Halolactonisation of (2Z,4E)-dienoic acids. A novel approach to γ- alkylidene butenolides

Article abstract of DOI:10.1055/s-2000-6485

Stereoselective synthesis of alkylidene butenolides was achieved from (2Z,4E)-dienoic acids by a sequence involving halocyclisation and elimination reactions. Selectivity was found to be highly dependent on the nature of the substituents. This methodology

Full text of DOI:10.1055/s-2000-6485

2
60
LETTER
Halolactonisation of (2Z,4E)-dienoic Acids. A Novel Approach to g-Alkylidene
Butenolides
a
a
a
a
b
Séverine Rousset, Jérôme Thibonnet, Mohamed Abarbri, Alain Duchêne, * Jean-Luc Parrain *
a
Laboratoire de Physicochimie des Interfaces et des Milieux Réactionnels, Faculté des Sciences de Tours, Parc de Grandmont,
3
7200 Tours, France
E-mail: duchene@delphi.phys.univ-tours.fr
b
Laboratoire de Synthèse Organique associé au CNRS (ESA 6009), Faculté des Sciences de Saint Jérôme, 13397 Marseille Cedex 20,
France
E-mail: jl.parrain@lso.u-3mrs.fr
Received 2 November 1999
acids 1a-f were prepared via the Stille cross coupling re-
Abstract: Stereoselective synthesis of alkylidene butenolides was
action of vinyltin reagents with (Z)-3-iodoalk-2-enoic ac-
achieved from (2Z,4E)-dienoic acids by a sequence involving halo-
cyclisation and elimination reactions. Selectivity was found to be
6
ids. Several electrophilic halogen sources (ICl, I /KI,
2
highly dependent on the nature of the substituents. This methodolo- NBS,…) were used and only the best results in terms of
gy has been applied to the synthesis of a retinoid containing the yield are shown in Table 1. First, we tested procedures in-
alkylidene butenolide core.
volving in situ oxidation either using potassium iodide
7
Key words: halolactonisation, elimination reaction, dienoic acids, with sodium persulfate in aqueous solution or a NBS pro-
butenolides, g-alkylidene butenolides
8
cedure; however the yields obtained were relatively low.
9
Interestingly, under non-basic conditions, ICl was found
to be the best system to obtain iodolactones 2a-j in fair to
good yields. With 5-substituted dienoic acids and in all
cases, the diastereoselectivity of the halolactonization was
In recent years, great interest has been focused on the syn-
thesis of molecules containing the butenolide moiety
10
1
up to 98%. The stereochemistry was assigned on the ba-
sis of mechanistic considerations compared to other
(
g-lactones and a,b-unsaturated-g-lactones). Among
these molecules, alkylidene butenolides constitute the
core of many natural and unnatural compounds which dis-
play a wide range of biological activities. Very simple ex-
amples of these naturally occurring substances include
protoanemonin, tetrenolin, the furanosesquiterpenoid
freelingyne and rubrolides; their synthesis was recently
11
halolactonisation and haloetherification reactions. Aryl,
alkyl, methoxymethyl, trifluoromethyl, and trimethylsilyl
2
groups can be accommodated as R substituents. In most
cases, only the 5-exo-trig-iodocyclisation mode was
favoured.
2
reviewed. The construction of the g-alkylidene moiety
was mainly achieved via four major routes or approach-
2b
R2
R2
es. Lewis acid catalysed coupling of aldehydes with
oxofurans, alkenylation of g-lactones and olefination of
maleic anhydride were described as efficient methods but
with a major drawback, the non-selective construction of
the exocyclic double bond. The fourth route allows com-
plete control of the exocyclic double bond through a tran-
sition metal (Pd, Ag) catalysed lactonisation.
Nevertheless, although Z-selectivity of the exocyclic dou-
ble bond is relatively easy to control, clean access to the
"
X +
"
R1
X
O
O
COOH
X = Br, I
1a-j
R1
2a-j
Scheme 1
Attention was next directed towards the formation of the
exocyclic double bond via base-mediated anti elimina-
(
E)-stereoisomer still remains a challenge for organic
12
tion. With DBU in dichloromethane as base, the elimi-
chemists (with the exception of the stereoselective synthe-
nation reaction took place and gave the desired alkylidene
butenolides in fair to good yields (Scheme 2). The results
3
sis of g-(E)-freelingyne). Moreover, recent efforts have
been centred on the construction of tin methylidene-
13
are summarised in Table 2. Other bases tested (triethyl-
4
butenolides by using palladium catalyst systems. In this
amine, DBN) led to less efficent transformation. As ex-
pected, the selectivity observed was largely in favour of
paper we report our results related to the stereoselective
preparation of (E)-alkylidenebutenolides through a se-
quence involving halocyclisation of conjugated (2Z,4E)-
dienoic acids and basic elimination as well as its applica-
tion to the synthesis of a butenolide analogue of retinoic
acid.
14
the (E)-stereochemistry of the exocyclic double bond.
R2
R2
DBU, -78 °C
CH2Cl2
2a-j
+
R1
O
O
The halolactonisation reaction is easily obtained upon ex-
O
O
R1
(
E)-3 a-g
(Z)-3 a-g
posure of substituted dienoic acids 1a-f to a halogen
5
source following a common procedure (Scheme 1). The
Scheme 2
Synlett 2000, No. 1, 260–262 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Halolactonisation of (2Z,4E)-dienoic Acids. A Novel Approach to g-Alkylidene Butenolides
261
explained by the greater thermodynamic stability of the
Z)-isomer of 3b vs (E)-3b where the large interaction of
(
the ortho hydrogens of the phenyl group and the methyl
substituent prevents conjugation. For the same reasons, 3j
was obtained as an equimolecular mixture of (E)-and (Z)-
isomers which evolved after few days to the (Z)-isomer.
Stereoselective iododesilylation of 3a and 3d occurred in
the presence of silver trifluoroacetate in good yields.16
Nethertheless, the iodobutenolides (E)-4a and 4d formed
were found to be unstable and quantitatively isomerized
1
7
into the thermodynamically more stable (Z)-isomers as
we previously observed for the iododestannylation of
tributyltin analogue of 3a.4
R2
R2
I2, CF3CO2Ag
(
E)-3a;d
I
O
ether
THF, -78 °C, 4h
O
O
O
2
5 °C, 1 h
I
(
E)-4a;d
(Z)-4a;d
Scheme 3
Finally, as a possible application, we investigated the syn-
thesis of yne analogues of retinoic acid containing the
18
alkylidene butenolide moiety. Heck-Sonogashira cross-
1
9
coupling reaction of (Z)-4d with (7E)-1-(but-3-en-1-yn-
-yl)-2,6,6-trimethylcyclohex-1-ene 5 gave the desired
4
butenolide 6 in 65% yield.
H
Pd(PPh3)4, CuI
(Z)-4d
+
O
O
n-BuNH2, benzene
5
6
Scheme 4
In conclusion, we demonstrated that the sequence halolac-
tonisation of conjugated dienoic acids / DBU-promoted
elimination selectively yields alkylidene butenolides
which are potential precursors of numerous alkylidene
butenolides. This methodology was then applied to syn-
thesis of a retinoid containing the alkylidene butenolide
Nevertheless, selectivity was highly dependent on tem- core. Further studies are currently aimed at broadening the
perature, and the best results were obtained at low temper- application of iodolactones to the synthesis of natural
ature (entries 3; 7 or 9). The methyl and trimethylsilyl alkylidene butenolides.
homologues of protoanemonin (entries 5 and 8) were ob-
tained in good yields and no product of dimerisation was
Acknowledgement
1
5
detected. Interestingly, for the first time g-silylmeth-
ylidenebutenolides 3a, d, and h were obtained with high We thank the CNRS and MESR for providing financial support, the
"
Service d’analyse chimique du vivant de Tours" for recording
selectivity in favour of the (E) configuration (E/Z > 95/5)
of the exocyclic double bond which was confirmed by the
Noesy experiments. It should be noted that, at room tem-
NMR and mass spectra.
perature, 3a and 3d slowly isomerise from 98/2 to approx- References and Notes
imatively 25/75 after 48h. In the case of the formation of
(
1) For recent syntheses of butenolides see a) Xu, C.; Negishi, E.
3
b, elimination reaction gave the desired arylidene
Tetrahedron Lett. 1999, 40, 431; b) Ma, S.; Shi, Z. J. Org.
Chem. 1998, 63, 6387; c) Rossi, R.; Bellina, F.; Biagetti, M.;
Mannina, L. Tetrahedron Lett. 1998, 39, 7799; d) Rossi, R.;
butenolide in 70% yield (entry 4) but with a complete (Z)-
configuration of the exocyclic double bond. This can be
Synlett 2000, No. 2, 260–262 ISSN 0936-5214 © Thieme Stuttgart · New York

2
62
S. Rousset et al.
LETTER
Bellina, F.; Biagetti, M.; Mannina, L. Tetrahedron Lett. 1998,
methylidene-furan-2-(5H)-one 3b: IR: 2962, 2900, 1783,
1
39, 7599; e) Rossi, R.; Bellina, F.; Mannina, L. Tetrahedron
1750, 1629, 1445; H NMR (200MHz, CDCl ) d (ppm): 0.16
3
5
Lett. 1998, 39, 3017; f) Rossi, R.; Bellina, F.; Bechini, C.;
Mannina, L.; Verganini, P. Tetrahedron 1998, 54, 135; g) Liu,
F.; Negishi, E. J. Org. Chem. 1997, 62, 8591; h) Marshall,
J.A.; Wolf, M.A.; Wallace, E.M. J. Org. Chem. 1997, 62, 367.
2) For a review on butenolides see a) Rao, Y.S. Chem. Rev. 1976,
(9H, s), 2.06 (3H, m), 5.27 (1H, q, J = 1Hz), 5.90 (1H, q,
J3H = 1Hz); C NMR (50.1 MHz, CDCl ) d (ppm):-0.1; 12.5;
3
H
4
13
3
110.3; 117.9, 154.8; 161.1; 170.2; MS m/z = 182 (M,7), 167
(51), 154 (17), 139 (18), 123 (39), 99 (11), 93 (43), 83 (53), 76
(21), 75 (100), 65 (18), 45 (21), 43 (21), 39 (29); (E)-4-
(
1
76, 625; b) Rao, Y.S. Chem. Rev. 1964, 64, 353; c) Negishi,
methyl-5-trimethylsilyl-methylidenefuran-2-(5H)-one 3b: H
E.; Kotora, M. Tetrahedron 1997, 53, 6707.
3) Van der Ohe, F.; Brückner, R. Tetrahedron Lett. 1998, 39,
NMR (200MHz, CDCl ) d(ppm): 0.09 (9H, s), 2.08 (3H, d,
3
4
5
(
(
(
J = 2.7Hz), 5.51 (1H, bd), 5.92 (1H, J = 1.4Hz), 6.1 (1H,
1
H
1
H
4
5
13
1909.
dq, J = 2.7Hz, J = 1.4Hz), C NMR (CDCl ) d (ppm):
3
H
1H
3
4) Rousset, S.; Abarbri, M.; Thibonnet, J.; Duchêne, A.; Parrain,
J.L. Org. Lett. 1999, 1, 701.
1.3, 14.8, 112.6, 121.3, 154.3; 159.2; 169.3.
Preparation of 3d: At -78 °C via a syringe, DBU (1.35 g, 8.5
5) a) Doyle, M.D.; Davies, D.I. Chem. Soc. Rev. 1979, 171;
b) Bartlett, P.A. In Asymmetric Synthesis vol 3 Academic
Press: New York, 1984; c) Neukom, C.; Richardson, D.P.;
Myerson, J.H.; Bartlett, P.A. J. Am. Chem. Soc. 1986, 108,
mmol,1.1 eq) diluted in CH Cl (5 mL)was added to a solution
2
2
of iodolactone 2d (2.51 g, 8.1 mmol) in CH Cl (20 mL). After
2
2
3 h at -78 °C, the mixture was hydrolysed with a sat aq NH Cl
4
and extracted with CH Cl (3 × 10 mL). After usual work-up,
2
2
5559; d) Evans, R.D.; Magee, J.W.; Schauble, J.H. Synthesis
1988, 862; e) Simonot, B.; Rousseau, G. J. Org. Chem. 1994,
59, 5912.
the alkylidene butenolide 3d was obtained as a E/Z mixture of
isomers (98/2) which slowly isomerised at r.t. to a mixture of
E/Z = 5/95. (Z)-4-methyl-6-trimethylsilyl-methylidene-
(
6) a) Abarbri, M.; Parrain, J.L.; Cintrat, J.C.; Duchêne, A.
Synthesis 1996, 82; b) Thibonnet, J.; Abarbri, M.; Parrain,
J.L.; Duchêne, A. Main Group Metal Chemistry 1997, 20,
furan-2-(5H)-one 3d: IR: 2962, 2900, 1783, 1750, 1629, 1445;
1
H NMR (200 MHz, CDCl ) d (ppm): 0.16 (9H, s), 2.06 (3H,
3
5
4
13
m), 5.27 (1H, q, J = 1Hz), 5.90 (1H, q, J = 1Hz);
C
3
H
3H
1
95.
7) Royer, A.C.; Mebane, R.C.; Swafford, A.M. Synlett 1993,
99.
8) a) Jew, S.S.; Terashima, S.; Koga, K. Tetrahedron 1979, 35,
NMR (50.1 MHz, CDCl ) d (ppm): -0.1; 12.5; 110.3; 117.9,
3
(
(
154.8; 161.1; 170.2; MS m/z = 182 (M,7), 167 (51), 154 (17),
139 (18), 123 (39), 99 (11), 93 (43), 83 (53), 76 (21), 75 (100),
65 (18), 45 (21), 43 (21), 39 (29); (E)-4-methyl-5-
8
1
5912, b) Ohfune, Y.; Hori, K.; Sakaitani, M. Tetrahedron Lett.
trimethylsilyl-methylidenefuran-2-(5H)-one 3d: H NMR
1
986, 27, 6079.
(200 MHz, CDCl ) δ(ppm): 0.09 (9H, s), 2.16 (3H, d,
3
4
4
5
(
9) Miller, R.B.; McGarvey, G. Synth. Commun. 1978, 8, 291.
J1H = 2.7Hz), 5.57 (1H, d, J = 1.4Hz), 5.96 (1H, qd,
1H
13
5
(
10) Typical procedure: Preparation of 2d: Iodine monochloride
1.97 g, 12.1 mmol) in dry dichloromethane (10 mL) was
added dropwise, at 0 °C, to 3-methyl-5-trimethylsilylpent-
,4-dienoic acid 1d (2.2 g,12 mmol). Stirring was then
J3H = 2.7Hz, J = 1.4Hz); C NMR (CDCl ) d (ppm): 1.3,
1H
3
(
14.8, 112.6, 121.3, 154.3; 159.2; 169.3.
(14) As suggested by one of the referee, due to the acidity of
butenolides, an E1cb mechanism cannot be excluded and
2
2
maintained for 4 h. at r.t., the mixture was hydrolysed with a
saturated solution of sodium bicarbonate followed by the
dropwise addition of a 5% solution of sodium thiosulfate until
the solution became clear. The solution was then extracted
with CH Cl (3 x 20 mL) and dried with MgSO . After
could explain the lack of selectivity in the case where R is
different to the trimethylsilyl group (table 2, entry 4 and 10).
(15) Moriarty, R.M.; Romain, C.M.; Karle, I.L.; Karle, J. J. Am.
Chem. Soc. 1965, 87, 3251.
(16) Ye, X.-S.; Wong, H. N. C. J. Chem. Soc., Chem. Commun.
1996, 339.
2
2
4
evaporation of the solvent, 2.72 g of 4-methyl-5-
iodotrimethylsilylmethylfuran-2-(5H)-one 2d were obtained
after crystallisation (diethylether/hexane:1/3). Yield: 73%;
mp = 72-74 °C; IR: 2958, 2929, 2880, 1750, 1638, 1254,
(17) Experimental procedure: Iodine (1.49 g, 5.88 mmol) diluted in
THF (22 mL) were added to a stirred THF solution (45 mL) of
silylmethylidene butenolide 3d (0.527 g, 2.9 mmol) and silver
trifluoroacetate (1.23 g, 5.88 mmol) at -78 °C. The mixture
was stirred for 4h at -78 °C then hydrolysed with a sat. aq.
1
113, 996, 854; Raman: 3097, 2959, 2898, 1746, 1638.5,
1
1
187, 627; H NMR (200 MHz) CDCl ) d (ppm): 0.26 (9H, s),
3
4
4
2
.2 (3H, dd, J = 1.6Hz, J = 0.8Hz), 3.46 (1H, d,
NH Cl (30 mL). The organic layer was washed with a 5%
1H
1H
3
4
3
4
J1H = 4.4Hz), 5.14 (1H, dq, J = 4.4Hz, J = 0.8Hz), 5.95
solution of sodium thiosulfate (3 x 15 mL), dried over
magnesium sulphate and concentrated in vaccuo. IR: 3056,
1H
3H
4
13
(
0
1H, q, J3 = 1.6Hz); C NMR (50 MHz, CDCl ) d (ppm):
H
3
1
.5, 15.8, 16.4, 88.7, 119, 168.4, 171.8. MS: m/z = 182 ((M-
1775, 1753, 1627, 15551, 1290, 1151, 931; (Z)-4d: H NMR
4
HI), 19), 168 (13), 167 (91), 154 (47), 139 (35), 123 (68), 99
(200 MHz) (CDCl ) d(ppm): 2.50 (3H, d, J = 1.4 Hz), 6.19
3
1H
5
4
(
(
14), 93 (40), 83 (58), 77 (10), 76 (19), 75 (100), 73 (10), 65
24), 53 (10), 47 (10), 45 (25), 43 (25), 39 (38).
(1H, d, J = 1.5Hz), 6.57 (1H,qd, J = 1.4Hz,
1H 3H
5
13
J1H = 1.5Hz); C NMR (50 MHz) (CDCl ):12.6, 60.6, 118.6,
3
(
(
11) Rodriguez, J.; Dulcère, J.P. Synthesis 1993, 1177.
12) a) Wolkoff, P. J. Org. Chem. 1982, 47, 1944 and ref therein;
b) Short, K.M.; Ziegler, C.B. Tetrahedron Lett. 1995, 36,
153.2, 158.6, 168.3; SM m/z = 236 (M, 91), 168 (26), 81 (14),
69 (11), 68 (19), 53 (100), 52 (11), 51 (14), 50 (16), 40 (67),
39 (81), 38 (28), 37 (13)(100), 38 (24), 37 (15).
3
55.; c) Barluenga, J.; Alvarez-Garcia, L.; Romanelli, G.P.;
(18) a) Dawson, M.I.; Hobbs, P.D. The Synthetic Chemistry of
Retinoids. In The Retinoids, 2nd ed.; Sporn, M.B., Roberts,
A.B., Goodman, D.,S., Eds.; Raven Press: New York, 1994;
p 5; b) Klaus, M. Actual. Chim. Ther. 1985, 12, 63.
(19) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
1975, 4467.
Gonzalez, J.M. Tetrahedron Lett. 1997, 38, 6763.
13) Typical procedure:
(
Preparation of 3b: At -78 °C via a syringe, DBU (1.35 g,8.5
mmol,1.1 eq) diluted in CH Cl (5 mL)was added to a solution
of iodolactone 2e (2.51 g, 8.1 mmol) in CH Cl (20 mL). After
2
2
2
2
3
h at -78 °C, the mixture was hydrolysed with a sat. aq.
NH Cl and extracted with CH Cl (3 x 10 mL). After usual
4
2
2
work-up, the alkylidene butenolide 3b was obtained as a E/Z
mixture of isomers (98/2) which slowly isomerised at r.t. to a
mixture of E/Z = 5/95. (Z)-4-methyl-6-trimethylsilyl-
Article Identifier:
1437-2096,E;2000,0,02,0260,0262,ftx,en;G26599ST.pdf
Synlett 2000, No. 2, 260–262 ISSN 0936-5214 © Thieme Stuttgart · New York