A palladium-catalyzed approach to polycyclic sulfur heterocycles

Article abstract of DOI:10.1021/jo8020105

(Chemical Equation Presented) The synthesis of a variety of polycyclic thiophenes and benzothiophenes is accomplished via a palladium-catalyzed domino ortho-alkylation/direct arylation reaction. An examination of the intramolecular direct arylation of thi

Full text of DOI:10.1021/jo8020105

A Palladium-Catalyzed Approach to Polycyclic Sulfur Heterocycles
Andrew Martins and Mark Lautens*
DaVenport Research Laboratories, Department of Chemistry, UniVersity of Toronto,
80 St. George Street, Toronto, Ontario, Canada M5S 3H6
mlautens@chem.utoronto.ca
ReceiVed September 15, 2008
The synthesis of a variety of polycyclic thiophenes and benzothiophenes is accomplished via a palladium-
catalyzed domino ortho-alkylation/direct arylation reaction. An examination of the intramolecular direct
arylation of thiophenes suggests that an electrophilic metalation mechanism may be present. This method
was further extended to include the synthesis of a (thieno)benzoxepine.
Introduction
generate polycyclic thiophenes from aryl iodides and 3-(bro-
moalkyl)thiophenes (Scheme 1).7
Polycyclic thiophene-based heterocycles are key intermediates
and relevant targets in the fields of synthetic, medicinal, and
materials chemistry. Recently, numerous thiophenes and ben-
zothiophenes have emerged as classes of molecules with
synthetic utility1 and a wide array of biological activities.2 As
such, an efficient and expedient method to synthesize a wide
variety of this class of molecules would be highly desirable.
Although numerous methods have been devised to generate
these heterocycles, there are seldom, if any general, catalytic
methods for their synthesis. With this in mind, we endeavored
to extend the ortho-alkylation/C-C coupling methodology
developed in our laboratories3 to the synthesis of annulated
polycyclic thiophene-based heterocycles. By combining the
strategies of palladium-catalyzed aromatic ortho-alkylation
derived from the Catellani reaction4 with the direct arylation5
of thiophene-based heterocycles,6 we foresaw a method to
Results and Discussion
Thiophene-Based Heterocycles. In order to enable expedient
access to polycyclic thiophenes, the bromoalkylthiophene
component must be accessible through simple, straightforward
chemistry (Scheme 2). From commercially available 3-formylth-
iophene, 3-(3-bromopropyl)thiophene 2a is easily accessed
through a Wittig/reduction/hydrogenation/bromination reaction
sequence. Alternatively, (2E)-3-(3-thienyl)acrylic acid can be
used as a precursor to 2a to avoid the Wittig olefination step,
although this route is much less cost-effective. To access 2b,
commercially available 2-(3-thienyl)ethanol is converted to the
alkyl bromide with PBr3. The aforementioned methods worked
(4) (a) Catellani, M.; Frignani, F.; Rangoni, A. Angew. Chem., Int. Ed. Engl.
1997, 36, 119–122. (b) Catellani, M.; Mealli, C.; Motti, E.; Paoli, P.; Perez-
Carreno, E.; Pregosin, P. S. J. Am. Chem. Soc. 2002, 124, 4336–4346. (c)
Catellani, M. Synlett 2003, 298–313.
(5) Selected reviews: (a) Alberico, D.; Scott, M. E.; Lautens, M. Chem. ReV.
2007, 107, 174–238. (b) Campeau, L.-C.; Fagnou, K. Chem. Commun. 2006,
1253–1264. (c) Miura, M.; Satoh, T. Top. Organomet. Chem. 2005, 14, 55–83.
(d) Wolfe, J. P.; Thomas, J. S. Curr. Org. Chem. 2005, 9, 625–655. (e) Ritleng,
V.; Sirlin, C.; Pfeffer, M. Chem. ReV. 2002, 102, 1731–1769. (f) Kakiuchi, F.;
Murai, S. Acc. Chem. Res. 2002, 35, 826–834. (g) Hassan, J.; Se´vignon, M.;
Gozzi, C.; Schulz, E.; Lemaire, M. Chem. ReV. 2002, 102, 1359–1469. (h) Miura,
M.; Nomura, M. Top. Curr. Chem. 2002, 219, 211–241. (i) Dyker, G. Angew.
Chem., Int. Ed. 1999, 38, 1698–1712.
(6) Selected examples: (a) Ohta, A.; Akita, Y.; Ohkuwa, T.; Chiba, M.;
Fukunaga, R.; Miyafuji, A.; Nakata, T.; Tani, N.; Aoyagi, Y. Heterocycles 1990,
31, 1951–1958. (b) Gozzi, C.; Lavenot, L.; Ilg, K.; Penalva, V.; Lemaire, M.
Tetrahedron Lett. 1997, 38, 8867–8870. (c) Pivsa-Art, S.; Satoh, T.; Kawamura,
Y.; Miura, M.; Nomura, M. Bull. Chem. Soc. Jpn. 1998, 71, 467–473. (d)
McClure, M. S.; Glover, B.; McSorley, E.; Millar, A.; Osterhout, M. H.;
Roschangar, F. Org. Lett. 2001, 3, 1677–1680. (e) Glover, B.; Harvey, K. A.;
Liu, B.; Sharp, M. J.; Tymoschenko, M. F. Org. Lett. 2003, 5, 301–304.
(7) Martins, A.; Alberico, D.; Lautens, M. Org. Lett. 2006, 8, 4827–4829.
(1) Carpino recently reported a polycyclic thiophene as an easily cleaved
protecting group for amino acids; see: Carpino, L. A.; Abdel-Maksoud, A. A.;
Ionescu, D.; Mansour, E. M. E.; Zewail, M. A. J. Org. Chem. 2007, 72, 1729–
1736.
(2) As retinoic acid receptor antagonists for the treatment of leukemia and
related carcinoma, see: (a) Yoshimura, H.; Nagai, M.; Hibi, S.; Kikuchi, K.;
Abe, S.; Hida, T.; Higashi, S.; Hishinuma, I.; Yamanaka, T. J. Med. Chem. 1995,
38, 3163–3173. As PTP 1B modulators for antiobesity/antidiabetic treatments
see: (b) Lee, J. et al. US2006135488. As DNA Topoisomerase II inhibitors in
multidrug-resistant cells, see: (c) Zhu, H.; et al. Mol. Cancer Therapeut. 2007,
6, 484–495. As an intercalating agent and displaying cytotoxicity toward human
lung carcinoma cells, see: (d) Xu, Y.; Qu, B.; Qian, X.; Li, Y. Bioorg. Med.
Chem. Lett. 2005, 15, 1139–1142.
(3) Selected examples: (a) Bressy, C.; Alberico, D.; Lautens, M. J. Am. Chem.
Soc. 2005, 127, 13148–13149. (b) Blaszykowski, C.; Aktoudianakis, V.; Bressy,
C.; Alberico, D.; Lautens, M. Org. Lett. 2006, 8, 2043–2045. (c) Jafarpour, F.;
Lautens, M. Org. Lett. 2006, 8, 3601–3604. (d) Blaszykowski, C.; Aktoudianakis,
E.; Alberico, D.; Bressy, C.; Hulcoop, D. G.; Jafarpour, F.; Joushaghani, A.;
Laleu, B.; Lautens, M. J. Org. Chem. 2008, 73, 1888–1897.
10.1021/jo8020105 CCC: $40.75
Published on Web 10/18/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 8705–8710 8705

Martins and Lautens
SCHEME 1. Our Approach toward Polycyclic Sulfur Heterocycles
SCHEME 2. Synthesis of 3-(Bromoalkyl)thiophenesa
partner (Scheme 3). Although we screened a variety of condi-
tions for this reaction, we were not able to obtain the annulated
product, but instead only observed 4, the product of ortho-
alkylation followed by arylpalladium(II) reduction.10
SCHEME 3. Attempt To Form a Five-Membered Ring
Product
a Key: (a) Ph3PdCHCO2Me (1.5 equiv), CH2Cl2, 84%; (b) LiAIH4 (2
equiv), THF; (c) H2, Pd/C, EtOH, 64% (two steps); (d) PPh3 (1.1 equiv),
Br2 (1.1 equiv), CH2Cl2, 82%; (e) PBr3 (1 equiv), benzene, 45%.
quite well on large scale, enabling access to gram-scale
quantities of 2a and 2b.
With compounds 2a and 2b readily available, we sought to
develop reaction conditions for the domino palladium-catalyzed
ortho-alkylation/direct arylation sequence. Through the screen-
ing of reaction parameters such as palladium source, phosphines,
solvents, bases, and concentration of each reagent, we arrived
at the optimized reaction conditions shown in Table 1. From
these optimized conditions, we were able to synthesize a variety
of polycyclic thiophenes with central seven- and six-membered
rings from aryl iodides which contained a pre-existing ortho
functional group. A variety of ortho functional groups were
tested under the reaction conditions; however, with only one
exception (vide infra), a methyl group was the only ortho
substitutent which could afford acceptable amounts of product.
In addition, the electronic character of the aryl iodide was
important to the success of the reaction, as only electron-
deficient aryl iodides afforded acceptable amounts of product
(Table 1, entries 1-14). When we tried to extend the scope to
electroneutral or electron-rich aryl iodides, little to no desired
product was formed. Although all aryl iodides containing solely
electron-donating substituents afforded no desired product, when
the aryl iodide contained both strongly electron-donating and
electron-withdrawing substituents such as 1l, the desired product
3o was obtained. This product was crystalline and confirmed
the structure of the products via X-ray crystallography.7,8 We
attempted to improve the yield with electroneutral aryl iodides
such as 2-iodotoluene (1m) by screening a wide variety of
conditions, including the use of additives such as silver salts to
promote the direct arylation reaction. However, after screening,
we were only able to isolate 3p in 22% optimized isolated yield
using microwave irradiation.
a See Table 1.
Our insight into the importance of the electronic character
of the aryl iodide to product formation prompted us to study
this effect on the direct arylation itself. While both electron-
rich and electron-deficient aryl iodides have been effectively
employed in numerous ortho-alkylation/coupling processes,3 we
proposed that the dramatic dependence of the isolated yield on
electronic character relates specifically to the direct arylation
step. In order to gain further insight, we synthesized several
molecules of varying electronic character with a thiophene
tethered to a pendant aryl iodide (Scheme 4, 5a-c). We
performed these experiments with two goals in mind: to gain
further insight into the mechanism of the direct arylation reaction
and to examine if our reaction conditions (i.e., the conditions
above including norbornene, in the presence of an alkyl halide)
enhance or hinder the terminal direct arylation reaction. Under
our optimized conditions in the absence of norbornene, 5a-c
were reacted to form the corresponding annulated products
6a-c. The conversion of nitro-substituted 5a to 6a occurred in
87% isolated yield, which is comparable to the yields obtained
using nitro substituted aryl iodides. When we tried electroneutral
compound 5b, the yield of 6b was an unexpectedly high 81%,
recalling that in the domino reaction, a maximum yield of 22%
was obtained with 2-iodotoluene. Furthermore, electron-deficient
thiophene-containing compound 5c only afforded product 6c
in 32% yield.
In terms of mechanistic insight into the intramolecular direct
arylation of thiophenes, we initially proposed an electrophilic
metalation mechanism7,11 based upon the good yields of product
with electron-deficient aryl iodides and lack of product with
electron-rich ones. Our data from Scheme 4 suggest that the
product yield is not directly proportional to the electron-richness
The success in synthesizing a variety of annulated six- and
seven-membered rings prompted us to explore the analogous
coupling to form five-membered rings. While benzylic bromides
often give messy reaction mixtures under our reaction condi-
tions, our recent success in the coupling of benzyl chlorides9
led us to try 3-(chloromethyl)thiophene (2c) as a coupling
(10) Wilhelm, T.; Lautens, M. Org. Lett. 2005, 7, 4053–4056.
(11) (a) Lane, B. S.; Brown, M. A.; Sames, D. J. Am. Chem. Soc. 2005,
127, 8050–8057. (b) Park, C.-H.; Ryabova, V.; Seregin, I. V.; Sromek, A. W.;
Gevorgyan, V. Org. Lett. 2004, 6, 1159–1162. (c) Li, W.; Nelson, D. P.; Jensen,
M. S.; Hoerner, R. S.; Javadi, G. J.; Cai, D.; Larsen, R. D. Org. Lett. 2003, 5,
4835–4837.
(8) The crystallographic information file (CIF) for this compound can also
be found on the Cambridge Crystallographic Data Centre database (data_request@
ccdc.cam.ac.uk) as CCDC 614852.
(9) Mariampillai, B.; Alliot, J.; Li, M.; Lautens, M. J. Am. Chem. Soc. 2007,
129, 15372–15379.
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Pd-Catalyzed ortho-Alkylation/Thiophene Direct Arylation
TABLE 1. Domino ortho-Alkylation/Direct Arylation of Thiophenesa
a µwave, 150 °C, 30 min.
of the aryl iodide. In addition, the electron-deficient thiophene
5c which would react poorly as a nucleophile (in an electrophilic
metalation reaction) but would react well via a Heck-type
mechanism6e (due to lowering of the LUMO energy by the
presence of an electron-withdrawing group) fared poorly,
suggesting an electrophilic mechanism. We were unable to
obtain conclusive rate data on the annulation reactions; however,
we can say that the conversion of 5a to 6a was complete within
4 h, the conversion of 5b to 6b was complete within 10 h, and
the conversion of 5c to 6c was complete within 18 h, suggesting
that an electrophilic mechanism is still a possibility for the direct
arylation reaction.
Our next goal was to determine whether the reaction
conditions of the domino reaction enhance or hinder the yield
of the direct arylation reaction. As the domino reaction is
performed in the presence of norbornene and excess 3-(bro-
moalkyl)thiophene, we decided to mimic the reaction conditions
after ortho-alkylation to observe the effect on the direct
arylation. As the presence of norbornene would initiate palla-
dacycle formation (which is not possible in the domino reaction
due to the presence of a pre-existing ortho substitutent) it was
omitted from the reaction. To approximate the additional 1 equiv
of 3-(bromoalkyl)thiophene, we chose 1-bromo-3-phenylpro-
pane, which does not undergo direct arylation reactions under
the reaction conditions. When this reagent was added to the
reactions converting 5a-c to 6a-c, the yield of 6a was
unchanged, 6b was dramatically reduced to 57%, and 6c was
not observed. These results suggest that the presence of alkyl
halides initiates an unproductive reaction pathway, which is
competitive with the direct arylation reaction for the slower-
reacting substrates 5b and 5c.
As the data obtained in Scheme 4 demonstrated that an
electron-deficient thiophene is a poor substrate for the reaction,
we supposed that an electron-rich thiophene would be a suitable
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Martins and Lautens
SCHEME 4. Intramolecular Direct Arylation of Thiophenes
SCHEME 7. Attempts To Cyclize onto the 3-Position of
Thiophene
SCHEME 8. Synthesis of 3-(Bromoalkyl)benzothiophenesa
a Key: (a) n-BuLi (1 equiv), Et2O, -78 °C, then DMF (1.5 equiv), 87%;
(b) Ph3PdCHCO2Me (1.5 equiv), CH2Cl2, 82%; (c) H2, Pd/C, EtOAc, 96%;
(d) LiAlH4 (2 equiv), THF, 83%; (e) PPH3 (1.1 equiv), Br2 (1.1 equiv),
CH2Cl2, 83%; (f) n-BuLi (1.1 equiv), Et2O, -78 °C, then ethylene oxide
(excess), 39%; (g) PPh3 (1.05 equiv), Br2 (1.05 equiv), CH2Cl2, 79%.
SCHEME 5. Possible Electrophilic Mechanism for Direct
Arylation
obtained in 66% yield. This result demonstrates the utility and
potential of the domino reaction to generate an interesting class
of heterocyclic compounds.
Our success in developing an efficient domino ortho-alkylation/
direct arylation at the 2-position of thiophene prompted us to
explore the analogous terminal coupling at the 3-position of
thiophene. While intramolecular cyclizations upon the 3-position
of thiophene have been reported,13 they typically employ the use
of Ag2CO3 to generate cationic palladium(II) species to promote
the cyclization. We synthesized 9a and 9b and subjected them to
the optimized reaction conditions and a variety of other conditions
(including variation of solvent, temperature, conventional versus
microwave heating, and using Ag2CO3 as base) in the presence of
1a (Scheme 7). We were only able to obtain traces of impure
product, with varying amounts of the ortho-alkylation/reduction
products 10a and 10b.
SCHEME 6. Access to (Thieno)benzoxepinea
Benzothiophene-Based Heterocycles. Our study of the ortho-
alkylation/direct arylation of thiophenes led us to also study
3-(bromoalkyl)benzothiophenes as bifunctional substrates. Both
3-(bromopropyl)benzothiophene 11a and 2-(bromoethyl)ben-
zothiophene 11b are accessible from commercially available
3-bromobenzothiophene (Scheme 8). The synthetic route toward
11a involves lithium-halogen exchange of 3-bromoben-
zothiophene, followed by formylation, Wittig olefination, hy-
drogenation, reduction, and bromination. Compound 11b is
accessible via lithium-halogen exchange followed by addition
to ethylene oxide and bromination. As with the synthetic routes
toward 2a and 2b, gram-scale quantities of these compounds
were accessible.
a Key: (a) glyoxaldehyde dimethyl acetal (2 equiv), CuI (10 mol %),
1,10-phenanthroline (20 mol %), Cs2CO3 (2 equiv), toluene, 110 °C,
88-91%; (b) HCl/acetone, then (c) NaBH4, MeOH, 24% (two steps); (d)
PPh3 (1.1 equiv), Br2 (1.05 equiv), CH2Cl2, 54%; (e) Pd(OAc)2 (10 mol
%), P(2-furyl)3 (20 mol %), norbornene (2 equiv), Cs2CO3 (2 equiv),
CH3CN, 95 °C, 66%.
substrate, prompting us to synthesize compound 7. This com-
pound was accessible via the CuI-catalyzed coupling of aryl
iodides with aliphatic alcohols developed by Buchwald12 and
subsequent synthetic transformations listed in Scheme 6. When
compound 7 was subjected to the optimized reaction conditions
in the presence of 1a, the (thieno)benzoxepine product 8 was
We explored the scope of the domino coupling reaction
of 11a and 11b with a variety of aryl iodides (Table 2). A
similar trend with respect to the electronic character of the
aryl iodide was observed in that only electron-deficient aryl
(13) (a) Joucla, L.; Putey, A.; Joseph, B. Tetrahedron Lett. 2005, 46, 8177–
8179. (b) Beccalli, E. M.; Broggini, G.; Martinelli, M.; Paladino, G.; Zoni, C.
Eur. J. Org. Chem. 2005, 2091–2096. (c) Putey, A.; Joucla, L.; Picot, L.; Besson,
T.; Joseph, B. Tetrahedron 2007, 63, 867–869.
(12) Wolter, M.; Nordmann, G.; Job, G. E.; Buchwald, S. L. Org. Lett. 2002,
4, 973–976.
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Pd-Catalyzed ortho-Alkylation/Thiophene Direct Arylation
TABLE 2. Domino ortho-Alkylation/Direct Arylation of Benzothiophenes
and H2O (3 mL) added. The mixture was then washed with Et2O
(3 × 5 mL), and the organic extracts were combined, dried with
Na2SO4, filtered, and concentrated in vacuo. The crude product was
then purified by column chromatography on silica gel to afford
product.
iodides afforded the desired products. In comparison to the
domino reaction with 3-(bromoalkyl)thiophenes, the analo-
gous coupling with 3-(bromoalkyl)benzothiophenes generally
required higher reaction temperatures and afforded lower
yields of product.
9-Fluoro-10-methyl-5,6-dihydro-4H-benzo[6,7]cyclohepta[1,2-b]-
thiophene (3i). Following the domino general procedure, 2-iodo-
6-fluorotoluene 1f (47.0 mg, 0.200 mmol) and 3-(3-bromopropyl)-
thiophene 2a (82.0 mg, 0.400 mmol) were reacted at 105 °C for
18 h. The crude mixture was purified by flash chromatography on
silica gel (Rf 0.68 in 2% Et2O/hexane) using 1% Et2O/hexane to
afford 3i as a clear colorless oil: yield 32 mg (69%). At 95 °C, the
yield was 52%: 1H NMR (300 MHz, CDCl3) δ 2.07-2.18 (m, 2H),
2.36 (t, 2H), 2.40 (d, J ) 2.6 Hz, 3H), 2.47 (br t, J ) 7.0 Hz, 2H),
6.92 (t, J ) 8.5 Hz, 1H), 6.96 (d, J ) 5.3 Hz, 1 H), 7.06 (dd, J )
8.2, 5.9 Hz, 1H), 7.33 (d, J ) 5.0 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ 13.1 (d, J ) 5.5 Hz), 25.4, 32.5, 34.4 (d, J ) 1.6 Hz),
113.9 (d, J ) 23.2 Hz), 123.2 (d, J ) 16.6 Hz), 124.9, 127.5 (d, J
) 8.8 Hz), 128.1, 134.3 (d, J ) 3.3 Hz), 136.2 (d, J ) 4.4 Hz),
136.9 (d, J ) 3.3 Hz), 141.6, 160.5 (d, J ) 241.6 Hz); 19F NMR
(376 MHz, CDCl3) δ -118.5; IR thin film, ν (cm-1) 818 (m), 1102
(m), 1241 (m), 1255 (m), 1382 (w), 1448 (m), 1473 (s), 1581 (m),
2856 (m), 2932 (s); HRMS (EI) calcd for C14H13FS 232.0722 (M+),
found 232.0726.
Conclusion
In summary, we have developed a route to a variety of
polycyclic sulfur heterocycles based upon a palladium-
catalyzed ortho-alkylation/direct arylation reaction sequence.
The method works well with electron-deficient aryl iodides,
allowing efficient domino annulation of six- and seven-
membered rings. An examination of the intramolecular direct
arylation of thiophenes lends support to an electrophilic
metalation mechanism.
Experimental Section
The following represents experimental procedures toward the
synthesis of products 3i and 12b. This includes experimental details
and characterization data for the aforementioned compounds. The
information for all other compounds can be found in the Supporting
Information.
General Procedure for the Domino Reaction. To a 2.5-5 mL
microwave reaction vial with a magnetic stir bar were added
sequentially Cs2CO3 (2 equiv, 0.400 mmol), Pd(OAc)2 (10 mol %,
0.020 mmol), P(2-furyl)3 (20 mol %, 0.040 mmol), and norbornene
(2 equiv, 0.400 mmol). In a separate vial, aryl iodide (1 equiv,
0.200 mmol) and 3-(bromoalkyl)heteroaryl (2 equiv, 0.400 mmol)
were combined and added to the reaction vial. CH3CN (0.1 M of
Ar-I, 2 mL) was added and the vial capped, sealed, and flushed
with N2(g). The vial was then heated in an oil bath until the reaction
was complete (appearance of Pd-black usually signifies completion
of reaction). The vial was then removed from the oil bath and cooled
1-Methyl-2-nitro-5,6-dihydrobenzo[b]naphtho[2,1-d]thiophene
(12b). Following the domino general procedure, 2-iodo-6-
nitrotoluene 1a (52.0 mg, 0.200 mmol) and 3-(2-bromoethyl)-
benzothiophene 11b (96.0 mg, 0.400 mmol) were reacted at 105
°C for 24 h. The crude mixture was purified by flash chroma-
tography on silica gel (Rf 0.17 in 5% Et2O/hexane) using 5%
Et2O/hexane to afford 12b as a viscous yellow oil: yield 25 mg
1
(42%); H NMR (300 MHz, CDCl3) δ 2.78 (s, 3H), 2.99-3.05
(m, 4H), 7.25 (d, J ) 8.2 Hz, 1H), 7.35-7.46 (m, 2H), 7.55 (d,
J ) 7.9 Hz, 1H), 7.76-7.80 (m, 1H), 7.86-7.90 (m, 1H); 13C
NMR (75 MHz, CDCl3) δ 17.4, 21.6, 30.7, 121.9, 122.1, 124.5,
125.1, 126.2, 127.1, 128.0, 132,8 133.1, 133.6, 134.8, 137.1,
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Martins and Lautens
140.0, 142.1; IR neat, ν (cm-1) 729 (m), 754 (m), 831 (m), 1155
(w), 1248 (w), 1346 (m), 1519 (s), 1589 (w), 1736 (w), 2931
(m); HRMS (EI) calcd for C17H13NO2S:295.0667 (M+), found
295.0662.
additional support. We also wish to thank Dr. Dino Alberico
for preliminary work and helpful discussions.
Supporting Information Available: Experimental details
and characterization data for compounds all compounds listed
above and their precursors. This information is available free
of charge via the Internet at http://pubs.acs.org.
Acknowledgment. We thank the National Science and
Engineering Research Council of Canada and Merck Frosst
Canada & Co. for financial support in the form of an
Industrial Research Chair and the University of Toronto for
JO8020105
8710 J. Org. Chem. Vol. 73, No. 22, 2008