Tetrahedron Letters 48 (2007) 109–112
Overcoming steric effects in the coupling reaction of
alkyloxycarbonyloxymethyl (AOCOM) halides with phenols:
an efficient synthesis of AOCOM phenolic prodrugs
Joshua D. Thomas and Kenneth B. Sloan*
J. Hillis Miller Health Science Center, Department of Medicinal Chemistry, College of Pharmacy,
University of Florida, Gainesville, FL 32610, United States
Received 6 September 2006; revised 25 October 2006; accepted 30 October 2006
Available online 21 November 2006
Abstract—Steric hindrance is a key factor in the coupling reaction of AOCOM halides with phenols. Sterically unhindered alkoxy
groups favor the formation of acylated phenol. Under phase-transfer conditions, alkylated phenol is favored regardless of steric
hindrance.
Ó 2006 Elsevier Ltd. All rights reserved.
Alkyloxycarbonyloxymethyl (AOCOM) prodrugs are
members of a class of ‘soft alkyl’1 derivatives of active
drugs that are often used to overcome bioavailability
problems related to stability and solubility.2 Given the
prevalence of the phenolic functional group in biological
and pharmaceutical compounds, there are surprisingly
few examples in the literature of AOCOM prodrugs of
phenol. Although the synthesis of some AOCOM ethers
of phenol has been reported in the patent literature,3–5
we are aware of only one report of this technique being
applied to a phenol for the purpose of prodrug derivati-
zation.6 In that study, Seki et al. note that 4-ethoxy-
carbonyloxymethylacetanilide was obtained in a 20%
yield from the coupling of 4-hydroxyacetanilide with
ethoxycarbonyloxymethyl iodide following a reaction
time of seven days. In an effort to improve the yield
and ascertain the reaction parameters by which this
reaction is governed, we have synthesized a series of
AOCOM derivatives of 4-hydroxyacetanilide, a model
phenol, by Seki’s method6 and by a more efficient meth-
od involving phase-transfer catalysis (PTC). Although
the synthesis of AOCOM ethers of phenol via PTC is
unprecedented, others7–9 have shown that PTC forma-
tion of phenolic ethers is applicable to a broad range
of phenols and alkylating agents.10 Sloan and Koch11
briefly mention in their report that the reaction of pival-
yloxymethyl chloride with phenol gave only acylated
product under PTC conditions. However, Wolff and
Hoffman9 have successfully coupled 5-bromo-2(5H)-
furanones with phenols under PTC conditions. Thus it
was of interest to determine whether PTC could improve
the yield of 3 in the present case. We have compared our
results to those obtained from the coupling reaction of
ACOM halides with phenols—an analogous system
whose reaction parameters are known11,12 (Scheme 1).
In the present investigation, 4-hydroxyacetanilide
(APAP) was chosen as a model phenol in order to make
a direct comparison between this work and the work of
Seki et al.6 As shown in Scheme 2, AOCOM iodides may
be obtained from the corresponding chlorides via halo-
gen exchange in acetone. A subsequent reaction with
phenols under standard conditions (acetonitrile or ace-
tone as the solvent, K2CO3 as the base)6,11 or in a bipha-
sic system in the presence of tetrabutylammonium
hydrogen sulfate (Scheme 2) gave mixtures of 3 and 4.
Although the data presented in Table 1 is not exhaus-
tive, it suggests that the trends observed in the reactions
of ACOM halides with phenols11,12 are operative in the
analogous reactions of AOCOM halides. For example,
under the standard conditions, if X is a poor leaving
group, 4 is favored, but as the nucleofugicity of X
increases, the product distribution shifts toward 3
Keywords: Steric hindrance; Alkyloxycarbonyloxymethyl halide;
Phenol; Prodrug.
*
Corresponding author. Tel.: +1 352 846 1957; fax: +1 352 392
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.10.160