Copper(II) acetate catalysed ring-opening cross-coupling of cyclopropanols with sulfonyl azides

Abstract

A copper(II) acetate catalyzed ring-opening cross-coupling of cyclopropanol with sulfonyl azide has been developed. By this method, various β-amino ketones have been made efficiently in medium to high yields and venerable functional groups such as benzylic C–H, alkyl and aryl bromides, alkyl sulfonate, silyl ether and alkene are compatible with these reaction conditions. Control experiments have precluded the involvement of both radical and simple copper nitrene intermediates and a possible mechanism featuring key steps of ring-opening metalation and alkyl group migratory insertion into copper nitrene has been proposed.

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The energy favouring ring-opening of the cyclopropanyl group has been exploited to develop a plethora of elegant synthetic methodologies.¹ Factors that induce the C–C bond breaking in this small ring are extremely diverse depending on the nature of the ring itself, which is defined by the substitution pattern on the ring, and reaction conditions. For simple cyclopropanol, the ring opening event normally occurs in a high regioselective fashion due to the effect of the hydroxyl group.² Roughly, these reactions fall into three categories in the mechanistic respect: (a) base and electrophile promoted heterolytic cleavage of cyclopropanol ring through the intermediacy of homoenolate I or oxonium ion II (Scheme 1, a);³ (b) single electron oxidation induced homolytic breaking of C–C bond resulting in β-carbonyl radical III which can be intercepted by various carbon radical receptors (Scheme 1, b);⁴ (c) activation and removal of the hydroxyl group to give rise to cyclopropanyl cation IV, which would open up to form more stable allylic cation V for further reactions (Scheme 1, c).⁵

Scheme 1 Three common ring-opening mechanisms of cyclopropanol.

The incorporation of a transition metal would expand the reaction scope and improve their usefulness via the intermediary of metal homoenolate M-I. Indeed, both palladium and copper are reported to mediate ring-opening coupling reactions of cyclopropanol with carbon-based partners.⁶ Very recently, transition metal catalysed conversion of cyclopropanol to β-F, β-CF₃/SCF₃ and β-NR₂ substituted ketones have appeared in literature.⁷ On the other hand, sulfonyl azide has been used in various metal catalysed transformations via metal nitrene M-VI, metal-nitrene radical M-VII or other reactive species as key reaction intermediates.⁸ In line with our interests in azide chemistry,⁹ we are curious that if the chemistry of cyclopropanol and sulfonyl azide could interwoven through transition metal catalysis (Fig. 1).

Fig. 1 Conceptual depiction of interweaving of cyclopropanol chemistry with sulfonyl azide chemistry by metal catalysis.

Our investigation started with catalyst screening for reaction of phenyl cyclopropanol 1a with tosyl azide 5a (Table 1). In most cases, propiophenone 6a was the only observable product (see ESI-Table 1†). To our delight, when a solution of 1a and 5a in dichloroethane (DCE) was heated to reflux in the presence of a catalytic amount Cu(OAc)₂, ring-opening cross coupling product 7aa was isolated in 40% yield along with 6a (Table 1, entry 1). Interestingly, while Cu(acac)₂ was slightly less effective in terms of yield when DCE was used for reaction media (entry 1 vs. 2), CuBr₂ was totally ineffective for the cross-coupling reaction (entry 3) indicating the importance of ligand effect. Common copper(I) complexes all failed to deliver 7aa (entries 4–6) and only 6a was obtained. When the reaction was performed in reflux toluene using Cu(OAc)₂ as catalyst, the yield of cross-coupling product 7aa increased to 69% (entry 7). More electron deficient Cu(hfacac)₂ showed much poorer activity than Cu(acac)₂ in toluene (entry 8 vs. 9). Toluene was superior solvent than DCE, THF and chloroform (entries 10 and 11). Interestingly, in polar solvents such as acetonitrile, DMF and DMSO, 1a remained intact under the same conditions (entries 12–14).

Table 1 Optimization of conditions for ring opening cross-coupling reaction^a

Entry	Cat	Solvent	Temp	Products^b^,^c (yield)
a Conditions 1a (0.5 mmol), 5a (0.75 mmol), cat (20% mol%), solvent (2 mL), heating, 12 h.b Isolated yields.c Yields for 7aa are reported.
1	Cu(OAc)2	DCE	Reflux	6a + 7aa (40%)
2	Cu(acac)2	DCE	Reflux	6a + 7aa (37%)
3	CuBr2	DCE	Reflux	6a only
4	CuCl	DCE	Reflux	6a only
5	CuBr	DCE	Reflux	6a only
6	CuI	DCE	Reflux	6a only
7	Cu(OAc)2	Toluene	Reflux	6a + 7aa (69%)
8	Cu(acac)2	Toluene	Reflux	6a + 7aa (51%)
9	Cu(hfacac)2	Toluene	Reflux	6a + 7aa (15%)
10	Cu(OAc)2	THF	Reflux	6a + 7aa (29%)
11	Cu(OAc)2	CHCl3	Reflux	6a + 7aa (27%)
12	Cu(OAc)2	CH3CN	Reflux	No reaction
13	Cu(OAc)2	DMF	120 °C	No reaction
14	Cu(OAc)2	DMSO	120 °C	No reaction

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The effect of sulfonyl azide was also checked with Cu(OAc)₂ as catalyst and toluene as solvent (Table 2). TsN₃, MbsN₃ and MsN₃ afforded corresponding sulfonyl amides in comparable yields (entries 1–3). MtsN₃, TcesN₃ and CamsN₃ were much inferior reaction partners for this reaction (entries 4–6), and electron deficient NsN₃ reacted with 1a to give a complex mixture.‡

Table 2 Effects of different sulfonyl azides in the ring-opening cross-coupling reaction^a

Entry	RSO2N3 5	Product 7a, yield^b
a Conditions, 1a (0.5 mmol), 5 (0.75 mmol), Cu(OAc)2 (0.1 mmol), toluene (2 mL) in N2, 120 °C, 8 h.b Isolated yields.
1	TsN3 5a	7aa, 69%
2	MbsN3 5b	7ab, 56%
3	MsN3 5c	7ac, 61%
4	MtsN3 5d	7ad, 31%
5	TcesN3 5e	7ae, 18%
6	CamsN3 5f	7af, 44%
7	NsN3 5g	—

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Next the scope of cyclopropanol was investigated with TsN₃ as the amination agent (Table 3). For aryl cyclopropanols 1a–d, the yield of corresponding β-tosylamidylaryl ketones increased from 52% to 76%, suggesting that the electron-donating group on the phenyl ring favor the ring open/coupling reaction (from entry 3 to 1, 2 and 4). Substrates with benzylic C–H group which is potential reactive site in metal catalyzed reactions involving sulfony azide were also viable for this reaction, as both 7ea and 7fa were obtained smoothly (entries 5 and 6) in comparable yields. 1-Cyclohexylcyclopropanol 1g reacted with TsN₃ in the same conditions to give 7ga in an excellent yield (entry 7, 95%). Methyl cyclohexylcyclopropanol 1h afford 7ha in 88% yield (entry 8). The slight decrease in yield for 7ha than for 7ga might reflect the effect of increased bulkiness at the alkyl group in 1h. Functional groups such as alkyl/aryl bromide, alkyl silyl ether, alkylsulfonate and alkylsulfonamide were all tolerated in this reaction conditions and related β-tosylamide aryl ketones 7ia-ma were all generated in medium to high yields (entries 9–13). It is worth to note that 1n bearing a vulnerable alkene group was also a good substrate to give 7na in 57% (entry 14).

Table 3 Substrate scope for cyclopropanol ring-opening cross-coupling reaction^a

Entry	Cyclopropanol 1	Product 7, yield^b	Entry	Cyclopropanol 1	Product 7, yield^b
a Conditions, 1a (0.5 mmol), 5 (0.75 mmol), Cu(OAc)2 (0.1 mmol), toluene (2 mL) in N2, 120 °C, 8 h.b Isolated yields.
1			8
2			9
3			10
4			11
5			12
6			13
7			14

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Cyclobutanol 8, cyclopentanol 9 and adamantanol 10 failed to undergo analogous ring breaking/coupling reaction when subjected under the same reaction conditions. These experiments underscore the necessity of three-membered ring for the reaction.

To gain more information about this reaction, control experiments have been carried out (Scheme 2, eqn 1–4). It was found that TEMPO has neglectable effect on this reaction. When a mixture of 1a (1 equiv.), 5a (1.5 equiv.), TEMPO (2 equiv.) and Cu(OAc)₂ was heated in DCE for 8 hours, 7aa and 6a were isolated as sole products (Scheme 2, 1), while increasing the amount of TEMPO to 10 equiv., the formation of 7aa was not observed. Interestingly, in the presence of 2 equiv. TEMPO but free of Cu(OAc)₂, 7aa could be isolated in 20% yield (Scheme 2, 2). Reaction without sulfonyl azide, phenyl cyclopropanol 1a was converted to ketone 6a in a high isolated yield (Scheme 2, 3). In the presence of 1.5 equiv. styrene, the reaction took place as normal and no phenyl tosylaziridine was observed (Scheme 2, 4). No reaction happened when styrene and TsN₃ was heated with catalytic amount of Cu(OAc)₂ (Scheme 2, 5). These results suggested there was no simple copper nitrene species TsN = Cu(OAc) in the reaction system.¹⁰

Scheme 2 Several control experiments.

In view our results and literature precedence,¹¹ a mechanism depicted in Scheme 3 was proposed even though a free radical alternate couldn't be excluded at this stage.¹² The catalytic circle starts with a Cu(OAc)₂ promoted ring-opening metalation of cyclopropanol 1 to give alkyl copper(II) homoenolate I. Protonation of this species would lead to the side product ketone 6. On the other hand, Cu(II) species I could be harnessed by sulfonyl azide 5 either through a transition metal mediated mechanism or a copper coupled radical process to construct the key C–N bond giving rise to intermediate II which, upon release of N₂, would produce intermediate III. Subsequently, ligand exchange would take place with AcOH to release product 7 and Cu(OAc)₂ to complete the catalytic circle. This mechanism is also in line with the ineffectiveness of Cu(I) salts as catalyst for this reaction.

Scheme 3 Proposed mechanisms for ring-opening cross-coupling reaction of cyclopropanol.

Conclusions

In summary, we have described a copper(II) acetate catalysed ring-opening cross-coupling of cyclopropanol with sulfonyl azide to produce β-amino ketone. The conditions of this reaction are mild enough to be compatible with a number of fragile functionalities.

Acknowledgements

The authors wish to thank the Natural Science Foundation of China (21402014 and 21272077), the Natural Science Foundation of Jiangsu Province (BK20131143), the Priority Academic Program Development of Jiangsu Higher Education Institutions (PADA), and Jiangsu Key Laboratory of Advanced Catalytic Materials and Technology (BM2012110). We also thank Prof. Lei Zhu at Florida State University for mechanism discussion.

References

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Footnotes

† Electronic supplementary information (ESI) available: Experimental procedures, characterization of compounds and copies of spectra. See DOI: 10.1039/c5ra20729k

‡ Sulfonyl azides are known explosive compounds and therefore special precautions are paid for their preparation and purification. In some reactions, significant amount of both TsN₃ and TsNH₂ were observed after 8 h heating, suggesting that some sulfonyl azides are safe for laboratory use at least in small scale.

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