Fluorinated 1-phenyl-1H-tetrazol-5-yl sulfone derivatives as general reagents for fluoroalkylidene synthesis

Article abstract of DOI:10.1021/jo901313k

(Figure Presented) Julia - Kocienski olefination reagents 1-fluoropropyl, (cyclopropyl)fluoromethyl, 1-fluoro-2-methyl-2-propenyl, and 1-fluoro-5-hexenyl 1-phenyl-1H-tetrazol-5-yl (PT) sulfones were prepared by metalation followed by electrophilic fluorin

Full text of DOI:10.1021/jo901313k

pubs.acs.org/joc
Fluorinated 1-Phenyl-1H-tetrazol-5-yl Sulfone Derivatives as General
Reagents for Fluoroalkylidene Synthesis
Arun K. Ghosh and Barbara Zajc*
Department of Chemistry, The City College and The City University of New York, 160 Convent Avenue,
New York, New York 10031
barbaraz@sci.ccny.cuny.edu
Received June 19, 2009
Julia-Kocienski olefination reagents 1-fluoropropyl, (cyclopropyl)fluoromethyl, 1-fluoro-2-methyl-
2-propenyl, and 1-fluoro-5-hexenyl 1-phenyl-1H-tetrazol-5-yl (PT) sulfones were prepared by metalation
followed by electrophilic fluorination. Although metalation-fluorination of n-propyl, 5-hexenyl, and
(cyclopropyl)methyl PT-sulfones proceeded under homogeneous conditions, fluorination of 2-methyl-
2-propenyl PT-sulfone required heterogeneous fluorination conditions. Condensation reactions of fluoro
PT-sulfones with aldehydes resulted in fluoroalkylidenes in high yields. Screening of olefination conditions
showed that stereoselectivity depended on reagent and carbonyl structure and can in many cases be tuned
either toward E- or Z-selectivity. For example, LHMDS-mediated condensations of 1-fluoropropyl PT-
sulfone in the presence of MgBr2 OEt2 were Z-selective with electron-rich aromatic aldehydes, a hindered
3
aromatic aldehyde, and cinnamaldehyde. Low-temperature KHMDS-mediated condensations were
E-selective with electron-rich and electron-deficient aromatic aldehydes and Z-selective with n-octanal.
Dialkyl, aryl alkyl, and diaryl ketones reacted as well to give fluoro olefin products in 71-99% yields.
Introduction
synthetic strategies for the synthesis of fluoroorganics, either
via introduction of fluorine atom into specific molecules2 or
development of molecules via a building block assembly
using fluorinated precursors.4 As synthetic intermediates,
fluoroolefins are pivotal compounds, and several methods
have been developed for their synthesis,5a including Wittig
and Horner-Wittig like reactions.5
Introduction of fluorine is known to alter physical, biolo-
gical, and chemical properties of organic compounds.1 Ac-
cess to regiospecifically fluorinated compounds2 continues
to be of interest in many areas, such as pharmaceuticals,3a
materials,3b and agrochemistry.3c There are principally two
*To whom correspondence should be addressed. Tel: (212) 650-8926. Fax:
(212) 650-6107.
(1) (a) Welch, J. T., Ed. Selective Fluorination in Organic and Bioorganic
Chemistry; American Chemical Society: Washington, DC, 1991. (b) Ojima, I.,
McCarthy, J. R., Welch, J. T., Eds. Biomedical Frontiers of Fluorine Chemistry;
ꢀ
ꢀ
(3) See, for example, the following reviews: (a) Begue, J.-P.; Bonnet-
Delpon, D. J. Fluorine Chem. 2006, 127, 992–1012. (b) Pagliaro, M.;
Ciriminna, R. J. Mater. Chem. 2005, 15, 4981–4991. (c) Jeschke, P. Chem-
BioChem 2004, 5, 570–589.
(4) (a) Special Issue on Fluorinated Synthons. J. Fluorine Chem. 2004, 125,
477-645. (b) Soloshonok, V. A., Ed. Fluorine-Containing Synthons; American
Chemical Society: Washington, DC, 2005.
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American Chemical Society: Washington, DC, 1996. (c) Begue, J.-P.; Bonnet-Delpon,
D. Bioorganic and Medicinal Chemistry of Fluorine; John Wiley & Sons, Inc.:
Hoboken, NJ, 2008.
(5) For recent reviews, see: (a) van Steenis, J. H.; van der Gen, A. J. Chem.
Soc., Perkin Trans. 1 2002, 2117–2133. (b) Burton, D. J.; Yang, Z.-Y.; Qiu,
W. Chem. Rev. 1996, 96, 1641–1716. (c) Romanenko, V. D.; Kukhar, V. P.
Chem. Rev. 2006, 106, 3868–3935. For examples on the reactions of
fluoroalkylphosphonium salt and fluoroalkylphosphonate, see: (d) Blackburn,
G. M.; Parratt, M. J. J. Chem. Soc., Chem. Commun. 1983, 886–888. (e)
Blackburn, G. M.; Parratt, M. J. J. Chem. Soc., Perkin Trans. 1 1986, 1425–
1430. (f ) El-Khoury, M.; Wang, Q.; Schlosser, M. Tetrahedron Lett. 1996, 37,
9047–9048.
(2) (a) Kirsch, P. Modern Fluoroorganic Chemistry. Synthesis, Reactivity,
Applications; Wiley-VCH Verlag: Weinheim, 2004. (b) Chambers, R., Ed.
Fluorine in Organic Chemistry; Blackwell Publishing Ltd.: Oxford, 2004. (c)
Laali, K. K., Ed. Modern Organofluorine Chemistry-Synthetic Aspects;
Bentham Science Publishers: San Francisco, 2006; Vol. 2. (d) Soloshonok,
V. A., Mikami, K., Yamazaki, T., Welch, J. T., Hoenk, J. F., Eds. Current
Fluoroorganic Chemistry: New Synthetic Directions, Technologies, Materials,
and Biological Applications; American Chemical Society: Washington, DC, 2007.
DOI: 10.1021/jo901313k
r
Published on Web 10/15/2009
J. Org. Chem. 2009, 74, 8531–8540 8531
2009 American Chemical Society

Ghosh and Zajc
JOCArticle
SCHEME 1. Attempts at Synthesis of Fluoroalkyl Benzothiazolyl Sulfones via Metalation-Fluorination
Since the original report on the one-pot Julia olefination,6
SCHEME 2. Details of Metalation-Fluorination of Benzothiazolyl
Sulfone Derivatives
this and its Kocienski variation have found wide use in
synthetic organic chemistry for olefin synthesis via conden-
sation reactions of heteroarylsulfonyl- or arylsulfonyl-sub-
stituted carbanions with aldehydes or ketones.7 Despite this,
such a method has not received much attention for the
synthesis of vinyl fluorides until recently. Synthesis of vari-
ously functionalized fluoroolefins has been since reported by
us and others, i.e., R-fluoro-R-methylvinyl derivatives,8 stil-
bene- and styrene-like fluoroolefins,9 fluoroacrylates,10
fluoroacrylonitriles,11 R-fluorovinyl phenyl sulfones,12
R-fluorovinyl Weinreb amides,10c,13 and enones.13 Several
approaches have been undertaken for the synthesis of fluori-
nated Julia-Kocienski reagents. These range from synthesis
utilizing commercial fluorinated precursors8,10b,10d,11 to ha-
logen exchange reaction of the appropriate chloro deriva-
tive8 to metalation-electrophilic fluorination.9,10a,10c,11-13
Among these, we have extensively investigated the metala-
tion-fluorination approach9,10a,11-13 since it offers the most
general access to fluorinated Julia-Kocienski reagents.
During these investigations, we discovered that although
benzylic fluorination of 1,3-benzothiazol-2-yl benzyl sulfo-
nes could be successfully conducted under heterogeneous
metalation-electrophilic fluorination conditions,9 reactivity
of comparable 1,3-benzothiazol-2-yl alkyl sulfones was
much more complex. On the basis of these observations,
synthesis of the more stable Kocienski reagents 1-phenyl-
1H-tetrazol-5-yl fluoroalkyl sulfones was considered appro-
priate. Herein, we report our results on the generality of the
metalation-fluorination of 1,3-benzothiazol-2-yl and 1-phenyl-
1H-tetrazol-5-yl alkyl sulfones and the generally efficient con-
densation reactions of the resulting 1-phenyl-1H-tetrazol-5-yl
fluoroalkyl sulfones with aldehydes and ketones.
method for the synthesis of Julia olefination reagents via
heterogeneous metalation-fluorination of appropriate pre-
cursors, specifically 1,3-benzothiazol-2-ylsulfonyl (BT-
sulfonyl) derivatives.9,10a,11-13 Further, to date the only
reported Julia olefination reagent for the synthesis of fluoro-
alkylidene derivatives was the benzothiazolyl-based R-fluoro-
ethyl BT-sulfone.8 Since its preparation via fluorination of
ethyl BT-sulfide with F-TEDA-BF4 (Selectfluor) gave only
30-35% of the R-fluoro sulfide precursor, R-fluoroethyl
BT-sulfone reagent was synthesized from either commer-
cially available 1-bromo-1-fluoroethane or from the
R-chloroethyl sulfide via chlorine-fluorine substitution.8
While this work was in progress, decarbethoxylation of
appropriate BT-sulfone derivatives was reported to yield
1-fluoroethyl and 1-fluoropropyl BT-sulfones in 51% and
33% yield, respectively.10d On the basis of our earlier work,
our initial attempts were therefore directed toward the
synthesis of fluorinated BT-sulfone derivatives, specifically
propyl and cyclopropyl BT-derivatives (Scheme 1).
Reaction of the sodium salt of 2-mercapto-1,3-benzothia-
zole with n-bromopropane or (bromomethyl)cyclopropane
gave the sulfides 1a14 and 1b15a that were subjected to m-
CPBA oxidation to give the corresponding sulfones 2a14 and
2b.15 Both sulfones were subjected to metalation-fluorina-
tion using our heterogeneous conditions.9 Typically, metala-
tions were performed in toluene at -78 °C using LDA,
followed by quenching of the carbanion with solid N-fluor-
odibenzenesulfonimide (NFSI). In the case of 2a, the highest
isolated yield of the desired monofluoro derivative 2-[(1-
fluoropropyl)sulfonyl]-1,3-benzothiazole10d (3a, Scheme 2)
was 18%. In addition, a product resulting from self-con-
densation (3a-FD, Scheme 2) was also isolated in 37% yield.
Metalation-fluorination of 2b gave a complex reaction
mixture. The 1H and/or 19F NMR spectra showed the
presence of about 30% of starting material 2b, 3% of the
Results and Discussion
Our first goal was synthesis of appropriate fluoroalkyl
derived heteroaryl sulfones for the Julia-Kocienski olefina-
tion. In our previous studies, we have developed a general
(6) Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O. Tetrahedron Lett.
1991, 32, 1175–1178.
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Lett. 2003, 44, 8127–8130.
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(10) (a) Zajc, B.; Kake, S. Org. Lett. 2006, 8, 4457–4460. (b) Pfund, E.;
Lebargy, C.; Rouden, J.; Lequeux, T. J. Org. Chem. 2007, 72, 7871–7877. (c)
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8211.
(12) He, M.; Ghosh, A. K.; Zajc, B. Synlett 2008, 999–1004.
(13) Ghosh, A. K.; Banerjee, S.; Sinha, S.; Kang, S. B.; Zajc, B. J. Org.
Chem. 2009, 74, 3689–3697.
(15) (a) Ueno, Y.; Kojima, A.; Okawara, M. Chem. Lett. 1984, 2125–
2128. (b) Sanderson, P. E. J.; Cutrona, K. J.; Savage, K. L.; Naylor-Olsen,
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8532 J. Org. Chem. Vol. 74, No. 22, 2009

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TABLE 1. Synthesis of Alkyl 1-Phenyl-1H-tetrazol-5-yl Sulfones
desired monofluoro product 3b, and 8% of the fluorinated
dimer (3b-FD, Scheme 2), in addition to other unidentified
products. In either case, variation of reaction conditions, i.e.,
base (NaHMDS, t-BuLi), as well as stoichiometry of re-
agents led to little improvement. For example, deprotona-
tion of 2b with t-BuLi at -78 °C in toluene followed by
addition of solid NFSI resulted in a complex reaction
mixture that showed the desired monofluoro derivative
and starting 2b in a 43%:57% ratio, in addition to other
unidentified byproducts (1H NMR). Attempted metala-
tion-fluorination of 2a using NaH/F-TEDA-BF4 (THF,
0 °C to rt) led to recovered starting material only. Next, we
decided to perform the reaction under homogeneous fluor-
ination conditions using THF as solvent. Metalation of 2a in
THF at -78 °C using LDA, followed by addition of a THF
solution of NFSI, resulted in a mixture that showed the
presence of sulfone 2a and product 3a-FD in a ratio of
73%:27%, but no monofluoro derivative 3a, as assessed by
1H NMR. Metalation-fluorination of 2b under homo-
geneous conditions resulted in a mixture that contained
sulfone 2b and the self-condensation product in ∼30%:70%
ratio, respectively (3b-FD, 48% isolated yield, Scheme 2). It
has been reported7,16 that 1,3-benzothiazol-2-yl sulfone deri-
vatives containing sterically unencumbered substituents tend
to undergo self-condensations even at low temperatures.
Metalated 1-phenyl-1H-tetrazol-5-yl sulfones have been
found to be more stable compared to benzothiazolyl sul-
fones,17 and the stability of 1-tert-butyl-1H-tetrazol-5-yl
sulfones has been reported to be even greater.16 Among the
tetrazolyl derivatives, 1-phenyl-1H-tetrazol-5-yl n-alkyl sul-
fones have shown higher E-selectivity in condensation reac-
tions compared to the tert-butyl analogues.7,16 Further,
synthesis of R-bromo and R-chloromethyl 1-phenyl-1H-tet-
razol-5-yl sulfones and condensation reactions with alde-
hydes have recently been reported.18 These results led us to
pursue the synthesis and fluorination of alkyl 1-phenyl-1H-
tetrazol-5-yl sulfones. A series of 1-phenyl-1H-tetrazol-5-yl
sulfones was synthesized in a simple two-step procedure
(5a-d, Table 1).
Next, fluorination of sulfones 5a-d was undertaken.
Various reaction conditions were tested, and the results are
displayed in Table 2. In all cases studied, a slight excess of
LDA was added to a solution of sulfone 5a-d at -78 °C in
the solvent indicated, and after 15 min, a slight excess of
NFSI was added either as solid or as a solution (Table 2).
After completion of reaction and workup, the crude reaction
mixture was analyzed by NMR spectroscopy. The ratios of
starting sulfone 5a-d to monofluoro product 6a-d were
1
determined by H NMR. The ratios of fluorinated com-
pounds, i.e., monofluoro product 6a-d, the difluoro deriva-
tive (diF) and fluorinated dimer (6-FD, if present), were
assessed by 19F NMR (Table 2).
The results in Table 2 reveal that the reaction is sensitive to
both reaction conditions as well as the structure of the
sulfone. Initially, the reaction was performed with n-propyl
derivative 5a under our heterogeneous fluorination condi-
tions, where LDA was added to solution of sulfone in
toluene, followed by addition of solid NFSI (entry 1, Table
2).9 The crude reaction mixture showed a ratio of 79%:21%
of monofluoro derivative 6a and starting sulfone 5a, with
trace amounts of the difluoro byproduct. In order to assess
the influence of solvent, THF was used instead of toluene,
and NFSI was added as solid (entry 2, Table 2). The resulting
product mixture showed a similar composition, with a
decrease in product yield. When the reaction was performed
in THF under homogeneous metalation-fluorination con-
ditions (addition of NFSI in solution), little change in
product composition was again observed, with the yield of
6a similar to that obtained under heterogeneous conditions
(entry 3, Table 2). Metalation-fluorination of cyclopropyl
derivative 5b under heterogeneous conditions resulted in a
more complex reaction mixture that contained monofluoro
derivative 6b and starting compound 5b (56%:44%, entry 4,
Table 2), along with a fluorinated dimer (6b:6b-FD
68%:32%). Minor dimer formation was observed when the
reaction was performed under homogeneous metalation-
fluorination conditions, and monofluoro product 6b was
isolated in 58% yield (entry 5, Table 2). This contrasts
substantially to metalation-fluorination of benzothiazolyl
ꢀ
(16) Kocienski, P. J.; Bell, A.; Blakemore, P. R. Synlett 2000, 365–366.
ꢀ
(17) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A. Synlett
1998, 26–28.
(18) Lebrun, M.-E.; Marquand, P. L.; Berthelette, C. J. Org. Chem. 2006,
71, 2009–2013.
(19) Egorova, N. G.; Artamonova, T. V.; Koldobskii, G. I. Russ. J. Org.
Chem. 2007, 43, 475–477.
(20) Takeda, K.; Tsuboyama, K.; Torii, K.; Murata, M.; Ogura, H.
Tetrahedron Lett. 1988, 29, 4105–4108.
(21) Wang, X.; Bowman, E. J.; Bowman, B. J.; Porco, J. A. Jr. Angew.
Chem., Int. Ed. 2004, 43, 3601–3605.
J. Org. Chem. Vol. 74, No. 22, 2009 8533

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TABLE 2. Fluorination of Alkyl 1-Phenyl-1H-tetrazol-5-yl Sulfones
aFluorinated byproducts: difluoro derivative (diF) and fluorinated dimer (6-FD). bYields of isolated, purified products. cNo fluorinated dimer (6-FD)
observed by 19F NMR. dComplex reaction mixture. No desired product 6c was observed by 19F NMR; 6c was isolated in 59% yield when reaction was
performed on a 100 mg scale but could not be repeated on larger scales.
sulfone analogue 2b, where fluorinated dimer 3b-FD was the
only product formed under homogeneous reaction condi-
tions (Scheme 2) and formation of only minor amounts
of 3b-FD was observed under heterogeneous fluorination
conditions. In the fluorination of 2-propenyl derivative 5c
under heterogeneous conditions, fluorinated product 6c was
isolated in 53% yield (Table 2, entry 6). Under homogeneous
conditions, fluorination of 5c worked well on a small scale,
but could not be repeated on a larger scale and resulted in
complex reaction mixtures. Finally, fluorination of 5-hexe-
nyl sulfone 5d under homogeneous conditions resulted in the
monofluoro derivative 6d as the major fluorinated product,
along with small amount of difluoro derivative (entry 8,
Table 2).
In metalation-fluorination reactions, an electron-trans-
fer (ET) mechanism has been suggested as a competing
path to the SN2 fluorination.22 We have shown in the past
that metalation-fluorination of 1,3-benzothiazol-2-yl aryl-
methyl sulfones proceeded well under heterogeneous condi-
tions (formation of carbanion in toluene, followed by
addition of solid NFSI). In these cases, no product, or a
low amount of product, was isolated when the reaction was
performed under homogeneous conditions, along with large
amounts of recovered starting material. ET was suggested to
compete with the fluorination.9 This was also shown to occur
in metalation-fluorination of nucleosides using NFSI,23
where ET prevailed under homogeneous fluorination con-
ditions,23a but under heterogeneous conditions fluorinated
products were isolated.23b We were therefore surprised to
find that metalation-fluorination of 1-phenyl-1H-tetrazol-
5-yl sulfone derivatives could be performed under homo-
geneous conditions to yield the fluorinated products. Im-
portantly, only the desired fluorinated 6d was observed in the
case of 5-hexenyl sulfone 5d, with no detectable formation of
cyclized or olefin migration products (entry 8, Table 2).
Thus, it appears that the ET process is substantially lower
in the case of PT-sulfones. Further, in the fluorination of
1,3-benzothiazolyl sulfone 2b under homogeneous condi-
tions, a self-condensation resulting in 3b-FD was the major
process (Scheme 2). This was not the case with its phenylte-
trazolyl sulfone analogue 5b, where only a minor amount of
dimer formation was detected in the reaction mixture (entry
5, Table 2). Moreover, formation of fluorinated dimers was
not observed for other substrates, when reactions were
performed in THF.
€
(22) (a) Differding, E.; Ruegg, G. M. Tetrahedron Lett. 1991, 32, 3815–
3818. (b) Differding, E.; Wehrli, M. Tetrahedron Lett. 1991, 32, 3819–3822.
(c) Barnes, K. D.; Hu, Y.; Hunt, D. A. Synth. Commun. 1994, 24, 1749–1755.
(23) (a) Roy, A.; Schneller, S. W. Org. Lett. 2005, 7, 3889–3891. (b)
Ghosh, A. K.; Lagisetty, P.; Zajc, B. J. Org. Chem. 2007, 72, 8222–8226.
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TABLE 3. Effect of Reaction Conditions on Stereoselectivity and Yield of Condensations of 6a with 2-Naphthaldehyde
(%) E/Z ratio;a
entry
base (molar equiv)
LHMDS (1.3)
LHMDS (2.4)
LHMDS (1.1)
LHMDS (2.5)
LHMDS (1.3)
LHMDS (2.5)
LHMDS (2.5)
LHMDS (2.5)
LHMDS (2.5)
LHMDS (2.5)
LHMDS (3.0)
LHMDS (3.0)
LHMDS (3.0)
phosphazene base-P2-Et (1.4)
phosphazene base-P4-t-Bu (1.4)
phosphazene base-P4-t-Bu (1.4)
KHMDS (1.3)
NaHMDS (1.3)
KHMDS (1.3)
KHMDS (1.1)
solvent
additive (molar equiv)
T (°C), reaction time (h)
yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
THF
THF
THF
DMF
DMF
DMF
DMF
HMPA
DMPU
THF
THF
THF
THF
THF
THF
THF
DME
DME
THF
THF
0, 2
0, 2
59/41; 90
58/42; 92
59/41; 90
43/57; 84
37/63; 34
37/63; 82
37/63; 98
30/70; 74
25/75; 78
48/52; 78
17/83; 86
14/86; 94
34/66; 78
42/58; 55
24/76; 70
29/71; 97
58/42; 39
58/42; 39
60/40; 75
73/27; 64
-78 to -65, 3; -45-0, 1.5; rt, 1
-55 to þ15, 4
DMPUc
DMPUc
HMPAd
-70, 1; -45, 0.5; rt, overnight
-70, 1; -45, 0.5; rt, overnight
-44 to þ15, 4
0 to þ15, 4
-20 to þ15; 4
BF3 OEt2
3
0, 2; rt, 1
rt, 4.5
MgBr2 (anh)
MgBr2 OEt2
MgBr2 OEt2
rt, 4.5
0, 2
3
3
0, 2
0, 2
-82, 2
-55, 2.5; rt, overnight
-55, 2.5; rt, overnight
0, 2
-78, 2
aRelative ratio of diastereomers in the crude reaction mixture determined by 19F NMR prior to isolation. No change in ratio was observed after
purification. bYields of isolated, purified products. cCosolvent, ratio of DMF/DMPU 1:1 (v/v). dCosolvent, ratio of DMF/HMPA 3:1 (v/v).
With the desired reagents in hand, we decided to test the
olefination and the associated stereoselectivity under various
reaction conditions. Effect of base counterion and solvent on
the olefination stereoselectivity using unfluorinated PT-sul-
fones has originally been reported by Blakemore et al.17
Effect of additives on olefinations using a PT-sulfone has
subsequently been screened.24 Recently, condensation reac-
tions of R-chloromethyl PT-sulfones have been studied:
room-temperature LHMDS-mediated condensations with
electron-rich aromatic aldehydes were E-selective in the
HMPA was used as additive (entry 7). An additional increase
in Z-selectivity was observed upon use of HMPA or DMPU
alone as solvent (entries 8 and 9). Condensation in the
presence of BF3 OEt2 produced no stereoselection. High
3
Z-selectivity was observed in THF at rt in the presence of
anhydrous MgBr2 (entry 11) or MgBr2 OEt2 (entry 12), and
3
this decreased with a decrease in temperature (entry 13).
Next, the effect of various bases on selectivity and yield of
condensations was tested. Marginal Z-selectivity was ob-
served with phosphazene base P2-Et (entry 14), and this
selectivity increased to 24/76 when the phosphazene base
P4-t-Bu was used (entries 15 and 16).
presence of MgBr2 OEt2, whereas Z-stereoselectivity was
3
observed in condensation with a series of aldehydes in the
presence of HMPA.18 Stereoselectivity and olefination yields
under various reaction conditions was therefore assessed
using 1-fluoropropyl sulfone 6a and 2-naphthaldehyde.
The results are displayed in Table 3. All reactions were
performed under Barbier conditions;7 i.e., base was added
to a solution of 1 molar equiv of aldehyde and 1.2-1.5 molar
equiv of sulfone (and additive, when used).
The role of counterion on stereoselectivity has been de-
monstrated in LHMDS, KHMDS, and NaHMDS mediated
condensations of unfluorinated n-alkyl PT-sulfones with n-
alkanals.17 An increase in E-selectivity was observed in
solvents of higher polarity/coordinating capability. High
E-selectivity was obtained when KHMDS/THF was used,
and this improved in DME;17 similar high trans selectivity
was also observed in the reaction of unfluorinated n-alkyl
PT-sulfone with benzaldehyde.16 In the present case, the use
of KHMDS or NaHMDS in DME showed modest E-
selectivity (cis arrangement of alkyl and aryl moieties) simi-
lar to that obtained when LHMDS/THF was used (entries 17
and 18, compare to entries 1 and 2), and gave the product in a
poor 39% yield. The use of KHMDS/THF instead improved
the yield to 75% (entry 19). A further increase in E-selectivity
was achieved by lowering the reaction temperature (73/27,
entry 20). From the results in Table 3 it can be concluded that
the use of polar solvents or additives (DMPU, HMPA,
MgBr2) favors Z-selectivity. Lower temperature and
KHMDS as base gave highest E-selectivity (cis arrangement
of the alkyl and aryl groups), opposite to what was observed
Use of LHMDS as base in THF at 0 °C gave the con-
densation product in a high 90% yield with an E/Z ratio of
59/41 (entry 1, Table 3). Increasing the amount of base (entry
2) or decreasing reaction temperature (entry 3) had no effect
on either the E/Z ratio or the yield. The change of solvent to
the more polar DMF reversed the E/Z ratio (43/57, entry 4).
Addition of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimi-
dinone (DMPU) increased the Z-selectivity (entry 5, 34%
yield), and the yield improved upon increasing the amount of
base (entry 6, 82%). A similar result was obtained when
(24) (a) Liu, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2001, 123, 10772–
10773. (b) Albrecht, B. K.; Williams, R. M. Proc. Natl. Acad. Sci. U.S.A.
2004, 101, 11949–11954.
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TABLE 4. Study of E/Z-Stereoselectivity in the Condensations of 6a-c with Various Aldehydes
aRelative ratio of diastereomers in the crude reaction mixture determined by 19F NMR prior to isolation. bYields of isolated, purified products. cRatio
of isomers determined by ratio of E/Z doublets in 19F NMR; pure product could not be isolated due to decomposition upon chromatography on both
SiO2 and Al2O3.
in reaction of unfluorinated n-alkyl PT-sulfone with benzal-
dehyde (trans disposition of alkyl and phenyl groups).16
Next, the generality of the Z-stereoselective condensation
of 6a with 2-naphthaldehyde observed in the presence of
aldehyde. The following conclusions can be drawn from the
two tables.
LHMDS/MgBr2 OEt2-Mediated Condensations. With
3
the n-propyl olefination substrate 6a, reactions are Z-selec-
tive under these conditions (Table 4) for electron-rich
(entries 1, 4, 13) and hindered aromatic aldehydes (entry 7)
as well as cinnamaldehyde (entry 16). For the electron-poor
aromatic aldehyde and n-octanal (entries 10 and 19), con-
densations are not stereoselective. Reactions of cyclopropyl
derivative 6b show moderate to good Z-selectivity with
electron-rich aromatic aldehydes (entries 2, 5, and 14), E-
selectivity in the case of p-nitrobenzaldehyde (entry 11), and
no stereoselectivity for the hindered o-methylbenzaldehyde,
cinnamaldehyde, and n-octanal (entries 8, 17, and 20,
MgBr2 OEt2 (Table 3, entry 12) was tested with a series
3
of aldehydes. Condensations of (cyclopropyl)fluoromethyl
PT-sulfone 6b and of 1-fluoro-2-methyl-2-propenyl PT-
sulfone 6c with various aldehydes were performed as well.
The results of the condensations are shown in Table 4. Simi-
larly, the generality of E-selective condensation of 2-naphthal-
dehyde (KHMDS/THF, -78 °C, entry 20, Table 1) was also
tested in reactions of 6a-c with a series of aldehydes (Table 5).
From the results in Tables 4 and 5 it is observed that the
stereoselectivity depends highly on the reagent, as well as the
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TABLE 5. Low-Temperature Condensations of 6a-c Using KHMDS/THFa
aReactions were performed under Barbier conditions (ref 7). bRelative ratio of diastereomers in the crude reaction mixture determined by 19F NMR
prior to isolation. cYields of isolated, purified products.
respectively). With the 2-methyl-2-propenyl derivative 6c,
good to excellent Z-stereoselectivity was observed under the
LHMDS/MgBr2 OEt2-mediated conditions with electron-
rich aromatic systems and the sterically hindered o-methyl-
benzaldehyde (entries 3, 6, 9, and 15), whereas moderate
Z-selectivity was observed with cinnamaldehyde (entry 18).
In contrast, reactions with p-nitrobenzaldehyde and n-octa-
nal were E-selective (Table 4, entries 12 and 21).
KHMDS-Mediated Condensations. Condensations of 6a
mediated by KHMDS at low temperature (Table 5) are E-
selective with electron-rich and electron-poor aromatic alde-
hydes (entries 1 and 4) and Z-selective with n-octanal (entry
6). The selectivity with n-octanal parallels that observed by
Blakemore et al. in reactions of unfluorinated PT-sulfones
(trans disposition of alkyl chains).17 Condensations of 6b
showed no stereoselectivity in the reaction of 2-naphthalde-
hyde, moderate E-selectivity with p-nitrobenzaldehyde, and
moderate Z-selectivity with n-octanal (entries 2, 5, 7). The
two KHMDS-mediated low-temperature condensations of
6c with 2-naphthaldehyde and n-octanal were not stereo-
selective (Table 5, entries 3, 8).
and 6, and 7 and 8). For unsymmetrical ketones acetophe-
none and 1-indanone, stereochemistry of the major isomer
formed in the condensations with 6a was determined by
NOESY. In both cases, condensations were E-selective.
3
Conclusions
In conclusion, a series of phenyltetrazolyl fluoroalkyl
sulfones has been prepared via metalation-fluorination.
Successful fluorination of the structurally different n-propyl,
(cyclopropyl)methyl, 2-methyl-2-propenyl, and 5-hexenyl
1-phenyl-1H-tetrazol-5-yl sulfones demonstrates generality
of the approach. Metalation-fluorination of n-alkyl and
(cyclopropyl)methyl sulfones proceeds under homogeneous
conditions, whereas fluorination of 2-methyl-2-propenyl
PT-sulfone requires heterogeneous fluorination conditions.
The fluorinated PT-sulfones undergo condensation reac-
tions with aldehydes to give R-fluoroalkylidenes in high
yields. Screening of olefinations with a series of aldehydes
showed that stereoselectivity depended on both, the struc-
ture of PT-sulfone as well as the aldehyde. Reaction condi-
tions can in many cases be modulated toward E- or
Z-selectivity. Condensations also proceeded with dialkyl,
aryl alkyl, and diaryl ketones, and the products were isolated
in yields ranging from 71 to 99%.
No further attempts were made to optimize condensation
conditions for each specific reagent. However, there is the
possibility of tuning the condensation toward E- or
Z-stereoselectivity by modulation of reaction conditions in
several cases.
Experimental Section
Finally, reactivity of ketones with 6a and 6b was tested.
Condensation reactions proceeded with dialkyl, alkyl aryl, as
well as diaryl ketones. The yield strongly depended on
stoichiometry of reagents, and typically, best yields were
obtained when the molar equivalence of ketone/sulfone/
LHMDS was 1:2:3 (compare entries 1 and 2, 3 and 4, 5
5-{[(Cyclopropyl)methyl]sulfanyl}-1-phenyl-1H-tetrazole (4b).
(Bromomethyl)cyclopropane: 2.11 g (15.6 mmol); DMF: 78 mL;
sodium salt of 1-phenyl-1H-tetrazol-5-thiol (4.07 g, 20.3 mmol);
reaction time 5 h; extraction: EtOAc (3 ꢀ 150 mL). Yield: 3.55 g
(98%) of white solid 4b. Mp (recrystallized from 50% CH2Cl2 in
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TABLE 6. Reactivity of 6a and 6b with Ketonesa
aReactions were performed under Barbier conditions (ref 7). bYields of isolated, purified products. cRelative ratio of isomers in the crude reaction
mixture determined by 19F NMR prior to isolation (more downfield: more upfield resonance). dStereochemistry of major isomer was determined by
NOESY; E/Z 74/26. eStereochemistry of major isomer was determined by NOESY; E/Z 78/22.
hexanes): 53-54 °C. 1H NMR (500 MHz, CDCl3): δ 7.60-7.52
(m, 5H, Ar-H), 3.35 (d, 2H, J = 7.3), 1.30-1.22 (m, 1H),
0.71-0.61 (m, 2H), 0.42-0.32 (m, 2H). 13C NMR (125 MHz,
CDCl3): δ 154.7, 133.9, 130.2, 129.9, 124.0, 39.7, 10.6, 6.4.
HRMS (APCI): calcd for C11H13N4S [M þ H]þ 233.0855, found
233.0859.
5-[(5-Hexenyl)sulfanyl]-1-phenyl-1H-tetrazole (4d). 6-Bromo-
1-hexene: 1.00 g (6.13 mmol); DMF: 30.6 mL; sodium salt of
1-phenyl-1H-tetrazol-5-thiol (1.60 g, 7.97 mmol); reaction
time 5.5 h; extraction: EtOAc (3 ꢀ 100 mL). Yield: 1.58 g
(99%) of colorless oily 4d. 1H NMR (500 MHz, CDCl3): δ
7.59-7.52 (m, 5H, Ar-H), 5.78 (ddt, 1H, J=17.0, 10.1, 6.9), 5.01
(dd, 1H, J=17.0, 1.4), 4.96 (br d, 1H, J=10.1), 3.40 (t, 2H,
J=7.4), 2.10 (q, 2H, J=7.2), 1.84 (quint, 2H, J=7.4), 1.55
(quint, 2H, J = 7.4). 13C NMR (125 MHz, CDCl3): δ 154.5,
138.1, 133.8, 130.2, 129.9, 123.9, 115.1, 33.2, 33.1, 28.6, 27.8.
HRMS (APCI): calcd for C13H17N4S [M þ H]þ 261.1168, found
261.1171.
125.5, 61.6, 4.8, 3.8. HRMS (APCI): calcd for C11H13N4O2S
[M þ H]þ 265.0754, found 265.0758.
5-[(2-Methyl-2-propenyl)sulfonyl]-1-phenyl-1H-tetrazole (5c).
Sulfide 4c: 1.50 g (6.47 mmol, 1.0 molar equiv); Mo27O24-
(NH4)6.4H2O: 0.652 g (0.527 mmol); EtOH: 130 mL; H2O2
(50% in water): 3.63 mL (64.6 mmol, 10 molar equiv); extrac-
tion: EtOAc (3 ꢀ 150 mL). Yield of 5c: 1.14 g (66%) of white
solid. Mp: (recrystallized from 50% CH2Cl2 in hexanes) 72-
73 °C. 1H NMR (500 MHz, CDCl3): δ 7.64-7.58 (m, 5H, Ar-H),
5.27 (d, 1H, J=1.0), 5.15 (d, 1H, J=1.0), 4.40 (s, 2H), 1.92 (s,
3H). 13C NMR (125 MHz, CDCl3): δ 153.5, 133.2, 131.7, 130.7,
129.8, 125.5, 123.7, 63.8, 23.2. HRMS (APCI): calcd for
C11H13N4O2S [M þ H]þ 265.0754, found 265.0758.
General Procedure for Fluorination of Alkyl 1-Phenyl-1H-
tetrazol-5-yl Sulfones 5a-d. Method A. A solution of sulfone
5a-c (1 molar equiv) in dry toluene was cooled to -78 °C (dry
ice/i-PrOH) under nitrogen. LDA (2 M solution in heptane/
THF/EtPh, 1.05 molar equiv for 5a and 5b, 1.1 molar equiv for
5c) was added to the reaction mixture. After 12 min, solid NFSI
(1.25 molar equiv) was added, the mixture was allowed to stir at
-78 °C for 50 min and warmed to rt, 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 (3ꢀ), and the combined organic
layer was washed with saturated aq NaHCO3 and brine. The
organic layer was dried over Na2SO4, and the solvent was evapo-
rated under reduced pressure. The crude reaction mixtures were
5-{[(Cyclopropyl)methyl]sulfonyl}-1-phenyl-1H-tetrazole (5b).
Sulfide 4b: 3.55 g (15.3 mmol) in CHCl3 (45.2 mL); m-CPBA:
7.91 g (45.9 mmol, 3.0 molar equiv) in CHCl3 (106 mL);
extraction: CH2Cl2 (3 ꢀ 50 mL). Yield of 5b: 3.59 g (89%) of
a white solid. Mp (recrystallized from 50% CH2Cl2 in hexanes):
1
54-55 °C. H NMR (500 MHz, CDCl3): δ 7.70-7.68 (m, 2H,
Ar-H), 7.65-7.59 (m, 3H, Ar-H), 3.67 (d, 2H, J = 6.9),
1.31-1.24 (m, 1H), 0.79-0.69 (m, 2H), 0.53-0.44 (m, 2H).
13C NMR (125 MHz, CDCl3): δ 153.9, 133.3, 131.7, 129.9,
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Ghosh and Zajc
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purified by column chromatography on silica gel, and the product
was eluted by 10% EtOAc in hexanes (5a and 5b) or CH2Cl2 (5c).
Method B. A solution of sulfone 5a, 5b, or 5d (1 molar equiv)
in dry THF was cooled to -78 °C (dry ice/i-PrOH) under
nitrogen. LDA (1.10 molar equiv, 2 M solution in heptane/
THF/EtPh) was added to the reaction mixture. After 15 min, a
solution of NFSI (1.25 molar equiv) in dry THF (1.3 mL per
mmol of sulfone) was added, the mixture was allowed to stir at
-78 °C for 50 min and then warmed to rt, 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 (3ꢀ), and the
combined organic layer was washed with saturated aq NaHCO3
and brine. The organic layer was dried over Na2SO4, and the
solvent was evaporated under reduced pressure. The crude
reaction mixtures were purified by column chromatography
on silica gel with 10% EtOAc in hexanes as eluting solvent.
For each substrate, the amount of substrate, reagents, and
solvent and product yield are given under the specific compound
heading below.
extraction: EtOAc (3 ꢀ 30 mL). Yield of 6d: 208 mg (65%) of a
white solid. Mp (recrystallized from 50% CH2Cl2 in hexanes):
42-43 °C. 1H NMR (500 MHz, CDCl3): δ 7.66-7.59 (m, 5H,
Ar-H), 5.86 (ddd, 1H, J=48.3, 9.7, 3.2), 5.76 (ddt, 1H, J=17.0,
10.1, 6.7), 5.07-5.02 (m, 2H), 2.30-2.06 (m, 4H), 1.81-1.64 (m,
2H). 13C NMR (125 MHz, CDCl3): δ 151.8, 136.9, 133.0, 131.9,
129.8, 125.8, 116.4, 103.3 (d, JCF=224.3), 32.9, 25.7 (d, JCF
=
19.2), 23.4 (d, JCF =1.8). 19F NMR (CDCl3): δ -177.5 (ddd,
J
FH = 48.8, 33.6, 15.3). HRMS (APCI): calcd for C13H16-
FN4O2S [M þ H]þ 311.0973, found 311.0972.
Representative Procedure for Condensations of 6a-c Using
LHMDS/MgBr2 OEt2. Condensations with 2-Thiophenecarbo-
3
xaldehyde. Reaction with 6c. A mixture of 2-thiophenecarbo-
xaldehyde (112 mg, 1 mmol), sulfone 6c (395 mg, 1.4 mmol, 1.4
molar equiv), and MgBr2 OEt2 (77.5 mg, 3 mmol, 3 molar equiv)
3
in dry THF (12.5 mL) was allowed to stir at rt for 10 min.
LHMDS (3.00 mL, 1 M solution in THF, 3.00 mmol, 3 molar
equiv) was added dropwise, and stirring was continued at rt for
3 h (until complete consumption of starting material was ob-
served by TLC). Saturated aq NH4Cl was added, and the mixture
was extracted withEt2O(3 ꢀ 50 mL). Thecombinedorganic layer
was washed with H2O and brine and dried over anhydrous
Na2SO4, and the solvent was evaporated under reduced pressure
at rt. Analysis of the crude reaction mixture by 19F NMR showed
the presence of Z isomer only. The crude product was purified by
column chromatography (CH2Cl2) to yield 131 mg (78%) of 11c
as a pale yellow oil (due to product volatility, solvent was care-
fully evaporated under a stream of nitrogen gas).
5-[(1-Fluoropropyl)sulfonyl]-1-phenyl-1H-tetrazole (6a).
(Method A) Sulfone 5a: 1.00 g (3.97 mmol, 1 molar equiv);
toluene: 12 mL; LDA: 2.08 mL (4.17 mmol, 1.05 molar equiv,
2 M solution in heptane/THF/EtPh); NFSI: 1.56 g (4.94 mmol,
1.25 molar equiv); extraction: EtOAc (3 ꢀ 50 mL). Yield of
6a:10d 760 mg (71%) of a white solid. Mp (recrystallized from
50% CH2Cl2 in hexanes): 77-78 °C. (Method B) Sulfone 5a:
1.00 g (3.97 mmol, 1 molar equiv) in THF (8 mL); NFSI: 1.56 g
(4.94 mmol, 1.25 molar equiv) in THF (5 mL). Yield of 6a:10d
722 mg (67%) of a white solid. 1H NMR (500 MHz, CDCl3): δ
7.67-7.60 (m, 5H, Ar-H), 5.81 (ddd, 1H, J = 47.9, 9.2, 3.7),
2.37-2.11 (m, 2H), 1.23 (t, 3H, J=7.6). 13C NMR (125 MHz,
1
2-[(1Z)-2-Fluoro-3-methyl-1,3-butadienyl]thiophene (11c). H
NMR (500 MHz, CDCl3): δ 7.31 (d, 1H, Ar-H, J=5.2), 7.14 (d,
1H, Ar-H, J=3.0), 7.03-7.02 (m, 1H, Ar-H), 6.14 (d, 1H, JHF
=
38.1), 5.52 (br s, 1H), 5.13-5.12 (narrow m, 1H), 1.96 (narrow
m, 3H). 13C NMR (125 MHz, CDCl3): δ 156.9 (d, JCF=258.2),
136.4 (d, JCF=3.7), 134.5 (d, JCF=21.5), 127.6 (d, JCF=3.7),
CDCl3): δ 151.8, 133.0, 131.9, 129.8, 125.8, 104.2 (d, JCF
=
224.7), 20.3 (d, JCF = 19.2), 8.71 (d, JCF = 3.2). 19F NMR
(CDCl3): δ -178.8 (ddd, JFH=48.8, 33.6, 15.3). HRMS (APCI):
calcd for C10H12FN4O2S [M þ H]þ 271.0660, found 271.0656.
5-{[(Cyclopropyl)fluoromethyl]sulfonyl}-1-phenyl-1H-tetra-
zole (6b). (Method B) Sulfone 5b: 1.00 g (3.79 mmol, 1 molar
equiv) in dry THF (7 mL); NFSI: 1.49 g (4.73 mmol, 1.25 molar
equiv) in THF (5 mL); LDA: 2.08 mL (4.17 mmol, 1.10 molar
equiv); extraction: EtOAc (3 ꢀ 50 mL). Yield of 6b: 616 mg
(58%) of a white solid. Mp (recrystallized from 50% CH2Cl2 in
hexanes): 72-73 °C. 1H NMR (500 MHz, CDCl3): δ 7.67-7.60
(m, 5H, Ar-H), 5.28 (dd, 1H, J=47.2, 8.5), 1.57-1.48 (m, 1H),
1.04-0.85 (m, 3H), 0.79-0.74 (m, 1H). 13C NMR (125 MHz,
127.1, 126.6 (d, JCF=9.6), 114.3 (d, JCF=6.4), 101.7 (d, JCF
=
=
14.7), 18.9 (d, JCF=3.7). 19F NMR (CDCl3): δ -112.7 (d, JFH
36.6). HRMS (CI): calcd for C9H9FS [M]þ 168.0409, found
168.0421.
The crude reaction mixture obtained in reaction of 6a and
thiophene-2-carboxaldehyde showed an E/Z product ratio 1:99
that was purified by column chromatography (SiO2, CH2Cl2,
75% of E/Z-11a as a pale yellow oil). HRMS (APPI): calcd for
C8H10FS [M þ H]þ 157.0482, found 157.0478. 2-[(Z)-2-Fluoro-1-
butenyl]thiophene (11a). 1H NMR (500 MHz, CDCl3): δ 7.22 (d,
1H, Ar-H, J=4.9), 7.00 (d, 1H, Ar-H, J=3.0), 6.98-6.96 (m, 1H,
Ar-H), 5.80(d, 1H, JHF=38.5), 2.38 (dq, 2H, J=14.8, 7.5), 1.18 (t,
CDCl3): δ 152.0, 133.1, 131.8, 129.8, 125.8, 106.4 (d, JCF
=
225.2), 7.1 (d, JCF = 23.8), 3.7, 3.4 (d, JCF = 7.3). 19F NMR
(CDCl3): δ -169.8 (dd, JFH=47.3, 10.7). HRMS (APCI): calcd
for C11H12FN4O2S [M þ H]þ 283.0660, found 283.0664. For
fluorination of 5b using method A and spectral data of 6b-FD,
see the Supporting Information.
3H, J=7.5). 13C NMR (125 MHz, CDCl3): δ 161.4 (d, JCF
265.5), 136.3 (d, JCF=3.7), 126.7, 125.7 (d, JCF=3.7), 125.0 (d,
CF=9.2), 99.7 (d, JCF=12.8), 25.8 (d, JCF=26.6), 10.9 (d, JCF
3.7). 19F NMR (CDCl3): δ -97.8 (app dt, JFH=41.0, 13.5).
=
J
=
The crude reaction mixture obtained in reaction of 6b and
thiophene-2-carboxaldehyde showed an E/Z product ratio 9:91,
that was purified by column chromatography (SiO2, CH2Cl2,
60% of E/Z-11b as a pale yellow oil). HRMS (APPI): calcd for
C9H10FS [M þ H]þ 169.0482, found 169.0483. NMR data are
reported only for the major isomer. 2-[(Z)-2-Fluoro-2-cyclopro-
5-[(1-Fluoro-2-methyl-2-propenyl)sulfonyl]-1-phenyl-1H-tetra-
zole (6c). (Method A) Sulfone 5a: 1.00 g (4.02 mmol, 1 molar
equiv); toluene: 24.7 mL; LDA: 2.08 mL (4.17 mmol, 1.1 molar
equiv); NFSI: 1.58 g (5.02 mmol, 1.25 molar equiv); extraction:
EtOAc (3 ꢀ 50 mL). Yield of 6c: 600 mg (53%) of a white solid.
Mp (recrystallized from 50% CH2Cl2 in hexanes): 80-81 °C. 1H
NMR (500 MHz, CDCl3): δ 7.67-7.60 (m, 5H, Ar-H), 6.26 (d,
1H, JHF=46.2), 5.59 (narrow m, 1H), 5.54 (narrow m, 1H), 1.98
(s, 3H). 13C NMR (125 MHz, CDCl3): δ 152.1, 133.0, 131.9,
131.2 (d, JCF=17.8), 129.8, 125.8, 124.5 (d, JCF=8.7) 104.1 (d,
1
pyl-1-ethenyl]thiophene (11b). H NMR (500 MHz, CDCl3): δ
7.20-7.18 (m, 1H, Ar-H), 6.97-6.96 (m, 2H, Ar-H), 5.88 (d,
1H, JHF =38.2), 1.67-1.57 (m, 2H), 0.87-0.79 (m, 4H). 13C
NMR (125 MHz, CDCl3): δ 159.9 (d, JCF =260.9), 136.5 (d,
J
J
CF=4.1), 126.8, 125.3 (d, JCF=3.7), 124.7 (d, JCF=9.2), 99.2 (d,
J
CF=226.6), 18.6 (d, JCF=3.2). 19F NMR (CDCl3): δ -172.2 (d,
CF=14.6), 12.7 (d, JCF=29.3), 5.4 (d, JCF=1.8). 19F NMR
JFH=48.8). HRMS (APCI): calcd for C11H12FN4O2S [M þ H]þ
(CDCl3): δ -110.2 (dd, JFH=36.6, 18.3).
283.0660, found 283.0660.
Representative Procedure for Condensations Using KHMDS/
THF at Low Temperature. Condensation of 6a with 2-Naphthal-
dehyde. To a stirring solution of 2-naphthaldehyde (156 mg, 1
mmol) and sulfone 6a (405 mg, 1.5 mmol) in dry THF (15.5 mL)
at -78 °C was added KHMDS (2.30 mL, 0.5 M solution in
5-[(1-Fluoro-5-hexenyl)sulfonyl]-1-phenyl-1H-tetrazole (6d).
(Method B) Sulfone 5d: 300 mg (1.03 mmol, 1 molar equiv) in
THF (1.63 mL); NFSI: 405 mg (1.28 mmol, 1.25 molar equiv) in
THF (1.35 mL); LDA: 0.565 mL (1.13 mmol, 1.10 molar equiv);
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Ghosh and Zajc
JOCArticle
toluene, 1.15 mmol, 1.15 molar equiv) dropwise. Under stirring,
the reaction temperature was allowed to increase from -78 to
-60 °C over 2.0 h. The reaction was quenched with saturated
aq NH4Cl, diluted with water, and extracted with Et2O (3 ꢀ
50 mL). The combined organic layer was thoroughly washed
with water and then with brine and dried over anhydrous
Na2SO4, and the solvent was evaporated in vacuo. Analysis of
the crude reaction mixture by 19F NMR showed the E/Z
product in a 75:25 ratio. The crude product was purified by
column chromatography (SiO2, CH2Cl2) to afford (E/Z)-7a as a
white solid (128 mg, 64%). HRMS (APPI): calcd for C14H13F
[M]þ 200.0996, found 200.0996. For 1H NMR analysis, a small
amount of the E and Z isomers was separated by column
chromatography (SiO2, hexanes). E-7a. White solid. Mp
(3 ꢀ 30 mL). The combined organic layer was washed with
water and brine and then dried over anhydrous Na2SO4.
The solvent was evaporated under reduced pressure, and
the crude product was purified by column chromatography
(SiO2, CH2Cl2) to yield 15b as a white solid (109 mg, 91%).
Mp (recrystallized from 50% CH2Cl2 in hexanes): 43-44 °C.
1H NMR (500 MHz, CDCl3): δ 7.38-7.23 (m, 9H, Ar-H),
7.20-7.18 (m, 1H, Ar-H), 1.69 (dm, 1H, JHF = 27.6),
0.98-0.89 (m, 2H), 0.75-0.65 (m, 2H). 13C NMR (125 MHz,
CDCl3): δ 157.1 (d, JCF =255.9), 139.2 (d, JCF =8.2), 138.3,
131.1 (d, JCF =2.8), 129.7 (d, JCF =5.0), 128.5, 128.1, 127.2,
126.7, 119.1 (d, JCF=16.9), 11.4 (d, JCF=27.0), 5.7 (d, JCF=2.3).
19F NMR (CDCl3): δ -125.4 (d, JFH=27.5). HRMS (APPI):
calcd for C17H15F [M]þ 238.1152, found 238.1148.
1
(recrystallized from 50% CH2Cl2 in hexanes): 40-41 °C. H
Reaction with 6a. The crude reaction mixture obtained in the
reaction of 6a and benzophenone was purified by column
chromatography (SiO2, CH2Cl2) to yield 75% of 15a as a clear
thick liquid. 1H NMR (500 MHz, CDCl3): δ 7.33 (t, 2H, Ar-H,
J=7.1), 7.30-7.25 (m, 5H, Ar-H), 7.21-7.18 (m, 3H, Ar-H),
2.32 (dq, 2H, J=23.0, 7.4), 1.15 (t, 3H, J=7.4). 13C NMR (125
MHz, CDCl3): δ 159.5 (d, JCF =261.4), 139.4 (d, JCF =8.2),
137.9, 130.4 (d, JCF =2.7), 129.8 (d, JCF =5.0), 128.6, 128.1,
NMR (500 MHz, CDCl3): δ 7.82-7.79 (m, 3H, Ar-H), 7.63 (s,
1H, Ar-H) 7.49-7.44 (m, 2H, Ar-H), 7.32 (d, 1H, J=8.4), 6.31
(d, 1H, JHF=21.7), 2.55 (dq, 2H, J=23.2, 7.4), 1.24 (t, 3H, J=
7.4). 13C NMR (125 MHz, CDCl3): δ 164.2 (d, JCF =254.0),
133.6, 132.3, 132.1 (d, JCF=14.2), 128.2, 127.9, 127.8, 127.2 (d,
J
CF=3.2), 127.0 (d, JCF=2.3), 126.5, 126.0, 107.8 (d, JCF=28.8),
22.8 (d, JCF=27.9), 11.3. 19F NMR (CDCl3): δ -100.4 (app q,
FH = 22.4). Z-7a. White solid. mp (recrystallized from 50%
J
127.4, 126.9, 119.9 (d, JCF=15.1), 24.2 (d, JCF=27.9), 11.7. 19
F
CH2Cl2 in hexanes) 53-54 °C. 1H NMR (500 MHz, CDCl3): δ
7.89 (s, 1H, Ar-H), 7.80-7.77 (m, 3H, Ar-H), 7.65 (d, 1H, J=
8.4), 7.46-7.41 (m, 2H, Ar-H), 5.62 (d, 1H, JHF =39.5), 2.42
(dq, 2H, J=15.1, 7.5), 1.23 (t, 3H, J=7.6). 13C NMR (125 MHz,
CDCl3): δ 163.1 (d, JCF =266.4), 133.8, 132.4 (d, JCF =1.9),
NMR (CDCl3): δ -108.44 (d, JFH=24.4). HRMS (APPI): calcd
for C16H15F [M]þ 226.1152, found 226.1155.
Acknowledgment. This work was supported by NSF
Grant No. CHE-0516557 and PSC CUNY-38, 39 awards.
Infrastructural support and support for A.K.G. were pro-
vided by NIH RCMI Grant No. 5G12 RR03060. We thank
Dr. Andrew Poss (Honeywell) for a sample of NFSI.
131.7 (d, JCF = 2.8), 128.2, 128.1, 127.7, 127.2 (d, JCF
=
7.3), 126.8 (d, JCF = 7.8), 126.2, 125.8, 105.0 (d, JCF = 8.7),
26.6 (d, JCF=27.5), 11.2 (d, JCF=3.2). 19F NMR (CDCl3): δ
-100.6 (dt, JFH=39.7, 15.3).
Representative Procedure for Condensations of 6a and 6b with
Ketones. Condensations with Benzophenone: Reaction with 6b. A
stirring solution of benzophenone (91.0 mg, 0.50 mmol) and
sulfone 6b (282 mg, 1.00 mmol, 2 molar equiv) in dry THF
(9.1 mL) was cooled to 0 °C under nitrogen gas. LHMDS
(1.5 mL, 1.5 mmol, 3.0 molar equiv of 1 M solution in THF)
was added, and the reaction mixture was allowed to stir at 0 °C
until complete consumption of benzophenone was observed
by TLC (2.0 h). The reaction was quenched with saturated
aq NH4Cl at rt, diluted with water, and extracted with Et2O
Supporting Information Available: Synthetic procedures for
1 and 2; fluorination of 2a,b; general synthetic procedures for
4a-d and 5a-d; fluorination of 5b using method A; spectral
data for 1, 2, 3a, 3a-FD, 3b-FD, 4a,c, 5a,d, and 6b-FD; 19F and
HRMS data of 7-17; 13C data of Z-8 and 14; copies of 1H and
13C spectra of 3a, 3a-FD, 3b-FD, 4b,d, 5b,c, 6, and 6b-FD; E- and
Z-7a, Z-11a, Z-11c, 14, and 15; and copies of 1H NMR spectra
of 1, 2, 4a,c, 5a,d, 7-11, 12a,b, and 13-17. This material is
available free of charge via the Internet at http://pubs.acs.org.
8540 J. Org. Chem. Vol. 74, No. 22, 2009