Catalysed Cyclocarbonylative Sonogashira Reaction as a
Valuable Route to Phthalans, Isochromanes and Isoindolines
Gianluigi Albano
[a]and Laura Antonella Aronica*
[a]Abstract: Oxygen and Nitrogen-heterocyclic compounds are found in a vast number of natural substrates and biologically active molecules. In particular, phthalan, isochroman and isoindoline scaffolds are present in many classes of products such as antimicotics, antibiotics, antioxidants, pigments and fluorophores. Therefore several procedure dedicated to the buiding of such heterocycles have been developed. In this review a detailed analysis of literature data regarding these nuclei is described. Particular attention has been devoted to their biological and chemical potentialities and a deep investigation on the most important synthetic methods is reported. Cyclocarbonylative Sonogashira reaction of suitable alcohols and amides has been especially considered, since it represents a valuable and atom economic route to construct alkylidene phthalans, isochromans and isoindolines.
Gianluigi Albano, born in Bari (Italy) in 1989, studied Chemistry at the University of Pisa (Italy), where he received his Master’s Degree in February 2015. In November 2015 he started his PhD studies at the same university, under the supervision of Prof. Lorenzo Di Bari and Dr. Laura Antonella Aronica. His main research topics are focused on the synthesis and characterization of chiral conjugated oligomers for innovative optoelectronic applications and on the development of new protocols for the synthesis of heterocyclic compounds through transition metals-promoted reactions.
Laura Antonella Aronica graduated cum laude in Chemistry in 1995 from the University of Pisa. In 1999 she obtained her Ph.D. in Chemical Sciences. During this period she spent six months as research assistant at University of Ottawa with Prof. Howard Alper. She is presently a researcher at the University of Pisa and her major research interests are concerned with organometallic chemistry directed towards organic synthesis and in particular with carbonylative cross coupling reactions and
their application to the synthesis of heterocyclic compounds.
1. Introduction
Oxygen and nitrogen-containing heterocycles are widespread in
nature and their applications in biologically active drugs, agrochemicals and functional materials are well known. So it is not surprising that among the top 25 best-selling pharmaceuticals from the year of 2015 there have been several small molecules with heterocycles moieties such as Sofosbuvir, a medication used for the treatment of hepatitis C, Rosuvastatin employed to treat high cholesterol and related conditions, Lenalidomide intended as treatment of multiple myeloma, Alpiprazole, an atypical antipsychotic, Ibrutinib, used to treat mantle cell lymphoma and chronic lymphocytic leukemia and Apixaban, an anticoagulant for venous thromboembolic events. As a consequence, the interest of the scientific community in developing efficient strategies for the synthesis of these systems has been enormous and a wide range of different methodologies have been described depending on the structure of the heterocyclic target.
In this review we have taken into account three different heterocycles scaffolds depicted in Figure 1: phthalans, isochromans and isoindolines. The literature regarding each nucleus and its derivatives has been examined and organized into the following sections: biologically active molecules, chemical reactivity of substrates and principal methods for the synthesis of the heterocycle derivatives with particular attention to the synthesis of alkylidene heterocycles via palladium catalysed cyclocarbonylative Sonogashira reactions.
Figure 1. Scaffolds of reviewed heterocycles.
2. Oxygen heterocycles
2.1. Phthalans
2.1.1. Applications, reactivity and general synthetic methods
The 1,3-dihydroisobenzofuran (better known as phthalan) moiety (Figure 2) has been found in a growing number of naturally occurring compounds.[1]
[a] Dipartimento di Chimica e Chimica Industriale University of Pisa
Via G. Moruzzi 13, 56124 Pisa, Italy Fax: (+)390502219260
E-mail: laura.antonella.aronica@unipi.it https://people.unipi.it/laura_antonella_aronica/home
Figure 2. 1,3-Dihydroisobenzofuran (phthalan) nucleus.
One of the most representative examples is pestacin (Figure 3, A), isolated in 2003 by Grant et al. from Pestalotiopsis microspora, with good antimycotic and antioxidant properties. [1i]
Many synthetic phthalans also revealed remarkable pharmacological activities:[2] citalopram (Figure 3, B), developed in 1989, is a selective serotonin re-uptake inhibitor (SSRI) used in the treatment of depressive syndromes and anxiety disorder.[2d]
Moreover, some of them have applications in the agrochemicals, colorants and perfumes industries.[3]
Figure 3. Chemical structure of selected bioactive phthalans: pestacin (A),
citalopram (B).
Exploiting the opening of heterocyclic ring and/or the reactivity of substituents in the benzylic position, 1,3-dihydroisobenzofurans are powerful building blocks for the synthesis of several class of compounds: phthalides[4], benzylic alcohols,[5] isochroman-3-ones[5]
and complex Diels-Alder cycloadducts.[6] In addition, alkylidenephthalans can give access to a variety of heterocycles, such as functionalized phenanthro[10,1-bc]furans,[7] isoquinolin-1(2H)-ones,[8] and pyrazoles[9] (Scheme 1).
Although many procedures for phthalans preparation have been developed,[10] including reduction of phthalides,[11] hydrogenation of isobenzofurans,[12] Garratt-Braverman cyclizations,[13]
oxa-Pictet-Spengler reactions[14] and cycloadditions (in particular
Diels-Alder[15] or [2+2+2] cyclotrimerization of alkynes[16]), the most common is based on cycloetherification of benzyl alcohols (or their derivatives) having an appropriate ortho-substituent: epoxides,[17] oxetanes,[18] quaternary ammonium salts,[19] benzyl halides or alcohols,[20] alkenes[21] and, in the specific case of 1-alkylidene-1,3-dihydroisobenzofurans synthesis, also 1,2,3-triazole rings[22] and alkyne groups.
The cyclisation of ortho-alkynyl O-benzyl-functionalized aromatics can be promoted by means of a base. Padwa et al. described 5-exo-dig cyclisation of 2-(arylethynyl)benzyl alcohols with different basic conditions.[23] Unwanted 6-endo-dig ring closure is actually due to a rearrangement of the initially formed alkylidenephthalans during acid work-up step (Scheme 2).
Interestingly, Larock et al. proposed the iodocyclization of 2-(1-alkynyl)benzylic alcohols with I2 and NaHCO3 as base: although
6-endo-dig cyclization mode is generally preferred, in the case of
tertiary alcohols only (Z)-alkylidenephthalan products were obtained, owing to the gem-dialkyl effect.[24]
.
Scheme 1. Main synthetic applications of phthalans and alkylidenephthalans.
Scheme 2. Base-promoted cycloetherification of 2-(arylethynyl)benzyl alcohols
proposed by Padwa et al.
Synthetic routes to 1-alkylidene-1,3-dihydroisobenzofurans based on
t-BuOK-promoted cycloetherification of o-alkynylbenzaldehydes[25]
or o-alkynylbenzyl alcohols[26] and similar fluoride-induced reaction of silyl-protected 2-ethynylbenzyl alcohols[27] were also reported
2.1.2. Synthesis of alkylidenephthalans by metal-catalysed 5-exo-dig cyclization of ortho-alkynyl aromatics
Metal-catalyzed cyclisation of ortho-alkynyl aromatics bearing a nucleophilic oxygen atom at the benzylic position is a more general approach to afford alkylidenephthalans.
A very intriguing synthetic methodology was proposed by Barrett et al.: alkaline earth bis(trimethylsilyl)amides [M[N(SiMe3)2]2]2 (M =
Ca, Sr, Ba) complexes were found to act as efficient precatalysts for stereoselective hydroalkoxylation/cyclisation of 2-alkynylbenzyl alcohols to yield corresponding (E)-alkylidenephthalans depicted in Scheme 3.[28]
Scheme 3. (E)-Alkylidenephthalans synthesis by alkaline earth metal-catalysed
hydroalkoxylation/cyclization of 2-alkynylbenzyl alcohols.
Rare earth-mediated intramolecular hydroalkoxylation of alkynyl alcohols was also investigated: lanthanide bis(trimethylsilyl)amides Ln[N(SiMe3)2]3 (Ln = La, Sm, Y, Lu) and their derivatives, in fact,
showed high activity and selectivity in the 5-exo-dig cyclization into 1-methylene-1,3-dihydrobenzofuran.[29] More recently, Marks et al. extended the same protocol to some organothorium complexes.[30] Although many examples of cycloetherification promoted by means of transition metals (including mercury,[31] platinum,[32] zinc,[33] gold[34] and rhodium[35]) were reported, most of them are based on copper or palladium catalysts.
During the development of a new protocol for Cu(I)-catalyzed cross-coupling of alkynes with aryl iodides, Lee et al. surprisingly obtained (Z)-alkylidenephthalans when phenylacetylene was treated with 2-iodobenzyl alcohols, using Cu2O and
4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (xantphos) as catalytic system (Scheme 4).[36]
Scheme 4. Cu2O-promoted synthesis of (Z)-Alkylidenephthalans discovered by Lee et al.
Moreover, copper(I) complexes bearing N-heterocyclic carbene ligands were found to be powerful catalysts in the intramolecular hydroalkoxylation of alkynols[37], while, Perumal et al. described a copper(II)-catalyzed synthesis of alkylidenephthalans by treatment of 2-alkynylbenzyl alcohols with Cu(OTf)2.[38]
Switching to palladium catalysis, Gabriele and coworkers reported the cycloisomerization of 2-alkynylbenzyl alcohols into corresponding (Z)-alkylidenephthalans and 1H-isochromenes by using PdI2 (1–2
mol%) as catalyst and KI (2 eq.) as additive.[39] Substrates bearing
alkyl-substituted triple bond gave preferentially 6-endo-dig ring closure, while benzyl alcohols (i.e. with an aryl-substituted triple bond) afforded 1,3-dihydroisobenzofurans as main product (Scheme 5).
Subsequently, they extended PdI2/KI catalytic system to the
oxidative carbonylation of benzyl alcohols, benzaldehydes and phenyl ketones ortho-alkynyl-substituted[40] which gave
1-(alkoxycarbonyl)methylene-1,3-dihydroisobenzofurans in good yields. More recently, the authors have exploited a similar protocol for (Z)-alkylidenephthalans synthesis from o-alkynyl aryloxiranes, through a nucleophilic ring opening–heterocyclization–oxidative carbonylation process.[41]
Scheme 5. Cyclization of 2-alkynylbenzyl alcohols into (Z)-alkylidenephthalans
and 1H-isochromenes by mean of PdI2/KI catalytic system.
Palladium species were also used for the 5-exo-dig cyclization of highly-functionalized 2-alkynylbenzyl alcohols, yielding structurally complex heterocycles such as(E)-3-(isobenzofuran-3(1H)-ylidene) indolin-2-ones[42] or
(E)-4-(isobenzofuran-1(3H)-ylidene)-1,2,3,4-tetrahydroisoquinolines.[43]
A different synthetic route to 1-alkylidene-1,3-dihydroisobenzofurans was proposed by Kwon’s group and consisted in a tandem Michael-Heck reaction of 2-iodobenzyl alcohols with electron-poor alkynes, giving a β-(o-iodobenzyloxy)acrylate intermediate which provides alkylidenephthalan product with good (Z)-stereoselectivity through intramolecular Heck coupling (Scheme 6).[44]
Scheme 6. Tandem Michael-Heck reaction of 2-iodobenzyl alcohols with
electron-poor alkynes proposed by Kwon’s group.
However, most of the Pd-catalyzed protocols for alkylidenephthalans synthesis involved a sequential Sonogashira coupling followed by 5-exo-dig cyclization. Abbiati et al. described the preparation of (Z)-1-alkylidene-3-methoxy-1,3-dihydroisobenzofurans in high yields (79-99%) by microwave-assisted treatment of o-bromobenzaldehydes and arylacetylenes with PdCl2(PPh3)2, CuI, t-BuOK as base and
CH3OH as both reactant and solvent (Scheme 7).[45]
Scheme 7. Synthesis of (Z)-1-alkylidene-3-methoxy-1,3-dihydroisobenzofurans
Kundu and Khan reported the reactions of 2-iodobenzyl alcohol with a slight excess of acetylenic carbinols: through a domino Sonogashira/5-exo-dig cyclization process, they obtained (E)-alkylidenephthalans as the only products (80-96% yields, Scheme 8).[46]
Scheme 8. Preparation of (E)-alkylidenephthalans by domino
Sonogashira/5-exo-dig cyclization of 20 with acetylenic carbinols.
A versatile protocol for tandem Sonogashira/hydroalkoxylation of functionalized 2-bromo- and 2-chlorobenzyl alcohols with several arylalkynes was developed by Buxaderas et al. [47] They obtained
(Z)-alkylidenephthalansin good yields(over 50%) but a central role in the optimization of experimental conditions is played by microwave irradiation. Very recently, Pd nanoparticles dispersed in a glycerol phase have found wide application in the multi-step synthesis of various heterocycles, including (Z)-alkylidenephthalans by reaction of ortho-iodobenzyl alcohols with phenylacetylene.[48]
Gundersen and co-workers[49] reported a very intriguing work: the
one-pot Sonogashira coupling/5-exo-dig cyclization reaction between 2-ethynylbenzyl alcohol which gave alkylidenephthalan mainly as the (E)-isomer. However, a very fast isomerization into the (Z)-isomer was found by acid-catalysed treatment (Scheme 9).
Scheme 9. One-pot Sonogashira cross-coupling/5-exo-dig cyclization between
2-ethynylbenzyl alcohol and 6-iodopurine reported by Gundersen and co-workers.
2.1.3. Synthesis of alkylidenephthalans via Palladium-catalysed cyclocarbonylative Sonogashira reaction
The first example of alkylidenephthalans synthesis promoted by palladium-catalyzed cyclocarbonylative Sonogashira reaction of
o-ethynylbenzyl alcohols and aryl iodides has been recently reported by Aronica et al.[50]
First of all, commercially available 2-ethynylbenzyl alcohol was tested with iodobenzene. The reaction was performed at 100 °C under CO pressure with PdCl2(PPh3)2 as catalyst and Et3N as both
solvent and base (Scheme 10).
Scheme 10. Synthesis of 1-carbonylmethylene-1,3-dihydroisobenzofuran by
Pd-catalyzed cyclocarbonylative Sonogashira reaction.
After 24 h, it gave 1-carbonylmethylene-1,3-dihydroisobenzofuran as mixture of both stereoisomers (Z) and (E). Surprisingly, the Z/E ratio changed after chromatographic separation, passing from 63:37 (crude) to 68:25 (pure): this suggested an isomerization of (E)- into (Z)-phthalan during the purification, probably due to the presence of acid traces in SiO2 used as stationary phase
(Scheme 11).
Scheme 11. Interconversion between (E)/(Z) stereoisomers
The reaction mechanism proposed by Aronica and coworkers the authors involved, first of all, a Pd-catalyzed carbonylative Sonogashira coupling between the alkynyl group and the aryl iodide (Scheme 12, step I), followed by the insertion of Pd(0) into the O-H bond of the Sonogashira product (Scheme 12, step II). Then, the obtained palladium hydride species gave syn hydropalladation to the triple bond (Scheme 12, step III). Finally, a reductive elimination step afforded the (E)-isomer of phthalan product (Scheme 11, step IV), which equilibrated with the (Z)-isomer (Scheme 12, step V).
The reaction scope has been investigated and the most interesting results are described in Table 1. The protocol has been successfully extended to aryl iodides bearing electron-donating or electron-withdrawing substituents in the ortho and para position (Table 1). In almost all cases alkylidenephthalans were obtained quantitatively except for the reactions performed with o- and p-cianoaryl iodides, where significant amount of carbonylative Sonogashira products were also found (Table 1, entries 8-9).
Scheme 12. Hypothetical mechanism for cyclocarbonylative Sonogashira reaction
of ortho-ethynylbenzyl alcohols with aryl iodides.
Table 1. Cyclocarbonylative Sonogashira reaction of ortho-ethynylbenzyl
alcohols with aryl iodides.
Entry R Ar Yield (%) (after purification) Z E 1 H Ph 63 (68) 37 (25) 2 H 1-naph 86 (87) 14 (10) 3 H 4-MeOC6H4 75 (83) 25 (14) 4 H 2-MeOC6H4 81 (81) 19 (14) 5 H 4-MeC6H4 59 (60) 41 (33) 6 H 2-MeC6H4 71 (72) 29 (27) 7 H 4-ClC6H4 61 (51) 39 (11) 8 H 2-NCC6H4 83 (69) - 9 H 4-NCC6H4 50 (33) 25 (13) 10 t-Bu Ph 22 (15) 78 (57) 11 t-Bu 2-MeOC6H4 44 (32) 56 (35)
According to the proposed mechanism, Aronica et al. the authors[50] justify this result considering that the presence of a strong electron-withdrawing –C≡N group can reduced the electron density on triple bond of Sonogashira coupling products, thus slowing the syn hydropalladation step (Scheme 12, step III). As it is clear from Table 1, when 2-ethynylbenzyl alcohol was used the reaction proceeded with good stereoselectivity toward the (Z)-isomer (Table 1, entries 1-9), while when tert-butylalcohol derivative was employed, the major isomer resulted to have (E) configuration (Table 1, entries 10-11). This unexpected result has been explained with the reduction of the global rate of the
catalytic cycle due to the steric hindrance of the alcohol, resulting in a lower conversion of the (E)-isomer into (Z)-isomer (Scheme 12, step V).
Finally, a curious behaviour for the reaction of 2-ethynylbenzyl alcohol with 1-iodo-4-nitrobenzene has been described: in addition to the expected phthalan, almost equal amounts of aminoderivative were obtained (Scheme 13). Its formation could derive from the reduction of –NO2 into –NH2 due to the presence of
Pd-hydride species in the catalytic cycle (Scheme 12, step II).
Scheme 13 Palladium catalysed cyclorcarbonylative Sonogashira reaction of
2-ethynylbenzyl alcohol and 1-iodo-4-nitrobenzene.
2.2. Isochromans
2.2.1. Biological properties, chemical reactivity and common synthetic methods
The 3,4-dihydro-1H-benzo[c]pyran (isochroman, Figure 4) nucleus constitutes the framework of a wide range of naturally occurring molecules. Its derivatives have been found in olive oil,[51] pine wood,[52] herbs,[53] flowers[54] and fungi.[55] Many of them show antimicrobial and antifulgal activities,[56] possess antioxidant power,[57] exhibit antiplatelet,[58] antitumoral[59],[55g] and anti-inflammatory[60] properties.
Figure 4. Isochroman structure.
Furthermore, some synthetic 1-aryl-dihydroxyisochromans (Figure 5, A) display radical scavenger capacity[61],
pseudoflectusin[62] (Figure 5, B) shows cytotoxicity against several human cancer cell lines, polysubstituted isochroman derivatives[63] (Figure 5, C) exhibit growth regulating properties on wheat and Galaxolide[64] (Figure 5, D) is one of the most used musk fragrance present in many products including surface cleaners, laundry products, air fresheners, cosmetics and perfumes.
Beyond its biological properties and industrial application, isochroman represents an important building block for the construction of several polyfunctionalised molecules.
Figure 5. Interesting synthetic isochromans.
Indeed, isochroman can be easily submitted to oxidation affording isochromanone by means of CrO2, ammonium salts or
molecular oxygen catalysed by ferric complexes or by TEMPO derivatives[65],[4d] (Scheme 14, a).
Moreover C-C bond formation at C(1) position of isochroman has been widely studied. This transformation is commonly performed through the so-called cross-dehydrogenative coupling (CDC) reaction[66] which generally requires catalysts such as
copper and iron salts, oxidants such as hydrogen peroxide, O2,
tert-butylhydroperoxide (TBHP) or 2,3-dichloro-5,6-dicianobenzoquinone (DDQ) and carbon nucleophiles. For instance, Muramatsu et al.[67] reported several examples of arylation of the benzylic position of isochromans performed with Grignard reagents and DDQ or 2-hydroxy-2-azaadamantane (AZADOL) as oxydants, while Todd and co-workers[68] described efficient C-C(1) bond formation between isochroman and anisoles in the presence of DDQ and CuCl2 (Scheme 14, b).
Recently, successful heteroarylation with indole derivatives have been described by Cai et al.[69] using di-tert-butylperoxide (DTBP) as the oxidant (Scheme 14, c).
Ketones and malonates (Scheme 14, d) have been introduced by Li and co-workers[70] in the C(1) position of isochroman ring employing molecular oxygen or DDQ in the presence of indium or copper salts. Two similar approaches were developed by Mancheno et al.[71] using Cu(OTf)2 as catalyst and
2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) oxoammonium salt as the oxidant and by Lou et al.[72] using MnO2 and methanesulfonic
acid as oxidation system under aerobic conditions. Very recently, Huo and co-workers[73] reported the CBr4 mediated
dehydrogenative coupling of isochromans with aromatic ketones, while Wo et al.[74] demonstrated that the nucleophilic addition of β-keto esters to isochroman can be achieved by photoredox-neutral catalysis using a commercial dyad photosensitizer. Analogously thioethers[75] and ciano groups[76] can be introduced in the C(1) position via a CDC strategy using DTBP or DDQ as oxidant (Scheme 14, e). Amination and amidation[77] of
isochroman can be obtained with FeCl3/TBHP or under
metal-free conditions in the presence of DTBP (Scheme 14, f).
Scheme 14. Reactivity of isochromans.
Watson[78] and Huang[79] reported that alkenylation or alkynylation of isochroman can be achieved starting from its acetal via iron or copper-catalysed cross-dehydrogenative couplings (Scheme 14, g). On the other hand 1-chloroisochroman can be alkylated when reacted with silyl ketene acetals in the presence of thiourea,[80] pyridinium[81] or polyfluoro[82] organocatalysts (Scheme 14, h).
Finally, isochroman can be submitted to reductive[83] or oxidative[84] ring-opening giving rise to intermediates useful for the building of several polyfunctionalised compounds.
Numerous synthetic routes for the formation of the isochroman skeleton are described in the literature. Many of them are based on the oxa-Pictet-Spengler reaction[85] which consists of the condensation of a β-arylethanol derivative with a carbonyl compound to form a hemiacetal which undergoes cyclization to give the isochroman ring (Scheme 15).
Scheme 15. Oxa-Pictet-Spengler synthesis of isochromans.
Depending on the nature of the starting β-arylethanols and carbonyl components (aldehydes, ketones, and their surrogates such as acetals) this condensation can be used to provide 1-substituted and 1,1-di1-substituted isochromans as well as poly-functionalized derivatives in C-3 and C-4 positions.
The reaction is generally promoted by acid catalysts that should increase the electrophilic behavior of the carbonyl compounds. Typically, H2SO4, HCl, TFA, perfluorooctanesulfonic acid,
p-TsOH, CH3COOH, oleic acid, BF3.Et2O, AlCl3, TiCl4, ZnCl2,
SnCl4, are used, but also zeolites, bismuth triflate and
trimethylsilyltriflate have been shown to be effective.[14a],[57a],[86]
Although many reports of oxa-Pictet-Spengler reaction are described in the literature, many of them suffer from drawbacks such as harsh reaction conditions, substrate specificity and use of highly toxic reagents.
Two different approach were developed by Florio et al.[87] and are based on the cyclization of ortho-hydroxyalkylated aziridenes and on the reaction of arylepoxides with enaminones. Analogously, Kobayashi and coworkers[88] employed epoxides
for the synthesis of 1-(2-vinylphenyl)propan-2-ols which were then converted into the corresponding isochromans by treatment with HI in acetonitrile. Finally, Temperini et al.[89] reported a selenium-mediated strategy for the stereoselective preparation of 1- and 4-substituted isochromans.
2.2.2. Palladium catalysed synthesis of alkylideneisochromans via cyclocarbonylative Sonogashira reaction
The synthesis of isochromans has also been accomplished via palladium catalysed cyclisation reactions of suitable substrates (Scheme 16). White and coworkers[90] used benzyl alcohols
(Scheme 16, a) and a Pd(II)/bis-sulfoxide catalyst to obtain 3-vinylisochroman derivatives in good yields (65-76%). Later on the same group reported[91] the synthesis of 1-functionalised isochromans promoted by Pd(OAc)2 and a sulfoxide-based
ligand (Scheme 16, b). Han et al.[92] described the first palladium-catalysed heteroannulation of 1,3-dienes and 2-iodobenzylic alcohol; this protocol provides an efficient way to optically active chiral isochromans (Scheme 16, c).
In 2011 Perumal groups[93] reported the first detailed study on
the synthesis of 4-arylmethyleneisochromans (Scheme 16, d) starting from (2-bromobenzyloxy)prop-1-ynyl-4-methylbenzene derivatives promoted by Pd(PPh3)4. This cyclisation reaction
occurs with high regio- and stereoselectivity leading to one isomer in high yields.
Scheme 16. Palladium catalysed synthesis of isochromans.
1-Methylene-functionalised isochromans were obtained also by Yu and coworkers[94] through a Pd(II) catalysed hydroxyl-directed C-H olefination of homobenzylic alcohols (Scheme 16, e). Also in this case, the cyclisation process took place with complete stereoselectivity affording the E-isochroman derivatives exclusively.
As already discussed (see section 2.1.3) Sonogashira cyclocarbonylative reaction demonstrated to be a valuable route for the synthesis of carbonylmethylene-1,3-dihydrobenzofurans from 2-ethynylbenzyl alcohols and aryl iodides. Aronica et al. applied this methodology to the preparation of alkylideneisochromans.[95]
The starting material, 2-(2-ethynylphenyl)ethanol was easily generated through a synthetic sequence which involved: i) reduction of 2-iodophenylacetic acid to the corresponding benzyl alcohol; ii) cross coupling reaction with trimethylsilylacetylene and iii) final desilylation with TBAF.
At the beginning of their study, Aronica and co-workers performed a cyclocarbonylative Sonogashira reaction using 2-(2-ethynylphenyl)ethanol with iodobenzene under the experimental conditions optimized for dihydrobenzofurans. (Scheme 17).
Scheme 17. Preliminary carbonylative reaction between
2-(2-ethynylphenyl)ethanol and iodobenzene.
After 24 h, the complete conversion of the reagents was reported and the formation of 2-(isochroman-1-yliden)-1-phenyletanone as principal product was observed. The reaction resulted completely stereoselective since the exclusive synthesis of the Z isomer with two double bonds in an s-cis geometry was detected (Scheme 17).
In agreement with Baldwin’s rules,[96] only the 6-membered isochroman ring was generated (6-exo-dig cyclisation) while no traces of the possible tetrahydrobenzoxepine derivative were detected. Nevertheless, together with the methyleneisochroman derivative, a small amount of an opened by-product was isolated. It resulted to be 3-(2-(2-phenoxyethyl)phenyl)-1-phenyl-2-yn-1-one, shown in Figure 6.
The formation of both products was explained with the proposed mechanism (Scheme 18) which involved, first of all, the Sonogashira carbonylative reaction between iodobenzene and ethynyl alcohol that should form 3-(2-(2-hydroxyethyl)phenyl)-1-phenylprop-2-yn-1-one as intermediate of both products. At this point, Pd(0) insertion into the O-H bond would generate the palladium hydride specie I which can undergo two different transformations: i) hydropalladation reaction to the triple bond (Scheme 18, II) followed by reductive elimination which should afford isochroman; ii) a direct insertion of palladium into the C-I bond of iodobenzene (Scheme 5, III) with subsequent reductive elimination of Pd0, generating the benzylether.
Scheme 18. Plausible mechanism for the formation of isochroman and ether.
The importance of the carbonylation step in the cyclisation process was demonstrated by reacting 2-(2-ethynylphenyl)ethanol and iodobenzene under nitrogen atmosphere. In this case only 2-(2-(phenylethynyl)phenyl)ethanol was formed (Scheme 19).
Scheme 19. Sonogashira reaction between 2-(2-ethynylphenyl)ethanol and
iodobenzene.
The cyclocarbonylation process was successfully extended to iodoaryl substrates possessing both electron donating and electron withdrawing substituents in ortho or para position (Table 2). In all cases, the reactions generated the isochroman derivatives with good to excellent yields (68-89 %) and with complete stereoselectivity towards the formation of the (Z)-isomer, regardless the stereoelectronic features of Ar-I.
A particular behaviour was observed when 4-iodonitrobenzene was tested. Indeed, In this case, the reaction afforded (Z)-1-(4-aminophenyl)-2-(isochroman-1-ylidene) ethanone exclusively (Scheme 20 path I). The structure of this product was confirmed by means of a cyclocarbonylative reaction performed between
the ethynylalcohol and 4-iodoaniline (Scheme 20 path II). In this case the exclusive formation of amino derivative was detected and the product was isolated chemically pure with a good yield (53 %).
Table 2. Cyclocarbonylative Sonogashira reaction of
2-(2-ethynylphenyl)ethanol and aryl iodides.
Entry Ar Yield(%, isolated)
1 Ph 89 2 1-Naphthyl 87 3 2-MeC6H4 89 4 4-MeC6H4 81 5 2-MeOC6H4 75 6 4-MeOC6H4 80 7 4-ClC6H4 83 8 4-NCC6H4 72 9 2-NCC6H4 68
The in situ reduction of nitro group has been already described for the cyclocarbonylative Sonogashira reaction of ethynylbenzylalcohols (Scheme 13), indicating a very similar reaction mechanism for both processes.
Scheme 20. Sonogashira cyclocarbonylative reaction between
2-(2-ethynylphenyl)ethanol and 4-iodonitrobenzene or 4-iodoianiline.
3. Nitrogen heterocycles
3.1. Isoindolines
3.1.1 Biological properties, chemical reactivity
Isoindoline (Figure 7) can be considered the hydrogenated analogue of isoindole, whose scaffold is widespread in naturally occurring compounds such as alkaloids and antibiotics.[97]
On the contrary, isoindoline nucleus is almost absent in nature but is present in a large variety of biologically active synthetic derivatives. For instance, some of them act as inhibitor of dipeptidyl peptidases,[98] a drug target for type II diabetes.
N-Acylisoindolines (Figure 8, A) showed high activity in the inhibition of heat shock protein 90 (HSP90),[99] a molecular chaperon responsible for the correct folding and proper conformation of many signaling proteins, especially some oncogenic ones.
Figure 7. Isoindoline nucleus.
Similar compounds (Figure 8, B) were reported[100] to act as
efficient pyruvate dehydrogenase kinase (PDK) inhibitors by entering in the ATP-binding pocket of the enzyme. This is particularly interesting since different PDKs are up-regulated in obesity, diabetes,heart failure,ischemia,and cancer. Shultz and co-workers[101] synthesized a novel series of isoindolines-based hydroxamates which were able to inhibit cellular proliferation of human colon cancer cells (Figure 8, C). Benzoylisoindolines D (Figure 8) were discovered[102] as potent and selective inhibitors
of glycine transporter-1 (GlyT1), a mediator of glycine uptake probably involved in the pathophysiology of schizophrenia.
Figure 8. Isoindoline- based biologically active compounds
Some synthetic polysubstituted isoindolines[103] (Figure 8, E) derivatives were able to bind to the human dopamine receptor, thus suggesting a potential application as antipsychotic agents. Danoprevir (Figure 9), discovered in 2013,[104] is a novel
small-molecule inhibitor of the hepatitis C virus NS3/4A protease, a clinical candidate based on its favorable potency profile against multiple HCV genotypes.
Figure 9. Danoprevir structure.
Mancilla Percino et al.[105] described the synthesis of two series
of N-alkylated isoindolines (Figure 10) that were tested as inhibitors of cyclooxygenase 1 and 2, and possessed antitumoral properties against cervical cancer cells. The same compounds resulted[106] to be effective as brain and cardiac Ca2+ channel blockers, potentially active for epilepsy treatment and for the correct performance of atrial and ventricular myocites.
Figure 10. Mancilla-Percino’s isoindolines.
The isoindoline class of nitroxides are stable free radical species which are finding increased use in a wide range of applications. Compared with the more common nitroxides containing piperidine or pyrrolidine units, isoindoline ones contain a fused aromatic moiety which imparts rigidity to the ring system, making it less susceptible to opening side reactions. One of the most common use for nitroxides is as sensitive probes for the study of process involving reactive free radical species using EPR spectroscopy. In this field, the first class of isoindoline nitroxides were developed by Bottle and co-workers in 1999[107] and are depicted in Figure 11.
Figure 11. First example of isoindoline nitroxides.
Subsequently, isoindolines nitroxides bearing a stilbene fluorophore, a benzophenone moiety, anthracene structural cores, porphyrin groups and fullerenol have been synthesized and tested as free radical traps, antioxidants, therapeutic agents and other biomedical researches.[108]
Finally, isoindolidine diylidene derivatives are the nucleus of several pigments which cover the range from greenish yellow, to orange, red and brown (Figure 12).[109]
Figure 12. Isoindoline-based pigments.
From the point of view of chemical reactivity isoindolines can be submitted to many chemical transformation both on the nitrogen atom and on the carbon atoms of the pyrrolidine moiety. For instance, Pd-catalysed hydroamination of isoindoline has provided N-benzylated derivative,[110] while isoindoline has been N-alkylated with a cyclopropyl group through a reaction of copper-mediated cyclopropanation with cyclopropylboronic acid[111] (Scheme 21, a). Analogously, a naphtalene ring has
been added on the nitrogen atom using the corresponding boronic acid under microwave irradiation[112] (Scheme 21, b).
Besides the typical protection of NH with Boc, isoindoline can be N-acylated via aerobic oxidative amidation of aromatic aldehydes[113] (Scheme 21, c).
Scheme 21. Synthetic applications of isoindolines.
C-alkylation of isoindoline has been achieved using Meyers methodology, a three steps sequence consisting in the conversion of the isoindoline into a formamidine derivative, metallation and C-alkylation followed by deprotection of nitrogen with LiAlH4[114] (Scheme 21, d). Moreover, isoindoline can be
precursors of isoindoles (Scheme 21, e) via palladium-catalysed dehydrogenation[115] and of 4,5,6,7-tetrahydroisoindoles by means of Pd(OH)2 promoted reduction[116] (Scheme 21, f).
Recently, Galletti et al.[117] have reported a chemo-enzymated
aerobic oxidation of isoindoline that generate isoindolinone selectively (Scheme 21, g).
Finally, N-phenylisoindoline has been submitted to reductive opening of the pyrrolidine ring[118] with lithium powder and
subsequent quenching with a suitable electrophile (Scheme 21, h).
3.1.2 General synthetic methods
A very large number of synthetic routes to isoindolines are reported in the literature: reduction of phthalimides,[98c],[119] isoindolinones[120]
or isoindoles,[121] photolysis of aromatic fused 2 -1,2,3-triazolines,[122] [2+2+2] cycloaddition of dipropargylamines with alkynes,[16p],[123] Diels-Alder reaction and its analogues[124] or formation of the benzofused five-membered N-heterocycle. Although many protocols belong to this last approach, they can be grouped into three main pathways, depicted in Scheme 22. The first route involves reaction of aliphatic and aromatic primary amines with phthalaldehydes[125] or o-xylenyl dihalides,[126] often
base- or metal-promoted (Scheme 22, a).
The second one is based on a 5-exo-dig cyclization by C-C bond formation (Scheme 22, b), achieved through intramolecular -arylation of -amino acid esters[127] or cyclization of unsaturated amines or amides.[128]
Scheme 22. Main synthetic pathways to isoindolines by N-heterocyclization.
Similar to phthalan synthesis, the most common approach to isoindolines is the 5-exo-dig cyclization of benzyl amines (or their derivatives) having an ortho-substituent: hydroxymethyl groups[98b],[129] (often protected as ethers[130] or esters[131]), methyl or ethyl groups,[132] alkenes[133] (including tandem alkenylation–
cyclization[134] and nucleophilic addition–cyclization[135] processes)
and also alkynes, with the help of a base or of a metal catalyst (Scheme 22, c). Domínguez et al. described the 5-exo-dig cyclization of N-acetyl 2-ethynylbenzylamine with NaH affording, the corresponding alkylideneisoindoline with 90% of yield (Scheme 23). However, this protocol suffers the presence of hindered substituents at the benzylic position.[136]
Scheme 23. NaH-promoted protocol for cyclization of ortho-ethynylbenzylamides
Sakamoto and co-workers reported an extensive study on the TBAF-promoted cyclisation of several o-alkynylbenzylamine derivatives. Interestingly, the authors found that substrates bearing alkyl-substituted triple bond gave preferentially 6-endo-dig ring closure, affording 1,2-dihydroisoquinolines as main product, while benzyl amides having a TMS- or aryl-substituted triple bond yielded only alkylideneisoindolines (Scheme 24).[27a]
Scheme 24. TBAF-promoted cyclization of ortho-alkynylbenzylamine derivatives
proposed by Sakamoto and co-workers.
Moving to transition metal catalysts, the only examples of 5-exo-dig cyclization of ortho-alkynylbenzylamine derivatives described in the literature are based on gold or palladium organometallic compounds. Catalán et al. reported the synthesis of many alkylideneisoindolines by gold(I)-catalyzed intramolecular hydroamination of enantiopure o-alkynylbenzyl carbamates bearing a fluorinated alkyl substituent at the benzylic position (Scheme 25).[137]
Scheme 25. Au(I)-catalyzed intramolecular hydroamination of enantiopure
ortho-alkynylbenzyl carbamates described by Catalán et al.
Switching to palladium catalysis, Mori et al. found that ortho-alkynylbenzylamine derivatives, in the presence of Pd2dba3·CHCl3
as catalyst, and N-methyltosylamide as nucleophile, yielded comparable amounts of alkylideneisoindoline and isoquinoline derivatives, generated from a parallel 6-endo-dig cyclization (Scheme 26).[138]
Scheme 26. Mori’s cyclization of a ortho-alkynylbenzylamine derivative catalyzed by Pd2dba3·CHCl3.
More interestingly, Luo and Wang reported the cyclization of many N-tosyl acetylenic amines by deprotonation with n-BuLi in THF at 0°C, followed by a domino Sonogashira/hydroamination process with the one-pot addition of a (hetero)aryl iodide, Pd(OAc)3 and PPh3. This
protocol was successfully extended to N-tosyl 2-ethynylbenzylamine, which afforded the corresponding (E)-alkylideneisoindoline with 63% of yield (Scheme 27).[139]
Scheme 27. One-pot deprotonation/Sonogashira/hydroamination process of
N-tosyl 2-ethynylbenzylamine proposed by Luo and Wang.
3.1.3 Synthesis of alkylideneisoindolines via Palladium-catalysed cyclocarbonylative Sonogashira reaction
The first application of Palladium-catalyzed cyclocarbonylative Sonogashira reaction to the synthesis of alkylideneisoindoline ring was reported very recently by Aronica et al.[140]
2-Ethynylbenzylamine could not be used directly as substrate, since its reaction with iodobenzene did not give any isoindoline product, although a total consumption of reagents was observed (Scheme 28).
Scheme 28. Reaction between 2-ethynylbenzylamine and iodobenzene under
Sonogashira cyclocarbonylative conditions: no alkylideneisoindoline was found.
In order to overcome this problem, maybe ascribable to a possible interaction between NH2 group and palladium, the amine moiety
was protected with tert-butyloxycarbonyl (Boc) and tosyl (Ts) groups (Figure 13).
Figure 13. Structure of N-protected 2-ethynylbenzylamines.
The first reaction of N-Boc 2-ethynylbenzylamine with iodobenzene (Scheme 29) gave the tert-butyl 2-(3-oxo-3-phenylprop-1-yn-1-yl)benzylcarbamate as main product which derived from carbonylative Sonogashira coupling of iodobenzene with the alkynyl benzylamide. Only small amounts of the desired alkylideneisoindoline were detected (19%) but the formation of the five-membered product was completely stereoselective: (E) isomer was obtained exclusively.
However, increasing the reaction time to 24h, higher chemoselectivity towards the cyclisation product was observed (86%).
Scheme 29. Cyclocarbonylative Sonogashira reaction of tert-butyl
2-ethynylbenzylcarbamate with iodo benzene .
When Aronica and coworkers authors switched to N-tosyl 2-ethynylbenzylamine (Table 3, entry 1), the reaction afforded 1-phenyl-2-(2-tosylisoindolin-1-ylidene)ethanone quantitatively and with complete E-stereoselectivity (72% of yield after purification). The protocol was then successfully extended to iodoarenes characterised by different functional groups such electron donating (2-OMe, 4-OMe, 2-naphtyl) or electron withdrawing (2-Cl, 4-CN) substituents (Table 3, entries 2-6). A quantitative conversion of the reagents was detected in all cases affording the corresponding (E)-1-carbonylmethyleneisoindoline products with good yields (55-72%).
Table 3. Cyclocarbonylative Sonogashira reactions of N-Boc and N-tosyl ortho-ethynylbenzylamines with aryl iodides.
Entry Ar t (h) Yield (isolated, %)
1 Ph 2 72 2 4-MeOC6H4 4 72 3 4-ClC6H4 4 65 4 4-NCC6H4 4 60 5 2-naphthyl 4 68 6 2-MeOC6H4 4 55
3.2. Serendipitous synthesis of 2,3-dihydro-1H-benzo[d]azepine via cyclocarbonylative Sonogashira reaction
Prompted by the good results obtained in the Sonogashira cyclocarbonylative reactions applied to the synthesis of alkylidene phtalans, isochromans and isoindolines, Aronica and coworkers tried to extend this method to the preparation of tetrahydroisoquinolines (Figure 14).[140]
Figure 14. General structure of alkylidenetetraisoquinolines.
The requiring starting material was easily prepared starting from 2-(2-iodophenyl)acetonitrile which was converted into the corresponding amine and then protected with the tosyl group affording N-(2-iodophenethyl)-4-methylbenzenesulfonamide. Subsequent ethynylation/desilylation steps yielded homobenzylic amide (Scheme 30).
Scheme 30. Synthesis of N-(2-ethynylphenethyl)-4-methylbenzenesulfonamide.
The first Sonogashira cyclocarbonylative reaction of N-(2-ethynylphenethyl)-4-methylbenzenesulfonamide with iodobenzene was tested working under the experimental conditions optimised for isoindolines, i.e. CO (20 atm), 100°C, PdCl2PPh3, in a
toluene/triethylamine mixture. Surprisingly the formation of a mixture of three products was detected. One resulted to be 4-methyl-N-(2-(3-oxo-3-phenylprop-1-yn-1-yl)phenethyl)benzenesulfonamide (Figure 15), generated by Sonogashira carbonylative reactions without cyclisation step.
Figure 15. Structure of 4-methyl-N-(2-(3-oxo-3-phenylprop-1-yn-1-yl)phenethyl)benzenesulfonamide.
The other two compounds were identified after purification as two conformational isomers (s-trans and s-cis) of phenyl(3-tosyl-2,3-dihydro-1H-benzo[d]azepin-4-yl)methanone (Figure 16).
Figure 16. Conformational isomers of
phenyl(3-tosyl-2,3-dihydro-1H-benzo[d]azepin-4-yl)methanone.
Even if the generation of the seven membered ring is permitted by Baldwin’s rules[96]
since a 7-endo-dig cyclisation is favored compared with the 6-exo-dig one, the serendipitous formation of the dihydrobenzoazepine (Figure 17) derivatives was extremely interesting considering that these substrates could be precursors of the corresponding tetrahydrobenzoazepines which have been studied for more than 30 years due to their very important biological and pharmacological properties.[141]
Figure 17. 2,3-Dihydro-1H-benzo[d]azepine moiety.
The chemoselectivity of the reaction was optimised working on Pd loading, reaction time and temperature. Dihydrobenzoazepine was exclusively formed when the reactions were performed for 6 h, at 110°C and with 0.4mol% PdCl2(PPh3)2. The extension of the
Sonogashira cyclocarbonylative reaction to functionalised iodoarenes resulted in the quantitative conversion of the reagents. The (2,3-dihydro-1H-benzo[d]azepin-4-yl)arylmethanones were obtained chemically pure in good yield (46-65%) (Scheme 31).
Scheme 31. Sonogashira cyclocarbonylative reaction of
N-(2-ethynylphenethyl)-4-methylbenzenesulfonamide and aryl iodides.
Finally, when 1-iodo-4-nitrobenzene was reacted with N-(2-ethynylphenethyl)-4-methylbenzenesulfonamide (Scheme 32), aminobenzazepine derivative was obtained as sole product, in agreement with the results already discussed for phtalans, isochromans and isoindolines.
Scheme 32. Sonogashira cyclocarbonylative reaction of
N-(2-ethynylphenethyl)-4-methylbenzenesulfonamide and 1-iodo-4-nitrobenzene.
4. Conclusions
In this review has been focused on the biological activities, chemical reactivity and synthetic approaches to phthalans, isochromans and isoindolines have been taken into account. A particular attention has been paid to cyclocarbonylative Sonogashira reaction which can be used to afford alkylidene derivatives with good yields and stereoselectivities. Moreover instead of the expected tetrahydroisoquinolines, dihydrobenzoazepines were exclusively generated when the reaction was performed with homobenzylic amide.
We hope that this review will stimulate further research on the application of cyclocarbonylative Sonogashira reactions such as the extension of this protocol to the synthesis of sulphur containing heterocycles, or the investigation on the possible use of heterogeneous palladium catalysts in order to improve the “greenness” of the process.
Keywords: Carbonylation • Cross-coupling • Phthalan • Isochroman • Isoindoline
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