Selective O-difluoromethylation of 1,3-diones by bromodifluoromethylating reagents

Article abstract of DOI:10.1021/ol4000313

The regioselective O-difluoromethylation of 1,3-diones was achieved via in situ generation of difluorocarbene from bromodifluoromethylating reagents in the presence of an organic base. A wide variety of difluormethyl enol ethers were obtained in good to excellent yields. The reaction mechanism is discussed based on ab initio calculations (kcal/mol).

Full text of DOI:10.1021/ol4000313

ORGANIC
LETTERS
2013
Vol. 15, No. 5
1044–1047
Selective O‑Difluoromethylation of
1,3-Diones by Bromodifluoromethylating
Reagents
Guokai Liu,† Xin Wang,† Xiu-Hua Xu,† Xu Lu,† Etsuko Tokunaga,†
Seiji Tsuzuki,‡ and Norio Shibata*,†
Department of Frontier Materials, Graduate School of Engineering, Nagoya Institute of
Technology, Gokiso, Showa-ku, Nagoya, Japan, and National Institute of Advanced
Industrial Science and Technology (AIST), Tsukuba, Ibaraki, Japan
nozshiba@nitech.ac.jp
Received January 5, 2013
ABSTRACT
The regioselective O-difluoromethylation of 1,3-diones was achieved via in situ generation of difluorocarbene from bromodifluoromethylating
reagents in the presence of an organic base. A wide variety of difluormethyl enol ethers were obtained in good to excellent yields. The reaction
mechanism is discussed based on ab initio calculations (kcal/mol).
Fluoro-organic compounds play an important role
in the development of pharmaceuticals, agrochemicals,
and advanced materials.1 Inparticular, compounds having
a difluoromethyl group (CF2H) have attracted much
attention recently, since the CF2H moiety could act as an
isostere to the unit of methanol (CH2OH) with improved
lipophilicity and resistance to oxidation.2 Thus, the di-
fluoromethylated variants of biologically active mol-
ecules having a CH2OH group are highly likely to show
increased membrane permeability with metabolic stability,
which might be potential candidates in the future drug
market.3 Direct introduction of a difluoromethyl group
into target molecules is an ideal strategy for the synthesis
of CF2H compounds. The building strategy is not
often suitable since the acidic CF2H moiety might not be
tolerated during the overall synthetic process. Despite
the success of direct trifluoromethylation,4 methodologies
for the introduction of a CF2H unit into molecules is still
under development.5ꢀ7 With this background in mind, we
were interested in so-called self-stable electrophilic difluoro-
methylating reagents (þCF2H-reagents) for this purpose
and selected successful examples are shown in Figure 1
including the reagents by Prakash and Hu.6f,i,k
Xiao et al. recently reported the synthesis of sym-
metrical S-(bromodifluoromethyl)diarylsulfoniumsal-ts
(ArSþ(CF2Br)Ar) and their utility in the electrophilic
bromodifluoromethylation reaction (þCF2Br).6j Shortly
afterwards, we also disclosed the synthesis of a series of
† Nagoya Institute of Technology.
‡ AIST.
ꢀ
ꢀ
(1) (a) Begue, J.-P.; Bonnet-Delpon, D. Bioorganic and Medicinal
Chemistry of Fluorine; Wiley-VCH: Weinheim, 2008. (b) Kirsch, P. Modern
Fluoroorganic Chemistry: Synthesis, Reactivity, Applications; Wiley-
VCH: Weinheim, 2004. (c) Umemoto, T. Chem. Rev. 1996, 96, 1757–
1777. (d) Thayer, A. M. Chem. Eng. News 2006, 84, 15–24. (e) Meanwell,
N. A. J. Med. Chem. 2011, 54, 2529–2591.
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J. U.; Frederick, R.; Denny, W. A.; Baguley, B. C.; Kestell, P.; Singh, R.;
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Nakamura, S.; Toru, T.; Shiro, M. Eur. J. Org. Chem. 2008, 3465–
3468. (b) Kawai, H.; Kusuda, A.; Nakamura, S.; Shiro, M.; Shibata, N.
Angew. Chem., Int. Ed. 2009, 48, 6324–6327. (c) Matsnev, A.; Noritake,
S.; Nomura, Y.; Tokunaga, E.; Nakamura, S.; Shibata, N. Angew.
Chem., Int. Ed. 2010, 49, 572–576. (d) Allen, A. E.; Macmillan,
D. W. C. J. Am. Chem. Soc. 2010, 132, 4986–4987. (e) Kawai, H.; Tachi,
K.; Tokunaga, E.; Shiro, M.; Shibata, N. Angew. Chem., Int. Ed. 2011,
50, 7803–7806. (f) Pham, P. V.; Nagib, D. A.; Macmillan, D. W. C.
€
Angew. Chem., Int. Ed. 2011, 50, 6119–6122. (g) Niedermann, K.; Fruh,
N.; Vinogradova, E.; Wiehn, M. S.; Moreno, A.; Togni, A. Angew.
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r
10.1021/ol4000313
Published on Web 02/13/2013
2013 American Chemical Society

more stable than CF2H-type reagents due to the lack of an
acidic H-atom. As a part of our research toward the
development of efficient methodologies for the synthesis
of fluoro-organic compounds, we disclose herein the di-
fluoromethylation of 1,3-diketones 2 with 1 mediated by
DBU or P2-Et to provide difluoromethyl enol ethers 3 in
high yields with complete oxygen selectivity.10 It is note-
worthy that the O-selective difluoromethylation of 2 was
observed, while C-difluoromethylation predominated on
the β-ketoesters 4 under the same conditions (Scheme 1).
Figure 1. Selected examples of electrophilic difluoromethylating
reagents having a CF2H moiety.
unsymmetrical S-(bromodifluoromethyl)-diarylsulfonium
salts (ArSþ(CF2Br)Ar0, 1) as þCF2Br-reagents of terminal
alkynes in response to n-BuLi.8 Interestingly, we observed
a phenomenon in which 1 acts as efficient þCF2H-reagents
rather than þCF2Br-reagents for sp3-C nucleophiles, in-
cluding β-ketoesters, by using organic bases in high to
excellent yields.9 In situ generation of difluorocarbene
(CF2 carbene) from 1 under low reaction temperature is
responsible for the transfer of CF2H. The use of CF2Br-
reagents 1 as a source of CF2H is advantageous since 1 are
Scheme 1. Electrophilic Difluoromethylation of 1,3-Dicarbonyl
Compounds with CF2Br-Reagents 1
(5) For nucleophilic difluoromethylation protocols, see: (a) Hine, J.;
Porter, J. J. J. Am. Chem. Soc. 1960, 82, 6178–6181. (b) Burton, D. J.;
Hartgraves, G. A.; Hu, J. Tetrahedron Lett. 1990, 31, 3699–3702. (c)
Hagiwara, T.; Fuchikami, T. Synlett 1995, 7, 717–718. (d) Piettre, S. R.;
Cabanas, L. Tetrahedron Lett. 1996, 37, 5881–5884. (e) Yudin, A. K.;
Prakash, G. K. S.; Deffieux, D.; Bradley, M.; Bau, R.; Olah, G. A. J. Am.
Chem. Soc. 1997, 119, 1572–1581. (f) Prakash, G. K. S.; Hu, J.; Wang,
Y.; Olah, G. A. Angew. Chem., Int. Ed. 2004, 43, 5203–5206. (g) Li, Y.;
Hu, J. Angew. Chem., Int. Ed. 2005, 44, 5882–5886. (h) Qin, Y.; Qiu, X.;
Yang, Y.; Meng, W.; Qing, F. J. Org. Chem. 2005, 70, 9040–9043. (i) Ni,
C.; Liu, J.; Zhang, L.; Hu, J. Angew. Chem., Int. Ed. 2007, 46, 786–789. (j)
Li, Y.; Hu, J. Angew. Chem., Int. Ed. 2007, 46, 2489–2492. (k) Zhao, Y.;
Huang, W.; Zhu, L.; Hu, J. Org. Lett. 2010, 12, 1444–1447. (l) Prakash,
G. K. S.; Ni, C.; Wang, F.; Hu, J.; Olah, G. A. Angew. Chem., Int. Ed.
2011, 50, 2559–2563. (m) Wang, F.; Zhang, W.; Zhu, J.; Li, H.; Huang,
K.; Hu, J. Chem. Commun. 2011, 47, 2411–2413. (n) Wang, F.; Luo, T.;
Zhu, J.; Wang, Y.; Krishnan, H. S.; Jog, P. V.; Ganesh, S. K.; Prakash,
G. K. S.; Olah, G. A. Angew. Chem., Int. Ed. 2011, 50, 7153–7157. (o)
Zhao, Y.; Cao, B.; Hu, J. J. Am. Chem. Soc. 2012, 134, 5790–5793.
(6) For electrophilic difluoromethylation protocols, see: (a) Rico, I.;
Wakselman, C. Tetrahedron Lett. 1981, 22, 323–326. (b) Chen, Q.; Wu,
S. J. Fluorine Chem. 1989, 44, 433–440. (c) Tian, F.; Kruger, V.; Bautista,
O.; Duan, J.; Li, A.; Dolbier, W. R.; Chen, Q. Org. Lett. 2000, 2, 563–
564. (d) Cai, X.; Wu, K.; Dolbier, W. R., Jr. J. Fluorine Chem. 2005, 126,
479–482. (e) Ando, J. M.; Wada, T.; Sato, N. Org. Lett. 2006, 8, 3805–
3808. (f) Prakash, G. K. S.; Weber, C.; Chacko, S.; Olah, G. A. Org. Lett.
2007, 9, 1863–1866. (g) Zheng, J.; Li, Y.; Hu, J.; Meuzelaar, G. J.;
Federsel, H. J. Chem. Commun. 2007, 5149–5151. (h) Zhang, W.; Zhu, J.;
Hu, J. Tetrahedron Lett. 2008, 49, 5006–5008. (i) Zhang, W.; Wang, F.;
Hu, J. Org. Lett. 2009, 11, 2109–2112. (j) Zhang, C.; Cao, H.; Wang, Z.;
Zhang, C.; Chen, Q.; Xiao, J. Synlett 2010, 7, 1089–1092. (k) Prakash,
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Koseki, Y.; Aono, T.; Sasagawa, H.; Ichikawa, J. J. Fluorine Chem.
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Tokunaga, E.; Shibata, N. ChemistryOpen. 2012, 1, 221–226.
2-Methyl-1,3-cyclopentanedione 2a was chosen as a
model substrate for optimization of the reaction condi-
tions (Table 1). First, treatment of 2a with 1 (1.0 equiv) and
DBU (1.2 equiv) at ꢀ75 °C in CH2Cl2 was carried out.
Despite our expectation, a regioselective O-difluoromethyl-
ation product (O-CF2H, 3a) was solely obtained in 45%
yield without any C-CF2H product (entry 1). Enthused by
this outcome, we further optimized the reaction conditions
to improve the yield of 3a. Increasing the equivalence of
DBU showed no influence on the yield of 3a (entry 2), but
excess 2a (2.0 equiv) with 1.0 equiv of DBU gave 69% of
3a based on the use of reagents 1 (entry 3). The yield of
3a was further improved to 84% under the conditions
of 2a/DBU/1 at a ratio of 2.2/2.0/1.0 (entry 4). We next
investigated the effect of base, and the most organic bases
performed well with good yields (entries 5ꢀ9). P2-Et
reacted slightly better than DBU to give 3a in 88% yield
(entry 7). Reaction temperature was also investigated
(entries 10 and 11). The reaction was unresponsive to tem-
perature, and 3a was obtained in excellent yields at both
rt and 0 °C. Solvent screening showed dichloromethane
to be the best choice (entries 12ꢀ14). In all cases, O-CF2H
product 3a was selectively observed.
With the optimum conditions in hand, we explored the
generality of this O-regioselective difluoromethylation
using various 1,3-dione substrates (Table 2). A series of
1,3-cyclopentanediones 2aꢀe and 1,3-cyclohexanediones
2fꢀi with different substituents at the C-2 position pro-
vided the corresponding difluoromethyl enol ethers 3aꢀe
(entries 1ꢀ5) and 3fꢀi (entries 6ꢀ9) in good to high
yields. 1,3-Cyclohexanediones 2jꢀo with substituents at
the C-5 position also gave high to excellent yields for 3jꢀo
(entries 10ꢀ15). The reaction of 1,3-indandiones 2p and 2q
(7) For radical difluoromethylation protocols, see: (a) Cao, P.; Duan,
J.; Chen, Q. J. Chem. Soc., Chem. Commun. 1994, 6, 737–738. (b)
Miethchen, R.; Hein, M.; Reinke, H. Eur. J. Org. Chem. 1998, 919–
923. (c) Thongpaisanwong, V.; Reutrakul, T.; Tuchinda, P.; Kuhakarn,
C.; Pohmakotr, M. J. Org. Chem. 2004, 69, 6913–6915. (d) Wegert, A.;
Miethchen, R.; Hein, M.; Reinke, H. Synthesis 2005, 11, 1850–1858. (e)
Li, Y.; Liu, J.; Zhang, L.; Zhu, L.; Hu, J. J. Org. Chem. 2007, 72, 5824–
5827. (f) Fujiwara, Y.; Dixon, J. A.; Rodriguez, R. A.; Baxter, R. D.;
Dixon, D. D.; Collins, M. R.; Blackmond, D. G.; Baran, P. S. J. Am.
Chem. Soc. 2012, 134, 1494–1497.
(8) Liu, G.; Mori, S.; Wang, X.; Noritake, S.; Tokunaga, E.; Shibata,
N. New J. Chem. 2012, 36, 1769–1773.
(9) Liu, G.; Wang, X.; Lu, X.; Xu, X.; Tokunaga, E.; Shibata, N.
ChemistryOpen 2012, 1, 227–231.
(10) Xiao et al. observed a single example of O-difluoromethylation
of 1,3-dicyclopentane dione (not bromodifluoromethylatioþn) with NaH
during their study of bromodifluoromethylation by PhS (CF2Br)Ph,
although the generality of the reaction was not discussed. See ref 6j.
Org. Lett., Vol. 15, No. 5, 2013
1045

Table 1. Optimization of Reaction Conditionsa
Table 2. O-Difluoromethylation of 1,3-Diones 2aꢀqa
temp
3a yield
(%)b
entry
base
DBU
(°C)
2a/base/1
1
ꢀ75
ꢀ75
ꢀ75
ꢀ75
ꢀ75
ꢀ75
ꢀ75
ꢀ75
ꢀ75
rt
1.0/1.2/1.0
1.0/2.0/1.0
2.0/1.0/1.0
2.2/2.0/1.0
2.2/2.0/1.0
2.2/2.0/1.0
2.2/2.0/1.0
2.2/2.0/1.0
2.2/2.0/1.0
2.2/2.0/1.0
2.2/2.0/1.0
2.2/2.0/1.0
2.2/2.0/1.0
2.2/2.0/1.0
45
43
69
84
76
80
88
39
20
85
93
77
78
57
2
DBU
3
DBU
4
DBU
5
P1-t-Oct
P1-t-Bu
P2-Et
Et3N
6
7
8
9
Cs2CO3
P2-Et
P2-Et
P2-Et
P2-Et
P2-Et
10
11
12c
13d
14e
0
0
0
0
a The reaction was carried out with 0.1 mmol of 2a in dichloromethane.
DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene, P1-t-Oct: ter-Octylimino-tris-
(dimethylamino)phosphorane, P1-t-Bu: tert-butylimino-tri(pyrrolidino)-
phosphorane, P2-Et: tetramethyl-(tris(dimethylamino) phosphoranylidene)-
phosphorictriamid-Et-imin, Et3N: triethylamine. b Determined by 19F
NMR. c THF was used as the solvent. d CH3CN was used as the solvent.
e DMF was used as the solvent.
with 1 also proceeded successfully to furnish correspond-
ing O-CF2H products 3p and 3q in 55% and 66% yields,
respectively (entries 16 and 17). However, acyclic 1,3-dione
2f gave a complex mixture (entry 18). DBU performed
more effectively in some cases (entries 6, 9, 10, 12, 13, and
15), and in some cases it proceeded even at ꢀ75 °C (entries
6ꢀ7, 9ꢀ10, 12ꢀ13, 15ꢀ17).
To demonstrate the further utility of difluoromethyl
enol ethers, the transformation of 3 was examined.
Difluoromethyl enol ether 3p was selectively reduced into
compound 5 by 6 equiv of NaBH4 quantitatively in 30 min
(Scheme 2).
a The reaction was carried out with 2.2 equiv of 2, 1.0 equiv of
1 (0.1 mmol), and 2.0 equiv of base in CH2Cl2 at 0 or ꢀ75 °C. DBU:
1,8-diazabicyclo[5.4.0]undec-7-ene, P2-Et: tetramethyl-(tris(dimethyl-
amino)phosphoranylidene)phosphorictriamid-Et-imin. For detailed re-
action conditions, see Supporting Information. b Small amounts of
2-bromo-O-difluoromethyl enol ethers were separated as byproducts.
c DBU was used as the base. d The reaction was carried out at ꢀ75 °C.
e Isolated yields were calculated based on 1.
A plausible mechanism for O-difluoromethylation of
1,3-diones 2 with 1 is shown in Scheme 3. Initially, dike-
tones 2reactwith a base to provide enolates A, whichattack
at the Br-atom in 1 to furnish CF2 carbene, PhSC6HMe4,
brominated products B, and TfOꢀ[Base-H]þ. Although we
did not detect B, some structurally unidentified complex
mixtures were observed after the completion of the reac-
tion. The generated CF2 carbene reacted with enolates A
to furnish O-difluoromethyl anions C, and the latter should
be protonated by [Base-H]þto give 3 with a base. The last
protonation step from C to 3 and base may be reversible
due to the acidity of the CF2H moiety, andthishypothesisis
supported by the fact that 2 equiv of base are desirable for
better yields (see entries 3 and 4, Table 1).
3(100% selectivity) underthe same reaction conditions.11,12
Molecular orbital calculations were therefore carried out
to study the reaction of anions 6 and 7 with CF2 carbene
providing O-CF2H or C-CF2H products (Scheme 4).
The interactions between CF2 carbene with anion 6 or 7
were studied by ab initio molecular orbital calculations.13
The geometry of the complex of 6 with a singlet CF2
carbene was optimized from 24 initial geometries. The
(11) O-Difluoromethylation of ketones is often observed (see refs 6d
and 6m); however, as far as we know, the reason for the oxygen preference
has not actively been discussed except by us (see refs 6q and 12).
(12) We previously discussed the C- and O-selectivity for electrophilic
or radical fluoromethylations of β-ketoesters, but not for carbene-
mediated fluoromethylations (see ref 6q).
Finally, we discuss the complete O-regioselectivity. As
mentioned in the introduction part of this manuscript,
β-ketoesters 4 furnish C-CF2H products predominantly
(8:2 ratio),9 while 1,3-diketones 2 afford O-CF2H products
1046
Org. Lett., Vol. 15, No. 5, 2013

most stable O- and C-CF2H products are shown in
Figure 2b. In contrast to 6, the calculated relative energies
show that the C-CF2H product is more stable than the
O-CF2H product by 4.18 kcal/mol. The difluoromethyla-
tion of an O-atom of the ester group did not occur after
the geometry optimizations. The complex of 7 with CF2
carbene was also obtained by the geometry optimizations.
The complex is substantially less stable (10.97 kcal/mol)
than the C- and O-CF2H products. These calculated
relative energies of the CF2H products explain well the
experimentally observed selectivity of the difluoromethyl-
ation reaction of diketones 2 (O-difluoromethylation) and
β-ketoesters 4 (C-difluoromethylation).
Scheme 2. Selective Reduction of 3p
Scheme 3. Proposed Reaction Mechanism
Figure 2. (a) Geometries and relative energies of CF2H products
of 6; (b) Geometries and relative energies of CF2H products of 7
and complex of 7 with CF2 carbene. Energy in kcal/mol.
Scheme 4. Models of Anions 6 and 7with the Reaction of CF2
Carbene for Caluculations
In conclusion, we developed selective O-difluoromethyl-
ation of 1,3-diones 2 by S-(bromodifluoromethyl)diaryl sulfo-
nium salts 1 in the presence of an organic base. A wide variety
of difluoromethyl enol ethers 3were synthesized nicely in good
to excellent yields by 1. This approach provides a synthetic
entry to biologically relevant difluoromethyl ethers of interest
to the pharmaceutical and agrochemical industries.1a,b,e The
further application of S-(bromodifluoromethyl)diaryl sulfo-
nium salt 1 is currently underway in our laboratory.
O- or C-CF2H products were spontaneously produced by
geometry optimizations of the complex. The optimized
geometries of the most stable O- or C-CF2H products with
their relative energies are shown in Figure 2a. The calcu-
lated relative energies show that the O-CF2H product is
morestablethanthe C-CF2H product by 3.7 kcal/mol. The
reaction of β-ketoester was investigated next (Figure 2b).
The geometry of the complex of 7 with a singlet CF2
carbene was optimized from 19 initial geometries. The
Acknowledgment. This study was financially supported
in part by the Platform for Drug Discovery, Informatics,
andStructural LifeSciencefrom theMinistryofEducation,
Culture, Sports, Science and Technology, Japan; Grants-
in-Aid for Scientific Research from MEXT (Ministry
of Education, Culture, Sports, Science and Technology)
(24105513, Project No. 2304: Advanced Molecular Trans-
formationbyOrganocatalysts);andJST(ACT-C:Creation
of Advanced Catalytic Transformation for the Sustainable
Manufacturing at Low Energy, Low Environmental Load).
We thank Tosoh F-Tech Ltd. for partial support. G.L.
thanks the Hori Sciences & Arts Foundation for support.
(13) The Gaussian 03 program was used for the ab initio molecular
orbital calculations. The 6-311G** basis set was used for the calcula-
tions. Electron correlation was accounted for by the second-order
MφllerꢀPlesset perturbation (MP2) method. See: Gaussian 03, Revision
D.01, Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Montgomery, Jr., J. A.; Vreven, T.;
Kudin, K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.;
Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson,
G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.;
Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai,
H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken,
V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev,
O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.;
Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski,
V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D.
K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui,
Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.;
Liashenko, A.;Piskorz, P.;Komaromi, I.;Martin, R. L.; Fox, D. J.; Keith,
T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.;
Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople,
J. A. Gaussian, Inc.: Wallingford, CT, 2004.
Supporting Information Available. Experimental pro-
cedures, full characterization of new products, and copies
of NMR spectra. This material is available free of charge
via the Internet http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 5, 2013
1047