Nickel-mediated reductive coupling of neopentyl bromides with activated alkenes at room temperature and its synthetic application
Graphical abstract
Introduction
The notorious steric hindrance of neopentyl halides is typically demonstrated in bimolecular nucleophilic substitution reactions (SN2) [1]. The extreme difficulty resulting from ‘backside attack’ of the electrophilic carbon in this kind of halides by the nucleophile, had been demonstrated by Ingold and co-workers in a series of seminal papers about kinetic studies [2,3], and further approved by computational studies later [2](f), [4]. The limited successful examples mainly focused on the cases with hetero- [2](b), [2](c), [2](d), [5] rather than carbon nucleophiles. An alternative nucleophilic displacement reactions via unimolecular process (SN1) also could give corresponding products; however, more favourable carbocation rearrangement [2](e), [6] always accompanied in most of cases.
In a synthetic project, we needed to realize homologation of (+)-8-bromocamphor ethylene ketal 1. Many attempts such as enolate alkylation and direct cross–coupling failed [7], which should be attributed to the remarkable steric encumbrance embedded this neopentyl structure. We then turned to conjugate addition reaction promoted by n-Bu3SnH or Zn/Cu couple [8], but both of them still cannot effectively work on this unique substrate since competitive reduction of the bromide 1 was predominant. Although Money and co-workers [9] had realized a cross–coupling between (−)-8-iodocamphor and an π-allyl Ni complex [10] [generated from prenyl bromide and 8 equiv of Ni(CO)4] in 40% yield at 60 °C after 36 h, the inherent danger and inconveniency of this protocol (e.g., Ni(CO)4 is a volatile, flammable, highly toxic liquid [11], and its preparation and subsequent reaction is needed to run in nonpolar and polar solvents respectively) limited its practical utilization. Even in their hands, the yield of this transformation was poor and irreproducible, hence they abandoned this procedure eventually and utilized an umpolung route involving cyanation, alkylation and decyanation [[12], [12](a)] in the total synthesis of (+)-longifolene [12b]. Consequently, an effective alkylation approach of neopentyl halides is still in high demand.
Direct cross-electrophile coupling has already emerged as an advantageous method for the formation of C−C bonds. It can avoid some problems associated with preformed organometallic reagents which are inevitable in conventional cross-coupling of a nucleophile with an electrophile, therefore leading to generally excellent functional-group compatibility. A noteworthy advance is Ni-catalyzed reductive coupling of the challenging unactivated alkyl halides [[13], [14], [15], [16]]. Recently, Weix [13a] and Gong [14](a), [14](d), [14](f) developed bi- or tridentate amine ligated Ni complex-catalyzed reactions toward C(sp3)−C(sp2) and C(sp3)−C(sp3) bond construction, and these catalytic systems had been further expanded to couplings of acyl halides [13](b), [14](b), [14](c) and allyl acetates [14](d), [14](e) with alkyl halides under reductive conditions. In particular, Ni/(R,R)-diphenyl-Box-catalyzed asymmetric reductive acyl cross-coupling with secondary benzyl chlorides had been reported by Reisman [15a]; Ni/PCy3-catalyzed reductive carboxylation of benzyl halides with CO2 had also been realized by Martin [15b]. More importantly, Weix [13c] provided an elegant mechanism insight to this kind of cross-electrophile couplings, which would enable rational improvement and reliable application of this strategy. Independently, we [16] have disclosed inter- and unprecedented intramolecular reductive coupling reactions catalyzed by Ni(0)•2EC•Py (Scheme 1a: EC = ethyl crotonate; Py = pyridine), where EC act as π-ligands to Ni and plays an important role on those transformations with unactivated alkenes. Herein, switch of this unique ligand (EC) to methyl acrylate (MA) led to a formation of Ni(0)•2MA•Py complex, which eventually solved the problem mentioned above and achieved carbon chain elongation of (+)-1 (Scheme 1b). The resulting (−)-2a could be easily converted to (−)-11a and (−)-11b, thereby constituting a formal synthesis of tricyclic sesquiterpenoids (−)-copacamphor and (−)-ylangocamphor (vide infra). Moreover, several other electron-deficient olefins were suitable as well, and the generated analogous Ni complexes promoted reductive coupling of various neopentyl bromides successfully. The hypotheses involving radical species were supported by the radical clock experiments and an efficient synthesis of Corey aldehyde homolog 8.
Section snippets
Results and discussion
As shown in Scheme 1b and the Experimental Section, once subjection of (+)-1 to red-brown Ni(0)•2MA•Py complex in situ generated from a mixture of regular Zn/NiCl2·6H2O/pyridine/methyl acrylate [17], the desired reductive coupling reaction was smoothly completed within 0.5 h at room temperature, and ester (−)-2a was isolated in 80% yield. Notably, the efficiency of this transformation remains to be almost identical on a scale of 30 mmol. The reaction catalyzed by the above complex generated
Conclusion
We have demonstrated in this work a solution on the effective alkylation of various neopentyl bromides with steric bulk by means of Ni(0)•2MA•Py complex and analogues-initiated reductive conjugate addition reactions. As an application of this alternative C–C coupling protocol, three-carbon homologation product (−)-2a allowed rapid access to a class of sesquiterpenes with a unique tricyclo[5.3.0.03,8]decane skeleton. In addition to the radical clock experiments, the realization of a synthesis of
General
For product purification by flash column chromatography, silica gel (200–300 mesh) and petroleum ether (bp 60–90 °C) were used. All solvents were purified and dried by standard techniques, and distilled prior to use. Organic extracts were dried over MgSO4 or Na2SO4, unless otherwise specified. Experiments were conducted under an argon or nitrogen atmosphere in oven-dried or flame-dried glassware with magnetic stirring, unless otherwise noted. NMR spectra were measured on 200, 300 and 400 MHz
Acknowledgments
We thank Dr. Shou-Jie Shen and Dr. Yu-Rong Yang for their assistance. Y. Ouyang thanks the Key Program of Natural Science Foundation of Xinjiang Autonomous Region Colleges (XJEDU20181018). Y. Peng thanks the National Natural Science Foundation of China (No. 21772078), and the Fundamental Research Funds for the Central Universities by Ministry of Education of China (2682019CX70 and 2682019CX71). W.-D. Z. Li thanks the National Natural Science Foundation of China (No. 21672030), and the scholars
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