Solvent-free and efficient synthesis of highly functionalized cyclohexa-1,3-diene derivatives via a novel one-pot three-component reaction

Article abstract of DOI:10.1055/s-0030-1260208

A catalyst-free and convenient approach for the preparation of cyclohexa-1,3-dienecarboxylate derivatives is described. This three-component reaction between primary amines, alkyl acetoacetate, and dibenzylideneacetone proceeds under solvent-free condition in good to excellent yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1260208

PAPER
3491
Solvent-Free and Efficient Synthesis of Highly Functionalized Cyclohexa-1,3-
diene Derivatives via a Novel One-Pot Three-Component Reaction
Synthesis of
Highl
b
yFunctional
d
ized
C
yclohe
o
xa-1,3-diene
l
D
erivatives li Alizadeh,* Atieh Rezvanian, Javad Mokhtari
Department of Chemistry, Tarbiat Modares University, P.O. Box 14115-175, Tehran, Iran
Fax +98(21)88006544; E-mail: abdol_alizad@yahoo.com; E-mail: aalizadeh@modares.ac.ir
Received 30 June 2011; revised 31 July 2011
and alkyl acetoacetate are mixed first and then diben-
Abstract: A catalyst-free and convenient approach for the prepara-
tion of cyclohexa-1,3-dienecarboxylate derivatives is described.
This three-component reaction between primary amines, alkyl ace-
toacetate, and dibenzylideneacetone proceeds under solvent-free
condition in good to excellent yields.
zylideneacetone is added) produces the alkyl 2-(alkyl-
amino)-6-phenyl-4-styrylcyclohexa-1,3-dienecarboxylate
derivatives 3 in excellent yields.
Key words: primary amines, alkyl acetoacetate, dibenzylideneace-
tone, cyclohexa-1,3-dienecarboxylate, solvent-free
Br
Cyclohexadienes are very important subunits in a number
of biologically active compounds1–3 such as antibacterial-
ly active agent A,1a,b antimicrobially active agent B,1c and
calcium channel modulator C,2 as well as versatile
intermediates4,5 in organic synthesis (Figure 1). Cyclo-
hexa-1,3-diene has also been used successfully to produce
a high-molecular-weight all-cis polymer.6 Although sev-
eral methods have been reported for the synthesis of cy-
clohexadienes,7,8 they all rely on multistep reactions or
their yields are low and the reaction times are long. New
methodologies for rapid access to chemical diversity
space include multicomponent reactions (MCRs), which
are noteworthy tools for the quick and efficient synthesis
of an extensive variety of organic compounds.
MeO2C
CO2Me
NH
CHO
antibacterial agent A
Br
antimicrobial agent B
F
MeO2C
CO2Me
During the last two decades multicomponent reactions
have been exploited by combinatorial chemists as a source
of appendage diversity. One-pot multicomponent reac-
tions are often resource-effective and environmentally ac-
ceptable and, thus, greener as compared to multistep
reactions. They can offer significant advantages over con-
ventional single-step syntheses by reducing time and sav-
ing money, energy, and raw materials, thus resulting in
both economical and environmental benefits. At the same
time, diversity can be achieved by building up libraries by
varying each component.9
calcium channel
modulator C
Figure 1
In order to establish the generality and scope of this new
synthesis, we used different derivatives of primary amines
1a–e and alkyl acetoacetate 2a,b (Table 1). As anticipated
from our initial results, these reactions proceed very
cleanly under solvent-free conditions at room temperature
and undesirable side-reactions are not observed.
As part of our continuing effort in the design of new routes
for the preparation of biologically active heterocycles and
new organic compounds using the synthesis and reactions
of enamines,10 herein, we describe an efficient synthesis
of fully substituted cyclohexadienes via a new one-pot
three-component reaction. Our new synthetic route is
shown in Table 1. Reaction between primary amines 1,
alkyl acetoacetates 2, and dibenzylideneacetone under
solvent-free conditions at room temperature (the amine
The structures of compounds 3a–i (Table 1) were deduced
from their elemental analysis, IR, and high-field H and
1
13C NMR spectra. The mass spectrum of 3a displayed the
molecular ion peak at m/z 373, which is in agreement with
the proposed structure. In the IR spectrum of 3a, three ab-
sorption bands at 3264, 1643, 1607, and two absorption
bands at 1561 and 1446 cm–1, which are related to NH,
CO2Me, NC=C groups and aromatic stretching frequen-
cies, clearly indicated the most significant functional
groups of the product. The 1H NMR spectrum of 3a exhib-
ited one triplet signal at d = 1.04 (J = 7.4 Hz), readily rec-
ognized as methyl of propyl group. One sextet signal at
SYNTHESIS 2011, No. 21, pp 3491–3495
x
x.
x
x
.
2
0
1
1
Advanced online publication: 05.09.2011
DOI: 10.1055/s-0030-1260208; Art ID: N65711SS
© Georg Thieme Verlag Stuttgart · New York

3492
A. Alizadeh et al.
PAPER
center in the molecule, these hydrogens are diastereotopic
to each other and one of them would be coupled with the
geminal (2J) and vicinal (3J) hydrogens. The other hydro-
gen is probably positioned in a space so that it cannot cou-
ple with the vicinal hydrogen and it can only be split with
the geminal hydrogen (2J). However, both of them show a
weak coupling with the hydrogen which is linked to C3 of
cyclohexadiene ring (4J). The spectrum also contains one
multiplet and one sharp singlet at d = 3.27–3.36 and 3.68
which are attributed to the hydrogens of the CH2N and
OCH3 groups, respectively. There are two doublet signals
at d = 4.24 (3J = 6.9 Hz) and 6.38 (4J = 1.6 Hz), which cor-
respond to two CH groups of the cyclohexadiene ring. For
both of the trans hydrogens of the CH=CH group, the sig-
nals appear as two doublets at d = 6.72 (3J = 16.1 Hz,
CH=CHPh) and 6.86 (3J = 16.1 Hz, CH=CHPh). Ten aro-
matic hydrogens gave rise to characteristic signals in the
aromatic region of the spectrum. Finally, the signal of NH
group appears as singlet at d = 9.01. The 1H-decoupled 13C
NMR spectrum of 3a showed 21 distinct resonances in
agreement with the suggested structure.
Table 1 Methyl or Ethyl 2-(Alkylamino)-6-phenyl-4-styrylcyclo-
hexa-1,3-dienecarboxylate Derivatives Prepared
H
O
R1NH2
R1
OR2
Ph
N
1
O
O
solvent free
r.t 3 h
+
R2O
Ph
Ph
O
Ph
3
2
Entry R1 1
R2 2
Product 3 Yield (%)
1
2
3
4
5
6
7
8
9
Pr (1a)
Pr (1a)
Me (2a)
Et (2b)
Me (2a)
Et (2b)
Me (2a)
Et (2b)
Me (2a)
Et (2b)
3a
90
81
74
77
70
65
82
80
64
3b
3c
3d
3e
3f
i-Bu (1b)
i-Bu (1b)
Bn (1c)
Bn (1c)
Bu (1d)
Bu (1d)
3g
3h
3i
Although no detailed mechanistic studies have been car-
ried out at this point, a tentative mechanism for this trans-
formation is proposed in Scheme 1. Initially the reaction
of primary amine 1 and alkyl acetoacetate 2 leads to the
enaminone intermediate 4. Enaminone 4 attacks the dou-
ble bond of dibenzylideneacetone to produce intermediate
5, which in turn is converted into intermediate 6. At this
stage, considering the chemistry of enaminones,11–15 we
would normally expect nonbonding electron pairs of the
nitrogen atom to attack to the carbonyl group and cause
the creation of product 8 by elimination of a molecule of
water (path A). But considering IR and 1H and 13C NMR
CH2CH=CH2 (1e) Me (2a)
d = 1.68 (J = 7.2 Hz) was attributed to the methylenes
(CH2) of the propyl group. One of the hydrogens of the cy-
clohexadiene ring (CH2) appears as doublet of doublet of
3
doublet (ddd) at d = 2.84 (2J = 16.5 Hz, J = 7.9 Hz,
4J = 2.0 Hz), and the other hydrogen appears as doublet of
doublet (dd) resonance at d = 2.91 (2J = 16.5 Hz, 4J = 1.65
Hz). The appearance of these hydrogen signals could be
explained as follows: due to the existence of a stereogenic
O
R1
O
HN
R1
R2O
Ph
O
O
HN
Ph
Ph
CO2R2
R1NH2
R2O
1
2
4
5
O
Ph
O
O
O
R1
R1
R2O
Ph
NHR1
R2O
N
R2O
N
OH
– H2O
Ph
Ph
Ph
R1
O
Ph
Ph
8
O
HN
7
6
path A
path B
R2O
Ph
R1
R1
R1
O
HN
O
HN
O
N
O
Ph
H
R2O
Ph
R2O
Ph
6
R2O
3
Ph
– H2O
Ph
OH
O
Ph
O
Ph
10
9
Scheme 1 Mechanism for the formation of alkyl 2-(alkylamino)-6-phenyl-4-styrylcyclohexa-1,3-dienecarboxylates 3
Synthesis 2011, No. 21, 3491–3495 © Thieme Stuttgart · New York

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Synthesis of Highly Functionalized Cyclohexa-1,3-diene Derivatives
3493
127.9 (2 CHPh), 128.2 (CHpara), 128.6 (2 CHPh), 129.7 (CH3), 131.8
(C=CPh), 136.6 (Cipso), 144.1 (C4), 145.8 (Cipso), 155.2 (C2), 170.5
(CO2Me).
MS: m/z (%) = 373 (85) [M+], 330 (15), 314 (100), 296 (88), 208
(19), 165 (14), 82 (27), 41 (14).
spectra, this product was not created and another consid-
erable event occurs. In fact, in this stage intermediate 6
undergoes an enamine–iminium ion–enamine isomeriza-
tion process to form enamine 9. Cyclization of the inter-
mediate 9 to generate compound 10 and finally, by
elimination of a molecule of water gives cyclohexa-1,3-
dienecarboxylate derivatives 3 (path B). The reaction pro-
ceeds under path B, because of compounds 3 are more sta-
ble than compounds 8. Compounds of type 3 are produced
under equilibrium conditions and the vinylogous amide in
all of the products (Table 1) is stabilized by an internal hy-
drogen bond.
Anal. Calcd for C25H27NO2 (373.49): C, 80.40; H, 7.29; N, 3.75.
Found: C, 80.36; H, 7.24; N, 3.79.
Ethyl 6-Phenyl-2-(propylamino)-4-styrylcyclohexa-1,3-diene-
carboxylate (3b)
Orange oil; yield: 0.31 g (81%).
IR (KBr): 3279 (NH), 1632 (CO2Et), 1601 (NC=C), 1557 (Ph),
1445 (Ph), 1260 (ester C–O), 1226 cm–1 (ester C–O).
In summary, we have developed a simple, one-pot, three-
component synthesis of methyl or ethyl 2-(alkylamino)-6-
phenyl-4-styrylcyclohexa-1,3-dienecarboxylate deriva-
tives, which are of potential synthetic interest. High yields
of the products, relatively short reaction times, using sim-
ple and inexpensive starting materials as well as the sol-
vent-free reaction condition are the main advantages of
this method. Also, product could have high diversity via
various functional groups instead of amine and ester
groups. The simplicity of the present procedure makes it
an interesting alternative to complex multistep approach-
es.
1H NMR (500.13 MHz, CDCl3): d = 1.03 (t, 3J = 7.4 Hz, 3 H,
CH2CH3), 1.15 (t, 3J = 7.1 Hz, 3 H, OCH2CH3), 1.68 (sextet,
3J = 7.1 Hz, 2 H, CH2), 2.85 (ddd, 2J = 16.2 Hz, 3J = 7.9 Hz, 4J = 1.9
Hz, 1 H, CH2), 2.91 (dd, 2J = 16.2 Hz, 4J = 1.8 Hz, 1 H, CH2), 3.26–
3.35 (m, 2 H, CH2NH), 4.01–4.11 (m, 2 H, OCH2CH3), 4.24 (d,
4
3J = 7.9 Hz, 1 H, CH5), 6.39 (d, J = 1.8 Hz, 1 H, CH3), 6.73 (d,
3J = 16.0 Hz, 1 H, CH=CHPh), 6.88 (d, 3J = 16.0 Hz, 1 H,
3
CH=CHPh), 7.12 (t, J = 7.0 Hz, 1 H, CHPh), 7.18–7.27 (s, 5 H, 5
CHPh), 7.31 (d, 3J = 7.3 Hz, 2 H, 2 CHPh), 7.41 (d, 3J = 7.3 Hz, 2 H,
2 CHPh), 8.98 (s, 1 H, NH).
13C NMR (125.75 MHz, CDCl3): d = 11.5 (CH3), 14.4 (OCH2CH3),
23.9 (CH2CH3), 31.3 (CH2), 36.4 (CH2NH), 44.6 (OCH2CH3), 58.6
(CH6), 90.6 (CH1), 119.7 (C=CPh), 125.7 (CHpara), 126.7 (2 CHPh),
127.1 (2 CHPh), 127.8 (2 CHPh), 128.2 (CHpara), 128.6 (2 CHPh),
129.8 (CH3), 131.7 (C=CPh), 136.6 (Cipso), 144.0 (C4), 146.2 (Cipso),
154.9 (C2), 170.1 (CO2Me).
All reactions were carried out in oven-dried glassware. Progress of
reactions was monitored by TLC while purification was effected by
column chromatography, using silica gel (Merck 230–240 mesh).
Primary amines, and alkyl acetoacetate and dibenzylideneacetone
were obtained from Merck (Germany) and Fluka (Switzerland) and
were used without further purification. Melting points were mea-
sured on an Electrothermal 9100 apparatus. Elemental analyses for
C, H and N were performed using a Heraeus CHN-O-Rapid analyz-
er. Mass spectra were recorded on a Finnigan-Matt 8430 mass spec-
trometer operating at an ionization potential of 70 eV. 1H and 13C
NMR spectra were measured (CDCl3 soln) with a Bruker DRX-500
Avance spectrometer at 500.13 and 125.8 MHz, respectively. IR
spectra were recorded on a Shimadzu IR-460 spectrophotometer.
MS: m/z (%) = 387 (74) [M+], 344 (11), 314 (100), 234 (10), 208
(23), 194 (15), 91 (23), 77 (12), 43 (7).
Anal. Calcd for C26H29NO2 (387.52): C, 80.59; H, 7.54; N, 3.61.
Found: C, 80.53; H, 7.59; N, 3.66.
Methyl 2-(Isobutylamino)-6-phenyl-4-styrylcyclohexa-1,3-di-
enecarboxylate (3c)
Orange oil; yield: 0.28 g (74%).
IR (KBr): 3270 (NH), 1641 (CO2Me), 1605 (NC=C), 1559 (Ph),
1445 (Ph), 1285 (ester C–O), 1223 cm–1 (ester C–O).
1H NMR (500.13 MHz, CDCl3): d = 0.98 (d, 3J = 6.7 Hz, 3 H, CH3),
1.03 (d, 3J = 6.7 Hz, 3 H, CH3), 1.87–1.92 (m, 1 H, Me2CH), 2.86
Methyl 6-Phenyl-2-(propylamino)-4-styrylcyclohexa-1,3-diene-
carboxylate (3a); Typical Procedure
2
3
4
(ddd, J = 16.3 Hz, J = 7.6 Hz, J = 2.3 Hz, 1 H, CH2), 2.91 (dd,
2J = 16.3 Hz, J = 2.1 Hz, 1 H, CH2), 3.17 (q, J = 6.7 Hz, 2 H,
CH2NH), 3.61 (s, 3 H, OCH3), 4.25 (d, 3J = 6.8 Hz, 1 H, CH6), 6.37
(d, 4J = 2.1 Hz, 1 H, CH3), 6.72 (d, 3J = 16.0 Hz, 1 H, CH=CHPh),
6.86 (d, J = 16.0 Hz, 1 H, CH=CHPh), 7.12 (t, J = 6.6 Hz, 1 H,
CHPh), 7.18–7.26 (5 CHPh), 7.31 (d, 3J = 7.3 Hz, 2 H, 2 CHPh), 7.40
(d, 3J = 7.3 Hz, 2 H, 2 CHPh), 9.12 (s, 1 H, NH).
4
3
To a magnetically stirred 5-mL flat-bottomed flask containing
PrNH2 (1a, 0.059 g, 1 mmol) was added methyl acetoacetate (2a,
0.116 g, 1 mmol). After 30 min, dibenzylideneacetone (0.234 g, 1
mmol) was added to the reaction mixture which was allowed to stir
for 2.5 h. Purification of the crude product by column chromatogra-
phy (silica gel, Merck 230–240 mesh, n-hexane–EtOAc, 12:1)]
gave 3a as an orange oil; yield: 0.31 g (90%).
3
3
13C NMR (125.75 MHz, CDCl3): d = 20.3 (2 CH3), 29.5 (CH), 31.5
(CH2), 36.2 (CH2NH), 50.3 (OCH3), 50.6 (CH6), 89.9 (CH1), 119.6
(C=CPh), 125.8 (CHpara), 126.8 (2 CHPh), 127.1 (2 CHPh), 127.9 (2
CHPh), 128.2 (CHpara), 128.6 (2 CHPh), 129.8 (CH3), 131.8
(C=CPh), 136.6 (Cipso), 144.1 (C4), 145.8 (Cipso), 155.3 (C2), 170.5
(CO2Me).
IR (KBr): 3264 (NH), 1643 (CO2Me), 1608 (NC=C), 1561 (Ph),
1446 (Ph), 1261 (ester C–O), 1207 cm–1 (ester C–O).
1H NMR (500.13 MHz, CDCl3): d = 1.04 (t, 3J = 7.4 Hz, 3 H, CH3),
1.68 (sextet, 3J = 7.2 Hz, 2 H, CH2), 2.84 (ddd, 2J = 16.5 Hz,
3J = 7.9 Hz, 4J = 2.0 Hz, 1 H, CH2), 2.91 (dd, 2J = 16.5 Hz, 4J = 1.65
Hz, 1 H, CH2), 3.27–3.36 (m, 2 H, CH2NH), 3.68 (s, 3 H, OCH3),
4.24 (d, 3J = 6.9 Hz, 1 H, CH6), 6.38 (d, 4J = 1.6 Hz, 1 H, CH3), 6.72
MS: m/z (%) = 387 (93) [M+], 328 (100), 310 (92), 272 (24), 208
(21), 194 (18), 91 (26), 77 (10), 41 (13).
3
3
(d, J = 16.1 Hz, 1 H, CH=CHPh), 6.86 (d, J = 16.1 Hz, 1 H,
CH=CHPh), 7.12 (t, 3J = 6.7 Hz, 1 H, CHPh), 7.19–7.26 (m, 5 H, 5
CHPh), 7.31 (d, 3J = 7.4 Hz, 2 H, 2 CHPh), 7.41 (d, 3J = 7.6 Hz, 2 H,
2 CHPh), 9.01 (s, 1 H, NH).
Anal. Calcd for C26H29NO2 (387.52): C, 80.59; H, 7.54; N, 3.61.
Found: C, 80.63; H, 7.49; N, 3.55.
Ethyl 2-(Isobutylamino)-6-phenyl-4-styrylcyclohexa-1,3-diene-
carboxylate (3d)
Orange oil; yield: 0.30 g (77%).
13C NMR (125.75 MHz, CDCl3): d = 11.4 (CH3), 23.9 (CH2CH3),
31.5 (CH2), 36.2 (CH2NH), 44.6 (CH6), 50.3 (OCH3), 90.0 (CH1),
119.6 (C=CPh), 125.8 (CHpara), 126.8 (2 CHPh), 127.1 (2 CHPh),
Synthesis 2011, No. 21, 3491–3495 © Thieme Stuttgart · New York

3494
A. Alizadeh et al.
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IR (KBr): 3277 (NH), 1633 (CO2Et), 1600 (NC=C), 1559 (Ph),
1438 (Ph), 1260 (ester C–O), 1228 cm–1 (ester C–O).
CH2), 139.1 (Cipso), 143.9 (C4), 146.0 (Cipso), 154.1 (C2), 170.1
(CO2Et).
1H NMR (500.13 MHz, CDCl3): d = 0.96 (d, 3J = 6.7 Hz, 3 H, CH3),
MS: m/z (%) = 435 (1) [M+], 385 (19), 312 (62), 234 (49), 181 (17),
149 (27), 131 (54), 103 (61), 91 (75), 77 (69), 43 (100).
1.03 (d, 3J = 6.7 Hz, 3 H, CH3), 1.15 (t, 3J = 7.1 Hz, 3 H, CH2CH3),
2
3
1.85–1.91 (m, 1 H, CHMe2), 2.85 (ddd, J = 16.5 Hz, J = 7.8 Hz,
Anal. Calcd for C30H29NO2 (435.56): C, 82.73; H, 6.71; N, 3.22.
Found: C, 82.77; H, 6.68; N, 3.20.
4J = 1.9 Hz, 1 H, CH2), 2.91 (dd, J = 16.5 Hz, J = 1.6 Hz, 1 H,
CH2), 3.16 (t, 3J = 6.1 Hz, 2 H, CH2NH), 4.01–4.12 (m, 2 H,
OCH2CH3), 4.24 (d, 3J = 7.8 Hz, 1 H, CH6), 6.38 (s, 1 H, CH3), 6.73
(3J = 16.1 Hz, 1 H, CH=CHPh), 6.88 (d, 3J = 16.1 Hz, 1 H,
CH=CHPh), 7.13 (t, 3J = 5.5 Hz, 1 H, 1 CHPh), 7.18–7.27 (m, 5 H,
5 CHPh), 7.30 (t, 3J = 7.7 Hz, 2 H, 2 CHPh), 7.41 (d, 3J = 7.7 Hz, 2
H, 2 CHPh), 9.08 (s, 1 H, NH).
2
4
Methyl 2-(Butylamino)-6-phenyl-4-styrylcyclohexa-1,3-diene-
carboxylate (3g)
Orange oil; yield: 0.31 g (82%).
IR (KBr): 3276 (NH), 1634 (CO2Me), 1610 (NC=C), 1571 (Ph),
1445 (Ph), 1275 (ester C–O), 1234 cm–1 (ester C–O).
13C NMR (125.75 MHz, CDCl3): d = 15.3 (OCH2CH3), 21.0 (2
CH3), 30.4 (CH), 32.2 (CH2), 37.3 (CH2NH), 51.5 (OCH2CH3),
59.5 (CH6), 91.5 (CH1), 120.7 (CH=CHPh), 126.6 (CHPh), 127.6 (2
CHPh), 128.0 (2 CHPh), 128.7 (2 CHPh), 129.0 (CHPh), 129.5 (2
CHPh), 130.7 (CH3), 132.6 (C=CPh), 137.5 (Cipso), 144.8 (C4), 147.1
(Cipso), 155.9 (C2), 171.0 (CO2Me).
1H NMR (500.13 MHz, CDCl3): d = 0.98 (t, 3J = 7.3 Hz, 3 H, CH3),
1.44–1.51 (m, 2 H, CH2), 1.62–1.69 (m, 2 H, CH2), 2.85 (ddd,
2J = 16.5 Hz, 3J = 7.9 Hz, 4J = 1.9 Hz, 1 H, CH2), 2.91 (dd, 2J = 16.5
Hz, 4J = 1.7 Hz, 1 H, CH2), 3.29–3.42 (m, 2 H, CH2NH), 3.60 (s, 3
H, OCH3), 4.24 (d, 3J = 7.9 Hz, 1 H, CH6), 6.39 (d, 4J = 1.7 Hz, 1 H,
CH3), 6.72 (d, 3J = 16.0 Hz, 1 H, CH=CHPh), 6.87 (d, 3J = 16.0 Hz,
1 H, CH=CHPh), 7.12 (t, 3J = 7.1 Hz, 1 H, CHPh), 7.18–7.28 (m, 5
H, 5 CHPh), 7.31 (t, 3J = 7.7 Hz, 2 H, 2 CHPh), 7.41 (d, 3J = 7.7 Hz,
2 H, 2 CHPh), 8.99 (br, 1 H, NH).
13C NMR (125.75 MHz, CDCl3): d = 13.8 (CH3), 20.1 (CH2), 31.5
(CH2), 32.7 (EtCH2), 36.2 (CH2NH), 42.5 (CH6), 50.3 (CH3), 89.9
(CH1), 119.6 (C=CPh), 125.8 (CHpara), 126.7 (2 CHPh), 127.1 (2
CHPh), 127.9 (2 CHPh), 128.2 (CHpara), 128.6 (2 CHPh), 129.7 (CH3),
131.8 (C=CPh), 136.6 (Cipso), 144.2 (C4), 145.8 (Cipso), 155.2 (C2),
170.5 (CO2Me).
MS: m/z (%) = 401 (83) [M+], 344 (18), 328 (100), 312 (19), 272
(25), 208 (31), 142 (29), 96 (57), 57 (25), 41 (26).
Anal. Calcd for C27H31NO2 (401.55): C, 80.76; H, 7.78; N, 3.49.
Found: C, 80.82; H, 7.71; N, 3.44.
Methyl 2-(Benzylamino)-6-phenyl-4-styrylcyclohexa-1,3-diene-
carboxylate (3e)
Orange oil; yield: 0.29 g (70%).
IR (KBr): 3262 (NH), 1642 (CO2Me), 1608 (NC=C), 1561 (Ph),
1445 (Ph), 1284 (ester C–O), 1228 cm–1 (ester C–O).
MS: m/z (%) = 387 (58) [M+], 91 (72), 81 (64), 280 (27), 234 (40),
199 (62), 91 (49), 71 (68), 57 (79), 43 (100).
1H NMR (500.13 MHz, CDCl3): d = 2.85 (ddd, 2J = 16.4 Hz,
3J = 7.6 Hz, 4J = 2.0 Hz, 1 H, CH2), 2.91 (dd, 2J = 16.5 Hz, 4J = 2.1
Anal. Calcd for C26H29NO2 (387.52): C, 80.59; H, 7.54; N, 3.61.
Found: C, 80.55; H, 7.49; N, 3.64.
3
Hz, 1 H, CH2), 3.61 (s, 3 H, OCH3), 4.26 (dd, J = 7.6 Hz, 1 H,
3
4
CH5), 4.58 (t, J = 5.5 Hz, 2 H, CH2), 6.33 (d, J = 2.1 Hz, 1 H,
CH3), 6.68 (d, 3J = 16.1 Hz, 1 H, CH=CHPh), 6.76 (d, 3J = 16.1 Hz,
1 H, CH=CHPh), 7.11–7.40 (m, 15 H, 15 CHPh), 9.36 (s, 1 H, NH).
Ethyl 2-(Butylamino)-6-phenyl-4-styrylcyclohexa-1,3-dienecar-
boxylate (3h)
Orange oil; yield: 0.32 g (80%).
13C NMR (125.75 MHz, CDCl3): d = 31.6 (CH2), 36.3 (CH2NH),
46.7 (OCH3), 50.5 (CH6), 91.3 (CH1), 119.5 (C=CPh), 125.9
(CHpara), 126.7 (CHpara), 126.8 (2 CHPh), 126.8 (2 CHPh), 127.1 (2
CHPh), 128.0 (2 CHPh), 128.2 (CHpara), 128.6 (2 CHPh), 128.8 (2
CHPh), 129.7 (CH3), 131.9 (C=CPh), 136.5 (Cipso-CH2), 139.3
(Cipso), 144.3 (C4), 145.6 (Cipso), 155.1 (C2), 170.5 (CO2Me).
IR (KBr): 3275 (NH), 1635 (CO2Et), 1603 (NC=C), 1558 (Ph),
1446 (Ph), 1260 (ester C–O), 1220 cm–1 (ester C–O).
1H NMR (500.13 MHz, CDCl3): d = 0.98 (t, 3J = 7.2 Hz, 3 H, CH3),
3
1.15 (t, J = 7.1 Hz, 3 H, OCH2CH3), 1.44–1.47 (m, 2 H, CH2),
2
3
1.61–1.66 (m, 2 H, CH2), 2.86 (ddd, J = 16.0 Hz, J = 6.4 Hz,
MS: m/z (%) = 421 (34) [M+], 387 (10), 362 (23), 332 (27), 300
(17), 141 (14), 91 (100), 69 (18), 43 (17).
4J = 1.9 Hz, 1 H, CH2), 2.91 (dd, J = 16.0 Hz, J = 1.7 Hz, 1 H,
CH2), 3.28–3.41 (m, 2 H, CH2NH), 4.00–4.12 (s, 2 H, OCH2CH3),
4.24 (d, 3J = 6.4 Hz, 1 H, CH6), 6.39 (d, 4J = 1.7 Hz, 1 H, CH3), 6.72
(d, J = 16.1 Hz, 1 H, CH=CHPh), 6.88 (d, J = 16.1 Hz, 1 H,
CH=CHPh), 7.10 (t, 3J = 7.05 Hz, 1 H, CHPh), 7.18–7.26 (m, 5 H, 5
CHPh), 7.31 (t, 3J = 7.6 Hz, 2 H, 2 CHPh), 7.41 (d, 3J = 7.6 Hz, 2 H,
2 CHPh), 9.01 (br, 1 H, NH).
2
4
Anal. Calcd for C29H27NO2 (421.53): C, 82.63; H, 6.46; N, 3.32.
Found: C, 82.69; H, 6.43; N, 3.27.
3
3
Ethyl 2-(Benzylamino)-6-phenyl-4-styrylcyclohexa-1,3-diene-
carboxylate (3f)
Orange oil; yield: 0.28 g (65%).
13C NMR (125.75 MHz, CDCl3): d = 13.8 (CH3), 14.4 (OCH2CH3),
20.1 (CH2), 31.2 (CH2), 32.7 (CH2), 36.4 (CH2NH), 42.6 (CH6),
58.6 (OCH2CH3), 90.5 (CH1), 119.7 (C=CPh), 125.7 (CHpara),
126.7 (2 CHPh), 127.1 (2 CHPh), 127.8 (2 CHPh), 128.1 (CHpara),
128.6 (2 CHPh), 129.8 (CH3), 131.7 (C=CPh), 136.6 (Cipso), 144.0
(C4), 146.2 (Cipso), 154.8 (C2), 170.1 (CO2Me).
IR (KBr): 3440 (NH), 1632 (CO2Et), 1608 (NC=C), 1567 (Ph),
1445 (Ph), 1264 (ester C–O), 1224 cm–1 (ester C–O).
1H NMR (500.13 MHz, CDCl3): d = 1.17 (t, 3J = 6.8 Hz, 3 H, CH3),
2
3
4
2.85 (ddd, J = 16.4 Hz, J = 7.6 Hz, J = 2.0 Hz, 1 H, CH2), 2.87
(dd, 2J = 16.4 Hz, 4J = 2.1 Hz, 1 H, CH2), 4.06–4.12 (s, 2 H,
OCH2CH3), 4.26 (dd, 3J = 7.6 Hz, 1 H, CH5), 4.58 (t, 3J = 5.8 Hz, 2
H, CH2), 6.33 (d, 4J = 2.1 Hz, 1 H, CH3), 6.70 (d, 3J = 16.0 Hz, 1 H,
CH=CHPh), 6.82 (d, 3J = 16.0 Hz, 1 H, CH=CHPh), 7.12–7.46 (m,
15 H, 15 CHPh), 9.08 (s, 1 H, NH).
MS: m/z (%) = 401 (76) [M+], 328 (100), 234 (55), 208 (26), 103
(30), 91 (27), 77 (27), 41 (16), 91 (100).
Anal. Calcd for C27H51NO2 (401.55): C, 80.76; H, 7.78; N, 3.49.
Found: C, 80.71; H, 7.74; N, 3.55.
13C NMR (125.75 MHz, CDCl3): d = 14.4 (OCH2CH3), 31.3 (CH2),
36.4 (CH2NH), 45.0 (CH6), 58.7 (OCH2CH3). 91.8 (CH1), 119.6
(C=CPh), 125.7 (CHpara), 126.7 (CHpara), 127.0 (2 CHPh), 127.5 (2
CHPh), 127.9 (2 CHPh), 128.1 (2 CHPh), 128.3 (CHpara), 128.6 (2
Methyl 2-(Allylamino)-6-phenyl-4-styrylcyclohexa-1,3-diene-
carboxylate (3i)
Orange oil; yield: 0.23 g (64%).
CHPh), 128.8 (2 CHPh), 129.7 (CH3), 131.8 (C=CPh), 135.3 (Cipso
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Synthesis 2011, No. 21, 3491–3495 © Thieme Stuttgart · New York

PAPER
Synthesis of Highly Functionalized Cyclohexa-1,3-diene Derivatives
3495
IR (KBr): 3434 (NH), 1649 (CO2Me), 1621 (NC=C), 1594 (Ph),
1446 (Ph), 1266 (ester C–O), 1226 cm–1 (ester C–O).
(4) (a) Hong, B. C.; Wu, M. F.; Tseng, H. C.; Huang, G. F.; Su,
C. F.; Liao, J.-H. J. Org. Chem. 2007, 72, 8459.
(b) Vosburg, D. A.; Weiler, S.; Sorensen, E. J. Angew.
Chem. Int. Ed. 1999, 38, 971. (c) Maurinsh, Y.; Schraml, J.;
Winter, H. D.; Blaton, N.; Peeters, O.; Lescrinier, E.;
Rozenski, J.; Aerschot, A. V.; Clercq, E. D.; Busson, R.;
Herdewijn, P. J. Org. Chem. 1997, 62, 2861.
(5) (a) Davies, S. G.; Bhalay, G. Tetrahedron: Asymmetry 1996,
7, 1595. (b) Urones, J. G.; Marcos, I. S.; Basabe, P.; Diez,
D.; Garrido, N. M. Phytochemistry 1994, 35, 713.
(6) Patai, S.; Rappoport, Z. The Chemistry of Dienes and
Polyenes, Vol. 1; Rappoport, Z., Ed.; Wiley: Chichester,
1997.
(7) (a) Hong, B. C.; Wu, M.-F.; Tseng, H. C.; Liao, J.-H. Org.
Lett. 2006, 8, 2217. (b) Newman, L. M.; Garcia, H.;
Hudlicky, T.; Selifonov, S. A. Tetrahedron 2004, 60, 729.
(c) Stratakis, M.; Stavroulakis, M.; Sofikiti, N. J. Phys. Org.
Chem. 2003, 16, 16.
1H NMR (500.13 MHz, CDCl3): d = 2.86 (ddd, 2J = 16.4 Hz,
3J = 7.5 Hz, 4J = 2.0 Hz, 1 H, CH2), 2.91 (dd, 2J = 16.4 Hz, 4J = 2.1
Hz, 1 H, CH2), 3.61 (s, 3 H, OCH3), 3.99 (br, 2 H, CH2), 4.27 (d,
3J = 7.5 Hz, 1 H, CH5), 5.23 (d, 3J = 10.5 Hz, 1 H, CH=CH2), 5.35
(d, 3J = 14.5 Hz, 1 H, CH=CH2), 5.94–6.02 (m, 1 H, CH=CH2), 6.32
(d, 4J = 2.1 Hz, 1 H, CH3), 6.72 (d, 3J = 16.4 Hz, 1 H, CH=CHPh),
3
6.82 (d, J = 16.4 Hz, 1 H, CH=CHPh), 7.08–7.77 (m, 10 H, 10
CHPh), 9.12 (br, 1 H, NH).
13C NMR (125.75 MHz, CDCl3): d = 31.5 (CH2), 36.3 (CH2NH),
45.0 (OCH3), 50.4 (CH1), 90.9 (CH3), 116.0 (CH=CH2), 119.5
(CH5), 125.4 (CHpara), 125.9 (2 CHPh), 127.1 (2 CHPh), 128.3 (2
CHPh), 128.6 (CHpara), 128.9 (2 CHPh), 130.4 (C=CPh), 131.9
(C=CPh), 134.8 (Cipso), 143.3 (CH=CH2), 144.1 (C4), 145.6 (Cipso),
155.2 (C2), 170.5 (CO2Me).
MS: m/z (%) = 371 (3) [M+], 312 (6), 280 (4), 234 (100), 205 (29),
(8) (a) Xi, Z.; Li, Z.; Umeda, C.; Guan, H.; Li, P.; Kotora, M.;
Takahashi, T. Tetrahedron 2002, 58, 1107. (b) Saito, S.;
Sone, T.; Murase, M.; Yamamoto, H. J. Am. Chem. Soc.
2000, 122, 10216.
191 (17), 165 (16.5), 131 (58), 103 (90), 91 (35), 77 (79), 51 (35).
Anal. Calcd for C25H25NO2 (371.48): C, 80.83; H, 6.78; N, 3.77.
Found: C, 80.79; H, 6.73; N, 3.81.
(9) (a) Dömling, A. Chem. Rev. 2006, 106, 17. (b) Dömling,
A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39, 3168.
(c) Multicomponent Reactions; Zhu, J.; Bienaymé, H., Eds.;
Wiley-VCH: Weinheim, 2005.
(10) (a) Alizadeh, A.; Rezvanian, A. Synlett 2011, 1105.
(b) Alizadeh, A.; Zarei, A.; Rezvanian, A. Synthesis 2011,
497. (c) Alizadeh, A.; Mokhtari, J. Tetrahedron 2011, 67,
3567. (d) Alizadeh, A.; Rezvanian, A.; Zhu, L. G.
Tetrahedron 2010, 66, 6924. (e) Alizadeh, A.; Rezvanian,
A.; Yuan, D. Tetrahedron 2010, 66, 9933.
(11) Greenhill, J. V. Chem. Soc. Rev. 1977, 6, 277.
(12) Lue, P.; Greenhill, J. V. Adv. Heterocycl. Chem. 1996, 67,
207.
(13) Elassar, A. Z. A.; El-Khair, A. A. Tetrahedron 2003, 59,
8463.
References
(1) (a) Watanabe, C. M. H.; Bench, B. J. US 2007,232,813,
2007; Chem. Abstr. 2007, 147, 427217. (b) Barf, T.;
Hammer, K.; Luthman, M.; Lehmann, F.; Ringom, R.
WO 2004,063,156, 2004; Chem. Abstr. 2004, 141, 157124.
(c) Gein, V. L.; Gein, N. V.; Voronina, E. V.; Kriven’ko,
A. P. J. Pharm. Chem. 2002, 36, 131.
(2) (a) Mimoun, H.; Giersch, W. K. EP 0,955,290, 1999; Chem.
Abstr. 1999, 131, 337203. (b) Urbahns, K.; Mauler, F. DE
19,612,645, 1997; Chem. Abstr. 1997, 127, 307213.
(3) (a) Morgan, A. R.; Selman, S. H. US 5,563,262, 1996;
Chem. Abstr. 1996, 125, 300695. (b) Urbahns, K.; Heine,
H.-G.; Junge, B.; Schohe-Loop, R.; Wollweber, H.;
Sommermeyer, H.; Glaser, T.; Wittka, R.; De Vry, J.-M.-V.
EP 0,698,597, 1996; Chem. Abstr. 1996, 124, 342867.
(14) Negri, G.; Kascheres, C.; Kascheres, A. J. J. Heterocycl.
Chem. 2004, 41, 461.
(15) Stanovnik, B.; Svete, J. Chem. Rev. 2004, 104, 2433.
Synthesis 2011, No. 21, 3491–3495 © Thieme Stuttgart · New York