Synthesis of 3-Azabicyclo[3.0]hex-1-ylamines by Ti-Mediated Intramolecular Reductive Cyclopropanation

1.1. Synthesis of N,N-dialkylamides from L-serine

The first aim of this project was the development of a synthetic method for the synthesis of 3-azabicyclo[3.2.1]hexane and 3-azabicyclo[4.2.1]heptane derivatives by Ti-mediated intramolecular reductive cyclopropanation, which may be applied to different types of substrates. Initially this transformation was investigated with the natural amino acid L-serine (48) as the starting material for the synthesis of the corresponding amides, precursors for the intramolecular cyclopropanation. L-Serine (48) was transformed into its methyl ester (49, 93%)^[24], and this protected as the tert-butyldimethylsilyl ether^[25] 50 by treatment with tert-butyldimethylsilyl chloride (TBDMSCl), N,N-dimethylaminopyridine (DMAP) and Et₃N in 65% yield (Scheme 8).

OH Scheme 8. Transformations of L-serine.

When compound 50 was treated with PhCHO and NaBH₄ in MeOH,^[26] the N-benzyl derivative 51-TBDMS and the O-deprotected derivative 51-H were obtained in a ratio of 1 : 1.1. The alcohol 51-H could be removed by column chromatography, but its formation as the major product limited the use of this method. The problem of the partial deprotection of compound 51 was solved by performing the reductive N-alkylation on serine methyl ester hydrochloride (49), followed by TBDMS protection (Scheme 9). The hydrochloride 49 was converted into the N-benzyl derivative 52 in 87% yield.^[26] Protection of the hydroxy function was carried out by treatment with TBDMSCl, Et₃N/DMAP in CH₂Cl₂ to give compound 51-TBDMS in 75% yield.^[25] The latter was transformed into the N-allyl-N-benzyl derivative 53 in 82% yield, when allyl bromide and K₂CO₃ in MeCN were used.^[27] The methyl ester 53 was then converted into the corresponding N,N-dimethyl amide 54 by treatment with AlMe₃, HNMe₂^.HCl in benzene/THF^[23] in 51% yield (Scheme 9).

Scheme 9. Synthesis of N,N-dimethylamide 54.

The possibility to prepare N,N-dibenzyl derivatives was also considered, in order to be able to deprotect the amino group after intramolecular cyclopropanation of the corresponding amide.

The synthesis of such derivatives required a different set of reactions than was used for the N,N-dimethylamides (Scheme 10). N,N-dibenzylamide 56 was prepared starting from N-benzylserine (55) in a ''one-pot'' synthesis by treatment with TBDMSCl and imidazole (Im-H) in DMF at ambient temperature for 24 h,^[28] followed by treatment with dicyclohexylcarbodiimide (DCC), hydroxybenzotriazole (HOBT) and HNBn₂^[29] at ambient temperature for 24 h in 49% overall yield. The desired N-allyl derivative 57 was obtained from the N,N-dibenzylamide 56 in 64% yield using allyl bromide and K₂CO₃ in MeCN (Scheme 10).^[27]

Scheme 10. Synthesis of (S)-2-(allylbenzylamino)-N,N-dibenzyl-3-(tert-butyldimethyl-silyloxy)propionamide 57.

1.2. Synthesis of endo- and exo-(2R)-N,N-dialkyl-3-benzyl-2-(tert-butyldimethylsilyloxy-methyl)-3-azabicyclo[3.1.0]hex-1-ylamines

Under the conditions published by Joullié^[23] for the reductive intramolecular cyclopropanation of α-substituted N-allylglycine N,N-dimethylamides [4.50 equiv.

cPentMgCl, 1.00 equiv. ClTi(OiPr)3, THF, 20 °C, see Section A], the serine N,N-dimethyl-amide 54 and the N,N-dibenzylamide 57 did not cyclize to the corresponding bicyclic diamines. However, the target 1-amino-3-azabicyclo[3.1.0]hexane derivatives 58 and 59 were obtained from the amides 54 and 57 applying a slightly different protocol [1.50 equiv.

methyltitanium triisopropoxide, MeTi(OiPr)₃, instead of ClTi(OiPr)₃ and 5.00 equiv. Of cyclohexylmagnesium bromide, cHexMgBr, instead of cPentMgCl] in 89 and 83% yield, respectively (Scheme 11). The observed diastereoselectivity was endo-58 : exo-58 = 2 : 1 and endo-59 : exo-59 = 2.5 : 1.

Scheme 11. Intramolecular reductive cyclopropanation of N-allyl-N-benzyl aminoserine N,N-dialkylcarboxamides 54 and 57.

Earlier experiments^[30] had disclosed that MeTi(OiPr)3 gave consistently better yields of cyclopropylamines from N,N-dialkylcarboxamides. This was confirmed for the conversion of esters to cyclopropanols when ligand exchange was involved in the generation of the reactive titanium intermediate.^[31] Cyclohexylmagnesium bromide also gave better yields and purer products than cyclopentylmagnesium halides (bromide or chloride).^[20b]

The formation of the endo- and exo-isomers can be explained on the basis of the following mechanism (Scheme 12).^[23]

Scheme 12. Mechanism and explanation of diastereoselectivity in the Ti-mediated intramolecular cyclopropanation of amide 54 and 57.

The titanacyclopropane intermediate 60, formed in the reaction between MeTi(OiPr)₄ and cHexMgBr, undergoes ligand exchange with the allyl moiety of 54 and 57 to give the titanacyclopropane intermediate 61 and 62. The latter undergo titanacyclopropane ring expansion by insertion of the amide carbonyl group between titanium and the most highly substituted carbon atom. The more favorable conformation 61 has the hydroxymethyl group anti to the hydrogen of the most highly substituted carbon atom of the titanacyclopropane and to the NR₂ group. The titanacyclopropane ring expansion in the intermediate 61 may lead to the formation of a titanaoxacyclopentane of type 63 which, through the intermediate iminium ion 65, leads to the endo-isomer as the major product. In the case of N,N-dibenzyl derivatives the more severe steric interaction in the intermediate of type 62, which leads to the formation of the exo-isomer, may explain the diastereoselectivity observed.

2. Synthesis of 1-Amino-3-azabicyclo[3.1.0]hexanes and 1-Amino-3-azabi-cyclo[4.1.0]heptanes

2.1. Synthesis of N,N-dialkylamides from bromoacetyl bromide

The results obtained in Section 1 stimulated the application of the intramolecular cyclo-propanation towards the synthesis of the bicyclic amines 28 and 29 (see Section A).

The N-allylglycine N,N-dialkylamides 70–73 were prepared from 2-bromoacetamides 67 and 68 by nucleophilic substitution^[32,33] with the appropriately N-substituted allyl- or homoallylamine in good yields (Table 1).

Table 1. Synthesis of amides 70–73.

base, solv.

The preparation of amides 74 and 75 containing the N-tert-butoxycarbonyl (Boc) group required a different synthetic approach, because the N-allyl-N-tert-butoxycarbonylamine reacted sluggish in the nucleophylic substitution with bromoacetamides 67 and 69 (Table 1).

Compounds 74 and 75 were obtained by treating 2-bromoacetamides 67 as well as 69 with allylamine in THF followed by N-Boc-protection of the amino group in 57 and 54% yield, respectively (Scheme 13).^[34]

20 °C, 12 h

67 74

2) Boc₂O, Et₃N MeOH, 60 °C, 2 h

R = Bn 69 R = Ph

R = Bn (57%) R = Ph (54%) 75

1) Allylamine, Et₃N, K₂CO₃, NaI, DMF

NR₂ Br

O

NR₂ Boc O N

Scheme 13. Synthesis of N-Boc-protected amides 74 and 75.

2.2. Ti-mediated reductive intramolecular cyclopropanation of N,N-dialkylamides

The amides 70–75 were subjected to the optimized conditions for the reductive intramolecular cyclopropanation of serine derivatives. The targets 1-amino-3-azabicyclo[3.1.0]hexane and 1-amino-3-azabicyclo[4.1.0]heptane derivatives 76–81 were obtained from the corresponding amides in moderate to good yields, when MeTi(OiPr)₃ (1.50 equiv.) and cHexMgBr (5.00 equiv.) were used (Table 2). Only in the case of compound 75 the formation of the desired product 81 was not observed.

Table 2. Intramolecular cyclopropanation of amides 70–75.

The structural features of the homologous N,N,3-tribenzyl-3-azabicyclo[3.1.0]hex-1-ylamine (76) and N,N,3-tribenzyl-3-azabicyclo[4.1.0]hept-1-ylamine (79) were established by X-ray crystal structure analyses (Figure 5). The structural parameters of the two compounds are very similar, and in both cases the two phenyl rings of the dibenzylamino fragment are orthogonal with respect to each other. The N-benzyl group on the heterocycle in both cases adopts an equatorial position bending the envelope of the azacyclopentane moiety in 76 and the chair of the azacyclohexane in 79 in such a way that the whole azabicyclo[3.1.0]hexane and azabicyclo[4.1.0]heptane systems adopt boat conformations.

Figure 5. Molecular structures of N,N,3-tribenzyl-3-azabicyclo[3.1.0]hex-1-ylamine 76 and N,N,3-tribenzyl-3-azabicyclo[4.1.0]hept-1-ylamine 79 in the crystal (top) and their superpositions (bottom).

Both compounds are racemates and therefore crystallized in a centrosymmetric space group.

The geometry of the molecules and their packing in the crystals are quite similar, however the conformations of the molecules are different, as demonstrated by the superpositions of

molecules with their 3-membered ring carbon and their nitrogen atoms of the dibenzylamino groups held at the same places (Figure 5). Molecule 76 has an ap orientation (with respect to the heterocycle) of the quasi-equatorial N2-C20 bond [dihedral angle C2-N2-C20-C21 = – 163.0(1)°] and an sc orientation of the quasi-axial N2-C13 bond [angle C2-N2-C13-C14 = 69.7(1)°]. In contrast, molecule 79 has an ap orientation of the quasi-axial bond N2-C14 and an sc orientation of the quasi-equatorial bond N2-C7 [dihedral angles C1-N2-C14-C15 = – 169.9(1)° and C1-N2-C7-C8 = 66.0(1)°, respectively].

The unprotected diamine hydrochlorides 28-HCl, 29-HCl and partially unprotected diamine hydrochlorides 82-HCl, 83-HCl and 84 were obtained from the corresponding amines 76–80 by catalytic hydrogenation in the presence of an HCl/iPrOH solution in MeOH (Table 3).

Table 3. Deprotection of the benzyl-protected 3-azabicyclo[3.1.0]hex-1-ylamines 76, 77, 78, 80 and N,N,3-tribenzyl-3-azabicyclo[4.1.0]hept-1-ylamine (79).

76–80 28, 29, 82–84

aCompound 84 was obtained as a free base.

R¹ R² R³ R⁴ n Yield (%)