Table 1. Reaction of Amines with Acyl Imidazole 8 in the
Presence and Absence of DBU
Figure 3. Comparison of DBU and CO2 addition to the reaction of
o-toluic acid imidazole with sec-phenethylamine (11).
DBU was especially pronounced in the case of electron-
deficient anilines (entries 4-6, Table 1) wherein the uncata-
lyzed reactions were <5% complete even after 24 h.
We had previously observed that the CO2 evolved in the
acyl imidazole formation step catalyzed the subsequent
amidation step.4 To better understand the effects of CO2 and
DBU, acyl imidazole 20 derived from o-toluic acid (19) was
treated with sec-phenethylamine (11).16 In one case, the
reaction was carried out with 0.5 equiv of DBU under a
nitrogen blanket. The second experiment was conducted with
0.5 equiv of DBU under a CO2 atmosphere. Two more
experiments were carried out in the absence of DBU under
N2 and CO2, respectively. It was found that DBU provided
approximately 6-fold acceleration over CO2, and 20-fold
acceleration over the reaction with no additive.17 Interest-
ingly, the reaction with both DBU and CO2 was substantially
a Time taken for the reaction to reach 50% conversion. b 0.5 equiv of
DBU was added. c Isolated yield. d 42% conversion in 24 h. e <2%
conversion in 22.5 h. f Isolation experiments used 1.0 equiv of DBU to
g
maximize conversion within a reasonable time period. ∼2% conversion
in 24 h. h 67% conversion in 0.5 h. i <1% conversion in 24 h. j Reaction
run at 60 °C. k 71% conversion at 0.5 h.
and Im·HCl.13 We then examined the amidation using
4-aminobenzonitrile (10)san electron-deficient aniline, and
hence an exigent test case (Figure 2B). For this substrate, it
was found that DBU was unique among the practical
additiVes, proViding substantial rate enhancement compa-
rable to that of HOBt. In the case of sec-phenethylamine
(11)san aliphatic aminesthe reaction with DBU was
comparable to that with HOBt, and slightly faster than those
with NO2-HOPyr and Im·HCl (Figure 2C). Interestingly,
in all of these cases, the background reactions in the absence
of additives, as well as the reactions with i-Pr2NEt and
DMAP, were substantially slower.
In an effort to explore the generality and scalability of
this method, several amines were coupled with 8 in the
presence of DBU (Table 1).14 For all of these reactions,
2-methyltetrahydrofuran15 was used as the solvent to simplify
solvent removal, workup, and product isolation. In all cases,
DBU provided appreciable rate enhancement, excellent
conversions, and respectable yields. The catalytic effect of
(13) For the sake of consistency, 0.5 equiv of the appropriate additive
was used for the rate comparison experiments. However, Woodman et al.
used 1.5 equiv of Im·HCl in their studies (ref 8).
(14) Most of the preparative examples in Table 1 utilized 0.5 equiv of
DBU. In some cases, 1.0 equiv of DBU was added in order to achieve
reaction completion within 24 h as indicated by footnote f in Table 1.
(15) Ripin, D. H. B.; Vetelino, M. Synlett 2003, 2353.
(16) On the basis of prior experience, we knew that the amidation of
20 with 11 would proceed at room temperature. Under these conditions, it
was easier to retain the CO2 in the reaction vessel without recourse to pres-
sure-rated equipment. Therefore, this system was chosen as the test case.
(17) In all cases, the reaction mixtures were concentrated in vacuo after
formation of acyl imidazole 20 in order to remove the CO2 evolved. The
residue was then dissolved in 2-MeTHF for the coupling reaction. For
reactions with CO2, the gas was bubbled into a solution of 20 in 2-MeTHF
for 1-2 min and the reactions were sealed under a CO2 atmosphere. The
reactions without carbon dioxide were run under a nitrogen atmosphere.
(18) DBU and other amidines are known to form adducts with CO2.
See: (a) Desset, S. L.; Cole-Hamilton, D. J. Angew. Chem., Int. Ed. 2009,
48, 1472–1474. (b) Phan, L.; Chiu, D.; Heldebrant, D. J.; Huttenhower,
H.; John, E.; Li, X.; Pollet, P.; Wang, R.; Eckert, C. A.; Liotta, C. L.; Jessop,
P. G. Ind. Eng. Chem. Res. 2008, 47, 539–545. (c) Heldebrant, D. J.; Jessop,
P. G.; Thomas, C. A.; Eckert, C. A.; Liotta, C. L. J. Org. Chem. 2005, 70,
5335–5338. (d) Pe´rez, E. R.; da Silva, M. O.; Costa, V. C.; Rodrigues-
Filho, U. P.; Franco, D. W. Tetrahedron Lett. 2002, 43, 4091–4093.
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