Synthesis of Polysubstituted Pyridines via a One-Pot Metal-Free Strategy

Article abstract of DOI:10.1021/acs.orglett.5b02903

An efficient strategy for the one-pot synthesis of polysubstituted pyridines via a cascade reaction from aldehydes, phosphorus ylides, and propargyl azide is reported. The reaction sequence involves a Wittig reaction, a Staudinger reaction, an aza-Wittig reaction, a 6π-3-azatriene electrocyclization, and a 1,3-H shift. This protocol provides quick access to the polysubstituted pyridines from readily available substrates in good to excellent yields.

Full text of DOI:10.1021/acs.orglett.5b02903

Letter
pubs.acs.org/OrgLett
Synthesis of Polysubstituted Pyridines via a One-Pot Metal-Free
Strategy
Hongbo Wei,† Yun Li,*,† Ke Xiao,† Bin Cheng,† Huifei Wang,‡ Lin Hu,§ and Hongbin Zhai*,†,‡,∥
†The State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engeneering, Lanzhou University,
Lanzhou 730000, China
‡Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School of Peking University,
Shenzhen 518055, China
§Department of Chemistry, Brandeis University, Waltham, Massachusetts 02454-9110, United States
∥Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300071, China
S
* Supporting Information
ABSTRACT: An efficient strategy for the one-pot synthesis of
polysubstituted pyridines via a cascade reaction from aldehydes,
phosphorus ylides, and propargyl azide is reported. The reaction
sequence involves a Wittig reaction, a Staudinger reaction, an aza-
Wittig reaction, a 6π-3-azatriene electrocyclization, and a 1,3-H
shift. This protocol provides quick access to the polysubstituted
pyridines from readily available substrates in good to excellent
yields.
Scheme 1. Synthesis of Pyridines from Benzaldehyde
ubstituted pyridines are an important class of N-
Sheterocyclic compounds with many roles in natural
products, active pharmaceuticals, functional materials, and
synthetic intermediates.1 Development of mild and efficient
methods for the synthesis of substituted pyridines remains
highly desirable. As a consequence, considerable efforts have
been directed to construct these privileged heterocycles.2
Currently, many powerful methodologies for the synthesis of
pyridine rings rely mainly on one-pot multicomponent
reactions,3 condensation of amines and carbonyl compounds,
metal-catalyzed cycloaddition reactions,4 or 6π-electrocycliza-
tion.5 However, a literature survey reveals that most of the
published approaches involve multistep preparation for the
substrates, the usefulness of which is limited by lack of
generality. Therefore, an efficient and general procedure for the
synthesis of substituted pyridines from readily available
substrates under mild reaction conditions is still of considerable
interest.
Consistent with what green chemistry advocates, the cascade
reactions involving simple operational procedures and equip-
ment are commonly used to save time and energy, to avoid
isolating intermediates, and to improve reaction efficiency.6 We
herein present an efficient one-pot synthesis of substituted
pyridines from an aldehyde, a phosphorus ylide, and propargyl
azide through a metal-free, multicomponent, one-pot sequence
involving Wittig reaction, Staudinger reaction, aza-Wittig
reaction, 6π-3-azatriene electrocyclization reaction, and 1,3-H
shift (Scheme 1).
room temperature and propargyl azide along with triphenyl-
phosphine was added. The reaction was maintained at room
temperature for 0.5 h, and then at 80 °C for 96 h. To our
delight, the expected product, 2,5-dimethyl-4-phenylpyridine,
was obtained in 79% yield (Table 1, entry 1). We next
investigated the reaction parameters in order to enhance the
efficiency of the process. The reaction temperature was first
evaluated. The desired product was isolated in 78% yield after
36 h at 100 °C and in 80% yield after 24 h at 120 °C (entries 2
and 3). It is noteworthy that higher temperatures (e.g., 140 °C)
failed to further increase the yield (entry 4). The solvent effect
was then examined (entry 5−9). When PhH, PhCl, CH3CN, or
THF was used as the solvent, the reaction proceeded smoothly
to render the product in moderate to good yields (65−72%).
However, DCE was unfit for the process since it almost shut
down the reaction completely. Thus, entry 3 in Table 1 reflects
the optimized reaction conditions for this protocol.
With the optimized conditions in hand, various aldehydes
and phosphorus ylides were screened to investigate the
generality of the current synthesis of substituted pyridines.
As a pilot experiment, Wittig reaction of benzaldehyde and a
phosphorus ylide was conducted at 90 °C in PhMe for 5 h.
After benzaldehyde was consumed, the mixture was cooled to
Received: October 7, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02903
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Letter
a
phenyl ring) retarded the reaction to some extent and resulted
in relatively low yields for the pyridine products (3l−3o, 63−
74%). For the latter case, decreased electron density in the π-
conjugative system may slow down the rate of 6π-electro-
cyclization.7 However, substrates with a heteroaryl substituent
(furanyl or pyridyl) showed good tolerance (3q, 3r). Good
yields were also achieved with 4-biphenyl (3s, 91%), 2-naphthyl
(3t, 88%), and 4-styryl (3u, 85%), indicating that the steric
effect of the R1 substituent had little influence on the reaction.
Moreover, the reaction with an aliphatic aldehyde (phenyl-
propyl aldehyde) as the substrate proceeded smoothly and
provided the desired product (3v) in 51% yield. The scope of
phosphorus ylides was subsequently evaluated. It was observed
that phosphorus ylides with a bulky alkyl group were also
accommodated for this process, yet generating the product in
slightly low yields (3w−3y). Similarly, the substrate bearing a
simple phenyl group was suitable for this process (3z).
However, 4-methoxylphenyl and 4-bromophenyl substituted
phosphorus ylides led to much lower efficiency and afforded
products in the yields of 40% (3aa) and 41% (3ab),
respectively. Notably, when R2 group is H, no expected
product (3ac) was obtained, probably due to inefficient
formation of the imine via a Staudinger reaction. Nevertheless,
the disubstituted pyridine 3ac could be synthesized in
reasonable yield via direct condensation of propargylamine
and cinnamaldehyde (Scheme 3) and followed by a similar 6π-
3-azatriene electrocyclization reaction and a [1,3] hydrogen
shift sequence.
Table 1. Optimization of the Reaction Conditions
b
entry
solvent
temperature (°C)
time (h)
yield (%)
1
2
3
4
5
6
7
8
9
PhMe
PhMe
PhMe
PhMe
PhH
80
96
36
24
15
24
24
96
50
35
79
100
120
140
120
120
120
120
120
78
80
78
75
PhCl
70
DCE
trace
62
CH3CN
THF
68
a
Reaction conditions: 1a (0.94 mmol), 2a (0.99 mmol), azidoprop-1-
yne (3.77 mmol), Ph3P (1.09 mmol), solvent (5 mL) Isolated yield.
DCE = 1,2-dichloroethane.
b
The results are summarized in Scheme 2. The substitution
pattern of benzaldehydes was first examined. In general, a wide
range of aldehydes bearing various functional groups gave rise
to the substituted pyridines in moderate to high yields (3a−
3p). Aldehydes containing one or two electron-donating groups
(Me or MeO, 3b−3e, 3p) or a relatively weak electron-
withdrawing group (halogen or CO2Me, 3f−3k) on the phenyl
ring led to pyridines in good yields (78−90%). In contrast, a
more electron-deficient phenyl ring within the aldehyde
substrate (CF3, NO2, CN, or multiple halogen atoms, on the
A plausible mechanism for the formation of pyridine 3a is
shown in Scheme 4. Initially, α,β-unsaturated ketone 4a is
formed through Wittig reaction of benzaldehyde 1a and
phosphorus ylide 2a.8 Independently, azide 7 reacts with
triphenylphosphine to furnish phosphazene 8 via Staudinger
a
Scheme 2. Synthesis of Pyridines
a
b
1
Isolated yield. The yield was determined by H NMR analysis.
B
DOI: 10.1021/acs.orglett.5b02903
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Scheme 3. Direct Condensation Approach with
Cinnamaldehyde as the Substrate
ACKNOWLEDGMENTS
■
We thank NSFC (21302077; 21472072; 21172100; 21272105;
21290183) and “111” Program of MOE for financial support.
REFERENCES
■
(1) (a) O’Hagan, D. Nat. Prod. Rep. 1997, 14, 637−651. (b) Abe, Y.;
Kayakiri, H.; Satoh, S.; Inoue, T.; Sawada, Y.; Inamura, N.; Asano, M.;
Aramori, I.; Hatori, C.; Sawai, H.; Oku, T.; Tanaka, H. J. Med. Chem.
1998, 41, 4062−4079. (c) Li, A. H.; Moro, S.; Forsyth, N.; Melman,
N.; Ji, X.-D.; Jacobsen, K. A. J. Med. Chem. 1999, 42, 706−721.
(d) Vacher, B.; Bonnaud, B.; Funes, F.; Jubault, N.; Koek, W.; Assie,
M. B.; Cosi, C.; Kleven, M. J. Med. Chem. 1999, 42, 1648−1660.
(e) Knip, M.; Douek, I. F.; Moore, W. P. T.; Gillmor, H. A.; McLean,
A. E. M.; Bingley, P. J.; Gale, E. A. M. Diabetologia 2000, 43, 1337−
1345. (f) O’Hagan, D. Nat. Prod. Rep. 2000, 17, 435−446. (g) Joule, J.
A.; Mills, K. In Heterocyclic Chemistry, 4th ed.; Blackwell: Oxford, U.K.,
2000. (h) Scriven, E.; Berry, D. Speciality Chem. Mag. 2001, 24.
(i) Farhanullah; Agarwal, N.; Goel, A.; Ram, V. J. J. Org. Chem. 2003,
68, 2983−2985. (j) Carey, J. S.; Laffan, D.; Thomson, C.; Williams, M.
T. Org. Biomol. Chem. 2006, 4, 2337−2347. (k) Roughley, S. D.;
Jordan, A. M. J. Med. Chem. 2011, 54, 3451−3479.
Scheme 4. Proposed Reaction Mechanism
(2) (a) Henry, G. D. Tetrahedron 2004, 60, 6043−6061. (b) Heller,
B.; Hapke, M. Chem. Soc. Rev. 2007, 36, 1085−1094. (c) Hill, M. D.
Chem. - Eur. J. 2010, 16, 12052−12062. (d) Bull, J. A.; Mousseau, J. J.;
Pelletier, G.; Charette, A. B. Chem. Rev. 2012, 112, 2642−2713.
(e) Allais, C.; Grassot, J. M.; Rodriguez, J.; Constantieux, T. Chem. Rev.
2014, 114, 10829−10868.
(3) (a) Senaiar, R. S.; Young, D. D.; Deiter, A. Chem. Commun. 2006,
1313−1315. (b) Evdokimov, N.; Magedov, I. V.; Kireev, A. S.;
Kornienko, A. Org. Lett. 2006, 8, 899−902. (c) Dash, J.; Lechel, T.;
Reissig, H. U. Org. Lett. 2007, 9, 5541−5544. (d) Ranu, B. C.; Jana, R.;
Sowmiah, S. J. Org. Chem. 2007, 72, 3152−3154. (e) Sasada, T.; Sakai,
N.; Konakahara, T. J. Org. Chem. 2008, 73, 6905−6908. (f) Zhu, S. L.;
Ji, S. J.; Su, X. M.; Sun, C.; Liu, Y. Tetrahedron Lett. 2008, 49, 1777−
reaction.9 Subsequently, aza-Wittig reaction between phospha-
zene 8 and ketone 4a gives rise to imine 9,10 which
spontaneously undergoes isomerization to form intermediate
A, which features an allene moiety conjugated with α,β-
unsaturated imine.11 Then, 6π-3-azatriene electrocyclization of
A was triggered, followed by 1,3-H shift, to render the final
trisubstituted pyridine 3a.
In conclusion, we have developed a new, metal-free, and one-
pot synthetic route to substituted pyridines, which employs a
cascade reaction sequence from an α,β-unsaturated ketone and
a phosphazene (both produced in situ), involving an aza-Wittig,
a 6π-3-azatriene electrocyclization reaction, and a [1,3]-
hydrogen shift. Based upon advantages such as simple
operation, broad functionality tolerance, and significance of
the multisubstituted pyridine products, this method should find
broad applications in organic synthesis.
́ ́
1781. (g) Barluenga, J.; Jimenez-Aquino, A.; Fernandez, M. A.; Aznar,
F.; Valdes, C. Tetrahedron 2008, 64, 778−786. (h) Chen, M. Z.;
́
Micalizio, G. C. J. Am. Chem. Soc. 2012, 134, 1352−1356. (i) Zheng,
L.; Ju, J.; Bin, Y.; Hua, R. J. Org. Chem. 2012, 77, 5794−5800.
(j) Cheng, G.; Zeng, X.; Shen, J.; Wang, X.; Cui, X. Angew. Chem., Int.
Ed. 2013, 52, 13265−13268. (k) He, Z.; Dobrovolsky, D.; Trinchera,
P.; Yudin, A. K. Org. Lett. 2013, 15, 334−337.
(4) (a) Krohnke, F. Synthesis 1975, 1−24. (b) Kelly, T. R.; Liu, H. J.
̈
Am. Chem. Soc. 1985, 107, 4998−4999. (c) Boger, D. L. Chem. Rev.
1986, 86, 781−793. (d) Ciufolini, M. A.; Hermann, C. Y.; Dong, W.
Q.; Shimizu, T.; Swaminathan, S.; Xi, N. Synlett 1998, 1998, 105−114.
(e) Sklenicka, H. M.; Hsung, R. P.; McLaughlin, M. J.; Wei, L. L.;
Gerasyuto, A. I.; Brennessel, W. W. J. Am. Chem. Soc. 2002, 124,
́
10435−10442. (f) Varela, J. A.; Saa, C. Chem. Rev. 2003, 103, 3787−
3802. (g) Sangu, K.; Fuchibe, K.; Akiyama, T. Org. Lett. 2004, 6, 353−
355. (h) Sydorenko, N.; Hsung, R. P.; Vera, E. L. Org. Lett. 2006, 8,
2611−2614. (i) Movassaghi, M.; Hill, M. D. J. Am. Chem. Soc. 2006,
128, 4592−4593. (j) Movassaghi, M.; Hill, M. D. J. Am. Chem. Soc.
2006, 128, 14254−14255. (k) Heller, B.; Hapke, M. Chem. Soc. Rev.
2007, 36, 1085−1094. (l) Movassaghi, M.; Hill, M. D.; Ahmad, O. K. J.
Am. Chem. Soc. 2007, 129, 10096−10097. (m) Trost, B. M.; Gutierrez,
A. C. Org. Lett. 2007, 9, 1473−1476. (n) Meketa, M. L.; Weinreb, S.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02903.
́
M. Org. Lett. 2007, 9, 853−855. (o) Domínguez, G.; Perez-Castells, J.
Experimental procedures and characterization data for
new compounds (PDF)
Chem. Soc. Rev. 2011, 40, 3430−3444. (p) Zhou, H.; Liu, L.; Xu, S. J.
Org. Chem. 2012, 77, 9418−9421. (q) Cheng, G.; Cui, X. Org. Lett.
2013, 15, 1480−1483.
(5) (a) Barluenga, J.; Ferrero, M.; Palacios, F. J. Chem. Soc., Perkin
Trans. 1 1990, 2193−2197. (b) Molina, P.; Pastor, A.; Vilaplana, M. J.
AUTHOR INFORMATION
Corresponding Authors
■
́
Tetrahedron 1993, 49, 7769−7778. (c) Palacios, F.; Herran, E.; Alonso,
C.; Rubiales, G.; Lecea, B.; Ayerbe, M.; Cossio, F. P. J. Org. Chem.
2006, 71, 6020−6030. (d) Liu, S. B.; Liebeskind, L. S. J. Am. Chem.
Soc. 2008, 130, 6918−6919. (e) Kobayashi, T.; Hatano, S.; Ts
uchikawa, H.; Katsumura, S. Tetrahedron Lett. 2008, 49, 4349−4351.
(f) Chen, Z. B.; Hong, D.; Wang, Y. G. J. Org. Chem. 2009, 74, 903−
*E-mail: liyun@lzu.edu.cn.
*E-mail: zhaih@lzu.edu.cn.
Notes
The authors declare no competing financial interest.
C
DOI: 10.1021/acs.orglett.5b02903
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
905. (g) Nakamura, I.; Zhang, D.; Terada, M. J. Am. Chem. Soc. 2010,
132, 7884−7886.
(6) (a) Posner, G. H. Chem. Rev. 1986, 86, 831−844. (b) Ho, T. L.
Tandem Organic Reactions; Wiley-Interscience: New York, 1992.
(c) Tietze, L. F.; Beifuss, U. Angew. Chem., Int. Ed. Engl. 1993, 32,
131−163. (d) Burk, M. J.; Lee, J. R.; Martinez, J. P. J. Am. Chem. Soc.
1994, 116, 10847−10848. (e) Hall, N. Science 1994, 266, 32−34.
(f) Tietze, L. F. Chem. Rev. 1996, 96, 115−136. (g) Denmark, S. E.;
Thorarensen, A. Chem. Rev. 1996, 96, 137−166. (h) Balema, V. P.;
Hey-Hawkins, E. Z. Z. Anorg. Allg. Chem. 1996, 622, 2053−2056.
(I) Wasilke, J. C.; Obrey, S. J.; Baker, R. T.; Bazan, G. C. Chem. Rev.
2005, 105, 1001−1020.
(7) For a computational study on the electrocyclizations of 1-amino-
1,3,5-hexatrienes, see: Guner, V. A.; Houk, K. N.; Davies, I. W. J. Org.
Chem. 2004, 69, 8024−8028.
(8) (a) Ohno, H.; Okumura, M.; Maeda, S.; Iwasaki, H.; Wakayama,
R.; Tanaka, T. J. Org. Chem. 2003, 68, 7722−7732. (b) Alonso, D.;
́
Caballero, E.; Medarde, M.; Tome, F. Tetrahedron Lett. 2005, 46,
4839−4841. (c) Zhou, F.; Han, X. L.; Lu, X. Y. J. Org. Chem. 2011, 76,
1491−1494. (d) Byrne, P. A.; Rajendran, K. V.; Muldoon, J.; Gilheany,
D. G. Org. Biomol. Chem. 2012, 10, 3531−3537. (e) Wu, X.; Li, M. L.;
Chen, D. F.; Chen, S. S. J. Org. Chem. 2014, 79, 4743−4750.
(9) (a) Staudinger, H.; Meyer, J. Helv. Chim. Acta 1919, 2, 635−646.
(b) Kohn, M.; Breinbauer, R. Angew. Chem., Int. Ed. 2004, 43, 3106−
̈
3116. (c) Lin, F. L.; Hoyt, H. M.; van Halbeek, H.; Bergman, R. G.;
Bertozzi, C. R. J. Am. Chem. Soc. 2005, 127, 2686−2695. (d) Liang, Y.;
Jiao, L.; Zhang, S. W.; Yu, Z. X.; Xu, J. X. J. Am. Chem. Soc. 2009, 131,
1542−1549. (e) Vallee
́
, M. R. J.; Majkut, P.; Wilkening, I.; Weise, C.;
Muller, G.; Hackenberger, C. P. R. Org. Lett. 2011, 13, 5440−5443.
̈
(f) Kumar, R.; Ermolat’ev, D. S.; Van der Eycken, E. V. J. Org. Chem.
2013, 78, 5737−5743.
(10) (a) Williams, D. R.; Shamim, K. J.; Reddy, P.; Amato, G. S.;
Shaw, S. M. Org. Lett. 2003, 5, 3361−3364. (b) Freifeld, I.; Shojaei, H.;
Dede, R.; Langer, P. J. Org. Chem. 2006, 71, 6165−6170. (c) Luo, Z.
S.; Peplowski, K.; Sulikowski, G. A. Org. Lett. 2007, 9, 5051−5054.
(d) Yang, Y.-Y.; Shou, W.-G.; Chen, Z.-B.; Hong, D.; Wang, Y.-G. J.
Org. Chem. 2008, 73, 3928−3930.
(11) (a) Menges, N.; Sari, O.; Abdullayev, Y.; Erdem, S. S.; Balci, M.
J. Org. Chem. 2013, 78, 5184−5195. (b) Cetinkaya, Y.; Balci, M.
Tetrahedron Lett. 2014, 55, 6698−6702. (c) Keskin, S.; Balc, M. Org.
Lett. 2015, 17, 964−967.
D
DOI: 10.1021/acs.orglett.5b02903
Org. Lett. XXXX, XXX, XXX−XXX