Molecular sieve (MS 4A) promoted cyclocondensation of hindered, aromatic nitrile oxides and cyclic diketones under mild conditions

Article abstract of DOI:10.1055/s-2003-41436

Molecular sieves (MS 4A) serve as efficient promoters for the cyclocondensation of stable, hindered nitrile oxides and a variety of cyclic diketones to afford fused isoxazoles in good yield. The operational simplicity and remarkably mild reaction conditions compliment our amine-promoted cyclocondensation conditions and demonstrate broad substrate scope.

Full text of DOI:10.1055/s-2003-41436

1746
LETTER
Molecular Sieve (MS 4A) Promoted Cyclocondensation of Hindered,
Aromatic Nitrile Oxides and Cyclic Diketones under Mild Conditions
M
olecular Sieve
o
Promoted C
m
yclocondensation oo Matsuura, Jeffrey W. Bode, Yoshifumi Hachisu, Keisuke Suzuki*
Department of Chemistry, Tokyo Institute of Technology and CREST, Japan Science and Technology Corporation, O-okayama,
Meguro-ku, Tokyo 152-8551, Japan
Fax +81(3)57342228; E-mail: ksuzuki@chem.titech.ac.jp
Received 6 June 2003
Dedicated to the memory of the late Professor Oyo Mitsunobu
Table 1 Optimization of MS Promoted Cyclocondensationsa
Abstract: Molecular sieves (MS 4A) serve as efficient promoters
for the cyclocondensation of stable, hindered nitrile oxides and a va-
riety of cyclic diketones to afford fused isoxazoles in good yield.
The operational simplicity and remarkably mild reaction conditions
compliment our amine-promoted cyclocondensation conditions and
demonstrate broad substrate scope.
O
Me
O
N
O
N
Me
see Table 1
C
+
Me
iPrOH, 50 °C
O
Me
O
Me
Me
1
2
3
Key words: cycloadditions, ketones, condensation, isoxazoles,
Entry Additive
Loading
(g/mmol)
Time
(h)
Yieldb
(%)
molecular sieves
1
2
none
10 mol% NEt3
–
–
1
1
1
1
1
1
1
3
40
100
10
24c
56
79
Recently, we reported the base-promoted coupling of sta-
ble aromatic nitrile oxides with cyclic diketones, afford-
ing highly functionalized fused isoxazoles in good yield.1
Although preliminary results indicated that the reaction
was catalytic with respect to the base, in practice the ex-
tended reaction times required for high yielding, catalytic
cyclocondensations hampered studies towards the devel-
opment of more active and enantioselective reagents
(Equation 1).
3
10 mol% NEt3 +MS 4A
Drierite
d
4
180
23
–
5
Basic alumina
MS 5A
62
d
6
72
–
d
7
MS 13 Xe
MS 3A
72
–
8
24
66
O
Me
O
N
O
N
Me
C
10 mol% NEt3
9
MS 4A
9.5 78
5.5 81
+
EtOH, 50 °C
60 h
O
Me
O
Me
Me
10
MS 4A
Me
a Unless otherwise indicated, all reactions were performed at 0.1 M in
i-PrOH at 50 °C for the indicated reaction time.
67% yield
b Yield refers to isolated yield of pure product.
Equation 1
c Nitrile oxide 1 was recovered in 54% yield.
d Significant amounts of nitrile oxide 1 remained at the indicated time.
e All molecular sieves were purchased from commercial sources in
powdered form and dried prior to use.
In hopes of accelerating the reaction, we sought to identify
a more active amine catalyst or suitable additive with the
goal of increasing the reaction rate while maintaining the
mild reaction conditions. In the course of these studies, we
noted that the addition of 4A molecular sieves (MS 4A) to
tertiary amine catalyzed reactions resulted in a significant
acceleration of the reaction rate, without an apparent in-
crease in starting material decomposition or reaction by-
products (Table 1, entry 3). To our surprise, however, fur-
ther studies revealed that molecular sieves alone, in the
absence of base, effectively promoted the cycloconden-
sations.2,3 Based on these observations, we now report
general and exceptionally mild conditions for efficient
cyclocondensations of aromatic nitrile oxides and di-
ketones: MS 4A (1 g/mmol of nitrile oxide), i-PrOH,
50 °C (Equation 2).
R1
O
O
N
O
R1
N
4A Mol. Sieves
C
+
i-PrOH, 50 °C
10–36 h
O
2O
R2
R
R
R
72–84% yield
Equation 2
Synlett 2003, No. 11, Print: 02 09 2003. Web: 25 08 2003.
Art Id.1437-2096,E;2003,0,11,1746,1748,ftx,en;U10903ST.pdf.
DOI: 10.1055/s-2003-41436
© Georg Thieme Verlag Stuttgart · New York

LETTER
Molecular Sieve Promoted Cyclocondensation
1747
Using stable nitrile oxide 1 and cyclic diketone 2 as model (data not shown), a variety of solid desiccants effectively
substrates, a variety of heterogeneous bases and desic- promoted the desired reaction (Table 1). A survey of com-
cants were screened for cyclocondensation promotion to monly available reagents and molecular sieves revealed
afford isoxazole 3. While solid bases including K2CO3 that powdered MS 3A and MS 4A promoted the cyclocon-
and Na2CO3 proved inferior to base-promoted conditions densation reaction (entries 8–10) in good yield and ac-
Table 2 Synthesis of Isoxazoles by 4A Molecular Sieve-Promoted Cyclocondensation Reactionsa
Entry
1
Nitrile oxide
Compd
Ketone
Compd Product
Compd Time (h) Yieldb (%)
N
O
1
O
2
3
9.5
78
Me
Me
O
O
N
C
Me
O
O
Me
Me
Me
2
3
4
1
6
8
4
2
2
5
7
9
20
15
10
81
80
53
O
N
O
Me
Me
N
N
C
O
O
Me
Me
Me
Me
O
O
O
O
Cl
Cl
N
C
Cl
O
O
O
Cl
N
O
OMe
MeO
O
N
C
O
5
6
7
8
10
12
12
12
2
11
14
16
18
36
24
23
12
81
84
54c
72
O
O
O
O
N
O
O
O
O
O
O
O
N
C
O
O
O
O
O
N
MOM
OMOM
13
15
17
O
O
O
O
O
O
O
O
N
C
Me
Me
O
O
Me
Me
Me
OMe
N
O
H
O
N
C
O
O
Me
COOEt
COOEt
OMe
OH
O
O
N
O
O
O
O
O
N
C
O
O
O
O
Me
OMe
9
8
17
19
10
53
N
O
O
OH
O
OMe
MeO
O
N
C
O
a Unless otherwise indicated, all reactions were performed using 1.0 equiv nitrile oxide, 1.2 equiv diketone, and 1 g/mmol of powdered
MS 4A in 0.1 M i-PrOH at 50 °C for the indicated time.
b Chemical yield of isolated, spectroscopically pure product.
c Combined yield for cyclocondensation and acetal deprotection based on 12. Small amounts of stereo- and/or regioisomers were observed prior
to purification by precipitation.
Synlett 2003, No. 11, 1746–1748 ISSN 1234-567-89 © Thieme Stuttgart · New York

1748
T. Matsuura et al.
LETTER
ceptable reaction times.4 In contrast, molecular sieves ated by molecular sieves offers unique mechanistic in-
with a larger cavity size were ineffective (entries 6, 7). Al- sights with implications for the further development of
though cyclocondensation reactions occurred in the pres- highly active and enantioselective catalysts, and of novel
ence of basic alumina, it offered no advantages to either carbon–carbon bond forming processes.9
the molecular sieve or amine-promoted conditions (entry
5).
A typical experimental procedure is described for the reaction of
2,6-dichlorobenzonitrile oxide (6) and cyclohexane-1,3-dione (2):
To a solution of 6 (56 mg, 0.30 mmol) in 3 mL i-PrOH at r.t. was
added 2 (41 mg, 0.37 mmol) followed by powdered MS 4A (0.30
g). The yellowish slurry was heated to 50 °C and maintained at this
The use of MS 4A to promote the cyclocondensation is
notable for both the mildness of the reaction conditions
and its operational simplicity. Neither strongly basic nor
Lewis acidic reagents are required for effective isoxazole
formation. The use of an insoluble promoter simplifies the
reaction work-up, as only filtration and solvent removal
temperature for 15 h. After cooling to r.t., the mixture was filtered,
concentrated, and purified by recrystalization (hexane/EtOAc) to
1
afford 7 (67 mg, 80% yield) as colorless crystals. H NMR (400
are necessary. Molecular sieve promoted cyclocondensa- MHz, CDCl3): d = 2.27–2.34 (2 H, m), 2.55 (2 H, dd, J = 5.6, 7.6
Hz), 3.13 (2 H, t, J = 6.3 Hz), 7.36 (1 H, dd, J = 6.5, 9.3 Hz), 7.42
tions have proven to be general for a wide variety of reac-
tion partners. Isoxazole products previously prepared by
amine-promoted cyclocondensation reactions were easily
obtained in essentially identical chemical yields under the
milder molecular sieve conditions (Table 2, entries 1, 5
and 6).
(1 H, d, J = 9.3 Hz), 7.42 (1 H, d, J = 6.5 Hz). 13C NMR (100 MHz,
CDCl3): d = 22.2, 23.2, 37.8, 115.4, 126.7, 128.0, 131.3, 135.2,
155.5, 181.3, 191.2. IR (KBr pellet): 3066, 2960, 1688, 1597, 1560,
1460, 1408, 1350, 1197, 1017, 792, 600 cm–1. Anal Calcd for
C13H9Cl2NO2: C, 55.34; H, 3.22; N, 4.96. Found: C, 55.12; H, 3.25;
N, 4.81. Mp 209.6–211.3 °C.
In addition, using these reaction conditions, we have real-
ized a broader scope for both the nitrile oxide and dike-
tone reaction partners in the cyclocondensation process.
Thus cyclohepta-1,3-dione (entry 2), and 2-hydroxy-
napthoquinone (entries 8 and 9) were readily employed in
the cyclocondensation reaction,5 affording synthetically
useful, highly functionalized products. Stable nitrile ox-
ides 6 and 8 underwent clean cyclocondensation in the
presence of MS 4A (entries 3 and 4). Unsymmetrical dike-
tones, such as 15, also served as viable substrates, giving
preferentially one regioisomer (entry 7). Isoxazole prod-
ucts possessing a C-centered stereogenenic center (entries
6 and 7) were observed to be diastereomeric mixtures due
to hindered rotation about the aryl–isoxazole bond. Pre-
liminary studies, however, suggest that these molecules
are not configurationally stable about the biaryl axis.
Acknowledgment
J.W.B. thanks the Japan Society for the Promotion of Science for a
postdoctoral fellowship. Partial support of this work was provided
by the 21st Century COE Program.
References
(1) (a) Bode, J. W.; Hachisu, Y.; Matsuura, T.; Suzuki, K.
Tetrahedron Lett. 2003, 44, 3555. (b) Bode, J. W.; Hachisu,
Y.; Matsuura, T.; Suzuki, K. Org. Lett. 2003, 5, 391.
(2) For a review of molecular sieve and zeolite promoted
reactions, see: Sen, S. E.; Smith, S. M.; Sullivan, K. A.
Tetrahedron 1999, 55, 12657.
(3) The use of 4 Å MS as a base for the elimination of C-
chloroximes to form nitrile oxides and subsequent
cycloaddition with acrylates has been reported. However,
under these conditions long reaction times (7–10 d) were
necessary, see: Kim, J. N.; Ryu, E. K. Heterocycles 1990, 31,
1693.
(4) MS 4A have the general formula Na2O·Al2O3·xSiO2·yH2O.
(5) Thermal cycloadditions of 2-hydroxynaphthoquinone and
nitrile oxides have been previously reported: Brahmeshwari,
G.; Rao, V. R.; Rao, T. V. P. Indian J. Chem., Sect. B 1995,
34, 139.
(6) Bode, J. W.; Suzuki, K. Org. Lett. 2003, 5, 394.
(7) Hachisu, Y.; Bode, J. W.; Suzuki, K. J. Am. Chem. Soc.
2003, 125, 8432.
In conclusion, we have documented the utility of MS 4A
as effective reagents for promoting the cyclocondensation
of stable, hindered aromatic nitrile oxides with cyclic
diketones. The chemical yields, decreased reaction times,
and operational simplicity offered by this method enhance
its utility for the synthesis of complex heterocycles. The
highly functionalized isoxazoles products have found use
for the synthesis of benzophenones,1b xanthones,6 stereo-
chemically complex preanthraquinones,7 and natural
products.8 New methodologies for facile isoxazole syn-
thesis enhance their attractiveness as a platform for the
synthesis of complex molecules. The recognition that
cyclocondensation reactions can be promoted and acceler-
(8) Bode, J. W.; Suzuki, K. Tetrahedron Lett. 2003, 44, 3559.
(9) For a Diels–Alder type cycloaddition reaction promoted by
molecular sieves, see: Pindur, U.; Haber, M. Heterocycles
1991, 32, 1463.
Synlett 2003, No. 11, 1746–1748 ISSN 1234-567-89 © Thieme Stuttgart · New York