Nickel-catalyzed enantioselective arylation of pyridine

Article abstract of DOI:10.1039/c6sc00702c

We report an enantioselective Ni-catalyzed cross coupling of arylzinc reagents with pyridinium ions formed in situ from pyridine and a chloroformate. This reaction provides enantioenriched 2-aryl-1,2-dihydropyridine products that can be elaborated to numerous piperidine derivatives with little or no loss in ee. This method is notable for its use of pyridine, a feedstock chemical, to build a versatile, chiral heterocycle in a single synthetic step.

Full text of DOI:10.1039/c6sc00702c

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Nickel-Catalyzed Enantioselective Arylation of Pyridine
J. Patrick Lutz, Stephen T. Chau and Abigail G. Doyle*
Received 00th January 20xx,
Accepted 00th January 20xx
We report an enantioselective Ni-catalyzed cross coupling of arylzinc reagents with pyridinium ions formed in situ from
pyridine and a chloroformate. This reaction provides enantioenriched 2-aryl-1,2-dihydropyridine products that can be
elaborated to numerous piperidine derivatives with little or no loss in ee. This method is notable for its use of pyridine, a
feedstock chemical, to build a versatile, chiral heterocycle in a single synthetic step.
DOI: 10.1039/x0xx00000x
www.rsc.org/
Introduction
Pyridine and its derivatives comprise one of the most
important classes of heterocycles in the field of chemistry. For
example, a recent analysis showed that piperidine and pyridine
are the two most common nitrogen heterocycles in US FDA-
approved pharmaceuticals, together found in approximately
12% of these drugs.1 Dihydropyridines are particularly valuable
precursors to these motifs and exhibit biological activities in
their own right.2,3 While the synthetic and biological utility of
1,4-dihydropyridines is well recognized, a recent review has
singled out 1,2-dihydropyridines as a class of compounds that
is understudied due to limitations in synthetic methodology.2e
Scheme
1
(A) Classes of 1,2-dihydropyridine and piperidinone accessible by
asymmetric addition of a nucleophile to a pyridinium salt. (B) Asymmetric arylation of
pyridine.
In particular, there is
a dearth of methods for the
enantioselective formation of 1,2-dihydropyridines.
By contrast, access to chiral 1,2-dihydropyridines from
pyridinium ions in an asymmetric catalytic manner remains
largely an unsolved, albeit highly important, problem. Only a
few such methods have been disclosed. The first reported
example, from Shibasaki, featured the asymmetric addition of
cyanide to the 6-position of pyridinium salts derived from
nicotinate amides (Scheme 1A).12 Another 1,6-addition was
achieved by Nadeau and the process group of Merck Frosst in
their rhodium-catalyzed coupling of aryl boronic acids with
N-benzyl nicotinate esters.13 These two methods rely on the
presence of a carbonyl group conjugated to the pyridinium
ring to achieve reactivity, but other reports have
The most common methods for the synthesis of
1,2-dihydropyridines involve cyclizations or cycloadditions of
linear precursors.4 Regioselective reductions of substituted
pyridines to 1,2-dihydropyridines have also been reported.5
However, these strategies have rarely been rendered
stereoselective and require the use of prefunctionalized
substrates that are accessible only by multi-step synthesis.6–8
A
third approach involves the addition of a carbon nucleophile to
an activated pyridinium salt, which is typically formed in situ
from the corresponding pyridine and an acylating agent. This
approach is particularly attractive, as it employs readily
available starting materials and provides 2-substituted
demonstrated
enantioselective
carbon–carbon
bond
1,2-dihydropyridines in
a
single step. Furthermore,
formation in the absence of this structural feature. For
example, Feringa and Minnaard reported a copper-catalyzed
enantioselective synthesis of 2-alkyl piperidinones from
4-methoxypyridinium salts.14 In 2013, we disclosed a catalytic
protocol for enantioselective arylation of this same
electrophile class. In this process, a Ni(0) catalyst ligated by a
chiral phosphoramidite ligand undergoes oxidative addition to
stereoselective variants have been reported. Comins,9
Wanner,10 and Charette11 have pioneered the use of chiral
auxiliaries to control the facial selectivity of Grignard additions
to pyridinium salts, though a blocking group at the C3 position
is often required for high regio- and diastereoselectivity.
the
π
system of the pyridinium ion, followed by
transmetalation with arylzinc halides and reductive elimination
to yield 2-aryl-4-methoxy-1,2-dihydropyridines, which are
hydrolyzed to the corresponding piperidinones upon workup
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Table 1 Evaluation of Reaction Conditions
Scheme 2 Proposed mechanism for the Ni-catalyzed arylation of 4-methoxypyridinium
ions.
Entry
1
Conditionsa
standard conditions
Yield (%)b
64
ee (%)c
86
76
80
87
0
with aq. HCl (Scheme 2).15 Numerous arylzinc nucleophiles
2
Ni(cod)2 instead of Ni(acac)2
NiBr2ꢀdiglyme instead of Ni(acac)2
5 mol% Ni(acac)2, 6 mol% L3
no Ni or ligand
71
were
successful
coupling
partners;
nevertheless,
3
58
4-methoxypyridinium salt was the only competent electrophile
under the reported reaction conditions.
4
38
5
72
In light of the potential utility of simple 2-aryl-
1,2-dihydropyridines, we sought to expand this activation
strategy to achieve the enantioselective arylation of
unsubstituted pyridinium ions formed in situ directly from
pyridine and an acylating agent.16,17 Pyridine is a stable,
abundant and inexpensive feedstock chemical, rendering it an
ideal prochiral starting material for organic synthesis. Despite
this, pyridine has seen very limited use as a substrate for
6
0.02 M instead of 0.1 M
ligand L1 instead of L3
ligand L2 instead of L3
ligand L4 instead of L3
–78 °C rt instead of –40 °C
ArZnBr derived from ArMgBr
+3 equiv. MgBr2
56
74
74
7
7
64
8
18
9
24
0
10
11
12
63
85
20
0
43
13
metal-catalyzed reactions, and
a number of potential
challenges were evident for the development of the proposed
methodology. First, because pyridine is an excellent ligand, it
might simply poison the nickel catalyst. While this obstacle
was surmountable with 4-methoxypyridine, pyridine is
acylated less efficiently than 4-methoxypyridine, so a greater
amount of free pyridine would be expected to be present in
the reaction mixture.18 Another principal concern was whether
the catalyst could enforce high regioselectivity for 1,2-addition
in the absence of a blocking group installed at the C4 position
of the ring. Indeed, only two nucleophile classes have
succumbed to coupling with unsubstituted pyridinium ions in
an asymmetric fashion: copper acetylides,19 and most recently,
silyl ketene acetals, though poor regioselectivity for the
1,2-dihydropyridine over the 1,4-dihydropyridine was
observed in the latter case.20 Here we report the successful
translation of our Ni-catalyzed iminium activation mode to the
development of a highly regio- and enantioselective catalytic
arylation of pyridinium salts derived from pyridine itself
(Scheme 1B). Furthermore, we show that the enantioenriched
dihydropyridine products of this new reaction can serve as
highly valuable precursors to numerous complex piperidine
derivatives.
a
b
Reactions run on a 0.5-mmol scale with 3 equiv. 4-F-PhZnBr. Isolated yield.
c Determined using chiral HPLC analysis after Pd/C-catalyzed hydrogenation to the
piperidine.
yield and enantioselectivity (entry 1). The enantioselectivity
was not strongly affected by the Ni loading, though below
10 mol% Ni, the reaction yield diminished (entry 4). In the
absence of Ni, there is a substantial racemic background
reaction, which proceeds to a greater extent than that for
4-methoxypyridine under the original conditions (entry 5).15
We also found that concentration has a significant effect on
reaction efficiency and selectivity, with higher yields and ee’s
observed at higher concentration (entry 6). Since equilibrium
favors the pyridinium salt at higher reaction concentrations,
these results may be explained by diminished catalyst
poisoning by free pyridine in solution.
With the modifications described above, the original BINOL-
derived phosphoramidite ligand L1 provided
yield and moderate ee (entry 7). When we investigated the use
of (R)–Monophos, L2 as ligand, we found that
1 with reasonable
,
a
3,3′-substitution was critical for high enantioselectivity,
showing a dramatic decrease from 74% ee to only 7% ee
(entry 8). In an attempt to identify a more selective ligand, we
evaluated several Monophos derivatives possessing differing
Results and Discussion
Optimization studies
The previously described reaction conditions, which used
PhOCOCl as an acylating agent, provided only trace product
when using pyridine in place of 4-methoxypyridine. However,
we found that EtOCOCl gave measurable amounts of the
3,3′-substitution, but we were unable to identify
a
3,3′-substituent that gave higher ee than On-Pr. Consequently,
we prepared a number of phosphoramidites that retained the
3,3′-On-Pr substitution but that differed in the identity of the
N-substituent.22 Pyrrolidine-derived ligand L3 was optimal,
desired dihydropyridine product
1, albeit initially in only
14% NMR yield and 42% ee.21 Evaluation of precatalysts
showed that both Ni(0) and Ni(II) sources were effective (Table
1, entries 2–3), with Ni(acac)2 providing the best balance of
providing
1
in 64% yield and 86% ee (entry 1).
2 | Chem. Sci., 2012, 00, 1-3
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Table 2 Evaluation of Acylating Agentsa
Table 3 Evaluation of Nucleophile Scopea
a Isolated yields on a 0.5-mmol scale with 3 equiv. 4-F-PhZnBr. b Determined after
Pd/C-catalyzed hydrogenation to the piperidine. c Average of two runs.
In the course of our optimization studies, we also found that
the method of preparation of the arylzinc reagent had a strong
influence on the outcome of the reaction. When
4-fluorophenylzinc bromide was prepared by transmetalation
of the corresponding aryllithium reagent with ZnBr2, the
reaction proceeded smoothly and with high ee (entry 1).
However, if the zinc reagent was instead prepared by
transmetalation between ZnBr2 and a Grignard reagent, the
yield and enantioselectivity fell off dramatically (entry 11). We
believe that this effect is due to the presence of Mg(II) salts, as
the reaction also fails when exogenous MgBr2 is added to a
reaction with an organolithium-derived zinc reagent (entry 12).
Our early observations regarding the difference in reactivity
between EtOCOCl and PhOCOCl led us to investigate the
identity of the acylating agent more thoroughly in an attempt
to further increase the enantioselectivity of the reaction
(Table 2). In doing so, we found that more sterically
demanding chloroformates tended to give higher
enantioselectivity: methyl chloroformate provided compound
3
in 83% ee, while neopentyl chloroformate provided
92% ee. Noting that there was only a slight difference in
enantioselectivity between isobutyl and neopentyl
6 in
chloroformate, we elected to use the less expensive reagent,
i-BuOCOCl, as the acylating agent in our investigation of the
reaction scope. Notably, we found that these optimized
conditions provided 1,2-adduct 5a with high regioselectivity;
none of the 1,4-adduct was observed by NMR.22
a Isolated yields and ee’s are the average of two runs on a 0.5-mmol scale with
b
Scope elucidation
3 equiv. RZnBr. Reaction was run with 20 mol% Ni(acac)2 and 24 mol% L3.
c Reaction was run with RZnI. Yield and ee determined after Pd/C-catalyzed
d
The scope of the reaction with respect to the arylzinc
nucleophile was explored (Table 3). π-Electron-withdrawing
hydrogenation to the piperidine. e Reaction was run with 1.25 equiv. i-BuOCOCl.
f Reaction was run from –78 °C rt.
groups are well tolerated
(
5c
lead
, 5f). Neutral arylzinc bromides give well, providing a handle for subsequent functionalization at
,
5d), though strong
σ-withdrawing
substituents
to depressed arylation. Furthermore, Cl-substituted nucleophiles perform
enantioselectivity (5e
acceptable levels of selectivity (5g–j), as do electron-rich these positions, though the meta-Cl nucleophile (5n) gave
nucleophiles (5k 5l); the latter is notable as electron-rich higher enantioselectivity than the para-Cl nucleophile (5m).
,
nucleophiles deliver low enantioselectivity due to a facile This trend was observed in a few other cases as well (5i vs. 5j
,
background reaction in our previously described arylation of 5k vs. 5l).
4-methoxypyridinium ions. Importantly, many functional
groups are compatible with the nickel chemistry: nucleophiles reaction, providing access to compounds derived from
containing nitriles (5c), esters (5d), silyl-protected alcohols benzofuran 5s), furan 5t), and N-methylindole 5u in
Several heteroaromatic nucleophiles are amenable to the
(
(
(
)
(
5o), and tertiary amines (5p) all afford >90% ee in the
≥89% ee. Nucleophiles substituted at the ortho position
generally perform poorly in terms of reaction efficiency and
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selectivity 5v). However, we found that
Chemical Science
(
a nucleophile
containing coordinating functionality at the ortho position,
2-methoxyphenylzinc bromide, delivers a moderate 74% ee
(
5w). Finally, an alkenylzinc iodide provides 5x in 55% ee. In
this case, no reaction was observed at the typical reaction
temperature of –40 °C, possibly suggesting slower
transmetalation for this class of alkenyl nucleophile.23
a
Scheme
4
Hydrogenation/deprotection of Cbz-protected dihydropyridine.
While the isolated yields are generally moderate, we believe
that the use of pyridine as limiting reagent renders this
method practical. Furthermore, upon scaling up the reaction,
we observed an increase in reaction efficiency with no
influence on selectivity. Under the conditions shown in Table
3, a gram-scale reaction with 4-fluorophenylzinc provided 5a in
80% yield and 90% ee (average of two runs).24 Notably, these
gram-scale reactions were set up on the benchtop using
Schlenk technique, obviating the need for a glovebox.
a Determined after Boc protection.
tetrahydropyridine 7 20
the regioisomeric tetrahydropyridine 8 4d
are valuable synthetic building blocks in their own right. For
example, tetrahydropyridine was further functionalized by
iodination with NIS followed by Suzuki cross coupling to
provide disubstituted tetrahydropyridine . Compound was
,
or with Lindlar’s catalyst and H2 to give
These compounds
.
8
9
7
dihydroxylated with OsO4 with >20:1 dr (10), demonstrating
that the stereocenter set in the pyridinium arylation can
Product derivatization
provide high substrate control for
reaction.
a diastereoselective
With the scope of the reaction established, we sought to
illustrate the utility of the 1,2-dihydropyridine products as
valuable building blocks for further organic synthesis. To do so,
we explored a number of derivatization reactions, each of
which was performed with only minimal optimization
(Scheme 3). Importantly, these reactions proceeded with
essentially no erosion of ee. The 1,2-dihydropyridine 5a can be
selectively reduced with triethylsilane to give
Full hydrogenation of 5a yields the piperidine product 11
,
which can be lithiated at low temperature and trapped with an
appropriate electrophile with almost no loss in ee, allowing for
the formation of a fully substituted, stereodefined carbon
(
12).25 The diene system of 5a is also amenable to Diels–Alder
cycloaddition. An interesting example is the Diels–Alder
reaction with nitrosobenzene, which provides an unusual
bicycle that can be opened with CuCl to afford the chiral
pyrrole derivative 13 26
The carbamate protecting group can be removed from
.
9
with LiAlH4 to provide N-methyl piperidine derivative 14. For
access to the free N–H piperidine 15, we found that the most
convenient route was the hydrogenation of the Cbz-protected
dihydropyridine 4, which was prepared in only slightly lower
ee than 5a (88% vs. 91%, Scheme 4) under our standard
reaction conditions.
Conclusions
In summary, we have developed an enantioselective synthesis
of 2-aryl-1,2-dihydropyridines, previously only accessible in a
diastereoselective or racemic fashion. The reaction proceeds
through a pyridinium salt derived from pyridine and an
inexpensive chloroformate, and the products are formed by
Ni-catalyzed cross coupling with arylzinc halide nucleophiles.
The dihydropyridine products are valuable chiral building
blocks, as demonstrated by a number of transformations that
proceed with little or no loss in ee, providing a variety of chiral
piperidine derivatives. More generally, this methodology is
noteworthy for its use of pyridine, a feedstock chemical, as a
prochiral substrate in a transition metal-catalyzed asymmetric
reaction.
Scheme 3 Derivatization of dihydropyridine 5a. Ar = 4-fluorophenyl. Reagents and
conditions: (a) Et3SiH (1.05 equiv.), trifluoroacetic acid (20 equiv.), CH2Cl2, –10 °C, 45 s;
(b) H2 (1 atm.), Lindlar catalyst (3 mol%), MeOH, rt, overnight; (c) N-iodosuccinimide
(3 equiv.), DMF, rt, 2 hr; (d) Buchwald precatalyst (2 mol%), Xphos (4 mol%), K3PO4
(2 equiv.), 4-MeO-PhB(OH)2 (1.5 equiv.), THF, 80 °C, overnight; (e) OsO4 (4 mol%),
N-methylmorpholine-N-oxide (1.2 equiv.), THF:H2O (2:1), rt, 3 hr; (f) H2 (100 psi), Pd/C
(5 mol%), MeOH, rt, overnight; (g) n-BuLi (1.2 equiv.), THF, –50 °C, 30 min., then MeI
(3 equiv.), THF, –78 °C, 2 h; (h) nitrosobenzene (2 equiv.), CH2Cl2, rt, 2 hr; (i) CuCl
(20 mol%), MeOH, rt, overnight; (j) LiAlH4 (4 equiv.), THF, 50 °C, overnight, then HCl in
Et2O.
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EDGE ARTICLE
and A. B. Charette, J. Am. Chem. Soc. 2003, 125, 6360. (c) A.
Lemire, M. Grenon, M. Pourashraf and A. B. Charette, Org.
Lett. 2004, 6, 3517.
Acknowledgements
Financial support from NIGMS (R01 GM100985), Eli Lilly, and
Amgen is gratefully acknowledged. This material is based upon
work supported by the National Science Foundation Graduate
Research Fellowship under Grant No. DGE-1148900 (to J.P.L.).
We thank Jake Essman for ligand synthesis and assistance with
product derivatization, and Dr. István Pelczer and Ken Conover
for help with NMR experiments. A.G.D. is a Camille Dreyfus
Teacher-Scholar and Arthur C. Cope Scholar.
12 E. Ichikawa, M. Suzuki, K. Yabu, M. Albert, M. Kanai and M.
Shibasaki, J. Am. Chem. Soc. 2004, 126, 11808.
13 C. Nadeau, S. Aly and K. Belyk, J. Am. Chem. Soc. 2011, 133,
2878.
14 M. Á. Fernández-Ibáñez, B. Maciá, M. G. Pizzuti, A. J.
Minnaard, and B. L. Feringa, Angew. Chem. Int. Ed. 2009, 48,
9339.
15 S. T. Chau, J. P. Lutz, K. Wu, and A. G. Doyle, A. G. Angew.
Chem. Int. Ed. 2013, 52, 9153.
16 (a) T. J. A. Graham, J. D. Shields and A. G. Doyle, A. G. Chem.
Sci. 2011, 2, 980. (b) K. T. Sylvester, K. Wu, and A. G. Doyle, J.
Am. Chem. Soc. 2012, 134, 16967. (c) J. D. Shields, D. T.
Notes and references
Ahneman, T. J. A. Graham and A. G. Doyle, Org. Lett. 2014
16, 142.
17 For an example of asymmetric arylation of pyridine N-oxide,
see: M. Hussain, T. S.-L. Banchelin, H. Andersson, R. Olsson
and F. Almqvist, Org. Lett. 2013, 15, 54.
18 J. Pabel, C. E. Hösl, M. Maurus, M. Ege and K. Th. Wanner, J.
Org. Chem. 2000, 65, 9272.
19 (a) Z. Sun, S. Yu, Z. Ding and D. Ma, J. Am. Chem. Soc. 2007
129, 9300. (b) D. A. Black, R. E. Beveridge and B. A. Arndtsen,
J. Org. Chem. 2008, 73, 1906.
20 O. G. Mancheño, S. Asmus, M. Zurro and T. Fischer, Angew.
Chem. Int. Ed. 2015, 54, 8823.
21 Reaction conditions: pyridine (0.05 mmol, 1 equiv.), EtOCOCl
(4 equiv.), THF, 0 °C, 10 min., then NiBr2•diglyme (10 mol%),
L1 (12 mol%), 4-fluorophenylzinc bromide (4 equiv.), THF
(0.01 M), –78 °C rt, overnight.
,
1
E. Vitaku, D. T. Smith and J. T. Njardarson, J. Med. Chem.
2014, 57, 10257.
For reviews on the synthesis of dihydropyridines, see: (a) U.
Eisner and J. Kuthan, Chem. Rev. 1972, 72, 1. (b) D. M. Stout
and A. I. Meyers, Chem. Rev. 1982, 82, 223. (c) R. Lavilla, J.
Chem. Soc., Perkin Trans. 1, 2002, 1141. (d) J. A. Bull, J. J.
2
Mousseau, G. Pelletier and A. B. Charette, Chem. Rev. 2012
,
,
112, 2642. (e) E. M. P. Silva, P. A. M. M. Varandas and A. M.
S. Silva, Synthesis, 2013, 45, 3053.
For a review on the biological activity of dihydropyridines,
see: N. Edraki, A. R. Mehdipour, M. Khoshneviszadeh and R.
Miri, Drug Discovery Today, 2009, 14, 1058.
Selected examples: (a) T. Koike, Y. Shinohara, M. Tanabe, N.
Takeuchi and S. Tobinaga, Chem. Pharm. Bull. 1999, 47,
1246. (b) K. Tanaka, H. Mori, M. Yamamoto and S.
Katsumura, J. Org. Chem. 2001, 66, 3099. (c) T. Harschneck
and S. F. Kirsch, J. Org. Chem. 2011, 76, 2145. (d) B. M. Trost
and B. Biannic, Org. Lett. 2015, 17, 1433.
Selected examples: (a) T. J. Donohoe, A. J. McRiner and P.
Sheldrake, Org. Lett. 2000, 2, 3861. (b) T. J. Donohoe, A. J.
McRiner, M. Helliwell and P. Sheldrake, J. Chem. Soc., Perkin
Trans. 1, 2001, 1435.
3
4
22 See ESI for details.
23 We have found that other pyridine electrophiles, including
pyridinium salts derived from 4-methoxypyridine,
4-methylpyridine, and 3-ethylpyridine, have limited success
under the reported reaction conditions. See ESI for details.
24 Similarly, 5j was prepared on gram scale with 96% ee and an
improved 58% yield.
25 N. S. Sheikh, D. Leonori, G. Barker, J. D. Firth, K. R. Campos,
A. J. H. M. Meijer, P. O’Brien and I. Coldham, J. Am. Chem.
Soc. 2012, 134, 5300.
5
6
For
cyclization
reactions
to
prepare
chiral
1,2-dihydropyridines from single-enantiomer compounds,
see: (a) T. Shono, Y. Matsumura, O. Onomura and Y. Yamada,
Tetrahedron Lett. 1987, 28, 4073. (b) Y. Matsumura, Y.
26 F. Berti, V. Di Bussolo and M. Pineschi, M. J. Org. Chem.
2013, 78, 7324.
Nakamura, T. Maki and O. Onomura, Tetrahedron Lett. 2000
41, 7685. (c) D. Monguchi, S. Majumdar and T. Kawabata,
Heterocycles 2006 68, 2571. (d) M. Motamed, E. M.
,
,
Bunnelle, S. W. Singaram and R. Sarpong, Org. Lett. 2007, 9,
2167.
7
8
For a diastereoselective synthesis of 1,2-dihydropyridines,
see: K. Tanaka, T. Kobayashi, H. Mori and S. Katsumura, J.
Org. Chem. 2004, 69, 5906.
For
enantioselective
syntheses
of
substituted
1,2-dihydropyridines via [2+2+2] or [4+2] cycloadditions, see:
(a) M. Amatore, D. Leboeuf, M. Malacrian, V. Gandon and C.
Aubert, J. Am. Chem. Soc. 2013, 135, 4576. (b) P. Ramaraju,
N. A. Mir, D. Singh, V. K. Gupta, R. Kant and I. Kumar Org.
Lett. 20154, 17, 5582.
9
(a) D. L. Comins, R. R. Goehring, S. P. Joseph and S. O’Connor,
J. Org. Chem. 1990, 55, 2574. (b) D. L. Comins, H. Hong and J.
M. Salvador, J. Org. Chem. 1991, 56, 7197. (c) D. L. Comins, S.
P. Joseph and R. R. Goehring, J. Am. Chem. Soc. 1994, 116,
4719. (d) D. L. Comins and L. Guerra-Weltzien, Tetrahedron
Lett. 1996, 37, 3807. (e) D. L. Comins, J. Heterocyclic Chem.
1999, 36, 1491.
10 (a) C. E. Hoesl, M. Maurus, J. Pabel, K. Polborn, and K. Th.
Wanner, Tetrahedron, 2002, 58, 6757. (b) C. E. Hoesl, J.
Pabel, K. Polborn and K. Th. Wanner, Heterocycles, 2002, 58,
383.
11 (a) A. B. Charette, M. Grenon, A. Lemire, M. Pourashraf and
J. Martel, J. Am. Chem. Soc. 2001, 123, 11829. (b) C. Legault
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