Intramolecular Transannulation of Alkynyl Triazoles via Alkyne-Carbene Metathesis Step: Access to Fused Pyrroles

Abstract

An intramolecular Rh-catalyzed transannulation reaction of alkynyl triazoles has been developed. This method allows efficient construction of various 5,5-fused pyrroles, including tetrahydropyrrolo and spiro systems. The method demonstrates excellent functional group compatibility. A rhodium carbene-alkyne metathesis mechanism is proposed for this transformation.

Rhodium-imino carbenes B, which are easily generated from N-sulfonyl-1,2,3-triazoles (A),^1,2 open wide opportunities for formation of diverse heterocycles C through various transannulation reactions (eq 1).^3-7 We have recently reported a transannulation of triazoles with terminal alkynes into pyrroles E, which operates via an ylide mechanism (D).⁵

Apparently, ylide path limits this method to terminal alkynes, which disqualifies a possibility of an intramolecular transannulation reaction toward valuable fused pyrroles. Inspired by a recent report by May,⁸ in which a carbene - alkyne metathesis⁹ has been employed as a key step in an efficient synthesis of bridged polycyclic ring systems, we hypothesized that this key step can potentially be employed in an intramolecular transannulation reaction. Thus, iminocarbene F would undergo a carbene-alkyne metathesis to form a new Rh carbene intermediate G. A subsequent nucleophilic attack of the N atom at the Rh carbene and the following tautomerizaiton would produce a fused pyrrole 2 (eq 2).^10,11 Herein we report that indeed this concept can be realized. Hence, a novel, general, and efficient method for the construction of 5,5-fused pyrrole units¹² from easily available alkynyl triazoles has been developed.

(1)

(2)

To test the above hypothesis, alkynyl triazole 1a was subjected to the reaction with rhodium octanoate. To our delight, the desired 5,5-fused pyrrole 2a was formed in 60% yield (Table 1, entry 1). A brief optimization indicated reactions conditions of entry 9 to be sufficient for this transformation.

Table 1.

Optimization of Reaction Conditions^a

entry	catalyst	solvent	t/°C	yield/%b
1	Rh2(Oct)4	ClCH2CH2Cl	80	62d(60c)
2	Rh2(Oct)4	CHCl3	80	63d
3	Rh2(Oct)4	Dioxane	80	19
4	Rh2(Oct)4	THF	80	trace
5	Rh2(Oct)4	PhMe	80	0
6	Rh2(S-NTTL)4	CHCl3	80	41d
7	Rh2(esp)2	CHCl3	80	63d
8	Rh2(S-DOSP)4	CHCl3	80	46d
9	Rh2(esp)2	CHCl3	90	78e
10	Rh2(esp)2	CHCl3	70	76d,f
11	Rh2(esp)2	CHCl3	60	78(78c,f)
12	Rh2(esp)2	CHCl3	50	59g

^a1a (0.1 mmol) and Rh(II) (1 mol %) were dissolved in solvent (1.0 mL) and heated at indicated temperature for 12 h.

^bGC yield.

^cIsolated yield.

^dDesilylation of product was observed.

^eHeated for 2 h.

^fHeated for 15 h.

^gHeated for 42 h.

Next, the scope of this transformation has been examined. First, we tested a series of aryl substituents at the alkyne moiety (Figure 1, b-m). It was found that a variety of groups, including OMe (d, j), F (g), Br (f), CO₂Me (h), CF₃ (i), and protected diol (e), were perfectly tolerated under these reaction conditions to produce the corresponding fused pyrroles 2d-m in reasonable to excellent yields. Likewise, naphthalene- (2l) and heterocycle-substituted pyrroles (2m) were obtained in good yields. It was also found that triazoles, bearing ortho- or meta-substituted aryl groups, could also participate in this transannulation reaction to give fused pyrroles 2j, k.

Figure 1.

Transannulation of Alkynyl Triazoles – R Substituents Variations^{a, b}

Further investigation indicated that this reaction is not limited to aryl alkynes. Thus, we found that alkynyl- (n) or alkenyl (o) groups can also be efficiently utilized in this transformation to produce the corresponding pyrroles possessing an unsaturated unit at the C-2 position. Notably, the reaction of alkynyl triazole bearing a phenylthio group proceeded smoothly to afford thiopyrrole 2p in excellent yield. Moreover, TMS- (2a) and Br- (2q) groups were compatible with these reaction conditions, thus providing opportunities for further functionalization of the obtained pyrroles .^13,14

We also investigated the scope of the reaction with respect to a triazole-alkyne tether (Figure 2). It was found that substrates possessing C-3¹⁵ tether reacted well, including those possessing ketone (2r), nitrile (2t), and protected alcohol (2u, 2v) functional groups to produce the corresponding fused pyrroles in good yields. Notably, this method also allows efficient access to polycyclic spiro systems 2r, 2s. Furthermore, substrate with a nitrogen tether underwent smooth transannulation reaction to give a bicyclic tetrahydropyrrolo-pyrrole skeleton 2w.

Figure 2.

Transannulation of Alkynyl Triazoles - Tether Variations^{a, b}

In summary, we developed an efficient rhodium-catalyzed intramolecular transannulation reaction of alkynyl N-tosyltriazoles, which involves a Rh-carbene-alkyne metathesis step. This new method provides expeditious access to various 5,5-fused pyrroles from easily available starting materials. It can also be used for efficient construction of spiro systems, as well as a fused tetrahydropyrrolo-pyrrole cores.