Convenient preparation of aryl ether derivatives using a sequence of functionalized polymers

Article abstract of DOI:10.1016/S0040-4039(03)01117-1

A four-step synthesis to aryl ether derivatives, three of which utilize polymer-supported reagents, has been developed. Supported triphenylphosphine was successfully utilized in two distinct synthetic processes in the first step, whilst supported base and ionic and covalent scavengers were employed to complete the synthesis and purification of the target compounds.

Full text of DOI:10.1016/S0040-4039(03)01117-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4873–4876
Convenient preparation of aryl ether derivatives using a sequence
of functionalized polymers
Mike E. Lizarzaburu and Stephen J. Shuttleworth*
Tularik Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA
Received 25 March 2003; revised 28 April 2003; accepted 28 April 2003
Abstract—A four-step synthesis to aryl ether derivatives, three of which utilize polymer-supported reagents, has been developed.
Supported triphenylphosphine was successfully utilized in two distinct synthetic processes in the first step, whilst supported base
and ionic and covalent scavengers were employed to complete the synthesis and purification of the target compounds. © 2003
Elsevier Science Ltd. All rights reserved.
Current synthetic approaches in organic chemistry have
benefited greatly from the pioneering work conducted
in the area of functionalized polymers during the 1970s
and 80s.1 In particular, multi-step synthesis using sup-
ported reagents has become a common approach in
synthetic organic chemistry and has been the subject of
steady literature attention from both academic and
industrial laboratories over the past 10 years.2,3 In a
previous communication we outlined an optimized pro-
cedure for the construction of aryl ethers from amino-
alcohols and phenols using polymer-supported
triphenylphosphine.4 That chemistry was carried out as
part of a larger exercise focused towards the develop-
ment of a four-step synthesis of functionalised aryl
ether derivatives; details of this exercise are outlined
below (Fig. 1).
Aryl ethers 1 were designed using a pharmacophore
model as putative ligands for a family of cellular recep-
tors, and we chose to synthesize a targeted combinato-
rial library of derivatives using a sequence of supported
reagents. For the first step, we examined two distinct
uses of supported triphenylphosphine 2.5 As outlined
previously,4 the Mitsunobu coupling of phenols 3 with
N-protected aminoalcohols 4 using 2 in the presence of
triethylamine served as a successful route to the inter-
mediate compounds 8 (Scheme 1), and several deriva-
tives prepared using this approach were used in the
subsequent steps in the compound library synthesis.
In addition to the Mitsunobu route, we also developed
an alternative approach to 8 by using 2 to mediate
chlorination of N-protected aminoalcohol substrates.6
In a typical procedure, 4 was first dissolved in an equal
volume mixture of carbon tetrachloride and
dichloromethane, and the resulting solution was treated
with 2. After 12 h stirring at reflux the corresponding
Figure 1.
Scheme 1.
* Corresponding author.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01117-1

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M. E. Lizarzaburu, S. J. Shuttleworth / Tetrahedron Letters 44 (2003) 4873–4876
alkyl chlorides were isolated in high yields. This proce-
dure was successful for the production of both primary
and secondary alkyl chlorides 5, as illustrated by the
representative examples shown in Table 1.
Upon completion of the reactions, the crude product
mixtures were poured onto sulfonic acid resin 7;8 after
10 min, the suspensions were filtered, and the resins
washed extensively with methanol and dried. The resins
were then treated with a methanolic ammonia solution,
and the products 8 were subsequently isolated following
evaporation of the filtrate in vacuo. A representative set
of data for this step, illustrating the use of substrate 5a,
is shown in Table 2.
To complement the set of protected aminoalcohols
previously synthesized using the Mitsunobu reaction,4
alkyl chloride 5a was treated with phenolates, generated
by treating the phenol substrates 3 with polymer-sup-
ported 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) 6 in
chloroform.7 These nucleophilic displacements were
conducted over the course of 12 h at reflux in the
presence of a catalytic quantity of potassium iodide.
Removal of the N-benzyl or N-BOC protecting groups
from intermediates 8 was then accomplished using 10%
trifluoroacetic acid in dichloromethane or transfer
Table 1.
Entry
1
2
3
4
5
Substrate
4a
4b
4c
4d
4e
Isolated yield of 5 (%)
88
80
94
80
45
Table 2.
Entry
Phenol
Alkyl halide
Conversion to 8 (%)9
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3f
3g
3h
3i
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
99
95
95
85
95
95
95
95
85
60
10
3j

M. E. Lizarzaburu, S. J. Shuttleworth / Tetrahedron Letters 44 (2003) 4873–4876
4875
Table 3.
Entry
1
2
3
4
5
6
7
8
9
10
Amine
9a
10a
90
9a
10b
90
9a
10c
90
9a
10d
90
9a
10e
85
9a
10f
85
9a
10g
85
9a
10h
90
9a
10i
90
9a
10j
85
Sulfonyl chloride
Conversion to 14 (%)9
Entry
Amine
11
9b
10a
60
12
9b
10b
80
13
9b
10c
80
14
9b
10d
80
15
9b
10e
85
16
9b
10f
90
17
9b
10g
75
18
9b
10h
60
19
9b
10i
85
20
9b
10j
60
Sulfonyl chloride
% Conversion to 149
Entry
Amine
21
9c
22
9c
23
9c
24
9c
25
9c
26
9c
27
9c
28
9c
29
9c
30
9c
Sulfonyl chloride
10a
90
10b
50
10c
90
10d
90
10e
90
10f
90
10g
90
10h
85
10i
90
10j
90
% Conversion to 149
Entry
Amine
31
9d
10a
85
32
9d
10b
85
33
9d
10c
85
34
9d
10d
85
35
9d
10e
85
36
9d
10f
85
37
9d
10g
80
38
9d
10h
85
39
9d
10i
85
40
9d
10j
90
Sulfonyl chloride
% Conversion to 149
hydrogenation,10 respectively, to furnish the desired
secondary amines 9. Finally, these products were
treated with a structurally diverse set of sulfonyl chlo-
rides 10 in the presence of polymer-supported Hu¨nig’s
base 1111 using an equal volume mixture of N,N-
dimethylformamide and acetonitrile as solvent. After 16
h stirring at room temperature, the suspensions were
filtered into a bed of aminomethyl polystyrene 1212 to
remove excess sulfonyl chloride. Finally, following
filtration, the product solutions were treated with sup-
ported mesatoic anhydride 1313 to remove any unre-
acted amine 9 and to furnish the desired target
compounds 14. Table 3 depicts examples of products
isolated in this exercise.14
tionalized covalent and ionic scavengers were used for
purification. This method enabled us to rapidly produce
several hundred structurally diverse aryl ether ana-
logues in high conversion.
Acknowledgements
We would like to thank Richard Connors and Mal-
gorzata Wan˜ska for their assistance with this work.
References
In summary, a convenient multi-step sequence to func-
tionalised aryl ether derivatives using a series of poly-
mer supported reagents has been developed, in which
supported triphenylphosphine was utilized efficiently in
both Mitsunobu coupling and chlorination, and func-
1. (a) Akelah, A.; Sherrington, D. C. Chem. Rev. 1981, 81,
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1369 and references cited therein.
2. (a) Parlow, J. J.; Flynn, D. L. Tetrahedron 1998, 54, 4013;
(b) Parlow, J. J. Tetrahedron Lett. 1995, 36, 1395.

4876
M. E. Lizarzaburu, S. J. Shuttleworth / Tetrahedron Letters 44 (2003) 4873–4876
3. (a) Kirshning, A.; Monenshein, H.; Wittenberg, R.
10. Typical protocol involved treating a methanolic solution
of the substrate with wet palladium on carbon (Aldrich
catalogue c 33,010-8, 3 weight equivalents) with 5%
formic acid over a 12 h period. Following removal of the
inorganic residue by filtration, the product was isolated
following evaporation of the filtrate under reduced pres-
sure.
Angew. Chem., Int. Ed. 2001, 40, 650; (b) Dahmen, S.;
Bra¨se, S. Synthesis 2001, 1431; (c) Ley, S. V.; Baxendale,
I. R.; Bream, R. N.; Jackson, P. S.; Leach, A. G.;
Longbottom, D. A.; Nesi, M.; Scott, J. S.; Storer, R. I.;
Taylor, S. J. J. Chem. Soc., Perkin Trans. 1 2000, 3815.
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11. Commercially-available from Polymer Laboratories Ltd.,
catalogue c 3413-4679.
5. Commercially-available from Sigma-Aldrich Inc., cata-
12. Commercially available from Novabiochem Inc.; cata-
logue c 01-64-0177.
logue c36,645-5.
6. For examples of halogenation mediated by supported
triphenylphosphine, see: (a) Harrison, C. R.; Hodge, P.;
Hunt, B. J.; Khoshdel, E.; Richardson, G. J. Org. Chem.
1983, 48, 3721; (b) Dabbagh, A.-H.; Mallakpour, S. E.;
Faghihi, K. Ir. Polym. J. 1998, 7, 149.
13. Commercially available from Novabiochem Inc.; cata-
logue c 01-64-0317.
14. Data for selected examples: Table 3 entry 3: lH (400
MHz, CDCl3) 7.8 (2H, d), 7.60 (2H, d), 6.65 (1H, d), 6.40
(1H, s), 6.25 (1H, d), 5.90 (2H, s), 4.15 (1H, m), 3.20–3.15
(4H, m), 2.10–1.80 (4H, m) 1.10 (9H, s); M+1 found
418.1; C22H27NO5S exact mass: 417.16. Table 3 entry 30:
lH (400 MHz, CDCl3) 7.45 (2H, d), 6.7 (1H, s), 6.50 (1H,
s), 6.35 (1H, s), 5.90 (2H, s), 4.20 (2H, d), 3.75 (3H, s),
3.20 (1H, m), 2.10-1.40 (6H, m); M+1 found 366.1;
C16H19N3O5S requires 365.10.
7. Commercially-available from Polymer Laboratories Ltd.,
catalogue c3414-1679.
8. Commercially-available from Polymer Laboratories Ltd.,
catalogue c 3404-4679.
9. Percentage conversion to the desired products was deter-
mined by HPLC at 220 nm and 254 nm using an Agilent
1100 LC/MSD VL ESI system.