4
Tetrahedron Letters
Scheme 2. Possible reaction mechanisms.
Pathway A: urea coupling
Pathway B: N-acylurea coupling
O
I
O
O
I
O
O
O
Cu(i)
R
R
R
N C N R
elimination
R
rearrangement
N
O
OH
O
Cu(I)
N
R
N
H
N
H
I
I
I
HN
R
N-acylurea intermediate
amide byproduct
oxidative
addition
Cu(I)
O
O
(III)
Cu
O
O
R
R
N
N
O
(III) N
Cu
I
O
N
R
O
condensation
R
R
R
N
N
I
H
H
quinazolinedione
O
O
reductive C-N
bond formation
O
(III)
OH
Cu
R
N
N
R
Cu(I)
O
O
NH
R
HN
R
acylurea intermediate
This work was supported partly by the Development and
Promotion of Science and Technology Project (DPST) (grant
no. 012/2558) and Thailand Research Fund (MRG6180298).
Further support was generously provided by Faculty of
Science, Prince of Songkla University for Ms. Duangjan as a
research assistant scholarship (grant no. 1-2559-02-006).
Scheme 3. Control experiments.
O
O
I
O
O
Cy
O
Cy
(1)
Cu2O (50 mol%)
Cy
N
N
N
N
H
+
H
Cy
DMSO
90 oC, 18 h
N
I
Cy
44%
A. Supplementary data
N-acylurea intermediate
7%
Supplementary data associated with article can be found in the
online version, at http://…
O
O
I
O
Cu2O (50 mol%)
O
Cy
Cy
1.0 equiv. of DCC
Cy
N
N
N
H
(2)
N
+
H
Cy
DMSO
90 oC, 18 h
References
N
O
I
Cy
1.
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N-acylurea intermediate
65%
12%
O
O
O
Cu2O (50 mol%)
Cy
+
Cy
Cy
N
OH
(3)
N
N
DMSO
90 oC, 18 h
H
H
N
O
I
N,N'-dicyclohexyl
Cy
urea
no product
2.
3.
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To examine the possibility of pathway A, N,N’-
dicyclohexylurea and 2-iodobenzoic acid were subjected to the
reaction, however, the desired quinazolinedione was not
observed (Scheme 3, eq. 3). Based on this result, we propose
that quinazolinediones are not generated from the urea.
4.
5.
Conclusion
The synthesis of quinazolinediones from 2-iodobenzoic
acids and carbodiimides via a copper-catalyzed domino
reaction is reported. The non-catalyzed pathway, leading to N-
acylureas, crucially impacted the product yields, resulting in
the requirement of high copper loading. Non-external base
conditions were required in order to minimize the amount of
amide by-product resulting from elimination of the N-acylurea
intermediate.
A
variety of 2-iodobenzoic acids were
applicable, although those with electron-withdrawing
substituents provided low yields. Although the exact
mechanism could not be determined, based on control
experiments we believe that the quinazolinediones are obtained
from N-acylurea intermediates. Further mechanistic studies are
ongoing.
6.
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Acknowledgments