The Hexadehydro-Diels-Alder (HDDA) Reaction

Transcription

The HexaDehydro-Diels-Alder
(HDDA) Reaction
CEM 958 Organic Seminar
Jun Zhang
Michigan State University
January 22, 2014
1
One Day in the Lab
Several hours later.
Product!
Yes!
Test Results
Unfortunately
Decision
Surprising!
Analysis
Redo it
2
Unexpected Result
Intermediate
?
53%
Hoye, T. R.; Baire, B.; Niu, D. W.; Willoughby, P. H.; Woods, B. P. Nature 2012, 490, 208-212.
3
Proposed Intermediate
Benzyne intermediate?
4
Proposed Mechanism
Retro-Brook Rearrangement
5
Benzyne
Nucleophilic?
Electrophilic?
LUMO
More electrophilic
HOMO
Frontier orbitals and energies (eV) by ab initio calculation on 4-31G basis set.
6
Rondan, N. G.; Domelsmith, L. N.; Houk, K. N.; Bowne, A. T.; Levin, R. H. Tetrahedron Lett 1979, 20, 3237-3240.
The Hexadehydro-Diels-Alder Reaction
Hexadehydro-Diels-Alder (HDDA)
Diels-Alder
Didehydro-Diels-Alder
Tetradehydro-Diels-Alder (TDDA)
7
First Reported Triyne Cyclization
Stepwise or Concerted Mechanism ?
Bergman Stepwise Cyclization ?
Bradley, A. Z.; Johnson, R. P. J Am Chem Soc 1997, 119, 9917-9918.
8
Bergman Cyclization
Calicheamicin ϒ1
Bergman
Cyclization
9
Walker, S.; Landovitz, R.; Ding, W. D.; Ellestad, G. A.; Kahne, D. P Natl Acad Sci USA 1992, 89, 4608-4612.
Possible Mechanism
Stepwise
Pathway
Concerted
Pathway
A
B
Only A is observed after the reaction
Bradley, A. Z.; Johnson, R. P. J Am Chem Soc 1997, 119, 9917-9918.
10
A Concerted or Stepwise Mechanism?
Concerted
2.24Å
0.0 kcal/mol
Stepwise
0.5 kcal/mol
difference.
Concerted
TS 1
36.5 kcal/mol
-51.4 kcal/mol
2.78Å
1.81 Å
Stepwise
TS 2
37.0 kcal/mol
30.8 kcal/mol
Stepwise
TS 3
35.8 kcal/mol
CCSD(T)//M05-2X energetics of diyne−yne cycloadditions.
Ajaz, A.; Bradley, A. Z.; Burrell, R. C.; Li, W. H. H.; Daoust, K. J.; Bovee, L. B.; DiRico, K. J.; Johnson, R. P.
11
J Org Chem 2011, 76, 9320-9328.
First Reported Triyne Cyclization
Or
Stepwise Mechanism ?
Miyawaki, K.; Suzuki, R.; Kawano, T.; Ueda, I. Tetrahedron Lett 1997, 38, 3943-3946.
Ueda, I.; Sakurai, Y.; Kawano, T.; Wada, Y.; Futai, M. Tetrahedron Lett 1999, 40, 319-322.
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Miyawaki, K.; Ueno, F.; Ueda, I. Heterocycles 2000, 54, 887.
Diradical Benzyne
Miyawaki, K.; Kawano, T.; Ueda, I. Tetrahedron Lett 1998, 39, 6923-6926
13
Mechanism Difference
Ueda’s Work
Mechanism:
Radical pathway
Hoye’s Work
Mechanism: 2 electron transfer
Intermediate: Diradical benzene
Intermediate: Benzyne
Evidence: Cyclization with alkyne
Evidence: Retro-Brook rearrangement
Alkane desaturation
14
Solvent Role in HDDA Reaction
75%
Where do the 2 H come from?
15
Niu, D. W.; Willoughby, P. H.; Woods, B. P.; Baire, B.; Hoye, T. R. Nature 2013, 501, 531-534.
THF Desaturation
H-Product
Deuterated-Product
Solvent
Product ratio (H : D)
THF-h8
100:0
THF-d8
0:100
THF-h8 : THF-d8 (1:1)
6:1
THF-h8 : THF-d8 (1:6)
1:1
No mono-deuterated product is observed.
16
Alkane Desaturation
Benzyne
intermediate
17
2H Donor
Entry
2H donor
Product Yield (%)
1
Cyclooctane
97
2
Cycloheptane
94
3
Cyclopentane
84
4
Norbornane
86
5
Cyclohexane
20
6
THF
60
7
1,4-Dioxane
0
18
Desaturation Requirements
Dominant Conformer
Cyclopentane
84 %
Cyclohexane
20 %
19
Desaturation Requirements
Cycloheptane
94 %
Cyclooctane
97 %
Dihedral Angle Argument
20
HDDA Reaction Scope
21
HDDA Intramolecular Trapping
Ene Type Reaction
Diels-Alder Type Reaction
22
Aryne-ene Reaction
Niu, D.; Hoye, T. R. Nature chemistry 2014, 6, 34-40.
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2 Atom Spacer
Only Diels-Alder
Product, 83 %
Only Aromatic Ene
Product, 88 %
24
3 Atom Spacer
Only Diels-Alder
Product, 85 %
Spacer
R
Ene product yield
D-A product yield
2
H
N/A
83
2
Me
88
N/A
3
Me
N/A
85
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Calculation Summary
Or
TS energy 50
kcal/mol
45.6
Diels –Alder
TS
40
Aromatic Ene
TS
30
Energies in
kcal/mol
22
20
18.3
13.2
10
1
2
14.4
13
3
Spacer number
26
Rearrangement
Possible ways:
No Reaction
Keto-enol Type Tautomerization
27
Rearomatization
Can H2O catalyze the reaction?
28
Water Supported H Shift
29
Bimolecular Alder Ene Reaction
1) HDDA Reaction
2) Aromatic Ene Reaction
3) Alder Ene Reaction
Single diastereomer
30
Reaction Scope
X=O, N-PG
55 %~ 90 %
X=Y: O=C, TsN=C
63 %~ 85 %
31
HDDA Intermolecular Trapping
R=(CH2)3OAc
Benzene solvent
70%
Norbornene
(0.1 M) 63%
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HDDA Intermolecular Trapping
R=(CH2)3OAc
PhNHAc (0.15 M) 82%
19:1 ratio of isomers
Acetic acid (0.8 M) 89%
Single isomer
Phenol (0.1 M), 85%
Single isomer
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4,5-Indolyne Regioselectivity
Trapping agent
(Nuc)
Yield (Ratio)
91%
(12.5:1)
80%
(3:1)
34
Cheong, P. H.; Paton, R. S.; Bronner, S. M.; Im, G. Y.; Garg, N. K.; Houk, K. N. J Am Chem Soc 2010, 132, 1267-9.
4,5-Indolyne Distortions
∠3=110°
∠4=125°
∠5=129°
C-5 Attack
4
C-4 Attack
3
5
4
3
5
∠3=118°
∠4=112°
∠5=137°
ΔE ‡ = 3.5 kcal/mol
ΔH ‡ = -0.9 kcal/mol
ΔG‡ = 9.9 kcal/mol
∠3=108°
∠4=134°
∠5=115°
ΔE‡ = 4.9 kcal/mol
ΔH ‡ = 1.6 kcal/mol
B3LYP/6-31G(d)-optimized structures.
35
6,7-Indolyne Regioselectivity
Trapping agent
(Nuc)
Yield (Ratio)
91%
C-6 Single
53%
C-6 Single
36
6,7-Indolyne Distortions
6
7
ΔH‡ = 5.5 kcal/mol
37
Benzyne Distortions
+
Large C angle: More p character and a slight positive charge
38
Preferred Site of Attack
θC-4 θC-5
θC-5 θC-6
θC-6 θC-7
125° 129°
1
3.3
129° 127°
1.7
1
135° 116°
19
1
θC-1 θC-2
θC-1 θC-2
θC-1 θC-2
122° 130°
128° 127°
130° 126°
Preferred side of attack.
Product ratio of Nuc= CN- , optimized geometries by B3LYP/6-31G(d)
lm, G. Y.; Bronner, S. M.; Goetz, A. E.; Paton, R. S.; Cheong, P. H.; Houk, K. N.; Garg, N. K. 39
J Am Chem Soc 2010, 132, 17933-44.
Preferred Site of Attack
θC-2
θC-3
119° 135°
2
Aniline
Electronic factors
θC-2
Mixture
θC-3
1
134° 122°
Steric factors
J Am Chem Soc 2010, 132, 17933-44.
Model Summary
1
Procedure
2
3
• Building the structure
• Calculation work
• Attack from large angel ( >4°)
J Am Chem Soc 2010, 132, 17933-44.
HDDA Regioselectivity
∠a=135°
∠b=119°
How to tune the regioselectivity of HDDA reaction?
42
Karmakar, R.; Yun, S. Y.; Wang, K. P.; Lee, D. Org Lett 2014, 16, 6-9.
Bu vs SiEt3
+
major
4.8: 1
Single
43
Steric Effect
+
major
1.4:1
Single
44
Electronic Effect
+
1:1.8
major
+
major
9:1
45
Ways to Tune the Regioselectivity
•
•
•
•
•
Electron donating groups
Silicon effect
Oxygen nucleophile attack.
Building bulky R2 groups
Nitrogen bulky nucleophile attack.
46
Summary
The Hexadehydro Diels-Alder reaction:
•
Alkane desaturation
• Intramolecular trapping: ene reaction
• Distortion of the aryne
•
Alter the regioselectivity of HDDA
reaction
47
Acknowledgements
Dr. Babak Borhan
Dr. Xuefei Huang
Dr. Chrysoula Vasileiou
All my group members: Ipek, Bardia, Kumar, Nastaran,
Ding, Wei, Hadi, Liz, Yi, Edy, Arvind, Tanya, Calvin,
Carmin.
Liz, Ding, Xiaopeng
All my friends.
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Calculation Study of 2 Atom Spacer
Diels-Alder
Aromatic Ene
TS-2
18.3 kcal/mol
TS-1
13.2 kcal/mol
0.0 kcal/mol
-40.9 kcal/mol
-46.7 kcal/mol
n=2
-83.8 kcal/mol
Calculation based on Density Functional Theory (DFT, M062X18/6-31G(d)).
49
Calculation Study of 3 Atom Spacer
Aromatic Ene
Diels-Alder
TS-3
14.4 kcal/mol
TS-4
13.0 kcal/mol
0.0 kcal/mol
n=3
Calculation based on Density Functional Theory (DFT, M062X18/6-31G(d)).
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The Hexadehydro-Diels-Alder (HDDA) Reaction

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