Reaction of alkylcarbonyloxymethyl halides with phenols: reevaluating the influence of steric hindrance

Article abstract of DOI:10.1016/j.tetlet.2006.09.118

Evidence is presented that contradicts an earlier finding that, in the absence of steric hindrance, the coupling reaction of alkylcarbonyloxymethyl (ACOM) halides with phenols favors acylated product. A one-step synthesis is used to generate sterically unhindered ACOM iodides, which are then reacted with several phenols to give mainly alkylated phenol.

Full text of DOI:10.1016/j.tetlet.2006.09.118

Tetrahedron Letters 47 (2006) 8785–8787
Reaction of alkylcarbonyloxymethyl halides with
phenols: reevaluating the influence of steric hindrance
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 4 July 2006; revised 20 September 2006; accepted 21 September 2006
Available online 20 October 2006
Abstract—Evidence is presented that contradicts an earlier finding that, in the absence of steric hindrance, the coupling reaction of
alkylcarbonyloxymethyl (ACOM) halides with phenols favors acylated product. A one-step synthesis is used to generate sterically
unhindered ACOM iodides, which are then reacted with several phenols to give mainly alkylated phenol.
Ó 2006 Elsevier Ltd. All rights reserved.
It has been known for quite some time that ACOM ha-
lides 1 display an ambient reactivity—sometimes nucleo-
philes react at the carbonyl to give acylated products,
while at other times the alkyl halide carbon is attacked
to give alkylated products (Scheme 1). In the initial re-
port on the reactions of ACOM halides 1 with phenols
2,1 it was noted that the nucleophilicity of 2 and the
nucleofugicity of the halide in 1 are the key determinants
of the product distribution. Recently, Ouyang et al. have
suggested that both 1 and 2 must be sterically hindered
in order to shift the product distribution in favor of 3.2
The conclusions of Ouyang et al.2 were based on the
reactions of 1 with 2, where R0 was an N-protected leu-
cine derivative. For example, when R0 was Alloc-D-Leu
(Table 1, entry 1), the product distribution was shifted
almost entirely toward acylated phenol 4. However,
when both the protecting group and the phenol were ste-
rically hindered (Table 1, entry 2), the percentage of
alkylated phenol 3 increased substantially. Although
only one aliphatic ACOM iodide was examined2 (i.e.,
R = H, R0 = (CH3)3C, 2 = phenol), the authors argued
that steric hindrance was essential for the successful cou-
pling of 1 with 2 regardless of whether R0 was aliphatic
or an amino acid.
As part of our work in developing a prodrug database
from which flux through skin may be modeled,3 we were
interested in synthesizing a homologous series of
ACOM prodrugs of 4-hydroxyacetanilide (acetamino-
phen, or APAP), a sterically unhindered model phenol,
O
R
O
O
R
R''
R''
R''
+
HO
+
R'
O
O
O
R'
R'
O
X
2
1
3
4
X = Cl, Br, I
R = H, alkyl
R' = alkyl, aryl, etc.
R'' = alkyl, aryl, etc.
Scheme 1. Reaction of ACOM halides 1 with phenols 2.
Keywords: Steric hindrance; Alkylcarbonyloxymethyl halide; Phenol; Prodrug.
*
Corresponding author. Tel.: +1 352 846 1957; fax: +1 352 392 9455; e-mail: sloan@cop.ufl.edu
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.09.118

8786
J. D. Thomas, K. B. Sloan / Tetrahedron Letters 47 (2006) 8785–8787
Table 1. Product distributiona of the reactionb of ACOM iodides 1 with phenols 2c
Entry
Distribution (%)
1
+
+
2
3
4
ƒƒƒƒƒƒƒƒƒƒ!
O
H
N
O
O
I
1
2
5
95
OH
O
O
OH
H
N
O
O
I
+
38
62
O
CO2CH3
OH
O
3
4
+
+
63
73
37
24
O
I
O
H3COCHN
OH
O
I
a Product distribution determined from 1H NMR spectrum of the crude reaction mixture.
b Reaction conditions: base = K2CO3 (all entries), solvent = acetone (entries 1 and 2) or acetonitrile (entries 3 and 4), room temperature.
c Data in entries 1 and 2 from Ref. 2. Data in entries 3 and 4 from the present work.
though it was unclear whether sterically unhindered
ACOM derivatives of APAP could be synthesized given
the report of Ouyang et al.2 First, we required synthetic
routes to 1 that allowed X = I, R = H, and R0 = short-
chain aliphatic groups.4 This was accomplished by
adopting the method of Fleischmann et al.5 to the pres-
ent case. By this approach, compounds 1a and 1b were
synthesized in one step and in a good yield starting from
trioxane 5 and acid chlorides 6 in the presence of NaI6
(Scheme 2).7 Compounds 1a and 1b were then reacted
with various phenols using a standard protocol1 to
obtain various percentages of 3 and 4.8
If steric hindrance is a key determinate of product distri-
bution as postulated by Ouyang,2 then the coupling of
short-chain aliphatic ACOM iodides with sterically
unhindered phenols should generate mainly acylated
product 4. This did not occur. On the contrary, for the
straight-chain ACOM derivatives studied here, 3 was
the major product in every case regardless of the steric
hindrance presented by 2 or 1. The only instance where
4 formed in preference to 3 was when chloride was used
as the leaving group X9—a result that agrees with an
earlier study.1 It should also be noted that others10,11
have found that the good yields of 3 may be obtained
HO
R''
R
K2CO3, acetone
60-90%
O
O
NaI
R'COCl
6
R'CO2CH(R)I
1
+
Cl2CH2
2a: R'' = NHCOCH3
2b: R'' = H
R
R
O
5
R = H
a: R' = CH3
b: R' = C3H7
a: R' = CH3, R = H (72%)
b: R' = C3H7, R = H (82%)
R'COO
R''
R'CO2CH(R)O
R''
+
3
4
a: R' = CH3, R'' = NHCOCH3
b: R' = C3H7, R'' = H
a: R' = CH3, R = H, R'' = NHCOCH3
b: R' = C3H7, R = H, R'' = H
Scheme 2. Synthesis of ACOM iodides 1 and subsequent reactions of 1 with phenols 2.

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.