Synthesis of regiospecifically fluorinated conjugated dienamides

Article abstract of DOI:10.3390/molecules19044418

Modular synthesis of regiospecifically fluorinated 2,4-diene Weinreb amides, with defined stereochemistry at both double bonds, was achieved via two sequential Julia-Kocienski olefinations. In the first step, a Z-?-fluorovinyl Weinreb amide unit with a benzothiazolylsulfanyl substituent at the allylic position was assembled. This was achieved via condensation of two primary building blocks, namely 2-(benzo[d]thiazol-2-ylsulfonyl)- 2-fluoro-N-methoxy-N- methylacetamide (a Julia-Kocienski olefination reagent) and 2-(benzo[d]thiazol- 2-ylthio)acetaldehyde (a bifunctional building block). This condensation was highly Z-selective and proceeded in a good 76% yield. Oxidation of benzothiazolylsulfanyl moiety furnished a second-generation Julia-Kocienski olefination reagent, which was used for the introduction of the second olefinic linkage via DBU-mediated condensations with aldehydes, to give (2Z,4E/Z)-dienamides in 50%-74% yield. Although olefinations were 4Z-selective, (2Z,4E/Z)-2-fluoro-2,4-dienamides could be readily isomerized to the corresponding 5-substituted (2Z,4E)-2-fluoro-N-methoxy-Nmethylpenta- 2,4-dienamides in the presence of catalytic iodine.

Full text of DOI:10.3390/molecules19044418

Molecules 2014, 19, 4418-4432; doi:10.3390/molecules19044418
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Synthesis of Regiospecifically Fluorinated Conjugated
Dienamides
Mohammad Chowdhury, Samir K. Mandal, Shaibal Banerjee and Barbara Zajc *
Department of Chemistry, The City College and The City University of New York,
160 Convent Avenue, NY 10031, USA
* Author to whom correspondence should be addressed; E-Mail: barbaraz@sci.ccny.cuny.edu;
Tel.: +1-212-650-8926; Fax: +1-212-650-6107.
Received: 16 February 2014; in revised form: 22 March 2014 / Accepted: 31 March 2014 /
Published: 10 April 2014
Abstract: Modular synthesis of regiospecifically fluorinated 2,4-diene Weinreb amides,
with defined stereochemistry at both double bonds, was achieved via two sequential
Julia-Kocienski olefinations. In the first step, a Z--fluorovinyl Weinreb amide unit with a
benzothiazolylsulfanyl substituent at the allylic position was assembled. This was achieved
via condensation of two primary building blocks, namely 2-(benzo[d]thiazol-2-ylsulfonyl)-
2-fluoro-N-methoxy-N-methylacetamide (a Julia-Kocienski olefination reagent) and
2-(benzo[d]thiazol-2-ylthio)acetaldehyde (a bifunctional building block). This condensation
was highly Z-selective and proceeded in a good 76% yield. Oxidation of
benzothiazolylsulfanyl moiety furnished a second-generation Julia-Kocienski olefination
reagent, which was used for the introduction of the second olefinic linkage via
DBU-mediated condensations with aldehydes, to give (2Z,4E/Z)-dienamides in 50%–74%
yield. Although olefinations were 4Z-selective, (2Z,4E/Z)-2-fluoro-2,4-dienamides could
be readily isomerized to the corresponding 5-substituted (2Z,4E)-2-fluoro-N-methoxy-N-
methylpenta-2,4-dienamides in the presence of catalytic iodine.
Keywords: fluoro dienamides; Julia-Kocienski olefination; Weinreb amide; fluoro dienes
1. Introduction
The conjugated diene and polyene amide structural units are found in many naturally occurring
compounds that possess biological activity [1]. These compounds have a variety of uses, ranging from

Molecules 2014, 19
4419
medicinal purposes, to insecticides, as well as culinary flavoring agents [1]. Some examples of
dienamides are shown in Figure 1. Trichostatin A is an antifungal antibiotic [2], and as an inhibitor of
mammalian histone deacetylase [3], is a potential anticancer agent [4]. Pellitorine has insecticidal [5]
and cytotoxic [6] activities. Piperlonguminine has broad-ranging therapeutic activities [7]
such as antibacterial, antifungal, antitumor [8], anticoagulant [9], antimelanogenesis [10], and
anti-inflammatory [11], to name a few. Piperovatine exhibits local anesthetic [12] and antinflammatory
activities [11]. Due to their interesting biological activities, several analogs, such as a fluorinated
Trichostatin A analog [13], have been synthesized as well.
Figure 1. Examples of naturally occurring, biologically active 2,4-dienamides.
O
O
O
OH
N
N
H
H
Me2N
Trichostatin A [2–4]
Pellitorine [5,6]
MeO
O
O
O
N
H
N
H
O
Piperlonguminine [7–11]
Piperovatine [11,12]
Fluorine is an attractive substituent in pharmaceuticals, in agrochemicals, and in materials
chemistry [14–16] due to its effect on physical, chemical, and biological properties of compounds [17–19].
Julia-Kocienski olefinations [20–23] have been explored for the synthesis of various functionalized
fluoroolefins [24–26] by us [27–35] and by others [36–46]. In the course of our recent work, we
became interested in the use of bifunctional Julia-Kocienski reagents, or their precursors, for novel
modular assembly of vinyl [33,47] and fluorovinyl [33] compounds. Herein, we report the synthesis of
regiospecifically fluorinated dienamides, via sequential olefination of a bifunctional Julia-Kocienski
building block. As the amide functionality, we chose the Weinreb amide, both to test the feasibility of
the methodology and due to its versatility via its unique reactivity properties [48–51].
2. Results and Discussion
Key to our approach was the assembly of a -fluorovinyl Weinreb amide moiety with functionality
at the beta position that could be used in a sequential condensation. We have previously reported the
synthesis and studied the reactivity of a Julia-Kocienski reagent for the preparation of -fluorovinyl
Weinreb amides (1, Scheme 1) [31]. Condensation of 2-(benzo[d]thiazol-2-ylsulfonyl)-2-fluoro-N-
methoxy-N-methylacetamide (1) with a 2-(heteroarylthio)ethanal (2, heteroaryl = benzothiazolyl,
Scheme 1) and subsequent oxidation would furnish a second-generation Julia-Kocienski reagent for
dienamide synthesis. A retrosynthetic approach to conjugated dieneamides is outlined in Scheme 1.

Molecules 2014, 19
Scheme 1. Retrosynthetic analysis for the preparation of conjugated dieneamides.
4420
The requisite Julia-Kocienski reagent, 2-(benzo[d]thiazol-2-ylsulfonyl)-2-fluoro-N-methoxy-N-
methylacetamide (1), was synthesized as reported [31]. Synthesis of the other key reactive partner,
2-(benzo[d]thiazol-2-ylthio)acetaldehyde (2), was initially attempted via the dioxolane derivative of 2.
Although the dioxolane derivative of 2 could be readily prepared from 2-(bromomethyl)-1,3-dioxolane
and the sodium salt of 2-mercapto-1,3-benzothiazole, attempts at deprotection of 2-[(1,3-dioxolan-2-
yl)methylthio]benzo[d]thiazole under various conditions proved unsuccessful. Therefore, synthesis via
the dimethyl acetal was considered (Scheme above Table 1).
Table 1. Synthesis of 2-(benzo[d]thiazol-2-ylthio)acetaldehyde 2.
OMe
OMe
Br
Na
S
S
S
N
N
N
OMe
Conditions
OMe
O
S
S
S
DMF, 40 C, 4 h
3
2
Entry
Reagent
I2
Solvent
acetone
T (°C)
Time
Yield (%) a
1
2
3
4
5
6
rt
overnight
3 days
3 days
24 h
-- b
-- b
-- b
20 c
56
CBr4
CH3CN–H2O 1:3
THF–H2O 1:1
acetone
80
rt
PTSA
HCl (4 M)
HCl (4 M)
HCl (12 M)
HCl (12 M)
40
40
50
50
acetone
4 h
acetone
30 min
40 min
81
7
acetone–H2O 10:1
84
a
Aldehyde 2 was unstable under chromatographic conditions, either on silica gel or on alumina. Therefore,
the yield reported for 2 is without purification, unless stated otherwise; b 1H-NMR and TLC showed only
dimethyl acetal 3, and no product formation was observed; c Isolated yield after column chromatography.
Various conditions were tested to unmask the aldehyde functionality (Table 1). Upon reaction of
dimethyl acetal 3 with I2 (entry 1), CBr4 (entry 2), or PTSA (entry 3), no hydrolysis was observed.
Reaction of 3 with 4 M HCl at 40 °C resulted in complete consumption of 3, but aldehyde 2 was
isolated in a low 20% yield after column chromatography (entry 4). Subsequently, we found that
compound 2 is unstable under chromatography conditions, on silica gel and alumina [52]. The yield of
crude 2 after hydrolysis with 4 M HCl, but without chromatography, was 56%. Hydrolysis with 12 M
HCl at 50 °C was complete within 30 min, yielding crude 2 in 81% yield (entry 6). However, due to
the solubility of 2 in water, we obtained inconsistent results in repeat experiments. After extensive

Molecules 2014, 19
4421
experimentation we found that crude 2 could be isolated in consistent yields when aqueous workup
was avoided. Briefly, acetal 3 was reacted with 12 M HCl in acetone–H2O (10:1) at 50 °C for 40 min
(entry 7), solid NaHCO3 was added portion-wise at 5 °C to neutralize the acid, and excess water was
removed by addition of anhydrous Na2SO4. The solution was then passed through a bed of anhydrous
Na2SO4 and the solvent was evaporated to afford 2 in >80% yield. When acetone alone was used as
solvent, complete hydrolysis of 3 occurred, but the crude product showed the presence of an unidentified
byproduct that could possibly result from the condensation of acetone and 2. The use of water as a
co-solvent therefore seems to be crucial in order to minimize the formation of the byproduct.
With both desired building blocks in hand, i.e., the Julia-Kocienski reagent 1 and aldehyde 2, we
tested reaction conditions for the olefination reaction (Table 2). All condensation reactions were
performed at −78 °C in the presence of LHMDS, and gave (Z)-4-(benzo[d]thiazol-2-ylthio)-2-fluoro-
N-methoxy-N-methylbut-2-enamide (4) as the only stereoisomer. Comparably, exclusive Z-selectivity
has also been observed in NaH-mediated condensations of 1 with aldehydes [31]. In the reactions
herein, the molar ratio of sulfone 1, aldehyde 2, and LHMDS was critical for obtaining a good yield of
4 (Table 2). When aldehyde 2 was used as a limiting reactant (entry 1), or in an equimolar amount
(entry 2), enamide 4 was obtained in low yield. On the other hand, with excess aldehyde 2 and
LHMDS, a substantial yield improvement was observed. Thus, product 4 was isolated in 76% yield
when 2 molar equiv of 2 and 3 molar equiv of LHMDS were used (entry 4). Since the desired product
was obtained with exclusive Z-selectivity and in a good yield, we did not attempt to use other bases,
such as KHMDS or NaHMDS.
Table 2. Synthesis of (Z)-4-(benzo[d]thiazol-2-ylthio)-2-fluoro-N-methoxy-N-methylbut-
2-enamide (4).
O
O
O
O
S
S
Me
S
Me
N
N
N
LHMDS
N
N
O
+
S
S
F
OMe
S
F
OMe
THF, –78 C
1
2
4
Entry
Molar Ratio of 1:2:LHMDS
Time
3 h
Yield (%) a
1
2
3
4
1.5:1:1.5
1:1:2
32
20
60
76
2.5 h
4 h
1:3:5
1:2:3
3.5 h
a Yield is of isolated and purified product 4. Reactions were monitored for completion by 19F-NMR. LHMDS
was added portion-wise (please see Experimental Section).
In order to obtain the second generation Julia-Kocienski reagent 5, sulfide 4 was oxidized using
H5IO6 and catalytic CrO3. Sulfone 5, obtained in 63% yield, was then used for the screening of
reaction conditions for the olefination with 2-naphthaldehyde (Table 3).

Molecules 2014, 19
Table 3. Conditions tested for olefination reactions using the second generation
4422
Julia-Kocienski reagent 5 and 2-naphthaldehyde.
CHO
O
O O
S
O
4E
2Z
Me
N
Me
O
N
N
+
4Z
2Z
Me
N
S
F
OMe
F
OMe
Conditions
5
F
OMe
(2Z,4E)-6a
(2Z,4Z)-6a
Entry
Base
Solvent
T
−78 to 0 °C
0 °C to rt
rt
Time
overnight
12 h
% 4E/4Z Ratio a
Yield (%) b
1
2
3
4
5
6
7
8
LHMDS
LHMDS
DBU
THF
THF
--
--
-- c
-- c
-- c
35
-- c
55
-- c
THF
2 h
--
DBU
THF
−78 to 0 °C
0 °C
overnight
overnight
overnight
overnight
overnight
57/43
--
Cs2CO3
DBU
THF
THF
0 °C
43/57
--
Cs2CO3
CH2Cl2
CH2Cl2
0 °C
DBU
0 °C
35/65
66
a
The relative ratio of isomers in the crude reaction mixtures was determined by 19F-NMR prior to isolation.
No change in the relative ratio was observed after purification; b Yield is of isolated and purified product 6a;
c No product was detected either by 19F-NMR or by TLC.
Both selectivity and product yield depended upon the reaction conditions. No product formation
occurred when LHMDS was used as base (entries 1 and 2), or with DBU as base in THF at room
temperature (entry 3). Similarly, Cs2CO3 in either THF or CH2Cl2 at 0 °C did not show product
formation (entries 5 and 7). Product 6a was obtained in a low 35% yield and with a moderate 4E
selectivity in an overnight reaction with DBU in THF, at −78 to 0 °C (E/Z 57/43, entry 4). When the
condensation reaction was allowed to run overnight at 0 °C (entry 6), product 6a was isolated in a
better 55% yield, but with a reversed selectivity as compared to entry 4 (E/Z 43/57). Yield and
selectivity increased when the condensation reaction was performed overnight using DBU as base in
CH2Cl2, at 0 °C (66%, entry 8).
Using these conditions, the generality of condensation reactions of Julia-Kocienski reagent 5 with
other aldehydes was tested. Table 4 shows yields, the 4E/4Z ratios, and 19F-NMR data of the products.
Table 4. Reactions of reagent 5 with aldehydes: yields, E/Z ratios, and 19F-NMR data.
O
O
O O
S
Me
Me
R
N
O
N
N
R
S
F
OMe
F
OMe
DBU, CH2Cl2
0 C
5
(2Z,4E/Z)-6a–e

Molecules 2014, 19
4423
Table 4. Cont.
Product (6a–e);
% 4E/4Z Ratio a; Yield (%) b
19F-NMR Data: c
Entry
RCHO
 (ppm); Mult, J (Hz)
(4E)-6a: −123.4; d, 30.5
(4Z)-6a: −121.2; d, 30.5
(4E)-6b: −125.2; d, 33.6
(4Z)-6b: −122.6; d, 33.6
O
1
6a: 35/65; 66
6b: 23/77; 50
O
2
MeO
O
O
(4E)-6c: −119.6; d, 30.5
(4Z)-6c: −118.4; d, 30.5
3
6c: 40/60; 74
O2N
S
(4E)-6d: −123.7; d, 30.5
(4Z)-6d: −120.7; d, 33.6
(4E)-6e: −125.7; d, 30.5
(4Z)-6e: −124.2; d, 33.6
O
4
5
6d: 10/90; 63
6e: 15/85; 51
a The relative ratio of isomers in the crude reaction mixtures was determined by 19F-NMR prior to isolation;
Yield is of isolated and purified product 6; c 19F-NMR spectra were recorded at 282 MHz, in CDCl3 with
b
CFCl3 as an internal reference.
Moderate to high 4Z selectivity was obtained with electron-rich aryl and heteroaryl aldehydes, with
yields ranging from 50%–66% (entries 1, 2 and 4). The electron-deficient p-nitrobenzaldehyde gave
product 6c in a good 74% yield, but with poor 4Z selectivity (entry 3). Reaction of 5 with
3-phenylpropanal gave product 6e in a moderate 51% yield and with high 4Z selectivity (entry 5). In
the 19F-NMR spectra of all products, the doublet from the (4E)-isomer appears more upfield as
compared to the doublet from the (4Z)-isomer (Table 4, entries 1–5).
Next, we considered isomerization of the (2Z,4Z)-isomer to the (2Z,4E)-isomer. Several techniques
were evaluated to effect this isomerization. Overnight exposure of the 4E/4Z isomer mixture to light
(20 watt bulb) did not cause any isomerization. Treatment of the isomer mixtures with silica powder in
CHCl3 at room temperature or at 0 °C showed the desired isomerization, but the isomerization did not
proceed to completion. A convenient method for the isomerization using catalytic I2 in CHCl3 at room
temperature has been reported [53]. Using this method, complete isomerization of (2Z,4E/Z)-6a–d to
(2Z,4E)-6a–d was achieved (Table 5).
Table 5. Isomerization of (2Z,4E/Z)-6a–d to (2Z,4E)-6a–d.
O
O
Me
Me
I2 (cat)
N
R
N
R
F
OMe
F
OMe
CHCl3, rt
(2Z,4E/Z)-6a–d
(2Z,4E)-6a–d
Entry
Isomer Mixture
(2Z,4E/Z)-6a
(2Z,4E/Z)-6b
(2Z,4E/Z)-6c
(2Z,4E/Z)-6d
Time
3 h
Product a
(2Z,4E)-6a
(2Z,4E)-6b
(2Z,4E)-6c
(2Z,4E)-6d
Yield (%) b
1
2
3
4
75
86
89
92
3 h
1.5 h
overnight
a Olefin geometry was determined by 1H-NMR; b Yield is of the isolated and purified isomer.

Molecules 2014, 19
4424
3. Experimental
3.1. General Information
THF was distilled over LiAlH4 and then over sodium. CH2Cl2, EtOAc, and hexanes were distilled
over CaCl2. For reactions performed under a nitrogen atmosphere, glassware was dried with a heat gun
under vacuum. LHMDS (1.0 M in THF) was obtained from commercial sources. Julia Kocienski
reagent 2-(benzo[d]thiazol-2-ylsulfonyl)-2-fluoro-N-methoxy-N-methylacetamide (1) was prepared
from the known 2-(benzo[d]thiazol-2-ylsulfonyl)-N-methoxy-N-methylacetamide [54], via metalation-
fluorination using our previously reported procedure [31]. All other reagents were obtained from
commercial sources and used without further purification. Thin layer chromatography was performed
on Analtech silica gel plates (250 m). Column chromatographic purifications were performed on
200–300 mesh silica gel. 1H-NMR spectra were recorded at 500 MHz in CDCl3 and are referenced to
residual solvent. 13C-NMR spectra were recorded at 125 MHz and are referenced to the carbon resonance
of the deuterated solvent. 19F-NMR spectra were recorded at 282 MHz with CFCl3 as an internal standard.
Chemical shifts () are reported in parts per million and coupling constants (J) are in hertz (Hz).
3.2. Synthesis of “Second-Generation” Julia-Kocienski Reagent 5
2-(2,2-Dimethoxyethylthio)benzo[d]thiazole 3. To a solution of the sodium salt of 2-mercapto-1,3-
benzothiazole (1.67 g, 8.83 mmol, 1.49 molar equiv.) in DMF (20 mL) was added 2-bromo-1,1-
dimethoxyethane (1.00 g, 5.91 mmol), and the mixture was allowed to stir at 40 °C for 4 h. Upon
completion of the reaction, as observed by TLC, the reaction mixture was diluted with EtOAc and
washed with water. The aqueous layer was extracted with EtOAc (3 × 30 mL). The combined organic
layer was washed with saturated NaHCO3 (30 mL), brine, dried over anhydrous Na2SO4, and
evaporated. The crude product was purified by column chromatography using 20% EtOAc in hexanes
to obtain compound 3 (0.769 g, 51%) as a colorless viscous liquid. Rf (SiO2, 20% EtOAc in hexanes):
0.48. 1H-NMR (CDCl3):  7.85 (d, 1H, Ar-H, J = 7.8 Hz), 7.75 (d, 1H, Ar-H, J = 8.3 Hz), 7.41 (t, 1H,
Ar-H, J = 7.8 Hz), 7.29 (t, 1H, Ar-H, J = 7.8 Hz), 4.72 (t, 1H, J = 5.3 Hz), 3.58 (d, 2H, J = 5.3 Hz),
3.44 (s, 6H, OCH3). 13C-NMR (CDCl3):  166.4, 153.2, 135.5, 126.1, 124.4, 121.6, 121.1, 103.0, 54.3,
35.5. HRMS (ESI) calcd for C11H14NO2S2 [M+H]+ 256.0460, found 256.0462.
2-(Benzo[d]thiazol-2-ylthio)acetaldehyde 2. To a stirred solution of 2-(2,2-dimethoxyethylthio)benzo
[d]thiazole (3, 1.60 g, 6.26 mmol) in acetone (48 mL), was slowly added a mixture of HCl (12 M, 10.6 mL)
and water (5.2 mL) at rt. The mixture was stirred for 40 min at 50 °C. Upon completion of the reaction,
as observed by TLC, the mixture was cooled to 5 °C and the reaction was quenched by portion-wise
addition of solid NaHCO3 up to the neutralization point, and then passed through a bed of anhydrous
Na2SO4. The anhydrous Na2SO4 bed was washed with a minimum amount of acetone, the combined
eluent was dried over anhydrous Na2SO4, and concentrated under reduced pressure. Crude product 2
(1.10 g, 84%) was used in the next step without purification. Rf (SiO2, 20% EtOAc in hexanes): 0.29.
1H-NMR (CDCl3):  9.73 (br, 1H), 7.85 (d, 1H, Ar-H, J = 7.9 Hz), 7.76 (d, 1H, Ar-H, J = 8.2 Hz), 7.42
(t, 1H, Ar-H, J = 7.6 Hz), 7.32 (t, 1H, Ar-H, J = 7.6 Hz), 4.09 (d, 2H, J = 1.8 Hz).

Molecules 2014, 19
4425
(Z)-4-(Benzo[d]thiazol-2-ylthio)-2-fluoro-N-methoxy-N-methylbut-2-enamide 4. To a stirred solution of
2-(benzo[d]thiazol-2-ylsulfonyl)-2-fluoro-N-methoxy-N-methylacetamide (1, 0.700 g, 2.20 mmol) and
2-(benzo[d]thiazol-2-ylthio)acetaldehyde (2, 0.930 g, 4.44 mmol, 2.0 molar equiv.) in dry THF (48.0 mL)
at −78 °C (dry ice/iPrOH), was added LHMDS (4.39 mL, 1 M, 4.39 mmol, 2.0 molar equiv.) dropwise
under a nitrogen atmosphere. The mixture was allowed to stir at −78 °C (dry ice/iPrOH) for 2 h and
checked for the disappearance of 1 by 19F-NMR (a small sample was removed by syringe and checked
19
by NMR). Since F-NMR showed the presence of 1, more LHMDS (2.19 mL, 1 M, 2.19 mmol,
1 molar equiv.) was added and the mixture was allowed to stir at −78 °C for an additional 1 h at which
time complete consumption of sulfone 1 was observed by 19F-NMR. The reaction was quenched by the
addition of saturated aq. NH4Cl, the solvent was partially removed under reduced pressure, and the
mixture was extracted with EtOAc (3×). The combined organic layer was washed with 5% aq. NaOH,
followed by water and brine, and then dried over Na2SO4. The organic layer was concentrated under
reduced pressure and the crude product was purified by column chromatography using 10%, 15%, and
20% EtOAc in hexanes, to afford compound 4 as a yellow wax (0.523 g, 76%). Rf (SiO2, 30% EtOAc
in hexanes): 0.54. 1H-NMR (CDCl3):  7.87 (d, 1H, Ar-H, J = 8.3 Hz), 7.75 (d, 1H, Ar-H, J = 7.8 Hz),
7.43–7.40 (m, 1H, Ar-H), 7.32–7.28 (m, 1H, Ar-H), 6.22 (dt, 1H, J = 32.7; 8.0 Hz), 4.15 (dd, 2H,
J = 8.0; 1.5 Hz), 3.69 (s, 3H, OCH3), 3.22 (s, 3H, CH3). 13C-NMR (CDCl3):  165.2, 161.8 (d,
JCF = 27.9 Hz), 153.3, 152.4 (d, JCF = 271.9 Hz), 135.7, 126.3, 124.6, 121.9, 121.2, 113.0 (d,
19
3
JCF = 10.5 Hz), 62.1, 33.9, 26.9 (d, JCF = 5.5 Hz). F-NMR (CDCl3):  −119.9 (d, JHF = 30.5 Hz).
HRMS (ESI) calcd for C13H14FN2O2S2 [M+H]+ 313.0475, found 313.0480.
(Z)-4-(Benzo[d]thiazol-2-ylsulfonyl)-2-fluoro-N-methoxy-N-methylbut-2-enamide 5. H5IO6 (0.477 g,
2.09 mmol, 3.0 molar equiv) was dissolved in CH3CN (80.0 mL) by vigorous stirring at rt for 20 min.
CrO3 (25.0 mg, 0.25 mmol) was added and the reaction mixture was stirred for an additional 5 min to
give an orange-colored solution. A solution of (Z)-4-(benzo[d]thiazol-2-ylthio)-2-fluoro-N-methoxy-N-
methybut-2-enamide (4, 0.218 g, 0.698 mmol) in CH3CN (10.0 mL) was added dropwise to this
mixture, resulting in an exothermic reaction and the formation of a yellowish precipitate. After
complete addition, the mixture was stirred for 3 h, at which time TLC showed complete consumption
of amide 4. The mixture was filtered through a Celite pad, the pad was washed with CH3CN, and the
filtrate was concentrated under reduced pressure. Water was added to the residue and the mixture was
extracted with EtOAc (3 × 30 mL). The combined organic layer was washed with saturated
aq. NaHCO3 (5 × 30 mL) and brine (30 mL), and dried over anhydrous Na2SO4. The organic layer was
concentrated under reduced pressure and the crude product was purified by column chromatography
using 15%, 20%, and 25% EtOAc in hexanes to afford compound 5 as a white solid (0.152 g, 63%). Rf
(SiO2, 40% EtOAc in hexanes): 0.43. 1H-NMR (CDCl3):  8.24 (d, 1H, Ar-H, J = 7.8 Hz), 8.02 (d, 1H,
Ar-H, J = 7.8 Hz), 7.67–7.59 (m, 2H, Ar-H), 5.96 (dt, 1H, J = 31.2; 8.3 Hz), 4.43 (dd, 2H, J = 8.3; 1.5 Hz),
3.53 (s, 3H, OCH3), 3.17 (s, 3H, CH3). 13C-NMR (CDCl3):  164.8, 160.8 (d, JCF = 28.4 Hz), 155.6 (d,
JCF = 279.7 Hz), 152.8, 137.2, 128.4, 127.9, 125.8, 122.6, 102.7 (d, JCF = 10.1 Hz), 62.1, 51.1 (d,
3
JCF = 4.6 Hz), 33.6. 19F-NMR (CDCl3):  −113.6 (d, JHF = 30.5 Hz). HRMS (ESI) calcd for
C13H14FN2O4S2 [M+H]+ 345.0374, found 345.0376.

Molecules 2014, 19
4426
3.3. Condensation Reactions of Julia-Kocienski Reagent 5
General experimental procedure. To a stirred solution of aldehyde (0.20 mmol) in dry CH2Cl2 (10.0 mL)
was added DBU (121.7 mg, 0.80 mmol, 4.0 molar equiv.) and the mixture was cooled to 0 °C.
A solution of (Z)-4-(benzo[d]thiazol-2-ylsulfonyl)-2-fluoro-N-methoxy-N-methylbut-2-enamide (5,
103.3 mg, 0.300 mmol, 1.5 equiv.) in dry CH2Cl2 (10.0 mL) was then added slowly, dropwise (over
about 2 h). The reaction mixture was allowed to stir overnight at 0 °C. After completion of the
1
19
reaction, the solvent was evaporated under a stream of nitrogen gas, and the H and F-NMR spectra
of the crude product mixture were recorded for determination of the E/Z ratio. The combined E/Z
product mixture was purified by column chromatography. For eluting solvents see the specific
compound headings. The mixture of (4E)- and (4Z)-isomers was analyzed and characterized based on
the 1H-NMR; the assignment and integration of specific olefinic proton(s) allowed for other signals to
be assigned based on the integration, along with a comparison to the pure (2Z,4E)-isomer (obtained
after isomerization, vide infra). Assignment of the 19F-NMR signals to the (4E)- and (4Z)-isomers was
based on the integration.
(2Z,4E/Z)-2-Fluoro-N-methoxy-N-methyl-5-(naphthalen-2-yl)penta-2,4-dienamide 6a. Isomer ratio of
(4E)-6a:(4Z)-6a = 35:65. Column chromatography using 8%, 10%, and 15% EtOAc in hexanes gave a
mixture of (2Z,4E/Z)-6a as a white solid (38.0 mg, 66%). Rf (SiO2, 30% EtOAc in hexanes): 0.49 for
1
(4E)-6a and 0.58 for (4Z)-6a. H-NMR (CDCl3):  7.85–7.80 (m, Ar-H, 4H, (4E)-isomer and 4H,
(4Z)-isomer), 7.68 (dd, 1H, Ar-H, J = 8.3; 1.5 Hz, (4E)-isomer), 7.50–7.45 (m, Ar-H, 2H, (4E)-isomer
and 3H, (4Z)-isomer), 7.21 (dd, 1H, J = 15.6; 11.2 Hz, (4E)-isomer), 7.06 (ddd, 1H, J = 32.7; 12.0; 1.0 Hz,
(4Z)-isomer), 6.97 (d, 1H, J = 15.6 Hz, (4E)-isomer), 6.91 (d, 1H, J = 11.2 Hz, (4Z)-isomer), 6.72 (dd,
1H, J = 32.5; 11.5 Hz, (4E)-isomer), 6.66 (t, 1H, J = 11.7 Hz, (4Z)-isomer), 3.80 (s, 3H, OCH3,
(4E)-isomer), 3.76 (s, 3H, OCH3, (4Z)-isomer), 3.29 (s, 3H, CH3, (4E)-isomer), 3.25 (s, 3H, CH3,
19
3
3
(4Z) isomer). F-NMR (CDCl3):  –121.2 (d, JHF = 30.5 Hz, (4Z)-isomer), −123.4 (d, JHF = 30.5 Hz,
(4E)-isomer). HRMS (ESI) calcd for C17H17FNO2 [M+H]+ 286.1238, found 286.1242.
(2Z,4E/Z)-2-Fluoro-N-methoxy-N-methyl-5-(4-methoxyphenyl)penta-2,4-dienamide 6b. Isomer ratio of
(4E)-6b:(4Z)-6b = 23:77. Column chromatography using 8%, 15%, and 20% EtOAc in hexanes gave a
mixture of (2Z,4E/Z)-6b as a pale yellow solid (26.5 mg, 50%). Rf (SiO2, 30% EtOAc in hexanes):
0.35. 1H-NMR (CDCl3):  7.42 (d, 2H, Ar-H, J = 8.8 Hz, (4E)-isomer), 7.29 (d, 2H, Ar-H, J = 8.8 Hz,
(4Z)-isomer), 6.99 (ddd, 1H, J = 32.7; 11.7; 0.9 Hz, (4Z)-isomer), 6.95 (dd, 1H, J = 15.6; 11.2 Hz,
(4E)-isomer), 6.91–6.87 (m, Ar-H, 2H, (4Z)-isomer and 2H, (4E)-isomer), 6.75 (d, 1H, J = 15.6 Hz,
(4E)-isomer), 6.69 (br d, 1H, J = 11.7 Hz, (4Z)-isomer), 6.65 (dd, 1H, J = 32.7; 11.4 Hz, (4E)-isomer),
6.47 (t, 1H, J = 11.7 Hz, (4Z)-isomer), 3.83 (s, 3H, OCH3, (4E)-isomer), 3.82 (s, 3H, OCH3,
(4Z)-isomer), 3.77 (s, 3H, OCH3, (4E)-isomer), 3.76 (s, 3H, OCH3, (4Z)-isomer), 3.27 (s, 3H, CH3,
3
(4E)-isomer), 3.25 (s, 3H, CH3, (4Z)-isomer). 19F-NMR (CDCl3):  −122.6 (d, JHF = 33.6,
3
(4Z)-isomer), −125.2 (d, JHF = 33.6, (4E)-isomer). HRMS (ESI) calcd for C14H17FNO3 [M+H]+
266.1187, found 266.1191.
(2Z,4E/Z)-2-Fluoro-N-methoxy-N-methyl-5-(4-nitrophenyl)penta-2,4-dienamide 6c. Isomer ratio of
(4E)-6c:(4Z)-6c = 4:6. Column chromatography using 10% and 15% EtOAc in hexanes gave a mixture

Molecules 2014, 19
4427
of (2Z,4E/Z)-6c as a yellow solid (41.3 mg, 74%). Rf (SiO2, 30% EtOAc in hexanes): 0.47 for (4E)-6c
1
and 0.72 for (4Z)-6c. H-NMR (CDCl3):  8.23 (d, 2H, Ar-H, J = 8.8 Hz, (4Z)-isomer), 8.21 (d, 2H,
Ar-H, J = 8.7 Hz, (4E)-isomer), 7.60 (d, 2H, Ar-H, J = 8.8 Hz, (4E)-isomer), 7.48 (d, 2H, Ar-H,
J = 8.3 Hz, (4Z)-isomer), 7.23 (dd, 1H, J = 15.9; 11.5 Hz, (4E)-isomer), 6.86–6.61( m, 3H, (4Z)-isomer
and 2H, (4E)-isomer), 3.79 (s, 3H, OCH3, (4E)-isomer), 3.77 (s, 3H, OCH3, (4Z)-isomer), 3.28 (s, 3H,
19
3
CH3, (4E)-isomer), 3.25 (s, 3H, CH3, (4Z)-isomer). F-NMR (CDCl3):  −118.4 (d, J HF = 30.5 Hz,
(4Z)-isomer), −119.6 (d, J HF = 30.5 Hz, (4E)-isomer). HRMS (ESI) calcd for C13H14FN2O4 [M+H]+
3
281.0932, found 281.0935.
(2Z,4E/Z)-2-Fluoro-N-methoxy-N-methyl-5-(thiophen-2-yl)penta-2,4-dienamide 6d. Isomer ratio of
(4E)-6d:(4Z)-6d = 1:9. Column chromatography using 8% and 10% EtOAc in hexanes gave a mixture
of (2Z,4E/Z)-6d as a yellow solid (30.2 mg, 63%). Rf (SiO2, 30% EtOAc in hexanes): 0.34 for (4E)-6d
and 0.37 for (4Z)-6d. 1H-NMR (CDCl3):  7.36 (d, 1H, Ar-H, J = 4.9 Hz, (4Z)-isomer), 7.27 (ddd, 1H,
J = 31.7; 12.2; 1.0 Hz, (4Z)-isomer), 7.27–7.25 (overlapping with CHCl3, 1H, Ar-H, (4E)-isomer),
7.12 (d, 1H, Ar-H, J = 3.4 Hz, (4Z)-isomer), 7.09 (d, 1H, Ar-H, J = 3.4 Hz, (4E)-isomer), 7.04 (dd, 1H,
Ar-H, J = 5.1; 3.7 Hz, (4Z)-isomer), 7.00 (dd, 1H, Ar-H, J = 5.1; 3.7 Hz, (4E)-isomer), 6.92 (d, 1H,
J = 15.6 Hz, (4E)-isomer), 6.86 (dd, 1H, J = 15.6; 10.7 Hz, (4E)-isomer), 6.76 (br d, 1H, J = 11.2 Hz,
(4Z)-isomer), 6.61 (dd, 1H, J = 32.2; 10.7 Hz, (4E)-isomer), 6.42 (t, 1H, J = 12.0 Hz, (4Z)-isomer),
3.78 (s, 3H, OCH3, (4Z)-isomer), 3.77 (s, 3H, OCH3, (4E)-isomer), 3.28 (s, 3H, CH3, (4Z)-isomer),
3.26 (s, 3H, CH3, (4E)-isomer). 19F-NMR (CDCl3):  −120.7 (d, 3JHF = 33.6 Hz, (4Z)-isomer), −123.7
(d, 3JHF = 30.5 Hz, (4E)-isomer). HRMS (ESI) calcd for C11H13FNO2S [M+H]+ 242.0646, found 242.0647.
(2Z,4E/Z)-2-Fluoro-N-methoxy-N-methyl-7-phenylhepta-2,4-dienamide
6e.
Isomer
ratio
of
(4E)-6e:(4Z)-6e = 15:85. Column chromatography using 6%, 8%, and 12% EtOAc in hexanes gave a
mixture of (2Z,4E/Z)-6e as a colorless oil (26.6 mg, 51%). Rf (SiO2, 30% EtOAc in hexanes): 0.30. We
were unable to resolve the 1H-NMR signals for both isomers, so the signals reported are for the major
(2Z,4Z)-isomer. For the minor isomer, only diagnostic vinylic C4-H could be unequivocally assigned
1
(separately listed, vide infra). H-NMR (CDCl3) of (2Z,4Z)-isomer:  7.30–7.27 (m, 2H, Ar-H),
7.20–7.18 (m, 3H, Ar-H), 6.68 (ddd, 1H, J = 32.7; 11.7; 1.0 Hz), 6.34 (t, 1H, J = 11.2 Hz), 5.80 (dt, 1H,
J = 10.7; 7.8 Hz), 3.74 (s, 3H, OCH3), 3.24 (s, 3H, CH3), 2.73 (t, 2H, J = 7.8 Hz), 2.55 (q, 2H,
19
J = 7.8 Hz). Minor (2Z,4E)-isomer (CDCl3):  6.04 ppm (1H, C4-H, J = 14.7; 7.3 Hz). F-NMR
3
3
(CDCl3):  −124.2 (d, JHF = 33.6 Hz, (4Z)-isomer), −125.7 (d, JHF = 30.5 Hz, (4E)-isomer). HRMS
(ESI) calcd for C15H19FNO2 [M+H]+ 264.1394, found 264.1407.
3.4. Isomerization of the (2Z,4E/Z)-Isomer Mixture of 6a–d to the (2Z,4E)-Isomer
General experimental procedure. To a stirred solution of the (2Z,4E/Z)-isomer mixture 6 in dry CHCl3
was added I2 (7–10 mol %) and the mixture was stirred at rt. The reaction was monitored by 19F-NMR
and when only one isomer was observed, the reaction mixture was diluted with EtOAc (30 mL). The
mixture was washed with water, saturated aq. Na2S2O3 (2 × 10 mL), and dried over Na2SO4. The
organic layer was concentrated under reduced pressure to afford the desired (2Z,4E)-isomer. HMQC
data were obtained for (2Z,4E)-6c and (2Z,4E)-6d, and where unequivocally assigned, through-bond

Molecules 2014, 19
4428
C–F couplings are reported as 1JCF, 2JCF, etc. Due to the close structural similarity, these couplings are
also reported for (2Z,4E)-6a and (2Z,4E)-6b, where possible.
(2Z,4E)-2-Fluoro-N-methoxy-N-methyl-5-(naphthalene-2-yl)penta-2,4-dienamide
(2Z,4E)-6a.
Isomerization was performed with (2Z,4E/Z)-6a (16.0 mg, 0.056 mmol) in CHCl3 (8.0 mL) using I2
(1.2 mg, 4.7 × 10−3 mmol, 8.4 mol %), in a reaction time of 3 h, to yield isomer (2Z,4E)-6a as a white
solid (12.0 mg, 75%). Rf (SiO2, 30% EtOAc in hexanes): 0.49. 1H-NMR (CDCl3):  7.83–7.80 (m, 4H,
Ar-H), 7.69 (dd, 1H, Ar-H, J = 8.3; 1.5 Hz), 7.50–7.46 (m, 2H, Ar-H), 7.21 (dd, 1H, J = 15.8; 11.3 Hz),
6.97 (d, 1H, J = 15.8 Hz), 6.72 (dd, 1H, J = 32.4; 11.3 Hz), 3.80 (s, 3H, OCH3), 3.29 (s, 3H, CH3).
13C-NMR (CDCl3):  162.8 (d, 2JCF = 26.5 Hz), 150.2 (d, 1JCF = 275.6 Hz), 137.9 (d, 4JCF = 4.5 Hz), 134.1
(d, J = 1.9 Hz), 133.7, 128.7, 128.4, 128.0 (d, J = 1.8 Hz), 127.9, 126.8, 126.7, 123.6, 119.6 (d,
3JCF = 3.7 Hz), 118.2 (d, 2JCF = 9.2 Hz), 62.1 (d, 5JCF = 2.8 Hz), 34.3. 19F-NMR (CDCl3):  −123.4 (d,
3JHF = 30.5 Hz).
(2Z,4E)-2-Fluoro-N-methoxy-N-methyl-5-(4-methoxyphenyl)penta-2,4-dienamide
(2Z,4E)-6b.
Isomerization was performed with (2Z,4E/Z)-6b (14.0 mg, 0.053 mmol) in CHCl3 (8.0 mL) using I2
(1.3 mg, 5.1 × 10−3 mmol, 10 mol %), in a reaction time of 3 h, to yield isomer (2Z,4E)-6b as a pale
1
yellow solid (12.0 mg, 86%). Rf (SiO2, 30% EtOAc in hexanes): 0.35. H-NMR (CDCl3):  7.42 (d,
2H, Ar-H, J = 7.3 Hz), 6.95 (dd, 1H, J = 15.6; 11.2 Hz), 6.88 (d, 2H, Ar-H, J = 6.8 Hz), 6.75 (d, 1H,
J = 15.6 Hz), 6.65 (dd, 1H, J = 32.2; 11.2 Hz), 3.83 (s, 3H, OCH3), 3.77 (s, 3H, OCH3), 3.26 (s, 3H,
13
2
1
CH3). C-NMR (CDCl3):  162.9 (d, JCF = 26.8 Hz), 160.4, 149.5 (d, JCF = 272.8 Hz), 137.5 (d,
4JCF = 4.3 Hz), 129.5, 128.7, 118.7 (d, 2JCF = 9.1 Hz), 117.2, 114.5, 62.1, 55.6, 34.3. 19F-NMR (CDCl3):
 –125.2 (d, 3JHF = 33.6 Hz).
(2Z,4E)-2-Fluoro-N-methoxy-N-methyl-5-(4-nitrophenyl)penta-2,4-dienamide
(2Z,4E)-6c.
Isomerization was performed with (2Z,4E/Z)-6c (4.5 mg, 0.017 mmol) in CHCl3 (1.6 mL) using I2 (0.3 mg,
1.2 × 10−3 mmol, 7 mol %), in a reaction time of 1.5 h, to yield isomer (2Z,4E)-6c as a yellow solid
1
(4.0 mg, 89%). Rf (SiO2, 30% EtOAc in hexanes): 0.47. H-NMR (CDCl3):  8.21 (d, Ar-H, 2H,
J = 8.8 Hz), 7.60 (d, Ar-H, 2H, J = 8.8 Hz), 7.23 (dd, 1H, J = 15.6; 11.2 Hz), 6.83 (d, 1H,
13
J = 15.6 Hz), 6.65 (dd, 1H, J = 31.7; 11.2 Hz), 3.79 (s, 3H, OCH3), 3.28 (s, 3H, CH3). C-NMR
2
1
(CDCl3):  162.3 (d, C=O, JCF = 26.6 Hz), 151.8 (d, C-F, JCF = 280.1 Hz), 147.6, 142.9, 134.7 (d,
4JCF = 4.6 Hz), 127.6, 124.4, 123.6 (d, 3JCF = 3.7 Hz), 116.8 (d, 2JCF = 9.2 Hz), 62.2 (d, 5JCF = 2.3 Hz),
34.2. 19F-NMR (CDCl3):  −119.6 (d, 3JHF = 30.5 Hz).
(2Z,4E)-2-Fluoro-N-methoxy-N-methyl-5-(thiophen-2-yl)penta-2,4-dienamide
(2Z,4E)-6d.
Isomerization was performed with (2Z,4E/Z)-6d (12.0 mg, 0.050 mmol) in CHCl3 (7.5 mL) using I2
(1.2 mg, 4.7 × 10−3 mmol, 10 mol %), in an overnight reaction, to yield isomer (2Z,4E)-6d as an
off-white solid (11.0 mg, 92%). Rf (SiO2, 30% EtOAc in hexanes): 0.34. 1H-NMR (CDCl3):  7.26 (d,
1H, Ar-H, J = 5.4 Hz), 7.09 (d, 1H, Ar-H, J = 3.4 Hz), 7.00 (dd, 1H, Ar-H, J = 5.1; 3.7 Hz), 6.92 (d,
1H, J = 15.6 Hz), 6.86 (dd, 1H, J = 15.6; 10.7 Hz), 6.61 (dd, 1H, J = 32.2; 10.7 Hz), 3.77 (s, 3H,
OCH3), 3.26 (s, 3H, CH3). 13C-NMR (CDCl3):  162.7 (d, 2JCF = 26.5 Hz), 150.1 (d, 1JCF = 275.5 Hz),
4
142.1 (d, J = 2.3 Hz), 130.4 (d, JCF = 5.0 Hz), 128.1 (d, J = 1.8 Hz), 128.0, 126.5 (d, J = 1.4 Hz),

Molecules 2014, 19
4429
3
19
118.9 (d, JCF = 3.2 Hz), 117.9 (d, 2JCF = 9.6 Hz), 62.1 (d, J = 2.7 Hz), 34.3. F-NMR (CDCl3): 
−123.7 (d, 3JHF = 30.5 Hz).
4. Conclusions
In conclusion, we have developed a highly modular approach to (2Z,4E)-2-fluoro-2,4-dienamides.
This was achieved via two sequential Julia-Kocienski olefinations. In the first olefination, a
Z--fluorovinyl Weinreb amide unit, with a benzothiazolylsulfanyl substituent at the allylic position,
was assembled. For this, two key building blocks, a known fluorinated Julia-Kocienski reagent with a
Weinreb amide moiety (1) and 2-(benzo[d]thiazol-2-ylthio)acetaldehyde (2), a precursor to the second
Julia-Kocienski reagent, were reacted. Condensation proceeded with high Z-stereoselectivity and in a
good 76% yield. Oxidation of the sulfide to the sulfone furnished the “second-generation”
Julia-Kocienski olefination reagent, which underwent reactions with aldehydes to furnish the
dienamides in 50%–74% yields. The second set of olefinations proceeded under DBU-mediated
conditions and with Z-stereoselectivity. Isomeric (2Z,4E/Z)-mixtures underwent iodine-mediated
isomerization to a single (2Z,4E)-dienamide isomer. Although the method was performed with a
Weinreb amide moiety, it is potentially applicable to other amides as well. Moreover, due to versatile
chemistry of the Weinreb amide moiety, the (2Z,4E)-2-fluoro Weinreb dienamides are potentially
useful synthetic building blocks, which can undergo a variety of conversions leading to more complex
molecules. In this context, the present method offers a straightforward access to synthetically valuable
entities that are not otherwise easily prepared by traditional synthetic approaches to Weinreb amides.
Supplementary Materials
Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/19/4/4418/s1.
Acknowledgments
This work was supported by NSF Grant CHE-1058618 and a PSC CUNY award. Infrastructural
support was provided by NIH NCRR Grant 2G12RR03060-26A1 and by NIMHD Grant
8G12MD007603-27.
Conflicts of Interest
The authors declare no conflict of interest.
References and Notes
1. Nájera, C.; Yus, M. Natural products with polyene amide structures. In Bioactive Natural
Products (Part B). Studies in Natural Products Chemistry; Rahman, A., Ed.; Elsevier Science B.
V.: Amsterdam, The Netherlands, 2000; Volume 21, pp. 373–455.
2. Tsuji, N.; Kobayashi, M.; Nagashima, K. A new antifungal antibiotic, trichostatin. J. Antibiot.
1976, 29, 1–6.

Molecules 2014, 19
4430
3. Yoshida, M.; Kijima, M.; Akita, M.; Beppu, T. Potent and specific inhibition of mammalian
histone deacetylase both in vivo and in vitro by trichostatin A. J. Biol. Chem. 1990, 265,
17174–17179.
4. Drummond, D.C.; Noble, C.O.; Kirpotin, D.B.; Guo, Z.; Scott, G.K.; Benz, C.C. Clinical development
of histone deacetylase inhibitors as anticancer agents. Annu. Rev. Pharmacol. Toxicol. 2005, 45,
495–528.
5. Jacobson, M. The structure of pellitorine. J. Am. Chem. Soc. 1949, 71, 366–367.
6. Ee, G.C.L.; Lim, C.M.; Rahmani, M.; Shaari, K.; Bong, C.F.J. Pellitorine, a potential anti-cancer
lead compound against HL60 and MTC–7 cell lines and microbial transformation of piperine from
Piper nigrum. Molecules 2010, 15, 2398–2404.
7. Bezerra, D.P.; Pessoa, C.; de Moraes, M.O.; Saker-Neto, N.; Silveira, E.R.; Costa-Lotufo, L.V.
Overview of the therapeutic potential of piplartine (piperlongumine). Eur. J. Pharm. Sci. 2013,
48, 453–463.
8. Bezerra, D.P.; Pessoa, C.; de Moraes, M.O.; de Alencar, N.M.N.; Mesquita, R.O.; Lima, M.W.;
Alves, A.P.N.N.; Pessoa, O.D.L.; Chaves, J.H.; Silveira, E.R.; et al. In vivo growth inhibition of
sarcoma 180 by piperlonguminine, an alkaloid amide from the Piper species. J. Appl. Toxicol.
2008, 28, 599–607.
9. Lee, W.; Yoo, H.; Ku, S.-K.; Kim, J.A.; Bae, J.-S. Anticoagulant activities of piperlonguminine
in vitro and in vivo. BMP Rep. 2013, 46, 484–489.
10. Kim, K.-S.; Kim, J.A.; Eom, S.-Y.; Lee, S.H.; Min, K.R.; Kim, Y. Inhibitory effect of
piperlonguminine on melanin production in melanoma B16 cell line by downregulation of
tyrosinase expression. Pigment Cell Res. 2006, 19, 90–98.
11. Rodrigues Silva, D.; Baroni, S.; Svidzinski, A.E.; Bersani-Amado, C.A.; Cortez, D.A.G.
Anti-inflammatory activity of the extract, fractions and amides from the leaves of Piper ovatum
Vahl (Piperaceae). J. Ethnopharmacol. 2008, 116, 569–573.
12. Makapugay, H.C.; Soejarto, D.D.; Kinghorn, A.D.; Bordas, E. Piperovatine, the tongue-numbing
principle of Ottonia frutescens. J. Ethnopharmacol. 1983, 7, 235–238.
13. Charrier, C.; Roche, J.; Gesson, J.-P.; Bertrand, P. Biological activities of substituted trichostatic
acid derivatives. J. Chem. Sci. 2009, 121, 471–479.
14. Welch, J.T., Ed. Selective Fluorination in Organic and Bioorganic Chemistry; American
Chemical Society: Washington, DC, USA, 1991.
15. Kirsch, P. Modern Fluoroorganic Chemistry. Synthesis, Reactivity, Applications; Wiley-VCH
Verlag GmbH & Co. KGaA: Weinheim, Germany, 2004.
16. Bégué, J.-P.; Bonnet-Delpon, D. Bioorganic and Medicinal Chemistry of Fluorine; John Wiley &
Sons, Inc.: Hoboken, NJ, USA, 2008.
17. Smart, B.E. Fluorine substituent effects (on bioactivity). J. Fluorine Chem. 2001, 109, 3–11.
18. Lemal, D.M. Perspective on fluorocarbon chemistry. J. Org. Chem. 2004, 69, 1–11.
19. O’Hagan, D. Understanding organofluorine chemistry. An introduction to the C–F bond. Chem.
Soc. Rev. 2008, 37, 308–319.
20. Blakemore, P.R. The modified Julia olefination: alkene synthesis via the condensation of
metallated heteroarylalkylsulfones with carbonyl compounds. J. Chem. Soc. Perkin Trans. I 2002,
2563–2585.

Molecules 2014, 19
4431
21. Plesniak, K.; Zarecki, A.; Wicha, J. The Smiles rearrangement and the Julia-Kocienski olefination
reaction. Top. Curr. Chem. 2007, 275, 163–250.
22. Aïssa, C. Mechanistic manifold and new developments of the Julia-Kocienski reaction. Eur. J.
Org. Chem. 2009, 1831–1844.
23. Blakemore, P.R. Olefination of carbonyl compounds by main-group element mediators. In
Comprehensive Organic Synthesis, 2nd ed.; Knochel, P., Molander, G.A., Eds.; Elsevier Ltd:
Oxford, UK, 2014; Volume 1, pp. 516–608.
24. Zajc, B.; Kumar, R. Synthesis of fluoroolefins via Julia-Kocienski olefination. Synthesis 2010,
1822–1836.
25. Landelle, G.; Bergeron, M.; Turcotte-Savard, M.-O.; Paquin, J.-P. Synthetic approaches to
monofluoroalkenes. Chem. Soc. Rev. 2011, 40, 2867–2908.
26. Yanai, H.; Taguchi, T. Synthetic methods for fluorinated olefins. Eur. J. Org. Chem. 2011,
5939–5954.
27. Ghosh, A.K.; Zajc, B. High-yield synthesis of fluorinated benzothiazolyl sulfones: General synthons
for fluoro-Julia olefinations. Org. Lett. 2006, 8, 1553–1556.
28. Zajc, B.; Kake, S. Exceptionally mild, high-yield synthesis of -fluoro acrylates. Org. Lett. 2006, 8,
4457–4460.
29. He, M.; Ghosh, A.K.; Zajc, B. Julia olefination as a general route to phenyl (-fluoro)vinyl
sulfones. Synlett 2008, 999–1004.
30. del Solar, M.; Ghosh, A.K.; Zajc, B. Fluoro-Julia olefination as a mild, high-yielding route to
-fluoro acrylonitriles. J. Org. Chem. 2008, 73, 8206–8211.
31. Ghosh, A.K.; Banerjee, S.; Sinha, S.; Kang, S.B.; Zajc, B. -Fluorovinyl Weinreb amides and
-fluoroenones from a common fluorinated building block. J. Org. Chem. 2009, 74, 3689–3697.
32. Ghosh, A.K.; Zajc, B. Fluorinated 1-phenyl-1H-tetrazol-5-yl sulfone derivatives as general
reagents for fluoroalkylidene synthesis. J. Org. Chem. 2009, 74, 8531–8540.
33. Kumar, R.; Pradhan, P.; Zajc, B. Facile synthesis of 4-vinyl- and 4-fluorovinyl-1,2,3-triazoles via
bifunctional “click-olefination” reagents. Chem. Commun. 2011, 47, 3891–3893.
34. Mandal, S.K.; Ghosh, A.K.; Kumar, R.; Zajc, B. Expedient synthesis of -substituted
fluoroethenes. Org. Biomol. Chem. 2012, 10, 3164–3167.
35. Kumar, R.; Zajc, B. Stereoselective synthesis of conjugated fluoro enynes. J. Org. Chem. 2012,
77, 8417–8427.
36. Chevrie, D.; Lequeux, T.; Demoute, J.P.; Pazenok, S. A convenient one-step synthesis of
fluoroethylidene derivatives. Tetrahedron Lett. 2003, 44, 8127–8130.
37. Pfund, E.; Lebargy, C.; Rouden, J.; Lequeux, T. Modified Julia fluoroolefination: Selective
preparation of fluoroalkenoates. J. Org. Chem. 2007, 72, 7871–7877.
38. Alonso, D.A.; Fuensanta, M.; Gómez-Bengoa, E.; Nájera, C. Highly efficient and stereoselective
Julia-Kocienski protocol for the synthesis of -fluoro-,-unsaturated esters and Weinreb amides
employing 3,5-bis(trifluoromethyl)phenyl (BTFP) sulfones. Adv. Synth. Catal. 2008, 350, 1823–1829.
39. Calata, C.; Catel, J.-M.; Pfund, E.; Lequeux, T. Scope and limitations of the Julia-Kocienski
reaction with fluorinated sulfonylesters. Tetrahedron 2009, 65, 3967–3973.
40. Calata, C.; Pfund, E.; Lequeux, T. Toward the synthesis of benzothiazolyl fluoroaminosulfones.
J. Org. Chem. 2009, 74, 9399–9405.

Molecules 2014, 19
4432
41. Zhao, Y.; Huang, W.; Zhu, L.; Hu, J. Difluoromethyl 2-pyridyl sulfone: A new gem-
difluoroolefination reagent for aldehydes and ketones. Org. Lett. 2010, 12, 1444–1447.
42. Prakash, G.K.S.; Shakhmin, A.; Zibinsky, M.; Ledneczki, I.; Chacko, S.; Olah, G.A. Synthesis of
monofluoroalkenes via Julia-Kocienski reaction. J. Fluorine Chem. 2010, 131, 1192–1197.
43. Allendörfer, N.; Es-Sayed, M.; Nieger, M.; Bräse, S. Novel aromatic fluoroolefins via fluoro-
Julia-Kocienski olefination. Synthesis 2010, 3439–3448.
44. Calata, C.; Pfund, E.; Lequeux, T. Convergent synthesis of functionalized fluoroallylamines by
the Julia-Kocienski reaction. Tetrahedron 2011, 67, 1398–1405.
45. Jacobsen, C.B.; Nielsen, M.; Worgull, D.; Zweifel, T.; Fisker, E.; Jørgensen, K.A. Asymmetric
organocatalytic monofluorovinylations. J. Am. Chem. Soc. 2011, 133, 7398–7404.
46. Larnaud, F.; Malassis, J.; Pfund, E.; Linclau, B.; Lequeux, T. Ready synthetic access to
enantiopure allylic (F)-branched fluoroalkenes. Org. Lett. 2013, 15, 2450–2453.
47. Singh, G.; Kumar, R.; Swett, J.; Zajc, B. Modular Synthesis of N-Vinyl Benzotriazoles.
Org. Lett. 2013, 15, 4086–4089.
48. Nahm, S.; Weinreb, S.M. N-Methoxy-N-methylamides as effective acylating agents. Tetrahedron
Lett. 1981, 22, 3815–3818.
49. Khlestkin, V.K.; Mazhukin, D.G. Recent advances in the application of N,O-dialkylhydroxylamines
in organic chemistry. Curr. Org. Chem. 2003, 7, 967–993.
50. Balasubramaniam, S.; Aidhen, I.S. The growing synthetic utility of the Weinreb amide. Synthesis
2008, 3707–3738.
51. For a recent example of the synthetic application of Weinreb amides please see: Pace, V.;
Castoldi, L.; Holzer, W. Synthesis of ,-unsaturated ’-haloketones through the chemoselective
addition of halomethyllithiums to Weinreb amides. J. Org. Chem. 2013, 78, 7764–7770.
52. Benzothiazole-derived -sulfonyl aldehydes, employed in intramolecular olefinations leading to
,-unsaturated lactones, have been reported to be unstable under chromatographic conditions:
Giesbrecht, H.E.; Knight, B.J.; Tanguileg, N.R.; Emerson, C.R.; Blakemore, P.R. Stereoselective
synthesis of Z-configured ,-unsaturated macrocyclic lactones and diolides by intramolecular
Julia-Kocienski olefination. Synlett 2010, 374–378.
53. Gaukroger, K.; Hadfield, J.A.; Hepworth, L.A.; Lawrence, N.J.; McGown, A.T. Novel syntheses
of cis and trans isomers of combretastatin A-4. J. Org. Chem. 2001, 66, 8135–8138, and
references therein.
54. Manjunath, B.N.; Sane, N.P.; Aidhen, I.S. New reagent for convenient access to the
,-unsaturated N-methoxy-N-methyl-amide functionality by a synthesis based on the Julia
olefination protocol. Eur. J. Org. Chem. 2006, 2851–2855.
Sample Availability: Contact the authors.
© 2014 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article
distributed under the terms and conditions of the Creative Commons Attribution license
(http://creativecommons.org/licenses/by/3.0/).