Catalytic asymmetric nitroaldol (Henry) reaction with a zinc-fam catalyst

Article abstract of DOI:10.1021/jo8010073

(Chemical Equation Presented) Ferrocenyl-substituted aziridinylmethanol (Fam-1) was used as a catalyst with zinc for the asymmetric nitroaldol (Henry) reaction. This catalyst worked with a variety of aldehydes (aromatic, aliphatic, α,β-unsaturated, and he

Full text of DOI:10.1021/jo8010073

Catalytic Asymmetric Nitroaldol (Henry)
Reaction with a Zinc-Fam Catalyst
‡
,†
Adnan Bulut,*,‡ Ayhan Aslan, and Ozdemir Dogan*
¨
FIGURE 1. Structures of chiral ligands Fam 1-4.
Department of Chemistry, Middle East Technical UniVersity,
06531 Ankara, Turkey, and Department of Chemistry,
Kırıkkale UniVersity, 71450, Kırıkkale, Turkey
methylephedrine as the catalyst in the reaction of aliphatic
and aromatic aldehydes to give nitroaldol products in
68-92% yields and with ee’s of mostly above 90%.3k
Another zinc catalyst, reported by Lin et al., gave the products
in good yields but in low ee’s, the highest ee being 74%.3i
Very recently, Wolf et al. reported another efficient zinc
catalyst for the asymmetric Henry reaction of aliphatic and
aromatic aldehydes.3y This catalyst yields nitroaldol products
in up to 99% yield and 95% ee. Two other zinc catalysts
reported by Reiser et al.3f and Demirel et al.3v did not work
very efficiently, and both the yields and ee’s were quite low.
We recently reported a new set of chiral ferrocenyl-
substituted aziridinylmethanols Fam ligands 1-4 (Figure 1).
These ligands were used for enantioselective asymmetric
azomethine ylide cycloaddition reactions to produce pyrro-
lidines in up to 95% ee,4 for enantioselective diethylzinc
addition to enones to produce ꢀ-ethylated ketones in up to
80% ee,5 for enantioselective diethylzinc addition to alde-
hydes to produce secondary alcohols in up to 99% ee,6 and
for alkynylzinc addition to aldehydes to produce propargylic
alcohols in up to 98% ee.7 The performance of these ligands
has been tested for the zinc-catalyzed enantioselective Henry
or nitroaldol reaction. Herein, we wish to report that ligand
Fam-1 serves as a good catalyst for the nitroaldol reaction.
Chiral ligands Fam 1-4 (Figure 1) were prepared4 in three
easy steps starting with readily available acryloyl ferrocene8
on gram scales in enantiomerically pure forms by employing
dogano@metu.edu.tr
ReceiVed May 9, 2008
Ferrocenyl-substituted aziridinylmethanol (Fam-1) was used
as a catalyst with zinc for the asymmetric nitroaldol (Henry)
reaction. This catalyst worked with a variety of aldehydes
(aromatic, aliphatic, R,ꢀ-unsaturated, and heteroaromatic) and
R-ketoesters to give the nitroaldol product in up to 97% yield
and 91% ee. The chiral ligand can be recovered and recycled
without losing its activity.
The asymmetric nitroaldol or Henry reaction is one of the
important carbon-carbon bond formation reactions.1 The
product obtained from this reaction is highly valuable as the
starting material for 1,2-amino alcohols and ꢀ-hydroxy acids.2
The development of new chiral catalysts for this important
reaction has attracted the interest of many groups.3 Although
a reasonable number of catalysts having copper as the metal
were reported to induce high enantiselectivity, only a few
catalysts having zinc as the metal are known. Trost et al.
reported the first efficient dinuclear ligand for the zinc catalyst
for the asymmetric Henry reaction. This catalyst worked
efficiently with aliphatic and aromatic aldehydes to give the
nitroaldol products in up to 90% yield and 93% ee.3d,e
Another zinc catalyst was reported by Palamo et al. They
employed 30 mol % of Zn(OTf)2 and 45 mol % of (+)-N-
(3) Selected examples: (a) Sasai, H.; Suziki, T.; Arai, S.; Arai, T.; Shibasaki,
M. J. Am. Chem. Soc. 1992, 114, 4418. (b) Iseki, K.; Oishi, S.; Sasai, H.;
Shibasaki, M. Tetrahedron Lett. 1996, 37, 9081. (c) Arai, T.; Yamada, Y. M. A.;
Yamamoto, N.; Sasai, H.; Shibasaki, M. Chem.sEur. J. 1996, 2, 1368. (d) Trost,
B. M.; Yeh, V. S. C. Angew. Chem., Int. Ed. 2002, 41, 861. (e) Trost, B. M.;
Yeh, V. S. C.; Ito, H.; Bremeyer, N. Org. Lett. 2002, 4, 2621. (f) Klein, G.;
Pandiaraju, S.; Reiser, O. Tetrahedron Lett. 2002, 43, 7503. (g) Evans, D. A.;
Seidel, D.; Rueping, M.; Lam, H. W.; Shaw, J. T.; Downey, C. W. J. Am. Chem.
Soc. 2003, 125, 12692. (h) Gao, J.; Martell, A. E. Org. Biomol. Chem. 2003, 1,
2801. (i) Zhong, Y. W.; Tian, P.; Lin, G. Q. Tetrahedron: Asymmetry 2004, 15,
771. (j) Palomo, C.; Oiarbide, M.; Laso, A. Angew. Chem., Int. Ed. 2005, 44,
3881. (k) Gan, C.; Lai, G.; Zhang, Z.; Wang, Z.; Zhou, M. M. Tetrahedron:
Asymmetry 2006, 17, 725. (l) Saa, J. M.; Tur, F.; Gonzalez, J.; Vega, M.
Tetrahedron: Asymmetry 2006, 17, 99. (m) Blay, G.; Climent, E.; Fernandez, I.;
Hernandez-Olmos, V.; Pedro, J. R. Tetrahedron: Asymmetry 2006, 17, 2046.
(n) Maheswaran, H.; Prasanth, K. L.; Krishna, G. G.; Ravikumar, K.; Sridhar,
B.; Kantam, M. L. Chem. Commun. 2006, 4066. (o) Arai, T.; Watanabe, M.;
Fujiwara, A.; Yokoyama, N.; Yanagisawa, A. Angew. Chem., Int. Ed. 2006, 45,
5978. (p) Ma, K.; You, J. Chem. Eur. J. 2007, 13, 1863. (q) Xiong, Y.; Wang,
F.; Huang, X.; Wen, Y. H.; Feng, X. M. Chem. Eur. J. 2007, 13, 829. (r) Qin,
B.; Xiao, X.; Liu, X.; Huang, J.; Wen, Y.; Feng, X. J. Org. Chem. 2007, 72,
9323. (s) Arai, T.; Watanabe, M.; Yanagisawa, A. Org. Lett. 2007, 9, 3595. (t)
C¸ olak, M.; Aral, T.; Hosgo¨ren, H.; Demirel, N. Tetrahedron: Asymmetry 2007,
18, 1129. (u) Jiang, J.-J.; Shi, M. Tetrahedron: Asymmetry 2007, 18, 1376. (v)
Bandini, M.; Benaglia, M.; Sinisi, R.; Tommasi, S.; Umani-Ronchi, A. Org.
Lett. 2007, 9, 2151. (y) Liu, S.; Wolf, C. Org. Lett. 2008, 10, 1831. (z) Gan, C.
Can. J. Chem. 2008, 86, 261.
‡ Kırıkkale University.
† Middle East Technical University.
(1) For recent reviews, see: (a) Luzzio, F. A. Tetrahedron 2001, 57, 915.
(b) Boruwa, J.; Gogoi, N.; Saikia, P. P.; Barua, N. C. Tetrahedron: Asymmetry
2006, 17, 3315. (c) Palomo, C.; Oiarbide, M.; Laso, A. Eur. J. Org. Chem. 2007,
2561.
(2) (a) Ono, N. The Nitro Group in Organic Synthesis; Wiley-VCH: New
York, 2001. (b) Shibasaki, M.; Gro¨ger, H. In ComprehensiVe Asymmetric
Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin,
Germany, 1999; Vol. III, pp 1075-1090. (c) Shibasaki, M.; Gro¨ger, H.; Kanai,
M. In ComprehensiVe Asymmetric Catalysis Supplement 1; Jacobsen, E. N.,
Pfaltz, A., Yamamoto, H., Eds.; Springer: Heidelberg, Germany, 2004; pp 131-
133. (d) Rosini, G. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming,
I., Heathcock, C. H., Eds.; Pergamon: New York, 1991; Vol. 2, pp 321-340.
¨
(4) Dogan, O.; Koyuncu, H.; Garner, P. P.; Bulut, A.; Youngs, W.; Panzner,
M. Org. Lett. 2006, 8, 4687.
¨
(5) Isleyen, A.; Dogan, O. Tetrahedron: Asymmetry 2007, 18, 679.
¨
(6) Bulut, A.; Aslan, A.; Izgu¨, E. C.; Dogan, O. Tetrahedron: Asymmetry
2007, 18, 1013.
10.1021/jo8010073 CCC: $40.75
Published on Web 08/14/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 7373–7375 7373

TABLE 1. Nitroaldol Reaction of Benzaldehyde and Nitromethane under Different Conditions
ligand
(mol %)
MeNO2
(equiv)
Et2Zn
(mol %)
Et3N
(mol %)
entry
ligand
T (°C)
solvent
concn (M)
% yielda
% eeb
1
2
3
4
5
6
7
8
1
2
3
4
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
10
10
10
10
10
10
10
10
10
10
10
10
10
5
15
10
10
10
10
15
15
20
20
6
6
6
6
6
6
6
3
12
6
6
6
9
9
9
6
6
18
18
18
18
18
18
18
18
18
9
36
18
18
18
18
18
18
18
54
54
54
54
54
-50
-50
-50
-50
-50
-50
-50
-50
-50
-50
-50
-40
-40
-40
-40
-20
-50
-50
-20
-50
-50
-50
-50
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
-
-
-
-
-
-
-
THF
THF
THF
THF
Et2O
DCM
MeCN
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
0.24
0.24
0.24
0.24
0.24
0.24
0.24
0.24
0.24
0.24
0.24
0.10
0.10
0.10
0.10
0.10
0.24
0.24
0.10
0.24
0.24
0.24
0.24
78
57
72
77
41
33
22
23
82
27
62
49
63
62
61
90
29
54
36
35
66
83
87
59
27
15
41
22
32
11
26
29
5
59
71
77
57
45
64
57
45
65
88
85
87
86
9
10
11
12
13
14
15
16
17
18
19
20
21c
22
23c
12
12
6
24
24
24
a Isolated yield. b Determined by chiral HPLC. c Reaction time was 24 h.
the Gabriel-Cromwell reaction.9 First, ligands 1-4 were
screened as catalysts for the enantioselective nitroaldol reaction
between benzaldehyde and nitromethane in the presence of
diethylzinc. Results of these studies are summarized in Table
1. As can be seen from this table, ligand 1 gave the highest ee
(Table 1, entries 1-4). Therefore, we continued optimization
studies with this ligand. Reactions using diethylether, dichlo-
romethane, or acetonitrile in the place of THF gave the product
in low yield and enantioselectivity (Table 1, entries 5-7). When
the amount of nitromethane was lowered to 3 equiv, the yield
and ee dropped to 23% and 26%, respectively (Table 1, entry
8). Increasing the amount of nitromethane to 12 equiv increased
the yield to 82% while the ee remained almost the same (Table
1, entry 9). Optimization experiments at -40 °C and lower
reaction concentration (Table 1, entries 12-15) were also not
very successful, the highest enantioselectivity being 77% and
the yield was around 60%. When the reaction was carried out
at -20 °C, the highest yield was reached but again, the
enantioselectivity was not satisfactory (Table 1, entry 16).
We have also carried out experiments without using amine
(Table 1, entries 17-23). Under the same reaction conditions
as in entry 1 but without the amine, the nitroaldol product was
obtained in low yield with about the same ee (Table 1, entry
17). Doubling the amount of nitromethane to 12 equiv increased
the yield as expected to 54% but lowered the ee to 45% (Table
1, entry 18). Further optimizations showed that good yields and
ee’s can be obtained for the enantioselective nitroaldol reaction
by using 20 mol % of ligand 1, 24 equiv of nitromethane, and
54 mol % of diethylzinc at -50 °C. Under these conditions,
the reaction was also repeated in the presence of amine (5 mol
%), giving the product in almost quantitative yield and 66%
ee.
After determining the optimum conditions, the scope of the
reaction was explored with different aldehydes. The results are
summarized in Table 2. As can be seen from this table, the
nitroaldol reaction with aromatic, heteroaromatic, aliphatic, and
R,ꢀ-unsaturated aldehydes gave the product in good yields and
enantioselectivities. In the case of aromatic aldehydes, the
substituents on the aromatic ring did not show a significant effect
on the enantioselectivity, which varied between 82 and 91%
except in the case of anisaldehyde (Table 2, entries 1-11). For
most of the aromatic aldehydes, yields were above 80% and
moderate for p-Br, p-CF3, and o-Cl substituted ones. Extending
the reaction time from 16 to 24 h had a significant effect on the
yields for o-chlorobenzaldehyde and 1-naphthaldehyde (Table
2, entries 9 and 10). For the remaining aromatic aldehydes, this
effect was not so significant. In the case of aliphatic, R,ꢀ-
unsaturated, and heteroaromatic aldehydes (Table 2, entries
12-18), extending the reaction time increased the yield between
7 and 16%. However, the enantioselectivity remained almost
the same except for isobutyraldehyde (Table 2, entry 14). The
catalytic performance of the Fam-1 ligand was also tested for
R-ketoesters, which have been used as substrates for nitroaldol
reactions in only a limited number of studies.3r,9 Under the same
reaction conditions, ethyl pyruvate and ethyl benzoylformate
reacted with nitromethane to give nitroaldol products in 88%
yield with 86% ee and 85% yield with 82%, respectively (Table
2, entries 19 and 20).
¨
(7) Koyuncu, H.; Dogan, O. Org. Lett. 2007, 9, 3477.
¨
(8) Dogan, O.; S¸enol, V.; Zeytinci, S.; Koyuncu, H.; Bulut, A. J. Organomet.
Chem. 2005, 690, 430.
In conclusion, we have shown that a zinc complex with the
Fam-1 ligand serves as a good catalyst for the enantioselective
nitroaldol or Henry reaction. It works for a wide spectrum of
aldehydes including aromatic, aliphatic, R,ꢀ-unsaturated, and
heteroaromatic aldehydes. For the aromatic aldehydes, in
general, there is no significant effect of the substituents on the
(9) (a) Christensen, C.; Juhl, K.; Hazell, R. G.; Jorgensen, K. A. J. Org.
Chem. 2002, 67, 4875. (b) Lu, S.-F.; Du, D.-M.; Zhang, S.-W.; Xu, J.
Tetrahedron: Asymmetry 2004, 15, 3433. (c) Choudary, B. M.; Ranganath,
K. V. S.; Pal, U.; Kantam, M. L.; Sreedhar, B. J. Am. Chem. Soc. 2005, 127,
13167. (d) Du, D. M.; Lu, S. F.; Fang, T.; Xu, J. J. Org. Chem. 2005, 70, 3712.
(e) Li, H.; Wang, B.; Deng, L. J. Am. Chem. Soc. 2006, 128, 732. (f) Blay, G.;
Hernandez-Olmos, V.; Pedro, J. R. Org. Biomol. Chem. 2008, 6, 468.
7374 J. Org. Chem. Vol. 73, No. 18, 2008

TABLE 2. Nitroaldol Reaction of Various Aldehydes and
r-Ketoesters
yield and enantioselectivity of the reaction. Besides aldehydes,
the catalyst developed in this study also works efficiently in
the asymmetric Henry reaction of R-ketoesters to give ꢀ-nitro-
R-hydroxy esters in good yields and ee’s. Up to now, no other
catalyst has been reported to be effective for a wide variety of
substrates. Although the asymmetric nitroaldol reaction requires
20 mol % of the Fam-1 ligand, the ligand can be recovered in
more than 90% yield and used without losing its activity. In
addition, its antipode can easily be prepared by using (S)-
methylbenzylamine at the aziridination step. This will allow the
synthesis of nitroaldol products with the opposite configuration.
Experimental Section
General Procedure for the Nitroaldol Reaction. The chiral
ligand (1.11 mL, used from a 0.1 M stock solution in THF) was
added to a reaction flask under Ar. After cooling the reaction flask
to 0 °C, Et2Zn (0.3 mL, 1.0 M in hexane) was added. After stirring
30 min at this temperature, to this solution was added MeNO2 (0.72
mL, 13.3 mmol). The resulting mixture was stirrred at this
temperature for 2 h then cooled to -50 °C, and then benzaldehyde
(56 µL, 0.55 mmol) was added (furfural and thiophenealdehyde
were freshly distilled). The reaction mixture was stirred for 16 h at
this temperature then quenched with a saturated solution of NH4Cl.
After separating the two layers, the aqueous layer was extracted
with diethylether (3 × 20 mL). The combined organic layers were
dried over Na2SO4, concentrated, and purified by flash column
chromatography (silica gel, hexane:EtOAc, 7:1) to provide 6a (76
mg, 0.46 mmol, 87% ee).
(R)-2-Nitro-1-phenylethanol (6a).3g 1H NMR (400 MHz,
CCl4-CDCl3, ppm): δ 7.35-7.20 (m, 5H), 5.32-5.25 (m, 1H),
4.46-4.40 (dd, 1H, J ) 13.1, 9.9 Hz), 4.36-4.32 (dd, 1H, J )
13.1, 3.1 Hz), 3.07 (d, 1H, J ) 3.6 Hz). 13C NMR (100 MHz,
CCl4-CDCl3, ppm): δ 138.3, 128.9, 128.8, 125.9, 81.2, 70.9. HPLC
analysis (Chiralcel OD-H column, 0.8 mL/min, 15% i-PrOH in
hexane). Retention times: 15.64 min [major (R)-enantiomer] and
19.56 min [minor (S)-enantiomer]. [R]23 ) -37.0 (c ) 3.55,
D
CHCl3).
(R)-2-Nitro-1-p-tolylethanol (6b).3z The title compound was
prepared according to the general procedure as colorless oil (76.4
mg, 0.42 mmol, 86% ee). 1H NMR (400 MHz, CCl4-CDCl3, ppm):
δ 7.27 (d, 2H, J ) 8.0 Hz), 7.20 (d, 2H, J ) 8.0 Hz), 5.45-5.38
(m, 1H), 4.62-4.56 (dd, 1H, J ) 13.3, 9.6 Hz), 4.50-4.46 (dd,
1H, J ) 13.3, 3.0 Hz), 2.78 (s, 1H), 2.35 (s, 3H). 13C NMR (100
MHz, CDCl3, ppm): δ 138.9, 135.3, 129.7, 125.9, 81.3, 70.9, 21.1.
HPLC analysis (Chiralcel OD-H column, 0.8 mL/min, 15% i-PrOH
in hexane). Retention times: 16.82 min [major (R)-enantiomer] and
21.22 min [minor (S)-enantiomer]. [R]23 ) -75.7 (c ) 5.30,
D
CHCl3).
Acknowledgment. The authors thank the Scientific and
Technical Research Council of Turkey (TUBITAK, Grant No.
TBAG-106T071), Middle East Technical University, and Kir-
ikkale University Research Foundations for financial support.
Supporting Information Available: Synthetic procedures
and characterization data of products. This material is available
free of charge via the Internet at http://pubs.acs.org.
a Isolated yield. b Determined by chiral HPLC. c Obtained from
recovered ligand.
JO8010073
J. Org. Chem. Vol. 73, No. 18, 2008 7375