N-Silylenamines as Reactive Intermediates: Hydroamination for the Modular Synthesis of Selectively Substituted Pyridines

Article abstract of DOI:10.1021/acs.orglett.8b02703

A modular and selective synthesis of mono-, di-, tri-, tetra-, and pentasubstituted pyridines is reported. Hydroamination of alkynes with N-silylamine using a bis(amidate)bis(amido)titanium(IV) precatalyst furnishes the regioselective formation of N-silylenamines. Addition of α,β-unsaturated carbonyls to the crude mixtures followed by oxidation affords 47 examples of pyridines in yields of up to 96%. This synthetic route allows for the synthesis of diverse pyridines containing variable substitution patterns, including pharmaceutically relevant 2,4,5-trisubstituted pyridines, using this one-pot protocol.

Full text of DOI:10.1021/acs.orglett.8b02703

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
N‑Silylenamines as Reactive Intermediates: Hydroamination for the
Modular Synthesis of Selectively Substituted Pyridines
Erica K. J. Lui, Daniel Hergesell, and Laurel L. Schafer*
Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia, Canada V6T 1Z1
S
* Supporting Information
ABSTRACT: A modular and selective synthesis of mono-, di-,
tri-, tetra-, and pentasubstituted pyridines is reported. Hydro-
amination of alkynes with N-silylamine using a bis(amidate)-
bis(amido)titanium(IV) precatalyst furnishes the regioselec-
tive formation of N-silylenamines. Addition of α,β-unsaturated
carbonyls to the crude mixtures followed by oxidation affords
47 examples of pyridines in yields of up to 96%. This synthetic route allows for the synthesis of diverse pyridines containing
variable substitution patterns, including pharmaceutically relevant 2,4,5-trisubstituted pyridines, using this one-pot protocol.
wide variety of pyridines can be found in natural products1
Scheme 1. Synthesis of 2,4,5-Trisubstituted Pyridines
A
and pharmaceutical agents,2 thus, significant effort has
been employed toward their efficient preparation. In order to
access pyridines with selected substitution patterns, two
approaches are commonly employed: stepwise functionalization
of the pyridine core3 or formation of the six-membered aromatic
ring through condensation, cycloisomerization, or cyclo-
addition.4 Selective functionalization of the pyridine core is a
useful approach, although in the cases of multisubstituted
pyridines, it can be material and labor intensive. On the other
hand, combining two or more simple molecules via thermal or
metal-catalyzed reactions can readily assemble variously
substituted pyridines.4b−d Established condensation methods
using 1,3- or 1,5-dicarbonyl derivatives are easy to use but offer
restricted substitution patterns. For example, the Hantzsch
pyridine synthesis reacts 1,3-dicarbonyls, an aldehyde, and an
ammonia source in one pot to typically form substituted
pyridines with specifically electron-withdrawing substituents in
5
̈
the 3- and/or 5-positions. The Krohnke synthesis, on the other
hand, starts with a pyridinium salt and an α,β-unsaturated
carbonyl to form a 1,5-dicarbonyl intermediate, which can then
react with ammonium acetate to deliver 2,4,6-trisubstituted
pyridines selectively.6 However, yields can be problematic as
dicarbonyls are prone to side reactions, such as intra- or
intermolecular condensations, especially in cases where
aldehydes are required to make pyridines without ortho-
substituents. Thus, a flexible and selective approach for the
rapid assembly of a library of pyridines with diverse substitution
patterns would allow for the modular assembly of important
substituted pyridine products and building blocks.
N-Silylated enamines have been used to construct select
substituted pyridines (Scheme 1A),7 although few preliminary
results were disclosed due to the difficult preparation and
handling of moisture-sensitive N-silylenamines using traditional
stoichiometric approaches. However, our recently reported
regioselective catalytic alkyne hydroamination reaction to give
N-silylamines enables reliable and efficient access to a wide
range of monosilylated enamines.8 Such masked primary
enamines are reactive nucleophilic synthons that allow for
subsequent reactivity. Here, we show how the in situ generation
of silylenamines by the anti-Markovnikov regioselective hydro-
amination of alkynes followed by six-membered ring formation
Received: August 23, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02703
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
via addition to an α,β-unsaturated aldehyde or ketone and
subsequent oxidation affords a range of selectively substituted
pyridines, including 3-mono-, 2,5-di-, 3,4-di-, 2,3,5-tri-, 2,4,5-tri-,
2,3,4,5-tetra-, 2,3,4,6-tetra-, and even 2,3,4,5,6-pentasubstituted
pyridines. In three sequential steps, 47 examples of substituted
pyridines were synthesized, including 30 examples of 2,4,5-
trisubstituted pyridines. This specific substitution pattern was
important for the development of a new class of NK1 receptor
antagonists,9 the preparation of radiolabels for PET imaging,10
and the synthesis of alkaloids, such as flavocarpine and
dihydrovincarpine.11 Notably, there are few general syntheses
of 2,4,5-trisubstituted pyridines,7b,12 and it is rare to find an
approach where the 5-position is something other than methyl
(Scheme 1B).12a−d,f
Furthermore, the alkyne and α,β-unsaturated carbonyl
starting materials are both commercially available. Commer-
cially available N-triphenylsilylamine can also be used (vide
infra). The intermolecular synthesis of pyridines using
unactivated alkynes is commonly performed using late transition
metals with coupling partners such as nitriles,12d,f,13 haloviny-
limines,14 enamides,15 α,β-unsaturated imines,16 and α,β-
unsaturated ketoximes,17 which are typically presynthesized.
Although α,β-unsaturated carbonyls are readily available, they
have been most typically applied toward the synthesis of 2,4,6-
trisubstituted pyridines18 or pyridines containing electron-
withdrawing groups (amide, cyano, ester, and ketone groups)
at the 3-position,19 with few examples that reach beyond these
limitations.7a,b,12e,20 Here, we show how alkynes and α,β-
unsaturated carbonyls can be used to access a variety of
selectively substituted pyridines in moderate to excellent yields,
in particular, 2,4,5-substituted pyridines (Scheme 1C).
desired product was increased to 43%. By changing the fluoride
source to TBAF, the yield was not improved; however, a 1 M
solution of TBAF in THF is procedurally easier to handle.22 The
addition of 3 Å molecular sieves further increased the yield to
62% (entry 4). Finally, addition of DDQ as an oxidant allowed
for the isolation of the desired product in 78% yield (entry 5).23
A slight improvement in the yield was obtained using DMSO as
the solvent (entry 6). Furthermore, a 5 mmol scale of the
reaction was performed to give more than a gram of the desired
pyridine (entry 6, yield in parentheses). To demonstrate that the
titanium and amidate ligand present no deleterious effect upon
this one-pot reaction, intermediate N-silylenamine was purified
by vacuum distillation prior to ring closure and oxidation. This
resulted in a comparable yield (entry 7). The reaction was also
successful using commercially available N-triphenylsilylamine
with a somewhat diminished yield (65%, entry 8).
With optimized conditions in hand, the scope of the
sequential procedure was investigated (Scheme 2). We first
examined the reaction of ethynylbenzene, with a variety of α,β-
unsaturated aldehydes and ketones, which were commercially
available or easily synthesized through aldol condensation.24 By
Scheme 2. Various α,β-Unsaturated Carbonyl Substrates can
a
be Incorporated
Preliminary studies on the feasibility of synthesizing
substituted pyridines using this approach were performed
using ethynylbenzene and (N-tert-butyldimethylsilyl)amine to
generate the reactive N-silylenamine synthon in situ. Sub-
sequently trans-chalcone was added for the development of
optimized conditions for the second step of the reaction (Table
1).21 Whereas the reaction does occur in the absence of additives
at 100 °C, the 11% yield is unsatisfactory. The addition of
catalytic amounts of a fluoride source helped activate the N−Si
bond. For example, by adding 0.05 equiv of CsF, the yield of the
Table 1. Optimization of Conditions for the Pyridine
Formation
a
entry
fluoride source
additive
yield (%)
b
1
2
3
4
5
6
7
8
11
43
43
62
78
c
0.05 equiv of CsF
0.1 equiv of TBAF
0.1 equiv of TBAF
0.1 equiv of TBAF
0.1 equiv of TBAF
0.1 equiv of TBAF
0.1 equiv of TBAF
3 Å MS
3 Å MS; 1 equiv of DDQ
3 Å MS; 1 equiv of DDQ
3 Å MS; 1 equiv of DDQ
3 Å MS; 1 equiv of DDQ
d
e
85 (74)
f
83
65
g
a
b
c
d
a
b
Isolated yields. Heated to 100 °C. Heated to 50 °C. DMSO as
Isolated yields. One-pot reaction: hydroamination reaction
e
f
g
solvent. 5 mmol scale. Using isolated N-silylenamine. Commercially
available Ph3SiNH2.
performed under neat conditions followed by addition of α,β-
unsaturated carbonyl. Second step performed at 80 °C.
c
B
DOI: 10.1021/acs.orglett.8b02703
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
reacting the hydroamination product mixture with prop-2-enal,
an example of a monosubstituted pyridine was obtained in 34%
yield (2a). By using a monosubstituted α,β-unsaturated
carbonyl substrate, disubstituted pyridines, with 2,5- or 3,4-
substitution patterns, were obtained in 40 and 13% yields,
respectively (2b and 2c). Reduced yields observed for the
reactions using aldehydes are likely due to ill-defined side
reactions of these substrates in the presence of the Lewis acidic
titanium catalyst. The flexibility of this approach is highlighted
by the fact that 2,5-diphenylpyridine is commonly prepared via a
double Suzuki coupling.25 However, synthesis of 2,5-disub-
stituted pyridines with different substituents demands sequen-
tial and chemospecific reaction conditions to distinguish
between (pseuso)halogens. For 3,4-diphenylpyridine, only six
procedures have been disclosed, all of which require multistep
protocols.26 Meanwhile, our approach is completely regiose-
lective and features a common reaction protocol in all cases.
Disubstituted α,β-unsaturated ketones can be used to access
trisubstituted pyridines with excellent regioselectivity for either
2,3,5- or 2,4,5-positions. These variably substituted products
were synthesized in a variety of yields ranging from 11 to 96%
(2d−q). In medicinal chemistry, a trifluoromethyl group can
drastically change the physical and biological properties of
heterocycles.27 Thus, a noteworthy example is pyridine 2j, which
contains a trifluoromethyl group at the 2-position. This desirable
motif was synthesized in 68% yield from 1,1,1-trifluoro-4-
phenylbut-3-en-2-one.28 The regioselectivity of pyridine for-
mation was confirmed by X-ray diffraction of crystalline product
2m (Figure 1). Finally, the synthesis of 2,3,4,5-tetrasubstituted
Scheme 3. Effect of Alkyne Substituents on Sequential
Reaction for Pyridine Synthesis
a
a
b
c
Isolated yields. Second step performed at 50 °C. Second step
performed at 80 °C.
presence of chloro and bromo substituents could allow for
further cross-coupling transformations to be performed. Other
para-substituted ethynylbenzenes bearing electron-donating
and electron-withdrawing substituents were used to give
products (3d−f) in great yields. The meta- (3g) and ortho-
substituted (3h) ethynylbenzenes were also tolerated with no
notable decrease in pyridine yield.
The synthesis of pyridines containing other heterocycles on
the 3- or 5-positions is important, as seen in current commercial
drugs such as Crizotinib, Etoricoxib, and Imatinib. Using our
developed methodology, alkynes containing various nitrogen or
sulfur heterocycles (3i−o) were also compatible with these
reaction conditions, and the resultant pyridines could be
synthesized and isolated in good yields (60−82%).
Importantly, our reaction conditions are not limited to
arylalkyne substrates, as shown with an enyne precursor (3p), as
well as the use of an alkylamide to give product (3q) and
silylether to furnish pyridine (3r). Although these different
derivatives were tolerated, the latter two were noted to be lower
yielding. Synthetic routes to access such alkylated pyridines are
rarely reported.30
Figure 1. X-ray crystallographic structure of pyridine 2m.
pyridines could also be achieved using trisubstituted α,β-
unsaturated ketones. Notably, this transformation features
symmetrical and unsymmetrical α,β-unsaturated ketones in
yields of up to 78% (2r−w). In particular, 4 of the 5 examples of
2,3,4,5-tetrasubstituted pyridines reported here are new
compounds, which suggests that routine methods for accessing
these more highly substituted pyridines are underdeveloped.29
Next, the effect of different alkyne substituents on the
sequential reaction was examined using 4,4-dimethyl-1-phenyl-
pent-1-en-3-one as a consistent α,β-unsaturated carbonyl
substrate (Scheme 3). In all cases, full consumption of starting
Finally, internal alkynes could be used in combination with
disubstituted α,β-unsaturated ketones to give 2,3,4,6-tetrasub-
stituted pyridines in 64−79% yields (3s−v). In the case of
unsymmetrical aryl−alkyl internal alkynes, the regioselective
hydroamination reaction allowed for the selective synthesis of
1
materials in the hydroamination step is observed, and the H
NMR yields for the synthesized N-silylenamines vary between
69 and 99%.8 Halogenated para-substituted ethynylbenzenes
(3a−c) were successfully employed in 81−88% yields. The
C
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Letter
tetrasubstituted pyridines containing an alkyl group at the 2-
position and an aryl group on the 3-position (3s−u). None of
these examples has been reported previously.
The synthesis of pentasubstituted pyridines is a synthetic
challenge, particularly in cases where the pyridine core contains
five-carbon substitutents.12c,16,17,31 However, using the devel-
oped sequential methodology, pentasubstituted pyridines can be
readily assembled in yields of 23−47% (4a−c) using the same
three-step sequential protocol (Scheme 4).
pathways, a Stork enamine reaction, where the β-carbon of the
enamine attacks the α,β-unsaturated carbonyl in a 1,4-addition
followed by a condensation event (Scheme 5A, pathway A-1), or
a condensation followed by a cylization event (Scheme 5A,
pathway A-2). After oxidation, the correct pyridine regioisomer
would be obtained in both pathways. An alternative pathway
could have been an aza-Michael addition, where the nitrogen of
the enamine nucleophilically attacks the β-position of the α,β-
unsaturated carbonyl (Scheme 5B). However, the product
resulting from this mechanism would not furnish the observed
regioisomer. Carbon-based enamines are known to preferen-
tially react through the β-carbon of the enamine moiety.
However, as shown from our previous study on N-silylen-
amines,8 which were notably resistant to tautomerization, in
contrast to their carbon-substituted variants, the reactivity of
enamines containing silicon-based substituents can be different
from enamines containing carbon-based substituents. Thus,
further investigation on the nucleophilicity of monosilylated
enamines is necessary to confirm the mechanistic pathway of this
reaction.
a
Scheme 4. Synthesis of Pentasubstituted Pyridines
In conclusion, one simple, modular method to prepare mono-,
di-, tri-, tetra-, and pentasubstituted pyridines has been
disclosed. The one-pot method we have developed employs a
sequential regioselective hydroamination of alkynes with N-
silylamine followed by the addition of an α,β-unsaturated
carbonyl substrate to give a six-membered nitrogen-containing
ring intermediate that can undergo oxidation to afford pyridines.
A broad range of targeted products could be isolated in typically
good yields. The generality of the transformation is demon-
strated by using a wide scope of both α,β-unsaturated carbonyl
and alkyne substrates. Notably, both of these starting materials
are commercially available and/or easily synthesized. The ring
formation is proposed to proceed by a Stork enamine 1,4-
addition to furnish the observed selectively substituted pyridine
products. Mechanistic investigations and applications in the
synthesis of selectively substituted pharmaceutically relevant
pyridine compounds are ongoing.
a
Isolated yields.
Analysis of the substitution patterns obtained, as confirmed by
crystallographic analysis of product 2m, provides insight into the
mechanistic path for the cycloaddition step of pyridine
formation (Scheme 5). As observed, R3 is located in the 4-
position, which is consistent with two different mechanistic
Scheme 5. Potential Pathways for the Formation of Pyridines
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b02703.
Full experimental procedures and spectroscopic data
(PDF)
Accession Codes
CCDC 1864356 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: schafer@chem.ubc.ca.
ORCID
Erica K. J. Lui: 0000-0001-9916-9700
Laurel L. Schafer: 0000-0003-0354-2377
Notes
The authors declare no competing financial interest.
D
DOI: 10.1021/acs.orglett.8b02703
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
A.; Leonard, N. J. J. Am. Chem. Soc. 1973, 95, 4891. (c) Katritzky, A. R.;
Belyakov, S. A.; Sorochinsky, A. E.; Henderson, S. A. J. Org. Chem. 1997,
62, 6210. (d) Katritzky, A. R.; Abdel-Fattah, A. A. A.; Tymoshenko, D.
O.; Essawy, S. A. Synthesis 1999, 1999, 2114. (e) Boruah, R.; Borthakur,
M.; Dutta, M.; Gogoi, S. Synlett 2008, 2008, 3125.
ACKNOWLEDGMENTS
■
The authors thank NSERC for financial support of this work.
D.H. thanks the PROMOS scholarship from DAAD.
(19) (a) Sakurai, A.; Midorikawa, H. Bull. Chem. Soc. Jpn. 1968, 41,
430. (b) Palacios, F.; Herran, E.; Alonso, C.; Rubiales, G.; Lecea, B.;
Ayerbe, M.; Cossio, F. P. J. Org. Chem. 2006, 71, 6020. (c) Lieby-
Muller, F.; Allais, C.; Constantieux, T.; Rodriguez, J. Chem. Commun.
2008, 4207. (d) Allais, C.; Constantieux, T.; Rodriguez, J. Chem. - Eur. J.
2009, 15, 12945. (e) Tenti, G.; Ramos, M. T.; Menendez, J. C. ACS
Comb. Sci. 2012, 14, 551. (f) Xia, Y. J.; Cai, J. H.; Huang, H. W.; Deng,
G. J. Org. Biomol. Chem. 2018, 16, 124.
(20) (a) Donohoe, T. J.; Basutto, J. A.; Bower, J. F.; Rathi, A. Org. Lett.
2011, 13, 1036. (b) Wei, Y.; Yoshikai, N. J. Am. Chem. Soc. 2013, 135,
3756. (c) Hardegger, L. A.; Habegger, J.; Donohoe, T. J. Org. Lett. 2015,
17, 3222. (d) Rieckhoff, S.; Hellmuth, T.; Peters, R. J. Org. Chem. 2015,
80, 6822. (e) Huang, H.; Cai, J.; Tang, L.; Wang, Z.; Li, F.; Deng, G. J. J.
Org. Chem. 2016, 81, 1499.
REFERENCES
■
(1) Kiuru, P.; Yli-Kauhaluoma, J. Pyridine and Its Derivatives. In
Heterocycles in Natural Product Synthesis; Majumdar, K. C.,
Chattopadhyay, S. K., Eds.; Wiley-VCH Verlag GmbH & Co. KGaA:
Weinheim, Germany, 2011.
(2) (a) Baumann, M.; Baxendale, I. R. Beilstein J. Org. Chem. 2013, 9,
2265. (b) Vitaku, E.; Smith, D. T.; Njardarson, J. T. J. Med. Chem. 2014,
57, 10257.
(3) (a) Nakao, Y. Synthesis 2011, 2011, 3209. (b) Bull, J. A.;
Mousseau, J. J.; Pelletier, G.; Charette, A. B. Chem. Rev. 2012, 112,
2642. (c) Murakami, K.; Yamada, S.; Kaneda, T.; Itami, K. Chem. Rev.
2017, 117, 9302.
(4) (a) Varela, J. A.; Saa, C. Synlett 2008, 2008, 2571. (b) Hill, M. D.
Chem. - Eur. J. 2010, 16, 12052. (c) Gulevich, A. V.; Dudnik, A. S.;
Chernyak, N.; Gevorgyan, V. Chem. Rev. 2013, 113, 3084. (d) Allais, C.;
Grassot, J. M.; Rodriguez, J.; Constantieux, T. Chem. Rev. 2014, 114,
10829.
(21) Further optimization conditions can be found in the Supporting
Information, Tables S1−S3.
(22) Other fluoride sources were also attempted, but no improvement
in the yield was obtained (Supporting Information, Table S2).
(23) Further screening of stoichiometric and catalytic oxidant sources
were attempted to no avail (Supporting Information, Table S3).
(24) (a) Harrison, C. R. Tetrahedron Lett. 1987, 28, 4135. (b) Peach,
P.; Cross, D. J.; Kenny, J. A.; Mann, I.; Houson, I.; Campbell, L.;
Walsgrove, T.; Wills, M. Tetrahedron 2006, 62, 1864. (c) Smith, C. D.;
Rosocha, G.; Mui, L.; Batey, R. A. J. Org. Chem. 2010, 75, 4716.
(25) (a) Berthiol, F.; Kondolff, I.; Doucet, H.; Santelli, M. J.
Organomet. Chem. 2004, 689, 2786. (b) Pierrat, P.; Gros, P. C.; Fort, Y.
J. Comb. Chem. 2005, 7, 879. (c) El Kadib, A.; McEleney, K.; Seki, T.;
Wood, T. K.; Crudden, C. M. ChemCatChem 2011, 3, 1281. (d) Quan,
Z.-J.; Jing, F.-Q.; Zhang, Z.; Da, Y.-X.; Wang, X.-C. Eur. J. Org. Chem.
2013, 2013, 7175. (e) Shen, Y.; Chen, J.; Liu, M.; Ding, J.; Gao, W.;
Huang, X.; Wu, H. Chem. Commun. 2014, 50, 4292. (f) Zhang, E.; Tang,
J.; Li, S.; Wu, P.; Moses, J. E.; Sharpless, K. B. Chem. - Eur. J. 2016, 22,
5692. (g) Lamei, K.; Eshghi, H.; Bakavoli, M.; Rounaghi, S. A.; Esmaeili,
E. Catal. Commun. 2017, 92, 40.
(5) Henry, G. D. Tetrahedron 2004, 60, 6043.
(6) (a) Krohnke, F. Synthesis 1976, 1976, 1. (b) Sasaki, I. Synthesis
2016, 48, 1974.
(7) (a) Corriu, R. J. P.; Huynh, V.; Moreau, J. J. E.; Pataudsat, M.
Tetrahedron Lett. 1982, 23, 3257. (b) Corriu, R. J. P.; Moreau, J. J. E.;
Pataudsat, M. J. Org. Chem. 1990, 55, 2878. (c) Hojahmat, M.;
Konakahara, T.; Tamura, S. Heterocycles 2000, 53, 629.
(8) Lui, E. K. J.; Brandt, J. W.; Schafer, L. L. J. Am. Chem. Soc. 2018,
140, 4973.
(9) Harrington, P. J.; Johnston, D.; Moorlag, H.; Wong, J. W.; Hodges,
L. M.; Harris, L.; McEwen, G. K.; Smallwood, B. Org. Process Res. Dev.
2006, 10, 1157.
(10) Damont, A.; Lemee, F.; Raggiri, G.; Dolle, F. J. Heterocycl. Chem.
2014, 51, 404.
(11) Hirose, Y.; Tsuchikawa, H.; Kobayashi, T.; Katsumura, S.
Heterocycles 2015, 90, 150.
(12) (a) Katritzky, A. R.; Mazurkiewicz, R.; Stevens, C. V.; Gordeev,
M. F. J. Org. Chem. 1994, 59, 2740. (b) Liu, S.; Liebeskind, L. S. J. Am.
Chem. Soc. 2008, 130, 6918. (c) Yu, N.; Wang, C.; Zhao, F.; Liu, L.;
Zhang, W. X.; Xi, Z. Chem. - Eur. J. 2008, 14, 5670. (d) Ohashi, M.;
Takeda, I.; Ikawa, M.; Ogoshi, S. J. Am. Chem. Soc. 2011, 133, 18018.
(e) Wei, H.; Li, Y.; Xiao, K.; Cheng, B.; Wang, H.; Hu, L.; Zhai, H. Org.
Lett. 2015, 17, 5974. (f) Sheng, J. Y.; Wang, Y.; Su, X.; He, R.; Chen, C.
Angew. Chem., Int. Ed. 2017, 56, 4824.
(26) (a) Yamamoto, K.; Yamazaki, S.; Murata, I.; Fukazawa, Y. J. Org.
Chem. 1987, 52, 5239. (b) Chang, M. Y.; Lin, C. Y.; Hung, C. Y.
Tetrahedron 2007, 63, 3312. (c) Chiba, S.; Xu, Y. J.; Wang, Y. F. J. Am.
Chem. Soc. 2009, 131, 12886. (d) Chang, M. Y.; Lin, C. H.; Chen, Y. L.
Tetrahedron Lett. 2010, 51, 1430. (e) Gati, W.; Rammah, M. M.;
Rammah, M. B.; Couty, F.; Evano, G. J. Am. Chem. Soc. 2012, 134, 9078.
(f) Gati, W.; Rammah, M. M.; Rammah, M. B.; Evano, G. Beilstein J.
Org. Chem. 2012, 8, 2214.
(13) (a) Wakatsuki, Y.; Yamazaki, H. J. Chem. Soc., Chem. Commun.
1973, 280a. (b) Suzuki, D.; Tanaka, R.; Urabe, H.; Sato, F. J. Am. Chem.
Soc. 2002, 124, 3518. (c) Takahashi, T.; Tsai, F. Y.; Li, Y.; Wang, H.;
Kondo, Y.; Yamanaka, M.; Nakajima, K.; Kotora, M. J. Am. Chem. Soc.
2002, 124, 5059. (d) Satoh, Y.; Obora, Y. J. Org. Chem. 2013, 78, 7771.
(e) Wang, K.; Meng, L. G.; Wang, L. Org. Lett. 2017, 19, 1958.
(14) (a) Roesch, K. R.; Larock, R. C. J. Org. Chem. 1998, 63, 5306.
(b) Roesch, K. R.; Zhang, H.; Larock, R. C. J. Org. Chem. 2001, 66,
8042.
(15) (a) Movassaghi, M.; Hill, M. D.; Ahmad, O. K. J. Am. Chem. Soc.
2007, 129, 10096. (b) Yamamoto, S.; Okamoto, K.; Murakoso, M.;
Kuninobu, Y.; Takai, K. Org. Lett. 2012, 14, 3182. (c) Wu, J. C.; Xu, W.
B.; Yu, Z. X.; Wang, J. J. Am. Chem. Soc. 2015, 137, 9489.
(16) Colby, D. A.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc.
2008, 130, 3645.
(17) (a) Parthasarathy, K.; Jeganmohan, M.; Cheng, C. H. Org. Lett.
2008, 10, 325. (b) Cheng, C.-H.; Parthasarathy, K. Synthesis 2009,
2009, 1400. (c) Chiba, S.; Li, X.; Too, P.; Noji, T.; Lim, Y. Synlett 2011,
2011, 2789. (d) Hyster, T. K.; Rovis, T. Chem. Commun. 2011, 47,
11846. (e) Martin, R. M.; Bergman, R. G.; Ellman, J. A. J. Org. Chem.
2012, 77, 2501.
(27) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc.
Rev. 2008, 37, 320.
(28) Wang, Y.; Han, J.; Chen, J.; Cao, W. Tetrahedron 2015, 71, 8256.
(29) Compound 2s has been recently synthesized by Chen and co-
workers. In their synthesis, an alkenylation of nitriles with
presynthesized vinyliodonium salts is performed. Refer to reference 12f.
(30) Palacios, F.; Vicario, J.; Aparicio, D. Tetrahedron Lett. 2007, 48,
6747.
(31) (a) Chibiryaev, A. M.; De Kimpe, N.; Tkachev, A. V. Tetrahedron
Lett. 2000, 41, 8011. (b) Doebelin, C.; Wagner, P.; Bihel, F.; Humbert,
N.; Kenfack, C. A.; Mely, Y.; Bourguignon, J. J.; Schmitt, M. J. Org.
Chem. 2014, 79, 908. (c) Reimann, S.; Ehlers, P.; Petrosyan, A.; Kohse,
S.; Spannenberg, A.; Surkus, A. E.; Ghochikyan, T. V.; Saghyan, A. S.;
Lochbrunner, S.; Kuhn, O.; Ludwig, R.; Langer, P. Adv. Synth. Catal.
2014, 356, 1987. (d) Tan, W. W.; Ong, Y. J.; Yoshikai, N. Angew. Chem.,
Int. Ed. 2017, 56, 8240.
(18) (a) Krohnke, F.; Zecher, W. Angew. Chem., Int. Ed. Engl. 1962, 74,
626. (b) Del Carmen, M.; Barrio, G.; Barrio, J. R.; Walker, G.; Novelli,
E
DOI: 10.1021/acs.orglett.8b02703
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