伊藤肇 集中講義(名古屋大学 教員+大学院生参加の講演会)
TRANSCRIPT
有機ホウ素化合物の合成方法とその反応
北海道大学大学院工学研究院 伊藤 肇
名古屋大学工学部応用化学科 集中講義 2015年5月15日
伊藤研究室(2010~)の研究
Cu catalysis (2000−)
Ir catalysis (Ishiyama, 2002−)
Si-B/base Chemistry (2012−)
J. Am. Chem. Soc., 2012, 134, 19997.
新規ホウ素化反応の開発
Ishiyama, Miyaura, Hatrwig, et al, J. Am. Chem. Soc. 2002, 124, 390.
Ar H Ar BpinIr cat.
B2pin2
X pinBCu cat.
J. Am. Chem. Soc. 2008, 130, 10044.
Nature Communications 2013, 4, 2009.
Angew. Chem., Int. Ed 2013, 52, 12828, VIP.
発光性金(I)錯体の研究
本日の講演内容
3. BBSホウ素化反応:遷移金属フリーでかつ官能基共存性のある芳香族ホウ素化合物の合成方法
1. 有機ホウ素化学の基礎
2. 銅触媒/ジボロンによるホウ素化反応:光学活性アルキルホウ素化合物の新合成方法
ホウ素-銅触媒反応系の発見(2000年)
Segawa, Y.; Yamashita, M.; Nozaki, K. Science 2006, 314, 113.
NNBBr
iPr
iPr iPr
iPr
NNBLi
iPr
iPr iPr
iPrLi, naphthalene
THF
■ホウ素アニオンは合成が困難であった。
CuCl/KOAc: Takahashi, K.; Ishiyama, T.; Miyaura, N. Chem. Lett. 2000, 982. CuX/PR3: Ito, H.; Yamanaka, H.; Tateiwa, J.; Hosomi, A. Tetrahedron Lett. 2000, 41, 6821.
+
cat. CuX PR3
DMI, rt
H3O+
OO
BB B
O
OO
O
OO
87%
■エノンへのホウ素基の形式的求核付加
CuX
BB
Cu BL
L
ホウ素-銅触媒活性種•求核的な反応特性•選択性のコントロールが可能
銅触媒/ジボロン を用いた有機ホウ素化合物の合成法 を詳しく検討
過去に合成できなかった有機ホウ素化合物の新合成方法
early study:Tetrahedron Lett. 2000
BOO
J. Am. Chem. Soc. 2005J. Am. Chem. Soc. 2007
B
OR
OO
Angew. Chem., Int. Ed. 2010
BR OO
J. Am. Chem. Soc. 2010
(rac)-
R
BO
O
Angew. Chem., Int. Ed. 2008J. Am. Chem. Soc. 2010
C C CB
BuMe
H
OO
J. Am. Chem. Soc. 2008
BO
O
J. Am. Chem. Soc. 2010
BO
O
or
B
B
O
O
O
OJ. Am. Chem. Soc. 2013
BO
O
Org. Lett. 2012
RB
O
O
Nature Chem. 2010
Bu
BO
O
Angew. Chem., Int. Ed. 2011
B BO
OO
O
LCu X+ LCu B
O
OX B(pin)–
� ����������������������� ����
■
Latitar, D. S.; Tsui, E. Y.; Sadighi, J. P. J. Am. Chem. Soc. 2006, 128, 11036.
O
H1.0 mol % ICyCu(O-t-Bu)
(pin)B−B(pin), toluene
86%
O
B(pin)
B(pin)
Catalytic diboration
(pin)B−B(pin)MeOH, toluene
O
H
1.5 mol %ICyCu(O-t-Bu) OH
B(pin)
crude product
KHF2
MeOH/H2O
OH
BF3K
81%Molander, G. A.; Wisnieski, S. R. J. Am. Chem. Soc. 2012, 134, 16856.
■ Catalytic monoborylation
N N
ICy
カルボニル化合物のホウ素化
Molander, G. A.; Wisnieski, S. R. J. Am. Chem. Soc. 2012, 134, 16856.
For a review of Matteson homologation chemistry: Matteson, D. S. Tetrahedron 1998, 54, 10555.
Matteson homologation chemistry
■Stoichiometric amount of chiral auxiliary■
B O
OPh
Phn-BuLiCH2Cl2
ZnCl2THF
H
B Cl
BnOLi
THFDMSO
H
BnO B OO
Ph
Ph
OO
Ph
Ph
KHF2
MeCN/H2O H
BnO BF3K
>99% ee
75% (4 steps)
B(OH)2
HO OH
Ph Ph
Et2O
Multistep synthesis
不斉補助基を用いたαーアルコキシアルキルホウ素
H
BnO BF3K
H
BnO
N
N+Cl
CsOH•H2O (5.0 equiv)
CPME/H2O (0.5 M)105 °C
NH2PdP OTfBu
Pd catalyst(7.5 mol %)
86%, 99% ee (>99% es)
99% ee
(S)(R)
Molander, G. A.; Wisnieski, S. R. J. Am. Chem. Soc. 2012, 134, 16856.
High yield and excellent stereospecificity (>99% ee)■Various aryl halides can be used. ■
Cross-coupling reaction
鈴木カップリングで立体特異的な誘導が可能
R H
O
R = Alkyl, Ary
B BO
O O
O+
cat. Cu(I) / L*
R H
B(pin)HO
Can be asymmetric catalysis?
O
H
1.5 mol % ICyCuClB2pin2 (1.0 equiv)
3 mol % Na(O-t-Bu)MeOH (2.0 equiv)toluene, rt, 1 h1a
protection
H
B(pin)PO
H
B(pin)BnO
BnBr, NaH, THF
H
B(pin)PhOCO
PhCOOH, EDC, DMAP
H
B(pin)BnMe2SiO
BnMe2SiCl, imidazole
isolated yield (%)rac-3
conditions: conditions:33% 8% 72%
conditions:
K. Kubota
Kubota, K.; Yamamoto, E.; Ito, H. J. Am. Chem. Soc. 2015, 137, 1, 420.
不斉反応開発の7は単離方法の開発
Ph
O
1. CuCl / L* (5 mol %) K(O-t-Bu) (10 mol %) MeOH (2.0 equiv) THF, 30 °C, 6 h
2. BnMe2SiCl, imidazole CH2Cl2, 3 h
Ph HH
BnMe2SiO B
(S)NMR yield (%)
B BO
O O
O+
1.0 equiv
OO
O
O
O
O
PP
tBuOMe
tButBu
OMetBu
2
2
(R)-DTBM-SEGPHOS72%, 96% ee
O
O
O
O
PP
Me
MeMe
Me
2
2(R)-DM-SEGPHOS
71%, 32% ee(R)-SEGPHOS74%, 24% ee
O
O
O
O
PP
2
2
steric hinderance enantioselectivity
■ This is the first enantioselective nucleophilic borylation of a C=O double bond
配位子の探索:DTBMーSEGPHOSがベスト
R
O
1. 5 mol % CuCl/ (R)-DTBM-SEGPHOS K(O-t-Bu) (10 mol %) MeOH (2.0 equiv) THF, 30 °C, 6 h
2. R3SiCl, imidazole CH2Cl2, 3 h
HB B
O
O O
O+
1.0 equiv
R H
R3SiO B
(S)isolated yield (%)
OO
Ph
B(pin)BnMe2SiO
H
B(pin)Me3SiO
H
B(pin)Me3SiO
HB(pin)Me3SiO
H
70%, 96% ee 51%, 96% ee 61%, 95% ee 84%, 95% ee
B(pin)HO
H
61%, 96% ee
B(pin)HO
H
61%, 92% ee
B(pin)HO
H
B(pin)HO
HPh
Ph
trace trace
基質適用範囲の確認:フリーで単離できるものもあり
R
O
1. 5 mol % CuCl/ (R)-DTBM-SEGPHOS K(O-t-Bu) (10 mol %) MeOH (2.0 equiv) THF, 30 °C, 6 h
2. R3SiCl, imidazole CH2Cl2, 3 h
HB B
O
O O
O+
1.0 equiv
R H
R3SiO B
(S)isolated yield (%)
OO
B(pin)BnMe2SiO
HN
B(pin)Me3SiO
HNBoc Ts
81%, 95% ee 52%, 91% ee
B(pin)BnMe2SiO
HO
O
66%, 85% ee
B(pin)BnMe2SiO
H
69%, 90% ee
BzO
B(pin)BnMe2SiO
H
69%, 95% ee
BnO
良好な官能基許容性
H
O
H
B(pin)HOCuCl / L* (5 mol %)(pin)B−B(pin) (1.0 equiv)
K(O-t-Bu) (10 mol %)MeOH (2.0 equiv)THF (0.5 M), 30 °C, 6 h
Ph2MeSiClimidazole
CH2Cl2, 3 h
>99% conversionL* = (R)-DTBM-SEGPHOS
H
B(pin)Ph2MeSiO
22% yield99% ee
H
BF3KHOKHF2 (4.0 equiv)
MeOH/H2O, 30 min
71% yield
■ Poor stability of the product toward silica gel column
Good isolated yield (71%) by converting into trifluoroborate■
芳香族アルデヒドの生成物は不安定
CuCl / ligand (5 mol %)(pin)B−B(pin) (1.0 equiv)K(O-t-Bu) (10 mol %)MeOH (2.0 equiv)
solvent, 30 °C, 18 hthen Me3SiClimidazole, 3 h (R,S)
H
O
Me
TBSO
B(pin)
OSiMe3
Me
TBSO
(R,R)
B(pin)
OSiMe3
Me
TBSO
+
(R)
α-Stereocenter
ICy⋅HCl (2 mol %), toluene: 69%, (R,S):(R,R) = 30:70
(R)-DTBM-SEGPHOS, THF: 73%, (R,S):(R,R) = 89:11(S)-DTBM-SEGPHOS, THF: 77%, (R,S):(R,R) = 5:>95
■ Strong catalyst-controlled selectivity over substrate vias
基質の不斉点との干渉少ない:Catalyst Control
For a review of Matteson homologation chemistry: Matteson, D. S. Tetrahedron 1998, 54, 10555.
Sadhu, K. M.; Matteson, D. S. Organometallics 1985, 4, 1687.
Stereospecific Csp3-Csp3 bond formation; One-carbon homologation
Larouche-Gauthier, R.; Elfold, T. G.; Aggarval, V. K. J. Am. Chem. Soc. 2011, 133, 16794.
Ph H
B(pin)BnMe2SiO
96% ee
ClCH2Br n-BuLi
THF−78 °C→rt3 h
Ph H
BnMe2SiO B(pin)
92%, 96% ee
H2O2NaOH Ph H
HO OH
77%, 96% ee
chiral 1,2-diol
chiral 1,2-haloalcohol
Ph H
R3SiO Br
80%, 96% ee3,5-(CF3)2C6H3Lithen NBS, −78 °C
誘導1:Matteson ホモロゲーション
H
(pin)B OSiMe3
95% ee
(S)
Benzofuran (1.2 equiv)n-BuLi (1.2 equiv)
THF, −78 °C, 1 h
NBS (1.2 equiv)
−78 °C, 1 hthen TBAF, 2 hH
Li
H
52%, 95% ee
(pin)B OSiMe3
OOH
O
(R)
Bonet, A.; Odachowski, M.; Leonori, D.; Essafi, S.; Aggarwal, V. K. Nature. Chem. 2014, 6, 584.
Stereospecific Csp3-Csp2 bond formation; Cross-coupling with a heteroaromatic compound
誘導2:Aggarwal アリレーション
coordination
σ-bond metathesis
protonation
insertion
isomerization (racemization?)
Cu B(pin)P
P
CuB(pin)
PP
O CHR
O CCu
R
B(pin)
H
PP
O CH
R
B(pin)
H
Cu ORP
P
O C(pin)B Cu
PP
R = OMe or O-t-Bu
O CHR
(pin)B−B(pin)
MeOH
(pin)B−OR
A
B
C
D
E RH
P
P= (R)-DTBM-SEGPHOS
cf. Zhao, H.; Dang, L.; Marder, T. B.; Lin, Z. J. Am. Chem. Soc. 2008, 130, 5586.
推定反応機構
Kubota, K.; Yamamoto, E.; Ito, H. J. Am. Chem. Soc. 2015, 137, 1, 420.
北海道大学総合化学院
北海道大学大学院総合化学院
工学研究院 応用化学部門
理学研究院化学部門
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>120名
2014年より実践的計算化学という授業をスタート■ 受講者各自のノートPCに Gasssian 09Wをインストール
■ 教員がプロジェクトに 映写しながらソフトの使い方を説明
■ 構造最適化、遷移状態の求め方 励起状態計算の基礎を指導
K. KubotaM. Jing
■ 武次徹也教授、長谷川淳也教授 伊藤、島田敏宏教授が担当
■ 伊藤研M2以上は Gaussian、量子計算 が考察のツールとして 使えるようになった。
Cu
B
P PO
HHH
Cu
B
P PO
H
HH
Ph Ph
Ph Ph
Ph
Ph Ph
Ph
Si-face (favored) Re-face (disfavored)
0 kcal/mol +1.04 kcal/mol
<
TS3 ((R)-SEGPHOS) TS4 ((R)-SEGPHOS)
Observed result 24%ee Relative G value
(kcal/mol) at 298 K 1.0 atm, gas phase.
B3PW91/cc-PVDZ
DFT計算による遷移状態の構造、比較
M. Jing
K. Kubota
Kubota, K.: Jing, M.; Ito, H. manuscript preparation
Cu
B
P PO
HHH
Cu
B
P PO
H
HH
Ar Ar
Ar Ar
Ar
Ar Ar
Ar
Si-face TS (favored) Re-face TS (disfavored)
Relative G value (kcal/mol) at 298 K, 1.0 atm, gas phase.
0 kcal/mol +1.97 kcal/mol
<observed result
96% ee
B3PW91/cc-PVDZ
DTBMーSEGPHOS: t-Buが効果的
Ph
O
Ph HH
BnMe2SiO B OO
R H
CuCl / L* (5 mol %) K(O-t-Bu) (10 mol %)(pin)B−B(pin) (1.0 equiv)
THF, 30 °CBHO O
OBnMe2SiClimidazole
CH2Cl2, 3 h
unstable
with MeOH: 72%, 96% eewithout MeOH: 34%, 22% ee
L* = (R)-DTBM-SEGPHOS
Mechanism
slow
isomerization
opposite enantiomer
fast protonation
O CCu
R
B(pin)PP
O C(pin)B
R
B(pin)
H
H
(pin)B B(pin)
LCu−B(pin)
O CRH
Cu
B
P P
O C RH(pin)B
Cu
PP
(pin)B B(pin)
O C RH(pin)B
B(pin)
(S)
(R)
MeOHCu OR
P
P+ O CH
R
B(pin)
H(S)
+(S)
cf. Zhao, H.; Dang, L.; Marder, T. B.; Lin, Z. J. Am. Chem. Soc. 2008, 130, 5586.
プロトンソースがない場合は ee低下
0
I
IICu B(eg)
P
P
OC+
HH
P
P=
P
P
CuP
P
O C
B(eg)
HH
IIICuP
P
O CB(eg)HH
TSA
CuP
P
O CB(eg)
HH
P1+1.4
+6.7
-19.9
B(eg) = BO
O
Free
Ene
rgy
(kca
l/mol
)
B3PW91/cc-PVDZRelative G value (kcal/mol) at 298 K, 1.0 atm, gas phase.
-30.5
P2CuP
P
C OB(eg)
HH
TSB
TSCO
CH H
B(eg)CuP
P
O C
B(eg)
HH
CuP
P
-15.7
-1.4
isomerization step
addition step
cf. Zhao, H.; Dang, L.; Marder, T. B.; Lin, Z. J. Am. Chem. Soc. 2008, 130, 5586.
プロトンソースなしでは異性化(ラセミ化)が進行する
B(eg) = BO
O P
P=
P
P
P1 major
0 (0)
-5.4 (-14.2)
CuP
P
O CB(eg)
HHH
OMe
IV
-2.9 (-15.0)
TSC
+1.76 (+2.9)
P2
CuO C
B(eg)
HHH
OMe
P P
Cu OMeP
P
O CB(eg)
HHH
+CuP
P
O CB(eg)
HH
MeOH+
MeOH
CuOMe
Free
Ene
rgy
(kca
l/mol
)
V
O
Cu
Me
P P
HO
CH
B(eg)
H
-4.1 (-14.4)
Relative G value (kcal/mol) at 298 K, 1.0 atm, gas phase. Electronic energies are shown in parentheses.
B3PW91/cc-PVDZ
プロトン化の活性化エネルギーは小さい
O
O
O
O
P
PCu
tBu tBuOMe
tBu
tBu
OMe
OMetBu tBu
tBuOMe
tBu
OB(pin)
Me
MeOH
+
O
O
O
O
P
PCu
tBu tBuOMe
tBu
tBu
OMe
OMetBu tBu
tBuOMe
tBu
OMe
HOB(pin)
+
0 kcal/mol -9.0 kcal/molRelative G value (kcal/mol) at 298 K, 1.0 atm, gas phase. B3PW91/cc-PVDZ
protonation
leading to more stable intermediate
熱力学支配によるプロトン化の促進
Kubota, K.: Jing, M.; Ito, H. manuscript preparation
Liu, D.; Zhao, G.; Xiang, L. Eur. J. Org. Chem. 2010, 3975.
chiral indolineindole
Enantioselective dearomatization strategy
chiral catalyst
Zhuo, C.-X.; Zhang, W.; You, S.-L. Angew. Chem. Int. Ed. 2012, 51, 12662.
NPG
R2
R3R1NPG
R4R2
R5R3
R1
NCO2H
O
CH3CH3
CO2Et
strychnine (+)-aspidospermidine pentopril
N O
N
O
HH N
NCH3
H3C
HCH3
O
(−)-physostigmine
NH
N H
H
H
ONCH3
H3C
光学活性インドリン誘導体
Hydrogenation
Electrophilic allylic substitution
Kuwano, R.; Sato, K.; Kurokawa, T.; Karube, D.; Ito, Y. J. Am. Chem. Soc. 2000, 122, 7614.
Trost, B. M.; Quancard, J. J. Am. Chem. Soc. 2006, 128, 6314.
Trost ligand
(S,S)-(R,R)-PhTRAP
FeFe
PPh2PPh2
O NH
HN O
Ph2PPPh2
2.5 mol % Pd2(dba)3CHCl37.5 mol % chiral ligand
9-BBN-C6H13 (1.05 equiv)CH2Cl2, 4 °C
NH
N+
HO
MeO
MeO
3 equiv92%, 85% ee
1.0 mol % [Rh(nbd)2]SbF61.05 mol % PhTRAP10 mol % Cs2CO3
i-PrOH, H2 (5.0 MPa)60 °C, 2 h
NAc
NAc
91%, 91% ee
芳香族のインドールから合成するのは有力な方法
N OR
O
PG R OH
Nucleophilic borylative dearomatization
Electron deficient indole
Consecutive stereogenic centers
*LCu B
N OR
O
PG
B
**
H
K. Kubota K. Hayama Kubota, K.; Hayama, K. Ito, H. Angew. Chem., Int. Ed. 2015, accepted.
世界初の方法:インドールの不斉ホウ素化
N OR
O
PG R OH
*LCu B
N OR
O
PG
B
**
H
N OR
O
PG
OH
**
H
N OR
O
PG
NH2
**
H
Nucleophilic borylative dearomatization
Stereospecific functionalizations
N OR
O
PG
C
**
H
Kubota, K.; Hayama, K. Ito, H. Angew. Chem., Int. Ed. 2015, accepted.K. Kubota K. Hayama
世界初の方法:光学活性インドリン誘導体
10 mol % Cu(O-t-Bu) 10 mol % chiral ligand10 mol % Na(O-t-Bu)
N
O
OMeCbz
N
O
OMeCbz
B(pin)
0.5 mmol
+OB
OB
O
O
2.0 equiv
t-BuOH (2.0 equiv) THF, 30 °C, 18−48 h
NMR yield (%)
PP
Me
Me
Me
Me
Me
Me
Me
Me PP
P
P
MeMe
Me
Me
(R,R)-BenzP*77%, d.r. 91:9
61% ee
(R,R)-Me-Duphos71%, d.r. 97:3
37% ee
P
P
Me
tBu
tBu
MeN
N P
P
Me
tBu
tBu
Me
(R,R)-3,5-xyl-BDPP98%, d.r. 97:3
93% ee
(R,R)-BDPP98%, d.r. 89:11
74% ee
(R,R)-QuinoxP*93%, d.r. 90:10
27% ee
Kubota, K.; Hayama, K. Ito, H. Angew. Chem., Int. Ed. 2015, accepted.
反応条件、不斉配位子の検討
N
O
OR3Cbz
N
O
OR3Cbz
B(pin)
+OB
OB
O
O
2.0 equiv
10 mol % Cu(O-t-Bu) 10 mol % (R,R)-3,5-xyl-BDPP10 mol % Na(O-t-Bu)
t-BuOH (2.0 equiv) THF, 30 °C, 4−18 h
0.5 mmol
R1
R2
R1
R2
isolated yield (NMR yield)
74% (93%)d.r. 97:3, 95% ee
64% (93%)d.r. 97:3, 95% ee
74% (96%)d.r. 93:7, 92% ee
74% (99%)d.r. 97:3, 97% ee
N
O
OMeCbz
B(pin)
N
O
OMeCbz
B(pin)
N
O
OMeCbz
B(pin)
N
O
OMeCbz
B(pin)F Cl Br MeO
76% (88%)d.r. 94:6, 93% ee
N
O
OMeCbz
B(pin)
62% (99%)d.r. 93:7, 86% ee
N
O
OMeCbz
B(pin)
Br MeO
52% (55%)d.r. 86:14, 95% ee
N
O
OEtCbz
B(pin)
71% (82%)d.r. 83:17, 89% ee
N
O
OMeCbz
B(pin)
Ph
基質の適用範囲
10 mol % Cu(O-t-Bu) 10 mol % (R,R)-3,5-xyl-BDPP10 mol % Na(O-t-Bu)
NMe
CbzN
Me
Cbz
B(pin)
0.5 mmol
+OB
OB
O
O
2.0 equiv
t-BuOH (2.0 equiv) THF, 30 °C, 24 h
not detected
LUMO -1.51 eV
LUMO+1 -0.68 eV
NO
O
Ph
O
O Me
NMe
OO
Ph
DFT analysis (B3PW91/ccpVDZ)
電子吸引基が必要:LUMOの比較
Optically active alcohol was obtained with high stereospecificity.✓
N
O
OMeCbz
B
TBSCl (2.0 equiv)imidazole (3.0 equiv)
N
O
OMeCbz
OHNaBO3•4H2O (4.0 equiv)
d.r. 97:3, 95% ee
N
O
OMeCbz
OTBS
THF/H2O, rt, air, 2 h
CH2Cl2, rt, 4 h
OO
64% yieldd.r. >99:1, 94% ee
F F
F
誘導反応:酸化
Cu BP
P
P
P= (R,R)-3,5-xyl-BDPP
(pin)B−(O-t-Bu)
σ-bondmethathesis
addition
NCbz
OOMe
Cu BPP
NCbz
O
OMeBPP
NCbz
O
OMeB
HO
HO
coordination
Cu(O-t-Bu)P
P
diastereoselectiveprotonation
HO
disfavored
favored
N
BOMe
OCbz
H
Cu
CuPP
(pin)B−B(pin)
N OMe
O
Cbz
Kubota, K.; Hayama, K. Ito, H. Angew. Chem., Int. Ed. 2015, accepted.
反応機構:t-BuOHが鍵
10 mol %Cu(O-t-Bu) / L*(pin)B−B(pin)
Na(O-t-Bu)t-BuOH, THF
N
O
OR3
CbzN
O
OR3
Cbz
B OO
R1
R2
R1
R2
up to 97:3 d.r.up to 99%up to 97% ee
N
O
OMeBoc
N
O
OMeBoc
B(pin)
0.5 mmol 45%, d.r. 54:46
10 mol % Cu(O-t-Bu)10 mol % Xantphos(pin)B−B(pin) (2.0 equiv)
20 mol % K(O-t-Bu)t-BuOH (2.0 equiv) THF, 30 °C, 11 h
N
O
OMeBoc
54%, d.r. 57:432 stereoisomers
OH
Ph
toluene60 °C, 16 h
Ph
O
H(3.0 equiv)
The first enantioselective borylative dearomatization of heteroaromatic compounds has been achieved.
L* = (R,R)-xyl-BDPP
PP
MeMe
MeMe
Me
Me
Me
Me
Current study
インドールの脱芳香族ホウ素化
Kubota, K.; Hayama, K. Ito, H. Angew. Chem., Int. Ed. 2015, accepted.
■ シリルボラン/塩基法 遷移金属フリーのホウ素化
92% yield
(1.5 equiv)KOMe (1.2 equiv)
DME, 30 °C, 1 h
Si BO
O
Br BO
O
Ph
Yamamoto, E.; Izumi, K.; Horita, Y.; Ito, H. J. Am. Chem. Soc. 2012, 134, 19997.
Dr. E. Yamamoto
Y. Horita K. Izumi
■ 有機リチウムやGrignard試薬利用
B
X LiBuLi
BX
官能基許容性に問題あり
■ 宮浦パラジウム触媒法
XPd cat.
B B
B
パラジウム触媒の残存 立体障害に弱い、反応が遅い
C(sp2)ーX へのホウ素置換反応
シリルボランの性質シリルボランは塩基による活性化でケイ素求核剤となる
OB
OSiMes
MesOMe Si
Mes
MesOMeLi
BuLi (2 equiv)toluene–78 °C, 1 h
Me3SiCl (2.45 equiv)
SiMes
MesOMeMe3Si
88% yield
Kawachi, A.; Minamimoto, T.; Tamao, K. Chem. Lett. 2001, 1216.
Chiral NHC (10 mol%)
OB
OSi Ph R1
O
R2
1
R1
O
R2
Si
up to 98% yieldup to 98:2 er
R1 = alkyl, aryl, OMe, H
DBU (15 mol%)
Ph
N N
Ph Ph
Ph Ph
Me Me
Chiral NHC
O'Brien, J. M.; Hoveyda, A. H. J. Am. Chem. Soc. 2011, 133, 7712.
Si BO
OPh + RO–M+
Si BO
OPhOR
Si BO
OPhOR
Brbase (1.2 equiv)
solvent, 30 oC , 1 h
B(pin)
MeO MeO
SiMe2Ph1
MeO
OB
OSi Ph
(1.5 equiv)
なぜか芳香族ハロゲン化物のホウ素化が進行!
Yamamoto, E.; Izumi, K.; Horita, Y.; Ito, H. J. Am. Chem. Soc. 2012, 134, 19997.
baseLiOMeNaOMeKOMeKOtBuK2CO3
KFDBU
B/Si
80:2095:573:27
total yield (%)0819266000
bSolvent: DME
“tBuO”では選択性・収率低下
ナトリウムでは選択性低下
アルコキシド塩基: カリウムメトキシドがベスト
BBS法と名付けた base promoted borylation with silylborane
山本英治博士
良好な収率で反応が進行する。早い(一時間以内完結)
Yamamoto, E.; Izumi, K.; Horita, Y.; Ito, H. J. Am. Chem. Soc. 2012, 134, 19997–20000.
官能基や立体障害があってもスムーズに反応が進行する
B(pin)
R' = H, 64(85)%
B(pin)
50(84)%OS
B(pin)
63(78)%R'
R' = Ph, 62(87)%
Yamamoto, E., Ukigai, S., Ito, H. Chem. Sci. 2015, 6, 2943 - 2951.
官能基や立体障害があってもスムーズに反応が進行する
B(pin) B(pin)Me Me
72% (isolated) 85% (isolated)
Murata, M.; Smbommatsu, T.; Watanabe, S.; Masuda, Y. Synlett. 2006, 1867.
Br B(pin)H-B(pin) (2.0 equiv)Pd(dba)2, t-Bu-DPEphos (5 mol%)
1,4-dioxane, Et3N (3.0 equiv)100 ºC, 6 h
72% (isolated)
O(t-Bu)2P P(t-Bu)2
t-Bu-DPEphos:
Br B(pin)PMe2Si B(pin) (1.5 equiv)KOMe (1.2 equiv)
DME, 30 ºC, 1 h
92% (NMR)82% (isolated)
BBS法はヘテロ環化合物についても適用可能
Yamamoto, E., Ukigai, S., Ito, H. Chem. Sci. 2015, 6, 2943 - 2951.
(87)% 58(63)%
NNBn
B(pin)
ON
B(pin)
S B(pin) NN
B(pin)N
O
B(pin)
Ph Ph59(68)% 67%c 51d(74)%
52%
B(pin)
S
(77)%74(85)%
OB(pin)N
Et
B(pin)
61(75)%S
B(pin)
N
SEt B(pin) N
N
B(pin)N
N
B(pin) N
N
B(pin)
MeO N46(68)%
not detected(38)% 73%
S. Ukigai
BBS法はヘテロ環化合物についても適用可能
Yamamoto, E., Ukigai, S., Ito, H. Chem. Sci. 2015, 6, 2943 - 2951.
(66)%
N
B(pin)
58%
N
B(pin)
N(1.0 equiv) 3w 20% isolated yield
KOMe (1.2 equiv)
DME, 30 oC, 1 h
PhMe2Si–B(pin) (1.5 equiv)
N SiMe2Ph
N SiMe2PhR
work-upborylationconditions
■ シリル付加が収率を下げるケースもある。
アルケニルハライドは立体特異的に変換される
Yamamoto, E., Ukigai, S., Ito, H. Chem. Sci. 2015, 6, 2943 - 2951.
Si-B equiv base solvent yield of B (%) Z/E B/Si
1.5 KOMe DME 53 92:8 95:5
1.5 NaOMe DME 72 96:4 96:4
1.5 NaOEt DME 79 97:3 96:4
2.0 NaOEt DME 89 97:3 96:4
2.0 NaOEt 1,4-dioxane 81 98:2 99:1
2.0 NaOEt CH2Cl2 2
2.0 NaOEt toluene 0
PhMe2Si–B(pin)Base (1.2 equiv)
solvent, 30 ˚C, 1 h
CyI
CyB(pin)
CySiMe2Ph
Z/E = 98:2
アルケニルハライドは立体特異的に変換される
Yamamoto, E., Ukigai, S., Ito, H. Chem. Sci. 2015, 6, 2943 - 2951.
DME, 30 ˚C, 1 hAlkenyl X
NaOEt (1.2 equiv)Alkenyl B(pin)
X = Br, I
PhMe2Si–B(pin) (2 equiv)
B(pin)Cy
B(pin)
B(pin)Ph
B(pin)
OMOM
B(pin)
B(pin)B(pin)
B(pin)O 5
B(pin)O
B(pin)
Ph
Ph
O
OBuO
B(pin)
Cy
(E)-6a, X = I, 68% (Z)-6b, X = I, 72% (Z)-6c, X = I, 64%
(Z)-6g, X = I, 51(70)% (Z)-6h, X = I, 74%
6d, X = Br, 43%
(E)-6e, X = I, 64% 6f, X = Br, (60)%
6j, X = Br, 68%6i, X = B, 58%r 6k, X = Br, 53%
OPh
O
5
アルケニルハライドは立体特異的に変換されるi) 1 (1.5 equiv)
KOMe (1.2 equiv)DME, 30 ˚C, 1 h
2 4Ar–B(pin)Ar–Br
3
Pd(PPh3)4 (5 mol %)
K2CO3 (2 equiv)solvent, temp.
Ar'–I (2 equiv)Ar–Ar'
ii) TBAF treatment
NO2NC
4x, 36%b
4l, 74%c
N
NN
4t, 78%d
O
NO2
4h, 84%b
NO2S
N4u, 64%d
N4v, 58%d
アルケニルハライドは立体特異的に変換される
1 (1.5 equiv)KOMe (1.2 equiv)
DME, 30 ˚C, 1 h
3y, 61(51)%a
NN
Br
NBoc
NN
B(pin)
NBoc
2yN
NHN
NNH2
OCl
Cl F
Crizotinib(anti-cancer drug)
N
NNBocN Br
1 (1.5 equiv)KOMe (1.2 equiv)DME, 30 ˚C, 1 h
N
NNBocN OH
2z
ii) oxidation
3z, 71%a
N
NNBocN B(pin)
N
NNBocN O
SO
O
GPR119 agonist
■ Key Features of Boron Element
NN
PtOO
B
Wang, Suning et al. Chem. Commun. 2011.
■ Triarylboron-‐‑‒Containing Materials
N B N BB
BS
SB
n
Shirota, Y et al. J. Am. Chem. Soc. 1998.
Doty, J. C.; Babb, B.; Grisdale, P. J.; Glogowski, M.; Williams, J. L. R. J. Organomet. Chem. 1972, 38, 229.
含ホウ素有機電子材料:トリアリールボラン
K. IzumiDr. E. Yamamoto
BBS法をトリアリールボランに適用
base solvent temp. (℃) yield (%) B/Si
KOMe DME 30 28 39:61
NaOMe 1,4-dioxane 50 76 77:23
Na(O-t-Bu) 1,4-dioxane 50 78 87:13
Na(O-t-Bu) 1,4-dioxane/hexane (1:1) 50 80 90:10
Si B
Et Brbase (1.2 equiv), 24 h
BEt SiEt+
含ホウ素有機電子材料:トリアリールボラン
manuscript under preparation
MeO BMes
Mes
94% yield (90% purity)B:Si=88:12 (NMR)61% isolated yield
B
Me
Mes
Mes
90% yield (NMR)B:Si=92:8 (NMR)66% isolated yield
F3C BMes
Mes
69% yield (NMR)B:Si=84:16 (NMR)53% isolated yield
B
Me
Mes
Mes
46% yieldB:Si=67:33 (NMR)20% isolated yield
N BMes
Mes
77% yield (NMR)B:Si=96:4 (NMR)50% isolated yield
NMe B
Mes
Mes89% yield (NMR)B:Si=93:7 (NMR)62% isolated yield
Cl BMes
Mes
81% yield (NMR)B:Si=91:9 (NMR)69% isolated yield
BMes
Mes
89% yieldB:Si=90:10 (NMR)43% isolated yield
BSS Mes
Mes
55% yieldB:Si=89:11 (NMR)42% isolated yield
Me
Br BMes
Mes
78% yieldB:Si=92:8 (NMR)57% isolated yield
Me
Br
BMes
Mes
49% yieldB:Si=91:9 (NMR)29% isolated yield
安定なシリルボラン:スーパーシリルボラン
manuscript under preparation
■ 最大の欠点:空気に不安定
PMe2Si B(pin) PMe2Si OB(pin)Air
R. Shishido
安定なシリルボラン:スーパーシリルボラン
R1: 0.096�GOF: 1.06 �
Space Group P21/c (#14)�
安定なシリルボラン:スーパーシリルボラン
安定なシリルボラン:スーパーシリルボラン
ホウ素化で同等以上の性能
ホウ素化で同等以上の性能
BBS法の反応機構は?
■ なぜ (形式的)求核的芳香族置換反応が進行するのか?
■ なぜケイ素でなくホウ素へ置換されるのか?
■ 官能基許容性はなぜ生じるのか?
■ なぜ立体障害に強いのか?
反応機構、四つの可能性
1. 遷移金属のコンタミネーション
Ph Br
Si–B
base
2. アニオンラジカル経由
3. 中性ラジカル経由
4. アニオン経由
Ph B(pin)
Br
遷移金属の触媒作用ではないPd, Cu, Fe, Ni, Rh, Ag, Co, Pt, Ru, Ir の添加による加速効果は見られず
KOMe 試薬のICP発光分析 遷移金属は検出限界以下
Yamamoto, E.; Izumi, K.; Horita, Y.; Ito, H. J. Am. Chem. Soc. 2012, 134, 19997–20000.
反応機構に関する実験:遷移金属コンタミネーション?
このような反応は、どのような遷移金属の触媒反応においても、知られていない
一電子移動&アニオンラジカル経由の機構
I+
K(O-t-Bu) (3 equiv)EtOH (cat)
DMF, 80 °C, 2 h73%
Shirakawa, E.; Zhang, X.; Hayashi, T. Angew. Chem., Int., Ed. 2011, 50, 4671.
X+
IO-t-Bu
I
Php-Tol Ph
RO– M+
Si BO
OPh
OBO
OR
SiPh
M X X
Si BO
OPh OR Si B
O
OPh RO
? ?
反応速度の比較で電子移動を考察:関与ない?
Br
KOMe (1.2 equiv)
DME, 30 ˚C, 15 min
F3C
PhMe2Si–B(pin)(1.5 equiv)
Br
Ph
B(pin)
F3C
B(pin)
Ph3d, 7% yield
3a', 52% yield
reduction potential: lower
reduction potential: higher
electrophilicity of C1: lower
electrophilicity of C1: higher
1
1
2d (1.0 equiv)
2a' (1.0 equiv)
3d:3a' = 15:85
Yamamoto, E., Ukigai, S., Ito, H. Chem. Sci. 2015, 6, 2943 - 2951.
別のラジカル経由のパスがあるかもしれない。
ラジカル反応の可能性は?:関与の可能性は低い
ラジカル反応の可能性は?:関与の可能性は低い
CyI
CyB(pin)
Cy
(Z)-6a (E)-6a
Cy H CyH
fast
B(pin)
(Z)-5a
silylborane/alkoxy baseborylation with
反応機構、四つの可能性
1. 遷移金属のコンタミネーション
Ph Br
Si–B
base
2. アニオンラジカル経由
3. 中性ラジカル経由
4. アニオン経由
Ph B(pin)
Br
AFIR自動反応経路探索: 北海道大学 前田・武次先生
Ref: 前田理、畑中美穂、植松遼平、 武次徹也、諸熊奎治人工力誘起反応法による化学反応経路の自動探索: 有機合成化学への応用と展望 有機合成化学協会誌, 2014, 5, 567.
Dr. S. Maeda Pro. T. Taketsugu
RO– M+
Si BO
OPh X
R. Uematsu(天然物合成経験あり)
M06-L/6-311+G(2d,p), 303.15K, 1.0 atm
Uematsu, R., Yamamoto, E., Maeda, S., Ito, H., Taketsugu, T. J. Am. Chem. Soc. 2015, 137, 4090.
ハロゲンへのアタックとアリールアニオン生成が鍵
なぜケイ素でなくホウ素へ置換されるのか? 官能基許容性はなぜ生じるのか? なぜ立体障害に強いのか?
Uematsu, R., Yamamoto, E., Maeda, S., Ito, H., Taketsugu, T. J. Am. Chem. Soc. 2015, 137, 4090.
RO– M+
Si BO
OPh
OBO
OR
SiPh
M
BrAr
Si BrPh
OBO
OR
Ar
MB
O
OAr
– MBr
B OO
O
R
M
Ar
BrSi
MeMePh
– ROSiMe2Ph
R = Me, EtM = K, Na
ArBr
OBO
RO
SiPh
M
M06-L/6-311+G(2d,p), 303.15K, 1.0 atm
なぜケイ素でなくホウ素に置換されるのか?
ArBr
OBO
RO
SiPh
M B OO
O
R
M
Ar
BrSi
MeMePh
Ar
HBr
OBO
RO
SiPh
M
ΔG‡: 18.4 kcal/mol0 kcal/molΔG: -11.7 kcal/mol
B OO
O
R
M
Ar
BrSi
MeMePh
BO
OAr
ΔG‡: 1.0 kcal/mol
B OO
O
R
M Ar
Br Si MeMe
Ph
Ar SiMe2Ph
ΔG‡: 2.4 kcal/mol
■ この活性化エネルギーが非常に小さい ”アリルカリウム”が迅速に消費される。 =官能基許容性が高い
M06-L/6-311+G(2d,p), 303.15K, 1.0 atm
Uematsu, R., Yamamoto, E., Maeda, S., Ito, H., Taketsugu, T. J. Am. Chem. Soc. 2015, 137, 4090.
なぜ立体障害に強いのか?
ArBr
OBO
RO
SiPh
M B OO
O
R
M
Ar
BrSi
MeMePh
Ar
HBr
OBO
RO
SiPh
M
ΔG‡: 18.4 kcal/mol0 kcal/molΔG: -11.7 kcal/mol
B OO
O
R
M
Ar
BrSi
MeMePh
BO
OAr
ΔG‡: 1.0 kcal/mol
B OO
O
R
M Ar
Br Si MeMe
Ph
Ar SiMe2Ph
ΔG‡: 2.4 kcal/mol
■ ハロゲンアタックが律速段階
profiles provided several points that can be beneficial for furtheroptimization of the BBS method.At first, the activation energy in the halogenophilic attack on
sterically hindered 2,4,6-triisopropylbromobenzene (3e) was inves-tigated and found to be reasonably low (ΔΔG⧧ = 1.9 kcal/mol,Figure 4). TS(B2′/B3) was slightly lower than TS(B3/B4) for 3e
as shown in Figure S5-1, and the reaction thus is expected toproceed smoothly with 3e. This is consistent with the highreactivity of the BBS method toward sterically hinderedsubstrates.2
Second, the halide effect [PhBr (3b) vs PhCl (3f) vs PhI(3g)] and substitution effect of para position [PhBr (3b) vsp-MeO−C6H4Br (3h) vs p-F−C6H4Br (3i)] were investi-gated experimentally and theoretically (see the SupportingInformation: S11 for experimental data and Figures S5-2, S5-4,S6-2, and S6-3 for theoretical energy profiles.) Experimentally,it was shown that the reactivity increases as 3g > 3b > 3f and3i > 3b > 3h.26 These experiments also showed that reactionsof different substrates are in competition when two substratesare combined together. Consistently, ΔG⧧ values at the rate-determining TS(B2′/B3) are very close to each other for thesesubstrates; ΔG⧧ values at TS(B2′/B3) are 7.5, 8.7, 7.3, 6.9, and7.2 kcal/mol for 3b, 3f, 3g, 3h, and 3i, respectively, in our bestestimate with inclusion of the solvent effect by C-PCM. Thesevalues reproduce the experimental reactivity trends qualita-tively; only the ΔG⧧ for 3h showed deviation from theexperimental trend. Nevertheless, these <1 kcal/mol energydifferences are too small to be discussed with the presentcomputational level. Moreover, the computational trendchanged by inclusion of the solvent effect with C-PCM (seeSupporting Information). Treatment with more accurate abinitio theory and explicit consideration of movements ofsurrounding solvent molecules are required for furtherquantitative predictions.Third, the impact of the base is investigated. We reported
that KOMe (2a) gave the borylation and minor silylationproducts of p-MeO−C6H4Br (3h) in 92% yield with high B/Siratio (95:5). The reaction with NaOMe (2c) resulted in 81%yield (5b + 6b) with a B/Si ratio of 80:20. We also foundthat the borylation of PhBr (3b) with K(O-t-Bu) (2d) andLi(O-t-Bu) (2e) as the base gave moderate to high yield andB/Si selectivity [66% yield (5b + 6b), B/Si = 73:27; 94% yield(5b + 6b), B/Si = 85:15, respectively] under previouslyreported reaction conditions.2 Theoretical results showed thatall of the bases shown in Scheme 4 provide ΔΔG⧧ values thatare low enough to promote the borylation reaction. However, itis difficult to fully elucidate the reactivity and selectivity trends
of the experimental results. This is probably because of thesolubility difference of the bases (for details, see Figure S10 inthe Supporting Information). KOMe (2a), LiOMe (2b), andNaOMe (2c) are only partially soluble in dimethoxyethane,whereas K(O-t-Bu) (2d) and Li(O-t-Bu) (2e) are fairly solublein the solvent. It is noteworthy that the reaction of LiOMe (2b)afforded no borylation/silylation products in the experiment,although the theoretical results for LiOMe indicate its moderatereactivity. This inconsistency is attributable to the very slowSi−B bond cleavage in the real LiOMe reaction system becauseof the extremely low solubility of LiOMe in the reactionmedium and relatively higher ΔΔG⧧ value at the Si−B bondcleavage step (B2′ → B3) (for details, see the SupportingInformation). Furthermore, in this study, we optimized TSsobtained for the reaction with 2a after substituting thecorresponding metal atom without further conformationalanalysis. The B/Si selectivity would be determined by a subtleenergy gap between the silylation TS and the borylation TS,and its quantitative prediction further requires an extensiveconformational sampling. Such an analysis for quantitativediscussions of the B/Si selectivity will be a future subject.
■ DISCUSSIONThe pathways computed in the current study for the case-A andcase-B reactions provide adequate explanations of many of thecharacteristic features of the BBS method. The BBS methodwas initially highlighted for its good functional groupcompatibility and high reactivity toward sterically hinderedsubstrates.2 In the reaction profiles shown in Figures 1 and 3,the step involving the cleavage of the Si−B bond throughTS(AorB2′/AorB3) was identified as the rate-determining step.The reaction proceeded rapidly beyond this point, withunstable intermediates such as the silyl anion and carbanionspecies being immediately consumed with very low energybarriers (see the steps from AorB3 to AorB5 in Figures 1 and 3).This result indicated that all of these intermediates almostexclusively underwent the borylation reaction, even when theycontained other reactive functional groups. Furthermore, thestructures of the TSs involved in these steps provide somerationale for the high borylation reactivity observed in theBBS method toward sterically hindered aryl bromides. TheTS(B3/B4) structure shows that the steric hindrance providedby the substrate would be too far removed from the reactiveσ*(C−Br) orbital to have a noticeable impact on the reactivity,whereas catalysts usually interact with the carbon and bromoatoms in the C−Br bond directly in the transition metal-catalyzed boryl substitution of aryl bromides. Actually, a bulkysubstrate 3e showed a reasonable potential profile with lowbarriers.The BBS method proceeded to give a product with a
counterintuitive borylation reaction as well as a small amount ofthe silylation product (5−10%).2 This distribution of productssuggests that these two channels are competing with each otherand that the energy barrier for the borylation reaction must beslightly lower than that of the silylation reaction by a fewkcal/mol. This feature of the BBS method was effectivelyreproduced in the current reaction profiles. Furthermore, theresults of simple thermodynamic analyses on the basis of theirfree energy barriers and Boltzmann distributions predictedborylation/silylation ratios of the case-A and case-B reactions tobe 97:3 and 92:8, respectively. These ratios were qualitativelyconsistent with the experimental ratios of 91:9 and 94:6. Theenergy profiles for these reactions showed that all of the
Figure 4. TS structures, free energies (ΔG⧧) relative to the reactants(1, 2a, and 3b/3e), and activation free energies (ΔΔG⧧) for the halo-genophilic attack reaction steps. Free energy values (303.15 K, 1.0 atm)based on M06-L/6-311+G(2d,p) calculations are given in kcal/mol.
Journal of the American Chemical Society Article
DOI: 10.1021/ja507675fJ. Am. Chem. Soc. 2015, 137, 4090−4099
4096
改めてアリールアニオン種発生の確認
the detachment/attachment coordinate of 3b at B2′ was−20.9 kcal/mol. This is much lower than TS(B2′/B3). Theprofile shown in Figure 2 thus is the best path concerning exis-tence or nonexistence of 3b. Details of this analysis are de-scribed in Supporting Information Figures S4, S6-1, and S6-2.Decomposition of reaction complexes with dissociation of
species that do not directly participate in the reaction can be afavored process. However, this is not the case in the reactionsteps from B3 to B5 and B7 of the present reaction. This isbecause activation free energies required in these steps are allvery low. In other words, these steps proceed rapidly beforedissociation of such species. In order to confirm this, we calcu-lated free energy values along dissociation coordinates of thesespecies. For example, for reaction complex B4, the distanceRK−B between the K atom and the B atom in (pin)B−OMe waschosen as the dissociation coordinate of (pin)B−OMe. Then,we performed a constrained optimization, fixing the distanceat RK−B = 8 Å and the normal-mode analysis for the pro-jected Hessian. This gave an estimate of the free energy of−27.0 kcal/mol at RK−B = 8 Å. This is much higher than theTSs for the forward reactions: −35.3 kcal/mol for borylationand −33.9 kcal/mol for silylation. Thus, the reaction proceedsbefore dissociation of (pin)B−OMe. In this way, we confirmedthat the reaction proceeds with the path from B3 to B5 and B7shown in Figure 3 without dissociation of any species. Details ofthis analysis are described in Supporting Information Figure S6-1.The possibility of radical reaction pathways was checked
using several calculations. Strohmann et al.14a suggested theexistence of a radical-mediated pathway in the reaction of silylanions with organic halides, which is mechanistically relatedto the BBS method,14a and TS(B3/B4), which involves thehalogenophilic attack step, that could possess some radicalcharacter. The results of a CIS-based MO stability check22 atthe UM06-L/6-311+G(2d,p) level, however, indicated thatTS(B3/B4) was closed-shell at the electronic ground state.Furthermore, TDDFT-based electronic excitation energycalculations for the complex composed of B2 and PhBrrevealed that the closed-shell electronic ground state was wellseparated from the first electronic excited state by 103.6 and122.2 kcal/mol at the CAM-B3LYP23/6-311+G(2d,p) andLC-BLYP24/6-311+G(2d,p) levels, respectively. These resultstherefore excluded the possibility of an open-shell radicalspecies being involved in this reaction.A significant difference was found between the case-A and
case-B pathways in terms of the complexes containing theanionic intermediates PhCH2CH2
− and Ph− (A4′ and B4). Inthe case-B reaction, cleavage of the C−Br bond resulted inthe formation of the stable intermediate B4 bearing a K−Cbond. The interaction between the terminal C atom of thePhCH2CH2
− anion and the potassium cation in A4′ wasweakened, however, by the strong interaction between thepotassium cation and the Ph group, which separated thepotassium cation from the terminal C atom. The relativelystrong interaction between the potassium cation and the Phgroup of the PhCH2CH2
− anion could explain why themetastable intermediate A4′ was identified as a local potentialenergy minimum in the case-A reaction.In a similar manner to the case-A reaction, the case-B
reaction also involved two reaction pathways at B4 (i.e.,borylation and silylation reactions). Experimental resultsshowed that the borylation reaction occurred in preference tothe silylation reaction. This preference can be understood interms of the difference in the free energy values of TS(B4/B5)
and TS(B4/B7), with the former being 1.4 kcal/mol lower inenergy than the latter. This energy difference was very similarto the corresponding energy gap of 1.5 kcal/mol in the case-Areaction. Taken together, these results indicated that theborylation reaction was kinetically favored over the silylationreaction. On the basis of this free energy gap and theBoltzmann distribution, the B/Si branching ratio of the case-Breaction was estimated to be 92:8, and this ratio was consistentwith the experimental borylation/silylation ratio of 94:6 fromthe BBS method.
Experimental Results. The validity of the proposed arylanion-mediated mechanism was supported by the results of anexperiment involving the borylation of an aryl halide (3c) bearinga TBS ether group next to its bromine atom (Scheme 3a). The
reaction of 3c with silylborane 1 in the presence of potassiummethoxide proceeded as an intramolecular silyl substitutionreaction instead of a boryl substitution reaction to give TBS-substituted product 12c in moderate yield (53% isolated yield),without detection of borylation product 5c. This resultsuggested that the corresponding aryl anion species wasgenerated in situ and that this species subsequently attackedthe silicon atom of the proximal TBS group at a greater ratethan the boron or phenyldimethylsilyl electrophile derived fromthe silylborane. It is noteworthy that Hudrlik et al.25 recentlyreported an intramolecular retro-Brook rearrangement, whichproceeded via a similar mechanism (Scheme 3b).
Substrate and Base Dependence. We now have themajor reaction path for the BBS method. Thus, it would beinteresting to look at energy profiles of this path for differentsubstrates and bases. In practice, five aryl halides, 3e−3i, andfour bases, 2b−2e, listed in Scheme 4 were considered. In the
Supporting Information, all computed energy profiles arecompared in Figure 3. Some trends seen in these energy
Scheme 3. Intramolecular Retro-Brook Rearrangement of aSilylborane Species in the Presence of an Alkoxy Base
Scheme 4. Aryl Halides and Bases Used in Discussions onthe Reactivity of the BBS Method
Journal of the American Chemical Society Article
DOI: 10.1021/ja507675fJ. Am. Chem. Soc. 2015, 137, 4090−4099
4095
MeO
SiMe2Ph8d', 51% GC yieldSi LiPh
p-MeOC6H4Br(1 equiv)
THF, 30 ˚C, 1 h
Si LiPh Br OMe Si BrPh OMeLi
AFIR/DFTによる反応機構解析
■ なぜ (形式的)求核的芳香族置換反応が進行するのか?
● アリールアニオン種の生成
■ なぜケイ素でなくホウ素へ置換されるのか?
● アリールアニオン種のホウ素中心への攻撃のほうが速い
■ 官能基許容性はなぜ生じるのか?
● アリールアニオン種の寿命が短い
■ なぜ立体障害に強いのか?
● 律速段階のハロゲンへの攻撃が立体障害から離れている
最新設備:フロンティア応用科学研究棟
2 6
ご協力いただいた先生方への謝辞
1. ホウ素化反応(銅触媒、BBS法)
2. メカノ応答性をもつ発光性金錯体
澤村 正也 教授 鈴木 孝紀 教授 武次 徹也 教授
前田 理 准教授 谷野 圭司 教授
北海道大学
喜多村 曻 教授 石坂 昌司 准教授 (現広島大学) 日夏 幸雄 教授 分島 亮 准教授 朝倉 清高 教授 佐々木 陽一 名誉教授
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関 修平 教授(大阪大学) オラフカートハウス教授(千歳科技大)
北海道大学
細見彰 筑波大学名誉教授 今本 恒雄 千葉大学名誉教授
謝辞
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石塚 智子 川上 千佳 小坂 由紀 伊藤 慎一郎 大島 直哉 齋藤 智久 松浦 耕 野々山 浩輔 豊田 昂
仲 崇民 佐々木 悠祐 大倉 拓真 國井 峻 堀田 優子 榑沼 紗也佳 宮 貴紀 室本 麻衣 久保田 浩司
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石山竜生 山本靖典
関朋宏 佐々木郁雄
山本英治