Facile, regioselective [4 + 2] cycloaddition involving 1-aryl-4-phenyl-1-azadienes and allenic esters: An efficient route to novel substituted 1-aryl-4-phenyl-1,4-dihydropyridines

Article abstract of DOI:10.1021/ol010026a

(Matrix presented) 1-Aryl-4-phenyl-1-azadienes undergo facile, regioselective [4 + 2] cycloaddition to the C2,C3 π-bond of allenic esters in refluxing benzene, and the formed adducts undergo a 1,3-H shift to afford novel 2-alkyl-1-aryl-3-ethoxycarbonyl-4-

Full text of DOI:10.1021/ol010026a

ORGANIC
LETTERS
2001
Vol. 3, No. 14
2133-2136
Facile, Regioselective [4 + 2]
Cycloaddition Involving
1-Aryl-4-phenyl-1-azadienes and Allenic
Esters: An Efficient Route to Novel
Substituted
1-Aryl-4-phenyl-1,4-dihydropyridines
M. P. S. Ishar,* Kamal Kumar,† Sumanjit Kaur, Shiv Kumar, Navdeep K. Girdhar,
Satish Sachar, Alka Marwaha, and Ashish Kapoor
Department of Pharmaceutical Sciences, Guru Nanak DeV UniVersity,
Amritsar-143 005, Punjab, India
mpsishar@angelfire.com
Received February 14, 2001
ABSTRACT
1-Aryl-4-phenyl-1-azadienes undergo facile, regioselective [4 + 2] cycloaddition to the C2,C3 π-bond of allenic esters in refluxing benzene,
and the formed adducts undergo a 1,3-H shift to afford novel 2-alkyl-1-aryl-3-ethoxycarbonyl-4-phenyl-1,4-dihydropyridines (78−97%). However,
when the reaction is carried at room temperature, besides the [4 + 2] addition, the [2 + 2] mode of addition involving CdN of azadiene and
C3,C4 π-bond of allenic esters also intervenes. The resulting N-aryl-2-ethoxy-carbonyl-methylidene-4-styrylazetidines (17−28%) undergo
reorganization on silica gel to afford 2-cyclohexen-1-ones.
As compared to extensive preparative, mechanistic and
theoretical investigations on Diels-Alder reaction, the het-
ero-Diels-Alder processes have attracted relatively less
attention despite comparable synthetic utility. However, in
the past couple of decades, a considerable amount of work
has been reported in the field of hetero-Diels-Alder
methodology, with definite advancements in theoretical
understanding and synthetic utilization.1 Among the hetero-
dienes, the 1-azadienes have been reported to be sluggish as
dienes in hetero-Diels-Alder reactions, and their 4π par-
ticipation is marred by, inter alia, competing [2 + 2]
Progress in Heterocyclic Chemistry; Suschitzky, H., Sceiven, E. F. V., Eds.;
Pergamon Press: London, 1989; Vol. 1, p 30. (f) McCarrick, M. A.; Wu,
Y. D.; Houk, K. N. J. Org. Chem. 1993, 58, 3330. (g) Sisti, N. J.; Motorina,
I.A.; Dau, M. E. T. H.; Riche, C.; Fowler, F. W.; Grievson, D. S. J. Org.
Chem. 1996, 61, 3715. (h) Motorina, I. A.; Grierson, D. S. Tetrahedron
Lett. 1999, 40, 721. (i) Mogen, J.; Jorgensen, K. A. J. Chem. Soc.,
PerkinTrans. 2 1997, 1183. (j) Sylvie, P.; Masure, D.; Halle, J.-C.; Chaquin,
P. J. Org. Chem. 1997, 62, 8687. (k) Boger, D.; Schaum, R. P.; Garbaccia,
R. M. J. Org. Chem. 1998, 63, 6329. (l) Stainhagen, H.; Corey, E. J. Angew.
Chem., Int. Ed. 1999, 38, 1928. (m) Wijnen, J. W.; Zavarise, S.; Engberts,
J. B. F. N.; Charton, M. J. Org. Chem. 1996, 61, 2001. (n) Fabian, W. M.
F.; Janoschek, R. J. Am. Chem. Soc. 1997, 119, 4253. (o) Graven, A.;
Johannsen, M.; Jorgenson, K. A. Chem. Commun. 1996, 2373. (p) Cuerva,
J. M.; Cardenas, D. J.; Echavarren, A. M. Chem. Commun. 1999, 1721. (q)
Augusti, R.; Gozzo, F. C.; Moraes, L. A. B.; Sparrapan, R.; Eberlin, M. N.
J. Org. Chem. 1998, 63, 4889. (r) Hedegus, L. S.; Montgomery, J.;
Narukawa, Y.; Snustad, O. C. J. Am. Chem. Soc. 1991, 113, 5784.
† Present address: Kyoto Pharmaceutical University, Misasagi, Ya-
mashina, 607-8414, Kyoto, Japan.
(1) (a) Boger, D. L.; Weinreb, S. M. In Hetero Diels-Alder Methodology
in Organic Synthesis; Academic Press Inc.: San Diego, 1987; Chapter 9,
p 239. (b) Boger, D. L. Tetrahedron 1983, 39, 2869. (c) Barulenga, J.;
Tomas, M. AdV. Heterocycl. Chem. 1993, 57, 1. (d) Behforouz, M.;
Ahamadian, M. Tetrahedron 2000, 56, 5259. (e) Boger, D. L.; Patel, M.
10.1021/ol010026a CCC: $20.00 © 2001 American Chemical Society
Published on Web 06/13/2001

additions.1a,b Various strategies that have been devised1a-h,2
to ensure their 4π participation include the introduction of
electron-withdrawing substituent(s) on azadienes so as to
improve their frontier orbital complementarity for inverse
electron demand Diels-Alder reaction. It has been reported3
that reaction of 1-aza-1,4-diphenyl-1,3-butadiene (1, Ar )
Ph) and allenic esters (2) leads to formation of cyclohex-
enones (3) in low yield (25-30%); the latter are postulated
to be derived from (2 + 2) cycloadducts (Scheme 1), though
refluxing benzene, with strict exclusion of moisture. Contrary
to the earlier report,3 this led to almost exclusive formation
of 2-alkyl-1-aryl-3-ethoxycarbonyl-4-phenyl-1,4-dihydropyri-
dines (4). Apparently, these dihydropyridines are derived
from an initial (4 + 2) cycloaddition followed by a
1,3-hydrogen shift. The earlier reported3 cyclohexenones (3)
were detected in trace amount only in some cases, and it
was observed that the rate of the reaction decreased with
increasing size of the 4-alkyl substituent on the allenic esters
(Scheme 2, Table 1).
Scheme 1
Scheme 2
The dihydropyridines have been characterized by detailed
spectroscopic analysis, microanalytical data, and comparison
of the spectroscopic data with the reported data for related
system.6 In their IR spectra these molecules displayed a band
due to ester carbonyl at ∼1690 cm-1, indicating an exten-
sively conjugated ester carbonyl, which was reminiscent of
the IR band of ester carbonyl in Hantzsch esters. In its proton
NMR spectrum compound 4f displayed, besides resonances
in the aromatic region, a doublet at δ 5.99, which was
coupled to a double doublet at δ 4.88; the latter was coupled
to a doublet at δ 4.58. These resonances have been assigned,
respectively, to C6-H, C5-H, and C4-H (compare ref 6).
The assigned structures (4a-h) are also corroborated by the
13C NMR spectral data.
no such proposed intermediate had been isolated and/or
characterized, and no other reaction product has been
reported.
Taking cognizance of a recent report on cycloadditions
of cyclic and acyclic dienes with ketenes, wherein intercon-
vertibility of initially formed (4 + 2), and (2 + 2)
cycloadducts has been described,4 we decided to reinvestigate
the above azadiene-allenic ester cycloadditions with the aim
of establishing the mechanism of the reported3 cyclohexenone
formation and to develop a protocol for 4π participation of
azadienes in reactions with allenic esters. The latter was of
particular interest for development of a simple route to novel
substituted 1,4-dihydropyridines, which are highly sought on
account of both their diverse biological activities and
synthetic applications.1g,p,2,5
Initially, the reactions were carried out by heating equiva-
lent amounts of azadiene (1) and allenic ester (2) in dry
Table 1. Reactions of Azadiene (1) and Allenic Esters (2) in
Refluxing Benzene
(2) (a) Boger, D. L.; Corbett, W. C.; Wiggins, J. M. J. Org. Chem. 1990,
55, 2999. (b) Teng, M.; Fowler, W. Tetrahedron Lett. 1989, 30, 2481. (c)
Teng, M.; Fowler, W. J. Org. Chem. 1990, 55, 5646. (e) Boger, D. L.;
Nakahara, S. J. Org. Chem. 1991, 56, 880. (f) Boger, D. L.; Curran, T. T.
J. Org. Chem. 1990, 55, 5439. (g) Boger, D. L.; Corbett, W. L.; Curran, T.
T.; Kasper, A. M. J. Am. Chem. Soc. 1991, 113, 1713.
(3) Gandhi, R. P.; Ishar, M. P. S.; Wali, A. Tetrahedron Lett. 1987, 6679
(4) Machiguchi, T.; Hasegawa, T.; Ishiwata, A.; Terashima, S.; Yamabe,
S.; Minato, T. J. Am. Chem. Soc. 1999, 121, 4771.
(5) (a) Eisner, U.; Kuthan, J. Chem. ReV. 1972, 72, 1. (b) Stout, D. M.;
Meyers, A. I. Chem. ReV. 1982, 82, 223. (c) Calzoli, L.; Gaggelli, E.;
Maccotta, A.; Valensin, G. J. Chem. Soc., Perkin Trans. 2 1997, 363 and
references therein. (d) Straub, A.; Goehert, A. Angew. Chem., Int. Ed. Engl.
1996, 35, 2662, (e) Zhao, B.; Zhu, X.; Lu, Y.; Xia, C. Z.; Chang, J. P.
Tetrahedron Lett. 2000, 41, 257. (f) Vadecia, Y.; Suaraz, M.; Morales, A.;
Rodriguez, E.; Ochoa, E.; Gonzalaz, L.; Martin, N.; Quinterio, M.; Seorane,
C.; Soto, J. L. J. Chem. Soc., Perkin Trans. 1 1996, 947. (g) Breitenbucher,
J. G.; Figliozzi, G. Tetrahedron Lett. 2000, 41, 4311 and references therein.
(h) Bossert, F.; Meyer, H.; Wehinger, E. Angew. Chem., Int. Ed. Engl. 1981,
20, 762. (i) Lavilla, R.; Coll. O.; Kumar, R.; Bosch, J. J. Org. Chem. 1998,
63, 2728 and references therein. (j) Wenkert, E. Pure Appl. Chem. 1981,
53, 1271. (k) Bosch, J.; Bennasar, M.-L. Synlett 1995. 587. (l) Levecher,
V.; Benoit, R.; Duflos, J.; Dupas, G.; Boutguignon, J.; Queguiner, G.
Tetrahedron 1991, 47, 429.
reaction
no.
R
R1
time (h)
4 (% yield)a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
H
H
H
H
Me
Me
OMe
OMe
OMe
Cl
58
70
80
57
65
55
68
80
55
65
85
55
65
85
4a (96)
4b (85)
4c (79)
4d (95)
4e (88)
4f (97)
4g (92)
4h (85)
4i (94)
4j (89)
4k (78)
4l (97)
4m (90)
4n (85)
Me
Et
H
Me
H
Me
Et
H
Me
Et
H
Cl
Cl
F
F
F
Me
Et
a Yield refers to isolated pure product.
2134
Org. Lett., Vol. 3, No. 14, 2001

As almost exclusively the (4 + 2) mode of cycloaddition
was obtained under these conditions, and in the light of recent
report on formation of (2 + 2) adducts on reacting ketenes
with cyclic/acyclic dienes at room temperature,4 we attempted
the reactions of azadienes with allenic esters by stirring at
ambient temperature. Our goal was the isolation of the (2 +
2) adduct and investigation of its transformation to cyclo-
hexenones (3). Equimolar solutions of azadiene (1) and
allenic esters (2) in dry benzene were stirred at room
temperature for 45-65 days. The 1H NMR spectrum of the
crude sample obtained after evaporation of the solvent
showed the presence of considerable amounts of (2 + 2)
cycloadducts (5, Scheme 3) in addition to the dihydropyri-
1-azadienes with ketenes.1g,7 The trans-arrangement around
3
the C3-C4 bond is based on the low value of J3,4 (∼2.5
Hz),7c and the obtained spectral data indicates single geom-
etry at the exocyclic double bond. However, the assigned
geometry is tentative, based mainly on nonobservance of
NOE for C1′-H on irradiating C3-Me resonance in 5a.
To confirm the formation of cyclohexenones through (2
+ 2) adduct, the isolated (2 + 2) adducts (5) were stirred
with silica gel, in chloroform, for 2 days at which time most
of the (2 + 2) adduct were converted to cyclohexenones (3,
Scheme 4); the latter were separated by column chromatog-
raphy and identified spectroscopically.3
Scheme 4
Scheme 3
Mechanistic aspects of the reported observations are far
from clear. In keeping with the mechanistic proposals for
reactions of 1-azadienes/imines with ketenes1g,h,7a,b,8 and
reported detection of zwitterionic intermediates in additions
to allenes9 and in view of the fact that allenic esters are
related to ketenes, it is often tempting3 to consider the
formation of both (2 + 2) and (2 + 4) adducts through a
common zwitterionic intermediate, B (Scheme 5). However,
the involvement of a common zwitterionic intermediate (B),10
though in consonance with the obtained single geometric
arrangement around the exocyclic double bond in 5 as well
orientation of the azadiene moiety in adducts, fails to explain
the differential π-bond selectivity of the two modes of
addition and the complete stereoselectivity of (2 + 2) mode
of addition, i.e., trans-arrangement around the C3-C4 bond
in azetidines (5). Heating 5 in refluxing benzene for extended
dines (4); the relative ratios of 4 and 5 determined from 1H
NMR of crude reaction products are given in Table 2 along
with reaction times.
Table 2. Reactions of Azadiene (1) and Allenic Ester (2) at
Room Temperature
reaction
4/5 product
no.
R1
R
time (days)
ratioa
5 (% yield)b
1
2
3
4
5
6
Me
Cl
Cl
Cl
H
Me
Me
Et
H
Me
Me
62
52
45
49
60
65
2.5/1.0
2.3/1.0
1.9/1.0
4.0/1.0
2.2/1.0
2.8/1.0
5a (27)
5b (28)
5c (28)
5d (17)
5e (26)
5f (25)
OMe
(7) (a) Brady, W. T.; Shieh, C. H. J. Org. Chem. 1983, 48, 2499. (b)
Arrastia, I.; Arrieta, A.; Ugalde, J. M.; Cossio, F. P.; Lecea, B. Tetrahedron
Lett. 1994, 35, 7825 (c) Gaudemer, A. In Stereochemistry; Kagan, H. B.,
Ed.; Georg Thieme: Stuttgart, 1977; Vol 1, pp 44-136.
a Ratio measured from the 1H NMR spectra of crude reaction products.
b Yield refers to the isolated pure adducts (5) and amount of cyclohexenones
(3) formed.
(8) (a) Lecea, B.; Arrastia, I.; Arrieta, A.; Roa, G.; Lopez, X.; Arriortua.
M. I.; Ugalde, J. M.; Cossio, F. P. J. Org. Chem. 1996, 61, 3070. (b) Arrieta,
A.; Cossio, F. P.; Lecea, B. J. Org. Chem. 1999, 64, 1831. (c) Lopez, R.;
Sordo, T. L.; Sordo, J. A.; Gonzalez, J. J. Org. Chem. 1993, 58, 7036. (d)
Sordo, J. A.; Gonzalez, J.; Sordo, T. J. Am. Chem. Soc. 1992, 114, 6249.
(e) Cossio, F. P.; Ugalde, J. M.; Lopez, X.; Lecea, B.; Palomo, C. J. Am.
Chem. Soc. 1993, 115, 995. (f) Lecea, B.; Arrastia, I.; Rao, G.; Lopez, X.;
Arriortua, M.; Ugald, J. M.; Cossio, F. P. J. Org. Chem. 1996, 61, 3070.
(g) Pacansky, J.; Chang, J. S.; Brown, D. W.; Schwarz, W. J. Org. Chem.
1982, 47, 2333. (h) Moore, H. W.; Hughes, G. Tetrahedron Lett. 1982, 23,
4003.
The (2 + 2) cycloadducts were isolated by flash column
chromatography and characterized spectroscopically. In its
1H NMR, 5a (R ) Me) revealed a 1H double doublet at δ
6.35 (C5-H), a 1H split singlet at δ 5.34 (C7-H), a double
doublet at δ 4.56 (1H, J ) 7.56, 2.44 Hz, C4-H), a quartet
at δ 4.15 (2H, -CO2CH2), another split quartet at δ 3.41
(C3-H), and a doublet at δ 1.59 (3H, C3-CH3); some of
these 1H NMR spectral assignments were aided by compari-
son of the spectral data reported for (2 + 2) cycloadducts of
(9) Gompper, R. G.; Lach, D. Angew Chem., Int. Ed. Engl. 1970, 10,
70.
(10) The formation of zwitterionic intermediate B shall involve the
interaction of a nitrogen lone pair of electrons with the LUMO of the C2-
C3-π bond at the central allenic carbon; the azadiene shall approach from
the side opposite to substituent R on the allenic moiety. In the intermediate
B, substituents on the allenic moiety are kept away from the azadiene
component, and reported low-energy anti-arrangement around CdN (An-
teuis, N.; Bruyn, A. De.; Sandhu, J. S. J. Magn. Reson. 1972, 8, 7) has
been maintained.
(6) (a) Alberola, A.; Gonzalez, A. M.; Gonzalez, B.; Laguna, M. A.;
Fulido, F. J. Tetrahedron Lett. 1986, 27, 2027. (b) Saunders, M.; Gold, E.
H. J. Org. Chem. 1962, 27, 1439. (c) Eynde, J. J. V.; Delfosse, F.; Mayence,
A.; Haverbele, Y. V. Tetrahedron 1995, 51, 6511.
Org. Lett., Vol. 3, No. 14, 2001
2135

The involved orbital interactions are depicted in H (Figure
1). A HOMO-C3-C4 π bond and LUMOs of CdN, and
Scheme 5
Figure 1.
C2-C3 π bond interaction may be the reason for the
observed involvement of only the relatively electron-rich π
bond of allenic esters in this mode of cycloaddition. The
obtaining of relatively higher yields of (2 + 2) adducts from
allenic esters bearing electron-donating alkyl substituents at
C4 supports such a contention. It may be mentioned here
that similar divergent π-bond selectivities for formation of
(4 + 2) and (2 + 2) addition products from reaction of
electron-rich siloxy-dienes with allenic esters have been
recently reported.16
periods led to their slow deterioration, and not a trace of
dihydropyridine (4) was detected at any stage, thereby
indicating the complete irreversibility of azetidine formation
or at least that of 5, under the reaction conditions. Therefore,
the major mode of transformation has to be the cyclization
in D leading to G, followed by 1,3-H shift in G to afford 4;
such facile 1,3-H shifts are precedented in allene chemistry.11
Alternatively, the obtained C2-C3 π-bond selectivity for
the (4 + 2) mode of addition is consistent with a concerted
cycloaddition through a HOMO-diene-LUMO-dienophile
interaction; therefore, only the electron-deficient C2-C3 π
bond of allenic esters is involved. Involvement of such
electron-neutral 1-azadienes in HOMO-diene controlled
hetero-Diels-Alder reactions with electron-deficient dieno-
philes is anticipated.1a-h,2,12 It may be mentioned here that
geometric outcome at the exocyclic double bond and the
stereochemistry of addition (at C3) in (4 + 2) adducts, which
could have provided useful information, is lost due to H-shift
leading to 4.
Though the mechanistic details of the reported transforma-
tions need further probing, the facile 4 π participation of
1-azadienes, leading to valuable 1,4-diaryl-1,4-dihydropy-
ridines, in very high yields is of significant synthetic value.17
The investigations have also led to the isolation of azetidines
(5), and their reorganization to cyclohexenones (3) has been
established.
Acknowledgment. Financial support for this research
work by Council of Scientific and Industrial Research
(CSIR), New Delhi, under research project 01/1591/99-EMR-
II, is gratefully acknowledged.
Supporting Information Available: Experimental pro-
cedures and full characterization of compound 4a-n, 5a-f
and 3a. This material is available free of charge via the
Internet at http://pubs.acs.org.
The formation of azetidines can also be rationalized as a
concerted (π2 + π2 + π2 ) process; though such a
s
s
s
mechanism for observed facile (2 + 2) additions of allene
was proposed13a and latter discarded in favor of a diradical
mechanism,13b many of the recently obtained results have
been rationalized in terms of such a concerted mechanism.14,15
OL010026A
(14) (a) Horino, Y.; Kimura, M.; Wakamiya, Y.; Okajima, T.; Tamaru,
Y.; Angew. Chem., Int. Ed. 1999, 38, 121. (b) Kimura, M.; Horino, Y.;
Wakamiya, Y.; Okajima, T.; Tamaru, Y. J. Am. Chem. Soc. 1997, 119,
10869. (c) Kimura, M.; Wakamiya, Y.; Tamaru, Y. Tetrahedron Lett. 1997,
38, 3963.
(15) Regiochemistry for both modes of addition, when considered as
concerted processes, is in consonance with atomic orbital coefficients in
the frontier molecular orbitals of both reactants.1g,13b
(11) Hayakawa, K.; Nishiyama, H.; kanematsu, K. J. Org. Chem. 1985,
50, 512.
(12) (a) Dau, M. E. T. H.; Flament, J.-P.; Lefour, J.-M.; Riche, C.;
Grierson, D. S. Tetrahedron Lett. 1992, 33, 2343. (b) Boger, D. L.; Kasper,
A. M. J. Am. Chem. Soc. 1989, 111, 1517. (c) Trione, C.; Toledo, L. M.;
Kuduk, S. D.; Fowler, F. W.; Grierson, D. S. J. Org. Chem. 1993, 58, 2075.
(d) Greoigre, P. J.; Mellor, J. M.; Merriman, G. D. Tetrahedron 1995, 51,
6115. (e) Jurisc, B. S.; Zdravkovski, Z. J. Org. Chem. 1995, 61, 3163.
(13) (a) Pasto, D. J. J. Am. Chem. Soc. 1979, 101, 37. (b) Pasto, D. J.
Tetrahedron 1984, 40, 2805.
(16) Jung, M. E.; Nishimura, N. J. Am. Chem. Soc. 1999, 121, 3529.
(17) This approach is all the more important in the light of reported low
reactivity of 1-azadienes towards acetylenic dienophiles.1a,b
2136
Org. Lett., Vol. 3, No. 14, 2001