Base-catalyzed and solvent-dependent cascade reaction in the regioselective synthesis of novel fused polycycles

Article abstract of DOI:10.1002/adsc.200700581

A novel base-catalyzed cascade reaction induced by Knoevenegal condensation that can regioselectively generate cyanoflavanones and heavily fused polycycles with intensive fluorescence and high quantum yields is reported. The reaction is solvent-dependent, low-polarity solvents promote the formation of polycycles while high-polarity solvents favor the conversion to cyanoflavanones. A possible mechanism for such serial transformations is proposed.

Full text of DOI:10.1002/adsc.200700581

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DOI: 10.1002/adsc.200700581
Base-Catalyzed and Solvent-Dependent Cascade Reaction in the
Regioselective Synthesis of Novel Fused Polycycles
Min Xia,a,* Guo-Feng Xiang,a Bin Wu,a and Yi-Feng Hana
a
Department of Chemistry, Zhejiang Sci-Tech University, Hangzhou 310018, Peopleꢀs Republic of China
Phone: (+86)-571-8684-3224; fax: (+86)-571-8684-3224; e-mail: xiamin@zstu.edu.cn
Received: December 11, 2007; Revised: February 12, 2008; Published online: March 31, 2008
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: A novel base-catalyzed cascade reaction
induced by Knoevenegal condensation that can re-
gioselectively generate cyanoflavanones and heavily
fused polycycles with intensive fluorescence and
high quantum yields is reported. The reaction is sol-
vent-dependent, low-polarity solvents promote the
formation of polycycles while high-polarity solvents
favor the conversion to cyanoflavanones. A possible
mechanism for such serial transformations is pro-
posed.
reasonable to good yields by the reaction of two
easily available starting molecules, that is, a-cyano-o-
hydroxyacetophenone and aldehydes. Moveover, the
chemical outcome of the reaction involving the two
substrates can be regioselectively controlled by con-
venient adjustment of the solvent polarity.
For example, when 4-methylbenzaldehyde (1c) and
3-(2-hydroxy-5-methylphenyl)-3-oxopropionitrile (2)
are treated with 0.2 equivalents of triethylamine for
3 h in toluene or 10 h in CH2Cl2 at room temperature,
polycyclic product 3c is isolated in 78% or 76% yield,
respectively (Scheme 1). However, when the same re-
action is executed in MeOH or DMF for 4 h at room
temperature, a mixture of the cyanoflavanones 4c/4c’
is generated in, respectively, 91% or 87% yield as the
single product instead (Scheme 1). Apparently, the re-
gioselective products of the reaction are solvent-de-
pendent, the polycycle is favorably formed in low-po-
Keywords: base-catalyzed reactions; cyanoflava-
nones; domino reactions; Knoevenegal condensa-
tion; polycycles; solvent effects
In recent years, there has been great interest in cas- larity solvents and the cyanoflavanone is preferential-
cade reactions since they involve two or more bond- ly generated in high-polarity solvents. The cases for
forming transformations from simple starting materi- other tested aldehydes are analogous to that of 1c
als that take place under the same reaction condi- when these cascade reactions are performed at room
tions.[1] This results in an increased synthetic efficien- temperature in toluene under the catalysis of 0.2
cy and ecologically and economically favorable syn- equivalents of triethylamine (Scheme 1) and the re-
thesis of compounds with complicated or highly func- sults of the production of polycycles are listed in
tionazlied chemical structures. Among them, the cas- Table 1. It is notable that the corresponding cyanofla-
cade reactions originating from the Knoevenagel vanones are not detected in the process involving the
condensation are useful approaches to the construc- formation of polycycles.
tions of fused heterocycles, like Knoevenagel-hetero-
For all the selected aldehydes 1a–m, the reactions
Diels–Alder reactions,[2] Knoevenagel-hydrogenation- to produce polycycles 3a–m smoothly occur at room
Robinson sequences,[3] Knoevenagel-electrocycliza- temperature and the isolation of products can be
tion[4] and Knoevenagel-epimerization[5] processes and readily accomplished by simple filtration and washing
so on. In order to develop a cascade reaction induced rather than a prolonged chromatography method. Ad-
by a Knoevenagel condensation for obtaining some ditionally, they display observable high bond-forming
novel fused polycycles, herein we report the triethyl- efficiency and atom economy, since six new bonds are
ACHTREUNG
cen-8-ones which exhibit intensive yellow fluorosence Both electronic and vicinal effects exist in these reac-
and excellent quatum yields. Although these com- tions. For example, it is difficult for m-nitrobenzalde-
pounds have highly complicated structures with five hyde to accomplish the serial bond-forming process,
fused rings, they can be straightforwardly obtained in the corresponding polycycle cannot be obtained.
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Min Xia et al.
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Scheme 1.
Table 1. Triethylamine-catalyzed cascade synthesis of poly-
cycles 3a–m in toluene at room temperature.
Entry Product R
Yield
[%][a]
Quantum
yield
[FF][b]
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
3g
3h
3i
C6H5
72
85
78
58
71
68
47
61
79
80
84
0.823
0.840
0.826
0.826
0.836
0.836
0.845
0.844
0.874
0.846
0.874
4-CH3OC6H4
4-CH3C6H4
4-FC6H4
4-BrC6H4
4-ClC6H4
2-ClC6H4
2-C2H5OC6H4
4-(CH3)2NC6H4
3,4-OCH2OC6H3
3-CH3O-4-
C2H5OC6H3
2,4-Cl2C6H3
PhCH=CH
9
10
11
3j
3k
12
13
3l
3m
49
41
0.861
0.832
Figure 1. Fluorescence excitation (solid line) and emission
(dotted line) spectra of 3c in THF (2 mM) solution .
[a]
[b]
Isolated yields referred to 2.
Using naphthacence (FF =0.6, lex =443 nm) as a stan-
dard in THF.
The flavanone structure is abundant in natual prod-
ucts that possess a broad array of biological activi-
ties.[6] Surprisingly, there has been no report in the lit-
Compounds 3a–m are molecules with intensively erature about the preparation of 3-cyanoflavanones,
yellow fluorescence and outstandingly high quantum herein we describe an effective and convenient ap-
yields in solutions. All the polycycles display analo- proach to these compounds via a base-catalyzed cas-
gous excitation and emission spectra, with their exci- cade reaction of aldehyde and 3-(2-hydroxyl-5-meth-
tation wavelengths around 440 nm and emission ylphenyl)-3-oxopropionitrile (2) at room temperature
peaks about 510 nm. A typical fluorescent excitation in high-polarity solvents like methanol (Scheme 1)
and emission spectrum of sample 3c is displayed in and the results are given in Table 2. It is found that
Figure 1. The molecular structures of polycycles were cyanoflavanones can be obtained as the single prod-
determined by X-ray crystallography, as shown for ucts in good yields from the respective transforma-
the example 3b (Figure 2).
tions of the screened aldehydes 1a–f. Importantly, 3-
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Base-Catalyzed and Solvent-Dependent Cascade Reaction
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Table 3. Transformatons of 4a–e/4a’–e’ mixtures into 3a–e on
catalysis of Et3N under heating.
Entry Product[a]
R
Yield [%][b] Yield [%][c]
1
2
3
4
5
3a
3b
3c
3d
3e
C6H5
4-CH3C6H5
4-CH3OC6H5 90
4-FC6H5
83
86
80
82
91
74
82
72
87
4-BrC6H5
[a]
[b]
[c]
Isolated yields referred to 4/4’.
Yields in toluene.
Yields in DMF.
Et3N (Scheme 1) and the results are listed in Table 3.
Notably, 4f/4f’ is unable to undergo such a conver-
sion. When the transformation is executed for just
10 min and quenched by 0.1N HCl aqueous solution,
the intermediates 6b and 6c are obtained in 51% and
42% yields as white solids, and their structures are de-
termined by various NMR experiments (1H, 13C,
DEPT1358, H-D exchange in D2O, HMBC and
HMQC) and confirmed by IR and MSanalysis. The
separated intermediates 6b and 6c cannot be trans-
formed to the polycycles
Compounds 3b and 3c are stable unless they are
treated with triethylamine under heating. Also, the in-
termediates 6b and 6c are unable to be trapped in the
reactions of aldehydes 1b and 1c with 2 in toluene at
room temperature.
A possible mechanism is presented in Scheme 2.
The intermediate A derived from a Knoevenagel con-
densation goes through either of the solvent-depen-
dent routes to form cyanoflavanone in high-polarity
solvents or the intermediate B in low-polarity solvents
when 1 and 2 react at room temperature. Therefore,
the further reaction will take place between B and un-
reacted 2 to provide the precursor C which subse-
Figure 2. The molecular structure of structure of 3b.
Table 2. Triethylamine-catalyzed preparation for the mix-
tures of 4a–f/4a’–f’ in methanol.
Entry Product
R
Yield [%][a] Ratio[b] of
4
4’
1
2
3
4
5
6
4a
4b
4c
4d
4e
4f
C6H5
4-CH3OC6H4 95
4-CH3C6H4
4-FC6H4
4-BrC6H4
3-O2NC6H4
86
88
~100
92
~100
72
72
12
–
8
–
28
28
91
78
83
74
[a]
[b]
Isolated yield referred to 2.
Ratio determined on H NMR.
1
nitrobenzaldehyde is also an efficient substrate to quently undergoes an intramolecular nucleophilic ad-
generate the corresponding cyanoflavanone in good dition followed by the final formation of polycycle 3.
yield (entry f). Unfortunately, these cyanoflavanones It seems that the cyanoflavanone can be reversibly re-
are mixtures containing two diastereomers which verted back to A under heating, which is further con-
cannot be independently isolated by silica gel chroma- verted to B at the increased temperature. Hence, the
tography. The distribution of the two diastereomers in isolated 4/4’ can be transformed to 3 through a base-
1
their mixture can be determined by H NMR inte- catalyzed elimination of aldehyde from the intermedi-
grals, while syn and anti conformations are assigned ate 6.
from JH1–H2. It is attractive that an outstanding stereo-
In summary, we describe a novel Knoevenagel con-
selectivity of anti addition is achieved in our reactions densation-induced cascade reaction for the solvent-
in the presence of a non-chiral catalyst like triethyl- dependent synthesis of new compounds with nice pol-
ACHTREUNG
It is interesting to find that the isolated cyano flava- Further research on the application of this protocol to
nones 4a–e/4a’–e’ can be converted to the correspond- develop new fluorescent materials and using cyanofla-
ing polycycles 3a–e under heating at 1108C in either vanones as building blocks in the synthesis of natural
toluene or DMF under catalysis of 0.2 equivalents of products will be reported in due course.
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Min Xia et al.
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Scheme 2.
6-Amino-2,10-dimethyl-7-(4-N,N-dimethylaminophenyl)-
7H-5,13-dioxa-14-azabenzo[a]naphthacen-8-one (3i): Yield:
79%; yellow solid; mp 252–2548C; FT-IR (KBr): n=3431,
Experimental Section
General Procedure for 6-Amino-2,10-dimethyl-7-
substituted-7H-5,13-dioxa-14-azabenzo[a]naphthacen-
8-ones 3
1
1637, 1557, 1498, 1384, 1265, 814 cmÀ1; H NMR (400 MHz,
DMSO-d6): d=2.34 (s, 3H), 2.43 (s, 3H), 2.73 (s, 6H), 5.30
(s, 1H), 6.50 (d, J=8.8 Hz, 2H), 7.17 (d, J=8.8 Hz, 2H),
7.28 (d, J=8.4 Hz, 1H), 7.36–7.46 (m, 3H), 7.65 (s, 1H),
8.10 (s, 1H), 8.24 (bs, NH2); 13C NMR (100 MHz, DMSO-
d6): d=20.88, 20.96, 34.02, 40.66, 93.62, 102.07, 112.53,
116.50, 117.65, 119.99, 123.85, 124.51, 125.15, 128.31, 133.43,
133.50, 133.65, 134.85, 135.07, 149.55, 149.76, 152.57, 156.83,
161.41, 164.55, 174.56; EI-MS(70eV): m/z (%)=463 (M+,
At room temperature, Et3N (0.2 mmol) is added to a solu-
tion of 3-(2-hydroxy-5-methylphenyl)-3-oxopropionitrile
(1 mmol) and aldehyde (1 mmol) in toluene (5 mL) and the
resultant solution is stirred for 3 h. A yellow precipitate is
gradually generated. After filtration, the solid is washed
with some ether and ethyl acetate. The dried solid 3 is pure
enough for spectral analysis.
27), 343 [M+À
C
6-Amino-2,10-dimethyl-7-(4-methylphenyl)-7H-5,13-
dioxa-14-azabenzo[a]naphthacen-8-one (3c): Yield: 78%;
yellow solid; mp 231–2338C; FT-IR (KBr): n=3400, 1616,
1556, 1496, 1384, 1263, 813 cmÀ1
;
1H NMR (400 MHz,
At room temperature, Et3N (0.2 mmol) is added to the so-
lution of 3-(2-hydroxy-5-methylphenyl)-3-oxopropanenitrile
(1 mmol) and aldehyde (1.2 mmol) in methanol (5 mL), the
resultant mixture is stirred for 4 h and then quenched by
0.1N HCl aqueous solution. The solution is poured into
water and extracted by EtOAc for two times. The combined
organic layers are dried over anhydrous Na2SO4 and the sol-
vent is removed under the reduced pressure. The residue is
isolated on a silica gel column chromatography using petro-
leum/ethyl acetate (3:1) as the eluent to afford the mixture
of 4/4’ in good yields.
DMSO-d6): d=2.15 (s, 3H), 2.36 (s, 3H), 2.45 (s, 3H), 5.42
(s, 1H), 6.96 (d, J=8.0 Hz, 2H), 7.30 (dd, J=8.0, 14.4 Hz,
3H), 7.39–7.50 (m, 3H), 7.67 (s, 1H), 8.12 (s, 1H), 8.36 (bs,
NH2); 13C NMR (100 MHz, DMSO-d6): d=20.38, 20.47,
20.51, 34.16, 92.60, 101.18, 116.06, 117.19, 119.40, 123.28,
124.04, 124.69, 127.21, 128.38, 133.12, 133.36, 134.66, 135.22,
143.02, 149.30, 152.08, 156.69, 160.93, 164.22, 174.02; EI-MS
(70 eV): m/z (%)=434 (M+, 88), 343(M+ÀCH3C6H4, 100),
217 (14), 91 (7); anal. calcd. for C28H22N2O3: C 77.38, H
5.11, N, 6.45; found: C 77.45, H 5.13, N 6.38%.
820
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Base-Catalyzed and Solvent-Dependent Cascade Reaction
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6-Methyl-4-oxo-2-(4-methoxylphenyl)-3,4-dihydro-2H-
chromene-3-carbonitrile (4b/4b’): Yield: 95%; white solid:
FT-IR (KBr): n=3004, 2889, 2261, 1702, 1615, 1488, 1293,
Chem. Int. Ed. 2006, 45, 354; b) H. Pellissier, Tetahedron
2006, 62, 2143; c) J. C. Wasilke, S. J. Obrey, R. T. Baker,
G. C. Bazan, Chem. Rev. 2005, 105, 1001; d) D. J.
Ramon, M. Yus, Angew. Chem. 2005, 117, 1628; Angew.
Chem. Int. Ed. 2005, 44, 1602; e) K. C. Nicolaou, T.
Montagnon, S. A. Snyder, Chem. Commun. 2003, 551;
f) S. F. Mayer, W. Kroutil, K. Faber, Chem. Soc. Rev.
2001, 30, 332; g) L. F. Tietze, Chem. Rev. 1996, 96, 115;
h) D. E. Cane, Chem. Rev. 1990, 90, 1089; i) L. F. Tietze,
A. Modi, Med. Res. Rev. 2000, 20, 304.
1
1248, 1130, 830 cmÀ1; H NMR (400 MHz, CDCl3): d=2.35
(s, 3H), 3.82 (s, 3H), 4.14 (d, J=12.4 Hz, 1H), 5.40 (d, J=
12.0 Hz, 1H), 6.96 (d, J=8.8 Hz, 1H), 7.00 (d, J=8.4 Hz,
2H), 7.39 (d, J=8.4 Hz, 1H), 7.47 (d, J=8.4 Hz, 2H), 7.75
(s, 1H); 13C NMR (100 MHz, CDCl3): d=20.45, 47.40, 55.41,
80.62, 113.39, 114.50, 118.07, 118.39, 127.36, 127.41, 128.40,
132.48, 138.60, 158.94, 160.86, 182.94; EI-MS(70 eV): m/z
(%)=292 (M+À1, 100), 278 (15), 159 (32), 134 (70), 107
(11), 77 (23); anal. calcd. for C18H15NO3: C 73.69, H 5.16, N
4.78; found: C 73.55, H 5.11, N 4.83%.
[2] a) S. JimØnez-Alonso, A. EstØvez-Braun, . G. Ravelo,
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Bioorg. Med. Chem. Lett. 2007, 17, 978; c) R. D. S.
Manian, J. Jayashankaran, R. Raghunathan, Synlett
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Raghunathan, Tetrahedron Lett. 2006, 47, 2265; e) G. Sa-
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dari, C. F. Barbas, Angew. Chem. 2003, 115, 4365;
Angew. Chem. Int. Ed. 2003, 42, 4233.
6-Methyl-4-oxo-2-(4-fluorophenyl)-3,4-dihydro-2H-chrom-
ene-3-carbonitrile (4d): Yield: 78%; white solid; FT-IR
A
(KBr): n=2259, 1707, 1615, 1515, 1489, 1298, 845, 833 cmÀ1
;
1H NMR(400 MHz, CDCl3): d=2.36 (s, 3H), 4.10 (d, J=
12.4 Hz, 1H), 5.45 (d, J=12.4 Hz, 1H), 6.97 (d, J=8.4 Hz,
1H), 7.19 (t, J=8.4 Hz, 2H), 7.41 (d, J=8.4 Hz, 1H), 7.56
(dd, J=5.6, 8.0 Hz, 2H), 7.77 (s, 1H); 13C NMR (100 MHz,
2
CDCl3): d=20.48, 47.53, 80.17, 113.18, 116.48 (d, JCF
=
3
21 Hz), 118.02, 118.34, 127.43, 128.90 (d, JCF =9 Hz), 131.26,
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1
132,78, 136.75, 158.69, 163.54 (d, JCF =248 Hz), 182.46; EI-
MS(70 eV): m/z (%)=280
(M+À1, 94), 134 (100), 106 (46),
78 (38), 51 (18); anal. calcd. for C17H12FNO2: C 72.57, H
4.30, N 4.98; found: C 72.51, H 4.33; N 4.95%.
Comb. Sci. 2004, 23, 895.
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Acknowledgements
We are grateful for the financial support of this research from
the Natural Science Foundation of Zhejiang Province
(R405465).
References
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Adv. Synth. Catal. 2008, 350, 817 – 821
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