A novel photoinduced ring opening and isomerization of adamantane-2-spiro isoxazolines using Mo(CO)6

Article abstract of DOI:10.1016/j.tetlet.2006.07.156

The Mo(CO)₆-mediated photoinduced ring-opening reactions of adamantane isoxazolines involve novel rearrangement that provide enaminoketones as major products and β-hydroxy ketones as minor ones; in contrast, only β-hydroxy ketones and α,β-unsaturated ketones were obtained under thermal condition.

Full text of DOI:10.1016/j.tetlet.2006.07.156

Tetrahedron Letters 47 (2006) 7179–7183
A novel photoinduced ring opening and isomerization of
adamantane-2-spiro isoxazolines using Mo(CO)6
Annamalai Senthilvelan,a Gene-Hsiang Leeb and Wen-Sheng Chunga,*
aDepartment of Applied Chemistry, National Chiao-Tung University, Hsinchu 30050, Taiwan, ROC
bInstrumentation Center, National Taiwan University, Taipei 106, Taiwan, ROC
Received 28 February 2006; revised 21 July 2006; accepted 31 July 2006
Available online 17 August 2006
Abstract—The Mo(CO)6-mediated photoinduced ring-opening reactions of adamantane isoxazolines involve novel rearrangement
that provide enaminoketones as major products and b-hydroxy ketones as minor ones; in contrast, only b-hydroxy ketones and
a,b-unsaturated ketones were obtained under thermal condition.
Ó 2006 Elsevier Ltd. All rights reserved.
Isoxazolines are an interesting heterocyclic family
because of their diverse biological applications. When
treated with proper reducing reagents, isoxazolines can
yield c-amino alcohols, b-hydroxy ketones, a,b-unsatur-
ated ketones, and b-hydroxy nitriles;1 therefore, they are
frequently used as precursors in the synthesis of
various acyclic compounds.
isoxazolines to enaminoketones was observed (vide
infra).
The adamantane-isoxazolines 1a–d were synthesized in
moderate yields (Table 1) by refluxing a mixture of
methyleneadamantane and the corresponding nitrile
oxides in dry THF using the reported method of 1,3-
dipolar addition reactions.11 The structures of each ada-
mantane-isoxazolines 1a–d were confirmed by spectral
data, in which 1a has been reported previously.11
Photoinduced ring-opening reactions of five-membered
heterocycles and their subsequent rearrangements have
received much attention both as synthetic intermediates
and in the study of their reaction mechanisms.2–4 The
photoreactions of 2-isoxazolines were studied by Sch-
mid,5 Matsuura,6 and Mukai,7 who showed that N–O
bond fission occurs on irradiation. It has also been re-
ported8 that irradiation of 3-phenyl-2-isoxazoline gave
isomeric 4-phenyl-2-oxazoline, ring opened b-amino
aldehyde and benzonitrile. Nitta et al.9 reported that
the iron carbonyls induced an isoxazoline ring cleavage
under thermal and photochemical conditions.
We performed the ring-opening reaction of 1c initially
under direct photolysis conditions; after irradiation for
16 h, however, only complex mixture of products along
with starting material were observed; therefore, we
sought an alternative approach. In addition to direct
Table 1. Synthesis of substituted adamantane-isoxazolines 1a–d
R
N
Based on these findings and our interest in the studies of
adamantane containing five-membered heterocyclic ring
systems,10 we hereby report the ring-opening reactions
of adamantane-2-spiro isoxazolines under thermal and
photochemical conditions using Mo(CO)6. Interestingly,
a novel photoisomerization reaction of adamantane
O
R
OH
Et3N
+
N
Cl
Dry THF
24 h
1a-d
Yield (%)
Compound
R
1a
1b
1c
1d
Phenyl
p-Tolyl
p-Anisyl
59
55
52
58
Keywords: Adamantane isoxazolines; Photorearrangement; Isomeriza-
tion; Enaminoketones.
*
Corresponding author. Tel.: +886 3 5131517; fax: +886 3 5723764;
e-mail: wschung@cc.nctu.edu.tw
5-Chlorofuran-2-yl
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.07.156

7180
A. Senthilvelan et al. / Tetrahedron Letters 47 (2006) 7179–7183
photolysis, several other methods are known for achiev-
ing N–O bond cleavage in an isoxazoline ring, including
reduction with Raney Ni,12 LiAlH4,13 H2/Pd–C,14
TiCl3,15 SmI2,16 and Mo(CO)6.17 Among these methods,
the Mo(CO)6-mediated ring opening of isoxazolines
appears to be the most efficient one. To the best of
our knowledge, Mo(CO)6-mediated ring-opening reac-
tions of adamantane isoxazolines have not been
reported previously.
and we confirmed its structure through X-ray crystallo-
graphy (Fig. 1).19
It is noteworthy that the enaminoketone 4a has been re-
ported previously by Eguchi and co-workers to arise
through an interesting rearrangement that occurred
from the unstable adduct of aldonitrone and phenylacet-
ylene.20 Our spectral data of 4a–d support the previous
structural assignment. We also performed the ring-open-
ing reactions of 1a–d with Mo(CO)6 under thermal con-
ditions to determine whether the enaminoketones 4a–d
are also obtained thermally. When we reacted 1a with
Mo(CO)6 (3.5 equiv) in CH3CN/H2O at 80 °C, we ob-
tained only the a,b-unsaturated ketone 3a in 29% yield.
Under the same reaction conditions, 1b gave 3b in 49%
yield; in contrast, cycloadduct 1c afforded both the b-
hydroxyketone 2c and the a,b-unsaturated ketone 3c
in 44% and 31% yields, respectively. Cycloadduct 1d
gave 2d in 23% yield (Table 3).21 In none of these cases
did we observe even a trace amount of the correspond-
ing enaminoketone.
Table 2 presents the products and yields of the
Mo(CO)6-mediated photochemical cleavages of the ada-
mantane isoxazolines 1a–d. The expected b-hydroxy-
ketones 2b–d and the a,b-unsaturated ketone 3a were
obtained as minor products (<18%); surprisingly, unex-
pected novel photorearrangements occurred to give the
ring-expanded enaminoketones 4a–d as major products
(30–59% yields). For example, the irradiation (254 nm,
Rayonet) of 1a (R = Ph) in the presence of 1.5 equiv
of Mo(CO)6 in acetonitrile/water gave enaminoketone
4a in 58% yield and a,b-unsaturated ketone 3a in 10%
yield (entry 1, Table 2).18
In order to extend the scope of this novel photore-
arrangement with other sprio systems, the ring-opening
reaction of isoxazoline-5-spiro cyclobutane 522 was car-
ried out. Irradiation of 5 with Mo(CO)6 (1.5 equiv) in
wet acetonitrile (Scheme 1) using 254 nm for 3 h gave
the expected enaminoketone 6 and b-hydroxy ketone 7
in 32% and 15% yield, respectively. Whereas thermal
reaction of 5 in wet acetonitrile containing Mo(CO)6
(3.5 equiv) for 24 h gave only 7 (30%) with recovery of
5 (60%). No trace of spiro ring opened or rearranged
product was observed in this condition (Scheme 1).
Although we eventually confirmed the structures of the
photoproducts 2b–d, 3a, and 4a–d spectroscopically,
the determination of the major products was not
straightforward. For example, in the 1H NMR
spectrum of 4c, a broad singlet appears at d 11.8, which
is quite unusual for phenyl or adamantyl protons; we as-
sign this signal to the enamine NH proton. In addition,
a vinylic CH proton appears as a broad singlet at d 5.6.
It is noteworthy that these signals for the vinyl CH and
enamine NH protons disappeared upon the addition of
D2O. The 13C NMR spectrum of 4c displays the charac-
teristic signals of a carbonyl carbon atom at d 187.4, a
quaternary enamino carbon atom [NH(CHR2)C@CH–]
at d 174.6, and a vinylic CH carbon atom at d 89.3.
The mass spectrum of 4c exhibits the molecular ion at
m/z 297, the same mass as that of its starting material
1c. This finding implies that product 4c is a geometrical
isomer of 1c, that is, no net addition or fragmentation
occurred during photolysis. Taken together, these spec-
tral data of 4c are consistent with the enaminoketone
structure. Gratifyingly, 4b is a crystalline compound
The structures of compounds 6 and 7 were confirmed by
spectral data (see Supplementary data). From the for-
mation of enaminoketone 6 it is clear that, in addition
to the N–O bond cleavage of the isoxazoline ring, C1–
C2 bond cleavage of spiro cyclobutane ring was also in-
volved in the photolysis of 5 mediated by Mo(CO)6. The
rearrangement of isoxazoline-5-spiro cyclobutanes22 and
cyclopropanes,23 via N–O bond cleavage, under flash
vacuum pyrolysis conditions and irradiation conditions
has already been reported; however, their observed
products are different from ours. Mo(CO)6 mediated
ring-opening reaction of isoxazoline-5-spiro cyclopro-
pane to enaminoketone has also been reported.18a
Table 2. Mo(CO)6-Mediated photochemical ring-opening reactions of
adamantane-isoxazolines
R
R
R
O
O
H
hν
O
H
OH
CH3CN/ H2O
NH
+
+
1a-d
Mo(CO)6
4a-d
3a
2b-d
Compound
R
2 Yield 3 Yield 4 Yield
(%)a
(%)a
(%)a
1a
1b
1c
1d
Phenyl
p-Tolyl
p-Anisyl
—
12
18
10
—
—
—
58
59
30
30
5-Chlorofuran-2-yl 15
a Isolated yields based on recovered starting materials.
Figure 1. ORTEP plot of the solid state structure of 4b.

A. Senthilvelan et al. / Tetrahedron Letters 47 (2006) 7179–7183
7181
Table 3. Mo(CO)6-Mediated thermal ring-opening reactions of
adamantane-isoxazolines
R
R
O
hν
H
O
+
OH
CH3CN/ H2O
O
O
1a-d
+
OH
9 (47%)
+
OH
10 (19%)
Mo(CO)6
80 oC
O
N
O
Δ
9
10
(34%)
8
80 oC
(62%)a
3a-c
2 Yield (%)a 3 Yield (%)a
2c-d
Compound
R
Scheme 2. Mo(CO)6-Mediated ring-opening reactions of isoxazoline 8.
(aIsolated yield based on recovered starting material.)
1a
1b
1c
1d
Phenyl
p-Tolyl
p-Anisyl
—
—
44
29
49
31
—
5-Chlorofuran-2-yl 23
a Isolated yields based on recovered starting material.
Mo(CO)5
Mo(CO)5
R
R
R
N
N
NH
O
O
O
hν
hν/ or Δ
1
Mo(CO)6
CH3CN/H2O
O
C
A
B
OH
hν
+
NH2
O
N
O
R
H2O
NH
OH
O
6
(32%)
(15%)
7
R
NH
H2O
2
5
4
7
+
80 oC
(30%)a
(60%)
5
Scheme 1. Mo(CO)6-Mediated ring-opening reactions of isoxazoline 5.
(aIsolated yield based on recovered starting material.)
E
D
Scheme 3. A plausible mechanism of the Mo(CO)6-Mediated ring
opening reactions of 1.
Further, we investigated the ring-opening reaction of
3,5-disubstituted isoxazoline 8 (containing no 5-spiro
group) using Mo(CO)6. Compound 8 was synthesized
by 1,3-dipolar cycloaddition reaction of 1-allyloxy-4-
tert-butyl benzene with phenyl nitrile oxide, using the
reported method.11 The reaction of 8 with Mo(CO)6
(1 equiv) in CH3CN/H2O, under photochemical condi-
tion for 2 h gave the expected b-hydroxy ketone 9 in
47% yield, in addition to cleaved t-butyl phenol 10
(19% yield) (Scheme 2). Thermal ring-opening reaction
of 8 with Mo(CO)6 (3 equiv) under similar condition
for 36 h also gave b-hydroxy ketone 9 in 62% yield with
recovered 10 (34% yield). The structures of compounds
8–10 were confirmed by spectral data. Furthermore,
compound 10 was compared with the authentic sample.
water complex B gave b-iminoalcohol E, which hydro-
lyzes subsequently to form b-hydroxyketone 2. Similar
mechanisms for the formation of b-hydroxyketones
from isoxazolines under thermal9,24 and photochemical9
reaction conditions have been reported previously. The
photochemical formation of 4 came from complex A25
via the aziridine intermediates D (itself obtained from
complex B via C26) and was followed by a homologous
Beckmann rearrangement.27 Although such a rearrange-
ment may seem strange, a related but different rear-
rangement from an adamantane oxaziridine inter-
mediate to an amide has been reported.28
From these observations, it is clear that the ring-opening
reactions of isoxazolines 1a–d, 5 and 8 were mediated by
Mo(CO)6 under both the reaction conditions. The read-
ily occurred rearrangement of isoxazolines 1a–d and 5 to
the corresponding enaminoketones 4a–d and 6 under
photolysis is mainly due to the 5-spiro substituents: ada-
mantane and cyclobutane moieties.
In summary, we report here a convenient method for the
Mo(CO)6-mediated ring-opening reactions of adaman-
tane-2-spiro isoxazolines under photochemical and ther-
mal conditions. This cycloaddition-cleavage protocol
provides a novel isomerization pathway for the synthesis
of substituted enaminoketones under photochemical
conditions.29
Based on our experimental results and literature evi-
dences, we proposed a plausible mechanism for the for-
mation of b-hydroxyketones 2 and the enaminoketones
4 (Scheme 3). Complex A, formed initially between the
isoxazoline and Mo(CO)6, undergoes N–O bond cleav-
age to provide a nitrene complex B. In the presence of
Acknowledgements
We thank the National Science Council (NSC) of
Taiwan, ROC for financial support.

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A. Senthilvelan et al. / Tetrahedron Letters 47 (2006) 7179–7183
0.1572). Crystallographic data for the structure in this
Supplementary data
letter have been deposited with the Cambridge Crystallo-
graphic Data Centre as supplementary publication num-
ber CCDC 299771. Copies of the data can be obtained,
free of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK [fax: +44 (0) 1223 336033 or
e-mail: data_request@ccdc.cam.ac.uk].
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2006.07.156.
20. Yu, Y.; Ohno, M.; Eguchi, S. Tetrahedron 1993, 49, 823–
832.
References and notes
21. In addition to Mo(CO)6-mediated ring-cleavage, we also
attempted to cleave cycloadduct 1a using Zn/AcOH,
LiAlH4 and Raney-Ni. In each of these cases, only
complex mixtures of products were observed without
any major product.
22. Goti, A.; Brandi, A.; De Sarlo, F.; Guarna, A. Tetra-
hedron 1992, 48, 5283–5300, and references cited therein.
23. Guarna, A.; Brandi, A.; De Sarlo, F.; Goti, A.; Pericciuoli,
F. J. Org. Chem. 1988, 53, 2426–2429.
1. (a) Kozikowski, A. P. Acc. Chem. Res. 1984, 17, 410–416;
(b) Easton, C.; Hughes, C. M. M.; Savage, G. P.; Simpson,
G. W. Adv. Heterocycl. Chem. 1994, 60, 261–327.
2. Lablache-Combier, A. In Photochemistry of Heterocyclic
Compounds; Buchardt, O., Ed.; Wiley: New York, 1976.
3. Padwa, A. In Rearrangements in Ground and Excited
States; de Mayo, P., Ed.; Academic Press: New York,
1980; Vol. 3, p 501.
4. (a) Lablache-Combier, A. In CRC Handbook of Organic
Photochemistry and Photobiology; Horspool, W., Song,
P.-S., Eds.; CRC: Boca Raton, FL, 1995; pp 1063–1120;
(b) Buscemi, S.; Pace, A.; Pibiri, I.; Vivona, N. J. Org.
Chem. 2002, 67, 6253–6255; (c) Buscemi, S.; D’Auria, M.;
Pace, A.; Pibiri, I.; Vivona, N. Tetrahedron 2004, 60,
3243–3249.
5. Claus, P.; Gilgen, P.; Hansen, H.-J.; Heimgartner, H.;
Jackson, B.; Schmid, H. Helv. Chim. Acta 1974, 57, 2173–
2192.
24. Baraldi, P. G.; Barco, A.; Benetti, S.; Manfredini, S.;
Simoni, D. Synthesis 1987, 276–278.
25. Nitta, M.; Kobayashi, T. J. Chem. Soc., Perkin Trans 1
1985, 1401–1406.
26. Combier, A. L.; Pollet, A. Tetrahedron 1972, 28, 3141–
3151.
27. Cunningham, M.; Lim, L. S. N.; Just, G. Can. J. Chem.
1971, 49, 2891–2896.
28. Okada, K.; Saito, Y.; Oda, M. J. Chem. Soc., Chem.
Commun. 1992, 1731–1732.
6. Itoh, Y.; Matsuura, T. Tetrahedron 1975, 31, 1373–1380.
7. (a) Mukai, T.; Sukawa, H. Tetrahedron Lett. 1973, 1835–
1838; (b) Seshimoto, O.; Kumagai, T.; Shimizu, K.;
Mukai, T. Chem. Lett. 1977, 1195–1198; (c) Saiki, H.;
Miyashi, T.; Mukai, T.; Ikegami, Y. Tetrahedron Lett.
1977, 4619–4622.
29. Procedures for the photochemical ring-opening reaction of
1b: An acetonitrile (18 mL) solution of isoxazoline 1b
(0.09 mmol) and molybdenum hexacarbonyl (0.135 mmol)
containing water (three drops) was irradiated by using a
Rayonet multilamp reactor (254 nm) for 4 h. The solvent
was removed under reduced pressure and the residue was
purified by column chromatography to give 1b (20%), in
addition to 2b and 4b (yields are summarized in Table 2).
Procedures for the thermal ring-opening reaction of 1c: A
mixture of 1c (0.105 mmol) and molybdenum hexacar-
bonyl (0.105 mmol) in acetonitrile (18 mL) containing
water (three drops) was refluxed at 80 °C for 48 h. After
removing the solvent, the residue was purified over silica
gel column to give 1c (43%), in addition to 2c and 3c.
Spectral data of some selected compounds: For 2b: colorless
8. Kumagai, T.; Shimizu, K.; Kawamura, Y.; Mukai, T.
Tetrahedron 1981, 37, 3365–3376.
9. Nitta, M.; Kobayashi, T. J. Chem. Soc., Perkin Trans 1
1984, 2103–2108, and references cited therein.
10. (a) Tsai, T.-L.; Chen, W.-C.; Yu, C.-H.; le Noble, W. J.;
Chung, W.-S. J. Org. Chem. 1999, 64, 1099–1107; (b) Chu,
J.-H.; Li, W.-S.; Chao, I.; Chung, W.-S. Tetrahedron 2004,
60, 9493–9501.
11. Chung, W.-S.; Tsai, T.-L.; Ho, C.-C.; Chiang, M. Y. N.; le
Noble, W. J. J. Org. Chem. 1997, 62, 4672–4676.
12. Curran, D. P. J. Am. Chem. Soc. 1983, 105, 5826–5833.
13. Ja¨ger, V.; Colinas, P. A. In The Chemistry of Heterocyclic
Compounds; John Wiley & Sons: New York, 2002; Vol. 59,
Chapter 6.
14. Asaoka, M.; Mukuta, T.; Takei, H. Tetrahedron Lett.
1981, 22, 735–738.
15. Andersen, S. H.; Sharma, K. K.; Torssell, K. B. G.
Tetrahedron 1983, 39, 2241–2245.
16. Bode, J. W.; Carreira, E. M. Org. Lett. 2001, 3, 1587–
1590.
17. (a) Tranmer, G. K.; Tam, W. Org. Lett. 2002, 4, 4101–
4104; (b) Gelabert, L. I.; Fascio, M. L.; D’Accorso, N. B.
J. Heterocycl. Chem. 2003, 40, 341–344.
1
solid; mp 88–90 °C; Rf = 0.60 (hexane/EtOAc = 5/1); H
NMR (CDCl3, 300 MHz) d 1.48–1.91 (m, 12H), 2.29–2.35
(m, 2H), 2.42 (s, 3H, CH3), 3.36 (s, 2H, 40-CH2), 4.42 (s,
1H, OH), 7.26–7.29 (m, 2H, ArH), 7.85–7.89 (m, 2H,
ArH); 13C NMR (CDCl3, 125 MHz) d 22.3 (CH3), 28.0
(CH), 28.6 (CH), 33.2 (CH2), 35.4 (CH2), 37.5 (CH), 40.0
(CH2), 44.3 (CH2), 75.6 (Cq), 129.1 (CH), 130.0 (CH),
135.8 (Cq), 145.1 (Cq), 202.7 (Cq); MS (EI) m/z (%): 284
(M+, 5), 266 (40), 265 (50), 251 (20), 134 (50), 119 (100), 91
(50); HRMS calcd for C19H24O2 284.1776; found 284.1780.
For 3c: colorless solid; mp 97–99 °C; Rf = 0.63 (hexane/
EtOAc = 5/1); 1H NMR (CDCl3, 300 MHz) d 1.88–2.05
(m, 12H), 2.54 (br s, 1H), 3.87 (s, 4H), 6.56 (s, 1H), 6.91–
6.95 (m, 2H, ArH), 7.94–7.98 (m, 2H, ArH); 13C NMR
(CDCl3, 75.4 MHz) d 28.0 (CH), 33.6 (CH), 36.9 (CH2),
39.3 (CH2), 40.4 (CH2), 41.8 (CH), 55.4 (CH3), 113.5
(CH), 114.3 (CH), 130.5 (CH), 132.4 (Cq), 162.9 (Cq),
170.4 (Cq), 191.2 (Cq); MS (EI) m/z (%): 283 (M++1, 5),
282 (M+, 40), 254 (10), 251 (30); HRMS calcd for
C19H22O2 282.1620; found 282.1628.
18. The recovery of starting material is commonly observed in
the ring-opening reaction of isoxazolines using Mo(CO)6,
see: (a) Guarna, A.; Guidi, A.; Goti, A.; Brandi, A.; De
Sarlo, F. Synthesis 1989, 175–178; (b) Bode, J. W.;
Carreira, E. M. J. Org. Chem. 2001, 66, 6410–6424.
19. Crystal structure data for 4b: C19H23NO, M =
˚
281.38, triclinic, a = 9.8122(1) A, a = 106.8226(9)°,
For 4c: colorless solid; mp 96–98 °C; Rf = 0.25 (hexane/
EtOAc = 5/1); 1H NMR (CDCl3, 300 MHz) d 1.72–1.97
(m, 10H), 2.09 (br s, 2H), 2.55 (br s, 1H), 3.66 (br s, 1H),
3.81 (s, 3H, OCH3), 5.59 (s, 1H), 6.88 (d, J = 8.7 Hz, 2H,
ArH), 7.84 (d, J = 8.7 Hz, 2H, ArH), 11.83 (br s, 1H,
NH); 13C NMR (CDCl3, 75.4 MHz) d 27.0 (CH), 32.9
˚
˚
b = 12.9988(2) A, b = 101.9080(8)°, c = 13.1727(2) A,
3
˚
c = 94.8232(9)°, V = 1554.97(4) A , T = 295(2) K, space
group Pꢀı, Z = 4, l = 0.073 mmꢀ1, 29,260 reflections col-
lected (R1 = 0.0495, wR2 = 0.1329), 7122 independent
reflections
(R(int) = 0.0393,
R1 = 0.0879,
wR2 =

A. Senthilvelan et al. / Tetrahedron Letters 47 (2006) 7179–7183
7183
(CH2), 34.9 (CH2), 36.0 (CH2), 40.4 (CH), 48.9 (CH), 55.3
(CH3), 89.3 (CH), 113.3 (CH), 128.6 (CH), 133.4 (Cq),
161.4 (Cq), 174.6 (Cq), 187.4 (Cq); MS (EI) m/z (%): 297
(M+, 15), 296 (100), 280 (10), 190 (10), 162 (5), 135 (18), 91
(7); HRMS calcd for C19H23NO2 297.1729; found
297.1715.