Enantioselective Michael addition of 2-hydroxy-1,4-naphthoquinones to nitroalkenes catalyzed by binaphthyl-derived organocatalysts

Article abstract of DOI:10.3762/bjoc.8.78

The highly enantioselective Michael addition of 2-hydroxy-1,4- naphthoquinones to nitroalkenes, promoted by binaphthyl-modified chiral bifunctional organocatalysts is described. This reaction afforded the chiral functionalized naphthoquinones in high yiel

Full text of DOI:10.3762/bjoc.8.78

Enantioselective Michael addition of 2-hydroxy-1,4-
naphthoquinones to nitroalkenes catalyzed by
binaphthyl-derived organocatalysts
Saet Byeol Woo and Dae Young Kim*
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2012, 8, 699–704.
Department of Chemistry, Soonchunhyang University, Asan,
Chungnam, 336-745, Korea
doi:10.3762/bjoc.8.78
Received: 07 March 2012
Accepted: 17 April 2012
Published: 07 May 2012
Email:
Dae Young Kim* - dyoung@sch.ac.kr
* Corresponding author
This article is part of the Thematic Series "Organocatalysis".
Guest Editor: B. List
Keywords:
asymmetric catalysis; Michael addition; 1,4-naphthoquinones;
nitroalkenes; organocatalysis
© 2012 Woo and Kim; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
The highly enantioselective Michael addition of 2-hydroxy-1,4-naphthoquinones to nitroalkenes, promoted by binaphthyl-modified
chiral bifunctional organocatalysts is described. This reaction afforded the chiral functionalized naphthoquinones in high yields
(81–95%) and excellent enantioselectivities (91–98% ee) under low catalyst loading (1 mol %).
Introduction
Quinone and naphthoquinone structures exist in a large number reactions, which are both powerful and environmentally
of natural products and biologically active molecules [1-4]. friendly, have been subjected to rigorous investigation in recent
Many of these naturally occurring naphthoquinones and their years [16-22]. The asymmetric Michael addition of various
synthetic analogues are important precursors for the synthesis of nucleophiles to nitroalkenes is of great interest, because the
natural products and pharmaceuticals [5-9]. The stereoselective products obtained are versatile intermediates in organic syn-
formation of C–C bonds is of great importance for the syn- thesis [23-26]. Extensive studies have been devoted to the
thesis of enantiomerically pure, biologically active organic development of asymmetric conjugate additions of 1,3-dicar-
compounds [10,11]. It is widely recognized that the Michael ad- bonyl compounds to various Michael acceptors [27-33].
dition is one of the most versatile and general methods for C–C Recently, the groups of Du and Zhou reported a highly enantio-
bond formation in organic synthesis [12], and intensive research selective Michael addition of 2-hydroxy-1,4-naphthoquinones
efforts have been directed toward the development of enantiose- to nitroalkenes catalyzed by chiral, bifunctional tertiary-amine
lective catalytic protocols for this reaction [13-15]. The thioureas, thiophosphorodiamides, and squaramide-based
organocatalyst-mediated enantioselective conjugate addition organocatalysts [34-36].
699

Beilstein J. Org. Chem. 2012, 8, 699–704.
Findings
We initially investigated the reaction system with 2-hydroxy-
In the framework of our research program for the development 1,4-naphthoquinone (1) and nitrostyrene 2a in the presence of
of synthetic methods for the enantioselective construction of 10 mol % of Takemoto's catalyst I in acetonitrile at room
stereogenic carbon centers [37-42], we recently reported the temperature, to determine the optimum reaction conditions for
enantioselective Michael addition of active methines to the catalytic, enantioselective Michael addition. This reaction
nitroalkenes [43,44]. Herein, we describe the direct enantiose- exhibited good yield and high enantioselectivity (89% ee,
lective Michael addition of 2-hydroxy-1,4-naphthoquinone with Table 1, entry 1). In order to enhance the enantioselectivity,
nitroalkenes, catalyzed by bifunctional organocatalysts other bifunctional organocatalysts II–VIII were evaluated in
(Figure 1) that bear both central and axial chiral elements the model reaction (Table 1, entries 2–8). The quinine-derived
[45-47].
thiourea catalyst II was less effective (Table 1, entries 1 and 2),
Figure 1: Structures of chiral organocatalysts.
700

Beilstein J. Org. Chem. 2012, 8, 699–704.
whereas the binaphthyl-modified, chiral, bifunctional selectivities (89–99% ee, Table 1, entries 3 and 9–12). Remark-
organocatalysts III–VIII, bearing both central and axial chiral ably, water and brine also afforded products in good yields;
elements, effectively promoted the addition reaction in high however, the selectivity dropped significantly (Table 1, entries
yield, with high enantioselectivity (78–97% ee, Table 1, entries 13 and 14). Among the solvents probed, the best results (92%
3–8). Catalyst III gave the desired product 3a with high yield and 99% ee) were achieved when the reaction was
enantioselectivity (97%, Table 1, entry 3), whereas the dia- conducted in THF (Table 1, entry 11). The present catalytic
stereomeric catalyst VII afforded product 3a in lower enantio- system tolerates catalyst loading down to 5, 2.5, and 1 mol %
selectivity (78% ee, Table 1, entry 7). These results demon- without compromising the yield or enantioselectivity (Table 1,
strate that the central and axial chiral elements in the chiral entries 11 and 15–17).
amine-thiourea catalyst III are matched, thus enhancing the
stereochemical control, whereas in the diastereomeric catalyst With the optimized reaction conditions in hand, the scope of the
VII this is not the case.
methodology was investigated in reactions with 2-hydroxy-1,4-
naphthoquinone (1) and various nitroalkenes 2a–l in the pres-
Different solvents were then tested in the presence of 10 mol % ence of 1 mol % of catalyst III in THF at room temperature
of catalyst III together with 2-hydroxy-1,4-naphthoquinone (1) (Table 2). A range of electron-donating and electron-with-
and nitrostyrene 2a in order to further improve the selectivity of drawing substitutions on the β-aryl ring of the nitrostyrenes
the reaction. Aprotic solvents, such as acetonitrile, toluene, 2b–h provided reaction products in high yields and excellent
dichloromethane, THF, diethyl ether, were well tolerated in this enantioselectivities. Heteroaryl- and naphthyl-substituted
conjugate addition without a significant decrease of enantio- nitroalkenes 2i and 2j provided products with high selectivity
Table 1: Optimization of the reaction conditions.
entry
cat.
solvent
time (h)
yield (%)a
ee (%)b
1
2
I
II
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
toluene
DCM
2
2
84
87
96
95
93
90
85
88
75
93
92
81
89
86
90
90
89
89
77
97
87
81
93
78
93
95
89
99
91
19
37
98
99
99
3
III
IV
V
2
4
2
5
2
6
VI
VII
VIII
III
III
III
III
III
III
III
III
III
2
7
2
8
2
9
4
10
11
12
13
14
15c
16d
17e
4
THF
2
Et2O
3
H2O
17
17
2
brine
THF
THF
2
THF
2
aIsolated yield.
bEnantiopurity was determined by HPLC analysis using chiralcel OJ-H column.
cReaction was carried out in the presence of 5 mol % catalyst.
dReaction was carried out in the presence of 2.5 mol % catalyst.
eReaction was carried out in the presence of 1 mol % catalyst.
701

Beilstein J. Org. Chem. 2012, 8, 699–704.
Table 2: Catalytic asymmetric Michael addition of 2-hydroxy-1,4-naphthoquinone 1 to nitroalkenes 2.
entry
2, R
time (h)
yield (%)a
ee (%)b
1
2
2a, Ph
2
2
4
3
3
3
4
4
5
5
5
3a, 89
3b, 93
3c, 81
3d, 95
3e, 90
3f, 95
3g, 95
3h, 95
3i, 93
3j, 93
3k, 90
99
95
99
95
91
95
95
95
93
99
97
2b, p-MeC6H4
2c, p-MeOC6H4
2d, p-FC6H4
2e, p-ClC6H4
2f, p-BrC6H4
2g, o-FC6H4
2h, o-BrC6H4
2i, 2-thienyl
3
4
5
6
7
8
9
10
11
2j, 2-naphthyl
2k, isobutyl
aIsolated yield.
bEnantiopurity was determined by HPLC analysis using chiralcel OJ-H (3a–j) and chiralpak AD-H (for 3k) columns.
(93–99% ee, Table 2, entries 9 and 10). The β-alkyl-substituted 2–5 h at room temperature. After completion of the reaction, the
nitroalkene, 4-methyl-1-nitropent-1-ene (2k), was also an resulting solution was concentrated in vacuo and the obtained
acceptable starting material and provided the corresponding residue was purified by flash chromatography (EtOAc–hexane)
Michael adducts in high yield and excellent enantioeselectivity to afford the corresponding Michael adducts 3. Products 3 are
(97% ee, Table 2, entry 11).
known compounds, and their data were identical to those
reported in the literature [34-36].
In conclusion, we have developed a highly efficient catalytic,
enantioselective Michael addition of 2-hydroxy-1,4-naphtho-
quinone to nitroalkenes using a binaphthyl-derived tertiary
amine-thiourea organocatalyst. The various types of nitroalkyl-
ated naphthoquinone derivatives were obtained in good to high
yields with excellent enantioselectivities (91–99% ee) for all the
substrates examined in this work. We believe that this method
should provide a practical entry for the preparation of chiral
nitroalkylated naphthoquinone derivatives. Further details and
application of this asymmetric Michael addition of 2-hydroxy-
1,4-naphthoquinone nucleophiles will be presented in due
course.
Supporting Information
Supporting Information File 1
Characterization data of products 3.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-8-78-S1.pdf]
Acknowledgements
This work was supported in part by the Soonchunhyang Univer-
sity Research Fund.
References
Experimental
1. de Andrade-Neto, V. F.; Goulart, M. O. F.; da Silva Filho, J. F.;
da Silva, M. J.; Pinto, M. C. F. R.; Pinto, A. V.; Zalis, M. G.;
Carvalho, L. H.; Krettli, A. U. Bioorg. Med. Chem. Lett. 2004, 14,
1145–1149. doi:10.1016/j.bmcl.2003.12.069
General procedure for the Michael addition of 2-hydroxy-
1,4-naphthoquinone (1) with nitroalkenes 2: A mixture of
2-hydroxy-1,4-naphthoquinones (1, 34.8 mg, 0.2 mmol) and
catalyst III (1.3 mg, 0.002 mmol) in THF (0.4 mL) was stirred
at room temperature for 5 min. A solution of nitroalkene 2
(0.2 mmol) was added. The reaction mixture was stirred for
2. Tandon, V. K.; Yadav, D. B.; Singh, R. V.; Chaturvedi, A. K.;
Shukla, P. K. Bioorg. Med. Chem. Lett. 2005, 15, 5324–5328.
doi:10.1016/j.bmcl.2005.08.032
702

Beilstein J. Org. Chem. 2012, 8, 699–704.
3. Glänzel, M.; Bültmann, R.; Starke, K.; Frahm, A. W.
Eur. J. Med. Chem. 2005, 40, 1262–1276.
27.Hamashima, Y.; Hotta, D.; Sodeoka, M. J. Am. Chem. Soc. 2002, 124,
11240–11241. doi:10.1021/ja027075i
doi:10.1016/j.ejmech.2005.07.007
28.Wu, F.; Li, H.; Hong, R.; Deng, L. Angew. Chem., Int. Ed. 2006, 45,
947–950. doi:10.1002/anie.200502658
4. Gomez-Monterrey, I.; Santelli, G.; Campiglia, P.; Califano, D.;
Falasconi, F.; Pisano, C.; Vesci, L.; Lama, T.; Grieco, P.; Novellino, E.
J. Med. Chem. 2005, 48, 1152–1157. doi:10.1021/jm0408565
5. Gomez-Monterrey, I.; Campiglia, P.; Carotenuto, A.; Califano, D.;
Pisano, C.; Vesci, L.; Lama, T.; Bertamino, A.; Sala, M.;
Mazzella di Bosco, A.; Grieco, P.; Novellino, E. J. Med. Chem. 2007,
50, 1787–1798. doi:10.1021/jm0612158
29.Kang, Y. K.; Kim, D. Y. Tetrahedron Lett. 2006, 47, 4565–4568.
doi:10.1016/j.tetlet.2006.05.003
30.Bartoli, G.; Bosco, M.; Carlone, A.; Cavalli, A.; Locatelli, M.;
Mazzanti, A.; Ricci, P.; Sambri, L.; Melchiorre, P.
Angew. Chem., Int. Ed. 2006, 45, 4966–4970.
doi:10.1002/anie.200600370
6. Castellano, S.; Bertamino, A.; Gomez-Monterrey, I.; Santoriello, M.;
Grieco, P.; Campiglia, P.; Sbardella, G.; Novellino, E. Tetrahedron Lett.
2008, 49, 583–585. doi:10.1016/j.tetlet.2007.11.148
7. Hsin, L.-W.; Wang, H.-P.; Kao, P.-H.; Lee, O.; Chen, W.-R.;
Chen, H.-W.; Guh, J.-H.; Chan, Y.-L.; His, C.-P.; Yang, M.-S.; Li, T.-K.;
Lee, C.-H. Bioorg. Med. Chem. 2008, 16, 1006–1014.
doi:10.1016/j.bmc.2007.10.012
31.Rigby, C. L.; Dixon, D. J. Chem. Commun. 2008, 3798–3800.
doi:10.1039/B805233F
32.Jung, S. H.; Kim, D. Y. Tetrahedron Lett. 2008, 49, 5527–5530.
doi:10.1016/j.tetlet.2008.07.041
33.Capuzzi, M.; Perdicchia, D.; Jørgensen, K. A. Chem.–Eur. J. 2008, 14,
128–135. doi:10.1002/chem.200701317
34.Zhou, W.-M.; Liu, H.; Du, D.-M. Org. Lett. 2008, 10, 2817–2820.
doi:10.1021/ol800945e
8. Wei, P.; Zhang, X.; Tu, S.; Yan, S.; Ying, H.; Ouyang, P.
Bioorg. Med. Chem. Lett. 2009, 19, 828–830.
35.Wu, R.; Chang, X.; Lu, A.; Wang, Y.; Wu, G.; Song, H.; Zhou, Z.;
Tang, C. Chem. Commun. 2011, 47, 5034–5036.
doi:10.1039/c1cc10797f
doi:10.1016/j.bmcl.2008.12.006
9. Zhang, G.; Wang, Y.; Zhang, W.; Xu, X.; Zhong, A.; Xu, D.
Eur. J. Org. Chem. 2011, 2142–2147. doi:10.1002/ejoc.201001570
10.Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. 1998, 37,
388–401.
36.Yang, W.; Du, D.-M. Adv. Synth. Catal. 2011, 353, 1241–1246.
doi:10.1002/adsc.201000981
37.Kang, Y. K.; Kwon, B. K.; Mang, J. Y.; Kim, D. Y. Tetrahedron Lett.
2011, 52, 3247–3249. doi:10.1016/j.tetlet.2011.04.084
38.Kang, Y. K.; Suh, K. H.; Kim, D. Y. Synlett 2011, 1125–1128.
doi:10.1055/s-0030-1259932
doi:10.1002/(SICI)1521-3773(19980302)37:4<388::AID-ANIE388>3.0.
CO;2-V
11.Christoffers, J.; Mann, A. Angew. Chem., Int. Ed. 2001, 40, 4591–4597.
doi:10.1002/1521-3773(20011217)40:24<4591::AID-ANIE4591>3.0.CO
;2-V
39.Kang, Y. K.; Kim, D. Y. Tetrahedron Lett. 2011, 52, 2356–2358.
doi:10.1016/j.tetlet.2011.02.087
12.Leonard, J. Contemp. Org. Synth. 1994, 1, 387–415.
doi:10.1039/CO9940100387
40.Kang, S. H.; Kim, D. Y. Adv. Synth. Catal. 2010, 352, 2783–2786.
doi:10.1002/adsc.201000515
13.Krause, N.; Hoffmann-Röder, A. Synthesis 2001, 171–196.
doi:10.1055/s-2001-10803
41.Moon, H. W.; Kim, D. Y. Tetrahedron Lett. 2010, 51, 2906–2908.
doi:10.1016/j.tetlet.2010.03.105
14.Berner, O. M.; Tedeschi, L.; Enders, D. Eur. J. Org. Chem. 2002,
1877–1894.
42.Kang, Y. K.; Kim, S. M.; Kim, D. Y. J. Am. Chem. Soc. 2010, 132,
11847–11849. doi:10.1021/ja103786c
doi:10.1002/1099-0690(200206)2002:12<1877::AID-EJOC1877>3.0.C
O;2-U
43.Kwon, B. K.; Kim, S. M.; Kim, D. Y. J. Fluorine Chem. 2009, 130,
759–761. doi:10.1016/j.jfluchem.2009.06.002
15.Christoffers, J.; Baro, A. Angew. Chem., Int. Ed. 2003, 42, 1688–1690.
doi:10.1002/anie.200201614
44.Oh, Y.; Kim, S. M.; Kim, D. Y. Tetrahedron Lett. 2009, 50, 4674–4676.
doi:10.1016/j.tetlet.2009.06.003
16.Connon, S. J. Angew. Chem., Int. Ed. 2006, 45, 3909–3912.
doi:10.1002/anie.200600529
45.Lee, H. J.; Kang, S. H.; Kim, D. Y. Synlett 2011, 1559–1562.
doi:10.1055/s-0030-1260770
17.Tylor, M. S.; Jacobson, E. N. Angew. Chem., Int. Ed. 2006, 45,
1520–1543. doi:10.1002/anie.200503132
46.Yoon, S. J.; Kang, Y. K.; Kim, D. Y. Synlett 2011, 420–424.
doi:10.1055/s-0030-1259319
18.Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713–5743.
doi:10.1021/cr068373r
47.Kim, S. M.; Lee, J. H.; Kim, D. Y. Synlett 2008, 2659–2662.
doi:10.1055/s-0028-1083510
19.Yu, X.; Wang, W. Chem.–Asian J. 2008, 3, 516–532.
doi:10.1002/asia.200700415
20.Connon, S. J. Synlett 2009, 354–376. doi:10.1055/s-0028-1087557
21.Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 1701–1716.
doi:10.1002/ejoc.200600653
22.Almaşi, D.; Alonso, D. A.; Nájera, D. Tetrahedron: Asymmetry 2007,
18, 299–365. doi:10.1016/j.tetasy.2007.01.023
23.Ono, N. The Nitro Group in Organic Synthesis; Wiley-VCH: New York,
2001.
24.Calderari, G.; Seebach, D. Helv. Chim. Acta 1985, 68, 1592–1604.
doi:10.1002/hlca.19850680611
25.Ballini, R.; Petrini, M. Tetrahedron 2004, 60, 1017–1047.
doi:10.1016/j.tet.2003.11.016
26.Czekelius, C.; Carreira, E. M. Angew. Chem., Int. Ed. 2005, 44,
612–615. doi:10.1002/anie.200461879
703

Beilstein J. Org. Chem. 2012, 8, 699–704.
License and Terms
This is an Open Access article under the terms of the
Creative Commons Attribution License
(http://creativecommons.org/licenses/by/2.0), which
permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
The license is subject to the Beilstein Journal of Organic
Chemistry terms and conditions:
(http://www.beilstein-journals.org/bjoc)
The definitive version of this article is the electronic one
which can be found at:
doi:10.3762/bjoc.8.78
704