Chlorodifluoromethyl phenyl sulfone: A novel non-ozone-depleting substance-based difluorocarbene reagent for O- and N-difluoromethylations

Article abstract of DOI:10.1039/b713156a

Chlorodifluoromethyl phenyl sulfone, a previously unknown compound that can be readily prepared from non-ODS-based precursors, was found to act as a robust difluorocarbene reagent for O- and N-difluoromethylations. The Royal Society of Chemistry.

Full text of DOI:10.1039/b713156a

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Chlorodifluoromethyl phenyl sulfone: a novel non-ozone-depleting
substance-based difluorocarbene reagent for O- and
N-difluoromethylations{{
Ji Zheng,a Ya Li,a Laijun Zhang,a Jinbo Hu,*a Gerrit Joost Meuzelaarb and Hans-Ju¨rgen Federselb
Received (in Cambridge, UK) 28th August 2007, Accepted 28th September 2007
First published as an Advance Article on the web 16th October 2007
DOI: 10.1039/b713156a
as a robust non-ODS-based difluorocarbene reagent for O- and
N-difluoromethylations.
Chlorodifluoromethyl phenyl sulfone, a previously unknown
compound that can be readily prepared from non-ODS-based
precursors, was found to act as a robust difluorocarbene
reagent for O- and N-difluoromethylations.
Fluorinated sulfones have increasingly become a class of highly
useful compounds in nucleophilic fluoroalkylations,8 but the
reports on their use as difluorocarbene reagents are rare.9
Chlorodifluoromethyl phenyl sulfone (2) is a previously unknown
compound. Initially, we prepared compound 2 in 79% yield
through a nucleophilic (phenylsulfonyl)difluoromethylation reac-
tion between difluoromethyl phenyl sulfone (3) and N-chloro-
succinimide (NCS, 3.4 equiv.) in the presence of lithium
hexamethyldisilazide (LHMDS, 2.5 equiv.) in THF at 278 uC
(Scheme 1, eqn (1)). To achieve a non-ODS-based practical
synthesis of compound 2, we developed a three-step synthesis of 2
with good yield starting from readily available and inexpensive
thioanisole (4). The synthetic procedures include chlorination with
Cl2, selective fluorination with Olah’s reagent (HF–pyridine, molar
ratio = 10 : 1), and oxidation with NaIO4 (Scheme 1, eqn (2)).
With compound 2 in hand, we carried out the O-difluoro-
methylation reactions by using phenol (7a) as a model compound.
The results are summarized in Table 1. Potassium hydroxide
(25 wt% in H2O) was used both as a base to deprotonate phenol
(7a) and as an activating agent for reagent 2 to generate :CF2
species. It was found that the reaction between phenol 7a and
reagent 2 (in a sealed pressure tube) was successful in different
solvent systems (such as THF–H2O, DME–H2O, and CH3CN–
H2O) at 50–80 uC. CH3CN–H2O (7 : 2 v/v) was found to be the
best solvent system for the reaction (Table 1, entries 6–10).
Decreasing or increasing the reaction temperature did not show a
significant impact on the product yield (entries 6–8). The optimal
product yield (72%) was obtained when the reaction proceeded
at 50 uC for 5 h with reactant ratio 7a : 2 : KOH = 1 : 2.3 : 11
Selective introduction of fluorine atoms or fluorine-containing
moieties into organic molecules is well-recognized as a powerful
strategy to modulate the target molecules’ physical, chemical
and biological properties.1 As a result, the development of mild,
efficient and environmentally friendly fluorination and fluoro-
alkylation methods is highly useful for life science- and material
science-related research.1,2 One major effort in the field is to
develop new non-ODS-based fluoroalkylation methods (ODS =
ozone-depleting substances) to replace the conventional ODS-
based ones.3 For instance, most of the currently known difluoro-
carbene reagents for O- and N-difluoromethylations (Fig. 1), such
as chlorodifluoromethane and chlorodifluoroacetic acid deriva-
tives, are either ODS themselves or derived from ODS-based
precursors.4–6 Furthermore, although S-(difluoromethyl)diaryl-
sulfonium tetrafluoroborate was developed as a new electrophilic
difluoromethylating agent, this reagent could not transfer the
difluoromethyl group to phenols and secondary amines.7
2-Chloro-2,2-difluoroacetophenone (1) was developed by us as a
non-ODS-based difluorocarbene reagent for O-difluoromethyla-
tion of phenol derivatives.4 However, the fact that a large excess of
reagent 1 (¢5 equiv.) was generally required in reactions4 has
driven us to seek more efficient non-ODS-based difluorocarbene
reagents. In this communication, we disclose our recent success in
developing chlorodifluoromethyl phenyl sulfone (PhSO2CF2Cl, 2)
Fig. 1 O- And N-difluoromethylations with difluorocarbene reagents.
aKey Laboratory of Organofluorine Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road,
Shanghai 200032, China. E-mail: jinbohu@mail.sioc.ac.cn;
Fax: +86 21-64166128
bGlobal Process R&D, So¨derta¨lje site, AstraZeneca, S-151 85
So¨derta¨lje, Sweden
{ Zheng and Li contributed equally to this work.
{ Electronic supplementary information (ESI) available: Experimental
details and characterization data. See DOI: 10.1039/b713156a
Scheme 1 Synthesis of difluorocarbene reagent 2.
Chem. Commun., 2007, 5149–5151 | 5149
This journal is ß The Royal Society of Chemistry 2007

View Article Online
difluorocarbene character under similar reaction conditions (in the
Table 1 Survey of reaction conditions
case of compound 11, CF3H was formed as a major product).
As shown in Table 2, compound 2 showed the highest reactivity
among these five fluorinated sulfones.
Next, we carefully examined the scope of the O- and
N-difluoromethylation reaction with reagent 2. The results are
summarized in Table 3 and Table 4. It was found that by using the
2–KOH–CH3CN–H2O system, a wide range of phenol derivatives
were readily difluoromethylated in good to excellent yields with
a simple experimental procedure (Table 3). It is particularly
remarkable that, although only 2.3 equiv. of reagent 2 were used,
the product yields were still notably higher than those of the
reported reactions using 5 equiv. of PhCOCF2Cl reagent.4
Furthermore, the present difluoromethylation reaction was also
found to be applicable to N-heterocyclic compounds 12a–12e to
give difluoromethylated products 13a–13e in satisfactory product
yields (see Table 4), which broadens the synthetic application of
reagent 2.
Reactant ratio
Entrya (7a : 2 : KOH) Solvent
Temperature/
uC
Yield
Time/h (%)b
1
2
1 : 2 : 11
1 : 2 : 11
1 : 2 : 11
1 : 2 : 11
1 : 2 : 16
1 : 2 : 11
1 : 2 : 11
1 : 2 : 11
1 : 2 : 5.5
1 : 2.3 : 11
1 : 2 : 11
1 : 2 : 11
Dioxane–H2O 50
H2O
4
4
4
6
6
4
4
4
6
5
4
4
13
0c
50
80
80
60
3
4
5
THF–H2O
DME–H2O
DME–H2O
56
64
63
68
65
67
68d
72
38e
0f
6
7
8
9
10
11
12
a
CH3CN–H2O 50
CH3CN–H2O 60
CH3CN–H2O 80
CH3CN–H2O 60
CH3CN–H2O 50
CH3CN 50
CH3CN–H2O 50
Typical reaction procedures: 7a (1 mmol), KOH (25 wt% in H2O,
2 mL, ca. 11 mmol), 7 mL of organic solvent (except entry 5) and 2
were mixed in a pressure tube at rt, and the tube was sealed. The
reaction mixture was heated to the desired temperature for a certain
The synthetic application of reagent 2 was further demonstrated
in the synthesis of the compounds 16 and 17, which are
highly useful intermediates for making pharmacologically active
b
time. Yields were determined by 19F NMR spectroscopy using
c
PhCF3 as internal standard. Even when the phase transfer catalyst
Table 3 O-Difluoromethylation with reagent 2
tris[2-(2-methoxyethoxy)ethyl]amine was added, no product was
observed. Half amount of KOH (25 wt% in H2O, 1 mL, ca.
Entrya Substrate
Product
Yield (%)b
d
e
5.5 mmol) was applied. Anhydrous KOH (instead of aqueous
f
solution) was used. K2CO3 (instead of KOH) was used as a base.
1
2
3
4
5
6
7
8
9
8a R = H
72c
79
70
74
65
8b R = o-I
8c R = p-I
8d R = p-Br
8e R = p-Cl
(entry 10). It was evident that water played an important role in
the current difluorocarbene reaction; when the reaction was carried
out under anhydrous conditions, a poor product yield (38%) was
obtained (entry 11). However, the reactions in water alone or in
the presence of a phase transfer catalyst (tris[2-(2-methoxyethoxy)
ethyl]amine) could not give any desired product (entry 2).
Furthermore, we found that potassium carbonate was not a
suitable base (to replace KOH) for the reaction (entry 12).
8f R = o-NO2 93
8g R = p-NO2 96
8h R = p-tBu 77
8i R = p-Ph
87
10
11
8j R = o-OCH3 70c
83
Thereafter, we compared the reactivity of reagent 2 with those
of other potential difluorocarbene reagents, including bromodi-
fluoromethyl phenyl sulfone 9, iododifluoromethyl phenyl sulfone
10, difluoromethyl phenyl sulfone 3,8,9 and trifluoromethyl phenyl
sulfone 11 (see Table 2). It was found that compounds 9, 10 and 3
were also able to act as difluorocarbene reagents for O-difluoro-
methylation of phenol, while compound 11 did not show any
12
95
13
14
94
79
Table 2 Difluoromethylation with different sulfone reagents
15
16
81
93
Entrya
Sulfone reagent
Yield (%)b
1
2
3
4
5
a
PhSO2CF2Cl (2)
PhSO2CF2Br (9)
PhSO2CF2I (10)
PhSO2CF2H (3)
PhSO2CF3 (11)
72
70
25
23
0
a
For all cases, the reactant conditions were similar to those of
b
c
For all cases, the reactant conditions were similar to those of
entry 10 in Table 1. Isolated yields. Yields were determined by
19F NMR spectroscopy using PhCF3 as internal standard due to the
volatile nature of the product.
entry 10 in Table 1. Yields were determined by 19F NMR spectro-
scopy using PhCF3 as internal standard.
b
5150 | Chem. Commun., 2007, 5149–5151
This journal is ß The Royal Society of Chemistry 2007

View Article Online
with 2.0 equiv. of reagent 2 under similar reaction conditions,
product 16 was obtained in 85% yield.
Table 4 N-Difluoromethylation with reagent 2
Entrya
Substrate
Product
Yield (%)b
86
In summary, we have successfully developed a non-ODS-based
preparation of chlorodifluoromethyl phenyl sulfone (2).
Compound 2 was found to be a novel and efficient difluoro-
carbene reagent for O- and N-difluoromethylation of phenols and
N-heterocycles. The present synthetic methodology was success-
fully applied to the synthesis of two highly useful intermediates,
16 and 17, which are both relevant for the preparation of
pharmaceutically interesting compounds. The present synthetic
methodology promises to act as a useful synthetic tool for many
other applications.
1
2
3
4
66
69
58
Support of our work by the NSF of China (20772144,
20502029), the Shanghai Rising-Star Program (06QA14063), the
Chinese Academy of Sciences (Hundreds Talent Program), and
AstraZeneca (Global Process R&D) is gratefully acknowledged.
Notes and references
1 (a) Organofluorine Compounds: Chemistry and Applications, ed.
T. Hiyama, Springer, New York, 2000; (b) Organofluorine Chemistry:
Principles and Commercial Applications, ed. R. E. Banks, B. E. Smart and
J. C. Tatlow, Plenum, New York, 1994; (c) A. M. Thayer, Chem. Eng.
News, 2006, 84(23), 15.
5
44
2 (a) K. Uneyama, Organofluorine Chemistry, Blackwell, Oxford, 2006; (b)
P. Kirsch, Modern Fluoroorganic Chemistry: Synthesis, Reactivity,
Applications, Wiley-VCH, Weinheim, 2004; (c) R. D. Chambers,
Fluorine in Organic Chemistry, Blackwell, Oxford, 2004.
a
For all cases, the reactant conditions were similar to those of
entry 10 in Table 1. Isolated yield.
b
3 (a) S. Large, N. Roques and B. R. Langlois, J. Org. Chem., 2000, 65,
8848; (b) S. Ait-Mohand, N. Takechi, M. Medebielle and W. R. Dolbier,
Jr., Org. Lett., 2001, 3, 4271; (c) G. K. S. Prakash, J. Hu and G. A. Olah,
J. Org. Chem., 2003, 68, 4457.
4 L. Zhang, J. Zheng and J. Hu, J. Org. Chem., 2006, 71, 9848, and the
references therein.
5 (a) T. G. Miller and J. W. Thanassi, J. Org. Chem., 1960, 25, 2009; (b)
T. Y. Shen, S. Lucas and L. H. Sarett, Tetrahedron Lett., 1961, 2, 43; (c)
B. R. Langlois, J. Fluorine Chem., 1988, 41, 247; (d) K. Morimoto,
K. Makino and G. Sakata, J. Fluorine Chem., 1992, 59, 417; (e)
´
A. Jonczyk, E. Nawrot and M. Kisielewski, J. Fluorine Chem., 2005, 126,
1587.
6 (a) S. B. Christensen, H. E. Dabbs and J. M. Karpinski, WO 96/23754,
1996; (b) J. Z. Ho, C. S. Elmore, M. A. Wallace, D. Yao, M. P. Braun,
D. C. Dean, D. G. Melillo and C.-Y. Chen, Helv. Chim. Acta, 2005, 88,
1040; (c) P. D. O’shea, C.-Y. Chen, W. Chen, P. Dagneau, L. F. Frey,
E. J. J. Grabowski, K. M. Marcantonio, R. A. Reamer, L. Tan,
R. D. Tillyer, A. Roy, X. Wang and D. Zhao, J. Org. Chem., 2005, 70,
3021; (d) M. Ando, T. Wada and N. Sato, Org. Lett., 2006, 8, 3805.
7 G. K. S. Prakash, C. Weber, S. Chacko and G. A. Olah, Org. Lett., 2007,
9, 1863.
Scheme 2 Synthesis of compounds 16 and 17.
compounds. As shown in Scheme 2, the reaction between 2 and
3-bromo-5-chlorophenol (14) smoothly gave product 16 in 89%
isolated yield. When the same procedure was applied to precursor
15, product 17 was obtained in 92% yield (Scheme 2). It is
important to mention that the present new difluoromethylation
method can be easily used in relatively large-scale reactions. For
example, when 9.28 g (44 mmol) of compound 14 were treated
8 See a recent review: G. K. S. Prakash and J. Hu, Acc. Chem. Res., 2007,
40, DOI: 10.1021/ar700149s.
9 Previously, difluoromethyl phenyl sulfone (PhSO2CF2H) was reported as
2
a poor difluorocarbene precursor (via decomposition of the PhSO2CF2
intermediate). See: (a) J. Hine and J. J. Porter, J. Am. Chem. Soc., 1960,
82, 6178; (b) G. P. Stahly, J. Fluorine Chem., 1989, 43, 53.
This journal is ß The Royal Society of Chemistry 2007
Chem. Commun., 2007, 5149–5151 | 5151