A direct synthesis of functionalized styrenes and terminal 1,3-dienes via aqueous Wittig chemistry with formalin

Article abstract of DOI:10.1016/j.tetlet.2010.10.090

A direct synthesis of functionalized styrenes including synthetically valuable styryl halides and terminal 1,3-dienes is reported directly from benzylic and allylic alcohols and aqueous formalin involving microwave assisted phosphonium salt formation and Wittig olefination under mildly basic conditions.

Full text of DOI:10.1016/j.tetlet.2010.10.090

Tetrahedron Letters 52 (2011) 199–201
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A direct synthesis of functionalized styrenes and terminal 1,3-dienes via
aqueous Wittig chemistry with formalin
⇑
Priyabrata Das, David McLeod, James McNulty
Department of Chemistry and Chemical Biology, McMaster University, 1280 Main Street West, Hamilton, Ontario, Canada L8S 4M1
a r t i c l e i n f o
a b s t r a c t
Article history:
A direct synthesis of functionalized styrenes including synthetically valuable styryl halides and terminal
1,3-dienes is reported directly from benzylic and allylic alcohols and aqueous formalin involving micro-
wave assisted phosphonium salt formation and Wittig olefination under mildly basic conditions.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 23 August 2010
Revised 13 October 2010
Accepted 15 October 2010
Available online 13 November 2010
1. Introduction
kylallyl18b phosphonium salts with a range of carbonyl-containing
compounds yielding a range of stilbenes, alkenes, and 1,3-dienes.
Styrene and functionalized styrenes are among the most versa-
tile of olefins with an extensive range of applications in fine chem-
ical synthesis and as precursors to functionalized polymers.1
Functionalized styrenes are routinely employed in developments
in a variety of processes including the Mizoroki–Heck reaction,2
hydrogenation,3 epoxidation,4 metathesis,5 hydroboration,6 car-
bonylation,7 hydroamination,8 hydrophosphination,9 hydroaryla-
tion,10 and aziridination.11 In addition, applications in the area of
functionalized polymers have called for efficient access to styrene
and functionalized styrene monomers.1,12
Unfunctionalized styrene is prepared industrially via a two step
sequence from benzene involving a Friedel–Crafts alkylation (Bad-
ger process) with ethylene yielding ethylbenzene followed by
either of two high temperature, metal catalyzed dehydrogenation
processes.1 Mild conditions are necessary for the synthesis of sty-
renes due to their propensity toward polymerization under a wide
range of conditions. On a laboratory scale, functionalized styrenes
have been prepared by elimination reactions, partial reduction of
alkynes over Lindlar’s catalyst and via carbonyl olefination based
methods. More recently several transition metal catalyzed meth-
ods have been developed based on the cross-coupling of aryl or vi-
nyl organometallic reagents with vinyl or aryl halides, respectively,
including Suzuki–Miyaura,13 Stille,14 Hiyama,15 and other pro-
cesses.16 The synthesis of styrenes containing aryl bromide and io-
dide functionalities would be complicated with crossover
couplings using these methods and we were particularly interested
in the synthesis of aryl-ring halogenated styrenes from which use-
ful polymer supported ligands/catalysts and reagents could be
generated.17
As an extension of this work, we have now investigated the corre-
sponding Wittig reaction with aqueous formalin. Herein, we report
a new microwave-assisted synthesis of triethylbenzyl and triethyl-
allyl phosphonium salts from the corresponding benzyl and allyl
alcohol and their direct aqueous Wittig reactions with aqueous for-
malin in the presence of potassium carbonate as a highly efficient
route to functionalized styrenes and terminal 1,3-dienes.
2. Results and discussion
In our earlier report,18a trialkylbenzyl phosphonium salts were
prepared in traditional fashion from the reaction of a trialkylphos-
phine and a corresponding benzylic or allylic halide. The resulting
olefin generally precipitated during the course of the reaction and
solid products could be isolated by simple filtration while extrac-
tion could be used in the case of oils. A significant advantage of this
process is the high aqueous solubility of short-chain trialkylphos-
phine oxides that allows for clean separation through simple
phase-separation. Phosphine oxides are ubiquitous, difficult to re-
move side products in traditional triarylphosphine mediated Wit-
tig chemistry.
In terms of green chemistry, the use of water as a solvent is a
considerable improvement, however, disadvantages include the
need to handle triethylphosphine itself and benzylic or allylic ha-
lides. Triethylphosphine is an odoriferous lachrymator and is a
pyrophoric liquid requiring specialized handling. Benzylic and
allylic halides are also lachrymators and in some cases are consid-
ered toxic alkylating agents. Further consideration of the green as-
pects19 of the above process in terms of safety, atom economy,
economy of steps, and avoidance of auxiliary chemicals, prompted
us to develop the route shown in Scheme 1 as an alternate to the
desired trialkyl phosphonium salts. Prior to our work, we were not
aware of any reports on the direct conversion of benzylic alcohols
to phosphonium salts. A synthesis of allylic triphenylphosphonium
We recently described the successful aqueous Wittig reactions
of semi-stabilized ylides derived from trialkylbenzyl18a and trial-
⇑
Corresponding author. Tel.: +1 905 525 9140x27393; fax: +1 905 522 2509.
E-mail address: jmcnult@mcmaster.ca (J. McNulty).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.10.090

200
P. Das et al. / Tetrahedron Letters 52 (2011) 199–201
H
+
H
+
1)
Br-
P
X
1
X
P
Br
OH
Neat, 100 °C, MW, 10 min
R
R
Neat, 100 °C, MW, 10 min
OH
K2CO3, H2O, Aq HCHO
MW, 100 °C, 5 min
2)
3a-3b
4a-4b
4a (90%)
4b (81%)
95-98 % yield
2a-2h
2) K2CO3, H2O, Aq HCHO
MW, 100 °C, 5 min.
1a-1h
3a R = H
3b R= Me
Scheme 1. Microwave-assisted synthesis of styrenes.
salts from allylic alcohols and acidic Ph3P–HBr was reported by
chemists at BASF in the late 1950’s in the synthesis vitamin A
and analogs.20 It is not obvious that triethylphosphine hydrobro-
mide (pKa = 8.69)20d would be acidic enough to allow conversion
of such a species to the corresponding phosphonium salt. Triethyl-
phosphine hydrobromide was prepared directly from the reaction
of triethylphosphine with 47% HBr. The salt proved to be a hygro-
scopic, colorless crystalline solid, stable to aerial oxidation upon di-
rect exposure to open laboratory conditions over several weeks. In
addition, the salt is almost odorless and proved easy to handle.
We first determined that heating a mixture of a benzylic alcohol
with triethylphosphine hydrobromide without solvent in an oil bath
at 100 °C allowed slow conversion to the phosphonium salt. This
process required up to 8 h to achieve full conversion. We next
determined that the reaction was subject to a remarkable micro-
wave-effect, the same reaction was completed with microwave
irradiation at 100 °C in 10 min and within 15 min for ortho-substi-
tuted derivatives. The addition of water, potassium carbonate, and
37% aqueous formaldehyde followed by microwave irradiation
again at 100 °C induced rapid Wittig olefination, which was com-
pleted within 5 min.21 This overall process could be conducted
sequentially in a single microwave reaction vial and proved to be
general for a range of both ortho- and para-electron rich and elec-
tron deficient benzylic alcohols, shown in Table 1.22 Notably, elec-
tron deficient styrenes undergo rapid polymerization, for example,
OH
as above
5
6 (85%)
Scheme 2. Synthesis of terminal 1,3-dienes from allylic alcohols.
both 2-chlorostyrene and 4-chlorostyrene are employed in rapid-
cure resins and are also used in flame-resistant styrene compos-
ites.1 The preparation of desirable aryl bromo and iodo styrenes
was likewise achieved in near quantitative yield under the mild
conditions employed.
In all cases, the triethylphosphonium salts were prepared in the
first part of the two-step sequence shown (Scheme 1) from the cor-
responding benzylic alcohol followed by addition of aqueous
potassium carbonate and formalin solution. The graphical abstract
depicts the appearance of a suspension of 4-methoxybenzyltrieth-
ylphosphonium bromide in aqueous sodium carbonate solution
before (left) and after the addition of aqueous formalin/microwave
irradiation (right). The styrene precipitates as an oil and upon cool-
ing can be directly separated from the aqueous phase or extracted
with hexane. In all cases, a clear partition of the styrene product
was observed. It proved convenient to extract the styrene deriva-
tive into a small volume of hexane, the only organic solvent uti-
lized at any stage of this process. The hexane extract contains no
trace of triethylphosphine oxide, which remains fully dissolved in
the aqueous phase. Tripropylphosphine hydrobromide can also
be used in an identical manner, allowing clean phase separation
of the phosphine oxide. The chemistry works equally well with
tributylphosphine hydrobromide, however, in this case clean parti-
tioning of tributylphospine oxide does not occur, contaminating
the styrene product.
Table 1
Synthesis of functionalized styrenes in water with aqueous formalin
Entry
1
Alcohol
Styrene
Yield (%)
98
OH
(2a)
OH
Using the same two-stage method, cinnamyl alcohol 3a and the
2-methyl analog 3b could be successfully converted to the terminal
1,3-diene through the intermediacy of the allylic phosphonium
salts, Scheme 2. In addition, geraniol 5 could likewise be converted
to triethylgeranylphosphonium bromide, which underwent ylide
formation and olefination with aqueous formalin to give 6 under
these mildly basic conditions. Thus, the overall process appears
to be general for both benzylic and allylic alcohols.
(2b)
2
3
96
95
97
98
96
97
96
92
96
97
MeO
Me
MeO
Me
OH
(2c)
OH
OH
(2d)
4
Cl
Cl
(2e)
5
NO2
NO2
OH
3. Conclusion
(2f)
6
Br
Br
In conclusion, we advance a green approach to the synthesis of
functionalized styrenes and terminal 1,3-dienes employing aque-
ous Wittig chemistry. We show that triethylbenzyl and allyl phos-
phonium salts can be prepared directly from the corresponding
alcohol using triethylphosphine hydrobromide conventionally
(100 °C, 8 h) or under microwave irradiation (100 °C, 10 min). Fur-
thermore, addition of aqueous potassium carbonate and formalin
followed by microwave irradiation (100 °C, 5 min) is sufficient to
allow the aqueous Wittig reaction. The product olefin generally oils
out upon cooling the reaction mixture and could be directly re-
moved, or more conveniently on a small scale, isolated by extrac-
tion into a small volume of hexane, the only organic solvent
OH
OH
(2g)
7
Cl
Cl
(2h)
8
OMe
OMe
OH
(2g)
9
Br
Br
I
OH
(2h)
10
11
I
OH
(2h)
I
I

P. Das et al. / Tetrahedron Letters 52 (2011) 199–201
201
14. (a) Badone, D.; Cecchi, R.; Guzzi, U. J. Org. Chem. 1992, 57, 6321; (b) Grasa, G.;
Nolan, S. P. Org. Lett. 2001, 3, 119; (c) Chretien, J. M.; Mallinger, A.; Zammattio,
F.; Le Grognec, E.; Paris, M.; Montavon, G.; Quintard, J. P. Tetrahedron Lett. 2007,
48, 1781.
15. (a) Tuet, J. Tetrahedron Lett. 1999, 40, 1673; (b) Denmark, S. E.; Butler, C. R. Org.
Lett. 2006, 8, 63; (c) Denmark, S. E.; Butler, C. R. J. Am. Chem. Soc. 2008, 130,
3690.
16. (a) Mikami, S.; Yorimitsu, H.; Oshima, K. Synlett 2002, 1137; (b) Schumann, H.;
Kaufman, J.; Schmalz, H. G.; Bottcher, A.; Gotov, B. Synlett 2003, 1783.
17. (a) McNamara, C. A.; Dixon, M. J.; Bradley, M. Chem. Rev. 2002, 102, 3275; (b)
Leadbeater, N. E.; Marco, M. Chem. Rev. 2002, 102, 3217.
employed at any stage of this process. The overall procedure, con-
version of a substituted benzylic alcohol to a functionalized sty-
rene derivative, can be conducted in under 30 min, including
product isolation. High yields of functionalized styrenes and termi-
nal 1,3-dienes, uncontaminated with phosphine oxide, are rapidly
accessible by this general method.
Acknowledgments
18. (a) McNulty, J.; Das, P. Eur. J. Org. Chem. 2009, 24, 4031; (b) McNulty, J.; Das, P.
Tetrahedron Lett. 2009, 50, 5737; (c) McNulty, J.; Das, P.; McLeod, D. Chem. Eur.
J. 2010, 16, 6756.
19. Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and Practice; Oxford
University Press: Oxford, UK, 1998.
20. (a) Sarnecki, W.; Pommer, H.; German Patent, Auslegeschrift 1046046, 1958.;
(b) Sarnecki, W.; Pommer, H.; German Patent, Auslegeschrift 1060386, 1959.;
(c) Wegner, C.; Paust, J.; Lambsheim, J. U.S. Patent, US 6433,226 B1 2002.; (d)
Henderson, W. A.; Streuli, C. A. J. Am. Chem. Soc. 1960, 82, 5791.
21. For prior reports on microwave assisted Wittig and related reactions see: (a)
Sabitha, G.; Reddy, M. M.; Srinivas, D.; Yadav, J. S. Tetrahedron Lett. 1999, 40,
165; (b) Westman, J. Org. Lett. 2001, 3, 3745; (c) Wu, J.; Sun, L.; Dai, W. M.
Tetrahedron 2006, 62, 8360; (d) Duvall, J. R.; Wu, F.; Snider, B. B. J. Org. Chem.
2006, 71, 8579; (e) Su, C. R.; Shen, Y. C.; Kuo, P. C.; Leu, Y. L.; Damu, A. G.; Wang,
Y. H.; Wu, T. S. Bioorg. Med. Chem. Lett. 2006, 16, 6155; (f) Herrero, M. A.;
Kresmsner, J. M.; Kappe, C. O. J. Org. Chem. 2008, 73, 36; (g) Obermayer, D.;
Gutmann, B.; Kappe, C. O. Angew. Chem., Int. Ed. 2009, 48, 8321.
We thank the NSERC, Cytec Canada Inc. and McMaster Univer-
sity for financial support of this work.
References and notes
1. James, D. H.; Castor, W. M. Styrene. In Ullmann’s Encyclopedia of Industrial
Chemistry; Wiley-VCH: Weinheim, 2005.
2. Beletskaya, I. P.; Ceprakov, A. V. Chem. Rev. 2000, 100, 3009.
3. Noyori, R.; Kitamura, M.; Ohkuma, T. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5356.
4. Matsumoto, K.; Oguma, T.; Katsuki, T. Angew. Chem., Int. Ed. 2009, 48, 7432.
5. (a) Chatterjee, A. K.; Choi, T. L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc.
2003, 125, 11360; (b) Grubbs, R. H. Handbook of Metathesis; Wiley: VCH, New
York, 2003.
6. Moteki, S. A.; Wu, D.; Chandra, K. L.; Reddy, D. S.; Takacs, J. Org. Lett. 2006, 8,
3097.
7. Brennfuhrer, A.; Neumann, H.; Beller, M. ChemCatChem 2009, 1, 28.
8. Hartwig, J. F. Pure Appl. Chem. 2004, 76, 507.
9. Shulyupin, M. O.; Kazankova, M. A.; Beletskaya, I. P. Org. Lett. 2002, 4, 761.
10. (a) Rueping, M.; Nachtshelm, B. J.; Scheidt, T. Org. Lett. 2006, 8, 3717; (b) Sun, H.
B.; Li, B.; Hua, R.; Yin, Y. Eur. J. Org. Chem. 2006, 18, 4231.
11. Kwong, H. L.; Liu, D.; Chan, K. Y.; Lee, C. S.; Huang, K. H.; Che, C. M. Tetrahedron
Lett. 2004, 45, 3965.
12. (a) Modern Styrenic Polymers: Polystyrenes and Styrenic Copolymers; Scheirs, J.,
Priddy, D. B., Eds.; John Wiley: Chichester, 2003; (b) Hirao, A.; Loykulnant, S.;
Ishizone, T. Prog. Polym. Sci. 2002, 27, 1399.
13. (a) Darses, S.; Michaud, G.; Genet, J. P. Tetrahedron Lett. 1998, 39, 5045; (b)
Molander, G. A.; Brown, A. R. J. Org. Chem. 2006, 71, 9681; (c) Kerins, F.; O’Shea,
D. F. J. Org. Chem. 2002, 67, 4968; (d) Coleman, C. M.; O’Shea, D. F. J. Am. Chem.
Soc. 2003, 125, 4054.
22. Representative procedure. Synthesis of Styrene 2a: Into
microwave vial, containing magnetic stirring bar was weighed benzyl
alcohol (207.2 L, 2 mmol, 1 equiv) under argon. Triethylphosphine
a flame-dried
a
l
hydrobromide (396.2 mg, 2 mmol, 1 equiv) was added to the vial. The vial
was septa-sealed and heated in the microwave for 10 min at 100 °C. The
septum was removed and water (800
K2CO3 powder (552.8 mg, 4 mmol, 2 equiv) was added to the vial followed by
the addition of formalin solution (37% w/w solution in water, 812 L, 10 mmol,
lL) was added to make a 2.5 M solution.
l
5 equiv). The vial was now crimp-capped and irradiated in the microwave for
5 min at 100 °C. Upon cooling, the contents of the flask were partitioned
between water and hexane (3 Â 10 mL). The combined hexane phase was dried
(Na2SO4), filtered, and concentrated under reduced pressure to afford 2a, 98%
(203.9 mg).