Kinetic Resolution of [2.2]Paracyclophane-Derived Cyclic N-Sulfonylimines via Palladium-Catalyzed Addition of Arylboronic Acids

Yang Zhao, Xiao-Qing Wang, Yan-Jiang Yu, and Yong-Gui Zhou*

Note

Kinetic Resolution of [2.2]Paracyclophane-Derived Cyclic

N‑Sulfonylimines via Palladium-Catalyzed Addition of Arylboronic

Acids

Cite This: https://dx.doi.org/10.1021/acs.joc.0c02509

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ABSTRACT: A facile method for kinetic resolution of [2.2]-

paracyclophane-derived cyclic N-sulfonylimines based on palla-

dium-catalyzed addition of arylboronic acids was developed, giving

two kinds of planar chiral [2.2]paracyclophane derivatives in

excellent diastereoselectivities and up to 99% of enantioselectivities

with high selectivity factors (s up to 128).

[

2.2]Paracyclophane derivatives are fascinating, considering

distinguish the planar chirality of [2.2]paracyclophane-derived

cyclic N-sulfonylimines. Herein, we report a facile method for

kinetic resolution of [2.2]paracyclophane-derived cyclic N-

sulfonylimines based on palladium-catalyzed addition of

arylboronic acids. Two kinds of planar chiral [2.2]-

paracyclophane derivatives could be obtained in excellent

diastereoselectivities and enantioselectivities with high selectiv-

ity factors (Scheme 1c).

their intriguing structural and electronic properties. As a result of

their rigid scaﬀold, mono- and polysubstituted [2.2]-

paracyclophanes are representative frameworks for planar

chirality. Enantiopure [2.2]paracyclophanes have been success-

fully utilized as chiral materials, including mesoporous polymers,

metal−organic frameworks, and circularly polarized light-

emitting compounds. Planar chiral [2.2]paracyclophanes have

also found ample applications as one of the most commonly

used classes of chiral inductors for asymmetric synthesis. A

major method for the optical resolution of planar chiral

At the outset of the investigation, [2.2]paracyclophano[5,6-

d]-1,2,3-benzoxathiazine 2,2-dioxide 1a was chosen as model

substrate for condition optimization. Based on previous work on

g,8

asymmetric addition with arylboronic acids,

bidentate

[2.2]paracyclophanes has been developed by chromatographic

phosphine-oxazoline ligands performed well for the palladium-

catalyzed asymmetric addition of arylboronic acids to imines. In

techniques or chiral reagents, but there are few examples of the

catalytic asymmetric process for accessing the enantioenriched

this context, the experiment was conducted using Pd-

[2.2]paracyclophanes.

(

OCOCF ) /(S)- Bu-Phox as a catalyst. To our delight, the

Cyclic N-sulfonylimines play an important role in the

3 2

reaction proceeded cleanly in TFE (2,2,2-triﬂuoroethanol) at 60

C, albeit with low diastereoselectivity (Table 1, entry 1, s =

4.4). Aiming to further enhance the stereoselectivity, a number

synthesis of functionalized benzosulfamidate heterocycles.

These chiral cyclic sulfamidate compounds display important

biological activities including antiviral, antibiotic, anticonvul-

sant, anticancer, antiobesity, and antiosteoporosis activities.

Thus, some reactions exist using cyclic N-sulfonylimines for the

of ferrocene-derived phosphinooxazoline ligands with planar

chirality were tested. High diastereoselectivity was obtained

when using L3 and L4 as ligands (Table 1, entries 3 and 4). L3

was selected as the best ligand considering the kinetic resolution

selectivity factor. Changing the solvent to 1,2-dichloroethane,

synthesis of sulfamidate derivatives, involving asymmetric

nucleophilic addition and hydrogenation (Scheme 1a).

Recently, palladium-catalyzed enantioselective addition of

arylboronic acids has emerged as an eﬃcient method for the

rapid and diversiﬁed construction of central-chiral sulfamidate-

s. Considering that the planar chiral [2.2]paracyclophane

derivatives containing the sulfamidate motif have potential

applications in organocatalysis and biologically active molecules

and in connection with our previous work on the palladium-

catalyzed kinetic resolution of [2.2]paracyclophane-derived

acyclic N-sulfonylimines with arylboronic acids (Scheme

,4-dioxane, or hexaﬂuoroisopropanol, the reactions gave worse

results (Table 1, entries 6−8). In addition, the eﬀects of reaction

temperature and the amounts of phenylboronic acid were

evaluated (Table 1, entries 9−12). Finally, the optimal reaction

conditions were established: using Pd(OCOCF ) /L3 as a

Received: October 21, 2020

b), we speculated this approach could be extended to kinetic

resolution of [2.2]paracyclophane-derived cyclic N-sulfonyli-

mines. The key point in the development of an eﬃcient kinetic

resolution method is to ﬁnd a suitable chiral catalyst to

XXXX American Chemical Society

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The Journal of Organic Chemistry

Note

Scheme 1. Kinetic Resolution of [2.2]Paracyclophane-Derived Cyclic Imines via Pd-Catalyzed Addition of Arylboronic Acids

Table 1. Optimization of the Kinetic Resolution

entry

solvents

TFE

1a conversion (%)

1a ee (%)

2a ee (dr)

93.0

97.0

94.6

96.6

90.1

98.9 (8:1)

99.1 (9:1)

94.2 (>20:1)

87.2 (>20:1)

98.6 (16:1)

44.4

119.5

132.0

34.1

TFE

59.2

DCE

1,4-dioxane

HFIP

TFE

40.5

96.3

96.4

63.2

96.3 (>20:1)

91.5 (>20:1)

93.8 (>20:1)

96.8 (>20:1)

52.6

103.2

105.2

71.9

TFE

Conditions: rac-1a (0.10 mmol), PhB(OH) (0.10 mmol), Pd(OCOCF ) (5.0 mol %), L (5.0 mol %), TFE (2.0 mL), 60 °C, 12 h. Determined

3 2

by H NMR analysis using 1,3,5-trimethoxybenzene as the internal standard. Determined by chiral HPLC analysis. Calculated selectivity factors:

C = conversion, s = ln[(1 − C)(1 − ee of 1a)]/ln[(1 − C)(1 + ee of 1a)]. The reaction was carried out at 40 °C. The reaction was carried out at

0 °C. Using 1.5 equiv of PhB(OH) (0.15 mmol). Using 0.6 equiv of PhB(OH) (0.06 mmol).

catalyst (5.0 mol % catalyst loading), arylboronic acid as a

nucleophile (1.0 equiv), 2,2,2-triﬂuoroethanol (2.0 mL) as a

solvent to perform the reaction at 60 °C, delivering excellent

selectivity factor (s = 132.0).

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Note

Table 2. Substrate Scope for the Kinetic Resolution of [2.2]Paracyclophane Imines

entry

rac-1 conversion (%)

1 yield (%)

1 ee (%)

2 yield (%)

2 ee (%)

2 dr

97.3

40.0

95.6

83.3

98.7

81.4

63.6

68.6

23.5

50.1

29.8

65.9

36.4

93.7

94.2

87.3

79.7

91.9

97.1

96.1

45.9

91.0

75.6

95.6

97.1

88.5

>20:1

128.0

42.9

61.2

23.3

107.2

111.3

81.9

5.3

40.7

11.5

46.2

74.9

17.5

Conditions: rac-1 (0.20 mmol), PhB(OH) (0.20 mmol), Pd(OCOCF ) (5.0 mol %), L3 (5.0 mol %), TFE (4.0 mL), 60 °C, 12 h. Determined

3 2

by H NMR analysis using 1,3,5-trimethoxybenzene as the internal standard. Determined by chiral HPLC analysis. Calculated selectivity factors:

C = conversion, s = ln[(1 − C)(1 − ee of 1)]/ln[(1 − C)(1 + ee of 1)].

After establishing the optimal conditions, we examined the

substrate generality of kinetic resolution. A broad range of

arylboronic acids could be resolved. The steric hindrance of the

arylboronic acids had a negligible eﬀect on the selectivity factor

sulfonylketimines (1b, 1c) and 8-substituted [2.2]-

paracyclophane-based cyclic N-sulfonylimine (1d) were synthe-

sized. Probably owing to steric eﬀects, no desired products were

observed when 1b and 1c were used as substrates. Fortunately,

the 8-substituted [2.2]paracyclophane-based cyclic N-sulfony-

limine (1d) was also a suitable reaction partner, and the reaction

worked well with moderate selectivity (Table 2, entries 12 and

13).

(Table 2, entries 2−4). In addition, the arylboronic acid bearing

an ortho substituent showed very low reactivity. The electron-

deﬁcient arylboronic acids containing halo- or triﬂuoromethyl

were also well tolerated (Table 2, entries 5−7 and 9).

Arylboronic acids bearing electron-donating groups showed

slightly higher activity than those bearing electron-withdrawing

groups but with a very low selectivity factor (Table 2, entry 8).

Moreover, the addition of 4-tert-butylphenylboronic acid and 2-

naphthaleneboronic acid to imine 1a proceeded smoothly

Next, the potential synthetic utility of this method was

demonstrated. We performed a gram-scale reaction and

derivatizations of recovered material (R )-1a and addition

adduct (S ,R)-2a. Gratifyingly, this strategy could be successfully

applied to the scale-up reaction of rac-1a (2 mmol) with

phenylboronic acid under the standard conditions (Scheme 2a),

and the kinetic selectivity factor of this reaction was similar to

those obtained in the small-scale reaction. The addition of

phenylboronic acid and imine (+)-1a (49.6% ee) proceeded

again to get the material (+)-1a with 99% ee. In addition, some

transformations of [2.2]paracyclophane-based planar chiral

(Table 2, entries 10 and 11). For aliphatic boronic acids

including methylboronic acid and trans-2-phenylvinylboronic

acid, no reaction occurred under the standard conditions.

Besides, boronate esters including 2,4,4,5,5-pentamethyl-

[1,3,2]dioxaborolane, 2-phenyl-4,4,5,5-tetramethyl-1,3,2-dioxo-

borole, and 4,4,5,5-tetramethyl-2-((E)-styryl)-[1,3,2]-

dioxaborolane were not reactive. To further estimate the

application possibility, [2.2]paracyclophane-derived cyclic N-

imine (R )-1a were performed (Scheme 2b). Planar chiral

products (R ,S)-2a, (R ,S)-3, and (R )-4 were obtained in high

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Note

Scheme 2. Scale-up Reaction and Elaborations of Recovered Material (R )-1a and Product (S ,R)-2a

Scheme 3. Proposed Mechanism and Stereochemical Model

yields with excellent retention of the enantiopurity. The

magnesium bromide and methyl magnesium bromide were used

carbon−nitrogen double bond of (R )-1a was reduced with

as nucleophiles to react with (R )-1a, good stereoselectivity was

sodium borohydride conveniently to (R )-4. When phenyl

observed in these cases because of the substantial rigidity of the

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

2.2]paracyclophane backbone. With lithium aluminum hydride

Note

[

chromatography was performed on silica gel (200−300 mesh). All

reactions were monitored by TLC analysis. High-resolution mass

spectrometry (HRMS (ESI-TOF) m/z) was measured on an

electrospray ionization (ESI) apparatus using time-of-ﬂight (TOF)

mass spectrometry. The heat source in reaction procedures was an oil

bath.

as the nucleophilic reagent, the ring opening of addition adduct

S_p,R)-2a was carried out to synthesize [2.2]paracyclophane-

(

derived amino phenol (S ,R)-5 in 77% yield without the loss of

optical purity (Scheme 2c).

To obtain more insight into the mechanism, we performed the

Procedures for Synthesis of [2.2]Paracyclophane-Derived

Cyclic N-Sulfonylimine. [2.2]Paracyclophane-derived cyclic N-

sulfonylimine 1 could be synthesized from substituted hydroxy[2.2]-

paracyclophane and sulfamoyl chloride according to the literature

addition of (R )-1a with 99% ee under the standard conditions,

and no reaction occurred. According to the above experimental

results and putative mechanism on palladium-catalyzed

arylation of imines, a proposed mechanism was shown in

procedures. The substituted hydroxy[2.2]paracyclophane 5-formyl-4-

Scheme 3a. First, the cationic palladium complex A was

hydroxy[2.2]paracyclophane, 5-acetyl-4-hydroxy[2.2]-paracyclophane,

and 5-benzoyl-4-hydroxy[2.2]paracyclophane are known compounds

generated in the presence of Pd(TFA) , phosphinooxazoline

and prepared by the literature procedures. 4-Hydroxy-5-formyl-7-

methyl[2.2]paracyclophane could be conveniently synthesized from 4-

formyl-7-methyl[2.2]paracyclophane. 4-Formyl-7-methyl[2.2]-

ligand, and 2,2,2-triﬂuoroethanol. After that, the cationic

palladium complex A underwent transmetalation with arylbor-

onic acid to form ArPd complex B. Coordination of cyclic N-

sulfonylimine 1a with B led to form intermediate C, which

allowed insertion of the CN bond into the PdC bond to

form D. Alcoholysis of intermediate D aﬀorded the addition

product 2a and regenerated the active Pd(II) complex A. The

key to achieving kinetic resolution was the selective reaction of

intermediate B with a single enantiomer of 1a. On the basis of

the above experimental results and absolute conﬁguration of

addition product (S ,R)-2a, (S )-1a matched the ligand (S ,R)-

paracyclophane was prepared by the literature procedures.

Following a known literature procedure, anhydrous formic acid

(

1.841 g, 1.51 mL, 40 mmol) was added dropwise to neat

chlorosulfonyl isocyanate (5.661 g, 3.48 mL, 40 mmol) at 0 °C with

rapid stirring. Vigorous gas evolution was observed during the addition

process. The resulting viscous suspension was stirred at room

temperature until gas evolution ceased (1−2 h). The liquid was

removed to give the product sulfamoyl chloride (H NSO Cl).

Method A. To a solution of substituted hydroxy[2.2]paracyclophane

1.0 equiv) in N,N-dimethylacetamide (0.24 M) was quickly

(

L3. The stereochemical model of this reaction was proposed as

shown in Scheme 3b. The N-sulfonylimine 1a coordinated with

Pd(II) cis to an oxazoline motif with the benzene ring of the

transferred at once solid H NSO Cl (5.2 equiv) at 0 °C. Caution: the

combination of these two compounds is slightly exothermic. The

solution was allowed to warm to room temperature and was stirred for

[

2.2]paracyclophane framework oriented upward as a result of a

12 h. The reaction was quenched by the addition of water (30 mL), and

steric eﬀect, and the insertion of ArPd species to 1a occurred

the aqueous layer was extracted with ethyl acetate (3 × 20 mL). After

drying over anhydrous sodium sulfate, ﬁltration, and volatile removal

under the reduced pressure, the crude residue was puriﬁed by silica gel

column chromatography to aﬀord the compound.

at the downward face. The favored model in which (S )-1a

bound to the palladium center avoided the steric interaction

between the benzyl group of oxazoline moiety and the benzene

ring of [2.2]paracyclophane framework, giving the product 2a

Method B. A mixture of substituted hydroxy[2.2]paracyclophane

(1.0 equiv) was dissolved in toluene (0.10 M), and H NSO Cl (2.0

with the observed (S ,R) conﬁguration.

In conclusion, we have demonstrated the feasibility of the

kinetic resolution of [2.2]paracyclophane-derived cyclic N-

sulfonylimine using the palladium-catalyzed addition of

arylboronic acids. This strategy oﬀers two kinds of planar chiral

equiv) was added. Then the reaction mixture was heated at reﬂux for 10

h. The reaction was quenched by the addition of water (30 mL), and the

aqueous layer was extracted with ethyl acetate (3 × 20 mL). After

drying over anhydrous sodium sulfate, ﬁltration, and volatile removal

under the reduced pressure, the crude residue was puriﬁed by silica gel

column chromatography as an eluent to aﬀord the compound.

[2.2]paracyclophane derivatives in good diastereoselectivities

up to >20:1 dr) and excellent enantioselectivities (up to 99%

(

[

2.2]Paracyclophano[5,6-d]-1,2,3-benzoxathiazine 2,2-Diox-

ee) with high selectivity factors (s up to 128). This method not

only provides easy access to the planar chiral [2.2]-

paracyclophane-derived cyclic N-sulfonylimines but also oﬀers

a robust method for synthesizing cyclic sulfamidate derivatives

bearing both planar and central chirality. The obtained

enantioenriched derivatives incorporating reactive groups are

suitable for late-stage functionalization. As a result, these

compounds may reveal particular uses as synthetic intermediates

to rapidly access more complex planar chiral [2.2]-

paracyclophanes in their enantiopure form. Such work is

ongoing, and the results will be reported in due course.

ide (1a). The reaction was performed according to Method A using 5-

formyl-4-hydroxy[2.2]paracyclophane (3.071 g, 12 mmol, 1.0 equiv)

and H NSO Cl (7.168 g, 62 mmol, 5.2 equiv) for 12 h, and the crude

mixture was puriﬁed using hexanes and ethyl acetate as an eluent to give

N-sulfonylimine 1a: 2.371 g, 63% yield, yellow solid, mp = 232−234 °C.

New compound: R

= 0.50 (hexanes/ethyl acetate 2:1). H NMR (400

MHz, CDCl ): δ 8.49 (s, 1H), 6.90−6.83 (m, 2H), 6.69−6.62 (m, 2H),

.52−6.45 (m, 1H), 6.36−6.29 (m, 1H), 3.70−3.59 (m, 1H), 3.52−

.43 (m, 1H), 3.41−3.31 (m, 1H), 3.26−2.97 (m, 4H), 2.84−2.72 (m,

H). C{ H} NMR (100 MHz, CDCl ): δ 164.7, 153.8, 144.7, 143.1,

39.9, 137.8, 133.9, 133.0, 132.1, 131.1, 129.5, 128.2, 117.1, 35.5, 34.0,

1.5, 28.6. HRMS (ESI-TOF): m/z calcd for C H NO S [M + H] ,

14.0845; found, 314.0845.

EXPERIMENTAL SECTION

All reactions were carried out under an atmosphere of nitrogen using

the standard Schlenk techniques, unless otherwise noted. Commer-

cially available reagents were used without further puriﬁcation. Solvents

-Methyl-[2.2]paracyclophano[5,6-d]-1,2,3-benzoxathia-

■

zine 2,2-Dioxide (1b). The reaction was performed according to

Method A using 5-acetyl-4-hydroxy[2.2]paracyclophane (1.224 g, 4.6

mmol, 1.0 equiv) and H NSO Cl (2.761 g, 23.9 mmol, 5.2 equiv) for 12

h, and the crude mixture was puriﬁed using hexanes and ethyl acetate as

an eluent to give N-sulfonylimine 1b: 1.301 g, 87% yield, yellow solid,

were treated prior to use according to the standard methods. H NMR

and C NMR spectra were recorded at 400 and 100 MHz with a Bruker

spectrometer, respectively. F NMR spectra were recorded at 376

MHz with a Bruker spectrometer. Chemical shifts are reported in ppm

mp = 183−185 °C. New compound: R

= 0.70 (hexanes/ethyl acetate

): δ 6.95−6.90 (m, 1H), 6.76−6.67

2:1). H NMR (400 MHz, CDCl

using tetramethylsilane as an internal standard when using CDCl as a

(m, 2H), 6.66−6.61 (m, 1H), 6.57−6.52 (m, 1H), 6.37−6.31 (m, 1H),

solvent for H NMR spectra. The following abbreviations were used to

3.65−3.53 (m, 1H), 3.51−3.41 (m, 1H), 3.35−3.14 (m, 3H), 3.08−

symbolize the multiplicities: s = singlet, d = doublet, t = triplet, m =

multiplet, brs = broad singlet. X-ray crystallography data were collected

using a Bruker D8 Venture with 3.0 ius cu and 3.0 ius mo. Flash column

2.95 (m, 2H), 2.87−2.77 (m, 1H), 2.70 (s, 3H). C{ H} NMR (100

MHz, CDCl ): δ 176.3, 154.0, 143.7, 142.0, 139.8, 137.8, 133.8, 133.7,

132.4, 130.4, 129.2, 117.7, 37.2, 35.9, 34.5, 28.5, 28.1. HRMS (ESI-

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Note

TOF): m/z calcd for C H NO S [M + H] , 328.1002; found,

evaporated at reduced pressure. The crude product was puriﬁed by

column chromatography on silica gel using hexanes and ethyl acetate as

an eluent to aﬀord 4-hydroxy-5-formyl-7-methyl[2.2]paracyclophane 8

(yellow solid, 0.232 g, 19% yield). Mp: 145−147 °C. New compound:

28.1004.

-Phenyl-[2.2]paracyclophano[5,6-d]-1,2,3-benzoxathiazine

,2-Dioxide (1c). The reaction was performed according to Method B

using 5-benzoyl-4-hydroxy[2.2]paracyclophane (1.641 g, 5.0 mmol, 1.0

equiv) and H NSO Cl (1.155 g, 10.0 mmol, 2.0 equiv) for 10 h, and the

R = 0.50 (hexanes/ethyl acetate 20:1). H NMR (400 MHz, CDCl ): δ

12.04 (s, 1H), 9.83 (s, 1H), 6.98−6.90 (m, 1H), 6.85−6.78 (m, 1H),

6.41−6.35 (m, 2H), 6.30−6.24 (m, 1H), 3.48−3.37 (m, 2H), 3.29−

3.12 (m, 3H), 3.08−2.97 (m, 1H), 2.95−2.83 (m, 1H), 2.57−2.44 (m,

crude mixture was puriﬁed using hexanes and ethyl acetate as an eluent

to give N-sulfonylimine 1c: 1.197 g, 63% yield, yellow solid, mp = 262−

64 °C. New compound: R = 0.30 (hexanes/ethyl acetate 20:1). H

1H), 2.16 (s, 3H). C{ H} NMR (100 MHz, CDCl ): δ 193.9, 160.9,

NMR (400 MHz, CDCl ): δ 7.78−7.57 (m, 3H), 7.53−7.43 (m, 2H),

145.0, 143.3, 140.3, 137.9, 133.0, 132.8, 129.4, 128.9, 128.0, 127.0,

.05−6.97 (m, 1H), 6.80−6.75 (m, 1H), 6.74−6.62 (m, 2H), 6.53−

.48 (m, 1H), 6.41−6.35 (m, 1H), 3.62−3.48 (m, 1H), 3.46−3.32 (m,

22.3, 34.4, 33.6, 29.3, 26.8, 19.8. HRMS (ESI-TOF): m/z calcd for

C H O [M + H] , 267.1380; found, 267.1379.

H), 3.08−2.96 (m, 1H), 2.93−2.73 (m, 4H), 2.48−2.34 (m, 1H).

(

8-Methyl[2.2]paracyclophano)[5,6-d]-1,2,3-benzoxathia-

C{ H} NMR (100 MHz, CDCl ): δ 175.0, 155.5, 146.0, 142.8, 139.4,

zine 2,2-Dioxide (1d). The reaction was performed according to

Method A using 4-hydroxy-5-formyl-7-methyl[2.2]paracyclophane 8

(0.232 g, 0.9 mmol, 1.0 equiv) and H NSO Cl (0.543 g, 4.7 mmol, 5.2

38.0, 137.4, 134.3, 133.6, 133.0, 132.4, 131.7, 131.4, 130.3, 128.9,

28.5, 116.3, 36.8, 35.9, 34.9, 28.2. HRMS (ESI-TOF): m/z calcd for

C H NO S [M + H] , 390.1158; found, 390.1151.

equiv) for 12 h, and the crude mixture was puriﬁed using hexanes and

ethyl acetate as an eluent to give N-sulfonylimine 1d: 0.234 g, 72% yield,

-Formyl-7-methyl[2.2]paracyclophane (2.466 g, 10 mmol) was

dissolved in a 9:1 mixture of dichloro-methane/methanol (50 mL/50

mL). Then concentrated sulfuric acid (40 drops) and aqueous

hydrogen peroxide (2.00 mL, 30% wt in water) were subsequently

added, and the solution was stirred for 4 h. The mixture was quenched

with aqueous sodium thiosulfate. The two phases were separated, and

the aqueous phase was extracted with dichloromethane (50 mL). The

combined organic phases were dried over anhydrous sodium sulfate and

concentrated under reduced pressure. The crude product was puriﬁed

by column chromatography on silica gel using hexanes and ethyl acetate

as an eluent to aﬀord 4-hydroxy-7-methyl[2.2]paracyclophane 6

yellow solid, mp = 83−85 °C. New compound: R = 0.50 (hexanes/

ethyl acetate 5:1). H NMR (400 MHz, CDCl ): δ 8.53 (s, 1H), 6.91−

6.84 (m, 2H), 6.53 (s, 1H), 6.45−6.39 (m, 1H), 6.34−6.28 (m, 1H),

3.50−3.15 (m, 5H), 3.14−3.01 (m, 2H), 2.75−2.60 (m, 1H), 2.23 (s,

3H). C{ H} NMR (100 MHz, CDCl ): δ 165.0, 152.4, 145.1, 143.0,

139.8, 137.8, 135.7, 132.9, 132.7, 129.0, 128.8, 128.2, 117.3, 34.0, 33.8,

28.2, 26.7, 20.2. HRMS (ESI-TOF): m/z calcd for C H NO S [M +

H] , 328.1002; found, 328.1003.

General Procedure for Kinetic Resolution. A Schlenk tube (25

mL) was charged with Pd(OCOCF ) (3.3 mg, 0.01 mmol, 5 mol %)

(

colorless solid, 1.904 g, 80% yield). Mp: 185−187 °C. New

and (S ,S)-L3 (5.0 mg, 0.01 mmol, 5 mol %) under nitrogen, and

compound: R = 0.30 (hexanes/ethyl acetate 20:1). H NMR (400

degassed anhydrous acetone (2.0 mL) was added. The mixture was

stirred at room temperature for 1 h. The solvent was removed under a

vacuum to give the catalyst. Then substrate rac-1 (0.20 mmol),

arylboronic acids (0.20 mmol) and 2,2,2-triﬂuoroethanol (4.0 mL)

were added into the tube under nitrogen. The mixture was heated to 60

°C. After stirring at 60 °C for 12 h, the reaction mixture was cooled to

room temperature, and the solvent was removed by rotary evaporation.

The resulting mixture was dried under a vacuum, and the conversion of

MHz, CDCl ): δ 7.08−7.01 (m, 1H), 6.86−6.80 (m, 1H), 6.49−6.44

(

m, 1H), 6.43−6.38 (m, 1H), 6.08 (s, 1H), 5.51 (s, 1H), 4.66 (brs, 1H),

.40−3.29 (m, 1H), 3.28−3.18 (m, 1H), 3.18−3.02 (m, 4H), 2.69−

.52 (m, 2H), 2.14 (s, 3H). C{ H} NMR (100 MHz, CDCl ): δ

52.0, 139.9, 139.7, 139.0, 137.5, 132.9, 132.2, 129.7, 129.0, 128.9,

24.9, 123.5, 33.7, 33.5, 32.9, 30.9, 19.3. HRMS (ESI-TOF): m/z calcd

for C H O [M + H] , 239.1430; found, 239.1430.

A dry 250 mL round-bottom ﬂask was loaded with sodium hydride

0.152 g, 3.8 mmol, 60% wt) in a 9:1 mixture of anhydrous diethyl

rac-1 was conﬁrmed by H NMR analysis with 1,3,5-trimethoxybenzene

(

as an internal standard. The solvent was removed under reduced

pressure, and the recovered material (+)-1 and addition product 2 were

isolated by column chromatography on silica gel using hexanes and

ethyl acetate as an eluent. The optical purity of products and starting

materials was determined by chiral HPLC analysis.

ether/N,N-dimethylformamide (18 mL:2 mL). 4-Hydroxy-7-

methyl[2.2]paracyclophane 6 (0.773 g, 3.2 mmol) was added slowly,

and the mixture was allowed to be stirred for 10 min at 0 °C; after that,

chloromethyl methyl ether (2.2 mL, 4.8 mmol) was added under

nitrogen while stirring. After 2 h, water (10 mL) was added, and the

organic phase was separated and worked up as above. The crude

product was puriﬁed by column chromatography on silica gel using

hexanes and ethyl acetate as an eluent to aﬀord 4-methoxymethoxy-7-

-Phenyl-3,4-dihydro-[2.2]paracyclophano[5,6-d]-1,2,3-

benzoxathiazine 2,2-Dioxide (2a): 37.9 mg, 48% yield, >20:1 dr,

white solid, mp = 183−185 °C. New compound: R = 0.50 (hexanes/

ethyl acetate 10:1), 93.7% ee, [α] = +49.57 (c 0.94, CHCl ). H NMR

methyl-[2.2]paracyclophane 7 (white solid, 0.596 g, 66% yield). Mp:

(400 MHz, CDCl ): δ 7.39−7.30 (m, 3H), 7.26−7.20 (m, 2H), 7.03−

3−55 °C. New compound: R = 0.30 (hexanes). H NMR (400 MHz,

6.97 (m, 1H), 6.90−6.82 (m, 1H), 6.63−6.55 (m, 3H), 6.39−6.32 (m,

1H), 5.51 (d, J = 8.8 Hz, 1H), 4.63 (d, J = 8.8 Hz, 1H), 3.46−3.34 (m,

1H), 3.29−3.16 (m, 1H), 3.10−2.90 (m, 3H), 2.82−2.70 (m, 1H),

CDCl ): δ 6.91−6.85 (m, 1H), 6.83−6.77 (m, 1H), 6.50−6.44 (m,

H), 6.42−6.36 (m, 1H), 6.08 (s, 1H), 5.91 (s, 1H), 5.16 (d, J = 6.4 Hz,

H), 5.05 (d, J = 6.4 Hz, 1H), 3.55 (s, 3H), 3.47−3.36 (m, 1H), 3.30−

.19 (m, 1H), 3.16- 2.98 (m, 4H), 2.77−2.65 (m, 1H), 2.59−2.47 (m,

2.62−2.45 (m, 2H). C{ H} NMR (100 MHz, CDCl ): δ 151.6, 141.0,

139.9, 139.2, 138.5, 135.7, 133.4, 132.9, 131.6, 130.4, 129.2, 129.2,

129.1, 129.1, 128.3, 119.9, 61.3, 34.4, 34.0, 33.7, 29.1. HPLC: Chiracel

IA column, 254 nm, 30 °C, n-hexane/i-PrOH = 60:40, ﬂow = 0.6 mL/

min, retention time 10.5 min (major) and 15.3 min. HRMS (ESI-

H), 2.12 (s, 3H). ¹C{ H} NMR (100 MHz, CDCl ): δ 154.1, 140.0,

39.8, 139.0, 137.3, 132.7, 132.3, 130.7, 129.6, 128.8, 127.8, 122.0, 95.0,

6.4, 34.0, 33.7, 33.2, 31.1, 19.4. HRMS (ESI-TOF): m/z calcd for

C H O [M + H] , 283.1693; found, 283.1690.

TOF): m/z calcd for C H N O S [M + NH ] , 409.1580; found,

23 25

4-Methoxymethoxy-7-methyl[2.2]paracyclophane 7 (1.034 g, 3.7

409.1553.

mmol) was dissolved in diethyl ether (16 mL) containing N,N,N′,N′-

tetramethylethylenediamine (0.860 g, 1.10 mL, 7.4 mmol), and n-

butyllithium (3.00 mL, 2.5 M in hexane, 7.4 mmol) was added at 0 °C

under nitrogen while stirring. The mixture was allowed to react for 1.5 h

at 0 °C, N,N-dimethylformamide (0.57 mL, 7.4 mmol) was added, and

the reaction was allowed to proceed for 4 h at room temperature. Water

was added, the organic phase was separated and washed with water, and

the solvent was evaporated. The resulting crude oil was dissolved in

tetrahydrofuran (4 mL), concentrated hydrochloric acid (2.00 mL) was

added, and the mixture was kept at room temperature overnight. After

neutralization with aqueous sodium bicarbonate, the mixture was

extracted with dichloromethane (3 × 10 mL), and the solvent was

[2.2]Paracyclophano[5,6-d]-1,2,3-benzoxathiazine 2,2-Diox-

ide (1a): kinetic resolution from addition of imine 1a with

phenylboronic acid, 30.0 mg, 48% yield, 97.3% ee, [α]²= +440.68 (c

0.70, CHCl ). HPLC: Chiralcel OD-H column, 254 nm, 30 °C, n-

hexane/i-PrOH = 60:40, ﬂow = 0.6 mL/min, retention time 19.6 min

(major) and 23.8 min.

4-Phenyl-3,4-dihydro-[2.2]paracyclophano[5,6-d]-1,2,3-

benzoxathiazine 2,2-Dioxide (2a′): white solid, mp = 233−235 °C.

New compound: R = 0.30 (hexanes/ethyl acetate 10:1). H NMR (400

MHz, CDCl ): δ 7.87−7.71 (m, 2H), 7.64−7.42 (m, 3H), 6.65−6.55

(m, 3H), 6.51−6.45 (m, 1H), 6.33−6.26 (m, 1H), 5.46 (d, J = 7.0 Hz,

1H), 5.37−5.29 (m, 1H), 5.10 (d, J = 7.0 Hz, 1H), 3.57−3.40 (m, 1H),

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Note

.31−3.15 (m, 1H), 3.13−2.96 (m, 1H), 2.94−2.65 (m, 4H), 2.59−

>20:1 dr, white solid, mp = 224−226 °C. New compound: R = 0.30

.40 (m, 1H). ¹³C{ H} NMR (100 MHz, CDCl ): δ 149.3, 139.9,

(hexanes/ethyl acetate 5:1), 91.9% ee, [α] = +52.69 (c 0.78, CHCl ).

39.2, 138.6, 137.1, 136.2, 133.2, 132.9, 132.9, 131.2, 130.0, 129.5,

H NMR (400 MHz, CDCl ): δ 7.24−7.15 (m, 2H), 7.09−6.92 (m,

29.4, 128.9, 124.5, 61.2, 35.1, 34.6, 32.0, 28.7. HRMS (ESI-TOF): m/

3H), 6.92−6.77 (m, 1H), 6.68−6.55 (m, 3H), 6.46−6.29 (m, 1H), 5.48

(d, J = 8.5 Hz, 1H), 4.91 (d, J = 8.5 Hz, 1H), 3.49−3.31 (m, 1H), 3.28−

3.11 (m, 1H), 3.11−2.87 (m, 3H), 2.83−2.65 (m, 1H), 2.64−2.44 (m,

z calcd for C H N O S [M + NH ] , 409.1580; found, 409.1591.

-(o-Tolyl)-3,4-dihydro-[2.2]paracyclophano[5,6-d]-1,2,3-

benzoxathiazine 2,2-Dioxide (2b): 23.0 mg, 28% yield, >20:1 dr,

white solid, mp = 201−203 °C. New compound: R = 0.50 (hexanes/

H). C{ H} NMR (100 MHz, CDCl ): δ 162.9 (C−F, J = 248.6

C−F

Hz), 151.3, 140.6, 140.0, 138.4, 135.7, 135.0 (C−F, J

= 3.5 Hz),

C−F

ethyl acetate 5:1), 94.2% ee, [α] = +61.33 (c 0.60, CHCl ). H NMR

133.6, 133.1, 131.5, 130.1, 130.1 (C−F, J = 12.5 Hz), 129.5, 128.9,

C−F

(

400 MHz, CDCl ): δ 7.28−7.22 (m, 2H), 7.09−6.97 (m, 2H), 6.92−

119.4, 115.9 (C−F, J

= 21.7 Hz), 60.4, 34.3, 33.9, 33.5, 29.2. F

C−F

.86 (m, 1H), 6.83−6.77 (m, 1H), 6.65−6.53 (m, 3H), 6.36−6.29 (m,

H), 5.75 (d, J = 9.3 Hz, 1H), 4.45 (d, J = 9.3 Hz, 1H), 3.45−3.34 (m,

H), 3.29−3.19 (m, 1H), 3.09−2.89 (m, 3H), 2.82−2.72 (m, 1H), 2.62

NMR (376 MHz, CDCl ): δ −112.3. HPLC: Chiracel IA column, 254

nm, 30 °C, n-hexane/i-PrOH = 60:40, ﬂow = 0.6 mL/min, retention

time 10.3 min (major) and 13.2 min. HRMS (ESI-TOF): m/z calcd for

(

s, 3H), 2.57−2.48 (m, 1H), 2.41−2.31 (m, 1H). C{ H} NMR (100

C H FN O S [M + NH ] , 427.1486; found, 427.1471.

MHz, CDCl ): δ 151.9, 140.8, 140.0, 138.4, 137.5, 136.6, 135.6, 133.2,

[2.2]Paracyclophano[5,6-d]-1,2,3-benzoxathiazine 2,2-Diox-

32.7, 131.7, 130.9, 130.8, 129.3, 129.2, 129.1, 127.8, 126.8, 120.4, 57.8,

4.5, 34.5, 33.8, 29.0, 19.3. HPLC: Chiracel IA column, 254 nm, 30 °C,

ide (1a): kinetic resolution from the addition of [2.2]paracyclophane

imine 1a with 4-ﬂuorophenylboronic acid, 29.0 mg, 46% yield, 98.7%

ee. HPLC: Chiralcel OD-H column, 254 nm, 30 °C, n-hexane/i-PrOH

= 60:40, ﬂow = 0.6 mL/min, retention time 19.4 min (major) and 23.5

min.

n-hexane/i-PrOH = 60:40, ﬂow = 0.6 mL/min, retention time 10.8 min

(

[

major) and 21.5 min. HRMS (ESI-TOF): m/z calcd for C H N O S

M + NH ] , 423.1737; found, 423.1765.

24 27 2 3

[

2.2]Paracyclophano[5,6-d]-1,2,3-benzoxathiazine 2,2-Diox-

4-(4-Chlorophenyl)-3,4-dihydro-[2.2]paracyclophano[5,6-

ide (1a): kinetic resolution from the addition of [2.2]paracyclophane

imine 1a with 2-methylphenylboronic acid, 42.0 mg, 67% yield, 40.0%

ee. HPLC: Chiralcel OD-H column, 254 nm, 30 °C, n-hexane/i-PrOH

d]-1,2,3-benzoxathiazine 2,2-Dioxide (2f): 38.0 mg, 45% yield,

>20:1 dr, white solid, mp = 247−249 °C. New compound: R

= 0.30

(hexanes/ethyl acetate 5:1), 97.1% ee, [α]

= +44.21 (c 0.76, CHCl ).

60:40, ﬂow = 0.6 mL/min, retention time 19.5 min (major) and 23.5

min.

H NMR (400 MHz, CDCl ): δ 7.32−7.27 (m, 2H), 7.21−7.14 (m,

2H), 7.01−6.96 (m, 1H), 6.84−6.78 (m, 1H), 6.64−6.57 (m, 3H),

6.43−6.36 (m, 1H), 5.46 (d, J = 8.4 Hz, 1H), 4.94 (d, J = 8.5 Hz, 1H),

3.44−3.32 (m, 1H), 3.26−3.14 (m, 1H), 3.12−2.90 (m, 3H), 2.81−

-(m-Tolyl)-3,4-dihydro-[2.2]paracyclophano[5,6-d]-1,2,3-

benzoxathiazine 2,2-Dioxide (2c): 39.0 mg, 48% yield, >20:1 dr,

white solid, mp = 247−249 °C. New compound: R = 0.45 (hexanes/

ethyl acetate 5:1), 87.3% ee, [α] = +41.11 (c 0.90, CHCl ). H NMR

2.69 (m, 1H), 2.67−2.47 (m, 2H). C{ H} NMR (100 MHz, CDCl ):

δ 151.3, 140.5, 140.0, 138.4, 137.5, 135.8, 134.9, 133.6, 133.1, 131.4,

129.9, 129.7, 129.6, 129.2, 128.8, 119.0, 60.4, 34.2, 33.9, 33.5, 29.2.

HPLC: Chiracel IA column, 254 nm, 30 °C, n-hexane/i-PrOH = 60:40,

ﬂow = 0.6 mL/min, retention time 11.3 min (major) and 12.6 min.

(

400 MHz, CDCl ): δ 7.24−7.18 (m, 1H), 7.18−7.13 (m, 1H), 7.09−

(

.04 (m, 1H), 7.03−6.96 (m, 2H), 6.88−6.81 (m, 1H), 6.64−6.54 (m,

H), 6.37−6.30 (m, 1H), 5.47 (d, J = 9.0 Hz, 1H), 4.40 (d, J = 9.0 Hz,

H), 3.48−3.35 (m, 1H), 3.29−3.18 (m, 1H), 3.09−2.90 (m, 3H),

HRMS (ESI-TOF): m/z calcd for C H ClNO S [M + H] , 426.0925;

found, 426.0927 ( Cl) and 428.0898 ( Cl).

.83−2.72 (m, 1H), 2.59−2.47 (m, 2H), 2.32 (s, 3H). C{ H} NMR

100 MHz, CDCl ): δ 151.7, 141.1, 139.9, 139.2, 139.0, 138.5, 135.7,

[2.2]Paracyclophano[5,6-d]-1,2,3-benzoxathiazine 2,2-Diox-

ide (1a): kinetic resolution from the addition of [2.2]paracyclophane

imine 1a with 4-chlorophenylboronic acid, 31.0 mg, 50% yield, 81.4%

ee. HPLC: Chiralcel OD-H column, 254 nm, 30 °C, n-hexane/i-PrOH

= 60:40, ﬂow = 0.6 mL/min, retention time 19.3 min (major) and 23.3

min.

33.3, 132.8, 131.7, 130.6, 130.0, 129.3, 129.1, 129.1, 129.0, 125.2,

20.2, 61.4, 34.5, 34.1, 33.8, 29.0, 21.5. HPLC: Chiracel IA column, 254

nm, 30 °C, n-hexane/i-PrOH = 60:40, ﬂow = 0.6 mL/min, retention

time 10.3 min (major) and 14.9 min. HRMS (ESI-TOF): m/z calcd for

C H N O S [M + NH ] , 423.1737; found, 423.1751.

[

ide (1a): kinetic resolution from the addition of [2.2]paracyclophane

imine 1a with 3-methylphenylboronic acid, 28.0 mg, 45% yield, 95.6%

ee. HPLC: Chiralcel OD-H column, 254 nm, 30 °C, n-hexane/i-PrOH

60:40, ﬂow = 0.6 mL/min, retention time 19.4 min (major) and 23.4

min.

2.2]Paracyclophano[5,6-d]-1,2,3-benzoxathiazine 2,2-Diox-

4-(4-Bromophenyl)-3,4-dihydro-[2.2]paracyclophano[5,6-

d]-1,2,3-benzoxathiazine 2,2-Dioxide (2g): 35.0 mg, 37% yield,

>20:1 dr, white solid, mp = 247−249 °C. New compound: R

= 0.40

= +41.00 (c 0.50,

CHCl ). H NMR (400 MHz, CDCl ): δ 7.48−7.41 (m, 2H), 7.15−

3 3

(hexanes/ethyl acetate 10:1), 96.1% ee, [α]

7.07 (m, 2H), 7.01−6.94 (m, 1H), 6.83−6.77 (m, 1H), 6.63−6.56 (m,

3H), 6.42−6.36 (m, 1H), 5.44 (d, J = 8.5 Hz, 1H), 4.90 (d, J = 8.5 Hz,

1H), 3.45−3.33 (m, 1H), 3.25−3.14 (m, 1H), 3.12−2.90 (m, 3H),

-(p-Tolyl)-3,4-dihydro-[2.2]paracyclophano[5,6-d]-1,2,3-

benzoxathiazine 2,2-Dioxide (2d): 40.0 mg, 49% yield, >20:1 dr,

white solid, mp = 259−261 °C. New compound: R = 0.45 (hexanes/

ethyl acetate 5:1), 79.7% ee, [α] = +39.30 (c 0.72, CHCl ). H NMR

2.82−2.69 (m, 1H), 2.68−2.47 (m, 2H). C{ H} NMR (100 MHz,

CDCl ): δ 151.4, 140.5, 140.0, 138.4, 138.1, 135.8, 133.6, 133.1, 132.1,

(

400 MHz, CDCl ): δ 7.17−7.08 (m, 4H), 7.02−6.95 (m, 1H), 6.88−

131.4, 130.0, 129.9, 129.6, 128.7, 123.1, 119.0, 60.4, 34.2, 33.9, 33.5,

29.2. HPLC: Chiracel IC column, 254 nm, 30 °C, n-hexane/i-PrOH =

60:40, ﬂow = 0.6 mL/min, retention time 9.2 min (major) and 10.2

.81 (m, 1H), 6.63−6.54 (m, 3H), 6.37−6.30 (m, 1H), 5.48 (d, J = 8.9

Hz, 1H), 4.53 (d, J = 8.8 Hz, 1H), 3.46−3.34 (m, 1H), 3.30−3.15 (m,

H), 3.09−2.89 (m, 3H), 2.81−2.70 (m, 1H), 2.61−2.47 (m, 2H), 2.34

(

min. HRMS (ESI-TOF): m/z calcd for C H BrNO S [M + H] ,

s, 3H). ¹³C{ H} NMR (100 MHz, CDCl ): δ 151.6, 141.1, 139.9,

470.0420; found, 470.0419 (Br ) and 472.0397 (Br ).

39.1, 138.5, 136.3, 135.6, 133.3, 132.8, 131.6, 130.5, 129.8, 129.2,

29.1, 128.1, 120.2, 61.1, 34.5, 34.1, 33.8, 29.1, 21.3. HPLC: Chiracel

[2.2]Paracyclophano[5,6-d]-1,2,3-benzoxathiazine 2,2-Diox-

ide (1a): kinetic resolution from the addition of [2.2]paracyclophane

imine 1a with 4-bromophenylboronic acid, 37.0 mg, 59% yield, 63.6%

ee. HPLC: Chiralcel OD-H column, 254 nm, 30 °C, n-hexane/i-PrOH

IA column, 254 nm, 30 °C, n-hexane/i-PrOH = 60:40, ﬂow = 0.6 mL/

min, retention time 12.8 min (major) and 20.9 min. HRMS (ESI-

TOF): m/z calcd for C H NO S [M + H] , 406.1471; found,

60:40, ﬂow = 0.6 mL/min, retention time 19.0 min (major) and 22.9

406.1474.

[2.2]Paracyclophano[5,6-d]-1,2,3-benzoxathiazine 2,2-Diox-

ide (1a): kinetic resolution from the addition of [2.2]paracyclophane

imine 1a with 4-methylphenylboronic acid, 30.0 mg, 48% yield, 83.3%

ee. HPLC: Chiralcel OD-H column, 254 nm, 30 °C, n-hexane/i-PrOH

20:1 dr, white solid, mp = 192−194 °C. New compound: R = 0.50

(

hexanes/ethyl acetate 5:1), 45.9% ee, [α] = +21.46 (c 0.82, CHCl ).

H NMR (400 MHz, CDCl ): δ 7.18−7.11 (m, 2H), 7.01−6.95 (m,

60:40, ﬂow = 0.6 mL/min, retention time 19.1 min (major) and 23.0

min.

1H), 6.87−6.80 (m, 3H), 6.62−6.54 (m, 3H), 6.37−6.31 (m, 1H), 5.47

(d, J = 8.7 Hz, 1H), 4.57 (d, J = 8.7 Hz, 1H), 3.79 (s, 3H), 3.44−3.34

(m, 1H), 3.27−3.16 (m, 1H), 3.08−2.89 (m, 3H), 2.81−2.69 (m, 1H),

-(4-Fluorophenyl)-3,4-dihydro-[2.2]paracyclophano[5,6-

d]-1,2,3-benzoxathiazine 2,2-Dioxide (2e): 39.0 mg, 47% yield,

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Note

.60−2.47 (m, 2H). C{ H} NMR (100 MHz, CDCl ): δ 160.0, 151.5,

60:40, ﬂow = 0.6 mL/min, retention time 15.4 min (major) and 24.5

41.1, 139.9, 138.5, 135.6, 133.3, 132.9, 131.6, 131.3, 130.5, 129.5,

29.2, 129.2, 120.3, 114.4, 60.8, 55.4, 34.4, 34.1, 33.8, 29.1. HPLC:

min. HRMS (ESI-TOF): m/z calcd for C H KNO S [M + K] ,

480.1030; found, 480.1053.

Chiracel IA column, 254 nm, 30 °C, n-hexane/i-PrOH = 60:40, ﬂow =

[2.2]Paracyclophano[5,6-d]-1,2,3-benzoxathiazine 2,2-Diox-

ide (1a): kinetic resolution from the addition of [2.2]paracyclophane

imine 1a with 2-naphthaleneboronic acid, 47.0 mg, 75% yield, 29.8% ee.

HPLC: Chiralcel OD-H column, 254 nm, 30 °C, n-hexane/i-PrOH =

60:40, ﬂow = 0.6 mL/min, retention time 19.3 min (major) and 23.3

min.

0.6 mL/min, retention time 16.8 min (major) and 20.5 min. HRMS

(

ESI-TOF): m/z calcd for C H NO S [M + H] , 422.1421; found,

24 24 4

22.1428.

[2.2]Paracyclophano[5,6-d]-1,2,3-benzoxathiazine 2,2-Diox-

ide (1a): kinetic resolution from the addition of [2.2]paracyclophane

imine 1a with 4-methoxyphenylboronic acid, 24.0 mg, 38% yield, 68.6%

ee. HPLC: Chiralcel OD-H column, 254 nm, 30 °C, n-hexane/i-PrOH

4-(4-Phenyl)-3,4-dihydro-(8-methyl[2.2]paracyclophano)-

[5,6-d]-1,2,3-benzoxathiazine 2,2-Dioxide (2l): 31.0 mg, 38%

60:40, ﬂow = 0.6 mL/min, retention time 19.3 min (major) and 22.7

yield, >20:1 dr, white solid, mp = 220−222 °C. New compound: R =

min.

0.50 (hexanes/ethyl acetate 5:1), 97.1% ee, [α]

= +79.99 (c 0.28,

CHCl ). H NMR (400 MHz, CDCl ): δ 7.35−7.30 (m, 3H), 7.24−

3 3

-(4-Triﬂuoromethylphenyl)-3,4-dihydro-[2.2]-

paracyclophano[5,6-d]-1,2,3-benzoxathiazine 2,2-Dioxide (2i):

7.18 (m, 2H), 7.08−7.03 (m, 1H), 6.89−6.78 (m, 2H), 6.52−6.48 (m,

1H), 6.21 (s, 1H), 5.55 (d, J = 8.9 Hz, 1H), 4.39 (d, J = 8.9 Hz, 1H),

3.44−3.31 (m, 1H), 3.26−3.13 (m, 1H), 3.07−2.83 (m, 3H), 2.74−

6.0 mg, 17% yield, >20:1 dr, white solid, mp = 221−223 °C. New

compound: R = 0.45 (hexanes/ethyl acetate 10:1), 91.0% ee, [α]

53.00 (c 0.20, CHCl ). H NMR (400 MHz, CDCl ): δ 7.62−7.54

2.56 (m, 2H), 2.44−2.30 (m, 1H), 2.04 (s, 3H). C{ H} NMR (100

(

m, 2H), 7.41−7.34 (m, 2H), 7.01−6.94 (m, 1H), 6.82−6.75 (m, 1H),

MHz, CDCl ): δ 150.4, 139.8, 139.8, 139.5, 138.3, 138.0, 135.1, 132.1,

.67−6.58 (m, 3H), 6.45−6.39 (m, 1H), 5.56−5.48 (m, 1H), 4.98−

.89 (m, 1H), 3.49−3.34 (m, 1H), 3.26−3.14 (m, 1H), 3.13−3.02 (m,

H), 3.02−2.92 (m, 1H), 2.83−2.71 (m, 1H), 2.69−2.58 (m, 1H),

131.0, 129.5, 129.2, 129.0, 128.3, 128.3, 127.7, 119.9, 61.8, 34.1, 32.7,

29.3, 28.7, 20.5. HPLC: Chiracel IA column, 254 nm, 30 °C, n-hexane/

i-PrOH = 60:40, ﬂow = 0.6 mL/min, retention time 11.6 min (major)

.55−2.44 (m, 1H). C{ H} NMR (100 MHz, CDCl ): δ 151.4, 142.8,

and 13.9 min. HRMS (ESI-TOF): m/z calcd for C24H N O S [M +

27 2 3

40.4, 140.1, 138.3, 136.0, 133.8, 133.2, 131.4, 131.1 (C−F, J

NH ] , 423.1737; found, 423.1735.

C−F

2.5 Hz), 129.8, 129.8, 128.7, 128.6, 126.0 (C−F, J

= 3.6 Hz),

(8-Methyl[2.2]paracyclophano)[5,6-d]-1,2,3-benzoxathia-

zine 2,2-Dioxide (1d): kinetic resolution from the addition of

[2.2]paracyclophane imine 1d with phenylboronic acid, 37.0 mg, 57%

C−F

23.9 (C−F, J

= 272.3 Hz), 118.5, 60.5, 34.2, 33.9, 33.4, 29.3. F

C−F

NMR (376 MHz, CDCl ): δ −62.7. HPLC: Chiracel AD-H column,

54 nm, 30 °C, n-hexane/i-PrOH = 60:40, ﬂow = 0.6 mL/min,

yield, 65.9% ee, [α] = +232.84 (c 0.42, CHCl ). HPLC: Chiralcel AD-

retention time 9.4 and 10.3 min (major). HRMS (ESI-TOF): m/z calcd

H column, 254 nm, 30 °C, n-hexane/i-PrOH = 60:40, ﬂow = 0.6 mL/

min, retention time 11.2 and 13.1 min (major).

4-(p-Tolyl)-3,4-dihydro-(8-methyl[2.2]paracyclophano)[5,6-

d]-1,2,3-benzoxathiazine 2,2-Dioxide (2m): 21.0 mg, 25% yield,

for C H F NO S [M + H] , 460.1189; found, 460.1178.

[

2.2]Paracyclophano[5,6-d]-1,2,3-benzoxathiazine 2,2-Diox-

ide (1a): kinetic resolution from the addition of [2.2]paracyclophane

imine 1a with 4-triﬂuoromethylphenylboronic acid, 49.0 mg, 78% yield,

>20:1 dr, white solid, mp = 223−225 °C. New compound: R

= 0.60

= +106.85 (c 0.35,

CHCl ). H NMR (400 MHz, CDCl ): δ 7.15−7.02 (m, 5H), 6.88−

3 3

3.5% ee. HPLC: Chiralcel OD-H column, 254 nm, 30 °C, n-hexane/i-

(hexanes/ethyl acetate 5:1), 88.5% ee, [α]

PrOH = 60:40, ﬂow = 0.6 mL/min, retention time 19.3 min (major)

.77 (m, 2H), 6.52−6.46 (m, 1H), 6.19 (s, 1H), 5.51 (d, J = 8.9 Hz,

and 23.3 min.

-(4-tert-Butylphenyl)-3,4-dihydro-[2.2]paracyclophano-

5,6-d]-1,2,3-benzoxathiazine 2,2-Dioxide (2j): 32.0 mg, 36%

yield, >20:1 dr, white solid, mp = 119−121 °C. New compound: R =

1H), 4.28 (d, J = 8.8 Hz, 1H), 3.44−3.29 (m, 1H), 3.27−3.11 (m, 1H),

3.06−2.85 (m, 3H), 2.75−2.54 (m, 2H), 2.43−2.30 (m, 4H), 2.03 (s,

3H). C{ H} NMR (100 MHz, CDCl ): δ 150.3, 139.7, 139.6, 138.9,

[

.60 (hexanes/ethyl acetate 10:1), 75.6% ee, [α] = +37.78 (c 0.54,

138.3, 137.8, 136.9, 135.1, 132.0, 131.0, 129.8, 129.5, 128.2, 128.2,

127.6, 120.1, 61.5, 34.1, 32.7, 29.3, 28.7, 21.3, 20.5. HPLC: Chiracel

AD-H column, 254 nm, 30 °C, n-hexane/i-PrOH = 60:40, ﬂow = 0.6

CHCl ). H NMR (400 MHz, CDCl ): δ 7.38−7.31 (m, 2H), 7.18−

.13 (m, 2H), 7.02−6.97 (m, 1H), 6.89−6.83 (m, 1H), 6.63−6.54 (m,

H), 6.37−6.30 (m, 1H), 5.54−5.46 (m, 1H), 4.55−4.46 (m, 1H),

.46−3.33 (m, 1H), 3.29−3.16 (m, 1H), 3.09−2.89 (m, 3H), 2.81−

mL/min, retention time 16.0 min (major) and 22.7 min. HRMS (ESI-

TOF): m/z calcd for C25

25NNaO

S [M + Na] , 442.1447; found,

.70 (m, 1H), 2.61−2.47 (m, 2H), 1.30 (s, 9H). C{ H} NMR (100

442.1446.

MHz, CDCl ): δ 152.2, 151.6, 141.1, 139.9, 138.5, 136.1, 135.6, 133.3,

(8-Methyl[2.2]paracyclophano)[5,6-d]-1,2,3-benzoxathia-

zine 2,2-Dioxide (1d): kinetic resolution from the addition of

32.8, 131.6, 130.5, 129.3, 129.1, 127.9, 126.1, 120.3, 61.0, 34.8, 34.5,

4.1, 33.9, 31.4, 29.0. HPLC: Chiracel IA column, 254 nm, 30 °C, n-

[

2.2]paracyclophane imine 1d with 4-methylphenylboronic acid, 45.0

mg, 69% yield, 36.4% ee. HPLC: Chiralcel AD-H column, 254 nm, 30

C, n-hexane/i-PrOH = 60:40, ﬂow = 0.6 mL/min, retention time 11.4

hexane/i-PrOH = 60:40, ﬂow = 0.6 mL/min, retention time 10.5 min

(

major) and 13.7 min. HRMS (ESI-TOF): m/z calcd for

and 13.3 min (major).

C H NaNO S [M + Na] , 470.1760; found, 470.1746.

Synthesis of (−)-4-Phenyl-3,4-dihydro-[2.2]paracyclophano-

[

2.2]Paracyclophano[5,6-d]-1,2,3-benzoxathiazine 2,2-Diox-

[

5,6-d]-1,2,3-benzoxathiazine 2,2-Dioxide (2a). To a solution of

ide (1a): kinetic resolution from the addition of [2.2]paracyclophane

imine 1a with 4-tert-butylphenylboronic acid, 37.0 mg, 59% yield,

(+)-1a (63 mg, 0.20 mmol, 99% ee) in dry tetrahydrofuran (3.0 mL)

was added phenyl magnesium bromide (1.00 mL, 1 M in THF, 1.00

mmol) at 0 °C under nitrogen. The reaction mixture was allowed to

warm to room temperature and stirred at room temperature overnight.

Water (5.0 mL) was added and extracted with ethyl acetate (10 mL ×

3). The combined organic layer was washed with brine, dried by

anhydrous sodium sulfate, and ﬁltered. The solvent was removed in

vacuo, and the residue was puriﬁed by column chromatography on silica

gel using hexanes and ethyl acetate as an eluent to aﬀord sulfamidate

0.1% ee. HPLC: Chiralcel OD-H column, 254 nm, 30 °C, n-hexane/i-

PrOH = 60:40, ﬂow = 0.6 mL/min, retention time 19.0 min (major)

and 22.8 min.

-(2-Naphthyl)-3,4-dihydro-[2.2]paracyclophano[5,6-d]-

,2,3-benzoxathiazine 2,2-Dioxide (2k): 19.0 mg, 22% yield, >20:1

dr, white solid, mp = 124−126 °C. New compound: R = 0.50 (hexanes/

ethyl acetate 10:1), 95.6% ee, [α] = +22.17 (c 0.23, CHCl ). H NMR

(

400 MHz, CDCl ): δ 7.86−7.79 (m, 2H), 7.79−7.73 (m, 1H), 7.72−

.67 (m, 1H), 7.55−7.45 (m, 2H), 7.38−7.32 (m, 1H), 7.06−7.00 (m,

H), 6.92−6.85 (m, 1H), 6.65−6.56 (m, 3H), 6.40−6.34 (m, 1H), 5.68

(−)-2a: 76 mg, 97% yield, white solid. New compound: R

= 0.50

= −55.78 (c 1.66, CHCl ).

H NMR (400 MHz, CDCl ): δ 7.37−7.30 (m, 3H), 7.26−7.21 (m,

(hexanes/ethyl acetate 10:1), 98% ee, [α]

(d, J = 8.8 Hz, 1H), 4.69 (d, J = 8.8 Hz, 1H), 3.54−3.38 (m, 1H), 3.30−

.17 (m, 1H), 3.11−2.92 (m, 3H), 2.88−2.71 (m, 1H), 2.62−2.44 (m,

2H), 7.03−6.98 (m, 1H), 6.89−6.84 (m, 1H), 6.63−6.55 (m, 3H),

6.40−6.32 (m, 1H), 5.51 (d, J = 8.8 Hz, 1H), 4.77 (d, J = 8.8 Hz, 1H),

3.44−3.32 (m, 1H), 3.27−3.15 (m, 1H), 3.10−2.90 (m, 3H), 2.81−

H). ¹³C{ H} NMR (100 MHz, CDCl ): δ 151.7, 141.1, 140.0, 138.5,

36.4, 135.8, 133.5, 133.4, 133.2, 132.9, 131.7, 130.5, 129.3, 129.2,

28.3, 127.9, 127.7, 127.0, 126.8, 125.6, 119.9, 61.5, 34.4, 34.1, 33.8,

9.1. HPLC: Chiracel IA column, 254 nm, 30 °C, n-hexane/i-PrOH =

2.70 (m, 1H), 2.62−2.45 (m, 2H). C{ H} NMR (100 MHz, CDCl ):

δ 151.5, 140.9, 139.9, 139.1, 138.5, 135.6, 133.4, 132.9, 131.5, 130.3,

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

https://pubs.acs.org/doi/10.1021/acs.joc.0c02509.

Note

29.2, 129.1, 129.1, 129.1, 128.3, 119.9, 61.2, 34.4, 34.0, 33.7, 29.1.

Scale-up Reaction. A Schlenk tube (250 mL) was charged with

Pd(OCOCF ) (33.0 mg, 0.1 mmol, 5 mol %) and (R ,S)-L2 (53.0 mg,

HPLC: Chiracel IA column, 254 nm, 30 °C, n-hexane/i-PrOH = 60:40,

ﬂow = 0.6 mL/min, retention time 10.4 and 15.3 min (major).

Synthesis of (−)-4-Methyl-3, 4-dihydro-[2. 2]-

paracyclophano[5,6-d]-1,2,3-benzoxathiazine 2,2-Dioxide (3).

To a solution of (+)-1a (63 mg, 0.20 mmol, 99% ee) in dry

tetrahydrofuran (3.0 mL) was added methyl magnesium bromide (0.34

0.1 mmol, 5 mol %) under nitrogen, and degassed anhydrous acetone

(5.0 mL) was added. The mixture was stirred at room temperature for 1

h. The solvent was removed under a vacuum to give the catalyst. Then

substrate rac-1a (626 mg, 2.00 mmol), phenylboronic acid (243 mg,

2.00 mmol), and 2,2,2-triﬂuoroethanol (40 mL) were added into the

tube under nitrogen. The mixture was heated to 60 °C. After stirring at

60 °C for 12 h, the reaction mixture was cooled to room temperature,

and the solvent was removed by rotary evaporation. The resulting

mixture was dried under a vacuum; the conversion of rac-1a (34%

conversion) and the diastereomeric ratio (>20:1 dr) of the addition

mL, 3 M in Et O, 1.00 mmol) at 0 °C under nitrogen. The reaction

mixture was allowed to warm to room temperature and stirred at room

temperature overnight. Water (5.0 mL) was added and extracted with

dichloromethane (10 mL × 3). The combined organic layer was washed

with brine, dried by anhydrous sodium sulfate, and ﬁltered. The solvent

was removed in vacuo, and the residue was puriﬁed by column

chromatography on silica gel using hexanes and ethyl acetate as an

eluent to aﬀord sulfamidate (−)-3: 61 mg, 92% yield, white solid, mp =

product were conﬁrmed by H NMR analysis with 1,3,5-trimethox-

ybenzene as an internal standard. The solvent was removed in vacuo,

and recovered material (+)-1a (406.0 mg, 65% yield with 49.6% ee) and

addition product (+)-2a (250.0 mg, 30% yield with 97.6% ee) were

isolated by column chromatography on silica gel using hexanes and

ethyl acetate as an eluent.

Determination of the Absolute Conﬁguration of Compound 2f.

To determine the absolute conﬁguration of addition product (+)-2f,

the (+)-2f was obtained as a colorless crystal after the recrystallization

from chloroform/hexanes. Based on single-crystal X-ray diﬀraction

23−225 °C. New compound: R = 0.50 (hexanes/ethyl acetate 5:1),

8% ee, [α] = −46.61 (c 1.24, CHCl ). H NMR (400 MHz, CDCl ):

δ 7.02−6.92 (m, 1H), 6.65−6.57 (m, 2H), 6.56−6.49 (m, 2H), 6.46−

.40 (m, 1H), 5.11 (d, J = 6.8 Hz, 1H), 4.46 (p, J = 7.1 Hz, 1H), 3.41−

.28 (m, 1H), 3.24−2.99 (m, 5H), 2.98−2.83 (m, 1H), 2.74−2.56 (m,

H), 1.59 (d, J = 7.1 Hz, 3H). C{ H} NMR (100 MHz, CDCl ): δ

49.6, 140.1, 138.3, 138.1, 134.6, 134.1, 133.3, 131.0, 129.6, 128.9,

28.3, 122.5, 53.7, 33.8, 32.6, 29.7, 22.6. HPLC: Chiracel OD-H

analysis, the structure of compound (+)-2f was determined as (S ,R) 4-

(4-chlorophenyl)-3,4-dihydro-[2.2]paracyclo-phano[5,6-d]-1,2,3-ben-

column, 254 nm, 30 °C, n-hexane/i-PrOH = 60:40, ﬂow = 0.6 mL/min,

retention time 9.5 and 10.6 min (major). HRMS (ESI-TOF): m/z calcd

for C H NNaO S [M + Na] , 352.0978; found, 352.0972.

zoxathiazine 2,2-dioxide (see the Supporting Information). The CCDC

number is 2023207 . These details can be obtained free of charge via

www.ccdc.com.ac.uk/data_request/cif from the Cambridge Crystallo-

graphic Data Centre.

Synthesis of (−)-3,4-Dihydro-[2.2]paracyclophano[5,6-d]-

,2,3-benzoxathiazine 2,2-Dioxide (4). Sodium tetrahydroborate

(

38 mg, 1.00 mmol) was added to a solution of aldimine (+)-1a (63 mg,

.20 mmol, 99% ee) in methanol (5.0 mL). The reaction was performed

ASSOCIATED CONTENT

sı Supporting Information

The Supporting Information is available free of charge at

■

at room temperature overnight. The reaction mixture was quenched by

the addition of saturated aqueous ammonium chloride solution (15

mL). After being extracted with ethyl acetate (15 mL × 3), the

combined organic layer was dried by anhydrous sodium sulfate,

concentrated in vacuo, and then puriﬁed by silica gel chromatography

using hexanes and ethyl acetate as an eluent to give product (−)-4: 60

mg, 95% yield, white solid, mp = 142−144 °C. New compound: R =

CHCl ). H NMR (400 MHz, CDCl ): δ 6.99−6.85 (m, 1H), 6.77−

Determination of absolute conﬁguration and NMR and

HPLC spectra (PDF)

Accession Codes

.60 (hexanes/ethyl acetate 5:1), 98% ee, [α] = −22.87 (c 1.36,

CCDC 2023207 contains the supplementary crystallographic

data for this paper. These data can be obtained free of charge via

www.ccdc.cam.ac.uk/data_request/cif , or by emailing data_

request@ccdc.cam.ac.uk , or by contacting The Cambridge

Crystallographic Data Centre, 12 Union Road, Cambridge

CB2 1EZ, UK; fax: +44 1223 336033.

.65 (m, 1H), 6.61−6.49 (m, 3H), 6.43−6.33 (m, 1H), 4.74−4.60 (m,

H), 4.35−4.15 (m, 2H), 3.40−3.26 (m, 1H), 3.21−2.76 (m, 6H),

.74−2.59 (m, 1H). C{ H} NMR (100 MHz, CDCl ): δ 151.0, 139.9,

38.8, 138.2, 134.7, 133.7, 133.2, 130.3, 129.5, 128.8, 128.0, 118.3, 45.1,

4.1, 33.8, 31.8, 29.3. HPLC: Chiracel IA column, 254 nm, 30 °C, n-

hexane/i-PrOH = 60:40, ﬂow = 0.6 mL/min, retention time 10.7 and

4.2 min (major). HRMS (ESI-TOF): m/z calcd for C H N O S [M

NH ] , 333.1267; found, 333.1266.

Synthesis of (−)-5-(Amino(phenyl)methyl)[2.2]-

17 21 2 3

AUTHOR INFORMATION

Corresponding Author

■

Yong-Gui Zhou − State Key Laboratory of Catalysis, Dalian

Institute of Chemical Physics, Chinese Academy of Sciences,

Dalian 116023, People’s Republic of China; State Key

Laboratory of Organometallic Chemistry, Shanghai Institute of

Organic Chemistry, Chinese Academy of Sciences, Shanghai

paracyclophan-4-ol (5). To a suspension of lithium aluminum

hydride (30 mg, 0.80 mmol) in THF (4 mL) was added asolution of

(+)-2a (78 mg, 0.20 mmol, 99% ee) dropwise. The mixture was reﬂuxed

overnight and then cooled to room temperature; aqueous potassium

sodium tartrate was added to destroy the lithium aluminum hydride,

and the aqueous layer was extracted with ethyl acetate (10 mL × 3).

Then, the combined organic layers were dried and concentrated to

provide the crude product. The residue was puriﬁed by column

chromatography on silica gel using hexanes and ethyl acetate as an

eluent to aﬀord product (−)-5: 51 mg, 77% yield, white solid, mp =

00032, People ’s Republic of China; orcid.org/0000-

0002-3321-5521 ; Email: ygzhou@dicp.ac.cn

Authors

Yang Zhao − State Key Laboratory of Catalysis, Dalian Institute

of Chemical Physics, Chinese Academy of Sciences, Dalian

16023, People’s Republic of China; University of Chinese

50−152 °C. New compound: R = 0.50 (hexanes/ethyl acetate 5:1),

9% ee, [α]²= −226.98 (c 0.40, CHCl ). H NMR (400 MHz,

CDCl ): δ 7.26−7.13 (m, 5H), 7.05−7.00 (m, 1H), 6.64−6.56 (m,

Academy of Sciences, Beijing 100049, People’s Republic of

China

H), 6.52−6.46 (m, 1H), 6.40−6.33 (m, 1H), 6.11−6.05 (m, 1H), 5.25

(

s, 1H), 3.56−3.42 (m, 1H), 3.27−2.99 (m, 5H), 2.75−2.50 (m, 2H).

Xiao-Qing Wang − State Key Laboratory of Catalysis, Dalian

Institute of Chemical Physics, Chinese Academy of Sciences,

Dalian 116023, People’s Republic of China

Yan-Jiang Yu − State Key Laboratory of Catalysis, Dalian

Institute of Chemical Physics, Chinese Academy of Sciences,

Dalian 116023, People’s Republic of China

C{ H} NMR (100 MHz, CDCl ): δ 157.0, 144.1, 140.7, 138.5, 137.9,

34.6, 134.1, 132.7, 129.0, 129.0, 128.8, 127.7, 126.9, 126.1, 123.7, 57.7,

4.4, 34.0, 33.4, 30.6. HPLC: Chiracel OD-H column, 254 nm, 30 °C,

n-hexane/i-PrOH = 60:40, ﬂow = 0.6 mL/min, retention time 19.4 and

34.9 min (major). HRMS (ESI-TOF): m/z calcd for C H ClNO [M

23 23

−

Cl] , 364.1474; found, 364.1485.

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Complete contact information is available at:

Note

https://pubs.acs.org/10.1021/acs.joc.0c02509

Chem. 2017, 2017, 1760−1764. (f) Meyer-Eppler, G.; Sure, R.;

Schneider, A.; Schnakenburg, G.; Grimme, S.; Lutzen, A. Synthesis,

Chiral Resolution, and Absolute Configuration of Dissymmetric 4,15-

Difunctionalized [2.2]Paracyclophanes. J. Org. Chem. 2014, 79, 6679−

Notes

6687.

The authors declare no competing ﬁnancial interest.

(4) (a) Rossen, K.; Pye, P. J.; Maliakal, A.; Volante, R. P. Kinetic

Resolution of rac -4,12-Dibromo[2.2]-paracyclophane in a Palladium

[2.2]Phanephos Catalyzed Amination. J. Org. Chem. 1997, 62, 6462−

6463. (b) Delcourt, M.-L.; Turcaud, S.; Benedetti, E.; Micouin, L.

Efficient and Scalable Kinetic Resolution of Racemic 4-Formyl[2.2]-

paracyclophane via Asymmetric Transfer Hydrogenation. Adv. Synth.

Catal. 2016, 358, 1213−1218. (c) Delcourt, M.-L.; Felder, S.;

Benedetti, E.; Micouin, L. Highly Enantioselective Desymmetrization

of Centrosymmetric pseudo -para -Diformyl[2.2]paracyclophane via

Asymmetric Transfer Hydrogenation. ACS Catal. 2018, 8, 6612−

ACKNOWLEDGMENTS

■

Financial support from the National Natural Science Founda-

tion of China (21532006 and 21690074) and Chinese Academy

of Sciences (XDB17020300 and SLH035) is acknowledged.

REFERENCES

■

1) (a) Morisaki, Y.; Gon, M.; Chujo, Y. Conjugated Microporous

Polymers Consisting of Tetrasubstituted [2.2]Paracyclophane Junc-

tions. J. Polym. Sci., Part A: Polym. Chem. 2013, 51, 2311−2316.

b) Cakici, M.; Gu, Z.-G.; Nieger, M.; Burck, J.; Heinke, L.; Brase, S.

6616. (d) Delcourt, M.-L.; Felder, S.; Turcaud, S.; Pollok, C. H.;

Merten, C.; Micouin, L.; Benedetti, E. Highly Enantioselective

Asymmetric Transfer Hydrogenation: A Practical and Scalable Method

to Efficiently Access Planar Chiral [2.2]Paracyclophanes. J. Org. Chem.

T.; Tokitoh, N.; Chujo, Y. Planar Chiral Tetrasubstituted [2.2]-

Planar-Chiral Building Blocks for Metal-Organic Frameworks. Chem.

Commun. 2015, 51, 4796−4798. (c) Morisaki, Y.; Gon, M.; Sasamori,

Paracyclophane: Optical Resolution and Functionalization. J. Am.

Chem. Soc. 2014 , 136 , 3350 −3353. (d) Morisaki, Y.; Inoshita, K.;

Chujo, Y. Planar-Chiral Through-Space Conjugated Oligomers:

Synthesis and Characterization of Chiroptical Properties. Chem. - Eur.

J. 2014 , 20 , 8386 −8390. (e) Gon, M.; Morisaki, Y.; Chujo, Y. Optically

Active Cyclic Compounds Based on Planar Chiral [2.2]-

Paracyclophane: Extension of the Conjugated Systems and Chiroptical

Properties. J. Mater. Chem. C 2015 , 3 , 521 −529. (f) Gon, M.; Morisaki,

Y.; Chujo, Y. Highly Emissive Optically Active Conjugated Dimers

Consisting of a Planar-Chiral [2.2]Paracyclophane Showing Circularly

Polarized Luminescence. Eur. J. Org. Chem. 2015 , 2015 , 7756 −7762.

019, 84, 5369−5382. (e) Dorizon, P.; Martin, C.; Daran, J.-C.; Fiaud,

J.-C.; Kagan, H. B. A Practical Kinetic Resolution of 4-Acetyl[2.2]-

paracyclophane. Tetrahedron: Asymmetry 2001, 12 , 2625 −2630.

(f) Akagawa, K.; Nishi, N.; Yoshikawa, I.; Kudo, K. Kinetic Resolution

of a Planar-Chiral [2.2]Paracyclophane Derivative by Helical-Peptide-

Catalyzed Michael Addition of Nitromethane. Eur. J. Org. Chem. 2015,

015 , 5055 −5059. (g) Zhao, Y.; Wang, H.; Wu, B.; Zhou, Y.-G.

Synthesis of Paracyclophanes with Planar and Central Chirality: Kinetic

Resolution of [2.2]Paracyclophane Aldimines via Palladium-Catalyzed

Addition of Arylboronic Acids. Org. Chem. Front. 2019 , 6 , 3956 −3960.

5) Sattur, P. B.; Kamal, A. A Facile Synthesis of 1,2,3-Benzoxathiazine

(

,2-Dioxides. Synthesis 1981 , 1981 , 272 −273.

6) (a) Williams, S. J. Sulfatase Inhibitors: A Patent Review. Expert

g) Morisaki, Y.; Sawada, R.; Gon, M.; Chujo, Y. New Types of Planar-

Opin. Ther. Pat. 2013 , 23 , 79 −98. (b) Woo, L. W. L.; Purohit, A.;

Potter, B. V. L. Development of Steroid Sulfatase Inhibitors. Mol. Cell.

Endocrinol. 2011, 340, 175−185. (c) Winum, J.-Y.; Scozzafava, A.;

Montero, J.-L.; Supuran, C. T. The Sulfamide Motif in the Design of

Enzyme Inhibitors. Expert Opin. Ther. Pat. 2006, 16, 27−47.

Chiral [2.2]Paracyclophanes and Construction of One-Handed Double

Helices. Chem. - Asian J. 2016 , 11 , 2524 −2527. (h) Morisaki, Y.; Chujo,

Y. Planar Chiral [2.2]Paracyclophanes: Optical Resolution and

Transformation to Optically Active π -Stacked Molecules. Bull. Chem.

Soc. Jpn. 2019, 92, 265−274.

7) (a) Quan, M.; Wu, L.; Yang, G.; Zhang, W. Pd(II), Ni(II) and

d) Winum, J.-Y.; Scozzafava, A.; Montero, J.-L.; Supuran, C. T.

Sulfamates and Their Therapeutic Potential. Med. Res. Rev. 2005, 25,

86−228.

2) (a) Rowlands, G. J. Planar Chiral Phosphines Derived from

[

2.2]Paracyclophane. Isr. J. Chem. 2012 , 52 , 60 −75. (b) David, O. R. P.

Syntheses and Applications of Disubstituted [2.2]Paracyclophanes.

Tetrahedron 2012, 68, 8977 −8993. (c) Fringuelli, F.; Piermatti, O.;

Pizzo, F.; Ruzziconi, R. [2.2]Paracyclophane-Derived N -Acyloxazol-

Co(II)-Catalyzed Enantioselective Additions of Organoboron Re-

agents to Ketimines. Chem. Commun. 2018, 54, 10394−10404.

(3H )-one as a Suitable Planar Chiral Auxiliary for the Enantioselective

(b) Wang, Y.-Q.; Yu, C.-B.; Wang, D.-W.; Wang, X.-B.; Zhou, Y.-G.

Synthesis of β -Hydroxy Acids. Chem. Lett. 2000, 29, 38−39. (d) Liu, S.;

Li, S.; Chen, H.; Yang, Q.; Xu, J.; Zhou, Y.; Yuan, M.; Zeng, W.; Fan, B.

Asymmetric Alkynylative Ring Opening Reaction of Oxabenzonorbor-

nadienes Promoted by Palladium/Silver Cocatalytic System. Adv.

Synth. Catal. 2014 , 356 , 2960 −2964. (e) Enders, D.; Ludwig, M.;

Raabe, G. Synthesis and Application of the First Planar Chiral Strong

Brønsted Acid Organocatalysts. Chirality 2012 , 24 , 215 −222. (f) Lu, Y.;

Ma, Y.; Yang, S.; Ma, M.; Chu, H.; Song, C. Synthesis of Planar Chiral

Enantioselective Synthesis of Cyclic Sulfamidates via Pd-Catalyzed

Hydrogenation. Org. Lett. 2008, 10, 2071 −2074. (c) Li, B.; Chen, J.;

Zhang, Z.; Gridnev, I. D.; Zhang, W. Nickel-Catalyzed Asymmetric

Hydrogenation of N -Sulfonyl Imines. Angew. Chem., Int. Ed. 2019, 58,

7329−7334. (d) Liu, G.; Zhang, X.; Wang, H.; Cong, H.; Zhang, X.;

Dong, X.-Q. Synthesis of Chiral α -Substituted α -Amino Acid and

Amine Derivatives through Ni-Catalyzed Asymmetric Hydrogenation.

Chem. Commun. 2020, 56, 4934−4937. (e) Quan, M.; Wang, X.; Wu,

L.; Gridnev, I. D.; Yang, G.; Zhang, W. Ni(II)-Catalyzed Asymmetric

Alkenylations of Ketimines. Nat. Commun. 2018, 9, 2258−2268. (f) Li,

B.-S.; Wang, Y.; Jin, Z.; Zheng, P.; Ganguly, R.; Chi, Y. R. Carbon-

Carbon Bond Activation of Cyclobutenones Enabled by the Addition of

Chiral Organocatalyst to Ketone. Nat. Commun. 2015 , 6 , 6207 −6211.

(g) Zhang, H.-X.; Nie, J.; Cai, H.; Ma, J.-A. Cyclic Aldimines as Superior

Electrophiles for Cu-Catalyzed Decarboxylative Mannich Reaction of

β -Ketoacids with a Broad Scope and High Enantioselectivity. Org. Lett.

2014, 16 , 2542 −2545. (h) Chen, W.; Meng, D.; N ’Zemba, B.; Morris,

W. J. Palladium-Catalyzed Enantioselective Synthesis of Cyclic

Sulfamidates and Application to a Synthesis of Verubecestat. Org.

Lett. 2018, 20, 1265−1268.

[

2.2]Paracyclophane-Based Amino Thioureas and Their Application in

Asymmetric Aldol Reactions of Ketones with Isatins. Tetrahedron:

Asymmetry 2013, 24, 1082−1088. (g) Rozenberg, V. I.; Sergeeva, E. V.;

Hopf, H. Modern Cyclophane Chemistry; Wiley-VCH: Weinheim, 2004.

3) (a) Enders, D.; Noll, S.; Bats, J. W. Efficient Entry to Diastereo-

and Enantiomerically Pure α -Branched [2.2]Paracyclo-Phanylalkyl-

amines. Synlett 2005 , 2679 −2681. (b) Jiang, B.; Zhao, X.-L. A Simple

and Efficient Resolution of (±)-4,12-Dihydroxy[2.2]paracyclophane.

Tetrahedron: Asymmetry 2004, 15 , 1141 −1143. (c) Kramer, J. J. P.;

Yildiz, C.; Nieger, M.; Bras

2.2]Paracyclophanes by Selective ortho -Halogenation with Pd-

Catalyzed C-H Activation. Eur. J. Org. Chem. 2014 , 2014 , 1287 −

295. (d) Wang, Y.; Yuan, H.; Lu, H.; Zheng, W.-H. Development of

e, S. Direct Access to 4,5-Disubstituted

[

Planar Chiral Iodoarenes Based on [2.2]Paracyclophane and Their

Application in Catalytic Enantioselective Fluorination of β -Ketoesters.

Org. Lett. 2018 , 20 , 2555 −2558. (e) Braun, C.; Brase, S.; Schafer, L. L.

Planar-Chiral [2.2]Paracyclophane-Based Amides as Proligands for

(8) (a) Yan, Z.; Wu, B.; Gao, X.; Zhou, Y.-G. Enantioselective

Synthesis of Quaternary α -Aminophos-phonates by Pd-Catalyzed

Arylation of Cyclic α -Ketiminophosphonates with Arylboronic Acids.

Chem. Commun. 2016, 52, 10882 −10885. (b) Zhao, Z.-B.; Shi, L.;

Meng, F.-J.; Li, Y.; Zhou, Y.-G. Synthesis of Chiral Seven-Membered

Titanium- and Zirconium-Catalyzed Hydroamination. Eur. J. Org.

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Cyclic Sulfamidates through Palladium-Catalyzed Arylation of Cyclic

Note

Imines. Org. Chem. Front. 2019, 6, 1572−1576.

(9) Spielmann, K.; van der Lee, A.; de Figueiredo, R. M.; Campagne,

J.-M. Diastereoselective Palladium-Catalyzed [3 + 2]-Cycloadditions

from Cyclic Imines and Vinyl Aziridines. Org. Lett. 2018, 20, 1444−

10) Dahmen, S.; Brase, S. Preparation of Planar-Chiral Amino

447.

Phenols Based on the [2.2]Paracyclophane Backbone. Tetrahedron:

Asymmetry 2001, 12, 2845−2850.