Nitrostyrenes as 1,4-CCNO-dipoles: diastereoselective formal [4+1] cycloaddition of indoles

Article abstract of DOI:10.1039/C8CC07451H

An unusual reactivity of nitrostyrenes in phosphorous acid was discovered, which permits the employment of these readily available synthons as 1,4-CCNO-dipole surrogates in a highly diastereoselective (4+1)-cycloaddition of indoles to afford 4′H-spiro[ind

Full text of DOI:10.1039/C8CC07451H

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Nitrostyrenes as 1,4-CCNO-dipoles:
diastereoselective formal [4+1] cycloaddition
of indoles†
Cite this: Chem. Commun., 2018,
4, 13260
5
Received 13th September 2018,
Accepted 5th November 2018
a
a
a
Alexander V. Aksenova, * Nicolai A. Aksenov,
Dmitrii A. Aksenov,
ab
Vladislav F. Khamraev and Michael Rubin
*
DOI: 10.1039/c8cc07451h
rsc.li/chemcomm
An unusual reactivity of nitrostyrenes in phosphorous acid was
discovered, which permits the employment of these readily available
synthons as 1,4-CCNO-dipole surrogates in a highly diastereoselective
0
0
(
4+1)-cycloaddition of indoles to afford 4 H-spiro[indole-3,5 -isoxazoles]
in a diastereomerically pure form.
0
0
Although heterocyclic compounds with 4 H-spiro[indoline-3,5 -
0
0
isoxazole] and 4 H-spiro[indole-3,5 -isoxazole] cores do not occur in
nature, these synthetic drug-like molecules demonstrated promising
1
,2
antimicrobial, antifungal, and anticancer activities. They were
also employed as advanced intermediates in total syntheses of
3
natural pyrrolidinoindoline alkaloids and their analogs. Unsur-
prisingly, preparation of these structures became the focus of
attention for many research groups around the world. Typically,
such spiro-heterocyclic scaffold can be accessed via acid-assisted
1
,5-spiro-cyclization of mono-oximes of 3-ene-2,5-diones (Scheme 1,
4
Path A), [3+2]-cycloaddition of nitrile-oxides to 3-methylene-
oxindoles (Path B), or metal-catalyzed selective vinylation of
isatine-oximes with vinyl-boronic acids (Path C). It should be
3,5
6
pointed out that all these methods were demonstrated employing
0
0
isatines, providing various derivatives of 4 H-spiro[indoline-3,5 -
isoxazol]-2-one (1). However, to the best of our knowledge, currently Scheme 1 Synthetic approaches to spirocyclic indolines.
there are no methods of accessing closely related spirocyclic
scaffold 2, bearing a carbon-based substituent (alkyl, aryl or hetaryl)
at the C-2 of indole moiety. Herein, we wish to report an efficient
and highly diastereoselective route towards 4 H-spiro[indole-3,5 - ment of Brønsted acid-assisted cascade heterocyclizations of
isoxazoles] (2) proceeding via unusual formal [4+1] cycloaddition nitro-compounds. While studying the conjugate addition of
reaction involving nitroalkene as 1,4-CCNO-dipole and nucleophilic indoles to nitroolefins (Scheme 2, Path D), we observed an unusual
Our group has had a long-standing interest in the develop-
0
0
7
,8
C-3 of indole as the dipolarophilic C
1
-moiety.
reactivity when the reaction was performed in polyphosphoric
acid (PPA). Careful optimization of the reaction conditions allowed
for achieving selective rearrangement of the nitro group into
a
b
Department of Chemistry, North Caucasus Federal University, 1a Pushkin St.,
Stavropol 355009, Russian Federation
9
hydroxamic acid 6 (Path E). The former underwent an unusual
10
Department of Chemistry, University of Kansas, 1251 Wescoe Hall Dr., Lawrence,
KS 66045-7582, USA. E-mail: mrubin@ku.edu; Fax: +1-785-864-5396;
Tel: +1-785-864-5071
ANRORC cascade at higher temperatures affording 2-quinolones 7
7
(
Path F). While experimenting with PPA, we came across a poor
2 5
quality batch of P O containing notable amounts of red phos-
†
Electronic supplementary information (ESI) available: Experimental details,
phorus (arising from incomplete combustion during reagent
manufacturing). Polyphosphoric acid prepared from this material
had a distinct pink color, and the reaction between nitrostyrene
spectral, crystallographic, and computational information (PDF). CCDC
834625. For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/c8cc07451h
1
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Scheme 2 Diversity of products obtained upon alkylation of nitrostyrenes
with indoles.
(3a, Ar = Ph) and 2-phenylindole (4a, R = Ph) carried out at room
temperature in this medium led to the formation of notable
amounts of unexpected spirocyclic structure 2aa (R = Ar = Ph)
alongside 2-quinolone 7 (Scheme 2) and other minor unidentified
products. The molecular structure of 2aa was unambiguously
confirmed by single crystal X-ray crystallography (Fig. 1).
0
Remarkably, this product was formed with perfect (3R*,4 S*)-
diastereoselectivity, as shown. This finding justified further
efforts towards the optimization of the reaction conditions for
the selective synthesis of 3-indolinones 2. We believed that the
presence of low valent phosphorus additives must have caused
this side reaction, so we continued to explore phosphorus(III)
additives. Attempts to substitute PPA with PCl
3
resulted in in situ
1
1
conversion of the nitro-group into a nitrile 8 (Path G) or a
1
2
carboxamide 9 (Path H). We further tested the reaction in the
presence of 2 equiv. of phosphorous acid in various organic
media. It was found that 2aa could be obtained in good yield if
Scheme 3 Spirocycles obtained in H
3
PO
3
-assisted reactions of indoles
with nitrostyrenes.
Fig. 1 ORTEP drawings of 2aa (CCDC #1834625†) showing atom numbering
schemes and 50% probability ellipsoids.
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Table 1 Optimization of spiro-cyclization towards 2aa
a
c
c
Acid (time, h)
5aa (yield, %)
2aa (yield, %)
1
2
3
4
5
6
CF COOH (1.5)
3
82
13
60
0
83
0
10
76
8
33
8
H
CH
H
3
PO
4
(1.5)
3
SO
3
H (1.5)
b
2
SO
4
(1.5)
HCOOH (15)
PO (0.75)
H
3
3
98
a
All acids were used as 1 : 1 mixture with 85% formic acid, unless
b
specified otherwise. A mixture of 150 mg of 98% sulfuric acid and
5
c
1
00 mg of 85% formic acid. Yields were determined by H NMR
analysis of crude reaction mixtures.
the reaction is carried out for 45 min in H PO /HCOOH at room
3
3
temperature (Scheme 3). It should be pointed out, that for-
mation of 2aa along with nitroalkane 5aa (R = Ar = Ph) was Scheme 4 Mechanistic rationale of the featured transformation.
observed in reaction between 3a and 4a in the presence of other
strong Brønsted acids as well (Table 1). Weaker acids (such as
acetic or benzoic) mediated Michael addition, affording 5aa as substituted derivative 2fa (Scheme 3). Replacing the phenyl group at
sole product. At the same time, we also found that hydroxamic C-2 with a methyl group resulted in very complex reaction mixtures
acid 6aa (R = Ar = Ph) could not be converted into 2aa under the and total decomposition of the initially formed spirocyclic product
same conditions, which proves that it does not serve as an 2ga. Lowering the temperature to 10 1C allowed for isolation of
intermediate in the featured transformation. Reaction in the 2ga, albeit in a marginal yield (Scheme 3). Also, it should be pointed
presence of phosphorous acid (4 equiv.) provided nearly quanti- out that 2-(trifluoromethyl)- (4k) and 2-(methoxycarbonyl)- (4l)
tative yield of 2aa (Table 1, entry 6). It was also shown, that this 1H-indoles did not provide any spirocyclic products at all, even at
cyclization can proceed in the presence of catalytic amounts of 50 1C. Starting materials were recovered unchanged in both cases.
H
3
PO
reach ca. 60% conversion. Provided relatively low cost of this aryl ring of the indole. 5-Isopropyl-2-phenyl-1H-indole (4h) reacted
catalyst, we decided to use it in excess. smoothly under standard reaction conditions with both nitros-
3
(10 mol%), but very slowly, requiring more than a weak to Finally, we tested the possibility of introducing substituents in the
With optimized conditions in hand, we moved on to explore tyrenes 3a and 3d affording the corresponding products 2ha and
the scope and limitations of this transformation. We first tested 2hd in high yields. Likewise, reactions of 5-methoxy- (4i) and
the reactivity of indole 4a against nitrostyrenes bearing different 7-chloro- (4j) substituted substrates allowed for the facile prepara-
substituents at C-4 (3a–d). All these reactions afforded the tion of spirocyclic scaffolds 2ia and 2ja, respectively (Scheme 3).
corresponding spiranes 2aa–2ad in excellent yields (Scheme 3).
Reactions of 4a with nitro-olefins bearing primary (3e) or secondary propose the following mechanistic rationale (Scheme 4). Expo-
3f) alkyl substituents proved to be somewhat less efficient and sure of nitrostyrene 3 to phosphorous acid makes it susceptible
Analysis of the obtained experimental data has led us to
(
sluggish, requiring 2 h for complete conversion, but the yields of to Michael addition of indole 4. The reduced nucleophilicity
the corresponding products 2ae and 2af were still reasonably high of indoles with electron-deficient substituents at C-2 at this
(
Scheme 3). Reaction of 4a with (E)-2-(2-nitrovinyl)furan (3g) stage explains unsuccessful reactions of substrates 4k and 4l
0
allowed the preparation of 4 -(furan-2-yl)-substituted analog 2ag, (vide supra). Subsequent deprotonation at C3 of the indole in
thus showing the possibility of introducing even acid-sensitive 11, followed by intramolecular abstraction of a proton from the
heteroaryl groups to the featured scaffold (Scheme 3). The reaction benzylic position by the phosphite ester of aci-nitro moiety in
proved to be compatible with various aryl substituents at C-2 of 12, gives rise to N-phosphoryloxyenamine oxide species 13. The
the indole unit. Substrates bearing electron rich phenyl substi- latter, upon re-protonation, tautomerizes into hydroxylamine
tuents (4b, 4d) reacted smoothly affording the corresponding 14. Next, acid-promoted 5-endo-trig cyclization of 14 takes place
1
3
spiro-heterocycles 2ab–2ad in excellent yields. Indoles bearing to give spiro-2,5-dihydroisoxazole species 15, which under the
0
moderately electron poor aryl 4c or 2-naphthyl (4e) substituents reaction conditions may tautomerize into either (3R*,4 S*)- (2)
0
14
at C-2 reacted more sluggishly requiring extended reaction time or (3R*,4 R*)-4,5-dihydroisoxazole 17. Our DFT-modelling
2 h), but still affording the corresponding products 2ca and 2ea suggests that the former one is thermodynamically favored
(
ꢀ1
quite efficiently. The introduction of heteroaryl substituents was by ca. 4.1 kcal mol , which explains high diastereoselectivity
also tolerated as demonstrated by the preparation of the thienyl of the featured transformation. It should be stressed, that
1
5
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proper acid–base balance is highly important for the successful
spiro-cyclization. The acid should be sufficiently strong for
initial activation of nitro-group in 3, but at the same time it
should be weak enough so it’s conjugate base would be able to
deprotonate species 12.
6 C.-H. Chen, Q.-Q. Liu, X.-P. Ma, Y. Feng, C. Liang, C.-X. Pan, G.-F. Su
and D.-L. Mo, J. Org. Chem., 2017, 82, 6417–6425.
7
(a) A. V. Aksenov, A. N. Smirnov, N. A. Aksenov, I. V. Aksenova,
L. V. Frolova, A. Kornienko, I. V. Magedov and M. Rubin, Chem.
Commun., 2013, 49, 9305–9307; (b) A. V. Aksenov, A. N. Smirnov,
N. A. Aksenov, I. V. Aksenova, A. S. Bijieva and M. Rubin, Org.
Biomol. Chem., 2014, 12, 9786–9788; (c) A. V. Aksenov, A. N. Smirnov,
N. A. Aksenov, I. V. Aksenova, J. P. Matheny and M. Rubin, RSC Adv.,
2015, 5, 8647–8656.
In conclusion, nitroalkenes were successfully employed as
synthetic equivalents of 1,4-dipoles of CCNO-type in a highly
diastereoselective formal (4+1)-cycloaddition reaction of indoles in
8
9
(a) N. A. Aksenov, A. V. Aksenov, O. N. Nadein, D. A. Aksenov,
A. N. Smirnov and M. Rubin, RSC Adv., 2015, 5, 71620–71626;
0
0
phosphorous acid to afford 4 H-spiro[indole-3,5 -isoxazole] deriva-
tives 2. Work for biological evaluation of spiro-heterocyclic systems 2
and synthetic application of these novel scaffolds is currently under-
way in our laboratories.
(
b) A. V. Aksenov, A. N. Smirnov, N. A. Aksenov, A. S. Bijieva,
I. V. Aksenova and M. Rubin, Org. Biomol. Chem., 2015, 13,
289–4295.
4
A. V. Aksenov, A. N. Smirnov, I. V. Magedov, M. R. Reisenauer,
N. A. Aksenov, I. V. Aksenova, A. L. Pendleton, G. Nguyen,
R. K. Johnston, M. Rubin, A. De Carvalho, R. Kiss, V. Mathieu,
F. Lefranc, J. Correa, D. A. Cavazos, A. J. Brenner, B. Bryan, S. Rogelj,
A. Kornienko and L. V. Frolova, J. Med. Chem., 2015, 58, 2206–2220.
Financial support from Russian Science Foundation (Grant
#18-13-00238) is gratefully acknowledged.
1
1
0 Acronym ANRORC stands for Addition of Nucleophile-Ring
Opening-Ring Closure cascade mechanism, see for example:
I. S. Young, ANRORC Mechanism in Name Reactions in Heterocyclic
Chemistry II, ed. J. J. Li, Wiley, 2011, pp. 516–526.
1 (a) A. V. Aksenov, N. A. Aksenov, Z. V. Dzhandigova, D. A. Aksenov
and M. Rubin, RSC Adv., 2015, 5, 106492–106497; (b) A. V.
Aksenov, N. A. Aksenov, Z. V. Dzhandigova, I. V. Aksenova, L. G.
Voskressensky, A. N. Smirnov and M. Rubin, Chem. Heterocycl.
Compd., 2016, 52, 299–302.
Conflicts of interest
There are no conflicts to declare.
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1
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