A new mild method for the cleavage of the amide bond: Conversion of secondary and tertiary amides to esters

Full text of DOI:10.1055/s-1998-1612

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A New Mild Method for the Cleavage of the Amide Bond: Conversion of Secondary and
Tertiary Amides to Esters
André B. Charette* and Peter Chua
Département de Chimie, Université de Montréal, P.O. Box 6128, Station Downtown, Montréal, Québec, Canada, H3C 3J7
Fax (514) 343-5900; e-mail: charetta@chimie.umontreal.CA
Received 23 September 1997
Amides are one of the most robust carboxylic acid derivatives or
protecting groups. However, breaking the amide bond or converting
amides to more labile carboxylic acid derivatives is often a very
surprisingly difficult task to achieve which has resulted in their
novel approach of using triflic anhydride and alcohol to allow access to
alkyl imidates and alkyl iminium esters at low temperatures and near
neutral pH (Scheme 1).
1
infrequent application to synthesis. Conditions typically used to cleave
the amide bond in synthesis are very strongly acidic or basic and usually
2
involve high temperatures and pressures. Primary amides are the most
reactive and some milder methods do exist for this functional group
3
transformation. On the contrary, secondary and tertiary amides are
much more difficult to cleave. Existing methods which are somewhat
4
5
milder still often require fairly harsh acidic, basic, or oxidative
6
conditions. The hydrolysis of imidates derived from secondary amides
can occur at ambient temperature under very mildly acidic conditions
7
and allows the recovery of both the acid and the amine. However, the
difficulty in generating the required iminium ester prevents the general
use of this method for tertiary amides even when using the highly
8
reactive Meerwein reagent. Thus, the challenge in cleaving the amide
Scheme 1
bond has received much attention from organic and bio-organic
9
chemists alike. In this communication, we wish to describe a one-pot
conversion of both secondary and tertiary amides to esters based on a
Some elegant pioneering work has been done on the chemistry of imino
and iminium triflates such as the generation of ketiminium cations at

1
64
LETTERS
SYNLETT
1
0
elevated temperatures, or the addition of nucleophiles such as
A spectacular reaction is shown in entry 5 where the benzamide group
can be removed in presence of the primary acetate in 77% yield.
1
1
12
16
cyanide or azide. However, to the best of our knowledge, this is the
first example of multiple additions of nucleophiles to these highly
electrophilic species as well as the first demonstration that imidates can
be generated from the imino or iminium triflate and an alcohol.
The mildness of this methodology is also illustrated by the ability to
convert a readily racemizable amide such as the benzamide of (S)-2-
methyl-6-methoxynaphthylacetic acid to its corresponding ethyl ester in
82% yield with only a 8% drop in enantiomeric excess (eq 1).
Tertiary and secondary amides 1 are activated towards nucleophilic
attack by forming their electrophilic triflate intermediates 2a and in the
presence of an alcohol, these species are readily converted to alkyl
iminium esters and alkyl imidates 2b which can then be converted to
orthoesters 2c by subsequent exposure to excess alcohol under very
mildy acidic conditions (pyridine/ pyridinium hydrotriflate). After
aqueous workup, the corresponding carboxylic esters 3 are obtained in
good to excellent yields (Table 1).
This two-step, one-pot procedure consists of first activating the amide
with triflic anhydride. Triflic anhydride is added slowly to the amide in
CH Cl containing pyridine. The reaction is kept below 0 °C during the
2
2
activation period to prevent elimination of triflic acid to give
ketiminium species. The second step involves the addition of a primary
1
3
alcohol to the reaction mixture. Typically, at least 10 equivalents of
alcohol are required to achieve consistently high yields.
Generally, secondary amides give good yields of the esters (entry 9-15).
This is a welcome result since the hydrolyses of secondary amides are
usually more problematic and require more specialized conditions.14
The power of this methodolgy is most apparent when benzamides can
be removed in presence of various hydroxy, and carbonyl or 1,2-diol
protecting groups (Table 2).15
The primary amide 4 is quantitatively dehydrated to nitrile 5 under these
conditions (Scheme 2). To the best of our knowledge, pyridine and
triflic anhydride have not been used for converting primary amides to
nitriles, however, this result is not surprising considering the literature
17
precedents for doing this transformation with other acid anhydrides.
Scheme 2
This method also constitutes a very mild way for the deprotection of
amides to produce the corresponding amine. For example, N-alkyl
phenethyl amides were quantitatively alkylated to give rise to tertiary
amides 6a and 6b and these are converted to the corresponding esters in
excellent yields (eq 2). In this case, N-methyl-α-phenethylamine 8 was
recovered in an unoptimized 68% yield through a simple acid-base
extraction.

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In conclusion, we have found an approach towards the longstanding
problem of cleaving the amide bond. Since this transformation can be
accomplished in the presence of various functionality, a greater use of
amides as amine and carboxylic acid protecting groups may develop.
Secondary and tertiary amides can be converted to highly electrophilic
imino or iminium triflates using a stoichiometric amount of triflic
anhydride and pyridine. These species can be used to generate alkyl
imino esters and alkyl iminium esters which are readily converted to
esters. Further studies on the mechanism, scope and limitations of this
reaction are underway. The use of other nucleophiles is also being
studied and will be reported in due course.
8.
Oxazolines can alkylated to give rise to iminium esters:
(a) Deslongchamps, P.; Lebreux, C.; Taillefer, R. Can. J. Chem.,
1973, 51, 1665-1669. (b) Smith, M. B.; Shroff, H. N. J. Org.
Chem., 1984, 49, 2900-2906.
9.
(a) Roberts, V. A.; Stewart, J. D.; Benkovic, S. J.; Getzoff, E. D.
J. Mol. Biology, 1994, 235, 1098-1116. (b) Stewart, J. D.; Roberts,
V. A.; Thomas, N. R.; Getzoff, E. D.; Benkovic, S. J.
Biochemistry, 1994, 33, 1994-2003.
1
0. (a) Falmagne, J. B.; Escudero, J.; Taleb-Saharaoui, S.; Ghosez, L.
Angew. Chem. Int. Ed. Engl., 1981, 20, 879-880. (b) Barbaro, G.;
Battaglia, A.; Bruno, C.; Giorgianni, P.; Guerrini, A. J. Org.
Chem., 1996, 61, 8480-8488. For a review on triflic anhydride,
see: (c) Ritter, K. Synthesis, 1993, 735-762. (d) Stang, P. J.;
Hanack, M.; Subramanian, L. R. Synthesis, 1982, 85-126.
Acknowledgments. This research was supported by the Natural Science
and Engineering Research Council (NSERC) of Canada, Alfred P.
Sloan Foundation, Servier Canada, F.C.A.R. (Québec), and the
Université de Montréal. A FCAR predoctoral fellowship to P.C. is also
gratefully acknowledged.
1
1. (a) Sisti, N. J.; Fowler, F. W.; Grierson, D. S. Synlett, 1991, 816-
818. (b) Sisti, N. J.; Zeller, E.; Grierson, D. S.; Fowler, F. W.
J. Org. Chem., 1997, 62, 2093-2097.
1
1
2. Thomas, E. W. Synthesis, 1993, 767-768.
References and Notes
3. Methanol could be used instead of ethanol with equally good
results. Amide in entry 1 was converted to the corresponding
methyl ester in identical yield.
1
.
(a) Buehler, C. A.; Pearson, D. E. Survey of Organic Syntheses,
Vol. 1; Wiley: New York, 1970, p 751. and 1977, vol. 2, p 660
(
b) B. C. Challis, J. A. Challis, in The Chemistry of Amides: The
14. (a) Martin, J. C.; Franz, J. A. J. Am. Chem. Soc., 1975, 97, 6137-
Chemistry of Functional Groups (Ed.: J. Zabicky), Wiley
Interscience: New York, 1970, p 816.
6
(
144. (b) Kuehne, M. E. J. Am. Chem. Soc., 1961, 83, 1492-1498.
c) Sonnet, P. E. J. Org. Chem., 1982, 47, 3793-3796.
5. Typical procedure: N,N-Diethyl hydrocinnamide (205 mg, 1.0
2.
For selected examples of syntheses which required the removal of
simple amides using vigorous conditions, see (a) Kende, A. S.;
Bentley, T. J.; Draper, R. W.; Jenkins, J. K.; Joyeux, M.; Kubo, I.
Tetrahedron Lett., 1973, 14, 1307-1310 (b) Corey, E. J.;
Balanson, R. D. J. Am. Chem. Soc., 1974, 96, 6516-6517 (c) Ben-
Ishai, D.; Altman, J.; Peled, N. Tetrahedron, 1977, 33, 2715-2717.
1
mmol), CH Cl2 (5 ml) and pyridine (245 µl 3.0 mmol) were
2
combined in a dry 25 ml flask under argon. The resulting solution
was cooled to -40 °C and then neat triflic anhydride (220 µl, 1.3
mmol) was added slowly to the solution. Following completion of
the addition of triflic anhydride, the reaction mixture was allowed
to warm up with stirring to 0 °C slowly (approximately 2 hours)
and then stirred at 0 °C for another 10 hours. Ethanol (2 ml, >30
mmol) was then added and the reaction was allowed to warm up
to room temperature. Stirring was continued for another 12 hours.
3
.
(a) Anelli, P. L.; Brocchetta, M.; Palano, D.; Visigalli, M.
Tetrahedron Lett., 1997, 2367-2368. b) Fisher, L. E.; Caroon, J.
M.; Stabler, S. R.; Lundberg, S.; Zaidi, S.; Sorensen, C. M.;
Sparacino, M. L.; Muchowski, J. M. Can. J. Chem., 1994, 72,
142-145. (c) Greenlee, W. J.; Thorsett, E. D. J. Org. Chem., 1981,
The reaction was then diluted with 120 ml of Et O and washed
2
46, 5351-5353.
once with 1 N HCl (25 ml), twice with NaHCO (saturated) and
3
dried over Na SO . The solvent was removed in vacuo and flash
4
.
.
Hamilton, D. J.; Price, M. J. Chem. Commun., 1969, 414.
2
4
chromatography afforded
167 mg (94%) of ethyl
5
(a) Gassman, P. G.; Hodgson, P. K. G.; Balchunis, R. J. J. Am.
Chem. Soc., 1976, 98, 1275-1276. (b) Tsunoda, T.; Sasaki, O.; Ito,
S. Tetrahedron. Lett., 1990, 31, 731-734.
hydrocinnamate. Reaction times could be shortened for specific
cases (ie. equally high yields could be obtained for the cleavage of
N,N-diethyl hydrocinnamide if the reaction was stirred only for 2
hours at 0 °C before the addition of ethanol, and only 4 hours
after).
6.
(a) White, E. H. J. Am. Chem. Soc., 1955, 77, 6008-6010 and
6011-6014 and 6014-6021. (b) A novel approach has been
recently disclosed for the hydrolysis of secondary amides through
a selective nitrosation and a subsequent mild hydrolysis of the N-
nitrosyl secondary amide, see Evans, D. A.; Carter, P. H.;
Dinsmore, C. J.; Barrow, J. C.; Katz, J. L.; King, D. W.
Tetrahedron Lett., 1997, 38, 4535-4538.
1
6. For an elegant method for the selective hydrolysis of primary
amides in the presence of esters. see: Eschenmoser, A.; Wintner,
C. E. Science 1977, 196, 1410-1420 and references therein.
1
7. (a) Triflic anhydride and triethylamine has been reported to
dehydrate aldoximes: Hendrickson, J. B.; Bair, K. W.; Keehn, P.
M. Tetrahedron Lett., 1976, 603-604. (b) Dehydration of primary
amides have been demonstrated with other reagents many times in
the past. See Campagna, F.; Carotti, A.; Casini, G. Tetrahedron
Lett., 1977, 21, 1813-1816 and references therein.
7
.
(a) Okuyama, T.; Sahn, D. J.; Schmir, G. L. J. Am. Chem. Soc.,
1973, 95, 2345-2352. (b) Pletcher, T. C.; Koehler, S.; Cordes, E.
H. J. Am. Chem. Soc., 1968, 90, 7072-7076. (c) Hanessian, S.
Tetrahedron Lett. 1967, 8, 1549-1552. (d) Schmir, G. L.;
Cunningham, B. A. J. Am. Chem. Soc., 1965, 87, 5692-5701.