Tandem [3 + 2] Cycloaddition Reaction of Azo-alkenes and Thiocyanic Acid: Extending the Scope of the Classical "Criss-Cross" Cycloaddition Reaction

Abstract

Phenylazoalkenes 4 with full substitution at the terminal carbon atom react with thiocyanic acid affording 2,3,5,6,7,7a-hexahydro-3-phenyl-1H-imidazo [1,5-b][1,2,4]triazole-2,5-dithiones 8. The bicyclic compounds 8 result from two consecutive [3+2] cycloaddition steps, thus adding a novel facet to the classical "Crisscross" reaction.The heterodiene system of conjugated azoalkenes (1,2-diaza-1,3-butadienes) is capable of participating in various cycloaddition reactions. 1,2 Azoalkenes can react as the dipolarophile (olefinic moiety) in [3 + 2] cycloaddition reactions 3-5 or as the three-center component (olefinic π-bond and the nonbonding electron pair at the adjacent nitrogen atom), thus resembling an isoelectronic hetero equivalent of the allyl anion. [6][7][8][9][10][11] Recently, we reported the reaction of conjugated phenylazoalkenes 4 (R 3 = H) and thiocyanic acid 12 giving rise to the formation of 1-anilino-2,3-dihydro-1H-imidazole-2-thiones 7 (Scheme 1). 13,14 This reaction is considered to be initiated by a [3+2] cycloaddition step forming cycloadduct 5. Protonation at the exocyclic nitrogen atom of intermediate 5 followed by deprotonation of 6 (R 3 = H) at C-4 yields the final heteroaromatic product 7. Compounds 7 can be obtained also in the course of a one-pot reaction; the two reagents undergoing the cycloaddition reaction are generated in situ from α-halo carbonyl compounds 1 (X = Br, Cl), potassium thiocyanate, and phenylhydrazine. 15These findings prompted the investigation of this reaction with phenylazoalkenes 4 being fully substituted at the terminal carbon atom (R 2 , R 3 ≠ H;) and an excess of potassium thiocyanate in acetic acid (Scheme 1). Cycloadduct 5 (R 2 , R 3 ≠ H) is envisaged to be the first formed intermediate; however, lacking a hydrogen atom at 4-C, adduct 5 undergoes a further [3+2] cycloaddition reaction with thiocyanic acid at the azomethine imine function giving rise to the bicyclic product imidazo[1,5-b][1,2,4]triazole-2,5-dithione 8. 16 An alternative one-pot procedure also providing bicyclic products 8 involves the treatment of an α,α-disubstituted α-bromo carbonyl compound 1 (X = Br; R 2 , R 3 ≠ H) with excess of potassium thiocyanate in acetic acid and one equivalent of phenylhydrazine (Scheme 1). The presumed initial substitution of 1 with potassium thiocyanate is followed by conversion of the resultant α-thiocyanato carbonyl compound 2 into phenylhydrazone 3. The subsequent conjugate elimination reaction provides phenylazoalkene 4 and thiocyanic acid, both intermediates reacting further in the fashion outlined above and furnishing 8.Following this procedure 2-bromo-2-methylpropanal 1a gave (7aRS)-8a, 2-bromo-2-phenylpropanal 1b provided a 4:1 mixture of diastereomers 8b, which were separated by column chromatography (silica gel, ether) into colorless crystals of (7R*,7aS*)-8b and (7S*,7aS*)-8b; 17 similarly, 3-bromo-3-methylbutan-2-one 1c was converted into (7aRS)-8c. 18 The dithione structure of compounds 8 (as opposed to a conceivable thiazole structure) is support...

The Criss‐Cross Cycloaddition: A Simple Access to Valuable Heterocycles and Polymers

“…Interestingly, a CCC product 123 was isolate by the reaction of quadricyclane 122 with HFAA along with a 1 : 1 adduct 124 , and the exo,exo‐bis ‐cycloadduct 125 , was formed via the reaction of the C=N bond in 124 with quadricyclane [36j] . Remarkably, Schantl's research group [37a] has advanced the scope of the traditional CCC reaction by preparing the bicyclic 2,3,5,6,7,7‐hexahydro‐3‐phenyl‐ 1H ‐imidazo[1,5‐ b ][1,2,4]triazole‐2,5‐dithiones 129 from the fully terminal substituted phenylazoalkenes 127 (which was prepared from 126 ) [37b] and potassium thiocyanate in AcOH involving two key consecutive [3+2]‐cycloaddition steps Scheme 17. As can be seen from the Scheme 17, they first prepared the phenylazoalkenes 127 from the corresponding αα ‐disubstituted‐ α ‐halo carbonyl compounds 126 , which upon treatment with an excess of KNCS in acetic acid furnished the required bicyclic adduct imidazo[1,5‐ b ][1,2,4]triazole‐2,5‐dithione 129 via an intermediate 128 .…”

O‐Isocyanates as Uncharged 1,3‐Dipole Equivalents in [3+2] Cycloadditions

“…The scarcity of uncharged dipole equivalents in the literature is likely a consequence of the unfavorable thermodynamic profile of the reaction. While pioneering work with azines demonstrated the potential of uncharged dipole equivalents to engage in [3+2] cycloadditions, [6n–v] the resulting ylide must be trapped by a subsequent cycloaddition reaction (Scheme 1 C). In contrast, our lab developed intermolecular [3+2] cycloadditions of imino‐isocyanates with alkenes to form stable cycloadducts, azomethine imines [6k] .…”

Sequential MCR via Staudinger/Aza-Wittig versus Cycloaddition Reaction to Access Diversely Functionalized 1-Amino-1H-Imidazole-2(3H)-Thiones

“…To date, the most widespread method used for the synthesis of N -substituted 1-amino-1 H -imidazol-2(3 H )-thiones can be referred to the Schantl’s protocol, which consists of reacting α-haloketones with potassium thiocyanate and monosubstituted arylhydrazines in weak acidic medium (Scheme 1) [13,14,15,16,17,18,19]. This multistep reaction is considered to proceed via the formation of conjugated azoalkenes, derived from α-thiocyanatohydrazones D (Scheme 2) and dipolarophile isothiocyanic acid intermediate that in turn undergo a [3+2] cycloaddition reaction providing substituted 1-arylamino-1 H -imidazole-2(3 H )-thione I scaffolds [20,21].…”