Radical (phenylsulfonyl)difluoromethylation with iododifluoromethyl phenyl sulfone

Article abstract of DOI:10.1021/jo070618s

(Chemical Equation Presented) An unprecedented radical (phenylsulfonyl) difluoromethylation of terminal alkenes with PhSO₂CF₂I has been achieved by using Et₃B/air as an initiator. This synthetic methodology was also used i

Full text of DOI:10.1021/jo070618s

Radical (Phenylsulfonyl)difluoromethylation with
Iododifluoromethyl Phenyl Sulfone
tion of (phenylsulfonyl)difluoromethyl group (PhSO2CF2) into
organic molecules, based on the fact that the PhSO2CF2 group
is a versatile functionality that can be readily converted to other
highly useful difluorinated moieties such as difluoromethyl
(
Ya Li, Jun Liu, Laijun Zhang, Lingui Zhu, and Jinbo Hu*
CF2H) and difluoromethylene (-CF2- or dCF2) groups.4
-6
Key Laboratory of Organofluorine Chemistry, Shanghai Institute
of Organic Chemistry, Chinese Academy of Sciences,
The known methods for directly introducing PhSO2CF2 group
-
are all based on nucleophilic reactions with the PhSO2CF2
354 Fenglin Road, Shanghai 200032, China
anion, which is commonly derived from PhSO CF H, PhSO -
2
2
2
4
-6
CF2SiMe3, or PhSO2CF2Br reagents.
However, we are not
jinbohu@mail.sioc.ac.cn
aware of any reports of either radical (phenylsulfonyl)difluo-
romethylation or the (phenylsulfonyl)difluoromethyl radical
(PhSO2CF2 ) itself. As our continuing effort in developing
•
ReceiVed March 25, 2007
selective difluoromethylation and difluoromethylenation meth-
4
odologies, we have been seeking new approaches of transferring
PhSO2CF2 group under neutral reaction conditions that tolerate
more sensitive functional groups. In this note, we report our
recent success in the generation of (phenylsulfonyl)difluorom-
•
ethyl radical species (PhSO2CF2 ) and its use in the radical
(phenylsulfonyl)difluoromethylation of alkenes.
Taking advantage of the simple preparation of iododifluo-
7
romethyl phenyl sulfone (PhSO2CF2I, 1), we chose compound
1
as the (phenylsulfonyl)difluoromethyl radical precursor. By
An unprecedented radical (phenylsulfonyl)difluoromethy-
lation of terminal alkenes with PhSO CF I has been achieved
by using Et B/air as an initiator. This synthetic methodology
was also used in the one-pot regioselective preparation of
PhSO CF -substituted alkanes, and in the regio- and stereo-
selective preparation of PhSO CF -substituted alkenes with
high E/Z ratio (up to g100:1).
using 1-hexene (2a) as a model compound, we examined the
radical atom transfer reaction between 1 and 2a (Table 1). After
trying several radical initiators, we found that copper powder
2
2
3
0
(Cu ), Pd(PPh3)4, and Na2S2O4 are not suitable for the reaction
2
2
(entries 1-3), which is surprisingly different from other known
radical polyfluoroalkylation reactions. Nevertheless, we found
that Et B/air was an efficient initiating system for the present
8
2
2
9
3
radical atom transfer process between 1 and 2a (Table 1, entries
4
1
-13). To ensure a high conversion of reagent 1 in the reaction,
Recently, fluorine has been highlighted as a fabulous element
for life sciences-related applications. It is well-known that the
.0 equiv of Et3B was used for all cases. Furthermore, while
1
(4) (a) Li, Y.; Hu, J. Angew. Chem., Int. Ed. 2005, 44, 5882-5886. (b)
incorporation of one or just a few fluorine atom(s) into organic
molecules can often have profound effects on their bioactivities,
and as a result, a significant portion of agrochemicals and
pharmaceuticals on the market contain fluorine.1 Fluorination
and fluoroalkylation are the two major synthetic methods to
prepare partially fluorinated organic compounds. In the selective
fluoroalkylation arena, while nucleophilic, electrophilic, and
radical trifluoromethylations have been extensively studied over
the past 30 years, the systematic exploration of the analogous
difluoromethylation and difluoromethylenation has emerged
Ni, C.; Hu, J. Tetrahedron Lett. 2005, 46, 8273-8277. (c) Liu, J.; Ni, C.;
Li, Y.; Zhang, L.; Wang, G.; Hu, J. Tetrahedron Lett. 2006, 47, 6753-
6756. (d) Ni, C.; Liu, J.; Zhang, L.; Hu, J. Angew. Chem., Int. Ed. 2007,
46, 786-789. (e) Liu, J.; Li, Y.; Hu, J. J. Org. Chem. 2007, 72, 3119-
-3
3121.
(5) (a) Prakash, G. K. S.; Hu, J.; Olah, G. A. J. Org. Chem. 2003, 68,
4
457-4463. (b) Prakash, G. K. S.; Hu, J.; Mathew, T.; Olah, G. A. Angew.
Chem., Int. Ed. 2003, 42, 5216-5219. (c) Prakash, G. K. S.; Hu, J.; Wang,
Y.; Olah, G. A. Org. Lett. 2004, 6, 4315-4317. (d) Prakash, G. K. S.; Hu,
J.; Wang, Y.; Olah, G. A. Angew. Chem., Int. Ed. 2004, 43, 5203-5206.
(e) Prakash, G. K. S.; Hu, J.; Wang, Y.; Olah, G. A. Eur. J. Org. Chem.
2005, 2218-2223. (f) Prakash, G. K. S.; Wang, Y.; Hu, J.; Olah, G. A. J.
Fluorine Chem. 2005, 126, 1361-1367. (g) Prakash, G. K. S.; Hu, J.; Wang,
Y.; Olah, G. A. J. Fluorine Chem. 2005, 126, 529-534.
2
more recently. In this context, there is an increasing interest
in developing efficient synthetic methods for selective introduc-
(6) (a) Edwards, J. A.; Obukhova, E. M.; Prezhdo, V. V. U.S. Patent
3
705182, 1972. (b) Stahly, G. P. J. Fluorine Chem. 1989, 43, 53-66. (c)
(
1) Thayer, A. M. Chem. Eng. News 2006, 84, 15-14; 27-32.
Sabol, J. S.; McCarthy, J. R. Tetrahedron Lett. 1992, 33, 3101-3104. (d)
Boger, D. L.; Jenkins, T. J. J. Am. Chem. Soc. 1996, 118, 8860-8870. (e)
Serafinowski, P. J.; Barnes, C. L. Synthesis 1997, 225-228. (f) Ye, J.-D.;
Liao, X.; Piccirilli, J. A. J. Org. Chem. 2005, 44, 5882-5886. (g) Reutrakul,
V.; Thongpaisanwong, T.; Tuchinda, P.; Kuhakarn, C.; Pohmakotr, M. J.
Org. Chem. 2004, 69, 6913-1915.
(2) (a) Uneyama, K. Organofluorine Chemistry; Blackwell: New Delhi,
2
006. (b) Chambers, R. D. Fluorine in Organic Chemistry; Blackwell:
Oxford, 2004. (c) Kirsch, P. Modern Fluoroorganic Chemistry: Synthesis,
ReactiVity, Applications; Wiley-VCH: Weinheim, 2004. (d) Organofluorine
Compounds: Chemistry and Applications; Hiyama, T., Ed.; Springer: New
York, 2000. (e) Organofluorine Chemistry: Principles and Commercial
Applications; Banks, R. E., Smart, B. E., Tatlow, J. C., Eds.; Plenum
Press: New York, 1994.
(7) Compound 1 can be readily prepared from PhSO2CF2H and I2 in the
t
presence of BuOK in 92-95% isolated yields. See: Prakash, G. K. S.;
Hu, J.; Wang, Y.; Olah, G. A. Org. Lett. 2004, 6, 4315-4317.
(8) For selected examples on radical polyfluoroalkylation, see: (a) Yang,
Z.-Y.; Burton, D. J. J. Org. Chem. 1991, 56, 5125-5132. (b) Qiu, Z. M.;
Burton, D. J. Tetrahedron Lett. 1993, 34, 3239-3242. (c) Yang, Z.-Y.;
Burton, D. J. J. Org. Chem. 1992, 57, 4676-4683. (d) Li, A.-R.; Chen,
Q.-Y. Synthesis 1996, 606-608. (e) Huang, W.-Y.; Wu, F.-H. Isr. J. Chem.
1999, 39, 167-170.
(
3) (a) McCarthy, J. R. Fluorine in Drug Design: A Tutorial ReView;
1
7th Winter Fluorine Conference: St. Pete Beach, FL, 2005. (b) McCarthy,
J. R. Utility of Fluorine in Biologically ActiVe Molecules; 219th National
Meeting of the American Chemical Society: San Francisco, CA, 2000;
Division of Fluorine Chemistry Turtorial. (c) Biomedical Frontiers of
Fluorine Chemistry; Ojima, L., McCarthy, J. R., Welch, J. T., Eds.;
American Chemical Society: Washington, DC, 1996. (d) Organofluorine
Compounds in Medicinal Chemistry and Biomedical Applications; Filler,
R., Kobayashi, Y., Yagupolskii, L. M., Eds.; Elsevier: Amsterdam, 1993.
(9) Yorimitsu, H.; Oshima, K. In Radical Chain Reactions: Organobo-
rane Initiators, in Radicals in Organic Synthesis; Renaud, P., Sibi, M. P.,
Eds.; Wiley-VCH: Weinheim, 2001.
10.1021/jo070618s CCC: $37.00 © 2007 American Chemical Society
5
824
J. Org. Chem. 2007, 72, 5824-5827
Published on Web 06/23/2007

TABLE 1. Survey of Reaction Conditions
initiator
(equiv)
molar ratio
(1:2a)
temperature
concentration
(mol/L)b
a
yield (%)c
0
entry
solvent
DMF
(°C)
1
2
3
4
5
6
7
8
9
Cu (0.5)
1:2.0
1:2.0
1:2.0
1:2.0
1:2.0
1:1.3
1:2.0
1:2.0
1:2.0
1:2.0
1:2.0
1:2.0
1:2.0
55
60
24
24
0
0
0
0
0
0.20
0.20
0.50
0.15
0.15
0.15
0.25
0.15
0.15
0.15
0.15
0.15
0.15
d
Pd(PPh3)4 (0.03)
Na2S2O4 (1.5)
Et3B (1.0)/air
Et3B (1.0)/air
Et3B (1.0)/air
Et3B (1.0)/air
Et3B (1.0)/air
Et3B (1.0)/air
Et3B (1.0)/air
Et3B (1.0)/air
Et3B (1.0)/air
Et3B (1.0)/air
benzene
CH3CN/H2O
benzene
benzene
benzene
benzene
toluene
CH2Cl2
THF
5
-
e
56
69
56
70
55
70
68
75
56
46
10
11
12
13
0
CH2Cl2
CH2Cl2
THF
-30
-78
-78
a
b
The molar equivalent of the initiator was calculated relative to the amount of compound 1. The concentration of 1 in the reaction mixture before an
initiator was added. Isolated yield. Determined by F NMR spectroscopy. e A complex product mixture was obtained.
c
d
19
TABLE 2. Et3B-Initiated Radical Atom Transfer Reactions
between 1 and Alkenes 2
TABLE 3. One-Pot (Phenylsulfonyl)difluoromethylation of Alkenes
2
entry
R
product
yield (%)a
entry
R
product
yield (%)a
1
2
3
4
5
6
7
8
1-butyl
1-decyl
3a
3b
3c
3d
3e
3f
75
72
71
70
78
73
64
56
1
2
3
4
5
6
1-butyl
1-decyl
5a
5b
5c
5d
5e
5f
75
70
65
69
78
57
trimethylsilyl
trimethylsilyl
CH3C(O)CH2CH2-
EtOC(O)CH2CH2CH2-
HO2CCH2CH2-
HOCH2-
CH3C(O)CH2CH2-
EtOC(O)CH2CH2CH2-
p-CH3OC6H4OCH2-
3g
3h
p-CH3OC6H4OCH2-
a
Isolated yield.
a
Isolated yield.
SCHEME 1. Preparation of Compound 4 and Proposed
Mechanism
solvents and reactant concentration did not exhibit a significant
effect, the reaction temperature played an important role in the
reaction (entries 4-13). The best yield (75%) was obtained
when the reaction was carried out in CH2Cl2 at -30 °C (entry
1
1).
By using this optimized reaction condition, we studied the
scope of the Et3B/air-initiated radical reactions between the new
phenylsulfonyl)difluoromethylating reagent 1 and a variety of
(
structurally diverse terminal alkenes. In all cases as shown in
Table 2, the reactions proceeded smoothly to give the regiose-
lective products 3a-3h in satisfactory to good yields, with the
reaction being compatible with different functionalities such as
carbonyl, ester, carboxylic acid, ether, and hydroxyl groups. It
is interesting that the reaction between 1 and vinyl ethyl ether
gave the acetal 4 as the product (Scheme 1), possibly via an
oxonium ion intermediate (see proposed mechanism in
Scheme 1).
applied in the reaction between 1 and 2a, the reaction was
sluggish. We then used a one-pot two-step procedure to
accomplish a clean (phenylsulfonyl)difluoromethylation of
alkenes with 1 by adding the Et3B/air to initiate the addition
reaction to give intermediate 3, followed by adding Bu3SnH
reagents to facilitate the de-iodination reaction (see Table 3).
The reactions proceed smoothly to give the (phenylsulfonyl)-
difluoromethylated alkanes in 57-78% isolated yields, with
good toleration of several types of functional groups. This one-
pot approach is a good alternative for the previously reported
It has been reported that Zn/NiCl2 can be used as a mild and
efficient reagent for the one-pot addition/reductive de-iodination
reactions between polyfluoroalkyl iodides and terminal alk-
enes.10 However, we found that when Zn/NiCl2 reagent was
(
10) (a) Yang, Z.-Y.; Burton, D. J. J. Chem. Soc., Chem. Commun. 1992,
2
5
33-234. (b) Yang, Z.-Y.; Burton, D. J. J. Org. Chem. 1992, 57, 5144-
149.
J. Org. Chem, Vol. 72, No. 15, 2007 5825

SCHEME 2. Preparation of Compound 6
TABLE 5. Stereoselective Preparation of
Phenylsulfonyl)difluoromethylated Alkenes 7
(
preparative method for product 5 under strong basic conditions.5c,d
Furthermore, this reaction also worked for vinyl ethyl ethers
yield (%)a
E/Zb
entry
R
product
1
2
3
4
5
6
7
1-butyl
1-decyl
7a
7b
7c
7d
7e
7f
71
69
69
61
68
58
55
64:1
70:1
51:1
38:1
60:1
(Scheme 2). In the presence of Bu3SnH and Et3B/air, the reaction
between 1 and excess amount of vinyl ethyl ether (5 equiv) in
toluene at -78 °C gave the corresponding product 6 in 61%
isolated yield (in this case, the formation of acetal 4 was not
observed).
With the expectation that the intermediate compounds 3 can
also undergo base-mediated dehydroiodination to give (phenyl-
sulfonyl)difluoromethylated alkenes, we carried out a one-pot
preparation of fluoroalkylated alkenes from 1 and terminal
alkenes 2. First, we scanned the reaction conditions by using
trimethylsilyl
CH3C(O)CH2CH2-
EtOC(O)CH2CH2CH2-
HOCH2-
56:1
p-CH3OC6H4OCH2-
7g
g100:1
a
Isolated yields. b Determined by 19F NMR spectroscopy.
tion of 1-substituted-2-(phenylsulfonyl)difluoromethyl alkenes
7 was achieved with the isomeric ratio E/Z up to g100:1. The
present radical (phenysulfonyl)difluoromethylating methodology
promises to find useful applications in organic synthsis, and
further exploration of this interesting chemistry is underway in
our laboratory.
1
-hexene (2a) as a model compound, and the results are shown
in Table 4. It was found that triethyl amine was unable to
dehydroiodinate the intermediate product 3a (entries 1 and 2).
In polar solvent, inorganic base such as K2CO3 and KOH can
promote the reaction, but only moderate E/Z isomeric ratios were
observed (entries 3-5). 1,5-Diazabicyclo[4.3.0]non-5-ene (DBU)
was found to be a good base for the reaction, and in nonpolar
solvent toluene at 0 °C, an excellent E/Z ratio (64:1) of product
Experimental Section
Typical Procedure for the Radical Addition of Iododifluo-
romethyl Phenyl Sulfone with Alkenes. In the presence of air,
into a sealed 30-mL Schlenk flask containing iododifluoro-
methyl phenyl sulfone (1) (64 mg, 0.2 mmol) and 1-hexene (2a)
34 mg, 0.4 mmol) in 1.2 mL of CH Cl at -30 °C was added
2 2
Et B (0.2 mL, 1.0 mol in hexane) via a syringe. The reaction
7
a was observed (Table 4, entry 9).
Encouraged by this result, we extended this synthetic
methodology (using the optimized reaction conditions as those
for Table 4, entry 9) to other structurally diverse terminal alkenes
(
3
(see Table 5). The present one-pot procedure was found to be
mixture was stirred at this temperature for 0.5 h. After the removal
an efficient method to prepare (phenylsulfonyl)difluoromethy-
lated 1,2-disubstituted alkenes 7a-7g in 55-71% isolated yields
and with remarkable stereoselectivity (E/Z ratio up to g100:1;
see Table 5, entry 7).
of volatile solvents under vacuum, the crude product was further
purified by silica gel column chromatography with ethyl acetate/
petroleum ether (1:30) to give product 3a as an oily liquid, yield
75% (60 mg).
2 2
Typical Procedure for the Preparation of PhSO CF -
Substituted Alkanes 5. In the presence of air, into a sealed 30-
mL Schlenk flask containing iododifluoromethyl phenyl sulfone
In conclusion, an unprecedented radical (phenylsulfonyl)-
difluoromethylation methodology has been described by using
•
the readily available PhSO2CF2I as the PhSO2CF2 precursor.
(1) (95 mg, 0.3 mmol) and 1-hexene (2a) (50 mg, 0.6 mmol) in 2
Et3B/air was found to be a good initiating system for the
mL of CH Cl B (1.0 mL, 1.0 mol in
2
2
at -30 °C was added Et
3
0
reaction, while Cu , Pd(PPh3)4, and Na2S2O4 are not efficient
hexane) via a syringe. The reaction mixture was stirred at this
temperature for 0.5 h. After the removal of volatile solvents under
to initiate the reaction. A one-pot procedure for the regiose-
lective preparation of PhSO2CF2-substituted alkanes
5
vacuum, to the flask were further added Bu
mmol) and toluene (2.0 mL). Under N atmosphere, the reaction
mixture was heated for 0.5 h at 90 °C, followed by adding a
saturated KF-H O solution (5 mL) at rt. The mixture was extracted
with Et
O (25 mL × 3), and the combined organic phase was dried
over anhydrous MgSO . After the removal of volatile solvents under
3
SnH (114 mg, 0.39
has been successfully developed, by applying Et3B/air and Bu3-
SnH reagents. A remarkably regio- and stereoselective prepara-
2
2
2
TABLE 4. Tuning the E/Z Ratio of Product 7 by Using Different
Basic Reaction Conditions
4
vacuum, the crude product was further purified by silica gel column
chromatography with ethyl acetate/petroleum ether (1:50) to give
product 5a as an oily liquid, yield 75% (62 mg).
2 2
Typical Procedure for the Preparation of PhSO CF -
Substituted Alkanes 6. In the presence of air, into a sealed 30-
isomer ratio (E/Z)b
mL Schlenk flask containing iododifluoromethyl phenyl sulfone
(
1) (159 mg, 0.5 mmol), vinyl ether (180 mg, 2.5 mmol), and Bu
SnH (189 mg, 0.65 mmol) in 2.5 mL of toluene at -78 °C was
added Et B (0.65 mL, 1.0 mol in hexane) via a syringe. The reaction
mixture was stirred at this temperature for 0.5 h, followed by adding
a saturated KF-H O solution (10 mL) at rt. The mixture was
extracted with Et
O (25 mL × 3), and the combined organic phase
was dried over anhydrous MgSO . After the removal of volatile
3
-
entry
basic conditions
7a
1
2
3
4
5
6
7
8
9
CH2Cl2, NEt3, rt
DMF, NEt3, rt
DMF, K2CO3, rt
DMF, K2CO3, 0 °C
CH3CN, KOH, rt
DMF, DBU, rt
CH2Cl2, DBU, rt
toluene, DBU, rt
toluene, DBU, 0 °C
no reaction
no reaction
6:1
7:1
4:1
3
2
2
20:1
4
27:1
51:1
64:1
solvents under vacuum, the crude product was further purified by
silica gel column chromatography with ethyl acetate/petroleum ether
(
1:50) to give product 6 as an oily liquid, yield 64% (85 mg).
Typical Procedure for the Preparation of PhSO CF
Substituted Alkenes 7. In the presence of air, into a sealed 30-
a
Determined by 19F NMR spectroscopy.
2
-
2
5
826 J. Org. Chem., Vol. 72, No. 15, 2007

mL Schlenk flask containing iododifluoromethyl phenyl sulfone
1) (318 mg, 1.0 mmol) and 1-hexene (2a) (168 mg, 2.0 mmol) in
mL of CH Cl at -30 °C was added Et B (1.0 mL, 1.0 mol in
Acknowledgment. We thank the National Natural Science
Foundation of China (20502029), Shanghai Rising-Star Program
06QA14063), and the Chinese Academy of Sciences (Hundreds-
(
6
2
2
3
(
hexane) via a syringe. The reaction mixture was stirred at this
temperature for 0.5 h. After the removal of volatile solvents
under vacuum, to the flask were further added DBU (182 mg, 1.2
mmol) and toluene (8 mL) at 0 °C. The reaction mixture was stirred
at this temperature for 3.0 h, followed by removal of volatile
solvents under vacuum. The crude product was further purified by
silica gel column chromatography with ethyl acetate/petroleum ether
Talent Program) for funding.
Supporting Information Available: General experimental
information and characterization data of the isolated compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(
(
1:50) to give product 7a as an oily liquid, yield 71%
195 mg).
JO070618S
J. Org. Chem, Vol. 72, No. 15, 2007 5827