Aza-Riley Oxidation of Ugi-Azide and Ugi-3CR Products toward Vicinal Tricarbonyl Amides: Two-Step MCR-Oxidation Methodology Accessing Functionalized α,β-Diketoamides and α,β-Diketotetrazoles

Abstract

Direct oxidative deamination of glyoxal-derived Ugi-azide and Ugi three-component reaction products readily affords vicinal tricarbonyls (α,β-diketoamides) and α,β-diketotetrazoles with two diversity elements. This significant extension of our previously described multicomponent reaction–oxidative deamination methodology is proposed to proceed through a mechanistically distinct SeO₂-mediated C–N oxidation derived from an active enol of α-amino-β-ketone systems, effectively an aza-Riley oxidation. This methodology accesses diverse VTC systems from prototypical amines, glyoxaldehydes, and isocyanide building blocks in a mere two steps.

Graphical Abstract

Vicinal tricarbonyls (VTCs) are structures of paramount importance as building blocks and often behave as unusual turn-promoting structural elements in macrolide natural products.¹ Particularly noteworthy are vicinal tricarbonyl amides (VTAs, α,β-diketoamides) found in the biologically active natural product macrolides YM47141–2,² FK-506,³ FR-900525,⁴ and rapamycin.^5,6 Rapamycin and tacrolimus (FK-506) are venerable FDA-approved immunosuppressive agents that exist in a hemiketal form (Scheme 1). Additionally, the electrophilic polycarbonyl framework can be seen foundationally embedded in many heterocyclic structures, accessible through nucleophilic additions to the VTC system. Privileged heterocycles⁷ accessible through such additions are exemplified by pyrroles, imidazoles, isoquinolines, quinoxalines, and furans.^8–11

Scheme 1.

Natural Product Macrolides Embedded with Vicinal Tricarbonyl Amides

Notable examples of VTCs as building blocks in the total synthesis of natural products¹² include cladoniamide F/G,¹³ papaveraldine, polstatin, prodigiosin,¹⁴ and vasicine.¹⁵ Perhaps even more interesting, cyclic VTC ninhydrin (indane-1,2,3-trione) and acyclic VTCs have been used as carbonyl sources in multicomponent reactions (MCRs).^16–18 Two approaches toward vicinal tricarbonyls predominate: direct or indirect oxidation of β-diketones. The most common is indirect oxidation of β-diketones by Regitz diazo transfer/oxidation with t-BuOCl or DMDO.¹⁹ One step direct oxidation is more attractive, of which previous methods involving organoiodine-chemistry have recently been improved upon.^20,21

Ultimately, these protocols rely on an oxidative reaction involving a (modified) central C₂ methylene of a β-diketone, typically in the form of β-ketoesters and β-ketoamides (Scheme 2). The former are readily prepared by the Claisen reaction.²² However, diverse sets of β-ketoamides are difficult to prepare, with recent methodology offering some improvement.²³ Unfortunately, in both cases β-diketone syntheses require catalysts or metal reagents and are restricted by a lack of diversity elements.

Scheme 2.

Routes to Vicinal Tricarbonyls

As such, we rationalized that our previous postcondensation oxidative deamination methodology,²⁴ which employed aldehydes, could be utilized analogously on glyoxal derived α-amino-β-ketoamides 1 and α-amino-β-ketotetrazoles 3, affording α,β-diketoamides 2 and α,β-diketotetrazoles 4 (Scheme 2).

Fundamentally, the key C₂ center is derived from the terminal aldehydic carbon of the glyoxal, and the C₃ carbonyl is generated as a functionalized secondary amide, derived from the isocyanide diversity reagent. Interestingly, to the best of our knowledge, MCR products have never been rationally utilized as pro-VTC β-diketone synthons. As such, this work provides a substantial improvement on current direct oxidation methodology of β-keto-amides as the challenges associated with their syntheses and the restriction in diversity elements are negated due to the wide availability of diverse glyoxals and isocyanides; notably, the latter have high compatibility with MCR methodology.²⁵

A collection of secondary-amide-containing α,β-diketoamide building blocks (9, Scheme 3) was produced by direct oxidative deamination of α-amino-β-ketoamide products 8 of the Ugi-3CR¹⁸ derived from the phenylphosphinic acid catalyzed condensation of aniline, 5, glyoxals 6, and isocyanides 7. The oxidative deamination of the corresponding Ugi-3CR products 8a–f [2 equiv of SeO₂, dioxane/H₂O (9:1), microwave 160 °C, 5 min to 1 h] ultimately afforded products with a variety of aryl groups 9a–c, a naphthalene 9d, and 3,4-(methylenedioxy)-benzene 9e, coupled with examples of aromatic and aliphatic functionality at R₂ in good yield (49–78%). The related formation of oxomalonamide 9f was also feasible (53%). Attempts to optimize yields by replacement of aniline 5 with piperidine, pyrrolidine, or o-aminoacetophenone in the MCR proved detrimental, and that process was not investigated further. Note that the purified α,β-diketoamides 9a–f were characterized as a mixture of the tricarbonyl ketone and hydrate (i.e., a gem-diol), as is commonly observed with this functional group. To show utility as building blocks to access further diversity,²⁶ pyrazines 11a–c and quinoxaline 11d were produced by condensation of ethylenediamines 10 (2 equiv) with the corresponding α,β-diketoamides 9 by heating at 120 °C for 0.5 h in EtOH/AcOH (ratio 9:0.5 v/v) under microwave irradiation (Scheme 4) (61–81% yield).

Scheme 3.

Ugi-3CR of Amines, Glyoxals, and Isonitriles by Oxidative Deamination

^a Aniline used in the initial MCR. ^b Anhydrous dioxane used.

Scheme 4.

Condensations of Vicinal Tricarbonyls

Satisfied with these results, further study of the oxidative deamination methodology was directed toward unreported α,β-diketotetrazoles. Containing a 1,5-disubstituted tetrazole, these VTC analogues were proposed to be potential cis-amide bioisosteres²⁷ of α,β-diketoamides and, thus, potentially valuable electrophilic tetrazole building blocks.²⁸

The Ugi-azide reaction proceeded smoothly with the amine 5, glyoxal 6, and isocyanide 7 (stoichiometry 1:1:1) to afford the α-amino-β-ketotetrazole 12 (Scheme 5). Interestingly, initial oxidative deamination attempts on 12 under similar conditions to those employed to generate α,β-diketoamides 9 (60 min, 160 °C, MW) produced none of the desired α,β-diketotetrazole 13. However, reducing the reaction time from 1 h to 1 min afforded the desired product 13 (20% yield) and its imine congener 14 (40% yield). Attempts to convert the imine 14 to 13 in situ with addition of 3 M aqueous HCl to the reaction mixture failed to garner 13 yet surprisingly afforded 1-(4-bromophenyl)tetrazole 15 (48%, yield) and an unidentifiable side product (Scheme 5).

Scheme 5.

Ugi-Azide Reaction of Amines, Glyoxals, and Isonitriles Proceded by Oxidative Deamination

To circumvent formation of the stable imine 14, N-methylaniline and piperidine were used as 2° amine inputs 16 in the Ugi-azide MCR. Subsequently, optimization of the temperature and reaction time of the oxidative deamination step on the 3° amine 17 (140 or 150 °C, 5 min) afforded a collection of α,β-diketotetrazoles 18a–h (Scheme 6) with good reaction scope and yields. Products were prepared from a variety of isocyanides and aryl glyoxals 18a–g (30–74% yield) or ethyl glyoxylate 18h (78% yield).

Scheme 6.

Ugi-Azide Reaction of Amines, Glyoxals, and Isonitriles by Oxidative Deamination

^a5 min, 150 °C, ^bN-Methylaniline used in the initial MCR. ^cPiperidine used in the initial MCR. ^d5 min, 140 °C. ^ePercent yield based on recovery of starting material. ^f1 min, 140 °C.

Encouragingly, the protocol was amenable to convertible isocyanides, which feasibly will allow access to free tetrazoles upon cleavage of the isocyanide substituent.²⁵ A noteworthy example is the α,β-diketotetrazole 18h, which may be viewed as the tetrazole isologue of ethyl benzoyl formate and cis-amide bioisostere of oxomalonamide. Unfortunately, access to the pyruvaldehyde-derived 18i proved incompatible with these reaction conditions. No starting material was recovered, and the only identified product was the N₁-benzyl tetrazole analogue of 15.

Mechanistically, we propose the reactivity of these α-amino-β-ketoamide systems with SeO₂ at elevated temperatures follows what could be called an aza-Riley oxidation. In previous work, we described oxidative deamination of α-amino amides mediated by [2,3]-sigmatropic rearrangement of a penultimate N-selenamidate.²⁴ Indeed, early studies of SeO₂ mediated α-oxidations of carbonyls,²⁹ alongside a pK_a analysis of the α-hydrogens of these respective systems indicates that α-amino-β-ketoamides and α-amino-β-ketotetrazoles 19 can form enol 20 and then react which SeO₂, generating selenohemiaminal 21 (Scheme 7). Note that 2 equiv of SeO₂ are required as incomplete conversion and isolation of imines are observed when 1 equiv is used.

Scheme 7.

Proposed Mechanism for Aza-Riley Oxidation of α-Amino β-Ketones

We believe that this enolization-mediated oxidation pathway does not seem to occur with α-amino amides as previously reported due to their lack of acidic α-hydrogens.

Selenohemiaminal 21 is then unable to undergo the traditional Riley oxidation pathway via a Pummerer-like rearrangement³⁰ to the corresponding ketone due to a lack of available ipso hydrogens. Instead, 21 is oxidized to iminium species 22 via elimination of selanediol, which is then hydrolyzed to α,β-diketoamide 23. In the case of α,β-diketotetrazole congeners of 23 (18a–18h), upon prolonged heating we have also observed the benzilic acid rearrangement³¹ with loss of formic acid to form α-ketotetrazoles 24. The previous observation of 1-(4-bromophenyl)tetrazole 15, likely originates from a nonspecific addition–elimination pathway due to the stability of the substituted tetrazole nucleus as a leaving group. These are observed as common major side products upon prolonged heating. X-ray crystallography of 18f (see the Supporting Information) supports our claims regarding the unstable nature of the α,β-diketotetrazole systems under the conditions employed. The O₃–C₈–C₉–O₄ torsion angle is ∼90° (92.09°), while the bond angles at C₈ and C₉ are close to those typical for sp₂ hybridization.

Hence, the π-system between C₈ and C₉ is broken, leading to an elongated C₈–C₉ bond (1.543 Å). Indeed, the torsion angles, bond lengths, and perpendicularity of both halves of each carbonyl system are nearly identical to that seen in the 1,2-diketone benzil.³² Such 1,2-diketone character might further support our proposed mechanisms of rapid conversion to observed decomposition side-products.

Indeed, in comparison to X-ray structures of other α,β-diketoamides,^1,21 the α,β-diketotetrazoles do not appear to show exact structural bioisosterism. However, α,β-diketotetrazoles do appear to behave analogously to α,β-diketoamides in carbonyl addition reactions and ultimately produce bioisosteric products, although they are much more reactive than the corresponding α,β-diketoamides in both their synthetic procurement and synthetic utilization.

To demonstrate utility, we employed straightforward 1,2-dicarbonyl chemistry (Scheme 8). Thus, condensation of 18c with 4,5-dimethylphenylenediamine 25 in methanol/acetic acid promoted by microwave irradiation followed by direct crystallization from the reaction mixture produced 2-tetrazoylquinoxaline 26 (31% yield). However, condensation of 18c with 1,2-ethylenediamine 27 afforded the 2-tetrazolylpyrazine 28 (37%) and the α-ketoamide 29 (50%), respectively, demonstrating that α,β-diketotetrazoles can function as acylating agents analogous to ethyl benzoyl formate in the synthesis of α-ketoamides. Although not directly competitive with many of the methods to synthesize α-ketoamides,^24,33 optimization of conditions will allow for the synthesis of other challenging N-bifunctional α-ketoamide analogues of 29.

Scheme 8.

Condensations of α,β-Diketotetrazoles

In summary, we have revealed an appealing and highly concise route to vicinal tricarbonyl amides containing two points of embedded diversity. The method improves upon existing routes in its simplicity while offering the ability to rapidly assemble collections of a fundamental key building block for further diversification. Moreover, we have reported the first route to unique VTA pro-bioisosteric building blocks, α,β-diketotetrazoles, which display interesting geometry and reactivity, worthy of further investigation.