Several straightforward synthetic transformations of
aryl-SF5 compounds are described. (Pentafluorosulfanyl)-
benzene is nitrated to give the meta-substituted product 2
in 81% yield. The nitroderivatives 1 and 2 undergo reduc-
tion to corresponding (pentafluorosulfanyl)anilines in
very good yields. These aniline derivatives can be acylated,
halogenated, or diazotized. The diazonium salts may be
coupled (for example to β-naphthol), hydrolyzed to phe-
nol, converted to halides by the Sandmeyer reaction, or
reduced with H3PO2 to (pentafluorosulfanyl)benzene.
Halo-(pentafluorosulfanyl)benzenes were reported to
undergo lithiation, Grignard salt formation, or Pd(0)-
catalyzed cross-coupling reactions.2,6,7,10 Recently, it
was shown that the fluorine atom of 1-fluoro-4-nitro-
2-(pentafluorosulfanyl)benzene and 1,3-dichloro-2-fluoro-
5-(pentafluorosulfanyl)benzene can be replaced by a variety
of nucleophiles in moderate yields.2,11
The strong electron-withdrawing character of the nitro
group makes the aromatic nitro compounds suitable for
nucleophilic aromatic substitution.12 The nitro group also
shows high nucleofugacity, and its departure from the
aromatic system frequently occurs if there is appropriate
activation by other electron-withdrawing groups such as
NO2, CN, CO2R, and CF3.13 Intriguingly, the SNAr
chemistry of the para- and meta-isomers 1 and 2 has not
been studied, and we hypothesized that under appropriate
conditions it should be possible to substitute the nitro
group by suitable nucleophiles. In this Letter, we report
successful outcomes which now provide access to a variety
ofnewaromaticSF5-containing compounds and should be
of high utility.
Table 1. Initial Optimization in the Preparation of 3a from 1a
no. MeONa/equiv (time of addition/min) time/min 3a, conv, %b
1
2
3
4
5
6
7
8
9
1.5
5
30
30
42
1.5
1.5 þ 1.5 (420)
1 þ 1 (13) þ 1 (33)
1 þ 1 (13) þ 1 (33) þ 1 (240)
1.5 þ 1.5 (30)
1.5 þ 1.5 (30)
1.5 þ 1.5 (30)
3
450
150
270
35
76
65
87
69
45
84
60
90 (83)
>95 (76)
30
a Reaction conditions: 1 (0.5 mmol), MeONa, DMF (1 mL), rt.
b Conversion of 3a was determined by GCMS, in brackets isolated
yields.
8 identified DMF as the best solvent (toluene or methanol
0%, THF <2%, DMF 90%, DMA 73%, DMSO 75%,
DMP 13%, DMPU 13%, HMPA 81%); using DMF as
the optimal solvent, concentration optimization in the
range 0.1-4.0 M was explored. The reaction tolerates a
wide concentration range where high product conversions
can be achieved. However, the optimal concentration
range was found to be 0.25-2.0 M, where 3a was prepared
in 83% yield (97% based on recovered 1).
The scope of the SNAr reaction with various metal
alkoxides and thiolates (Table 2) was explored. Commer-
cial reagents were added to the solution of 1 in DMF.
Alternatively, they were prepared in situ by the reaction of
alcohol or thiol with sodium metal or t-BuOK. The pre-
sence of t-BuOH in the reaction mixture did not have any
detrimental effect. Alkoxides derived from primary alco-
hols gave products in good to excellent yields (Table 2,
entries 1-5). A reduced yield in the reaction with 2-phe-
nylethanolate was due to the formation of styrene as a side
product (Table 2, entry 6). Sodium trifluoroethanolate
gave only a moderate yield of 3g, presumably because of
its relatively low nucleophilicity (Table 2, entry 7). The
potassium salt of 1,2-isopropylideneglycerol generated 3h
in good yield (Table 2, entry 8). Straightforward ketal
deprotection14 gave 3-(4-(pentafluorosulfanyl)phenoxy)-
propane-1,2-diol (4) in 97% yield ; a derivative of the
commercially successful beta-blocker drugs used as anti-
arrhythmic, muscle relaxant, antihypertensive, antiangi-
nal, and antifungal agents.
Nucleophilic addition of MeONa provided the initial
focus. The addition of MeONa (1.5 equiv) to a solution of
1 in DMF at ambient temperature resulted in a moderately
exothermic reaction with formation of a dark violet to black
reaction mixture. After 5 min the color changed to light
brown and 1-methoxy-4-(pentafluorosulfanyl)benzene (3a)
formed in 30% conversion as judged by GCMS analysis
(Table 1, entry 1). Optimization of the nucleophile equiva-
lence and reaction time revealed that a 3-fold excess of
MeONa is necessary for a >90% conversion in 1-2 h. It
proved to be beneficial to add MeONa sequentially in two
portions rather than all at once (Table 1).
Solvent screening measuring conversions under other-
wise identical conditions to those reported in Table 1, entry
(10) Kirsch, P.; Bremer, M.; Heckmeier, M.; Tarumi, K. Angew.
Chem., Int. Ed. 1999, 38, 1989–1992.
(11) Sipyagin, A. M.; Bateman, C. P.; Tan, Y.-T.; Thrasher, J. S. J.
Fluorine Chem. 2001, 112, 287–295.
(12) (a) Ono, N. The Nitro Group in Organic Synthesis; Wiley & Sons:
New York, 2001; pp 302-324. (b) Beck, J. R. Tetrahedron 1978, 34, 2057–
2068.
(13) (a) Kornblum, N.; Cheng, L.; Kerber, R. C.; Kestner, M. M.;
Newton, B. N.; Pinnick, H. W.; Smith, R. G.; Wade, P. A. J. Org. Chem.
Sterically more demanding alkoxides derived from sec-
ondary alcohols gave satisfactory results (Table 2, entry 9),
while the use of t-BuOK was largely unsuccessful despite
the formation of a deep violet complex in the reaction
mixture (Table 2, entry 10). The reaction of 1 with potas-
sium phenolate also gave 1-nitro-4-phenoxybenzene as a
ꢀ
1976, 41, 1560–1564. (b) Tejero, I.; Huertas, I.; Gonzalez-Lafont, A.;
Lluch, J. M.; Marquet, J. J. Org. Chem. 2005, 70, 1718–1727. (c) Adams,
D. J.; Clark, J. H. Chem. Soc. Rev. 1999, 28, 225–231. (d) Boechat, N.;
Clark, J. H. J. Chem. Soc., Chem. Commun. 1993, 921–922. (e) Sun, H.;
DiMagno, S. G. Angew. Chem., Int. Ed. 2006, 45, 2720–2725. (f) Denney,
D. B.; Denney, D. Z.; Perez, A. J. Tetrahedron 1993, 49, 4463–4476. (g)
Heller, R. A.; Weiler, R. Can. J. Chem. 1987, 65, 251–255. (h) Shifman,
A.; Palani, N.; Hoz, S. Angew. Chem., Int. Ed. 2000, 39, 944–945.
(14) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 3rd ed.; Wiley & Sons: New York, 1999; p 211.
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