Toward the synthesis of benzothiazolyl fluoroaminosulfones

Article abstract of DOI:10.1021/jo901540c

(Chemical Equation Presented) Due to the importance of allylamines in organic synthesis, the synthesis of reagents as potent precursors of aminofluoroolefins is reported from functionalized benzothiazolylsulfones. The key intermediate, a fluorovinyl sulfo

Full text of DOI:10.1021/jo901540c

pubs.acs.org/joc
Toward the Synthesis of Benzothiazolyl Fluoroaminosulfones
ꢀ
Charlene Calata, Emmanuel Pfund, and Thierry Lequeux*
ꢁ ꢁ
Laboratoire de Chimie Moleculaire et Thioorganique, UMR CNRS 6507 & FR3038, ENSICAEN Universite
ꢁ
de Caen Basse-Normandie, 6 Bd du Marechal Juin 14050 Caen Cedex, France
thierry.lequeux@ensicaen.fr
Received July 17, 2009
Due to the importance of allylamines in organic synthesis, the synthesis of reagents as potent
precursors of aminofluoroolefins is reported from functionalized benzothiazolylsulfones. The key
intermediate, a fluorovinyl sulfone, was prepared and functionalized by addition of aliphatic,
aromatic amines and amino acid alkyl esters through an aza-Michael addition reaction.
KEYWORDS:
Introduction
of R-fluoro-R,β-unsaturated esters I. In general, this latter
was prepared from II and carbonyl compounds through
Horner-Wadsworth-Emmons, modified Julia, or Peterson
reactions (Figure 1).4
It is known that peptides are not suitable as therapeutic
agents due to their in vivo degradation by peptidases. Thus,
synthetic peptidomimetics, stable toward enzymatic clea-
vage, were developed as potential drug substances.1 Among
the large variety of peptidomimetics, it was shown that the
replacement of a specific amide bond by a fluorinated
carbon-carbon double bond acted as a surrogate of a
natural peptide.2 Recent examples include the preparation
of peptide nucleic acid (PNA) analogues and dipeptidyl
peptidase IV inhibitors, which exhibit high affinity toward
receptors of the original peptides.3 Most synthetic routes to
prepare fluorinated peptidomimetics involved the use of
allylamine III obtained after further chemical modifications
However, these approaches with II were limited by the
chemical tolerance of the other functions toward reductive,
oxidizing, and cross-coupling reagents. To circumvent these
limitations, we decided to prepare functionalized heteroaro-
matic fluoroalkylsulfones such as IV (Y = SO2Ar) as poten-
tial reagents for the synthesis of fluoroallylic amines III.
As the HWE reaction cannot be applied to the synthesis of
fluoroalkylidene derivatives from fluoroalkylphosphonate
such as IV (Y = P(O)(OEt)2),5 we previously developed an
alternative one-step synthesis from heteroaromatic fluor-
oalkylsulfones 1 (Figure 2, R = alkyl) and carbonyl com-
pounds based on the modified Julia reaction.6 Except for this
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DOI: 10.1021/jo901540c
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Published on Web 11/18/2009
J. Org. Chem. 2009, 74, 9399–9405 9399
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Calata et al.
JOCArticle
FIGURE 2. Benzothiazolylsulfones as reagents for the modified
Julia reaction.
It was converted into its corresponding mesylate and then
treated with an excess of triethylamine (2.5 equiv) at 0 °C to
afford the expected R-fluorovinylsulfone 8 in 92% yield
(Scheme 2).11 An alternative synthesis, realized from the
fluorinated phosphonosulfone 9 and paraformaldehyde
through a HWE reaction,12 proceeded in 77% yield.
FIGURE 1. Fluoroolefins as peptidomimetics.
example, until now only fluorinated benzothiazolyl, tetra-
zolyl, and bis-trifluoromethylphenyl sulfones bearing elec-
tron-withdrawing or aromatic groups have been known.7 In
continuation of our efforts regarding the synthesis of pepti-
domimetics, the present work focuses on the synthesis of
benzothiazolyl aminosulfones IV as potential reagents for
the preparation of functionalized fluoroalkylidenes through
the modified Julia reaction (Figure 2).
To access to a variety of targeted aminosulfones IV, the
introduction of functional groups onto 8 was studied. Sev-
eral methods are reported in the literature to introduce a
heteroalkyl function or an alkyl group to electron deficient
vinylic compounds.13 The Michael addition constitutes a
very useful synthetic method for construction of C-N,14
C-S,15 or C-C bonds.16 To prepare fluoroaminosulfone
derivatives IV, the aza-Michael addition of aliphatic and
aromatic amines onto vinylsulfone 8 was studied first
(Scheme 3). Conjugated addition of primary and secondary
aliphatic amines (1.3 equiv) onto 8 proceeded smoothly at
room temperature (Table 1). The reaction reached comple-
tion after 5 min under stirring at 20 °C. Expected aminosul-
fones 10a-g were isolated in good yield after purification by
flash chromatography. The addition reaction worked as well
from primary and secondary amines, except from propyl-
amineand allylamine, for which no additionof theamine onto
the ipso position of the benzothiazolyl ring was observed. In
these last two cases, despite a high conversion of 8, the
corresponding aminosulfones 10h,i were not isolated, due
to difficulties occurring during their purification by flash
chromatography.
Results and Discussion
Initially, preparation of amine IV was attempted from
sulfone 2.8 The electrophilic fluorination of the carbanion of
2 (NaHMDS) appeared difficult to control. Several attempts
realized at -78 °C or from -78 to 0 °C with electrophilic
reagents (1.2 equiv of (PhSO2)2NF or Selectfluor) were
unsuccessful. In most cases, a mixture of mono-, difluori-
nated products and unidentified byproduct were obtained.
Having in hand a straightforward method to prepare fluori-
nated benzothiazolyl sulfide 3 by alkylation of 2-mercapto-
benzothiazole with ethyl bromofluoroacetate,9 its chemical
modification was preferred in order to access to compound
IV. Sulfide 3 was treated with NaBH4 at 0 °C in EtOH to
afford the corresponding alcohol 4 in 75% yield,10 which
after oxidation (m-CPBA) led to hydroxysulfone 5 in good
yield (Scheme 1). Alcohols 4 and 5 were found to be sensitive,
and partial degradation occurred when 4 was submitted to
Mitsunobu conditions (PhCO2H, PPh3, DIAD) or when
sulfone 5 was reacted with Ac2O or MsCl in the presence
of amine. In these two cases, the elimination product 8 was
mainly formed. In contrast, it was possible to prepare acetate
6 in 81% yield from sulfide 4. After oxidation (m-CPBA)
pure sulfone 7 was obtained (Scheme 1). However, com-
pound 7 appeared to be unstable after several days of storage
at 20 °C, and traces of elimination product 8 were detected.
As nucleophilic substitution reactions from 4 or 5 were
limited, synthesis of aminosulfones IV was explored by
conjugated addition reactions onto the Michael acceptor 8.
Preparation of vinylsulfone 8 was optimized from sulfone 5.
However, from aromatic amines, such as aniline, no trace
of adduct was observed under these experimental conditions,
and an overnight stirring under refluxing CH2Cl2 was needed
to drive the reaction to completion. Corresponding sulfone
10j was isolated in quite low yield (29%), probably due to the
(11) (a) Esteves, A.; Silva, M. E.; Rodrigues, L. M.; Oliveira-Campos,
A. M. F.; Hrdina, R. Tetrahedron Lett. 2007, 48, 9040–9043. (b) Galli, U.;
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2008, 73, 8206–8211. (d) He, M.; Ghosh, A. K.; Zajc, B. Synlett 2008, 999–
1004. (e) Ghosh, A. K.; Banerjee, S.; Sinha, S.; Kang, S. B.; Zajc, B. J. Org.
Chem. 2009, 74, 3689–3697. (f) Calata, C.; Catel, J. M.; Pfund, E.; Lequeux,
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2-hydroxybenzothiazole exclusively even when the reaction was conducted
at -78 °C.
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SCHEME 1. Preparation of Fluorohydroxyethyl Sulfone Derivatives
SCHEME 2. Preparation of Fluorovinylsulfone by Elimination
or HWE Reactions
TABLE 1. Synthesis of Aminosulfones 10a-j
SCHEME 3. Aza-Michael Addition onto Vinylsulfone 8
weak nucleophilic character of the amine. Other reported
experimental conditions involving metal catalyst or ionic
liquid,17 Yt(NO3)3 6H2O,18 β-cyclodextrin,19 DBU,20 silica
3
gel,21 CAN,22 or aqueous solvent23 were tested but unsuc-
cessful. Under these conditions, no addition product was
detected, and the starting material was recovered.
To access to the potent precursor of conformationally
constrained peptidomimetic and N-terminal peptide iso-
steres, the N-alkylation of heterocycles was then tested
(Scheme 4). No product was observed at room temperature
from pyrrole, pyrazole, and benzimidazole, even in the
presence of additives such as silica gel,21 TBAF,24 DBU,20
TMSCl/PPh3,15a and CAN.22 In contrast, alkylation of
imidazole proceeded after 16 h under stirring at 20 °C. The
addition was slow but realized under milder conditions than
(17) Yang, L.; Xu, L.-W.; Zhou, W.; Li, L.; Xia, C.-G. Tetrahedron Lett.
2006, 47, 7723–7726.
(18) Bhanushali, M. J.; Nandukar, N. S.; Jagtap, S. R.; Bhanage, B. M.
Catal. Commun. 2008, 9, 1189–1195.
(19) Surendra, K.; Krishnaveni, S.; Sridhar, R.; Rao, K. R. Tetrahedron
Lett. 2006, 47, 2125–2127.
(20) Yeom, C. E.; Kim, M. J.; Kim, B. M. Tetrahedron 2007, 63, 904–909.
(21) You, L.; Feng, S.; Wang, X.; Bai, D. Tetrahedron Lett. 2008, 49,
5147–5149.
(22) Duan, Z.; Xuan, X.; Li, T.; Yang, C.; Wu, Y. Tetrahedron Lett. 2006,
47, 5433–5436.
(23) Ziyaei-Halimehjani, A.; Saidi, M. R. Tetrahedron Lett. 2008, 49,
1244–1248.
(24) Sharma, G. V. M.; Reddy, V. G.; Chander, A. S.; Reddy, K. R.
Tetrahedron: Asymmetry 2002, 13, 21–24.
aIsolated yield after 5 min at 20 °C. bConversion of 8 determined by
19F NMR analysis of the crude mixture is shown in parentheses.
cIsolated yield after 18 h under refluxed solvent.
those reported from enones as Michael’s acceptors.25 Corres-
ponding imidazolosulfone 11 was isolated in 76% yield. In
the presence of TBAF (1 equiv), the reaction reached com-
pletion after 1 h at 20 °C, but the isolated yield was much
(25) (a) Liu, B. K.; Wu, Q.; Lu, D. S.; Lin, X. F. Synthesis 2007, 2653–
2659. (b) Uddin, M. I.; Nakano, K.; Ichikawa, Y.; Kotsuki, H. Synlett 2008,
1402–1406.
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SCHEME 4. Conjugated Addition of Imidazole and Phthalimide
SCHEME 5. Aza-Michael Addition of Amino Acid Alkyl Es-
ters HCl
TABLE 2. Aza-Michael Reaction with Amino Acid Alkyl Esters HCl
3
3
lower (<55%). However, the conjugated addition of phtha-
limide was efficient in these conditions, and corresponding
phthalimidosulfone 12 was isolated in 61% yield (Scheme 4).
Conjugated addition of amino acid alkyl esters was
attempted from vinylsulfone 8. Three esters of amino acids
under their hydrochloride form (glycine, L-proline ethyl
esters, and L-aspartate di-tert-butyl ester) were tested. The
addition reaction performed in the presence of triethylamine
(1.5-3 equiv) at room temperature in dichloromethane was
slow and did not reach completion after 48 h. In refluxed
solvent no trace of starting sulfone 8 was detected after 10 h,
and the corresponding fluorinated aminoesters 13 were
isolated in modest yields (33-46%) (Scheme 5).
In the presence of silica and an excess of triethylamine (3
equiv) the reaction reached completion after 4-6 h when
performed in refluxing acetonitrile.26 Corresponding sulfone
derivatives 13a-f were isolated in 66-90% yields by filtra-
tion of the crude product on a short silica pad (Table 2).
From L-valine, L-phenylalanine, L-proline, L-aspartine, L,D-
methionine, and glycine alkyl esters hydrochloride the pro-
ducts were isolated in good yields. However, from β-amino
acid alkyl ester, such as ethyl β-alanine, aminosulfone was
obtained in low yield (<20%) despite a total conversion of 8
(19F NMR).
The last approach investigated to cover the field in the
synthesis of functionalized fluorosulfones from 8 was the
introduction of an alkyl chain. The most used approaches to
functionalized Michael’s acceptor are based on the free
radical conjugated addition performed from alkyl halides
in the presence of indium in protic solvent27 or complex
formed in situ from Zn and CuI.16 In the first attempts, the
free radical addition was explored from alkyl iodide in the
presence of free radical initiators (Na2S2O4, BEt3, or lauroyl
peroxide). In these cases no addition product was observed
and the degradation of the starting sulfone 8 occurred.
aReagents and conditions: amino acid (1 equiv), silica, NEt3 (3 equiv),
CH3CN, 4-6 h, 70 °C. bIsolated yields. cRatio determined by 19F NMR
analysis of the crude product.
Conjugated addition reactions of a carbanion were at-
tempted from organocuprate, -lithium, -magnesium, and -
indium.28 From these anion sources the ipso substitution
reaction was mainly observed. In contrast, the in situ Zn/CuI
(26) Bigotti, S.; Meille, S. V.; Volonterio, A.; Zanda, M. J. Fluorine Chem.
2008, 129, 767–774.
(27) (a) Lu, W.; Chan, T. H. J. Org. Chem. 2001, 66, 3467–3473.
(b) Miyabe, H.; Ueda, M.; Nishimura, A.; Naito, T. Tetrahedron 2004, 60,
4227–4235. (c) Jang, D. O.; Cho, D. H.; Chung, C.-M. Synlett 2001, 1923–
1924. (d) Jang, D. O.; Cho, D. H. Synlett 2002, 1523–1525. (e) Miyabe, H.;
Ueda, M.; Nishimura, A.; Naito, T. Org. Lett. 2002, 4, 131–134. (f) Cho,
D. H.; Jang, D. O. Tetrahedron Lett. 2005, 46, 1799–1802.
(28) (a) Bos, P. H.; Minnaard, A. J.; Feringa, B. L. Org. Lett. 2008, 4219–
4222. (b) Desrosiers, J. N.; Bechara, W. S.; Charette, A. B. Org. Lett. 2008,
10, 2315–2318.
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SCHEME 6. Synthesis of Fluoroalkylsulfone
TABLE 3. Preparation of Fluoroalkylsulfones from Alkyl Iodides
SCHEME 7. Synthesis of a Fluoroallylamine from 10e
preliminary result validates the synthetic potential of func-
tionalized fluorosulfones as fluoroallylamine precursors.
Further works are now in progress to cover the limits and
the scope of these sulfones in the Julia-Kocienski reaction to
open a direct route for the synthesis of functionalized
fluoroalkylidene derivatives.
Conclusions
In conclusion, we reported the synthesis of unknown
fluorovinylsulfone bearing a benzothiazolyl group prepared
by elimination or HWE reactions. This vinylsulfone was
involved in aza-Michael reaction allowing the preparation of
aminosulfone and amino acid derivatives. The introduction
of a heterocycle was realized in good yield, but this addition
was limited to imidazole and phthalimide. In addition, alkyl
chains were added by using bimetallic complex and alkyl
iodides. This large variety of new benzothiazolyl sulfones
could open a new route for the preparation of fluoroolefins
bearing a functionalized alkyl chain and in particular for the
synthesis of allylamines, as exemplified by a preliminary
result. Their synthetic potentials as building blocks for the
study of the olefination of carbonyl compounds through the
Julia-Kocienski reaction are underway, and results will be
reported in due course.
aReagents and conditions: alkyl iodide (1 equiv), Zn (2 equiv), CuI
(0.5 equiv), DMSO/formamide (2:1), 100 °C, 3 h. bIsolated yield.
complex formation gave us better results and partial conver-
sion of 8 was observed at room temperature,16a without
formation of ipso substitution product. By heating the
mixture in formamide at 100 °C over 3 h, the expected
product 14a, and 15 issued from the conjugate addition of
the solvent onto the vinylsulfone 8, were formed (Scheme 6).
These were isolated in 25% and 38% yield, respectively.
Other polar solvents were tried such as formic acid,
DMSO, and DMF in the same conditions. In these solvents,
no total conversion of 8 was observed. Other parameters
were changed like the ratio of alkyl iodide, or the ratio
between Zn and CuI, and reaction temperature, but these
were not successful. The reaction reached completion when
performed in the presence of alkyl iodide (1 equiv), Zn
(2 equiv), and CuI (0.5 equiv) in anhydrous DMSO/forma-
mide (2:1) at 100 °C over 3 h. From primary alkyl halides,
products 14a-d were obtained in 53-66% yields (Table 3).
The synthetic potential of aminosulfones as reagents in the
modified Julia reaction was tested by reacting fluorosulfone
10e with 4-bromobenzaldehyde under Barbier conditions
(Scheme 7). The reaction was performed from -78 to 0 °C
over 2 h in THF in the presence of NaHMDS (1 M in THF).
After workup and flash column chromatography, the ex-
pected allylamine 16 was isolated in 70% yield. Although a
mixture of Z and E fluoroolefins was obtained, the isomers
were separated on silica gel column chromatography. This
Experimental Section
2-Benzothiazolylsulfanyl-2-fluoroethanol (4). To a solution of
ethyl 2-benzothiazolylsulfanyl-2-fluoroacetate 3 (7.00 g, 25.79
mmol, 1 equiv) in EtOH (106 mL) cooled to 0 °C was added
NaBH4 (1.36 g, 36.12 mmol, 1.4 equiv) in small portions. The
mixture was stirred for 2 h and then quenched with a saturated
solution of NH4Cl (30 mL) and brine (10 mL). The aqueous
layer was extracted with CH2Cl2 (2 ꢀ 100 mL). Combined
organic layers were washed with brine (20 mL), dried over
MgSO4, filtered, and evaporated under reduced pressure. The
crude product was purified by flash column chromatography
(silica, pentane/AcOEt 7:3) to afford 4 (4.47 g, 75%) as a white
solid: mp 92-94 °C; 1H NMR (CDCl3, 400 MHz) δ 3.97-4.13
(m, 2H), 6.61 (ddd, 3JHH =3.9Hz,3JHH =5.0Hz,2JHF = 51.5 Hz,
3
1H), 7.29-7.43 (m, 2H), 7.74-7.76 (m, 1H), 7.90 (d, JHH
=
=
2
8.2 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 103.4 (d, JCF
8.5 Hz), 121.3, 124.8, 126.9, 127.6, 136.4, 151.7, 155.8, 160.2 (d,
1JCF = 270.6 Hz); 19F NMR (CDCl3, 376 MHz) δ -159.5 (ddd,
2JFH = 51.5 Hz, 3JFH = 16.4 Hz, 3JFH = 20.2 Hz); MS (EI) m/z
J. Org. Chem. Vol. 74, No. 24, 2009 9403

Calata et al.
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230 [M þ H]þ (100), 210 (89); HRMS (ESI) m/z[Mþ H]þ calcd for
2-[[1-Fluoro-2-(1H-imidazol-1-yl)ethyl]sulfonyl]-1,3-benzothi-
azole (11). To a solution of 2-[(1-fluorovinylsulfonyl)]-1,3-ben-
zothiazole (8) (100 mg, 0.41 mmol, 1 equiv) in CH2Cl2 (8 mL) was
added imidazole (30 mg, 0.45 mmol, 1.1 equiv). The mixture was
stirred for 16 h at room temperature, quenched with a saturated
solution of NH4Cl (3 mL), and extracted with CH2Cl2 (2 ꢀ
10 mL). The combined organic layers were dried over MgSO4,
filtered, and evaporated under reduced pressure. The crude
product was purified by flash column chromatography (silica,
CH2Cl2 then CH2Cl2/AcOEt 90:10) to give 11 (100 mg, 76%) as a
C9H9FNOS2 230.0110, found 230.0102.
2-Benzothiazolylsulfonyl-2-fluoroethanol (5). To a solution of
sulfide 4 (2.00 g, 8.73 mmol, 1 equiv) in CH2Cl2 (22 mL) at 0 °C
was added dropwise a solution of m-CPBA (9.04 g, 52.40 mmol,
6 equiv) in CH2Cl2 (18 mL). The mixture was stirred for 48 h at
room temperature and washed with a saturated solution of
NaHCO3 (2 ꢀ 30 mL). Aqueous layers were extracted with
CH2Cl2 (2 ꢀ 50 mL), and the combined organic layers were
dried over MgSO4, filtered, and evaporated under reduced
pressure. The crude product was purified by flash column chro-
matography (silica, pentane/AcOEt 7:3) to afford 5 (1.60 g, 75%)
as a colorless solid: mp 123-125 °C; 1H NMR (CDCl3, 250 MHz)
1
white solid: mp 129 -132 °C; H NMR (CDCl3, 400 MHz) δ
4.59-4.93 (m, 2H), 5.82 (dd, 2JHF = 48.2 Hz, 3JHH = 8.5 Hz,
1H), 6.90 (d, 3JHF = 22.4 Hz, 2H), 7.51-7.77 (m, 3H), 7.96-7.98
(m, 1H), 8.14-8.16 (m, 1H); 13C NMR (CDCl3, 100 MHz) δ 44.4
3
δ 2.38 (s, 1H), 3.93-4.14 (m, 2H), 6.59 (dt, JHH = 4.0 Hz,
2JHF = 46.8 Hz, 1H), 7.18-7.43 (m, 2H), 7.73 (d, 3JHH = 8.0 Hz,
1H), 7.89 (d, 3JHH = 7.9 Hz, 1H); 13C NMR (CDCl3, 100 MHz)
δ 59.1 (d, 2JCF = 21.2 Hz), 101.4 (d, 1JCF = 225.4 Hz), 122.4,
125.8, 128.0, 128.7, 137.5, 152.6, 162.3; 19F NMR (CDCl3,
(d, JCF = 20.5 Hz), 99.7 (d, JCF = 227.4 Hz), 119.5, 122.4,
2
1
125.8, 128.2, 128.9, 130.5, 137.5, 137.8, 152.7, 161.1; 19F NMR
2
3
(CDCl3, 376 MHz) δ -179.0 (ddd, JFH = 48.2 Hz, JFH
=
30.9 Hz, 3JFH = 17.3 Hz); MS (EI) m/z 312 [M þ H]þ (100), 244
(85); HRMS (ESI) m/z [M þ H]þ calcd for C12H11FN3O2S2
312.0277, found 312.0276.
2
3
235 MHz) δ -185.4 (dt, JFH = 46.8 Hz, JFH = 18.8 Hz);
MS (EI) m/z 262 [M þ H]þ (100), 244 (10), 200 (20), 182 (73);
HRMS (ESI) m/z [M þ H]þ calcd for C9H9FNO3S2 262.0008,
found 261.9997.
2-[2-(1,3-Benzothiazol-2-ylsulfonyl)-2-fluoroethyl]phthalimide
(12). To a solution of phthalimide (80 mg, 0.53 mmol, 1.3 equiv)
in THF (2 mL) were added a 1 M solution of TBAF in THF
(410 μL, 0.41 mmol, 1 equiv) and 2-[(1-fluorovinylsulfonyl)]-
1,3-benzothiazole (8) (100 mg, 0.41 mmol, 1 equiv). The mixture
was stirred for 1 h at room temperature, quenched with a
saturated solution of NH4Cl (1 mL), and extracted with CH2Cl2
(2 ꢀ 5 mL). The combined organic layers were dried over
MgSO4, filtered, and evaporated under reduced pressure. The
crude product was purified by flash column chromatography
(silica, CH2Cl2/pentane 80:20) to afford 12 (100 mg, 61%) as a
2-[(1-Fluorovinyl)sulfonyl]-1,3-benzothiazole (8). To a solu-
tion of 2-benzothiazolylsulfonyl-2-fluoroethanol (5) (300 mg,
1.14 mmol, 1 equiv) and MsCl (110 μL, 1.38 mmol, 1.2 equiv)
in CH2Cl2 (4 mL) cooled to 0 °C was added dropwise NEt3
(400 μL, 2.85 mmol, 2.5 equiv). The mixture was stirred for
30 min at 0 °C and then quenched with a saturated solution of
NH4Cl (1 mL). The aqueous layer was extracted with CH2Cl2
(2 ꢀ 10 mL). Combined organic layers were washed with a
saturated solution of NaHCO3 (2 ꢀ 1 mL), dried over MgSO4,
filtered, and evaporated under reduced pressure to furnish pure
1
white solid: mp 166-168 °C; H NMR (CDCl3, 400 MHz) δ
1
8 (259 mg, 92%) as a white solid: mp 141-142 °C; H NMR
4.44-4.53 (m, 2H), 5.99 (ddd, 2JHF = 48.0 Hz, 3JHH = 8.3 Hz,
3JHH = 4.3 Hz, 1H), 7.48-7.61 (m, 2H), 7.66-7.69 (m, 2H),
(CDCl3, 250 MHz) δ 5.65 (dd, 2JHH = 5.0 Hz, 3JHF = 11.7 Hz,
1H), 6.06 (dd, 2JHH = 5.0 Hz, 3JHF = 40.7 Hz, 1H), 7.54-7.64
(m, 2H), 7.96-7.99 (m, 1H), 8.19-8.22 (m, 1H); 13C NMR
7.78-7.82 (m, 2H), 7.93-7.97 (m, 1H), 8.17-8.19 (m, 1H); 13
C
NMR (CDCl3, 100 MHz) δ 35.5 (d, 2JCF = 22.1 Hz), 97.5 (d,
1JCF = 226.8 Hz), 122.4, 123.8, 125.9, 128.0, 128.7, 131.6, 134.5,
137.5, 152.8, 161.5, 167.2; 19F NMR (CDCl3, 376 MHz) δ -182.8
(ddd, 2JFH = 48.0 Hz, 3JFH = 24.2 Hz, 3JFH = 14.3 Hz); MS (EI)
m/z 391 [M þ H]þ (65), 307 (28), 192 (100), 172 (9); HRMS (ESI)
m/z [M þ H]þ calcd for C17H12FN2O4S2 391.0223, found
391.0207.
(CDCl3, 100 MHz) δ 64.1 (d, 2JCF = 25.2 Hz), 99.5 (d, 1JCF
=
224.2 Hz), 121.2, 122.4, 125.2, 126.5, 136.0, 152.8, 161.3; 19F
2
NMR (CDCl3, 235 MHz) δ -114.2 (dd, JFH = 40.7 Hz,
3JFH = 11.7 Hz); MS (EI) m/z 244 [M þ H]þ (100), 214 (8),
158 (13), 141 (7), 99 (4); HRMS (ESI) m/z [M þ H]þ calcd for
C9H7FNO2S2 243.9902, found 243.9913.
General Procedure for the Preparation of Aliphatic Fluoro-
aminosulfones (10a-i). To a solution of 2-[(1-fluorovinylsulfonyl)]-
1,3-benzothiazole (8) (1 equiv) in CH2Cl2 was added aliphatic
amine (1.3 to 1.5 equiv). The mixture was stirred for 5 min at
room temperature then quenched with a saturated solution of
NH4Cl (3 mL). The aqueous layer was extracted with CH2Cl2
(2 ꢀ 10 mL). The combined organic layers were dried over
MgSO4, filtered, and evaporated under reduced pressure. The
crude product was purified by flash column chromatography to
give fluoroaminosulfones 10a-i.
2-[(1-Fluoro-2-pyrrolidin-1-ylethyl)sulfonyl]-1,3-benzothiazole
(10e). The general procedure was followed with 2-[(1-fluoro-
vinylsulfonyl)]-1,3-benzothiazole (8) (1 g, 4.11 mmol, 1 equiv),
pyrrolidine (440 μL, 5.34 mmol, 1.3 equiv), and CH2Cl2 (17 mL).
The purification by flash column chromatography (silica, pen-
tane/AcOEt 95:5 then 90:10) afforded 10e (1.23 g, 95%) as a
colorless solid: mp 73 -77 °C; 1H NMR (CDCl3, 250 MHz) δ
1.60-1.70 (m, 4H), 2.60-2.70 (m, 4H), 3.13-3.57 (m, 2H),
5.69-5.93 (m, 1H), 7.61-7.66 (m, 2H), 8.01-8.04 (m, 1H),
8.24-8.28 (m, 1H); 13C NMR (CDCl3, 62 MHz) δ 23.6, 52.5 (d,
2JCF = 19.5 Hz), 54.4, 101.7 (d, 1JCF = 225.2 Hz), 122.3, 125.7,
127.8, 128.3, 137.4, 152.7, 162.6; 19F NMR (CDCl3, 235 MHz) δ
-178.5 (ddd, 2JFH = 49.0 Hz, 3JFH = 31.5 Hz, 3JFH = 20.0 Hz);
MS (EI) m/z 315 [M þ H]þ (87), 244 (100), 180 (5), 116 (88), 84
(22); HRMS (ESI) m/z [M þ H]þ calcd for C13H16FN2O2S2
315.0637, found 315.0626.
General Procedure for the Preparation of Fluorinated Sulfo-
nylamino Acid Alkyl Esters (13a-f). To a solution of chlorhy-
drate amino acid alkyl ester (1 equiv) and NEt3 (3 equiv) in
MeCN were introduced 2-[(1-fluorovinylsulfonyl)]-1,3-ben-
zothiazole (8) (1 equiv) and silica (2 equiv w/w). The solution
was stirred under reflux for 4-6 h. The reaction mixture was
cooled to room temperature, hydrolyzed with a saturated solu-
tion of NH4Cl (1 mL), and extracted with CH2Cl2 (2 ꢀ 5 mL).
The combined organic layers were dried over MgSO4, filtered,
and evaporated under reduced pressure. The crude product was
purified on a short silica pad to give fluorinated sulfonylamino
acid alkyl esters 13a-f.
N-[2-(1,3-Benzothiazol-2-ylsulfonyl)-2-fluoroethyl]glycine
Ethyl Ester (13a). The general procedure was followed with
2-[(1-fluorovinylsulfonyl)]-1,3-benzothiazole (8) (100 mg, 0.41
mmol, 1 equiv), chlorhydrate glycine ethyl ester (60 mg, 0.41
mmol, 1 equiv), NEt3 (170 μL, 1.23 mmol, 3 equiv), and silica
(204 mg) for 4 h in refluxing MeCN (2 mL). The purification on
a short silica pad (CH2Cl2 then CH2Cl2/AcOEt 98:2 and
CH2Cl2/AcOEt 95:5) afforded 13a (100 mg, 69%) as a colorless
oil: 1H NMR (CDCl3, 400 MHz) δ 1.17 (t, 3JHH = 7.2 Hz, 3H),
1.94-1.95 (m, 1H), 3.37-3.52 (m, 4H), 4.09 (q, 3JHH = 7.2 Hz,
2H), 5.70 (ddd, 2JHF = 48.0 Hz, 3JHH = 7.4 Hz, 3JHH = 3.4 Hz,
1H), 7.53-7.58 (m, 2H), 7.93-7.95 (m, 1H), 8.15-8.17 (m, 1H);
13C NMR (CDCl3, 100 MHz) δ 13.1, 49.9 (d, 2JCF = 23.4 Hz),
54.4, 61.4, 102.6 (d, 1JCF = 212.7 Hz), 116.7, 120.4, 123.0, 124.9,
9404 J. Org. Chem. Vol. 74, No. 24, 2009

Calata et al.
JOCArticle
126.6, 144.0, 166.2, 168.2; 19F NMR (CDCl3, 376 MHz)
mixture was stirred for 5 min at -80 °C and 5 min at room
temperature and then quenched with a saturated solution of
NH4Cl (2 mL). The aqueous layer was extracted with CH2Cl2
(2 ꢀ 10 mL). The combinedorganic layerswere washedwithbrine
(3 mL), dried over MgSO4, filtered, and evaporated under
reduced pressure to afford a crude mixture of (E)- and (Z)-alkene
16 in a ratio of 51:49. This crude product was purified by flash
column chromatography (silica, pentane/AcOEt gradient from
90:10 to 80:20) to afford successively the (E) (32 mg, 35%) andthe
2
3
3
δ -181.01 (ddd, JFH = 48.0 Hz, JFH = 28.4 Hz, JFH
=
19.2 Hz); MS (EI) m/z 347 [M þ H]þ (100), 282 (33), 281 (18),
236 (100); HRMS (ESI) m/z [M þ H]þ calcd for C13H16FN2O4S2
347.0536, found 347.0541.
General Procedure for the Preparation of Alkylated Fluoro-
sulfones 14a-d. To a suspension of zinc (2 equiv) in dry DMSO
were added formamide (few drops) and CuI (0.5 equiv). After
3 min of stirring at room temperature, 2-(1-fluorovinylsulfonyl)-
1,3-benzothiazole (8) (1.2 equiv) and iodoalkyl (1 equiv) were
introduced. The solution was heated to 100 °C for 3 h. After being
cooled to room temperature, the reaction mixture was diluted
with CH2Cl2 (5 mL) and hydrolyzed with a 0.6 M aqueous
solution of HCl (1 mL). The aqueous layer was extracted with
CH2Cl2 (2 ꢀ 5 mL), and the combined organic layers were dried
over MgSO4, filtered, and evaporated under reduced pressure.
The crude product was purified by flash column chromatography
to give alkylated fluorosulfones 14a-d.
2-[(1-Fluorohexyl)sulfonyl]-1,3-benzothiazole (14a). The gen-
eral procedure was followed with 2-[(1-fluorovinylsulfonyl)]-
1,3-benzothiazole (8) (110 mg, 0.45 mmol, 1.2 equiv), iodobu-
tane (40 μL, 0.37 mmol, 1 equiv), Zn (50 mg, 0.75 mmol,
2 equiv), CuI (40 mg, 0.19 mmol, 0.5 equiv), DMSO (340 μL),
and formamide (170 μL). The purification by flash column
chromatography (silica, CH2Cl2/pentane 8:2) afforded 14a
1
(Z) isomers (30 mg, 33%) as yellow oils. Isomer E: H NMR
(CDCl3, 400 MHz) δ 1.70-1.74 (m, 4H), 2.48-2.50 (m, 4H), 3.28
(d, 3JHFvic = 22.7 Hz, 2H), 6.19 (d, 3JHFcis = 20.6 Hz, 1H), 7.08
(d, 3JHH = 8.3 Hz, 2H), 7.37 (d, 3JHH = 8.4 Hz, 2H); 13C NMR
(CDCl3, 100 MHz) δ 22.5, 51.6 (d, 2JCF = 26.1 Hz), 53.0, 109.1
(d, 2JCF = 28.2 Hz), 119.9, 129.4, 129.5, 129.8, 130.5, 131.6 (d,
3JCF = 13.7 Hz), 158.9 (d, 1JCF = 256.5 Hz); 19F NMR (CDCl3,
376 MHz) δ -97.8 (dt, 3JFHcis = 20.6 Hz, 3JFHvic = 22.7 Hz); MS
(EI) m/z 284 [M þ H]þ (100), 213 (50), 134 (30); HRMS (ESI) m/z
[M þ H]þ calcd for C13H16BrFN 284.0450, found 284.0444.
1
Isomer Z: H NMR (CDCl3, 400 MHz) δ 1.75-1.78 (m, 4H),
3
2.56-2.58 (m, 4H), 3.24 (d, JHFvic = 16.9 Hz, 2H), 5.57 (d,
3JHFtrans = 38.2 Hz, 1H), 7.29 (d, 3JHH = 8.6 Hz, 2H), 7.36 (d,
3JHH = 8.9 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ 22.5, 53.0,
56.0 (d, 2JCF = 28.2 Hz), 106.3 (d, 2JCF = 7.0 Hz), 119.8, 119.9,
129.0, 129.1, 130.5, 131.1 (d, JCF = 2.0 Hz), 157.3 (d, 1JCF
=
=
3
1
(60 mg, 55%) as a yellow oil: H NMR (CDCl3, 500 MHz) δ
269.6Hz); 19FNMR (CDCl3, 376 MHz) δ-103.3(dt, 3JFHtrans
0.84 (t, 3JHH = 7.0 Hz, 3H), 1.25-1.33 (m, 4H), 1.50-1.62 (m,
38.2 Hz, 3JFHvic = 16.9 Hz); MS (EI) m/z 284 [M þ H]þ (70), 213
(100), 134 (33); HRMS (ESI) m/z [M þ H]þ calcd for
C13H16BrFN 284.0450, found 284.0446.
2
3
2H), 2.06-2.25 (m, 2H), 5.58 (ddd, JHF = 48.6 Hz, JHH
=
=
9.9 Hz, 3JHH = 2.9 Hz, 1H), 7.53-7.60 (m, 2H), 7.96 (d, 3JHH
7.8 Hz, 1H), 8.20 (d, JHH = 7.9 Hz, 1H); 13C NMR (CDCl3,
3
125 MHz) δ 13.8, 22.2, 24.0 (d, 3JCF = 3.2 Hz), 26.8 (d, 2JCF
=
Acknowledgment. This work was supported by the CNRS
and the Crunch (interregional organic chemistry network).
The “Region Basse-Normandie” and ERDF (ISCE Chem,
INTERREG IVa program) are gratefully thanked for their
financial support.
19.2 Hz), 31.0, 102.3 (d, 1JCF = 221.8 Hz), 122.3, 125.8, 127.8,
128.4, 137.4, 152.8, 162.6; 19F NMR (CDCl3, 376 MHz) δ -177.8
(ddd, 2JFH = 48.6 Hz, 3JFH = 34.5 Hz, 3JFH = 15.9 Hz); MS(EI)
m/z 302 [M þ H]þ (87), 200 (36), 182 (100); HRMS (ESI) m/z
[M þ H]þ calcd for C13H17FNO2S2 302.0685, found 302.0677.
(Z/E)-N-[3-(4-Bromophenyl)-2-fluoroprop-2-enyl]pyrrolidine
ꢁ
(16). To
a
solution of 2-[(1-fluoro-2-pyrrolidin-1-ylethyl)-
Supporting Information Available: Additional experimental
procedures for the preparation of 6, 7, 9, 10a-d,f-g,j, 13b-f,
14b-d and 1H and 13C NMR spectra of the compounds 4-12,
10a-g, 13a-f, 14a-d, and 16. This material is available free of
charge via the Internet at http://pubs.acs.org.
sulfonyl]-1,3-benzothiazole (10e) (100 mg, 0.32 mmol, 1 equiv)
and 4-bromobenzaldehyde (62 mg, 0.33 mmol, 1.05 equiv) in
THF (5 mL) cooled to -80 °C was added a 1 M solution of
NaHMDS (100 μL, 0.70 mmol, 2.1 equiv) in THF. The reaction
J. Org. Chem. Vol. 74, No. 24, 2009 9405