Amine-promoted one-pot, Multicomponent route to spiro-fused-pyran derivatives in aqueous media

Article abstract of DOI:10.1002/hlca.201300387

The primary amine-promoted synthesis of spiro-fused-pyran derivatives via the three-component reaction of ninhydrin, malononitrile, and cyclic 1,3-diketo compounds is described. This new methodology affords the title compounds in high yields and short time, and with easy workup without chromatographic purification steps or extraction. All structures were confirmed by IR, ¹H- and ¹³C-NMR spectroscopy, and mass spectroscopy. A plausible mechanism for this type of reaction is proposed (Scheme 2). Copyright

Full text of DOI:10.1002/hlca.201300387

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Helvetica Chimica Acta – Vol. 97 (2014)
Amine-Promoted One-Pot, Multicomponent Route to Spiro-Fused-Pyran
Derivatives in Aqueous Media
by Abdolali Alizadeh*, Atieh Rezvanian, and Fahimeh Bayat
Department of Chemistry, Tarbiat Modares University, P.O. Box 14115-175, Tehran, Iran
(
phone: þ 98-21-88006631; fax: þ 98-21-88006544; e-mail: abdol alizad@yahoo.com,
aalizadeh@Modares.ac.ir)
The primary amine-promoted synthesis of spiro-fused-pyran derivatives via the three-component
reaction of ninhydrin, malononitrile, and cyclic 1,3-diketo compounds is described. This new method-
ology affords the title compounds in high yields and short time, and with easy workup without
1
13
chromatographic purification steps or extraction. All structures were confirmed by IR, H- and C-NMR
spectroscopy, and mass spectroscopy. A plausible mechanism for this type of reaction is proposed
(
Scheme 2).
1. Introduction. – The routine procedure for the synthesis of pyrans is the
condensation reaction of aldehydes with b-dicarbonyl compounds and alkyl malonates
via a three-component reaction. Various catalytic systems such as (hexadecyl)(trime-
thyl)ammonium bromide (HMTAB) [1], (benzyl)(triethyl)ammonium chloride
(
TEBA) [2], rare-earth perfluorooctanoate (RE(PFO) ) [3], (S)-proline [4], amino-
3
functionalized ionic liquids [5], MgO, SiO nanoparticles [6], and silica-bonded propyl-
2
4-aza-1-azoniabicyclo[2.2.2]octane chloride (SB-DABCO) [7] have been used for the
synthesis of pyrans so far. However, most of these methods suffer from several
drawbacks such as low yields, long reaction times, harsh reaction conditions, tedious
workup, tiresome steps for the preparation of catalyst, application of toxic and
expensive catalysts, application of hazardous solvents for the workup, and lack of
general applicabilitiy. Therefore, the development of an efficient and more practical
procedure for the synthesis of pyrans is of considerable interest.
With this background, and also in the context of our investigations aimed to develop
syntheses of biologically important fused polycyclic heterocycles via multicomponent
reactions [8], herein, we report an efficient method for the synthesis of polyfunction-
alized spiro-fused-pyran derivatives 3 via the three-component condensation of
ninhydrin (¼2,2-dihydroxy-2H-indene-1,3-dione), malononitrile, and cyclic 1,3-diketo
compounds 1 in the presence of aliphatic primary amines 2 as organopromoter
(
Scheme 1).
2
. Results and Discussion. – Recently, our research group reported the synthesis of a
novel series of polysubstituted aza[3.3.3]propellanes from the reaction of ninhydrin,
malononitrile, primary amines, and dialkyl acetylenedicarboxylate or alkyl acetoace-
tate [9]. We also have investigated synthesis of oxa-thia-aza[3.3.3]propellanes by
ꢀ
2014 Verlag Helvetica Chimica Acta AG, Zꢁrich

Helvetica Chimica Acta – Vol. 97 (2014)
533
Scheme 1. Synthesis of Spiro-Fused Pyrans via an Amine-Promoted Three-Component Reaction
treatment of ninhydrin, malononitrile, primary amines, and aryl isothiocyanates [10].
However, both of the mentioned syntheses were performed via one-pot multicompo-
nent reactions (MCRs).
In connection with these studies, we became interested to know how a Knoevenagel
adduct generated in situ from ninhydrin and malononitrile could be trapped by an
enamine ꢂderived from the various aliphatic primary amines and cyclic 1,3-diketo
compoundsꢃ to give a heterocyclic product.
Therefore, we investigated the reaction of ninhydrin, malononitrile, cyclic 1,3-
diketo compounds 1, and an aliphatic primary amine 2 in aqueous EtOH at room
temperature. It was interesting to note that neither propellanes [9] nor spiro-
compounds [10] were detected at all, while spiro-fused-pyrans 3 were obtained in good
yields (Scheme 1).
Initially, we explored the reaction of ninhydrin with malononitrile at room
temperature in the presence of Et N (0.1 mmol) that afforded the expected
3
Knoevenagel adduct intermediate. Next, the sequential one-pot addition of cyclic 1,3-
diketo compound 1 in the presence of aliphatic primary amine 2 as organocatalyst in
EtOH at room temperature successfully gave the spiro-fused pyran derivatives 3 in 62 –
84% yields. It was found that the reaction using an equimolar amount of primary amine
(
such as EtNH , PrNH , or BuNH ) resulted in a higher yield (Table) and shorter time.
2
2
2
When this reaction was carried out without a promoter, product 3 was not formed.
The molecular structures of all products 3a – 3d were elucidated from their mass
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13
spectrometric analyses, and IR, and H- and C-NMR spectra as described for 3a. The
mass spectrum of 3a displayed the molecular-ion peak at m/z 320, which is in
agreement with the proposed structure. In the IR spectrum of 3a, two absorption bands
ꢀ
1
at 3380 and 3271, a sharp band at 2194, and two absorption bands at 1732 and 1666 cm ,
corresponding to NH , CN, C¼O, and NC¼C stretching frequencies, respectively,
2
1
clearly indicated the most significant functional groups of the product. The H-NMR
spectrum of 3a exhibited three broad signals and one sharp singlet at d(H) 1.94, 2.27,
2
.70, and 7.64, respectively, attributed to CH and NH groups. Four aromatic H-atoms
2 2
gave rise to characteristic signals in the aromatic region of the spectrum. Observation of
1
13
1
4 distinct signals in the H-decoupled C-NMR spectrum of 3a was in agreement with
the proposed structure. In the aliphatic region, there were five characteristic signals at
d(C) 19.7, 26.3, 39.0, 52.0, 53.4, corresponding to CH , CCN, and Cspiro. Resonances due
2
to C¼CC and CN appeared at d(C) 110.9 and 116.7, respectively.
We could not establish an exact mechanism for the formation of 3, however, a
plausible way to it is shown in Scheme 2. It is assumed that product 3 results from the

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Helvetica Chimica Acta – Vol. 97 (2014)
Table. Spiro-Fused-Pyran Derivatives 3 Prepared by a Three-Component Reaction
Cyclic 1,3-diketone 1
Product 3
Yield [%]
1
a
3a
81
1
1
b
c
3b
3c
86
82
1
b
3d
75
initial formation of 4 by standard Knoevenagel condensation of ninhydrin and
malononitrile. Subsequent Michael-type addition of the enamine 5 (formed in situ by
reaction of cyclic 1,3-diketo compounds 1 and primary amine 2) to 4 yields intermediate
6
, which is transformed to intermediate 7, by a formal 1,3-H shift. Finally,
intermolecular nucleophilic substitution of H O on 7, followed by cyclization and
2
tautomerization, affords the corresponding product 3. To support the proposed
mechanism, first, the Knoevenagel adduct 4 was synthesized via condensation of
ninhydrin and malononitrile, and then reaction of 4 with cyclic 1,3-diketo compounds 1
in the presence of primary amine 2 afforded the corresponding product 3 in 75 – 86%
yield (Table).
In summary, we have developed a primary amine-driven three-component
condensation reaction using ninhydrin, malononitrile, and cyclic 1,3-diketo compounds
that affords corresponding spiro-fused-pyran derivatives. The facile and convenient
reaction conditions, the inexpensive reagents, and avoiding expensive transition metal
catalysts when compared to existing procedures render this reaction the method of
choice for the preparation of substituted spiro-fused-pyran derivatives for both the
economic and the environmental reasons.
Financial support of this work from Tarbiat Modares University, Iran is gratefully acknowledged.

Helvetica Chimica Acta – Vol. 97 (2014)
535
Scheme 2. Mechanism Proposed for the Synthesis of 3
Experimental Part
General. The primary amines, cyclic 1,3-diketo compounds, ninhydrin, and malononitrile, were
obtained from Merck (Germany) and Fluka (Switzerland), and were used without further purification.
ꢀ1
1
IR Spectra: KBr pellets, NICOLET FT-IR 100 spectrometer; ˜n cm . H- (400 and 500 MHz) and
13
C-NMR (100 and 125 MHz): Bruker DRX-400 AVANCE and Bruker DRX-500 AVANCE spectro-
meters. MS: FINNIGAN-MAT 8430 mass spectrometer; at an ionization potential of 70 eV. Elemental
analyses for C, H, and N: Heraeus CHNꢀOꢀRapid analyzer.
General Procedure (exemplified for 3a). A soln. of ninhydrin (0.16 g, 1 mmol), malononitrile (0.66 g,
1
mmol), and Et N (0.01 g, 0.1 mmol) in EtOH (3 ml) was stirred for 1 h, then treated with a soln. of
3
cyclohexane-1,3-dione 1a (0.112 g, 1 mmol) and BuNH (0.073 g, 1 mmol) in EtOH (1 ml). The mixture
2
was stirred at r.t. for 7 h. After completion of the reaction (TLC (AcOEt/hexane 1:2)), the mixture was
filtered, and the precipitate was washed with EtOH (5 ml) to afford pure 3a. All products gave
satisfactory spectroscopic data in accordance with the assigned structures.
2-Amino-1’,3’,5,6,7,8-hexahydro-1’,3’,5-trioxospiro[chromene-4,2’-indene]-3-carbonitrile (3a). Yield:
0
1
8
1
.27 g (81%). Yellow powder. M.p. 180 – 1828 (dec.). IR: 3380 and 3271 (NH ), 2194 (CN), 1732 (C¼O),
2
1
666 (NC¼C). H-NMR: 1.94 (br. s, 2 H); 2.27 (br. s, 2 H); 2.70 (br. s, 2 H); 7.64 (s, 2 H); 7.99 (br. s, 2 H);
13
.02 (br. s, 2 H). C-NMR: 19.7; 26.3; 35.2; 50.0; 53.1; 110.9; 116.7; 123.0; 136.53; 140.5; 159.7; 168.2;
þ
96.0; 199.6. EI-MS (70 eV): 338 (1, M ), 280 (100), 232 (4), 159 (3), 133 (1), 85 (2), 57 (4). Anal. calc.
for C H N O (320.30): C 67.50, H 3.78, N 8.75; found C 67.54, H 3.76, N 8.73.
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2
4

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Helvetica Chimica Acta – Vol. 97 (2014)
2-Amino-1’,3’,5,6,7,8-hexahydro-7,7-dimethyl-1’,3’,5-trioxospiro[chromene-4,2’-indene]-3-carbonitrile
(
1
(
3b). Yield: 0.30 g (86%). Yellow powder. M.p. 300 – 3028 (dec.). IR: 3378 and 3313 (NH ), 2192 (CN),
2
1
716 (C¼O), 1661 (NC¼C). H-NMR: 1.04 (s, 6 H); 2.20 (s, 2 H); 2.63 (s, 2 H); 7.68 (s, 2 H); 7.68 – 8.06
13
m, 4 H). C-NMR: 27.1; 32.4; 48.9; 54.1; 53.1; 110.0; 116.9; 123.1; 136.6; 140.5; 159.8; 166.5; 196.0; 199.6.
þ
EI-MS (70 eV): 348 (77, M ), 264 (87), 236 (41), 104 (39), 83 (100), 69 (46), 55 (81). Anal. calc. for
C H N O (348.35): C 68.96, H 4.63, N 8.04; found C 68.89, H 4.60, N 8.15.
20
16
2
4
2
-Amino-1’,3’,6,7-tetrahydro-1’,3’,5-trioxo-5H-spiro[cyclopenta[b]pyran-4,2’-indene]-3-carbonitrile
(
1
4
3c). Yield: 0.25 g (82%). Yellow powder. M.p. 294 – 2968 (dec.). IR: 3362 and 3300 (NH ), 2198 (CN),
2
1
715 (C¼O), 1675 (NC¼C). H-NMR: 2.51 (br. s, 2 H); 2.92 (br. s, 2 H); 7.92 (s, 2 H); 8.10 – 8.11 (m,
13
H). C-NMR: 25.4; 32.8; 50.8; 52.3; 113.4; 117.0; 123.5; 137.4; 140.8; 161.5; 179.5; 198.7; 200.3. EI-MS
þ
(
70 eV): 306 (71, M ), 194 (43), 139 (40), 104 (39), 76 (100), 50 (49). Anal. calc. for C H N O (306.27):
17
10
2
4
C 66.67, H 3.29, N 9.15; found C 66.65, H 3.31, N 9.16.
7
’-Amino-1,1’,2’,3,3’,4’-hexahydro-1’,3’-dimethyl-1,2’,3,4’-tetraoxospiro[indene-2,5’-pyrano[2,3-d]pyr-
imidine]-6’-carbonitrile (3d). Yield: 0.27 g (75%). Yellow powder. M.p. 247 – 2498 (dec.). IR: 3385 and
1
3
4
301 (NH ), 2197 (CN), 1706 (C¼O). H-NMR: 3.01 (s, 3 H); 3.38 (s, 3 H); 8.01 (s, 2 H); 8.07 – 8.06 (m,
2
13
H). C-NMR: 27.7; 29.4; 54.1; 53.1; 116.3; 123.2; 130.1; 136.9; 140.4; 149.5; 153.0; 159.4; 167.4; 199.7.
EI-MS (70 eV): 364 (2, M ), 264 (3), 208 (22), 152 (34), 104 (42), 83 (68), 57 (100). Anal. calc. for
þ
C H N O (364.31): C 59.34, H 3.32, N 15.38; found C 60.10, H 3.25, N 16.11.
18
12
4
5
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Received October 31, 2013