Preparation of 2-(N,N-dialkylamino)-2,4,6-cycloheptatrien-1-one derivatives from an isocyanide, a primary amine, propionaldehyde, and tropolone via Ugi-Smiles coupling reaction in the presence of silica nanoparticles

Article abstract of DOI:10.3906/kim-1202-8

The use of Smiles rearrangement in Ugi-type couplings with tropolone allows very straightforward multicomponent formation of 2-(N,N-dialkylamino)-2,4,6- cycloheptatrien-1-one derivatives. The 4-component reaction of isocyanides, tropolone (2-hydroxy-2,4,6-cycloheptatrien-1-one), primary amines, and propionaldehyde in the presence of silica nanoparticles (silica NPs, ca. 42 nm) proceeds easily in methanol to form the title compounds in a new Ugi-Smiles-type reaction. TUeBITAK.

Full text of DOI:10.3906/kim-1202-8

Turk J Chem
36 (2012) , 779 – 787.
¨
˙
c
ꢀ TUBITAK
doi:10.3906/kim-1202-8
Preparation of 2-(N ,N -dialkylamino)-2,4,6-
cycloheptatrien-1-one derivatives from an isocyanide, a
primary amine, propionaldehyde, and tropolone via
Ugi-Smiles coupling reaction in the presence of silica
nanoparticles
Abdolhossain MASSOUDI1, Issa AMINI1, Ali RAMAZANI2,∗
,
Fatemeh ZEINALI NASRABADI3
1Department of Chemistry, Payame Noor University, P.O. Box 19395-3697, Tehran-IRAN
2Department of Chemistry, Zanjan Branch, Islamic Azad University,
P.O. Box 49195-467, Zanjan-IRAN
e-mail: aliramazani@gmail.com
3Department of Chemistry, University of Zanjan, P.O. Box 45195-313, Zanjan-IRAN
Received: 03.02.2012
The use of Smiles rearrangement in Ugi-type couplings with tropolone allows very straightforward mul-
ticomponent formation of 2-(N ,N -dialkylamino)-2,4,6-cycloheptatrien-1-one derivatives. The 4-component
reaction of isocyanides, tropolone (2-hydroxy-2,4,6-cycloheptatrien-1-one), primary amines, and propionalde-
hyde in the presence of silica nanoparticles (silica NPs, ca. 42 nm) proceeds easily in methanol to form the
title compounds in a new Ugi–Smiles-type reaction.
Key Words: Ugi-type coupling, tropolone, isocyanides, primary amines, silica (NP), Ugi–Smiles-type
reaction
Introduction
Multicomponent reactions (MCRs) allow more than 2 simple and flexible building blocks to be combined in
practical, timesaving one-pot operations. Due to their valued features such as atom economy, inherent simple
∗Corresponding author
779

Preparation of 2-(N ,N -dialkylamino)-2,4,6-cycloheptatrien-1-one..., A. MASSOUDI, et al.
experimental procedures, and their one-pot character, they are perfectly suited for automated synthesis.1
Therefore, MCRs have attracted much attention because of their exceptional synthetic efficiency. 2−5 Since
all the organic reagents employed are used and moved toward the target compound the purification of products
resulting from MCRs is simple.6,7 Isocyanide-based multicomponent reactions (abbreviated to IMCRs by Ugi
and Do¨mling) have an advantageous position. The special features of IMCRs including unique synthetic
potential, high atom economy, convergent nature, ease of implementation, and the molecular diversity generation
are considered acceptable factors in the relative advantage of the reactions.6−13
In recent years, nanoparticles (NPs) have attracted tremendous attention in catalysis because of their
improved efficiency under mild and environmentally benign conditions in the context of ecological (green)
synthesis.14,15 Due to their enormously large and highly reactive surface area, NPs have potential to exhibit
superior catalytic activity in comparison to their bulk counterparts.16,17 In the past, we established a one-pot
method for the preparation of organic compounds.18−24 As part of our ongoing program to develop efficient and
robust methods for the synthesis of heteroatom-containing compounds,25−32 we wish to report the preparation
of a new class of 2-(N ,N -dialkylamino)-2,4,6-cycloheptatrien-1-one derivatives 5a-h by a novel 4-component
condensation reaction of propionaldehyde 1, primary amines 2, isocyanides 3, and tropolone 4 in the presence
of silica NPs in excellent yields (Scheme 1).
Experimental
The starting materials and solvents were obtained from Merck (Germany) and Fluka (Switzerland) and were
used without further purification. The methods used to follow the reactions were TLC and NMR. TLC and NMR
indicated that there were no side products. IR spectra were measured on a Jasco 6300 FTIR spectrometer. 1 H-
and 13 C-NMR spectra (CDCl3) were recorded on a BRUKER DRX-400 AVANCE spectrometer at 400.22 and
100.63 MHz, respectively. Elemental analyses were performed using a Heraeus CHN-O-Rapid analyzer. Mass
spectra were recorded on a FINNIGAN-MATT 8430 mass spectrometer operating at an ionization potential of
70 eV. Preparative layer chromatography (PLC) plates were prepared from Merck silica gel (F254) powder.
General procedure for the preparation of compounds 5a-5h
To magnetically stirred silica NPs (0.2 g) and solution of propionaldehyde 1 (1 mmol), primary amine 2 (1
mmol), and tropolone 4 (1 mmol) in CH3 OH (7 mL) was added dropwise a solution of isocyanide 3 (1 mmol) in
CH3 OH (2 mL) at 60 ◦ C over 5 min. The reaction mixture was refluxed for 6 h. The solvent was removed under
reduced pressure and the viscous residue was purified by preparative layer chromatography (silica gel (F254);
petroleum ether–ethyl acetate (4:1)). The solvent was removed under reduced pressure and the products (5a-h)
were obtained. The characterization data of the compounds are given below.
2-[Benzyl(7-oxo-1,3,5-cycloheptatrienyl)amino]-N1-cyclohexylbutanamide (5a)
Yellow oil, (Yield: 92%). IR (neat): v = 3440, 2952, 1745, 1651, 1600, 1466, 1227, 1077 cm−1
.
1 H-NMR
(400.22 MHz, CDCl3) δ (ppm): 0.79 (t, 3H, J = 7.4 Hz, CH3), 0.86-2.1 (m, 10H, 5CH2 of cyclohexyl and m,
2H, CH2 of propyl), 3.80-4.02 (m, 1H, CH–N of cyclohexyl), 4.50 (AB, 2H, J = 16.8 Hz, PhCH2), 4.55 (t,
780

Preparation of 2-(N ,N -dialkylamino)-2,4,6-cycloheptatrien-1-one..., A. MASSOUDI, et al.
1H, J = 7.0 Hz, CH), 6.53 (d, 1H, J = 10.4 Hz, CH of tropone), 6.63 (t, 1H, J = 9.0 Hz, CH of tropone),
6.84 (t, 1H, J = 10.2 Hz, CH of tropone); 7.07-7.35 (m, 7H, CH of tropone and ph); 8.69 (d, 1H, J = 8.0
Hz, NH exchanged by D2 O addition).13 C-NMR (100.63 MHz, CDCl3) δ (ppm): 11.74 (CH3), 22.35 (CH2
of propyl), 24.81, 25.66, 33.11 (3CH2 of cyclohexyl), 47.84 (CH of cyclohexyl), 49.56 (PhCH2), 63.55 (CH),
121.51, 126.58, 126.98, 127.22, 128.55, 133.83, 134.56, 136.56 (8 CH of tropone and Ph), 135.93 (Cip of Ph),
158.12 (C of tropone), 169.80 (C=O of amide), 184.38 (C=O of tropone). Analysis of C24 H30 N2 O2 (378.23).
(% calculation/found): C: 76.16/76.12, H: 7.99/7.96, N: 7.40/7.45. MS, m/z(%): 378 (4), 287 (14), 252 (95),
210 (63), 188 (21), 160 (33), 148 (44), 132 (20), 106 (20), 105 (13), 91 (100), 77 (17), 65 (18), 57 (15), 55 (34),
41 (32).
2-[Benzyl(7-oxo-1,3,5-cycloheptatrienyl)amino]-N1- (tert-butyl)butanamide (5b)
Yellow oil, (Yield: 90%). IR (neat): v = 3423, 2922, 1742, 1636, 1620, 1461, 1234, 1030 cm−1
.
1 H-NMR
(400.22 MHz, CDCl3) δ (ppm): 0.78 (t, 3H, J =7.4 Hz, CH3), 1.37 (s, 9H, CMe3), 1.70-2.10 (m, 2H, CH2 of
propyl), 4.50 (AB, 2H, J = 16.8 Hz, PhCH2), 4.51 (t, 1H, J = 6.4 Hz, CH), 6.51 (d, 1H, J = 10.4 Hz, CH
of tropone), 6.66 (t, 1H, J = 9.0 Hz, CH of tropone), 6.85 (t, 1H, J = 10.2 Hz, CH of tropone), 7.07-7.38 (m,
7H, CH of tropone and Ph), 8.65 (s, 1H, NH exchanged by D2 O addition). 13 C-NMR (100.63 MHz, CDCl3) δ
(ppm): 11.77 (CH3), 22.20 (CH2 of propyl), 28.72 (3CH3), 49.43 (PhCH2), 50.67(CMe3), 64.01 (CH), 121.25,
126.47, 126.91, 127.24, 128.57, 133.85, 134.37, 136.57 (8 CH of tropone and Ph), 135.91 (Cip of Ph), 158.18
(C of tropone), 170.02 (C=O of amide), 184.46 (C=O of tropone). Analysis of C22 H28 N2 O2 (352.22). (%
calculation/found): C: 74.97/74.94, H: 8.01/8.05, N: 7.95/7.92. MS, m/z(%): 352 (14), 280 (10), 261 (25), 252
(100), 210 (67), 188 (24), 160 (56), 148 (14), 132 (41), 106 (15), 105 (20), 91 (89), 77 (36), 65 (26), 57 (48), 41
(37).
N1 -(tert-butyl)-2-[(7-oxo-1,3,5-cycloheptatrienyl)(propyl)amino]butanamide (5c)
Yellow oil, (Yield: 83%). IR (neat): v = 3444, 2922, 1746, 1650, 1608, 1469, 1256, 1084 cm−1
.
1 H-NMR
(400.22 MHz, CDCl3) δ (ppm): 0.70 (t, 3H, J = 7.4 Hz, CH3 of (CH2)2 CH3), 0.88 (t, 3H, J = 7.4 Hz, CH3
of CH2 CH3), 1.39 (s, 9H, CMe3), 1.23-2.20 (m, 4H, 2CH2), 3.07-3.37 (m, 2H, NCH2), 4.35 (t, 1H, J = 7.0
Hz, H-C), 6.66 (d, 1H, J = 10.4 Hz, CH of tropone), 6.72 (t, 1H, J = 9.2 Hz, CH of tropone), 7.00-7.30 (m,
3H, CH of tropone), 8.39 (s, 1H, NH exchanged by D2 O addition).13 C-NMR (100.63 MHz, CDCl3) δ (ppm):
11.46 and 11.68 (2 CH3), 19.06 and 21.85 (2CH2), 28.69 (3CH3), 47.01 (CH2 N); 50.51 (CMe3), 64.07 (CH),
119.92, 125.98, 133.93, 134.12, 136.43 (5 CH of tropone), 158.61 (C of tropone), 170.21 (C=O of amide), 184.42
(C=O of tropone). Analysis of C18 H28 N2 O2 (304.22). (% calculation/found): C: 71.02/71.05, H: 9.27/9.25,
N: 9.20/9.23. MS, m/z(%): 304 (28), 261 (10), 252 (91), 236 (15), 220 (42), 210 (31), 205 (98), 204 (100), 188
(13), 162 (85), 160 (33), 132 (28), 105 (13), 91 (24), 77 (14), 57 (10), 41 (8).
N1 -cyclohexyl-2-[(7-oxo-1,3,5-cycloheptatrienyl)(propyl)amino]butanamide (5d)
Yellow oil, (Yield: 80%). IR (neat): v = 3445, 2927, 1740, 1654, 1616, 1465, 1260, 1018 cm−1
.
1 H-NMR
(400.22 MHz, CDCl3) δ (ppm): 0.71 (t, 3H, J = 7.4 Hz, CH3 of (CH2)2 CH3), 0.85 (t, 3H, J = 7.4 Hz,
CH3 of CH2 CH3), 0.96-2.39 (m, 14H, 5 CH2 of cyclohexyl and 2 CH2 of acyclic), 3.07-3.41 (m, 2H, NCH2),
781

Preparation of 2-(N ,N -dialkylamino)-2,4,6-cycloheptatrien-1-one..., A. MASSOUDI, et al.
3.70-3.91 (m, 1H, CH–N of cyclohexyl), 4.40 (t, 1H, J = 7.0 Hz, CH), 6.66 (d, 1H, J = 10.4 Hz, CH of
tropone), 6.72 (t, 1H, J = 9.2 Hz, CH of tropone), 7.04-7.30 (m, 3H, CH of tropone), 8.43 (d, 1H, J = 8.0 Hz,
NH exchanged by D2 O addition). 13 C-NMR (100.63 MHz, CDCl3) δ (ppm): 11.41 and 11.65 (2 CH3), 19.00
and 21.99 (2 CH2), 24.79, 26.65, 32.96 (2 CH2 of cyclohexyl), 47.03 (CH2 N); 47.79 (CH of cyclohexyl), 63.60
(CH), 120.02, 126.07, 133.94, 136.44 (5 CH of tropone), 158.57 (C of tropone), 170.03 (C=O of amide), 184.28
(C=O of tropone). Analysis of C20 H30 N2 O2 (330.23). (% calculation/found): C: 72.69/72.65, H: 9.15/9.18,
N: 8.48/8.44.
2-[benzyl (7-oxo-1,3,5-cycloheptatrienyl) amino]-N1 -(2,4,4-trimethyl sec. pentyl) butanamide
(5e)
Yellow oil, (Yield: 85%). IR (neat): v = 3429, 2923, 1748, 1651, 1619, 1417, 1221, 1020 cm−1
.
1 H-NMR
(400.22 MHz, CDCl3) δ (ppm): 0.79 (t, 3H, J = 7.4 Hz, CH3), 1.05 (s, 9H, CMe3), 1.43 (s, 6H, CMe2 NH),
1.62-2.20 (m, 2H, CH2 of propyl and s, 2H, CH2 CMe3), 4.49 (t, 1H, J = 7.0 Hz, CH), 4.51 (AB, 2H, J =
16.8 Hz, PhCH2), 6.51 (d, 1H, J = 10.4 Hz, CH of tropone), 6.63 (t, 1H, J = 9.0 Hz, CH of tropone), 6.85
(t, 1H, J = 10.4 Hz, CH of tropone), 7.08-7.38 (m, 7H, CH of tropone and ph), 8.50 (s, 1H, NH exchanged
by D2 O addition). 13 C-NMR (100.63 MHz, CDCl3) δ (ppm): 11.80 (CH3), 22.26 (CH2 of propyl), 29.27
(CMe2 NH), 31.51 (CMe3), 31.64 (CMe3), 49.48 (PhCH2), 51.16 (CH2 CMe3), 54.63 (CMe2 NH), 64.08 (CH),
121.10, 126.35, 126.91, 127.18, 128.53, 133.75, 134.44, 136.37 (8 CH of tropone and Ph), 135.92 (Cip of Ph),
158.02 (C of tropone), 169.71 (C=O of amide), 184.27 (C=O of tropone). Analysis of C26 H36 N2 O2 (408.28).
(% calculation/found): C: 76.43/76.45, H: 8.88/8.91, N: 6.86/6.82.
N1 -(tert-butyl)-2-[cyclohexyl(7-oxo-1,3,5-cycloheptatrienyl)amino]butanamide (5f)
Yellow oil, (Yield: 75%). IR (neat): v = 3424, 2921, 1743, 1652, 1616, 1473, 1220, 1032 cm−1
.
1 H-NMR
(400.22 MHz, CDCl3) δ (ppm): 0.88 (t, 3H, J = 7.4 Hz, CH3), 1.33 (s, 9H, CMe3), 0.89-2.20 (m, 10H, CH2
of cyclohexyl and m, 2H, CH2 of propyl), 3.30 (t, 1H, J = 11.4 Hz, CH–N of cyclohexyl), 4.00 (t, 1H, J =
7.0 Hz, H-C), 6.68 (t, 1H, J = 9.0 Hz, CH of tropone), 6.95-7.30 (m, 4H, CH of tropone), 8.23 (s, 1H, NH,
exchanged by D2 O addition).13 C-NMR (100.63 MHz, CDCl3) δ (ppm): 12.53 (CH3), 24.00 (CH2 of propyl),
25.73, 26.23, 26.47, 30.62, 33.32 (5 CH2 of cyclohexyl), 28.58 (3CH3), 50.49 (CMe3), 60.98 (CH of cyclohexyl),
65.20 (CH), 120.01, 126.44, 133.15, 133.91, 135.92 (5 CH of tropone), 158.42 (C of tropone), 170.88 (C=O of
amide), 185.61 (C=O of tropone). Analysis of C21 H32 N2 O2 (344.25). (% calculation/found): C: 73.22/73.18,
H: 9.36/9.33, N: 8.13/8.09.
2-[cyclohexyl (7-oxo-1,3,5-cycloheptatrienyl) amino]-N1 -(2,4,4-trimethyl sec. pentyl) butanamide
(5g)
Yellow oil, (Yield: 70%). IR (neat): v = 3291, 2933, 1741, 1659, 1608, 1461, 1250, 1071 cm−1
.
1 H-NMR
(400.22 MHz, CDCl3) δ (ppm): 0.90 (t, 3H, J = 7.4 Hz, CH3), 1.01 (s, 9H, CMe3), 1.42 (s, 6H, CMe2 NH),
1.07-2.30 (m, 10H, 5 CH2 of cyclohexyl and m, 2H, CH2 of propyl and s, 2H, CH2 CMe3), 3.37 (t, 1H, J = 11.6
Hz, CH–N of cyclohexyl), 3.98 (t, 1H, J = 7.0 Hz, H-C), 6.68 (t, 1H, J = 9.0 Hz, CH of tropone), 6.95-7.30 (m,
4H, CH of tropone), 8.04 (s, 1H, NH, exchanged by D2 O addition).13 C-NMR (100.63 MHz, CDCl3) δ (ppm):
782

Preparation of 2-(N ,N -dialkylamino)-2,4,6-cycloheptatrien-1-one..., A. MASSOUDI, et al.
12.78 (CH3), 24.18 (CH2 of propyl), 25.75, 26.23, 26.49, 30.64, 33.35 (5 C H2 of cyclohexyl), 28.71 (CMe2),
31.48 (CMe3), 31.56 (CMe3), 51.36 (CH2 CMe3), 54.54 (CMe2 NH), 60.88 (CH of cyclohexyl), 65.11 (CH),
121.57, 126.22, 133.06, 133.87, 135.72 (5 CH of tropone), 158.23 (C of tropone), 170.44 (C=O of amide), 185.33
(C=O of tropone). Analysis of C25 H40 N2 O2 (400.31). (% calculation/found): C: 74.95/74.99, H: 10.06/10.10,
N: 6.99/6.94.
N1 -cyclohexyl-2-[cyclohexyl (7-oxo-1,3,5-cycloheptatrienyl)amino] butanamide (5h)
Yellow oil, (Yield: 79%). IR (neat): v = 3340, 2971, 1740, 1653, 1612, 1478, 1222, 1080 cm−1
.
1 H-NMR
(400.22 MHz, CDCl3) δ (ppm): 0.88 (t, 3H, J = 7.4 Hz, CH3), 0.91-2.20 (m, 20H, 10 CH2 of 2 cyclohexyl
and m, 2H, CH2 of propyl), 3.20-3.80 (m, 2H, 2 CH of 2 cyclohexyl), 4.01 (t, 1H, J = 7.0 Hz, H-C), 6.72 (t, 1H,
J = 9.0 Hz, CH of tropone), 6.96-7.30 (m, 4H, CH of tropone), 8.31 (d, 1H, J = 8.0 Hz, NH, exchanged by D2 O
addition). 13 C-NMR (100.63 MHz, CDCl3) δ (ppm): 12.67 (CH3), 24.09 (CH2 of propyl), 24.72, 24.80, 25.60,
25.74, 26.22, 26.37, 30.74, 32.81, 32.95, 33.03 (10 CH2 of 2 cyclohexyl), 64.77 (CH), 122.94, 126.92, 133.09,
134.39, 135.95 (5 CH of tropone), 158.38 (C of tropone), 170.99 (C=O of amide), 185.83 (C=O of tropone).
Analysis of C23 H34 N2 O2 (370.26). (% calculation/found): C: 74.55/74.59, H: 9.25/9.22, N: 7.56/7.59.
Results and discussion
The 1:1 imine intermediate generated by the addition of primary amine 2 to propionaldehyde 1 is trapped by
isocyanide 3 and tropolone 4 in the presence of silica NPs, leading to the formation of 2-(N ,N -dialkylamino)-
2,4,6-cycloheptatrien-1-one derivatives 5 (Scheme 1 and Table 1). The reaction proceeds smoothly and cleanly
under mild conditions, and no side reactions are observed.
Silica NPs were found to catalyze the synthesis of 2-(N ,N -dialkylamino)-2,4,6-cycloheptatrien-1-one
derivatives from propionaldehyde 1, primary amines 2, isocyanides 3, and tropolone 4 in methanol at 60 ◦ C
with high efficiency (Scheme 1 and Table 1). We also used silica gel powder (Merck) instead of silica NPs in this
reaction, but increasing reaction times and decreasing 2-(N ,N -dialkylamino)-2,4,6-cycloheptatrien-1-one yields
were observed (Scheme 1 and Table 1). The use of just 0.2 g of silica NPs per mmol of reactants is sufficient
to push the reaction forward. Higher amounts of silica NPs (0.3 g) did not improve the result to a great extent
(Table 2, entries 4-7). In order to investigate the effects of other reaction media in this reaction, we also carried
out the described condensation in MeOH, H2 O and solvent-free (neat) systems (Table 2, entries 1-3).
A possible mechanism for the present reaction is shown in Scheme 2, which envisages a tandem sequence.
On the basis of the chemistry of isocyanides, it is reasonable to assume that the first step may involve the
formation of imine 6 by the condensation reaction of primary amine 2 with propionaldehyde 1; the next
step may involve nucleophilic addition of the isocyanide 3 to the imine intermediate 7, leading to nitrilium
intermediate 8. This intermediate may be attacked by the conjugate base of the tropolone 4 to form 1:1:1 adduct
9. The intermediate 9 may undergo Smiles rearrangements to afford the isolated 2-(N ,N -dialkylamino)-2,4,6-
cycloheptatrien-1-one derivatives 5 via intermediate 10. It may be speculated that the polar amphoteric surface
(hydroxyl groups of the silica NPs) facilitates the interaction of adsorbed weak acidic and basic components due
to stabilization of the corresponding transition states and intermediates by H-bonding. This interaction with
783

Preparation of 2-(N ,N -dialkylamino)-2,4,6-cycloheptatrien-1-one..., A. MASSOUDI, et al.
O
R1
N
OH
H
O
60 oC
MeOH
HN
H3C
R1 NH2
R2 NC
+
+
+
R2
H3C
SiO2 NP, 6h
O
O
1
2
3
4
5
5a: R1 = Benzyl, R2 = Cyclohexyl; 5b: R1 = Benzyl, R2 = tert-Butyl; 5c: R1 =n-Propyl, R2 = tert-Butyl; 5d:
R1 =n-Propyl, R2 = Cyclohexyl; 5e: R1 = Benzyl, R2 = 1,1,3,3-tetramethylbutyl; 5f: R1 = Cyclohexyl, R2
tert-Butyl; 5g: R1 = Cyclohexyl, R2 = 1,1,3,3-tetramethylbutyl; 5h: R1 = Cyclohexyl, R2 = Cyclohexyl.
=
Scheme 1. Four-component synthesis of 2-(N ,N -dialkylamino)-2,4,6-cycloheptatrien-1-one derivatives 5 in the pres-
ence of silica NPs (see Table 1).
Table 1. SiO2 NP-promoted synthesis of 2-(N ,N -dialkylamino)-2,4,6-cycloheptatrien-1-one derivatives 5a .
5
a
b
c
d
e
f
R1
R2
Cyclohexyl
Yield (%)b
Benzyl
92
90
83
80
85
75
70
79
b
Benzyl
tert-Butyl
n-Propyl
n-Propyl
Benzyl
tert-Butyl
Cyclohexyl
1,1,3,3-Tetramethylbutyl
tert-Butyl
Cyclohexyl
g
h
Cyclohexyl 1,1,3,3-Tetramethylbutyl
Cyclohexyl Cyclohexyl
a See Scheme 1; 0.2 g SiO2 NP/mmol reactants were applied. Yield of isolated 5.
Table 2. Synthesis of 2-(N ,N -dialkylamino)-2,4,6-cycloheptatrien-1-one derivatives 5a from the reaction of propi-
onaldehyde, benzylamine, cyclohexyl isocyanide, and tropolone under various conditions.
Entry
Catalysta or solvent
Temp (◦C) Time (h) Yield (%)b
1
2
3
4
5
6
7
MeOH
60
90
90
60
60
60
60
24
24
24
24
6
65
57
35
77
83
92
92
H2O
neat
MeOH/Silica gel powder (Merck) (0.2 g)
MeOH/SiO2 NP (0.1 g)
MeOH/SiO2 NP (0.2 g)
MeOH/SiO2 NP (0.3 g)
b
6
6
a Amount of SiO2 catalyst per mmol of reactants. Yields of isolated 5a.
784

Preparation of 2-(N ,N -dialkylamino)-2,4,6-cycloheptatrien-1-one..., A. MASSOUDI, et al.
the neighboring silanol groups is shown in Scheme 2 for the first reaction step. Participation of 2 proximate
silanol groups (one as H-bond donor and the other as H-bond acceptor) in the reaction mechanism also seems
plausible.
R1
H
O
H
N
H
OH
O
H
H
1 +
2
H3C
O
O
H
CH3
N
R1
H
O
O
R1
H
O
O
N
R1
H
C
R1
H
N
H
H3C
H
N
3,4
H3C
H3C
N
OH
C
N
R2
R2
-H2O
7
3
6
8
R2
R2
N
CH3
N
O
CH3
O
O
H
O
5
H
NH
R1
HN
R1
9
10
Scheme 2. Proposed mechanism for the formation of 2-(N ,N -dialkylamino)-2,4,6-cycloheptatrien-1-one derivatives 5
in the presence of silica NPs.
The structures of the products were deduced from their IR, 1 H-NMR, and 13 C NMR-spectra and mass
spectrometry. For example, the 1 H-NMR spectrum of 5a consisted of a triplet for the CH3 of n-proyl (δ =
0.79 ppm, J = 7.4 Hz), several multiplets for the cyclohexyl and n-propyl (δ =0.86-2.10 ppm) moieties, a
multiplet for the NCH (δ = 3.80-4.02 ppm) of cyclohexyl moiety, an AB-quartet for CH2 of PhCH2 (δ =
4.50 ppm, J = 16.8 Hz), a triplet for the NCH (δ = 4.55 ppm, J = 7.0 Hz) of the acyclic part, a doublet for
785

Preparation of 2-(N ,N -dialkylamino)-2,4,6-cycloheptatrien-1-one..., A. MASSOUDI, et al.
the tropolone hydrogen (δ = 6.53 ppm, J = 10.4 Hz), a triplet for the tropolone hydrogen (δ = 6.63 ppm,
J = 9.0 Hz), a triplet for the tropolone hydrogen (δ = 6.84 ppm, J = 10.2 Hz), a multiplet for a tropolone
hydrogen and phenyl group (δ = 7.07-7.35 ppm), and a doublet for the NH that was exchangeable with D2 O
(δ = 8.69 ppm, J = 8.0 Hz). The 13 C-NMR spectrum of 5a showed 20 distinct signals. Partial assignment
of these signals is given in the experimental section. The 1 H- and 13 C-NMR spectra of compounds 5b–h were
similar to those of 5a, except for the aromatic or aliphatic moieties, which exhibited characteristic signals with
appropriate chemical shifts.
Conclusions
In summary, the reported method offers a mild, simple, and efficient route for the preparation of 2-(N ,N -
dialkylamino)-2,4,6-cycloheptatrien-1-one derivatives 5 from propionaldehyde 1, primary amine 2, isocyanide
3, and tropolone 4 in the presence of silica NPs. Its ease of work-up, high yields, and fairly mild reaction
conditions make it a useful addition to modern synthetic methodologies.
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