One-pot synthesis of substituted 4H-chromenes by nickel ferrite nanoparticles as an efficient and magnetically reusable catalyst

Article abstract of DOI:10.3906/kim-1710-14

Nickel ferrite magnetic nanoparticles (NiFe 2 O 4 MNPs) were prepared via the autocombustion assisted sol-gel method. The efficient catalyst was investigated by FT-IR, XRD, ICP, SEM, and TEM techniques. A one-pot, three-component reaction is reported for

Full text of DOI:10.3906/kim-1710-14

Turk J Chem
Turkish Journal of Chemistry
(2018) 42: 719 – 734
¨
http://journals.tubitak.gov.tr/chem/
˙
c
⃝ TUBITAK
doi:10.3906/kim-1710-14
Research Article
One-pot synthesis of substituted 4H -chromenes by nickel ferrite nanoparticles as
an efficient and magnetically reusable catalyst
2
2
Hamideh AHANKAR1, Ali RAMAZANI1,∗, Katarzyna SLEPOKURA , Tadeusz LIS ,
´
Sang Woo JOO3
1Department of Chemistry, University of Zanjan, Zanjan, Iran
2Faculty of Chemistry, University of Wroc law, Wroc law, Poland
3School of Mechanical Engineering, Yeungnam University, Gyeongsan, Republic of Korea
Received: 09.10.2017
•
Accepted/Published Online: 05.02.2018
•
Final Version: 01.06.2018
Abstract: Nickel ferrite magnetic nanoparticles (NiFe2 O4 MNPs) were prepared via the autocombustion assisted sol-
gel method. The efficient catalyst was investigated by FT-IR, XRD, ICP, SEM, and TEM techniques. A one-pot,
three-component reaction is reported for the synthesis of substituted 4H -chromenes in the presence of NiFe2 O4 MNPs
as a reusable catalyst in a green solvent at 40 ◦ C under clean, efficient, and mild conditions. Furthermore, selected
products were characterized by FT-IR, 1 H NMR, and 13 C NMR. The single-crystal X-ray analysis of product 4u
was also conclusively confirmed. Easy workup procedure, high purity of products via simple recrystallization, and
environmentally benign conditions are the outstanding benefits of this method.
Key words: Nickel ferrite, magnetic nanoparticles, multicomponent reactions, 4H -chromenes, green methodology
1. Introduction
In recent decades, multicomponent reactions (MCRs) have been frequently used by synthetic chemists as an
effective method to generate molecular diversity because of the high variability in reaction components and
conditions. Moreover, these reactions have gained remarkable interest for chemists as an appropriate, atom-
economical, and time-saving procedure for the synthesis of various compounds with interesting properties.1−3
In recent years, many trends have emerged for the application of types of nanoparticles due to their potential
features in various fields of modern organic synthesis and especially in MCRs.4,5 These types of reactions in the
presence of magnetic nanoparticles (MNPs) have many advantages such as high yield, short reaction times, low
cost, selectivity, clean reaction profiles, and ecofriendly and environmentally benign conditions in comparison to
the various strategies of the classical chemistry.6−8 MNPs, and especially different ferrite MNPs with interesting
properties as recoverable and reusable catalysts, are widely used in a variety of MCRs. The separation of MNPs
with external magnets is one of the most promising strategies in organic synthesis.9,10 Spinel-type bimetal
oxides such as NiFe2 O4 MNPs show great potential in the catalysis field, although they have so far been less
investigated.11,12
Benzopyran is a class of heterocyclic organic compounds called chromene according to IUPAC nomen-
clature. Some structural scaffolds such as chromane, 2H−chromene, and 4H−chromene contain a benzopyran
∗Correspondence: aliramazani@znu.ac.ir
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nucleus (Figure 1).13 Chromenes are an important class of compounds found in many pharmaceuticals and
active natural products.
Figure 1. Different structural scaffolds containing a benzopyran nucleus.
Vitamin E (1) as a fat-soluble antioxidant14 and cromakalim (2), a potassium channel-opening vasodilator
as an antihypertensive agent, are substances that include chromane moiety (Figure 2).15
Figure 2. Selected drugs with chromane moiety.
Natural products with chromene moiety are rather unusual and only a few examples containing this
structure have been isolated (Figure 3). Uvafzelin (3) was separated from the stems of Uvaria afzelii and presents
a broad spectrum of antimicrobial activity versus gram-positive and acid-fast bacteria like Mycobacterium
tuberculosis.16 Erysenegalensein C (4), isolated from the bark of Erythrina senegalensis, found potential use
in the treatment of gonorrhea, female infertility, and stomach pain.17 Meanwhile, 7-hydroxy-6-methoxy-4H -
chromene (5) was obtained from the flowers of Wisteria sinensis and shows organoleptic features.18 Another
natural compound, conrauinone A (6), was isolated from the bark of the tree Millettia conraui and used for the
treatment of intestinal parasites.19
Substituted chromenes are known as interesting heterocyclic compounds with attractive biological and
pharmacological activities including antioxidant,14 antitumor,20 anti-HIV,21 antiinflammatory,22 antimicrobial
and antifungal,23 anticoagulant,24 and diuretic activities.25 Some drugs have chromene skeletons for the
treatment of neurodegenerative diseases like Parkinson and Alzheimer disease or Down syndrome.26 In addition,
compounds with chromene moiety are often utilized in the fields of biodegradable agrochemicals, cosmetics,
and pigments.13,27 Because of the significance of substituted chromenes, diverse synthetic methods have been
reported,28−37 but there are fewer references about the use of MNPs for synthesis of these compounds.38−40
Synthesis of heterocyclic compounds containing 4H -chromene skeletons has gained importance in organic
synthesis because of their significant activities. Their various applications and high consumption, the small
amounts of these compounds in natural resources, and, most importantly, the difficulty of their extraction have
caused chemists to try synthesizing 4H -chromene derivatives. It should be noted that using various ferrite
nanoparticles as green catalysts in MCRs is part of our ongoing program. In this study, we report a new
method for the synthesis of substituted 4H -chromenes in the presence of nickel ferrite nanoparticles (NiFe2 O4
MNPs) in a green solvent at 40 ◦ C (Scheme 1).
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Figure 3. Selected natural products with chromene moiety.
Scheme 1. Synthesis of substituted 4H -chromenes.
2. Results and discussion
2.1. Characterization of catalyst
First, the structure of the NiFe2 O4 MNPs was checked by Fourier transform infrared (FT-IR) spectroscopy. As
shown in Figure 4, a broad absorption band above 3400 cm−1 is the stretching mode of H2 O molecules. Two
principal absorption bands are observed in the range of 400–600 cm−1 . Two absorption bands are observed at
587 and 458 cm−1 that demonstrate the longer and shorter bond length of oxygen metal ions in the octahedral
and tetrahedral sites in the spinel structure, respectively. The atomic ratio of Ni/Fe was about 0.59, which is
attributed to NiFe2 O4 and 27.61% of its weight inclusive of nickel element according to ICP analysis.
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AHANKAR et al./Turk J Chem
Figure 4. FT-IR spectrum of NiFe2 O4 MNPs.
The strong diffraction peaks at the Bragg angles at 2θ of 30.45, 35.76, 37.30, 43.43, 53.84, 57.34, and
63.01 correspond to the (220), (311), (222), (400), (422), (511), and (440) facets of elemental nickel and iron,
respectively, in X-ray diffraction (XRD) analysis (Figure 5). The average diameter was estimated to be about
59.7 nm by the Debye–Scherrer equation. It became clear that the structure of NiFe2 O4 MNPs is a cubic spinel
(JCPDS: 01-074-2081).
Figure 5. XRD pattern of NiFe2 O4 MNPs.
In addition, the monotonous spherical morphology of the NiFe2 O4 MNPs can be seen in the scanning
electron microscopy (SEM) images. Measurements show that the mean size of the nanoparticles is 58.8 nm
(Figure 6).
Furthermore, transmission electron microscopy (TEM) images show that NiFe2 O4 MNPs have spherical
morphology and the average particles size is 46 nm (Figure 7).
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AHANKAR et al./Turk J Chem
Figure 6. SEM images (a and b) of NiFe2 O4 MNPs.
Figure 7. TEM images (a and b) of NiFe2 O4 MNPs with magnification of 63,000×.
2.2. Application of NiFe2 O4 MNPs in the synthesis of substituted 4H -chromenes
In order to find the optimal experimental conditions in this work, various conditions like reaction temperature,
solvent, and catalyst were investigated in a convenient and easy method for synthesis of substituted 4H -
chromenes. In primary research on the synthesis of compound 4a from the reaction of 4-chlorobenzaldehyde,
dimedone, and malononitrile in a suitable solvent by a magnetically reusable catalyst as a model reaction, it
was found that the reaction did not proceed well at room temperature and a higher temperature was required.
First, we optimized the effect of temperature through some experiments. To find the optimum temperature,
synthesis of compound 4a as a model of reaction was carried out at room temperature (20 ◦ C) and 30, 40,
50, and 60 ◦ C in ethanol solvent in the presence of NiFe2 O4 MNPs (the results are shown in Table 1). The
reaction yield was 48% after 60 min at room temperature (Table 1, entry 1), whereas yield of 95% was obtained
at 40 ◦ C after 30 min (Table 1, entry 3).
Then, to find the best solvent, different solvents such as H2 O, H2 O-C2 H5 OH, C2 H5 OH, CH3 OH,
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AHANKAR et al./Turk J Chem
Table 1. The effect of temperature on the synthesis of substituted 4H -chromenes.
Entry Temperature (◦C) Time (min) Yield (%)a
1
2
3
4
5
20 (r.t.)
60
30
30
30
30
48
62
95
95
97
30
40
50
60
Reaction conditions: 4-chlorobenzaldehyde 1a (1 mmol), dimedone 2 (1 mmol), malononitrile 3 (1 mmol), and 11.7 mg
of NiFe2 O4 MNPs (5% mol) in ethanol and at various temperatures.
a : Isolated yield.
CH3 CN, and CH2 Cl2 were examined in the synthesis of 4a as a model compound. The best result was
obtained in ethanol, which occurred with 95% yield in 30 min at 40 ◦ C (Table 2, entry 3). Other solvents were
tested at the same time and temperature (Table 2, entries 1, 2, and 4–6), but the yield of the reaction was
highest in ethanol. We thus selected ethanol as a green solvent for all our further reactions.
Table 2. The effect of the solvents on the synthesis of substituted 4H -chromenes.
Entry Solvent
Temperature (◦C) Time (min) Yield (%)a
1
2
3
4
5
6
H2O
40
30
30
30
30
30
30
76
80
95
78
75
73
H2O–C2H5OH 40
C2H5OH
CH3OH
CH3CN
CH2Cl2
40
40
40
40
Reaction conditions: 4-chlorobenzaldehyde 1a (1 mmol), dimedone 2 (1 mmol), malononitrile 3 (1 mmol), and 11.7 mg
of NiFe2 O4 MNPs (5% mol) in various solvents at 40 ◦ C.
a : Isolated yield.
Afterwards, the amount of the required catalyst was investigated in the model reaction mentioned above
for synthesis of compound 4a, as shown in Table 3 (entries 2–4). A yield of 38% for the desired reaction
without catalyst was obtained after 30 min. No significant increase in yield was observed increasing the amount
of catalyst by 2.5% mol. When 11.7 mg of NiFe2 O4 MNPs (5% mol) was used, the maximum target product
was produced.
After obtaining favorable results from the optimization of temperature, solvent, and catalyst amount,
various aromatic aldehydes carrying electron-withdrawing and electron-donating groups on the aromatic ring in
the ortho, meta, and para positions and heterocyclic, aliphatic, and unsaturated aldehydes were investigated.
Yields of all the reactions were excellent. It was found that the aldehydes with electron-withdrawing groups re-
acted faster and better than the aldehydes with electron-donating groups (Table 4). The corresponding product
4 could not be generated when we used formaldehyde, glyoxal, acetaldehyde, isobutyraldehyde, salicylalde-
hyde, 5-bromosalicylaldehyde, and 2-hydroxy-1-naphthaldehyde under the reaction conditions, and in all cases,
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AHANKAR et al./Turk J Chem
Table 3. The effect of catalyst amount on the synthesis of substituted 4H -chromenes.
Entry Catalyst (% mol) Time (min) Yield (%)a
1
2
3
4
None
2.5
5
30
30
30
30
38
66
95
93
7.5
Reaction conditions: 4-chlorobenzaldehyde 1a (1 mmol), dimedone 2 (1 mmol), and malononitrile 3 (1 mmol), in ethanol
solvent and various amounts of catalyst at 40 ◦ C .
a : Isolated yield.
a mixture of several products and starting materials was observed based on thin-layer chromatography (TLC)
investigation.
The proposed mechanism for the synthesis of substituted 4H -chromenes is shown in Scheme 2. First a
Knoevenagel reaction in the presence of NiFe2 O4 MNPs, then Michael addition, and finally an intramolecular
cyclization of the intermediate cause the target products.
Scheme 2. The proposed mechanism for the synthesis of substituted 4H -chromenes.
Ultimately, the reusability of the reaction catalyst was examined. After the magnetic separation of
NiFe2 O4 MNPs from the reaction mixture, the catalyst was rinsed with acetone and dried to eliminate any
remaining acetone and reused again. NiFe2 O4 MNPs were reused at least six times without serious reduction
in their capability (Figure 8).
The structures of the selected products were confirmed by 1 H NMR, 13 C NMR, and FT-IR spectroscopy.
Melting points of products 4a–4y were also measured. Finally, single-crystal X-ray analysis of 4u conclusively
confirmed its structure (Figure 9).
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Table 4. Synthesis of substituted 4H -chromenes via a three-component reaction.
Time
(min)
Yield
(%)a
Entry Aldehyde
Product
Mp (°C)
MpRef (°C)
215–21632
1
30
95
214–216
4a
4b
2
3
35
30
92
91
237–239
215–218
235–23733
214–21534
4c
4d
4e
205–20730
40
88
214–217
4
5
30
86
209–211
210–21132
6
7
25
40
90
88
181–183
213–215
180–18234
4f
214–21629
4g
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Table 4. Continued.
Time Yield
Entry Aldehyde
Product
Mp (°C)
231–233
MpRef (°C)
(min) (%)a
8
25
85
233–23432
4h
234–23532
230–23240
214–21533
204–20629
9
35
30
50
50
90
92
87
89
235–237
248–252
210–212
206–208
4i
10
11
12
4j
4k
4l
217–21832
13
45
90
216–218
4m
201–20232
14
91
60
201–203
4n
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Table 4. Continued.
Time
(min)
Yield
(%)a
Entry Aldehyde
Product
Mp (°C)
225–227
MpRef (°C)
222–22429
15
60
60
87
4o
239–242
224–226
180–182
211–21235
90
89
83
16
17
4p
45
226–22832
4q
18
19
20
35
50
4r
4s
226–22834
85
82
228–230
179–182
55
45
178–18035
4t
223–225
225–22631
21
85
4u
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Table 4. Continued.
Time Yield
(min) (%)a
Entry Aldehyde
Product
Mp (°C)
216–218
MpRef (°C)
214–21636
35
88
22
4v
184–186
180–18229
23
70
87
4w
185–18839
24
65
84
187–189
4x
203–20534
25
70
88
204–206
4y
Reaction conditions: aldehyde 1a–1y (1 mmol), dimedone 2 (1 mmol), malononitrile 3 (1 mmol), and 11.7 mg of
NiFe2 O4 MNPs (5% mol) in ethanol solvent at 40 ◦ C.
a : Isolated yield.
2.3. Conclusions
In this study, the application of an inexpensive, ecofriendly, magnetically recoverable, and reusable catalyst
provides an efficient and suitable method for the synthesis of substituted 4H -chromenes in recent synthetic
methodologies. The present procedure has many advantages such as the use of a green solvent and nanocatalyst,
operational simplicity, easy workup of products, nonchromatographic purification technique, environmentally
benign conditions, short reaction time, and high yields.
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Figure 8. Reusability of NiFe2 O4 MNPs for the synthesis of compound 4a.
Figure 9. (a) Two crystallographically independent molecules of 4u present in the asymmetric unit of its crystal,
showing the partial atom-numbering scheme and the symmetry-independent hydrogen bonds (dashed lines). The R
enantiomers are shown (inverted model for molecule A has been used). Displacement ellipsoids are drawn at the 50%
probability level. (b) Comparison of the conformations of both molecules. H atoms are omitted for clarity. The common
reference points are chromene atoms.
3. Experimental
3.1. General comments
All chemical materials were purchased from Sigma-Aldrich (USA), Merck (Germany), Fluka (Switzerland), or
Daejung (Korea) and were applied without any further purification. The structure of NiFe2 O4 MNPs was
analyzed by XRD with an X’Pert-PRO advanced diffractometer using Cu(Kα) radiation (wavelength: 1.5406
◦
A), operated at 40 kV and 40 mA in the range of 2θ from 20 to 70◦ at room temperature. The morphology
and particle size of the nanoparticles were evaluated by SEM (KYKY Co., Model EM 3200, China). The disk
was covered with gold in an ionization chamber. TEM was analyzed using a Zeiss-EM10C TEM instrument
with accelerating voltage of 80 kV.
˚
All of the reactions were monitored by TLC with UV light. FT-IR spectrophotometer spectra were
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AHANKAR et al./Turk J Chem
obtained on a Jasco 6300 FT-IR spectrometer. Melting points of products were measured by an Electrothermal
9100 apparatus (Labequip Ltd., Markham, Canada) and are uncorrected. 1 H and 13 C NMR (DMSO-d6)
spectra were recorded on a Bruker DRX-250 Avance spectrometer at 250.13 and 62.90 MHz, respectively.
3.2. Procedure for the preparation of NiFe2 O4 MNPs
NiFe2 O4 was synthesized via the autocombustion assisted sol-gel method from Fe(III) and Ni(II) ions (molar
ratio 2:1) in ammonia solution. In summary, iron(III) nitrate nonahydrate (2 mmol), nickel(II) nitrate hexahy-
drate (1 mmol), and citric acid as a chelating agent (3 mmol) were dissolved in deionized water. The pH value
of the solution was controlled at 7 by adding ammonia solution (25%) dropwise to the reaction mixture under
fixed stirring. The solution was heated on a water bath at 60 ◦ C until the formation of a gummy gel and then
the temperature was increased to 80 ◦ C to produce a stiff gel. Subsequently, the temperature of the prepared
gel was increased to ca. 200 ◦ C for autocombustion. With the exhaust of gases like CO2 , H2 O, and N2 a dark
brown powder was obtained. The ferrite powder was rinsed with deionized water and acetone several times and
separated with a strong external magnet.
3.3. General procedure for the synthesis of substituted 4H -chromenes (4a–4y)
A solution of aldehyde 1a–1y (1 mmol), dimedone 2 (1 mmol), malononitrile 3 (1 mmol), and ethanol (4 mL)
was magnetically stirred at room temperature. To the mixture, NiFe2 O4 MNPs (5 mol%) were added and
the content was heated at 40 ◦ C for the appropriate time. The progress of the reaction was checked by TLC
(n-hexane:EtOAc, 10:6). After completion, the resulting product was heated in ethanol. The catalyst was
magnetically removed from the mixture and washed several times with ethanol for reuse. The pure product was
collected from the filtrate after cooling to room temperature with an ice bath and then was recrystallized from
hot ethanol.
3.3.1. Representative procedure for synthesis of 4a
A solution of 4-chlorobenzaldehyde (141 mg, 1 mmol), dimedone (140 mg, 1 mmol), malononitrile (66 mg, 1
mmol), and ethanol (2 mL) was magnetically stirred at room temperature. To the mixture, NiFe2 O4 MNPs (5
mol%) were added and the content was heated at 40 ◦ C for the appropriate time. The progress of the reaction
was checked by TLC (n-hexane:EtOAc, 10:6). After completion, the resulting product was heated in ethanol.
The catalyst was magnetically removed from the mixture and washed several times with acetone for reuse. The
pure product was collected from the filtrate after cooling to room temperature with an ice bath. The pure
product was obtained by recrystallization from hot ethanol.
3.3.2. Spectral data of the selected products
3.3.2.1. 2-Amino-4-(4-chlorophenyl)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3- car-
bonitrile (4a)
White crystal; yield 95%; mp 214–216 ◦ C. IR (KBr): νmax 3390, 3321, 3188, 2940, 2891, 2192, 1683, 1714
cm−1 1 H NMR (DMSO-d6 , 250.13 MHz): δH 0.91 (s, 3H, CH3), 1.00 (s, 3H, CH3), 2.34 (d, J = 16.01 Hz,
.
1H, CH2), 2.07 (d, J = 16.01 Hz, 1H, CH2), 2.23 (s, 2H, CH2), 4.16 (s, 1H, CH), 7.03 (s, 2H, NH2), 7.13
(d, J = 7.00 Hz, 2H, arom.), 7.33 (d, J = 7.00 Hz, 2H, arom.) ppm. 13 C NMR (DMSO-d6, 62.90 MHz):
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AHANKAR et al./Turk J Chem
δC 27.28, 28.76, 31.11, 32.23, 35.56, 50.37, 58.21, 112.78, 120.02, 128.75, 129.58, 131.60, 144.19, 158.95, 163.08,
196.15 ppm.
3.3.2.2. 2-Amino-4-(4-isopropylphenyl)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-
carbonitrile (4l)
White solid; yield 89%; mp 206–208 ◦ C. IR (KBr): νmax 3390, 3325, 3213, 2963, 2872, 2189, 1682, 1603, 1365
cm−1
.
1 H NMR (DMSO-d6 , 250.13 MHz): δH 0.95 (s, 3H, CH3), 1.02 (s, 3H, CH3), 1.14 (d, 3H, CH3),
1.17 (d, 3H, CH3), 2.09 (d, J = 16.01 Hz, 1H, CH2), 2.37 (d, J = 16.26 Hz, 1H, CH2), 2.50 (s, 2H, CH2),
2.96 (hpt, 1H, CH(CH3)2), 4.12 (s, 1H, CH), 6.94 (s, 2H, NH2), 7.03 (d, J = 7.75 Hz, 2H, arom.), 7.14 (d, J
= 8.00 Hz, 2H, arom.) ppm. 13 C NMR (DMSO-d6, 62.90 MHz): δC 24.34, 27.36, 28.81, 32.25, 33.44, 35.58,
50.46, 59.00, 113.29, 120.25, 126.69, 127.43, 142.61, 146.95, 158.91, 162.90, 196.12 ppm.
3.3.2.3. 2-Amino-7,7-dimethyl-4-(4-(methylthio)phenyl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-
3-car- bonitrile (4p)
White crystal; yield 90%; mp 239–242 ◦ C; IR (KBr): νmax 3355, 3257, 3188, 2963, 2192, 1683, 1652, 1369
cm−1 1 H NMR (DMSO-d6 , 250.13 MHz): δH 0.94 (s, 3H, CH3), 1.01 (s, 3H, CH3), 2.08 (d, J = 15.25 Hz,
.
1H, CH2), 2.23 (d, J = 14.26 Hz, 1H, CH2), 2.42 (s, 2H, CH2), 2.48 (s, 3H, SCH3), 4.14 (s, 1H, CH), 6.98
(s, 2H, NH2), 7.15 (d,J = 7.25 Hz, 2H, arom.), 7.09 (d,J = 7.00 Hz, 2H, arom.) ppm. 13 C NMR (DMSO-d6,
62.90 MHz): δC 15.19, 27.27, 28.84, 32.22, 35.58, 50.44, 58.66, 113.09, 120.13, 126.43, 128.29, 136.55, 141.98,
144.19, 158.91, 162.84, 196.08 ppm.
3.3.2.4. 2-Amino-7,7-dimethyl-4-(5-nitrofuran-2-yl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-car-
bonitrile (4r)
Yield 83%; pale yellow solid; mp 180–183 ◦ C. IR (KBr): νmax 3406, 3335, 3221, 2964, 2199, 1686, 1490, 1350
cm−1 1 H NMR (DMSO-d6 , 250.13 MHz): δH 1.00 (s, 3H, CH3), 1.04 (s, 3H, CH3), 2.17 (d, J = 16.01 Hz,
.
1H, CH2), 2.32 (d, J = 16.01 Hz, 1H, CH2), 2.46 (d, J = 17.51 Hz, 1H, CH2), 2.58 (d, J = 17.51 Hz, 1H,
CH2), 4.51 (s, 1H, CH), 6.63 (d, J = 6.5 Hz, 1H, arom.), 7.31 (s, NH2), 7.61 (1H, d, J = 6.75 Hz, 2H, arom.)
ppm. 13 C NMR (DMSO-d6, 62.90 MHz): δC 26.75, 28.87, 30.28, 32.33, 50.17, 54.02, 109.02, 110.52, 114.92,
119.33, 150.92, 159.65, 160.62, 164.56, 196.04. 3406, 3335, 3221, 2964, 2199, 1686, 1490, 1350 ppm .
3.3.2.5. 2-Amino-7,7-dimethyl-5-oxo-4-(pyridin-3-yl)-5,6,7,8-tetrahydro-4H-chromene-3-carbonit-
rile (4u)
Yield 85%; white crystal; 223–225 ◦ C; IR (KBr): νmax 3315, 3181, 2961, 2184, 1682, 1652, 1373 cm−1
.
1 H
NMR (DMSO-d6 , 250.13 MHz): δ 0.93 (s, 3H, CH3), 1.02 (s, 3H, CH3), 2.10 (d, J = 16.01 Hz, 1H, CH2),
2.24 (d, J = 16.26 Hz, 1H, CH2), 2.54 (s, 2H, CH2), 4.23 (s, 1H, CH), 7.09 (s, 2H, NH2), 7.31 (d, J = 7.75
Hz, 1H, arom.), 7.52 (d, J = 7.75 Hz, 1H, arom.), 8.38 (d, 2H, arom.) ppm. 13 C NMR (DMSO-d6, 62.90
MHz): δC 27.37, 28.66, 32.27, 33.84, 40.12, 50.36, 57.80, 112.26, 119.91, 124.08, 135.17, 128.75, 140.46, 148.29,
149.13, 159.04, 163.40, 196.16 ppm.
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3.3.3. X-ray crystallography
After recrystallization of compound 4u, the pure solid was dissolved in hot ethanol. By X-ray, proper crystals
of 4u appeared after slow evaporation of its solvent at room temperature.
The crystallographic measurement of 4u was performed on an Xcalibur R κ-geometry automated four-
circle diffractometer equipped with a Ruby CCD camera and graphite-monochromated Mo Kα radiation (λ =
˚
0.71073 A). The data were collected at 80(2) K using an Oxford Cryosystems cooler. Data were corrected for
Lorentz and polarization effects. Data collection, cell refinement, data reduction and analysis, and empirical
absorption correction were carried out with Xcalibur R software and CrysAlisPro.41 The structure was solved
by direct methods with SHELXS9742 and refined by a full-matrix least-squares technique with SHELXL201643
with anisotropic thermal parameters for non-H atoms. All H atoms were found in different Fourier maps and were
refined isotopically. In the final refinement cycles, the C-bonded H atoms were repositioned in their calculated
˚
positions and refined using a riding model, with C–H = 0.95–1.00 A and with Uiso (H) = 1.2Ueq (C) for CH
and CH2 or 1.5Ueq (C) for CH3 . Amine H atoms were refined freely. The figure was made with the DIAMOND
program.44 The crystallographic information file (CIF) was deposited with the Cambridge Crystallographic
Data Centre (http://www.ccdc.cam.ac.uk/; deposition number CCDC 1511770) and provided as ESI.
Crystal data for 4u: C17 H17 N3 O2 , Mr = 341.33, colorless block, crystal size 0.48 × 0.32 × 0.13
◦
¯
˚
mm, triclinic, space group P1 (No. 2), a = 8.623(2), b = 13.632(4), c = 14.824(4) A, α = 114.65(3) , β
◦
◦
3
= 94.60(3) , γ = 99.80(3) , V = 1538.2(8) A , T = 80(2) K, Z = 4, µ = 0.09 mm−1 , 12,458 reflections
˚
measured, 8255 unique (Rint = 0.020), 6420 observed (I > 2σ(I)), (sin θ/λ)max 0.720 A−1 , 413 parameters,
˚
0 restraints, R = 0.047, wR = 0.103 (observed refl.), GOOF =S = 1.03, (∆ρmax) = 0.38 and (∆ρmin) = –0.24
−3
˚
e A
.
Acknowledgment
This work was funded by grant NRF-2015-002423 of the National Research Foundation of Korea.
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