Palladium-Catalyzed Sequential Alkylation-Alkenylation Reactions: New Three-Component Coupling Leading to Oxacycles

Article abstract of DOI:10.1021/ol035806t

(Equation Presented) A new three-component domino reaction catalyzed by palladium was devised, producing polysubstituted bicyclic molecules in good yields from readily available substrates. The reaction conditions and the scope of the process were examine

Full text of DOI:10.1021/ol035806t

ORGANIC
LETTERS
2003
Vol. 5, No. 25
4827-4830
Palladium-Catalyzed Sequential
Alkylation−Alkenylation Reactions: New
Three-Component Coupling Leading to
Oxacycles
Sandrine Pache and Mark Lautens*
DaVenport Research Laboratories, Chemistry Department, UniVersity of Toronto,
Toronto, Ontario, Canada M5S 3H6
mlautens@chem.utoronto.ca
Received September 18, 2003
ABSTRACT
A new three-component domino reaction catalyzed by palladium was devised, producing polysubstituted bicyclic molecules in good yields
from readily available substrates. The reaction conditions and the scope of the process were examined, and a possible mechanism is proposed.
Multicomponent reactions have proven to be a very elegant
and rapid way to access complex structures from simple
building blocks in a one-pot procedure.1 Over the past few
years, various sequential reactions have been developed using
metal-catalyzed processes, most notably using palladium.2
We became interested in this field and recently reported a
modified Catellani method for the formation of fused aro-
matic rings from aryl iodides and bromoenoates under pallad-
ium catalysis in which two carbon-carbon bonds are formed
in a one-pot process.3,4 This procedure was extended to the
formation of benzoxepines.5 We now report a new three-com-
ponent coupling using substrates 1-3, an alkyl halide, and
a Heck acceptor (Scheme 1), leading to heterocycles 4-6.
Scheme 1. New Three-Component Coupling
(1) Tietze, L. F. Chem. ReV. 1996, 96, 115-136.
(2) Poli, G.; Giambastiani, G.; Heumann, A. Tetrahedron 2000, 56,
5959-5989.
(3) (a) Lautens, M.; Piguel, S. Angew. Chem., Int. Ed. 2000, 39, 1045-
1046. (b) Lautens, M.; Paquin, J.-F.; Piguel, S.; Dahlmann, M. J. Org. Chem.
2001, 66, 8127-8134.
(4) This type of reaction was first reported by Catellani and co-workers:
(a) Catellani, M.; Fagnola, M. C. Angew. Chem. 1994, 106, 2559-2561.
Catellani, M.; Fagnola, M. C. Angew. Chem., Int. Ed. Engl. 1994, 33, 2421-
2422. (b) Catellani, M.; Frignani, F.; Rangoni, A. Angew. Chem. 1997, 109,
142-145. Catellani, M.; Frignani, F.; Rangoni, A. Angew. Chem., Int. Ed.
Engl. 1997, 36, 119-122. (c) Catellani, M.; Mealli, C.; Motti, E.; Paoli,
P.; Perez-Carreno, E.; Pregosin, P. S. J. Am. Chem. Soc. 2002, 124, 4336-
4346. (d) Catellani, M. Synlett 2003, 298-313.
This coupling is considerably more ambitious than the one
previously described,3,4 since both ortho positions of the
iodoarene are to be functionalized by different alkyl halides,
(5) Lautens, M.; Paquin, J.-F.; Piguel, S. J. Org. Chem. 2002, 67, 3972-
3974.
10.1021/ol035806t CCC: $25.00 © 2003 American Chemical Society
Published on Web 11/13/2003

and several byproducts (A, B and C) can be formed if the
Heck reaction occurs before the catalytic cycle is completed
(Figure 1). Oligomeric structures such as D and E can be
or “naked” palladium species give only the Heck product
C. With bidentate phosphines, C is still a major byproduct,
but its formation can be greatly diminished using Pd(OAc)2/
PPh3 in a ratio of 1:2.9 A and B were never detected in the
mixture, indicating that once carbopalladation of norbornene
occurs, ortho alkylation is faster than decarbopalladation.10
Using iodoalkyl substrates11 and the optimized conditions
described in Scheme 3 (Pd(OAc)2 (10 mol %), PPh3 (20 mol
Scheme 3. Coupling Using Optimized Conditions
Figure 1. Possible byproducts.
generated if the substrate reacts with itself instead of reacting
with the external alkyl halide. The value of this approach is
in its brevity and ease of synthesis of the substrates, as well
as the ease of variation of the external alkyl halide and the
Heck acceptor. Access to five-, six-, and seven-membered
oxacycles that are widely found in natural products and
related compounds showing interesting biological and phar-
maceutical properties6,7 is now possible.
The first reaction was carried out on substrate 1a using
our previously optimized conditions:3 Pd(OAc)2 (10 mol %),
2-furylphosphine (20 mol %), norbornene (2 equiv), Cs2CO3
(2 equiv), n-BuBr (2 equiv), and t-Bu acrylate (2 equiv) in
refluxing acetonitrile (Scheme 2). The desired product 4a
%), norbornene (5 equiv), Cs2CO3 (5 equiv), n-BuI (10
equiv), and t-Bu acrylate (5 equiv) in DME at 80 °C), the
reaction gave the five-, six-, and seven-membered rings with
good to excellent isolated yields.12
The proposed mechanism for this sequence is outlined in
Scheme 4.13 Pd(0) inserts into the Ar-I bond of 1 and then
incorporates a norbornene and inserts into the most accessible
ortho C-H aryl bond, forming a palladacycle. Elimination
of HI by the base (here Cs2CO3) regenerates a tetracoordi-
nated Pd(II). Oxidative addition of the external alkyl halide
leads to a cyclic Pd(IV) species. A reductive elimination puts
the alkyl group on the arene. An insertion into the second
ortho C-H aryl bond occurs, followed by elimination of HX.
Intramolecular oxidative addition of the alkyl halide present
on the side chain takes place, followed by a reductive
elimination that forms the five-membered oxacycle. Extru-
sion of norbornene, probably due to steric factors, gives an
aryl-Pd(II) species. This intermediate undergoes a Heck
reaction, leading to product 4.
Scheme 2
It is possible to envisage an alternative mechanism leading
to 4, where the first ortho alkylation would occur with the
intramolecular alkyl halide and the second one with the
was obtained in 24% yield, showing that the reaction is viable
and indeed highly selective. Trace amounts of compound C
(where the Heck coupling occurs immediately) and of the
oligomeric structures D and E were also observed.8
Many subtle factors influence the ratio and range of prod-
ucts, but the more important ones proved to be the phosphine
ligand and the solvent. The use of alkylphosphine ligands
(8) The moderate yield of 4a can be explained by the instability of the
substrate under the reaction conditions. Control experiments showed that
after 24 h at 80 °C in the presence of Cs2CO3, 50% of the substrate 1a is
degraded, whereas 4a is stable and can be recovered quantitatively.
(9) Furylphosphine and triphenylphosphine give comparable yields.
(10) Compounds C-E were isolated and characterized by 1H NMR, mass
spectrometry, HPLC, and UV. They are identical to the byproducts observed
by HPLC of the crude reaction mixtures.
(11) Best yields were obtained with an alkyl iodide side chain. The bromo
equivalent reacts more slowly, and part of the substrate decomposes before
being transformed.
(6) (a) Fall, Y.; Vidal, B.; Alonso, D.; Gomez, G. Tetrahedron Lett. 2003,
44, 4467-4469. (b) Mukai, C.; Yamashita, H.; Hanaoka, M. Org. Lett.
2001, 3, 3385-3387. (c) Hoberg, J. O. Tetrahedron 1998, 54, 12631-
12670. (d) Yasumoto, T.; Murata, M. Chem. ReV. 1993, 93, 1897-1909.
(7) (a) Takaki, K. S.; Epperson, J. R. Annu. Rep. Med. Chem. 1999, 34,
41-50. (b) Uchikawa, O.; Fukatsu, K.; Tokunoh, R.; Kawada, M.;
Matsumoto, K.; Imai, Y.; Hinuma, S.; Kato, K.; Nishikawa, H.; Hirai, K.;
Miyamoto, M.; Ohkawa, S. J. Med. Chem. 2002, 45, 4222-4239.
(12) Purity of the reagents proved to be important: the triphenylphosphine
has to be recrystallized and the dimethoxyethane freshly distilled to obtain
reproducible yields. Careful degassing of the reaction mixture prior to
heating is necessary to avoid decomposition of the catalytic system before
completion of the reaction.
(13) Proposed mechanism is based on mechanistic studies published by
Catellani, Pregosin, and co-workers (see for example refs 4c and 4d) and
on the byproducts that we observed in this reaction.
4828
Org. Lett., Vol. 5, No. 25, 2003

Scheme 4. Postulated Mechanism
Table 1. Variation of the Heck Acceptor
entry
R
product
yield (%)
1
2
3
4
5
6
CO2tBu
C(O)NMe2
C(O)NHtBu
C(O)Et
SO2Ph
CN
4a
4b
4c
4d
85
60
87
37
traces
40 (trans/cis 7:1)
4e
acrylonitrile (entry 6) affords a nonseparable mixture of trans
and cis isomers. The use of a sulfone (entry 5) totally inhibits
the reaction, probably by coordination to palladium. Heck
acceptors with additional R or â substituents on the double
bond give poor yields and complex mixtures.
Variation on the alkyl iodide side chain is also possible.
Iodides with a substituent in the R-position (i-PrI, entry 6)
are too slow, but the reaction proceeds with substituents in
the â-position (Table 2, entries 2 and 4). Chloride and oxygen
Table 2. Variation of External Alkyl Iodide
yield
entry
RI
1-iodobutane
1-iodo-2-methylpropane
1-chloro-3-iodopropane
2-iodomethyloxirane
tert-butyl-(3-iodo-propoxy)-
dimethylsilane
product
(%)
external alkyl halide. It seems difficult to distinguish between
the mechanisms, and both pathways may be occurring
simultaneously, but this alternative mechanism is less favor-
able because it requires the first C-H insertion to take place
on the more hindered ortho position. The presence of small
amounts of oligomeric compounds D and E (see Figure 1)
in the reaction mixture, even when the reaction was done
with a large excess of external alkyl halide, seems to indicate
that the first ortho alkylation occurs very easily and on the
less hindered position. This is also supported by the fact that
the coupling conducted without external alkyl halide gives
compounds E and D but no traces of A.
1
2
3
4
5
4a
4f
4g
4h
4i
85
86
53
35
60
6
7
2-iodopropane
iodomethane
mixture of
products
atoms on the chain are tolerated; even a sensitive functional-
ity like an epoxide can be introduced, although with a lower
The generality of this sequence was demonstrated on the
five-membered ring system, first by variation of the Heck
acceptor, and then by variation of the external alkyl iodide.14
Changing from an ester (Table 1, entry 1) to an amide
(entries 2 and 3) does not diminish the yield, even with a
free NH present. However, the yield drops when a vinyl
ketone with enolizable protons is used (entry 4). Using
(14) General Procedure for the Coupling Reaction. 1-Iodo-3-(2-iodo-
ethoxy)-benzene 1b (75 mg, 0.2 mmol), the external alkyl iodide (2 mmol,
10 equiv), the Heck acceptor (1 mmol, 5 equiv), norbornene (96 mg, 1
mmol, 5 equiv), Cs2CO3 (326 mg, 1 mmol, 5 equiv), Pd(OAc)2 (4.5 mg,
10 mol %), and PPh3 (10.5 mg, 20 mol %) were dissolved in 2 mL of
degassed dry dimethoxyethane. The mixture was flushed with N2 and heated
at 80 °C for 16 h. After cooling at room temperature, the mixture was diluted
with diethyl ether, washed with water, dried over magnesium sufate, and
purified by flash chromatography (silica, hexane/AcOEt).
Org. Lett., Vol. 5, No. 25, 2003
4829

yield. Introduction of a methyl group using MeI is not pos-
sible, but the methyl-substituted product can be obtained in
good yield using substrate 715 (Scheme 5).
Scheme 6. Benzyl Alcohol Substrates
Scheme 5. Ortho-Substituted Substrate
esting structures in only two steps from commercially
available 3-iodo-phenol. Further exploration of this reaction
is under way.
Acknowledgment. We thank Dino Alberico and Jean-
Franc¸ois Paquin for practical help and useful discussions.
We gratefully acknowledge the financial support of the
University of Toronto, NSERC, and the Merck Frosst Centre
for Therapeutic Research for an Industrial Research Chair.
S.P. thanks the Swiss National Science Foundation and the
Roche Research Foundation for postdoctoral fellowships.
We extended the method to include a substrate based on
a benzylic alcohol derivative instead of a phenol. Using our
newly optimized catalytic system at a lower temperature of
50 °C, we were able to obtain cyclized products in satisfac-
tory yields (Scheme 6).
In summary, we have shown that this new three-com-
ponent coupling whereby three C-C bonds are formed in
one pot is viable and tolerates a variety of functional groups.
The palladium-catalyzed process efficiently produces inter-
Supporting Information Available: Experimental details
and characterizations for substrates 1a, 1b, 2b, 3b, 7, 9, and
10, for cyclized products 4a-i, 5a, 6a, 8, 11, and 12, and
for byproducts C-E (with n ) 1). This material is available
free of charge via the Internet at http://pubs.acs.org.
(15) Substrate 7 was obtained in good yield from the corresponding
iodophenol. 3-Iodo-4-methyl phenol is not commercially available but can
be obtained in two steps from 4-methyl-3-nitro phenol using literature
procedures.
OL035806T
4830
Org. Lett., Vol. 5, No. 25, 2003