Regioselective intramolecular [3-2] annulation of allene-nitrones

Article abstract of DOI:10.1248/cpb.60.381

The regioselective intramolecular 1,3-dipolar cycloaddition of the phenylsulfonylallene-nitrone derivatives has been developed. This reaction showed that the distal double bond of the allene exclusively reacted with the nitrone group to produce the bicyclic isoxazolidine derivatives regardless of the substitution pattern on the allenyl moiety.

Full text of DOI:10.1248/cpb.60.381

—
March 2012
Regular Article
Chem. Pharm. Bull. 60(3) 381 384 (2012)
381
Regioselective Intramolecular [3+2] Annulation of Allene-Nitrones
Fuyuhiko Inagaki, Harumi Kobayashi, and Chisato Mukai*
Division of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University;
Kakuma-machi, Kanazawa 920–1192, Japan.
Received December 15, 2011; accepted January 4, 2012; published online January 6, 2012
The regioselective intramolecular 1,3-dipolar cycloaddition of the phenylsulfonylallene-nitrone deriva-
tives has been developed. This reaction showed that the distal double bond of the allene exclusively reacted
with the nitrone group to produce the bicyclic isoxazolidine derivatives regardless of the substitution pattern
on the allenyl moiety.
Key words allene; nitrone; 1,3-dipolar cycloaddition
Allene serves as a unique and powerful π-component different substitution patterns on the allenyl moiety.
in various types of cycloaddtions with an additional Treatment of a 0.1M solution of the aldehyde 8a24) in EtOH
—
4)
π-counterpart.1
°
It has been clarified that the intermolecular with 3eq of MeNHOH·HCl and NaHCO3 at 0 C for 2h effect-
1,3-dipolar cycloaddition of substituted-allenes with nitrones ed the formation of the nitrone derivative 7a, followed by the
tends to undergo the regioselective ring closure to produce the 1,3-dipolar cycloaddition to give the 2-phenylsulfonyl-8-oxa-
corresponding methylene-substituted isoxazolidine derivatives. 7-azabicyclo[4.3.0]non-1-ene (9a) in 54% yield (Table 1, entry
The thus formed initial products sometimes collapsed into sec- 1). The ring closure exclusively occurred at the distal double
ondary products via the N–O bond fission depending on the bond of the allenyl moiety. This is in good accordance with
property of the substituent on the allenyl moiety and/or reac- the behavior of the phenylsulfonylallene-azido derivative 523)
—
15)
tion conditions.5
In contrast to the intermolecular reaction, (Chart 2). A better yield (63%) was obtained when the reaction
there are very few examples of the intramolecular 1,3-diploar was performed at room temperature (entry 2). It was found
—
22)
cycloaddition between the nitrone and allene groups.16
Of that 1.3eq of MeNHOH·HCl and NaHCO3 were enough to get
—
particular interest among them is the reaction of the nitrone satisfactory yields (entries 3 6). Dimethyl sulfoxide (DMSO)
116) derived from the reaction of 5,6-heptadien-2-one with N- was superior to EtOH or CH3CN as the solvent (entries 4 6).
—
methylhydroxylamine (Chart 1). The in situ formed 1 (n=1) Thus, the best result was obtained as follows. Upon exposure
furnished the bicyclic isoxazolidine 2 in 45% yield via the to MeNHOH·HCl and NaHCO3 (1.3eq) in DMSO (0.05M)
cycloaddition with the distal double bond of the allenyl group, at room temperature for 0.5h, 8a produced 9a in 96% yield
while the nonselective formation of the two bicyclic cycload- (entry 6).
ducts 3 (36%, two diastereoisomers in a ratio of 26 to 10) and
4 (29%) was observed when the one carbon-elongated nitrone
1 (n=2) was employed. The production of 3 could be rational-
ized in terms of the initial formation of compound 3′, which
must have been derived by the participation of the proximal
double bond of the allene. On the other hand, we have previ-
ously reported that the phenylsulfonylallene-azido derivative 5
was susceptible to the intramolecular 1,3-dipolar cycloaddition
Since the 1,1-disubstituted allene 8a exclusively afforded
to exclusively produce the triazabicyclo[m.3.0]ring system 6
23)
Chart 2. Intramolecular 1,3-Dipolar Cycloaddition of 1,1-Disubstituted
Allene-Azide
—
(m=3 5), in which the distal double bond of the allene of
5 consistently took part in the ring-closing process unlike the
case of compound 1 (n=2) (Chart 2). We describe here the
highly regioselective intramolecular 1,3-dipolar cycloaddition
of a series of phenylsulfonylallene-nitrone derivatives 7 with
Table 1. Intramolecular 1,3-Dipolar Cycloaddition of 1,1-Disubstituted
Allene-Nitrone 7a
Time
(h)
Yield
(%)
Entry
X (eq)
Temp.
Solvent (M)
°
1
2
3
4
5
6
3
0 C
EtOH (0.1)
2
0.1
1
54
63
70
85a)
75
96
3
rt
rt
rt
rt
rt
EtOH (0.1)
1.3
1.3
1.3
1.3
EtOH (0.1)
EtOH (0.05)
CH3CN (0.05)
DMSO (0.05)
4
48
0.5
Chart 1. Intramolecular 1,3-Dipolar Cycloaddition of Monosubstituted
Allene-Nitrone
a) Starting material 8a was recovered in 6% yield.
*To whom correspondence should be addressed. e-mail: mukai@p.kanazawa-u.ac.jp
© 2012 The Pharmaceutical Society of Japan

382
Vol. 60, No. 3
the 8-oxa-7-azabicyclo[4.3.0]nonene 9a via the regioselective standard conditions produced a mixture of 13 and its isomer
28)
’
reaction with the distal double bond of the allenyl moiety, 13 in 67% yield in the ratio of 2 to 1. In addition, the one-
we next investigated the regioselectivity regarding the distal carbon larger-sized 9-oxa-8-azabicyclo[5.3.0] derivative 15
versus proximal double bonds of the 1,1,3-trisubstituted- and could also be formed from the allene-aldehyde 1424) in 74%
1,1,3,3-tetrasubstituted allene-nitrones (Chart 3). Based on the yield29) (Chart 5).
optimal conditions described in Table 1, entry 6, the 1,1,3-tri-
As already shown in Chart 1, the nitrone group of the
substituted allene 8b25) was treated with MeNHOH·HCl in allene-nitrone 1 (n=2) nonselectively reacted with both the
DMSO to provide the 8-oxa-7-azabicyclo[4.3.0] derivative distal and proximal double bonds of the allene. This is in
9b in 87% yield as a mixture of two diastereoisomers in a sharp contrast to the results obtained for the 1,3-diploar cy-
ratio of 3 to 2. The distal double bond of the allene again cloaddition of the phenylsulfonylallene-nitrone derivatives
exclusively took part in the ring-closing step. The preparation 7, where the distal double bond exclusively participated in
of the 1,1,3,3-tetrasubstituted allene-aldehyde 8c was unex- the reaction. Thus, our interests became directed toward the
pectedly troublesome. The oxidation of the primary alcohol 1,3-diploar cycloaddition of the phenylsulfonylallene-nitrone
10c26) with Dess–Martin periodinane afforded a mixture of derivative 17 (Chart 6). Treatment of the allene-ketone 16
several compounds that involves the desired aldehyde 8c, with MeNHOH·HCl and NaHCO3 (1eq) in DMSO at room
which was found to be unstable and partially decompose dur- temperature for 2d did not give any cycloadducts. Heating the
°
ing the work-up process. The alcohol 10c was oxidized with reaction mixture at 80 C provided the 6,7-dimethyl-2-phenyl-
IBX (3eq) in DMSO (the formation of the aldehyde 8c was sulfonyl-8-oxa-7-azabicyclo[4.3.0]non-1-ene (18) in 29% yield.
monitored by TLC) and the resulting reaction mixture was Several experiments indicated that the formation of the keto-
directly treated with MeNHOH·HCl and NaHCO3 to furnish nitrone must be the rate-determining step in this transforma-
1
9c in 37% yield. We assumed that the unreacted oxidant might tion (monitored by H-NMR spectrum). It was reported30) that
mainly cause the low yield (37%). After carefully screening a Lewis acid accelerates the formation of the ketonitrones in
several conditions, we finally developed the following con- the reaction between the ketone and hydroxylamines groups.
secutive procedure. The oxidation of 10c with IBX (3eq) in Thus, we examined some Lewis acids and finally found that
30)
DMSO at room temperature for 3h was followed by the ad- the combination of ZnCl2 and MgSO4 is suitable for our
dition of 2-propanol (5eq) for complete consumption of the purpose. In fact, 16 was exposed to MeNHOH·HCl in the
30)
°
excess IBX. The resulting reaction mixture was subsequently presence of ZnCl2 and MgSO4 in CH2Cl2/DMSO at 30 C
exposed to MeNHOH·HCl and NaHCO3 to produce 9c in 74% for 28.5h to give the desired product 18 in 73% yield as the
yield in a highly regioselective manner. Thus, it became obvi- sole isolatable product. Introduction of a phenylsulfonyl group
ous that the intramolecular 1,3-diploar cycloaddition of the on the allenyl moiety of 1 (n=2) led to the highly regioselec-
phenylsulfonylallene-nitrone derivatives 7 consistently pro- tive construction of the oxa-azabicyclo[m.3.0] frameworks
—
vided the corresponding bicyclo[4.3.0] skeletons irrespective (m=3 5).
of the substitution pattern on the allenyl moiety.
In summary, we have developed the intramolecular 1,3-di-
The one-pot procedure was then applied to the other two polar cycloaddition of phenylsulfonylallene-nitrones for the
primary alcohols 10a,b to afford 9a and b in 80% and 69% highly regioselective formation of bicyclo[m.3.0] derivatives
—
yields, respectively (Chart 4). It should be mentioned that the (m=3 5). The distal double bond of the phenylsulfonylallene
methylallene-alcohol 1127) did not provide the cycloadducts
under these conditions in spite of the fact that the formation of
the corresponding methylallene-aldehyde was unambiguously
1
confirmed by the H-NMR spectrum.
The one-carbon shortened allene-aldehyde 1225) under the
Chart 4. One-Pot Oxidation and 1,3-Dipolar Cycloaddition of Allene-
Alcohols
Chart 3. Intramolecular 1,3-Dipolar Cycloaddition of 1,1,3-Tri- and
Chart 5. Intramolecular 1,3-Dipolar Cycloaddition with 12 and 14
1,1,3,3-Tetrasubstituted Allene-Nitrones

March 2012
383
Chart 6. Intramolecular 1,3-Dipolar Cycloaddition of Allene-Ketonitrone 16
—
regioselectively reacted with the nitrone moiety. No cycload- 7.64 (m, 1H), 7.56 7.52 (m, 2H), 5.21 (q, 1Hx3/5, J=7.9Hz),
ducts derived from the reaction between the proximal double 4.73 (q, 1Hx2/5, J=7.2Hz), 3.66 (d, 1Hx2/5, J=4.1Hz), 3.60
— —
(d, 1Hx3/5, J=4.8Hz), 2.61 2.51 (m, 4Hx2/5, 1Hx3/5), 2.45
bond could be isolated.
—
—
2.38 (m, 4Hx3/5), 2.07 2.04 (m, 1Hx2/5), 1.97 1.76 (m,
—
4Hx3/5, 2Hx2/5), 1.81 (d, 3Hx3/5, J=7.9Hz), 1.70 1.66 (m,
Experimental
General Melting points are uncorrected. IR spectra were 2Hx2/5), 1.60 (d, 3Hx2/5, J=7.2Hz); 13C-NMR δ: 150.6, 149.7,
1
measured in CHCl3. H-NMR spectra were taken in CDCl3 136.11, 136.08, 134.00, 139.95, 130.5, 130.2, 128.82, 128.75,
unless otherwise indicated. CHCl3 (7.26ppm) for silyl com- 102.6, 100.1, 84.8, 84.6, 78.0, 75.6, 45.1, 44.6, 34.2, 32.5, 31.3,
pounds and tetramethylsilane (0.00ppm) for compounds with- 30.8, 25.5, 25.0, 11.3, 11.1; MS m/z 293 (M+, 36.6); HR-MS
out a silyl group were used as internal standards. 13C-NMR Calcd for C15H19NO3S 293.1086, Found 293.1088.
spectra were recorded in CDCl3 with CDCl3 (77.00ppm) as an
7,9,9-Trimethyl-2-phenylsulfonyl-8-oxa-7-azabicyclo-
—
—
°
internal standard unless otherwise stated. All reactions were [4.3.0]non-1-ene (9c) Colorless plates, mp 110 111.5 C
1
carried out under a nitrogen atmosphere. Silica gel (silica gel (AcOEt/hexane); IR 1688cm−1; H-NMR δ: 7.82 7.81 (m,
—
60, 230 400 mesh) was used for chromatography. Organic 2H), 7.65 (t, 1H, J=7.6Hz), 7.53 (t, 2H, J=7.6Hz), 3.62 (d,
—
1H, J=4.5Hz), 2.61 2.56 (m, 1H), 2.46 (s, 3H), 2.41 (dd, 1H,
extracts were dried over anhydrous Na2SO4.
—
—
General Procedure for 1,3-Dipolar Cycloaddition J=13.4, 6.5Hz), 1.99 1.89 (m, 2H), 1.88 (s, 3H), 1.84 1.77
with Aldehydes (A) To a solution of aldehyde derivative (m, 1H), 1.69 1.67 (m, 1H), 1.62 (s, 3H); 13C-NMR δ: 143.4,
—
(0.10mmol) in DMSO (2mL) were added MeNHOH·HCl 136.2, 133.9, 130.0, 128.5, 112.3, 85.1, 78.7, 44.3, 31.4, 30.5,
(11mg, 0.13mmol) and NaHCO3 (11mg, 0.13mmol) at room 25.7, 19.0, 18.7; MS m/z 307 (M+, 100.0); HR-MS Calcd for
temperature. After stirring until the complete disappearance C16H21NO3S 307.1242, Found 307.1238.
of the starting material as indicated by TLC, the reaction mix-
2-Methyl-6-phenylsulfonyl-3-oxa-2-azabicyclo[3.3.0]-
ture was quenched by addition of water, extracted with Et2O. oct-5-ene (13), 2-Methyl-6-phenylsulfonyl-3-oxa-2-azabi-
The extract was washed with water and brine, dried, and cyclo[3.3.0]oct-1(5)-ene (13′) A 2:1 mixture of 13 and 13′
concentrated to dryness. The residue was chromatographed was obtained as a colorless oil. The ratio was determined
1
with hexane–AcOEt to afford oxa-azabicyclo[m.3.0] derivative by H-NMR analysis of both the crude and purified prod-
—
(m=3 5).
uct. Analytically pure 13 and 13′ were obtained by column
General Procedure for One-Pot Oxidation and 1,3- chromatography. Compound 13: colorless oil; IR 1647cm−1;
1
°
H-NMR (50 C) δ: 7.94 (d, 2H, J=7.6Hz), 7.68 (t, 1H,
Dipolar Cycloaddition from Alcohols (B) To a solution of
alcohol derivative (0.10mmol) in DMSO (2mL) was added J=7.6Hz), 7.57 (t, 2H, J=7.6Hz), 4.57 (brs, 1H), 4.28 (t, 1H,
IBX (84mg, 0.30mmol) at room temperature. After stirring J=7.2Hz), 4.03 (brs, 1H), 2.97 (q, 1H, J=10.3Hz), 2.53 (s, 3H),
—
—
—
for 3h at the same temperature, 2-propanol (40μL, 0.52mmol) 2.39 2.31 (m, 1H), 2.28 2.22 (m, 1H), 2.05 2.01 (m, 1H);
was added to the mixture, which was further stirred for 3h.
13
°
C-NMR (50 C) δ: 158.7, 136.5, 134.3, 130.3, 129.3, 129.1,
Then, MeNHOH·HCl (11mg, 0.13mmol) and NaHCO3 (11mg, 85.4, 76.5, 68.0, 26.7, 19.6; MS m/z 265 (M+, 100); HR-MS
0.13mmol) were added to the mixture at room temperature. Calcd for C13H15NO3S 265.0773, Found 265.0776. Compound
−1
1
°
—
After stirring until the complete disappearance of the start- 13′: colorless oil; IR 1684cm ; H-NMR (45 C) δ: 7.90 7.88
ing material as indicated by TLC, the reaction mixture was (m, 2H), 7.66 (t, 1H, J=7.6Hz), 7.57 (t, 2H, J=7.6Hz), 4.72
quenched by addition of water, extracted with Et2O. The and 4.68 (ABq, 2H, JAB=15.5Hz), 3.83 (t, 1H, J=6.9Hz),
—
extract was washed with water and brine, dried, and concen- 3.13 3.07 (m, 1H), 2.79 (dd, 1H, J=15.1, 8.9Hz), 2.70 (s, 3H),
13
—
—
°
trated to dryness. The residue was chromatographed with hex- 2.12 2.07 (m, 1H), 1.86 1.79 (m, 1H); C-NMR (45 C) δ:
ane-AcOEt to afford oxa-azabicyclo[m.3.0] derivative (m=3,4). 163.9, 139.3, 133.8, 131.5, 129.4, 127.7, 80.2, 65.5, 44.3, 37.6,
7-Methyl-2-phenylsulfonyl-8-oxa-7-azabicyclo[4.3.0]non- 28.2; MS m/z 265 (M+, 100); HR-MS Calcd for C13H15NO3S
−1
1
—
1-ene (9a) Colorless oil; IR 1655cm ; H-NMR δ: 7.97
265.0773, Found 265.0775.
—
7.95 (m, 2H), 7.71 7.66 (m, 1H), 7.56 (t, 2H, J=7.8Hz), 4.60
8-Methyl-2-phenylsulfonyl-9-oxa-8-azabicyclo[5.3.0]dec-
(d, 1H, J=2.7Hz), 4.35 (d, 1H, J=2.7Hz), 3.70 (brs, 1H), 1-ene (15) To a solution of 1425) (26mg, 0.10mmol) in
—
—
—
2.64 2.54 (m, 4H), 2.13 2.08 (m, 1H), 1.93 1.79 (m, 4H); DMSO (2mL) were added MeNHOH·HCl (8.4mg, 0.10mmol)
13C-NMR δ: 157.7, 135.6, 134.2, 130.8, 128.6, 87.5, 85.1, 75.2, and NaHCO3 (8.4mg, 0.10mmol) at room temperature. After
45.1, 35.1, 32.5, 24.7; MS m/z 279 (M+, 100.0); high resolution stirring for 48h at the same temperature, the reaction mixture
(HR)-MS Calcd for C14H17NO3S 279.0929, Found 279.0926.
(6R*,9R*)- and (6R*,9S*)-7,9-Dimethyl-2-phenylsulfonyl- extract was washed with water and brine, dried, and con-
8-oxa-7-azabicyclo[4.3.0]non-1-ene (9b) mixture of centrated to dryness. The residue was chromatographed with
(6R*,9R*)-9b and (6R*,9S*)-9b in the ratio of 3 to 2 was hexane–AcOEt (2:1) to afford 15 (22mg, 74%) as colorless
was quenched by addition of water, extracted with Et2O. The
A
−1
1
—
°
—
°
obtained as pale yellow powder, mp 108.5 109.5 C (AcOEt/ plates: mp 87 88 C (AcOEt/hexane); IR 1651cm ; H-NMR
−1
1
—
—
—
(DMSO-d6) δ: 7.89 7.87 (m, 2H), 7.76 (t, 1H, J=7.6Hz),
hexane); IR 1684cm ; H-NMR δ: 7.90 7.87 (m, 2H), 7.67

384
Vol. 60, No. 3
7.63 (t, 2H, J=7.6Hz), 4.39 (d, 1H, J=2.4Hz), 4.24 (d, 1H,
J=2.4Hz), 3.26 (brs, 1H), 2.49 (s, 3H), 2.39 2.33 (m, 1H),
References and Notes
—
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—
—
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—
—
—
1.91 1.87 (m, 1H), 1.79 1.66 (m, 2H), 1.62 1.59 (m, 1H),
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”
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—
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at the same temperature, the reaction mixture was quenched
by addition of saturated aqueous NaHCO3 at −78 C, and ex-
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(2:1) to afford the crude sulfoxide. To a solution of the crude
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—
°
—
—
—
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—
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—
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—
orless oil: IR 1969, 1938, 1715cm ; H-NMR δ: 7.90 7.88
—
—
(m, 2H), 7.64 (tt, 1H, J=7.3, 0.9Hz), 7.57 7.53 (m, 2H), 5.40
—
(t, 2H, J=3.7Hz), 2.44 (t, 2H, J=7.3Hz), 2.25 (tt, 2H, J=7.3,
3.7Hz), 2.10 (s, 3H), 1.72 (quin, 2H, J=7.3Hz); 13C-NMR δ:
207.8, 207.6, 139.9, 133.5, 129.0, 128.0, 112.7, 84.7, 42.1, 29.9,
25.9, 21.3; MS m/z 264 (M+, 3.5); HR-MS Calcd for C14H16O3S
264.0820, Found 264.0825.
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6,7-Dimethyl-2-phenylsulfonyl-8-oxa-7-azabicyclo[4.3.0]-
non-1-ene (18) To a solution of 16 (26mg, 0.10mmol)
in CH2Cl2 (2mL) were added ZnCl2 (48mg, 0.35mmol),
MeNHOH·HCl (29mg, 0.35mmol), MgSO4 (42mg, 0.35mmol)
at room temperature. After stirring for 13h at the same tem-
perature, the reaction mixture was filtered through a short pad
of Celite and extracted with Et2O. The extract was washed
with water and brine, dried, and concentrated to dryness.
The residue was chromatographed with hexane–AcOEt (3:2)
—
24) Kitagaki S., Teramoto S., Mukai C., Org. Lett., 9, 2549 2552
(2007).
25) Kitagaki S., Teramoto S., Ohta Y., Kobayashi H., Takabe M., Mukai
—
C., Tetrahedron, 66, 3687 3694 (2010).
26) Miyakoshi N., Ohgaki Y., Masui K., Mukai C., Heterocycles, 74,
—
185 189 (2007).
27) Johnston M. I., Kwass J. A., Beal R. B., Snider B. B., J. Org.
—
Chem., 52, 5419 5424 (1987).
28) One-pot reaction of 19 provided a mixture of 13 and 13′ (5:3) in
67% yield.
to afford 18 (21mg, 73%) as a colorless oil: IR 1639cm−1;
1
—
H-NMR δ: 7.93 7.91 (m, 2H), 7.63 (t, 1H, J=7.3Hz), 7.51
(t, 2H, J=7.3Hz), 4.41 (d, 1H, J=2.3Hz), 3.60 (brs, 1H), 2.88
—
(dt, 1H, J=12.8, 8.2Hz), 2.64 (s, 3H), 2.14 2.02 (m, 2H), 1.86
(quin, 2H, J=8.2Hz), 1.63 (s, 3H), 1.54 (brs, 1H); 13C-NMR
δ: 158.9, 138.4, 133.6, 131.0, 128.2, 84.4, 83.5, 78.2, 38.3, 34.9,
29.7, 21.0, 19.0; MS m/z 293 (M+, 100); HR-MS Calcd for
C15H19NO3S 293.1086, Found 293.1084.
29) The 1,3-dipolar cycloaddition of 14 under the standard condition
(1.3eq of MeNHOH·HCl and NaHCO3) for 21h gave 15 in a lower
yield (41%). Decrease of MeNHOH·HCl and NaHCO3 (1eq) would
prevent some side reactions, because the formation of another type
of nitrone by the reaction of sulfonylallene and methylhydroxyl-
amine was reported (see ref. 18).
Acknowledgment This work was supported in part by
a Grant-in-Aid for Scientific Research from the Ministry of
Education, Culture, Sports, Science and Technology of Japan,
for which we are thankful.
30) Franco S., Merchan F. L., Merino P., Tejero T., Synth. Commun., 25,
—
2275 2284 (1995).
—
31) Johnston B. D., Oehlschlager A. C., J. Org. Chem., 47, 5384 5386
(1982).