The Hexadehydro-Diels-Alder (HDDA) Reaction Hexadehydro-Diels-Alder Reaction Diels-Alder Didehydro-Diels-Alder…

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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?

Hoye, T. R.; Baire, B.; Niu, D. W.; Willoughby, P. H.; Woods, B. P. Nature 2012, 490, 208-212.4

Proposed Mechanism

Retro-Brook Rearrangement

Hoye, T. R.; Baire, B.; Niu, D. W.; Willoughby, P. H.; Woods, B. P. Nature 2012, 490, 208-212.5

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)

Hoye, T. R.; Baire, B.; Niu, D. W.; Willoughby, P. H.; Woods, B. P. Nature 2012, 490, 208-212.7

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 1

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 diyneyne 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

2.78

2.24

1.81

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

Uedas Work Hoyes 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

Niu, D. W.; Willoughby, P. H.; Woods, B. P.; Baire, B.; Hoye, T. R. Nature 2013, 501, 531-534.17

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

Niu, D. W.; Willoughby, P. H.; Woods, B. P.; Baire, B.; Hoye, T. R. Nature 2013, 501, 531-534.18

Desaturation Requirements

Dominant Conformer

Cyclopentane

84 %

Cyclohexane

20 %

Niu, D. W.; Willoughby, P. H.; Woods, B. P.; Baire, B.; Hoye, T. R. Nature 2013, 501, 531-534.19

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

Hoye, T. R.; Baire, B.; Niu, D. W.; Willoughby, P. H.; Woods, B. P. Nature 2012, 490, 208-212.21

HDDA Intramolecular Trapping

Diels-Alder Type Reaction

Ene Type Reaction

Hoye, T. R.; Baire, B.; Niu, D. W.; Willoughby, P. H.; Woods, B. P. Nature 2012, 490, 208-212.22

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 %

Niu, D.; Hoye, T. R. Nature chemistry 2014, 6, 34-40.24

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

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

Energies in

kcal/mol

26

Rearrangement

No Reaction

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

Keto-enol Type Tautomerization

Possible ways:

27

Rearomatization

Can H2O catalyze the reaction?

Niu, D.; Hoye, T. R. Nature chemistry 2014, 6, 34-40.28

Water Supported H Shift

Niu, D.; Hoye, T. R. Nature chemistry 2014, 6, 34-40.29

Bimolecular Alder Ene Reaction

Single diastereomer

1) HDDA Reaction

2) Aromatic Ene Reaction

3) Alder Ene Reaction

Niu, D.; Hoye, T. R. Nature chemistry 2014, 6, 34-40.30

Reaction Scope

X=O, N-PG

55 %~ 90 %

X=Y: O=C, TsN=C

63 %~ 85 %

Niu, D.; Hoye, T. R. Nature chemistry 2014, 6, 34-40.31

HDDA Intermolecular Trapping

R=(CH2)3OAc

Benzene solvent

70%Norbornene

(0.1 M) 63%

Hoye, T. R.; Baire, B.; Niu, D. W.; Willoughby, P. H.; Woods, B. P. Nature 2012, 490, 208-212.32

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

Hoye, T. R.; Baire, B.; Niu, D. W.; Willoughby, P. H.; Woods, B. P. Nature 2012, 490, 208-212.33

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=1104=1255=129

3=1184=1125=137

3=1084=1345=115

C-5 Attack C-4 Attack

4,5-Indolyne Distortions

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

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.

E = 3.5 kcal/molH = -0.9 kcal/molG = 9.9 kcal/mol

E = 4.9 kcal/molH = 1.6 kcal/molG = 12.9 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.

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.

E = 8.8 kcal/molH = 5.5 kcal/molG = 18.4 kcal/mol

7

6

37

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

+

Benzyne Distortions

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.

E = 4.0 kcal/molG = 9.1 kcal/mol

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

C-4 C-5

125

1

129

3.3

C-5 C-6

129

1.7

127

1

C-6 C-7

135

19

116

1

C-1 C-2

122 130

C-1 C-2

128 127

C-1 C-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

C-2 C-3

119 135

C-2 C-3

134 122

Steric factors

Electroni

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