Phosphine-Catalyzed Dearomative [3 + 2] Cycloaddition of Benzoxazoles with a Cyclopropenone

Abstract

The triphenylphosphine-catalyzed dearomative [3 + 2] cycloaddition of benzoxazoles with 1,2-diphenylcyclopropenone is herein described. The reaction scope, mechanism, and possible future applications of this rare organocatalyzed cycloaddition are herein discussed.

“[···] The cyclopropenone system must have strong resonance stabilization indeed to compensate for its high angle strain.” So did Breslow and his team express their surprise at the unexpected relative stability of 1,2-diphenylcyclopropenone (1959).¹

The activation of C–C bonds is a powerful concept for the reorganization or coupling of organic scaffolds, yet it is a relatively challenging process to achieve in the context of synthetic methodology because of their inherent stability.² In order to enable such methods, one can use C–C-strained, often cyclic, building blocks that are consequently spring loaded for C–C bond activation.³ In this context, 1,2-diphenylcyclopropenone, a particularly strained cyclic substance known since the late 1950s,¹ is currently witnessing a spectacular rebirth in the context of synthetic method developments that rely on C–C bond activation. Even though its highly strained structure makes it an ideal building block for C–C bond activation, it usually still requires a precious metal salt as catalyst.⁴⁻⁷ Because 1,2-diphenylcyclopropenone is a particularly versatile building block for organic coupling reactions, yielding both open and (poly)cyclic complex skeletons (Scheme 1, eqs 1–4), its activation with more trivial and less onerous (organo)catalysts would constitute an important objective for rendering such methods sustainable and practical.⁸ We propose herein such a method with the simple triphenylphosphine-catalyzed⁹ dearomative [3 + 2] cycloaddition of benzoxazoles with 1,2-diphenylcyclopropenone.

Scheme 1. Selected Couplings with Cyclopropenones.

Prescher and co-workers recently utilized a triphenylphosphine organocatalyst in order to elegantly ring open 1,2-diphenylcyclopropenone with amines (Scheme 1, eq 4).⁸ We therefore reasoned that other highly important coupling partners, such as benzoxazoles, might intercept the cyclopropenone ring opening under simple phosphine catalysis, leading to unprecedented fused poly-heterocyclic rings.

We commenced our study by engaging 1,2-diphenylcyclopropenone 2a in the presence of an excess of test substrate benzoxazole 1a and triphenylphosphine (PPh₃, 12.5 mol %, 1:8 ratio) in chloroform at 25 °C for 15 h. This afforded a new dearomatized polycyclic substance 3aa in impressive 96% isolated yield (Table 1, entry 1). This particular scaffold, a benzopyrrolo-oxazolone, is relevant, as similar structures are found at the core of several bioactive substances of interest (Scheme 1).¹⁰ Its direct synthesis from trivial building blocks such as presented here would therefore represent a significant advancement for the field. No conversion was observed in the absence of the PPh₃ catalyst (Table 1, entry 2) nor with bulkier phosphines such as BINAP (Table 1, entry 3). This is an important result because PPh₃ is by far the cheapest triarylphosphine available. No other solvents performed any better than chloroform (entries 4–7), nor any other relative ratio between the coupling partners (entries 8–10).

Table 1. Optimization Table^a.

entry	variations from standard conditionsa	yield (%)b of 3aa
1	none	97 (96)c
2	without PPh3	NR
3	BINAP instead of PPh3	NR
4	toluene instead of CHCl3	60
5	DCM instead of CHCl3	78
6	EtOAc instead of CHCl3	64
7	CDCl3 instead of CHCl3	93
8	1 equiv of 1a	46
9	2 equiv of 1a	82
10	0.2 mmol 1a and 2 equiv of 2a	20

^aUnless otherwise noted, the standard reaction conditions were as follows: 1a (0.6 mmol), 2a (0.2 mmol), solvent (0.5 mL).

^bThe yield was determined by ¹H NMR analysis of the crude reaction mixture using 1,3,5-trimethoxybenzene as an internal standard.

^cIsolated yield.

With these simple reaction conditions in hand, we then investigated the reaction scope with various benzoxazoles (Scheme 2). First, we tested C5-substituted benzoxazole substrates. Electron-neutral (3ba) and electron-donating (3aa, 3fa, 3ga, 3ha) functional groups afforded the corresponding benzopyrrolo-oxazolone coupling products in excellent yields (88–97%). Although electron-withdrawing substituents performed somewhat less well at 25 °C (3ca–3ea), increasing the reaction temperature to 70 °C afforded promising yields (56–60%). Next, C6-substitution was also explored (3ja–3ma), as well as C7 (3pa, 3qa) with promising to excellent yields. Di- and trisubstituted benzoxazole structures (3na, 3oa, 3ra–3ua) as well as bulky C4-substitutents were likewise well tolerated (3ga, 3ha), with 97 and 96% yields, respectively. Interestingly, even fused or alternatively tethered dibenzoxazole substrates were found applicable, yielding the corresponding single coupling cycloaddition products (3va–3za) in 22–60% yields. Moreover, the 1,2-diphenylcyclopropen-3-one 2a could be replaced with a different cyclopropenone 2b (product 3bb).

Scheme 2. Scope, Isolated Yields.

All reactions were carried out on a 0.2 mmol scale for 15 h under the standard conditions.

The reaction was carried out at 70 °C.

In order to demonstrate the practicality of our reaction, a 1 mmol scale batch was conducted for product 3aa. This product was thus obtained in remarkably preserved 94% isolated yield (320 mg) in moreover only 1 mL of chloroform. In addition, the X-ray diffraction analysis of product 3ca confirmed the structural interpretation, in particular its fused cyclic nature (Figure 1).

Figure 1.

X-ray structure of product 3ca (CCDC: 2093753), ORTEP view,¹¹ 50% probability level.

Based on some literature precedents,¹² we assume that the phosphine organocatalyst activates the strained and electrophilic cyclopropenone to form zwitterionic intermediate I, which would then progress to ketene ylide intermediate II (Scheme 3). The latter species would then undergo a nucleophilic dearomative attack from the benzoxazole coupling partner to generate intermediate III. This would rapidly cyclize to form the second C–C bond toward intermediate IV. Phosphine elimination would then regenerate the organocatalyst, releasing coupling product 3.

Scheme 3. Proposed Mechanism.

In order to further investigate this mechanism, we then performed some key ³¹P NMR experiments (Figure 2). Experiment A shows that the ³¹P NMR signal of PPh₃ shifts at −5.4 ppm in CDCl₃, a solvent which we know accommodates the reaction well (Table 1, entry 7). The addition of benzoxazole 1a does not alter this signal, even in large excess (24 equiv, experiment B). However, the addition of strained electrophilic cyclopropenone 2a (8 equiv) leads to the appearance of two new signals at +16.1 and +29.2 ppm, presumably corresponding to two new species (experiment C). One or both might correspond to intermediates I and/or II, as the observed chemical shifts are compatible. If one adds to this 24 equiv of benzoxazole 1a, the signal at +29.1 ppm disappears (experiment D), demonstrating that this particular species is probably a productive intermediate of the reaction. If one stirs this mixture for another 15 h, only the PPh₃ signal remains (−5.4 ppm, experiment E), thus demonstrating the intermediacy of the noted signals in experiments C and D as well as the catalytic role of the phosphine.

Figure 2.

Comparison of the ³¹P NMR spectra of (A) only PPh₃ in CDCl₃; (B) PPh₃ and 1a (1:24); (C) PPh₃ and 2a (1:8); (D) PPh₃, 1a, and 2a (1:24:8); (E) PPh_3,1a and 2a (1:24:8) after the mixture was stirred for 15 h.

Finally, because of the envisaged mechanism involving a very rigid and covalent proximity of the catalyst to the reaction sites in intermediates II and III (Scheme 3), it occurred to us that an optically active phosphine might render the reaction enantioselective.¹³ In order to explore this possibility, we screened a series of commercially available chiral and optically active phosphines (phosphines P1–P7, Scheme 4). Unfortunately, none performed with an enantiomeric excess above 48% for product 3aa (chiral phosphine P4) in moreover moderate yields. While we could not improve these results so far, these at least demonstrate the feasibility of an enantioselective version of this organocatalyzed synthetic method. We are currently designing and synthetizing new chiral phosphines in order to achieve this objective.

Scheme 4. Action of Optically Active Phosphine Catalysts.

For the diphosphines, a catalytic loading of 6.25 mol % was utilized, thus giving a 1:16 ratio versus substrate 2a.

Control run under strict argon atmosphere.

In conclusion, we have developed a triphenylphosphine organocatalyzed dearomative [3 + 2] cycloaddition of benzoxazoles with 1,2-diphenylcyclopropenone. The cyclic and fused nature of the coupling product was confirmed by X-ray crystallography. Moreover, a mechanistic investigation was conducted with ³¹P NMR, leading to important insights regarding the existence of phosphorus based catalytic intermediates. This contribution should encourage the further development of organocatalyzed C–C bond activation coupling methods.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.orglett.1c04045.

• Experimental procedures, characterization, and NMR spectra of new compounds (PDF)

Accession Codes

CCDC 2093753 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_request@ccdc.cam.ac.uk, or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

The authors declare no competing financial interest.