Spirocyclopropanes from Intramolecular Cyclopropanation of Pyranopyrazoles and Pyranopyrimidine-diones and Lewis Acid Mediated (3 + 2) Cycloadditions of Spirocyclopropylpyrazolones

Article abstract of DOI:10.1021/acs.joc.7b00089

A robust intramolecular cyclopropanation reaction was first performed on pyranopyrazole and pyranopyrimidine-dione derivatives to obtain spirocyclopropylpyrazolones and barbiturates, using iodosylbenzene (PhIO) or the combination of iodobenzene diacetate (PIDA)/molecular iodine (I₂), under mild reaction conditions. Syntheses of functionally and stereochemically diversified, novel spiropyrazolone fused 2-iminothiophene and spiropyrazolone fused pyrroline scaffolds were also demonstrated via Lewis acid catalyzed highly diastereoselective (3 + 2) cycloaddition reactions of the synthesized spiro-cyclopropyl pyrazolones with phenyl isothiocyanate and benzonitrile, respectively.

Full text of DOI:10.1021/acs.joc.7b00089

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Note
Spiro-cyclopropanes from Intramolecular Cyclopropanation of
Pyranopyrazoles and Pyranopyrimidine-diones and Lewis Acid
Mediated (3+2)-Cycloadditions of Spirocyclopropylpyrazolones
Prasun Mukherjee, and Asish R. Das
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b00089 • Publication Date (Web): 09 Feb 2017
Downloaded from http://pubs.acs.org on February 10, 2017
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Spiro-cyclopropanes from Intramolecular Cyclopropanation of Pyranopyrazoles and
Pyranopyrimidine-diones and Lewis Acid Mediated (3+2)-Cycloadditions of
Spirocyclopropylpyrazolones
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Prasun Mukherjee, Asish R. Das*
Department of Chemistry, University of Calcutta, Kolkata-700009, India
*
Tel.: +913323501014, +919433120265; fax: +913323519754; E-mail: ardchem@caluniv.ac.in,
ardas66@rediffmail.com.
Graphical abstract
Abstract
A robust intramolecular cyclopropanation reaction was first performed on pyrano-pyrazole and
pyrano-pyrimidine dione derivatives to obtain spiro-cyclopropyl pyrazolones and barbiturates,
using iodosylbenzene (PhIO) or the combination of iodobenzene diacetate (PIDA)/ molecular
iodine (I ), under mild reaction conditions. Syntheses of functionally and stereochemically
2
diversified, novel spiropyrazolone fused 2-iminothiophene and spiropyrazolone fused pyrroline
scaffolds were also demonstrated via Lewis acid catalyzed highly diastereoselective (3+2)
cycloaddition reactions of the synthesized spiro-cyclopropyl pyrazolones with phenyl
isothiocyanate and benzonitrile respectively.
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Spirocyclopropyl functionality is the key structural motif in several natural products and
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synthetic compounds of prevalent biological and medicinal activities. In addition,
spirocyclopropanes are essential in organic synthesis due to their affinity towards several
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transformations. In particular, donor-acceptor (D-A) cyclopropanes and their spiro-analogues
have been proficiently exploited to synthesize numerous valuable heterocycles through countless
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cycloaddition reactions. In this context, synthesis of functionalized spiro-cyclopropyl
barbiturates and pyrazolones will be worthwhile, since pyrazolone and barbituric acid derivatives
along with their spiro-equivalents have well recognized for their extensive use in medicinal and
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pharmacological fields. Also, a number of spiro-cyclopropyl pyrazolones have established as
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antifungal agents and advanced AGE formation inhibitors. Considering their biological and
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b,7
synthetic utilities,
several synthetic routes have been developed to synthesize them, such as,
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reaction of Michael acceptors with ylids (Scheme 1, 1a), electrocatalytic cyclopropanation
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(
Scheme 1, 1b), reaction of Michael acceptors with α-halo active methylene compounds
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b,10
(Scheme 1, 1c and d)
. However, an operationally simple, mild and competent strategy to
access spiro-cyclopropyl barbiturates and pyrazolones from simple starting materials using less
toxic reagents is still challenging and highly desirable.
In our previous work, we have demonstrated PhIO promoted intramolecular aziridination
reaction to synthesize 2-oxa-7-azabicyclo[4.1.0]hept-3-en-1-yl carboxylates from 2-amino-
1
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pyrans in presence of triethylamine (Et N) and several carboxylic acids (Scheme 1, entry 2).
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Interestingly, during the investigation of substrate scope of that reaction, unusual products were
detected when pyranopyrimidine-dione 1a and pyrano-pyrazole 1b were employed as reactants.
Complete characterization of those isolated products has led us to recognize them as spiro-
cyclopropyl
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Scheme 1. Synthetic routes to construct spiro-cyclopropylpyrazolones and barbiturates
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barbiturate and pyrazolone (2a and 2g respectively). As part of our ongoing efforts towards the
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hypervalent iodine mediated synthesis of valuable heterocycles, herein, we wish to disclose an
Scheme 2. (3+2) cycloaddition reactions of donor-acceptor spiro-cyclopropyl pyrazolones
unparalleled synthesis of spirocyclopropyl barbiturates and pyrazolones from their corresponding
amino-pyrans using PhIO or the combination of PIDA and molecular I (1:1) in presence of Et N
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at room temperature (rt) (Scheme 1, entry 1). Experimental results and literature review suggest
that the oxidants used in this transformation are superior to the molecular iodine oxidants used
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for cyclopropanation in other systems. In this present endeavor, we have also established the
competency of the obtained D-A (donor-acceptor) spirocyclopropyl pyrazolones towards Lewis
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acid catalyzed (3+2) cycloaddition reactions to afford functionalized novel 7-thia-2,3-
diazaspiro[4.4]non-3-en-1-ones and 2,3,7-triazaspiro[4.4]nona-3,6-dien-1-ones (Scheme 2).
In order to optimize the reaction conditions, pyranopyrimidine-dione 1a was synthesized using a
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known method and 1.0 equiv of 1a was then reacted with several iodine oxidants in presence of
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Et N using dichloromethane (DCM) as the solvent at rt. After investigating several conditions,
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best results were obtained when the reaction was performed in presence of PhIO (1.2 equiv) and
Et N (1.0 equiv) in DCM (Method A) as well as in presence of PIDA (0.5 equiv), I (0.5 equiv)
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and Et N (2.0 equiv) in DCM (Method B). To explore the scope and limitation of this protocol a
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variety of pyranopyrimidine-diones and pyranopyrazoles were readily synthesized following the
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above mentioned procedure. The intramolecular cyclopropanation reaction was then carried out
applying both Method A and B (Table 1). Both of them proceeded smoothly on
pyranopyrimidine-diones and pyranopyrazoles producing spirocyclopropanes 2a-v in excellent
yields (Table 1, entry 2a-v). However, spirocyclopropanes 2g-l and 2n-p were obtained as
diastereomeric mixtures from 3-methyl-pyranopyrazoles. In contrast, the reaction proceeded in a
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diastereospecific manner to afford 2q-v and 2m which is probably due to the steric effect of the
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carbethoxy group with R in 3-carbethoxy-pyranopyrazoles and the electronic repulsion between
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the carbonyl ‘O’ and thienyl ‘S’ atoms in 1m respectively (Table 1). The presence of thienyl
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and substituted aryl groups (R ) had virtually no effect on the competency of both of these
methods (Table 1,
Table 1. Substrate scope for the synthesis of spiro-cyclopropyl barbiturates and
pyrazolones
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Method A: PhIO (1.2 equiv), Et N (1.0 equiv), DCM (3 mL), rt. Method B: PIDA (0.5 equiv),
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I (0.5 equiv), Et N (2.0 equiv), DCM, rt. ratio calculated from yield. ratio calculated from H
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NMR
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entry 2a-v). Moreover, the key advantage of methods A and B was revealed when pure products
were isolated after completion of the reaction by simply evaporating the solvent and triturating
the crude mass with MeOH followed by filtration of the resulting precipitate. All synthesized
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compounds were well characterized through H and C NMR, IR, HRMS, and elemental
analysis data. The structural motif of the spirocyclopropanes was confirmed through X-ray
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crystallographic analysis of compound 2q. The special reactivity of pyranopyrazoles and
pyranopyrimidine-diones towards iodine oxidants to afford cyclopropanes may be due to less
electron withdrawing ability of the fused pyrazole and pyrimidine-dione scaffolds through
resonance which makes the non-bonding electrons of pyran oxygen more available for the
conjugation with enaminonitrile fragment, thereby increasing the nucleophilicity as well as the
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reactivity of C than that of the –NH group (Scheme 3, 1).
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Scheme 3. Plausible mechanism for the intramolecular cyclopropanation reaction
A plausible mechanism for this reaction is depicted in Scheme 3. For method A, initial
electrophilic attack of PhIO to the enamine fragment of 1 generates the intermediate I. A
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rearrangement within I in presence of Et N ruptures the pyran moiety and produces intermediate
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II which then immediately undergoes a rapid intramolecular cyclization, involving a nucleophilic
substitution reaction, to afford the spirocyclopropane 2. In case of method B, the in-situ formed
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IOAc from PIDA and I2 acts as the active electrophile to generate the desired product 2 via the
intermediates III and IV, following essentially the same course of reaction as for method A.
The synthetic utility of these synthesized spirocyclopropyl pyrazolones was explored by
successfully transforming them into unique 7-thia-2,3-diazaspiro-[4.4]non-3-en-1-one and 2,3,7-
triazaspiro[4.4]nona-3,6-dien-1-one derivatives through their Lewis-acid catalyzed (3+2)
cycloaddition reaction with phenyl isothiocyanate (1.2 equiv) in presence of FeCl (1.0 equiv)
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and benzonitrile (1.1 equiv) in presence of AlCl (1.1 equiv) respectively. These reactions have
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proceeded efficiently for the major as well as minor
a
Table 2. Synthesis of spiropyrazolone fused 2-iminothiophene derivatives
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Reaction Condition: 2 (1.0 mmol), PhNCS (1.2 mmol), FeCl (1.0 mmol), 4Å MS (200 mg),
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DCM (3 mL), rt.
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(
Table 2, entry 3g) diastereomers of the corresponding cyclopropyl pyrazolones, affording the
spiro-compounds in excellent yields at a short reaction time (Table 2 and 3). Both of these
cycloaddition reactions were carried out using diastereomerically pure spirocyclopropyl
pyrazolones and in all the cases the ring-enlarged products were obtained in diastereomerically
pure form which establishes these (3+2) cycloaddition reactions to be highly stereospecific in
nature. All these products were well characterized and the structural motifs of these new
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spiropyrazolones were established through X-ray analysis of compound 3g and 4q.
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Table 3. Synthesis of spiropyrazolone fused pyrroline derivatives
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Reaction Condition: 2 (1.0 mmol), PhCN (1.1 mmol), AlCl (1.1 mmol), 4Å MS (200 mg),
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o
DCE (3 mL), 80 C, 2 h.
Literature review and X-ray analysis data for both compound 3g and 4q suggest that both of
these (3+2) cycloaddition reactions follow the stereospecific intimate-ion pair mechanism with
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the inversion of configuration in the benzylic carbon center (Scheme 4). Initial coordination of
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Lewis acids with carbonyl functionality of 2 results in the weakening of the C –C bond, thereby
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facilitates the S 2 attack of dipolarophiles (PhNCS and PhCN) to the C center of 2 and a
N
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Scheme 4. Plausible mechanism of the (3+2) cycloaddition reactions
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o
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subsequent 120 rotation through the C -C bond generate intermediates IV and V which then
undergo an intramolecular cyclization reaction to afford products 3 and 5.
In conclusion, we have demonstrated the first example of intramolecular cyclopropanation
reaction in pyranopyrazole and pyranopyrimidine-dione system by using PhIO and PIDA/
molecular I combination in presence of Et N at rt to synthesize biologically significant
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functionalized spiro-cyclopropyl barbiturates and pyrazolone scaffolds. The obtained spiro-
cyclopropyl pyrazolones has been efficiently transformed into novel spiropyrazolone fused 2-
iminothiophene and spiropyrazolone fused pyrroline scaffolds through Lewis acid catalyzed
(3+2) cycloaddition reactions with phenyl isothiocyanate and benzonitrile respectively. These
new types of highly functionalized spiropyrazolone heterocycles may be suitable candidates for
biological and pharmacological studies.
Experimental section
Materials and method
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H-NMR and C-NMR spectral analysis were carried out on 300 MHz, 75 MHz, 500 MHz and
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25 MHz instruments where tetramethylsilane (TMS) was used as internal standard. Infrared
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spectra were recorded in KBr pallets in reflection mode on a FTIR spectrophotometer. HRMS
analysis was performed on an ESI - TOF mass analyzer. Elemental analyses were done using an
auto analyzer. Suitable single crystals of compound 2q, 3g and 4q were mounted on an X-ray
diffractometer equipped with a graphite monochromator. All the reactions were monitored by
thin layer chromatography carried out on aluminum-blocked silica gel plates coated with silica
gel G under UV light and also by exposure to iodine vapor for detection. Melting points were
recorded on a Köfler Block apparatus and are uncorrected. Synthetic grade chemicals from
available companies were used for carrying out the organic reactions. For column
chromatography 100-200 mesh silica gel was used. All the organic solvents, used in the reaction,
were appropriately dried and distilled prior to use.
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General procedure for the synthesis of required pyrazolone derivatives
Sodium acetate (328 mg, 4.0 mmol) was added in a suspension of aromatic hydrazine
hydrochloride derivatives (4.0 mmol) in 5 mL EtOH and 1mL water and the mixture was stirred
at rt for 5 min. Then to the mixture ethyl acetoacetate (521 mg, 4.0 mmol) or diethyl
acetylenedicarboxylate (681 mg, 4.0 mmol) was added and the resultant mixture was heated to
reflux for 3h. After that the mixture was poured drop wise onto crushed ice (50 g) with vigorous
stirring and the resulting precipitate then filtered off and crystallized from EtOH. The obtained
pyrazolone derivatives were then used for the synthesis of pyranopyrimidine-diones and
pyranopyrazoles without further purification.
General procedure for the synthesis of pyranopyrimidine-diones 1a-f and pyranopyrazoles
1
g-v
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Triethylamine (1 drop) was added to a mixture of aromatic aldehydes (2.0 mmol), malononitrile
(132 mg, 2.0 mmol), and 1,3-dimethylbarbituric acid (312 mg, 2.0 mmol) or pyrazolones (2.0
mmol) in EtOH (5 mL) and the reaction mixture was refluxed for 15 min. The precipitate that
was formed after cooling the reaction mixture to room temperature was filtered off, washed with
water (2×5 mL), EtOH (1×5 mL), and finally crystallized from EtOH. The crystallized pure
pyranopyrimidine-diones and pyranopyrazoles were then employed for the synthesis of
spirocyclopropyl barbiturates and pyrazolones without further purification.
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General method A for the synthesis of spirocyclopropyl barbiturates 2a-f and pyrazolones
2
g-v
To a stirring suspension of pyranopyrimidine-diones (1.0 mmol) or pyranopyrazoles (1.0 mmol)
in DCM (3 mL) at rt, PhIO (264 mg, 1.2 mmol) was added and the resulting mixture was stirred
for 2 min at rt. Then to it 1.0 mmol of triethylamine was added and the reaction mixture was
stirred at rt for 30 min for the complete conversion of the starting 2-aminopyrans (monitored by
TLC). After that the solvent was evaporated from the reaction mixture under reduced pressure
and the resulting crude mass was triturated with MeOH (5 mL). The solid precipitate thus
obtained was then filtered off and washed with MeOH (2×5 mL) and finally crystallized from
ethyl acetate to get the pure spirocyclopropyl derivatives. For compound 2g-k, the diastereo
isomers were separated through column chromatography (silica gel 100 - 200 mesh) with ethyl
acetate and petroleum ether (1:6 - 1:3, v/v) as the eluent.
General method B for the synthesis of spirocyclopropyl barbiturates 2a-f and pyrazolones
2
g-v
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A mixture of PIDA (161 mg, 0.5 mmol) and I (127 mg, 0.5 mmol) in DCM (3 mL) was stirred
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at rt for 5 min. Then to it pyranopyrimidine-diones (1.0 mmol) or pyranopyrazoles (1.0 mmol)
was added followed by the addition of triethylamine (2.0 mmol) and the resulting mixture was
stirred for 30 min at rt. After completion of the reaction (monitored by TLC) the solvent was
evaporated from the reaction mixture under reduced pressure and the resulting crude mass was
triturated with MeOH (5 mL). The solid precipitate thus appeared was then filtered off and
washed with MeOH (2×5 mL) and finally crystallized from ethyl acetate to obtain the pure
products. In case of compound 2g-k, the diastereomers were separated through column
chromatography (silica gel 100 - 200 mesh) with ethyl acetate and petroleum ether (1:6 - 1:3,
v/v) as the eluent.
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General procedure for the synthesis of 7-thia-2,3-diazaspiro[4.4]non-3-en-1-one derivatives
(3g, 3i, 3o, 3p and 3q)
In a 25 mL oven dried RB fitted with calcium chloride guard tube, some selected
spirocyclopropyl pyrazolones (1.0 mmol), phenyl isothiocyanate (162 mg, 1.2 mmol), 4Å MS
(
200 mg) and DCM (3 mL) were taken and stirred for 1 min. Then to it anhydrous FeCl (1.0
3
mmol) was added and the reaction mixture was stirred at rt. After completion of the reaction
(monitored by TLC), the reaction mixture was diluted with DCM (10 mL) and filtered through a
pad of celite and the filtrate was then subjected for column chromatography (silica gel 100-200
mesh) with ethyl acetate and petroleum ether (1:9 - 1:6, v/v) as the eluent to afford the pure
products.
General procedure for the synthesis of 2,3,7-triazaspiro[4.4]nona-3,6-dien-1-one derivatives
(4g, 4i, 4k, 4p and 4q)
In a 25 mL oven dried RB, some selected spirocyclopropyl pyrazolones (1.0 mmol), PhCN (114
mg, 1.1 mmol), 4Å MS (200 mg) and DCE (3 mL) were taken and stirred at rt for 1 min under
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calcium chloride guard tube. Then to it AlCl (147 mg, 1.1 mmol) was added followed by the
3
fitting of a oven dried condenser and calcium chloride guard tube and the mixture was then
o
heated at 80 C for 2h. After completion of the reaction (monitored by TLC), the reaction
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mixture was diluted with ethyl acetate (10 mL) and MeOH (5 mL) and filtered through a pad of
celite and the filtrate was then subjected for column chromatography (silica gel 100 - 200 mesh)
with ethyl acetate and petroleum ether (1:9 - 1:6, v/v) as the eluent to afford the pure products.
For compounds 2a-v, the characterization data of samples, provided by Method B, are
documented.
9
a
5
,7-Dimethyl-4,6,8-trioxo-2-phenyl-5,7-diazaspiro[2.5]octane-1,1-dicarbonitrile (2a)
o
1
White solid (Method A: 284 mg, 92%, Method B: 290 mg, 94%); Mp: 258-260 C; H NMR
(
300 MHz; DMSO d ; Me Si): δ 3.13 (s, 3H), 3.28 (s, 3H), 4.37 (s, 1H), 7.37 (d, J = 6 Hz, 3H),
6
4
1
3
1
7.46 (d, J = 6 Hz, 2H); C{ H}NMR (75 MHz; DMSO d ; Me Si): δ 23.9, 29.0, 29.5, 41.8, 44.4,
6
4
1
1
1
11.3, 112.8, 128.6, 128.7, 129.0, 129.7, 151.3, 161.0, 163.4; IR (KBr): 3004, 2960, 2253, 1698,
-1
454, 1444, 1424, 1388, 1298, 752 cm ; Anal. Calcd for C H N O : C, 62.33; H, 3.92; N,
16 12
4
3
8.17. Found: C, 62.25; H, 4.00; N, 18.12.
5
,7-Dimethyl-2-(4-nitrophenyl)-4,6,8-trioxo-5,7-diazaspiro[2.5]octane-1,1-dicarbonitrile
9
a
(2b)
o
1
Light-yellow solid (Method A: 311 mg, 88%, Method B: 311 mg, 88%); Mp: 220-222 C; H
NMR (300 MHz; DMSO d ; Me Si): δ 3.10 (s, 3H), 3.27 (s, 3H), 4.55 (s, 1H), 7.81 (d, J = 8.4
6
4
1
3
1
Hz, 2H), 8.23 (d, J = 8.7 Hz, 2H); C{ H}NMR (75 MHz; DMSO d ; Me Si): δ 24.2, 29.1, 29.5,
6
4
41.9, 42.8, 111.0, 112.5, 123.6, 131.4, 137.0, 147.7, 151.3, 161.1, 163.0; IR (KBr): 2998, 2958,
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6
-1
2
5
254, 1704, 1688, 1525, 1458, 1420, 1388, 1350, 760 cm ; Anal. Calcd for C H N O : C,
1
6
11
5
5
4.40; H, 3.14; N, 19.82. Found: C, 54.34; H, 3.20; N, 19.80.
2-(4-Cyanophenyl)-5,7-dimethyl-4,6,8-trioxo-5,7-diazaspiro[2.5]octane-1,1-dicarbonitrile
2c)
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(
o
1
Off-white solid (Method A: 300 mg, 90%, Method B: 300 mg, 90%); Mp: 226-228 C; H NMR
(500 MHz; DMSO d ; Me Si): δ 3.10 (s, 3H), 3.27 (s, 3H), 4.49 (s, 1H), 7.71 (d, J = 13.0 Hz,
6
4
13
1
2
4
H), 7.85 (d, J = 14.0 Hz, 2H); C{ H}NMR (125 MHz; DMSO d ; Me Si): δ 24.3, 29.2, 29.7,
6 4
2.0, 43.3, 111.2, 111.6, 112.7, 119.1, 131.1, 132.6, 135.1, 151.5, 161.2, 163.2; IR (KBr): 2990,
-1
2966, 2252, 2244, 1700, 1450, 1382, 1296, 1104, 746 cm ; Anal. Calcd for C H N O : C,
1
7
11
5
3
6
1.26; H, 3.33; N, 21.01. Found: C, 61.20; H, 3.40; N, 20.97.
2
-(4-Bromophenyl)-5,7-dimethyl-4,6,8-trioxo-5,7-diazaspiro[2.5]octane-1,1-dicarbonitrile
(2d)
Off-white solid (Method A: 364 mg, 94%, Method B: 364 mg, 94%); Mp: 240-242 C; H NMR
o
1
(
500 MHz; DMSO d ; Me Si): δ 3.11 (s, 3H), 3.26 (s, 3H), 4.33 (s, 1H), 7.44 (d, J = 8.0 Hz, 2H),
6
4
1
3
1
7.57 (d, J = 8.0 Hz, 2H); C{ H}NMR (125 MHz; DMSO d ; Me Si): δ 24.2, 29.2, 29.6, 41.8,
6
4
4
3.6, 111.3, 112.8, 122.3, 128.8, 131.7, 132.1, 151.5, 161.2, 163.4; IR (KBr): 2996, 2969, 2252,
-1
1
710, 1450, 1380, 1292, 1106, 750, 625 cm ; Anal. Calcd for C H BrN O : C, 49.63; H, 2.86;
16 11 4 3
N, 14.47. Found: C, 49.58; H, 2.90; N, 14.41.
5
,7-Dimethyl-2-(3-nitrophenyl)-4,6,8-trioxo-5,7-diazaspiro[2.5]octane-1,1-dicarbonitrile
(2e)
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o
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Off-white solid (Method A: 318 mg, 90%, Method B: 325 mg, 92%); Mp: 218-220 C; H NMR
(
300 MHz; DMSO d ; Me Si): δ 3.1 (s, 3H), 3.30 (s, 3H), 4.51 (s, 1H), 7.70 (t, J = 7.95 Hz, 1H),
6 4
1
3
1
8
.02 (d, J = 7.5 Hz, 1H), 8.21 (d, J = 8.1 Hz, 1H), 8.53 (s, 1H); C{ H}NMR (75 MHz; DMSO
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d ; Me Si): δ 24.1, 28.7, 29.2, 41.5, 42.0, 110.7, 112.2, 123.3, 124.8, 129.8, 131.3, 136.2, 147.6,
6
4
151.1, 160.9, 162.8; IR (KBr): 2990, 2948, 2252, 1700, 1684, 1530, 1458, 1420, 1388, 1326, 758
-1
cm ; Anal. Calcd for C H N O : C, 54.40; H, 3.14; N, 19.82. Found: C, 54.34; H, 3.18; N,
1
6
11
5
5
1
9.78.
9
a
5,7-Dimethyl-4,6,8-trioxo-2-(p-tolyl)-5,7-diazaspiro[2.5]octane-1,1-dicarbonitrile (2f)
o
1
Light-yellow solid (Method A: 297 mg, 92%, Method B: 303 mg, 94%); Mp: 184-186 C; H
NMR (500 MHz; DMSO d ; Me Si): δ 2.29 (s, 3H), 3.11 (s, 3H), 3.26 (s, 3H), 4.27 (s, 1H), 7.16
6
4
1
3
1
(
d, J = 7.5 Hz, 2H), 7.32 (d, J = 7.5 Hz, 2H); C{ H}NMR (125 MHz; DMSO d ; Me Si): δ
6 4
2
6.1, 28.8, 33.9, 34.4, 46.7, 49.3, 116.2, 117.8, 130.8, 134.1, 134.4, 143.0, 156.2, 165.8, 168.3;
-1
IR (KBr): 2992, 2955, 2252, 1684, 1445, 1382, 1297, 1107, 748 cm ; Anal. Calcd for
C H N O : C, 63.35; H, 4.38; N, 17.38. Found: C, 63.30; H, 4.42; N, 17.35.
17
14
4
3
9
b
4
-Methyl-7-oxo-2,6-diphenyl-5,6-diazaspiro[2.4]hept-4-ene-1,1-dicarbonitrile (2g)
o
1
Off-white solid (Method A: 294 mg, 90%, Method B: 300 mg, 92%); Mp: 188-190 C; H NMR
of major isomer (300 MHz; CDCl ; Me Si): δ 1.77 (s, 3H), 3.89 (s, 1H), 7.17-7.42 (m, 8H), 7.88
3
4
1
3
1
(d, J = 7.5 Hz, 2H); C{ H}NMR of major isomer (75 MHz; CDCl ; Me Si): δ 16.3, 18.3, 42.6,
3
4
4
1
2.7, 44.4, 109.2, 109.8, 118.4, 118.5, 118.53, 125.8, 126.0, 128.8, 128.84, 129.0, 129.04, 129.1,
1
29.2, 129.3, 129.4, 129.9, 137.0, 151.1, 163.8; H NMR of minor isomer (300 MHz; CDCl ;
3
13
1
Me Si): δ 2.38 (s, 3H), 4.02 (s, 1H), 7.23-7.45 (m, 8H), 7.90 (d, J = 8.7 Hz, 2H); C{ H}NMR
4
of minor isomer (75 MHz; CDCl ; Me Si): δ 14.0, 19.2, 40.9, 44.0, 107.3, 111.7, 118.4, 118.44,
3
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24.9, 125.7, 128.7, 128.7, 128.9, 128.94, 129.0, 129.6, 137.1, 151.4, 161.6; IR (KBr): 3002,
-1
946, 2252, 1708, 1600, 1500, 1450, 1376, 1110, 836, 742 cm ; Anal. Calcd for C H N O: C,
20 14
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3.61; H, 4.32; N, 17.17. Found: C, 73.56; H, 4.37; N, 17.14.
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-Methyl-2-(4-nitrophenyl)-7-oxo-6-phenyl-5,6-diazaspiro[2.4]hept-4-ene-1,1-dicarbonitrile
(2h)
o
1
Off-white solid (Method A: 319 mg, 86%, Method B: 327 mg, 88%); Mp: 184-186 C; H NMR
of major isomer (300 MHz; DMSO d ; Me Si): δ 1.71 (s, 3H), 4.34 (s, 1H), 7.28 (t, J = 7.4 Hz,
6
4
1
H), 7.52 (t, J = 7.8 Hz, 2H), 7.93 (d, J = 7.8 Hz, 2H), 8.00 (d, J = 8.4 Hz, 2H), 8.34 (d, J = 8.4
1
3
1
Hz, 2H); C{ H}NMR of major isomer (75 MHz; DMSO d ; Me Si): δ 16.5, 20.2, 41.8, 44.8,
6
4
1
1
10.7, 111.4, 118.4, 123.9, 125.5, 129.1, 129.2, 131.9, 135.4, 137.9, 148.1, 151.3, 165.0; H
NMR of minor isomer (300 MHz; DMSO d ; Me Si): δ 2.23 (s, 3H), 5.01 (s, 1H), 7.15 (t, J =
6
4
7
.05 Hz, 1H), 7.37 (t, J = 7.05 Hz, 2H), 7.71 (d, J = 8.1 Hz, 4H), 8.16 (d, J = 7.5 Hz, 2H);
13
1
C{ H}NMR of minor isomer (75 MHz; DMSO d ; Me Si): δ 14.3, 21.2, 44.7, 109.3, 112.9,
6
4
118.5, 123.5, 125.5, 129.1, 131.7, 135.2, 137.8, 147.7, 153.9, 163.2; IR (KBr): 3004, 2969, 2249,
-1
1
719, 1596, 1528, 1501, 1449, 1371, 1350, 1328, 1119, 835, 740 cm ; Anal. Calcd for
C H N O : C, 64.69; H, 3.53; N, 18.86. Found: C, 64.62; H, 3.58; N, 18.80.
20
13
5
3
2-(4-Bromophenyl)-4-methyl-7-oxo-6-phenyl-5,6-diazaspiro[2.4]hept-4-ene-1,1-
dicarbonitrile (2i)
o
1
Off-white solid (Method A: 373 mg, 92%, Method B: 373 mg, 92%); Mp: 182-184 C; H NMR
of major isomer (300 MHz; CDCl ; Me Si): δ 1.91 (s, 1H), 3.91 (s, 1H), 7.29 (d, J = 7.5 Hz, 3H),
3
4
1
3
1
7
.48 (t, J = 7.8 Hz, 2H), 7.66 (d, J = 8.1 Hz, 2H), 7.96 (d, J = 8.1 Hz, 2H); C{ H}NMR of
major isomer (75 MHz; CDCl ; Me Si): δ 16.7, 18.5, 42.2, 44.5, 109.2, 109.9, 118.7, 124.7,
3
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25.3, 126.2, 129.1, 130.8, 132.9, 137.2, 150.9, 163.8; H NMR of minor isomer (300 MHz;
CDCl ; Me Si): δ 2.34 (d, J = 4.8 Hz, 3H), 3.90 (s, 1H), 7.16-7.24 (m, 3H), 7.40 (d, J = 5.7 Hz,
3
4
1
3
1
2
H), 7.52 (d, J = 7.8 Hz, 2H), 7.85 (d, J = 6.9 Hz, 2H); C{ H}NMR of minor isomer (75 MHz;
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CDCl ; Me Si): δ 14.3, 19.4, 40.4, 44.2, 107.4, 111.8, 118.8, 124.3, 124.4, 126.2, 129.1, 131.0,
3
4
132.5, 137.3, 151.6, 161.8; IR (KBr): 2996, 2960, 2246, 1710, 1592, 1499, 1444, 1369, 1330,
-
1
1
5
112, 840, 755, 626 cm ; Anal. Calcd for C H BrN O: C, 59.28; H, 3.23; N, 13.83. Found: C,
20 13 4
9.25; H, 3.27; N, 13.79.
6-(4-Chlorophenyl)-4-methyl-2-(4-nitrophenyl)-7-oxo-5,6-diazaspiro[2.4]hept-4-ene-1,1-
dicarbonitrile (2j)
o
1
Off-white solid (Method A: 357 mg, 88%, Method B: 365 mg, 90%); Mp: 192-194 C; H NMR
of major isomer (300 MHz; DMSO d ; Me Si): δ 1.70 (s, 3H), 4.34 (s, 3H), 7.58 (d, J = 7.5 Hz,
6
4
1
3
1
2
H), 7.94 (d, J = 7.5 Hz, 2H), 8.00 (d, J = 7.5 Hz, 2H), 8.33 (d, J = 7.8 Hz, 2H); C{ H}NMR of
major isomer (75 MHz; DMSO d ; Me Si): δ 16.5, 20.4, 41.9, 44.9, 108.7, 110.7, 111.3, 1119.8,
6
4
1
123.9, 129.2, 131.9, 135.3, 136.7, 148.1, 151.7, 165.1; H NMR of minor isomer (300 MHz;
DMSO d ; Me Si): δ 2.32 (s, 3H), 5.12 (s, 1H), 7.52 (d, J = 8.4 Hz, 2H), 7.82 (d, J = 6.3 Hz,
6
4
13
1
4
H), 8.24 (d, J = 7.8 Hz, 2H); C{ H}NMR of minor isomer (75 MHz; DMSO d ; Me Si): δ
6 4
14.3, 21.3, 44.7, 109.2, 112.8, 120.0, 123.4, 129.1 131.7, 135.1, 136.7, 147.7, 154.2, 163.3; IR
KBr): 3000, 2960, 2250, 1711, 1592, 1530, 1501, 1449, 1370, 1346, 1324, 1120, 840, 742, 706
(
-1
cm ; Anal. Calcd for C H ClN O : C, 59.20; H, 2.98; N, 17.26. Found: C, 59.16; H, 3.01; N,
20 12
5
3
17.24.
6
-(4-Methoxyphenyl)-4-methyl-2-(4-nitrophenyl)-7-oxo-5,6-diazaspiro[2.4]hept-4-ene-1,1-
dicarbonitrile (2k)
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o
1
Pale yellow solid (Method A: 369 mg, 92%, Method B: 369 mg, 92%); Mp:204-206 C; H
NMR of major isomer (500 MHz; DMSO d ; Me Si): δ 1.67 (s, 1H), 3.75 (s, 1H), 3.78 (s, 3H),
6
4
7
2
.06 (d, J = 8.5 Hz, 2H), 7.78 (d, J = 8.0 Hz, 2H), 7.96 (d, J = 8.0 Hz, 2H), 8.31 (d, J = 8.5 Hz,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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7
8
9
0
1
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8
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5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
1
H); C{ H}NMR of major isomer (125 MHz; DMSO d ; Me Si): δ 17.0, 20.6, 45.1, 55.9,
6
4
1
111.2, 111.9, 114.8, 118.1, 120.9, 124.4, 131.6, 132.4, 135.9, 148.6, 154.0, 157.4, 165.0; H
NMR of minor isomer (300 MHz; DMSO d ; Me Si): δ 2.32 (s, 3H), 3.77 (s, 3H), 5.09 (s, 1H),
6
4
7
.03 (d, J = 8.4 Hz, 2H), 7.70 (d, J = 8.1 Hz, 2H), 7.81 (d, J = 8.4 Hz, 2H), 8.26 (d, J = 8.1 Hz,
1
3
1
2H); C{ H}NMR of minor isomer (75 MHz; DMSO d ; Me Si): δ 14.2, 21.0, 44.5, 55.4, 109.3,
6
4
1
2
12.9, 114.2, 120.5, 123.4, 131.1, 131.7, 135.3, 147.7, 153.5, 156.9, 162.8; ; IR (KBr): 3081,
-1
956, 2842, 2252, 1723, 1602, 1516, 1342, 1247, 1178, 1025, 837, 737 cm , Anal. Calcd for
C H N O : C, 62.84; H, 3.77; N, 17.45. Found: C, 62.81; H, 3.79; N, 17.41.
21
15
5
4
2
-(4-Methoxyphenyl)-4-methyl-7-oxo-6-phenyl-5,6-diazaspiro[2.4]hept-4-ene-1,1-
9
b
dicarbonitrile (2l)
o
1
Off-white solid (Method A: 339 mg, 95%, Method B: 342 mg, 96%); Mp: 172-174 C; H NMR
of major isomer (300 MHz; CDCl ; Me Si): δ 1.90 (s, 3H), 3.87 (s, 3H), 3.93 (s, 1H), 7.01 (d, J
3
4
13
1
=
8.7 Hz, 2H), 7.28-7.33 (m, 3H), 7.45-7.50 (m, 2H), 7.98 (d, J = 7.8 Hz, 2H); C{ H}NMR of
major isomer (75 MHz; CDCl ; Me Si): δ 16.3, 18.5, 42.5, 44.5, 55.1, 109.2, 109.9, 114.7, 117.5,
3
4
1
18.4, 125.8, 128.8, 130.2, 137.0, 151.2, 160.5, 163.8; IR (KBr): 3001, 2967, 2252, 1711, 1596,
-1
1
501, 1450, 1366, 1328, 1115, 840, 752 cm ; Anal. Calcd for C H N O : C, 70.77; H, 4.53; N,
21 16 4 2
15.72. Found: C, 70.75; H, 4.51; N, 15.74.
6
-(4-Methoxyphenyl)-4-methyl-7-oxo-2-(thiophen-2-yl)-5,6-diazaspiro[2.4]hept-4-ene-1,1-
dicarbonitrile (2m)
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o
1
Yellow solid (Method A: 308 mg, 85%, Method B: 312 mg, 86%); Mp: 188-190 C; H NMR
(
300 MHz; DMSO d ; Me Si): δ 1.78 (s, 3H), 3.79 (s, 3H), 4.16 (s, 1H), 7.10 (d, J = 15.6 Hz,
6 4
13
1
3
3
H), 7.51 (1H), 7.73-7.78 (m, 3H); C{ H}NMR (75 MHz; DMSO d ; Me Si): δ 16.2, 20.9,
6 4
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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53
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59
60
8.2, 45.3, 55.4, 110.7, 111.5, 114.3, 120.4, 127.3, 129.2, 129.3, 130.7, 131.0, 151.5, 156.9,
164.4; IR (KBr): 2996, 2960, 2246, 1700, 1592, 1552, 1480, 1321, 1248, 1180, 1012, 856, 752
-1
cm ; Anal. Calcd for C H N O S: C, 62.97; H, 3.89; N, 15.46. Found: C, 62.94; H, 3.94; N,
19
14
4
2
1
5.42.
4-Methyl-2-(3-nitrophenyl)-7-oxo-6-phenyl-5,6-diazaspiro[2.4]hept-4-ene-1,1-dicarbonitrile
2n)
(
o
1
Off-white solid (Method A: 334 mg, 90%, Method B: 334 mg, 90%); Mp: 208-210 C; H NMR
of major isomer (300 MHz; DMSO d ; Me Si): δ 1.59 (s, 3H), 4.15 (s, 1H), 7.19 (s, 1H), 7.40-
6
4
7
7
.45 (m, 2H), 7.68-7.72 (m, 1H), 7.83 (d, J = 6.3 Hz, 2H), 8.08 (d, J = 6.6 Hz, 1H), 8.23 (d, J =
13
1
.8 Hz, 1H), 8.66 (s, 1H); C{ H}NMR of major isomer (75 MHz; DMSO d ; Me Si): δ 16.5,
6
4
20.4, 41.4, 44.9, 110.8, 111.5, 118.3, 124.4, 125.4, 125.5, 129.2, 130.3, 130.6, 137.0, 137.9,
1
48.0, 151.2, 165.1; IR (KBr): 3004, 2969, 2248, 1719, 1596, 1529, 1501, 1449, 1371, 1348,
-1
1
328, 1119, 835, 744 cm ; Anal. Calcd for C H N O : C, 64.69; H, 3.53; N, 18.86. Found: C,
20 13 5 3
64.66; H, 3.51; N, 18.90.
2
-(4-Chlorophenyl)-4-methyl-7-oxo-6-phenyl-5,6-diazaspiro[2.4]hept-4-ene-1,1-
dicarbonitrile (2o)
o
1
Off-white solid (Method A: 325 mg, 90%, Method B: 325 mg, 90%); Mp: 190-192 C; H NMR
of major isomer (300 MHz; CDCl ; Me Si): δ 1.81 (s, 3H), 3.85 (s, 1H), 7.19-7.42 (m, 7H), 7.87
3
4
13
1
(
d, J = 8.1 Hz, 2H); C{ H}NMR of major isomer (75 MHz; CDCl ; Me Si): δ 16.7, 18.6, 42.2,
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4.6, 109.3, 109.9, 118.8, 124.8, 126.2, 129.2, 129.9, 130.0, 130.7, 136.6, 137.2, 151.0, 163.8;
-1
IR (KBr): 2996, 2959, 2254, 1720, 1596, 1501, 1449, 1370, 1328, 1119, 835, 746, 708 cm ;
Anal. Calcd for C H ClN O: C, 66.58; H, 3.63; N, 15.53. Found: C, 66.56; H, 3.65; N, 15.50.
2
0
13
4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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7
8
9
0
1
2
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7
8
9
0
1
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6
7
8
9
0
1
2
3
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7
8
9
0
4
-Methyl-7-oxo-6-phenyl-2-(p-tolyl)-5,6-diazaspiro[2.4]hept-4-ene-1,1-dicarbonitrile (2p)
o
1
Off-white solid (Method A: 306 mg, 90%, Method B: 313 mg, 92%); Mp: 178-180 C; H NMR
of major isomer (300 MHz; CDCl ; Me Si): δ 1.79 (s, 3H), 2.33 (s, 3H), 3.86 (s, 1H), 7.20 (s,
3
4
13
1
5
H), 7.38 (t, J = 6.9 Hz, 2H), 7.89 (d, J = 7.2 Hz, 2H); C{ H}NMR of major isomer (75 MHz;
CDCl ; Me Si): δ 16.7, 18.7, 21.3, 43.0, 44.8, 109.6, 110.2, 118.8, 123.2, 126.1, 129.1, 130.3,
3
4
137.4, 140.5, 151.6, 164.1; IR (KBr): 3004, 2969, 2249, 1719, 1596, 1501, 1449, 1371, 1328,
-1
1
119, 835, 740 cm ; Anal. Calcd for C H N O: C, 74.10; H, 4.74; N, 16.46. Found: C, 74.06;
2
1
16
4
H, 4.78; N, 16.44.
Ethyl 1,1-dicyano-7-oxo-2,6-diphenyl-5,6-diazaspiro[2.4]hept-4-ene-4-carboxylate (2q)
o
1
Off-white solid (Method A: 338 mg, 88%, Method B: 346 mg, 90%); Mp: 160-162 C; H NMR
(300 MHz; CDCl ; Me Si): δ 1.48 (t, J = 7.05 Hz, 3H), 4.44-4.59 (m, 2H), 5.27 (s, 1H), 7.28-
3
4
13
1
7.50 (m, 8H), 7.91 (d, J = 8.1 Hz, 2H); C{ H}NMR (75 MHz; CDCl ; Me Si): δ 13.8, 21.8,
3
4
4
1
2.0, 42.8, 62.9, 107.4, 110.9, 119.4, 119.44, 119.5, 125.0, 126.9, 128.8, 128.9, 129.0, 129.03,
29.1, 129.5, 136.3, 141.0, 158.9, 161.9; IR (KBr): 3012, 2974, 2250, 1729, 1599, 1245, 1120,
-1
+
1016, 851, 740 cm ; HRMS (ESI-TOF) m/z Calcd for [C H N O +Na] : 407.1115, found:
2
2
16
4
3
4
07.1114.
Ethyl
1,1-dicyano-2-(4-nitrophenyl)-7-oxo-6-phenyl-5,6-diazaspiro[2.4]hept-4-ene-4-
carboxylate (2r)
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o
1
Off-white solid (Method A: 365 mg, 85%, Method B: 365 mg, 85%); Mp:194-496 C; H NMR
(
300 MHz; DMSO d ; Me Si): δ 1.36 (t, J = 7.1 Hz, 3H), 4.40 (t, J = 8.0 Hz, 2H), 5.23 (s, 1H),
6 4
7
8
.36 (t, J = 7.2 Hz, 1H), (t, J = 7.65 Hz, 2H), 7.76 (d, J = 7.8 Hz, 2H), 7.91 (d, J = 8.4 Hz, 2H),
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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31
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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
13
1
.26 (d, J = 8.4 Hz, 2H); C{ H}NMR (75 MHz; DMSO d ; Me Si): δ 14.0, 23.7, 43.3, 62.3,
6
4
109.3, 112.5, 119.9, 123.3, 126.8, 129.3, 132.0, 134.7, 137.1, 142.3, 147.7, 159.0, 163.5; IR
-1
(
KBr): 3017, 2984, 2251, 1729, 1599, 1519, 1349, 1245, 1120, 1016, 851, 740 cm ; Anal. Calcd
for C H N O : C, 61.54; H, 3.52; N, 16.31. Found: C, 61.52; H, 3.56; N, 16.28.
2
2
15
5
5
Ethyl 1,1-dicyano-6-(4-methoxyphenyl)-2-(4-nitrophenyl)-7-oxo-5,6-diazaspiro[2.4]hept-4-
ene-4-carboxylate (2s)
o
1
white solid (Method A: 404 mg, 88%, Method B: 422mg, 92%); Mp: 210-212 C; H NMR (300
MHz; CDCl ; Me Si): δ 1.41 (t, J = 7.05 Hz, 3H), 3.78 (s, 3H), 4.37-4.52 (m, 2H), 5.24 (s, 1H),
3
4
6
2
.92 (d, J = 7.8 Hz, 2H), 7.49 (d, J = 8.1 Hz, 2H), 7.77 (d, J = 9.3 Hz, 2H), 8.22 (d, J = 8.7 Hz,
13
1
H); C{ H}NMR (75 MHz; CDCl ; Me Si): δ 14.1, 21.9, 40.8, 42.8, 55.6, 63.3, 107.5, 110.7,
3
4
114.4, 114.5, 121.7, 124.2, 129.5, 130.6, 132.4, 140.5, 148.5, 158.8, 159.3, 161.9; IR (KBr):
-1
3
027, 2986, 2254, 1723, 1604, 1516, 1437, 1349, 1249, 1126, 1019, 834, 736 cm ; Anal. Calcd
for C H N O : C, 60.13; H, 3.73; N, 15.24. Found: C, 60.10; H, 3.76; N, 15.22.
2
3
17
5
6
Ethyl
1,1-dicyano-2-(4-cyanophenyl)-7-oxo-6-phenyl-5,6-diazaspiro[2.4]hept-4-ene-4-
carboxylate (2t)
white solid (Method A: 352 mg, 86%, Method B: 352 mg, 86%); Mp: 194-196 C; H NMR (300
MHz; DMSO d ; Me Si): δ 1.36 (t, J = 7.1 Hz, 3H), 4.34-4.47 (m, 2H), 5.20 (s, 1H), 7.36 (t, J =
o
1
6
4
7
.2 Hz, 1H), 7.54 (t, J = 7.8 Hz, 2H), 7.76 (d, J = 8.1 Hz, 2H), 7.82 (d, J = 8.1 Hz, 2H), 7.90 (d, J
13
1
=
8.1 Hz, 2H); C{ H}NMR (75 MHz; DMSO d ; Me Si): δ 14.0, 23.6, 43.2, 62.3, 109.3, 111.7,
6 4
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5
5
6
1
3
12.6, 118.6, 119.9, 126.8, 129.3, 131.4, 132.2, 132.8, 137.1, 142.2, 159.0, 163.5; IR (KBr):
-1
015, 2982, 2254, 2242, 1715, 1600, 1245, 1120, 1016, 851, 742cm ; Anal. Calcd for
C H N O : C, 67.48; H, 3.69; N, 17.11. Found: C, 67.44; H, 3.74; N, 17.08.
23
15
5
3
0
1
2
3
4
5
6
7
8
9
0
1
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0
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0
1
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7
8
9
0
Ethyl
1,1-dicyano-2-(3-nitrophenyl)-7-oxo-6-phenyl-5,6-diazaspiro[2.4]hept-4-ene-4-
carboxylate (2u)
o
1
white solid (Method A: 369 mg, 86%, Method B: 378 mg, 88%); Mp: 188-190 C; H NMR (300
MHz; DMSO d ; Me Si): δ 1.36 (t, J = 6.6 Hz, 3H), 4.35-4.43 (m, 2H), 5.21 (s, 1H), 7.36 (t, J =
6
4
7
.5 Hz, 1H), 7.54 (t, J = 7.4 Hz, 2H), 7.69-7.78 (m, 3H), 8.09 (d, J = 7.8 Hz, 1H), 8.26 (d, J = 8.1
1
3
1
Hz, 1H), 8.66 (s, 1H); C{ H}NMR (75 MHz; DMSO d ; Me Si): δ 14.0, 23.9, 43.3, 62.2,
6
4
1
1
09.4, 112.6, 119.8, 123.8, 125.6, 126.8, 129.4, 129.5, 129.9, 137.1, 137.3, 142.4, 147.6, 159.0,
-1
63.6; IR (KBr): 3012, 2974, 2252, 1729, 1599, 1525, 1345, 1245, 1120, 1016, 851, 740 cm ;
+
HRMS (ESI-TOF) m/z Calcd for [C H N O +Na] : 452.0965, found: 452.0979.
2
2
15
5
5
Ethyl
1,1-dicyano-7-oxo-6-phenyl-2-(thiophen-2-yl)-5,6-diazaspiro[2.4]hept-4-ene-4-
carboxylate (2v)
o
1
Yellow solid (Method A: 320 mg, 82%, Method B: 328 mg, 84%); Mp: 176-178 C; H NMR
(300 MHz; CDCl ; Me Si): δ 1.47 (t, J = 7.1 Hz, 3H), 4.46-4.59 (m, 2H), 5.34 (s, 1H), 7.11 (t, J
3 4
=
4.2 Hz, 1H), 7.35 (d, J = 7.5 Hz, 1H), 7.45-7.55 (m, 4H), 7.89 (d, J = 7.8 Hz, 2H);
1
3
1
C{ H}NMR (75 MHz; CDCl ; Me Si): δ 14.0, 22.9, 38.2, 43.3, 63.2, 107.7, 110.8, 119.9,
3
4
1
1
26.1, 127.3, 127.6, 128.4, 129.2, 130.5, 136.5, 140.8, 159.3, 162.0; IR (KBr): 3010, 2936, 2249,
-1
739, 1711, 1592, 1552, 1488, 1321, 1248, 1180, 1116, 1015, 856, 754 cm ; HRMS (ESI-TOF)
+
m/z Calcd for [C H N O S+H] : 391.0859, found: 391.0865.
2
0
14
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(
Z)-1-Methyl-4-oxo-3,8-diphenyl-6-(phenylimino)-7-thia-2,3-diazaspiro[4.4]non-1-ene-9,9-
dicarbonitrile (3g)
Off-white solid (425 mg, 92%); Mp: 194-196 C; H NMR (300 MHz; CDCl ; Me Si): δ 2.52 (s,
o
1
3
4
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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47
48
49
50
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52
53
54
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56
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58
59
60
3
H), 6.37 (s, 1H), 6.98 (d, J = 7.5 Hz, 2H), 7.16-7.42 (m, 9H), 7.59 (d, J = 4.8 Hz, 2H), 7.83 (d, J
13
1
=
7.8 Hz, 2H); C{ H}NMR (75 MHz; CDCl ; Me Si): δ 15.9, 29.3, 29.6, 31.9, 47.5, 54.2, 72.0,
3 4
1
1
09.8, 110.0, 119.8, 120.0, 126.6, 128.8, 129.0, 129.2, 129.4, 131.0, 136.5, 148.9, 154.0, 158.4,
-1
65.5; IR (KBr): 3032, 2976, 2249, 1732, 1629, 1591, 1489, 1304, 1193, 1107, 1010, 760 cm ;
+
HRMS (ESI-TOF) m/z Calcd for [C H N OS+H] : 462.1383, found: 462.1362.
2
7
19
5
(Z)-8-(4-Bromophenyl)-1-methyl-4-oxo-3-phenyl-6-(phenylimino)-7-thia-2,3-
diazaspiro[4.4]non-1-ene-9,9-dicarbonitrile (3i)
o
1
Off-white solid (465 mg, 86%); Mp: 264-266 C; H NMR (300 MHz; CDCl ; Me Si): δ 2.51 (s,
3
4
3H), 6.33 (s, 1H), 6.98 (d, J = 7.5 Hz, 2H), 6.99-7.55 (m, 10H), 7.82 (d, J = 8.1 Hz, 2H);
13
1
C{ H}NMR (75 MHz; CDCl ; Me Si): δ 15.9, 29.6, 30.2, 47.2, 53.6, 71.8, 109.6, 109.8, 119.8,
3
4
1
1
6
19.84, 119.9, 120.0, 125.6, 126.7, 126.8, 127.8, 129.1, 129.5, 130.7, 132.7, 136.5, 148.8, 153.9,
57.8, 165.3; IR (KBr): 3062, 2953, 2251, 1699, 1635, 1590, 1487, 1370, 1279, 1072, 998, 765,
-1
+
20 cm ; HRMS (ESI-TOF) m/z Calcd for [C H BrN OS+H] : 540.0488, found: 540.0488.
2
7
18
5
(Z)-8-(4-Chlorophenyl)-1-methyl-4-oxo-3-phenyl-6-(phenylimino)-7-thia-2,3-
diazaspiro[4.4]non-1-ene-9,9-dicarbonitrile (3o)
o
1
White solid (417 mg, 84%); Mp: 272-274 C; H NMR (300 MHz; CDCl ; Me Si): δ 2.53 (s,
3
4
3
H), 6.37 (s, 1H), 6.99 (d, J = 7.8 Hz, 2H), 7.16-7.42 (m, 8H), 7.55 (d, J = 8.4 Hz, 2H), 7.84 (d, J
1
3
1
= 8.1, 2H); C{ H}NMR (75 MHz; CDCl ; Me Si): δ 16.0, 47.3, 53.6, 71.9, 109.7, 109.9, 119.9,
3
4
1
20.0, 120.1, 126.7, 126.8, 127.4, 129.2, 129.3, 129.5, 129.53, 129.8, 130.6, 136.5, 137.4, 148.9,
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6
54.0, 157.9, 165.4; IR (KBr): 3030, 2966, 2253, 1730, 1627, 1590, 1486, 1302, 1200, 1110,
-1
008, 756, 705 cm ; Anal. Calcd for C H ClN OS: C, 65.38; H, 3.66; N, 14.12. Found: C,
27 18
5
5.36; H, 3.70; N, 14.08.
0
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8
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0
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0
(Z)-1-Methyl-4-oxo-3-phenyl-6-(phenylimino)-8-(p-tolyl)-7-thia-2,3-diazaspiro[4.4]non-1-
ene-9,9-dicarbonitrile (3p)
o
1
Off-white solid (456 mg, 96%); Mp: 222-224 C; H NMR (300 MHz; CDCl ; Me Si): δ 2.40 (d,
3
4
J = 4.5 Hz, 3H), 2.60 (d, J = 5.4 Hz, 3H), 6.43 (d, J = 4.5 Hz, 1H), 7.08 (d, J = 7.8Hz, 2H), 7.23-
1
3
1
7
.58 (m, 10H), 7.92 (d, J = 8.1 Hz, 2H); C{ H}NMR (75 MHz; CDCl ; Me Si): δ 15.7, 21.0,
3 4
47.3, 53.8, 71.7, 109.6, 109.8, 119.5, 119.8, 125.3, 126.3, 128.8, 129.1, 129.8, 129.84, 136.3,
1
1
7
41.1, 148.7, 153.8, 158.4, 165.2; IR (KBr): 3030, 2954, 2251, 1705, 1636, 1593, 1493, 1369,
-
1
277, 766, 691, 510 cm ; Anal. Calcd for C H N OS: C, 70.72; H, 4.45; N, 14.73. Found: C,
28 21
5
0.68; H, 4.50; N, 14.71.
Ethyl (Z)-9,9-dicyano-4-oxo-3,8-diphenyl-6-(phenylimino)-7-thia-2,3-diazaspiro[4.4]non-1-
ene-1-carboxylate (3q)
o
1
Off-white solid (468 mg, 90%); Mp: 182-184 C; H NMR (300 MHz; CDCl ; Me Si): δ 1.41 (t,
3
4
J = 7.2 Hz, 3H), 4.36-4.56 (m, 2H), 6.09 (s, 1H), 6.9675 6.98 (d, J = 8.0 Hz, 2H), 7.15-7.88 (m,
1
3
1
1
3H); C{ H}NMR (75 MHz; CDCl ; Me Si): δ 13.9, 48.0, 55.0, 62.9, 70.2, 109.4, 110.2,
3 4
119.4, 119.5, 119.8, 120.2, 120.6, 120.64, 120.7, 126.4, 127.7, 128.2, 129.0, 129.1, 129.2, 129.3,
1
1
5
31.0, 135.6, 145.9, 149.4, 157.5, 157.8, 166.8 ; IR (KBr): 3033, 2977, 1735, 1628, 1590, 1489,
-1
+
304, 1193, 1107, 1006, 760, 691 cm ; HRMS (ESI-TOF) m/z Calcd for [C H N O S+H] :
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5
3
20.1438, found: 520.1453.
1
-Methyl-4-oxo-3,6,8-triphenyl-2,3,7-triazaspiro[4.4]nona-1,6-diene-9,9-dicarbonitrile (4g)
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White solid (361 mg, 84%); Mp: 162-164 C; H NMR (300 MHz; CDCl ; Me Si): δ 2.22 (s,
3
4
1
3
1
3
5
1
H), 6.49 (s, 1H), 7.23-7.89 (m, 15H); C{ H}NMR (75 MHz; CDCl ; Me Si): δ 16.9, 29.7,
3 4
0.3, 75.1, 79.7, 110.6, 111.5, 119.6, 126.8, 127.1, 127.12, 127.2, 127.3, 127.4, 127.43, 129.1,
29.2, 129.23, 129.3, 129.5, 129.54, 130.0, 130.3, 130.5, 132.9, 134.1, 136.7, 137.5, 155.1,
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165.5, 166.0; IR (KBr): 3069, 2923, 2854, 2249, 1715, 1595, 1494, 1363, 1291, 1267, 1118, 757,
-1
+
6
89 cm ; HRMS (ESI-TOF) m/z Calcd for [C H N O+H] : 430.1662, found: 430.1642.
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-(4-Bromophenyl)-1-methyl-4-oxo-3,6-diphenyl-2,3,7-triazaspiro[4.4]nona-1,6-diene-9,9-
dicarbonitrile (4i)
o
1
Off-white solid (417 mg, 82%); Mp: 170-172 C; H NMR (300 MHz; CDCl ; Me Si): δ 2.23 (s,
3
4
3
H), 6.44 (s, 1H), 7.26 (t, J = 7.5 Hz, 1H), 7.36-7.62 (m, 11H), 7.87 (d, J = 8.1 Hz, 2H);
1
3
1
C{ H}NMR (75 MHz; CDCl ; Me Si): δ 16.6, 49.7, 74.7, 78.6, 110.2, 110.9, 119.3, 119.4,
3
4
1
24.1, 126.6, 126.8, 128.7, 129.0, 129.2, 129.23, 130.0, 132.2, 132.8, 136.3, 154.7, 165.0, 166.2;
-1
IR (KBr): 3066, 2926, 2255, 1719, 1628, 1595, 1491, 1368, 1296, 1270, 1124, 1070, 763 cm ;
+
HRMS (ESI-TOF) m/z Calcd for [C H BrN O+H] : 508.0767, found: 508.0780.
2
7
18
5
8
-(4-Methoxyphenyl)-1-methyl-4-oxo-3,6-diphenyl-2,3,7-triazaspiro[4.4]nona-1,6-diene-9,9-
dicarbonitrile (4k)
o
1
White solid (395 mg, 86%); Mp: 158-160 C; H NMR (300 MHz; CDCl ; Me Si): δ 2.33 (s,
3
4
3H), 3.90 (s, 3H), 6.56 (s, 1H), 7.08 (d, J = 8.4 Hz, 2H), 7.36 (t, J = 7.2 Hz, 1H), 7.45-7.67 (m,
13
1
9
7
1
H), 7.99 (d, J = 8.4 Hz, 2H); C{ H}NMR (75 MHz; CDCl ; Me Si): δ 16.6, 50.2, 55.0, 74.7,
3 4
9.3, 110.5, 111.2, 114.3, 1193, 125.6, 126.4, 126.6, 126.8, 128.4, 128.42, 129.0, 129.1, 129.3,
30.2, 132.5, 136.4, 154.8, 160.5, 165.2, 165.4; IR (KBr): 3070, 2929, 2836, 2254, 1713, 1630,
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602, 1504, 1368, 1299, 1247, 1173, 1123, 1029, 831, 765 cm ; HRMS (ESI-TOF) m/z Calcd
+
for [C H N O +Na] : 482.1587, found: 482.1564.
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1-Methyl-4-oxo-3,6-diphenyl-8-(p-tolyl)-2,3,7-triazaspiro[4.4]nona-1,6-diene-9,9-
dicarbonitrile (4p)
0
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2
3
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7
8
9
0
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2
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7
8
9
0
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9
0
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8
9
0
1
2
3
4
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7
8
9
0
o
1
White solid (372 mg, 84%); Mp: 168-170 C; H NMR (300 MHz; CDCl ; Me Si): δ 2.33 (s,
3
4
1
3
1
3H), 2.46 (s, 3H), 6.57 (s, 1H), 7.33-7.67 (m, 12H), 7.99 (d, J = 8.4 Hz, 2H); C{ H}NMR (75
MHz; CDCl ; Me Si): δ 16.6, 21.1, 50.1, 74.7, 79.4, 110.4, 111.2, 119.3, 119.4, 126.4, 126.7,
3
4
1
26.8, 126.9, 128.9, 129.0, 129.1, 129.13, 129.5, 129.6, 130.2, 130.7, 132.5, 136.3, 139.7, 154.9,
165.2, 165.5; IR (KBr): 3060, 2921, 2254, 1717, 1625, 1596, 1496, 1368, 1297, 1270, 1122,
-1
1
4
035, 767 cm ; Anal. Calcd for C H N O: C, 75.83; H, 4.77; N, 15.79. Found: C, 75.80; H,
2
8
21
5
.74; N, 15.82.
Ethyl 9,9-dicyano-4-oxo-3,6,8-triphenyl-2,3,7-triazaspiro[4.4]nona-1,6-diene-1-carboxylate
4q)
(
o
1
Off-white solid (390 mg, 80%); Mp: 160-162 C; H NMR (300 MHz; CDCl ; Me Si): δ 1.31-
3
4
1.37 (m, 3H), 4.29-4.47 (m, 2H), 6.67 (d, J = 3.3 Hz, 1H), 7.29-7.55 (m, 13H), 7.85 (d, J = 8.1
13
1
Hz, 2H); C{ H}NMR (75 MHz; CDCl ; Me Si): δ 20.1, 56.5, 69.6, 78.2, 90.8, 114.5, 118.4,
3
4
1
26.2, 126.3, 133.6, 133.64, 133.7, 133.9, 135.3, 135.6, 136.2, 136.5, 138.9, 140.7, 142.2, 151.1,
165.1, 169.4, 172.1; IR (KBr): 3010, 2950, 2252, 1725, 1714, 1624, 1594, 1500, 1365, 1300,
-1
1
268, 1130, 1122, 1030, 760 cm ; Anal. Calcd for C H N O : C, 71.45; H, 4.34; N, 14.37.
2
9
21
5
3
Found: C, 71.42; H, 4.36; N, 14.35.
Acknowledgement
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We acknowledge the financial support from the center of CAS-V (Synthesis and functional
materials) (support offered by UGC, New Delhi) of the department of Chemistry, University of
Calcutta. P. M. thanks U.G.C. New Delhi, India for the grant of his Senior Research Fellowship.
Crystallography was performed at the DST-FIST, India-funded Single Crystal Diffractometer
Facility at the Department of Chemistry, University of Calcutta.
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Supporting Information
Supporting Information: Optimization of the reaction conditions and stereochemical course of
the intramolecular cyclopropanation reaction, X-ray crystallography data of compounds 2q, 3g
1
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and 4q and H and C NMR spectra of all compounds (file type pdf) and X-ray crystallography
data of compound 2q, 3g and 4q (file type cif).
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15 See Table S1 in Supporting Information for the optimization of reaction conditions.
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6 The anti-relationship between the carbethoxy group and R was established through X-ray
analysis data of 2q, see Figure S1 in Supporting Information.
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7 See Scheme S1 in Supporting Information for the stereochemical course of the intramolecular
cyclopropanation reaction.
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8 Ethyl-2-cyano-3-arylacrylate, instead of the desired spirocyclopropane, was obtained when –
CN was replaced by the –CO Et in the starting aminopyrans. This may be due to the decrease in
2
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