Palladium-Catalyzed Heck Reaction on 1-Alkoxy-1,3-dienes: A Regioselective γ-Arylation of α,β-Unsaturated Carbonyl Compounds

Article abstract of DOI:10.1021/ol035258j

(Matrix presented) α,β-Unsaturated acetals afford, in the presence of the LIC-KOR superbase, 1-alkoxybuta-1,3-dienes. These substrates cross couple with aryl derivatives in the presence of Pd catalyst (Heck conditions) in a regio- and stereoselective mode

Full text of DOI:10.1021/ol035258j

ORGANIC
LETTERS
2003
Vol. 5, No. 21
3815-3817
Palladium-Catalyzed Heck Reaction on
1-Alkoxy-1,3-dienes: A Regioselective
γ-Arylation of r,â-Unsaturated Carbonyl
Compounds
,†
Annamaria Deagostino,† Cristina Prandi,‡ and Paolo Venturello*
Dipartimento di Chimica Generale ed Organica Applicata dell’UniVersita`,
Corso Massimo D’Azeglio, 48, I 10125 Torino, Italy,
Dipartimento di Scienze e Tecnologie AVanzate dell’UniVersita`,
Corso Borsalino, 54, I 15100 Alessandria, Italy
paolo.Venturello@unito.it
Received July 8, 2003
ABSTRACT
r,â-Unsaturated acetals afford, in the presence of the LIC−KOR superbase, 1-alkoxybuta-1,3-dienes. These substrates cross couple with aryl
derivatives in the presence of Pd catalyst (Heck conditions) in a regio- and stereoselective mode. With dialkyl acetals, the reaction affords
arylated dienes; on the other hand, in the case of 1,3-dioxane derivatives, the final outcome of the process formally corresponds to the direct
γ-arylation reaction of the starting r,â-unsaturated material.
Metal-catalyzed coupling reactions are very efficient and
reliable procedures for the construction of new carbon-
carbon bonds.1 In particular, the Heck reaction has been used
extensively over the past three decades for the elaboration
of alkenes.2 The reaction is a straightforward way to achieve
substituted alkenes, dienes, and other unsaturated structures,
many of which are important intermediates for the prepara-
tion of dyes, UV screens, and drugs.3 Although arylation of
two-carbon vinyl fragments might sometimes result in
scarcely regioselective reactions,4,5 highly regioselective
R-arylation and R-vinylation procedures have been reported
under specific experimental conditions.6 In particular, 100%
regioselective R-functionalization of vinyl ethers can be
achieved by favoring the coordination of the Pd complex to
(3) Baker, R.; Bradshaw J. W. S. In Aliphatic and Related Natural
Product Chemistry; Gunstone, F. D., Ed.; Royal Society of Chemistry:
London 1983; Specialist Periodical Report, Vol. 3. Nicolaou, K. C.;
Ramphal, J. Y.; Petasis, N. A.; Serhan, C. N. Angew. Chem., Int. Ed. Engl.
1991, 30, 1100-1116. Launay, V.; Beaude, I.; Quintard, J.-P. Bull. Soc.
Chim. Fr. 1997, 134, 937-946. Dominguez, B.; Iglesia, B.; de Lera, A. R.
J. Org. Chem. 1998, 63, 4135-4139. Lipshutz, B. H.; Ullman, B.; Lindsley,
C.; Pecchi, S.; Buzard, D. J.; Dickson, D. J. Org. Chem. 1998, 63, 6092-
6093. Peng, Z. H.; Li, Y. L.; Wu, W. L.; Liu, C. X.; Wu, Y. L. J. Chem.
Soc., Perkin Trans. 1 1996, 1057-1066. Chem. ReV. 1994, 94, 1-278.
Molecular Engineering for AdVanced Materials; Becher, J., Schaumburg,
K., Eds.; Kluwer Academic Publisher: Dordrecht, 1995; Vol. 456, p 159.
(4) Heck, R. F., Trost, B. M., Fleming, I., Eds., ComprehensiVe Organic
Synthesis; Pergamon Press: Oxford 1991; Vol. 4, p 833.
† Dipartimento di Chimica Generale ed Organica Applicata dell’Universita`.
‡ Dipartimento di Scienze e Tecnologie Avanzate dell’Universita`.
(1) Franze´n, R. Can. J. Chem. 2000, 78, 957-962. Poli, G.; Giambastiani,
G.; Heumann, A. Tetrahedron 2000, 56, 5959-5989. Jones, W. D. Science
2003, 295, 289-290.
(5) Daves, G. D., Jr.; Hallberg, A. Chem. ReV. 1989, 89, 1433-1446.
Andersson, C.-M.; Hallberg, A.; Daves, G. D., Jr. J. Org. Chem. 1987, 52,
3529-3536. Hegedus, L. S.; Toro, J. L.; Miles, W. H.; Harrington, P. J. J.
Org. Chem. 1987, 52, 3319-3322.
(2) Heck, R. F.; Nolley, J. P., Jr. J. Org. Chem. 1972 37, 2320-2322.
For reviews: Beletskaya, I. P.; Cheprakov, A. V. Chem. ReV. 2000, 100,
3009-3066. de Meijere, A.; Meyer, F. E. Angew. Chem., Int. Ed. Engl.
1994, 33, 2379-2411 and references therein.
(6) Cabri, W.; Candiani, I.; Bedeschi, A.; Penco, S.; Santi, R. J. Org.
Chem. 1992, 57, 1481-1486. Cabri, W.; Candiani, I.; Bedeschi, A.; Santi,
R. J. Org. Chem. 1990, 55, 3654-3655. Andersson, C.-M.; Hallberg, A. J.
Org. Chem. 1989, 54, 1502-1505.
10.1021/ol035258j CCC: $25.00 © 2003 American Chemical Society
Published on Web 09/23/2003

the carbon-carbon double bond via dissociation of the anion
ligand. Such a mechanism can be promoted by using triflate
as a leaving group or adding a sequestering agent of halide
anions.7 Otherwise, a mixture of isomers is obtained when
the coordination-insertion process proceeds via dissociation
of one neutral ligand. On the other hand, regioselective
â-arylation of vinyl ethers have been achieved when the
olefinic substrate contains groups that control the palladium-
catalyzed reaction through chelation. Such a procedure has
been reported as a useful access to arylethylamines or
arylacetic acids of significant pharmaceutical value.8
Our interest in the synthesis of stereodefined substituted
dienes requires the development of protocols for the prepara-
tion of key building blocks. In the present communication,
we wish to report the results that we have obtained studying
the arylation reaction of 1-alkoxy-1,3-butadienes obtained
by conjugate elimination promoted by the LIC-KOR super
base.
Scheme 2. Heck Reaction on 1-Ethoxybuta-1,3-dienes
Treatment of R,â-unsaturated acetals 1-5 at -95 °C with
Schlosser’s LIC-KOR superbase (LIC, butyllithium; KOR,
potassium tert-butoxide)9 readily promotes a conjugate
elimination reaction that gives 1-alkoxy-1,3-butadienes 6-12.
In particular, in the presence of an excess of base, the
metalation reaction gives R-metalated 1-alkoxybuta-1,3-
dienes.10 Subsequent quenching with a suitable electrophile
leads to R-functionalized unsaturated derivatives 6-8 (Scheme
1).
been isolated with (1E,3E)-configuration. Reaction yields are
reported in Scheme 2.11 The regio- and stereoselective
outcome of the arylation process is clearly suggested by the
presence in the H NMR spectrum of the crude reaction
mixture of a single doublet of doublets centered at 6.86 ppm
1
(J ) 15.7, 11.5 Hz, derivative 13 as an example).
On the other hand, derivatives 15 and 16 were isolated in
the cross coupling process of dienes 7 and 8 (Scheme 2).
These products (path B) are isomers of the expected dienes.12
Derivatives 13, 14 and 15, 16 probably come from the
common π-allylpalladium intermediate shown in Scheme 2,
which undergoes â-hydride elimination at two different
sites.13 In particular, in case B, the structure of diene 15 has
been confirmed on the basis of the following 1H NMR data:
two broad singlets centered at 3.95 and 3.98 ppm, a doublet
at 5.65 ppm (J ) 15.0 Hz), and a doublet of triplets centered
at 6.21 ppm (J ) 15.0, 6.6). In contrast, diene 13, coming
from path A, shows two doublets centered at 6.80 and 6.92
ppm (J ) 15.7 and 11.1, respectively) and a doublet of
doublets at 7.20 ppm (J ) 15.7, 11.1). The π-allylpalladium
intermediate that leads to dienes 15 and 16 could, in principle,
undergo â-hydride elimination according to either pathway
A or B. The B pathway prevails probably due to steric
reasons. In the case of dienes 13 and 14, â-hydride
elimination at the B site is clearly impossible because of the
lack of a C-H bond.
Scheme 1. LIC-KOR-Promoted Conjugate Elimination
Reaction of R,â-Unsaturated Acetals 1-5: Syntheses of
1-Ethoxybuta-1,3-dienes 6-8 and
1-(3-Hydropropoxy)buta-1,3-dienes 9-12
Moreover, when the Heck cross-coupling is carried out
on 1-(3-hydropropoxy)buta-1,3-dienes 9-12 obtained from
(10) Venturello, P. J. Chem. Soc., Chem. Commun. 1992, 1032-1033.
Balma Tivola, P.; Deagostino, A.; Prandi, C.; Venturello, P. J. Chem. Soc.,
Perkin Trans. 1 2001, 437-441. Deagostino, A.; Prandi, C.; Venturello, P.
Curr. Org. Chem. 2003, 7, 821-839.
(11) Reaction yields range from 41 to 48% (pure isolated products, by
column chromatography); on the other hand, reaction conversions, deter-
mined on the crude reaction mixture, are higher and range from 95 to 100%.
(12) In the case of diene 15, a Diels-Alder reaction has been carried
out using N-methylmaleimide as a dienophile. The corresponding cyclo-
addition product has been isolated in quantitative yield and an endo:exo
ratio of 80:20.
As shown in Scheme 2, the cross-coupling reaction of
diene 6 affords arylated products 13 and 14 in a regio- and
stereoselective manner (path A). Only 4-aryl derivatives have
(7) Cabri, W.; Candiani, I. Acc. Chem. Res. 1995, 28, 2-7.
(8) Andersson, C.-M.; Larsson, J.; Hallberg, A. J. Org. Chem. 1990, 55,
5757-5761. Larhed, M.; Andersson, C.-M.; Hallberg, A. Acta Chem. Scand.
1993, 47, 212-217.
(9) Schlosser, M. J. Organomet. Chem. 1967, 8, 9-16. Schlosser M.
Mod. Synth. Methods 1992, 6, 227-271. Mordini, A. In AdVances in
Carbanion Chemistry; Snieckus, V., Ed.; JAI Press, Inc.: Greenwich, CT,
1992; Vol. 1, pp 1-45. Schlosser, M.; Faigl, F.; Franzini, L.; Geneste, H.;
Katsoulos, G.; Zhong, G. Pure Appl. Chem. 1994, 66, 1439-1446.
Lochmann, L. Eur. J. Inorg. Chem. 2000, 1115-1126.
(13) Chemo-, regio-, and stereoselective palladium-catalyzed arylation
of 1,3-dienes has been reported. See, for example: Jeffery, T. Tetrahedron
Lett. 1992, 33, 1989-1992. Also, those results are consistent with a
â-elimination step proceeding from the π-allylpalladium complex derived
from the σ-complex, which is obtained by the carbopalladation of the
terminal double bond of the diene.
3816
Org. Lett., Vol. 5, No. 21, 2003

cyclic acetals, the reaction follows a different pathway,
probably promoted by the presence of the hydroxy group:
the 1,3-dioxane ring is reformed, and the the process formally
leads to γ-arylation of the R,â-unsaturated protected carbonyl
compound.14 For example, in the case of product 19, the
crude reaction mixture shows a doublet of triplets (6.00 ppm,
J ) 15.4, 6.6 Hz) and a doublet of doublets (5.45 ppm, J )
15.4, 5.4 Hz). The reaction products are shown in Scheme
3, and Table 1 reports reaction yields.
Scheme 4. Proposed Mechanism that Takes into Account the
γ-Arylation of 1-(3-Hydropropoxy)buta-1,3-dienes
Scheme 3. Heck Reaction on
1-(3-Hydropropoxy)buta-1,3-dienes
Acknowledgment. The authors thank Dr. J. Maddaluno
and Prof. S. Piettre (University of Rouen) for helpful
discussions and criticism and MIUR (Italy) for financial
support.
It was previously reported that the Heck reaction allows
the formation of several new bonds in a domino reaction
mode.15 More recently, intramolecular variants were devel-
oped by several groups. In Scheme 4, a possible mechanism
is suggested that takes into account the γ-arylation of
conjugate dienes and the closure to the 1,3-dioxane ring. The
formation of the product can be explained on the basis of
the addition of the arylpalladium intermediate to the terminal
double bond of the diene followed by the arrangement to
the π-allylic complex and iodide ion-acetate ligand ex-
change. The final attack of the hydroxy group upon the
complex with displacement of the palladium complex gives
the cyclic acetal, while palladium catalyst oxidatively adds
more aryl halide to start the catalytic cycle once more.16
Supporting Information Available: Experimental details
for the chromatographic purification procedures and spectral
data for all new compounds (1H NMR, 13C NMR, MS, IR,
and C,H analysis). This material is available free of charge
via the Internet at http://pubs.acs.org.
OL035258J
(14) Typical Procedure. 3-(2-Methyl-buta-1,3-dienyloxy)propan-1-ol (9)
(0.28 g, 2.0 mmol) was added to a mixture of 4-iodobenzoic acid methyl
ester (0.52 g, 1.0 mmol), Pd(AcO)2 (1.12 10-3 g, 5.0 10-3 mmol), and
K2CO3 (1 mmol) in 6.0 mL of anhydrous DMSO degassed with argon for
10 min. The reaction mixture was stirred under argon in a sealed tube for
16 h at 85 °C. Samples were periodically taken and partitioned between
Et2O and H2O. The organic layer was analyzed by GC and TLC. After
complete consumption of the starting aryl halide, the reaction was cooled
to room temperature and H2O was added (10 mL). The reaction was worked
up by extraction with Et2O (3 × 20 mL), and the organic phases were
washed three times with brine (10 mL). Drying (K2CO3) and removal of
the solvent gave the crude reaction mixture that was purified by column
chromatography on silica gel deactivated with Et3N (1%) (eluent: petroleum
ether/diethyl ether, 90/10), affording 0.22 g (80%) of pure 4-(3-[1,3]dioxan-
2-yl-but-2-enyl)benzoic acid methyl ester (26) as a colorless oil: 1H NMR
(200 MHz, CDCl3) δ 1.10-2.20 (m, 2 H), 1.72 (s, 3 H), 3.38 (d, J ) 7.3
Hz, 2 H), 3.70-3.95 (m, 5 H), 4.08 (m, 2 H), 4.78 (s, 1 H), 5.72 (t, J ) 7.3
Hz, 2 H), 7.15 (d, J ) 7.2 Hz, 2 H), 7.80 (d, J ) 7.2 Hz, 2 H); 13C NMR
(50 MHz, CDCl3) δ 12.34, 26.42, 34.40, 52.65, 67.71, 105.15, 126.41,
127.44, 128.74, 130.87, 135.38, 146.64, 167.79; MS (EI, 70 eV) m/z 276
(M+, 48), 261 (100), 203 (46), 159 (53), 59 (58); νmax (neat; cm-1) 3020,
1721, 1609, 1280, 1238, 1108, 840, 760. Anal. Calcd for C16H20O4: C,
69.55; H, 7.30. Found: C, 70.05; H, 7.26.
(15) Trost, B. M.; Luengo, J. I. J. Am. Chem. Soc. 1988, 110, 8239-
8241. Grigg, R.; Sridharan, V.; Sukirthalingam, S.; Worakun, T. Tetrahedron
Lett. 1990, 30, 1139-1142. Larock, R. C.; Colleeen, A. F. J. Am. Chem.
Soc. 1990, 112, 5882-5884. Ohshima, T.; Kagechika, K.; Adachi, M.;
Sodeoka, M.; Shibasaki, M. J. Am. Chem. Soc. 1996, 118, 7108-7116.
Larock, R. C. J. Organomet. Chem. 1999, 576, 111-124 and references
cited therein. de Meijere, A.; Bra¨se, S. J. Organomet. Chem. 1999, 576,
88-110. Flubacher, D.; Helmchen, G. Tetrahedron Lett. 1999, 40, 3867-
3868.
(16) An analogous mechanism was first proposed by F. Heck himself
upon studying the palladium-catalyzed vinylation of conjugate dienes in
the presence of morpholine or piperidine that affords 2,5-dienylamines:
Patel, B. A.; Kao, L.-C; Cortese, N. A.; Minkiewicz, J. V.; Heck, R. F. J.
Org. Chem. 1979, 44, 918-921.
Table 1. Heck Reaction of 1-(3-Hydropropoxy)buta-1,3-dienes
7-9 with Various Aryl Iodides
diene
ArI
product
E/Z
yield (%)
9
9
9
9
9
10
10
10
10
10
10
11
11
11
11
11
12
PhI
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
100/0
100/0
100/0
100/0
100/0
83/17a
79/21a
100/0a
75/25b
77/23a
79/21a
100/0a
100/0
100/0
100/0
100/0
100/0
60
66
68
73
70
50
83
78
70
72
90
65
87
80
70
80
76
p-MeOPhI
o-MeOPhI
m-EtCO2PhI
1-NaphI
PhI
o-MePhI
o-MeOPhI
m-EtCO2PhI
p-MeCO2PhI
1-NaphI
PhI
o-MePhI
m-MePhI
p-MeOPhI
p-MeCO2PhI
PhI
a Determined on the basis of the ratio between the pure isolated isomers.
1
b By H NMR analysis on the crude reaction mixture.
Org. Lett., Vol. 5, No. 21, 2003
3817