M. Schmittel, J.-P. Steffen, M. E. Cinar
Universität Siegen, FB 8,
Adolf Reichwein Str. 2, D-57068 Siegen,
Tel. +49-271-740-4356,
e-mail:schmittel@chemie.uni-siegen.de
Universität Siegen
Mechanistic Studies of the Thermal C2-C6 Cyclization of
Enyne-Carbodiimides
Introduction:
The cyclization of enyne-carbodiimides,1 C2-C6 or C2-C7 depending
on the substituent at the alkyne termini, has a wide range of
applications, e.g. for the synthesis of 5-aza analogues of ellipticine,
an alkaloid and potent antitumor antibiotics, and also for the
production of pharmaceutically active indolo[2,3-b]quinoline.
R1
N
A
N
2
R2
7
C -C
Δ
H3C
2
N
C
N
N
R2
C -C
Δ
N
H3 C
C2-C6
Δ
N
R2
N
C
N
H3 C
C2-C6
Δ
R2
N
N
R2
Enyne-carbodiimides cyclize through either a biradical or a
carbene intermediate.
Hammet Correlation
►To get an idea about the character of the transition state,
qualitative correlation was done with the Hammet σ-values.
H3C
6
R1
R1
H3 C
R1
R1
H3C
Possible Mechanisms
R1
N
R2
y = -1,5747x + 0,2236
R2 = 0,868
log (k /k o) vs σ + Graph
B
4
3
Substituent X
2
log ( k /k o)
Our Goal:
To highlight the mechanism of the C2-C6 cyclization of enyecarbodiimides by studying the electronic effects of the substituent, at
the alkyne termini or at the carbodiimide termini, on the cyclization.
1
0
-2
-1,5
-1
-0,5
0
0,5
1
-1
-2
σ p+
y = -1,5932x + 0,6458
R2 = 0,8813
log (k /k o) vs σ p + Graph
5
4
3
Substituent Y
log ( k /k o)
Thermal Cyclization
Onset Temperatures and kinetic data of enyne-carbodiimide
cyclizations were obtained from solid state reactions (DSC) using
Eyring equation.
2
1
0
Entry
1
2
3
4
5a
6
7
8
9a
R1
Ph
4-NO2C6H4
4-CNC6H4
4-MeOC6H4
4-Me2NC6H
Ph
Ph
Ph
Ph
R2
Ph
Ph
Ph
Ph
Ph
4-NO2C6H4
4-CNC6H4
4-MeOC6H4
4-Me2NC6H4
Ea [kcal mol-1]
27.7
29.4
28.6
27.2
21.6
28.4
27.9
25.7
20.8
Tonset [°C]
97
126
110
73
35
115
111
64
18
k120 [10-3 s-1]
2.60
0.33
0.98
7.71
9.66 x 103
1.29
2.56
43.0
2.37 x 104
-2
krel =
Ea =
Me
N
N
X =H, Y =
krel =
Y
Ea =
OMe
3.72 x 103 2.96
21.57
27.24
NMe2
OMe
9.12 x 103 16.5
20.82
25.69
H
CN
NO2
1.00
0.38
0.13
27.72
28.68
29.49
H
CN
NO2
1.00
0.98
0.50
27.72
27.89
28.42
0,5
1
Proposed mechanism
These kinetic studies and Hammet correlations support a
carbenoide intermediate C, stabilized by electron donating groups.
ED
ED
NMe2
0
+
The best correlation was received with σp+ values, showing
that electron donating group stabilize the transition state but
electron withdrawing group destabilize it.2
ED
Me
Me
X=
-0,5
σp
Electronic Effects
X
-1
-1
[a] DSC data were obtained without purification.
Y =H,
-1,5
N
N
Me
N
ED
N
ED
N
ED
N
C
Conclusion:
The C2-C6 cyclization proceeds via singlet carbene intermediate,
which is stabilized by electron donating groups but destabilized by
electron withdrawing groups.
*Activation energies are in kcal mol-1.
Electron donating groups accelerate the rate of cyclization, in
contrast electron withdrawing groups impede it.
Acknowledgments:
We are greatly indebted to the Deutsche Forschungsgemeinschaft
for financial support and to the Fonds der Chemischen Industrie
for continued assistance.
References:
1)a) Schmittel, M.; Steffen, J.-P; Engels, B.; Lennartz, C.; Hanrath, M.
Angew. Chem., Int. Ed. 1998, 37, 2371-2373.b) b) Schmittel, M.; Steffen,
J.-P.; Wencesla Ángel, M. A.; Engels, B.; Lennartz, C.; Hanrath, M.
Angew. Chem., Int. Ed. 1998, 37, 1562-1564. c) Engels, B.; Lennartz, C.;
Hanrath, M.; Schmittel, M.; Strittmatter, M. Angew. Chem. Int. Ed. 1998,
37, 1960 - 1963; Angew. Chem. 1998, 110, 2067 - 2070. 2) Engels, B.;
Hanrath, M. J. Am. Chem. Soc. 1998, 120, 6356 - 6361.