Synthesis of planar chiral pseudo-ortho-substituted aryl[2.2] paracyclophanes by stepwise successive palladium-catalyzed coupling reactions

Article abstract of DOI:10.1016/j.tetasy.2011.05.023

Planar chiral aryl[2.2]paracyclophanyl-thioureas and -phosphine with a pseudo-ortho substitution pattern have been designed and efficiently synthesized by stepwise successive palladium-catalyzed cross-coupling reactions.

Full text of DOI:10.1016/j.tetasy.2011.05.023

Tetrahedron: Asymmetry 22 (2011) 986–991
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Tetrahedron: Asymmetry
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Synthesis of planar chiral pseudo–ortho-substituted aryl[2.2]paracyclophanes
by stepwise successive palladium-catalyzed coupling reactions
⇑
Shinji Kitagaki , Yuu Ohta, Shoichirou Tomonaga, Ryohei Takahashi, Chisato Mukai
Division of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 14 April 2011
Accepted 13 May 2011
Planar chiral aryl[2.2]paracyclophanyl-thioureas and -phosphine with a pseudo–ortho substitution pat-
tern have been designed and efficiently synthesized by stepwise successive palladium-catalyzed cross-
coupling reactions.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
electronic element, which interacts with the substrate and/or reac-
tant, but also the conformational flexibility that makes the distance
The use of the planar chirality of the substituted [2.2]paracyclo-
phanes as a source of asymmetric induction has recently attracted
growing attention. The substituted [2.2]paracyclophanes serve as
chiral building blocks from which some substituents protrude in
various directions.1,2 Of all such species, two functional groups in
a pseudo–ortho relationship to each other in the [2.2]paracyclo-
phane molecule seem to create the most effective chiral environ-
ment. Indeed, [2.2]PHANEPHOS, the pseudo–ortho-disubstituted
[2.2]paracyclophane ligand possessing both identical substituents
(a phosphinyl group) at the specified positions, has realized a
highly enantioselective hydrogenation catalyzed by a rhodium or
ruthenium complex in several unsaturated systems.3 Some
pseudo–ortho-disubstituted [2.2]paracyclophanes bearing two dif-
ferent functional groups have also proven to be effective ligands
in asymmetric catalysis.4 However, there have not yet been many
examples of the use of pseudo–ortho-type cyclophane ligands com-
pared to those bearing other substitution patterns (mono-,5 ortho-
di-,6,7 or pseudo-gem-di-substitution),8–11 probably due to a lack of
their efficient synthetic methodology. Their preparation usually
starts with the dibromination of [2.2]paracyclophane.12 However,
it is not always easy to catalytically transform only one of the
two bromo groups of the resulting pseudo–ortho-dibromo-
[2.2]paracyclophane,13 while some methods via a single bro-
mine–lithium exchange have been established.
between two functional groups suitable for performing the dual
activation of the substrate and reactant (Fig. 1).
active site
R1
pseudo-ortho-disubstituted
[2.2]paracyclophane backbone
R2
spacer
steric or electronic
element
Figure 1.
Recently, Paradies et al. synthesized some enantiopure
pseudo-gem-disubstituted [2.2]paracyclophanylthioureas, and
demonstrated their potential in organocatalytic transformations.18
These results prompted us to report the concise and efficient syn-
thesis of chiral [2.2]paracyclophanyl-thioureas and -phosphines
designed based on the aforementioned concept. The characteristic
feature of our synthetic methodology is the stepwise successive
palladium-catalyzed cross-coupling for the [2.2]paracyclophane
bearing two different leaving groups in
relationship.
a
pseudo–ortho
We have been interested in the development of bifunctional14
organocatalysts15 based on the pseudo–ortho-substituted aryl-
[2.2]paracyclophane backbone,16 which is expected to construct a
novel type of efficient asymmetric environment. Our design con-
cept was as follows: (1) the [2.2]paracyclophane backbone would
provide conformational rigidity; and (2) a spacer aryl group17 con-
nected to the pseudo–ortho position would offer not only a steric or
2. Results and discussion
Our common synthetic plan for the thiourea and phosphine
derivatives is illustrated in Scheme 1. Triflation of the pseudo–
ortho-bromo[2.2]paracyclophanol 3, which is readily available in
an enantiopure form, would set the stage for the stepwise succes-
sive palladium-catalyzed installation of two functional groups, that
is, the polar functionality (R1) to directly connect to the backbone
and an aryl group equipped with the second functionality (R2). The
different leaving groups (Br and OTf) in 4 might make it easier to
⇑
Corresponding author. Tel.: +81 76 234 4450; fax: +81 76 234 4410.
E-mail address: kitagaki@p.kanazawa-u.ac.jp (S. Kitagaki).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.05.023

S. Kitagaki et al. / Tetrahedron: Asymmetry 22 (2011) 986–991
987
acetic acid, was found to selectively give the desired mono-aminat-
ed cyclophanyl triflate (Sp)-5 in good yield.21,22 The next
installation of an aryl group at the pseudo–ortho position was at-
tained by conducting the Suzuki–Miyaura coupling. Thus, a non-
functionalized phenyl group or a 3,5-dimethoxyphenyl one was
introduced onto the cyclophane core in high yield using the corre-
sponding boronic acid, and the latter product was demethylated
using boron tribromide. Finally, treatment of the amine (Sp)-6 with
3,5-bis(trifluoromethyl)phenyl isothiocyanate produced the corre-
sponding thiourea (Sp)-7.
The synthesis of cyclophanylphosphine (Sp)-10 was examined
next. In this case, the installation of an aryl group by a Suzuki–
Miyaura coupling was undertaken prior to the palladium-catalyzed
phosphinylation (Scheme 3).23 Thus, the reaction of (Sp)-4 with
1.3 equiv of 3,5-dimethoxyphenyboronic acid in the presence of
5 mol % PdCl2(dppf) and K3PO4 gave the monoarylated triflate
(Sp)-8 in 80% yield together with a trace amount of the diarylated
one. Next, the palladium-catalyzed phosphinylation of (Sp)-8 with
diphenylphosphine oxide afforded the desired product (Sp)-9 in
91% yield. Demethylation of the pseudo–ortho-aryl group and the
subsequent reduction of the phosphine oxide with trichlorosilane
gave the target compound (Sp)-10. An alternative sequence of the
phosphinylation/Suzuki–Miyaura coupling was also screened.
Thus, monophosphinylation of ( )-4 with 1.2 equiv of diphenyl-
phosphine oxide gave the desired coupling products as a 2.5:1 mix-
ture of the bromide ( )-11a and triflate ( )-11b in 69% yield
together with the recovered starting material ( )-4 (20%) when
1,10-bis(diphenylphosphino)ferrocene (dppf) was used as the
bidentate ligand (Scheme 3).24 Exposure of the resulting mixture
( )-11a and ( )-11b to the Suzuki–Miyaura coupling conditions
afforded an arylated product ( )-9 in 67% yield, and of the sub-
strates, only triflate ( )-11b was recovered in 23%. The moderate
yield of the desired product in each step was attributed to the
insufficient reactivity of the phosphinylation25 and excessively
Br
Br
Br
ref. 4c
and 19
Br
HO
TfO
2
3
4
B(OH)2
R1
H
+
R1
R2
stepwise successive
Pd-catalyzed
R2
cross-coupling
1
Scheme 1. Synthetic plan towards pseudo–ortho-substituted aryl[2.2]paracyclo-
phanes 1.
obtain the singly-coupled product, due to their different reactivi-
ties. Based on this plan, our initial investigation focused on the syn-
thesis of optically active thioureas
(CF3)2].
Compound (Sp)-3, prepared according to Rozenberg’s proce-
dure,19 was triflated by conventional means (Scheme 2), and the
palladium-catalyzed amination of the obtained (Sp)-4 was investi-
gated. As a result, a two-step procedure, which consists of the
Buchwald–Hartwig amination using N-tert-butyl carbamate as
the ammonia equivalent20 and subsequent exposure to trifluoro-
1
[R1 = NHCSNHC6H3-3,5-
1. BocNH2 (1.2 eq)
Pd2(dba)3 (1.3 mol%)
P(t-Bu)3 (10 mol%)
PhONa, toluene
Br
Br
Tf2O, pyridine
110 °C, 10 h
B(OH)2
CH2Cl2, 0 °C
96%
→ rt
2. TFA, CH2Cl2, rt, 1 d
78% (2 steps)
Ph2P(O)H (2 eq)
MeO
MeO
Pd(OAc)2
(10 mol%)
MeO
(1.3 eq)
OMe
HO
(Sp)-3
TfO
(Sp)-4
Br
dppf (18 mol%)
PdCl2(dppf)
(5 mol%)
K3PO4, toluene
80 °C, 5.5 h
i-Pr2NEt
DMSO
100 °C, 8 h
B(OH)2
TfO
(Sp)-4
TfO
(Sp)-8
H2N
(3 eq)
H2N
91%
R
R
80%
Pd(PPh3)4 (5 mol%), Na2CO3
DMSO/H2O = 10/1
MeO
MeO
HO
HO
R
1. BBr3, CH2Cl2
0 °C rt
TfO
(Sp)-5
85 °C, 12-20 h
→
R
(Sp)-6a: R = H (88%)
(Sp)-6b: R = OMe (89%)
(Sp)-6c: R = OH (quant)
2. HSiCl3, i-Pr2NEt
xylene, 140 °C
BBr3, CH2Cl2
Ph2(O)P
Ph2P
0 °C
→
rt
81% (2 steps)
(Sp)-10
(Sp)-9
CF3
CF3
S
B(OH)2
F3C
N
H
N
H
F3C
THF, 0 °C
NCS
rt
MeO
(1.8 eq)
OMe
Ph2P(O)H (1.2 eq)
Pd(OAc)2 (10 mol%)
dppf (18 mol%)
→
X
( )-9
( )-4
R
PdCl2(dppf) (5 mol%)
K3PO4, toluene
100 °C, 1 d
i-Pr2NEt, DMSO
100 °C, 7 h
R
Ph2(O)P
69%
(Sp)-7a: R = H (87%)
(Sp)-7c: R = OH (71%)
67%
(11a:11b = 2.5:1) ( )-11a: X = Br
( )-11b: X = OTf
Scheme 2. Preparation of pseudo–ortho-substituted cyclophanylthioureas (Sp)-7.
Scheme 3. Preparation of pseudo–ortho-substituted cyclophanylphosphine (Sp)-10.

988
S. Kitagaki et al. / Tetrahedron: Asymmetry 22 (2011) 986–991
low reactivity of the Suzuki–Miyaura coupling23 by the trif-
luoromethanesulfonyloxy group. Therefore, the successive cou-
plings in reverse order could have provided better results.
solution of the crude amide (668 mg) in CH2Cl2 (15 mL) was added
TFA (0.92 mL, 12 mmol) at room temperature. The reaction mix-
ture was stirred for 1 day, quenched by the addition of saturated
aqueous NaHCO3, and extracted with CH2Cl2. The extract was
washed with brine, dried, and concentrated to dryness. The residue
was chromatographed with hexane–AcOEt (20:1) to afford (Sp)-5
3. Conclusion
(326 mg, 78% for two steps) as a colorless oil: ½a D25
ꢀ
¼ ꢁ22:0 (c
In conclusion, we have developed a concise and efficient syn-
thetic method for preparing planar chiral pseudo–ortho-substituted
aryl[2.2]paracyclophane molecules through the stepwise succes-
sive palladium-catalyzed coupling of the corresponding bromocy-
clophanyl triflate. The evaluation of the catalytic activity of the
newly synthesized chiral cyclophanyl-thioureas and -phosphine
based on the Morita–Baylis–Hillman reaction or other asymmetric
catalysis is currently under investigation.
1.00, CHCl3); IR 3470, 3389, 1420, 1207, 1142 cmꢁ1
;
1H NMR
(600 MHz, CDCl3): d 7.07 (d, J = 1.4 Hz, 1H), 6.66 (d, J = 7.9 Hz,
1H), 6.49 (dd, J = 7.9, 1.4 Hz, 1H), 6.32 (d, J = 7.9 Hz, 1H), 6.10 (dd,
J = 7.9, 1.4 Hz, 1H), 5.80 (s, 1H), 3.52 (br s, 2H), 3.36–3.28 (m,
1H), 3.16–3.07 (m, 2H), 3.06–3.01 (m, 1H), 3.00–2.93 (m, 1H),
2.92–2.85 (m, 1H), 2.81–2.72 (m, 1H), 2.71–2.60 (m, 1H); 13C
NMR (100 MHz, CDCl3): d 148.1, 144.9, 142.6, 141.1, 135.5, 135.3,
132.8, 131.0, 124.3, 122.8, 121.3, 118.2, 117.1, 33.4, 32.1, 31.9,
31.3; MS (EI): m/z (%) = 371 (14.6, M+); HRMS calcd for
C17H16F3NSO3: 371.0803, found 371.0805.
4. Experimental
4.1. General
4.4. Typical procedure for the synthesis of (Sp)-4-amino-12-aryl
[2.2]paracyclophane (Sp)-6
Melting points are uncorrected. IR spectra were measured in
CHCl3. 1H NMR spectra were taken in CDCl3 unless otherwise sta-
ted. CHCl3 (7.26 ppm) for silyl compounds and tetramethylsilane
(0.00 ppm) for compounds without a silyl group were used as
internal standards. 13C NMR spectra were recorded in CDCl3 with
CDCl3 (77.00 ppm) as an internal standard. Reactions were carried
out under a nitrogen atmosphere unless otherwise stated. Silica gel
(Silica Gel 60, 230–400 mesh) was used for chromatography. Or-
ganic extracts were dried over anhydrous Na2SO4. Compound
(Sp)-3 was prepared according to literature procedures.4c,19
To a solution of (Sp)-5 (36.2 mg, 0.0975 mmol), phenylboronic
acid
(37.4 mg,
0.307 mmol),
and
Pd(PPh3)4
(5.9 mg,
5.1 ꢂ 10ꢁ3 mmol) in DMSO (0.7 mL) was added aqueous Na2CO3
(2 M, 70 lL, 0.14 mmol) at room temperature under an argon
atmosphere. After stirring for 12 h at 85 °C, the reaction mixture
was cooled and diluted with saturated aqueous NaHCO3. The
whole was extracted with Et2O and the extract was washed with
brine, dried, and concentrated to dryness. The residue was chro-
matographed with hexane–acetone (29:1) to afford (Sp)-6a
(25.6 mg, 88%) as a pale yellow solid.
4.2. (Sp)-12-Bromo[2.2]paracyclophan-4-yl
trifluoromethanesulfonate (Sp)-4
4.4.1. (Sp)-4-Amino-12-phenyl[2.2]paracyclophane (Sp)-6a
Mp 140–141 °C;
½
a 2D5
ꢀ
¼ þ92:1 (c 0.47, CHCl3); IR 3462,
3383 cmꢁ1 1H NMR (600 MHz, CDCl3): d 7.52 (dd, J = 8.2, 1.0 Hz,
;
To a solution of (Sp)-3 (363 mg, 1.20 mmol) in CH2Cl2 (12 mL)
were added pyridine (0.58 mL, 7.2 mmol) and Tf2O (0.45 mL,
2.4 mmol) at 0 °C. After being stirred for 1.5 h at room tempera-
ture, the reaction mixture was quenched by the addition of water
and extracted with AcOEt. The extract was washed with water and
brine, dried and concentrated to dryness. The residue was chro-
matographed with hexane–AcOEt (10:1) to afford (Sp)-4 (502 mg,
2H), 7.46 (t, J = 7.6 Hz, 2H), 7.34 (t, J = 7.6 Hz, 1H), 7.20 (d,
J = 2.1 Hz, 1H), 6.71 (d, J = 7.6 Hz, 1H), 6.43 (dd, J = 7.6, 1.7 Hz,
1H), 6.41 (d, J = 7.9 Hz, 1H), 6.20 (dd, J = 7.6, 1.7 Hz, 1H), 5.61 (d,
J = 1.4 Hz, 1H), 3.56 (br s, 2H), 3.49–3.32 (m, 1H), 3.25–3.04 (m,
3H), 2.94–2.79 (m, 1H), 2.78–2.60 (m, 2H), 2.42–2.27 (m, 1H);
13C NMR (150 MHz, CDCl3): d 144.3, 141.5, 141.3, 140.7, 139.0,
136.2, 134.9, 134.8, 132.3, 129.5, 128.4, 127.7, 126.6, 124.5,
123.1, 117.9, 34.1, 34.0, 32.3, 32.2; MS (EI): m/z (%) = 299 (10.2,
M+); HRMS calcd for C22H21N: 299.1674, found 299.1675.
96%) as a colorless solid: mp 112–113 °C; ½a D26
¼ þ35:9 (c 1.00,
ꢀ
CHCl3); IR 1420, 1207, 1140 cmꢁ1 1H NMR (600 MHz, CDCl3): d
;
6.94 (d, J = 1.4 Hz, 1H), 6.92 (d, J = 1.4 Hz, 1H), 6.66 (d, J = 7.6 Hz,
1H), 6.60 (dd, J = 8.2, 1.4 Hz, 1H), 6.53 (d, J = 7.6 Hz, 1H), 6.49 (dd,
J = 7.6, 1.4 Hz, 1H), 3.49–3.39 (m, 2H), 3.17–2.99 (m, 4H), 2.86–
2.76 (m, 2H); 13C NMR (150 MHz, CDCl3): d 148.1, 143.0, 141.3,
138.7, 136.1, 135.1, 133.8, 132.7, 131.8, 131.7, 126.6, 123.2, 118.7
(q, JC-F = 320.8 Hz), 35.4, 33.1, 32.4, 31.6; MS (EI): m/z (%) = 434
(31.9, M+), 436 (31.4, M+); HRMS calcd for C17H14O3F3SBr:
433.9799, found 433.9800; calcd for C17H14O3F3S81Br: 435.9779,
found 435.9779.
4.4.2. (Sp)-4-Amino-12-(3,5-dimethoxyphenyl)
[2.2]paracyclophane (Sp)-6b
Compound (Sp)-6b was obtained as a colorless solid (89% yield):
mp 158–159 °C; ½a D25
ꢀ
¼ ꢁ78:7 (c 1.00, CHCl3); IR 3462, 3381 cmꢁ1
;
1H NMR (400 MHz, CDCl3): d 7.18 (d, J = 1.8 Hz, 1H), 6.70–6.66 (m,
3H), 6.45 (t, J = 2.3 Hz, 1H), 6.44–6.36 (m, 2H), 6.19 (dd, J = 7.8,
1.8 Hz, 1H), 5.65 (d, J = 1.8 Hz, 1H), 3.86 (s, 6H), 3.61–3.43 (m,
3H), 3.20–3.06 (m, 3H), 2.91–2.81 (m, 1H), 2.80–2.68 (m, 2H),
2.51–2.39 (m, 1H); 13C NMR (100 MHz, CDCl3): d 160.6, 144.2,
143.7, 141.3, 140.7, 139.0, 136.3, 134.9, 134.8, 132.4, 127.7,
124.5, 123.1, 118.0, 107.8, 98.3, 55.4, 34.2, 34.1, 32.3, 32.1; MS
(EI): m/z (%) = 359 (14.0, M+); HRMS calcd for C24H25O2N:
359.1885, found 359.1880.
4.3. (Sp)-12-Amino[2.2]paracyclophan-4-yl
trifluoromethanesulfonate (Sp)-5
To a solution of (Sp)-4 (489 mg, 1.12 mmol), t-butyl carbamate
(158 mg, 1.35 mmol), Pd2(dba)3 (12.8 mg, 0.0141 mmol), and
NaOPh (196 mg, 1.69 mmol) in toluene (5.6 mL) was added P(t-
Bu)3 (10 wt % in hexane, 0.33 mL, 0.11 mmol) at room temperature
under an argon atmosphere. After stirring for 10 h at 110 °C, the
reaction mixture was cooled and diluted with saturated aqueous
NaHCO3. The whole was extracted with Et2O and the extract was
washed with water and brine, dried, and concentrated to dryness.
The residue was chromatographed with hexane–AcOEt (14:1) to
afford the crude amide (668 mg) contaminated with PhOH. To a
4.5. (Sp)-5-(12-Amino[2.2]paracyclophan-4-yl)resorcinol (Sp)-6c
To a solution of (Sp)-6b (30.0 mg, 0.0834 mmol) in CH2Cl2
(0.8 mL) was added BBr3 (20.6 lL, 0.217 mmol) at 0 °C. The reac-
tion mixture was stirred for 1 h, quenched by the addition of satu-
rated aqueous NaHCO3, and extracted with CH2Cl2. The extract was
washed with brine, dried, and concentrated to dryness. The residue

S. Kitagaki et al. / Tetrahedron: Asymmetry 22 (2011) 986–991
989
was chromatographed with hexane–AcOEt (3:2) to afford (Sp)-6c
as a colorless solid: mp 149–152 °C; ½a D23
ꢀ
¼ ꢁ58:8 (c 1.00, CHCl3);
(28.9 mg, quant) as
a
colorless solid: mp 148–149 °C;
IR 1421, 1205, 1155, 1140 cmꢁ1 1H NMR (600 MHz, CDCl3): d
;
½
a 2D6
ꢀ
¼ ꢁ93:7 (c 0.96, MeOH); IR 3595, 3312 cmꢁ1
;
1H NMR
6.96 (s, 1H), 6.74 (d, J = 7.8 Hz, 1H), 6.69 (d, J = 8.2 Hz, 1H), 6.64
(d, J = 7.8 Hz, 1H), 6.61 (d, J = 1.4 Hz, 2H), 6.48–6.46 (m, 2H), 6.40
(s, 1H), 3.87 (s, 6H), 3.62–3.45 (m, 2H), 3.23–3.07 (m, 2H), 2.97–
2.83 (m, 3H), 2.69–2.61 (m, 1H); 13C NMR (150 MHz, CDCl3): d
161.0, 147.7, 143.3, 142.5, 141.9, 139.2, 136.6, 135.9, 135.8,
132.8, 132.5, 131.9, 129.2, 124.6, 118.7 (q, JC-F = 320.8 Hz), 107.3,
99.4, 55.4, 34.0, 33.8, 33.2, 31.8; MS (EI): m/z (%) = 492 (45.5,
M+); HRMS calcd for C25H23F3O5S: 492.1218, found 492.1213.
(600 MHz, CD3OD): d 7.09 (d, J = 1.7 Hz, 1H), 6.64 (d, J = 7.6 Hz,
1H), 6.47 (d, J = 2.1 Hz, 2H), 6.39 (dd, J = 7.6, 1.7 Hz, 1H), 6.32 (d,
J = 7.6 Hz, 1H), 6.26 (t, J = 2.1 Hz, 1H), 6.07 (dd, J = 7.6, 1.7 Hz,
1H), 5.65 (d, J = 1.7 Hz, 1H), 3.58–3.45 (m, 1H), 3.30–3.18 (m,
1H), 3.17–3.08 (m, 1H), 3.07–2.97 (m, 1H), 2.83–2.58 (m, 3H),
2.41–2.26 (m, 1H); 13C NMR (150 MHz, CD3OD): d 159.3, 146.6,
145.3, 142.2, 142.1, 140.5, 137.3, 136.2, 136.1, 133.2, 128.4,
125.4, 123.2, 118.9, 109.1, 101.8, 35.4, 35.0, 33.2, 33.2; MS (EI):
m/z (%) = 331 (53.7, M+); HRMS calcd for C22H21O2N: 331.1572,
found 331.1578.
4.8. (Sp)-{12-(3,5-Dimethoxyphenyl)[2.2]paracyclophan-4-
yl}diphenylphosphine oxide (Sp)-9
4.6. Typical procedure for the synthesis of thioureas (Sp)-7
To a solution of (Sp)-8 (70.8 mg, 0.144 mmol), Ph2P(O)H
(58.2 mg, 0.288 mmol), Pd(OAc)2 (3.2 mg, 0.014 mmol) and dppf
(14.3 mg, 0.0259 mmol) in DMSO (0.7 mL) was added diisopropyl-
To a solution of (Sp)-6a (10.8 mg, 0.0361 mmol) in THF (0.7 mL)
was added 3,5-bis(trifluoromethyl)phenyl isothiocyanate (21.0
lL,
ethylamine (75 lL, 0.43 mmol) at room temperature under an ar-
0.108 mmol) at 0 °C. The reaction mixture was stirred for 18 h at
room temperature and concentrated to dryness. The residue was
chromatographed with hexane–AcOEt (10:1) to afford (Sp)-7a
(17.9 mg, 87%) as a colorless solid.
gon atmosphere. After being stirred for 18.5 h at 100 °C, the
reaction mixture was cooled, quenched by the addition of 10%
aqueous HCl, and extracted with AcOEt. The extract was washed
with water and brine, dried and concentrated to dryness. The res-
idue was chromatographed with hexane–AcOEt (2:1) to afford (Sp)-
4.6.1. (Sp)-N-[3,5-Bis(trifluoromethyl)phenyl]-N0-{12-
phenyl[2.2]paracyclophan-4-yl}thiourea (Sp)-7a
9
½
(71.7 mg, 91%) as
a yellowish solid: mp 220–223 °C;
a 2D4
ꢀ
¼ ꢁ41:1 (c 1.00, CHCl3); IR 1180, 1155 cmꢁ1
;
1H NMR
Mp 78–79 °C; ½a 2D5
ꢀ
¼ ꢁ21:2 (c 0.48, CHCl3); IR 3402, 3348 cmꢁ1
;
(600 MHz, CDCl3): d 7.76–7.70 (m, 4H), 7.46–7.34 (m, 6H), 7.17
(s, 1H), 6.86 (d, J = 2.1 Hz, 2H), 6.76 (d, J = 7.2 Hz, 1H), 6.71–6.65
(m, 3H), 6.59 (d, J = 6.9 Hz, 1H), 6.40 (s, 1H), 3.83 (s, 6H), 3.70
(td, J = 13.7, 9.6 Hz, 1H), 3.32–3.27 (m, 1H), 3.12 (t, J = 13.1 Hz,
1H), 3.02 (t, J = 11.7 Hz, 1H), 2.94 (dd, J = 13.1, 9.6 Hz, 1H), 2.81–
2.73 (m, 2H), 2.36–2.31 (m, 1H); 13C NMR (150 MHz, CDCl3): d
160.7, 145.8 (d, JC-P = 8.7 Hz), 142.6, 140.7, 139.8, 139.4 (d, JC-P
= 11.6 Hz), 136.7, 136.3, 136.2 (d, JC-P = 102.6 Hz), 135.5 (d, JC-P
= 11.6 Hz), 135.1, 134.5 (d, JC-P = 13.0 Hz), 133.4, 132.5, (d, JC-P
= 98.3 Hz), 132.2 (d, JC-P = 8.7 Hz), 131.2, 131.1 (d, JC-P = 2.9 Hz),
131.0 (d, JC-P = 2.9 Hz), 130.9 (d, JC-P = 10.1 Hz), 129.5 (d, JC-P
= 105.5 Hz), 128.2 (d, JC-P = 11.6 Hz), 128.0 (d, JC-P = 11.6 Hz),
107.9, 98.2, 55.4, 36.0 (d, JC-P = 4.3 Hz), 35.4, 34.9, 33.7; 31P NMR
(161 MHz, CDCl3): d 24.1; MS (EI): m/z (%) = 544 (100.0, M+); HRMS
calcd for C36H33O3P: 544.2167, found 544.2164.
1H NMR (600 MHz, CDCl3): d 7.97 (s, 2H), 7.67 (s, 1H), 7.64 (s, 1H),
7.57 (s, 1H), 7.51 (t, J = 7.6 Hz, 2H), 7.43 (dd, J = 8.2, 1.4 Hz, 2H),
7.39 (t, J = 7.6 Hz, 1H), 6.95 (d, J = 2.1 Hz, 1H), 6.81 (d, J = 7.9 Hz,
1H), 6.76 (dd, J = 7.9, 1.7 Hz, 1H), 6.71 (d, J = 7.9 Hz, 1H), 6.51 (dd,
J = 7.6, 1.7 Hz, 1H), 6.35 (s, 1H), 3.54–3.46 (m, 1H), 3.40–3.33 (m,
1H), 3.33–3.24 (m, 1H), 3.14–3.07 (m, 1H), 3.00–2.86 (m, 3H),
2.63–2.55 (m, 1H); 13C NMR (150 MHz, CDCl3): d 179.4, 143.5,
141.9, 140.1, 139.7, 139.1, 136.9, 136.4, 136.0, 135.5, 133.5,
133.1, 132.6, 131.9 (q, JC-F = 33.2 Hz), 129.3, 129.0, 128.1, 127.4,
127.4, 124.4, 122.9 (q, JC-F = 274.6 Hz), 119.3, 34.0, 33.8, 33.4,
32.8; MS (EI): m/z (%) = 570 (1.5, M+); HRMS calcd for C31H24F6N2S:
570.1564, found 570.1560.
4.6.2. (Sp)-N-[3,5-Bis(trifluoromethyl)phenyl]-N0-{12-(3,5-
dihydroxyphenyl)[2.2]paracyclophan-4-yl}thiourea (Sp)-7c
Compound (Sp)-7c was obtained as a colorless solid (71% yield):
4.9. (Sp)-{12-(3,5-Dihydroxyphenyl)[2.2]paracyclophan-4-
yl}diphenylphosphine (Sp)-10
mp 103–104 °C; ½a D25
¼ ꢁ211:5 (c 0.30, CHCl3); IR 3595, 3394,
ꢀ
3342 cmꢁ1 1H NMR (600 MHz, CDCl3): d 7.91 (s, 2H), 7.74 (br s,
;
1H), 7.69 (s, 1H), 7.66 (s, 1H), 6.74 (d, J = 7.9 Hz, 1H), 6.72 (s, 1H),
6.67 (d, J = 6.9 Hz, 1H), 6.65–6.59 (m, 2H), 6.56 (d, J = 2.1 Hz, 2H),
6.44 (dd, J = 7.9, 2.1 Hz, 1H), 6.35 (s, 1H), 3.49–3.39 (m, 1H),
3.36–3.24 (m, 1H), 3.24–3.13 (m, 1H), 3.12–3.02 (m, 1H), 3.01–
2.84 (m, 2H), 2.83–2.74 (m, 1H), 2.64–2.54 (m, 1H); 13C NMR
(150 MHz, CDCl3): d 179.4, 157.5, 143.6, 142.5, 141.7, 139.2,
To a solution of (Sp)-9 (47.9 mg, 8.80 ꢂ 10ꢁ2 mmol) in CH2Cl2
(0.9 mL) was added BBr3 (83
l
L, 0.88 mmol) at ꢁ78 °C. After being
stirred for 2 h at room temperature, the reaction mixture was
quenched by the addition of dry MeOH and concentrated to dry-
ness. The residue was chromatographed with hexane–AcOEt
(1:1) to give the demethylation product (46.3 mg, quant.) as a
brownish solid. To the demethylation product (46.3 mg) in xylene
(0.9 mL) were added HSiCl3 (0.50 mL, 3.0 mmol) and diisopropyl-
ethylamine (0.90 mL, 5.2 mmol) at 0 °C. After being stirred for 2
d at 140 °C, the reaction mixture was cooled and quenched by
the addition of saturated aqueous NaHCO3, filtered on Celite and
extracted with AcOEt. The extract was washed with brine, dried
and concentrated to dryness. The residue was chromatographed
with hexane–AcOEt (3:1) to give (Sp)-10 (35.9 mg, 81%) as a color-
138.8, 137.1, 136.0, 135.9, 134.2, 133.2, 133.0, 132.9, 132.1 (q, JC-F
=
33.2 Hz), 127.5, 127.3, 124.9, 122.8 (q, JC-F = 274.6 Hz), 119.9
(q, JC-F = 4.3 Hz), 109.0, 101.7, 34.0, 33.5, 33.3, 31.7; MS (EI): m/z
(%) = 602 (6.3, M+); HRMS calcd for C31H24F6N2O2S: 602.1463,
found 602.1461.
4.7. (Sp)-12-(3,5-Dimethoxyphenyl)[2.2]paracyclophan-4-yl
trifluoromethanesulfonate (Sp)-8
less solid: ¼ ꢁ113:8 (c 0.81, CHCl3); IR 3447, 3344,
½
a 2D0
ꢀ
To
a
mixture of (Sp)-4 (101 mg, 0.232 mmol), 3,5-dim-
3277 cmꢁ1 1H NMR (400 MHz, CDCl3): d 7.74–7.69 (m, 2H),
;
ethoxyphenylboronic acid (54.8 mg, 0.301 mmol), PdCl2(dppf)
(9.5 mg, 0.012 mmol) and K3PO4 (148 mg, 0.696 mmol) was added
toluene (2.3 mL) at room temperature under an argon atmosphere.
After being stirred for 5.5 h at 80 °C, the reaction mixture was
cooled and concentrated to dryness. The residue was chromato-
graphed with hexane–CH2Cl2 (2:1) to afford (Sp)-8 (91.5 mg, 80%)
7.47–7.33 (m, 5H), 7.22–7.19 (m, 3H), 6.95 (s, 1H), 6.67 (d,
J = 7.3 Hz, 1H), 6.62–6.60 (m, 3H), 6.39 (d, J = 8.2 Hz, 1H), 6.24 (t,
J = 2.3 Hz, 1H), 6.19 (d, J = 2.3 Hz, 2H), 4.55 (br s 2H), 3.49–3.27
(m, 3H), 3.13 (t, J = 10.0 Hz, 1H), 2.91 (dd, J = 13.3, 9.6 Hz, 1H),
2.78–2.66 (m, 2H), 2.29–2.21 (m, 1H); 13C NMR (100 MHz, CDCl3):
d 156.6, 143.6 (d, JC-P = 23.0 Hz), 143.5, 140.1, 139.9, 139.7 (d, JC-P

990
S. Kitagaki et al. / Tetrahedron: Asymmetry 22 (2011) 986–991
= 11.5 Hz), 139.4, 137.9 (d, JC-P = 11.5 Hz), 137.0, 136.3 (d, JC-P
= 23.0 Hz), 135.7, 135.5 (d, JC-P = 10.5 Hz), 134.7 (d, JC-P = 4.8 Hz),
133.1, 132.7 (d, JC-P = 1.9 Hz), 132.4 (d, JC-P = 20.1 Hz), 131.9,
130.2, 129.9 (d, JC-P = 2.9 Hz), 128.9 (d, JC-P = 8.6 Hz), 128.4 (d, JC-P
= 11.5 Hz), 128.3, 108.5, 101.0, 36.0 (d, JC-P = 9.6 Hz), 35.2, 33.8,
33.2 (d, JC-P = 2.9 Hz); 31P NMR (161 MHz, CDCl3): d ꢁ1.67; MS
(EI): m/z (%) = 500 (100.0, M+); HRMS calcd for C34H29O2P:
500.1905, found 500.1903.
at 100 °C, the reaction mixture was cooled and concentrated to
dryness. The residue was chromatographed with hexane–AcOEt
(10:1) to afford ( )-9 (57.7 mg, 67%) as a colorless solid.
4.12. ( )-4,12-Bis(diphenylphosphinyl)[2.2]paracyclophane ( )-
123a
According to the procedure for the synthesis of (Sp)-9, ( )-4
(387 mg, 0.888 mmol) was phosphinylated using Ph2P(O)H
(360 mg, 1.78 mmol), Pd(OAc)2 (20 mg, 8.9 ꢂ 10ꢁ2 mmol), dppf
(89 mg, 0.16 mmol) and diisopropylethylamine (0.46 mL,
2.7 mmol) to afford ( )-12 (336.3 mg, 65%) as a brownish solid:
1H NMR (400 MHz, CDCl3): d 7.70–7.65 (m, 4H), 7.57–7.49 (m,
10H), 7.40–7.36 (m, 2H), 7.31–7.26 (m, 4H), 7.13 (dd, J = 14.7,
1.4 Hz, 2H), 6.77 (d, J = 7.8 Hz, 2H), 6.64 (dd, J = 7.3, 4.1 Hz, 2H),
3.39–3.32 (m, 2H), 3.22 (br t, J = 11.7 Hz, 2H), 3.02 (br t,
J = 11.7 Hz, 2H), 2.73 (ddd, J = 12.8, 10.1, 6.4 Hz, 2H); 13C NMR
4.10. Phosphinylation of ( )-4
According to the procedure for the synthesis of (Sp)-9, ( )-4
(100 mg, 0.230 mmol) was phosphinylated using Ph2P(O)H
(55.8 mg, 0.276 mmol), Pd(OAc)2 (5.2 mg, 0.023 mmol), dppf
(23.0 mg, 0.0414 mmol) and diisopropylethylamine (0.12 mL,
0.69 mmol) to afford a mixture of ( )-11a and ( )-11b (80.3 mg,
69%, 11a:11b = 2.5:1) as a colorless solid. Analytically pure ( )-
11a and ( )-11b were obtained by careful column chromatography
with CH2Cl2.
(100 MHz, CDCl3):
d 145.6 (d, JC-P = 8.6 Hz), 139.9 (d, JC-P =
13.4 Hz), 138.3 (d, JC-P = 12.4 Hz), 136.8 (d, JC-P = 102.6 Hz), 136.5
(d, JC-P = 2.9 Hz), 134.8 (d, JC-P = 11.5 Hz), 132.3 (d, JC-P = 8.6 Hz),
131.7 (d, JC-P = 103.5 Hz), 131.6 (d, JC-P = 2.9 Hz), 130.9, 130.8 (d,
JC-P = 8.6 Hz), 129.9 (d, JC-P = 105.4 Hz), 128.0 (d, JC-P = 11.5 Hz),
127.9 (d, JC-P = 11.5 Hz), 36.2 (d, JC-P = 4.8 Hz), 34.7.
4.10.1. {12-Bromo[2.2]paracyclophan-4-yl}diphenylphosphine
oxide 11a4c
IR 1180 cmꢁ1 1H NMR (400 MHz, CDCl3): d 7.79–7.74 (m, 2H),
;
7.58–7.52 (m, 3H), 7.48–7.43 (m, 3H), 7.39–7.35 (m, 2H), 7.28 (d,
J = 1.8 Hz, 1H), 6.82 (dd, J = 14.6, 1.8 Hz, 1H), 6.66 (dd, J = 7.8,
4.1 Hz, 1H), 6.62 (s, 1H), 6.59 (dd, J = 7.8, 1.8 Hz, 1H), 6.49 (d,
J = 7.8 Hz, 1H), 3.50–3.36 (m, 3H), 3.06–2.91 (m, 3H), 2.86–2.80
(m, 1H), 2.73 (ddd, J = 13.3, 10.5, 6.9 Hz, 1H); 13C NMR (100 MHz,
CDCl3): d 145.5 (d, JC-P = 7.7 Hz), 142.0, 138.9 (d, JC-P = 13.4 Hz),
138.5, 138.4, 137.2 (d, JC-P = 2.9 Hz), 135.5 (d, JC-P = 11.5 Hz),
135.2 (d, JC-P = 103.5 Hz), 133.8, 133.2 (d, JC-P = 13.4 Hz), 132.7 (d,
JC-P = 9.6 Hz), 131.6 (d, JC-P = 102.6 Hz), 131.5 (d, JC-P = 2.9 Hz),
131.4 (d, JC-P = 9.6 Hz), 131.4 (d, J = 2.9 Hz), 130.9, 129.9 (d, JC-P
= 105.4 Hz), 128.2 (d, JC-P = 11.5 Hz), 128.0 (d, JC-P = 11.5 Hz),
127.1, 35.7 (d, JC-P = 2.9 Hz), 35.7, 34.5, 32.2; MS (EI): m/z
(%) = 486 (100.0, M+), 488 (100.0, M+); HRMS calcd for C28H24OBrP:
486.0748, found 486.0747; calcd for C28H24O81BrP: 488.0728,
found 488.0724.
Acknowledgments
This work was supported in part by a Grant-in Aid for Scientific
Research from the Ministry of Education, Culture, Sports, Science,
and Technology, Japan, for which we are thankful.
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IR 1420, 1178, 1140 cmꢁ1 1H NMR (400 MHz, CDCl3): d 7.70–
;
7.65 (m, 2H), 7.60–7.55 (m, 3H), 7.51–7.46 (m, 3H), 7.42–7.37
(m, 2H), 7.16 (d, J = 0.9 Hz, 1H), 6.69–6.59 (m, 4H), 6.53 (d,
J = 14.7 Hz, 1H), 3.53–3.43 (m, 2H), 3.37 (ddd, J = 11.4, 9.6, 1.4 Hz,
1H), 3.10 (br t, J = 11.4 Hz, 1H), 3.01–2.93 (m, 1H), 2.90–2.83 (m,
2H), 2.78–2.70 (m, 1H); 13C NMR (100 MHz, CDCl3): d 148.1,
145.3 (d, JC-P = 7.7 Hz), 143.9, 139.1 (d, JC-P = 12.5 Hz), 137.1
(d, JC-P = 2.9 Hz), 135.6 (d, JC-P = 11.5 Hz), 134.9, 134.6 (d, JC-P
= 104.5 Hz), 134.0 (d, JC-P = 13.4 Hz), 133.3 (d, JC-P = 101.6 Hz),
132.1 (d, JC-P = 9.6 Hz), 131.8 (d, JC-P = 1.9 Hz), 131.7, 131.6 (d,
J = 2.9 Hz), 131.4 (d, J = 9.6 Hz), 131.0, 129.7 (d, JC-P = 99.7 Hz),
129.0, 128.4 (d, JC-P = 8.6 Hz), 128.3 (d, JC-P = 8.6 Hz), 118.7 (q, JC-F
= 321.1 Hz), 35.2 (d, JC-P = 4.8 Hz), 34.2, 32.9, 31.8; MS (EI): m/z
(%) = 556 (100.0, M+); HRMS calcd for C29H24F3O4PS: 556.1085,
found 556.1083.
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( )-11b
To
a mixture of ( )-11a and ( )-11b (2.5:1, 80.3 mg,
0.158 mmol) and 3,5-dimethoxyphenylboronic acid (54.6 mg,
0.300 mmol) in toluene (1.7 mL) were added PdCl2(dppf) (6.8 mg,
8.3 ꢂ 10ꢁ3 mmol) and K3PO4 (106 mg, 0.498 mmol) at room tem-
perature under an argon atmosphere. After being stirred for 23 h

S. Kitagaki et al. / Tetrahedron: Asymmetry 22 (2011) 986–991
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24. This reaction did not proceed when diphenylphosphinopropane (dppp), the
most popular ligand for this type of reaction, was used. The use of 2 equiv of
diphenylphosphine oxide under the influence of Pd(OAc)2 and dppf gave the
diphosphinylated product 12 in 65% yield together with a mixture of the
monophosphinyl triflate 11b and the hydrogenated phosphine oxide 13 (34%,
1.3:1). Since the diphosphinylated product 12 is known as
a synthetic
intermediate of [2.2]PHANEPHOS,3a this could be an alternative synthetic
method for PHANEPHOS.
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Ph2(O)P
16. There are only
a
few examples of organocatalysts based on
a
[2.2]paracyclophane backbone: (a) Braddock, D. C.; MacGilp, I. D.; Perry, B. G.
Adv. Synth. Catal. 2004, 346, 1117–1130; (b) Zhang, T.-Z.; Dai, L.-X.; Hou, X.-L.
Tetrahedron: Asymmetry 2007, 18, 1990–1994; (c) Negru, M.; Schollmeyer, D.;
Kunz, H. Angew. Chem., Int. Ed. 2007, 46, 9339–9341; (d) Ref. 13c.; The use of
Ph2P(O)H (2 eq)
Pd(OAc)2 (10 mol%)
dppf (18 mol%)
Ph2(O)P
( )-12 (65%)
Br
chiral cyclophanyl phosphine as
a reagent for the kinetic resolution of
hydroperoxides has been reported by: (e) Driver, T. G.; Harris, J. R.; Woerpel,
K. A. J. Am. Chem. Soc. 2007, 129, 3836–3837.
i-Pr2NEt, DMSO
100 °C, 4.5 h
+
17. For syntheses of pseudo–ortho-substituted aryl[2.2]paracyclophanes with the
axial chirality of the biaryl fragment, see: (a) Rosenberg, V.; Zhuravsky, R.;
Sergeeva, E. Chirality 2006, 18, 95–102; (b) Ref. 13a.
18. (a) Schneider, J. F.; Falk, F. C.; Fröhlich, R.; Paradies, J. Eur. J. Org. Chem. 2010,
2265–2269; (b) Schneider, J. F.; Fröhlich, R.; Paradies, J. Synthesis 2010, 3486–
3492.
TfO
( )-4
TfO
Ph2(O)P
( )-11b
Ph2(O)P
19. Zhuravsky, R.; Starikova, Z.; Vorontsov, E.; Rozenberg, V. Tetrahedron:
Asymmetry 2008, 19, 216–222.
20. Hartwig, J. F.; Kawatsura, M.; Hauck, S. I.; Shaughnessy, K. H.; Alcazar-Roman,
L. M. J. Org. Chem. 1999, 64, 5575–5580.
( )-13
(34%, 1.3:1)
21. Before examination of the bromocyclophanyl triflate 4, we explored the
palladium-catalyzed amination reaction using the MOM-protected pseudo–
ortho-bromo[2.2]cyclophanol ( )-40 as a substrate. As a result, the method
using N-tert-butyl carbamate was shown to be more effective than those using
benzylamine3b or benzophenone imine13b as an ammonia equivalent, and it
was applied to the reaction of (Sp)-4.
25. (a) Matsumura, K.; Shimizu, H.; Saito, T.; Kumobayashi, H. Adv. Synth. Catal.
2003, 345, 180–184; (b) Tappe, F. M. J.; Trepohl, V. T.; Oestreich, M. Synthesis
2010, 3037–3062.
Br
MOMO
4'