Microwave-assisted, aqueous wittig reactions: Organic-solvent- And protecting-group-free chemoselective synthesis of functionalized alkenes

Article abstract of DOI:10.1002/chem.201000438

(Chemical Equation Presented) Free from protection! A general, chemoselective, protecting-group- and organic-solvent-free route to stilbenes and heterostilbenes involving the direct synthesis of triethyl benzylic and allylic phosphonium salts from the corresponding alcohols and their microwave-assisted, aqueous Wittig reactions is described.

Full text of DOI:10.1002/chem.201000438

DOI: 10.1002/chem.201000438
Microwave-Assisted, Aqueous Wittig Reactions: Organic-Solvent- and
Protecting-Group-Free Chemoselective Synthesis of Functionalized Alkenes
James McNulty,* Priyabrata Das, and David McLeod[a]
The Wittig olefination reaction[1] is regarded as one of the
most strategic, widely applicable carbon–carbon double-
bond-forming processes available in organic synthesis.[2–4]
The reaction has had an enormous impact on the sophistica-
tion of the total synthesis of organic molecules.[5] Some
drawbacks of the reaction are the lack of stereocontrol ach-
ieved in certain cases, for example, in the synthesis of stil-
benes from semistabilised ylides,[6] and the practical issue of
phosphane oxide side-product removal. Also, protecting
groups are usually required on any acidic protons (OH, NH,
etc.) on both the ylide and carbonyl components.
Water is a desirable solvent for organic reactions for envi-
Scheme 1. Synthesis of stilbenes, alkenes, and dienes (etc.) by using aque-
ous Wittig chemistry with semistabilised ylides.
ronmental, economical, safety and chemical processing rea-
sons.[7,8] It has been used as the reaction medium for Wittig
reactions of stabilised ylides to give unsaturated esters.[9] Re-
cently, we reported the first examples of aqueous Wittig re-
actions of semistabilised ylides derived from trialkylbenzyl
and trialkylallyl phosphonium salts.[10a,b] Semistabilised tri-
also the central component in light-emitting diodes
(LEDs)[12] and organic-based photovoltaic solar cells.[13]
In our original work, the phosphonium salts were pre-
pared in the usual fashion, by direct substitution of benzylic
or allylic halides with triethylphosphane. Triethylphosphane
is a highly odoriferous lachrymator that undergoes rapid ox-
idation in air and is considered pyrophoric. Allyl and benzyl
halides are also known lachrymators and are hydrolytically
unstable, generally toxic, alkylating agents. We have now de-
veloped a direct alkylation strategy that circumvents these
issues, allowing a safe, “off-the-shelf” approach to achieving
the above Wittig chemistry. Triethylallyl and triethylbenzyl
phosphonium salts are directly available from the reaction
of a benzylic or allylic alcohol and air-stable triethylphos-
phane hydrobromide. We also uncovered a pronounced “mi-
crowave effect” in the aqueous olefination reaction, leading
to successful Wittig reactions by using weak bases, such as
potassium carbonate. The innate reactivity of these ylides in
water drew our attention to chemoselectivity issues. We
report the unprecedented protecting-group-free, aqueous
Wittig reactions of phenols, indoles, pyrroles and ketones,
including enolisable substrates.
ACHTUNGTRENNUNGethylbenzylidenyl and triethylallylidenyl ylides were shown
to be formed chemoselectively in water by using sodium or
lithium hydroxide and to react with aromatic, unsaturated,
aliphatic and even enolisable aliphatic aldehydes in water,
yielding a wide array of olefinic products (Scheme 1). These
reactions proceeded with high (E)-olefin selectivity. The
triethylphosphane oxide side-product is readily removed
from these processes due to its water solubility and, hence,
the Wittig reactions of triethylphosphane-derived, semistabi-
lised ylides encapsulate a single solution to two outstanding
problems with Wittig olefinations leading to (E)-olefins.
This method was applied to the synthesis of valuable trans-
stilbenes, such as resveratrol and trans-3,4,5,4’-tetrameth-
ACHTUNGTRENNUNG
oxystilbene (DMU-212).[11] High-purity trans-stilbenes are
[a] Dr. J. McNulty, Dr. P. Das, D. McLeod
Department of Chemistry and Chemical Biology
McMaster University, 1280 Main Street West
Hamilton, Ontario, L8S 4M1 (Canada)
Fax : (+1)905-522-2509
The chemistry employed in the direct synthesis of trieth-
AHCTUNGTREGyNNUN lallyl and triethylbenzyl phosphonium salts is outlined in
E-mail: jmcnult@mcmaster.ca
Scheme 2. The synthesis of allylic triphenylphosphonium
salts from allylic alcohols and acidic Ph3P–HBr was first re-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201000438.
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Chem. Eur. J. 2010, 16, 6756 – 6760

COMMUNICATION
However, it was not evident that triethylphosphane hydro-
bromide (pKa =8.69)[14d] would be acidic enough to allow
the conversion of a benzylic or allylic alcohol into its corre-
sponding phosphonium salt. Triethylphosphane hydrobro-
mide was prepared directly from triethylphosphane and
47% HBr. The salt proved to be a hygroscopic, colourless,
crystalline solid, which is stable to air oxidation upon direct
exposure to open laboratory conditions for several weeks. In
addition, the salt is almost odourless and proved to be easy
to handle.
Initial attempts to transform benzyl alcohol into its tri-
AHCTUNGTREGeNNNU thylphosphonium salt were disappointing. No reaction
occurs at room temperature in various solvents or solvent
free, most likely due to the lower acidity of the salt. None-
theless, we quickly determined that heating a mixture of
benzyl alcohol and triethylphosphane hydrobromide without
a solvent, in an oil bath, at 1008C allowed slow conversion
to the desired salt, which was completed within 8 h. This
process proved to be very general and was successful with
ortho-substituted benzyl alcohols containing either electron-
withdrawing or -donating groups. A wide range of differently
substituted benzylic and allylic alcohols (1a–j) could be con-
verted safely and efficiently to the desired phosphonium
salts (2a–j), as summarised in Table 1.
Scheme 2. Direct synthesis of triethylbenzyl and triethylallyl phosphoni-
um bromides from the corresponding alcohols.
ported by chemists at BASF in the late 1950s in their, now
classical, Wittig approach to vitamin A and its analogues.[5,14]
Table 1. Synthesis of triethylbenzyl and triethylallyl phosphonium salts
directly from the corresponding alcohol using Et3P–HBr.
Entry
Alcohol
Phosphonium salt
Yield
[%]
This new approach can readily be applied to the synthesis
of trans-stilbenes by using the aqueous Wittig reactions pre-
viously reported.[10a] Under our original conditions the olefi-
nation requires four equivalents of base (10.0m; NaOH or
LiOH) reacting with triethylbenzylphosphonium bromide
and an aromatic aldehyde with conventional heating at
708C for 3 h in order to achieve high conversion. Encour-
aged by recent reports of microwave-assisted Wittig reac-
tions, mainly employing stabilised ylides, the above aqueous
Wittig reaction was subjected to microwave dielectric heat-
ing with remarkable results.[15] Under microwave irradiation
in a sealed vial, at 758C, for only 0.5 h (Scheme 3, Table 2),
the use of only 1.1 equivalents of base (NaOH or LiOH) re-
sulted in high conversion (>98%). An otherwise identical
reaction conducted with thermal heating gave only 15%
conversion in 0.5 h. Furthermore, the choice of base can be
1
1a
1b
1c
2a
2b
2c
98
99
99
2
3
4
5
6
7
1d
1e
1 f
1g
2d
2e
2 f
2g
98
99
97
99
Table 2. Comparison of conventional versus microwave-assisted aqueous
Wittig reactions by using benzyl alcohol and benzaldehyde.[a]
Base
(1.1 equiv)
Oil bath
[h]
Conversion
[%]
Microwave
ACHTUNGTNER[NUNG min]
Conversion
[%]
NaOH
NaOH
NaOH
NaOH
LiOH
LiOH
LiOH
LiOH
K2CO3
K2CO3
K2CO3
K2CO3
1
2
3
6
1
2
3
6
1
2
3
6
20
30
35
81
27
30
40
78
20
33
40
70
10
20
30
30
60
98
8
9
1h
1i
2h
2i
99
96
98
15
25
30
30
65
97
15
25
30
32
60
98
10
1j
2j
[a] All reactions were performed at 758C.
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J. McNulty et al.
Table 3. Scope of the microwave-assisted synthesis of stilbenes and heterostil-
benes in water.
Entry ArCH2OH RCHO
Product
Yield E:Z
[%]
Scheme 3. Microwave-assisted one-pot synthesis of trans-stilbenes and
heterostilbenes.
1[a] 1a
3a
3b
6a 98
100:0
90:10
successfully extended to the weaker potassium carbonate
(1.1 equivalents), which also provides 98% conversion with
0.5 h of microwave heating.
The two steps, that is, formation of the initial triethylphos-
phonium salt and the aqueous Wittig reaction, can be con-
veniently conducted as a one-pot process. A microwave vial
is charged with the desired benzylic or allylic alcohol and
2[a] 1b
6b 99
6 f 97
3[a] 1 f
3c
3d
95:5
triACHTUNGTRENNUNGethylphosphane hydrobromide in a 1:1 ratio. After heat-
4[b] 1a
6c 83
7a 75
>99 (E)
ing to 1008C for 8 h, the flask is cooled to room temperature
and charged with potassium carbonate, water and the alde-
hyde. The flask is then re-sealed and subjected to microwave
irradiation at 758C for 30 min.
5[c] 1a
4
4
>99 (E)
>99 (E)
The scope of this microwave accelerated synthesis of stil-
benes was extended to a range of substituted aldehydes
(3a–d; Table 3, entry 1–4) that yield trans-stilbenes (6a–c
and f) in high yields, similar to those in the original aqueous
Wittig report.[10a] The solid stilbenes can be isolated by
direct filtration upon cooling and dilution with water. Sur-
prisingly, under these mildly basic aqueous conditions un-
protected 2-hydroxybenzaldehyde also entered into the
Wittig reaction to yield the hydroxyl-substituted stilbene di-
rectly in high yield and with E stereocontrol (Table 3,
entry 4).
6[c] 1b
7b 75
7[c] 1c
4
7c 77
>99 (E)
We next attempted the reaction with both indole-3-car-
boxaldehyde (4) and pyrrole-2-carboxaldehdye (5) and were
delighted to find that both aldehydes readily reacted with a
range of ylides, generated under the aforementioned condi-
tions, without requiring NH protection (Table 3, entries 5–
15). The heterostilbenes were isolated in good yields in both
the indole (7a–f) and pyrrole (8a–e) series and essentially
as the single E isomer in all cases.
Wittig reactions on substituted indoles typically require
prior protection of the NH group and side reactions are
known to occur during Wittig reactions on pyrroles with a
free NH group.[16] In addition to the wide array of naturally
occurring biologically active stilbenes,[11i] heteroatom-con-
taining trans-stilbenes include the asthma drug Singulair.
Other heterostilbenes have recently been shown to posses
potent antibacterial activity against the tuberculosis-causing
pathogen[11j] and vinylheterocycles have proven to be valua-
ble intermediates in the synthesis of pharmaceuticals, fla-
vourings and agrochemical agents.[11k] Heterosubstituted stil-
8[c] 1d
4
4
7d 83
>99 (E)
>99 (E)
9[c] 1e
7e 82
10[c] 1 f
4
7 f 80
>99 (E)
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Wittig Reactions
COMMUNICATION
reacted more efficiently and yielded the phenyl chalcone de-
rivative 11 in near quantitative yield. In contrast to the mi-
crowave-assisted Wittig reaction, little or no conversion oc-
curred with these ketones if conventional heating was em-
ployed. Recent discussions on the nature of microwave-as-
sisted reactions conclude that microwave-enhanced reac-
tions involve only a thermal effect.[15f,g] We believe that the
controlled heating in a sealed, pressurised microwave vial
are relevant factors in the remarkable acceleration in this
case.
Table 3. (Continued)
Entry ArCH2OH RCHO
Product
Yield E:Z
[%]
11[d] 1a
5
5
8a 98
>99 (E)
>99 (E)
12[d] 1b
8b 93
In conclusion, we have shown that triACTHNUTRGNEUNGethylallyl and trie-
13[d] 1c
14[d] 1d
15[d] 1e
5
5
5
8c 93
8d 92
8e 95
>99 (E)
>99 (E)
>99 (E)
thylbenzyl phosphonium bromides are formed in quantita-
tive yields from the direct reaction of triethylphosphane hy-
drobromide with allylic and benzylic alcohols. Triethylphos-
phane hydrobromide is an air-stable, easy-to-handle solid
and this new protocol allows for the use of chemically
stable, innocuous allylic or benzylic alcohols in place of
their more reactive halide counterparts. This allows a con-
venient, safer alternative approach to valuable trans-stil-
benes in very high yield and E stereoselectivity by employ-
ing aqueous Wittig chemistry. Furthermore, we also demon-
strate a significant microwave-effect on the Wittig reaction
if it is conducted with these salts in water. In addition, semi-
stabilised ylides can now be generated by using potassium
carbonate as the base. The ylides were shown to add to vari-
ous benzaldehydes as well as aldehydes containing acidic
protons, which includes phenols, indoles and pyrroles, dem-
onstrating remarkable chemoselectivity. This new process
allows access to a wide range of heterostilbene derivatives
and should find applications in the synthesis of a wide range
of pharmacologically active stilbenes[11] as well as other de-
rivatives of interest in the design of organic chromophores
for LEDꢁs and dye-sensitised solar cells.[12,13] Further investi-
gations along these lines are currently being performed in
our laboratory.
[a] K2CO3, 758C, 30 min. [b] NaOH, 1008C, 30 min. [c] K2CO3, 1008C, 30 min.
[d] NaOH, 1008C, 25 min.
benes are also of interest in the development of the organic
components in dye-sensitised solar cells.[13e]
The microwave-assisted Wittig reaction can also be ex-
tended to ketones in the presence of sodium or lithium hy-
droxide. Under these conditions, the ylide derived from trie-
thylbenzylphosphonium bromide reacted with benzophe-
none and the enolisable ketone cyclohexanone to form com-
pounds 9 and 10 in moderate yields (Table 4, entries 1 and
2). Under similar conditions, 1,2-diphenyl-1,2-ethanedione
Table 4. One-pot microwave-assisted synthesis of olefins from ketones.
Experimental Section
The Supporting Information includes general details, synthetic protocols
and characterisation data for phosphonium salts and the compounds re-
ported in the Tables. Tables comparing various olefination reactions
under conventional thermal versus microwave heating with various bases
are also included.
Entry ArCH2OH Ketone
Product
Yield
[%]
1[a]
1a
9
48
Acknowledgements
We thank Cytec Canada Inc. and NSERC for financial support of this
work.
2[a]
1a
1a
10 63
11 99
Keywords: alkenes
·
chemoselectivity
·
microwave
chemistry · water chemistry · Wittig reactions
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6759

J. McNulty et al.
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Received: February 19, 2010
Published online: May 10, 2010
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Chem. Eur. J. 2010, 16, 6756 – 6760