Synthesis of dialkyl 2-(alkylamino)-4,9-dihydro-9-oxocyclohepta[b]pyran-3, 4-dicarboxylates

Article abstract of DOI:10.1002/hlca.201000222

Dialkyl 2-(alkylamino)-4,9-dihydro-9-oxocyclohepta[b]pyran-3,4- dicarboxylates are prepared in a one-pot three-component reaction of alkyl isocyanide, dialkyl acetylenedicarboxylate, and α-tropolone (=2-hydroxycyclohepta-2,4,6-trienone). The reaction proc

Full text of DOI:10.1002/hlca.201000222

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Synthesis of Dialkyl 2-(Alkylamino)-4,9-dihydro-9-oxocyclohepta[b]pyran-
3,4-dicarboxylates
by Javad Azizian*a), Ali Ramazani*b), and Mohammad Hajia)
a) Chemistry Department, Science and Research Branch, Islamic Azad University, P.O. Box 19395-1775,
Tehran, Iran
b) Chemistry Department, Islamic Azad University, Zanjan Branch, P.O. Box 45195-467, Zanjan, Iran
(fax: þ 982414213955; e-mail: aliramazani@gmail.com)
Dialkyl 2-(alkylamino)-4,9-dihydro-9-oxocyclohepta[b]pyran-3,4-dicarboxylates are prepared in a
one-pot three-component reaction of alkyl isocyanide, dialkyl acetylenedicarboxylate, and a-tropolone
(¼2-hydroxycyclohepta-2,4,6-trienone). The reaction proceeds smoothly at room temperature and
under neutral conditions to afford tropolone derivatives in high yield.
Introduction. – Heterocycle-fused tropolones, an important class of compounds
with varied pharmacological and biological properties have attracted great attention
since the beginning of tropoid chemistry [1 – 4]. The cyclohepta[b]pyran ring system is
the backbone of some natural products such as paulitine (Fig.), which displays several
biological activities, and some derivatives of this system exhibit platelet anti-aggre-
gating, HIV protease inhibition, anesthetic, histaminic response-reducing, antimalarial,
anti-inflammatory, and analgesic activities [5 – 8]. Only a few methods have been
reported for the construction of cyclohepta[b]pyran ring systems. In a first method, a
cyclohepta[e][1,3,2]dioxaborin ring is formed by reaction of cycloheptanone with Ac2O
in presence of BF3, and subsequent reaction with Vilsmeier reagent provides the
cyclohepta[b]pyran system [6]. In a second method, reaction of 3-acetyltropolone with
benzaldehydes yields 3-cinnamoyltropolones, which are cyclized to 2-arylcyclohep-
ta[b]pyran-4,9-diones in presence of oxidizing reagents such as SeO2 [9], 2,3-dichloro-
5,6-dicyano-1,4-benzoquinone [10], HClO4 [11], Br2 [12], and I2/DMSO/H2SO4 [13].
Also the reaction of chloro(phenyl)ketene with 2-(aminomethylidene)cyclohepta-
nones, followed by dehydrochlorination of the primary adducts, yields 4-amino-6,7,8,9-
tetrahydro-3-phenylcyclohepta[b]pyran-2(5H)-ones [14].
Figure. Molecular structure of paulitine (see text)
ꢀ 2011 Verlag Helvetica Chimica Acta AG, Zꢁrich

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In continuation of our previous studies on the development of new routes to
heterocyclic systems (see [15] and refs. cit. therein), we now report an efficient and
facile synthetic route to dialkyl 2-(alkylamino)-4,9-dihydro-9-oxocyclohepta[b]pyran-
3,4-dicarboxylates 4 using a-tropolone (¼2-hydroxycyclohepta-2,4,6-trienone; 3),
alkyl isocyanides 1, and dialkyl acetylenedicarboxylates 2 without any catalyst
(Scheme 1).
Scheme 1. Synthesis of Tropolone Derivatives 4 from Alkyl Isocyanide 1, Dialkyl Acetylenedicarboxylate
2, and Tropolone (3)
Results and Discussion. – The three-component reaction of alkyl isocyanide 1,
dialkyl acetylenedicarboxylate 2, and 3 proceeded in CH2Cl2 at ambient temperature
and was completed after 24 h to afford dialkyl 2-(alkylamino)-4,9-dihydro-9-oxocy-
clohepta[b]pyran-3,4-dicarboxylates 4 in yields of 65 – 86% (Scheme 1).
The structures of the products 4a – 4g were deduced from their IR, 1H- and
13C-NMR, and MS data. For example, the mass spectrum of 4a displayed the molecular-
ion peak at 373 m/z, which is consistent with a 1:1:1 adduct of 1a, 2a, and 3. The
1H-NMR spectrum of 4a exhibited a multiplet for the cyclohexyl substituent (d(H)
1.16 – 2.07), two singlets for two MeO groups (d(H) 3.63 and 3.68), a multiplet for
(CH2)5CHꢀN (d(H) 3.99), a singlet for HꢀC(4) (d(H) 4.55) and two multiplets for
three H-atoms of the tropone ring (d(H) 6.83 – 6.91 and d(H) 7.12 – 7.20), and a doublet
(d(H) 7.06, 3J ¼ 11.2), as well as a broad singlet for NH (d(H) 8.26). The 1H-decoupled
13C-NMR spectrum of 4a showed 20 distinct resonances, partial assignments of these
1
resonances is given in the Exper. Part. The H- and 13C-NMR spectra of 4b – 4g are
similar to those of 4a, except for N-alkyl and esters moieties.
Although the mechanism of this reaction has not been established experimentally, a
reasonable proposal is depicted in Scheme 2. On the basis of isocyanide chemistry [16],
the zwitterionic intermediate 5 from reaction of alkyl isocyanide 1 and dialkyl
acetylenedicarboxylate 2 is protonated by OH of 3. Subsequent reaction of the
nitrilium ion 6 with the deprotonated tropolone produces ketenimine 7. This addition
product may tautomerize and then cyclize, under the employed reaction conditions, to
form tropolone derivatives 4.

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Scheme 2. Proposed Mechanism for the Formation of Tropolone Derivatives 4
Conclusions. – We have developed a new and efficient synthetic method for the
preparation of dialkyl 2-(alkylamino)-4,9-dihydro-9-oxocyclohepta[b]pyran deriva-
tives. The present method has the advantage that the reaction is performed under
neutral conditions with easily available starting materials to give high yields.
Experimental Part
General. Starting materials and solvents were obtained from Merck (Germany) and Fluka
(Switzerland), and were used without further purification. Column chromatography (CC): Merck
silica-gel powder. M.p.: Electrothermal 9100 apparatus; uncorrected. IR Spectra: Shimadzu IR-460
spectrometer; in KBr. 1H- and 13C-NMR spectra (CDCl3 soln.): BRUKER DRX-250 AVANCE
spectrometer at 250.0, and 62.9 MHz, resp. MS: Agilent-Technologies-(HP)-5973 mass spectrometer
operating at an ionization potential of 70 eV. Elemental analyses: Heraeus CHN-O-Rapid analyzer.
General Procedure for the Preparation of Compounds 4. To a magnetically stirred soln. of tropolone
(3, 1 mmol) and dialkyl acetylenedicarboxylate 2 (1 mmol) in dry CH2Cl2 (5 ml) was added a soln. of
alkyl isocyanide 1 (1 mmol) in dry CH2Cl2 (2 ml). The mixture was stirred for 24 h. The solvent was
evaporated, and the residue was purified by CC using petroleum ether/AcOEt mixtures.
Dimethyl 2-(Cyclohexylamino)-4,9-dihydro-9-oxocyclohepta[b]pyran-3,4-dicarboxylate (4a). Yield
1
320 mg (86%). Brown semisolid. IR: 3292 (NH), 2924, 1744, 1684, 1620, 1441, 1269, 1084. H-NMR:
1.16 – 2.07 (m, 5 CH2 of cyclohexyl); 3.63 (s, MeO); 3.68 (s, MeO); 3.90 – 4.11 (m, NꢀCH); 4.55 (s, CH);
6.83 – 6.91 (m, 1 H of tropone); 7.06 (d, J ¼ 11.2, 1 H of tropone); 7.12 – 7.20 (m, 2 H of tropone); 8.26 (br.
s, NH). 13C-NMR: 24.40, 24.45, 25.47, 33.44, 33.62 (5 CH2 of cyclohexyl); 45.52 (CH); 50.20 (CHꢀNH);
50.94, 52.73 (2 MeO); 70.22, 125.66, 130.34, 135.37, 135.97, 139.57, 154.67, 159.46 (C of alkene and
tropone); 168.53, 172.32, 177.87 (3 C¼O). EI-MS: 373 (2, Mþ), 314 (100, [M ꢀ CO2Me]þ), 232 (48,
[314 ꢀ C6H10]þ), 200 (14, [M þ H ꢀ CO2Me ꢀ C6H10 ꢀ MeO]þ), 172 (19, [200 ꢀ CO]þ), 157 (9, [172 ꢀ
NH2]þ). Anal. calc. for C20H23NO6 (373.40): C 64.33, H 6.21, N 3.75; found: C 64.26, H 6.13, N 3.68.
Diethyl 2-(Cyclohexylamino)-4,9-dihydro-9-oxocyclohepta[b]pyran-3,4-dicarboxylate (4b). Yield
1
330 mg (83%). Brown semisolid. IR: 3281 (NH), 2932, 1737, 1682, 1616, 1440, 1229, 1086. H-NMR:
1.15 (t, J ¼ 7.0, Me); 1.22 (t, J ¼ 7.2, Me); 1.23 – 2.10 (m, 5 CH2 of cyclohexyl); 3.90 – 4.00 (m, NꢀCH);
3.99 – 4.20 (m, 2 CH2O); 4.51 (s, CH); 6.80 – 6.92 (m, 1 H of tropone); 7.07 (d, J ¼ 11.40, 1 H of tropone);
7.12 – 7.31 (m, 2 H of tropone); 8.25 (br. s, NH). 13C-NMR: 14.07, 14.56 (2 Me); 24.40, 24.42, 25.48, 33.45,

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33.59 (5 CH2 of cyclohexyl); 45.65 (CH); 50.11 (CHꢀNH); 59.36, 61.47 (2 CH2O); 70.34, 125.59, 130.16,
135.38, 135.95, 139.48, 154.58, 159.22 (C of alkene and tropone); 168.23, 172.00, 177.93 (3 C¼O). EI-MS:
401 (1, Mþ), 328 (100, [M ꢀ CO2Et]þ), 246 (46, [328 ꢀ C6H10]þ), 218 (12, [246 ꢀ Et]þ), 200 (12, [246 ꢀ
EtO]þ), 172 (15, [200 ꢀ CO]þ), 157 (6, [172 ꢀ NH2]þ). Anal. calc. for C22H27NO6 (401.46): C 65.82, H
6.78, N 3.49; found: C 65.73, H 6.83, N 3.34.
Dimethyl 2-(tert-Butylamino)-4,9-dihydro-9-oxocyclohepta[b]pyran-3,4-dicarboxylate (4c). Yield
280 mg (81%). Yellow powder. M.p. 115 – 1178. IR: 3314 (NH), 2954, 1731, 1676, 1616, 1430, 1166, 1081.
1H-NMR: 1.51 (s, t-Bu); 3.65, 3.69 (2s, 2 MeO); 4.56 (s, CH); 6.83 – 6.94 (m, 1 H of tropone); 7.07 (d, J ¼
11.5, 1 H of tropone); 7.11 – 7.21 (m, 2 H of tropone); 8.51 (br. s, NH). 13C-NMR: 29.95 (3 Me); 45.32
(CH); 51.01, 52.77 (2 MeO); 53.16 (CꢀNH); 70.70, 125.35, 130.35, 135.44, 135.91, 139.66, 154.67, 160.54
(C of alkene and tropone); 168.71, 172.38, 177.82 (3 C¼O). EI-MS: 347 (2, Mþ), 288 (56, [M ꢀ
CO2Me]þ), 232 (100, [288 ꢀ Me2CCH2]þ), 200 (17, [232 ꢀ MeO]þ), 172 (23, [200 ꢀ CO]þ), 157 (9,
[172 ꢀ NH2]þ). Anal. calc. for C18H21NO6 (347.37): C 62.24, H 6.09, N 4.03; found: C 62.32, H 5.91, N 3.92.
Diethyl 2-(tert-Butylamino)-4,9-dihydro-9-oxocyclohepta[b]pyran-3,4-dicarboxylate (4d). Yield
300 mg (80%). Yellow powder. M.p. 118 – 1208. IR: 3260 (NH), 2979, 1733, 1673, 1613, 1433, 1185,
1087. 1H-NMR: 1.160 (t, J ¼ 7.0, Me); 1.22 (t, 3J ¼ 7.2, Me); 1.48 (s, t-Bu); 4.01 – 4.20 (m, 2 CH2O); 4.51 (s,
CH); 6.79 – 6.92 (m, 1 H of tropone); 7.06 (d, J ¼ 11.6, 1 H of tropone); 7.11 – 7.18 (m, 2 H of tropone);
8.49 (br. s, NH). 13C-NMR: 14.06, 14.55 (2 Me); 29.93 (3 Me); 45.47 (CH); 53.01 (CꢀNH); 59.41, 61.47
(2 CH2O); 70.82, 125.30, 130.17, 135.42, 135.88, 139.55, 154.59, 160.31 (C of alkene and tropone); 168.34,
172.04, 177.84 (3 C¼O). EI-MS: 375 (1, Mþ), 302 (59, M ꢀ CO2Et]þ), 246 (100, [302 ꢀ Me2CCH2]þ), 218
(10, [246 ꢀ Et]þ), 200 (12, [246 ꢀ EtO]þ), 172 (17, [200 ꢀ CO]þ), 157 (6, [172 ꢀ NH2]þ). Anal. calc. for
C20H25NO6 (375.42): C 63.99, H 6.71, N 3.73; found: C 64.12, H 6.83, N 3.61.
Dimethyl 4,9-Dihydro-9-oxo-2-[(1,1,3,3-tetramethylbutyl)amino]cyclohepta[b]pyran-3,4-dicarboxy-
late (4e). Yield 330 g (80%). Yellow powder. M.p. 156 – 1588. IR: 3380 (NH), 2947, 1727, 1669, 1604, 1436,
1161, 1079. 1H-NMR: 0.99 (s, Me3C); 1.56 (s, Me2C); 1.95 (AB, J ¼ 15.6, CH2); 3.65, 3.70 (s, 2 MeO); 4.57
(s, CH); 6.83 – 6.95 (m, 1 H of tropone); 7.08 (d, J ¼ 11.2, 1 H of tropone); 7.12 – 7.24 (m, 2 H of tropone);
8.57 (br. s, NH). 13C-NMR: 30.65, 30.98 (2 Me); 31.41 (Me3C); 31.60 (C); 45.43 (CH); 50.97 (MeO);
52.20 (CH2); 52.71 (MeO); 56.63 (CꢀNH); 70.38, 125.40, 130.33, 135.42, 135.87, 139.68, 154.59, 160.42 (C
of alkene and tropone); 168.74, 172.43, 177.74 (3 C¼O). EI-MS: 401 (1, [M ꢀ 2]þ), 344 (9, [M ꢀ
CO2Me]þ), 328 (100, [344 ꢀ Me]þ), 246 (40, [344 ꢀ C7H14]þ), 232 (31, [246 ꢀ Me]þ), 200 (15, [232 ꢀ
MeO]þ), 172 (17, [200 ꢀ CO]þ), 157 (8, [172 ꢀ NH2]þ). Anal. calc. for C22H29NO6 (403.48): C 65.49, H
7.24, N 3.47; found: C 65.38, H 7.32, N 3.58.
Diethyl 4,9-Dihydro-9-oxo-2-[(1,1,3,3-tetramethylbutyl)amino]cyclohepta[b]pyran-3,4-dicarboxy-
late (4f). Yield 340 mg (79%). Yellow powder. M.p. 154 – 1568. IR: 3269 (NH), 2952, 1727, 1669, 1615,
1434, 1177, 1082. 1H-NMR: 0.96 (s, Me3C); 1.160 (t, J ¼ 7.0, Me); 1.23 (t, J ¼ 7.0, Me); 1.53 (s, Me2C); 1.92
(AB, J ¼ 14.2, CH2); 4.01 – 4.17 (m, 2 CH2O); 4.52 (s, CH); 6.80 – 6.92 (m, 1 H of tropone); 7.08 (d, J ¼
11.6, 1 H of tropone); 7.11 – 7.19 (m, 2 H of tropone); 8.58 (br. s, NH). 13C-NMR: 14.07, 14.55, 30.71, 30.96
(4 Me); 31.42 (Me3C); 31.60 (C); 45.60 (CH); 52.11 (CH2); 56.48 (CꢀNH); 59.35, 61.43 (2 CH2O); 70.53,
125.30, 130.13, 135.41, 135.84, 139.57, 154.56, 160.13 (C of alkene and tropone); 168.41, 172.08, 177.77
(3 C¼O). EI-MS: 431 (1, Mþ), 358 (29, [M ꢀ CO2Et]þ), 328 (4, [358 ꢀ 2 Me]þ), 246 (100, [358 ꢀ
CMe2CH2CMe3]þ), 218 (9, [246 ꢀ Et]þ), 200 (15, [246 ꢀ EtO]þ), 172 (19, [200 ꢀ CO]þ), 157 (8, [172 ꢀ
NH2]þ). Anal. calc. for C24H33NO6 (431.53): C 66.80, H 7.71, N 3.24; found: C 66.92, H 7.64, N 3.31.
Di(tert-butyl) 2-(Cyclohexylamino)-4,9-dihydro-9-oxocyclohepta[b]pyran-3,4-dicarboxylate (4g).
Yield 300 mg (65%). Yellow semisolid. IR: 3305 (NH), 2931, 1729, 1674, 1619, 1443, 1156, 1086.
1H-NMR: 1.10 – 2.15 (m, 5 CH2 of cyclohexyl); 1.38 (s, Me3C); 1.48 (s, Me3C); 3.87 – 4.04 (m, HꢀCꢀN);
4.35 (s, CH); 6.81 – 6.92 (m, 1 H of tropone); 7.12 (d, J ¼ 11.3, 1 H of tropone); 7.13 – 7.25 (m, 2 H of
tropone); 8.18 (br. s, NH). 13C-NMR: 24.73, 25.56 (2 CH2 of cyclohexyl); 27.89 (Me3C); 27.99 (CH2);
28.59 (Me3C); 32.74, 33.77 (2 CH2 of cyclohexyl); 47.23 (CH); 50.26 (CHꢀNH); 77.22, 79.31, 81.46 (2 C
and C of alkene); 126.07, 129.68, 135.72, 135.85, 139.41, 154.18, 158.86 (C of alkene and tropone); 168.21,
171.35, 178.11 (3 C¼O). EI-MS: 457 (1, Mþ), 356 (29, [M ꢀ CO2t-Bu]þ), 300 (100, [356 ꢀ t-Bu]þ), 218
(33, [300 ꢀ C6H10]þ), 57 (17, [t-Bu]þ). Anal. calc. for C26H35NO6 (457.57): C 68.25, H 7.71, N 3.06; found:
C 68.37, H 7.62, N 3.11.

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Received June 4, 2010