Stereoselective synthesis of functionalized 1,4-dienes

Article abstract of DOI:10.1080/00397910802116609

The article reports a stereoselective synthesis of functionalized 1,4-dienes 5, 6 by coupling allylic Baylis-Hillman acetates 1 and vinyl magnesium chloride at low temperature and in the presence of a catalytic amount of LiCuBr2 (3%). Copyright Taylor & Francis Group, LLC.

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Stereoselective Synthesis of
Functionalized 1,4-Dienes
Sonia Khamri a , Taoufik Turki a & Hassen Amri a
a Laboratoire de Chimie Organique et
Organométallique, Université de Tunis El Manar,
Faculté des Sciences , Tunis, Tunisia
Published online: 12 Sep 2008.
To cite this article: Sonia Khamri , Taoufik Turki & Hassen Amri (2008) Stereoselective
Synthesis of Functionalized 1,4-Dienes, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 38:19, 3277-3284,
DOI: 10.1080/00397910802116609
To link to this article: http://dx.doi.org/10.1080/00397910802116609
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Synthetic Communications1, 38: 3277–3284, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910802116609
Stereoselective Synthesis of Functionalized
1,4-Dienes
Sonia Khamri, Taoufik Turki, and Hassen Amri
´
´
Laboratoire de Chimie Organique et Organometallique, Universite de Tunis El
´
Manar, Faculte des Sciences, Tunis, Tunisia
Abstract: The article reports a stereoselective synthesis of functionalized 1,4-
dienes 5, 6 by coupling allylic Baylis–Hillman acetates 1 and vinyl magne-
sium chloride at low temperature and in the presence of a catalytic amount of
LiCuBr2 (3%).
Keywords: Baylis–Hillman acetates, conjugate addition, functionalized 1,4-dienes
INTRODUCTION
We have previously reported the substitution of Baylis–Hillman acetates
of type 1 by various nucleophilic reagents (i.e., Grignard and Gilman
reagents, lithium ester enolates,[1] 1,3-diketone salts,[2] primary and
secondary amines,[3] and sodium nitronates).[4] This procedure provides
a solid carbon–carbon bond-forming reaction in organic chemistry,
leading to a reliable method of obtaining some biologically active com-
pounds (a-methylene-d-valerolactones 2,[1] ( ꢀ )-sarkomycin 3,[5] and
( ꢀ )-mitsugashwalactone 4[6]) (Scheme 1).
In addition to these methods for the introduction of a hydrocarbon
group to the b-position of activated esters or ketones 1,[7] we show that
organocuprates, prepared in situ without additives, are selective reagents
in the synthesis of functionalized 1,4-dienes 5. The chemistry of functio-
nalized 1,3- and 1,4-dienes has drawn particular attention because of
their various applications in the synthesis of natural products, such as
Received February 4, 2008.
Address correspondence to Hassen Amri, Laboratoire de Chimie Organique et
´
Organometallique, Facultedes Sciences, Campus Universitaire 2092, Tunis, Tuni-
sia. E-mail: hassen.amri@fst.rnu.tn
´
3277

3278
S. Khamri, T. Turki, and H. Amri
Scheme 1.
terpenoids and carotenoids. In the case of the first class of dienes, pre-
vious syntheses include multistep protocols commencing from methyl
pyruvate and ethyl acrylate,[8] Pd-catalyzed carbonylation of alkyne-
diols,[9] pyrolysis of 1,2-diacetoxycyclobutene,[10] Stobbe condensation
in a straightforward manner of dimethyl itaconate-anthracene then
pyrolysis,[11] bismethylenation of the succinic ester phosphonate,[12]
nickel(0)-catalyzed coupling reaction of a-halomethyl acrylate,[13]
addition–elimination of nitronate salt to dimethyl a-(bromomethyl)
fumarate,[14] and conjugate elimination on unsaturated acetals.[15] Fur-
thermore, the homologous 1,4-dienes have been investigated extensively:
several tandem reactions coupling readily available E allylic and homo-
allylic sulfones and aldehydes,[16] chelation-controlled reduction of ben-
zothiazole b-oxosulfides,[17] cross-coupling reaction of 2-benzensulfonyl
1,4-dienes and alkyl magnesium under transition-metal catalysis,[18] and
addition of functionalized allylic bromides to terminal alkynes.[19] Herein,
we report findings on the stereoselective synthesis of the functionalized
1,4-dienes 5, 6 in order to obtain new terminal functionalized 1,4-dienes
in a simple one-pot and atom-economical procedure (Scheme 2).
Scheme 2.
RESULTS AND DISCUSSION
Commercial vinyl magnesium chloride was selected as a nucleophilic
Grignard reagent to carry out conjugate addition of organocopper to
the allylic Baylis–Hillman acetates 1. The reaction of this reagent and 1

Functionalized 1,4-Dienes
3279
(1:1.1–1.5 ratio) in tetrahydrofuran (THF) at ꢀ30 ꢁC in the presence of a
catalytic amount of LiCuBr2 (3%) gives, after quenching with aqueous
ammonium chloride, the desired functionalized 1,4-dienes 5 or 6 in satis-
factory yields and total stereoselectivity with 100%-E isomer based on
spectroscopic evidence (downfield position of the vinylic proton
d > 6.50 ppm in the trisubstituted ethylenic moiety).[20,21] First, the cata-
lytic activity of Cu(I) including CuCl, CuBr, and CuI was tested. It
seemed to be effective, but their solubility and the reaction complexity
were globally inconclusive. Thus, the use of the lithium dibromocuprate
(LiCuBr2) as catalyst in the reaction medium significantly accelerates the
overall rate of the reaction. This catalytic method was applied to various
Grignard reagents as illustrated in Table 1.
Table 1. Synthesis of functional 1,4-dienes 5a–f and 6a,b
Entry
EWG
R
Time (min)
1,4-diene
Yield (%)
1
2
3
4
5
6
7
8
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
COMe
COMe
CH3
C2H5
nC3H7
iC3H7
iC4H9
C6H5
CH3
10
15
20
25
25
20
20
20
5a
5b
5c
5d
5e
5f
52
50
71
47
59
60
41
48
6a
6b
C6H5
In conclusion, this work reports an efficient substitution of the
Baylis–Hillman acetates 1 by Grignard reagent in the presence of a cata-
lytic amount of LiCuBr2. The procedure has several advantages including
good yields, short reaction time, total stereoselectivity, and simple
workup.
EXPERIMENTAL
All the reactions involving anhydrous conditions were conducted in dry
glassware under a nitrogen atmosphere. The solvents were distilled under
nitrogen prior to use. Commercial Grignard reagent was titrated prior to
use,[22] with 1 M solution of benzyl alcohol in anhydrous toluene and
2,20-bipyridyl as indicator. Reactions were monitored by thin-layer chro-
matography (TLC) on silica-gel plates (Fluka kieselgel 60 F254), Fluka
Kieselgel 70–230 mesh was used for purification on column chromato-
1
graphy. H and 13C NMR (fully decoupled) were recorded on a Bruker
AMX 300 in CDCl3 as solvent with TMS as the internal standard.

3280
S. Khamri, T. Turki, and H. Amri
Mass spectrometry was performed on an Autospec 200, Micromass
(Waters) instrument.
Synthesis of Functional 1,4-Dienes 5, 6: Typical Procedure
In a 100-mL round-bottomed flask, fitted with a 25 mL pressure-
equalizing addition funnel, 5 mmol of allylic acetate 1 diluted in THF
(20 mL) and 0.15 mmol (0.15 mL) of a 1 M LiCuBr2 solution were intro-
duced. The mixture was stirred and cooled to ꢁ30ꢂC, followed by the
addition of the vinyl magnesium chloride during 20 min. After the
addition, stirring was continued until the reaction was complete as
monitored by TLC. The mixture was quenched with saturated NH4Cl
solution (15 mL), then extracted with ether (3 ꢃ 20 mL), and the com-
bined organic layers were dried (MgSO4) and evaporated under reduced
pressure. The resulting oil was purified by chromatography on silica
(AcOEt=hexane, 1:9).
(E)-Ethyl 2-Ethylidene Pent-4-enoate 5a
1H NMR (300 MHz, CDCl3): d 1.20 (t, 3H, J ¼ 6.99 Hz, CH3-CH2OCO);
=
1.72 (d, 3H, J ¼ 6.96 Hz, CH3CH C); 3.00 (d, 2H, J ¼ 5.88 Hz, –CH2–
=
CH ); 4.11 (q, 2H, J ¼ 6.99 Hz, CH3CH2OCO); 4.88–4.96 (m, 2H,
=
=
CH2 CH); 5.73 (m, 1H, CH2 CH–CH2–); 6.87 (q, 1H, J ¼ 6.96 Hz,
CH3CH C). 13C NMR (75 MHz, CDCl3): d 14.20 (CH3–CH2O); 14.30
=
=
(CH3–C ); 30.50 (CH2–CH ); 60.60 (CH2O); 114.90 (CH2 ); 131.00
=
=
=
( C–CO); 135.20 (CH CH2); 137.50 ( CH–Me); 167.40 (C O). HRMS
=
=
=
calcd. for C9H14O2: 154.0994; found: 154.0992.
(E)-Ethyl 2-Propylidene Pent-4-enoate 5b
1
=
H NMR (300MHz, CDCl3): d 1.05 (t, 3H, J ¼ 7.35 Hz, CH3CH2CH C–);
1.29 (t, 3H, J ¼ 6.99 Hz, CH3CH2OCO); 2.21 (qd, 2H, J¼ 7.35 Hz,
=
J¼ 7.35 Hz, CH3CH2CH C–); 3.07 (d, 2H, J ¼ 5.88Hz, –CH2–
=
CH ); 4.19 (q, 2H, J ¼ 6.99 Hz, CH3CH2OCO); 4.96–5.04 (m, 2H,
=
=
CH2 CH); 5.81 (m, 1H, CH2 CH–CH2–); 6.83 (t, 1H, J¼ 7.35 Hz,
C CHCH2CH3). 13C NMR (75 MHz, CDCl3): d 13.21 (CH3–CH2O);
=
=
14.16 (CH3–CH2); 21.89 (CH3–CH2–CH); 30.76 (CH2–CH ); 60.46
=
(CH2O); 114.95 (CH2 ); 129.45 ( C–CO); 135.67 (CH CH2); 145.14
=
=
=
( CH–C2H5); 167.67 (C O). HRMS calcd. for C10H16O2: 168.1150; found:
=
168.1150.

Functionalized 1,4-Dienes
3281
(E)-Ethyl 2-Allyl Hex-2-enoate 5c
1H NMR (300 MHz, CDC13): d 0.95 (t, 3H, J ¼ 7.50 Hz, CH3CH2CH2);
1.29 (t, 3H, J ¼ 7.50 Hz, CH3CH2OCO); 1.48 (qt, 2H, J ¼ 7.50 Hz,
J ¼ 7.50 Hz, CH3CH2CH2); 2.17 (dt, 2H, J ¼ 7.50 Hz, J ¼ 7.50 Hz, CH3
=
=
CH2CH2–CH ); 3.07 (d, 2H, J ¼ 7.50 Hz, –CH2–CH ); 4.19 (q, 2H,
=
J ¼ 7.50 Hz, CH3CH2OCO); 4.95–5.04 (m, 2H, CH2 CH–CH2); 5.79
(m, 1H, CH2 CH–CH2–); 6.84 (t, 1H, 7.50 Hz, C CHCH2CH2). 13C
=
=
NMR (75 MHz, CDCI3): d 14.18 (CH3–CH2O); 14.23 (CH3–CH2);
=
22.71 (CH3–CH2–CH2); 30.90 (CH3–CH2–CH2); 31.63 (CH2–CH );
=
=
=
60.36 (CH2O); 115.06 (CH2 ); 130.15 ( C–CO); 135.67 (CH CH2);
=
143.87 ( CH–Pr); 167.57 (C O). HRMS calcd. for C11H18O2: 182.
=
1303; found: 182.1307.
(E)-Ethy1 2-(2-methylpropylidene) Pent-4-enoate 5d
1H NMR (300 MHz, CDC13): d 0.91 [d, 6H, J ¼ 6.82 Hz, (CH3)2CH];
1.20 (t, 3H, J ¼ 7.10 Hz, CH3CH2OCO); 2.59 [m, 1H, (CH3)2–CH];
=
2.98 (d, 2H, J ¼ 5.90 Hz, –CH2–CH CH2); 4.15 (q, 2H, J ¼ 7.10 Hz,
=
CH3CH2OCO); 4.91–5.01 (m, 2H, CH2 CH–CH2); 5.75 (m, 1H,
=
CH2 CH–CH2–); 6.55 [d, 1H, J ¼ 7.30 Hz, (CH3)2CH–CH ]. 13C
=
NMR (75 MHz, CDC13): d 14.21 (CH3–CH2O); 22.99 [CH(CH3)2];
=
=
28.34 [CH(CH3)2]; 32.47 (CH2–CH ); 60.62 (CH2O); 114.94 (CH2 );
i
128.34 ( C–CO); 136.11 (CH CH2); 143.98 ( CH– Pr); 167.79 (C O).
HRMS calcd. for C11H18O2: 182.1307; found: 182.1307.
=
=
=
=
(E)-Ethyl 2-Allyl-5-methyl Hex-2-enoate 5e
1H NMR (300 MHz, CDC13): d 0.86 [d, 6H, J ¼ 6.00 Hz, (CH3)2CH];
1.22 (t, 3H, J ¼ 7.50 Hz, CH3CH2OCO); 1.69 [m, 1H, (CH3)2–CH–
CH2]; 2.01 [dd, 2H, J ¼ 7.50 Hz, J ¼ 7.50 Hz, (CH3)2–CH–CH2–
=
=
CH ]; 3.00 (d, 2H, J ¼ 6.00 Hz, –CH2–CH CH2); 4.13 (q, 2H, J ¼
7.50 Hz, CH3CH2OCO); 4.88–4.97 (m, 2H, CH2 ¼ CH–CH2); 5.74 (m,
=
=
lH, CH2 CH–CH2); 6.79 [t, 1H, J ¼ 7.50 Hz, (CH3)2–CH–CH2–CH ].
13C NMR (75 MHz, CDC13): d 14.28 (CH3–CH2O); 23.07 [CH(CH3)2];
i
28.82 [CH(CH3)2]; 30.90 (CH2–CH ); 37.79 (CH2– Pr); 60.61 (CH2O);
=
i
115.01 (CH2 ); 130.45 ( C–CO); 135.58 (CH CH2); 142.71 ( CH– Bu);
=
=
=
=
=
167.60 (C O). HRMS calcd. for C12H20O2: 196.1463; found: 196.1463.
(E)-3-Ethyl 2-Benzylidene Pent-4-enoate 5f
1H NMR (300 MHz, CDC13): d 1.23 (t, 3H, J ¼ 7.00 Hz, CH3CH2OCO);
=
3.18 (d, 2H, J ¼ 5.86 Hz, –CH2–CH ); 4.15 (q, 2H, J ¼ 7.00 Hz,

3282
S. Khamri, T. Turki, and H. Amri
=
CH3CH2OCO); 4.99–5.08 (m, 2H, CH2 CH–CH2–); 5.89 (m, 1H,
CH2 CH–CH2); 7.23 (m, 5H, C6H5); 7.71 (s, 1H, Ph–CH ). 13C
=
=
=
NMR (75 MHz, CDC13): d 14.28 (CH3–CH2O); 31.66 (CH2–CH );
=
60.81 (CH2O); 116.56 (CH2 ); 128.57; 128.64; 129.01; 135.50 (C6H5);
=
130.49 ( C–CO); 135.70 (CH CH2); 140.17 ( CH–Ph); 167.91 (C O).
=
=
=
HRMS calcd. for C14H16O2: 216.1150; found: 216.1150.
(E)-3-Ethylidene Hex-5-en-2-one 6a
1
=
H NMR (300 MHz, CDCl3): d 1.88 (d, 3H, J ¼ 6.92 Hz, CH3–CH C);
=
=
2.31 (s, 3H, CH3CO); 3.06 (d, 2H, J ¼ 5.86 Hz, –CH2 CH–CH2–C );
=
=
4.95–5.03 (m, 2H, CH2 CH–); 5.75 (m, lH, CH2 CH); 6.85 (q,lH,
=
J ¼ 6.92 Hz, CH3–CH C). 13C NMR (75 MHz, CDC13): d 14.30 (CH3–
=
=
CH ); 25.16 (CH3–CO); 29.27 (CH2–CH ); 115.69 (CH2 ); 135.27
=
=
(CH CH2); 140.64 (CH3–CH ); 141.21 ( C–CO); 198.59 (C O).
=
=
=
HRMS calcd. for C8H12O: 124.0862; found: 124.0888.
(E)-3-Benzylidene Hex-5-en-2-one 6b
1H NMR (300 MHz, CDC13): d 2.37 (s, 3H, CH3CO); 3.17 (d, 2H,
=
=
=
J ¼ 5.86 Hz, CH2 CH–CH2–C ); 4.93–5.03 (m, 2H, CH2 CH); 5.86
13
=
(m, 1H, CH2 CH–CH2); 7.30 (m, 5H, C6H5); 7.58 (s, 1H, Ph–CH ).
C NMR (75 MHz, CDC13): d 26.18 (CH3–CO); 32.46 (CH2–CH );
=
=
=
117.09 (CH2 ); 128.25; 128.98; 129.50; 129.81 (C6H5); 135.11
=
=
=
(CH CH2); 139.21 (CH–Ph); 141.20 ( C–CO); 199.64 (C O). HRMS
calcd. For C13H14O: 186.1045: found: 186.1045.
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