Synthesis of tricyclic heterocycles via a tandem aryl alkylation/Heck coupling sequence

Article abstract of DOI:10.1021/jo0617868

(Chemical Equation Presented) A norbornene-mediated palladium-catalyzed sequence is described in which two alkyl-aryl bonds and one alkenyl-aryl bond are formed in one pot with use of microwave irradiation. A variety of symmetrical and unsymmetrical oxygen-, nitrogen-, silicon-, and sulfur-containing tricyclic heterocycles were synthesized from a Heck acceptor and an aryl iodide containing two tethered alkyl halides. This approach was further applied to the synthesis of a tricyclic mescaline analogue.

Full text of DOI:10.1021/jo0617868

Synthesis of Tricyclic Heterocycles via a Tandem Aryl
Alkylation/Heck Coupling Sequence
Dino Alberico,† Alena Rudolph, and Mark Lautens*
DaVenport Research Laboratories, Department of Chemistry, UniVersity of Toronto,
80 St. George Street, Toronto, Ontario, M5S 3H6, Canada
mlautens@chem.utoronto.ca
ReceiVed August 30, 2006
A norbornene-mediated palladium-catalyzed sequence is described in which two alkyl-aryl bonds and
one alkenyl-aryl bond are formed in one pot with use of microwave irradiation. A variety of symmetrical
and unsymmetrical oxygen-, nitrogen-, silicon-, and sulfur-containing tricyclic heterocycles were
synthesized from a Heck acceptor and an aryl iodide containing two tethered alkyl halides. This approach
was further applied to the synthesis of a tricyclic mescaline analogue.
Introduction
developing annulation and cyclization reactions3 based on a
process first reported by Catellani4 involving a palladium-
catalyzed norbornene-mediated tandem process, wherein the
alkylation of an ortho C-H bond is followed by a Heck reaction
at the ipso carbon of the aryl iodide. This process relies on the
high reactivity of norbornene to mediate the relative rates of
several competing processes. Using this method, we were able
to generate a number of highly functionalized bi- and tricyclic
carbocycles and oxygen-containing heterocycles (Figure 1).3
Herein, we describe an extension of these studies whereby
tricyclic oxygen-, nitrogen-, silicon-, and sulfur-containing
The formation of multiple carbon-carbon bonds in a tandem
process is a powerful method for generating complex molecules
from simple substrates.1 Unlike stepwise carbon-carbon bond
formation, tandem processes allow for rapid access of target
molecules in fewer steps and with reduced waste. Those
involving carbon-carbon bond formation via the direct func-
tionalization of aromatic C-H bonds2 have an added advantage,
as they avoid the need for activating groups. We have been
* Author to whom correspondence should be addressed.
† Current address: De´partement de Chimie, Universite´ de Montre´al, P.O. Box
6128, Station Downtown, Montre´al (Que´bec), Canada, H3C 3J7.
(3) (a) Lautens, M.; Piguel, S. Angew. Chem., Int. Ed. 2000, 39, 1045.
(b) Lautens, M.; Paquin, J.-F.; Piguel, S.; Dahlmann, M. J. Org. Chem.
2001, 66, 8127. (c) Lautens, M.; Paquin, J.-F.; Piguel, S. J. Org. Chem.
2002, 67, 3972. (d) Pache, S.; Lautens, M. Org. Lett. 2003, 5, 4827. (e)
Alberico, D.; Paquin, J.-F.; Lautens, M. Tetrahedron 2005, 61, 6283. (f)
Martins, A.; Marquardt, U.; Kasravi, N.; Alberico, D.; Lautens, M. J. Org.
Chem. 2006, 71, 4937. (g) Jafarpour, F.; Lautens, M. Org. Lett. 2006, 8,
3601. (h) Alberico, D.; Lautens, M. Synlett 2006, 2969.
(4) (a) Catellani, M.; Frignani, F.; Rangoni, A. Angew. Chem., Int. Ed.
Engl. 1997, 36, 119. (b) Catellani, M.; Mealli, C.; Motti, E.; Paoli, P.; Perez-
Carreno, E.; Pregosin, P. S. J. Am. Chem. Soc. 2002, 124, 4336. (c) Catellani,
M. In Handbook of Organopalladium Chemistry for Organic Synthesis;
Negishi, E. I., de Meijere, A., Eds.; John Wiley & Sons: Hoboken, NJ,
2002; pp 1479-1489. (d) Catellani, M. Synlett 2003, 298. (e) Tsuji, J.
Palladium Reagents and Catalysis-New PerspectiVes for the 21st Century;
John Wiley & Sons: New York, 2004; pp 409-416. (f) Catellani, M. Top.
Organomet. Chem. 2005, 14, 21.
(1) (a) Tietze, L. F. Chem. ReV. 1996, 96, 115. (b) Denmark, S. E.;
Thorarensen, A. Chem. ReV. 1996, 96, 137. (c) Poli, G.; Giambastiani, G.;
Heumann, A. Tetrahedron 2000, 56, 5959. (d) Tietze, L. F.; Rackelmann,
N. Pure Appl. Chem. 2004, 76, 1967. (e) Wasilke, J.-C.; Obrey, S. J.; Baker,
R. T.; Bazan, G. C. Chem. ReV. 2005, 105, 1001. (f) Pellissier, H.
Tetrahedron 2006, 62, 1619. (g) Pellissier, H. Tetrahedron 2006, 62, 2143.
(h) Tietze, L. F.; Brasche, G.; Gericke, K. Domino Reactions in Organic
Synthesis; Wiley-VCH: Weinheim, Germany, 2006.
(2) (a) Kakiuchi, F.; Murai, S. Top. Organomet. Chem. 1999, 3, 47. (b)
Guari, Y.; Sabo-Etienne, S.; Chaudret, B. Eur. J. Inorg. Chem. 1999, 1047.
(c) Dyker, G. Angew. Chem., Int. Ed. 1999, 38, 1699. (d) Jia, C.; Kitamura,
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9, 685. (i) Miura, M.; Satoh, T. Top. Organomet. Chem. 2005, 14, 55.
10.1021/jo0617868 CCC: $37.00 © 2007 American Chemical Society
Published on Web 12/29/2006
J. Org. Chem. 2007, 72, 775-781
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Alberico et al.
FIGURE 1. Bi- and tricyclic carbocyclic and oxygen-containing heterocyclic scaffolds.
SCHEME 1. Norbornene-Mediated Palladium-Catalyzed Synthesis of Tricyclic Heterocycles
heterocycles are generated in a tandem process involving two
intramolecular ortho alkylations of aromatic C-H bonds
followed by an intermolecular Heck reaction (Scheme 1).5
Tricyclic compounds of this type are found in natural products
exhibiting notable biological and pharmaceutical properties.6
Tricyclic analogue 2 and other rotationally restricted analogues
of mescaline 1 (Figure 2) are of particular interest since they
may be valuable in SAR studies of hallucinogenic agents.6 To
demonstrate the synthetic potential of our methodology, we
report a synthesis of 2, first synthesized by Nichols,6a and later
by Bergman and Ellman.7 The disconnections for a synthesis
of 2 utilizing the new methodology are illustrated in Figure 3.
The key step is the bis-alkylation/Heck reaction sequence
involving aryl iodide 3 and a Heck acceptor. This step would
introduce two rings and form three new C-C bonds in one pot.
the synthesis of 5,6,5-ring systems containing phenolic oxygens
(Table 1) from various Heck acceptors using iodoarene 5
(1 equiv), Pd(OAc)2 (10 mol %), triphenylphosphine (22 mol
%), Cs2CO3 (5 equiv), norbornene (3 equiv),8 and Heck acceptor
(5 equiv) in degassed dimethoxyethane (0.05 M) under micro-
wave irradiation9 for 5 min at 190 °C (Table 1). While the use
of unsubstituted acrylates afforded the corresponding products
in good yields (entries 1-3), tert-butyl methacrylate gave a
modest yield of 9 as a 1:1 mixture of internal (9a) and terminal
(9b) alkenes (entry 4). N-tert-Butyl acrylamide gave only a
modest yield (entry 5), while acrylonitrile gave 11 in 71% yield
(entry 6). Product 11 was observed to be light-sensitive,
undergoing partial isomerization to the cis-alkene upon standing
in solution. When phenyl vinyl sulfone and phenyl vinyl
sulfoxide were reacted with 5, low yields of the desired tricyclic
products were obtained (entries 7 and 8). Vinyl pyridine Heck
acceptors were also compatible under the reaction conditions
(entries 9 and 10), giving modest yields of the tricyclic products.
We also investigated the feasibility of employing a mixed
acetal with this methodology since it allows for further
functionalization of the product. Acetal 16 is available in one
step from the corresponding bisphenol via an alkoxy-bromina-
tion with tert-butyl vinyl ether in the presence of N-bromosuc-
cinimide.10 Subjecting 16 to the standard reaction conditions
with tert-butyl acrylate afforded the desired product 17 in 52%
yield as a 1:1 mixture of diastereomers (Scheme 2).
FIGURE 2. Mescaline and tricyclic mescaline analogue.
(6) (a) Monte, A. P.; Waldman, S. R.; Marona-Lewicka, D.; Wainscott,
D. B.; Nelson, D. L.; Sanders-Bush, E.; Nichols, D. E. J. Med. Chem. 1997,
40, 2997. (b) Huang, K.-S.; Lin, M.; Yu, L.-N.; Kong, M. Tetrahedron
2000, 56, 1321. (c) Chambers, J. J.; Kurrasch-Orbaugh, D. M.; Nichols,
D. E. Bioorg. Med. Chem. Lett. 2002, 12, 1997.
FIGURE 3. Retrosynthesis of mescaline analogue 2.
(7) (a) Ahrendt, K. A. A.; Bergman, R. G.; Ellman, J. A. Org. Lett. 2003,
5, 1301. (b) Thalji, R. K.; Ahrendt, K. A. A.; Bergman, R. G.; Ellman,
J. A. J. Org. Chem. 2005, 70, 6775.
Results and Discussion
Synthesis of Annulated Phenyl Ethers. Starting materials
for the synthesis of annulated phenyl ethers were prepared by
converting commercially available 5-bromo-1,3-dimethoxyben-
zene to the iodide via lithium-halogen exchange and quenching
with iodine. Demethylation with aqueous HI, followed by
alkylation of the bisphenol with the corresponding dibromo-
alkane furnished the desired aryl iodides. We initially explored
(8) While norbornene is theoretically only required in a catalytic amount,
an excess is used to suppress the competing Heck reaction. This excess,
however, often results in the formation of various norbornane-containing
aromatic compounds. For examples see ref 4d and the following: Motti,
E.; Ippomei, C. P.; Deledda, S.; Catellani, M. Synthesis 2003, 2671.
(9) (a) Lindstrom, P.; Tierney, J.; Wathey, B.; Westman, J. Tetrahedron
2001, 57, 9225. (b) Larhed, M.; Moberg, C.; Hallberg, A. Acc. Chem. Res.
2002, 35, 717. (c) Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43, 6250.
(d) Hayes, B. L. Aldrichim. Acta 2004, 37, 66.
(10) Ueno, Y.; Moriya, O.; Chino, K.; Wantanabe, M.; Okawara, M.
J. Chem. Soc., Perkin Trans. I 1986, 1351.
(5) For a preliminary communication, see ref 3h.
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Synthesis of Tricyclic Heterocycles
TABLE 1. Formation of Phenyl Ether 5,6,5-Ring Systems
SCHEME 2. Formation of a 5,6,5-Mixed Acetal Ring System
The successful preparation of compounds containing a 5,6,5-
ring system prompted us to determine the efficiency with other
ring sizes. Reaction of 18 with tert-butyl acrylate (Table 2, entry
1) resulted in a good yield of an unsymmetrical tricycle having
a 5,6,6-ring system. Products with 6,6,6-ring systems (entries
2 and 3) and 7,6,7-ring systems (entry 4) were also isolated in
good yields. Under the optimized reaction conditions, longer
heating times were required as the ring size being formed
increased.
Synthesis of Annulated Benzyl Ethers. Having successfully
generated products with phenolic oxygens, we next investigated
the effect of having oxygen at other positions within the
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Alberico et al.
TABLE 2. Formation of Phenyl Ether 5,6,6-, 6,6,6-, and 7,6,7-Ring
Systems
TABLE 4. Formation of Phenyl Thioether-Containing 5,6,5-Ring
Systems
a Reaction run for 20 min.
a Reaction run for 5 min. b Reaction run with 20 mol % of Pd(OAc)2.
TABLE 3. Formation of Benzyl Ether 6,6,6-Ring Systems
replaced with a sulfur atom (Table 4). Starting with tert-butyl
acrylate as the Heck acceptor, 30 was isolated in 27% yield
under the optimized conditions (entry 1). Extending the reaction
time to 10 min increased the yield to 43% (entry 2), while
decreasing the reaction temperature to 160 °C for 10 min showed
no improvement. In addition, increasing the catalyst loading to
20 mol % gave a modest increase in yield (entry 3). Various
other ligands were examined including tris(p-fluorophenyl)-
phosphine, tris(p-trifluoromethylphenyl)phosphine, tris(p-meth-
oxyphenyl)phosphine, and tri-n-butylphosphine; however, triph-
enylphosphine proved to be the best. We also conducted an
analogous alkylation/alkenylation reaction in a sealed tube with
heating in an oil bath at 190 °C for 10 min, and a comparable
yield of 43% for 30 was obtained. Under our previously reported
conditions,3d which employed conventional heating at 80 °C
for 16 h, the reaction of 29 with tert-butyl acrylate only gave
trace amounts of 30. Finally, reactions with N,N-dimethylacry-
lamide (entry 4) and acrylonitrile (entry 5) also afforded the
desired products, albeit in lower yields.
a With 3 equiv of norbornene.
bromoalkyl tether. For example, substrate 25 was prepared with
oxygen at the benzylic positions and subjected to the optimized
reaction conditions with tert-butyl acrylate as the Heck acceptor
(Table 3). The 6,6,6-ring product 26 was obtained in 45% yield
(entry 1). Extending the reaction time did not have an effect on
the isolated yield; however, increasing the amount of norbornene
to 5 equiv improved the yield of 26 to 65% (entry 2). While
tert-butyl acrylate and N,N-dimethylacrylamide afforded the
corresponding products in moderate yields (entries 2 and 3),
acrylonitrile (entry 4) gave a reduced yield of annulated product.
As observed in our previous studies, the decreased reactivity
of the benzyl ether analogues compared to the phenol ethers
might be explained by a complexation between the oxygen atom
and the palladium center, which inhibits subsequent steps in
the catalytic cycle.3b
Synthesis of an Annulated Silaoxacycle. We envisioned
adding a silyl group to the alkyl halide tether, as in 33, which
would allow for the formation of a benzylic silane as part of
the newly formed fused six-membered ring (Scheme 3). Under
our standard conditions, 33 resulted in the desired product 34
in 47% yield. However, when the reaction temperature was
lowered to 160 °C for 5 min, the yield improved to 60%. The
preparation of tricycle 34 represents the first example in
norbornene-mediated ortho-alkylation chemistry that utilizes a
primary alkyl halide containing a heteroatom in the R-position.
Previous attempts at incorporating other heteroatoms, such as
oxygen and nitrogen, at the R-position to the alkyl halide have
failed. Since silyl groups can be selectively manipulated in a
variety of ways,11 incorporation of the SiMe2 moiety offers a
route to products that have not otherwise been accessible by
this methodology. For example, protodesilation would give
Synthesis of Annuated Phenyl Thioethers. We next pre-
pared a series of compounds wherein the phenolic oxygen was
778 J. Org. Chem., Vol. 72, No. 3, 2007

Synthesis of Tricyclic Heterocycles
SCHEME 3. Formation of a Silyl-Containing 6,6,6-Ring System
SCHEME 4. Formation of a Nitrogen-Containing 5,6,5-Ring System
SCHEME 5. Proposed Mechanism
SCHEME 7. Initial Proposed Route toward 2
Synthesis of a Bisindoline. We also tested the feasibility of
using a substrate containing a tosyl protected nitrogen in the
tether (Scheme 4). With use of the optimized reaction conditions
employed in the synthesis of annulated phenyl ethers, 36 was
isolated in 17% yield from 35. When the reaction temperature
was decreased to 160 °C and the amount of norbornene was
increased to 5 equiv, the yield improved to 39%. It should be
noted that unlike other annulated products containing an acrylate,
36 readily isomerizes completely to the cis-alkene in solution
when exposed to light.
Mechanism. The proposed mechanism (Scheme 5) for these
reactions is based upon the findings of Catellani4 and begins
with the oxidative addition of Pd(0) to 5, forming arylpalladium
iodide 37. Syn insertion of norbornene into 37 affords the
cis,exo-complex 38. Due to the rigidity of the alkene, and the
absence of a syn â-hydrogen, 38 forms palladacycle 39 rather
than undergo a disfavored anti â-hydride elimination. Intermedi-
ate 39 then undergoes oxidative addition with the tethered
alkylbromide forming Pd(IV) complex 40. Reductive elimination
of 40 results in the formation of the C(sp3)-C(sp2) bond and
generates the first ring in 41. The same sequence of steps,
namely the oxidative addition of the alkyl halide followed by
reductive elimination, is repeated generating the second ring in
42. Finally, extrusion of norbornene generates 43, which then
undergoes an intermolecular Heck coupling to afford 6.
SCHEME 6. Preparation of Mescaline Analogue
Precursor 3
Application to the Synthesis of a Tricyclic Mescaline
Analogue. We applied the bisannulation methodology to the
synthesis of tricyclic mescaline analogue 2. To access bisphenol
precursor 4, we began by methylation of commercially available
2,4,6-triiodophenol 44 to give 45 in 98% yield (Scheme 6).
Subjecting 45 to regioselective lithium-halogen exchange,
followed by addition of trimethyl borate and oxidation with
products arising from the use of methyl iodide as the alkylation
agent, a reaction that fails under all conditions that we have
tried.
(11) Brook, M. A. Silicon in Organic, Organometallic and Polymer
Chemistry; John Wiley and Sons, Inc.: Toronto, Canada, 2000; Chap-
ter 16.
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Alberico et al.
SCHEME 8. Alkylation/Alkenylation Approach Employing tert-Butyl Acrylate
SCHEME 9. Alternate Approach Employing Benzyl
Acrylate in the Alkylation/Alkenylation Reaction
The second approach used benzyl acrylate as the Heck
acceptor, and resulted in the desired tricyclic product 50 in 73%
yield (Scheme 9). The one-pot olefin reduction/benzyl cleavage16
to afford 49 was achieved in 79% yield via hydrogenation with
Pt/C. The use of Pd/C as the catalyst for this hydrogenation
resulted in olefin reduction without benzyl cleavage whereas
the use of Pd(OH)2/C resulted in recovered starting material.
Although this route required fewer steps, the tert-butyl acrylate
approach is more attractive with regard to yield as it gives a
69% yield over three steps, rather than 58% over two steps.
Final conversion to the mescaline analogue was readily
achieved via a Curtius rearrangement17 of 49 to give 51,
followed by hydrogenolysis and salt formation with HCl (1 M
in ether) to afford 2‚HCl in a combined yield of 62% over the
two steps (Scheme 10). Our most efficient route toward
mescaline analogue 2‚HCl was achieved in 8 steps with an
overall yield of 27%.
SCHEME 10. Completion of Mescaline Analogue Synthesis
peracetic acid (32 wt % in acetic acid) afforded 4 in 77% yield.12
Alkylation of 4 with 1,2-dibromoethane (15 equiv) provided
bisannulation precursor 3 in 84% yield.
Conclusions
We have developed a route to tricyclic heterocycles using a
palladium-catalyzed norbornene-mediated tandem process in-
volving two intramolecular ortho alkylations of aromatic C-H
bonds followed by an intermolecular Heck reaction. The reaction
tolerates alkyl halide tethers of various lengths containing
oxygen, sulfur, nitrogen, or silicon moieties. A number of
functionalized, mono- or disubstituted alkenes are compatible
as Heck acceptors and the products are rapidly accessed within
minutes with use of microwave irradiation. Furthermore, the
synthetic utility of this reaction was demonstrated by the
synthesis of tricyclic mescaline analogue 2.
The next step was to form the tricyclic core of 2 by using
the alkylation/alkenylation sequence. We envisaged the final
coupling using a vinyl nitrogen compound as the Heck acceptor
to give 46, which places the nitrogen atom in the desired position
(Scheme 7). Initial attempts with nitroethylene13 did not produce
the desired product and afforded a messy reaction mixture.
When N-vinylacetamide or N-vinylphthalimide were used,
starting material was recovered, which is surprising since the
Heck reaction of N-vinylphthalimide has been previously
reported.14
The next approach involved a Heck reaction with an acrylate,
followed by functional group interconversions to introduce the
amine moiety. Two pathways were examined. We first examined
the alkylation/alkenylation reaction of 3 with tert-butyl acrylate,
which afforded the desired product 47 in 81% yield (Scheme
8). Having successfully assembled the tricyclic core, we next
reduced the alkenyl double bond by catalytic hydrogenation to
afford the aryl propionate 48 in 98% yield. Hydrolysis of 48
with trifluoroacetic acid15 gave the desired carboxylic acid 49
in 87% yield.
Experimental Section
The following is a representative experimental procedure toward
the synthesis of products 6-15, 17, 19, 21, 22, 24, 26-28, 30-
32, 34, 36, 47, and 50. Specific experimental details and charac-
terization data for the aforementioned compounds and other new
compounds can be found in the Supporting Information.
General Procedure for the Alkylation/Alkenylation Reaction.
To a microwave reaction vessel were added Cs2CO3 (1.00 mmol,
5 equiv), norbornene (0.600 mmol, 3 equiv), Pd(OAc)2 (10 mol
%), triphenylphosphine (22 mol %), aryl iodide (0.200 mmol, 1
equiv), and the Heck acceptor (1.00 mmol, 5 equiv). The vessel
was sealed and flushed with N2. Through the septa was added
degassed dry DME (4 mL). The reaction vessel was subjected to
microwave irradiation at 190 °C for 5 min. The mixture was diluted
with ether (4 mL) and quenched with water (4 mL). The aqueous
layer was extracted with ether (3×) and the combined organic layers
were washed with brine, dried with anhydrous MgSO4, and filtered.
Removal of the solvent gave a crude product that was purified by
flash chromatography.
(12) Green, K. J. Org. Chem. 1991, 56, 4325.
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A. K.; Iyengar, R. J. Org. Chem. 1980, 45, 1185. (b) Zimmerman, H. E.;
Wang, P. J. Org. Chem. 2002, 67, 9216.
(14) (a) Ziegler, C. B., Jr.; Heck, R. F. J. Org. Chem. 1978, 43, 2949.
(b) Hutchison, A. J.; Williams, M.; de Jesus, R.; Yokoyama, R.; Oei,
H. H.; Ghai, G. R.; Webb, R. L.; Zoganas, H. C.; Stone, G. A.; Jarvis,
M. F. J. Med. Chem. 1990, 33, 1919. (c) Furstner, A.; Mamane, V. Chem.
Commun. 2003, 2112.
(15) Chen, Z.; Fan, J.; Kende, A. S. J. Org. Chem. 2004, 69, 79.
(16) (a) Harris, J. M.; Watkins, W. J.; Hawkins, A. R.; Coggins, J. R.;
Abell, C. J. Chem. Soc., Perkin Trans. 1 1996, 2371. (b) Ding, P.; Miller,
M. J.; Chen, Y.; Helquist, P.; Oliver, A. J.; Wiest, O. Org. Lett. 2004, 3,
1805.
(17) Go´mez-Sa´nchez, E.; Marco-Contelles, J. Tetrahedron 2005, 61,
1207.
Acknowledgment. We gratefully acknowledge the financial
support of the Natural Sciences and Engineering Research
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Synthesis of Tricyclic Heterocycles
Supporting Information Available: Experimental details and
characterization data for compounds 2-5, 16, 18, 20, 23, 25, 29,
33, 35, 45-51, and their precursors. This material is available free
of charge via the Internet at http://pubs.acs.org.
Council (NSERC) of Canada, the Merck Frosst Centre for
Therapeutic Research for an Industrial Research Chair, and the
University of Toronto. We thank Olga Lifchits for preliminary
investigations in the preparation of starting materials. A.R.
thanks NSERC for financial support in the form of a Postgradu-
ate Scholarship.
JO0617868
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