Facile synthesis of cross-conjugated gem-disubstituted trienes via palladium-catalyzed cross-coupling protocol of 1,1-disubstituted 2,4-diiodo-but-1-ene with alkenes

Article abstract of DOI:10.1055/s-2004-820017

Cross-conjugated coupling products described in the title are obtained in moderate to high yields by the reactions of the corresponding 1,1-disubstituted 2,4-diiodo-but-1-enes, which are derived from the ring-opening reaction of methylenecyclopropanes with iodine, with substituted alkenes in the presence of palladium(II) catalyst under simple Heck-type reaction conditions.

Full text of DOI:10.1055/s-2004-820017

LETTER
807
Facile Synthesis of Cross-Conjugated gem-Disubstituted Trienes via
Palladium-Catalyzed Cross-Coupling Protocol of 1,1-Disubstituted
2,4-Diiodo-But-1-ene With Alkenes
F
acile Synthesis of Cro
i
ss-Con
n
jugated gem-Disub
S
stitutedTriene
h
s
i,* Li-Xiong Shao
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Lu, Shanghai 200032, P. R. China
Fax +86(21)64166128; E-mail: mshi@pub.sioc.ac.cn.
Received 4 February 2004
(Lewis acids) to give the homoallylic halides in high
yields in CH2Cl2 under mild conditions. In that paper, we
also found that in the presence of TiI4 or iodine (I2), the
ring-opening reaction of 1,1-diphenylmethylenecyclopro-
Abstract: Cross-conjugated coupling products described in the title
are obtained in moderate to high yields by the reactions of the cor-
responding 1,1-disubstituted 2,4-diiodo-but-1-enes, which are de-
rived from the ring-opening reaction of methylenecyclopropanes
with iodine, with substituted alkenes in the presence of palladi- pane (1d) produced 1,1-diphenyl-2,4-diiodo-but-1-ene
(2d) in high yield.12 Herein we wish to report a facile
um(II) catalyst under simple Heck-type reaction conditions.
method for the synthesis of cross-conjugated gem-disub-
stituted trienes 5 by a one-step palladium-catalyzed cou-
pling reaction of diiodides 2 with substituted alkenes.
Key words: methylenecyclopropanes, cross-conjugated trienes,
cross-coupling reaction, palladium catalyst, alkenes, diiodides
The corresponding 1,1-disubstituted 2,4-diiodo-but-1-
enes 2 were prepared from the reactions of various MCPs
1 with iodine in moderate to high yields in 1,2-dichloroet-
hane (DCE).13 The results are summarized in Table 1. For
MCPs 1a, 1c–e (both R1 and R2 are aromatic groups), the
reaction proceeded smoothly to give the corresponding di-
iodinated products 2a and 2c–e in good to excellent yields
(Table 1, entries 1, 3–5). For the unsymmetric MCP 1b
(R1 is an aromatic group and R2 is an aliphatic group), the
reaction produced the product 2b in 27% yield under the
same conditions exclusively as E-configuration (Table 1,
entry 2). The E-configuration of 2b was determined by 1H
NMR NOESY spectroscopic data (Supporting Informa-
tion). The stereospecificity of 2b can be explained by the
steric effect between iodine atom and phenyl ring. There-
fore, the E-2b is thermodynamically more stable.
In recent years acyclic polyenes of the so-called den-
dralene-type1 are beginning to receive steadily increasing
attention2 because of their unusual cross-conjugated prop-
erties and emerging synthetic potential. The cross-conju-
gated triene is of particular interest because its two
conjugated dienes systems can form polymeric Diels–
Alder adduct with bifunctional dienophile. In addition, the
trienes 5 (cross-conjugated gem-disubstituted trienes), for
the same reason, should be of interest as a cross-linking
agent for vinyl polymers. Moreover, cross-conjugation is
a commonly encountered phenomenon in natural product
and dyestuff chemistry, although in the majority of cases
the various p-systems are polarized either by heteroatoms
and/or by electron-donating or -accepting substituents.3
Since the preparation of the parent 3-methylene-penta-
1,4-diene was first reported by Bloomquist and Verdol in
19554 and also by Bailey and Economy5 shortly thereaf- Table 1 The Ring-opening of MCPs 1 by Iodine in 1,2-Dichloro-
ethane (DCE)
ter, various synthetic methods have been developed for
the preparation of the parent trienes and its derivatives.1
R1
R2
R1
R2
I
But to the best of our knowledge, there are no more mild
conditions were reported for the synthesis of cross-conju-
gated trienes6 though Yamaguchi reported an efficient
synthesis of trienes by catalytic dimerization of monosub-
stituted allenes in the presence of P(o-Tol)3.7
DCE
I2
+
I
2
1
1a: R1 = R2 = p-CH3OC6H4; 1b: R1 = p-EtOC6H4, R2 = CH3;
1c: R1 = R2 = p-CH3C6H4; 1d: R1 = R2 = C6H5; 1e: R1 = R2 = p-
ClC6H4.
Palladium-catalyzed reactions are versatile methods for
carbon-carbon bond formations as a result of their gener-
ality and ability to tolerate a wide range of important or-
ganic functional groups.8 Among them, the Heck-type9–11
and related chemistry occupy a special place. Recently,
we reported that the ring-opening reactions of methyle-
necyclopropanes (MCPs) 1 promoted by metal halides
Entry
Substrate
Yielda (%)
2a (90)
2b (27)
2c (90)
1
1a
1b
1c
1d
1e
2
3
4
2d (88)
2e (92)
SYNLETT 2004, No. 5, pp 0807–0810
0
2.
0
4.
2
0
0
4
5
Advanced online publication: 24.02.2004
DOI: 10.1055/s-2004-820017; Art ID: U03404ST
© Georg Thieme Verlag Stuttgart · New York
a Isolated yields.

808
M. Shi, L.-X. Shao
LETTER
Next, we carried out the typical Heck-type reactions of improved as well (Table 2, entries 6, 7, 12 and 13). There-
diiodides 2 with some alkenes. Using 1,1-diphenyl-2,4-di- fore, the optimized conditions for this Heck-type reaction
iodo-but-1-ene (2d) (0.25 mmol) and methyl acrylate (0.3 are using DMF as a solvent, NaHCO3 as a base in the
mmol) as the substrates, we attempted to develop the op- presence of additive TBAC (Table 2, entry 2).14
timized reaction conditions for this Heck-type reaction.
To survey the generality of this Heck-type reaction, we
The results are shown in Table 2. The configuration of 5a
next investigated the reaction using other diiodides 2 with
1
was determined as 1E,4E by H NMR NOESY spectro-
some substituted alkenes such as methyl acrylate 3a, me-
scopic data (Supporting Information). The original set of
thyl vinyl sulfone 3b and styrene 3c under the optimized
conditions. The results are summarized in Table 3. As can
be seen from Table 3, the corresponding trienes 5 were
obtained in moderate to excellent yields in most cases
reaction conditions is 20 mol% of Pd(OAc)2, 2.0 equiva-
lents of NaHCO3, 1.0 equivalent of Bu4NCl (TBAC) at
60–70 °C in DMF. This Heck-type reaction was complet-
ed within 24 hours to give the corresponding product 5a
(Table 3). For substrates 2 in which both R1 and R2 are ar-
in 55% yield along with the uncross-coupled product 4 in
omatic groups such as 2a, 2c and 2d, the cross-coupling
17% yield (Table 2, entry 1). In a second experiment, we
reactions proceeded very well to give the normal Heck-
type reaction products 5b, 5c, 5e, 5f and 5h in good to
found that when the temperature was raised to 100 °C, the
cross-conjugated triene 5a was obtained exclusively in
80% yield (Table 2, entry 2). When the base NaHCO3 was
replaced by Et3N, KOAc or NaOH at 100 °C, 5a was also
obtained as a sole product but in slightly lower yields
(Table 2, entries 3, 5 and 8). In addition, when Na2CO3
was used as the base, only the uncross-coupled product 4
was given in 59% yield (Table 2, entry 4). The addition of
high yields (Table 3, entries 1, 2, 4, 5, and 7). Only for
substrate 2b (R1 is an aryl group and R2 is a methyl group),
this Heck-type reaction produced the isomerized product
6 in 30% yield, which is presumably derived from the nor-
mal coupling product (Table 3, entry 3). For styrene 3c,
the corresponding Heck-type reaction product was ob-
tained in moderate yields (Table 3, entries 6, 8). The prod-
uct 5g was obtained as a mixture of (trans,trans)-5g and
(cis,trans)-5g and the relative configuration was deter-
PPh3 (40 mol%) did not significantly improve the yields
of the reaction product (Table 2, entries 2–9, 3–10 and 5–
11). Using CH3CN or Et3N as the solvent under the similar
mined by 1H NMR (Supporting Information).
reaction conditions, the yields of 5a were not significantly
Table 2 The Optimization Reaction Conditions of the Heck-Type Reaction
C6H5
C6H5
C6H5 C6H5
C6H5
I
C6H5
Pd(OAc)2
24 h
+
+
CO2CH3
I
I
3a
H3CO2C
2d
4
5a
Entry
Solvent
Base
Additivea
Temp. (°C)
Yieldb (%)
4
5a
55
80
77
–
1
2
DMF
DMF
DMF
DMF
DMF
NaHCO3
NaHCO3
Et3N
TBAC
60–70
100
17
–
TBAC
3
–
100
–
4
Na2CO3
AcOK
Et3N
TBAC
100
59
–
5
–
100
75
51
47
64
75
65
50
66
–
6
CH3CN
CH3CN
DMF
DMF
DMF
DMF
Et3N
–
100
20
37
Trace
–
7
NaHCO3
NaOH
NaHCO3
Et3N
TBAC
100
8
TBAC
100
9
TBAC–PPh3
TBAC–PPh3
TBAC–PPh3
–
100
10
11
12
13
100
–
AcOK
–
100
–
Reflux
Reflux
–
Et3N
–
PPh3
69
a TBAC = Tetrabutylammonium chloride.
b Isolated yields.
Synlett 2004, No. 5, 807–810 © Thieme Stuttgart · New York

LETTER
Facile Synthesis of Cross-Conjugated gem-Disubstituted Trienes
809
Table 3 The Heck-Type Reaction of Diiodides 2 (0.25 mmol) with
Substituted Alkenes 3 (0.3 mmol) under the Optimized Conditions
(3) For some examples, please see: (a) Corey, E. J.; d’Alarcao,
M. Tetrahedron Lett. 1986, 27, 3589. (b) Shen, G.-Y.; de
Lera, A. R.; Norman, T. C.; Haces, A.; Okamura, W. H.
Tetrahedron Lett. 1987, 28, 2917. (c) Johannes, H.-H.;
Grahn, W.; Reisner, A.; Jones, P. G. Tetrahedron Lett. 1995,
36, 7225; and references cited therein. (d) Johansen, J. E.;
Liaaen-Jensen, S. Tetrahedron 1977, 33, 381. (e) Vanelle,
P.; Benakli, K.; Maldonado, J.; Roubaud, C.; Crozet, M. P.
Heterocycles 1996, 43, 731.
OEt
R2
R1
R1 R2
Pd(OAc)2/NaHCO3
+
I
R3
DMF/TBAC/100 oC
24 h
I
3
R3
2
5
H3CO2S
6
2a: R1 = R2 = p-CH3OC6H4; 2b: R1 = p-EtOC6H4, R2 = CH3;
2c: R1= R2 = p-ClC6H4; 2d: R1 = R2 = C6H5.
3a: R3 = CO2CH3; 3b: R3 = SO2CH3; 3c: R3 = C6H5.
(4) Bloomquist, A. T.; Verdol, J. A. J. Am. Chem. Soc. 1955, 77,
81.
(5) Bailey, W. J.; Economy, J. J. Am. Chem. Soc. 1955, 77,
1133.
Entry
Substrates
Product
5b
5c
Yielda (%)
(6) For more examples, please see: (a) Gadogan, J. I. G.;
Cradock, S.; Gillam, S.; Cosney, I. Chem. Commun. 1991,
114. (b) Trahanovsky, W. S.; Koeplinger, K. A. J. Org.
Chem. 1991, 57, 4711. (c) Moriya, T.; Furuuchi, T.;
Miyaura, N.; Suzuki, A. Tetrahedron 1994, 50, 7961.
(d) Bräse, S.; de Meijere, A. Angew. Chem. Int. Ed. Engl.
1995, 34, 2545. (e) Nüske, H.; Bräse, S.; Kozhushkov, S. I.;
Nolteweyer, M.; Es-Sayed, M.; de Meijere, A. Chem.–Eur.
J. 2002, 8, 2350. (f) de Meijere, A.; Schelper, M.; Knoke,
M.; Yucel, B.; Sünnemann, H. W.; Scheurich, R. P.; Arve,
L. J. Organomet. Chem. 2003, 687, 249.
1
2
3
4
5
6
7
8
2a
2a
2b
2c
2c
2c
2d
2d
3a
3b
3b
3a
3b
3c
3b
3c
81
80
6
30
5e
99
5f
61
5g
53 (6:1)b
72
(7) Arisawa, M.; Sugihara, T.; Yamaguchi, M. Chem. Commun.
1998, 2615.
5h
5i
44
(8) (a) Trost, B. M. Science 1991, 234, 1471. (b) Tsuji, J.
Palladium Reagents and Catalysis: Innovations in Organic
Synthesis; Wiley: New York, 1995. (c) Handbook of
Organopalladium Chemistry for Organic Synthesis;
Negishi, E.; de Meijere, A., Eds.; John Wiley & Sons: New
York, 2002.
a Isolated yields.
b (trans,trans)/(cis,trans) (Supporting Information).15
In conclusion, we have synthesized some cross-conjugat-
ed gem-disubstituted trienes 5 via a simple Heck-type re-
action of diiodides 2, derived from MCPs 1 with iodine
under mild conditions, with some alkenes. A range of sub-
stituted alkenes has been examined. This process provides
a novel and efficient route for the synthesis of cross-con-
jugated gem-disubstituted trienes 5 under simple Heck-
type conditions without special phosphine ligand. Efforts
are in progress to elucidate the mechanistic details of this
reaction and to disclose its scope and limitations.
(9) (a) Heck, R. F. J. Am. Chem. Soc. 1968, 90, 5518. (b)Tsuji,
J. Palladium Reagents and Catalysts; Wiley: New York,
1995.
(10) Reviews: (a) de Meijere, A.; Meyer, F. E. Angew. Chem.,
Int. Ed. Engl. 1994, 33, 2379. (b) Cabri, W.; Candiani, I.
Acc. Chem. Res. 1995, 28, 2. (c) Crisp, G. T. Chem. Soc.
Rev. 1998, 27, 427. (d) Geret, J. P.; Savignac, M. J. J.
Organomet. Chem. 1999, 576, 305. (e) Beletskaya, I. P.;
Cheprakov, A. V. Chem. Rev. 2000, 100, 3009.
(11) For a recent mechanistic study on Heck-type reaction see:
Amatore, C.; Jutand, A. J. Organomet. Chem. 1999, 576,
254.
(12) Shi, M.; Xu, B. Org. Lett. 2003, 5, 1415.
Acknowledgment
(13) Typical Procedure for the Ring-Opening of MCPs 1 by I2
in 1,2-Dichloroethane (DCE): Under an ambient
atmosphere, MCP 1a (10 mmol), I2 (10 mmol) and 1,2-
dichloroethane (2.5 mL) were added into a Schlenk tube.
The mixture was stirred at r.t. for 8 h. The solvent was
removed under reduced pressure and the residue was then
purified by a flash column chromatography to give product
2a as a yellow solid; mp 112–114 °C. 1H NMR (300 MHz,
CDCl3) d = 3.08 (t, J = 7.2 Hz, 2 H), 3.37 (t, J = 7.2 Hz, 2 H),
3.80 (s, 3 H, CH3O), 3.84 (s, 3 H, CH3O), 6.84 (d, J = 9.0 Hz,
4 H, Ar), 7.07 (d, J = 6.9 Hz, 2 H, Ar), 7.16 (d, J = 6.9 Hz, 2
H, Ar). 13C NMR (75 MHz, CDCl3): d = 6.58, 44.53, 55.13,
55.19, 105.46, 113.31, 113.75, 129.91, 130.11, 132.54,
138.99, 149.71, 158.73, 158.79. IR (CH2Cl2): 3046, 2954,
2833, 2676, 2299, 2050, 1605, 1508, 1265, 1247, 741, 705
cm–1. MS: m/z (%) = 520 (84.92) [M+], 393 (28.23), 266
(100). HRMS: m/z calcd for C18H18I2O2: 519.9396; found:
519.9406.
We thank the State Key Project of Basic Research (Project 973)
(No. G2000048007), Chinese Academy of Sciences (KGCX2-210-
01), Shanghai Municipal Committee of Science and Technology,
and the National Natural Science Foundation of China for financial
support (203900502, 20025206 and 20272069).
References
(1) For a review of cross-conjugated polyenes of the dendralene
type, see: Hopf, H. Angew. Chem., Int. Ed. Engl. 1984, 23,
948.
(2) (a) Kanemasa, S.; Sakoh, H.; Wada, E.; Tsuge, O. Bull.
Chem. Soc. Jpn. 1985, 58, 3312. (b) Kanemasa, S.; Sakoh,
H.; Wada, E.; Tsuge, O. Bull. Chem. Soc. Jpn. 1986, 59,
1869. (c) Kaupp, G.; Frey, H.; Behmann, G. Chem. Ber.
1988, 121, 2127.
Synlett 2004, No. 5, 807–810 © Thieme Stuttgart · New York

810
M. Shi, L.-X. Shao
LETTER
131.11, 132.61, 135.14, 141.10, 141.48, 144.32, 147.80,
167.82. IR (CH2Cl2): 3067, 2978, 2304, 115, 1605, 1265,
739 cm–1. MS m/z (%) = 290 (35.94) [M+], 258 (32.98), 215
(100). HRMS: m/z calcd for C20H18O2: 290.1301; found:
290.1290.
(14) Typical Procedure for the Heck-Type Reaction: Under an
ambient atmosphere, 2a (0.25 mmol), 3a (0.30 mmol),
Pd(OAc)2 (0.05 mmol), tetrabutylammonium chloride
(TBAC) (0.25 mmol), NaHCO3 (0.5 mmol) and N,N-
dimethylformamide (DMF) (1.0 mL) were added into a
Schlenk tube. The reaction mixture was stirred at 100 °C for
about 24 h. The reaction solution was washed with saturated
brine, dried over anhyd MgSO4, and then purified by a flash
column chromatography to give 5a as a pale yellow solid.
Mp: 85–88 °C. 1H NMR (300 MHz, CDCl3) d = 3.72 (s, 3 H),
5.36 (dd, J = 1.2, 11.4 Hz, 1 H), 5.39 (dd, J = 1.2, 17.7 Hz, 1
H), 6.21 (d, J = 15.9 Hz, 1 H), 6.39 (dd, J = 11.4, 17.7 Hz, 1
H), 7.09–7.18 (m, 5 H, Ar), 7.27–7.33 (m, 5 H, Ar), 7.47 (d,
J = 15.9 Hz, 1 H). 13C NMR (75 MHz, CDCl3): d = 51.49,
119.71, 121.65, 127.73, 127.81, 127.89, 128.13, 131.06,
(15) To clarify the selectivity of the reaction, an experimental run
was carried out on a larger scale of 2d (2.0 mmol) and 3a
(2.4 mmol) as the substrates. We found that no other isomer
was obtained based on the 1H NMR spectroscopic data of the
reaction mixtures. At present stage, we are not sure of the
reason on the selectivity of the reaction of 2c and 3c yet. We
have determined the relative configuration of 5g by 1H NMR
as the corresponding coupling constant of the former is 16.5
Hz and 8.7 Hz for the latter (Supporting Information).
Synlett 2004, No. 5, 807–810 © Thieme Stuttgart · New York