Baylis Hillman Adducts Research Articles

Synthesis, cytotoxicity, and antitubercular studies of novel thiophene containing 2-methyl-3-methyl/ethyl acrylates from Baylis–Hillman adducts

Herein, we describe the synthesis, cytotoxicity effect and antitubercular activity of thiophene containing Baylis–Hillman adducts (2a–l), Baylis–Hillman bromides (3a–l) and 2-methyl-3-methyl/ethyl acrylates (4a–l). Their structures were elucidated by elemental analysis, IR, 1H NMR, 13C NMR, and mass spectroscopic data. All the compounds were evaluated for their in vitro cytotoxicity effect using the MTT assay method against two human cancer cell lines (MCF-7 and K562). The compounds demonstrated a growth inhibitory effect on both the cell lines with significant IC50 values. Among the compounds synthesized, 3h and 4g showed excellent activities on both the cell lines, whereas the other compounds exhibited moderate activity. The antitubercular activity of the obtained compounds was tested against Mycobacterium tuberculosis H37Rv in vitro using the agar microdilution method. Sevenfold dilutions ranging between 0.65 and 50 μg/ml of each test compound were used to find out their minimum inhibitory concentration. Among the tested compounds, compound 3l showed almost equal activity with the standard drug Isoniazid (INH), whereas the rest of all compounds have shown less to moderate activity against Mycobacterium tuberculosis H37Rv.

Weak Coordination-Guided Regioselective Direct Redox-Neutral C4 Allylation of Indoles with Morita-Baylis-Hillman Adducts.

A weak carbonyl coordination-guided regioselective C4 allylation of indoles is demonstrated using the versatile Morita-Baylis-Hillman adduct in the presence of Rh catalysts in a redox-neutral fashion. The substrate scope, functional group diversity, oxidant free character, mechanistic aspects, and synthetic utilities are important practical features.

Asymmetric Synthesis of 2,3,6-Trisubstituted Piperidines via Baylis–Hillman Adducts and Lithium Amide through Domino Reaction

A convenient asymmetric synthesis of methyl (2S,3S,6R)-6-(4-fluorophenyl)-2-(4-hydroxyphenyl)-piperidine-3-carboxylate is described, starting from Baylis–Hillman adducts. The route involves a domino process: allylic acetate rearrangement, stereoselective Ireland–Claisen rearrangement and asymmetric Michael addition, which provides a δ-amino acid derivative with full stereochemical control. A subsequent chemoselective transformation of one of the side-chain groups allows an effective cyclization leading to biologically interesting polysubstituted piperidines in which the 2,6-aryl groups could be attached sequentially.

Nucleophilic Addition of Potassium O-Ethyl Dithiocarbonate to Baylis-Hillman Adducts Using 9-BBN as Catalyst

An efficient diastereoselective Michael addition of the commercial potassium O-ethyl dithiocarbonate to Baylis-Hillman adducts in the presence of 9-BBN (9-borabicyclo[3.3.1]nonane) as a Lewis acid is reported. 9-BBN both protected the hydroxyl group and activated the carbonyl of the Michael acceptor.

Diastereoselective peroxidation of derivatives of Baylis–Hillman adducts

Cyclic derivatives of Baylis–Hillman adducts were synthesized. Cobalt-catalyzed peroxidation of these cyclic lactones afforded silyl peroxides in diastereomeric ratios ranging from 91:9 to 97:3.

Asymmetric Allylic Amination of Morita–Baylis–Hillman Adducts with Simple Aromatic Amines by Nucleophilic Amine Catalysis

Asymmetric allylic amination of Morita–Baylis–Hillman (MBH) adducts with simple aromatic amines is successfully realized by nucleophilic amine catalysis. A range of substituted α-methylene-β-arylamino esters is accessed in moderate to high yields (up to 88%) and with excellent enantioselectivities (up to 97% ee). Inorganic fluorides are found to be able to improve the enantioselectivity of the allylic amination reaction. A pyrrole-2-carboxylate and a cyclic imide are also compatible with this catalytic system. A chiral 2,3-dihydroquinolin-4-one derivative is easily obtained from the allylic amination product.

Multicomponent domino protocol for the stereoselective synthesis of novel pyrrolo[3,2-c]quinolinone hybrid heterocycles

A series of structurally intriguing novel pyrrolo[3,2-c]quinolinone heterocyclic hybrids have been synthesized for the first time via a one-pot multicomponent domino reaction sequence that involves a 1,3-dipolar cycloaddition and two subsequent annulation steps. Baylis-Hillman adducts derived from various substituted benzaldehyde and methyl acrylate in presence of DABCO were used as a dipolarophiles, while the 1,3-dipole components were azomethine ylides, formed in situ from isatin derivatives and l-phenylalanine. The reaction generated five new bonds, three new rings and four contiguous stereocenters, which were created with full diastereomeric control.

Synthesis of chiral allene moiety from Morita–Baylis–Hillman adduct of isatin derivatives via Claisen rearrangement

Chiral allenes are synthesized from Morita–Baylis–Hillman adduct of isatin derivatives via Claisen rearrangement for the first time. The chiral 1,3-substituted allene entity is achieved using (R)-but-3-yn-2-ol. The details of the work are elaborately discussed in this letter.

Facile synthesis of biarylmethanes and tetrasubstituted arenes via a base-mediated [3 + 3] benzannulation reaction of Morita-Baylis-Hillman adducts and unsaturated sulfones.

A facile DBU-mediated [3 + 3] benzannulation reaction of 1,3-bis-sulfonyl propenes and Morita-Baylis-Hillman (MBH) bromides is described. The benzannulation reaction afforded bis-sulfonyl biarylmethanes/arenes with complete regioselectivity. The products may be converted readily into corresponding benzophenones via site-selective benzylic oxidation.

A simple and convenient synthesis of 3-salicyloylquinoline-4-carboxylic esters from chromone and isatin.

A simple and convenient synthesis of 3-salicyloylquinoline-4-carboxylic esters has been developed through an AlCl3-catalyzed reaction of easily available Baylis–Hillman adducts from chromones and isatin-derivatives. This reaction involves esterification, cyclization and ring opening in a one-step process, and provides an efficient approach for easy access to a series of valuable salicyloylquinoline derivatives with high yields. Moreover, this protocol offers several advantages, such as availability of starting materials, economic availability, operational simplicity and mild reaction conditions.

Unprecedented E-stereoselectivity on the sigmatropic Hurd-Claisen rearrangement of Morita-Baylis-Hillman adducts: a joint experimental-theoretical study.

Herein we report the first systematic investigation of the tandem mercury(ii) catalysed transvinylation/Hurd-Claisen rearrangement of MBH adducts derived from alkyl acrylates. This is the first report of E-selectivity for MBH adducts with alkyl side chains and is complementary to the previously reported Johnson-Claisen and Eschenmoser-Claisen rearrangements. The rearrangement products were obtained in good yields and could be readily converted to 2-alkenyl δ-valerolactones. Combined DFT and F-SAPT studies demonstrate that reaction rates are primarily governed by non-covalent interactions dictating the relative stability of the transition states. Our F-SAPT calculations revealed that the hyperconjugative effects are not so significant, but that electrostatic interactions, instead, are the driving forces for the relative E : Z stereoselectivity.

Diastereodivergent Synthesis of Pyrazoline Derivatives through [3 + 2] Cycloaddition of Baylis–Hillman Adducts and Nitrilimines

In this paper, a [3 + 2] cycloaddition of Baylis–Hillman adducts and nitrilimines has been achieved under mild reaction conditions, providing a concise approach to access biologically important pyrazoline derivatives.

Reactivity of Morita-Baylis-Hillman Adducts in C-H Functionalization of (Hetero)aryl Nitrones: Access to Bridged Cycles and Carbazoles.

The rhodium(III)-catalyzed cross-coupling of (hetero)aryl nitrones with Morita-Baylis-Hillman (MBH) adducts is described. An allylated intermediate derived from aryl nitrones and MBH adducts allows the formation of bridged cyclic compounds via an exotype [3 + 2] cycloaddition. In sharp contrast, electron-rich indolinyl or aniline substrates were found to couple with MBH adducts to generate naphthalene or carbazole derivatives, respectively.

Abstract 5523: Allele-specific restoration of biological function of the mutant p53 by Baylis-Hillman adducts

Abstract p53 is the most frequently mutated gene in human cancer, and the p53R175 mutant is the third most frequently found missense mutant that confers resistance to anticancer drugs and apoptosis. Therefore, small-molecule reactivation of mutant p53 function(s) represents an important and novel anticancer strategy. We have previously reported that induction of oxidative protein modifications primarily underlies the mechanistic conversion of mutant to wt or wt-like p53 forms (Eur J Medchem 107:233, 2016; Int J Oncol 48:1426, 2016). Here, we describe the identification of Baylis-Hillman (BH) adducts as potent and novel mutant p53 reactivators through cell-based, high-throughput small-molecule screening procedures. An extensive structure-activity relationship studies indicated that carbon-carbon double bond and the presence of an electron-withdrawing substituent at the aromatic ring were essential for the activity. Cell lines used in this study includes SKBR3, AU565 (p53R175H), MCF7 (p53 wt), MDA-MB-231 (p53del), MDA-MB-468 (p53R273H) and MCF10a normal breast epithelial cells. BH adducts displayed preferential cytotoxicity against cancer cells expressing the allele-specific R175H mutation (SKBR3 and AU565) in comparison with the wt p53 or p53-null cancer cell lines. Additionally, the BH adducts did not show significant cytotoxicity against normal cells (MCF10a). Further, we developed isogenic cell lines expressing the p53R175H in the p53-null H1299 lung cancer cells and evaluated their sensitivities towards BH adducts; these models again verified the greater drug efficacy. To prove the hypothesis the higher efficacy of BH adduct stems from the reactivation of mutant p53, the conformation-specific antibodies (Pab1620 for wt and Pab420 for mutant) were employed. Immunoprecipitation and immunostaining using confocal microscopy showed that BH adduct treatment of p53R175H cells resulted in a marked reciprocal loss of mutant protein and gradual increase of wt-like protein. EMSA revealed a time-dependent restoration of DNA-binding of the mutant p53, which was accompanied by a distinct upregulation of pro-apoptotic signaling pathways mediated by PUMA, Bax, p21cip1 and MDM2 proteins. A strong G2/M arrest and significant apoptosis were observed with BH adduct in a time and concentration-dependent manner. Other data showed that BH adduct restores the wt-structure and function by covalently binding with the mutant p53R175H. In conclusion, BH adduct is an attractive lead compound for further development because of its potent p53 reactivation of nonfunctional mutant protein (supported by CPRIT grants RP130266 and RP170207 to KSS). Citation Format: Surendra R. Punganuru, Viswanath Arutla, Hanumantha Rao Madala, Kalkunte S. Srivenugopal. Allele-specific restoration of biological function of the mutant p53 by Baylis-Hillman adducts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5523.

Baylis–Hillman Reaction Assisted by aliquat-336 and triphenylphosphine Under Ultrasound Radiation

The activation of Baylis–Hillman reaction by aliquat-336 and triphenylphosphine under ultrasound radiation is described. A significant improvement of the yield of Baylis–Hillman reaction was observed. We illustrate the effects of the solvent, the nature of the nucleophilic agent, the phase transfer catalyst and ultrasound, on the Baylis–Hillman reaction efficiency. The reaction examined involves methyl acrylate, which, in the presence of nucleophilic agent, forms a zwitterionic intermediate, which reacts with the aldehyde to subsequently give the product of the reaction. For all the aldehydes tested, it was found that ultrasound radiation in the presence of aliquat-336 could reduce the duration of the Baylis–Hillman reaction and improve the reaction efficiency. This method could be a clean, economical, efficient and safe technology in organic synthesis to prepare Baylis–Hillman adducts.

Evaluation of Some Salicylaldehyde-derived Baylis-Hillman Adducts and Coumarin Derivatives as Potential Antisickling Compounds

Abstract Some salicylaldehyde-derived Baylis-Hillman adducts and 3-(chloromethyl)coumarins have been synthesised and evaluated in vitro for their antisickling activities. The compounds were screened for inhibitory and reversal activity against mutated haemoglobin (HbSS) in red blood cells at four different concentrations (4 mg/mL, 2 mg/mL, 1 mg/mL and 0.5 mg/mL) as a measure of their antisickling potentials. Among the synthesized compounds, 6-chloro-3-(chloromethyl)coumarin 4d showed the highest inhibitory activity (83.75±1.90%), followed by 6-chlorocoumarin-3-methylsulfinic acid 5d (80.90 ±0.91%) and the least was tert-butyl-3-hydroxy- 3-(2-hydroxyphenyl)-2-methylenepropanoate 3a (33.33±1.86%). The results obtained from the reversal antisickling experiment showed that the percentage of sickle cells able to revert to the normal biconcave shape was dose dependent. Compound 5d had the highest reversal activity (66.49±1.39%) followed by 6-bromo-3- (chloromethyl)coumarin 4c (59.66±2.95) and 4d (55.50±1.95%) at 4 mg/mL. Compound 4c had higher reversal activity than the standard p-hydroxybenzoic acid at 2 mg/mL, 1 mg/mL and at 0.5 mg/mL. The 3-substituted coumarins 4a-d, and 5d had higher inhibitory antisickling activities than their Baylis-Hillman precursors 3a-d. Effect of 4a-d and 5d on the rate of polymerization of sickle cell heamoglobin was further studied spectrophotomerically using hemolysate of HbSS. The considerable inhibitory and reversal activities of these compounds make them good candidates for further antisickling studies.

Rhodium(II)-Catalyzed Reaction of 1-Tosyl-1,2,3-triazoles with Morita-Baylis-Hillman Adducts: Synthesis of 3,4-Fused Pyrroles.

A cascade reaction of rhodium azavinylcarbenes with Morita-Baylis-Hillman (MBH) adducts enables a novel synthetic approach to 3,4-fused pyrroles. The cascade reaction begins with the insertion of O-H bond into rhodium azavinylcarbenes, subsquent sigmatropic rearrangement provides substituted α,β-unsaturated cyclic ketone intermediates. Then the intramolecular aza Michael addition/oxidative aromatization sequence give rise to a wide range of 3,4-fused pyrroles in good yields, and with excellent functional group compatibility.

Fe(III)-Catalyzed Hydroallylation of Unactivated Alkenes with Morita-Baylis-Hillman Adducts.

An Fe(III)-catalyzed hydroallylation of unactivated alkenes with Morita-Baylis-Hillman adducts via an Fe-catalyzed process is described. A variety of alkenes, including mono-, di-, and trisubstituted alkenes, could all smoothly convert to structural diversified cinnamates in this protocol. Interestingly, when the hydroxyl-containing alkenes were used, various lactones could be rapidly assembled. Moreover, this protocol could be applied to late-stage functionalization of natural products.

Synthesis of Baylis-Hillman adduct under Microwave irradiation using Indium (III) trifluoromethane sulphonate catalyst

Synthesis of Baylis-Hillman adduct under Microwave irradiation using Indium (III) trifluoromethane sulphonate catalyst

Visible light catalyzed synthesis of quinolines from (aza)-Morita-Baylis-Hillman adducts.

A mild and efficient protocol for the synthesis of quinoline scaffolds from (aza)-MBH adducts under visible light catalysis has been established. The reaction involves visible light catalyzed generation of amidyl radicals from (aza)-MBH adducts followed by intramolecular radical cyclization. The reaction exhibits a wide substrate scope, good functional group tolerance and high regioselectivity. This is the first example of utilizing (aza)-MBH adducts for the generation of amidyl radicals and synthesizing aza-heterocycles under visible light photoredox catalyzed reaction conditions.