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Palladium-catalysed enantioselective hydroaryloxycarbonylation of styrenes by 4-substituted phenols
Molecular Catalysis 438 (2017) 15–18
Contents lists available at ScienceDirect
Molecular Catalysis journal homepage: www.elsevier.com/locate/mcat
Research Paper
Palladium-catalysed enantioselective hydroaryloxycarbonylation of styrenes by 4-substituted phenols Péter Pongrácz a,b , Anas Abu Seni a , László T. Mika c , László Kollár a,b,∗ a b c
Department of Inorganic Chemistry, University of Pécs and János Szentágothai Science Centre, H-7624 Pécs, Hungary MTA-PTE Research Group for Selective Chemical Syntheses, H-7624 Pécs, Hungary Department of Chemical and Environmental Process Engineering, Budapest University of Technology and Economics, H-1111 Budapest, Hungary
a r t i c l e
i n f o
Article history: Received 29 March 2017 Received in revised form 10 May 2017 Accepted 11 May 2017 Available online 25 May 2017 Keywords: Carbon monoxide Hammett-constants Palladium Ester Regioselectivity Carbonylation Phenol
a b s t r a c t Palladium-catalysed hydroaryloxycarbonylation of a set of styrenes was performed under carbon monoxide atmosphere towards the corresponding propanoic acid aryl esters. The reaction conditions were optimized and several phosphine ligands (achiral mono- and bidentate, chiral (enantiopure) bidentate) were investigated in Pd-catalyst systems generated in situ. In general, the application of mono- and diphosphines favours the formation of branched and linear regioisomers, respectively. Carrying out the reaction in enantioselective fashion, the DIOP modified catalyst proved to be the most efficient one among the chiral ligands studied. The substituent effect on the regio- and enantioselectivity was also investigated regarding both the substrate (styrene) and the O-nucleophile (phenol) with Pd-DIOP system. Simultaneous modifications of substituents of the ‘reactants’ were also carried out. The preference of the linear ester regioisomer and low enantiomeric excesses were obtained. © 2017 Published by Elsevier B.V.
1. Introduction Transition metal catalysed carbonylation reactions are widely used as synthetic tools to get valuable molecules with practical importance or building blocks in subsequent syntheses [1–3]. Optically active esters, aldehydes, carboxylic acids and their derivatives are intermediates for pharmaceuticals or other fine chemicals [4], for example enantioselective carbonylation of vinyl aromatics to 2-arylpropanoic acids has potential application in the synthesis of nonsteroidal anti-inflammatory drugs, such as ibuprofen or suprofen. The addition of nucleophiles and carbon monoxide to alkenes and alkynes, known as Reppe carbonylation, is a well-studied versatile reaction, where alcohols have been utilized in most cases [5–7]. The hydroaryloxycarbonylation reaction using phenols as O-nucleophiles in the carbonylation reaction is a promising strategy for the syntheses of aryl esters. However, it is hard to develop and only sporadic results can be found in the literature. For instance, Miura and Nomura have reported the carbonylation of terminal alkynes using palladium-phosphine complexes in
∗ Corresponding author at: Department of Inorganic Chemistry, University of Pécs and János Szentágothai Science Centre, H-7624 Pécs, Hungary. E-mail address: [email protected] (L. Kollár). http://dx.doi.org/10.1016/j.mcat.2017.05.010 2468-8231/© 2017 Published by Elsevier B.V.
the presence of 3- or 4-substituted phenols at low pressure [8]. Another study showed that some internal alkynes are also active substrates in Reppe carbonylation with phenol in the presence of excess amount of Zn [9]. The only example of using phenol derivative as O-nucleophile in the hydroaryloxycarbonylation of an alkene, was the reaction of cyclohexene with m-cresol catalysed by Pd-triphenylphosphine catalyst system [10]. The published results confirm the observation that the reactivity of the alcohol nucleophiles is much higher than that of the phenols for the carbonylation of alkenes. Furthermore, the reaction rate differences are also considerable between alkenes and alkynes in favour of the latter [11]. Developing carbon monoxide-free carbonylation reactions, numerous alternative CO surrogates were tested [12]. Beside a number of alkynes, various alkenes such as norbornene and styrene were also readily reacted with aryl formates towards the corresponding aryl esters in hydroesterification reaction, i.e., in the aryl formate addition on the alkene functionality [13,14]. The substrate scope for the asymmetric hydroesterification reaction was also investigated [15]. Katafuchi et al. [13] suggested the decomposition of the formates under catalytic conditions to produce CO and phenol derivatives, which is based on the observation of pressure increase up to 40 bar in the reaction vessel. Based on the above results, the detailed investigation of hydroaryloxycarbonylation reaction of terminal alkenes under
16
P. Pongrácz et al. / Molecular Catalysis 438 (2017) 15–18
Table 1 Optimisation of hydrophenoxycarbonylation reaction.a Entry c
1 2 3 4 5 6 7d 8e 9 10 11 12 13 14 15 16 17 18 19f 20g 21h
Ligand
Acid
R. time [h]
Conversion [%]
Rbr b [%](ee,abs.conf)
PPh3 PPh3 PPh3 PPh3 PPh3 PPh3 PPh3 PPh3 DPPB XANTPHOS (S, S)- BDPP (R)-BINAP (R)-(S)-JOSIPHOS DPPP (R)-PHANEPHOS (R)-DIOP (R)-DIOP (R)-DIOP (R)-DIOP (R)-DIOP (R)-DIOP
TsOH (COOH)2 CCl3 COOH HCl (1 drop) HCl (3 drops) HCl (5 drops) HCl HCl HCl HCl HCl HCl HCl HCl HCl HCl HCl HCl HCl HCl HCl
24 24 24 24 24 24 24 24 48 24 72 24 24 24 48 24 48 72 144 72 24
>99 6 1 50 90 78 8 98 12 28 0 0 0 2 45 22 77 >99 85 50 >99
47 >99 – 81 96 75 94 75 25 16 – – – 45 24 (18 R) 18 16 14 (2 R) 9 (2 R) 20 (6 R) 18 (1 R)
a Reaction conditions: 0.01 mmol of Pd(OAc)2 (entries 1–8) or 0.01 mmol of PdCl2 (PhCN)2 (entries 9–21), 0.06 mmol monodentate P-ligand or 0.04 mmol bidentate P-ligands, 6 mmol phenol, 1 mmol styrene, T = 100 ◦ C, p(CO) = 100 bar, solvent: 10 mL of toluene, HCl = 3 drops ≈ 30 L ≈ 0.35 mmol, other acids = 0.35 mmol. b Regioselectivity towards branched ester (3aa). [moles of 3aa/(moles of 3aa + moles of 4aa) × 100]. c Chemoselectivity towards esters is 17%. High extent of ether formation was observed. d Styrene nucleophile ratio was 1:2. e Styrene nucleophile ratio was 1:10. f p(CO) = 10 bar. g T = 80 ◦ C. h T = 120 ◦ C.
moderate reaction conditions seemed to be realistic. We report here the optimization of the conditions of hydroesterification reaction using styrene and its 4-substituted derivatives as substrates, as well as 4-substituted phenol derivatives as O-nucleophiles under carbon monoxide atmosphere. Furthermore, the substituent effect on the reactivity, chemo-, regio- and enantioselectivity was also investigated both in case of the substrate (styrenes) and the nucleophile (phenols). 2. Experimental 2.1. General
concentrated HCl was transferred under argon atmosphere into a 100 mL stainless steel autoclave. The autoclave was pressurized with carbon monoxide to 100 bar total pressure and placed in a preheated oil bath. The mixture was stirred with a magnetic stirrer for the time given in Table 1. The pressure was monitored throughout the reaction. After cooling and venting of the autoclave, the solution was removed and immediately analysed by GC and GC–MS.
2.3. Reduction of esters 2 mL of LiAlH4 solution (1 mol/dm3 in THF) was transferred into a dry two-necked flask equipped with a magnetic stirrer. Condenser and dropping funnel containing solution of the esters (1 mmol in 5 mL THF, purified by column chromatography) was connected to the flask. From the dropping funnel the solution was added slowly to the reducing agent under continuous stirring (5 min). After adding the whole amount of solution, the mixture was heated to reflux temperature (66 ◦ C) and stirred for overnight. After the reaction was completed, the reaction mixture was cooled in water and ice, then cold water was added cautiously to the reaction mixture to decompose the excess of the reagent. When no hydrogen was evolved by water addition, diluted sulphuric acid (10%) was added to dissolve the Al(OH)3 precipitate. The products were extracted with diethyl ether (10 mL) and the organic phase was washed with saturated NaCl solution and dried over Na2 SO4 . After filtration and evaporation of the solvent the alcohols were analysed by chiral GC to determine the enantiomeric excess.
The PdCl2 (PhCN)2 precursor was synthesised from PdCl2 (Aldrich) according to standard procedures [16]. The ligands (TPP, DIOP, XANTPHOS, etc.) were purchased from Sigma-Aldrich Kft., Budapest, Hungary. Toluene was distilled and purified by standard methods and stored under argon. All reactions were carried out under argon using standard Schlenk techniques. The 1 H- and 13 C NMR spectra were recorded on a Bruker AvanceIII 500 spectrometer. Chemical shifts are reported in ppm relative to TMS (downfield) for 1 H- and 13 C NMR spectroscopy. Conversions and selectivities were determined using GC and GC–MS. The enantiomeric excess was determined by using a chiral capillary column (CycloSil-B (30m × 0,25 mm)): (injection temperature: 250 ◦ C; starting oven temperature: 50 ◦ C; 1st rate: 2 ◦ C/min; final temperature: 150 ◦ C; 2nd rate 25 ◦ C/min; final temperature: 230 ◦ C/min; carrier gas: He 1.30 mL/min). The esters were purified by column chromatography (Silica gel, 0.063 mm; CHCl3 ) and isolated as colourless liquids.
3. Results
2.2. Hydroaryloxycarbonylation experiments
3.1. Optimisation of the hydrophenoxycarbonylation reaction
In a typical experiment, a solution of PdCl2 (PhCN)2 (3.8 mg; 0.01 mmol) and (R)-DIOP (19.9 mg; 0.04 mmol) in toluene (10 mL) containing 1 mmol substrate, 6 mmol nucleophile and 3 drops of
Initially, we examined the feasibility of the palladium-catalysed hydrophenoxycarbonylation of styrene (1a) with phenol (2a) to give the corresponding ester regioisomers (3a and 4a). As starting
P. Pongrácz et al. / Molecular Catalysis 438 (2017) 15–18
17
Scheme 1. Hydrophenoxycarbonylation of styrene in the presence of palladium catalyst.
Scheme 2. Hydroaryloxycarbonylation reactions using 4-substituted styrenes as substrates and 4-substituted phenol nucleophiles.
reaction conditions, Pd(OAc)2 precursor and PPh3 ligand under carbon monoxide pressure (100 bar) at 100 ◦ C were chosen (Scheme 1). It is known [6–8] that in order to obtain high activities in hydroalkoxycarbonylation reaction it is crucial to have an excess of an acid in the reaction mixture. In the presence of paratoluenesulfonic acid (PTSA) only small amount (17%) of ester regioisomers could be detected (Table 1 entry 1) and the main products were ethers that formed via a simple acid catalysed nucleophilic addition reaction [17]. In the presence of oxalic acid and trichloroacetic acid no phenol addition was occurred, but low conversions to esters were achieved (entries 2, 3, respectively). By the use of concentrated hydrochloric acid, remarkable increase in activity was observed. Increasing the amount of the acid additive the reaction was accelerated but upon addition of more than 3 drops of cc. HCl small decrease of activity took place (entries 4–6). It is known that the excess of the nucleophile, over the stoichiometric amount has positive impact on activity in hydroalkoxycarbonylation reaction, therefore the effect of phenol excess was also examined. It was found, that 1:6 substrate:nucleophile ratio was optimal in the reaction. Further increase of the phenol excess did not cause remarkable increase in activity (entries 7, 8). Next, the optimized conditions were applied examining the activity of in situ generated palladium catalysts incorporated with a series of achiral and chiral bidentate ligands (entries 9–14). All of the ligands examined gave lower catalytic activity than the monodentate PPh3 but after exploring the wide array of conditions we found that the application of another Pd-precursor, PdCl2 (PhCN)2 slightly increases the catalytic activity in case of bidentate ligands. Interestingly, most of the tested ligands were inactive. It seems that ligands with smaller bite angle (BDPP, BINAP, DPPP, DBBP and JOSIPHOS) are not effective or give low conversions in the hydroaryloxycar-
bonylation reaction, whereas the application of larger bite angle ligands (XANTPHOS, PHANEPHOS and DIOP) resulted in the formation of the target esters. Since the highest activities were obtained with DIOP-containing in situ systems, this ligand was chosen for further investigations. As it was expected, the regioselectivity towards branched ester (3aa) using bidentate ligands was also much lower than in case of PPh3 . The reaction temperature substantially effects the activity of the Pd-DIOP catalyst system, but no strong influence on the regioselectivity was obtained (entries 20, 21). It is worth noting that the reaction can be carried out under low CO pressure, but much longer reaction time was required and the regioselectivity also decreased (entries 19) It has to be added that under atmospheric conditions (1 bar CO) only side-products, that is, styrene-phenol adducts and styrene dimers can be detected. 3.2. Substituent effect To determine whether the substituents of styrene and phenol have any influence on the regio- and enantioselectivity, hydroaryloxycarbonylation experiments of various 4-substituted derivatives (1a–g and 2a–j) in the presence of in situ system, formed from PdCl2 (PhCN)2 and (R)-DIOP were conducted under optimized conditions (Scheme 2). The regioselectivity towards branched esters (3(a–g)(a–j)) does not show significant differences by varying the para-substituents either on the styrene or on the phenol. A small increase in branched ester formation can be observed using styrene substituents possessing electron donating properties (1b, 1c, 1d) (Table 2, entries 2–4). Electron withdrawing substituents have reversed influence on regioselectivity. The formation of branched ester regioisomers
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P. Pongrácz et al. / Molecular Catalysis 438 (2017) 15–18
Table 2 Substituent effects on the hydroaryloxycarbonylation reaction.a Entry
Styrene (substituent)
Phenol (substituent)
R. time [h]
Conv. [%]
Rbr b [%]
eec
1 2 3 4 5 6 7d 8 9 10 11 12 13 14 15 16 17 18 19 20
1a (H) 1b (Me) 1c (OMe) 1d (Ph) 1e (F) 1f (Cl) 1f (Cl) 1g (CF3 ) 1a (H) 1a (H) 1a (H) 1a (H) 1a (H) 1a (H) 1a (H) 1a (H) 1a (H) 1f (Cl) 1f (Cl) 1b (Me)
2a (H) 2a (H) 2a (H) 2a (H) 2a (H) 2a (H) 2a (H) 2a (H) 2b (Me) 2c (OMe) 2d (Ph) 2e (F) 2f (Cl) 2g (CF3 ) 2h (Br) 2i (iPr) 2j (CHO) 2j (CHO) 2h (Br) 2c (OMe)
48 96 96 96 72 48 120 96 48 48 48 48 48 48 48 48 72 120 48 48
77 96 >99 91 >99 75 77 >99 53 56 98 68 68 37 65 52 >99 42 83 87
16 22 20 18 16 14 17 9 16 20 18 19 19 15 17 20 25 17 16 20
2 (R) 7 (R) 0 n.d. 0 10 (R) 14 (R) 0 1 (R) 5 (R) 1 (R) 5 (R) 0 (R) 5 (R) 9 (R) 0 (R) 8 (R) 11 (R) 4 (R) 2 (R)
a b c d
Reaction conditions: 0.01 mmol of PdCl2 (PhCN)2 , 0.04 mmol (R)-DIOP, 6 mmol nucleophile, 1 mmol substrate, T = 100 ◦ C, p(CO) = 100 bar, solvent: 10 mL of toluene. Regioselectivity towards branched ester (3a). [moles of 3a/(moles of 3a + moles of 4a) × 100]. Enantioselectivities were determined after reduction by chiral GC. (S)-2-phenylpropanol was eluted before the (R) enantiomer. T = 80 ◦ C.
are less preferred in these cases, especially low preference for branched ester regioisomer was observed with 4-trifluoromethyl styrene, that is, when 1g was reacted with the parent nucleophile (2a) resulting in the formation of branched ester 3ga (entry 8). The 4-substituents of phenol ring have no such clear effect on regioselectivity. Similar branched selectivities were obtained in case of all substituents, irrespectively to electronic properties. That is, the regioselectivities were very close to that obtained for the parent derivative 3aa (branched ester obtained from unsubstituted styrene (1a) and phenol (2a)). In general, low enantioselectivities (ee-s up to 14%) were observed and the formation of aryl (R)-2-arylpropanoates were favoured in all cases. In some cases, racemic or close to racemic mixtures were formed. No obvious correlation can be observed between enantiomeric excesses and electronic properties (characterised by Hammett substituent constant (p )) of para-substituents of styrene and phenol. The best ee-s were achieved with methyl and chloro substituted styrenes (entry 2 and 6) and further increase can be obtained by lowering the reaction temperature to 80 ◦ C (entry 7). The bromo and formyl substitution of phenol derivative provided the best optical yields on the perspective of the nucleophile (entries 15, 17). Low preference of the R-enantiomer can be seen in case of methoxy, fluoro and trifluoromethyl substituents while close to racemic mixture was produced in the presence of methyl, phenyl, isopropyl and chloro substituents. Further experiments were carried out to examine the combined effect of the substituents, modifying the substrate and the nucleophile side at the same time. It can be stated that the influences of the substituents are not strengthening each other. In case of 3fh even lower ee was obtained than that of 3fa and 3ah. Similarly, lower ee was obtained for 3bc than for 3ba and 3ac (entries 18–20).
the synthesis of the variety of aryl 2-arylpropionates and their linear regioisomers. Acknowledgements The authors thank the Hungarian Research Fund (K113177) for the financial support. This work was also supported by the GINOP2.3.2-15-2016-00049 grant. The present scientific contribution is dedicated to the 650th anniversary of the foundation of the University of Pécs, Hungary. L.T. Mika is grateful for support from the János Bolyai Research Scholarship of the Hungarian Academy of Sciences. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.mcat.2017.05. 010. References [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13]
4. Summary Hydroaryloxycarbonylation and enantioselective hydroaryloxycarbonylation (hydroesterification) of 4-substituted styrenes were carried out in the presence of palladium-catalysts. The reaction shows high functional group tolerance regarding both the substrates and the O-nucleophiles. The catalytic process enabled
[14] [15] [16] [17]
R. Franke, D. Selent, A. Boerner, Chem. Rev. 112 (2012) 5675–5732. X.-F. Wu, H. Neumann, M. Beller, Chem. Rev. 113 (2013) 1–35. Q. Liu, H. Zhang, A.W. Lei, Angew. Chem. Int. Ed. 50 (2011) 10788–10799. K. Nozaki, I. Ojima, Catalytic Asymmetric Synthesis, second edition, Wiley-VCH, 2000. G. Kiss, Chem. Rev. 101 (2001) 3435–3456. P. Kalck, M. Urrutigoïty, Inorg. Chim. Acta 431 (2015) 110–121. ˇ C. Godard, B.K. Munoz, A. Ruiz, C. Claver, Dalton. Trans. (2008) 853–860. I.K.M. Miura, M. Nomura, Tetrahedron Lett. 33 (1992) 5369–5372. H. Kuniyasu, T. Yoshizawa, N. Kambe, Tetrahedron Lett. 51 (2010) 6818–6821. V.A. Aver’yanov, N.M. Nosova, E.V. Astashina, N.T. Sevost’yanova, Pet. Chem. 47 (2007) 186–195. Shell (Drent E.) EP 0,441,446 (1991). L. Wu, Q. Liu, R. Jackstell, M. Beller, Angew. Chem. Int. Ed. 53 (2014) 6310–6320. Y. Katafuchi, T. Fujihara, T. Iwai, J. Terao, Y. Tsui, Adv. Synth. Catal. 353 (2011) 475–482. I. Fleischer, R. Jennerjahn, D. Cozzula, R. Jackstell, R. Franke, M. Beller, ChemSusChem 6 (2013) 417–420. J. Li, W. Chang, W. Ren, J. Dai, Y. Shi, Org. Lett. 18 (2016) 5456–5459. F.R. Hartley, Organomet. Chem. Rev. Sect. A 6 (1970) 119. Z. Li, J. Zhang, C. Brouwer, C. Yang, N.W. Reich, C. He, Org. Lett. 8 (2006) 4175–4178.
Contents lists available at ScienceDirect
Molecular Catalysis journal homepage: www.elsevier.com/locate/mcat
Research Paper
Palladium-catalysed enantioselective hydroaryloxycarbonylation of styrenes by 4-substituted phenols Péter Pongrácz a,b , Anas Abu Seni a , László T. Mika c , László Kollár a,b,∗ a b c
Department of Inorganic Chemistry, University of Pécs and János Szentágothai Science Centre, H-7624 Pécs, Hungary MTA-PTE Research Group for Selective Chemical Syntheses, H-7624 Pécs, Hungary Department of Chemical and Environmental Process Engineering, Budapest University of Technology and Economics, H-1111 Budapest, Hungary
a r t i c l e
i n f o
Article history: Received 29 March 2017 Received in revised form 10 May 2017 Accepted 11 May 2017 Available online 25 May 2017 Keywords: Carbon monoxide Hammett-constants Palladium Ester Regioselectivity Carbonylation Phenol
a b s t r a c t Palladium-catalysed hydroaryloxycarbonylation of a set of styrenes was performed under carbon monoxide atmosphere towards the corresponding propanoic acid aryl esters. The reaction conditions were optimized and several phosphine ligands (achiral mono- and bidentate, chiral (enantiopure) bidentate) were investigated in Pd-catalyst systems generated in situ. In general, the application of mono- and diphosphines favours the formation of branched and linear regioisomers, respectively. Carrying out the reaction in enantioselective fashion, the DIOP modified catalyst proved to be the most efficient one among the chiral ligands studied. The substituent effect on the regio- and enantioselectivity was also investigated regarding both the substrate (styrene) and the O-nucleophile (phenol) with Pd-DIOP system. Simultaneous modifications of substituents of the ‘reactants’ were also carried out. The preference of the linear ester regioisomer and low enantiomeric excesses were obtained. © 2017 Published by Elsevier B.V.
1. Introduction Transition metal catalysed carbonylation reactions are widely used as synthetic tools to get valuable molecules with practical importance or building blocks in subsequent syntheses [1–3]. Optically active esters, aldehydes, carboxylic acids and their derivatives are intermediates for pharmaceuticals or other fine chemicals [4], for example enantioselective carbonylation of vinyl aromatics to 2-arylpropanoic acids has potential application in the synthesis of nonsteroidal anti-inflammatory drugs, such as ibuprofen or suprofen. The addition of nucleophiles and carbon monoxide to alkenes and alkynes, known as Reppe carbonylation, is a well-studied versatile reaction, where alcohols have been utilized in most cases [5–7]. The hydroaryloxycarbonylation reaction using phenols as O-nucleophiles in the carbonylation reaction is a promising strategy for the syntheses of aryl esters. However, it is hard to develop and only sporadic results can be found in the literature. For instance, Miura and Nomura have reported the carbonylation of terminal alkynes using palladium-phosphine complexes in
∗ Corresponding author at: Department of Inorganic Chemistry, University of Pécs and János Szentágothai Science Centre, H-7624 Pécs, Hungary. E-mail address: [email protected] (L. Kollár). http://dx.doi.org/10.1016/j.mcat.2017.05.010 2468-8231/© 2017 Published by Elsevier B.V.
the presence of 3- or 4-substituted phenols at low pressure [8]. Another study showed that some internal alkynes are also active substrates in Reppe carbonylation with phenol in the presence of excess amount of Zn [9]. The only example of using phenol derivative as O-nucleophile in the hydroaryloxycarbonylation of an alkene, was the reaction of cyclohexene with m-cresol catalysed by Pd-triphenylphosphine catalyst system [10]. The published results confirm the observation that the reactivity of the alcohol nucleophiles is much higher than that of the phenols for the carbonylation of alkenes. Furthermore, the reaction rate differences are also considerable between alkenes and alkynes in favour of the latter [11]. Developing carbon monoxide-free carbonylation reactions, numerous alternative CO surrogates were tested [12]. Beside a number of alkynes, various alkenes such as norbornene and styrene were also readily reacted with aryl formates towards the corresponding aryl esters in hydroesterification reaction, i.e., in the aryl formate addition on the alkene functionality [13,14]. The substrate scope for the asymmetric hydroesterification reaction was also investigated [15]. Katafuchi et al. [13] suggested the decomposition of the formates under catalytic conditions to produce CO and phenol derivatives, which is based on the observation of pressure increase up to 40 bar in the reaction vessel. Based on the above results, the detailed investigation of hydroaryloxycarbonylation reaction of terminal alkenes under
16
P. Pongrácz et al. / Molecular Catalysis 438 (2017) 15–18
Table 1 Optimisation of hydrophenoxycarbonylation reaction.a Entry c
1 2 3 4 5 6 7d 8e 9 10 11 12 13 14 15 16 17 18 19f 20g 21h
Ligand
Acid
R. time [h]
Conversion [%]
Rbr b [%](ee,abs.conf)
PPh3 PPh3 PPh3 PPh3 PPh3 PPh3 PPh3 PPh3 DPPB XANTPHOS (S, S)- BDPP (R)-BINAP (R)-(S)-JOSIPHOS DPPP (R)-PHANEPHOS (R)-DIOP (R)-DIOP (R)-DIOP (R)-DIOP (R)-DIOP (R)-DIOP
TsOH (COOH)2 CCl3 COOH HCl (1 drop) HCl (3 drops) HCl (5 drops) HCl HCl HCl HCl HCl HCl HCl HCl HCl HCl HCl HCl HCl HCl HCl
24 24 24 24 24 24 24 24 48 24 72 24 24 24 48 24 48 72 144 72 24
>99 6 1 50 90 78 8 98 12 28 0 0 0 2 45 22 77 >99 85 50 >99
47 >99 – 81 96 75 94 75 25 16 – – – 45 24 (18 R) 18 16 14 (2 R) 9 (2 R) 20 (6 R) 18 (1 R)
a Reaction conditions: 0.01 mmol of Pd(OAc)2 (entries 1–8) or 0.01 mmol of PdCl2 (PhCN)2 (entries 9–21), 0.06 mmol monodentate P-ligand or 0.04 mmol bidentate P-ligands, 6 mmol phenol, 1 mmol styrene, T = 100 ◦ C, p(CO) = 100 bar, solvent: 10 mL of toluene, HCl = 3 drops ≈ 30 L ≈ 0.35 mmol, other acids = 0.35 mmol. b Regioselectivity towards branched ester (3aa). [moles of 3aa/(moles of 3aa + moles of 4aa) × 100]. c Chemoselectivity towards esters is 17%. High extent of ether formation was observed. d Styrene nucleophile ratio was 1:2. e Styrene nucleophile ratio was 1:10. f p(CO) = 10 bar. g T = 80 ◦ C. h T = 120 ◦ C.
moderate reaction conditions seemed to be realistic. We report here the optimization of the conditions of hydroesterification reaction using styrene and its 4-substituted derivatives as substrates, as well as 4-substituted phenol derivatives as O-nucleophiles under carbon monoxide atmosphere. Furthermore, the substituent effect on the reactivity, chemo-, regio- and enantioselectivity was also investigated both in case of the substrate (styrenes) and the nucleophile (phenols). 2. Experimental 2.1. General
concentrated HCl was transferred under argon atmosphere into a 100 mL stainless steel autoclave. The autoclave was pressurized with carbon monoxide to 100 bar total pressure and placed in a preheated oil bath. The mixture was stirred with a magnetic stirrer for the time given in Table 1. The pressure was monitored throughout the reaction. After cooling and venting of the autoclave, the solution was removed and immediately analysed by GC and GC–MS.
2.3. Reduction of esters 2 mL of LiAlH4 solution (1 mol/dm3 in THF) was transferred into a dry two-necked flask equipped with a magnetic stirrer. Condenser and dropping funnel containing solution of the esters (1 mmol in 5 mL THF, purified by column chromatography) was connected to the flask. From the dropping funnel the solution was added slowly to the reducing agent under continuous stirring (5 min). After adding the whole amount of solution, the mixture was heated to reflux temperature (66 ◦ C) and stirred for overnight. After the reaction was completed, the reaction mixture was cooled in water and ice, then cold water was added cautiously to the reaction mixture to decompose the excess of the reagent. When no hydrogen was evolved by water addition, diluted sulphuric acid (10%) was added to dissolve the Al(OH)3 precipitate. The products were extracted with diethyl ether (10 mL) and the organic phase was washed with saturated NaCl solution and dried over Na2 SO4 . After filtration and evaporation of the solvent the alcohols were analysed by chiral GC to determine the enantiomeric excess.
The PdCl2 (PhCN)2 precursor was synthesised from PdCl2 (Aldrich) according to standard procedures [16]. The ligands (TPP, DIOP, XANTPHOS, etc.) were purchased from Sigma-Aldrich Kft., Budapest, Hungary. Toluene was distilled and purified by standard methods and stored under argon. All reactions were carried out under argon using standard Schlenk techniques. The 1 H- and 13 C NMR spectra were recorded on a Bruker AvanceIII 500 spectrometer. Chemical shifts are reported in ppm relative to TMS (downfield) for 1 H- and 13 C NMR spectroscopy. Conversions and selectivities were determined using GC and GC–MS. The enantiomeric excess was determined by using a chiral capillary column (CycloSil-B (30m × 0,25 mm)): (injection temperature: 250 ◦ C; starting oven temperature: 50 ◦ C; 1st rate: 2 ◦ C/min; final temperature: 150 ◦ C; 2nd rate 25 ◦ C/min; final temperature: 230 ◦ C/min; carrier gas: He 1.30 mL/min). The esters were purified by column chromatography (Silica gel, 0.063 mm; CHCl3 ) and isolated as colourless liquids.
3. Results
2.2. Hydroaryloxycarbonylation experiments
3.1. Optimisation of the hydrophenoxycarbonylation reaction
In a typical experiment, a solution of PdCl2 (PhCN)2 (3.8 mg; 0.01 mmol) and (R)-DIOP (19.9 mg; 0.04 mmol) in toluene (10 mL) containing 1 mmol substrate, 6 mmol nucleophile and 3 drops of
Initially, we examined the feasibility of the palladium-catalysed hydrophenoxycarbonylation of styrene (1a) with phenol (2a) to give the corresponding ester regioisomers (3a and 4a). As starting
P. Pongrácz et al. / Molecular Catalysis 438 (2017) 15–18
17
Scheme 1. Hydrophenoxycarbonylation of styrene in the presence of palladium catalyst.
Scheme 2. Hydroaryloxycarbonylation reactions using 4-substituted styrenes as substrates and 4-substituted phenol nucleophiles.
reaction conditions, Pd(OAc)2 precursor and PPh3 ligand under carbon monoxide pressure (100 bar) at 100 ◦ C were chosen (Scheme 1). It is known [6–8] that in order to obtain high activities in hydroalkoxycarbonylation reaction it is crucial to have an excess of an acid in the reaction mixture. In the presence of paratoluenesulfonic acid (PTSA) only small amount (17%) of ester regioisomers could be detected (Table 1 entry 1) and the main products were ethers that formed via a simple acid catalysed nucleophilic addition reaction [17]. In the presence of oxalic acid and trichloroacetic acid no phenol addition was occurred, but low conversions to esters were achieved (entries 2, 3, respectively). By the use of concentrated hydrochloric acid, remarkable increase in activity was observed. Increasing the amount of the acid additive the reaction was accelerated but upon addition of more than 3 drops of cc. HCl small decrease of activity took place (entries 4–6). It is known that the excess of the nucleophile, over the stoichiometric amount has positive impact on activity in hydroalkoxycarbonylation reaction, therefore the effect of phenol excess was also examined. It was found, that 1:6 substrate:nucleophile ratio was optimal in the reaction. Further increase of the phenol excess did not cause remarkable increase in activity (entries 7, 8). Next, the optimized conditions were applied examining the activity of in situ generated palladium catalysts incorporated with a series of achiral and chiral bidentate ligands (entries 9–14). All of the ligands examined gave lower catalytic activity than the monodentate PPh3 but after exploring the wide array of conditions we found that the application of another Pd-precursor, PdCl2 (PhCN)2 slightly increases the catalytic activity in case of bidentate ligands. Interestingly, most of the tested ligands were inactive. It seems that ligands with smaller bite angle (BDPP, BINAP, DPPP, DBBP and JOSIPHOS) are not effective or give low conversions in the hydroaryloxycar-
bonylation reaction, whereas the application of larger bite angle ligands (XANTPHOS, PHANEPHOS and DIOP) resulted in the formation of the target esters. Since the highest activities were obtained with DIOP-containing in situ systems, this ligand was chosen for further investigations. As it was expected, the regioselectivity towards branched ester (3aa) using bidentate ligands was also much lower than in case of PPh3 . The reaction temperature substantially effects the activity of the Pd-DIOP catalyst system, but no strong influence on the regioselectivity was obtained (entries 20, 21). It is worth noting that the reaction can be carried out under low CO pressure, but much longer reaction time was required and the regioselectivity also decreased (entries 19) It has to be added that under atmospheric conditions (1 bar CO) only side-products, that is, styrene-phenol adducts and styrene dimers can be detected. 3.2. Substituent effect To determine whether the substituents of styrene and phenol have any influence on the regio- and enantioselectivity, hydroaryloxycarbonylation experiments of various 4-substituted derivatives (1a–g and 2a–j) in the presence of in situ system, formed from PdCl2 (PhCN)2 and (R)-DIOP were conducted under optimized conditions (Scheme 2). The regioselectivity towards branched esters (3(a–g)(a–j)) does not show significant differences by varying the para-substituents either on the styrene or on the phenol. A small increase in branched ester formation can be observed using styrene substituents possessing electron donating properties (1b, 1c, 1d) (Table 2, entries 2–4). Electron withdrawing substituents have reversed influence on regioselectivity. The formation of branched ester regioisomers
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Table 2 Substituent effects on the hydroaryloxycarbonylation reaction.a Entry
Styrene (substituent)
Phenol (substituent)
R. time [h]
Conv. [%]
Rbr b [%]
eec
1 2 3 4 5 6 7d 8 9 10 11 12 13 14 15 16 17 18 19 20
1a (H) 1b (Me) 1c (OMe) 1d (Ph) 1e (F) 1f (Cl) 1f (Cl) 1g (CF3 ) 1a (H) 1a (H) 1a (H) 1a (H) 1a (H) 1a (H) 1a (H) 1a (H) 1a (H) 1f (Cl) 1f (Cl) 1b (Me)
2a (H) 2a (H) 2a (H) 2a (H) 2a (H) 2a (H) 2a (H) 2a (H) 2b (Me) 2c (OMe) 2d (Ph) 2e (F) 2f (Cl) 2g (CF3 ) 2h (Br) 2i (iPr) 2j (CHO) 2j (CHO) 2h (Br) 2c (OMe)
48 96 96 96 72 48 120 96 48 48 48 48 48 48 48 48 72 120 48 48
77 96 >99 91 >99 75 77 >99 53 56 98 68 68 37 65 52 >99 42 83 87
16 22 20 18 16 14 17 9 16 20 18 19 19 15 17 20 25 17 16 20
2 (R) 7 (R) 0 n.d. 0 10 (R) 14 (R) 0 1 (R) 5 (R) 1 (R) 5 (R) 0 (R) 5 (R) 9 (R) 0 (R) 8 (R) 11 (R) 4 (R) 2 (R)
a b c d
Reaction conditions: 0.01 mmol of PdCl2 (PhCN)2 , 0.04 mmol (R)-DIOP, 6 mmol nucleophile, 1 mmol substrate, T = 100 ◦ C, p(CO) = 100 bar, solvent: 10 mL of toluene. Regioselectivity towards branched ester (3a). [moles of 3a/(moles of 3a + moles of 4a) × 100]. Enantioselectivities were determined after reduction by chiral GC. (S)-2-phenylpropanol was eluted before the (R) enantiomer. T = 80 ◦ C.
are less preferred in these cases, especially low preference for branched ester regioisomer was observed with 4-trifluoromethyl styrene, that is, when 1g was reacted with the parent nucleophile (2a) resulting in the formation of branched ester 3ga (entry 8). The 4-substituents of phenol ring have no such clear effect on regioselectivity. Similar branched selectivities were obtained in case of all substituents, irrespectively to electronic properties. That is, the regioselectivities were very close to that obtained for the parent derivative 3aa (branched ester obtained from unsubstituted styrene (1a) and phenol (2a)). In general, low enantioselectivities (ee-s up to 14%) were observed and the formation of aryl (R)-2-arylpropanoates were favoured in all cases. In some cases, racemic or close to racemic mixtures were formed. No obvious correlation can be observed between enantiomeric excesses and electronic properties (characterised by Hammett substituent constant (p )) of para-substituents of styrene and phenol. The best ee-s were achieved with methyl and chloro substituted styrenes (entry 2 and 6) and further increase can be obtained by lowering the reaction temperature to 80 ◦ C (entry 7). The bromo and formyl substitution of phenol derivative provided the best optical yields on the perspective of the nucleophile (entries 15, 17). Low preference of the R-enantiomer can be seen in case of methoxy, fluoro and trifluoromethyl substituents while close to racemic mixture was produced in the presence of methyl, phenyl, isopropyl and chloro substituents. Further experiments were carried out to examine the combined effect of the substituents, modifying the substrate and the nucleophile side at the same time. It can be stated that the influences of the substituents are not strengthening each other. In case of 3fh even lower ee was obtained than that of 3fa and 3ah. Similarly, lower ee was obtained for 3bc than for 3ba and 3ac (entries 18–20).
the synthesis of the variety of aryl 2-arylpropionates and their linear regioisomers. Acknowledgements The authors thank the Hungarian Research Fund (K113177) for the financial support. This work was also supported by the GINOP2.3.2-15-2016-00049 grant. The present scientific contribution is dedicated to the 650th anniversary of the foundation of the University of Pécs, Hungary. L.T. Mika is grateful for support from the János Bolyai Research Scholarship of the Hungarian Academy of Sciences. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.mcat.2017.05. 010. References [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13]
4. Summary Hydroaryloxycarbonylation and enantioselective hydroaryloxycarbonylation (hydroesterification) of 4-substituted styrenes were carried out in the presence of palladium-catalysts. The reaction shows high functional group tolerance regarding both the substrates and the O-nucleophiles. The catalytic process enabled
[14] [15] [16] [17]
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