The second part of review is devoted to the catalytic role of DABCO in Michael and Biginelli reactions, as well as nucleophilic addition at C=X and C≡X bonds.
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The catalytic role of DABCO in Michael reaction and nucleophilic addition at C=Х and C≡Х bonds
The first part of this review article1a demonstrated the important and versatile applications of DABCO as a reagent for organic synthesis,1b–f in particular, in the role of a catalyst for the commonly used classic Morita–Baylis–Hillman and Knoevenagel reactions. In the second part, we will describe the use of DABCO as a catalyst for nucleophilic addition reactions at activated C=С bonds (Michael reaction), as well as at C=Х and С≡Х bonds. The primary attention will be focused on the Michael reaction, which is of particular importance in the synthesis of heterocyclic compounds. DABCO is most often employed in this reaction as a basic organic catalyst, which deprotonates the reactants, producing reactive anionic nucleophiles of various nature, which are readily added to unsaturated substrates.
For example, the key step during the synthesis of pyrrolidin-2-one 1 from oxazole 2 and nitroalkene 3 was the initial Michael addition of С(4)-anion derived from isoxazol-5(4Н)-one 2 to the activated alkene 3 in the presence of DABCO as a catalyst (Scheme 1).2 The intermediate Michael adduct 4 then underwent a series of one-pot transformations – nitro group reduction, ring cleavage, and recyclization – with the formation of pyrrolidin-2-one derivative 1. The reaction was characterized by high diastereoselectivity, with the predominant formation of trans-isomer.
Scheme 1
A new type of one-pot synthesis in aqueous media in the absence of transition metal catalysts was achieved using methyl (3-formyl-1Н-indol-2-yl)acetic acid ester (6) and alkyl/aryl-substituted β-acroleins 7 in the presence of 20 mol % DABCO, followed by treatment with HCl at elevated temperature, providing moderate yields (51–68%) of functionalized 2-alkyl(aryl)-1-methoxycarbonyl-9Н-carbazole derivatives 5 (Scheme 2).3 The initial step involved the addition of C-nucleophile to the unsaturated carbonyl compound according to Michael reaction mechanism. The Michael adduct further underwent a series of transformations, including intramolecular cyclization to tricyclic hemiaminal 8, followed by ring cleavage and Friedel–Crafts recyclization and concluding with decarbonylation and oxidation.
Scheme 2
The efficient, solvent-free domino reactions of 5-membered cyclic sulfamidate imines 9 with various β,γ-unsaturated α-ketocarbonyl compounds 10 proceeded under mild conditions in the presence of DABCO as catalyst upon microwave irradiation and were employed for the assembly of new types of polyfunctionalized picolinates 114 (Scheme 3). The mechanism of these reactions also started by a Michael addition step. Analogous reactions were performed with the participation of 6-membered cyclic sulfamidate imines.4 2,4-Disubstituted pyridines were obtained from sulfamidate imines 9 and α,β-unsaturated aldehydes in the presence of proline and DABCO.5
Scheme 3
As the first step, DABCO deprotonated the methylene group of cyclic sulfamidate imine, resulting in carbanionic intermediate 9’ (Scheme 4). This intermediate subsequently underwent a Michael addition to β,γ-unsaturated α-keto ester 10 with the formation of adduct 12, which immediately underwent the elimination of SO3 by the action of a base, leading to the reactive intermediate 13. The latter was converted into intermediate 14via an iminocyclization step, followed by dehydration that gave the final product of this reaction.
Scheme 4
The [3+2] annulation of cyclic imine sulfamates 15 with isocyanoacetates 16 in the presence of DABCO as catalyst occurred under mild conditions and led to 2-imidazolines 17 that were condensed with cyclic sulfamates. This reaction was diastereoselective and gave moderate to excellent yields (Scheme 5).6In the presence of DABCO in the role of a Lewis base, isocyanoacetate 16 was deprotonated, generating the nucleophilic anion А. This intermediate attacked the sulfamate moiety of cyclic imine 15, leading to the formation of intermediate В. The subsequent nucleophilic addition at the activated С≡N bond and protonation led to the target compound 17, while regenerating DABCO.
Scheme 5
A simple and efficient one-pot synthesis of hetarylsubstituted benzene derivatives 18 proceeded via the cyclocondensation of vinylmalononitriles 19 with hetarylnitroalkenes 20 in the presence of DABCO (Scheme 6).7 The reaction included a Michael addition of С-anion, generated in the presence of DABCO, to the hetarylnitroalkene. Aromatization of the formed dihydro species occurred in the presence of air oxygen. The obtained compounds exhibited tuberculostatic, antibacterial, and antifungal activity at various concentrations.
Scheme 6
A three-component reaction of acetylenedicarboxylic ester 21, arylidenemalononitriles 22, and malononitrile in the presence of DABCO as catalyst led to 4-amino-3,5-dicyanophthalate esters 23 (Scheme 7).8 DABCO in this case played the role of N-nucleophile, which reacted with acetylenedicarboxylic ester 21, resulting in the formation of reactive zwitterionic intermediate 24, which then underwent a Michael addition to arylidenemalononitrile 22 (Scheme 7). The obtained zwitterion 24 reacted with malononitrile anion, resulting in nucleophilic substitution of DABCO, followed by the cyclization of adduct 25, accompanied by elimination of an HCN molecule.
Scheme 7
Hexahydroquinolines 26 were obtained in good to excellent yields according to a simple and effective procedure, including the reaction of enamines 27 with substituted arylidenemalononitriles 22 while employing DABCO as a basic catalyst (Scheme 8).9 The regiochemical outcome of the Michael addition was confirmed by 2D NMR spectroscopy (1H–13C HMBC experiment).
Scheme 8
A series of naphthalene derivatives 28 bearing carbonyl and nitro groups at positions 1 and 3, respectively, were synthesized in good yields by a one-pot domino reaction of some 2-(2-formylaryl)acetophenone derivatives 29 with various 1-aryl/hetaryl-2-nitroalkenes 30 in alcohol medium in the presence of DABCO as a catalyst (30 mol %) (Scheme 9).10 The reaction mechanism involved an interaction with basic catalyst via the formation of a stable benzyl carbanion, its Michael addition to nitroalkene, closure of a 6-membered ring through an intramolecular Henry reaction and, finally, aromatization by elimination of a water molecule.10
Scheme 9
Isatindihydrofuran spiro compounds 31 were synthesized in good yields (up to 95%) and excellent diastereoselectivity (de 99%) by a simple tandem Michael addition of α-anions derived from α -hydroxycarbonyl compounds 32 to the exocyclic double bond of isatinylidenemalononitrile 33, followed by a cyclization in aqueous medium at room temperature in the presence of DABCO as catalyst and sodium dodecyl sulfate (SDS) as promoter (Scheme 10).11 Some of the synthesized compounds showed antibacterial properties that were superior to those of the antibiotic ampicillin.
Scheme 10
The generation of С-nucleophiles for the addition to Michael acceptors can be also associated with the enolization of carbonyl compounds by the action of DABCO. This process, for example, occurs during the domino [4+4] annulation reactions of ynones 34 and α -cyano-α,β-unsaturated ketones 35 that are promoted by DABCO (Scheme 11).12 This method provides an alternative route to eight-membered cyclic ketones 36 in good yields under mild conditions.
Scheme 11
The mechanism of this process can be illustrated by using the example of reaction with 4-phenylbut-3-yn-2-one (34а). As the first step, compound 34а was enolized by the action of DABCO (intermediate I), then enolate I underwent a conjugated nucleophilic addition to the α,β -unsaturated ketone 35, with the formation of intermediate II, where DABCO served as a base in this process (Scheme 12). The subsequent protonation of enol II led to vinyl alcohol III, which after another Michael addition step generated zwitterion IV. The further steps of 1,7-hydride shift, intramolecular nucleophilic addition, and, finally, the elimination of DABCO led to the reaction product 36.
Scheme 12
DABCO has been used as an efficiently regenerated basic catalyst for rapid “green” synthesis of fused pyran systems 37via the reactions of various cyclic enols or 1,3-diketones 38 with tetracyanoethylene (39) under the conditions of microwave irradiation (Scheme 13).13 These conditions allowed to obtain excellent yields while using a short reaction duration (5–7 min). The СН-acidic compound 38 in the presence of DABCO was converted to enolate, which underwent a Michael addition to tetracyanoethylene, followed by an intramolecular cyclization.
Scheme 13
A convenient and effective formal [4+2] cycloaddition of 3-acyl- or 3-(alkoxycarbonyl)-1,4-enediones 40 to 2,3-butadienes (allenes) 41 in the presence of DABCO as catalyst proceeded under mild conditions and also led to polysubstituted pyrans 42 in moderate to good yields (Scheme 14).14
Scheme 14
The mechanism of this process can be illustrated in the following way (Scheme 15): DABCO added to allene 41a, leading to the active zwitterionic intermediate 43, which underwent a Michael addition to 3-acyl-1,4-enedione 40. After a series of proton shifts, the О-anion site in the enol form of the adduct attacked the electrophilic carbon atom of the quaternized enamine fragment, leading to intramolecular cyclization into dihydropyran, which was converted to the respective pyran by eliminating a molecule of DABCO.
Scheme 15
An example of separated synthesis of pyrano[2,3-b]-indole and dihydropyrano[2,3-b]indole from the same starting materials has been described. During these domino reactions of oxindoles 44 and allenoates 41, by controlling the reaction conditions it is possible to obtain three types of products – pyrano[2,3-b]indole 45 or dihydropyrano[2,3-b]-indoles 46 with E- or Z-exocyclic double bond (Scheme 16).15 By using DABCO as catalyst in THF medium, dihydropyrano[2,3-b]indole (Е)-46 was obtained at room temperature, while pyrano[2,3-b]indole 45 formed at 65°С.
Scheme 16
In contrast to that, dihydropyrano[2,3-b]indole (Z)-46 was obtained by using DMAP as catalyst in PhMe medium at 80°С. Under these conditions, oxindole derivatives played the role of Michael acceptors. The reaction mechanism of this formal [2+4] cycloaddition of methyl allenoate to 3-methylideneoxindole in the presence of DABCO as catalyst was studied by density functional theory calculations (М06-2Х method).16 The reaction included nucleophilic addition of catalyst to methyl allenoate, the addition of a second reactant, and intramolecular cycloaddition followed by the elimination of catalyst.
The diastereoselective reaction of isatin ketimines 47 with allenoates 41 was also based on the activation of allenoates with DABCO. The generated zwitterionic allyl carbanion added at the imine C=N bond, followed by intramolecular nucleophilic attack that led to azetidine 48 while regenerating a molecule of DABCO (Scheme 17).17 By using the stereodirecting effect of the bulky tert-butylsulfinyl auxiliary group, it was possible to achieve the formation of spiroisatins in the form of single diastereomer with 4-methylideneazetidine moiety at the spiro atom. The advantages of this method were demonstrated by the possibilities for further transformations of azetidines 48 into spiro-β-lactams 49.
Scheme 17
The [2+2] annulation reaction of allenoates 41 with azodicarboxylate esters 50 in the presence of Lewis base catalyst (DABCO) led to 3-alkylidene-1,2-diazetidines 51 in moderate yields, with excellent regio- and stereoselectivity (Scheme 18).18,19 Allenoate in the presence of DABCO as catalyst generated the reactive unsaturated zwitterion 52, which was added to azodicarboxylate 50, after which a second Michael addition occurred at the С=С double bond.
Scheme 18
DABCO was employed as an effective general base in a
simple one-pot synthesis of polysubstituted 2,4-dihydropyrano[
2,3-c]pyrazoledicarboxylates 53 from β-keto esters, hydrazine, acetylenedicarboxylate ester, and malononitrile in
alcohol medium20 (Scheme 19). The spontaneous condensation of β-keto ester with hydrazine led to pyrazol-5-one А, while the Michael addition of malononitrile to acetylenedicarboxylate ester gave intermediate В. Subsequently, the addition of intermediate С to intermediate В in the presence of DABCO resulted in the formation of intermediate D, which underwent nucleophilic attack of oxygen atom at the nitrile group, leading to the formation of intermediate Е. In the final step, intermediate E was isomerized to the bicyclic target molecule 53.
Scheme 19
An effective domino process involving a tandem Michael reaction of ω-nitro-α,β-unsaturated esters 54 with 3-alkylidenepyrazolones 55 was accomplished by using DABCO as organocatalyst (Scheme 20).21 The process led to carbocyclic spiropyrazolones 56 containing tertiary and quaternary stereogenic centers with excellent diastereoselectivity (dr > 30:1).
Scheme 20
A convenient, environmentally benign method for obtaining new derivatives of 3-oxo-3Н-benzo[a]pyrano[2,3-c]- phenazines 57 and 3-(5-hydroxybenzo[a]phenazin-6-yl)- acrylates 58 comprised a three-component domino condensation of 2-hydroxynaphthalene-1,4-dione 59, 1,2-di aminobenzenes 60, and acetylenedicarboxylate esters 61a,b in H2O and in the presence of DABCO as a basic catalyst (Scheme 21).22 This “green” process led to the biologically and pharmacologically relevant heterocycles 57 and 58via a simple one-pot procedure characterized by several substantial advantages: the simplicity of experimental procedure, short reaction duration, high yields, multiple cycles of catalyst reuse, lack of laborious workup and purification steps, avoidance of hazardous reagents and solvents. The nucleophilic addition of DABCO to acetylenedicarboxylate ester formed a zwitterion, which was protonated by phenolic intermediate adduct А. As a result of this, the two components were activated, an enolate anion and activated double bond were formed, creating favorable conditions for a carbo-Michael reaction. The subsequent lactonization step provided the target compounds 57 and 58. It should be noted that the regioselectivity issues and the formation of quinoxaline derivative A have not been studied in detail and, in our opinion, remain unresolved.
Scheme 21
The one-pot synthesis of imidazo[1,2-a]pyridines 62 relied on the interaction of various 2-aminopyridines, benzaldehydes, and phenacyl bromides in the presence of DABCO, with the introduction of an alkylamino functionality at position 3 of the formed bicyclic molecule (Scheme 22).23
Scheme 22
As the initial step, the reaction of 2-aminopyridine and aldehyde in the presence of DABCO (which catalyzed the formation of imine) gave imine intermediate (I) (Scheme 23). After the addition of phenacyl bromide to the aminopyridine and the formation of 2-arylimidazo-[1,2-a]pyridine (II) (with DABCO playing a role during the deprotonation of amidine system), the latter immediately added to imine, with the formation of the target compound 62.23 The use of 2-aminothiazoles according to an analogous methodology led to the formation of imidazo-[2,1-b]thiazoles.24
Scheme 23
A variant of enantioselective Michael reaction assisted by a chiral catalyst is also known. Thus, 4,5-dihydrofuran-2-carboxylate esters 63 were efficiently formed in the presence of organic catalysts by an enantioselective sequence of reactions between (Z)-(2-chloro-2-nitroethenyl) benzenes 64 and α-keto esters 65 (Scheme 24).25 This sequence consisted of a Michael addition promoted by (R,R)-TUC as catalyst and an intramolecular О-alkylation in the presence of DABCO, leading to a single diastereomer with the enantiomeric excess ranging from 86 to 97%.
Scheme 24
Aza-Michael reactions involve the addition of N-nucleophiles to activated multiple bonds. The role of DABCO in these processes consists, as a rule, of generating reactive N-anions by the deprotonation of NH-acidic compounds.
Thus, a method for the synthesis of 2,4-disubstituted 1,2,3-triazoles was based on the alkylation of triazoles in basic medium (Scheme 25).26 This synthesis can be performed as a Michael addition of 4-aryl-1H-1,2,3-triazoles 67 to α,β-unsaturated ketones 68 in the presence of DABCO as a catalyst. The reaction proceeded regioselectively and the Michael adducts – 1,3-diaryl-3-(4-aryl-2Н-1,2,3-triazol-2-yl)propan-1-ones 66 – were obtained in high yields.
Scheme 25
The complex cascade reaction of salicylhydrazones 69 with electron-deficient internal alkynes 70 was achieved in the absence of metal catalysts by using only DABCO and led to the formation of oxygen-bridged heterocyclic products – 2,6-epoxy-1,5-benzoxazocines 71 (Scheme 26).27
Scheme 26
The developed method includes the generation of o-quinoidal intermediate I, an aza-Michael addition, stereoselective protonation, aromatization with the participation of enamine moiety, the formation of acetal and cyclic hemiaminal 71 (Scheme 27).
Scheme 27
An effective, universal method for the synthesis of 4-methylthiazol-2(3Н)-ylideneamides 72 in good yields from various acylated thiourea derivatives 73 and propargyl bromide also includes a sequence of alkylation and cyclization according to the aza-Michael reaction mechanism in the presence of DABCO in refluxing EtOH (Scheme 28).28
Scheme 28
The interaction of 2-[(1-(benzofuran-2-yl)ethylidene]-hydrazinecarbothioamide (74) with arylidenemalononitriles 22 and hydrazonoyl halides 75 in the presence of DABCO led to the formation of 1,3-thiazines 76 and thiazoles 77 containing benzofuran ring systems in their molecules (Scheme 29). The reaction between thioamide 74 and malononitrile derivative 22 proceeded as a conjugated Michael addition, while the reaction of thioamide 74 with hydrazonoyl halide 75 followed an addition–elimination mechanism.29
Scheme 29
An effective strategy has been described for the preparation of substituted acyl hydrazides through the reactions of various hydrazides with α,β-unsaturated esters in the presence of DABCO as an affordable base for deprotonating the hydrazide and tetrabutylammonium bromide (ТВАВ) as organic salt under solvent-free conditions. When acrylates were used as Michael acceptors, double addition products 78 were formed in good yields (Scheme 30), while fumarate esters unexpectedly gave only monoadducts 79.30
Scheme 30
The interaction of 4-phenylurazole (80) with fumarate ester 81 led to the substituted hydantoin alkylidene derivatives 82 (Scheme 31).31 The reaction proceeded in the presence of ТВАВ and DABCO without solvents at 70°С. The first step of this cascade process was an aza-Michael reaction, which was catalyzed by DABCO.
Scheme 31
The reaction was initiated by deprotonation of urazole 80 in the presence of DABCO, leading to the formation of anionic intermediate A, which underwent a Michael addition to fumarate ester 81 with the formation of adduct B (Scheme 32). This adduct in the presence of DABCO was capable of transformation into anionic intermediate C. The urazole ring opening in this intermediate led to compound D, which was hydrolyzed by the liberated water and then decarboxylated with the formation of compound E. The elimination of an ammonia molecule led to compound F, which was converted to alkyl (Z)-(2,5-dioxo-1-phenylimidazolidin-4-ylidene)acetate 82.
Scheme 32
The aza-Michael reaction of 4-aryl-1Н-1,2,3-triazoles 83 and 2-cyclohex-2-en-1-ones (84) in MeCN at room temperature in the presence of DABCO as organic base led to a mixture of 1,4- and 1,5-disubstituted triazoles 85a,b, with the former identified as the major component (Scheme 33).32 The isomers could be separated chromatographically. Substituents of any electronic nature were found to be compatible with the reaction conditions.
Scheme 33
The Michael addition of lactams, imides, (S)-4-benzyl-1,3-oxazolidin-2-one, 2-pyridone, pyrimidine-2,4-dione, or inosines at the electron-deficient triple bond of methyl propionate, tert-butyl propionate, 3-butyn-2-one, N-methoxy-N-methylpropynamide in the presence of DABCO gave a superior outcome (faster reaction rate, higher E/Z ratio) compared to the other catalysts, for example, DMAP, while RuCl3, RuClCp*(PPh3)2, AuСl, AuCl(PPh3), CuI, and Cu2(OTf) failed to catalyze this process (Scheme 34).33 DABCO was capable of nucleophilic addition to the triple bond, forming an activated allene system, as well as generating N-anions from the starting materials.
Scheme 34
A [3+2] cycloaddition reaction of azomethine imines 86 to maleimide 87 was achieved in the presence of DABCO as catalyst, providing access to fused heterocyclic compounds 88 containing two nitrogen atoms, while providing a high degree of diastereoselectivity (dr up to 25:1) and good yields (76–98%) (Scheme 35).34 The process was initiated by a reaction of the catalyst with N-arylmaleimide 87 with the formation of zwitterionic intermediate А, which then added to the azomethine imine (giving intermediate В). The elimination of a catalyst molecule provided intermediate С, which was converted to the target compound by an intramolecular aza-Michael reaction.
Scheme 35
Scheme 36
A new, convenient synthesis of 2-aryl-2,3-dihydroquinolin-4(1Н)-ones 89 was based on the intramolecular cyclization of 2-aminochalcones 90 (aza-Michael reaction), catalyzed by a novel catalyst on the basis of DABCO – [C8dabco]Br.35 The remarkable advantages of this procedure included the potential for catalyst recovery, high yields, straightforward workup of the reaction mixture, and good atom economy.
At least equally promising was the addition of О-nucleophiles to Michael acceptors in the presence of DABCO as catalyst, including applications for the synthesis of oxygencontaining heterocycles. For example, a convenient general procedure is known for the synthesis of β-alkoxyacrylates 91 from primary, secondary, and tertiary alcohols by using an oxa-Michael reaction in the presence of tertiary amines as catalysts (Scheme 37).36 Among the examined basic catalysts, DABCO showed the best results. Correct selection of the reaction conditions enabled the conversion of primary and secondary alcohols, as well as a large set of tertiary alcohols into the respective β-alkoxyacrylate derivatives. The different reactivity of alcohols provided an opportunity for selective transformations of diols containing two different hydroxy groups.
Scheme 37
The Michael addition of phenols and alcohols to ethyl 2,3-butadienecarboxylate (allenoate) in the presence of DABCO as catalyst also provided synthetic access to (Е)-β-aryloxy- and (Е)-β-alkoxyacrylates (Scheme 38).37 The notable advantages of this method included the great molecular diversity of substrates, mild reaction conditions, high E-selectivity (>99:1), and good yields.
Scheme 38
The intramolecular cyclization of enols and nitrostyrenes in the presence of DABCO as catalyst proceeded regioselectively, giving high yields of the fused coumarin derivatives 92 after the elimination of nitro group (Scheme 39).38a The method was applicable to various enol derivatives, including 4-hydroxyquinolinones, 4-hydroxycoumarins, and 4-hydroxypyranones. Coumarins, which are analogs of compounds 92, are of interest for potential applications in fluorescent probes.38b
Scheme 39
DABCO as catalyst also promoted the reaction of propargylic alcohols 93 with methyl 2-trifluoroalkynylcarboxylate (94), leading to the formation of trifluoromethylated furans 95 under mild conditions in up to 98% yields (Scheme 40).39 Control experiments showed that the reaction proceeded via Michael addition with the formation of the respective vinyl esters, a Claisen rearrangement, and cyclization.
Scheme 40
A domino reaction of 3-oxo-4-(2-oxindolyl-3-ylidene)-butanoates 96 and allenoates 41 occurred in the presence of DABCO as catalyst and gave good yields of 2,3,5-substituted tetrahydrofuran derivatives 97 containing an oxindole substituent and two exocyclic double bonds (Scheme 41).40 One of the steps in this complex process was an oxo-Michael reaction.
Scheme 41
The reaction of 1,3-nitroenynes 98 with 4-hydroxy-6-methyl-2-pyrones 99 in the presence of the chiral catalyst 100 led to the formation of annulated pyrans 101 in high yields (up to 88%) and excellent stereoselectivity (dr >20:1 and ee >99%) (Scheme 42).41 The reaction proceeded through a sequence of conjugated addition, allene formation, stereoselective intramolecular oxo-Michael reaction (6-endo-dig cyclization), and alkene isomerization in the presence of DABCO as catalyst. The analogous transformation in the presence of DABCO instead of specialized organocatalyst also allowed to obtain pyrano-[3,2-c]chromenes with excellent stereoselectivity (Z- and E-isomer ratio up to >96:4) and good yields (72–89%).42
Scheme 42
Terminal alkynes containing an ester or amide group (Michael acceptors 102) reacted regioselectively with salicylic aldehyde 103 in the presence of DABCO in aqueous dioxane medium, forming 3-substituted 4-hydroxy-4Н-chromenes 104 (Scheme 43).43 The reaction comprised deprotonation of salicylic aldehyde in the presence of DABCO, a Michael addition of phenolate anion to the triple bond, an intramolecular aldol condensation, and deprotonation.
Scheme 43
The stereoselective formal [4+2] annulation of fully substituted alkenes with allenoates in the presence of DABCO, which led to smooth formation of functionalized 4Н-pyran derivatives, represented a cascade of carbo- and oxo-Michael reactions.44,45 The addition of DABCO to allenoate 41а at the β-position generated the active stabilized zwitterion 105, which added to alkene molecule according to the carbo-Michael mechanism, leading to the formation of intermediate 106, which underwent further intramolecular cyclization via the addition of enolate anion at the double bond (Scheme 44).44
Scheme 44
An environmentally benign, simple, and effective method for the synthesis of ethyl 3-amino-1-aryl-1Н-benzo-[f]chromene-2-carboxylates 107 consists of a reaction between β-naphthol (108) and 3-arylcyanoacrylates 109 in aqueous medium in the presence of DABCO as catalyst (Scheme 45).46 All of the reaction products precipitated from the reaction mixture and were isolated by simple filtration, without need for further purification.
Scheme 45
Tetrahydro-1,3-benzoxazolones 113a,b were synthesized stereoselectively from p-quinol 114via a reaction with tosylaldimine 115 under the conditions of basic catalysis (Scheme 46).47 It is important to note that after changing the solvent to THF the reaction proceeded toward the formation of tricyclic product through the addition of another molecule of tosylaldimine 115 to tetrahydro-1,3-benzoxazolone 113. The process consisted of an experimentally straightforward domino sequence of oxaand aza-Michael reactions.
Scheme 46
A one-pot methodology has been described, starting from 1,5-benzodiazepine amidoximes 117a,b that were obtained from nitrile derivatives 116a,b, enabling the synthesis of new pyrimidine derivatives 118a,b in the presence of DABCO as catalyst under the conditions of microwave irradiation, which were then characterized with respect to their antimicrobial properties (Scheme 47).48
Scheme 47
The mechanism for the formation of pyrimidine ring can be interpreted according to this route: an oxa-Michael reaction is followed by a rearrangement of the N-adduct and then a cyclization step (Scheme 48).
Scheme 48
S-Nucleophiles also actively participated in the addition to activated multiple bonds. Thus, an effective diastereoselective [3+2] annulation of mercaptoacetaldehyde, obtained from 1,4-dithiane-2,5-diol (119) by the action of DABCO, with the trifluoromethyl-substituted styrylisoxazoles 120, also catalyzed by DABCO, led to the formation of functionalized tetrahydrothiophenes 121 containing a quaternary atom decorated with a trifluoromethyl group, resulting in excellent yields and diastereoselectivity (Scheme 49).49 The process consisted of a cascade of sulfo-Michael reaction and a Henry reaction.
Scheme 49
The selection of 1,3-enynes 122 as Michael acceptors for the reactions with mercaptoacetaldehyde, which was generated in situ from 1,4-dithiane-2,5-diol (119) in the presence of DABCO at room temperature, enabled the preparation of tetrasubstituted thiophenes 123 (Scheme 50).50 The domino process consisted of a Michael reaction, 5-exo-dig cyclization, and an oxidation step.
Scheme 50
The highly diastereoselective (dr >20:1) intermolecular [3+2] annulation reaction of 1,4-dithiane-2,5-diol (119) to maleimide 87 in the presence of DABCO as catalyst led to the formation of a series of polyfunctionalized bisheterocyclic tetrahydrothiophene and pyrrolidine derivatives 124 in up to 97% yields (Scheme 51).51 The sequence consisting of a Michael reaction and enol reaction can be performed in organic solvents, as well as in water.
Scheme 51
The mechanism of the domino reaction between 1,4-dithiane-2,5-diol (119) and azomethine imines 125, leading to the formation of 4-hydroxytetrahydropyrazolo[1,2-c]- [1,3,4]thiadiazin-6-ones 126 (Scheme 52), was studied by a computational approach using the B3LYP and МО6-2Х functionals (for the case of R1 = H, R2 = Ph).52 The most energetically favorable reaction pathway consisted of three steps: the deprotonation of mercaptoacetaldehyde by the action of DABCO, accompanied by the formation of thiolate anion, which then acted as a nucleophile by attacking azomethine imine 125, leading to intramolecular cyclization. It was noted that the reaction proceeded most effectively in the presence of DABCO and MeOH, while hydrogen bonds played a key role in the diastereoselectivity of this process.
Scheme 52
The products from the Michael addition of 2-mercaptobenzyl alcohol to nitroalkenes containing a carbohydrate moiety were used as starting materials for the synthesis of chiral 3-nitro-2Н-thiochromenes 127a,b (Scheme 53), which exhibited antioxidative and antiproliferative properties against human tumor cells.53
Scheme 53
The diastereoselective formation of spiro[pyrazole-3,3’-tetrahydrothiophene] 128 was achieved by a tandem Michael cyclization (Scheme 54).54 DABCO deprotonated mercaptoester 129, the obtained intermediate participated in intermolecular addition to the exocyclic double bond of pyrazolone 130, followed by the second, intramolecular Michael addition. The reaction was demonstrated using the example of ethyl trans-4-mercaptobutenoate (129) with various 4-benzylidene-5-methyl-2-phenylpyrazolones 130 in the presence of DABCO as catalyst in PhMe medium at 0°С. The process proceeded rapidly and led to the respective spiro derivatives 128 with excellent yields and diastereoselectivity (dr >20:1).
Scheme 54
An effective method was also developed for the synthesis of naphtho[2,3-b]thiophene-4,9-diones 131 by a three-component reaction of 1,4-naphthoquinone, various α,β-unsaturated ketones, and aqueous Na2S in the presence of DABCO as catalyst (Scheme 55).55 The process included a sequential Michael addition of Na2S to α,β-unsaturated ketones, the obtained sulfide adduct – to naphthoquinone, followed by intramolecular oxidative cyclization and aromatization.
Scheme 55
A simple and effective one-pot procedure for the synthesis of 2-aryl-3-nitro-2,9-dihydrothiopyrano[2,3-b]-indole derivatives 132, which are of interest to researchers in the field of medicinal chemistry,56a was performed in CH2Cl2 at room temparature by a sequence of threecomponent reactions between N-protected 2-chloro-3-formylindole 133, NaHS, and β-substituted nitroalkenes 134 or β-substituted nitrodienes, while using DABCO in the role of organocatalyst and performing dehydration in the presence of activated 4Å molecular sieves (Scheme 56).56b
Scheme 56
One of the key steps in this process was apparently a thio-Michael reaction, followed by a cyclization according to the Henry reaction. The synthesized compounds were fluorescent and showed a large positive Stokes shift (5632–6081 cm–1).
Analogous thiopyrano[2,3-b]indoles 135 were obtained in the reactions of β-acetoxyallenoates 136 with indoline-2-thione (137) by addition of DABCO and K2CO3, followed by intramolecular Friedel–Crafts reaction at position 3 of indole ring and the central atom of allene (Scheme 57).57 The proposed reaction mechanism is shown in Scheme 58.
Scheme 57
Scheme 58
In some cases, the Michael addition served as the initial step in very complex cascade transformations. For example, an effective and rapid synthesis of enamides 136 from alkenes 137, promoted by DABCO, proceeded through an unusual cascade of transformations, including an aza-Michael reaction, bromination, elimination, and a Morita–Baylis–Hillman-type reaction that concluded by the elimination of DABCO, resulting in regio- and stereoselective synthesis of enamides 136 (Scheme 59).58
Scheme 59
Biginelli reaction catalyzed by DABCO
While it appears quite logical that DABCO can serve as a good catalyst in traditionally base-catalyzed reactions, we consider it rather unexpected that DABCO has been employed also in well-known acid-catalyzed processes. Thus, for example, the classic variant of the Biginelli reaction represents a synthesis of tetrahydropyrimidines by an acid-catalyzed condensation of ureas, β-keto esters, and aldehydes.59 However, studies published in recent years have shown that this process can be successfully performed in the presence of Lewis base catalysts, such as DABCO.
Heterocyclic compounds containing a pyrimidine ring are of particular interest to researchers in the field of medicinal chemistry. Some of these compounds have been characterized with respect to antifungal, antibacterial, anticancer, and tuberculostatic activity. Due to these reasons, the Biginelli reaction has a great practical value. For example, a series of tetrahydropyrimidine derivatives 138 were synthesized on the basis of Biginelli reaction by using DABCO as a catalyst. Some of these products exhibited pronounced antibacterial activity (Scheme 60).60
Scheme 60
An effective, environmentally benign regio- and stereoselective method was also developed for the synthesis of 5-aroyl-1,3-dimethyl-7-thioxo-5,6,7,8-tetrahydro[4,5-d]pyrimidine-2,4-(1Н,3Н)-dione derivatives 139a and 5-aroyl-1,3-dimethyl-2,7-dithioxo-2,3,5,6,7,8-hexahydro[4,5-d]pyrimidin-4(1Н)-one derivatives 139b in good to excellent yields by a one-pot three-component Biginelli-type condensation between arylglyoxal monohydrates, N,N-di-methylbarbituric acid or N,N-dimethyl-2-thiobarbituric acid, and thiourea in H2O at 50°С in the presence of DABCO as a “green” catalyst (Scheme 61).61
Scheme 61
The reaction mechanism has been described in the literature:62 the anion of barbituric acid enol form, created by the action of DABCO, underwent a condensation step with glyoxal, leading to the formation of biselectrophilic intermediate А, which was cyclized by a reaction with the bisnucleophilic thiourea (Scheme 62).
Scheme 62
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This review article was prepared with financial support from the Russian Foundation for Basic Research (grant 18-33-01100).
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* For Communication 1, see1а.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, 2020, 56(2), 145–160
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Bugaenko, D.I., Karchava, A.V. & Yurovskaya, M.A. The versatility of DABCO: synthetic applications of its basic, nucleophilic, and catalytic properties Part 2*. Catalysis of Michael and Biginelli reactions and nucleophilic addition at C=X and C≡X bonds. Chem Heterocycl Comp 56, 145–160 (2020). https://doi.org/10.1007/s10593-020-02637-0
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DOI: https://doi.org/10.1007/s10593-020-02637-0