Rh-Catalyzed Transannulation of Pyridotriazoles with Alkynes and Nitriles

Transition-metal-catalyzed annulations are widely used in the synthesis of heterocyclic compounds.^[1] One of the most efficient methods for the construction of five-membered oxygen-containing heterocycles involves the annulation of diazocarbonyl compounds with alkynes and nitriles. Thus, Davies et al.^[2] and Padwa et al.^[3] have employed this method^[4] for the synthesis of furans (X = CH), and Helquist et al.^[5] for the preparation of oxazoles (X = N) [Eq. (1)]. In contrast, analogous transformations of α-imino diazo compounds, which may lead to the formation of pyrrole and imidazole rings, are unknown. Herein we report an efficient, direct, Rh-catalyzed transannulation of pyridotriazoles with alkynes and nitriles that leads to indolizines (X= CH) and imidazopyridines (X = N), respectively [Eq. (2)].

(1)

(2)

It has been shown that 2-pyridyl diazo compounds 1^[6] transform into their cyclic triazole form 2^[7] upon storage [Eq. (3)], and it is also known that some of these cyclic triazoles can still undergo transformations that are characteristic of diazo compounds.^[8] This phenomenon has been attributed to the closed/open form equilibrium of N-fused triazoles in solution,^[9] which can produce trace to significant amounts of 1. The position of this equilibrium depends on the temperature and the substitution pattern of the triazole.^[9b] Thus, introduction of a halogen substituent at C7 (R¹ = Cl) shifts the equilibrium to the left, which has been explained in terms of nonbonding repulsion between the lone pair of the halogen and that of the nitrogen in the peri position.^[10]

(3)

To evaluate the feasibility of using triazoles as precursors of Rh carbenoids we investigated the reaction of triazoles 3a and 3b with triethylsilane in the presence of a catalytic amount of rhodium(II) acetate, which is a method developed by Doyle and coworkers^[11] for the efficient trapping of Rh carbenoids [Eq. (4)]. Not surprisingly, pyridotriazoles 3a and 3b behave differently under these reaction conditions. Thus, while the 7-H derivative 3a remains unaffected, the 7-chloro-substituted compound 3b is smoothly converted into 4, which is the product of carbenoid insertion into the Si–H bond. These experiments clearly indicate that 7-halo-substituted pyridotriazoles can indeed serve as convenient precursors of Rh carbenoids.

(4)

Next, to test our hypothesis regarding the annulation of α-imino diazo compounds with alkynes to form a pyrrole ring, we treated triazole 3b with phenylacetylene in the presence of rhodium(II) acetate. This reaction proceeded smoothly to produce a mixture of cyclopropene 5 and indolizine 6a with yields of 68% and 28% of isolated product, respectively [Eq. (5)]. Surprisingly, cyclopropene 5 does not undergo further isomerization into indolizine 6a under these reaction conditions.^[12] The ratio of these products remained constant throughout the course of the reaction, thereby suggesting an independent path for the formation of 6a.

(5)

We found, however, that the selectivity of the transannulation (6 over 5) could be dramatically improved by using rhodium(II) heptafluorobutyrate as catalyst.^[13] Thus, transannulation of 3b with a series of aryl and alkenyl alkynes^[14] proceeded highly chemoselectively (90:10 to 95:5 vs. cyclopropene) to produce indolizines 6^[15] in good yields (Table 1). Electron-rich, electron-deficient, and sterically hindered aryl alkynes were nearly equally effective in this reaction.

Table 1.

Rhodium(II)-catalyzed transannulation of triazole 3b with alkynes.

Entry	Alkyne	Product	Yield [%][a]
1		6a	78
2		6b	80
3		6c	73
4		6d	85
5		6e	70
6		6f	65
7		6g	57

^[a]Yield of isolated product. Indolizines 6 were accompanied by 5–10% of the corresponding cyclopropenes 5; these compounds were readily separable by column chromatography.

Inspired by the successful formation of an N-fused pyrrole ring from the transannulation of triazoles with alkynes, we examined the formation of an N-fused imidazole ring in the reaction of 3 with nitriles and found that pyridotriazoles 3 react smoothly with a variety of aryl, alkyl, and alkenyl nitriles in the presence of Rh₂(OAc)₄ (1 mol%) in toluene at 60°C (Table 2) to afford N-fused imidazopyridines 7 in reasonable to high yields.

Table 2.

Rhodium(II)-catalyzed transannulation of triazoles with nitriles.

Entry	R1	R2	Triazole	R3	Product	Yield [%][a]
1	Cl	CO2Me	3b	p-Tol	7a	89
2	Cl	CO2Me	3b	Ph	7b	83
3	Cl	CO2Me	3b	p-Me(O)CC6H4	7c	54
4	Cl	CO2Me	3b	Bn	7d	63
5	Cl	CO2Me	3b	nPr	7e	75
6	Cl	CO2Me	3b	cPr	7f	74
7	Cl	CO2Me	3b	tBu	7g	69
8	Cl	CO2Me	3b		7h	66
9	Cl	CO2Me	3b	CH2SiMe3	7i	70
10	Cl	p-CF3C6H4	3c	Ph	7j	82
11	Br	p-CF3C6H4	3d	p-Tol	7k	73
12	OMe	p-CF3C6H4	3e	nPr	7l	51

^[a]Yield of isolated product.

Both 3-carbomethoxy-(Table 2, entries 1–9) and 3-aryl-(Table 2, entry 10) pyridotriazoles are equally efficient in this reaction. Moreover, 7-bromo-(Table 2, entry 11) and even 7-methoxy-substituted (Table 2, entry 12) triazoles proved to be good substrates for this transannulation reaction.

We propose the following mechanism for this novel Rh-catalyzed transformation (Scheme 1). First, pyridotriazole 3 undergoes closed/open form equilibrium^[9] to produce small amounts of diazo compound 1 which, upon reaction with rhodium(II) carboxylate, generates the Rh-carbenoid species I. A direct nucleophilic attack^[18] of alkyne or nitrile 8 on species I produces ylide species II, according to path A, which then cyclizes to form 6 or 7 via cyclic zwitterion III. Alternatively (path B), [2+2] cycloaddition of I and 8 leads to metallacyclobutene IV, which can also be formed by cyclization of II.^[19] Rhodacycle IV then undergoes metathesis to produce Rh carbenoid V which, upon 6π-electrocyclization and subsequent reductive elimination, furnishes product 6 or 7. [2+1] Cycloaddition of I with 8 (path C) accounts for the formation of cyclopropene 5 in the presence of rhodium(II) acetate [see Eq. (5)]. As discussed above, 5 does not transform into heterocycle 6 under these reaction conditions.^[12]

Scheme 1.

Plausible mechanisms for the Rh-catalyzed transannulation of pyridotriazoles with alkynes and nitriles. Y=N, CR″.

In summary, we have developed an efficient Rh-catalyzed transannulation of pyridotriazoles for the formation of pyrrolo- and imidazopyridines, which are important fused heterocyclic scaffolds.^[20] We have also demonstrated that some of these pyridotriazoles can serve as stable^[13] and convenient^[21] precursors of Rh carbenoids.