Synthesis and nucleophilic aromatic substitution of 3-fluoro-5-nitro-1-(pentafluorosulfanyl)benzene

Article abstract of DOI:10.3762/bjoc.12.21

3-Fluoro-5-nitro-1-(pentafluorosulfanyl)benzene was prepared by three different ways: as a byproduct of direct fluorination of 1,2-bis(3-nitrophenyl)disulfane, by direct fluorination of 4-nitro-1-(pentafluorosulfanyl)benzene, and by fluorodenitration of 3,5-dinitro-1-(pentafluorosulfanyl)benzene. The title compound was subjected to a nucleophilic aromatic substitution of the fluorine atom with oxygen, sulfur and nitrogen nucleophiles affording novel (pentafluorosulfanyl)benzenes with 3,5-disubstitution pattern. Vicarious nucleophilic substitution of the title compound with carbon, oxygen, and nitrogen nucleophiles provided 3-fluoro-5-nitro-1-(pentafluorosulfanyl)benzenes substituted in position four.

Full text of DOI:10.3762/bjoc.12.21

Synthesis and nucleophilic aromatic substitution of 3-fluoro-5-
nitro-1-(pentafluorosulfanyl)benzene
Javier Ajenjo1, Martin Greenhall2, Camillo Zarantonello2 and Petr Beier*1,§
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2016, 12, 192–197.
1Institute of Organic Chemistry and Biochemistry, v.v.i., Academy of
Sciences of the Czech Republic, Flemingovo nám. 2, 166 10 Prague
6, Czech Republic and 2F2 Chemicals Ltd, Lea Lane, Lea Town,
Preston, PR4 0RZ, UK
doi:10.3762/bjoc.12.21
Received: 19 November 2015
Accepted: 25 January 2016
Published: 03 February 2016
Email:
Petr Beier* - beier@uochb.cas.cz
Associate Editor: D. Y.-K. Chen
* Corresponding author
© 2016 Ajenjo et al; licensee Beilstein-Institut.
License and terms: see end of document.
§ Tel.: +420 739002221; fax: +420 220183578
Keywords:
direct fluorination; fluorine; nucleophilic aromatic substitution;
pentafluorosulfanyl group; vicarious nucleophilic substitution
Abstract
3-Fluoro-5-nitro-1-(pentafluorosulfanyl)benzene was prepared by three different ways: as a byproduct of direct fluorination of 1,2-
bis(3-nitrophenyl)disulfane, by direct fluorination of 4-nitro-1-(pentafluorosulfanyl)benzene, and by fluorodenitration of 3,5-
dinitro-1-(pentafluorosulfanyl)benzene. The title compound was subjected to a nucleophilic aromatic substitution of the fluorine
atom with oxygen, sulfur and nitrogen nucleophiles affording novel (pentafluorosulfanyl)benzenes with 3,5-disubstitution pattern.
Vicarious nucleophilic substitution of the title compound with carbon, oxygen, and nitrogen nucleophiles provided 3-fluoro-5-nitro-
1-(pentafluorosulfanyl)benzenes substituted in position four.
Introduction
Organic compounds with a pentafluorosulfanyl (SF5) group are one is a direct fluorination of nitro-substituted diaryl disulfides
promising candidates in the development of new agrochemicals, leading to 3- or 4-nitro-1-(pentafluorosulfanyl)benzenes [7-10].
pharmaceuticals and advanced materials [1-3]. This is due to an This reaction is conducted in tens of kilogram scale in industry.
unusual combination of properties such as high stability [4], The second method is known as Umemoto’s synthesis and starts
lipophilicity [5] and strong electron-withdrawing character [6] with aromatic thiols or diaryl disulfides which are converted to
similar but more extreme than the trifluoromethyl group. Cur- arylsulfur chlorotetrafluorides [11,12]. Fluorination in the
rently, the limiting factor for a more widespread use of SF5 second step affords arylsulfur pentafluorides [11,13].
compounds is the low accessibility of basic building blocks and Umemoto’s synthesis does not require handling the elemental
the lack of understanding their chemical behavior. For aromatic fluorine, gives better yields, and displays a wider substrate
SF5 compounds, two main synthetic approaches exist. The first scope than the direct fluorination method. However,
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Beilstein J. Org. Chem. 2016, 12, 192–197.
nitro(pentafluorosulfanyl)benzenes are widely-available prima- Results and Discussion
ry industrial products and starting materials to other SF5- Direct fluorination of 1,2-bis(3-nitrophenyl)disulfane on kilo-
benzenes which were prepared by reduction followed by con- gram scale led to the main product 3-nitro-1-(pentafluoro-
densation or diazotization chemistry [8,14-16], SEAr [17], SNAr sulfanyl)benzene (1) which was isolated in 39% yield [8] and a
[18-24], or metal-catalyzed cross-coupling reactions [25-27]. byproduct 3-fluoro-5-nitro-1-(pentafluorosulfanyl)benzene (2)
Synthetic methods to novel SF5-containing building blocks are in 6% GC yield (2–3% isolated yield, Scheme 1). Compound 2
sought after and drive the development of applications of these was isolated from the mixture by distillation; redistillation
compounds. In this work, we explore SNAr chemistry of afforded 2 in 99% purity (detected by GC). However, for inves-
3-fluoro-5-nitro-1-(pentafluorosulfanyl)benzene which was tigations of SNAr of 2, a more efficient process for its synthesis
initially obtained as a minor byproduct of direct fluorination of was required. With higher excess of fluorine, the 2:1 ratio in-
1,2-bis(3-nitrophenyl)disulfane but can be also prepared by creased. Therefore, the synthesis of 2 by the direct fluorination
other methods, and show that substitution for aromatic fluorine of 1 was investigated (Scheme 2 and Figure 1). The reaction
or hydrogen atoms provide a range of novel structurally diverse progress was monitored by GC analysis. In acetonitrile, the
SF5-benzenes.
reaction required more than 16 equivalents of F2 to reach
Scheme 1: Direct fluorination of 1,2-bis(3-nitrophenyl)disulfane.
Scheme 2: Direct fluorination of 3-nitro-1-(pentafluorosulfanyl)benzene (1).
Figure 1: Conversion vs added fluorine equivalents for the fluorination of 1 in MeCN (left) and anhydrous HF (right).
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Beilstein J. Org. Chem. 2016, 12, 192–197.
maximal conversion of 2 (around 60%). With higher amounts of Another method for the synthesis of 2 is the fluorodenitration of
fluorine gas the conversion of 2 sharply decreased and the known 3,5-dinitro-1-(pentafluorosulfanyl)benzene (5) [10,28].
amounts of (poly)fluorinated aromatic byproducts 3 and 4 in- The reaction with TBAF hydrate resulted in clean substitution
creased (Figure 1, left). The amount of non-volatile material of only one nitro group for the fluorine atom (Scheme 4).
(tar) in the final product mixture (after 20 equiv of F2 added)
was 28% by weight as determined by Kugelrohr distillation.
When the direct fluorination was performed in anhydrous HF a
markedly different result was obtained. To reach maximal
conversion of 2 (around 60%), only a 3.6-fold excess of F2 was
required (Figure 1, right). However, in this case, higher
amounts of byproducts, particularly difluoroderivatives 4 were
observed. The amount of tar after the addition of 4.2 equiva-
lents of F2 was only 5%. Purification of compound 2 from 3 and
4 by distillation or column chromatography was not successful.
Scheme 4: Synthesis of 2 by fluorodenitration of 5.
Therefore, for preparative experiments we decided to run the
fluorination in MeCN to about 40% conversion and isolated 2
from unreacted 1 by flash chromatography (Scheme 3).
Nucleophilic aromatic substitution of fluorine leading to com-
pounds 3 was investigated (Table 1). With low-boiling alcohols
(MeOH, EtOH), the reactions were heated under reflux using
the alcohol as a solvent and excess of potassium hydroxide
(Table 1, entries 1 and 2). For alcohols with higher boiling
points, the reactions were performed with sodium hydride
(Table 1, entries 3 and 4). For phenol, thiophenol and dialkyl-
amines, heating with potassium carbonate in DMF gave good
results (Table 1, entries 5–9). Finally, the reaction with potas-
sium hydroxide was sluggish even under high temperature
(Table 1, entry 10) and for amination, heating with aqueous
ammonia solution in DMSO in a pressure vessel was required to
form aniline 3k (Table 1, entry 11).
Scheme 3: Preparative fluorination of 3-nitro-1-(pentafluoro-
sulfanyl)benzene (1).
Table 1: SNAr reactions of 2.
Entry
NuH (equiv)
Base (equiv)
Solvent
Temp. (°C)
Time (h)
3, Yield (%)a
1
MeOH (excess)
EtOH (excess)
iPrOH (excess)
HC≡C-CH2OH (1.5)
PhOH (1.5)
KOH (5)
MeOH
EtOH
iPrOH
THF
80
80
rt
0.5
0.6
6
3a, 85
3b, 83
3c, 72
3d, 70
3e, 67
3f, 46
3g, 63
3h, 51
3i, 67
3j, 33
3k, 44
2
KOH (3)
3
NaH (3)
4
NaH (3)
rt
2
5
K2CO3 (3)
K2CO3 (3)
K2CO3 (3)
K2CO3 (3)
K2CO3 (3)
KOH (5)
DMF
80
90
85
85
85
135
135
3
6
PhSH (1.5)
DMF
3
7
Morpholine (3)
Piperidine (3)
Pyrrolidine (3)
’OH’
DMF
7
8
DMF
3
9
DMF
2
10
11
DMSOb
DMSO
6
’NH2’
NH4OHc (2.5)
5
aIsolated yield. bDMSO/H2O (2:1, v/v). c28% aqueous ammonia solution.
194

Beilstein J. Org. Chem. 2016, 12, 192–197.
It is well known that ipso attack of nitroaromatics by nucleo- carbon, oxygen or nitrogen nucleophiles [29]. VNS is a very
philes (SNAr) is only a secondary process. Under kinetic condi- powerful process for selective alkylation, amination and
tions the aromatic system is initially attacked by a nucleophile hydroxylation of nitroaromatics and was reported to proceed
in ortho or para position to the nitro group, which was efficiently on 1 and its para-isomer [19-21]. In general, the
exploited in oxidative nucleophilic substitution for hydrogen reactions are characterized by short reaction times, low temper-
reactions (ONSH) with organolithium or magnesium species or atures and an equimolar amount of the nucleophile. The results
in vicarious nucleophilic substitution reactions (VNS) with of VNS reactions with compound 2 are shown in Table 2. With
Table 2: VNS reactions of 2.
Entry
X-NuH (equiv)
Solvent
DMF
Temp. (°C)
Time (min)
4, Yield (%)a
4a, 71
4:4’b
1
Cl-CH2CO2Et (1)
−30
10
97:3
2
3
4
Cl-CH2PO3Et2 (1)
PhO-CH2CN (1)
Br-CHBr2 (1.1)
DMF
−60
−30
−70
10
10
2
4b, 31
4c, 50
4d, 81
97:3c
DMF
87:13
>98:2c
DMF/THFd
5
PhC(CH3)2O-OH (1)
NH3/THFe
DMSO
−50
15
4e, 60
4f, 85
96:4
6f
I− Me3N+-NH2 (1.8)
rt
5
>98:2
aIsolated yield of the major isomer 4. bDetermined by GC–MS of the crude reaction mixture. cDetermined by 19F NMR of the crude reaction mixture.
dDMF/THF (7:2, v/v). eNH3/THF (4:1, v/v). fUsing t-BuOK (4 equiv).
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In conclusion, 3-fluoro-5-nitro-1-(pentafluorosulfanyl)benzene
was prepared by direct fluorination and fluorodenitration path-
ways. It underwent nucleophilic aromatic substitutions of the
fluorine atom with oxygen, sulfur and nitrogen nucleophiles
affording novel 3-substituted-5-nitro-1-(pentafluorosulfan-
yl)benzenes. Regioselective vicarious nucleophilic substitution
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Acknowledgements
This work was supported by the Academy of Sciences of the
Czech Republic (Research Plan RVO: 61388963) and by the
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