九州大学学術情報リポジトリ
Kyushu University Institutional Repository
遷移金属触媒を用いた直接的と化学選択的置換反応 の開発
林, 璐
http://hdl.handle.net/2324/1866281
出版情報：Kyushu University, 2017, 博士（創薬科学）, 課程博士 バージョン：
権利関係：Public access to the fulltext file is restricted for unavoidable reason (3)
Development of Transition Metal .. catalyzed Direct and Chemoselective Alkylation Reactions
(Introduction]
The allyl group is widely ence;untered in orgiu1ic and phannaceutical chemistry. It could work as a crucial structure of natural ai1d u1u1itural compounds, which may possess various biological function or could work as j preeusor in 1yuthesizh1g these compounds. In order to h1troduce allyl groµp into compeuiidi, allylio iloohcdi would be idea.I allylating agents because of their availability and stability. Due to th@ poor l@avinQ ability of hydroxyl group, however allylic alcohols should be prtM:tetivated into titJ:i;r 1~tivated iubstrates such as allyl halides, carbonates and acetates, followed by Ts\:\ii· i'roESt reactkm to afford the desired compounds. In these synthesizing procedure, mere than stoiohimn.etric amount of unwanted waste are produced during both pre .. activation and Tsuji .. "lrost reaction. Thus, a direct catalytic substitution of allylic alcohols, which forms water as the sole coproductt has recently attracted much attention from an environmental and atom .. economieal point of view (Scheme A-1).
Scheme A·1 Direct eatalytle Rtactlon
~ -.. ,. .,. " ,, .. ., " '?' .. ,. .. ., ~ ., ,., " ., ,. ,, ,. ~ .. ~ " .. "' ,, • Direct Catalytic Reaction . -~ 1
Catalyst .. :
rf~_,_OH ----r'\ ., '. "··· "111 R~Nu:
'· .... + ...
~~~-...
~?-~ ... -... -. -.·l· ----_:
Pre-Activation Tsuji- Trost Reaction
I .'\ . R ~ X \ I
Waste Waste
X = Cl, OC02R, OAc, etc.
Our group is also working on the direct catalytic substitution of allylic alcohols without pre- activation, by the function of Pt catalyst and large bite angle ligand DPEphos or Xantphos, the amination of allylic alcohols was occurred with aromatic amine and aliphatic amine or even ammonia solution. And in these reactions, high mono-selectivity was obtained, which is difficult to realize in conventional methods (Scheme A .. 2) 1•
+ ~
1
~ N R 5
» di
mono/di= 88/12 to >99/1
To dig the investigation deeper, we developed the research of direct mono-selective alkylation of ally lie alcohols via Platinum-pyrrolidine catalytic system and also chemoselective substitution between different electrophiles via transition metal.
[Contents]
1. The Development of Direct Mono .. selective Alkylation of Allylic Alcohols via Platinum ..
Pyrrolidine Catalytic System
[Purpose]
The allylation of activated methylene compounds has attract many researchers' attention during recent years. But the existence of di-allylation compounds produced from overreaction perplexed the researchers. So we focused on the direct mono~selective alkylation of allylic alcohols by former catalytic system2.
[Method and Result]
From the report of Dr. Shibuya in our research group3, byproducts were suppressed by adding acetic acid and pyrrolidine, thus the mono,.selective alkylation of allylic alcohols was achieved in high yield and high selectivity. With this optimized condition in hand, I explored the substrate scope, both aromatic alcohols and aliphatic alcohols lead to good yield, also acid sensitive group, fused rings and heterocycle tolerant well (Scheme A~3).
Scheme A-3a Direct Mono--selective Alkylation of Ally/le Alcohols Pt(cod)Cl2 (2 mol%)
R3 pyrrolidine (10"50 mol%) Xantphos (2 mol%) (
Af3
oCH3C.OOH (10 .. 50 mol%l R1 ~
2
. · .. OEt DMF, 50 °C, 5 h. R· no
/',-. l_ 0 0 R1 y "OH + AAoet
R2 1
P h ~ O E I
90%, 3/4 = 9(5/4
0
~ O E t
69%, 3/4 ~ 93/7 0 P h ~ O E t
lo~
85%b, 3/4: 96/4
2 Mlerowave n= 1 n=2
3 4
0 .· ~ 0
~ o e t1
I~ OE!
THPO,-V 0 ~ // 0
84%, 3/4 = 96/4 84%, 3/4 = 95/5
~ O E ! P h ~ O E I
V o~ o
90%b, 3/4 = 95/5 80%b, 3/4 = 97/3
0 0
P h ~ .. OEt CsH7~ 0 E t
0 ~ 0 ~
78%", 3/4 = 96/4 67%b, 3/4 = 95/5
a 2.0 mmol scale, 0.4 ml OMF was used, yield is isolated yield and the 3/4 ratio is determined by 1 H NMR analysis. b 50 molo/o of pyrrolidlne and 50 mol% of CH3COOH was used.
2. The Development of Chemoselective Substitution via Transition Metal between Allylic Alcohols and Allylic Amines as Electrophiles
[Purpose]
Chemoselectivity describes the preferential reaction of a given reagent with one of two or more functional groups that are present in a reactant or a group of reactants. Our group reported chemoselective reactions between two different nucleophiles4, but chemoselectivity between different electrophiles has not been studied. On the other hand, just like allylic alcohols, allylic amine is seldom used in Tsuji-Trost reaction due to the poor leaving ability of amino group. So, combine the study reported above, I focused on the chemoselective substitution between allylic alcohols and allylic amines as electrophiles. This means under one condition, only allylic alcohols proceed the substitution, and under the other condition, only allylic amines proceed the substitution.
[Method and Result]
Between allylic alcohol lb, allylic amine 2a and nucleophile 3a, the chemoselective reactions were examined (Scheme A .. 4)5• Under the function of palladium catalyst, 84% yield and 88/12 alcohol selectivity was obtained with the existence of activator boronic acid B12, and 93% yield and 89/11 amine selectivity was achieved by the
activation of solvent MeOH. Aromatic alcohols ~nd a.mines including fused rings and heterocycles lead to very good yield and selectivity.
Aliphatic alcohols and w11ines ijflOW some difficulties on achieving high yield and selectivity.
~ ( O H h
l
S12 .. JScheme A·4 chemoselectlve Substitution between Ally/le Alcohols a.nd Allylic; Amines [Pd(allyl)Clfa (1 mol%)
~ O H
~ 1b 1.0 eq.
~ N H 2
V 2a
1.0 eq.
[Reference]
+
3a 2.1 eq.
DPEphos (4 mo!%) 612 (25 mo!%) Toluene, 30 9C, 2.5 h
r Q.Se/eat/ve ,__
[Pd{allyl)Clfa (1 mo!%) DPEphos (4 mol%)
MeOH, 30 °C, 2 h N~Selective
~
4ba 84%
4/5 = 88/12
~ C N
u -
6NSaa 93%
4/5 = 11/89
1 (a) Utsunomiya, M.; Miyamoto, Y.; Ipposhi, J.; Ohshima, T.; Mashima, K. Org. Lett. 2007, 9, 3371. (b) Ohshima, T.; Miyamoto, Y.; Ipposhi, J.; Nakahara, Y.; Utsunomiya, M.; Mashima, K.
J Am. Chem. Soc. 2009, 131, 14317. (c) Das, K.; Shibuya, R.; Nakahara, Y.; Germain, N.;
Ohshima, T.; Mashima, K. Angew. Chem. Int. Ed. 201.2, 51, 150.
2 Shibuya, R.; Lin, L.; Nakahara,, Y.; Mashima, K.; Ohshima, T. Angew. Chem. Int. Ed 2014, 53, 4377.
3 Shibuya, R. The Development of Direct Mono-selective Alkylation of Allylic Alcohols via Platinum-Pyrrolidine Catalytic System, Master thesis, 2013.
4 (a) Ohshima, T.; Iwasaki, T.; Maegawa, Y.; Yoshiyama, A.; Mashima, K. J Am. Chem. Soc.
2008, 130, 2944. (b) Uesugi, S.; Li, Z.; Yazaki, R.; Ohshima, T. Angew. Chem. Int. Ed. 2014, 53, 1611.
5 Lin, L.; Shibuya, R.; Morimoto, H.; Ohshima, T. Manuscript in Preparation.
