Ring expansions of 1-azabicyclo[n.1.0]alkanes. Recent developments

In the past decade ring expansion of aziridines and aziridiniums fused to other rings has developed into an attractive alternative method to classical pyrrolidine, piperidine and azepine ring construction approaches. This short review provides an update on recent reports and demonstrates the usefulness and the efficiency of this approach.


Introduction
Non-aromatic aza-heterocycles, such as pyrrolidines, piperidines and azepines, their benzo-, spiro-, bridged and polycyclic derivatives can be found in numerous natural products.They represent a vast variety of cyclic and substitution patterns.Their synthesis, properties, biological activity and isolation from the natural products are well-documented.1a-d Several recent reviews have been published covering pharmaceutically active compounds, 2 spiro-derivatives, 3a-b marine alkaloids, 4 iminosugar di-and oligosaccharides, 5a-b and alkaloid lipids. 6Advances in synthetic methods include catalytic asymmetric aza Diels-Alder reactions, 7 benzotriazole mediated syntheses, 8 asymmetric synthesis, 9a-b and cyclization of allylsilyl-substituted N-acyliminium and iminium ions. 10A special case of the preparation of n-membered non-aromatic azacycles is a ring expansion of (n-1) cyclic precursors fused to aziridine ring.Thus, azabicyclo[3.1.0]hexane2 (n = 1), 11a-b serves as a reactive precursor to piperidine 3 (Figure 1).Additional N-diversification in aziridinium species (R ≠ H) is a valuable source of N-substituted derivatives.

Figure 1
Bicycles 4 are expected to meet the general reactivity profile of aziridines, 12 (Scheme 1) with the unfavorable predominant formation of 2-aminomethyl derivatives 5 due to nucleophilic attack on the least substituted C2-carbon.Strain of the fused ring, nature of the nucleophile and catalyst can significantly further affect the process.Additionally, the high reactivity of the species 2 makes isolation of fused aziridines and aziridiniums difficult to achieve.Nevertheless, ring expansion methodology is of continuous interest as it provides vast opportunities for the transfer of substitution patterns and stereochemistry from more accessible smaller (n-1) rings onto n-membered aza-cycles.

Scheme 1
The current account surveys the literature from 2001 until 2010 on ring enlargement of the systems 2 (n = 1) and includes results of a deeper retrospective literature search for other azabicyclo[3.1.0]alkanes(n ≠ 1).The discussion is organized in the order of ring sizes followed by reactivity of aziridines fused to bridged and polycyclic systems.

Ring Expansions of 1-Azabicyclo[2.1.0]pentanes
High energy for the strained 1-azabicyclo[2.1.0]pentane2 (n = 0) results in its instability and isolatable entities are quite rare. 13At the same time high reactivity of the precursors 1 results in the desired ring expansion process.A series of 2-(α-hydroxyalkyl)azetidines 7 with a variety of substituents both on the four-membered ring and on the adjacent hydroxy group are treated with either thionyl chloride or methanesulfonyl chloride in the presence of triethylamine (Scheme 2).The obtained intermediate 2-α-chloro-or 2-α-methanesulfonyloxyalkyl azetidines rearrange stereospecifically providing good to excellent yields of 3-(chloro-or methanesulfonyloxy)pyrrolidines 8. Thus, a single isomer of the highly substituted pyrrolidine 9 was reported in 77% isolated yield.When this rearrangement is conducted in the presence of nucleophile (NaN 3 , KCN, KOH, or NaOAc), the produced pyrrolidines 10 stereospecifically incorporate the added nucleophile at C-3. 14a-b The relative configuration of the substituents in the formed pyrrolidines is consistent with a mechanism involving the formation of an intermediate bicyclic aziridinium ion, which is opened regioselectively at the bridgehead carbon atom.14b

Ring Expansions of 1-Azabicyclo[3.1.0]hexanes
Since an early report by Fuson and Zirkle, 16 ring expansion of 2-substituted pyrrolidines through 1-azabicyclo[3.1.0]hexaneintermediates become a useful synthetic tool and the reader is referred to the preceding reviews.11a-b Recent reports include further developments of functionalized mono-and polycyclic systems.
Substituted silyl compounds 15a-c were prepared from the corresponding prolinols 14 by well-established treatment with trifluoroacetic anhydride followed by the addition of triethylamine and then by treatment with sodium hydroxide (Scheme 4).17a-c Subsequent reaction and protection/deprotection steps resulted in N-tert-Bu-piperidine 17 which was applied as a catalyst for enantioselective addition of diethylzinc to aldehydes.In a similar manner (Scheme 5), 18 successive O-activation of the protected hydroxyprolinederivatives 20a (trans) and 20b (cis) followed by nucleophilic displacement using LiCN resulted in formation of the nitriles 21a and 21b in 51 and 70% yield, respectively.Under the reported reaction conditions (DMF, 0 o C to rt) rearrangement occurs only to a minor extent giving the piperidine derivatives 22a-b as side products.In the case of the trans-substituted derivatives, the pyrrolidine-and the piperidine-derivatives were formed in a 7:3 mixture of isomers.For the cisisomers 4:1 ratio was observed.

Scheme 5
Attempted Swern oxidation of spiro-2-(bromomethyl)pyrrolidine 23 into corresponding 2aldehyde (DMSO, 30 o C, 14 h, 2 equiv of potassium carbonate) resulted in piperidin-3-one 26 instead (Scheme 6). 19The addition of potassium carbonate appeared to be essential, as piperidin-3-one 26 was isolated in very low yields (10%) if no K 2 CO 3 was used.According to the suggested mechanism 2-(bromomethyl) pyrrolidines 23 are first transformed into intermediate bicyclic aziridinium salts 24 which are converted into piperidines 26 upon ring opening with dimethylsulfoxide.The last step of the proposed mechanism could occur either via direct nucleophilic ring opening at the less substituted aziridine carbon atom or via spontaneous ring opening and subsequent substitution of the formed carbenium ion.Abstraction of the acidic proton at the oxygenated carbon atom in intermediate 25 by potassium carbonate is important for further liberation of dimethylsulfide and formation of final piperidin-3-ones 26.

Scheme 6
Synthesis of enantiopure cis-decahydroquinoline 28 is performed in a straightforward manner staring from octahydroindole 27 (Scheme 7). 20As above, reaction conditions include Otrifluoroacetylation to form a better leaving group followed by rearrangement in the presence of hydroxy anion as a nucleophile.Interestingly, when hydroxyl group activation is achieved through mesylation, the chloride anion serves as an internally generated nucleophile resulting in high yield of 3-chloro decahydroquinoline which can be subsequently transformed into an acetoxy derivative 29.

Scheme 11
Reaction of the alcohol 53 with methanesulfonyl chloride and subsequently with KCN in DMSO at room temperature provided 1,4-diazepane derivative 56 as a minor product (11% yield) along with the major cyanomethyl derivative 55 (54% yield).Surprisingly, in addition to these main products, careful chromatographic separation provided the isomeric nitrile 59 (0.4%).The formation of the isomeric nitriles 55 and 56 is apparent through intermediate aziridinium ion 54.Chloride anion generated during mesylation step competes with cyanide and forms chloro diazepane 57.The latter undergoes formation of regioisomeric aziridinium ion 58 and subsequent cyanide attack to afford small but detectable amounts of compound 59 (Scheme 12). 30

Scheme 14
Compounds 65, 33 rapidly undergo aziridine ring cleavage followed by elimination of pyrazole leaving group, analogous to previously reported, 34 MeO-derivatives, when treated with tetrabutylammonium fluoride (Scheme 15).Ester and aryl substitution on R 2 stabilize a negative charge and pyridones 66 are formed as exclusive products of C6-C7 bond cleavage.In the case of R 2 = H, the negative charge cannot be delocalized and cleavage of C6-N1 bond occurs with expansion to the seven membered ring 67.

Scheme 15
Synthesis of aziridine 69 was reported starting from o-azidobenzaldehyde 68 through a synthetic sequence which includes fully diastereoselective 1,3-dipolar cycloaddition and irradiation of triazoline intermediate.Although compound 69 is surprisingly stable, as compared to other allylsilane-derived aziridines, its exposure to TBAF or Bu 4 NOH in DMF at −20 °C promotes conversion to benzazepenol 70 (Scheme 16). 35Similarly, starting from oazidophenylacetaldehyde through aziridine intermediate 71 azocenol 72 was isolated as ca.5:1 mixture with unsaturated aziridine 73.The formation of the latter was attributed to the side Peterson olefination reaction.

Scheme 16
The same ring opening strategy was used in the synthesis of the antitumor agent FR-66979, structurally related to the mitomycins (Scheme 17). 36Scheme 17

Ring expansions of aziridines fused to bridged and bicyclic ring systems
The reactivity of aziridines fused to bicyclic systems is in accordance with the general rules described above.Thus, reaction of diastereomeric iodide 76 with AgOAc in toluene gives an inseparable 45:55 mixture of the pyrrolidine 77 and piperidine 78 acetates in 82% overall yield.The suggested mechanism includes the formation of an intermediate aziridinium ion.In the proof of concept experiment, treatment of the iodide 76 with AgBF 4 gave a quantitative yield of aziridinium derivative 79, which upon reaction with NaOAc in toluene gave a 45:55 mixture of the acetates 77 and 78 in 62% isolated yield (Scheme 18). 37

Scheme 22
On the other hand, more accessible strained aziridine moiety in the bridged 1azabicyclo[4.1.0]heptane91 easily undergoes stereoselective ring opening by magnesium bromide (as well as other magnesium halides) to produce chiral ester 92 in 55% yield (Scheme 23).42a-b Scheme 23

Summary
The past decade has witnessed a growing interest in non-aromatic cyclic amines as related to natural product synthesis.The need for new and more efficient synthesis has served as the driving force for research efforts and resulted in non-trivial ring construction strategies, and ring expansion of 1-azabicyclo[n.1.0]alkanesis undoubtedly among them.The present review has outlined the importance of this transformation as an advantageous methodology for synthesis of diverse pyrrolidines, piperidines and medium size cyclic amines.