Aryliododifluoromethylsulfides, sulfoxides and sulfones: The first optically active compounds with polyfluoroalkyliodo groups

Article abstract of DOI:10.1070/MC2006v016n03ABEH002314

Aryliododifluoromethyl sulfoxides, which were transformed in aryliododifluoromethyl sulfides and sulfones, were obtained by the coupling of mercury salts of arylsulfoxydifluoromethylacetic acids with iodine.

Full text of DOI:10.1070/MC2006v016n03ABEH002314

Mendeleev Commun., 2006, 16(3), 135–134
Aryliododifluoromethylsulfides, sulfoxides and sulfones: the first optically active
compounds with polyfluoroalkyliodo groups
Lev M. Yagupolskii* and Andrej V. Matsnev
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, 02094 Kiev, Ukraine.
Fax: +38 044 573 2643; e-mail: yagupolskii@bpci.kiev.ua
DOI: 10.1070/MC2006v016n03ABEH002314
Aryliododifluoromethyl sulfoxides, which were transformed in aryliododifluoromethyl sulfides and sulfones, were obtained by
the coupling of mercury salts of arylsulfoxydifluoromethylacetic acids with iodine.
Fluorinated alkyl iodides are among the most wide-applied
reagents in organofluorine chemistry. They are used for the
perfluoroalkylation of unsaturated compounds and thiols. They
react with metals, sulfur, phosphorus, etc. Many publications
are dedicated to the synthesis and study of the reactivity of
fluoroalkyl iodides.1–4 The syntheses of polyfluoroalkyl iodides
that contain different functional groups are of great interest.
In this work, we synthesised fluoroalkyl iodides that contain
thio,5 sulfinyl and sulfonyl6,7 groups. Fluoroalkyl iodides with
sulfinyl groups are chiral; this opens a route to optically active
fluoroalkyl iodides. The presence of a difluoromethylene group
at the chiral sulfur atom may allow one to monitor the optical
activity and purity of the compounds by 19F NMR spectroscopy.
Earlier, we reported the synthesis of a new type of fluoro-
containing sulfoxides: arylsulfinyldifluoroacetic acids.8,9 These
acids are starting compounds for the synthesis of sulfinyl-
difluoromethyl iodides.
Arylsulfinyldifluoromethyl iodides were transformed to the
corresponding sulfides and sulfones. During the reaction of
arylsulfinyldifluoromethyl iodides with PCl5 in a POCl3 solution,
the replacement of oxygen by two chlorine atoms takes place10
with the formation of corresponding arylthiodifluoromethyl
iodides 2a–c.‡
The reaction occurred at 15–20 °C for 30 min. At a higher
temperature, arylthiodifluoromethyl chlorides are formed as
by-products. Corresponding arylsulfonyldifluoromethyl iodides
3a–c were obtained from sulfinyldifluoromethyl iodides by
oxidation with m-chloroperbenzoic acid (MCPBA).§
Cl
Cl
S
S
CF2I
CF2I
– Cl2
X
X
X
2a–c
PCl5, POCl3
O
S
O
S
O
S
O
S
HgO, I2,
C2H4Cl2
CF2COOH
CF2I
MCPBA
CF2I
CF2I
87 °C
O
X
X
X
1a X = H
1b X = MeO
1c X = Cl
1a–c
3a–c
Scheme 2 Transformation of aryliododifluoromethyl sulfoxides into cor-
responding sulfides and sulfones.
Scheme 1 Synthesis of aryliododifluoromethyl sulfoxides.
The Borodin–Hunsdiecker reaction is most widely used for
the syntheses of polyfluoroalkyl iodides. In the reaction with
iodine, a silver or sodium salt of a corresponding carboxylic
acid is commonly used. In the case of arylsulfoxydifluoroacetic
acids, the sodium salt does not give the Borodin–Hunsdiecker
reaction, and the silver salt leads to a product free of fluorine.
We managed to get arylsulfinyldifluoromethyl iodides using
mercury salts of arylsulfoxydifluoroacetic acids, which react
with iodine giving arylsulfinyldifluoromethyl iodides 1a–c.†
‡
Preparation of arylthiodifluoromethyl iodides 2. PCl5 (0.01 mol) was
added by small portions with intense stirring to a solution of 0.01 mol
of arylsulfoxydifluoromethyl iodide 1 in 2 ml of POCl3 at 0–5 °C. After
that it was heated to 15–20 °C. The chlorine evolved vigorously. The
reaction progress was controlled by TLC. At the end of the reaction, the
reaction mixture was poured on ice with intense stirring. The product
was extracted by CH2Cl2 (2×5 ml) and dried over MgSO4. The solvent
was distilled off, the product was purified by column chromatography
from hexane. Yields 45–65%.
2a: oil. 1H NMR (CDCl3) d: 7.58–7.93 (m, 5H). 19F NMR, d: –27.9 (s).
Found (%): I, 44.68; S, 11.45. Calc. for C7H5IF2S (%): I, 44.40; S, 11.19.
2b: oil. 1H NMR (CDCl3) d: 3.93 (s, 3H), 6.52–7.63 (m, 4H). 19F NMR,
d: –28.3 (s). Found (%): I, 40.32; S, 10.30. Calc. for C8H7IF2OS (%):
I, 40.19; S, 10.13.
†
General procedures. Boiling and melting points are uncorrected.
NMR spectra were measured on a Varian VXR-300 instrument
(300 MHz for 1H, TMS as internal standard; 288 MHz for 19F, CCl3F as
internal standard).
Preparation of arylsulfinyldifluoromethyl iodides 1. Mercury oxide
(0.05 mol) was added to a mixture of 0.05 mol of corresponding aryl-
sulfoxidifluoroacetic acid in 10 ml of anhydrous dichloroethane. The
mixture was heated to boiling point and stirred for 30 min until bulky
precipitate of mercury salt formed. A solution of 0.05 mol of iodine in
10 ml of anhydrous dichloroethane was added to the reaction mixture.
The reaction mixture was refluxed with stirring for 4 h, controlled by
TLC. On completeness of the reaction it was cooled to 10 °C and
filtered. The solvent was distilled off, the product was purified by column
chromatography (benzene–hexane). Yields 35–75%.
2c: oil. 1H NMR (CDCl3) d: 7.55–7.71 (m, 4H). 19F NMR, d: –28.7 (s).
Found (%): I, 40.07; S, 10.21. Calc. for C7H4ClIF2S (%): I, 39.69; S, 10.02.
§
Preparation of arylsulfonyldifluoromethyl iodides 3a–c. At room
temperature, 0.03 mol of MCPBA was added to a solution of 0.02 mol
of arylsulfoxydifluoromethyl iodide 1 in 5 ml of anhydrous CH2Cl2.
The reaction mixture was stirred at room temperature until iodide 1
disappeared according to TLC data. At the end of the reaction, the
mixture was cooled to –10 °C and the precipitated m-chlorobenzoic acid
was filtered off. The solvent was distilled off. The product was purified
by column chromatography (ethyl acetate–hexane). Yields 70–85%.
3a: mp 66–68 °C. 1H NMR (CDCl3) d: 7.61–8.01 (m, 5H). 19F NMR,
d: –52.5 (s). Found (%): I, 40.11; S, 10.32. Calc. for C7H5IF2O2S (%):
I, 39.94; S, 10.08.
1
1a: oil. H NMR (CDCl3) d: 7.52–7.73 (m, 5H). 19F NMR, d: –44.2
(d, 1F, J 169 Hz), –48.9 (d, 1F, J 169 Hz). Found (%): I, 41.76; S, 10.40.
Calc. for C7H5IF2OS (%): I, 42.05; S, 10.59.
1
1
1b: H NMR (CDCl3) d: 3.97 (s, 3H), 6.53–7.72 (m, 4H). 19F NMR,
3b: mp 93–95 °C. H NMR (CDCl3) d: 3.92 (s, 3H), 7.06–7.92 (m,
d: –44.8 (d, 1F, J 170 Hz), –49.1 (d, 1F, J 170 Hz). Found (%): I, 38.53;
4H). 19F NMR, d: –54.7 (s). Found (%): I, 36.32; S, 9.30. Calc. for
C8H7IF2O3S (%): I, 36.49; S, 9.19.
S, 9.44. Calc. for C8H7IF2O2S (%): I, 38.25; S, 9.64.
1
1c: oil. H NMR (CDCl3) d: 7.55–7.71 (m, 4H). 19F NMR, d: –44.3
3c: mp 104–105 °C. 1H NMR [(CD3)2CO] d: 7.86–8.09 (m, 4H).
19F NMR, d: –55.5 (s). Found (%): I, 35.92; S, 9.12. Calc. for
C7H4ClIF2O2S (%): I, 36.07; S, 9.09.
(d, 1F, J 172 Hz), –49.0 (d, 1F, J 172 Hz). Found (%): I, 37.73; S, 9.51.
Calc. for C7H4ClIF2OS (%): I, 37.79; S, 9.52.
132 Mendeleev Commun. 2006

Mendeleev Commun., 2006, 16(3), 135–134
The obtained difluoromethyl iodides were introduced into
reactions with aldehydes and unsaturated compounds, and reduc-
tion reaction.
Thus, p-chlorophenylsulfinyldifluoromethyl iodide reacts with
p-methylbenzaldehyde in the presence of tetrakis(diethylamino)-
ethylene (TDAE) and gives corresponding secondary alcohol 4
in 60% yield as a diastereomer mixture. Likewise, the p-chloro-
phenylsulfonyldifluoromethyl iodide reacts with p-methylbenz-
aldehyde.¶
We established that it is possible to obtain the corresponding
optically active sulfinyldifluoromethyl iodides and difluoromethyl
sulfoxides from optically active sulfinyldifluoroacetic acids.
Optically active (+)-p-chlorophenylsulfinyldifluoroacetic acid
(98% ee) was taken as a model compound. The optically active
difluoromethyl iodide containing the sulfinyl group was obtained
from this acid according to the above method in 75% yield.‡‡
O
S
O
*
*
S
H
HgO, I2
C2H4Cl2
CF2COOH
CF2I
S(O)n
O
CF2I
+
Cl
Cl
7
Cl
Me
[a]D20 +171.4° (c 0.01, CH2Cl2), 98% ee
1c n = 1
3c n = 2
TDAE – 15 to 25 °C
OH
Scheme 5 Synthesis of optically active p-chlorophenylsulfinyldifluoro-
methyl iodide.
S(O)n
CF2
H
The optically active p-chlorophenyldifluoromethyl sulfoxide
was synthesised in a reaction of (+)-p-chlorophenylsulfinyl-
difluoromethyl iodide with zinc in DMF.§§
Cl
Me
4 n = 1
5 n = 2
O
S
O
Scheme 3 Reaction of 1c and 3c with p-methylbenzaldehyde.
*
*
S
p-Chlorophenylsulfinyldifluoromethyl iodide reacts with zinc
in dimethylformamide (DMF) at room temperature to form
corresponding difluoromethylsulfoxide 6 in high yield.††
CF2I
CF2H
Zn, DMF
Cl
Cl
[a]D20 +227.8° (c 0.01, CH2Cl2), 98% ee
7
8
O
S
O
S
CF2I
CF2H
Zn, DMF
Scheme 6 Synthesis of optically active p-chlorophenyldifluoromethyl
sulfoxide.
Cl
Cl
The enantiomer purity was defined using 19F NMR spectro-
scopy in the presence of a chiral shift reagent, (+)-phenyl-
tert-butylthiophosphonic acid.11
Thus, we found a new method for the synthesis of compounds
with the difluoromethyliodide group directly connected to sulfide
or sulfonyl groups. Sulfoxides and their optically active forms
with difluoroiodomethyl and difluoromethyl groups bound to
sulfur were synthesised for the first time.
1c
6
Scheme 4 Reaction of 1c with zinc.
An attempt to add sulfinyldifluoromethyl iodide to the double
bond of styrene under UV irradiation of the reaction mixture
yielded a hard-to-separate mixture of products. The use of azo-
isobutyronitrile (AIBN) as a catalyst did not cause the addition
of difluoromethyl iodides to double bonds, and benzoyl peroxide
oxidised the sulfinyldifluoromethyl group to sulfone.
Earlier, we have elaborated the synthesis of the first optically
active fluorocontaining sulfoxides with fluorinated groups bounded
directly to the centre of optical activity, namely, sulfur.8
References
1 C. Wakselman and A. Lantz, in Organofluorine Chemistry, ed. R. E.
Banks, Plenum Press, New York, 1994, pp. 177–190.
2 R. D. Chambers, Fluorine in Organic Chemistry, Blackwell Publishing,
Oxford, 2004, pp. 122–126.
¶
The synthesis of p-chlorophenylsulfinyl- and sulfonyldifluoromethyl-
p-tolylcarbinols 4 and 5. Iodide 1c or 3c (0.02 mol) was added to 1 ml
of p-methylbenzaldehyde, the mixture was cooled to –15 °C under argon,
after that 0.02 mol of TDAE was added with intense stirring. The reaction
mixture was kept at this temperature for 1.5 h. Then, the temperature was
slowly raised to room temperature, the mixture was stirred until the orange-
brown colour disappeared. After the end of the reaction, water was added,
the mixture was acidified to pH 4–5. The product was extracted by
3×5 ml of CH2Cl2. The combined organic phase was washed with ice-cold
water and dried over MgSO4. The solvent was distilled off, the product
was purified by column chromatography (ethyl acetate–hexane).
3 P. Kirsch, Modern Fluoroorganic Chemistry I, Wiley-VCH, Weinheim,
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4 L. E. Deev, T. I. Nazarenko, K. I. Pashkevich and V. G. Ponomarev, Usp.
Khim., 1992, 61, 75 (Russ. Chem. Rev., 1992, 61, 40).
‡‡ Preparation of optically active p-chlorophenylsulfinyldifluoromethyl
iodide 7. Mercury oxide (0.05 mol) was added to a solution of 0.05 mol
of optically active p-chlorophenylsulfoxydifluoracetic acid in 10 ml of
anhydrous dichloroethane. The mixture was heated to the boiling point
and stirred for 30 min until the precipitate of mercury salt formed. Then,
the solution of 0.05 mol of iodine in 10 ml of anhydrous dichloroethane
was added dropwise to the reaction mixture. The mixture was refluxed
with stirring for 4 h. The end of the reaction was controlled by TLC.
Then, the reaction mixture was cooled down to 10 °C and filtered. The
solvent was distilled off; the product was purified by column
1
4: H NMR [(CD3)2CO] d: 2.66 (d, 3H), 4.69 (br. s, 1H), 5.49–5.73
(m, 1H), 7.47–7.97 (m, 8H). 19F NMR, d: –111.2 (ddd, JFF 217 Hz,
JFH 14 Hz), –111.5 (d, JFF 222 Hz), –117.5 (ddd, JFF 222 Hz, JFH 23 Hz),
–118.9 (ddd, JFF 217 Hz, JFH 14 Hz). MS, m/z (RI): 330 (4.5), 162 (37),
160 (100), 121 (30), 112 (27).
1
1
5: H NMR [(CD3)2CO] d: 2.43 (s, 3H), 4.89 (br. s, 1H), 5.51 (dd,
chromatography (benzene–hexane); oil. H NMR (CDCl3) d: 7.54–7.69
1H, J1 20 Hz, J2 3 Hz), 7.17–7.93 (m, 8H). 19F NMR, d: –104.5 (d,
JFF 234 Hz), –118.2 (dd, JFF 234 Hz, JFH 20 Hz). MS, m/z (RI): 175
(0.2), 170 (2), 121 (100), 94 (11).
(m, 4H). 19F NMR, d: –44.4 (d, 2F, J 172 Hz), –49.0 (d, 2F, J 172 Hz).
Found (%): I, 37.54; S, 9.23. Calc. for C7H4ClIF2OS (%): I, 37.79; S,
9.52.
†† Preparation of p-chlorophenyldifluoromethyl sulfoxide 6. Zinc dust
(0.02 mol) was added to a solution of iodide 1c in 2 ml of DMF and
stirred at room temperature until the iodide disappeared, according to
TLC; then, the mixture was poured into water. The product was extracted
by 3×5 ml of diethyl ether. The combined organic phase was washed with
2×5 ml of cold water and dried over MgSO4. The solvent was distilled
off, the product was purified by column chromatography (benzene–
hexane); mp 74–75 °C. 1H NMR (CDCl3) d: 5.6 (t, 1H, J 54 Hz),
7.54–7.63 (m, 4H). 19F NMR, d: –119.7 (dd, 2F, J 252 Hz), –121.5
(dd, 2F, J 252 Hz). Found (%): C, 40.33; H, 2.43; S, 15.30. Calc. for
C7H5ClF2OS (%): C, 39.91; H, 2.38; S, 15.23.
§§ Preparation of optically active p-chlorophenylfluoromethyl sulfoxide 8.
Zinc dust (0.02 mol) was added to a solution of iodide 7 in 2 ml of DMF,
the mixture was stirred at room temperature until iodide 7 disappeared
according to TLC data. After the end of the reaction, the mixture was
poured into water. The product was extracted with 3×5 ml of diethyl ether.
The combined organic phase was washed with 2×5 ml of cold water and
dried over MgSO4. The solvent was distilled off; the product was purified
1
by column chromatography (benzene–hexane); mp 91–92 °C. H NMR
(CDCl3) d: 6.0 (t, 1H, J 55 Hz), 7.57–7.68 (m, 4H). 19F NMR, d: –119.0
(dd, 2F, J 252 Hz), –120.6 (dd, 2F, J 252 Hz). Found (%): C, 39.71;
H, 2.55; S, 15.52. Calc. for C7H5ClF2OS (%): C, 39.91; H, 2.38; S, 15.23.
Mendeleev Commun. 2006 133

Mendeleev Commun., 2006, 16(3), 135–134
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Received: 27th January 2006; Com. 06/2656
134 Mendeleev Commun. 2006