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Rhodium-catalyzed boronic acid additionsJagt, Roelof Bauke Christiaan

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Publication date:2006

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Citation for published version (APA):Jagt, R. B. C. (2006). Rhodium-catalyzed boronic acid additions: a combinatorial approach tohomogeneous asymmetric catalysis. s.n.

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10_Chapter_6.doc

Chapter 6 An Entry to Diversity in 3-Aryl- and 3-Alkenyl-3-hydroxyoxindoles

NH

O

OR1

+

NH

OR1

HO R2

R2B(OH)2

P(OPh)3 (7 mol%)

or phosphoramidite (9 mol%)

acetone, reflux, 4 h

Up to 99% yield

Up to 55% ee

(94% ee after cryst.)

Rh(acac)(C2H4)2 (3 mol%)

(R2 = Aryl, Alkenyl)

A general method for the catalytic 1,2-addition of aryl and alkenylboronic acids to isatins is

described using a rhodium(I)/triphenylphosphite catalyst.1 The application of this

transformation allows the synthesis of a variety of 3-aryl-3-hydroxyoxindole building

blocks in high yields. As far as we know this is the first example of a rhodium-catalyzed

arylation of ketones. An enantioselective version of this reaction using a

rhodium/phosphoramidite system is also presented.

Part of this chapter has been published: P. Y. Toullec, R. B. C. Jagt, J. G. de Vries, B. L.

Feringa, A. J. Minnaard, “Rhodium-Catalyzed Addition of Arylboronic Acids to Isatins: An

Entry to Diversity in 3-Aryl-3-hydroxyoxindoles”, Org. Lett. 2006, 8, 2715.

114

10_Chapter_6.doc

Chapter 6

6.1 Introduction

Oxindoles (2-indolinones) are a class of heterocyclic compounds found in many natural

products2 and in a number of marketed drugs.3 Of particular interest are 3-substituted

3-hydroxyoxindoles. This substructure is encountered in a large variety of natural alkaloids

with a wide spectrum of biological activities.4 Especially 3-alkyl-substituted

3-hydroxyoxindoles occur frequently in nature, e.g., convolutamydines,4a,4c

donaxaridine,4b,4c maremycins,4d dioxibrassinine,4e celogentin K,4f 3’-hydroxy-

hydroxyglucoisatisins,4g and TMC-95A4h (see Figure 6.1).

donaxaridine

NH

O

HO NHMe

NH

O

HOBr

Br R

convolutamydine A (R = COMe)

convolutamydine E (R = CH2OH)

NH

O

OH

HN

O

NH

O

HNO

NH

O

O

HN N

H

OHN

NH2

NHHN

O O NH

CO2HN

HN

celogentin K

N

R

NHHN

O

O

S

H

H

maremycin A (R = )

maremycin B (R = )OH

OH

NH

O

HONH

SMe

S

dioxibrassinine

NH

O

HO

HO

NH

O

O

O

HN

HNO

OH O

NH

O

NH2

TMC-95A

NH

O

HOOO

N

S

OSO3-

O

OHHOHO

OH

3'-hydroxyglucoisatisin

Figure 6.1 Natural products containing the 3-substituted 3-hydroxyoxindole moiety

115

10_Chapter_6.doc

An Entry to Diversity in 3-Aryl- and 3-Alkenyl-3-hydroxyoxindoles

Considering the frequency in which 3-hydroxyoxindoles are found in biologically active

molecules, it is not surprising that these compounds, and derivatives thereof, constitute

important targets in the development of drug candidates.5,6 Here, also 3-aryl-substituted

3-hydroxyoxindoles are of particular importance. Compounds with this structural element

also serve as important intermediates en route to indole containing alkaloids

(e.g. diazonamide A7). Recently, chemists at Sumitomo Pharmaceuticals have reported the

growth hormone secretagogue activity of the nonpeptidyl oxindole derivative SM-130686

(Figure 6.2).8 Aryl-substituted 3-hydroxyoxindoles have also been identified as potent

maxi-K9 calcium-activated potassium (KCa) channel openers.5 Maxi-K channels are thought

to be important regulators of cellullar excitability and function and are present in many

excitable cell types including neurons and various types of smooth muscle cells.10

Therefore, modulators of these channels are potentially useful agents in the therapy of

various disease states associated with both the central nervous system and smooth muscle

tissue.11 Compound (−)-1 was identified as an effective activator of maxi-K channels. For

both these drugs the biological activity was found to be sensitive to the pattern and nature

of substitution as well as the absolute configuration at the stereogenic center.

HN

ClOH

OH

F3CO

(−)-1

N

HO

O

ClCF3

(CH2)2NEt2H2NOC

SM-130686

Figure 6.2 Commercial pharmacophore SM-130686 and maxi-K channel opener (−)-1

In order to evaluate the biological activity of this type of compounds by systematic

structural variation in a library approach it is essential that a general synthetic procedure is

developed that makes it possible to introduce a large variety of aryl-groups, preferably in an

enantioselective fashion. There are a number of recent reports on the catalytic

enantioselective formation of quaternary carbon centers at the 3-position of oxindoles.12

However, the catalytic enantioselective formation of a tertiary alcohol at this position has

116

10_Chapter_6.doc

Chapter 6

not been achieved until now. Racemic 3-phenyl-3-hydroxyoxindoles have been prepared by

cyclization of N-aryl-2-oxo-2-phenylacetamide,13 radical oxidation of oxindoles,14 or

addition of Grignard reagents to isatins 2 (Scheme 6.1, see first transformation of route a).15

A modification of this last method has allowed the preparation of enantiomerically enriched

3-aryl-3-hydroxyoxindoles 3 by asymmetric hydroxylation using chiral oxaziridines 5 as

oxidizing agents (route a).5b

NH

O

O

NH

O

R1

HO

R2

R1

1) NaH/ THF, 0 oC2) ArMgBr/ -20 oC Et3SiH/ CF3CO2H

110-120 oCa)

b)

1) KHMDS/THF/Ar, -78 to 0 oC

NH

OR2

R1

HO

SNO

OO

2) -78 to 0 oC

2 (+/-)-3

(S)-3

H

Ph

HO2C

HO

(S)-6

t-BuCHO

H+ O

OO

H

Pht-Bu

H R

F

LDA, THF-HMPA

NH

O

Ph

R

HOZn/HCl

(R)-3

(S)-5

NO2

NH

O

R2

R1

(+/-)-4

O

OO

Pht-Bu

H

R

NO2

(+/-)-4

(2S,5R)-7

(2S,5R)-7EtOH-H2O

>95% ee

Scheme 6.1 Current methodology for the preparation of enantiopure 3

117

10_Chapter_6.doc


The racemic 3-aryloxindole substrates 4 were prepared by dehydroxylation of the Grignard-

isatin adducts 3. Recently, Pedro et al. reported the synthesis of enantiopure 3-hydroxy-3-

phenyloxindoles via the highly diastereoselective arylation of mandelic acid 6 (route b).16

Neither of the two current methodologies gives easy and direct access to a variety of

substituted 3-aryl-3-hydroxyoxindoles. A more practical one-step synthesis of enantiopure

3 would be achieved by the catalytic asymmetric addition of arylmetal reagents to isatins 2.

However, the formation of quaternary carbon centers17 via addition of carbon nucleophiles

to ketone derivatives still constitutes a major challenge in synthetic chemistry.18 Catalytic

enantioselective synthesis of α-hydroxycarbonyl compounds via addition of organometallic

nucleophiles to 1,2-dicarbonyl substrates has so far been limited to alkynylations19 and

alkylation reactions using zinc reagents.20 Inspired by the progress in the field of rhodium-

catalyzed additions of sp2-hybridized carbon nucleophiles to a variety of electrophiles,21

and the results described in the preceeding chapters, we decided to investigate the arylation

and alkenylation of isatin substrates using a combination of boronic acids22,23 and rhodium

catalysts to achieve the synthesis of 3.

6.2 Results and Discussion

6.2.1 The Synthesis of Racemic 3-Substituted-3-hydroxyoxindoles

We first focused on the synthesis of racemic 3-aryl-3-hydroxyoxindoles. Experiments

conducted with isatin 2a and 2 equiv of phenylboronic acid (8a) in the presence of a

catalyst generated in situ from 3 mol% of Rh(acac)(C2H4)2 and 7 mol% of P(OPh)3 led to

full conversion and 91% isolated yield of 3a after 4h at reflux temperature (Table 6.1, entry

1). To the best of our knowledge, this is the first report of rhodium-catalyzed arylboronic

acid addition to ketones.24 This reaction was applied to isatin substrates 2a-c and a variety

of arylboronic acids 8a-k. As already observed by Frost for the addition of arylboronic

acids to aldehydes,25 this 1,2-addition reaction is influenced by the electronic substitution

pattern of both reaction partners.

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10_Chapter_6.doc

Chapter 6

Table 6.1 Rhodium/triphenylphosphite-catalyzed 1,2-addition of aryl- and alkenylboronic

acids 8 to isatin substrates 2

NH

O

ONH

OR1

HO R2Rh(acac)(C2H4)2 (3 mol%)

P(OPh)3 (7 mol%)

2 equiv R2B(OH)2 (8)

acetone, reflux, 4 h2 3

R2 = phenyl

R2 = p-tolyl

R2 = 3,5-dimethylphenyl

R2 = o-tolyl

R2 = m-nitrophenyl

R2 = p-ethoxycarbonylphenyl

Boronic Acids:

8a: 8b: 8c:

8d:

8g:

8h:

R1

R2 = o-fluorophenyl

R2 = 3-thienyl

R2 = 2-trans-phenylvinyl

8i: 8j: 8k:

R2 = p-methoxyphenyl

R2 = 2-naphthyl

8e: 8f:

2a:

2b:

2c:

Substrates:

R1 = H

R1 = Me

R1 = Cl

entrya substrate boronic acid product yield (%)b

1 2a 8a 3a 91

2 2b 8a 3b 79

3 2c 8a 3c 99

4 2a 8b 3d 99

5 2a 8c 3e 99

6 2a 8d 3f 99

7 2a 8e 3g 98

8 2a 8f 3h 87

9 2a 8g 3i 66

10 2c 8h 3j 62

11 2a 8i 3k 43

12 2a 8j 3l 54

13 2a 8k 3m 96

a All reactions were performed on a 0.2 mmol scale with 3 mol% of Rh(acac)(C2H4)2 and 7 mol%

triphenylphosphite in acetone at reflux temperature for 4 h. b Isolated yields of 3.

119

10_Chapter_6.doc


Electron-donating groups on the isatin substrate lower the reactivity (entry 2), while

electron-withdrawing substituents cause an increase of reactivity (entry 3). Electron-

donating substituents on the boronic acid result in high yields (entries 4-8), while electron-

withdrawing ones lead to moderate yields (entries 9-11). Steric hindrance in the boronic

acid does not influence the yield (compare entries 4-6). Phenyl groups with m-nitro and

p-ethoxycarbonyl electrophilic substituents, which are generally not tolerated by

organomagnesium or organolithium reagents, were introduced here with success (entries

9-10).24 Also o-fluorophenyl, for which the Grignard reagent is not available, was

successfully introduced (entry 11). An additional advantage of the present strategy is the

fact that it proceeds without protecting the amide functionality of the substrate.

6.2.2 Enantioselective Synthesis of 3-Phenyl-3-hydroxyoxindoles

In relation with the previous studies on asymmetric 1,2-arylations using substrates with

carbon-heteroatom double bonds as described in Chapter 4 and 5,26 we investigated a small

collection of phosphoramidites (Table 6.2) in the development of an enantioselective

version of the current transformation (Scheme 6.2). Reactions were performed using the

conditions described for the synthesis of racemic 3-phenyl-3-hydroxyoxindoles, replacing

triphenylphosphite for chiral phosphoramidite ligands.

NH

O

ONH

O

HO PhRh(acac)(C2H4)2 (3 mol%)

phosphoramidite L (7.5 mol%)

2 equiv PhB(OH)2 (8a)

acetone, reflux, 4 h2a 3a

Scheme 6.2 Enantioselective addition of phenylboronic acid to isatin

With a few exceptions, phosphoramidites are highly suitable for the rhodium-catalyzed

1,2-addition of arylboronic acids to isatin. In general, quantitative conversions were

reached after 4 h.

120

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Chapter 6

Table 6.2 Phosphoramidites studied in the rhodium-catalyzed 1,2-addition of

phenylboronic acid to isatin

OO

P ROO

P ROO

P R

L1 L2 L3

NMe2

NEt2

NiPr2

N

N

N

NBn

NH

Na

b

c

d

e

f

g

h

i

j

Amine moieties R:

OMe

NH(R)

NMe

)2k

(S) (S)(S)

entrya ligand ee (%)b,c entrya ligand ee (%)b,c

1 L1a 14 (S) 9 L1g 23 (S)

2 L2a 7 (S) 10 L1h 38 (S)

3d L3a nd 11 L2h 39 (S)

4 L1b 11 (S) 12 L1i 4 (S)

5 L1c 20 (S) 13 L2i 10 (S)

6 L1d 27 (S) 14 L1j 14 (S)

7d L1e nd 15 L2j 11 (S)

8d L1f nd 16 L1k 33 (R)

a All reactions were performed on a 0.2 mmol scale with 3 mol% of Rh(acac)(C2H4)2 and 7.5 mol% of

phosphoramidite L in acetone at reflux temperature for 4 h. All reactions went to completion, except for entry 3, 7,

and 8. b Enantiomeric excess determined by chiral HPLC. c The absolute configuration of 3a was established by

comparison of the optical rotation with literature values (see experimental section). d Not determined: the

conversion was too low to determine the enantioselectivity.

121

10_Chapter_6.doc


However, phosphoramidites based on primary amines, which gave rise to both high

enantioselectivity and activity in the addition of arylboronic acids to imines (Chapter 5),

performed unsatisfactory in the current reaction (L1e and L1f, entries 7 and 8). Although

an explanation for this result is not evident, possibly the orientation of the substrate towards

the rhodium-center is hindered because of hydrogen-bonding by the NH moiety of the

ligand with functional groups in the substrate. For ligand L3a (entry 3), with a bulky 3,3’-

dimethyl-substituted BINOL-backbone, also no conversion was observed. Here, it is most

likely that the sterics of the BINOL-backbone prevent coordination of the substrate to

rhodium. The bidentate phosphoramidite ligand L1k, which was proven to be successful in

the addition of arylboronic acids to aldehydes (Chapter 4), gave a promising 33% ee (entry

16). However, the best results were obtained with ligands based on 1,2,3,4-

tetrahydroisoquinoline (entries 10 and 11). BINOL-based ligand L1h and octahydro-

BINOL based L2h showed no significant difference in enantioselectivity and provided the

product in 38% and 39% ee, respectively. In both cases the (S)-enantiomer of the ligand

gave the (S)-enantiomer of the product.

Searching for the ideal reaction conditions, the effect of important parameters like the

ligand-to-rhodium ratio, temperature, and nature of solvent were investigated using ligand

L2h. A series of experiments was performed in which the phosphoramidite-to-rhodium

ratio was varied between 0.5 and 6.0 (Figure 6.3). A ligand/rhodium ratio of 3/1 gave the

optimum result. Using a lower ratio, the ee decreases slightly. This is probably due to

competitive chelating properties of both substrate 2 and product 3. Using a higher ratio,

enantioselectivity increases (53% ee for a ligand/rhodium ratio of 6/1). However,

dramatically lower activity was observed. The fact that the ee increases with the

ligand/rhodium ratio suggests that either substrate or product compete with the ligand for

coordination to rhodium. In order to investigate this effect further, the substrate was

gradually added to the reaction-mixture over a period of 4 h using a syringe pump. Using

this procedure, the substrate concentration should be low during the entire course of the

reaction and therefore competition for coordination should be reduced considerable.

However, no change in enantioselectivity was observed in this experiment. When the

reaction was followed over time in intervals of 15 min for the duration of the reaction, the

122

10_Chapter_6.doc

Chapter 6

variation in the enantiomeric excess turned out to be negligable. This effectively rules out

competition for coordination to rhodium between the product and the ligand, as a

decreasing enantiomeric excess would be expected when there is more product formed. It

was decided not to investigate this effect any further, since the difference in ee of 13% for a

ligand/rhodium ratio of 2.5 and 6.0 represents only a small difference in transition-state

Gibbs energy and is therefore most probably due to subtle effects.

6.04.53.02.52.01.51.00.50

20

40

60

80

100

Ligand/rhodium ratio

(%)

Conversion Enantiomeric Excess

Figure 6.3 Effects of the variation of the Rh/L2 ratio

In order to determine the effect of the solvent upon the conversion and enantioselectivity,

different solvents were examined at 40 oC (Table 6.3). 1,4-Dioxane (entry 3) appears to be

the most suitable solvent for this reaction, increasing both reactivity and enantioselectivity.

Full conversion is obtained within 2 h resulting in 55% ee. At reflux temperature the ee

does not decrease significantly. With substrate 2a and phenylboronic acid 8a in the

presence of a catalyst generated from 3 mol% of Rh(acac)(C2H4)2 and 9 mol% of ligand

L2h, 3-phenyl-3-hydroxyoxindole (3a) was obtained in virtually quantitative yield and

55% ee (Scheme 6.3).27 Upon recrystallization from 2-propanol, the supernatant gives the

enantioenriched product in 59% yield and 94% ee. Unfortunately, when 5-methyl

substituted (2b) and 5-chloro substituted (2c) isatins were used as substrates, under the

same conditions the products 3b and 3c were obtained with only 30% and 31% ee,

respectively.

123

10_Chapter_6.doc


Table 6.3 Solvent variation in the rhodium-catalyzed asymmetric addition of phenylboronic

acid to isatin

NH

O

ONH

O


(S)-L2h (9.0 mol%)


solvent, reflux, 4 h2a (S)-3a

entrya solvent conversion (%) b ee (%)c

1 acetone > 99 39

2 tert-butyl methylether > 99 44

3d 1,4-dioxane > 99 55

4 1,2-dimethoxyethane > 99 47

5 ethylacetate > 99 46

6 2-propanol 80 39

7 tetrahydrofuran > 99 45

8 toluene > 99 53

a Reactions were carried out on 0.2 mmol scale in 2 mL of solvent at reflux for 4 h with 2 equiv of phenylboronic

acid in the presence of a catalyst generated from 3 mol% Rh(acac)(C2H4)2 and 9.0 mol% of phosphoramidite L2h. b Conversion determined by 1H-NMR. c Determined by chiral HPLC. The product could be recrystallized from

2-propanol; the supernatant gives the enantioenriched product in 59% yield and 94% ee.

NH

O

ONH

O


(S)-L2h (9.0 mol%)


1,4-dioxane, 40 oC, 2 h3a (R = H)

3b (R = Me)

3c (R = Cl)

R

2a (R = H)

2b (R = Me)

2b (R = Cl)

55% ee (S)

30% ee (S)

31% ee (S)

R

Scheme 6.3 Phenylboronic acid addition to isatins under optimum conditions

124

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Chapter 6

6.3 Further Developments

Almost simultaneous with the publication of our results on this subject,28 Hayashi et al.

reported the rhodium/MeO-MOP-catalyzed addition of aryl- and alkenylboronic acids to

N-p-methoxybenzyl (PMB) protected isatins (Scheme 6.4) achieving excellent yields (90-

98%) and high enantioselectivities (82-91%).29

N

O

ON

O

HO Ph[RhCl(C2H4)2]2 (5 mol%)

(R)-MeO-MOP (10 mol%)

2 equiv ArB(OH)2

KOH (15 mol%)

THF/H2O (20:1)

50 oC, 24 h

Cl Cl MeOPPh2

(R)-MeO-MOP

PMB PMB

90-98% y

82-92% ee

Scheme 6.4 Asymmetric1,2-addition of boronic acids to isatins reported by Hayashi et al.

NH isatins underwent the addition with only moderate efficiency and a slight drop in

enantioselectivity (49% yield and 87% ee for the addition of phenylboronic acid to 5-chloro

isatin compared to 92% yield and 90% ee for its addition to PMB protected 5-chloro isatin).

6.4 Conclusions

In conclusion, we have developed a new catalyst system for the 1,2-addition of arylboronic

acids to isatin substrates based on a combination of a rhodium(I) precursor and 2 equiv of

triphenylphosphite. This method represents a general procedure for the formation of 3-aryl-

3-hydroxyoxindoles in good to excellent yields. Promising enantioselectivities have been

obtained in an asymmetric version of this reaction employing a phosphoramidite ligand.

Further studies to expand this methodology to other classes of substrates and to improve the

enantioselection of the asymmetric addition are required. The enantioselectivity might be

increased by screening a library of ligands, as discussed in chapter 4 and 5, varying both the

diol and the amine part of the phosphoramidite ligands.

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10_Chapter_6.doc


6.5 Experimental Section

General remarks. For general information, see Chapter 2. Phosphoramidites were

prepared according to a literature procedure.30 Spectral data for L1a, L2a, L1b, L1g, L1h,

L2h, L1i, L2i, L1j, and L2j can be found in reference 30. Spectral data for L1c, L1k, and

L3a can be found in reference 31. Spectral data for L1b can be found in reference 32.

Spectral data for L1e can be found in reference 33. A procedure for the preparation of L1f,

including spectral data, can be found in Chapter 4.

General Procedure for Table 6.1. In a flame dried Schlenk tube flushed with nitrogen,

1.55 mg (6.0 µmol, 3 mol%) of Rh(acac)(C2H4)2 and 3.7 µL (14.0 µmol, 7 mol%) of

triphenylphosphite were dissolved in 2 mL of acetone. After stirring for 5 min at room

temperature, 0.2 mmol of substrate 2 and 0.4 mmol of arylboronic acid 8 were added and

the resulting mixture was stirred at reflux temperature. After 4 h the reaction mixture was

cooled to RT and the solvent evaporated under reduced pressure. Products 3 were obtained

as a solid and purified by column chromatography using eluent conditions reported for

TLC.

(+/-)-3-Phenyl-3-hydroxy-2-oxindole (3a). Obtained as a solid (mp 205-207 oC, dec) in

91% isolated yield (entry 1, Table 6.1). Spectral and physical data are in

accordance with literature.16 TLC conditions: (CH2Cl2/ethylacetate:

80/20), Rf = 0.24. 1H NMR (DMSO-d6) δ = 10.26 (s, 1H), 7.19-7.08 (m,

6H), 6.96 (d, J = 7.0 Hz, 1H), 6.81 (dt, J = 0.7, 7.7 Hz 1H), 6.76 (d, J =

7.7 Hz, 1H), 6.48 (s, 1H); 13C NMR (DMSO-d6) δ = 178.44, 141.92, 141.52, 133.72,

129.20, 128.04, 127.38, 125.39, 124.75, 122.01, 109.8, 77.28; HRMS calcd for C14H11NO2:

m/z 225.0790, found: 225.0795; Anal. calcd for C14H11NO2: 74.6 (C), 4.93 (H), 6.22 (N),

found: 74.6 (C), 5.01 (H), 6.28 (N).

NH

O

HO

126

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Chapter 6

(+/-)-5-Methyl-3-phenyl-3-hydroxyoxindole (3b). Obtained as a solid (mp 212-214 oC,

dec) in 79% isolated yield (entry 2, Table 6.1). Spectral and physical

data are in accordance with literature.16 TLC conditions:

(CH2Cl2/ethylacetate: 80/20), Rf = 0.29. 1H NMR (DMSO-d6) δ =

10.15 (s, 1H), 7.19-7.10 (m, 5H), 6.90 (d, J = 8.1 Hz, 1H), 6.76 (s,

1H), 6.65 (d, J = 7.7 Hz, 1H), 6.42 (d, J = 1.5 Hz, 1H), 2.06 (s, 3H); 13C NMR (DMSO-d6)

δ = 178.51, 141.67, 139.41, 133.86, 130.87, 129.37, 128.04, 127.31, 125.34, 125.26,

109.58, 77.41, 20.60; HRMS calcd for C15H13NO2: m/z 239.0946, found: 239.0952; Anal.

calcd for C15H13NO2: 75.3 (C), 5.48 (H), 5.86 (N), found: 75.0 (C), 5.65 (H), 5.56 (N).

(+/-)-5-Chloro-3-phenyl-3-hydroxyoxindole (3c). Obtained as a solid (mp 240-242 oC,

dec) in 99% isolated yield (entry 3, Table 6.1). TLC conditions:


10.41 (s, 1H), 7.22-7.12 (m, 5H), 6.96 (d, J = 2.2 Hz, 1H), 6.78 (d, J =

8.4 Hz, 1H), 6.64 (s, 1H), 2.52 (s, 6H); 13C NMR (DMSO-d6) δ =

178.06, 140.80, 135.69, 130.26, 129.10, 128.22, 127.66, 125.96, 125.29, 124.68, 111.46,

77.34; HRMS calcd for C14H10NO237Cl: m/z 259.0399, found: 259.0397.

(+/-)-3-(4-Methylphenyl)-3-hydroxyoxindole (3d). Obtained as a solid (mp 209-211 oC,



10.28 (s, 1H), 7.17 (dt, J = 1.1, 7.7 Hz, 1H), 7.10-7.00 (m, 4H), 6.89

(dt, J = 1.1, 7.7 Hz, 1H), 6.82 (d, J = 7.7 Hz, 1H), 6.46 (s, 1H), 2.19 (s,

3H); 13C NMR (DMSO-d6) δ = 178.54, 141.89, 138.58, 136.54, 133.81, 129.12, 128.57,

125.35, 124.72, 121.96, 109.77, 77.13, 20.63; HRMS calcd for C15H13NO2: m/z 239.0946,

found: 239.0961.

(+/-)-3-(3,5-Dimethylphenyl)-3-hydroxyoxindole (3e). Obtained as a solid (mp 235-236

°C, dec) in 99% isolated yield (entry 5, Table 6.1). TLC conditions:


10.20 (s, 1H), 7.09 (dt, J = 1.5, 7.7 Hz, 1H), 6.93 (d, J = 7.3 Hz, 1H),

6.81 (t, J = 7.3 Hz, 1H), 6.75-6.71 (m, 4H), 6.37 (s, 1H), 2.07 (s, 6H);

NH

O

HOMe

NH

O

HOCl

NH

O

HO

NH

O

HO

127

10_Chapter_6.doc


13C NMR (DMSO-d6) δ = 178.51, 141.89, 141.46, 136.94, 133.94, 129.10, 128.78, 124.68,

123.01, 121.96, 109.76, 77.19, 21.04; HRMS calcd for C16H15NO2: m/z 253.11027, found:

253.1117.

(+/-)-3-(2-Methylphenyl)-3-hydroxyoxindole (3f). Obtained as a solid (mp 229-231 °C,


(CH2Cl2/ethylacetate: 80/20), Rf = 0.33. 1H NMR (DMSO-d6) δ = 10.40

(s, 1H), 7.73 (dt, J = 1.1, 7.7 Hz, 1H), 7.14 (t, J = 7.3 Hz, 1H), 7.10 (dt, J

= 0.7, 7.7 Hz, 1H), 7.05 (dt, J = 1.5, 7.3 Hz, 1H), 6.90 (d, J = 7.3 Hz, 1H),

6.77 (d, J = 7.0 Hz, 1H), 6.75 (d, J = 7.7 Hz, 1H), 6.68 (d, J = 7.0 Hz, 1H), 6.45 (s, 1H),

1.65 (s, 3H); 13C NMR (DMSO-d6) δ = 177.74, 142.53, 139.16, 134.28, 132.31, 130.86,

129.36, 127.42, 126.55, 125.39, 124.31, 121.96, 109.69, 76.61, 18.76; HRMS calcd for

C15H13NO2: m/z 239.0946, found: 239.0961.

(+/-)-3-(4-Methoxyphenyl)-3-hydroxyoxindole (3g). Obtained as a solid (mp 219-221 °C,



10.18 (s, 1H), 7.10 (t, J = 7.7 Hz, 1H), 7.06-7.02 (m, J = 8.8 Hz, 2H),

6.96 (d, J = 7.3 Hz, 1H), 6.32 (d, J = 7.3 Hz, 1H), 6.75-6.70 (m, 3H),

6.37 (s, 1H), 3.57 (s, 3H); 13C NMR (DMSO-d6) δ = 178.62, 158.64, 141.86, 133.72,

133.45, 129.11, 126.79, 124.77, 121.95, 113.44, 109.77, 76.87, 55.08; HRMS calcd for

C15H13NO3: m/z 225.0895, found: 255.0885.

(+/-)-3-Naphthyl-3-hydroxyoxindole (3h). Obtained as a solid (223-225 °C, dec) in 87%

isolated yield (entry 8, Table 6.1). TLC conditions: (CH2Cl2/

ethylacetate: 80/20), Rf = 0.42. 1H NMR (DMSO-d6) δ = 10.34 (s,

1H), 7.77-7.71 (m, 3H), 7.69 (d, J = 7.7 Hz, 1H), 7.37 (s, 1H), 7.35

(d, J = 4.8 Hz, 1H), 7.18 (d, J = 9.9 Hz, 1H), 7.13 (t, J = 7.7 Hz,

1H), 6.99 (d, J = 7.0 Hz, 1H), 6.83 (t, J = 7.7 Hz, 1H), 6.80 (d, J = 7.7 Hz, 1H), 6.64 (s,

1H); 13C NMR (DMSO-d6) δ = 178.38, 142.01, 139.01, 133.69, 132.53, 132.30 129.35,

127.97, 127.76, 127.41, 126.27, 126.06, 124.83, 123.88, 123.75, 122.12, 109.95, 77.45;

HRMS calcd for C18H13NO2: m/z 275.0946, found: 275.0974.

NH

O

HO

OMe

NH

O

HO

NH

O

HO

128

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Chapter 6

(+/-)-3-(3-Nitrophenyl)-3-hydroxyoxindole (3i). Obtained as a solid (205-208 °C, dec) in

66% isolated yield (entry 9, Table 6.1). TLC conditions:


10.52 (s, 1H), 8.13 (s, 1H), 8.10 (d, J = 7.7 Hz, 1H), 7.57 (t, J = 7.7

Hz, 1H), 7.53 (t, J = 8.1 Hz, 1H), 7.25 (t, J = 7.7 Hz, 1H), 7.09 (d, J

= 7.3 Hz, 1H), 6.98 (s, 1H), 6.95 (t, J = 7.3 Hz, 1H), 6.90 (d, J = 7.7 Hz, 1H); 13C NMR

(DMSO-d6) δ = 177.48, 147.73, 143.70, 142.04, 132.52, 132.19, 129.99, 129.88, 124.88,

122.64, 122.45, 120.12, 110.24, 76.84; HRMS calcd for C14H10N2O4: m/z 270.0640, found:

270.0648; Anal. calcd for C14H10O4N2: 62.2 (C), 3.73 (H), 10.37 (N), found: 61.8 (C), 3.96

(H), 9.88 (N).

(+/-)-5-Chloro-3-(4-carbethoxyphenyl)-3-hydroxyoxindole (3j). Obtained as a solid (mp

196-198 °C, dec) in 50% isolated yield (entry 10, Table 6.1).

TLC conditions: (CH2Cl2/ ethylacetate: 80/20), Rf = 0.18. 1H

NMR (DMSO-d6) δ = 10.60 (s, 1H), 7.87 (d, J = 8.4 Hz, 2H),

7.36 (d, J = 8.8 Hz, 2H), 7.27 (ddd, J = 8.5 Hz, J = 2.2 Hz, J =

1.1 Hz, 1H), 7.04 (d, J = 1.8 Hz, 1H), 6.92 (s, 1H), 6.88 (d, J = 8.1 Hz, 1H), 4.24 (q, J = 7.0

Hz, 2H), 1.24 (t, J = 7.0 Hz, 3H); 13C NMR (DMSO-d6) δ = 177.53, 165.42, 145.91,

140.84, 135.20, 129.42, 129.27, 129.20, 129.16, 125.65, 124.70, 111.68, 77.38, 60.72,

14.17; HRMS calcd for C17H14N4O4Cl: m/z 331.0611, found: 331.0600. Anal. calcd for

C17H14NO437Cl: 61.6 (C), 4.26 (H), 4.23 (N), found: 61.6 (C), 4.52 (H), 4.10 (N).

(+/-)-3-(2-Fluorophenyl)-3-hydroxyoxindole (3k). Obtained as a solid (mp 200-202 °C,



(s, 1H), 7.85 (dt, J = 1.8, 7.7 Hz, , 1H), 7.32-7.21 (m, 2H), 7.15 (dt, J =

1.1, 7.0 Hz, 1H), 6.96 (dd, J = 9.1, 10.6 Hz, 1H), 6.85-6.79 (m, 3H),

6.73 (s, 1H); 13C NMR (DMSO-d6) δ = 177.42, 158.41 (d, JCF = 244.7 Hz), 142.33, 132.36,

129.51 (d, JCF = 8.5 Hz), 129.35, 128.93 (d, JCF = 13.0 Hz), 127.95 (d, JCF = 3.8 Hz),

124.09, 121.74, 115.05 (d, JCF = 21.5 Hz), 109.66, 74.26; HRMS calcd for C14H10NO2F:

m/z 243.0695, found: 243.0691; Anal. calcd for C14H10NO2F: 69.1 (C), 4.15 (H), 5.76 (N),

found: 69.0 (C), 4.44 (H), 5.93. (N).

NH

O

HONO2

NH

O

HO

CO2Et

Cl

NH

O

HOF

129

10_Chapter_6.doc


(+/-)-3-Thienyl-3-hydroxyoxindole (3l). Obtained as a solid (107-209 °C, dec) in 54%

isolated yield (entry 12, Table 6.1). TLC conditions:


(s, 1H), 7.32 (dd, J = 3.3, 5.1 Hz, 1H), 7.12-7.08 (m, 2H), 7.06 (dd, J =

0.7, 2.9 Hz, 1H), 6.87 (dd, J = 0.7, 5.1 Hz, 1H), 6.84 (t, J = 7.3 Hz, 1H),

6.73 (d, J = 8.1 Hz, 1H), 6.42 (s, 1H); 13C NMR (DMSO-d6) δ = 177.82, 142.49, 141.53,

132.89, 129.24, 126.42, 126.21, 124.70, 122.10, 121.92, 109.82, 75.47; HRMS calcd for

C12H9NO2S: m/z 231.0353, found: 231.0354; Anal. calcd for C12H9NO2S: 62.3 (C), 3.93

(H), 6.06 (N), found: 62.2 (C), 4.18 (H), 5.84 (N).

(+/-)-3-(β-Styryl)-3-hydroxyoxindole (3m). Obtained as a solid (219-221 °C, dec) in 96%

isolated yield (entry 13, Table 6.1). TLC conditions:


10.23 (s, 1H), 7.27 (d, J = 7.3 Hz, 2H), 7.17 (t, J = 7.0 Hz, 2H), 7.14-

7.07 (m, 3H), 6.87 (t, J = 7.3 Hz, 1H), 6.72 (d, J = 7.7 Hz, 1H), 6.41

(d, J = 15.8 Hz, 1H), 6.23 (s, 1H), 6.20 (d, J = 16.1 Hz, 1H); 13C NMR (DMSO-d6) δ =

177.78, 141.57, 135.93, 131.71, 129.36, 129.25, 129.22, 128.65, 127.82, 126.50, 124.71,

121.87, 109.85, 76.36; HRMS calcd for C16H13NO2: m/z 251.0946, found: 251.0961.

General procedure for the enantioselective synthesis of 3-phenyl-3-hydroxyoxindoles.

In a flame dried Schlenk tube flushed with nitrogen, 1.55 mg (6.0 µmol, 3 mol%) of

Rh(acac)(C2H4)2 and 8.0 mg (18.0 µmol, 9 mol%) of (S)-L were dissolved in 2 mL of

1,4-dioxane. After stirring for 5 min at room temperature, 0.2 mmol of substrate 2 and 0.4

mmol of phenylboronic acid (8a) were added and the resulting mixture was stirred at 40 oC.

After 2 h the reaction mixture was cooled to RT and the solvent evaporated under reduced

pressure. Product 3 was purified by column chromatography using eluent conditions

reported for TLC (vide supra).

(S)-3-Phenyl-3-hydroxyoxindole (3a). Obtained as a solid (mp 205-207 oC, dec) in 99%

isolated yield with 55% ee. After recrystallisation from 2-propanol the supernatant gave the

enantioenriched product in 59% isolated yield and 94% ee. The ee was determined on a

Chiralcel OD-H column with heptane/2-propanol: 90/10, flow = 0.5 mL/min. Retention

NH

O

HO

NH

O

HO S

130

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Chapter 6

times: 25.5 [(S)-enantiomer] and 29.5 [(R)-enantiomer] min. [α]D = +16.5 (c = 1.06, MeOH,

94% ee), lit. [α]D = -12.3 (c = 0.91, MeOH, (R)).16

(S)-5-Methyl-3-phenyl-3-hydroxyoxindole (3b). Obtained as a solid (mp 212-214 oC, dec)

in 99% isolated yield with 30% ee. The ee was determined on a Chiralcel OD-H column

with heptane/2-propanol: 90/10, flow = 0.5 mL/min. Retention times: 23.2 [(S)-enantiomer]

and 25.8 [(R)-enantiomer] min. The absolute configuration was deduced by analogy.

(S)-5-Chloro-3-phenyl-3-hydroxyoxindole (3c). Obtained as a solid (mp 240-242 oC, dec)

in 99% isolated yield with 31% ee. The ee was determined on a Chiralcel AD column with

heptane/2-propanol: 90/10, flow = 1.0 mL/min. Retention times: 16.3 [(S)-enantiomer] and

18.0 [(R)-enantiomer] min. The absolute configuration was deduced by analogy.

6.6 References and Notes

1. Patrick Y. Toullec is gratefully acknowledged for carrying out part of the experiments described in this chapter. We would like to thank André de Vries of DSM for useful discussions.

2. (a) S. Hibino, T. Choshi, Nat. Prod. Rep. 2002, 19, 148 and previous articles of this series. (b) M. Somei, F. Yamada, Nat. Prod. Rep. 2003, 20, 216.

3. (a) H. R. Howard, J. A. Lowe III, T. F. Seeger, P. A. Seymour, S. H. Zorn, P. R. Maloney, F. E. Ewing, M. E. Newman, A. W. Schmidt; J. S. Furman, G. L. Robinson, E. Jackson, C. Johnson, J. Morrone, J. Med. Chem. 1996, 29, 143. (b) J. Haynes, B. Obiako, P. Babal, T. Stevens, Am. J. Physiol. Heart Circul. Physiol 1999, 276, H1877. (c) Y. Liu, D. Liu, D. Printzenhoff, M. J. Coghlan, R. Harris, D. S. Krafte, Eur. J. Pharmacol. 2002, 435, 153. (d) R. Maggio, M. Scarselli, F. Novi, M. J. Millan, G. U. Corsini, J. Neurochem. 2003, 87, 631.

4. (a) J. Kohno, Y. Koguchi, M. Nishio, K. Nakao, M. Kuroda, R. Shimizu, T. Ohnuki, S. Komatsubara, J. Org. Chem. 2000, 65, 990. (b) A. Fréchard, N. Fabre, C. Péan, S. Montaut, M.-T. Fauvel, P. Rollin, I. Fourasté, Tetrahedron Letters 2001, 42, 9015. (c) K. Monde, K., K. Sasaki, A. Shirata, M. Tagusuki, Phytochemistry 1991, 30, 2915. (d) Y. Kamano, H.-P. Zhang, Y. Ichihara, H. Kizu, K. Komiyama, G. R. Pettit, Tetrahedron Lett. 1995, 36, 2783. (e) W. Balk-Bindseil, E. Helmke, H. Weyland, H. Laatsch, Liebigs Ann. Chem. 1995, 1291. (f) H. B. Rasmussen, J. K. MacLeod, J. Nat. Prod. 1997, 60, 1152. (g) T. Kawasaki, M. Nagaoka, T. Satoh, A. Okamoto, R.

131

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Ukon, A. Ogawa, Tetrahedron 2004, 60, 3493. (h) H. Suzuki, H. Morita, M. Shiro, J. Kobayashi, Tetrahedron 2004, 60, 2489.

5. For recent pharmaceutical studies of 3-aryl-substituted 3-hydroxyoxindoles, see: a) P. Hewawasam, N. A. Meanwell, V. K. Gribkoff, S. I. Dworetzky, C. G. Biossard, Bioorg. Med. Chem. Lett. 1997, 7, 1255; (b) P. Hewawasam, M. Erway, S. L. Moon, J. Knippe, H. Weiner, C. G. Biossard, D. J. Post-Munson, Q. Gao, S. Huang, V. K. Gribkoff, N. A. Meanwell, J. Med. Chem. 2002, 45, 1487.

6. For recent pharmaceutical studies of derivatives of 3-alkenyl and 3-aryl substituted 3-hydroxyoxindoles, see: (a) P. Hewawasam, N. A. Meanwell, V. K. Gribkoff, US Patent, US5602169, 1997; Chem. Abstr. 1997, 126, 181369. (b) I. A. Cliffe, E. L. Lien, H. L. Mansell, K. E. Steiner, R. S. Todd, A. C. White, R. M. Black, J. Med. Chem. 1992, 35, 1169. (c) V. K. Gribkoff, J. E. Starrett Jr., S. I. Dworetzky, P. Hewawasam, C. G. Boissard, D. A. Cook, S. W., Frantz, K. Heman, J. R. Hibbard, K. Huston, G. Johnson, B. S. Krishnan, G. G. Kinney, L. A. Lombardo, N. A. Meanwell, P. B. Molinoff, R. A. Myers, S. L. Moon, A. Ortiz, L. Pajor, R. L. Pieschl, D. J. Post-Munson, L. J. Signor, N. Srinivas, M. T. Taber, G. Thalody, J. T. Trojnacki, H. Weiner, K. Yeleswaram, S. W. Yeola, Nat. Med. 2001, 7, 471. (d) A. Natarajan, Y.-H. Fan, H. Chen, Y. Guo, J. Iyasere, F. Harbinski, W. J. Christ, H. Aktas, J. A. Halperin, J. Med. Chem. 2004, 47, 1882. (e) A. Natarajan, Y. Guo, F. Harbinski, Y.-H. Fan, H. Chen, L. Luus, J. Diercks, H. Aktas, M. Chorev, J. A. Halperin, J. Med. Chem. 2004, 47, 4979.

7. For a recent total synthesis of diazonamide A, via a 3-aryl substituted 3-hydroxy-2-oxindole intermediate, see: K. C. Nicolaou, J. Hao, M. V. Reddy, P. B. Rao, G. Rassias, S. A. Snyder, X. Huang, D. Y.-K. Chen, W. E. Brenzovich, N. Giuseppone, P. Giannakakou, P. A. O’Brate, J. Am. Chem. Soc. 2004, 126, 12897

8. (a) T. Tokunaga, W. E. Hume, T. Umezome, K. Okazaki, Y. Ueki, K. Kumagai, S. Hourai, J. Nagamine, H. Seiki, M. Taiji, H. Noguchi, R. Nagata, J. Med. Chem. 2001, 44, 4641. (b) W. E. Hume, T. Tokunaga, R. Nagata, Tetrahedron 2002, 58, 3605.

9. On the basis of their single-channel conductance in symmetrical K+ solutions, KCa channels have been broadly classified into three categories: the large conductance (BK or maxi-K) channels (>150 pS), intermediar conductance channels (50-150 pS), and small conductance channels (<50 pS).

10. (a) R. Latorre, A. Oberhauser, P. Labarca, O. Alvarez, Ann. Rev. Physiol. 1989, 51, 385. (b) P. Sah, Trends Neurosci. 1996, 19, 150.

11. (a) J. E. Starret, S. I. Dworetzky, V. K. Gribkoff, Curr. Pharm. Des. 1996, 413. (b) V. K. Gribkoff, J. E. Starrett, S. I. Dworetzky, Adv. Pharmacology 1996, 37, 319.

12. Palladium-catalyzed intramolecular α-arylation: (a) S. Lee, J. F. Hartwig J. Org. Chem. 2001, 66, 3402. Intramolecular Heck reaction: (b) A. B. Dounay, K. Hatanaka,

132

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Chapter 6

J. J. Kodanko, M. Oestreich, L. E. Overman, L. A. Pfeifer, M. M. Weiss, J. Am. Chem. Soc. 2003, 125, 6261. Organocatalytic acyl transfer: (c) I. D. Hills, G. C. Fu, Angew. Chem. Int. Ed. 2003, 42, 3921. Biocatalytic desymmetrization of prochiral substrates: S. Akai, T. Tsujino, E. Akiyama, K. Tanimoto, T. Naka, Y. Kita, J. Org. Chem. 2004, 69, 2478. Lewis-catalyzed α-fluorination of carbonyl groups: (e) Y. Hamashima, T. Suzuki, H. Takano, Y. Shimura, M. Sodeoka, J. Am. Chem. Soc. 2005, 127, 10164. Palladium-catalyzed allylation of prochiral nucleophiles: (f) B. M. Trost, M. U. Frederiksen, Angew. Chem. Int. Ed. 2005, 44, 308. Organocatalytic aldol reaction: (g) G. Luppi, P. G. Cozzi, M. Monari, B. Kaptein, Q. B. Broxterman, C. Tomasini, J. Org. Chem. 2005, 70, 7418.

13. M. S. Mashevskaya, M. E. Konshin, U.S.S.R. Patent, SU929632 A1 19820523, 1982; Chem. Abstr. 1982, 97, 215994r.

14. S. Ghosal, S. K. Dutta, Indian J. Chem. 1970, 8, 687.

15. (a) P. Hewawasam, N. A. Meanwell, Tetrahedron Lett. 1994, 35, 7303. (b) P. Hewawasem, V. K. Gribkoff, Y. Pendri, S. I. Dworetzky, N. A. Meanwell, E. Martínez, C. G. Boissard, D. J. Post-Munson, J. T. Trojnacki, K. Yeleswaram, L. M. Pajor, J. Knipe, Q. Gao, R. Perrone, J. E. Starrett Jr., Biorg. Med. Chem. Lett. 2002, 12, 1023. (c) B. S. Jensen, CNS Drug Rev. 2002, 8, 353. (d) L. Zoute, C. Audouard, J.-C. Plaquevent, D. Cahard, Org. Biomol. Chem. 2003, 1, 1833. (e) N. Shibata, T. Ishimaru, E. Suzuki, K. L. Kirk, J. Org. Chem. 2003, 68, 2494.

16. S. Barroso, G. Blay, L. Cardona, I. Fernandez, B. Garcia, J. R. Pedro, J. Org. Chem. 2004, 69, 6821

17. For reviews on the formation of quaternary carbon centers, see: (a) E. J. Corey, A. Guzman-Perez, Angew. Chem. Int. Ed. 1998, 37, 388; (b) I. Denissova, L. Barriault Tetrahedron 2003, 59, 10105; (c) D. J. Ramón, M. Yus, Curr. Org. Chem. 2004, 8, 149; (e) J. Christoffers, A. Baro, Adv. Synth. Catal. 2005, 247, 1473. (f) J. Christoffers, A. Baro (Eds.), Quaternary Stereocenters: Challenges and Solutions for Organic Synthesis, Wiley-VCH: Weinheim, 2005; (d) B. M. Trost, C. Jiang, Synthesis 2006, 369.

18. For a recent review on enantioselective additions to ketones using zinc reagents, see: (a) D. J. Ramón, M. Yus, Angew. Chem. Int. Ed. 2004, 43, 284. For leading references in the field of catalytic enantioselective additions of organometallic aryl and alkenyl reagents to carbonyl compounds, see: (b) C. García, P. J. Walsh, Org. Lett. 2003, 5, 3641; (c) H. Li, P. J. Walsh, J. Am. Chem. Soc. 2005, 127, 8355; (d) D. Tomita, R. Wada, M. Kanai, M. Shibasaki, J. Am. Chem. Soc. 2005, 127, 4138.

19. (a) E. F. DiMauro, M. C. Kozlowski, J. Am. Chem. Soc. 2002, 124, 12668. (b) E. F. DiMauro, M. C. Kozlowski, Org. Lett. 2002, 4, 3781. (c) K. Funabashi, M. Jachmann, M. Kanai, M. Shibasaki, Angew. Chem. Int. Ed. 2003, 42, 5489.

20. (a) B. Jiang, Z. Chen, X. Tang, Org. Lett. 2002, 4, 3451. (b) P. K. Dhondi, J. D. Chisholm, Org. Lett. 2006, 8, 67.

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21. (a) T. Hayashi, Synlett 2001, 879. (b) T. Hayashi, K. Yamasaki, Chem. Rev. 2003, 103, 2829. (c) K. Fagnou, M. Lautens, Chem. Rev. 2003, 103, 169.

22. (a) N. Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2457. (b) D. G. Hall (Ed.), Boronic Acids: Preparation and Applications in Organic Synthesis and Medicine, Wiley-VCH: Weinheim, 2005.

23. For a discussion of the advantages of arylboronic acids in 1,2-addition reactions regarding functional group tolerance, see: A. Fürstner, H. Krause, Adv. Synth. Catal. 2001, 343, 343.

24. For the asymmetric addition of arylzinc reagents − generated in situ from arylboronic acids and diethylzinc − to acetophenones, see: O. Prieto, D. J. Ramón, M. Yus, Tetrahedron: Asymmetry 2003, 14, 1955.

25. C. Moreau, C. Hague, A. S. Weller, C. G. Frost, Tetrahedron Lett. 2001, 42, 6957.

26. (a) R. B. C. Jagt, P. Y. Toullec, J. G. de Vries, B. L. Feringa, A. J. Minnaard, Org. Biomol. Chem. 2006, 4, 773. (b) R. B. C. Jagt, P. Y. Toullec, D. Geerdink, J. G. de Vries, B. L. Feringa, A. J. Minnaard, Angew. Chem. Int. Ed. 2006, 45, 2789.

27. Ligand (S)-L2h gives product (S)-3a. For determination of the absolute configuration of compound 3a, see: reference 16 and the discussion in the experimental section of this chapter.

28. P. Y. Toullec, R. B. C. Jagt, J. G. de Vries, B. L. Feringa, A. J. Minnaard, Org. Lett. 2006, 8, 2715.

29. R. Shintani, M. Inoue, T. Hayashi, Angew. Chem. Int. Ed. 2006, 45, 3353.

30. J.-G. Boiteau, R. Imbos, A. J. Minnaard, B. L. Feringa, Org. Lett. 2003, 5, 681, also see: Org. Lett. 2003, 68, 9481.

31. L. A. Arnold, R. Imbos, A. Mandoli, A. H. M. de Vries, R. Naasz, B. L. Feringa, Tetrahedron 2000, 56, 2865.

32. D. Peña, A. J. Minnaard, J. G. de Vries, B. L. Feringa, J. Am. Chem. Soc. 2002, 124, 14552.

33. A. Duursma, Asymmetric Catalysis with Chiral Monodentate Phosphoramidite Ligands, Ph.D. Thesis, University of Groningen, 2004.

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