High-yield synthesis of fluorinated benzothiazolyl sulfones: General synthons for fluoro-Julia olefinations

Article abstract of DOI:10.1021/ol060002+

General, high-yield tandem electrophilic fluorination and modified Julia olefination for the synthesis of fluoro olefins is reported. A series of α-fluoro 1,3-benzothiazol-2-yl sulfone-based synthons were synthesized via deprotonation-fluorination. Of critical importance for high-yield fluorinations were heterogeneous reaction conditions, as under homogeneous conditions only starting sulfones were recovered. The α-fluoro 1,3-benzothiazol-2-yl sulfones so obtained were subjected to condensations with a variety of aldehydes and ketones to afford high yields of regiospecifically fluorinated olefins.

Full text of DOI:10.1021/ol060002+

ORGANIC
LETTERS
2006
Vol. 8, No. 8
1553-1556
High-Yield Synthesis of Fluorinated
Benzothiazolyl Sulfones: General
Synthons for Fluoro-Julia Olefinations
Arun K. Ghosh and Barbara Zajc*
Department of Chemistry, The City College and The City UniVersity of New York,
138th Street at ConVent AVenue, New York, New York 10031
barbaraz@sci.ccny.cuny.edu
Received January 1, 2006
ABSTRACT
General, high-yield tandem electrophilic fluorination and modified Julia olefination for the synthesis of fluoro olefins is reported. A series of
-fluoro 1,3-benzothiazol-2-yl sulfone-based synthons were synthesized via deprotonation fluorination. Of critical importance for high-yield
fluorinations were heterogeneous reaction conditions, as under homogeneous conditions only starting sulfones were recovered. The -fluoro
r
−
r
1,3-benzothiazol-2-yl sulfones so obtained were subjected to condensations with a variety of aldehydes and ketones to afford high yields of
regiospecifically fluorinated olefins.
Vinyl fluorides are of considerable interest for their biological
properties, such as enzyme inhibition,1 as well as their use
as versatile synthetic building blocks.2 Therefore, several
notable approaches have been developed for their synthesis,
such as electrophilic fluorination of vinyllithiums3 or stan-
nanes,4 fluorodesilylation of vinylsilanes,5 the Horner-
Wadsworth-Emmons condensation of R-fluorophosphonates
with carbonyls,6a-c and Peterson fluoro olefination.6d
An attractive method for introduction of unsaturation is
the modified (one-pot) Julia olefination.7,8 For this, the 1,3-
benzothiazol-2-yl sulfones (BT-sulfones) have been reported
to provide the best yields and/or stereoselectivities.9 We
rationalized that synthesis of fluorinated BT-sulfones might
provide new fluorinated synthons2 for vinyl fluorides. To
our knowledge, there is only a single example where a
metalated R-fluoroethyl BT-sulfone has been used for the
synthesis of vinyl fluorides.10 In this case, direct fluorination
of corresponding ethyl BT-sulfide with F-TEDA gave only
30-35% of the R-fluorosulfide. The requisite R-fluorosul-
fone was therefore synthesized either from commercially
available 1-bromo-1-fluoroethane or from the R-chlorosulfide
via chlorine-fluorine substitution.
Since direct fluorination is of a wider scope, we have
evaluated a general method for the synthesis of R-fluoro BT-
sulfones and studied their reactivities in the fluoro olefination.
(6) (a) Tsai, H.-J.; Thenappan, A.; Burton, D. J. J. Org. Chem. 1994,
59, 7085-7091. (b) Tsai, H.-J. Tetrahedron Lett. 1996, 37, 629-632. (c)
Tsai, H.-J.; Lin, K.-W.; Ting, T.-h.; Burton, D. J. HelV. Chim. Acta 1999,
82, 2231-2239. (d) Lin, J.; Welch, J. T. Tetrahedron Lett. 1998, 39, 9613-
9616.
(7) Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O. Tetrahedron Lett.
1991, 32, 1175-1178.
(8) Blakemore, P. R. J. Chem. Soc., Perkin Trans. 1 2002, 2563-2585.
(9) (a) Blakemore, P. R.; Cole, W. J.; Kocie´nski, P. J.; Morley, A. Synlett
1998, 26-28. (b) Albrecht, B. K.; Williams, R. M. Proc. Natl. Acad. Sci.
U.S.A. 2004, 101, 11949-11954.
(10) Chevrie, D.; Lequeux, T.; Demoute, J. P.; Pazenok, S. Tetrahedron
Lett. 2003, 44, 8127-8130.
(1) Bey, P.; McCarthy, J. R.; McDonald, I. A. In SelectiVe Fluorination
in Organic and Bioorganic Chemistry; Welch, J. T., Ed.; American Chemical
Society: Washington, DC, 1991; pp 105-133.
(2) (a) Soloshonok, V. A., Ed. Fluorine-Containing Synthons; American
Chemical Society: Washington, DC, 2005. (b) Also see: Special Issue on
Fluorinated Synthons J. Fluorine Chem. 2004, 125, 477-645.
(3) (a) Lee, S. H.; Schwartz, J. J. Am. Chem. Soc. 1986, 108, 2445-
2447. (b) Differding, E.; Ofner, H. Synlett 1991, 187-189.
(4) (a) Lal, G. S.; Pez, G. P.; Syvret, R. G. Chem. ReV. 1996, 96, 1737-
1755. (b) Tius, M. A.; Kawakami, J. K. Tetrahedron 1995, 51, 3997-
4010.
(5) Gouverneur, V.; Greedy, B. Chem.sEur. J. 2002, 8, 766-771.
10.1021/ol060002+ CCC: $33.50
© 2006 American Chemical Society
Published on Web 03/16/2006

Described herein are initial results from this exploration and
a novel, general avenue to vinyl fluorides.
At the onset, the sodium salt of 2-mercapto-1,3-benzothia-
zole was allowed to react with benzyl bromide in DMF to
afford the corresponding sulfide (2a in Scheme 1) in 93%
Table 1. Conditions Tested for the Fluorination of 3a
products
3a, 4a, di-F, others
entry
1
rxn. mixture
addition of
a
a
3a, THF, t-BuLi,
-78 °C, 1 h
3a, THF, NFSi,
-78 °C
NFSi, THF
solution, rt
t-BuLi
x , -, -, x
a
a
2
3
4
5
x , -, -, x
Scheme 1. Synthesis of Fluorinated Benzothiazolyl Sulfones
3a, PhMe, t-BuLi, NFSi, PhMe
68b, 32b, trace, x
62b, 38b, trace, x
(BT-Sulfones)
a
a
-85 °C, 0.5 h
3a, PhMe, NFSi,
-85 °C
solution, rt
t-BuLi
a
3a, PhMe, t-BuLi, NFSi, PhMe
7b, 93b, trace, x
-85 °C, 6 min
suspension,
-60 °C
6
7
3a, PhMe, LDA,
-85 °C, 11 min
NFSi, PhMe
suspension,
-70 °C
3b, 97b, tracec, -
-d, 90e, 3e, -
3a, PhMe, LDA,
-85 °C, 11 min
solid NFSi
a Observed by TLC, not isolated. b Relative ratio determined by 1H NMR.
c Relative ratio of 4a to difluoro derivative ∼98:2, determined by 19F NMR.
d By TLC some 3a was observed, but was not recovered. e Isolated yields
of purified products.
ensure reproducibility of the reaction as well as feasibility
on the large scale, solid NFSi was added to metalated 3a at
-85 °C rather than as a suspension in toluene.14 These
conditions were reproducible, and 4a was routinely isolated
in excellent yields (90%).15
yield. Initial unoptimized attempts were directed at introduc-
tion of fluorine into 2a using various reagents. These,
including the reported use of FTEDA-NEt3 for fluorination
of ethyl BT-sulfide,10 were unsuccessful.11
An electron transfer (ET) mechanism leading to recovery
of starting material is possibly a competing process to the
SN2 fluorination16 (entries 1-4), and such recovery of starting
materials has previously been observed when electron-rich
systems were subjected to metalation-fluorination with
NFSi.17 In one instance, it has been shown that adventitious
moisture is not the cause for the competing protonation.17a
Therefore, it seems plausible that under the heterogeneous
fluorination conditions (entries 5-7) the rate of the ET
process is slower compared to the displacement leading to
fluorination. To test the generality of this fluorination,
sulfones 3b-d (Scheme 1) were subjected to LDA depro-
tonation in toluene, followed by addition of solid NFSi. In
every case, monofluoro derivatives 4b-d were isolated in
82-87% yield (purified products).
On the basis of these results as well as to avoid complica-
tions due to the potential instability of the R-fluorosulfide,
functionalization of the sulfone appeared more desirable.
Benzyl BT-sulfone 3a was therefore prepared in 94% yield
via m-CPBA oxidation of 2a. To minimize difluorination,12
the bulky t-BuLi was used for deprotonation of 3a in THF
at -78 °C, followed by addition of N-fluorobenzenesulfon-
imide (NFSi) in THF. However, no fluorinated products were
formed, and only starting material and unidentified nonpolar
byproducts were observed (Table 1, entry 1). Therefore, other
conditions were studied for the monofluorination of 3a, and
Table 1 shows results of these experiments. Addition of
t-BuLi to a mixture of NFSi and 3a at -78 °C (entry 2)
gave results similar to entry 1.13 The use of toluene as solvent
instead of THF (entries 3 and 4) gave the desired 4a, along
with recovered 3a and unidentified nonpolar byproducts. The
formation of 4a increased substantially, when a suspension
of NFSi in toluene was added to metalated 3a (entry 5).
Although not conclusive, the formation of nonpolar byprod-
ucts appears to be related to decomposition of 3a in the
presence of t-BuLi since such byproducts were not observed
when LDA was used for proton abstraction (entry 6). To
(14) Typical fluorination procedure. A stirred solution of sulfone 3a (1.00
g, 3.46 mmol) in dry toluene (25 mL) was cooled to -85 °C (dry ice/iso-
PrOH) under nitrogen, and 2.07 mL (4.15 mmol, 1.2 molar equiv) of LDA
(2 M solution in heptane/THF/EtPh) was added to the reaction mixture.
After 11 min, solid NFSi (1.34 g, 4.25 mmol, 1.23 molar equiv) was added.
The mixture was allowed to stir at -85 °C for 50 min, then warmed to
room temperature, and the stirring continued for an additional 50 min.
Saturated aq NH4Cl was added to the mixture, and the layers were separated.
The aqueous layer was extracted with EtOAc three times, and the combined
organic layer was washed with saturated aq NaHCO3 followed by brine.
The organic layer was dried over Na2SO4, and the solvent was evaporated
under reduced pressure. The crude reaction mixture was purified by column
chromatography (SiO2, 20% EtOAc in hexanes) to yield 0.951 g (90%) of
fluorosulfone 4a as a white solid.
(11) Reactions of 2a using XeF2, FTEDA-NEt3, N-fluoropyridinium
triflate, or DAST (with corresponding sulfoxide) resulted in little to only
trace (with XeF2) amounts of the fluorinated derivative. Attempts at
obtaining the benzylic chloro derivative of 2a for subsequent chlorine-
fluorine substitution, as reported in ref 10 for ethyl BT-sulfide, were
unsuccessful.
(12) Kotoris, C. C.; Chen, M.-J.; Taylor, S. D. J. Org. Chem. 1998, 63,
8052-8057.
(13) Hill, B.; Liu, Y.; Taylor, S. D. Org. Lett. 2004, 6, 4285-4288.
(15) Use of fresh LDA in these reactions is critical for good yields.
(16) (a) Differding, E.; Ru¨egg, G. M. Tetrahedron Lett. 1991, 32, 3815-
3818. (b) Differding, E.; Wehrli, M. Tetrahedron Lett. 1991, 32, 3819-3822.
(17) (a) Barnes, K. D.; Hu, Y.; Hunt, D. A. Synth. Commun. 1994, 24,
1749-1755. (b) Zajc, B. J. Org. Chem. 1999, 64, 1902-1907.
1554
Org. Lett., Vol. 8, No. 8, 2006

Olefination reactions of fluoro BT-sulfones 4a-d were
performed with a series of aldehydes and ketones. In a typical
experiment, LHMDS (2.4 molar equiv) was added to a
solution of 4a-d (1.2 molar equiv) and a carbonyl compound
(1 molar equiv) in THF at 0 °C, and the reaction mixture
was stirred for 1.5-2 h at 0 °C.18 Excellent yields were
obtained in the condensation reactions, and these, along with
E/Z ratios, are displayed in Table 2.
Table 3. Stereoselectivity in the Condensation of 4a with
2-Naphthaldehyde
Table 2. General Synthesis of Vinyl Fluorides
entry
conditions
E/Z ratioa
1
2
3
4
5
6
LHMDS, DMF-DMPU (1:1), rt, 2 h
LHMDS, DMF-DMPU (1:1), 0 °C, 1.5 h
LHMDS, DMF-DMPU (1:1), -78 °Cb
LHMDS, THF, 0 °C, 2 h
1:1.4
1:3.6
1:11.9
2.3:1
2.2:1
2.0:1
LHMDS, THF, -78 °Cb
NaHMDS, THF, -78 °Cb
a Relative isomer ratio from the crude reaction mixtures determined by
19F NMR. b Reactions were stirred at -78 °C for 40 min, -45 °C for 35
min, rt for 2 h.
LHMDS and THF, and temperature had little effect on the
isomer ratio (entries 4 and 5). Similar stereoselectivity was
observed with NaHMDS (entry 6).
To assess the influence of the fluorine substituent on
stereochemical outcome of the olefination step, a condensa-
tion of unfluorinated 3c with octanal was performed under
conditions identical to those that yielded 7c. In this case,
the E/Z ratio was ∼1:10, indicating that presence of fluorine
alters the stereoselectivity of the olefination.
Finally, in an attempt at simplifying the two-step fluorina-
tion-olefination method, an unoptimized one-pot reaction
was performed (Scheme 2). After fluorination of 3a, the
Scheme 2. A Two-Step, One-Pot Synthesis of Vinyl Fluorides
a Yields of isolated, purified products. b Relative ratio of purified
diastereomers determined by 19F NMR (reactions were performed under
similar conditions but were not optimized for individual cases). c Ratio of
isomers (more downfield : more upfield resonance); E,Z configuration was
not determined (however, in the reactions with aldehydes, the 19F resonance
of E isomer appeared more downfield consistently).
Appropriate choice of coupling partners leads to regio-
isomeric vinyl fluorides via this method. This is exemplified
by the synthesis of fluoroalkenes 5c and 8b.
We then studied the effect of reaction conditions, reported
by Liu and Jacobsen19 as well as Albrecht and Williams,9b
on the E/Z ratio in the condensation reactions of 4a with
naphthaldehyde. These results are shown in Table 3.
The use of LHMDS in DMF/1,3-dimethyl-3,4,5,6-tetrahy-
dro-2(1H)-pyrimidinone (DMPU) favored formation of the
Z isomer, and the stereoselectivity increased significantly as
temperature was lowered (entries 1-3). On the other hand,
in this particular case, the E isomer was favored with
resulting 4a was subjected to olefination without isolation,
by addition of a THF solution of 2-naphthaldehyde at 0 °C
to the reaction mixture, followed by addition of LHMDS.
The yield of purified 5a was 72% (93% based on recovered
aldehyde), and the E/Z ratio (2.7:1) was similar to the
sequential transformation.
The benzothiazolyl sulfone derivatives clearly are excellent
substrates for benzylic fluorination-olefinations. On the basis
of the purported higher stability of metalated 1-phenyl-1H-
Org. Lett., Vol. 8, No. 8, 2006
1555

tetrazol-5-yl sulfone derivatives (PT-sulfones) and the fact
that these are less prone to self-condensation,8,9a we have
briefly investigated fluorination of this system as well.
Furthermore, n-alkyl PT-sulfones are reported to produce
higher yields of alkenes in condensation reactions compared
to their n-alkyl BT-sulfone counterparts.9a Thus, in our
preliminary experiments, as shown in Scheme 3, we syn-
conditions described herein. The overall sequence may be
suitably applicable to other alkyl systems, and work is
ongoing in our laboratories to delineate the scope.
Introduction of fluorine atom into organic molecules poses
a considerable challenge. This communication reports a
general, high-yield tandem electrophilic fluorination and
modified Julia olefination to yield fluoro olefins. Heteroge-
neous reaction conditions appear critical for successful
fluorination of metalated BT-sulfones affording the R-fluoro
1,3-benzothiazol-2-yl sulfone derivatives in excellent yields.
Condensation of the R-fluoro benzothiazolyl synthons pre-
pared via this method with a variety of aldehydes and ketones
afforded high yields of regiospecifically fluorinated olefins.
Current work in our laboratories is aimed at a more detailed
understanding of the BT- and PT-sulfone-based synthons as
general reagents for synthesis of fluoroalkenes as well as
the stereochemical outcome from these reactions.
Scheme 3. Synthesis and Condensation of 1-Fluoropropyl
PT-Sulfone
Acknowledgment. This work was supported by NSF
Grant CHE-0516557 and by NIH RCMI Grant 5G12
RR03060-20. Acquisition of a 500 MHz NMR spectrometer
and a mass spectrometer has been funded by NSF Grants
CHE-0210295 and CHE-0520963. We thank Dr. B. Boggess
and Ms. N. Sevova (U. of Notre Dame) for mass spectral
analyses, and Dr. G. Shia (Honeywell) for a sample of NFSi.
Supporting Information Available: Experimental de-
1
1
tails, H NMR spectra of 3a-d to 11a-d, and H and 19F
NMR spectra of 14. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL060002+
(18) Typical olefination procedure. A stirred solution of 2-naphthaldehyde
(43.0 mg, 0.275 mmol) and 1,3-benzothiazol-2-yl (phenyl)fluoromethyl
sulfone 4a (101.5 mg, 0.330 mmol, 1.2 molar equiv) in dry THF (3.5
mL) was cooled to 0 °C under nitrogen, and 0.660 mL (0.660 mmol, 2.4
molar equiv) of LHMDS (1 M solution in THF) was added. The reaction
mixture was allowed to stir at 0 °C for 1.5 h. Saturated aq NH4Cl (5 mL)
was added to the mixture, and the mixture was extracted with EtOAc
three times. The combined organic layer was washed with brine, dried over
Na2SO4, and the solvent was evaporated under reduced pressure. The crude
E/Z product mixture was purified by column chromatography (SiO2, 5%
EtOAc in hexanes) to yield 68.3 mg (quantitative yield) of 5a as an off
white solid.
thesized 1-phenyl-1H-tetrazol-5-yl n-propyl sulfide 12 (quan-
titative). Oxidation of 12 with m-CPBA yielded the sulfone
13 in 89% yield, which was subjected to fluorination with
LDA/NFSi. The R-fluoro derivative 14 was isolated in 80%
yield. Subsequent condensation of 1-fluoropropyl PT-sulfone
14 with 2-naphthaldehyde using LHMDS in THF afforded
the E/Z product mixture in 92% yield after chromatographic
purification. The ratio of E/Z isomers in this case was 1.3:1.
This experiment demonstrates that PT-sulfones can po-
tentially also be subjected to the metalation and fluorination
(19) Liu, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2001, 123, 10772-
10773.
1556
Org. Lett., Vol. 8, No. 8, 2006