin-1-one (6) [27].
After having obtained the optimal conditions for the Au-catalyzed cyclization of carboxylic acid 15, we attempted to determine the scope and limitation of this transformation. Then we investigated the cyclization reaction of a range of substituted N-propargyl-pyrrole-2-carboxylic acids 17, 21, 25, 29 and  Table 2). The Sonogashira cross-coupling reaction [56][57][58][59][60][61] was used for the synthesis of the desired starting materials 29 and 33. For the Sonogashira coupling reaction we used a palladium catalyst and a copper(I) cocatalyst in the presence of triphenylphosphine and triethylamine as the base. The Table 2: AuCl 3 -catalyzed cyclization reaction of carboxylic acids.

Esters
Carboxylic acids Cyclization products Isomerization products carboxylic acids were then submitted to a gold-catalyzed cyclization reaction ( Table 2).
The optimized reaction conditions for cyclization was employed for pyrrole-and indole-carboxylic acids. We observed that all substituted pyrrole as well as indole carboxylic acids underwent a smooth gold-catalyzed cyclization reaction to afford the corresponding oxazinones 18, 22, 26, 30, 34, 38, 42 and 46 in high yields (Table 2). Substitution at the terminal carbon atom of the propargyl group with methyl and phenyl groups did not affect the mode of the cyclization reaction.
Further investigation of cyclic products involved examining the isomerization of the exocyclic double bond. For this purpose,  In order to address this question, we carried out some DFT calculations [66].
Although 31 is thermodynamically more stable than 30, the resistance of 30 to isomerization in the presence of TFA can be explained by the regioselective protonation of the double bond. The proton is added to the carbon atom to generate the most stable carbocation. The most stable carbocation is the benzylic carbocation which would not undergo a rearrangement.
As discussed above, when the cyclization reaction of 15 was carried out with [(NHC)AuCl] complexes (Table 1, entry 5), the starting material was fully recovered. Gold N-heterocyclic carbene complexes, in conjunction with a silver salt, were found to efficiently catalyze different types of reactions [67][68][69]. Therefore, 15 was reacted with [(NHC)AuCl] complex in the presence of AgOTf as the cocatalyst in chloroform. Beside the expected cyclization product 7 (10%), the product 47 was formed conclusively through incorporation of ethanol present in chloroform (<1%) as the major product in 51% yield (Scheme 4). NMR spectral analysis of the mixture revealed also the formation of 48 in 39% yield, which is the hydrolysis product of 47. Attempts to isolate 47 failed. Chromatography on silica gel converted 47 to 48 in almost quantitative yield. However, the products 6 and 7 only were isolated when the reaction was carried out in EtOH-free chloroform in 83% and 17% yields, respectively (Scheme 4).
To reveal the mechanism for the formation of the products we carried out two different reactions. First, 15 was reacted with CD 3 OD under the same reaction conditions. The 1 H NMR spectral analysis indicated the formation of 49 and 50 in 65% and 35% yields, respectively. Furthermore, the amount of deuterium atoms in 49 and 50 attached to the methylene group as -CH 2 D was about 64% (Scheme 4).
To prove whether 7 was involved as the intermediate, the cyclization product 7 was reacted with Au(I)/AgOTf with EtOH under the same reaction conditions. As a result, the products 47 and 48 were formed in yields of 39% and 61%, respectively (Scheme 5). Based on all this information obtained, we propose the following gold-catalyzed cascade reaction mechanism. The proposed catalytic cycle was initiated with π-activation of the triple bond by the carbene-based cationic gold species to form the intermediate 51, which triggers a gold-promoted intramolecular addition of a carboxy group to the alkyne functionality to give methylene-oxazin-1-one derivative 7 (or 18) (Scheme 6).
In the next step, the double bond is activated by π-coordination of the gold(I) catalyst. This enables a nucleophilic attack by the alcohol oxygen, which affords hemiacetal 47. In case of internal alkynes, two isomeric Eand Z-oxazinones during the cyclization reaction can be formed. However, we observed exclusive formation of a single isomer. Recently, Michelet et al. [70] and others [41,71,72]

Conclusion
We have developed a general synthetic methodology of pyrroloand indolo-oxazin-1-one derivatives. The key step was a goldcatalyzed cyclization reaction of N-propargyl-substituted pyrrole and indole carboxylic acid derivatives. The hydroxy groups of carboxylic acids attacked the activated triple bond to form 6-exo-dig cyclization products, oxazin-1-one derivatives. Some of the exo-cyclic double bonds underwent isomerization to endo-cyclic compounds upon treatment with TFA, while some did not. DFT studies supported our findings. Moreover, cyclization reactions in the presence of alcohol formed hemiacetal derivatives after gold-catalyzed cascade reactions.