The clean and mild synthesis, crystal structure, and intra-molecular hydrogen bond study of substituted new 4,8-dihydropyrano[3,2-b]-pyrans containing chlorokojic acid moiety

Article abstract of DOI:10.1007/s11164-019-03848-7

A safe, green and convenient process was developed for the synthesis of a novel group of 4,8-dihydropyrano[3,2-b]-pyrans by dialkyl acetylenedicarboxylates and alkyl isocyanides being trapped by chlorokojic acid in good to excellent yields at ambient temperature. Characterization of all structures was carried out by FT-IR and ¹H and ¹³C NMR spectrometers, and two compounds were analyzed using X-ray diffraction technique. Crystal structures showed an intramolecular hydrogen bond and stacking of the dimeric (RS) molecules with the unit cell along the a-axis.

Full text of DOI:10.1007/s11164-019-03848-7

Research on Chemical Intermediates
https://doi.org/10.1007/s11164-019-03848-7
The clean and mild synthesis, crystal structure,
and intra‑molecular hydrogen bond study of substituted
new 4,8‑dihydropyrano[3,2‑b]‑pyrans containing
chlorokojic acid moiety
Khadijeh Ojaghi Aghbash · Nader Noroozi Pesyan · Ghasem Marandi1 ·
1
1
2
3
Necmi Dege · Ertan Şahin
Received: 10 March 2019 / Accepted: 28 April 2019
Springer Nature B.V. 2019
©
Abstract
A safe, green and convenient process was developed for the synthesis of a novel
group of 4,8-dihydropyrano[3,2-b]-pyrans by dialkyl acetylenedicarboxylates and
alkyl isocyanides being trapped by chlorokojic acid in good to excellent yields at
ambient temperature. Characterization of all structures was carried out by FT-IR and
1
13
H and C NMR spectrometers, and two compounds were analyzed using X-ray dif-
fraction technique. Crystal structures showed an intramolecular hydrogen bond and
stacking of the dimeric (RS) molecules with the unit cell along the a-axis.
Keywords Chlorokojic acid · Isocyanides · Acetylene esters · Nucleophilic
addition · 4H-Pyran · 4,8-Dihydropyrano[3,2-b]-pyran · Intramolecular H bond ·
Inversion dimers
Introduction
4
-Pyrones, heterocyclic multifunctional six-membered compounds, are widely used
in active biological and pharmaceutical [1] compounds (natural and synthetic) [2–5].
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s1116
4
-019-03848-7) contains supplementary material, which is available to authorized users.
*
Nader Noroozi Pesyan
n.noroozi@urmia.ac.ir; nnp403@gmail.com
1
2
Department of Organic Chemistry, Faculty of Chemistry, Urmia University, Urmia 57159, Iran
Department of Physics, Faculty of Art and Sciences, Ondokuz Mayıs University, 55139 Samsun,
Turkey
3
Department of Chemistry, Faculty of Science, Atatürk University, 25240 Erzurum, Turkey
Vol.:(012
1
3456789)
3

K. Ojaghi Aghbash et al.
5-OH-(2-hydroxymethyl)-4-pyrone (an organic acid) is commercially known as
Kojic acid (KA). KA is a secondary fungal metabolite, commonly generated biolog-
ically from various substrates (glucose, saccharose, starch, etc.) in aerobic fermen-
tation by several types of microorganisms (species of bacterium and fungi, such as
Acetobacter, Penicillium, and Aspergillus [6, 7]. KA and its derivatives have some
economic uses in various ꢀelds such as oily food, cosmetics, pharmaceutical prod-
ucts, and chemical industries [8, 9]. KA derivatives are a remarkable series of struc-
tural moieties of many products (synthetic and natural) and are used as anti-fun-
gal [10], anti-melanogenic [11], anti-bacterial [10], tyrosinase inhibitory [12, 13],
anti-inꢁammatory [14], antibiotic [15], anti-neoplastic [16], anti-diabetic [17], anti-
microbial [18], antiviral [16], anti-proliferative [19], whitening [20], depigmenting
[
21], antioxidant [22], and anticonvulsant compounds [19].
2
-Chloromethyl-5-OH-4H-pyran-4-one (Cl-KA) is produced using chlorina-
tion of KA. Chlorokojic acid (chloro-KA) and other halogenated derivatives of KA
exhibit signiꢀcant antifungal, antimicrobial, antibacterial, antiviral, and anticonvul-
sant activities [16, 18, 23–28].
Pyranopyrans indicate proper fatigue resistance, as well as excellent colorability,
which are utilized for the preparation of resources in the ꢁuorescence modulation,
ꢀ
lter, and display as novel photochromic dyes [29].
Recently, the synthesis of various KA derivatives is of current attention. Litera-
ture study indicated that KA is a derivative of 4-pyrons, generated via a regioselec-
tive three-component reaction (TCR) with acetylenic esters and isocyanide or triph-
enylphosphine [30] as OH acid, by which O- or C-vinylated derivatives of KA are
derived. The various derivatives of fused pyrans have been produced using several
methods [31, 32].
In continuation of our works to synthesize heterocyclic scaꢂolds by one-pot reac-
tions [33–35] and according to the above-cited facts, in the outline of this study, the
aim is to improve a novel class of heterocyclic systems that contain various biologi-
cal groups such as chloro-KA and pyranopyrans moieties in a single compound with
hope to develop biologically active systems and provide a way to discover drugs.
Thus, in this research, TCR of chloro-KA with acetylenic esters was studied in the
presence of isocyanide in ethanol as a clean solvent at ambient temperature to obtain
the corresponding functionalized fused pyrano[3,2-b]-pyrans.
Experimental
Melting points were measured using an Electro-thermal device (numerical melting
point set) and were uncorrected. The Fourier transform infrared (FT-IR) spectra of
the prepared products were documented on a NEXUS 670 FT-IR spectrometer in the
−
1
area 400–4000 cm using KBr pellets (Urmia University, Urmia, Iran). The carbon
1
3
1
1
3 ( C) and proton ( H) nuclear magnetic resonance (NMR) spectra were deter-
mined at 75 and 300 MHz on a Bruker 300 FT NMR spectrometer (Urmia Uni-
versity, Urmia, Iran). X-ray diꢂraction (XRD) data were analyzed on a two-circle
STOE imaging plate diꢂraction system (IPDS 2) diꢂractometer (Atatürk University,
Erzurum, Turkey). For more information, see the crystallographic data section.
1
3

The clean and mild synthesis, crystal structure, and…
2
‑(Chloromethyl)‑5‑hydroxy‑4H‑pyran‑4‑one (2, C H ClO )
6 5 3
KA (7 mmol, 1.0 g) in thionyl chloride (14 mmol, 1.67 ml) was dissolved and stirred
at ambient temperature for 1 h. Next, the resulting precipitate was washed several
times with petroleum ether and dried. Recrystallization of the rudimentary prod-
uct was done with acetonitrile to give chloro-KA 2 [36] as yellow solid, with 1.2 g
(
90%) of yield. M.p.: 161–163 °C; FT-IR (KBr): υ=3236, 2963, 1665 (pyrone-CO),
−
1
1
616, 1452, 1371, 1222, 1163, 1120, 952, 889, 740 cm .
Typical procedure for the synthesis of a variety of dialkyl 2‑(alkylamino)‑6‑(chloro
methyl)‑8‑oxo‑4,8‑dihydropyrano[3,2‑b]pyran‑3,4‑dicarboxylates (3a–4f)
To a stirred solution of chloro-KA (0.5 mmol) and dialkyl acetylenedicarboxy-
late (0.5 mmol) in ethanol (5 ml), isocyanide (0.55 mmol) was added dropwise at
ambient temperature for up 10 min and stirred for 12 h [controlled in ethyl acetate
(
1/V):n-hexane (2/V) by thin-layer chromatography (TLC)]. After the end of the
reaction, the solvent was evaporated. The rudimentary product was washed several
times with diethyl ether and, ꢀnally, pure product was obtained by recrystallization
from ethanol.
Spectral data
Dimethyl
2‑(tert‑butylamino)‑6‑(chloromethyl)‑8‑oxo‑4,8‑dihydropyrano[3,2‑b]
pyran‑3,4‑dicarboxylate (3a, C H ClNO ) Yellow solid; yield 0.38 g (98%);
17
20
7
m.p.: 128–130 °C; FT-IR (KBr): ν=3449 (–NH), 3256, 3179, 3083, 2958, 1744
(
ester-CO), 1672 (pyrone-CO), 1607, 1447, 1366, 1311, 1209, 1106, 1055, 993,
−1
1
t
8
73, 779 cm ; H NMR (CDCl , 300 MHz): δ=1.48 (s, 9H, but-CH ), 3.705,
3 3
3
.749 (s, 6H, –OCH ), 4.33 (s, 2H, –CH Cl), 4.65 (s, 1H, chiral–CH–), 6.49 (s, 1H,
3
2
1
H-pyrone) and 8.73 (s, 1H, –NH) ppm; H NMR (CDCl +D O, 300 MHz): δ=1.48
3
2
t
(
s, 9H, but-CH ), 3.703, 3.746 (s, 6H, –OCH ), 4.33 (s, 2H, –CH Cl), 4.65 (s, 1H,
3
3
2
1
3
chiral–CH–), 6.49 (s, 1H, H-pyrone) and 8.72 (s, 1H, –NH) ppm; C NMR (CDCl ,
3
t
t
7
1
1
5 MHz): δ=29.0 ( but-CH ), 40.7 (C- but), 53.3 (–CH Cl), 70.6 (–OCH ), 114.3,
3 2 3
16.7, 127.3, 138.0, 147.5, 160.0, 161.3, 168.9 (ester-CO), 169.8 (pyrone-CO),
70.5 (ester-CO) ppm.
Diethyl 2‑(tert‑butylamino)‑6‑(chloromethyl)‑8‑oxo‑4,8‑dihydropyrano[3,2
b]pyran‑3,4‑dicarboxylate (3b, C H ClNO ) Yellow solid; yield 0.4 g (96%);
‑
1
9
24
7
m.p.: 104–106 °C; FT-IR (KBr): ν=3256 (–NH), 3166, 3078, 2980, 1737 (ester-
−
1
CO), 1668 (pyrone-CO), 1612, 1438, 1371, 1303, 1207, 1104, 1046, 880, 787 cm ;
1
t
H NMR (CDCl , 300 MHz): δ=1.22–1.29 (m, 6H, Et-CH ), 1.47 (s, 9H, but-CH ),
3
3
3
4
.05–4.25 (m, 4H, –OCH –), 4.31 (s, 2H, –CH Cl), 4.63 (s, 1H, chiral–CH–), 6.47
2 2
1
3
(
s, 1H, H-pyrone) and 8.72 (s, 1H, –NH) ppm; C NMR (CDCl , 75 MHz): δ=14.1
3
1
3

K. Ojaghi Aghbash et al.
t
t
(
Et-CH ), 30.2 ( but-CH ), 40.7 (C- but), 53.2 (–CH Cl), 70.7 (–OCH –), 114.2,
3
3
2
2
1
16.6, 138.0, 147.6, 159.8, 161.2, 168.5 (ester-CO), 169.8 (pyrone-CO), 170.2
(
ester-CO) ppm.
Dimethyl
6‑(chloromethyl)‑2‑(cyclohexylamino)‑8‑oxo‑4,8‑dihydropyran
o[3,2‑b]pyran‑3,4‑dicarboxylate (3c, C H ClNO ) Cream solid; yield 0.4 g
19
22
7
(
97%); m.p.: 123–125 °C; FT-IR (KBr): ν=3417 (–NH), 3253, 3109, 3056, 2930,
2
1
5
2
–
853, 1720 (ester-CO), 1660 (pyrone-CO), 1595, 1436, 1360, 1279, 1239, 1195,
−
1 1
173, 1050, 946, 894, 739 cm ; H NMR (CDCl , 300 MHz): δ=1.20–1.34 (m,
3
H, cyclohexyl–CH –), 1.51–1.55 (m, 3H, cyclohexyl–CH –), 1.64–1.68 (m,
2
2
H, cyclohexyl–CH –), 2.94–2.99 (m, 1H, cyclohexyl–CH–), 3.81, 3.89 (s, 6H,
2
OCH ), 4.35 (s, 2H, –CH Cl), 6.51 (s, 1H, chiral–CH–), 7.09 (s, 1H, H-pyrone)
3
2
1
and 8.46 (s, 1H, –NH) ppm; H NMR (CDCl +D O, 300 MHz): δ=1.20–1.37 (m,
3
2
5
H, cyclohexyl–CH –), 1.50–1.54 (m, 3H, cyclohexyl–CH –), 1.64–1.70 (m, 2H,
2
2
cyclohexyl–CH –), 2.96–2.98 (m, 1H, cyclohexyl–CH–), 3.81, 3.89 (s, 6H, –OCH ),
2
3
4
.35 (s, 2H, –CH Cl), 6.52 (s, 1H, chiral–CH–), 7.08 (s, 1H, H-pyrone) and 8.46
2
1
3
(
s, 1H, –NH) ppm; C NMR (CDCl , 75 MHz): δ=23.5, 32.8, 40.9, 52.4, 54.1 (–
3
CH Cl), 59.5 (–OCH ), 115.4, 133.0, 136.3, 142.4, 147.7, 150.3, 161.2, 163.7, 169.9
2
3
(
pyrone-CO), 172.9 (ester-CO) ppm.
Diethyl 6‑(chloromethyl)‑2‑(cyclohexylamino)‑8‑oxo‑4,8‑dihydropyrano[3,2
‑
b]pyran‑3,4‑dicarboxylate (3d, C H ClNO ) Yellow solid; yield 0.42 g (95%);
21
26
7
m.p.: 91–93 °C; FT-IR (KBr): ν=3453 (–NH), 3245, 3160, 3079, 2978, 2931, 2854,
1
1
740 (ester-CO), 1666 (pyrone-CO), 1606, 1450, 1367, 1304, 1270, 1210, 1178,
−
1 1
104, 1054, 1025, 932, 881, 795 cm ; H NMR (CDCl , 300 MHz): δ=1.24–1.47
3
(
(
m, 10H, cyclohexyl–CH –, –CH ), 1.57–1.71 (m, 4H, cyclohexyl–CH –), 1.93–2.00
2
3
2
m, 2H, cyclohexyl–CH –), 3.90–3.93 (m, 1H, cyclohexyl–CH–), 4.13–4.23 (s, 4H,
2
–
OCH –), 4.32 (s, 2H, –CH Cl), 4.64 (s, 1H, chiral–CH–), 6.48 (s, 1H, H-pyrone)
2 2
1
3
and 8.64 (s, 1H, –NH) ppm; C NMR (CDCl , 75 MHz): δ=15.5, 24.2, 40.7, 50.7,
3
5
1
9.6 (–CH Cl), 61.8, 70.1 (–OCH ), 114.9, 138.0, 147.8, 149.9, 158.5, 161.2, 168.4,
2 3
69.9 (pyrone-CO), 170.3 (ester-CO) ppm.
Dimethyl 6‑(chloromethyl)‑2‑((2,6‑dimethylphenyl)amino)‑8‑oxo‑4,8‑dihydr
opyrano[3,2‑b]pyran‑3,4‑dicarboxylate (3e, C H ClNO ) Orange solid; yield
21
20
7
0
2
1
3
.37 g (85%); m.p.: 61–63 °C; FT-IR (KBr): ν=3445 (–NH), 3090, 3008, 2956,
925, 2853, 1741 (ester-CO), 1661 (pyrone-CO), 1441, 1361, 1265, 1207, 1172,
−
1 1
025, 864, 795 cm ; H NMR (CDCl , 300 MHz): δ=1.23 (s, 6H, –CH ), 3.67–
3
2
3
.71 (m, 6H, –OCH ), 4.35 (s, 2H, –CH Cl), 5.33 (s, 1H, chiral–CH–), 6.27 (s, 1H,
3
Ph-H), 6.45 (s, 1H, H-pyrone), 6.58 (s, 1H, Ph-H), 7.98–8.01 (m, 2H, Ph-H and –
1
3
NH) ppm; C NMR (CDCl , 75 MHz): δ=40.5, 52.3, 54.1 (–CH Cl), 115.3, 142.6,
3
2
1
45.5, 146.0, 147.3, 150.1, 156.7, 162.2, 165.0, 171.4 (pyrone-CO), 172.9 (ester-
CO) ppm.
1
3

The clean and mild synthesis, crystal structure, and…
Scheme 1 The reaction of chloro-KA 2 with dialkyl acetylenedicarboxylate and isocyanide to form 3
Table 1 The yield of reaction
Compound no.
Yield (%)
for the formation of 3
3
3
3
3
3
3
a
b
c
d
e
f
98
96
97
95
85
80
Diethyl 6‑(chloromethyl)‑2‑((2,6‑dimethylphenyl)amino)‑8‑oxo‑4,8‑dihydro
pyrano[3,2‑b]pyran‑3,4‑dicarboxylate (3f, C H ClNO ) Orange liquid; yield
23
24
7
0
.37 g (80%); FT-IR (KBr): ν=3443(–NH), 2985, 2940, 1740 (ester-CO), 1657
−
1
1
(
pyrone-CO), 1443, 1374, 1209, 1093, 1023, 861, 784 cm ; H NMR (CDCl ,
3
3
–
00 MHz): δ=1.19–1.34 (m, 12H, –CH ), 3.68–3.91 (m, 4H, –OCH –), 5.19 (s, 2H,
3 2
CH Cl), 5.43 (s, 1H, chiral–CH–), 6.41 (s, 1H, Ph-H), 6.56 (s, 1H, H-pyrone), 6.92
2
1
3
(
s, 1H, Ph-H), 7.87–7.89 (m, 2H, Ph-H and –NH) ppm; C NMR (CDCl , 75 MHz):
3
δ=12.8, 14.1, 53.6 (–CH Cl), 62.1 (–OCH –), 103.1, 105.1, 109.3, 131.9, 140.0,
2
2
1
45.8, 154.9, 157.4, 164.3, 169.3 (pyrone-CO), 172.5 (ester-CO) ppm.
Results and discussion
At the start, chloro-KA (2) was formed from the reaction of SOCl (thionyl chloride)
2
with KA (1) at ambient temperature [36], then followed by dialkyl 6-(chloromethyl)-
8
-oxo-4,8-dihydropyrano[3,2-b]pyran-3,4-dicarboxylate (3) in the reaction with
dialkyl acetylenedicarboxylate and isocyanide at ambient temperature in ethanol
(
Scheme 1). Finally, the evaluation of the reaction generality was successfully done
using a variety of acetylenic esters and diꢂerent derivatives of isocyanides as pre-
sented in Table 1 and Scheme 1.
1
3

K. Ojaghi Aghbash et al.
Fig. 1 Representatively, intramolecular H bonds in 3a and 3d
Scheme 2 A possible proposed mechanism for the generation of compound 3
Representatively, the FT-IR spectrum of 3a indicated a peak at the frequency
−
1
−1
of 3449 cm corresponded to stretching vibrations of –NH, and 2958 cm cor-
responding to the vinylic-CH functional group. Two sharp peaks at 1744 and
−
1
1
1
672 cm are related to ester and pyrone carbonyl groups, respectively. H NMR
spectroscopy of this compound displayed a singlet peak at δ = 1.48 ppm corre-
t
sponding to but-Me protons. A singlet at δ = 3.70 and 3.74 ppm is assignable to
esteric methyl protons, and at δ = 4.33 ppm is related to methylene protons con-
nected to a chloro functional group. A singlet peak at δ = 8.73 displays the exist-
1
ence of an amine group. Of course, by comparing the H NMR spectrum of 3a
in CDCl and CDCl + D O, an interesting point is that the strong intramolecular
3
3
2
hydrogen bond between the amine and oxygen of the carbonyl group (Fig. 1) pre-
vented the deuterium isotope from exchanging [37].
1
3
C NMR spectrum of 3a conꢀrmed the proposed structure with 14 distinct
peaks. Four peaks at δ = 29.019, 40.764, 53.349, and 70.622 ppm are related to
1
3

The clean and mild synthesis, crystal structure, and…
methylene and methyl carbon atoms, and three peaks at δ= 168.900, 169.830, and
1
70.520 ppm are assigned to ester and pyrone carbonyl carbons (See Supplemen-
tary data and experimental section).
A possible proposed mechanism for the generation of dialkyl 6-(chloromethyl)-8-
oxo-4,8-dihydropyrano[3,2-b]pyran-3,4-dicarboxylate (3a–f) is shown in Scheme 2
[
30, 38].
According to the isocyanides chemistry [39–43], it is reasonable to assume that
dialkyl 6-(chloromethyl)-8-oxo-4,8-dihydropyrano[3,2-b]pyran-3,4-dicarboxylate
3
product from nucleophilic addition reaction of isocyanide and acetylene leads to
zwitterionic intermediate 4, followed by protonation using chloro-Kojic acid to form
intermediate 5. Next, ketenimine 6 is created with attack of the negative oxygen
atom of chloro-Kojic acid. 1,3-Proton transfer in 6 and then cyclization of interme-
diate 7 produced compound 3 (Scheme 2).
Similar to our work, these reactions have been previously performed by Asghari
et al. with Kojic acid. Their method’s disadvantages included the use of tetrahy-
drofuran as a toxic solvent and chromatography column to isolate the ꢀnal prod-
ucts [38]. But in the present study, products of new 4,8-dihydropyrano[3,2-b]-pyrans
from chloro-KA were obtained using a green solvent of ethanol with high yields
without using a chromatography column. Also, the intramolecular hydrogen bond
and its eꢂects in these compounds were studied using crystallographic technique
and D O experiment.
2
One of the interesting phenomena in compound 3 is the unexchanging of the
amine proton by adding D O (D O experiment). It can be related to the formation
2
2
of very strong intramolecular H bond (quasi-covalent H bond) that prohibited the
deuterium exchange [37] (Fig. 1; see Supplementary data and experimental section).
X‑ray diꢀraction analysis of 3a and 3d
Crystal structure analysis of single crystals of molecules 3a and 3d was carried out
on a two-circle STOE IPDS 2 (diꢂractometer with a 2-dimensional IP detector).
For data collection, spin scans and planar Mo-K graphite-monochromated radia-
α
tion technique (λ=0.71073 Å) to one picture were employed. The lattice param-
2
2
eters were determined based on all reꢁections with F >2σ (F ) by the least-squares
procedures. Cell reꢀnement, intensity integration, polarization eꢂects, and Lor-
entz correction were done using X-AREA software [44]. The compound structure
was reꢀned by the program SHELXL-97 using a full-matrix minimum-squares
method and solved in SHELXS-97 using direct ways [45]. Hydrogen atoms were
reꢀned and geometrically located by using a riding model. No peaks of chemical
importance were observed in the terminal diꢂerence of the Fourier maps. Crystal
data for 3a: C H O Cl , crystal system, P-1, triclinic: space group; (no. 15) ; vol-
1
3
18
3
5
2
ume: 950.3(2) Å ; Z=2; unit (one) cell dimensions: a=9.794(1), b=10.347(1),
c=10.784(1) Å, α=108.074(8), β=93.491(8), γ=111.151(8)°; calculated density:
1
3

K. Ojaghi Aghbash et al.
−
1
3
1
0
.348 g cm ; range of θ for gathering the data 2.0–27.8°; absorbency coeꢃcient:
−
2
.238 mm ; F(000)=404; reꢀnement procedure: all matrix minimum-square on F ;
ultimate R indices [I>2σ(I)]: R =0.052, wR =0.124; data/parameters: 3732/240;
1
2
−3
great diꢂ. hole and peak: −0.240 and 0.210 e Å ; good agreement between ꢀt and
2
experiment on F : 0.93. Crystal data for 3d: C H O Cl , crystal system, P-1, tri-
1
3
18
5
2
3
clinic: space group; (no. 15); volume: 1068.6(3) Å ; Z=2; unit (one) cell dimen-
sions: a=10.222(2), b=10.862(2), c=11.978(2) Å, α=103.26(2), β=106.50(2),
−3
γ=114.18(2)°; calculated density: 1.367 g cm ; range of θ for gathering the data
−1
2
.4–26.0°; absorbency coeꢃcient: 0.221 mm ; F(000)=464; reꢀnement procedure:
2
all matrix minimum-square on F ; data/parameters: 4126/273; great diꢂ. hole and
−3
2
peak: −0.180 and 0.140 e Å ; good agreement between ꢀt and experiment on F :
.884; ultimate R indices [I>2σ(I)]: R =0.046, wR =0.106. X-ray analysis of the
0
1
2
molecules (3a and 3d) was performed to ensure the structures, conꢀgurations and to
see the possible intra- and intermolecular interactions. Molecular structures with the
atom labeling and the dimeric structures in the unit cells are shown in Figs. 2 and 3.
Molecules (3a and 3d) crystallize in the triclinic centrosymmetric P-1 space
group. Compounds 3a and 3d have isomorphous crystal structures, despite one hav-
t
c
ing Bu and the other having Hex electron-donating substituents; the geometries of
the molecules are very similar. In the structure 3d, cyclohexane takes a chair con-
formation; C–C (cyclohexane) distances are in the range of 1.490(3)–1.513(3) Å.
Fig. 2 (Up) Molecular structure of 3a. The drawing of thermic ellipsoids at the 40% probability level has
been done. (Down) Stacking of the dimeric (RS) molecules with the unit cell along the a-axis
1
3

The clean and mild synthesis, crystal structure, and…
Fig. 3 (Up) Molecular structure of 3d. The drawing of thermic ellipsoids at the 40% probability level has
been done. (Down) Stacking of the dimeric (RS) molecules with the unit cell along the a-axis
Structures show six-membered N–H···O intramolecular H bonds between the car-
bonyl group of OMe and OEt units and NH (Figs. 1 and 4 and Table 2). Further-
more, in the crystals, the molecules are connected by π–π stacking contacts forming
inversion dimers and pairs of C–H···N and C–H···O. Each unit cell has a dimeric
structure and possesses two stereogenic centers C7 (RS, Figs. 2 and 3).
1
3

K. Ojaghi Aghbash et al.
Fig. 4 Strong intramolecular H bonds in 3a (A) and 3d (B) based on X-ray data
Table 2 Geometries of H bonds of the crystal structures of 3a and 3d
Compd.
D–H···A
d(D–H)
d(H···A)
d(D···A)
<(DHA)
Directionality
3
a
N1–H1C···O7
C3–H3···O4i
0.86
0.93
0.96
0.96
0.86
0.93
0.97
2.01
2.61
2.51
2.36
2.00
2.60
2.50
2.691(3)
3.309(3)
3.062(4)
2.897(4)
2.674(3)
3.437(3)
3.410(4)
135
133
116
115
134
150
157
Strong
Weak
Weak
Weak
Strong
Weak
Weak
C16–H16C···O2
C15—H15A···O2
N1–H1C···O4
3
d
ii
C3—H3···O7
iii
C20—H20B···O7
Symmetry codes: (i) − x, − y + 1, − z + 1; (ii) − x + 1, − y + 2, − z + 1; (iii) − x, − y + 1, − z + 1
1
3

The clean and mild synthesis, crystal structure, and…
Conclusions
In this research, a clean, safe and eꢃcient procedure was developed for the synthe-
sis of dialkyl 6-(chloromethyl)-8-oxo-4,8-dihydropyrano[3,2-b]pyran-3,4-dicarbox-
ylate using various isocyanides and dialkyl acetylenedicarboxylate in high yields.
No need for prior modiꢀcation or activation of the starting material makes the pre-
sent process a remarkable alternative to complex multistep procedures. Representa-
tively, two compounds were analyzed by X-ray crystallography technique. The crys-
tal structures showed an intramolecular hydrogen bond and stacking of the dimeric
(
RS) molecules with the unit cell along the a-axis.
Acknowledgements For all the crystal structures in this research, the reported crystallography data
was published by the Cambridge Crystallographic Data Center (CCDC) as a supplemental publica-
tion [nos. CCDC-1874431 (3a) and 1874430 (3d)]. These data copies can be obtained free on applica-
tion to the CCDC, UK, Cambridge CB2 1EZ, 12 Union Road; FAX: (+44) 1223 336033, or emailing
data_request@ccdc.cam.ac.uk or by online via www.ccdc.cam.ac.uk/data_request/cif. Also, we thank the
Research Council of the Urmia University that supported this work.
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