Download pdf - The Hexadehydro-Diels-Alder (HDDA) Reaction Hexadehydro-Diels-Alder Reaction Diels-Alder Didehydro-Diels-Alder Tetradehydro-Diels-Alder (TDDA) Hexadehydro-Diels-Alder (HDDA) Hoye,

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.

Test ResultsYes!

Unfortunately

Decision

Product!

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?


Proposed Mechanism

Retro-Brook Rearrangement


LUMO

HOMO

Benzyne

More electrophilic

Nucleophilic?

Electrophilic?

Rondan, N. G.; Domelsmith, L. N.; Houk, K. N.; Bowne, A. T.; Levin, R. H. Tetrahedron Lett 1979, 20, 3237-3240.

Frontier orbitals and energies (eV) by ab initio calculation on 4-31G basis set.6

The Hexadehydro-Diels-Alder Reaction

Diels-Alder

Didehydro-Diels-Alder

Tetradehydro-Diels-Alder (TDDA)

Hexadehydro-Diels-Alder (HDDA)


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

Walker, S.; Landovitz, R.; Ding, W. D.; Ellestad, G. A.; Kahne, D. P Natl Acad Sci USA 1992, 89, 4608-4612.

Bergman

Cyclization

9

Possible Mechanism

Only A is observed after the reaction

Bradley, A. Z.; Johnson, R. P. J Am Chem Soc 1997, 119, 9917-9918.

A B

Concerted

Pathway

Stepwise

Pathway

10

A Concerted or Stepwise Mechanism?

Ajaz, A.; Bradley, A. Z.; Burrell, R. C.; Li, W. H. H.; Daoust, K. J.; Bovee, L. B.; DiRico, K. J.; Johnson, R. P.

J Org Chem 2011, 76, 9320-9328.

0.5 kcal/mol

difference.

CCSD(T)//M05-2X energetics of diyne−yne cycloadditions.

Concerted

TS 1

36.5 kcal/mol

Stepwise

TS 2

37.0 kcal/mol

Stepwise

TS 3

35.8 kcal/mol

30.8 kcal/mol

-51.4 kcal/mol 0.0 kcal/mol

Concerted

Stepwise

2.78Å

2.24Å

1.81 Å

11

First Reported Triyne Cyclization

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.

Miyawaki, K.; Ueno, F.; Ueda, I. Heterocycles 2000, 54, 887.

Stepwise Mechanism ?

Or

12

Diradical Benzyne

Miyawaki, K.; Kawano, T.; Ueda, I. Tetrahedron Lett 1998, 39, 6923-692613

Mechanism Difference

Ueda’s Work Hoye’s Work

Mechanism: Radical pathway

Intermediate: Diradical benzene

Evidence: Cyclization with alkyne

Mechanism: 2 electron transfer

Intermediate: Benzyne

Evidence: Retro-Brook rearrangement

Alkane desaturation14

Solvent Role in HDDA Reaction

75%

Where do the 2 H come from?

Niu, D. W.; Willoughby, P. H.; Woods, B. P.; Baire, B.; Hoye, T. R. Nature 2013, 501, 531-534.15

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


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


Desaturation Requirements

Dominant Conformer

Cyclopentane

84 %

Cyclohexane

20 %


Desaturation Requirements

Cycloheptane

94 %

Cyclooctane

97 %

Niu, D. W.; Willoughby, P. H.; Woods, B. P.; Baire, B.; Hoye, T. R. Nature 2013, 501, 531-534.

Dihedral Angle Argument

20

HDDA Reaction Scope


HDDA Intramolecular Trapping

Diels-Alder Type Reaction

Ene Type Reaction


Aryne-ene Reaction

Niu, D.; Hoye, T. R. Nature chemistry 2014, 6, 34-40.23

Only Diels-Alder

Product, 83 %

2 Atom Spacer

Only Aromatic Ene

Product, 88 %


3 Atom Spacer

Only Diels-Alder

Product, 85 %

Niu, D.; Hoye, T. R. Nature chemistry 2014, 6, 34-40.

Spacer R Ene product yield D-A product yield

2 H N/A 83

2 Me 88 N/A

3 Me N/A 85

25

22

13.214.4

45.6

18.3

1310

20

30

40

50

1 2 3Spacer number

TS energy

kcal/mol

Or

Aromatic Ene

TS

Diels –Alder

TS

Calculation Summary


Energies in

kcal/mol

26

Rearrangement

No Reaction


Keto-enol Type Tautomerization

Possible ways:

27

Rearomatization

Can H2O catalyze the reaction?


Water Supported H Shift


Bimolecular Alder Ene Reaction

Single diastereomer

1) HDDA Reaction

2) Aromatic Ene Reaction

3) Alder Ene Reaction


Reaction Scope

X=O, N-PG

55 %~ 90 %

X=Y: O=C, TsN=C

63 %~ 85 %


HDDA Intermolecular Trapping

R=(CH2)3OAc

Benzene solvent

70%Norbornene

(0.1 M) 63%


HDDA Intermolecular Trapping

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

R=(CH2)3OAc


Trapping agent

(Nuc)

Yield (Ratio)

91%

(12.5:1)

80%

(3:1)

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 Regioselectivity

34

∠3=110°∠4=125°∠5=129°

∠3=118°∠4=112°∠5=137°

∠3=108°∠4=134°∠5=115°

C-5 Attack C-4 Attack

4,5-Indolyne Distortions

B3LYP/6-31G(d)-optimized structures.


ΔE ‡ = 3.5 kcal/mol

ΔH ‡ = -0.9 kcal/mol

ΔG‡ = 9.9 kcal/mol

ΔE‡ = 4.9 kcal/mol

ΔH ‡ = 1.6 kcal/mol


34

5

34

5

35

Trapping agent

(Nuc)

Yield (Ratio)

91%

C-6 Single

53%

C-6 Single

6,7-Indolyne Regioselectivity

Cheong, P. H.; Paton, R. S.; Bronner, S. M.; Im, G. Y.; Garg, N. K.; Houk, K. N. J Am Chem Soc 2010, 132, 1267-9.36

6,7-Indolyne Distortions

B3LYP/6-31G(d)-optimized structures.



ΔH‡ = 5.5 kcal/mol


7

6

37

Large C angle: More p character and a slight positive charge

+

Benzyne Distortions




B3LYP/6-31G(d)-optimized structures.38

θC-4 θC-5

125°

1

129°

3.3

θC-5 θC-6

129°

1.7

127°

1

θC-6 θC-7

135°

19

116°

1

θC-1 θC-2

122° 130°

θC-1 θC-2

128° 127°

θC-1 θC-2

130° 126°

Preferred side of attack.

lm, G. Y.; Bronner, S. M.; Goetz, A. E.; Paton, R. S.; Cheong, P. H.; Houk, K. N.; Garg, N. K.

J Am Chem Soc 2010, 132, 17933-44.

Preferred Site of Attack

Product ratio of Nuc= CN- , optimized geometries by B3LYP/6-31G(d)

39

θC-2 θC-3

119° 135°

θC-2 θC-3

134° 122°

Steric factors

Electronic factors Mixture

Preferred Site of Attack


J Am Chem Soc 2010, 132, 17933-44.

Aniline

2

1

40

Model Summary

1• Building the structure

2• Calculation work

3• Attack from large angel ( >4°)



J Am Chem Soc 2010, 132, 17933-44.

Procedure

41

∠a=135°∠b=119°

How to tune the regioselectivity of HDDA reaction?

Karmakar, R.; Yun, S. Y.; Wang, K. P.; Lee, D. Org Lett 2014, 16, 6-9.

HDDA Regioselectivity


4.8: 1

Single

major

Bu vs SiEt3


+

43

1.4:1major

Single

Steric Effect


+

44

1:1.8

9:1

major

Electronic Effect


+

+

major

45

Ways to Tune the Regioselectivity

• Electron donating groups

• Silicon effect

• Oxygen nucleophile attack.

• Building bulky R2 groups

• Nitrogen bulky nucleophile attack.

Karmakar, R.; Yun, S. Y.; Wang, K. P.; Lee, D. Org Lett 2014, 16, 6-9.46

Summary

The Hexadehydro Diels-Alder reaction:

• Alkane desaturation

• Intramolecular trapping: ene reaction

• Alter the regioselectivity of HDDA

reaction

• Distortion of the aryne

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.

48

Calculation based on Density Functional Theory (DFT, M062X18/6-31G(d)).

Calculation Study of 2 Atom Spacer

0.0 kcal/mol

TS-1

13.2 kcal/mol

TS-2

18.3 kcal/mol

-40.9 kcal/mol-46.7 kcal/mol

-83.8 kcal/mol

Aromatic Ene

Diels-Alder

n = 2


Calculation Study of 3 Atom Spacer

Aromatic Ene

Diels-Alder

0.0 kcal/mol

TS-3

14.4 kcal/mol

TS-4

13.0 kcal/mol

n = 3

Calculation based on Density Functional Theory (DFT, M062X18/6-31G(d)).
