An atom-economic green approach: Oxidative synthesis of functionalized 1,4-dihydropyridines from N,N-dimethylenaminones and amines

Article abstract of DOI:10.1016/j.tetlet.2014.12.118

We report the first oxidative condensation between N,N-dimethylenaminones with amines to form 1,4-dihydropyridines in moderate to good yields, promoted by oxone and trifluoroacetic acid in PEG-400. This reaction features an unusual oxidation of in situ fo

Full text of DOI:10.1016/j.tetlet.2014.12.118

Tetrahedron Letters xxx (2015) xxx–xxx
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Tetrahedron Letters
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An atom-economic green approach: oxidative synthesis of
functionalized 1,4-dihydropyridines from N,N-dimethylenaminones
and amines
a,
⇑
b
a
a
a,
⇑
Fu-Chao Yu , Bei Zhou , Hui Xu , Kwen-Jen Chang , Yuehai Shen
a
Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650504, PR China
Key Laboratory of Medicinal Chemistry for Natural Resource (Yunnan University), Ministry of Education, School of Chemical Science and Technology, Yunnan University,
b
Kunming 650091, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
We report the first oxidative condensation between N,N-dimethylenaminones with amines to form
Received 18 November 2014
Revised 15 December 2014
Accepted 21 December 2014
Available online xxxx
1
4
,4-dihydropyridines in moderate to good yields, promoted by oxone and trifluoroacetic acid in PEG-
00. This reaction features an unusual oxidation of in situ formed dimethylamine to efficiently provide
the 4-methylene of 1,4-dihydropyridines, and a highly environment-friendly reaction condition.
Ó 2014 Published by Elsevier Ltd.
Keywords:
1
,4-Dihydropyridines (1,4-DHPs)
N,N-Dimethylenaminones
Oxidative condensation
Oxone
Atom-economic green approach
Introduction
enaminones have been devised recently.12 For instance, the group
of Wan reported a one-pot reaction of N,N- dimethylenaminones 1,
1
,4-Dihydropyridines (1,4-DHPs) are an important class of het-
amines 2 and aromatic aldehydes 5 to directly afford 4-substituent
1,4-DHPs 6 (Scheme 1).
1
2b–e
erocyclic compounds and are attractive targets both in medicinal
chemistry and in organic synthesis in recent years. Calcium channel
blockers containing 1,4-DHP subunit, such as felodipine, amlodip-
ine, nifedipine, nicardipine and isradipine (Fig. 1), are widely used
as cardiovascular and antihypertensive drugs. Other pharmacolog-
ical activities of 1,4-DHPs include anti-HIV,
Alternatively, the group of Li developed an effective two-com-
ponent reaction between enaminones 4, which are derived from
1
1j,13
N,N-dimethylenaminones 1,
and aromatic aldehydes 5 to
1
12f
obtain 4-substituent 1,4-DHPs 6 (Scheme 1). Notably, an aldehyde
1
c,2
3
anti-bacterial, anti-
4
5
6
7
convulsant, anti-tumour, neuroprotection, radioprotection and
8
9
others. Synthetically, 1,4-DHPs like Hantzsch ester (Fig. 1) are very
N
N
Cl
useful reducing agents, and are valuable intermediates.9
f,10
O
Cl
NO2
In view of its high significance, tremendous efforts have been
taken to develop efficient synthetic methods for this privileged
structure. Conventionally, the preparation of 1,4-DHPs mainly
relies on the Hantzsch reaction,11 a three-component condensation
reaction of a 1,3-dicarbonyl compound, an aldehyde and an amine
or ammonium salt. While this process remains a gold standard to
access structurally diverse 1,4-DHPs and an emblematic example
of multicomponent reactions (MCRs), new methods based on
MeO2C
CO2Me MeO2C
CO2Me
MeO2C
CO2Me
N
H
N
H
N
H
Israpidine
Felodipine
Nifedipine
H
H
NH2
MeO2C
CO2Me
MeO2C
CO2Me
N
H
O
N
H
NH2
Hantzsch ester
⇑
Corresponding authors. Tel.: +86 871 65920747.
E-mail addresses: yufuchao05@126.com (F.-C. Yu), yuehaishen@gmail.com
Amlodipine
(
Y. Shen).
Figure 1. Representative 1,4-DHPs.
http://dx.doi.org/10.1016/j.tetlet.2014.12.118
040-4039/Ó 2014 Published by Elsevier Ltd.
0
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F.-C. Yu et al. / Tetrahedron Letters xxx (2015) xxx–xxx
O
O
Table 1
O
O
a
Ref 11j, 13
H
R2
this work
NH2 PEG-400, TFA,
Optimization of reaction conditions
R1
R1
R1
R1
O
O
NH
R2
N
N
N
R2
4
1
2
Oxone (1.2 eq),
3
o
O
NH
2
120 C, 20 min
R
R3 CHO Ref 12b-e
33 examples
yields 50-72%
F
N
F
F
e
f
1
5
H
2
f
N
R3 CHO
F
N
5
F
NH2
R2
2
O
R3
O
1
a
2a
3aa
R1
R1
N
R2
6
Entry
Solvent
Oxidant (equiv)
Catalyst
T (°C)
Yieldb (%)
1
2
3
4
5
6
7
8
9
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
BQ (0.5)
DDQ (0.5)
IBD (0.5)
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
TFA
Lactic acid
TMSCl
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
120
120
120
120
120
120
120
120
120
120
120
120
Reflux
120
Reflux
120
120
120
120
120
120
120
120
120
120
110
130
140
Trace
Trace
Trace
—
—
—
20
28
32
42
Scheme 1. Current synthesis of 1,4-DHPs.
3
AgNO (1.0)
H
2
O
2
(1.5)
partner is required for these methods. 4-Substituent 1,4-DHPs
could not be prepared from the condensation of N,N-dimethyle-
naminones 1 and amines 2. Based on our previous work on
enaminone-based heterocycle synthesis,14 we wish to report here
an oxone/TFA-promoted direct synthesis of 1,4-DHPs 3 from N,N-
dimethylenaminones 1 and amines 2 in PEG-400 (Scheme 1). Our
protocol involves a unique oxidation of dimethylamine released
from the amine-exchange of N,N-dimethylenaminones 1. To the
best of our knowledge, this is the first example of 1,4-DHPs synthe-
sis with an in situ-formed aldehyde partner.
TBHP (0.5)
CAN (1.0)
2
K S
2
O
8
(1.0)
Oxone (1.0)
Oxone (1.0)
Oxone (1.0)
Oxone (1.0)
Oxone (1.0)
Oxone (1.0)
Oxone (1.0)
Oxone (1.0)
Oxone (1.0)
Oxone (1.0)
Oxone (1.0)
Oxone (1.0)
Oxone (1.0)
Oxone (1.0)
Oxone (0.8)
Oxone (1.2)
Oxone (2.0)
Oxone (1.2)
Oxone (1.2)
Oxone (1.2)
10
11
28
12
13
14
15
Trace
Trace
22
20
30
26
27
48
50
55
40
43
68
37
34
67
63
1,4-Dioxane
p-Xylene
Toluene
DMSO
16
17
EG
18
19
20
21
22
23
24
25
Glycerol
PEG-200
PEG-300
PEG-400
PEG-600
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
Results and discussion
In the beginning of our study, N,N-dimethylenaminone 1a and
-fluoroaniline (2a) were selected as model substrates for screen-
4
TFA
TFA
TFA
TFA
ing the reaction conditions. As shown in Table 1, different solvents,
oxidants, catalysts and reaction temperatures were tested. First,
oxidants were investigated in the presence of AcOH. 1,4-Benzoqui-
none (BQ), DDQ and iodobenzene diacetate (IBD) afforded only
trace amounts of the desired 1,4-DHPs 3aa in DMF at 120 °C
26
27
28
TFA
a
Reagents and conditions: N,N-dimethylenaminone 1a (1.0 mmol), 4-fluoroani-
line 2a (0.5 mmol), catalyst (0.2 mL), solvent (5.0 mL).
(
(
entries 1–3), whereas AgNO
entries 4–6). To our delight, formation of 3aa were observed for
(entries 7–8), and oxone was found
3
, H
2
O
2
and TBHP was ineffective
b
Isolated yield based on N,N-dimethylenaminone 1a.
2 2 8
reactions with CAN and K S O
more efficient (entry 9). Next, the role of the acid was studied using
oxone as the oxidant. Among the acids tested, TFA was more effi-
cient (entries 9, 11–12 vs entry 10). Various solvents were then
screened in the presence of TFA and oxone (entries 10, 13–22).
The reaction in PEG-400 provided an increased yield of the desired
product 3aa (55%, entry 21).15 After further investigation of the
oxone amount and reaction temperature, we found that the reac-
tion with 1.2 equiv oxone to the amine in the presence of TFA in
PEG-400 at 120 °C provided the best result (68%, entry 24 vs entries
2
3, 25–28). Various reaction times have also been tested. The reac-
tion could not reach complete conversion while the reaction time
is less than 20 min (5, 10 or 15 min). But for longer reaction times
(
25 and 30 min), the desired product 3aa decomposed signifi-
cantly. A 20-min reaction time was thus adopted.
With the optimal reaction condition in hand (Table 1, entry 24),
the scope of substrates was explored. The results are summarized
1
in Table 2. N,N-Dimethylenaminones 1 with various R group,
including electron-poor (1a–1b), electron-neutral (1c) and elec-
tron-rich (1d–1e), proceeded smoothly and afforded the desired
Figure 2. ORTEP diagram of 3ce; ellipsoids are drawn at the 30% probability level.
1
,4-DHPs 3 in moderate to good yields. Similarly, variation of the
amine partner 2 showed little impact on the results, although
cyclohexylamine tends to give lower yields than arylamines. All
of electron-rich and electron-poor anilines (2a–2g) are effective
substrates and able to generate the expected 3 in moderate to good
yields. Moreover, cyclohexylamine 2h is also a suitable substrate.
The structure of 3ce was further confirmed by X-ray single-crystal
diffraction studies (Fig. 2, CCDC 1026867).1
To provide insights into the reaction mechanism, several con-
trol experiments were carried out (Scheme 2). For the reaction of
N,N-dimethylenaminone 1c and aniline 2c in the absence of oxone,
1
3a
no 3cc was detected. Instead, N-phenylenaminone 4a
was iso-
lated in 95% yield (Scheme 2, Eq. 1). N-Phenylenaminone 4a could
react with 1c under the standard condition to give 3cc in an
impressive 45% yield (Scheme 2, Eq. 2). Furthermore, while 4a
6
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F.-C. Yu et al. / Tetrahedron Letters xxx (2015) xxx–xxx
3
Table 2
a,b
Substrate scope of the 1,4-DHPs 3
O
O
O
PEG-400, 120 o
TFA, oxone, 20 min
C
2 2
R NH
R
1
R
1
R
1
N
N
R
1
2
3
2
1
a, R
a, R
f, R
1
= 4-FC
= 4-FC
= 3,5-(Me)2 C
6
H
4
; 1b, R
; 2b, R
; 2g, R
1
= 4-ClC
= 4-ClC
= 3,4,5-(OMe)
6
H
4
; 1c, R
1
= Ph; 1d, R
= Ph; 2d, R
; 2h, R
2
1
= 4-MeC
= 4-MeC
= cyclohexyl;
6
H
4
; 1e, R
1
= 4-OMeC
6 4
H ;
2
2
2
6
H
4
2
6
H
4
; 2c, R
2
2
6
H
4
; 2e, R
2
= 4-OMeC H ;
6 4
2
6
H
3
2
3
C
6
H
2
O
O
O
O
O
O
O
O
O
O
O
O
F
N
F
F
N
F
F
N
F
3ac, 69%
F
N
F
3
aa, 68%
3ab, 67%
3ad, 70%
F
Cl
N
Me
N
O
O
O
O
F
N
F
F
F
F
N
F
F
F
3ae, 63%
3af, 59%
3ag, 50%
3ah, 50%
Me
Me
MeO
OMe
OMe
N
OMe
N
O
O
O
O
O
O
O
O
O
Cl
Cl
ba, 66%
Cl
N
Cl
3bb, 67%
Cl
Cl
3bc, 69%
Cl
N
Cl
3bd, 69%
3
F
Cl
N
Me
O
O
O
O
O
O
O
O
Cl
N
Cl
Cl
Cl
Cl
N
O
Cl
3bh, 56%
N
3bf, 62%
3bg, 52%
OMe
3ca, 67%
Me
Me
MeO
OMe
O
F
O
O
O
O
O
O
N
N
N
N
3
cb, 69%
3cc, 71%
3cd, 70%
3ce, 72%
Cl
N
Me
N
OMe
O
O
O
O
O
O
O
N
Me
N
Me
Me
3
Me
cf, 67%
3cg, 54%
OMe
3ch, 55%
3da, 68%
Me
MeO
OMe
O
F
O
O
O
O
O
O
O
Me
Me
N
Me
Me
Me
N
Me
3dc, 70%
Me
N
Me
3dd, 72%
Me
N
3db, 70%
3de, 69%
Cl
N
Me
N
OMe
N
O
O
O
O
O
O
O
O
MeO
N
OMe
3eb, 69%
MeO
OMe
3ec, 68%
MeO
OMe
3ed, 66%
3df, 66%
Me
Me
Cl
Me
(
continued on next page)
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4
F.-C. Yu et al. / Tetrahedron Letters xxx (2015) xxx–xxx
Table 2 (continued)
O
O
MeO
N
OMe
3ef, 62%
Me
Me
a
Reagents and conditions: N,N-dimethylenaminones 1 (1.0 mmol), amines 2 (0.5 mmol), TFA (0.2 mL), oxone (1.2 equiv), PEG-400 (5.0 mL).
Isolated yield based on N,N-dimethylenaminones 1.
b
O
O
Tetrahedron 1997, 53, 2803; (c) Hilgeroth, A. Mini-Rev. Med. Chem. 2002, 2, 235;
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(
Ph
NH2
Ph
PEG-400
TFA, 120 o
Ph
a, 95%
(
1)
N
C
NH
Ph
4
1
c
c
2c
PEG-400, Oxone (1.2 eq)
3
4.
.
Refat, H. M.; Fadda, A. A. Eur. J. Med. Chem. 2013, 70, 419.
1
4a
3cc, 45% (2)
TFA, 120 o
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C
PEG-400, Oxone (1.2 eq)
N.R.
(3)
4
a
TFA, 120 o
5.
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C
(
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(
6
7
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of 3cc was detected (Scheme 2, Eq. 3). These results clearly indi-
cated that oxone plays an important role in this reaction, and the
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4
-methylene of 3cc is derived from dimethylamine formed in situ.
Based on these observations, it is safe to propose that in our
system, oxone reacts with dimethylamine released from the
amine-exchange of N,N-dimethylenaminone 1c, giving rise to
formaldehyde through the fragmentation of an unclear oxidized
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Conclusion
In summary, we successfully developed an atom-economic
method for the synthesis of structurally diverse 1,4-DHPs, from
N,N-dimethylenaminones 1 and amines 2 via a unique oxidative
three-component reaction under a green condition. Attempts to
further understand the reaction mechanism and applications are
underway in our laboratory.
Acknowledgments
We gratefully acknowledge the financial support from the
National Natural Science Foundation of China (Nos. 21402070),
Foundation of Kunming University of Science and Technology
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Supplementary data
Supplementary data (experimental procedures, characteriza-
1
13
tion data and H and C NMR spectra of the compounds) associ-
ated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2014.12.118. These data include
MOL files and InChiKeys of the most important compounds
described in this article.
1
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(
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1625; (e) Yu, F.-C.; Yan, S.-J.; Lin, J. Chin. J. Org. Chem. 2010, 30, 1421; (f) Yu, F.-
C.; Chen, Z.-Q.; Hao, X.-P.; Yan, S.-J.; Huang, R.; Lin, J. RSC Adv. 2014, 4, 6110; (g)
Yu, F.-C.; Yan, S.-J.; Hu, L.; Wang, Y.-C.; Lin, J. Org. Lett. 2011, 18, 4782; (h) Yu,
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References and notes
1
.
(a) Rovnyak, G. C.; Kimball, S. D.; Beyer, B.; Cucinotta, G.; Dimarco, J. D.;
Gougoutas, J.; Hedberg, A.; Malley, M.; MaCarthy, J. P.; Zhang, R.; Mereland, S. J.
Med. Chem. 1995, 38, 119; (b) Kappe, C. O.; Fabian, W. M. F.; Semones, M. A.
Please cite this article in press as: Yu, F.-C.; et al. Tetrahedron Lett. (2015), http://dx.doi.org/10.1016/j.tetlet.2014.12.118

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5
1
5. General Procedure for the synthesis of compounds 3aa: N,N-Dimethylenaminone
(1.0 mmol), 4-fluoroaniline 2a (0.5 mmol), PEG-400 (5 mL), oxone
1.2 equiv) and trifluoroacetic acid (TFA) (0.2 mL) were charged into a 25 mL
mp 164–166 °C; IR (KBr): 1662, 1632, 1599, 1505, 1396, 1232, 1147, 1105,
1
À1
1
(
a
837, 751, 596 cm
2H, C@CHN), 7.06–7.14 (m, 8H, ArH), 7.61–7.65 (m, 4H, ArH); C NMR
(100 MHz, CDCl ): d = 22.1, 116.0, 116.0 (d, J = 21.6 Hz), 117.3, 117.4 (d,
; H NMR (400 MHz, CDCl ): d = 3.60 (s, 2H, CCH C), 7.03 (s,
3
2
13
round-bottom flask, and the mixture was stirred at 120 °C for 20 min until the
3
N,Ndimethylenaminones 1a were completely consumed. The mixture was
J = 22.9 Hz), 123.4 (d, J = 8.4 Hz), 131.1 (d, J = 8.7 Hz), 135.3 (d, J = 2.7 Hz),
139.7, 141.5, 161.4 (d, J = 246.6 Hz), 164.8 (d, J = 250.5 Hz), 193.5; HRMS (TOF
ES ): m/z calcd for C25H F NO [(M+H) ], 420.1206; found, 420.1209.
17 3 2
cooled to room temperature, neutralized with a saturated solution of Na
to pH 8–9, and then EtOAc (30 mL Â 2) was added. The organic phase was
washed with water (20 mL), dried over Na SO , concentrated and purified by
2 3
CO
+
+
2
4
16. CCDC 1026867 contains the supplementary crystallographic data of compound
3ce. These data can be obtained free of charge from The Cambridge
Crystallographic Data Center via www.ccdc.cam.ac.uk/data_request/cif.
flash column chromatography to afford 1,4-DHPs 3aa. (1-(4-Fluorophenyl)-1,4-
dihydropyridine-3,5-diyl)bis((4-fluorophenyl)methanone) (3aa): yellow solid;
Please cite this article in press as: Yu, F.-C.; et al. Tetrahedron Lett. (2015), http://dx.doi.org/10.1016/j.tetlet.2014.12.118