Axially Chiral 1,1'-Binaphthyl-2-Carboxylic Acid (BINA-Cox) as Ligands for Titanium-Catalyzed Asymmetric Hydroalkoxylation

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Accepted Article

Title: Axially Chiral 1,1’-Binaphthyl-2-Carboxylic Acid (BINA-Cox) as

Ligands for Titanium-catalyzed Asymmetric Hydroalkoxylation

Authors: Sebastian L. Helmbrecht, Johannes Schlüter, Max Blazejak,

and Lukas Hintermann

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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201901895

Link to VoR: http://dx.doi.org/10.1002/ejoc.201901895

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10.1002/ejoc.201901895

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Axially Chiral 1,1’-Binaphthyl-2-Carboxylic Acid (BINA-Cox) as

Ligands for Titanium-catalyzed Asymmetric Hydroalkoxylation

Sebastian L. Helmbrecht,^[a,b]Johannes Schlüter,^[a,b]Max Blazejak,^[a,b]and Lukas Hintermann*^[a,b]

Abstract: Axially chiral, enantiopure 1,1’-binaphthyl-2-carboxylic

acids (BINA-Cox) have recently been introduced as chiral ligands for

transition metal catalysis. Together with equimolar, co-catalytic

amounts of Ti(OiPr)₄and water they form an in situ catalyst that

performs the asymmetric catalytic hydroalkoxylation of 2-allylphenols

to 2-methylcoumarans at high temperature (240 °C, microwave

heating). The synthesis of reference ligand 2’-MeO-BINA-Cox (L1)

has been optimized and performed at molar scale. Synthetic routes

have been developed to access a variety of substituted BINA-Cox

ligands (>30 examples), which have been tested for ligand effects on

the reference asymmetric cyclization of 2-allylphenol. The substrate

range of asymmetric catalytic hydroalkoxylation has been explored

through systematic substrate structure variations to define scope and

limitations of the titanium-catalyzed process. The new substrates 2-

(1-vinylcycloalkyl)phenols (1j, 1k), 2-(2-vinylphenyl)propan-2-ol (1t)

and 2'-vinyl-[1,1'-biphenyl]-2-ol (1u) are shown to undergo asym-

metric catalytic cyclization to benzodihydrofurans and benzo[c]-

chromene, respectively.

bifunctional

aminocarboxylic

acids

in

enamine

type

organocatalysis,^[5]unifunctional chiral carboxylic acids have been

explored as metal-free chiral Brønsted acid catalysts,^[6]and

among those, designer 1,1’-binaphthyl-2,2’-dicarboxylic acids

(BINA-DiCox) with 3,3’-diarylsubstitution have shown particular

versatility.^[7–9]Axially chiral 1,1-binaphthyl-2-monocarboxylic

acids including MeO-BINA-Cox^[10,11]and MNCB (2-{2’-methoxy-

1’-naphthyl}-3,5-dichlorobenzoic acid)^[12]have been synthetically

developedand investigated for use as chiral derivatizing reagents

for absolute configuration determination by NMR spectrosco-

py,^[12,13]as chiral inductor in polymer chemistry,^[14,15]and as buil-

ding block for accessing chiral ligands.^[9b,16–18]

R

CO₂H

OMe

O

CO₂H

N H

O

Rh

O

R

4

(aS)-BINA-DiCox

(R = H, Ar)

(aS)-MeO-BINA-Cox

Introduction

Figure 1. Examples of chiral carboxylic acids used in asymmetric catalysis,

either as ligands for transition metals, or as chiral organocatalysts.

Chiral steering ligands for asymmetric catalysis with transition

metal compounds mostly rely on phosphane, phosphite, hetero-

cyclic imine, amine, imine, N-heterocyclic carbene, alkene,

alcohol or phenol donors, and combinations thereof.^[1]Chiral

carboxylic acids are currently much less developed, even if their

potential is evident through uses of Rh₂(O₂CR*)₄complexes

based on a-amidocarboxylic acids as catalyst in asymmetric

metal-carbenoid induced reactions (Figure 1),^[2]or of similar a-

amidocarboxylic acids in asymmetric palladium-catalyzed C–H-

coupling reactions.^[3,4]Aside from a plethora of applications of

We have recently described an intramolecular asymmetric

catalytic hydroalkoxylation of 2-allylphenols (1) to 2-methylcou-

marans (2) that is catalyzed by a peculiar titanium complex

generated by mixing Ti(OR)₄, the axially chiral carboxylic acid

MeO-BINA-Cox (L1) and H₂O in a 1:1:1 ratio.^[19]The process is

an example of asymmetric catalytic hydrofunctionalization, and a

rare example of asymmetric catalysis with high enantioselectivity

at the exceptionally high reaction temperature of 240 °C (HOT-

CAT, homogenous thermal catalysis; Scheme 1).^[20]

[a]

M. Sc. S. Helmbrecht, Dr. J. Schlüter, Dr. M. Blazejak, Prof. Dr. L.

Hintermann

Ti(OiPr)₄(5 mol-%)

L1-type ligand (5 mol-%)

H₂O (5 mol-%)

Department Chemie

Technische Universität München

Lichtenbergstr. 4

OH

O

Me

PhMe, 240 °C (µW)

20 min

85748 Garching bei München, Germany

E-Mail: lukas.hintermann@tum.de

http://www.oca.ch.tum.de

1a

2a

http://orcid.org/0000-0003-2622-8663

Scheme 1. Asymmetric titanium-carboxylate catalytic hydroalkoxylation of 2-

allylphenol.

[b]

TUM Catalysis Research Center

Technische Universität München

Ernst-Otto-Fischer-Str. 1

85748 Garching bei München, Germany

The ligand-effect in the titanium-carboxylate-catalyzed reaction is

critical, and preliminary ligand variation studies covering a

number of chiral O,O- N,N- or O,N- potentially chelate-forming

ligands failed to induce notable activity or any enantioselectivity.

Supporting information for this article is given via a link at the end of

the document.

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Another round of ligand screening that focused on combinations

of titanium alkoxide with a variety of simple bifunctional chiral

carboxylic acids (including proline, N-anisoylprolines (o-, m-, p-

anisoyl isomers), mandelic acid, mandelic acid O-methyl ether,

camphoric acid, camphoric acid monoamides) likewise failed to

show catalytic activity.^[21]After such unsuccessful forays into

alternative basic ligand structures, it transpired that the 1,1’-biaryl-

2-carboxylic acid skeleton should be conserved. A first successful

ligand variation involved the substitution of H-6’ in 2-MeO-BINA-

Cox (L1), by a tert-butyl group (L18), which slightly increased both

activity and enantioselectivity of the model reaction.^[19]The goal

for further ligand variation studies was to retain the biaryl-2’-

alkoxy-2-carboxylic acid substructure and substitute any available

position. Since the number of readily accessible, enantiopure

biaryl-carboxylic acids is limited, new synthetic routes had to be

developed to access the desired products, either by de novo

asymmetric synthesis, or by substitution of the more readily

available enantiopure MeO-BINA-Cox (L1).

Here, we first present the various synthetic approaches that

we have followed to prepare a variety of C₁-symmetric axially

chiral, enantiopure biarylcarboxylic acids. Next, their evaluation

as ligands in titanium-catalyzed asymmetric hydroalkoxylation in

the model cyclization of 2-allylphenol to 2-methylcoumaran will be

compared; finally, we present studies towards the extension of the

substrate range in the titanium-carboxylate catalyzed asymmetric

catalytic hydroalkoxylation.

Results and Discussion

Scaled synthesis of MeO-BINA-Cox (L1)

Syntheses of unsymmetrical 1,1’-binaphthyl-2-carboxylic

acids mostly proceed along a few key routes, exemplified by:^[22]

(I) Coupling approaches, such as Ullmann coupling of 1-halo-2-

naphthoic acid derivatives to BINA-DiCox derivatives,^[23]or cross-

coupling of 1-metalated 2-methylnaphthalene to 2-methyl-1,1-

binaphthyls,^[22]followed by oxidation (CH₃→CO₂H).^[11](II) S_NAr

reactions of 1-naphthyl Grignard reagents with 1-alkoxy-2-

naphthoates or 1-alkoxy-2-naphthyl-oxazolines, developed by

Meyers^[24], Cram,^[10]and Miyano,^[25]which afford enantiomerically

or diastereomerically enriched BINA-Cox derivatives if chiral

alkoxy leaving groups are present.^[26](III) Partial syntheses of

BINA-DiCox or BINA-Cox derivatives from 2,2’-BINOL by

alkoxycarbonylation of sulfonates,^[22,27,28]reductive carboxylation

of phosphates,^[29]or alternatively via Sandmeyer cyanation of the

bis-diazonium salt from 2,2-diamino-1,1’-binaphthyl.^[23b](IV)

Progress has also been achieved in asymmetric catalytic

syntheses of biaryl-2-carboxylic acids (or potential precursor

aldehydes), as for example through Suzuki biaryl couplings,^[30]

oxidative phenol coupling,^[31]phenol–quinone coupling,^[32]alkyne

trimerization,^[33]or asymmetric aldol condensation.^[34]

An evaluation of such pathways pointed to Miyano’s synthesis

of (aS)-2’-methoxy-(1,1’-binaphthyl)-2-carboxylic acid (MeO-

BINA-Cox; L1) as the best option for establishing an economic,

scalable and enantioselective route to binaphthyl-2-carboxylic

acid derivatives, and that L1 could then serve as synthetic

platform to access modified ligand structures.

Me

b) MenOH (5)

NaOMen

HO

CO₂H

MeO

CO₂Me

Me

OH

O

a)

NaOMen

– NaOMe

d)

O

Me

O

MeO

O

Me

OMen

Me₂SO₄

K₂CO₃

– MeOH

Me

O

4

6

8

3

Me

(I) 2%^c)

7

(I) 18%^c)

(II) 7%^c)

(I) 78% (63% cryst.)^c)

(II) 90% (78% cryst.)^c)

(I) <1%^c)

(II) <1%^c)

MgBr

e)

OMe

THF–PhMe (1:5)

35 °C 15 h

9

side products:

OH

O

OMe

O

f) KOH

(5.0)

OMen

OMe

O

OMe

O

crude:

99.2 mol-%

dr 96.7:3.3

OMe

+

CO₂H

PEG-200

150 °C

5 h

OMen

OH-Nap (8)

OH-Ketone (11)

L1

(aR)-10, minor

(aS)-10, major

78–80% (cryst.), dr 99.8:0.2

86% (99.8% ee)

Scheme 2: Synthesis of (aS)-2’-methoxy-(1,1’-binaphthyl)-2-carboxylic acid (MeO-BINA-Cox; L1). a) Me₂SO₄(2.1 equiv.), K₂CO₃(2.2 equiv.), acetone, 50 °C, 7 h;

96%. b) MenOH (2.5 equiv.), NaOMen (0.5 equiv.), DMF, (II). c) (I) 250 mmol scale, 60 °C, 2 h static conditions, then 2.5 h of slow solvent distillation; (II) 750 mmol

scale, 60 °C, 1 h static conditions, 3 h slow solvent distillation, new solvent addition, 2.5 h slow distillation. d) Side reaction. e) 9 (1.2 equiv.), toluene, 35 °C, 15 h.

f) KOH (5.0 equiv.), PEG-200, 150 °C; 5 h. Men = menthyl, based on menthol or (1R,2S,5R)-2-isopropyl-5-methylcyclohexanol.

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The Miyano synthesis of L1 involves a key S_NAr-reaction of 1-

naphthylmagnesium bromide (9) with menthyl 1-menthyloxy-2-

napthoate (7; Scheme 2),^[25]in which the etheric menthyloxy

leaving group is responsible for induction,^[10]and the menthyl

ester suppresses acyl substitution through shielding of the ester

carbonyl.^[35]The methodology has been applied by other

groups,^{[14,16a–c,17]}and we also got satisfactory results at small

scale. Various issues emerged upon scale-up, which were

resolved step by step: Methylation of acid 3 to methoxyester 4

with methyl iodide in DMF^[25]is uneconomic. Equally good results

were obtained with Me₂SO₄–K₂CO₃in acetone (Scheme 2). The

methoxy groups of 4 next are exchanged with (1R)-menthol (5)

under basic conditions. The reported procedure uses three molar

equivalents of sodium menthoxide to push the alkoxy-exchange

equilibrium^[36]towards product 7.^[25]The handling and use of NaH

for generating the menthoxide base becomes unsafe and

wasteful at large scale. We considered performing a catalytic

alkoxide exchange with substoichiometric amounts of base, since

the exchange product methoxide can be regenerated to sodium

menthoxide by reaction with menthol and release of methanol. To

drive the reaction towards product 7, methanol as the most

reaction parameters on the reaction. To learn about effects of

specific variables on stereoselectivity and yield, data from

published examples^[17,25]was collected and supplemented with

selected new experiments, in which we analyzed the composition

of crude reaction mixtures by qNMR methods (Table S4; Scheme

2, c). The strategy of Miyano et al to work in a low-polarity medium

(Et₂O–PhH; Table S4, entry I, II)^[25,43]at high dilution (0.05 M),

while seemingly optimal to support the chelated transition state of

the stereoselective reaction,^[25,26b]is inconvenient for scale-up

considering the resulting large reaction volumes. Hoveyda et al

had obtained equally good results in THF–PhH at 0.25 M (entry

III),^[17]which implies that neither the low polarity of co-solvent

ether nor high dilution are necessary. To circumvent solubility

issues with Grignard reagent 9, we generate the latter in situ from

aryl bromide and magnesium in the presence of substrate 7, but

this resulted in a low yield of 10, and reductive C–O-cleavage in

7 to 8 became the major reaction pathway (Scheme 2, d; Table

S4, entries 2, 3).^[44]It emerged that reagent 9 is best prepared

separately at 1 mol/L in THF–toluene (1:5) and transferred while

still hot (at 50 °C, to prevent crystallization) into a solution of 7 in

toluene. Remarkable analytical yields of 99% of 10 with a d.r.

volatile component may be removed from the reaction equilibrium. (aS:aR) of 97:3 were thus achieved at a reaction concentration of

In our experiments, sodium menthoxide (NaOMen) was

generated by stirring 50 mol-% of sodium metal in excess (2.5

equivalents) molten menthol (5) at 190 °C.^[37]After cooling, the

exchange reaction was performed in DMF solution by addition of

4. NMR analyses showed that a rapid transesterification to

methoxy-menthylester 6 occurs, followed by the slower S_NAr-

alkoxy-exchange to 7. Dealkylation to 8 occurs as side-reaction at

higher temperature, but remains insignificant (<1 mol-% 8) at

≤60 °C. A dynamic vacuum (15 mbar) was applied to induce slow

distillation of MeOH–DMF from the reaction mixture, presumably

as an azeotrope.^[38]Plenty of product 7 emerged in the process,

but a portion of 6 remained unreacted (Scheme 2, I). Renewed

addition of DMF to the concentrated reaction mixture, followed by

a second dynamic vacuum distillation raised the conversion to 90

mol-% (Scheme 2, II).^[39]Crystallization of the reaction mixture

from ethanol gave pure 7 at molar scale in 78% yield, matching

the result of the reaction with excess base.^[25]

The precursor 1-bromo-2-methoxynaphthalene required for

the key S_NAr-reaction (via Grignard reagent 9) has often been

prepared by methyl iodide alkylation from commercial 1-bromo-2-

naphthol.^[40]A more economic access at large scale is by

bromination of the fragrant compound 2-methoxynaphthalene,

which is high-yielding and selective when performed in acetic acid

as solvent (see Table S3 for variations).^[41]

We were now in a position to approach the critical,

diastereoselective S_NAr coupling step of 7 and Grignard reagent

9 to give (aS)-10. The scale-up of the reaction met with some

difficulties, starting with the limited solubility of 9, which

complicated its transfer to the reaction vessel and required using

large amounts of solvent. In the actual S_NAr reaction with 7,

incomplete conversion was often noted even after extending the

reaction time to several days. Heating such reactions with the aim

to raise the conversion of 7 induced dealkylation to 8 instead.

Unfortunately, neither the original methodological work^[25,42]nor

later applications^{[14,16a–c,17]}reported on the impact of specific

0.5 M (based on initial 7) by applying a slight excess of 9 at 35 °C

(Scheme 2, e and Table S4, entries 5–8). Precipitation of the

crude product and recrystallization gave very satisfactory yields

of (aS)-10 (d.r. ≥99.8:0.2) at scales up to 0.4 mol with no need for

chromatography (Scheme 2, d; Table S4, entry 8).

Finally, saponification of ester 10 to MeO-BINA-Cox (L1) with

50–70 equivalents of KOH in hot (80 °C) ethanol is wasteful at

large scale. To speed up hydrolysis, we intensified the reaction

conditions by working in polyethylene glycol (PEG-200) at 150 °C,

which effected hydrolysis within a few hours with only 5

equivalents of base (Scheme 2, e; for additional tests of

conditions, see Table S5). The product was precipitated by

acidification and recrystallized to raise the ee of (aS)-L1 to

1

≥99.7%, as determined by Fukushi's H NMR shift method with

nicotine as chiral base.^[45]This step was also readily scaled with

one example performed at 0.25 mol and providing 80 g of L1. The

overall yield of L1 from 3 was 51% over 5 steps, and all

purification steps are performed either by distillation or

recrystallization, with no need for chromatography.

Structural modifications of MeO-BINA-Cox Ligands

The singular success of MeO-BINA-Cox (L1) as ligand in the

titanium catalyzed intramolecular asymmetric hydroalkoxylation

(cf. Scheme 1)^[19]created a demand for incremental structure

variations of the basic ligand structure, whose defining element is

an axially chiral 1,1'-biaryl-2'-alkoxy-2-carboxylic acid. The

following sections present various synthetic approaches towards

such modified structures.

De novo asymmetric syntheses of 1,1'-biaryl-2-carboxylic

acids. A few target structures with variations at C-3' of the

alkoxynaphthalene subunit were accessed following the Cram–

Miyano-S_NAr route from

7

and the respective alkoxy-

bromonaphthalene derived Grignard reagents. The syntheses,

performed in analogy to that of L1 tended to proceed sluggishly

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and with lower stereoselectivity. Even so, the major

diastereomers could be obtained in all cases and were saponified

to the enantiopure target acids L2–4 (Scheme 3). The sparse

results of those syntheses did not recommend further exploration

of the de novo asymmetric synthesis approach. It was used once

more to access the chiral carboxylic acid and NMR shift reagent

MNCB (L5) as another potential ligand for catalytic

hydroalkoxylation (Table 1), following Fukushi’s synthetic route.^[45]

variations (Scheme 4). Dealkylation of 10 with BBr₃at 0 °C or r.t.

returned lactone 12a, which suffers fast racemization at ambient

temperature.^[46]At –78 °C, the same reagent permitted

demethylation to give diastereomerically and enantiomerically

pure ester 12, whose successive Williamson etherification and

saponification return various 2'-alkoxy-BINA-Cox ligands L23–25

(Scheme 4, b, c). Notably, alkylation with a,a'-dibromoxylenes

gave tethered bis-carboxylic acids L20 and L21. Phenoxy

derivative L22 was accessed via Chan-Lam coupling,^[47,48]after

initial attempts at Ullmann coupling had failed. No epimerization

occurred in the alkylation or arylation of 12, whose substitution

products were diastereomerically pure. Absence of racemization

under the conditions of saponification was further proven for the

Ph

OMe

O

a) ArMgBr

b) KOH

O

OMe

7

CO₂H

1

free acids by H NMR spectroscopy with nicotine as chiral shift

reagent.^[45]Tosylate 13 derived from 12 was prepared with the

intention to explore cross coupling approaches towards 2'-aryl

substituted derivatives of MeO-BINA-Cox. Nickel-catalyzed

Suzuki coupling (Ni(COD)₂, PCy₃, K₃PO₄) of 13 with phenyl

boronic acid,^[49]followed by saponification, initially returned

hydroxyacid L27, besides target L26 (17%) and hydro-de-

metalation product (aS)-1,1’-binaphthyl-2-carboxylic acid (L32;

6%). Repeat experiments with careful exclusion of water provided

the desired coupling product in superior selectivity. It was then

saponified to L26 (Scheme 4, f and c). An analogous coupling

with 3-methoxyphenylboronic acid gave L28, which reintroduces

a methoxy group into the ligand periphery.

L2

L3

L4

1. S_NAr yield

S_NAr dr

2. yield Ln

n.d.

5% (2 steps)

57%

99.5:0.5

51%

10%

99.4:0.6

21%

Scheme 3. De novo asymmetric synthesis of L2-4 from 7. a) ArMgBr (0.8–1.0);

THF, 66 °C, 1 h for L2, PhMe, 50 °C, 60 h for L3, THF–PhMe (1:3), 80 °C, 1 h

for L4. b) KOH (5.0); EtOH, 80 °C, 48 h for L2, PEG-200, 150 °C, 5 h for L3,

PEG-200, 150 °C, 20 h for L4.

Transformation of the 2'-methoxy group. Based on the well-

developed route to L1, either the latter or its precursor 10

recommended themselves as synthetic platform for structure

L23 (R = Et)

L24 (R = allyl)

HO₂C

O

OR

OPh

L25 (R = Bn)

O

CO₂H

d, c

CO₂H

HO₂C

CO₂H

L21

L22

L20

b, c

a

e

f, c

Ph

OTs

OMe

OH

CO₂Men

OMe

O

OMe

+

CO₂H

CO₂Men

CO₂H

CO₂Men

O

10

12a

12

13

L14 + L14'

L26

g, c

f, c

(Scheme 2)

q

OMe

k, l

h, j

h, i

OMe

OH

OMe

CO₂H

m, n, o

CO₂H

Ph

I

Me

L1

L12

L11

L13

L27

L28

p

Scheme 4. Synthesis of MeO-BINA-Cox derivatives from 10. a) BBr₃, CH₂Cl₂, –78 °C, 5 h, 82% 12. b) Alkyl bromide, K₂CO₃, MeCN, 82 °C. c) KOH, EtOH, 80 °C,

24–72 h. L20: 72% (2 steps); L21: 64% (2 steps); L22: 73% (2 steps); L23: 62%, 82%; L24: 83%, 60%; L25: 72%, 56%; L26: 68%, 84%; L27: 32% (2 steps); L28:

57%. d) Ph-B(OH)₂, Cu(OAc)₂, NEt₃, CH₂Cl₂, MS 4 Å, r.t., 16 h. e) TsCl, DMAP, NEt₃, CH₂Cl₂, 0 °C → r.t., 18 h, 88%. f) Ar-B(OH)₂, K₃PO₄, Ni(COD)₂, PCy₃, THF,

MS 4 Å, 45/50 °C, 60/48 h; to L26: 68% / L28: 84%, respectively. g) Conditions as in f), but with "wet" base and no MS 4Å present; hydrolysis occurred as side-

reaction. h) sec-BuLi, TMEDA, THF, –78 °C. i) MeI, 22%.^[51]j) I₂, THF, –78 °C → r.t., 24 h, 48%. k) K₂CO₃, MeI, acetone, 56 °C, 16 h. l) Na₂CO₃, Ph-B(OH)₂,

[PdCl₂(PPh₃)₂], THF–H₂O (1:1), 50 °C, 18 h. m) LiAlH₄, THF, 0 °C → 65 °C, 16 h. n) IBX, DMSO, r.t., 4 h. o) H₂O₂aq, NaClO₂, NaH₂PO₄∙H₂O, MeCN–H₂O (1:1),

50 °C, 18 h; 22% (5 steps).^[54]p) Ag₂CO₃, K₂CO₃, Pd(OAc)₂, N-acetylglycin, PhI–HOAc, 90 °C, 3 d, 51%. q) Ni–Al alloy, 1 % aq NaOH, H₂O–iPrOH (7:1), 90 °C, 24

h, 90% (14:14’ = 1:1).

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Br

O

N

h, j

e

f

OMe

CO₂Men

CO₂H

OMe

CO₂H

L19

Br

10

L1

14

j

tBu

a

b

L29

OMe

CO₂H

OMe

a

i, j

BuO

CO₂H

L18

L15

O

OMe

Br

Ph

CO₂H

Me

f

g, a

OMe

d, a

OMe

CO₂H

OMe

CO₂Me

CO₂H

L30

c, a

L17

15

16

L16

Scheme 5. Syntheses of ligands L15–19, L29 and L30 from esters 10/15 of MeO-BINA-Cox (L1). a) KOH, EtOH, 80 °C, 18–21 h; L15: 83%; L16: 92%; L17: 37%;

L18: 82%; see Scheme 2 for L1. b) K₂CO₃, MeI, acetone, 56 °C, 2 h, 94%. c) MeCOCl, AlCl₃, CH₂Cl₂, 0 °C → r.t., 45 min, 91%. d) tBuCl, AlCl₃, CH₂Cl₂, 0 °C →

r.t., 60 h, 72%. e) 1-AdBr, InCl₃, CH₂Cl₂, 60 °C, 14 h, 53% (in situ ester cleavage). f) Br₂, HOAc, r.t., 4–29 h, 98% for 14, 84% for 16. g) Na₂CO₃, Ph-B(OH)₂,

PdCl₂(PPh₃)₂, THF–H₂O (1:1), 50 °C, 18 h, 65%. h) morpholine, Pd(OAc)₂, XPhos, NaOtBu, PhMe, 110 °C, 1 h. i) n-BuOH, K₃PO₄, CuI, 8-hydroxyquinoline, 110 °C,

48 h. j) KOH, PEG-200, 150 °C, 2–8 h. L15: 55%; L29: 20%; L30: 78%. XPhos = 2-dicyclohexylphosphino-2’,4’,6’-triisopropylbiphenyl.

Ligand syntheses via metalation or reduction of L1. According

to Metz et al, H-3’ of MeO-BINA-Cox (L1) was regioselectively

lithiated with sec-BuLi–TMEDA^[50]and then alkylated with MeI to

give L13 (Scheme 4, h, i).^[51]An analogous metalation followed by

quenching with iodine gave L11, whose direct Suzuki coupling

with phenyl boronic acid to L12 failed, but was realized at the

stage of its methyl ester. Unfortunately, the resulting ester

resisted standard saponification and thus was laboriously

converted to L12 via LiAlH₄reduction, IBX-oxidation and

Lindgren^[52]NaClO₂oxidation. More efficiently, a phenyl group

was introduced at C-3 of L1 following a protocol for Pd-catalyzed

ortho-C–H-arylation^[53]to give L12 in a single step (Scheme 4, p).

Hydrogenation of L1 with in situ activated Raney-Nickel in

aqueous isopropanol^[55]led to a 1:1 mixture of tetrahydro- and

octahydrogenated derivatives L14/L14', whose ratio remained

unchanged when the mixture was exposed once more to the

hydrogenation conditions. The two components could not be

separated either by chromatography or fractional crystallization.

S_EAr Functionalization of MeO-BINA-Cox esters. Friedel-

Crafts type functionalization at methoxynaphthalene C-6’ were

performed on methyl ester 15 as substrate and succeeded in case

of alkylation with tert-butyl chloride^[56]or acylation with acetyl

chloride^[15]to provide L17 and L18, respectively, after

saponification (Scheme 5, b–d). When the evaluation of ligand

L18 in catalysis returned superior results over L1, we thought it

worthwhile to study the effect of 1-adamantyl as typical dispersion

energy donor substituent (DED^[57]). Its introduction at C-6' was

attempted through InCl₃-catalyzed Friedel-Crafts alkylation of

menthyl ester 10 with 1-bromoadamantane.^[58]Curiously,

adamantylated acid L19 was the major product from this reaction

besides the expected ester. It appears that HBr, which is released

in the alkylation step, also cleaves the menthyl ester by

dealkylation, and this was supported by detecting both menthyl-

(d_H3.99) and neomenthyl-bromide (d_H4.67) in the crude reaction

mixture. Saponification was thus spared in the synthesis of L19.

The absence of racemization under S_EAr reaction conditions was

checked for L17 and L18 through ¹H NMR analysis with nicotine

as shift reagent.^[45]

Cross-coupling of 6'-bromoester. Bromination of either

menthyl (10) or methyl (15) esters of MeO-BINA-Cox proceeded

in the C-6’ position to give monobromides 14 or 16 in excellent

yields. Either ester was saponified to bromoacid L15. Standard

coupling methodologies for heteronucleophiles (amines, alcohols)

with 14 gave access to 6’-amino- (L29)^[59]or 6’-alkoxy- (L30)^[60]

substituted MeO-BINA-Cox after saponification (Scheme 5, h–j).

Brominated ester 16 was also arylated by Suzuki coupling and

furnished 6'-phenyl acid L16 after saponification (Scheme 5, b, g).

Ligand effects in titanium-catalyzed asymmetric

hydroalkoxylation

The cycloisomerization of 2-allylphenol (1a) to 2-methylcou-

maran (2a) served as reference reaction for comparing the

performance of ligands L2–L34 in titanium-carboxylate catalyzed

asymmetric hydroalkoxylation by determining ligand effects on

catalyst activity and stereoselectivity (Table 1).^[19]We opted for a

short reaction time of 20 min, such that the analytical yields of 2a

reflect relative catalytic activities. The reaction is generally

sensitive to variations in the reaction temperature, the water-

content of substrates and solvent and the purity of starting allyl

phenol 2a. As a means of quality control and to ascertain the

integrity of the reaction setup, the standard reaction with L1 was

repeated with each new experiment series. Any notable deviation

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Table 1. Structure variations of L1 and their effects on the asymmetric catalytic hydroalkoxylation of 1a to 2a.^[a]

Ti(OiPr)₄(5 mol-%)

L (5 mol-%)

H₂O (5 mol-%)

OH

O

Me

PhMe, 240 °C (µW)

20 min

1a

2a

Entry

1^[d]

Ligand

Ln

Yield^[b]

[%]

ee^[c]

[%]

Entry

Ligand

Ln

L4

Yield^[b]

[%]

ee^[c]

[%]

no ligand

1

–

O

2^[e]

3a

3b^[f]

4^[f]

L1, no Ti(OR)₄

L1

0

54

75–84

0

–

75

71–75

–

O

OMe

22^[f]

56

43

CO₂H

L10 (H = Na)

23

24

25

L13 (R = Me)

L11 (R = I)

L12 (R = Ph)

80

22

2

57

35

5

OMe

OH

5

L8

10

0

CO₂H

R

26

27

L17 (R = COMe)

L15 (R = Br)

L30 (R = OnBu)

L18 (R = tBu)

L18

0

–

R

52

73

71

79

85

60

72

73

80

78

76

28^[f]

29a

29b^[f]

30^[f]

31

OMe

R

6

7^[f]

L9 (R = OMe)

L31 (R = NH₂)

15

13

0

OMe

CO₂H

L19 (R = 1-Ad)

L16 (R = Ph)

N

8^[g]

9

10

11

L32 (R = H)^[h]

L27 (R = OH)

L26 (R = Ph)

18

5

13

9

4

O

R

n.d.

20

OMe

32

70

L29

55

CO₂H

L28 (R = m-An)

O-BINA-Cox

CO₂R

CO₂H

12

13

L6 (R = H)

L7 (R = Me)

10

3

36

0

L20

1

10

33a

13

70

33b^[i]

OMe

14

15

L33 (R = H)

L34 (R = tBu)

8

14

0

L21

2

6

34a

14

67

O

34b^[i]

CONHR

BINA-Cox

16

17

18

19

L23 (R = Et)

L24 (R = All)

L25 (R = Bn)

L22 (R = Ph)

29

30

21

24

51

49

36

OR

OMe

35^[f]

20

71

L14/L14’

36

38

CO₂H

R

OMe

20

L2 (R = Ph)

L3 (R = OMe)

23

68

49

46

OMe

Cl

CO₂H

36

L5

21^[f]

CO₂H

Cl

[a] Conditions: 2-allylphenol (1.5 mmol), PhMe (3 mL); Ti(OiPr)₄(5 mol-%). [b] Yield of 2a determined by qNMR analysis. [c] ee of 2a determined by chiral HPLC

of purified product. [d] Without H₂O. [e] Without Ti(OiPr)₄. [f] Reaction time 50 min. [g] Reaction time 30 min. [h] 45% ee. [i] 2.5 mol-% of chiral ligand (-CO₂H:Ti

ratio 1:1). n.d. = not determined; m-An = meta-anisyl or 3-(C₆H₄OMe); Ad = adamantyl.

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in either yield or enantioselectivity of 2a pointed to problems

with either reagents or the microwave unit. The temperature

sensor of the latter was also regularly recalibrated.

subunit (L5)^[12,45]was well tolerated; the lower activity vs L1 is

consistent with assuming a deactivating s-acceptor effect exerted

by chlorine (entry 36).

In spite of the thermally forcing conditions of this reaction

(“HOT-CAT”, homogeneous thermal catalysis), initial blank

experiments with titanium(IV)alkoxide in the absence of

carboxylic acid ligand show very little substrate conversion (entry

1), and carboxylic acid L1 in the absence of titanium precursor

gave no conversion at all (entry 2). Standard catalytic runs with

L1 gave (2S)-2-methylcoumaran (2a) in yields that increased with

the holding time at 240 °C (entries 3a vs. 3b).

The influence of polar functional groups in the ligand sphere

upon catalytic activity was explored with suitably modified

structures: Converting L1 to its sodium salt L10 quenches the

catalytic activity of the in situ catalyst with Ti(OiPr)₄and water

(entry 4). This negative buffering effect points to the importance

of a minimal acidity level within the reaction system. Runs with

variously functionalized 1,1-binaphthyl-derivatives (entries 2–15)

imply that the presence of a single carboxyl (entry 8), or chelation

by two coordinating donors (-CO₂H, -OR, -NH₂, -CONHR > CO₂R;

entries 5–7, 9, 12–15) are minimal requirements for catalytic

activity. However, enantioselectivity is only achieved with free

carboxyls (entries 3, 8, 12), and high activity and selectivity are

Substrate scope of asymmetric cycloisomerization

The cyclization of 2-allylphenols (1) to 2-methylcoumarans (2)

was the original assay used for the discovery of the Ti(OiPr)₄–L1–

H₂O catalyst system; results with various core-substituted 2-

allylphenols were already reported in our communication^[19]and

are included in Table 2 for completeness. The catalytic runs for

the substrate scope were typically performed with L1 and

additional selected examples with L18, or other ligands. The

heating phase was extended to 50 minutes in order to approach

complete conversion of substrates.

2-Allylphenol substrates. Results obtained with methylated

and halogenated allylphenols are shown in Table 2 (entries 1–8).

Besides simple allylphenol (1a), the alkylated analogues 1b,c

cyclized in excellent yields at enantiomeric ratios of er 85:15–

90:10 (entries 1–3). Sterically demanding substituents para to

phenolic hydroxyl (1d,e) are less well tolerated (entries 4, 5b), and

1e only showed conversion with the more active catalyst

incorporating L18 (entry 5b). Halogenated 2-allylphenols 1f–h

cyclize fairly well, but at slightly lower enantiomeric excesses

(entries 6–8). Reactions performed at 220 °C tend to be more

selective, but also lower yielding (cf. entries 1b, 2b, 3b vs. 1c, 2c,

3c). The highest enantioselectivity was achieved with substrate

1c in combination with ligand L18 (entry 3b).

Cycloisomerizations typically profit from the Thorpe-Ingold

effect.^[61]The geminal dimethylallyl-phenol 1i was prepared with

this in mind and tested additionally with ligands L13 and L5, which

gave lower yields and ee-values (entries 9), consistent with the

ligand screen of 1a (Table 1). Spirocyclic cycloalkyl derivatives

1j,k cyclized successfully with yields of 1j surpassing those of 1k

(entry 10 vs. 11) at stable enantiomeric excesses slightly below

1a. The lower yields obtained with those substrates are ascribed

to competing homo-1,5-rearrangements giving regioisomeric

coumarans (Scheme S1). The extent of rearrangement was lower

for the titanium catalyst than in the previously reported results with

Al(OiPr)₃as (achiral) catalyst.^[62]

only reached by combining one carboxyl with

a weakly

coordinating 2’-methoxy group (entry 3). Replacing 2'-methoxy

with sterically active non-donors retains some selectivity at low

activity (entries 10,11). Shifting of the methoxy group from the 2'-

position into the periphery by inserting a 2’-meta-anisyl group is

ineffective (entry 11). Increasing the size of the 2'-alkoxy-group

beyond methoxy successively reduces catalyst activity and

selectivity (entries 16–19).

Attaching a group to the 3'-position (while retaining 2’-alkoxy)

reduces catalyst activity and selectivity (entries 20–22).

Substitution at C-3 in the naphthoic acid fragment has similar

effects (entries 23–25), although the small methyl group boosts

catalyst activity at somewhat reduced selectivity (entry 23). The

increased activity of L13 might be a consequence of the s-donor

effect of methyl. By placing specific groups into the remote 6'-

position of the MeO-BINA-Cox core structure, their electronic

influence can be studied with minimal disturbance of the

coordination sphere around the metal. Entries 26–31 show that

electron-rich +s and +p groups induce high activity and

enantioselectivity similar to, and sometimes surpassing that

obtained with L1 (entries 29, 30). The most successful groups are

the bulky ones, and thus a steric (or: dispersion donor) influence

on catalyst properties cannot be discounted, besides the electron

donor effect. In any case, the p-acceptor group of L17 completely

suppresses catalyst activity (entry 26).

The in situ catalyst from Ti(OiPr)₄, Ln and H₂O is presumably

a multinuclear titanium-µ-oxo species.^[19]Tethered dicarboxylic

acids L20 and L21 were prepared to potentially bridge metal

centers more effectively than separate units of L1. Their low

catalytic activity points to a steric misfit of the tethering unit,

however (entries 33, 34). The partially hydrogenated ligand

mixture L14/L14’ displayed lowered activity and selectivity (entry

35), whereas replacing the naphthoic with a dichlorobenzoic acid

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Table 2. Asymmetric catalytic cyclization of variably substituted 2-allylphenols (1) to coumarans (2).^[a]

Ti(OiPr)₄(5 mol-%)

OH

O

L (5 mol-%)

Me

R

H₂O (5 mol-%)

PhMe

µW-heating

1

2

Entry

1

Ln

T

[°C]

t

Product (2)

yield^[b]

[%]

ee^[c]

[%]

Entry

1

Ln

T

[°C]

t

Product (2)

yield^[b]

[%]

ee^[c]

[%]

[min]

1a

1b

1c

1a

L1

L18

240

220

240

50

84

81

92

75

85

80

7a

7b

7c

1g

L1

L18

240

220

240

50

90

88

93

62

73

69

O

Me

Cl

2a

2g

2a

2b

2c

1b

1c

L1

L18

240

220

240

50

O

71

78

79

72

81

75

8a

8b

1h

1i

L1

L18

240

50

O

71

86

62

73

Me

Br

2h

2b

3a

3b

3c

L1

L18

240

220

240

50

88

93

78

87

84

9a

9b

9c

9d

9e

L1

L5

L13

190

220

240

20

48^[e]

76

88^[e]

63

71

66

53

50

Me

O

Me

2i

Me

2c

64

4a

4b^[d]

1d

L1

L18

240

50

51

83

61

77

10a

10b

1j

L1

220

240

20

50

84^[e]

74^[e]

68

65

O

Me

iPr

2d

2j

5a

5b

1e

1f

L1

L18

240

50

0

31

–

59

11a

11b^[f]

11c^[f]

1k

L1

220

240

20

50

55^[e]

48^[e]

64

60

61

O

Me

Ph

2e

2f

2k

6

L1

240

50

56

72

O

Me

F

[a] Conditions: allylphenol (1.5 mmol), toluene (3 mL); Ti(OiPr)₄was added using an Eppendorf pipette or as a 0.15 M stock solution in toluene (0.5 mL per

experiment). [b] Isolated yields after work-up by column chromatography except otherwise stated. [c] ee values were determined by chiral HPLC of the purified

reaction product. [d] Conditions: substrate (0.95 mmol), Ti(OiPr)₄(8 mol-%), L18 (8 mol-%), H₂O (8 mol-%), toluene (3 mL). [e] Yields were determined by qNMR

analysis using tetradecane as internal standard. [f] Reaction scale: substrate (1.4 mmol), toluene (3 mL). n.d. = not determined.

Further extension of the substrate range. To probe further

variations of the substrates for titanium-catalyzed (asymmetric)

hydroalkoxylation we next concentrated on allylphenols bearing

additional substituents within the alkene unit. Crotylphenol (1l)

showed little conversion under standard conditions with L1, and

lower enantioselectivity (Table 3, entry 1); 1m with a further

extended allyl chain failed to cyclize entirely (entry 7). Core-

methylation of crotylphenol to 1n likewise did not improve

reactivity (entry 2). Based on those results, we assumed that there

is a detrimental steric effect of alkene substitution, but were next

surprised to find catalytic activity restored with the still higher

substituted 2,3-dimethyl-allyl-substrates 1o and 1p (entries 4, 5).

The presence of inseparable side products prevented a reliable

determination of the ee of the reaction products. Cyclization of 1q

and 1r took a different path in that 6-endo-trig cyclization to

chromanes was preferred (entries 5, 6); chromane 2q is achiral.

Aliphatic alkenol 1s cyclized only with difficulty (entry 8). With

substrate 1t we found a new type of substrate for the reaction,

whose asymmetric 5-exo-trig cyclization also illustrates

compatibility of tertiary alkanol substrates (entries 9). Finally, a 6-

exo-trig cyclization could also be realized asymmetrically with 2’-

vinyl-1,1’-biphenyl-2-ol 1u, which bears an alkene and a phenolic

moiety on separate phenyl groups; product 2u was obtained in

limited yield and enantioselectivity, however (entries 10).

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Table 3. Extended substrate range of intramolecular asymmetric catalytic hydroalkoxylation.^[a]

Ti(OiPr)₄(5 mol-%)

L (5 mol-%)

OH

H

O

H₂O (5 mol-%)

*

n

PhMe

µW-heating

1

2

T

[°C]

t

Yield^[b]

[%]

ee^[c]

[%]

Entry

1

Substrate (1)

1

Ln

L1

Product (2)

2

[min]

OH

Me

O

250

20

1l

2l

8

0

30

–

Me

OH

nPr

O

L1

2

3

1m

1n

2m

2n

nPr

Me

OH

Me

O

Me

250

20

traces

n.d.

Me

OH

Me

O

n.d.^[d]

n.d.

L1

250

20

4

5

1o

1p

2o

2p

76

Me

OH

Me

O

Me

56^[e]

Me

Cl

OH

Me

O

Me

L1

250

20

6

1q

2q

63

n.a.

O

Ph

OH

7

8

1r

2r

<3^[e,f]

n.d.

0

L1

250

240

20

O

HO

Me

1s

2s

6

Ph

Ph Ph

Me

Me Me

9a

9b

9c

32+62^[e]

32+26^[e]

52^[g]

71^[g]

L1

L19

220

50

30

Me

O

1t

+

2t+2t’

OH

Me

OH

O

Me

10a^[h]

10b^[i]

11^[e]

44^[e]

34

24

L1

240

20

30

1u

2u

[a] Conditions: allylphenol (1.5 mmol), toluene (3 mL); Ti(OiPr)₄was added using an Eppendorf pipette or as a 0.15 M stock solution in toluene (0.5 mL per

experiment). [b] Isolated yields after work-up by column chromatography except otherwise stated. [c] ee values were determined by chiral HPLC of the purified

reaction product. [d] ee-value could not be determined due to contamination of the purified product by side-products. [e] Yields were determined by qNMR

analysis using tetradecane as internal standard. [f] Yields could not be determined precisely and do not exceed the given value. [g] ee was determined by chiral

GC analysis of the purified reaction product. [h] Reaction scale: substrate (1.38 mmol), toluene (3 mL). [i] Reaction scale: substrate (0.73 mmol), toluene (3 mL).

n.d. = not determined; n.a. = not applicable.

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Substrates failing to cyclize. Additional substrates that failed to

cyclize will be shortly discussed: 2-Allylphenols with substituents

ortho to hydroxyl fail in the model reaction (Figure 2). A methyl

group is sufficient to suppress the catalysis (1aa), disregarding

more hindered substrates (1ab, 1ac). The presence of polar,

coordinating or p-acceptor groups, even remote ones, is another

limitation, judging from the inactivity of substrates 1ad and 1af–

1ai. The case of 2-prop-1-enylphenol (1aj) is of interest, since this

compound could principally be formed by isomerization from 1a.

The 5-endo-trig cyclization of 1aj to 2a was not observed under

catalytic reaction conditions, even though the starting material

was fully converted. This points to a relatively fast polymerization

of 1aj under reaction conditions, which also explains why the latter

is not observed as side-product in the model cyclization 1a®2a,

where it escapes analytical detection through fast polymerization.

Conclusions

The present work extends our studies of the high-temperature

asymmetric catalytic cyclization of 2-allylphenols to 2-methyl-

coumarans.^[19]A first focus was placed on the role played by the

chiral carboxylic acid ligand in the novel titanium alkoxide–

carboxylic acid–water in situ catalyst.

Preliminary work had indicated strict structural requirements

imposed on the chiral carboxylic acid ligand, and that successful

ligands should be axially chiral biaryl-2-carboxylic acids with a

methoxy group in the 2’-position. Such compounds are not readily

available in enantiomerically pure form and have to be

synthesized along laborious routes. To perform the ligand

structure variations required for structure-activity studies of the

catalyst, modification at the stage of enantiopure MeO-BINA-Cox

(L1) as platform chemical emerged as the most convenient

approach. We have improved the asymmetric synthesis of L1 by

determining key reaction parameters in all steps and adapting the

reaction conditions to molar scales with no need for

chromatography in any reaction step. Among the key findings are

a base-catalyzed version of the S_NAr alkoxide exchange reaction

of methoxyester 4 with menthol to give menthyloxy menthoate 7,

and the analytically driven reaction development towards

conditions with near optimal yield in the asymmetric S_NAr reaction

of Grignard reagent 9 with 7. Finally, a new protocol for

saponification of sterically hindered, resilient esters in hot PEG-

200 at elevated temperature was introduced, which permits the

saponification of ester 10 to acid L1 at quarter-molar scale in short

reaction time with only a moderate excess of base.

deactivated or coordinating allylphenols

R

CF₃

Me

OH

F₃C

1aa

1ab (R = H)

1ad

1ae

1ac (R = Me)

propenylphenol

O

OMe

OH

R

Me

1af

1ag (R = OMe)

1ah (R = CN)

1ai

1aj

Based on established and newly developed synthetic routes,

including direct substitutions in L1, more than 30 novel axially

chiral biaryl-2-carboxylic acids have been synthesized in

enantiopure form and tested as ligands in the titanium-catalyzed

asymmetric cycloisomerization of 2-allylphenol to 2-

methylcoumaran. The results confirm that biaryl-based ligand

structures incorporating a carboxylic acid and a methoxy group in

the 2- and 2’-positions, respectively, are crucial for achieving high

catalyst activity and stereoselectivity. Compared with L1, an

increase of catalytic activity was observed in ligands having

electron-donating and sterically demanding substituents at the

remote 6’-position (L18, L19). Sterically demanding substituents

are not tolerated in proximity of the polar functional groups of the

ligands, presumably since they interfere with the coordination

sphere of the catalytically active titanium centre.

ortho-vinyl-benzylalcohols

(CH₂)_n

R

Me Me

OH

R R

OH

Ph

Me

1ak (R = H)

1al (R = Ph)

1am (n = 1)

1an (n = 2)

1ao

1ap (R = H)

1aq (R = Me)

alkenols

R R

1ar (R = H)

1as (R = Me)

OH

Figure 2. Substrates 1aa-as, which did not cyclize under the standard reaction

conditions of the asymmetric titanium catalyzed hydroalkoxylation.

The second focus topic of this work was to study potential

extensions of the substrate scope of this rare example of an

asymmetric catalytic hydroalkoxylation reaction with non-

activated alkenes. Alkylated and halogenated allylphenols, as

well as allylphenols having aryl or alkyl groups attached to the

alkene unit or to the a-allylic (benzylic) position were tolerated in

the catalytic reaction, although with various levels of success

regarding the yield and enantiomeric excess of the products.

Notably, the introduction of a methyl group in the b-allylic position

is better tolerated than in the g-allylic position.

The group of ortho-alkenyl-benzyl alcohols (1t, 1ak–1ao) has

their reactive centers homologously shifted relative to allylphenols.

Unlike for a,a-dimethylcarbinol 1t, which cyclized to coumaran 2t

under standard conditions (cf. Table 3, entries 9), experiments

with 1ak–1am returned only starting material. The formal

introduction of a b-methyl group into 1t prevented cyclization in

the resulting 1ao, which suffered elimination of water to give a

dialkenylbenzene instead (Scheme S2). The 2-styryl alcohols 1ap

and 1aq failed to cyclize under conditions of the model catalysis.

In another attempt at converting aliphatic alkenols (cf. 1s in Table

3, entry 8), both substrates 1ar and 1as failed to cyclize.

New examples of asymmetric catalytic hydroalkoxylation

reactions have been identified in the course of this study, such as

the cyclization of 2’-vinylphenyl-(1,1-dialkyl)methanol (cf. 1t) or of

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100 °C). After cooling to r.t. and addition of H₂O and Et₂O, the layers were

separated. The aqueous layer was acidified using aqueous 2 M HCl and

extracted with several portions of Et₂O. The organic layers were combined

and washed with aqueous 2 M HCl and saturated aqueous NaCl. After

drying over Na₂SO₄and filtration, the solvent was evaporated giving the

crude reaction product.

2’-vinyl-1,1’-biphenyl-2-ol (1u) to 1,3-dihydrobenzofuran (2t) or

6H-benzo[c]chromene (2u), respectively.

Based on the ready access to L1, we plan to isolate and study

the chiral titanium carboxylate complexes that appear to catalyze

the hydroalkoxylation reaction. In combination with the findings

from the substrate structure variations, we hope to gain insight

into the mechanism of this peculiar reaction.

General procedure for saponification of biarylcarboxylic acid esters

with KOH in EtOH (GP-1B): To a solution of 1.00 equiv. ester and solid

KOH (85% content) in EtOH (5–10 mL/mmol), a little water (0.2 mL/mmol)

was added and the reaction mixture was heated to reflux overnight (bath

100 °C). After cooling to r.t. and addition of H₂O and Et₂O, the layers were

separated. The organic layer was extracted with saturated aqueous LiOH,

then discarded. The combined aqueous layers were acidified with aqueous

2 M HCl and extracted with several portions of Et₂O. The combined extracts

were dried over Na₂SO₄. After filtration, the solvent was evaporated to give

the crude product. Note: use of aqueous LiOH can be beneficial for

bringing carboxylate into the aqueous layer, in case the potassium salt is

partially soluble in the organic layer.

Experimental Section

General remarks. Unless otherwise specified, all reagents were obtained

from commercial suppliers and used without further purification. 2-

Allylphenol (1a) was distilled in high vacuum (short-path distillation) and

stored under exclusion of air in the dark; typical water content 200 ppm.

K₂CO₃was dried in high vacuum with heating to 120 °C. K₃PO₄was finely

powdered and dried in high vacuum at 100 °C. Commercial KOH flakes

(85% content) were ground to a fine powder before use. Solvents for

synthesis were commercially obtained and used without purification.

Solvents for column chromatography were of technical grade and used

after distillation. Water-free solvents were obtained by passing commercial

solvents through a column of dry Al₂O₃and storing under argon over 4 Å

molecular sieves. Residual water was analyzed by coulometric Karl-

Fischer titration.

General procedure for saponification of biarylcarboxylic acid esters

with KOH in PEG-200 (GP-1C): The ester (1.00 equiv.) and solid KOH

(85% content; 5.00 equiv.) were added to PEG-200 (ca. 5 mL/mmol) at r.t.

The reaction mixture was heated to 150 °C with stirring for the indicated

time. After cooling to r.t. and addition of H₂O, aqueous 6 M HCl and EtOAc,

the layers were separated and the aqueous layer was extracted with

EtOAc (2–3´). The combined organic phases were washed with H₂O (5´),

dried over MgSO₄and filtered. After removal of the solvent in vacuo, the

crude residue was dissolved in a small amount of CH₂Cl₂and a defined

amount of trichloroethene was added as an internal standard for qNMR

analysis. After the NMR analysis, solvent and internal standard were

removed in vacuo to give the crude reaction product.

Abbreviations: The term (1R)-menthyl denotes (1R,2S,5R)-2-isopropyl-

5-methylcyclohexyl, or (–)-menthyl (in the older literature), within a

menthyloxy group. PEG is polyethylene glycol.

Chromatography. Column chromatography (CC) was performed on silica

gel 60 (35–70 µm particle size) with 0.2 bar positive air pressure. Thin layer

chromatography (TLC) was performed on glass plates coated with silica

gel 60 F₂₅₄and visualized with UV light (254 nm) and by staining with

Mostain [10 g (NH₄)₆[Mo₇O₂₄]∙4 H₂O, 0.2 g Ce(SO₄)₂∙4 H₂O, 190 mL H₂O;

12 mL H₂SO₄(conc.) added last with stirring].

General procedure for determining the enantiomeric excess of

biarylcarboxylic acids (GP2). The enantiomeric excess of chiral

carboxylic acids was determined by an NMR chiral shift method using (–)-

nicotine as chiral base according to Fukushi:^[45]A sample of the chiral

carboxylic acid (15–30 µmol, 1.0 equiv.) was dissolved in CDCl₃and (–)-

nicotine (10 µL, 60 µmol, 2–4 equiv.) was added. The ¹H NMR spectrum

was recorded using a relaxation delay (d1) of 20 seconds. For MeO-BINA-

Cox derivatives, the methoxy signals for enantiomeric anions appear at

different chemical shifts (e.g., Dd_H0.05 for L1). Integration of the methoxy

singlets – by means of deconvolutive peak analysis, if necessary – gave

the relative amounts of diastereomeric ion pairs (d.r.), from which the ee

of the acid is derived.

Microwave Syntheses were carried out in an Anton Paar Monowave 300

reactor equipped with a MAS 24 autosampler. The temperature was

monitored by an external IR thermometer, which was regularly calibrated

against an internal optical ruby thermo-probe. Specified reaction times

correspond to the holding time at target temperature.

Analytical data: NMR spectra were recorded at ambient temperature (19–

25 °C). Chemical shifts (d) are given in ppm. ¹H NMR spectra are internally

referenced to tetramethylsilane (TMS, d_H0.00) or residual solvent peak

(CHCl₃: d_H7.26; [D₅]-DMSO: d_H2.50). ¹³C NMR spectra are referenced to

solvent (CDCl₃, d_C77.16; [D₆]-DMSO, d_C39.52). Quantitative ¹H NMR

analysis (qNMR) was performed with a prolonged relaxation delay (d1) of

20 s, with either tetradecane (d_H0.88) or 1,1,2,2-tetrachloroethane (d_H

5.90) or trichloroethene (d_H6.45) as internal standard. The symbol y

denotes a “pseudo”-signal (appearing as). Chiral HPLC analysis was

performed on Chiralcel OJ or OD stationary phases (250´4.6 mm). EI

HRMS were recorded using a DFS High Resolution MS, ESI HRMS using

a LTQ FT Ultra, equipped with a Fourier-transform ion cyclotron resonance

(FT-ICR) MS detector.

General procedure for asymmetric catalytic hydroalkoxylation (GP3).

Under argon, the ligand (0.05 equiv.) was combined with titanium(IV)

isopropoxide (0.05 equiv.; a stock solution in toluene may be used) in a

borosilicate glass vial. H₂O (0.05 equiv.) was added to the lower vessel

wall by micro-syringe, followed by dry toluene (3 mL). The resulting mixture

was stirred for 10 min at 60 °C. The substrate (1.00 equiv.) was added and

the mixture was heated in a microwave reactor to the target temperature,

where it was held for the indicated reaction time. After cooling, an internal

standard (tetradecane) was added to the crude reaction mixture and an

aliquot was removed for qNMR analysis. The reaction mixture was placed

on top of a solvent-filled silica gel column for purification by CC.

Enantiomeric excess was determined by chiral HPLC analysis of

chromatographically purified reaction product.

General procedures

General procedure for saponification of biarylcarboxylic acid esters

with KOH in EtOH (GP-1A): To a solution of 1.00 equiv. ester and KOH

(85% content) in EtOH (5–10 mL/mmol), a little water was added (ca. 0.2

mL/mmol) and the reaction mixture was heated to reflux overnight (bath

Scaled-up synthesis of MeO-BINA-Cox (L1)

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Methyl 1-methoxy-2-naphthoate (4): A three-necked 4 L round-bottom

flask was charged with 1-hydroxy-2-naphthoic acid (3; 400 g, 2.13 mol,

1.00 equiv.), acetone (2 L) and dimethyl sulfate (424 mL, 4.48 mol, 2.10

equiv.; CAUTION).^a)To the mechanically stirred suspension,^b)potassium

carbonate (648 g, 4.69 mol, 2.20 equiv.) was added in portions over the

course of 5 h. The internal reaction temperature was initially kept at 20 °C

by an external water bath, to which ice was added as needed. After half

the amount of the base had been added, the reaction mixture was allowed

to warm by the reaction heat, and the water bath was additionally heated

to 50 °C.^c)After completion of the base addition, the reaction mixture was

stirred for 2 h at 50 °C, when TLC indicated consumption of both starting

material (3) and the intermediary methyl 1-hydroxynaphthoate (R_f0.49;

EtOAc–hexanes 1:10). After cooling to r.t., aqueous 25% NH₃(100 mL)

and H₂O (1.2 L) were added slowly with continued stirring.^d)The top

organic layer was removed^e)from the aqueous layer. The aqueous layer

was extracted with Et₂O (2´) and the combined organic layers were

washed with saturated aqueous NaCl (2´). After drying (MgSO₄) and

filtration, solvents were evaporated. The crude oil was distilled (118–

122 °C, oil-pump vacuum, ca 0.1 mbar) to give bright-yellow liquid (442 g,

96%). Notes: a) Safety measures for the case of spilling of dimethyl sulfate

or bursting of the reaction vessel were taken. The reaction vessel was

placed into a water bath in a metallic pan, and aqueous 25% ammonia was

kept in reach for decontamination of spills. b) Motor-driven mechanical

stirring is required at large scale. c) Stirring of the heated suspension

proved to be considerably easier than of the cooled reaction mixture.

External ice-cooling may not be necessary at all, if K₂CO₃is added at a

rate to keep the temperature of the water bath below the boiling point of

the reaction mixture. d) The addition of ammonia (EXOTHERM!) is a

safety-measure to quench excess dimethyl sulfate by alkylation, which

renders the ensuing work-up more safely. e) Since no sufficiently large

separatory funnel was available, phase separation was effected by

transfer of the upper organic layer through PTFE tubing under a positive

nitrogen pressure. The lower aqueous phase was extracted by mechanical

stirring with new solvent added to the reaction vessel. R_f0.35 (EtOAc–

hexanes 1:10). B. p. 118–122 °C (ca. 0.1 mbar). ¹H NMR (500 MHz,

CDCl₃): d = 3.98 (s, 3 H), 4.07 (s, 3 H), 7.53–7.60 (m, 2 H), 7.61 (d, J = 8.8

Hz, 1 H), 7.85 (dd, J = 8.9, 6.4 Hz, 2 H), 8.28 (d, J = 7.6 Hz, 1 H). ¹³C NMR

(101 MHz, CDCl₃): d = 52.32, 63.47, 119.27, 123.69, 123.71, 126.60,

126.74, 127.95, 128.40, 128.65, 136.85, 158.37, 166.75. Known

compound, CAS 6039-59-4.

R_f0.46 (EtOAc–hexanes 1:20). ¹H NMR (500 MHz, CDCl₃): d = 0.73 (d, J

= 6.6 Hz, 3 H), 0.87 (d, J = 7.0 Hz, 4 H), 0.89–0.99 (m, 2 H), 0.93 (d, J =

7.1 Hz, 3 H), 0.95 (d, J = 6.6 Hz, 3 H), 1.02 (d, J = 6.9 Hz, 3 H), 1.05 (d, J

= 7.0 Hz, 3 H), 1.05–1.26 (m, 4 H), 1.52–1.67 (m, 4 H), 1.70–1.76 (m, 4

H), 2.04 (sept´d, J = 7.0, 2.6 Hz, 1 H), 2.18 (dtd, J = 11.9, 4.0, 1.6 Hz, 1

H), 2.67 (sept´d, J = 7.0, 2.2 Hz, 1 H), 4.33 (td, J = 10.4, 4.1 Hz, 1 H), 5.03

(td, J = 10.9, 4.4 Hz, 1 H), 7.45–7.56 (m, 3 H), 7.67 (d, J = 8.6 Hz, 1 H),

7.79 (dd, J = 7.8, 1.4 Hz, 1 H), 8.32 (dd, J = 8.3, 1.4 Hz, 1 H). ¹³C NMR

(101 MHz, CDCl₃): d = 16.57, 16.78, 21.05, 21.60, 22.23, 22.24, 23.44,

23.51, 25.84, 26.39, 31.62, 31.68, 34.46, 34.59, 39.98, 41.18, 47.28, 49.64,

74.59, 82.11, 121.15, 122.39, 124.46, 126.00, 126.22, 127.73, 127.85,

130.12, 136.24, 154.10, 166.76. Known compound, CAS 129656-73-1.

1-Bromo-2-methoxynaphthalene. This was obtained by bromination of

2-methoxynaphthalene in acetic acid.^[41a]Attempts to diminish the solvent

volume by partially replacing HOAc with CH₂Cl₂(1:1), in which starting

material and product are well soluble, led to a significantly reduced yield

(76% at the 1.25 mol scale). This was due to lower chemoselectivity, with

partial over-bromination to 1,6-dibromo-2-methoxynaphthalene, besides

leaving unreacted starting material. Procedure: To a suspension of 2-

methoxynaphthalene (198 g, 1.25 mol, 1.00 equiv.) in acetic acid (1 L), a

solution of bromine (65.0 mL, 1.25 mol, 1.00 equiv.) in acetic acid (250 mL)

was added at r.t. over the course of 2.5 h. After addition of ca. 80 mL of

the solution, the starting material had completely dissolved; after addition

of ca. 120 mL, product crystallization set in. After the addition was

completed, H₂O (500 mL) was added dropwise with stirring to the reaction

mixture to complete the crystallization. The resulting suspension was

filtered and solids were washed with H₂O to neutrality. The resulting

colorless solid was left to dry in an open dish in the fume hood for 1 day,

giving 276 g (93%) of colorless crystals. R_f0.46 (EtOAc–hexanes 1:10). M.

p. 84.7–86.0 °C. ¹H NMR (500 MHz, CDCl₃): d = 4.00 (s, 3 H), 7.24 (d, J =

8.9 Hz, 1 H), 7.38 (ddd, J = 8.0, 6.8, 1.1 Hz, 1 H), 7.55 (ddd, J = 8.4, 6.7,

1.2 Hz, 1 H), 7.76 (d, J = 9.2 Hz, 1 H), 7.79 (d, J = 9.1 Hz, 1 H), 8.21 (d, J

= 8.6 Hz, 1 H). ¹³C NMR (101 MHz, CDCl₃): d = 57.22, 108.84, 113.79,

124.46, 126.28, 127.88, 128.18, 129.10, 129.97, 133.28, 153.91. Known

compound, CAS 3401-47-6.

(1R)-Menthyl (aS)-2’-methoxy-(1,1’-binaphthyl)-2-carboxylate ((aS)-

10). Under argon, a solution of 1-bromo-2-methoxynaphthalene (119 g,

500 mmol, 1.25 equiv.) in dry toluene (460 mL) was added to magnesium

(14.6 g, 600 mmol, 1.50 equiv.) in dry THF (90 mL) in portions; initiation of

the reaction was assured after the first addition. The reaction temperature

was kept at 40–50 °C by means of an external water bath to prevent either

over-reaction at elevated or crystallization of the Grignard reagent at lower

temperature. After completion of the addition, the reaction solution was

heated to 55 °C for another 1 h. The resulting Grignard solution was

transferred (while warm) continuously or in several portions through PTFE

(1R)-Menthyl 1-(1R)-menthyloxy-2-naphthoate (7): (1R)-Menthol (5;

351.6 g, 2.25 mol, 3.00 equiv.) was placed in a 1 L three-necked glass

vessel and heated to 100 °C. Sodium (8.63 g, 0.375 mol, 0.50 equiv.) was

added to the melt and the reaction temperature raised to 190 °C with

intense magnetic stirring. Gas evolution was monitored with a silicon

bubbler. After consumption of the liquid metal (3 h), the reaction mixture

was cooled to 60 °C, then diluted with dry DMF (200 mL). Methyl 1-

methoxynaphthyl-2-carboxylate (4; 163 g, 0.750 mol, 1.00 equiv.) was

added at 50 °C with stirring. After 1 h at 50 °C, the temperature was raised

to 60 °C and 160 mL of a DMF–MeOH mixture was slowly distilled out of

the vessel over the course of 5 h by applying a dynamic vacuum (15 mbar).

Another portion of dry DMF (160 mL) was added to the thickened and

foaming reaction solution, while the reaction mixture was kept at 60 °C.

The slow distillation was continued at 15 mbar for 2 h (120 mL of DMF–

MeOH distillate). The mixture, having thickened to the extent that stirring

became impossible, was cooled to r.t. and aqueous 6 M HCl (60 mL) and

H₂O (100 mL) were added. After separation of the layers, the aqueous

layer was extracted with Et₂O (3´). The combined organic layers were

washed with aqueous 2 M NaOH (2´), saturated aqueous NaCl (2´) and

H₂O (2´), then dried (MgSO₄) and filtered. After evaporation in vacuum,

the oily residue was taken up in EtOH (400 mL), which induced

crystallization of colorless crystalline solid overnight at r.t. Filtration and

washing with cooled (0 °C) MeOH gave 272 g (78%) of colorless crystals.

tubing into

a solution of (1R)-menthyl 1-(1R)-menthyloxynaphtyl-2-

carboxylate (7; 186 g, 400 mmol, 1.00 equiv.) in dry toluene (220 mL) kept

at r.t. by a water bath, also ensuring that no magnesium-metal was

transferred. The reaction mixture was stirred at 35 °C for 15 h, then the

reaction was quenched by addition of aqueous 6 M HCl (100 mL),

saturated aqueous NH₄Cl (200 mL) and H₂O (300 mL). The layers were

separated, the aqueous layer was extracted with EtOAc (3´) and the

combined organic layers were washed with aqueous 2 M NaOH (2´) and

saturated aqueous Na₂CO₃(2´), dried (MgSO₄) and filtered. Volatiles were

removed in a rotatory evaporated and the residue was dissolved in MeOH

(900 mL). A colorless solid crystallized from the brown crude reaction

mixture overnight at r.t., which was filtered and washed with cooled (0 °C)

MeOH. Recrystallization from boiling EtOH (1200 mL) with toluene (80 mL)

added to increase solubility gave 145 g (78%) colorless solid (> 99.7% de).

R_f0.39 (EtOAc–hexanes 1:10). ¹H NMR (500 MHz, CDCl₃): d = –0.22 (td,

J = 12.2, 10.9 Hz, 1 H), 0.49 (d, J = 7.0 Hz, 3 H), 0.50–0.60 (m, 1 H), 0.64

(d, J = 6.5 Hz, 3 H), 0.66–0.69 (m, 1 H), 0.71 (d, J = 7.0 Hz, 3 H), 0.82 (m,

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1 H), 1.19 (m, 1 H), 1.34 (m, 1 H), 1.47 (m, 3 H), 3.74 (s, 3 H), 4.48 (td, J

= 10.8, 4.4 Hz, 1 H), 6.96 (d, J = 8.5 Hz, 1 H), 7.16 (ddd, J = 8.3, 6.7, 1.3

Hz, 1 H), 7.28 (m, 2 H), 7.35 (m, 1 H), 7.41 (d, J = 9.0 Hz, 1 H), 7.52 (ddd,

J = 8.1, 6.6, 1.3 Hz, 1 H), 7.84 (d, J = 7.9 Hz, 1 H), 7.93 (d, J = 8.1 Hz, 1

H), 7.98 (m, 2 H), 8.13 (d, J = 8.6 Hz, 1 H). ¹³C NMR (101 MHz, CDCl₃): d

= 15.83, 21.06, 21.99, 22.92, 25.66, 31.12, 34.20, 39.68, 46.69, 56.52,

74.41, 113.30, 122.41, 123.58, 124.97, 126.52, 126.62, 126.66, 127.61,

127.63, 127.82, 127.98, 128.10, 129.14, 129.38, 129.94, 133.07, 134.31,

135.19, 136.59, 154.32, 167.59. Known compound, CAS 116741-64-1.

(1R)-Menthyl

(aS)-2’-ethoxy-[1,1’-binaphthyl]-2-carboxylate.

A

solution of (1R)-menthyl (aS)-2’-hydroxyl-[1,1’-binaphthyl]-2-carboxylate

(12; 250 mg, 552 µmol, 1.00 equiv.) in dry MeCN (3 mL) was stirred with

K₂CO₃(122 mg, 884 µmol, 1.60 equiv.) and ethylbromide (410 µL, 5.52

mmol, 10.0 equiv.) at 30 °C for 3 d. Remaining ethylbromide was quenched

by addition of NEt₃(0.7 mL) and stirring for a few minutes. H₂O (30 mL)

and Et₂O (30 mL) were added and the layers separated. The aqueous

layer was extracted with Et₂O (30 mL). The combined organic layers were

washed with aqueous 2 M HCl (2´15 mL), H₂O (20 mL) and saturated

aqueous NaCl (20 mL). After drying (Na₂SO₄) and filtration, the solvent

was removed in vacuo to give 164 mg (62%) slightly yellow solid. ¹H NMR

(360 MHz, CDCl₃): d = −0.17 (y-q, J = 12.1 Hz, 1 H), 0.50 (d, J = 6.9 Hz,

3 H), 0.56 (td, J = 12.2, 3.0 Hz, 1 H), 0.60–0.75 (m, 1 H), 0.65 (d, J = 6.5

Hz, 3 H), 0.70 (d, J = 7.0 Hz, 3 H), 0.81 (td, J = 12.8, 3.1 Hz, 1 H), 1.02 (t,

J = 7.0 Hz, 3 H), 1.12–1.54 (m, 5 H), 3.95–4.09 (m, 2 H), 4.49 (td, J = 10.8,

4.4 Hz, 1 H), 6.98 (d, J = 8.3 Hz, 1 H), 7.16 (ddd, J = 8.2, 6.8, 1.2 Hz, 1 H),

7.23–7.32 (m, 2 H), 7.32–7.42 (m, 2 H), 7.51 (ddd, J = 8.1, 6.7, 1.3 Hz, 1

H), 7.82 (d, J = 8.1 Hz, 1 H), 7.90–8.01 (m, 3 H), 8.12 (d, J = 8.6 Hz, 1 H).

¹³C NMR (91 MHz, CDCl₃): d = 15.14, 15.89, 21.03, 21.99, 22.98, 25.67,

31.15, 34.23, 39.75, 46.73, 64.89, 74.41, 114.85, 122.91, 123.00, 123.55,

125.09, 126.48, 126.48, 126.50, 127.51, 127.79, 127.81, 128.01, 129.18,

129.23, 129.98, 133.14, 134.46, 135.15, 136.82, 153.76, 167.67. ESI HR-

MS calcd. for [C₃₃H₃₇O₃]⁺([M+H]⁺): 481.2737, found 481.2738.

(aS)-2’-Methoxy-(1,1’-binaphthyl)-2-carboxylic acid (MeO-BINA-Cox;

L1). (1R)-Menthyl (aS)-2’-methoxy-(1,1’-binaphthyl)-2-carboxylate (10;

70.0 g, 150 mmol, 1.00 equiv.) and finely powdered 85% KOH (49.5 g, 750

mmol, 5.00 equiv.) were added to PEG-200 (750 mL) at r.t. The mixture

was heated to 150 °C with stirring and kept at that temperature for 5 h.

Reaction progress was followed by TLC (EtOAc–hexanes 1:10+1% HOAc;

product R_f0.17). After cooling to r.t., the reaction was quenched by

addition of H₂O (200 mL), aqueous 6 M HCl (400 mL) and EtOAc (300 mL).

The phases were separated and the aqueous phase was extracted with

EtOAc (3´300 mL). The combined organic phase was washed with H₂O

(5´300 mL) and dried over MgSO₄. After filtration and evaporation of the

solvent, the sticky residue was suspended in MeOH (150 mL), the

homogenized suspension filtered through a glass filter and sucked dry in

vacuum. The material was recrystallized from boiling EtOH (ca. 90 mL) to

give 44.2 g (86%) of colorless solid (≥99.8% ee, by GP2). R_f0.17 (EtOAc–

hexanes 1:10+1% HOAc). ¹H NMR (500 MHz, CDCl₃): d = 3.62 (s, 3 H),

6.86 (d, J = 8.5 Hz, 1 H), 7.14 (ddd, J = 8.3, 6.8, 1.4 Hz, 1 H), 7.20–7.27

(m, 2 H), 7.29 (ddd, J = 8.1, 6.8, 1.1 Hz, 1 H), 7.32 (d, J = 9.1 Hz, 1 H),

7.51 (ddd, J = 8.1, 6.1, 1.8 Hz, 1 H), 7.87 (d, J = 8.1 Hz, 1 H), 7.91 (d, J =

8.2 Hz, 1 H), 7.96 (m, 2 H), 8.12 (d, J = 8.7 Hz, 1 H), 10.93 (br. s, 1 OH).

¹³C NMR (101 MHz, CDCl₃): d = 56.72, 113.72, 121.55, 123.61, 124.92,

126,62, 126.60, 126.85, 127.81, 127.87, 128.03, 128.08 (2C), 128.13,

129.06, 129.73, 133.05, 133.88, 135.63, 138.13, 154.28, 171.87. Known

compound.

(aS)-2’-Ethoxy-[1,1’-binaphthyl]-2-carboxylic acid (L23). (1R)-Menthyl

(aS)-2’-ethoxy-[1,1’-binaphthyl]-2-carboxylate (160 mg, 333 µmol, 1.00

equiv.) and 85% KOH (934 mg, 14.1 mmol, 42.5 equiv.) in EtOH (5 mL)

were combined for 48 h according to GP-1A. The crude reaction product

was purified by CC (SiO₂, EtOAc–hexanes 1:4) to give 93 mg (82%)

1

colorless solid; (≥95% ee, by GP2). H NMR (360 MHz, CDCl₃): d = 1.02

(t, J = 7.0 Hz, 3 H), 4.01 (q, J = 7.0 Hz, 2 H), 6.92 (d, J = 8.5 Hz, 1 H), 7.19

(ddd, J = 8.2, 6.8, 1.3 Hz, 1 H), 7.22–7.34 (m, 3 H), 7.39 (d, J = 9.0 Hz, 1

H), 7.55 (ddd, J = 8.1, 6.4, 1.6 Hz, 1 H), 7.88 (d, J = 8.2 Hz, 1 H), 7.95 (d,

J = 8.2 Hz, 1 H), 7.99 (t, J = 8.2 Hz, 2 H), 8.15 (d, J = 8.7 Hz, 1 H), 8.62

(br. s, 1 OH). ¹³C NMR (126 MHz, CDCl₃): d = 14.92, 65.06, 115.01, 121.92,

123.72, 125.02, 126.53, 126.66, 126.78, 127.90, 128.00, 128.03, 128.07

(2 C), 128.10, 129.06, 129.77, 133.01, 134.00, 135.50, 137.79, 153.47,

170.64. ESI HR-MS calcd. for [C₂₃H₁₇O₃]^–: 341.1183, found 341.1182.

Synthesis of selected chiral biaryl carboxylic acids (Ln)

(1R)-Menthyl (aS)-2’-hydroxy-[1,1’-binaphthyl]-2-carboxylate (12).

Under argon, a solution of (1R)-menthyl (aS)-2’-methoxy-(1,1’-binaphthyl)-

2-carboxylate (10; 2.53 g, 5.32 mmol, 1.00 equiv.) in dry CH₂Cl₂(60 mL)

was cooled to –78 °C. BBr₃(1 M in CH₂Cl₂; 10.8 mL, 10.8 mmol, 2.00

equiv.) was added dropwise over 15 min and the reaction mixture was

stirred at –78 °C for 5 h. Saturated aqueous LiOH (15 mL) was added and

the mixture warmed to r.t. After addition of H₂O (20 mL), the layers were

separated. The aqueous layer was extracted with CH₂Cl₂(50 mL) and the

combined organic layers were washed with saturated aqueous NaCl (100

mL). After drying (Na₂SO₄) and filtration, the solvent was removed in vacuo.

The crude product was purified by CC (SiO₂, EtOAc–hexanes 1:40→1:4)

to give 2.01 g (82%) colorless solid. ¹H NMR (360 MHz, CDCl₃): d = −0.05

(q, J = 12.0 Hz, 1 H), 0.41 (d, J = 6.9 Hz, 3 H), 0.66 (d, J = 7.0 Hz, 3 H),

0.67 (d, J = 6.5 Hz, 3 H), 0.76–0.90 (m, 2 H), 1.16–1.28 (m, 1 H), 1.34–

1.55 (m, 5 H), 4.53 (td, J = 10.6, 4.5 Hz, 1 H), 4.85 (br. s, 1 OH), 6.88 (dd,

J = 8.4, 1.1 Hz, 1 H), 7.17 (ddd, J = 8.3, 6.8, 1.3 Hz, 1 H), 7.23–7.42 (m, 4

H), 7.57 (ddd, J = 8.2, 6.3, 1.8 Hz, 1 H), 7.78–7.86 (m, 1 H), 7.90 (d, J =

8.9 Hz, 1 H), 7.97 (d, J = 8.2 Hz, 1 H), 8.07 (s, 2 H). ¹³C NMR (91 MHz,

CDCl₃): d = 15.90, 20.82, 21.98, 23.10, 25.91, 31.18, 34.15, 39.70, 46.63,

75.20, 117.86, 118.40, 123.50, 124.61, 126.08, 126.75, 127.11, 127.69,

127.97, 128.19, 128.37, 129.19, 129.37, 129.89, 132.32, 132.51, 132.94,

134.18, 135.27, 151.14, 167.75. ESI HR-MS calcd. for [C₃₁H₃₃O₃]⁺:

453.2424, found 453.2424. ESI HR-MS calcd. for [C₃₁H₃₁O₃]^–: 451.2279,

found 451.2285.

The allyloxy (L24) and benzyloxy (L25) derivatives were analogously

prepared starting from 12; see the supporting information.

(1R)-Menthyl (aS)-2’-tosyloxy-[1,1’-binaphthyl]-2-carboxylate (13).

Under argon, (1R)-menthyl (aS)-2’-hydroxy[1,1’-binaphthyl]-2-carboxylate

(12; 600 mg, 1.36 mmol, 1.00 equiv.), tosyl chloride (278 mg, 1.46 mmol,

1.10 equiv.) and DMAP (32.5 mg, 266 µmol, 0.20 equiv.) in dry CH₂Cl₂(10

mL) was cooled to 0 °C. NEt₃(220 µL, 1.60 mmol, 1.20 equiv.) was added

and the reaction mixture stirred at 0 °C for 2 h, then at r.t. for 18 h.

Saturated aqueous NH₄Cl (10 mL) was added and the layers were

separated. The aqueous layer was extracted with CH₂Cl₂(20 mL) and the

combined organic layers were washed with aqueous 2 M NaOH (20 mL)

and saturated aqueous NaCl (20 mL). After drying (Na₂SO₄) and filtration,

1

the solvent was removed in vacuo to give 708 mg (88%) yellow solid. H

NMR (360 MHz, CDCl₃): d = 0.09 (q, J = 12.1 Hz, 1 H), 0.55 (d, J = 6.9 Hz,

3 H), 0.60–0.94 (m, 3 H), 0.70 (d, J = 6.5 Hz, 3 H), 0.77 (d, J = 7.0 Hz, 3

H), 1.12–1.30 (m, 1 H), 1.45–1.63 (m, 4 H), 2.27 (s, 3 H), 4.54 (td, J = 10.6,

4.2 Hz, 1 H), 6.79 (d, J = 8.1 Hz, 2 H), 7.01 (y-d, J = 8.3 Hz, 3 H), 7.08 (d,

J = 8.4 Hz, 1 H), 7.13–7.28 (m, 2 H), 7.42 (ddd, J = 8.1, 6.7, 1.3 Hz, 1 H),

7.49 (ddd, J = 8.1, 6.7, 1.3 Hz, 1 H), 7.76 (d, J = 9.0 Hz, 1 H), 7.82–7.95

(m, 3 H), 8.00 (d, J = 8.9 Hz, 1 H), 8.04 (d, J = 8.9 Hz, 1 H). ¹³C NMR (91

MHz, CDCl₃): d = 16.02, 21.03, 21.70, 22.02, 23.03, 25.77, 31.22, 34.20,

40.03, 46.75, 74.75, 121.19, 126.02, 126.35, 126.44, 126.78, 126.98,

127.26, 127.56, 127.71, 128.05, 128.12, 128.39, 128.47, 129.19, 129.54,

129.94, 131.75, 132.77, 133.53, 133.93, 133.96, 134.83, 144.21, 145.35,

(aS)-2’-Ethoxy-[1,1’-binaphthyl]-2-carboxylic acid (L23).

10.1002/ejoc.201901895

European Journal of Organic Chemistry

FULL PAPER

166.59. ESI HR-MS calcd. for [C₃₈H₃₉O₅S]⁺([M+H]⁺): 607.2513, found

607.2519. ESI HR-MS calcd. for [C₃₈H₃₈O₅S+NH₄]⁺: 624.2778, found

624.2782.

H), 7.45–7.59 (m, 3 H), 7.84 (d, J = 8.1 Hz, 1 H), 7.88–8.04 (m, 3 H). ¹³C

NMR (101 MHz, CDCl₃): d = 56.84, 113.75, 120.33, 123.86, 125.56,

126.86, 126.90, 126.96, 127.48, 127.51, 127.86, 128.38, 128.47, 128.82,

128.89, 129.01, 130.31, 131.73, 132.17, 133.50, 133.85, 134.23, 137.16,

140.77, 154.95, 172.85. ESI HR-MS calcd. for [C₂₈H₁₉O₃]^–: 403.1340,

found 403.1343.

(aS)-2’-Phenyl-[1,1’-binaphthyl]-2-carboxylic acid (L26)

(1R)-Menthyl (aS)-2’-phenyl-[1,1’-binaphthyl]-2-carboxylate. Under

argon, a solution of phenylboronic acid (604 mg, 4.95 mmol, 10.0 equiv.)

in dry THF (8 mL) was added to K₃PO₄(1.05 g, 4.95 mmol, 10.0 equiv.)

and degassed with an argon bubbling (15 min). Ni(COD)₂(20.0 mg, 74.3

µmol, 0.15 equiv.) and PCy₃(83.0 mg, 297 µmol, 0.60 equiv.) were added,

followed by (1R)-menthyl (aS)-2’-tosyloxy-[1,1’-binaphthyl]-2-carboxylate

(13; 300 mg, 495 µmol, 1.00 equiv.). The reaction mixture was heated to

45 °C for 48 h. After filtration, EtOAc (25 mL) and H₂O (25 mL) were added

to the filtrate and the layers were separated. The aqueous layer was

extracted with EtOAc (25 mL) and the combined organic layers were

washed with saturated aqueous NaCl (2´25 mL). After drying (Na₂SO₄)

and filtration, the solvent was removed in vacuo. The crude product was

purified by CC (SiO₂, EtOAc–hexanes 1:20) to give 172 mg (68%)

colorless solid. ¹H NMR (500 MHz, CDCl₃): d = −0.05 (q, J = 12.1 Hz, 1 H),

0.53 (d, J = 6.9 Hz, 3 H), 0.67 (d, J = 7.0 Hz, 3 H), 0.69 (d, J = 6.5 Hz, 3

H), 0.76–0.88 (m, 2 H), 1.14–1.37 (m, 2 H), 1.41–1.54 (m, 4 H), 4.54 (td, J

= 10.6, 4.4 Hz, 1 H), 6.94–6.98 (m, 3 H), 7.11–7.30 (m, 6 H), 7.37–7.45

(m, 2 H), 7.61 (d, J = 8.5 Hz, 1 H), 7.78 (d, J = 8.2 Hz, 1 H), 7.85 (d, J =

8.6 Hz, 1 H), 7.92 (d, J = 8.2 Hz, 1 H), 8.01 (d, J = 8.8 Hz, 2 H). ¹³C NMR

(91 MHz, CDCl₃): d = 15.86, 21.01, 22.01, 22.91, 25.76, 31.20, 34.16,

39.86, 46.66, 74.78, 125.76, 126.04, 126.47, 126.51, 126.53, 126.55,

127.45, 127.49, 127.93, 127.97, 128.00, 128.02, 128.25, 129.12, 130.84,

132.80, 132.85, 133.44, 134.71, 134.86, 138.70, 141.92, 167.51. EI HR-

MS calcd. for [C₃₆H₃₆O₂]⁺: 512.2710, found 512.2703.

(aS)-6’-Adamantyl-2’-methoxy-(1,1’-binaphthyl)-2-carboxylic

acid

(L19). Under argon, a suspension of (1R)-menthyl (aS)-2’-methoxy-(1,1’-

binaphthyl)-2-carboxylate (10; 4.67 g, 10.0 mmol, 1.00 equiv.), 1-bromo-

adamantane (2.15 g, 10.0 mmol, 1.00 equiv.) and indium(III) chloride (111

mg, 0.50 mmol, 0.05 equiv.)^[58]in dry CH₂Cl₂(20 mL) was stirred at 60 °C

for 14 h. The crude reaction product obtained by evaporation of the solvent

was purified by CC (SiO₂, EtOAc–hexanes 1:10→EtOAc–hexanes+HOAc

1:10+1%). The resulting yellow solid was dissolved in Et₂O and the organic

layer was extracted with aqueous 2 M NaOH (3´). The combined aqueous

layers were washed with Et₂O (2´), acidified with aqueous 6 M HCl and

extracted with Et₂O. Drying (MgSO₄), filtration and removal of the solvent

in vacuo gave 2.460 g (53%) slightly yellow solid (≥99.7% ee by GP2). R_f

0.22 (EtOAc–hexanes 1:10+1% HOAc). ¹H NMR (500 MHz, CDCl₃): d =

1.70–1.85 (m, 6 H), 1.96 (d, J = 2.9 Hz, 6 H), 2.10 (m, 3 H), 3.70 (s, 3 H),

6.84 (d, J = 9.0 Hz, 1 H), 7.18–7.28 (m, 3 H), 7.37 (d, J = 9.0 Hz, 1 H), 7.53

(ddd, J = 8.1, 6.3, 1.6 Hz, 1 H), 7.74 (d, J = 2.0 Hz, 1 H), 7.88–8.05 (m, 3

H), 8.16 (d, J = 8.7 Hz, 1 H), 8.58 (br. s, 1 OH). ¹³C NMR (101 MHz, CDCl₃):

d = 29.10, 36.21, 37.01, 43.20, 56.82, 113.56, 121.07, 122.91, 124.59,

125.08, 126.59, 126.81, 127.93, 128.00, 128.02, 128.04, 128.09, 129.17,

129.86, 132.16, 133.07, 135.58, 138.06, 146.42, 153.94, 171.20. ¹³C APT

NMR (101 MHz, CDCl₃): d = 29.09 (CH), 36.19 (C), 37.00 (CH₂), 43.20

(CH₂), 56.78 (CH₃), 113.57 (CH), 121.18 (C), 122.88 (CH), 124.59 (CH),

124.98 (CH), 126.58 (CH), 126.77 (CH), 127.89 (C), 127.97 (CH), 128.00

(CH), 128.01 (CH), 128.07 (CH), 129.15 (C), 129.74 (CH), 132.14 (C),

133.08 (C), 135.58 (C), 138.25 (C), 146.32 (C), 153.93 (C), 171.97 (CO₂H).

EI HR-MS calcd. for [C₃₂H₃₀O₃]⁺: 462.2189, found 462.2187.

(aS)-2’-Phenyl-[1,1’-binaphthyl]-2-carboxylic acid (L26). The above

ester (167 mg, 326 µmol, 1 equiv.) was saponified with 85% KOH (2.19 g,

33.2 mmol, 102 equiv.) in EtOH (6 mL) over 24 h, followed by addition of

LiOH·H₂O (625 mg, 26.1 mmol, 80 equiv.) and continued saponification for

24 h according to GP-1B. The crude product was purified by CC (SiO₂,

EtOAc–hexanes 1:4) to give 103 mg (84%) yellowish solid (≥ 95% ee by

Acknowledgements

1

GP2). H NMR (500 MHz, CDCl₃): d = 6.87–6.95 (m, 4 H), 6.96–7.01 (m,

The reported research received funding by the Deutsche

Forschungsgemeinschaft (HI 854/5-1).

1 H), 7.07 (d, J = 8.5 Hz, 1 H), 7.21–7.31 (m, 2 H), 7.34 (d, J = 8.5 Hz, 1

H), 7.45 (ddd, J = 8.1, 6.6, 1.2 Hz, 1 H), 7.50 (ddd, J = 8.1, 6.6, 1.2 Hz, 1

H), 7.55 (d, J = 8.4 Hz, 1 H), 7.83 (d, J = 8.6 Hz, 1 H), 7.85 (d, J = 8.0 Hz,

1 H), 7.93 (d, J = 8.7 Hz, 1 H), 7.97 (d, J = 8.2 Hz, 1 H), 8.02 (d, J = 8.5

Hz, 1 H), 10.03 (br. s, 1 OH). ¹³C NMR (126 MHz, CDCl₃): d = 125.77,

126.28, 126.41, 126.53, 126.58, 126.96, 127.53, 127.92, 128.04, 128.08,

128.11, 128.13, 128.17, 128.29, 128.45, 128.91, 132.62, 132.95, 133.53,

134.08, 135.11, 138.93, 140.69, 141.63, 171.10. ESI HR-MS calcd. for

[C₂₇H₁₇O₂]^–: 373.1234, found 373.1233.

Keywords: asymmetric catalysis • hydroalkoxylation • titanium •

carboxylate ligand • microwave chemistry

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10.1002/ejoc.201901895

European Journal of Organic Chemistry

FULL PAPER

Sebastian L. Helmbrecht, Johannes

Schlüter, Max Blazejak, and Lukas

Hintermann*

Page No. – Page No.

Axially Chiral 1,1’-Binaphthyl-2-

Carboxylic Acid (BINA-Cox) as

Ligands for Titanium-catalyzed

Asymmetric Hydroalkoxylation

By mixing titanium isopropoxide, water and 1,1’-biaryl-2-carboxylic acids, a catalyst for the asymmetric addition of phenolic hydroxyl

to non-activated alkene at HOT temperature (240 °C) is formed! This work systematically develops scalable syntheses of variably

decorated, enantiopure 1,1’-biaryl-2’-carboxylic acids, which are then tested as steering ligands in intramolecular asymmetric catalytic

hydroalkoxylation reactions.

Article Doi

Axially Chiral 1,1'-Binaphthyl-2-Carboxylic Acid (BINA-Cox) as Ligands for Titanium-Catalyzed Asymmetric Hydroalkoxylation

DOI: 10.1002/ejoc.201901895

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