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フルオロアルコール溶媒を用いるらせん状多環式芳香族炭化水素の
高効率合成法
氏 名 庄司訓章
指導教員 市川淳士
1
代表的なヘリセン類
2
カルボヘリセン
多重ヘリセン
ヘテロヘリセン
ヘリセン類S
◆ 円偏光発光素子◆ 非線形光学材料◆ 不斉配位子
ヘリセン合成の従来法
3
OTIPS
TIPSOh!
Toluene (0.0002 M)90 ºC, 48 h
I2 (6 eq)
O
Me(100 eq)
7%
Murase, T.; Fujita, M. et al. Angew. Chem., Int. Ed. 2015, 54, 6847.
OTIPSTIPSO
Ru
NMesMesN
PCy3PhCl
Cl
CH2Cl2, 100 °C, 60 min
(15 mol%)
80%
Collins, S. et al. Angew. Chem., Int. Ed. 2006, 45, 2923.
HFIP溶媒による触媒的芳香環増環法
4
HCF3O
CF3
HHigh ionizing power
Cation-stabilizing effect
!– !+ CF3O
CF3
Steric effect and Inductive effect
Low nucleophilicity
1,1,1,3,3,3-Hexafluoropropan-2-ol (HFIP)
cat. TfOH
HFIP
Ichikawa, J. et al. Eur. J. Org. Chem. 2017, 262.
O+
TfO– –
– TfOH
TfOH
O
O
HO
O
HO
HO OH
オキソカルベニウムイオン
タンデム型芳香環増環法
5
OO 99%
TfOH (10 mol%)
HFIP (0.3 M), 0 oC, 15 min
Ichikawa, J. et al. Chem. Lett. 2017, 46, 392.
97%
TfOH (10 mol%)
HFIP (0.3 M), 0 oC, 15 min
OO
O
O
O
O
6
カルボヘリセンの合成戦略
O
O O
O
O
O O
O
X X
XX
Y
O
O
Y
O
O
+
+
カルボヘリセンの合成
7
O
O O
O
O
O O
O
I I
BrBr
BOO
pin
TfOH (15 mol%)
HFIP0 °C, 40 min
92%
90%
HFIP0 ºC to RT, 40 min
TfOH (20 mol%)
cat. Pd92%
45%
1
Method A1 (2.2 eq), Pd2(dba)3･CHCl3 (2.5 mol%)SPhos (5.0 mol%), K3PO4 (6.0 eq)Dioxane–H2O (2/1), 120 ºC, 11.5 h
Method B1 (2.2 eq), Pd2(dba)3･CHCl3 (2.5 mol%)SPhos (5.0 mol%), K3PO4 (6.0 eq)DMF–H2O (2/1), 90 ºC, 9.5 h
Method A
Method B
PCy2MeO
MeO
SPhos
蛍光特性を示すヘテロヘリセン
8
N
NN
N
Otani, T.; Shibata, T. et al. Angew. Chem., Int. Ed. 2017, 56, 3906.
λemmax = 492 nm, φ = 0.80
(CH2Cl2–TFA, 6.7 × 10–5 M)
O
OO
Bedekar, A. V. et al. Org. Lett. 2015, 17, 5808.
λemmax = 432 nm, Φ = 0.19
(CH3CN, 9.1 × 10–5 M)
ヘテロヘリセン合成の従来法
9
aq. HCl (excess)
OH I
DMSO (0.05 M), 110 ºC, 12 h
KOH (1.7 eq)
DMF, 160 ºC, 4 h
NaSMe (20 mol%)SMe
MeS
O
S
98%
91%
NH2
H2N
HN
85%
Dioxane, reflux, 8 h
Yorimitsu, H. et al. Angew. Chem., Int. Ed. 2018, 57, 4663.
Chatani, N.; Tobisu, M. et al. Synlett 2019, 30, 1995.
Cho, C.-G. et al. Tetrahedron 2011, 52, 6015.
ヘテロヘリセンの合成戦略
10
S
O
OO
O
S S
O
OO
O
Y
X
+
Z Z
O
OZ
X+
(Z = O, S, NTs)
(Z = O, NTs)ZO
O O
OZ
Z
X X+
Y
O
O
Y
O
O
ヘテロ[4]ヘリセンの合成
11
Z
Br
Z
O
O
NTs = 93%
Pd2(dba)3･CHCl3 (1.2–2.5 mol%)PPh3 (5.0–10 mol%)
K3PO4 (6.0 eq)Dioxane–H2O (2/1)
120 °C, 10–17 h(1.1 eq) O = 92%
S = 81%
BOO
pin+
(Z = O, S, NTs)
NTsO S
93%96% 88%
Z
O
O
TfOH (10 mol%)
HFIP, 0 °C, 40 min
Z
ヘテロ[5]ヘリセンの合成
12
BOO
pinZ
Br Br
Pd2(dba)3･CHCl3 (2.5–2.6 mol%)SPhos (5–10 mol%)K3PO4 (6.0–6.1 eq)
Dioxane–H2O (2/1)120 °C, 5–15 h ZO
O O
O
(2.2 eq)NTs = 78%
O = 53%
+
(Z = O, NTs)
ZO
O O
O
TfOH (15–20 mol%)
HFIP, 0 ºC to RT, 40 min
O NTs
90% 88%
チア[6]ヘリセンの合成
13
S
O
OO
O
S
O
OO
O
BpinO
O
Pd2(dba)3･CHCl3 (2.6 mol%)SPhos (10 mol%)
K3PO4 (6.0 eq)
Dioxane–H2O (2/1)reflux, 9 h
(1.1 eq)
92%
S
63%
HFIP, 0 ºC to RT, 40 min
TfOH (20 mol%)
S
Br O
O
ダブルヘリセンの光学特性
14
DNH
DPC
HH
–2.5
–2.1
–0.9
–2.5
–2.1
–1.5
In dichloromethane at 25 °C. glum: luminescencedissymmetry factor; g/n: dissymmetry factor per one benzene unit.
DNH DPC HH
Helicene glum/10–3 (glum/n)/10–4
Mori, T. et al. Commun. Chem. 2018, 38.
多重ヘリセン合成の従来法
15
OTf
TMS
CsF (6.0 eq)Pd2(dba)3 CHCl3 (10 mol%)
MeCN, RT, 24 h54%
Tsurusaki, A.; Kamikawa, K. et al. J. Am. Chem. Soc. 2017, 139, 18512.See also: Segawa, Y.; Itami, K. et al. Chem. Sci. 2019, 10, 2326.
Wang, J. et al. Angew. Chem., Int. Ed. 2019, 58, 587.
t-Bu
t-Bu
t-Bu
t-Bu
DDQ (4.8 eq)TfOH (20 eq)
CH2Cl2, 0 ºC, 2 h75%
Müllen, K.; Narita, A. et al. Angew. Chem., Int. Ed. 2017, 56, 3374.
16
ダブルヘリセンの合成戦略
O
O O
O
XX
Y
O
O+
O O
YOO
+
OO
O O
X X
O
O O
O
X
X
Y
O O
OO
+
ダブル[4]ヘリセンの合成
17
90%
O
O O
O
OOOO
86%
HFIP0 °C, 40 min
HFIP0 ºC, 40 min
B(OH)2
Br
Br
Br Br
O
O O
O
OOOO
TfOH (15 mol%)
TfOH (15 mol%)
cat. Pd
Method A2 (2.2 eq), Pd2(dba)3･CHCl3 (2.9 mol%), SPhos (12 mol%), K3PO4 (5.5 eq)Dioxane–H2O (2/1), 120 ºC, 5 h
Method B2 (5.0 eq), Pd2(dba)3･CHCl3 (2.4 mol%), PPh3 (9.2 mol%), Na2CO3 (5.5 eq)Dioxane–H2O (2/1), 120 ºC, 8 h
86%
2
70%
Method A
Method B
18
ダブル[4]ヘリセンの合成
90%
O
O O
O
OOOO
86%
HFIP0 °C, 40 min
HFIP0 ºC, 40 min
B(OH)2
Br
Br
Br Br
O
O O
O
OOOO
TfOH (15 mol%)
TfOH (15 mol%)
cat. Pd
Method A2 (2.2 eq), Pd2(dba)3･CHCl3 (2.9 mol%), SPhos (12 mol%), K3PO4 (5.5 eq)Dioxane–H2O (2/1), 120 ºC, 5 h
Method B2 (5.0 eq), Pd2(dba)3･CHCl3 (2.4 mol%), PPh3 (9.2 mol%), Na2CO3 (5.5 eq)Dioxane–H2O (2/1), 120 ºC, 8 h
86%
2
70%
Method A
Method B
ダブル[5]ヘリセンの合成
19
Br
Br
O
O O
O
O
O
O
O
O
OO
O
Bpin
OO
+
Suzuki–MiyauraCoupling
cat. TfOH HFIP
Bpin
ダブル[5]ヘリセン環化前駆体の調製
20
BOO
(1.1 eq)
Br
Br
OO
65%O
O
O
O
O
OO
OBr
BrBpin
OO
+
(2.2 eq)
Pd2(dba)3･CHCl3 (2.5 mol%)SPhos (10 mol%)K3PO4 (6.1 eq)
DMF–H2O (2/1)90 °C, 18.5 h
OOI
88%
Pd2(dba)3･CHCl3 (1.6 mol%)PPh3 (6.4 mol%)K3PO4 (4.0 eq)
Dioxane–H2O (2/1)120 °C, 2 h
(Bpin)2 (1.1eq)AcOK (4.1 eq)
PdCl2dppf･dcm (1.0 mol%)
Dioxane, reflux, 14 h
Bpin
51%
O
O O
O
PCy2MeO
MeO
SPhos
pin
ダブルヘリセンの作り分け
21
FeCl3 (10 eq)
CH2Cl2–CH3NO2
(20/3, 0.01 M)0 ºC to RT, 21 h
[4,4] 18%TfOH (50 mol%)
HFIP–CH2Cl2(10/1, 0.18 M)60 ºC, 40 min
O
O
O
O
O
OO
O
[5,5] 14%
[5,4] 26%
TfOH (50 mol%)
HFIP–CH2Cl2 (10/1, 0.18 M)0 ºC, 40 min
TfOH (400 mol%)
HFIP–CH2Cl2 (10/1, 0.018 M)0 ºC, 40 min
分子内酸化的C–Hカップリング（Scholl反応）
22
t-Bu
t-Bu
t-Bu
t-Bu
TfOH (110 eq)DDQ (2.1 eq)
CH2Cl2, 0 ºC, 5 h
91%
Riu, R.-S. et al. Org. Lett. 2011,13, 4644.
23
ダブルヘリセンの作り分け
FeCl3 (10 eq)
CH2Cl2–CH3NO2
(20/3, 0.01 M)0 ºC to RT, 21 h
[4,4] 18%TfOH (50 mol%)
HFIP–CH2Cl2(10/1, 0.18 M)60 ºC, 40 min
O
O
O
O
O
OO
O
[5,5] 14%
[5,4] 26%
TfOH (50 mol%)
HFIP–CH2Cl2 (10/1, 0.18 M)0 ºC, 40 min
TfOH (400 mol%)
HFIP–CH2Cl2 (10/1, 0.018 M)0 ºC, 40 min
24
[5]ヘリセン骨格を2つ有するダブルヘリセンの合成
BrBr
O O O O
OO OO
O O O O
Bpin
OO
(2.2 eq)
Pd2(dba)3･CHCl3 (2.5 mol%)SPhos (10 mol%)K3PO4 (6.0 eq)
DMF–H2O (2/1)90 °C, 19 h
52%
HFIP0 ºC to RT, 40 min
TfOH (210 mol%)
OO OO
O O O O
N.D.
＋
22%
＋
25
[7]ヘリセン骨格を有するらせん状分子の合成
BrBr
O O O O
OO OO
O O O O
Bpin
OO
(2.2 eq)
Pd2(dba)3･CHCl3 (2.5 mol%)SPhos (10 mol%)K3PO4 (6.0 eq)
DMF–H2O (2/1)90 °C, 19 h
52%
HFIP0 ºC to RT, 40 min
TfOH (210 mol%)
OO OO
O O O O
N.D.
＋
22%
＋
総括
26
S
X(X = O, NTs)
BOO
Bpin
OO
HFIPcat. TfOHBr
Br
Br Br
OO OO
I I
OO
O O
X
Br Br
SBr
OO
(X = O, NTs)
CycloaromatizationSuzuki–MiyauraCoupling
cat. TfOH
HFIPO
O
pin
27
28
HFIPのイオン化力
29
ROH
Solvolysisk
ROH
Nucleophilicty (NOTs)
EtOH
0.00
(CH3)2CHOH
0.12
(CF3)2CHOH
-4.27
H2O
-0.44
CF3CH2OH
-3.0
80% EtOH / H2O
0.0
Tsuno, Y. et al. Bull. Chem. Soc. Jpn. 1994, 67, 2233.Bentley, T. W. et al. Prog. Phys. Org. Chem. 1990, 17, 121.
OTs OR
HFIPの求核力
30
ブレンステッド酸による反応性の違い
ブレンステッド酸による反応性の違い
SO O
F3COH
F3C O
OH
pKa = –14 pKa = –0.25
������ ��� �
(TfOH)
�������(TFA)
Entry
1
2
3
4
OAcid (X mol%)
HFIP, Conditions
Acid
CF3COOH
CF3COOH
CF3SO3H
CF3SO3H
X / mol%
100
10
10
4
Conditions
RT, 16 h
RT, 16 h
0 °C, 20 min
0 °C, 20 min
Yield
92
(41)
98
93Isolated yield. 1H NMR is shown in parentheses
溶媒検討
O OH
H+
OH
�������H+, H2O
H
推定反応機構 (エノール型中間体への異性化)
OH
H+
Ph
OH
OHOPolymer
H+
O OH
H+
OH
�������H+, H2O
H
推定反応機構 (カチオン中間体の安定化)
OH
H+
Ph
OH
OHOPolymer
H+in HFIP
推定反応機構
OH OH OH OH2H+
HH
H+
H+
H+, H2O
�������
OTfOH (4 mol%)
HFIP, 0 °C to RT, 20 min
36
OO
OO
H OO
H
O
HO
O
HO
HHH+
H+
HOOH
反応機構
37
OO
H
O
OH
Ph
O
OH
Ph
O
OH
polymerization
副生成物の反応機構
38
◆臭素化
◆ Friedel-Crafts型環化
Balci, M. Tetrahedron 1999, 55, 12853.
Br2 (1.0 eq)
120 oC
Br
90%
Br
0%
αβ
MeO α -0.234
β -0.235
OMe
OMe
3.5 kcal/mol
6.7 kcal/molminor
major
ブレンステッド酸による反応性の違い
39
O
O
1st Cyclization 2ed Cyclizationa
b
O
O
OO
O
O
1st CyclizationO
O
a
b2ed Cyclization
O
O
ブレンステッド酸による反応性の違い
40
271
1'
TfOH (X mol%)
HFIP (Y M), 0 oC, 15 min
Entry
1
2
3
4
5
X (mol %)
15
15
15
10
3
Y (M)
0.1
0.3
1.0
0.3
0.3
Total yield (%)a
quant.
quant.
86
quant. (97)
77
1/1'b
>99/1
>99/1
93/7
>99/1
>99/1
a) 1H NMR yield. Isolated yield is shown in parentheses.b) Isomer ratio was determined by 1H NMR spectroscopy.
OO
O
O
ビスアセタールの酸の当量および濃度検討
41
-0.279
-0.178O
OH
OHO
OHO
minor
major
1.3 kcal/mol
8.9 kcal/mol
環化における位置選択性の説明①
42
OH
O
O
OO
O
OOH
O
O
O
–0.248
–0.389
OH
環化における位置選択性の説明②
トリフルオロメタンスルホン酸の水和
SPhosの安定構造
45
Br
O (Ph3PCH2OMe) Cl (2.0 eq)t-BuONa (3.0 eq)
THF, 0 oC, 10 minBr
OMe
HCl (10 eq)
Acetone-H2O (2:1)0 oC to RT, 12 h
Br
O
TsOH H2O (10 mol%)ethylene glycol (3.0 eq)
Toluene, reflux, 11 hdean-stark
BrO
O
B(pin)O
OPdCl2(dppf) CH2Cl2 (5 mol%)B2(pin)2 (1.1 eq)AcOK (6.0 eq)
Dioxane, reflux, 8 h
88%(E/Z = 50:50)
78% (2 steps) 86%
アセタール部位を有するボロン酸エステルの調製
46
I I O
O O
O
cat. [Pd] (X mol%)Ligand (Y mol%)
K3PO4 (6 eq)
Dioxane–H2O (2/1)120 °C, 2–14 h
(2.2 eq)
Entry Ligand[Pd] Yield / % n
dppe: n = 2dppp: n = 3
O
Me Me
PPh2PPh2
XantPhos
Determined by 1H NMR using CH2Br2 as an internal standard.
PdCl Cl
N
NN
Cl
i-Pr
i-Pr i-Pr
i-Pr
PEPPSI-IPr
+
1
2
3
4
5
6
7
8
Pd(PPh3)4
PdCl2(PCy3)2
Pd2(dba)3･CHCl3
Pd2(dba)3･CHCl3
Pd2(dba)3･CHCl3
Pd2(dba)3･CHCl3
Pd2(dba)3･CHCl3
PEPPSI-IPr
PPh3
P(o-tol)3
XantPhos
dppe
dppp
31
25
32
26
9
10
9
21
PPh2Ph2P
5
5
3
3
3
3
3
5
10
10
10
10
10
—
X / mol% Y / mol%
—
——
— —
BOO
pin
条件検討
47
条件検討
P R2
R4
R1R1 Cy-JohnPhos: R1 = Cy, R2, R3, R4 = Ht-Bu-JohnPhos: R1 = t-Bu, R2, R3, R4 = HDavePhos: R1 = Cy, R2, R3 = H, R4 = NMe2Ph-DavePhos: R1 = Ph, R2, R3 = H, R4 = NMe2SPhos: R1 = Cy, R2, R4 = OMe, R3 = H
R3
I I O
O O
O
cat. [Pd] (X mol%)Ligand (Y mol%)
K3PO4 (6 eq)
Dioxane–H2O (2/1)120 °C, 2–14 h
(2.2 eq)
Entry Ligand[Pd] Yield / %
Determined by 1H NMR using CH2Br2 as an internal standard.
+
1
2
3
4
5
Pd2(dba)3･CHCl3
Pd2(dba)3･CHCl3
Pd2(dba)3･CHCl3
Pd2(dba)3･CHCl3
Pd2(dba)3･CHCl3
Cy-JohnPhos
t-Bu-JohnPhos
DavePhos
Ph-DavePhos
SPhos
35
36
39
28
49
3
3
3
3
3
11
11
11
10
11
X / mol% Y / mol%
BOO
pin
48
Entry
1
2
3
4
5
6
7b
Yield / %
49
28
28
34
50
50
(45)
Solvent
Dioxane
Toluene
THF
DMA
DMF
DMF
DMF
T / °C
120
120
120
160
160
90
90
Determined by 1H NMR using CH2Br2 as an internal standard.Isolated yield is shown in parentheses. a) 0.1 mmol scale. b) 2.0 mmol scale.
I I O
O O
O
Pd2(dba)3･CHCl3 (3 mol%)SPhos (X mol%)
K3PO4 (6 eq)
Solvent–H2O (2/1)T °C, 2–20 h
(2.2 eq)
+
X / mol%
10
10
10
10
10
10
5
BOO
pin
条件検討
49
環化前駆体の構造①
O
O O
O O
O
O
O
anti/syn = 2/1
Br Br BrBr
Prim, D. et al. Org. Lett. 2011, 13, 4450.
multiplet
回転しにくく完全にddが2つ見える
50
環化前駆体の構造②
O
OO
O O
OO
O
anti/syn = 3/1
Kharafi, A.; Panihi, F. J. Organomet. Chem. 2012, 717, 141.
51
S OMe
Br
S O
Br
S
Br
S
S
Br
Br
Br2 (2.3 eq)NaOAc (2.8 eq)
CH2Cl20 ºC, 2 h
95%
n-BuLi (1.1 eq)DMF (5.0 eq)
Et2O–78 ºC to RT, 0.5 h
ClPPh3CH2OMe (1.5 eq)t-BuONa (2.0 eq)
THF–CH2Cl2 (8/3)0 ºC, 2 h
90%
TsOH･H2O (1.0 eq)
Toluelereflux, 3 h
80%(2 steps)
OOHO
OH (2.0 eq)
アセタールと臭素置換基を併せ持つベンゾチオフェンの調製
52
TfOH (50 mol%)
[5,5] [5,4]
+Solvent, Temp40–100 min
Entry
1
2
3
4b
5
[5,5] / %a
13
13
13
9
15
[5,4] / %a
24
23
21
18
23
a) Determined by 1H NMR using CH2Br2 as internal standard. b) microwave
O
O
O
O
O
OO
O
Temp / °C
60
60
80
80
60
[5,5]+[5,4] / %a
37
36
34
27
38
Solvent
HFIP
HFIP–DCE (10/1, 0.18 M)
HFIP–DCE (10/1, 0.18 M)
HFIP–DCE (10/1, 0.18 M)
HFIP–CH2Cl2 (10/1, 0.18 M)
九環式のS字型ダブルヘリセンの条件検討
53
Entry
1
2
3
4
5
X / mol%
50
420
50
100
50
[5,5] / %
15
3
trace
11
21
[5,4] / %
23
10
trace
23
11
Determined by 1H NMR using CH2Br2 as an internal standard. Isolated yield is shown in parentheses.
Temp / °C
60
0
0
60
60
[5,5]+[5,4] / %
38
13
trace
34
32
Solvent
HFIP–CH2Cl2 (10/1, 0.18 M)
HFIP–CH2Cl2 (10/1, 0.18 M)
HFIP–CH2Cl2 (10/1, 0.018 M)
HFIP–CH2Cl2 (10/1, 0.18 M)
HFIP–CH2Cl2 (1/1, 0.18 M)
TfOH (X mol%)
[5,5] [5,4]
+Solvent, Temp40–100 min
O
O
O
O
O
OO
O
九環式のS字型ダブルヘリセンの条件検討
54
SO O
CF3OH
CF3 O
OH
TsOH
pKa = –2.8
H3O+
pKa = –1.7
CF3
CF3OH
pKa = 9.3
MeOH
H
pKa = –2.2
pKa = –0.25
pKa = –14
HCl
pKa = –8.0
pKa
