Enantiopure cis- and trans-2-(2-Aminocyclohexyl)phenols: Effective Preparation, Solid-State Characterization, and Application in Asymmetric Organocatalysis

A Journal of

Accepted Article

Title: Enantiopure cis- and trans-2-(2-Aminocyclohexyl)phenols:

Effective Preparation, Solid-State Characterization, and

Application in Asymmetric Organocatalysis

Authors: Mustafa A. Tezeren, Tolga A. Yeşil, Yunus Zorlu, Tahir Tilki,

and Erkan Ertürk

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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801445

Link to VoR: http://dx.doi.org/10.1002/ejoc.201801445

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Enantiopure cis- and trans-2-(2-Aminocyclohexyl)phenols:

Effective Preparation, Solid-State Characterization, and

Application in Asymmetric Organocatalysis

Mustafa A. Tezeren,^[a,b]Tolga A. Yeşil,^[a,b]Yunus Zorlu,^[c,d]Tahir Tilki,^[b]and Erkan Ertürk*^[a]

Abstract:

Effective

synthesis

of

cis-

and

trans-2-(2-

primary amines having an additional Lewis- or Brønsted-acidic

moiety.^[3]Recent studies demonstrated that chiral bifunctional

primary amines can be more efficient and selective in

aminocatalysis, e.g. in enantioselective functionalization of

carbonyl compounds, compared to their secondary amine

counterparts.^[3,4]

methoxyphenyl)cyclohexylamine as well as their multigram-scale

optical resolution by diastereomeric salt formation with dibenzoyl

tartaric acid have been described. Assignment of absolute

configurations to the enantiomers has been made by X-ray

crystallography. Starting from the resolved precursor, diverse

aminoalkylphenols (AAPs) having primary, secondary, and tertiary

amine group as well as a quaternary ammonium phenol have been

prepared as potential bifunctional organocatalysts based on the

cyclohexane backbone. We furthermore report herein that AAPs

carrying a primary amine and a phenolic hydroxyl group can catalyze

the direct aldol reaction with high activity and setereoselectivity, and

thus up to 97% yield, 90:10 syn/anti diastereomeric ratio, and 80%

enantiomeric excess can be achieved.

Despite impressive progress in asymmetric organocatalysis,

bifunctional organocatalysts that bear an amine and phenolic

hydroxyl group (amine-phenol organocatalyst) remain relatively

unexplored. The well-known examples of this class are the

demethylated derivatives of cinchona alkaloids that have been

reported to effect some reactions with high degree of activity and

enantioselectivity, such as [4+2] cycloaddition reactions,^[5a]the

Morita-Baylis-Hillman reactions,^[5b]the aza Morita-Baylis-Hillman

reactions,^[5c–e]conjugate additions to α,β-unsaturated systems,^[5f–

o]

enantioselective addition to the activated carbonyl

compounds,^[5p–r]enantioselective transamination,^[5s]and some

other asymmetric transformations as well.^[5t–v]The Betti base^[6]

and its derivatives^[7]are the further prominent representatives of

the chiral aminoalkylphenols (AAPs) which served as chiral

ligands in the enantioselective addition reactions of

diethylzinc^[6a,7a]as well as as hydrogen-bond donor

organocatalysts for the hetero Diels-Alder reaction^[7b]of ethyl

glyoxylate with Danishefsky’s diene and the asymmetric acyl-

Strecker reaction.^[7c]In addition, Maruoka and co-workers recently

developed a binaphthyl-based axially chiral secondary amine-

phenol bifunctional organocatalyst for the highly anti-diastero-

and enantioselective Mannich reaction.^[8]A remarkable 7:1

anti/syn diastereomeric ratio and a 98% enantiomeric excess (ee)

were achieved in their striking work. Nevertheless, AAPs have not

been examined extensively so far though they seem to be

promising structural motif for asymmetric (organo)catalysis.

Because of these intriguing facts on AAPs, we were involved in

effective synthesis of the enantiopure 1,4-AAPs based on the

cyclohexane backbone (1 and 2) as well as in their use as

organocatalyst (Figure 1). Additionally, closer inspection of the

Introduction

Over the past two decades, organocatalysis, the use of small

organic molecules as catalysts, has had a tremendous impact in

chemical synthesis. Usually, organocatalysts offer practically

favorable advantages over metal-based ones, such as being non-

toxic, air- and water-tolerant, inexpensive as well as easy to

synthesize and handle. Furthermore, they have also proven to be

complementary to metal-based catalysts, by enabling the

synthesis of important target structures via unique activation

modes, which is not possible using metal catalysts.^[1]In particular,

the development of novel chiral bifunctional motifs that bear Lewis

and/or Brønsted basic and acidic functional groups for a

simultaneous activation of both nucleophilic and electrophilic

substrates (e.g. combination of a tertiary amine group with a

thiourea moiety in a catalyst for the non-covalent organocatalysis)

has been one of the major endeavors in the field.^[2]Another

remarkable facet of the field is aminocatalysis that employs chiral

[a]

Institute of Chemical Technology, TÜBITAK Marmara Research

Center, 41470 Gebze, Kocaeli, Turkey

E-mail: erkan.erturk@tubitak.gov.tr

[b]

[c]

[d]

Department of Chemistry, Süleyman Demirel University, 32260

Isparta, Turkey

Department of Chemistry, Gebze Technical University, 41400

Gebze, Kocaeli, Turkey

Institute of Nanotechnology, Gebze Technical University, 41400

Gebze, Kocaeli, Turkey

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

the document.

Figure 1. Structure of chiral 1,4-aminoalkylphenols (1,4-AAPs).

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structure of 1,4-AAPs revealed that the distances between the

hydrogen bond-donating phenolic H atom and the hydrogen

bond-accepting N atom are larger than those of 1,2- and 1,3-

AAPs, which was expected to provide an ideal spatial pocket for

simultaneous activation of the both (electrophilic and nucleophilic)

substrates. On the other hand, 1,4-AAPs rather tend to form

intermolecular hydrogen bonding between OH and NH₂

functionalities whereas 1,2- and 1,3-AAPs are generally prone to

form stronger intramolecular hydrogen bonding; this can result in

a higher activity of 1,4-AAPs as organocatalyst.

Results and Discussion

Scheme 2. Preparation of racemic trans-2-(2-methoxyphenyl)cyclohexylamine

(rac-12). Ar = ortho-methoxyphenyl. Reagents and conditions: (a) (1) Mg, THF

(2) Cyclohexanone (1.00 equiv), THF, 0 °C → rt, 3 h; (b) AcOH/H₂SO₄(5:1),

0 °C → rt, 3 h; (c) NaBH₄(0.40 equiv), BF₃·OEt₂(0.55 equiv), Diglyme, 0 °C →

rt, 3 h; (d) H₂NOSO₃H (1.10 equiv), 100 °C, 3 h.

The racemic synthesis of the cis-AAP 1 started with the ring-

opening of cyclohexene oxide (3) with ortho-lithioanisole (4) in the

presence of BF₃·OEt₂, as described in our previous report

(Scheme 1).^[9]The ring-opened product rac-5 could be easily

prepared in almost quantitative yield (99%). The Mitsunobu

reaction of the trans-alcohol rac-5 with diphenylphosphoryl azide

cascade” that was originally developed by H. C. Brown and co-

workers enabled us to synthesize the racemic trans-amine 12 in

30% yield.^[11]Thus, we accomplished the synthesis of racemic cis-

and trans-2-(2-methoxyphenyl)cyclohexylamines, rac-7 and rac-

12, respectively. It should be mentioned that similar synthetic

pathways to racemic cis- and trans-2-phenylcyclohexanamines

were reported by Gotor and co-workers who then subjected those

compounds to the enzymatic kinetic resolution by using Candida

antarctica lipase A (CAL-A) and CAL-B in the presence of some

esters as the acylating agents, thereby providing moderate

selectivity for cis-2-phenylcyclohexanamines with CAL-A (E = 34)

as well as high selectivity for trans-2-phenylcyclohexanamines (E

> 200) with CAL-B.^[12]It was also reported that enantiopure

primary amines could be obtained via the asymmetric

hydroboration of alkenes with monoisopinocamphenylborane

(IpcBH₂) and the subsequent amination with hydroxylamine-O-

sulfonic acid.^[13]However, a brief literature survey indicated that

this chiral auxiliary technique was inadequate for providing

enantiopure 2-aryl-cyclohexanamines.^[13]

((PhO)₂P(O)N₃)

gave

racemic

cis-2-(2-methoxyphenyl)-

cyclohexyl azide (rac-6) in good yield (65%). Upon treatment with

lithium aluminum hydride in diethyl ether, the azide rac-6 could be

converted into the cis-amine rac-7 with a yield of 97%. Thus, the

protected form of the racemic AAP 1 could be prepared in an

effective manner. It should be noted that a similar synthetic route

to rac-7 has already been reported in the literature.^[10]

Over recent decades, a dramatic increase in the development

of catalytic enantioselective methods has been observed, which

allow access to chiral compounds in their enantiopure forms in an

efficient and step-economic manner. Nevertheless, resolution by

diastereomeric salt formation is still one of the most favorable

technique for this purpose.^[14]There have been also many cases

in which this classical technique of resolution has proven to be

particularly effective for preparing enantiopure chiral compounds

on a large scale.^[15]Accordingly, we started looking for a suitable

acidic resolving agent, for the resolution of the racemic cis-amine

rac-7. L-Tartaric acid (L-TA), (R)-(+)-mandelic acid, (1S)-(+)-10-

camphorsulfonic acid, and dibenzoyl-L-tartaric acid (L-DBTA)

were the resolving agents of choice. In the first setting, equimolar

amounts of rac-7 and all 4 selected resolving agent candidates

were mixed in 50% aqueous ethanol in consecutive experiments,

hoping for the formation of a crystalline salt. All of these attempts

by using 50% aqueous EtOH as the solvent failed.^[16]After

extensive examination of the above-mentioned chiral acids with

unary as well as binary solvent systems, an effective resolution of

Scheme 1. Preparation of racemic cis-2-(2-methoxyphenyl)cyclohexylamine

(rac-7). Reagents and conditions: (a) 4 (3.00 equiv), BF₃·OEt₂(2.50 equiv), THF,

−78 °C, 1 h; (b) (PhO)₂P(O)N₃(1.50 equiv), DEAD (1.30 equiv), PPh₃(1.50

equiv), THF −20 °C → rt, 16 h; (c) LiAlH₄(3.00 equiv), Et₂O, 0 °C → rt, 16 h.

For the racemic synthesis of the trans-AAP 2, 1-(2-

methoxyphenyl)cyclohexene (10) was choosen to be as the

intermediate, which could be prepared through the Grignard

reaction between ortho-methoxyphenyl magnesium bromide and

cylohexanone and the subsequent acid-catalyzed dehydration

(Scheme 2). The olefin compound 10 was then subjected to

hydroboration —which led to formation of the dialkylborane rac-

11— and the subsequent amination with hydroxylamine-O-

sulfonic acid. This simple procedure “hydroboration-amination

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Scheme 3. Resolution of racemic cis-2-(2-methoxyphenyl)cyclohexylamine (rac-7). Ar = ortho-methoxyphenyl. Reagents and conditions: (a) NaOH_(aq)(4 N), DCM;

(b) PhCOCl (2.00 equiv), NaOH_(aq)(4 N), DCM, 15 min.

rac-7 could eventually be achieved with L-DBTA as the resolving

agent and 2-propanol–water mixture as the binary solvent system

(Scheme 3). Addition of rac-7 solution in 2-propanol into the

suspension of L-DBTA in water instantaneously delivered the

ammonium tartarate salt 13 as white crystals in 45% yield (with

respect to total amount of rac-7) and 95% diastereomeric excess.

Note that, 7 was converted into its benzamide derivatives 17 and

ent-17 (at the bottom of Scheme 3) so that the diastereomeric

excess of 13 (as well as 14 and 15), or rather the enantiomeric

excess of 7 could be determined by HPLC on a chiral column. A

further recrystallization of 13 (95% de) from the 2-propanol–water

DBTA salt (15) from the 2-propanol–water mixture (ⁱPrOH–H₂O,

approx. 50:50, v/v) as described above afforded 15 in

diastereomerically pure form (>99% de) and high overall yield

(40%

y with respect to starting amount of rac-7). The

enantiomerically pure amine ent-7 was liberated from the D-DBTA

salt 15 by addition of 4.0 N NaOH and a subsequent extraction

with DCM, in quantitative yield as a colorless oil.

As a consequence of the remarkable success in the optical

resolution of rac-7 by employing dibenzoyl tartaric acid, we

immediately turned our attention to resolution of the racemic

trans-amine (rac-12) by using the same resolving agents

(Scheme 4). However, it was relatively complicated: Mixing rac-

12 with L-DBTA in 2-propanol–water mixture simply did not form

any crystalline salt. Therefore, we first prepared a diastereomeric

mixture of 18 and 19, by treatment of rac-12 with L-DBTA in

EtOAc and subsequent removal of EtOAc. Then, we sought after

a suitable recrystallization solvet or solvent mixture for separation

of the diastereomers 18 and 19 from each other. Pleasingly, we

found out that a methanol-acetone mixture is an excellent binary

solvent system for this purpose: After a single recrystallization

from methanol–acetone (ca. 1:2, v/v), 18 was obtained as a white

crystalline product in 36% yield and >99% de. The diastereomeric

mixture

(ⁱPrOH–H₂O,

approx.

50:50,

v/v)

afforded

diastereomerically pure 13 in 40% overall yield, based on the

amount of the starting rac-7. Treatment of 13 (>99% de) with

aqueous NaOH (4.0 N) followed by extraction with DCM furnished

the chiral amine 7 in enantiomerically pure form (>99% ee), in

quantitative yield. The combined filtrates that predominantly

contained 14 were evaporated under reduced pressure, treated

with 4.0 N NaOH, and exracted with DCM, thus liberating

enantiomerically enriched ent-7 (60% ee) from L-DBTA. Then,

treatment of ent-7 (60% ee) with equimolar amount of dibenzoyl-

D-tartaric acid (D-DBTA) and recrystallization of the resulting D-

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Scheme 4. Resolution of racemic trans-2-(2-methoxyphenyl)cyclohexylamine (rac-12). Ar = ortho-methoxyphenyl. Reagents and conditions: (a) NaOH_(aq)(4 N),

DCM ; (b) PhCOCl (2.00 equiv), NaOH_(aq)(4 N), DCM, 15 min.

excess of 18 as well as enantiopurity of 12 and ent-12 in turn were

determined by their derivatization to the benzamide 22 and ent-

22, and the subsequent chiral HPLC analysis thereof (on the

bottom of Scheme 4). The enantiopure amine 12 was isolated in

quantitative yield by treatment of 18 with 4.0 aqueous NaOH and

extraction with DCM consecutively. The filtrate was evaporated

under reduced pressure, treated with 4.0 N aqueous NaOH

solution, and extracted with DCM, thus obtaining enantiomerically

enriched ent-12 in 60% ee. Then, ent-12 (60% ee) was treated

with an equimolar amount of dibenzoyl-D-tartaric acid (D-DBTA)

in EtOAc, which was followed by removal of the solvent by rotary

evaporation under reduced pressure. The residue containing

predominantly the diastereomer 20 was recrystallized from

methanol/acetone (ca. 1:2, v/v), which delivered the

diastereomerically pure 20 in 41% yield, with respect to starting

rac-12. Treatment of 20 with 4.0 N aqueous NaOH and

subsequent extraction with DCM as usual produced the

enantiopure amine ent-12 as a colorless oil in quantitative yield.

After the preparation of the enantiopure cis- and trans-2-(2-

methoxyphenyl)cyclohexylamines, we turned our attention to

modify the substituents attached to the amino group in order to

add some diversity to our work. Starting from 7, secondary and

tertiary amines 24 and 25 could be easily accessed in good yields

Scheme 5. Synthesis of the di- and trisubstituted cyclohexylamines 24 and 25.

Ar = ortho-methoxyphenyl. Reagents and conditions: (a) PhCHO (1.00 equiv),

MgSO₄, DCM, rt, 16 h; (b) NaBH₃CN (2.00 equiv), AcOH (4.00 equiv), MeCN,

0 °C → rt, 16 h; (c) HCHO_(aq)(5.00 equiv), NaBH₃CN (2.00 equiv), AcOH (5.00

equiv), MeCN, 0 °C → rt, 16 h.

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by exploiting the conventional organic transformations, as

illustrated in Scheme 5.

found to work sufficiently well, delivering the corresponding

phenols in high yields. Thus, the effective preparation of both

enantiomers of cis- and trans-2-(2'-aminocyclohexyl)phenols (1,

ent-1, 2, ent-2) as well as the secondary- and tertiary-

aminoalkylphenols 26 and 27 was established. Additionally, the

quaternarization of AAP 27 was successfully achieved by

refluxing it with benzyl bromide in acetonitrile, providing the

quaternary ammonium salt 28 possessing a phenolic hydroxyl

group.

At this stage, a suitable procedure for the demethylation of the

chiral anisoles 7, ent-7, 12, ent-12, as well as 24 and 25 was

needed in order to synthesize the corresponding AAPs as

potential organocatalysts (Sheme 6). Ethanethiol–sodium tert-

butoxide couple in DMF did not appear to be suitable for the

demethylation of these substrates; instead, it formed unidentified

side products. To our delight, boron tribromide (BBr₃) in DCM was

Scheme 6. Enantiopure AAPs. Reagents and conditions: (a) BBr₃(3.00 equiv), DCM, 0 °C → rt, 6 h; (b) BnBr (1.10 equiv), MeCN, reflux, 24 h.

Single crystals of cis-AAP 1 and the trans-AAP 2 suitable for X-

ray crystallography could also be obtained in our studies. So, we

were able to determine the absolute configurations of the AAPs 1

and 2. The X-ray crystal structures of the both isomers (1 and 2)

with the atom numbering schemes are shown in Figure 2. Suitable

crystals of 1 for single-crystal X-ray analysis were grown from

methanol whereas single crystals of 2 for single-crystal X-ray

analysis were obtained from benzene at room temperature. The

AAP 1 (Fig. 2A) crystallizes in the hexagonal P6₁space group

whereas the trans AAP 2 (Fig. 2B) crystallizes in the monoclinic

P2₁space group. These are the first crystal structures according

network along the c-axis (Fig. 2D). In contrast, trans-isomer (2)

exhibit highly dense-packed nonporous structure (Fig. 2E).

Recently, we prepared a number of enantiopure chiral

alcohols of type 29 in order to develop 2-(2-hydroxyaryl)alcohols

(HAROLs) as chiral ligands and hydrogen-bond donor

organocatalysts (Scheme 7).^[17]We reasoned that 29 might be a

useful starting material for the synthesis of linear types of 1,4-

AAPs that are based on cyclohexane backbone (1, ent-1, 2, ent-

2). The classical Mitsunobu reaction of the alcohol 29 by

employing phthalimide delivered 30 in 75% yield. Enantiopurity of

the stereo-inversed phthalimide 30 was checked by HPLC on a

to the results of the Cambridge Structural Database (CSD) survey. chiral column and determined to be >99%. Subsequent

The hydrogen atoms in the cis-AAP 1 and the trans-AAP 2 occupy

the cis- and trans-positions relative to the C(1)–C(6) bond,

respectively (Fig. 2). To highlight similarities and contrasts

between the cis-AAP 1 and the trans-AAP 2 some equivalent

bond lengths and angles are tabulated in Table S2. The bond

distances and angles are in good aggreement, but the overall

conformations around the C(6)-C(7) bond are quite different (Fig.

2C), i.e. the torsion angles of C(1)–C(6)–C(7)–C(8) in cis-AAP 1

and trans-AAP 2 are −73.8(9)° and −142.9(3)°, respectively. It is

worth mentioning that self-assembly of cis-isomer (1) results in

the formation of honeycomb-like hexagonal porous molecular

aminolysis of 30 with hydrazine hydrate provided the amine 31.

However, demethylation of 31 proved to be somewhat

complicated: In contrast to the counterparts 7 and 12 that are

based on cyclohexane backbone, demethylation of 31 by

employing BBr₃unexpectedly did not deliver the desired AAP (33).

Formation of various by-products was observed. On the other

hand, the ethanethiol–sodium tert-butoxide couple in DMF yielded

the formamide derivative 32 (78%), which could be formed via a

base-catalyzed formylation of the intermediate 33 with DMF.^[18]

Saponification of the formamide 32 gave the linear AAP 33 with a

yield of 90%. The demethylation of 31 with NaSEt was also tried

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Figure 2. X-ray crystal structures of (A) the AAP 1 (cis) and (B) the AAP 2 (trans). Displacement ellipsoids are drawn at the 50% probability level. (C) Superimposed

crystal structures of 1 (light blue) and 2 (green). (D) Schematic representation of honeycomb-like porous molecular structures of 1. (E) Schematic representation

for higly-dense crystal packing of 2.

in hexamethylphosphoramide (HMPA) and N-methyl-2-

pyrrolidone (NMP) as the solvents, in order to obtain 33 directly.

However, the former gave rise to the formation the AAP 33 in 28%

yield whereas the latter provided only traces of 33. Note that the

AAP 33 is not stable enough for chromatographic separation on

silica gel; it rapidly undergoes decomposition on it. But, its reason

as well as mechanism was not further investigated.

Next, our novel enantiopure AAPs were employed in the

asymmetric enamine catalysis to examine their organocatalytic

performances (Table 1). Because a number of chiral primary

amines exhibited high activity and stereoselectivity in enamine

catalysis in previous studies,^[4f,g,j–l]the aldol reaction between

cyclohexanone (34) and 4-nitrobenzaldehyde (35a) served as the

test reaction. Almost all the reaction factors were tested carefully

in order to identify the best reaction conditions in terms of reaction

yield and stereoselectivity.^[19]In addition to AAPs 1, 2, and 33,

their O-protected forms 7, 12, and 31 were also employed as the

potential catalysts. In the absence of any additives, all the cis- and

trans-cylohexanamine compounds performed the aldol

condensation with

a similar activity and stereoselectivity,

producing the diasteromers 36a and 37a with yields in the range

of 24–32% (in favor of the syn-diastereomer 36a) and up to 60%

ee (Table 1, entries 1–4). Among the acidic additives examined,

benzoic acid was the best in terms of the stereoselectivity and it

dramatically enhanced the reaction yields (up to 97% y), albeit the

diastero- and enantioselectivities could only be increased fairly

under neat conditions (entries 5–8). Comparison of the

enantioselectivities observed with the cis-AAP 1 and 7 as the

catalyst underpins the bifunctional behavior of the AAP 1 (entries

5 and 6). Based on the first screening, the cis-AAP 1 was

determined to effect the reaction with the highest level of

stereoselectivities (see, Supporting Informations). Additionally, a

high solvent effect on the stereochemical outcome of the reaction

was observed so that toluene and THF achieved the most

remarkable values (entries 9 and 10). THF provided the highest

diastereomeric ratio in favor of the syn-diastereomer (36a/37a =

91:9), but led to modest yield and enantioselectivities (46% ee for

36a and 48% ee for 37a, entry 10). It is noteworthy that there have

been only a few catalytic systems that effect aldol reaction with

syn-selectivity.^[20]On the other hand, toluene resulted in a

significant enhancement in both diastereo- and enantioselectivity

(86% y; 36a/37a =70:30; 64% ee for 36a and 78% ee for 37a;

entry 9). When the reaction temperature was decreased from

t

Scheme 7. Synthesis of the enantiopure linear AAP 33. R¹= Bu, NPhth =

Phthalimido. Reagents and conditions: (a) Ph₃P (4.00 equiv), HNPhth (3.00

equiv), DIAD (4.00 equiv), THF, 0 °C, 12 h; (b) H₂NNH₂·H₂O (10.00 equiv), EtOH,

reflux, 6h; (c) EtSH (8.00 equiv), NaO^tBu (3.00 equiv), DMF, 120 °C, 2 h; (d)

NaOH, MeOH, reflux, 2 h.

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Table 1. Enantioselective aldol condensation between cyclohexanone (34) and 4-nitrobenzaldehyde (35a) catalyzed by chiral AAPs.^[a]

T

(°C)

Time

(h)

Yield^[b]

(%)

36a : 37a

(syn/anti)^[c]

ee^[d]for 36a

ee^[d]for 37a

Entry

1

Catalyst

Additive

Solvent

(%)

7

1

—

rt

ʺ

48

ʺ

29

27

24

32

94

84

97

86

24

87

0

63:37

60:40

59:41

53:47

63:37

60:40

61:39

62:38

70:30

91:9

16

19

28

20

44

54

8

46

44

58

60

44

54

24

6

2

—

3

12

2

—

ʺ

4

—

ʺ

5

7

Benzoic acid

—

ʺ

6

1

ʺ

—

ʺ

7

12

2

—

ʺ

8

—

ʺ

6

9

1

Toluene

ʺ

36

ʺ

64

46

70

8

78

48

80

8

10

11

12

13

1

THF

ʺ

1

Toluene

0

rt

ʺ

73:27

58:42

–

31

33

ʺ

24

ʺ

–

[a] Reactions were performed with 4-nitrobenzaldehyde (0.25 mmol) and cyclohexanone (2.0 mmol) in the solvent (0.5 mL). [b] Combined yield of the isolated

isomers 36a and 37a. [c] Diastereomeric ratio (36a/37a) was determined by HPLC analysis. [d] Enantiomeric excesses (ee) were determined by HPLC analysis

on a chiral phase: Chiralpak AD-H; n-hexane/ⁱPrOH (85:15), 1 mL/min; 254 nm (UV–vis); t_R= 15.1 min (ent-36a), t_R= 16.9 min (36a), t_R= 18.6 min (37a), t_R

24.6 min (ent-37a).

=

room temperature to

0

°C, higher diastereo- and

Catalytic activity of the AAP 1 and its O-protected form 7 were

enantioselectivities were achieved (36a/37a = 73:27, 70% and

80% ee, respectively; entry 11). It was interesting to see that the

linear AAP 33 did not show catalytic activity (entry 13), while its

O-protected form 31 could catalyze the reaction with high yield

and low stereoselectivities (entry 12). The inactivity of the linear

AAP 33 might be attributed to the potential but very strong

intramolecular hydrogen bonding between the amine N and the

phenolic H atoms, which could not be true regarding the

cyclohexane-based AAPs 1 and 2. This entirely different behavior

of 1 and 33 in catalytic activity is reminiscent of the importance of

the cyclohexane framework in bifunctional organocatalysts. Note

that there have been numerous cases in the literature, where

bifunctional organocatalysts incorporating cyclohexane backbone

have exhibited higher catalytic activities and selectivities, which is

mainly due to their diminished ability to build aggregates via

intermolecular hydrogen bonding than their linear analogues.^[21]

also explored for the aldol reaction between acetone (38) and 4-

nitrobenzaldehyde (35a) (Table 2). All individual factors were

basically screened. Remarkably, it was observed that 2,4,6-

triisopropylbenzoic acid (TRIBA) that is sterically more

demanding than benzoic acid affected the stereochemical

outcome of the reaction, compared to benzoic acid (entries 3 and

4). To the best of our knowledge, this is the first report showing

the advantageous effect of TRIBA. More remarkably, the O-

protected AAP 7 exhibited a slightly higher catalytic activity and

enantioselectivity than AAP 1 (entries 4 and 5). The best result in

terms of enantiomeric excess was obtained in the presence of 7

as the catalyst and TRIBA as the additive at 0 °C (up to 62% ee).

Extending the reaction time enabled the formation of the aldol

product 39 in high yield (85% y after 192 h, entry 6). It should be

noted that TRIBA was also employed in the aldol reaction of

cyclohexanone with 4-nitrobenzaldehyde. However, it did not

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respectively. Diastereomeric ratio (36b/37b = 67:33) and ee

values for 36b (74% ee) and 37b (84% ee) were determined to

be comparable with those of 36a and 37a whereas these values

for 36c and 37c were lower (36c/37c = 57:43, 52% ee and 60%

ee respectively). This indicates that the AAP 1 catalyzed aldol

reactions of cyclohexanone with benzaldehyde and p-

nitrobenzaldehyde proceed via similar pathways. Finally, some

plausible transition states that are dictated by the stereochemical

outcome of the reactions can be proposed (Figure 2):

Benzaldehyde (35b) can form a hydrogen bond with phenolic

hydroxyl group; additionally, a  interaction between the

aromatic rings of 1 and the aldehyde can take place (TS-I). On

the other hand, the contribution of benzoic acid must be also

taken into account because higher syn/anti ratio as well as higher

enantiomeric excesses were observed in the presence of benzoic

acid, which suggests that benzoic acid not only accelerates the

formation of the enamine, but also participates in the stereo-

determinig step. Accordingly, in TS-II benzoic acid is estimated to

be able to build a supramolecular catalyst through multiple

hydrogen bondings. Furthermore, the lower syn/anti ratio and

enantiomeric excesses obtained in the aldol reaction of p-

anisaldehyde (35c) might be attributed to lower (or no)

contribution of  interaction between the aromatic rings of the

catalyst 1 and p-anisaldehyde. This might be due to the similar

electron distributions of aromatic rings of the phenol moiety and

p-anisaldehyde.

Table 2. Enantioselective aldol condensation catalyzed by the chiral primary

amines 1 and 7.^[a]

Yield^[b]

(%)

ee^[c]

(%)

Entry

Catalyst

1

Reaction conditions

TRIBA (10 mol%), solvent-free,

rt, 66 h

TRIBA (10 mol%), Toluene

(0.25 mL), rt, 66 h

TRIBA (20 mol%), Toluene (0.1

mL), 0 °C, 60 h

BA (20 mol%), Toluene (0.1

mL), 0 °C, 92 h

BA (20 mol%), Toluene (0.1

mL), 0 °C, 90 h

TRIBA (20 mol%), Toluene (0.1

mL), 0 °C, 192 h

1

42

21

19

23

85

40

42

55

52

58

62

2

3

4

5

6

1

7

[a] 0.25 mmol (1.00 equiv) 35a and 2.0 mmol (8.00 equiv) 38 were

employed. [b] Isolated yield of the NMR-pure product. [c] Enantiomeric

excesses (ee) were determined by HPLC analysis on a chiral phase:

Chiralpak AS-H; n-hexane/ⁱPrOH (85:15), 1 mL/min; 254 nm (UV–vis); t_R

25.1 min (ent-39), t_R= 32.4 min (39).

=

bring about any improvement in the stereoselectivity (Supp Info.,

Table S3, entries 59 and 60).

Last, cyclohexanone (34) was reacted with benzaldehyde

(35b) and p-anisaldehyde (35c), in the presence of 1 and benzoic

acid (Scheme 8). As expected, the aldol products 36b/37b and

36c/37c were obtained in lower yields, 40% and 18% yields

Figure 2. Plausible transition states for the syn-selective aldol reaction

catalyzed by the AAP 1.

Conclusions

In summary, we have achieved effective racemic synthesis of

both cis- and trans-2-(2-methoxyphenyl)cyclohexylamine as well

as their multigram-scale resolution via diastereomeric salt

formation, thus delivering the enantiomerically pure precursors for

aminoalkylphenols (AAPs) based on cyclohexane framework.

Diverse AAPs bearing primary, secondary, and tertiary amine

group, as well as a quaternary ammonium phenol have been

prepared, in their enantiopure form in an effective manner. In

addition, primary AAPs were evaluated as organocatalysts in the

direct aldol reaction, thereby exhibiting good catalytic activity and

providing syn-aldol product predominantly with good

enantioselectivity. As far as we know, this is one of the rare

examples of catalytic systems that provide syn-aldol product

selectively.^[20]2-Aryl-substituted cyclic amines are also of great

importance due to their diverse pharmacological properties.^[12,22]

Scheme 8. AAP 1 catalyzed aldol reaction of cyclohexanone (34) with

benzaldehyde (35b) and p-anisaldehyde (35c). 8.00 equiv of cyclohexanone

were used in the absence of any solvents.

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BF₃·OEt₂(10.80 g, 9.30 mL, 75.0 mmol, 2.50 equiv) were added

sequentially. The reaction mixture was stirred at −78 °C for 1 h and

quenched with saturated NaHCO₃solution (180 mL). THF was removed

by rotary evaporation under reduced pressure and the aqueous residue

was extracted with Et₂O (3 × 150 mL). The combined organic extracts were

dried over Na₂SO₄, filtered, and concentrated by rotary evaporation in

vacuo. The residue was then purified by silica gel column chromatography

eluting with hexanes/EtOAc (9:1) to afford rac-5 (6.12 g, 29.7 mmol, 99%)

Therefore, we believe that the methdology disclosed herein can

also become a general and useful technique for the preparation

of enantiopure 2-aryl-substituted cycloalkylamines.

Experimental Section

as

a colorless solid. Mp: 52–54 °C. TLC: R_f= 0.11 (silica gel;

General Remarks. All air-sensitive reactions were performed under an

inert atmosphere of dry nitrogen (N₂) using oven-dried glassware. All

reagents and solvents were transferred using gas-tight syringe and

cannula techniques under N₂. Reactions were monitored by thin layer

chromatography (TLC) on aluminum sheets that were pre-coated with

silica gel SIL G/UV₂₅₄from MN GmbH & Co., in which the spots were

hexanes/EtOAc, 9:1). FTIR (KBr): ṽ_max(cm⁻¹) = 3372 (m), 3103 (w), 3073

(w), 3012 (w), 2919 (s), 2661 (w), 2008 (w),1911 (w), 1876 (w), 1756 (w)

1599 (s), 1585 (s), 1492 (s), 1463 (s), 1438 (s),1326 (m), 1290 (m), 1240a

(s), 1191 (m), 1126 (m), 1090 (w), 1051 (s), 961 (m), 824 (w), 746 (s), 730

1

(s), 577 (w), 565 (w). H NMR (500 MHz, CDCl₃): δ = 7.23 (m, 1 H), 7.20

(m, 1 H), 6.97 (dt, J = 7.5, 1.0 Hz, 1 H), 6.89 (dd, J = 8.2, 1.0 Hz, 1 H), 3.83

(s, 3 H), 3.77–3.71 (m, 1 H), 2.98-3.04 (m, 1 H), 2.16–2.12 (m, 1 H), 1.86–

1.73 (m, 4 H), 1.54–1.33 (m, 4 H). ¹³C NMR (125 MHz, CDCl₃): δ = 157.6

(C), 131.5 (C), 127.3 (CH), 127.2 (CH), 120.9 (CH), 110.7 (CH), 73.8 (CH),

55.4 (CH₃), 45.0 (CH), 35.1 (CH₂), 32.3 (CH₂), 26.1 (CH₂), 25.1 (CH₂).

GCMS: t_R= 28.19 min, m/z (%) = 206 ([M]⁺, 73), 188 ([M-18]⁺, 7), 173 ([M-

33]⁺, 43), 147 (23), 134 (7), 121 (100), 107 (9), 91 (47), 77 (10). HRMS

(ESI): ([M+Na]⁺) calcd for C₁₃H₁₈O₂Na: 229.1199; found: 229.1196.

visualized in UV-light (λ

= 254 nm) and/or by staining with

phosphomolybdic acid solution in EtOH (10%, w/v). Chromatographic

separations were performed using silica gel (MN-silicagel 60, 230-400

mesh). All melting points were determined in open glass capillary tube by

means of a BÜCHI Melting Point B-540 apparatus and values are

uncorrected. Infrared (FT-IR) spectra were recorded on a PerkinElmer

Spectrum One FT-IR spectrometer, ṽ_maxin cm⁻¹. Bands are characterized

as broad (br), strong (s), medium (m), and weak (w). ¹H and ¹³C NMR

spectra were recorded on a 500 MHz or 600 MHz NMR spectrometer.

Chemical shifts δ are reported in parts per million (ppm) relative to the

residual protons in the NMR solvent (CHCl₃: δ 7.26) and carbon resonance

of the solvent (CDCl₃: δ 77.00). NMR peak multiplicities were given as

follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br =

broad. Mass spectra were recorded on a gas chromatography with mass

sensitive detector from Agilent Technologies 6890N Network GC System

(EI, 70 eV) using Standard Method (column: HP-5MSI, 30 m, 0.25 mm ID,

0.25 μm film tickness; inlet: 300 °C (split modus); det: 300 °C; He, 1 mL/min

(constant flow modus); oven: 40 °C (5 min), 5 °C/min, 280 °C (5 min)).

High resolution electrospray ionization mass spectra (HR-ESI-MS) were

obtained with MeOH on a Bruker micrOTOF-Q. The specific rotations ([α])

were measured on a Optical Activity Ltd. AA-65 polarimeter using 1 mL

cell with a 1.0 dm path length and the sample concentrations are given in

g/100 mL unit. Tetrahydrofuran (THF), diethyl ether (Et₂O), and diglyme

were freshly distilled from sodium/benzophenone prior to use under

nitrogen atmosphere. N,N-dimethylformamide (DMF) and anisole were

distilled under reduced pressure from calcium hydride (CaH₂). Acetonitrile

(MeCN), dichloromethane (DCM), triethylamine (TEA), and N,N,N′,N′-

tetramethylethylenediamine (TMEDA) were dried by distillation over CaH₂

under N₂. Some reagents, such as boron trifluoride-diethyl ether complex

(BF₃·OEt₂), ⁿBuLi (2.5 M or 1.7 M solution in hexane), EtSH, LiAlH₄, PPh₃,

NaBH₄, NaBH₃CN, diethyl azodicarboxylate (DEAD), diphenyl phosphoryl

azide ((PhO)₂P(O)N₃), and 2-bromoanisole were purchased from

commercial suppliers and used as received. Hydroxylamine-O-sulfonic

acid (H₂NOSO₃H),^[23]2,4,6-triisopropylbenzoic acid (TRIBA)[^24]and L-

DBTA^[25]were prepared according to procedures given in literature.

cis-1-(2-Azidocyclohexyl)-2-methoxybenzene (rac-6). An oven-dried

250 mL round-bottomed Schlenk flask, capped with a glass stopper and

equipped with a magnetic stirring bar, was charged with rac-5 (5.175 g,

25.0 mmol, 1.00 equiv) and triphenylphosphine (PPh₃) (9.825 g, 37.5 mmol,

1.50 equiv). After dry THF (100 mL) was added into the reaction flask by

means of a gas-tight syringe, the reaction system was slightly evacuated

and back-filled with dry N₂, at least three times. The glass stopper was

replaced with a rubber septum under positive pressure of dry nitrogen and

the flask was cooled down to −78 °C in an acetone-dry ice bath. Then,

DEAD (14.16 g, 14.8 mL, 32.5 mmol, 1.30 equiv) and (PhO)₂P(O)N₃(10.3

g, 8.1 mL, 37.5 mmol, 1.50 equiv) were added at −78 °C sequentially, using

syringes. The reaction mixture was then stirred for 16 h while the

temperature was allowed to rise to ambient temperature. THF was

removed by rotary evaporation under reduced pressure. The yellow

residue was filtered through a column filled with silica gel, by using a

hexanes/EtOAc (95:5) mixture as the mobile phase. Purification by flash

chromatography (hexanes) on silica gel gave rac-6 (3.76 g, 16.3 mmol,

65%) as a colorless oil. TLC: R_f= 0.22 (silica gel, hexanes). FTIR (KBr):

ṽ_max(cm⁻¹) = 2935 (s), 2102 (s), 1601 (w), 1492 (s), 1239 (s), 1031 (w),

753 (s). ¹H NMR (500 MHz, CDCl₃): δ = 7.24–7.21 (m, 2H), 6.96 (td, J =

7.5, 1.0 Hz, 1H), 6.85 (d, J = 7.7 Hz, 1H), 4.05 (d, J = 2.5 Hz, 1H), 3.83 (s,

3H), 3.22 (dt, J = 12.9, 2.9 Hz, 1H), 2,06–1.99 (m, 2 H), 1,91–1.87 (m, 1H),

1,80–1.70 (m, 1H), 1,61–1.54 (m, 3H), 1,48–1.36 (m, 1H). ¹³C NMR (APT,

125 MHz, CDCl₃): δ = 156.6 (C), 131.2 (C), 128.1 (CH), 127.6 (CH), 120.5

(CH), 109.9 (CH), 62.0 (CH), 55.3 (CH₃), 39.5 (CH), 30.7 (CH₂), 26.3 (CH₂),

25.0 (CH₂), 20.4 (CH₂). HRMS (ESI): ([M−N₂+H]⁺) calcd for C₁₃H₁₈NO:

204.1383; found: 204.1403.

trans-2-(2-Methoxyphenyl)cyclohexanol (rac-5).^[9]An oven-dried 1 L

round-bottomed Schlenk flask, capped with a glass stopper and equipped

with a magnetic stirring bar, was evacuated under heating with a blow-drier

for 15 min. After the flask was cooled down to ambient temperature, dry

nitrogen was back-filled and the glass stopper was replaced with a rubber

septum, under a positive pressure of nitrogen. The flask was charged with

anisole (9.8 mL, 9.7 g, 90.0 mmol, 3.00 equiv) and TMEDA (2.1 g, 2.7 mL,

18.0 mmol, 0.60 equiv), which was succeeded by the addition of dry THF

(180 mL) as the solvent. After the mixture was cooled in an ice-bath, 36

mL of 2.50 M solution of ⁿBuLi in hexanes (90.0 mmol, 3.00 equiv of ⁿBuLi)

were drop-wise added to the mixture. The mixture was then stirred for 2 h

while the temperature was allowed to rise to ambient temperature. After

cooling the reaction mixture down to −78 °C in an acetone-dry ice bath,

cyclohexene oxide (3) (3.6 g, 3.45 mL, 30.0 mmol, 1.00 equiv) and

cis-2-(2-Methoxyphenyl)cyclohexylamine (rac-7).^[10]Oven-dried 250

mL and 500 mL round-bottomed schlenk flasks, capped with a glass

stoppers and equipped with a magnetic stirring bars, were evacuated

under heating with a blow-drier for 15 min. After the flasks were cooled

down to ambient temperature, dry nitrogen was back-filled and the glass

stoppers were replaced with rubber septums, under a positive pressure of

nitrogen. The 500 mL flask was charged with LiAlH₄(1.71 g, 45.0 mmol,

3.00 equiv) and dry Et₂O (120 mL) was added into the flask by means of a

gas-tight syringe. In the 250 mL Schlenk flask was prepared a solution of

rac-6 (3.5 g, 15.0 mmol, 1.00 equiv) in dry Et₂O (120 mL) which was then

drop-wise added to the suspension of LiAlH₄in Et₂O present in the 500 mL

flask, by using cannula technique. The resulting mixture was stirred for 16

h while the temperature was allowed to rise to ambient temperature. After

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European Journal of Organic Chemistry

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the reaction mixture was carefully poured into 10.0 N NaOH (250 mL), the

organic phase was separated by means of a separatory funnel, the

aqueous residue was extracted twice with Et₂O (2 × 50 mL) and the

organic phases were combined. Purification process for rac-7 without

performing any column chromatography: The combined organic phases in

Et₂O were treated with aqueous HCl (37%, 3 × 100 mL). After the resulting

aqueous and ethereal phases were separated by means of a separatory

funnel, the aqueous phase was extracted with Et₂O (100 mL). The pH

value of the aqueous phase was adjusted to 13–14 with 4.0 N NaOH and

the resulting suspension was extracted with DCM (3 × 100 mL). The

combined organic extracts were dried over Na₂SO₄, filtered, and

concentrated by rotary evaporation in vacuo. After drying the residue under

high vacuum (10⁻²mbar) overnight, rac-7 (3.0 g, 14.7 mmol, 98%) was

obtained as a colorless oil in high purity for the next step. TLC: R_f= 0.36

(silica gel; hexanes/EtOAc/TEA/MeOH, 8:1.4:0.4:0.2). FTIR (KBr): ṽ_max

(cm⁻¹) = 3440 (br), 3190 (w), 2941 (w), 1736 (s), 1699 (s), 1600 (w), 1529

(w), 1493 (w), 1285 (s), 1244 (s), 1128 (s), 1026 (s), 710 (s). ¹H NMR (500

MHz, CDCl₃): δ = 7.24–7.21 (m, 2H), 6.96 (td, J = 7.5, 1.0 Hz, 1H), 6.85

(d, J = 7.7 Hz, 1H), 4.05 (d, J = 2.5 Hz, 1H), 3.83 (s, 3H), 3.22 (dt, J = 12.9,

2.9 Hz, 1H), 2.06–1.99 (m, 2 H), 1.91–1.87 (m, 1H), 1.80–1.70 (m, 1H),

1.48–1.36 (m, 1H), 1.61–1.54 (m, 3H). ¹³C NMR (APT, 125 MHz, CDCl₃):

δ = 156.6 (C), 131.2 (C), 128.1 (CH), 127.6 (CH), 120.5 (CH), 109.9 (CH),

62.0 (CH), 55.3 (CH₃), 39.5 (CH), 30.7 (CH₂), 26.3 (CH₂), 25.0 (CH₂), 20.4

(CH₂). HRMS (ESI): ([M+H]⁺) calcd for C₁₃H₂₀NO: 206.1539; found:

206.1551.

2H), 1.92–1.67 (m, 5H), 1.63–1.54 (m, 2H), 1.29–1.21 (m, 1H). ¹³C NMR

(APT, 125 MHz, CDCl₃): δ = 157.2 (C), 136.5 (C), 127.9 (CH), 125.8 (CH),

121.0 (CH), 111.4 (CH), 73.1 (C), 55.3 (CH₃), 36.7 (CH₂), 26.0 (CH₂), 22.0

(CH₂).

1-(Cyclohexen-1-yl)-2-methoxybenzene (10).^[27]

A 100 mL round-

bottomed flask was charged with 9 (19.2 g, 93.0 mmol, 1.00 equiv) and

AcOH (18.5 mL). After the mixture was cooled in an ice-bath, H₂SO₄(3.7

mL) was drop-wise added and it was then stirred for 3 h while the

temperature was allowed to rise to ambient temperature. The reaction

mixture was then quenched with a mixture of Et₂O and saturated aqueous

NaHCO₃solution (600 mL, 1:1, v/v), the organic phase was separated and

the aqueous layer was extracted with Et₂O (2 × 150 mL). The combined

organic phases were washed with saturated aqueous NaHCO₃(3 × 150

mL), dried over Na₂SO₄, filtered, and concentrated by rotary evaporation

in vacuo. The residue was purified by silica gel column chromatography

eluting with hexanes (100%) to afford 17.5 g (92 mmol, 99%) of the title

compound (10) as a colorless oil. TLC: R_f= 0.60 (silica gel; hexanes,

100%). FTIR (KBr): ṽ_max(cm⁻¹) = 2929 (s), 2834 (s), 1597 (w), 1489 (s),

1435 (s), 1246 (s), 1117 (s), 1029 (s), 918 (w), 791 (w), 751 (s), 648 (w).

¹H NMR (500 MHz, CDCl₃): δ = 7.22 (ddd, J = 8.2, 7.5, 1.8 Hz, 1H), 7.14

(dd, J = 7.4, 1.8 Hz, 1H), 6.92 (td, J = 7.4, 1.1 Hz, 1H), 6.87 (dd, J = 8.2,

0.8 Hz, 1H), 5.78 (tt, J = 3.7, 1.7 Hz, 1H), 3.82 (s, 3H), 2.39–2.35 (m, 2H),

2.23–2.18 (m, 2H), 1.79–1.68 (m, 4H). ¹³C NMR (APT, 125 MHz, CDCl₃):

δ = 156.2 (C), 137.1 (C), 133.4 (C), 129.1 (CH), 127.2 (CH), 125.7 (CH),

120.1 (CH), 110.3 (CH), 55.0 (CH₃), 28.4 (CH₂), 25.2 (CH₂), 22.6 (CH₂),

21.8 (CH₂).

1-(2-Methoxyphenyl)cyclohexanol (9).^[26]An oven-dried 500 mL three-

neck round-bottom flask, capped with a glass stopper as well as equipped

with a reflux condenser, a dropping funnel with a pressure equalizing arm

and a magnetic stirring bar, was evacuated under heating with a blow-drier

for 15 min. After the flask was cooled down to ambient temperature, dry

nitrogen was back-filled and the glass stopper was replaced with a rubber

septum, under a positive pressure of nitrogen. The flask was charged with

magnesium turnings (2.92 g, 120.0 mmol, 1.20 equiv) and activated under

heating with a blow-drier for 15 min. After the flask was cooled down to

ambient temperature, a few piece small iodine crystals were added into

the flask, under positive pressure of N₂and activation process of

magnesium was completed by gentle heating with a blow-drier for a very

short time. After the flask was cooled down to ambient temperature, dry

THF (60 mL) was added with a gas-tight syringe. A solution of o-

bromoanisole (8) (20.6 g, 13.8 mL, 110.0 mmol, 1.10 equiv) in dry THF (60

mL) that was prepared by mixing them simply in the separatory funnel was

drop-wise added with magnetic stirring into the reaction flask at such a rate

that overheating of the reaction mixture was prevented. After the addition

was completed, the mixture was refluxed for 3 h in order to drive the

formation of the Grignard reagent to completion and cooled down to

ambient temperature. After the reaction mixture was cooled to 0 °C in an

ice-bath, a solution of cyclohexanone (9.86 g, 10.4 mL, 100.0 mmol, 1.00

equiv) in dry THF (30 mL) that was prepared in another Schlenk flask

under N₂was drop-wise added. The ice bath was removed, the resulting

mixture was stirred at ambient temperature for 3 h. It was then quenched

with saturated NH₄Cl solution, THF was removed removed by rotary

evaporation under reduced pressure, and the aqueous residue was

extracted with Et₂O (3 × 75 mL) sequentially. The combined organic

phases were dried over Na₂SO₄, filtered, and concentrated by rotary

evaporation in vacuo. Purification of the residue by flash column

chromatography on silica gel (hexanes/EtOAc, 9:1) gave 19.2 g (93 mmol,

93%) of the title compound (9) as a colorless oil that became a solid upon

standing in time. Mp: 53–54 °C. TLC: R_f= 0.35 (silica gel; hexanes/EtOAc,

9:1). FTIR (KBr): ṽ_max(cm⁻¹) = 3547 (s), 3445 (s), 2930 (s), 2856 (s), 1599

(s), 1582 (s), 1464 (s), 1390 (s), 1342 (w), 1230 (s), 1179 (s), 1027 (s),

967 (s), 929 (w), 906 (w), 854 (w), 753 (s), 635 (w). ¹H NMR (500 MHz,

CDCl₃): δ = 7.32 (dd, J = 7.7, 1.7 Hz, 1H), 7.25–7.19 (m, 1H), 6.95 (td, J =

7.6, 1.2 Hz, 1H), 6.92 (dd, J = 8.2, 0.9 Hz, 1H), 3.89 (s, 3H), 2.07–1.97 (m,

trans-2-(2-Methoxyphenyl)cyclohexylamine (rac-12).^[28]An oven-dried

250 mL three-neck round bottomed flask, capped with a glass stopper and

equipped with a magnetic stir bar, reflux condenser and dropping funnel,

was evacuated under heating with a blow-drier for 15 min and back-filled

with dry nitrogen. After the flask was cooled down to room temperature,

the alkene 10 (28.24 g, 27.9 mL, 150.0 mmol, 1.00 equiv), dry diglyme (75

mL), and NaBH₄(2.27 g, 60.0 mmol, 0.40 equiv) were sequentially added

into the flask, under positive pressure of N₂. To the cooled reaction mixture

in an ice-bath was drop-wise added BF₃·OEt₂(11.71 g, 10.2 mL, 82.5

mmol, 0.55 equiv) via dropping funnel over a period of 15 minutes and it

was then stirred for 3 h while the temperature was allowed to rise to

ambient temperature. A solution of H₂N-OSO₃H (18.7 g, 165.0 mmol, 1.10

equiv) in dry THF (100 mL) that was prepared in a 100 mL Schlenk flask

under N₂was introduced into the 250 mL flask via cannula technique over

a period of 1h. The mixture was then heated to 100 °C and stirred at this

temperature for 3 h. After the temperature was allowed to cool down to

ambient temperature, aqueous HCl (45 mL, 37%) was drop-wise added to

the reaction mixture. The mixture was poured into water (500 mL) and

extracted with Et₂O (3 × 150 mL). 45 g NaOH (pellets) were portionswise

added to the aqueous residue under ice-cooling, which was followed by

extraction with Et₂O (3 × 150 mL). The combined organic phases were

dried over Na₂SO₄, filtered, and concentrated by rotary evaporation in

vacuo. Purification of the crude product by flash column chromatography

on silica gel (hexanes/EtOAc/TEA/MeOH, 7:2:0.5:0.5) gave 9.24 g (50

mmol, 30%) of the title compound (rac-12) as a colorless oil. TLC: R_f=

0.62 (silica gel; hexanes/EtOAc/TEA/MeOH, 7:2:0.5:0.5). FTIR (KBr): ṽ_max

(cm⁻¹) = 3367 (br), 2999 (w), 2853 (s), 2054 (w), 1771 (w), 1599 (s), 1492

(s), 1361 (w), 1240 (s), 1130 (w), 1029 (s), 965 (w), 822 (w), 753 (s). ¹H

NMR (500 MHz, CDCl₃): δ = 7.23–7.15 (m, 2H), 6.94 (td, J = 7.5, 1.0 Hz,

1H), 6.87 (dd, J = 8.2, 0.9 Hz, 1H), 3.81 (s, 3H), 2.85 (br, 2H), 2.04–1.97

(m, 1H), 1.83–1.75 (m, 3H), 1.48–1.20 (m, 4H), 1.08 (br s, 1H). ¹³C NMR

(APT, 125 MHz, CDCl₃): δ = 157.7 (C), 133.0 (C), 126.9 (2 × CH,

corresponds two CH groups, which was determined by HSQC NMR

experiment.), 120.9 (CH), 110.7 (CH), 55.5 (CH₃), 55.5 (2 × CH, they could

be determined by HSQC NMR because these ¹³C signals had very low

intensities.) 36.1 (CH₂), ca. 33.0 (CH₂, this ¹³C peak had very low intensity

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and was only be determined by HSQC NMR experiment.) 26.6 (CH₂), 25.9

(CH₂). HRMS (ESI): ([M+H]⁺) calcd for C₁₃H₂₀NO: 206.1539; found:

206.1548.

salt 15 in 41% yield (with respect to the amount of starting rac-7, 6.21

mmol) and 93% de. For the second recrystallization, the diastereomerically

enriched ammonium salt 15 (93% de) was dissolved in boiling 2-propanol

(20 mL) and 20 mL of distilled water were drop-wise added to the solution

with vigorous stirring, whereupon crystals began to precipitate. The

precipitation continued while the reaction mixture was allowed to cool

down to ambient temperature, with vigorous strirring, over 2 h. The product

was separated by filtration, washed with Et₂O (2 × 15 mL), and dried under

reduced pressure overnight, thereby furnishing the diastereomerically pure

ammonium salt 15 in 40% yield (3.38 g, 6.0 mmol) with respect to the

amount of rac-7, as a white powder. Mp: 119–122 °C. [α]²_D⁸= +135 (c =

0.5, MeOH). FTIR (KBr): It was determined to be identical with that of 13.

¹H NMR (500 MHz, DMSO-d₆): δ = 7.96 (d, J = 7.9 Hz, 4H), 7.63 (t, J = 7.4

Hz, 2H), 7.50 (t, J = 7.7 Hz, 4H), 7.28 – 7.21 (m, 1H), 7.12 (d, J = 7.5 Hz,

1H), 6.98 (d, J = 8.2 Hz, 1H), 6.90 (t, J = 7.4 Hz, 1H), 5.66 (s, 2H), 3.77 (s,

3H), 3.50 (d, J = 2.5 Hz, 1H), 3.19 (d, J = 13.4 Hz, 1H), 2.13 (qd, J = 13.2,

2.9 Hz, 1H), 1.97 (d, J = 13.8 Hz, 1H), 1.74 (d, J = 12.3 Hz, 1H), 1.62 (dd,

J = 12.3, 9.1 Hz, 1H), 1.52 – 1.26 (m, 4H). ¹³C NMR (APT, 125 MHz,

DMSO-d₆): δ = 168.4 (C), 165.4 (C), 157.3 (C), 133.8 (C), 130.2 (C), 129.7

(CH), 129.1 (CH), 129.0 (C), 128.6 (CH), 128.2 (CH), 121.1 (CH), 111.2

(CH), 72.7 (CH₃), 55.9 (CH), 49.6 (CH), 38.1 (CH), 29.6 (CH₂), 25.9 (CH₂),

23.8 (CH₂), 19.3 (CH₂).

(2R,3R)-2,3-Bis(benzoyloxy)butanedioic

Acid

(1R,2R)-2-(2-

Methoxyphenyl)cyclohexylamine Salt (13). A 250 L two-necked, round-

bottomed flask equipped with a magnetic stir bar and a reflux condenser

was charged with dibenzoyl-L-tartaric acid (L-DBTA) (5.37 g, 15.0 mmol,

1.00 equiv) and distilled water (60 mL). After the resulting suspension was

heated to the reflux temperature, a solution of rac-7 (3.08 g, 15.0 mmol,

1.00 equiv) in 2-propanol (30 mL) was drop-wise added with vigorous

stirring, during which a crystalline product precipitated. The mixture was

then stirred for 2 h while the temperature was allowed to down to ambient

temperature. The colorless crsytals formed were filtered off, washed with

Et₂O (2 × 15 mL), and dried under reduced pressure to give the ammonium

salt 13 in 45% yield (with respect to the amount of rac-7, 3.83, 6.8 mmol)

and 98.6% diastereomeric excess. For the second recrystallization, the

diastereomerically enriched ammonium salt 13 (98.6% de) was dissolved

in boiling 2-propanol (20 mL) and 20 mL of distilled water were drop-wise

added to the solution with vigorous stirring, whereupon crystals began to

precipitate. The precipitation continued while the reaction mixture was

allowed to cool down to ambient temperature, with vigorous strirring, over

2 h. The product was separated by filtration, washed with Et₂O (2 × 15 mL),

and dried under reduced pressure overnight, thereby giving the

diastereomerically pure ammonium salt 13 in 40% yield (3.38 g, 6.0 mmol)

with respect to the amount of rac-7, as a white powder. Mp: 118–121 °C.

[α]²_D⁸= −132 (c = 0.5, MeOH). FTIR (KBr): ṽ_max(cm⁻¹) = 3580 (w), 3190 (s),

2941 (s), 2530 (w), 1736 (s), 1600 (s), 1493 (s), 1329 (s), 1266 (s), 1122

(s), 1025 (s), 852 (w), 760 (s), 709 (s). ¹H NMR (500 MHz, DMSO-d₆): δ =

7.97–7.92 (m, 4H), 7.64–7.61 (t, J = 7.4 Hz, 2H), 7.50 (t, J = 7.7 Hz, 4H),

7.29–7.20 (m, 1H), 7.16–7.08 (m, 1H), 6.97 (d, J = 8.0 Hz, 1H), 6.90 (t, J

= 7.4 Hz, 1H), 5.65 (s, 2H), 3.77 (s, 3H), 3.49 (d, J = 2.7 Hz, 1H), 3.19 (d,

J = 13.4 Hz, 1H), 2.13 (qd, J = 13.2, 3.1 Hz, 1H), 1.96 (d, J = 13.6 Hz, 1H),

1.74 (d, J = 12.3 Hz, 1H), 1.68–1.56 (m, 1H), 1.53–1.28 (m, 4H). ¹³C NMR

(APT, 125 MHz, DMSO-d₆): δ = 168.3 (C), 165.3 (C), 157.3 (C), 133.8 (C),

130.1 (C), 129.7 (CH), 129.1 (CH), 129.0 (C), 128.6 (CH), 128.1 (CH),

121.1 (CH), 111.3 (CH), 72.4 (CH₃), 55.9 (CH), 49.6 (CH), 38.1 (CH), 29.6

(CH₂), 25.8 (CH₂), 23.8 (CH₂), 19.2 (CH₂). HRMS (ESI): ([M+H]⁺) calcd for

C₃₁H₃₄NO₉: 564.2228; found: 564.2234.

(1S,2S)-2-(2-Methoxyphenyl)cyclohexylamine (ent-7). The ammonium

salt 15 (3.38 g, 6.0 mmol) was treated with 4.0 N NaOH solution (100 mL)

and the resulting aqueous mixture was extracted with DCM (3 × 100 mL).

The combined organic phases were dried over Na₂SO₄, filtered, and

concentrated by rotary evaporation in vacuo. After drying the residue under

high vacuum (10⁻²mbar) overnight, enantiopure ent-7 (1.224 g, 5.96 mmol,

99% y, >99% ee) was obtained as a pale yellow oil. [훂]^ퟐ_퐃^ퟓ= +90 (c = 0.5,

CHCl₃). Derivatization and Enantiomeric Excess Determination: cis-N-2-

(2-Methoxyphenyl)cyclohexylbenzamide (rac-17). A 50 mL one-necked,

round-bottomed flask equipped with a magnetic stirr bar was charged with

205 mg of rac-7 (1.0 mmol, 1.00 equiv), 12 mL of DCM, and 4 mL of 4.0 N

aqueous NaOH. 163 µL of benzoyl chloride (197 mg, 1.4 mmol, 1.40 equiv)

were drop-wise added with stirring, at ambient temperature. After the two-

phase reaction mixture was stirred at ambient temperature for 15 min, the

aqueous phase was removed by pulling with a pipette. The organic phase

was dried over Na₂SO₄, filtered, and concentrated by rotary evaporation in

vacuo. Purification of the crude product by flash column chromatography

on silica gel (hexanes/EtOAc, 9:1) gave 263 mg (0.85 mmol, 85% y) of the

title compound (rac-17) as a white solid. Mp: 150–151 °C. TLC: R_f= 0.15

(silica gel; hexanes/EtOAc, 9:1). HPLC: Daicel Chiralpak OD-H (4.60 mm

ID × 250 mm column length); n-hexane/ⁱPrOH (85:15), 1.0 mL/min; 254 nm

(UV–vis); t_R= 6.2 min (17), t_R= 7.3 min (ent-17). FTIR (KBr): ṽ_max(cm⁻¹) =

3429 (s), 3028 (w), 2927 (s), 2873 (m), 2063 (w), 1808 (w), 1641 (s), 1577

(s), 1491 (s), 1439 (m), 1239 (s), 1100 (m), 1034 (m), 922 (m), 832 (m),

756 (s), 512 (m). ¹H NMR (600 MHz, DMSO-d₆): δ = 7.73 (d, J = 9.1 Hz,

1H), 7.58 (d, J = 7.3 Hz, 2H), 7.43 (t, J = 7.3 Hz, 1H), 7.36 (t, J = 7.6 Hz,

2H), 7.25 (d, J = 7.5 Hz, 1H), 7.11–7.07 (m, 1H), 6.88 (d, J = 8.1 Hz, 1H),

6.82 (t, J = 7.4 Hz, 1H), 4.47 (dd, J = 8.8, 2.7 Hz, 1H), 3.78 (s, 3H), 3.27

(dt, J = 13.7, 3.2 Hz, 1H), 2.40–2.30 (m, 1H), 1.85–1.76 (m, 2H), 1.68–

1.56 (m, 2H), 1.38–1.51 (m, 3H). ¹³C NMR (APT, 150 MHz, DMSO-d₆): δ

= 168.2 (C=O), 160.0 (C), 138.0 (C), 135.1 (C), 133.8 (CH), 131.1 (CH),

130.1 (CH), 130.0 (CH), 129.9 (CH), 123.3 (CH), 113.7 (CH), 58.4 (CH₃),

53.6 (CH), 36.6 (CH₂), 29.1 (CH₂), 28.4 (CH₂). HRMS (ESI): ([M+H]⁺) calcd

for C₂₀H₂₄NO₂: 310.1802; found: 310.1798. Determination of the

diastereomeric excesses of the 13 and 15 could be carried out as

described as follows: The separated salt 13 or 15 (500 mg, 0.89 mmol,

1.00 equiv) was mixed with 12 mL of DCM and 4 mL of 4.0 N aqueous

NaOH solution with stirring, in a flask. Benzoyl chloride (120 µL, 1.03 mmol,

1.40 equiv) was added to the two-phase mixture, with stirring, at ambient

temperature. After the mixture was stirred at ambient temperature for 15

min, the aqueous upper phase was removed by pulling with a pipette. The

(1R,2R)-2-(2-Methoxyphenyl)cyclohexylamine (7). The ammonium salt

13 (3.38 g, 6.0 mmol) was treated with 4.0 N NaOH solution (100 mL) and

the resulting aqueous mixture was extracted with DCM (3 × 100 mL). The

combined organic phases were dried over Na₂SO₄, filtered, and

concentrated by rotary evaporation in vacuo. After drying the residue under

high vacuum (10⁻²mbar) overnight, enantiopure 7 (1.224 g, 5.96 mmol,

99% y, >99% ee) was obtained as a pale yellow oil. [훂]^ퟐ_퐃^ퟓ= –92 (c = 0.5,

CHCl₃).

(2S,3S)-2,3-Bis(benzoyloxy)butanedioic

Acid

(1S,2S)-2-(2-

Methoxyphenyl)cyclohexylamine Salt (15). All the filtrates that were

obtained during the separation of 13 were combined and organic solvents

were evaporated under reduced pressure. The remaining aqueous slurry

was treated with 4.0 N NaOH (100 mL) and extracted with DCM (3 × 100

mL). The combined organic phases were dried over Na₂SO₄, filtered, and

concentrated by rotary evaporation in vacuo, thereby affording

enantiomerically enriched ent-7 (1.7 g, 8.3 mmol, 60% ee) as a colorless

oil. It was dissolved in ⁱPrOH (16.5 mL) and drop-wise added to a

suspension of dibenzoyl-D-tartaric acid (D-DBTA) (2.97 g, 8.3 mmol, 1.00

equiv) in distilled water (33 mL) at reflux temperature, following the same

procedure described for the separation of 13. The mixture was then stirred

for 2 h while the temperature was allowed to down to ambient temperature.

The colorless crsytals formed were filtered off, washed with Et₂O (2 × 15

mL), and dried under reduced pressure to give 3.50 g of the ammonium

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organic phase was dried over Na₂SO₄, filtered, and concentrated by rotary

evaporation in vacuo. Purification of the crude product by flash column

chromatography on silica gel (hexanes/EtOAc, 9:1) gave 185 mg (0.60

mmol, 85% y) of the benzamide derivative 17 or ent-17 as a white solid.

20 was obtained in 41% yield (12.47 g, 22.1 mmol), with respect to the

molar amount of the starting rac-12, as a white powder. Mp: 179–180 °C.

[α]²_D¹= +78 (c = 0.5, MeOH). ¹H NMR (600 MHz, DMSO-d₆): δ = 7.98–7.94

(m, 4H), 7.66–7.62 (m, 2H), 7.51 (t, J = 7.8 Hz, 4H), 7.24–7.15 (m, 2H),

6.98 (d, J = 8.1 Hz, 1H), 6.91 (t, J = 7.3 Hz, 1H), 5.67 (s, 2H), 3.77 (s, 3H),

3.34 (t, J = 9.4 Hz, 1H), 2.93 (s, 1H), 2.04 (t, J = 11.5 Hz, 2H), 1.77 (s, 1H),

(2R,3R)-2,3-Bis(benzoyloxy)butanedioic

Acid

(1S,2R)-2-(2-

1.63 (d, J = 10.6 Hz, 4H), 1.47 (d, J = 9.7 Hz, 1H), 1.38–1.15 (m, 3H). ¹³

C

Methoxyphenyl)cyclohexylamine Salt (18). A solution of dibenzoyl-L-

tartaric acid (L-DBTA) (19.35 g, 54.0 mmol, 1.00 equiv) in EtOAc (150 mL)

was added to a solution of rac-12 (11.1 g, 54.0 mmol, 1.00 equiv) in EtOAc

(150 mL) with stirring and the homogeneous mixture was stirred at ambient

temperature for 15 min. The solvent was removed by rotary evaporation in

vacuo. The residue consisting of the ammonium salts 18 and 19 was then

suspended in acetone (300 mL). Upon heating at reflux temperature with

stirring, complete dissolution was observed. MeOH (170 mL) was drop-

wise added to the homogeneous solution at reflux temperature,

whereupon the homogeneous mixture became turbid. The mixture was

then stirred for 2 h with vigorous stirring as the temperature was allowed

to down to ambient temperature. The precipitated salt was isolated by

filtration, washed with Et₂O (2 × 15 mL), and and dried under reduced

pressure overnight. The diastereomerically pure ammonium salt 18 was

obtained in 36% yield (10.96 g, 19.44 mmol) as a white powder. Mp: 179–

180 °C. [α]²_D²= −64 (c = 0.5, MeOH). FTIR (KBr): ṽ_max(cm⁻¹) = It was

determined to be identical with that of reported for 13. ¹H NMR (600 MHz,

DMSO-d₆): δ = 7.95 (d, J = 7.3 Hz, 4H), 7.63 (t, J = 7.4 Hz, 2H), 7.50 (t, J

= 7.7 Hz, 4H), 7.24–7.20 (m, 2H), 6.98 (d, J = 8.1 Hz, 1H), 6.90 (t, J = 6.5

Hz, 1H), 5.66 (s, 2H), 3.76 (s, 3H), 3.39–3.34 (m, 1H), 2.93 (br, 1H), 2.04

(br s, 1H), 1.65–1.62 (m, 3H), 1.54–1.13 (m, 4H). ¹³C NMR (APT, 150 MHz,

DMSO-d₆): δ = 170.9 (C), 168.0 (C), 160.3 (C), 136.5 (CH), 132.8 (C),

132.3 (CH), 131.8, 131.1 (CH), 123.9 (CH), 114.5 (CH), 75.1 (CH), 58.5

(CH₃), 33.9 (CH₂), 33.8 (CH), 28.4 (CH₂), 27.1 (CH₂). HRMS (ESI):

([M+H]⁺) calcd for C₃₁H₃₄NO₉: 564.2228; found: 564.2234.

NMR (APT, 150 MHz, DMSO-d₆): δ = 168.4 (C), 165.4 (C), 157.7 (C),

133.8 (CH), 130.1 (C), 129.7 (CH), 129.1 (CH), 128.5, 121.2 (CH), 111.9

(CH), 72.6 (CH), 55.8 (CH₃), 31.2 (CH₂), 31.1 (CH), 25.8 (CH₂), 24.5 (CH₂).

HRMS (ESI): ([M+H]⁺) calcd for C₃₁H₃₄NO₉: 564.2228; found: 564.2234.

(1R,2S)-2-(2-Methoxyphenyl)cyclohexylamine

(ent-12).

The

ammonium salt 20 (12.47 g, 22.1 mmol) was treated with 4.0 N NaOH

solution (100 mL) and the resulting aqueous mixture was extracted with

DCM (3 × 100 mL). The combined organic phases were dried over Na₂SO₄,

filtered, and concentrated by rotary evaporation in vacuo. After drying the

residue under high vacuum (10⁻²mbar) overnight, enantiopure ent-12

(3.59 g, 21.9 mmol, 99% y, >99% ee) was obtained as a colorless oil. [훂]_퐃^ퟐퟓ

=

−44 (c

=

0.5, CHCl₃). Derivatization and Enantiomeric Excess

trans-N-2-(2-Methoxyphenyl)cyclohexylbenzamide

Determination:

(rac-22). rac-22 was prepared from rac-12, by following the same

procedure that was described for the synthesis of rac-17. Mp: 145–146°C.

TLC: R_f= 0.23 (silica gel; hexanes/EtOAc, 9:1). HPLC: Daicel Chiralcel

OD-H (4.60 mm ID × 250 mm column length); n-hexane/ⁱPrOH (85:15), 1.0

mL/min; 254 nm (UV–vis); t_R= 7.4 min (ent-22), t_R= 8.2 min (22). FTIR

(KBr): ṽ_max(cm⁻¹) = 3345 (m), 3288 (m), 2915 (m), 2833 (w), 1629 (s),

1558 (m), 1492 (s), 1325 (m), 1243 (s), 1098 (m), 1027 (m), 870 (w), 750

(m), 695 (m). ¹H NMR(600 MHz, DMSO-d₆): δ = 7.96 (d, J = 8.9 Hz, 1H),

7.60–7.55 (m, 2H), 7.44–7.39 (m, 1H), 7.36–7.32 (m, 2H), 7.20 (dd, J =

7.6, 1.6 Hz, 1H), 7.09–7.05 (m, 1H), 6.88 (dd, J = 8.2, 0.8 Hz, 1H), 6.80

(td, J = 7.5, 0.9 Hz, 1H), 4.23 (d, J = 8.7 Hz, 1H), 3.78 (s, 3H), 3.22–3.11

(m, 1H), 1.96–1.90 (m, 1H), 1.87–1.75 (m, 2H), 1.72 (d, J = 12.0 Hz, 1H),

1.53–1.25 (m, 4H). ¹³C NMR (APT, 150 MHz, DMSO-d₆): δ = 165.1 (C=O),

156.9 (C), 134.9 (C), 132.0 (C), 130.7 (CH), 128.0 (CH), 127.0 (CH), 126.8

(CH), 120.2 (CH), 110.5 (CH), 55.3 (CH₃), 50.4 (CH), 33.5 (CH₂), 26.00

(CH₂), 25.3 (CH₂). HRMS (ESI): ([M+H]⁺) calcd for C₂₀H₂₄NO₂: 310.1802;

found: 310.1800. Determination of the diastereomeric excesses of the 18

and 20 was carried out by following the procedure that was described for

13 and 15 above.

(1S,2R)-2-(2-Methoxyphenyl)cyclohexylamine (12). The ammonium

salt 18 (10.96 g, 19.44 mmol) was treated with 4.0 N NaOH solution (100

mL) and the resulting aqueous mixture was extracted with DCM (3 × 100

mL). The combined organic phases were dried over Na₂SO₄, filtered, and

concentrated by rotary evaporation in vacuo. After drying the residue under

high vacuum (10⁻²mbar) overnight, enantiopure 12 (3.94 g, 19.2 mmol,

99% y, >99% ee) was obtained as a colorless oil. [α]²_D³= +48 (c = 0.5,

CHCl₃).

N-[(1R,2R)-2-(2-Methoxyphenyl)cyclohexyl]-N-benzylamine (24). An

oven-dried 25 mL Schlenk flask equipped with a magnetic stir bar was

charged with the enantiopure amine 7 (410 mg, 2.0 mmol, 1.00 equiv). The

flask was capped with a glass stopper, evacuated for 15 min, and back-

filled with dry N₂. Dry DCM (10 mL), anhydrous MgSO4, and benzaldehyde

(205 µL, 212 mg, 2.0 mmol, 2.00 equiv) were added sequentially and the

resulting heterogeneous mixture was stirred at ambient temperature for 16

hours. The mixture was then filtered, the solid was washed with DCM (3 ×

10 mL), the filtrate was concentrated by rotary evaporation in vacuo, thus

delivering a light yellow oil which was employed in the next step directly.

The intermediate 23 was not subjected to column chromatography

because it was rapidly decomposed on silica gel. Thereafter, the crude 23

(ca. 590 mg, 2.0 mmol, 1.00 equiv) was taken into an oven-dried 25 mL

Schlenk tube and it was then evacuated for 15 minutes. After dry nitrogen

was back-filled and the glass stopper was replaced with a rubber septum

under a positive pressure of nitrogen, dry MeCN (14 mL) was added.The

resulting solution was cooled in an ice-bath and NaBH₃CN (250 mg, 4.0

mmol, 2.00 equiv) were added to the solution in one portion under positive

pressure of N₂. The resulting mixture was stirred for 15 minutes in the ice-

bath. After AcOH (460 µL, 8.0 mmol, 4.00 equiv) was drop-wise added at

0 °C, the mixture was stirred for 2 h while the temperature was allowed to

rise to ambient temperature. After diluting with 50 mL of a DCM–MeOH

mixture (DCM/MeOH, 49:1, v/v), it was extracted with 1.0 N NaOH (2 × 50

(2S,3S)-2,3-Bis(benzoyloxy)butanedioic

Acid

(1R,2S)-2-(2-

Methoxyphenyl)cyclohexylamine Salt (20). All the filtrates that were

saved during the separation of 18 were combined and organic solvents

such as MeOH, acetone, and Et₂O were evaporated under reduced

pressure. The residue was treated with 100 mL of 4.0 N NaOH and

extracted with DCM (3 × 100 mL). The combined organic phases were

dried over Na₂SO₄, filtered, and concentrated by rotary evaporation in

vacuo, thereby affording enantiomerically enriched ent-12 (7.15 g, 34.8

mmol, 65% y) as a colorless oil. A 250 mL one-necked, round-bottomed

flask equipped with a magnetic stir bar was charged with ent-12 (7.15 g,

34.8 mmol, 1.00 equiv) and EtOAc (97 mL). A solution of dibenzoyl-D-

tartaric acid (D-DBTA) (12.47 g, 34.8 mmol, 1.00 equiv) in EtOAc (97 mL)

was added with stirring in one portion and the resulting homogeneous

mixture was stirred at ambient temperature for 15 min. The solvent was

removed by rotary evaporation in vacuo. The residue consisting of the

ammonium salts 20 and 21 was then suspended in acetone (198 mL).

Upon heating at reflux temperature with stirring, complete dissolution was

observed. MeOH (130 mL) was drop-wise added to the solution at reflux

temperature, whereupon the homogeneous mixture became turbid. The

mixture was then stirred for 2 h with vigorous stirring as the temperature

was allowed to down to ambient temperature. The precipitated salt was

isolated by filtration, washed with Et₂O (2 × 15 mL), and and dried under

reduced pressure overnight. The diastereomerically pure ammonium salt

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European Journal of Organic Chemistry

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mL). The organic extracts were dried over Na₂SO₄, filtered, and

concentrated by rotary evaporation in vacuo. Purification by flash column

chromatography (silica gel, hexanes/EtOAc/TEA, 9:0.8:0.2) afforded 537

mg (1.82 mmol, 91%) of the title compound (24) as a colorless oil. TLC: R_f

= 0.27 (silica gel; hexanes/EtOAc/TEA, 9:0.8:0.2). [α]²_D⁸= −176 (c = 0.5,

CHCl₃). FTIR (KBr): ṽ_max(cm⁻¹) = 3436 (br), 2929 (s), 2853 (s), 1599 (w),

1491 (s), 1627 (s), 1289 (w), 1238 (s), 1103 (w), 1030 (s), 786 (w), 753 (s),

698 (s). ¹H NMR (500 MHz, CDCl₃): δ = 7.24 – 7.09 (m, 5H), 6.96 – 6.89

(m, 3H), 6.82 – 6.78 (m, 1H), 3.67 (s, 3H), 3.63 (d, J = 13.9 Hz, 1H), 3.36

(d, J = 13.9 Hz, 1H), 3.23 (dt, J = 13.2, 3.0 Hz, 1H), 3.03 (d, J = 2.9 Hz,

1H), 2.14 (qd, J = 12.8, 3.5 Hz, 1H), 1.95 – 1.86 (m, 2H), 1.78 – 1.66 (m,

1H), 1.55 – 1.35 (m, 4H), 1.21 (s, 1H). ¹³C NMR (APT, 125 MHz, CDCl₃):

δ = 157.1 (C), 141.3 (C), 132.7 (C), 128.0 (CH), 127.9 (CH), 127.7 (CH),

126.9 (CH), 126.2 (CH), 120.2 (CH), 110.2 (CH), 55.1 (CH₃), 53.2 (CH),

51.4 (CH₂), 40.5 (CH), 29.7 (CH₂), 26.9 (CH₂), 24.9 (CH₂), 20.0 (CH₂).

HRMS (ESI): ([M+H]⁺) calcd for C₂₀H₂₆NO: 296.2009; found: 296.1981.

product was dissolved with Et₂O (75 mL) and it was extracted with 5% HCl

(3 × 50 mL). The combined aqueous fractions were again extracted with

Et₂O (75 mL). After the pH value of the aqueous phase was adjusted to 9–

9.5 with 4.0 N NaOH, the resulting suspension was extracted with DCM (3

× 100 mL). The combined organic extracts were dried over Na₂SO₄, filtered,

and concentrated by rotary evaporation in vacuo. After drying the residue

under high vacuum (10⁻²mbar) overnight, the title compound (1) (0.94 g,

4.9 mmol, 98% y, >99% ee) was obtained as a colorless solid. Mp: 153–

156 °C. TLC: R_f

= 0.15 (silica gel; hexanes/EtOAc/TEA/MeOH,

8:1.4:0.4:0.2). [α]_D²⁵= +36 (c = 0.5, CHCl₃). FTIR (KBr): ṽ_max(cm⁻¹) = 3343

(w), 3064 (w), 2931 (s), 2573 (w), 1890 (w), 1597 (s), 1453 (s), 1277 (s),

1247 (s), 1137 (w), 1047 (w), 984 (w), 959 (w), 837 (w), 753 (s), 459 (w).

¹H NMR (500 MHz, DMSO-d₆): δ = 7.01–6.90 (m, 2H), 6.63 (ddd, J = 8.6,

7.8, 1.1 Hz, 2H), 5.93 (br, 2H), 3.21 (d, J = 2.6 Hz, 1H), 2.74 (dt, J = 12.9,

2.8 Hz, 1H), 2.07 (qd, J = 12.8, 3.3 Hz, 1H), 1.80–1.57 (m, 4H), 1.48–1.25

(m, 3H). ¹H NMR (500 MHz, CDCl₃): δ =7.10 (ddd, J = 8.0, 7.3, 1.7 Hz,

1H), 6.97 (dd, J = 7.5, 1.7 Hz, 1H), 6.85 (dd, J = 8.0, 1.2 Hz, 1H), 6.74 (td,

J = 7.4, 1.3 Hz, 1H), 3.45 (d, J = 2.7 Hz, 1H), 2.65 (dt, J = 13.0, 3.0 Hz,

1H), 2.19 (ddd, J = 26.5, 13.0, 3.7 Hz, 1H), 1.91–1.84 (m, 1H), 1.84–1.75

(m, 1H), 1.73–1.63 (m, 2H), 1.60–1.39 (m, 3H). ¹³C NMR (APT, 125 MHz,

CDCl₃): δ = 156.7(C), 131.5 (CH), 131.0 (C), 128.2 (CH), 119.1 (CH),

118.7 (CH), 52.0 (CH), 50.4 (CH), 34.5 (CH₂), 26.6 (CH₂), 24.9 (CH₂), 19.1

(CH₂). HRMS (ESI): ([M+H]⁺) cald for C₁₂H₁₈NO: 192.1383; found:

192.1386. X-ray structural data of 1 (CCDC 1848756): Colorless crystals

of 1, suitable for X-ray crystallography, were obtained by crystallization

from MeOH. C₁₂H₁₇NO; formula weight 191.27; crystal size 0.05 × 0.06 ×

0.48 mm; crystal system hexagonal; space group P 6₁; unit cell dimensions

a = 16.5654(18) Å, b = 16.5654(18) Å, c = 7.7871(13) Å; α = 90°, β = 90°,

γ = 120°; Z = 6; D_calcd1.030 g cm⁻³; absorption coefficient 0.065 mm;

wavelength 0.71073 Å; T = 173(2) K; θ range for data collection = 2.98 to

25.00°; 9384/1990 collected/unique reflections (R(int) = 0.1918); final R

(1R,2R)-N,N-Dimethyl-2-(2-methoxyphenyl)cyclohexylamine (25). An

oven-dried 25 mL Schlenk flask equipped with a magnetic stir bar was

charged with the enantiopure amine 7 (410 mg, 2.0 mmol, 1.00 equiv). The

flask was capped with a glass stopper, evacuated for 15 min, back-filled

with dry N₂, and the glass stopper was replaced with a rubber septum

under positive pressure of N₂. Dry MeCN (10 mL), 745 µL of 37% aqueous

formaldehyde (10.0 mmol HCHO, 5.00 equiv) were added sequentially and

the resulting mixture was stirred at ambient temperature for 15 minutes.

After NaBH₃CN (250 mg, 4.0 mmol, 2.00 equiv) was added to the reaction

mixture, the resulting mixture was stirred for 15 minutes at ambient

temperature. Finally, AcOH (570 µL, 10.0 mmol, 5.00 equiv) was added

into the Schlenk tube and the mixture was stirred at ambient temperature

for 2 hours. After diluting with 50 mL of the DCM–MeOH mixture

(DCM/MeOH, 49:1, v/v), it was extracted with 1.0 N NaOH (2 × 50 mL).

The organic extract was dried over Na₂SO₄, filtered, and concentrated by

rotary evaporation in vacuo. Purification by flash column chromatography

on silica gel by applying gradient elution (the first eluent: hexanes/EtOAc,

9:1 (750 mL); the second eluent: hexanes/EtOAc/TEA, 9:0.8:0.2) gave 392

mg (1.7 mmol, 84%) of the title compound (25) as a colorless oil. TLC: R_f

= 0.22 (silica gel; hexanes/EtOAc/TEA, 9:0.8:0.2). [α]²_D⁸= +6 (c = 0.5,

CHCl₃). FTIR (KBr): ṽ_max(cm⁻¹) = 3430 (br), 2935 (s), 2762 (s), 1599 (s),

1490 (s), 1366 (w), 1341 (w), 1290 (w), 1238 (s), 1109 (w), 1038 (s), 888

(w), 749 (s). ¹H NMR (500 MHz, CDCl₃): δ = 7.52 (dd, J = 7.6, 1.5 Hz, 1H),

7.15 (td, J = 8.0, 1.6 Hz, 1H), 6.89 (td, J = 7.5, 1.0 Hz, 1H), 6.84 (dd, J =

8.1, 0.8 Hz, 1H), 3.53 (dt, J = 6.5, 4.3 Hz, 1H), 3.82 (s, 3H), 2.43 (dt, J =

8.7, 4.3 Hz, 1H), 2.06 (s, 6H), 2.03–1.92 (m, 2H), 1.90–1.75 (m, 2H), 1.66–

1.58 (m, 1H), 1.56–1.47 (m, 1H), 1.47–1.34 (m, 2H). ¹³C NMR (APT, 125

MHz, CDCl₃): δ = 157.1 (C), 133.2 (C), 129.8 (CH), 126.4 (CH), 120.0 (CH),

110.2 (CH), 65.7 (CH), 55.3 (CH₃), 44.6 (CH₃), 36.7 (CH), 29.4 (CH₂), 28.7

(CH₂), 24.1 (CH₂), 23.0 (CH₂). HRMS (ESI): ([M+H]⁺) calcd for C₁₅H₂₄NO:

234.1852; found: 234.1841.

indices [I > 2σ(I)] R₁= 0.0858, wR₂= 0.1792; R indices (all data) R₁

=

.

0.1882, wR₂= 0.2154; largest diff. peak and hole 0.192 and −0.235 e Å⁻³

2-[(1′S,2′S)-2′-Aminocyclohexyl]phenol (ent-1). Mp: 153–156 °C. TLC:

R_f= 0.38 (silica gel; hexanes/EtOAc/TEA/MeOH, 4:0.8:0.3:0.3). [α]_D²⁵

−36 (c = 0.5, CHCl₃).

=

2-[(1′R,2′S)-2′-Aminocyclohexyl]phenol (2). Following the general

procedure I as described above, 2-[(1′R,2′S)-2-aminocyclohexy]phenol

(12) (821 mg, 4.0 mmol, 1.00 equiv) was treated with BBr₃(1.15 mL, 3.0

g, 12.0 mmol, 3.00 equiv) in 20 mL DCM in an ice-bath. The temperature

allowed to rise to ambient temperature as the mixture was stirred for 6 h

under N₂. The pH value was adjusted to 9–9.5, by drop-wise addition of an

aqueous saturated NaHCO₃solution. The organic phase separated and

the aqueous phase was shaken with DCM (3 × 50 mL). The combined

organic phases were dried over Na₂SO₄, filtered, and concentrated by

rotary evaporation in vacuo. Purification of the crude product by flash

column chromatography on silica gel (hexanes/EtOAc/TEA/MeOH,

3:1:0.5:0.5) afforded 500 mg (2.6 mmol, 65%) of the title compound (2) as

General Procedure I (Demethylation of Anisoles): 2-[(1′R,2′R)-2′-

Aminocyclohexyl]phenol (1). An oven-dried 50 mL Schlenk tube

equipped with a magnetic stir bar was charged with the enantiopure amine

7 (1.03 g, 5.0 mmol, 1.00 equiv). The tube was capped with a glass stopper,

evacuated for 15 min, back-filled with dry N₂, and the glass stopper was

replaced with a rubber septum under positive pressure of N₂. Dry DCM (30

mL) was added to the tube by means of syringe and the resulting mixture

was cooled in an ice-bath. Boron tribromide (1.45 mL, 3.76 g, 15.0 mmol,

3.00 equiv) was drop-wise added to the ice-cooled mixture and it was

stirred for 6 hours while the temperature was allowed to rise to ambient

temperature. The pH value of the reaction mixture was adjusted to 9–9.5,

by a drop-wise addition of an aqueous saturated NaHCO₃solution. The

organic phase separated and the aqueous phase was shaken with DCM

(3 × 50 mL). The combined organic phases were dried over Na₂SO₄,

filtered, and concentrated by rotary evaporation in vacuo. The crude

a

colorless solid. Mp: 177–178 °C. TLC: R_f= 0.49 (silica gel;

hexanes/EtOAc/TEA/MeOH, 3:1:0.5:0.5). [α]²_D³= −72 (c = 0.5, CHCl₃).

FTIR (KBr): ṽ_max(cm⁻¹) = 3343 (w), 3064 (w), 2931 (s), 2573 (w), 1890 (w),

1597 (s), 1453 (s), 1277 (s), 1247 (s), 1137 (w), 1047 (w), 984 (w), 959

(w), 837 (w), 753 (s), 459 (w). ¹H NMR (600 MHz, DMSO-d₆): δ = 7.09 (dd,

J = 7.6, 1.5 Hz, 1H), 6.98 (td, J = 7.9, 1.6 Hz, 1H), 6.75 (ddd, J = 15.0, 7.8,

1.1 Hz, 2H), 4.32 (s, 2H), 2.74 (td, J = 10.6, 3.9 Hz, 1H), 2.67 – 2.60 (m,

1H), 1.91 – 1.85 (m, 1H), 1.74 – 1.68 (m, 2H), 1.66 – 1.61 (m, 1H), 1.42 (tt,

J = 12.7, 6.2 Hz, 1H), 1.36 – 1.17 (m, 3H). ¹³C NMR (APT, 150 MHz,

DMSO-d₆): δ = 155.8 (C), 131.3 (C), 127.0 (CH), 126.5 (CH), 119.0 (CH),

115.8 (CH), 54.0 (CH), 45.5 (CH), 36.0 (CH₂), 32.1 (CH₂), 26.2 (CH₂), 25.4

(CH₂). HRMS (ESI): ([M+H]⁺) cald for C₁₂H₁₈NO: 192.1383; found:

192.1388. X-ray structural data of 2 (CCDC 1848757): Colorless crystals

of 2, suitable for X-ray crystallography, were obtained by crystallization

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European Journal of Organic Chemistry

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from benzene. C₁₂H₁₇NO; formula weight 191.27; crystal size 0.12 × 0.15

× 0.50 mm; crystal system monoclinic; space group P 2₁; unit cell

dimensions a = 7.5222(5) Å, b = 7.0571(5) Å, c = 10.4522(7) Å; α = 90°, β

= 95.961(4)°, γ = 90°; Z = 2; D_calcd1.151 g cm⁻³; absorption coefficient

0.073 mm; wavelength 0.71073 Å; T = 300(2) K; θ range for data collection

= 1.96 to 25.00°; 7973/1922 collected/unique reflections (R(int) = 0.1478);

final R indices [I > 2σ(I)] R₁= 0.0561, wR₂= 0.1485; R indices (all data) R₁

= 0.0609, wR₂= 0.1521; largest diff. peak and hole 0.268 and −0.208 e

(1R,2R)-N,N-Dimethyl-N-benzyl-2-(2ʹ-

hydroxyphenyl)cyclohexylammonium bromide (28). An oven-dried 25

mL Schlenk tube was charged with 27 (439 mg, 2.0 mmol, 1.00 equiv).

The tube was for 15 minutes and back-filled with N₂. Dry MeCN (10 mL)

and benzyl bromide (1.19 mL, 1.71 g, 10.0 mmol, 5.00 equiv) were added

sequentially and the resulting mixture was refluxed at 90 °C for 24 h. The

precipitate was filtered off, washed with EtOAc (2 × 5 mL), and dried under

high vacuum (10⁻²mbar) overnight, thereby furnishing the title compound

28 (508 mg, 1.3 mmol, 65%) as a colorless solid. Mp: 212–214 °C. TLC:

R_f= 0.23 (silica gel; CHCl₃/MeOH, 9:1). [α]²_D⁸= +26 (c = 0.5, MeOH). FTIR

(KBr): ṽ_max(cm⁻¹) = 3056 (s), 2937 (s), 2660 (w), 2526 (w), 240a4 (w),

1599 (s), 1498 (s), 1454 (s), 1336 (s), 1262 (s), 1214 (s), 1097 (s), 998 (s),

964 (w), 858 (s), 765 (s), 727 (s), 670 (w), 641 (w), 515 (w). ¹H NMR (500

MHz, CDCl₃): δ = 9.71 (br s, 1H), 7.76 (dd, J = 8.2, 1.1 Hz, 1H), 7.64 (d, J

= 7.0 Hz, 1H), 7.35–7.29 (m, 3H), 7.29–7.26 (m, 2H), 7.20–7.14 (m, 1H),

6.88–6.81 (m, 1H), 4.87 (d, J = 12.5 Hz, 1H), 4.73–4.58 (m, 3H), 2.86 (s,

3H), 2.67 (s, 3H), 2.36–2.28 (m, 2H), 2.20 (d, J = 9.5 Hz, 1H), 2.12–2.04

(m, 1H), 1.93–1.77 (m, 2H), 1.73 (d, J = 13.5 Hz, 1H), 1.54 (d, J = 9.9 Hz,

1H). ¹³C NMR (APT, 125 MHz, CDCl₃): δ = 154.4 (s), 133.3 (CH), 130.3

(CH), 130.3 (CH), 129.1 (CH), 128.8 (CH), 127.3 (C), 126.4 (C), 119.9

(CH), 118.2 (CH), 65.3 (CH₂), 47.8 (CH₃), 46.8 (CH₃), 32.8 (CH₂), 29.7

(CH), 25.5 (CH₂), 21.7 (CH₂), 19.1 (CH₂). HRMS (ESI): ([M−Br+H]⁺) calcd

for C₂₁H₂₉BrNO: 390.1427, found: 310.2067.

Å⁻³

.

2-[(1′S,2′R)-2′-Aminocyclohexyl]phenol (ent-2). Mp: 177–178 °C. TLC:

R_f= 0.49 (silica gel; hexanes/EtOAc/TEA/MeOH, 3:1:0.5:0.5). [α]²_D³= +72

(c = 0.5, CHCl₃).

2-[(1′R,2′R)-2′-Benzylaminocyclohexyl]phenol (26). Following the

general procedure I as described above, 24 (295 mg, 1.0 mmol, 1.00

equiv) was treated with BBr₃(290 µL, 752 mg, 3.00 mmol, 3.00 equiv) in

10 mL DCM in an ice-bath. The temperature allowed to rise to ambient

temperature as the mixture was stirred for 6 h under N₂. The pH value was

adjusted to 9–9.5, by drop-wise addition of of an aqueous saturated

NaHCO₃solution. The organic phase separated and the aqueous phase

was shaken with DCM (3 × 50 mL). The combined organic phases were

dried over Na₂SO₄, filtered, and concentrated by rotary evaporation in

vacuo. Purification of the crude product by flash column chromatography

on silica gel (Hexanes/EtOAc/TEA, 9:0.8:0.2) afforded 210 mg (0.75 mmol,

75%) of the title compound (26) as a colorless oil. TLC: R_f= 0.29 (silica

gel; hexanes/EtOAc/TEA, 9:0.8:0.2). [α]²_D⁸= −94 (c = 0.5, CHCl₃). ¹H

NMR(500 MHz, CDCl₃): δ = 13.51 (br, 1H), 7.41–7.31 (m, 4H), 7.31–7.25

(m, 1H), 7.11 (ddd, J = 8.0, 7.3, 1.7 Hz, 1H), 6.96 (dd, J = 7.5, 1.7 Hz, 1H),

6.89 (dd, J = 8.0, 1.2 Hz, 1H), 6.72 (td, J = 7.4, 1.3 Hz, 1H), 3.84–3.70 (m,

2H), 3.19 (d, J = 2.4 Hz, 1H), 2.66 (dt, J = 13.0, 3.0 Hz, 1H), 2.12–2.04 (m,

1H), 1.92–1.79 (m, 2H), 1.69–1.53 (m, 3H), 1.50–1.32 (m, 2H). ¹³C

NMR(APT, 125 MHz, CDCl₃): δ = 157.1 (C), 138.0 (C), 131.5 (CH), 130.8

(C), 128.9 (CH), 128.7 (CH), 128.2 (CH), 127.8 (CH), 118.8 (CH), 118.5

(CH), 57.4 (CH), 53.1 (CH₂), 51.9 (CH), 29.6 (CH₂), 26.4 (CH₂), 25.9 (CH₂),

19.8 (CH₂). HRMS (ESI): ([M+H]⁺) calcd for C₁₉H₂₄NO: 282.1852; found:

282.1860.

(R)-2-[2ʹ-(3ʹʹ,5ʹʹ-di-tert-butyl-2ʹʹ-methoxyphenyl)-1ʹ-

phenylethyl]isoindoline-1,3-dione (30). A 1 L, round-bottomed, oven-

dried Schlenk flask equipped with a magnetic stir bar was charged with

(S)-(−)-2-(3,5-di-tert-butyl-2-methoxyphenyl)-1-phenylethanol (29) (3.4 g,

10.0 mmol, 1.00 equiv), triphenylphosphine (PPh₃, 10.5 g, 40.0 mmol, 4.00

equiv) and phthalimide (PhthNH, 4.4 g, 30.0 mmol, 3.00 equiv). The

reaction flask was evacuated for 15 minutes and back-filled with dry N₂

and its content was dissolved by the addition of dry THF (400 mL).

Diisopropyl azodicarboxylate (DIAD, 7.9 mL, 8 g, 40.0 mmol, 4.00 equiv)

was drop-wise added to the ice-cooled reaction mixture. The mixture was

then stirred for 16 h while the temperature was allowed to rise to ambient

temperature. Purification by flash column chromatography (silica gel;

Hexane/EtOAc, 9:1) afforded 3.52 g (7.5 mmol, 75%) of the title compound

(30) as a colorless oil. TLC: R_f= 0.26 (silica gel; hexanes/EtOAc, 9:1).

[α]²_D²= +140 (c = 0.5, CHCl₃). HPLC: Daicel Chiralpak AD-H (4.60 mm ID

× 250 mm column length); n-hexane/ⁱPrOH (98:2), 0.5 mL/min; 254 nm

2-[(1′R,2′R)-2′,2′-Dimethylaminocyclohexyl]phenol (27). Following the

general procedure I as described above, 25 (233 mg, 1.0 mmol, 1.00

equiv) was treated with BBr₃(290 µL, 752 mg, 3.00 mmol, 3.00 equiv) in

10 mL DCM in an ice-bath. The temperature allowed to rise to ambient

temperature as the mixture was stirred for 6 h under N₂. The pH value was

adjusted to 9–9.5, by the drop-wise addition of of an aqueous saturated

NaHCO₃solution. The organic phase separated and the aqueous phase

was shaken with DCM (3 × 50 mL). The combined organic phases were

dried over Na₂SO₄, filtered, and concentrated by rotary evaporation in

vacuo. Purification of the crude product by flash column chromatography

on silica gel (hexanes/EtOAc/TEA, 9:0.8:0.2) afforded 200 mg (0.91 mmol,

91%) of the title compound (27) as a colorless oil. TLC: R_f= 0.19 (silica

gel; hexanes/EtOAc/TEA, 9:0.8:0.2). [α]²_D⁸= −10 (c = 0.5, CHCl₃). FTIR

(KBr): ṽ_max(cm⁻¹) = 2933 (s), 2600 (br), 1843 (br), 1605 (s), 1472 (s), 1236

(s), 1104 (w), 1029 (s), 974 (s), 881 (s), 834 (w), 752 (s), 563 (w), 526 (w).

¹H NMR (500 MHz, CDCl₃): δ = 7.31 (dd, J = 7.7, 0.7 Hz, 1H), 7.11–7.06

(m, 1H), 6.84 (dd, J = 8.0, 1.3 Hz, 1H), 6.77 (td, J = 7.7, 1.4 Hz, 1H), 3.55

(dd, J = 8.1, 4.0 Hz, 1H), 2.70 (ddd, J = 11.5, 4.7, 3.4 Hz, 1H), 2.30 (s, 6H),

2.27 (ddd, J = 7.1, 4.6, 2.8 Hz, 1H), 1.91–1.83 (m, 1H), 1.82–1.72 (m, 2H),

1.66–1.52 (m, 2H), 1.51–1.44 (m, 1H), 1.43–1.32 (m, 1H). ¹³C NMR (APT,

125 MHz, CDCl₃): δ = 158.1 (C), 129.6 (CH), 127.9 (C), 127.6 (CH), 118.6

(CH), 118.3 (CH), 68.1 (CH), 42.5 (CH₃), 40.5 (CH), 31.2 (CH₂), 26.1 (CH₂),

23.5 (CH₂), 22.4 (CH₂). HRMS (ESI): ([M+H]⁺) calcd for C₁₄H₂₂NO:

220.1696; found: 220.1703.

(UV–vis); t_R= 17.1 min (ent-30), t_R= 19.4 min (30). FTIR (KBr): ṽ_max(cm⁻¹

)

= 2959 (br), 1771 (s), 1713 (s), 1603 (m), 1478 (s), 1386 (s), 1331 (s),

1229 (s), 1158 (m), 1124 (s), 1087 (s), 1010 (s), 883 (m), 757 (s), 720 (s),

667 (w), 530 (m). ¹H NMR (500 MHz, CDCl₃):  = 7.78–7.72 (m, 2H), 7.68–

7.60 (m, 4H), 7.41–7.34 (m, 2H), 7.33–7.28 (m, 1H), 7.15 (td, J = 8.1, 1.7

Hz, 1H), 7.09 (dd, J = 7.4, 1.5 Hz, 1H), 6.83 (d, J = 8.1 Hz, 1H), 6.74 (td, J

= 7.4, 0.9 Hz, 1H), 5.85 (dd, J = 10.9, 5.1 Hz, 1H), 3.93 (dd, J = 13.5, 10.9

Hz, 1H), 3.84 (s, 3H), 3.61 (dd, J = 13.5, 5.1 Hz, 1H). ¹³C NMR (APT, 125

MHz, CDCl₃): δ = 168.3 (C), 157.8 (C), 139.9 (C), 133.8 (CH), 131.8 (C),

130.8 (CH), 128.4 (CH), 128.0 (CH), 128.0 (CH), 127.7 (C), 126.4 (C),

123.1 (CH), 120.3 (CH), 110.3 (CH), 55.3 (CH₃), 54.1 (CH), 32.4 (CH₃).

HRMS: ([M+H]⁺) calcd for C₃₁H₃₆NO₃: 470.2690, found: 470.2668.

(R)-2-(3ʹ,5ʹ-di-tert-butyl-2ʹ-methoxyphenyl)-1-phenylethan-1-amine

(31). A 250 mL, round-bottomed, oven-dried Schenk flask equipped with a

magnetic stir bar was charged with 30 (2.82 g, 6.0 mmol, 1.00 equiv) and

capped wih a glass stopper. The flask was evacuated for 15 min and back-

filled with N₂. After addition of ethanol (90 mL) as the solvent, hydrazine

.

hydrate (H₂NNH₂H₂O) (2.9 mL, 3 g, 60.0 mmol, 10.00 equiv) was drop-

wise added into the flask, under a positive pressure of N₂. The reaction

mixture was then heated to 90 °C and stirred at this temperature for 6 h.

After the reaction mixture was cooled to the room temperature, diethyl

ether (50 mL) was added to the mixture and it was filtered in order to

separate from the white precipitate. The filtrate was dried over Na₂SO₄,

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European Journal of Organic Chemistry

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filtered, and concentrated by rotary evaporation in vacuo. This procedure

was repeated one more time. Thus, the title compound 31 (1.41 g, 4.15

mmol, 69%) was obtained as a colorless solid. Mp: 85–86 °C. TLC: R_f=

0.25 (silica gel; hexanes/EtOAc/TEA, 9.2:0.4:0.4). [α]²_D⁶= −4 (c = 0.5,

CHCl₃). FTIR (KBr): ṽ_max(cm⁻¹) = 3370 (s), 3305 (w), 2962 (s), 2862 (s),

1989 (w), 1951 (w), 1728 (w), 1589 (m), 1361 (s), 1224 (s), 1111 (s), 1000

(s), 844 (s), 756 (s), 697 (s). ¹H NMR (600 MHz, CDCl₃):  = 7.36 (d, J =

7.4 Hz, 2H), 7.31 (t, J = 7.4 Hz, 2H), 7.25–7.18 (m, 2H), 6.92 (d, J = 1.9

Hz, 1H), 4.28 (dd, J = 8.3, 5.4 Hz, 1H), 3.79 (s, 3H), 3.01 (dd, J = 13.7, 5.2

Hz, 1H), 2.94 (dd, J = 13.6, 8.6 Hz, 1H), 1.63 (br, 2H), 1.40 (s, 9H), 1.24

(s, 9H). ¹³C NMR (150 MHz, CDCl₃):  = 156.3 (C), 146.2 (C), 145.5 (C),

141.9 (C), 131.7 (C), 128.4 (CH), 126.9 (CH), 126.5 (CH), 126.4 (CH),

122.6 (CH), 61.6 (CH₃), 56.5 (CH), 42.0 (CH₂), 35.26 (C), 34.34 (C), 31.46

(CH₃), 31.23 (CH₃). HRMS: ([M+H]⁺) calcd for C₂₃H₃₄NO: 340.2635, found:

340.2627.

3458 (br), 2955 (s), 1605 (m), 1536 (m), 1479 (s), 1361 (s), 1296 (w), 1194

(s), 1121 (s), 879 (w), 758 (m) , 698 (s). ¹H NMR (500 MHz, CDCl₃):  =

7.23 (d, J = 6.9 Hz, 2H), 7.16–7.03 (m, 4H), 6.20 (s, 1H), 4.42 (d, J = 6.3

Hz, 1H), 3.66 (d, J = 11.6 Hz, 1H), 3.04–2.98 (m, 1H), 1.35 (s, 9H), 1.01

(s, 9H). ¹³C NMR (125 MHz, CDCl₃):  = 153.5 (C), 144.3 (C), 139.4 (C),

131.4 (CH), 131.2 (CH), 130.1 (CH), 129.0 (CH), 125.2 (CH), 59.1 (CH),

ca. 40.0 (CH₂, this signal was missing, but, it was determined by HSQC

experiment.) 37.6 (C), 36.5 (C), 34.0 (CH₃), 32.7 (CH₃). Two substituted

aromatic carbon atoms did not give resolved ¹³C peaks, thus they were

missing. HRMS: ([M+H]⁺) calcd for C₂₂H₃₂NO: 326.2478, found: 326.2479.

(2S,1'S)-2-[Hydroxy(4-nitrophenyl)methyl]cyclohexanone (36a) and

(2S,1'R)-2-[Hydroxy(4-nitrophenyl)methyl]cyclohexanone

(37a)

(Table 1, entry 9). The AAP 1 (4.8 mg, 25 μmol, 10 mol%) and benzoic

acid (3.1 mg, 25 μmol, 10 mol%) were placed in a 5 mL vial and they are

dissolved in 0.5 mL toluene. After cyclohexanone (207 μL, 196 mg 2.0

mmol, 8.00 equiv) was added into the vial, the homogenous mixture was

stirred for 15 minutes. 4-Nitrobenzaldehyde (37 mg, 0.25 mmol, 1.00

equiv) was added in one portion and the mixture was stirred at rt for 36 h,

in the closed vial. The progress of the reaction was monitored by TLC. The

title products 36a and 37a were obtained by column chromatography on

silica gel. A 70:30 syn/anti ratio (36a:37a) as well as 64% ee for 36a and

78% ee for 37a were determined by HPLC on a chiral column. R_f(36a)=

0.42 (silica gel; hexanes/EtOAc, 7:3). R_f(37a)= 0.41 (silica gel;

hexanes/EtOAc, 7:3). HPLC: Daicel Chiralpak AD-H (4.60 mm ID × 250

mm column length); n-hexane/ⁱPrOH (85:15), 1.0 mL/min; 254 nm (UV–

(R)-N-[2-(3ʹ,5ʹ-di-tert-butyl-2ʹ-hydroxyphenyl)-1-

phenyl]ethylformamide (32). An oven-dried 50 mL Schlenk tube, capped

with a glass stopper and equipped with a magnetic stir bar, was evacuated

for 15 minutes, back-filled with dry N₂, and the glass stopper was replaced

with a rubber septum under positive pressure of dry N₂. Dry DMF (7.5 mL)

and EtSH (881 µL, 732 mg, 11.78 mmol, 8.00 equiv) were mixed in the

tube. To the cooled reaction mixture in an ice-bath was added NaO^tBu

(423 mg, 4.41 mmol, 3.00 equiv) at once and it was stirred at 0 °C for 30

minutes. Then, the anisole 31 (500 mg, 1.47 mmol, 1.00 equiv) was added

into the Schlenk tube at 0 °C and the reaction tube was heated to 120 °C

and stirred at this temperature for 3 hours. Conversion of the starting

material 31 was followed by TLC. After cooling down to 0 °C, pH value of

the reaction mixture was adjusted to 9–10, by the addition of 1.0 N HCl.

The organic components were extracted with Et₂O (3 × 75 mL). The

combined organic phases were dried over Na₂SO₄, filtered, and

concentrated by rotary evaporation in vacuo. Purification of the residue by

flash column chromatography on silica gel (hexanes/EtOAc, 7:3) gave 407

mg (1.15 mmol, 78%) of the title compound (32) as a colorless solid. Mp:

68–70 °C. TLC: Rf = 0.41 (silica gel; hexanes/EtOAc, 7:3). [α]²_D⁶= +28 (c

= 0.5, CHCl₃). FTIR (KBr): ṽ_max(cm⁻¹) = 3297 (br s), 2958 (s), 2869 (m),

1646 (br,s), 1525 (m), 1480 (s), 1362 (s), 1221 (s), 1121 (w), 879 (w), 759

vis); t_R= 15.1 min (ent-36a), t_R= 16.9 min (36a), t_R= 18.6 min (37a), t_R

24.6 min (ent-37a).

=

(S)-4-Hydroxy-4-(4-nitrophenyl)-2-butanone (39) (Table 2, entry 6).

The primary amine (5.1 mg, 25 μmol, 10 mol%) and 2,4,6-

7

triisopropylbenzoic acid (12.5 mg, 50 μmol, 20 mol%) were placed in a 5

mL vial and they are suspended in 0.1 mL toluene. After acetone (150 μL,

118 mg, 2.0 mmol, 8.00 equiv) was added into the vial, the resulting

homogenous mixture was cooled to 0 °C in a cooling bath and stirred for

15 minutes. 4-Nitrobenzaldehyde (37 mg, 0.25 mmol, 1.00 equiv) was

added in one portion and the mixture was stirred at 0 °C for 192 h, in the

closed vial. The progress of the reaction was monitored by TLC. The title

product 39 was isolated by column chromatography on silica gel, in 85%

yield and 62% ee. R_f= 0.41 (silica gel; hexanes/EtOAc, 6:4). HPLC: Daicel

Chiralpak AS-H (4.60 mm ID × 250 mm column length); n-hexane/ⁱPrOH

(85:15), 1.0 mL/min; 254 nm (UV–vis); t_R= 25.1 min (ent-39), t_R= 32.4 min

(39).

1

(m) , 699 (s). H NMR (500 MHz, CDCl₃):  = 8.22 (s, 1H), 7.35–7.29 (m,

3H), 7.21–7.18 (m, 2H), 7.15 (d, J = 2.3 Hz, 1H), 7.09 (s, 1H), 6.42 (s, 1H),

6.37 (d, J = 2.3 Hz, 1H), 4.82 (ddd, J = 8.8, 5.4, 3.2 Hz, 1H), 3.48 (dd, J =

14.0, 3.1 Hz, 1H), 2.85 (dd, J = 14.0, 9.4 Hz, 1H), 1.65 (d, J = 3.1 Hz, 1H),

1.45 (s, 9H), 1.11 (s, 9H). ¹³C-NMR (APT, 125 MHz,CDCl₃): δ = 162.0 (CH),

151.3 (C), 141.1 (C), 139.7 (C), 135.8 (C), 128.8 (CH), 128.1 (CH), 127.1

(CH), 125.7 (CH), 122.5 (CH), 122.4 (C), 55.6 (CH), 38.6 (CH₂), 34.9 (C),

33.9 (C), 31.4 (CH₃), 29.9 (CH₃). HRMS: ([M+H]⁺) calcd for C₂₃H₃₂NO₂:

354.2428, found: 354.2402.

(2S,1'S)-2-[Hydroxy(phenyl)methyl]cyclohexanone

(36b)

and

(2R,1'S)-2-[Hydroxy(phenyl)methyl]cyclohexanone (37b) (Scheme 8).

The AAP 1 (4.8 mg, 25 μmol, 10 mol%) and benzoic acid (3.1 mg, 25 μmol,

10 mol%) were placed in a 5 mL vial. After cyclohexanone (207 μL, 196

mg 2.0 mmol, 8.00 equiv) was added into the vial, the homogenous mixture

was stirred for 15 minutes. Then, benzaldehyde (27 mg, 0.25 mmol, 1.00

equiv) was added in one portion and the mixture was stirred at rt for 36 h,

in the closed vial. The progress of the reaction was monitored by TLC. The

title products 36b and 37b were obtained by column chromatography on

silica gel (82 mg, 10 µmol, 40%). R_f(36b)= 0.44 (silica gel; hexanes/EtOAc,

8:2). R_f(37b)= 0.39 (silica gel; hexanes/EtOAc, 8:2). HPLC: Daicel

Chiralpak AS-H (4.60 mm ID × 250 mm column length); n-hexane/ⁱPrOH

(90:10), 0.5 mL/min; 220 nm (UV–vis); t_R= 20.6 min (36b), t_R= 25.5 min

(ent-36b), t_R= 27.5 min (ent-37b), t_R= 28.5 min (37b).

(R)-2-(2ʹ-amino-2ʹ-phenylethyl)-4,6-di-tert-butylphenol

(33).

The

formamide 32 (232 mg, 0.66 mmol, 1.00 equiv) was dissolved in 3 mL

MeOH and 3 mL of 10% sodium hydroxide solution in MeOH (w/w) were

added to this solution. The resulting homogenous mixture was refluxed for

2 h under N₂, with magnetic stirring. Conversion of the formamide 32 was

followed by TLC. Methanol was removed by rotary evaporation under

reduced pressure. To the oily residue was added water (ca. 5 mL) and

then, 20 mL of 20% hydrochloric acid were drop-wise added to the mixture.

The resulting homogenous mixture was extracted with Et₂O (2 × 50 mL),

organic phase was discharged. pH value of the aqueous phase was

adjusted to 9 by adding saturated sodium bicarbonate solution under ice

cooling. Organic component of the resulting slurry was extracted with DCM

(2 × 50 mL). The organic phase was dried over Na₂SO₄, filtered, and

concentrated by rotary evaporation in vacuo. The title compound (33) was

obtained as a beige colored solid (193 mg, 0.59 mmol, 90%). Mp: 241–

syn-2-[Hydroxy(4-methoxyphenyl)methyl]cyclohexanone (36c) and

anti-2-[Hydroxy(4-methoxyphenyl)methyl]cyclohexanone

(37c)

(Scheme 8). The AAP 1 (4.8 mg, 25 μmol, 10 mol%) and benzoic acid (3.1

mg, 25 μmol, 10 mol%) were placed in a 5 mL vial. After cyclohexanone

(207 μL, 196 mg 2.0 mmol, 8.00 equiv) was added into the vial, the

242 °C. TLC: R_f

= 0.55 (silica gel; hexanes/EtOAc/TEA/MeOH,

4:0.5:0.25:0.25). [α]_D²¹= −98 (c = 0.5, CHCl₃). FTIR (KBr): ṽ_max(cm⁻¹) =

10.1002/ejoc.201801445

European Journal of Organic Chemistry

FULL PAPER

homogenous mixture was stirred for 15 minutes. Then, p-anisaldehyde (34

mg, 0.25 mmol, 1.00 equiv) was added in one portion and the mixture was

stirred at rt for 36 h, in the closed vial. The progress of the reaction was

monitored by TLC. The title products 36c and 37c were obtained by

column chromatography on silica gel (42 mg, 4.5 µmol, 18%). R_f(36c)=

0.38 (silica gel; hexanes/EtOAc, 7:3). R_f(37c)= 0.35 (silica gel;

hexanes/EtOAc, 7:3). HPLC: Daicel Chiralpak AS-H (4.60 mm ID × 250

mm column length); n-hexane/ⁱPrOH (90:10), 0.5 mL/min; 220 nm (UV–

vis); t_R= 25.7 min (36c, minor), t_R= 29.5 min (36c, major), t_R= 42.4 min

(37c, major), t_R= 43.8 min (37c, minor).

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Acknowledgments

This work was financially supported by the Scientific and

Technological Research Council of Turkey (TÜBITAK, project

111T597).

Keywords: Asymmetric synthesis, Chiral resolution,

Organocatalysis, Aldol reaction, Chiral primary amines

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Entry for the Table of Contents

FULL PAPER

Effective preparation of enantiopure

cis- and trans-2-(2-

aminocyclohexyl)phenols, novel 1,4-

aminoalkylphenols, as well as their

performance as chiral organocatalyst

are presented.

Asymmetric Catalysis

Mustafa A. Tezeren, Tolga A. Yeşil,

Yunus Zorlu, Tahir Tilki, Erkan Ertürk*

Page No. – Page No.

Enantiopure cis- and trans-2-(2-

Aminocyclohexyl)phenols: Effective

Preparation, Solid-State

Characterization, and Application in

Asymmetric Organocatalysis

Article Doi

Enantiopure cis- and trans-2-(2-Aminocyclohexyl)phenols: Effective Preparation, Solid-State Characterization, and Application in Asymmetric Organocatalysis

DOI: 10.1002/ejoc.201801445

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Full text of DOI:10.1002/ejoc.201801445

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