S_NAr-Derived Decomposition By-products Involving Pentafluorophenyl Triazolium Carbenes

Abstract

Pentafluorophenyl triazolium carbenes, widely used in NHC-catalysis, can decompose by several mechanisms. Under high concentration conditions, the azolium may undergo a pentafluorophenyl exchange by a proposed S_NAr mechanism to give an inactive salt. In the presence of appropriate substrates, cyclization on the ortho-position of the arene can occur, also by S_NAr. These adducts provide a potential pathway for catalyst decomposition and serve as a caveat to the development of new reactions and catalysts.

N-Heterocyclic carbene (NHC) catalysis is dominated by the triazolium scaffold, with the huge majority of such catalysts bearing at least one aryl group on the azolium ring.¹ The nature of the aromatic ring has been documented to have a profound impact on both reactivity and selectivity across a range of transformations.² The pentafluorophenyl substituent on the triazolium salt, first introduced by us in 2004,³ exhibits high activity and selectivity across a range of NHC-catalyzed transformations and has become a substituent of choice across a range of reactions, including the intermolecular Stetter,⁴ redox,⁵ cascade,⁶ cycloadditions⁷ and others.⁸ Catalyst loadings as low as 0.1 mol% may be used for some reactions (intramolecular Stetter, e.g. ^4d) but this is an exception. Given our long history with NHC catalysis and interest in extending the utility of these systems, we expended some effort at identifying decomposition pathways for these carbenes with an eye at the development of the next generation of catalysts. Herein, we disclose our results.

When morpholine-based scaffold pentafluorophenyl triazolium salt 1 was treated with 1 equivalent KOAc as the base in wet MeOH at room temperature for 16 hours (eq. 1), the hydrate 2 and anion-exchanged triazolium salt 3 were observed.⁹ The hydrate 2 was obtained in 30% isolated yield.¹⁰ The hydrate is not particularly stable and slowly decomposed to the salt 3 on standing. We tested the catalytic activity of 3 with aldehyde 5 (eq. 2). Interestingly, the desired product 6 is produced in around 20% conversion in the presence of 20 mol% acetic acid but is not formed in its absence. This suggests that the salt 3 might convert to the corresponding carbene as the catalytic species under acidic conditions.

(1)

(2)

When the salt 1 was scaled up to 800 mg, the hydrate 2 and a significant amount of 3 were observed. Surprisingly, the interesting inner salt 4 was generated in trace amount.¹¹ The structure of the inner salt 4 was confirmed by X-ray crystallographic analysis (Figure 1). The two fluorinated aryl groups are twisted relative to the triazolium plane. It is clear that one fluoro group on the phenyl ring has been replaced by oxygen.¹²

Figure 1.

X-ray structure of the triazolium inner salt 4. Thermal ellipsoids are shown at the 50% probability level.

To account for the formation of 4, we propose the mechanism shown below (Scheme 1). The triazolium salt 1 is deprotonated by KOAc to give the free carbene A. Trace water in the reaction results in the formation of triazolium salt 3 with hydroxide as the anion. The hydroxide group can attack the triazolium cation to give the hydrate 2. Additionally, the carbene A nucleophilically attacks the triazolium cation B by S_NAr to produce the inner salt D and the neutral compound C. Hydroxide anion present in solution then likely displaces the fluoride on the more activated pentafluorophenyl group to give 4.

Scheme 1.

Proposed mechanism for the formation of 4.

The S_NAr mechanism is also at play in the decomposition of carbenes covalently bound to some substrates. For example, we have found that pentafluorophenyl carbene can react with a Michael acceptor to give a new side product.¹³ The treatment of Boc-protected oxindole 7 with achiral pentafluorophenyl carbene 8 at room temperature for 48 hours in THF in the presence of potassium carbonate forms the spirocyclic adduct 9 in good yield (75%, eq. 3).^14,15 We have shown previously that carbenes can form adducts with electrophiles and carbenes can be released from the adducts.¹⁶ In this case, however, the process appears irreversible and carbenes cannot be regenerated. When the reaction time decreased to 16 hours, the yield of the adduct diminished.¹⁷

(3)

An X-ray quality single crystal of adduct 9 was obtained by slow volatilization of its solution in hexane and dichloromethane. The structure was confirmed by X-ray crystallography (Figure 2). Clearly, the fluoro-substituted phenyl group connects to the spirocenter.

Figure 2.

X-ray structure of spirocyclic oxindole 9. Thermal ellipsoids are shown at the 50% probability level.

The mechanism is proposed as shown below (Scheme 2). The triazolium salt 8 first reacts with potassium carbonate to generate the free carbene E. Then E attacks the double bond on the substrate oxindole to give intermediate F. The enolate anion displaces fluoro group by S_NAr to form triazolium salt G. Finally, base induced deprotonation results in sequestration of HF to deliver adduct 9.

Scheme 2.

Proposed mechanistic pathway

In conclusion, we report two decomposition pathways involving pentafluorophenyl-derived triazolium salt organocatalysts. The structures of these byproducts were confirmed by X-ray crystallographic analysis. Taken together, these results shed light on potential pathways for catalyst decomposition and may lead to the design of new, more efficient catalysts for NHC-mediated transformations.