Synthesis of heterocycles containing an N-O bond by ring-closing metathesis of dienes tethered by hydroxylamine

Article abstract of DOI:10.1055/s-2003-39319

The dienes tethered by hydroxylamine were efficiently cyclized into 6- to 10-membered heterocycles containing an N-O bond by catalytic ring-closing metathesis.

Full text of DOI:10.1055/s-2003-39319

LETTER
1043
Synthesis of Heterocycles Containing an N-O Bond by Ring-Closing Meta-
thesis of Dienes Tethered by Hydroxylamine
Synthesis of
Heter
o
ocycles Cont
u
aining anN
-
n
O
B
ond g-Keun Yang, Jinsung Tae*
Department of Chemistry, Yonsei University, Seoul 120-749, Korea
Fax +82(2)3647050; E-mail: jstae@yonsei.ac.kr
Received 15 March 2003
also prepared from 5 with acryloyl chloride in the pres-
ence of triethylamine.
Abstract: The dienes tethered by hydroxylamine were efficiently
cyclized into 6- to 10-membered heterocycles containing an N-O
bond by catalytic ring-closing metathesis.
The substrates 3a–i were reacted with 10 mol% Grubbs’
catalyst (7) under refluxing dichloromethane solution
(Scheme 3). The results of the metathesis reactions were
summarized in Table 1. We first tried the synthesis of 1,2-
oxazine and 1,2-oxazepine. The O,N-Diallyl-hydroxy-
lamine (3a) cyclized smoothly into the 1,2-oxazine (8a) in
less than 4 hours in 93% yield (Table 1, entry 1). The next
homologues (3b–c) required a little longer reaction times
(24 h and 14 h respectively), however, produced the 1,2-
oxazepines (8b–c) in good yields (Table 1, entries 2 and
3).
Key words: cyclizations, heterocycles, metathesis, ring closure, ru-
thenium
Heterocyclic compounds containing an N-O bond are
valuable synthetic intermediates. The 1,2-oxazines (6-
membered rings) are easily accessible by Diels–Alder re-
actions of nitroso compounds1 and by many other synthet-
ic methods.2 But the synthesis of medium rings of this
class are still difficult. Recently, ring-closing metathesis
(RCM)3 have been applied extensively in organic synthe-
sis, but little attention has been given to the synthesis of
heterocycles containing the 1,2-oxaza group. Only few
references were reported in the literature concerning the
synthesis of 1,2-oxazines and 1,2-oxazepines by RCM.4
Herein, we report a general synthetic method of 6- to 10-
membered heterocycles containing an N-O bond (1) by
ring-closing metathesis of alkenes tethered by hydroxyl-
amine (3) as shown in Scheme 1.
NaH, THF
O
m
BocNHOH
BocNH
Br
m
4
5
NaH, THF
Cl
Et3N
CH2Cl2
Br
n
O
O
m
O
m
O
BocN
Diels-Alder
+
BocN
n
N
(m, n = 1)
R
O
3a–i
6a–c
2
O
N
m
n
Scheme 2
R
1
PCy3
Cl
Cl
RCM
O
m
n
Ru
7
(m, n = 1, 2, 3)
N
Ph
O
N
m
n
R
PCy3
O
N
m
3
Boc
(10 mol %)
CH2Cl2
45 °C
Boc
n
8a–i
3a–i
Scheme 1
(m, n = 1, 2, 3)
The starting dienes (3a–i) were prepared by double alkyl-
ation reactions of the N-Boc-hydroxylamine (4) with suit-
able bromoalkenes under the standard alkylation
conditions (Scheme 2). The alkylations of 4 with the first
bromoalkenes afforded the O-alkylation products (5)
which were further reacted with the second bromoalkenes
to give 3a–i. The N-alkenyloxyacrylamides (6a–c) were
Scheme 3
We then moved to the synthesis of medium rings. The
synthesis of 1,2-oxazocines (8d–f, 8-membered rings),
from the corresponding substrates 3d–f required high di-
lution conditions (0.006 M) for the best cyclization yields
(Table 1, entry 4–6). The product yields (82–90%) were
good under the optimized conditions. Interestingly, the
positions of the double bond in 1,2-oxazocine products af-
fected little to the metathesis reactions. Treatments of the
Synlett 2003, No. 7, Print: 02 06 2003.
Art Id.1437-2096,E;2003,0,07,1043,1045,ftx,en;U05203ST.pdf.
© Georg Thieme Verlag Stuttgart · New York

1044
Y.-K. Yang, J. Tae
LETTER
next homologues 3g and 3h with Grubbs’ catalyst (7) af- To see the effects of the protecting groups in the metathe-
forded the 1,2-oxazonines (8g and 8h, 9-membered rings) sis reactions, the N-benzoyl-protected substrates (9a–c)
in 63% and 80% yields (Table 1, entry 7 and 8). Further- were examined (Table 2). In general, N-benzoyl-protect-
more, the metathesis approach can even be applicable for ed substrates (9a–c) cyclized faster than the correspond-
the preparation of a 1,2-oxazecine (10-membered ring) as ing N-Boc-protected ones (3a, 3b, and 3d) and delivered
exemplified in the synthesis of 8i (Table 1, entry 9).
the cyclized products in higher yields.
According to the literature surveys, only few examples of
the preparation of 1,2-oxazocines were known,5 however,
no metathesis approaches to this class of heterocycles
were reported. Surprisingly, the related 9- and 10-mem-
bered heterocycles are, to our knowledge, unprecedented
structures.6
Table 2 Metathesis of N-Benzoyl-protected Substratesa
O
m
O
N
7
m
N
CH2Cl2
Bz
Bz
10a–c
9a–c
Entry Substrate
Conditions
Product
Yields (%)b
98
Table 1 Metathesis of N-Boc-protected Substratesa
1
2
9a, m = 1
9b, m = 2
3 h
0.02 M
O
BzN
Entry Substrate
Conditions Product
Yields (%)b
93
10a
1
2
3a, m = 1
n = 1
4 h
0.02 M
11 h
0.02 M
96
90
O
O
BocN
BzN
8a
10b
3b, m = 2
24 h
0.02 M
84
90
82
O
3
9c, m = 3
13 h
0.006 M
n = 1
O
BocN
BzN
8b
10c
3
4
3c, m = 1
n = 2
14 h
0.02 M
O
a Conditions: 10 mol% 7, CH2Cl2, 45 °C.
BocN
b Isolated yields.
8c
3d, m = 3
20 h
0.006 M
O
Next, the N-alkenyloxyacrylamides (6a–c) were subject-
ed to the metathesis conditions (Table 3). Cyclizations of
the substrate 6a and 6b produced the corresponding 3-
oxo-1,2-oxazine 11a (88%) and 3-oxo-1,2-oxazepine 11b
(84%) respectively (Table 3, entries 1 and 2). The next ho-
mologue 6c, however, was unreactive under the reaction
conditions and the starting material was recovered
(Table 3, entry 3). To our surprise, only a few patents of
the synthesis of 3-oxo-3,6-dihydro-[1,2]oxazine were
known7 and none of the 3-oxo-6,7-dihydro-3H-[1,2]ox-
azepine structures were reported in the literature.6
n = 1
BocN
8d
5
6
7
3e, m = 2
n = 2
14 h
0.006 M
90
85
63
O
BocN
8e
3f, m = 1
n = 3
18 h
0.006 M
O
BocN
8f
3g, m = 3
n = 2
26 h
0.005 M
In conclusion, the ring-closing metathesis was successful-
ly applied for the synthesis of small and medium hetero-
cycles containing an N-O bond. We were able to
synthesize several unprecedented structures, such as 1,2-
oxazonine, 1,2-oxazecine, and 3-oxo-6,7-dihydro-3H-
[1,2]oxazepine.
O
BocN
8g
8
9
3h, m = 2
n = 3
23 h
0.005 M
80
88
O
BocN
General procedure for the ring-closing metathesis: A so-
lution of 3h (60 mg, 0.24 mmol) and Grubbs’ catalyst 7
(10 mg, 0.012 mmol) in CH2Cl2 (48 mL) was refluxed at
45 °C for 7 h under N2 and treated with another portion of
Grubbs’ catalyst 7 (10 mg, 0.012 mmol). The reaction
mixture was refluxed for a total of 23 h before cooled to
room temperature. The solvent was removed under re-
duced pressure and the product mixture was column chro-
matographed on silica gel (elution with 5% ethyl acetate
in hexanes) to give 44 mg (80%) of 8h.8
8h
3i, m = 3
n = 3
17 h
0.005 M
O
BocN
8i
a Conditions: 10 mol% 7, CH2Cl2, 45 °C.
b Isolated yields.
Synlett 2003, No. 7, 1043–1045 ISSN 1234-567-89 © Thieme Stuttgart · New York

LETTER
Synthesis of Heterocycles Containing an N-O Bond
1045
Table 3 Metathesis of N-Alkenyloxy-acrylamidesa
References
(1) For reviews on the synthesis of 1,2-oxazines by Diels–Alder
reactions, see: (a) Streith, J.; Defoin, A. Synlett 1996, 198.
(b) Denmark, S. E.; Thorarensen, A. Chem. Rev. 1996, 96,
137. (c) Vogt, P. F.; Miller, M. J. Tetrahedron 1998, 54,
1317.
O
N
m
O
N
7
m
CH2Cl2
Boc
Boc
O
O
6a–c
11a–c
(2) (a) Peglow, T.; Blechert, S.; Streckhan, E. Chem. Commun.
1999, 433. (b) Schade, W.; Reissig, H.-U. Synlett 1999,
632. (c) Shin, I.; Lee, M.-R.; Lee, J.; Jung, M.; Lee, W.;
Yoon, J. J. Org. Chem. 2000, 65, 7667. (d) Koenig, S. G.;
Leonard, K. A.; Lowe, R. S.; Austin, D. J. Tetrahedron Lett.
2000, 41, 9393. (e) Ishikawa, T.; Senzaki, M.; Kadoya, R.;
Morimoto, T.; Miyake, N.; Izawa, M.; Saito, S. J. Am. Chem.
Soc. 2001, 123, 4607.
Entry Substrate
Conditions Product
Yields (%)b
88
1
2
6a, m = 1
6b, m = 2
3 h
0.02 M
O
BocN
O
11a
(3) For reviews on metathesis, see: (a) Chang, S.; Grubbs, R. H.
Tetrahedron 1998, 54, 4413. (b) Fürstner, A. Angew. Chem.
Int. Ed. 2000, 39, 3012.
11 h
0.02 M
84
O
BocN
(4) (a) Koide, K.; Finkelstein, Z. B.; Verdine, G. L. J. Am.
Chem. Soc. 2001, 123, 398. (b) Miyabe, H.; Yoshida, K.;
Matsumura, A.; Yamauchi, M.; Takemoto, Y. Synlett 2003,
567.
(5) (a) Hu, J.; Miller, M. J. Tetrahedron Lett. 1995, 36, 6379.
(b) Oyama, H.; Morita, T.; Ono, T. Jap. Pat. Appl., JP
02229175, 1990; Chem. Abstr. 1991, 114, 81858.
(c) Carruthers, W.; Johnstone, R. A. W. J. Chem. Soc. 1965,
1653.
O
11b
3
6c, m = 3
13 h
0.006 M
0c
O
BocN
O
11c
a Conditions: 10 mol% 7, CH2Cl2, 45 °C.
b Isolated yields.
(6) The Scifinder searches for 1,2-oxazonine, 1,2-oxazecine,
and 3-oxo-6,7-dihydro-3H-[1,2]oxazepine hit no known
related compounds.
c Starting material was recovered.
(7) (a) Wolfe, S.; Shustov, G. P. C. T. Int. Appl., WO 0311298,
2003; Chem. Abstr. 2003, 138, 153829. (b) Zong, K.; Shin,
S. I.; Kim, H. K.; Kim, H. R.; Jeon, D. J.; Ryu, E. K. Bull.
Kor. Chem. Soc. 1999, 20, 965.
Acknowledgment
This work was supported by a Korea Research Foundation Grant
(KRF-2002-003-C00080).
(8) Spectral data for 8h: colorless oil; Rf = 0.5 (hexane/EtOAc =
2:1); 1H NMR (250 MHz, CDCl3): d = 5.64–5.53 (m, 2 H),
4.10–4.02 (t, J = 5.6 Hz, 2 H), 3.44–3.35 (t, J = 6.0 Hz, 2 H),
2.48–2.32 (m, 2 H), 2.36–2.24 (m, 2 H), 1.79–1.68 (m, 2 H),
1.49 (s, 9 H); 13C NMR (62.9 MHz, CDCl3): d = 158.3,
130.8, 128.3, 81.2, 72.6, 52.7, 28.6, 26.2, 25.9, 23.0; IR
(film, cm–1) 2971, 2931, 1729, 1709, 1459, 1393, 1368,
1337, 1164, 1123, 1082; MS: m/z (rel. intensity): 18 (7), 29
(10), 41 (20), 57 (100), 69 (7), 83 (8), 96 (15), 110 (3), 127
(10), 207 (M+, 1).
Synlett 2003, No. 7, 1043–1045 ISSN 1234-567-89 © Thieme Stuttgart · New York