Figure 1. Regioisomers of bis-TB derived from benzene as the central unit. The space-filling computer models of syn isomers are shown,
wherein the central benzene rings have the same orientations as those in the structure formulas.
in preparing the other isomers can be bypassed by blocking
the reactive positions. Thus, protecting the positions with
two methyl groups4 or methyl and chlorine2 enabled prepara-
tions of 1,2:4,5-bis-TB regioisomers. However, the blocking
strategy is not acceptable in all cases. Another complication
is the lack of commercially available starting compounds
for bis-TB sidewall construction, i.e., the lack of aromatic
ortho-nitrocarboxylic acids or their synthetic equivalents.
This situation necessitates an alternative synthetic strategy.
The first step should be the preparation of the requisite (with
respect to the targeted bis-TB regioisomer) dinitrodicarboxy-
lic acid or its synthetic equivalent. This, in turn, would be
used for the preparation of the diamide by treatment with
the desired aromatic amine (hundreds are commercially
available), followed by reduction to tetramine and “trogera-
tion”.
Herein, we present the first examples of this reverse
synthetic approach, as well as the first synthesis of 1,6:3,4-
bis-TB regioisomers.
First, we prepared known diastereoisomers of bis-TB 1a
as an example of 1,2:4,3-bis-TB regioisomers. The prepara-
tion starts from dinitrophthalic acid 2, which can be easily
prepared by the known10 nitration-oxidation of dinitronaph-
thalene by fuming HNO3.
diarylamides via generation of dichlorides are known,11 all
attempts (different ratios, temperatures, addition sequences)
to convert diacid 2 directly to diamide 3 failed. Treatment
of diacid 2 with SOCl2 or (COCl)2 followed by p-anisidine
always afforded monoamide 4 with no traces of diamide 3
or imide 5a (Scheme 1). This can be explained by the
formation of anhydride 6.12 Fortunately, the treatment of
monoamide 4 with COCl2 at room temperature for 10 min
(DMF is necessary), followed by quenching with p-anisidine,
gave targeted diamide 3 in 67% preparative yield and only
traces of imide 5a. Longer reaction times (1-2 h) led to
formation of imide 5a quantitatively. Although direct con-
versions of phthalic acids13 or phthalimides14 to diamides
via treatment with amines are known, in the case of diacid
2 and imide 5a, we did not obtain satisfactory results.
Treatment of diacid 2 or monoamide 4 with DCC and
p-anisidine afforded a complex mixture with no traces of
diamide 3.
In the next step, the nitro groups were reduced to amines
(3 to 7) by catalytic hydrogenation in near quantitative yield.
It should be noted that the reaction temperature as well as
the temperature during the workup procedures had to be kept
at at least less than 40 °C, or aminoimide 5b was formed
spontaneously. Following reduction of the amide groups with
LAH, tetraamine 8 was obtained in 62% yield. Direct
reduction of 3 to 8 proceeded in 50% yield.
The preparation of diamide 3 was found to be a nontrivial
procedure. Although direct conversions of phthalic acids to
Treatment of tetraamine 8 with paraformaldehyde in TFA
at 60 °C for 2 h furnished the targeted bis-TB 1 in 8%
(6) Pardo, C.; Sesmilo, E.; Gutierrez-Puebla, E.; Monge, A.; Elguero,
J.; Fruchier, A. J. Org. Chem. 2001, 66, 1607-1611.
(7) Mas, T.; Pardo, C.; Salort, F.; Elguero, J.; Torres, M. R. Eur. J. Org.
Chem. 2004, 1097-1104.
(11) Sherrill, M. L.; Schaeffer, F. L.; Shoyer, E. P. J. Am. Chem. Soc.
1928, 50, 474-485.
(8) Hansson, A.; Wixe, T.; Bergquist, K.-E.; Wa¨rnmark, K. Org. Lett.
2005, 7, 2019-2022.
(12) McMaster, L.; Ahmann, F. F. J. Am. Chem. Soc. 1928, 50, 145-
(9) Mas, T.; Pardo, C.; Elguero, J. HelV. Chim. Acta 2005, 88, 1199-
1207.
(10) (a) Hinze, W. L.; Liu, L.; Fendler, J. H. J. Chem. Soc.; Perkin Trans.
2 1975, 1751-1767. (b) Ward, E. R.; Johnson, C. D.; Day, L. A. J. Chem.
Soc. 1959, 487-493. (c) Will, W. Chem. Ber. 1895, 28, 367-379.
149.
(13) Kauffmann, H.; Beisswenger, A. Chem. Ber. 1904, 37, 2610-2612.
(14) (a) Augustin, M.; Kohler, M.; Faust, J.; Al-Holly, M. M. Tetrahedron
1980, 36, 1801-1805. (b) Ammar, Y. A.; Ismail, M. M. F.; El-Gaby, M.
S. A.; Zahran, M. A. Indian J. Chem., Sect. B 2002, 41, 1486-1491.
4868
Org. Lett., Vol. 8, No. 21, 2006