In contrast to acids 1a-d, carboxylic acids 1e-h lacking
electron-withdrawing groups failed to give measurable
amounts of the corresponding tert-butyl esters under these
conditions. Similarly, competition studies involving the
acylation of tert-butyl alcohol with a 1:1 mixture of dieth-
ylphosphonoacetic acid and acetic, bromoacetic, or diphen-
ylacetic acids and 1 equiv of DCC provided exclusively the
esterification product 2a derived from the diethylphospho-
noacetic acid (1a).
To demonstrate the synthetic utility of the method, we
performed the acylation of the highly sterically hindered and
chemically sensitive peroxide alcohol 3 known as a key
compound in the synthesis of highly potent antimalarial
derivatives.4 The reported acylation of the alcohol 3 proceeds
with a very big excess of acetyl chloride and provides a low
yield of the ester.5 In contrast, treatment of the alcohol 3
with diethylphosphonoacetic acid/DCC provides the ester 4
in a high yield (92%) under very mild conditions (eq 2).
drolysis or aminolysis of activated esters including ac-
etoacetyl and malonyl coenzyme A derivatives.7 Furthermore,
it has been reported that some specific, highly stabilized
ketenes can be prepared in a direct reaction from carboxylic
acids and DCC in the presence of triethylamine, although
under relatively harsh conditions.8 The reaction of carboxylic
acids with various dehydrating reagents such as dialkylchlo-
rophosphates in the presence of triethylamine is also known
to provide ketenes.9 The preparation of ketenes under mild
conditions is highly important, and several approaches
including photolysis reactions, Wolff rearrangement of
diazoketones,10a the use of insoluble bases,10b,c and mixed
anhydride methods10d have been tried. We believe that the
proposed approach provides a simple and efficient alternative
to these methods.
The validity of the ketene pathway was investigated by
deuteration experiments. Neither diethylphosphonoacetic acid
(1a) nor its ester 2a undergo deuteration in the presence of
weak bases such as DCC.11 In contrast, reaction of 1a with
tert-butyl alcohol-d and 1 equiv of DCC resulted, as
1
evidenced by H and 31P NMR, in the incorporation of
deuterium into the R-position of the resultant ester 2a in full
agreement with the ketene mechanism (eq 5).12
The very high reactivity of acids of type 1a-d coupled
with the very low reactivity of “regular” carboxylic acids of
type 1e-h under identical reaction conditions can be
rationalized through the intermediacy of a highly electrophilic
species with relatively low steric demand, e.g., the formation
of the corresponding ketene. In contrast to “regular” car-
boxylic acids such as 1e-h that acylate alcohols through
acid-DCC adducts of type 5,6 the presence of a strongly
electron withdrawing group in the R-position to the carboxyl
can enable an elimination pathway through an E1cB mech-
anism to give the corresponding ketenes of type 6 (eq 4).
The 31P NMR of the deuterated ester 2a strongly evidences
in favor of the E1cB mechanism of ketene formation vs a
(7) (a) Cho, B. R.; Kim, Y. K.; Seung, Y. J.; Kim, J. C.; Pyun, S. Y. J.
Org. Chem. 2000, 65, 1239-1242. (b) Cevasco, G.; Vigo, D.; Thea, S. J.
Org. Chem. 2000, 65 (23), 7833-7838. (c) Inoue, M.; Bruice, T. C. J. Am.
Chem. Soc. 1982, 104, 1644-1653. (d) Isaac, N. S.; Najem, T. S. J. Chem.
Soc., Perkin Trans. 2 1988, 557-562. (e) Douglas, K. T.; Alborz, M.; Rullo,
G. R.; Yaggi, N. F. J. Chem. Soc., Chem. Commun. 1982, 242-246. (f)
Chandrasekar, R.; Venkatasubramanian, N. J. Chem. Soc., Perkin Trans. 2
1982, 1625-1631. (g) Inoue, M.; Bruice, T. C. J. Org. Chem. 1982, 47,
959-963. (h) Broxton, T. J.; Duddy, N. W. J. Org. Chem. 1981, 46, 1186-
1191. (i) William, A.; Douglas, K. T. Chem. ReV. 1975, 75, 7-649 and
references therein.
(8) Olah G. A.; Wu A. H.; Farooq O. Synthesis 1989, 568-568.
(9) (a) Allen, A. D.; Andraos, J.; Kresge, A. J.; Mcallister, M. A.; Tidwell,
T. T. J. Am. Chem. Soc. 1992, 114, 1878-1879. (b) Maas, G.; Bruckmann,
R. J. Org. Chem. 1985, 50, 2801-2802. (c) Regitz, M.; Ruter, J. Chem.
Ber. 1969, 102, 3877-3890. (d) Concannon, P. W.; Ciabattoni, J. J. Am.
Chem. Soc. 1973, 95, 3824-3289.
(10) For recent works involving preparation of ketenes, see: (a) Allen,
A. D.; Cheng, B.; Fenwick, M. H.; Huang, W. W.; Missiha, S.; Tahmassebi,
D.; Tidwell, T. T. Org. Lett. 1999, 1, 693-696. (b) Taggi, A. E.; Hafez, A.
M.; Wack, H.; Young, B.; Drury, W. J.; Lectka, T. J. Am. Chem. Soc. 2000,
122, 7831-7832. (c) Wack, H.; Taggi, A. E.; Hafez, A. M.; Drury, W. J.;
Lectka, T. J. Am. Chem. Soc. 2001, 123, 1531-1532. (d) Bonini, B. F.;
Femoni, C.; Comes-Franchini, M.; Foschi, M.; Mazzanti, G.; Ricci, A.;
Varchi, G. SYNLETT 2001, 1092-1096.
The formation of ketene intermediates through an E1cB
mechanism has been well established in reactions of hy-
(4) Bachi, M. D.; Korshin, E. E. SYNLETT 1998, 122-124.
(5) Bachi, M. D.; Korshin, E. E.; Ploypradith, P.; Cumming, J. N.; Xie,
S. J.; Shapiro, T. A.; Posner, G. H. Bioorg. Med. Chem. Lett. 1998, 8, 903-
908.
(6) Bodansky, M. Peptide Chemistry: A Practical Textbook; Springer;
New York, 1988.
(11) No deuteration product was detected after treatment of 2a with
t-BuOD/DCC for 5 h or with t-BuOD/triethylamine for 30 min in
dichloromethane at room temperature.
3734
Org. Lett., Vol. 3, No. 23, 2001