Divergent, Strain‐Release Reactions of Azabicyclo[1.1.0]butyl Carbinols: Semipinacol or Spiroepoxy Azetidine Formation

Abstract The azetidine moiety is a privileged motif in medicinal chemistry and new methods that access them efficiently are highly sought after. Towards this goal, we have found that azabicyclo[1.1.0]butyl carbinols, readily obtained from the highly strained azabicyclo[1.1.0]butane (ABB), can undergo divergent strain‐release reactions upon N‐activation. Treatment with trifluoroacetic anhydride or triflic anhydride triggered a semipinacol rearrangement to give keto 1,3,3‐substituted azetidines. More than 20 examples were explored, enabling us to evaluate selectivity and the migratory aptitude of different groups. Alternatively, treatment of the same alcohols with benzyl chloroformate in the presence of NaI led to iodohydrin intermediates which gave spiroepoxy azetidines upon treatment with base. The electronic nature of the activating agent dictates which pathway operates.


Introduction
Thep ast decade has seen as urge in the application of azetidines in pharmaceutical drug candidates. [1] This is due in part to their improved pharmacokinetics in comparison to their larger ring analogues:molecules with the azetidine motif were shown to exhibit greater metabolic stability and increased bioavailability. [2] 1,3-Substituted azetidines also benefit from having 3D character,w hich has been shown to improve clinical success, [3] but without introducing chirality and so are more amenable to synthesis.T his specific substitution pattern is featured on the azetidine scaffold of the marketed drugs azelnidipine, [4] cobimetinib [1a] and baricitinib [1b] (Scheme 1a).
We wanted to further develop the use of 2 as asynthon for 1,3,3-substituted azetidines by exploring alternative electrophiles which could also trigger strain-release reactivity and considered the use of ketones and aldehydes (Scheme 1c). We envisaged that after formation of azabicyclo[1.1.0]butyl carbinols (ABB-carbinols, 5), subsequent N-activation by asuitable electrophile could trigger apinacol-type rearrange-Scheme 1. a) Marketed drugs containing 1,3-substituted azetidine scaffolds. b) Electrophilic activationo fABB, nucleophilic addition to ABB and lithiation of ABB followed by reaction with boronic esters. c) Reaction of ABB-Li with carbonyls and subsequent divergent reactivity. ment, cleaving the bridging CÀNb ond and releasing ring strain. [9,10] Such apinacol-type rearrangement is analogous to the semipinacol rearrangement of a-hydroxy epoxides. [11] This would lead to azetidines bearing aq uaternary centre (6/7). Alternatively,N -activation of ABB-carbinols could result in an ucleophilic addition of the alcohol to form spiroepoxy azetidines (8) [1a, 12, 13] which would be interesting synthetic targets as they could display further strain-release reactivity. [12] In this paper,w er eport our success in discovering two divergent pathways from ac ommon ABB-carbinol intermediate that lead to either 1,3,3-substituted azetidines,v ia asemipinacol rearrangement, or spirocyclic epoxides.

Results and Discussion
We began our investigation by studying the reaction of ABB-Li with acetophenone (Scheme 2). [14] ABB-Li was formed in situ by the sequential reaction of amine salt 9 with phenyllithium and sec-butyllithium, [8a] and subsequently reacted with acetophenone at À78 8 8Ctoform ABB-carbinol 5a in good yield. This procedure was successfully applied to awide range of ketones and aldehydes.T he alcohol products were stable to aqueous work-up and could be stored at À18 8 8C with no evidence of degradation. However,a part from the trifluoromethylated example 5r,t he ABB-carbinols were found to partially decompose on silica gel and so yields of the products were determined by 1 HNMR. Presumably,t he electron-withdrawing nature of the CF 3 group present in 5r reduces the basicity of the nitrogen and minimizes acidmediated decomposition.
Having gained access to ar ange of ABB-carbinols,t heir reactivity with different activating agents was investigated. Firstly,t he addition of benzyl chloroformate (CbzCl) to 5a resulted in the formation of chlorohydrin 10 in 83 %y ield (Scheme 3a). This result is consistent with previous reports of the 1,3-functionalisation of ABB with chloroformates. [15] However,w hen trifluoroacetic anhydride (TFAA) was employed as the activating agent, the desired semipinacol rearrangement occurred to form keto azetidine 6a in 71 % yield (Scheme 3b).
Thed ivergent reactivity of 5a can be rationalised by the extent of positive charge build-up at the electrophilic bridgehead carbon. When TFAA is used as an activator, the trifluoroacetyl group,b eing more electron-withdrawing than the Cbz group,results in agreater build-up of positive charge, thereby favouring the semipinacol reaction pathway.W e postulated that the different counterions could also play arole in determining the outcome of the reaction, therefore,w e investigated whether product formation was determined by the nucleophilicity of the counterion or by the nature of the activating group.T his was achieved by performing the reactions in the presence of NaI in order to keep the counterion (iodide) constant (Scheme 3c). [16] Once again, with CbzCl, nucleophilic addition dominated to give exclusively iodohydrin 11 via the nucleophilic addition pathway. With TFAA, both nucleophilic addition and semipinacol rearrangement occurred to give 12 and 6a in 40 %a nd 49 %  yield, respectively.F inally,w hen moving to an even more electrophilic activating agent, triflic anhydride (Tf 2 O), the semipinacol rearrangement dominated to give sulfonamide 7ain 50 %yield with no nucleophilic addition observed. Thus, the outcome of the reaction is predominantly determined by the electronic nature of the activating group on nitrogen:the more electron-withdrawing it is the more the semipinacol pathway is favored.
We sought to optimise the semipinacol pathway and found that, in the absence of NaI, the reaction yields with TFAA and Tf 2 Ow ere improved by switching the solvent to CH 2 Cl 2 and performing the reaction at À78 8 8C( conditions Aa nd B; see Supporting Information for optimisation study). In the case of Tf 2 O, the yield was further increased by the addition of 2,6lutidine.W et hen explored the scope of the reaction using both sets of conditions (A and B) with abroad range of ABBcarbinols (Scheme 4).
Fornon-symmetrical alcohols bearing an aryl and methyl group,inall cases,and under both sets of conditions,wefound exclusive migration of the aryl group to give azetidines 6/7a-c in good yields,even in the cases of electron-poor aryl groups. Furthermore,e lectron-rich and electron-deficient heteroaromatic groups (indolyl and 3-pyridyl) also worked well, giving compounds 6/7d-f in good yields-again exclusive migration of the aryl group was observed. However,4 -pyridyl carbinol 5g was found to be ap oor substrate,a st he reaction was unsuccessful with TFAA and low yielding with Tf 2 O.
Cyclic ketones were also explored as the semipinacol rearrangement would result in ar ing expansion to give valuable spirocyclica zetidine scaffolds.A zetidines 6h-k and 7h-k were obtained after ring expansions from ABBcarbinols bearing 4-, 5-, 6-, and 7-membered rings in yields of 27-54 %using TFAA (method A) and 50-87 %using Tf 2 O (method B). Thel ower yields when using TFAA were attributed to competing nucleophilic addition of trifluoroacetate due to the lower migratory aptitude of alkyl groups. [17] Thes emipinacol rearrangement of ABB-carbinol 5l gave azetidines 6/7l with an intriguing 2,6-diazaspiro [3.4]octane core in 48 %and 63 %yields,respectively. [18] This example is particularly noteworthy as aR eaxys search identified this motif in > 250 patents with > 1300 unique examples where pharmacological data is presented. Furthermore,i ti se asily prepared in just two steps from N-Boc azetidinone.I no rder to further probe the selectivity over which group migrates, anon-symmetrical alcohol bearing two different alkyl groups (a cyclohexyl and am ethyl group) was explored. Using both TFAA (method A) and Tf 2 O(method B), exclusive migration of the more substituted alkyl group [11b] was observed, giving 6/ 7m,t he latter in almost quantitative yield.
We subsequently compared the migration of aP hg roup over other substituents,i ncluding more substituted alkyl groups and other functional groups.Comparing Ph with H, we found that the Ph group migrated exclusively to give aldehydes 6/7n in 51 %a nd 84 %y ields,r espectively. [9] Comparing Ph/ethyl and Ph/alkynyl, again resulted in exclusive migration of the Ph group,g iving azetidines 6/7o,p in excellent yields.H owever,c omparing Ph/Cy resulted in high selectivity but only in the case of TFAA to give 6q;Tf 2 Ogave a1 :1.5 ratio of products 7q/7q' ',n ow in favour of Cy migration. In both cases,t he yield of the ketone was low.I n fact, the main component of the latter reaction was spirocyclic epoxide 13,formed in 66 %. Tr ifluoromethyl carbinol 5r was tested and as expected, [19] exclusive migration of the Ph group was observed. This substrate was substantially less reactive than the others,r equiring 0 8 8Ct ot rigger the semipinacol rearrangement. Azetidine 6r was formed in only 25 %y ield with competing nucleophilic addition of trifluoroacetate observed. Selectivity for the semipinacol rearrangement was much higher with Tf 2 O(conditions B), giving azetidine 7r in 72 %y ield.
Azetidines 6s and 7s were obtained from ABB-carbinol 5s derived from benzophenone in 42 %and 90 %yields under conditions Aand B, respectively.Inthe case of 6s,the lower yield observed was due to competing nucleophilic addition. Finally,c omparing Ph/p-MeOC 6 H 4 ,w ef ound that the more electron-rich aryl group migrated preferentially, [20] but not by much:a3.2:1 ratio of 6t/6t' ' and 1.3:1 ratio of 7t/7t' ' were obtained under conditions Aa nd B, respectively.
Thec ommonly observed relative migratory aptitude in semipinacol rearrangements [9,17,20] of aryl > alkenyl > hydride > substituted alkyl > less substituted alkyl is mirrored here in reactions using TFAA. Asimilar pattern is seen with the more electron-withdrawing Tf 2 O, but the selectivity is lower since it induces af aster reaction. In the case of the especially hindered substrate 7q,containing both phenyl and cyclohexyl migrating groups,noselectivity is observed. Here,C ÀCbond rotation of the hindered substrate is likely to have ah igher barrier than 1,2-migration, [21] which results in migration of whichever group is antiperiplanar to the central C À Nu pon reaction with Tf 2 O.
Thef ormation of spirocyclic epoxide 13 from 5q under conditions Bw as intriguing,a nd we were keen to establish whether this pathway could be promoted more generally.W e reasoned that iodohydrin 11,formed from the reaction of 5a with CbzCl and NaI (Scheme 3c), could potentially serve as an intermediate in the selective synthesis of spiroepoxy azetidines.I ndeed, addition of potassium carbonate to as olution of 11 in methanol resulted in the quantitative formation of epoxy azetidine 8a after 15 minutes. [22] This method was telescoped to ao ne-pot procedure,a nd ABBcarbinol 5a was converted to 8a in 96 %y ield (Scheme 5).
We then extended this protocol to produce ar ange of spirocyclic epoxides from selected ABB-carbinols (Scheme 5). Employing ABB-carbinols with heteroaryl groups (indolyl and pyridyl) gave 8d and 8f in good yields of 62 %and 66 %, respectively.Electron-rich indolyl epoxide 8d was found to be unstable on silica gel, which complicated purification. However,w ef ound that if the intermediate iodohydrin was purified prior to base-induced cyclization, no further purification of 8d was necessary.D ispiro compounds 8j and 8l were obtained from ABB-carbinols 5j and 5l in excellent yields of 90 %and 91 %, respectively.Compound 8l is particularly interesting, as the nitrogen protecting groups are orthogonal and serve to desymmetrize the molecule. Tr isubstituted epoxide 8n was also accessible in 80 %y ield from benzaldehyde derived 5n.W ef ound that with less substitution, the rate of cyclization was much slower and required 42 hours to reach completion. We were also able to synthesize the sensitive propargylic epoxide 8p in excellent yield (86 %). Due to its instability on silica gel (as with 8d), purification of the intermediate iodohydrin was necessary in order to isolate analytically pure 8p.
In the case of trifluoromethyl ABB-carbinol 5r,C bzCl was found to be unreactive,but treatment with TFAA in the presence of NaI led to selective formation of the iodohydrin intermediate.A fter the addition of potassium carbonate, epoxide 8r was isolated in 49 %yield. Thehigh selectivity for iodohydrin formation from 5r contrasts with the reactivity of 5a,w here treatment with TFAA in the presence of NaI resulted in the formation of both iodohydrin 12 and the semipinacol product 6a.T his is ar esult of the slower rate of the semipinacol rearrangement with the trifluoromethyl ABB-carbinol 5r.D espite the reaction of 5a with TFAA/ NaI leading to am ixture of 12 and 6a,t reating this mixture with potassium carbonate led to the formation of epoxide 14 in 38 %y ield. Interestingly,o ther activators could also be employed with NaI. Tosyl chloride (TsCl) behaved similarly to CbzCl to give sulfonamide 15 in 87 %yield, whereas di-tertbutyl dicarbonate (Boc 2 O) was slower to react and required heating to activate ABB-carbinol 5a.Under these conditions with Boc 2 O, cyclization of the iodohydrin occurred without additional base to give epoxide 16 in 57 %yield.

Conclusion
We have discovered novel, divergent reactivity of azabicyclo[1. with carbonyl compounds.W ef ound that strongly electrophilic activating reagents (TFAA and Tf 2 O) induce as emipinacol rearrangement in ABB-carbinols to give either amide or sulfonamide azetidines.T he semipinacol rearrangement proceeds with migration of the group best able to stabilize the positive charge,sofollows the order aryl > substituted alkyl > less substituted alkyl. Even electron-deficient aromatics and heteroaromatics migrate in preference to am ethyl group. When two alkyl groups are present, the semipinacol rearrangement is much slower and in the case of TFAA as the activator,n ucleophilic addition of the counterion begins to compete,leading to lower yields.However,switching to Tf 2 O as the activator allows the semipinacol rearrangement to dominate,leading to good reaction yields.
Conversely,w hen ABB-carbinols are treated with less electrophilic activating agents,such as CbzCl, no semipinacol rearrangement occurs.I nstead, nucleophilic addition of the counterion dominates to exclusively form chlorohydrin products.Performing the reactions in the presence of NaI leads to the formation of iodohydrins that can be easily converted into structurally interesting spiroepoxy azetidines through abasemediated cyclization.T hus,f rom ac ommon ABB-carbinol starting material, we can now access either keto azetidines or spiroepoxy azetidines through semipinacol rearrangements and spirocyclizations,respectively.