Julia olefination as a general route to phenyl (α-fluoro)vinyl sulfones

Article abstract of DOI:10.1055/s-2008-1072513

Mild and efficient synthesis of phenyl (α-fluoro)vinyl sulfones via condensation of aldehydes and a ketone with a novel benzothiazolyl based bis-sulfone reagent is reported and this proceeds with moderate to good Z-stereoselectivity. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1072513

LETTER
999
Julia Olefination as a General Route to Phenyl (a-Fluoro)vinyl Sulfones
S
ynthesis of Fluorovin
a
yl Sulfonesggie He,1 Arun K. Ghosh, Barbara Zajc*
Department of Chemistry, The City College and The City University of New York, 160 Convent Avenue, New York, NY 10031, USA
Fax +1(212)6506107; E-mail: barbaraz@sci.ccny.cuny.edu
Received 2 September 2007
conversion proceeded only at high temperatures. In order
Abstract: Mild and efficient synthesis of phenyl (a-fluoro)vinyl
to increase the reactivity of the halomethyl phenyl sul-
sulfones via condensation of aldehydes and a ketone with a novel
benzothiazolyl based bis-sulfone reagent is reported and this pro-
ceeds with moderate to good Z-stereoselectivity.
fone, the iodo derivative was synthesized (sodium ben-
zenesulfinate and CH2I2).14 As anticipated, reaction of the
iodomethyl sulfone derivative proceeded at the milder 70
°C to give 1 in 83% isolated yield, that was subjected to
Key words: fluorination, olefination, Julia, fluorovinyl sulfones,
benzothiazole
oxidation to bis-sulfone 2 using catalytic ammonium mo-
15
lybdate [(NH4)6Mo7O24·4H2O] and H2O2
(75%,
Scheme 1). Subsequent fluorination of 2 using NaH and
Selectfluor in THF resulted in a mixture of starting 2,
monofluoro 3 and difluoro 4 derivatives (39:55:6) and
upon chromatographic purification, the monofluoro de-
rivative was isolated in 40% yield. The use of KOt-Bu and
Selectfluor in DMF reported for the fluorination of
bis(benzenesulfonyl)methane16 resulted in a mixture of
2:3:4 in approximately 1:1:1 ratio. Much better results
were obtained when 1 was first subjected to deprotonation
using LDA in toluene, followed by electrophilic fluorina-
tion with NFSi. This resulted in a mixture of 1, mono-
fluoro and difluoro derivatives in a ratio (%) of 23:69:8,
respectively. Since separation of the mono and difluoro
derivatives proved to be problematic, 1 was initially sep-
arated from the products. The mixture of mono and difluo-
ro derivatives was then oxidized to bis-sulfones 3 and 4
using H5IO6 and catalytic CrO3.17 At this stage, 3 could be
easily separated from the difluoro byproduct 4, to give the
monofluoro bis-sulfone 3 in 49% yield (over two steps).
Herein we report the development and application of a
novel reagent for the preparation of phenyl (a-fluoro)vi-
nyl sulfones. Sulfones in general are important synthetic
intermediates, leading to a variety of compounds.2 Specif-
ically, (a-fluoro)vinyl sulfones have been subjected to a
range of transformations, such as desulfonylation leading
to vinyl fluorides,3 stannyldesulfonylation,4 or silyl and
germyldesulfonylation,5 and thus they serve as versatile
synthetic intermediates to a variety of fluoroolefins. Also,
vinyl sulfones can be used for cycloadditions and are
Michael acceptors.3b,6 (a-Fluoro)vinyl sulfones can be
prepared by various approaches, such as: addition of fluo-
romethyl phenyl sulfone anion to carbonyl compounds,3a
Horner–Wadsworth–Emmons3–5 or Peterson’s olefina-
tion,7 syn elimination of sulfoxides,8 or via electrochemi-
cal method.9 Synthesis of vinyl fluorides using
fluorobis(phenylsulfonyl)methane has also been shown.10
An attractive method for the synthesis of carbon–carbon
double bonds is the modified or one-pot Julia–Kocienski
olefination.11 The use of Julia reaction for the synthesis of
vinyl fluorides has recently begun to receive attention.12,13
In this context, our synthesis of vinyl fluorides hinges on
development of general routes to fluorinated 1,3-ben-
zothiazolyl sulfones via metalation–electrophilic fluori-
nation.13 The a-fluoro 1,3-benzothiazol-2-yl sulfones so
derived were subjected to condensations with a series of
aldehydes and ketones to afford high yields of regiospe-
cifically fluorinated 1,2-diaryl olefins13a as well as a-fluo-
ro acrylates.13b Encouraged by these results, we decided to
explore the utility of Julia olefination for the synthesis of
phenyl (a-fluoro)vinyl sulfones.
With the desired reagent 3 in hand, condensation reactions
with carbonyl compounds were tested. The use of Julia re-
action for the synthesis of acrylates18 and a-fluoro
acrylates12b,13b under mild, DBU-mediated conditions has
been reported. Aldehydes were therefore subjected to con-
densation reactions under similar mild conditions. In a
typical experiment, aldehyde (1 mol equiv) and bis-sul-
fone 3 (1.3 mol equiv) were dissolved in freshly distilled
CH2Cl2 at room temperature, and DBU (1.5 or 4.0 mol
equiv, entry 1, Table 1) in CH2Cl2 was added to the reac-
tion mixture. The progress of the reaction was monitored
by TLC for the disappearance of the aldehyde and the re-
actions were typically complete within 35–120 minutes.
The reaction mixtures were partially concentrated and
then directly loaded onto a dry silica gel column. The
combined E/Z-product mixture was eluted and the E/Z ra-
tio was analyzed by 19F NMR spectroscopy.
Briefly, our synthesis of the desired reagent for the prepa-
ration of phenyl (a-fluoro)vinyl sulfones via modified
Julia olefination initially commenced from the commer-
cially available chloromethyl phenyl sulfone. Displace-
ment of chloride with the sodium salt of 2-mercapto-1,3-
benzothiazole provided the mono sulfone 1, however the
In the case of alkanals that could potentially lead to vola-
tile products, an internal standard was added to the E/Z-
fluoroalkene mixtures eluted from the column, and the
yield was assessed by 19F NMR spectroscopy, prior to
complete solvent removal. The yields and stereochemical
SYNLETT 2008, No. 7, pp 0999–1004
x
x.
x
x.
2
0
0
8
Advanced online publication: 28.03.2008
DOI: 10.1055/s-2008-1072513; Art ID: S07307ST
© Georg Thieme Verlag Stuttgart · New York

1000
M. He et al.
LETTER
S– Na+
DMF
N
O
O
O
S
O
,
S
I
S
S
N
83%
S
1
H2O2,
49%
of 3
1) LDA, NFSi,
toluene
2) H5IO6, cat. CrO3,
MeCN
cat. (NH4)6Mo7O24·4H2O,
EtOH, 75%
over
2 steps
O
S
O O O
O
O O O
S
S
S
N
N
base
Selectfluor
F
X
S
S
2
3: X = H
4: X = F
Scheme 1 Synthesis of the fluorinated bis-sulfone
outcomes of the reactions are shown in Table 1 and com- products were expected and were formed in the reaction.
parison to some alternative synthetic routes in the litera- These were isolated in 80% yield by column chromatog-
ture is included.
raphy (SiO2, CH2Cl2). For characterization purposes the
isomers from one reaction were partially separated by pre-
parative TLC (SiO2, 25% EtOAc in hexanes) to give Z-
trans, Z-cis and a mixture of E-trans and E-cis isomers.
Products formed in the reaction and their ratios, along
with chemical shifts of the vinylic F and H atoms that are
most diagnostic in isomer assignments, are shown in
Scheme 2.
All aldehydes tested gave high to excellent yields of fluo-
rovinyl sulfones. The use of 4.0 mol equivalents of DBU
instead of 1.5 mol equivalents did not change the yield or
E/Z ratio (entry 1). It should also be noted that the E/Z ra-
tio did not change significantly upon purification of the
products, except in the case of 13 (entry 9, unstable prod-
uct, E/Z ratio 22:78 after purification). In all cases studied,
the major isomer formed was Z. The observed stereoselec- As a test substrate for reactivity of ketones, N-benzylpip-
tivities in these cases can be rationalized on the same prin- eridone was subjected to olefination. Under the conditions
ciples as described in our synthesis of a- used for olefination of aldehydes (DBU, CH2Cl2), a slug-
fluoroacrylates.13b The stereochemical outcome in reac- gish reaction was observed, with 47% conversion after 24
tions with aldehydes using our methodology is comple- hours. Upon changing the reaction solvent to THF, the re-
mentary to other known methods, where the major or action was complete in 6 hours and the condensation
exclusive isomer formed was E.3,7,19 In the case of aromat- product was isolated in 65% yield.23 A comparable 70%
ic aldehydes stereoselectivity decreased with the bulk of yield was obtained in the reaction of N-benzylpiperidone
the aldehyde (entries 6, 8), however, branching of the al- (1 mol equiv) with 3 (2.4 mol equiv) in the presence of
dehyde did not appear to have any influence on the E/Z ra- LHMDS (2.4 mol equiv, 0 °C), after standard aqueous
tio in the case of aliphatic aldehydes (entries 10–12).
workup and purification by chromatography. On the other
hand, olefination of acetophenone and 1-indanone with 3
in the presence of LHMDS was inefficient. No further at-
tempts were made to optimize reactivity of ketones with 3
at this time.
Since MgBr2 has been shown to alter the E/Z ratio,12b,20
some experiments were conducted in its presence.21
Wherever tested, these data are also presented in Table 1.
In the case of aromatic aldehydes, stereoselectivity de-
pended on the aldehyde: it decreased for 4-nitrobenzalde- We were curious to compare the reactivity of the Horner–
hyde (entry 3), remained the same for thiophene-2- Wadsworth–Emmons (HWE) reagent to that of the bis-
carboxaldehyde (entry 7), and improved for 2-methoxy- sulfone 3 for the synthesis of fluorovinyl sulfones under
benzaldehyde (entry 6). A substantial improvement in ste- these mild condensation conditions, using DBU. For this,
reoselectivity was observed for octanal (entry 10). Similar reactions of 2-naphthaldehyde and 1-octanal were chosen.
(entry 3) or somewhat better yields (entries 6, 7, and 10) Indeed, PhSO2CHFP(O)(OEt)2 (1.3 mol equiv) under-
were obtained in the presence of MgBr2.
went reaction with 2-naphthaldehyde (1 mol equiv) in the
presence of DBU (4.0 mol equiv) in CH2Cl2 at room tem-
perature to give the condensation products in 80% yield
and a 40:60 E/Z ratio. Reaction with 1-octanal (1.5 mol
equiv of DBU) resulted in 48:52 E/Z product mixture in
65% yield. In this comparison substantially higher stereo-
selectivities were obtained in condensation reactions of 3
with 2-naphthaldehyde (Table 1, entry 1, 4.0 mol equiv of
We were further interested in the reactivity of bis-sulfone
3 with ethyl 2-formyl-1-cyclopropanecarboxylate, in or-
der to assess the applicability of the method to the synthe-
sis of fluorinated compounds with the pyrethrin structural
motif,22 that are of interest in agricultural chemistry. Since
the commercial cyclopropyl carboxaldehyde was a mix-
ture of trans and cis isomers in a 9:1 ratio, four isomeric
Synlett 2008, No. 7, 999–1004 © Thieme Stuttgart · New York

LETTER
Synthesis of Fluorovinyl Sulfones
1001
Table 1 Mild Synthesis of (a-Fluoro)vinyl Sulfones via the Julia Olefination
O
H
R
O
O O
O
O
O
O
O
S
S
S
S
R
H
N
R
H
+
DBU, CH2Cl2,
r.t., 35–120 min
S
F
F
F
3
(E)-5–16
(Z)-5–16
R = alkyl, aryl, hetaryl, vinyl
Entry Aldehyde
Time
Products 5–16
19F NMR: d (ppm)e,
J (Hz)
(min)a
Yield,b E/Z ratioc (lit.)d
5: 94%, 16:84
Using 4.0 mol equiv of DBU: 93%, 17:83
–111.64 (d, J = 21.4)
–125.20 (d, J = 33.6)
O
1
2
120
80
6: 90%, 16:84
–112.16 (d, J = 21.4)
–125.12 (d, J = 36.6)
O
(85%, 95:5),19 (52%, 77:23),7 (85%, E only),3b (67%, E only)3a
7: 85%, 22:78
–108.08 (d, J = 18.3)
–119.46 (d, J = 33.6)
O
3
90
With MgBr2: 84%, 29:71
(95%, 93:7)3b
O2N
8: 89%, 17:83
–111.06 (d, J = 21.4)
–124.23 (d, J = 36.6)
O
4
70
90
(85%, 81:19),3c (80%, E only)3a
Cl
9: 90%, 12:88
–114.09 (d, J = 24.4)
–128.86 (d, J = 33.6)
O
5
(81%, 98:2)3b
MeO
10: 75%, 48:52
With MgBr2: 91%, 36:64
–112.93 (d, J = 21.4)
–126.96 (d, J = 36.6)
O
6
120
90
OMe
O
11: 82%, 11:89
With MgBr2: 96%, 9:91
–116.85 (d, J = 21.4)
–124.46 (d, J = 36.6)
S
7
8
–117.25 (d, J = 24.4)
–130.52 (d, J = 33.6)
80
12: 72%, 44:56
Fe
O
13:f 87%, 13:87
(72%, E only)3b
–120.01 (d, J = 21.4)
–127.87 (d, J = 30.5)
9
40
90
O
O
14: 85% (91%),g 22:78
With MgBr2: 95%, 4:96
(44%, 83:17)7
–117.19 (d, J = 21.4)
–129.43 (d, J = 33.6)
10
O
15: 66%, 23:77
–116.21 (d, J = 21.4)
–128.08 (d, J = 33.6)
11
12
35
90
(90%, 68:32),19 (52%, 90:10)7
–116.09 (d, J = 24.4)
–129.60 (d, J = 33.6)
16: 59% (71%),g 23:77
O
a Time at isolation.
b Yields of isolated, purified products (reactions were performed under similar conditions but were not optimized for individual cases).
c Relative ratio of isomers determined by 19F NMR of the crude reaction mixture.
d Where applicable, literature data and references are provided for comparison.
e Referenced to CFCl3 as internal standard.
f The product is unstable and undergoes decomposition.
g Yield determined by addition of internal standard octafluoronaphthalene to the E/Z mixture eluted from the column, prior to complete solvent
evaporation.
DBU, 17:83 E/Z) and 1-octanal (Table 1, entry 10, 22:78 thaldehyde was monitored by 19F NMR in the presence of
E/Z). Finally, in order to compare the reactivity of 3 and octafluoronaphthalene as an internal standard. Reaction of
PhSO2CHFP(O)(OEt)2, a reaction of each with 2-naph- 3 (1.3 mol equiv) with 2-naphthaldehyde (1 mol equiv) in
Synlett 2008, No. 7, 999–1004 © Thieme Stuttgart · New York

1002
M. He et al.
LETTER
O
O O O
S
S
N
O
CO2Et
+
S
F
trans/cis = 9:1
3
DBU, CH2Cl2, r.t.
δ = –130.47 ppm
PhO2S
δ = –117.97 ppm
F
(d, J = 30.5 Hz)
F
CO2Et
PhO2S
CO2Et
+
(d, J = 18.3 Hz)
H
H
δ = 5.23 ppm
δ = 5.75 ppm
Z-trans
E-trans
δ = –130.81 ppm
PhO2S
δ = –116.64 ppm
F
(d, J = 30.5 Hz)
F
CO2Et
PhO2S
CO2Et
+
(d, J = 21.4 Hz)
H
H
δ = 6.07 ppm
δ = 6.42 ppm
Z-cis
E-cis
Z-trans/E-trans/Z-cis/E-cis = 69:19:9:3
Scheme 2 Condensation of 3 with ethyl 2-formyl-1-cyclopropane carboxylate
O
O O O
S
S
N
S
CHO
(1 mol equiv)
2 (1.3 mol equiv)
F
+
S
O
O O
O
CH2Cl2, 120 min
DBU (1.5 mol equiv)
O
O
S
S
N
E/Z mixture
only product
S
F
3 (1.3 mol equiv)
Scheme 3 Comparative reactivity of 2 and 3 with 2-naphthaldehyde
the presence of DBU (1.5 mol equiv) showed 60% con- In summary, we have developed an efficient synthesis of
version to products after 15 minutes. In contrast, in the re- a novel benzothiazolyl-based bis-sulfone reagent for the
action of the HWE reagent under identical conditions, preparation of fluorovinyl phenyl sulfones via a one-pot
only about 8% conversion to products occurred in 15 min- Julia olefination. Condensation reactions with aldehydes
utes, indicating a higher reactivity of 3 under these mild are high yielding and proceed under mild conditions to
condensation conditions.
give fluoroolefins with moderate to good Z-selectivity.
The bis-sulfone reagent also showed a greater reactivity as
compared to the HWE reagent PhSO2CHFP(O)(OEt)2. As
originally reported by us in the synthesis of a-fluoro acry-
lates,13b in this case as well fluorine substitution increases
the reactivity of the bis-sulfone reagent.
We then assessed the influence of fluorine atom substitu-
tion on the reactivity of the bis-sulfone reagent. For this a
competitive experiment was conducted, where the non-
fluorinated bis-sulfone 2 (1.3 mol equiv) and its fluorinat-
ed analogue 3 (1.3 mol equiv) were allowed to react with
2-naphthaldehyde (1 mol equiv) in CH2Cl2 using DBU
(1.5 mol equiv). After 120 minutes, the reaction was dilut-
ed with CH2Cl2 and washed with aqueous NH4Cl. The or-
ganic layer was washed with water, dried with anhydrous
Na2SO4, and analyzed by TLC (SiO2, 15% EtOAc in hex-
anes) and by 1H NMR. The only product obtained was flu-
orinated alkene 5. This was also confirmed by comparison
to the independently synthesized 1-phenylsulfonyl-2-(2-
naphthyl)ethene (Scheme 3).
Synthesis of (1,3-Benzothiazol-2-ylsulfanyl)methyl Phenyl Sul-
fone (1)
A solution of iodomethyl phenyl sulfone (3.00 g, 10.6 mmol, 1 mol
equiv) and the sodium salt of 2-mercapto-1,3-benzothiazole (6.04 g,
31.9 mmol, 3 mol equiv) in DMF (90.0 mL) was heated at 70 °C for
18 h. The reaction mixture was cooled to r.t., diluted with H2O and
extracted three times with EtOAc (300 mL). The organic layer was
thoroughly washed with H2O, aq NaOH (1 M), H2O, aq NH4Cl and
Synlett 2008, No. 7, 999–1004 © Thieme Stuttgart · New York

LETTER
Synthesis of Fluorovinyl Sulfones
1003
finally with brine, and dried over anhyd Na2SO4. The solvent was
evaporated under reduced pressure and the crude product was puri-
fied by column chromatography (SiO2, 0.1% acetone in CH2Cl2) to
was continued at r.t. until complete consumption of the aldehyde
was observed by TLC (SiO2, CH2Cl2, 70 min). The reaction mixture
was directly loaded onto a dry silica gel column (200–300 mesh)
and the product 8 was eluted with CH2Cl2 as an E/Z mixture. Upon
removal of solvent under reduced pressure, 187 mg (89%) of 8 was
isolated and E/Z ratio was determined by 19F NMR (Table 1, entry
4). HRMS: m/z calcd for C14H10ClFO2SNa [M+ + Na]: 318.9966;
1
give 2.82 g (83%) of 1 as an ivory solid. H NMR (500 MHz,
CDCl3): d = 7.96 (d, 2 H, ArH, J = 7.5 Hz), 7.72 (d, 1 H, ArH,
J = 7.9 Hz), 7.68 (d, 1 H, ArH, J = 7.9 Hz), 7.42–7.32 (m, 4 H,
ArH), 7.30 (t, 1 H, ArH, J = 7.9 Hz), 5.03 (s, 2 H, CH2). 13C NMR
(125 MHz, CDCl3): d = 161.5, 151.9, 137.0, 135.5, 133.9, 129.2,
128.7, 126.2, 124.9, 121.8, 121.0, 54.9. HRMS: m/z calcd for
C14H11NO2S3Na [M+ + Na]: 343.9844; found: 343.9837.
1
found: 318.9960. For H NMR analysis, a small amount of the E-
and Z-isomers was separated by TLC (SiO2, 20% acetone in hex-
ane). E-isomer: 1H NMR (500 MHz, CDCl3): d = 8.01 (d, 2 H, ArH,
J = 7.8 Hz), 7.71 (t, 1 H, ArH, J = 7.7 Hz), 7.61 (t, 2 H, ArH, J = 7.8
Hz), 7.51 (d, 2 H, ArH, J = 8.7 Hz), 7.37 (d, 2 H, ArH, J = 8.7 Hz),
Synthesis of (1,3-Benzothiazol-2-ylsulfonyl)fluoromethyl
Phenyl Sulfone (3)
2
7.02 (d, 1 H, JFH = 34.5 Hz). Z-isomer: 1H NMR (500 MHz,
Step 1: Fluorination
CDCl3): d = 7.88 (d, 2 H, ArH, J = 7.8 Hz), 7.69 (t, 1 H, ArH,
J = 7.4 Hz), 7.56 (t, 2 H, ArH, J = 7.6 Hz), 7.38 (ABq, 4 H, ArH,
J = 8.5 Hz), 6.84 (d, 1 H, 2JFH = 21.2 Hz).
A stirring solution of (1,3-benzothiazol-2-ylsulfanyl)methyl phenyl
sulfone 1 (2.00 g, 6.22 mmol, 1 mol equiv) in dry toluene (95 mL),
was cooled to –80 °C (dry ice/i-PrOH) under nitrogen gas. Lithium
diisopropylamide (3.58 mL, 7.16 mmol, 1.15 mol equiv of a 2.0 M
solution in heptane–THF–EtPh) was added to the reaction mixture
with stirring. After 15 min solid NFSi (2.45 g, 7.79 mmol, 1.25 mol
equiv) was added. The mixture was allowed to stir at –80 °C for 50
min, then warmed to r.t., and the stirring was continued for an addi-
tional 50 min. Then, sat. aq NH4Cl (80 mL) was added to the mix-
ture and the layers were separated. The aqueous layer was extracted
three times with EtOAc (200 mL), and the combined organic layer
was washed with H2O, sat. aq NaHCO3, and brine. The organic lay-
er was dried over Na2SO4, and the solvent was evaporated under re-
Acknowledgment
This work was supported by NSF Grant CHE-0516557; infrastruc-
tural support and support for A.K.G. were provided by NIH RCMI
Grant 5G12 RR03060. Support of M.H. through the Bristol-Myers
Squibb summer undergraduate research program is gratefully ack-
nowledged. Acquisition of a mass spectrometer was funded by NSF
Grant CHE-0520963. We thank Dr. Andrew Poss (Honeywell) for
a sample of NFSi, Dr. G. Sankar Lal (Air Products) for a sample of
Selectfluor and Dr. Padmanava Pradhan (NMR facility manager)
for assistance with the 2D NMR experiments.
1
duced pressure. The H NMR and 19F NMR spectra of the crude
reaction mixture showed the presence of 1, monofluoro and difluoro
derivatives in a ratio (%) of 23:69:8, respectively. Purification by
column chromatography (SiO2, CH2Cl2) afforded 1.55 g of a mix-
ture of mono and difluoro derivatives that were subjected to oxida-
tion.
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Step 2: Oxidation
To a solution of H5IO6 (4.68 g, 20.5 mmol) in MeCN (100 mL) was
added CrO3 (22.8 mg, 0.228 mmol), and after stirring at r.t. for 5
min a solution of the mono and difluoro derivatives (1.55 g, ob-
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proceed for another 5 h, when 19F NMR and TLC showed complete
conversion of the monosulfones to the bis-sulfones. The reaction
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brine, and dried over anhyd Na2SO4. The crude product mixture was
separated by column chromatography (SiO2, CH2Cl2) to give 1.13 g
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1
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Society, Boston MA, American Chemical Society:
Washington (DC), 2007, ORGN 846.
MHz, CDCl3): d = 8.27 (br d, 1 H, ArH, J = 8.3 Hz), 8.07 (d, 2 H,
ArH, J = 7.4 Hz), 8.04 (br d, 1 H, ArH, J = 8.3 Hz), 7.80 (br t, 1 H,
ArH, J = 7.6 Hz), 7.71–7.63 (m, 4 H, ArH), 6.37 (d, 1 H, 2JFH = 45.6
Hz). 13C NMR (125 MHz, CDCl3): d = 161.7, 152.6, 137.6, 136.0,
134.8, 130.5, 129.5, 129.0, 128.2, 126.1, 122.4, 105.0 (d,
1JCF = 268.2 Hz). 19F NMR (470 MHz): d = –169.95 (d, 2JFH = 45.8
Hz). HRMS: m/z calcd for C14H10FNO4S3Na [M+ + Na] 393.9648;
found: 393.9643.
(11) (a) Blakemore, P. R. J. Chem. Soc., Perkin Trans. 1 2002,
2563. (b) Plesniak, K.; Zarecki, A.; Wicha, J. Top. Curr.
Chem. 2007, 275, 163.
(12) (a) Chevrie, D.; Lequeux, T.; Demoute, J. P.; Pazenok, S.
Tetrahedron Lett. 2003, 44, 8127. (b) Pfund, E.; Lebargy,
C.; Rouden, J.; Lequeux, T. J. Org. Chem. 2007, 72, 7871.
Condensation of 4-Chlorobenzaldehyde with 3
To a stirring solution of 4-chlorobenzaldehyde (100 mg, 0.711
mmol, 1 mol equiv) and 3 (344 mg, 0.926 mmol, 1.3 mol equiv) in
freshly distilled CH2Cl2 (4.4 mL) was added DBU (163 mg, 1.07
mmol, 1.5 mol equiv) in CH2Cl2 (4.4 mL) at r.t. Upon addition of
DBU, the reaction mixture immediately turned yellow. The stirring
Synlett 2008, No. 7, 999–1004 © Thieme Stuttgart · New York

1004
M. He et al.
LETTER
(21) In a typical experiment, to a mixture of aldehyde (1 mol
(13) (a) Ghosh, A. K.; Zajc, B. Org. Lett. 2006, 8, 1553.
(b) Zajc, B.; Kake, S. Org. Lett. 2006, 8, 4457.
(14) Bordwell, F. G.; Clemens, A. H.; Smith, D. E.; Begemann,
J. J. Org. Chem. 1985, 50, 1151.
(15) Ono, K.; Yoshida, A.; Saito, N.; Fujishima, T.; Honzawa, S.;
Suhara, Y.; Kishimoto, S.; Sugiura, T.; Waku, K.;
Takayama, H.; Kittaka, A. J. Org. Chem. 2003, 68, 7407.
(16) Ni, C.; Li, Y.; Hu, J. J. Org. Chem. 2006, 71, 6829.
(17) Xu, L.; Cheng, J.; Trudell, M. L. J. Org. Chem. 2003, 68,
5388.
equiv), bis-sulfone 3 (1.3 mol equiv) and anhyd MgBr2 (1.8
mol equiv) in anhyd THF (5 mL per mmol of aldehyde), a
solution of DBU (3.9 mol equiv) in anhyd THF (5 mL per
mmol of aldehyde) was added. The mixture was stirred at
r.t., until the disappearance of the aldehyde was observed by
TLC. Aqueous NH4Cl was added and the mixture was
extracted with EtOAc (3×). The organic layer was washed
with H2O and brine, dried over anhyd Na2SO4 and the
solvent was evaporated.
(18) Blakemore, P. R.; Ho, D. K. H.; Nap, W. M. Org. Biomol.
Chem. 2005, 3, 1365.
(19) Andrei, D.; Wnuk, S. F. J. Org. Chem. 2006, 71, 405.
(20) Lebrun, M.-E.; Le Marquand, P.; Berthelette, C. J. Org.
Chem. 2006, 71, 2009.
(22) (a) Jeschke, P. ChemBioChem 2004, 5, 570. (b) Liu, W.;
Qin, S.; Gan, J. J. Agric. Food Chem. 2005, 53, 3814.
(23) Conditions as reported in ref. 12b were used (N-
benzylpiperidone: 1.2 mol equiv; 3: 1 mol equiv; DBU: 1.4
mol equiv; THF: 5 mL per mmol of 3; r.t., 6 h).
Synlett 2008, No. 7, 999–1004 © Thieme Stuttgart · New York

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