Cycloaddition of cyclobutenone and azomethine imine enabled by chiral isothiourea organic catalysts

An organocatalytic carbon–carbon bond activation of γ-mono-chlorine substituted cyclobutenone provides an α-carbon selective cycloadduct with excellent stereoselectivites.

Abstract

The addition of an organic catalyst to the ketone moiety of a γ-mono-chloride substituted cyclobutenone destroys its stable, conjugated and nearly planar structure. The C–C bond in the resulting less stable anionic oxy-substituted non-planar intermediate is then activated. The breaking of one C–C single bond leads to a catalyst-bound intermediate that undergoes α-carbon selective reactions with azomethine imines to afford nitrogen-containing heterocyclic compounds with excellent diastereo- and enantio-selectivities. Our organocatalytic approach provides a new reaction pattern for C–C bond activation of cyclobutenones that is unavailable with transition metal catalysis. In addition, the present study with isothioureas as the organocatalysts expands the potential in using organocatalysts for C–C bond breaking and selective reactions.

Introduction

The direct breakage of carbon–carbon (C–C) single bonds¹ provides unique opportunities for organic synthesis. Cyclobutane derivatives,^2,3 especially cyclobutenones,⁴ are privileged synthons because a release of the ring strain via carbon–carbon bond breakage can provide versatile reactive intermediates. The thermal four-electron electrocyclic cleavage of cyclobutenones (typically at 100 °C or above) can generate vinyl ketene intermediates that participate in a number of reactions, such as the benzannulation first reported by Danheiser in 1984.⁵ To achieve better reaction control and diversity, transition metal catalysts have been developed to activate cyclobutenones and modulate the subsequent reactions (Scheme 1a).⁴ Typically, the transition metal catalysis process is initiated by oxidative addition of a transition metal catalyst to the C–C bond of cyclobutenones. It has been observed that both chemo- and stereo-selectivities are difficult to control in these otherwise elegant reactions, likely due to the high reactivity of the metal catalyst and the metal-bound intermediates.^6,7

Scheme 1. Organocatalytic carbon–carbon activation of cyclobutenones.

We're interested in using organic catalysts to initiate selective and efficient reactions. It has been observed that the C–C bond of cyclobutenones (and cyclobutenes) can be weakened by destroying their nearly planar conjugated structures via substitutions, as indicated by computational findings from Houk and co-workers.^8a,8b Usually, an “outward” rotation of the thermal electrocyclic ring-opening process is favorable when a substituent is installed at the C4 carbon of cyclobutenone.⁸ In particular, studies from Baldwin suggested a preference for outward rotation of the chlorine substituent at the C4 carbon of cyclobutenone.^8c By taking advantage of this intrinsic property of cyclobutenone, we hypothesized that addition of an organic catalyst to the ketone moiety of cyclobutenone might achieve the activation of the carbon–carbon single bond via formation of a non-planar intermediate that leads to the breakage of its C–C bond for further reactions (Scheme 1b).⁹ This reaction would constitute a highly efficient approach in organocatalysis, in which all atoms of the substrate end up in the product (atom economy) and no overall redox process is involved (redox economy). Recently, we reported the addition of an N-heterocyclic carbene catalyst to the ketone moiety of cyclobutenones to initiate highly enantioselective formal [4 + 2] reactions, in which the γ-carbon of cyclobutenone reacted as a nucleophilic carbon.⁹ Here, we report highly selective [3 + 2] reactions by using an isothiourea organic catalyst to activate and modulate the reactivities/selectivities of mono-chloride substituted cyclobutenones (Scheme 1c).

Results and discussion

Under the catalysis of isothiourea with cyclobutenone 1a and azomethine imine¹⁰ 2a as the substrate, the reaction exclusively took place on the α-carbon of the cyclobutenone via a formal [2 + 3] process. Our result is consistent with an earlier report by Smith that the reaction of the isothiourea-generated dienolate intermediate is α-carbon selective.^12e Notably, Studer has recently reported the [2 + 3] cycloaddition of azomethine imines with enolates prepared using an isothiourea catalyst.^10d Briefly, in our reaction, nucleophilic 1,2-addition of the isothiourea catalyst to the ketone moiety of cyclobutenone 1a generates intermediate I (the conjugated structure is broken and an anionic oxy-substituted intermediate I is formed) that undergoes subsequent C–C bond cleavage to form intermediate II. The anionic oxy-substituent of I likely accelerates the electrocyclic ring opening process.^8d The α-carbon of the vinyl enolate^11,12 selectively reacts with azomethine imine 2a to form product 3a with excellent enantioselectivity and diastereoselectivity. The intermediate II likely adopts an s-cis diene configuration, and the cis-configuration of Cl and Ph substituents on the γ- and β-carbon of our product 3a suggests that intermediate II adopts an “outward” configuration.⁸ Previous studies from Houk and Baldwin have suggested that the ring-opening of cyclobutene led to an intermediate similar to II with an “outward” configuration.⁸ It is noteworthy that isothiourea as a Lewis base catalyst has not been exploited for the activation of cycloketones.

We started by using cyclobutenone 1a and azomethine imine 2a as the model substrates (Table 1). We first examined cinchona alkaloid nucleophilic catalysts and found that no product was obtained with either A or B as the catalysts (entries 1 and 2).¹³ We next evaluated chiral guanidines, organocatalysts previously explored by Corey,¹⁴ Tan¹⁵ and others.¹⁶ We were delighted to find that the proposed product 3a could be formed in moderate yields (entries 3 and 4), although attempts to obtain enantioselectivity using guanidine catalysts were unsuccessful. Encouraged by these results, we subsequently studied isothioureas, analogs of guanidines, as the organic catalysts. Notably, pioneering studies in using isothioureas as enantioselective organic catalysts have been reported by Birman,¹⁷ Smith¹⁸ and others.^19,20 Here, we found that when isothiourea E ¹⁷ was used as the catalyst with CHCl₃ as the solvent at room temperature, 3a could be obtained in 62% yield and with a promising 85 : 15 er (entry 5). The use of catalyst F ¹⁷ led to 3a in similar yield with improved er (96 : 4) under otherwise identical conditions (entry 6). Finally, we found that the use of Et₃N as an additive could slightly (and consistently) improve the enantioselectivity (97 : 3) and yield (67%) (entry 7). Decreasing the catalyst loading to 10 mol% gave the product 3a in lower yield (38%) without an apparent change in enantioselectivity (entry 7). Finally, we compared NHC catalysts that were used in our earlier [4 + 2] reactions (entries 8–10).⁹ These carbene catalysts could lead to products in low yields but with nearly no enantioselectivity.

Table 1. Optimization of the reaction conditions ^a .

Entry	Cat.	Additive	3a yield c (%)	3a e er
1	A	—	0	—
2	B	—	0	—
3	C	—	48	50 : 50
4	D	—	38	50 : 50
5	E	—	62	85 : 15
6	F	—	65	96 : 4
7	F	Et3N b	67 (38) d	97 : 3
8	G	Cs2CO3	35	50 : 50
9	H	Cs2CO3	40	52 : 46
10	I	Cs2CO3	42	52 : 46

^aAll reactions of 1a (0.10 mmol, 17.8 mg) with 2a (0.15 mmol, 38 mg) were carried out in the presence of catalyst (20 mol%; 20 mol% Cs₂CO₃ was added for G–I) in CHCl₃ (1.0 mL) for 3 days.

^bEt₃N (1.0 mmol, 14.0 μL) was added.

^cIsolated yield.

^d F (10 mol%) was used.

^eer of 3a was determined by chiral HPLC analysis.

With acceptable conditions in hand, we next evaluated the scope of the asymmetric reaction by first varying the substituents at the β-carbon of cyclobutenone substrate 1 (Table 2, 3a–f). Replacing the Ph substituent in 1a with an alkyl unit could give the desired product 3b with excellent enantioselectivity, albeit with a lower yield. Electron-donating and withdrawing substituents on the Ph group of 1a were also well tolerated, giving products 3c–f in good yields and excellent enantioselectivities. Azomethine imine substrates were then examined (3g–n). It appeared that sterically hindered substrates (3m, 3n) led to lower yields and er values under the current reaction conditions. The absolute configurations of the products were confirmed via X-ray diffraction of product 3a.²¹

Table 2. Reaction scope ^a .

^aConditions as Table 1 entry 7 unless otherwise specified, dr of products were determined via ¹H NMR analysis, isolated yields after column chromatography.

Notably, when the chlorine atom of substrate 1 was changed to a proton substituent or when γ,γ′-di-chloride substituted cyclobutenone was used, no cycloaddition products were obtained under our reaction conditions. In these cases, the cyclobutenone substrates remained unreacted. These results are constituent with Houk's computational findings that cyclobutenones bearing a mono-substituent at the C4 position are more reactive (less stable). When the chlorine atom of substrate 1 was changed to a methyl substituent, the methyl substituted substrate was unreactive under our catalytic conditions. It appears that with a methyl substituent the ketone moiety is not reactive enough (likely due to electronic reasons). This result is different from our early NHC-catalyzed reactions,⁹ likely because isothiourea organic catalysts are less nucleophilic than NHC catalysts.²²

1

2

The catalytic reaction can be carried out on a gram scale without loss of yield and selectivity (eqn (1)).²³ As a technical note, the catalyst (F) could be recovered (via SiO₂ column chromatography) and reused without loss of reaction efficiency and selectivity. The catalytic product 3a from our reaction could readily undergo further transformations to give nitrogen-containing heterocyclic compounds (eqn (2)).²⁴ For example, the N–N bond in 3a could be cleaved in the presence of SmI₂ with ethanol as the solvent to give product 4a. The vinyl chloride unit in 3a is a widely used functional group in organic synthesis. Here, we show that the chloride atom in 3a can be substituted by a sulfa substituent to give product 5a.

Conclusions

In summary, we have developed a new C–C bond activation of cyclobutenones enabled by an isothiourea organocatalyst. The catalytically generated intermediate undergoes an α-carbon selective reaction with azomethine imines to afford nitrogen-containing heterocyclic compounds with excellent diastereo- and enantio-selectivities. Our approach offers new reaction modes that are not readily available with transition metal catalysis. It also expands the potential in using organocatalysts for C–C bond breaking and selective reactions.