Synthesis of 4,5-Dianilinophthalimide and Related Analogues
SCHEME 3. Amination Reactions on 4,5-Dichlorophthalic Acid Dimethyl Ester
SCHEME 4. Synthesis of Phthalimide Ring via
easily accessible from commercially available 4,5-dichlo-
rophthalic acid and that the subsequent closure of the
phthalimide ring could be performed a number of ways.
The palladium-catalyzed amination has been con-
ducted under a wide variety of reaction conditions, with
seemingly countless permutations of palladium precata-
lyst, phosphine ligand, stoichiometric base, and solvent.10
However, based on the considerable research efforts
expended by our group on both synthetic11 and mecha-
nistic12 aspects of the amination, we chose to start our
studies using 2-dicyclohexylphosphino-2′,4′,6′-triisopro-
pylbiphenyl (XPhos, Figure 2) as the ligand for pal-
Ammonlysis
example, heating a solution of the diester with urea and
sodium methoxide, a procedure commonly used for this
transformation in cases of more simple phthalates,13 was
not successful when applied to these compounds (nor was
it when conducted under acid-catalyzed conditions).
Alternatively, no desired phthalimides were observed
when heating the diesters in the presence of excess
hexamethyldisilazane (commonly used as an ammonia
equivalent)14 and Lewis acids. Difficulties in the forma-
tion of this ring were also discussed in the initially
published synthesis (Scheme 1).8b When applying a
modification of the published ammonolysis protocol, we
were pleased to observe formation of the desired phthal-
imides albeit in disappointingly low yields (Scheme 4).
While the published procedure typically affords yields of
40-60% for this step, it requires larger quantities of
gaseous ammonia (a steady stream for a duration of 16
h) that were not immediately available in our laboratory
at the time of this work. Instead, we conducted the
reactions in sealed reaction vessels pressurized with
ammonia gas under otherwise identical conditions.
Due to the difficulties encountered in formation of the
phthalimide ring (both in our hands and in the previously
published route), we sought to develop an alternative
approach to the desired DAPH analogues by conducting
the palladium-catalyzed amination reactions on sub-
strates that already contained the phthalimide ring.
Amination on 4,5-Dichlorophthalimide Deriva-
tives. The most attractive and intuitively straightfor-
ward protocol for the synthesis of DAPH analogues would
be to conduct the palladium-catalyzed amination directly
on commercially available 4,5-dichlorophthalimide. Such
a route would obviate the need to use protecting groups
for the acidic phthalimide nitrogen and would afford the
desired compounds directly. However, while a variety of
reaction conditions were explored for this coupling, we
were unable to effect the amination on the unprotected
substrate.
FIGURE 2. XPhos (2-dicyclohexylphosphino-2′,4′,6′-triisopro-
pylbiphenyl).
ladium. This phosphine has proven to be superior for
amination in most synthetic applications. We also chose
Pd2(dba)3, a convenient Pd0 source, as the precatalyst
since the substrate combinations we planned to employ
were not amenable to in situ reduction of a Pd(II)
precatalyst. Last, we decided to avoid the use of sodium
tert-butoxide as the stoichiometric base due to the
potential for transesterification, which would hamper
subsequent formation of the phthalimide ring.
Gratifyingly, by heating a toluene solution of 4,5-
dichlorophthalic acid dimethyl ester (obtained in high
yield by treatment of the diacid with thionyl chloride in
methanol) and aniline in the presence of potassium
phosphate and catalytic quantities of Pd2(dba)3 and
XPhos, the desired dimethyl 4,5-dianilinophthalate can
be obtained in excellent yield (Scheme 3). Due to the low
solubility of the product in nonpolar organic media as
well as water, isolation is simplified by pouring the entire
reaction into a mixture of diethyl ether and water (to
dissolve any unreacted starting reagents as well as any
inorganic material) and filtration of the insoluble product.
The p-fluoroanilino analogue can be made in an analo-
gous fashion (Scheme 3).
Given the ease with which dimethyl 4,5-dianilinoph-
thalates could be assembled, we were disappointed to find
that the closure of the phthalimide ring was a nontrivial
problem despite the variety of protocols examined. For
We were pleased to observe that the amination reaction
does proceed on 4,5-dichlorophthalimides in which the
nitrogen is protected. For example, amination on the
p-methoxyphenyl (PMP)-protected substrate proceeds
(11) For example, see: (a) Huang, X.; Anderson, K. W.; Zim, D.;
Jiang, L.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125,
6653. (b) Harris, M. C.; Huang, K.; Buchwald, S. L. Org. Lett. 2002, 4,
2885. (c) Huang, X.; Buchwald, S. L. Org. Lett. 2001, 3, 3417.
(12) (a) Strieter, E. R.; Blackmond, D. G.; Buchwald, S. L. J. Am.
Chem. Soc. 2003, 125, 13978. (b) Singh, U. K.; Strieter, E. R.;
Blackmond, D. G.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 14014.
(13) For example, see: Rosowsky, A.; Vaidya, C. M.; Bader, H.;
Wright, J. E.; Teicher, B. A. J. Med. Chem. 1997, 40, 286.
(14) For example, see: Pellegata, R.; Italia, A.; Villa, M.; Palmisano,
G.; Lesma, G. Synthesis 1985, 517.
J. Org. Chem, Vol. 70, No. 18, 2005 7373