β-Chloro-α,β-unsaturated carbonyls as convenient precursors of highly substituted benzenes

Article abstract of DOI:10.1007/s13738-017-1263-1

The Diels–Alder reactions of three β-chloro-α,β-unsaturated carbonyl compounds 1–3 with different dienes were carried out to afford highly functionalized cyclohexenes 4–9, bearing quaternary centers, in good yields. These cycloadducts (CAs) undergo dehydr

Full text of DOI:10.1007/s13738-017-1263-1

Journal of the Iranian Chemical Society
https://doi.org/10.1007/s13738-017-1263-1
ORIGINAL PAPER
β‑Chloro‑α,β‑unsaturated carbonyls as convenient precursors of highly
substituted benzenes
T. M. Barhoumi‑Slimi1,2 · M. Ourévitch3
Received: 14 January 2017 / Accepted: 1 December 2017
©
Iranian Chemical Society 2017
Abstract
The Diels–Alder reactions of three β-chloro-α,β-unsaturated carbonyl compounds 1–3 with diꢀerent dienes were carried
out to aꢀord highly functionalized cyclohexenes 4–9, bearing quaternary centers, in good yields. These cycloadducts (CAs)
undergo dehydrochlorination with subsequent aromatization in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene DBU
to produce new substituted benzenes 11–14. Compound 10 is the product of lactonization and removal of an HCl molecule
from compound 7. All products were characterized by NMR, IR, elementary analysis and some of them by MS. Structure
assignments of isomers were carried out on the basis of NMR chemical shifts and coupling constants using 1D, 2D and
heteronOe NMR techniques.
Keywords β-Chloro-α,β-unsaturated carbonyls · Diels–Alder reaction · Substituted cyclohexenes · Aromatization ·
Substituted benzaldehydes · NMR
Introduction
temperature in the presence of catalysts could lead isomeri-
zation followed by aromatization [5].
Substituted aromatic compounds are abundant in nature and
have a wide range of biological and pharmacological activity
Indeed, it is well known that a spontaneously dehydro-
chlorination could lead to diene compounds could occur.
Cyclohexadienic compounds are suitable precursors of
cyclic aromatic compounds through a simple removal of a
dihydrogene molecule. According to the literature, it is nec-
essary to operate at high temperature in the presence of cata-
lysts [7, 8] such as platinum, palladium, selenium dioxide
[9] and chromic acid [10, 11] by binding hydrogen atom and
allowing dehydrogenation and consequently aromatization
to produce target dienes. However, 1,8-diazabicyclo[5.4.0]
undec-7-ene (DBU) was often cited in the literature as a
dehydrohalogenating reagent [12]. This paper describes a
speciꢁc process to prepare functionalized benzenes starting
from β-chloro-α,β-unsaturated carbonyls. The presence of
chlorine and hydrogen in trans relationship in compounds 1
and 3 used in Diels–Alder (DA) reaction aꢀord substituted
cyclohexenes with subsequent aromatization, leading to sub-
stituted aromatic compounds. In the case of compound 2,
Danishefsky’s diene is used to allow elimination of small
molecules and then aromatization.
[
1, 2]. They are considered as versatile synthetic building
blocks useful as precursors to the formation of numerous
compounds in diꢀerent areas [3–5]. For instance, methods
to synthesize substituted benzaldehydes have been investi-
gated for over a century. Speciꢁc positions of diꢀerent sub-
stituents on benzene are not easily available by electrophilic
substitution reactions because of the regioselectivity prob-
lems and eventually formation of undesirable by-products
[6]. Reactions of cyclohexa-1,3-diene with acetylene at high
*
T. M. Barhoumi-Slimi
thouraya.sbarhoumi@gmail.com
1
Laboratory of Structural Organic Chemistry: Synthesis
and Physicochemical Studies, Department of Chemistry,
Faculty of Sciences of Tunis, University of Tunis El Manar,
2
092 Tunis, Tunisia
2
3
High Institute of Environmental Science and Technology,
Technopark of Borj-Cedria, University of Carthage,
BP-1003, Carthage, Tunisia
In a previous paper, we have reported the DA reaction
of four β-chloro-α,β-unsaturated aldehydes used as dieno-
philes toward cyclopentadiene [13]. We have shown that
only two of them ethyl-2-chloro-3-formylacrylate 1 and
BIOmolécules: Conception, Isolement et Synthèse,
BioCIS, Faculté de Pharmacie, Université Paris-Sud, 5 Rue
Jean-Baptiste Clément, 92296 Châtenay-Malabry Cedex,
France
Vol.:(0
1
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3

Journal of the Iranian Chemical Society
ethyl 3-chloro-2-formyl-4,4,4-triꢂuorobut-2-enoate 2 were
reactive and gave substituted norbornenes. The substituent
eꢀect toward the reactivity of these aldehydes as dienophiles
in DA reactions was thus experimentally and theoretically
investigated. As an extension to this work, we describe
herein a further investigation of this reaction using dieno-
philes 1–3. The results show that DA–CAs and substituted
aromatic compounds are obtained under mild conditions in
good yields.
NMR (75 MHz, CDCl ) δ 13.7 (CH CH ); 14.6 (CH CH);
3
C
2
3
3
65.3 (OCH ); 69.7 (CHCH ); 128.4 (CCl); 135.2 (CH=);
2
3
161.8 (COOEt). Anal. calc. for C H ClO : C, 47.07; H,
7
11
3
6.21. Found C, 47.21; H, 6.24.
Ethyl 1‑chloro‑3‑oxo‑but‑1‑enoate (3) In a three-necked ꢂask
equipped with a condenser are introduced 1.6 g (8.96 mmol)
of alcohol 1′ in 20 mL of dichloromethane and 2.9 g
(13.4 mmol) of pyridinium chlorochromate (PCC); then,
they were undertaken under reꢂux for 24 h. The reaction was
monitored by TLC. After cooling, the solution was ꢁltered
and then washed three times with ether. The solvent was
evaporated and the crude product puriꢁed by column chro-
matography using petroleum ether/ether (1/1 v/v) mixture as
eluent. Yellow liquid. Yield = 63%. IR: 1608; 1702; 1732.
Experimental section
Instrumental
1
IR spectra were recorded in CHCl on a Perkin-Elmer FTIR
H NMR (300 MHz, CDCl ) δ 1.38 (t, 3H, OCH CH ,
3
3
H
2
3
3
3
Specter Pargon 1000 PC spectrometer. Mass spectra (GC/
MS) were recorded on Hewlett-Packard 5890 Series 2. Ele-
mental analyses were performed using Perkin-Elmer 2400
J
= 7.2 Hz); 2.46 (s, 3H, COCH ); 4.31 (q, 2H, OCH ,
H/H 3 2
13
JH/H = 7.2 Hz); 7.34 (s, 1H, CH=). C NMR (75 MHz,
CDCl ) δ 13.7 (OCH CH ); 31.3 (CH ); 65.5 (OCH CH );
3
C
2
3
3
2
3
1
13
19
analyzer. H, C, F and 2D NMR spectra were recorded
130.3 (CCl); 133.4 (CH); 161.6 (COOEt); 196.5 (COCH ).
3
on Bruker AC 300 and/or 400 MHz NMR spectrometers in
Anal. calc. for C H ClO : C, 47.61; H, 5.16. Found C, 47.79;
7
9
3
19
CDCl solution with TMS and CFCl (for F) as the internal
H, 5.31.
3
3
standard. Chemical shifts are reported in ppm relative to
tetramethylsilane in CDCl . Coupling constants (J values)
Synthesis of Diels–Alder cycloadducts 4–9
3
are given in Hertz. When indicated, assignments of signals
resulted from a complete assignment of the spectral through
HMBC, HMQC and COSY experiments performed on a
multinuclear probehead equipped with a Z-gradient coil. In
NMR data, numbering of atoms is presented according to
the numbering reported in schemes.
General procedure: In a sealed tube, 1 mmol of dienophile
1–3 and 1.2 mmol of diene were introduced. The tube was
sealed; then, the medium was raised to elevated temperature.
The progress of the reaction was monitored by NMR. The
crude product was then puriꢁed by column chromatography
using petroleum ether/ether mixture (4/1 v/v) as eluent.
Synthesis of α,β‑unsaturated carbonyls
1
‑Chloro‑4,5‑dimethyl‑1‑ethoxycarbonyl‑2‑formylcy‑
−
1
Ethyl 1‑chloro‑3‑hydroxybut‑1‑enoate (1′) In a three-
necked ꢂask equipped with a condenser and a dropping
funnel is introduced, under nitrogen atmosphere, 0.15 g
clohex‑4‑ene (4) Pale yellow liquid. Yield 80%. IR(cm ):
1
1635 (C=C); 1680 (CO); 1720 (CO); H NMR (400 MHz,
3
CDCl ) δ 1.29 (t, 3H, OCH CH ,; J
= 7.1 Hz); 1.62
3
H
2
3
H/H
(
6.14 mmol) of magnesium in 5 mL of anhydrous ether.
(s, 3H, C CH ); 1.65 (s, 3H, C CH ); 2.18 (dd, 1H, H ;
5
3
6
3
1α
2
2
2
3
0
.87 g (6.14 mmol) of methyl iodide in 10 mL of anhy-
J
= 17.0 Hz, J
= 6.5 Hz); 2.37 (dd, 1H, H ;
H1α/H1β
H1α/H2
1β
3
drous ether is added dropwise. After 1 h of stirring, orga-
nomagnesium was added on 1 g (6.15 mmol) of aldehyde
JH1β/H1α = 17.0 Hz, J
= 9.0 Hz); 2.50 (d, 1H, H ,
H1β/H2
4α
2
JH4β/H4α = 18.0 Hz); 2.77 (d, 1H, H , J
= 18.0 Hz);
4β
H4α/H4β
3
3
1
in 20 mL of ether at − 10 °C via a syringe. The reaction
3.00 (ddd, 1H, H ; J
= 1.9 Hz, J
= 6.5 Hz,
2
H2/H2′
H2/H1α
3
3
was stirred for 30 min and was monitored by TLC. Then,
hydrolysis was carried out with a 35 mL of a saturated solu-
tion of ammonium chloride and extracted with 2 × 25 mL
of ether. After drying the ether phase and evaporating the
solvent, the crude product was puriꢁed by column chro-
matography using petroleum ether/ether mixture (4/1 v/v)
J
= 9.0 Hz); 4.26 (q, 2H, OCH , J
= 7.1 Hz);
H2/H1β
2
H/H
3
13
9.7 (d, 1H, H ; J = 1.9 Hz). C NMR (100 MHz,
2
′
H2′/H2
CDCl ) δ 14.0 (OCH CH ); 19.1(C CH ); 19.3 (C CH );
3
C
2
3
5
3
6
3
30.5 (C ); 43.2(C ); 52.2(C ); 63.7 (OCH CH ); 67.2 (C );
1
4
2
2
3
3
121.1 (C );124.0 (C ); 170.0 (COO); 201.1 (CHO); M.S.
5
6
+
.
m/z(%): 244 M (10); 208 (22); 162 (52); 147 (100); 134
(63); 119 (38); 107 (55); 91 (68); 77 (26); 65 (18). Anal.
calc. for C H ClO : C, 58.90; H, 7.00. Found: C, 59.02;
−
1
as eluent. Colorless liquid. Yield 75%. IR (cm ): 1633;
1
1
723; 1770; 3401; 3599. H NMR (300 MHz, CDCl )
3
12 17
3
3
δ 1.3 (t, 3H, CH CH , J
= 6.9 Hz); 1.4 (d, 3H, CH ,
H, 7.12.
H
2
3
H/H
3
3
3
3
J
= 6.7 Hz); 2.8 (s, 1H, OH); 4.28 (q, 2H, OCH ,
H/CH3
2
3
JH/H = 6.9 Hz); 4.82 (dq, 1H, CHCH , J
= 6.7 Hz,
1‑Chloro‑4,5‑dimethyl‑1‑ethoxycarbonyl‑2‑acetylcy‑
3
H/CH3
= 7.7 Hz);
3
13
−1
JH/CH = 7.7 Hz); 7.05 (d, 1H, CH = , J
C
clohex‑4‑ene (5) Pale yellow liquid. Yield 65%. IR (cm ):
H/CH
1
3

Journal of the Iranian Chemical Society
1
1
610 (C=C); 1680 (CO); 1730 (CO); H NMR (400 MHz,
1‑Chloro‑1‑ethoxycarbonyl‑2‑acetyl‑5‑methylcyclohex‑4‑ene
3
1
CDCl ) δ 1.3 (t, 3H, OCH CH ; J
= 7.1 Hz); 1.76 (s,
(8b) H NMR (400 MHz, CDCl ) δ 1.3 (t, 3H, OCH ;
3
H
2
3
H/H
3
H
2
3
6
H, 2CH ); 2.23 (s, 3H, COCH ); 2.6 (m, 4H, 2H and 2H );
J
= 7.1 Hz); 1.7 (m, 3H, C CH ); 2.2 (s, 3H, COCH );
3
3
2
5
HH 3 3 3
3
3
.2–3.6 (m, 1H, H ); 4.3 (q, 2H, OCH , J
= 7.1 Hz).
2.3–2.4 (m, 2H, H ); 2.65–2.75 (m, 2H, H ); 3.4 (dd,
6
2
H/H
5
2
1
3
3
3
C NMR (100 MHz, CDCl ) δ 13.9 (OCH CH ); 18.9
1H, H , J
= 6.1 Hz, J
= 6.2 Hz); 4.25 (q,
3
C
2
3
H6
H6/H5α
H6/H5β
3
13
(
C CH and C CH ); 37.8 (C ); 44.0(C ); 51.9(C ); 64.0
2H, OCH , J = 7.1 Hz); 5.45 (m, 1H, H ). C NMR
3
3
4
3
2
5
6
2
HH
4
(
OCH ); 66.1 (C ); 122.8 (C );132.8 (C ); 169.7 (COO);
(100 MHz, CDCl ) δ 13.9 (OCH CH ); 22.9 (C CH ); 28.7
2
1
3
4
3 C 2 3 3 3
2
7
06.1 (COCH ). Anal. calc. for C H ClO : C, 60.35; H,
(COCH ); 31.1 (C ); 39.0 (C ); 53.3 (C ); 63.1 (OCH ); 66.0
3 5 2 6 2
3
13 19
3
.40. Found: C, 60.44; H, 7.46.
(C ); 117.7 (C ); 133.5 (C ); 169.8 (COO); 206.2 (COCH )
1 4 3 3
−
1
Ethyl 6‑chloro‑6‑trifluoromethyl‑1‑formyl‑3,4‑dimethylcy‑
clohex‑3‑ene‑1‑carboxylate (6) Yellow liquid. Yield 65%.
Compounds (9) Red oil (Yield 82%). IR (cm ): 1155
1
9
(C–F); 1640 (C=C); 1732 (CO). F NMR (400 MHz,
−
1
19
IR (cm ): 1154 (CF3); 1642 (CO); 1730 (CO). F: (6a,
CDCl ) δ (9a; 9b; 9c; 9d): (− 72.7; − 71.1; − 73.0; − 72.1),
3
F
+
6
b) (− 71.2, − 72.0) (80%, 20%)
MS(EI, 70 eV), m/z(%): 298 [M ], 253 (3); 189 (11); 161
(45); 141 (100); 127 (10); 91 (25); 77 (8). Anal. calc. for
C H ClF O : C, 48.25; H, 4.72. Found: C, 48.31; H, 4.81.
6
a: NMR (400 MHz, CDCl ) δ 1.25 (t, 3H, OCH CH ,
3 H 2 3
3J = 7.1 Hz); 1.68 (s, 6H, C CH and C CH ); 2.16–3.19
HH
1
3
2
3
12 14
3
3
3
(
m, 4H, 2H et 2H ); 4.2 (q, 2H, OCH , J = 7.1 Hz);
6 3 2 HH
1
3
9
1
.91 (m, 1H, CHO). C NMR (100 MHz, CDCl ) δ
Ethyl 6‑chloro‑6‑trifluoromethyl‑1‑formyl‑4‑methylcy‑
3
C
1
3.7 (COOCH CH ); 18.3 (C CH ); 18.7 (C CH ); 33.7
clohex‑3‑enoate (9a) (60%) H NMR (400 MHz, CDCl )
2
3
1
3
2
3
3
3
(
C ); 39.3 (C ); 58.9 (C ); 62.4 (OCH ); 68.4 (q, C ,
δ
1.3 (t, 3H, CH CH , J
= 7.1 Hz); 1.7 (s, 3H,
= 17 Hz); 2.4 (d, 1H,
6
3
5
2
4
H
2
3
HH
3
J
= 30.1 Hz); 119.7 (C ); 121.9 (C ); 167.8 (COOEt);
C CH ); 2.3 (d, 1H, H , J
CF
1
2
2
3
6α
H6α/H6β
+
1
93.6 (HCO). MS m/z(%): [M ] 312(5), 179 (52); 175
H , J
= 17 Hz); 2.9 (d, 1H, H , J
= 17 Hz);
3
α
H3α/H3β
6β H6β/H6α
(
53); 155 (100); 141 (11); 91 (22); 77 (15). Anal. calc. for
3.1 (d, 1H, H , J
= 17 Hz); 4.22 (q, 2H, OCH ,
H3β/H3α 2
3
β
3
C H ClF O : C, 49.93; H, 5.16. Found: C, 50.01; H, 5.21.
J
= 7.1 Hz); 5.45 (m, 1H, H ); 9.92 (m, 1H, CHO,
1
3
16
3
3
HH
1
1
3
JH–F = 1.8 Hz). C NMR (100 MHz, CDCl ) δ 13.7
3
C
1
‑Chloro‑1‑ethoxycarbonyl‑2‑formyl‑4‑methylcyclohex‑4‑ene
(OCH CH ); 22.6 (C CH ); 28.1 (C ); 38.1 (C ); 57.8 (C );
2 3 2 3 6 3 5
−
1
2
(
1
7a) Yellow liquid IR (cm ): 1610 (C=C); 1682 (CO);
62.4 (OCH ); 68.1 (q, C , J = 29); 116.7 (C ); 126.3
2 4 C/F 1
1
728(CO). Anal. calc. for C H ClO : C, 57.27; H, 6.55.
(q, CF , J = 283.7 Hz); 128.2 (C ); 167.7 (COOEt); 193.0
1
1
15
3
3
2
1
Found: C, 57.31; H, 6.55. H NMR (400 MHz, CDCl )
(CHO).
3
3
δ 1.3 (t, 3H, OCH ; J = 7.1 Hz); 1.76 (d, 3H, C CH ,
H
J
2
HH
4
3
4
= 1.86 Hz); 2.12–3.17 (m, 5H, 2H , 2H , H ); 4.18
3‑Ethoxy‑5,6‑dimethyl‑4,7‑dihydro‑2‑benzofuran‑1(3H)‑one
(10) Five hundred milligrams of the aldehyde 1 and 190 mg
(3.3 mmol) of dimethylbutadiene was introduced in a sealed
H/H3
5
2
6
3
(
q, 2H, OCH , J = 7.1 Hz); 5.32 (m, 1H, H ); 9.62 (d,
2
HH
3
3
13
1
H, H , J
= 2.3 Hz). C NMR (100 MHz, CDCl ) δ
H6′
H6′/H6
3
C
3
1
4.0 (OCH CH ); 18.5 (C CH ); 28.0 (C ); 30.6 (C ); 53.0
tube (50 cm ) and then heated to 65 °C for 72 h. The reaction
2
3
4
3
2
5
(
C ); 63.7 (C ); 122.7 (C ); 171.1 (COO); 201.0 (CHO);
was monitored by TLC. The sealed tube was cooled, and the
crude product was puriꢁed by column chromatography using
6
1
4
+
.
M.S. m/z (%): 230 M (2); 194 (7); 165 (28); 149 (23); 133
(
22); 121 (15); 105 (19); 93 (100); 91 (71); 77 (53); 65 (19).
ether/petroleum ether (1/4 v/v) mixture as eluent. We obtain
1
3
00 mg of compound 19. Yield = 50%. H NMR (400 MHz,
−1
3
Compounds (8) Red oil. IR (cm ): 1610 (C=C); 1682 (CO);
CDCl ) δ 1.27 (t, 3H, CH , J = 7.1 Hz); 1.7 (s, 6H,
3
H
3
HH
2
1
730(CO). Anal. calc. for C H ClO : C, 58.90; H, 7.00.
2CH ); 2.8 (m, 4H, 2CH ); 3.7 (qd, 1H, H , J
= 3 Hz
HA/HB
1
2
17
3
3
2
A
3
3
Found: C, 58.91; H, 7.03.
J
= 7.1 Hz); 3.9 (qd, 1H, H , J
= 3 Hz;
HB/HA
HA/CH3
B
13
JHB/CH3 = 7.1 Hz); 5.7 (s, 1H, H ). C NMR (100 MHz,
1
1
‑Chloro‑1‑ethoxycarbonyl‑2‑acetyl‑4‑methylcyclohex‑4‑ene
CDCl ) δ 14.9 (OCH CH ); 18.5 et 18.6 (2CH ); 28.0 et
3 C 2 3 3
1
(
8a) H NMR (400 MHz, CDCl ) δ 1.3 (t, 3H,
30.6 (2CH ); 65.6 (OCH ); 102.7 (C ); 121.3 et 122.7 (C
2 2 1 5
3
H
3
OCH ; J = 7.1 Hz); 1.7 (m, 3H, C CH ); 2.2 (s, 3H,
et C ); 127.9 (C ); 156.2 (C ); 170.7 (CO). Anal. calc. for
6 3 2
2
HH
4
3
COCH ); 2.3–2.7 (m, 4H, 2H , 2H ); 3.3 (dd, 1H, H ,
C H O : C, 69.21; H, 7.74. Found: C, 69.29; H, 7.81.
12 16 3
3
2
5
H6
3
3
3
J
= 6.1 Hz, J
= 6.2 Hz); 4.25 (q, 2H, OCH ,
H6/H5α
H6/H5β
2
13
JHH = 7.1 Hz); 5.45 (m, 1H, H ). C NMR (100 MHz,
Aromatization of cycloadducts 4–9
3
CDCl ) δ 13.9 (OCH CH ); 22.8 (C CH ); 26.5 (C ); 28.7
3
C
2
3
4
3
2
(
COCH ) 43.2 (C ); 52.5 (C ); 63.1 (OCH ); 66.2 (C );
General procedure: A solution of 2.2 mmol of the cycload-
duct in 10 mL of toluene is introduced in a round-bot-
tomed ꢂask equipped with a refrigerator. Then, 2.4 mmol
of 1,8-diazabicyclo[5-4-0]undec-7-ene (DBU) was added
3
5
6
2
1
1
18.4 (C ); 131.0 (C ); 169.8 (COO); 206.1 (COCH ).
3 4 3
1
3

Journal of the Iranian Chemical Society
dropwise at 0 °C. The whole mixture was heated. The
reactions were controlled by TLC. After evaporation of
the solvent, the residue was puriꢁed by chromatography
on silica gel using petroleum ether/ether (1/9 v/v) mixture
as eluent.
Ethyl 4‑hydroxy‑2‑(triꢀuoromethyl)benzoate (15) To 1 mmol
of the aldehyde 2 introduced in a three-necked ꢂask ꢁtted
with a refrigerator and under argon stream, 1 mmol of the
Danishefsky’s diene was added slowly. After 5 h, hydroly-
sis was carried out with 10 mL of an aqueous acid solution
HCl (0.01 M) and 10 mL of THF. The mixture was stirred
for 2 h at room temperature. The solution was washed with
Ethyl‑2‑formyl‑4,5‑dimethylbenzoate (11) Brown liquid. IR
−
1
1
(
cm ): 1675 (CO); 1730 (CO). H NMR (400 MHz, CDCl )
30 mL of saturated solution of NaCl and dried over MgSO ;
3
4
3
δ 1.4 (t, 3H, OCH CH , J = 7.1 Hz); 2.3 (s, 6H, 2CH );
then, the THF was evaporated. The crude product was chro-
matographed on silica gel column. We obtained 580 mg of
compound 15. Yield = 50%
H
2
3
HH
3
3
4
1
.3 (q, 2H, OCH , J = 7.1 Hz); 7.68 (s, 1H, H ); 7.72 (s,
2
HH
4
1
3
H, H ); 10.6 (s, 1H, CHO). C NMR (100 MHz, CDCl )
1
3
1
9
1
δ 13.8 (OCH CH ); 19.5 and 19.7 (2CH ); 61.4 (OCH );
F NMR: − 60.3 (s, CF ), H NMR (400 MHz,
C
2
3
3
2
3
3
{
142.4; 141.4; 134.5; 131.4; 129.8; 129.1: C
}; 166.2
CDCl ) δ 1.3 (t, 3H, OCH CH , J = 7.2 Hz); 4.3 (q,
arom
3
H
2
3
HH
3
(
COO); 191.9 (CO). Anal. calc. for C H O : C, 69.88; H,
2H, OCH CH , J = 7.2 Hz); 5.4 (s, OH); 7.0 (dd, 1H,
1
2
14
3
2
3
HH
3
4
6
.84. Found: C, 69.91; H, 6.85.
H , J
H2/H4
= 8.5 Hz, J
= 2.2 Hz); 7.2 (d, 1H, H ,
4
J
H4/H5
H4/H2 2
4
3
13
= 2.2 Hz); 7.8 (d, 1H, H , J = 8.5 Hz).
C
5
H5/H4
Ethyl‑2‑acetyl‑4,5‑dimethylbenzoate (12) Brown liq-
NMR (100 MHz, CDCl ) δ 13.8 (OCH CH ); 62.0
3
C
2
3
−
1
1
3
uid. IR (CHCl , cm ): 1685 (CO); 1732 (CO). H NMR
(OCH CH ); 115.4 (q, C , J = 5.7 Hz); 119.0 (C );
3
2 3 2 CF 4
3
1
(
400 MHz, CDCl ) δ 1.3 (t, 3H, OCH CH , J = 7.1 Hz);
123.3 (C ); 124.0 (q, CF , J = 273 Hz); 131.3 (q, C ,
6 3 CF 1
3
H
2
3
HH
2
2
.2 (s, 6H, 2CH ); 2.5 (s, 3H, COCH ); 4.2 (q, 2H, OCH ,
J
= 32.5 Hz); 137.2 (C ); 159.0 (C ); 168.1 (COOEt).
CF 5 3
3
3
2
3
13
+
J
= 7.1 Hz); 7.1 (s, 1H, H ); 7.53 (s, 1H, H ). C NMR
MS: m/z(%) [M ] 234 (10); 189 (100); 161 (17); 63 (5).
HH
4
2
(
(
(
100 MHz, CDCl ) δ 14.0 (OCH CH ); 19.5 (C CH ); 19.7
Anal. calc. for C H F O : C, 51.29; H, 3.87. Found: C,
3 C 2 3 3 3
10
9
3
3
C CH ); 30.1 (COCH ); 61.4 (OCH ); 127.8 (C ); 130.5
51.35; H, 3.90.
2
3
3
2
3
C ); {140.9; 140.2; 138.7; 126.5: C
}; 167.0 (COO);
2
arom
+
.
2
02.9 (COCH ); M.S. m/z (%): 220 (M ) (2); 205 (37);
3
1
77 (100). Anal. calc. for C H O : C, 70.8; H, 7.32. Found:
13
16
3
C, 70.91; H, 7.49.
Results and discussion
Ethyl‑2‑formyl‑4‑methylbenzoate (13) Brown liquid. IR
Ethyl-2-chloro-3-formylacrylate 1 [14], ethyl 3-chloro-2-for-
myl-4,4,4-triꢂuorobut-2-enoate 2 [15] and 1-chloro-1-ethox-
ycarbonyl-3-oxo-but-1-ene 3 are used as starting materials
in this work. The two aldehydes 1 and 2 were prepared as
previously described as mixtures of Z and E isomers, 95/5
for the aldehyde 1 and a ratio of (4:1) for the aldehyde 2 as
previously described [15]. To the best of knowledge, dieno-
phile 3 is a new compound and was obtained as described
in Scheme 1.
−
1
1
(
cm ): 1680 (CO); 1720 (CO). H NMR (400 MHz,
3
CDCl ) δ 1.3 (t, 3H, OCH CH , J = 7.1 Hz); 2.4 (s, 3H,
3
H
2
3
HH
3
ArCH ); 4.2 (q, 2H, OCH , J = 7.1 Hz); 7.3 (d, 1H, H ,
3
2
HH
3
3
3
J
= 7.8 Hz); 7.5 (d, 1H, H , J = 7.8 Hz); 8.0 (d, 1H,
HH
4
HH
3
3
H , J
= 1.6 Hz); 10.0 (d, 1H, H , J
= 1.6 Hz).
1
H1/H6′
6′
H6′/H1
1
3
C NMR (100 MHz, CDCl ) δ 14.1 (OCH CH ); OCH
3
C
2
3
2
(
61.0); 21.3 (CH C=C); 143.2 (C ); 129.4 (C ); 136.7 (C );
3
2
5
6
1
30.1 (C ); 130.3 (C ); 167.9 (COO); 192.4 (CHO); M.S.
1
4
+.
m/z (%): 192 (M ) (2); 119 (28); 91 (66); 77 (49); 65 (8).
Anal. calc. for C H O : C, 68.74; H, 6.29. Found: C,
β-Chloro-α,β-unsaturated carbonyls 1 and 3 have been
obtained as (Z) isomers upon puriꢁcation by column chro-
matography and 2 as a mixture of Z and E isomers. The reac-
tion with isoprene and dimethylbutadiene led to [4 + 2] CAs
4–9 isolated as inseparable isomer mixtures (Scheme 2). As
previously seen [16], the complete stereochemistry assign-
ment for the cycloadducts was based on NMR 2D (COSY,
HMBC and HMQC). The reaction conditions are shown in
Table 1.
1
1
12
3
6
8.77; H, 6.40.
E t h y l ‑ 2 ‑ a c e t y l ‑ 4 ‑ m e t h y l b e n z o a t e
( 1 4 a )
and Ethyl‑2‑acetyl‑5‑methylbenzoate (14b) Brown liquid.
−
1
1
IR (cm ): 1685 (CO); 1732 (CO). H NMR (400 MHz,
3
CDCl ) δ 1.3 (t, 3H, OCH CH , J = 7.1 Hz); 2.4
3
H
2
3
HH
(
s, 3H, PhCH ); 2.5 (s, 3H, COCH ); 4.3 (q, 2H, OCH ,
3 3 2
3
13
J
= 7.1 Hz); 7.3 (m, 3H, C ). C NMR (100 MHz,
All DA reactions aꢀorded cyclohexenes bearing quater-
nary centers variably substituted by ester, aldehyde, chlorine
and triꢂuoromethyl groups, which are interesting compounds
for pharmaceutical and material industries. As shown in
Table 2, reactions performed with formylated dienophile 1
require slightly milder conditions than the acetylated dieno-
phile 3: shorter reaction time and lower temperature. Yields
HH
arom
CDCl ) δ 13.9 (OCH CH ); 19.5 and 19.7 (2CH ); 30.1
3
C
2
3
3
(
COCH ); 61.5 (OCH ); (140.0; 139.0; 136.0; 137.7; 128.8;
3
2
1
29.2; 130.5;127.8:C ); 167.2 (COO); 201.0 (COCH ).
arom 3
Anal. calc. for C H O : C, 69.88; H, 6.84. Found: C,
1
2
14
3
6
9.93; H, 6.84.
1
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Journal of the Iranian Chemical Society
Scheme 1 Synthesis of com-
pound 3
O
OH
Cl
O
H
H
H
CH3
H
CH MgI
PCC
CH Cl EtOOC
3
Et O/-10°C
2
2
Cl
2
EtOOC
EtOOC
Cl
3
(63%)
1
'(75%)
5/95 E/Z)
1
(5/95 E/Z)
(
(5/95 E/Z)
O
R
(Z)-3 with dimethylbutadiene led to one isomer in each case,
and 5, respectively, while the reaction of the triꢂuorometh-
ylated dienophile 2 gave a mixture of two diastereoisomers
O
4
R'
6a and 6b with a ratio of 4:1 with respect to E/Z ratios of the
R
R'
+
starting aldehydes (Fig. 1). The cycloadducts 4–6 were fully
characterized by NMR and IR spectroscopy.
Cl
X
Cl
X
The DA reaction with the unsymmetrical isoprene
aꢀorded CA mixtures 7–9. The DA reaction with the dieno-
phile 1 led to two regioisomers 7a and 7b in 4:1 crude ratio,
while the DA reaction carried out with the dienophile 3 gave
the two regioisomers 8a and 8b in a 1:1 crude ratio (Fig. 2).
The diꢀerence in ratios observed in cycloadducts 7 and 8
could be explained by the more electron withdrawing eꢀect
of the aldehyde group compared to the acetyl group where
aldehyde may increase the diꢀerence between the coeꢃ-
cients and therefore aꢀects DA reaction regiochemistry.
The DA reaction of the mixture (Z/E 20/80) of the alde-
hyde 2 with isoprene aꢀorded a mixture of four stereo and
regioisomers cyclic adducts 9a-d (Fig. 3).
1-3
4-9
1
2
3
: R = R' = H, X = CO Et
: R = H, R' = CO Et, X = CF3
:R = CH , R' = H, X = CO Et
2
2
3
2
Scheme 2 Diels–Alder reaction with carbonyl compounds 1–3
were also slightly better than those obtained with the ketone
(
Z)-3. This is probably due to the higher electron withdraw-
ing eꢀect of the aldehyde 1 compared to the ketone 3.
The cycloaddition with the symmetrical diene as dimeth-
ylbutadiene gave the expected cycloadducts (Table 1). Due
to diene’s symmetry, the reaction of compounds (Z)-1 and
The CAs of mixtures of 6–9 could not be separated from
each other, but suꢃcient puriꢁcation was achieved by col-
umn chromatography allowing NMR spectral assignments to
be made and the individual isomers to be established. Only
the major isomer 7a, the two isomers 8a and 8b and 9a are
exclusively described (see “Experimental section” section).
It is worth to note that when the aldehyde 1 and dimeth-
ylbutadiene were heated at higher temperature (65 °C) and at
longer time reaction (72 h), cyclization into lactone occurred
in a 50% yield as described in Scheme 3. This was evident in
Table 2 Aromatization of CAs 4–9
Entry
Product
t (h)
T (°C)
Yield (%)a
a
b
c
11: R = H
1
24
3
25
80
25
90
80
64
75
41
12: R = CH3
13: R = H
1
the H NMR spectrum of the aged mixture which showed the
d
14: R = CH3
48
replacement of signals relating to aldehyde and ester groups
aIsolated yields
by the proton CH(OEt). The formation of compound 10,
Table 1 Synthesis of
cycloadducts 4–9
Yield (%)a
Entry
Diene
Cycloadduct
t (h)
T (°C)
a
b
c
d
e
f
2,3-Dimethylb-
utadiene
4: R = H, R′ = H, X = COOEt
7
32
24
20
48
30
65
80
65
80
90
80
80
65
90
75
65
82
5: R = CH , R′ = H, X = COOEt
3
6: R = H, R′ = COOEt, X = CF3
7: R = H, R′ = H, X = COOEt
Isoprene
8: R = CH , R′ = H, X = COOEt
3
9: R = H, R′ = COOEt, X = CF3
aIsolated yields
1
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Journal of the Iranian Chemical Society
O
O
6
6
3
1
H1α
H
EtOOC
O
H
EtOOC
5
4
1
5
H1β
O
1
5
2
H '
6
2
H C
4
2
3
2
F C
Cl
3
H2
2
H
Cl
6
4
5
Cl
Cl
F3C
3
3
4
EtOOC
3
1
EtOOC
H4β
H4α
4
5
6a
6b (6a:6b 4:1)
Fig. 1 Stereochemistry of cycloadducts 4–6
O
H5β
O
H5β
O
O
H5α
H
5
α
5
5
5
2
5
H '
4
H '
4
6
4
6
H C
H C
4
3
3
H
H
Cl
6
H
H
6
6
6
Cl
Cl
Cl
3
3
1
3
3
1
EtOOC
2
1
1
EtOOC
EtOOC
EtOOC
2
2
7
a
7b (7a:7b / 4:1)
8a
8b (8a:8b / 1:1)
Fig. 2 Stereochemistry of cycloadducts 7 and 8
O
O
O
H
5
O
6α
H
6
H6β
1
H
EtOOC
F3C
H
H
EtOOC
EtOOC
EtOOC
F3C
Cl
Cl
Cl
4
2
Cl
F3C
3
F3C
9a
9b
0% (9a:9b / 3:1)
9c
9d
20% (9c:9d/1.4:0.6)
8
Fig. 3 Stereochemistry of cycloadducts 9
whose structure was conꢁrmed by spectroscopy and elemen-
tal analysis, is presumably due to lactonization and elimina-
tion of an HCl molecule from compound 7. This is due to
the interaction between both carbonyls of aldehyde and ester
functions. Similar eꢀect was observed for compound 1 in a
previous work [14]. Such lactones are known to be present
in several pharmacologically important natural products [9].
Aromatization was carried out to obtain aromatic com-
pounds 11–14. When CAs 4–9 were kept for several days
at room temperature, partial conversion into 11–14 with
hydrogen-chloride evolution was observed (Scheme 4). By
carrying out aromatization reaction on varying only temper-
ature did not give aromatic compounds 11–14 properly; mild
temperatures did not led to the reaction and more elevated
temperatures up to 150 °C also failed to provide any polym-
erization of the reaction mixture. In addition, the use of tri-
ethylamine as base did not yield the desired products. How-
ever, 1,8-diazabicyclo[5-4-0]undec-7-ene (DBU) in toluene
at elevated temperatures aꢀorded the aromatic compounds
11–14 in good yields (Table 2). The reactions were moni-
tored by TLC and puriꢁed by column chromatography.
Before completion of the aromatization reaction, inter-
1
mediates I (Scheme 4) were detected by H NMR, but they
could not be isolated. However, we can postulate the for-
mation of intermediates I by referring to the formation of
compound 10. It has been noted, in the literature, that the
corresponding anion of compound 14 could be obtained by
base catalyzed ring ꢁssion of benzocyclobutenediones [16].
1
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Journal of the Iranian Chemical Society
Scheme 3 Lactonization of
CA 7
O
C
1
6
R
O
2
O
C
C
5
R
3
R
H
Cl
DBU/∆
EtOOC
4
11, 12
1
O
EtOOC
EtOOC
4
-9
I
C
R
6
2
5
3
1
1, 13 : R = H
2, 14 : R = CH3
EtOOC
4
1
13, 14
Scheme 4 Aromatization of CAs 4–9
Scheme 5 Reaction of Dan-
F3C
ishefsky’s diene with aldehyde 2
OSiMe3
EtOOC
F3C
CHO
OH
5
h / 70°C
THF
+
Cl
EtOOC
OMe
15
Aldehyde 2, with a lack of a hydrogen atom, was reacted
with Danishefsky’s diene in DA reaction aꢀording aromatic
compound 15 as shown in Scheme 5.
heteronOe (3.3%)
F3C
H
2
The hydroxyl group position was determined by two-
1
dimensional NMR. Indeed, a heteronOe between –CF
3
group and hydrogen atoms H(2) was detected and measured
OH
EtOOC
6
3
having a value of 3.3% showing a short distance between
–
CF and H(2), as shown in Fig. 4.
5
15
4
3
H
H
The production of this compound conꢁrms that 50%
cycloaddition occurs according to the unique arrangement
of two molecules: diene and dienophile. Elimination of two
Fig. 4 HeteronOe of compound 15
1
3

Journal of the Iranian Chemical Society
OMe
F
3C
H OMe
O
EtOOC
CHO
Cl
H+
-
MeOH
EtOOC
Cl
-CO et -HCl EtOOC
OH
F3C
OSiMe3
OH
F C
3
1
5
H
Scheme 6 Proposed mechanism for the synthesis of compound 15
molecules: MeOH and HCl accompanied by deformylation,
is suggested as proposed in Scheme 6.
References
This result, in agreement with our previous work [16],
indicates that the highest dienophile coeꢃcient is triꢂuo-
romethylated carbon, Danishefsky’s diene bearing highest
coeꢃcient at C(OMe). Then, the reaction is governed by the
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W. Steglich, B. Fugmann, S. Lang-Fugmann (eds.), Römpp
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of polyfunctionalized benzenes has been also reported using
DBU as a base to promote small molecule elimination and
then aromatization of cycloadducts. All the compounds have
been isolated and characterized by NMR, IR, MS and by
elementary analysis. Structure assignments of isomers were
made on the basis of NMR chemical shifts and coupling
constants using 1D, 2D and heteronOe NMR techniques.
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functionalized cyclohexenes and benzenes. Other β-chloro-
α,β-unsaturated carbonyl compounds are under investigation
for this purpose.
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Acknowledgements I would like to thank my supervisor Pr Moham-
med Moncef El Gaied for his support and encouragement during this
project. We are grateful to the Tunisian Ministry of High Education and
Scientiꢁc Research for ꢁnancial support (LR99ES14) of this research.
1
3