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of alkenes, in most cases with full chemoselectivity. A mixture of 3,4,5-trimethoxybenzoic acid (1 equiv) and ethyl vinyl ketone (2 equiv) was heated in dioxane at ...
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Received 00th January 20xx, Accepted 00th January 20xx

Rhodium-catalysed Tandem Dehydrogenative Coupling− −Michael addition: Direct Synthesis of Phthalides from Benzoic Acids and Alkenes

DOI: 10.1039/x0xx00000x

Andrea Renzetti,*

a,b,c

b

c

Hiroshi Nakazawa and Chao-Jun Li*

www.rsc.org/

[(COD)RhCl]2 catalyses the coupling of benzoic acids and alkenes in the presence of Cu(OAc)2·H2O and dicyclopentadiene to afford phthalides in 15− −93% yield. A 3-substituted or 3,7-disubstituted product is obtained selectively depending on alkene type. The reaction is highly atom-economical and uses readily available starting materials.

CO 2R

(a) Miura

[Cp*RhCl2]2 (0.01 eq)

COOH

+ COOR

(b) Shi

+

Phthalides (isobenzofuranones) are an important class of natu1-3 ral lactones, with a wide range of biological activities. They 2, 3 3, 4 are mainly used as folk medicines, flavorings, and building 1, 5-10 blocks for the preparation of bioactive compounds. Most of the methods for the synthesis of phthalides suffer from the 1 limited availability of starting materials. This limitation has been overcome by the advent of dehydrogenative coupling reactions, which allow to make a C−C bond from two C−H bonds using simple, unfunctionalised reactants with high atom 11-15 economy. In this context, Miura et al. have reported the synthesis of 3-alkylidenephthalides from benzoic acid and 16 acrylates (Scheme 1a). This method, although based on readily available starting materials, is not chemoselective and has a limited scope. Among the few direct and chemoselective 17-21 methods, some of us have recently reported the synthesis of 3-substituted phthalides from benzoic acids and aromatic 22 aldehydes catalysed by a Rh(III) complex (Scheme 1b). In this reaction, rhodium activates the ortho C−H bond of benzoic acid through the assistance of carboxylate group. Then, the aryl rhodium species undergoes a Grignard-type addition to aldehyde, which cyclizes dehydratively to afford phthalide. Because the ortho C−H bond activation directed by carboxylate 23, 24 group is a well-known reaction, we reasoned that a similar mechanism might take place by replacing the aldehyde with an α,β-unsaturated carbonyl compound (Scheme 1c).

a.

Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom. E-mail: [email protected]. Department of Chemistry, Graduate School of Science, Osaka City University, Osaka 558-8585, Japan. c. Department of Chemistry, McGill University, 801 Sherbrooke Street west, Montreal H3A 0B8, Quebec, Canada. E-Mail: [email protected]. †Electronic Supplementary Informa,on (ESI) available: Experimental procedure and characterisation data for all products. See DOI: 10.1039/x0xx00000x. b.

R2

R1

Cu(OAc)2—H2O (0.05 eq) o-xylene air, 120 °C

O

+

O

H

O

CO2R

Ag2CO3 (2.0 eq) dioxane, Ar, 150 °C

CO 2R

O

[Cp*RhCl2]2, (0.08 eq), AgOTf (0.40 eq)

O

COOH

CO2R O

O R1

R2

O

R2 = COEt, CONMe 2 [(COD)RhCl] 2 (0.08 eq) AgOTf (0.24 eq)

(c) This work COOH

+ R1

R2

Cu(OAc)2—H2O (4.0 eq) DCPD (0.32 eq) PhCl, air, 120 °C

O R1

R2

SO2Et O

R2 = SO2Et

O R1

SO2Et

Scheme 1 Synthesis of 3-substituted phthalides.

In this case, C−H olefination would take place via Michael addition of aryl rhodium to the β-carbon of the unsaturated compound. Subsequent attack of the carboxylate group to the olefin moiety would result into ring closing with generation of phthalide. Here we report a direct synthesis of 3-substituted phthalides from benzoic acids and alkenes. The reaction uses readily available starting materials and tolerates a wide range of alkenes, in most cases with full chemoselectivity. A mixture of 3,4,5-trimethoxybenzoic acid (1 equiv) and ethyl vinyl ketone (2 equiv) was heated in dioxane at 120 °C for 48 h in the presence of [Cp*RhCl2]2 (8 mol%), AgOTf (24 mol%), and Ag2CO3 (2 equiv). Under these conditions, two products were isolated (Table 1, entry 2): 1a (monosubstituted) and 2 (disubstituted). The catalytic activity was examined in the presence of several compounds of rhodium, iridium, and ruthenium (Table 1). Complex [Cp*Rh(MeCN)3](SbF6)2 displayed the highest activity, providing an overall 57% yield based on the amount of benzoic acid (Table 1, entry 5). However, cyclooctadienyl complex [(COD)RhCl]2 was selected for further optimisation studies as it afforded 1a as the only product (Table 1, entry 6).

J. Name., 2013, 00, 1-3 | 1

This journal is © The Royal Society of Chemistry 20xx

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Table 1 Catalyst screening (selected results).

Table 2. Additive, oxidant, and solvent optimisation (selected a results). H3CO

O

COOH

+

additive oxidant solvent 120 °C, 48 h

H3CO OCH3

b

Entry

Catalyst

1 2 3 4 e 5 6 f 7 8 9 e 10 11 12 13

none (Cp*RhCl2)2 (Cp*IrCl2)2 CpRuCl(PPh3)2 [Cp*Rh(MeCN)3](SbF6)2 [(COD)RhCl]2 [(COD)RhCl]2 [(COD)RhOH]2 [(nbd)RhCl]2 [(COD)2Rh]BF4 [(COD)IrCl]2 [(COD)RuCl2]n [(CH2=CH2)2RhCl]2

O

[(COD)RhCl]2 H CO 3 AgOTf

O

H3CO

O OCH3

1a

c

Yield (%) 1a 2 0 0 d d 23 (16) 48 (8) 3 5 0 0 30 27 29 0 21 0 28 0 46 7 13 0 9 0 0 0 16 0

a

Reaction conditions: 3,4,5-trimethoxybenzoic acid (0.1 mmol), ethyl vinyl ketone (0.2 mmol), catalyst (8 mol%), AgOTf (40 mol%), Ag2CO3 (0.2 mmol), dioxane (500 µL), 120 °C, 48 h, Ar. b Cp* = 1,2,3,4,5pentamethylcyclopentadienyl; Cp = cyclopentadienyl; COD = 1,5cyclooctadiene; nbd = norbornadiene. c NMR yield, calculated using 0.1 mmol of diethyl maleate as an internal standard. A 0 yield means no reaction. d Yield of purified product is shown in parentheses. e 16 mol% of catalyst were used. f Without AgOTf.

Screening of solvent and silver oxidant (Table 2, entries 1−5 and 6−8, respectively) revealed dioxane and Ag2CO3 to be the best combination (Table 2, entry 1). The use of 1,2,3,4tetraphenyl-1,3-cyclopentadiene (Ph4CpH2) as an additive in some dehydrogenative coupling reactions catalysed by 25-28 Rh(III) prompted us to investigate the effect of this compound on our reaction. The reaction in the presence of 0.16 equiv of Ph4CpH2 afforded a mixture of products 1a and 2a, as did 1,2,3,4,5-pentamethylcyclopentadiene (Table 2, entries 9 and 10, respectively). However, 1a was formed as the only product in 52% yield in the presence of dicyclopentadiene (DCPD, Table 2, entry 11). These results show that additive, in addition to metal complex, is crucial for chemoselectivity, presumably due to the effect played by the π acidity of diene 29 ligand on the Lewis acidity of metal. Yield further increased from 52 to 60% upon increasing the amount of DCPD from 0.16 to 0.32 equiv (Table 2, compare entries 11 and 12, respectively). Reoptimisation of oxidant and solvent allowed to obtain 1a in 93% isolated yield by using a combination of Cu(OAc)2·H2O in chlorobenzene (Table 2, entry 15). Under the optimised conditions, we investigated the reaction scope varying both benzoic acid and alkene (Table 3). In all cases, only product and unreacted starting materials were recovered after work-up, indicating a clean process. Benzoic acids bearing electron-donating groups provided higher yields than unsubsti-

b

Entry

Additive

Oxidant

Solvent

1 2 3 4 5 6 7 8 9 10 11 12 13 h 14 h 15

none none none none none none none none Ph4CpH2 Me5CpH DCPD g DCPD g DCPD g DCPD g DCPD

Ag2CO3 Ag2CO3 Ag2CO3 Ag2CO3 Ag2CO3 d AgOAc d AgNO3 Ag2O Ag2CO3 Ag2CO3 Ag2CO3 Ag2CO3 d Cu(OAc)2·H2O d Cu(OAc)2·H2O d Cu(OAc)2·H2O

dioxane THF DCE DMF EtOH dioxane dioxane dioxane dioxane dioxane dioxane dioxane dioxane PhCH3 PhCl

Yield c of 1a (%) 29 28 28 19 14 20 3 12 e 51 f 21 52 60 32 41 i 95 (93)

a Reaction conditions: 3,4,5-trimethoxybenzoic acid (0.1 mmol), ethyl vinyl ketone (0.2 mmol), [(COD)RhCl]2 (8 mol%), AgOTf (24 mol%), additive (16 mol%), oxidant (0.2 mmol), solvent (500 µL), 120 °C, 48 h, Ar. b Ph4CpH2 = 1,2,3,4-tetraphenyl-1,3-cyclopentadiene; Me5CpH = 1,2,3,4,5-pentamethylcyclopentadiene; DCPD = dicyclopentadiene. 16 mol% of additive were used, unless otherwise stated. c NMR yield, calculated using 0.1 mmol of diethyl maleate as an internal standard. d 0.4 mmol. e + 2 (22%). f + 2 (20%). g 32 mol%. h Under air. i Yield of purified product is shown in parentheses.

tuted benzoic acid or acids with electron-withdrawing groups (Table 3, compare the yields of 1b-f with those of 1g and 1h-k). This substituent effect suggests an aromatic electrophilic 30 substitution (SEAr) mechanism for C−H bond activation. 3,4,5-Tribenzyloxybenzoic acid was less reactive than 3,4,5trimethoxybenzoic acid, presumably due to the steric hindrance of substituents on the phenyl ring (75 and 93% yield, respectively). 2,3,4-Trimethoxybenzoic acid, having only one ortho position available for substitution, provided product 1b in about half the yield of 3,4,5-trimethoxybenzoic acid (40 and 93%, respectively). Meta-substituted benzoic acids, being non-symmetrical, afforded a mixture of regioisomers (1l/1l’ and 1n/1n’). m-Methoxybenzoic acid and β-naphthoic acid provided higher yield than the corresponding ortho- or parasubstituted compounds (Table 3, compare the yields of 1n/1n’ and 1l/1l’ with those of 1d and 1f, respectively). The high conversion observed for m-substituted benzoic acids can be explained by the fact that substituents in the meta position donate electrons to the benzene ring in the ortho position with respect to the carboxyl group, promo,ng C―H bond activation. In line with this trend, unsubstituted benzoic acid

2

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Table 3 Reaction scope.

a Reaction conditions: acid (0.3 mmol), alkene (0.6 [(COD)RhCl]2 (8 mol%), AgOTf (24 mol%), DCPD (32 Cu(OAc)2·H2O (1.2 mmol), PhCl (1.5 mL), 120 °C, 48 h, air. purified product is reported. b The ratio of regioisomers is parentheses and was determined by 1H NMR analysis.

mmol), mol%), Yield of given in

and para-substituted benzoic acids afforded the corresponding product in