Synthesis of aryl ethers from aminoalcohols using polymer-supported triphenylphosphine

Article abstract of DOI:10.1016/S0040-4039(02)00222-8

Optimum conditions for the preparation of aryl-alkyl ethers from N-protected aminoalcohols using polymer-supported triphenylphosphine have been developed. In contrast to previous literature reports, it was discovered that the progress of this reaction is

Full text of DOI:10.1016/S0040-4039(02)00222-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2157–2159
Synthesis of aryl ethers from aminoalcohols using
polymer-supported triphenylphosphine
Mike E. Lizarzaburu and Stephen J. Shuttleworth*
Tularik Inc., Two Corporate Drive, South San Francisco, CA 94080, USA
Received 31 October 2001; revised 29 January 2002; accepted 30 January 2002
Abstract—Optimum conditions for the preparation of aryl–alkyl ethers from N-protected aminoalcohols using polymer-supported
triphenylphosphine have been developed. In contrast to previous literature reports, it was discovered that the progress of this
reaction is greatly improved when a tertiary amine base is employed, along with minor modifications being made to the order of
reagent addition. © 2002 Elsevier Science Ltd. All rights reserved.
The Mitsunobu reaction has become a valuable syn-
thetic method in organic chemistry over the past two
decades. However, a drawback of the approach, which
to the desired products; further, in each case, HPLCMS
analysis of the products indicated the presence of multi-
ple components.
1
5
has implications for parallel synthesis, is the concomi-
tant formation of triphenylphosphine oxide. A number
of procedures geared towards efficient removal of this
by-product have recently been developed. Solid-phase
Mitsunobu syntheses have become established synthetic
protocols over the past 5 years; here, product purifica-
tion is facilitated by washing away triphenylphosphine
oxide and excess reagents from the resin-bound
Subsequently, we conducted a statistically designed
series of experiments in an effort to optimize the origi-
nal reaction conditions. Anhydrous conditions were
employed, the reaction temperature was varied, and
alternative solvents were used; additionally, the effect
of swelling the supported reagent prior to addition of
the other reactants was studied, and alternative azodi-
caboxylates were employed. Disappointingly, in all
cases we were unable to isolate the desired products in
sufficiently acceptable yields and purities.
2
product. Additionally, for solution chemistry, poly-
mer-supported triphenylphosphine has been examined;
upon completion of the reaction, triphenylphosphine
oxide remains bound to the resin, enabling the desired
3
products to be isolated cleanly by filtration.
We did, however, obtain some encouraging results
when a tertiary amine base was used as an additive.
Further, we noted improvements in the progress of the
reactions when the order of reagent addition was
modified, and when aminoalcohols with benzyl protect-
ing groups were used. Table 1 lists a representation of
our results using three synthetic approaches: two routes
developed by ourselves, conducted in the presence and
As part of our investigations into a targeted combinato-
rial library, we chose to study the synthesis of aryl–
alkyl ethers using a solution-based Mitsunobu coupling4
approach with polymer-supported triphenylphosphine.
As an initial point of reference, we examined the
method developed by Georg and co-workers, who had
shown that phenols and alcohols could be combined in
the presence of supported triphenylphosphine in
dichloromethane, and then treated with diethyl axodi-
carboxylate to furnish the desired aryl–alkyl ethers in
6
absence of base (methods A and B, respectively), and
the conditions reported by Georg (method C). All of
the reactions were conducted on a scale of 25 mg of
7
protected aminoalcohol.
3
high purities and yields. Our efforts centered on the
Mitsunobu coupling of phenols with N-Boc-protected
aminoalcohols. However, when we treated a collection
of phenols with N-Boc-(D)-prolinol using the condi-
tions reported by Georg, we observed poor conversion
Initially, we found that Mitsunobu coupling of N-ben-
zyl protected aminoalcohols using Georg’s approach
proceeded with excellent conversion; further, we noted
improved
product
purities
when
supported
triphenylphosphine and diethylazodicarboxylate were
first combined 0°C, followed by addition of a mixture
of aminoalcohol and phenol (Table 1, entries 1–4).
*
0
Corresponding author. E-mail: sshuttleworth@tularik.com
040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00222-8

2
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M. E. Lizarzaburu, S. J. Shuttleworth / Tetrahedron Letters 43 (2002) 2157–2159
Table 1.
Entry
Aminoalcohol
Phenol
Method
% Conversion5
1
2
3
4
5
6
7
8
9
1
1
2
2
3
3
3
3
4
4
4
4
5
6
5
6
5
5
6
6
5
5
6
6
A
A
A
A
A
B
C
B
C
B
C
B
72
64
68
98
15
61
49
75
34
75
16
99
10
11
12
Intrigued by the possible influence of the basic tertiary
amine on the progress of the reaction, we then con-
ducted a series of experiments using the corresponding
Boc-protected aminoalcohols, this time adding triethyl-
amine (1.5 equiv.) to the mixture of phenol and
aminoalcohol. Under these conditions, we observed
good conversion to the desired products (Table 1,
entries 6, 8, 10 and 12); this was in sharp contrast to
the results we obtained when additive base was not
employed (Table 1, entries 5, 7, 9 and 11).
A study of the mechanism of the Mitsunobu esterifica-
tion reaction has previously been conducted by Hughes
9
and co-workers, and we believe that their conclusions
help explain the results of our own investigations.
Scheme 1 summarizes the three steps involved in the
etherification process. The first step, leading to the
formation of the quaternary phosphonium adduct A,
proceeds more rapidly than the subsequent steps. In
order for activation of the protected aminoalcohol to
occur to form the alkoxyphosphonium salt B in Step 2,
8
Scheme 1.

M. E. Lizarzaburu, S. J. Shuttleworth / Tetrahedron Letters 43 (2002) 2157–2159
2159
the hydroxyl group must first be deprotonated prior to the
transfer of supported triphenylphosphine. The phenolate,
generated in Step 1, deprotonates the aminoalcohol, and
hence a key factor governing the rate of formation of B
is the basicity of the phenolate. In cases where the
phenolate is moderately basic, triethylamine assists in
catalyzing Step 2; further, triethylamine promotes the
2. Rano, T. A.; Chapman, K. T. Tetrahedron Lett. 1995, 36,
3789.
3. Tunoori, A. R.; Dutta, D.; Georg, G. I. Tetrahedron Lett.
1998, 39, 8751.
4
. Commercially available from Sigma Aldrich, catalogue
number 36,645-5; loading of 3.0 mmol phosphorous per
gram.
subsequent formation of the phenolate for the SN2
5. Percentage conversion to the desired products was deter-
mined by HPLC at 220 and 254 nm using an Agilent 1100
LC/MSD VL ESI system.
nucleophilic attack at B in Step 3, leading to the desired
product C, and thereby enabling an overall enhanced rate
of reaction. It is conceivable that the basic, N-benzyl
protected tertiary aminoalcohol substrates serve similar
catalytic roles to triethylamine in this process.
6
. Typical procedure for method A: triphenylphosphine on
polystyrene (1.5 equiv.) was treated with diethylazodicar-
boxylate (1.2 equiv.) at 0°C. Following agitation at this
temperature for 5 min, the suspension was treated with a
mixture of N-Boc-aminoalcohol (1.0 weight) and phenol
In summary, we have discovered that the solution-based
Mitsunobu etherification of N-protected aminoalcohols
usingpolymer-supportedtriphenylphosphineisimproved
in the presence of a basic tertiary amine, and also when
thesupportedreagentisinitiallytreatedwithdiethylazodi-
carboxylate followed by addition of a combination
mixture of the additional reagents. Aryl–alkyl ethers are
produced cleanly and rapidly under these conditions.
(
1.0 equiv.), and was then agitated at room temperature
for a further 16 h. The suspension was filtered under
reduced pressure; the filtrate was collected, evaporated
under reduced pressure, and dried to furnish the desired
product. Method B is identical to Method A, except
triethylamine (1.5 equiv.) is added to the aminoalcohol
and phenol mixture.
7
. This reaction was repeated in some, but not all cases, on a
scale of 825 mg of protected aminoalcohol, with similar
percentage conversion to aryl–alkyl ether final product
being observed.
Acknowledgements
We would like to thank Dr. Juan Jaen for his comments.
8. The effect of N-methylmorpholine on the progress of
solid-phase Mitsunobu etherification has been reported,
see: Richter, L. S.; Gadek, T. R. Tetrahedron Lett. 1994,
35, 4705.
References
9. Hughes, D. L.; Reamer, R. A.; Bergan, J. J.; Grabowski,
1
. Mitsunobu, O. Synthesis 1981, 1.
E. J. J. J. Am. Chem. Soc. 1988, 110, 6487.