Copper-catalyzed debenzoylative monofluoromethylation of aryl iodides assisted by the removable (2-Pyridyl)sulfonyl group

Article abstract of DOI:10.1021/cs4000574

A new method for aromatic monofluoromethylation was developed. Aryl iodides can be efficiently transformed into the corresponding monofluoromethylated products by a copper-catalyzed debenzoylative fluoroalkylation with 2-PySO ₂CHFCOR and subsequent reductive desulfonylation. The (2-pyridyl)sulfonyl moiety plays an important role in the copper-catalyzed cross-coupling, and it can be removed easily through Bu₃SnH-mediated desulfonylation.

Full text of DOI:10.1021/cs4000574

Letter
pubs.acs.org/acscatalysis
Copper-Catalyzed Debenzoylative Monofluoromethylation of Aryl
Iodides Assisted by the Removable (2-Pyridyl)sulfonyl Group
Yanchuan Zhao, Chuanfa Ni, Fanzhou Jiang, Bing Gao, Xiao Shen, and Jinbo Hu*
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Ling-Ling
Road, Shanghai 200032, China
S
* Supporting Information
ABSTRACT: A new method for aromatic monofluoromethylation was developed. Aryl iodides can be efficiently transformed
into the corresponding monofluoromethylated products by a copper-catalyzed debenzoylative fluoroalkylation with 2-
PySO2CHFCOR and subsequent reductive desulfonylation. The (2-pyridyl)sulfonyl moiety plays an important role in the
copper-catalyzed cross-coupling, and it can be removed easily through Bu3SnH-mediated desulfonylation.
KEYWORDS: monofluoromethylation, copper catalysis, (2-pyridy)sulfonyl group, cross-coupling, fluorine
Scheme 1. Transition Metal-Mediated Cross-Coupling To
Introduce a Functionalized Monofluoromethyl Group
luoroalkylated aromatic compounds are of great synthetic
Finterest because of their wide applications in pharmaceut-
ical and materials research.1−3 Transition metal (TM)-mediated
or catalyzed fluoroalkylations of aryl halides or boronic acids
are generally employed to construct the Rf-C (sp2) linkage,
among which copper- and palladium-catalyzed processes are
the most extensively investigated as a result of the wide scope
and high efficiency.4−13 Despite the fact that the TM-catalyzed
coupling reaction between a trifluoromethyl group and an aryl
group has been well documented,4−13 the analogous methods
for the incorporation of partially fluorinated methyl groups into
arenes remain largely unexplored.14,15
Recently, Amii et al. reported a three-step preparation of
difluoromethylated aromatics by copper-catalyzed cross-cou-
pling reaction with Me3SiCF2COOEt and subsequent decar-
boxylation.16 Moreover, the copper-mediated direct difluor-
omethylation of aryl iodides with Me3SiCF2H and Bu3SnCF2H
was reported by Hartwig et al. and Prakash et al.,
respectively.17,18 However, despite the various applications of
monofluoromethylated compounds in different fields,19−23
efficient methods for monofluoromethylation of aromatic
halides or boronic acids are scarce.24 Direct introduction of a
CH2F group was reported by Suzuki et al. in 2009 by the cross-
coupling reaction between CH2FI and pinacol phenylboronate;
however, the method employed a large excess amount of
pinacol phenylboronate (40 equiv) and the yield was low.25
Furthermore, a series of functionalized monofluoromethyl
groups (CFR1R2) could be introduced by coupling of aryl
halides (or boronic acids) with α-fluoro phosphonates, ketones
(or enolates), and esters, but further transformation of the
products in these reactions to monofluoromethylated com-
pound is difficult (Scheme 1, eq 1).26−30
aryl iodide could be achieved by a copper-mediated
fluoroalkylation with 2-PySO2CFHI and subsequent desulfo-
nylation (Scheme 1, eq 2).33 Herein, we report a new
monofluoromethylation of aryl iodides by a Hurtley-type
debenzoylative cross-coupling with an α-fluorinated active
methylene compound and subsequent desulfonylation. It was
found that the copper-catalyzed debenzoylative cross-coupling
proceeded smoothly in the presence of CuTc (copper
thiophene-2-carboxylate) and NaHCO3 with the aid of the
removable (2-pyridyl)sulfonyl group (Scheme 1, eq 3).
The Hurtley reaction is a well established method for cross-
coupling of aryl halides and active methylene compounds under
basic conditions. In the presence of a suitable ancillary ligand,
Recently, we became interested in investigating the versatile
chemical behaviors of fluoroalkyl 2-pyridyl sulfone re-
agents.31−35 We discovered that a monofluoromethylation of
Received: January 26, 2013
Revised: February 28, 2013
© XXXX American Chemical Society
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ACS Catalysis
Letter
the coupling reaction could proceed under mild reaction
conditions with a wide substrate scope;36 however, couplings
with activated α-fluoro methylene compounds are rarely
explored.37 Generally, it is difficult for α-substituted substrates
to participate in a Hurtley reaction. For instance, the reaction
with diethyl 2-methylmalonate was reported to give a trace
amount of product.38 Moreover, an α-fluoroalkyl anion tends to
decompose under elevated temperatures. These restrictions
make it challenging to achieve efficient Hurtley reactions with
fluorinated active methylene compounds.
We first focused on the copper-catalyzed cross-coupling
reaction between various phenylsulfonyl-substituted active
methylene compounds (1a−1c) and aryl iodide using 1-iodo-
4-methoxybenzene (3a) as a model substrate in the presence of
50% CuI under slightly basic conditions. The results are shown
in Table 1. To our surprise, only a trace amount of product was
under the reaction system. The authors thus proposed that a
bidentate binding of enolate to copper is crucial to the
reaction.40 Unlike carbonyl compounds and esters, sulfones
could not form “enolates” and are generally less efficient in
coordinating to a metal catalyst.41 As a result, sulfones are
challenging substrates in transition metal-catalyzed C−C bond
formation reactions,42 although the sulfonyl group possesses a
good ability to enhance the acidity of the substrate that is
beneficial to the reaction.
In our previous work, we discovered that the (2-pyridyl)-
sulfonyl group played an important role in copper-mediated
fluoroalkylations. The reactions with (2-pridyl)sulfones gave
much better yields than those with (phenyl)sulfones.33 In light
of the result, we envisioned that a copper-catalyzed Hurtley-
type reaction with α-fluorinated active methylene compound
might also be achieved by introducing the (2-pyridyl)sulfonyl
group as a coordinating group. A series of (2-pyridyl)sulfonyl-
substituted CHF acids were then synthesized to investigate
their behavior in the current copper-catalyzed fluoroalkya-
tions.43 To our delight, reaction with (2-pyridyl)sulfonyl CHF
acids 2a and 2b gave good yields of the coupling products
(entries 4 and 5), which suggested the (2-pyridyl)sulfonyl
group promoted the reaction efficiently. It should be noted that
no desired product was obtained when employing 2c as a
reagent, which indicated the presence of carbonyl or ester
group is still necessary to the success of the reaction.
Interestingly, both expected coupling product 5a and
debenzoylative product 7a were observed when the reaction
was carried out with 2a, but only the expected coupling product
5b was obtained when employing 2b as a reagent. This result is
probably due to the different electrophilicities of the carbonyl
and ester groups. Because debenzoylation of 5a could proceed
in the presence of Na2CO3 in DMSO, the product 7a is likely
to be generated through subsequent debenzoylation of 5a.44,45
With the suitable reagent 2a, we further optimized other
reaction parameters. K2CO3 and Cs2CO3 were found to be less
effective than Na2CO3 in the current reaction (Table 1, entry 4;
Table 2, entries 1 and 2). This is probably due to the tendency
of decomposition (via debenzoylation and defluorination) of
the reagent 2a under highly basic conditions. Interestingly, the
reaction could also proceed in the presence of N-ethyl-
diisopropylamine, which was reported to inhibit the Hurtley
reaction by saturating the coordination sphere of copper (Table
2, entry 3). Highly polar solvents DMSO and NMP were
beneficial to the reaction (Table 2, entry 5). A trace amount of
the desired product was observed when the reaction was carried
out in less-polar solvent 1,4-dioxane (Table 2, entry 6). CuTc
was found to be more effective than CuI in promoting the
current cross-coupling reaction (Table 2, entries 7 and 8). The
introduction of electron-donating groups into the phenyl ring
of reagent 2a was found to retard the debenzoylation of reagent
2 and improve the total yield of product 5 and 7 (Table 2,
entries 8−10). Finally, we found a highly selective debenzoy-
lative fluoroalkylation could be achieved by switching the base
to NaHCO3 (Table 2, entry 11). The small amount of 5 could
be easily converted into 7 by heating with NaHCO3 in MeOH.
With the optimized reaction conditions in hand (Table 2,
entry 11), we next explored the scope of the current copper-
catalyzed debenzoylative fluoroalkylation. As shown in Table 3,
various aryl iodides were converted to the corresponding
fluoroalkylated products in moderate to good yields (63−85%).
The method is amenable to a variety of functionalities,
including esters, ketones, and halides. The reactions with aryl
Table 1. Survey of Various Methylene Compounds
a
Unless otherwise stated, the reactions were run on a 0.2 mmol scale
in DMSO (2 mL) at 80 °C for 20 h in the presence of Na2CO3 (0.2
b
mmol) and CuI (0.1 mmol). The yield of coupling product based on
the amount of 3a, which was determined by 19F NMR spectroscopy
using PhCF3 as an internal standard.
observed when employing reagent 1a (substituted with benzoyl
group), and no desired product was obtained when the
reactions were carried out with reagents 1b and 1c (substituted
with an ester and sulfonyl group, respectively). Despite the long
history of the Hurtley reaction, the scope of the CH-acid is still
largely restricted to a specific type of active methylene
compound that is likely to serve as a chelating ligand for
copper under basic conditions.39 In 2002, Buchwald et al.
developed an efficient arylation of diethyl malonate in the
presence of CuI and 2-phenylphenol; however, arylation of
cyclic malonate ester and cyclic diketones was unsuccessful
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ACS Catalysis
Letter
in a cross-coupling reaction, probably as a result of steric
hindrance. The products 5 were subsequently converted to the
debenzoylative products 7 by treating with NaHCO3 and
MeOH.
Table 2. Survey of the Reaction Conditions
Reductive desulfonylation of 7 with Bu3SnH/AIBN enabled
facile access to monofluoromethylated arenes.46,47 Representa-
tive results are illustrated in Table 4. The reactions worked well
a
b
Table 4. Reductive Desulfonylation of 7
entry
base
solvent
CuX
x, %
yield (%)
1
2
3
4
5
6
7
8
K2CO3
DMSO
DMSO
DMSO
DMF
CuI
50
50
50
50
50
50
20
20
20
20
30
5a, 14; 7a, 52
5a, 17; 7a, 20
5a, 45; 7a, 0
5a, 9; 7a, trace
5a, 2; 7a, 51
5a, trace; 7a, 0
5a, 12; 7a, 53
5a, 19; 7a, 63
5d, 25; 7a, 60
5e, 37; 7a, 53
5e, 1; 7a, 90
Cs2CO3
i-Pr2NEt
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
NaHCO3
CuI
CuI
CuI
NMP
CuI
dioxane
DMSO
DMSO
DMSO
DMSO
DMSO
CuI
CuI
CuTc
CuTc
CuTc
CuTc
c
9
d
10
d
11
a
Unless otherwise stated, the reactions were run on a 0.2 mmol scale
b
in solvent (2 mL) at 80 °C for 20 h. Yield of coupling product based
on the amount of 3a, which was determined by 19F NMR spectroscopy
c
d
using PhCF3 as an internal standard. 2d was used instead of 2a. 2e
was used instead of 2a.
a
Yield determined by 19F NMR spectroscopy of the reaction mixture
b
using PhCF3 as an internal standard. Isolated yields.
Table 3. Copper-Catalyzed Debenzoylative Fluoroalkylation
of Aryl Iodides 3
with structurally diverse (2-pyridyl)sulfonylfluoromethylated
arenes 7 and smoothly gave the corresponding monofluor-
omethylated products 8 in moderate to good yields (60−77%).
It should be mentioned that an excess amount of AIBN is
necessary to drive the reaction to completion. The ipso
substitution of the (2-pyridyl)sulfonyl group by a tributyl-
stannyl radical is likely involved in the reaction, which is
supported by the observation of 2-(tributylstannyl)pyridine as a
byproduct in the reaction.
In conclusion, we have developed monofluoromethylation of
aryl iodides via a copper-catalyzed Hurtley-type debenzoylative
fluoroalkylation and subsequent desulfonylation. The (2-
pryridyl)sulfonyl group played an important role in promoting
the copper-catalyzed cross-coupling and could be removed
easily via a Bu3SnH-mediated desulfonylation. The use of
NaHCO3 as a base allowed a highly selective debenzoylative
cross-coupling reaction. Further explorations of the applications
of the (2-pyridyl)sulfonyl group in fluoroalkylation reactions
and a detailed mechanistic study are underway in our laboratory
and will be reported in due course.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, characterization data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
a
Isolated yield.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jinbohu@sioc.ac.cn.
iodides bearing either an electron-donating (including 7a, 7f,
7i) or electron-withdrawing group (7c) furnished satisfactory
yields of products. For ortho-substituted aryl iodides, a small
amount (5−10%) of undebenzoylative products 5 was obtained
Notes
The authors declare no competing financial interest.
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ACS Catalysis
Letter
(34) Zhao, Y.; Zhang, L.; Xu, G.; Zheng, J.; Hu, J. Sci. Sin. Chim.
2011, 41, 1833.
(35) Prakash, G. K. S.; Ni, C.; Wang, F.; Hu, J.; Olah, G. A. Angew.
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ACKNOWLEDGMENTS
■
This work was supported by the National Basic Research
Program of China (2012CB821600, 2012CB215500), the
National Natural Science Foundation of China (20825209,
21202189), and the Chinese Academy of Sciences.
(37) Very recently, the Hurtley-type reaction with fluorinated
activated methylene compounds has been presented in a patent.
See: Munenobu, I.; Keisuke, A. Jpn. Kokai Tokkyo Koho, 2011162521,
August 25, 2011.
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