An efficient synthetic pathway from cyclohepta-1,3,5-triene to 2,3- disubstituted 1,2,3,8-tetrahydroazulen-1-ones

Article abstract of DOI:10.1055/s-1999-3678

The Nazarov cyclization of substituted ethyl 3-(cyclohepta- 1,3,5- trien-1-yl)-2-methylen-3-oxopropionates, prepared from cyclohepta-1,3,5- triene in three steps, gave solely 2,3-disubstituted 1,2,3,8- tetrahydroazulen-1-ones without any detectable format

Full text of DOI:10.1055/s-1999-3678

184
PAPER
An Efficient Synthetic Pathway from Cyclohepta-1,3,5-triene to 2,3-
Disubstituted 1,2,3,8-Tetrahydroazulen-1-ones
Takanori Kajioka, Mitsunori Oda,* Shin'ichiro Yamada, Yoshio Kawamori, Ryuta Miyatake, Shigeyasu Kuroda
Department of Applied Chemistry, Faculty of Engineering, Toyama University, Gofuku 3190, Toyama 930-8555, Japan
Fax: +81(764)456819; E-mail: oda@eng.toyama-u.ac.jp
Received 29 May 1998; revised 8 July 1998
Reaction of 1-acetylcyclohepta-1,3,5-triene (1), which
Abstract: The Nazarov cyclization of substituted ethyl 3-(cyclo-
can be easily prepared from cyclohepta-1,3,5-triene by
hepta-1,3,5-trien-1-yl)-2-methylen-3-oxopropionates,
prepared
FriedelÐCrafts acylation,8 with diethyl carbonate in the
presence of sodium hydride gave the ester derivative 2 in
77 % yield. The Knoevenagel condensation of 2 with aryl
aldehydes under the influence of piperidine and p-tolu-
enesulfonic acid9 gave the arylidene derivatives 3aÐd in
good yields (81Ð93%). This condensation reaction gave
only one of the geometrical isomers for all aldehydes
used10 and their structures were assigned by NMR analysis
of long range coupling constants between carbonyl car-
bons and the neighboring hydrogens as shown in Figure
1.9,10,11
from cyclohepta-1,3,5-triene in three steps, gave solely 2,3-disub-
stituted 1,2,3,8-tetrahydroazulen-1-ones without any detectable for-
mation of its double bond regioisomer.
Key words: Nazarov reaction, electrocyclization, azulenones, trim-
ethylsilyl triflate
We recently reported a convenient synthesis of tetrahy-
droazulen-1-ones1 which can be used as synthetic interme-
diates for azulenes,2 homoazulenes,3 bridged homo-
tropylium cations,4 and guaiazulene type sesquiterpenes.5
The method involves the Nazarov cyclization6,7 of 1-acryl-
oylcyclohepta-1,3,5-triene, prepared from commercially
available cyclohepta-1,3,5-triene in four steps, as a key
step for constructing the bicyclic carbon framework. We
have now extended our investigations with the aim of pro-
viding further synthetic applications for the substituted
derivatives and wish to report here an efficient synthesis
of 2,3-disubstituted 1,2,3,8-tetrahydroazulen-1-ones start-
ing from cyclohepta-1,3,5-triene (Scheme).
Figure 1 CÐH Long Range Coupling Constants (in Hz) of 3a
The Nazarov reaction of 3aÐd was carried out in the pres-
ence of a mixture of phosphoric acid and formic acid,
stannic chloride, or trimethylsilyl triflate. The reaction
conditions and the results are summarized in the Table.
All the reactions afforded the sole cyclization products
4aÐd in moderate to good yields. The gross structural fea-
tures of 4aÐd were well characterized by their spectral da-
ta. The stereochemical relationship of two substituents in
4aÐd was determined to be anti to each other by the vici-
nal coupling constants between hydrogens at the 2 and 3
positions12 and NOE experiments as shown in Figure 2.
Scheme
Figure 2 Results of NOE Experiments of 4a
Synthesis 1999, No. 1, 184Ð187 ISSN 0039-7881 © Thieme Stuttgart á New York

PAPER
An Efficient Pathway to 1,2,3,8-Tetrahydroazulen-1-ones
185
Table Results of the Nazarov Cyclization of 3a–d
H), 6.29 (dd, J = 9.2, 5.6 Hz, 1 H), 6.70 (ddm, J = 11.2, 6.4 Hz, 1
H), 6.89 (dd, J = 11.2, 5.6 Hz, 1 H), 7.06 (d, J = 6.4 Hz, 1 H).
Entry Sub-
Acid/
Reaction
Conditions
Product
Yield
(%)
13C NMR: δ = 14.0, 25.3, 45.5, 61.3, 125.9, 127.3, 128.9, 130.3,
133.8, 136.6, 167.7, 191.6.
strate Solvent
MS (EI): m/z (%) = 206 (M+, 5), 118 (10), 91 (19), 65 (9), 28 (100).
1
2
3
4
5
6
7
8
9
3a
3a
3a
3b
3b
3c
3c
3d
3d
SnCl4/CH2Cl2
H3PO4/HCO2H
TMSOTf/CH2Cl2 r.t./0.5 h
SnCl4/CH2Cl2
TMSOTf/CH2Cl2 r.t./0.5 h
SnCl4/CH2Cl2
TMSOTf/CH2Cl2 r.t./2 h
SnCl4/CH2Cl2
TMSOTf/CH2Cl2 r.t./0.5 h
0°C/1 h
r.t./72 h
4a
4a
4a
68
73
91
52
83
54
93
77
86
HRMS: m/z calcd. for C12H14O3 206.0943, found 206.0958.
0°C/0.5 h 4b
Knoevenagel Condensation of 2 with Aldehydes; Typical Proce-
dure
4b
4c
4d
0°C/1.5 h 4c
A mixture of 2 (20 mmol), the appropriate aldehyde (20 mmol), pi-
peridine (0.8 mL), and TsOH (0.02 g) in benzene (20 mL) was re-
fluxed in a DeanÐStark apparatus until no more H2O distilled out.
The mixture was poured into H2O and extracted with benzene (3 ×
30 mL). The combined organic layer was washed with brine and
dried (MgSO4). The solvent was removed and the residual oil was
purified by column chromatography on silica gel (hexane/EtOAc
8:2) to give 3aÐd.
0°C/0.5 h 4d
The formation of the sole product in the Nazarov cycliza-
tions of 3aÐd was a contrast to the case of 1-acryloylcy-
clohepta-1,3,5-triene which gave two double bond
regioisomers under similar conditions.1 In various exam-
ples of the Nazarov cyclization, the reaction of substitued
(E)-Ethyl 3-(Cyclohepta-1,3,5-trien-1-yl)-2-benzylidene-3-oxo-
propionate (3a)
Yield 82%; pale yellow oil; bp 160Ð165¡C/3 Torr.
divinyl ketones gives the thermodynamically favored IR (film): ν = 1720s, 1650s, 1255s, 1200s cmÐ1.
1H NMR: δ = 1.23 (t, J = 6.8 Hz, 3 H), 2.81 (d, J = 7.2 Hz, 2 H),
4.23 (q, J = 6.8 Hz, 2 H), 5.63 (dt, J = 9.6, 7.2 Hz, 1 H), 6.24 (dd, J
= 9.6, 6.0 Hz, 1 H), 6.56 (dd, J = 11.2, 6.0 Hz, 1 H), 6.80 (dd, J =
11.2, 6.0 Hz, 1 H), 6.99 (d, J = 6.0 Hz, 1 H), 7.24Ð7.34 (m, 5 H), 7.81
(s, 1 H).
13C NMR: δ = 14.0, 24.8, 61.4, 125.7, 127.4, 128.7, 129.1, 130.1,
130.2, 130.7, 131.7, 132.9, 136.0, 136.5, 141.9, 165.0, 194.8.
double bond regioisomer, i.e., the more highly substituted
cyclopentenone.6 The result of this study, therefore, be-
longs to one of the typical examples in which only one of
the regioisomers is formed. These findings, the diastereo-
and regioselectivity, were also observed in some Nazarov
cyclizations of dienones having an ester substituent.7c
In conclusion we have demonstrated an efficient synthetic
pathway from cyclohepta-1,3,5-triene to 2,3-disubstituted
1,2,3,8-tetrahydroazulen-1-ones involving the Nazarov
cyclization as a key step for constructing the carbon skel-
eton. Particularly, the formation of the sole product in the
cyclization and the short step sequence from cyclohepta-
1,3,5-triene to azulenones gain an advantage over our pre-
vious result.1 Also, in view of the fact that various kinds
of aldehyde can be employed in the Knoevenagel conden-
sation of 2 and that further alkylation at the 2 position of
4 is a promising method for introducing suitable alkyl
substituents, the present method is applicable for synthe-
sizing a wide variety of azulen-1-one derivatives.
MS (EI): m/z (%) = 294 (M+, 22), 248 (63), 192 (36), 118 (100), 90
(84).
HRMS: m/z calcd. for C19H18O3 294.1253, found 294.1222.
(E)-Ethyl 3-(Cyclohepta-1,3,5-trien-1-yl)-2-(4-methoxybenzyl-
idene)-3-oxopropionate (3b)
Yield 81%; pale yellow oil.
IR (film): ν = 1720s, 1650s, 1610s, 1260s, 1205s, 1175s cmÐ1.
1H NMR: δ = 1.21 (t, J = 7.2 Hz, 3 H), 2.82 (d, J = 7.2 Hz, 2 H),
3.78 (s, 3H), 4.21 (q, J = 7.2 Hz, 2 H), 5.65 (dt, J = 9.2, 7.2 Hz, 1
H), 6.26 (dd, J = 9.2, 6.0 Hz, 1 H), 6.57 (dd, J = 11.2, 6.0 Hz, 1 H),
6.79 (d, J = 8.8 Hz, 2 H), 6.81 (dd, J = 11.2, 6.0 Hz, 1 H), 7.01 (d,
J = 6.0 Hz, 1 H), 7.29 (d, J = 8.8 Hz, 2 H), 7.75 (s, 1 H).
13C NMR: δ = 14.1, 24.1, 55.3, 61.3, 114.2, 125.5, 125.7, 129.0,
129.2, 130.9, 132.2, 135.8, 136.5, 141.6, 161.3, 165.4, 195.5.
MS (EI): m/z (%) = 324 (M+, 47), 278 (99), 210 (56), 118 (99), 90
(100).
Mps were uncorrected. IR spectra were recorded on a JASCO IRÐ
810 spectrometer; 1H (400 MHz), and 13C (100 MHz) NMR spectra
were recorded on a Jeol A400 spectrometer by use of CDCl3 as sol-
vent and TMS as internal standard; Mass spectra were recorded by
a Jeol JMSÐDÐ300 spectrometer.
HRMS: m/z calcd. for C20H20O4 324.1362, found 324.1379
(E)-Ethyl 3-(Cyclohepta-1,3,5-trien-1-yl)-2-(4-nitrobenz-
ylidene)-3-oxopropionate (3c)
Yield 86%; colorless needles, mp 92Ð93¡C.
IR (KBr): ν = 1715s, 1650s, 1600s, 1515s, 1350s, 1245s, 1200s,
855s, 720s cmÐ1.
1H NMR: δ = 1.25 (t, J = 7.2 Hz, 3 H), 2.79 (d, J = 6.8 Hz, 2 H),
4.27 (q, J = 7.2 Hz, 2 H), 5.63 (dt, J = 9.2, 6.8 Hz, 1 H), 6.26 (dd, J
= 9.2, 5.6 Hz, 1 H), 6.57 (dd, J = 11.2, 6.0 Hz, 1 H), 6.84 (dd, J =
11.2, 5.6 Hz, 1 H), 6.93 (d, J = 6.0 Hz, 1 H), 7.47 (d, J = 9.2, 2.0 Hz,
2 H), 7.82 (s, 1 H), 8.12 (dt, J = 9.2, 2.0 Hz, 2 H).
13C NMR: δ = 14.0, 24.7, 62.0, 123.8, 125.8, 127.7, 128.9, 130.3,
130.5, 135.8, 136.6, 137.2, 138.7, 139.2, 148.1, 164.3, 193.6.
MS (EI): m/z (%) = 339 (M+, 15), 293 (39), 191 (12), 118 (100), 91
(89).
Ethyl 3-(Cyclohepta-1,3,5-trien-1-yl)-3-oxopropionate (2)
A solution of 1 (15.0 g, 112 mmol) in dioxane (50 mL) was added
dropwise to a refluxing mixture of diethyl carbonate (39.6 g,
336 mmol) and NaH (16.2 g, 675 mmol) in dioxane (200 mL) under
N2 atmosphere. The resulting mixture was refluxed for 1 h after com-
pletion of the addition, and then was cooled to r.t., carefully poured
into aq 5% HCl (400 mL), and extracted with Et2O (3 × 100 mL). The
combined organic layers were washed with brine and dried (MgSO4).
Removal of the solvent gave a dark brown oil which was distilled to
give 2 (17.8 g, 77%) as a colorless oil; bp 125Ð127¡C/3 Torr.
IR (film): ν =1720s, 1650s, 1590s, 1300s, 1250s, 1230s, 1150s,
1130s cmÐ1.
1H NMR: δ = 1.25 (t, J = 7.2 Hz, 3 H), 2.68 (d, J = 7.2 Hz, 2 H),
3.75 (s, 2 H), 4.19 (q, J = 7.2 Hz, 2 H), 5.59 (dt, J = 9.2, 7.2 Hz, 1
Synthesis 1999, No. 1, 184–187 ISSN 0039-7881 © Thieme Stuttgart · New York

186
T. Kajioka et al.
PAPER
Anal. Calcd. for C19H17NO5: C 67.25; H 5.05; N 4.12. Found: C
67.21; H 5.11; N 4.18.
11.2, 6.0 Hz, 1 H), 6.85 (dm, J = 8.8 Hz, 2 H), 6.99 (dm, J = 8.8 Hz,
2 H).
13C NMR: δ = 14.2, 22.1, 48.7, 55.3, 61.7, 63.2, 114.4, 127.4, 128.0,
128.1, 128.8, 131.2, 132.7, 137.6, 159.0, 165.8, 168.5, 199.3.
MS (EI): m/z (%) = 324 (M+, 6), 219 (9), 181 (14), 131 (25), 119
(20), 69 (100).
(E)-Ethyl 3-(Cyclohepta-1,3,5-trien-1-yl)-2-(2-furyl)methylene-
3-oxopropionate (3d)
Yield 93%; yellow oil.
IR (film): ν = 1710s, 1655s, 1625s, 1245s, 1210s, 1020s cmÐ1.
1H NMR: δ = 1.22 (t, J = 7.2 Hz, 3 H), 2.85 (d, J = 7.2 Hz, 2 H),
4.21 (q, J = 7.2 Hz, 2 H), 5.67 (dt, J = 9.2, 7.2 Hz, 1 H), 6.27 (dd, J
= 9.2, 6.0 Hz, 1 H), 6.40 (dd, J = 3.6, 2.0 Hz, 1 H), 6.60 (dd, J =
11.2, 6.0 Hz, 1 H), 6.61 (d, J = 3.6 Hz, 1 H), 6.82 (dd, J = 11.2, 6.0
Hz, 1 H), 6.95 (d, J = 6.0 Hz, 1 H), 7.37 (m, 1 H), 7.55 (s, 1 H).
HRMS: m/z calcd. for C20H20O4 324.1362, found 324.1413
(±)-(2R*,3S*)-2-Ethoxycarbonyl-3-(4-nitrophenyl)-1,2,3,8-tet-
rahydroazulen-1-one (4c)
colorless needles, mp 95Ð97¡C.
IR (KBr): ν = 1735s, 1700s, 1610s, 1515s, 1350s cmÐ1.
13C NMR: δ = 14.1, 25.0, 61.4, 117.3, 112.4, 125.8, 127.3, 127.6,
1H NMR: δ = 1.31 (t, J = 7.2 Hz, 3 H), 2.72 (dd, J = 14.4, 6.4 Hz, 1
H), 2.99 (dd, J = 14.4, 6.8 Hz, 1 H), 3.40 (d, J = 3.6 Hz, 1 H), 4.25
(dq, J = 14.4, 7.2 Hz, 1 H), 4.26 (dq, J = 14.4, 7.2 Hz, 1 H), 4.65 (d,
J = 3.2 Hz, 1 H), 5.74 (dt, J = 10.0, 6.4 Hz, 1 H), 6.22 (dd, J = 10.0,
6.0 Hz, 1 H), 6.30 (d, J = 11.2 Hz, 1 H), 6.77 (dd, J = 11.2, 6.0 Hz,
1 H), 7.24 (dm, J = 8.8 Hz, 2 H), 8.19 (dm, J = 8.8 Hz, 2 H).
13C NMR: δ = 14.2, 22.2, 48.9, 62.1, 62.5, 124.4, 126.7, 128.1,
128.5, 128.7, 132.0, 138.5, 147.4, 148.3, 163.8, 167.7, 197.8.
MS (EI): m/z (%) = 339 (M+, 73), 267 (100), 191 (55), 178 (62), 69
(76).
127.8, 129.2, 131.3, 135.5, 136.2, 145.8, 149.3, 165.0, 193.9.
MS (EI): m/z (%) = 284 (M+, 61), 238 (37), 210 (51), 118 (100), 90
(98).
HRMS: m/z calcd. for C17H16O4 284.1046, found 284.1016.
Nazarov Cyclization of 3a in a Mixture of Formic Acid and
Phosphoric Acid; (±)-(2R*,3S*)-2-Ethoxycarbonyl-3-phenyl-
1,2,3,8-tetrahydroazulen-1-one (4a)
A mixture of 3 (294 mg, 1.0 mmol) in formic acid (4 mL) and phos-
phoric acid (4 mL) was stirred at r.t. for 72 h, and then poured into
H2O and extracted with Et2O (3 × 20 mL). The combined organic
layers were washed with satd NaHCO3 solution and brine. After
drying (MgSO4) and removal of the solvent, the residue was puri-
fied by column chromatography (silica gel; hexane/EtOAc, 7:3) to
give 182 mg of 4a (73%) as colorless leaflets; mp 97Ð98¡C.
Anal. Calcd. for C19H17NO5: C 67.25; H 5.05; N 4.12. Found: C
67.29; H 5.34; N 4.23.
(±)-(2R*,3S*)-2-Ethoxycarbonyl-3-(2-furyl)-1,2,3,8-tetrahy-
droazulen-1-one (4d):
colorless microcrystals; mp 55Ð56¡C.
IR (KBr): ν = 1735s, 1690s, 1150s, 705s cmÐ1.
1H NMR: δ = 1.29 (t, J = 7.2 Hz, 3 H), 2.79 (dd, J = 14.4, 6.4 Hz, 1
H), 2.88 (dd, J = 14.4, 6.4 Hz, 1 H), 3.45 (d, J = 2.8 Hz, 1 H), 4.22
(q, J = 7.2 Hz, 2 H), 4.48 (d, J = 2.8 Hz, 1 H), 5.71 (dt, J = 10.0, 6.4
Hz, 1 H), 6.17 (dd, J = 10.0, 6.0 Hz, 1 H), 6.35 (d, J = 11.2 Hz, 1
H), 6.71 (dd, J = 11.2, 6.4 Hz, 1 H), 7.07 (d, J = 7.2 Hz, 2 H), 7.29
(m, 3 H).
13C NMR: δ = 14.2, 22.1, 49.4, 61.7, 63.0, 127.4, 127.5, 127.8,
128.0, 128.1, 129.1, 131.4, 137.7, 140.7, 165.6, 168.4, 199.2.
MS (EI): m/z (%) = 294 (M+, 4), 222 (20), 191 (21), 178 (29), 45
(42), 31 (100).
IR (KBr): ν = 1720s, 1700s, 1150m, 1020m cmÐ1.
1H NMR: δ = 1.31 (t, J = 7.2 Hz, 3 H), 2.78 (dd, J = 14.4, 6.4 Hz, 1
H), 2.82 (dd, J = 14.4, 6.8 Hz, 1 H), 3.67 (d, J = 3.2 Hz, 1 H), 4.23
(dq, J = 14.0, 7.2 Hz, 1 H), 4.25 (dq, J = 14.0, 7.2 Hz, 1 H), 4.60 (d,
J = 3.2 Hz, 1 H), 5.66 (dt, J = 10.0, 6.4 Hz, 1 H), 6.15 (d, J = 3.2 Hz,
1 H), 6.17 (dd, J = 10.0, 6.4 Hz, 1 H), 6.31 (dd, J = 3.2, 2.0 Hz, 1
H), 6.51 (d, J = 11.6 Hz, 1 H), 6.77 (dd, J = 11.6, 6.0 Hz, 2 H), 7.34
(d, J = 2.0 Hz, 1 H).
13C NMR: δ = 14.2, 22.1, 42.8, 59.2, 61.9, 107.4, 110.4, 126.7,
127.9, 128.0, 130.8, 137.7, 142.6, 152.4, 162.7, 168.2, 198.3.
MS (EI): m/z (%) = 284 (M+, 83), 210 (100), 182 (61), 153 (44).
Anal. Calcd. for C19H18O3: C 77.53; H 6.16. Found: C 77.38; H
6.31.
Anal. Calcd. for C17H16O4: C 71.82; H 5.67. Found: C 71.60; H 5.94.
Nazarov Cyclization of 3 in the Presence of Stannic Chloride;
General Procedure
Nazarov Cyclization of 3 in the Presence of Trimethylsilyl
Triflate; General Procedure
SnCl4 (2.0 mmol) was added to a solution of 3 (1.5 mmol) in CH2Cl2
(15 mL) at 0¡C. The mixture was stirred at the same temperature for
0.5 to 1.5 h under N2 atmosphere, and then poured into satd
NaHCO3 solution (50 mL) and extracted with CH2Cl2 (2 × 20 mL).
The combined organic layers were washed with brine and dried
(MgSO4). The solvent was removed and the residue purified by col-
umn chromatography on silica gel (eluent hexane/EtOAc, 8:2) to
give 4.
Trimethylsilyl triflate (1.0 mmol) was added via a syringe to a solu-
tion of 3 (1.0 mmol) in CH2Cl2 (10 mL) at r.t. This mixture was
stirred at the same temperature for 0.5 to 2 h under N2 atmosphere,
and then poured into satd NaHCO3 solution (40 mL) and extracted
with CH2Cl2 (2 × 20 mL). The combined organic layers were
washed with brine and dried (Na2SO4). The solvent was removed
and the residue purified by column chromatography on silica gel
(eluent seee above) to give 4.
(±)-(2R*,3S*)-2-Ethoxycarbonyl-3-(4-methoxyphenyl)-1,2,3,8-
tetrahydroazulen-1-one (4b)
Acknowledgement
Colorless oil.
IR (film): ν = 1740s, 1700s, 1620s, 1515s, 1250s, 1180s cmÐ1.
We thank Miss M. Izawa for measurements of selective proton
decoupling 13C NMR spectra of 3 and conducting NOE experi-
ments of 4. This work was Þnancially supported by a Grant-in-Aid
ScientiÞc Research (No. 09640631) from the Ministry of Educa-
tion, Science, Sports and Culture, Japan.
1H NMR: δ = 1.29 (t, J = 7.2 Hz, 3 H), 2.75 (dd, J = 14.4, 6.4 Hz, 1
H), 2.87 (dd, J = 14.4, 6.4 Hz, 1 H), 3.41 (d, J = 3.2 Hz, 1 H), 3.79
(s, 3 H), 4.22 (dq, J = 14.4, 7.2 Hz, 1 H), 4.23 (dq, J = 14.4, 7.2 Hz,
1 H), 4.43 (d, J = 2.8 Hz, 1 H), 5.70 (dt, J = 9.6, 6.4 Hz, 1 H), 6.17
(dd, J = 10.0, 6.0 Hz, 1 H), 6.35 (d, J = 11.2 Hz, 1 H), 6.70 (dd, J =
Synthesis 1999, No. 1, 184–187 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
An Efficient Pathway to 1,2,3,8-Tetrahydroazulen-1-ones
187
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Synthesis 1999, No. 1, 184–187 ISSN 0039-7881 © Thieme Stuttgart · New York