Selective formation of spiro dihydrofurans from one-pot reaction of dimedone with BrCN and aldehydes in the presence of Et3N

Article abstract of DOI:10.1007/s13738-012-0190-4

Reaction of 5,5-dimethylcyclohexane-1,3-dione (dimedone), aldehydes and cyanogen bromide in the presence of triethylamine leads to the selective formation of spiro dihydrofurans in moderate to good yields at room temperature.

Full text of DOI:10.1007/s13738-012-0190-4

J IRAN CHEM SOC (2013) 10:565–575
DOI 10.1007/s13738-012-0190-4
ORIGINAL PAPER
Selective formation of spiro dihydrofurans from one-pot reaction
of dimedone with BrCN and aldehydes in the presence of Et3N
•
Nader Noroozi Pesyan Alireza Shokr
•
•
Mohammad Behroozi Ertan S¸ahin
Received: 17 September 2012 / Accepted: 16 November 2012 / Published online: 8 December 2012
Ó Iranian Chemical Society 2012
Abstract Reaction of 5,5-dimethylcyclohexane-1,3-dione
(dimedone), aldehydes and cyanogen bromide in the
presence of triethylamine leads to the selective formation
of spiro dihydrofurans in moderate to good yields at room
temperature.
Dimroth and Pasedach [5] have presented a methodol-
ogy to synthesize 2,3-dihydrofurans from the dehydration
of 1,4-diols under high temperature and pressure condi-
tions. The intramolecular cyclization of alkynyl alcohols to
generate 2,3-dihydrofurans was performed by the promo-
tion of a pentacarbonylmolybdenum/triethylamine com-
plex [6]. The dihydrofuran moiety was prepared by
Rh-catalyzed reactions of diazo compounds or iodonium
ylides with alkenes [7–9]. Metal salts, such as cerium(IV)
ammonium nitrate and manganese(III) acetate, catalyzed
the cyclization of active methylene compounds with
alkenes to generate the dihydrofurans [10–14]. Recently,
Wang et al. [15] reported an efficient methodology for the
oxidative addition reaction of aldehydes with 5,5-dimeth-
ylcyclohexane-1,3-dione (dimedone) and 1,3-indandione to
selectively afford spiro dihydrofuran and cyclopropane
derivatives, promoted by molecular iodine and dimethyl-
aminopyridine (DMAP) under mechanical milling condi-
tions. Yan et al. [16]. reported the synthesis of spiro
dihydrofurans using DABCO catalysis.
Keywords Dimedone ꢀ Spiro 2,3-dihydrofuran ꢀ
Cyanogen bromide ꢀ One-pot ꢀ Aldehyde
Introduction
The development of novel synthetic methodologies to
facilitate the preparation of compound libraries is a pivotal
focal point of research activity in the field of modern
medicinal and combinatorial chemistry [1]. Substituted
dihydrofurans in numerous natural compounds, showing
important biological activities and wide variety pharma-
ceutical applications [2]. Large variety of 2,3-dihydrofuran
compounds are of interest because they constitute impor-
tant class of compound and natural products, many of
which exhibit useful biological activities and clinical
applications (Fig. 1) [3, 4].
Dimedone have been used in several reaction conditions
with various aldehydes for the synthesis of 1,8-dioxo-
octahydroxanthenes such as 1-butyl-3-methylimidazolium
hydrogen sulfate [bmim]HSO4 as an acidic ionic liquid
[17], in the presence of selectfluorTM 1-(chloromethyl)-4-
fluoro-1,4-diazoniabicyclo[2, 2, 2]octane bis(tetrafluoro-
borate) as catalyst under solvent-free conditions [18], in the
presence of ferric hydrogen sulfate as an efficient hetero-
geneous catalyst [19] and etc.
Electronic supplementary material The online version of this
article (doi:10.1007/s13738-012-0190-4) contains supplementary
material, which is available to authorized users.
N. Noroozi Pesyan (&) ꢀ A. Shokr ꢀ M. Behroozi
Department of Chemistry, Faculty of Science,
Urmia University, 57159 Urmia, Iran
Although the cyanogen bromide (BrCN) is a capable
reagent for the synthesis of cyanamides [20], cyanates [21]
and it is used for selective cleavage of the methionyl
peptide bonds in ribonuclease [22]. This compound is used
as brominating and cyanating agent for bromination and
cyanation of imidazoles [23], free-radical reaction with
e-mail: n.noroozi@urmia.ac.ir; nnp403@gmail.com
E. S¸ahin
Department of Chemistry, Faculty of Science,
Atatu
¨rk University, 25240 Erzurum, Turkey
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J IRAN CHEM SOC (2013) 10:565–575
propionaldehyde were dissolved in 10 mL methanol in an
Erlenmeyer, 0.04 g (0.63 mmol) triethylamine was added
into solution and then was transferred it into a separatory
funnel, then it was added drop wise into solution of BrCN
in round bottom flask at 0 °C to room temperature. (Cau-
tion! The cyanogen bromide is toxic. Reactions should be
carried out in a well-ventilated hood). The progression of
reaction was monitored by thin layer chromatography
(TLC). After outstanding 24 h, the crystalline solid pre-
cipitate, filtered off, washed with few mL methanol and
dried.
O
OH
O
H
O
O
Anti-bacterial and
anti-fungal [3b]
Bisabolangelone (anti-ulcer) [3a]
Fig. 1 Structures of some biological compounds containing substi-
tuted dihydrofurans
alkanes that result in bromination of alkanes [24] and
a-bromination of b-aminoenones [25].
Here in, we report the synthesis of spiro 6,6-dimethyl-
2,3,6,7-tetrahydrobenzofuran-4(5H)-one derivatives by
applying the reaction of dimedone with cyanogen bromide
and aldehydes in the presence of triethylamine.
Triethylammonium-2-bromo-5,5-dimethylcyclohexane-1,3-
dione-2-ide (4)
Colorless crystalline solid, mp 75–76 °C. 1H NMR
(300 MHz, CDCl3) d: 7.27 (bs, 1H), 3.02 (q, J = 7.5 Hz,
6H), 2.18 (s, 4H), 1.17 (t, J = 7.5 Hz, 9H), 0.87 (s 6H);
13C NMR (75 MHz, CDCl3) d: 8.7, 28.3, 31.7, 46.2, 50.2,
96.7, 186.0; FTIR (KBr, cm-1) mmax: 3,417, 2,958, 2,870,
2,678, 2,495, 1,644, 1,610, 1,509, 472.
Experimental
General
40,40,6,6-Tetramethyl-3,5,6,7-tetrahydro-spiro[benzofuran-
Melting points were measured with a digital melting point
apparatus (Electrothermal) and were uncorrected. IR
spectra were determined in the region 4,000–400 cm-1 on
a NEXUS 670 FT IR spectrometer by preparing KBr pel-
lets. The 1H and 13C NMR spectra were recorded on Bruker
300 FT-NMR at 300 and 75 MHz, respectively (Urmia
2(4H),10-cyclohexane]-20,4,60-trione (3a)
Colorless crystalline powder in a 58 % yield; mp
1
208–210 °C (Lit.: 208–209 °C [15]). H NMR (300 MHz,
CDCl3) d: 3.13 (s, 2H), 2.78 (d, J = 13.9 Hz, 2H), 2.65 (d,
J = 13.9 Hz, 2H), 2.47 (s, 2H), 2.21 (s, 2H), 1.16 (s, 3H),
1.11 (s, 6H), 0.98 (s, 3H); 13C NMR (75 MHz, CDCl3) d:
26.9, 28.7, 29.8, 30.8, 34.2, 34.4, 37.4, 51.0, 98.2, 109.2,
176.0, 194.2, 199.8; FTIR (KBr, cm-1) mmax: 2,957, 2,871,
1,731, 1,690, 1,500, 1,398, 1,144.
1
University, Urmia, Iran). H and 13C NMR spectra were
obtained on solution in DMSO-d6 and/or in CDCl3 as
solvents using TMS as internal standard. The data are
reported as: s = singlet, d = doublet, t = triplet,
q = quartet, m = multiplet or unresolved, bs = broad
singlet, coupling constant(s) in Hz, integration. All reac-
tions were monitored by TLC with silica gel-coated plates
(EtOAc: n-hexane/8:10/v:v). The mass analysis performed
using mass spectrometer (Agilent Technology (HP) type,
MS Model: 5973 network Mass selective detector Electron
Impact (EI) 70 eV), ion source temperature was 230 °C
(Tehran University, Tehran, Iran). Cyanogen bromide was
synthesized based on reported references [26]. Compounds
1, all aldehydes, triethylamine and used solvents purchased
from Merck and Aldrich without further purification.
3,40,40,6,6-Pentamethyl-3,5,6,7-tetrahydro-
spiro[benzofuran-2(4H),10-cyclohexane]-20,4,60-trione (3b)
Colorless crystalline powder in a 62 % yield; mp
118–120 °C. 1H NMR (300 MHz, CDCl3) d: 3.46 (q,
J = 6.6 Hz, 1H), 3.15 (d, J = 7.5 Hz, 1H), 3.10 (d,
J = 7.2 Hz, 1H), 2.18–2.99 (m, 6H), 1.22 (s, 3H), 1.16 (d,
J = 6.6 Hz, 3H), 1.09 (s, 6H), 0.89 (s, 3H); 13C NMR
(75 MHz, CDCl3) d: 15.2, 26.0, 28.3, 28.6, 30.4, 34.2,
37.1, 43.3, 46.0, 50.0, 51.1, 54.4, 102.4, 114.0, 176.3.,
194.1, 199.7, 199.8; FTIR (KBr, cm-1) mmax: 2,958, 2,877,
1,738, 1,714, 1,642, 1,396, 1,231, 1,041.
General procedures for the preparation
of 3a–z, 3A and 3B
40,40,6,6-Tetramethyl-3-ethyl-3,5,6,7-tetrahydro-
spiro[benzofuran-2(4H),10-cyclohexane]-20,4,60-trione (3c)
The physical and spectral data of the selected compounds
from 3a–z, 3A and 3B are follows.
In a 25 mL round bottom flask equipped by a magnet-
ically stirrer, dissolved 0.05 g (0.48 mmol) cyanogen bro-
mide (BrCN) in 2 mL methanol at 0 °C. Then separately,
0.13 g (0.96 mmol) dimedone and 0.028 g (0.48 mmol)
Colorless crystalline powder in a 68 % yield; mp
1
130–131 °C (Lit.: 148–149 °C [15]). H NMR (300 MHz,
CDCl3) d: 3.84 (s, 1H), 3.61 (m, 1H), 3.12 (s, 1H), 2.82 (d,
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567
J = 14.4 Hz, 2H), 2.63 (d, J = 13.8 Hz, 2H), 2.46 (m,
2H), 2.20 (s, 2H), 1.15 (s, 3H), 1.10 (s, 9H), 0.96 (s, 3H);
13C NMR (75 MHz, CDCl3) d: 26.7, 27.9, 28.0, 28.3, 28.6,
29.6, 30.6, 34.1, 34.3, 37.2, 50.8, 50.9, 87.0, 97.0, 109.0,
176.2, 184.0, 194.3, 199.7; MS m/z (%): 319 (M? ? 1, 20),
303 (20), 289 (50), 261 (5), 234 (15), 207 (8), 191 (15), 135
(7), 83 (100, base peak), 69 (6), 55 (23), 41 (13); FTIR
(KBr, cm-1) mmax: 2,960, 2,871, 1,713, 1,641, 1,525, 1,396,
1,348.
40,40,6,6-Tetramethyl-3-(3-nitrophenyl)-3,5,6,7-tetrahydro-
spiro[benzofuran-2(4H),10-cyclohexane]-20,4,60-trione (3g)
(5), 83 (100, base peak), 55 (12), 41 (7); FTIR (KBr, cm-1
)
mmax: 3,462, 2,955, 2,929, 2,875, 1,714, 1,634, 1,399,
1,245.
Yellow crystalline powder in a 60 % yield; mp
1
202–204 °C (Lit.: 201–203 °C [15]). H NMR (300 MHz,
CDCl3) d: 8.16 (d, J = 7.7 Hz, 1H), 8.07 (s, 1H), 7.45-7.54
(m, 2H), 4.56 (s, 1H), 3.13 (d, J = 15.0 Hz, 1H), 2.70 (s,
2H), 2.62 (dd, J3 = 15.0, J4 = 2.7 Hz, 1H), 2.29-2.13 (m,
3H), 1.96 (d, J = 14.4 Hz, 1H), 1.18 (s, 3H), 1.16 (s, 3H),
1.15 (s, 3H), 0.85 (s, 3H); 13C NMR (75 MHz, CDCl3) d:
26.2, 28.4, 28.8, 30.4, 30.7, 34.4, 37.3, 49.9, 54.0, 53.7,
54.1, 103.0, 113.4, 123.5, 123.6, 130.0, 134.4, 138.4,
148.3, 177.6, 193.1, 198.3, 198.6; MS m/z (%): 411 (M?,
13), 394 (15), 311 (12), 299 (6), 282 (8), 127 (8), 83 (100,
40,40,6,6-Tetramethyl-3-propyl-3,5,6,7-tetrahydro-
spiro[benzofuran-2(4H),10-cyclohexane]-20,4,60-trione (3d)
Colorless crystalline powder in a 60 % yield; mp
1
169–171 °C (Lit.: 168–170 °C [15]). H NMR (300 MHz,
CDCl3) d: 3.42 (s, 1H), 2.43-3.03 (m, 7H), 2.22 (s, 2H),
1.56 (s, 3H), 1.29 (s, 3H), 1.13 (s, 6H), 0.89 (s, 3H), 0.87 (s,
3H); 13C NMR (75 MHz, CDCl3) d: 14.2, 19.7, 25.8, 28.5,
28.6, 30.5, 30.7, 33.7, 34.0, 37.3, 47.5, 49.9, 51.2, 54.7,
103.9, 113.5, 177.4, 194.2, 199.3, 200.0; FTIR (KBr,
cm-1) mmax: 2,960, 2,874, 1,738, 1,710, 1,392.
base peak), 69 (5), 55 (25), 41 (13); FTIR (KBr, cm-1
max: 3,068, 2,959, 2,875, 1,741, 1,712, 1,645, 1,533,
1,391, 1,531.
)
m
40,40,6,6-Tetramethyl-3-phenyl-3,5,6,7-tetrahydro-
spiro[benzofuran-2(4H),10-cyclohexane]-20,4,60-trione (3e)
40,40,6,6-Tetramethyl-3-(2-nitrophenyl)-3,5,6,7-tetrahydro-
spiro[benzofuran-2(4H),10-cyclohexane]-20,4,60-trione (3h)
Colorless crystalline powder in a 65 % yield; mp
267–269 °C. 1H NMR (300 MHz, CDCl3) d: 7.30 (t,
J = 8.1 Hz, 3H), 7.15 (d, J = 6.6 Hz, 2H), 4.44 (s, 1H),
3.08 (d, J = 14.7 Hz, 1H), 2.66 (s, 2H), 2.54 (d,
J = 14.4 Hz, 1H), 2.12-2.21 (m, 3H), 1.95 (d, J = 14.1 Hz,
1H), 1.16 (s, 6H), 1.12 (s, 3H), 0.83 (s, 3H); 13C NMR
(75 MHz, CDCl3) d: 26.3, 28.4, 28.9, 30.49, 30.52, 34.2,
37.3, 50.0, 51.1, 53.7, 55.1, 103.8, 113.6, 128.5, 128.6,
129.0, 136.0, 176.6, 193.1, 198.8, 199.3; MS m/z (%): 366
(M?, 50), 282 (50), 266 (25), 254 (85), 241 (15), 184 (10),
155 (6), 141 (7), 128 (32), 115 (12), 102 (11), 83 (100, base
peak), 55 (40), 41 (25); FTIR (KBr, cm-1) mmax: 3,050,
2,957, 2,872, 1,737, 1,713, 1,642, 1,390.
Pale yellow crystalline powder in a 70 % yield; mp
183–184 °C. 1H NMR (300 MHz, CDCl3) d: 7.83 (d,
J = 8.1 Hz, 1H), 7.51 (t, J = 7.5 Hz, 1H), 7.41 (t,
J = 7.5 Hz, 1H), 7.14 (d, J = 7.5 Hz, 1H), 6.04 (s, 1H),
3.56 (d, J = 15.3 Hz, 1H), 2.54–2.73 (m, 4H), 2.03–2.22
(m, 3H), 1.21 (s, 3H), 1.15 (s, 3H), 1.08 (s, 3H), 0.89 (s,
3H); 13C NMR (75 MHz, CDCl3) d: 26.6, 28.3, 28.9, 30.2,
30.8, 34.4, 37.2, 46.6, 49.4, 50.7, 52.8, 102.9, 114.9, 124.3,
127.1, 129.2, 130.9, 133.2, 149.1, 176.6, 192.5, 198.97,
199.03; FTIR (KBr, cm-1) mmax: 3,064, 2,959, 2,875,
1,721, 1,649, 1,616, 1,523, 1,388, 1,347.
40,40,6,6-Tetramethyl-3-(2-nitrocinamyl)-3,5,6,7-
tetrahydro-spiro[benzofuran-2(4H),10-cyclohexane]-
20,4,60-trione (3i)
40,40,6,6-Tetramethyl-3-(4-nitrophenyl)-3,5,6,7-tetrahydro-
spiro[benzofuran-2(4H),10-cyclohexane]-20,4,60-trione (3f)
Yellow crystalline powder in
a 70 % yield; mp
Yellow crystalline powder in
a
70 % yield; mp
263–265 °C. 1H NMR (300 MHz, CDCl3) d: 8.01 (d,
J = 7.8 Hz, 1H), 7.56 (t, J = 7.5 Hz, 1H), 7.43 (m, 2H),
7.21 (d, J = 15.3 Hz, 1H), 5.70 (dd, J3 = 15.2,
J3 = 10.2 Hz, 1H), 4.15 (d, J = 9.9 Hz, 1H), 3.12 (d,
J = 14.4 Hz, 1H), 2.88 (d, J = 15.0 Hz, 1H), 2.49–2.58
(m, 4H), 2.25 (s, 2H), 1.27 (s, 3H), 1.17 (s, 3H), 1.15 (s,
3H), 0.91 (s, 3H); 13C NMR (75 MHz, CDCl3) d: 26.6,
28.5, 28.6, 30.2, 30.7, 34.2, 37.4, 50.2, 51.3, 52.8, 54.2,
101.8, 110.7, 124.7, 128.4, 128.9, 129.8, 131.9, 132.1,
133.7, 147.4, 177.4, 193.5, 199.4, 200.0; MS m/z (%): 437
(M?, 10), 420 (20), 392 (5), 360 (15), 336 (7), 318 (15),
1
265–267 °C (Lit.: 265–266 °C [15]). H NMR (300 MHz,
CDCl3) d: 8.18 (d, J = 6.9 Hz, 2H), 7.36 (d, J = 6.9 Hz,
2H), 4.51 (s, 1H), 3.97 (d, J = 8.1 Hz, 1H), 3.06 (d,
J = 15.0 Hz, 1H), 2.69 (s, 2H), 2.60 (d, J = 15.0 Hz, 1H),
2.17–2.25 (m, 3H), 1.92 (d, J = 14.4 Hz, 1H), 1.17 (s, 3H),
1.15 (s, 6H), 0.86 (s, 3H); 13C NMR (75 MHz, CDCl3) d:
26.1, 28.4, 28.8, 30.4, 30.7, 34.4, 37.2, 49.9, 50.9, 53.9,
54.0, 103.2, 113.4, 125.3, 129.5, 143.4, 147.9, 177.4,
193.1, 198.2, 198.4; MS m/z (%): 411 (M?, 40), 327 (18),
299 (40), 282 (7), 229 (7), 191 (5), 173 (5), 152 (5), 115
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J IRAN CHEM SOC (2013) 10:565–575
302 (8), 287 (13), 266 (5), 231 (7), 206 (6), 178 (7), 152
(4), 120 (15), 83 (100, base peak), 55 (18); FTIR (KBr,
cm-1) mmax: 3,109, 3,073, 2,960, 2,929, 2,870, 1,746,
1,715, 1,636, 1,523, 1,394, 1,350, 1,041.
83 (100, base peak), 69 (5), 55 (24), 41 (15); FTIR (KBr,
cm-1) mmax: 2,963, 2,870, 1,740, 1,710, 1,640, 1,392, 1,045.
40,40,6,6-Tetramethyl-3-(3-bromophenyl)-3,5,6,7-
tetrahydro-spiro[benzofuran-2(4H),10-cyclohexane]-
20,4,60-trione (3m)
40,40,6,6-Tetramethyl-3-(4-cyanophenyl)-3,5,6,7-
tetrahydro-spiro[benzofuran-2(4H),10-cyclohexane]-
20,4,60-trione (3j)
Yellow crystalline powder in
a 67 % yield; mp
228–229 °C. 1H NMR (300 MHz, CDCl3) d: 7.42 (d,
J = 7.8 Hz, 1H), 7.32 (s, 1H), 7.18 (t, J = 7.8 Hz, 1H),
7.08 (d, J = 7.5 Hz, 1H), 4.37 (s, 1H), 3.06 (d,
J = 14.7 Hz, 1H), 2.66 (s, 2H), 2.55 (dd, J3 = 14.7,
J4 = 3 Hz, 1H), 2.13–2.24 (m, 3H), 1.98 (d, J = 14.4 Hz,
1H), 1.16 (s, 9H), 0.84 (s, 3H); 13C NMR (75 MHz,
CDCl3) d: 26.2, 28.4, 28.8, 30.5, 30.6, 34.3, 37.3, 49.9,
51.0, 53.9, 54.1, 103.5, 113.4, 123.0, 127.1, 130.5, 131.6,
131.8, 138.4, 177.0, 193.1, 198.4, 198.9; FTIR (KBr,
cm-1) mmax: 3,072, 2,958, 2,871, 1,741, 1,713, 1,643,
1,392, 1,042, 692.
Colorless crystalline powder in a 75 % yield; mp
1
271–272 °C (Lit.: 248-250 °C [15]). H NMR (300 MHz,
CDCl3) d: 7.62 (d, J = 8.1 Hz, 2H), 7.29 (d, J = 8.1 Hz,
2H), 4.46 (s, 1H), 3.05 (d, J = 14.7 Hz, 2H), 2.52–2.67 (m,
3H), 2.11–2.26 (m, 3H), 1.90 (d, J = 14.4 Hz, 1H), 1.17 (s,
3H), 1.14 (s, 6H), 0.85 (s, 3H); 13C NMR (75 MHz,
CDCl3) d: 26.1, 28.4, 28.8, 30.4, 30.6, 34.3, 37.2, 49.9,
50.9, 54.0, 54.2, 103.2, 112.7, 113.4, 118.1, 129.3, 132.7,
141.5, 177.3, 193.0, 198.2, 198.5; MS m/z (%): 391 (M?,
65), 307 (45), 293 (20), 279 (70), 256 (12), 209 (7), 153
(12), 127 (5), 83 (100, base peak), 55 (20), 41 (13); FTIR
(KBr, cm-1) mmax: 2,962, 2,928, 2,873, 2,230, 1,740, 1,709,
1,640, 1,395, 1,046.
40,40,6,6-Tetramethyl-3-(4-chlorophenyl)-3,5,6,7-
tetrahydro-spiro[benzofuran-2(4H),10-cyclohexane]-
20,4,60-trione (3n)
40,40,6,6-Tetramethyl-3-cinamyl-3,5,6,7-tetrahydro-
Colorless crystalline powder in a 70 % yield; mp
271–273 °C. 1H NMR (300 MHz, CDCl3) d: 7.29 (d,
J = 8.4 Hz, 2H), 7.10 (d, J = 8.4 Hz, 2H), 4.41 (s, 1H),
3.05 (d, J = 14.7 Hz, 1H), 2.66 (s, 2H), 2.55 (d,
J = 15.0 Hz, 1H), 2.12–2.23 (m, 3H), 1.97 (d,
J = 14.4 Hz, 1H), 1.16 (s, 3H), 1.15 (s, 6H), 0.85 (s, 3H);
13C NMR (75 MHz, CDCl3) d: 26.2, 28.4, 28.8, 30.5, 30.6,
34.3, 37.3, 50.0, 51.0, 53.9, 54.2, 103.5, 113.5, 129.2,
129.8, 134.6, 134.7, 176.8, 193.1, 198.6, 198.9; MS m/z
(%): 402 (M? ?2, 27), 400 (M?, 70), 372 (8), 341 (7), 316
(75), 302 (30), 288 (85), 274 (10), 218 (8), 191 (8), 162
(10), 127 (10), 83 (100, base peak), 55 (35), 41 (25); FTIR
(KBr, cm-1) mmax: 2,962, 2,872, 1,742, 1,711, 1,641, 1,393,
1,044.
spiro[benzofuran-2(4H),10-cyclohexane]-20,4,60-trione (3k)
Yellow crystalline powder in
a 70 % yield; mp
284–285 °C. 1H NMR (300 MHz, CDCl3) d: 7.32 (m, 5H),
6.73 (d, J = 15.9 Hz, 1H), 5.83 (dd, J3 = 15.5,
J3 = 9.6 Hz, 1H), 4.08 (d, J = 9.6 Hz, 1H), 3.00 (d,
J = 14.7 Hz, 1H), 2.51–2.65 (m, 5H), 2.22 (s, 2H), 1.20 (s,
3H), 1.15 (s, 6H), 0.91 (s, 3H); 13C NMR (75 MHz,
CDCl3) d: 26.4, 28.5, 28.6, 30.5, 30.6, 34.2, 37.4, 50.2,
51.3, 52.2, 54.4, 102.5, 111.4, 122.8, 126.8, 128.4, 128.6,
135.1, 135.6, 176.9, 193.4, 199.1, 199.3; FTIR (KBr,
cm-1) mmax: 2,959, 2,871, 1,740, 1,711, 1,635, 1,389.
40,40,6,6-Tetramethyl-3-(4-bromophenyl)-3,5,6,7-
tetrahydro-spiro[benzofuran-2(4H),10-cyclohexane]-
20,4,60-trione (3l)
40,40,6,6-Tetramethyl-3-(4-tolyl)-3,5,6,7-tetrahydro-
spiro[benzofuran-2(4H),10-cyclohexane]-20,4,60-trione (3o)
Yellow crystalline powder in
a
75 % yield; mp
Yellow crystalline powder in a 60 % yield; mp
283–285 °C. 1H NMR (300 MHz, CDCl3) d: 7.43 (d,
J = 7.2 Hz, 2H), 7.03 (d, J = 7.2 Hz, 2H), 4.38 (s, 1H),
3.03 (d, J = 14.7 Hz, 1H), 2.64 (s, 2H), 2.54 (d,
J = 14.1 Hz, 1H), 2.16 (m, 3H), 1.96 (d, J = 13.5 Hz,
1H), 1.13 (s, 9H), 0.84 (s, 3H); 13C NMR (75 MHz,
CDCl3) d: 26.2, 28.4, 28.8, 30.5, 30.6, 34.3, 37.2, 50.0,
51.0, 53.9, 54.2, 103.4, 113.5, 122.8, 130.1, 132.2, 135.2,
176.8, 193.1, 198.6, 198.9; MS m/z (%): 447 (M? ?2, 28),
445 (M?, 30), 412 (15), 385 (5), 362 (25), 334 (60), 319
(7), 300 (10), 281 (45), 253 (6), 183 (6), 155 (5), 127 (10),
254–255 °C. 1H NMR (300 MHz, CDCl3) d: 7.11 (d,
J = 7.8 Hz, 2H), 7.04 (d, J = 7.8 Hz, 2H), 4.42 (s, 1H),
3.08 (d, J = 14.7 Hz, 1H), 2.66 (s, 2H), 2.53 (d,
J = 14.7 Hz, 1H), 2.31 (s, 3H), 2.12–2.21 (m, 3H), 2.00 (d,
J = 14.4 Hz, 1H), 1.16 (s, 6H), 1.13 (s, 3H), 0.84 (s, 3H);
13C NMR (75 MHz, CDCl3) d: 21.1, 26.3, 28.4, 28.9, 30.5,
34.2, 37.3, 50.0, 51.1, 53.8, 54.8, 103.8, 113.7, 114.4,
128.8, 129.7, 133.0, 138.4, 176.4, 193.1, 199.0, 199.4; MS
m/z (%): 380 (M?, 80), 365 (7), 352 (9), 337 (6), 321 (10),
296 (50), 281 (60), 265 (100, base peak), 255 (12), 212 (7),
123

J IRAN CHEM SOC (2013) 10:565–575
569
198 (6), 141 (13), 115 (6), 83 (60), 55 (20), 41 (10); FTIR
(KBr, cm-1) mmax: 2,964, 2,874, 1,743, 1,714, 1,640, 1,391,
1,041.
3,061, 3,008, 2,959, 2,898, 2,872, 1,739, 1,711, 1,640,
1,511, 1,388, 1,192, 1,037.
40,40,6,6-Tetramethyl-3-(4-hydroxy-3-methoxyphenyl)-
3,5,6,7-tetrahydro-spiro[benzofuran-2(4H),10-
cyclohexane]-20,4,60-trione (3s)
40,40,6,6-Tetramethyl-3-(3-hydroxyphenyl)-3,5,6,7-
tetrahydro-spiro[benzofuran-2(4H),10-cyclohexane]-
20,4,60-trione (3p)
Colorless crystalline powder in a 62 % yield; mp
1
278–279 °C. H NMR (300 MHz, DMSO-d6) d: 9.04 (s,
Colorless crystalline powder in a 70 % yield; mp
1
238–240 °C. H NMR (300 MHz, DMSO-d6) d: 9.43 (s,
1H), 6.76 (s, 1H), 6.65 (d, J = 8.1 Hz, 2H), 4.63 (s, 1H),
3.68 (s, 3H), 2.35-2.68 (m, 4H), 2.01–2.16 (m, 4H), 1.08 (s,
3H), 1.05 (s, 6H), 0.66 (s, 3H); 13C NMR (75 MHz,
DMSO-d6) d: 26.4, 28.1, 28.6, 29.9, 30.6, 34.3, 36.8, 49.8,
51.1, 53.3, 53.4, 56.1, 103.9, 113.9, 113.4, 115.7, 121.9,
127.9, 146.8, 147.6, 176.5, 192.7, 199.6, 200.9; FTIR
(KBr, cm-1) mmax: 3,449, 2,960, 2,875, 1,737, 1,712, 1,639,
1,392, 1,280, 1,037.
1H), 7.07 (t, J = 7.8 Hz, 1H), 6.70 (d, J = 6.9 Hz, 1H),
6.63 (d, J = 7.8 Hz, 1H), 6.57 (s, 1H), 4.66 (s, 1H), 4.08
(d, J = 5.1 Hz, 1H), 3.58 (d, J = 15 Hz, 1H), 3.16 (d,
J = 5.1 Hz, 1H), 2.36–2.59 (m, 5H), 1.08 (s, 3H), 1.06 (s,
6H), 0.67 (s, 3H); 13C NMR (75 MHz, DMSO-d6) d: 26.4,
28.3, 28.6, 29.9, 30.6, 34.4, 36.8, 49.8, 51.1, 53.1, 53.4,
104.0, 113.4, 115.5, 116.1, 120.1, 129.6, 138.6, 157.7,
176.7, 192.6, 199.3, 200.7; MS m/z (%): 382 (M?, 100,
base peak), 367 (6), 323 (6), 298 (45), 270 (70), 256 (12),
214 (10), 200 (10), 144 (10), 115 (10), 83 (80), 55 (18), 41
(10); FTIR (KBr, cm-1) mmax: 3,444, 3,020, 2,961, 2,873,
1,738, 1,713, 1,625, 1,395.
40,40,6,6-Tetramethyl-3-(2-methoxyphenyl)-3,5,6,7-
tetrahydro-spiro[benzofuran-2(4H),10-cyclohexane]-
20,4,60-trione (3t)
Colorless crystalline powder in a 78 % yield; mp
227–228 °C. 1H NMR (300 MHz, CDCl3) d: 7.20–7.25 (m,
1H), 6.89 (t, J = 8.4 Hz, 2H), 6.88 (d, J = 6.0 Hz, 1H),
5.20 (s, 1H), 3.94 (s, 3H), 3.37 (d, J = 14.4 Hz, 1H), 2.66
(s, 2H), 2.48 (d, J = 14.4 Hz, 1H), 2.06–2.26 (m, 4H), 1.19
(s, 3H), 1.16 (s, 3H), 1.12 (s, 3H), 0.83 (s, 3H); 13C NMR
(75 MHz, CDCl3) d: 26.3, 28.7, 28.8, 30.4, 30.6, 34.2,
37.3, 45.7, 49.7, 51.2, 52.7, 55.7, 102.9, 111.1, 113.2,
119.1, 121.6, 124.0, 129.6, 155.9, 177.0, 193.0, 199.4,
200.0; FTIR (KBr, cm-1) mmax: 3,075, 3,029, 2,957, 2,874,
1,742, 1,715, 1,647, 1,388, 1,235, 1,041.
40,40,6,6-Tetramethyl-3-(2-hydroxyphenyl)-3,5,6,7-
tetrahydro-spiro[benzofuran-2(4H),10-cyclohexane]-
20,4,60-trione (3q)
Colorless crystalline powder in a 65 % yield; mp
225–226 °C. 1H NMR (300 MHz, DMSO-d6) d: 10.40 (bs,
1H), 7.05 (m, 1H), 6.93 (m, 3H), 5.01 (s, 1H), 1.95–2.52
(m, 8H), 0.84–1.02 (m, 12H); 13C NMR (75 MHz, DMSO-
d6) d: 25.6, 26.7, 28.1, 29.6, 31.8, 32.0, 32.04, 41.1, 50.9,
111.2, 115.7, 124.6, 126.0, 126.1, 127.3, 128.8, 150.1,
165.1, 192.0, 196.1, 196.2; FTIR (KBr, cm-1) mmax: 3,185,
2,955, 2,876, 1,642, 1,591, 1,377, 1,236, 756.
40,40,6,6-Tetramethyl-3-(3-methoxyphenyl)-3,5,6,7-
tetrahydro-spiro[benzofuran-2(4H),10-cyclohexane]-
20,4,60-trione (3u)
40,40,6,6-Tetramethyl-3-(3-hydroxy-4-methoxyphenyl)-
3,5,6,7-tetrahydro-spiro[benzofuran-2(4H),10-
cyclohexane]-20,4,60-trione (3r)
Yellow crystalline powder in
a 60 % yield; mp
214–216 °C. 1H NMR (300 MHz, CDCl3) d: 7.23 (t,
J = 7.8 Hz, 1H), 6.81 (dd, J3 = 8.1, J4 = 1.8 Hz, 1H),
6.76 (d, J = 7.5 Hz, 1H), 4.41 (s, 1H), 3.76 (s, 3H), 3.08
(d, J = 14.7 Hz, 1H), 2.66 (s, 2H), 2.53 (dd, J3 = 14.7,
J4 = 3 Hz, 1H), 2.00–2.27 (m, 4H), 1.17 (s, 6H), 1.12 (s,
3H), 0.84 (s, 3H); 13C NMR (75 MHz, CDCl3) d: 26.3,
28.3, 28.9, 30.5, 30.6, 34.2, 37.3, 50.0, 51.1, 53.7, 55.0,
55.2, 103.8, 113.5, 114.0, 114.4, 120.9, 130.0, 137.6,
159.9, 176.6, 193.1, 198.8, 199.3; MS m/z (%): 396 (M?,
35), 312 (37), 296 (18), 284 (50), 271 (10), 228 (8), 214
(6), 191 (8), 158 (15), 128 (14), 115 (20), 83 (100, base
Yellow crystalline powder in
a 65 % yield; mp
241–242 °C. 1H NMR (300 MHz, DMSO-d6) d: 8.94, 8.91
(2bs, 1H), 6.53–6.78 (m, 3H), 4.61, 4.58 (2 s, 1H), 3.71,
3.67 (2 s, 3H), 3.53 (m, 1H), 3.31, 3.27 (2 s, 1H),
2.31–2.55 (m, 6H), 1.04 (s, 6H), 1.02 (s, 3H), 0.66, 0.63
(2 s, 3H); 13C NMR (75 MHz, DMSO-d6) d: 26.4, 28.2,
28.6, 29.9, 30.5, 34.3, 36.8, 49.8, 51.1, 52.9, 53.4, 55.8,
103.9, 111.9, 113.4, 116.3, 120.3, 129.5, 146.6, 147.8,
176.3, 192.6, 199.3, 200.8; MS m/z (%): 412 (M?, 7), 328
(6), 313 (8), 300 (30), 287 (10), 191 (20), 178 (9), 165 (10),
152 (18), 128 (11), 115 (16), 102 (12), 83 (100, base peak),
69 (15), 55 (98), 41 (60); FTIR (KBr, cm-1) mmax: 3,442,
peak), 69 (18), 55 (60), 41 (47); FTIR (KBr, cm-1) mmax
3,050, 2,997, 2,962, 2,933, 2,872, 2,832, 1,740, 1,712,
:
1,639, 1,598, 1,392, 1,264, 1,041.
123

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J IRAN CHEM SOC (2013) 10:565–575
40,40,6,6-Tetramethyl-3-(4-methoxyphenyl)-3,5,6,7-
tetrahydro-spiro[benzofuran-2(4H),10-cyclohexane]-
20,4,60-trione (3v)
40,40,6,6-Tetramethyl-3-(4-dimethylaminocinamyl)-3,5,6,7-
tetrahydro-spiro[benzofuran-2(4H),10-cyclohexane]-
20,4,60-trione (3y)
Colorless crystalline powder in a 75 % yield; mp
236–237 °C. 1H NMR (300 MHz, CDCl3) d: 7.07 (d,
J = 8.1 Hz, 2H), 6.83 (d, J = 8.1 Hz, 2H), 4.42 (s, 1H),
3.78 (s, 3H), 3.49, (s, 1H), 3.07 (d, J = 14.7 Hz, 1H), 2.66
(s, 2H), 2.54 (d, J = 14.1 Hz, 1H), 2.14–2.21 (m, 2H), 2.0
(d, J = 14.4 Hz, 1H), 1.16 (s, 6H), 1.13 (s, 3H), 0.84 (s,
3H); 13C NMR (75 MHz, CDCl3) d: 26.3, 28.4, 28.9, 30.4,
30.5, 34.2, 37.3, 50.1, 51.1, 53.8, 54.6, 55.2, 103.7, 113.5,
114.4, 127.9, 129.7, 159.6, 176.4, 193.0, 199.1, 199.4; MS
m/z (%): 396 (M?, 50), 337 (10), 312 (40), 298 (20), 284
(100, base peak), 270 (8), 228 (8), 167 (10), 149 (30), 135
(20), 115 (15), 83 (70), 69 (10), 55 (35), 41 (25); FTIR
(KBr, cm-1) mmax: 2,960, 2,839, 1,739, 1,712, 1,639, 1,390,
1,036.
Colorless crystalline powder in a 87 % yield; mp
1
278–279 °C. H NMR (300 MHz, DMSO-d6) d: 7.14 (d,
J = 7.8 Hz, 2H), 6.63 (d, J = 7.8 Hz, 2H), 5.54 (dd,
J = 14.7, 9.3 Hz, 1H), 4.27 (d, J = 8.7 Hz, 1H), 3.50 (d,
J = 14.7 Hz, 1H), 2.88 (s, 6H), 2.68 (d, J = 14.7 Hz, 2H),
2.05-2.53 (m, 6H), 1.12 (s, 3H), 1.07 (s, 3H), 1.03 (s, 3H),
0.72 (s, 3H); 13C NMR (75 MHz, DMSO-d6) d: 26.5, 28.2,
28.5, 29.8, 30.7, 34.4, 36.9, 49.8, 50.9, 51.2, 53.8, 84.0,
103.0, 111.7, 112.6, 119.1, 124.0, 127.8, 134.6, 150.1,
176.7, 193.0, 200.0, 200.9; FTIR (KBr, cm-1) mmax: 3,094,
2,956, 2,874, 2,803, 1,735, 1,710, 1,637, 1,613, 1,525,
1,390.
40,40,6,6-Tetramethyl-3-(2-hydroxy-1-naphthyl)-3,5,6,7-
tetrahydro-spiro[benzofuran-2(4H),10-cyclohexane]-
20,4,60-trione (3z)
40,40,6,6-Tetramethyl-3-(3,4,5-trimethoxyphenyl)-3,5,6,7-
tetrahydro-spiro[benzofuran-2(4H),10-cyclohexane]-
20,4,60-trione (3w)
Colorless crystalline powder in a 60 % yield; mp
236–237 °C. 1H NMR (300 MHz, DMSO-d6) d: 10.46 (bs,
1H), 8.18 (s, 1H), 7.71–7.79 (m, 2H), 7.37 (m, 2H), 7.17
(m, 1H), 5.54 (s, 1H), 2.59 (d, J = 17.4 Hz, 1H), 2.01–2.47
(m, 7H), 1.03 (s, 3H), 0.95 (s, 3H), 0.76 (s, 6H); 13C NMR
(75 MHz, DMSO-d6) d: 23.8, 24.0, 26.3, 27.5, 28.0, 29.8,
31.9, 32.1, 40.9, 44.0, 50.5, 51.0, 111.1, 117.1, 117.8,
124.1, 124.7, 126.8, 128.1, 128.6, 131.0, 132.0, 148.5,
164.8, 172.5, 195.0, 196.3; FTIR (KBr, cm-1) mmax: 3,180,
2,945, 2,892, 2,870, 1,717, 1,644, 1,593, 1,375, 1,234, 811,
748.
Pale yellow crystalline powder in a 70 % yield; mp
1
227–228 °C. H NMR (300 MHz, CDCl3) d: 6.36 (s, 2H),
4.37 (s, 1H), 3.83 (s, 3H), 3.82 (s, 6H), 3.06 (d,
J = 14.7 Hz, 1H), 2.68 (s, 2H), 2.55 (dd, J3 = 14.4,
J4 = 2.7 Hz, 1H), 2.15–2.30 (m, 2H), 2.01 (d,
J = 14.4 Hz, 2H), 1.18 (s, 6H), 1.13 (s, 3H), 0.85 (s, 3H);
13C NMR (75 MHz, CDCl3) d: 26.3, 28.0, 29.1, 30.5, 30.6,
34.2, 37.3, 50.1, 51.1, 53.6, 55.6, 56.2, 60.8, 103.9, 105.8,
113.4, 131.8, 153.5, 168.0, 176.6, 193.2, 199.1, 199.2; MS
m/z (%): 456 (M?, 100, base peak), 428 (9), 397 (10), 372
(40), 357 (10), 341 (80), 317 (18), 289 (5), 273 (8), 168 (5),
83 (60), 55 (24), 41 (13); FTIR (KBr, cm-1) mmax: 2,959,
1,742, 1,714, 1,642, 1,393, 1,126.
40,40,6,6-Tetramethyl-3-(2-naphthyl)-3,5,6,7-tetrahydro-
spiro[benzofuran-2(4H),10-cyclohexane]-20,4,60-trione
(3A)
Colorless crystalline powder in a 70 % yield; mp
278–279 °C. 1H NMR (300 MHz, CDCl3) d: 7.79 (m, 3H),
7.70 (s, 1H), 7.50 (m, 2H), 7.21 (d, J = 8.7 Hz, 1H), 4.62
(s, 1H), 3.16 (d, J = 15.0 Hz, 1H), 2.72 (s, 2H), 2.58 (d,
J = 15 Hz, 1H), 1.97–2.22 (m, 4H), 1.18 (s, 6H), 1.11 (s,
3H), 0.84 (s, 3H); 13C NMR (75 MHz, CDCl3) d: 26.3,
28.4, 28.9, 30.5, 30.6, 34.3, 37.3, 50.0, 51.1, 53.8, 55.1,
104.0, 114.0, 125.6, 126.5, 127.7, 127.9, 128.0, 129.0,
131.0, 133.0, 133.2, 133.5, 176.6, 194.0, 198.7, 199.2; MS
m/z (%): 416 (M?, 50), 357 (8), 332 (60), 316 (20), 304
(100, base peak), 291 (10), 277 (12), 248 (10), 205 (10),
191 (10), 178 (32), 165 (15), 149 (40), 127 (16), 83 (80), 69
(22), 55 (50), 41 (40); FTIR (KBr, cm-1) mmax: 3,054,
2,957, 2,873, 1,740, 1,713, 1,391.
40,40,6,6-Tetramethyl-3-(4-dimethylaminophenyl)-3,5,6,7-
tetrahydro-spiro[benzofuran-2(4H),10-cyclohexane]-
20,4,60-trione (3x)
Colorless crystalline powder in a 90 % yield; mp
1
298–299 °C. H NMR (300 MHz, DMSO-d6) d: 7.07 (m,
4H), 4.41 (s, 1H), 3.05 (d, J = 14.4 Hz, 1H), 2.98 (s, 6H),
2.66 (s, 2H), 2.54 (d, J = 13.5 Hz, 1H), 2.02–2.26 (m, 3H),
1.16 (s, 6H), 1.14 (s, 3H), 0.85 (s, 3H); 13C NMR (75 MHz,
DMSO-d6) d: 25.9, 28.0, 28.6, 30.4, 30.5, 34.0, 37.0, 49.6,
50.7, 53.7, 54.0, 54.2, 106.0, 113.0, 120.0, 130.3, 132.0,
150.0, 176.0, 194.0, 198.4, 199.0; FTIR (KBr, cm-1) mmax
2,957, 2,929, 2,874, 1,737, 1,712, 1,639, 1,390.
:
123

J IRAN CHEM SOC (2013) 10:565–575
571
40,40,6,6-Tetramethyl-3-(1-naphthyl)-3,5,6,7-tetrahydro-
spiro[benzofuran-2(4H),10-cyclohexane]-20,4,60-trione
(3B)
Table 1 Reaction of dimedone 1 with various aldehydes mediated by
BrCN in the presence of Et3N
Entry
R
Product Yield (%)
1
H (2a)
3a
3b
3c
3d
3e
3f
58
62
68
60
65
70
60
70
70
75
70
75
67
70
60
70
65
65
62
78
60
75
70
90
87
Colorless crystalline powder in a 60 % yield; mp
229–230 °C. 1H NMR (300 MHz, CDCl3) d: 8.30 (d,
J = 8.4 Hz, 1H), 7.89 (d, J = 7.8 Hz, 1H), 7.77 (d,
J = 7.8 Hz, 1H), 7.52–7.62 (m, 2H), 7.39 (t, J = 7.2 Hz,
1H), 7.16 (d, J = 7.2 Hz, 1H), 5.50 (s, 1H), 3.23 (d,
J = 15.0 Hz, 1H), 2.73 (s, 2H), 2.56 (d, J = 14.7 Hz, 1H),
2.25 (d, J = 16.2 Hz, 1H), 2.16 (d, J = 16.2 Hz, 1H), 1.84
(d, J = 13.8 Hz, 1H), 1.59 (d, J = 14.1 Hz, 1H), 1.19 (s,
6H), 0.90 (s, 3H), 0.78 (s, 3H); 13C NMR (75 MHz,
CDCl3) d: 26.1, 28.6, 28.8, 30.3, 30.4, 34.3, 37.4, 47.8,
50.5, 51.1, 52.8, 103.8, 114.9, 121.9, 125.6, 125.9, 127.2,
127.5, 128.9, 129.6, 131.2, 132.0, 133.9, 176.6, 192.9,
199.0, 199.7; FTIR (KBr, cm-1) mmax: 3,058, 2,959, 2,872,
1,741, 1,712, 1,645, 1,387.
2
CH3 (2b)
3
CH3CH2 (2c)
4
CH3CH2CH2 (2d)
C6H5 (2e)
5
6
p–NO2–C6H4 (2f)
m–NO2–C6H4 (2g)
o–NO2–C6H4 (2h)
trans–o–NO2–C6H4CH = CH (2i)
p–CN–C6H4 (2j)
7
3g
3h
3i
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
3j
trans–C6H5CH = CH (2k)
p–Br–C6H4 (2l)
3k
3l
m–Br–C6H4 (2m)
p–Cl–C6H4 (2n)
3m
3n
3o
3p
3q
3r
3s
p–CH3–C6H4 (2o)
m–OH–C6H4 (2p)
o–OH–C6H4 (2q)
3–OH–4–CH3O–C6H3 (2r)
4–OH–3–CH3O–C6H3 (2s)
o–CH3O–C6H4 (2t)
m–CH3O–C6H4 (2u)
p–CH3O–C6H4 (2v)
3,4,5–tri–CH3O–C6H2 (2w)
p–(CH3)2N–C6H4 (2x)
2-Bromo-5,5-dimethylcyclohexane-1,3-dione (6)
Colorless crystalline solid, mp 157–158 °C (Lit.: 156 °C
[27]). 1H NMR (300 MHz, CDCl3) d: 6.54 (s, 1H), 2.54 (s,
2H), 2.44 (s, 2H), 1.13 (s, 6H); 13C NMR (75 MHz,
CDCl3) d: 28.0, 32.0, 42.4, 50.8, 100.8, 190.2. (Equilib-
rium mixtures of two tautomers); MS m/z (%): 218 (M?,
50), 220 (M? ? 2, 50), 162 (95), 164 (100, base peak), 139
(25), 111 (27), 86 (90), 69 (27), 55 (45), 41 (40); FTIR
(KBr, cm-1) mmax: 3,410, 2,958, 2,929, 1,732, 1,612, 1,384.
3t
3u
3v
3w
3x
3y
trans–p–(CH3)2N–C6H4CH = CH
(2y)
26
3z
60
H
O
Results and discussion
(2z)
The reaction of dimedone (1) with BrCN and various
aldehydes in the presence of Et3N affords spiro 6,6-dime-
thyl-2,3,6,7-tetrahydrobenzofuran-4(5H)-one derivatives
(3) and salt of triethylammonium-2-bromo-5,5-dimethyl-
cyclohexane-1,3-dione-2-ide (4) (Scheme 1; Table 1). The
formation of salt 4 has interesting applications in many
chemical transformations.
27
28
3A
3B
70
60
(2A)
(2B)
As a part of our current studies on dimedone 1 and its
reaction with BrCN and our interest in the chemistry of
BrCN, we discovered the unexpected bromination of 1 by
BrCN (in the presence and absence of aldehyde). Previ-
ously, dimedone has been a-brominated by bro-
modimethylsulfonium bromide (BDMS) [27]. Cyanation of
compounds via BrCN are well known [20, 21, 28].
6
BrCN, MeOH
5
4
7
, Et3N, r.t.
O
O
O
1
O
O
+
3
2
Br
O
O
O
1' 6'
2'
3' 4'
R
5'
1
O
Et3NH
R
H
2
Although the mechanism of the reaction of 1 with BrCN
has not yet been established experimentally, a possible
explanation is proposed in Scheme 2. Previously, it was
reported that the reaction of b-dicarbonyl compound with
3
4
-(Et3NHBr)
Scheme 1 Reaction of dimedone (1) with cyanogen bromide and
aldehydes in the presence of triethylamine
123

572
J IRAN CHEM SOC (2013) 10:565–575
singlet at d 0.87 ppm corresponding to geminal methyl
groups, and a triplet at d 1.17 ppm and a quartet at d
3.02 ppm corresponding to methyl and methylene groups
in triethylammonium salt moiety, respectively. A singlet at
d 2.18 ppm corresponds to cyclic methylene groups in
dimedone ring moiety. Finally, a broad singlet at d
7.27 ppm related to NH ammonium salt moiety. The 13C
NMR spectrum is in good agreement with the molecular
structure and show seven distinct peaks. Two peaks at d
8.70 and at 28.3 ppm correspond to three equivalent
methyl groups on triethylammonium salt and two geminal
methyl groups on dimedone ring moieties, respectively.
Three peaks at d 31.7, 46.2 and 50.2 ppm correspond to
quaternary carbon atom on dimedone ring, three equivalent
methylene groups on triethylammonium salt moiety and
two equivalent methylene groups on dimedone ring moiety,
respectively. Two peaks at d 96.7 and 186.0 ppm corre-
spond to C–Br and two equivalent carbonyl groups on
dimedone ring moiety, respectively (see experimental and
supplementary data). Other evidence for the formation of 4
(the existence of bromine atom in this molecule) was
performed by Beilstein test and the wet silver nitrate test
[37] (precipitate of pale yellow silver bromide).
Et3N, BrCN
- HCN
H
O
OH
Br
O
O
O
O
H
Br
5
Br
N
6
N
Et3N
O
O
1
O
O
Br
Et3NH
4
Scheme 2 Proposed mechanism for the formation of 4
O
X
H3C
O
CH3
R
O
R
O
N
N
N
N
O
O
X = O, R = H (a)
X = O, R = CH3 ( )
X = S, R = H (c)
H3C
H3C
Br
b
N CH3
O
O
N
H3C
Et3NH
10
9
The proposed mechanism for the formation of 3 is
shown in Scheme 3. First, the Knoevenagel condensation
of 1 [17–19] with an aldehyde afforded 2-alkylidene and/or
2-arylidene-5,5-dimethylcyclohexane-1,3-dione (7) then
Michael addition of the compound 7 with 4 as the key
Fig. 2 Structures of spiro[furo[2,3-d]pyrimidine-6,50-pyrimidine]
derivative (9) [33], triethylammonium-5-bromo-(thio)barbiturates
(10) [34–36]
iodine and bromine gave the a-iodinated [29–31] and
a-brominated products [32], respectively. Recently, we
reported the crystal structure of 1,10,3,30,5,50-hexamethyl-
1H,10H-spiro[furo[2,3-d]pyrimidine-6,50-pyrimidine]2,20,4,
40,60(3H,30H,5H)-pentaone (9) that derived from the reac-
tion of 1,3-dimethylbarbituric acid with BrCN and acetone
in the presence of Et3N [33]. We proposed that in these
reactions the salts of triethylammonium-5-bromobarbitu-
rates (10) are formed in the reaction of (thio)barbituric
acids with aldehydes [34], aromatic dialdehydes [35] and
ketones [36] in the presence of BrCN (Fig. 2). The salts of
10 plays a major role for the synthesis of spiro[furo[2,3-
d]pyrimidine-6,50-pyrimidine]2,20,4,40,60(3H,30H,5H)-pen-
taones. According to the mechanism of the bromination of
1-alkyl imidazoles by BrCN [23] and the mechanism of the
formation of 10 [34–36], it was assumed that the enolic
form of dimedone 1 reacted with BrCN was formed via
intermediate 5. Intramolecular rearrangement of 5 afforded
6 followed by the loss of HCN. Triethylamine as a base
captured the acidic methylene proton of 6 forming salt 4
(Scheme 2). The salt of triethylammonium hydrobromide
was filtered. Unfortunately, all attempts failed to separate
or characterize 5 and 6 in the reaction with aldehydes. The
RCHO
Et3N, r.t.
O
O
O
O
1
H
R
7
Br
O
O
Et3NH
4
O
O
O
Br
O-attack
O
R
O
O
Et3NH
-Et3NHBr
R
O
O
3
8
1
structure of 4 was characterized by IR, H and 13C NMR
Scheme 3 Knoevenagel condensation, Michael addition and cycli-
zation mechanism for the formation of 3
1
spectroscopy. The H NMR spectrum of 4 consists of a
123

J IRAN CHEM SOC (2013) 10:565–575
573
O
RCHO, Et3N
MeOH, r.t.
4
1
5
8
3
2
6
7
9
O
O
O
R
O
1
11
Scheme 4 Formation of xanthene derivatives (11) from the reaction
of dimedone 1 with various aldehydes in the absence of BrCN
Fourier maps showed no peaks of chemical significance.
Crystal data for 3x: C25H31NO4, crystal system, space
group: monoclinic, P21/c; (no:14); unit cell dimensions:
˚
a = 18.8,941(7), b = 6.0,009(6), c = 20.3,990(5) A; vol-
3
ume: 2,236.01(2) A ; Z = 4; calculated density:
˚
1.22 mg cm-3
;
absorption coefficient: 0.082 mm-1
;
F(000): 880; h-range for data collection 2.1–26.6°; refine-
ment method: full-matrix least-square on F2; data/param-
eters: 4,606/276; goodness-of-fit on F2: 1.048; final
R indices [I [ 2r(I)]: R1 = 0.087, wR2 = 0.239; R indices
(all data): R1 = 0.275, wR2 = 0.245; largest diff. peak and
Fig. 3 Molecular structure of compound 3x. Thermal ellipsoids are
shown at 30 % probability level
hole: 0.446 and –0.581 eA-3. Crystallographic data were
˚
deposited in CSD under CCDC registration number:
848718 and are available free of charge upon request to
CCDC, 12 Union Road, Cambridge, UK (fax: ?44-1,223-
336,033, e-mail: deposit@ccdc.cam.ac.uk).
intermediate gave the intermediate (8). Finally, an intra-
molecular nucleophilic O-attack via 8 followed by elimi-
nation of Et3NHBr afforded spiro 6,6-dimethyl-2,3,6,
7-tetrahydrobenzofuran-4(5H)-ones 3 in good yield. Unfor-
tunately, all attempts failed to separate or characterize 8.
Dimedone and its derivatives were most often studied as
C-nucleophiles. This compound gives mono- and bis-con-
densation products with aldehydes [40–42]. Therefore,
according to Scheme 2, the BrCN plays a major role in
these reactions through intermediates 5 and 6 to form 4.
We believe the compound 4 is the key reactant for the
synthesis of 3a–z, 3A and 3B. No 4 and 3a–z, 3A and 3B
were observed in the absence of BrCN and/or Et3N under
the same condition!
Crystallographic analysis of 3x
To analyse the structural peculiarities of the synthesized
compound 3x, its molecular structure was determined by
single crystal X-ray diffraction. A perspective view of
molecule 3x is given in Fig. 3. The compound crystallizes
in the monoclinic space group P21/c, with four molecules
in the unit cell. p–(CH3)2N–C6H4 substituted stereogenic
center possess the R-configuration.
We performed the reaction of 1 with BrCN and Et3N in
the absence of aldehyde so we only obtained the salts of 4
and triethylammonium hydrobromide. For understanding
about the role of BrCN, reaction of 1 with aldehydes was
performed in the absence of BrCN under the same condi-
tion. In this reaction, 9-alkyl- and/or 9-aryl-3,4,6,7-tetra-
hydro-3,3,6,6-tetramethyl-2H-xanthene-1,8(5H,9H)-diones
(11) was obtained (Scheme 4) [16–19, 43–45]. The for-
mation of 11 confirms the important role of the BrCN in the
formation of 4.
For the crystal structure determination, the single crystal
of the compound 3x was used for data collection on a four-
circle Rigaku R-AXIS RAPID-S diffractometer (equipped
with a two dimensional area IP detector). The graphite-
˚
monochromatised Mo Ka radiation (k = 0.71,073 A) and
oscillation scans technique with Dx = 5° for one image
were used for data collection. The lattice parameters were
determined by the least-squares methods on the basis of all
reflections with F2 [ 2r(F2). Integration of the intensities,
correction for Lorentz and polarization effects and cell
refinement was performed using CrystalClear (Rigaku/
MSC Inc., 2,005) software [38]. The structures were solved
by direct methods using SHELXS-97 [39] and refined by a
full-matrix least-squares procedure using the program
SHELXL-97 [39] H-atoms were positioned geometrically
and refined using a riding model. The final difference
Next, a variety of aldehydes (aromatics and aliphatics)
were selected (under optimum condition) to react with
dimedone (Table 1). Various aromatic aldehydes possess-
ing electron-donating and electron-withdrawing substituent
reacted smoothly and efficiently under the basic condition,
affording the corresponding spiro 6,6-dimethyl-2,3,6,7-
tetrahydrobenzofuran-4(5H)-one derivatives 3 in good
yields. The aldehyde with an electron-withdrawing
123

574
J IRAN CHEM SOC (2013) 10:565–575
´
2. S. Maiti, P.T. Perumal, J.C. Menendez, Tetrahedron 66, 9512
(2010)
3. J. Wang, L. Zhu, K. Zou, F. Cheng, F. Dan, Z. Guo, Z. Cai, J.
Yang, J. Ethnopharmacol. 123, 343 (2009)
4. E. Findik, A. Dingil, I. Karaman, Y. Budak, M. Ceylan, E-J.
Chem. 6(S1), S53 (2009)
5. P. Dimroth, H. Pasedach, Angew. Chem. 72, 865 (1960)
6. F.E. Mcdonald, C.B. Connolly, M.M. Gleason, T.B. Towne, K.D.
Treiber, J. Org. Chem. 58, 6952 (1993)
Acetone
Et3N, r.t.
1 + BrCN
O
OH
Br
6
7. M.C. Pirrung, F. Blume, J. Org. Chem. 64, 3642 (1999)
8. Y.R. Lee, J.Y. Suk, Tetrahedron 58, 2359 (2002)
9. Y.R. Lee, J.C. Hwang, Eur. J. Org. Chem. 58, 1568 (2005)
10. J.R. Hwu, C.N. Chen, S.S. Shiao, J. Org. Chem. 60, 856 (1995)
11. H. Nishino, V.H. Nguyen, S. Yoshinaga, K. Kurosawa, J. Org.
Chem. 61, 8264 (1996)
Scheme 5 Formation of 6 from the reaction of 1 with BrCN in
acetone
substituent gave a higher yield than those bearing an
electron-donating substituent. Aliphatic aldehydes, includ-
ing formaldehyde (2a), acetaldehyde (2b), propionalde-
hyde (2c) and butyraldehyde (2d) were also investigated
(see ‘‘Experimental’’ and Table 1).
´
12. F. Garzino, A. Meou, P. Brun, Tetrahedron Lett. 41, 9803 (2000)
13. E.V. Burgaz, M. Yilmaz, A.T. Pekel, A. Oktemer, Tetrahedron
¨
63, 7229 (2007)
14. G.-W. Wang, Y.W. Dong, P. Wu, T.T. Yuan, Y.B. Shen, J. Org.
Chem. 73, 7088 (2008)
15. G.-W. Wang, J. Gao, Org. Lett. 11, 2385 (2009)
16. J. Chen, J. Shi, C. Yan, Chem. Res. Chin. Univ. 27, 49 (2011)
17. K. Niknam, M. Damya, J. Chin. Chem. Soc. 56, 659 (2009)
18. M.R. Poorheravi, J. Iran. Chem. Soc. 6, 483 (2009)
19. H.R. Shaterian, A. Hosseinian, M. Ghashang, Turk. J. Chem. 33,
233 (2009)
The reaction of 1 with BrCN with less hindered ketone
(acetone) was explored under the same condition produc-
ing exclusively a-monobrominated 6 in moderate yield
(Scheme 5). Surprisingly, the proton of carbon atom of
1
a-brominated 6 was observed in H NMR time scale and
20. V. Kumar, Synlett 10, 1638 (2005)
the IR spectrum showed carbonyl and hydroxyl bonds
stretching (see ‘‘Experimental’’). Interestingly, this inter-
mediate in the solid state does exists as enol form [27].
21. D. Martin, M. Bauer, Org. Synth. Coll. 7, 435 (1990)
22. E. Gross, B. Witkop, J. Am. Chem. Soc. 83, 1510 (1961)
23. P.B.W. McCallum, M.R. Grimmett, A.G. Blackman, R.T.
Weavers, Aust. J. Chem. 52, 159 (1999)
24. D.D. Tanner, G. Lycan, N.J. Bunce, Can. J. Chem. 48, 1492
(1970)
25. A. Alberola, C. Andres, A.G. Ortega, R. Pedrosa, M. Vicente,
Synth. Commun. 16, 1161 (1986)
Conclusion
26. W.W. Hartman, E.E. Dreger, Org. Synth. Coll. 2, 150 (1943)
27. A.T. Khan, M.A. Ali, P. Goswami, L.H. Choudhury, J. Org.
Chem. 71, 8961 (2006)
28. G.A. Olah, Friedel-Crafts Chemistry, vol. 1 (Wiley, New York,
1963), p. 119
29. D. Yang, Q. Gao, C.S. Lee, K.K. Cheung, Org. Lett. 4, 3271
(2002)
30. J.F. Nierengarten, V. Gramlich, F. Cardullo, F. Diederich, Angew.
Chem. Int. Ed. 35, 2101 (1996)
31. S. Gogoi, R. Bhuyan, N.C. Barua, Synth. Commun. 35, 2811
(2005)
32. M.N. Elinson, A.N. Vereshchagin, N.O. Stepanov, P.A. Belya-
kov, G.I. Nikishin, Tetrahedron Lett. 51, 6598 (2010)
33. N. Noroozi Pesyan, S. Rastgar, Y. Hosseini, Acta Cryst. Sect. E.
65, o1444 (2009)
34. M. Jalilzadeh, N. Noroozi Pesyan, F. Rezaee, S. Rastgar, Y.
Hosseini, E. S¸ahin, Mol. Divers. 15, 721 (2011)
35. N. Noroozi Pesyan, M. Jalilzadeh, Turk. J. Chem. 36, xxx (2012).
doi:10.3906/kim-1201-27
In summary, a versatile one-pot reaction of dimedone with
aldehydes selectively affords spiro dihydrofurans in the
presence of cyanogen bromide and triethylamine in good
yields. The BrC-mediated oxidative cycloaddition provides
an efficient route to the preparation of a wide variety of
spiro dihydrofuran derivatives. The experimental results
indicated that the aromatic aldehydes possessing electron-
withdrawing are more reactive than those with electron-
donating substituent or aliphatic aldehydes. The notable
advantages of this protocol are mild, clean, good yields,
simple reaction conditions and no need of chromatographic
separations. The synthesis of spiro dihydrofuran deriva-
tives was not successful using ketones.
Acknowledgments We gratefully acknowledge financial support
by the Research Council of Urmia University (Grant Research
no. #9-10,523). The authors also gratefully acknowledge to Prof.
Dr. Dabbagh H. A. of Isfahan University of Technology (IUT) from
Iran for his helpful discussion and guidance.
¨
36. Y. Hosseini, S. Rastgar, Z. Heren, O. Bu¨yu¨kgu¨ngor, N. Noroozi
Pesyan, J. Chin. Chem. Soc. 58, 309 (2011)
37. R.L. Schriner, R.C. Fusan, D.Y. Curtin, T.C. Morrill, The Sys-
tematic Identification of Organic Compounds, 6th edn. (Wiley,
New York, 1980), p. 78
38. Rigaku/MSC, Inc., 9009 new Trails Drive, The Woodlands, TX
77381
39. G.M. Sheldrick, SHELXS-97 and SHELXL-97, ‘Program for
References
¨
Crystal Structure Solution and Refinement’ (University of Got-
tingen, Germany, 1997)
40. H.R. Shaterian, A. Hosseinian, M. Ghashang, ARKIVOC ii, 59
(2009)
1. A. Nefzi, J.M. Ostresh, R.A. Houghten, Chem. Rev. 97, 449
(1997)
123

J IRAN CHEM SOC (2013) 10:565–575
575
41. A.N. Pyrko, Chem. Heterocyc. Compd. 32, 635 (1996)
42. M.M. El-Sadek, S.Y. Hassan, N.N. El-Soccary, M.M.A. Hassan,
J. Saudi Chem. Soc. 8, 511 (2004)
44. Y.B. Shen, G.W. Wang, ARKIVOC, xvi, 1 (2008)
45. H.A. Oskooie, L. Tahershamsi, M.M. Heravi, B. Baghernejad,
E-J. Chem. 7, 717 (2010)
43. A. Kumbhar, S. Kamble, G. Rashinkar, K. Mote, R. Salunkhe,
Arch. Appl. Sci. Res. 2, 235 (2010)
123