Synthesis of functionalised azepanes and piperidines from bicyclic halogenated aminocyclopropane derivatives†

A series of 6,6-dihalo-2-azabicyclo[3.1.0]hexane and 7,7-dihalo-2-azabicyclo[4.1.0]heptane compounds were prepared by the reaction of dihalocarbene species with N-Boc-2,3-dihydro-1H-pyrroles or -1,2,3,4tetrahydropyridines. Monochloro substrates were synthesised as well, using a chlorine-to-lithium exchange reaction. The behaviour of several aldehydes and ketones under reductive amination conditions with deprotected halogenated secondary cyclopropylamines was investigated, showing that this transformation typically triggers cyclopropane ring cleavage to give access to interesting nitrogen-containing ring-expanded products.


Introduction
Our long-standing interest in fused bicyclic aminocyclopropanes has led us to develop several transformations of these compounds for the preparation of nitrogen-containing polycyclic systems. 1 All these methods involve cyclopropane substrates in which the amino group is the only activating substituent. 2 We recently decided to turn our attention to 2,2-dihalo-substituted aminocyclopropane derivatives. Indeed, the presence of a gem-dihalocyclopropane substructure offers extended opportunities for subsequent transformations. 3 Of special interest is the thermal ring-opening of halocyclopropanes, proceeding with concomitant departure of a halide ion, to generate allyl cation species. 3,4 Starting from fused bicyclic systems, ringenlarged products can thus be obtained. Many examples can be found in the literature, 3 some of which served in the syntheses of natural products. 5 Nevertheless, reports involving nitrogen-substituted gemdihalocyclopropane compounds are comparatively scarce. 5e, 6 Typically, the starting materials are stable amide, carbamate or urea derivatives, i.e. with the lone pair of the nitrogen atom being delocalised into a carbonyl group. These ring-opening reactions (Scheme 1) require heating and/or activation by silver salts (or a Pd catalyst as in the bottom example) and are often low-yielding. Interestingly, sporadic reports show that amines can be more reactive (Scheme 2), 7 which can be rationalised by

Synthesis of the substrates
In practice, two routes were investigated for the synthesis of the dihalocyclopropane substrates 2: the first one involved functional group transformation from lactams: installation of the Boc group, nucleophilic addition of a hydride or a methyl carbanion onto the carbonyl group and elimination of water. 15 Finally, the cyclic N-Boc enamines 1 thus obtained were reacted with dihalocarbene species generated from chloroform or bromoform, using the phase-transfer catalysis method developed by M. Mąkosza (Scheme 4). 16 The second route consisted of applying a Kharasch-Sosnovsky reaction onto N-Bocpiperidine (Scheme 5). This approach was much lower yielding but practical and low cost, since the unreacted starting material could be recycled after the cyclopropanation step.
Small amounts of the more complex cyclopropanes 2f and 2g were also isolated, resulting from cyclopropanation of the by-product 1f formed by oxidation of the N-Boc-enamine 1b. Application of the same method to N-Boc-pyrrolidine gave poor results in our hands. The stable N-Boc protected aminocyclopropane substrates 2a-f were then readily converted into secondary amine hydrochlorides by treatment with HCl (Scheme 6). In the process, the acetate group of 2f was hydrolysed into an alcohol function. Scheme 2 Reported ring-expansion reactions of 2,2-dihalogenated aminocyclopropanes.
Scheme 4 Synthesis of the dihalocyclopropane substrates 2a-e from lactams.

Reductive aminationring enlargement
When a set of aldehydes and ketones were reacted with 2,2dihalogenated aminocyclopropane salts 3a-e in the presence of NaBH(OAc) 3 , the reductive amination products 4 were initially formed, as evidenced by NMR after 30-60 minutes of reaction. ‡ However, from 3a-d, these were gradually transformed into ring-enlarged products 5, as anticipated (Table 1). § In particular, the 6,6-dichloro-2-azabicyclo[3.1.0] hexane 3a gives the chloroazacyclohexenes 5aa-ae in moderate to good yields. The presence of a methyl group in 3d is tolerated and the product 5da was isolated in 44% yield. Starting from the homologous 7,7-dihalo-2-azabicyclo[4.1.0]heptane substrates, yields were uniformly lower. This is due, at least in part, to competitive processes leading to by-products (vide infra). Interestingly, halogen-substituted tetrahydroazepine derivatives, with structures closely related to those of 5ba, 5bd-be and 5ca, have been demonstrated to be cycloallene precursors that can be used as intermediates in the preparation of valuable polycyclic building blocks. 17 The salt 3f containing a hydroxyl group proved to be unsuitable, affording, with benzaldehyde, the corresponding chloroazepine derivative in 6% yield only. Starting from the better substrate 3b, poor results were also obtained when butyraldehyde and indole-3-carboxaldehyde were employed. ‡ A much simpler version of the reaction involves the generation of secondary amines by deprotonation of the salts 3 with triethylamine. This was done on a few milligram scale in NMR tubes containing CDCl 3 solutions of 3a and 3d. The rearrangement is fast under these conditions and the clean formation of the 5-chloro-2,3-dihydropyridines 6a and 6d is observed after 5 minutes at room temperature (Scheme 7). ¶ Interestingly, starting from the methyl-substituted compound 3e and under the reductive amination conditions applied for substrates 3a-d, the reaction takes a different course. Indeed, 3-chloromethylenepiperidine derivatives 7ea and 7eb are isolated as single geometrical isomers (Scheme 8). A similar phenomenon is observed when 3b is reacted with cyclohexanone, with the formation of 7be as the major product.
The formation of compounds 7 can be explained by a 2,2dichloro-1-aminocyclopropane-ring opening proceeding at the C1-C2 bond (Scheme 8, bottom). 18 Steric hindrance around the nitrogen atom appears to be a key factor for this process, as well as the size of the nitrogen-containing heterocycle. Indeed, starting from 3a and 3d, which are the lower homologues of 3b and 3e, selectivity is in favour of the ring-expanded molecules 5ae and 5da (Table 1). Nonetheless, careful analysis of the crude products of all the reductive amination experi-Scheme 5 Synthesis of 2b-c and 2f-g using the Kharasch-Sosnovsky reaction.
Scheme 7 Simpler version of the reaction. ‡ See the ESI † for details. § The quality of the hydride reagent proved important. See the ESI † for a short study in the case of the reaction of benzaldehyde with 3b. ¶ Using K 2 CO 3 as the base, no reaction was observed after several hours, most certainly because of the very low solubility of this reagent in chloroform. With NaOH, complex mixtures of products were generated after 5 minutes. ments revealed, in several cases, the formation of minor amounts of compounds of type 7, as well as of other byproducts. ‡

Results with monochlorocyclopropane substrates
The reactivity of 2-monochloro aminocyclopropane derivatives was next investigated. The dichlorocyclopropane 2b was transformed into the monochloro diastereoisomers 8 by chlorineto-lithium exchange using sBuLi/TMEDA.∥ After separation by flash chromatography, these molecules were converted into the hydrochloride salts, exo-and endo-9 (Scheme 9).
Application of reductive amination conditions with benzaldehyde proceeds with high chemoselectivity: while the exo compound gives the tertiary cyclopropylamine exo-10, endo-9 is converted into the ring-expanded tetrahydroazepine 11 (Scheme 10), showing that the endo bicyclic aminocyclopropane endo-10 is not stable and readily undergoes rearrangement, like the dihalo derivatives 4. These divergent results are in agreement with the so-called Woodward-Hoffmann-DePuy rule. 19,20 Briefly, the reaction is thought to proceed by a mechanism where the departure of the halide ion and the two-electron electrocyclic cyclopropane-cleavage take place in a con-certed fashion. Moreover, the sense of the disrotatory ringopening is dictated by the relative configurations of the cyclopropane carbon atoms, so that substituents that are trans to the leaving group move outward (Scheme 11, framed). While the substrates having a halogen substituent in the endo relative configuration, i.e. endo-10 and all the dihalo substrates, can be transformed into cyclic cation intermediates 13, exo-10 cannot participate in such a process because the unacceptably strained E cation 12 would be produced (Scheme 11).
Finally, the successful transformation of endo-9 into the amide endo-14 demonstrates that the reaction of the acyl chloride is fast enough to trap the free secondary amine before it undergoes cyclopropane cleavage. Like the N-Boc derivative endo-8, endo-14 is a stable compound that can be purified by flash chromatography. However, when heated under microwave conditions, it is transformed into the dihydroazepine

Conclusions
In summary, endocyclic amine systems fused with a dihalocyclopropane ring undergo cyclopropane cleavage to typically afford ring-expanded products. A minor competitive pathway, which can become predominant with some substrates, is the cleavage of the other cyclopropane bonds adjacent to this atom. Monochloro substrates can also participate in the ringexpansion process, provided that relative configuration of the chlorine substituent is endo. All these transformations readily take place at room temperature, after the amine function is created by a reductive amination reaction or by simple deprotonation of the corresponding hydrochloride salt. In contrast, amides or N-Boc carbamate substrates require activation (e.g. heating) for the ring-expansion to proceed, still on the condition that a halogen substituent is present with the endo relative configuration.

Experimental
Selected experimental procedures and data are presented hereafter. Full details can be found in the ESI. † sec-Butyllithium (1.3-1.4 M solution in cyclohexane) was purchased from Sigma-Aldrich or Alfa Aesar and titrated according to a literature method. 21 Diethyl ether, and dichloromethane were purified using a MB SPS-800 solvent purification system (MBRAUN). Other solvents and commercial reagents were used as received, without purification. Petroleum ether refers to the 40-60°C fraction. The microwave-promoted experiments were run using a CEM Discover Microwave Synthesis System with the temperature and time parameters indicated; the reaction vessels were not flushed with an inert gas. All other reactions were carried out under nitrogen or argon. The temperatures mentioned are the temperatures of the cold baths or the oil baths used. Flash column chromatography was performed on VWR Chemicals or Merck silica gel 60 (40-63 μm). Concentration under reduced pressure was carried out using rotary evaporators at 40°C. NMR spectra were recorded with AM 400 or AVANCE 400 Bruker spectrometers ( 1 H at 400.2 MHz, 13 C at 100.6 MHz). Chemical shifts δ are given in ppm, referenced to the peak of tetramethylsilane, defined at δ = 0.00 ( 1 H NMR), or the solvent peak of CDCl 3 , defined at δ = 77.0 ( 13 C NMR). Multiplicities are abbreviated as follows: s = singlet, d = doublet, t = triplet, q = quadruplet, quint = quintuplet, sext = sextuplet, sept = septuplet, m = multiplet, and br = broad. Coupling constants J are given in Hz and are rounded to the closest multiple of 0.5. Infrared spectra were recorded with a PerkinElmer 2000 or a PerkinElmer Spectrum Two FT-IR spectrometer. Melting points were determined using a Büchi 535 apparatus and were not corrected. Low-resolution mass spectra were recorded on a Hewlett-Packard Quad GC-MS engine spectrometer via direct injection. High-resolution mass spectrometry was performed on a JEOL GC-mate II spectrometer. Underlined m/z values indicate the base peaks.
General procedure A: Cyclopropanation of N-Boc dihydropyrroles and N-Boc tetrahydropyridines with dichlorocarbene 22 10 M NaOH aqueous solution (20 mL) was slowly added to a solution of N-Boc cyclic enamine substrate 1 (1.00 equiv., 3.50 mmol) and benzyltriethylammonium chloride (0.63 equiv., 2.20 mmol) in CHCl 3 (20 mL). After 90-180 min of vigorous stirring at 20°C, the aqueous phase was removed. The organic layer was washed with H 2 O (20 mL) and brine (20 mL), then dried over MgSO 4 , filtered and concentrated under reduced pressure to afford the crude product, which was then purified by flash column chromatography on silica gel.  13   General procedure B: Reductive amination reactions of aldehydes and ketones with the cyclopropylammonium salts 3 or 9 Sodium triacetoxyborohydride (2.40 equiv., 240 μmol, 50.9 mg) was added at 20°C to a solution of aldehyde or ketone (1.00 equiv., 100 μmol) and cyclopropylammonium chloride 3 or 9 (1.00 equiv., 100 μmol) in dry CH 2 Cl 2 (1.0 mL). After 15 h of stirring at r.t., saturated NaHCO 3 aqueous solution (15 mL) was added. The mixture was extracted with CH 2 Cl 2 (2 × 15 mL). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to afford the crude product, which was then purified by flash column chromatography on silica gel (typically, a few drops of Et 3 N were added to the eluents used).