Oxidation of sulfides with hydrogen peroxide catalyzed by synthetic flavin adducts with dendritic bis(acylamino)pyridines

Tetrahedron 70 (2014) 495e501

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Oxidation of sulfides with hydrogen peroxide catalyzed by synthetic flavin adducts with dendritic bis(acylamino)pyridines Yasushi Imada a, b, *, Takahiro Kitagawa a, Shotaro Iwata a, Naruyoshi Komiya a, Takeshi Naota a, * a

Department of Chemistry, Graduate School of Engineering Science, Osaka University, Machikaneyama, Toyonaka, Osaka 560-8531, Japan Department of Chemical Sciences and Technology, Institute of Technology and Science, The University of Tokushima, Minamijosanjima, Tokushima 770-8506, Japan b

a r t i c l e i n f o

a b s t r a c t

Article history: Received 1 October 2013 Received in revised form 5 November 2013 Accepted 10 November 2013 Available online 15 November 2013

The catalytic activities of the cationic synthetic flavin adduct 1 with various dendritic and non-dendritic 2,6-bis(acylamino)pyridines 2 were examined for the oxidation of organic sulfides with H2O2. The adduct of 5-ethyllumiflavinium perchlorate 1a with 2bed bearing poly(benzyl ether) dendron units acts as an efficient organocatalyst for the oxidative transformation of sulfides to the corresponding sulfoxides under mild conditions. Ó 2013 Elsevier Ltd. All rights reserved.

Keywords: Flavin Dendrimer Oxidation Sulfide Sulfoxide

1. Introduction The simulation of flavoenzymes1 with synthetic flavin catalysts2 is important with respect to the exploitation of environmentally benign processes for oxidative transformation with organocatalysts.3e5 Model reactions of flavin-containing oxygenases include the reduction of an oxidized form of cationic synthetic flavins (Flþ) with a reductant (AH2) (Scheme 1, step a), the incorporation of O2 to give hydroperoxyflavin (FlOOH) (step b), oxygen atom transfer from FlOOH to the substrate (S) to form the oxygenated product (SO) (step c), and dehydration to complete the catalytic cycle (step d). When H2O2 is used as an oxidant instead of O2, the FlOOH active species are formed directly from Flþ via an anaerobic shunt process (step e).2 The principle of this organocatalytic process provides green methods for the oxidation of various heteroatom compounds including amines,6 sulfides,6 and ketones7 that proceed with H2O26aej,7a,b or O26ken,7c under mild conditions. To obtain higher efficiency and specificity in this process, much effort has been devoted to create novel flavin catalysts bearing enzyme-like reaction cavities8 circumferentially arranged at the

* Corresponding authors. Tel.: þ81 88 656 7407 (Y.I.); tel.: þ81 6 6850 6220 (T.N.); e-mail addresses: [email protected] (Y. Imada), naota@chem. es.osaka-u.ac.jp (T. Naota). 0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tet.2013.11.024

Scheme 1. Catalytic cycle for model reaction of flavin-containing monooxygenase with synthetic flavins.

foregoing FlOOH active center. Chemo and stereoselectivities are reportedly enhanced by employing synthetic flavin catalysts that are modified covalently9 or non-covalently10 with dendron units and cyclodextrins,11 where hydrophilic and hydrophobic interactions in artificial cavities serve as a key factor for the expression of selectivity. Our systematic studies on the development of new organocatalysts bearing novel functions have revealed adducts of 5-ethyllumiflavinium perchlorate (1a) with 2,6-bis(acylamino) pyridines bearing poly(benzyl ether)dendron unit 2bed that

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exhibit high catalytic activity for the oxidation of sulfides with H2O2 (Eq. 1 and Chart 1). The MichaeliseMenten kinetics indicate that the flavin-dendrimer 1a$2c adduct is reorganized to the corresponding association complex 5, which acts as a catalytically active species in the foregoing redox processes in Scheme 1. This is a new type of efficient supramolecular catalysis for the oxidative transformation of sulfides with H2O2, which has been performed reportedly with a variety of metallo-12 and organocatalysts.2,6a,cen,13

2. Results and discussion 2.1. Characterization of flavin adducts with 2,6bis(acylamino)pyridines Synthetic cationic flavin 1 (a, 5-ethyllumiflavinium perchlorate: R1¼Me, R2¼Me, R3¼H; b, 5-ethyl-3-methyllumiflavinium perchlorate: R1¼Me, R2¼Me, R3¼Me), 2,6-bis(acetylamino)pyridine (2a, AAP), and its dendritic analogues 2b (first generation: 2,6-bis(3-{4[3,5-bis(phenylmethoxy)phenylmethoxy]phenyl}propanoylamino) pyridine, abbreviated as G1PAP), 2c (second generation: G2PAP), and 2d (third generation: G3PAP) were synthesized according to procedures given in the literature (Chart 1).6l,10a,14 When an equimolar amount of 2,4-bis(acylamino)pyridine 2 was added to a solution of 1a

ð1Þ

R2 R1

N

N

R1

N

N

H N

O R3

–

·ClO4

H N

N

O

O

O

Et

2a (AAP)

1 a: R1 = Me, R2 = Me, R3 = H (FlEt+) 1

2

3

+

b: R = Me, R = Me, R = Me (3-MeFlEt )

O

O

O

O

O H N

N

O

H N

O

O

2b (G1PAP)

O

O

O

O

O

O

O

O

O

O H N

O

N

O

O

O

H N O

O

2c (G2PAP)

O

O

O

O

O O

O

O

O

O

O O

O

O

O

O

O

O

O H N O

O

O

N

H N

O

O

O

O

O

O

2d (G3PAP) O

O

O

Chart 1. Structures of cationic flavins 1 and 2,6-bis(acylamino)pyridines 2.

O

Y. Imada et al. / Tetrahedron 70 (2014) 495e501

in CH3CN/CHCl3 (1:1, v/v), the purple solution of 1a is immediately changed to a colorless clear solution. The color change is attributed to the formation of the 1a$2 adduct by nucleophilic addition at the 4aposition of 1a,15 as depicted in Eq. 2. Fig. 1 shows the change in the UVevis spectra of a solution of 1a in CH3CN/CHCl3 (1:1, v/v) for various concentrations of 2c, where hypo- and hyperchromic changes appear on the pep*/nep* band of 1a (420, 555 nm) and the pep* band (350 nm) of the 1a$2c adduct with a sharp isosbestic point at 385 nm. Similar changes in color and absorbance have been reported for the reaction of 1a with various nitrogen containing compounds, such as primary and secondary benzylamines, and glycine derivatives.15 Such quenching was also observed both in reactions of 1a with triethylamine, pyridine (Fig. S1, Supplementary data), and various 2,6-bis(acylamino)pyridines (Figs. S2 and S3, Supplementary data) and in reactions of 3-methylated flavin 1b with 2,6bis(acylamino)pyridines. The equilibrium constants K for the addition of 2a, 2b, and 2c to 1a in CH3CN/CHCl3 (1:1, v/v) at 298 K were determined to be 44223,1175, and 1265 M1, respectively, based on the concentration dependence of the absorbance at 555 nm (Fig. S4, Supplementary data). The K values are much smaller than that for the addition of ethyl glycinate (5104 M1),15 due to the lower nucleophilic properties of pyridine moieties.

Me Me

Me N N Et 1

Me N

O NH

+

H N

R

N

H N

N

N Et

O

R Me

O

Me N

O

O

H N

R 2

O NH

N

O

H N

R O

497

significant dendrimer effect was observed on the 1a$2c adduct catalyst, of which the catalytic activity is much higher than that of 1a (entries 1 and 2). In contrast, the catalytic activities of the 1b$2c dendritic adduct (entry 4) and 1a catalyst in combination with phase-transfer catalyst (entry 5) are comparable to that of single use 1b (entry 3) and 1a (entry 1). Given that the 3-methylated analogue 1b does not form an association complex with 2, these results strongly suggest that the acceleration effect with 1a is caused by the formation of an association complex 1a$2c, which would be generated through dissociative equilibrium of the 1a$2c adduct (Scheme 1). In a mixed solvent of CH3CN and CHCl3 (1:1, v/ v), the catalytic activity of the 1a$2c dendritic adduct is lower than that of single use 1a (entries 6 and 7), because the formation of the association complex 1a$2c is retarded in such a polar solvent. Table 1 Oxidation of 3a with flavin catalystsa Entry

Flavin catalyst

Additive

Yieldb/%

TOFc/h1

1 2 3 4 5 6 7

1a 1a 1b 1b 1a 1a 1a

None 2c None 2c TBACd Nonee 2ce

61 98 73 76 61 44 24

21 34 20 18 17 14 6.7

a The reaction of 3a (1.0101 M) with 30% H2O2 aqueous solution (2.5 equiv) in CHCl3 was conducted at 303 K in the presence of flavin catalyst 1 (2.5 mol %) and additive (12.5 mol %). b GLC yield of product sulfoxide 4a after stirring for 2 h. c Determined by GLC analysis. d Tetrabutylammonium chloride. e The reaction was conducted in CHCl3/CH3CN (1:1, v/v).

1 2 adduct

ð2Þ

The catalytic activities of the 1a adduct with various dendritic and non-dendritic 2,6-bis(acylamino)pyridines 2 were examined for the oxidation of aromatic methyl sulfides with H2O2 (2.5 equiv) under similar conditions (Table 2). Dendritic adducts 1a$2b, 1a$2c, and 1a$2d exhibit higher catalytic activities than those of 1a or the non-dendritic adduct 1a$2a (entries 3, 4, 7, 8, 9, 12, and 13). A positive generation effect of dendrimers was observed in the oxidation of reactive substrate (entries 12 and 13). For all substrates, the catalytic activities of adduct 1a$2a were significantly lower than those of 1a (entries 1, 2, 5, 6, 10, and 11), which indicates that the present positive dendrimer effect is the result of compensation for the negative effect of hydrogen bonding association. The reactivity of sulfides depends on nucleophilic nature of the sulfur atom. Thus, introduction of electron-donating substituents at para position accelerates the reaction as observed commonly in the flavin-catalyzed oxidation of sulfides with H2O2.6c,j,l 2.3. Kinetic studies and mechanistic rationale

Fig. 1. Change in UVevis spectra of 1a for various concentrations of 2c in CH3CN/CHCl3 (1:1, v/v) at 298 K. [1a]0¼2.61103 M. [2c]0¼0e3.37102 M.

2.2. Oxidation of sulfides with H2O2 The catalytic activities of various cationic flavins 1 and their adducts with 2,6-bis(acylamino)pyridines 2 (2.5 mol %) were examined for the oxidation of methyl p-methylphenyl sulfide (3a, 1.0101 M) with 30% hydrogen peroxide aqueous solution (2.5 equiv) in CHCl3 at 303 K. The flavin adducts were prepared by mixing 1 (2.5 mol %) and an excess amount of 2 (12.5 mol %) in CHCl3 prior to the reaction. Yields of methyl p-methylphenyl sulfoxide (4a) and the turnover frequency (TOF) for the reaction were evaluated using gas-liquid chromatography (GLC) analysis with an internal standard. Representative results are presented in Table 1. A

To elucidate the mechanism, the concentration dependency on the initial reaction rates with the 1a$2c catalyst were examined for the oxidation of sulfide 3a (0.43e4.0101 M) with 30% H2O2 aqueous solution (2.5e5.0101 M) in CHCl3 at 303 K. Figs. 2 and 3 show the initial reaction profiles with various concentrations of 3a and H2O2. The concentration of sulfide had a significant influence on the initial reaction rates with the 1a$2c catalyst under diluted conditions {[3a]0¼0.43e2.0101 M} (Fig. 2). On the other hand, the concentration of H2O2 did not significantly alter the reaction rate (Fig. 3), similar to the reaction with the 1a catalyst (Fig. S6). Such a concentration independence of H2O2 strongly suggest that the addition of H2O2 to Flþ (step e, Scheme 1) is not the rate-determining step for the 1a and (1a$2c)-catalyzed oxidations with H2O2. Thus, one can conclude that oxygen transfer from FlOOH 6 to substrate (step c, Scheme 1) is the rate-determining step of the

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Table 2 Oxidation of sulfides with catalyst 1aa Entry

Sulfide

Product

1

2 3 4

3b 3b 3b

4b 4b 4b

5

6 7 8 9

3a 3a 3a 3a

4a 4a 4a 4a

10

11 12 13

3c 3c 3c

4c 4c 4c

Additive

Time/min

Yieldb/%

TOFc/h1

None

280

72

12

2a (AAP) 2b (G1PAP) 2c (G2PAP)

280 280 280

57 73 81

6.8 16 18

None

120

61

21

2a (AAP) 2b (G1PAP) 2c (G2PAP) 2d (G3PAP)

120 120 120 120

49 97 98 99

11 34 34 37

None

60

74

30

2a (AAP) 2b (G1PAP) 2c (G2PAP)

60 60 60

16 62 91

6.4 25 36

a The oxidation of sulfide (1.0101 M) with 30% H2O2 aqueous solution (2.5 equiv) was conducted at 303 K in CHCl3 in the presence of 1a (2.5 mol %) and additive 2 (12.5 mol %). b GLC yield of the product sulfoxide after the reaction time indicated. c Determined by GLC analysis.

reaction with the 1a$2c catalyst, similar to the reaction with the 1a catalyst (Fig. S5).6l It is noteworthy that the concentrationindependence of the reaction rates is observed exclusively under concentrated conditions {[3a]0¼3.0e4.0101 M} (Fig. 2b), which are frequently encountered in enzyme reactions.

hydroperoxyflavin complex 6 (step a), which then performs the rate-determining oxygen transfer to sulfide to afford the product sulfoxide and the corresponding 4a-hydroxyflavin complex 7 (step b). Protonation and dehydration regenerates 5 to complete the catalytic cycle (step c).

Fig. 2. Concentration dependence of [3a]0 in the (1a$2c)-catalyzed oxidation of 3a with 30% H2O2 aqueous solution in CHCl3 at 303 K. (a) Time-dependence of [4a]. (b) Correlation between kobs and [3a]0. The fitting curve with error bars on data points in (b) was generated using a non-linear regression of the data based on the MichaeliseMenten equation. [1a]0¼2.5103 M, [2c]0¼1.25102 M; [3a]0¼4.3102 M (:), 1.0101 M (C), 2.0101 M (,), 3.0101 M (6), 4.0101 M (B); [H2O2]0¼2.5101 M.

The present oxidation with the 1a$2 catalyst can be rationalized by assuming the following mechanism, as shown in Scheme 2. Adduct 1a$2 forms the corresponding association complex 510a via equilibrated dissociation of 1 and 2. Isoalloxazine, a neutral lumiflavin, forms association complexes with 2,6-bis(acylamino)pyridines 2 in CDCl3 with association constants Ka, of 437 (2a), 404 (2b), 434 (2c), and 411 (2d) M1.10a Thus, a mixture of the liberated forms of 1 and 2 in the left-hand side of Eq. 2 exist as an equilibrated mixture with their association complexes, although their Ka values could not be determined because cationic flavin 1a is not detectable with NMR. Nucleophilic addition of H2O2 gives the 4a-

The foregoing rate stagnation, observed exclusively in the range of high concentrations of 3a (Fig. 2), can be explained by assuming a MichaeliseMenten type formation of active species 8 (Eq. 3) in the rate-determining step (step b, Scheme 2), where the increase in the concentration of the substrate reaches the limit of the concentration of 8 and leads to a plateau for the rate of oxygen transfer at a certain level of substrate concentration. To verify the presence of such intermediate species, the kinetic data measured at 303 K (Fig. 2) were analyzed using a nonlinear regression based on the MichaeliseMenten equation of {kobs¼Vmax[3a]0/([3a]0þKm)},16 where the MichaeliseMenten

Y. Imada et al. / Tetrahedron 70 (2014) 495e501

Fig. 3. Concentration dependence of [H2O2]0 in the (1a$2c)-catalyzed oxidation of 3a with 30% H2O2 aqueous solution in CHCl3 at 303 K. [1a]¼2.50103 M, [2c]¼ 1.25102 M; [3a]0¼1.00101 M; [H2O2]0¼2.50101 M (C), 5.0101 M (B).

499

Fig. 4. HaneseWoolf plot of [3a]0/kobs versus [3a]0 for the (1a$2c)-catalyzed oxidation of 3a with 30% H2O2 in CHCl3 at 303 K. [1a]0¼2.5103 M; [2c]0¼1.25102 M; [3a]0¼0.43e4.0101 M; [H2O2]0¼2.5101 M.

Scheme 2. Proposed catalytic cycle for the oxidation of sulfides with adduct catalyst 1a$2.

parameters Km and Vmax were estimated to be 7.8(1)102 M and 3.3(1)103 M min1, respectively (R2¼0.988). The Km and Vmax values were also independently estimated to be 7.5102 M and 3.3103 M min1 from a HaneseWoolf plot (Fig. 4).17 The linear dependence (R2¼0.992) of [3a]0/kobs versus [3a]0 indicates that the inclusion complex 8, which consists of the 1a$2c association complex and substrate 3a, acts as an active species for the rate-determining step of the catalytic process. Thus, the observed positive effect of dendritic 2bed on this catalytic reaction can be ascribed to the acceleration of the ratedetermining oxygen transfer step. The association complex 8 could include several sulfide molecules inside the cavity of benzyl ether dendron units through p-stacking and hydrophilic interactions. This induces a high concentration of sulfide around

the reactive 4a-position of associated 1a, which leads to an acceleration of second-order oxygen transfer. Such an equilibrated inclusioneoxidation process of sulfide would be much faster than the typical oxidative transfer from free 1a to a nonincluded sulfide. 3. Conclusions The adducts of 5-ethyllumiflavinium cation 1a with 2,6bis(acylamino)pyridines 2bed bearing poly(benzyl ether) dendron units act as a highly efficient organocatalyst for the oxidative transformation of organic sulfides with H2O2 to the corresponding sulfoxides under mild conditions. Kinetic studies based on the MichaeliseMenten equation revealed that the equilibrated

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Y. Imada et al. / Tetrahedron 70 (2014) 495e501

ð3Þ

formation of the association complexes 8 and their dendritic structure is the key to enhancing catalytic activity. This is a new supramolecular organocatalyst for the oxidative transformation of heteroatom compounds. 4. Experimental section 4.1. General NMR spectra were obtained on a Varian Unity-Inova 500 spectrometer (1H, 500 MHz; 13C, 126 MHz). UV spectra were recorded on a Shimadzu MultiSpec-1500 UVevis photodiode array spectrophotometer. GLC analyses were conducted using a Shimadzu GC-18A with a DB-1 glass capillary column (0.25 mm30 m). 4.2. Materials Commercially available methyl phenyl sulfide, methyl p-methylphenyl sulfide (3), p-methoxyphenyl methyl sulfide, and 30% H2O2 aqueous solution were used without further purification. 5-Ethyl7,8,10-trimethylisoalloxazinium perchlorate (1a),6l 5-ethyl-3,7,8,10tetramethylisoalloxazinium perchlorate (1b),6l 2,6-bis(acetylamino) pyridine (AAP; 2a),14 2,6-bis[3-[4-[3,5-bis(phenylmethoxy)phenylmethoxy]phenyl]propanoylamino]pyridine (G1PAP; 2b),10a 2,6-bis[3[4-[3,5-bis[3,5-bis(phenylmethoxy)phenylmethoxy]phenylmethoxy] phenyl]propanoylamino]pyridine (G2PAP; 2c),10a 2,6-bis[3-[4-[3,5-bis [3,5-bis[3,5-bis(phenylmethoxy)phenylmethoxy]phenylmethoxy] phenylmethoxy]phenyl]propanoylamino]pyridine (G3PAP; 2d)10a were prepared according to procedures in the literature. 4.3. Determination of equilibrium constants for the formation of flavin adducts with 2,6-bis(acylamino)pyridines A 2.61103 M solution of 1a in CHCl3 and CH3CN (1:1, v/v) was titrated in a UVevis quartz cuvette with a solution of 2a, 2b, and 2c in CHCl3 and CH3CN (1:1, v/v) (0e3.37102 M) at 298 K. The maximum absorbance at 555 nm was monitored as a function of the concentration of 2 to the point at which the change in absorbance reached saturation, as shown in Fig. S4, Supplementary data. The equilibrium constants for the addition of 2 to 1a were calculated to be 44223 (2a, R2¼0.998), 1175 (2b, R2¼0.999), and 1265 (2c, R2¼0.999) from the obtained isotherms (Dε vs [2]) by nonlinear regression analysis using OriginPro (version 8.6 by OriginLab Corporation) based on the following equation.

Dabsorbanceobs ¼

Dabsorbancemax h 

n

2K½1a0

1 þ K½20 þ K½1a0

1 þ K½20 þ K½1a0

2

 4K 2 ½20 ½1a0

o1=2 i

4.4. Oxidation of sulfides with H2O2 in the presence of flavin adduct catalysts A mixture of sulfide 3 (0.02 mmol), 30% H2O2 aqueous solution (5.0 ml, 0.05 mmol), 1a (0.50 mmol), and hexadecane (internal standard, 0.62 mg) was stirred with or without 2,6-bis(acylamino) pyridines 2 (2.5 mmol), at 303 K. The yields of the product sulfoxide 4 were determined periodically by means of GLC analysis. The results are summarized in Tables 1 and 2. Products were isolated by the large-scale reactions, and characterized by IR, 1H and 13C NMR, and HRMS analysis. 4.4.1. Methyl p-methylphenyl sulfoxide (4a).18 IR (KBr) 2994, 2917, 1651, 1597, 1448, 1414, 1297, 1088, 1036, 954, 813 cm1; 1H NMR (CDCl3, 500 MHz) d 2.42 (s, 3H), 2.71 (s, 3H), 7.33 (d, J¼8.5 Hz, 2H), 7.54 (d, J¼8.5 Hz, 2H); 13C NMR (CDCl3, 68 MHz) d 21.3, 44.0, 123.5, 130.0, 141.5, 142.6; EI-HRMS (m/z): [Mþ] calcd for C8H10SO 154.0452; found 152.0439. 4.4.2. Methyl phenyl sulfoxide (4b).18 IR (neat) 3054, 2996, 2911, 1720, 1652, 1581, 1476, 1443, 1415, 1296, 1089, 1071, 1043, 955, 752, 690 cm1; 1H NMR (CDCl3, 500 MHz) d 2.73 (s, 3H), 7.48e7.57 (m, 3H), 7.66 ppm (dm, J¼8.3 Hz, 2H); 13C NMR (CDCl3, 125 MHz) d 43.8, 123.3, 129.2, 130.9, 145.5; ESI-HRMS (m/z): [MþHþ] calcd for C7H9SO 141.0369; found 141.0354. 4.4.3. p-Methoxyphenyl methyl sulfoxide (4c).18 IR (KBr) 2959, 2876, 1647, 1465, 1411, 1380, 1016 cm1; 1H NMR (CDCl3, 270 MHz) d 2.71 (s, 3H), 3.86 (s, 3H), 7.03 (d, J¼8.9 Hz, 2H), 7.60 (d, J¼8.9, 2H); 13C NMR (CDCl3, 68 MHz) d 44.0, 55.6, 114.8, 125.4, 136.4, 161.8; EIHRMS (m/z): [M]þ calcd for C8H10SO2 170.0415; found 170.0390. 4.5. Kinetic measurement for oxidation of 3 with H2O2 in the presence of flavin adduct catalysts The concentration dependence of [3a]0 and [H2O2]0 for the oxidation of 3 with 30% H2O2 was examined in the presence of the 1a$2c adduct catalyst ([1a]0¼2.50103 M, [2c]0¼1.25102 M) in CHCl3 at 303 K. The time-dependent change in the concentration of product 4a with various initial concentrations of 3 was monitored periodically using GLC analysis with hexadecane as an internal standard. A linear least-squares fit of the acquired data provided initial rate constants (d[4a]/dt¼kobs) for the reactions as 1.2(1) 103 M min1 ([3a]0¼4.30102 M, R2¼0.983, data acquired during 11e34% conversion), 1.8(0)103 M min1 (1.00101 M, 0.998, 5.6e20%), 2.4(1)103 M min1 (2.00101 M, 0.991, 3.7e13%), 2.7(0)103 M min1 (3.00101 M, 0.999, 2.7e10%), and 2.7(1) 103 M min1 (4.00101 M, 0.994, 2.2e8.7%), respectively. Similarly, initial rate constants kobs, for reactions with the 1a$2c

Y. Imada et al. / Tetrahedron 70 (2014) 495e501

adduct catalyst with various initial concentrations of H2O2 {[3a]0¼1.00101 M} were estimated to be 1.8(0)103 M min1 ([H2O2]0¼2.50101 M, R2¼0.998, data acquired during 5.6e20% conversion) and 2.0(1)104 M min1 (5.00101 M, 0.991, 7.1e24%). These data are listed in Figs. 3 and 4. 4.6. Determination of MichaeliseMenten parameters The Michaelis constant Km, and maximum reaction rate Vmax, for the oxidation of 3a with H2O2 using the dendritic association catalyst 1a$2c in CHCl3 at 303 K were obtained as 7.8(1)102 M and 3.3(1)103 M min1, respectively, from the kinetic data in Fig. 3b by non-linear regression analysis (R2¼0.988) using OriginPro 8.6 based on the MichaeliseMenten equation:16

kobs ¼

Vmax ½3a ½3a0 þ Km

Km and Vmax were also estimated to be 7.5102 M and 3.3103 M min1, respectively, from the linear dependence (R2¼0.992) of [3a]0/kobs versus [3a]0 in a HaneseWoolf plot,17 as shown in Fig. 4. Acknowledgements This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.tet.2013.11.024. References and notes 1. (a) Palfey, B. A.; Massey, V. In Comprehensive Biological Catalysis; Sinnott, M., Ed.; Academic: San Diego, USA, 1996; Vol. 3, pp 83e154; (b) Ghisla, S.; Massey, V. Eur. J. Biochem. 1989, 181, 1e17; (c) Fitzpatrick, P. F. Acc. Chem. Res. 2001, 34, 299e307; (d) Moonen, M. J. H.; Fraaije, M. W.; Rietjens, I. M. C. M.; Laane, C.; van Berkel, W. J. H. Adv. Synth. Catal. 2002, 344, 1023e1035; (e) Kamerbeek, N. M.; Janssen, D. B.; van Berkel, W. J. H.; Fraaije, M. W. Adv. Synth. Catal. 2003, 345, 667e678; (f) van Berkel, W. J. H.; Kamerbeek, N. M.; Fraaije, M. W. J. Biotechnol. 2006, 124, 670e689. €ckvall, J.-E. In Modern 2. (a) Imada, Y.; Naota, T. Chem. Rec. 2007, 7, 354e361; (b) Ba €ckvall, J.-E., Ed.; Wiley-VCH: Weinheim, Germany, 2004; Oxidation Methods; Ba pp 193e222; (c) Gelalcha, F. G. Chem. Rev. 2007, 107, 3338e3361. 3. (a) Semmelhack, M. F.; Chou, C. S.; Cortes, D. A. J. Am. Chem. Soc. 1983, 105, 4492e4494; (b) Anelli, P. L.; Banfi, S.; Montanari, F.; Quici, S. J. Org. Chem. 1989, 54, 2970e2972; (c) De Mico, A.; Margarita, R.; Parlanti, L.; Vescovi, A.; Piancatelli, G. J. Org. Chem. 1997, 62, 6974e6977. 4. (a) Ohkubo, K.; Fukuzumi, S. Org. Lett. 2000, 2, 3647e3650; (b) Kotani, H.; Ohkubo, K.; Fukuzumi, S. J. Am. Chem. Soc. 2004, 126, 15999e16006; (c) Ohkubo, K.; Suga, K.; Fukuzumi, S. Chem. Commun. 2006, 2018e2020; (d) Xu, H.-J.; Lin, Y.-C.; Wan, X.; Yang, C.-Y.; Feng, Y.-S. Tetrahedron 2010, 66, 8823e8827.

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