1. Copper Catalysis
In 2013, Liu and co-workers developed a copper-catalyzed intramolecular arylation of Ugi-adducts
[1]. Under microwave heating, diverse tetracyclic benzo[
e][1,4]diazepines were synthesized within 40 min in high yields and with excellent chemoselectivities (
Scheme 2Scheme 1). Then they changed the amine and acid components, giving a series of new Ugi-adducts
[2]. By using the same conditions in 30 min, the Ugi-adducts were performed to deliver various 5,6-dihydroindolo[1,2-
a]quinoxalines with excellent yields and chemoselectivities (
Scheme 3Scheme 2).
Scheme 21.
Copper-catalyzed arylation for the synthesis of tetracyclic benzo[
e
][1,4]diazepines.
Scheme 32.
Synthesis of 5,6-dihydroindolo[1,2-a]quinoxalines via copper catalysis.
Van der Eycken’s group reported a post-Ugi copper-catalyzed intramolecular Ullmann coupling in 2014 (
Scheme 4Scheme 3). Microwave assistance promoted the diversity-oriented formation of 4
H-benzo[
f]imidazo[1,4]diazepin-6-ones with high yields, in 30 min
[3]. Ugi-adducts derived from imidazole-4-carbaldehyde and imidazole-2-carbaldehyde reacted smoothly to give the corresponding products. Notably, substrates derived from C-2 or C-5 substituted imidazole-4-carbaldehyde failed to deliver the corresponding products due to the decomposition of the starting materials.
Scheme 43.
Synthesis of 4
H
-benzo[
f
]imidazo[1,4]diazepin-6-ones through Ullmann coupling.
In 2016, a microwave-assisted intramolecular Ullmann etherification was established by Dai and co-workers for the efficient construction of dibenz[
b,f][1,4]oxazepine scaffold. When optimizing the reaction conditions, it was found that conventional heating gave 75% yield after 48 h, while microwave irradiation delivered 64% yield in 30 min, dramatically speeding up the reaction (
Scheme 5Scheme 4). Under the optimal reaction conditions of microwave irradiation, they explored the substrate limitation (
Scheme 6Scheme 5). By using 2-bromobenzoic acids or 2-bromobenzaldehydes, the diverse 6/7/6-fused tricyclic heterocycles were synthesized from Ugi-adducts via copper-catalyzed Ullmann coupling in 30 min
[4]. In contrast with their previous report through copper-catalyzed Goldberg amidation of Ugi-adducts
[5], this reaction exhibited excellent chemoselectivity to undergo Ullmann etherification under microwave assistance.
Scheme 54.
Intramolecular Ullmann etherification under conventional and microwave heating.
Scheme 65.
Construction of dibenz[
b,f
][1,4]oxazepines via Ullmann etherification.
2. Palladium Catalysis
Gracias and co-workers described a microwave-assisted intramolecular Heck cyclization of Ugi-adducts in 2004
[6]. Through palladium catalysis, highly functionalized N-heterocyclic scaffolds were synthesized with excellent yields in 2 h (
Scheme 7Scheme 6).
Scheme 76.
Microwave-assisted intramolecular Heck cyclization of Ugi-adducts.
In 2007, Judd’s group reported a sequenced RCM/Heck reaction of diverse Ugi-adducts
[7]. Under the assistance of microwave heating, various bridged bicyclic lactams were prepared with high yields and diastereoselectivities in 40 min (
Scheme 8). Compared to the homogeneous palladium catalyst Pd(Ph
3P)
2Cl
2, the immobilized palladium catalyst FibreCat 1032 showed similar performance for all cases. This method could also give [4.3.2] the bicycloundecane scaffold in high yield and diastereoselectivity, leading to a mixture of the alkene regioisomers (
Scheme 8Scheme 7b). The more constrained indole RCM product afforded the bridged indole scaffold with excellent selectivity (
Scheme 8Scheme 7c). Interestingly, by using microwave heating, the indole RCM product delivered the saturated bridged bicyclic lactam with high diastereoselectivity using FibreCat 1032 and sodium formate (
Scheme 8Scheme 7d).
Scheme 87.
Sequenced RCM/Heck reactions.
Under microwave irradiation, palladium and copper catalysts showed distinctly different catalytic properties
[1][2]. Highly selective C3-arylation of Ugi-adducts was achieved by Liu’s group in 2013
[1]. Under microwave-assisted palladium catalysis, various benzo[5,6]azepino[3,4-
b]indoles were constructed with high yields in 1 h (
Scheme 9Scheme 8). Subsequently, the same group employed this strategy using the Ugi-adducts derived from 2-halogenated anilines instead of 2-halogenated benzoic acids
[2]. With the assistance of microwave irradiation, diverse indole-fused 6,7-dihydroindolo[2,3-
c]quinolines were obtained with high yields in 2 h (
Scheme 10Scheme 9).
Scheme 98.
Synthesis of benzo[5,6]azepino[3,4-
b
]indoles through palladium catalysis.
Scheme 109.
Preparation of indole-fused 6,7-dihydroindolo[2,3-
c
]quinolines.
3. Other Transition Metal Catalysis
In 2018, Sieburth and Al-Tel discovered a zinc-catalyzed microwave-assisted post-Ugi cascade transformation (
Scheme 11Scheme 10). Based on a build/couple/pair strategy, the diastereoselective synthesis of various chromenopyrroles was performed in a one-pot fashion in 50 min
[8]. By using amino acids as chiral auxiliary, this method provided access to enantiopure chromenopyrroles. The polycyclic product was subjected to similar conditions, resulting in pyrrole formation in 62% yield through C-O bond cleavage and isomerization (
Scheme 12Scheme 11a). By using 3,4,5-trimethoxy- and 4,5-dimethoxyphenylacetic acids, pentacyclic products were produced via additional intramolecular Friedel–Crafts acylation (
Scheme 12Scheme 11b). As proposed, the Ugi-adduct first coordinates with Zn
2+, giving intermediate
A (
Scheme 13Scheme 12). This is followed by nucleophilic addition of the tertiary amide and deprotonation, generating the azomethine ylide
C. Sequential intramolecular [3 + 2] cyclization produces the strained intermediate
D, which undergoes the expulsion of CO
2 to give the desired chromenopyrrole product.
Scheme 110.
Zinc-catalyzed post-Ugi transformation for the construction of chromenopyrroles.
Scheme 121.
Special examples for zinc-catalyzed transformation.
Scheme 132.
Proposed mechanism for zinc-catalyzed post-Ugi transformation.
Van der Eycken and co-workers developed a microwave-assisted rhodium(III)-catalyzed intramolecular annulation of Ugi-adducts in 2019. It was observed that microwave heating (100 W) afforded the annulation product in 78% yield, while conventional heating only gave 36% yield in the same reaction time (
Scheme 14Scheme 13). Through chemoselective C(sp
2)-H activation (
Scheme 15Scheme 14), without installing a directing group, modification of peptidomimetics and oligopeptides was accomplished in a rapid and step-economical fashion, delivering various indolizinone and quinolizinone scaffolds in 1 h (
Scheme 16). Furthermore, this method was compatible with water and specifically added N-protected amino acids
[9].
Scheme 143.
Rhodium-catalyzed annulation under conventional and microwave heating.
Scheme 154.
Microwave-assisted rhodium(III)-catalyzed intramolecular annulation.
Scheme 165.
Chemoselective modification of oligopeptides.
In 2019, Van der Eycken’s group reported a gold-triggered dearomative spirocarbocyclization/Diels–Alder reaction of Ugi-adducts. When optimizing the reaction conditions, it was observed that microwave irradiation could not only accelerate the reaction and enhance the yield, but also significantly improve the diastereomeric ratio (
Scheme 17Scheme 16). By using microwave heating (
Scheme 18Scheme 17), the diversity-oriented synthesis of complex bridged polycyclic N-heterocycles was achieved with excellent chemo- and diastereoselectivity, in 10 min
[10]. According to the mechanism, the triple bond of the Ugi-adducts is activated by the in situ generated cationic gold(I) species, giving intermediate
A (
Scheme 19Scheme 18). This is followed by dearomatization, generating intermediate
B in a 5-
endo-dig fashion. The final products are formed by sequential [4 + 2] intramolecular cycloaddition.
Scheme 176.
Gold-triggered spirocarbocyclization under conventional and microwave heating.
Scheme 187.
Gold-triggered dearomative spirocarbocyclization/Diels–Alder reaction.
Scheme 198.
Proposed mechanism for gold-catalyzed post-Ugi transformation.
4. Transition Metal-Free Catalysis
In 2012, a simultaneous deprotection and cyclization process of Ugi-azide adducts was developed by Hulme (
Scheme 20Scheme 19). By using ethyl glyoxylate or phenylglyoxaldehydes, tricyclic tetrazolo-fused benzodiazepines and benzodiazepinones were prepared
[11]. This microwave-assisted transformation could be completed in 10 min.
Scheme 2019.
Microwave-assisted deprotection and cyclization process.
Later on, Gámez-Montaño synthesized the xanthates through one-pot sequential Ugi-azide/N-acylation/S
N2 reaction (
Scheme 21Scheme 20). Under free radical conditions, intramolecular cyclization of xanthates delivered 3-tetrazolylmethyl-azepino[4,5-b]indol4-ones in good yields. Compared to conventional heating requiring 280 min, microwave irradiation could shorten the reaction time to 70 min
[12]. Notably, based on a docking study, the final products showed the potential to inhibit 5-Ht
6 protein.
Scheme 210.
Intramolecular cyclization of xanthates through radical process.
In 2014, El Kaim and Gámez-Montaño reported an efficient Pictet–Spengler reaction of Ugi-azide adducts and formaldehyde (
Scheme 22Scheme 21). Under microwave heating, a series of 2-tetrazolylmethyl-2,3,4,9-tetrahydro1H-β-carbolines was synthesized in 73–83% yield in 5 h, while conventional heating gave 74–86% yield in 72 h, indicating that microwave irradiation remarkably shortens the reaction time of this transition metal-free process
[13].
Scheme 221.
Microwave-assisted Pictet–Spengler reaction of Ugi-azide adducts.
In 2018, Zhu’s group presented a one pot post-Ugi cyclization through nucleophilic substitution/deprotection/imine formation cascade (
Scheme 23Scheme 22). By using microwave irradiation, different kinds of 2-azetidinones were rapidly synthesized in moderate yields
[14]. The 2-azetidinones were screened against diverse cancer cell lines, showing good antitumor activities. Based on this method, the same group reported a similar microwave-assisted post-Ugi cyclization
[15]. Through tandem deprotection/nucleophilic addition/nucleophilic substitution process, diverse benzimidazopyrazinones were prepared in a one-pot fashion with high yields (
Scheme 24Scheme 23). Under the assistance of microwave heating, this transition metal-free protocol required only one purification procedure after three steps.
Scheme 232.
Microwave-assisted synthesis of 2-azetidinones.
Scheme 243.
Transition metal-free protocol for the preparation of benzimidazopyrazinones.