Unusual aluminum hydride-mediated reduction of N-(γ- or δ-oxoacyl)oxazolidinone

Article abstract of DOI:10.1246/cl.130975

Reduction of N-(γ-oxoacyl)oxazolidinone with a borohydride reagent, such as NaBH₄ or LiBEt₃H, resulted in formation of the corresponding lactone or lactol. In contrast, when an aluminum hydride reagent was used instead of a borohydride reagent, reduction of N-(γ- or δ-oxoacyl)oxazolidinone proceeded unexpectedly to give not the corresponding lactone or lactol, but a tetrahydrofuran or tetrahydropyran derivative, respectively, containing an oxazolidino group.

Full text of DOI:10.1246/cl.130975

Received: October 19, 2013 | Accepted: November 18, 2013 | Web Released: November 22, 2013
CL-130975
Unusual Aluminum Hydride-mediated Reduction of N-(γ- or δ-Oxoacyl)oxazolidinone
Jun-ichi Yamaguchi,* Mayuko Asano, and Youko Udono
Department of Applied Chemistry, Faculty of Engineering, Kanagawa Institute of Technology,
1030 Shimoogino, Atsugi, Kanagawa 243-0292
(E-mail: yamagu@chem.kanagawa-it.ac.jp)
Reduction of N-(γ-oxoacyl)oxazolidinone with a borohy-
dride reagent, such as NaBH4 or LiBEt3H, resulted in formation
of the corresponding lactone or lactol. In contrast, when an
aluminum hydride reagent was used instead of a borohydride
reagent, reduction of N-(γ- or δ-oxoacyl)oxazolidinone pro-
ceeded unexpectedly to give not the corresponding lactone or
lactol, but a tetrahydrofuran or tetrahydropyran derivative,
respectively, containing an oxazolidino group.
borohydride reagents. Results of the reduction of 1a or 1c with
various borohydride reagents are shown in Table 1. Using
sodium borohydride, the reduction of 1a in THF-H2O afforded
the corresponding lactone 2a (Entry 1). The reduction of 1a with
Zn(BH4)2 or LiBH4 also resulted in the formation of 2a in
moderate yield (Entries 2 and 3). Because LiBEt3H (Super
Hydrideμ) is a powerful reductant for reducing an ester to an
alcohol, the reduction of 1a with 2 equivalents of LiBEt3H gave
the corresponding lactol 3a (Entries 4 and 5). N-(5-Oxo-5-
phenylpentanoyl)oxazolidinone (1c) also was examined (Entries
6 and 7). The N-(5-hydroxy-5-phenylpentanoyl)oxazolidinone
(5) was produced by reaction of 1c with NaBH4 in moderate
yield (Entry 6 and Figure 1). In contrast to the reaction with
Reduction using a metal hydride reagent is an important
reaction in synthetic organic chemistry. Metal hydride reagents
are useful for the reduction of polarized multiple bonds, such as
a carbonyl or cyano group. Almost all metal hydride reagents
contain boron or aluminum atoms. Among the available metal
hydride reagents, diisobutylaluminum hydride (DIBAL) often is
the first choice for transformation of an ester, carboxamide, or
nitrile into an aldehyde.1
Reduction of N-(γ- or δ-oxoacyl)oxazolidinone 1 with a
metal hydride reagent was expected to give the corresponding
γ- or δ-lactone 2 or lactol 3 (Scheme 1). The reduction of N-(4-
oxo-4-phenylbutanoyl)oxazolidinone (1a) yielded the corre-
sponding lactone 2 or lactol 3 when a borohydride reagent
[e.g., NaBH4, Zn(BH4)2, or LiBEt3H] was used. However, no
lactone or lactol was isolated when N-(5-oxo-5-phenylpenta-
noyl)oxazolidinone (1c) was used as a substrate.
In contrast, when an aluminum hydride [e.g., bis(2-meth-
oxyethoxy)aluminum hydride (Red-Alμ), LiAlH4 (LAH), or
DIBAL] was used as a reductant, the corresponding tetrahydro-
furan or tetrahydropyran derivative 4 was provided as the main
product, not the lactone 2 (Scheme 2).
Starting materials 1a-1c were prepared in high yield from
condensation of carboxylic acid with oxazolidinone in the
presence of water-soluble carbodiimide hydrochloride (WSC
HCl) and 4-dimethylaminopyridine (DMAP). The first exami-
nation involved the reduction of 1 with several types of
1
Zn(BH4)2, H NMR analysis of the crude mixtures indicated no
formation of the corresponding lactone and lactol (Entry 7).
The second examination involved the reduction of 1 with
aluminum hydrides (Table 2). Reduction using lithium alumi-
num hydride (LAH) resulted in formation of an unexpected
1
product (Entry 1). The H NMR and MS spectra revealed that
the structure of the product was a diastereomeric mixture of
tetrahydrofuran derivative 4a containing an oxazolidinone group
at position 2 of the tetrahydrofuran ring. In contrast, 4a and also
3a was obtained when Red-Alμ instead of LAH was used as a
reductant (Entry 2). In addition, the use of DIBAL increased the
yield of 4a (Entry 3). Analysis using integration of the 1H NMR
spectra indicated that the ratio of major 4a to minor 4a was
57:43. A comparison among the three types of aluminum
hydride showed that DIBAL was the best reductant for
formation of 4a (Entries 1-3). In addition, the yield of 4a was
independent of the reaction solvent (Entries 3-5). Reduction of
another starting material such as 1b with DIBAL also resulted
in yield of the corresponding tetrahydrofuran derivative 4b
(Entry 6). Fortunately, each diastereomer could be isolated by
Table 1. Reduction of 1 with borohydride reductants
Reductant
/mol equiv
Time Temp.
Yield
/%
Entry Subst.
Solvent
Product
/h
/°C
O
OH
O
O
n
1) reduction
2) cyclization
reduction
1
2
3
4
5
6
7
1a NaBH4/3.5 THF-H2O 0.5
RT
2a
56
41
47
R
O
O
N
O
1a Zn(BH4)2/1.5 THF
1a LiBH4/1.0 THF
1a LiBEt3H/1.0 THF
1a LiBEt3H/2.1 THF
4
2
0.5
0.5
¹20-RT 2a
2a
n
n
O
R
R
0
1
2
3
¹78 2a (3a) 30 (15)
¹78 3a
RT
0
a: n=1, R=Ph. b: n=1, R=p-MeC6H4-. c: n=2, R=Ph.
61
37
1c NaBH4/1.0 THF-H2O 0.5
5
Scheme 1. Reduction of N-(γ- or δ-oxoacyl)oxazolidinone 1 to
lactone 2 or lactol 3 using borohydride reductant.
1c Zn(BH4)2/1.0 THF
0.25
®
O
O
O
O
O
n
O
OH
O
Aluminum hydride
O
R
or
R
O
N
O
N
O
R
N
O
N
O
5
1
4
Figure 1. Structure of 5.
Scheme 2. Reduction of 1 with aluminum hydride reductant.
Chem. Lett. 2014, 43, 371–372 | doi:10.1246/cl.130975
© 2014 The Chemical Society of Japan | 371

O
Table 2. Reduction of 1 with aluminum hydride reductants
M
O
O
O
n
route A
route B
1) reduction
2) cyclization
N
O
O
Reductant
/mol equiv
Time Temp. Product
R
Entry Subst.
Solvent
N
O
n
O
/h
/°C (Yield/%)
N
O
O
M
O
R
1
2
3
4
5
6
7
8
9
1a LAH/1.0
THF
1.5
1.5
0.5
¹60 4a (26)
¹40 4a (<6)a, 3a (46)
¹40 4a (62)b
1
6
1a Red-Alμ/1.5 THF
1a DIBAL/2.2 THF
O
OH
reduction
reduction
1a DIBAL/2.2 Toluene 0.5
¹40 4a (68)
route A
route B
O
O
1a DIBAL/2.2 CH2Cl2
1b DIBAL/2.5 CH2Cl2
1c DIBAL/2.2 THF
1c DIBAL/2.2 Toluene 0.5
1c DIBAL/2.2 CH2Cl2 0.5
0.5
2.0
0.5
¹40 4a (61), 3a (6)
¹40 4b (67)c, 3b (10)
¹40 4c (39), 3c (40)
¹40 4c (30), 3c (59)
¹40 4c (87)d, 3c (8)
n
n
R
R
2
3
O
N
O
O
O
O
O
R
R
N
n
a4a was difficult to isolate without contamination by by-products. All
ratios were determined using integration of 1H NMR spectra. b57:43.
n
7
4
d
c58:42. 56:44.
Scheme 3. Proposed reaction mechanism for the reduction.
O
N
O
N
H
H
Me/H
Me/H
O
O
H
H
H
H
O
O
O
n
O
n
DIBAL (2.2 equiv)
NOE correlation
Ph
Ph
N
N
major = trans
minor = cis
CH2Cl2, -40 °C, 1.5 h
O
OH
8: n=1
9: n=2
10: n=1, 55 %
11: n=2, 31 %
Figure 2. NOESY correlations for 1a and 1b.
Scheme 4. Reduction of γ- or δ-oxocarboxamide with DIBAL.
preparative TLC. When N-(5-oxo-5-phenylpentanoyl)oxazolidi-
none (1c) was used as the substrate, the corresponding
tetrahydropyran derivative mixture 4c was produced. However,
yields of 4c depended on the reaction solvent (Entries 7-9).
Among the three solvents used, CH2Cl2 performed the best in
the present reaction system. In addition, 4c was given as a 56:44
mixture of diastereomers, determined by integration of 1H NMR
spectra.
cis-trans Assignments in 4a and 4b were based on NOESY
analysis (Figure 2). The aromatic proton of the major product
at the ortho position showed NOESY cross-peaks with two
methine protons at the 2- and 5-positions of the tetrahydrofuran
ring. However, no cross-peak was observed for the methine
protons at the 2- and 5-positions of the tetrahydrofuran ring.
These data suggest that the stereochemistry of the major product
was trans. In contrast, the aromatic proton of the minor product
had a NOESY cross-peak only with the 5-position on the
tetrahydrofuran ring. Together with the cross-peak at the methine
protons of the 2- and 5-positions of the tetrahydrofuran ring,
these data indicate that the stereochemistry of the minor product
was cis. The stereochemistry of 4c was not clear from the
NOESY spectrum; however, the stereochemistry of the major
product is probably trans.
Scheme 3 shows the proposed reaction mechanism of the
present reduction. In the initial step, generation of cyclic
aluminum alkoxide 6 resulted from reduction of the ketone
group of 1. In the next step, 6 released the oxazolidinone anion
to give the corresponding lactone 2 and/or lactol 3 when a
borohydride was used (route A). In contrast, when an aluminum
hydride was used, the aluminum oxide species, not the
oxazolidinone anion, was eliminated from 6 to form the
iminium salt 7. In the final step, 7 was reduced by the aluminum
hydride to yield 4 as the final product (route B).
of carboxamide with LAH to the corresponding amine.2 Brown
reported that AlH3 or LAH reduced ketoximes to primary
amines.3 In the reduction of a specific ketoxime utilizing LAH4
or DIBAL,5 a rearranged product arose from an initial
Beckmann rearrangement of the ketoxime prior to reduction.
All of these reports, as well as the present results, indicate that
the leaving ability of aluminum oxide species is greater than that
of boron oxide species. Therefore, only aluminum oxide species
can act as leaving groups.
To reveal the scope and limitation, reduction of the amide
with DIBAL was examined (Scheme 4). Although the reduction
of 8 with DIBAL was complicated, the corresponding γ-
hydroxycarboxamide 10 was isolated in moderate yield only.
Furthermore, when 9 was used as a substrate, unfortunately, a
similar result was given.
In conclusion, a new role for aluminum hydride reagents
was discovered and described. Further investigation of the
limitations of this reaction system and new functional trans-
formations using aluminum hydrides is needed.6
This paper is dedicated to Professor Teruaki
Mukaiyama in celebration of the 40th anniversary of the
Mukaiyama aldol reaction.
References and Notes
1
Handbook of Reagents for Organic Synthesis, Oxidizing and
Reducing Agents, ed. by S. D. Burke, R. L. Danheiser, Wiley,
Chichester, 1999.
M. S. Newman, T. Fukunaga, J. Am. Chem. Soc. 1960, 82, 693.
N. M. Yoon, H. C. Brown, J. Am. Chem. Soc. 1968, 90, 2927.
a) S. H. Graham, A. J. S. Williams, Tetrahedron 1965, 21, 3263.
b) K. Kotera, K. Kitahonoki, Org. Synth. 1968, 48, 20.
S. Sasatani, T. Miyazaki, K. Maruoka, H. Yamamoto, Tetrahedron
Lett. 1983, 24, 4711.
2
3
4
Aluminum oxide species, such as dialuminum oxide and
aluminum hydroxide, can act as a leaving group. The first report
of this phenomenon by Newman et al. described the formation
of aluminum oxide species as a leaving group during reduction
5
6
Supporting Information is available electronically on the CSJ-
Journal Web site, http://www.csj.jp/journals/chem-lett/index.html.
372 | Chem. Lett. 2014, 43, 371–372 | doi:10.1246/cl.130975
© 2014 The Chemical Society of Japan