Rasta resin-PPh3 and its use in chromatography-free wittig reactions

Article abstract of DOI:10.1055/s-0030-1258130

Rasta resin-PPh₃, a new heterogeneous polystyrene-based phosphine, has been synthesized and used in one-pot Wittig olefination reactions of aldehydes. In these reactions an excess of rasta resin-PPh₃ was used for the in situ generation of the phosphorane reactant and allowed for isolation of a high yield of very pure alkene product after only filtration and solvent removal. The excellent results obtained in this study are attributed to the flexible nature of the rasta resin structure, which makes it less dependant upon swelling than other heterogeneous polystyrene materials previously used to support phosphine reagents in Wittig reactions. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1258130

CLUSTER
1997
Rasta Resin-PPh and its Use in Chromatography-Free Wittig Reactions
3
R
P
asta
R
esin-P
e
3
Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, P. R. of China
Fax +85228571586; E-mail: phtoy@hku.hk
Received 19 April 2010
oxide byproduct can be removed from the desired product
simply by filtration, and this is the focus of the current re-
search.
Abstract: Rasta resin-PPh , a new heterogeneous polystyrene-
based phosphine, has been synthesized and used in one-pot Wittig
olefination reactions of aldehydes. In these reactions an excess of
3
rasta resin-PPh was used for the in situ generation of the phospho-
3
There have been numerous reports in the literature regard-
rane reactant and allowed for isolation of a high yield of very pure
alkene product after only filtration and solvent removal. The excel-
lent results obtained in this study are attributed to the flexible nature
of the rasta resin structure, which makes it less dependant upon
swelling than other heterogeneous polystyrene materials previously
used to support phosphine reagents in Wittig reactions.
ing the use of heterogeneous polystyrene-supported Ph P
3
5
reagents in Wittig reactions. However, despite the fact
that such phosphines are commercially available from nu-
merous sources, this methodology has not been widely
used. This is perhaps due to the wide range of results re-
ported in the literature. For example, the most recent de-
tailed study of such polymer-assisted reactions was
Key words: polymer-supported reagent, polystyrene, phosphine,
phosphorane, Wittig reaction
6
reported by Westman. He performed one-pot reactions in
which the aldehyde substrate was mixed together with the
reagents required for the in situ generation of the phos-
phorane reagent, with microwave heating, and reported
isolated yields of pure product ranging from 0–95% (15
examples) after preparative reverse-phase HPLC
Carbon–carbon double bonds constitute one of the central
functional groups in organic chemistry and an important
method for synthesizing such bonds is the Wittig reaction.
This transformation involves the use of a phosphorane re-
agent to transfer an alkylidene group to an aldehyde or ke-
tone group, with concurrent transfer of the original
7
(
Scheme 2).
1
carbonyl oxygen to phosphorous (Scheme 1). Usually the
phosphorane is prepared by reaction of a tertiary phos-
PS
PPh3,
O
O
2
K CO , MeOH,
3
R1
+
R2
R2
+
PS
PPh3
Br
phine, typically Ph P, with an alkyl halide followed by
150 °C (MW), 5 min
3
R1
H
deprotonation of the thus formed phosphonium salt with
an appropriate base.
PS = divinylbenzene cross-linked polystyrene
Scheme 2 One-pot Wittig reactions
R1
R2
R4
R3
R1
R2
R4
R3
O
+
Ph3P
+
Ph3P
O
We have synthesized and studied numerous polymer-sup-
ported phosphines,8 and based on our observation that
the presence of polar groups reduces the ability of cross-
,9
Scheme 1 The Wittig reaction
1
0
linked polystyrene to swell, agreed with the notion that
While the Wittig reaction is very reliable and predictable, the poor results reported in the literature were most likely
one of its shortcomings is the fact that a stoichiometric due to the structure of the polymer-supported phosphines
amount of a phosphine oxide byproduct is formed that used and their need to be swollen so that substrate mole-
must be separated from the desired alkene product. This cules can access all of the phosphorane groups.11 There-
drawback and the associated costs of product purification fore, in order to avoid the issue of decreased polymer
in terms of manpower, solvent, and waste generated, lim- swelling caused by the presence of a high concentration of
its the use of the Wittig reaction in industrial applications, phosphorane groups, we wanted to prepare a heteroge-
and thus, more environmentally benign methods for per- neous polymer-supported phosphine for which substrate
2
forming this transformation are highly desirable. One accessibility is not dependant upon swelling, and use it in
strategy that has been examined to address this issue and Wittig reactions. While numerous organic polymer struc-
to make the Wittig reaction less polluting involves chang- tures have been used to support reagents for organic syn-
1
2
ing the role of the phosphine reagent, or a surrogate for it, thesis, we were drawn to the rasta resin architecture that
3
,4
to that of a catalyst. Another approach has been to use a has functional group bearing grafts attached to a cross-
heterogeneous supported phosphine reagent so that the linked polystyrene core, since the location of the reagent
groups on flexible and solvent-accessible ‘hairs’ should
reduce or eliminate the need for resin swelling
SYNLETT 2010, No. 13, pp 1997–2001
Advanced online publication: 09.07.2010
x
x
.x
x
.2
0
1
0
13
(
Figure 1).
DOI: 10.1055/s-0030-1258130; Art ID: Y01010ST
©
Georg Thieme Verlag Stuttgart · New York

1
998
P. S.-W. Leung et al.
CLUSTER
R
living radical polymerization
initiation groups
heterogeneous
core
nO N
PS
flexible functionalized
grafts
Figure 1 The rasta resin concept
Figure 2 SEM images
In order to prepare rasta resin-PPh (RR-PPh ), we first
3
3
synthesized the heterogeneous core 1, which bears living compared to the alkyl halide (1.5 equiv) so that the later
radical polymerization initiator groups (Scheme 3). This would completely react with the polymer-bound phos-
was achieved by suspension co-polymerization of the phine groups, and not be mixed with the desired product
1
4
16
JandaJel cross-linker (2), chosen over more typically at the end of the reaction. Furthermore, it was anticipat-
used divinylbenzene due to its increased flexibility, with ed that the triethylammonium salt formed could be re-
the ether formed between reduced TEMPO and 4-vinyl- moved by filtration through silica gel, and that the excess
1
5
benzyl chloride (3). It should be noted, however, that in Et N used would be volatile. Thus, only minimal product
3
principle any cross-linker, including divinylbenzene, purification would be required. As can be seen in Table 1,
should work with the rasta resin concept. Core 1 was then reaction conditions were optimized for each alkyl halide,
subjected to co-polymerization of phosphine bearing since some were less reactive than others, and from our
8
a
monomer 4 and styrene (for additional flexibility) to af- observations, formation of the phosphonium salt was gen-
ford RR-PPh . This material was characterized by ele- erally rate limiting in the reaction sequence. Some repre-
3
mental analysis to determine the phosphine loading level sentative literature results using Ph P in corresponding
3
3
1
(
0.97 mmol/g), and P NMR analysis was performed to reactions are included for comparison.
1
5
confirm the oxidation state of the phosphine groups. Fi-
nally, SEM analysis was conducted to compare the size
and morphology of 1 and RR-PPh . As can be seen in
Figure 2 (scale: 1 cm = 1 mm) both 1 and RR-PPh are
generally spherical in shape, and the latter grew to be
much larger in diameter than its precursor.
The alkyl halides studied in these reactions included a pri-
mary a-halo ester (entries 1–4), a secondary a-halo ester
entries 5–8), a pair of a-halo ketones (entries 9–13), and
a a-halo amide (entries 14 and 15). The aldehydes exam-
ined included various benzaldehydes (both electron rich
and poor), an aliphatic (3-phenylpropanal), and an allylic
3
(
3
After scaling up the synthesis and preparing 10’s of grams (trans-cinnamaldehyde) aldehyde. These reactants were
of RR-PPh , we examined its use in one-pot Wittig reac- combined randomly to test the versatility and generality of
3
tions with a range of aldehyde substrates and alkyl halide our methodology. Gratifyingly, conditions were found
reagents (Table 1). For these reactions we used Et N as that allowed for very high yield of all desired products to
3
the base for the deprotonation of the in situ formed phos- be formed. The fact that these reactions work well with
phonium salt, and a larger excess of RR-PPh (2.0 equiv) both CH Cl (entries 1–13) and 1-PrOH (entries 14 and
3
2
2
suspension
polymerization
O
N
+
JJ
AIBN, PhCl,
acacia solution, 85 °C
O
O
1
O
N
JJ = JandaJel
2
JandaJel
crosslinker
3
PPh2
styrene, 130 °C
1
+
JJ
6
O
N
1
PPh2
4
RR-PPh3
0.97 mmol/g)
(
Scheme 3 Synthesis of RR-PPh3
Synlett 2010, No. 13, 1997–2001 © Thieme Stuttgart · New York

CLUSTER
Rasta Resin-PPh3
1999
1
1
5) as the solvent highlights the versatility of RR-PPh3 ucts was detected by H NMR. Finally, the ratios of E- to
and demonstrates that resin swelling is not mandatory. Z-stereoisomers were similar to what has been reported in
7,15
Regardless of the exact conditions used, essentially quan- the literature for similar reactions using Ph P.
Thus,
3
titative yield of the expected mixture of E- and Z-stereo- these reactions were simple to perform, and isolation of
isomers of the alkene product was recovered after only pure products produced much less waste than is normally
filtration of the reaction mixture through a plug of silica the case with typical Wittig reactions.
gel, washing of the polymer and removal of the solvent.
Significantly, in all cases the product was highly pure and
no trace of contamination by phosphine or amine byprod-
Table 1 Wittig Reactions Using RR-PPh316
O
O
O
RR-PPh3, Et3N
X
+
R3
R1
R3
R1
solvent
H
R2
R2
X = Cl or Br
5 (major isomer)
Entry Aldehyde
Alkyl halide
Solvent
Temp (°C)
25
Time (h)
12
Yield (%)a
a 92
E/Zb
O
5
96:4
O
c
(99:1)c
1
CH Cl
(96)
2
2
2
2
2
2
H
H
Br
d
d
(
93)
(93:7)
OEt
Br
O
O
2
3
4
5
CH Cl
25
25
25
50
12
72
72
36
5b 98
5c 98
83:17
93:7
2
Br
OEt
O
H
O
O
CH Cl
2
Br
OEt
O
O
H
O
5d 96
90:10
CH Cl
2
(82)c
(99:1)c
Br
OEt
O
O
CH Cl
5e 97
5f 98
98:2
97:3
Br
2
H
OEt
O
H
O
6
CH Cl
50
30
Br
2
2
OEt
O2N
O
H
O
7
8
9
O
O
CH Cl
50
50
50
72
72
36
5g 98
5h 94
5i 96
97:3
92:8
99:1
Br
2
2
2
2
OEt
O
H
O
CH Cl
Br
2
OEt
O
O
CH Cl
2
H
Cl
O
H
O
1
0
CH Cl
50
24
5j 98
99:1
2
2
Cl
O2N
Synlett 2010, No. 13, 1997–2001 © Thieme Stuttgart · New York

2
000
P. S.-W. Leung et al.
CLUSTER
Table 1 Wittig Reactions Using RR-PPh316 (continued)
O
O
O
RR-PPh3, Et3N
X
+
R3
R1
R3
R1
solvent
H
R2
R2
X = Cl or Br
5 (major isomer)
Entry Aldehyde
Alkyl halide
Solvent
Temp (°C)
50
Time (h)
60
Yield (%)a
E/Zb
O
H
O
1
1
1
2
CH Cl
5k 98
99:1
2
2
2
Cl
O
O
5
(91)
l 98
96:4
(90:10)
Br
CH Cl
50
50
72
22
2
d
d
H
O
H
O
5
m 98
96:4
(93:7)
1
3
Br
CH Cl
2
2
d
d
(
93)
O2N
O
O
1
1
4
5
Br
1-PrOH
1-PrOH
50
50
36
72
5n 98
5o 97
96:4
94:6
H
N
O
H
O
Br
N
Br
a
b
c
d
Isolated yield of reactions using 0.5 mmol of aldehyde.
Determined by H NMR analysis.
Taken from ref. 7b.
Taken from ref. 7c.
1
In conclusion, we have applied the rasta resin architecture Acknowledgment
in the synthesis of a novel heterogeneous polystyrene-
This research was supported financially by the University of Hong
Kong and the Research Grants Council of the Hong Kong S. A. R,
P. R. of China (Project No. HKU 704108P). We thank Polymer
based phosphine, RR-PPh , and used this material as a re-
3
agent in a wide range of one-pot Wittig reactions. In all
cases studied, the product from these reactions did not re- Laboratories (Paul Boguszewski) for gifts of materials.
quire purification beyond filtration, and was isolated in
essentially quantitative yield. The high yields obtained in
this study are significantly better than what has been pre-
References and Notes
viously reported using other heterogeneous polymer-sup-
(1) (a) Wittig, G.; Geissler, G. Liebigs Ann. Chem. 1953, 580,
44. (b) Wittig, G.; Schollkopf, U. Chem. Ber. 1954, 87,
ported Ph P reagents. Encouraged by these findings, we
3
1318.
are currently examining the use of RR-PPh to prepare
3
(
2) Constable, D. J. C.; Dunn, P. J.; Hayler, J. D.; Humphrey,
G. R.; Leazer, J. L. Jr.; Linderman, R. J.; Lorenz, K.;
Manley, J.; Pearlman, B. A.; Wells, A.; Zaks, A.; Zhang, T.
Y. Green Chem. 2007, 9, 411.
preformed phosphoranes and the application of these with
microwave heating in order to improve the Wittig reaction
methodology we describe here by shortening the required
reaction time. Furthermore we are investigating the recy-
(3) For the use of a phosphine catalyst in Wittig reactions, see:
(a) O’Brien, C. J.; Tellez, J. L.; Nixon, Z. S.; Kang, L. J.;
Carter, A. L.; Kunkel, S. R.; Przeworski, K. C.; Chass, G. A.
Angew. Chem. Int. Ed. 2009, 48, 6836. (b) Marsden, S. P.
Nature Chem. 2009, 1, 685.
cling of the oxidized RR-PPh recovered at the end of the
3
reactions using the mild conditions recently reported by
1
7
Tanaka and co-workers. The results of these studies will
be reported in due course.
(
4) For the use of arsine or telluride catalysts in Wittig reactions,
see: (a) Shi, L.; Wang, W.; Wang, Y.; Huang, Y.-Z. J. Org.
Chem. 1989, 54, 2027. (b) Huang, Z.-Z.; Ye, S.; Xia, W.;
Yu, Y.-H.; Tang, Y. J. Org. Chem. 2002, 67, 3096.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
(
(
c) Huang, Z.-Z.; Tang, Y. J. Org. Chem. 2002, 67, 5320.
d) Cao, P.; Li, C.-Y.; Kang, Y.-B.; Xie, Z.; Sun, X.-L.;
Tang, Y. J. Org. Chem. 2007, 72, 6628.
Synlett 2010, No. 13, 1997–2001 © Thieme Stuttgart · New York

CLUSTER
Rasta Resin-PPh3
2001
(
5) (a) Camps, F.; Castells, J.; Font, J.; Vela, F. Tetrahedron
2001, 3, 1. (d) Wisnoski, D. D.; Leister, W. H.; Strauss,
K. A.; Zhao, Z.; Lindsley, C. W. Tetrahedron Lett. 2003, 44,
4321. (e) Fournier, D.; Pascual, S.; Montembault, V.;
Haddleton, D. M.; Fontaine, L. J. Comb. Chem. 2006, 8,
522. (f) Fournier, D.; Pascual, S.; Montembault, V.;
Fontaine, L. J. Polym. Sci. A: Polym. Chem. 2006, 44, 5316.
(g) Pawluczyk, J. M.; McClain, R. T.; Denicola, C.;
Mulhearn, J. J.; Rudd, D. J.; Lindsley, C. W. Tetrahedron
Lett. 2007, 48, 1497. (h) Chen, G.; Tao, L.; Mantovani, G.;
Geng, J.; Nystroem, D.; Haddleton, D. M. Macromolecules
2007, 40, 7513.
Lett. 1971, 1715. (b) McKinley, S. V.; Rakshys, J. W.
J. Chem. Soc., Chem. Commun. 1972, 134. (c) Heitz, W.;
Michels, R. Angew. Chem., Int. Ed. Engl. 1972, 11, 298.
(
d) Clarke, S. D.; Harrison, C. R.; Hodge, P. Tetrahedron
Lett. 1980, 21, 1375. (e) Akelah, A. Eur. Polym. J. 1982, 18,
59. (f) Bernard, M.; Ford, W. T.; Nelson, E. C. J. Org.
5
Chem. 1983, 48, 3164.
(6) Westman, J. Org. Lett. 2001, 3, 3745.
(
7) (a) Wu, J.; Yue, C. Synth. Commun. 2006, 36, 2939; and
references cited therein. (b) Choudary, B. M.; Mahendar,
K.; Kantam, M. L.; Ranganath, K. V. S.; Athar, T. Adv.
Symth. Catal. 2006, 348, 1977. (c) El-Batta, A.; Jiang, C.;
Zhao, W.; Anness, R.; Cooksy, A. L.; Bergdahl, M. J. Org.
Chem. 2007, 72, 5244.
(14) (a) Toy, P. H.; Janda, K. D. Tetrahedron Lett. 1999, 40,
6329. (b) Toy, P. H.; Reger, T. S.; Janda, K. D. Aldrichimica
Acta 2000, 33, 87. (c) Toy, P. H.; Reger, T. S.; Garibay, P.;
Garno, J. C.; Malikayil, J. A.; Liu, G.-Y.; Janda, K. D.
J. Comb. Chem. 2001, 3, 117. (d) Choi, M. K. W.; Toy,
P. H. Tetrahedron 2004, 60, 2903.
(
8) For cross-linked polymers, see: (a) Kwok, M.; Choi, W.;
He, H. S.; Toy, P. H. J. Org. Chem. 2003, 68, 9831.
(
b) Zhao, L. J.; He, H. S.; Shi, M.; Toy, P. H. J. Comb. Chem.
(15) See Supporting Information for details.
2
004, 6, 680.
(16) General Procedure for Wittig Reactions
(
9) For non-cross-linked polymers, see: (a) Harned, A. M.; He,
H. S.; Toy, P. H.; Flynn, D. L.; Hanson, P. R. J. Am. Chem.
Soc. 2005, 127, 52. (b) He, H. S.; Yan, J. J.; Shen, R.; Zhuo,
S.; Toy, P. H. Synlett 2006, 563. (c) Kwong, C. K.-W.;
Huang, R.; Zhang, M.; Shi, M.; Toy, P. H. Chem. Eur. J.
To a solution of the aldehyde (0.5 mmol) and the alkyl halide
(0.75 mmol) in the appropriate solvent (5 mL), was added
RR-PPh (1.0 mmol), followed by Et N (1.0 mmol). The
3
3
reaction mixture was stirred at the indicated temperature
until TLC analysis indicated that the aldehyde was
completely consumed, and then filtered through a plug of
silica gel. After washing the polymer with CH Cl (2 × 50
2007, 13, 2369.
(
10) Zhao, L.-J.; Kwong, C. K.-W.; Shi, M.; Toy, P. H.
2
2
Tetrahedron 2005, 61, 12026.
mL) the combined filtrate was concentrated in vacuo to
afford pure product. All alkene products were characterized
(
(
(
11) Bernard, M.; Ford, W. T. J. Org. Chem. 1983, 48, 326.
12) Lu, J.; Toy, P. H. Chem. Rev. 2009, 109, 815.
13) (a) Hodges, J. C.; Harikrishnan, L. S.; Ault-Justus, S.
J. Comb. Chem. 2000, 2, 80. (b) Lindsley, C. W.; Hodges,
J. C.; Filzen, G. F.; Watson, B. M.; Geyer, A. G. J. Comb.
Chem. 2000, 2, 550. (c) McAlpine, S. R.; Lindsley, C. W.;
Hodges, J. C.; Leonard, D. M.; Filzen, G. F. J. Comb. Chem.
1
13
by H NMR and C NMR spectroscopy. Steroeoisomeric
1
ratios were determined by H NMR spectroscopy.
(17) (a) Yano, T.; Kuroboshi, M.; Tanaka, H. Tetrahedron Lett.
2010, 51, 698. (b) Yano, T.; Hoshimo, M.; Kuroboshi, M.;
Tanaka, H. Synlett 2010, 801.
Synlett 2010, No. 13, 1997–2001 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.