Diels-Alder Reactions of Ethyl α-Bromoacrylate with Open-chain Dienes?Synthesis of Ethyl 1,3-/ 1,4-Cyclohexadienecarboxylates

Article abstract of DOI:10.1002/cjoc.201090121

The Diels-Alder reactions of ethyl α-bromoacrylate 1 with open-chain dienes 2 were conducted under thermal or Lewis acid-catalysis conditions. In most cases, the cyclic adducts of 1-bromocyclohex-3-enecarboxylates 3 were formed in high yields with good re

Full text of DOI:10.1002/cjoc.201090121

FULL PAPER
Diels-Alder Reactions of Ethyl α-Bromoacrylate with
Open-chain Dienes―Synthesis of Ethyl 1,3-/
Li, Yingjiea(李颖1杰,)4-Cyclohexadienecarboxylates
Wang, Quanrui*,a(王全瑞)
Andreas, Goeke*,b(高安德)
a Department of Chemistry, Fudan University, Shanghai 200433, China
b Shanghai Givaudan Ltd, 298 Li Shi-zhen Road, Shanghai 201203, China
The Diels-Alder reactions of ethyl α-bromoacrylate 1 with open-chain dienes 2 were conducted under thermal
or Lewis acid-catalysis conditions. In most cases, the cyclic adducts of 1-bromocyclohex-3-enecarboxylates 3 were
formed in high yields with good regio- and stereoselectivity. Subsequent E2-elimination by treatment with DBU
provided the corresponding 1,3- or 1,4-cyclohexadienecarboxylates depending on the relative configuration of the
products. Starting from myrcene (7-methyl-3-methyleneocta-1,6-diene) the reaction sequence afforded the ester pre-
cursor of Georgywood with good yields.
Keywords Diels-Alder reaction, cyclohexadienecarboxylate, stereochemistry, Georgywood ester
Introduction
α-bromoacrylate 1 is proved to be more stable under
ambient conditions, and less prone to undergo polym-
erization, thus rendering it to be a more appropriate di-
enophile. Remarkably, the potential of this
bromo-containing ester as a dienophile component re-
mains rarely touched.7 In this work, we wish to unravel
the Diels-Alder reaction between 1 and a series of
open-chain dienes 2, and to investigate the
base-mediated elimination to provide the cyclohexadi-
enecarboxylates.
The Diels-Alder reaction represents an extremely
versatile tool for the construction of six-membered rings.
The search for novel dienes and dienophiles has been
dominating a fundamental role in the development of
synthetic utilities since its discovery. Recently, a set of
α-halo-α,β-unsaturated carbonyl compounds, including
aldehydes,1 nitriles2 and ketones,3 have attracted much
interest regarding the use as dienophiles because many
types of further transformations can be envisioned due
to this added halogen functional handle. We felt that the
base-mediated dehydrohalogenation process to create
functionalized 1,3- or 1,4-cyclohexadienes merits par-
ticular attention since these structural motifs widely oc-
cur in the synthesis of natural products and other im-
portant compounds and possess utility as valuable syn-
thetic intermediates.4 For example, in a recent work by
Passacantilli toward the synthesis of several industrially
significant fragrances, the Diels-Alder reaction of myr-
cene with 3-bromobut-3-en-2-one was performed under
thermal or SnCl4-catalysis conditions, leading to the
formation of the 1-(1-bromocyclohex-3-enyl)ethanone
adduct and the cycloaddition-cyclization product with a
bromo-containing octahydronaphthalene skeleton, re-
spectively. Both of them could be dehydrobrominated
with DBU to give the respective cyclic dienone prod-
ucts.5
Results and discussion
Our initial studies were focused on the use of myr-
cene 2a as the diene moiety and two conditions were
attempted. In the presence of 5 mol% of aluminum
chloride the reaction of 1 with 2a proceeded smoothly at
low temperature (0 ℃) and went to completion in just 6
h. The reaction led to the high-yielding formation of a
mixture of regioisomeric adducts 3a and 4a, with the
“para” isomer 3a highly predominated (Table 1, Entry
1).9 We then carried out the same reaction under thermal
conditions without using any catalyst. A much longer
reaction time was required for completing the reaction
and, expectedly, a much poorer “para/meta” regioselec-
tivity was afforded despite of the slightly improved
yield (Table 1, Entry 2). Apparently, under the catalytic
influence of a Lewis acid like AlCl3, the Diels-Alder
reaction occurred under quite mild conditions without
harming the sensitive bromo-acrylate. This was further
verified by using isoprene 2b as the diene (Table 1, En-
Recently, a reliable general procedure for the prepa-
ration of α-haloacrylate derivatives via dimethyl sul-
foxide-mediated dehydrohalogenation of the dihalopro-
panoate derivatives has appeared.6 Among them ethyl
*
E-mail: qrwang@fudan.edu.cn; andreas.goeke@givaudan.com
Received September 9, 2009; revised October 24, 2009; accepted November 13, 2009.
Project supported by the Discovery-Project (No. 04174) from the Givaudan AG, Switzerland.
Chin. J. Chem. 2010, 28, 613— 616
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Li et al.
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try 3). Furthermore, applying AlCl3 as catalyst, the non-
branched diene penta-1,3-diene 2c reacted with 1 fur-
nishing the “ortho” adduct 3c with high yield, complete
regioselectivity and high endo:exo diastereoselectivity
(Table 1, Entry 4).
We then turned our attention to the reaction of
homomyrcene with the bromo-containing dienophile 1.
It was found that both of the Lewis acid catalyzed and
the thermal uncatalyzed conditions provided exclusively
the tetrasubstituted “para” cyclohexadiene product 3d
as a mixture of stereoisomers. The ratio of the products
seems to be in accordance with Alder’s endo rule. Again,
Lewis acid catalysis led to a more pronounced stereose-
lectivity (Table 1, Entry 5 vs. Entry 6).
An interesting cycloaddition/cyclization-domino se-
quence was observed for the reaction with myrcene 2a.
Under the Lewis acid-catalysis condition, the formation
of the octahydronaphthalene product 5 was detected
from the reaction mixture. Mechanistically, the outcome
of the reaction can be accounted for by invoking the
AlCl3 catalyzed Diels-Alder reaction followed by an
acid-mediated intramolecular cyclization of the
4-methylpent-3-enyl unit with the cyclohexene ring in
3a. Compound 3a could be completely transformed to 5
after refluxing in toluene with 1.1 equiv. of 62% sulfu-
ric acid for 12 h. The direct formation of 5 is beneficial
since the octahydronaphthalene skeleton becomes easily
accessible.10
Next, endeavor was made to conduct the dehydro-
bromination of 5 to the bicyclic dienecarboxylate 6,
which is a potential precursor of the industrially impor-
tant fragrance material Georgywood.8 As we expected,
the elimination reaction was efficiently performed by
treatment of 5 with two equivalents of the hindered or-
ganic base DBU in CH2Cl2 at room temperature. Com-
pound 6 was obtained as yellow oil in 80% yield.11 Un-
der the same conditions, elimination reaction of the
4-substituted 1-bromo-cyclohex-3-enecarboxylates 3a
and 3b led to the 4-substituted cyclohexa-1,3-diene-
carboxylates 7a and 7b in yields of 89% and 93%, re-
spectively (Scheme 1).
Table 1 The results of Diels-Alder reactions
Entry
2—4
R1
R2
H
Conditiona
Yieldb/%
3∶4c
96∶4
Endo∶Exod
—
1
2
3
4
5
6
a
a
b
c
(CH3)2C＝CH(CH2)2
(CH3)2C＝CH(CH2)2
CH3
A
B
A
A
A
B
83
87
86
83
87
56
H
69∶31
97∶3
—
H
—
H
CH3
CH3
CH3
100∶0
100∶0
100∶0
93∶7
89∶11
76∶24
d
d
(CH3)2C＝CH(CH2)2
(CH3)2C＝CH(CH2)2
a
b
Condition: (A) AlCl3 (5 mol%), CH2Cl2, 0 ℃, 6 h; (B) toluene, reflux, 24 h. Isolated yields of all isomers which are inseparable.
c Determined by GC. d Determined by 1H NMR.
Scheme 1 Synthesis of ethyl cyclohexa-1,3-dienecarboxylates 6, 7a, 7b via Diels-Alder reaction and elimination
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Chin. J. Chem. 2010, 28, 613— 616

Diels-Alder Reactions of Ethyl α-Bromoacrylate with Open-chain Dienes
Finally, the outcome of the base-promoted dehydro-
halogenation of the tetrasubstituted adducts 3d proofed
helpful to discriminate between the endo- and
exo-Diels-Alder adducts. We expected endo-3d to be
the major isomer of the mixture but the unambiguous
assignment by NMR is difficult as an NOE between the
bromo atom and the vicinal methyl group does not exist
and other couplings in distorted cyclohexenes are not
significant. However, since the DBU-promoted
E2-elimination of a proton is supposed to proceed anti
to the vicinal bromo substituent (conformer I in Scheme
2), dehydrohalogenation from the major isomer endo-3d
is expected to result in the unconjugated compound 9.
On the other hand, the elimination of the allylic proton
in conformer II of the minor adduct exo-3d can be as-
sumed to generate conjugated cyclohexadienyl deriva-
tive 8. Thus, after a long reaction time (4— 5 d) a mix-
ture of cyclohexadienecarboxylates 8— 10 was obtained.
The distribution corresponded well to the original di-
astereoisomeric endo∶ exo ratios of bromo compounds
3d (Scheme 2). The formation of the thermodynami-
cally more stable compound 10 via initially formed
isomer 9 can be regarded as a secondary process.
Conclusion
In summary, we have demonstrated for the first time
the dienophilicity of ethyl α-bromoacrylate with a set of
linear dienes including myrcene and homomyrcene un-
der thermal and Lewis acid (AlCl3)-catalyzed Di-
els-Alder reactions. The bromo-containing cyclic ad-
ducts successfully undergo DBU-mediated dehydro-
bromination leading to 1,3- and/or 1,4-cyclohexadiene-
carboxylates, which are of synthetic significance.
Scheme 2 Dehydrobromination in 3d (The ratio was determined by GC-MS. The structures of compounds 8—10 were assigned by
NMR.)
efficient synthesis of β-Georgywood, see Fráter, G.;
Schröder, F. J. Org. Chem. 2007, 72, 1112 and references
References and notes
cited therein. See also: Hong, S.; Corey, E. J. J. Am. Chem.
Soc. 2006, 128, 1346.
1
(a) Ishihara, K.; Kurihara, H.; Matsumoto, M.; Yamamoto,
H. J. Am. Chem. Soc. 1998, 120, 6920.
9
Procedure for preparation of 1-bromo-4-(4-methylpent-
3-enyl)cyclohex-3-enecarboxylic acid ethyl ester (3a): To a
stirred suspension of AlCl3 (67 mg, 0.5 mmol) in anhyd
CH2Cl2 (100 mL) was added ethyl α-bromoacrylate 1 (1.79
g, 10 mmol) under cooling in an ice bath. The mixture was
stirred for a couple of minutes, and then myrcene 2a (1.63 g,
12 mmol) was slowly added dropwise. The mixture was
stirred further for 6 h, and quenched with 10% HCl (20 mL).
The phases were separated and the aqueous phase was ex-
tracted with additional CH2Cl2 (50 mL). The combined or-
ganic phases were sequentially washed with saturated aq.
NaHCO3 (50 mL×3), H2O (50 mL) and saturated aq. NaCl
(50 mL), dried over Na2SO4 and concentrated. The residue
was subjected to vacuum distillation to afford 2.62 g of 3a
as colorless liquid (3a/4a ratio 96∶4). Yield 83%, b.p. 131
—134 ℃/15 Pa. IR (neat) ν: 2970, 2914, 1738, 1445, 1249,
(b) Fu, F.; Teo, Y. C.; Loh, T. P. Org. Lett. 2006, 8, 5999.
(c) Corey, E. J.; Shibata, T.; Lee, T. W. J. Am. Chem. Soc.
2002, 124, 3808.
Baldwin, J. E.; Otsuka, M.; Wallace, P. M. Tetrahedron
1986, 42, 3097.
(a) Kraus, G. A.; Kim, J. Org. Lett. 2004, 6, 3115.
(b) Rickerby, J.; Vallet, M.; Bernardinelli, G.; Viton, F.;
Kuendig, E. P. Chem. Eur. J. 2007, 13, 3354.
Nicolaou, K. C.; Snyder, S. A.; Montagnon, T.; Vassiliko-
giannakis, G. Angew. Chem., Int. Ed. 2002, 41, 1668.
Bella, M.; Cianflone, M.; Montemurro, G.; Passacantilli, P.;
Piancatelli, G. Tetrahedron 2004, 60, 4821.
Li, W.; Li, J.; Wan, Z.; Wu, J.; Massefski, W. Org. Lett.
2007, 9, 4607.
In one case, ethyl α-bromoacrylate was reacted with an-
thracene to give the adduct under AlCl3-catalyzed condition,
see Rachon, J.; Goedken, V.; Walborsky, H. M. J. Org.
Chem. 1989, 54, 1006.
2
3
4
5
6
7
1031 cm－ 1; H NMR (CDCl3, 300 MHz) δ: 1.31 (t, J＝7.2
1
Hz, 3H, CH3), 1.60 (s, 3H, CH3), 1.68 (s, 3H, CH3), 1.95—
2.35 (m, 8H, 4 CH2), 2.74 (d, J＝18 Hz, 1H, one H of
8
Georgywood® is a trademark of Givaudan SA. For a recent
Chin. J. Chem. 2010, 28, 613— 616
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Li et al.
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＝CCH2C(Br)), 2.93 (d, J＝18 Hz, 1H, the other H of
＝CCH2C(Br)), 4. 25 (q, J＝7.2 Hz, 2H, OCH2), 5.05—5.09
(m, 1H, CH＝), 5.28—5.32 (m, 1H, CH＝); 13C NMR
(CDCl3, 75 MHz) δ: 13.86 (CH3CH2O), 17.68 (CH3), 25.68
(CH3), 26.20, 27.18, 33.93, 37.04, 37.60 (CH2), 59.48 (CBr),
61.83 (CH2O), 117. 33, 123.86 (CH＝), 131.64, 137.01
(C＝), 170.88 (C＝O). HRMS (ESI) calcd for C15H23BrO2:
314.0881, found 314.0877.
((CH3)2C), 34.3, 37.2, 39.2 (CH2), 60.7 (CBr), 61.7 (OCH2),
126.4 (C＝), 132.4 (C＝), 170.6 (C＝O). HRMS (ESI)
calcd for C15H23BrO2 314. 0881, found 314. 0869.
11 Detailed procedure for the preparation of 8,8-dimethyl-
3,4,5,6,7,8-hexahydronaphthalene-2-carboxylic acid ethyl
ester (6): To a solution of 5 (3.14 g, 10 mmol) in anhydrous
CH2Cl2 (100 mL) was added dropwise DBU (2.28 g, 15
mmol) under cooling in an ice bath. The solution was stirred
at 0 ℃ for 6 h. The progress of the reaction was monitored
by GC. The reaction mixture was diluted with H2O (50 mL).
The phases were separated and the aqueous phase was ex-
tracted with additional CH2Cl2 (30 mL×2). The combined
organic phases were washed with aq. NH4Cl (50 mL×3),
aq. NaHCO3 (50 mL), H2O (50 mL) and saturated NaCl (50
mL), dried (MgSO4) and concentrated. The residue obtained
was purified by flash chromatography (SiO2, n-hexane/
EtOAc, V/V, 100∶ 1) to give 1.99 g of compound 6 as pale
yellow oil in 85% yield. IR (KBr) ν: 2932, 1701, 1584, 1462,
10 Procedure for conversion of 3a to 2-bromo-8,8-dimethyl-
1,2,3,4,5,6,7,8-octahydronaphthalene-2-carboxylic
acid
ethyl ester (5): To a solution of 3a (3.14 g, 10 mmol) in
toluene (100 mL) was added dilute sulfuric acid (62%, 1.74
g, 11 mmol). The mixture was refluxed for 12 h. After
cooling to r.t., the mixture was neutralized with aq. Na-
HCO3. The phases were separated and the organic phase
was washed with saturated aq. NaHCO3 (50 mL), H2O (50
mL) and saturated aq. NaCl (50 mL), dried over Na2SO4
and concentrated to give the crude product, which was puri-
fied by column chromatography (SiO2, n-hexane/EtOAc,
V/V, 100∶1). Compound 5 was obtained as pale yellow oil
in 65% yield. IR (neat) ν: 2959, 2931, 1737, 1463, 1206
cm－ 1; 1H NMR (CDCl3, 300 MHz) δ: 0.97 (s, 6H, (CH3)2C),
1.29 (t, J＝7.2 Hz, 3H, CH3CH2O), 1.44—2.37 (m, 10H, 5
CH2), 2.64 (d, J＝16.5 Hz, 1H, C(1)-H), 2.91 (d, J＝16.5
Hz, 1.18, 1H, C(1)-H), 4.23 (q, J＝7.2 Hz, 2H, CH3CH2O);
13C NMR (CDCl3, 75 MHz) δ: 13.8 (CH3CH2), 19.0 (CH2),
26.9, 27.3 ((CH3)2C), 29.9 (CH2), 30.5 (CH2), 33.7
1252, 1094 cm－ 1; H NMR (CDCl3, 300 MHz) δ: 1.04 (s,
1
6H, (CH3)2), 1.31 (t, J＝7.2 Hz, 3H, CH3), 1.47—1.51 (m,
2H, CH2), 1.61—1.65 (m, 2H, CH2), 2.05—2.13 (m, 4H,
2CH2), 2.37 (t, J＝9.6 Hz, 2H, CH2), 4.21 (q, J＝7.2 Hz, 2H,
CH2), 7.14 (s, 1H, ＝CH); 13C NMR (CDCl3, 75 MHz) δ:
167.7 (C＝O), 137.3, 134.6, 134.4, 125.1, 60.1, 38.8, 32.4,
31.3, 29.3, 28.40 (2C), 21.4, 19.1, 14.4; HRMS (ESI) calcd
for C15H22O2 234.1620, found 234.1615.
(E0908051 Cheng, F.; Lu, Z.)
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