Enolates ambushed – asymmetric tandem conjugate addition and subsequent enolate trapping with conventional and less traditional electrophiles

Introduction

The formation of complex chiral molecules is a crucial task of organic synthesis that enables the synthesis of pharmaceuticals, crop-protecting agents, or advanced materials. Their syntheses often involve numerous reaction steps requiring laborious isolation and intermediate product purification steps. An important strategy for improving syntheses’ effectiveness is the concept of domino reactions, cascade, or tandem reactions. These transformations combine several reactions into a sequence that uses functionalities generated in previous steps without isolating intermediates . Stabilized carbon-based nucleophiles, or in other words, conjugate bases of weak C–H acids, are termed enolates, and they participate in a large array of organic synthetic transformations. Enolates are usually formed by deprotonation of the corresponding organic compound. However, other synthetic approaches for their generation exist, such as cleavage of enol ethers and esters, halogen–metal exchange, transmetalations, and conjugate additions to α,β-unsaturated carbonyl compounds . In particular, the last-mentioned method is highly synthetically relevant. This approach has the advantage of being more selective and affording more molecular complexity in one step. In addition, transition-metal catalysis allows the introduction of stereogenic information, thus leading to chiral products. Enolate species are uniquely positioned for reactivity with a broad array of electrophiles and thus allowing quick and efficient construction of highly complex structures from readily available starting materials. Various polar organometallic reagents were successfully employed in asymmetric conjugate additions (ACA) , mainly organozinc , Grignard , trialkylaluminum , or organozirconium reagents . Additions with these reagents lead to corresponding zinc, magnesium, aluminum, and zirconium enolates, which all possess helpful and, to an extent, specific reactivity characteristics. Interesting boron and silicon enolates can be generated by asymmetric conjugate boration , or silylation . From several potentially catalytically active transition metals, copper combines beneficial properties for both activation of the Michael acceptor and the formation of intermediate organocuprates from stoichiometric organometallic reagents . Metal enolates formed in this way can react in many transformations (Scheme 1) . It has been documented that metal enolates from conjugate additions engaged in aldol, and Mannich-type reactions, Michael addition, nucleophilic substitutions, cyclopropanations, and reactions with carbocations. The field of asymmetric conjugate addition with its extension into enolate trapping reactions began to develop approximately in 1996. In this review article, we analyze more recent realizations of this strategy focusing on lesser-studied trapping reactions and works after 2010. We also present here our attempts to broaden the scope of these enolate trapping reactions by using different types of electrophilic reagents.

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Scheme 1: General scheme depicting tandem reactions based on an asymmetric conjugate addition followed by an enolate trapping.

Review Conjugate additions with organozinc reagents

Following the seminal work of Feringa in 1997 , the tandem asymmetric organozinc conjugate addition followed by subsequent aldol reaction was scarcely applied in the last decade. Welker and Woodward studied the reaction of zinc enolates 2 with chiral acetals 3 (Scheme 2) . The Lewis acid (TiCl4 or TMSOTf) promoted trapping gave the aldol adducts 4 in good to excellent diastereoselectivity (up to a single diastereomer), but the yields were relatively low (25–44%). To overcome this limitation, the authors used TMSOTf to prepare and isolate the corresponding silyl enol ethers, which were later successfully applied in the Mukiyama aldol reaction to gain the originally desired aldol adducts with improved yields and still good dr. Finally, the cerium ammonium nitrate (CAN) promoted one-step oxidative removal of the chiral auxiliary group was also successfully demonstrated.

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Scheme 2: Cu-catalyzed tandem conjugate addition of R2Zn/aldol reaction with chiral acetals.

In 2012, Aikawa et al. presented their work on the asymmetric desymmetrization of cyclopentene-1,3-diones 5 (Scheme 3) . Following the Cu(OTf)2-catalyzed conjugate addition of R2Zn, the enolate 6 was trapped by several aromatic aldehydes 7. These complex chiral cyclopentane derivatives 8 bearing all-carbon quaternary stereocenters were isolated in excellent yields and high diastereoselectivity. The authors have shown that catalyst loadings as low as 0.5 mol % can still be sufficient to promote the highly stereoselective reaction.

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Scheme 3: Cu-catalyzed asymmetric desymmetrization of cyclopentene-1,3-diones using a tandem conjugate addition/aldol reaction sequence.

Similarly to aldol reactions, Mannich-type additions are also suitable to trap the metal enolate. González-Gómez et al. studied the tandem conjugate addition of dialkylzincs to cyclic enones (9, 12) and the subsequent reaction of the enolate with N-tert-butanesulfinylimines 10 (Scheme 4) . Their method was applied to a broad range of substrates (5–7-membered rings) with equally high diastereoselectivity and good to excellent yields. In most cases, the authors detected only a single diastereomer in the crude reaction mixture (NMR). Using the enantiomeric form of the ligand or the chiral sulfoximine reagent, four diastereomeric β-aminoketones can be produced in excellent enantiomeric purity. Further transformations of the products were demonstrated in several examples, including reduction, acidic deprotection and subsequent base-mediated cyclization, or Baeyer–Villiger oxidation.

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Scheme 4: Stereocontrolled assembly of dialkylzincs, cyclic enones, and sulfinylimines utilizing a Cu-catalyzed tandem conjugate addition/Mannich reaction sequence.

At about the same time, Huang and co-workers have developed similar asymmetric tandem sequences using acyclic enones 14 . Their tandem conjugate addition/Mannich reaction methodology offers access to various non-cyclic β-aminoketones 16 with multiple contiguous stereocenters in high diastereo- and enantioselectivity (Scheme 5a). Additionally, chiral isoindolinones 18 and 2,3,4-trisubstituted azetidines 19 were also synthesized using this methodology (Scheme 5b).

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Scheme 5: Cu-catalyzed tandem conjugate addition/Mannich reaction (A). Access to chiral isoindolinones and trisubstituted azetidines with contiguous stereocenters (B).

Nitronate anions were also found suitable for Mannich-type trapping reactions . Anderson and co-workers accomplished several Cu-catalyzed conjugate additions of R2Zn to nitroolefins 20, followed by subsequent reaction with p-methoxyphenyl (PMP)-protected imines 21 (Scheme 6A). By varying the reaction conditions, the syn-anti and the syn-syn diastereomers can be prepared with good yields and excellent stereoselectivity. Using nitroacrylate 23, the authors have also demonstrated a tandem conjugate addition/nitro-Mannich/lactamization three-step reaction sequence resulting in trisubstituted nitropyrrolidinones 24 with exceptional enantioselectivity (Scheme 6B).

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Scheme 6: Cu-catalyzed tandem conjugate addition/nitro-Mannich reaction (A) with syn–anti or syn–syn selectivity (the products were isolated as trifluoroacetamide). Additional in situ lactamization results in nitropyrrolidinones with excellent stereoselectivity (B).

In contrast to conjugate additions to nitroolefins, these activated alkenes can also be utilized in the enolate trapping step. In the last decade, several highly stereoselective methodologies have been published that demonstrate the Cu- or Ni-catalyzed conjugate addition of organozincs to α,β-unsaturated ketones 14 followed by the reaction of the metal enolate with a nitroolefin (20) (Table 1) . These reactions were facilitated by different ligand families (phosphite/phosphine-pyridine amide, phosphine-sulfoxide, phosphoramidite, MINBOL, see Figure 1) and they usually showed excellent diastereoselectivity (dr >20:1). The catalytic systems even with low catalyst loadings tolerated both electron-donating and withdrawing groups on the aromatic substituents. Therefore, numerous structurally distinct substrates were successfully utilized.

Table 1: Tandem reactions composed of ACA of R2Zn and enolate trapping with nitroalkenes.

[Graphic 1] Reference Catalyst (mol %) Ligand (mol %) Conditions Yield (%) ee (%) Huang, 2011 CuCl (1.0) L3 (1.2) Et2O, − 20 °C, 24 h 52–90 91–97 Kang, 2011 Cu(OTf)2 (3.0) L6 (6.0) toluene, −40 °C 25–89 76–96 Uang, 2015 Ni(acac)2 (0.5) L7 (12.5) CH3CH2CN, −50 °C; then, 0 °C, 3 h 66–84 91–97 Hu, 2019 CuCl (2.0) L8 (2.5) toluene, 0 °C, 12 h 60–88 90–97
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Figure 1: Various chiral ligands utilized for the tandem conjugate addition/Michael reaction sequences.

Other than nitroolefins, Liao and co-workers have observed a side reaction of the α,β-unsaturated ketone 26 and the enolate 27 when they studied the conjugate addition of R2Zn reagents to chalcone and its derivatives (Scheme 7A) . Encouraged by this, they have also attempted an intramolecular tandem conjugate addition/Michael reaction sequence, which has resulted in the expected cyclization product 30 in a diastereopure form (Scheme 7B).

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Scheme 7: Cu-catalyzed tandem conjugate addition/Michael reaction: side-product formation with chalcone (A) and application to an intramolecular cyclization reaction (B).

Zinc enolates readily react with allyl iodides 31 or the structurally similar Stork–Jung vinylsilane reagents 33. Kawamura et al. performed zinc enolate trapping reactions using ligand L10, a chiral quinoline-based N,N,P-ligand (Scheme 8A) . The authors have concluded that the strict control of the amount of organozinc reagent added is essential to avoid side-product formation (diallylation) because the strongly basic R2Zn can form the enolate from the monoallylated product 32. Therefore, using only 1 equiv of dialkylzinc, the desired allylated products 32 were isolated in good yields and excellent diastereo- and enantioselectivity. Soon after, Jarugumilli et al. investigated the enolate-trapping tandem sequence using various vinylsilanes 33 (Scheme 8B), allyl halides 35, and benzyl bromide (37) (Scheme 8C) . Although the asymmetric conjugate addition step routinely provided excellent selectivity (93–96% ee), only a moderate to good diastereomeric ratio was achieved.

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Scheme 8: Zn enolate trapping using allyl iodides (A), Stork–Jung vinylsilane reagents (B), and allyl bromides or benzyl bromide (C).

Entrapping of the Zn enolate directly with acetyl chloride was found inefficient and led to a mixture of C-, O-, and diacylated products as described by Murphy and co-workers . Encouraged by the work of Noyori on the activation of Li enolates using Me2Zn , they have tried to facilitate the enolate trapping by adding MeLi (1.05 equiv), which indeed led to a significant increase in yield and selectivity due to the high reactivity of the lithium dialkyl zincate enolate. Various 1,3-diketones 39 were prepared using this method with good yields and excellent enantioselectivities while only the trans diastereomers were detected (Scheme 9A). Furthermore, the authors have also demonstrated a four-component coupling reaction: by simply increasing the amount of the organolithium reagent (2.05 equiv) used for the activation of the Zn enolate, β-hydroxyketones 40 were gained via 1,2-addition of the zincate nucleophile (R3Zn−) to the ketone with moderate yields but still good stereoselectivities (Scheme 9B).

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Scheme 9: Cu-catalyzed tandem conjugate addition/acylation through Li R2Zn enolate (A). A four-component coupling reaction using nucleophilic trialkyl zincate (B).

In 2018, Wang and co-workers extended the group of applicable electrophiles for the zinc enolate-based tandem reactions. Following the conjugate addition of Et2Zn to acyclic α,β-unsaturated ketones 41, they have shown that several electrophilic SCF3 reagents (e.g., 43) are suitable for enolate trapping (Scheme 10) . This way, the strong electron-withdrawing SCF3 group can be efficiently introduced stereoselectively allowing access to structurally diverse compounds with altered pharmacochemical properties. In several cases the α-SCF3-substituted ketones 44 were isolated in good yields and enantioselectivities but with low diastereoselectivities.

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Scheme 10: Selected examples for the Cu-catalyzed tandem conjugate addition/trifluoromethylthiolation sequence.

Even though no asymmetric catalyst was involved, Kawano et al. recently demonstrated an attractive one-pot procedure for preparing complex bicyclic and bridged compounds utilizing catalytically generated bicyclic Zn enolates .

Welker et al. have introduced the Pd-catalyzed trapping of zinc enolates with various vinyloxiranes . This way, several allylic alcohols 45 were synthesized with moderate yields and excellent enantioselectivities (up to 98%) but low trans/cis selectivity (Scheme 11). Organoaluminum reagents (Me3Al, Et3Al) were also compatible with the reaction, however, they gave lower yields than the corresponding organozincs. The authors have also shown that these products are suitable for forming [6,7]-bicyclic adducts.

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Scheme 11: Zn enolates trapped by vinyloxiranes: synthesis of allylic alcohols.

Conjugate addition with Grignard reagents

Feringa and co-workers realized the tandem conjugate addition of Grignard reagents to 4-chlorocrotonates 46 . The enolate 47, which was formed in this process, underwent an intramolecular nucleophilic substitution to form cyclopropane derivatives. Thioesters, esters as well as ketones were compatible with this process. The chiral ligand L12 afforded the highest enantioselectivities of up to 98% ee (Scheme 12).

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Scheme 12: Stereoselective cyclopropanation of Mg enolates formed by ACA of Grignard reagents to chlorocrotonates.

Conjugate addition of Grignard reagents to coumarin (49) generated the corresponding magnesium enolates 50 . In one instance, this enolate was trapped by benzaldehyde (51) (Scheme 13a). Related to this work, Feringa´s team realized also the conjugate addition to chromone (53) . The enolate was again trapped with benzaldehyde in an aldol reaction (Scheme 13b).

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Scheme 13: Domino aldol reactions of Mg enolates formed from coumarin and chromone.

Naphthol derivatives 55 bearing an α,β-unsaturated ester group undergo a copper(I)-catalyzed asymmetric conjugate addition. The magnesium enolates 56 then participated in a copper(II)-mediated intramolecular oxidative coupling to afford benzofused spirocyclic cycloalkanones 57 (Scheme 14) .

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Scheme 14: Oxidative coupling of ACA-produced Mg enolates.

Our team became interested in domino reactions of metal enolates generated by Cu-catalyzed asymmetric conjugate additions of Grignard reagents. At the outset of our studies, there were works in which dialkylzinc additions were utilized to generate zinc enolates, and these enolates were then trapped with chiral sulfonylimines . Specifically, we asked whether these magnesium enolates could be trapped with imines or their synthetic equivalents. Furthermore, we wanted to develop an enantioselective and diastereoselective process without adding chirality elements within the reagents.

For our initial studies, we have selected the well-studied cyclic enones as substrates and the Taniaphos ligand (L14) that has been shown to impart high levels of enantioselectivity for these ketones . We performed the conjugate addition for 2 h and then added imine 58 having a tosyl protecting group. The workup allowed the isolation of domino products 59 as a mixture of diastereomers with dr 3:2 and enantiomeric purities up to 97:3 er (Scheme 15) . These experiments showed that the concept of interception of magnesium enolates, derived from Cu-ACA, with imines can be realized. As it could have been predicted, chiral enolates reacted with high diastereoselectivity with their Si-face (attack anti to the R group introduced during the conjugate addition). On the other hand, a typical problem of these reactions was also revealed. The diastereoselectivity with respect to the addition to the imine was only very modest.

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Scheme 15: Tandem ACA of Grignard reagents to enones and Mannich reaction.

To address the problem of low facial selectivity of the imine addition, we continued our study with several imines bearing various N-protecting groups . We have argued that this protecting group could influence the enolate addition. Indeed, an effect of the nitrogen protecting group was observed. Interestingly, small sulfonyl-based protecting groups led to the (R,R,S)-diastereoisomer of the product 61. On the other hand, the sterically bulky diphenylphosphorane group afforded the (R,R,R)-diastereoisomer 63 as the main product. The large protecting group likely overrides the repulsive interaction between the enolate and a phenyl group in a preferred synclinal Mg-bound arrangement of the reagents (Scheme 16).

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Scheme 16: Diastereodivergent Mannich reaction of Mg enolates with differently N-protected imines.

Within the framework of these domino reactions, we have mainly employed ferrocenyl phosphane ligands such as Taniaphos or Josiphos. In collaboration with Prof. Schmalz from Cologne University, we have also tested phosphite-phosphine ligands (e.g., L15) from their lab. The advantage of these ligands is that they can also promote the conjugate additions of aryl-based or branched Grignard reagents (Scheme 17) .

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Scheme 17: Tandem Grignard–ACA–Mannich using Taddol-based phosphine-phosphite ligands.

Further extending this methodology, we have investigated formaldehyde imine equivalents. These kinds of imines are not readily available, but they are highly important synthetic building blocks providing an aminomethyl moiety upon adding nucleophiles. Protected formaldehyde aminals are useful synthetic equivalents to formaldehyde imines. The imine functionality can be unmasked (68) in the reaction medium by Lewis acids such as TiCl4. The formed Mg enolates 66 readily react with the transient iminium species 68 to afford the corresponding aminomethylation products 69 (Scheme 18) . As seen from Table 2, the diastereoselectivities were somewhat compromised compared to what one can expect from the reactions of cyclic enolates. This erosion was likely caused by Lewis acid-mediated epimerization.

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Scheme 18: Tandem reaction of Mg enolates with aminomethylating reagents.

Table 2: Domino aminomethylation of cyclic ketones with Grignard reagents.

RMgX Yield dr ee (trans) ee (cis) MeMgBr 66 2:1 92 95 MeMgI 27 2.7:1 84 88 n-PentMgBr 63 2.4:1 92 60 iPentMgBr 34 2.2:1 92 60 cyclopentylMgBr 16 n.d. 74 74 HexMgBr 41 1.8:1 92 92

Guénée et al. described the allylation, benzylation, and propargylation of magnesium enolates. These enolates were generated by a Cu-NHC-catalyzed conjugate addition of Grignard reagents to β-substituted cyclic enones (70) (Scheme 19) .

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Scheme 19: Tandem reaction composed of Grignard ACA to alkynyl enones.

Fox and co-workers developed an intriguing synthesis of enantiomerically enriched cyclobutanes 77 . Their strategy employed a three-component process in which tert-butyl (E)-2-diazo-5-arylpent-4-enoates 74 were treated with the chiral rhodium catalyst C1 to provide enantiomerically enriched bicyclobutanes 75. These highly strained compounds then participated in the Cu-catalyzed homoconjugate addition of Grignard reagents and subsequent enolate trapping to give densely functionalized cyclobutanes 77 with high diastereoselectivity (Scheme 20). The enolates were alkylated, allylated, benzylated, benzoylated, and thienylated.

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Scheme 20: Rh/Cu-catalyzed tandem reaction of diazo enoates leading to cyclobutanes.

Minnaard and co-workers developed a copper/Rev-Josiphos-catalyzed asymmetric conjugate addition of Grignard reagents to 2-methylcyclopentenone (78), which provided 2,3-disubstituted cyclopentanones in high yields and enantiomeric purities . The one-pot alkylation reaction of the in situ formed magnesium enolate with alkylating reagents required the presence of 1,3-dimethyltetrahydropyrimidine-2(1H)-one (DMPU) (Scheme 21). Reactive alkylating reagents such as iodomethane, benzyl bromide, allyl iodide, propargyl bromide, or bromoacetate reacted well and afforded the products 80 in good yields.

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Scheme 21: Tandem Grignard-ACA of cyclopentenones and alkylation of enolates.

In an attempt to expand the available electrophiles for reactions with metal enolates, we were inspired by the work of Cozzi and co-workers. They described reactions of organocatalytically generated enamines with stabilized carbenium ions . These seminal results prompted us to push this question further and we asked whether metal enolates generated by conjugate additions would be compatible and react productively with suitable carbenium ions (Scheme 22). To investigate this question, we started our study with the well-known conjugate additions of Grignard reagents to cyclic and linear enones 1, 85, and 87. At first, the addition of tropylium or benzodithiolium tetrafluoroborates were not highly productive because these onium compounds were not well soluble in typical solvents used for conjugate additions of organometallic reagents, e.g., Et2O, t-BuOMe or CH2Cl2. Therefore, we exchanged the BF4 anion in the onium compounds for the more lipophilic NTf2. This exchange led to more soluble onium compounds 81 and 83, and consequently, also significantly improved the reaction with the metal enolates. As a result, the corresponding products were successfully isolated with tropylium and benzodithiolium cations . The reaction worked well with Mg enolates generated from cyclic and linear enones 1 and 85 and enoyloxazolidinones 87. Apart from the most robust tropylium and benzodithiolium cations, reactions were also possible with the dianisylmethylium cation. Interestingly, tritylium cations reacted only in the para-position of a phenyl ring, while flavylium triflate and 2,4,6-triphenylpyrylium tetrafluoroborate were not compatible with our reaction conditions.

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Scheme 22: Tandem ACA of Grignard reagents followed by enolate trapping reaction with onium compounds.

Heterodonor ferrocenyl phosphane–carbene ligands efficiently promote the conjugate addition of Grignard reagents to α,β-unsaturated lactones . Building on this knowledge, we have investigated the domino reaction of the formed metal enolates with activated alkenes 91 . Alkenes with two activating groups were needed for efficient enolate-trapping reactions, sulfone or phosphonate activating groups being the most suitable ones (Scheme 23).

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Scheme 23: Mg enolates generated from unsaturated lactones in reaction with activated alkenes.

Harutyunyan and co-workers developed a Lewis acid-promoted conjugate addition to unreactive Michael acceptors such as amides or vinyl heterocycles . Trimethylsilyl triflate or boron trifluoride-activated unsaturated amides underwent highly efficient and enantioselective addition of Grignard reagents. When this methodology was applied to a substrate with a pending bromo substituent (93), the formed enolate 94 underwent a spontaneous cyclization via an SN2 displacement (Scheme 24).

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Scheme 24: Lewis acid mediated ACA to amides and SN2 cyclization of a Br-appended enolate.

The Harutyunyan team showed that this methodology also applies to aza-enolates that are generated by the conjugate addition of Grignard reagents to alkenyl heteroarenes . The aza-enolates were trapped with various Michael acceptors such as unsaturated ketones, esters, and amides (Scheme 25) . The authors noted a strong substrate dependence of this process. The trapping reaction worked best with benzoxazole-derived substrate, while thiazole was also possible. Among electrophilic reagents, unsaturated esters worked best.

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Scheme 25: Trapping reactions of aza-enolates with Michael acceptors.

In collaboration with the Harutyunyan group, we have further explored the possibilities of chiral enolate trapping which were obtained by asymmetric conjugate addition of organometallic reagents. We intended to employ the Lewis acid-mediated generation of magnesium enolates in the trapping reactions with carbocations. Indeed, unsaturated amides, alkenyl heterocycles, or even unsaturated carboxylic acids successfully participated in this process affording structurally interesting

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