Synthesis of Highly Functionalized Spirobutenolides via a Nitroalkane-Mediated Ring Contraction of 2-Oxobenzo[ h]chromenes through Denitration

Article abstract of DOI:10.1021/acs.joc.8b02257

A facile synthesis of highly functionalized spirobutenolides was carried out by a nitroalkane carbanion-induced ring opening and relactonization via a denitration reaction of 2-oxo-5,6-dihydro-2H-benzo[h]chromene-3-carbonitriles and 2-oxo-2,5-dihydrothioc

Full text of DOI:10.1021/acs.joc.8b02257

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Article
Synthesis of Highly Functionalized Spirobutenolides via Nitroalkane
Mediated Ring Contraction of 2-Oxobenzo[h]chromenes through Denitration
Amr Elagamy, Ranjay Shaw, Rahul Panwar, Shally ., Vishnu Ji Ram, and Ramendra Pratap
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02257 • Publication Date (Web): 04 Jan 2019
Downloaded from http://pubs.acs.org on January 4, 2019
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Synthesis of Highly Functionalized Spirobutenolides via
Nitroalkane Mediated Ring Contraction of 2-
Oxobenzo[h]chromenes through Denitration
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a
a
a
a
b, †
Amr Elagamy, Ranjay Shaw, Rahul Panwar, Shally, Vishnu Ji Ram, Ramendra
Pratap a,*
aDepartment of Chemistry, University of Delhi, North Campus, Delhi, India-110007
bDepartment of Chemistry, University of Lucknow, Lucknow, Uttar Pradesh, India-
2226007
ABSTRACT
CN
2
NR2
R N
CN
O
O
X
X
KOH, DMF
O
R
+
R
NO2
O
R=H, CH3
R1
R1
R3
R3
20 examples,
up to 89% yield
2
NR = sec.amino
3
1
X = CH ; R = H; R = H, OCH
2
3
3
1
X = S; R = H, Cl; R = H
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A facile synthesis of highly functionalized spirobutenolides was carried out by
nitroalkane carbanion induced ring opening and relactonization via denitration reaction
0
1
2
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of
2-oxo-5,6-dihydro-2H-benzo[h]chromene-3-carbonitriles
and
2-oxo-2,5-
dihydrothiochromeno[4,3-b]pyran-3-carbonitriles. However, when nitroethane was used as a
nucleophile source in lieu of nitromethane, a mixture of (E)- and (Z)-isomer of
corresponding spirobutenolides were obtained in different ratio. The structure and
geometry of the product was confirmed by single crystal X-ray diffraction. The isolated
(E)- and (Z)-butenolides on treatment with sodium ethoxide in DMF at room temperature
provided highly substituted trienes via allylic ring opening followed by decarboxylation.
INTRODUCTION
Butenolides are five membered lactones, which occur as a structural subunit in wide
range of natural products of biological importance.1,2 Butenolides based compounds
3
4
5
exhibit diverse biological activities as anti-inflammatory, anticancer, antimicrobial,
6
7
antifungal and anti-HIV-1. There importance is not only limited to their biodynamic
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properties, but they are also useful versatile building blocks for assembling different
isolated and fused heterocycles of high biological relevance.8-11
1
1
1
1
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Simple spirobutenolides are prepared by addition of lithium β-lithiopropionate to
carbonyl compounds followed by lactonization.12 Light mediated reaction of secondary
alcohols with acetylenic esters provided spiro-γ-butenolides.13 Three-component
condensation reaction of primary amines, dialkyl acetylenedicarboxylates and 1,3-
dimethylalloxan afforded oxaspirobutanolides.14 N. Sucman et al. prepared butenolide
functionalized spirooxindoles by reaction of N-substituted isatin with dimethyl
15
acetylenedicarboxylate in presence of triphenylphosphine. A gold catalyzed approach
has been established for constructing spirobutenolides from (Z)-enynols having cyclic
1
6
substituent at the C-1 position. Hejmanowska et al. developed a novel approach to
construct spirobutanolides via trienamine-mediated [4+2]-cycloaddition reaction of (E)-3-
17
alkylidene-5-arylfuran-2(3H)-ones and 2,4-dienals. Langer and Albrecht have reported the
synthesis of spirobutenolides through ring closing metathesis of vinylacrylates using Grubbs’
generation I catalyst and catalytic amounts of Ti(O-i-Pr)4.18 Spirobutenolides could also
achieved by condensation of α-hydroxy α-acetyl lactones or N-benzyl lactams with
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dimethyl malonate.19 Another approach was employed by M. Piltan to access spiro-
butenolide-indenetriones
by
heating
of
indeno[1,2-b]pyrrole-2,3-dicarboxylate
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derivatives in presence of catalytic amount of sulfuric acid in acetic acid.20 Recently,
Ram et al have reported the synthesis of various spiro compounds by ring
transformation of 5,6-dihydro-2-oxo-2H-benzo[h]chromene-3-carbonitriles with 2-
21
tetralone in the presence of NaH in THF by stirring for 7 days at 15 °C (Scheme 1).
Scheme 1. Synthesis of Spiro Compounds from 2H-Benzo[h]chromene
CN
R N
NR2
2
NR2
CN
O
CN
O
O
base, solvent
NaH(5eq.)
THF,15 °C
days
O
O
+
CH NO2
3
O
7
3
1
Currently synthesized spiro compounds
Earlier synthesized spiro compounds
Nitroalkanes act as valuable carbanion source and α proton has higher acidity due to
strong electron withdrawing nature of nitro group. It was proposed that same as enolate,
nitroalkane also stabilized as nitronate anion but oxygen of later compound is not
reactive as enolate ion. As per earlier reports, nitronate anions react with different
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electrophiles such as aldehydes, ketones, haloalkanes and α,β-unsaturated compounds
resulting carbon-carbon bond formation.22-24
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Herein, we have used α,β- and γ,δ-unsaturated compounds to study the effect of
nitronate anion. In our study, we have successfully achieved functionalized
spirobutenolides through ring opening and ring contraction followed by denitration.
Furthermore, the butenolides reacting with sodium ethoxide and produced
functionalized trienes, which can act as useful precursor for the construction of diverse
class of compounds.
RESULTS AND DISCUSSION
The required precursors, 4-substituted-2-oxo-5,6-dihydro-2H-benzo[h]chromene-3-
carbonitriles 1 were prepared in two steps. The reaction of ethyl 2-cyano-3,3
bis(methylthio)acrylate with 1-tetralone/6-methoxy-1-tetralone in DMSO under basic
conditions
provided
functionalized
4-(methylthio)-2-oxo-5,6-dihydro-2H-
benzo[h]chromene-3-carbonitriles, which underwent amination with various secondary
amine in ethanol to afford 4-sec.amino-2-oxo-5,6-dihydro-2H-benzo[h]chromene-3-
carbonitriles 1.25
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In order to optimize the conditions, a reaction of 2-oxo-4-(piperidin-1-yl)-5,6-dihydro-
2
H benzo[h]chromene-3-carbonitrile 1 and nitromethane 2 was selected as model
0
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reaction. Initially, we examined potassium hydroxide in THF at room temperature and
6
0 °C (Table 1, Entries 1 and 2), sodium hydride and lithium hydroxide in THF (Table 1,
Entries 3 and 4) and a complex
Table 1. Optimization of Reaction Conditionsa
CN
N
N
CN
O
base, solvent
rt, 24 h
O
+
CH3NO2
O
O
2
1
3
Yieldsd
Yieldsd
Entry Base
Solvent
Entry
Base
Solvent
(%)
-e
-e
-e
-e
(%)
1
2b
3
KOH
KOH
NaH
LiOH
KOH
KOH
DBU
NaH
THF
THF
11
12
13
14
15
16
17
18
19
20
CH COONa DMSO
trace
3
K CO
2
DMSO
EtOH
DMF
DMF
DMF
DMF
DMF
19
-e
3
THF
NaOEt
K CO
4
THF
25
31
38
56
69
-e
2
3
5
6c
DMSO
DMSO
DMSO
DMSO
43
NaOEt
NaOH
LiOH
Trace
-e
7
8
Trace
Trace
Trace
KOH
9
NaOH DMSO
LiOH DMSO
CH COONa DMF
3
10
DBU
DMF
-e
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aAll reactions were performed with 1 (0.25 mmol), 2 (0.375 mmol) and base (0.75 mmol) in
b
c
solvent (5.0 mL) at 30-35 °C; Reaction was performed at 60 °C; 2.5 mL DMSO was used;
d
e
Isolated yields are reported; Complex mixture formation.
mixture along with major unreacted starting material was observed in all the cases.
1
1
1
1
1
1
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1
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Further, ring transformation in the presence of potassium hydroxide in DMSO led to
yield 43% of desired product (Table 1, Entry 5). However, use of lesser amount of
DMSO provided, trace amount of product (Table 1, Entry 6). Use of DBU in DMSO
provided complex mixture (Table 1, Entry 7). However, use of bases NaH, NaOH, LiOH
and CH COONa separately in DMSO furnished trace amount (Table 1, Entries 8-11) of
3
the desired product. Further, trial of K CO in DMSO provided 19% of expected product
2
3
(Table 1, Entry 12) while sodium ethoxide in EtOH gave a complex mixture (Table 1,
Entry 13). Reactions using K CO , NaOEt, NaOH, and LiOH in DMF led to
2
3
Scheme 2. Scope of the Ring Contraction Strategy for the Synthesis of Spirobutenolides
Using Nitromethane
CN
NR2
O
R N
2
CN
O
O
KOH, DMF
rt, 24 h
O
+ CH NO
3
2
2
R1
R1
1
3
1
R = H, OMe
2
NR = sec.amino
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6
N
CN
CN
N
CN
N
N
O
O
O
O
O
O
0
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O
3
a, 69%
3b, 80%
3c, 40%
O
O
N
O
O
CN
CN
CN
N
N
N
O
O
O
O
O
O
O
O
3d, 55%
3e, 58%
3f, 69%
All reactions were performed by stirring 2-oxo-5,6-dihydro-2H-benzo[h]chromene-3-carbonitriles
1
(0.5 mmol) and nitromethane 2 (0.75 mmol) using KOH (1.5 mmol) in DMF (10.0 mL) at 30-35
°
C.
yield 25, 31, 38 and 56% of expected product respectively (Table 1, Entries 14-17),
and the best result was achieved by using KOH in DMF (69%) (Table 1, Entry 18). Use
of CH COONa
3
Scheme 3. Scope of the Ring Contraction Strategy for the Synthesis of (E)- and (Z)-
isomer of Spirobutenolides Using Nitroethane
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CN
R N
NR2
O
2
CN
O
KOH, DMF
rt, 24 h
O
+
CH CH NO
3
2
2
O
4
R1
1
R1
5
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
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9
0
1
2
3
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5
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9
0
1
2
3
4
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8
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3
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9
0
1
R = H, OMe
2
NR = sec.amino
CN
CN
CN
N
CN
N
N
N
O
O
O
O
O
O
O
O
O
O
5
a, 55%
5b, 46%
5c, 89%
5d, 77%
Ph
Ph
N
N
CN
O
CN
CN
CN
N
N
N
N
O
O
O
O
O
O
O
O
O
O
5
e, 78%
5f, 65%
5g, 64%
5h, 73%
O
O
O
O
O
O
CN
CN
CN
CN
N
N
N
N
O
O
O
O
O
O
O
O
O
5
i, 48%
5j, 54%
5k, 82%
5l, 85%
All reactions were performed by stirring 2-oxo-5,6-dihydro-2H-benzo[h]chromene-3-carbonitriles
1
(0.5 mmol) and nitroethane 4 (0.75 mmol) using KOH (1.5 mmol) in DMF (10.0 mL) at 30-35
°
C.
and DBU as base in DMF gave a complex mixture with major unreacted starting
material (Table 1, Entries 19 and 20).
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6
Under optimized conditions, reactions were carried out using differently functionalized
2
-oxo-5,6-dihydro-2H-benzo[h]chromene-3-carbonitriles 1 with nitromethane 2 and
0
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desired spirobutenolides 3 afforded in 40-80% yield. The presence of electron donating
substituent like methoxy group at position 8 of 2-oxobenzo[h]chromene enhanced the
yield of spirobutenolides (Scheme 2).
The optimized condition was further generalized by using nitroethane as carbanion
source in lieu of nitromethane and isolated the desired products in 46-89% yields
(Scheme 3). This reaction provided a mixture of (E)- and (Z)-isomer in different ratio. In
order to assign the geometry of the major and minor isomers, a compound 5d was
crystallized and structure was confirmed by single crystal X-ray (Figure S1, See SI).
1
Then crystal was taken and H NMR spectra were recorded to confirm the peak
corresponding to the crystal. The structure of the crystal sample was confirmed
unambiguously by single crystal X-ray diffraction as E isomer. Then, we also perform
1
1
the H NMR of the crude sample and compared with H NMR of crystal. Using this result, we
proposed that (E)-isomer is the major isomer in all mixtures of spirobutenolides obtained
from nitroethane.
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Interestingly, use of nitroethane gave the better yield of spirobutenolides as compared
to nitromethane. Probably, the carbanion generated from nitromethane is highly reactive
and stable compared to the carbanion produced from nitroethane and might be involved
in the side reactions and reduced the yields. To further study the scope of reaction, we
used 4-(methylthio)-2-oxo-5,6-dihydro-2H-benzo[h]chromene-3-carbonitrile as starting
material with nitroethane under the similar reaction condition and we found that the
starting material decomposed probably due to side reaction at C4.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 4. Proposed Mechanism for Ring Contraction of 2-Oxobenzo[h]chromenes 1
into Spirobutenolides
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6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
NR2
O
NR2
CN
R N
2
O
R
O
+
N
N
N
O
O
O
O
O
V
R
1
NO2
OH
NO2
R1
R1
R
NO2
-NO2
R1
1
R = H, OMe
I
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
R = sec.amino
R
CN
NR2
R = H, Me
NR2
R N
2
CN
O
-
CO2
O
-NO2
O
R
C
X
N
+
Path A
+
H
R
H
Path C
R
O
O N
R1
2
NO2
R1
R1
OH
III
3/5
II
-
N
O
+
H+
P
a
2
X
t
h
R2N
NR2
NR2
B
CN
Tautomerization or
aromatization
O
O
NH
NO2
NH2
NO /Me
R
2
R1
R 6
R1
R1
7
IV
A plausible reaction mechanism is shown in Scheme 4. The reaction is possibly
proceeding via attack of the nitronate anion generated from nitroalkane at C-10b
position of the 2-oxo-5,6-dihydro-2H-benzo[h]chromene-3-carbonitriles through Michael
addition, which probably provide the ring opening to generate the intermediate
carboxylate ion II which can follow three paths A, B and C. It has been earlier reported
that a stablilized carbanion could attack at the six-membered cyclic allylic nitro
26
compound provides mixture of two denitrated regioisomers, similarly we propose that
the intramolecular allylic denitration occurs via nucleophilic conjugate substitution
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reaction (S 2') by attack of carboxylate ion at C-4a to provide spirobutenolides 3/5 as
N
one regioisomer (Scheme 4, paths A). Alternatively, direct denitration was also possible
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
by attack of carboxylate ion II at α position to nitro group affords functionalized oxepin-
2(7H)-ones 6 as another regioisomer (Scheme 4, paths B). On the other hand,
decarboxylation may occur via reversal of charge on carboxylate ion to provide
intermediate III. In further step excess of base generates carbanion at α position to nitro
group and cyclized by involvement of nitrile group to produce imine IV, which may
tautomerize (in case of nitromethane) or aromatize through loss of nitro group (in case
of nitroethane) to provide functionalized dihydrophenanthrenes 7 (Scheme 4, path C).
Interestingly, only spirobutenolides was isolated and neither functionalized oxepinone
nor dihydrophenanthrene formed during reaction. Therefore, we propose that the
formation of five-membered butenolide ring is favorable than the seven-membered
oxepinone ring under the given reaction conditions. We also carried out the reaction in
presence of dimethyl sulfate in order to trap the carboxylate ion intermediate however,
we isolated only the spirobutenolide product. This result indicates that as soon as the
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6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
ring is opened, recyclization takes place to yield spirobutenolide 3/5 through
intermediate V.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 5. Scope of the Ring Contraction Strategy for the Synthesis of 4'-Ethylidene-5-
oxo-3-sec.amino-5H-spiro[furan-2,3'-thiochroman]-4-carbonitriles 9
O
CN
CN
CN
NR2
O
R2N
N
N
CN
O
O
O
S
S
S
S
KOH, DMF
rt, 24 h
O
O
O
+
CH CH NO
3 2 2
O
4
8
9
9a, 78%
9b, 56%
R3
R3
Cl
NR = sec.amino
2
3
R = H, Cl
All reactions were performed by stirring 2-oxo-2,5-dihydrothiochromeno[4,3-b]pyran-3-
carbonitriles 8 (0.5 mmol) and nitroethane 4 (0.75 mmol) using KOH (1.5 mmol) in DMF (10.0
mL) at 30-35 °C, precursors 8 were prepared using reported literature.27
To further expand the scope of this reaction we studied the ring transformation 4-
sec.amino-2-oxo-2,5-dihydrothiochromeno[4,3-b]pyran-3-carbonitrile 8 by nitroethane 4
as shown in Scheme 5. This reaction successfully provided the desired spirobutenolide
4'-ethylidene-5-oxo-3-sec.amino-5H-spiro[furan-2,3'-thiochroman]-4-carbonitriles in high
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yield. Interestingly, presence of an electron-withdrawing group (+M effect) such as
chloro group at C-9 position enhances the yield (Scheme 5).
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 6. Synthesis of Highly Substituted Trienes via Decarboxylative Rearrangement
CN
R N
2
H
R N
2
O
CN
O
NaOEt, DMF
rt, 2 h
R1
5
10
1
R1
R = H, OMe
NR = sec.amino
2
O
O
N
H
N
H
N
H
N
H
CN
CN
CN
CN
10a, 84%
10b, 82%
10c, 79%
10d, 81%
O
O
All reactions were performed by stirring 1'-ethylidene-5-oxo-3',4'-dihydro-1'H,5H-spiro[furan-2,2'-
naphthalene]-4-carbonitriles 5 (0.25 mmol) and sodium ethoxide (0.5 mmol) in DMF (2.0 mL) at
30-35 °C.
We also studied the synthetic application of 1'-ethylidene-5-oxo-3-sec.amino-3',4'-
dihydro-1'H,5H-spiro[furan-2,2'-naphthalene]-4-carbonitriles under basic condition.
Treatment of the compound with sodium ethoxide provides a functionalized trienes. The
mixture of (E)- and (Z)-isomer of spirobutenolides 5 undergoes decarboxylative
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3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
rearrangement in presence of sodium ethoxide to produce the desired trienes (Scheme
6). On the other hand, no product was obtained under similar reaction condition from
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
spirobutenolides generated from nitromethane. This reaction is under investigation.
CONCLUSION
In summary, a new method for synthesis of highly functionalized spirobutenolides has
been developed through ring opening and relactonization (via ring contraction) at C-4a
position of 2-oxobenzo[h]chromenes using nitroalkane as a carbanion source.
Nitroethane provides (E)- and (Z)-isomer of spirobutenolides in different ratio depending
on the substitution pattern. Most interesting finding in this reaction is base mediated
chemoselective allylic denitration. Structure and geometry of compound was confirmed
by single crystal X-ray. Moreover, spirobutenolides obtained from nitroethane
undergoes decarboxylative rearrangement in presence of sodium ethoxide to afford
trienes and can be used as a valuable precursor for the construction of different class of
compounds of pharmacological importance.
EXPERIMENTAL SECTION
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9
General remarks: Commercially available reagent and solvent purchased by Sigma
Aldrich and Alfa Aesar were used directly without further purification. Reactions were
monitored by analytical thin-layer chromatography (TLC). All reactions were conducted
using dried glassware. All the starting materials were synthesized earlier except two and
data is provided below. IR spectra were recorded on IR spectrophotometer and
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
-1
1
stretching frequencies were reported in wave number (cm ). The H NMR (400 MHz)
and 13C NMR (100 MHz) spectra were recorded in CDCl solution using chloroform
3
1
13
peak (7.24 ppm for H and 77.0 ppm for C) as reference. The coupling constant J are
reported in Hz and signal patterns reported as s, singlet; br, broad signal; d, doublet; t,
triplet; m, multiplet; dd, double doublet. High-resolution mass spectra were recorded on
a quadrupole-time-of-flight mass spectrometer. In case of 1'-ethylidene-5-oxo-3-
sec.amino-3',4'-dihydro-1'H,5H-spiro[furan-2,2'-naphthalene]-4-carbonitriles 5 and 4'-
ethylidene-5-oxo-3-sec.amino-5H-spiro[furan-2,3'-thiochroman]-4-carbonitriles, we have
isolated the mixture of (E)- and (Z)-isomer in different ratio and few sets of protons and
carbons are appearing separately and is reported as mixture.
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
General Procedure for Synthesis of 1'-methylene/ethylidene-5-oxo-3',4'-dihydro-
1
'H,5H-spiro[furan-2,2'-naphthalene]-4-carbonitriles 3a-f, 5a-l and 4'-ethylidene-5-oxo-3-
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
sec.amino-5H-spiro[furan-2,3'-thiochroman]-4-carbonitriles 9a-b. To a 25 mL round
bottom flask equipped with small magnet, 2-oxo-5,6-dihydro-2H-benzo[h]chromene-3-
carbonitriles/2-oxo-2,5-dihydrothiochromeno[4,3-b]pyran-3-carbonitriles 8 (0.5 mmol) (0.5
mmol) was dissolved in DMF (10.0 mL). Then powdered KOH (1.5 mmol, 87.0 mg) was
added
to
the
reaction
mixture
followed
by
drop-wise
addition
of
nitromethane/nitroethane (0.75 mmol). The reaction mixture was stirred for 24 h at room
temperature. After completion of reaction, excess of DMF was removed under reduced
pressure, and the mixture was poured onto ice cold water (25.0 mL). The cold solution
was neutralized with 10% HCl, and the obtained precipitate was filtered and dried under
vacuum. The crude product was purified by alumina column chromatography using 20%
ethyl acetate in hexane as an eluent. We observed that presence of DMF during work-
up dissolved some of the product, so DMF must be completely removed under vacuum
before addition of ice cold water.
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General Procedure for Synthesis of 3-(1-Vinyl-3,4-dihydronaphthalen-2-yl)acrylonitrile
1
0a-d.
A
mixture
of
1'-ethylidene-5-oxo-3',4'-dihydro-1'H,5H-spiro[furan-2,2'-
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
naphthalene]-4-carbonitrile (0.25 mmol) and sodium ethoxide (0.5 mmol, 34.0 mg) in
DMF (2.0 mL) was stirred for 2 h at room temperature. Completion of reaction was
monitored by TLC. After completion, reaction mixture was poured onto crushed ice and
neutralized with 10% HCl. The obtained precipitate was filtered, washed with water,
dried and purified by silica gel column chromatography, using 10% ethyl acetate-hexane
as an eluent.
2-Oxo-4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-5,6-dihydro-2H-benzo[h]chromene-3-
carbonitrile (1a). Yield: 65% (2.37g); 0.13 R (40% ethyl acetate-hexane), yellow solid, mp:
f
-1 1
2
05-207 °C; IR (KBr): 2965, 2212, 1707, 1616 cm ; H NMR (400 MHz, CDCl ): δ 1.88 (t,
3
J = 5.6 Hz, 4H), 2.64 (t, J = 7.4 Hz, 2H), 2.86 (t, J = 7.4 Hz, 2H), 3.62 (t, J = 5.6 Hz, 4H), 3.98
13
1
(
s, 4H), 7.20 (d, J = 7.6 Hz, 1H), 7.26-7.37 (m, 2H ), 7.78 (d, J = 7.6 Hz, 1H); C{ H} NMR
(
100 MHz, CDCl ): δ 23.2, 27.8, 35.7, 49.8, 64.7, 81.7, 105.8, 108.9, 116.6, 124.6, 127.5, 127.6,
3
+
1
27.9, 131.6, 137.8, 157.4, 161.2, 167.4; HRMS (ESI) m/z calcd for C H N O [M + H]
21
21
2
4
3
65.1501, found 365.1504.
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
8
-Methoxy-2-oxo-4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-5,6-dihydro-2H-
benzo[h]chromene-3-carbonitrile (1b). Yield: 75% (2.96 g); 0.10 R (40% ethyl acetate-
f
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
-
1 1
hexane), green solid, mp: 115-117 °C; IR (KBr): 2965, 2210, 1705, 1609 cm ; H NMR
(
400 MHz, CDCl ): δ 1.87 (s, 4H), 2.62 (t, J = 7.0 Hz, 2H), 2.82 (t, J = 7.0 Hz, 2H), 3.61 (s, 4H),
3
1
3
1
3
.82 (s, 3H), 3.98 (s, 4H), 6.71 (s,1H), 6.78 (d, J = 7.6 Hz, 1H), 7.73 (d, J = 8.8 Hz, 1H); C{ H}
NMR (100 MHz, CDCl ):δ 23.2, 28.2, 35.7, 49.8, 55.6, 64.7, 80.9, 105.8, 106.9, 112.5, 113.4,
3
1
16.8, 120.6, 126.7, 140.3, 157.9, 161.4, 162.4, 167.5; HRMS (ESI) m/z calcd for C H N O
22
23
2
5
+
[
M + H] 395.1607, found 395.1610.
1'-Methylene-5-oxo-3-(piperidin-1-yl)-3',4'-dihydro-1'H,5H-spiro[furan-2,2'-
naphthalene]-4-carbonitrile (3a). Yield: 69% (111.0 mg); 0.22 R (40% ethyl acetate-
f
-1
1
hexane), light yellow solid, mp: 115-117 °C; IR (KBr): 2928, 2210, 1742, 1603 cm ; H
NMR (400 MHz, CDCl ): δ 1.51-1.80 (m, 6H), 2.03-2.16 (m, 2H), 2.8 (d, J = 16.0 Hz,
3
1
H), 3.13-3.27 (m, 3H), 3.72 (br, 1H), 4.22 (br, 1H), 5.35 (s, 1H), 5.97 (s, 1H), 7.19-7.31
13
1
(
m, 3H), 7.62 (d, J = 6.9 Hz, 1H); C{ H} NMR (100 MHz, CDCl ): δ 23.2, 25.8, 25.9,
3
3
3.1, 50.9, 51.8, 69.3, 84.7, 114.9, 115.0, 124.3, 127.3, 128.8, 129.0, 131.1, 136.4,
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7
8
9
+
1
39.5, 169.0, 171.8; HRMS (ESI) m/z calcd for C H N O [M + H] 321.1598, found
20 21
2
2
321.1583.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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4
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6
7
8
9
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1
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4
5
6
7
8
9
0
6
'-Methoxy-1'-methylene-5-oxo-3-(piperidin-1-yl)-3',4'-dihydro-1'H,5H-spiro[furan-2,2'-
naphthalene]-4-carbonitrile (3b).Yield: 80% (140.0 mg); 0.16 Rf (40% ethyl acetate-
-1 1
hexane), yellow solid, mp: 154-155 °C; IR (KBr): 2936, 2210, 1740, 1602 cm ; H NMR
(
400 MHz, CDCl ): δ 1.48-1.75 (m, 6H), 2.03-2.07 (m, 2H), 2.72 (d, J = 16.0 Hz, 1H),
3
3
.06-3.25 (m, 3H), 3.68 (br, 1H), 3.78 (s, 3H), 4.17 (br, 1H), 5.15 (s, 1H), 5.77 (s, 1H),
13
1
6.66 (s, 1H), 6.77 (d, J = 6.4 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H); C{ H} NMR (100 MHz,
CDCl ): δ 23.1, 25.7, 26.2, 33.0, 50.8, 51.8, 55.3, 69.1, 84.7, 112.2, 112.9, 113.8, 115.0,
3
123.7, 125.9, 138.0, 139.0, 160.0, 169.1, 171.8; HRMS (ESI) m/z calcd for C H N O
21
23
2
3
+
[
M + H] 351.1703, found 351.1700.
3-(4-Benzylpiperazin-1-yl)-1'-methylene-5-oxo-3',4'-dihydro-1'H,5H-spiro[furan-2,2'-
naphthalene]-4-carbonitrile (3c). Yield: 40% (80.0 mg); 0.22 Rf (40% ethyl acetate-
-1 1
hexane), yellow solid, mp: 171-173 °C; IR (KBr): 2924, 2212, 1746, 1605 cm ; H NMR
(
400 MHz, CDCl ): δ 2.00-2.16 (m, 2H), 2.35-2.81 (m, 5H), 3.13-3.28 (m, 3H), 3.51 (s,
3
2H), 3.94 (br, 1H), 4.19 (br, 1H), 5.34 (s, 1H), 5.97 (s, 1H), 7.16-7.30 (m, 8H), 7.59 (d, J
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1
1
1
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2
2
2
2
2
2
2
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5
5
5
5
5
5
5
5
5
5
6
1
=
6
1
4
6.8 Hz, 1H); 13C{ H} NMR (100 MHz, CDCl ): δ 25.9, 33.2, 49.2, 50.5, 52.1, 52.3,
3
2.3, 70.1, 84.7, 114.8, 115.1, 124.3, 127.4, 127.5, 128.4, 128.8, 128.9, 129.1, 130.8,
0
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8
9
0
1
2
3
4
5
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7
8
9
0
1
2
3
4
5
6
7
8
9
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1
2
3
4
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6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
36.3, 136.7, 139.5, 168.7, 172.1; HRMS (ESI) m/z calcd for C H N O [M + H]
26
26
3
2
12.2020, found 412.2015.
3
-(4-Benzylpiperazin-1-yl)-6'-methoxy-1'-methylene-5-oxo-3',4'-dihydro-1'H,5H-
spiro[furan-2,2'-naphthalene]-4-carbonitrile (3d). Yield: 55% (120.0 mg); 0.17 R (40%
f
ethyl acetate-hexane), yellow solid, mp: 174-175 °C; IR (KBr): 2924, 2212, 1746, 1603
-1 1
cm ; H NMR (400 MHz, CDCl ): δ 2.02-2.12 (m, 2H), 2.34 (br, 2H), 2.60-2.75 (m, 3H),
3
3
.10-3.29 (m, 3H), 3.49 (s, 2H), 3.79 (s, 3H), 3.91 (br, 1H), 4.17 (br, 1H), 5.18 (s, 1H),
5.80 (s, 1H), 6.66 (s, 1H), 6.77 (d, J = 8.8 Hz, 1H); 7.24-7.29 (m, 5H), 7.52 (d, J = 8.8
Hz, 1H); 13C{ H} NMR (100 MHz, CDCl ): δ 26.1, 33.1, 49.1, 50.4, 52.0, 52.2, 55.2,
1
3
62.1, 69.8, 84.7, 112.4, 112.9, 113.9, 114.8, 123.4, 125.9, 127.4, 128.3, 128.9, 136.7,
+
1
37.9, 138.9, 160.0, 168.7, 172.1; HRMS (ESI) m/z calcd for C H N O [M + H]
27
28
3
3
442.2125, found 442.2118.
1
'-Methylene-5-oxo-3-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-3',4'-dihydro-1'H,5H-
spiro[furan-2,2'-naphthalene]-4-carbonitrile (3e). Yield: 58% (110.0 mg); 0.20 R (40%
f
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ethyl acetate-hexane), white yellow solid, mp: 196-198 °C; IR (KBr): 2930, 2212,
-1
1
1
1
1
2
1
746, 1607 cm ; H NMR (400 MHz, CDCl ): δ 1.55-2.18 (m, 6H), 2.81 (d, J = 15.6 Hz,
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
H), 3.11-3.40 (m, 3H), 3.84 (br, 1H), 3.96 (br, 4H), 4.34 (br, 1H), 5.34 (s, 1H), 5.98 (s,
H), 7.19-7.31 (m, 3H), 7.60 (d, J = 7.2 Hz, 1H); 13C{ H} NMR (100 MHz, CDCl ): δ
1
3
5.8, 33.2, 34.9, 47.7, 48.7, 64.6, 69.9, 84.7, 105.0, 114.6, 114.9, 124.2, 127.3, 128.7,
29.0, 130.9, 136.3, 139.4, 168.7, 172.0; HRMS (ESI) m/z calcd for C H N O [M +
22
23
2
4
+
H] 379.1652, found 379.1636.
6'-Methoxy-1'-methylene-5-oxo-3-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-3',4'-dihydro-
1'H,5H-spiro[furan-2,2'-naphthalene]-4-carbonitrile (3f). Yield: 69% (141.0 mg); 0.15 Rf
(40% ethyl acetate-hexane), white solid, mp: 167-168 °C; IR (KBr): 2930, 2212, 1744,
-1 1
1
607 cm ; H NMR (400 MHz, CDCl ): δ 1.54-2.09 (m, 6H), 2.71 (d, J = 15.6 Hz, 1H),
3
3.04-3.33 (m, 3H), 3.77 (s, 4H), 3.91 (br, 4H), 4.28 (br, 1H), 5.13 (s, 1H), 5.75 (s, 1H),
13
1
6
.65 (s, 1H), 6.75 (d, J = 8.8 Hz, 1H), 7.48 (d, J = 8.8 Hz, 1H); C{ H} NMR (100 MHz,
CDCl ): δ 26.1, 33.1, 34.8, 47.6, 48.7, 55.2, 64.5, 69.7, 84.7, 105.0, 112.2, 112.9, 113.8,
3
114.6, 123.5, 125.8, 137.9, 138.9, 160.0, 168.7, 172.1; HRMS (ESI) m/z calcd for
+
C H N O [M + H] 409.1758, found 409.1771.
23
25
2
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1
'-Ethylidene-5-oxo-3-(pyrrolidin-1-yl)-3',4'-dihydro-1'H,5H-spiro[furan-2,2'-
naphthalene]-4-carbonitrile (5a). Yield: 55% (88.0 mg); 0.23 Rf (40% ethyl acetate-
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
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2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
-
1 1
hexane), white solid, mp: 185-186 °C; IR (KBr): 2949, 2210, 1740, 1605 cm ; H NMR
(
400 MHz, CDCl ): δ 1.76-2.15 (m, 9H), 2.73 (d, J = 15.2 Hz, 1H), 2.96-3.11 (m, 2H),
3
3
.29-3.47 (m, 1H), 3.91-4.07 (m, 2H), 6.04 (q, J = 7.6 Hz, 0.75H [for E-isomer]), 6.43 (q,
J = 7.6 Hz, 0.25H [for Z-iosmer]), 7.14-7.30 (m, 3H), 7.39-7.43 (m, 1H); 13C{ H} NMR
1
(
100 MHz, CDCl ): δ 14.6, 16.3, 24.5, 24.6, 25.5, 25.6, 26.3, 26.7, 34.5, 37.2, 50.7,
3
51.2, 70.3, 84.4, 86.3, 115.3, 124.7, 126.4, 127.4, 127.6, 127.8, 128.0, 128.7, 130.1,
1
30.7, 131.5, 131.9, 133.0, 137.0, 139.2, 169.5, 172.0, 172.5; HRMS (ESI) m/z calcd for
+
C H N O [M + H] 321.1598, found 321.1589.
20
21
2
2
1'-Ethylidene-6'-methoxy-5-oxo-3-(pyrrolidin-1-yl)-3',4'-dihydro-1'H,5H-spiro[furan-2,2'-
naphthalene]-4-carbonitrile (5b). Yield: 46% (80.0 mg); 0.20 R (40% ethyl acetate-
f
-1 1
hexane), white yellow solid, mp: 185-186 °C; IR (KBr): 2949, 2210, 1740, 1603 cm ; H
NMR (400 MHz, CDCl ): δ1.74-2.10 (m, 9H), 2.63-2.68 (m, 1H), 2.95-3.08 (m, 2H),
3
3
.28-3.46 (m, 1H), 3.80 (s, 3H), 3.88-4.02 (m, 2H), 5.89 (q, J = 7.6 Hz, 0.75H [for E-
isomer]), 6.27 (q, J = 7.6 Hz, 0.25H [for Z-isomer]), 6.65-6.81 (m, 2H), 7.30-7.33 (m,
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1
1
3
1
H); 13C{ H} NMR (100 MHz, CDCl ): δ14.5, 16.2, 24.5, 25.5, 25.6, 26.6, 27.1, 34.4,
3
7.2, 50.5, 50.7, 51.2, 55.3, 70.3, 86.4, 87.1, 112.1, 112.5, 113.1, 113.5, 115.3, 124.4,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
26.1, 127.8, 130.0, 130.5, 131.1, 140.9, 158.9, 159.1, 169.5, 172.1; HRMS (ESI) m/z
+
calcd for C H N O [M + H] 351.1703, found 351.1711.
21
23
2
3
1
'-Ethylidene-5-oxo-3-(piperidin-1-yl)-3',4'-dihydro-1'H,5H-spiro[furan-2,2'-
naphthalene]-4-carbonitrile (5c). Yield: 89% (149.0 mg); 0.28 R (40% ethyl acetate-
f
-1 1
hexane), white solid, mp: 153-155 °C; IR (KBr): 2943, 2208, 1742, 1605 cm ; H NMR
(400 MHz, CDCl ): δ 1.46-1.93 (m, 7H), 2.06 (d, J = 16.8 Hz, 3H), 2.13-2.19 (m, 1H),
3
2
.70-2.75 (m, 1H), 2.95-3.13 (m, 2H), 3.38-3.52 (m, 2H), 4.34-4.49 (m, 1H), 6.04 (q, J =
7.6 Hz, 0.70H [for E-iosmer]), 6.42 (q, J = 7.6 Hz, 0.30H [for Z-iosmer]), 7.15-7.30 (m,
13
1
3
H), 7.38-7.41 (m, 1H); C{ H} NMR (100 MHz, CDCl ): δ 14.6, 16.3, 23.3, 26.0, 26.3,
3
26.8, 35.3, 37.7, 51.0, 51.6, 69.2, 84.5, 86.3, 87.2, 115.1, 124.5, 126.4, 127.5, 127.8,
1
27.9, 128.0, 128.2, 128.5, 129.7, 131.5, 132.3, 132.6, 134.9, 136.8, 138.9, 169.4,
+
172.3, 172.8; HRMS (ESI) m/z calcd for C H N O [M + H] 335.1754, found
21
23
2
2
3
35.1778.
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1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
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3
3
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4
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4
4
4
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5
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6
1
'-Ethylidene-6'-methoxy-5-oxo-3-(piperidin-1-yl)-3',4'-dihydro-1'H,5H-spiro[furan-2,2'-
naphthalene]-4-carbonitrile (5d). Yield: 77% (141.0 mg); 0.20 R (40% ethyl acetate-
f
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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4
5
6
7
8
9
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1
2
3
4
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6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
-1 1
hexane), white solid, mp: 187-189 °C; IR (KBr): 2943, 2208, 1742, 1605 cm ; H NMR
(
400 MHz, CDCl ): δ 1.43-1.85 (m, 7H), 1.99 (d, J = 7.2 Hz, 3H), 2.08-2.13 (m, 1H),
3
2
.62-2.68 (m, 1H), 2.81-3.05 (m, 2H), 3.24 (br, 1H), 3.49 (br, 1H), 3.81 (s, 3H), 4.30 (br,
1
H), 5.89 (q, J = 7.2 Hz, 0.85H [for E-iosmer]), 6.25 (q, J = 7.2 Hz, 0.15H [for Z-
13
1
iosmer]), 6.73-6.80 (m, 2H), 7.30 (d, J = 8.4 Hz, 1H); C{ H} NMR (100 MHz, CDCl ): δ
3
16.2, 23.3, 25.9, 27.1, 35.1, 50.9, 51.6, 55.2, 69.0, 86.4, 112.1, 113.3, 115.1, 124.0,
1
27.4, 129.8, 131.8, 140.5, 159.0, 169.6, 172.4 for E-iosmer, 14.4, 37.6, 52.7, 68.6,
84.5, 112.6, 125.9, 126.5, 138.2, 173.0 for Z-iosmer; HRMS (ESI) m/z calcd for
+
C H N O [M + H] 365.1860, found 365.1869.
22
25
2
3
1'-Ethylidene-3-(4-methylpiperidin-1-yl)-5-oxo-3',4'-dihydro-1'H,5H-spiro[furan-2,2'-
naphthalene]-4-carbonitrile (5e). Yield: 78% (136.0 mg); 0.4 Rf (40% ethyl acetate-
-1 1
hexane), light pink solid, mp: 160-162 °C; IR (KBr): 2928, 2210, 1742, 1605 cm ; H
NMR (400 MHz, CDCl ): δ 0.98 (d, J = 6.8 Hz, 3H), 1.30-2.17 (m, 10H), 2.70-2.86 (m,
3
2H), 3.02-3.17 (m, 2H), 3.31-3.54 (m, 1H), 4.57-4.84 (m, 1H), 6.05 (q, J = 7.6 Hz, 0.70H
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[
for E-iosmer]), 6.42 (q, J = 7.6 Hz, 0.30H [for Z-iosmer]), 7.15-7.29 (m, 3H), 7.34-7.41
m, 1H); 13C{ H} NMR (100 MHz, CDCl ): δ 14.5, 16.2, 21.4, 26.2, 26.7, 30.2, 33.9,
1
(
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
1
1
4.5, 35.1, 37.6, 50.3, 51.0, 68.5, 68.9, 84.4, 86.2, 115.0, 124.4, 126.4, 127.4, 127.8,
28.0, 128.1, 128.3, 129.6, 131.4, 131.8, 132.2, 132.5, 134.9, 136.7, 138.8, 169.5,
+
72.2, 172.7; HRMS (ESI) m/z calcd for C H N O [M + H] 349.1911, found 349.1916.
22
25
2
2
1'-Ethylidene-6'-methoxy-3-(4-methylpiperidin-1-yl)-5-oxo-3',4'-dihydro-1'H,5H-
spiro[furan-2,2'-naphthalene]-4-carbonitrile (5f). Yield: 65% (123.0 mg); 0.30 R (40%
f
ethyl acetate-hexane), yellow solid, mp: 72-73 °C; IR (KBr): 2953, 2210, 1744, 1607
-1 1
cm ; H NMR (400 MHz, CDCl ): δ 0.94 (d, J = 6.4 Hz, 3H), 1.26-2.10 (m, 10H), 2.61-
3
2.81 (m, 2H), 2.95-3.12 (m, 2H), 3.37-3.53 (m, 1H), 3.77 (s, 1H [for Z-iosmer]), 3.80 (s,
2
H [for E-iosmer]), 4.53-4.77 (m, 1H), 5.88 (q, J = 7.2 Hz, 0.64H [for E-iosmer]), 6.25 (q,
J = 8.0 Hz, 0.36H [forZ-iosmer]), 6.64-6.79 (m, 2H), 7.29 (d, J = 8.0 Hz, 1H); 13C{ H}
1
NMR (100 MHz, CDCl ): δ 14.4, 16.2, 21.5, 26.5, 27.0, 29.6, 30.2, 34.0, 34.5, 35.1,
3
37.6, 50.3, 51.1, 55.2, 68.6, 84.5, 86.3, 112.1, 112.6, 113.3, 113.5, 115.2, 124.0, 125.8,
1
27.4, 129.7, 130.2, 131.3, 131.7, 138.3, 140.5, 159.0, 159.2, 169.6, 172.3, 172.9;
+
HRMS (ESI) m/z calcd for C H N O [M + H] 379.2016, found 379.2022.
23
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2
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2
2
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3
-(4-Benzylpiperazin-1-yl)-1'-ethylidene-5-oxo-3',4'-dihydro-1'H,5H-spiro[furan-2,2'-
naphthalene]-4-carbonitrile(5g). Yield: 64% (0.135 g); 0.25 R (40% ethyl acetate-
f
0
1
2
3
4
5
6
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9
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1
2
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0
-1 1
hexane), yellow solid, mp: 71-73 °C; IR (KBr): 2924, 2212, 1746, 1607 cm ; H NMR
(
400 MHz, CDCl ): δ 1.79-1.90 (m, 2H), 2.04 (d, J = 7.2 Hz, 3H), 2.14-2.80 (m, 6H),
3
2
7
9
.99-3.26 (m, 2H), 3.46-3.54 (m, 2H), 3.74-3.87 (m, 1H), 4.16-4.35 (m, 1H), 6.02 (q, J =
.2 Hz, 0.70H [for E-iosmer]), 6.40 (q, J = 7.2 Hz, 0.30H [for Z-iosmer]), 7.19-7.37 (m,
H); 13C{ H} NMR (100 MHz, CDCl ): δ 14.6, 16.3, 26.2, 26.7, 35.2, 37.7, 49.2, 50.1,
1
3
52.2, 52.6, 62,2, 69.4, 69.8, 84.4, 86.3, 114.8, 114.9, 124.4, 126.5, 127.5, 127.8, 127.9,
1
28.0, 128.2, 128.3, 128.5, 128.9, 129.9, 131.3, 131.8, 132.3, 132.6, 134.5, 136.6,
136.7, 138.8, 169.1, 169.2, 172.7, 173.4; HRMS (ESI) m/z calcd for C H N O [M +
27
28
3
2
+
H] 426.2176, found 426.2179.
3-(4-Benzylpiperazin-1-yl)-1'-ethylidene-6'-methoxy-5-oxo-3',4'-dihydro-1'H,5H-
spiro[furan-2,2'-naphthalene]-4-carbonitrile (5h). Yield: 73% (165.0 mg); 0.20 R (40%
f
ethyl acetate-hexane), yellow solid, mp: 72-73 °C; IR (KBr): 2922, 2212, 1746, 1607
-
1 1
cm ; H NMR (400 MHz, CDCl ): δ 1.79-1.87 (m, 2H), 2.00 (d, J = 7.2 Hz, 3H), 2.12-
3
2.78 (m, 6H), 2.98-3.26 (m, 2H), 3.38-3.54 (m, 2H), 3.75-3.87 (m, 4H), 4.15-4.35 (m,
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The Journal of Organic Chemistry
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H), 5.89 (q, J = 7.2 Hz, 0.68H [for E-iosmer]), 6.27 (q, J = 7.2 Hz, 0.32H [for Z-
13
1
iosmer]), 6.66-6.80 (m, 2H) 7.27-7.34 (m, 6H); C{ H} NMR (100 MHz, CDCl ): δ14.4,
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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3
3
3
3
3
3
3
3
4
4
4
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4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
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9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
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0
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0
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6.2, 26.4, 27.0, 35.2, 37.7, 49.1, 50.1, 52.2, 52.6, 55.2, 62.2, 69.3, 69.7, 84.4, 86.4,
12.2, 112.7, 113.3, 113.5, 114.9, 115.0, 123.8, 125.8, 127.1, 127.4, 127.6, 128.3,
28.8, 129.8, 130.1, 131.3,131.8, 136.6, 136.7, 138.2, 140.5, 159.0, 159.3, 169.2,
+
72.8, 173.5; HRMS (ESI) m/z calcd for C H N O [M + H] 456.2282, found 456.2283.
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3
3
1'-Ethylidene-3-morpholino-5-oxo-3',4'-dihydro-1'H,5H-spiro[furan-2,2'-naphthalene]-4-
carbonitrile (5i). Yield: 48% (80.0 mg); 0.20 R (40% ethyl acetate-hexane), yellow
f
-1
1
solid, mp: 155-157 °C; IR (KBr): 2924, 2212, 1744, 1605 cm ; H NMR (400 MHz,
CDCl ): δ 1.80-1.87 (m, 1H), 1.90 (d, J = 7.2 Hz, 1H [for Z-iosmer]), 2.07 (d, J = 6.8 Hz,
3
2H [for E-iosmer]), 2.19 (d, J = 14.4 Hz, 1H), 2.74 (d, J = 13.6 Hz, 1H), 3.02-4.32 (m,
9H), 6.07 (q, J = 6.8 Hz, 0.60H [for E-iosmer]), 6.45 (q, J = 7.2 Hz, 0.40H [for Z-
iosmer]), 7.17-7.37 (m, 4H); 13C{ H} NMR (100 MHz, CDCl ): δ 14.6, 16.3, 26.1, 26.6,
1
3
35.2, 37.7, 49.4, 50.3, 66.1, 66.3, 69.9, 70.3, 84.4, 86.4, 114.7, 124.4, 126.6, 127.6,
128.0, 128.1, 128.2, 128.3, 128.5, 130.1, 131.2, 131.7, 132.2, 132.9, 134.4, 136.8,
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