Cascade synthesis of 1,2-dihydropyridine from dienaminodioate and an imine: A three-component approach

Article abstract of DOI:10.1016/j.tetlet.2013.05.037

A convenient synthesis of 1,2-dihydropyridine (1,2-DHP) has been developed from dienaminodioate and an imine mediated by trifluoroacetic acid in a one-pot cascade synthesis. The advantages associated with this transformation include conditions that are metal-free, room temperature, undistilled solvent, and expeditious in excellent yields. The substrate scope has been demonstrated with various aromatic, heteroaromatic, unsaturated aldehydes, and anilines, benzylic amines in impressive yields.

Full text of DOI:10.1016/j.tetlet.2013.05.037

Tetrahedron Letters 54 (2013) 3810–3812
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Tetrahedron Letters
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Cascade synthesis of 1,2-dihydropyridine from dienaminodioate and
an imine: a three-component approach
⇑
Chandrasekhar Challa, Manju John, Ravi S. Lankalapalli
Agroprocessing and Natural Products Division, National Institute for Interdisciplinary Science & Technology (NIIST), CSIR, Thiruvananthapuram 695019, Kerala, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient synthesis of 1,2-dihydropyridine (1,2-DHP) has been developed from dienaminodioate and
an imine mediated by trifluoroacetic acid in a one-pot cascade synthesis. The advantages associated with
this transformation include conditions that are metal-free, room temperature, undistilled solvent, and
expeditious in excellent yields. The substrate scope has been demonstrated with various aromatic,
heteroaromatic, unsaturated aldehydes, and anilines, benzylic amines in impressive yields.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 23 March 2013
Revised 6 May 2013
Accepted 9 May 2013
Available online 18 May 2013
Keywords:
Dienaminodioate
Imine
1,2-Dihydropyridine (1,2-DHP)
The chemistry of dihydropyridines (DHPs) dates back to more
than a century when Hantzsch published their synthesis in
1882.1 Since then, DHPs have been given a prominent place in
organic synthesis due their prevalence as intermediates in the
synthesis of a broad variety of pyridine derivatives.2 Among the
DHPs, 1,4-dihydropyridines (1,4-DHPs) are well studied scaffolds
in pharmaceuticals as calcium channel modulating agents viz.
Nifedipine, Amlodipine, Lacidipine, Diludine, etc.3 However, 1,2-
DHPs are relatively unexplored for their biological potential which
makes them a prospective candidate structure for the design of
heterocyclic drug libraries. 1,2-DHPs are regarded as important
synthetic intermediates for conversion to pyridine, piperidine
and pyridone derivatives,4 as a diene component in Diels–Alder
reaction,5 and as a key intermediate in the synthesis of marine
natural product oroidin.6 Some of the key synthetic approaches
towards 1,2-DHPs include [4+2] cycloaddition of azadienes and
phosphazenes,7 cascade synthesis using starting materials such
as acetylenic esters, propargyl vinyl ethers, enaminones8 and
nucleophilic addition onto N-acyl or alkylpyridinium salts.9
Recently, transition metal catalysts were engaged in the synthesis
of 1,2-DHPs in a sequential manner utilizing substrates such as
Reactive
groups
R3
R3
R3
R2
R1
R2-CHO
R1-NH2
+
N
R3
Allyl-NH
Diversity
elements
2
R3 = CO2Et
Figure 1. Proposed one-pot synthesis of 1,2-DHP from dienaminodioate 2.
have been published which accentuate its importance by synthetic
community. Herein, we report the use of a less explored substrate
sec-(allylamino)-dienaminodioate 2 (Fig. 1) in a one-pot cascade
reaction with in situ generated imine to afford 1,2-DHP, under mild
conditions, possessing two diversity elements and two reactive
ester groups which can be employed in building diversity oriented
synthetic library of 1,2-DHPs.
We serendipitously discovered the formation of dienaminodio-
ate 2 during our attempts to epoxidize enaminoate 1 (Scheme 1) in
the presence of mCPBA.11 Dienaminodioate 2 formation was
initially realized by Bottomley et al . by conjugate addition of
amines to methyl propiolate.12 Utilization of 2 as a substrate to-
wards its derivatives was restricted to the synthesis of pyrroles,
and pyridinones by bromocyclization.13 While dienaminodioate
was never utilized in the synthesis of DHPs, enaminoate was used
as a substrate in Lewis acid induced cyclization for the synthesis of
1,4-DHP.14 To expand the scope of utilization of 2 and inspired by a
variant of Povarov reaction which utilizes imine and enamine,15 we
envisioned synthetic utility of 2 as a suitable enamine component
for the synthesis of functionalized DHPs and other pyridine
propargyl vinyl ethers,
a,b-unsaturated N-benzyl aldimines,
aziridinyl propargylic esters, furans, vinyloxiranes and pyridines.10
By and large, some of the disadvantages associated with the
reports, vide supra, for the synthesis of 1,2-DHPs include harsh
conditions, metal-catalyst, long reaction time, moisture sensitive
and multi-step sequence with moderate to low yields. Recently,
several reports (see references) towards the synthesis of 1,2-DHPs
⇑
Corresponding author. Tel.: +91 471 2515353; fax: +91 471 2491795.
E-mail address: ravishankar@niist.res.in (R.S. Lankalapalli).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.05.037

C. Challa et al. / Tetrahedron Letters 54 (2013) 3810–3812
3811
1,2-DHP synthesis,7 followed by elimination of allyl amine in
the presence of an acid and rearrangement to afford 1,2-DHP
(Scheme 2).
O
+
CO2Et
EtO
H2N
THF, 0 ºC to rt
10 min, quant
HN
Encouraged by this result we proceeded to optimize the reac-
tion conditions for affording 1,2-DHP using different acids (Table
1). Initial attempt with TFA (25 mol %) using CH3CN as the solvent
provided 1,2-DHP 3 in an impressive 92% yield (entry 12) at room
temperature. To avoid longer reaction time we increased TFA con-
centration to stoichiometric amount (1 equiv) which led to com-
plete formation of the product in just 45 min with 95% yield
(entry 1). Increase in the number of equivalents to 1.5 or 2.5 led
to no considerable change in time or yield of the product (entries
13–14). Change of solvent to CH2Cl2, EtOH or THF (entries 9–11)
led to longer reaction time with 1 equiv of TFA. To ascertain the
generality of the acid, investigation of other common acids in stoi-
chiometric amounts (entries 2–6) led to a decrease in yield of 1,2-
DHP with longer reaction time. Interestingly, usage of 1 equiv of
acetic acid and trichloroacetic acid (entries 7–8) showed the influ-
ence of pKa over the outcome of the reaction with respect to yield
and time. Therefore, usage of 1 equiv of TFA and CH3CN as the sol-
vent was chosen as the optimized conditions for one-pot cascade
synthesis of 1,2-DHP. To determine the mildness of our approach,
all reactions were conducted without distillation of solvents and
in the absence of inert atmosphere.
All
1
CO2Et
O
EtO
CO2Et
Benzene,
reflux,4h
Allyl-NH
2
(52%)
Scheme 1. One-pot synthesis of dienaminodioate 2.
derivatives. Thus, to unveil the synthetic potential of dienamino
diesters in the construction of heterocyclic compounds we set forth
to synthesize 2 using ethyl propiolate as the starting material
(Scheme 1). A one-pot sequential reaction with ethyl propiolate
and allyl amine generated enaminoate 1 in a quantitative yield.
As our initial attempt using mCPBA offered 2 in a very low yield,
we adopted an alternative method16 of treating 1 after evaporation
in the same pot with one more equivalent of ethyl propiolate in
benzene which under reflux afforded 2 in a good yield.17
The scope of this transformation by variation of different alde-
hydes was studied using p-toluidine as the amine component un-
der optimized conditions (Table 2).18 Aromatic aldehydes, in
general, gave good yields of 1,2-DHP 4 in less than 2 h (entries
1–6). Heteroaromatic aldehydes, however, took longer reaction
time with the desired 1,2-DHPs as major products along with other
impurities (entries 7–8). Polycyclic aromatic hydrocarbons showed
similar behaviour towards reactivity as simple aromatic hydrocar-
bons without offering any steric hindrance in the formation of 1,2-
DHPs (entries 9–10).
The substrate scope was further investigated by variation of
amines along with a few representative aldehydes for the forma-
tion of 1,2-DHP 5 (Table 3). The results were as expected with
impressive yields showing tolerance towards both electron releas-
ing and withdrawing substituents in the para position (entries 1–
12). Even benzylic amines (entries 13–16) offered decent yields
for this transformation which prompted us to try butylamine but
we observed the product formation 5q (entry 17) in a lower yield
Initial investigation with an aromatic imine derived in situ from
4-methylbenzaldehyde and p-toluidine as model substrates in a
one-pot cascade reaction with 2 in the presence of catalytic
amount of trifluoroacetic acid (TFA) afforded a yellow coloured
spot on TLC in a trace amount which after isolation was character-
ized as 1,2-DHP 3 (Table 1), as expected. The 1H NMR analysis of 3
shows two discernible singlets for olefinic protons at d 7.70 and
8.05 ppm. A characteristic splitting pattern of the ethyl group of
both the esters akin to 1,2- and 1,4-DHPs, presence of both the
phenyl groups which was evident from the integration, established
the structure of 3. The mechanistic rationale behind the primary
event during the cascade sequence could be realized as a hetero
Diels–Alder cycloaddition as proposed by Palacios et al. in their
Table 1
Optimization of reaction conditions for the synthesis of 1,2-DHP 3
CHO
NH2
CH3
EtO2C
C6H4(4-Me)
C6H4(4-Me)
N
Acid
rt
under the reaction conditions. Interestingly, attempts with
a,b-
2
+
+
unsaturated aldehydes also yielded 1,2-DHPs in a moderate to
good yield (entries 18–21).
CO2Et
CH3
3
In summary, we have developed a one-pot cascade reaction of
in situ generated imine with dienaminodioate 2 for the formation
of 1,2-dihydropyridines. A broad aromatic substrate scope with
various aromatic, heteroaromatic, unsaturated aldehydes, and ani-
lines, benzylic amines in impressive yields, demonstrates synthetic
utility in diversification of 1,2-DHPs to produce pharmaceutically
Entrya
Acid
Solventb
Time
Yieldc (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
TFA
TMSOTf
p-TsOH
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH2Cl2
EtOH
45 min
8 h
8 h
95
12
27
30
68
38
61
82
84
61
93
92
95
94
4 M HCl in Dioxane
7 h
BF3ÁEt2O
FeCl3
AcOH
TCA
TFA
TFA
TFA
TFA
TFA
TFA
1.5 h
11 h
24 h
1.4 h
45 min
4 h
4 h
4 h
45 min
45 min
H
Ph
N
Ph
R
N+
Ph
Ph
R
NHAll
R
NHAll
R
[4 + 2]
H+
THF
CH3CN
CH3CN
CH3CN
2
, R = COOEt
Ph
+
Ph
N
Ph
N
Abbreviations: TFA = trifluoroacetic acid, TMSOTf = trimethylsilyl triflate, p-
TsOH = p-toluenesulfonic acid.
+
Ph
R
N
NH2All
Ph
Ph
R
a
All reactions were carried out with 1.2 equiv of both aldehyde and amine, and
1 equiv of acid except for entries 12–14 where 0.25, 1.5, and 2.5 equiv were used,
respectively.
R
R
R
R
H
1,2-DHP
b
Solvents were used without distillation.
Isolated yields.
c
Scheme 2. Proposed formation of 1,2-DHP.

3812
C. Challa et al. / Tetrahedron Letters 54 (2013) 3810–3812
Table 2
References and notes
Substrate scope: cascade synthesis of 1,2-DHP 4 by variation of aldehydes
1. Hantzsch, A. Justus Liebigs Ann. Chem. 1882, 215, 1–82.
NH2
R2
2. For a recent review on DHPs and references of reviews on DHPs cited therein,
see: Bull, J. A.; Mousseau, J. J.; Pelletier, G.; Charette, A. B. Chem. Rev. 2012, 112,
2642–2713.
3. For recent reviews on 1,4-DHP based pharmaceuticals, see: (a) Edraki, N.;
Mehdipour, A. R.; Khoshneviszadeh, M.; Miri, R. Drug Discovery Today 2009, 14,
1058–1066; (b) Wan, J.-Ping; Liu, Y. RSC Adv. 2012, 2, 9763–9777; (c) Safak, C.;
Simsek, R. Mini-Rev. Med. Chem. 2006, 6, 747–755.
R1
TFA (1 eq)
2
+ R1-CHO +
N
CH3CN, rt R2
C6H4(4-Me)
CH3
4
R2 = CO2Et
Entry
R1
Product
Yield (%)
4. (a) Charette, A. B.; Grenon, M.; Lemire, A.; Pourashraf, M.; Martel, J. J. Am. Chem.
Soc. 2001, 123, 11829–11830; (b) Lemire, A.; Grenon, M.; Pourashraf, M.;
Charette, A. B. Org. Lett. 2004, 6, 3517–3520; (c) Palacios, F.; Alonso, C.;
Rubiales, G.; Ezpeleta, J. M. Eur. J. Org. Chem. 2001, 2115–2122; (d) Young, D.
W.; Comins, D. L. Org. Lett. 2005, 7, 5661–5664.
5. (a) Takenaka, N.; Huang, Y.; Rawal, V. H. Tetrahedron 2002, 58, 8299–8305; (b)
Nakano, H.; Osone, K.; Takeshita, M.; Kwon, E.; Seki, C.; Matsuyama, N.; Kohari,
Y. Chem. Commun. 2010, 46, 4827–4829; (c) Krow, G. R.; Huang, Q.;
Szczepanski, S. W.; Hausheer, F. H.; Caroll, P. J. J. Org. Chem. 2007, 72, 3458–
3466; (d) Martin, R. M.; Bergman, R. G.; Ellman, J. A. Org. Lett. 2013, 15, 444–
447.
1
2
3
4
5
6
7
8
9
Ph
4-Cl-C6H4
4-Br-C6H4
4-CN-C6H4
4-NO2-C6H4
4-MeO-C6H4
5-Methyl-thiophene-2-
Furan-2-
4a
4b
4c
4d
4e
4f
4g
4h
4i
87
75
74
91
96
77
75
75
84
79
Naphthalene-2-
Pyrene-1-
6. Schroif-Gregoire, C.; Travert, N.; Zaparucha, A.; Al-Mourabit, A. Org. Lett. 2006,
8, 2961–2964.
10
4j
7. Palacios, F.; Herran, E.; Rubiales, G. J. Org. Chem. 1999, 64, 6239–6246.
8. (a) Yavari, I.; Bayat, M. J.; Sirouspour, M.; Souri, S. Tetrahedron 2010, 66, 7995–
7999; (b) Tejedor, D.; Mendez-Abt, G.; García-Tellado, F. Chem. Eur. J. 2010, 16,
428–431; (c) Wei, H.; Wang, Y.; Yue, B.; Xu, P. F. Adv. Synth. Catal. 2010, 352,
2450–2454; (d) Wan, J. P.; Gan, S. F.; Sun, G. L.; Pan, Y. J. J. Org. Chem. 2009, 74,
2862–2865. and the references cited therein.
9. Comins, D. L.; Hong, H.; Salvador, J. M. J. Org. Chem. 1991, 56, 7197–7199.
10. For recent metal catalyzed synthesis of 1,2-DHPs, see: (a) Harschneck, T.;
Kirsch, S. F. J. Org. Chem. 2011, 76, 2145–2156; (b) Colby, D. A.; Bergman, R. G.;
Ellman, J. A. J. Am. Chem. Soc. 2008, 130, 3645–3651; (c) Motamed, M.;
Bunnelle, E. M.; Singaram, S. W.; Sarpong, R. Org. Lett. 2007, 9, 2167–2170; (d)
Fructos, M. R.; Alvarez, E.; Mar Diaz-Requezo, M.; Perez, P. J. J. Am. Chem. Soc.
2010, 132, 4600–4607; (e) Maestre, L.; Fructos, M. R.; Díaz-Requejo, M. M.;
Pe´rez, P. J. Organometallics 2012, 31, 7839–7843; (f) Brunner, B.; Stoigaitis, N.;
Lautens, M. Org. Lett. 2006, 8, 3473–3476; (g) Oshima, K.; Ohmura, T.;
Suginome, M. J. Am. Chem. Soc. 2012, 134, 3699–3702; (h) Oshima, K.; Ohmura,
T.; Suginome, M. J. Am. Chem. Soc. 2011, 133, 7324–7327; (i) Ichikawa, E.;
Suzuki, M.; Yabu, K.; Albert, M.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2004,
126, 11808–11809. and the references cited therein.
Table 3
Substrate scope: cascade synthesis of 1,2-DHP 5 by variation of aldehydes and amines
R1
N
R2
R3
TFA (1 eq)
CH3CN, rt
2 + R1-NH2 + R2-CHO
R3
5
R3 = CO2Et
Entry
R1
R2
Product
Yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
Ph
Ph
5a
5b
5c
5d
5e
5f
5g
5h
5i
98
97
93
80
95
97
98
75
65
71
70
91
94
42
69
89
22
66
69
37
30
4-MeO-C6H4
4-MeO-C6H4
4-MeO-C6H4
4-MeO-C6H4
4-Cl-C6H4
4-Cl-C6H4
4-Cl-C6H4
4-I-C6H4
4-I-C6H4
4-I-C6H4
4-F-C6H4
Benzyl
4-MeO-C6H4
4-NO2-C6H4
4-CN-C6H4
4-Cl-C6H4
4-MeO-C6H4
4-NO2-C6H4
4-CN-C6H4
4-MeO-C6H4
4-CN-C6H4
4-Cl-C6H4
4-NO2-C6H4
4-Me-C6H4
4-Me-C6H4
4-NO2-C6H4
4-NO2-C6H4
Propyl
11.
H
N
H
N
mCPBA
CO2Et
All
All
N
H
All
CO2Et
CO2Et
O
CO2Et
1
CH2Cl2, rt
expected
but formed 2
(18%)
5j
5k
5l
12. For formation of dienaminodiesters, see: (a) Bottomley, W. Tetrahedron Lett.
1967, 8, 1997–1999; (b) Bottomley, W.; Phillips, J. N.; Wilson, J. G. Tetrahedron
Lett. 1967, 8, 2957–2961; (c) Khan, M. A.; Adams, H. Tetrahedron Lett. 1999, 40,
5389–5390.
13. Adams, J.; Hardin, A.; Vounatsos, F. J. Org. Chem. 2006, 71, 9895–9898. and
references cited therein.
14. Sirijindalert, T.; Hansuthirakul, K.; Rashatasakhon, P.; Sukwattanasinitt, M.;
Ajavakom, A. Tetrahedron 2010, 66, 5161–5167.
15. Stevenson, P. J.; Graham, I. ARKIVOC 2003, 139–144.
16. Anghelide, N.; Draghici, C.; Raileanu, D. Tetrahedron 1974, 30, 623–632.
5m
5n
5o
5p
5q
5r
5s
5t
4-F-Benzyl
Benzyl
4-F-Benzyl
4-MeO-C6H4
4-Me-C6H4
4-Me-C6H4
4-Me-C6H4
4-Me-C6H4
Prop-1-enyl
Styryl
4-NO2-Styryl
4-MeO-Styryl
17. To a solution of allyl amine (382
lL, 5.09 mmol) in THF was added ethyl
propiolate (520 L, 5.09 mmol) slowly at 0 °C and warmed to room
l
5u
temperature. After 10 min, the reaction mixture was concentrated and the
resulting enaminoate 1 was dissolved in benzene (5 mL). To the reaction
mixture ethyl propiolate (520 lL, 5.09 mmol) was added and stirred under
reflux for 4 h at 100 °C. The reaction mixture was then concentrated and
purified by flash column chromatography (10:1 hexane/EtOAc) affording
important libraries. The advantages associated with this transfor-
mation over the current methods of 1,2-DHP synthesis include
conditions that are metal-free, one-pot, room temperature, usage
of undistilled solvent and expeditious in excellent yields. Our fur-
ther endeavours involve utilization of bifunctional aldehydes/
amines to expand the substrate scope of this transformation, and
derivatization of 1,2-DHPs.
dienaminodioate
2 (669 mg, 52%) as a light yellow oily product. Rf 0.3
(hexane/EtOAc 4:1); 1H NMR (CDCl3) d 1.28 (t, 3H, J = 7 Hz, –CO2CH2CH3), 1.35
(t, 3H, J = 7 Hz, –CO2CH2CH3), 3.89 (app t, 2H, J = 5.5 Hz, –CH2–CH), 4.18 (q, 2H,
J = 7 Hz, –CO2CH2CH3), 4.25 (q, 2H, J = 7 Hz, –CO2CH2CH3), 5.24 (m, 2H, –
CH@CH2), 5.86 (ddt, 1H, J = 5.5, 10.5, 16 Hz, –CH@CH2), 6.03 (d, 1H, J = 15.5 Hz,
CH@CHCO2Et), 7.19 (d, 1H, J = 13.5 Hz, C@CH), 7.39 (d, 1H, J = 15.5 Hz,
CH@CHCO2Et), 8.94 (brs, 1H, NH); 13C NMR (CDCl3) d 14.4, 14.4, 51.1, 59.6,
59.8, 95.3, 108.2, 117.9, 133.4, 143.2, 156.9, 168.8,169.1; ESI-HRMS [M+Na]+
C13H19NO4Na calcd for m/z 276.12118, found 276.12000.
Acknowledgement
18. General procedure for 1,2-DHP synthesis. To a solution of 2 in CH3CN was added
pertinent aldehyde (1.2 equiv), amine (1.2 equiv), and TFA (1.0 equiv) in a
sequence at room temperature. The reaction mixture usually develops a bright
yellow color within 15 min which is an indication of the formation of 1,2-DHP.
After complete consumption of 2, as observed on TLC, the reaction mixture was
quenched with saturated NaHCO3, extracted with ethyl acetate, dried (Na2SO4)
and concentrated. The resulting residue was purified by flash column
chromatography to afford 1,2-DHP derivative.
Financial support from the Department of Science & Technology
(DST), India, grant SR/FT/CS-45/2010 is gratefully acknowledged.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.05.
037.