Reduction of Δ2-isoxazolines to β-hydroxy ketones with iron and ammonium chloride as reducing agent

Article abstract of DOI:10.1021/jo801831c

(Chemical Equation Presented) A detailed study of a procedure for the selective reduction of Δ²-isoxazolines to the corresponding β-hydroxy ketones is reported. The use of iron and ammonium chloride as the reducing agent in the presence of water results in a facile and chemoselective protocol for the preparation of β-hydroxy ketones, including the conjugated β-hydroxy ketones.

Full text of DOI:10.1021/jo801831c

Reduction of ∆2-Isoxazolines to ꢀ-Hydroxy
Ketones with Iron and Ammonium Chloride as
Reducing Agent
SCHEME 1. Reductive N-O Bond Cleavage of
∆2-Isoxazolines
Dahong Jiang†,‡ and Yuanwei Chen*,†
Chengdu Institute of Organic Chemistry, Chinese Academy
of Sciences, Chengdu 610041, P. R. China, and
Graduate School of Chinese Academy of Sciences,
Beijing 100049, P. R. China
Notwithstanding these antecedents, it still seems highly desirable
to develop a simple, economical, and general protocol as an
extension of this method for the reduction of both 3-vinyl and
saturated ∆2-isoxazolines to the corresponding ꢀ-hydroxy
ketones.
chenyw@cioc.ac.cn
ReceiVed August 21, 2008
In general, reductive ring opening of ∆2-isoxazolines can
result in either complete reduction to an amino alcohol or N-O
bond reduction/hydrolysis to ꢀ-hydroxy ketones (Scheme 1)
through hydroxyimine intermediates.2b We envisioned that a
judicious choice of reducing agent other than the reported
catalytic hydrogenolysis2b,c and transition metal induced
reduction2f,g,5 might also effect these transformations.
We have recently established a new method for the prepara-
tion of ∆2-isoxazolines via Pd-catalyzed carboetherification of
ꢀ,γ-unsaturated oximes [eq. 1].6 During the course of our
investigation of their N-O bond cleavage, we found that Fe/
NH4Cl can easily reduce the ∆2-isoxazolines to the correspond-
ing ꢀ-hydroxy ketones in the presence of water. Herein, we
would like to report the details of this facile and economical
procedure that has resulted in a new general method for the
chemoselective reduction of ∆2-isoxazolines to ꢀ-hydroxy
ketones.
A detailed study of a procedure for the selective reduction
of ∆2-isoxazolines to the corresponding ꢀ-hydroxy ketones
is reported. The use of iron and ammonium chloride as the
reducing agent in the presence of water results in a facile
and chemoselective protocol for the preparation of ꢀ-hydroxy
ketones, including the conjugated ꢀ-hydroxy ketones.
ꢀ-Hydroxy ketones have been well demonstrated as important
building blocks for the preparation of pharmaceuticals and
natural products,1 and their synthesis has attracted the interest
of many organic chemists. During recent decades, the conversion
of ∆2-isoxazolines to ꢀ-hydroxy ketone derivatives has devel-
oped into a powerful alternative to traditional carbonyl con-
densation methods for the stereoselective synthesis of aldol
adducts.2 However, the sensitivity of other functionalities to the
catalytic hydrogenolysis employed for the isoxazoline ring
opening remains a challenge.3,4 To avoid concomitant reduction
of a conjugated olefin, E. Carreira and J. Bode described a
selective method for the reduction of conjugated ∆2-isoxazolines
to the corresponding unsaturated ꢀ-hydroxy ketones.5
Aiming to develop an easier and less expensive method for
the cleavage of N-O bond in ∆2-isoxazolines, we became
interested in investigating whether the easily available reducing
agents that are effective in the reductive ring openings of
isoxazolidines7 and ∆4-isoxazolines8 would be applied in this
case. Our initial screening with these methods proved unsuc-
cessful in providing the desired γ-amino alcohol 3 or ꢀ-hydroxy
ketone 2a, so we began to investigate Fe/NH4Cl in the presence
of water as an alternative (Table 1).
* To whom correspondence should be addressed.
† Chengdu Institute of Organic Chemistry.
‡ Graduate School of Chinese Academy of Sciences.
At first, substrate 1a was subjected to a suspension of Fe
powder (5 equiv) and NH4Cl (5 equiv) in EtOH/H2O (1:1)
at 60 °C. It was found that only ꢀ-hydroxy ketones 2a along
with the unconsumed starting material were obtained after
5 h (entry 7, Table 1). No products from retroaldol reaction
(1) (a) McGarvey, G. J.; Mathys, J. A.; Wilson, K. J. J. Org. Chem. 1996,
61, 5704. (b) Bartoli, G.; Bosco, M.; Marcantoni, E.; Massaccesi, M.; Rinaldi,
S.; Sambri, L. Eur. J. Org. Chem. 2001, 4679. (c) Sinha, S. C.; Barbas, C. F.;
Lerner, R. A. Proc. Natl. Acad. Sci. USA. 1998, 95, 14603. (d) Paterson, I.;
Florence, G. J.; Gerlach, K.; Scott, J. P.; Sereinig, N. J. Am. Chem. Soc. 2001,
123, 9535. (e) Colle, S.; Taillefumier, C.; Chapleur, Y.; Liebl, R.; Schmidt, A.
Bioorg. Med. Chem. 1999, 7, 1049. (f) Muri, D.; Lohse-Fraefel, N.; Carreira,
E. M. Angew. Chem., Int. Ed. 2005, 44, 4036.
(2) (a) Torsell, K.; Zenthen, O. Acta Chem. Scand. Ser. B 1978, 32, 118. (b)
Curran, D. P. J. Am. Chem. Soc. 1982, 104, 4024. (c) Curran, D. P. J. Am.
Chem. Soc. 1983, 105, 5826. (d) Kozikowski, A. P.; Stein, P. D. J. Am. Chem.
Soc. 1982, 104, 4023. (e) Curran, D. P.; Scanga, S. A.; Fenk, C. J. J. Org. Chem.
1984, 49, 3474. (f) Baraldi, P.; Barco, A.; Benetti, S.; Manfredini, S.; Simoni,
D. Synthesis 1987, 276. (g) Guarna, A.; Guidi, A.; Goti, A.; Brandi, A.; de Sarlo,
F. Synthesis 1989, 175. (h) Kwiatkowshi, S. J. Chem. Soc., Chem. Commun.
1987, 1496.
(5) (a) Bode, J. W.; Carreira, E. M. Org. Lett. 2001, 3, 1587. (b) Bode, J. W.;
Carreira, E. M. J. Am. Chem. Soc. 2001, 123, 3611.
(6) Jiang, D.; Peng, J.; Chen, Y. Org. Lett. 2008, 10, 1695.
(7) (a) Boruah, M.; Konwar, D. J. Chem. Res. 2002, 601. (b) LeBel, N. A.;
Balasubramanian, N. J. Am. Chem. Soc. 1989, 111, 3363. (c) Iida, H.; Kasahara,
K.; Kibayashi, C. J. Am. Chem. Soc. 1986, 108, 4647. (d) Wovkulich, P. M.;
Uskokovic, M. R. Tetrahedron 1985, 41, 3455. (e) Jaeger, V.; Grund, H.; Buss,
V.; Schwab, W.; Mueller, I. Bull. Chem. Soc. Belg. 1983, 92, 1039.
(8) (a) Aschwanden, P.; Kvarno, L.; Geisser, R. W.; Kleinbeck, F.; Carreira,
E. M. Org. Lett. 2005, 7, 5741. (b) Freeman, J. P. Chem. ReV. 1983, 83, 241.
(3) Yadav, P. P.; Ahmad, G.; Maurya, R. Tetrahedron Lett. 2005, 46, 5621.
(4) Kozikowski, A. P. Acc. Chem. Res. 1984, 17, 410.
10.1021/jo801831c CCC: $40.75
Published on Web 10/22/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 9181–9183 9181

TABLE 1. Study into the Effects of Reducing Agent and Reaction
Condition
TABLE 2. Reduction of ∆2-Isoxazolines to ꢀ-Hydroxy Ketones
with Fe and Ammonium Chloride as Reducing Agenta
yield
yield
reducing agent
solv. (T[°C])
of 2a
of 3
1a
2a
3a
4a
5a
6a
7
ClSi(CH3)3, KI
LiAlH4
NaBH3CN, HCl
NaBH4
Zn
Zn
Fe, NH4Cl
Fe, NH4Cl
CH3CN, H2O (25)
THF (60)
MeOH, H2O (25)
AcOH (60)
0
0
0
0
0
0
46
91
0
0
0
0
0
0
0
0
AcOH (60)
AcOH, H2O (60)
EtOH, H2O (60)
EtOH, H2O (80)
8
a Complete recovery of the starting material.
or ꢀ-hydroxy elimination were observed. When the reaction
was carried out at 80 °C, the yield was increased dramatically
due to the complete consumption of starting material (entry
8, Table 1). Optimal conditions that were general with respect
to substrate scope were found to be the use of an excess (10
equiv) of Fe powder and NH4Cl. Thus, the starting material
was consumed completely within several hours. The use
of other H+ sources, such as acetic acid, led to decreased
yield.
We next examined the substrate scope of the conversion.
A range of substituted ∆2-isoxazolines were synthesized
according to our newly developed method6 or using a [3 +
2] dipolar cycloaddition reaction of a nitrile oxide and alkene.
The products were subjected to the optimized conditions for
the reductive ring cleavage. As shown in Table 2, this method
is effective for the reduction of a variety of substituted
∆2-isoxazolines to the corresponding ꢀ-hydroxy ketones.
Moderate to excellent yields were obtained in most cases.
∆2-Isoxazolines, which bear electron-neutral (entries 1, 11,
and 12) or electron-poor (entry 2) aryl substituents at the
3-position, provide high yields. With substrates bearing
electron-rich (entries 3, 4, 5, and 6) and especially o-
substituted (entries 5 and 6) aryl substituents at the 3-position,
the reaction was sluggish, and the yields were relatively low
due to the recovery of starting materials.
It is worth noting that various functional groups and sub-
stitution patterns are tolerated in the process. Chloride (entries
2, 4, and 9), ester (entry 8), and free hydroxyl groups (entry
12) survive the isoxazoline reduction unscathed. Easily
reduced benzyl (entry 5) and aldehyde groups (entry 10) were
untouched in the reductive reaction. In contrast to many
previously reported methods, these conditions can effect
reduction of conjugated 3-vinyl ∆2-isoxazolines without
concomitant reduction of the R,ꢀ-unsaturated olefin (entries
9 and 10).
When 5-hydroxymethyl ∆2-isoxazoline 1l was subjected to
the reductive conditions, the reaction occurred smoothly and
cleanly, as judged by TLC (entry 12, table 2). However, the
corresponding product 2l is not stable, and about 10% of it
undergoes hydroxyl elimination and subsequent condensation
to form 2-p-tolylfuran during the workup and purification pro-
cedure.
In summary, we have successfully developed a facile, eco-
nomical, and efficient protocol for the chemoselective reduction
of ∆2-isoxazolines to the corresponding ꢀ-hydroxy ketones using
Fe/NH4Cl as the reducing agent. The procedure revealed is
a Reaction conditions: 1.0 equiv of substrate 1, 10 equiv of Fe
powder, 10 equiv of NH4Cl, EtOH/H2O ) 1:1, 80 °C. b The product
was unstable, and 10% of it converted to p-(2-furanyl) toluene during
the workup procedure.
general and is particularly useful for the transformation of both
conjugated and nonconjugated ∆2-isoxazolines to ꢀ-hydroxy
ketones, a troublesome transformation with other known
reagents. This finding should be of considerable interest for the
construction of biologically active molecules.
9182 J. Org. Chem. Vol. 73, No. 22, 2008

4.64-4.69 (1H, m), 3.28 (1H, dd, J ) 16.7, 7.1 Hz), 2.95-3.14
(3H, m); 13C NMR (75 MHz, CDCl3) δ 198.2, 159.3, 148.6, 139.7,
136.7, 135.3, 129.6, 128.9, 123.9, 121.7, 67.7, 45.1, 43.0; IR (KBr,
cm-1) 3344, 3259, 3088, 3014, 2910, 1679, 1586, 1568, 1482, 1436,
1397, 1088, 1077, 818; HRMS-ESI (m/z): [M+Na]+ calcd for
C15H14ClNNaO2: 298.0605; found: 298.0612.
3-Hydroxy-1-(4-methoxyphenyl)-4-phenylbutan-1-one (2c).
White solid, mp 67-68 °C. 1H NMR (300 MHz, CDCl3) δ
7.87-7.91 (2H, m), 7.24-7.35 (5H, m), 6.90-6.94 (2H, m),
4.45-4.49 (1H, m), 3.86 (3H, s), 3.40 (1H, br), 3.12 (1H, dd, J )
17.4, 3.3 Hz), 2.94-3.05 (2H, m), 2.84 (1H, dd, J ) 13.5, 6.4
Hz); 13C NMR (75 MHz, CDCl3) δ 199.0, 163.8, 138.1, 130.4,
129.8, 129.4, 128.5, 126.5, 113.7, 69.0, 55.4, 43.5, 42.9; IR (KBr,
cm-1) 3423, 3058, 3027, 2934, 2893, 2838, 1672, 1599, 1575, 1509,
1452, 1416, 1376, 1257, 1091, 814; HRMS-ESI (m/z): [M+Na]+
calcd for C17H18NaO3: 293.1148; found: 293.1153.
Experimental Section
General Procedure for the Reduction of ∆2-Isoxazolines to
ꢀ-Hydroxy Ketones with Fe/NH4Cl as Reducing Agent. To a
stirred solution of ∆2-isoxazoline 1a (1b-l, 0.3 mmol) and NH4Cl
(161 mg, 3 mmol) in ethanol and water (1:1, 15 mL) was added
Fe powder (168 mg, 3 mmol). The mixture was heated to 80 °C
and was allowed to stir at this temperature for 6 h. The reaction
mixture was cooled to room temperature, diluted with ethyl acetate,
and filtered through a silica pad. The filtrate was washed with brine,
and the organic layer was separated, dried over MgSO4, and
evaporated in vacuo. The residue was then purified by flash chro-
matography on silica gel to give the desired product 2a (2b-l).
3-Hydroxy-1-phenyl-4-p-tolylbutan-1-one (2a). White solid,
1
mp 56-59 °C. H NMR (300 MHz, CDCl3) δ 7.90-7.93 (2H,
m), 7.56-7.58 (1H, m), 7.43–7.48 (2H, m), 7.15-7.18 (4H, m),
4.45-4.49 (1H, m), 3.25 (1H, s), 3.09-3.15 (2H, m), 2.94 (1H,
dd, J ) 7.0, 13.6 Hz), 2.82 (1H, dd, J ) 6.5, 13.6 Hz), 2.34 (3H,
s); 13C NMR (75 MHz, CDCl3) 200.5, 136.7, 136.0, 134.8, 133.5,
Acknowledgment. The authors thank the National Natural
Science Foundation of China (No. 20872138) and the 100-talent
program of the Chinese Academy of Sciences for generous
financial support of this work.
129.3, 129.2, 128.6, 128.0, 68.9, 44.1, 42.4, 21.0; IR (KBr, cm-1
)
3399, 3354, 3023, 2928, 1683, 1594, 1578, 1512, 1444, 1372, 1267,
1094; MS (GC-MS) calculated for C17H18NaO2 [M+Na+]: 277.12;
found: 277.12.
1-(4-Chlorophenyl)-3-hydroxy-4-(pyridin-2-yl)butan-1-one (2b).
Brown solid, mp 79-81 °C. 1H NMR (300 MHz, CDCl3) δ
8.48-8.49 (1H, m), 7.89 (2H, d, J ) 8.5 Hz), 7.59-7.64 (1H, m),
7.41 (2H, d, J ) 8.5 Hz), 7.14-7.19 (2H, m), 5.10 (1H, br),
Supporting Information Available: NMR spectra of 1d,
1j-l, and 2a-l. This material is available free of charge via
the Internet at http://pubs.acs.org.
JO801831C
J. Org. Chem. Vol. 73, No. 22, 2008 9183