Case Study:

(1)

Development of Complex Curricula for Molecular Bionics and Infobionics Programs within a consortial* framework**

Consortium leader

PETER PAZMANY CATHOLIC UNIVERSITY

Consortium members

SEMMELWEIS UNIVERSITY, DIALOG CAMPUS PUBLISHER

The Project has been realised with the support of the European Union and has been co-financed by the European Social Fund ***

**Molekuláris bionika és Infobionika Szakok tananyagának komplex fejlesztése konzorciumi keretben

PETER PAZMANY CATHOLIC UNIVERSITY SEMMELWEIS

UNIVERSITY

(2)

Compiled by dr. Péter Mátyus

with contribution by dr. Gábor Krajsovszky Formatted by dr. Balázs Balogh

Case Study:

How to explore the scope and limitation of an unexplored reaction

(Esettanulmány: hogyan derítsük fel egy ismeretlen reakció alkalmazhatósági körét és korlátait)

Organic and Biochemistry

(Szerves és Biokémia )

semmelweis-egyetem.hu

Organic and Biochemistry: Unexplored reaction case study

(3)

Outline

1. tert-Amino effect: types 2. Type 2 tert-amino effect:

with C=C: vinyl-tert-anilines and pyridazine analogues with C=O: aminobenzaldehydes

3. New types of tert-amino effect:

with biaryl systems with triaryl systems with peri-fused system

(4)

N(CH₃)₂

NH₂

N N

CH₃

N(CH₃)₂

NHAc

N

X

Y N

X Y

Pinnow et al. Chem. Ber., 27, 602 (1894)

Ac₂O

tert-Amino effect:

'Unusual' cyclization of a tert-aniline with ortho-X=Y group

The first synthetic example

e.g. X+Y: N=CH Generalization

Meth-Cohn and Suschitzky, 1972

(5)

(H₃C)₂N

NH₂

(H₃C)₂N

NH C O CH₃

(H₃C)₂N

N C CH₃

OAc

N N⁺ C H₃

C H₃

CH₃

N N

CH₃ C

H₃

OAc^- +CH₃OAc

Ac₂O Ac₂O

Mechanism proposal

(6)

tert-Amino effect: 6 types

by the size of the ring formed and/or by the mode of ring formation

Types 1-5: O. Meth-Cohn Adv. Heterocyclic Chem., 60, 1 (1996);

Type 6: V. Ojea et al. Synlett, 622, (2004);

X Y

N N

X Y

N X Y

N⁺ X

Y

N⁺

X Y

Type 1 Type 2 Type 3 Type 4

Type 5 Type 6

N X

Y X

(7)

Reviews, X+Y: vinyl:

Type 2 tert-amino effect: the 6-membered ring formation

Y X

N

X=Y: C=C, ring closure with C-C bond formation

L. C. Groenen et al. Tetrahedron, 44, 4637 (1988)

(8)

Reinhoudt et al.:

Carbo- and π-excessive heteroaromatics: Benzene, thiophene, benzothiophene vinyl: ββ-disubst.vinyl;

tert-amino: pyrrolidino, piperidino, morpholino stereo- and regiochemistry

Products: tetrahydropyrido-fused systems Mátyus et. al.:

π-deficient heteroaromatics; diazine vs. benzene

ββ-disubst.vinyl (in a ring); tert-amino (conf. restriction; buttressing) stereo- and regiochemistry

kinetics

thermochemistry reaction conditions

Products: tetrahydropyrido-fused systems; spiro-compounds

Type 2 tert-amino effect with X=Y vinyl

^X ^Y

N

(9)

N

NC CN

Ha Hb H

N⁺

C^-

NC CN

Ha Hb H

N⁺

C^- Hb Ha H

CN CN

N

Hb CN H CN Ha

A B C

Type 2 tert-amino effect X=Y: β,β-disubst.vinyl group

1,5-hydrogen migration followed by cyclization to 6-membered ring

L. C. Groenen et al. Tetrahedron, 44, 4637 (1988) Reviews

P. Mátyus et al. Synthesis, 16, 2625 (2006)

(10)

W. Verboom et al. Recl. Trav. Chim. Pay-Bas, 109, 311 (1990)

Type 2 tert-amino effect: regio- and stereochemical acpects

N

X

C R³

CN C NC

H R⁴

N⁺

X

C C(CN)₂

R⁴ R³

H

N

X

R⁴ CN

CN H R³

N

X

H CN

CN H R³ R⁴

H

N

X

R⁴ CN

CN R³ H

-

1,5-H

(11)

Reinhoudt et al.:

Carbo- and π-excessive heteroaromatics: Benzene, thiophene, benzothiophene vinyl: ββ-disubst.vinyl;

tert-amino: pyrrolidino, piperidino, morpholino stereo- and regiochemistry

Products: tetrahydropyrido-fused systems Mátyus et. al.:

π-deficient heteroaromatics; diazine vs. benzene

ββ-disubst.vinyl (in a ring); tert-amino (conf. restriction; buttressing) stereo- and regiochemistry

kinetics

thermochemistry

Type 2 tert-amino effect with X=Y vinyl

^X ^Y

N

(12)

- 9.82 - 9.58 - 9.60 - 9.37 - 8.91

- 1.49 - 1.06 - 0.89 - 0.48 - 0.12

The HOMO and LUMO energies (eV, AM1) of 3(2H)-pyridazinones

Cl C

H₃

Cl O

N N

C H₃

I O

N

N H₃C

O

N N

N C

H₃

O

N N C

H₃

O

N N

SO₂Et

(13)

N N

O C

H₃

I

N N

N

O C

H₃

O

CHO

N N C H₃

O

CHO

NR¹R²

N N

O C

H₃

NR¹R²

Synthesis of 5-(tert-amino)-4-pyridazinecarbaldehydes

i ii

iii

iv

Reaction conditions: (i) 1. morpholine, EtOH, rfx, 79% 2. POCl₃/DMF, 70 °C, 83%;

(ii) R¹R²NH;

R¹R²N = N(CH₃)₂, pyrrolidino

(14)

P. Mátyus et al.Heterocycles, 37, 171 (1994)

The first example of isomerization of tert-amino-ortho- vinyldiazine via tert-amino effect to tetrahydropyridodiazine

N N C H₃

O

N

CN CN N

N

N C

H₃

O

NC

CN N

N O

CHO

N C

H₃

DMSO 150 °C, 44h

35%

CN CN

EtOH, RT

80%

(15)

N N

O H₃C

N

CN CN

O

k (10^-4 sec^-1)

(DMSO) Ref.

Schwartz, Mátyus 150 ^oC

0.98

N

CN CN

O

0.19 90 ^oC Reinhoudt

Kinetics

(16)

a: X = morpholino, A = NCH₃, B = CO b: X = pyrrolidino, A = NCH₃, B = CO c: X = morpholino, A = O, B = C(CH₃)₂ a: X = CH₂O, A = NCH₃, B = CO

b: X = CH₂, A = NCH₃, B = CO c:X = CH₂O, A = O, B = C(CH₃)₂

Reaction conditions: (i) 1,3-dimethylbarbituric acid or Meldrum’s acid, toluene, AcOH, piperidine, rt, 45 min (a, b), 4 h, toluene, piperidine (c); (ii) xylene, AlCl₃, 150 °C, 8 h (a, b), DMF, 110 °C, 5 h (c)

The β-vinyl carbon incorporated into a ring: rate-increasing effect

N N C H₃

O

CHO

X

N N

X

A B A O

C H₃

O

N N

N X

B A A C

H₃

O O

O

i ii

A. Schwartz et al. J. Mol. Struct. (Theochem), 528, 49 (2000)

(17)

k (10^-4 sec^-1)

(DMSO, 90 °C) ΔH^# (kcal mol^-1)

ΔS^#

(cal mol^-1 K^-1)

N

CN CN

O

N

N N

O O

O CH₃

CH₃ O

0.19 n.d. n.d.

85 20.1±0.4 -13.3±0.5

Ref.

Reinhoudt et al.

Mátyus et al.

(18)

B. Halász-Dajka et al. 2008

Restriction of conformational flexibility of the tert.-amino group by buttressing: the rate of cyclization increases

N N C H₃

O

N(CH₃)₂

N N C H₃

O

N(CH₃)₂ CHO

N N C H₃

O

N(CH₃)₂ N N O CH₃

O

CH₃ O

N N

N

N N C

H₃

O

CH₃ O

CH₃ O CH₃ O

POCl₃/DMF 70 °C

100 °C DMF

DMB EtOH, rt

80%

85% 62%

(19)

N N

N

N N C

H₃

O

CH₃ O CH₃ O

X O N

N C H₃

O

N

X CHO

DMB ethanol, RT

X = CH₂, O X = CH₂ 82%

O 88%

(20)

N N

O H₃C

N

CN CN

O

N N

O H₃C

N

CN CN

O Ph

k (10^-4 sec^-1) (DMSO)

Ref.

Schwartz, Mátyus

Dajka, Mátyus 150 ^oC

100 ^oC 0.98

2.51

(21)

O

N OH CH₂

O N OH

H CH₂

O N

H O

O

CH₂ H₃CO

Δ

No cycloaddition (1,4-Claisen rearrangement occurs)

cycloaddition Δ

100%

Examples for the role of buttressing

(22)

N N

N X

X

Ph O

C H₃ N

N

N X O X

C H₃

N N

N X O X

C H₃

The conformational flexibility of the tert-amino group II:

The tert-amino nitrogen is in a fused ring

(23)

N N

N O

O C

H₃

R¹

R² O

( )_n

N N

N O

O C

H₃

N N

O

CH₃ C

H₃ O

R¹

R² ( )_n

( )_n N

N

N O

O C

H₃

R¹

R² N N

O

CH₃ C

H₃ O

i ii

R¹ R² n

a: H H 1

b: H H 2

c: Ph H 1

d: Ph H 2

e: –(CH ) – 1

Yield 95%

70%

82%

90%

81%

a-f a-f a-f

Reaction conditions: (i) 1,3-dimethylbarbituric acid, ethanol, 25 °C; (ii) for b-dand f: DMSO, 150 °C, for e: neat, 250 °C *.

Yield Time (h)

– –

93% 1

52% 3

56% 3

46% *

(24)

C_p - C_β H_m - C_α

X-ray 3.06 2.62

X-ray 3.24 2.60

X-ray 3.19 2.62

X-ray 3.29 2.60

X-ray 3.10 2.71

C_p - C_β and H_m- C_α distances in vinyl compounds

N N

N C

H₃ O

N N

O O

O

CH₃ C H₃

H_m C_α

C_β

C_p

N N

N O C H₃

O

Ph N

N

O O

O

CH₃ C H₃

N N C H3

O N

N

O O

O

CH3 C H3

N O

Ph

N N C H₃

O N

N

O O

O

CH₃ C H₃

N O

N N C H₃

O N

N

O O

O

CH₃ C H₃

N O

A^o

(25)

N N Me

O

CN CN

N

O

N N Me

O

N

O CN CN

μW

Solvent-phase reactions Solvent-free reactions

Heating Solvent °C/time Yield Heating °C/time Yield

Δ DMSO 150/44 h 35%

Δ 200/18 min 57%

Δ 200/20 min 78%

μW DMSO 210/42 min 29%

μW 200/18 min 75%

Optimization of reaction conditions

(26)

Reaction condition: (i) pyrrolidine, K₂CO₃, H₂O, μW, 130 °C, 3 min;

(ii) CH₂(CN)₂, H₂O, μW, 100 °C, 10 min, then 1 drop of TFA, 200 °C, 3 min

Green preparation:

S

_N

Ar – Knoevenagel condensation – cyclcization via tert-amino effect in one pot, in water in 0.3 h

N. Kaval et al. Green Chem., 6, 125 (2004)

CHO

F

CHO

N N

CN CN

50%

i ii

(27)

CHO N

1a

N

O OH

N

2a 3a

Entry Activation mode Conditions Product (yield, %)

1 MW H₂O, K₂CO₃(1 equiv), 90 W, 200 °C, 60 min 2a(41%), 1a(28%)

2 Δ H₂O, K₂CO₃(1 equiv), 200 °C, 60 min -

3 MW n-BuOH, K₂CO₃(1 equiv), 300 W, 200 °C, 60 min 3a

4 MW n-BuOH, 300 W, 250 °C, 60 min -

5 MW H₂O, 300 W, 194 °C, 60 min -

6 MW Neat, 300 W, 200 °C, 60 min -

7 MW Toluene, AlCl₃(cat), 300 W, 200 °C, 30 min -

8 MW H₂O, TFA (1 equiv), 150 W, 200 °C, 30 min -

9 MW Silica, 100 W, 200 °C, 60 min 2a(17%)

10 MW D₂O, K₂CO₃(1 equiv), 90 W, 200 °C, 60 min 2a(41%)

11 MW Al₂O₃-KF (3:1), 100 W, 200 °C, 60 min 2a(42%)

(28)

N

COCF₃

N O

COCF₃

CF₃ H

N X

COCF₃

N O

CF₃ H X

H⁺ H⁺

X = −, CH₂

W. Verboom et al. J. Org. Chem., 1982, 3339

Type 2 tert-amino effect: X=Y is C=O

T. Lett., 1988, 4599

(29)

New types of tert-amino effect:

Attachement of the amino and vinyl substituents to different rings

(30)

N

Ring closure exothermic (DFT//RB3LYP//6-31(D))

(31)

Br

NH₂

Br

N

CHO

( )_n N

N CH₃

CH₃

B(OH)₂

N CH₃

CH₃

N CH₃

CH₃ CHO

( )n

i ii

iii iv

(n=1) 80%

(n=2) 81%

(n=1) 90%

(n=2) 68%

37% 67%

Reaction conditions: (i) Br(CH ) Br,i-Pr EtN, toluene, 110 °C, 15h

n = 1,2

Synthesis of diphenyl aldehydes

(32)

CHO N

R R

CN CN

N R R malononitrile

EtOH, rt, 24h

N R R

: pyrrolidino, dimethylamino

95%

68%

(33)

CN CN

N

(34)

N CH₂ C H

CH

X-ray

N-CH: 2.878 Å CH₂-CH: 3.151 Å

N CH₃ CH₃ C H

CH

DFT//RB3LYP/6-31G(D) N-CH: 2.927 Å

CH₃-CH: 3.577 Å

(35)

N

A A

R R CHO

N R R

: pyrrolidino, dimethylamino indan-1,3-dione

or dimethybarbituric acid EtOH, rt , 24h

(36)

N⁺ N

N O

O^- O C

H₃

CH₃

CH₃ CH₃

(37)

N⁺ N

N O

O^- O C

H₃

CH₃

(38)

N

CH₃ CON₃ CH₃ CH₃

N⁺ N C CH₃ CH₃

CH₃

O C₆H₆ Δ -

81%

Type 4 tert-amino effect: Reaction of X=Y with the nitrogen atom

(39)

CN NC

N R²

R¹

N R²

R¹ CN CN DMSO, Ar

110 ºC R¹+R² = (CH₂)₃ 94%

160 ºC R¹= H, R² = CH₃23%

(40)

N CN

CN

(41)

Mechanism proposal I for dibenzo-fused derivatives

C^- N

N O CH₃

O

CH₃ N⁺ O

N

N O CH₃

O

CH₃ N O

[1,7] H C^-

N

N O CH₃

O

CH₃ N⁺ O

1 2 3

4

5 6 7

N

N O

O

O CH₃

CH₃

(42)

N⁺

N O N

O^- O C

H₃

CH₃ N

N O CH₃

O

CH₃ N O

H H

C^- N

N O CH₃

O

CH₃ N⁺ O

H

N

N O

O

O CH₃

CH₃ CHO

N

Mechanism proposal II for formation of 8-member system via two new types (7, 8) of tert-amio effect

DMB

(43)

i

Reaction condition: (i) μW, neat, 300 W, 100 ºC, 30 min, Ar atm.

23 % 35 %

i

N

CN CN

N

CN CN

+ N

(44)

N

CN CN

N NC CN

N

CN

+ CN

(45)

malononitrile EtOH, piperidine, rt, 24h

87%

96%

: pyrrolidino, dimethylamino

N N

CHO N

R R

C H₃

O

N N

N R R

C H₃

O

CN CN

N R R

(46)

38%

39%

DMSO, 160 ºC Ar, 24h

DMSO, 160 ºC Ar, 96h

N N C

H₃ O

CN CN

N N

CN CN

N N O

C H₃

N N

N CH₃ CH₃

C H₃

O

CN CN

N N

N O

C H₃

(47)

MeOH

N N

N

CN CN O

C H₃

(48)

First step: Buchwald SL, WO2004052939 (2004)

70% 71%

Synthesis of triphenyl aldehyde

I

Br

N CH₃

CH₃ B(OH)₂

Br N CH₃ C H₃

N CH₃ C H₃

OHC

B(OH)₂ CHO

Pd(PPh₃)₄, DME, 2M Na₂CO₃, rfx

Pd(PPh₃)₄, DME 2M Na₂CO₃, rfx

(49)

Isomerization of triphenyl derivative:

formation of a new tribenzazecine system

92% 70%

X-ray

OHC

N C H₃

CH₃

CN CN EtOH, RT

N C H₃

CH₃ NC

NC

μW, neat 200 W, 200 °C, 3h

N CH₃

CN CN

(50)

Naphtalene derivative:

formation of ortho- and peri-fused azepine system

98% 81%

N CH₃ C

H₃

CHO

CN CN

EtOH, RT

N CH₃ C

H₃

CN CN

80 °C, 12h DMSO

N

CN CN C

H₃

(51)

N CN NC

CH₃ N

C H₃ NC

CN

CH₃

(52)

N CN NC ^N

CN NC

(53)

X N Me

Me N X

Me Me

O NiPr₂

N Me Me

O NMe₂

N Me Me

O OMe

X N Me Me

O CH₃

N Me Me

H NC CO₂Me

N Me Me

H NC CN

N Me

Me H

O O O O

+

-

N N Me Me

Me

Me Me O O Me

1 X = sp²C 2 3 4 5

6 7 8 9 10

X Compound Me₂N-X distance/Å MeO-X distance in corresponding methoxynaphthalene/Å

CON(iPr)₂ 2 2.764(3) 2.623(2)

CH=CHBr 2.717(5)-2.758(2) ^―

CONMe₂ 3 2.698(3) 2.597(5)

CH=C(COPh)₂ 2.679(2) ―

CO₂H 2.606(5) 2.559(4)

CO₂Me 4 2.594(4) 2.588(3)

COMe 5 2.557(3) 2.606(9)

CH=C(CN)CO Et 6 2.531(2) ―

(54)

N Me

Me H O

N Me

Me H

NO₂

COPh

N Me

Me COPh

NO₂

+ -

PhCOCH₂NO₂

J. O’Leary, Org. Biomol. Chem. 3, 3273 (2005)

(55)

C N H₃

H NO₂

COPh H₃C N

O₂N COPh

C N H₃

O₂N

COPh

DMSO Δ

+ -

..

(56)

Solvent Reaction condition Reaction time (h) Yield (%)

i DMSO 100 °C 5 81

ii DMSO 100 °C, 105 W, µW 0.7 80

iii - 180 °C 2 67

iv - 180 °C, 105 W, µW 0.7 60

i-iv EtOH, RT

DMB

N⁺ CH₃ CH₃ N

N

O C H₃

O CH₃ O^-

N CH₃ C

H₃ N

N

O C

H₃ O

CH₃ OHC N O

CH₃ C

H₃

N CH₃ N

N

O C H₃

O CH₃

O

(57)

N⁺ CH₃

CH₃ C

H₃ N

O N

O CH₃

O^-

N⁺ CH₃

CH₃ C

H₃ N

O N

O CH₃

O^-

(58)

N N N O C H₃

O CH₃

O

(59)

Kinetic isotope effect

Conclusion

1. No deuterium is lost, the migration is intramolecular process

2. The magnitudes of k_H/k_D indicates that migration of a hydrogen takes place

73% 67%

DMSO-d₆ 100 °C, 3.5 h

N H3C

NC CN D

D

H D NH2

CN CN N

D3C CD3

k_H/k_D= 2.85 (CD₃)₂SO₄

(60)

Reaction conditions

solvent reaction condition reaction time (h) yield (%)₁ yield (%)₂

1. DMSO 60 ^oC 23.5 85 -

2. DMSO 100 ^oC 2.5 81 -

3. DMSO 100 ^oC, 105 W, MW 0.17 81 -

4. neat 160 ^oC 3 61 -

5. neat 160 ^oC, 106 W 0.3 80 -

6. H₂O MW, 40 W, 100 ^oC 3.5 31 67 7. D₂O MW, 40 W, 100 ^oC 6 39 59

N H3C

NC CN CN

CN N

H3C CH3

N H3C

CN NH₂ O

+

(61)

Mechanism proposal

for formation of ortho- and peri-fused azepine

98%

81% EtOH, RT

DMSO

DMSO 80 °C

80 °C

N CH₃ C

H₃

CHO CN

CN

N

CN CN C

H₃ N

C H H₃

CN CN

N⁺

C^- C

H₃

NC CN

(62)

Summary

1. tert-Amino effect with the involvement of a vinyl group may operate in mono-, bi- and triaryl systems to afford polycyclic systems with 6-10-member aza- rings

2. The reaction involves intramolecular hydrogen migration with 1,n-sigmatropic hydrogen and/or hydride migration.

3. Biological activity

4. tert-Amino effect in the nature; self-organization?