Facile synthesis of a family of H8BINOL-amine compounds and catalytic asymmetric arylzinc addition to aldehydes

pubs.acs.org/joc

Facile Synthesis of a Family of H₈BINOL-Amine Compounds and

Catalytic Asymmetric Arylzinc Addition to Aldehydes

Albert M. DeBerardinis, Mark Turlington, Jason Ko, Laura Sole, and Lin Pu*

Department of Chemistry, University of Virginia, Charlottesville, Virginia 22904

lp6n@virginia.edu

Received January 12, 2010

A family of optically active H₈BINOL-AM compounds containing 3,3⁰-bis-tertiary amine substituents are

synthesized by using a one-step reaction of H₈BINOL with amino methanols that were in situ generated

from various cyclic or acyclic secondary amines and paraformaldehyde. The H₈BINOL-AM compounds

are used to catalyze the reaction of functional arylzincs, in situ prepared from the reaction of aryliodides

with ZnEt₂, with aldehydes to produce chiral diaryl carbinols and a few arylalkyl carbinols. Through this

study, highly enantioselective catalysts were identified. It was found that the H₈BINOL-AM compounds

with sterically less congested cyclic or acyclic amino methyl substituents were more enantioselective than

those with more bulky substituents. The pyrrolidinyl derivative (S)-12 in most cases showed greater

enantioselectivity than other H₈BINOL-AM compounds, especially for the challenging ortho-substituted

aromatic aldehydes. A H₈BINOL-AM with 3,3⁰-bis-sec-amine substituents, prepared by a multistep

method, was also used to catalyze the arylzinc addition to aldehydes, but it showed enantioselectivity lower

than that of the compounds with tertiary amine groups. It was found for the first time that an aryl bromide,

2-bromothiophene, could be used to prepare an arylzinc reagent by reaction with ZnEt₂. The addition of

this heteroarylzinc reagent to an aldehyde in the presence of (S)-12 proceeded with good enantioselectivity.

Introduction

Among the 3,3⁰-substituted BINOL derivatives, compounds

containing amino methyl substituents, that is BINOL-AMs,

have received special attention in recent years.²It is found

that the Lewis basic amine atoms in the BINOL-AMs can

cooperate with the Lewis acidic metals introduced at the

central BINOL unit to enhance the catalytic activity and

enantioselectivity when used in asymmetric catalysis.

1,1⁰-Bi-2-naphthol (BINOL) and its 3,3⁰-substituted deri-

vatives have been extensively used in asymmetric catalysis.¹

The two hydroxyl groups of BINOL allow easy incorpora-

tion of Lewis acidic metal centers such as Ti(IV), Zn(II), and

Al(III) to prepare chiral Lewis acid complexes for asym-

metric catalysis. Substituents at the 3,3⁰-positions of BINOL

can modify both the steric and electronic properties of the

Lewis acid complexes and in many cases lead to more

efficient chiral catalysts for diverse organic reactions.¹

(1) For reviews on using BINOL-based compounds in asymmetric cata-

lysis, see: (a) Chen, Y.; Yekta, S.; Yudin, A. Chem. Rev. 2003, 103, 3155–

3211. (b) Kocovsky, P.; Vyskocil, S.; Smrcina, M. Chem. Rev. 2003, 103,

3213–3245. (c) Brunel, J. M. Chem. Rev. 2005, 105, 857–897. (d) Shibasaki,

M.; Matsunaga, S. Chem. Soc. Rev. 2006, 35, 269–279. (e) Pu, L. Chem. Rev.

1998, 98, 2405–2494.

A number of synthetic methods have been developed for

the preparation of the optically active BINOL-AMs.²

Although the most direct method should be the one-step

Mannich reaction of BINOL with morpholinomethanol to

ꢀ

(2) (a) For a review on BINOL-AMs, see: Najera, C.; Sansano, J. M.;

ꢀ

Saa, J. M. Eur. J. Org. Chem. 2009, 2385–2400. For examples of 2-

aminomethyl-substituted binaphthyl compounds, see: (b) Bringmann, G.;

Matthias Breuning, M. Tetrahedron: Asymmetry 1998, 9, 667–679. (c) Ko,

D. -H.; Kim, K. H.; Ha, D.-C. Org. Lett. 2002, 4, 3759–3762.

2836 J. Org. Chem. 2010, 75, 2836–2850

Published on Web 04/08/2010

DOI: 10.1021/jo1000516

r

2010 American Chemical Society

DeBerardinis et al.

JOCArticle

SCHEME 1. Synthesis of the H₈BINOL-AM Compounds

generate the BINOL-AM compound (S)-1,³this reaction

required an elevated temperature of 110 °C, which led to

partial racemization of the BINOL unit. Recrystallization

was needed in order to obtain the enantiomerically pure

(S)-1. However, when the partially hydrogenated BINOL,

H₈BINOL,⁴was used, the Mannich reaction with morpholino-

methanol could be conducted at a much lower temperature

of 60 °C to produce the optically active H₈BINOL-AM

compound (S)-2 with excellent enantiomeric purity and high

yield.⁵We have explored the use of (S)-2 to catalyze the

asymmetric reactions of arylzinc and alkynylzinc with alde-

hydes to generate the synthetically useful chiral alcohols, and

high enantioselectivity has been achieved.^5,6We have further

expanded the synthesis of (S)-2 by introducing structurally

diverse 3,3⁰-bis-aminomethyl groups and studied the use of

this family of compounds to catalyze the asymmetric arylzinc

addition to aldehydes. Herein, the synthesis of the new

H₈BINOL-AM compounds and their catalytic properties

are reported.

FIGURE 1. Structures of the newly prepared structurally diverse

H₈BINOL-AM compounds.

amines. It was found that in general the less sterically

hindered amines react more readily in the preparation of

both the aminomethanol intermediate and the H₈BINOL-

AM products. For example, lower temperature and less time

were required for the synthesis of compounds (S)-4 and (S)-

12, but higher temperature (up to refluxing in dioxane) and

longer reaction time were needed to prepare (S)-6 and (S)-9.

While imidazole reacted with paraformaldehyde under the

normal conditions, the resulting imidazole methanol failed

to react with H₈BINOL in dioxane at elevated temperature.

In order to prepare the H₈BINOL-imidazole compound,

(S)-H₈BINOL was heated with imidazole methanol in a

sealed tube at 135 °C, which produced the desired product

(S)-17 without racemization. This demonstrates that H₈BI-

NOL has a much more stable chiral configuration than

BINOL, which underwent partial racemization in the pre-

paration of (S)-1 at 110 °C. Compounds (S)-10, (S)-11, (S)-

12, (S)-13, and (S)-15 containing cyclic amines similar to the

previously reported (S)-2 were purified by recrystallization.

Compounds (S)-3, (S)-4, (S)-5, (S)-6, (S)-7, (S)-8 ,and (S)-9

containing acyclic amines proved to be more difficult to

purify. After workup of their synthesis, the resulting oily

residues could not form crystals. Column chromatography

on alumina or silica gel was necessary to remove a sufficient

amount of the excess amino alcohols before recrystallization.

Compound (S)-14 was made from the corresponding enan-

tiomerically pure amine, but compounds (S)-15 and (S)-16

were made from the corresponding racemic amines and

contained a mixture of diastereomers. The preparation of

(S)-2 was also scaled up with the use of 5 g of (S)-H₈BINOL,

which gave (S)-2 in 90% yield, >99% ee, and 99% purity.^5d

2. Application of H₈BINOL-AM Compounds in the Asym-

metric Arylzinc Addition to Aldehydes. Asymmetric arylzinc

additions to aldehydes can generate chiral diaryl and arylalkyl

Results and Discussion

1. Synthesis of a Family of H₈BINOL-AM Compounds

from the One-Step Mannich Reaction of H₈BINOL. Scheme 1

shows the general scheme used to prepare the H₈BINOL-

AM compounds. In the first step, a secondary aliphatic

amine was mixed with paraformaldehyde in dioxane at

0 °C and then heated at 60-90 °C depending on the amine

used. This led to the formation of an aminomethanol inter-

mediate that was then heated with the optically pure (S)-

H₈BINOL at varying temperatures depending on the amine

used. This one-pot Mannich reaction quickly produced a

family of H₈BINOL-AM compounds as listed in Figure 1.

Among these H₈BINOL-AMs, compounds (S)-3-(S)-6 are

made of acyclic aliphatic amines, (S)-7-(S)-9 are made of

benzylic amines, and (S)-10-(S)-17 are made of cyclic

(3) Qin, Y.-C.; Liu, L.; Pu, L. Org. Lett. 2005, 7, 2381–2383.

(4) For a review on H₈BINOL derivatives, see: Au-Yeung, T. T.-L.;

Chan, S.-S.; Chan, A. S. C. Adv. Synth. Catal. 2003, 345, 537–555.

(5) (a) Liu, L.; Pu, L. Tetrahedron 2004, 60, 7427–7430. (b) Qin, Y.-C.; Pu,

L. Angew. Chem., Int. Ed. 2006, 118, 279–283. (c) Qin, Y.-C.; Liu, L.; Sabat,

M.; Pu, L. Tetrahedron 2006, 40, 9335–9348. (d) Turlington, M.; Pu, L. Org.

Synth. 2010, 87, 59–67.

(6) (a) DeBerardinis, A. M.; Turlington, M.; Pu, L. Org. Lett. 2008, 10,

2709–2713. (b) DeBerardinis, A. M.; Turlington, M.; Pu, L. Org. Synth. 2010,

87, 68–76.

J. Org. Chem. Vol. 75, No. 9, 2010 2837

DeBerardinis et al.

JOCArticle

study on the asymmetric reaction of other functional aryl-

zincs with aldehydes is still very limited.⁹Since 2005, Walsh

has studied the in situ conversion of aryl bromide to arylzincs

by treatment with ⁿBuLi and ZnCl₂or EtZnCl and the

subsequent asymmetric arylzinc addition to aldehydes.^9a,b

High enantioselectivity was achieved for a number of sub-

strates. The catalytic asymmetric additions of other nucleo-

philic aryl reagents to carbonyl compounds have also been

reported.¹⁰

Earlier, we reported that the H₈BINOL-AM compound

(S)-2 can not only activate the arylzincs, in situ prepared with

a modification of Knochel’s method from aryliodides and

ZnEt₂,¹¹to react with aromatic and aliphatic aldehydes but

also provide high enantioselectivity for a number of sub-

strates.⁶In order to further expand the scope of this asym-

metric reaction we have examined the use of the newly

prepared and structurally diverse H₈BINOL-AM compounds

and compared their catalytic properties with those of (S)-2.

a. Asymmetric Reaction of Arylzinc Reagent Derived from

Methyl p-Iodobenzoate Catalyzed by the Chiral H₈BINOL-

AM Compounds. As shown in Scheme 2, an arylzinc species

was generated in situ from the reaction of methyl p-iodo-

benzoate with ZnEt₂in the presence of Li(acac) and NMP.¹¹

This reaction needed to be conducted at 0 °C since dimeriza-

tion of the aryliodide was observed at room temperature.

After the formation of the arylzinc, the H₈BINOL-AM

compounds (20 mol %) were added to catalyze the arylzinc

addition to aldehydes in CH₂Cl₂at 0 °C. We have chosen to

screen the H₈BINOL-AM compounds for the addition to

o-methoxybenzaldehyde to generate the chiral diaryl carbinol

18, since the ortho-substituted benzaldehydes were found to be

challenging substrates for the asymmetric arylzinc addition.^5c

The results for the formation of 18 in the presence of the

H₈BINOL-AM compounds are summarized in Table 1.

As shown in entry 1 of Table 1, (S)-2 catalyzed the arylzinc

addition to o-methoxybenzaldehyde with 79% ee. This en-

antioselectivity is significantly lower than those we pre-

viously reported for the reactions of p- or m-substituted

aromatic aldehydes and aliphatic aldehydes catalyzed by

(S)-2.⁶Compound (S)-10 in which the oxygen atom in the

morpholinyl groups of (S)-2 was replaced with a sulfur atom

was then tested and showed the same enantioselectivity as

(S)-2 (entry 2). That is, the oxygen and sulfur atoms in the

cyclic amine substituents of (S)-2 and (S)-10 did not interfere

with the catalysis and probably were not involved in the

coordination with the Lewis acidic catalyst center. Using

compound (S)-6, in which the sterically much more bulky

dicyclohexylamine was used in place of the morpholinyl

groups of (S)-2, gave only the racemic product (entry 3).

The cyclohexyl rings in (S)-6 might have generated an overly

crowded environment around the central chiral H₈BINOL

unit and prevent the reaction from taking place there. Thus,

no chiral induction could be provided by the H₈BINOL unit

of (S)-6. When the less sterically crowded benzylmethyla-

mine-based compound (S)-7 was used, good enantioselec-

tivity was observed (entry 4). As the steric congestion

increased from (S)-7 to (S)-8 and (S)-9, the enantioselectivity

decreased accordingly (entries 5 and 6). When the six-mem-

bered ring of the amine group of (S)-2 was replaced with the

FIGURE 2. Drug molecules made from diaryl carbinols.

carbinols that are ubiquitous in organic molecules including

those of biological significance. For example, the diaryl carbinol

derivatives shown in Figure 2 are found to be useful drug

molecules with antihistamine, anticholergenic, analgesic, and

other properties.⁷Although significant progress has been

made on the asymmetric Ph₂Zn addition to aldehydes,⁸the

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2838 J. Org. Chem. Vol. 75, No. 9, 2010

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SCHEME 2. Asymmetric Reaction of Methyl p-Iodobenzoate with o-Methoxybenzaldehyde Catalyzed by H₈BINOL-AM Compounds

JOCArticle

TABLE 1. Reaction of Methyl p-Iodobenzoate and o-Methoxybenzalde-

TABLE 2. Reaction of Methyl p-Iodobenzoate and o-Chlorobenzaldehyde

hyde in the Presence of ZnEt₂and H₈BINOL-AM Compounds to Form 18^a

in the Presence of ZnEt₂and H₈BINOL-AM Compounds to Form 19^a

isolated ee

yield (%) (%)^b

isolated

ee

entry

chiral ligand

entry

ligand

yield (%) (%)^b

1

2

3

4

5

6

7

8

9

(S)-2: NR₁R₂= N(CH₂CH₂)₂O

(S)-10: NR₁R₂= N(CH₂CH₂)₂S

83

98

80

95

75

65

90

98

60

80

79

0

81

74

48

93

92

46

83

1

2

3

4

5

6

7

8

(S)-2: NR₁R₂= N(CH₂CH₂)₂O

(S)-10: NR₁R₂= N(CH₂CH₂)₂S

(S)-11: NR₁R₂= N(CH₂)₅

(S)-3: NR₁R₂= NEt₂

(S)-4: NR₁R₂= NBu₂

(S)-5: NR₁R₂= NⁱPr₂

(S)-7: NR₁R₂= NMeBn

(S)-12: NR₁R₂= N(CH₂)₄

(S)-15: NR₁R₂= N(CH₂CH₂CH₂CHMe)

(S)-17: NR₁R₂= imidazole

92

98

96

90

98

95

98

87

96

55

57

59

64

67

33

55

79

61

48

35

(S)-6: NR₁R₂= N(^cC₆H_{11 2}

(S)-7: NR₁R₂= NMeBn

(S)-8: NR₁R₂= NEtBn

)

(S)-9: NR₁R₂= NⁱPrBn

(S)-12: NR₁R₂= N(CH₂)₄

(S)-13: NR₁R₂= N(CH₂CH₂SCH₂)

(S)-14: NR₁R₂= N(CH₂CH₂CH₂CHCH₂OMe)

9^c

10

11

10 (S)-16: NR₁R₂= octahydroindenyl

^aConditions: methyl p-iodobenzoate (2.2 equiv), Li(acac) (26 mol %),

Et₂Zn (1.21 equiv), NMP (1.5 mL), chiral ligand (20 mol %), CH₂Cl₂(20

mL), aldehyde (1.0 equiv). Step 1: 18 h, 0 °C. Step 2: 1 h, 0 °C; 15 min, rt.

Step 3: 16 h, 0 °C. ^bDetermined by using HPLC-chiral column.

^aThe following conditions were used unless otherwise noted: methyl

p-iodobenzoate (2.2 equiv), Li(acac) (26 mol %), Et₂Zn (1.21 equiv),

NMP (1.5 mL), chiral ligand (20 mol %), CH₂Cl₂(20 mL), aldehyde (1.0

equiv), 0 °C. Step 1: 18 h. Step 2: 1 h. Step 3: 12 h. ^bDetermined by using

HPLC-chiral column. ^cTi(OⁱPr)₄(1.0 equiv) was added after step 2 and

was stirred from 1 h prior to the addition of the aldehyde.

five-membered ring of the pyrrolidinyl-based compound (S)-

12, excellent enantioselectivity was achieved (entry 7). Thus,

the reduced ring size of the amine substituent greatly en-

hanced the enantioselectivity. Incorporation of a sulfur atom

into the five-membered ring of (S)-12 gave compound (S)-13,

which maintained the high enantioselectivity (entry 8). That

is, the additional heteroatom in the aminocycle had no

influence on the enantioselectivity, similar to that observed

for (S)-2 and (S)-10. Additional substituents on the five-

membered rings of (S)-12 decreased the enantioselectivity as

shown by the use of compounds (S)-14 and (S)-16 (entries

9 and 10). Although (S)-16 contained a mixture of diastereo-

mers, its enantioselectivity was still greater than that of

(S)-14, which contained only one stereoisomer. The extra

MeO groups of (S)-14 might lead to chelate coordination to

the Lewis acidic metal centers outside the chiral cavity of

the H₈BINOL unit, causing the dramatic reduction of the

enantioselectivity versus the use of (S)-12.

The use of the H₈BINOL-AM compounds to catalyze the

addition of the methyl p-iodobenzoate-derived arylzinc reagent

to o-cholorobenzaldehyde to generate the chiral diarylcarbinol

19 was also investigated, and the results are summarized in

Table 2. Compounds (S)-2, (S)-10, and (S)-11 containing six-

membered cyclic amine groups showed similarly low enantios-

electivity (entries 1-3). The oxygen and sulfur atoms in the six-

membered rings had little effect on the reaction. Changing the

cyclic amines of (S)-2, (S)-10, and (S)-11 to the acyclic dialkyl

amines (S)-3 and (S)-4 increased the enantioselectivity (entries 4

and 5). However, increasing the size of the alkyl groups from the

primary alkyls of (S)-3 and (S)-4 to the secondary alkyl groups

of (S)-5 diminished the enantioselectivity (entry 6). This is

similar to what was observed in the reaction of o-methoxyben-

zaldehyde shown in Table 1. The use of the benzylmethylamine-

based compound (S)-7 could not improve the enantioselectivity

(entry 7). When the pyrrolidinyl-based compound (S)-12 was

used, it again exhibited significantly improved enantioselectivity

over the other compounds (entry 8). Addition of another Lewis

acid, Ti(OⁱPr)₄, reduced the enantioselectivity (entry 9). Using

the substituted pyrrolidinyl compound (S)-15 also reduced the

enantioselectivity (entry 10).

When the imidazole-based compound (S)-17 was used, very

low enantioselectivity was observed (entry 11). The ¹H NMR

spectrum of (S)-17 shows the OH proton signal at δ 3.48, which

is much more upfield in comparison with those (δ 10-12) of all

the other H₈BINOL-AMs we have prepared. This dramatic

difference in the proton signals of the OH groups can be

attributed to the lack of intramolecular hydrogen bonding

between the OH groups of (S)-17 and its imidazole nitrogens.

In each of the imidazole rings, the nitrogen connected to the

3-methylene group is not basic, and the more basic nitrogen

atom in the ring is pointing away from the chiral H₈BINOL

unit of (S)-17, which makes it sterically incapable of forming an

intramolecular hydrogen bond. Participation of this more basic

nitrogen atom in the catalysis might have allowed the reaction

to take place outside the chiral H₈BINOL cavity, leading to the

diminished enantioselectivity. The results in Table 2 show that

o-chlorobenzaldehyde is still a quite challenging substrate for

this asymmetric arylzinc addition reaction.

The results in Tables 1 and 2 demonstrate that the pyrrodi-

nyl-based compound (S)-12 forms a more enantioselective

catalyst than (S)-2 and the other H₈BINOL-AM compounds

in the asymmetric arylzinc addition to the ortho-substituted

benzaldehydes. We used (S)-12 to catalyze the reaction of

additional aldehyde substrates with the arylzinc derived from

methyl p-iodobenzoate by using the conditions of entry 7 in

J. Org. Chem. Vol. 75, No. 9, 2010 2839

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TABLE 3. Comparison of (S)-2 and (S)-12 for the Asymmetric Reaction of Methyl p-Iodobenzoate with Additional Aldehydes^a

^aConditions: methyl p-iodobenzoate (2.2 equiv), Li(acac) (26 mol %), Et₂Zn (1.21 equiv), NMP (1.5 mL), chiral ligand (20 mol %), CH₂Cl₂(20 mL),

aldehyde (1.0 equiv), 0 °C. Step 1: 18 h. Step 2: 1 h. Step 3: 6-12 h. ^bDetermined by using HPLC-chiral column.

SCHEME 3. Asymmetric Reaction of m-Iodoanisole with

o-Methoxybenzaldehyde Catalyzed by H₈BINOL-AM Compounds

Table 1. The use of (S)-2 in these reactions is also compared

with the use of (S)-12, and the results are summarized in

Table 3. For all of the reactions, (S)-12 exhibited enantioselec-

tivity significantly higher than that of (S)-2. The enantioselec-

tivity for the addition to 4-pyridinyl aldehyde is low for both

(S)-2 and (S)-12, which indicates a possible coordination of the

pyridine nitrogen to the Lewis acidic catalyst to disturb the

catalytic process (entries 3 and 6).

b. Asymmetric Reaction of the Arylzinc Reagent Derived

from m-Iodoanisole Catalyzed by the Chiral H₈BINOL-AM

Compounds. Similar to methyl p-iodobenzoate, m-iodoani-

sole can be converted to an arylzinc reagent by using a

modified Knochel’s method in the presence of ZnEt₂and

Li(acac) in NMP at 0 °C.¹¹We investigated the asymmetric

addition of this arylzinc reagent to o-methoxybenzalde-

hyde in the presence of the H₈BINOL-AM compounds

(10 mol %) to generate the chiral diaryl carbinol 20 (Scheme 3).

As the results summarized in Table 4 show, increasing the

steric bulkiness of the amine substituents from (S)-2 to (S)-6

led to a significant reduction of the enantioselectivity (entries

1 and 2). A small improvement was observed with the use of

the benzylmethylamine-based compound (S)-7 (entry 3). As

the steric congestion increased from (S)-7 to (S)-8 and (S)-9,

the enantioselectivity diminished (entries 4 and 5). The pyrro-

lidinyl compound (S)-12 exhibited enhanced enantioselectivity

over the other compounds (entry 6). Decreasing the step 2 and

step 3 temperature to 0 °C (entry 7) or increasing the amount of

(S)-12 to 20 mol % (entry 8) could not significantly improve

the enantioselectivity. Incorporation of a sulfur atom into

the pyrrolidinyl ring of (S)-12 led to a small reduction in

enantioselectivity (entry 9). Compounds (S)-14 and (S)-16

containing additional substituents on the pyrrolidinyl rings

gave reduced enantioselectivity (entries 10 and 11). The

dramatic reduction of enantioselectivity from (S)-12 to

(S)-14 is similar to that observed in entry 9 of Table 1. This

could be attributed to the undesired participation of the MeO

groups of (S)-14 in the coordination to the Lewis acidic metal

centers.

TABLE 4. Reaction of m-Iodoanisole and o-Methoxybenzaldehyde in

the Presence of ZnEt₂and the H₈BINOL-AM Compounds to Form 20^a

isolated ee

yield (%) (%)^b

entry

ligand

1

2

3

4

5

6

(S)-2: NR₁R₂= N(CH₂CH₂)₂O

(S)-6: NR₁R₂= N(^cC₆H_{11 2}

98

91

98

70

98

86

91

98

74

13

78

72

16

80

82

80

72

31

74

)

(S)-7: NR₁R₂= NMeBn

(S)-8: NR₁R₂= NEtBn

(S)-9: NR₁R₂= NⁱPrBn

(S)-12: NR₁R₂= N(CH₂)₄

7^c(S)-12: NR₁R₂= N(CH₂)₄

8^d(S)-12: NR₁R₂= N(CH₂)₄

9

(S)-13: NR₁R₂= N(CH₂CH₂SCH₂)

10 (S)-14: NR₁R₂= N(CH₂CH₂CH₂CHCH₂OMe)

11 (S)-16: NR₁R₂= octahydroindenyl

^aFollowing conditions were used unless otherwise noted: m-iodoani-

sole (2.2 equiv), Li(acac) (26 mol %), Et₂Zn (1.21 equiv), NMP (1.5 mL),

chiral ligand (10 mol %), THF (5 mL), aldehyde (1.0 equiv). Step 1: 12 h,

0 °C. Step 2: 1 h, 0 °C. Step 3: 12 h, rt. ^bDetermined by using HPLC-chiral

column. ^cStep 3: 20 h, 0 °C. ^d20 mol % (S)-12. Step 3: 20 h, 0 °C.

reaction were used to catalyze the addition of the m-iodoani-

sole-derived arylzinc to other ortho-substituted benzaldehydes,

and the results are summarized in Table 5. Among these three

compounds, (S)-12 gave better enantioselectivity for the reac-

tion of o-chlorobenzaldehyde (entry 6); (S)-7 gave better

enantioselectivity for the reaction of o-methylbenzaldehyde

(entry 3) and o-bromobenzaldehyde (entry 9). Increasing the

amount of (S)-7 from 10 to 20 mol % and decreasing the step

2 and 3 temperature to 0 °C could not improve the enantios-

electivity (entry 4). These results demonstrate that the asym-

metric arylzinc addition to ortho-substituted benzaldehydes

still remains a challenging task, and further exploration in this

area is needed.

The three H₈BINOL-AM compounds (S)-2, (S)-7, and

(S)-12 that showed better enantioselectivity in the above

2840 J. Org. Chem. Vol. 75, No. 9, 2010

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TABLE 5. Reaction of m-Iodoanisole and Additional ortho-Substituted Benzaldehydes in the Presence of ZnEt₂and H₈BINOL-AMs^a

^aFollowing conditions were used unless otherwise noted: m-iodoanisole (2.2 equiv), Li(acac) (26 mol %), Et₂Zn (1.21 equiv), NMP (1.5 mL), chiral

ligand (10 mol %), THF (5 mL), aldehyde (1.0 equiv). Step 1: 12 h, 0 °C. Step 2: 1 h, 0 °C. Step 3: 12-16 h, rt. ^bDetermined by using HPLC-chiral column.

^c20 mol % (S)-7. Step 3: 20 h, 0 °C.

Compound (S)-12 was further used to catalyze the reac-

tion of the m-iodoanisole-derived arylzinc with other alde-

hydes, and the results are summarized in Table 6. Despite the

lower enantioselectivity for the addition to ortho-substituted

benzaldehydes, (S)-12 is highly enantioselective for the reac-

tion of other aromatic and aliphatic aldehydes as shown in

entries 1-4. For these substrates, the enantioselectivity of

(S)-12 is comparable with that of (S)-2 previously reported.^6a

The reaction of the m-iodoanisole derived arylzinc with

cyclohexanecarboxaldehyde in the presence of compound

(S)-2 was scaled up with the use of 29 mmol of the aldehyde.

This gave the corresponding alcohol product in 92% yield,

>99% ee, and >99% purity.^6b

Compounds (S)-2 and (S)-12 were also used to catalyze the

addition to heteroaromatic aldehydes. For the reaction of

2-furaldehyde, both showed high enantioselectivity (entries 5

and 6). However, lower ee’s were observed for the reaction of

4-pyridinecarboxaldehyde catalyzed by (S)-2and (S)-12 (entries

7 and 8), similar to that observed in entries 3 and 6 of Table 3.

The pyridine nitrogen atom of this aldehyde could interfere with

the catalysis probably through coordination to the Lewis acidic

metal center.

thus tested the use of these four compounds to catalyze the

reaction of p-methoxybenzaldehyde with the arylzinc reagent

derived from m-iodobenzonitrile to give the chiral diaryl

carbinol 21 (Scheme 4). As the results summarized in Table 7

show, compounds (S)-4, (S)-7, and (S)-12 improved the

enantioselectivity previously reported for (S)-2.^6aThe highest

enantioselectivity was obtained with the use of (S)-7 (entry 3).

In these reactions, 40 mol % of the ligands was needed.

d. Asymmetric Reaction of the Arylzinc Reagents Derived

from 2-Iodothiophene and 2-Bromothiophene Catalyzed by the

Chiral H₈BINOL-AMs. We also explored the use of the

H₈BINOL-AMs to promote the asymmetric reaction of thio-

phenyl halides with aldehydes. Scheme 5 shows the conversion

of 2-iodothiophene to a thiophenylzinc reagent using ZnEt₂,

Li(acac), and NMP and its subsequent asymmetric addition to

aldehydes in THF in the presence of 10 mol % of a chiral

H₈BINOL-AM. The entire process was conducted at room

temperature. The results are summarized in Table 8. Entry 1

shows that (S)-2 is a good catalyst for the thiophenyl

addition to benzaldehyde. When the thiophenylzinc for-

mation time in step 1 was shortened from 12 h in entry 1

to 6 h, the same result was obtained (entry 2). Entry 2 used

the dried and distilled 2-iodothiophene, and entry 1 used

the reagent as received, which did not affect the outcome

of the experiment. Using the dibutylamine derivative (S)-14

gave a slightly increased ee (entry 3). Compounds (S)-5

and (S)-6 with increased size of the alkyl groups on

the nitrogen atoms gave diminished ee’s (entries 4 and 5).

c. Asymmetric Reaction of the Arylzinc Reagent Derived

from m-Iodobenzonitrile Catalyzed by the Chiral H₈BINOL-

AM Compounds. The experiments for the asymmetric aryl-

zinc addition to aldehydes in the above sections show that

(S)-2, (S)-4, (S)-7, and (S)-12 have enantioselectivity higher

than that of all other H₈BINOL-AM compounds. We have

J. Org. Chem. Vol. 75, No. 9, 2010 2841

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JOCArticle

TABLE 6. Reaction of m-Iodoanisole and Other Aldehydes in the Presence of ZnEt₂and (S)-2 and (S)-12^a

^aConditions: m-iodoanisole (2.2 equiv), Li(acac) (26 mol %), Et₂Zn (1.21 equiv), NMP (1.5 mL), chiral ligand (10 mol %), THF (5 mL), aldehyde (1.0

equiv). Step 1: 12 h, 0 °C. Step 2: 1 h, 0 °C. Step 3: 6-12 h, rt. ^bDetermined by using HPLC-chiral column.

SCHEME 4. Asymmetric Reaction of m-Iodobenzonitrile with

p-Methoxybenzaldehyde Catalyzed by the H₈BINOL-AM

Compounds

TABLE 7. Reaction of m-Iodobenzonitrile and p-Methoxybenzaldehyde

in the Presence of ZnEt₂and the H₈BINOL-AM Compounds to Form 21^a

entry

ligand

isolated yield (%) ee (%)^b

1

2

3

4

(S)-2: NR₁R₂= N(CH₂CH₂)₂O

(S)-4: NR₁R₂= NBu₂

(S)-7: NR₁R₂= NMeBn

(S)-12: NR₁R₂= N(CH₂)₄

74

60

80

97

79

85

91

88

^aConditions: m-iodobenzonitrile (3.2 equiv), Li(acac) (37 mol %),

Et₂Zn (1.6 equiv), NMP (1.5 mL), chiral ligand (40 mol %), THF (25 mL),

p-methoxybenzaldehyde (1.0 equiv). Step 1: 2 h at 0 °C, then 34 h at rt. Step 2:

1 h, 0 °C. Step 3: 48 h, 0 °C. ^bDetermined by ¹H NMR spectroscopic analysis

of the mandelic ester of 21 prepared from the reaction with (R)-(-)-

(O-acetoxy)mandelic acid in the presence of DCC and DMAP in CH₂Cl₂.

The benzylmethylamine derivative (S)-7 gave enhanced

enantioselectivity over both (S)-2 and (S)-4 (entry 6). Inc-

reasing the size of the methyl group of (S)-7 to the ethyl of

(S)-8 and the isopropyl of (S)-9 reduced the enantioselec-

tivity (entries 7 and 8). When the pyrrolidinyl compound

(S)-12 was used, the highest enantioselectivity was achieved

(entry 9). Reducing the amount of NMP used in step 1 did

not cause significant change in the reaction (entry 10). The

imidazole-based compound (S)-17 could not carry out this

reaction enantioselectively (entry 11). The high enantio-

selectivity of (S)-12 for the reaction with benzaldehyde

prompted us to examine its use for the reaction of aliphatic

aldehydes. Good enantioselectivity was observed for the

reaction of cyclohexanecarboxaldehyde and octyl aldehyde

(entries 12 and 13). The four chiral compounds (S)-2, (S)-4,

(S)-7, and (S)-12 were used to catalyze the thiophenylzinc

addition to o-methoxybenzaldehyde. As the results in entries

14-17 show, the ortho-substituted benzaldehyde remains

a challenging substrate for this reaction. The highest ee

SCHEME 5. Asymmetric Reaction of 2-Iodothiophene with

Aldehydes Catalyzed by the H₈BINOL-AM Compounds

was 73%, obtained by using either (S)-7 or (S)-12 (entries

15 and 16).

The conditions for the reaction of 2-iodothiophene with

benzaldehyde in the presence of (S)-12 were further explored

in order to determine the effect of the solvent and additive on

this reaction. These experiments are summarized in Table 9.

As shown in entries 1-5, when the solvent was changed

from THF to others, the enantioselectivity was significantly

reduced. When the additive Li(acac) was replaced with

1,3-bis(diphenylphosphine)propane, a small reduction in

2842 J. Org. Chem. Vol. 75, No. 9, 2010

DeBerardinis et al.

JOCArticle

TABLE 8. Reaction of 2-Iodothiophene with Aldehydes in the Presence of ZnEt₂and H₈BINOL-AM Compounds^a

^aFollowing reaction conditions were used unless otherwise noted: 2-iodothiophene (2.2 equiv, dried, distilled), Li(acac) (26 mol %), Et₂Zn (1.21

equiv), NMP (1.5 mL), chiral ligand (10 mol %), 5 mL THF (5 mL), benzaldehyde (1.0 equiv), rt. Step 1: 6 h. Step 2: 1 h. Step 3. 12-16 h. ^bDetermined by

using HPLC-chiral column. ^cUndistilled 2-iodothiophene was used. ^d0.75 mL of NMP was used in step 1.

enantioselectivity was observed (entry 6). Removing both

Li(acac) and NMP led to no thiophenyl addition product,

only the ZnEt₂addition product (entry 7). This indicates that

the thiophenylzinc was not generated under these conditions.

In the presence of NMP but without Li(acac), high enantios-

electivity and excellent yield were obtained (entry 8). That is,

the additive Li(acac) that is necessary for the formation of

other arylzinc reagents¹¹is not needed for the reaction of

2-iodothiophene. This gives a simplified reaction procedure.

Previously, we found that aryl bromides could not be used in

place of aryl iodides for the asymmetric arylzinc addition to

aldehydes. For example, m-bromoanisole and methyl p-bromo-

benzoate did not react with ZnEt₂under the conditions used for

the reaction of the aryl iodides even with extended reaction time

and under refluxing. The excellent reactivity of 2-iodothiophene

described here encouraged us to test the use of 2-bromothio-

phene for the reaction with benzaldehyde in the presence of (S)-

12 and ZnEt₂to give the diaryl carbinol 22 (Scheme 6). We were

pleased to find that the thiophenylzinc could be generated from

2-bromothiophene to react with benzaldehyde in the presence of

(S)-12 with good enantioselectivity. The results are summarized

in Table 10. The use of distilled 2-bromothiophene in entry 4

showed enantioselectivity higher than that obtained using un-

distilled 2-bromothiophene (entries 1-3). This is the first

example that an arylbromide can be used to react with ZnEt₂

to form a diarylzinc reagent. The product was obtained with

slightly reduced enantioselectivity relative to that using

2-iodothiophene. Unlike that found for 2-iodothiophene shown

J. Org. Chem. Vol. 75, No. 9, 2010 2843

DeBerardinis et al.

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TABLE 9. Varying the Conditions for the Reaction of 2-Iodothiophene

TABLE 10. Asymmetric Reaction of 2-Bromothiophene and Benzalde-

and Benzaldehyde in the Presence of ZnEt₂and (S)-12^a

hyde in the Presence of (S)-12 and ZnEt₂to Form 22^a

isolated

yield

(%)

step 1

(h)

step 3

(h)

Isolated

Yield (%)

ee

NMP

(mL)

ee

entry

2-bromothiophene

(%)^b

entry solvent

additive

(%)^b

1

2

3

4

undistilled

distilled

12

24

6

24

16

10.5

10

80

90

87

98

82

79

83

86

1

THF

Li(acac) (26%)

1.5

none

1.5

95

91

92

91

92

none

98

90

84

82

78

75

86

n/a

91

2

3

CH₂Cl₂Li(acac) (26%)

toluene Li(acac) (26%)

6

^aConditions: 2-bromothiophene (2.2 equiv), Li(acac) (26 mol %), ZnEt₂

(1.21 equiv), (S)-12 (10mol%), NMP(1.5 mL), THF (5mL), benzaldehyde

(1.0 equiv), rt. Step 2: 1 h. ^bDetermined by using HPLC-chiral column.

4

5

ether

Li(acac) (26%)

hexanes Li(acac) (26%)

6^c

7^d

8^e

9^f

THF

(Ph₂PCH₂)₂CH₂(20%)

none

TABLE 11. Asymmetric Reaction Using Iodobenzene and p-Methoxy-

benzaldehyde in the Presence of H₈BINOL-AMs to Form 23^a

^aFollowing reaction conditions were used unless otherwise noted: 2-iodo-

thiophene (2.2 equiv), an additive, Et₂Zn (1.21 equiv), chiral ligand (10 mol

%), NMP (1.5 mL), THF (5 mL), benzaldehyde (1.0 equiv), rt. Step 1: 6 h.

Step 2: 1 h. Step 3: 8 h. ^bDetermined by using HPLC-chiral column. ^cStep 1:

16 h. ^dStep 1: THF (5 mL), no NMP, 16 h. Step 3: 16 h. The ethyl addition

product was obtained in 90% yield. ^eStep 1: 12 h. ^fStep 1: 6 h.

step 1

(h)

isolated

ee

entry

ligand

yield (%) (%)^(b)

1^(c)

2

(S)-2: NR₁R₂= N(CH₂CH₂)₂O

(S)-12: NR₁R₂= N(CH₂)₄

13

24

6

64

77

50

12

56

85

98

62

85

64

40

82

88

93

3

4^(d)

5

SCHEME 6. Use of 2-Bromothiophene for the Asymmetric

Arylzinc Addition in the Presence of (S)-12 and ZnEt₂

6

7

3

^aFollowing conditions were used unless otherwise noted: iodobenzene

(2.2 equiv, freshly distilled), Li(acac) (26 mol %), Et₂Zn (1.21 equiv),

NMP (1.5 mL), chiral ligand (10 mol %), THF (5 mL), p-anisaldehyde

(1.0 equiv, treated with NaHCO₃, passed through alumina, degassed), rt,

under nitrogen. Step 2: 1 h. Step 3: 12 h. ^(b)Determined by using HPLC-

chiral column. ^(c)Undistilled iodobenzene was used. ^(d)CH₂Cl₂was used in

place of THF.

in entry 8 of Table 9, without Li(acac) the thiophenylzinc could

not be generated from 2-bromothiophene and only ethyl addi-

tion product was observed in the presence of (S)-12. 2-Chlor-

othiophene did not react with ZnEt₂to form the arylzinc.

e. Asymmetric Reaction of the in situ Generated Diphenyl-

zinc from Iodobenzene Catalyzed by the Chiral H₈BINOL-

AM Compounds. We previously reported the use of (S)-2 to

catalyze the reaction of the commercially available Ph₂Zn

with aldehydes.^5b,cIn order to utilize iodobenzene for this

reaction, we examined the reaction of the in situ generated

Ph₂Zn from iodobenzene with p-methoxybenzaldehyde in the

presence of (S)-2 and (S)-12 to form the diaryl carbinol 23

(Scheme 7). The results are summarized in Table 11. Using

distilled iodobenzene led to significant enhancement of the

enantioselectivityfromentry 1toentry 2inthe presence of (S)-

2. The time for the in situ formation of Ph₂Zn in the first step

was found to strongly influence both the yield and ee of the

reaction. Increasing the time in the first step from entry 2 to

entry 3 reduced both the yield and ee, indicating a degradation

of Ph₂Zn over time. Changing the solvent from THF to

CH₂Cl₂diminished both the yield and ee (entry 4). The

optimal reaction time for the first step was 3 h, which led to

the formation of 23 with good enantioselectivity and yield

(entry 6). Under these conditions, replacing (S)-2 with (S)-12

enhanced both the yield and ee (entry 7). This demonstrates

that in the presence of (S)-12, iodobenzene could be used to

replace Ph₂Zn for the asymmetric Ph₂Zn addition to alde-

hydes. When the commercially pure Ph₂Zn was used for the

addition to p-methoxybenzaldehyde in the presence of (S)-2,

the product was obtained with 91% ee and 91% yield.^5b

f. Correlation between the Enantiomeric Purity of the Chiral

Ligand and That of the Addition Product, Absolute Configu-

ration Assignment, and NMR Study. In order to gain more in-

formation about the asymmetric arylzinc addition to aldehydes

in the presence of the H₈BINOL-AM compounds, we studied

the relationship between the enantiomeric purity of (S)-2 and

SCHEME 7. Use of Iodobenzene for the Asymmetric Arylzinc

Addition in the Presence of the H₈BINOL-AMs

SCHEME 8. Asymmetric Reaction of m-Iodoanisole with Cyclo-

hexanecarboxaldehyde Catalyzed by (S)-2

that of the product 24 from the reaction of m-iodoanisole with

cyclohexanecarboxaldehyde (Scheme 8). As shown in Figure 3,

a linear relationship was obtained between the ee of (S)-2and the

ee of 24. This indicates that the monomeric complex of (S)-2

rather than its intermolecular aggregates is responsible for the

catalysis. The observed linear relationship between the ee of (S)-

2 and that of the arylzinc addition product is similar to what we

previously reported for the reaction of the commercially avail-

able pure Ph₂Zn with aldehydes catalyzed by (S)-2.^5b,c

We have prepared the (R)- and (S)-R-methoxy-R-phenylace-

tic (MPA) ester derivatives of 24 in order to determine its ab-

solute configuration.¹²The ¹H NMR analysis showed that in

(12) (a) Trost, B. M.; Belletire, J. L.; Goldleski, P. G.; McDougal, P. G.;

Balkovec, J. M.; Baldwin, J. J.; Christy, M.; Ponticello, G. S.; Varga, S. L.;

Springer, J. P. J. Org. Chem. 1986, 51, 2370. (b) Seco, J.; Quinoa, E.; Riguera,

R. Chem. Rev. 2004, 104, 17–117.

2844 J. Org. Chem. Vol. 75, No. 9, 2010

DeBerardinis et al.

JOCArticle

NMR spectrum still showed complicated signals for the ligand-

zinc complex with no free (p-MeO₂CC₆H₄)₂Zn present.

FIGURE 3. Relationship of the enantiomeric purity of (S)-2 with

that of the corresponding product 24.

the (R)-MPA derivative of 24, the anisyl aromatic signals

of 24 shifted upfield in comparison with those in the (S)-MPA

derivative of 24.¹²This supports a R configuration for 24

prepared by using (S)-2. Thus, the nucleophilic arylzinc should

add to the si face of the aldehyde during the asymmetric

arylation.

When the H₈BINOL-AM compounds are used for the

arylzinc addition to aldehydes, the active catalysts are the zinc

complexes generated from the reaction of the arylzincs with the

chiral compounds. That is, for each arylzinc addition reaction,

the catalyst is different because different arylzincs are used. On

the basis of the reaction time described earlier, the following

order was found for the relative activity of the reactions

studied: (methyl p-benzoate)₂zinc > (2-thiophenyl)₂zinc >

(phenyl)₂zinc > (m-anisyl)₂zinc . (m-benzonitrile)₂zinc.

3. Synthesis of a H₈BINOL-AM Compound Containing

Secondary Amine Substituents and Their Use in the Asym-

metric Arylzinc Addition. The results in Tables 1, 2, 4, and 8

show that the H₈BINOL-AM compounds containing more

sterically crowded tertiary amine substituents are generally less

enantioselective than those containing sterically less crowded

tertiary amine substituents. It would be interesting to compare

the catalytic properties of these compounds with those contain-

ing the sterically less crowded secondary amines. We found that

the use of a primary amine in combination with paraformalde-

hyde could not undergo the Mannich-type reaction with H₈BI-

NOL like that shown in Scheme 1 to generate the corresponding

secondary amine-substituted H₈BINOL-AM. Therefore, a mul-

tistep synthesis was conducted to prepare such a compound. As

shown in Scheme 9, (S)-H₈BINOL was first protected with

methoxymethyl groups to give (S)-27. Treatment of (S)-27 with

ⁿBuLi and TMEDA followed by reaction with DMF and acidic

deprotection gave the 3,3⁰-diformylH₈BINOL (S)-28.¹³Reac-

tion of (S)-28 with 1-naphthylmethylamine followed by reduc-

tion with NaBH₄gave the H₈BINOL-AM derivative (S)-29

that contains 3,3⁰-secondary amine substituents.

We also conducted a NMR spectroscopic investigation for the

reaction of the in situ generated arylzinc catalyzed by (S)-2.

Under nitrogen, a portion of the reaction solution (prepared at

0°C for 18 h) of methyl p-iodobenzoate (0.067 mmol) with ZnEt₂

(0.037 mmol) in NMP (0.05 mL, 0.52 mmol) and Li(acac) (0.008

mmol) was added to C₆D₆, and the ¹H NMR spectrum of the

solution showed signals at δ8.34(d,J= 8.1 Hz, 4H), 8.24 (d, J=

7.8 Hz, 4H), 3.56 (s, 6H) corresponding to the desired diarylzinc

(p-MeO₂CC₆H₄)₂Zn. The conversion of methyl p-iodobenzoate

to (p-MeO₂CC₆H₄)₂Zn was almost complete. When 1 equiv of

the diarylzinc solution was added to a C₆D₆solution of (S)-2,

methyl benzoate was produced with a similar amount of un-

reacted (S)-2but no free (p-MeO₂CC₆H₄)₂Zn was observed. This

indicates that one molecule of (S)-2 probably consumed more

than one molecule of (p-MeO₂CC₆H₄)₂Zn. When 1.8 equiv of (p-

MeO₂CC₆H₄)₂Zn was added, (S)-2 was completely consumed,

but the structure of the resulting complex could not be established

because of the complicated NMR signals. This is quite different

from the reaction of (S)-2 with the commercially pure Ph₂Zn,

which gave much better defined NMR signals.^5bWhen (S)-2 was

treated with 1.5 equiv of Ph₂Zn, the NMR spectrum showed the

formation of a 2 þ 3 complex 25. This complex collapsed upon

reaction with excess Ph₂Zn to form a C₂-symmetric complex that

might have the structure of either 26a or 26b. This complex was

found to be the catalytically active species for the arylzinc

addition involving a possible transition state as shown. The much

more complicated NMR spectrum obtained for the reaction of

(S)-2 with the in situ generated (p-MeO₂CC₆H₄)₂Zn could be

partly attributed to the additional components such as NMP,

Li(acac), and EtI present in this reaction system. When up to 5

equiv of the (p-MeO₂CC₆H₄)₂Zn solution was added to (S)-2,the

Compound (S)-29 (10 mol %) was used to catalyze the

reactions of m-iodoanisole with o-methoxybenzaldehyde and

o-chlorobenzaldehyde under the same conditions as entry 1 in

Table 4 (see Scheme 3). For the reaction of o-methoxybenzal-

dehyde, it gave 96% yield and 68% ee. For the reaction of

(13) (a) Zhang, H. -C.; Huang, W. -S.; Pu, L. J. Org. Chem. 2001, 66, 481–

487. (b) Cox, P. J.; Wang, W.; Snieckus, V. Tetrahedron Lett. 1992, 33, 2253–

2256.

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SCHEME 9. Synthesis of the Secondary Amine-Substituted H₈BINOL-AM Compound (S)-29

o-cholorobenzaldehyde, it gave 80% yield and 40% ee. These

enantioselectivities are lower than those of (S)-2, (S)-7, and (S)-

12 shown in Tables 4 and 5. Thus, using the H₈BINOL-AM

containing secondary amine substituents did not improve the

enantioselectivity over those with tertiary amine substituents.

solution was reheated to 60 °C for 12 h. Upon completion of the

reaction, CH₂Cl₂(50 mL) was added to the reaction mixture. The

organic fraction was washed with NaHCO₃(saturated, aq) (3 ꢀ

35 mL) and H₂O(3ꢀ 50 mL). The organic layer was then dried over

Na₂SO₄, filtered, and concentrated. The residual oil was dissolved

in a minimal amount of ethyl acetate and passed through an

alumina column eluted with hexanes/ethyl acetate (3-5%) to give

pure (S)-3 as a white powder in 88% yield. ¹H NMR (300 MHz,

CDCl₃) δ 11.13 (bs, 2H), 6.70 (s, 2H), 3.86 (d, J = 14.1 Hz, 2H),

3.64 (d, J = 14.1 Hz, 2H), 2.73 (m, 4H), 2.59 (m, 8H), 2.44 (m, 2H),

2.18 (m, 2H), 1.71 (m, 8H), 1.07 (t, J = 7.2 Hz, 12H). ¹³C NMR (75

MHz, CDCl₃) δ 152.2, 135.3, 128.1, 126.7, 124.0, 119.1, 57.0, 46.0,

29.2, 26.8, 23.2, 14.0. [R]²⁵_D-55.6 (c 0.995, THF). Mp 95-100 °C.

HRMS calcd for C₃₀H₄₄N₂O₂þ H: 465.3476. Found for MH^þ:

465.3481.

4. Conclusion

In summary, we have prepared a family of optically active

H₈BINOL-AM compounds containing 3,3⁰-tertiary amine

substituents by using a one-step reaction of H₈BINOL with

amino methanols. These H₈BINOL-AM compounds were

used to catalyze the reaction of the in situ generated func-

tional arylzincs from aryliodides and ZnEt₂with a variety of

aldehydes to produce chiral diaryl carbinols and a few

arylalkyl carbinols. This study shows that the H₈BINOL-

AM compounds with less sterically congested cyclic or

acyclic tertiary amine substituents are more enantioselective

than those with more bulky tertiary amine substituents. A

linear correlation was observed between the enantiomeric

excess of the chiral ligand and that of the arylzinc addition

product, suggesting a monomeric active catalytic species.

Previously, we found that compound (S)-2 was highly

enantioselective for the asymmetric arylzinc addition to p-

and m-substituted aromatic aldehydes and aliphatic alde-

hydes. In the study described in this report, the newly

prepared pyrrolidinyl derivative (S)-12 was found in most

cases to give enhanced enantioselectivity over (S)-2 and the

other H₈BINOL-AM compounds, especially for the challen-

ging ortho-substituted aromatic aldehydes. The benzyl-

methylamine-based compound (S)-7 also gave better

enantioselectivity in several cases. A H₈BINOL-AM con-

taining 3,3⁰-bis-sec-amine substituents, prepared by a multi-

step method, was used to catalyze the arylzinc addition to

aldehydes but showed lower enantioselectivity than that

using the tertiary amine derivatives (S)-2, (S)-7 ,and (S)-12.

It was found for the first time that an aryl bromide, 2-

bromothiophene, could be used to prepare a heteroarylzinc

reagent by reaction with ZnEt₂. The addition of this hetero-

arylzinc reagent to an aldehyde in the presence of (S)-12

proceeded with good enantioselectivity.

Synthesis and Characterization of (S)-4. Paraformaldehyde

(301 mg, 10.0 mmol, 5 equiv) was added to a 2-neck round-

bottom flask fitted with a condenser under nitrogen. The flask

was then charged with dioxane (6 mL, degassed), and the

mixture was cooled to 0 °C. Dibutylamine (1.7 mL, 10.0 mmol,

5 equiv) was added dropwise into the mixture cautiously over

15-20 min. In order to prevent the complete freezing of the

reaction mixture, the addition was conducted in the following

fashion. The ice bath was removed followed by the addition of a

few drops of amine and was then replaced. After the addition

was complete, the mixture was warmed to room temperature for

30 min and then heated at 75 °C for 22 h. An amber-colored,

viscous solution formed, which was cooled to room temperature,

and (S)-H₈BINOL (590 mg, 2.01 mmol) was added. The solution

was reheated to 75 °C for 41 h. Upon completion of the reaction,

CH₂Cl₂(50 mL) was added, and the organic fraction was washed

with NaHCO₃(saturated, aq) (3 ꢀ 35 mL) and H₂O (2 ꢀ 35 mL).

The organic layer was then dried over Na₂SO₄, filtered, and

concentrated. The residual oil was dissolved in a minimal amount

of ethyl acetate and passed through an alumina column eluted

with hexanes/ethyl acetate (5%). This column chromatography

separation was repeated to give (S)-4 as a white powder in 60%

yield. ¹H NMR (300 MHz, CDCl₃) δ 10.89 (s, 2H), 6.56 (s, 2H),

3.92 (d, J = 13.8 Hz, 2H), 3.47 (d, J = 13.9 Hz, 2H), 2.73 (m, 4H),

2.54 (m, 4H), 2.37 (m, 6H), 2.11 (m, 2H), 1.69 (m, 8H), 1.46 (m,

8H), 1.25 (m, 8H), 0.85 (t, J = 8.3 Hz, 12H). ¹³C NMR (75 MHz,

CDCl₃) δ 152.5, 135.2, 128.1, 126.6, 123.9, 119.2, 58.4, 53.1, 29.2,

28.7, 26.8, 23.2, 20.6, 14.0. [R]²⁵-13.5 (c 0.955, THF). Mp

D

88-93 °C. Anal. Calcd for C₃₈H₆₀N₂O₂: C, 79.11; H, 10.48; N,

4.86. Found: C, 79.17; H, 10.68; N, 4.79. HRMS calcd for

C₃₈H₆₀N₂O₂þ H: 577.4733. Found for MH^þ: 577.4735.

Experimental Section

Synthesis and Characterization of (S)-5. Paraformaldehyde

(50 mmol) was added to a 2-neck round-bottom flask fitted with

condenser and vacuum adaptor. Dioxane (10 mL, degassed) was

added. Diisopropylamine (50 mmol, 7.07 mL) was added drop-

wise over 60 min at room temperature with aggressive stirring.

The mixture was then heated gently to 60 °C. After 16 h, a clear

solution was obtained, which was then cooled to room tempera-

ture and charged with (S)-H₈BINOL (1.47 g, 5 mmol). The

solution was heated at 60 °C for 17 h and then at 80 °C for 24 h.

After the same workup as in the preparation of (S)-4, the oily

residue was dissolved in a minimal amount of ethyl acetate and

passed through an alumina column eluted with hexanes/acetone

Synthesis and Characterization of (S)-3. Paraformaldehyde

(3.4 mmol, 102.1 mg, 5 equiv) was added to a 2-neck round-

bottom flask fitted with condenser under nitrogen. The flask was

then charged with dioxane (5 mL, degassed), and the mixture was

cooled to 0 °C. Diethylamine (3.4 mmol, 353 μL, 5 equiv) was added

dropwise into the mixture cautiously over 15-20 min. After the

addition was complete, the ice bath was removed, and the mixture

was warmed to room temperature for 30 min. It was then heated at

50 °C for about 20 h during which a slightly colored solution

formed. After the solution was cooled to room temperature,

(S)-H₈BINOL (200 mg, 0.68 mmol) was added, and the resulting

2846 J. Org. Chem. Vol. 75, No. 9, 2010

DeBerardinis et al.

JOCArticle

(5%). This chromatography purification was repeated two more

times to give pure (S)-5 as a light powdery white solid in 60%

yield. ¹H NMR (300 MHz, CDCl₃) δ 11.26 (s, 2H), 6.70 (s, 2H),

3.87 (d, J = 14.7 Hz, 2H), 3.77 (d, J = 14.4 Hz, 2H), 3.15 (septet,

J = 6.6 Hz, 4H), 2.70 (m, 4H), 2.44 (m, 2H), 2.13 (m, 2H), 1.69

was heated at 95-100 °C for 24 h. After the same workup as the

preparation of (S)-3, a residual oil was obtained that was purified

twice by column chromatography on alumina eluted with hexanes/

acetone (5-10%). The resulting crystals were recrystallized from

1

ethanol to give pure (S)-8 in 55% yield. H NMR (300 MHz,

(m, 8H), 1.07 (d, J = 6.6 Hz, 12H), 1.06 (d, J = 6.6 Hz, 12H). ¹³

C

CDCl₃) δ 10.73 (s, 2H), 7.29 (m, 10H), 6.78 (s, 2H), 3.98 (d, J =

13.8 Hz, 2H), 3.77 (d, J = 13.2 Hz, 2H), 3.63 (d, J = 13.8 Hz, 2H),

3.54 (d, J= 13.2 Hz, 2H), 2.77 (m, 4H), 2.64 (m, 2H), 2.49 (m, 4H),

2.17 (m, 2H), 1.71 (m, 8H), 1.10 (t, J = 7.2 Hz, 6H). ¹³C NMR (75

MHz, CDCl₃) δ 152.3, 137.3, 135.6, 129.5, 128.5, 128.2, 127.1,

124.0, 119.1, 57.5, 57.2, 46.2, 29.2, 26.9, 23.2, 10.9. [R]²⁵_D-17.6 (c

0.785, THF). Mp 76-82 °C. HRMS calcd for C₄₀H₄₈N₂O₂þ H:

589.3789. Found for MH^þ: 589.3787.

NMR (75 MHz, CDCl₃) δ 153.2, 135.1, 128.3, 126.5, 123.8,

D

119.4, 48.4, 47.2, 29.2, 26.8, 23.3, 19.9, 19.4. [R]²⁵-54.9 (c

0.925, THF) mp 184-188 °C. HRMS calcd for C₃₄H₅₂N₂O₂þ

H: 521.4102. Found for MH^þ: 521.4106.

Synthesis and Characterization of (S)-6. Dicyclohexylamine

(75 mmol) was added to paraformaldehyde (75 mmol) under

nitrogen at 0 °C. The resulting mixture was stirred at room

temperature for an additional 1 h and heated at 60 °C for 2 d.

Then, at room temperature (S)-H₈BINOL (880 mg, 3 mmol) and

degassed dioxane (20 mL, degassed) were added. The reaction

mixture was heated at 70 °C for 24 h and further heated at reflux for

another 12 h. The reaction was shown to be complete by ¹H NMR

spectroscopy. After the same workup and purification as in the

preparation of (S)-4, the product was further purified by recrys-

tallization in ethanol. Two crops of (S)-6 were obtained as a white

solid in 55% yield. One additional column chromatography was

Synthesis and Characterization of (S)-9. Under nitrogen,

paraformaldehyde (1.5 g, 50 mmol) was placed into a 2-neck,

50 mL round-bottom flask equipped with stir bar, condenser,

and vacuum adaptor. Dioxane (5 mL, degassed) was then

added, and the slurry was chilled to 0 °C. Benzyl isopropylamine

was added dropwise into the mixture with vigorous stirring.

After the addition was complete, the mixture was stirred for 25

min and then warmed to room temperature for 50 min. The

reaction mixture was heated at 60-65 °C for 18 h. Then, (S)-

H₈BINOL (734 mg, 2.49 mmol) and dioxane (5 mL, degassed)

were added at room temperature. The reaction mixture was

heated at 90-100 °C for 24 h. After the same workup as the

preparation of (S)-3, the resulting oily residue was purified twice

by column chromatography on alumina eluted with hexanes/

acetone (5-8%) and hexanes/acetone (4-10%), respectively.

The resulting crystals were recrystallized from ethanol to give

pure (S)-9 in 45% yield. ¹H NMR (300 MHz, CDCl₃) δ 10.76 (s,

2H), 7.23 (m, 10H), 6.76 (s, 2H), 3.94 (d, J = 13.8 Hz, 2H), 3.71

(d, J = 13.5 Hz, 2H), 3.60 (d, J = 13.8 Hz, 2H), 3.52 (d, J = 13.2

Hz, 2H), 3.05 (septet, J = 6.6 Hz, 2H), 2.74 (m, 4H), 2.44 (m,

2H), 2.10 (m, 2H), 1.65 (m, 8H), 1.11 (d, J = 6.9 Hz, 6H), 1.06 (d,

J = 6.6 Hz, 6H). ¹³C NMR (75 MHz, CDCl₃) 152.5, 138.2,

135.6, 129.4, 123.9, 119.0, 53.7, 52.2, 47.8, 29.3, 26.9, 23.3, 18.0,

15.4. [R]²⁵_D-17.9 (c 0.90, THF). Mp 165-168 °C. HRMS calcd

for C₄₂H₅₂N₂O₂þ H: 617.4122. Found for MH^þ: 617.4112.

Synthesis and Characterization of (S)-10. Under nitrogen,

thiomorpholine (5.0 mL, 50 mmol) was mixed with paraformal-

dehyde (1.5 g, 50 mmol) at 0 °C. The mixture was warmed to

room temperature after 30 min and then gently heated to 50 °C

for 12 h. The resulting slurry was further heated at 75-80 °C for

5 h to give a homogeneous solution. To the solution at room

temperature were added (S)-H₈BINOL (508.2 mg, 2 mmol) and

dioxane (10 mL, degassed). The reaction solution was heated at

80 °C for 16 h. After the same workup as the preparation of (S)-

3, the crude solid was recrystallized from ethanol, which gave

pure (S)-10 (crop 1, 65% yield). ¹H NMR (300 MHz, CDCl₃) δ

10.37 (s, 2H), 6.71 (s, 2H), 3.79 (d, J = 13.8 Hz, 2H), 3.62 (d, J =

13.8 Hz, 2H), 2.82 (m, 8H), 2.67 (m, 8H), 2.36 (m, 2H), 2.16 (m,

2H), 1.67 (m, 8H). ¹³C NMR (75 MHz, CDCl₃) δ 152.1, 135.8,

128.6, 127.5, 123.9, 117.8, 62.2, 54.3, 29.1, 27.7, 26.9, 23.2, 23.1.

[R]²⁵_D-50.8 (c 0.715, THF). Mp 162-176 °C. HRMS calcd for

C₃₀H₄₀N₂O₂S₂þ H: 525.2604. Found for MH^þ: 525.2611.

Synthesis and Characterization of (S)-11. Under nitrogen,

paraformaldehyde (901 mg, 30.0 mmol) was added to a 2-neck

round-bottom flask fitted with condenser. Then at 0 °C, piper-

idine (3 mL, 30.0 mmol) was added dropwise cautiously over

15-20 min with vigorous stirring. After the addition was

complete, the mixture was warmed to room temperature for

30 min and then heated at 80 °C for 9 h. The resulting amber-

colored viscous solution was cooled to room temperature, and

(S)-H₈BINOL (2.06 g, 7 mmol) and dioxane (15 mL, degassed)

were added. The reaction solution was reheated at 80 °C for 12 h.

Upon completion of the reaction, ethyl acetate was added to this

mixture. The organic fraction was washed with NaHCO₃

(saturated, aq) (3 ꢀ 35 mL) and H₂O (2 ꢀ 35 mL). Then, the

1

necessary to fully purify (S)-6. H NMR (300 MHz, CDCl₃) δ

11.26 (s, 2H), 6.62 (s, 2H), 3.99 (d, J = 14.1 Hz, 2H), 3.79 (d, J =

14.4 Hz, 2H), 2.91 (m, 2H), 2.66 (m, 6H), 2.43 (m, 2H), 2.10 (m,

4H), 1.69 (m, 24H), 1.22 (m, 16H). ¹³C NMR (75 MHz, CDCl₃) δ

153.4, 135.2, 128.3, 126.7, 124.0, 120.0, 57.3, 49.8, 31.6, 30.0, 29.5,

26.9, 26.4, 26.3, 23.6. [R]²⁵_D-4.5 (c 0.785, THF). Mp 234-238 °C.

HRMS calcd for C₄₆H₆₈N₂O₂þ H: 681.5354. Found for MH^þ:

681.5362.

Synthesis and Characterization of (S)-7. Paraformaldehyde

(301 mg, 10.0 mmol, 5 equiv) was added to a 2-neck round-

bottom flask fitted with condenser under nitrogen. The flask

was then charged with dioxane (6 mL, degassed), and the

mixture was cooled to 0 °C. Benzyl methylamine (10.0 mmol,

5 equiv) was added dropwise into the mixture cautiously over

15-20 min. The ice bath was removed, and the mixture was

warmed to room temperature for 1 h. The mixture was then

heated gently to 75 °C for 12 h, which gave a yellow-colored

solution. This solution was cooled to room temperature, and

(S)-H₈BINOL (590 mg, 2.01 mmol) was added. After the

reaction solution was reheated to 75 °C for 12 h, CH₂Cl₂(50

mL) was added to this mixture at room temperature. The

organic fraction was then washed with NaHCO₃(saturated,

aq) (3 ꢀ 35 mL) and H₂O (2 ꢀ 35 mL). The organic layer was

dried over Na₂SO₄, filtered, and concentrated. The residual oil

was dissolved in a minimal amount of ethyl acetate and passed

through an alumina column eluted with hexanes/ethyl acetate

(5%). Multiple column chromatography was sometimes needed

1

which gave (S)-7 as a white powder in >70% yield. H NMR

(300 MHz, CDCl₃) δ 10.67 (s, 2H), 7.29 (m, 10H), 6.82 (s, 2H),

3.99 (d, J = 13.5 Hz, 2H), 3.68 (d, J = 12.6 Hz, 2H), 3.66 (d, J =

13.5 Hz, 2H), 3.57 (d, J = 12.6 Hz, 2H), 2.81 (m, 4H), 2.49 (m,

2H), 2.23 (m, 8H), 1.79 (m, 8H). ¹³C NMR (75 MHz, CDCl₃) δ

152.3, 137.1, 135.6, 129.4, 128.3, 128.2, 127.2, 124.0, 118.9, 61.4,

61.3, 40.9, 29.2, 26.9, 23.2, 23.1. [R]²⁵_D-19.0 (c 0.81, THF). Mp

90-95 °C. Anal. Calcd for C₃₈H₄₄N₂O₂: C, 81.39; H, 7.91; N,

5.00. Found: C, 80.59; H, 7.90; N, 4.85. HRMS calcd for

C₃₈H₄₄N₂O₂þ H: 561.3481. Found for MH^þ: 561.3473.

Synthesis and Characterization of (S)-8. Paraformaldehyde

(50 mmol, 1.5 g) was placed into a 2-neck, 50 mL round-bottom

flask equipped with stir bar, condenser, and vacuum adaptor. At

0 °C, benzyl ethylamine was added dropwise to the flask with

vigorous stirring. After the addition was complete, the mixture was

stirred for 25 min and then warmed to room temperature for

50 min. The reaction mixture was heated at 50 °C for 18 h and then

cooled to room temperature. (S)-H₈BINOL (736 mg, 2.5 mmol)

and dioxane (5 mL, degassed) were added. The reaction mixture

J. Org. Chem. Vol. 75, No. 9, 2010 2847

DeBerardinis et al.

JOCArticle

organic layer was dried over Na₂SO₄, filtered, and evaporated.

The resulting crude crystals were recrystallized in acetone to give

pure (S)-11 as a white powder in 81% yield. ¹H NMR (300 MHz,

CDCl₃) δ 11.06 (s, 2H), 6.78 (s, 2H), 3.77 (d, J = 14.1 Hz, 2H),

3.51 (d, J = 13.8 Hz, 2H), 2.70 (m, 4H), 2.39 (m, 9H), 2.15 (m,

2H), 1.61 (m, 22H). ¹³C NMR (75 MHz, CDCl₃) δ 152.6, 135.4,

128.2, 126.8, 124.0, 118.7, 62.2, 53.7, 29.2, 26.9, 25.6, 24.0, 23.2.

[R]²⁵_D-72.2 (c 0.835, THF). Mp 128-133 °C. HRMS calcd for

C₃₂H₄₄N₂O₂þ H: 489.3476. Found for MH^þ: 489.3480.

CDCl₃) δ 9.52 (s, 2H), 6.74 (s, 2H), 4.05 (m, 4H), 3.82 (d, J = 13.5

Hz, 2H), 3.71 (d, J = 13.5 Hz, 2H), 3.13 (t, J = 6.6 Hz, 4H), 2.98 (t,

J = 6.3 Hz, 4H), 2.70 (m, 4H), 2.35 (m, 2H), 2.18 (m, 2H), 1.70 (m,

8H). ¹³C NMR (75 MHz, CDCl₃) δ 152.0, 136.5, 124.3, 119.0, 58.6,

56.4, 56.2, 29.4, 29.2, 27.2, 23.4, 23.3. [R]²⁵_D-42.8 (c 0.995, THF).

Mp 186-188 °C. HRMS calcd for C₂₈H₃₆N₂O₂S₂þ H: 497.2291.

Found for MH^þ: 497.2294.

Synthesis and Characterization of (S)-14. (1) Under nitrogen,

(S)-2-(methoxymethyl)pyrrolidine (5.4 mL, 43.7 mmol), pre-

pared according to Kipphardt’s method and vacuum distillation

through a Vigreux column,¹⁴was mixed with paraformaldehyde

(1.31 g, 43.7 mmol) at 0 °C for 1 h. The mixture was then heated at

65 °C for overnight, resulting in a thick yellowish solution. At room

temperature, (S)-H₈BINOL (650 mg, 2.2 mmol) and dioxane (10

mL, degassed) were added, and the reaction mixture was reheated

at 65-70 °C for 18 h. The reaction was shown to be complete by

TLC and NMR. After the same workup as in the preparation of

(S)-3, a thick yellow oily residue was obtained. After repeated

column chromatography on silica gel eluted with CH₂Cl₂/MeOH,

the NMR and HRMS spectra still showed impurities that could not

be completely removed. ¹H NMR (300 MHz, CDCl₃) δ 10.52 (bs,

2H), 6.71 (s, 2H), 4.24 (d, J = 13.8 Hz, 2H), 3.64 (d, J = 13.8 Hz,

2H), 3.46 (m, 2H), 3.29 (s, 6H), 3.11 (m, 2H), 2.77 (m, 6H), 2.49 (m,

Synthesis and Characterization of (S)-12. Method A. (1) Pre-

paration of pyrrolidinomethanol. Paraformaldehyde (15.0 g,

0.5 moL) was added into a 2-necked round-bottom flask

equipped with a stir bar and condenser. The vessel was flushed

under nitrogen for 15 min and then cooled to 0 °C. Pyrrolidine

(42 mL, 0.5 mol) was added dropwise through a side arm over

30 min with caution. After complete addition, the mixture was

stirred for 1 h. The ice bath was then removed, and the mixture

was stirred at room temperature for 1 h. It was then heated at

70 °C overnight to give a homogeneous syrup-like liquid. (2)

Preparation of (S)-12. (S)-H₈BINOL (2.519 g, 8.56 mmol) was

dissolved in dioxane (20 mL, degassed) in a 100 mL 2-neck

round-bottom flask equipped with stir bar and condenser.

Pyrrolidinomethanol (20 mL) was added into this solution,

and the flask was flushed with nitrogen. After 15 min, the

mixture was heated at 60 °C for 15 h. After the reaction was

complete as shown by TLC, the mixture was diluted with ethyl

acetate (120 mL) and washed with NaHCO₃(satd., aq) (3 ꢀ

80 mL) and H₂O (3 ꢀ 100 mL). The organic fraction was dried

over Na₂SO₄, filtered, and evaporated. The residue was recrys-

tallized from ethanol to give (S)-12 in 70% yield (crop 1).

Method B. Alternatively, the reaction could be conducted in

one pot by preparing an appropriate amount of pyrrolidino-

methanol (10-20 equiv relative to (S)-H₈BINOL). Step one

could be carried out in dioxane (to allow for safer addition) in a

2-neck, round-bottom flask equipped with stir bar, condenser,

and vacuum adaptor. After pyrrolidinomethanol was prepared,

(S)-H₈BINOL and degassed dioxane were introduced at room

temperature. The reaction was allowed to proceed for 8-12 h.

The reaction was monitored by TLC and ¹H NMR.

2H), 2.33 (m, 2H), 2.21 (m, 2H), 1.97 (m, 2H), 1.72 (m, 16H). ¹³

C

NMR (75 MHz, CDCl₃) δ 152.1, 135.2, 127.4, 126.5, 123.6, 119.4,

D

75.6, 63.2, 58.7, 58.5, 54.4, 29.0, 28.4, 26.7, 23.1, 23.1, 22.7. [R]²⁵

-82.1 (c1.13, THF). Mp 68-80 °C. HRMS calcd for C₄₆H₆₈N₂O₂þ

H: 549.3698. Found for MH^þ: 549.3691. The mass spectrum gave

an additional signal at 116.1073 corresponding to the starting

(S)-2-(methoxymethyl)pyrrolidine ([MH^þ] = 116.1075).

Synthesis and Characterization of (S)-15. (1) 2-Methylpyrro-

lidine was prepared from the commercially available 2-methyl-

1-pyrroline. 2-Methyl-1-pyrroline (5 mL, 53 mmol) was added

to a mixed solvent of MeOH (120 mL) and H₂O (30 mL) in a

round-bottom flask equipped with a stir bar. NaBH₄(64 mmol,

1.2 equiv) was then added in small quantities with vigorous

stirring at room temperature. The mixture was allowed to stir at

room temperature for 15 h. TLC (eluted with 5:1 CH₂Cl₂/

MeOH) showed the complete consumption of the starting

material. The reaction mixture was cooled with an ice bath

and quenched with a slow addition of 2 M HCl until pH = 1-3.

The solution was then stirred at room temperature for 1 h and

adjusted to pH = 13 with 2 M NaOH. CH₂Cl₂(3 ꢀ 100 mL) was

used for extraction, and the combined organic layers were dried

over Na₂SO₄, filtered, and concentrated. The crude compound

was then stirred with solid KOH pellets and dried over sodium

metal under nitrogen at 40-50 °C for 12 h. The subsequent

distillation over a glass fractionating column gave 2-methyl-

pyrrolidine. (2) Under nitrogen, 2-methylpyrrolidine (4.4 mL,

43.1 mmol) was added dropwise over 20 min to a 2-necked

round-bottom for containing paraformaldehyde (43 mmol) and

equipped with a stir bar, a condenser, and a vacuum adaptor at

0 °C. The resulting reaction mixture was heated at 60 °C for 7.5 h.

Then, (S)-H₈BINOL (3 mmol) and dioxane (20 mL, degassed)

were added at room temperature. The reaction mixture was

reheated at 70 °C for 24 h. Following the workup as described

for (S)-12 (basic aqueous and aqueous extraction using ethyl

acetate followed by recrystallization from ethanol), (S)-15 was

obtained as a white solid in 57% yield from two crops. ¹H NMR

(300 MHz, CDCl₃) δ 10.98 (s, 2H), 6.70 (s, 2H), 4.33 (m, 1H),

4.12 (m, 1H), 3.45 (m, 1H), 3.21 (m, 1H), 3.06 (m, 2H), 2.75 (m,

4H), 2.49 (m, 3H), 2.25 (m, 5H), 2.01 (m, 2H), 1.61 (m, 12H),

1.42 (m, 2H), 1.16 (m, 6H). ¹³C NMR (75 MHz, CDCl₃) δ 152.5,

135.3, 127.5, 126.7, 123.9, 119.8, 60.0, 59.8, 59.6, 57.0, 57.0, 56.9,

56.9, 53.8, 53.8, 32.8, 29.2, 26.8, 23.2, 23.2, 21.6, 21.6, 18.9, 18.8,

18.8, 18.7. This compound contains a mixture of diastereomers.

1

Characterization of (S)-12. H NMR (300 MHz, CDCl₃) δ

11.91 (bs, 2H), 6.70 (s, 2H), 4.03 (d, J = 13.8 Hz, 2H), 3.76 (m,

2H), 3.62 (d, J = 13.8 Hz, 2H), 2.72 (m, 2H), 2.61 (m, 8H), 2.37

(m, 2H), 2.18 (m, 2H), 1.84 (m, 2H), 1.72 (m, 16H). ¹³C NMR

(75 MHz, CDCl₃) δ 152.8, 135.5, 127.7, 127.1, 124.1, 119.6, 67.9,

58.8, 53.3, 29.2, 26.9, 25.5, 23.6, 23.2, 23.2. [R]²⁵_D-56.4 (c 1.07,

THF). Mp 152-156 °C. Anal. Calcd for C₃₀H₄₀N₂O₂: C, 78.22;

H, 8.75; N, 6.08. Found: C, 78.20; H, 9.00; N, 6.03. HRMS calcd

for C₃₀H₄₀N₂O₂þ H: 461.3168. Found for MH^þ: 461.3177.

Synthesis and Characterization of (S)-13. (1) Thiazolidine was

prepared by stirring 2-aminoethanethiol hydrochloride (88 mmol)

with paraformaldehyde (88 mmol) in water (60 mL) for 20 h. Then,

a solution of NaHCO₃(88 mmol) in water (55 mL) was added

rapidly in one addition. KCl was added to saturate the solution

which resulted in a pinkish color. It was extracted with diethyl ether

(4 ꢀ150 mL). The organic layers were combined, dried over

magnesium sulfate, filtered, and evaporated. This gave a clear

yellow oil, which was shown to be thiazolidine of high purity by

¹H NMR spectroscopy and was used without further purification

in the next step. (2) Under nitrogen, thiazolidine (88 mmol) was

stirred with paraformaldehyde (88 mmol) and heated at 55-62 °C

for 12 h. Then, (S)-H₈BINOL (1.1 g, 4.1 mmol) and dioxane (15

mL, degassed) were added at room temperature. The reaction

mixture was reheated at 60 °C for 10 h. It was then worked up in

the same manner as for the preparation of (S)-3. The resulting oily

reside was separated twice by column chromatography on silica gel

eluted with hexane/acetone (5%) and hexanes (10-12%), respec-

tively, to give the impure crystals of (S)-13. Recrystallization from

1

acetone yielded pure (S)-13 in 50% yield. H NMR (300 MHz,

(14) Enders, D.; Fey, P.; Kipphardt, H. Org. Synth. 1987, 65, 173.

2848 J. Org. Chem. Vol. 75, No. 9, 2010

DeBerardinis et al.

JOCArticle

See the NMR spectra in Supporting Information for more

details. [R]²⁵_D-43.6 (c 0.735, THF). Mp 162-166 °C. HRMS

calcd for C₃₂H₄₄N₂O₂þ H: 489.3476. Found for MH^þ:

489.3477.

issue, caution was taken to handle the warm reaction mixture;still

nonviscous;after 8 h reaction time]. After recyrstallization from

ethanol, (S)-17 was obtained in 82% yield (1.27 g). ¹H NMR (300

MHz CDCl₃) δ 7.38 (s, 2H), 6.94 (s, 2H), 6.89 (s, 2H), 6.76 (s, 2H),

5.11 (d, J = 15.0 Hz, 2H), 5.00 (d, J = 14.7 Hz, 2H), 3.48 (s, 2H),

2.67 (m, 4H), 2.16 (m, 4H), 1.68 (m, 8H). ¹³C NMR (75 MHz

CDCl₃) δ 150.0, 137.5, 136.9, 130.1, 129.6, 128.3, 121.0, 120.7,

119.3, 45.1, 29.2, 27.1, 22.9, 22.8. [R]²⁰_D-36.4 (c 1.01, CHCl₃). Mp

248-250 °C (decomposition). HRMS calcd for C₂₈H₃₀N₄O₂þ H:

455.2447; Found for MH^þ: 455.2442.

Synthesis and Characterization of (S)-16. (1) Octahydro-1H-

indole was prepared by adapting the method reported by

Jessup.¹⁵Pd/C (10 mol % Pd) was wetted with 50% water in a

Parr reactor equipped with a stir bar. Indoline (25, 42, or 84

mmol) and ethanol (30 or 100 mL) were charged into the vessel.

The vessel was closed, and hydrogen gas was flushed through the

mixture 3 times. Finally, the vessel was loaded with H₂(∼600

psi) and placed in a 100 °C bath. After 13 h, the reactor was

cooled to room temperature, and TLC (ninhydrin stain) showed

no starting material. The mixture was filtered through a packed

Celite pad and rinsed with chloroform and ethanol. The organ-

ics were concentrated, redissolved in NaOH (50 mL), and

extracted with chloroform. After it was dried over Na₂SO₄,

the solution was filtered and concentrated. It was then vacuum

Optical Rotation Studies of (S)-17. In order to determine

whether the reaction conditions caused racemization of (S)-17,

the reaction was conducted in 2 screw cap-sealed vials. In each

sealed vial were combined imidazole methanol (3.3 g, 34 mmol, 30

equiv), (S)-H₈BINOL (0.33 g, 1.2 mmol), and 1,4-dioxane (2 mL,

degassed). Both sealed vials were heated at 135 °C. After 4 h, one of

the sealed vials was removed from the heat and (S)-17 was isolated

upon purification. The optical rotation was recorded: [R]²⁰_D-34.4

(c 1.07, CHCl₃). The second sealed vial was removed from the heat

after 8 h. Upon isolation of (S)-17 the optical rotation was found to

˚

distilled over molecular sieves (4 A) at 40-60 °C to give

octahydro-1H-indole. (2) Under nitrogen, octahydro-1H-indole

(43.5 mmol) was mixed with paraformaldehyde (43.5 mmol) in

dioxane (5 mL, degassed) and heated at 50 °C for 16 h. Then (S)-

H₈BINOL (2.4 mmol) and dioxane (5 mL, degassed) were added

at room temperature and reheated at 60-70 °C for 18 h. After

the same workup as described for (S)-12, a residual oil was

obtained, which yielded impure crystals after evaporation.

Recrystallization from ethanol (seeded with a small amount of

the impure crystal) yielded pale yellow-whitish impure crystals.

Upon column chromatography on silica gel eluted with hex-

anes/ethyl acetate (95:5 to 90:10), (S)-16 was obtained as a

diastereomeric mixture in 70% yield. ¹H NMR (300 MHz,

CDCl₃) δ 10.30 (bs, 2H), 6.73 (s, 2H), 4.27 (m, 1H), 4.13 (d,

J = 13.5 Hz, 1H), 3.45 (d, J = 13.5 Hz, 1H), 3.27 (m, 2H), 3.07

(m, 2H), 2.73 (bs, 4H), 2.59-2.67 (m, 2H), 2.35-2.51 (m, 4H),

2.12 (bs, 2H), 1.22-1.93 (m, 30H). ¹³C NMR (75 MHz, CDCl₃)

153.1, 152.9, 152.8, 135.7, 135.6, 128.1, 127.0, 126.9, 124.1,

124.0, 120.0, 63.6, 63.4, 63.3, 57.5, 51.9, 38.3, 38.2, 29.5, 28.8,

28.7, 28.5, 28.3, 27.1, 26.1, 25.3, 25.1, 24.9, 24.3, 24.0, 23.6, 23.5,

21.5, 21.3, 21.1. This compound contains a mixture of diaster-

eomers. See the NMR spectra in Supporting Information for

be undiminished: [R]²⁰-34.8 (c 1.13, CHCl₃). The high optical

D

purity of (S)-17 was supported by studying the ¹H NMR spectra of

(S)-17 and racemic 17 in the presence of 1 equiv (S)-mandelic acid

(see Supporting Information).

Synthesis and Characterization of (S)-29. (1) (S)-3,3⁰-Difor-

mylH₈BINOL (480 mg, 1.37 mmol) was dissolved in CH₂Cl₂

(30 mL) and combined with naphthalen-1-yl methylamine

(6.85 mmol, 5 equiv). The reaction mixture was stirred at room

temperature for 4 h and was then concentration under vacuum.

The residue was passed through a silica gel column eluted with

hexanes/ethyl acetate (4-20%) to give the corresponding Schiff

base (818 mg, 1.37 mmol). (2) The Schiff base was dissolved in

ethanol (absolute, 50 mL) and cooled down to 0 °C. NaBH₄

(4 equiv) was added in small portions, and the solution was

then stirred at room temperature for 2 h to complete the

reaction. The product mixture was cooled to 0 °C to which

was added ∼1.2 N HCl (20 mL) portionwise to quench the reaction.

Water (20 mL) was added, and the mixture was stirred for about 2 h

at room temperature. The solution was then basified to pH ∼8-9.

Extraction with CH₂Cl₂(3 ꢀ 50 mL) followed by evaporation gave

an oily yellow solid. Column chromatography purification of the

product on silica gel gave (S)-29 in 80% yield as whitish to slight

yellow crystals. The compound could be further purified by

recrystallization from ethanol which gave 30% recovered yield

from 2 crops. ¹H NMR (300 MHz, CDCl₃) δ 10.30 (bs, 2H), 8.02

(d, J=8.7Hz, 3H), 7.86(m, 2H), 7.78(d,J= 7.5 Hz, 3H), 7.45 (m,

10H), 6.79 (s, 2H), 4.27 (bs, 4H), 4.14 (d, J = 13.5 Hz, 1H), 4.03 (d,

J = 13.5 Hz, 1H), 2.74 (m, 6H), 2.44 (m, 4H), 2.19 (m, 4H), 1.73

(m, 12H). ¹³C NMR (75 MHz, CDCl₃) δ 152.5, 135.9, 134.4, 133.3,

131.5, 128.7, 128.4, 128.1, 127.4, 126.7, 126.4, 125.7, 125.3, 124.2,

123.1, 119.6, 52.6, 50.2, 29.3, 27.0, 23.3, 23.2. [R]²⁵_D-33.4 (c 0.52,

THF). Mp 112-116 °C. HRMS calcd for C₄₆H₆₈N₂O₂þ H:

633.3476. Found for MH^þ: 633.3471.

more details. [R]²⁵-22.4 (c 1.14, THF). Mp 122-128 °C.

D

HRMS calcd for C₃₈H₅₂N₂O₂þ H: 569.4102. Found for MH^þ:

569.4103.

Synthesis and Characterization of (S)-17. (1) Under nitrogen,

imidazole (11.33 g, 166.5 mmol) was added to an ice cold mixture

of paraformaldehyde (5 g, 166.5 mmol) and 1,4-dioxane (45 mL,

degassed) in a 2-neck round-bottom flask equipped with a stir bar,

a condenser and a vacuum adapter. The mixture was warmed to

room temperature and stirred for 2 h. It was then heated at 70 °C

for 12 h. After removal of dioxane under reduced pressure,

imidazole methanol was obtained as a moist white solid. ¹H

NMR (300 MHz CDCl₃) δ 5.41 (s, 2H), 6.93 (s, 1H), 7.08 (s,

1H), 7.32 (s, 1H), 8.94 (s, 1H). (2) Imidazole methanol (10 g, 102

mmol, 30 equiv), (S)-H₈BINOL (1.0 g, 3.4 mmol), and 1,4-dioxane

(6 mL, degassed) were combined in a screw cap-sealed vial.

[NOTE: The vial and contents were placed under nitrogen and

sealed. Electrical tape was placed around the vial to prevent

potential evaporative loss and also as a precautionary safety

measure.] The reaction mixture was heated at 135 °C for 8 h.

[NOTE: The vial was placed behind a blast shield, although no

breakage of vial occurred.] Ethyl acetate was added to dilute the

warm reaction mixture, and the organic solution was washed with a

saturated aqueous NaHCO₃solution (3 ꢀ 25 mL) and water (2 ꢀ

25 mL) [NOTE: It was found that the reaction mixture could be

difficult to handle after cooling to room temperature; to bypass this

General Procedures for the Asymmetric Arylzinc Addition to

Aldehydes Catalyzed by the H₈BINOL-AM Compounds. Prior to

use for catalysis, all the H₈BINOL-AM compounds were dis-

solved in dry THF and pumped under vacuum to dryness.

Asymmetric Reaction of Methyl 4-Iodobenzoate with Alde-

hydes. Under nitrogen to a 25 mL round-bottom flask (flame-

dried under vacuum) were added Li(acac) (24 mg, 0.22 mmol,

0.24 equiv), methyl 4-iodobenzoate (524 mg, 2.0 mmol, 2.2

equiv), and NMP (1.5 mL) sequentially. This mixture was

cooled to 0 °C, and diethylzinc (115 μL, 1.1 mmol, 1.20 equiv)

was added dropwise. The mixture was stirred at 0 °C for 18 h. A

solution of a H₈BINOL-AM (0.181 mmol, 0.2 equiv) in CH₂Cl₂

(20 mL) was added. The reaction mixture was stirred at 0 °C for

1 h. The solution was warmed to room temperature for 15 min

and then cooled back to 0 °C. An aldehyde (0.91 mmol) was

(15) Cui, Y.; Kwok, S.; Bucholtz, A.; Davis, B.; Whitney, R. A.; Jessop, P.

G. New J. Chem. 2008, 32, 1027–1037.

J. Org. Chem. Vol. 75, No. 9, 2010 2849

DeBerardinis et al.

JOCArticle

added, and the reaction was monitored by TLC. Upon comple-

tion, ammonium chloride (3 mL, saturated, aq) was added

dropwise to quench the reaction. The resulting mixture was

transferred into a separatory funnel and combined with addi-

tional ammonium chloride (30 mL, saturated, aq). Diethyl

ether was used to extract the mixture three times (3 ꢀ 60 mL).

The organic fractions were combined and washed with water

(2 ꢀ 75 mL). It was then dried over MgSO₄and concentrated.

The residue was purified by column chromatography on

silica gel eluted with hexanes (or petroleum ether)/ethyl

acetate (0-12%) to give the alcohol products as either an oil

or solid.

Asymmetric Reaction of 3-Iodoanisole with Aldehydes. Under

nitrogen to a 10 mL round-bottom flask (flame-dried under

vacuum) were added Li(acac) (24 mg, 0.22 mmol, 0.24 equiv), 3-

iodoanisole (238 μL, 2.0 mmol, 2.2 equiv), and NMP (1.5 mL)

sequentially. This mixture was cooled to 0 °C, and diethylzinc

(115 μL, 1.1 mmol, 1.20 equiv) was added dropwise. The mixture

was stirred at 0 °C for 12 h. A solution of a H₈BINOL-AM (0.091

mmol, 0.1 equiv) in THF (5 mL) was added. The resulting reaction

mixture was stirred at 0 °C for 1 h and then warmed to room

temperature. An aldehyde (0.91 mmol) was added, and the reaction

was monitored by TLC. Upon completion, ammonium chloride (3

mL, saturated, aq) was added dropwise to quench the reaction. The

resulting mixture was transferred into a separatory funnel and com-

bined with additional ammonium chloride (30 mL, saturated, aq).

Diethyl ether was used to extract the mixture three times (3 ꢀ

60 mL). The organic fractions were combined and washed with

water (2 ꢀ 75 mL). It was then dried over MgSO₄and concentrated.

The residue was purified by column chromatography on silica gel

eluted with hexanes (or petroleum ether)/ethyl acetate (0-12%) to

give the alcohol products as either an oil or solid.

Asymmetric Reaction of 3-Iodobenzonitrile with Aldehydes.

Under nitrogen to a 25 mL round-bottom flask (flame-dried under

vacuum) were added Li(acac) (37 mg, 0.35 mmol, 0.38 equiv),

3-iodobenzonitrile (663 mg, 2.89 mmol, 3.2 equiv), and NMP

(1.5 mL) sequentially. It was then cooled to 0 °C, and diethylzinc

(167 μL, 1.59 mmol, 1.75 equiv) was added dropwise. The resulting

mixture was stirred at 0 °C for 2 h. It was then warmed to room

temperature and stirred for 34 h. A solution of a H₈BINOL-AM

(178 mg, 0.362 mmol, 0.4 equiv) in THF (25 mL) was added. It was

stirred at room temperature for 2 h. An aldehyde (0.91 mmoL) was

added and the reaction was monitored by TLC. Upon completion,

ammonium chloride (3 mL, saturated, aq) was added dropwise to

quench the reaction. The resulting mixture was transferred into a

separatory funnel and combined with additional ammonium chlo-

ride (30 mL, saturated, aq). Diethyl ether was used to extract the

mixture three times (3 ꢀ 60 mL). The organic fractions were com-

bined and washed with water (2 ꢀ 75 mL). It was then dried over

MgSO₄and concentrated. The residue was purified by column

chromatography on silica gel eluted with hexanes (or petroleum

ether)/ethyl acetate (0-12%) to give the alcohol products as either

oil or solid.

Asymmetric Reaction of 2-Iodothiophene with Aldehydes.

Under nitrogen to a 10 mL round-bottom flask (flame-dried

under vacuum) were added Li(acac) (24 mg, 0.22 mmol, 0.24

equiv), 2-iodothiophene (221 μL, 2.0 mmol, 2.2 equiv), and

NMP (1.5 mL) sequentially. Diethylzinc (115 μL, 1.1 mmol, 1.20

equiv) was added dropwise and was stirred at room temperature

for 6-12 h. A H₈BINOL-AM (0.091 mmol, 0.1 equiv) and THF

(5 mL) were added. After the reaction mixture was stirred for 1

h, an aldehyde (0.91 mmol) was added, and the reaction was

monitored by TLC. Upon completion, ammonium chloride

(3 mL, saturated, aq) was added dropwise to quench the

reaction. The resulting mixture was transferred into a separa-

tory funnel and combined with additional ammonium chloride

(30 mL, saturated, aq). Diethyl ether was used to extract the

mixture three times (3 ꢀ 60 mL). The organic fractions were

combined and washed with water (2 ꢀ 75 mL). The organic

fraction was dried over MgSO₄and concentrated. The residue

was purified by column chromatography on silica gel eluted with

hexanes (or petroleum ether)/ethyl acetate (1-8%) to give the

alcohol products as either oil or solid.

Asymmetric Reaction of Iodobenzene with p-Anisaldehyde.

Under nitrogen to a 10 mL round-bottom flask (flame-dried

under vacuum) were added Li(acac) (24 mg, 0.22 mmol, 0.24

equiv), iodobenzene (224 μL, 2.0 mmol, 2.2 equiv), and NMP

(1.5 mL) sequentially. Diethylzinc (115 μL, 1.1 mmol, 1.20

equiv) was added dropwise, and the mixture was stirred at room

temperature for 3 h. A H₈BINOL-AM (0.091 mmol, 0.1 equiv)

and THF (5 mL) were added, and it was then stirred for 1 h.

p-Anisaldehyde (0.91 mmol) was added, and the reaction was

monitored by TLC. Upon completion, ammonium chloride

(3 mL, saturated, aq) was added dropwise to quench the

reaction. The resulting mixture was transferred into a separa-

tory funnel and combined with additional ammonium chloride

(30 mL, saturated, aq). Diethyl ether was used to extract the

mixture three times (3 ꢀ 60 mL). The organic fractions were

combined and washed with water (2 ꢀ 75 mL). It was then dried

over MgSO₄and concentrated. The residue was purified by

column chromatography on silica gel eluted with hexanes (or

petroleum ether)/ethyl acetate (1-8%) to give the alcohol

product as either oil or solid.

Asymmetric Reaction of 2-Bromothiophene with Benzalde-

hyde. Under nitrogen to a 10 mL round-bottom flask (flame-

dried under vacuum) were added Li(acac) (24 mg, 0.22 mmol,

0.24 equiv), 2-bromothiopene (238 μL, 2 mmol, 2.2 equiv), and

NMP (1.5 mL) sequentially. Diethylzinc (115 μL, 1.1 mmol, 1.20

equiv) was added dropwise, and the mixture was stirred at room

temperature for 6-12 h. A solution of (S)-12 (45 mg, 0.091

mmol, 0.1 equiv) in THF (5 mL) was added, and the resulting

mixture was stirred for 1 h. Benzaldehyde (0.91 mmoL) was

added, and the reaction was monitored by TLC. Upon comple-

tion, ammonium chloride (3 mL, saturated, aq) was added

dropwise to quench the reaction. The resulting mixture was

transferred into a separatory funnel and combined with addi-

tional ammonium chloride (30 mL, saturated, aq). Diethyl ether

was used to extract the mixture three times (3 ꢀ 60 mL). The

organic fractions were combined and washed with water (2 ꢀ

75 mL). It was then dried over MgSO₄and concentrated. The

residue was purified by column chromatography on silica gel

eluted with hexanes (or petroleum ether)/ethyl acetate (1-8%)

to give the alcohol products as either oil or solid.

Acknowledgment. Partial support of this work from the

U.S. National Science Foundation (CHE-0717995 and

ECCS-0708923) and the donors of the Petroleum Research

Fund administered by the American Chemical Society is

gratefully acknowledged.

Supporting Information Available: Synthesis, characteriza-

tion, and ee determination of the chiral alcohol products,

¹H/¹³C NMR spectra of the ligands, preparation of (S)-28, the

ee correlation experiment, the absolute configuration assign-

ment for compound 24, and details of the NMR spectroscopic

studies. This material is available free of charge via the Internet

at http://pubs.acs.org.

2850 J. Org. Chem. Vol. 75, No. 9, 2010

Article Doi

Facile synthesis of a family of H8BINOL-amine compounds and catalytic asymmetric arylzinc addition to aldehydes

DOI: 10.1021/jo1000516

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Article abstract of DOI:10.1021/jo1000516

Full text of DOI:10.1021/jo1000516

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