Synthesis of SF5-containing benzisoxazoles, quinolines, and quinazolines by the Davis reaction of nitro-(pentafluorosulfanyl)benzenes

Article abstract of DOI:10.3762/bjoc.9.43

Meta- or para-nitro-(pentafluorosulfonyl)benzenes underwent the Davis reaction with arylacetonitriles to provide the SF₅- containing benzisoxazoles. Good yields were obtained with arylacetonitriles containing the electron-neutral or electron-do

Full text of DOI:10.3762/bjoc.9.43

Synthesis of SF5-containing benzisoxazoles,
quinolines, and quinazolines by the Davis reaction
of nitro-(pentafluorosulfanyl)benzenes
Petr Beier* and Tereza Pastýříková
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 411–416.
Institute of Organic Chemistry and Biochemistry, Academy of
Sciences of the Czech Republic, Flemingovo nám. 2, 166 10 Prague,
Czech Republic
doi:10.3762/bjoc.9.43
Received: 30 October 2012
Accepted: 31 January 2013
Published: 21 February 2013
Email:
Petr Beier* - beier@uochb.cas.cz
Associate Editor: J. A. Porco Jr.
* Corresponding author
© 2013 Beier and Pastýříková; licensee Beilstein-Institut.
Keywords:
License and terms: see end of document.
benzisoxazoles; pentafluorosulfanyl group; quinazolines; quinolines;
sulfurpentafluorides
Abstract
Meta- or para-nitro-(pentafluorosulfonyl)benzenes underwent the Davis reaction with arylacetonitriles to provide the SF5-
containing benzisoxazoles. Good yields were obtained with arylacetonitriles containing the electron-neutral or electron-donor
group, while those with the electron-acceptor group were found to be unreactive. Reductions of the benzisoxazoles gave ortho-
aminobenzophenones in high yields. Their synthetic utility was demonstrated by condensation reactions with carbonyl compounds
or amines to provide SF5-containing quinolines and quinazolines, respectively.
Introduction
Reactions of nitroarenes with nucleophiles have been the focus from substituted nitrobenzenes and arylacetonitriles in the pres-
of many investigations and represent processes that provide a ence of hydroxide in alcoholic solvent. This reaction was first
range of useful products. These reactions can proceed in several reported by Davis and Pizzini [7] and probably proceeds
ways: (a) ipso substitution of the nitro group of nitroarenes; (b) through the formation of σH adducts that give nitroso com-
substitution of a halogen in halogen-substituted nitroarenes; and pounds, which upon deprotonation enter an intramolecular addi-
(c) substitution of hydrogen in ortho- or para-positions to the tion–elimination process as shown in Scheme 1. Typical
nitro group through vicarious or oxidative nucleophilic substitu- reaction conditions are an excess of alkali metal hydroxide in a
tions. Mechanistic studies have revealed that in all of these low-boiling-point alcohol at ambient temperature [8-10].
reaction pathways, the primary process is the reversible addi-
tion of nucleophiles to the ring carbon atoms bearing hydrogen When the reaction was performed in pyridine, products 1
and the formation of anionic σH adducts [1-6]. One example of (Figure 1) of the nucleophilic substitution of halogen were
such a reaction is the formation of benzisoxazoles (anthraniles) formed. Reactions of para-nitroanisole with arylacetonitriles
411

Beilstein J. Org. Chem. 2013, 9, 411–416.
Scheme 1: Proposed mechanism of the Davis reaction giving benzisoxazoles.
Figure 1: Substitution products 1, oximes 2 and nitro-(pentafluorosulfanyl)benzenes 3 and 4.
(KOH/MeOH) failed to provide the benzisoxazoles [7], and also In this paper, we report our results on benzisoxazole formation
dinitrobenzenes were found to be problematic [9]. The reac- from nitrobenzenes 3 and 4 and further transformations to
tions of nitrobenzene with arylacetonitriles gave oximes 2 SF5-containing aminobenzophenones, quinolines and quinazo-
(Figure 1) [11].
lines. Of these compound types, only some SF5-substituted
quinolines are known. Wipf and co-workers have recently
Pentafluorosulfanyl-containing compounds (first synthesized by reported the synthesis of some SF5-substituted quinolines as
Sheppard in 1960 [12,13]) are relatively rare, and their chem- intermediates towards analogues of the antimalarial agent
istry is underdeveloped. These derivatives are promising for mefloquine and found that some analogues had improved
various applications due to an unusual combination of the prop- activity and selectivity against malaria parasites (Scheme 2)
erties of the SF5 group, such as high lipophilicity, with strong [29,30].
electron-acceptor character. One important property of the SF5
group is its high thermal and chemical stability [14-17]. The Results and Discussion
main reason that prevents further development of SF5 organics We started the investigations by the reaction of para-nitro-
is their limited availability. In SF5-aromatics, para- and meta- (pentafluorosulfanyl)benzene (3) with phenylacetonitrile (6a)
nitro-(pentafluorosulfanyl)benzenes (3 and 4) (Figure 1) are using excess sodium hydroxide in ethanol. The presence of the
available by the direct fluorination of the corresponding strongly electron-withdrawing SF5 group on nitrobenzene 3
bis(nitrophenyl)disulfides [18-20], and several other SF5- should be beneficial for the Davis reaction since nitrobenzenes
benzenes are available through Umemoto’s two-step procedure with electron-donor groups were found to be unreactive [7]. Ad-
starting from diaryldisulfides or mercaptoaromatics [21]. We dition of 1.5 equiv of 6a and 3 to a solution of 10 equiv NaOH
have recently reported SNAr reactions of the nitro group in in ethanol produced a deep red–brown reaction mixture with the
compounds 3 and 4 with alkoxides and thiolates [22], vicarious formation of a brown precipitate after a few minutes of stirring.
nucleophilic substitution (VNS) of the hydrogen with carbon After a further 15–30 minutes the precipitate dissolved, and
[23,24], oxygen [25] and nitrogen [26] nucleophiles, and oxida- after one hour the product 7a was isolated in 66% yield
tive nucleophilic substitution of hydrogen (ONSH) with Grig- (Table 1, entry 1). The benzisoxazole structure of 7a was
nard and organolithium reagents [27]. This chemistry signifi- confirmed by spectroscopic methods. The reaction also worked
cantly expanded the range of available SF5-benzene derivatives. in similar yields by using KOH in methanol, and no improve-
The synthetic chemistry and biological activity of pentafluoro- ments were observed when the reaction time, temperature and
sulfanyl organic molecules has been recently reviewed [28].
amount of base and 6 were varied. Next, an investigation of the
412

Beilstein J. Org. Chem. 2013, 9, 411–416.
Scheme 2: Synthesis of SF5-substituted quinolines and mefloquine analogues by Wipf and co-workers [29,30].
Table 1: Synthesis of SF5-containing benzisoxazoles 7–9.
Entry
3–5
X
Y
6, Ar
Time (h)
7–9, Yield (%)
1
3
3
3
3
3
3
4
4
5
4
4
4
4
4
4
SF5
SF5
SF5
SF5
SF5
SF5
H
H
6a, Ph
1
7a, 66
7b, traces
7c, 65
7d, 50
7e, 54
7f, 83
2
H
6b, 4-ClC6H4
48
1
3
H
6c, 3-MeOC6H4
6d, 3,4-(MeO)2C6H3
6e, 3,4,5-(MeO)3C6H2
6f, 4-PhC6H4
4
H
1
5
H
1
6
H
1
7
SF5
SF5
CF3
SF5
SF5
SF5
SF5
SF5
SF5
6a, Ph
1
8a, 83
8b, traces
9b, 58
8c, 59
8d, 55
8e, 57
8g, 0
8
H
6b, 4-ClC6H4
48
1
9
H
6b, 4-ClC6H4
10
11
12
13
14
15
H
6c, 3-MeOC6H4
6d, 3,4-(MeO)2C6H3
6e, 3,4,5-(MeO)3C6H2
6g, 3-IC6H4
2
H
1.5
1
H
H
48
168
120
H
6h, 4-NO2C6H4
6i, 2-F-6-ClC6H4
8h, 0
H
8i, 0
scope of the reaction was carried out. The presence of electron- reaction scope shows limitations and the electronic properties of
donor groups on the benzene ring of 6 gave good yields of the starting substrates have to be finely tuned for efficient
benzisoxazoles 7; however, the reaction with (4-chloro- reaction.
phenyl)acetonitrile (6b) provided only traces of 7b (no
improvement of the yield was observed by increasing the The benzisoxazoles 7 and 8 were reduced to ortho-aminoben-
amount of 6b or using a longer reaction time).
zophenones 10 and 11 in excellent yields by using iron powder
in aqueous acetic acid according to the literature procedure
Reactions with the meta-nitro-(pentafluorosulfanyl)benzene (4) (Table 2) [31].
proceeded well with electron-neutral- or electron-donor-substi-
tuted phenylacetonitriles. With electron-acceptor-substituted Aminoketones 10 and 11 were investigated as starting
phenylacetonitriles, the reactions failed. On the other hand, the substrates in the synthesis of various nitrogen heterocycles by
reaction with 1-nitro-3-trifluoromethylbenzene (5) provided the condensation reactions. Several reliable synthetic methods
benzisoxazole product in good yield. This observation is giving quinolones [32,33] or quinazolines [34,35] have been
surprising given the fact that the CF3 and SF5 groups have reported in the literature. One potential problem of this ap-
similar group electronegativities [14], and the steric difference proach is the reduced nitrogen nucleophilicity by the strongly
should not play a role here. These results indicate that the electron-withdrawing SF5 group, especially for compounds 10
413

Beilstein J. Org. Chem. 2013, 9, 411–416.
Table 2: Synthesis of ortho-aminobenzophenones 10 and 11.
Entry
7 or 8
X
Y
Ar
10 or 11, Yield (%)
1
2
3
4
5
7a
7f
SF5
SF5
H
H
Ph
10a, 98
10f, 98
11a, 93
11d, 98
11e, 98
H
4-PhC6H4
8a
8d
8e
SF5
SF5
SF5
Ph
H
3,4-(MeO)2C6H3
3,4,5-(MeO)3C6H2
H
where the SF5 group is in conjugation with the amino group. Finally, quinazoline 14 was synthesized by the reaction of
The reduced reactivity was indeed observed compared to unsub- aminoketone 11a with benzylamine in the presence of
stituted ortho-aminoacetophenone, but it could be overcome by t-BuOOH and catalytic iodine according to the literature condi-
using an excess of the condensation reagent and longer reaction tions (Scheme 5) [34]. However, the analogous reaction with
times. Quinoline 12 was prepared in high yield by the ketone 11e was found to be too slow (36% conversion after 26 h
Friedländer annulation reaction of 10a with excess ethyl as judged by GCMS analysis) to be synthetically useful. This
acetoacetate in the presence of catalytic CAN using modified reduced reactivity of 11e compared to 11a is due to the rela-
literature conditions (Scheme 3) [32].
tively low electrophilicity of the carbonyl group of 11e.
Similarly, aminoketone 11a was condensed in good yield with Conclusion
cyclohexanone to provide quinoline 13 in good yield In summary, reactions of meta- or para-nitro-(pentafluorosul-
(Scheme 4).
fonyl)benzenes with arylacetonitriles in the presence of NaOH
Scheme 3: Synthesis of quinoline 12.
Scheme 4: Synthesis of quinoline 13.
Scheme 5: Synthesis of quinazoline 14.
414

Beilstein J. Org. Chem. 2013, 9, 411–416.
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Acknowledgements
This work was financially supported by the Academy of
Sciences of the Czech Republic (RVO: 61388963) and by the
Grant Agency of the Czech Republic (P207/12/0072).
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