Microwave-assisted wittig reaction of semistabilized nitro-substituted benzyltriphenyl-phosphorous ylides with aldehydes in phase-transfer conditions

Article abstract of DOI:10.1080/00397911.2010.530378

We report here a simple entry into the nitrostilbene system in very short reaction times and good yields using the microwave-assisted Wittig reaction in phase-transfer conditions of nitro-substituted benzyltriphenylphosphonium ylides with aldehydes. Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2010.530378

This article was downloaded by: [Brown University]
On: 05 May 2012, At: 13:52
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/lsyc20
Microwave-Assisted Wittig Reaction
of Semistabilized Nitro-Substituted
Benzyltriphenyl-Phosphorous Ylides with
Aldehydes in Phase-Transfer Conditions
Tiago Rodrigues a , Francisca Lopes a & Rui Moreira a
a Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal
Available online: 17 Aug 2011
To cite this article: Tiago Rodrigues, Francisca Lopes & Rui Moreira (2012): Microwave-Assisted
Wittig Reaction of Semistabilized Nitro-Substituted Benzyltriphenyl-Phosphorous Ylides with
Aldehydes in Phase-Transfer Conditions, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 42:5, 747-755
To link to this article: http://dx.doi.org/10.1080/00397911.2010.530378
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden.
The publisher does not give any warranty express or implied or make any representation
that the contents will be complete or accurate or up to date. The accuracy of any
instructions, formulae, and drug doses should be independently verified with primary
sources. The publisher shall not be liable for any loss, actions, claims, proceedings,
demand, or costs or damages whatsoever or howsoever caused arising directly or
indirectly in connection with or arising out of the use of this material.

Synthetic Communications1, 42: 747–755, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.530378
MICROWAVE-ASSISTED WITTIG REACTION
OF SEMISTABILIZED NITRO-SUBSTITUTED
BENZYLTRIPHENYL-PHOSPHOROUS YLIDES WITH
ALDEHYDES IN PHASE-TRANSFER CONDITIONS
Tiago Rodrigues, Francisca Lopes, and Rui Moreira
Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal
GRAPHICAL ABSTRACT
Abstract We report here a simple entry into the nitrostilbene system in very short reaction
times and good yields using the microwave-assisted Wittig reaction in phase-transfer
conditions of nitro-substituted benzyltriphenylphosphonium ylides with aldehydes.
Keywords Microwave; nitrostilbenes; phase-transfer catalysis; stereoselectivity; Wittig
reaction
INTRODUCTION
(1H-Pyridin-4-ylidene)amines or 4-pyridonimines (A, Scheme 1) have recently
been reported as a novel class of antimalarial compounds active against multidrug-
resistant Plasmodium falciparum strains.[1] Diversity at the imine side-chain of A
was incorporated via the nitrostilbenes precursors (1, Scheme 1), which were reduced
to the corresponding phenethylanilines by Pd-C-catalyzed hydrogenation with
triethylsilane in methanol and then reacted with the appropriate N-alkyl-4-
chloropyridinium triflates to give the desired 4-pyridonimines. Nitrostilbenes 1 were
synthesized using the Wittig reaction of the appropriate nitro-substituted benzyltri-
phenyl phosphorous ylides with aromatic aldehydes, in phase-transfer catalysis
(PTC) conditions, which were usually complete in 2 to 3 h at room temperature. To
extend the structure–activity relationship studies, a more expeditious synthesis of
nitrostilbenes 1 was required. Furthermore, nitrostilbenes 1 are also key intermediates
in the synthesis of the amyloid aggregation inhibitors B[2] and liver X receptor
antagonists C.[3]
Received June 29, 2010.
Address correspondence to Rui Moreira, iMedUL, Faculty of Pharmacy, University of Lisbon,
Av. Prof. Gama Pinto, 1649-003, Lisbon, Portugal. E-mail: rmoreira@ff.ul.pt
747

748
T. RODRIGUES, F. LOPES, AND R. MOREIRA
Scheme 1. 4-Pyridonimines (A), anthranilic acids (B), and phthalimides (C) with pharmacological interest
and their stilbene precursors (1).
The Wittig reaction of an aldehyde with a phosphorus ylide is one of the most
commonly used carbon–carbon double-bond-forming reactions in organic chemistry
because of the unambiguous positioning of the double bond.[4,5] Typically, the
reaction is carried out using a hydride or organometallic base in anhydrous aprotic
solvents.[5,6] The use of water as solvent for Wittig reactions[7–11] and PTC[12–16]
methods has been a successful alternative to classical organic solvents. Herein, we
report the synthesis of nitrostilbenes via PTC Wittig reactions using the appropriate
nitrobenzylphosphonium salts in either room temperature or microwave (MW)–
assisted synthesis. As part of this work, we observed some interesting Z=E selectivity
trends and found that these can be rationalized in terms of the electronic effect exerted
by the nitro substituent on the acidity of the benzylphosphonium salts or by the
substituent at the aldehyde. Furthermore, the MW-assisted sysnthesis provided
shorter reaction times and greater reaction rates for stabilized phosphoranes.
RESULTS AND DISCUSSION
The PTC protocol previously reported,[1] which afforded the required stilbenes
1 after phase separation and flash chromatography purification, was optimized and
then adapted for the MW-assisted conditions. The reaction of 3-nitrobenzyltriphenyl
phosphonium bromide (1 molar equiv.) with benzaldehyde (1 molar equiv.) was per-
formed in dichloromethane in the presence of NaOH 0.1 N (1.2 molar equiv.) at room
temperature to give 1a in 92% yield, with a Z=E ratio of 84:16 (Table 1, entry 1). The
reaction extent and reaction time (2 h) were independent of the stirring rate, and no
significant changes on the reaction extent were observed using benzaldehyde in the
range of 1.0 to 1.5 molar equivalents. Thus, for an easier separation of the stilbene
from the aldehyde, 1 molar equivalent of the latter was used in subsequent reactions.
The effect of MW irradiation (100 W, 3 min) on the PTC protocol was first
studied at different temperatures (Table 1, entries 2 to 5). Interestingly, the conversion
rate decreased with higher temperatures. Also, the stereocontrol was poorer when

MW-ASSISTED WITTIG REACTION
749
Table 1. Temperature effect using the PTC=MW method and comparison with the traditional PTC
method
Entry
Method
A: PTC
Temperature
Time
Yield (%)
Z=E (ratio)
1
2
3
4
5
RT
30
50
70
90
2 h
92
84
88
70
64
84:16 (5.25)
73:27 (2.70)
71:29 (2.45)
69:31 (2.23)
68:32 (2.13)
B: PTC=MW=100 W
C: PTC=MW=100 W
D: PTC=MW=100 W
E: PTC=MW=100 W
3 min
3 min
3 min
3 min
compared to the reaction without microwaves. The selected temperature for further
MW-assisted Wittig reactions, varying the substitution pattern of the benzyltriphenyl
phosphonium salts and aldehydes, was 30 ꢀC.
From Table 2 it can be seen that the stereoselectivity[17] using the standard PTC
method depends significantly on the position of the nitro group in the phosphonium
halide 2. No isomerisation on chromatography from Z to E was detected for several
cases. Additionally, no light sensitiveness was noted. The use of a solvent such as
dichloromethane may favor Z-selectivity as reported by Hwang et al.[3]. For
example, a high Z-stereoselectivity was observed for the reaction of 3- and 3,5-dini-
trobenzylphosphonium salts with benzaldehyde (Table 2 entries 1 and 14, respect-
ively). In contrast, placement of the nitro group in the 2- or 4-positions of 2 led to
a significant increase in the proportion of the E-alkene and loss of stereoselectivity
(entries 7 and 10, respectively). The reaction of 2,4-dinitrobenzylphosphonium chlor-
ide with benzaldehyde shifted the stereoselectivity toward the formation of the
E-alkene (entry 13). Overall, this shift from Z- to E-stereoselectivity can be ascribed,
at least in part, to the stabilizing effect of the nitro groups in the 2- or 4-positions on
the phosphorous ylide and is consistent witþh the suggestion that the dominant struc-
-
=
ture of phosphonium ylides is the dipolar P -C zwitterion rather than the P C dou-
ble bond.[17] Indeed, the equilibrium acidities, pKHA (in dimethylsulfoxide, DMSO),
of 4-substituted ArCH2PPhþ3 cations correlate with the Hammett rꢁ constants of
the substituents in the aryl moiety, reflecting the direct conjugation of the negative
in the conjugate base (ylide) with electron-withdrawing groups such as NO2.[17]
The MW-assisted Wittig reaction was performed in 3 min with total consumption
of the aldehyde and resulted in a decrease of the Z-stereoselectivity (Table 2, e.g.,
entries 1=10 and 14=140). With the stabilized 4-nitrophosphorane, the reaction rate
increased, and inversion on the stereoselectivity was observed (entries 10=100). With
2,4-dinitrophosphorane, an untractable mixture was obtained (entries 13=130).
Variation of the substitution pattern in the aldehyde did not affect significantly
the PTC reaction yield, and although diastereoselection was variable, the
Z-isomer was predominant. For reactions with 2-halobenzaldehydes, the expected
Z-diastereoselectivity was observed even for the 2-nitro ylide (Table 2, e.g., entry 8).
The cooperative ortho halo effect[18,19] may be responsible for these results and over-
rides the stabilizing effect of resonance to the nitro group. The MW-assisted Wittig

750
T. RODRIGUES, F. LOPES, AND R. MOREIRA
Table 2. Reaction of nitro-substituted benzyltriphenyl phosphonium salts with aldehydes under standard
PTC conditions at room temperature (Method A) and microwave-assisted synthesis (Method B)
Method B: PTC,
100 W, 30 ꢀC, 3 min
Method A: PTC, RT, 2 h
Yield 1
(%)a
Z:E
(ratio)b
Yield 1
(%)a
Z:E
(ratio)b
Cpd
1a
Ar
Ar0
Entry
Entry
1
2
3
92
98
93
84:16 (5.25)
77:23 (3.35)
70:30 (2.33)
10
20
30
84
79
96
73:27 (2.70)
77:23 (3.33)
70:30 (2.38)
1b
1c
1d
1e
4
5
96
91:9 (10.11)
85:15 (5.67)
40
50
49
46
86:14 (6.14)
83:17 (4.88)
100
1f
6
7
52
95
81:19 (4.26)
57:43 (1.33)
60
70
45
24
80:20 (4.00)
69:31 (2.22)
1g
1h
8
90
83:17 (4.88)
80
88
76:24 (3.17)
1i
9
10
11
47
88
78:22 (3.54)
58:42 (1.37)
58:42 (1.37)
90
39
93
77
63:37 (1.70)
34:66 (0.52)
74:26 (2.85)
1j
100
110
1k
100
1l
12
92
67:33 (2.00)
120
96
80:20 (4.00)
(Continued )

MW-ASSISTED WITTIG REACTION
751
Table 2. Continued
Method B: PTC,
100 W, 30 ꢀC, 3 min
Method A: PTC, RT, 2 h
Yield 1
(%)a
Z:E
(ratio)b
Yield 1
(%)a
Z:E
(ratio)b
Cpd
1m
Ar
Ar0
Entry
13
Entry
130
34
76
17:83 (0.20)
88:12 (7.33)
NDc
67
NDc
1n
14
140
71:29 (2.45)
aYield is given for the isolated isomer mixture;.
bZ=E ratios were determined by 1H NMR;.
cUntractable mixture.
reaction with 2-halobenzaldehydes gave moderate (entry 40) to excellent yields (entry
120), although the cooperative ortho halo effect was not as pronounced when com-
pared to standard PTC reactions. The PTC and MW-assisted reactions carried out
with phenylacetaldehyde gave only moderate yields of the corresponding stilbene
(entries 6=60), and an increased rate of hydrolysis of the phosphorane into the
3-nitrotoluene was observed. Moreover, 3-nitrotoluene was the sole product when
the reactions were carried out with aliphatic aldehydes. Instability of stabilized
phosphoranes has already been reported while using MW-assisted synthesis.[20]
In conclusion, we have developed a very fast and efficient synthesis of nitro-
substituted stilbenes relying on appropriately substituted nitrobenzyltriphenyl
phosphonium salts and diverse aldehydes, based on a MW-assisted Wittig reaction
in PTC conditions. From these experiments, we conclude that the PTC MW protocol
was efficient for semistabilized ylides, at the expense of Z=E selectivity.
EXPERIMENTAL
1H and 13C NMR spectra were recorded as CDCl3 or MeOD solutions in a
Bruker AM 400 WB (Bruker Bioscience, Billerica, MA, USA); chemical shifts are
given in parts per million (ppm), and coupling constants, J, are quoted in hertz
(Hz). Fourier transform infrared (FTIR) spectra were recorded on a Nicolet Impact
400 spectrophotometer (Nicolet, Madison, WI, USA). Microwave-assisted synthesis
was carried out in a CEM Corporation Discover Labmate. Melting points were deter-
mined using a Bock Monoscop M. instrument and are uncorrected. All chemicals
were of reagent grade, used without further purification, and generally purchased
from Sigma-Aldrich.
General Procedure for the Synthesis of Nitrostilbenes
The phosphonium salt (1 molar equiv.) and distilled or crystallized aldehyde
(1 molar equiv.) were suspended in dichloromethane (3 mL). An aqueous solution
of NaOH 0.1–0.5 N (1.2 molar equiv.) was added to the mixture. The ylidic

752
T. RODRIGUES, F. LOPES, AND R. MOREIRA
characteristic color was noted immediately and gradually faded with time. The
biphasic mixture was stirred (1600 rpm) at room temperature (20–25 ꢀC) for 2 h, after
which the organic phase was separated and concentrated under reduced pressure, and
the crude product was purified by column chromatography (hexane–ethyl ether 4:1)
to afford, typically, yellowish oils corresponding to a diastereomer mixture. For most
cases, the isomers were not separated, and the Z=E ratios were calculated by compar-
1
ing the alkene H NMR peaks of the isomers after flash chromatography. The Z=E
ratio for 1i was obtained from the ratio of the OMe signal. Quoted yields are given
after purification. Generally, all aldehyde starting material was consumed, and little
hydrolysis of the phosphonium salt or ylide, to the corresponding nitrotoluene, was
noted. No other products were detected. Poor yield of 1e is accounted for by the
low solubility of the phosphonium salt in water.
Spectral Data
1-Nitro-3-styrylbenzene, 1a. Yellow oil. Z isomer: 1H NMR (CDCl3,
400.13 MHz) d 6.63 (1H, d, J ¼ 12.0 Hz, CH), 6.81 (1H, d, J ¼ 12.0 Hz, CH),
7.18–7.24 (2H, m, Ar-H), 7.27–7.30 (3H, m, Ar-H), 7.39 (1H, t, J ¼ 8.0 Hz, Ar-H),
7.56 (1H, br. d, J ¼ 7.6 Hz, Ar-H), 8.06 (1H, dd, J ¼ 8.4 and 1.6 Hz, Ar-H), 8.12
(1H, dd, J ¼ 1.6 Hz, Ar-H). E isomer: mp 92–95 ꢀC. 1H NMR (CDCl3,
400.13 MHz) d 7.16 (1H, d, J ¼ 16.4 Hz, CH), 7.27 (1H, d, J ¼ 16.4 Hz, CH), 7.35
(1H, d, J ¼ 6.4 Hz, Ar-H), 7.42 (2H, t, J ¼ 7.2 Hz, Ar-H), 7.55 (3H, m, Ar-H), 7.83
(1H, d, J ¼ 8.0 Hz, Ar-H), 8.13 (1H, d, J ¼ 8.4 Hz, Ar-H), 8.13 (1H, br. s, Ar-H).
1-(4-Methoxystyryl)-3-nitrobenzene, 1b. Yellow gum. Z isomer: 1H NMR
(CDCl3, 400.13 MHz) d 3.79 (1H, s, OCH3), 6.51 (1H, d, J ¼ 12.0 Hz, CH), 6.70 (1H,
d, J ¼ 12.0 Hz, CH), 6.79 (2H, d, J ¼ 8.4 Hz, Ar-H), 7.15 (2H, d, J ¼ 8.4 Hz, Ar-H),
7.37 (1H, t, J ¼ 8.0 Hz, Ar-H), 7.58 (1H, t, J ¼ 8.0 Hz, Ar-H), 8.03 (1H, m, Ar-H),
8.13 (1H, s, Ar-H). E isomer: 1H NMR (CDCl3, 400.13 MHz) d 3.85 (1H, s,
OCH3), 6.93 (2H, d, J ¼ 8.4 Hz, Ar-H), 6.98 (1H, d, J ¼ 16.0 Hz, CH), 7.02 (1H,
m, Ar-H), 7.50 (3H, m, Ar-H), 7.76 (1H, d, J ¼ 7.6 Hz, Ar-H), 8.03 (1H, m,
Ar-H), 8.32 (1H, s, Ar-H).
1
1-(4-Chlorostyryl)-3-nitrobenzene, 1c. Yellow gum. Z isomer: H NMR
(CDCl3, 400.13 MHz) d 6.65 (1H, d, J ¼ 12.0 Hz, CH), 6.73 (1H, d, J ¼ 12.0 Hz,
CH), 7.10–7.59 (6H, m, Ar-H), 8.08 (1H, d, J ¼ 8.8 Hz, Ar-H), 8.11 (1H, s, Ar-H).
1
E isomer: H NMR (CDCl3, 400.13 MHz) d 7.12 (1H, d, J ¼ 16.0 Hz, CH), 7.27
(1H, d, J ¼ 16.0 Hz, CH), 7.10–7.59 (5H, m, Ar-H), 7.81 (1H, d, J ¼ 7.6 Hz,
Ar-H), 8.13 (1H, d, J ¼ 8.8 Hz, Ar-H), 8.39 (1H, s, Ar-H).
1
1-Fluoro-2-(2-nitrostyryl)benzene, 1d. Yellow gum. Z isomer: H NMR
(MeOD, 400.13 MHz) d 6.83 (1H, d, J ¼ 12.0 Hz, CH), 6.79–6.96 (2H, m, Ar-H),
7.02 (1H, t, J ¼ 9.2 Hz, Ar-H), 7.05 (1H, d, J ¼ 12.0 Hz, CH), 7.15–7.26 (2H, m,
1
Ar-H), 7.36–7.50 (2H, m, Ar-H), 8.08–8.18 (1H, m, Ar-H). E isomer: H NMR
(CDCl3, 400.13 MHz) d 6.96–7.14 (1H, m, Ar-H), 7.15–7.26 (1H, m, Ar-H),
7.27–7.35 (2H, m, CH þAr-H), 7.36–7.50 (1H, m, Ar-H), 7.64 (1H, d, J ¼ 16.4 Hz,
CH), 7.62–7.72 (2H, m, Ar-H), 7.82 (1H, d, J ¼ 7.6, Ar-H), 8.01 (1H, d, J ¼ 8.0,
Ar-H).

MW-ASSISTED WITTIG REACTION
753
1-Chloro-2-(3-nitrostyryl)benzene, 1e. Yellow solid, mp 44–50 ꢀC. Z
1
isomer: H NMR (CDCl3, 400.13 MHz) d 6.76 (1H, d, J ¼ 12.4 Hz, CH), 6.89 (1H,
d, J ¼ 12.4 Hz, CH), 7.08–7.16 (2H, m, Ar-H), 7.23–7.28 (1H, m, Ar-H), 7.36 (1H,
t, J ¼ 8.0 Hz, Ar-H), 7.44–7.47 (2H, m, Ar-H), 8.00–8.10 (2H, m, Ar-H). E isomer:
1H NMR (CDCl3, 400.13 MHz) d 7.08–7.16 (1H, m, CH), 7.23–7.28 (1H, m,
Ar-H), 7.32–7.40 (1H, m, Ar-H), 7.44–7.47 (1H, m, Ar-H), 7.58 (1H, t, J ¼ 8.0 Hz,
Ar-H), 7.66 (1H, d, J ¼ 16.4 Hz, CH), 7.72 (1H, d, J ¼ 7.6 Hz, Ar-H), 7.89 (1H, d,
J ¼ 8.0 Hz, Ar-H), 8.16 (1H, d, J ¼ 8.0 Hz, Ar-H), 8.43 (1H, s, Ar-H).
1-Nitro-3-(3-phenylprop-1-en-1-yl)benzene, 1f. Colorless oil. Z isomer: 1H
NMR (CDCl3, 400.13 MHz) d 3.69 (2H, d, J ¼ 7.4 Hz, CH2), 6.07 (1H, dt, J ¼ 11.4
and 7.6 Hz, CH), 6.64 (1H, d, J ¼ 11.4 Hz, CH), 7.23–7.67 (7H, m, 7 Ar-H), 8.14
(1H, d, J ¼ 8.0 Hz, Ar-H), 8.21 (1H, s, Ar-H). E isomer: 1H NMR (CDCl3,
400.13 MHz) d 3.62 (2H, d, J ¼ 5.5 Hz, CH2), 6.46–6.59 (1H, m, CH), 6.64 (1H, d,
J ¼ 11.4 Hz, CH), 7.23–7.67 (8H, m, CH þ 7 Ar-H), 8.07 (1H, d, J ¼ 8.0 Hz, Ar-H),
8.21 (1H, s, Ar-H).
1-Nitro-2-styrylbenzene, 1g. Yellow gum. Z isomer: 1H NMR (CDCl3,
400.13 MHz) d 6.80 (1H, d, J ¼ 12.0 Hz, CH), 6.93 (1H, d, J ¼ 12.0 Hz, CH), 7.08
(2H, dd, J ¼ 7.0 and 3.2 Hz, Ar-H), 7.30 (1H, d, J ¼ 7.6 Hz, Ar-H), 7.38–7.48 (3H,
1
m, Ar-H), 7.54–7.67 (2H, m, Ar-H); 8.07–8.15 (1H, m, Ar-H). E isomer: H NMR
(CDCl3, 400.13 MHz) d 7.12 (1H, d, J ¼ 16.4 Hz, CH), 7.16–7.22 (3H, m, Ar-H),
7.26–7.34 (1H, m, Ar-H), 7.36 (1H, d, J ¼ 7.2 Hz, Ar-H), 7.38–7.48 (2H, m,
Ar-H), 7.63 (1H, d, J ¼ 16.4 Hz, CH), 7.80 (1H, d, J ¼ 8.0 Hz, Ar-H), 7.99 (1H, d,
J ¼ 8.2 Hz, Ar-H).
1
1-Fluoro-2-(3-nitrostyryl)benzene, 1h. Yellow gum. Z isomer: H NMR
(CDCl3, 400.13 MHz) d 6.75 (1H, d, J ¼ 12.4 Hz, CH), 6.81 (1H, d, J ¼ 12.4 Hz,
CH), 7.00 (1H, t, J ¼ 7.6 Hz, Ar-H), 7.08 (1H, t, J ¼ 9.2 Hz, Ar-H), 7.15 (1H, t,
J ¼ 7.6 Hz, Ar-H), 7.29 (1H, m, Ar-H), 7.39 (1H, m, Ar-H), 7.53 (1H, d, J ¼ 7.6 Hz,
1
Ar-H), 8.06 (1H, d, J ¼ 8.6 Hz, Ar-H), 8.09 (1H, s, Ar-H). E isomer: H-NMR
(CDCl3, 400.13 MHz) d 7.15–7.30 (4H, m, CH þ 3 Ar-H), 7.40 (1H, d, J ¼ 16.0 Hz,
CH), 7.56 (1H, d, J ¼ 8.2 Hz, Ar-H), 7.63 (1H, t, J ¼ 7.6 Hz, Ar-H), 7.85 (1H, d,
J ¼ 7.6 Hz, Ar-H), 8.13 (1H, d, J ¼ 8.0 Hz, Ar-H), 8.39 (1H, s, Ar-H).
1-Nitro-4-styrylbenzene, 1j. Yellow gum. Z isomer: 1H NMR (CDCl3,
400.13 MHz) d 6.64 (1H, d, J ¼ 12.0 Hz, CH), 6.84 (1H, d, J ¼ 12.0 Hz, CH),
7.23–7.72 (7H, m, Ar-H), 8.09 (2H, d, J ¼ 8.4 Hz, Ar-H). E isomer: 1H NMR
(CDCl3, 400.13 MHz) d 7.17 (1H, d, J ¼ 16.4 Hz, CH), 7.38 (1H, m, CH),
7.23–7.72 (7H, m, Ar-H), 8.25 (2H, d, J ¼ 8.4 Hz, Ar-H).
1-Fluoro-2-(4-nitrostyryl)benzene, 1k. Yellow oil. Z isomer: 1H NMR
(CDCl3, 400.13 MHz) d 6.67 (1H, d, J ¼ 12.0 Hz, CH), 6.84 (1H, d, J ¼ 12.0 Hz,
CH), 7.00 (1H, t, J ¼ 7.6 Hz, Ar-H), 7.04–7.32 (3H, m, Ar-H), 7.38 (2H, d, J ¼ 8.6 Hz,
1
Ar-H), 8.10 (2H, d, J ¼ 8.6 Hz, Ar-H). E isomer: H NMR (CDCl3, 400.13 MHz) d
7.04–7.32 (5H, m, CH þ 4 Ar-H), 7.45 (1H, d, J ¼ 16.4 Hz, CH), 8.68 (2H, d,
J ¼ 8.6 Hz, Ar-H), 8.25 (2H, d, J ¼ 8.6 Hz, Ar-H).
1-Chloro-2-(4-nitrostyryl)benzene, 1l. Yellow oil. Z isomer: 1H NMR
(CDCl3, 400.13 MHz) d 6.67 (1H, d, J ¼ 12.0 Hz, CH), 6.92 (1H, d, J ¼ 12.0 Hz,

754
T. RODRIGUES, F. LOPES, AND R. MOREIRA
CH), 7.05–7.13 (2H, m, Ar-H), 7.21–7.37 (3H, m, Ar-H), 7.46 (1H, d, J ¼ 8.2 Hz,
1
Ar-H), 8.07 (2H, d, J ¼ 8.6 Hz, Ar-H). E isomer: H NMR (CDCl3, 400.13 MHz)
d 7.15 (1H, d, J ¼ 16.4 Hz, CH), 7.21–7.37 (2H, m, CH þAr-H), 7.45 (1H, d,
J ¼ 8.0 Hz, Ar-H), 7.66–7.76 (4H, m, Ar-H), 8.26 (2H, d, J ¼ 8.6 Hz, Ar-H).
2,4-Dinitro-1-styrylbenzene, 1m. Yellow gum. Z isomer: 1H NMR (CDCl3,
400.13 MHz) d 6.90 (1H, d, J ¼ 12.0 Hz, CH), 6.99 (1H, d, J ¼ 12.0 Hz, CH),
7.06–7.12 (2H, m, Ar-H), 7.21–7.27 (3H, m, Ar-H), 7.38–7.51 (1H, m, Ar-H), 8.21
1
(1H, dd, J ¼ 8.6 and 2.2 Hz, Ar-H), 8.96 (1H, d, J ¼ 2.2 Hz, Ar-H). E isomer: H
NMR (CDCl3, 400.13 MHz) d 7.32 (1H, d, J ¼ 16.4 Hz, CH), 7.38–7.51 (3H, m,
Ar-H), 7.61 (2H, d, J ¼ 8.0 Hz, Ar-H), 7.66 (1H, d, J ¼ 16.4 Hz, CH), 8.02 (1H, d,
J ¼ 8.8 Hz, Ar-H), 8.46 (1H, dd, J ¼ 8.8 and 2.2 Hz, Ar-H), 8.86 (1H, d, J ¼ 2.2 Hz,
Ar-H).
1
3,5-Dinitro-1-styrylbenzene, 1n. Yellow gum. Z isomer: H NMR (CDCl3,
400.13 MHz) d 6.67 (1H, d, J ¼ 12.0 Hz, CH), 7.02 (1H, d, J ¼ 12.0 Hz, CH),
7.18–7.25 (2H, m, Ar-H), 7.30–7.37 (3H, m, Ar-H), 8.38 (2H, d, J ¼ 1.8 Hz,
1
Ar-H), 8.85 (1H, t, J ¼ 1.8 Hz, Ar-H). E isomer: H NMR (CDCl3, 400.13 MHz) d
7.36–7.50 (5H, m, 2 CH þ 3 Ar-H), 7.61 (2H, d, J ¼ 7.2 Hz, Ar-H), 8.68 (2H, d,
J ¼ 2.0 Hz, Ar-H), 8.91 (1H, t, J ¼ 7.2 Hz, Ar-H).
ACKNOWLEDGMENTS
ˆ
This work was funded by Fundac¸a˜o para a Ciencia e Tecnologia (FCT,
Portugal) through Project PTDC=SAU-FCF=098734=2008 and a PhD fellowship
to T.R. (SFRH=BD=30689=2006).
REFERENCES
1. Rodrigues, T.; Guedes, R. C.; dos Santos, D. J. V. A.; Carrasco, M.; Gut, J.; Rosenthal,
P. J.; Moreira, R.; Lopes, F. Design, synthesis, and structure–activity relationships of
(1H-pyridin-4-ylidene)amines as potential antimalarials. Bioorg. Med. Chem. Lett. 2009,
19, 3476–3480.
2. Simons, L. J.; Caprathe, B. W.; Callahan, M.; Graham, J. M.; Kimura, T.; Lai, Y.; LeVine,
H.; Lipinski, W.; Sakkab, A. T.; Tasaki, Y.; Walker, L. C.; Yasunaga, T.; Ye, Y.; Zhuang, N.;
Augelli-Szafran, C. E. The synthesis and structure–activity relationship of substituted
N-phenyl anthranilic acid analogs as amyloid aggregation inhibitors. Bioorg. Med. Chem.
Lett. 2009, 19, 654–657.
3. Motoshima, K.; Noguchi-Yachide, T.; Sugita, K.; Hashimoto, Y.; Ishikawa, M. Separation
of a -glucosidase-inhibitory and liver X receptor-antagonistic activities of phenethylphenyl
phthalimide analogs and generation of LXRa -selective antagonists. Bioorg. Med. Chem.
2009, 17, 5001–5014.
4. Wittig, G.; Geissler, G. Zur Reaktionsweise des Pentaphenyl-phosphors und einiger
Derivate. Liebigs Ann. Chem. 1953, 580, 44–57.
5. Maryanoff, B. E.; Reitz, A. B. The Wittig olefination reaction and modifications involving
phosphoryl-stabilized carbanions: Stereochemistry, mechanism, and selected synthetic
aspects. Chem. Rev. 1989, 89, 863–927.
6. Radix, S.; Barret, R. Total synthesis of two natural phenanthrenes: Confusarin and a
regioisomer. Tetrahedron 2007, 63, 12379–12387.

MW-ASSISTED WITTIG REACTION
755
7. Wu, J.; Li, D.; Zhang, D. Aqueous Wittig reactions of aldehydes with in situ formed
semistabilized phosphorus ylides. Synth. Commun. 2005, 35, 2543–2551.
8. Wu, J.; Yue, C. One-pot Wittig reactions in aqueous media: A rapid and environmentally
benign synthesis of a,b-unsaturated carboxylic esters and nitriles. Synth. Commun. 2006,
36, 2939–2947.
9. Wu, J.; Zhang, D.; Wei, S. Wittig Reactions of stabilized phosphorus ylides with
aldehydes in water. Synth. Commun. 2005, 35, 1213–1222.
10. Dambacher, J.; Zhao, W.; El-Batta, A.; Annes, R.; Jiang, C.; Bergdahl, M. Water is an
efficient medium for Wittig reactions employing stabilized ylides and aldehydes. Tetra-
hedron Lett. 2005, 46, 4473–4477.
11. Molander, G. A.; Oliveira, R. A. Wittig reaction of formyl-substituted organotrifluorobo-
rates and stabilized phosphonium ylides in an aqueous medium. Tetrahedron Lett. 2008,
49, 1266–1268.
12. Hwang, J.-J.; Lin, R.-L.; Shieh, R.-L.; Jwo, J.-J. Study of the Wittig reaction of benzyl-
triphenylphosphonium salt and benzaldehyde via ylide-mediated phase-transfer catalysis:
Substituent and solvent effects. J. Mol. Catal. A: Chem. 1999, 142, 125–139.
13. Antonioletti, R.; Bonadies, F.; Ciammaichella, A.; Viglianti, A. Lithium hydroxide as
base in the Wittig reaction: A simple method for olefin synthesis. Tetrahedron 2008, 64,
4644–4648.
14. Rodefeld, L.; Tochtermann, W. A new approach to (9Z)-dodec-9-en-12-olide (Yuzu
lactone) via phase-transfer catalysis cyclization. Tetrahedron 1998, 54, 5893–5898.
15. Piechucki, C. Wittig–Horner synthesis in an aqueous two-phase system using phase-
transfer catalysis. Synthesis 1974, 12, 869–870.
16. Ilia, G.; Popa, A.; Iliescu, S.; Dehelean, G.; Pescariu, A.; Macarie, L.; Plesu, N. Chemical
modification of functionalized copolymers with phosphonium groups by phase transfer–
catalysed Wittig reactions. Mol. Cryst. Liq. Cryst. 2004, 416, 175–182.
17. Zhang, X.-M.; Fry, A. J.; Bordwell, F. G. Equilibrium acidities and homolytic bond
dissociation enthalpies of the acidic C–H bonds in P-(para-substituted benzyl)triphenyl-
phosphonium cations and related cations. J. Org. Chem. 1996, 61, 4101–4106.
18. Dunne, E. C.; Coyne, E. J.; Crowley, P. B.; Gilheany, D. G. Co-operative ortho-effects on
the Wittig reaction: Interpretation of stereoselectivity in the reaction of ortho-halo-
substituted benzaldehydes and benzylidenetriphenylphosphoranes. Tetrahedron Lett.
2002, 43, 2449–2453.
19. Harrowven, D. C.; Guy, I. L.; Howell, M.; Packham, G. The synthesis of a combretastatin
A-4–based library and discovery of new cooperative ortho-effects in Wittig reactions
leading to (Z)-stilbenes. Synlett 2006, 18, 2977–2980.
20. Thiemann, T.; Watanabe, M.; Tanaka, Y.; Mataka, S. Solvent-free Wittig olefination with
stabilized phosphoranes: Scope and limitations. New J. Chem. 2004, 28, 578–584.