results of comparisons of their efficiencies in the esterifica-
tion reactions of representative tertiary alcohols with acetic
anhydride. We discovered that 5 and 6 were indeed very
potent nucleophilic catalysts, being about six times more
effective than DMAP and about 10% more effective than 2,
which is the best catalyst reported for the esterification
reaction of alcohols.
isodesmic acetyl-transfer reaction shown in eq 1 at the
B3LYP/6-311+G(d,p)//B3LYP/6-31G(d) level of theory
(Table 1).
The simplified, but well-accepted mechanism of esterifi-
cation of an alcohol using DMAP, is illustrated in Scheme
1
and is believed to involve initial reaction of the acyl donor
Table 1. Calculated Enthalpies -∆Hrxn (kcal mol-1) for Acetyl
Group Transfer (eq 1)
Scheme 1. Simplified Mechanism of Catalysis of
Esterification of an Alcohol by an Acyl Donor in the Presence
of DMAP
DMAP
20.0
PPY
22.7
1
2
3
5
-∆Hrxn
22.9
26.0
26.5
30.4
The results show that the acetyl derivatives of 1 and 2 are
more stable than those of DMAP by 2.9 and 6 kcal,
respectively. This extra stabilization energy results most
probably from conformational fixation of the 4-N lone pair
orbital parallel to the pyridine π system. Similar theoretical
results were obtained for conformationally restricted cyclic
N substituents on the stability of benzhydryl cations by Mayr
(
typically an acyl halide or anhydride) with DMAP to form
an acylpyridinium halide/acetate ion-pair intermediate. This
is followed by attack of the alcohol on this intermediate
22
et al.
Based on similar reasoning, we predicted that one or two
additional cyclic N-substituents on the meta positions of the
pyridine ring, as in 3-6, respectively, would provide an even
greater stabilization of the acylpyridinium intermediate
(usually in the presence of an auxiliary base like triethyl-
1
7,18
amine) to yield the ester and regenerate the DMAP.
superiority of DMAP over pyridine has been explained by
The
1
9
the strong +R effect of the 4-dimethylamino group, which
delocalizes the positive charge on the acylpyridinium inter-
mediate and thus stabilizes the intermediate.20
The design of improved catalysts 1 and 2 by Steglich and
co-workers was based on the reasoning that the rigid scaffold
of 2 would force the 4-N lone pair orbital to remain always
parallel to the pyridine ring π-orbitals, the orientation for
maximal overlap. This would result in an acylpyridinium
intermediate with greater stability than that derived from
DMAP because, in the latter, the N lone pair of the NMe
group can take up a nonparallel orientation with respect to
the pyridine π system due to free rotation around the C-N
single bond. Additionally, the two alkyl groups at the meta
because a m-dimethylamino substituent [σ
is more electron releasing than an alkyl group [σ
0.07], and the six-membered cyclic scaffold would also
m 2
(NMe ) ) -0.16]
m
(Et) )
-
force the substituent N lone pair orbital to be parallel to the
19
π-orbitals of the pyridine ring. This prediction of enhanced
stability was further supported by the results of DFT
calculations for the acetyl transfer reactions shown in Table
23
-1
1
. Acetyl transfer to 5 is predicted to be about 4 kcal mol
more favorable than to 2, the best reported esterification
catalyst until now.
Encouraged by the results of these calculations, we
developed syntheses of bicyclic diaminopyridines 3 and 4,
and tricyclic triaminopyridines 5 and 6.
2
21
positions of the pyridine ring would have stabilizing +I
Scheme 2 illustrates the synthesis of 3 and 4. Reaction of
19
effects. The net result of these stabilizing interactions should
be a significant increase in the concentration of the reactive
intermediate and/or lower activation energy for the reaction,
which might in turn lead to greater rate enhancement. Such
enhanced stability of the acylpyridinium intermediates orig-
inating from 1 and 2 is supported by the results of DFT
calculations of the enthalpy change associated with the
3
,4-diaminopyridine (7) with glyoxal in refluxing aqueous
24
ethanol gave pyrido[3,4-b]pyrazine (8), which was reduced
with sodium borohydride to yield 1,2,3,4-tetrahydro-pyrido-
25
[3,4-b]pyrazine (9). Use of lithium aluminum hydride in
place of sodium borohydride resulted in much lower yields.
Selective alkylation of the 3- and 4-NH groups of 9
necessitated the initial protection of the pyridine nitrogen,
which was achieved by reaction with trityl chloride. Reaction
of the trityl salt 10 with sodium hydride and methyl iodide,
or ethyl bromide in anhydrous tetrahydrofuran, resulted in
the formation of 11 and 12 respectively. Finally, detritylation
(
17) Xu, S.; Held, I.; Kempf, B.; Mayr, H.; Steglich, W.; Zipse, H. Chem.
Eur. J. 2005, 11, 4751-4757.
18) The role of the auxiliary base is to scavenge the acid generated and
prevent it from protonating DMAP.
19) σp(NMe2) ) -0.83; σm(Alkyl) ) -0.06; Hansch, C.; Taft, R. W.
Chem. ReV. 1991, 91, 165-195.
20) The acylpyridinium salt derived from DMAP has a higher solubility
(
(
(
(21) Barbieri, G.; Rois, B.; Grandi, R.; Pagnoni, U. M.; Taddei, F. J.
Chem. Soc., Perkin Trans. 2 1979, 330-336.
(22) Mayr, H.; Kempf, B.; Ofial, A. R. Acc. Chem. Res. 2003, 36, 66-
77.
than the pyridinium salt, and this could also contribute to its greater
effectiveness. Spivey, A. C.; Arseniyadis, S. Angew. Chem., Int. Ed. 2004,
4
3, 5436-5441.
402
Org. Lett., Vol. 9, No. 3, 2007