Microwave-assisted efficient and facile synthesis of tetramic acid derivatives via a one-pot post-Ugi cascade reaction

• Yong Li,
• Zheng Huang,
• Jia Xu,
• Yong Ding,
• Dian-Yong Tang,
• Jie Lei,
• Hong-yu Li,
• Zhong-Zhu Chen and
• Zhi-Gang Xu

Beilstein J. Org. Chem. 2020, 16, 663–669, doi:10.3762/bjoc.16.63

• University of Arts and Sciences, Chongqing 402160, China Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA 10.3762/bjoc.16.63 Abstract A facile microwave-assisted method for the synthesis of tetramic acid derivatives has been

• developed through an Ugi/Dieckmann cyclization strategy with DBU. This two-step one-pot procedure afforded the targeted tetramic acid analogues in good yields. With commercially available Ugi starting materials, microwave irradiation, a simple operation, excellent yields, and a broad scope, this reaction

• investigated the effect of different inorganic and organic bases (Table 1). It was interesting to note that all of the bases tested in the study afforded the desired enol tetramic acid derivative 7a after the reaction was heated under the microwave irradiation conditions. The ketone compound 6a could be the

A systematic review on silica-, carbon-, and magnetic materials-supported copper species as efficient heterogeneous nanocatalysts in “click” reactions

• Pezhman Shiri and
• Jasem Aboonajmi

Beilstein J. Org. Chem. 2020, 16, 551–586, doi:10.3762/bjoc.16.52

• condensation of phenylacetylene and 1‐azido‐4‐nitrobenzene on a 4 mmol scale in EtOH/H2O (1:1) using 5 mol % of 87 was performed. After completion of the reaction, the heterogeneous catalyst was centrifuged and washed with ethyl acetate/water. This nanocatalyst could be reused in up to ten cycles. A microwave

• , trimethylsilylacetylene (TMSA) was selected for coupling with aryl iodides in the presence of a catalytic amount of Pd–Cu/C and PPh3 using Et2NH as a base in methanol at 120 °C under microwave irradiation for 20 min. In the next step, the azide derivative was added to the reaction mixture. Finally, the reaction mixture

Aerobic synthesis of N-sulfonylamidines mediated by N-heterocyclic carbene copper(I) catalysts

• Faïma Lazreg,
• Marie Vasseur,
• Alexandra M. Z. Slawin and
• Catherine S. J. Cazin

Beilstein J. Org. Chem. 2020, 16, 482–491, doi:10.3762/bjoc.16.43

• , 58.39; H, 6.16; N, 6.08. 1-{2,6-(Diisopropyl)phenyl}-3-methyl-4-(4-tert-butylphenyl)-1,2,3-triazol-5-ylidene-(N,N’-bis{2,6-(diisopropyl)phenyl}imidazol-2-ylidene)copper(I) tetrafluoroborate, [Cu(IPr)(Triaz)]BF4 (5). In a glovebox, a microwave vial was charged with [Cu(Cl)(IPr)] (200.0 mg, 0.41 mmol

• ), NaOH (66.0 mg, 4 equiv, 1.64 mmol), Triaz.HBF4 (190.0 mg, 1 equiv, 0.41 mmol) and acetonitrile (2 mL). The reaction mixture was stirred during 2 h at 80 °C in a microwave. The solution was concentrated and diethyl ether (10 mL) was added. The precipitate was collected by filtration and washed with

• ). In a glovebox, a vial was charged with [Cu(Cl)(Triaz)] (150.0 mg, 0.32 mmol), NaOH (50 mg, 4 equiv, 1.28 mmol), Triaz.HBF4 (148 mg, 1 equiv, 0.32 mmol) and acetonitrile (2 mL). The reaction mixture was stirred during 2 h at 80 °C in a microwave. The solution was concentrated (0.5 mL) and diethyl

Architecture and synthesis of P,N-heterocyclic phosphine ligands

• Wisdom A. Munzeiwa,
• Bernard Omondi and
• Vincent O. Nyamori

Beilstein J. Org. Chem. 2020, 16, 362–383, doi:10.3762/bjoc.16.35

• bipyridyl- (6), quinolinyl- (7), phenanthrolinyl- (8) and terpyridinyl- (9) phosphine ligands (Figure 1) [60]. Trofimov et al. [61][62] reported on an alternative reaction pathway using microwave heating for the synthesis of tris(2-pyridyl)phosphine in which white and red phosphorus were used. On treating

• treated with triflic anhydride to afford the corresponding triflate 55. Microwave-assisted reduction of compound 55 with pyridinium chloride afforded the α-chloropyridine derivative 56, which was further catalytically dehalogenated with palladium on carbon and formic acid to generate the pyridine scaffold

Ultrasonic-assisted unusual four-component synthesis of 7-azolylamino-4,5,6,7-tetrahydroazolo[1,5-a]pyrimidines

• Yana I. Sakhno,
• Maryna V. Murlykina,
• Oleksandr I. Zbruyev,
• Anton V. Kozyryev,
• Svetlana V. Shishkina,
• Dmytro Sysoiev,
• Vladimir I. Musatov,
• Sergey M. Desenko and
• Valentyn A. Chebanov

Beilstein J. Org. Chem. 2020, 16, 281–289, doi:10.3762/bjoc.16.27

• such interactions can be tuned, for example, by application of a condition-based divergence strategy [25], which is based on the variation of solvents, catalysts, and activation methods [16][26][27][28][29]. Thus, using nonclassical activation methods such as ultrasonication and microwave irradiation

• applying different temperatures in the range of 0–110 °C (both with the help of conventional heating and microwave irradiation) and by using different solvents and catalysts, such as HOAc, DMSO, primary alcohols with and without the presence of HCl, Yb(OTf)3, or Et3N. In all these cases, mixtures of

Combination of multicomponent KA² and Pauson–Khand reactions: short synthesis of spirocyclic pyrrolocyclopentenones

• Riccardo Innocenti,
• Elena Lenci,
• Gloria Menchi and
• Andrea Trabocchi

Beilstein J. Org. Chem. 2020, 16, 200–211, doi:10.3762/bjoc.16.23

• following the reported method [48] employing copper catalysis, and tested on our starting material upon variation of copper salts, solvents and temperature, resulting in the neat reaction under CuI catalysis being optimal when carried out for 2 h at 100 °C under microwave irradiation (see Supporting

• -accessible chemical space. Experimental General procedure (A) for the KA2 coupling reaction. CuI (0.2 equiv) was added in a dry sealed vial for microwave synthesis under a nitrogen flow. Then, ketone (1 equiv), alkyne (1.2 equiv) and amine (1.2 equiv) were successively added under a nitrogen flow, and the

• mixture was heated under microwave irradiation to 100 °C for 2 h. Then, EtOAc was added and the organic phase was washed with 5% NH4OH (3 × 20 mL) and brine. The organic phase was dried with Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography using the

Efficient method for propargylation of aldehydes promoted by allenylboron compounds under microwave irradiation

• Jucleiton J. R. Freitas,
• Queila P. S. B. Freitas,
• Silvia R. C. P. Andrade,
• Juliano C. R. Freitas,
• Roberta A. Oliveira and
• Paulo H. Menezes

Beilstein J. Org. Chem. 2020, 16, 168–174, doi:10.3762/bjoc.16.19

• -560, Brazil Universidade Federal de Campina Grande, Centro de Educação e Saúde: Cuité, Paraíba, Brazil 10.3762/bjoc.16.19 Abstract The propargylation of aldehydes promoted by microwave irradiation using allenylboron compounds in a chemo- and regioselective way is described. The corresponding products

• were obtained in short reaction time, high yield and purity without the need of any solvent when allenylboronic acid pinacol ester was used, or using a minimal amount of acetone when potassium allenyltrifluoroborate was used. Keywords: boron compounds; microwave; propargylation; regioselectivity

• pharmaceutical synthesis [29]. Moreover, the removal of tributyltin residues from reaction mixtures is also a major issue. The use of microwave irradiation for the formation of new C–C bonds is nowadays widely used and offers several advantages such as the increment in the product yield, reduction of reaction

Microwave-assisted synthesis of 2-substituted 4,5,6,7-tetrahydro-1,3-thiazepines from 4-aminobutanol

• María C. Mollo,
• Natalia B. Kilimciler,
• Juan A. Bisceglia and
• Liliana R. Orelli

Beilstein J. Org. Chem. 2020, 16, 32–38, doi:10.3762/bjoc.16.5

• -substituted tetrahydro-1,3-thiazepines by MW-assisted cyclization of 4-thioamidobutanols is presented. The acyclic precursors were prepared in high overall yields by an expeditious three-step diacylation/thionation/deprotection sequence from 4-aminobutanol. Microwave-assisted ring closure of 4-thioamido

• seven- and even eight-membered 1,3-diheterocycles had already been achieved by our group using the PPA ester/MW system [48][50][52][53]. Considering the lack of efficient methods for 4,5,6,7-tetrahydro-1,3-thiazepines, we decided to explore their synthesis by microwave-assisted ring closure of N-(4

• literature. The method involves as the key step the microwave-assisted ring closure of thioamido alcohols promoted by PPSE, presumably via an intramolecular SN2-type displacement of the PPSE-activated OH group. The precursors were easily prepared in a three-step sequence from 4-aminobutanol in high overall

Functionalization of the imidazo[1,2-a]pyridine ring in α-phosphonoacrylates and α-phosphonopropionates via microwave-assisted Mizoroki–Heck reaction

• Damian Kusy,
• Agata Wojciechowska,
• Joanna Małolepsza and
• Katarzyna M. Błażewska

Beilstein J. Org. Chem. 2020, 16, 15–21, doi:10.3762/bjoc.16.3

• ]pyridine ring has been synthesized via the microwave-assisted Mizoroki–Heck reaction. The efficient modification of the imidazo[1,2-a]pyridine ring has been achieved as late-stage functionalization, enabling and accelerating the generation of a library of compounds from a common precursor. Keywords: α

• -phosphonoacrylates; α-phosphonopropionates; imidazo[1,2-a]pyridine; microwave-assisted reaction; Mizoroki–Heck reaction; Introduction In the last few decades, the Mizoroki–Heck reaction has become one of the main tools in organic synthesis. Its use for the functionalization of a wide range of compounds cannot be

• -bromoimidazo[1,2-a]pyridin-3-yl)-2-(diethoxyphosphoryl)acrylates 1, no desired product 3 was formed under standard heating conditions (Table 1, entry 1). Recently, multiple variants for the application of microwave heating for conducting Mizoroki–Heck reactions have been reported, including the use of

SnCl₄-catalyzed solvent-free acetolysis of 2,7-anhydrosialic acid derivatives

• Kesatebrhan Haile Asressu and
• Cheng-Chung Wang

Beilstein J. Org. Chem. 2019, 15, 2990–2999, doi:10.3762/bjoc.15.295

• have reported one-pot multienzyme synthetic protocols for 2,7-anhydro-Neu5Ac [17][18][19]. Our group has developed one-pot syntheses of several anhydro sugars via microwave (MW)-assisted intramolecular anomeric protection (iMAP) of silylated sugars as well as ring-opening protocols for their 1,6

Construction of trisubstituted chromone skeletons carrying electron-withdrawing groups via PhIO-mediated dehydrogenation and its application to the synthesis of frutinone A

• Qiao Li,
• Chen Zhuang,
• Donghua Wang,
• Wei Zhang,
• Rongxuan Jia,
• Fengxia Sun,
• Yilin Zhang and
• Yunfei Du

Beilstein J. Org. Chem. 2019, 15, 2958–2965, doi:10.3762/bjoc.15.291

• also be realized by DDQ-mediated dehydrogenation of chromanones under heating in dioxane (Scheme 1b) [3][59][60]. In 2005, Yang and co-workers reported that chromones could be formed by microwave irradiation of the corresponding chromanone reactants and N-bromosuccinimide (NBS) in the presence of a

Diversity-oriented synthesis of spirothiazolidinediones and their biological evaluation

• Sambasivarao Kotha,
• Gaddamedi Sreevani,
• Lilya U. Dzhemileva,
• Milyausha M. Yunusbaeva,
• Usein M. Dzhemilev and
• Vladimir A. D’yakonov

Beilstein J. Org. Chem. 2019, 15, 2774–2781, doi:10.3762/bjoc.15.269

• bromide (6a) in the presence of Mo(CO)6 in acetonitrile at 90 °C under microwave irradiation (MWI) conditions to give the co-trimerized spiro derivative 8a (Scheme 2). The free NH moiety of thiazolidinedione 3 was alkylated using alkyl or aryl halides in the presence of Et3N using DCM as solvent. To our

• 125 MHz spectrometers using tetramethylsilane (TMS) as an internal standard and chloroform-d as a solvent. High resolution mass spectrometry (HRMS) was performed using a Bruker (Maxis Impact) or a Micromass Q-ToF spectrometer. The melting points recorded are uncorrected. The microwave used here was a

• Discover® SP by CEM Corporation and all the microwave reactions were performed under the standard method, where time and temperature can be monitored manually. Cell culture: Cells (Jurkat, K562, U937) were purchased from the Russian Cell Culture Collection (Institute of Cytology of the Russian Academy of

Acid-catalyzed rearrangements in arenes: interconversions in the quaterphenyl series

• Sarah L. Skraba-Joiner,
• Carter J. Holt and
• Richard P. Johnson

Beilstein J. Org. Chem. 2019, 15, 2655–2663, doi:10.3762/bjoc.15.258

• microwave reactor for 30–60 min, with product formation assessed by high field NMR analysis. Under these reaction conditions, m,p'-quaterphenyl is the equilibrium product. This isomer is unchanged by the reaction conditions and all other quaterphenyl isomers rearrange to m,p' as the dominant or sole product

• . This supports thermodynamic control based on carbocation energies. Keywords: arenium ion; carbocation; density functional theory; microwave reaction; rearrangement; superacid; Introduction Carbocations are enigmatic reactive intermediates of enduring importance in chemistry. No other reactive species

• conducted in the capped tube of a microwave reactor. With this approach, we can safely and reproducibly heat reactions to ca. 170 °C, so far without incident. Other more complex rearrangements are easily observed. In the binaphthyl series 7–9, three sequential rearrangements occur at ambient temperature

Probing of local polarity in poly(methyl methacrylate) with the charge transfer transition in Nile red

• Aydan Yadigarli,
• Qimeng Song,
• Sergey I. Druzhinin and
• Holger Schönherr

Beilstein J. Org. Chem. 2019, 15, 2552–2562, doi:10.3762/bjoc.15.248

• get μe = 17 D for the charge transfer excited state of DMABN from the solvatochromic plot (Equation 1). The corresponding dipole moments were determined with cavity radius free techniques: μg = 6.60 D [39] by dielectric spectroscopy and μe = 17 D [65] by time-resolved microwave conductivity. For the

Combining the Ugi-azide multicomponent reaction and rhodium(III)-catalyzed annulation for the synthesis of tetrazole-isoquinolone/pyridone hybrids

• Gerardo M. Ojeda,
• Prabhat Ranjan,
• Pavel Fedoseev,
• Lisandra Amable,
• Upendra K. Sharma,
• Daniel G. Rivera and
• Erik V. Van der Eycken

Beilstein J. Org. Chem. 2019, 15, 2447–2457, doi:10.3762/bjoc.15.237

• Gerardo M. Ojeda Prabhat Ranjan Pavel Fedoseev Lisandra Amable Upendra K. Sharma Daniel G. Rivera Erik V. Van der Eycken Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC), Department of Chemistry, University of Leuven (KU Leuven), Celestijnenlaan 200F, B-3001 Leuven, Belgium Center for

• aldehydes were reacted in parallel with trimethylsilyl azide and tritylamine under microwave irradiation – followed by removal of the trityl group and acylation to afford the N-acylaminomethyltetrazoles 1a–s and 2a–l. The functionalized tetrazoles were obtained in moderate to excellent yields over three

Effect of ring size on photoisomerization properties of stiff stilbene macrocycles

• Sandra Olsson,
• Óscar Benito Pérez,
• Magnus Blom and
• Adolf Gogoll

Beilstein J. Org. Chem. 2019, 15, 2408–2418, doi:10.3762/bjoc.15.233

• well-established reactions (Scheme 2). The indanone is formed by intramolecular Friedel–Crafts acylation of 2 under microwave radiation as reported by Oliverio et al. [23]. The second step is the demethylation of indanone methyl ether 3 by aluminium trichloride in toluene at reflux [24]. Two indanone

• dichloromethane (DCM), ethyl acetate, pentane, tetrahydrofuran (THF) and toluene that were distilled before use. N,N-Dimethylformamide (DMF) was used as supplied (biotech. grade, ≥99.9%). Unless stated differently, all reactions were carried out under atmospheric pressure and with argon atmosphere. Microwave (MW

• ) heating was carried out in a Biotage+ Initiator microwave using 10–20 mL Biotech MW vials, applying MW irradiation at 2.45 GHz, with a power setting up to 40 W and an average pressure of 4–5 bar when DCM was the solvent and 90 W/1 bar when the solvent was DMF. Analytical TLC was performed using Merck

In water multicomponent synthesis of low-molecular-mass 4,7-dihydrotetrazolo[1,5-a]pyrimidines

• Irina G. Tkachenko,
• Sergey A. Komykhov,
• Vladimir I. Musatov,
• Svitlana V. Shishkina,
• Viktoriya V. Dyakonenko,
• Vladimir N. Shvets,
• Mikhail V. Diachkov,
• Valentyn A. Chebanov and
• Sergey M. Desenko

Beilstein J. Org. Chem. 2019, 15, 2390–2397, doi:10.3762/bjoc.15.231

• , Ukraine Bar-Ilan University Ramat Gan, 5290002, Israel 10.3762/bjoc.15.231 Abstract The three-component reaction of 5-aminotetrazole with aliphatic aldehydes (formaldehyde, acetaldehyde) and acetoacetic ester derivatives in water under microwave irradiation leads to the selective formation of 4,7

• in this case. The three-component reactions of 5-aminotetrazole (1) with aldehydes 7a,b (paraformaldehyde, acetaldehyde) and a set of acetoacetic ester derivatives 8a–d in water under microwave irradiation at 100 °C led to the formation of the corresponding 5,6,7-trisubstituted 4,7-dihydrotetrazolo

• product is the 5-hydroxy-containing tetrahydro derivative. In our experiments, the three-component reaction of amine 1 with aldehyde 7b and compound 13 in water under microwave irradiation afforded tetrahydro derivative 14 as a mixture of two stereoisomers. Inspection of the mixture by 1H NMR revealed

Recent advances in transition-metal-catalyzed incorporation of fluorine-containing groups

• Xiaowei Li,
• Xiaolin Shi,
• Xiangqian Li and
• Dayong Shi

Beilstein J. Org. Chem. 2019, 15, 2213–2270, doi:10.3762/bjoc.15.218

• transformation employed Pd2(dba)3/t-BuBrettPhos and CsF to convert aryl alcohols to aryl fluorides at 180 °C under microwave conditions (Scheme 14). The proposed catalytic cycle of this aryl fluorination is also shown. Only reductive elimination was investigated by Larhed, because this reaction step is crucial

Azologization and repurposing of a hetero-stilbene-based kinase inhibitor: towards the design of photoswitchable sirtuin inhibitors

• Christoph W. Grathwol,
• Nathalie Wössner,
• Sören Swyter,
• Adam C. Smith,
• Enrico Tapavicza,
• Robert K. Hofstetter,
• Anja Bodtke,
• Manfred Jung and
• Andreas Link

Beilstein J. Org. Chem. 2019, 15, 2170–2183, doi:10.3762/bjoc.15.214

• = quartet, m = multiplet and combinations thereof, br = broad. Infrared (IR) spectra were recorded on a Bruker Alpha FT-IR spectrometer equipped with a diamond ATR unit and are indicated in terms of absorbance frequency [cm−1]. Microwave synthesis was conducted in a Monowave 300 microwave synthesis reactor

• a microwave reaction vessel 3a (1.01 g, 5.00 mmol, 1.00 equiv) was mixed with styrene (651 mg, 6.25 mmol, 1.25 equiv), tris(o-tolyl)phosphine (61 mg, 0.20 mmol, 0.04 equiv), Pd2(dba)3 (92 mg, 0.10 mmol, 0.02 equiv) and NEt3 (863 ΜL, 0.63 g, 6.25 mmol, 1.25 equiv) and suspended in anhydrous DMF (6 mL

• ). The reaction was conducted at 120 °C for 40 min in a microwave reactor. After cooling to room temperature the mixture was taken up in EtOAc and filtered through a pad of Celite®. The filtrate was washed with water (3 × 30 mL) and sat. aq. NaCl solution (30 mL), dried over MgSO4 and concentrated under

Synthesis of 1-azaspiro[4.4]nonan-1-oxyls via intramolecular 1,3-dipolar cycloaddition

• Yulia V. Khoroshunova,
• Denis A. Morozov,
• Andrey I. Taratayko,
• Polina D. Gladkikh,
• Yuri I. Glazachev and
• Igor A. Kirilyuk

Beilstein J. Org. Chem. 2019, 15, 2036–2042, doi:10.3762/bjoc.15.200

• loss of a hydrogen atom is consistent with the susceptibility of 7c to oxidative decay (Scheme 3). Intramolecular cycloaddition of similar nitrones is known to lead to hexahydro-1H-cyclopenta[c]isoxazoles [6][12]. Indeed, heating of 7а–с at 145 °C in toluene for 30–60 min in a microwave oven produced

Archangelolide: A sesquiterpene lactone with immunobiological potential from Laserpitium archangelica

• Silvie Rimpelová,
• Michal Jurášek,
• Lucie Peterková,
• Jiří Bejček,
• Vojtěch Spiwok,
• Miloš Majdl,
• Michal Jirásko,
• Miloš Buděšínský,
• Juraj Harmatha,
• Eva Kmoníčková,
• Pavel Drašar and
• Tomáš Ruml

Beilstein J. Org. Chem. 2019, 15, 1933–1944, doi:10.3762/bjoc.15.189

• solution) and TBTA (3 mg, 5.6 µmol) were added. The mixture was placed into a microwave reactor and irradiated for 2 h at 70 °C. Then, the solvent was evaporated under reduced pressure and the residue was chromatographed (hexanes/AcOEt, 1:1). The obtained product 5 was re-chromatographed twice to obtain

Synthesis of a [6]rotaxane with singly threaded γ-cyclodextrins as a single stereoisomer

• Jason Yin Hei Man and
• Ho Yu Au-Yeung

Beilstein J. Org. Chem. 2019, 15, 1829–1837, doi:10.3762/bjoc.15.177

• first heated at 100 °C for 5 minutes in a microwave reactor to facilitate the dissolution of the CB[6] (Scheme 2). The solution was then added to a solution mixture of the biphenylene building block 1 and γ-CD at different ratios, and the mixture was heated at 60 °C overnight. The products were analyzed

Recent advances on the transition-metal-catalyzed synthesis of imidazopyridines: an updated coverage

• Gagandeep Kour Reen,
• Ashok Kumar and
• Pratibha Sharma

Beilstein J. Org. Chem. 2019, 15, 1612–1704, doi:10.3762/bjoc.15.165

• ]pyridines under microwave irradiation [115]. 1-Butyl-3-methylimidazolium tetrafluoroborate ([bmim]BF4) was used as ionic liquid for this three-component reaction of pyridine-2(1H)-one 70, acetophenone 71 and o-tosylhydroxylamine (72, Scheme 25). The reason behind the use of an ionic liquid as reaction

One-pot activation–alkynylation–cyclization synthesis of 1,5-diacyl-5-hydroxypyrazolines in a consecutive three-component fashion

• Christina Görgen,
• Katharina Boden,
• Guido J. Reiss,
• Walter Frank and
• Thomas J. J. Müller

Beilstein J. Org. Chem. 2019, 15, 1360–1370, doi:10.3762/bjoc.15.136

• -methoxyethanol not only gave high yields of 5b, but also proved to be practical with respect to work-up. Upon comparison between dielectric and conductive heating the reaction in the microwave cavity gave no detectable difference in reaction time and yield. All these optimized conditions were therefore directly

Mechanochemical Friedel–Crafts acylations

• Mateja Đud,
• Anamarija Briš,
• Iva Jušinski,
• Davor Gracin and
• Davor Margetić

Beilstein J. Org. Chem. 2019, 15, 1313–1320, doi:10.3762/bjoc.15.130

• mixture of 19 and 18 (3:2 ratio), accompanied with a small amount of 22. As a substitute for dianthracene 19, thermally more stable substrate, anthracene-N-methyl maleimide adduct 25 [54] was prepared by Diels–Alder reaction under high pressure conditions as well as by microwave-assisted reaction and