Synthesis of novel tetracycles via an intramolecular Heck reaction with anti-hydride elimination

Article abstract of DOI:10.1021/ol035354k

(Matrix presented) The catalytic combination of Pd₂(dba) ₃/HP(t-Bu)₃·BF₄ and DABCO gives an unusual intramolecular Heck reaction with dihydronaphthalene substrates, yielding formal anti-hydride elimination produ

Full text of DOI:10.1021/ol035354k

ORGANIC
LETTERS
2003
Vol. 5, No. 20
3679-3682
Synthesis of Novel Tetracycles via an
Intramolecular Heck Reaction with
anti-Hydride Elimination
Mark Lautens* and Yuan-Qing Fang
DaVenport Chemistry Laboratories, Department of Chemistry, UniVersity of Toronto,
80 St. George Street, Toronto, Ontario, M5S 3H6, Canada
mlautens@chem.utoronto.ca
Received July 21, 2003
ABSTRACT
The catalytic combination of Pd2(dba)3/HP(t-Bu)3‚BF4 and DABCO gives an unusual intramolecular Heck reaction with dihydronaphthalene
substrates, yielding formal anti-hydride elimination products in good to excellent yields under mild conditions. For dibromo substrates, multiple
Heck reactions are possible when an external acceptor is added to afford more highly functionalized products.
Rhodium- and palladium-catalyzed asymmetric ring-opening
(ARO) reactions of oxabenzonorbornadiene with various
nucleophiles give enantiomerically enriched dihydronaph-
thalene derivatives in good to excellent yields (Scheme 1).1
As part of our investigation to demonstrate the utility of ARO
products, we were interested in using functionalized nucleo-
philes to make multicyclic products using a ring-breaking/
ring-making strategy. Such compounds are biologically
interesting scaffolds for pharmaceutical research.2 Previously,
it was found that 1a underwent radical cyclization in the
presence of HSnBu3 to give a benzofuran skeleton (Scheme
1).3 In an effort to introduce further functionalization by
trapping the species following the furan-forming step, we
chose the Heck reaction, which has become a very important
tool for the formation of carbon-carbon bonds.4
The accepted catalytic cycle of the Heck reaction involves
oxidative addition, carbon-palladium insertion, and â-hy-
dride elimination.5 It is well established that both insertion
and elimination steps are cis-stereospecific. In some cases,
such as R,â-unsaturated carbonyl compounds or styrene-type
Scheme 1
(1) For a review, see: (a) Lautens, M.; Fagnou, K.; Hiebert, S. Acc.
Chem. Res. 2003, 36, 48-58. ARO using heteroatom nucleophiles: (b)
Lautens, M.; Fagnou, K.; Yang, D. J. Am. Chem. Soc. 2003, 125, in press.
(c) Lautens, M.; Fagnou, K.; Taylor, M.; Rovis, T. J. Organomet. Chem.
2001, 624, 259-270. ARO using carbon-based nucleophiles: (d) Lautens,
M.; Dockendorff, C.; Fagnou, K.; Malicki, A. Org. Lett. 2002, 4, 1311-
1314. (e) Lautens, M.; Renaud, J.-L.; Hiebert, S. J. Am. Chem. Soc. 2000,
122, 1804-1805.
(2) (a) Gordaliza, M.; Castro, M. A.; Miguel Del Corral, J. M.; San
Feliciano, A. Curr. Pharmaceut. Des. 2000, 6, 1811-1839. (b) Lautens,
M.; Rovis, T. Tetrahedron 1999, 55, 8967-8976 and references therein.
10.1021/ol035354k CCC: $25.00
© 2003 American Chemical Society
Published on Web 09/06/2003

Table 1. Effect of Amine Base on the Intramolecular Heck Reaction
yielda
yielda
entry
base
Et3N
iPr2NEt
Cy2NMe
proton sponge
DABCO
DBU
temp
(3a + 2a%)
entry
base
temp
(3a + 2a%)
1
2
3
4
5
6
80 °C
80 °C
80 °C
80 °C
60 °C
60 °C
52 + 4
37 + 0
48 + 0
52 + 35
94 + 0
21 + 54
7
8
9
10
11
12
TMEDA
iPr2NH
morpholine
Et2NH
piperidine
pyrolidine
60 °C
60 °C
60 °C
60 °C
60 °C
60 °C
23 + 66
87 + 0
53 + 32
63 + 8
28 + 53
51 + 32
a Yields (both the product 3a and starting material 2a) were measured by HPLC using naphthalene as an internal standard following aqueous NaHCO3
workup and hexane extraction of the crude reaction mixture.
systems, formal trans-elimination is possible.6 However,
the yields are generally low and the scope is limited. Herein,
we report a high-yielding synthesis of tetracyclic compounds
from ARO products (e.g., 1a) via a mild-condition intramo-
lecular Heck reaction with trans-elimination.
Milder conditions for the Heck reaction have been
extensively studied in recent years.7 Fu and Hartwig have
found that electron-rich and sterically hindered phosphine
ligands (e.g., P(t-Bu3)) facilitate oxidative addition and allow
for the use of less reactive aryl bromides at room tempera-
ture.8 To eliminate possible complications of the free OH
group, the ring-opening product 1a was protected as the tert-
butyldimethylsilyl (TBS) ether (2a) in quantitative yield.9
Exposure of 2a to Pd2(dba)3/HP(t-Bu)3‚BF4 in the presence
of Et3N gave the unusual intramolecular Heck product 3a
in moderate yield (Scheme 2).10
fashion in the rate-determining step,11 the geometry and
basicity of the base were believed to be important parameters
for the reaction. Therefore, a number of bases with varying
sterics and basicity were screened (Table 1). Generally,
inorganic bases such as K2CO3, Cs2CO3, and K3PO4 were
ineffective, presumably due to their strong basicity as well
as their low solubility in organic solvents. Most amines tested
showed some reactivity. The best amine found was 1,4-
diazabicyclo[2,2,2]octane (DABCO) (Table 1, entry 10).
Compared to Cy2NMe, the standard base reported by Fu and
Buchwald,12 DABCO is a less sterically hindered tertiary
amine base with an optimal shape for proton extraction.
Further optimization revealed that dioxane as well as other
solvents, including toluene and THF, worked well under
milder conditions (40 °C). The catalyst loading could be
decreased to 2 mol% Pd (Pd/L ) 1:2) with prolonged
reaction times (normally complete within 60 h). Interestingly,
Pd(P(t-Bu)3)2 usually gave lower turnover numbers (TON),
presumably due to the absence of a Pd(0)-stabilizing dba
Scheme 2
(6) Some recent examples: (a) Maeda, K.; Farrington, E. J.; Galardon,
E.; John, B. D.; Brown, J. M. AdV. Synth. Catal. 2002, 344, 104-109. (b)
Shea, K. M.; Lee, K. L.; Danheiser, R. L. Org. Lett. 2000, 2, 2353-2356.
(c) For examples before 1999, see: Ikeda, M.; El Bialy, S. A. A.; Yakura,
T. Heterocycles 1999, 51, 1957-1970 and references therein.
(7) Review: Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41,
4176-4211.
(8) (a) Littke, A. F.; Fu, G. C. J. Org. Chem. 1999, 64, 10-11. (b) Littke,
A. F.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 6989-7000. (c) Stambuli,
J. P.; Stauffer, S. R.; Shaughnessy, K. H.; Hartwig, J. F. J. Am. Chem. Soc.
2001, 123, 2677-2678.
(9) Unprotected substrates yielded a complicated mixture of products.
Other protecting groups such as Me, MOM, and TMS gave incomplete
conversion or low yields of the desired Heck product even under optimized
conditions.
(10) Air- and moisture-stable HP(t-Bu)3‚BF4 was used as a replacement
for P(t-Bu)3: Netherton, M. R.; Fu, G. C. Org. Lett. 2001, 3, 4295-4298.
(11) (a) Adams, N. J.; Bargon, J.; Brown, J. M.; Farrington, E. J.;
Galardon, E.; Giernoth, R.; Heinrich, H.; John, B. D.; Maeda, K. Pure Appl.
Chem. 2001, 73, 343-346. (b) ref 3a. (c) Although the mechanism via
epimerization of the benzylic center by an external Pd(0) attack followed
by cis-elimination cannot be completely excluded, we believe that this
mechanism is unlikely because of steric hindrance. Lau, K. S. Y.; Wong,
P. K.; Stille, J. K. J. Am. Chem. Soc. 1976, 98, 5832-5840.
(12) (a) Gurtler, C.; Buchwald, S. L. Chem. Eur. J. 1999, 5, 3107-
3112. (b) ref 8b.
With the hypothesis that the base removes a proton from
the benzylic palladium intermediate in an anti-periplanar
(3) Lautens, M.; Fagnou, K.; Taylor, M. Org. Lett. 2000, 2, 1677-1679.
(4) For reviews, see: (a) Beletskaya, I. P.; Cheprakov, A. V. Chem. ReV.
2000, 100, 3009-3066. (b) de Meijere, A.; Meyer, F. E. Angew. Chem.,
Int. Ed. Engl. 1994, 33, 2379-2411. (c) Shibasaki, M.; Boden, C. D. J.;
Kojima, A. Tetrahedron 1997, 53, 7371-7395.
(5) Crisp, G. T. Chem. Soc. ReV. 1998, 27, 427-436.
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Org. Lett., Vol. 5, No. 20, 2003

ligand, preventing aggregation.13 Excess ligand (Pd/L ) 1:4)
was found to slow the reaction significantly. Though it is
known that cationic palladium catalysts generally accelerate
the Heck reaction,14 in our case, it was found that use of
silver salts to generate a cationic Pd species completely
inhibited the reaction.
Table 3. Intramolecular Heck Reaction with Substituents on
the Dihydronaphthalene Moiety
The optimized conditions were then applied to different
substrates.15 Most substitution patterns on the aryl bromide
moiety give excellent yields (Table 2), including electron-
Table 2. Intramolecular Heck Reaction with Substituents on
the Bromophenoxy Moiety
a Isolated yields using column chromotography. b At 70 °C.
reactivity; however, side reactions did increase significantly.16
The isomer 4d was more reactive and gave the expected
product in high yield. Surprisingly, ortho-substituted dihy-
dronaphthalene (Table 3, entry 2) gave excellent yield despite
forming a hindered benzylic palladium intermediate.
When the standard conditions were applied to the dibromo-
substituted substrate 6a, the reaction failed to give the
expected monobromo product 7a even at elevated temper-
atures (80 °C). This is presumably due to the Pd catalyst
reacting with 7a to yield 8a, which cannot react further
(Scheme 3).
Scheme 3
a Isolated yield by column chromotography. b Pd2(dba)3 (10 mol%),
HP(t-Bu)3‚BF4 (40 mol %), 80 °C for 20 h.
rich (Table 2, entries 2, 3), fluoro- and chloro-substituted
(Table 2, entries 4, 5, 7), and heterocyclic (Table 2, entry 9)
systems. This suggests that oxidative addition occurs rapidly
regardless of the electronics of the aryl bromide. Lower yields
were obtained for the naphthyl substrate 2j (Table 2, entry
10), despite the use of elevated temperatures and higher
catalyst loadings, presumably due to steric hindrance that
disfavored elimination.
Substituents on the dihydronaphthalene moiety were found
to influence the reactivity and yields. With electron-rich
substituents (Table 3, entry 1), the reaction proceeded more
slowly, requiring higher temperatures in order to obtain an
excellent yield. Electron-withdrawing groups conjugated
(Table 3, entry 3) with the double bond did not affect the
To allow for catalytic turnover, an external Heck acceptor
(2 equiv of olefin) was added. This double-Heck reaction
proceeded smoothly to yield 9 in good to excellent yields
for different dibromo substrates and olefins (Tables 4 and
5). One of the double-Heck products 9a was unambiguously
characterized by X-ray crystallography (Figure 1). In no
case did the reaction proceed in the absence of an external
olefin.
(13) Commercially available (from STREM) Pd(P(t-Bu)3)2 was used.
When this catalyst was used, the TON was lower than 10 and a palladium
mirror was formed inside the reaction flask.
(14) Cabri, W.; Candiani, I. Acc. Chem. Res. 1995, 28, 2-7.
(15) All substrates are racemates obtained from the Rh-catalyzed ring-
opening reaction followed by TBS protection. See Supporting Information
for their preparation.
(16) For possible side reactions, see Pd-catalyzed triarylation on η6-1,2-
dihydronaphthalene-Cr(CO)3 complexes: Dongol, K. G.; Matsubara, K.;
Mataka, S.; Thiemann, T. Chem. Commun. 2002, 3060-3061.
Org. Lett., Vol. 5, No. 20, 2003
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Table 4. Double-Heck Reaction of Dibromo Substrates and an
External Acceptor
Figure 1. X-ray structure of compound 9a from the double-Heck
reaction. Only one of the enantiomers from the racemic crystal is
shown.
under the double-Heck reaction conditions allowed for the
isolation and characterization of the monobromo intermediate
7a, indicating that the intramolecular Heck reaction occurs
much faster than the intermolecular Heck process.
a Isolated yields using column chromotography.
Mechanistically, it is difficult to determine which Heck
reaction occurs first when the two bromo substituents are
nonequivalent (6b, 10a, 10b). However, treatment of 6a
In summary, we have discovered a palladium catalyst for
the intramolecular Heck reaction with dihydronaphthalene
substrates under mild conditions. The combination of Pd2-
(dba)3/HP(t-Bu)3‚BF4 and DABCO gives unusual anti-
hydride elimination products in good to excellent yields. For
dibromo substrates, an external olefin can be added so that
a second conventional Heck reaction can proceed. Further
exploration of the reaction scope, mechanistic studies, and
total syntheses of related natural products or their analogues
are currently under investigation.
Table 5. Double-Heck Reaction of Dibromo Substrates and an
External Acceptor
Acknowledgment. We thank NSERC (Canada), Astra-
Zeneca (Montreal), and the University of Toronto for the
funding of this research. We also thank Dr. Alan Lough for
X-ray structure determination. Y.-Q.F. thanks the University
of Toronto for financial support in the form of doctoral
fellowships.
Supporting Information Available: Crystallographic
data, full experimental details, and characterization, including
1H and 13C NMR spectroscopic data for all the new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
a Isolated yields using column chromotography.
OL035354K
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Org. Lett., Vol. 5, No. 20, 2003