A review on DBU-mediated organic transformations

ABSTRACT 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) has received a significant importance in organic synthesis during recent years because of its interesting ability to catalyze organic reaction sufficiently at mild conditions. DBU can work as a catalyst under simple conditions inducing the operational simplicity of the experimental procedures by reducing the side products and waste. The notable advantages in these cases include the less expensive catalyst which is commercially readily available, easy to handle, and most importantly recoverable. The DBU as a catalyst has been explored for several practical methodologies and is highly useful for the synthesis of a wide variety of organic materials. The selectivity (chemo-, regio-, and stereo-) of these reactions is highly impressive and applicable in modern chemical transformations. The DBU possesses enhanced basic properties and high mechanical as well as thermal stability. In recent years, a large number of organic transformations have been carried out using DBU as a catalyst. The DBU has successfully been employed to conduct a wide variety of organic reactions including usual chemical modifications, cyclizations, eliminations, esterifications, condensation reactions, multicomponent reactions, etc. In fact, during last few decades, a tremendous interest has sparked in various organic transformations promoted by DBU and a large number of publications have appeared in the literature. Since chemical transformations catalyzed by DBU have recently been proven to be highly important in organic synthesis we review in this article the recently appeared significant protocols using DBU as a catalyst. GRAPHICAL ABSTRACT

DBU is a sterically hindered base, which exists in liquid form with a boiling point of 261°C. It is one of the strongest organic base containing a pK a value of 12. The presence of adjacent nitrogen atoms is believed to stabilize the protonated species during its basic action (Scheme 1).
DBU is a non-nucleophilic base and due to this reason, it has been found to be useful in many reactions without side reactions due to inherent nucleophilicity of basic nitrogen of DBU (14,15).
Traditionally, DBU has been considered a non-nucleophilic base, but there are few reports where DBU has been shown to function as a better nucleophilic base catalyst than other similar organic bases such as 1,4-diazabicyclo [2.2.2] octane (DABCO) or 4-dimethylaminopyridine (DMAP) (16,17). Organic base catalysts with high reactivity have gained attention as an economically viable alternative to metal catalysts and environmentally green catalysts.
The notable advantages of DBU to be used in many organic reactions as it is less expensive, commercially readily available, homogenous, easy to handle, and most importantly recoverable. The benefit of the DBU catalyst has been explored for the practical methodologies useful for the synthesis of a wide variety of organic materials. In recent years, DBU has been used as a nucleophilic/non-nucleophilic base, catalyst, and complexing ligand and in many organic reactions.
DBU can be synthesized from a lactam, azepan-2-one (1). N-Cyanoethylation of lactam is carried out using acrylonitrile in the presence of a potassium hydroxide as base to produce the nitrite, 2, which is reduced using Raney-nickel in the presence of NH 3 to give N-(3aminopropyl)-azepan-2-one (3). The compound 3 further undergoes condensation in the presence of ptoluenesulphonic acid (p-TSA) to yield DBU (Scheme 2) (18, 19).
There is no comprehensive review on the DBU-catalyzed reactions in recent years. In this regard and the inspiration gained by the effectiveness of DBU in synthetic organic chemistry we review here the significant chemical transformations that are appeared in the literature by the application of DBU as a base and it is highly beneficial to the scientific community working in this area. The high selectivity (chemo-, regio-, and stereo-) of the reactions using DBU is found to be highly impressive and we hope that several methodologies may be developed in the future using DBU.

DBU-mediated organic transformations
A brief review of DBU-mediated organic transformations is discussed here.

Amidation reactions
Rajappa et al. have also described the DBU-catalyzed amidations of alkyl cyanoacetates, wherein, DBU acts as a nucleophilic base and replaces the alkoxy moiety and activates the carbonyl functional group attack by the amine (Scheme 3) (20).
The palladium-catalyzed coupling of aryl and heteroaryl chlorides with primary amides under mild homogeneous reaction conditions has been reported by   Gregory et al. Successful C-N coupling is enabled by the use of a unique 'dual-base' system consisting of DBU and NaTFA, which serve as proton acceptor and halide scavenger, respectively, using low catalyst loadings (0.5 mol %) with readily available, air-stable palladium precatalysts. The DBU/NaTFA system also enables the room-temperature coupling of primary aryl amines with aryl chlorides and is tolerant of a variety of basesensitive functional groups (Scheme 9) (26).

Elimination reactions
Wolf et al. have been used DBU as effective catalyst for the dehydrohalogenation and elimination of sulphonic acids in one pot conversion of tosylates to alkenes via primary (Scheme 10) (27).
Otter et al. have discussed the DBU-catalyzed efficient elimination of methanesulfonicacid from its ester in the final step during the synthesis of 1,3-dimethyl-6-propyluracil (Scheme 12) (29).
Zhang et al. have efficiently been synthesized symmetrical diynes from (Z )-aryl vinyl bromides catalyzed by DBU in the presence of CuI in DMF. The catalyst DBU carries out the dehydrohalogenation of aryl vinyl bromides resulting in the formation of aryl alkynyls, which is then deprotonated by DBU and in the presence of Cul forms copper aryl alkynylide. Then, the homocoupling of copper aryl alkynylide produces the target product (Scheme 13) (30).
The conjugated acid of DBU assists the intermolecular 5-exo cyclization of the carboxylate to the triple bond (Scheme 15). Kanazawa et al. have efficiently been used DBU as a catalyst for 5-exo intramolecular Scheme 9. Synthesis of amidation and amination of (Hetero) aryl chlorides.    For the first time, an eco-friendly and sustainable tandem [5C + 1C] cycloaromatization of α-alkenoyl ketene dithioacetals and nitroethane in water for the efficient synthesis of ortho-acylphenols was reported by Haifeng Yu et al. The green approach to ortho-acylphenols not only avoided the use of harmful organic solvents, which could result in serious environmental and safety issues, but also exhibited fascinating features such as good substrate scope, excellent yields, simple purification for desired products, ease of scale-up, and reusable aqueous medium (Scheme 23) (39).   corresponding methyl esters in excellent yields and this method is particularly valuable for the synthesis of methyl esters that bear acid-sensitive functionality (Scheme 28) (17). Zhao et al. have efficiently been synthesized diaryl thioethers and S-cycles from carbon disulfide and aryl iodides catalyzed by the CuI in the presence of DBU. This reaction was successfully operated in the construction of sulfur-containing cyclic moieties (Scheme 29) (44).

Etherification and (thio) esterification
Organic syntheses, such as that of N-substituted carbamic acid esters (CAEs), utilizing low purity and low concentrations of CO 2 directly, may help achieve two important goals-reducing CO 2 emission, and producing useful core chemicals without the energy-consuming processes of purifying and concentrating CO 2 . Here, Hiroki Koizumi et al. demonstrated a new synthetic approach for CAEs that uses a combination of two types of CO 2 capture mechanisms, which are constituted by combining an amine and 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU), and an alcohol and DBU, to form a protonated DBU carbamate salt and a protonated DBU alkyl carbonate salt, respectively. This new approach of CAE synthesis can be applied even to the simulated exhaust gas from fire-power plants, such as 3 vol % of CO 2 in N 2 or 15 vol % of CO 2 in N 2 , also containing SO 2 , NO 2 , and CO (Scheme 30) (45).

Halogenation reactions
Muathen et al. have successfully employed DBU hydrobromide perbromide (DBU.HBr) as a new mild, stable, and recoverable brominating agent for an array of aromatic compounds. This catalyst shows remarkable stability and remains unchanged for several months whereas compared with Py.HBr which loses 30% of its activity in a period of one month when it exposed to air (Scheme 31) (46).
An efficient one-pot method for selectively elimination bromine of allyl alcohol derivatives has been developed by Kutsumura

Isomerization reactions
A mixture of substituted pyrrolidin-2-ones was equilibrated using DBU, during the final step of a herbicide synthesis by Moriyaso et al. (Scheme 34) (49).
The first DBU-catalyzed Michael/Pinner/isomerization cascade of 3-hydrooxindoles with isatylidene malononitriles was developed by Zhu et al. This protocol also provides an efficient method for the synthesis of α-cyano-γbutyrolactonebispirooxindoles (Scheme 35) (50).
An easy approach to isomerization of δ-thiolactams to the conjugated α, β-unsaturated isomers was developed by Sosnicki et al. Jiahui Duan et al. have described a DBU-mediated cascade strategy of propargylamines with dimethyl 3oxoglutarate for constructing a functionalized benzo [c]chromen-6-one core has been achieved. This cascade process presumably involves a sequence of 1,4-conjugate addition, followed by lactonization, alkyne-allene isomerization, enol-keto tautomerization, 6π-electrocyclization, and aromatization. A photophysical survey reveals that the benzo[c]chromen-6-one products exhibit fluorescence properties and show potential for exploring fluorescent material applications. This protocol has few advantages such as mild reaction conditions, simple operation, transition metal-free, inert atmosphere-free, rich structural diversity, largescale synthesis and good functional group tolerance (Scheme 38) (54).
A straightforward, efficient yet effortless approach for the synthesis of structurally important triarylated pyrimidine derivatives has been successfully developed by Rimpa De et al. using secondary propargyl alcohol and commercially available amidines under mild basic conditions. The reaction is believed to proceed via basemediated redox isomerization of propargyl alcohol into a chalcone and a subsequent N-C-N fragment condensation reaction with the in situ generated chalcone. The procedure may be successfully employed to generate a large array of polysubstituted pyrimidine derivatives from milligram to multigram scale, atom and cost effective, operationally simple (Scheme 39) (55).

Horner-Wadsworth-Emmons reaction
The Horner-Wadsworth-Emmons reaction, a modification of the Wittig reaction has been employed frequently for the synthesis of α,β-unsaturated esters. aldehydes in the presence of DBU to give E-α,β-unsaturated esters and ketones in high yields. The E-selectivity of the product was high and the used DBU catalyst was recovered (Scheme 40) (56,57).

Baylis-Hillman reaction
Baylis-Hillman reaction of parthenin involved in the formation of the unexpected 1,3-dioxolanes (A) in the presence of catalytic amount of DBU, in the case of small aromatic and aliphatic aldehydes, whereas in case of higher aliphatic aldehydes resulted a normal Baylis-Hillman product (B) (Scheme 41) (58). A highly regioselective DBU-catalyzed annulation of Morita-Baylis-Hillman carbonates with isothiocyanates was developed. This method allows an efficient and rapid synthesis of spirocyclic oxindole dihydrothiophene products in moderate to high yields with excellent regioselectivities under simple conditions. A plausible reaction mechanism is also proposed by Zhao  DBU has been successfully employed as a catalyst to carry out Mannich-type of reaction of α-amido-p-tolysulfones treated with diethyl malonates/diethyl flouro malonates to produce β-amino esters/α-fluoro-β-amino esters A convenient CuI/DBU-catalyzed one-pot method has been developed for the synthesis of 1,4-disubstituted 1,2,3-triazoles through the coupling of aryl iodides with sodium azide, followed by the intermolecular cyclization between the generated aryl azides and phenyl acetaldehyde derivatives or alkynes derivatives in DMSO producing the desired products in excellent yields (Scheme 49) (66).

Nef reaction
Selective Nef reaction of different secondary nitro compounds has been converted into the corresponding ketones under basic conditions using DBU in acetonitrile. In this reaction, DBU acts a base (Scheme 50) (67).

Strecker-type reaction
Raj et al. have efficiently been used DBU based basic ammonium salt ([BnDBU]Br) for synthesis of α-aminonitriles and cyanohydrins utilizing TMSCN as the source of cyanide ion. In this reaction catalyst helps in activating the silyl group of TMSCN, thus releasing the cyanide ion (Scheme 51) (68).  Shieh et al. have efficiently been used catalytic amount of DBU along with dimethyl carbonate (DMC) to affect the methylation of bezimidazoles, phenols, and indoles (Scheme 53) (70).

Alkylation reactions
An efficient and atom-economic transformation of enones with electron-deficient alkenes in the presence of DBU under mild conditions has been developed by Tian et al. This protocol offers a direct access to 1,5-dicarbonyl compounds in synthetically useful yields using vinylogous strategy via dienolate intermediates (Scheme 54) (71).

Acylation reactions
A new method for the synthesis of diversely functionalized oxazoles has been developed by Cordaro et al. Catalytic amount of DBU has been employed to afford the reaction of oxazolone with enolizable cyclic 1,3-dicarbonyls resulting in the formation of C-acylated derivatives (Scheme 55) (72).
Zhang et al. have successfully been synthesized the corresponding O-acyl cyanohydrin adducts in higher yields from a variety of substituted acetone or pentan-3-one, cyclohexanones, cyclopentanone, and various acyl cyanides catalyzed by DBU (Scheme 57) (74).

Benzoin condensation
An efficient and simple one-pot procedure for the synthesis of α-diketones from a variety of aldehydes via benzoin condensation under the influence of a catalytic

Synthesis of azalactones and cyclic hemiacetals
The N-heterocyclic carbene (NHC)-catalyzed annulation of enals with nitroso compounds in the presence of DBU in THF has described by Yang et al. Unexpected seven membered 4-azalactone was formed according to a process involving a 1,2-Bamberger-type rearrangement (Scheme 59) (76).
DBU-NHC catalyzed transformation of α,β-unsaturated aldehydes and 4-formylbenzoates to cyclic hemiacetals was described by Yoshida et al. Various substrates were converted to the corresponding cyclic hemiacetals in a stereoselective manner (Scheme 60) (77).
DBU-silver salts catalyzed system has been utilized for the synthesis of β-oxoalkyl carbamates using three-      (3)) with diphenyl carbonate (DPC), used as an eco-friendly active carbonyl species in place of phosgene-derivatives. The immobilized catalyst is less active than unsupported DBU but can be recovered easily at the end of catalytic   DBU-H 2 O is an effective catalytic system for aldol condensation reactions. DBU alone is inactive for these types of reactions due to its a Lewis basic characteristic but along with equimolar amount of water, it is transformed into a structure with Bronsted basic characteristics (Scheme 88) and thus, catalyzes the reaction (Scheme 89) (106).
The DBU-catalyzed synthesis of 2-aryl-2H-indazoles via the reaction of 2-nitrobenzyl triphenylphosphonium bromide and aryl isocyanates has been reported by Taher   C-H acids such as dimedone, 2-hydroxy-naphthalene-1,4-dione, 5-methylcyclohexane-1,3-dione and cyclohexane-1,3-dione in PEG-400 has been reported under heating (Scheme 116) (134). Mohammad et al. have described Density functional theory (DFT) methods used to investigate the mechanism of diethylamine-catalyzed cycloaddition reaction of phenyl azide and pentanal. The computational results indicate that the catalyzed cycloaddition reaction is carried out via two one-step transition states that lead to 1,4-and 1,5-regioisomers, and favors the generation of the 1,4-regioisomer. In the absence of a catalyst, the 32CA reactions of azide and alkyne lack poor regioselectivity. Finally, distortion/interaction analysis along the reaction pathways was used to explain the 1,5-regioselectivity (Scheme 119) (137).
Anton et al. have described a general protocol for the formal Michael addition of acetone to α,β-unsaturated esters and amides, a transformation difficult to perform using current methods. The protocol comprises of an amidine catalyzed relay ring-opening and fragmentation of 3,4-dihydropyranones. The reaction proceeds under mild conditions has a broad substrate scope and the products can be isolated in good to excellent yields. The method can be applied to homochiral substrates with total preservation of chiral information, generating products in high optical purity. Kinetic experiments supported by quantum chemical modeling indicate a mechanism in which the catalyst takes a bifunctional role, acting both as a Brønsted base and as a hydrogenbond donor (Scheme 121a) (139). The plausible mechanism is depicted in Scheme 121b.
Attilio et al. have succefully reported a fully detailed mechanistic study involving an organocatalyzed 1,3dipolar cycloaddition via enolate or stabilized vinylogous carbanion intermediates and azide for the synthesis of 1,2,3-triazoles. A detailed investigation of the elementary steps, intermediates, and transition states of the two organocatalyzed metal-free click reactions is supported by DFT calculations and 1 H NMR monitoring experiments, providing detailed profiles for both reaction mechanisms. Distortion-interaction activation-strain (DIAS) analysis was also employed to further elucidate the regioselectivity in both reactions (Scheme 122) (140).

Rearrangement reactions
Miura et al. have described DBU catalyzed and triphenyl phosphine-mediated stereoselective asymmetric rearrangement of chiral α-sulfinyl enones and subsequent treatment with aqueous hydrogen peroxide (H 2 O 2 ) to afford γ-hydroxy-α-enones (Scheme 125a) (143). A possible mechanism depicting the catalyst role of DBU in this rearrangement reaction is shown in Scheme 125b. Sathishkannan    Yadagiri et al. have reported a two well-known synthetic reactions Ramirez olefination and Corey-Fuchs reactions are integrated in a one-pot sequential manner for the synthesis of arylacetylenes and 1,3enynes starting from aldehydes. DBU along with an additive NaOH not only exclusively afforded the terminal alkynes directly from the aldehydes, but also enhanced the rate of reaction. The dynamic nature of DBU also facilitated the isolation of 1-bromoalkynes intermediate products (Scheme 135) (154,155).
The reaction of 2-pyridylacetates and α,β-unsaturated pyrazolamides with DBU as the catalyst has been developed by Yao et al. A range of unexplored multisubstituted 2,3-dihydro-4H-quinolizin-4-ones are obtained with satisfactory yields (up to 94%) and excellent diastereoselectivities (all cases > 20: 1 dr) via a dearomative [3 + 3] annulation process. This practical method also has few advantages such as transition metal-free, mild reaction conditions, wide functional group tolerance, easy scale-up synthesis, and versatile further derivitizations (Scheme 136) (156). A DBU-catalyzed desymmetrization strategy between cyclohexdienones and isocynates was discovered, affording a series of vicinal diamine-containing heterocycle derivatives excellent diastereoselectivity under mild conditions has been reported by Hongxing et al. This method has advantages such as mild reaction conditions, good yields, excellent diastereoselectivity, most reactions within 30 min, broad substrate scope, this reaction could be performed on a 10 g scale using 1.0 mol% of catalyst loading (Scheme 137) (157).
Paresh et al. have described a DBU/O 2 -promoted novel method for oxidation of dienones to 2,6-dione derivatives. The reaction involves treatment of a dienone with DBU in acetonitrile employing molecular oxygen as the oxidant. This transformation proceeds through a peroxide intermediate that upon Kornblum-DeLaMare rearrangement produces 2,6-diones. The method was successfully utilized for the synthesis of (±)-pleodendione with improved yields versus those of the traditional PDC-TBHP method. Metal-free conditions, an eco-friendly reagent, operationally simplicity are the striking features of this protocol (Scheme 139) (159).
The cyclic organic amidine catalyst, 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU), is gaining popularity for its use in the synthesis of biodegradable aliphatic polyesters, such as poly(lactic-co-glycolic acid) (PLGA). PLGA is one of the most successful polymeric drug delivery materials in the pharmaceutical industry. Currently, commercial PLGA materials are produced via ringopening copolymerization of lactide and glycolide under the influence of metal catalysts such as tin octoate, and this chemistry has been extensively studied and has been reported by Samruddhi et al. However, not much is known yet about the details of the newer, DBU-catalyzed PLGA polymerization reactions. For this investigation, a full-scale kinetic population balance model was developed that takes into account all possible reactions of the copolymerization, including initiation via activated alcohol and nucleophilic attack pathways, self-and cross-propagation, combination via inter-and intrachain acylation, and DBU deactivation (Scheme 140) (160).

Conclusions
This review focuses on the catalytic activity of the organic bicyclic amidine base, 1,8-diazabicyclo [5.4.0]undec-7ene (DBU). DBU catalyst has received a significant importance in recent years due to its interesting ability to conduct organic transformations conveniently and efficiently. It is available commercially, cheap, and a homogenous catalyst. It has been used widely in a variety of reactions, namely amidation, halogenation, condensation, cyclization, esterification, elimination, multicomponent reactions, etc. The benefit of the DBU catalyst has been explored for the practical methodologies useful for the synthesis of a wide variety of organic materials. The selectivity (chemo-, regio-, and stereo-) of these catalysts is highly impressive and applicable in modern chemical transformations. Since chemical transformations catalyzed by DBU have recently been proven to be highly important in organic synthesis.