Y. Hagooly et al. / Tetrahedron Letters 50 (2009) 392–394
393
S
S
OCF2Cl
OH
Et3N
BrF3
+
1) ClC(=S)Cl
2) BrF3
ROH
Cl
Cl
RO
Cl
NO2
NO2
Bu3SnH
ABCN
1h
NaSH
ROCF2Clref.11
ROCF2H
1
2
OCF2Cl
OCF2H
Bu3SnH
ABCN
CH2
CH2
85%
90%
a
b
R =
R =
NH2
1i 90%
NH2
2i 90%
Scheme 3. Aromatic difluoromethyl ethers.
CH2
85%
75%
c
d
R =
R =
Acknowledgment
This work was supported by the USA-Israel Binational Science
Foundation (BSF), Jerusalem, Israel.
CH2
References and notes
80%
70%
CH2
e
f
R =
R =
1. Matsumura, Y.; Mori, N.; Nakano, T.; Sasakura, H.; Matsugi, T.; Hara, H.;
Morizawa, Y. Tetrahedron Lett. 2004, 45, 1527–1529.
2. Wang, R.; Qiu, X.; Bols, M.; Ortega-Caballero, F.; Qing, F. J. Med. Chem. 2006, 49,
2989–2997.
3. Liu, Y.; Ahmed, V.; Hill, B.; Taylor, S. D. Org. Biomol. Chem. 2005, 3, 3329–3335.
4. See for example: (a) Muller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881–
1886; (b) Kirsch, P. In Modern Fluoroorganic Chemistry; Wiley-VCH: Weinheim,
2004.
5. (a) Zheng, X.; Meng, W.; Qing, F. Tetrahedron Lett. 2004, 45, 8083–8085; (b)
Wang, C.; Zheng, X.; Meng, W.; Li, H.; Qing, F. Tetrahedron Lett. 2005, 46, 5399–
5402.
O
O
O
CH2
85%
N(CH2)2
g
R =
O
6. Sobolev, A.; Franssen, M. C. R.; Vigante, B.; Cekavicus, B.; Zhalubovskis, R.;
Kooijman, H.; Spek, A. L.; Duburs, G.; Groot, A. J. Org. Chem. 2002, 67, 401–410.
7. Yagupolskii, L. M.; Fialkov, Y. A.; Tarasova, E. V. Pharm. Chem. J. 2006, 40, 189–
193.
Scheme 2. Preparation of difluoromethyl ethers.
8. Kudzma, L. V.; Huang, C. G.; Lessor, R. A.; Rozov, L. A.; Afrin, S.; Kallashi, F.;
McCutcheon, C.; Ramig, K. J. Fluorine Chem. 2001, 111, 11–16.
9. Ben-David, I.; Rechavi, D.; Mishani, E.; Rozen, S. J. Fluorine Chem. 1999, 97, 75–
78 and references cited therein.
10. See for example (a) Zheng, J.; Li, Y.; Zhang, L.; Hu, J.; Meuzelaar, G. J.; Federsel,
H. Chem. Commun. 2007, 5149–5151; (b) Zhang, L.; Zheng, J.; Hu, J. J. Org. Chem.
2006, 71, 9845–9848; (c) Nawrot, E.; Jonczyk, A. J. Fluorine Chem. 2006, 127,
943–947; (d) Chupp, J. P.; Hemmerly, D. M.; Freeman, J. J. J. Org. Chem. 1993, 58,
Bi- and tricyclic compounds such as the norbornyl (1d) and
adamantylethyl (1e) derivatives also behaved similarly, and the
desired difluoromethyl-1-norbornylethyl ether (2d) and difluoro-
methyl-1-adamantylethyl ether (2e) were obtained in 75% and
80% yields, respectively. The ether function is also tolerated in this
reaction as demonstrated by the ethylene glycol derivative, chloro-
difluoromethyl-(2-methoxyethoxy)ethyl ether (1f), which was
converted into difluoromethyl-(2-methoxyethoxy)ethyl ether (2f)
in 70% yield. Amines can also serve as substrates although they
have to be protected prior to the reactions described in Scheme
1. This situation was demonstrated by amino ethanol which was
transformed into chlorodifluoromethyl-N-phthalimidoethyl ether
(1g), which was reduced easily with Bu3SnH in refluxing toluene
to difluoromethyl-N-phthalimidylethyl ether (2g) in high yield.
Since aromatics which are susceptible to electrophilic attack are
usually brominated by BrF3,17 it is easy to use deactivated ring
compounds such as 3-nitrophenol which was transformed to 3-
chlorodifluoromethoxynitrobenzene (1h). The nitro group, how-
ever, inhibits the radical chain reaction induced by tributyltin hy-
dride, but this difficulty can be circumvented by first reducing 1h
to the corresponding 3-chlorodifluoromethoxyaniline (1i), which
posed no problem for the key step with Bu3SnH to form 3-difluo-
romethoxyaniline (2i) in 90% yield (Scheme 3). Such aniline
derivatives could serve as substrates for numerous further
transformations.
245–248.
A somewhat more general synthesis is based on generating
difluorocarbenes: Chen, Q.; Wu, S. J. Fluorine Chem. 1989, 44, 433–440.
11. Hagooly, Y.; Sasson, R.; Welch, M. J.; Rozen, S. Eur. J. Org. Chem. 2008, 2875–
2880.
12. For example, it has been used to make hexafluorocyclopentadiene: Soelch, R.
R.; Mauer, G. W.; Lemal, D. M. J. Org. Chem. 1985, 50, 5845–5852.
13. (a) Rozen, S. Acc. Chem. Res. 1988, 21, 307–312; (b) Rozen, S. Acc. Chem. Res.
1996, 29, 243–248.
14. Rozen, S. Acc. Chem. Res. 2005, 38, 803–812.
15. Rozen, S.; Mishani, E.; Bar-Haim, A. J. Org. Chem. 1994, 59, 2918.
16. Sasson, R.; Hagooly, A.; Rozen, S. Org. Lett. 2003, 5, 769–771.
17. Rozen, S.; Lerman, O. J. Org. Chem. 1993, 58, 239–240.
18. Sasson, R.; Rozen, S. Tetrahedron 2005, 60, 1083–1086.
19. MS was measured under ESI-QqTOF conditions. In many cases, these methods
could not detect the molecular ion so we have successfully employed Amirav’s
supersonic GC–MS developed in our department. The main feature of this
method is to provide electron ionization, while the sample is vibrationally
cooled in a supersonic molecular beam. This enhances considerably the relative
abundance of molecular ions. (a) Dagan, S.; Amirav, A. J. Am. Mass. Spectrom.
1995, 6, 120–131. (b) Amirav, A.; Gordin, A.; Tzanani, N. Rapid Commun. Mass
Spectrom. 2001, 15, 811–820.
Typical procedure for the synthesis of difluoromethyl ethers (2): 2.7 Mmol of
chlorodifluoromethyl ether (1a) was dissolved in 20 mL of anhydrous THF
followed by the addition of 350 mg of 1,10-azobis(cyclohexane-carbonitrile)
(1.5 mmol), and 2.2 mL of tributyltin hydride (8.1 mmol). The solution was
refluxed for 2 h. For the preparation of 2g and 2i, toluene was used as the
solvent and the reflux continued for 6 h. After evaporation of the solvent, the
product was purified by flash chromatography, which also removed all traces
of any tin derivatives. All yields are for isolated compounds, and their
analytical purity was established by elemental microanalysis, which was
satisfactory for all the difluoromethyl ethers. Below are characteristic
analytical data for the compounds discussed in this work.
In conclusions, the method outlined above is an inviting way to
produce the still quite rare difluoromethoxy group that is becom-
ing important for biologically related, as well as for other fields
of chemistry.