Stereoselective synthesis of conjugated fluoro enynes

Article abstract of DOI:10.1021/jo300971w

Metalation-electrophilic fluorination of TMS- and TIPS-protected 1,3-benzothiazol-2-yl (BT) propargyl sulfones gave corresponding BT fluoropropargyl sulfones, Julia-Kocienski reagents for the synthesis of fluoro enynes. Both reagents reacted with aldehyde

Full text of DOI:10.1021/jo300971w

Article
pubs.acs.org/joc
Stereoselective Synthesis of Conjugated Fluoro Enynes
Rakesh Kumar and Barbara Zajc*
Department of Chemistry, The City College and The City University of New York, 160 Convent Avenue, New York, New York
10031, United States
S
* Supporting Information
ABSTRACT: Metalation−electrophilic fluorination of TMS- and
TIPS-protected 1,3-benzothiazol-2-yl (BT) propargyl sulfones gave
corresponding BT fluoropropargyl sulfones, Julia−Kocienski
reagents for the synthesis of fluoro enynes. Both reagents reacted
with aldehydes under mild DBU- or LHMDS-mediated conditions,
giving high yields of conjugated fluoro enynes with E-stereo-
selectivity. In comparison to DBU-mediated reactions, stereo-
selectivity was higher in low-temperature LHMDS-mediated
reactions. Two ketones were shown to react as well, using
LHMDS as base. In situ removal of the TMS group gave terminal
conjugated 2-fluoro 1,3-enynes. Synthetic utility of the fluoro
enynes was demonstrated by conversion to internal alkynes and to stereoisomeric fluoro dienes via Sonogashira and Heck
couplings.
pityocampa,3 (+)-brasilenyne and (+)-cis-dihydrorhodophytin
INTRODUCTION
Conjugated enynes are valuable synthetic intermediates1 where
chemistry leading to double- and triple-bond functionalization
can be further exploited. In addition, the 1,3-enyne structural
■
are antifeedants from a sea hare,4 and (2Z,8S,9Z)-heptadeca-
2,9-dien-4,6-diyn-1,8-diol was isolated from Bupleurum salicifo-
lium and demonstrates substantial antibiotic activity,5 whereas
terbinafine (Lamisil) is a synthetic antifungal agent.6
motif is in a broad range of compounds, from natural products
Several methods have been published for the synthesis of
to pharmaceuticals. Some examples are shown in Figure 1.
Dihydromatricaria acid is secreted by soldier beetles
(Cantharidae) for defense,2 (Z)-13-hexadecen-11-ynyl acetate
is a sex pheromone of the processionary moth Thaumetopoea
conjugated enynes, and in recent years, these have been focused
to a large extent on metal-catalyzed approaches.1c,7 Synthesis of
fluorinated 1,3-enynes, on the other hand, has been much less
explored despite widespread interest and importance of the
fluoroorganics.8 The few modular approaches reported involve
metal-catalyzed synthesis of 1-fluoro,9a−c 2-fluoro,9d−h di-9a,i−k
and trifluoro9a,j 1,3-enynes, as well as the Horner−Wadsworth−
Emmons approach to 2-fluoro 1,3-enynes (Figure 2).10 Among
natural products, synthesis of a (E)-13-fluoro-13-hexadecen-11-
ynyl acetate, a fluorinated analogue of a sex pheromone, has
been reported.11 Here, the fluoro enyne analogue was prepared
from the corresponding enyne by dehydration of a fluorohydrin
intermediate.11a,b Change in physical, chemical, and biological
properties upon introduction of a fluorine atom is well
recognized.12 For example, in the case of the pheromone
cited earlier, introduction of fluorine-induced antipheromone
activity.11c
The versatility of Julia−Kocienski13−16 heteroaryl sulfones
for modular assembly of fluoroorganics has been demonstrated
by us17 and others.18 Recently, we have developed a
bifunctionalizable fluorinated building block, 1,3-benzothiazol-
2-yl fluoropropargyl sulfone, and demonstrated its application
in the synthesis of fluorovinyl triazoles.17g To the best of our
knowledge, the use of Julia−Kocienski methodology for the
Figure 1. Examples of natural products and a pharmaceutical with an
enyne motif.
Received: May 28, 2012
© XXXX American Chemical Society
A
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Figure 3. Crystal structure of fluoropropargyl sulfone 3 (C, black; H,
gray; F, green; N, blue; O, red; S, orange; Si, yellow).
Figure 2. Modular approaches to fluoro enynes.
2.5 molar equiv of BT-sulfone 3, and additive, when used
(Barbier conditions). In DBU-mediated reactions, 2.5 molar
equiv of sulfone 3 was added to solution of aldehyde and base.
Since partial loss of the TMS group from the fluoro enyne
product was observed in some of the olefinations, in all cases
TBAF was added to the reaction mixture when complete
consumption of 2-naphthaldehyde had occurred. This led to
the isolation of the deprotected fluoro enyne 4 in a two-step,
one-pot operation. The results from these experiments are
displayed in Table 1.
synthesis of conjugated fluoro enynes has remained unknown.
Herein, we explore the utility of this reagent for modular
synthesis of conjugated fluoro enynes and further conversion of
fluoro enynes to stereoisomeric fluoro dienes.
RESULTS AND DISCUSSION
■
Synthesis of 1,3-benzothiazol-2-yl (BT) fluoropropargyl
sulfone17g commenced from TMS-protected propargyl bromide
and the sodium salt of BT-thiol, to give sulfide 1 (Scheme 1).
Synthesis of TMS-protected enynes, via Julia−Kocienski
olefination, using TMS-protected propargyl BT-sulfone 2 has
Scheme 1. Synthesis of TMS-Protected 1,3-Benzothiazol-2-yl
Fluoropropargyl Sulfone 3
Table 1. Screening of Olefination Conditions
b
T (°C);
time
(%) E/Z;
a
c
entry
base
solvent
THF
additive
yield (%)
d
1
KHMDS
−55;
82/18; 86
10 min
d
2
LHMDS
THF
−78;
88/12; 97
10 min
d
e
3
LHMDS
LHMDS
THF
DMF
MgBr2·Et2O
DMPU
rt; 4 h
89/11; 78
63/37; 74
Oxidation of 1 by m-CPBA to propargyl BT-sulfone 2, followed
by metalation−fluorination under heterogeneous conditions
gave fluoropropargyl BT-sulfone 3.17g Since our prior
communication, we noticed that yields of 3 could vary from
batch to batch. In the currently reported improved procedure,
to obtain consistent yields of 3 we have found that it is critical to
immediately remove any residual fluoride salts from the crude
reaction mixture. Therefore, immediately following workup, the
reaction mixture was suspended in toluene and filtered through
a short silica gel plug, prior to chromatographic purification.
A sample of fluoropropargyl sulfone 3 was crystallized from
hexanes and analyzed by X-ray diffraction (Figure 3). A slight
bend of the triple bond from the linearity was observed. The
Si−C1−C2 and C1−C2−C-3 angles are 177.0° and 176.7°,
respectively.
d
f
4
−78;
10 min
d
g
5
LHMDS
DBU
DMPU
CH2Cl2
0; 10 min 58/42; NA
rt; 69/31; 91
10 min
0; 10 min 70/30; 92
h
6
h
7
DBU
DBU
CH2Cl2
CH2Cl2
h
8
−55;
10 min
74/26; 95
h
g
g
9
DBU
CH2Cl2
−78;
10 min
74/26; NA
h
e
e
i
10
DBU
CH2Cl2
THF
MgBr2·Et2O
MgBr2·Et2O
rt; 30 h
rt; 30 h
rt; 6 h
60/40; inc
h
i
11
DBU
90/10; inc
h
12
Cs2CO3
CH2Cl2
74/26; NA
a
KHMDS and LHMDS: 2.4 molar equiv. DBU: 4.0 molar equiv.
b
Cs2CO3: 3.0 molar equiv. E/Z ratio of diastereomers in the crude
Conditions for condensation reactions with the TMS-
protected 1,3-benzothiazol-2-yl fluoropropargyl sulfone 3
were screened with 2-naphthaldehyde as substrate. In
KHMDS-, LHMDS-, and Cs2CO3-mediated reactions, the
base was added to 1 molar equiv of 2-naphthaldehyde, 2.0−
reaction mixture was determined by 19F NMR, prior to isolation.
c
d
Yields are of isolated and purified products. Sulfone 3, 2.0 molar
equiv. 3.0 molar equiv. Cosolvent, ratio of DMF/DMPU 1:1 (v/v).
Products were not isolated. Sulfone 3, 2.5 molar equiv. Reaction
e
f
g
h
i
was incomplete after 30 h.
B
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Table 2. Condensation Reactions of 3 with Aldehydes and Ketones
a
b
Yields of isolated and purified products. E/Z ratio of diastereomers in the crude reaction mixture was determined by 19F NMR prior to isolation.
c
No change in ratio was observed after purification. Method A: sulfone 3, 2.0−2.5 molar equiv; DBU, 4.0 molar equiv; TBAF, 0.20 molar equiv. For
11 and 13, 3.0 molar equiv of 3 was used. Sulfone was added to solution of aldehyde and base. Method B for aldehydes: sulfone 3, 2.0 molar equiv;
d
LHMDS, 2.4 molar equiv; TBAF, 2.0 molar equiv. Method B for ketones: sulfone 3, 3.0 molar equiv; LHMDS, 5.0 molar equiv; TBAF, 3.0 molar
e
equiv. LHMDS was added to a solution of sulfone and aldehyde. Yield was calculated using octafluoronaphthalene as an internal standard.
f
Determined by NOESY experiment on the diene obtained by Lindlar reduction of 17 (see Figure 5).
been reported.19 Yields were typically moderate, but high Z-
selectivity was obtained in KHMDS-mediated reactions at −55
°C.19 In the present case, KHMDS-mediated reaction of 3 with
2-naphthaldehyde at −55 °C gave product 4 in 82/18 E/Z ratio
and high 86% yield (entry 1). The use of LHMDS at −78 °C
resulted in an increased E/Z ratio (88/12) and 97% yield
(entry 2). Similarly, a high E/Z ratio was obtained when the
reaction was performed at rt and in the presence of
MgBr2·Et2O, but the yield was significantly lower (entry 3).
The use of polar and/or complexing solvents substantially
decreased both the selectivity and the yield (entries 4, 5). We
were also curious to assess whether reactions would proceed
with a weaker base. The use of DBU at room temperature
resulted in a high yield of 4, but with lowered selectivity (E/Z
69/31, entry 6). Lowering the temperature to −55 °C
marginally increased the E-selectivity and yield (entry 8),
whereas further lowering of temperature to −78 °C did not
improve the selectivity (entry 9). The effect of MgBr2·Et2O on
stereoselectivity of DBU-mediated olefinations depended on
the solvent used. In THF, a high 90/10 E/Z ratio was observed
(entry 11), whereas a substantially lower 60/40 ratio was
obtained in CH2Cl2 (entry 10). However, reactions under these
conditions were very slow and were incomplete even after 30 h.
Condensation could also be conducted with Cs2CO3 as base,
but the reaction was much slower than with DBU.
The scope of the condensation reactions of fluoropropargyl
BT-sulfone 3 with carbonyl compounds was next tested with 11
aldehydes and 2 ketones under mild DBU-mediated conditions
(method A) and/or under LHMDS-mediated conditions
(method B), Table 2.
Yields of products obtained via two methods were generally
comparable for all substrates, except for entries 3 and 5, where
there is no obvious reason for the differences observed. Partial
loss of the TMS group in the enyne products was observed in
C
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DBU-mediated reactions prior to addition of TBAF, but only
marginal in the LHMDS-mediated ones. We did not observe
any allene formation in the condensation reactions with TMS-
protected 1,3-benzothiazol-2-yl fluoropropargyl sulfone 3. In
our previous communication on the synthesis of fluorovinyl
triazoles via a click-olefination sequence using TMS-protected
1,3-benzothiazol-2-yl fluoropropargyl sulfone, we also did not
see any allene formation upon in situ TMS-deprotection and
click reaction.17g However, TMS-deprotected 1,3-benzothiazol-
2-yl fluoropropargyl sulfone produced a mixture of alkyne and
the corresponding rearranged allene upon chromatographic
purification.17g A similar influence of a trialkylsilyl group on the
reactivities of terminal alkynes has recently been reported.20a
Whereas allene formation was not observed in Cu(I)-catalyzed
cross-coupling of N-tosylhydrazones with terminal alkynes
bearing trialkylsilyl groups,20a allene formation occurred with
terminal alkynes.20b
Both methods gave alkenes with selectivity for a cis
arrangement of the bulkier groups at the double bond (E-
fluoro enyne). In DBU-mediated condensations with sub-
stituted benzaldehydes, this cis selectivity decreased with
increased electron-withdrawing power of the substituents,
ranging from E/Z 81/19 for methoxy substituent to no
selectivity in the case of nitro substituent (entries 1−5, method
A).
Ketones also reacted under LHMDS-mediated conditions
(entries 12, 13), and single isomer was formed in reaction with
acetophenone (17, entry 13). For determination of stereo-
chemistry in 17, the triple bond was subjected to partial
hydrogenation with Lindlar catalyst (Figure 5). The NOESY
Figure 5. Determination of stereochemistry in 17.
data of the resulting diene showed a correlation between the
ortho protons in the phenyl ring and the internal vinylic proton,
supporting the assignment of E-configuration in 17.
We have shown in the past that α-fluoro-substituted Julia−
Kocienski reagents are more reactive in olefination reactions
compared to their protio analogues.16,17b,c To test the relative
reactivities of the protio and fluoro analogues in the present
case (2 and 3, respectively), a competitive experiment was
performed under DBU-mediated conditions (Scheme 2).
Reaction of 2.5 molar equiv of each 2 and 3 with p-
methoxybenzaldehyde gave fluoro enyne E/Z-5 as the only
product.
As proposed by Julia, anti and syn adducts, formed via
addition of the sulfone carbanion to the aldehyde, undergo
spirocyclization/elimination to olefins. Syn adduct undergoes
faster Smiles rearrangement and gives cis olefin (Figure 4).13,15
Scheme 2. Competitive Reactivity of the Fluoro and the
Protio Julia−Kocienski Analogues
To assess whether size of the silyl protecting group had any
influence on stereoselectivity of the condensation reactions,
triisopropylsilyl (TIPS)-protected fluoropropargyl BT-sulfone
was synthesized (19, Scheme 3).
Figure 4. Mechanistic basis for the observed selectivity.
Scheme 3. Synthesis of TIPS-Protected Fluoropropargyl BT-
sulfone 19
In the present case, reversible addition of carbanion of sulfone
3 to aldehyde, with faster collapse of syn adduct, could explain
the preference for cis selectivity.21 The decrease in cis
selectivity, observed with increase in electron-withdrawing
power of substituent in substituted benzaldehydes (method
A), is likely the result of nonstereoselective formation of anti/
syn adducts, combined with a less favored/slower retroaddition
of initial adducts of less stable electron-deficient aromatic
aldehydes.22 Consistent with this, employing conditions that
favor syn addition of the metalated carbanion of 3 to the
carbonyl, via a chelated transition state (method B), led to
higher cis selectivity than when method A was used, ranging
from excellent to moderate.
D
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Briefly, TIPS-protected propargyl bromide23 was reacted
with the sodium salt of BT-thiol followed by oxidation to
furnish TIPS-protected BT-sulfone 18 (30% yield over three
steps, Scheme 3). Metalation−electrophilic fluorination of 18
under heterogeneous conditions afforded TIPS-protected
fluoropropargyl BT-sulfone 19 in 69% yield. Sulfone 19 was
more stable as compared to the TMS-derived reagent 3, and
after workup, the crude reaction mixture could be directly
loaded to a silica gel column for purification. Higher stability of
TIPS-protected sulfone 19 compared to 3 is also reflected in
the lower molar excess of sulfone required for complete
conversion of the aldehyde in the condensation reaction (1.3
versus 2.0−2.5 molar equiv). Unlike 3, reagent 19 did not
decompose under reaction conditions.
Scheme 5. Sonogashira Coupling of Terminal Fluoro Enynes
minor change in the E/Z ratio was observed in the reaction of
E/Z-4, this may be due to the loss of the minor isomer in the
workup/purification. No traces of products due to [4 + 2]
homobenzannulation of enynes were observed in the Pd-
catalyzed reactions, but a small amount (ca. 5%) of alkyne
dimerization occurred.24
Utility of the terminal fluoro enynes for the synthesis of
regiospecifically fluorinated dienes was demonstrated by further
conversions of fluoro enynes 16 and 23 to stereoisomeric
fluoro dienes (Scheme 6). Lindlar reduction of 16, followed by
Fluoropropargyl BT-sulfone 19 was reacted with 2-
naphthaldehyde and 4-nitrobenzaldehyde using method A
and/or method B (Scheme 4). Since no loss of the TIPS-
Scheme 4. Condensation Reactions of TIPS-Protected
Fluoropropargyl BT-sulfone 19
Scheme 6. Synthesis of Isomeric Dienes
protection was observed in the condensation reactions,
products were isolated as the TIPS-protected enynes. In all
cases tested, yields with the TIPS-protected reagent 19 and the
TMS-protected 3 were comparable. Stereoselectivities were
also comparable for the LHMDS-mediated reaction with 4-
nitrobenzaldehyde and for the DBU-mediated reaction with 2-
naphthaldehyde. However, in the DBU-mediated reaction with
4-nitrobenzaldehyde, 19 gave moderate E-selectivity, whereas
no selectivity was observed with 3 (compare to Table 2, entry
5). It is plausible that upon addition of the carbanion from 19
to the aldehyde the bulk of the triisopropylsilyl group decreases
the rate of spirocyclization of the adducts as compared to
spirocyclization of adducts resulting from 3. In the case of
reversible addition, this would allow for some equilibration
between syn/anti adducts of the less stable22 4-nitrobenzalde-
hyde. Since spirocyclization of the syn adduct occurs faster than
that of anti, this would lead to higher cis selectivity.
The Horner−Wadsworth−Emmons analogue, TIPS-pro-
tected (α-fluoropropargyl)phosphonate, has been studied in
reactions with aldehydes and ketones. High yields of TIPS-
protected fluoro enynes were obtained, with zero to moderate
E-selectivities.10c On the other hand, reactions of carbonyl
compounds and (α-fluoropropargyl)phosphonates, with phe-
nyl- or alkyl-substituted alkynes, gave internal enynes in poor
yields and typically with no selectivity.10a,b Since Sonogashira
coupling offers a convenient route to internal alkynes, we
wanted to explore conversions of the deprotected terminal
fluoro enynes, obtained from the condensations, to internal
fluoro enynes (Scheme 5). Fluoro enynes 4 and 16, when
subjected to Sonogashira couplings with phenyl iodide, gave
phenyl-derived fluoro enynes in good yields. Although some
Heck reaction of the resulting terminal fluoro diene 24,
furnished diene 25 with trans geometry at the newly formed
double bond. Its geometric isomer 26 was synthesized via
Lindlar reduction of fluoro enyne 23 (Scheme 6).
CONCLUSIONS
■
Synthesis of conjugated 2-fluoro 1,3-enynes has been
developed, using Julia−Kocienski reagents. The requisite
reagents, TMS- and TIPS-protected BT fluoropropargyl
sulfones, were synthesized from the corresponding sulfones
via heterogeneous metalation−electrophilic fluorination using
N-fluorobenzenesulfonimide. Both reagents reacted with
aldehydes under mild, DBU-mediated conditions or with
LHMDS. High yields of conjugated 2-fluoro 1,3-enynes were
obtained in both cases, with moderate to excellent E-
stereoselectivity. TMS-protected fluoro enynes were depro-
tected in situ due to lability of the TMS group. This was not the
case with the TIPS-protected products, which were isolated
with the silyl group present. Higher E-stereoselectivity was
obtained when LHMDS was used as base. Ketones were shown
to react as well.
To demonstrate the synthetic utility of terminal fluoro
enynes, two were converted to internal fluoro enynes via
Sonogashira reaction. Further, the use of fluoro enynes for the
preparation of stereoisomeric fluoro dienes was shown. For
this, 1-benzyl-4-(1-fluoroprop-2-ynylidene)piperidine was sub-
E
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molar equiv; for E/Z-5, 0.090 mL, 0.18 molar equiv was used) was
added, and the reaction mixture was concentrated under reduced
pressure. The crude reaction mixture was analyzed by 19F NMR, and
the combined E/Z product mixture was isolated by column
chromatography (10% EtOAc in hexanes, unless stated otherwise).
Method B. A solution of aldehyde (0.500 mmol, 1.0 molar equiv)
and sulfone 3 (1.00 mmol, 2.0 molar equiv) in dry THF (26.0 mL per
mmol of aldehyde) was cooled under nitrogen to −78 °C (dry ice/i-
PrOH). LHMDS (1.0 M solution in THF, 1.2 mL, 2.4 molar equiv)
was added, and upon addition, the reaction mixture turned intense
orange. The reaction mixture was stirred at −78 °C for 5 min and
checked by TLC (10% EtOAc in hexanes), which showed
disappearance of the aldehyde. TBAF (1.0 M solution in THF, 1.00
mL, 2.0 molar equiv) was added, and the reaction mixture was allowed
to stir for another 5 min. Saturated aq NH4Cl was added, and the
mixture was poured into EtOAc. The organic layer was separated, and
the aqueous layer was extracted with EtOAc (3×). The combined
organic layer was washed with water and brine and dried over
anhydrous Na2SO4, and the solvent was evaporated under reduced
pressure. The crude reaction mixture was analyzed by 19F NMR, and
the combined E/Z product mixture was isolated by column
chromatography (10% EtOAc in hexanes, unless stated otherwise).
Condensations of Sulfone 3 with Ketones: General
Procedure. A stirred solution of ketone (0.300 mmol, 1.0 molar
equiv) and sulfone 3 (294 mg, 0.900 mmol, 3.0 molar equiv) in dry
THF (2.5 mL) was cooled under nitrogen to −78 °C (dry ice/i-
PrOH). LHMDS (1.0 M solution in THF, 1.5 mL, 5.0 molar equiv)
was added, and the reaction mixture was stirred at −78 °C for 2 h and
checked by TLC (20% EtOAc in hexanes for 16 and 10% EtOAc in
hexanes for 17), which showed disappearance of the ketone. TBAF
(1.0 M solution in THF, 0.900 mL, 3.0 molar equiv) was added, and
the reaction mixture was allowed to stir for another 5 min. Saturated
aq NH4Cl was added, and the mixture was poured into EtOAc. The
organic layer was separated, and the aqueous layer was extracted with
EtOAc (3×). The combined organic layer was washed with water and
brine and dried over anhydrous Na2SO4, and the solvent was
evaporated under reduced pressure. The crude reaction mixture was
analyzed by 19F NMR, and the product was isolated by column
chromatography (10% EtOAc in hexanes).
Synthesis of (E/Z)-2-(2-Fluorobut-1-en-3-ynyl)naphthalene
(E/Z-4). Method B. 2-Naphthaldehyde: 78.0 mg (0.500 mmol);
sulfone 3: 327 mg (1.00 mmol, 2.0 molar equiv); LHMDS: 1.2 mL
(1.0 M, 1.2 mmol, 2.4 molar equiv); THF: 13.0 mL; TBAF: 1.00 mL
(1.0 M, 1.0 mmol, 2.0 molar equiv). Eluting solvent for column
chromatography: 10% EtOAc in hexanes. Yield of E/Z-4: 95.2 mg
(97%), as a white solid, E/Z ratio: 88/12. Rf (10% EtOAc in hexanes)
= 0.41. 1H NMR (500 MHz, CDCl3): δ 8.01 (s, 1H, Ar-H, E-isomer),
7.95 (s, 1H, Ar-H, Z-isomer), 7.85−7.80 (m, 3H, Ar-H, both E- and Z-
isomers and 1H, Ar-H, E-isomer), 7.66 (d, 1H, Ar-H, J = 8.5 Hz, Z-
isomer), 7.49−7.48 (m, 2H, Ar-H, both E- and Z-isomers), 6.84 (d,
1H, CH, 3JFH = 17.4 Hz, E-isomer), 6.27 (d, 1H, CH, 3JFH = 35.1
Hz, Z-isomer), 3.67 (d, 1H, CH, 4JFH = 4.3 Hz, E-isomer), 3.34 (d,
1H, CH, 4JFH = 3.7 Hz, Z-isomer). 19F NMR (282 MHz, CDCl3): δ
−104.69 (d, 3JFH = 15.3 Hz, E-isomer), −107.17 (d, 3JFH = 36.6 Hz, Z-
isomer). HRMS (APPI): calcd for C14H9F [M]+ 196.0683, found
196.0682.
jected to Sonogashira coupling and partial reduction of the
alkyne to yield the (Z)-1-benzyl-4-(1-fluoro-3-phenylallyl-
idene)piperidine. The E-isomer was synthesized by conversion
of 1-benzyl-4-(1-fluoroprop-2-ynylidene)piperidine to diene via
partial reduction of the triple bond followed by Heck reaction
at the terminal alkene.
EXPERIMENTAL SECTION
■
General Experimental Considerations. THF was distilled over
LiAlH4 and then over sodium, toluene was distilled over sodium, and
CH2Cl2 was distilled over CaCl2. For reactions performed under a
nitrogen atmosphere, glassware was dried with heat gun under
vacuum. LDA (2.0 M solution in heptane/THF/EtPh) and LHMDS
(1.0 M in THF) were obtained from commercial sources. All other
reagents were obtained from commercial sources and used without
further purification. N-fluorobenzenesulfonimide (NFSI) is commer-
cially available. Thin-layer chromatography was performed either on
aluminum foil-backed silica gel plates (200 μm) or glass-backed silica
gel plates (250 μm). Column chromatographic purifications were
performed on 200−300 mesh silica gel. 1H NMR spectra were
recorded at 500 MHz and were 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 internal standard. Proton
assignments have been made only for the acetylenic and some of the
vinylic protons in the E/Z mixtures of enynes and/or dienes. Because
the compounds are closely related, assignments of these protons are
supported by the data obtained from NOESY, HMQC, and HMBC of
one representative enyne (compound E-9). On the basis of these 2D
data, we have also made carbon assignments to E-9, but not to other
analogues. Assignment of stereochemistry in 17 is based upon the 2D
data of enyne 17 and its reduction product (E)-(3-fluoropenta-2,4-
dien-2-yl)benzene. Chemical shifts (δ) are reported in parts per
million and coupling constants (J) are in hertz (Hz). HRMS data were
gathered using a TOF analyzer, the ionization modes are specified
under each compound heading.
Improved Procedure for Synthesis of 2-[1-Fluoro-3-
(trimethylsilyl)prop-2-ynylsulfonyl]benzo[d]thiazole (3).17g
A
stirring solution of sulfone 217g (2.00 g, 6.46 mmol, 1 molar equiv) in
dry toluene (45.0 mL) was cooled to −78 °C (dry ice/i-PrOH) under
nitrogen. LDA (3.23 mL, 6.46 mmol, 1.0 molar equiv) was added, and
after 12 min, solid NFSI (2.24 g, 7.11 mmol, 1.1 molar equiv) was
added. The reaction mixture was allowed to stir at −78 °C for 50 min
and then warmed to room temperature, and the stirring was continued
for an additional 50 min. Saturated aq NH4Cl (20 mL) was added to
the reaction mixture, and the layers were separated. The aqueous layer
was extracted with EtOAc (25−30 mL, 3×), and the combined organic
layer was washed with saturated aq NaHCO3, water, and brine. The
organic layer was dried over anhydrous Na2SO4, and the solvent was
evaporated under reduced pressure. The crude reaction mixture
(brown oil) was suspended in toluene (7 mL) and passed through a
short silica column (100−200 mesh, 6 cm × 3 cm) using toluene (100
mL) as eluent. The solvent was removed under reduced pressure, and
the crude product (colorless oil) was purified by column
chromatography (19 cm × 2.8 cm, 10% EtOAc in hexanes) to yield
1.32 g (62%) of 317g as an off-white solid. Crystallization from hexanes
gave white crystals, mp 87−89 °C.
Synthesis of 1-(2-Fluorobut-1-en-3-ynyl)-4-methoxyben-
zene (E/Z-5). Method A. 4-Methoxybenzaldehyde: 68.0 mg (0.500
mmol); sulfone 3: 409 mg (1.25 mmol, 2.5 molar equiv); DBU: 305
mg (2.0 mmol, 4.0 molar equiv); CH2Cl2: 5.9 mL; TBAF: 0.090 mL
(1.0 M, 0.090 mmol, 0.18 molar equiv). Eluting solvent for column
chromatography: 10% EtOAc in hexanes. Yield of E/Z-5: 80.5 mg
(92%), as a light-yellow liquid, E/Z ratio: 81/19. Rf (10% EtOAc in
hexanes) = 0.47. 1H NMR (500 MHz, CDCl3): δ 7.58 (d, 2H, Ar-H, J
= 8.5 Hz, E-isomer), 7.46 (d, 2H, Ar-H, J = 8.0 Hz, Z-isomer), 6.89−
Condensations of Sulfone 3 with Aldehydes, General
Procedures. Method A. A solution of aldehyde (0.500 mmol, 1.0
molar equiv) and DBU (2.00 mmol, 4.0 molar equiv) in CH2Cl2 (6.8
mL per mmol of aldehyde) was cooled under nitrogen to −55 °C (dry
ice/i-PrOH). A solution of fluoropropargyl sulfone 3 (1.00 mmol, 2.0
molar equiv) in CH2Cl2 (2.0 mL per mmol of sulfone) was added via a
syringe, and the reaction mixture turned dark. The reaction mixture
was stirred for 5 min and checked by TLC (10% EtOAc in hexanes). If
TLC showed unreacted aldehyde, fluoropropargyl sulfone 3 (0.25 or
0.50 mmol, 0.5 or 1.0 molar equiv) in CH2Cl2 (2.0 mL per mmol of
sulfone) was added via a syringe, and the reaction mixture was stirred
for another 5 min. TBAF (1.0 M solution in THF, 0.100 mL, 0.20
6.88 (m, 2H, Ar-H, both E- and Z-isomers), 6.63 (d, 1H, CH, 3JFH
=
3
17.5 Hz, E-isomer), 6.06 (d, 1H, ArCH, JFH = 35.5 Hz, Z-isomer),
4
3.82 (s, 3H, OCH3, both E- and Z-isomers), 3.63 (d, 1H, CH, JFH
= 3.7 Hz, E-isomer), 3.29 (d, 1H, CH, 4JFH = 2.8 Hz, Z-isomer). 19
F
3
NMR (282 MHz, CDCl3): δ −108.90 (d, JFH = 18.3 Hz, E-isomer),
F
dx.doi.org/10.1021/jo300971w | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
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3
−110.93 (d, JFH = 33.6 Hz, Z-isomer). HRMS (APPI): calcd for
C11H9FO [M]+ 176.0632, found 176.0629.
Synthesis of 1-(2-Fluorobut-1-en-3-ynyl)-2-methoxyben-
zene (E/Z-6). Method B. 2-Methoxybenzaldehyde: 68.0 mg (0.500
mmol); sulfone 3: 327 mg (1.00 mmol, 2.0 molar equiv); LHMDS: 1.2
mL (1.0 M, 1.2 mmol, 2.4 molar equiv); THF: 13.0 mL; TBAF: 1.00
mL (1.0 M, 1.0 mmol, 2.0 molar equiv). Eluting solvent for column
chromatography: 10% EtOAc in hexanes. Yield of E/Z-6: 76.7 mg
(87%), as a colorless liquid, E/Z ratio: 90/10. Rf (10% EtOAc in
hexanes) = 0.47. 1H NMR (500 MHz, CDCl3): δ 7.94 (d, 1H, Ar-H, J
= 7.4 Hz, E-isomer), 7.79 (d, 1H, Ar-H, J = 7.4 Hz, Z-isomer), 7.29−
3
(d, 2H, Ar-H, J = 8.8 Hz, H-2, H-6), 6.72 (d, 1H, JFH = 16.1 Hz, H-
1′), 3.70 (d, 1H, JFH = 3.9 Hz, H-4′). 13C NMR (125 MHz, CDCl3)
4
1
of E-9: δ 147.5 (s, 1C, C-4), 142.6 (d, 1C, JCF = 240.3 Hz, C-2′),
138.4 (d, 1C, 3JCF = 10.1 Hz, C-1), 128.9 (d, 2C, 4JCF = 3.2 Hz, C-2, C-
2
6), 124.1 (s, 2C, C-3, C-5), 117.1 (d, 1C, JCF = 33.4 Hz, C-1′), 87.5
3
2
7.28 (m, 1H, Ar-H, both E- and Z-isomers), 7.05 (d, 1H, CH, 3JFH
=
(d, 1C, JCF = 6.0 Hz, C-4′), 75.1 (d, 1C, JCF = 41.6 Hz, C-3′).
Synthesis of (2-Fluorobut-1-en-3-ynyl)ferrocene (E/Z-10).
Method A. Ferrocenecarboxaldehyde: 107 mg (0.500 mmol); sulfone
3: 409 mg (1.25 mmol, 2.5 molar equiv); DBU: 305 mg (2.0 mmol,
4.0 molar equiv); CH2Cl2: 5.9 mL; TBAF: 0.100 mL (1.0 M, 0.10
mmol, 0.20 molar equiv). Eluting solvent for column chromatography:
10% EtOAc in hexanes. Yield of E/Z-10: 121 mg (95%), as an orange
18.0 Hz, E-isomer), 6.98−6.94 (m, 1H, Ar-H, both E- and Z-isomers),
6.89−6.88 (m, 1H, Ar-H, both E- and Z-isomers), 6.62 (d, 1H, CH,
3JFH = 36.8 Hz, Z-isomer), 3.85 (s, 3H, OCH3, both E- and Z-isomers),
4
4
3.52 (d, 1H, CH, JFH = 4.1 Hz), 3.28 (d, 1H, CH, JFH = 3.7
Hz). 19F NMR (282 MHz, CDCl3): δ −105.33 (d, 3JFH = 18.3 Hz, E-
isomer), −109.16 (d, 3JFH = 36.6 Hz, Z-isomer). HRMS (APPI): calcd
for C11H9FO [M]+ 176.0632, found 176.0635.
1
solid, E/Z ratio: 83/17. Rf (10% EtOAc in hexanes) = 0.53. H NMR
(500 MHz, CDCl3): δ 6.41 (d, 1H, CH, 3JFH = 15.6 Hz, E-isomer),
Synthesis of (2-Fluorobut-1-en-3-ynyl)benzene (E/Z-7).
Method B. Benzaldehyde: 53.0 mg (0.500 mmol); sulfone 3: 327
mg (1.00 mmol, 2 molar equiv); LHMDS: 1.2 mL (1.0 M, 1.2 mmol,
2.4 molar equiv); THF: 13.0 mL; TBAF: 1.00 mL (1.0 M, 1.0 mmol,
2.0 molar equiv). Eluting solvent for column chromatography: 10%
EtOAc in hexanes. Yield of E/Z-7: 43.0 mg (59%), as a colorless
3
5.94 (d, 1H, CH, JFH = 35.1 Hz, Z-isomer), 4.62 (s, 2H, Ar-H, E-
isomer), 4.49 (d, 2H, Ar-H, J = 1.5 Hz, Z-isomer), 4.30−4.29 (m, 2H,
Ar-H, both E- and Z-isomers), 4.17 (s, 5H, Ar-H, E-isomer), 4.16 (s,
4
5H, Ar-H, Z-isomer), 3.66 (d, 1H, CH, JFH = 4.0 Hz, E-isomer),
3.34 (d, 1H, CH, JFH = 3.4 Hz, Z-isomer). 19F NMR (282 MHz,
4
CDCl3): δ −111.06 (d, 3JFH = 15.3 Hz, E-isomer), −111.97 (d, 3JFH
=
1
liquid, E/Z ratio: 94/6. Rf (10% EtOAc in hexanes) = 0.54. H NMR
33.6 Hz, Z-isomer). HRMS (ESI): calcd for C14H11FFe [M]+
254.0189, found 254.0191.
(500 MHz, CDCl3): δ 7.63 (d, 2H, Ar-H, J = 7.4 Hz, E-isomer), 7.51
(d, 2H, Ar-H, J = 7.4 Hz, Z-isomer), 7.37−7.34 (m, 2H, Ar-H, both E-
and Z-isomers), 7.32−7.28 (m, 1H, Ar-H, both E- and Z-isomers),
Synthesis of 3-(2-Fluorobut-1-en-3-ynyl)-1-tosyl-1H-indole
(E/Z-11). Method A. 1-Tosyl-1H-indole-3-carboxaldehyde:25 150 mg
(0.500 mmol); sulfone 3: 490 mg (1.50 mmol, 3.0 molar equiv); DBU:
305 mg (2.0 mmol, 4.0 molar equiv); CH2Cl2: 6.4 mL; TBAF: 0.100
mL (1.0 M, 0.10 mmol, 0.20 molar equiv). Eluting solvent for column
chromatography: CH2Cl2. Yield of E/Z-11: 162 mg (95%), as an off-
3
6.68 (d, 1H, CH, JFH = 17.0 Hz, E-isomer), 6.11 (d, 1H, CH,
4
3JFH = 35.0 Hz, Z-isomer), 3.61 (d, 1H, CH, JFH = 4.6 Hz, E-
isomer), 3.29 (d, 1H, CH, 4JFH = 3.7 Hz, Z-isomer). 19F NMR (282
MHz, CDCl3): δ −105.32 (d, 3JFH = 15.3 Hz, E-isomer), −107.42 (d,
3JFH = 33.6 Hz, Z-isomer). HRMS (APPI): calcd for C10H7F [M]+
1
white solid, E/Z ratio: 75/25. Rf (CH2Cl2) = 0.74. H NMR (500
146.0526, found 146.0525.
MHz, CDCl3): δ 8.12 (s, 1H, Ar-H, E-isomer), 8.00−7.97 (m, 1H, Ar-
H, both E- and Z-isomers), 7.94 (s, 1H, Ar-H, Z-isomer), 7.80−7.77
(m, 2H, Ar-H, both E- and Z-isomers), 7.55 (d, 1H, Ar-H, J = 8.0 Hz,
Z-isomer), 7.51 (d, 1H, Ar-H, J = 7.5 Hz, E-isomer), 7.36−7.33 (m,
1H, Ar-H, both E- and Z-isomers), 7.29−7.23 (m, 3H, Ar-H, both E-
Synthesis of 1-Chloro-4-(2-fluorobut-1-en-3-ynyl)benzene
(E/Z-8). Method A. 4-Chlorobenzaldehyde: 70.3 mg (0.500 mmol);
sulfone 3: 327 mg (1.00 mmol, 2.0 molar equiv); DBU: 305 mg (2.00
mmol, 4.0 molar equiv); CH2Cl2: 5.4 mL; TBAF: 0.100 mL (1.0 M,
0.10 mmol, 0.20 molar equiv). Eluting solvent for column
chromatography: 10% EtOAc in hexanes. Yield of E/Z-8: 73.4 mg
(81%), as an orange liquid, E/Z ratio: 70/30. Rf (10% EtOAc in
hexanes) = 0.47. 1H NMR (500 MHz, CDCl3): δ 7.56 (d, 2H, Ar-H, J
= 8.8 Hz, E-isomer), 7.44 (d, 2H, Ar-H, J = 8.3 Hz, Z-isomer), 7.33−
3
and Z-isomers), 6.75 (d, 1H, CH, JFH = 14.3 Hz, E-isomer), 6.31
3
4
(d, 1H, CH, JFH = 35.0 Hz, Z-isomer), 3.83 (d, 1H, CH, JFH
=
3.7 Hz, E-isomer), 3.39 (d, 1H, CH, 4JFH = 3.7 Hz, Z-isomer), 2.35
(s, 3H, CH3, both E- and Z-isomers). 19F NMR (282 MHz, CDCl3): δ
−106.89 (d, 3JFH = 15.3 Hz, E-isomer), −100.96 (d, 3JFH = 33.6 Hz, Z-
isomer). HRMS (ESI): calcd for C19H15FNO2S [M + H]+ 340.0802,
found 340.0806.
7.31 (m, 2H, Ar-H, both E- and Z-isomers), 6.62 (d, 1H, CH, 3JFH
=
3
17.1 Hz, E-isomer), 6.06 (d, 1H, CH, JFH = 34.2 Hz, Z-isomer),
3.63 (d, 1H, CH, 4JFH = 3.9 Hz, E-isomer), 3.31 (d, 1H, CH, 4JFH
= 3.9 Hz, Z-isomer). 19F NMR (282 MHz, CDCl3): δ −104.25 (d, 3JFH
Synthesis of (E/Z)-2-(2-Fluorobut-1-en-3-ynyl)thiophene (E/
Z-12). Method A. 2-Thiophenecarboxaldehyde: 56.1 mg (0.500
mmol); sulfone 3: 409 mg (1.25 mmol, 2.5 molar equiv); DBU:
305 mg (2.00 mmol, 4.0 molar equiv); CH2Cl2: 5.9 mL; TBAF: 0.100
mL (1.0 M, 0.10 mmol, 0.20 molar equiv). Eluting solvent for column
chromatography: 10% EtOAc in hexanes. Yield of E/Z-12: 59.0 mg
(78%), as a light-brown liquid, E/Z ratio: 75/25. Rf (10% EtOAc in
hexanes) = 0.42. 1H NMR (500 MHz, CDCl3): δ 7.39 (d, 1H, Ar-H, J
= 4.6 Hz, Z-isomer), 7.31(d, 1H, Ar-H, J = 5.1 Hz, E-isomer), 7.24 (d,
1H, Ar-H, J = 2.8 Hz, E-isomer), 7.15 (d, 1H, Ar-H, J = 3.2 Hz, Z-
isomer), 7.04−7.02 (m, 1H, Ar-H, both E- and Z-isomers), 6.89 (d,
1H, CH, 3JFH = 14.3 Hz, E-isomer), 6.42 (d, 1H, CH, 3JFH = 33.6
Hz, Z-isomer), 3.85 (d, 1H, CH, 4JFH = 4.1 Hz, E-isomer), 3.38 (d,
1H, CH, 4JFH = 3.7 Hz, Z-isomer). 19F NMR (282 MHz, CDCl3): δ
−111.82 (d, 3JFH = 15.3 Hz, E-isomer), −106.40 (d, 3JFH = 33.6 Hz, Z-
isomer). HRMS (APPI): calcd for C8H5FS [M]+ 152.0091, found
152.0089.
Synthesis of (4-Fluorohexa-1,3-dien-5-ynyl)benzene (E/Z-
13). Method A. Cinnamaldehyde: 66.1 mg (0.500 mmol); sulfone
3: 490 mg (1.50 mmol, 3.0 molar equiv); DBU: 305 mg (2.0 mmol,
4.0 molar equiv); CH2Cl2: 6.4 mL; TBAF: 0.100 mL (1.0 M, 0.10
mmol, 0.20 molar equiv). Eluting solvent for column chromatography:
10% EtOAc in hexanes. Yield of E/Z-13: 82.1 mg (95%), as a deep-
orange liquid, E/Z ratio: 72/28. Rf (30% EtOAc in hexanes) = 0.60. 1H
3
= 15.3 Hz, E-isomer), −106.45 (d, JFH = 33.6 Hz, Z-isomer). HRMS
(APPI): calcd for C10H6ClF [M]+ 180.0137, found 180.0139.
Synthesis of 1-(2-Fluorobut-1-en-3-ynyl)-4-nitrobenzene (E/
Z-9). Method A. 4-Nitrobenzaldehyde: 75.6 mg (0.500 mmol);
sulfone 3: 409 mg (1.25 mmol, 2.5 molar equiv); DBU: 305 mg (2.0
mmol, 4.0 molar equiv); CH2Cl2: 5.9 mL; TBAF: 0.100 mL (1.0 M,
0.10 mmol, 0.20 molar equiv). Eluting solvent for column
chromatography: 10% EtOAc in hexanes. Yield of E/Z-9: 56.8 mg
(59%), as a yellow solid, E/Z ratio: 51/49. Rf (20% EtOAc in hexanes)
= 0.53. 1H NMR (500 MHz, CDCl3): δ 8.21 (d, 2H, Ar-H, J = 8.6 Hz,
both E- and Z-isomers), 7.79 (d, 2H, Ar-H, J = 8.9 Hz, E-isomer), 7.65
3
(d, 2H, Ar-H, J = 8.8 Hz, Z-isomer), 6.72 (d, 1H, CH, JFH = 15.9
Hz, E-isomer), 6.18 (d, 1H, CH, 3JFH = 33.6 Hz, Z-isomer), 3.70 (d,
4
4
1H, CH, JFH = 4.3 Hz, E-isomer), 3.38 (d, 1H, CH, JFH = 4.0
Hz, Z-isomer). 19F NMR (282 MHz, CDCl3): δ −97.63 (d, 3JFH = 15.3
3
Hz, E-isomer), −100.80 (d, JFH = 33.6 Hz, Z-isomer). HRMS (ESI)
calcd for C10H7FNO2 [M + H]+ 192.0455, found 192.0444.
For the purpose of proton and carbon assignments, a small amount
of E/Z-9 was separated by TLC (500 μm glass-backed silica gel plate,
mobile phase 5% EtOAc in hexanes) and H, 13C and 2D spectra
1
1
(NOESY, HMQC, HMBC) of E-9 were recorded. H NMR (500
MHz, CDCl3) of E-9: δ 8.21 (d, 2H, Ar-H, J = 8.8 Hz, H-3, H-5), 7.79
G
dx.doi.org/10.1021/jo300971w | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
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NMR (500 MHz, CDCl3): δ 7.45−7.43 (m, 2H, Ar-H, both E- and Z-
isomers), 7.35−7.32 (m, 2H, Ar-H, both E- and Z-isomers), 7.28−7.26
(m, 1H, Ar-H, both E- and Z-isomers), 7.07 (dd, 1H, CH, J = 15.7;
11.1 Hz, Z-isomer), 6.88 (dd, 1H, CH, J = 15.7; 11.5 Hz, E-isomer),
128.23 (2C, one d and one s), 127.4 (d, 2JCF = 22.4 Hz), 82.5 (d, 3JCF
= 7.3 Hz), 75.9 (d, 2JCF = 42.1 Hz), 16.3 (d, 3JCF = 4.1 Hz). 19F NMR
(282 MHz, CDCl3): δ −110.0 (s). HRMS (EI) calcd for C11H9F [M]+
160.0683, found 160.0667. Stereochemical Assignment. Fluoro enyne 17
(7.0 mg, 0.044 mmol) and Lindlar catalyst (5% Pd on CaCO3
poisoned with lead, 2.5 mg) were suspended in anhydrous hexanes
(0.600 mL) in a dry vial, and one small drop of quinoline was added.
The vial was evacuated and filled with hydrogen gas via a hydrogen
balloon, and the reaction was conducted at atmospheric pressure for 2
h. The mixture was filtered through Celite, and the residue was washed
with EtOAc (10.0 mL). The filtrate was evaporated under reduced
pressure and the crude mixture was purified by column chromatog-
raphy (10% EtOAc in hexanes). Yield of (E)-(3-fluoropenta-2,4-dien-
2-yl)benzene: 3.0 mg (42%), as a colorless liquid. Rf (10% EtOAc in
hexanes) = 0.78. 1H NMR (500 MHz, CDCl3): δ 7.35 (t, 2H, Ar-H, J
= 7.3 Hz), 7.28 (t, 1H, Ar-H, J = 7.3 Hz), 7.23 (d, 2H, Ar-H, J = 7.6
Hz), 6.25 (ddd, 1H, CH, J = 28.3, 17.1, 11.2 Hz), 5.51 (d, 1H,
CH2, J = 17.1 Hz), 5.07 (d, 1H, CH2, J = 10.7 Hz), 2.10 (d, 3H, J
6.68 (d, 1H, ArCH, J = 15.7 Hz, E-isomer), 6.63 (d, 1H, ArCH, J =
3
15.7 Hz, Z-isomer), 6.47 (t, 1H, CH, JFH
,
3JHH = 12.0 Hz, E-
3
3
isomer), 6.04 (dd, 1H, CH, JFH = 30.9 Hz; JHH = 11.1 Hz, Z-
isomer), 3.68 (d, 1H, CH, 4JFH = 3.2 Hz, E-isomer), 3.35 (d, 1H, 
4
CH, JFH = 3.2 Hz, Z-isomer). 19F NMR (282 MHz, CDCl3): δ
−110.55 (d, 3JFH = 12.2 Hz, E-isomer), −111.43 (d, 3JFH = 30.5 Hz, Z-
isomer). HRMS (APPI): calcd for C12H9 F [M]+ 172.0683, found
172.0683.
Synthesis of (4-Fluorohex-3-en-5-ynyl)benzene (E/Z-14).
Method A. 3-Phenylpropanal: 67.1 mg (0.500 mmol); sulfone 3:
327 mg (1.0 mmol, 2.0 molar equiv); DBU: 305 mg (2.0 mmol, 4.0
molar equiv); CH2Cl2: 5.4 mL; TBAF: 0.100 mL (1.0 M, 0.10 mmol,
0.20 molar equiv). Eluting solvent for column chromatography: 10%
EtOAc in hexanes. Yield of E/Z-14: 46.6 mg (54%), as a light-greenish
liquid, E/Z ratio: 80/20. Rf (10% EtOAc in hexanes) = 0.59. 1H NMR
(500 MHz, CDCl3): δ 7.31−7.18 (m, 5H, Ar-H, both E- and Z-
3
= 3.4 Hz). 19F NMR (282 MHz, CDCl3): δ −124.4 (d, JHF = 27.5
Hz). HRMS (ESI): calcd for C11H12F [M + H]+ 163.0918, found
163.0947. NOESY correlation between the vinylic proton at the C-2
and the ortho protons in the phenyl ring confirmed the E
stereochemistry of the double bond in fluoro enyne 17.
3
3
isomers), 5.69 (dt, 1H, CH, JFH = 14.3 Hz, JHH = 8.3 Hz, E-
3
3
isomer), 5.31 (dt, 1H, CH, JFH = 33.6 Hz, JHH = 7.8 Hz, Z-
4
isomer), 3.34 (d, 1H, CH, JFH = 3.2 Hz, E-isomer), 3.08 (d, 1H,
CH, 4JFH = 3.7 Hz, Z-isomer), 2.74−2.69 (m, 2H, CH2, both E- and
Synthesis of 2-[3-(Triisopropylsilyl)prop-2-ynylsulfonyl]-
benzo[d]thiazole (18). Step 1:23 A solution of 1.00 g of propargyl
bromide (80 wt % in toluene: 6.72 mmol) in THF (20.0 mL) was
cooled to −78 °C (dry ice/i-PrOH) and 4.20 mL (6.72 mmol, 1.0
molar equiv) of n-BuLi (1.6 M in hexane) was added dropwise. After
the mixture was stirred at −78 °C for 10 min, 1.42 mL (6.72 mmol, 1.0
molar equiv) of TIPS-Cl was added dropwise. The reaction mixture
was allowed to warm to room temperature and stirred for another 2 h.
The reaction was quenched by addition of saturated aq NH4Cl, and
the mixture was poured into EtOAc. The organic layer was separated,
and the aqueous layer was extracted with EtOAc (3×). The combined
organic layer was washed with water and brine, and dried over
anhydrous Na2SO4. The solvent was evaporated under reduced
pressure and the crude product was used in the next step without
purification.
Step 2: The yellow oil obtained in step 1 was diluted with DMF
(10.0 mL) and the sodium salt of 2-mercapto-1,3-benzothiazole (1.65
g, 8.74 mmol) was added. After the mixture was stirred for 2 h at room
temperature, 10.0 mL of water was added, and the mixture was poured
into EtOAc. The organic layer was separated, and the aqueous layer
was extracted with EtOAc (3×). The combined organic layer was
washed with water and brine and dried over anhydrous Na2SO4, and
the solvent was evaporated under reduced pressure.
Step 3: The crude product obtained in step 2 (1.23 g) was dissolved
in CHCl3 (15.0 mL) and cooled to −10 °C (ice/salt). A solution of m-
CPBA (1.85 g, 10.7 mmol) in CHCl3 (28 mL) was slowly added via an
addition funnel. After the addition was complete, the mixture was
allowed to warm to room temperature, and stirring was continued for
12 h. Saturated aq NaHCO3 (10.0 mL) was added, the organic layer
was separated, and the aqueous layer was extracted with CH2Cl2 (2×).
The combined organic layer was washed with water and brine and
dried over anhydrous Na2SO4. The solvent was evaporated under
reduced pressure. The crude product was purified by column
chromatography (20% EtOAc in hexanes). Yield of 18: 800 mg
(30% over three steps), as a white solid. Rf (10% EtOAc in hexanes) =
0.23. 1H NMR (500 MHz, CDCl3): δ 8.22 (d, 1H, Ar-H, J = 8.3 Hz),
8.00 (d, 1H, Ar-H, J = 7.8 Hz), 7.65−7.58 (m, 2H, Ar-H), 4.48 (s, 2H,
CH2), 0.878−0.873 (m, 21H, Si(iso-Pr)3). 13C NMR (125 MHz,
CDCl3): δ 164.3, 152.8, 137.3, 128.3, 127.8, 125.8, 122.3, 92.4, 92.3,
48.5, 18.5, 11.1. HRMS (ESI): calcd for C19H27NO2S2Si [M + H]+
394.1325, found 394.1330.
Z-isomers), 2.53−2.45 (m, 2H, CH2, both E- and Z-isomers). 19F
3
NMR (282 MHz, CDCl3): δ −110.43 (d, JFH = 12.2 Hz, E-isomer),
−112.51 (d, 3JFH = 33.6 Hz, Z-isomer). HRMS (CI): calcd for C12H11
F [M]+ 174.0839, found 174.0860.
Synthesis of 3-Fluoroundec-3-en-1-yne (E/Z-15). Method A.
Octanal: 64.1 mg (0.500 mmol); sulfone 3: 327 mg (1.00 mmol, 2.0
molar equiv); DBU: 305 mg (2.0 mmol, 4.0 molar equiv); CH2Cl2: 5.4
mL; TBAF: 0.100 mL (1.0 M, 0.10 mmol, 0.20 molar equiv). Eluting
solvent for column chromatography: 10% EtOAc in hexanes. Yield of
E/Z-15: 66.6 mg (79%), as a colorless liquid, E/Z ratio: 85/15. Rf
(10% EtOAc in hexanes) = 0.73. 1H NMR (500 MHz, CDCl3): δ 5.67
(dt, 1H, CH, 3JFH = 15.7 Hz, 3JHH = 8.3 Hz, E-isomer), 5.29 (dt, 1H,
3
CH, JFH = 33.2 Hz, 3JHH = 7.8 Hz, Z-isomer), 3.34 (d, 1H, CH,
4JFH = 3.2 Hz, E-isomer), 3.09 (d, 1H, CH, 4JFH = 3.7 Hz, Z-isomer),
2.19−2.11 (m, 2H, CH2, both E- and Z-isomers), 1.42−1.29 (m, 10H,
5CH2, both E- and Z-isomers), 0.86 (m, 3H, CH3, both E- and Z-
isomers). 19F NMR (282 MHz, CDCl3): δ −111.45 (d, 3JFH = 15.3 Hz,
E-isomer), −114.05 (d, 3JFH = 33.6 Hz, Z-isomer). HRMS (CI): calcd
for C11H17 F [M]+ 168.1309, found 168.1302.
Synthesis of 1-Benzyl-4-(1-fluoroprop-2-ynylidene)-
piperidine (16). N-Benzylpiperidin-4-one: 57.0 mg (0.300 mmol);
sulfone 3: 294 mg (0.900 mmol, 3.0 molar equiv); LHMDS: 1.5 mL
(1.0 M, 1.5 mmol, 5.0 molar equiv); THF: 2.5 mL; TBAF: 0.900 mL
(1.0 M, 0.90 mmol, 3.0 molar equiv). Eluting solvent for column
chromatography: 10% EtOAc in hexanes. Yield of 16: 52.7 mg (77%),
as a colorless liquid. Rf (20% EtOAc in hexanes) = 0.52. 1H NMR (500
MHz, CDCl3): δ 7.34−7.25 (m, 5H, Ar-H), 3.53 (s, 2H, CH2), 3.35
4
(d, 1H, CH, JFH = 3.7 Hz), 2.50 (t, 2H, CH2, 4JFH = 5.5 Hz), 2.45
(s, 4H, 2CH2), 2.40 (t, 2H, CH2, 4JFH = 5.1 Hz). 13C NMR (125 MHz,
CDCl3): δ 138.5, 134.9 (d, 1JCF = 227.0 Hz), 129.2 (2C), 128.4 (2C),
127.3, 127.0 (d, 2JCF = 18.3 Hz), 83.4 (d, 3JCF = 7.8 Hz), 74.7 (d, 2JCF
= 44.4 Hz), 62.9, 53.8 (d, 4JCF = 1.8 Hz), 53.3 (d, 4JCF = 1.4 Hz), 29.0
3
3
(d, JCF = 1.8 Hz), 26.0 (d, JCF = 3.2 Hz). 19F NMR (282 MHz,
CDCl3): δ −121.4 (s). HRMS (EI): calcd for C15H16FN [M]+
229.1261, found 229.1250.
(3E)-(3-Fluoropent-2-en-4-yn-2-yl)benzene (17). Acetophe-
none: 36.0 mg (0.300 mmol); sulfone 3: 294 mg (0.900 mmol, 3.0
molar equiv); LHMDS: 1.5 mL (1.0 M, 1.5 mmol, 5.0 molar equiv);
THF: 2.5 mL; TBAF: 0.900 mL (1.0 M, 0.90 mmol, 3.0 molar equiv).
Eluting solvent for column chromatography: 10% EtOAc in hexanes.
Yield of 17: 42.3 mg (88%), as a colorless liquid. Rf (10% EtOAc in
hexanes) = 0.76. 1H NMR (500 MHz, CDCl3): δ 7.47 (d, 2H, Ar-H, J
= 7.4 Hz), 7.37 (t, 2H, Ar-H, J = 7.4 Hz), 7.32 (t, 1H, Ar-H, J = 7.4
Hz), 3.18 (d, 1H, CH, 4JFH = 3.7 Hz), 2.14 (d, 3H, CH3, 4JFH = 4.1
Synthesis of 2-[1-Fluoro-3-(triisopropylsilyl)prop-2-
ynylsulfonyl]benzo[d]thiazole (19). A stirring solution of sulfone
18 (500 mg, 1.27 mmol, 1.0 molar equiv) in dry toluene (10.0 mL)
was cooled under nitrogen to −78 °C (dry ice/i-PrOH). LDA (0.700
mL, 1.1 molar equiv of a 2.0 M solution in heptane/THF/EtPh) was
added and after 15 min, and solid NFSI (479 mg, 1.52 mmol, 1.2
1
Hz). 13C NMR (125 MHz, CDCl3): δ 138.4 (d, JCF = 232.1 Hz),
137.6 (d, 3JCF = 4.7 Hz), 128.4 (2C), three resonances: 128.27, 128.25,
H
dx.doi.org/10.1021/jo300971w | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
molar equiv) was added. The reaction mixture was allowed to stir at
−78 °C for 50 min and then warmed to room temperature, and
stirring was continued for an additional 50 min. Saturated aq NH4Cl
was added to the reaction mixture and the layers were separated. The
aqueous layer was extracted with EtOAc (3×), and the combined
organic layer was washed with water, saturated aq NaHCO3 and brine.
The organic layer was dried over anhydrous Na2SO4, and the solvent
was evaporated under reduced pressure. The crude product was
purified by column chromatography (10% EtOAc in hexanes). Yield of
19: 359 mg (69%), as a white solid. Rf (20% EtOAc in hexanes) =
0.50. 1H NMR (500 MHz, CDCl3): δ 8.25 (d, 1H, Ar-H, J = 8.2 Hz),
8.02 (d, 1H, Ar-H, J = 7.6 Hz), 7.66−7.60 (m, 2H, Ar-H), 6.19 (d, 1H,
CHF, 2JFH = 48.5 Hz), 1.04−1.01 (m, 21H, Si(i-Pr)3). 13C NMR (125
MHz, CDCl3): δ 161.4, 152.9, 137.7, 128.7, 128.0, 126.1, 122.4, 101.9
(d, 3JCF = 8.2 Hz), 91.9 (d, 1JCF = 222.5 Hz), 91.6 (d, 2JCF = 23.3 Hz),
over anhydrous Na2SO4, and the solvent was evaporated under
reduced pressure. The crude reaction mixture was analyzed by 19F
NMR, and the combined E/Z product mixture was then isolated by
column chromatography (10% EtOAc in hexanes). Yield of E/Z-21:
39.7 mg (87%), as a light-yellow solid, E/Z ratio: 76/24.
Sonogashira Cross-Coupling of Fluoro Enynes. Synthesis of
2-(2-Fluoro-4-phenylbut-1-en-3-yn-1-yl)naphthalene (E/Z-22). A
solution of fluoro enyne E/Z-4 (E/Z 88/12, 17.0 mg, 0.09 mmol,
1.00 molar equiv), iodobenzene (35.5 mg, 0.18 mmol, 2.0 molar
equiv), [PdCl2(PPh3)2] (3.2 mg, 5 mol %), and CuI (1.7 mg, 10 mol
%) in Et3N (0.30 mL) was stirred at room temperature. After 2 h, TLC
(hexanes) showed complete disappearance of fluoro enyne 4. The
reaction mixture was diluted with EtOAc and washed with water and
brine. The organic layer was dried over anhydrous Na2SO4, and the
solvent was evaporated under reduced pressure. The crude reaction
mixture was analyzed by 19F NMR and then purified by column
chromatography (hexanes). Yield of E/Z-22: 16.0 mg (68%), as a
white solid, E/Z ratio: 93/7. Rf (hexanes) = 0.28. 1H NMR (500 MHz,
CDCl3): δ 8.12 (s, 1H, Ar-H, E-isomer), 7.91 (s, 1H, Ar-H, Z-isomer),
7.90 (dd, 1H, Ar-H, J = 8.5, 1.5 Hz, E-isomer), 7.85−7.82 (m, 3H, Ar-
H, both E- and Z-isomers), 7.72 (dd, 1H, Ar-H, J = 8.5, 1.5 Hz, Z-
isomer), 7.61−7.55 (m, 2H, Ar-H, both E- and Z-isomers), 7.51−7.39
(m, 5H, Ar-H, both E- and Z-isomers), 6.82 (d, 1H, CH, 3JFH = 16.5
18.48, 18.47, 11.0. 19F NMR (282 MHz, CDCl3): δ −164.46 (d, 2JFH
=
48.8 Hz). HRMS (ESI): calcd for C19H27FNO2S2Si [M + H]+
412.1231, found 412.1204.
Condensations of Sulfone 19 with Aldehydes. Synthesis of
(3-Fluoro-4-(naphthalen-2-yl)but-3-en-1-ynyl)triisopropylsilane (E/
Z-20). Method A. A solution of 2-naphthaldehyde (15.0 mg, 0.096
mmol) and DBU (58.5 mg, 0.385 mmol, 4.0 molar equiv) in CH2Cl2
(0.600 mL) was cooled under nitrogen to −55 °C (dry ice/i-PrOH). A
solution of fluoropropargyl sulfone 19 (51.5 mg, 0.125 mmol, 1.3
molar equiv) in CH2Cl2 (0.300 mL) was added via a syringe. The dark
reaction mixture was stirred for 15 min and checked by TLC (10%
EtOAc in hexanes), which showed disappearance of the aldehyde.
Reaction mixture was analyzed by 19F NMR, and the combined E/Z
product mixture was isolated by column chromatography (10% EtOAc
in hexanes). Yield of E/Z-20: 29.4 mg (87%), as a white solid, E/Z
ratio: 71/29. Rf (10% EtOAc in hexanes) = 0.81. 1H NMR (500 MHz,
CDCl3): δ 8.08 (s, 1H, Ar-H, E-isomer), 7.94 (s, 1H, Ar-H, Z-isomer),
7.91 (d, 1H, Ar-H, J = 8.5 Hz, E-isomer), 7.82−7.76 (m, 3H, Ar-H,
both E- and Z-isomers), 7.66 (d, 1H, Ar-H, J = 8.5 Hz, Z-isomer),
7.48−7.46 (m, 2H, Ar-H, both E- and Z-isomers), 6.74 (d, 1H, CH,
3
Hz, E-isomer), 6.27 (d, 1H, CH, JFH = 35.1 Hz, Z-isomer). 19F
3
NMR (282 MHz, CDCl3): δ −102.43 (d, JFH = 15.3 Hz, E-isomer),
3
−104.41 (d, JFH = 36.6 Hz, Z-isomer). HRMS (ESI): calcd for
C20H14F [M + H]+ 273.1074, found 273.1057.
Synthesis of 1-Benzyl-4-(1-fluoro-3-phenylprop-2-ynylidene)-
piperidine (23). A solution of fluoro enyne 16 (50.0 mg, 0.220
mmol, 1.00 molar equiv), iodobenzene (90.0 mg, 0.440 mmol, 2.0
molar equiv), [PdCl2(PPh3)2] (7.7 mg, 5 mol %), and CuI (4.0 mg, 10
mol %) in Et3N (0.750 mL) was stirred at room temperature. After 2
h, TLC (20% EtOAc in hexanes) showed complete disappearance of
fluoro enyne 16. The reaction mixture was diluted with EtOAc and
washed with water and brine. The organic layer was dried over
anhydrous Na2SO4, and the solvent was evaporated under reduced
pressure. The crude reaction mixture was analyzed by 19F NMR, and
then purified by column chromatography (20% EtOAc in hexanes).
Yield of 23: 53.0 mg (79%), as a pale-yellow oil. Rf (SiO2, 20% EtOAc
3
3JFH = 17.4 Hz, E-isomer), 6.23 (d, 1H, CH, JFH = 35.1 Hz, Z-
isomer), 1.17−1.14 (m, 21H, both E- and Z-isomers). 19F NMR (282
MHz, CDCl3): δ −101.66 (d, 3JFH = 18.3 Hz, E-isomer), −104.65 (d,
3JFH = 33.6 Hz, Z-isomer). HRMS (ESI): calcd for C23H30FSi [M +
1
H]+ 353.2095, found 353.2070.
in hexanes) = 0.34. H NMR (500 MHz, CDCl3): δ 7.48−7.46 (m,
2H, Ar-H), 7.34−7.27 (m, 8H, Ar-H), 3.54 (s, 2H), 2.55−2.47 (m,
Synthesis of (E/Z)-(3-Fluoro-4-(4-nitrophenyl)but-3-en-1-ynyl)-
triisopropylsilane (E/Z-21). Method A. A solution of 4-nitro-
benzaldehyde (20.0 mg, 0.132 mmol) and DBU (80.4 mg, 0.528
mmol, 4.0 molar equiv) in CH2Cl2 (0.900 mL) was cooled under
nitrogen to −55 °C (dry ice/i-PrOH). A solution of fluoropropargyl
sulfone 19 (70.8 mg, 0.172 mmol, 1.3 molar equiv) in CH2Cl2 (0.400
mL) was added via a syringe. The dark reaction mixture was stirred for
5 min and checked by TLC (10% EtOAc in hexanes), which showed
disappearance of the aldehyde. The reaction mixture was analyzed by
19F NMR, then loaded onto a silica gel column and the combined E/Z
1
8H). 13C NMR (125 MHz, CDCl3): δ 138.5, 135.6 (d, JCF = 227.0
5
Hz), 131.7 (2C, d, JCF = 1.8 Hz), 129.3 (2C), 129.1, 128.6 (2C),
128.4 (2C), 127.3, 125.8 (d, 2JCF = 19.7 Hz), 122.1 (d, 4JCF = 2.3 Hz),
2
4
94.9 (d, 3JCF = 7.8 Hz), 80.2 (d, JCF = 43.5 Hz), 63.0, 54.0 (d, JCF
=
=
1.8 Hz), 53.4 (d, 4JCF = 1.4 Hz), 29.3 (d, 3JCF = 1.3 Hz), 26.2 (d, 3JCF
3.2 Hz). 19F NMR (282 MHz, CDCl3): δ −118.85 (s). HRMS (ESI)
calcd for C21H21FN [M + H]+ 306.1653, found 306.1626.
Synthesis of Stereoisomeric Fluoro Dienes. Synthesis of
Fluoro Diene 25: Reduction of 16 to Diene 24 and Heck Coupling
of 24. Synthesis of 1-Benzyl-4-(1-fluoroallylidene)piperidine (24).
Fluoro enyne 16 (25.0 mg, 0.110 mmol) and Lindlar catalyst (5% Pd
on CaCO3 poisoned with lead, 5.0 mg) were suspended in anhydrous
hexanes (1.0 mL) in a dry vial, and one drop of quinoline was added.
The vial was evacuated and filled with hydrogen gas via a hydrogen
balloon, and the reaction was conducted at atmospheric pressure for 2
h. The mixture was filtered through Celite and the residue was washed
with EtOAc (10.0 mL). The filtrate was evaporated under reduced
pressure, and the crude mixture was purified by column chromatog-
raphy (20% EtOAc in hexanes). Yield of 24: 22.0 mg (87%), as a pale-
olefin mixture was eluted with 10% EtOAc in hexanes. Yield of E/Z-
21: 29.2 mg (64%), as a light-yellow solid, E/Z ratio: 67/33. Rf (10%
1
EtOAc in hexanes) = 0.58. H NMR (500 MHz, CDCl3): δ 8.20 (d,
2H, Ar-H, J = 8.8 Hz, Z-isomer), 8.17 (d, 2H, Ar-H, J = 8.8 Hz, E-
isomer), 7.86 (d, 2H, Ar-H, J = 8.8 Hz, E-isomer), 7.64 (d, 2H, Ar-H, J
3
= 8.8 Hz, Z-isomer), 6.63 (d, 1H, CH, JFH = 15.6 Hz, E-isomer),
3
6.13 (d, 1H, CH, JFH = 33.2 Hz, Z-isomer), 1.15−1.12 (m, 21H,
both E- and Z-isomers). 19F NMR (282 MHz, CDCl3): δ −94.43 (d,
3
3JFH = 15.3 Hz, E-isomer), −98.03 (d, JFH = 33.6 Hz, Z-isomer).
HRMS (ESI) calcd for C19H27FNO2Si [M + H]+ 348.1790, found
348.1774. Method B. A solution of 4-nitrobenzaldehyde (20.0 mg,
0.132 mmol, 1.0 molar equiv) and sulfone 19 (70.8 mg, 0.172 mmol,
1.3 molar equiv) in dry THF (3.4 mL) was cooled under nitrogen to
−78 °C (dry ice/i-PrOH). LHMDS (1.0 M solution in THF, 0.317
mL, 2.4 molar equiv) was added, and the reaction mixture was stirred
at −78 °C for 10 min and checked by TLC (10% EtOAc in hexanes),
which showed disappearance of the aldehyde. Saturated aq NH4Cl was
added, and the mixture was poured into EtOAc. The organic layer was
separated, and the aqueous layer was extracted with EtOAc (3×). The
combined organic layer was washed with water and brine and dried
1
yellow oil. Rf (20% EtOAc in hexanes) = 0.40. H NMR (500 MHz,
CDCl3): δ 7.33−7.24 (m, 5H, Ar-H), 6.44 (ddd, 1H, CH, J = 28.1,
17.0, 11.1 Hz), 5.47 (d, 1H, CH2, J = 17.0 Hz), 5.13 (d, 1H, CH2,
J = 11.1 Hz), 3.52 (s, 2H), 2.46 (br s, 6H), 2.31 (t, 2H, J = 5.5 Hz).
1
13C NMR (125 MHz, CDCl3): δ 149.9 (d, JCF = 238.9 Hz), 138.6,
2
129.3 (2C), 128.4 (2C), 127.2, 124.9 (d, JCF = 27.5 Hz), 117.8 (d,
2JCF = 17.9 Hz), 113.5 (d, 3JCF = 6.0 Hz), 63.1, 54.1 (d, 4JCF = 1.8 Hz),
53.8 (d, 4JCF = 1.4 Hz), 27.5 (d, 3JCF = 5.0 Hz), 26.0 (d, 3JCF = 7.8 Hz).
19F NMR (282 MHz, CDCl3): δ −130.47 (d, 3JHF = 27.5 Hz). HRMS
(ESI): calcd for C15H19FN [M + H]+ 232.1496, found 232.1519.
I
dx.doi.org/10.1021/jo300971w | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(E)-1-Benzyl-4-(1-fluoro-3-phenylallylidene)piperidine (25) via
Heck Coupling of 24. Et3N (0.045 mL, 5 molar equiv) was added
to a solution of fluoro diene 24 (15 mg, 0.065 mmol), iodobenzene
(26.5 mg, 0.130 mmol, 2 molar equiv), Pd(OAc)2 (1.5 mg, 10 mol %),
and P(o-tol)3 (4.0 mg, 20 mol %) in anhydrous DMF (0.650 mL) in a
dry vial.26 The vial was flushed with nitrogen gas and sealed with a
Teflon-lined cap. The reaction mixture was stirred at 100 °C for 15 h,
diluted with EtOAc (10 mL), and washed with water and brine. The
organic layer was dried over anhydrous Na2SO4, and the solvent was
evaporated under reduced pressure. The crude reaction mixture was
analyzed by 19F NMR and then purified by column chromatography
(10% EtOAc in hexanes). Yield of 25: 14.0 mg (70%), as a brown oil.
AUTHOR INFORMATION
Corresponding Author
*Tel: (212) 650-8926. Fax: (212) 650-6107. E-mail: barbaraz@
sci.ccny.cuny.edu.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by NSF Grant No. CHE-1058618
and by PSC CUNY awards. Infrastructural support was
provided by NIH Grant Nos. 2G12RR03060-26A1 from the
National Center for Research Resources and by
8G12MD007603-27 from the National Institute on Minority
Health and Health Disparities. We thank Dr. Andrew Poss
(Honeywell) for a sample of NFSI, Dr. Louis J. Todaro (The
CUNY X-ray Facility, Hunter College) for X-ray analysis, and
Ms. Nonka Sevova and Dr. Bill Boggess (University of Notre
Dame, Mass Spectrometry and Proteomics Facility) for HRMS
analyses supported by NSF Grant No. CHE-0741793.
1
Rf (20% EtOAc in hexanes) = 0.33. H NMR (500 MHz, CDCl3): δ
7.42 (d, 2H, J = 7.8 Hz, Ar-H), 7.35−7.23 (m, 8H, Ar-H), 6.84−6.75
(m, 2H), 3.54 (s, 2H), 2.52−2.40 (m, 6H), 2.42 (t, 2H, J = 5.4 Hz).
1
13C NMR (125 MHz, CDCl3): δ 150.2 (d, JCF = 238.0 Hz), 138.5,
3
137.0, 129.3 (2C), 128.9 (2C), 128.4 (2C), 128.1 (d, JCF = 5.5 Hz),
2
2
128.0, 127.3, 126.8 (2C), 118.4 (d, JCF = 18.8 Hz), 116.5 (d, JCF
=
25.2 Hz), 63.1, 54.2 (d, 4JCF = 1.8 Hz), 53.9 (d, 4JCF = 1.5 Hz), 27.8 (d,
3JCF = 5.0 Hz), 26.3 (d, 3JCF = 8.2 Hz). 19F NMR (282 MHz, CDCl3):
δ −128.10 to −128.20 (m). HRMS (ESI): calcd for C21H23FN [M +
H]+ 308.1809, found 308.1794.
Synthesis of Fluoro Diene 26 via Reduction of Sonogashira
Product 23. Synthesis of (Z)-1-Benzyl-4-(1-fluoro-3-
phenylallylidene)piperidine (26). Fluoro enyne 23 (10 mg, 0.033
mmol) and Lindlar catalyst (5% Pd on CaCO3 poisoned with lead, 2.5
mg) were suspended in CH3OH (0.80 mL) in a dry vial, and one drop
of quinoline was added. The vial was evacuated, filled with hydrogen
gas via a hydrogen balloon, and the reaction was conducted at
atmospheric pressure for 10 h. The mixture was filtered through
Celite, and the residue was washed with EtOAc (10.0 mL). The filtrate
was evaporated under reduced pressure and the crude mixture was
purified by column chromatography (20% EtOAc in hexanes). Yield of
26: 6.8 mg (68%), as a pale-yellow oil. Rf (20% EtOAc in hexanes) =
0.32. 1H NMR (500 MHz, CDCl3): δ 7.34−7.21 (m, 10H, Ar-H), 6.49
(d, 1H, CH, J = 12.2 Hz), 6.12 (dd, 1H, CH, J = 23.7, 12.5 Hz),
3.50 (s, 2H) 2.45−2.43 (m, 4H), 2.37 (t, 2H, J = 5.1 Hz), 2.21 (t, 2H,
REFERENCES
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1
J = 5.6 Hz). 13C NMR (125 MHz, CDCl3): δ 149.2 (d, JCF = 240.8
3
Hz), 138.6, 137.3, 131.4, 129.3 (2C), 129.2 (d, JCF = 6.0 Hz), 128.4
(2C), 128.0 (2C), 127.6 (2C), 127.2, 118.9 (d, 2JCF = 18.0 Hz), 117.8
2
4
4
(d, JCF = 26.1 Hz), 63.2, 53.9 (d, JCF = 1.7 Hz), 53.8 (d, JCF = 1.9
Hz), 28.1 (d, JCF = 4.6 Hz), 25.9 (d, JCF = 7.8 Hz). 19F NMR (282
MHz, CDCl3): δ −115.90 (d, 3JHF = 24.4 Hz). HRMS (ESI): calcd for
C21H23FN [M + H]+ 308.1809, found 308.1812.
3
3
(5) (a) Estevez-Braun, A.; Estevez-Reyes, R.; Moujir, L. M.; Ravelo,
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Single-Crystal X-ray Diffraction for 3. The intensity data for 3 were
measured on a KappaCCD diffractometer (graphite-monochromated
Mo Kα radiation, λ = 0.71073 Å, f-w scans) at 100(1) K. The data
were corrected for absorption. Details of the solution and refinements
for C13H14FNO2S2Si (3) are as follows. The crystals of 3, with
approximate dimensions 0.060 × 0.24 × 0.40 mm, were triclinic with
space group P-1. The final unit-cell constants of 3 were a = 6.9930(14)
Å, b = 8.7110(17) Å, c = 13.512(3) Å, α = 74.66(3)°, β = 75.88(3)°, γ
= 85.75(3)°, V = 769.8(3) Å3, Z = 2, ρ = 1.413 g cm−1, μ = 0.433
mm−1, formula weight = 327.46. The structure of 3 was solved with
SHELXS-97 and refined by full-matrix least-squares on F2 with
SHELXL-97. The hydrogen atoms were calculated with the riding
model in the structure-factor calculations, but their parameters were
not refined. The final discrepancy indices, 3.00 < q < 27.62°, were R =
0.0487 (calculated on F for 2681 reflections) and Rw = 0.1215
(calculated on F2 for all 3520 reflections) with 184 parameters varied.
The major peaks of the final difference map are −0.46 and +0.64 e Å3.
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■
S
* Supporting Information
1
Copies of H and 13C NMR spectra of 1−26, NOESY of the
reduced derivative of 17 [(E)-(3-fluoropenta-2,4-dien-2-yl)-
benzene] and X-ray data for 3 (CIF). This material is available
free of charge via the Internet at http://pubs.acs.org
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K
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