A cascade approach to pyridines from 2-Azido-2,4-dienoates and α-diazocarbonyl compounds

Article abstract of DOI:10.1021/jo802159g

A one-pot synthesis of substituted pyridines via a cascade reaction of 2-azido-2,4-dienoates with α-diazocarbonyl compounds and triphenylphosphine is reported. The process involves a Staudinger-Meyer reaction, a Wolff rearrangement, an aza-Wittig reaction, and an electrocyclic ring- closure. The procedure is general and efficient. The substrates are readily available.

Full text of DOI:10.1021/jo802159g

of organic reactions,6 such as nucleophilic-addition reactions,7
radical-addition reactions,8 [2+2] and [2+4] cycloaddition
reactions,9 and sigmatropic rearrangements.10 Herein, we de-
scribe a cascade synthesis of substituted pyridines via the
ketenimine intermediates.
A Cascade Approach to Pyridines from
2-Azido-2,4-dienoates and r-Diazocarbonyl
Compounds
Zheng-Bo Chen, Deng Hong, and Yan-Guang Wang*
In the context of our studies aimed for the development of
ketenimine-participated synthetic methods,11 we have focused
on the reaction of 2-azido-2,4-dienoates and R-diazocarbonyl
compounds. When the solution of ethyl 2-azido-5-phenylpenta-
2,4-dienoate (1a), 2-diazo-1-phenylethanone (2a), and triph-
enylphosphine in toluene was refluxed for 10 h, ethyl 6-benzyl-
5-phenylpicolinate (3a) was produced in 10% yield. In an
attempt to improve the yield, subsequent work focused on
optimization of the reaction conditions. We then examined the
reaction temperature and several other solvents such as xylene,
tetrahydrofuran, 1,2-dichloroethane, and CH3CN. The best yield
(80%) was obtained when the reaction was performed in xylene
at 140 °C for 2 h (Table 1, entry 1).
Department of Chemistry, Zhejiang UniVersity,
Hangzhou 310027, China
orgwyg@zju.edu.cn
ReceiVed September 26, 2008
With the suitable reaction conditions in hand, we examined
the scope of this process using various 2-azido-2,4-dienoates
112 and R-diazoketones 2.13 As shown in Table 1, all of the
reactions generated pyridines 3 in good yields (70-90%).
Furthermore, the electron-rich azides (Table 1, entries 11-14)
A one-pot synthesis of substituted pyridines via a cascade
reaction of 2-azido-2,4-dienoates with R-diazocarbonyl com-
pounds and triphenylphosphine is reported. The process
involves a Staudinger-Meyer reaction, a Wolff rearrange-
ment, an aza-Wittig reaction, and an electrocyclic ring-
closure. The procedure is general and efficient. The substrates
are readily available.
(4) For the synthesis of substituted pyridines via multicomponent reactions,
see recent examples: (a) Sasada, T.; Sakai, N.; Konakahara, T. J. Org. Chem.
2008, 73, 6905–6908. (b) Senaiar, R. S.; Young, D. D.; Deiter, A. Chem.
Commun. 2006, 1313–1315. (c) Evdokimov, N.; Magedov, I. V.; Kireev, A. S.;
Kornienko, A. Org. Lett. 2006, 8, 899–902. (d) Dash, J.; Lechel, T.; Reissig,
H.-U. Org. Lett. 2007, 9, 5541–5544. (e) Ranu, B. C.; Jana, R.; Sowmiah, S. J.
Org. Chem. 2007, 72, 3152–3154. (f) Zhu, S.-L.; Ji, S.-J.; Su, X.-M.; Sun, C.;
Liu, Y. Tetrahedron Lett. 2008, 49, 1777–1781.
(5) For the synthesis of substituted pyridines via 6π-electrocyclization of
azahexa-1,3,5-trienes, see: (a) Barluenga, J.; Ferrero, M.; Palacios, F. J. Chem.
Soc., Perkin. Trans. 1 1990, 2193–2197. (b) Molina, P.; Pastor, A.; Vilaplana,
M. J. Tetrahedron 1993, 49, 7769–7778. (c) Palacios, F.; Herra´n, E.; Alonso,
C.; Rubiales, G.; Lecea, B.; Ayerbe, M.; Cossio, F. P. J. Org. Chem. 2006, 71,
6020–6030.
(6) For a recent review, see: Perst, H. Sci. Synth. 2006, 23, 781–897.
(7) (a) Llamas, K.; Owens, M.; Blakeley, R. L.; Zerner, B. J. Am. Chem.
Soc. 1986, 108, 5543–5548. (b) Bae, I.; Han, H.; Chang, S. J. Am. Chem. Soc.
2005, 127, 2038–2039. (c) Fleming, F. F.; Wei, G. Q.; Zhang, Z. Y.; Steward,
O. W. Org. Lett. 2006, 8, 4903–4906.
Substituted pyridines are an important class of compounds
due to their abundance in biologically important natural and
synthetic substances and their utilities as intermediates in
synthetic chemistry.1 Not surprisingly, a large amount of work
has been devoted to the development of methods to provide
these products in a straightforward fashion,2 the majority of
which involve the transition metal mediated cycloadditions,3
one-pot multicomponent reactions,4 and 6π-electrocyclization
of the in situ generated azahexa-1,3,5-trienes.5 Ketenimines are
nitrogenated heterocumulenes, which can participate in a variety
(8) (a) De Vries, L. J. Org. Chem. 1973, 38, 4357–4362. (b) Russell, G. A.;
Chen, P.; Yao, C.-F.; Kim, B. H. J. Am. Chem. Soc. 1995, 117, 5967–5972. (c)
Kim, S. S.; Liu, B.; Park, C. H.; Lee, K. H. J. Org. Chem. 1998, 63, 1571–
1573.
(9) (a) Singer, L. A.; Davis, G. A. J. Am. Chem. Soc. 1967, 89, 598–605.
(b) Dondoni, A.; Battaglia, A.; Bernardi, F.; Giorgianni, P. J. Org. Chem. 1980,
´
(1) For reviews, see: (a) Babu, P. A.; Narasu, M. L.; Srinivas, K. ARKIVOC
2007, 247–265. (b) O’Hagan, D. Nat. Prod. Rep. 2000, 17, 435–446. (c) O’Hagan,
D. Nat. Prod. Rep. 1997, 14, 637–651. (d) Joule, J. A.; Mills, K. In Heterocyclic
Chemistry, 4th ed.; Blackwell: Oxford, UK, 2000.
(2) For reviews, see: (a) Henry, G. D. Tetrahedron 2004, 60, 6043–6061.
(b) Varela, J. A.; Saa, C. Chem. ReV. 2003, 103, 3787–3802. (c) Ciufolini, M. A.;
Chan, B. K. Heterocycles 2007, 74, 101–124.
45, 3773–3778. (c) Alajar´ın, M.; Bonillo, B.; Sa´nchez-Andrada, P.; Vidal, A.;
Bautista, D. J. Org. Chem. 2007, 72, 5863–5866. (d) Fabian, W. M. F.; Janoschek,
R. J. Am. Chem. Soc. 1997, 119, 4253–4257. (e) Alonso-Go´mez, J. L.; Pazos,
Y.; Navarro-Va´zquez, A.; Lugtenburg, J.; Cid, M. M. Org. Lett. 2005, 7, 3773–
´
3776. (f) Alajar´ın, M.; Ort´ın, M.-M.; Sa´nchez-Andrada, P.; Vidal, A.; Bautista,
D. Org. Lett. 2005, 7, 5281–5284.
(10) (a) Alajar´ın, M.; Bonillo, B.; Ort´ın, M.-M.; Sa´nchez-Andrada, P.; Vidal,
A Org. Lett. 2006, 8, 5645–5648. (b) Lee, K.-W.; Horowitz, N.; Ware, J.; Singer,
´
(3) For the transition metal-catalyzed synthesis of substituted pyridines, see
recent examples: (a) Varela, J. A.; Castedo, L.; Saa`, C. J. Org. Chem. 2003, 68,
8595–8598. (b) McCormick, M. M.; Duong, H. A.; Zuo, G.; Louie, J. J. Am.
Chem. Soc. 2005, 127, 5030–5031. (c) Tanaka, R.; Yuza, A.; Watai, Y.; Suzuki,
D.; Takayama, Y.; Sato, F.; Urabe, H. J. Am. Chem. Soc. 2005, 127, 7774–
7780. (d) Chang, H.-T.; Jeganmohan, M.; Cheng, C.-H. Org. Lett. 2007, 9, 505–
508. (e) Kase, K.; Goswami, A.; Ohtaki, K.; Tanabe, E.; Saino, N.; Okamoto,
S. Org. Lett. 2007, 9, 931–934. (f) Trost, B. M.; Gutierrez, A. C. Org. Lett.
L. A. J. Am. Chem. Soc. 1977, 99, 2622–2627. (c) Walters, M. A. J. Am. Chem.
Soc. 1994, 116, 11618–11619.
(11) (a) Yang, Y. Y.; Shou, W. G.; Hong, D.; Wang, Y. G. J. Org. Chem.
2008, 73, 3574–3577. (b) Yang, Y. Y.; Shou, W. G.; Chen, Z. B.; Hong, D.;
Wang, Y. G. J. Org. Chem. 2008, 73, 3928–3930. (c) Cui, S. L.; Wang, J.;
Wang, Y. G. Org. Lett. 2008, 10, 1267–1269. (d) Cui, S. L.; Wang, J.; Wang,
Y. G. Org. Lett. 2007, 9, 5023–5025. (e) Cui, S. L.; Lin, X. F.; Wang, Y. G.
Org. Lett. 2006, 8, 4517–4520.
`
2007, 9, 1473–1476. (g) Barluenga, J.; Ferna`ndez-Rodr´ıguez, M. A.; Garcia-
Garcia, P.; Aguilar, E. J. Am. Chem. Soc. 2008, 130, 2764–2765. (h) Colby,
D. A.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2008, 130, 3645–3651.
(i) Parthasarathy, K.; Jeganmohan, M.; Cheng, C.-H. Org. Lett. 2008, 10, 325–
328. (j) Movassaghi, M.; Hill, M. D. J. Am. Chem. Soc. 2006, 128, 4592–4593.
(k) Liu, S. B.; Liebeskind, L. S. J. Am. Chem. Soc. 2008, 130, 6918–6919.
(12) 2-Azido-2,4-dienoates were readily prepared by aldol condensation of
R,ꢀ-unsaturated aldehydes and ethyl azidoacetate. For the method, see: (a) Henn,
L.; Hickey, D. M. B.; Moody, C. J.; Rees, C. W. J. Chem. Soc., Perkin Trans.
1 1984, 2189–2196. (b) Bra¨se, S.; Gil, C.; Knepper, K.; Zimmermann, V. Angew.
Chem., Int. Ed. 2005, 44, 5188–5240.
10.1021/jo802159g CCC: $40.75
Published on Web 12/09/2008
2009 American Chemical Society
J. Org. Chem. 2009, 74, 903–905 903

TABLE 1. Synthesis of Pyridines 3a
TABLE 2. Synthesis of Pyridines 5a
entry
R1/R2
R3
Ph (4a)
4-BrC6H4 (4c)
Ph (4a)
4-MeC6H4 (4b)
4-BrC6H4 (4c)
4-MeOC6H4 (4d)
Me (4e)
product
yield (%)b
1
2
3
4
5
6
7
Ph/H (1a)
Ph/H (1a)
Ph/Me (1b)
Ph/Me (1b)
Ph/Me (1b)
Ph/Me (1b)
Ph/H (1a)
5a
5b
5c
5d
5e
5f
78
77
79
81
76
85
80
5g
a Reaction conditions: 1 (0.5 mmol), 4 (0.5 mmol), PPh3 (0.5 mmol),
toluene (20 mL), N2, 100 °C, 2 h. b The yield of the isolated product.
SCHEME 1. A Plausible Mechanism for the Synthesis of
Pyridines
Wittig reaction between phosphazene A and ketene B affords
N-vinylic ketenemine C.17 Finally, the electrocyclic ring
closure of C and a subsequent double bond isomerization
give pyridine 3.
a Reaction conditions: 1 (0.5 mmol), 2 (0.5 mmol), PPh3 (0.5 mmol),
xylene (20 mL), N2, 140 °C, 2 h. b The yield of the isolated product.
In summary, we have demonstrated an efficient synthesis of
substituted pyridines via a one-pot cascade reaction of 2-azido-
2,4-dienoates, R-diazocarbonyl compounds, and triphenylphos-
phine. The procedure is rapid and general, and the substrates
are readily available.12,13,18 This methodology will find applica-
tions in the synthesis of natural products and organic materials
as well as ligands.
gave better yields than the electron-deficient azides (Table 1,
entries 8-10 and 15-18).
Next, our attention was directed toward the reaction of
2-diazo-1,3-diones 414 (Table 2). It was found that all the
reactions could take place at lower temperature (100 °C) in
toluene, resulting in pyridines 5 in good yields (76-85%).
In all cases, pyridines 5 were isolated as the sole product.
Herein we described our working hypothesis of the mecha-
nism in Scheme 1. First, azide 1 reacts with triphenylphos-
phine to form phosphazene A via the Staudinger-Meyer
reaction,15 while R-diazoketone 2 transforms to ketene B
through the Wolff rearrangement reaction.16 Then the aza-
Experiment Section
General Procedure for the Synthesis of Pyridines 3. To a
solution of PPh3 (0.131 g, 0.5 mmol) in anhydrous xylene (10 mL)
(16) (a) Wolff, L. Liebigs Ann. Chem. 1912, 394, 23. (b) Kirmse, W. Eur. J.
Org. Chem. 2002, 219, 3–2256.
(13) R-Diazoketones were prepared by the reaction of acetophenones with
2,2,2-trifluoroethyl trifluoroacetate in the presence of LiHMDS and then treating
with MsN3/Et3N. For the method, see: Danheiser, R. L.; Miller, R. F.; Brisbois,
R. G.; Park, S. Z. J. Org. Chem. 1990, 55, 1959–1964.
(14) 2-Diazo-1,3-diones were prepared from 1,3-diones and p-toluenesulfonyl
azide. For the method, see: Regitz, C. J. Chem. Ber. 1966, 99, 3128–3147.
(15) (a) Staudinger, H.; Meyer, J. HelV. Chim. Acta 1919, 2, 635–646. (b)
Ko¨hn, M.; Breinbauer, R. Angew. Chem., Int. Ed. 2004, 43, 3106–3116.
(17) (a) Palacios, F.; Alonso, C.; Rubiales, G.; Villegas, M. Tetrahedron
2005, 61, 2779–2794. (b) Palacios, F.; Alonso, C.; Aparicio, D.; Rubiales, G.;
de los Santos, J. M. Tetrahedron 2007, 63, 523–575.
(18) Many azides have hazardous behavior and some of them are potential
energetic materials (see: Badgujar, D. M.; Talawar, M. B.; Asthana, S. N.;
Mahulikar, P. P. J. Hazard. Mater. 2008, 151, 289–305. ). Although we did not
encounter any danger in our experiment, the caution about the potential hazardous
behavior of azides should be indicated.
904 J. Org. Chem. Vol. 74, No. 2, 2009

was added dropwise a solution of 1 (0.5 mmol) and 2 (0.5 mmol)
in anhydrous xylene (10 mL) at 140 °C under nitrogen atmosphere
over 30 min. The mixture was stirred for 2 h. The solvent was
evaporated in vacuum and residual oil was purified by silica gel
column chromatography, using hexane/EtOAc (5:1) as the eluent,
to afford pure 3.
Ethyl 6-(1-oxo-1-phenylpropan-2-yl)-5-phenylpicolinate (5a):
yellow oil; IR (KBr) 1742, 1716, 1447, 1387, 1143, 1006, 764 cm-1
;
1H NMR (500 MHz, CDCl3) δ 7.97 (d, J ) 7.9 Hz, 1 H), 7.63 (d,
J ) 7.9 Hz, 1 H), 7.59-7.57 (m, 2 H), 7.43-7.39 (m, 4 H),
7.30-7.26 (m, 4 H), 4.91-4.89 (m, 1 H), 4.43-4.39 (m, 2 H),
1.64 (d, J ) 6.9 Hz, 3 H), 1.40 (t, J ) 7.1 Hz, 3 H) ppm; 13C
NMR (125 MHz, CDCl3) δ 200.0, 165.5, 158.6, 147.5, 140.2, 138.7,
137.1, 132.5, 129.1, 129.0, 128.6, 128.4, 128.3, 123.1, 61.8, 47.6,
17.3, 14.5 ppm; MS (ESI) m/z ([M + H]+) 360. Anal. Calcd for
C23H21NO3: C 76.86, H 5.89, N 3.90. Found: C 76.89, H 5.92, N
3.93.
Ethyl 6-benzyl-5-phenylpicolinate (3a): yellow oil; IR (KBr)
1
1741, 1495, 1445, 1386, 1137, 1007, 762 cm-1; H NMR (500
MHz, CDCl3) δ 8.03 (d, J ) 7.8 Hz, 1 H), 7.63 (d, J ) 7.8 Hz, 1
H), 7.38-7.36 (m, 3 H), 7.15-7.09 (m, 5 H), 6.96 (d, J ) 6.8 Hz,
2 H), 4.50 (q, J ) 7.1, 2 H), 4.26 (s, 2 H), 1.45 (t, J ) 7.1, 3 H)
ppm; 13C NMR (125 MHz, CDCl3) δ 165.6, 158.7, 147.0, 141.1,
139.5, 139.0, 138.8, 129.1, 129.0, 128.6, 128.3, 128.2, 126.2, 123.1,
62.0, 42.1, 14.6 ppm; MS (ESI) m/z ([M + H]+) 318. Anal. Calcd
for C21H19NO2: C 79.47, H 6.03, N 4.41. Found: C 79.40, H 6.03,
N 4.43.
Ethyl 6-(1-(4-bromophenyl)-1-oxopropan-2-yl)-5-phenylpicoli-
nate (5b): white solid, mp 90-91 °C; IR (KBr) 1743, 1710, 1443,
1
1387, 1140, 1007, 764 cm-1; H NMR (500 MHz, CDCl3) δ 7.98
(d, J ) 7.8 Hz, 1 H), 7.65 (d, J ) 7.9 Hz, 1 H), 7.46-7.40 (m, 7
H), 7.30-7.27 (m, 2 H), 4.82 (q, J ) 6.9 Hz, 1 H), 4.43-4.38 (m,
Ethyl 6-(4-methylbenzyl)-5-phenylpicolinate (3b): yellow oil; IR
2 H), 1.63 (d, J ) 6.9 Hz, 3 H), 1.40 (t, J ) 7.1 Hz, 3 H) ppm; 13
C
1
(KBr) 1742, 1513, 1444, 1384, 1137, 1007, 761 cm-1; H NMR
NMR (125 MHz, CDCl3) δ 198.8, 165.3, 158.3, 147.6, 140.1, 138.9,
138.5, 135.9, 131.7, 129.9, 129.1, 128.7, 127.4, 123.3, 61.8, 47.7,
17.3, 14.5 ppm; MS (ESI) m/z ([M + H]+) 438. Anal. Calcd for
C23H20BrNO3: C 63.02, H 4.60, N 3.20. Found: C 63.01, H 4.66,
N 3.20.
(500 MHz, CDCl3) δ 8.01 (d, J ) 7.9 Hz, 1 H), 7.62 (d, J ) 7.8
Hz, 1 H), 7.39-7.38 (m, 3 H), 7.17-7.15 (m, 2 H), 6.95 (d, J )
7.9 Hz, 2 H), 6.87 (d, J ) 8.0 Hz, 2 H), 4.49 (q, J ) 7.1 Hz, 2 H),
4.20 (s, 2 H), 2.25 (s, 3 H), 1.45 (t, J ) 7.1 Hz, 3 H) ppm; 13C
NMR (125 MHz, CDCl3) δ 165.6, 158.9, 147.0, 141.0, 139.1, 138.7,
136.5, 135.6, 129.2, 129.0, 128.9, 128.6, 128.2, 123.0, 62.0, 41.6,
21.2, 14.6 ppm; MS (ESI) m/z ([M + H]+) 332. Anal. Calcd for
C22H21NO2: C 79.73, H 6.39, N 4.23. Found: C 79.73, H 6.37, N
4.24.
General Procedure for the Synthesis of 5. To a solution of
PPh3 (0.131 g, 0.5 mmol) in anhydrous toluene (10 mL) was added
dropwise a solution of 1 (0.5 mmol) and 4 (0.5 mmol) in anhydrous
toluene (10 mL) under nitrogen atmosphere at 100 °C over 30 min.
After the mixture was stirred for 2 h, the solvent was evaporated
in vacuum and residual oil was purified by silica gel column
chromatography, using hexane/EtOAc (5:1) as the eluent, to afford
pure 5.
Acknowledgment. We thank the National Natural Science
Foundation of China (No. 20672093) and the Specialized
Research Fund for Doctoral Program of Higher Education
(20050335101).
Supporting Information Available: Detailed experimental
procedures, characterization data, and copies of 1H and 13C NMR
spectra for all products. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO802159G
J. Org. Chem. Vol. 74, No. 2, 2009 905