A simple method for chemoselective phenol alkylation

Article abstract of DOI:10.1016/j.tetlet.2007.08.030

A simple and effective method for chemoselective alkylation of phenol over carboxylic acid using a 40% aqueous solution of tetrabutylphosphonium hydroxide that affords the desired phenyl ethers in 82-99% yield is described.

Full text of DOI:10.1016/j.tetlet.2007.08.030

Tetrahedron Letters 48 (2007) 7380–7382
A simple method for chemoselective phenol alkylation
Pingli Liu,* Liang Huang and Margaret M. Faul
Chemical Process R&D, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States
Received 21 June 2007; revised 1 August 2007; accepted 3 August 2007
Available online 11 August 2007
Abstract—A simple and effective method for chemoselective alkylation of phenol over carboxylic acid using a 40% aqueous solution
of tetrabutylphosphonium hydroxide that affords the desired phenyl ethers in 82–99% yield is described.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Phenolic ethers and carboxylic acids are found in a vari-
ety of active pharmaceutical ingredients in the pharma-
ceutical industry, for instance the potent fibrinogen
receptor antagonist MK-383 (1),1 and the PPAR a/c
agonist (2)2 (Fig. 1). In addition, phenol ethers are
important intermediates in medicinal chemistry.3 Syn-
thesis of these compounds typically suffers from the need
to use protecting groups to obtain improved chemose-
lectivity of ether formation relative to esterification. A
variety of methods for chemoselective esterification have
been developed,4 however, a method for chemoselective
alkylation of phenols over carboxylic acids has not been
reported. Phenolic ethers are generally prepared in two
ways: (i) Fisher ester formation, phenol alkylation,
and ester saponification;5 or (ii) dialkylation of both
the phenol and carboxylic acid followed by selective es-
ter saponification.2,6 However, for rapid SAR evalua-
tion or large scale synthesis of compounds in clinical
development these methods are economically inefficient,
time consuming, require an excess of reagents and/or
precious alkylating agents, and are not suitable for mol-
ecules that are sensitive to acid and/or base.
In support of a recent medicinal chemistry SAR effort to
evaluate ether analogs of 3, we developed a one-step
method for chemoselectively synthesizing phenolic
ethers in the presence of carboxylic acid functional
groups. Although the original medicinal chemistry pro-
cedure proceeded in three steps with reasonable yields
via Fisher ester formation, phenol alkylation, and ester
saponification, it was inefficient due to the number of
steps and time required to perform this simple opera-
tion. Herein we report a new and practical method for
the chemoselective alkylation of phenols in the presence
of carboxylic acids. The process, which was demon-
strated with a variety of alkylating agents and across
multiple substrates, occurs in high yield (82–99%) using
readily available reagents.
Our initial screen to evaluate the chemoselective alkyl-
ation of phenols over carboxylic acids used 4-hydroxy-
benzoic acid 4 as a representative substrate. Treatment
of 4 with allyl bromide using a variety of bases (NaOH,
KOH, Cs(OH)2, and n-Bu4NOH) and solvents (THF,
N-methylpyrrolidinone, N,N-dimethylformamide, di-
methyl sulfoxide, and ethanol), afforded a mixture of
both allyl ether and allyl ester. The best selectivity was
observed using n-Bu4NOH. Using 2 equiv n-Bu4NOH
the bis-tetrabutylammonium salt of 4 was generated that
upon reaction with 1 equiv allyl bromide afforded an
85:15 ratio7 of allyl ether/allyl ester.
O
HN
MK-383 (1)
OH
(n-Bu)O2SNH
O
O
Me2N
O
Me
OH
Tetrabutylphosphonium salts exhibit good chemical8
and thermal stability9 and have lower toxicity10 than
ammonium salts. In addition, tetrabutylphosphonium
salts have been used to dramatically increase the
nucleophilicity of the fluoride anion, which has been
used to advantage in the chemoselective esterification
of hydroxybenzoic acids in ionic liquids.4b Since the
pKa difference of phenol relative to carboxylic acid is
H
N
OEt
CO2H
O
O
(3)
PPAR α/γ agonist (2)
Et
RO
Figure 1.
*
Corresponding author. Tel.: +1 805 477 0599; fax: +1 805 375
4531; e-mail: mfaul@amgen.com
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.08.030

P. Liu et al. / Tetrahedron Letters 48 (2007) 7380–7382
7381
about five orders of magnitude (ꢀ9.7–4.7 in H2O),
chemoselective alkylation of phenol relative to a carbox-
ylic acid should be feasible by selection of the right base,
counterion, and solvent.
variety of aromatic or heteroaromatic substrates affor-
ded the corresponding allyl or benzyl ethers in 82–99%
yield. All reactions were highly chemoselective (100:1)
with no competitive esterification observed by HPLC.
Thus, upon treatment of 4-hydroxybenzoic 4 with
2 equiv 40% aqueous tetrabutylphosphonium hydroxide
(n-Bu4POH) in THF at 0 ꢁC, the bis tetrabutylphospho-
nium salt was generated that upon reaction with 1 equiv
allyl bromide chemoselectively afforded 4-(allyloxy)ben-
zoic acid 5 with no competing esterification. The scope
of these conditions were evaluated using a variety of
alkylating reactants (Table 1, Eq. 1). Ethyl, allyl, and
benzyl bromide reacted chemoselectively to afford the
corresponding ether in 91–94% yield. In addition, allyl
chloride afforded an 86% yield of the corresponding allyl
ether and a 90% yield of the benzyl ether, although the
reaction times were longer.
Homogeneous, single-phase reaction mixtures were
maintained throughout the alkylation process. Upon
reaction completion, the mixtures were concentrated to
remove THF, and the resulting aqueous solution was
acidified to liberate the corresponding acid. All com-
pounds described in Tables 1 and 2 could be isolated
as a solid without chromatography. Those products that
were oils, for example, 5-hydroxy-1H–indole-carboxylic
acid (Table 2, entry 8) were converted into the corre-
sponding salt to facilitate isolation.
Finally, this method proved generally applicable for the
rapid synthesis of analogs of 3 for medicinal chemistry
and in vivo evaluation. For example, treatment of
hydroxy acid 8, with thiazalyl chloride 9 afforded the
desired ether 3 chemoselectively in 90% yield with no
competing esterification. This method proved very
robust for scaleup and further work in this area will
be reported in due course.
O
O
n-Bu4P+OH- (2.0 equiv)
R-X (1.0 equiv)
OH
OH
ð1Þ
HO
RO
5
4
THF
Table 1. Alkylation of 4-hydroxybenzoic acid 4 (Eq. 1)
Entry
R–X
Yield 5a,b,c (%)
n-Bu4P+OH-
(2.0 equiv)
Me2N
O
Me2N
O
1
2
3
4
5
Allyl –Br
Allyl–Cl
Ethyl–Br
Benzyl–Br
Benzyl–Cl
91
86
93
94
90d
CO2H
CO2H
R-X (1.0 equiv)
THF
RO
HO
3
8
ð3Þ
a Reactions were carried at 5 mmol substrate in 10 mL THF with
2 equiv 40% aq n-Bu4POH and 1 equiv R–X at 0 ꢁC.
b Yields are isolated and unoptimized.
S
N
Cl
Me
Me
HCl
R-X =
c All products exhibit satisfactory spectroscopic and physical
properties.
9
Yield = 90%
d 72 h reaction time.
In conclusion, we have developed a new method for the
chemoselective alkylation of phenols over carboxylic
acids using a 40% aqueous solution of tetrabutylphos-
phonium hydroxide that affords the corresponding phe-
nol ethers in high yields (82–99%).
The scope of substrates was evaluated using allyl or benz-
yl bromide as the alkylating agent (Table 2, Eq. 2).11
A
O
O
n-Bu4P+OH- (2.0 equiv)
R - Br (1.0 equiv), THF
(
(
n
HO
OH
RO
OH
n
ð2Þ
X
X
Acknowledgments
6
7
Table 2. Chemoselective alkylation of a variety of substrates (Eq. 2)
Entry Substrate, 6 R–Br
Yield 7a,b,c (%)
Dr. Eric Bercot and Dr. Shawn Walker are acknowl-
edged for providing helpful suggestions.
1
2
3
4
4-Hydroxyphenyl acetic acid Allyl–Br 89
3-Hydroxyphenyl acetic acid Allyl–Br 83
Supplementary data
3-Hydroxy benzoic acid
4-Hydroxy-3-methoxy
mandelic acid
Allyl–Br 84
Allyl–Br 99d
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2007.08.030.
5
4-Hydroxy-3-methoxy
mandelic acid
Bn–Br
83
6
7
8
2-Hydroxy nicotinic acid
2-Hydroxy nicotinic acid
5-Hydroxy-1H–indole-
carboxylic acid
Allyl–Br 85
Bn–Br
Bn–Br
88
82
References and notes
a Reactions were carried at 5 mmol substrate in 10 mL THF with
2 equiv 40% aq n-Bu4POH and 1 equiv R–Br at 0 ꢁC.
b Yields are isolated and optimized.
1. (a) Hartman, G. D.; Egberston, M. S.; Halczenko, W.;
Laswell, W. L.; Duggan, M. E.; Smith, R. L.; Naylor, A.
M.; Manno, P. D.; Lynch, R. J.; Zhang, G.; Chang,
C.T.-C.; Gould, R. J. J. Med. Chem. 1992, 35, 4640–4642;
(b) Chuang, J. Y. L.; Zhao, D.; Hughes, D. L.; Grabow-
ski, E. J. J. Tetrahedron 1993, 49, 5767–5776.
c All products exhibit satisfactory spectroscopic and physical
properties.
d Weight percent assay yield.

7382
P. Liu et al. / Tetrahedron Letters 48 (2007) 7380–7382
2. Aikins, J. A.; Haurez, M.; Rizzo, J. R.; Van Hoeck, J.-P.;
AS12DS031002WT; Temp 40 ꢁC; Flow rate 0.5 mL/min;
Detection—UV @ 220 nm and 280 n; Mobile Phase
A = CH3CN/0.07%HClO4; B = H2O/0.07%HClO4; Gra-
dient—T (0 min) 90% A:10% B. T (11 min) 10% A; 90% B.
8. Ramnial, T.; Ino, D. D.; Clyburne, J. A. C. Chem.
Commun. 2005, 325–327.
9. (a) Del Sesto, R. E.; Corley, C.; Robertson, A.; Wilkes, J.
S. J. Organomet. Chem. 2005, 690, 2536–2542; (b)
Kagimoto, J.; Fukumoto, K.; Ohno, H. Chem. Commun.
2006, 2254–2256.
Brione, W.; Kestemont, J.-P.; Stevens, C.; Lemair, X.;
Stephenson, G. A.; Marlot, E.; Forst, M.; Houpis, I. N.
J. Org. Chem. 2005, 70, 4695–4705.
3. (a) Rotella, D. P.; Sun, Z.; Zhu, Y.; Krupinski, J.;
Pongrac, R.; Seliger, L.; Normandin, D.; Macor, J. E.
J. Med. Chem. 2000, 43, 5037–5043; (b) Xu, G.; Hartman,
T. L.; Wargo, H.; Turpin, J. A.; Buckheit, R. W.;
Cushman, M. Bioorg. Med. Chem. 2002, 10, 283–290; (c)
Tillekeratne, L. M. V.; Sherette, A.; Grossman, P.; Hupe,
L.; Hupe, D.; Hudson, R. A. Bioorg. Med. Chem. Lett.
2001, 11, 2763–2767.
4. (a) Guo, W.; Li, J.; Fan, N.; Wu, W.; Zhou, P.; Xia, C.
Syn. Commun. 2005, 35, 145–152; (b) Biondini, D.;
Brinchi, L.; Germani, R.; Savelli, G. Lett. Org. Chem.
2006, 3, 207–211.
5. (a) Lewin, A. H.; Szewczyk, J.; Wilson, J. W.; Carroll, F.
I. Tetrahedron 2005, 61, 7144–7152; (b) Gaucher, A.;
Dutot, L.; Barbeau, O.; Hamchaoui, W.; Wakselman, M.;
Mazaleyrat, J.-P. Tetrahedron: Asymmetry 2006, 16, 857–
864; (c) Penso, M.; Albanese, D.; Landini, D.; Lupi, V.;
Scaletti, D. Synlett 2006, 741–744.
6. (a) Dostert, P.; Varasi, V.; Torre, A. D.; Monti, C.; Rizzo,
V. Eur. J. Med. Chem. 1992, 27, 57–59; (b) Casimir, J. R.;
Tourwe, D.; Iterbeke, K.; Guichard, G.; Briand, J.-P. J.
Org. Chem. 2000, 65, 6487–6492; (c) Eicher, T.; Ott, M.;
Speicher, A. Synthesis 1996, 755–762; (d) Belletire, J. L.;
Fry, D. F. J. Org. Chem. 1988, 53, 4724–4729.
10. Cieniecka-Roslonkiewicz, A.; Pernak, J.; Kubis-Feder, J.;
Ramani, A.; Robertson, A. J.; Seddon, K. R. Green Chem.
2005, 7, 855–862.
11. General procedure for phenol alkylation: To a solution of
phenol (5 mmol, 1 equiv) and 40% aq n-Bu4POH
(10 mmol, 2 equiv) in THF (10 mL) was added the
alkylating reagent (5 mmol, 1 equiv) at 0 ꢁC. The reaction
mixture was allowed to warm to ambient temperature and
stirred until complete, as monitored by HPLC. Typical
reactions times were 1–3 h using allyl bromide as the
alkylating agent, although longer reaction times >48 h
were observed using allyl chloride. With benzyl bromide
reaction times of 4–24 h were common. Upon reaction
completion, the solvent (THF) was removed in vacuo and
the aqueous residue acidified with 2N aqueous HCl. The
product precipitated out of solution and was isolated by
filtration, followed by water wash. The resultant wet cake
was dried in an oven under vacuum to give a white solid.
Products that were oils were converted to salts prior to
isolation (see Supplementary data).
7. Determined using an Aligent HPLC. Column YMC
Pro. C18 S-3 120A, 2.0 · 100 mm, Part No: