Stereoselective construction of fluorinated indanone derivatives via a triple cascade Lewis acid-catalyzed reaction

Article abstract of DOI:10.1039/b702114c

A one-pot three-component cascade reaction proceeds by way of a Lewis acid-catalyzed Knoevenagel condensation/Nazarov cyclization/electrophilic fluorination sequence to afford fluorinated 1-indanone derivatives in moderate to good yields with high diaster

Full text of DOI:10.1039/b702114c

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Stereoselective construction of fluorinated indanone derivatives via a
triple cascade Lewis acid-catalyzed reaction{
Han-Feng Cui,a Ke-Yan Dong,a Guang-Wu Zhang,a Lian Wanga and Jun-An Ma*ab
Received (in Cambridge, UK) 9th February 2007, Accepted 16th March 2007
First published as an Advance Article on the web 4th April 2007
DOI: 10.1039/b702114c
single catalyst. In this communication, we present a new cascade
transformation for the one-pot synthesis of fluorinated 1-indanone
derivatives. The reaction sequence that we have devised is depicted
in Scheme 1. This cascade transformation is a three-component
reaction comprising an aromatic b-ketoester 1, an aldehyde, a
fluorinating agent and a simple Lewis acid, which is capable of
catalyzing each step of this triple cascade. Initial screening of
electrophilic fluorinating reagents was done with AlCl3, methyl
benzoylacetate and benzaldehyde in nitroethane. It was found that
N-fluorobenzenesulfonimide (NFSI) was the only fluorinating
reagent to provide the desired cascade product in 68% yield with
excellent diastereoselectivity (trans/cis: 29/1). Commercially
available fluorinating reagents Selectfluor (1-chloromethyl-4-
fluoro-1,4-diazoniabicyclo[2,2,2]octane bis(tetrafluoroborate)) and
N-fluoropyridinium triflate were minimally reactive, and gave very
low yields (,10%). Therefore, NFSI was used for subsequent
reactions. Following this selection of an electrophilic fluorinating
reagent, a Lewis acid screen was undertaken. The screening
results revealed that other Lewis acids, such as TiCl4, SnCl4, BF3
and Pd(OAc)2, did not display reactivity for this cascade
transformation.
A one-pot three-component cascade reaction proceeds by way
of a Lewis acid-catalyzed Knoevenagel condensation/Nazarov
cyclization/electrophilic fluorination sequence to afford fluori-
nated 1-indanone derivatives in moderate to good yields with
high diastereoselectivities.
Organofluorine compounds have attracted considerable attention
because they show distinctive characteristics in comparison with
their nonfluorinated analogues.1 Construction of the structural
complex and diverse organofluorine molecules has become the
focus of intense research efforts for synthetic organic, medicinal
and material chemists.2 Traditionally, the synthesis approach to
organofluorine compounds has most usually focused on stepwise
bond formation processes. In contrast to this ‘‘stop and go’’
sequence of individual reactions, cascade or tandem transforma-
tion is a very appealing strategy as it favors the formation of
several bonds in one pot by using a single catalyst, without the
need for isolation of the intermediates.3 Furthermore, cascade
reactions also enable a rapid increase in molecular complexity
from readily available starting compounds. However, survey of the
literature reveals that cascade transformations for the construction
of organofluorine molecules are rare.4 Therefore, the design of
multi-component cascade reactions for the synthesis of complex
organofluorine compounds is a continuing challenge at the
forefront of fluorine chemistry.
To determine the scope of this cascade reaction, we subjected a
series of aromatic b-ketoesters and aldehydes to the optimized
conditions (Table 1). Not only electron-neutral and -donating
(entries 1–3) but also electron-withdrawing substituents (entries 4
and 5) on the phenyl ring of aldehydes were tolerated for this triple
cascade transformation to give the corresponding fluorinated
indanone derivatives in good yields (62–71%) with good to high
diastereoselectivities (trans/cis: 3/1–29/1). For these aromatic
aldehydes with multi-substituents, low cascade yields were
obtained probably owing to steric hindrance (entries 6 and 7). A
variation of aromatic b-ketoesters was probed next. It appears that
the nature of the electronic properties of the substituents in the
aromatic systems have a remarkable effect on this cascade
reaction. Substrates possessing the electron-neutral (entries 1–5)
and -donating groups (entries 6–14) on the aromatic rings were
Indanone derivatives are useful compounds serving as building
blocks for the synthesis of natural products, medicines and
agrochemicals.5 Over the past few years, there have been a few
reports on the construction of fluorine-containing indanone
molecules by stepwise bond formation.6 We have an interest in
developing cascade protocols that give access to fluorinated
1-indanone derivatives involving a minimum number of isolation
and purification steps.
It is well established that Knoevenagel condensation of aromatic
b-ketoesters and aldehydes with Lewis acid catalysts gives
alkylidene b-ketoesters,7 followed by Nazarov cyclization to form
1-indanone derivatives.8 In addition, reports for fluorination
reactions of b-ketoesters catalyzed by Lewis acids,9 such as zinc,
titanium, aluminium, palladium, copper and nickel salts, suggested
us that a cascade Knoevenagel condensation/Nazarov cyclization/
electrophilic fluorination process might be possible by using a
aDepartment of Chemistry, Tianjin University, Tianjin, 300072, China.
E-mail: majun_an68@tju.edu.cn; Fax: +86 22 27403475;
Tel: +86 22 27402903
bState Key Laboratory of Elemento-Organic Chemistry, Nankai
University, Tianjin, 300071, China
{ Electronic supplementary information (ESI) available: Experimental
details. See DOI: 10.1039/b702114c
Scheme 1 Lewis acid-catalysed triple cascade reaction.
2284 | Chem. Commun., 2007, 2284–2286
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Table 1 One-pot three-component cascade reaction
Entry
1
Producta
Yieldb (%)
68
Trans/cisc
Entry
8
Producta
Yieldb (%)a
Trans/cisc
2a
2b
29/1
2h
2i
72
29/1
2
62
29/1
9
45
29/1
3
4
2c
2d
60
70
26/1
24/1
10
11
2j
65
50
24/1
25/1
2k
5
6
2e
2f
71
15
3/1
12
13
2l
59
48
24/1
21/1
24/1
2m
7
2g
12
3/1
14
2n
46
29/1
a
b-Ketoester (1 eq.), aldehyde (1 eq.) and AlCl3 (1.2 eq.) in EtNO2 at room temperature for 24–48 h, then NFSI (1.5 eq.) was added and
stirred for 2–6 h at 110 uC. Isolated yield. Determined by 1H NMR or 19F NMR.
b
c
transformed with good to excellent diastereoselectivities. For
b-ketoesters with electron-withdrawing substituents (such as F, Cl
and NO2) on the aromatic rings, the desired products were not
observed in the cascade reaction.
trans to the R group of Nazarov cyclization intermediate B, and the
cis attack was sterically restricted by the b-aromatic group of R.
In summary, we have reported the first examples of a triple
cascade Knoevenagel condensation/Nazarov cyclization/electro-
philic fluorination process. This Lewis acid-catalyzed sequence
Notably, when NFSI was replaced by chlorination and
bromination reagents for extension of this triple cascade
transformation, preliminary results were promising (Scheme 2).
In the presence of AlCl3, the reaction of methyl benzoylacetate and
benzaldehyde with NCS and NBS affords the cascade products 3
and 4 in moderate to good yields with excellent diastereoselec-
tivities (for 3: trans/cis 24/1 with 44% yield and for 4: trans/cis 29/1
with 60% yield, respectively).
The major diastereomers for the cascade products 2d and 3 were
recrystallized in pure form by using an ethyl acetate–petroleum
mixture. The relative stereochemistry confirmed by X-ray crystal-
lography (Fig. 1){ indicates that subsequent halogenation occurs
Scheme 2 Lewis acid-catalysed cascade Knoevenagel condensation/
Nazarov cyclization/electrophilic chlorination and bromination.
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C(16)–C(1)–Cl(1) 108.82(14), C(2)–C(1)–Cl(1) 110.55(13), C(16)–C(1)–
C(15) 109.62(16); torsion angles (u): C(16)–C(1)–C(2)–C(3) 27.4(2), C(9)–
C(2)–C(3)–C(4) –152.26(19), Cl(1)–C(1)–C(15)–O(1) 46.6(2). CCDC
635729 and 635730. For crystallographic data in CIF or other electronic
format see DOI: 10.1039/b702114c
1 (a) R. Filler, Y. Kobayashi and Y. L. Yagupolskii, Organofluorine
Compounds in Medicinal Chemistry and Biological Applications, Elsevier,
Amsterdam, 1993; (b) I. Ojima, J. R. McCarthy and J. T. Welch,
Biomedical Frontiers of Fluorine Chemistry, American Chemical Society,
Washington, DC, 1996.
2 (a) P. Krisch, Modern Fluoroorganic Chemistry: Synthesis, Reactivity, and
Applications, Wiley-VCH, Weinheim, Germany, 2004; (b) K. Mikami,
Y. Itoh and M. Yamanaka, Chem. Rev., 2004, 104, 1; (c) M. Shimizu and
T. Hiyama, Angew. Chem., Int. Ed., 2005, 44, 214; (d) K. K. Laali,
Advances in Organic Synthesis: Modern Organofluorine Chemistry-
Synthetic Aspects, Bentham, Hilversum, Netherlands, 2006.
3 (a) L. F. Tietze and N. Rackelmann, Pure Appl. Chem., 2004, 76, 1967;
(b) J.-C. Wasilke, S. J. Obrey, R. T. Baker and G. C. Bazan, Chem. Rev.,
2005, 105, 1001; (c) H.-C. Guo and J.-A. Ma, Angew. Chem., Int. Ed.,
2006, 45, 345; (d) H. Pellissier, Tetrahedron, 2006, 62, 1619–2143.
4 (a) S. Hara, S. Okamoto, M. Narahara, T. Fukuhara and N. Yoneda,
Synlett, 1999, 411; (b) P. C. Andrews, V. Bhaskar, K. M. Bromfield,
A. M. Dodd, P. J. Duggan, S. A. M. Duggan and T. D. McCarthy,
Synlett, 2004, 791; (c) Y. Huang, A. M. Walji, C. H. Larsen and
D. W. C. MacMillan, J. Am. Chem. Soc., 2005, 127, 1501.
5 (a) J. A. Lowe, D. L. Hageman, S. E. Drozda, S. McLean, D. K. Bryce,
R. T. Crawford, S. Zorn, J. Morrone and J. Bordner, J. Med. Chem.,
1994, 37, 3789; (b) M. A. Lago, J. I. Luengo, C. E. Peishoff and
J. D. Elliot, Annu. Rep. Med. Chem., 1996, 31, 81; (c) D. G. Nagle,
Y. Zhou, P. U. Park, V. J. Paul, I. Rajbhandari, C. J. G. Duncan and
D. S. Pasco, J. Nat. Prod., 2000, 63, 1431; (d) A. K. Sharma,
A. V. Subramani and C. B. Gorman, Tetrahedron, 2006, 63, 389.
6 (a) H. Ibrahim and A. Togni, Chem. Commun., 2004, 1147; (b) J.-A. Ma
and Q. Cahard, Chem. Rev., 2004, 104, 6119; (c) G. K. S. Prakash and
P. Beier, Angew. Chem., Int. Ed., 2006, 45, 2172, and references therein.
7 (a) E. Knoevenagel, Ber. Dtsch. Chem. Ges., 1898, 31, 2585. For recent
examples of Lewis acid-catalyzed Knoevenagel condensation, see: (b)
D. Prajapati, K. C. Lekhok, J. S. Sandhu and A. C. Ghosh, J. Chem.
Soc., Perkin Trans. 1, 1996, 959; (c) A. V. Narsaiah and K. Nagaiah,
Synth. Commun., 2003, 21, 3825; (d) J. S. Yadav, B. V. S. Reddy,
A. K. Basak, B. Visali, A. V. Narsaiah and K. Nagaiah, Eur. J. Org.
Chem., 2004, 546; (e) P. Leelavathi and S. R. Kumar, J. Mol. Catal. A:
Chem., 2005, 240, 99.
8 For reviews of Nazarov cyclization, see: (a) K. L. Habermas,
S. E. Denmark and T. K. Jones, Org. React., 1994, 45, 1; (b)
H. Pellissier, Tetrahedron, 2005, 61, 6479; (c) A. Frontier and
C. Collison, Tetrahedron, 2005, 61, 7577; (d) M. Tius, Eur. J. Org.
Chem., 2005, 11, 2193. For recent examples of Nazaorov type
reactions forming indanone derivatives, see: (e) D. L. J. Clive,
M. Sannigrahi and S. Hisaindee, J. Org. Chem., 2001, 66, 954; (f)
D. J. Kerr, C. Metje and B. L. Flynn, Chem. Commun., 2003, 1380; (g)
W. He, X. Sun and A. J. Frontier, J. Am. Chem. Soc., 2003, 125, 14278;
(h) M. Janka, W. He, A. J. Frontier and R. Eisenberg, J. Am. Chem.
Soc., 2004, 126, 6864; (i) M. Janka, W. He, I. E. Haedicke,
F. R. Fronczek, A. J. Frontier and R. Eisenberg, J. Am. Chem. Soc.,
2006, 128, 5313.
Fig. 1 X-Ray crystal structure of the major diastereomers for the
fluorinated indanone 2d and chlorinated indanone 3 (ORTEP).
proceeds with high stereoselectivity to afford trans fluorinated
1-indanone derivatives. The further development of catalytic
enantioselective systems and the full extension of this triple
cascade with other halogenation agents will be reported in due
course.
We thank the NSFC (No. 20542008) and the Ministry of
Education of China for generous financial support. We also
acknowledge Dr. Richard Goddard (Max-Planck-Institut fu¨r
Kohlenforschung) for his great help for X-ray structure analysis.
Notes and references
{ Crystal data for 2d: C17H12ClFO3, M = 318.72, colorless prism, crystal
size: 0.24 6 0.20 6 0.10 mm, monoclinic, space group P21/c, a = 17.213(4),
˚
b = 8.458(2), c = 10.468(2) A, b = 96.925(4)u, T = 294(2) K, Reflections
collected/unique: 8209/3082, final R indices were R1 = 0.0421 and wR2 =
˚
0.0941 Selected bond lengths (A): F(1)–C(1) 1.395(2), C(1)–C(2) 1.547(3),
C(2)–C(9) 1.518(3); bond angles (u): F(1)–C(1)–C(16) 106.86(16),
F(1)–C(1)–C(15) 109.72(16), F(1)–C(1)–C(2) 110.65(16); torsion angles
(u): F(1)–C(1)–C(2)–O(1) 245.6(3), F(1)–C(1)–C(2)–C(3) 296.4(2), C(16)–
C(1)–C(2)–C(3) 24.1(2). Crystal data for 3: C17H13ClO3, M = 300.72,
colorless prism, crystal size: 0.24 6 0.14 6 0.10 mm, monoclinic, space
9 (a) T. Umemoto, S. Fukami, G. Tomizawa, K. Harasawa, K. Kawada
and K. Tomita, J. Am. Chem. Soc., 1990, 112, 8563; (b) L. Hintermann
and A. Togni, Angew. Chem., Int. Ed., 2000, 39, 4359; (c) Y. Hamashima,
K. Yagi, H. Takano, L. Tamas and M. Sodeoka, J. Am. Chem. Soc.,
2002, 124, 14530; (d) J.-A. Ma and D. Cahard, Tetrahedron: Asymmetry,
2004, 14, 1007; (e) N. Shibata, T. Ishimura, T. Nagai, J. Kohno and
T. Toru, Synlett, 2004, 1703; (f) J.-A. Ma and D. Cahard, J. Fluorine
Chem., 2004, 125, 1357.
˚
group P21/c, a = 16.228(4), b = 8.599(2), c = 10.594(3) A, b = 98.122(5)u,
T = 294(2) K, Reflections collected/unique: 8103/2968, final R indices were
˚
R1 = 0.0438 and wR2 = 0.0702. Selected bond lengths (A): Cl(1)–C(1)
1.781(2), C(1)–C(16) 1.532(3), C(2)–C(9) 1.515(3); bond angles (u):
2286 | Chem. Commun., 2007, 2284–2286
This journal is ß The Royal Society of Chemistry 2007