Co-Catalyzed Transannulation of Pyridotriazoles with Isothiocyanates and Xanthate Esters

Abstract

An efficient radical transannulation reaction of pyridotriazoles with isothiocyanates and xanthate esters was developed. This method features conversion of pyridotriazoles into two N-fused heterocyclic aromatic systems—imino-thiazolopyridines and oxo-thiazolopyridine derivatives—via one-step Co(II)-catalyzed transannulation reaction proceeding via a radical mechanism. The synthetic usefulness of the developed method was illustrated in the synthesis of amino acid derivatives and further transformations of obtained reaction products.

Graphical Abstract

Heteroaromatic rings are paramount motifs of drugs and bioactive molecules.¹ Thus, not surprisingly that, in drug discovery research, the development of novel synthetic approaches for the rapid construction of new heterocyclic ring systems from easily available precursors is of central importance.² Recently, transition-metal-catalyzed denitrogenative transformations of pyridotriazoles have been emerging as a powerful tool for the synthesis of diverse N-heterocyclic frameworks.^3,4 These protocols take advantage of the well-known ring-chain tautomerism of the pyridotriazole core in solution into the corresponding diazo tautomer A, which then can be trapped by a transition-metal catalyst to form the reactive pyridyl metal carbene intermediate B (see Scheme 1a). First reported in 2007,⁵ the transannulation reaction of pyridotriazoles was then quickly extended to other transannulations,⁶ as well as X–H insertions,⁷ cyclopropanation,⁸ and other reactions.⁹ These protocols operate through an ionic pathway, involving transition-metal carbene intermediate B.

Scheme 1.

Concepts for Transannulation of Pyridotriazoles

Recently, metalloradical catalysis employing open-shell metalloradical complexes has been introduced as a conceptually new strategy featuring alternative trends in reactivity and selectivity. Of particular importance are stable metalloradicals of cobalt(II) porphyrins ([Co(Por)]), which form strong metal-carbon single bonds, thus behaving as carbene radical surrogates.¹⁰ Lately, a rich chemistry of Co(II)-based metalloradicals toward a variety of useful synthetic transformations has been developed.^11,12 Surprisingly, engagement of this strategy in denitrogenative transannulation reaction is scarce.¹³ In continuation of our studies on application of pyridotriazoles in synthesis of nitrogen-containing heterocycles,^5a–e herein, we report a Co-catalyzed denitrogenative transannulation of pyridotriazoles with isothiocyanates and xanthate esters toward the synthesis of two N-heterocyclic aromatic systems proceeding via carbene radical intermediate C (see Scheme 1b).

First, transannulation of pyridotriazole 1a and t-butyl isothiocyanate 2a¹⁴ en route to imino-thiazolopyridine 3a was examined in the presence of several synthesized metal-porphyrin-based catalysts (Table 1). It was found that Co(TPP) (TPP = tetraphenyl porphyrin) was a superior catalyst delivering 3 in 72% isolated yield (Table 1, entry 1). Employment of other Co-porphyrin-based catalysts was less efficient (Table 1, entries 2 and 3), whereas use of other Fe- and Ru-porphyrin-based catalysts was inefficient (Table 1, entries 4–6).

Table 1.

Optimization of Reaction Conditions^a

entry	deviation from standard conditions	yield of 3ab (%)
1	none	72c
2	Co(F20TPP)	64
3	Co[(p-OMe)4TPP]	48
4	Fe(TPP)Cl	0d
5	Fe(F20TPP)Cl	0d
6	Ru(TPP)CO	0d

^a0.05 mmol scale; 1:2 = 1:5.

^bDetermined by gas chromatography/mass spectroscopy (GC/MS), using pentadecane as an internal standard with a catalyst loading of 8 mol %.

^c0.2 mmol scale, isolated yields.

^dPyridotriazole 1a was mostly recovered.

Next, the generality of this methodology was examined. With regard to the pyridotriazole component, several differently substituted heterocycles at C5 and C6 turned out to be capable substrates for transannulation with t-butyl isothiocyanate (2a) (Scheme 2). Thus, halogenated and methylated pyridotriazoles reacted smoothly to give the corresponding imino-thiazolopyridine products 3b–3f in good to excellent yields. Employment of methyl ester-containing substrate 3g and thiophene-containing pyridotriazole 3i posed no problem. Notably, this reaction was equally efficient with N-fused pyrazinotriazole to deliver imino-thiazolopyrazine derivative 3h in high yield. This reaction also appeared to be very general for isothiocyanates (see Scheme 3). A variety of functional groups was tolerated at the para-position of arylisothiocyanates, providing the corresponding products 3k–3p in good to excellent yields. Similarly, transannulation of isothiocyanates possessing substituents at the meta and ortho positions of the arene proceeded uneventfully (3q–3u). Benzodioxolyl- and naphthyl-containing isothiocyanates smoothly underwent transannulation, affording 3v and 3w in good yields. In addition, it was found that alkyl isothiocyanates also are capable partners for this transformation. Thus, isothiocyanates possessing various benzyl and alkyl groups all reacted well, providing products 3x–3z in good to high yields. Moreover, this reaction chemoselectively gave transannulation products 3aa with allyl-containing isothiocyanate, the double bond moiety of which was not compromised. Notably, chiral isothiocyanates could also be efficiently employed in this reaction. Thus, isothiocyanates derived from amino acid esters smoothly underwent transannulation reaction to produce derivatives 3ab–3ad in moderate yields.

Scheme 2.

Scope of Pyridotriazoles^a

^a0.2 mmol scale, isolated yields. See the Supporting Information for experimental details. ^bReaction was performed in 1 mmol scale. ^cToluene (0.5 M) used as a solvent.

Scheme 3.

Scope of Isothiocyanates^a

^a0.2 mmol scale, isolated yields. See Supporting Information for experimental details. ^bToluene (0.5 M) used as a solvent.

Encouraged by the successful transannulation of pyridotriazoles with isothiocyanates, we examined reactivity of carbonyl sulfide (OCS) in this transformation (Scheme 4). Because of its gaseous nature, carbonyl sulfides are experimentally difficult to handle. Hence, xanthate ester, which is a stable precursor of carbonyl sulfide that is produced via Chugaev elimination, was examined.¹⁵ Gratifyingly, xanthate ester successfully underwent transannulation reactions with pyridotriazoles in the presence of 12 mol % Co(TPP) catalyst, providing oxo-thiazolopyridine derivatives 5a–5f in moderate yields.

Scheme 4.

Scope of Transannulation with Xanthate Ester^{a a}0.2 mmol scale, isolated yields.

It was also shown that the tert-butyl group at imino-thiazolopyridine 3a can easily be removed (under nonoptimized conditions) to access 6 possessing an N–H moiety, which can routinely be further functionalized, for instance, into benzoylated derivative 7 (see Scheme 5). Note that the latter cannot be accessed directly via the transannulation reaction of acylated isothiocyanates under the reaction conditions tested. It is believed that 6 can serve as a convenient synthon for a modular one-step synthesis of library of N-substituted imino-thiazolopyridines.

Scheme 6.

Radical Scavenging Experiment Used to Trap the Co(III)-Carbene Radical Intermediate

Scheme 5.

Product Transformations

The radical nature of this transformation was validated by the following radical trapping experiment (see Scheme 6). The reaction in the presence of dibenzoyl peroxide 8 resulted in the formation of benzoyloxy-containing product 9, thus supporting involvement of the carbene radical intermediate C.

On the basis of the above study and literature reports, the following plausible mechanism for this transannulation reaction is proposed. Xanthate ester 4, which is obtained via Chugaev elimination, acts as a carbonyl sulfide (12) surrogate in this transformation (see Scheme 7a). Pyridotriazole 1 exist in equilibrium with its open diazo tautomer A, which, upon denitrogenative reaction with Co(II)-based metalloradical catalyst D, produces a key α-Co(III)-pyridyl radical intermediate C (Scheme 7b). A subsequent trapping of this eletrophilc radical with isothiocyanate 2¹⁶ or the in-situ-generated carbonyl sulfide 12 produces radical intermediate E, which, upon radical cyclization, leads to imino-thiazolopyridine 3 or oxo-thiazolopyridines 5 and regenerates the Co catalyst.

Scheme 7.

Proposed Radical Activation Mechanism

In summary, we have developed general and efficient Co(II)-catalyzed radical transannulation reactions of pyridotriazoles with isothiocyanates and carbonyl sulfide. This operationally simple protocol exhibits wide functional-group tolerance, efficiently producing N-fused imino-thiazolopyridines and oxothiazolopyridines.