IBX mediated reaction of β-enamino esters with allylic alcohols: A one pot metal free domino approach to functionalized pyridines

Article abstract of DOI:10.1039/c3cc44274h

IBX facilitated the reaction of β-enamino esters with allylic alcohols affording a direct, one-pot and metal free synthesis of functionalized pyridines including 2-substituted nicotinic acids, densely substituted pyridines and precursors of azafluorenones. The methodology also afforded the racemic pyridine core of cyclothiazomycin.

Full text of DOI:10.1039/c3cc44274h

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IBX mediated reaction of b-enamino esters with allylic
alcohols: a one pot metal free domino approach to
functionalized pyridines†
Cite this: Chem. Commun., 2013,
49, 7926
Received 6th June 2013,
Accepted 9th July 2013
Narendar Reddy Gade, V. Devendram, Manojit Pal* and Javed Iqbal*
DOI: 10.1039/c3cc44274h
www.rsc.org/chemcomm
IBX facilitated the reaction of b-enamino esters with allylic alcohols
affording a direct, one-pot and metal free synthesis of functionalized
pyridines including 2-substituted nicotinic acids, densely substituted
pyridines and precursors of azafluorenones. The methodology also
afforded the racemic pyridine core of cyclothiazomycin.
While a broad array of attractive methodologies are available for
the synthesis of functionalized N-heterocycles the development
of direct, simple and efficient strategies that offer considerable
challenges is still of high demand in modern organic synthesis.
Thus continuing efforts have been made in this direction by
both academic and industrial organizations.
Pyridine, one of the simplest and well known N-heterocycles, is
an important structural motif and has received vast attention
from the scientific community over the last century. The presence
of pyridine scaffolds in several natural products, pharmaceuticals
and materials has prompted synthetic chemists to develop several
routes for the synthesis of pyridine derivatives.1 Though effective
in many cases several of these methodologies however suffer
from some drawbacks such as longer route, lower yields etc.
Thus design and development of simple and efficient strategies
Scheme 1 Synthesis of functionalized pyridines.
to synthesize substituted pyridines are of high interest. Domino ketones or aldehyde in two steps4 (Scheme 1). After the pioneering
reactions2 are known to be promising strategies in increasing the work of Bagley and his group on this reaction it became one of the
efficiency of several synthetic methods. Since multiple transforma- effective methods for the synthesis of substituted pyridines.5 While
tions occur under the same conditions in a single pot, domino effort has been devoted to improve the reaction conditions further,
reactions often avoid the isolation of intermediates and subsequent to date there have been no reports6 on the use of inexpensive, readily
purification steps. Herein, we report a simple, direct and metal-free available and easy to handle allylic alcohol as a key precursor.
domino approach towards functionalized pyridines starting from This is noteworthy as the previously used enones3 and ynones4
readily available reactants.
are polymeric in nature and often cause handling problems. We
In 1956 Tsuda et al.3 reported the synthesis of pyridine derivatives envisioned that a flexible domino reaction between b-enamino
via the reaction of acrolein with ethyl b-aminocrotonate (Scheme 1). esters and allylic alcohols can afford substituted pyridines in
Subsequently, in 1957 Bohlmann and Rahtz reported the synthesis the presence of a suitable oxidizing agent. We now present our
of substituted pyridines using a stabilized enamine and ethynyl preliminary results on a IBX mediated one pot metal free
approach to functionalized pyridines (Scheme 1).
IBX (2-iodoxybenzoic acid), a versatile reagent,7 has found wide
applications in organic synthesis and was chosen as an oxidizing
Dr Reddy’s Institute of Life Sciences, University of Hyderabad Campus, Gachibowli,
Hyderabad 500 046, India. E-mail: manojitpal@rediffmail.com,
jiqbal@ilsresearch.org; Tel: +91 40 6657 1500
agent in our study. Accordingly, we designed a domino reaction
† Electronic supplementary information (ESI) available: Experimental proce-
between allyl alcohols and b-enamino esters using IBX as an oxidant.
Initially, the reaction of (Z)-ethyl 3-amino-3-phenylacrylate (1a) and
dures, spectral data for all new compounds and copies of NMR spectra. See
DOI: 10.1039/c3cc44274h
c
7926 Chem. Commun., 2013, 49, 7926--7928
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Table 1 Effect of conditions on the reaction of 1a with 2a
Table 2 IBX-mediated synthesis of 2-substituted nicotinic acid derivatives (3)a
Entry
Temp (1C)
Time (h)
Yieldb (%)
Temp (1C)/
Time (h)
Product
3
Yieldb
(%)
Entry
Enamine R1; 1
1
2
3
4
5
6
7
8
30
50
70
70
70
70
70
90
24
24
3
24
10
10
10
3
0
25
1
2
3
4
5
6
7
8
Phenyl, 1a
70/3
70/3
70/3
70/3
70/3
70/3
90/5
90/5
90/5
90/5
90/5
90/5
90/5
3a
3b
3c
3d
3e
3f
3g
3h
3i
74
75
74
73
72
74
70
68
72
72
80
85
69
74
o-Cl-phenyl, 1b
m-Cl-phenyl, 1c
p-Cl-phenyl, 1d
o-Br-phenyl, 1e
p-Br-phenyl, 1f
Benzyl, 1g
p-Br-benzyl, 1h
3,4-Dimethoxybenzyl, 1i
4-Pyridyl, 1j
0c
10d
40e
50 f
68
a
All reactions were performed using the b-enamino ester 1a (0.2 mmol),
allyl alcohol 2 (2 equiv.) and IBX (1.2 equiv.) in DMSO (3 mL) under
9
10
11
12
13
3j
3k
3l
b
c
open air. Isolated yields. The reaction was performed in the absence
2-Furyl, 1k
d
e
of IBX. 0.05 equiv. of IBX was used. 0.5 equiv. of IBX was used.
N-Methyl-5-indolyl, 1l
1-Oxo-1,3-dihydroisobenzo
furan-5-yl, 1m
Cinnamyl, 1n
f
1.2 equiv. of allyl alcohol was used.
3m
14
15
90/5
110/12
3n
3o
73
76
allyl alcohol (2) was performed in DMSO to establish the optimized
reaction conditions. After assessing various reaction conditions
(Table 1) the best result was achieved by performing the reaction
using b-enamino ester 1a (0.2 mmol), allyl alcohol 2 (2 equiv.) and
IBX (1.2 equiv.) in DMSO (3 mL) at 70 1C for 3 h when the desired
ethyl 2-phenylnicotinate (3a) was obtained in good yield (entry 3,
Table 1). The reaction did not proceed in the absence of IBX
(entry 4, Table 1) or in the presence of other oxidants e.g. Ag2O
indicating the key role played by IBX. The use of lower quantity of
IBX (entries 5 and 6, Table 1) or alcohol 2 (entry 7, Table 1) decreased
the product yield whereas an increase in reaction temperature
to 90 1C did not improve the yield of 3a (entry 8, Table 1).
With the optimized reaction conditions in hand we then examined
the scope and generality of this method. Thus, a range of b-enamino
esters (containing aryl/heteroaryl/benzyl/cinnamyl/aliphatic groups)
were reacted with allyl alcohols in the presence of IBX to
give various 2-substituted nicotinic acid derivatives (Table 2).
All these reactions were performed either at 70 (entries 1–6,
Table 2) or 90 1C (entries 7–14, Table 2) except for one case
(entry 15, Table 2). Since these reactions do not require the use
of any inert or anhydrous atmosphere they were performed under
open air. Notably, all the nicotinate derivatives synthesized
(Table 2, entries 1–6) can be converted easily to azafluorenones
in a single step.8 Azafluorenones, common skeletons in many
Methyl, 1o
a
All reactions were performed using the b-enamino ester 1 (0.2 mmol),
allyl alcohol 2 (0.4 mmol), IBX (1.2 equiv.) in DMSO (3 mL) under open
b
air. Isolated yields.
Table 3 IBX-mediated synthesis of densely substituted pyridinesa
Entry Enamine 1 Alcohol R2, R3; 4
Product 5 Yieldb (%)
1
2
3
4
5
6
7
8
1a
1f
1o
1a
1j
1a
1j
1n
H, Ph; 4a
H, p-NO2C6H4; 4b
4a
CO2Et, Ph; 4c
4c
CO2Et, p-NO2C6H4; 4d 5f
4d
4d
5a
5b
5c
5d
5e
70
65
72c
68
60
70
62
60
5g
5f
a
All reactions were performed using b-enamino ester 1 (0.1 mmol),
allylic alcohol 2 (0.1 mmol), IBX (1.2 equiv.) in DMSO (3 mL) at 30 1C
under open air. Isolated yields. The reaction was performed at 50 1C.
b
c
Mechanistically, the reaction seems to proceed (Scheme 2) via (i)
natural products and useful agents in medicinal chemistry, IBX mediated conversion11a of the alcohol (2 or 4) to the corre-
are generally accessed via multistep sequences using metal sponding carbonyl compound which upon (ii) Michael addition with
mediated reactions.9
b-enamino ester (1) followed by (iii) intramolecular cyclization gives
To expand the scope of this reaction further, we examined the B that (iv) aromatizes to 3 or 5 in the presence of air.11b
use of substituted allylic alcohols. Thus various allylic alcohols (4)
The potential of this methodology was demonstrated in the
were treated with b-enamino esters (1) in the presence of IBX to synthesis of the pyridine core of cyclothiazomycin12 i.e. one of the
give the corresponding pyridines (5) in good yields (Table 3).
Notably, unlike the case of alcohol 2 all these reactions proceeded
well at 30 1C. This method therefore provides a facile entry to
unsymmetrically tetrasubstituted pyridines (Table 3, entries 4–8)
and seemed to have advantages over the traditional Hantzsch
synthesis10 which affords symmetrical pyridines. However, the
methodology was not successful in the preparation of 4-substituted
pyridines from the corresponding allylic alcohols which appeared
Scheme 2 The proposed reaction mechanism.
to be the limitation of this methodology.
c
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4 F. Bohlmann and D. Rahtz, Chem. Ber., 1957, 90, 2265.
5 (a) M. C. Bagley, J. W. Dale and J. Bower, Synlett, 2001, 1149;
(b) M. C. Bagley, C. Brace, J. W. Dale, M. Ohnesorge, N. G. Philips,
X. Xiong and J. Bower, J. Chem. Soc., Perkin Trans. 1, 2002, 1663;
(c) M. C. Bagley, J. W. Dale and J. Bower, Chem. Commun., 2002, 1682;
(d) M. C. Bagley, D. D. Hughes, H. M. Sabo, P. H. Taylor and X. Xiong,
Synlett, 2003, 1443; (e) X. Xiong, M. C. Bagley and K. Chapaneri,
Tetrahedron Lett., 2004, 45, 6121; ( f ) M. C. Bagley, K. Chapaneri,
J. W. Dale, X. Xiong and J. Bower, J. Org. Chem., 2005, 70, 1389.
6 For an informative account, see: M. C. Bagley, C. Glover and
E. A. Merritt, Synlett, 2007, 2459.
Scheme 3 Synthesis of the pyridine core of cyclothiazomycin.
7 For an in depth review, see: A. Duschek and S. F. Kirsch, Angew.
Chem., Int. Ed., 2011, 50, 1524.
76 structurally distinct actinomycete thiopeptide antibiotics.13 Many
thiopeptides contain the 2,3,6-trisubstituted pyridine core and several
groups have developed different synthetic routes to this moiety.5f,14
Our strategy was mainly based on just bringing the corresponding
enamine and allylic alcohol together under the conditions of
the newly developed methodology. Thus, the required enamine
6 (racemic) and the allylic alcohol 7 were prepared15 and then
reacted in the presence of IBX in DMSO at 50 1C for 4 h to give
the pyridine core (racemic) of cyclothiazomycin 8 (Scheme 3).12
In conclusion, a direct, one-pot and metal free synthesis of
functionalized pyridines has been developed for the first time
via the IBX mediated reaction of readily available b-enamino esters
and allylic alcohols under open air. The methodology afforded
2-substituted nicotinic acids, tetra substituted unsymmetrical
pyridines and precursors of azafluorenones. The use of a b-enamino
amide afforded the racemic pyridine core of cyclothiazomycin.
The methodology may find wide applications in the construction
of a pyridine based library of small molecules for medicinal uses
or natural product synthesis.
´
´
8 (a) A. S. Rebstock, F. Mongin, F. Trecourt and G. Queguiner, Tetra-
´
hedron, 2003, 59, 4973; (b) A. S. Rebstock, F. Mongin, F. Trecourt and
´
G. Queguiner, Tetrahedron, 2004, 60, 2181.
9 (a) J. Koyama, I. Morita, N. Kobayashi, T. Osakai, Y. Usuki and
M. Taniguchi, Bioorg. Med. Chem. Lett., 2005, 15, 1079;
(b) G. A. Kraus and A. Kempema, J. Nat. Prod., 2010, 73, 1967.
10 (a) A. Hantzsch, Ber. Dtsch. Chem. Ges., 1881, 14, 1637; (b) A. Hantzsch,
Justus Liebigs Ann. Chem., 1882, 215, 1; (c) D. M. Stout and A. I. Meyers,
Chem. Rev., 1982, 82, 223; (d) U. Eisner and J. Kuthan, Chem. Rev.,
1972, 72, 1.
11 (a) T. Zoller, P. Breuilles, D. Uguen, A. De Cian and J. Fischer,
Tetrahedron Lett., 1999, 40, 6253; (b) While IBX mediated aromatiza-
tion of 1,4-dihydropyridine has been reported earlier (see:
J. S. Yadav, B. V. S. Reddy, A. K. Basak, G. Baishya and
A. V. Narsaiah, Synthesis, 2006, 451) a similar reaction is unlikely
in the present case considering the fact that only 1.2 equivalents of
IBX were used (we thank reviewers for pointing out this). Thus
aromatization of B was aided by the aerial oxygen, see for example:
L. Shen, S. Cao, J. Wu, J. Zhang, H. Li, N. Liuand and X. Qian, Green
Chem., 2009, 11, 1414.
12 (a) A. Okabe, A. Ito, K. Okumura and C. G. Shin, Chem. Lett., 2001,
380; (b) C. G. Shin, A. Okabe, A. Ito and Y. Yonezawa, Bull. Chem. Soc.
Jpn., 2002, 75, 1583; (c) M. C. Bagley and X. Xiong, Org. Lett., 2004,
6, 3401; (d) For a recent and elegant synthesis, see: Y. Zou, Q. Liu
and A. Deiters, Org. Lett., 2011, 13, 4352.
NRG and DV thank CSIR, New Delhi, India, for research
fellowships. The authors thank DRILS for analytical support.
13 M. C. Bagley, J. W. Dale, E. A. Merritt and X. Xiong, Chem. Rev., 2005,
105, 68.
14 (a) R. A. Hughes, S. P. Thompson, L. Alcaraz and C. J. Moody, J. Am.
Chem. Soc., 2005, 127, 15644; (b) K. C. Nicolaou, B. S. Safina, M. Zak,
A. A. Estrada and S. H. Lee, Angew. Chem., Int. Ed., 2004, 43, 5087;
(c) M. C. Bagley, K. E. Bashford, C. L. Hesketh and C. J. Moody,
J. Am. Chem. Soc., 2000, 122, 3301.
15 Compound 6 was prepared by treating tert-butyl-2-methyl-3,5-dioxo-
pyrrolidine-1-carboxylate with NH4OAc whereas 7 was prepared by
reacting ethyl-2-formylthiazole-4-carboxylate with vinyl magnesium
bromide. For a detailed procedure, see ESI†.
Notes and references
1 (a) M. Z. Chen and G. C. Micalizio, J. Am. Chem. Soc., 2012,
134, 1352, and references therein; (b) G. D. Henry, Tetrahedron,
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2 L. F. Tietze, Chem. Rev., 1996, 96, 115.
3 K. Tsuda, Y. Satch, N. Ikekawa and H. Mishima, J. Org. Chem., 1956,
21, 800.
c
7928 Chem. Commun., 2013, 49, 7926--7928
This journal is The Royal Society of Chemistry 2013