Fluoro-Julia olefination as a mild, high-yielding route to α-fluoro acrylonitriles

Article abstract of DOI:10.1021/jo801235x

(Chemical Equation Presented) Synthesis of a novel, stable reagent (1,3-benzothiazol-2-ylsulfonyl)fluoroacetonitrile from readily synthesized ethyl α-(1,3-benzothiazol-2-ylsulfanyl)-α-fluoroacetate is reported. Aldehydes undergo condensations with (1,3-be

Full text of DOI:10.1021/jo801235x

Fluoro-Julia Olefination as a Mild, High-Yielding Route to r-Fluoro
Acrylonitriles†
Maria del Solar, 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 10031-9198
barbaraz@sci.ccny.cuny.edu
ReceiVed June 8, 2008
Synthesis of a novel, stable reagent (1,3-benzothiazol-2-ylsulfonyl)fluoroacetonitrile from readily
synthesized ethyl R-(1,3-benzothiazol-2-ylsulfanyl)-R-fluoroacetate is reported. Aldehydes undergo
condensations with (1,3-benzothiazol-2-ylsulfonyl)fluoroacetonitrile in the presence of DBU leading to
R-fluoro acrylonitriles in high yields and with good Z-stereoselectivity. Lowering of reaction temperature
increases the Z selectivity.
Introduction
the synthesis of variously functionalized vinyl fluorides, such
as R-fluoro acrylates7 or fluorovinyl sulfones.6a,8 Synthetic routes
to R-fluoro acrylonitriles, on the other hand, are scarce. Patrick
and Nadji9 reported in situ preparation of diethyl R-cyano-R-
fluoromethanephosphonate from fluoroacetonitrile that reacted
as expected with aromatic aldehydes. On the other hand,
aliphatic aldehydes were reported to give complex reaction
mixtures resulting from aldol-type reactions.9 Xu and DesMar-
teau10 prepared and isolated the Horner-Wadsworth-Emmons
(HWE) reagent by fluorination of diethyl cyanomethanephos-
phonate using N-fluorobis(trifluoromethanesulfonyl)imide, a
fluorinating agent that is not available commercially. Although
the HWE reagent prepared in this manner was isolated, its use
Interest in fluorinated organic molecules stems from the
altered biological and other properties excerted by fluorine atom
introduction.1 As a consequence, a significant number of
pharmaceuticals currently on the market contain fluorine atoms.2
A convenient approach toward the synthesis of fluoroorganic
compounds is through modular assembly via fluorinated building
blocks.3 Functionalized fluoroolefins are attractive building
blocks and in many instances they are biologically useful
entities.4 For example, fluoroolefins act as dipeptide isosteres,1,5
whereas examples of mechanism-based enzyme inhibitors1,4
include fluorovinyl nucleoside,6a amino acid,4 or steroid6b,c based
derivatives. Several methods have therefore been developed for
(6) (a) McCarthy, J. R.; Matthews, D. P.; Stemerick, D. M.; Huber, E. W.;
Bey, P.; Lippert, B. J.; Snyder, R. D.; Sunkara, P. S. J. Am. Chem. Soc. 1991,
113, 7439–7440. (b) Burkhart, J. P.; Weintraub, P. M.; Gates, C. A.; Resvick,
R. J.; Vaz, R. J.; Friedrich, D.; Angelastro, M. R.; Bey, P.; Peet, N. P. Bioorg.
Med. Chem. 2002, 10, 929–934. (c) Weintraub, P. M.; Holland, A. K.; Gates,
C. A.; Moore, W. R.; Resvick, R. J.; Bey, P.; Peet, N. P. Bioorg. Med. Chem.
2003, 11, 427–431.
(7) For synthesis via Wittig and Horner-Wadsworth-Emmons see for
example: (a) Etemad-Moghadam, G.; Seyden-Penne, J. Bull. Soc. Chim. Fr. 1985,
448–454. (b) Thenappan, A.; Burton, D. J. J. Org. Chem. 1990, 55, 4639–4642.
(c) Burton, D. J.; Yang, Z.; Qui, W. Chem. ReV. 1996, 96, 1641–1715. (d) Sano,
S.; Ando, T.; Yokoyama, K.; Nagao, Y. Synlett 1998, 777–779. (e) Bargiggia,
F.; Dos Santos, S.; Piva, O. Synthesis 2002, 427–437. (f) Sano, S.; Teranishi,
R.; Nagao, Y. Tetrahedron Lett. 2002, 43, 9183–9186. (g) Sano, S.; Saito, K.;
Nagao, Y. Tetrahedron Lett. 2003, 44, 3987–3990. (h) Suzuki, Y.; Sato, M.
Tetrahedron Lett. 2004, 45, 1679–1681. (i) Zoute, L.; Dutheuil, G.; Quirion,
J.-C.; Jubault, P.; Pannecoucke, X. Synthesis 2006, 3409–3418. For synthesis
via Julia-Kocienski olefination see: (j) Zajc, B.; Kake, S. Org. Lett. 2006, 8,
4457–4460. (k) Pfund, E.; Lebargy, C.; Rouden, J.; Lequeux, T. J. Org. Chem.
2007, 72, 7871–7877. (l) Alonso, D. A.; Fuensanta, M.; Go´mez-Bengoa, E.;
Na´jera, C. AdV. Synth. Catal. 2008, 350, 1823–1829.
* Address correspondence to this author. Phone (212) 650-8926. Fax: (212)
650-6107.
† This paper is dedicated to the memory of Dr. John W. Daly (1933-2008),
an outstanding scientist and individual.
(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;
American Chemical Society: Washington, DC, 1996.
(2) Be´gue´, J.-P.; Bonnet-Delpon, D. J. Fluorine Chem. 2006, 127, 992–1012.
(3) (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. (c) 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.
(4) Welch, J. T. Tetrahedron 1987, 43, 3123–3197.
(5) See for example: (a) Allmendinger, T.; Felder, E.; Hungarbu¨hler, E.
Tetrahedron Lett. 1990, 31, 7301–7304. (b) Welch, J. T.; Lin, J. Tetrahedron
1996, 52, 291–304. (c) Dutheuil, G.; Couve-Bonnaire, S.; Pannecoucke, X.
Angew. Chem., Int. Ed. 2007, 46, 1–4.
8206 J. Org. Chem. 2008, 73, 8206–8211
10.1021/jo801235x CCC: $40.75 2008 American Chemical Society
Published on Web 10/08/2008

Mild, High-Yielding Route to R-Fluoro Acrylonitriles
SCHEME 1. Attempts at an Efficient Synthesis of 4
SCHEME 2. Successful Synthesis of 4
in condensation reactions with aldehydes and ketones was
successful only when prepared in situ. Van der Gen et al.11
prepared (diphenylphosphinoyl)fluoroacetonitrile in situ from
the fluoroacetonitrile anion, but attempts at its isolation were
unsuccessful.11 Condensations proceeded with aldehydes as well
as ketones in reasonable yields. Common to these methods
is the necessity for in situ prepared reagent. Herein, we report
the preparation of a novel, stable reagent and its reactivity
in R-fluoro acrylonitrile synthesis.
of 3, whereas dimethyldioxirane or oxone led mainly to the
sulfoxide derivative. Use of MoO24(NH4)6 ·4H2O/H2O2 gave
17
75% of 3, which increased to 90% upon use of H5IO6/CrO3.18
Fluorination of 3 with NaH and Selectfluor in THF resulted in
a mixture of monofluoro derivative 4 and a difluoro amide
byproduct 5 (2.2:1 ratio, respectively), along with starting
material. Laborius chromatographic purification, which pre-
vented synthesis on larger scales, gave (1,3-benzothiazol-2-
ylsulfonyl)fluoroacetonitrile 4 in 32% isolated yield. To improve
the efficiency of synthesis of 4, alternate synthetic routes were
tested. Metalation and fluorination of benzylic nitriles with
various strong bases (LDA, NaHMDS, KHMDS, LHMDS,
n-BuLi) and NFSI gave fluorinated derivatives in 9-16%, and
the reaction of the bases with the cyano functionality was suggested
as the possible cause for the low yields.19 However, the use of
t-BuLi and NFSI improved the yield of monofluoro derivative to
60%.19 Fluorination of 1,3-benzothiazol-2ylsulfanyl derivative 2a
by using t-BuLi and NFSI was therefore performed, resulting in a
complex reaction mixture. Since metalated 1-phenyl-1H-tetrazol-
5-yl sulfone derivatives (PT-sulfones) were suggested to be more
stable and less prone to self-condensation,15,20 PT-sulfide 2b was
synthesized21 and subjected to t-BuLi and NFSI fluorination to give
6b21 in 45% isolated yield (Scheme 1). Attempts at oxidizing 6b
to the corresponding sulfone by using MoO24(NH4)6 ·4H2O/H2O2,
or H5IO6/CrO3, were unsuccessful.
Modified Julia olefination12 has been reported as an alternative
to Horner-Wadsworth-Emmons olefination for the preparation
of fluoroalkylidenes.13,14 In this context, we have recently de-
veloped novel reagents for the synthesis of fluorinated stilbene
and styrene derivatives,14 R-fluoro-R,ꢀ-unsaturated esters,7j and
phenyl sulfones8i via Julia olefination. Specifically, mild condi-
tions, combined with high yields obtained in the synthesis of
the latter two prompted our interest in exploring Julia fluo-
roolefination for the preparation of R-fluoro acrylonitriles.
Results and Discussion
Our initial goal was synthesis of an appropriate heteroaryl-
sulfonyl derivative as the reagent for a one-pot Julia-Kocienski
olefination.15 We first focused on the synthesis of (1,3-
benzothiazol-2-ylsulfonyl)fluoroacetonitrile. Reaction of bro-
moacetonitrile (1) with the sodium salt of 2-mercapto-1,3-
benzothiazole resulted in 2a16 in 88% yield, which was subjected
to oxidation to 1,3-benzothiazol-2-ylsulfonyl (BT-sulfonyl)
derivative 3 (Scheme 1). The use of m-CPBA gave a low yield
Since little success was achieved with conversions of BT- or
PT-derivatives containing a preinstalled cyano functionality, we
decided on an alternate method, wherein fluorine introduction
into the molecule would precede that of the cyano group. Olah
and co-workers have reported high-yielding conversions of
amides to cyano derivatives using cyanuric chloride.22 Ethyl
R-(1,3-benzothiazol-2-ylsulfanyl)-R-fluoroacetate (8, 88% yield,
Scheme 2) was therefore synthesized from commercially avail-
able ethyl bromofluoroacetate 7.7k Alternatively, unfluorinated
precursor ethyl bromoacetate 9 (Scheme 2) was converted to
(8) (a) Inbasekaran, M.; Peet, N. P.; McCarthy, J. R.; LeTourneau, M. E.
J. Chem. Soc., Chem. Commun. 1985, 678–679. (b) Koizumi, T.; Hagi, T.; Horie,
Y.; Takeuchi, Y. Chem. Pharm. Bull. 1987, 35, 3959–3962. (c) McCarthy, J. R.;
Matthews, D. P.; Edwards, M. L.; Stemerick, D. M.; Jarvi, E. T. Tetrahedron
Lett. 1990, 31, 5449–5452. (d) Kunugi, A.; Yamane, K.; Yasuzawa, M.; Matsui,
H.; Uno, H.; Sakamoto, K. Electrochim. Acta 1993, 38, 1037–1041. (e) McCarthy,
J. R.; Huber, E. W.; Le, T.-B.; Laskovics, F. M.; Matthews, D. P. Tetrahedron
1996, 52, 45–58. (f) Nakamura, T.; Guha, S. K.; Ohta, Y.; Abe, D.; Ukaji, Y.;
Inomata, K. Bull. Chem. Soc. Jpn. 2002, 75, 2031–2041. (g) Asakura, N.; Usuki,
Y.; Iio, H. J. Fluorine Chem. 2003, 124, 81–88. (h) Wnuk, S. F.; Garcia, P. I.,
Jr.; Wang, Z. Org. Lett. 2004, 6, 2047–2049. (i) He, M.; Ghosh, A. K.; Zajc, B.
Synlett 2008, 999–1004.
(9) Patrick, T. B.; Nadji, S. J. Fluorine Chem. 1990, 49, 147–150.
(10) Xu, Z.-Q.; DesMarteau, D. D. J. Chem. Soc., Perkin Trans. I 1992,
313–315.
(11) van Steenis, J. H.; van den Nieuwendijk, A. M. C. H.; van der Gen, A.
J. Fluorine Chem. 2004, 125, 107–117.
(12) Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O. Tetrahedron Lett. 1991,
32, 1175–1178.
(17) Ono, K.; Yoshida, A.; Saito, N.; Fujishima, T.; Honzawa, S.; Suhara,
Y.; Kishimoto, S.; Sugiura, T.; Waku, K.; Takayama, H.; Kittaka, A. J. Org.
Chem. 2003, 68, 7407–7415.
(18) Xu, L.; Cheng, J.; Trudell, M. L. J. Org. Chem. 2003, 68, 5388–5391.
(19) Kotoris, C. C.; Chen, M. J.; Taylor, S. D. J. Org. Chem. 1998, 63, 8052–
8057.
(13) Chevrie, D.; Lequeux, T.; Demoute, J. P.; Pazenok, S. Tetrahedron Lett.
2003, 44, 8127–8130.
(14) Ghosh, A. K.; Zajc, B. Org. Lett. 2006, 8, 1553–1556.
(15) (a) Blakemore, P. R. J. Chem. Soc., Perkin Trans. I 2002, 2563–2585.
(b) Plesniak, K.; Zarecki, A.; Wicha, J. Top. Curr. Chem. 2007, 275, 163–250.
(16) Hou, Y.; Higashiya, S.; Fuchigami, T. J. Org. Chem. 1997, 62, 9173–
9176.
(20) (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. 2004,
101, 11949–11954.
(21) Zagipa, B.; Nagura, H.; Fuchigami, T. J. Fluorine Chem. 2007, 128,
1168–1173.
(22) Olah, G. A.; Narang, S. C.; Fung, A. P.; Balaram Gupta, B. G. Synthesis
1980, 657–658.
J. Org. Chem. Vol. 73, No. 21, 2008 8207

del Solar et al.
ethyl (1,3-benzothiazol-2-ylsulfanyl)acetate 1023 (89% yield),
followed by fluorination of 10 by using LDA and NFSI in
toluene to afford 8 in 57% yield.24 Ester conversion to amide
11 with NH3 in EtOH proceeded in high 96% isolated yield.
Reaction of 11 with cyanuric chloride afforded (1,3-benzothia-
zol-2-ylsulfanyl)fluoroacetonitrile 6a and the crude reaction
mixture was subjected to oxidation with H5IO6/CrO3without
prior purification, to give the desired 4 in isolated yields ranging
from 38% to 42% (over two steps). Reversal of synthetic steps
involving initial oxidation of the amide 11 to the corresponding
sulfone was tested as well, but in this case subsequent conversion
to the cyano derivative was unsuccessful.
The reactions resulted in good to high yields of R-fluoro-
acrylonitriles. In the case of p- and o-nitrobenzaldehyde, Barbier
conditions15 were found to give higher yields of products (72%
and 60%, respectively, entries 6 and 7, Table 1, see the
Experimental Section for details).
Imidazole-4-carboxaldehyde and indole-3-carboxaldehyde
gave high yields of products only upon N-Boc protection26
(Table 1, entries 10 and 11).
In all the reactions studied, the Z-isomer predominated, and
stereoselectivity was nearly independent of the structure of the
aldehyde. For aromatic aldehydes the E/Z ratio ranged from 15/
85 to 20/80, and was independent of the electronic nature of
the substituent (entries 1-3 and 5-12). The only exception was
o-methoxybenzaldehyde (entry 4), where the E/Z ratio dropped
to 37/63. At this point, we are unable to offer any explanation
for this. We do not believe that this is due to electronic or steric
influence, since no changes in E/Z ratios were observed in the
case of p-methoxy, o-methyl, o-nitro, or o-fluoro substituents
(E/Z ratios 16:84, 17:83, 15:85, and 16:84, respectively). In the
case of R,ꢀ-unsaturated aldehyde a similar E/Z ratio of 17:83
(entry 13) was observed, whereas aliphatic aldehydes gave E/Z
ratios of 23/77 for the unbranched (entries 14 and 15) and 15/
85 for the branched aldehyde (entry 16). The effect of
temperature on E/Z ratio was tested in the condensation reactions
of 4 with 2-naphthaldehyde, 2-methoxybenzaldehyde, octanal,
3-phenylpropanal, and 2-ethylbutanal. In all cases tested,
lowering of reaction temperature to -78 °C improved the
stereoselectivity, whereas the yield remained unchanged (Table
1, entries 1, 4, 14, 15, and 16).
Scheme 3 shows the mechanism that was proposed by Julia
(for X ) H).15,27,28 Reactions can proceed via competing
pathways, leading to different stereochemical outcomes. The
initial anti and syn addition product (I1 and I2) can either
undergo retroaddition, if the BT-sulfone anion is stabilized, or
collapse to products via the spirocyclic intermediates SI1 and
SI2. Intermediate SI2 has been suggested to form faster than
SI1 due to steric reasons. Thus, if retroaddition occurs,
predominant stereoselectivity leading to cis arrangement of R1
and R (Scheme 3) can be expected. An additional pathway
involving stabilized zwitterionic intermediates Z1 and Z2 has
been proposed for aryl and vinyl aldehydes.15,27,28 In these cases
formation of alkenes with a trans arrangement of R and R1
through Z2 is favored. This is in fact the case with Julia reactions
of aryl and vinyl aldehydes leading to the unfluorinated
acrylates.23 On the other hand, in our prior work on fluorinated
acrylates a predominant cis arrangement of R and R1 was
observed.7j This led us to suggest that in the case of fluorinated
sulfones, reaction involving zwitterionic intermediates Z1 and
Z2 is disfavored due to the destabilizing effect a ꢀ-fluorine
substituent has on carbocation stability.
With the desired (1,3-benzothiazol-2-ylsulfonyl)fluoroaceto-
nitrile 4 in hand, condensations with carbonyl compounds were
undertaken. Initially, DBU mediated condensation of 4 with
2-naphthaldehyde under Barbier conditions15 was performed.
Although R-fluoro acrylonitrile was formed, the isolated yield
of the product was only 32%. Even lower product formation
was observed in the condensation of 4 and 2-naphthaldehyde
in the presence of LHMDS at -78 °C and under Barbier
conditions25 and no product was observed when NaHMDS was
used as base.25 A much higher 98% yield of the product was
obtained upon a slow, dropwise addition of 4 to the solution of
DBU and aldehyde (Table 1, entry 1). In a typical procedure,
aldehyde (1 molar equiv) and DBU (4 molar equiv) were
dissolved in CH2Cl2 (5 mL/mmol of aldehyde) and under stirring
at room temperature, a solution of 4 (2 molar equiv) in CH2Cl2
(7.5 mL/mmol of 4) was slowly added dropwise to the reaction
mixture. This resulted in the change of color from clear to black
brown. The conversions were checked by TLC after 1 h and if
the aldehyde was still present, 1 molar equiv of sulfone in
CH2Cl2 was added and the reaction was allowed to proceed for
another 0.5 h, checked by TLC, and if starting aldehyde was
not consumed, DBU (2 molar equiv) in CH2Cl2 was added
(Table 1, entries 3 and 4). Upon disappearance of the aldehyde
(15-150 min) the crude reaction mixtures were analyzed by
19F NMR for E/Z ratios of products, partially concentrated, then
directly loaded on a dry silica gel column and the products were
eluted (for purification of 21, see the Experimental Section).
Although E/Z isomers were not separated, we wanted to assess
the ease of separation by tlc. For this purpose, tlc analysis
was conducted for several product mixtures. In all cases tested
the separation of isomers was easily achieved (please see
the Supporting Information for details). The yields obtained
in the condensation reactions with a series of aldehydes and
the E/Z ratios are displayed in Table 1. Wherever applicable,
comparison to literature data is included.
(23) Blakemore, P. R.; Ho, D. K. H.; Nap, W. M. Org. Biomol. Chem. 2005,
3, 1365–1368.
(24) We have previously reported fluorination of ethyl (1,3-benzothiazol-2-
ylsulfonyl)acetate using NaH/Selectfluor, which yielded the fluoro derivative in
71% yield.7j In the present case, due to the lower acidity of sulfanyl analogue
10, stronger base LDA in combination with NFSI was chosen. Indeed, as
anticipated fluorination of 10 using NaH/Selectfluor under conditions described
for the fluorination of sulfonyl acetate derivative7j resulted in a complex reaction
mixture. Proton NMR showed 39:61 percent ratio of monofluoro derivative 8
and starting sulfide 10, whereas 19F NMR showed 74:26 percent ratio of 8 and
difluoro derivative, along with unidentified fluorinated byproduct. Chromato-
graphic separation afforded 8 in 14% isolated yield.
(25) LHMDS (2.4 molar equiv) mediated condensation of 4 (2.4 molar equiv)
and 2-naphthaldehyde (1.0 molar equiv) was performed under Barbier conditions
in THF at-78 °C under N2. After stirring at-78 °C for 3 h and at room
temperature for 1 h followed by the usual workup, 1H NMR showed a 1:3 ratio
of product 12 (24% isolated yield) and 2-naphthaldehyde, whereas the percent
E/Z ratio of 12 was 30:70, as assessed by 19F NMR. Similar reaction with
NaHMDS as base gave no product 12, although sulfone 4 was consumed.
In connection to our previous work on the fluoro-Julia
olefination, we were interested in comparing the stereochemistry
obtained in DBU mediated olefinations leading to R-fluoro
acrylates7j and to phenyl R-fluorovinyl sulfones8i to those
observed in the present synthesis of R-fluoro acrylonitriles.
Interestingly, alkenes with the cis disposition of R (from RCHO)
(26) (a) Kimura, R.; Nagano, T.; Kinoshita, H. Bull. Chem. Soc. Jpn. 2002,
75, 2517–2525. (b) Wasser, J.; Gaspar, B.; Nambu, H.; Carreira, E. M. J. Am.
Chem. Soc. 2006, 128, 11693–11712.
(27) Baudin, J. B.; Hareau, G.; Julia, S. A.; Lorne, R.; Ruel, O. Bull. Soc.
Chim. Fr. 1993, 130, 856–878.
(28) Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O. Bull. Soc. Chim. Fr.
1993, 130, 336–357.
8208 J. Org. Chem. Vol. 73, No. 21, 2008

Mild, High-Yielding Route to R-Fluoro Acrylonitriles
TABLE 1. Efficient, Mild Route to r-Fluoro Acrylonitriles
a Yields of isolated, purified products (reactions were performed under similar conditions but were not optimized for individual cases). b Relative ratio
of diastereomers in the crude reaction mixture determined by 19F NMR prior to isolation. No change in ratio was observed after purification.
c Referenced to CFCl3 as internal standard. d Where applicable, literature data and references are included for comparison. e Since no literature data for
n-octanal are available, data for n-heptanal are included for comparison.
J. Org. Chem. Vol. 73, No. 21, 2008 8209

del Solar et al.
SCHEME 3. Fluoro-Julia Olefination Stereoselectivities
(39 mL) was allowed to vigorously stir for 30 min at rt. CrO3 (4.9
mg, 0.05 mmol, 0.02 molar equiv) was added, and the stirring was
continued for another 5 min. A solution of 1,3-benzothiazol-2-
ylsulfanyl)acetonitrile (2a, 500 mg, 2.43 mmol, 1 molar equiv) in
CH3CN (5 mL) was slowly added dropwise and formation of
precipitate was observed. After being stirred at rt for 1 h, the
reaction mixture was filtered, and the solid was washed with
CH3CN. The filtrate was concentrated under reduced pressure,
EtOAc was added to the residue, and the organic layer was washed
with water 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 on silica
gel with CH2Cl2 as eluting solvent to yield 3 as a white solid (523
mg, 91% yield). Mp (recrystallized from 50% EtOAc in hexanes)
173-174 °C. 1H NMR (500 MHz) δ 8.27 (d, 1H, Ar-H, J ) 7.9
Hz), 8.07 (d, 1H, Ar-H, J ) 7.6 Hz), 7.69 (m, 2H, Ar-H, J )
7.6 Hz), 4.56 (s, 2H, CH2CN). HRMS (positive ion ESI) calcd for
C9H6N2O2S2Na+ (M+ + Na) 260.976290, found 260.976192.
Ethyl (1,3-Benzothiazol-2-ylsulfanyl)fluoroacetate (8) via Fluo-
rination of Ethyl (1,3-Benzothiazol-2-ylsulfanyl)acetate (10). A
stirred solution of ethyl (1,3-benzothiazol-2-ylsulfanyl)acetate (10,
200 mg, 0.791 mmol, 1 molar equiv) in 1.3 mL of dry toluene was
cooled to -80 °C (dry ice/i-PrOH) under nitrogen. LDA (0.455
mL, 0.909 mmol, 1.15 molar equiv of a 2 M solution in heptane/
THF/EtPh) was added to the reaction mixture and the stirring was
continued at -80 °C. After 1.5 h solid NFSI (312 mg, 0.988 mmol,
1.25 molar equiv) was added, then the reaction mixture was allowed
to stir at -80 °C for another 1 h and then warmed to room
temperature over 1 h. Saturated aq NH4Cl was added to the mixture
and the layers were separated. The aqueous layer was extracted
with EtOAc (3×), 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 mixture was purified by column chromatography
on silica gel with CH2Cl2 to yield 8 as a clear thick pale-yellow
liquid (123 mg, 57%). 1H NMR (500 MHz) δ 7.99 (d, 1H, Ar-H,
J ) 7.9 Hz), 7.83 (d, 1H, Ar-H, J ) 7.9 Hz), 7.49 (t, 1H, Ar-H,
J ) 7.6 Hz), 7.39 (t, 1H, Ar-H, J ) 7.6 Hz), 6.94 (d, 1H, CHF,
2JFH ) 51.0 Hz), 4.34 (q, 2H, OCH2, J ) 7.1 Hz), 1.33 (t, 3H,
CH3, J ) 7.1 Hz). 19F NMR (282 MHz) δ -161.7 (d, 2JFH ) 47.0
Hz). HRMS (positive ion ESI) calcd for C11H10FNO2S2Na+ (M+
+ Na) 294.002919, found 294.002247.
and COOR2 or SO2Ph moiety were the major products in the
synthesis of acrylates7j and phenyl sulfones.8i On the other hand,
an opposite stereochemical outcome was observed in the present
case. Assuming the lesser probability of Z1 and Z2 in fluoro-
Julia olefinations,7j due to lower stability of ꢀ-fluorocarboca-
tions, the plausible reasons for the present outcome could be as
follows. In the event that the initial addition products I1 and I2
do not equilibrate, that is addition/retroaddition of the initially
formed ꢀ-alkoxy sulfone anion does not occur, then the
E/Zproduct ratio reflects the initial ratio of I1/I2. Alterna-
tively, if equilibration of I1 and I2 does occur, then collapse
of adduct I1 through SI1 may not be unfavorable, due to a
small steric effect of the cyano functionality. Supportive of
the latter, the selectivity in the condensation of the branched
aldehyde 2-ethylbutanal (Table 1, entry 16) increased from
15:85 (E/Z) at rt to 8:92 (E/Z) at -78 °C. This may imply a
lower energy barrier to Smiles rearrangement for adduct I1
as compared to I2.
For synthesis of 8 from 7, please see the Supporting Information.
(1,3-Benzothiazol-2-ylsulfanyl)fluoroacetamide (11). Into a
solution of ethyl (1,3-benzothiazol-2-ylsulfanyl)fluoroacetate 8
prepared from 7 (3.88 g, 14.3 mmol) in ethanol (50 mL) at room
temperature was bubbled a gentle stream of NH3 gas until
disappearance of the starting material was observed by TLC (SiO2,
50% EtOAc in hexanes), and after 1 h the solvent was evaporated
under reduced pressure. The product was dried overnight under
vacuum to yield 3.33 g (96%) of 11 as a white solid that did not
require any further purification. Mp (recrystallized from 50% EtOAc
1
in hexanes) 134-135 °C. H NMR (500 MHz) δ 7.98 (d, 1H,
Ar-H, J ) 8.2 Hz), 7.82 (d, 1H, Ar-H, J ) 7.9 Hz), 7.47 (t, 1H,
Ar-H, J ) 7.9 Hz), 7.39 (t, 1H, Ar-H, J ) 7.9 Hz), 7.01 (d, 1H,
CHF, 2JFH ) 51.9 Hz), 6.53 (br s, 1H, NH2), 5.84 (br s, 1H, NH2).
Conclusions
In conclusion, we have developed the synthesis of (1,3-
benzothiazol-2-ylsulfonyl)fluoroacetonitrile, a stable, isolable
reagent for the preparation of R-fluoro acrylonitriles via a
modified Julia olefination. The reagent undergoes reactions with
aldehydes under mild, DBU mediated conditions to give
R-fluoro acrylonitriles in good yields and with predominant
Z-stereoselectivity. The structure of the aldehyde generally does
not influence the stereochemical outcome of the olefination.
2
19F NMR (282 MHz) δ -158.4 (d, JFH ) 52.8 Hz). HRMS
(positive ion ESI) calcd for C9H7FN2OS2Na+ (M+ + Na) 264.987604,
found 264.987469.
(1,3-Benzothiazol-2-ylsulfonyl)fluoroacetonitrile (4). Step 1.
To a stirred solution of cyanuric chloride (3.89 g, 21.1 mmol, 1.7
molar equiv) in DMF (57 mL) was added (1,3-benzothiazol-2-
ylsulfanyl)fluoroacetamide (11, 3.00 g, 12.4 mmol, 1 molar equiv)
at rt. The stirring was continued at rt for 1.5 h, until TLC (SiO2,
50% EtOAc in hexanes) showed disappearance of starting material.
The reaction mixture was diluted with water and extracted with
EtOAc (3×). The combined organic layer was thoroughly washed
with water and brine and dried over anhydrous Na2SO4, then the
solvent was evaporated under reduced pressure to yield 2.49 g of
Experimental Section
(1,3-Benzothiazol-2-ylsulfonyl)acetonitrile (3). A solution of
periodic acid (H5IO6, 2.21 g, 9.71 mmol, 4.0 molar equiv) in CH3CN
8210 J. Org. Chem. Vol. 73, No. 21, 2008

Mild, High-Yielding Route to R-Fluoro Acrylonitriles
the crude product 6a (see the Supporting Information for analytical
data on a purified sample), which was subjected to oxidation without
further purification.
4 molar equiv) in freshly distilled CH2Cl2 (5.1 mL) at rt. Upon
addition of 4, the reaction mixture turned black brown. The stirring
was continued at rt until complete consumption of the aldehyde
was observed (1.5 h) by TLC (SiO2, 50% EtOAc in hexanes). The
solvent was concentrated under reduced pressure to about 2-3 mL
and the reaction mixture was loaded onto a dry silica gel column
(200-300 mesh) and the E/Z product mixture was eluted with 50%
EtOAc in hexanes. The solvent was evaporated and the E/Z ratio
was determined by 19F NMR (18/82, Table 1, entry 15, the E/Z
ratio does not change upon purification). Since the E/Z product
mixture was contaminated with 1,3-benzothiazol-2-ol byproduct,
the mixture was dissolved in CH2Cl2 (30 mL), aqueous NaOH was
added (0.5 M NaOH, 6 mL), and the mixture was stirred at rt for
10 min, then the organic layer was separated, washed with water
and brine, and dried over anhydrous Na2SO4. Upon removal of
solvent under reduced pressure, 143 mg (59%) of 21 was isolated
Step 2. A solution of periodic acid (H5IO6, 10.1 g, 44.5 mmol,
4.0 molar equiv) in CH3CN (100 mL) was allowed to vigorously
stir for 30 min at rt, CrO3 (22.3 mg, 0.222 mmol, 0.02 molar equiv)
was added, and the stirring was continued for another 5 min. A
solution of 1,3-benzothiazol-2-ylsulfanyl)fluoroacetonitrile (2.49 g,
11.1 mmol, 1 molar equiv, crude reaction mixture from step 1) in
CH3CN (20 mL) was slowly added dropwise and formation of
precipitate was observed. After being stirred at rt for 1 h, the
reaction mixture was filtered and concentrated under reduced
pressure. EtOAc was added to the residue and the mixture was
washed with water 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 chromatog-
raphy on silica gel with CH2Cl2 as eluting solvent to yield 4 as an
off-white solid (1.21 g, 38% yield over two steps). Mp (recrystal-
1
as an off-white solid. H NMR (500 MHz, CDCl3) δ 8.12 (s, 1H,
Ar-H, E-isomer), 8.09 (s, 1H, Ar-H, Z-isomer), 7.75 (s, 1H,
1
lized from 50% EtOAc in hexanes) 149-150 °C. H NMR (500
Ar-H, Z-isomer), 7.71 (s, 1H, Ar-H, E-isomer), 6.94 (d, 1H, 2JFH
2
MHz) δ 8.33 (d, 1H, Ar-H, J ) 7.9 Hz), 8.09 (d, 1H, Ar-H, J )
) 14.6 Hz, E-isomer), 6.63 (d, 1H, JFH ) 34.5 Hz, Z-isomer),
7.6 Hz), 7.73 (m, 2H, Ar-H), 6.24 (d, 1H, CHF, 2JFH ) 46.7 Hz).
1.64 (s, 9H, t-Bu, Z-isomer), 1.635 (s, 9H, t-Bu, E-isomer). 19F
NMR (282 MHz, CDCl3) δ -117.9 (d, 3JFH ) 33.6 Hz, Z isomer),
2
19F NMR (282 MHz) δ -179.4 (d, JFH ) 47.0 Hz). HRMS
(positive ion ESI) calcd for C9H5FN2O2S2Na+ (M+ + Na)
278.966868, found 278.966867.
-125.3 (d, JFH ) 15.3 Hz, E isomer). HRMS (positive ion ESI)
3
calcd for C11H12FN3O2Na+ (M+ + Na) 260.080576, found
260.080458.
Subsequent repetition of the two-step procedure with 5.00 g of
11 resulted in a 42% yield of 4.
General Procedure for Synthesis of 12, 15, 25, 26, and 27
via Condensation of Aldehydes with Fluorinated Sulfone 4 at
-78 °C. A solution of 4 (2 molar equiv) in CH2Cl2 (7.5 mL/mmol
of 4) was added slowly, dropwise to a stirring solution of aldehyde
(1 molar equiv) and DBU (4 molar equiv) in freshly distilled CH2Cl2
(5 mL/mmol of aldehyde) that was cooled to -78 °C under N2.
Upon addition of 4, the reaction mixture turned black brown. The
reaction mixture was stirred at -78 °C for 1 h and then allowed to
warm to rt. In all cases studied, TLC showed complete conversions.
Analysis of reaction mixtures by 19F NMR and isolation of E/Z
product mixtures was performed as described for the rt condensations.
General Procedure for the Synthesis of 17 and 18 via
Condensation of Aldehydes with Fluorinated Sulfone 4. In the
case of p-nitrobenzaldehyde and o-nitrobenzaldehyde, the conden-
sations were performed under Barbier conditions as follows:
aldehyde (1 molar equiv) and 4 (2 molar equiv) were dissolved in
CH2Cl2 (19 mL/mmol of aldehyde), and under stirring at rt, DBU
(4 molar equiv) in CH2Cl2 (1 mL/mmol of DBU) was slowly added
dropwise to the reaction mixture. Upon addition of DBU, the
reaction mixture turned black brown. The reaction was monitored
by TLC and upon consumption of the aldehyde, the E/Z ratio was
determined by 19F NMR. The reaction mixture was concentrated
to about 2 mL in vacuo and directly loaded onto a dry silica gel
column (200-300 mesh). The E/Z product mixture was eluted with
CH2Cl2 and the solvent was evaporated.
(1,3-Benzothiazol-2-ylsulfonyl)fluoroacetonitrile (4) via Fluo-
rination of (1,3-Benzothiazol-2-ylsulfonyl)acetonitrile (3). A
suspension of NaH (49.9 mg, 2.08 mmol, 1.1 molar equiv) in dry
THF (6 mL) was cooled to 0 °C under nitrogen and a solution of
(1,3-benzothiazol-2-ylsulfonyl)acetonitrile (3, 450 mg, 1.89 mmol,
1 molar equiv) in dry THF (6.5 mL) was added dropwise with
stirring. After the addition, the reaction mixture was allowed to
warm to rt and left to stir for 45 min. The mixture was then cooled
to 0 °C, Selectfluor (804 mg, 2.27 mmol, 1.2 molar equiv) was
added, the cooling bath was removed, and the reaction mixture was
allowed to stir at rt for 1.5 h, and then quenched with aqueous
NH4Cl solution. The aqueous layer was extracted with EtOAc (3×),
the combined organic layers were washed with aqueous NaHCO3,
water, and brine and dried over Na2SO4, then the solvent was
evaporated. Separation of the crude reaction mixture by column
chromatography on silica gel with CH2Cl2 as eluting solvent
afforded 4 as an off-white solid (155 mg, 32% yield).
General Procedure for the Synthesis of 12-16, 19-20,
and 22-27 via Condensation of Aldehydes with Fluorinated
Sulfone 4 at Room Temperature. A solution of 4 (2 molar equiv)
in CH2Cl2 (7.5 mL/mmol of 4) was added slowly, dropwise to a
stirring solution of aldehyde (1 molar equiv) and DBU (4 molar
equiv) in freshly distilled CH2Cl2 (5 mL/mmol of aldehyde) at rt.
Upon addition of 4, the reaction mixture turned black brown. The
conversions were checked by TLC after 1 h and if the aldehyde
was still present, a solution of 1 molar equiv of sulfone in CH2Cl2
(7.5 mL/mmol of 4) was added dropwise and the reaction was
allowed to proceed for another 0.5 h, checked by TLC, and if
starting aldehyde was still not consumed, DBU (2 molar equiv) in
CH2Cl2 (1 mL/mmol of DBU) was added. The stirring was
continued at rt until complete consumption of the aldehyde was
observed by TLC (SiO2, CH2Cl2), usually 15-150 min. The E/Z
ratio was determined by 19F NMR of an aliquot; the reaction mixture
was concentrated to about 2 mL and directly loaded onto a dry
silica gel column (200-300 mesh). The E/Z product mixture was
obtained by elution with CH2Cl2 and the solvent was evaporated
(except in the case of 21, please see the detailed experimental
procedure below).
Acknowledgment. This work was supported by NSF Grant
CHE-0516557, infrastructural support and support for AKG
were provided by NIH RCMI Grant 5G12 RR03060. Support
of M.d.S through the NIH-RISE program is gratefully acknowl-
edged. Acquisition of a mass spectrometer was funded by NSF
Grant CHE-0520963. We thank Dr. Andrew Poss (Honeywell)
for a sample of NFSI and Dr. G. Sankar Lal (Air Products) for
a sample of Selectfluor.
Supporting Information Available: Experimental details for
synthesis of 2a, 8 from 7, 6b, analytical data of pure 6a, details
of TLC separation of some E/Z isomer mixtures, HRMS and
19F NMR data and 1H NMR spectra of 2a, 3, 4, 6a, 6b, 8, and
11-27 and 13C NMR spectrum of 4. This material is available
free of charge via the Internet at http://pubs.acs.org.
Synthesis of 21 via Condensation of 4 with 1-Boc-imidazole-
4-carboxaldehyde. A solution of 4 (522 mg, 2.04 mmol, 2 molar
equiv) in CH2Cl2 (15 mL) was added slowly, dropwise (for about
10 min) to a stirring solution of 1-Boc-imidazole-4-carboxaldehyde
(200 mg, 1.01 mmol, 1 molar equiv) and DBU (618 mg, 4.06 mmol,
JO801235X
J. Org. Chem. Vol. 73, No. 21, 2008 8211