catalytic heterocycle synthesis group 万伯顺 杂环合成中的 环加成与环化反应
DESCRIPTION
Why Iron? Iron (0.02 US$/mol) US$ per mol 2011 Iron(0) complex Organometallics, 1996, 15, 2713 Organometallics, 2002, 21, 2578 Iron(I) complex WanTRANSCRIPT
Catalytic Heterocycle Synthesis Group http://www.chs.dicp.ac.cn/
杂环合成中的环加成与环化反应
N[2 + 2 + 2]
R2
R1
R4
R3
NR5
Why Cycloadditon?
Advantages: Two C-C bonds & One C-N bond simultaneously High atom efficiency
Problems: Regioselectivity Chemoselectivity
D. Siegel et al, J. Am. Chem. Soc. 2010, 132, 5924.
N
N
NR'
NR'
H
Me
MeH
Complanadine A
NNR'
H
Me
SiR3
Desilylation
[2 + 2 + 2] cycloaddition
+
NR'
H
Me
CNNR'
H
Me
CN+
SiR3
SiR3
[2 + 2 + 2] cycloaddition
2
Why Iron?
Iron (0.02 US$/mol)
Oct/92
Oct/93
Oct/94
Oct/95
Oct/96
Oct/97
Oct/98
Oct/99
Oct/00
Oct/01
Oct/02
Oct/03
Oct/04
Oct/05
Oct/06
Oct/07
Oct/08
Oct/09
Oct/10
Oct/11
0
5000
10000
15000
20000
25000
30000
35000Pt (9357 US$/mol)Pd (2011 US$/mol)Rh (5468 US$/mol)Ir (6705 US$/mol)Ru (513 US$/mol)
US
$ pe
r mol
2011
1876Ramsay
HCN (g)
C2H2 (g) hot iron N
HH
HH
H 1996Zenneck
Iron(0) complexOrganometallics, 1996, 15, 2713
2002Guerchais
Organometallics, 2002, 21, 2578Iron(I) complex
Co, Ru, Rh, Ni, Ti, etc....
Wan
Cheap Nontoxic
Benign Abundant
Iron Catalytic System
C N
+
Fe
20 oC, 48~96 h NR1 R2
R1
+
TON(pyridine): TON(benzene) = 0.24~0.69
R2
CHC
R1
HCC
R1
Two regioisomers
R1
R1
R1
Two regioisomers
PSiMe3
FeNCCH3
NCCH3CH3CN
HC C
N
EtOOC
H3C COOEt
73% yield
2
SolventFe
NH3C
R
RR
Zenneck's Work: Organometallics 1996, 15, 2713
Guerchais's Work:
Organometallics 2002, 21, 2578.
Harsh reaction condition for the formation of iron complexLow chemoselectivity
R = COOEtSolvent = CH3CN
or
R = COOEt, CH2NMe2Solvent = CH2Cl2
R
L1 (5 mol%)Zn (10 mol%)
ZnI2 (10 mol%)
CH3CN, 50 C
RR
R
+
R
R R
11~94% yieldRatio of I:II : 58:42~>99:1
NN
Me
N
NMe
Me
Me
FeCl Cl
L1
Catal. Commun. 2011, 12, 489.Yang's Work:
I II
Holland’s investigation:
The binding affinity toward the low-valent iron:
Holland, P. L. et al. Inorg. Chem. 2006, 45, 5742.
Problems and Solutions
Ph > Et Et > Ph >Et
Et~ PPh3 > benzene
Low-valent Iron "P"R R
Low-valent Iron
R
R"P"
??
Simple iron salt
Phosphine ligands
Reductant
Low-valentiron species
[2 + 2 + 2] N
R2R1
R1
R1
R1
R1 R1
NR2
in situ
Step 1
Fe(L)nNR2
orOxidative Cyclization
Fe(L)nR1
R1
R1 R1 NR2
R1R1
R1R1
R1 R1
NR2
azaferracyclopentadiene ferracyclopentadiene
benzenes(byproduct)
chemoselectivity
Step 2
Step 3
Fe(0)/P
Problems and Solutions
Entry Iron salt Ligand Fe% Conv.(%) 3a%
1 FeCl3 - 20% 0 02 FeCl3 dppe 20% 99 973 FeCl3 dppp 20% 100 974 FeBr3 dppp 20% 99 895 FeBr2 dppp 20% 100 996 FeI2 dppp 20% 100 >997 FeCl3 dppp 10% 16 98 FeBr2 dppp 10% 75 689 FeI2 dppp 10% 100 >99
10 FeI2 dppp 5% 100 9911 FeI2 dppp 2.5% 13 6
MeO2C
MeO2C+ PhCN
x% Iron salt/L (1:2)N
PhMeO2C
MeO2C2x% Zn, THFRT, 24 h
1a 2a 3an = 2, dppen = 3, dpppPh2P PPh2n
NMeO2C
MeO2C
Ph
3a, 98% (94%)a
NMeO2C
MeO2C
3b, 96%
NMeO2C
MeO2C
3c, 62%
NMeO2C
MeO2C
CH3
3d, 91% (93%)b
NMeO2C
MeO2C
3e, 48%
NMeO2C
MeO2C
3f, 96%
NMeO2C
MeO2C
3g, 96%
PhN
MeO2C
MeO2C
3h, 66%
NMeO2C
MeO2C
3i, 49%
NMeO2C
MeO2C
3j, 43%
NN
R3
Ts
3k, R3 = Ph, 98%3l, R3 = Me, 93%
NO
Ph
3m, 98%
N
Et
Et
R3
3n, R3 = Ph, 95%3o, R3 = Me, 85%
ZR1
R2+
10 mol% FeI2/dppp (1:2)
N
R2
R1
ZR3
20 mol% Zn, THF, RT
1 3
R3 CN
2
a 5% catalyst b 5% catalyst, 20 equiv nitrile
10 equiv(unactivated)
Cycloaddition of Diynes and Unactivated Nitriles
Cycloaddition of Diynes and Unactivated Nitriles(Continued)
Cycloaddition of Tetrayne
NN
R3
Ts
3q, R3 = Ph, 69%3r, R3 = Me, 64%
NO
PhR3
3t, R3 = Ph, 65%3u, R3 = Me, 56%
NMeO2C
MeO2C
3p, 83%
NMeO2C
MeO2C
3s, 79%
NMeO2C
MeO2C
TMSR3
3v, R3 = Ph, 91%3w, R3 = Me, 83%
E
E E
E
10 mol%FeI2/2dppp/Zn
THF, rt+ PhCN
N
N
Ph
Ph
E
E
E
E
+N
PhE
E
E
E
(E = CO2Me)4 (85%)
10 equiv
5 (<5%)
All-intramolecular Cycloaddition
Cycloaddition of Alkynenitrile and Alkyne
E
E
N
E
E
10 mol%FeI2/2dppp/Zn
THF, rtN
E
E
EE
(E = CO2Me) 6 (72%)
N
Ph
PhN
+ PhTHF, 48 h N
Ph20 mol%
FeI2/2 dppp/Zn
(3 equiv)
+
7 (39%) 8 (trace)nPr TMSFor , no reaction.or
Control Experiments
Ph
10 mol%FeI2/2dppp/Zn
THF, rt, 48 h
Ph
Ph
Ph+
Ph
Ph
5 (55%) 6 (trace)
Ph(1)
Ph + CH3CN
10 mol%FeI2/2dppp/Zn
THF, rt
Ph
Ph
Ph Ph
Ph PhN
Ph
Ph
CH3
N
PhCH3
Ph
6 8
+ + +
5 748 hours: ND ND ND
96 hours:
8%
ND ND47%7%
(1/3 equiv)(2)
Ph + CH3CN(5 equiv)
N
Ph
Ph
CH3+
N
PhCH3
Ph
7 (60%) 8 (6%)
10 mol%FeI2/2dppp/Zn
THF, rt, 48 h
(3)
Fe(L)n
R'
R
ferracyclopentadieneintermediate
Fe(L)nNR'
R
azaferracyclopentadieneintermediate
TMSMeO2C
MeO2C
20 mol%FeI2/2dppp/Zn
rt, 24 h+ PhCN
N
MeO2C
MeO2C
TMS
NMeO2C
MeO2C
TMS
Ph
Ph
3v (58%)
(1 equiv)
8 (ND)
1b
More bulky
Less bulky
RL
RS
R CN[FeLn],
FeN
RL R
RS
Ln
Less bulkyFavorable
N
RL
RS
R
Observed56~91% yield
regioselectivity: >99:1
Zn
19
Pathway B
17
Z
Z
Z
or
FeN
RS R
RL
Ln
18
Z
N
RL
RS
R
Not Observed
Fe
RL
RS
Ln
[FeLn]
N
R
Zn
Fe
RL
RSLn
Fe
RL
RS
Ln
N
R
More bulkyLess favorable
Less favorableintermediate
R CN
R CN
13
14
15
16
Z
Z
Z
Pathway A
Z
Supposed to be favoredbut not observed
More bulkyLess favorable
Possible Pathways to Form Pyridines
With Wang, C. X. Angew. Chem. Int. Ed. 2011, 50, 7162
a 5 mol% catalyst, 5 equiv nitrileb 10 mol% catalyst, 2 equiv nitrile
XR1
R2+
x mol% FeI22x mol% dppp2x mol% Zn
THF, rt NX
R1
R2
NR3
R4N
NR4R3
N
NE
E
92%a (88%)b
N
NE
EE = CO2Me
82% (85%)
N
E
E
N
N
E
E
N
N
E
E
NPh
N
E
E
NO
N
E
E
N
NN
NBn
Bn
Ts
NN
N
86% (96%) 78% (95%)
76% (83%)
Ts
83% (91%) 40% (75%) 91% (99%)
98% (90%)
N
E
E
N
NN
NTs N
ON
N
NE
E
48% (67%)
N
PhNE
E
94%selectivity: 74/26
96% (95%) 81% (78%) 70% (73%)
N
N
(75%)
With Wang, C. X. J. Org. Chem. 2013, 78, 3065
[2+2+2] Cycloaddition in Pure Water
+N
R1
R1
R2
[2 + 2 + 2]cycloaddition
H2O
R2
R1 R1
R1
R1
N
Problems:
[M], Substrates
H2O
poor solubility
R2 N
R2 NH2
O
H2O hydrolysis
1) 2)
H2O/Organic Solventh or
water-soluble catalyst
water-soluble substrates
Previous Work: Our Work:
in situgenerated catalyst
pure water(no organic solvent)
+Solutions:
With Xu, F. ChemSusChem. 2012, 5, 854
[2+2+2] Cycloaddition in Pure Water
P
SO3Na
SO3Na
NaO3S
Up to 87%
XR1
R2+
N
R2
R1
XR
R CNCp*Ru(COD)Cl, tppts
H2O, 50 oC
X = C(CO2Me)2, NTs, O, CH2R1, R2 = H, MeR = CH2Cl, CH2Br, CHCl2
[2+2+2] Cycloaddition
H
NOH
RX
N
R
NX
R
NX
R
New Cycloaddition of Oximes and Diynes
Aldehyde
[Ru]
H
O
R
NH2OH
+Oxime
Catalyst
H2O
Reactivity of the C=N double bond Water generated from cycloadducts
Rearrangement of oximes into amides
New Cycloaddition of Oximes and Diynes
NR3
N R3N R3
OH
sp bondaddition
sp2 bondaddition - H2O
2)
higher energy
R3 H
NOH
XR1
R2+
R3 H
NOH
NX
R1
R2
R3
Challenges:R3 H
NOH
R3
HN H
O
1) [M]
+TsNN
TsNCO2Et
[Rh(NBD)2BF4]/L
80 C, 48 hN
EtO2C
OH
entry Rh (mol%) ligand yield (%)
1 5 BINAP 382 5 Segphos 543 5 MeO-Biphep 754 5 dppf trace5 10 dppe trace6 10 MeO-Biphep 96
PPh2
PPh2
BINAP
O
O
O
O
PPh2
PPh2
Segphos
PPh2
PPh2
MeOMeO
MeO-Biphep
Fe
PPh2
PPh2
PPh2
PPh2
dppe
dppf
New Cycloaddition of Oximes and Diynes
NR
R'
RhI
N
R'
R
R
HO
H
- H2OR
RhIII
R R
NRhIII
R' R
RHOHorN
RhIII
R'R
R
HOH
R
RhIN
OH
R'
R
R
R
R'
NOH
RhI
NHO
R'
R
R
R R
R
RR
R
R
R
R
R
RhIIINHO
R' R
RRhIIINHO
R' R
R
New Cycloaddition of Oximes and Diynes
XR1
R2+
R3 H
N OH
NX
R1
R2
R310 mol% Rh(NBD)2BF4/L
EtOHMeOMeO PPh2
PPh2
Up to 96% yieldKey Point
With Xu, F. Chem Eur J 2013, 19, 2252.
TsN +N
TsNPh
(4 equiv) 19% yield
PhCN
N
Ph
OH
PhCN<5% yield
+ dimer
N
R
OH - H2ONR
[2 + 2 + 2]N
R
Pathway A: Dehydration/Cycloaddition NO
Pathway B: Cycloaddition/Dehydration Yes
N
R
OH
[2 + 2 + 2]N
R
OH - H2O N
R
Nickel-catalyzed [3 + 2] cycloaddition of diynes with MAs
Chem. Commun. 2013, ASAP C3CC41061G
C-C bond cleavage
XRL
RS
NR N
R
RL X RS1,4-dioxane
rt
Ni(cod)2+
1
NR
2 3
CO
R'
O
NR
O
NR'
R
Alper's work
Yamamoto's workO
R'
R'O
N
O
NRN
Methyleneaziridine(MAs)
a
b
c
N-C bond cleavage
NR XRS
RL
NR
Me
XRS
RL
3
NR
XRS
RL
NR
XRS
RL
Ni
C
Ni (0)1+ 2
4
H
oxidative addition
reductive elimination
-carbon elimination
N
XRS
RL
Ni
B
N
XRL
RS
Ni
A orfavoredless favored
N
XRS
RL
Ni
D
RN
Me
X
RSRL
R
H
5 (not observed)
possible C-N cleavage process
RR
Proposed mechanism
CO2Me
CO2Me
R2N
R1
SO2R3
Building blocks
What ?
Synthesis of Pyrroles via Cyclization
R5XR3
R2
R1
R4
杂原子
叁键双键
电子 /空间调控基团
×Ph
Ph N CO2Me
CO2Me
Ts
×
N
CO2Me
CO2Me
Ph
Ph
O TsN CO2Me
CO2MePh
Ts
Ph
HDMF, Ar140 oC
Synthesis of Pyrroles via Cyclization
Ts = p-CH3PhSO2-
Synthesis of Pyrroles via Cyclization
With Xin, X. Y. Angew. Chem. Int. Ed. 2012, 51, 1693.
R2
R1 NSO2R3
CO2Me
CO2MeNH
CO2Me
CO2Me
R1
DMF
140 °C, 6 h
R3O2S
R2
"" Migration
up to 98%
"" MigrationN
CO2Me
CO2MeR1
H
R2
R3O2S
DMF, 80 C, 4 h
Cs2CO3 (10 mol%)
up to 97%
"α" Migration
R2
R1
CO2Me
CO2MeNSO OR3
N
CO2Me
CO2Me
R2
R1
SOR3
ON
CO2Me
CO2Me
R2
R1
S OOR3
N
CO2Me
CO2Me
S
R2
R1
OOR3
R2
R1 NSO2R3
CO2Me
CO2Me Aza-Claisen Rearrangement
NH
CO2Me
CO2Me
R2
R1
S OOR3Ion-Pair
Mechanism Study
"β" MigrationMechanism Study
R1 N CO2Me
CO2Me
S OOR3
HR2
SO
O
R3
N
CO2Me
CO2MeR1
R2
N CO2Me
CO2Me
R1
R2
SO
OR3
N
CO2Me
CO2MeR1
R2
S OOR3
R2
R1 NSO2R3
CO2Me
CO2Me
NH
CO2Me
CO2Me
R1
R2
SO
OR3
Ion-Pair
Base
H
R1 N CO2Me
CO2Me
S OOR3
R2 H Base
CO2MeN
TsPh
CO2MeH
F
N
CO2Me
CO2MePh
H
TsCs2CO3
DMF, 80 oC, 4 h
F
CO2MeNTs
Ph
CO2Me
F
Cs2CO3
94%DMF, 80 oC, 4 h
94%
Mechanism Study
Crossover Experiment
CO2MeNSO2Ph
Ph
CO2Me
F
CO2MeNSO2Tol
Ph
CO2Me
Br
DMF140 oC
N
CO2Me
CO2Me
Ph
PhO2S H
F
N
CO2Me
CO2Me
Ph
TolO2S HBr
41%
47%
N
CO2Me
CO2Me
Ph
PhO2S HBr
N
CO2Me
CO2Me
Ph
TolO2S H
F
46%
52%
Crossover Experiment
Competition Experiment
DMF, 80 oC
Cs2CO3 (10 mol%)
CO2MeNSO2Ph
Ph
CO2Me
Br
TolSO2Na+(1 equiv.) N
CO2Me
CO2Me
H
PhPhO2S
Br
N
CO2Me
CO2Me
H
Ph
Br
TolO2S
+
36% 59%
CO2MeNSO2Tol
Ph
CO2Me
Br
PhSO2Na+(1 equiv.) N
CO2Me
CO2Me
H
PhPhO2S
Br
N
CO2Me
CO2Me
H
Ph
Br
TolO2S+
36%60%
DMF, 80 oC
Cs2CO3 (10 mol%)
DMF, 80 oC
Cs2CO3 (10 mol%)CO2MeN
SO2Ph
Ph
CO2Me
F
CO2MeNSO2Tol
Ph
CO2Me
Br
N
CO2Me
CO2Me
H
Ph
F
N
CO2Me
CO2Me
H
Ph
Br
PhO2S
TolO2S
40%
47%
N
CO2Me
CO2Me
H
Ph
F
N
CO2Me
CO2Me
H
PhO2S
TolO2S
Br
Ph
43%
38%
Cyclization of Aza-enynes
Entry Catalyst Solvent 3a(%) 1 - DMF - 85
2 BPO (20) DMF 15 263 AIBN (20) DMF 29 434 NHPI (20) DMF 42 315 TEMPO (20) DMF - 666 Anthraquinone (20) DMF - 93
7 DDQ (20) DMF 84 - 8 DDQ (20) CCl4 80 -
9 DDQ (20) Benzene 85 -11 DDQ (10) THF 89 -12 DDQ (10) THF 92 -
N
CO2Me
CO2Me
Ph
Ph
Ts H
3a
O
OO
O
AIBN
NNH3C
NCH3C
CN
CH3CH3
NHPI
N
O
O
OH
TEMPO
NO
H3CH3C
CH3
CH3
Anthraquinone
O
O
BPO
ClCl
NC CN
OO
DDQ
CO2MeNTs
Ph
Ph
CO2Me
1a 2a
N
PhCO2Me
CO2MePhTs
Catalyst +
2a(%)
J. Org. Chem. 2013 ASAP jo400387b
Entry Catalyst Solvent Time(h)
2a%
1 DDQ-H2 THF 48 972 Hydroquinone THF 48 953 Phenol THF 48 744 H2O THF 48 875 MeOH (50) THF 48 936 MeOH
(solvent)MeOH 48 97
OHHO
Hydroquinone
ClCl
NC CN
OHHO
DDQ-H2
OH
Phenol
ClCl
NC CN
OO
DDQ
Cyclization of Aza-enynes
CO2MeNTs
Ph
Ph
CO2Me
1a 2a
N
PhCO2Me
CO2MePhTs
Catalyst
J. Org. Chem. 2013 ASAP jo400387b
N
CO2Me
CO2Me
Ph
Ts
R
EWG2NSO2R3
R2
R1
EWG1
N
R2
R1
SO2R3
EWG1
EWG2
1 2
MeOH 60 oC 48-120 h
(1) R = H, 2a (95%, 65%[c])(2) R = 2-Me, 2b (91%)(3) R = 3-Me, 2c (95%)(4) R = 4-Me, 2d (78%)(5) R = 2-CF3, 2e (81%)(6) R = 4-F, 2f (88%)(7) R = 2-Cl, 2g (87%)(8) R = 2-Br, 2h (86%)
N
CO2Me
CO2Me
Ph
Ts
(9) 2i, (72%)
N
CO2Me
CO2Me
Ph
Ts N
CO2Me
CO2Me
Ph
Ts(10) 2j[d], (97%)(11) 2k[e], (69%)
N
CO2Me
CO2MePhTs
R'(12) R' = 2-Me, 2l (94%)(13) R' = 3-Me, 2m (95%)(14) R' = 4-Me, 2n (93%)(15) R' = 4-MeO, 2o (73%)(16) R' = 4-F, 2p (88%)(17) R' = 4-Cl, 2q (87%)
N
CO2Me
CO2Me
nPr
PhTs
N
CO2Me
CO2Me
nBu
PhTs
N
CO2Me
CO2Me
Cy
PhTs
(18) 2r, (96%)
(19) 2s, (97%)
(20) 2t, (93%)
N
CO2Me
CO2Me
Ph
PhSO2Ph
N
CO2Me
CO2Me
Ph
PhO2S
Cl
N
CO2Et
CO2Et
Ph
PhTs
(21) 2u, (92%)
(22) 2v, (95%)(23) 2w, (94%)
2a-D
N
PhCO2Me
CO2MeTs
(a) 60 oC, 48h
DC6D5
(100 % D) (100 % D)CO2MeN
Ts
Ph
CO2Me
1a-D
DC6D5
H H12
345
6
123
45
6
60 oC, 48hMeOD
CO2MeNTs
Ph
Ph
CO2Me
1a 2a-D'
N
PhCO2Me
CO2MePhTs
D(96% D)
MeOH
(b)
2a
N
PhCO2Me
CO2MePhTs
H(c)
60 oC, 48h
MeOD
2a-D'
N
PhCO2Me
CO2MePhTs
D
Mechanism Study
R2
R1 NSO2R3
CO2Me
CO2Me
1
2
O HMe
N
R2
R1
SO2R3
CO2Me
CO2Me
H
A
B
R2
R1 NSO2R3
CO2Me
CO2MeO HMe
R1 NSO2R3
CO2Me
CO2Me
N
R2
R1
SO2R3
CO2Me
CO2Me
HH
O Me
C
HOMe
R2
Proposed Mechanism
J. Org. Chem. 2013 ASAP jo400387b
With Yu, X. Z. J. Org. Chem. 2013, jo4004635
Another example of cyclization with Ts migrationR1
R2 NTs
R3
O DBU
N
OR3
R2
R1
Ts
CH3CN, rt.
DABCO
R2 N
TsR3
O
R1
DCM, rt.
HDG
R
N
Ar
SO2R+
[Cp*RhCl2]2 (5 mol%)AgSbF6 (30 mol%)
PhCl, 100 oC
DG
R
NHSO2RAr
RhNN
O
Ph
SO
R
+
Via
25 examples
SbF6-
Xingwei Li,* Boshun Wan*, Angew. Chem. Int. Ed. 2013, 52, 2577
Other important finding
环加成与环化反应小结
六元环 : (1) JOC jo400387b (2) Unpublished results五元环 : ACIE, 2012, 51, 1693四元环 : Unpublished results三元环 : Unpublished results
R2
R1 NS
CO2R4
CO2R4
OOR3
R1 R1
NR2
N
R3
OH
N
R1
R1
R2R1
R1
[Ru][2]
in water
[Fe][1]
r.t.
[2+2+2]
[Rh][3]
[1] ACIE, 2011, 50, 7162.[2] CSC, 2012, 5, 854.
[3] CEJ, 2013,19, 2252