J. D. Thomas, K. B. Sloan / Tetrahedron Letters 47 (2006) 8785–8787
8787
5. Fleischmann, K.; Adam, F.; Durckheimer, W.; Hertzsch,
W.; Horlein, R.; Jendralla, H.; Lefebvre, C.; Mackiewicz,
P.; Roul, J.; Wollmann, T. Liebigs Ann. 1996, 11, 1735–
1741.
6. In some cases, the addition of AlCl3 (0.1 mol %) and I2
(0.02 mol %) to the reaction mixture was necessary to
achieve good yields of ACOM iodide.
under essentially the same conditions used by Ouyang
et al.2 but from sterically unhindered ACOM halides
(X = Br or I). The weak dependence of the product dis-
tribution on steric hindrance when R0 is aliphatic is most
apparent when comparing entries 3 and 4 with entries 1
and 2 (Table 1). In these cases, sterically unhindered 1
and 2 (entries 3 and 4) gave higher percentages of 3 than
sterically hindered 1 and 2 (entries 1 and 2). Evidently,
amino acid-derived ACOM iodides exhibited a different
reactivity with phenols than carboxylic acid-derived
ACOM iodides.
7. In order to minimize exposure to potentially toxic prod-
ucts, no effort was made to purify 1a and 1b before their
use in coupling reactions with phenols. Thus, crude 1a and
1b used in the coupling reactions contained 6–19% ACOM
chloride and 3–11% bis(alkylcarbonyloxy)methane; no
acid halide remained. All compounds in the mixture gave
1H NMR spectra that were consistent with the previously
reported spectra (see Ref. 4). Crude yield was calculated
on the basis of the mole ratio of the products as
determined by 1H NMR. Note: the percentage of 4 in
the reaction mixture did not increase significantly as the
percentage of ACOM chloride (within the range of 6–19%)
in crude 1 increased.
8. Compounds 3 and 4 were separated by column chroma-
tography on silica gel. 4-Butryloxymethyloxyacetanilide
(3b) as a representative: 25% yield; mp = 56–58 °C; one
spot on TLC (EtOAc/hexane, 1:1) Rf 0.16; 1H NMR
(CDCl3) d 7.42 (d, J = 8 Hz, 2H), d 7.13 (br s, 1H), d 6.99
(d, J = 8 Hz, 2H), d 5.74 (s, 2H), d 2.34 (t, J = 7 Hz, 2H), d
2.17 (s, 3H), d 1.65 (m, 2H), d 0.94 (t, J = 7 Hz, 3H); Anal.
Calcd for C13H17NO4: C, 62.14; H, 6.82; N, 5.57. Found:
C, 61.92; H, 6.85; N, 5.52.
In conclusion, steric hindrance does not appear to be a
‘key’ determinate of product distribution when R0 = ali-
phatic, contrary to the assertions of Ouyang et al. As the
assertions of Ouyang et al.2 is the only report, where R0
is a protected amino acid, such ACOM halides may
react with phenols by a different mechanism than that
described1 for the simple derivatives of 1 (i.e., where
R0 = aliphatic).
References and notes
1. Sloan, K. B.; Koch, S. J. Org. Chem. 1983, 48, 3777–3783.
2. Ouyang, H.; Borchardt, R.; Siahaan, T. Tetrahedron Lett.
2002, 43, 577–579.
3. Sloan, K. B.; Wasdo, S. Med. Res. Rev. 2003, 23, 763–793.
4. The most common synthetic route to short-chain ACOM
iodides is a typically low-yielding, two-step synthesis. See
Iyer, R.; Yu, D.; Ho, N.; Agrawal, S. Synth. Commun.
1995, 25, 2739–2749, for examples.
9. Thomas, J. D. Ph.D. Dissertation, University of Florida,
2006.
10. Bundgaard, H.; Klixbull, U.; Falch, E. Int. J. Pharm.
1986, 30, 111–121.
11. Bensel, N.; Reymond, M.; Reymond, J. Chem. Eur. J.
2001, 7, 4604–4612.