A Versatile Route to Unstable Diazo Compounds via Oxadiazolines and their Use in Aryl–Alkyl Cross‐Coupling Reactions

Abstract Coupling of readily available boronic acids and diazo compounds has emerged recently as a powerful metal‐free carbon–carbon bond forming method. However, the difficulty in forming the unstable diazo compound partner in a mild fashion has hitherto limited their general use and the scope of the transformation. Here, we report the application of oxadiazolines as precursors for the generation of an unstable family of diazo compounds using flow UV photolysis and their first use in divergent protodeboronative and oxidative C(sp2)−C(sp3) cross‐coupling processes, with excellent functional‐group tolerance.

Abstract: Coupling of readily available boronic acids and diazoc ompounds has emerged recently as ap owerfulm etalfree carbon-carbon bond forming method. However,t he difficulty in forming the unstable diazoc ompound partner in am ild fashion has hitherto limited their general use and the scope of the transformation. Here,wereport the application of oxadiazolines as precursors for the generation of an unstable family of diazo compounds using flow UV photolysis and their first use in divergent protodeboronative and oxidative C(sp 2 )À C(sp 3 )c ross-coupling processes,w ith excellent functionalgroup tolerance.
Diazo compounds represent ah ighly useful class of compounds in organic synthesis, [1] forexample in cyclopropanation, [2] and heteroatomÀH [3] and CÀHinsertion [4] reactions. In particular,t he reaction of diazo compounds with organoboron species has attracted considerable interest over the past few years,such as in C(sp 2 ) À C(sp 3 )cross-coupling reactions. [5] Our previous studies on the flow oxidation of hydrazones, [6] showed the effectiveness of utilizing mild conditions to generate and react diazo compounds with boronic acid. In particular,t his allowed us to intercept the putative unstable boronic species and thereby enable access to alcohols [6] and powerful iterative bond-forming processes. [7] Nevertheless, these studies were limited to the generation of "semistabilized diazo compounds", bearing either an aryl or vinyl group adjacent to the diazo moiety.T ot ruly generalize this concept would require expansion into the elusive realm of "non-stabilized diazo compounds", ac lass of compounds notorious for their intrinsic instability,t oxic/hazardous nature,a nd difficulty of preparation (Scheme 1). [1b] Within this class of reactive intermediates,d ialkyl-substituted diazo compounds pose am ajor challenge to both access and safely utilize these reactive species.I fam ild method to generate these non-stabilized diazo compounds could therefore be realized, am ore general method to enable aryl-alkyl crosscoupling may become possible,a long with potential interception of the intermediate boron species to afford new reactions.
While am ultitude of methods have been developed to access diazo compounds,few allow the generation of the nonstabilized members of the family with sufficient generality.An interesting report by Warkentin et al. in 1989 showed that UV photolysis of 1,3,4-oxadiazolines at around 300 nm led to diazoalkanes. [8] Surprisingly,t his approach has been largely overlooked by chemists as ap otential route to forming unstable diazo compounds,a nd has never before been engaged in the development of new synthetic methods. Oxadiazolines are available by atwo-step,one-pot procedure from readily available ketones through condensation of acetic hydrazide and subsequent PhI(OAc) 2 -mediated oxidation. In contrast to alternative diazo precursors such as hydrazones and nitrosoamides,o xadiazolines were found to be benchstable over many months (also see Supporting Information for differential scanning calorimetry data).
At the outset of our investigation, we decided to exploit enabling flow technologies to achieve more efficient irradiation compared with abatch reactor, [9] and to avoid the buildup of hazardous quantities of any unstable diazo compounds. [10][11][12] Initial studies began with the generation of oxadiazoline 1,apotential precursor for the cyclic, nonstabilized diazo compound, 4-diazotetrahydropyran (2; Scheme 2). Passage of an ethereal solution of 1 through a1 0mLr eactor coil held at 10  Using an umber of oxadiazolines and readily available boronic acids (forming boroxines in situ), [13] we were able to demonstrate ar emarkably broad reaction scope and unusually high functional-group compatibility (Table 1). With respect to the oxadiazoline component, av ariety of pharmaceutically relevant 4-, 5-and 6-membered saturated heterocyclic examples were viable coupling partners,i ncluding pyran (3a), tetrahydrofuran (3b), tetrahydrothiopyran (3c), tetrahydrothiophene (3d), thietane (3e), N-Boc piperidine (3f), N-Boc pyrrolidine (3g), and N-Boc azetidine (3h)rings, providing moderate to excellent yields of the desired C(sp 2 )À C(sp 3 )c ross-coupling products.I ti sp articularly notable that the 4-membered rings were viable examples given the instability of 4-membered cyclic diazo compounds, [14] which arises from the relief of ring strain when moving from an sp 2 to an sp 3 carbon center on reaction with electrophiles. Furthermore,t olerance of the tetrahydrothiophene and thietane moieties highlights examples where approaches using at osylhydrazone route or carbon-centered radical approaches would fail, due to the tendency of these systems to undergo elimination/ring-opening.Anumber of carbocyclic examples containing cycloalkyl groups (3i-3l)w ere also permissible substrates,along with ahighly hindered adamantane substituent (3m). Tolerance of acyclopropyl group (3n) is not only indicative of an on-radical based process for this C(sp 2 )ÀC(sp 3 )cross-coupling,but also further exemplifies the advantages of this procedure over methods utilizing carboncentered radicals (where cyclopropane ring-opened products would be obtained instead). In terms of functional-group compatibility for the oxadiazoline component, olefins (3o), alkynes (3p), acetals (3q), phosphonates (3r), sulfones (3s), furans (3v), and pyrimidines (3w)w ere all viable substrates. Remarkably,both an epoxide (3t)and an alkyl bromide (3u) could participate in this coupling process,products that would be intractable to access using metal-catalyzed methods or harsh basic conditions.W ith respect to the boronic acid component, av ariety of electron-deficient aromatic rings harboring various functional groups were suitable substrates, including those with 4-bromo (3x), 4-trifluoromethyl (3y), 4-   cyano (3z), and 4-methoxycarbonyl (3aa)s ubstituents.E lectron-rich groups were also tolerated, including 3-acetamide (3ab), 4-methoxy (3ac), and o-methyl (3ad)s ubstituents, although for the two latter cases,ahigher temperature was required to achieve protodeboronation. Although loweryielding,h eterocyclic boronic acids could also be employed in this method to provide useful amounts of desired crosscoupled product, for example,3 -pyridyl (3ae)a nd 2-thienyl (3af)s ubstituents.
Asimple switch in the workup procedure to stirring under air provided the oxidized C(sp 2 ) À C(sp 3 )c ross-coupled products,a nd this reaction exhibited as imilar broad scope and high functional-group compatibility (Table 1). Again, avariety of 4-, 5-and 6-membered saturated heterocyclic oxadiazolines could be coupled with 4-chlorophenylboronic acid to generate av ariety of tertiary alcohols (4a-4h)i ng enerally similar yields to the protodeboronative method. Similar yields were obtained for carbocyclic examples (4i-4l, 4n), with the exception of adamantane derivative 4m,w here oxidation appeared to be extremely slow.I nt erms of functional-group compatibility,o lefins (4o), alkynes (4p), acetals (4q), phosphonates (4r), sulfones (4s), furans (4v)a nd pyrimidines (4w)a ll proceeded smoothly.Aparticular highlight was the tolerance of highly reactive functionalities such as an epoxide (4t)and alkyl bromide (4u). Electron-poor boronic acids (4x, 4y)a nd electron-rich boronic acids (4ab)w ere also viable coupling partners,a lthough in the case of 4aa,p rotodeboronation appeared to be facile and 30 %o ft he protodeboronative C(sp 2 ) À C(sp 3 )c ross-coupled product 3aa was also obtained. This overall method is complementary to conventional Grignard addition but in many cases afforded products that are not compatible with organometallic species.
To illustrate the utility of our newly developed method, we first turned to the trapping of the tertiary boronic acid derived from the coupling of 4-chlorophenylboronic acid and the cyclobutane oxadiazoline precursor,u sing excess pinacol as the final workup quench, which provided the valuable Bpin product 5 in 74 %y ield (Scheme 3a). General methods to access and assess the reactivity of these tertiary alkylboron pinacol esters are vastly underdeveloped, so these examples serve as testament to this versatile cross-coupling route,f or the synthesis of highly valued organoboron intermediates. Utilization of 5 for the generation of valuable and pharmaceutically relevant tertiary cyclobutylamines was successfully demonstrated, providing the benzyl protected derivative 6 in 70 %yield over two steps. [15] Furthermore,wewere also able to construct quaternary carbon centers using two recently developed methodologies for C(sp 2 ) À C(sp 3 )cross-coupling of boronic esters:r eaction of 5 with 2-lithiofuran and as ubsequent quench with N-bromosuccinimide (NBS) led to cyclobutylated furan derivative 7 in 47 %y ield; [16] whereas an iridium-catalyzed photoredox flow process [17] allowed us to couple 1-isoquinolinecarbonitrile to 5,l eading to cyclobutylated isoquinoline derivative 8 in 49 %yield. Finally,wewere further able to apply this process to the short three-step synthesis of the GABAr eceptor agonist drug, baclofen (10; Scheme 3b). [18] In summary,t his work clearly demonstrates how oxadiazolines may be used as efficient, bench-stable precursors for non-stabilized diazo compounds.Indeed, with these improvements in metal-free C(sp 2 ) À C(sp 3 )cross-coupling,this process complements the well-established organometallic and organohalide cross-coupling procedures.I nc ombination with readily available arylboronic acids,t his newly developed flow method allows amyriad of potent, divergent, metal-free C(sp 2 )ÀC(sp 3 )c ross-coupling processes exhibiting av ery general reaction scope and unparalleled functional-group tolerance,a sw ell as access to new tertiary alkyl boronic pinacol ester derivatives.F urther applications of these unstable diazo compounds are currently ongoing in our laboratories.