One-pot synthesis of small spirocarbocycles through the catalytic cyclometalation reactions of unsaturated compounds

The mild and efficient one-pot methods to synthesize substituted spirocyclopropanes and spirocyclobutanes are reported. The elaborated procedures based on consecutive cycloalumination of methylenecyclopropanes, methylenecyclobutanes or cycloalkynes assisted by alkyl aluminums and Cp 2 ZrCl 2 as a catalyst provide the formation of target products through Pd catalyzed carbocyclization of the aluminacyclopentane and aluminacyclopentene intermediates with Me 2 SO 4 or allyl chloride.


Introduction
Small carbocycles are of special interest due to a variety of rearrangements into isomeric unsaturated compounds that have defined their wide use as building blocks for the directed synthesis of strained cyclic organic systems.In addition, among those containing three-and fourmembered carbocycles, one can often meet medical and biological preparations, plant protection products, and energy-rich components for jet fuel.
Ordinary approaches to small carbocycles are based on the classical procedures 1 such as 1,ωelimination, Favorskii rearrangement, Dieckmann, Perkin and Simmons-Smith reactions, cyclopropanation of unsaturated hydrocarbons with diazocompounds as well as through concerted cycloaddition and cyclization reactions and also new ones, e.g.nontrivial transformations of acetylenes to mono-and biscyclopropanes mediated by aluminum carbenoids. 2 Of real interest are the methods, elaborated in the last 10-15 years, for the construction of cyclopropane alcohols 3 and ethers 4 by the interaction between esters and Grignard reagents or alkylhalogenalanes in the presence of Ti and Zr complexes through the three-membered metallacarbocycles.
To a number of promising procedures in the synthesis of small carbocycles, in our opinion, it should be also added those including intramolecular transformations of the five-membered nontransition metallacarbocycles such as aluminacyclopentanes 5 , aluminacyclopentenes, 6 magnesacyclopentanes 7 and their derivatives in situ generated in the cycloalumination and cyclomagnesiation reactions of unsaturated compounds with alkyl aluminums or alkyl magnesiums under the effect of Ti and Zr catalysts (Dzhemilev reaction). 8s known, 6d,9 the interaction between 2,3-dialkylsubstituted aluminacyclopent-2-enes 1 and dimethyl sulphate or bromomethyl methyl ether as well as carbocyclization of 3alkylaluminacyclopentanes 2 with allyl chloride in the presence of Ni(acac)2 provides the formation of cyclopropanes 3-5.At the same time, the Pd catalyzed intramolecular cyclization of monoalkyl and dialkyl substituted aluminacyclopentanes represents an effective method for the construction of cyclobutanes 6 (Scheme 1). 10

Scheme 1
As described above, the aluminum-based transformations of the five-membered metallacarbocycles have been studied on the example of the simplest alkyl substituted aluminacyclopentanes and aluminacyclopent-2-enes.Meanwhile, the investigation of such transformations with the aid of more complicated organoaluminum and organomagnesium compounds is thought to initiate the development of novel one-pot procedures for the synthesis of polycycles containing spirocyclopropane and spirocyclobutane moieties.
In this paper, we report new approaches to small spirocycles via intramolecular carbocyclization of di-, tri-and polycyclic aluminacyclopentanes and aluminacyclopentenes

Results and Discussion
Recently, 11 we have synthesized the first representative of a new class of cyclic organoaluminum compounds (OACs) of a spirane structure, namely 6-ethyl-6-aluminaspiro [3.4]octane 7, via the interaction between methylenecyclobutane and Et3Al in the presence of 5 mol% Cp2ZrCl2 (pentane, 4 h).It was found that the OAC 7, without preliminary isolation, can enter into reaction with allyl chloride easily converted into spiro [3.3]heptane 8 (90%) in the presence of 2 mol% Pd(acac)2 (Scheme 2).

Scheme 4
Very encouraging results, obtained in the course of developing one-pot methods to synthesize spiro [3.3]heptanes by the intramolecular carbocyclization reaction of 6-ethyl-6aluminaspiro [3.4]octanes, prompted us to apply the same approach to the construction of spiro [2.3]hexane systems.
Initially, we investigated the activities of 2-pentyl-and 2-phenylmethylenecyclopropanes, as selected samples, in the reaction of catalytic cycloalumination with Et3Al and also their ability to give substituted aluminaspiro [2.4]heptanes.
The interaction between Et3Al and 2-pentyl-1-methylenecyclopropanes in the presence of 5 mol% Cp2ZrCl2 (hexane, 4 h) was found to afford a mixture of two theoretically possible regioisomeric aluminacyclopentanes 24 and 25 (81% total) bearing cyclopropane ring in αand β-position towards to Al atom respectively.Deuterolysis of this regioisomeric mixture led to hydrocarbons 26 and 27 at a 2:1 ratio.The Pd catalyzed reaction with allyl chloride provided the formation of spirocyclobutane 28 in 73% yield (Scheme 5).

Scheme 5
We revealed that the nature of a substituent in the methylenecyclopropane ring determines the selectivity of the reaction.Thus, under previously developed conditions, 2phenylmethylenecyclopropane entered into reaction with Et3Al furnishing 4-ethyl-1-phenyl-4 aluminaspiro [2.4]heptane 30 with high regioselectivity (Scheme 6).

Scheme 6
The structure of the new OACs 24, 25 and 30 has been proven through analysis of the onedimensional ( 1 Н, 13 С, АРТ) and two-dimensional (HH COSY, HSQC and HMBC) NMR spectra of the acid hydrolysis 31 and deuterolysis products 26, 27, and 32.
Thus, the 1 H and 13 C NMR spectra of the hydrocarbon 31 show the low field signals corresponding to the aromatic protons and carbons of the phenyl ring, while the alkyl substituent and cyclopropane moiety manifest themselves in the high field of the spectra.The methylene protons at the α-carbon [δ(С-10) 30.7 ppm] attributable to the alkenyl substituent are observed as two multiplets [δН (C-10) 0.91 and 1.18 ppm] due to diastereotopic splitting at the chiral C-2 center.1,2-Disubstituted cyclopropane fragment is represented by a four spin systems associated with two methine [δ Н(С-1) 2.13 and δ (Н-2) 1.13 ppm] and also two methylene protons [δ Н(С-3) 0.67 and 0.99 ppm].
Assignment of cis and trans isomers has been performed on the basis of vicinal coupling constants (SSCC).Thus, in the 1 H NMR spectrum of trans-isomer, theoretically, the signal resonated in a low field [δ H (C-1) 2.13 ppm] must comply with one large ( 3 Jcis ≈ 8-10 Hz) and two average ( 3 Jtrans ≈ 4-6 Hz) coupling constants.
In the experimental spectrum, there are two large vicinal ( 3 Jcis = 8 Hz) and one average ( 3 Jtrans = 5 Hz) coupling constants corresponding to the signal at δ 2.13 ppm.These data clear indicate cis-arrangement of phenyl and propyl substituents with respect to the cyclopropane ring.
Location of deuteriums in compound 32 obtained from deuterolysis of OAC 30 is determined by the splitting of signals assigned to the methyl С-3 and С-6 carbons (δ 18.9 and 14.0 ppm) with a shift of a triplet centre towards the high field (ΔδС 0.3 ppm).These data and also the SSCC magnitude ( 1 JCD = 19 Hz) are the additional arguments for the formation of a cyclic OAC 30.
We believe that the above reactions have considerable synthetic potential and their further studies will lead in future to the development of a general method to synthesize spiro[2.3]hexanes,spiro [2.3]heptanes and spiro [4.3]octanes, including those containing functional substituents.
In the development of the other approach to small carbocycles, based on intramolecular carboalumination of 2,3-dialkylaluminacyclopent-2-ene, with the aid of dimethyl sulfate 9 or bromomethyl methyl ether 6d , for the first time the catalytic cycloalumination reaction of cycloalkynes has been performed (Scheme 1).

Scheme 8
For comparison, we presented perhaps the single example of intramolecular cyclization of five-membered magnesacarbocycle successfully obtained from cyclonona-1,2-diene through the catalytic cyclomagnesiation reaction.

Conclusions
Thereby, the five-membered organoaluminum and organomagnesium compounds obtained by the Dzhemilev reaction have proven to be promising synthons while designing efficient one-pot procedures to obtain various spirocyclopropanes and spirocyclobutanes from accessible methylenecycloalkanes, cyclic 1,2-dienes and acetylenes.

Synthesis of 4,4-dimethylspiro[2.7]decane (36a)
Cyclic alkyne (5 mmol), Cp2ZrCl2 (0.25 mmol), hexane (10 mL), and Et3Al (15 mmol) were placed into a glass reactor under dry argon at 0 °C with stirring.The temperature was elevated to ambient (20-21 °C) and the reaction mixture was stirred for 6 h, then, Me2SO4 (8 mmol) were added dropwise at 0 °C, the temperature was raised to ambient and the stirring was continued for 12 h.The reaction mixture was worked up with 7-10% aq.HCl, the reaction products were extracted with diethyl ether, dried with MgSO4 and isolated by distillation in vacuo.