Enantioselective three-component Kabachnik-Fields reaction catalyzed by chiral scandium(III) N,N'-dioxide complexes

Article abstract of DOI:10.1021/ol9000813

The N,N'-dioxide-Sc(lll) complex has been applied in the three-component Kabachnik-Fields reaction of aldehydes, 2-aminophenol, and diphenyl phosphite, giving the corresponding α-amino phosphonates in good yields with high enantioselectivities (up to 87%

Full text of DOI:10.1021/ol9000813

ORGANIC
LETTERS
2009
Vol. 11, No. 6
1401-1404
Enantioselective Three-Component
Kabachnik-Fields Reaction Catalyzed
by Chiral Scandium(III)-N,N′-Dioxide
Complexes
Xin Zhou,† Deju Shang,† Qi Zhang,† Lili Lin,† Xiaohua Liu,† and
Xiaoming Feng*,†,‡
Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of
Chemistry, Sichuan UniVersity, Chengdu 610064, P. R. China, and State Key Laboratory
of Applied Organic Chemistry, Lanzhou UniVersity, Lanzhou 730000, P. R. China
xmfeng@scu.edu.cn
Received January 15, 2009
ABSTRACT
The N,N′-dioxide-Sc(III) complex has been applied in the three-component Kabachnik-Fields reaction of aldehydes, 2-aminophenol, and
diphenyl phosphite, giving the corresponding r-amino phosphonates in good yields with high enantioselectivities (up to 87% ee). The direct
Kabachnik-Fields reaction proceeded with extremely high reactivity under mild reaction conditions and could be used for large-scale synthesis
of the r-amino phosphonates.
As mimics of R-amino acids,1 chiral R-amino phosphonates
exhibit intriguing biological activities and have found
widespread use as antibacterial2 and anti-HIV agents,3 as
well as protease inhibitors.4,5 Thus their synthesis has
attracted great attentions.6 To the best of our knowledge,
the asymmetric hydrophosphonylation of imines provides one
of the most efficient methods for the preparation of chiral
R-amino phosphonates.7 The Shibasaki group reported the
first enantioselective hydrophosphonylation of imine using
various heterobimetallic complexes.8 Subsequently, organo-
catalysts such as chiral thiourea derivatives,9 chiral binol-
derived phosphoric acid,10 and cinchona alkaloids11 were
successfully applied in the reaction. Chiral aluminum(III)
(5) (a) Allen, M. C.; Fuhrer, W.; Tuck, B.; Wade, R.; Wood, J. M.
J. Med. Chem. 1989, 32, 1652. (b) Ding, J.; Fraser, M. E.; Meyer, J. H.;
Bartlett, P. A.; James, M. N. G. J. Am. Chem. Soc. 1998, 120, 4610. (c)
Smith, W. W.; Bartlett, P. A. J. Am. Chem. Soc. 1998, 120, 4622, and
references therein. (d) Bird, J.; De Mello, R. C.; Harper, G. P.; Hunter,
D. J.; Karran, E. H.; Markwell, R. E.; Miles-Williams, A. J.; Rahman, S. S.;
Ward, R. W. J. Med. Chem. 1994, 37, 158.
† Sichuan University.
‡ Lanzhou University.
(1) Smith, A. B., III; Yager, K. M.; Taylor, C. M. J. Am. Chem. Soc.
1995, 117, 10879.
(2) (a) Allen, J. G.; Atherton, F. R.; Hall, M. J.; Hassall, C. H.; Holmes,
S. W.; Lambert, R. W.; Nisbet, L. J.; Ringrose, P. S. Nature 1978, 272, 56.
(b) Atherton, F. R.; Hassall, C. H.; Lambert, R. W. J. Med. Chem. 1986,
29, 29.
(6) For reviews on noncatalytic variants, see: (a) Dhawan, B.; Redmore,
D. Phosphorus Sulfur 1987, 32, 119. (b) Kukhar, V. P.; Soloshonok, V. A.;
Solodenko, V. A. Phosphorus Sulfur Silicon Relat. Elem. 1994, 92, 239.
(c) Kolodiazhnyi, O. I. Tetrahedron: Asymmetry 1998, 9, 1279. For recent
examples of auxiliary-controlled asymmetric hydrophosphonylations, see:
(d) Davis, F. A.; Lee, S.; Yan, H.; Titus, D. D. Org. Lett. 2001, 3, 1757.
(3) Alonso, E.; Alonso, E.; Solis, A.; del Pozo, C. Synlett 2000, 698.
(4) Hirschmann, R.; Smith, A. B., III; Taylor, C. M.; Benkovic, P. A.;
Taylor, S. D.; Yager, K. M.; Sprengeler, P. A.; Benkovic, S. J. Science
1994, 265, 234
.
10.1021/ol9000813 CCC: $40.75
Published on Web 02/18/2009
2009 American Chemical Society

complexes based on salalen and tethered bis(8-quinolinato)
ligands have also proved effective for the hydrophosphony-
lation of aldimine.12,13 Despite these achieved works as well
as the merit of in situ formation of imine, the direct catalytic
asymmetric three-component Kabachnik-Fields reaction was
scarcely investigated.12,14 Only the List group reported such
a reaction with great success using a phosphoric acid as the
catalyst.14 However, this research was focused on the
Kabachnik-Fields reaction of R-branched aldehydes, and a
long reaction time (168 h) was necessary to achieve high
yield of product. Thus, searching for a new catalyst system
that could achieve high reactivity and enantioselectivity for
the Kabachnik-Fields reaction is still challenging and
interesting. As part of our interest and ongoing programs on
the asymmetric synthesis of biologically active functionalized
phosphonates,15 we describe herein a highly efficient asym-
metric three-component Kabachnik-Fields reaction using
chiral N,N′-dioxide-Sc(III) complex as the catalyst, provid-
ing R-amino phosphonates in high ee and yields within 1 h.
In the previous studies, the chiral N,N′-dioxide-Sc(III)
complexes have exhibited an excellent ability for the
activation of various electrophiles and showed strong asym-
metry-inducing capability for many reactions.16,17 As for the
reaction of a bidentate substrate, chiral scandium(III) com-
plexes were generally thought to coordinate in a bidentate
manner, leading to high reactivity and excellent enantiose-
lectivity.18 In light of these successes, we envisioned that
such a catalyst might be effective for the three-component
Kabachnik-Fields reaction of aldehydes, 2-aminophenol, and
diphenyl phosphite.
Figure 1. N,N′-Dioxide ligands evaluated.
Indeed, the direct asymmetric three-component Kabachnik-
Fields reaction proceeded smoothly in the presence of N,N′-
dioxide-Sc(III) complex (the molar ratio of ligand/Sc(OTf)3
was 2:1) in THF.19 To obtain the most effective ligand
structure, various N,N′-dioxides were complexed in situ with
Sc(OTf)3 to catalyze the reaction. As shown in Table 1, the
chiral backbone of the N,N′-dioxides had significant impact
on the enantioselectivity of the reaction. L-Ramiprol acid
derived N,N′-dioxide 3 was superior to 1 (derived from
L-proline) and 2 (derived from L-pipecolic acid). Furthermore,
the steric effect of the amide moiety played a crucial role
on the asymmetric induction of the Kabachnik-Fields
reaction. Decreasing the steric hindrance of the amide moiety
led to dramatic reduction in the enantioselectivity (Table 1,
entries 3-5). Racemic product was obtained when aniline-
derived N,N′-dioxide 5 was used as the chiral ligand. It is
noteworthy that just changing the substituent of the amide
moiety may result in opposite stereoinduction of the reaction
(Table 1, entry 3 vs 4).
Lanthanides (Ln) have numerous similar properties such
as Lewis acidity, multifunctionality, and high coordination
capability, thus showing somewhat analogical actions in
organic synthesis. Promoted by the great successes obtained
in asymmetric reactions using chiral Ln complexes,20 we
carried out a systematic screen of Ln complexes in the
(7) For reviews on enantioselective catalytic hydrophosphonylations, see:
(a) Gro¨ger, H.; Hammer, B. Chem. Eur. J. 2000, 6, 943. (b) Ma, J. A.
Chem. Soc. ReV. 2006, 35, 630. (c) Merino, P.; Marque´s-Lo´pez, E.; Herrera,
R. P. AdV. Synth. Catal. 2008, 350, 1195. (d) Ordo´n˜ez, M.; Rojas-Cabrera,
H.; Cativiela, C. Tetrahedron 2009, 65, 17.
(8) (a) Sasai, H.; Arai, S.; Tahara, Y.; Shibasaki, M. J. Org. Chem. 1995,
60, 6656. (b) Gro¨ger, H.; Saida, Y.; Arai, S.; Martens, J.; Sasai, H.;
Shibasaki, M. Tetrahedron Lett. 1996, 37, 9291. (c) Gröger, H.; Saida, Y.;
Sasai, H.; Yamaguchi, K.; Martens, J.; Shibasaki, M. J. Am. Chem. Soc.
1998, 120, 3089. (d) Schlemminger, I.; Saida, Y.; Gro¨ger, H.; Maison, W.;
Durot, N.; Sasai, H.; Shibasaki, M.; Martens, J. J. Org. Chem. 2000, 65,
4818.
(17) For examples of enantioselective reactions catalyzed by N,N′-
dioxide-scandium(III) complexes, see: (a) Shang, D. J.; Xin, J. G.; Liu,
Y. L.; Zhou, X.; Liu, X. H.; Feng, X. M. J. Org. Chem. 2008, 73, 630. (b)
Li, X.; Liu, X. H.; Fu, Y. Z.; Wang, L. J.; Zhou, L.; Feng, X. M. Chem.
Eur. J. 2008, 14, 4796. (c) Kokubo, M.; Ogawa, C.; Kobayashi, S. Angew.
Chem., Int. Ed. 2008, 47, 6909. Chiral N,N′-dioxide-Sc(III) complexes
also exhibited excellent asymmetric activating abilities for other carbonyl
compounds and bidentate substrates. For selected examples of asymmetric
reactions catalyzed by chiral scandium complexes based on other chiral
ligands, see: (d) Kobayashi, S.; Araki, M.; Hachiya, I. J. Org. Chem. 1994,
59, 3758. (e) Ishikawa, S.; Hamada, T.; Manabe, K.; Kobayashi, S. J. Am.
Chem. Soc. 2004, 126, 12236. (f) Mai, E.; Schneider, C. Chem. Eur. J.
2007, 13, 2729. (g) Nojiri, A.; Kumagai, N.; Shibasaki, M. J. Am. Chem.
Soc. 2008, 130, 5630, and reference therein.
(9) Joly, G. D.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 4102.
(10) Akiyama, T.; Morita, H.; Itoh, J.; Fuchibe, K. Org. Lett. 2005, 7,
2583.
(11) (a) Pettersen, D.; Marcolini, M.; Bernardi, L.; Fini, F.; Herrera,
R. P.; Sgarzani, V.; Ricci, A. J. Org. Chem. 2006, 71, 6269. (b) Nakamura,
S.; Nakashima, H.; Yamamura, A.; Shibata, N.; Toru, T. AdV. Synth. Catal.
2008, 350, 1209.
(12) For a one-pot in situ sequence, see: Saito, B.; Egami, H.; Katsuki,
T. J. Am. Chem. Soc. 2007, 129, 1978.
(13) Abell, J. P.; Yamamoto, H. J. Am. Chem. Soc. 2008, 130, 10521.
(14) Cheng, X.; Goddard, R.; Buth, G.; List, B. Angew. Chem., Int. Ed.
2008, 47, 5079.
(18) For some selected reports in which the chiral scandium complexes
chelated with bidentate substrate, see: (a) Yang, D.; Yang, M.; Zhu, N. Y.
Org. Lett. 2003, 5, 3749. (b) Evans, D. A.; Wu, J. J. Am. Chem. Soc. 2005,
127, 8006. (c) Evans, D. A.; Aye, Y. J. Am. Chem. Soc. 2006, 128, 11034.
(d) Evans, D. A.; Fandrick, K. R.; Song, H.-J.; Scheidt, K. A.; Xu, R. J. Am.
Chem. Soc. 2007, 129, 10029, and reference therein.
(15) (a) Huang, J. L.; Wang, J.; Cheng, X. H.; Wen, Y. H.; Liu, X. H.;
Feng, X. M. AdV. Synth. Catal. 2008, 350, 287. (b) Zhou, X.; Liu, X. H.;
Yang, X.; Shang, D. J.; Xin, J. G.; Feng, X. M. Angew. Chem., Int. Ed.
2008, 47, 392. (c) Gou, S. H.; Zhou, X.; Wang, J.; Liu, X. H.; Feng, X. M.
Tetrahedron 2008, 64, 2864. (d) Liu, J.; Yang, Z. G.; Wang, Z.; Wang, F.;
Chen, X. H.; Liu, X. H.; Feng, X. M.; Su, Z. S.; Hu, C. W. J. Am. Chem.
Soc. 2008, 130, 5654. (e) Cheng, X. H.; Wang, J.; Zhu, Y.; Shang, D. J.;
Gao, B.; Liu, X. H.; Feng, X. M.; Su, Z. S.; Hu, C. W. Chem. Eur. J. 2008,
14, 10896. (f) Wang, F.; Liu, X. H.; Cui, X.; Xiong, Y.; Zhou, X.; Feng,
X. M. Chem. Eur. J. 2009, 15, 589.
(19) (a) The N,N′-dioxide-Sc(III) complexes (molar ratio of ligand/
Sc(OTf)3 was 2:1 and 1:1) were both effective for the asymmetric activation
of 2-aminophenol masked aldimine in the previous works. Thus the molar
ratio of ligand/Sc(OTf)3 was first investigated, and N,N′-dioxide-Sc(III)
complex (molar ratio of ligand/Sc(OTf)3 was 2:1) was shown to be superior.
(b) Aliphatic aldehydes were also investigated. The reactions proceeded
smoothly to give the corresponding products with only moderate enantio-
selectivities (n-butyraldehyde, 63% yield, 41% ee; cyclohexanecarbaldehyde,
82% yield, 38% ee).
(16) For reviews of chiral N-oxides, see: (a) Chelucci, G.; Murineddu,
G.; Pinna, G. A. Tetrahedron: Asymmetry 2004, 15, 1373. (b) Malkov, A. V.;
Koˇcovsky´, P. Eur. J. Org. Chem. 2007, 29, and references therein
.
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Org. Lett., Vol. 11, No. 6, 2009

an excellent substrate with respect to enantioselectivity and
yield of the reaction (Table 2, entry 6).19b
Table 1. Direct Catalytic Asymmetric Three-Component
Kabachnik-Fields Reaction under the Indicated Conditionsa
Table 2. Substrate Scope for the Direct Catalytic Asymmetric
Three-Component Kabachnik-Fields Reactiona
entry
ligand
metal
yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
9
1
2
3
4
5
3
3
3
3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Y(OTf)3
La(OTf)3
Sm(OTf)3
Yb(OTf)3
87
89
86
91
83
49
13
17
38
25 (+)
63 (+)
84 (+)
41 (-)
0
45 (-)
24 (-)
30 (-)
45 (-)
a Reactions were carried out with ligand (10 mol %), metal (5 mol %),
6a (0.2 mmol), 7 (0.2 mmol), and 8 (0.2 mmol) in THF (1.0 mL) at -20
°C within 30 min. b Isolated yield. c Determined by HPLC using chiral AS-H
column.
presence of the N,N′-dioxide ligand 3 (Table 1, entries 6-9).
It was interesting that products with the opposite configu-
ration were obtained using such catalysts. Furthermore, the
activating and asymmetry-inducing capabilities of N,N′-
dioxide 3-Ln complexes showed a similar trend. The
enantioselectivity of the reaction improved with increasing
reactivity, which may ascribed to the different Lewis acidity
of N,N′-dioxide 3-Ln complexes. Unfortunately, no better
result was obtained. Thus, the best result was obtained when
the three-component Kabachnik-Fields reaction of aldehyde,
2-aminophenol, and diphenyl phosphite was performed in
THF by using 5 mol % N,N′-dioxide 3-Sc(III) complex
(Table 1, entry 3).
a Unless otherwise noted, reactions were carried out with N,N′-dioxide
3 (10 mol %), Sc(OTf)3 (5 mol %), 6 (0.2 mmol), 7 (0.2 mmol), and 8 (0.2
mmol) in THF (1.0 mL) at -20 °C within 1 h. b Isolated yield. c Determined
by HPLC using commercial chiral columns.
To test the synthetic potential of the present approach, a
large-scale synthesis of the chiral R-amino phosphonates was
performed. As shown in Scheme 1, by treatment of 5 mmol
of starting materials under the optimal reaction conditions,
the desired product was produced without loss of reactivity
or enantioselectivity.
Under the optimized reaction conditions, the substrate
scope of the Kabachnik-Fields reaction was investigated,
and the cooresponding R-amino phosphonates were obtained
in good yields with high enantioslectivities. It is noteworthy
that the reaction showed extremely high reactivity and was
completed within 1 h. As shown in Table 2, the electronic
properties of the substituent on the aromatic ring had no
obvious effect on the enantioselectivity of the reaction.
Moreover, the multisubstituted aromatic aldehyde, which was
rarely investigated previously, underwent the reaction smoothly
and gave the corresponding product with 87% ee (Table 2,
entry 13). The condensed ring aldehyde also proved to be
Scheme 1
.
Scaled-Up Version of the Kabachnik-Fields
Reaction
In conclusion, we have demonstrated the highly enanti-
oselective three-component Kabachnik-Fields reaction of
aldehydes, 2-aminophenol, and diphenyl phosphite using
chiral N,N′-dioxide-Sc(III) complex as the catalyst. The
reaction was performed with extremely high reactivity and
produced R-amino phosphonates with high yield and high
enantioselectivies within 1 h. Moreover, the present catalytic
approach provided a potential for large-scale synthesis of
(20) For reviews of lanthanide complexes in asymmetric reactions, see:
(a) Shibasaki, M.; Sasai, H.; Arai, T. Angew. Chem., Int. Ed. 1997, 36,
1236. (b) Aspinall, H. C. Chem. ReV. 2002, 102, 1807. (c) Shibasaki, M.;
Yoshikawa, N. Chem. ReV. 2002, 102, 2187. (d) Inanaga, J.; Furuno, H.;
Hayano, T. Chem. ReV. 2002, 102, 2211. (e) Kobayashi, S.; Sugiura, M.;
Kitagawa, H.; Lam, W. W.-L. Chem. ReV. 2002, 102, 2227. (f) Mikami,
K.; Terada, M.; Matsuzawa, H. Angew. Chem., Int. Ed. 2002, 41, 3554. (g)
For N,N′-dioxide-La complex catalyzed reaction, see: Yang, X.; Zhou, X.;
Lin, L. L.; Chang, L.; Liu, X. H.; Feng, X. M. Angew. Chem., Int. Ed.
2008, 47, 7079.
Org. Lett., Vol. 11, No. 6, 2009
1403

chiral R-amino phosphonates. Further studies of the reaction
mechanism are in progress.
Supporting Information Available: Experimental pro-
cedures and spectral and analytical data for the products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. We appreciate the National Natural
Science Foundation of China (nos. 20732003 and 20872096)
and the Ministry of Education (no. 20070610019) for
financial support. We also thank Sichuan University Analyti-
cal & Testing Center for NMR analysis.
OL9000813
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Org. Lett., Vol. 11, No. 6, 2009