Copper-catalyzed difluoromethylation of β,γ-unsaturated carboxylic acids: An efficient allylic difluoromethylation

Article abstract of DOI:10.1002/anie.201206556

Not one but two! A new strategy for the regiospecific construction of compounds with allylic CF₂H groups has been developed. The decarboxylative (phenylsulfonyl)difluoromethylation of β,γ- unsaturated carboxylic acids is catalyzed by a Lewis acid (CuCl ₂·2 H₂O), and the resulting product easily undergoes desulfonylation. Copyright

Full text of DOI:10.1002/anie.201206556

Angewandte
Chemie
DOI: 10.1002/anie.201206556
Synthetic Methods
Copper-Catalyzed Difluoromethylation of b,g-Unsaturated Carboxylic
Acids: An Efficient Allylic Difluoromethylation**
Zhengbiao He, Mingyou Hu, Tao Luo, Lingchun Li, and Jinbo Hu*
À
À
The difluoromethyl group (CF2H) is an intriguing structural
motif, which has great potential for many applications in life-
science-related fields.[1–5] It has been realized that the CF2H
group can act as lipophilic hydrogen-bond donors and as
a bioisostere of alcohols and thiols.[1–4] In this context, the
development of efficient methods for the incorporation of the
CF2H group into organic molecules has attracted much
attention.[1,2,6–9] Recently, transition-metal-mediated or tran-
sition-metal-catalyzed difluoromethylation (or difluoroalky-
Csp3 CF2H (or allylic Csp3 CF2R) bonds by copper-catalyzed
decarboxylative difluoromethylation of b,g-unsaturated car-
boxylic acids [Scheme 1, Eq. (2)].
Recently, we discovered the copper-catalyzed decarbox-
ylative fluoroalkylation of a,b-unsaturated carboxylic acids,
a method which provides a powerful tool for vinylic di- and
trifluoromethylations.[13] We envisaged that this decarboxyla-
tive fluoroalkylation strategy might be also used to tackle the
challenging allylic difluoromethylation problem when the b,g-
unsaturated carboxylic acids are used as substrates. With this
consideration in mind, we chose the reaction between the
I(III)-CF2SO2Ph reagent 1[14] and 3-(p-tolyl)-3-butenoic acid
(2a) as a model reaction to survey the reaction conditions. As
shown in Table 1, selection of the proper Lewis acid catalyst,
solvent, and temperature was found to be crucial for the
reaction. In the absence of a Lewis acid, the desired
decarboxylative fluoroalkylation reaction could hardly pro-
ceed (entry 21). While Ni(OAc)2·4H2O and Pd(OAc)2 were
À
lation) of aryl halides and aryl boronic acids to construct Csp2
[6–9]
À
CF2H (or Csp2 CF2R) bonds have been intensively studied.
Baran and co-workers also reported an elegant process for the
direct difluoromethylation of arenes by a free radical
process.[10] However, the transition-metal-mediated or tran-
sition-metal-catalyzed difluoromethylation and difluoroalky-
À
À
lation for the construction of allylic Csp3 CF2H (or allylic Csp3
CF2R) bonds are scarce. Previously, Burton and Hartgraves
reported the difluoromethylations of allyl halides using either
a difluoromethyl cadmium or copper reagent.[11,12] However,
the regioselectivity of these reactions was not well controlled,
and in many cases, both a-attack and g-attack products were
obtained [Scheme 1, Eq. (1)]. Herein, we disclose a new
catalytic protocol for the regiospecific construction of allylic
Table 1: Survey of reaction conditions.
Entry Equiv. Solvent[a]
Catalyst (equiv)
T
Yield
2a
[8C] [%][b]
1
2
3
4
5
6
7
8
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
1.0
0.5
2.0
2.0
2.25
2.25
dioxane
THF
CH3CN
CCl4
DCE
CuCl (0.25)
CuCl (0.25)
CuCl (0.25)
CuCl (0.25)
CuCl (0.25)
CuCl (0.25)
CuCl (0.25)
70 21
70 18
70 33
70 33
70 30
70 52
70 48
70 42
70 53
70 55
H2O/DME (1:4)
H2O/THF (1:4)
H2O/CH3CN (1:4) CuCl (0.25)
H2O/DMF (1:4) CuCl (0.25)
H2O/dioxane (1:4) CuCl (0.25)
H2O/dioxane (1:4) Ni(OAc)2·4H2O (0.25) 70
H2O/dioxane (1:4) Zn(OAc)2·2H2O (0.25) 70 46
H2O/dioxane (1:4) Pd(OAc)2 (0.25) 70
H2O/dioxane (1:4) Cu(OAc)2·H2O (0.25) 70 51
H2O/dioxane (1:4) CuCl2·2H2O (0.25)
H2O/dioxane (1:4) CuCl2·2H2O (0.25)
H2O/dioxane (1:4) CuCl2·2H2O (0.25)
H2O/dioxane (1:4) CuCl2·2H2O (0.06)
H2O/dioxane (1:4) CuCl2·2H2O (0.03)
H2O/dioxane (1:4) CuCl2·2H2O (0.016)
9
10
11
12
13
14
15
16
17
18
19
20
21
0
Scheme 1. Allylic difluoromethylations.
0
[*] Dr. Z. He, M. Hu, T. Luo, L. Li, Prof. Dr. J. Hu
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences
345 Ling-Ling Road, Shanghai, 200032 (China)
E-mail: jinbohu@sioc.ac.cn
70 62
70 40
70 20
70 75
90 80
90 85
90 trace
[**] Support of our work by the National Basic Research Program of
China (2012CB215500 and 2012CB821600) and the National
Natural Science Foundation of China (20825209, 20832008) is
gratefully acknowledged. Professor Kuo-Wei Huang is thanked for
helpful discussions.
H2O/dioxane (1:4)
–
[a] The data within the parentheses refer to the volume ratio. [b] Deter-
mined by 19F NMR spectroscopy using PhCF3 as an internal standard.
DCE=1,2-dichloroethane, DME=1,2-dimethoxyethane, DMF=N,N-
dimethylformamide.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201206556.
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.
Angewandte
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À
unable to promote the present C CF2SO2Ph bond formation
(entries 11 and 13), other Lewis acids such as CuCl, Zn-
(OAc)2·2H2O, Cu(OAc)2·2H2O, and CuCl2·2H2O catalyzed
the reaction (entries 1–10, 12, and 15–20).[15] It is particularly
interesting that the addition of water as a cosolvent can
significantly increase the product yield (entries 1–3, 7, 8, and
10). Finally, the optimal yield (85%) of the product 3a was
obtained when 1 and 2a (molar ratio 1:2.25) were stirred in
H2O/1,4-dioxane (1:4 v/v) in the presence of CuCl2·2H2O
(1.6 mol%) at 908C for 12 hours (entry 20). It is noteworthy
to mention that the reaction is not sensitive to air, thus
simplifying the reaction.
relatively electron-rich b,g-unsaturated carboxylic acids 2a–
e and 2i reacted with 1 to give the corresponding products 3a–
e and 3i in high yields, and the reactions with carboxylic acids
bearing an electron-withdrawing group gave lower yields (3h
and 3l). Many synthetically important functional groups,
including bromine, hydroxy, alkynyl, and ester groups, are
well tolerated in the reaction. Notably, the aldehyde group,
which is usually fragile under oxidative conditions, remained
intact in the reaction. To our delight, alkyl-substituted b,g-
unsaturated acids (2m,n) and cyclic substrates (2p–t) were
also found to react smoothly with 1 to give the corresponding
products in satisfactory yields. To our surprise and delight, the
allenoic acid 4 could also react smoothly with 1 using our
method to afford the (penylsufonyl)difluoromethylated prod-
uct 5 in 55% yield (Scheme 3).
By using the optimized reaction conditions (Table 1,
entry 20), we examined the substrate scope of the present
decarboxylative fluoroalkylation reaction. The results are
summarized in Scheme 2. The reaction proved to be general
and amenable to a wide range of structurally diverse
substrates (2a–t), and the desired products 3a–t were pro-
duced in satisfactory yields. In particular, we found that the
Scheme 3. (Phenylsufonyl)difluoromethylation of allenoic acid 4.
Since the (phenylsulfonyl)difluoromethyl group is a ver-
satile functionality that can be readily transformed into other
highly useful functionalities such as difluoromethylidene
( CF2) and difluoromethyl (CF2H),[16,17] the present synthetic
=
method opens up new avenues for the synthesis of a wide
range of difluorinated compounds. For instance, when we
treated the product 3e with lithium hexamethyldisilazide
(LiHMDS) in THF at room temperature, the 3-substituted
gem-difluoro-1,3-butadiene 6 was produced in nearly quanti-
tative yield (Scheme 4). Furthermore, upon reductive desul-
Scheme 4. Conversion of 3e into the gem-difluoroolefine 6.
fonylation with our previously developed Mg/HOAc/NaOAc
system in DMF solution at room temperature,[18] the com-
pounds 3n and 3o were smoothly transformed into the
corresponding difluoromethylated products 7n and 7o in
98% and 85% yield, respectively (Scheme 5).
In summary, we have developed a new strategy for
regiospecific allylic difluoromethylations. Lewis acid-cata-
lyzed decarboxylative fluoroalkylations of the b,g-unsatu-
rated carboxylic acids 2 with the I(III)-CF2SO2Ph reagent
1 gives the corresponding (phenylsulfonyl)difluoromethy-
lated products 3 in high yields. The products can be addition-
ally transformed into allylic CF2H-substituted products by
reductive desulfonylation. Furthermore, an allenoic acid also
reacted smoothly with 1 in moderate yield to construct
Scheme 2. (Phenylsufonyl)difluoromethylation of the b,g-unsaturated
acids 2 with 1. Reaction conditions: 1 (0.8 mmol), 2 (1.8 mmol),
CuCl2·2H2O (0.0125 mmol ca. 1.6 mol%), 1,4-dioxane (4 mL), and
H2O (1 mL) were stirred at 908C for 12 h. Yield is that of the isolated
compound.
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silica gel column chromatography (petroleum ether/EtOAc 30:1) to
give the product 7n (124 mg, 98% yield).
Received: August 14, 2012
Published online: October 12, 2012
Keywords: allylic compounds · copper · homogenous catalysis ·
.
fluorine · synthetic methods
[1] For a recent review on difluoromethylation reactions, see: J. Hu,
W. Zhang, F. Wang, Chem. Commun. 2009, 7465, and references
therein.
[2] For recent examples of difluoromethylations, see: a) Y. Zhao, W.
Huang, J. Zheng, J. Hu, Org. Lett. 2011, 13, 5342; b) A. A.
Tyutyunov, V. E. Boyko, S. M. Igoumnov, Fluorine Notes 2011,
78, 1; c) F. Wang, W. Huang, J. Hu, Chin. J. Chem. 2011, 29, 2717;
d) K. Fuchibe, Y. Koseki, T. Aono, H. Sasagawa, J. Ichikawa, J.
Fluorine Chem. 2012, 133, 52; e) G. K. S. Prakash, Z. Zhang, F.
Wang, C. Ni, G. A. Olah, J. Fluorine Chem. 2011, 132, 792; f) Y.
Zhao, B. Gao, J. Hu, J. Am. Chem. Soc. 2012, 134, 5790; g) T.
Iida, R. Hashimoto, K. Aikawa, S. Ito, K. Mikami, Angew. Chem.
2012, 124, 9673; Angew. Chem. Int. Ed. 2012, 51, 9535.
[3] J. A. Erickson, J. I. Mcloughlin, J. Org. Chem. 1995, 60, 1626.
[4] N. A. Meanwell, J. Med. Chem. 2011, 54, 2529.
[5] For a recent example of CF2H-containing drug candidates, see:
G. W. Rewcastle, et al., J. Med. Chem. 2011, 54, 7105.
[6] a) K. Fujikawa, Y. Fujioka, A. Kobayashi, H. Amii, Org. Lett.
2011, 13, 5560; b) K. Fujikawa, A. Kobayashi, H. Amii, Synthesis
2012, 44, 3015.
Scheme 5. Reductive desulfonylation.
À
C(vinyl) CF2SO2Ph bonds under our reaction conditions.
This decarboxylative difluoromethylation has a wide sub-
strate scope and shows good functional-group tolerance, and
promises to find many applications in life-science-related
fields. Further investigations into the reaction mechanism and
the application of the current strategy in other fluoroalkyla-
tions, as well as fluorinations are currently underway in our
laboratory.
[7] P. S. Fier, J. F. Harting, J. Am. Chem. Soc. 2012, 134, 5524.
[8] Q.-Q. Qing, Q.-L. Shen, L. Lu, J. Am. Chem. Soc. 2012, 134,
6548.
Experimental Section
[9] Z. Feng, F. Chen, X. Zhang, Org. Lett. 2012, 14, 1938.
[10] Y. Fujiwara, J. A. Dixon, R. A. Rodriguez, R. D. Baxter, D. D.
Dixon, M. R. Collins, D. G. Blackmond, P. S. Baran, J. Am.
Chem. Soc. 2012, 134, 1494.
[11] G. A. Hartgraves, D. J. Burton, J. Fluorine Chem. 1988, 39, 425.
[12] G. A. Hartgraves, D. J. Burton, J. Fluorine Chem. 2007, 128,
1198.
Typical procedure for difluoromethylation of the b,g-unsaturated
carboxylic acids 2 with the reagent 1. The reagent 1 (362 mg,
0.8 mmol, 1.0 equiv), 2n (986 mg, 1.8 mmol, 2.25 equiv), and
CuCl2·2H2O (2.0 mg, 0.0125 mmol, 1.6 mol%) were added to a reac-
tion flask equipped with a magnetic stirring bar and a reflux
condenser. 1,4-Dioxane (4 mL) and H2O (1 mL) were then added
to the reaction mixture, which was heated to 908C and stirred for 12 h.
The reaction mixture was then cooled to ambient temperature and
extracted with diethylether (15 mL ꢀ 3), and dried over MgSO4. After
filtration and and removal of solvent under vacuum, the residue was
purified by silica gel chromatography (petroleum ether/EtOAc 20:1)
to provide the pure product 3n (350 mg, 75% yield).
[13] Z. He, T. Luo, M. Hu, Y. Cao, J. Hu, Angew. Chem. 2012, 124,
4010; Angew. Chem. Int. Ed. 2012, 51, 3944.
[14] W. Zhang, J. Zhu, J. Hu, Tetrahedron Lett. 2008, 49, 5006.
[15] We found that the CuF2·2H2O/TMEDA catalyst system (as used
in Ref. [12]) was less efficient than CuCl2 for the current
reaction. When we used CuF2·2H2O (20 mol%) as the catalyst
and TMEDA (25 mol%) as ligand, H2O (4 mL) and DCE
(3 mL) as solvent, and 2a (2.25 equiv) and 1 (1.0 equiv) as
reactants, at 808C for 12 h; the yield of the product 3a was only
58%. When we used CuF2 (20 mol%) as the catalyst and
TMEDA (25 mol%) as ligand, H2O (1 mL) and 1,4-dioxane
(4 mL) as solvent, and 2a (2.25 equiv) and 1 (1.0 equiv) as
reactants, at 908C for 12 h, the yield of 3a was only 49%.
[16] J. Hu, J. Fluorine Chem. 2009, 130, 1130.
Typical procedure for reductive desulfonylation of 3. A HOAc/
NaOAc (1:1) buffer solution (4 mL; 8 molLÀ1) was added to a 50 mL
Schlenk flask containing the sulfone compound 3n (166 mg,
0.285 mmol) in 4 mL DMFat room temperature. Magnesium turnings
(288 mg, 12 mmol) were then added in portions at 08C. The reaction
mixture was stirred at room temperature for 96 h, and then 30 mL
water were added. The solution mixture was extracted with Et2O
(20 mL ꢀ 3), and the combined organic phase was washed with
saturated NaHCO3 solution and brine, and then dried over MgSO4.
After the removal of the ethyl ether, the crude residue was purified by
[17] G. K. S. Prakash, J. Hu, Acc. Chem. Res. 2007, 40, 921.
[18] C. Ni, J. Hu, Tetrahedron Lett. 2005, 46, 8273.
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