Efficient Transamidation of Primary Carboxamides
A R T I C L E S
formamidinyl transfer. Unlike the ester formation described by
Anelli et al.,6 the proposed amide formation would likely not
have the advantage of reversibility if transfer of the formamidi-
nyl group to the nucleophile occurred. Here, we show that
N-acyl formamidines do indeed react irreversibly with amines
by formamidinyl transfer in the absence of additives, but that
in the presence of certain Lewis acids efficient acyl transfer
occurs, providing useful processes for amide exchange.
molecular sieves. Products formed in the absence of sieves
contained ∼15% of an impurity believed to be the partially
condensed orthoamide intermediate depicted in eq 3 (bracketed
1
structure, on the basis of H NMR analysis of crude reaction
mixtures), a substance found to be a catalyst poison in one of
the two transamidation protocols we report (vide infra). The
impurity is largely transformed to the corresponding N′-acyl-
N,N-diisopropylformamidine on silica gel, for isolated yields
of the latter typically exceed 95% after flash-column chroma-
tography. Crude products formed in the presence of 5 Å
molecular sieves typically contain <3% of the orthoamide
impurity. Like N′-acyl-N,N-dimethylformamidines, N′-acyl-N,N-
diisopropylformamidines are typically solids, and as implied
above, they are stable to chromatography. N′-Acyl-N,N-diiso-
propylformamidines are typically slightly less polar than the
starting primary amides, whereas N′-acyl-N,N-dimethylforma-
midines are typically slightly more polar.
We first explored the reaction of chromatographically purified
(>95%) N′-benzoyl-N,N-dimethylformamidine (1) with benzy-
lamine (2 equiv) in the absence of any additive, in the aprotic
solvent tetrahydrofuran (THF), and observed that nearly com-
plete conversion to benzamide and N′-benzyl-N,N-dimethylfor-
mamidine occurred within 15 h at 23 °C (eq 4, R ) CH3). Thus,
as Lin et al. had found using hydrazine as the nucleophile in
protic media,7a amidinyl transfer proceeded to the exclusion of
acyl transfer and was apparently irreversible. We attempted to
alter the course of reaction by increasing the size of the amidinyl
N-alkyl substituents, examining the reaction of N′-benzoyl-N,N-
diisopropylformamidine (2) with benzylamine (2 equiv) in THF
at 23 °C (eq 4, R ) i-Pr). Although the rate of amidinyl transfer
was indeed greatly slowed, this was nevertheless the primary
course of reaction; after 4 d at 23 °C, ∼25% of the starting
material had been transformed cleanly to benzamide. Lewis acid
additives were found to dramatically alter the rate and course
of reaction. From an initial screen of the influence of different
Lewis acids upon the reaction of 1 with benzylamine, scandium
triflate emerged as particularly efficacious.9 In the presence of
10 mol % scandium triflate and 3 equiv of benzylamine in THF
a 5:1 mixture of N-benzylbenzamide, the product of acyl
transfer, and benzamide, the product of amidinyl transfer,
respectively, was formed within 2 h at 23 °C. Amidinyl transfer
Results and Discussion
The synthesis of N′-acyl-N,N-dimethylformamidines from
primary amides and DMF-DMA is well precedented.7 While
there are several examples of reaction occurring at 23 °C,7b-e
in other precedents the amidine formation is conducted at much
higher temperatures.7a,f-k In our studies both aliphatic and
aromatic primary amide substrates were typically transformed
to the corresponding N,N-dimethylformamidine derivatives
within 2-4 h upon exposure to DMF-DMA (1.3 equiv) in
refluxing dichloromethane (∼0.1 M in substrate) containing
crushed, activated 5 Å molecular sieves (100 mg/mL). The more
hindered substrate pivalamide required 24 h for complete
conversion under the same conditions. The transformations are
readily monitored by thin-layer chromatography, and the
products are stable to column chromatography (though we
typically do not isolate them, vide infra). When isolated, N′-
acyl-N,N-dimethylformamidines are often solids, and they are
produced in near-quantitative yields, as previously documented.7
In addition to N′-acyl-N,N-dimethylformamidines, we pre-
pared N′-acyl-N,N-diisopropylformamidines by the reaction of
primary amides with N,N-diisopropylformamide dimethyl acetal
(DIF-DMA, 1.25 equiv, eq 3). The latter reagent is not presently
available commercially, but it is readily prepared in quantity
from N,N-diisopropylformamide.8 The reactions of primary
amides with DIF-DMA are much faster than those with DMF-
DMA and typically proceed to completion within 2-4 h at 23
°C when conducted in the presence of crushed, activated 5 Å
(7) (a) Lin, Y.; Lang, S. A., Jr.; Lovell, M. F.; Perkinson, N. A. J. Org. Chem.
1979, 44, 4160. (b) Chorvat, R. J.; Desai, B. N.; Radak, S. E.; Bloss, J.;
Hirsch, J.; Tenen, S. J. Med. Chem. 1983, 26, 845. (c) Macleod, A. M.;
Baker, R.; Freedman, S. B.; Patel, S.; Merchant, K. J.; Roe, M.; Saunders,
J. J. Med. Chem. 1990, 33, 2052. (d) Showell, G. A.; Gibbons, T. L.; Kneen,
C. O.; Macleod, A. M.; Merchant, K.; Saunders, J.; Freedman, S. B.; Patel,
S.; Baker, R. J. Med. Chem. 1991, 34, 1086. (e) Ospina, C. A.; Rodr´ıguez,
A. D.; Sa´nchez, J. A.; Ortega-Barria, E.; Capson, T. L.; Mayer, A. M. S.
J. Nat. Prod. 2005, 68, 1519. (f) Weidinger, H.; Eilingsfeld, H. N′-Acyl-
N,N-Dialkylformamidines. Belgian Patent BE 629 972, 1963. (g) Lin, Y.;
Lang, S. A. J. Synthesis 1980, 119. (h) Lin, Y.; Jennings, M. N.; Sliskovic,
D. R.; Fields, T. L.; Lang, S. A. J. Synthesis 1984, 946. (i) Blake, A. J.;
McNab, H.; Murray, M. E. J. Chem. Soc., Perkin Trans. 1 1989, 589. (j)
Chen, C.; Dagnino, R. J.; McCarthy, J. R. J. Org. Chem. 1995, 60, 8428.
(k) Kuo, G.-H.; DeAngelis, A.; Emanuel, S.; Wang, A.; Zhang, Y.;
Connolly, P. J.; Chen, X.; Gruninger, R. H.; Rugg, C.; Fuentes-Pasquera,
A.; Middleton, S. A.; Jolliffe, L.; Murray, W. V. J. Med. Chem. 2005, 48,
4535.
was completely suppressed when 2 was used as the substrate,
in an otherwise identical transformation, but the reaction
required 3 d to achieve complete conversion at 23 °C. Use of
ether as the solvent rather than THF led to a significant increase
in the rate of the latter reaction, and a high selectivity for acyl
transfer was maintained. Thus, treatment of 2 with benzylamine
(9) Titanium isopropoxide, titanium tetra(dimethylamide), tris(dimethylamido)-
aluminum(III) dimer, ytterbium triflate, and zinc chloride were ineffective
or were substantially less active than scandium triflate in promoting the
transamidation of N,N-dialkyl-N′-acylformamidines with benzylamine as
the nucleophile at 23 °C.
(8) Bredereck, H.; Simchem, G.; Rebsdat, S.; Kantlehn, W.; Horn, P.; Wahl,
R.; Hoffmann, H.; Grieshab, P. Chem. Ber. 1968, 101, 41.
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