9-Phenyl-10-methylacridinium: A highly efficient and reusable organocatalyst for mild aromatization of 1,4-dihydropyridines by molecular oxygen

Article abstract of DOI:10.1021/jo701796n

(Chemical Equation Presented) The mild, efficient, and general aerobic aromatization of Hantzsch 1,4-dihydropyridines was realized at room temperature with 5 mol % of 9-phenyl-10-methylacridinium Perchlorate as the photocatalyst, which could be easily rec

Full text of DOI:10.1021/jo701796n

been developed for the aromatization.5-9 These include the use
of stoichiometric or excess amount of inorganic oxidants5 such
as Zr(NO3)4, CAN, CrO2, HNO3, MnO2, NaIO4, and Mn(OAc)3
or organic oxidants6 such as NO, phenyliodine(III) bis(trifluo-
roacetate), S-nitrosoglutathione, and 4-phenyl-1,2,4-triazole-3,5-
dione. To carry out the aromatization in a catalytic way, Tung
and Wu et al. reported the elegant photocatalytic aromatization
of 1,4-DHP by platinum(II) terpyridyl complexes leading to the
generation of H2.7 In order to make the aromatization more
atom-economical and environmentally benign, the use of
molecular oxygen as a clean source of oxidant is, of course,
highly desirable. Since oxygen itself does not oxidize 1,4-DHP
effectively, the help of an appropriate catalyst is necessary.8,9
RuCl3, silica gel-supported Co/Mn p-aminobenzoate, Pd/C, and
ferric perchlorate in acetic acid have thus been developed as
catalysts for such a purpose.10 However, harsh reaction condi-
tions such as high temperature and long reaction time are usually
required and the yields of products are sometimes low.10 More
recently, Liu and co-workers reported the photostimulated
aerobic aromatization of 1,4-DHP by catalysis of N-hydroxy-
phthalimide.11 This method is advantageous over the previous
ones in terms of organocatalysis. However, it suffers from the
low catalytic efficiency (20 mol % of catalyst loading) and the
limited scope of application. For example, 4-(nitrophenyl)-
substituted 1,4-DHP are inert under such conditions. Besides,
the catalyst underwent decomposition under the experimental
conditions (CH3CN, reflux). Therefore, the development of more
9-Phenyl-10-methylacridinium: A Highly
Efficient and Reusable Organocatalyst for Mild
Aromatization of 1,4-Dihydropyridines by
Molecular Oxygen
Xinqiang Fang,† You-Cheng Liu,*,‡ and Chaozhong Li*,†,‡
Joint Laboratory of Green Synthetic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, Shanghai 200032, China, and Department of
Chemistry, UniVersity of Science and Technology of China,
Hefei, Anhui 230026, China
clig@mail.sioc.ac.cn; ycliu@ustc.edu.cn
ReceiVed August 15, 2007
The mild, efficient, and general aerobic aromatization of
Hantzsch 1,4-dihydropyridines was realized at room tem-
perature with 5 mol % of 9-phenyl-10-methylacridinium
perchlorate as the photocatalyst, which could be easily
recovered and reused.
(5) (a) Bocker, R.; Guengerich, F. P. J. Med. Chem. 1986, 29, 1596. (b)
Pfister, J. R. Synthesis 1990, 689. (c) Garcia, O.; Delgado, F. Tetrahedron
Lett. 1992, 34, 623. (d) Eynde, J.; Delfaese, F.; Mayence, A.; Haverbeke,
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Yadav, J. S. Synthesis 2003, 1267. (i) Xia, J.-J.; Wang, G.-W. Synthesis
2005, 2379. (j) Bagley, M. C.; Lubinu, M. C. Synthesis 2006, 1283. (k)
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2006, 14, 2720.
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Perkin Trans. 1 1999, 1755. (c) Yadav, J. S.; Reddy, B. V. S.; Sabitha, G.;
Kreddy, G. S. K. K. Synthesis 2000, 1532. (d) Mao, Y.-Z.; Jin, M.-Z.; Liu,
Z.-L.; Wu, L.-M. Org. Lett. 2000, 2, 741. (e) Zhu, X.-Q.; Zhao, B.-J.; Cheng,
J.-P. J. Org. Chem. 2000, 65, 8158. (f) Zolfigol, M. A.; Choghamarani, A.
G.; Shahamirian, M.; Safaiee, M.; Mohammadpoor-Baltork, I.; Mallakpour,
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Esfahani, M.; Moghadam, M.; Tangestaninejad, S.; Mirkhani, V. Bioorg.
Med. Chem. Lett. 2005, 15, 3276.
Hantzsch 1,4-dihydropyridines (1,4-DHP) are an important
class of drugs for the treatment of cardiovascular diseases such
as hypertension and angina pectoris.1 The reduced nicotinamide
adenine dinucleotide (NADH) as a 1,4-DHP derivative acts as
the electron source for the reduction of O2 to H2O in the
respiratory chain.2 Hantzsch esters (2,6-dialkyl-3,5-dialkoxy-
carbonyl-1,4-dihydropyridines) have been widely used to model
the biological hydride transfer mechanism of coenzyme NADH.3
In the meantime, 1,4-DHP also serve as important intermediates
in the synthesis of multisubstituted pyridine compounds.4 The
oxidative aromatization of 1,4-DHP has thus drawn enormous
attention in both synthetic and biomechanistic points of view
and continues to be actively pursued. A variety of reagents have
(7) Zhang, D.; Wu, L.-Z.; Zhou, L.; Han, X.; Yang, Q.-Z.; Zhang, L.-
P.; Tung, C.-H. J. Am. Chem. Soc. 2004, 126, 3440.
(8) The direct photo-oxidation of 1,4-DHP with chloroform as both the
solvent and the oxidant was reported. See: Memarian, H. R.; Mirjafari, A.
Bioorg. Med. Chem. Lett. 2005, 15, 3423.
(9) The photoinduced intramolecular electron transfer of some nitrophen-
yl-substituted 1,4-DHP was reported. See: Fasani, E.; Fagnoni, M.; Dondi,
D.; Albini, A. J. Org. Chem. 2006, 71, 2037.
(10) (a) Mashraqui, S. H.; Kamik, M. A. Tetrahedron Lett. 1998, 39,
4895. (b) Nakamichi, N.; Kawashita, Y.; Hayashi, M. Org. Lett. 2002, 4,
3955. (c) Hashemi, M. M.; Ahmadibeni, Y. Monatsh. Chem. 2003, 134,
411. (d) Nakamichi, N.; Kawashita, Y.; Hayashi, M. Synthesis 2004, 1015.
(e) Heravi, M. M.; Behbahani, F. K.; Oskooie, H. A.; Shoar, R. H.
Tetrahedron Lett. 2005, 46, 2775.
† Shanghai Institute of Organic Chemistry.
‡ University of Science and Technology of China.
(1) (a) Meyer, H. Annu. Rep. Med. Chem. 1982, 17, 71. (b) Janis, R. A.;
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Ann. Rep. Med. Chem. 1986, 21, 85. (d) Guengerich, F. P.; Brain, W. R.;
Iwasaki, M.; Sari, M. A.; Berntsson, P. J. Med. Chem. 1991, 34, 1838. (e)
Toniolo, R.; Narda, F. D.; Bontempelli, G.; Ursini, F. Bioelectrochem. 2000,
51, 193.
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Harrenga, A.; Kannt, A. Ann. ReV. Biophys. Biomol. Struct. 1988, 27, 329.
(c) Babcock, G. T.; Wikstrom, M. Nature 1992, 356, 301. (b) Babcock, G.
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Soc. 1987, 109, 305.
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W. Synlett 2005, 2333. (b) Han, B.; Liu, Z.; Liu, Q.; Yang, L.; Liu, Z.-L.;
Yu, W. Tetrahedron 2006, 62, 2492.
10.1021/jo701796n CCC: $37.00 © 2007 American Chemical Society
Published on Web 10/05/2007
8608
J. Org. Chem. 2007, 72, 8608-8610

TABLE 1. Optimization of Conditions for Aromatization of 1a
TABLE 2. Aromatization of Symmetrical 1,4-DHP
R1
R2
time (h) product yielda (%)
entry
catalyst (mol %)
solvent
conditions
yielda (%)
entry
1
1
2
3
4
5
6
7
8
A-1 (10)
A-1 (10)
A-1 (5)
none
A-1 (5)
A-1 (5)
A-2 (5)
A-3 (5)
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH2Cl2
CH3CN
CH3CN
reflux, hV, 10 h
rt, hv, 12 h
rt, hV, 12 h
rt, hV, 12 h
rt, 27 h
rt, hV, 12 h
rt, hV, 12 h
rt, hV, 12 h
20
99
96
2
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
1a
1b
1c
1d
1e
1f
1g
1h
1i
CO2Et Ph
13
7
10
10
9
10
10
10
1
7
7
5
4
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m, 2i
2i
2i
98
99
91
96
93
96
91
96
CO2Et m-NO2C6H4
CO2Et p-MeOC6H4
CO2Et o-BrC6H4
COMe Ph
COMe m-NO2C6H4
COMe p-MeOC6H4
0
50
77
81
CN
m-NO2C6H4
CO2Et
H
99
a Isolated yield based on 1a.
1j
1k
1l
CO2Et Me
CO2Et Et
CO2Et n-Pr
99
77b
90
efficient, general and catalytic aerobic oxidation of 1,4-DHP
remains a challenging task and in turn justifies further research
in this area.
1m CO2Et Bn
1n
1o
50, 50
99
94
CO2Et i-Pr
CO2Et 2-furyl
3
3
Acridinium salts are a group of mild photo-oxidants with the
maximum absorption of λ > 350 nm.12,13e They have recently
been shown by Fukuzumi’s pioneering works to be effective
catalysts in the chemoselective photo-oxidation of xylene, benzyl
alcohol and R-methylstyrene with molecular oxygen.13 Owing
to our interest in the reactions and mechanism of coenzyme
NADH models,14 we envisioned that acridinium ions might also
be utilized in the oxidation of 1,4-DHP with O2. Thus, we chose
4-phenyl-substituted 1,4-DHP 1a as the model substrate and
9-phenyl-10-methylacridinium perchlorate (A-1), 10-methyl-
acridinium perchlorate (A-2) and 9-ethyl-10-methylacridinium
perchlorate (A-3) as catalysts to explore this possibility. The
results are listed in Table 1.
a Isolated yield based on 1. b The dealkylation poduct 2i was isolated in
15% yield.
proceeded smoothly and a 96% yield of 2a was achieved within
the same period of time (entry 3, Table 1). Moreover, 1H NMR
of the crude product indicated that the catalyst remained
unchanged. Thus, after the evaporation of solvent CH3CN and
dissolution of the crude product in anhydrous ether, the
acridinium A-1 precipitated out. By filtration, it was easily
recovered and could be directly reused.
Our control experiments revealed that both the catalyst and
the UV irradiation are essential for the aromatization (entries 4
and 5, Table 1). The reaction had a better performance in CH3-
CN than in CH2Cl2 (entry 6, Table 1). Acridinium salts A-2
and A-3 showed similar catalytic activity, but in a lower
efficiency (entries 7 and 8, Table 1). In all the above experi-
ments, the formation of 2a was always accompanied by the
generation of H2O2. This was evidenced by the iodometric
titration experiments.15 When 2a was obtained in 96% yield
(entry 3, Table 1), the amount of H2O2 was titrated to be ∼85%
yield, implying the approximately 1:1 generation of 2a and
H2O2.
With the optimized conditions (entry 3, Table 1) in hand,
we then conducted the aerobic aromatization of a variety of
1,4-DHP (Table 2). In all the cases, the expected products 2
were achieved in excellent yields. 4-Aryl-1,4-DHP containing
either an electron-withdrawing group or an electron-donating
group all afforded the corresponding products smoothly (entries
1-8, Table 2). 4-Alkyl-1,4-DHP were more reactive, and their
aromatization was complete in a shorter period of time (entries
9-14, Table 2).
Our initial trial used 10 mol % of A-1 as the catalyst, and
the O2-saturated CH3CN solution of 1a was refluxed under the
irradiation of a 150 W high-pressure mercury lamp by cutting
off the light of λ < 310 nm. The expected product 2a was
obtained in only 20% yield (entry 1, Table 1). To our delight,
when the reaction was carried out at room temperature (rt), 2a
was produced in quantitative yield (entry 2, Table 1). When
the amount of A-1 was decreased to 5 mol %, the reaction also
(12) (a) Fukuzumi, S.; Okamoto, K.; Tokuda, Y.; Gros, C. P.; Guilard,
R. J. Am. Chem. Soc. 2004, 126, 17059. (b) Fukuzumi, S.; Yorisue, T.
Bull. Chem. Soc. Jpn 1992, 65, 715.
(13) (a) Ohkubo, K.; Fukuzumi, S. Org. Lett. 2000, 2, 3647. (b) Suga,
K.; Ohkubo, K.; Fukuzumi, S. J. Phys. Chem. A 2003, 107, 4339. (c)
Ohboku, K.; Nanjo, T.; Fukuzumi, S. Org. Lett. 2005, 7, 4265. (d) Suga,
K.; Ohkubo, K.; Fukuzumi, S. J. Phys. Chem. A 2005, 109, 10168. (e)
Ohkubo, K.; Suga, S.; Fukuzumi, S. Chem. Commun. 2006, 2018.
(14) (a) Xu, H.-J.; Liu, Y.-C.; Fu, Y.; Wu, Y.-D. Org. Lett. 2006, 8,
3449. (b) Jiang, H.; Liu, Y.-C.; Li, J.; Wang, G.-W.; Wu, Y.-D.; Wang,
Q.-M.; Mak, T. C. W. Chem. Commun. 2002, 882. (c) Zhu, X.-Q.; Wang,
H.-Y.; Wang, J.-S.; Liu, Y.-C. J. Org. Chem. 2001, 66, 344. (d) Zhu, X.-
Q.; Zou, H.-L.; Yang, P.-W.; Liu, Y.-C.; Cao, L.; Cheng, J.-P. J. Chem.
Soc., Perkin Trans. 2 2000, 1875. (e) Zhu, X.-Q.; Liu, Y.-C.; Wang, H.-
Y.; Wang, W. J. Org. Chem. 1999, 64, 8982. (f) Zhu, X.-Q.; Liu, Y.-C.;
Cheng, J.-P. J. Org. Chem. 1999, 64, 8980. (g) Zhu, X.-Q.; Liu, Y.-C. J.
Org. Chem. 1998, 63, 2786.
The above reactions in Table 2 dealt with structurally
symmetrical Hantzsch 1,4-DHP. To broaden the scope of
application, the oxidation of structurally unsymmetrical 1,4-
DHP, which should be of more synthetic value but has never
been reported, was carried out for the first time. Thus, 1,4-
DHP 3a-g were prepared and subjected to the treatment with
A-1/O2 under the optimized conditions (Table 3). Again the
aromatization proceeded efficiently under the above optimized
conditions.
(15) Mair, R. D.; Graupner, A. J. Anal. Chem. 1964, 36, 194.
J. Org. Chem, Vol. 72, No. 22, 2007 8609

TABLE 3. Aromatization of Unsymmetrical 1,4-DHP
SCHEME 1. Plausible Mechanism for Catalytic
Aromatization
Experimental
Typical Procedure for the Oxidative Aromatization of 1,4-
DHP. 9-Phenyl-10-methylacridinium perchlorate (A-1, 19 mg, 0.05
mmol) and 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-
dicarbonitrile (1h, 280 mg, 1.0 mmol) were dissolved in anhydrous
CH3CN (10 mL), and the solution was saturated with O2 with the
aid of a rubber balloon. The mixture was irradiated at rt with a
150 W high-pressure mercury lamp by cutting off the light of λ <
310 nm. After 10 h, TLC monitoring indicated that the starting
material 1h was all consumed. The light was turned off. The
resulting solution was concentrated under reduced pressure, and
the residue was added into anhydrous ether (10 mL). The ethereal
solution was filtered, and the filtrate was concentrated in vacuo.
The crude product was then passed through a short gel column
with ethyl acetate-hexane (1:1, v:v) as the eluent to give the pure
product 2h as a white solid: yield 290 mg (96%); mp 177-178
°C; 1H NMR (300 MHz, CDCl3) δ 8.48-8.41 (2H, m), 7.85-7.81
(2H, m), 2.90 (6H, s); 13C NMR (75 MHz, CDCl3) δ 165.5, 154.0,
148.4, 124.5, 130.6, 125.7, 123.9, 114.5, 107.2, 24.7; EIMS m/z
(rel intensity) 278 (M+, 100), 232 (78), 205 (77), 164 (36), 63 (42),
51 (43), 50 (44), 42 (46). Anal. Calcd for C15H10N4O2: C, 64.74;
H, 3.62; N, 20.13. Found: C, 64.81; H, 3.81; N, 20.10.
a The reaction conditions in Table 2 were used. b Isolated yield based
on 3.
By comparison with the literature methods, the catalysis of
acridinium salt A-1 is much superior in view of its high catalytic
efficiency, mild reaction conditions, general scope of application,
and easy recovery and reuse.
Based on the above results and literature reports,13e a plausible
mechanism could be drawn for the catalytic aerobic aromati-
zation, as illustrated in Scheme 1. The photoexcitation of
9-phenyl-10-methylacridinium ion (PhAcr+) allows it to abstract
an electron from 1,4-DHP to generate the 1,4-DHP cation radical
and PhAcr•. The fast deprotonation of 1,4-DHP radical cation
gives the 1,4-DHP radical, which reacts with O2 to afford the
•
aromatization product along with the formation of HO2 . The
electron transfer from PhAcr• to HO2• gives HO2- and regener-
ates the catalyst PhAcr+ to complete the catalytic circle.
Acknowledgment. This work was supported by the National
NSF of China (Grant Nos. 20325207, 20672136 and 20772115).
In summary, we have demonstrated that 9-phenyl-10-methyl-
acridinium serves as an efficient catalyst for the room temper-
ature aromatization of 1,4-DHP by molecular oxygen under
metal-free conditions. The easy recovery and reuse of the
catalyst make the process more environmental benign and
practical.
Supporting Information Available: Synthesis and character-
izations of 1-4. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO701796N
8610 J. Org. Chem., Vol. 72, No. 22, 2007