A convenient synthesis of medium-sized lactams through RCM reaction of oxyoxazolidinones

Article abstract of DOI:10.1016/j.tetlet.2006.03.152

Oxyoxazolidinones, which are prepared from secondary O-acylmandelamides by treatment with TBSOTf, underwent the RCM reaction in the presence of Grubbs catalyst to give oxazoloazepines or oxazoloazecines, which were readily converted into N-unsubstituted seven-membered or eight-membered lactams by the reductive treatment.

Full text of DOI:10.1016/j.tetlet.2006.03.152

Tetrahedron Letters 47 (2006) 3625–3627
A convenient synthesis of medium-sized lactams through
RCM reaction of oxyoxazolidinones
Akio Kamimura,* Keiichi Tanaka, Takahiro Hayashi and Yoji Omata
Department of Applied Chemistry, Faculty of Engineering, Yamaguchi University, Ube 755-8611, Japan
Received 30 January 2006; revised 22 March 2006; accepted 24 March 2006
Available online 12 April 2006
Abstract—Oxyoxazolidinones, which are prepared from secondary O-acylmandelamides by treatment with TBSOTf, underwent the
RCM reaction in the presence of Grubbs catalyst to give oxazoloazepines or oxazoloazecines, which were readily converted into
N-unsubstituted seven-membered or eight-membered lactams by the reductive treatment.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Recently, we have discovered a new type of heterocyclic
compounds, oxyoxazolidinones, which are readily pre-
pared from O-acylmandelamides on treatment with
TBSOTf.1 The formation of the ring takes place in a
stereoselective manner and they are usually isolated as
a single diastereomer. These compounds have sufficient
stability toward chromatographic purification as well
as further transformation, despite the structure which
is isoelectronic to orthoester in most cases which are
labile on touch with aqueous media.2 We have succeeded
in providing a new method to prepare N-unsubstituted
pyrrolidinones and piperidinones through trans-selective
radical cyclization between the side chains of oxyoxazo-
lidinones.3 Medium-sized lactams sometimes give rise to
difficulties in their preparation4 for which so many use-
ful methods have been devised so far.5 Recently, the ring
closing metathesis (RCM) reaction attracted synthetic
chemists toward the construction of medium-sized
rings.6 In this letter, we describe the RCM reaction
between the side chains of oxyoxazolidinones, followed
by reductive treatment to provide a useful method for
the preparation of medium-sized N-unsubstituted
lactams.7
O
TBSO
O
TBSOTf
2,6-lutidine/0 ºC
n
O
n
N
H
N
Ph
R
Ph
O
O
R
1
2
Scheme 1.
Table 1. Preparation of oxyoxazolidinone 1
Entry
2
n
R
1
Yielda (%)
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
0
1
2
2
2
2
3
4
H
H
H
i-Pr
i-Bu
Ph
H
1a
1b
1c
1d
1e
1f
60
0
93
83
87
85
95
95
2g
2h
1g
1h
H
a Isolated yields.
idine 2b. This is probably due to the isomerization of
the alkenyl part toward a conjugated system which pre-
dominated before the cyclization reaction took place.
Preparation of precursors 1 was performed by the
method reported before (Scheme 1). The results are
summarized in Table 1. Treatment of O-acylmandel-
amide 2 with TBSOTf in the presence of 2,6-lutidine
smoothly afforded oxyoxazolidinone 1 in good yields,
except for the preparation of 2-(3-butenyl)oxyoxazol-
We next examined the RCM reaction for 1 (Scheme 2).
The results are summarized in Table 2. Two types of
Grubbs catalysts were employed in the reaction. Treat-
ment of 3a with catalyst A failed to form the desired
bicyclic compound 3a due to steric hindrance caused
at the C2-position of oxyoxazolidinone (entry 1),
while compound 1c underwent smooth ring closure
*
Corresponding author. Tel.: +81 836 85 9231; fax: +81 836 85
9201; e-mail: ak10@yamaguchi-u.ac.jp
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.03.152

3626
A. Kamimura et al. / Tetrahedron Letters 47 (2006) 3625–3627
TBSO
O
Mes
N
Cl
N Mes
PCy3
TBSO
O
Cl
Cl
n
n
catalyst (5 mol%)
Ph
Ru CHPh
PCy3
Ru CHPh
PCy3
N
N
Cl
CH2Cl2 (abt 10-2 M)
O
Ph
O
A
B
3
1
Scheme 2.
reaction. These results were in contrast to the fact that
compound 1c smoothly underwent the RCM reaction
to give 3c in 91% yield (Table 2, entry 1). Thus, the oxy-
oxazolidinone ring offers an excellent bias to proceed the
cyclization of medium-sized rings, through the RCM
reaction, that are usually hard to form.
Table 2. RCM reaction of 1
Entry
1
n
R
Catalyst
3
Yielda (%)
1
2
3
4
5
6
7
8
1a
1c
1d
1e
1f
0
2
2
2
2
3
3
4
H
H
i-Pr
i-Bu
Ph
H
A
A
A
B
B
A
B
B
3a
3c
3d
3e
3f
0
91
79
78
66
0
To remove the mandelic unit, treatment of 3 with TBAF
was examined. To our surprise, the obtained product
still contained mandelic amide unit and the formation
of N-free azepine was not observed. The obtained imide
8 was reluctant to hydrolysis under usual conditions.
Thus, simple removal of mandelic unit by treatment
with TBAF, which was achieved in the formation of
pyrrolidinone, never occurred in this case. After several
efforts to seek a method to remove the mandelic unit, we
finally succeeded under hydrogenation conditions
(Scheme 4).8 Under these conditions, N-unsubstituted
azepinones 9 or azecinones 10 were successfully isolated
(Scheme 4), although the alkene unit in the ring dis-
appeared during the reductive conversion.
1g
1g
1h
3g
3g
3h
H
H
98
0
a Isolated yields.
metathesis reaction to give 3c in 91% yield (entry 2).
Other oxazoloazepines 3d to 3f were also prepared in
good yields. Some starting materials were required to
use catalyst B to achieve high yields from the RCM
reaction (entries 3–5). The reaction was not sensitive
to reaction concentrations of the range from 5 · 10À3
to 2 · 10À2 M, and the RCM products were obtained
in good yields. The formation of oxazoloazecine 3g
could not be achieved by the reaction catalyzed by
catalyst A and precursor 1g was recovered (entry 6).
Exposure of 1g to catalyst B, on the other hand, suc-
cessfully resulted in the formation of eight-membered
ring 3g in 98% yield (entry 7), while compound 1h
never gave oxazoloazonine 3h.
O
OH
TBAF
N
Ph
OTBS
O
O
R
n
Ph
8; R = H, 45%
N
R
The merit of the present method is well demonstrated by
the fact that neither of the noncyclic compounds 4, 5,
and 6 gave the corresponding cyclized products effi-
ciently under the same RCM conditions (Scheme 3).
For example, no trace amounts of cyclized product
was observed in the reaction mixture of 4 and 5. Even
Boc group at the nitrogen atom afforded insufficient bias
for the cyclization because the exposure of N-Boc deriv-
ative 6 under the same reaction conditions gave only 2%
of cyclized product 7; most of 6 was recovered after the
O
n
1) H2, Pd/C, MeOH
2) NaOH, MeOH-H2O
3
O
N
H
R
9a; n = 1, R = H, 76%
9b; n = 1, R = iPr, 56%
9c; n = 1, R = iBu, 50%
10; n = 2, R = H, 35%
Scheme 4.
O
catalyst A
5 mol%
H
N
O
or
H
N
No Reaction
CH2Cl2
abt. 1.0 x 10-2M
Ph
O
O
4
5
Boc
N
catalyst A
5 mol%
+ recovery of 6 (61%)
CH2Cl2
abt. 1.0 x 10-2M
N
Boc
O
O
6
7; 2%
Scheme 3.

A. Kamimura et al. / Tetrahedron Letters 47 (2006) 3625–3627
3627
Wipf, P.; Xu, W. J. Org. Chem. 1993, 58, 5880; (e)
In conclusion, we have succeeded in providing a new
method to prepare N-unsubstituted medium-sized lac-
tams through the RCM reaction of oxyoxazolidinones.
These unique heterocyclic compounds are prepared eas-
ily from O-acylmandelamides and effectively offer steric
bias for the RCM reaction to give seven- or eight-mem-
bered ring. This is in contrast to the fact that secondary
amides never form cyclized products due to favorable
conformation of an amide moiety. Further application
of the present method is now underway in our
laboratory.
Waldmuller, D.; Braun, M.; Steigel, A. Synlett 1991, 160;
¨
(f) Corey, E. J.; Raju, N. Tetrahedron Lett. 1983, 24, 5571;
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2294.
3. Kamimura, A.; Omata, Y.; Tanaka, K.; Shirai, M. Tetra-
hedron 2003, 59, 6291.
4. Nubbemeyer, U. Top. Curr. Chem. 2001, 216, 125.
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1995, 51, 9767.
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Rutjues, F. P. J. T.; Schoemaler, H. E. Tetrahedron Lett.
1997, 38, 677; Creighton, C. J.; Reitz, A. B. Org. Lett. 2001,
3, 893.
References and notes
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