Palladium-catalyzed sequential alkylation - Alkenylation reactions and their application to the synthesis of fused aromatic rings

Article abstract of DOI:10.1021/jo0107296

The synthesis of fused aromatic carbocycles from aryl iodides and difunctional acceptors is outlined. This methodology is based on a palladium-catalyzed aromatic substitution followed by an intramolecular Heck sequence. Under the optimized conditions (Pd(OAc)₂ (10 mol %), tri-2-furylphosphine (20-30 mol %), norbornene (2 equiv), Cs₂CO₃ (2 equiv), CH₃CN, reflux), bromoenoates react with aryl iodides bearing numerous substituents (F, Cl, CF₃, Me, etc.). The expanded description of our initial work as well as the use of polysubstituted aryl iodides is described.

Full text of DOI:10.1021/jo0107296

J . Org. Chem. 2001, 66, 8127-8134
8127
P a lla d iu m -Ca ta lyzed Sequ en tia l Alk yla tion -Alk en yla tion
Rea ction s a n d Th eir Ap p lica tion to th e Syn th esis of F u sed
Ar om a tic Rin gs
Mark Lautens,* J ean-Franc¸ois Paquin, Sandrine Piguel, and Marc Dahlmann
Davenport Laboratories, Department of Chemistry, University of Toronto, Toronto,
Ontario Canada M5S 3H6
mlautens@chem.utoronto.ca
Received J uly 19, 2001
The synthesis of fused aromatic carbocycles from aryl iodides and difunctional acceptors is outlined.
This methodology is based on a palladium-catalyzed aromatic substitution followed by an
intramolecular Heck sequence. Under the optimized conditions (Pd(OAc)2 (10 mol %), tri-2-
furylphosphine (20-30 mol %), norbornene (2 equiv), Cs2CO3 (2 equiv), CH3CN, reflux), bromo-
enoates react with aryl iodides bearing numerous substituents (F, Cl, CF3, Me, etc.). The expanded
description of our initial work as well as the use of polysubstituted aryl iodides is described.
Sch em e 1
In tr od u ction
The ability to catalyze multistep processes is one of the
most useful and interesting features of transition metal
reactivity,1and by fine-tuning the ligands around the
metal, reactivity can be controlled and even directed in
a logical manner.2,3 A particularly interesting system that
combines multistep processes with selective aromatic
substitution4,5 was described by Catellani.6 In this case,
a palladium-catalyzed cascade allows the creation of
three new carbon-carbon bonds in a one-pot process
(Scheme 1). This methodology is based on a sequential
double aromatic substitution and an intermolecular Heck
reaction leading to ortho,ortho′-disubstituted vinylarenes
1.
Sch em e 2
We sought to modify this sequence by using a difunc-
tional acceptor 3 so that an intramolecular Heck reaction
can follow the ortho-alkylation leading to fused aromatic
compounds 2 (Scheme 2). This route is interesting since
many bioactive molecules contain a substituted tetra-
hydronaphthalene core.7-9 We have recently described
our preliminary results in this area10and now report an
expanded description of our studies including the use of
functionalized aryl iodides for the synthesis of fused
aromatic six- and seven-membered carbocycles.
(1) (a) Wender, P. A. Chem. Rev. 1996, 96, 1-2. (b) Lautens, M.;
Klute, W.; Tam, W. Chem. Rev. 1996, 96, 49-92. (c) Tietze, L. F. Chem.
Rev. 1996, 96, 115-136. (d) Padwa, A.; Weingarten, M. D. Chem. Rev.
1996, 96, 223-270. (e) Harvey, D. F.; Sigano, D. M. Chem. Rev. 1996,
96, 271-288. (f) Malacria, M. Chem. Rev. 1996, 96, 289-306. (g)
Negishi, E.-i.; Cope´ret, C.; Ma, S.; Liou, S.-Y.; Liu, F. Chem. Rev. 1996,
96, 365-394.
Resu lts a n d Discu ssion
Op tim iza tion . Our initial studies were carried out
with iodobenzene (4) and ethyl (E)-6-bromohex-2-enoate
(5) using the conditions described by Catellani6 (i.e., the
PNP dimer as catalyst11 in DMA). The desired six-
membered ring compound 6 was obtained in up to 33%
yield as a single stereoisomer (Scheme 3). The most
serious problem was the variability of the yield, which
could be as low as 7% depending on the batch of catalyst.
It was necessary to find improved conditions, and toward
this end ligand effects as well as different palladium
sources and solvents were examined.
(2) Reetz, M. T. Pure Appl. Chem. 1992, 64, 351-359.
(3) Van Koten, G. Pure Appl. Chem. 1989, 61, 1681-1694.
(4) Tamao, K. Comprehensive Organic Chemistry; Trost, B. M.;
Flemming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 3, pp 435-
480.
(5) Catellani, M. Transition Metal Catalysed Reaction; Murahashi,
S.-I.; Davies, S. G., Eds.; Blackwell Science: Oxford, 1999; pp 168-
193.
(6) (a) Catellani, M.; Frignani, F.; Rangoni, A. Angew. Chem. 1997,
109, 142-145 and references therein.; Angew. Chem., Int. Ed. Engl.
1997, 36, 119-122 and references therein. (b) Catellani, M.; Fagnola,
M. C. Angew. Chem. 1994, 106, 2559-2560; Angew. Chem., Int. Ed.
Engl. 1994, 33, 2421-2422. (c) Catellani, M.; Cugini, F. Tetrahedron
1999, 55, 6595-6602.
(7) Kamal, A.; Gayatri, N. L. Tetrahedron Lett. 1996, 37, 3359-3362
and references therein.
(8) Snyder, S. E.; Avilesgaray, F. A.; Chakraborti, R.; Nichols, D.
E.; Watts, V. J .; Mailman, R. B. J . Med. Chem. 1995, 38, 2395-2409.
(9) Kim, K.; Guo, Y.; Sulikowski, G. A. J . Org. Chem. 1995, 60,
6866-6871.
(10) Lautens, M.; Piguel, S. Angew. Chem., Int. Ed. Engl. 2000, 39,
1045-1046.
(11) Horino, H.; Arai, M.; Inoue, N. Tetrahedron Lett. 1974, 674-
650.
10.1021/jo0107296 CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/27/2001

8128 J . Org. Chem., Vol. 66, No. 24, 2001
Lautens et al.
Other parameters including base or additives13,14 were
then surveyed to further optimize the reaction. We found
that using Cs2CO3 instead of K2CO3 provided the desired
product in higher yield. For R ) Me (entry 1), the yield
increased to 92%. With the protected benzylic alcohol
(entries 2 and 3), the yields improved but were still
moderate, giving the carbocycles in 35% and 60% for the
methyl ether and the TBS ether, respectively. The
difference of the reactivity between Cs2CO3 and K2CO3
might be explained by the better solubility of Cs2CO3.15
Other bases (Et3N, K3PO4) were tried under the same
conditions but were found to be less effective.
Sch em e 3
Ta ble 1. Effects of Or th o-Su bstitu tion a n d Ba se
To complete our optimization studies, the effect of the
nature of the Heck acceptor and the halogen on the
difunctional acceptor was examined using 7 as the aryl
iodide (Table 2). Comparison of the R,â-unsaturated
esters 5 (Table 1, entry 1) and 15 (Table 2, entry 1)
showed that the bromide gave better yields than the
iodide probably because the iodide undergoes a variety
of other side reactions.6c The geometry of the double bond
does not seem to influence the yield since going from the
trans (Table 1, entry 1) to cis enoate (Table 2, entry 2)
gave the product in similar yield. The use of menthyl
ester 17 or amide 18 gave the desired products 23 and
24 in 81 and 90%, respectively. The use of a Weinreb
amide 19 or an acceptor bearing the Evans auxiliary 20
also gave the carbocycle in good yield. By using a cyano
group (entry 7) as the acceptor, the bicyclic compound
was obtained as a mixture of cis and trans isomers (2:1
in favor of the cis isomer) but in moderate yield. Utilizing
a phenyl sulfone or a trimethylsilyl as acceptor group led
to unreacted starting material and decomposition, re-
spectively.
yielda (%)
entry
R
aryl iodide product
K2CO3 Cs2CO3
1
2
3
4
CH3
7
8
11
12
13
14
85
20
41
29
92
35
60
26
CH2OMe
CH2OTBS
OMe
9
10
a
Isolated yield.
Among the combination of palladium sources and
ligands examined, Pd(OAc)2/tri-2-furylphosphine12 proved
to be the most encouraging catalytic system since the
desired compound 6 was obtained in 24% yield as a single
stereoisomer and in reproducible albeit, very low yield.
Other systems such as Pd(PPh3)4, Pd(dppf)Cl2/HgCl,
Pd2(dba)3, Pd(OAc)2/PPh3, Pd(OAc)2/n-Bu3P, Pd(OAc)2/
tri-o-tolylphosphine, and Pd(OAc)2/P(OMe)3 gave little or
none of the expected product.
Using the Pd(OAc)2/tri-2-furylphosphine combination
of catalyst/ligand, we then changed other variables
(solvent, base) in order to improve the yield. An inves-
tigation of the solvent revealed that acetonitrile was the
solvent of choice with the yield increasing from 24% in
DMA to 43% in MeCN. Other solvents (CH2Cl2, benzene,
THF) gave only traces of the desired product.
A possible mechanism for the formation of fused
aromatic carbocycle 11 is shown in Scheme 4 and follows
a similar pathway to that proposed by Catellani.6 The
complex 28, obtained after oxidative addition of 7,
undergoes carbopalladation with norbornene exclusively
from the exo face6a,11,16-20 to give complex 29. Formation
of palladacycle 30 occurs6a,16,21-26 via C-H activation,
and subsequent oxidative addition of 5 gives the
palladium(IV) complex6a 31, which undergoes a reductive
elimination to afford 32. Expulsion of norbornene6b occurs
presumably due to steric effects leading to 33 which
undergoes an intramolecular Heck reaction to give the
desired carbocycle.
A variety of ortho-substituted aryl iodides were reacted
under the optimized conditions to determine the scope
of the reaction (Table 1). Using Pd(OAc)2 (10 mol %), tri-
2-furylphosphine (20 mol %), norbornene (2 equiv),
K2CO3 (2 equiv), MeCN, reflux, we were able to obtain
the desired six-membered carbocycle in moderate to good
yield with a variety of ortho-substituted aryl iodides. Two
new carbon-carbon bonds were formed in a one-pot
reaction, and the bicyclic compounds were isolated as
exclusively E-configured stereoisomers as determined by
NOE experiments.
Effects of Or th o-Su bstitu tion a n d Rin g Size. We
have extended the reaction to include the formation of
seven-membered carbocycles as well as determining the
reactivity of other ortho-substituted aryl iodides in order
to demonstrate the functional group tolerance at this
position. The result shown in Table 3 indicates that the
scope of the reaction is quite broad since even halogens
and heteroatoms are well tolerated.
With R ) Me (entry 1), the desired product 11 was
isolated in 85% yield, whereas R ) OMe (entry 4) gave a
moderate yield of 14. Interestingly, going from a methyl
ether (entry 2) to a TBS ether protected benzyl alcohol
(entry 3) improved the yield from 20 to 41%. This lack of
reactivity might be explained by a complexation between
the oxygen atom and the palladium center, which inhibits
the subsequent steps in the catalytic cycle. We suppose
that this phenomenon is minimized in the case of R )
CH2OTBS (entry 3) because of the steric bulk of the silyl
group.
The production of a seven-membered ring using the
same aryl iodides presented in Table 1 gave comparable
results for all the substituents except with R ) OMe
(13) For a recent example of the importance of the choice of base in
palladium catalysis, see Viciu, M. S.; Grasa, G. A.; Nolan, S. P.
Organometallics 2001, 20, 3607-3612.
(14) J effery, T. Tetrahedron 1996, 52, 10113-10130, and references
therein.
(15) Wolfe, J . P.; Buchwald, S. L. J . Org. Chem. 2000, 65, 1144-
1157, and references therein.
(12) Anderson, N. G.; Keay, B. A. Chem. Rev. 2001, 101, 997-1030.

Pd-Catalyzed Alkylation-Alkenylation Reactions
J . Org. Chem., Vol. 66, No. 24, 2001 8129
Ta ble 2. Effect of th e Heck Accep tor
a
b
Isolated yield. Estimated by NMR spectroscopy. c 21 is a mixture of cis/trans isomer (3.5:1) and 27 is a mixture of E/Z isomer (2:1).
where the desired carbocycle 41 was isolated in much
better yield (entry 4). The same trends observed previ-
ously for the protected benzylic alcohol also applied here
where the TBS ether protected alcohol gave a better yield
than the methyl ether (entries 2 and 3). Methyl 2-iodo-
benzoate gave no desired product whereas 2-iodobenzyl
chloride gave only decomposition of the starting material
in the six- and seven-membered ring series. The cyclic
acetal of 2-iodobenzaldehyde [2-(2-iodophenyl)-5,5-di-
methyl-1,3-dioxane] yielded only traces of the desired
product. 2-Iodobenzotrifluoride (34) reacts to form the six-
membered ring 42 in 76% yield but failed to give the
desired seven-membered ring. 2-Chloroiodobenzene (35)
gave the carbocycle 43 in 80% yield, which is of great
interest, since it opens the way to the introduction of
otherwise incompatible substituents on the aromatic ring.
The presence of bromine was not tolerated on the ring
since 2-bromoiodobenzene and 1,2-dibromobenzene gave
mainly decomposition of the starting material. The
presence of a pyrrolidine ring at the ortho position (entry
7) had some effect, but 44 was still isolated in 55% yield.
Changing the iodide to bromide [2-bromotoluene] or
triflate [2-(trifluoromethylsulfonyl)toluene] led to degra-
dation and unreacted starting material, respectively.

8130 J . Org. Chem., Vol. 66, No. 24, 2001
Lautens et al.
Sch em e 4
Ta ble 3. Effect of Or th o Su bstitu tion of th e Ar yl Iod id es
a
Isolated yield.
When iodoamide 45 was reacted under the standard
conditions, disappearance of the starting material oc-
curred within 10-12 h (eq 1).
However, only traces of the desired product 46 were
observed along with formation of 47 in 87% yield. This
compound can be formed if, after carbopalladation of the
aryl palladium species onto norbornene, an intramolecu-
lar amination occurred instead of the standard pallada-
cycle formation. This reactivity has been observed before
and used for the synthesis of fused dihydrofurans and

Pd-Catalyzed Alkylation-Alkenylation Reactions
J . Org. Chem., Vol. 66, No. 24, 2001 8131
Ta ble 4. Effect of P olysu bstitu ted Ar yl Iod id es
-pyrroles.27 The use of the tertiary amide [N-acetyl-N-
methyl-2-iodoaniline] also failed to undergo cyclization
to form the six or the seven-membered ring and only
consumption of the starting material was observed along
with traces of the desired product.
P olysu bstitu ted Ar yl Iod id es. We next investigated
the reactivity of polysubstituted aryl iodides (Table 4) and
found that many functional groups are tolerated on the
aromatic ring including an amide (entry 3), phenyl
(entries 4 and 5), methyl (entries 1-3, 6-8, 10), methoxy
(entry 10), chlorine (entries 1 and 2, 8-9), and fluorine
(entries 6 and 7) with yields ranging from 52 to 90%.
Although the presence of an ester at position 2 [methyl
2-iodobenzoate] or 5 [methyl 3-iodo-4-methylbenzoate] is
not tolerated, Catellani showed6a that its presence did
not affect the reaction when it was present at position 4,
extending the possibility for further manipulation. It is
interesting to note that the type of substituent at position
5 seemed relevant to the success of the reaction. Aryl
iodides having a methyl [2-iodo-p-xylene], an ester [meth-
yl 3-iodo-4-methylbenzoate], an aldehyde [3-iodo-4,5-
dimethoxybenzaldehyde], or a protected aldehyde [2-(3-
iodo-4,5-dimethoxyphenyl)-5,5-dimethyl-1,3-dioxane] at
this position completely inhibited the annulation al-
though all the starting aryl iodides were consumed. The
formation of the palladacycle (e.g., 30) was postulated26
to occur via an electrophilic attack of the palladium on
the ortho-position of the phenyl ring to give a Wheland-
type intermediate, which then formed the palladacycle.
Therefore, any substituents that destabilize this inter-
mediate may be not tolerated. Although this may explain
the lack of reactivity for the ester and the aldehyde, our
(16) Li, C.-S.; J ou, D.-C.; Cheng, C.-H. J . Chem. Soc., Chem.
Commun. 1991, 710-712.
(17) Li, C.-S.; Cheng, C.-H.; Liao, F.-L.; Wang, S.-L. Organometallics
1993, 12, 3945-3954.
(18) Markies, B. A.; Verkerk, K. A. N.; Rietveld, M. H. P.; Boersma,
J .; Kooijman, H. Spek, A. L.; van Koten, G. J . Chem. Soc., Chem.
Commun. 1993, 1317-1319.
(19) Portnoy, M.; Ben-David, Y.; Rousso, I.; Milstein, D. Organo-
metallics 1994, 13, 3465-3479.
(20) van Asselt, R.; Gielens, E. E. C. G.; Ru¨lke, R. E.; Vrieze, K.;
Elsevier: C. J . J . Am. Chem. Soc. 1994, 116, 977-985.
(21) Catellani, M.; Chiusoli, G. P. J . Organomet. Chem. 1988, 346,
C27-C30.
(22) Catellani, M.; Chiusoli, G. P. J . Organomet. Chem. 1992, 425,
151-154.
(23) Catellani, M.; Mann, B. E. J . Organomet. Chem. 1990, 390,
251-255.
(24) Bocelli, G.; Catellani, M.; Ghelli, J . J . Organomet. Chem. 1993,
458, C12-C15.
a
Isolated yield.
(25) Liu, C.-H.; Li, C.-S.; Cheng, C.-H. Organometallics 1994, 13,
18-20.
results cannot exclude steric effects or side reactions for
the methyl and the protected aldehyde.28 Further experi-
ments in order to better understand the reactivity are
underway.
(26) Markies, B. A.; Wijkens, P.; Kooijman, H.; Spek, A. L.; Boersma,
J .; van Koten, G. J . Chem. Soc., Chem. Commun. 1992, 1420-1423.
(27) Catellani, M.; Del Rio, A. Russ. Chem. Bull. 1998, 47, 928-
931.

8132 J . Org. Chem., Vol. 66, No. 24, 2001
Lautens et al.
Sch em e 5
2-(trifluoromethylsulfonyl)toluene,36 methyl 2-iodobenzoate,29
N-acetyl-N-methyl-2-iodoaniline30), or prepared as described
in the Supporting Information section (9, 36, 49, 52, 54, 2-(2-
iodophenyl)-5,5-dimethyl-1,3-dioxane, 2-(3-iodo-4,5-dimethoxy-
phenyl)-5,5-dimethyl-1,3-dioxane, methyl 3-iodo-4-methylben-
zoate). The difunctional acceptors were synthesized using
literature procedures (5,31 3731), or prepared as described in
the Supporting Information section (15, 16, 17, 18, 19, 20, 21,
65, 68).
We also investigated the effect of having a trisubsti-
tuted Heck acceptor (Scheme 5). Under the standard
conditions, the E-isomer 65 reacted with 7 to give a
mixture of the external olefin 66 and the internal olefin
67 in 40 and 27% yield, respectively. More interestingly,
using the Z-isomer 68 under the same conditions led only
to the formation of the external olefin 66 in 64% yield.
The reasons for this behavior are not fully understood
but it appears that diastereomeric palladium complexes
undergo â-elimination with different propensities. Fur-
ther investigation is underway and will be reported in
due course.
Cycliza tion Usin g Iod oben zen e. Gen er a l P r oced u r e.
Eth yl (E)-6-[(8E)-8-(2-Eth oxy-2-oxoeth ylid en e)-5,6,7,8-tet-
r a h yd r on a p h th a len -1-yl]h ex-2-en oa te (6). Under inert
atmosphere, a flame-dried round-bottom flask equipped with
a condenser was charged with iodobenzene (20 µL, 0.179
mmol), 5 (174.6 mg, 0.79 mmol), Cs2CO3 (116.7 mg, 0.358
mmol), norbornene (36.2 mg, 0.384 mmol), tri-2-furylphosphine
(8.3 mg, 0.035 mmol), Pd(OAc)2 (4.7 mg, 0.021 mmol), and
CH3CN (5 mL). The resulting mixture was heated at 85 °C
for 19 h and then quenched by addition of satd NH4Cl. The
organic layer was separated, and the aqueous layer was
extracted with Et2O (3×). The organic layers were combined,
washed with brine, and dried over MgSO4. The crude product
was purified by flash chromatography on silica gel with 1-3%
ether in hexane to afford 6 (30 mg, 47%) as a yellow pale oil.
IR (neat) ν ) 1619, 1654, 1713, 2936 cm-1; 1H NMR δ 1.28 (t,
3H, J ) 7.2 Hz), 1.31 (t, 3H, J ) 7.2 Hz), 1.76 (m, 4H), 2.21
(q, 2H, J ) 7.2 Hz), 2.58 (t, 2H, J ) 6.0 Hz), 2.83 (t, 2H, J )
6.0 Hz), 3.13 (dt, 2H, J ) 7.2, 2.0 Hz), 4.17 (q, 2H, J ) 7.2
Hz), 4.19 (q, 2H, J ) 7.2 Hz), 5.80 (dt, 1H, J ) 16.0, 1.6 Hz),
5.86 (t, 1H, J ) 1.6 Hz), 6.91-7.18 (m, 4H); 13C NMR δ 14.2,
14.3, 21.3, 27.8, 30.0, 30.1, 31.9, 32.3, 59.7, 60.1, 118.0, 121.6,
125.1, 127.9, 128.1, 136.8, 138.5, 141.9, 148.5, 154.8, 166.5,
166.6; HRMS calcd for C22H29O4 357.2070, found 357.2065.
Con clu sion
We have developed a new approach for the synthesis
of fused carbocycles, which proceeds by a palladium-
catalyzed process based on a sequential aromatic sub-
stitution and an intramolecular Heck reaction of substi-
tuted aryl iodides. Two new carbon-carbon bonds are
formed in one pot. Numerous functional groups are
tolerated including amide, amine, protected alcohol,
halogen, trifluoromethyl, alkyl, and aryl groups. Sub-
stituent at position 5 of the aryl iodide seems to be
important for the success of the reaction. Under opti-
mized conditions, we were able to obtain polyfunction-
alized six- and seven-membered carbocycles as single
stereoisomers. Application of these methods to the syn-
thesis of more complex carbocycles as well as heterocyclic
compounds is currently in progress in our laboratory.
Cycliza tion Usin g Or th o-Su bstitu ted a n d P olysu bsti-
tu ted Ar yl Iod id es. Gen er a l P r oced u r e. Eth yl (E)-(8-
Me t h y l-3,4-d ih y d r o n a p h t h a le n -1(2H )-y lid e n e )e t h a -
n oa te (11). A round-bottom flask equipped with a condenser
was charged with Cs2CO3 (130 mg, 0.400 mmol), Pd(OAc)2 (4.5
mg, 0.020 mmol), tri-2-furylphosphine (9.2 mg, 0.040 mmol),
and norbornene (37.7 mg, 0.400 mmol). A solution of 5 (88.4
mg, 0.400 mmol) and iodotoluene (25.5 µL, 0.200 mmol) in
CH3CN (2 mL) was added. The resulting mixture was heated
at 85 °C for 19 h and then quenched by addition of satd NH4Cl.
The organic layer was separated, and the aqueous layer was
Exp er im en ta l Section
The following includes general experimental procedures,
specific details for representative reactions, and isolation and
spectroscopic information for illustrative compounds. Specific
information for all other new compounds can be found in the
Supporting Information. All 1H and 13C NMR spectra were
recorded in deuterated chloroform using tetramethylsilane or
residual chloroform as internal standard. High-resolution mass
spectra were obtained at 70 eV. Aryl iodides were purchased
from commercial sources (4, 7, 10, 34, 35, 48, 50, 51, 53,
2-bromotoluene, 1,2-dibromobenzene, 2-bromoiodobenzene, 2-io-
dobenzyl chloride, 2-iodo-p-xylene, 3-iodo-4,5-dimethoxybenz-
aldehyde), synthesized using literature procedures (8,29 45,30
(31) Somekawa, K.; Okuhira, H.; Sendayama, M.; Suishu, T.; Shimo,
T. J . Org. Chem. 1992, 57, 5708-5712.
(32) Tan, D. S.; Foley, M. A.; Stockwell, B. R.; Shair, M. D.;
Schreiber, S. L. J . Am. Chem. Soc. 1999, 121, 9073-9087.
(33) Kajigaeshi, S.; Kakimami, T.; Yamasaki, H.; Fujisaki, S.;
Okamoto, T. Bull. Chem. Soc. J pn. 1988, 61, 600-602.
(34) Enders, D.; Scherer, H. J .; Runsink, J . Chem. Ber. 1993, 126,
1929-1944.
(28) No side products were isolated since only unreacted 5 or 37
along with baseline material was detectable by TLC after workup.
(29) Larock, R. C.; Harrison, W. L. J . Am. Chem. Soc. 1984, 106,
4218-4227.
(30) Curran, D. P.; Yu, H.; Liu, H. Tetrahedron, 1994, 50, 7343-
7366.
(35) Cooke, M. P.; Widener, R. K. J . Org. Chem. 1987, 52, 1381-
1396.
(36) J utand, A.; Mosleh, A. J . Org. Chem. 1997, 62, 261-274.

Pd-Catalyzed Alkylation-Alkenylation Reactions
J . Org. Chem., Vol. 66, No. 24, 2001 8133
extracted with Et2O (3×). The organic layers were combined,
washed with brine, and dried over MgSO4. Removal of the
solvent gave a crude oil that was purified by flash chroma-
tography using EtOAC/hexane (1:19) as the eluant to yield 11
(42.2 mg, 92%) as a colorless oil. IR (neat) ν ) 1615, 1708,
2951 cm-1;1H NMR δ ) 1.31 (t, 3H, J ) 7.2 Hz), 1.70 (m, 2H),
2.47 (s, 3H), 2.60 (t, 2H, J ) 6.1 Hz), 3.10 (td, 2H, J ) 7.0, 2.0
Hz), 4.20 (q, 2H, J ) 7.2 Hz), 5.90 (t, 1H, J ) 2.0 Hz), 6.90 (m,
1H), 7.10 (m, 2H); 13C NMR δ 14.3, 21.6, 21.7, 28.2, 30.2, 59.7,
118.2, 125.2, 127.8, 129.5, 134.9, 136.3, 141.8, 154.7, 166.9;
HRMS calcd for C15H18O2 230.1311, found 230.1306.
183.1048, found 183.1044. Z-isomer; IR (neat) ν ) 1468, 1611,
1
2214, 2866, 2949, 3056 cm-1. H NMR δ 1.85 (m, 2H), 2.49 (s,
3H), 2.61 (m, 4H), 5.45 (t, 1H, J ) 1.2 Hz), 7.00 (d, 1H, J )
7.2 Hz), 7.14-7.26 (m, 2H); 13C NMR δ 20.1, 20.6, 29.1, 33.0,
96.0, 117.6, 124.5, 128.8, 128.9, 134.1, 135.0, 140.6, 161.0;
HRMS calcd for C15H13N 183.1048, found 183.1047.
Eth yl (E)-(4-Meth yl-6,7,8,9-tetr a h yd r o-5H-ben zo[a ][7]-
a n n u len -5-ylid en e)eth a n oa te (38). Following the general
procedure on a 0.157 mmol scale using 37 and 7, 38 was
isolated as a colorless oil (31.7 mg, 83%) by preparative TLC
using Et2O/hexane (1:9) as eluant. IR (neat) ν ) 1637, 1715,
2854, 2927, 3063 cm-1;1H NMR δ 1.31 (t, 3H, J ) 7.2 Hz),
1.56 (m, 1H), 1.89 (m, 3H), 2.03 (m, 1H), 2.25 (s, 3H), 2.61 (m,
1H), 2.74-3.68 (m, 2H), 4.21 (q, 2H, J ) 7.2 Hz), 5.69 (s, 1H),
6.94-7.07 (m, 3H); 13C NMR δ 14.2, 20.1, 27.9, 29.5, 31.8, 34.9,
59.7, 118.4, 126.1, 127.1, 128.2, 133.0, 139.5, 143.2, 162.7,
166.4; HRMS calcd for C16H20O2 244.1470, found 244.1463.
N-Acet yl-1,4-m et h a n o-1,2,3,4,4a ,9b -h exa h yd r oca r b a -
zole (47). Following the general procedure on a 0.200 mmol
scale using 5 and 45, 47 was isolated as a yellow solid (39.7
mg, 87%) by flash chromatography using EtOAc/hexane (1:4)
as eluant. IR (neat) ν ) 1392, 1482, 1660, 2961 cm-1; 1H NMR
δ 0.82-2.52 (m, 8H), 2.29 (s, 3H), 3.39 (d, 1H, J ) 7.5 Hz),
4.11 (d, 1H, J ) 7.8 Hz), 7.00 (t, 1H, J ) 7.2 Hz), 7.15 (m,
2H), 8.19 (d, 1H, J ) 8.4 Hz); 13C NMR δ 23.8, 25.7, 28.0, 32.1,
42.8, 43.2, 50.7, 68.0, 116.6, 123.8, 124.0, 127.6, 133.7, 144.6,
169.2; HRMS calcd for C15H17O4 227.1310, found 227.1313.
Eth yl (E)-(7-Ch lor o-8-m eth yl-3,4-d ih yd r on a p h th a len -
1(2H)-ylid en e)eth a n oa te (55). Following the general pro-
cedure on a 0.200 mmol scale using 5 and 48, 55 was isolated
as a colorless oil (45.4 mg, 86%) by flash chromatography using
EtOAc/hexane (1:19) as eluant. IR (neat) ν ) 1163, 1622, 1713,
1′-(1′R,2′S,5′R)-Men th yl-(E)-(8-m eth yl-3,4-dih ydr on aph -
th a len -1(2H)-ylid en e)eth a n oa te (23). Following the general
procedure (using 30 mol % of tri-2-furylphosphine instead of
20 mol %) on a 0.157 mmol scale using 17 and 7, 23 was
isolated as a colorless oil (43.4 mg, 81%) by flash chromatog-
raphy using Et2O/hexane (1:15) as eluant. IR (neat) ν ) 1162,
1
1261, 1364, 1703, 2863, 2947 cm-1; H NMR δ 0.80 (d, 3H, J
) 7.2 Hz), 0.84-2.13 (m, 17H), 2.47 (s, 3H), 2.63 (t, 2H, J )
6.0 Hz), 3.15 (m, 2H), 4.76 (dt, 1H, J ) 10.8, 4.5 Hz), 5.91 (t,
1H, J ) 1.8 Hz), 6.98 (m, 1H), 7.11 (m, 2H); 13C NMR δ 16.6,
20.7, 21.6, 21.8, 22.1, 23.7, 26.4, 28.3, 30.3, 31.4, 34.3, 41.1,
47.0, 73.4, 118.7, 125.3, 127.8, 129.6, 134.9, 136.4, 141.8, 154.4,
166.5; HRMS calcd for C23H32O2 340.2402, found 340.2413.
1-[(E)-2-(8-Met h yl-3,4-d ih yd r on a p h t h a len -1(2H )-yli-
d en e)et h a n oyl]p yr r olid in e (24). Following the general
procedure (using 30 mol % of tri-2-furylphosphine instead of
20 mol %) on a 0.157 mmol scale using 18 and 7, 24 was
isolated as a colorless oil (36.0 mg, 90%) by flash chromatog-
raphy using toluene/EtOAc (1:2) as eluant. IR (neat) ν ) 1135,
1
1189, 1349, 1550, 1634, 2863, 2939 cm-1; H NMR δ 1.79 (m,
2H), 1.92 (m, 4H), 2.48 (s, 3H), 2.64 (t, 2H, J ) 6.3 Hz), 3.05
(dt, 2H, J ) 6.9, 1.5 Hz), 3.45 (t, 2H, J ) 6.6 Hz), 3.56 (t, 2H,
J ) 6.6 Hz), 6.09 (t, 1H, J ) 1.5 Hz), 6.98 (m, 1H), 7.10 (m,
2H); 13C NMR δ 21.6, 22.1, 24.3, 26.2, 27.8, 30.1, 45.5, 46.9,
120.7, 125.3, 127.2, 129.3, 134.3, 137.2, 141.4, 148.2, 166.1;
HRMS calcd for C17H21NO 255.1623, found 255.1623.
1
2942 cm-1; H NMR δ 1.31 (t, 3H, J ) 7.2 Hz), 1.76 (m, 2H),
2.48 (s, 3H), 2.56 (t, 2H, J ) 6.0 Hz), 3.14 (dt, 2H, J ) 7.2, 1.8
Hz), 4.21 (q, 2H, J ) 7.2 Hz), 5.85 (t, 1H, J ) 2.4 Hz), 6.93 (d,
1H, J ) 8.4 Hz), 7.24 (d, 1H, J ) 8.1 Hz); 13C NMR δ 14.3,
18.8, 21.4, 27.8, 29.8, 59.9, 119.6, 125.8, 128.6, 132.7, 133.8,
138.6, 140.3, 154.1, 166.5; HRMS calcd for C15H17O2Cl 264.0917,
found 264.0929.
(E)-N-Meth oxy-N-m eth yl-2-(8-m eth yl-3,4-dih ydr on aph -
th a len -1(2H)-ylid en e)eth a n a m id e (25). Following the gen-
eral procedure (using 30 mol % of tri-2-furylphosphine instead
of 20 mol %) on a 0.157 mmol scale using 19 and 7, 25 was
isolated as a colorless oil (32.5 mg, 84%) by flash chromatog-
raphy using EtOAc/hexane (1:1) as eluant. IR (neat) ν ) 1178,
Cycliza tion Usin g Tr isu bstitu ted Difu n ction a l Accep -
tor s. Gen er a l P r oced u r e. Eth yl (E)-2-(8-Meth yl-3,4-d ih y-
d r on a p h th a len -1(2H)-ylid en e)p r op a n oa te (66) a n d Eth yl
2-(8-Met h yl-1,2,3,4-t et r a h yd r on a p h t h a len -1-yl)a cr yla t e
(67). To a mixture of Pd(OAc)2 (8.1 mg, 0.036 mmol) and tri-
2-furylphosphine (15.6 mg, 0.066 mmol) was added CH3CN (2
mL), and the resulting mixture was stirred 30 min at room
temperature. Cs2CO3 (205.8 mg, 0.632 mmol), 2-iodotoluene
(40 µL, 0.314 mmol), norbornene (0.207M/CH3CN, 3.48 mL,
0.720 mmol), and a solution of 65 (149.5 mg, 0.636 mmol) in
CH3CN (2 mL) were added successively. The resulting mixture
was heated at 85 °C for 16 h and then quenched by addition
of satd NH4Cl (6 mL). The organic layer was separated, and
the aqueous layer was extracted with Et2O (3×). The organic
layers were combined, washed with brine, and dried over
MgSO4. The solvent was evaporated to give a yellow oil that
was purified by flash chromatography using hexane/toluene
(1:1) as eluant to yield 66 (30.3 mg, 40%) and 67 (20.7 mg,
27%). 66: IR (film) ν ) 1127, 1255, 1465, 1708, 2859, 2945,
2978, 3056 cm-1; 1H NMR δ 1.34 (t, 3H, J ) 7.2 Hz), 1.50 (m,
1H), 1.80 (s, 3H), 1.98 (m, 1H), 2.18-2.26 (m, 4H), 2.40 (m,
1H), 2.59 (ddd, 1H, J ) 14.0, 5.2, 2.4 Hz), 3.29 (m, 1H), 4.25
(m, 2H), 6.98 (d, 1H, J ) 7.2 Hz), 7.08 (d, 1H, J ) 6.8 Hz),
7.14 (t, 1H, J ) 8.0 Hz); 13C NMR δ 14.3, 17.7, 19.4, 21.0, 28.4,
29.1, 60.3, 124.0, 124.8, 127.2, 127.8, 134.4, 137.6, 141.3, 143.9,
169.8; HRMS calcd for C16H20O2 244.1463, found 244.1466.
67: IR (film) ν ) 1129, 1255, 1460, 1624, 1718, 2859, 2934,
2978, 3056 cm-1; 1H NMR δ 1.34 (t, 3H, J ) 7.2 Hz), 1.68 (m,
2H), 1.84 (m, 2H), 2.10 (s, 3H), 2.78 (m, 2H), 4.20 (t, 1H, J )
4.0 Hz), 4.27 (q, 2H, J ) 7.2 Hz), 4.84 (t, 1H, J ) 1.2 Hz), 6.21
(d, 1H, J ) 1.6 Hz), 6.96 (d, 2H, J ) 7.6 Hz), 7.06 (t, 1H, J )
7.6 Hz); 13C NMR δ 14.2, 17.1, 19.0, 27.3, 29.5, 36.7, 60.7, 126.0,
126.3, 126.9, 127.7, 135.9, 136.8, 137.7, 144.0, 167.0; HRMS
calcd for C16H20O2 244.1463, found 244.1460.
1
1377, 1435, 1642, 2862, 2935 cm-1; H NMR δ 1.79 (m, 2H),
2.49 (s, 3H), 2.64 (t, 2H, J ) 6.4 Hz), 3.12 (t, 2H, J ) 6.8 Hz),
3.26 (s, 3H), 3.67 (s, 3H), 6.39 (br s, 1H), 6.99 (m, 1H), 7.13
(m, 2H); 13C NMR δ 21.6, 22.0, 28.0, 30.2, 61.6, 117.0, 125.3,
127.5, 129.5, 134.6, 137.2, 141.7, 151.7, 153.4, 159.7; HRMS
calcd for C15H19NO2 245.1416, found 245.1411.
(4S)-4-Isop r op yl-3-[(E)-2-(8-m et h yl-3,4-d ih yd r on a p h -
th a len -1(2H)-ylid en e)eth a n oyl]-1,3-oxa zolid in -2-on e (26).
Following the general procedure (using 30 mol % of tri-2-
furylphosphine instead of 20 mol %) on a 0.157 mmol scale
using 20 and 7, 26 was isolated as a colorless oil (46.6 mg,
95%) by flash chromatography using Et2O/hexane (1:2) as
eluant. IR (neat) ν ) 1139, 1269, 1383, 1463, 1592, 1672, 1771,
1
2870, 2954 cm-1; H NMR δ 0.93 (m, 4H), 1.78 (m, 2H), 2.45
(m, 1H), 2.54 (s, 3H), 2.63 (m, 2H), 3.16 (m, 2H), 4.25 (m, 2H),
4.54 (m, 1H), 6.98 (m, 1H), 7.13 (m, 2H), 7.35 (t, 1H, J ) 2.1
Hz); 13C NMR δ 14.7, 18.0, 21.7, 21.9, 28.5, 29.8, 30.4, 58.5,
63.0, 117.1, 125.2, 128.2, 129.8, 135.7, 136.4, 142.1, 153.9,
157.3, 164.9; HRMS calcd for C19H23NO3 313.1678, found
313.1672.
(8-Me t h y l-3,4-d ih y d r o n a p h t h a le n -1(2H )-y lid e n e )-
eth a n en itr ile (27). Following the general procedure on a
0.157 mmol scale using 21 and 7, 27 was isolated as a mixture
of isomers that were separable by flash chromatography using
Et2O/hexane (1:2) as eluant. The E-isomer was isolated as a
colorless oil (6.2 mg, 22%) and the Z-isomer as a colorless oil
(12.1 mg, 42%). E-isomer; IR (neat) ν ) 1465, 1602, 2211, 2932
cm-1;1H NMR δ 1.90 (m, 2H), 2.45 (s, 3H), 2.74 (t, 2H, J ) 6.4
Hz), 2.89 (dt, 2H, J ) 7.2, 1.6 Hz), 5.43 (s br, 1H), 7.02 (d, 1H,
J ) 7.6 Hz), 7.11 (d, 1H, J ) 7.6 Hz), 7.18 (d, 1H, J ) 7.6 Hz);
13C NMR δ 21.8, 22.0, 30.1, 31.4, 96.6, 117.4, 126.1, 129.0,
E t h yl (E)-2-(8-Met h yl-3,4-d ih yd r on a p h t h a len -1(2H )-
ylid en e)p r op a n oa te (66). Following the same procedure on
129.8, 133.6, 135.1, 140.7, 159.7; HRMS calcd for C15H13
N

8134 J . Org. Chem., Vol. 66, No. 24, 2001
Lautens et al.
a 0.157 mmol scale using 68 and 7, 66 was isolated as the
only product as a colorless liquid (24.6 mg, 64%) by flash
chromatography using hexane/toluene (1:1) as eluant.
tion Bettencourt-Schueller, and M.D. the Deutsche
Forschungsgemeinschaft for postdoctoral fellowships.
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails for selected aryl iodides and difunctional acceptors as well
as characterization information for new compounds prepared.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Ack n ow led gm en t. We gratefully acknowledge the
financial support of the Natural Sciences and Engineer-
ing Research Council (NSERC) of Canada, the Ontario
Research and Development Challenge Fund (ORDCF),
and the University of Toronto. J .-F.P. acknowledges
NSERC for a PGS scholarship. S.P. thanks the Fonda-
J O0107296