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Synthesis 2020; 52(24): 3764-3780
DOI: 10.1055/s-0040-1707255
short review

Synthetically Important Ring-Opening Acylations of Alkoxybenzenes

Ranadeep Talukdar  ∗

The author would like to thank the Science and Engineering Research Board, India (DST-SERB; grant number PDF/2018/000072/CS) for financial support.
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Dedicated to Professor Yashwant D. Vankar on the occasion of his 70th birthday

Abstract

Cyclic ketones, anhydrides, lactams and lactones are a particular class of molecules that are often used in synthesis, wherein their electrophilic properties are leveraged to enable facile Friedel–Crafts ring openings through nucleophilic attack at the carbonyl sp2 centre. The use of electron-rich alkoxybenzenes as nucleophiles has also become important since the discovery of the Friedel–Crafts reaction. As a result, various isomeric alkoxybenzenes are used for preparing starting materials in target-oriented syntheses. This review covers the instances of different alkoxybenzenes that are used as nucleophiles in ring-opening acylations with carbonyl-containing cyclic electrophiles, for the construction of important building blocks for multistep transformations. This review summarizes the ring-opening functionalization of three- to seven-membered molecular rings with alkoxybenzenes in a Friedel–Crafts fashion. Sometimes the rings need subtle or considerable activation by the help of Lewis acid(s), followed by nucleophilic attack. This review is aimed to be a summary of the important acylations of electron-rich alkoxybenzenes by nucleophilic ring-opening of cyclic molecules. The works cited employ a wide range of conditions and differently substituted substrates for target-oriented syntheses.

1 Introduction and Scope

2 Arenes for Acylative Ring Opening

2.1 Three-Membered Rings: Ring Opening of Oxirane-2,3-dione

2.2 Four-Membered Rings

2.2.1 Ring Opening of Cyclobutanones

2.2.2 Ring Opening of β-Lactams

2.2.3 Ring Opening of β-Lactone

2.3 Five-Membered Rings

2.3.1 Ring Opening of Phthalimides

2.3.2 Ring Opening of γ-Lactones

2.3.3 Ring Opening of Anhydrides

2.4 Six-Membered Rings

2.5 Seven-Membered Rings

3 Conclusion


#

Key words

Friedel–Crafts acylation - methoxybenzene - dimethoxybenzene - trimethoxybenzene - Lewis acid - β-lactam - β-lactone
1

Introduction and Scope

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Dr. Ranadeep Talukdarreceived his BSc Honours in chemistry in 2007 from University of Calcutta. He then moved to the Indian Institute of Technology Kanpur to complete his Masters in 2009. He also completed his PhD in organic synthesis working on domino-ring opening-cyclization of DA-cyclopropanes and small nitrogen-containing rings from the same institute. He completed his first post-doctoral research on selenium chemistry and Hauser annulation chemistry in 2017. He is currently pursuing his research on organic photo-redox chemistry and asymmetric N-heterocyclic carbene catalysis as a National Post-Doctoral Fellow.

The appearance of the Haworth reaction in 1932 tore open a new portal to access tetralones and subsequently to polyaromatic systems in a step-economic manner.[1a] [b] The principle behind this chemistry, the famous Friedel–Crafts (FC) acylation (Figure [1]),[1c–e] displaying the nucleophilic character of the aromatic π-electrons, has unquestionably upgraded organic synthesis to its modern state.[2] On the other hand, small rings (3–5 carbons, with no sp2 carbons, such as cyclopropane, aziridine, epoxide, thiirane, and azetidine) always contain varying amounts of angle strain, and ring opening is a suitable option to release such strain.[3] For small rings with sp2 carbon (cyclic ketone, anhydride, lactam or lactone) the angle strain is even more severe. Larger rings (6–7 carbons) with sp2 carbon require activation by Lewis acids, although this is often also required to open smaller rings.[4] This review article describes such ring-opening FC reactions of different sized rings by electron-rich alkoxybenzenes (acylations), as this more than 140-year-old name reaction never ceases to amaze organic chemists.[5]

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Figure 1 The Friedel–Crafts and Haworth reactions[1`] [d] [e]

# 2

Arenes for Acylative Ring Opening

The two intertwined streams of FC reaction, the alkylation and acylation, are well canvassed in organic chemistry research for electrophilic functionalization by arenes.[5] Whether as ‘neutral arenes’ (FC reaction)[6] or as ‘metallo-arene complexes’ (nucleophilic anionic/radical arenes),[7] [8] their unique nucleophilic properties have proven especially important for the preparation of various starting materials. Utilizing this, their ability to attack the sp2 carbons of cyclic systems with a Lewis acid activating the latter has also gained much popularity.[4]

2.1

Three-Membered Rings: Ring Opening of Oxirane­-2,3-dione (Oxalic Anhydride)

Friedel–Crafts acylation of arenes have proven fruitful for achieving building blocks for the synthesis of a myriad of bioactive molecules (Figure [2]).[9] Such reactions, when performed with cyclic acylating partners as discussed later in this article (anhydrides, lactam, lactone etc.), have also earned the same popularity.

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Figure 2 Importance of the acylation products of different alkoxyarenes for multistep syntheses

Many piperazine derivatives show CCR1 receptor antagonist activities in mammals.[10a] [b] Blumberg et al. performed the AlCl3-assisted ring-opening of oxirane-2,3-dione with 4-chloroanisole (Scheme [1]).[10c] The product keto acids are further masked by a chiral chloro amide under basic environment to obtain chiral piperazine amide ethers. The 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) mediated coupling step was performed in polystyrene solid-state base containing 2% divinylbenzene as coupling agent.

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Scheme 1 Ring opening of oxirane-2,3-dione for the preparation of chiral piperazine

The invented fluoro-substituted piperazine is a potent inhibitor of MIP1α binding to CCR1, thus can be used for treating inflammation, type-1 diabetes, allergies, and bronchitis.


# 2.2

Four-Membered Rings

As the ring size increases, the ring stability also increases; therefore, the tendency towards ring opening decreases.[4] In many cases, four-membered rings are considered important building blocks for the synthesis of larger molecules.[11] [12]

2.2.1

Ring Opening of Cyclobutanones

Matsuo and co-workers reported the ring opening of 3-arylcyclobutanones under the influence of TiCl4 as an oxophilic Lewis acid (Scheme [2]).[13] Mono-, isomeric di- and trimethoxybenzene nucleophiles were all taken into consideration. Here, TiCl4 was found to be more effective than AlCl3 Lewis acid in terms of yield. The para ring opening by methoxybenzenes was favoured over the ortho ring opening process.

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Scheme 2 TiCl4-assisted ring opening of 3-arylcyclobutanones

For the case of trimethoxybenzene nucleophile, 8% yield of the double addition byproduct was obtained. The Ti(IV) first coordinates with the ketone oxygen of cyclobutanone to give a stable benzyl cation. The cation further reacts with methoxybenzene in a FC fashion to give the product (Scheme [3]).

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Scheme 3 Mechanism of ring opening of 3-arylcyclobutanones[13]

# 2.2.2

Ring Opening of β-Lactams

β-Lactam[14] ring opening by electron-rich benzenes can also lead to various biologically important molecules, including γ-amino butyric acid (GABA) derivatives.[15] Kano et al. showed an acid-catalyzed Fries-type ring-opening rearrangement of 1-arylazetidin-2-ones to afford 2,3-dihydro-4(1H)-quinolones.[16] The reaction involves a trifluoroacetic acid promoted amide N–C bond cleavage followed by intramolecular acyl migration (Scheme [4]). For symmetrical substrates, single isomers were obtained. Apart from methoxy-bearing substrates, the reaction also occurred with unsubstituted as well as hydroxy-, chloro-, bromo-, and dimethylamino-substituted phenyl groups, with varying yields.

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Scheme 4 Fries-type ring-opening rearrangement of symmetrical β-lactams

For unsymmetrical β-lactams, a 1:1 mixture of regio­isomers was obtained by carbonyl migration to both ortho- and para-positions of the phenyl ring (Scheme [5]).

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Scheme 5 Fries-type ring-opening rearrangement of unsymmetrical β-lactams

The mechanism followed a similar FC sequence. The intramolecular attack to the acid-activated lactam ring from the equivalent ortho/para sites give rise to different regioisomeric 2,3-dihydro-4(1H)-quinolone products (o/p product 1:2 ratio) (Scheme [6]). The product arising from the para attack was found to be major because of higher resonating stability of the aromatic electron cloud in the transition state compared to ortho attack.

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Scheme 6 Mechanism of ring-opening rearrangement of β-lactams to 2,3-dihydro-4(1H)-quinolones[16]

The same reaction was investigated by the group of Tepe with trifluoromethanesulfonic acid at much lower temperature, using dichloroethane as solvent. Anisole was used as nucleophile for the intermolecular case to afford β-amino­propiophenone (Scheme [7]).[17]

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Scheme 7 Intra- and intermolecular ring opening of β-lactams by a methoxybenzene moiety

The reaction was utilized by Webb and co-workers to synthesize different derivatives of ligand scaffolds, which behave as non-peptide drugs for targeting somatostatin receptors (Scheme [8]).[18]

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Scheme 8 Synthesis of non-peptide ligands for targeting somatostatin receptors

A similar study was performed by Lange et al. with substituted β-lactams, and a good yield of the quinolone product was achieved (Scheme [9]).[19]

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Scheme 9 Ring opening of substituted β-lactam by methoxy benzene

# 2.2.3

Ring Opening of β-Lactone

The formal synthesis of natural mycotoxin, aflatoxin M2, was achieved in just five steps starting with the ring opening of β-lactone by 1,3,5-trimethoxybenzene (1,3,5-TMB) in the presence of AlCl3 (Scheme [10]).[20] During the ring opening, the ortho-methoxy group was demethylated, giving an intermediate diol ketone. This was followed by the addition of dichloromethyllithium to the intermediate, resulting in the triol. The next steps involved the generation of the hemiacetal, then acid-catalyzed ring-closure and demethylation of the second ortho methoxy to give the phenol, which was converted into aflatoxin M2 in a single step by Von Pechmann condensation with activated vinyl ester bromide.[21] The overall yield was 26%.

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Scheme 10 Synthesis of aflatoxin M2 by ring opening of β-lactone by 1,3,5-TMB

#
# 2.3

Five-Membered Rings

Given that the increased ring size leads to more relaxation, the ring opening of simple cyclopentanes or related hetero rings by alkoxy benzenes is very rare.

2.3.1

Ring Opening of Phthalimides

Arief and co-workers studied the ring-opening reaction of different N-hydroxyphthalimides by anisole in the presence of excess AlCl3 to give a mixture of p-methoxy-substituted 2-(2-oxo-2-phenylethyl)isoindoline-1,3-dione and 2-benzoyl-N-hydroxybenzamide (Scheme [11]).[22] The latter further formed 4-(4-methoxyphenyl)-1H-benzo[d][1,2]oxazin-1-one via AlCl3-assisted Beckmann rearrangement. When the reaction was performed in the presence of aniline in refluxing benzene, 2-(4-methoxybenzoyl)-N-phenyl­benzamide was obtained.

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Scheme 11 Derivations of the ring-opening products of N-hydroxyphthalimide derivatives by anisole

# 2.3.2

Ring Opening of γ-Lactones

Nagashima performed a reductive ring-opening of γ-lactone by 1,3,5-TMB in the presence of hydrosilane. The reaction was catalyzed by the tri-ruthenium cluster (μ3,η2,η3,η5-acenaphthylene)Ru3(CO)7 to form a silyl ether, which, upon desilylation, gave the corresponding alcohol (Scheme [12]).[23]

The reaction of hydrosilane on the Ru-cluster A generated a silyl cation and Ru-hydride anion complex (Scheme [13]). First the dual action of this combination led to the formation of silyl lactol B. The reaction of the latter with Si+ generated the silyl coordinated ring-opened aldehyde C, which could react via two pathways. With the hydride complex it gave the reduced disilyl ether D. With 1,3,5-TMB it also gave the Friedel–Crafts product E. The benzyl cation formed from E is then again reduced by the Ru-hydride anion complex to afford the product silyl ether F.


# 2.3.3

Ring Opening of Anhydrides

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Scheme 12 Hydrosilane reductive ring-opening of γ-lactone
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Scheme 13 Mechanism of reductive ring opening of γ-lactone by a ruthenium­ cluster catalyst (substitutions on silicon are omitted for clarity­)[23]

The use of succinic anhydride as a five-membered electrophile for ring opening by methoxybenzenes is an established practice in the syntheses of 4-oxo-4-arylbutanoic acid structures.[24] The acid is an important scaffold for synthesizing tetralones in high yields, and has been deployed to make lignans, phenanthrenes and hydrophenanthrenes, γ-butyrolactones, immobilized sensors, molecular probes, protein kinase inhibitors, anti-inflammatory agents, and to perform total syntheses of bioactive molecules (Figure [3]).[24]

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Scheme 14 Diels–Alder reaction of benzoylacrylic acids
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Figure 3 Evolution of succinic anhydride ring-opened products by alkoxy benzenes

Like succinic anhydride, other anhydrides have also become important precursors for carrying out different synthetic methodologies or synthesizing bioactive molecules via the acid formed by ring opening with different alkoxy arenes. Unsaturated substrates such as maleic anhydride have been used by Wheeler and co-workers to obtain the 4-aryl-4-oxo-2-butenoic or benzoacrylic acid, which was converted into the cyclohexenoic acid by Diels–Alder (DA) reaction with isoprene (Scheme [14]).[25] When monomethoxybenzene was used, the yield of the benzoacrylic acid was only 10%. Attempts to synthesize the cyclohexene acid directly by the DA reaction of electron-rich arene with anhydride only resulted in the formation of the bridged lactones with 47% combined yield.

Later, the benzoacrylic acids were isolated as the corresponding ethyl esters when Itoh used diethyl sulfate as additive along with the Lewis acid AlCl3 (Scheme [15]).[26]

It was hypothesized that, in the presence of (EtO)2SO2, the small amount of (E)-acyl cation C that was generated from the (Z)-acyl cation B via equilibrium, which was in turn generated by the AlCl3 mediated ring-opening of maleic anhydride, was trapped and could not go back to the (Z)-acyl cation again (Scheme [16]), giving better product yields, as esters. Simple methoxybenzene was an exception.

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Scheme 15 FC ring opening of maleic anhydride of benzoylacrylic esters; yields of the corresponding acids without diethyl sulfate are given in parentheses

It is worth mentioning that methoxy aryl acrylic acids are found to have antiproliferative effects against chronic myelogenous leukemia, cervix carcinoma, and colon tumour cell lines in humans.[27] The marine natural product lamellarin G trimethyl ether was synthesized by Yadav et al. in four steps starting from maleic anhydride by using an electron-rich arene (Scheme [17]).[28] Lamellarins have cytotoxic activities against various cancer cell lines and are, to greater or lesser degrees, also inhibitors of HIV-1 integrase.[29] The synthetic strategy depicted by the authors could be used to synthesize other isomers of the natural product in the shortest routes developed to date.

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Scheme 16 Mechanism of diethyl sulfate mediated esterification[26]
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Scheme 17 Total synthesis of marine natural product lamellarin-G

Ring-opening reaction of anhydride by 1,4-dimethoxybenzene was used by Sridhar to synthesize quinone in three steps by an initial ring opening followed by a Krapcho decarboxylation strategy (Scheme [18]).[30] The final product was found to have similar kinase inhibitory activity as emodin[31] against PIM1 kinase, which is responsible for acute myeloid leukemia and prostate cancer in mice.

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Scheme 18 Synthesis of PIM1 kinase inhibitor quinone

Given that quinolines have some toxic effects inside cells, Wang synthesized less toxic quinoline derivatives 2,3-dihydro-2,3-epoxy-2-propylsulfonyl-5,8-dimethoxy-1,4-naphthoquinone (EPDMNQ) and 2,3-dihydro-2,3-epoxy-2-nonylsulfonyl-5,8-dimethoxy-1,4-naphthoquinone (ENDMNQ) in five steps involving the oxidative coupling of the alkyl sulphide chains in the quinoline ring (Scheme [19]).[32]

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Scheme 19 Synthesis of EPDMNQ and ENDMNQ

Such compounds were examined against the human lung cancer cell lines A549, NCI-H23 and NCI-H460. For the first type of cells, the cytotoxicity of EPDMNQ was threefold higher compared to ENDMNQ due to the better cell membrane permeability of the former because of the smaller size. Kagayama used cis-1,2-cyclohexenedicarboxylic anhydride for the synthesis of phthalazinone derivatives, which are potent phosphodiesterase-4 (PDE4) inhibitors having anti-inflammatory properties.[33] The ring opening by veratrole under Friedel–Crafts conditions first provided the keto acid, and the desired phthalazinones were obtained in four more steps starting with treatment with hydrazine in ethanol (Scheme [20]). In addition to cis-1,2-cyclohexenedicarboxylic anhydride, some of its saturated analogues were used to make a series of phthalazinones for biological studies against human acute promyelocytic leukemia cell line HL-60 and whole rat blood cells for the suppression of TNF-α production.

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Scheme 20 Synthesis of phthalazinones as PDE4 inhibitors and TNF-α suppressors by FC ring opening of anhydrides by veratrole

Using phthalic anhydride, Akine and co-workers synthesized tetrafunctionalized pentiptycenequinone dimers with a boronate ester linkage via ring opening of phthalic anhydride by 2,3-dimethoxybenzene (Scheme [21]).[34] Triptycenes are used in the synthesis of a vast range of molecules.[35] 2,3-Dimethoxyanthracene was prepared from 2,3-dimethoxyanthraquinone by following the procedure described by Pozzo.[36]

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Scheme 21 Synthesis of 2,3-dimethoxyanthraquinone and tetrafunctionalized pentiptycenequinone dimers by FC ring opening of phthalic anhydride

The Sterk group reported a synthesis of biologically active phenylpyridazinone derivatives in three steps by using this approach (Scheme [22]). These products could act as potent cyclic nucleotide phosphodiesterase (PDE) inhibitors. Compounds NPD-1 and VUF13525 are known phenylpyridazinone derivative TbrPDE inhibitors that show the best reported antitrypanosomal activities.[37]

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Scheme 22 Synthesis of bioactive phenylpyridazinone by FC ring opening of phthalic anhydride

The work of Su dealt with visible photocatalytic oxidation of the amino ether group of the anti-spasmic drug pitophenone to amino-ester by singlet oxygen (Scheme [23]). The reaction occurred via direct insertion of singlet O2 into the α-ethereal C–H bond in a single step. meso-Tetraphenylporphyrin was used as a photosensitizer under solvent-free conditions.[38]

Zhang reported the Rh-catalyzed facile hydrogenation of α,α-disubstituted terminal olefins to synthesize important enantioselective acids (Scheme [24]). These compounds, which possess an α-benzylmethyl group, have many biologically important applications.[39]

The amine group of the tBu-Wudaphos ligand made an ion pair noncovalent interaction with the acid of the olefin substrates to give the products with high enantioselectivity (Figure [4]).

Wang’s group performed a Cu(I) catalyzed γ-lactonization-difluoroalkylation of unsaturated acid with ethyl bromodifluoroacetate­ (Scheme [25]).[40a] Among several reductants­ screened, such as sodium thiosulphate and quinol, sodium metabisulfite in the presence of pentamethyldiethylenetriamine (PMDETA) base was identified as the best reagent. Difluoroalkylation has become a very important strategy for configuring a range of bioactive materials.[40`] [c] [d]

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Scheme 23 Photocatalytic oxidation of pitophenone via singlet oxygen
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Scheme 24 Rh-catalyzed enantioselective hydrogenation of α,α-disubstituted terminal olefins
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Figure 4 Schematic diagram of ion-pair noncovalent interaction between tBu-Wudaphos and substrate[39]
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Scheme 25 Cu(I) catalyzed γ-lactonization-difluoroalkylation of unsaturated acid by ethyl bromodifluoroacetate

First the ligated Cu(I) interacted with bromoester A to give difuoroacetate radical B while forming Cu(II). The difluoroacetate radical then added to the double bond of unsaturated acid C to give radical D. The latter was then oxidized by Cu(II) to give difuoroacetate ester cation E. In the presence of PMDETA base, the lactone product F was then formed (Scheme [26]).

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Scheme 26 Mechanism of difluoroalkylation–lactonization of unsaturated acid[40]

Working on polymer chemistry, pyromellitic anhydride was used by Shan and co-workers to afford the diketo di­acid, which was then transformed into ladder-type electroactive polymer polydiaryldibenzo[1,5]diazocines in a further four steps (Scheme [27]).[41]

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Scheme 27 Synthesis of novel ladder-type polydiaryldibenzo[1,5]-diazocines­

The non-planar diazocene fragment in this kind of polymer shows aromaticity by changing the conformation from boat to planar in its dianion state (Scheme [28]). This enables the polymers to act as electromechanical actuators; that is, having the property to transduce electrical energy to mechanical energy.

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Scheme 28 Electroactivity of polydiaryldibenzo[1,5]diazocines according­ to Hückel’s aromaticity[41]

Kraikin and co-workers developed a phthalide based polymer, polyarylenediphthalide, by NaI mediated dehalogenative polymerization[42a] of pseudo diacid chlorides (Scheme [29]). Degradation products of this class of polymers possess high toughness.

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Scheme 29 Synthesis of polyarylenediphthalide via ring opening of phthalic anhydride

The monomers were synthesized by using a similar procedure (Scheme [30]). Recently, the authors reported a separation method for the corresponding racemic and meso dia­stereoisomers of the monomers.[42b]

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Scheme 30 Synthesis of monomeric pseudo acid chlorides[42a]

#
# 2.4

Six-Membered Rings

Tan described the first racemic total syntheses of natural products demethyldactyloidin and dactyloidin starting from glutaric anhydride and anisole (Scheme [31]). The keto-acid obtained was subjected to 14- and 16-step transformation, respectively, to obtain the final molecules.[43] The interesting oxygen-bridged tricyclic ketal structural subunit that these two natural products contain are shared by several other important naturally occurring molecules.[44]

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Scheme 31 Total syntheses of dactyloidin and demethyldactyloidin

The conversion of the ketone into the tricyclic ketal was the heart of this transformation and was achieved by Knoevenagel condensation of the ketone group with 1,3-cyclohexanedione followed by a [4+2] cycloaddition in a cascade fashion (Scheme [32]). Otsuki used the long-chained 1,3,5-tridodecyl benzene for the FC ring opening of glutaric anhydride. The product 5-oxopentanoic acid was converted into fullerene alcohol in five steps (Scheme [32]).[45] The fullerene system was installed by the decomposition of in situ generated tosyl-hydrazone ester in the presence of C60. The initially obtained [5,6] isomers in the mixture were completely converted into the [6,6] isomer by refluxing in o-dichlorobenzene.

The synthesized fullerene alcohols were coupled with pyridine-bearing Zn-chlorophyl carboxylates to obtain the corresponding esters ZnPyC60. Mixing the latter with the non-fullerene ester ZnPy, formed different co-tetramers with (ZnPy)3(ZnPyC60) prevailing in solution (Scheme [33]).

The presence of both porphyrine and fullerene systems meant that the co-tetramer (ZnPy)3(ZnPyC60) acted as the best antenna-charge separated system, showing 100% fluorescence quantum efficiency also in benzene. Therefore, it can be used as a molecule for efficient photo-harvesting. Gautam et al. described a ring opening of 3,3-dimethyl­dihydro-2H-pyran-2,6(3H)-dione with anisole to obtain a keto acid (Scheme [34]). With three further steps the product was transformed into 6,7,8,9-tetrahydro-5H-benzo[7]-annulenes­.[46]

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Scheme 32 Synthesis of fullerene alcohol by ring opening of glutaric anhydride

Giordanetto and co-workers prepared 4,5,6,7-tetra­hydro-1H-1,2-diazepin-7-one derivatives by taking the ring-opened product 5-oxopentanoic acid (Scheme [35]). The reaction with hydrazine hydrate followed by N-alkylation afforded the desired final seven-membered cyclic products.[47]

The synthesized products are potential phosphodiesterase 4 (PDE4) inhibitors. The N-protected products were much more reactive than the unprotected ones and they exhibited activities comparable to those of rolipram and zardaverine (Figure [5]).

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Figure 5 Known phosphodiesterase 4 (PDE4) inhibitors[47]

Jiang’s group carried out the bromolactonization of some α,β-unsaturated ketone olefinic acids to afford chiral γ-lactones by using an electron-rich bifunctional urea based catalyst (Scheme [36]).[48]

The chiral bromo γ-lactone products were found to have anti-inflammatory activities. Some substituted molecules were synthesized from the products, and it was apparent that substitution did not affect the chirality (Scheme [37]).

Based on the HRMS model study of a controlled reaction with analogous 1-methyl-3-phenylurea and N-bromosuccinimide (NBS), with no product formation in the absence of the latter, the proposed mechanism is described in Scheme [38]. First the aniline N-H proton of electron-rich catalyst is substituted by bromine. This species then brominated the electron-rich olefin group of the substrate. The high yield and the fast reaction rate was due to very little electron conjugation between the carbonyl and olefin group of the keto acid, which was the result of a hydrogen bond between the N-H of the brominated catalyst and the substrate carbonyl. This also greatly distorted the transition-state geometry, ensuring high enantioselectivity.

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Scheme 33 Co-assembly of ZnPy and ZnPyC60 [45]

A highly efficient synthesis of chiral hydroxyamides was performed by Zhang et al. (Scheme [39]) by the asymmetric hydrogenation of ketoamides.[49a] The substrates were synthesized in two steps starting from alkoxy benzene and glutaric anhydride, followed by amidation. The catalyst [Ir(COD)Cl]2/f-amphox used showed a staggering turnover number (TON) of 10000 under high pressure of H2 atmosphere, with a quantitative conversion and excellent enantioselectivity.

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Scheme 34 Syntheses of 6,7,8,9-tetrahydro-5H-benzo[7]annulenes
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Scheme 35 Synthesis of 4,5,6,7-tetrahydro-1H-1,2-diazepin-7-ones

Later, the same strategy was adopted by the same group for the asymmetric hydrogenation of 2,3-dimethoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one with similar extreme product yield and enantioselectivity, with 5000 TON (Scheme [40]).[49b]

Taylor synthesized tetrahydrofurans and tetrahydropyrans from diols via pentafluoroaryl boronic acid-mediated dehydrative substitution (Scheme [41]).[50] This is an example of a synthetically very important heteroatom alkylation strategy using pentafluoroaryl boronic acid assisted etherification.[51]

Oxalic acid works as a ligand for the boron catalyst in its +3 oxidation state. While it coordinates with the boron it releases its protons to give the hydroxonium complex (A), which protonates the benzylic hydroxy group of diol (B) to generate the carbocation C (Scheme [42]). The other terminal hydroxy group attacks the carbocation to form the tetrahydrofuran (n = 1) or tetrahydropyran (n = 2) product, leaving the protonated complex D. The latter accepts a water molecule to generate A again.

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Scheme 36 Synthesis of chiral γ-lactones by bromolactonization
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Scheme 37 Functionalizations of chiral bromo γ-lactone[48]
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Scheme 38 Proposed mechanism for enantioselective bromo-lactonization[48]
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Scheme 39 [Ir(COD)Cl]2/f-amphox catalyzed highly efficient reduction of ketoamides

# 2.5

Seven-Membered Rings

The ring-opening of seven-membered cyclic anhydrides by different alkoxy arenes was studied by the groups of Orzalesi­[52a] and Rothstein.[52b] In their described works they used 1,8,8-trimethyl-3-oxabicyclo[3.2.1]octane-2,4-dione (camphoric anhydride) for the nucleophilic ring opening with different alkoxy benzenes (Scheme [43]). The final product aryl cycloalkyl ketone carboxylic acids possess choleretic and anorectic properties.[53]


#
# 3

Conclusion

As summarized in this review, the ring-opening acylation and functionalization of alkoxybenzenes with different sized molecular rings (3–7 membered) with sp2 carbons such as cyclic ketones, anhydrides, lactones and lactams, can give rise to various synthetic building blocks that are required for multistep synthetic routes. Not only carbon-based, but heteroatom-containing cyclic electrophiles may also be suitable for this kind of ring opening in a target-oriented synthesis. The reactions are often made more facile by applying Lewis acids for ring activation. As a result, the seminal FC acylation reaction is applied to access many interesting target molecules, including pharmaceutically important products, polymeric substances, polyaromatic hydrocarbons (PAHs), supramolecules, photosensors, and energy transformers.

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Scheme 40 Asymmetric reduction of 2,3-dimethoxy-6,7,8,9-tetra­hydro-5H-benzo[7]annulen-5-one
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Scheme 41 Synthesis of tetrahydrofurans and pyrans
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Scheme 42 Mechanism of formation of tetrahydrofurans and pyrans from diols[50]
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Scheme 43 Synthesis of aryl cycloalkyl ketone carboxylic acids

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#

Corresponding Author

Ranadeep Talukdar
Molecular Synthesis and Drug Discovery Laboratory, Centre of Biomedical Research
Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014
India   

Publication History

Received: 18 June 2020

Accepted after revision: 20 July 2020

Article published online:
08 September 2020

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Dr. Ranadeep Talukdarreceived his BSc Honours in chemistry in 2007 from University of Calcutta. He then moved to the Indian Institute of Technology Kanpur to complete his Masters in 2009. He also completed his PhD in organic synthesis working on domino-ring opening-cyclization of DA-cyclopropanes and small nitrogen-containing rings from the same institute. He completed his first post-doctoral research on selenium chemistry and Hauser annulation chemistry in 2017. He is currently pursuing his research on organic photo-redox chemistry and asymmetric N-heterocyclic carbene catalysis as a National Post-Doctoral Fellow.
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Figure 1 The Friedel–Crafts and Haworth reactions[1`] [d] [e]
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Figure 2 Importance of the acylation products of different alkoxyarenes for multistep syntheses
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Scheme 1 Ring opening of oxirane-2,3-dione for the preparation of chiral piperazine
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Scheme 2 TiCl4-assisted ring opening of 3-arylcyclobutanones
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Scheme 3 Mechanism of ring opening of 3-arylcyclobutanones[13]
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Scheme 4 Fries-type ring-opening rearrangement of symmetrical β-lactams
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Scheme 5 Fries-type ring-opening rearrangement of unsymmetrical β-lactams
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Scheme 6 Mechanism of ring-opening rearrangement of β-lactams to 2,3-dihydro-4(1H)-quinolones[16]
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Scheme 7 Intra- and intermolecular ring opening of β-lactams by a methoxybenzene moiety
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Scheme 8 Synthesis of non-peptide ligands for targeting somatostatin receptors
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Scheme 9 Ring opening of substituted β-lactam by methoxy benzene
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Scheme 10 Synthesis of aflatoxin M2 by ring opening of β-lactone by 1,3,5-TMB
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Scheme 11 Derivations of the ring-opening products of N-hydroxyphthalimide derivatives by anisole
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Scheme 12 Hydrosilane reductive ring-opening of γ-lactone
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Scheme 13 Mechanism of reductive ring opening of γ-lactone by a ruthenium­ cluster catalyst (substitutions on silicon are omitted for clarity­)[23]
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Scheme 14 Diels–Alder reaction of benzoylacrylic acids
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Figure 3 Evolution of succinic anhydride ring-opened products by alkoxy benzenes
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Scheme 15 FC ring opening of maleic anhydride of benzoylacrylic esters; yields of the corresponding acids without diethyl sulfate are given in parentheses
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Scheme 16 Mechanism of diethyl sulfate mediated esterification[26]
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Scheme 17 Total synthesis of marine natural product lamellarin-G
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Scheme 18 Synthesis of PIM1 kinase inhibitor quinone
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Scheme 19 Synthesis of EPDMNQ and ENDMNQ
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Scheme 20 Synthesis of phthalazinones as PDE4 inhibitors and TNF-α suppressors by FC ring opening of anhydrides by veratrole
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Scheme 21 Synthesis of 2,3-dimethoxyanthraquinone and tetrafunctionalized pentiptycenequinone dimers by FC ring opening of phthalic anhydride
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Scheme 22 Synthesis of bioactive phenylpyridazinone by FC ring opening of phthalic anhydride
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Scheme 23 Photocatalytic oxidation of pitophenone via singlet oxygen
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Scheme 24 Rh-catalyzed enantioselective hydrogenation of α,α-disubstituted terminal olefins
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Figure 4 Schematic diagram of ion-pair noncovalent interaction between tBu-Wudaphos and substrate[39]
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Scheme 25 Cu(I) catalyzed γ-lactonization-difluoroalkylation of unsaturated acid by ethyl bromodifluoroacetate
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Scheme 26 Mechanism of difluoroalkylation–lactonization of unsaturated acid[40]
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Scheme 27 Synthesis of novel ladder-type polydiaryldibenzo[1,5]-diazocines­
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Scheme 28 Electroactivity of polydiaryldibenzo[1,5]diazocines according­ to Hückel’s aromaticity[41]
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Scheme 29 Synthesis of polyarylenediphthalide via ring opening of phthalic anhydride
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Scheme 30 Synthesis of monomeric pseudo acid chlorides[42a]
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Scheme 31 Total syntheses of dactyloidin and demethyldactyloidin
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Scheme 32 Synthesis of fullerene alcohol by ring opening of glutaric anhydride
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Figure 5 Known phosphodiesterase 4 (PDE4) inhibitors[47]
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Scheme 33 Co-assembly of ZnPy and ZnPyC60 [45]
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Scheme 34 Syntheses of 6,7,8,9-tetrahydro-5H-benzo[7]annulenes
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Scheme 35 Synthesis of 4,5,6,7-tetrahydro-1H-1,2-diazepin-7-ones
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Scheme 36 Synthesis of chiral γ-lactones by bromolactonization
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Scheme 37 Functionalizations of chiral bromo γ-lactone[48]
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Scheme 38 Proposed mechanism for enantioselective bromo-lactonization[48]
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Scheme 39 [Ir(COD)Cl]2/f-amphox catalyzed highly efficient reduction of ketoamides
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Scheme 40 Asymmetric reduction of 2,3-dimethoxy-6,7,8,9-tetra­hydro-5H-benzo[7]annulen-5-one
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Scheme 41 Synthesis of tetrahydrofurans and pyrans
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Scheme 42 Mechanism of formation of tetrahydrofurans and pyrans from diols[50]
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Scheme 43 Synthesis of aryl cycloalkyl ketone carboxylic acids