Synthesis of Spiro[indole-3,5′-isoxazoles] with Anticancer Activity via a Formal [4 + 1]-Spirocyclization of Nitroalkenes to Indoles

Article abstract of DOI:10.1021/acs.joc.9b00808

An acid-assisted [4 + 1]-cycloaddition of indoles with nitrostyrenes affords 4′H-spiro[indole-3,5′-isoxazoles] in a diastereomerically pure form. Several of these spirocyclic molecules exhibit promising anticancer activity by reducing viability and inducing differentiation of neuroblastoma cells.

Full text of DOI:10.1021/acs.joc.9b00808

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Article
Synthesis of Spiro[indole-3,5'-isoxazoles] with Anticancer Activity
via a Formal (4+1)-Spirocyclization of Nitroalkenes to Indoles
Alexander V. Aksenov, Dmitrii A Aksenov, Nikolai A Arutiunov, Nicolai A Aksenov, Elena
V Aleksandrova, Zhenze Zhao, Liqin Du, Alexander Kornienko, and Michael Rubin
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00808 • Publication Date (Web): 09 May 2019
Downloaded from http://pubs.acs.org on May 9, 2019
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The Journal of Organic Chemistry
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Synthesis of Spiro[indole-3,5'-isoxazoles] with Anticancer Activity via a
Formal (4+1)-Spirocyclization of Nitroalkenes to Indoles
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Alexander V. Aksenov,†,* Dmitrii A. Aksenov,† Nikolai A. Arutiunov,† Nicolai A. Aksenov,†
Elena V. Aleksandrova,† Zhenze Zhao,‡ Liqin Du,‡ Alexander Kornienko,‡,* Michael Rubin.†,§,*
† Department of Chemistry, North Caucasus Federal University, 1a Pushkin St., Stavropol 355009, Russian Federation;
‡Department of Chemistry and Biochemistry, Texas State University, San Marcos, TX 78666, USA
§ Department of Chemistry, University of Kansas, 1567 Irving Hill Road – Lawrence, KS 66045, USA.
R4
NO2
R3
R3
N
R4
+
H
RT
O
R1
R2
R1
R2
N
H
N
ABSTRACT: An acid-assisted (4+1)-cycloaddition of indoles with nitrostyrenes affords 4'H-spiro[indole-3,5'-isoxazoles] in a
diastereomerically pure form. Several of these spirocyclic molecules exhibit promising anti-cancer activity by reducing via-
bility and inducing differentiation of neuroblastoma cells.
INTRODUCTION
Scheme 1
Natural and synthetic spiro-heterocycles are important
synthetic targets due to their diverse biological profiles
and manifold reactivity.1 Although the subject of the pre-
sent study, 4’H-spiro[indole-3,5’-isoxazoles] (2), do not
occur in nature and have not been obtained synthetically,
they share the privileged polycyclic framework with an
array of highly potent natural products (Scheme 1).2,3 Re-
lated 4'H-spiro[indoline-3,5'-isoxazol]-2-one (1) have re-
ceived some attention from the synthetic community and
methods toward their synthesis have been developed.
These rely on ready availability of isatin precursors 5 and
include an acid-assisted 1,5-spiro-cyclization of mono-
oximes of 3-ene-2,5-diones,4 [3+2]-cycloaddition of nitrile-
oxides to 3-methyleneoxindoles,5 and metal-catalyzed se-
lective vinylation of isatin oximes with vinylboronic acids.6
Any subsequent manipulations at the carbonyl moiety,
should they be required, are limited by the vulnerability of
the alpha-spirocyclic fragment in 1. Recently, we commu-
nicated on the novel, efficient and highly diastereoselective
route to 4’H-spiro[indole-3,5’-isoxazoles] (2) proceeding
via a formal [4+1] cycloaddition reaction of nitroalkene 3
as 1,4-CCNO-dipole and the C-3 of indole 4 as the dipolaro-
philic C1-moiety.7 To the best of our knowledge, this is the
only direct spirocyclization approach to 4’H-spiro[indole-
3,5’-isoxazoles] substituted with an alkyl, aryl or hetaryl
group at C-2 (Scheme 1). Herein we report a full account
of this unusual transformation, which includes studies on
R4
N
O
R3
O
R2
O
R2
O
N
N
R1
R1
5
1
R4
N
O
R3
R2
R1
N
R2
R1
H
4
R4
N
NO2
2
R3
3
the scope and limitations, assessment of the side process-
es, and biological evaluation of the spirocyclic products for
anti-cancer activities.
RESULTS AND DISCUSSION
Our groups have been exploring polyphosphoric acid
(PPA)-assisted cascade heterocyclizations of indoles with
nitro compounds (Scheme 2).8 For example, we discovered
conditions allowing for a selective rearrangement of the
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nitro group into hydroxamic acid 6,9 or under modified
Page 2 of 18
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conditions, an unusual ANRORC10 cascade to give 2-
quinolones 7.8 In other examples, substitution of PPA with
PCl3 resulted in in situ conversion of the nitro-group into a
nitrile 811 or a carboxamide 9.12 During this work, we
came across a poor quality batch of P2O5 containing nota-
ble amounts of red phosphorus (arising from incomplete
combustion during reagent manufacturing). Poly-
phosphoric acid prepared from this material had a distinct
pink color. In this medium, the reaction between nitrosty-
rene 3a and 2-phenylindole (4a) carried out at room tem-
perature led to the formation of notable amounts of unex-
pected spirocyclic structure 2aa (Table 1). The molecular
structure of 2aa was unambiguously confirmed by single
crystal X-ray crystallography.13 Remarkably, this product
was formed with complete (3R*,4’S*)-diastereoselectivity,
as shown. This finding justified further efforts towards the
optimization of the reaction conditions for the selective
synthesis of spirocycles 2. We further tested the reaction
in the presence of 2 equiv. of phosphorous acid (H3PO3, pKa
1.30) in various organic media. It was discovered that reac-
tions carried out in ethyl alcohol, THF or dimethoxyethane
afforded nitroalkane 5aa as the sole product (Table 1, en-
tries 1-3). Formation of spirocyclic product 2aa in minute
amounts was observed in such solvents as DMF and ace-
tonitrile (entries 4,5), but the best results were obtained
when reactions were carried out at room temperature in
solutions of acetic or formic acid (entries 6,7). Indeed, it
was found that H3PO3-assisted reaction in formic acid af-
fords 2aa as the sole product in nearly quantitative yield
(entry 7). We also tested the reaction mediated by ortho-
phosphoric acid (H3PO4, pKa 2.16), which also proceeded
smoothly affording 2aa in 76% yield along with 13% of
nitroalkane 10aa (entry 8). This prompted us to test a
number of different Brønsted acids. It was found that
weaker carboxylic acids such as CH3COOH (pKa 4.75) me-
diate Michael type addition to afford nitroalkane 10aa
exclusively (entry 9). Reactions mediated by stronger ac-
ids, such as formic (pKa 3.75, entry 10), trifluoroacetic (pKa
0.00, entry 11), afforded 5aa as the major product along
with minute amounts of spirocyclic material 2aa. Even
stronger acid such as methanesulphonic (pKa -2.00, entry
12) allowed for predominant formation of 2aa. In the
presence of sulfuric acid, whose acidity could be estimated
using the pKa of the protonated carboxylic acid (c.a. -6.0),
compound 2aa was formed exclusively, albeit in marginal
yield, due to partial decomposition of the products, but
importantly, no nitroalkane 10aa was detected (entry 13).
Taking into account the supreme performance of phospho-
rous acid, which provided nearly quantitative yield of the
target product, we made it a reagent of choice.With opti-
mized conditions in hand, we evaluated the featured trans-
formation on preparative scale employing 2-phenyl-1H-
indole (4a) and aromatic nitrostyrenes 3a-f. We were
pleased to find that these reactions proceeded smoothly
affording the corresponding spirocyclic products 2aa-2af
in high yields and diastereoselectivities (Scheme 4, entries
1-6). Next, the possibility to employ aliphatic nitroalkenes
bearing primary (3g) or secondary (3h) alkyl substituents
was assessed. These reactions proved to be somewhat
less efficient and sluggish, requiring about 2 h for complete
conversion, but the corresponding spirocyclic indolines
2ag and 2ah were also obtained as sole diastereomers in
good yields.
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Table 1. Optimization of spiro-cyclization towards 2aa
NO2
Ph
N
O
Ph
Ph
Acid
+
NO2
3a
Solvent
20 o
+
Ph
Ph
Ph
C
N
N
H
N
H
4a
10aa
2aa
Acida (Time, h) Solvent
2aa:10aa
Scheme 2
(yields, %)c
0:91
1
2
3
4
5
6
7
8
H3PO3 (0.75)
H3PO3 (0.75)
H3PO3 (0.75)
H3PO3 (0.75)
H3PO3 (0.75)
H3PO3 (0.75)
H3PO3 (0.75)
H3PO4 (1.5)
EtOH
DME
THF
DMF
MeCN
CH3COOH
HCOOH
HCOOH
O
0:92
0:91
7:87
16:81
95:0
98:0
76:13
0:95
8:83
10:82
60:8
Ar
Ar
O
NHOH
R
N
H
7
N
H
6
R
N
H
4
9
CH3COOH (15)
HCOOH (15)
CF3COOH (1.5)
CH3SO3H (1.5)
H2SO4 (1.5)b
10
11
12
13
NO2
Ar
HCOOH
HCOOH
HCOOH
3
O
Ar
Ar
33:0
CN
R
NH2
a) All acids were used as 1:1 mixture with 85% for-
mic acid, unless specified otherwise.
b) A mixture of 150 mg of 98% sulfuric acid and 500
mg of 85% formic acid.
R
N
H
N
H
9
8
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c) Yields were determined by 1H NMR analysis of
and an unexpected formation of triarylmethane 11aa as
the major product (Scheme 3). By carrying out the reac-
tion the presence of MeSO3H we managed to improve the
2ak/11aa selectivity ratio and isolated
crude reaction mixtures.
2
Reaction of 4a with (E)-2-(2-nitrovinyl)furan (3i) allowed the
preparation of 4'-(furan-2-yl)-substituted analog 2ai, thus
showing the possibility of introducing even acid-sensitive
heteroaryl groups to the featured scaffold (entry 9). Next, the
influence of the substituent at C-2 of indole was investigated.
Facile and highly efficient spirocyclization was shown to pro-
ceed with indole substrates bearing electron rich substituents
(4b,d,g,h). Typically, these reactions progressed to comple-
tion within 30-40 min, affording the corresponding spirocyclic
products in good yields (2ba, 2da, 2ga, 2ha: entries 10, 12,
15, 16). Indoles bearing moderately electron poor (4c) or ste-
rically encumbered (4e,f) aryl substituents at C-2 reacted more
sluggishly requiring extended reaction time (about 2 h) for
complete conversion, but the yields of the corresponding
products 2aс, 2ae, and 2af were still reasonably high (en-
tries 11, 13, 14). The introduction of heteroaryl substitu-
ents was also tolerated as demonstrated by the prepara-
tion of the thienyl substituted derivative 2ja (entry 17).
Replacing the phenyl group at C-2 with a methyl group
resulted in complex reaction mixtures and total decompo-
sition of the initially formed spirocyclic product 2ka, but
3
4
5
6
7
8
9
Scheme 3
NO2
H2SO4
Ph
Ph
+
N
HCOOH
20 oC
Me
H
10
11
12
13
14
15
16
17
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4a
3k
Me
N
O
Ph
NH
+
HN
Ph
Ph
N
2ak, 28%
11aa, 67%
2ak in 58% yield as a mixture of diastereomers 93:7
(Scheme 5, entry 1). However, formation of 11aa (38%
yield) still represents a challenge as we failed to identify
conditions for the spirocyclization that avoid the formation
of this byproduct.
o
lowering the temperature to 10 C allowed for isolation of
2ka in marginal yield (entry 18). Also, it should be pointed
out
that
2-(trifluoromethyl)-
(4o)
and
2-
Reaction of indole 4a with (2-nitrobut-1-en-1-
yl)benzene (3l) also proceed uneventfully affording a mix-
ture of 54% of spirocyclic product 2al and 42% of the
same triarylmethane 11aa (Scheme 5, entry 2). Reaction
of indole 4a with 1-chloro-4-(2-nitroprop-1-en-1-
yl)benzene (3m) afforded comparable amounts of spirocy-
clic product 2am along with triarylmethane 11ac (Scheme
5, entry 3). Interestingly, byproduct 11 incorporates only
the substituent R3 with the adjacent olefinic carbon atom,
while the other olefinic carbon, together with the NO2
group and substituent R4, are absent. Testing this reaction
with substituted nitroalkenes 3k-m and indoles 4a,e,g
always gave the spirocyclic product in marginal yield with
lower diastereoselectivity, along with notable amounts of
triarylmethane byproduct 11 (Scheme 5, entries 4-8).
(methoxycarbonyl)- (4p) 1H-indoles did not provide any
spirocyclic products at all, even at 50 oC. Starting materials
were recovered unchanged in both cases.
Next, we evaluated tolerance of this transformation to
the presence of other substituents at C-5 or C-7 of indole
core. To this end, indoles bearing 5-isopropyl (4l), 5-
methoxy (4m), and 7-chloro (4n) substituent were sub-
jected to the reaction with nitrostyrene 3a under standard
reaction conditions. All these reactions proceeded une-
ventfully affording spirocyclic products 2ia, 2ma and 2na
efficiently with high selectivity (entries 19-21). Finally, for
further evaluation of the reaction scope, several variously
substituted indoles were tested in reactions with different
nitrostyrenes to obtain more complex representatives of
this class of compounds (entries 22-25).
Next, we tested the possibility to involve β-alkyl ni-
trostyrenes in order to access spirocyclic compounds 2
with additional substituents at C-3’. To this end, (2-
nitroprop-1-en-1-yl)benzene (3k) was subjected to the
reaction with 2-phenyl-1H-indole (4a) in the presence of
H3PO3 in formic acid. Unfortunately, this reaction did not
proceed at all with the recovery of the starting materials
In the next stage of our investigation we designed a
three-component one-pot transformation involving the
assembly of indoles 4 from arylhydrazines 12 and aceto-
phenones 13 via the Fischer reaction, followed by spirocy-
clization towards structure 2 (Scheme 6). To this end,
equimolar mixtures of 12a and 13a were first refluxed in
glacial acetic acid to obtain the corresponding hydrazones
14a (R2 = H, R1 = Ph). Here, acetic acid was used instead of
formic acid since the latter notably decomposes upon con-
tact with H2SO4 upon heating. Addition of sulfuric acid
triggered the Fischer indolization, which proceeded
smoothly at 90 oC furnishing intermediate indole 4a
(Scheme 6). Upon completion of this process, nitroalkene
3a was added at room temperature and spirocyclic prod-
uct 2aa was formed in isolated 79% yield. The one-pot
transformation was also successful with diversely substi-
tuted 12, 13 and 3 (Scheme 6). Expectedly, triarylmethane
byproducts 11 were formed in reactions involving β-alkyl
nitrostyrenes 3k-m. In this one-pot version of the reaction
o
even after heating at 80 C. Similar lack of reactivity was
observed in an attempted reaction carried out in the pres-
ence of H3PO4. Evidently, such a modification in the ni-
trostyrene structure introduces unfavorable steric de-
mands and reduces polarization of the double bond mak-
ing it inefficient as a Michael acceptor. To address this
issue, we enforced the reaction by applying stronger acids,
such as sulfuric or methanesulfonic. In the presence of
H2SO4, the reaction between 3k and 4a proceeded at room
temperature affording spirocyclic product 2ak in low yield
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Page 4 of 18
it was not possible to employ H3PO3, which provides the yield of the one-pot process is somewhat lower compared
1
2
best results for spirocyclization reaction, since this acid
failed to mediate the Fischer indolization step. The overall
to the normal synthetic routine involving isolation and
purification of the intermediate indoles. Nevertheless,
3
4
5
Scheme 4
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7
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11
12
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The Journal of Organic Chemistry
NO2
3g: R3 = n-C6H13
3h: R3 = i-Pr;
3i: R3 = 2-furyl;
3j: 4-EtC6H4
;
3a: R3 = Ph;
R3
R3
N
1
H3PO3
(3.5-4.0 equiv.)
3b: R3 = 4-FC6H4;
3c: R3 = 4-ClC6H4;
3d: R3 = 4-MeOC6H4;
3e: R3 = 4-Me2NC6H4;
3f: R3 = 2-FC6H4;
+
3
O
2
3
R1
R1
R2
HCOOH
RT
R2
N
H
N
2
4
5
4
6
7
8
9
4g: R1 = 2,3-dihydrobenzo[b]-
[1,4]dioxin-6-yl, R2 = H;
4a: R1 = Ph, R2 = H;
4m: R1 = Ph, R2 = 5-MeO;
4n: R1 = Ph, R2 = 7-Cl;
4o: R1 = CF3, R2 = H;
4b: R1 = 4-MeC6H4, R2 = H;
4c: R1 = 4-ClC6H4, R2 = H;
4d: R1 = 4-EtC6H4, R2 = H;
4e: R1 = 2-naphthyl, R2 = H;
4h: R1 = 3,4-(MeO)2C6H3, R2 = H;
4i: R1 = 4-MeC6H4, R2 = H;
4j: R1 = 2-thienyl, R2 = H;
4k: R1 = Me, R2 = H;
4p: R1 = CO2Me, R2 = H.
4f: R1
= (5,6,7,8-tetrahydro-
10
11
12
13
14
15
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17
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20
21
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23
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4l: R1 = Ph, R2 = 5-i-Pr;
naphthalen-2-yl), R2 = H;
MeO
Me2N
F
Cl
F
(S)
(R)
(S)
(S)
(S)
(R)
(S)
(R)
(S)
N
N
(R)
N
N
(R)
N
N
O
O
O
O
O
(R)
O
N
N
N
N
N
N
(1) 2aa: 96%
(2) 2ab: 94%
dr > 20:1
dr > 20:1
(4) 2ad: 86%
dr > 20:1
(5) 2ae: 63%
dr > 20:1
(6) 2af: 84%
dr > 20:1
(3) 2ac: 83%
dr > 20:1
O
(S)
(R)
(S)
(R)
(S)
(S)
(R)
(S)
(R)
N
N
N
N
O
N
N
(R)
(R)
O
(R)
O
O
O
O
N
N
N
N
N
N
(7) 2ag: 73%
(8) 2ah: 71%
dr > 20:1
(9) 2ai: 62%
dr > 20:1
(12) 2da: 87%
(10) 2ba: 91%
dr > 20:1
(11) 2ca: 86%
dr > 20:1
dr > 20:1
Cl
dr > 20:1
Me
(S)
(R)
(S)
(S)
(R)
(S)
(R)
(S)
(R)
N
N
N
N
N
(R)
O
O
O
O
O
OMe
O
N
N
N
N
N
(15) 2ga: 74%
dr > 20:1
(17) 2ja: 72%
(13) 2ea: 77%
(14) 2fa: 68%
dr > 20:1
(16) 2ha: 61%
dr > 20:1
S
OMe
Cl
O
dr > 20:1
dr > 20:1
(S)
(S)
MeO
(S)
(R)
(S)
(S)
N
N
N
N
N
(R)
O
(R)
O
(R)
O
(R)
O
O
Cl
N
N
N
Me
N
N
(18) 2ka: 44%
(at 10 oC)
(20) 2ma: 90%
dr > 20:1
(19) 2la: 91%
dr > 20:1
(21) 2na: 86%
dr > 20:1
(22) 2ic: 87%
Me
dr > 20:1
dr > 20:1
MeO
MeO
(S)
(R)
(S)
(S)
N
N
N
O
(R)
O
O
(R)
N
O
N
N
(23) 2gd: 57%
dr > 20:1
(24) 2ej: 72%
dr > 20:1
(25) 2ld: 84%
dr > 20:1
O
Scheme 5
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H
N
R4
R1
R3
R1
NO2
R2
1
2
3
4
R3
R3
N
R4
3
+
MeSO3H
CH3COOH
20 oC
O
R1
R1
R2
R2
R2
N
H
N
2
5
4
N
H
10
6
7
8
9
4a: R1 = Ph, R2 = H;
3k: R3 = Ph, R4 = Me;
3l: R3 = Ph, R4 = Et;
3m: R3 = ClC6H4, R4 = Me;
4e: R1 = 2-naphthyl, R2 = H;
4g: R1 = 2,3-dihydrobenzo[b]-
[1,4]dioxin-6-yl, R2 = H;
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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32
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45
46
47
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51
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Cl
Me
Me
Me
(S)
(S)
(R)
(S)
(S)
N
O
N
N
N
(R)
(R)
(R)
O
O
O
N
N
N
N
(1) 2ak: 58%
dr = 93:7
+ 38% 11aa
(2) 2al: 54%
dr = 93:7
+ 42% 11aa
(3) 2am: 53%
dr = 93:7
+ 44% 11ac
(4) 2ek: 51%
dr = 96:4
+ 46% 11ea
Cl
Cl
Me
N
Me
(S)
(R)
(S)
Me
N
(S)
(R)
(S)
(R)
N
(R)
N
O
O
O
O
O
N
N
O
N
N
(5) 2el: 46%
dr > 20:1
+ 50% 11ea
(7) 2gk: 34%
dr = 91:9
+ 55% 11ga
(8) 2gm: 47%
dr = 84:16
+ 48% 11gc
O
(6) 2em: 48%
dr = 91:9
+ 49% 11ec
O
H
N
H
N
H
N
H
N
Cl
Cl
N
H
N
H
N
H
N
H
11aa
11ac
11ec
11ea
O
O
H
N
H
N
O
O
Cl
N
H
N
H
O
O
11ga
11gc
O
O
the one-pot approach still looks attractive as it allows for
the reduction of the number of synthetic operations and
elimination of waste products.
Michael-type attack by C-3 of indole 4, affording iminium
species 16, which upon deprotonation is transformed into
nitronate form 17. It should be pointed out, that species
Scheme 6
Analysis of the experimental observations has led us to
propose the following mechanistic rationale (Scheme 7).
Initial protonation of nitroalkene 3 leads to the formation
of activated N-oxo-N-vinylhydroxylammonium 15 (which
can be O-phosphorylated in H3PO3 or H3PO4 media, making
it even more stable).14 This species is highly susceptible to
6
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The Journal of Organic Chemistry
R2
Scheme 7
R1
1
2
3
4
5
6
R4
R4
+
AcOH
reflux
NH
O
R3
R3
O
Me
OH
H
N
O
N
NH2
12
13
O
15
12a: R2 = H;
12l: R2 = i-Pr
13a: R1 = Ph; 13b: R1 = 4-MeC6H4;
13g: R1 = 2,3-dihydrobenzo[b]-[1,4]dioxin-6-yl
3
R1
7
8
9
R2
N
H
R2
4
R3
O
H2SO4
R1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
NH
N
Me
R1
N
N
H
AcOH
90 oC
O
OH
R3
13
4a,b,g,l
B
N
H
R4
OH
N
R1
17
R4
R4
H
R1
NO2
3a-d,
3g,h,
3k-m
R3
N
R3
N
H
16
R4
R2
O
R1
H2SO4/AcOH
20 oC
R3
O
N
N
2
tautomerization
O
2aa: R1 = R3 = Ph, R2 = R4 = H, 79%;
R4
2ab: R1 = Ph, R3 = 4-FC6H4, R2 = R4 = H, 72%;
2ac: R1 = Ph, R3 = 4-ClC6H4, R2 = R4 = H, 68%;
2ad: R1 = Ph, R3 = 4-MeOC6H4, R2 = R4 = H, 74%;
2ag: R1 = Ph, R3 = n-C6H13, R2 = R4 = H, 49%;
2ah: R1 = Ph, R3 = i-Pr, R2 = R4 = H, 53%;
N
H
R1
10
2ak: R1 = R3 = Ph, R2 = H, R4 = Me, 41% + 11aa, 27%;
2al: R1 = R3 = Ph, R2 = H, R4 = Et, 42% + 11aa, 31%;
2ba: R1 = 4-MeC6H4, R2 = R4 = H, R3 = Ph, 77%;
2ga: R1 = 2,3-dihydrobenzo[b]-[1,4]dioxin-6-yl, R2 = R4 = H, R3 = Ph, 59%;
2gm: R1 = 2,3-dihydrobenzo[b]-[1,4]dioxin-6-yl, R2 = H,
Scheme 8
R3
O
N
R
3 = 4-ClC6H4, R4 = Me, 36% + 11gc, 32%;
O
H3PO3
2la: R1 = R3 = Ph, R2 = i-Pr, R4 = H, 73%.
No reaction
HCOOH
20 oC
N
H
R1
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
17 can tautomerize to form nitroalkane form 10. Unlike
17, form 10 is non-reactive in the spirocyclization reac-
tion. Indeed, when pre-isolated compound 10aa was sub-
jected to the action of H3PO3 in formic acid (best optimized
reaction conditions), it failed to provide any spiro-product
2aa, and was recovered unchanged (Scheme 8). At the
same time, when potassium nitronates 18, generated upon
basic treatment of nitroalkanes 10 in EtOH, were isolated
and re-subjected to the spirocyclization under the same
conditions spiro-products were formed, albeit in marginal
yields along with recovered nitroalkanes 10 (Scheme 8).
These experiments are consistent with the idea that nitro-
nates 17 are essential intermediates in the featured pro-
cess.
10aa: R1 = R3 = Ph;
10ac: R1 = Ph, R3 = 4-ClC6H4;
10ca: R1 = 4-ClC6H4, R3 = Ph
KOH/EtOH
20 oC
R3
O
N
K
H3PO3
O
HCOOH
20 oC
N
H
R1
18aa: R1 = R3 = Ph;
18ac: R1 = Ph, R3 = 4-ClC6H4;
18ca: R1 = 4-ClC6H4, R3 = Ph
R3
N
It could be further reasoned, that protonation of nitro-
nate 17 under acidic conditions should provide nitronic
acid 20, which is susceptible to acid-mediated dehydration
to afford conjugated oxime 21. Subsequent acid-assisted
5-endo-trig cyclization should provide spiro-2,5-
dihydroisoxazole species 22, which under the reaction
conditions may isomerize into either (3R*,4’S*)- (2) or
(3R*,4’R*)-4,5- dihydroisoxazole 23 (Scheme 9).
Our DFT modeling13 suggests that diastereomer 2 is
more thermodynamically favored by about 4.1 kcal/mol,
which explains high diastereoselectivity of the featured
transformation.
O
2aa: R1 = R3 = Ph, 26% + 10aa;
2ac: R1 = Ph, R3 = 4-ClC6H4, 27% + 10ac;
2ca: R1 = 4-ClC6H4, R3 = Ph, 34% + 10ca
R1
N
It could be also envisioned that N-alkylidene-N-
hydroxyhydroxylammonium species 19 formed upon pro-
tonation of nitronate 17 exists in tautomeric equilibrium
with N-alkyl-N-oxohydroxylammonium form 24 (Scheme
10). The latter species should be susceptible to a fragmen-
tation with extrusion of nitronic (azinic) acid 25 to afford
highly electrophilic (E)-3-alkylidene-2-methyl-3H-indole
species 26.
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Page 8 of 18
Scheme 9
kinetically controlled protonation of negatively charged
1
2
3
4
5
6
7
8
oxygen moiety in structure 17 should take place much to a
greater extent, and key intermediate 19 would be generat-
ed in significant concentrations. The following spirocy-
clization can also be additionally assisted by phosphoryla-
tion of the hydroxylamine functions in both 19 and 20,
which should promote the elimination step leading to for-
mation of oxime 20. However, for sterically hindered ni-
trostyrenes 3k-m (R4 ≠ H) the initial Michael addition step
in such acids is not efficient, probably, also due to the
phosphorylation of the anionic oxygen atom in species 3,
introducing additional steric encumbrance. With strongest
Brønsted acids, such as sulfuric or methanesulfonic, an
alternative route for the thermodynamically controlled
protonation of species 17 at carbon atom should also take
place to afford species 24, which ultimately leads to the
formation of triarylmethane byproduct 11.
R3
R3
HO
N
HO
N
H
O
OH
OH
H
R4
R4
N
H
N
R1
R1
H
17
19
B
R3
HO
N
R3
N
H
9
OH
-H2O
R4
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
R4
N
N
R1
R1
20
H
21
H
- H
R4
R4
R4
R3
(S*)
R3
R3
(R*)
N
NH
O
N
(R*)
(R*)
O
O
R1
R1
Table 2. The effects of the synthesized compounds on
the viability of neuroblastoma cells
R1
N
N
N
compound #
2aa
2ab
2ac
% mean cell viability a
% SD
2: more stable
22
23: less stable
75
95
97
47
58
92
93
102
95
65
74
20
49
48
26
94
18
96
40
73
94
73
56
18
37
101
92
101
2
8
6
10
4
7
2
7
8
7
8
2
7
4
8
6
3
7
7
9
5
6
4
0
1
3
4
7
Scheme 10
2ad
2ae
2af
R3
R3
HO
HO
N
N
O
OH
H
R4
R4
N
N
H
R1
2ag
2ah
2ai
R1
24
19
H
B
- R4СH=N(O)OH
2ba
2ca
HN
R1
25
R3
R3
R1
2da
2ea
2fa
R1
N
H
4
N
N
H
R1
26
11
2ga
2ha
2ja
In the presence of excess amount of slowly reacting in-
dole starting material 4 nucleophilic attack of this species
is expected to furnish alkylation product 11. It should be
pointed out, that intermediates 24 derived from nitrosty-
renes substituted at C-β (R4 ≠ H) should experience signifi-
cant unfavorable steric repulsion between groups R3 and
R4, and thus are expected to be more prompt to the extru-
sion of 25. This might be the reason that formation of by-
products 11 was detected only in such cases. An alterna-
tive reason for the observed phenomenon might be in the
unfavored formation of key intermediate 20 in reaction of
substrates bearing bulky R4.
2ka
2la
2ma
2na
2ic
2ld
2gd
2ej
2ak
2ek
The above considerations also provide an explanation to
the observed dependence of the reaction outcome on the
strength of the employed Brønsted acid. Indeed, in the
presence of weak acids (such as AcOH) protonation of ni-
tronate 17 to afford nitronic acid 19 is not expected to be
efficient. Instead, tautomerization would take place to
yield non-reactive nitoalkane 10. Employment of Lewis-
basic solvents (alcohols, ethers, amides) provides the same
effect. In the presence of stronger acids (H3PO3, H3PO4),
2em
a
BE(2)-C cells were treated with the indicated com-
pounds (25 µM) in triplicates for 4 days. Cell viability was
then determined by the MTT assay. Shown are the com-
pound name, % mean cell viability relative to DMSO con-
trol, and standard deviation (SD).
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The Journal of Organic Chemistry
An unusual acid-assisted reaction of nitroalkenes as syn-
1
thetic equivalents of CCNO-type 1,4-dipoles with indoles
2 .0
1 .5
1 .0
0 .5
0 .0
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
2 2 m a m
a
C o m p o u n d s (2 5 µ M )
Figure 1. Effect of compounds on neurite outgrowth in neu-
roblastoma cell line BE(2)-C. 1,000 cells were treated with the
compounds (25 µM) for 8 days. Shown is the scatter plot of
normalized neurite lengths, sorted in ascending order, associ-
ated with individual compounds. Black dashed line is the
mean of the library.
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Due to their interesting natural product-like framework,
the synthesized compounds were tested for biological ac-
tivities. For example, they were found to reduce viability of
BE(2)-C human neuroblastoma cells (Table 2). The effect
was particularly pronounced with compounds 2da, 2ga,
2ja and 2gd, which at the concentration of 25 µM reduced
cell viability to 20, 26, 18 and 18%, respectively. Although
a more extensive testing with the determination IC50 val-
ues against several cancer cell lines would be necessary to
understand the structure-activity relationship (SAR)
trends in this series of compounds, it is interesting that
two of these four compounds (2ga and 2gd) contain the
benzodioxane moiety at the C2-position of the indole ring
revealing the initial SAR.
In another assay, the synthesized compounds were test-
ed for their ability to induce differentiation of the BE(2)-C
neuroblastoma cells. Neuroblastoma is a major type of
childhood cancer responsible for ~15% of cancer-related
deaths among children. 15 It is believed that neuroblasto-
ma tumors result the from the failure of neural crest pre-
cursor cells to undergo differentiation and lead to uncon-
trolled cell proliferation cycle.16 Retinoic acid has been a
mainstay therapy for neuroblastoma that works by induc-
ing differentiation of cancer cells. However, resistance of
this type of cancer to treatment with retinoic acid is com-
mon and generates the need for identification of new clas-
ses of differentiation agents.17
Figure 2. Compound 2ma induces neurite outgrowth in
BE(2)-C cells. Shown are representative phase-contrast im-
ages for cells treated with (A) DMSO control, (B) 2ma (25 µM)
and (C) retinoic acid (2 µM) for 8 days. Neurites are highlight-
ed in pink and cell bodies in yellow color.
As shown in quantitatively in Figure 1 and visually in
Figure 2, compound 2ma induced visible neurite out-
growth, the morphological marker of neuroblastoma cell
differentiation, in BE(2)-C cells. Although its effect was not
as potent as that of retinoic acid.
affords H-spiro[indole-3,5-isoxazole] derivatives in a high-
ly diastereoselective formal (4+1)-cycloaddition process.
Here, we describe the preparation of a small library of spi-
rocyclic compounds, reaction scope and limitations, effects
CONCLUSION
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The Journal of Organic Chemistry
Page 10 of 18
ous ammonia, and once again with water. After drying, the result-
of the medium acidity and propose a plausible mechanistic
rationale. Several of the synthesized compounds reduced
the viability of neuroblastoma cells to 20, 26, 18 and 18%,
respectively, at the concentration of 25 µM. Furthermore,
compound 2ma was found to induce differentiation of
neuroblastoma cells in a manner similar to the clinically
used drug, retinoic acid. Given the rapid development of
resistance to retinoic acid, this promising finding warrants
further exploration of compounds with this spirocyclic
skeleton as potential agents to combat neuroblastoma, a
deadly childhood cancer.
ing crystalline material was sufficiently pure for any practical
purposes, but it could be additionally purified by Flash column
chromatography on Silica gel eluting with a mixture of hexane
and ethyl acetate (4:1), or by re-crystallization from a mixture of
hexane and benzene (1:1). The titled material was obtained as
light-grey solid, m.p. 103-105 oC (benzene/hexanes), Rf 0.47 (hex-
anes/EtOAc, 1:4). Yield 156 mg, (0.48 mmol, 96%). 1H NMR (400
MHz, CDCl3) δ 8.17 (dd, J = 7.8, 1.8 Hz, 2H), 7.70 (d, J = 1.6 Hz, 1H),
7.59 – 7.49 (m, 3H), 7.40 (d, J = 7.7 Hz, 1H), 7.15 (td, J = 7.6, 1.3 Hz,
1H), 7.12 – 7.08 (m, 3H), 6.94 (d, J = 6.7 Hz, 1H), 6.91 – 6.82 (m,
3H), 5.10 (d, J = 1.4 Hz, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ
177.4, 152.9, 149.5, 135.7, 133.1, 131.8, 131.7, 130.1, 129.2 (2С),
128.7 (2С), 128.4 (2С), 128.2, 127.8 (2С), 126.0, 124.7, 121.2,
97.7, 61.8; FT IR (KBr, film, cm-1): 3059, 3034, 2360, 1691, 1657,
1561, 1544, 1461, 1198; HRMS (ES TOF) calc`d for C22H16N2NaO
(M+Na)+ 347.1155, found 347.1167 (3.4 ppm).
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
EXPERIMENTAL PART
General
(3R*,4'S*)-4'-(4-Fluorophenyl)-2-phenyl-4'H-spiro[indole-
3,5'-isoxazole] (2ab): This compound was obtained via Typical
Procedure A from 2-phenyl-1H-indole (4a) (97 mg, 0.50 mmol)
and 1-fluoro-4-(2-nitrovinyl)benzene (3b) (92 mg, 0.55 mmol).
The titled material was obtained as light yellow crystals, m.p. 94-
96 oC (benzene/hexanes), Rf 0.41 (hexanes/ EtOAc, 1:4). Yield
161 mg (0.47 mmol, 94%); 1H NMR (400 MHz, CDCl3) δ 8.15 (dd, J
= 7.9, 1.5 Hz, 2H), 7.68 (d, J = 1.5 Hz, 1H), 7.61 – 7.49 (m, 3H), 7.42
(d, J = 7.7 Hz, 1H), 7.22 – 7.15 (m, 1H), 6.96 – 6.88 (m, 2H), 6.86 –
6.76 (m, 4H), 5.08 (d, J = 1.0 Hz, 1H); 13C{1H} NMR (101 MHz,
CDCl3) δ 177.2, 162.3 (d, J = 242.1 Hz), 161.1, 152.9, 149.2, 135.6,
131.9, 131.5, 130.2, 129.4 (d, J = 8.2 Hz), 129.2 (2С), 128.9 (2C, d, J
= 3.3 Hz), 128.3 (2С), 126.2, 124.5, 121.3, 115.7 (2C, d, J = 21.8
Hz), 97.7, 61.0; FT IR (KBr, film, cm-1): 3062, 2923, 2855, 2210,
1696, 1603, 1509, 1460, 1235, 1160, 1104; HRMS (ES TOF) calc’d
for C22H16FN2O (M+H)+ 343.1241, found 343.1231 (2.9 ppm);
calc’d for C22H15FN2ONa (M+Na)+ 365.1061, found 365.1058 (0.8
ppm).
1H and 13C NMR spectra were recorded on a Bruker Avance-III
spectrometer (400 or 100 MHz, respectively) equipped with BBO
probe in CDCl3 or DMSO-d6, using TMS as internal standard. High-
resolution mass spectra were registered with a Bruker Maxis
spectrometer (electrospray ionization, in MeCN solution, using
HCO2Na–HCO2H for calibration). Melting points were measured
with a Stuart smp30 apparatus. All reactions were performed in
oven-dried 3 mL Weaton microreactor equipped with magnetic
spin-vane and Mininert valve, employing magnetic stirring. Reac-
tion progress and purity of isolated compounds were controlled
by TLC on Silufol UV-254 plates, eluting with hexanes/EtOAc
mixture 4:1. Indoles 4d,18 4h,19 and 4j,20 as well as nitroalkene
3e21 were synthesized according to known procedures. All other
reagents and solvents were purchased from commercial vendors
and used as received.
Detection of Neurite outgrowth
Human neuroblastoma cell line BE(2)-C cells were grown in
DMEM / F-12 (Corning Cellgro) supplemented with 10% Equafe-
tal bovine serum (Atlas Biologicals). 1,000 cells were plated and
treated in 96-well plates with different concentration of com-
pounds in triplicates for 4 days. Cell images were taken under 20X
magnification using IncuCyte ZOOM Live Cell Imaging System
(Essen BioScience). Neurite lengths were analyzed in the acquired
images using the neurite definition defined by NeuroTrack system
(Essen BioScience) as described previously.22
(3R*,4'S*)-4'-(4-Chlorophenyl)-2-phenyl-4'H-spiro[indole-
3,5'-isoxazole] (2ac): This compound was obtained via Typical
Procedure A from 2-phenyl-1H-indole (4a) (97 mg, 0.50 mmol)
and 1-chloro-4-(2-nitrovinyl)benzene (3c) (101 mg, 0.55 mmol).
The titled material was obtained as yellow crystals, m.p. 125-128
oC (benzene/ hexanes), Rf 0.22 (hexanes/benzene, 5:2). Yield 148
mg. (0.42 mmol, 83%). 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J =
7.1 Hz, 2H), 7.67 (s, 1H), 7.59 – 7.49 (m, 3H), 7.42 (d, J = 7.6 Hz,
1H), 7.23 – 7.14 (m, 1H), 7.08 (d, J = 8.1 Hz, 2H), 6.93 (d, J = 4.0 Hz,
2H), 6.78 (d, J = 8.1 Hz, 2H), 5.06 (s, 1H); 13C{1H} NMR (101 MHz,
CDCl3) δ 177.1, 152.7, 149.0, 135.4, 134.1, 131.9, 131.6, 131.4,
130.4, 129.3 (2C), 129.0 (2C), 128.9 (2C), 128.3 (2C), 126.3, 124.5,
121.4, 97.6, 61.1; FT IR (KBr, film, cm-1): 3649, 3568, 3061, 2360,
1682, 1652, 1513, 1455, 1242; HRMS (ES TOF) calc`d for
C22H15ClN2NaO (M+Na)+ 381.0765, found 381.0763 (0.5 ppm).
Cell viability measured by MTT Assay
The effect of compound treatment of cell viability was meas-
ured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium
bromide (MTT) assay, which is based on measuring the metabolic
(mitochondrial dehydrogenase) activity in viable cells. Briefly,
BE(2)-C cells were treated with compounds in 96 well plates for 4
days, the MTT reagent (15 µl at 2.5 mg/ml in 1X PBS) was then
(3R*,4'S*)-4'-(4-Methoxyphenyl)-2-phenyl-4'H-
o
added into each well and incubated for 1 hour at 37 C. Precipi-
spiro[indole-3,5'-isoxazole] (2ad): This compound was ob-
tained via Typical Procedure A from 2-phenyl-1H-indole (4a) (97
mg, 0.50 mmol) and 1-methoxy-4-(2-nitrovinyl)benzene (3d) (99
mg, 0.55 mmol). The titled material was obtained as grey crys-
tals, m.p. 122-123 oC (benzene/hexanes), Rf 0.20 (benzene). Yield
152 mg, (0.43 mmol, 86%). 1H NMR (400 MHz, CDCl3) δ 8.15 (dd,
J = 7.6, 1.4 Hz, 2H), 7.65 (d, J = 1.1 Hz, 1H), 7.53 (q, J = 6.1 Hz, 3H),
7.41 (d, J = 7.7 Hz, 1H), 7.16 (t, J = 7.5 Hz, 1H), 6.96 (d, J = 7.0 Hz,
1H), 6.91 (t, J = 7.4 Hz, 1H), 6.77 (d, J = 8.6 Hz, 2H), 6.62 (d, J = 8.6
Hz, 2H), 5.05 (s, 1H), 3.66 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3)
δ 177.4, 159.2, 152.9, 149.9, 135.8, 131.7, 131.7, 130.0, 129.1
(2C), 129.0 (2C), 128.3 (2C), 126.1, 125.0, 124.7, 121.2, 114.0
(2C), 97.8, 61.2, 55.2; FT IR (KBr, film, cm-1): 3069, 2829, 2363,
1895, 1689, 1614, 1513, 1456, 1250, 1179, 1033; HRMS (ES TOF)
calc`d for C23H18N2NaO2 (M+Na)+ 377.1260, found 377.1263 (0.7
ppm).
tates were spun down and dissolved in DMSO. Optical density
values at wavelength 570 nm and 630 nm were measured using
SpectroMAX 190 (Molecular Device), and the difference in the
two optical density values was used to determine the relative cell
survival.
Preparative procedures
(3R*,4'S*)-2,4'-Diphenyl-4'H-spiro[indole-3,5'-isoxazole]
(2aa), Typical Procedure A: Reaction vessel was charged with 2-
phenyl-1H-indole (4a) (97 mg, 0.50 mmol), (2-nitrovinyl)benzene
(3a) (82 mg, 0.55 mmol), phosphorous acid (500 mg), and formic
acid (500 mg). The mixture was vigorously stirred for 2 h at
room temperature. Resulting dark-red homogenous solution was
poured into water (50 mL), and the formed precipitate was fil-
tered and washed consecutively with water (4 times), 10% aque-
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The Journal of Organic Chemistry
N,N-Dimethyl-4-((3R*,4'S*)-2-phenyl-4'H-spiro[indole-3,5'-
2-(2-nitrovinyl)furan (3i) (77 mg, 0.55 mmol). The titled materi-
al was obtained as yellow oil, Rf 0.21 (hexane/ acetone 6:1). Yield
97 mg (0.31 mmol, 62%). 1H NMR (400 MHz, CDCl3) δ 8.08 (d, J =
7.0 Hz, 2H), 7.61 (d, J = 0.8 Hz, 1H), 7.56 – 7.46 (m, 4H), 7.27 (t, J =
7.6 Hz, 1H), 7.11 (dd, J = 9.0, 4.1 Hz, 2H), 7.01 (d, J = 7.5 Hz, 1H),
6.17 – 6.08 (m, 1H), 6.01 (d, J = 3.2 Hz, 1H), 5.10 (s, 1H); 13C{1H}
NMR (101 MHz, CDCl3) δ 176.5, 153.1, 147.1, 146.0, 142.9, 135.4,
131.8, 131.4, 130.4, 129.2 (2C), 128.2 (2C), 126.3, 124.2, 121.3,
110.6, 109.0, 96.5, 55.9; FT IR (film, cm-1): 3073, 2930, 2855,
1606, 1539, 1505, 1464, 1445, 1318, 1269, 1246, 1201, 1145,
1073; HRMS (ES TOF) calc`d for C20H15N2O2 (M+H)+ 315.1128,
found 315.1137 (2.9 ppm); calc`d for C20H14N2NaO2 (M+Na)+
337.0947, found 337.0940 (2.2 ppm).
isoxazol]-4'-yl)aniline (2ae): This compound was obtained via
Typical Procedure A from 2-phenyl-1H-indole (4a) (97 mg, 0.50
mmol) and N,N-dimethyl-4-(2-nitrovinyl)aniline (3e) (106 mg,
0.55 mmol). Yield 116 mg, (0.32 mmol, 63%), yellow solid,
m.p.147.4-150.5 oC (benzene), Rf 0.19 (benzene); 1H NMR (400
MHz, CDCl3) δ 8.18 – 8.10 (m, 2H), 7.62 (s, 1H), 7.53 (q, J = 5.5 Hz,
3H), 7.41 (d, J = 7.6 Hz, 1H), 7.16 (t, J = 7.5 Hz, 1H), 7.01 (d, J = 7.3
Hz, 1H), 6.92 (t, J = 7.4 Hz, 1H), 6.72 (d, J = 8.5 Hz, 2H), 6.43 (d, J =
8.5 Hz, 2H), 5.01 (s, 1H), 2.82 (s, 6H); 13C{1H} NMR (101 MHz,
CDCl3) δ 177.7, 153.1, 150.4, 150.1, 136.0, 131.9, 131.6, 129.9,
129.1 (2C), 128.7 (2C), 128.3 (2C), 126.0, 124.9, 121.1, 120.1,
112.2 (2C), 97.9, 61.4, 40.4 (2C); IR (KBr, film, cm-1): 2976, 1744,
1618 ,1527, 1458, 1363, 1241; HRMS (ES TOF) calc`d for
C24H22N3O (M+H)+ 368.1757, found 368.1749 (2.4 ppm);
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(3R*,4'S*)-4'-Phenyl-2-(p-tolyl)-4'H-spiro[indole-3,5'-
isoxazole] (2ba): This compound was obtained via Typical Pro-
cedure A from 2-(p-tolyl)-1H-indole (4b) (104 mg, 0.50 mmol)
and (2-nitrovinyl)benzene (3a) (82 mg, 0.55 mmol). The titled
material was obtained as light grey solid, m.p. 55-57 oC (ben-
zene/hexanes), Rf 0.27 (hexane/benzene 2:5). Yield 154 mg,
(0.46 mmol, 91%). 1H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 8.0 Hz,
2H), 7.70 (s, 1H), 7.38 (d, J = 7.6 Hz, 1H), 7.34 (d, J = 8.0 Hz, 2H),
7.20 – 7.03 (m, 4H), 6.94 (d, J = 7.3 Hz, 1H), 6.91 – 6.80 (m, 3H),
5.10 (s, 1H), 2.45 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 177.3,
153.0, 149.4, 142.4, 135.7, 133.1, 130.0, 129.9 (2C), 128.9, 128.6,
128.3, 128.1, 127.7 (2C), 125.8, 124.6, 121.0, 97.7, 62.0, 21.8; FT
IR (KBr, film, cm-1): 3032, 2882, 2589, 2364, 1925, 1813, 1614,
1543, 1516, 1456, 1190; HRMS (ES TOF) calc`d for C23H18N2NaO
(M+Na)+: 361.1311, found 361.1311 (0.2 ppm).
(3R,4'S)-4'-(2-Fluorophenyl)-2-phenyl-4'H-spiro[indole-
3,5'-isoxazole] (2af): This compound was obtained via Typical
Procedure A from 2-phenyl-1H-indole (4a) (97 mg, 0.50 mmol)
and 1-fluoro-2-(2-nitrovinyl)benzene (3f) (92 mg, 0.55 mmol).
Yield 144 mg (0.42 mmol, 84%), Rf 0.54 (benzene/petroleum
ether, 5:2). Light yellow crystals, mp 143-145 oC (ben-
zene/hexane). 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 6.7 Hz, 2H),
7.69 (s, 1H), 7.57 – 7.49 (m, 3H), 7.45 (d, J = 7.7 Hz, 1H), 7.18 (t, J =
7.5 Hz, 1H), 7.14 – 7.05 (m, 2H), 7.00 (t, J = 7.4 Hz, 1H), 6.90 (dt, J
= 14.7, 7.2 Hz, 2H), 6.74 (t, J = 9.1 Hz, 1H), 5.23 (s, 1H); 13C{1H}
NMR (101 MHz, CDCl3) δ 177.1, 160.4 (d, J = 248.1 Hz), 153.4,
148.5, 135.3, 131.8, 131.7, 130.3, 130.2 (d, J = 8.2 Hz), 129.1 (2C),
128.9 (d, J = 3.6 Hz), 128.2 (2C), 126.0, 124.3, 124.2 (d, J = 3.6 Hz),
121.3, 121.1 (d, J = 15.2 Hz), 115.6 (d, J = 21.3 Hz), 97.0, 55.9 (d, J
= 1.4 Hz); IR (KBr, film, cm-1): 3065, 2368, 1614, 1542, 1501,
1460, 1246, 1220, 1201, 1100. HRMS (ES TOF) calc’d for
C22H16FN2O (M + H)+ 343.1241, found 343.1235 (1.8 ppm).
(3R*,4'S*)-2-(4-Chlorophenyl)-4'-phenyl-4'H-spiro[indole-
3,5'-isoxazole] (2ca): This compound was obtained via Typical
Procedure A from 2-(4-chlorophenyl)-1H-indole (4c) (114 mg,
0.50 mmol) and (2-nitrovinyl)benzene (3a) (82 mg, 0.55 mmol).
The titled material was obtained as light-yellow solid, m.p. 152-
(3R*,4'S*)-4'-Hexyl-2-phenyl-4'H-spiro[indole-3,5'-
o
isoxazole] (2ag): This compound was obtained via Typical Pro-
cedure A from 2-phenyl-1H-indole (4a) (97 mg, 0.50 mmol) and
1-nitrooct-1-ene (3g) (86 mg, 0.55 mmol). The titled material
was obtained as yellowish oil, Rf 0.33 (hexane/acetone 6:1). Yield
122 mg (0.37 mmol, 73%); 1H NMR (400 MHz, CDCl3) δ 8.08 –
8.03 (m, 2H), 7.61 (d, J = 7.7 Hz, 1H), 7.53 – 7.44 (m, 3H), 7.44 –
7.38 (m, 2H), 7.37 – 7.33 (m, 1H), 7.22 (td, J = 7.5, 1.0 Hz, 1H),
3.73 (td, J = 7.9, 1.4 Hz, 1H), 1.50 (tdd, J = 13.2, 6.7, 4.1 Hz, 1H),
1.29 – 1.18 (m, 1H), 1.12 – 0.78 (m, 8H), 0.75 (t, J = 7.1 Hz, 3H);
13C{1H} NMR (101 MHz, CDCl3) δ 177.7, 153.4, 151.1, 135.8, 131.6,
131.5, 130.4, 128.9 (2C), 128.1 (2C), 126.2, 124.0, 121.7, 96.4,
56.2, 31.2, 28.7, 28.3, 27.5, 22.3, 13.9; FT IR (KBr, film, cm-1):
3043, 2979, 2972, 2930, 2882, 1719, 1614, 1543, 1453, 1374,
1355, 1262, 1033; HRMS (ES TOF) calc`d for C22H25N2O (M+H)+
333.1961, found 333.1969 (2.3 ppm); calc`d for C22H24N2NaO
(M+Na)+ 355.1781, found 355.1783 (0.5 ppm).
153 C (benzene/hexanes), Rf 0.32 (hexane/ benzene 2:5). Yield
154 mg (0.43 mmol, 86%). 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J
= 8.4 Hz, 2H), 7.71 (s, 1H), 7.51 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 7.7
Hz, 1H), 7.10 (d, J = 4.4 Hz, 4H), 6.97 – 6.79 (m, 4H), 5.04 (s, 1H);
13C{1H} NMR (101 MHz, CDCl3) δ 176.2, 152.8, 149.6, 138.0, 135.6,
132.9, 130.2, 130.1, 129.6 (2C), 129.5 (2C), 128.7 (2C), 128.3,
127.7 (2C), 126.2, 124.7, 121.3, 97.6, 61.7; FT IR (KBr, film, cm-1):
2994, 2360, 1749, 1655, 1490, 1456, 1377, 1250, 1096; HRMS (ES
TOF) calc`d for C22H16ClN2O (M+H)+ 359.0946, found 359.0940
(1.4 ppm); calc`d for C22H15ClN2NaO (M+Na)+ 381.0765, found
381.0751 (3.7 ppm).
(3R*,4'S*)-2-(4-Ethylphenyl)-4'-phenyl-4'H-spiro[indole-
3,5'-isoxazole] (2da): This compound was obtained via Typical
Procedure A from 2-(4-ethylphenyl)-1H-indole (4d) (111 mg,
0.50 mmol) and (2-nitrovinyl)benzene (3a) (82 mg, 0.55 mmol).
Yield 118 mg (0.33 mmol, 67%). Light yellow crystals, mp 92-94
oC (benzene/hexane), Rf 0.21 (benzene/hexane, 5:2). 1H NMR
(400 MHz, CDCl3) δ 8.09 (d, J = 8.2 Hz, 2H), 7.71 (s, 1H), 7.37 (t, J =
7.6 Hz, 3H), 7.13 (t, J = 7.7 Hz, 1H), 7.11 – 7.07 (m, 3H), 6.93 (d, J =
7.2 Hz, 1H), 6.89 – 6.84 (m, 3H), 5.12 (s, 1H), 2.75 (q, J = 7.6 Hz,
2H), 1.30 (t, J = 7.6 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ
177.4, 153.0, 149.5, 148.6, 135.7, 133.2, 130.0, 129.1, 128.7 (2C),
128.6 (2C), 128.4 (2C), 128.2, 127.7 (2C), 125.8, 124.6, 121.0,
97.7, 62.0, 29.1, 15.4; IR (KBr, film, cm-1) 2942, 2356, 1685, 1610,
1539, 1498, 1453, 1273, 1198; HRMS (ES TOF) calc’d for
C24H21N2O (M + H)+ 353.1648, found 353.1641 (2.0 ppm).
(3R*,4'S*)-4'-Isopropyl-2-phenyl-4'H-spiro[indole-3,5'-
isoxazole] (2ah): This compound was obtained via Typical Pro-
cedure A from 2-phenyl-1H-indole (4a) (97 mg, 0.50 mmol) and
3-methyl-1-nitrobut-1-ene (3h) (63 mg, 0.55 mmol). The titled
material was obtained as colorless solid, m.p. 148-150 oC (ben-
zene/hexanes), Rf 0.21 (hexane/ acetone 7:1). Yield 103 mg (0.35
mmol, 71%); 1H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 6.9 Hz, 2H),
7.62 (d, J = 7.7 Hz, 1H), 7.55 – 7.45 (m, 4H), 7.42 (t, J = 7.6 Hz, 1H),
7.38 (d, J = 7.2 Hz, 1H), 7.22 (t, J = 7.4 Hz, 1H), 3.45 (dd, J = 11.1,
0.8 Hz, 1H), 1.99 – 1.83 (m, 1H), 1.03 (d, J = 6.6 Hz, 3H), 0.29 (d, J =
6.4 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 178.0, 153.9, 150.2,
135.9, 131.8, 131.6, 130.7, 129.0 (2C), 128.2 (2C), 126.5, 123.8,
121.9, 96.3, 63.9, 28.1, 22.5, 20.3; FT IR (KBr, film, cm-1): 3039,
2972, 2930, 2874, 1723, 1543, 1456, 1374, 1273, 1036 cm-1;
HRMS (ES TOF) calc`d for C19H19N2O (M+H)+ 291.1492, found
291.1485 (2.5 ppm).
(3R*,4'S*)-2-(Naphthalen-2-yl)-4'-phenyl-4'H-
spiro[indole-3,5'-isoxazole] (2ea): This compound was ob-
tained via Typical Procedure A from 2-(naphthalen-2-yl)-1H-
indole (4e) (122 mg, 0.50 mmol) and (2-nitrovinyl)benzene (3a)
(82 mg, 0.55 mmol). The titled material was obtained as green
solid, m.p. 154-156 oC (benzene/hexanes), Rf 0.32 (benzene).
Yield 144 mg (0.38 mmol, 77%). 1H NMR (400 MHz, CDCl3) δ 8.61
(s, 1H), 8.35 (d, J = 8.6 Hz, 1H), 8.04 – 7.95 (m, 2H), 7.91 (d, J = 7.6
Hz, 1H), 7.76 (s, 1H), 7.64 – 7.54 (m, 2H), 7.45 (d, J = 7.7 Hz, 1H),
(3R*,4'R*)-4'-(Furan-2-yl)-2-phenyl-4'H-spiro[indole-3,5'-
isoxazole] (2ai): This compound was obtained via Typical Pro-
cedure A from 2-phenyl-1H-indole (4a) (97 mg, 0.50 mmol) and
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7.17 (t, J = 7.5 Hz, 1H), 7.14 – 7.05 (m, 3H), 7.00 (d, J = 7.2 Hz, 1H),
– 7.13 (m, 1H), 7.06 (d, J = 8.3 Hz, 2H), 6.91 (d, J = 6.1 Hz, 2H), 6.77
6.94 – 6.83 (m, 3H), 5.19 (s, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ
177.3, 152.9, 149.6, 135.8, 134.9, 133.1, 133.0, 130.1, 129.4,
129.0, 129.0, 128.8, 128.6 (2C), 128.2, 128.0, 127.9, 127.7 (2C),
126.9, 126.0, 124.9, 124.6, 121.2, 97.8, 62.2. FT IR (KBr, film,
cm-1): 3058, 2360, 1693, 1509, 1456, 1231, 909; HRMS (ES TOF)
calc`d for C26H18N2NaO (M+Na)+ 397.1311, found 397.1324 (3.2
ppm).
(d, J = 8.3 Hz, 2H), 5.06 (s, 1H), 2.44 (s, 3H); 13C{1H} NMR (101
MHz, CDCl3) δ 177.1, 152.9, 149.0, 142.5, 135.4, 134.0, 131.6,
130.3, 129.9, 129.0 (2C), 128.8 (2C), 128.7 (2C), 128.2 (2C), 126.0,
124.4, 121.1, 97.6, 61.3, 21.8; IR (KBr, film, cm-1): 3036, 2937,
1748, 1607, 1508, 1462, 1244, 1191, 1092; HRMS (ES TOF) calc`d
for C23H18ClN2O (M+H)+ 373.1102, found 373.1107 (1.3 ppm);
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(3R*,4'S*)-4'-Phenyl-2-(thiophen-2-yl)-4'H-spiro[indole-
3,5'-isoxazole] (2ja): This compound was obtained via Typical
Procedure A from 2-(thiophen-2-yl)-1H-indole (4j) (100 mg, 0.50
mmol) and (2-nitrovinyl)benzene (3a) (82 mg, 0.55 mmol). The
(3R*,4'S*)-4'-Phenyl-2-(5,6,7,8-tetrahydronaphthalen-2-
yl)-4'H-spiro[indole-3,5'-isoxazole] (2fa): This compound was
obtained via Typical Procedure
A
from 2-(5,6,7,8-
9
o
tetrahydronaphthalen-2-yl)-1H-indole (4f) (124 mg, 0.50 mmol)
and (2-nitrovinyl)benzene (3a) (82 mg, 0.55 mmol). Yield 129
mg (0.34 mmol, 68%), green crystals, mp 122-125 oC (ben-
zene/hexane), Rf 0.17 (benzene/hexane, 5:2). 1H NMR (400 MHz,
CDCl3) δ 7.93 (s, 1H), 7.86 (dd, J = 7.8, 1.2 Hz, 1H), 7.70 (d, J = 1.3
Hz, 1H), 7.39 (d, J = 7.7 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 7.13 (ddd,
J = 7.8, 7.4, 0.8 Hz, 1H), 7.10 – 7.05 (m, 3H), 6.94 (d, J = 7.2 Hz, 1H),
6.89 – 6.83 (m, 3H), 5.14 (d, J = 0.7 Hz, 1H), 2.90 – 2.84 (m, 4H),
1.89 – 1.82 (m, 4H); 13C{1H} NMR (101 MHz, CDCl3) δ 177.5,
153.0, 149.3, 141.8, 138.1, 135.6, 133.1, 129.91, 129.85, 128.9,
128.7, 128.5 (2C), 128.0, 127.6 (2C), 125.6, 125.2, 124.5, 120.8,
97.6, 62.0, 29.7, 29.5, 23.1, 23.0; IR (KBr, film, cm-1): 2930, 2855,
2364, 1741, 1606, 1538, 1464, 1246, 1194; HRMS (ES TOF) calc’d
for C26H23N2O (M + H)+ 379.1805, found 379.1808 (0.8 ppm).
titled material was obtained as green solid, m.p. 57-60 C (ben-
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zene/hexanes), Rf 0.27 (benzene). Yield 119 mg (0.36 mmol,
72%). 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 1.6 Hz, 1H), 7.69
(dd, J = 3.8, 1.0 Hz, 1H), 7.62 (dd, J = 5.0, 1.0 Hz, 1H), 7.37 (dt, J =
7.7, 0.8 Hz, 1H), 7.20 (dd, J = 5.0, 3.8 Hz, 1H), 7.15 – 7.08 (m, 4H),
6.91 – 6.79 (m, 4H), 5.19 (d, J = 1.6 Hz, 1H); 13C{1H} NMR (101
MHz, CDCl3) δ 173.2, 153.2, 149.2, 135.4, 135.0, 133.1, 131.3,
130.3, 130.1, 128.7 (2C), 128.7, 128.3, 127.8 (2C), 125.7, 124.7,
120.9, 97.1, 62.9; FT IR (KBr, film, cm-1): 3080, 2360, 1753, 1550,
1505, 1423, 1243, 1190, 1059 cm-1; HRMS (ES TOF): calc`d for
C20H14N2NaOS (M+Na)+ 353.0719, found 353.0706 (3.8 ppm).
(3R*,4'S*)-2-Methyl-4'-phenyl-4'H-spiro[indole-3,5'-
isoxazole] (2ka): This compound was obtained via Typical Pro-
cedure A from 2-methyl-1H-indole (4k) (66 mg, 0.50 mmol) and
(2-nitrovinyl)benzene (3a) (82 mg, 0.55 mmol). The reaction was
carried out at 10 oC. The titled material was obtained as red solid,
m.p. 64-65oC (benzene/ hexanes), Rf 0.70 (benzene). Yield 58 mg
(0.22 mmol, 44%). 1H NMR (400 MHz, CDCl3) δ 7.49 (d, J = 1.4 Hz,
1H), 7.24 (d, J = 7.7 Hz, 1H), 7.20 – 7.13 (m, 3H), 7.07 (t, J = 7.6 Hz,
1H), 6.82 (dd, J = 6.4, 2.8 Hz, 2H), 6.65 (t, J = 7.5 Hz, 1H), 6.28 (d, J
= 7.4 Hz, 1H), 4.51 (d, J = 1.2 Hz, 1H), 2.27 (s, 3H); 13C{1H} NMR
(101 MHz, CDCl3) δ 181.1, 154.25, 149.3, 133.0, 132.8, 130.3,
129.0 (2C), 128.7, 128.5 (2C), 125.6, 125.3, 120.3, 96.4, 58.6, 15.4;
FT IR (KBr, film, cm-1): 3062, 3039, 2930, 2863, 1726, 1595, 1464,
1381, 1246, 1194, 1074; HRMS (ES TOF) calc’d for C17H15N2O (M
+ H)+ 263.1179, found 263.1176 (0.9 ppm).
(3R*,4'S*)-2-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-4'-
phenyl-4'H-spiro[indole-3,5'-isoxazole] (2ga): This compound
was obtained via Typical Procedure
A
from 2-(2,3-
dihydrobenzo[b][1,4]dioxin-6-yl)-1H-indole (4g) (126 mg, 0.50
mmol) and (2-nitrovinyl)benzene (3a) (82 mg, 0.55 mmol). The
titled material was obtained as yellow solid, m.p. 116-119 oC
(benzene/hexanes); Rf 0.22 (hexane/benzene 2:5). Yield 141 mg
(0.37 mmol, 74%). 1H NMR (400 MHz, CDCl3) δ 7.71 (s, 2H), 7.68
(s, 1H), 7.34 (d, J = 7.8 Hz, 1H), 7.18 – 7.05 (m, 4H), 6.99 (d, J = 8.3
Hz, 1H), 6.92 (d, J = 7.4 Hz, 1H), 6.87 – 6.80 (m, 3H), 5.12 (s, 1H),
4.31 (d, J = 5.6 Hz, 4H); 13C{1H} NMR (101 MHz, CDCl3) δ 176.7,
153.0, 149.5, 147.0, 143.9, 135.6, 133.1, 130.0, 128.6 (2C), 128.1,
127.7 (2C), 125.6, 125.0, 124.5, 122.1, 120.8, 118.0, 117.4, 97.6,
64.8, 64.3, 62.1; FT IR (KBr, film, cm-1): 3065, 2360, 1681, 1565,
1513, 1288, 1246, 1066; HRMS (ES TOF) calc`d for C24H19N2O3
(M+H)+ 383.1390, found 383.1393 (0.8 ppm); calc`d for
C24H18N2NaO3 (M+Na)+ 405.1210, found 405.1208 (0.3 ppm).
(3R*,4'S*)-5-Isopropyl-2,4'-diphenyl-4'H-spiro[indole-
3,5'-isoxazole] (2la): This compound was obtained via Typical
Procedure A from 5-isopropyl-2-phenyl-1H-indole (4l) (118 mg,
0.50 mmol) and (2-nitrovinyl)benzene (3a) (82 mg, 0.55 mmol).
The titled material was obtained as grey solid, m.p. 108-110oC
(benzene/hexanes), Rf 0.43 (hexanes/ benzene, 2:5). Yield 166
mg, (0.46 mmol, 91%). 1H NMR (400 MHz, CDCl3) δ 8.14 (dd, J =
7.5, 1.7 Hz, 2H), 7.70 (d, J = 1.1 Hz, 1H), 7.53 (d, J = 6.8 Hz, 3H),
7.30 (d, J = 7.9 Hz, 1H), 7.09 (d, J = 6.5 Hz, 3H), 7.02 – 6.92 (m, 1H),
6.88 – 6.81 (m, 2H), 6.75 (s, 1H), 5.07 (s, 1H), 2.69 (hept, J = 6.9
Hz, 1H), 1.04 (d, J = 6.9 Hz, 3H), 1.01 (d, J = 6.9 Hz, 3H); 13C{1H}
NMR (101 MHz, CDCl3) δ 176.6, 150.9, 149.4, 147.1, 135.7, 133.4,
131.8, 131.5, 129.1 (2C), 128.6 (2C), 128.2 (2C), 128.1, 128.1,
127.8 (2C), 122.9, 120.8, 97.5, 61.6, 34.1, 24.3, 23.6; FT IR (KBr,
film, cm-1): 2960, 2360, 1955, 1670, 1494, 1381, 1186; HRMS (ES
TOF) calc`d for C25H23N2O (M+H)+ 367.1805, found 367.1794 (2.9
ppm).
(3R*,4'S*)-2-(3,4-Dimethoxyphenyl)-4'-phenyl-4'H-spiro-
[indole-3,5'-isoxazole] (2ha): This compound was obtained via
Typical Procedure A from 2-(3,4-dimethoxyphenyl)-1H-indole
(4h) (127 mg, 0.50 mmol) and (2-nitrovinyl)benzene (3a) (82
mg, 0.55 mmol). Yield 117 mg, (0.31 mmol, 61%), orange solid,
o
m.p. 158.7-161.2 C (benzene/hexanes), Rf 0.43 (EtOAc/hexanes
1:3); 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 1.9 Hz, 1H), 7.72 (d, J
= 1.5 Hz, 1H), 7.68 (dd, J = 8.4, 2.0 Hz, 1H), 7.36 (d, J = 7.6 Hz, 1H),
7.15 – 7.07 (m, 4H), 6.98 (d, J = 8.5 Hz, 1H), 6.93 (d, J = 7.0 Hz, 1H),
6.88 – 6.81 (m, 3H), 5.14 (d, J = 1.2 Hz, 1H), 4.02 (s, 3H), 3.97 (s,
3H); 13C{1H} NMR (101 MHz, CDCl3) δ 177.0, 153.0, 152.3, 149.47,
149.45, 135.7, 133.2, 130.0, 128.6 (2C), 128.2, 127.7 (2C), 125.6,
124.6, 124.4, 122.0, 120.8, 111.0, 110.6, 97.7, 62.6, 56.21, 56.17;
IR (KBr, film, cm-1): 3065, 2937, 2041, 1703, 1602, 1509, 1457,
1351, 1273, 1228, 1145, 1021; HRMS (ES TOF) calc`d for
C24H21N2NaO3 (M+H)+ 385.1547, found 385.1559 (3.1 ppm);
calc`d for C24H20N2NaO3 (M+Na)+ 407.1366, found 407.1375 (2.1
ppm);
(3R*,4'S*)-5-Isopropyl-4'-(4-methoxyphenyl)-2-phenyl-
4'H-spiro[indole-3,5'-isoxazole] (2ld): This compound was
obtained via Typical Procedure A from 5-isopropyl-2-phenyl-1H-
indole (4l) (118 mg, 0.50 mmol) and 1-methoxy-4-(2-
nitrovinyl)benzene (3d) (99 mg, 0.55 mmol). The titled material
was obtained as green solid, m.p. 61-63oC (benzene/ hexanes), Rf
0.33 (benzene). Yield 166 mg (0.42 mmol, 84%). 1H NMR (400
MHz, CDCl3) δ 8.13 (dd, J = 7.7, 1.9 Hz, 2H), 7.66 (d, J = 1.5 Hz, 1H),
7.55 – 7.47 (m, 3H), 7.31 (d, J = 7.9 Hz, 1H), 6.98 (dd, J = 7.9, 1.5
Hz, 1H), 6.77 (d, J = 8.6 Hz, 3H), 6.65 – 6.58 (m, 2H), 5.02 (d, J = 1.2
Hz, 1H), 3.66 (s, 3H), 2.71 (hept, J = 6.9 Hz, 1H), 1.07 (d, J = 6.9 Hz,
3H), 1.04 (d, J = 6.9 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ
176.7, 159.3, 151.0, 149.7, 147.1, 135.8, 131.9, 131.5, 129.1 (2C),
129.0 (2C), 128.2 (2C), 128.2, 125.4, 122.9, 120.7, 114.0 (2C),
(3R*,4'S*)-4'-(4-Chlorophenyl)-2-(p-tolyl)-4'H-
spiro[indole-3,5'-isoxazole] (2ic): This compound was obtained
via Typical Procedure A from 2-(p-tolyl)-1H-indole (4i) (104 mg,
0.50 mmol) and 1-chloro-4-(2-nitrovinyl)benzene (3c) (101 mg,
0.55 mmol). Yield 153 mg, (0.41 mmol, 82%), grey solid, m.p.
178.8-181.3 oC (benzene/hexanes), Rf 0.27 (benzene/hexanes
2:1); 1H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 8.1 Hz, 2H), 7.66 (d, J
= 0.8 Hz, 1H), 7.39 (d, J = 7.7 Hz, 1H), 7.33 (d, J = 8.0 Hz, 2H), 7.21
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The Journal of Organic Chemistry
97.6, 61.1, 55.3, 34.1, 24.3, 23.6; FT IR (KBr, film, cm-1): 2957,
64.8, 64.3, 61.7, 55.3; IR (KBr, film, cm-1): 3065, 2929, 2849, 1739,
1540, 1507, 1462, 1283, 1242, 1192, 1130, 1063; HRMS (ES TOF)
calc`d for C25H21N2O4 (M+H)+ 413.1496, found 413.1492 (0.9
ppm);
2919, 2364, 1749, 1606, 1516, 1254, 1179, 1033; HRMS (ES TOF),
calc`d for C26H25N2O2 (M+H)+ 397.1911, found 397.1901 (2.5
ppm); calc`d for C26H24N2NaO2 (M+Na)+ 419.1730, found
419.1737 (1.7 ppm).
1
2
3
4
5
6
7
8
9
(3R*,4'S*)-3'-Methyl-2,4'-diphenyl-4'H-spiro[indole-3,5'-
isoxazole] (2ak), Typical Procedure B: Reaction vessel was
charged with 2-phenyl-1H-indole (4a) (97 mg, 0.50 mmol), (2-
nitroprop-1-en-1-yl)benzene (3k) (90 mg, 0.55 mmol), and glacial
acetic acid (500 mg, 0.48 mL). Methanesulfonic acid (13 mg, 0.14
mmol) was added in a single portion and the resulting mixture
was stirred at room temperature for 6 hr. Then, the mixture was
quenched with water (50 mL) and 33% aqueous ammonia (1 mL).
The product was extracted with ethyl acetate (3 x 50 mL), con-
centrated and separated by preparative column chromatography
on Silica gel eluting with a mixture of hexanes and ethyl acetate
3:1. Unreacted nitro compound 3k was eluted first Rf 0.65
(EtOAc/hexanes 1:3), then compound 11aa (see below, Rf 0.52
(EtOAc/hexanes 1:4)), followed by the title compound 2ak, which
was obtained as light-brown solid, m.p. 87.7-90.3 oC (benzene), Rf
0.44 (EtOAc/hexanes 1:3), dr 14.3:1. Yield 98 mg (0.29 mmol,
(3R*,4'S*)-5-methoxy-2,4'-diphenyl-4'H-spiro[indole-3,5'-
isoxazole] (2ma): This compound was obtained via Typical Pro-
cedure A from 5-methoxy-2-phenyl-1H-indole (4m) (112 mg,
0.50 mmol) and (2-nitrovinyl)benzene (3a) (82 mg, 0.55 mmol).
The titled material was obtained as yellow oil, Rf 0.33 (hex-
1
ane/acetone 6:1). Yield 160 mg (0.45 mmol, 90%), H NMR (400
MHz, CDCl3) δ 8.16 – 8.08 (m, 2H), 7.71 (d, J = 1.6 Hz, 1H), 7.56 –
7.49 (m, 3H), 7.32 (d, J = 8.4 Hz, 1H), 7.17 – 7.10 (m, 3H), 6.87 (dd,
J = 6.5, 3.0 Hz, 2H), 6.66 (dd, J = 8.4, 2.5 Hz, 1H), 6.46 (d, J = 2.5 Hz,
1H), 5.10 (d, J = 1.5 Hz, 1H), 3.61 (s, 3H); 13C{1H} NMR (101 MHz,
CDCl3) δ 175.6, 158.3, 149.4, 146.2, 137.2, 133.1, 131.7, 131.5,
129.2 (2C), 128.7 (2C), 128.3, 128.1 (2C), 127.8 (2C), 121.7, 115.3,
111.0, 97.5, 61.7, 55.8; FT IR (KBr, film, cm-1): 3065, 3035, 2964,
2934, 2837, 1606, 1546, 1475, 1359, 1292, 1201, 1175, 1028;
HRMS (ES TOF) calc`d for C23H19N2O2 (M+H)+ 355.1441, found
355.1438 (0.7 ppm); calc`d for C23H18N2NaO2 (M+Na)+: 377.1260,
found 377.1268, (2.0 ppm).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
58%), H NMR (400 MHz, CDCl3) δ 8.16 (dd, J = 7.7, 1.7 Hz, 2H),
7.57 – 7.50 (m, 3H), 7.37 (d, J = 7.7 Hz, 1H), 7.18 – 7.10 (m, 4H),
6.98 (d, J = 7.2 Hz, 1H), 6.90 (t, J = 7.4 Hz, 1H), 6.86 – 6.80 (m, 2H),
4.76 (s, 1H), 2.10 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 177.9,
157.9, 152.9, 136.0, 132.6, 132.1, 131.6, 130.0, 129.1 (2C), 129.0
(2C), 128.6 (2C), 128.4 (2C), 128.2, 125.8, 125.0, 121.1, 99.0, 64.6,
12.9; IR (KBr, film, cm-1): 3037, 2933, 2854, 1967, 1743, 1540,
1466, 1366, 1267; HRMS (ES TOF) calc`d for C23H18N2NaO
(M+Na)+: 361.1311, found 361.1313 (0.4 ppm);
(3R*,4'S*)-4'-(4-Ethylphenyl)-2-(naphthalen-2-yl)-4'H-
spiro[indole-3,5'-isoxazole] (2ej): This compound was obtained
via Typical Procedure A from 2-(naphthalen-2-yl)-1H-indole (4e)
(122 mg, 0.50 mmol) and 1-ethyl-4-(2-nitrovinyl)benzene (3j)
(97 mg, 0.55 mmol). Yield 145 mg, (0.36 mmol, 72%), white
solid, m.p. 144.6-149.8 oC (benzene/hexanes), Rf 0.38 (ben-
zene/hexanes 2:1); 1H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 8.34
(dd, J = 8.6, 1.0 Hz, 1H), 7.99 (d, J = 8.8 Hz, 2H), 7.91 (d, J = 7.6 Hz,
1H), 7.73 (d, J = 0.7 Hz, 1H), 7.62 – 7.53 (m, 2H), 7.46 (d, J = 7.6 Hz,
1H), 7.17 (t, J = 7.5 Hz, 1H), 7.00 (d, J = 7.2 Hz, 1H), 6.92 (t, J = 8.3
Hz, 3H), 6.78 (d, J = 7.9 Hz, 2H), 5.15 (s, 1H), 2.47 (q, J = 7.6 Hz,
2H), 1.09 (t, J = 7.6 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ
177.4, 153.0, 149.9, 144.3, 135.9, 134.9, 133.1, 130.1, 130.0,
129.4, 129.1, 128.9, 128.8, 128.1 (2C), 128.0, 127.9, 127.7 (2C),
126.9, 126.0, 125.0, 124.7, 121.2, 97.8, 62.0, 28.4, 15.4; IR (KBr,
film, cm-1): 3028, 2966, 2937, 2854, 2361, 1743, 1540, 1511,
1457, 1271, 1250; HRMS (ES TOF) calc`d for C28H23N2O (M+H)+
403 1805, found 403.1814 (2.2 ppm); calc`d for C28H22N2NaO
(M+Na)+ 425.1624, found 425.1624 (0.1 ppm);
3,3'-(Phenylmethylene)bis(2-phenyl-1H-indole)
(11aa):
Was isolated as a byproduct along with material 2ak, as greenish
solid, m.p. 234.4-237.0 oC (benzene), Rf 0.52 (EtOAc/hexanes
1:3); yield 45 mg, (0.095 mmol, 38%). 1H NMR (400 MHz, CDCl3)
δ 8.04 (s, 2H), 7.33 (d, J = 8.1 Hz, 4H), 7.28 – 7.07 (m, 15H), 7.00
(d, J = 8.1 Hz, 2H), 6.83 (t, J = 7.6 Hz, 2H), 6.12 (s, 1H); 13C{1H}
NMR (101 MHz, CDCl3) δ 145.0 (2C), 136.1 (2C), 135.6, 133.1
(2C), 129.4 (2C), 129.0 (2C), 128.5 (4C), 128.39 (2C), 128.35 (4C),
127.6 (2C), 126.2, 121.9 (2C), 121.8 (2C), 119.7 (2C), 115.8 (2C),
110.7 (2C), 40.1; IR (KBr, film, cm-1): 3422, 2937, 2862, 1702,
1561, 1457, 1238; HRMS (ES TOF) calc`d for C35H25N2 (M-H)-
473.2023, found 473.2029 (1.1 ppm);
(3R*,4'S*)-7-Chloro-2,4'-diphenyl-4'H-spiro[indole-3,5'-
isoxazole] (2na): This compound was obtained via Typical Pro-
cedure A from 7-chloro-2-phenyl-1H-indole (4j) (114 mg, 0.50
mmol) and (2-nitrovinyl)benzene (3a) (82 mg, 0.55 mmol). The
titled material was obtained as pink solid, m.p. 162-165oC (ben-
zene/hexanes), Rf 0.34 (benzene/hexanes 1:0.4). Yield 154 mg,
(0.43 mmol, 86%). 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J = 7.1 Hz,
2H), 7.70 (s, 1H), 7.59 – 7.50 (m, 3H), 7.16 – 7.09 (m, 4H), 6.89 –
6.78 (m, 4H), 5.12 (s, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 178.3,
149.7, 149.5, 137.8, 132.8, 132.2, 131.3, 130.6, 129.2 (2C), 128.8
(2C), 128.6 (2C), 128.4, 127.7 (2C), 127.0, 126.3, 123.0, 98.3, 62.2;
FT IR (KBr, film, cm-1): 2923, 2360, 1749, 1531, 1460, 1246, 1190,
1044; HRMS (ES TOF) calc`d for C22H15ClN2NaO (M+Na)+
381.0765, found 381.0751 (3.8 ppm);
(3R,4'S)-3'-Ethyl-2,4'-diphenyl-4'H-spiro[indole-3,5'-
isoxazole] (2al): This compound was obtained via Typical Proce-
dure B from 2-phenyl-1H-indole (4a) (97 mg, 0.50 mmol) and (2-
nitrobut-1-en-1-yl)benzene (3l) (97 mg, 0.55 mmol) as colorless
oil, Rf 0.51 (EtOAc/ hexanes 1:4), dr 12.5:1. Yield 95 mg, (0.27
mmol, 54%). 1H NMR (400 MHz, CDCl3) δ 8.20 – 8.08 (m, 2H), 7.53
(t, J = 6.6 Hz, 3H), 7.39 (d, J = 7.7 Hz, 1H), 7.21 – 7.06 (m, 4H), 7.00
– 6.78 (m, 4H), 4.75 (s, 1H), 2.65 (dq, J = 15.1, 7.5 Hz, 1H), 2.23
(dq, J = 15.1, 7.5 Hz, 1H), 1.09 (t, J = 7.5 Hz, 3H); 13C{1H} NMR (101
MHz, CDCl3) δ 178.2, 162.4, 153.0, 135.8, 132.9, 132.1, 131.5,
129.9, 129.0 (2C), 128.9 (2C), 128.6 (2C), 128.5 (2C), 128.2, 125.8,
125.1, 121.1, 98.8, 63.1, 20.9, 10.9; IR (KBr, film, cm-1): 3057,
2979, 1962, 1540, 1457, 1263, 1188; HRMS (ES TOF) calc`d for
C24H21N2O (M+H)+ 353.1648, found 353.1647 (0.5 ppm). In addi-
tion, compound 11aa was also isolated as a byproduct, yield 50
mg (0.105 mmol, 42%). Physical and spectral properties of this
material were identical to those described above for the sample of
11aa isolated along with spirocyclic compound 2ak.
(3R*,4'S*)-2-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-4'-(4-
methoxyphenyl)-4'H-spiro[indole-3,5'-isoxazole] (2gd): This
compound was obtained via Typical Procedure A from 2-(2,3-
dihydrobenzo[b][1,4]dioxin-6-yl)-1H-indole (4g) (126 mg, 0.50
mmol) and 1-methoxy-4-(2-nitrovinyl)benzene (3d) (99 mg, 0.55
mmol). Yield 111 mg, (0.29 mmol, 57%), orange solid, m.p.161.1-
(3R*,4'S*)-4'-(4-Chlorophenyl)-3'-methyl-2-phenyl-4'H-
spiro[indole-3,5'-isoxazole] (2am): This compound was ob-
tained via Typical Procedure B from 2-phenyl-1H-indole (4a) (97
mg, 0.50 mmol) and 1-chloro-4-(2-nitroprop-1-en-1-yl)benzene
(3m) (109 mg, 0.55 mmol) as yellowish oil, Rf 0.47
(EtOAc/hexanes 1:3), dr 14.3:1. Yield 99 mg, (0.27 mmol, 53%),
1H NMR (400 MHz, CDCl3) δ 8.15 (dd, J = 7.8, 1.3 Hz, 2H), 7.58 –
7.48 (m, 3H), 7.40 (d, J = 7.7 Hz, 1H), 7.24 – 7.16 (m, 1H), 7.12 (d, J
= 8.4 Hz, 2H), 7.02 – 6.92 (m, 2H), 6.76 (d, J = 8.4 Hz, 2H), 4.73 (s,
o
163.4 C (benzene); Rf 0.35 (EtOAc/hexanes 1:1). 1H NMR (400
MHz, CDCl3) δ 7.71 – 7.63 (m, 3H), 7.35 (d, J = 7.7 Hz, 1H), 7.17 –
7.09 (m, 1H), 7.03 – 6.92 (m, 3H), 6.91 – 6.84 (m, 1H), 6.77 (d, J =
8.6 Hz, 2H), 6.61 (d, J = 8.7 Hz, 1H), 5.07 (d, J = 1.0 Hz, 1H), 4.39 –
4.28 (m, 4H), 3.67 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 176.8,
159.2, 153.0, 149.9, 146.9, 143.9, 135.8, 130.0 (2C), 129.0, 125.7,
125.1 (2C), 124.6, 122.2, 120.9, 118.0, 117.5, 114.0 (2C), 97.8,
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1H), 2.07 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 177.7, 157.5,
IR (KBr, film, cm-1): 3675, 2979, 2361, 1706, 1536, 1457; HRMS
152.7, 135.7 (2C), 134.2, 131.8, 131.1, 130.34 (2C), 130.29, 129.2
(2C), 128.9 (2C), 128.4 (2C), 126.1, 124.8, 121.3, 99.0, 64.0, 12.9;
IR (KBr, film, cm-1): 3061, 2933, 2365, 1743, 1557, 1540, 1499,
1461, 1246; HRMS (ES TOFF) calc`d for C23H18ClN2O (M+H)+
373.1102, found 373.1100 (0.7 ppm); calc`d for C23H17ClN2NaO
(M+Na)+ 395.0922, found 395.0927 (1.3 ppm); In addition, com-
pound 11ac was isolated as a byproduct, yield 56 mg (0.11 mmol,
44%).
(ES TOF) calc`d for C28H23N2O (M+H)+ 403.1805, found 403.1815,
(2.4. ppm); In addition, compound 11ea was also isolated as a
byproduct, yield 72 mg (0.125 mmol, 50%). Physical and spectral
properties of this material were identical to those described
above for the sample of 11ea isolated along with spirocyclic com-
pound 2ek.
1
2
3
4
5
6
7
8
(3R*,4'S*)-4'-(4-Chlorophenyl)-3'-methyl-2-(naphthalen-
2-yl)-4'H-spiro[indole-3,5'-isoxazole] (2em): This compound
was obtained via Typical Procedure B from 2-(naphthalen-2-yl)-
1H-indole (4e) (122 mg, 0.50 mmol) and 1-chloro-4-(2-
nitroprop-1-en-1-yl)benzene (3m) (109 mg, 0.55 mmol) as green-
ish solid, m.p. 188.1-191.5 oC (benzene/hexanes), Rf 0.35
(EtOAc/hexanes 1:3). Yield 102 mg, (0.24 mmol, 48%), dr 91:9.
1H NMR (400 MHz, CDCl3) δ 8.62 (s, 1H), 8.29 (d, J = 8.6 Hz, 1H),
7.99 (d, J = 8.2 Hz, 2H), 7.91 (d, J = 7.8 Hz, 1H), 7.63 – 7.53 (m, 2H),
7.43 (d, J = 7.7 Hz, 1H), 7.21 (t, J = 7.5 Hz, 1H), 7.12 (d, J = 7.9 Hz,
2H), 7.04 (d, J = 7.3 Hz, 1H), 6.98 (t, J = 7.4 Hz, 1H), 6.77 (d, J = 7.9
Hz, 2H), 4.83 (s, 1H), 2.11 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3)
δ 177.6, 157.7, 152.9, 135.9, 134.9, 134.2, 133.2, 131.1, 130.4
(2C), 130.3, 129.5, 129.2, 129.0, 128.92, 128.90 (2C), 128.1, 128.0,
126.9, 126.1, 125.1, 124.9, 121.4, 99.1, 64.5, 12.9; IR (KBr, film,
cm-1): 2925, 2858, 1913, 1747, 1548, 1494, 1469, 1288, 1208;
HRMS (ES TOF) calc`d for C27H20ClN2O (M+H)+ 423.1259, found
423.1247 (2.8 ppm). In addition, compound 11ec was isolated as
a byproduct.
3,3'-((4-Chlorophenyl)methylene)bis(2-phenyl-1H-
indole) (11ac): Was isolated as a byproduct along with material
9
o
2al as colorless solid, m.p. 238.6-240.4 C (benzene/hexanes), Rf
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
0.48 (EtOAc/hexanes 1:2); Yield 56 mg, (0.11 mmol, 44%). 1H
NMR (400 MHz, CDCl3) δ 8.07 (s, 2H), 7.32 (t, J = 9.4 Hz, 2H), 7.25
– 7.10 (m, 16H), 7.04 (d, J = 8.1 Hz, 2H), 6.86 (t, J = 7.6 Hz, 2H),
6.06 (s, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 143.6 (2C), 136.1
(2C), 135.8 (1C), 133.0 (2C), 131.8 (1C), 130.7 (2C), 128.7 (2C),
128.54 (4C), 128.49 (2C), 128.3 (4C), 127.7 (2C), 122.0 (2C),
121.7 (2C), 119.8 (2C), 115.1 (2C), 110.8 (2C), 39.6 (1C); IR (KBr,
film, cm-1): 3401, 2933, 1706, 1557, 1254; HRMS (ES TOF) calc`d
for C35H24ClN2 (M-H)- 507.1634, found 507.1629 (0.9 ppm);
(3R*,4'S*)-3'-methyl-2-(naphthalen-2-yl)-4'-phenyl-4'H-
spiro[indole-3,5'-isoxazole] (2ek): This compound was ob-
tained via Typical Procedure B from 2-(naphthalen-2-yl)-1H-
indole (4e) (122 mg, 0.50 mmol) and (2-nitroprop-1-en-1-
yl)benzene (3k) (90 mg, 0.55 mmol) as light grey solid, m.p. 92-
94.2 oC (hexanes), Rf 0.48 (EtOAc/hexanes 1:3). Yield 99 mg,
3,3'-((4-Chlorophenyl)methylene)bis(2-(naphthalen-2-yl)-
1H-indole) (11ec): Was isolated as a byproduct along with mate-
rial 2em, as grey solid, m.p. 245.8-247.3 oC (benzene/hexanes), Rf
0.55 (EtOAc/hexanes 1:3). Yield 75 mg, (0.12 mmol, 49%). 1H
NMR (400 MHz, CDCl3) δ 8.05 (s, 2H), 7.65 (d, J = 8.0 Hz, 2H), 7.48
– 7.27 (m, 16H), 7.16 (d, J = 8.5 Hz, 2H), 7.12 (t, J = 7.6 Hz, 2H),
7.03 (d, J = 8.1 Hz, 2H), 6.88 (t, J = 7.6 Hz, 2H), 6.30 (s, 1H); 13C{1H}
NMR (101 MHz, CDCl3) δ 143.4 (2C), 136.2 (2C), 135.9, 133.0
(2C), 132.6 (2C), 132.0, 130.9 (2C), 130.3 (2C), 128.7 (2C), 128.6
(2C), 128.1 (2C), 128.0 (2C), 127.6 (2C), 127.5 (2C), 126.2 (4C),
126.0 (2C), 122.0 (2C), 121.6 (2C), 119.9 (2C), 115.5 (2C), 110.8
(2C), 39.8; IR (KBr, film, cm-1): 3389, 2933, 1756, 1507, 1453,
1308, 1288, 1250; HRMS (ES TOF) calc`d for C43H28ClN2 (M-H)-
607.1947, found 607.1934 (2.1 ppm);
1
(0.26 mmol, 51%), dr 25:1. H NMR (400 MHz, CDCl3) δ 8.65 (s,
1H), 8.32 (dd, J = 8.7, 1.4 Hz, 1H), 8.00 (s, 2H), 7.91 (d, J = 7.5 Hz,
1H), 7.65 – 7.54 (m, 2H), 7.42 (d, J = 7.7 Hz, 1H), 7.15 (dt, J = 12.2,
6.5 Hz, 4H), 7.05 (d, J = 7.3 Hz, 1H), 6.93 (t, J = 7.4 Hz, 1H), 6.84
(dd, J = 7.4, 1.5 Hz, 2H), 4.87 (s, 1H), 2.14 (s, 3H); 13C{1H} NMR
(101 MHz, CDCl3) δ 177.8, 158.1, 153.0, 136.1, 134.8, 133.2,
132.6, 130.0, 129.42, 129.36, 129.0 (2C), 128.9, 128.8, 128.6 (2C),
128.1, 128.0, 127.9, 126.9, 125.9, 125.1, 125.0, 121.1, 99.2, 65.1,
12.9; IR (KBr, film, cm-1): 3045, 2929, 1739, 1706, 1540, 1462,
1275, 1238, 1192; HRMS (ES TOF) calc`d for C27H20N2NaO
(M+Na)+ 411.1468, found 411.1466 (0.6 ppm). In addition, com-
pound 11ea was isolated as a byproduct.
3,3'-(Phenylmethylene)bis(2-(naphthalen-2-yl)-1H-
indole) (11ea): Was isolated as a byproduct along with material
2ek, as colorless solid, m.p. 237.4-238.9 oC (benzene), Rf 0.49
(EtOAc/hexanes 1:3). Yield 66 mg, (0.12 mmol, 46%). 1H NMR
(400 MHz, CDCl3) δ 8.01 (s, 2H), 7.64 (d, J = 8.3 Hz, 2H), 7.50 –
7.28 (m, 17H), 7.18 (d, J = 8.5 Hz, 2H), 7.11 (t, J = 7.6 Hz, 2H), 7.01
(d, J = 8.1 Hz, 2H), 6.86 (t, J = 7.6 Hz, 2H), 6.35 (s, 1H); 13C{1H}
NMR (101 MHz, CDCl3) δ 144.8 (2C), 136.2 (2C), 135.7 (1C), 133.0
(2C), 132.5 (2C), 130.4 (2C), 129.6 (2C), 129.0 (2C), 128.5 (2C),
128.2 (2C), 127.9 (2C), 127.6 (2C), 127.5 (2C), 126.4 (1C), 126.1
(4C), 126.0 (2C), 121.84 (2C), 121.77 (2C), 119.7 (2C), 116.2 (2C),
110.7 (2C), 40.3 (1C); IR (KBr, film, cm-1): 3405, 3057, 1702,
1602, 1490, 1461, 1317, 1035; HRMS calc`d for C43H29N2 (M-H)-
573.2336, found 573.2341 (0.9 ppm);
(3R*,4'S*)-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3'-
methyl-4'-phenyl-4'H-spiro[indole-3,5'-isoxazole] (2gk): This
compound was obtained via Typical Procedure B from 2-(2,3-
dihydrobenzo[b][1,4]dioxin-6-yl)-1H-indole (4g) (126 mg, 0.50
mmol) and (2-nitroprop-1-en-1-yl)benzene (3k) (90 mg, 0.55
mmol) as yellowish oil, Rf 0.47 (EtOAc/hexanes 1:3). Yield 67
mg, (0.17 mmol, 34%), dr 10:1. 1H NMR (400 MHz, DMSO-d6) δ
7.59 (d, J = 8.5 Hz, 1H), 7.54 (s, 1H), 7.27 (d, J = 7.6 Hz, 1H), 7.16 –
7.06 (m, 6H), 6.91 (t, J = 7.5 Hz, 1H), 6.86 (d, J = 7.3 Hz, 2H), 5.04
(s, 1H), 4.43 – 4.30 (m, 4H), 2.08 (s, 3H); 13C{1H} NMR (101 MHz,
DMSO-d6) δ 176.4, 158.2, 152.4, 146.7, 143.6, 136.1, 132.4, 129.8,
129.2 (2C), 128.3 (2C), 127.7, 125.3, 125.0, 124.4, 121.5, 120.3,
117.9, 116.5, 97.9, 64.6, 64.5, 64.1, 12.4; IR (KBr, film, cm-1): 3066,
2945, 1739 ,1589, 1503, 1462, 1436, 1325, 1292, 1263, 1200,
1134, 1072; HRMS (ES TOF) calc`d for C25H21N2O3 (M+H)+
397.1547, found 397.1537 (2.3 ppm); In addition, compound
11ga was isolated as a byproduct.
(3R*,4'S*)-3'-Ethyl-2-(naphthalen-2-yl)-4'-phenyl-4'H-
spiro[indole-3,5'-isoxazole] (2el): This compound was obtained
via Typical Procedure B from 2-(naphthalen-2-yl)-1H-indole (4e)
(122 mg, 0.50 mmol) and (2-nitrobut-1-en-1-yl)benzene (3l) (97
mg, 0.55 mmol) as greenish solid, m.p. 134.7-138.5 oC (ben-
zene/hexanes); Rf 0.55 (EtOAc/ hexanes 1:4). Yield 92 mg, (0.23
mmol, 46%), dr 20:1. 1H NMR (400 MHz, CDCl3) δ 8.60 (s, 1H),
8.31 (d, J = 8.6 Hz, 1H), 7.98 (d, J = 8.4 Hz, 2H), 7.91 (d, J = 7.7 Hz,
1H), 7.63 – 7.52 (m, 2H), 7.42 (d, J = 7.7 Hz, 1H), 7.20 – 7.10 (m,
4H), 6.99 (d, J = 7.4 Hz, 1H), 6.91 (t, J = 7.4 Hz, 1H), 6.84 (d, J = 7.1
Hz, 2H), 4.87 (s, 1H), 2.71 (dq, J = 15.1, 7.5 Hz, 1H), 2.26 (dq, J =
15.1, 7.4 Hz, 1H), 1.13 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (101 MHz,
CDCl3) δ 178.2, 162.6, 153.1, 136.1, 134.8, 133.2, 132.9, 130.0,
129.4, 129.3, 129.0 (2C), 128.9, 128.8, 128.6 (2C), 128.2, 128.0,
127.9, 126.9, 125.9, 125.23, 125.15, 121.1, 98.9, 63.7, 21.1, 11.2;
3,3'-(Phenylmethylene)bis(2-(2,3-
dihydrobenzo[b][1,4]dioxin-6-yl)-1H-indole) (11ga): Was
isolated as a byproduct along with material 2gk, as yellowish oil,
Rf 0.61 (EtOAc). Yield 81 mg, (0.14 mmol, 55%), 1H NMR (400
MHz, CDCl3) δ 7.98 (s, 2H), 7.30 (d, J = 7.6 Hz, 4H), 7.23 (t, J = 6.5
Hz, 3H), 7.07 (t, J = 7.5 Hz, 2H), 6.99 (d, J = 8.1 Hz, 2H), 6.81 (t, J =
7.6 Hz, 2H), 6.74 – 6.68 (m, 4H), 6.65 (d, J = 8.2 Hz, 2H), 6.06 (s,
1H), 4.21 (s, 8H); 13C{1H} NMR (101 MHz, CDCl3) δ 145.0 (2C),
143.27 (2C), 143.26 (2C), 135.9 (2C), 135.4, 129.3 (2C), 128.9
(2C), 128.3 (2C), 126.6 (2C), 126.0, 121.9 (2C), 121.7 (2C), 121.5
(2C), 119.5 (2C), 117.5 (2C), 117.2 (2C), 115.3 (2C), 110.6 (2C),
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64.5 (2C), 64.3 (2C), 40.0; IR (KBr, film, cm-1): 2929, 2858, 1747,
1702, 1461, 1288, 1246; HRMS (ES TOF) calc`d for C39H29N2O4
(M-H)- 589.2133, found 589.2129 (0.7 ppm);
(m, 5H), 7.14 (t, J = 7.6 Hz, 1H), 5.29 (t, J = 7.9 Hz, 1H), 5.14 (ddd, J
= 30.3, 12.5, 8.0 Hz, 2H); 13C{1H} NMR (101 MHz, CDCl3) δ 138.6,
137.2, 136.2, 133.2, 132.1, 129.19 (2C), 129.18 (2C), 129.0 (2C),
128.94, 128.89 (2C), 126.9, 122.8, 120.6, 119.9, 111.6, 109.3, 79.0,
40.4; IR (KBr, film, cm-1): 3434, 3057, 2920, 1553, 1478, 1453,
1382, 1317, 1250; HRMS (ES TOF) calc`d for C22H17ClN2NaO2
(M+Na)+ 399.0871, found 399.0872 (0.3 ppm);
1
2
3
4
5
6
7
8
(3R*,4'S*)-4'-(4-Chlorophenyl)-2-(2,3-
dihydrobenzo[b][1,4]dioxin-6-yl)-3'-methyl-4'H-
spiro[indole-3,5'-isoxazole] (2gm): This compound was ob-
tained via Typical Procedure B from 2-(2,3-dihydrobenzo[b][1,4]-
dioxin-6-yl)-1H-indole (4g) (126 mg, 0.50 mmol) and 1-chloro-4-
(2-nitroprop-1-en-1-yl)benzene (3m) (109 mg, 0.55 mmol) as
colorless solid, m.p. 209.2-211.8 oC (EtOAc/hexanes), Rf 0.61
(EtOAc/hexanes 1:1). Yield 101 mg, (0.24 mmol, 47%), dr 5.3:1.
1H NMR (400 MHz, CDCl3) δ 7.70 (s, 1H), 7.67 (d, J = 8.5 Hz, 1H),
7.33 (d, J = 7.7 Hz, 1H), 7.15 (t, J = 7.6 Hz, 1H), 7.10 (d, J = 8.2 Hz,
2H), 6.99 (t, J = 6.8 Hz, 2H), 6.92 (t, J = 7.0 Hz, 1H), 6.75 (d, J = 8.2
Hz, 2H), 4.79 (s, 1H), 4.38 – 4.28 (m, 4H), 2.10 (s, 3H); 13C{1H}
NMR (101 MHz, CDCl3) δ 176.9, 157.4, 152.8, 147.0, 144.0, 135.7,
134.1, 131.1, 130.4 (2C), 130.2, 128.8 (2C), 125.6, 125.1, 124.7,
122.2, 121.0, 118.0, 117.5, 98.9, 64.8, 64.5, 64.3, 12.9; IR (KBr,
film, cm-1): 3070, 2933, 1747, 1507, 1457, 1296, 1250, 1122;
HRMS calc`d for C25H20ClN2O3 (M+H)+ 431.1157, found 431.1150
(1.6 ppm); In addition, compound 11gc was isolated as a byprod-
uct.
2-(4-Chlorophenyl)-3-(2-nitro-1-phenylethyl)-1H-indole
(10ca):24 This compound was obtained via Typical Procedure C
from 2-(4-chlorophenyl)-1H-indole (4c) (114 mg, 0.50 mmol) and
(2-nitrovinyl)benzene (3a) (82 mg, 0.55 mmol). The titled mate-
9
o
rial was obtained as yellowish solid, m.p. 164.3-167.8 C (EtOH),
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Rf 0.60 (EtOAc/hexanes 1:4); Rf 0.43 (benzene). Yield 162 mg,
(0.43 mmol, 86%), 1H NMR (400 MHz, CDCl3) δ 8.13 (s, 1H), 7.54
(d, J = 8.0 Hz, 1H), 7.43 (t, J = 6.8 Hz, 2H), 7.41 – 7.20 (m, 9H), 7.14
(t, J = 7.5 Hz, 1H), 5.26 (t, J = 7.9 Hz, 1H), 5.17 (d, J = 7.8 Hz, 2H);
13C{1H} NMR (101 MHz, CDCl3) δ 139.7, 136.3, 135.9, 134.9, 130.7,
130.2 (2C), 129.4 (2C), 129.1 (2C), 127.6 (2C), 127.5, 127.0, 123.0,
120.7, 120.2, 111.6, 110.1, 79.2, 41.0; IR (KBr, film, cm-1): 3410,
3066, 1548, 1499, 1461, 1432, 1383, 1317; HRMS (ES TOF) calc`d
for C22H17ClN2NaO2 (M+Na)+ 399.0871, found 399.0861 (2.5
ppm).
3,3'-((4-Chlorophenyl)methylene)bis(2-(2,3-
Base-assisted spirocyclization of nitroalkanes 10
dihydrobenzo[b][1,4]dioxin-6-yl)-1H-indole) (11gc): Was
isolated as a byproduct along with material 2gm, as light-brown
amorphous solid with m.p. 152.3-173.0 oC, Rf 0.33
(EtOAc/hexanes 1:1). Yield 75 mg, (0.12 mmol, 48%). 1H NMR
(400 MHz, CDCl3) δ 8.00 (s, 2H), 7.29 (d, J = 8.1 Hz, 2H), 7.21 (q, J
= 8.6 Hz, 4H), 7.09 (t, J = 7.6 Hz, 2H), 7.04 (d, J = 8.1 Hz, 2H), 6.85
(t, J = 7.6 Hz, 2H), 6.73 – 6.63 (m, 6H), 6.02 (s, 1H), 4.20 (d, J = 2.4
Hz, 8H); 13C{1H} NMR (101 MHz, CDCl3) δ 143.6 (2C), 143.3 (2C),
143.2 (2C), 135.8 (2C), 135.5, 131.6, 130.7 (2C), 128.6 (2C), 128.4
(2C), 126.4 (2C), 121.8 (2C), 121.6 (2C), 121.5 (2C), 119.6 (2C),
117.5 (2C), 117.2 (2C), 114.6 (2C), 110.7 (2C), 64.4 (2C), 64.3
(2C), 39.5; IR (KBr, film, cm-1): 3401, 3070, 2986, 2870, 1735,
1499, 1466, 1288, 1250; HRMS (ES TOF) calc`d for C39H28ClN2O4
(M-H)- 623.1743, found 623.1740 (0.6 ppm);
(3R*,4'S*)-2,4'-Diphenyl-4'H-spiro[indole-3,5'-isoxazole]
(2aa), Typical Procedure D: Reaction vessel was charged with
potassium hydroxide (56 mg, 1.00 mmol), 3-(2-nitro-1-
phenylethyl)-2-phenyl-1H-indole (10aa) (68 mg, 0.20 mmol) and
ethanol (0.40 mL). The mixture was stirred for 60 min at room
temperature, and then the resulted solution was added over 5
min to another vessel, containing a mixture of phosphorous acid
(320 mg) and formic acid (0.30 mL) stirred at room temperature.
After 30 min the mixture was quenched with water (10 mL) and
brine (20 mL) and extracted with ethyl acetate (3 x 15 mL).
Combined organic phases were concentrated in vacuum and the
residual oil was separated by column chromatography to afford
two fractions: unreacted nitroalkane 5aa was eluting first with Rf
0.63 (EtOAc/hexanes 1:1), yield 47 mg (0.14 mmol, 69%) fol-
lowed by spirocyclic product 2aa Rf 0.47 (hexanes/EtOAc, 1:4),
yield 17 mg (0.052 mmol, 26%). Chromatographical and spectral
properties of compounds 2aa and 10aa isolated in this experi-
ment were identical to those of authentic samples described
above.
Preparation of authentic samples of nitroalkanes 10
3-(2-Nitro-1-phenylethyl)-2-phenyl-1H-indole
(10aa),23
Typical Procedure C: Reaction vessel was charged with 2-
phenyl-1H-indole (4a) (97 mg, 0.50 mmol), (2-nitrovinyl)benzene
(3a) (82 mg, 0.55 mmol), phosphorous acid (500 mg), and etha-
nol (500 mg). The mixture was vigorously stirred for 2 h at room
temperature. Resulting dark-red homogenous solution was
poured into water (50 mL), and the formed precipitate was fil-
tered and washed consecutively with water (4 times), 10% aque-
ous ammonia, and once again with water. After drying, the result-
ing crystalline material was purified by Flash column chromatog-
raphy on Silica gel eluting with a mixture of hexane and ethyl
acetate (4:1), or by re-crystallization from a mixture of hexane
and benzene (1:1). Yield 156 mg, (0.46 mmol, 91%), colorless
solid, m.p. 142.3-143.4 oC (benzene/hexanes), Rf 0.63
(EtOAc/hexanes 1:1), Rf 0.65 (benzene/CH2Cl2 1:1); 1H NMR (400
MHz, CDCl3) δ 8.07 (s, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.38 – 7.06 (m,
12H), 7.01 (t, J = 7.4 Hz, 1H), 5.22 (t, J = 7.9 Hz, 1H), 5.13 – 4.91
(m, 2H); 13C{1H} NMR (101 MHz, CDCl3) δ 140.0, 137.1, 136.2,
132.3, 129.03 (2C), 128.97 (2C), 128.9 (2C), 128.7, 127.6 (2C),
127.3, 127.1, 122.6, 120.4, 120.0, 111.6, 109.6, 79.2, 40.9; IR (KBr,
film, cm-1): 3414, 3057, 2357, 1544, 1457, 1370, 1304; HRMS (ES
TOF) calc`d for C22H18N2NaO2 (M+Na)+ 365.1260, found 365.1257
(1.0 ppm);
(3R*,4'S*)-4'-(4-Chlorophenyl)-2-phenyl-4'H-spiro[indole-
3,5'-isoxazole] (2ac): This compound was obtained via Typical
Procedure D from 3-(1-(4-chlorophenyl)-2-nitroethyl)-2-phenyl-
1H-indole (10ac) (75 mg, 0.2 mmol). The title compound was
obtained as yellow solid, yield 19 mg (0.054 mmol, 27%) along
with unreacted 5ac isolated back in a yield of 53 mg (0.14 mmol,
70%). Chromatographical and spectral properties of compounds
2ac and 5ac isolated in this experiment were identical to those of
authentic samples described above.
(3R*,4'S*)-2-(4-Chlorophenyl)-4'-phenyl-4'H-spiro[indole-
3,5'-isoxazole] (2ca): This compound was obtained via Typical
Procedure D from 2-(4-chlorophenyl)-3-(2-nitro-1-phenylethyl)-
1H-indole (10ca) (75 mg, 0.2 mmol). The title compound was
obtained as off-white solid, yield 24 mg (0.068 mmol, 34%) along
with unreacted 5ca isolated back in a yield of 47 mg (0.126 mmol,
63%).
Three-component one-pot procedure involving Fischer in-
dolization
3-(1-(4-Chlorophenyl)-2-nitroethyl)-2-phenyl-1H-indole
(10ac):23 This compound was obtained via Typical Procedure C
from 2-phenyl-1H-indole (4a) (97 mg, 0.50 mmol) and 1-chloro-
4-(2-nitrovinyl)benzene (3c) (101 mg, 0.55 mmol). Yield 169
mg, (0.45 mmol, 90%), yellowish solid, m.p. 118.0-123.2 oC
(EtOH), Rf 0.40 (benzene), Rf 0.57 (EtOAc/hexanes 1:4); 1H NMR
(400 MHz, CDCl3) δ 8.18 (s, 1H), 7.52 – 7.39 (m, 7H), 7.29 – 7.21
(3R*,4'S*)-2,4'-Diphenyl-4'H-spiro[indole-3,5'-isoxazole]
(2aa), Typical Procedure E: Reaction wessel was charged with
phenylhydrazine (12a) (98 µL, 108 mg, 1.00 mmol),
acetophenone (13a) (117 µL, 120 mg, 1.00 mmol), and glasial
acetic acid (1.00 g). The reaction mixture was refluxed for 20 min
monitoring the reaction progress by TLC. When hydrazone
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formation was complete, the mixture was cooled down to room
(3R*,4'S*)-4'-Phenyl-2-(p-tolyl)-4'H-spiro[indole-3,5'-
temperatre and concentrated sulfuric acid (125 mg) was added in
a single portion. The mixture was heated to 90 oC in oil bath for 4
hr monitoring the indolization step by TLC. Then the mixture was
cooled down, (2-nitrovinyl)benzene (3a) (149 mg, 1.00 mmol)
was added, and the stirring at room temperature was continued
for 4 hr. After purification by column chromatography the titled
compound was afforded as off-white solid identical to the sample
obtained via method A. Yield 256 mg (0.79 mmol, 79%).
isoxazole] (2ba): This compound was obtained via Typical Pro-
cedure E starting from phenylhydrazine (12a) (98 µL, 108 mg,
1.00 mmol), 4′-methylacetophenone (13b) (133 µL, 134 mg, 1.00
mmol), and (2-nitrovinyl)benzene (3a) (149 mg, 1.00 mmol). The
titled material was afforded as light grey solid identical to the
sample obtained via method A. Yield 258 mg, (0.77 mmol, 77%).
1
2
3
4
5
6
7
8
(3R*,4'S*)-2-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-4'-
phenyl-4'H-spiro[indole-3,5'-isoxazole] (2ga): This compound
was obtained via Typical Procedure E starting from phenyl-
hydrazine (12a) (98 µL, 108 mg, 1.00 mmol), 1-(2,3-
dihydrobenzo[b][1,4]dioxin-6-yl)ethan-1-one (13g) (150 µL, 178
mg, 1.00 mmol), and (2-nitrovinyl)benzene (3a) (82 mg, 0.55
mmol). The titled material was afforded as yellow solid identical
to the sample obtained via method A. Yield 225 mg (0.59 mmol,
59%).
(3R*,4'S*)-4'-(4-Fluorophenyl)-2-phenyl-4'H-spiro[indole-
3,5'-isoxazole] (2ab): This compound was obtained via Typical
Procedure E starting from phenylhydrazine (12a) (98 µL, 108 mg,
1.00 mmol), acetophenone (13a) (117 µL, 120 mg, 1.00 mmol),
and 1-fluoro-4-(2-nitrovinyl)benzene (3b) (167 mg, 1.00 mmol).
The titled material was afforded as light-yellow crystals identical
to the sample obtained via method A. Yield 246 mg (0.72 mmol,
72%).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(3R*,4'S*)-4'-(4-Chlorophenyl)-2-(2,3-
dihydrobenzo[b][1,4]dioxin-6-yl)-3'-methyl-4'H-
(3R*,4'S*)-4'-(4-Chlorophenyl)-2-phenyl-4'H-spiro[indole-
3,5'-isoxazole] (2ac): This compound was obtained via Typical
Procedure E starting from phenylhydrazine (12a) (98 µL, 108 mg,
1.00 mmol), acetophenone (13a) (117 µL, 120 mg, 1.00 mmol),
and 1-chloro-4-(2-nitrovinyl)benzene (3c) (184 mg, 1.00 mmol).
The titled material was afforded as yellow crystals identical to the
sample obtained via method A. Yield 243 mg (0.68 mmol, 68%).
spiro[indole-3,5'-isoxazole] (2gm): This compound was ob-
tained via Typical Procedure E starting from phenylhydrazine
(12a) (98 µL, 108 mg, 1.00 mmol), 1-(2,3-dihydrobenzo-
[b][1,4]dioxin-6-yl)ethan-1-one (13g) (150 µL, 178 mg, 1.00
mmol), 1-chloro-4-(2-nitroprop-1-en-1-yl)benzene (3m) (198
mg, 1.00 mmol). The titled material was afforded as colorless
solid identical to the sample obtained via method A. Yield 152
mg, (0.36 mmol, 36%). In addition, compound 11gc was isolated
as a byproduct in a yield of 100 mg, (0.16 mmol, 32%).
(3R*,4'S*)-4'-(4-Methoxyphenyl)-2-phenyl-4'H-
spiro[indole-3,5'-isoxazole] (2ad): This compound was ob-
tained via Typical Procedure E starting from phenylhydrazine
(12a) (98 µL, 108 mg, 1.00 mmol), acetophenone (13a) (117 µL,
120 mg, 1.00 mmol), and 1-methoxy-4-(2-nitrovinyl)benzene
(3d) (180 mg, 0.55 mmol). The titled material was afforded as
grey crystals identical to the sample obtained via method A. Yield
261 mg, (0.74 mmol, 74%).
(3R*,4'S*)-5-Isopropyl-2,4'-diphenyl-4'H-spiro[indole-3,5'-
isoxazole] (2la): This compound was obtained via Typical Proce-
dure E starting from (4-isopropylphenyl)hydrazine (12l) (146 µL,
150 mg, 1.00 mmol), acetophenone (13a) (117 µL, 120 mg, 1.00
mmol), and (2-nitrovinyl)benzene (3a) (82 mg, 0.55 mmol). The
titled material was afforded as grey solid identical to the sample
obtained via method A. Yield 263 mg, (0.73 mmol, 73%).
(3R*,4'S*)-4'-Hexyl-2-phenyl-4'H-spiro[indole-3,5'-
isoxazole] (2ag): This compound was obtained via Typical Pro-
cedure E starting from phenylhydrazine (12a) (98 µL, 108 mg,
1.00 mmol), acetophenone (13a) (117 µL, 120 mg, 1.00 mmol),
and 1-nitrooct-1-ene (3g) (156 mg, 1.00 mmol). The titled mate-
rial was afforded as yellowish oil identical to the sample obtained
via method A. Yield 162 mg (0.49 mmol, 49%).
ASSOCIATED CONTENT
Supporting Information
1H and 13C NMR spectral data (PDF)
HRMS data (PDF)
Computational data (PDF)
X-Ray crystallography data (CIF)
(3R*,4'S*)-4'-Isopropyl-2-phenyl-4'H-spiro[indole-3,5'-
isoxazole] (2ah): This compound was obtained via Typical Pro-
cedure E starting from phenylhydrazine (12a) (98 µL, 108 mg,
1.00 mmol), acetophenone (13a) (117 µL, 120 mg, 1.00 mmol),
and 3-methyl-1-nitrobut-1-ene (3h) (115 mg, 1.00 mmol). The
titled material was afforded as colorless solid identical to the
sample obtained via method A. Yield 156 mg (0.53 mmol, 53%).
The Supporting Information is available free of charge on the
ACS Publications website.
(3R*,4'S*)-3'-Methyl-2,4'-diphenyl-4'H-spiro[indole-3,5'-
isoxazole] (2ak): This compound was obtained via Typical Pro-
cedure E starting from phenylhydrazine (12a) (98 µL, 108 mg,
1.00 mmol), acetophenone (13a) (117 µL, 120 mg, 1.00 mmol),
and (2-nitroprop-1-en-1-yl)benzene (3k) (163 mg, 1.00 mmol).
The titled material was afforded as light-brown solid identical to
the sample obtained via method B. Yield 139 mg (0.41 mmol,
41%). In addition, compound 11aa was isolated in a yield of 64
mg (0.14 mmol, 27%).
AUTHOR INFORMATION
Corresponding Authors
*E-mail for A.V.A.: alexaks05@rambler.ru.
*E-mail for A.K.: a_k76@txstate.edu.
*E-mail for M.R.: mrubin@ku.edu.
ORCID
(3R,4'S)-3'-Ethyl-2,4'-diphenyl-4'H-spiro[indole-3,5'-
isoxazole] (2al): This compound was obtained via Typical Proce-
dure E starting from phenylhydrazine (12a) (98 µL, 108 mg, 1.00
mmol), acetophenone (13a) (117 µL, 120 mg, 1.00 mmol), and (2-
nitrobut-1-en-1-yl)benzene (3l) (176 mg, 1.00 mmol). The titled
material was afforded as colorless oil identical to the sample
obtained via method B. Yield 148 mg, (0.42 mmol, 42%). In
addition, compound 11aa was isolated in a yield of 73 mg (0.16
mmol, 31%).
Alexander V. Aksenov: 0000-0002-6644-9949
Dmitrii A. Aksenov: 0000-0002-0727-9652
Nicolai A. Aksenov: 0000-0002-7125-9066
Elena V. Alexandrova: 0000-0002-6220-6229
Zhenze Zhao: 0000-0001-9070-6178
Liqin Du: 0000-0002-7097-5861
Alexander Kornienko: 0000-0003-2041-7367
Michael Rubin: 0000-0002-1668-9311
Notes
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The Journal of Organic Chemistry
The authors declare no competing financial interest.
ACKNOWLEDGMENT
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2
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4
5
6
7
Synthetic studies performed in the frame of this project were
supported by grants from the Russian Science Foundation
(Grant number 18-13-00238). LD and AK acknowledge the
National Cancer Institute (1 R15 CA213199-01A1) for sup-
porting biological studies.
(8)
See, for example: (a) Aksenov, A. V.; Smirnov, A. N.;
Aksenov, N. A.; Aksenova, I. V.; Frolova, L. V.; Kornienko, A.; Mage-
dov, I. V.; M. Rubin, Metal-Free Transannulation Reaction of In-
doles with Nitrostyrenes: A Simple Practical Synthesis of 3-
Substituted 2-Quinolones. Chem. Commun. 2013, 49, 9305-9307.
8
9
(9)
Aksenov, A. V.; Smirnov, A. N.; Magedov, I. V.; Reisenau-
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