Lewis acid-catalyzed one-pot sequential reaction for the synthesis of α-halogenated β-keto esters

Article abstract of DOI:10.1016/j.tetlet.2010.02.158

A Lewis acid-catalyzed one-pot sequential transformation of β-keto esters, aromatic aldehydes, and NCS/NBS was reported. The reaction proceeds by way of Knoevenagel condensation/Nazarov cyclization/halogenation to give α-chloro- and α-bromo-β-keto esters in moderate yields with high diastereoselectivities. However, several aromatic aldehydes with electron-withdrawing substituents afforded unexpected α,β′-dichloro-β-keto esters in good to high yields.

Full text of DOI:10.1016/j.tetlet.2010.02.158

Tetrahedron Letters 51 (2010) 2374–2377
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Lewis acid-catalyzed one-pot sequential reaction for the synthesis
of a-halogenated b-keto esters
*
Han-Feng Cui, Ke-Yan Dong, Jing Nie, Yan Zheng, Jun-An Ma
Department of Chemistry, Tianjin University, Tianjin 300072, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A Lewis acid-catalyzed one-pot sequential transformation of b-keto esters, aromatic aldehydes, and NCS/
Received 13 January 2010
Revised 22 February 2010
Accepted 26 February 2010
Available online 2 March 2010
NBS was reported. The reaction proceeds by way of Knoevenagel condensation/Nazarov cyclization/halo-
genation to give a-chloro- and a-bromo-b-keto esters in moderate yields with high diastereoselectivities.
However, several aromatic aldehydes with electron-withdrawing substituents afforded unexpected a
,b0-
dichloro-b-keto esters in good to high yields.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Lewis acid
One-pot reaction
Halogenation
b-Ketoester
a-Chlorinated and
a-brominated carbonyl compounds are ver-
ent a Lewis acid-catalyzed one-pot sequential reaction of b-keto
satile intermediates in organic synthesis, natural product chemis-
try, and in biomedical and pharmaceutical sciences.1–4 Therefore,
the preparation of the structural complex and diverse chlorinated
and brominated compounds has received much attention in syn-
thetic chemistry.5–18 The most commonly used process is the ‘stop
and go’ sequence of individual reactions. However, the quest for
efficient methods for the construction of the halogenated mole-
cules is just at the beginning. Multicomponent sequential transfor-
mations try to meet these more challenging requirements because
this new strategy favors the formation of several bonds in one-pot
by using a single catalyst, without the need for isolation and puri-
fication of the intermediates.19,20 For example, Lectka and co-
workers have developed a one-pot halogenation/esterification pro-
cess of acyl halides using perhaloquinone-derived reagents as the
halogen source. The reactions were catalyzed by benzoylquinine.21
Togni and co-workers presented [TiCl2(TADDOLato)]-catalyzed
one-pot heterodihalogenation of b-keto esters with F-TEDA and
esters, aromatic aldehydes, and NCS/NBS to give a-chloro and a-
bromo-b-keto esters.
This one-pot sequence is a three-component reaction compris-
ing an aromatic b-keto ester, an aromatic aldehyde, a halogenating
agent (NXS: X = Cl, Br, I), and a simple Lewis acid, which is capable
of catalyzing each step of this triple transformation of Knoevenagel
condensation/Nazarov cyclization/halogenation (Scheme 1). In the
presence of AlCl3, the reaction of methyl benzoylacetate and benz-
aldehyde with NCS in nitroethane affords the desired product 1a in
moderate yield (50%) with high diastereoselectivity (trans/cis: 26/
1) (Table 1, entry 1). When the reaction solvent was changed to tol-
uene, CHCl3, DMF, or CH3CN, no desired product was obtained, thus
EtNO2 gave the best results. Next we tested the possibility of using
NBS and NIS in this one-pot sequential reaction. Interestingly, the
desired brominated product 1h was obtained in good yield (62%)
with excellent diastereoselectivity (trans/cis: 29/1) (Table 1, entry
8), whereas the iodinated product was not observed. Various other
b-keto esters and aromatic aldehydes were converted to their cor-
NCS to afford a-chloro-a-fluoro-b-keto esters in moderate to good
yields.22 Apparently one-pot multistep reactions involving C–X
bond-formation remain very rare, and the design of novel catalytic
systems is still in great demand for the rapid advancement of the
fields of organic synthesis and medicinal agents. As a part of a re-
search program aimed at the development of catalytic methods for
the construction of halogenated molecules, we recently reported
several one-pot multistep sequential transformations for the syn-
thesis of organofluorine compounds.23–25 Herein, we wish to pres-
responding a-chlorinated and a-brominated products (1b–g and
1i–k) in moderate to good yields with excellent diastereoselectiv-
ties using this procedure (Table 1, entries 2–7 and 9–11).26 Surpris-
ingly, the dichlorinated reaction occurred on the aromatic ring and
a
-position of ethyl 3-(30-methoxyphenyl)-3-oxopropanoate in the
presence of over 2 equiv of NCS. However, this phenomenon was
not observed for other substrates and NBS.
It is noteworthy that the one-pot sequential reaction of methyl
benzoylacetate and 3,4-dichlorobenzaldehyde with NCS in nitroe-
thane gave
diastereomer for the product 2a was recrystallized in pure form by
a
,b0-dichloro-b-keto ester 2a in high yield.27 The major
* Corresponding author. Tel.: +86 22 27402903; fax: +86 22 27403475.
E-mail address: majun_an68@tju.edu.cn (J.-A. Ma).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.02.158

H.-F. Cui et al. / Tetrahedron Letters 51 (2010) 2374–2377
2375
O
O
O
O
NXS
X
R1
R1
OR2
(X = Cl, Br, I)
OR2
RCHO
Lewis Acid
R
Knoevenagel
condensation
Halogenation
O
O
R
O
O
R1
R1
Nazarov
OR2
OR2
cyclization
R
Scheme 1.
O
O
CHO
Cl
O
O
O
Me
AlCl3
O
Me
2a
90% yield
O
Cl
N
+
Cl
+
Cl
Cl
C2H5NO2
1.5/1 (anti/syn)
Cl
O
Cl
O
O
Cl
Me
O
Cl
H
Cl
Cl
Scheme 2.
O
O
O
O
O
O
Cl
Cl
Cl
Et
Me
O
Me
O
O
Cl
Cl
Cl
MeO
Br
Cl
Cl
Cl
Me
Cl
2b: 81% yield, 2/1 dr
Cl
Cl
2c: 65% yield, 2.6/1 dr
2d: 40% yield, 1.5/1 dr
O
O
O
O
O
O
Cl
Cl
Cl
Me
Et
Et
O
O
Me
Cl
O
Cl
Cl
Cl
CF3
Cl
2g: 84% yield, 7.6/1 dr
Cl
2e: 93% yield, 1.8/1 dr
2f: 60% yield, 1.3/1 dr
Figure 1.
using an ethyl acetate–petroleum mixture. The relative stereochem-
istry confirmed by X-ray crystallography shows the anti configura-
tion (Scheme 2).28 In the presence of AlCl3, the reaction of methyl
benzoylacetate and 3,4-dichlorobenzaldehyde without NCS affor-
ded the Knoevenagel condensation product in nearly quantitative
yield. However, the Nazarov product was not observed in this reac-
tion system. These results indicated that the electron-withdrawing
substituents on the alkylidene moiety of b-keto esters could restrain
NCS was replaced by NBS or NIS, only the Knoevenagel condensation
intermediate was obtained, and the corresponding halogenated
products were not observed. Several
2b–i were also obtained from the one-pot sequential reaction of aro-
matic b-keto esters with 3,4-dichlorobenzaldehyde, 4-chlorobenz-
aldehyde, and 4-trifluoromethyl benzaldehyde in the presence of
NCS and AlCl3 (Fig. 1).30 Interestingly, the position differences of
a
,b0-dichloro-b-keto esters
the electron-donating substituents on the phenyl ring of
esters also changed the reaction course dramatically. For example,
methyl 3-(40-methoxyphenyl)-3-oxopropanoate gave ,b0-di-
a-keto
4p
-electrocyclization of the polarized enone. The mechanism for
this intriguing sequential reaction is not clear at this stage.29 When
a

2376
H.-F. Cui et al. / Tetrahedron Letters 51 (2010) 2374–2377
Table 1
Lewis acid-catalyzed one-pot sequential reaction of b-keto ester, aldehyde, and NCS/NBS
Entry
Halogenating reagent
Producta
Yieldb (%)
Trans/cisc
26/1
O
O
Cl
Me
Me
O
1
NCS
50
1a
1b
O
O
Cl
O
2
3
4
5
NCS
NCS
NCS
NCS
45
53
32
63
22/1
28/1
25/1
25/1
OMe
O
O
Cl
Me
Cl
O
O
Br
O
1c
O
Et
MeO
O
1d
O
Cl
MeO
Et
O
Cl
1e
O
O
Cl
MeO
Et
O
6
NCS
32
25/1
Cl
Cl
1f
O
O
Cl
MeO
Et
O
7
8
NCS
NBS
37
62
28/1
29/1
OMe
1g
O
O
Br
Me
O
1h
O
O
O
Br
Br
Me
O
O
9
NBS
NBS
42
22
22/1
24/1
Cl 1i
O
Me
10
Br
1j

H.-F. Cui et al. / Tetrahedron Letters 51 (2010) 2374–2377
2377
Table 1 (continued)
Entry
Halogenating reagent
Producta
Yieldb (%)
Trans/cisc
O
O
Br
Me
O
11
NBS
31
24/1
MeO
Cl 1k
a
b-Keto ester (1.0 equiv), aldehyde (1.2 equiv), AlCl3 (2.0 equiv) in EtNO2 at room temperature for 24–48 h, then NCS/NBS (1.2 equiv) was added and stirred for 12 h at
80 °C. All products were characterized by 1H NMR, 13C NMR, IR, and mass spectroscopy.
b
Isolated yield.
c
Determined by 1H NMR.
chloro-b-keto ester 2d, whereas methyl 3-(30-methoxyphenyl)-3-
oxopropanoate proceeded by way of a Lewis acid-catalyzed Knoeve-
13. Marigo, M.; Bachmann, S.; Halland, N.; Braunton, A.; Jøgensen, K. A. Angew.
Chem., Int. Ed. 2004, 43, 5507.
14. Marigo, M.; Kumaragurubaran, N.; Jøgensen, K. A. Chem. Eur. J. 2004, 10, 2133.
nagel condensation/Nazarov cyclization/chlorination sequence to
afford chlorinated 1-indanone derivative 1f in moderate yield with
high diastereoselectivity (Table 1, entry 6). In addition, ethyl 3-oxo-
15. Zhang, Y.; Shibatomi, K.; Yamamoto, H. J. Am. Chem. Soc. 2004, 126, 15038.
16. Wang, C.; Tunge, J. Chem. Commun. 2004, 2694.
17. Yang, D.; Yan, Y.-L.; Lui, B. J. Org. Chem. 2002, 67, 7429.
18. Hintermann, L.; Togni, A. Helv. Chim. Acta 2000, 83, 2425.
19. Review, see: Zhu, J.; Bienaymé, H. Multicomponent Reactions; Wiley-VCH:
Weinheim, 2005.
20. Review, see: Guillena, G.; RamUn, D. J.; Yus, M. Tetrahedron: Asymmetry 2007,
18, 693.
21. Wack, H.; Taggi, A. E.; Hafez, A. M.; Drury, W. J., III; Lectka, T. J. Am. Chem. Soc.
2001, 123, 1531.
22. Frantz, R.; Hintermann, L.; Perseghini, M.; Broggini, D.; Togni, A. Org. Lett. 2003,
5, 1709.
23. Zhang, G.-W.; Wang, L.; Nie, J.; Ma, J.-A. Adv. Synth. Catal. 2008, 350, 1457.
24. Cui, H.-F.; Dong, K.-Y.; Zhang, G.-W.; Wang, L.; Ma, J.-A. Chem. Commun. 2007,
2284.
25. Nie, J.; Zhu, H.-W.; Cui, H.-F.; Hua, M.-Q.; Ma, J.-A. Org. Lett. 2007, 9, 3053.
26. General procedure for Knoevenagel condensation/Nazarov cyclization/electrophilic
chlorination: anhydrous AlCl3 (0.2 mmol) was added to a solution of b-keto
ester (0.1 mmol) and aldehydes (0.12 mmol) in EtNO2 (1.0 mL) under an inert
atmosphere and the resulting mixture was stirred at room temperature for 24–
48 h (monitored by TLC). Then a solution of NCS/NBS (0.12 mmol) in 1.0 mL
EtNO2 was added and the reaction mixture was heated to 80 °C for 12–24 h
(monitored by TLC). After cooling to ambient temperature, the reaction was
quenched by 2 M HCl, and the reaction mixture was extracted with ethyl
acetate, washed with brine, dried by MgSO4, filtered, and concentrated under
vacuum. The crude oil was purified by silica gel flash chromatography to give
the desired product.
butanoate also gave the corresponding a
, b0-dichloro-b-keto ester 2g
in 84% yields and with 7.6/1 diastereoselective ratio.
In conclusion, we have demonstrated a Lewis acid-catalyzed
one-pot sequential reaction via triple transformation of Knoevena-
gel condensation/Nazarov cyclization/halogenation to afford chlo-
rinated and brominated 1-indanone derivatives in moderate
yields with high diastereoselectivities. In this catalytic system,
unexpected
a
,b0-dichloro-b-keto esters were obtained by the use
of several aromatic aldehydes bearing electron-withdrawing sub-
stituents. Further investigation of the reaction mechanism, as well
as the development of catalytic asymmetric systems are currently
being explored and will be reported in due course.
Acknowledgments
The financial support from NSFC (No. 20772091 and 20972110)
and Tianjin Municipal Science & Technology Commission (No.
08JCYBJC09500) is gratefully acknowledged.
27. The reaction of methyl benzoylacetate and 3,4-dichlorobenzaldehyde with
NFSI in nitroethane proceeded by way of a Lewis acid-catalyzed Knoevenagel
condensation/Nazarov cyclization/fluorination sequence to afford fluorinated
1-indanone derivative in 62% yield with high diastereoselectivity (trans/cis:
25/1). The electrophilic fluorination trapping as a terminating step for Nazarov
cyclization may facilitate catalyst turnover.
28. CCDC 758804 contains the supplementary crystallographic data for the
product anti-2a. These data can also be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
References and notes
1. De Kimpe, N.; Verhé, R. The Chemistry of
a-Haloketones, a-Haloaldehydes, and a-
Haloimines; John Wiley & Sons: New York, 1990.
2. Larock, R. C. Comprehensive Organic Transformations, second ed.; VCH: New
York, 1999.
3. Thomas, G. Medicinal Chemistry: An Introduction; John Wiley & Sons: New York,
2000.
4. Feske, B. D.; Kaluzna, I. A.; Stewart, J. D. J. Org. Chem. 2005, 70, 9654.
5. Mei, Y.; Bentley, P. A.; Du, J. Tetrahedron Lett. 2008, 49, 3802.
6. Meshram, H. M.; Reddy, P. N.; Vishnu, P.; Sadashiv, K.; Yadav, J. S. Tetrahedron
Lett. 2006, 47, 991.
29. Electrophilic chloronium ion could be generated from
a-alkylidene b-keto
ester and opened by nucleophilic chloride. Relative reported, see:
Ranganathan, S.; Muraleedharan, K. M.; Vaish, N. K.; Jayaraman, N.
Tetrahedron 2004, 60, 5273.
7. Halland, N.; Lie, M. A.; Kjærsgaard, A.; Marigo, M.; Schiøt, B.; Jøgensen, K. A.
Chem. Eur. J. 2005, 11, 7083.
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Chem., Int. Ed. 2005, 44, 6219.
9. Meshram, H. M.; Reddy, P. N.; Sadashiv, K.; Yadav, J. S. Tetrahedron Lett. 2005,
46, 623.
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30. General procedure for Knoevenagel condensation/chlorination: anhydrous AlCl3
(0.2 mmol) was added to a solution of b-keto ester (0.1 mmol) and aldehydes
(0.1 mmol) in EtNO2 (1.0 mL) under an inert atmosphere and the resulting
mixture was stirred at room temperature for 24–48 h (monitored by TLC). Then
a solution of NCS (0.20 mmol) in 1.0 mL EtNO2 was added and the reaction
mixture was heated to 110 °C for 12 h. After cooling to ambient temperature,
the reaction was quenched by 2 M HCl, and the reaction mixture was extracted
with ethyl acetate, washed with brine, dried by MgSO4, filtered, and
concentrated under vacuum. The crude oil was purified by silica gel flash
chromatography to give the desired product.
12. Brochu, M. P.; Brown, S. P.; MacMillan, D. W. C. J. Am. Chem. Soc. 2004, 126,
4108.