Tandem one-pot synthesis of polysubstituted pyridines using the blaise reaction intermediate and 1,3-enynes

Article abstract of DOI:10.1021/ol202691b

A tandem one-pot method for the construction of a pyridine moiety with selective control of substitution patterns has been developed through the sequential reactions of nitrile with a Reformatsky reagent and 1,3-enyne involving regio- and chemoselective a

Full text of DOI:10.1021/ol202691b

ORGANIC
LETTERS
2011
Vol. 13, No. 24
6390–6393
Tandem One-Pot Synthesis of
Polysubstituted Pyridines Using the
Blaise Reaction Intermediate and
1,3-Enynes
Yu Sung Chun, Jun Hee Lee, Ju Hyun Kim, Young Ok Ko, and Sang-gi Lee*
Department of Chemistry and Nano Science (BK21), Ewha Womans University, Seoul
120-750, Korea
sanggi@ewha.ac.kr
Received October 8, 2011
ABSTRACT
A tandem one-pot method for the construction of a pyridine moiety with selective control of substitution patterns has been developed through the
sequential reactions of nitrile with a Reformatsky reagent and 1,3-enyne involving regio- and chemoselective addition of the Blaise reaction
intermediate to 1,3-enyne, followed by isomerization, cyclization, and an aromatization cascade.
The pyridine moiety is an important component of
various natural products, pharmaceuticals, and functional
materials.1 Consequently, the development of a new syn-
thetic method for the construction of pyridines is always
important. Although substantial progress has been made
in the derivatization of pre-existing pyridine frameworks
using metal-catalyzed cross-coupling protocols,2 de novo
methods for the convergent construction of regiocon-
trolled pyridine cores would provide important comple-
mentary approaches.3 The value of these methods would
greatly increase if the reactions were run in tandem since
this would minimize the synthetic steps and waste
generation.4 Due to their functional group tolerance, zinc
enolate intermediates have attracted particular attention in
the development of tandem reactions.5 Here, we report an
unprecedented tandem one-pot method for the modular
construction of pyridine moieties through the sequential
(1) (a) Jones, G. In Comprehensive Heterocyclic Chemistry, Vol. 5;
Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V.; Eds.; Pergamon:
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4th ed.; Wiley-Blackwell: Oxford, 2000. (c) Michael, J. P. Nat. Prod. Rep.
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(2) (a) For a review, see: Fairlamb, I. J. S. Chem. Soc. Rev. 2007, 36,
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S. I.; Stuart, D. R.; Campeau, L.-C.; Fagnou, K. J. Org. Chem. 2010, 75,
8180. (d) Mousseau, J. J.; Bull, J. A.; Charette, A. B. Angew. Chem., Int.
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(3) For recent reviews on pyridine synthesis, see: (a) Henry, G. D.
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2007, 36, 1084. (c) Zeni, G.; Larock, R. C. Chem. Rev. 2006, 106, 4644.
(d) Hill, M. D. Chem.;Eur. J. 2010, 16, 12052. (e) Groenendaal, B.;
Ruijter, E.; Orru, R. V. A. Chem. Commun. 2008, 5474. For selected
recent papers for the synthesis of selectively substituted pyridine deri-
vatives, see:(f) Movassaghi, M.; Hill, M. D.; Ahmad, O. K. J. Am. Chem.
Soc. 2007, 129, 10096. (g) Manning, J. R.; Davies, M. H. J. Am. Chem.
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Chem., Int. Ed. 2009, 48, 8325. (k) Sha, F.; Huang, X. Angew. Chem., Int.
Ed. 2009, 48, 3458.
(4) (a) Ho, T.-L. Tandem Organic Reactions; Wiley: New York, 1992.
(b) Tietze, L. F.; Brasche, G.; Gericke, K. Domino Reactions in Organic
Synthesis; Wiley-VCH: Weinheim, 2006. (c) Nicolaou, K. C.; Edmonds,
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D. J.; Bulger, P. G. Angew. Chem., Int. Ed. 2006, 45, 7134. (d) Furstner, A.
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Shell, A. J. Chem. Rev. 1996, 96, 195.
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Vries, A. H. M. Angew. Chem., Int. Ed. Engl. 1997, 36, 2620.
(b) Alexakis, A.; Trevitt, G. P.; Bernardinelli, G. J. Am. Chem. Soc.
2001, 123, 4358. (c) Mizutani, H.; Degrado, S. J.; Hoveyda, A. H. J. Am.
Chem. Soc. 2002, 124, 779. (d) Agapiou, K.; Cauble, D. F.; Krische, M. J.
J. Am. Chem. Soc. 2004, 126, 4528. (e) Greszler, S. N.; Johnson, J. S.
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r
10.1021/ol202691b
Published on Web 11/10/2011
2011 American Chemical Society

reaction of nitriles with Reformatsky reagents (the Blasie
reaction) and 1,3-enynes (Scheme 1). This reaction can
provide an operationally simple, scalable, and flexible
method for constructing pyridine rings with controllable
substitution patterns around the pyridine core. To the best
of our knowledge, this represents the first use of a Refor-
matsky reagent in the tandem construction of the pyridine
ring moiety. The direct incorporation of 1,3-enynes into
the pyridine rings is also noteworthy.6
and/or cycloaddition to produce the pyridines 4 after
elimination of HZnBr (Scheme 1).8 Compared to the
previously reported construction of a substituted pyridine
moiety from the N-lithium 1-azatrienes with limited func-
tional group compability,9 our approach using organozinc
reagents could provide the additional advantage of broad
functional group tolerance.
To test our hypothesis, we commenced our investigation
with the Blaise reaction intermediate 5a, formed from the
reaction of benzonitrile (1a) with a Reformatsky reagent
2a generated in situ from ethyl bromoacetate (1.5 equiv)
and zinc (2.0 equiv) in THF (over 96% of 1a was converted
to the 5a). The tandem reaction of 5a with commericially
available 1-ethynylcyclohexene (3a, 1.1 equiv) was carried
out in THF under reflux for 2 h to afford the tetrahydro-
quinoline 4aa in 70% yield along with the R-dienylated
β-enaminoester 9 (13%) (Scheme 2). This result clearly
indicated that the zincated aminotriene 6 was formed as
an intermediate. When the tandem reaction was carried
out in 1,4-dioxane at 110 °C, the yield of 4aa increased to
90% (entry 1, Table 1).The structure of 4aa was unam-
bigously determined by X-ray analysis (Figure 1).10 Under
standard conditions, various aromatic nitriles with elec-
tron-donating or -withdrawing group such as methyl,
methoxy, halides, and ester groups were readily converted
to the corresponding tetrahydroquinolines 4aaÀ4ka in
good to excellent yields (entries 2À11, Table 1).
Scheme 1. Tandem One-Pot Synthetic Strategy for Construc-
tion of Pyridine Moiety
We recently became interested in the tandem use of the
Blaise reaction intermediate 5 as an aza-zinc enolate with a
unique ambivalent C-/N-nucleophilic nature for tandem
CÀC or CÀC/CÀN bond formations.7 During these
studies, we observed the balanced propensity of the inter-
mediate 5 to play the dual function of a carbon nucleophile
as well as a Lewis acid in activating unactivated terminal
alkynes for regio- and chemoselective R-vinylation.7c
A mechanistic study suggested that a zinc bromide complex
of the R-vinylated β-enaminoester was formed first, which
was then converted to the corresponding R-vinylated
β-enaminoesters after workup. We reasoned that, if identical
tandem reactions were conducted with a 1,3-enyene 3, the
resulting R-dienylated β-enaminozincate 6 might then be
capable of undergoing an isomerization to the N-zincated
1-azatriene 7, which could facilitate a 6π electrocyclization
Scheme 2. Initial Probe Experiment
One of the nitrile groups of the terephthalonitrile was
selectively converted to a pyridine ring to produce the
nitrile-functionalized 4la in 60% yield, which could be
further manipulated (entry 12, Table 1). With an excess
of the Reformatsky reagent, both of the nitrile groups
could be converted to the bis-enaminozincate intermediate
5lb, which then reacted with 2.2 equiv of 3a to afford the
bipyridyl compound 4lb in 56% yield. Based on the unique
reactivity of the Blaise reaction intermediate toward pro-
piolates affording pyridones,7d the sequential tandem re-
actionsof 5lb with1,3-enyne 3aand ethyl phenylpropiolate
enabled divergent construction of two different heterocyc-
lic rings, pyridine and pyridone, in one molecule 9 (39%)
(6) Recently, syntheses of pyridines by the Au-catalyzed intermole-
cular cycloaddition of dienynes with nitriles have been disclosed:
ꢀ
Barluenga, J.; Fernandez-Rodrıguez, M. A.; Garcıa-Garcıa, P.; Aguilar,
E. J. Am. Chem. Soc. 2008, 130, 2764.
(7) (a) Chun, Y. S.; Lee, K. K.; Ko, Y. O.; Shin, H.; Lee, S.-g. Chem.
Commun. 2008, 5098. (b) Ko, Y. O.; Chun, Y. S.; Park, C.-L.; Lee, Y.;
Shin, H.; Ahn, S.; Hong, J.; Lee, S.-g. Org. Biomol. Chem. 2009, 7, 1132.
(c) Chun, Y. S.; Ko, Y. O.; Shin, H.; Lee, S.-g. Org. Lett. 2009, 11, 3414.
(d) Chun, Y. S.; Ryu, K. Y.; Ko, Y. O.; Hong, J. Y.; Hong, J.; Shin, H.;
Lee, S.-g. J. Org. Chem. 2009, 74, 7556. (e) Ko, Y. O.; Chun, Y. S.; Kim,
Y.; Kim, S. J.; Shin, H.; Lee, S.-g. Tetrahedron Lett. 2010, 51, 6893.
(f) Chun, Y. S.; Ryu, K. Y.; Kim, J. H.; Shin, H.; Lee, S.-g. Org. Biomol.
Chem. 2011, 9, 1317. (g) Kim, J. H.; Lee, S.-g. Org. Lett. 2011, 13, 1350.
(8) Pyridine synthesis via 6π electrocyclization, see: (a) Colby, D. A.;
Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2008, 130, 3645. (b)
Liu, S.; Liebeskind, L. S. J. Am. Chem. Soc. 2008, 130, 6918. (c)
Nakamura, I.; Zhang, D.; Terada, M. J. Am. Chem. Soc. 2010, 132,
7884. For pronounced acceleration of the electrocyclic closure of
trienes, see:(d) Magomedov, N. A.; Ruggiero, P. L.; Tang, Y. J. Am.
Chem. Soc. 2004, 126, 1624. (e) Greshock, T. J.; Funk, R. L. J. Am.
Chem. Soc. 2006, 128, 4946.
(9) Chen, J.; Song, Q.; Wang, C.; Xi, Z. J. Am. Chem. Soc. 2002, 124,
6238.
(10) The crystallographic data can be obtained from The Cambridge
Crystallographic Data Centre (CCDC 847154) via www.ccdc.cam.ac.
uk/data_request/cif.
Org. Lett., Vol. 13, No. 24, 2011
6391

along with 4lb (15%) (Scheme 3). Heteroaromatic and
aliphatic nitriles were also readily converted to the corre-
sponding tetrahydroquinoline derivatives 4maÀ4pa in
high yield (entries 13À16, Table 1). The use of Reformats-
ky reagents with different R2 groups did not diminish the
yield of the tandem reaction, allowing 3-methylester 4ab
(entry 17, Table 1) and 3-isopropyl ester tetrahydroquino-
lines 4ac (entry 18, Table 1) to be prepared in high yield.
Table 1. Tandem One-Pot Synthesis of Tetrahydroquinolinesa
Scheme 3. Double Tandem Reactions with Bisnitrile for One-
Pot Construction of Two Heterocycles in One Molecule
The generality of types of 1,3-enyene 3 that could be
employed was investigated using the Blaise reaction inter-
mediate 5a (Table 2). Both seven- and eight-membered
carbocyclic 1,3-enyenes were successfully incorporated
into the pyridine moieties to afford the corresponding
carbocycle-fused pyridines 4ad (82% yield, entry 1,
a Reaction conditions: nitrile 1 (3.0 mmol), Zn (6.0 mmol), alkyl bro-
moacetate (4.5 mmol), 3a (3.3 mmol) in 1,4-dioxane (1.5 mL). 3a was added
when nitrile 1 was converted to intermediate 5 in over 95% by GC, and the
reaction was continued until all of 5 was consumed by GC. b Isolated yield.
Table 2. Tandem One-Pot Synthesis of Pyridines with Various
1,3-Enynesa
a Reaction conditions: nitrile 1a (3.0 mmol), Zn (6.0 mmol), ethyl
bromoacetate (4.5 mmol), 1,3-enyne 3 (3.3 mmol) in 1,4-dioxane (1.5
mL). Enyne 3 was added when 1a was converted to intermediate 5a in
over 95% by GC, and the reaction was continued until all of 5a was
consumed by GC. b Isolated yield (average of two experiments). c Yield
from the reaction with (E)-3i. d Yield from the reaction with (Z)-3i.
Figure 1. X-ray structure of 4aa.
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Org. Lett., Vol. 13, No. 24, 2011

Table 2) and 4ae (70% yield, entry 2, Table 2), respectively.
Benzofused 4af was also synthesized in good yield (entry 3,
Table 2). Although these yields were lower than those
obtained from cyclic 1,3-enynes, likely due to the entropic
effects, a series of acyclic 1,3-enyenes with phenyl/methyl
(entry 4, Table 2), phenyl/phenyl and phenyl/H (entries 5
and 6, Table 2), and propyl/propyl (entry 7, Table 2)
substituents was also smoothly reacted with5a in a tandem
manner to produce the corresponding polysubstituted
pyridines 4agÀ4aj. Noteworthy is that the stereochemistry
of the enyne did not affect the reactivity of the reactions.
Thus, tandem reactions with the enynes (E)- and (Z)-3i
afforded the same pyridine 4ai with almost the same yield
(entry 6, Table 2). However, it was found that the 1,3-
enynes with internal alkynes such as 1-prop-1-ynylcyclo-
hexene and cyclohex-1-enylethynylbenzene were not sui-
table substrates for this tandem reaction.
available nitriles, Reformatsky reagents, and 1,3-enynes.
The tandem reaction proceeded via the regio- and
chemoselective addition of the Blaise reaction inter-
mediate to 1,3-enyne followed by an isomerization/
cyclization/aromatization cascade. Extrapolation to di-
vergent tandem reactions allowed the construction of
two different heterocycles, pyridine and pyridone rings,
in one molecule.
Acknowledgment. We thank the National Research
Foundation of Korea funded by the Ministry of Educa-
tion, Science and Technology (NRF-20110002962 and
NRF-20110016344) for financial support. Y.S.C. thanks
Ewha Womans University for RP-support.
Supporting Information Available. Experimental de-
tails; characterization data of 4aaÀ4pa, 4abÀ4aj, 8, 9 and
their 1H, 13C NMR and HRMS spectra; and CIF for 4aa.
This material is available free of charge via the Internet at
http://pubs.acs.org.
In summary, an efficient tandem one-pot method was
developed for the synthesis of polysubstituted pyridines
with complete control of substitution patterns from readily
Org. Lett., Vol. 13, No. 24, 2011
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