Ring-Closing Metathesis of Enynes Tethered by an N-O Bond: Synthesis of 1,2-Oxaza Polycycles by Diels-Alder Reaction of the Ring-Closing Metathesis Products

Article abstract of DOI:10.1055/s-2003-42038

Ring-closing metathesis (RCM) reaction of enynes tethered by an N-O bond produced 6- to 8-membered 1,2-oxaza heterocyclic compounds in high yields. Diels-Alder reaction of the cyclic 1,3-dienes with various dienophiles afforded bi- or tri-cyclic compounds

Full text of DOI:10.1055/s-2003-42038

LETTER
2017
Ring-Closing Metathesis of Enynes Tethered by an N–O Bond: Synthesis of
1,2-Oxaza Polycycles by Diels–Alder Reaction of the Ring-Closing Metathesis
Products
R
ing-Closing Meta
o
thesis of En
u
ynes Tethere
n
d by an
N
–O
g
B
ond -Keun Yang, Jinsung Tae*
Center for Bioactive Molecular Hybrids (CBMH), Department of Chemistry, Yonsei University, Seoul 120-749, South Korea
Fax +82(2)3647050; E-mail: jstae@yonsei.ac.kr
Received 8 August 2003
alkylation sequence afforded enynes 8a–e. The substrates
Abstract: Ring-closing metathesis (RCM) reaction of enynes teth-
6a–e were reacted with 10 mol% Grubbs’ catalyst (9) in a
ered by an N–O bond produced 6- to 8-membered 1,2-oxaza hetero-
refluxing CH2Cl2 solution and the results of the metathesis
cyclic compounds in high yields. Diels–Alder reaction of the cyclic
reactions were summarized in Table 1. The 1,7- and 1,8-
enynes (6a–d) cyclized to 6- and 7-membered cyclic com-
pounds 10a–d in high yields (Table 1, entries 1–4). The
next homologue, 1,9-enyne (6e) required a little longer
reaction times (34 h) and highly dilution conditions (0.007
M) to produce 8-membered ring 10e in 76% yield
(Table 1, entry 5).
1,3-dienes with various dienophiles afforded bi- or tri-cyclic com-
pounds efficiently.
Key words: cyclizations, Diels–Alder reaction, enynes, metathesis,
ruthenium
In recent years, ring-closing enyne metathesis1–3 has been
recognized as a powerful method in organic synthesis.
Especially, the RCM followed by Diels–Alder reaction
sequence has been extensively utilized in the rapid gener-
ation of molecular complexities.2a,d,e Although several
temporarily tethered enynes, such as silylether-,4 boronic
ester-,5 and ester-tethered enynes,6 were successfully in-
troduced in the enyne metathesis, hydroxylamine-tethered
enyne metathesis has not been studied up to now. The
N–O linkage could be reductively cleaved to generate
amino alcohol functionalities7 which are synthetically
valuable. As a part of our research program directed to-
ward diversity-oriented synthesis8 of heterocyclic com-
pounds, we have recently reported efficient synthesis of 6-
to 10-membered 1,2-oxaza heterocyclic compounds by
ring-closing metathesis of dienes tethered by an N–O
bond.9,10 Herein, we report the first ring-closing metathe-
sis of enynes tethered by hydroxylamine 1 to afford 1,2-
oxaza heterocycles 2. Subsequent Diels–Alder reaction of
cyclic 1,3-dienes 2 could generate polycyclic compounds
3 smoothly as shown in Scheme 1.
O
n
O
n
b)
a)
b)
BocN
BocNH
R
5
6a–e
BocNHOH
4
a)
BocNH
O
BocN
O
n
n = 1, 2, 3
R
R
R = H, CH3
7
8a–e
Scheme 2 Conditions: a) NaH (1.2 equiv), n-Bu4NI (catalyst), THF,
Br(CH2)n–CH=CH2 (1.1 equiv), 25 °C; b) NaH (1.2 equiv), n-Bu4NI
(catalyst), THF, BrCH2CCR (1.1 equiv), 25 °C
Table 1 Ring-Closing Enyne Metathesis of 6a
PCy3
Cl
Ru
Cl
O
Ph
n
PCy3
O
n
BocN
BocN
9
R
R
6a–e
10a–e
Entry Substrate
Conditionsb
Product Yield (%)c
A
X
1
2
3
4
5
6a R = H,
n = 1
4 h
0.02 M
10a
92
94
87
90
76
B
O
N
PG
O
N
PG
O
N
PG
D-A
X
RCM
R
6b R = CH3,
n = 1
8 h
0.02 M
10b
10c
10d
10e
R
R
2
3
1
Scheme 1
6c R = H,
n = 2
12 h
0.02 M
The starting enynes (6a–e) were prepared by double alky-
lation reactions of the N-Boc-hydroxylamine (4) with
suitable bromoalkenes and bromoalkynes under the
standard alkylation conditions (Scheme 2). The reverse
6d R = CH3,
n = 2
24 h
0.02 M
6e R = H,
n = 3
34 h
0.007 M
a Conditions: 10 mol% 9, CH2Cl2, 45 °C.
b Reaction time and concentration.
c Isolated yields.
SYNLETT 2003, No. 13, pp 2017–2020
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Advanced online publication: 08.10.2003
DOI: 10.1055/s-2003-42038; Art ID: U16103ST
© Georg Thieme Verlag Stuttgart · New York

2018
Y.-K. Yang, J. Tae
LETTER
Table 3 Diels–Alder Reactions of the Conjugate Dienesa
Product (% yield)b
The analogous substrates 8a–e where nitrogen and oxy-
gen atoms were switched from 6a–e were also suitable for
the cyclization reaction. The yields were uniformly good
(Table 2). Again, 8-membered ring formation was per-
formed under high dilution conditions (Table 2, entry 5).
Entry Diene Dienophile
1
10a
CO2Me
CO2Me
MeO2C
CO2Me
12
O
BocN
Table 2 Ring-Closing Enyne Metathesis of 8a
16 (94)
CO2Me
CO2Me
BocN
O
n
2
10b
12
9
BocN
O
n
O
R
R
BocN
8a–e
11a–e
CH3
17 (96)
Entry Substrate
Conditionsb
Product Yield (%)c
3
4
10c
10d
12
12
CO2Me
CO2Me
1
2
3
4
5
8a R = H,
n = 1
4 h
0.02 M
11a
11b
11c
11d
11e
97
95
90
91
91
O
BocN
8b R = CH3,
n = 1
8 h
0.02 M
18 (90)
CO2Me
O
8c R = H,
n = 2
10 h
0.02 M
BocN
CO2Me
H3C
8d R = CH3,
n = 2
24 h
0.02 M
19 (89)
5
6
10e
11e
12
12
O
8e R = H,
n = 3
10 h
0.007 M
CO2Me
BocN
CO2Me
a Conditions: 10 mol% 9, CH2Cl2, 45 °C.
b Reaction time and concentration.
c Isolated yields.
20 (75)c
BocN
O
CO2Me
CO2Me
With these cyclic 1,3-dienes in hand, we investigated
Diels–Alder reaction of the enyne metathesis products.
First, dimethyl acetylenedicarboxylate (12) was tested as
a dienophile. When a solution of 6-membered cyclic 1,3-
dienes 10a,b was treated with 12 in toluene at 110 °C, Di-
els–Alder adducts 16 and 17 were obtained in 94% and
96% isolated yields, respectively, within 6 hours (Table 3,
entries 1 and 2). The 7-membered dienes 10c,d afforded
the Diels–Alder products 18 and 19 in good yields
(Table 3, entries 3 and 4). The next homologues 10e and
11e afforded 20 and 21 (Table 3, entries 5 and 6). The
product 20 turned out to be an aromatic compound, which
could have resulted from the air-oxidation under the iso-
lation conditions.11 Interestingly, the analogous 8-mem-
bered compound 21 was not oxidized under the same
isolation conditions. Reactions of 10a–c with diethyl
azodicarboxylate (13) afforded bicyclic compounds 22–
24 in good yields (Table 3, entries 7–9). Thus, bicyclic
compounds highly functionalized with N–O and N–N
bonds were synthesized efficiently by this reaction se-
quence. The reaction of N-phenylmaleimide (14) and 11a
produced the tricyclic compound 25 in 91% yield
(Table 3, entry 10).
21 (94)
CO2Et
CO2Et
7
8
10a
10b
EtO2C
N N CO2Et
N
13
O
N
BocN
22 (90)
CO2Et
CO2Et
13
N
O
N
BocN
CH3
23 (92)
9
10c
11a
13
CO2Et
N
O
BocN
N
CO2Et
24 (91)
10
O
N
O
H
H
O
BocN
Ph
H
N
O
14
O
Ph
25 (91)
a Conditions: toluene, 110 °C, 6–9 h.
b Isolated yields.
When 1,4-benzoquinone (15) was used as a dienophile,
tricyclic compounds were obtained as shown in
Scheme 3. However, the compounds isolated from the
reactions of 10a and 10c with 15 were aromatic com-
pounds 26 and 27, respectively. The Diels–Alder products
c Aromatized under the reaction conditions.
Synlett 2003, No. 13, 2017–2020 © Thieme Stuttgart · New York

LETTER
Ring-Closing Metathesis of Enynes Tethered by an N–O Bond
2019
CO2Me
CO2Me
O
CO2Me
CO2Me
a)
2 equiv.
DDQ
O
N
O
O
10 h
28 +
(62%)
O
O
BocN
BocN
BocN
O
16
31 (30%)
10a
26 (74%)
15
4 equiv.
31 (only)
16
O
DDQ
O
O
O
BocN
BocN
1.5 equiv.
DDQ
CO2Me
a)
9 h
CO2Me
CO2Me
O
O
O
BocN
BocN
CO2Me
10c
27 (87%)
32 (83%)
H3C
19
Scheme 3 Conditions: a) toluene, 110 °C.
H3C
+
CO2Me
O
N
aromatized spontaneously under the isolation conditions
as seen in entry 5 of Table 3.
CO2Me
33 (12%)
H3C
The spontaneous oxidations observed in the previous
examples led us to investigate the oxidation of the Diels–
Alder products to the corresponding aromatic com-
pounds.12 The selected 1,4-dienes (16–18) were treated
with 1 equivalent of 2,3-dichloro-5,6-dicyano-1,4-benzo-
quinone (DDQ) in refluxing benzene to afford aromatic
compounds 28–30 in 86–94% yields (Table 4). Oxidation
of 16 with 2 equivalents of DDQ produced 31 (30%) in
addition to 28 (62%). Presumably, Boc group was re-
moved oxidatively after aromatization under the present
reaction conditions (Scheme 4). Compound 16 was com-
pletely converted to 31 by 4 equivalents of DDQ. Similar-
ly, treatment of 7-membered compound 19 with 1.5
equivalents of DDQ afforded 32 (83%) along with 33
(12%).
Scheme 4
action of the metathesis products with dienophiles
produced structurally diverse heterocyclic compounds
efficiently.
General Procedures
For Enyne Metathesis: A solution of 6a (40 mg, 0.19 mmol) and
Grubbs’ catalyst 9 (16 mg, 0.020 mmol) in CH2Cl2 (10 mL) was re-
fluxed at 45 °C for 4 h under N2. The solvent was removed under
reduced pressure and the residue mixture was column chromato-
graphed on silica gel (hexane–EtOAc = 20:1) to give 37 mg (92%)
of 10a.13
For Diels–Alder Reaction: A mixture of 10a (20 mg, 0.090 mmol)
and dimethyl acetylenedicarboxylate (12) (0.014 mL, 0.11 mmol) in
toluene (1.5 mL) was refluxed for 6 h, cooled to r.t., and the solvent
was removed under reduced pressure. The residue was column
chromatographed on silica gel (hexane–EtOAc = 10:1) to give 30
mg (94%) of 16.14
In conclusion, we have demonstrated for the first time that
the hydroxylamine-tethered enyne metathesis is generally
applicable to the synthesis of 6- to 8-membered heterocy-
cles containing a N–O bond. Subsequent Diels–Alder re-
Table 4 DDQ Oxidation of Selected Diels–Alder Productsa
Acknowledgment
Entry
1
Diene
Reaction time (h)
10
Product (% yield) b
This work was supported by a Korea Research Foundation Grant
(KRF-2002-003-C00080).
16
CO2Me
CO2Me
O
BocN
References
28 (88)
CO2Me
CO2Me
(1) For reviews on enyne-metathesis, see: (a) Poulsen, C. S.;
Madsen, R. Synthesis 2003, 1. (b) Mori, M. Top.
Organomet. Chem. 1998, 1, 133.
2
3
17
18
5
O
(2) For recent examples of ring-closing enyne metathesis, see:
(a) Poulsen, C. S.; Madsen, R. J. Org. Chem. 2002, 67,
4441. (b) Stephen, C. J.; Elustondo, F.; Trevitt, G. P.;
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Chem. Commun. 1998, 23, 2629.
BocN
CH3
29 (94)
13
CO2Me
CO2Me
O
BocN
30 (86)
a Conditions: 1 equiv. DDQ, benzene, 80 °C.
b Isolated yields.
(3) For reviews on metathesis, see: (a) Chang, S.; Grubbs, R. H.
Tetrahedron 1998, 54, 4413. (b) Fürstner, A. Angew. Chem.
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Synlett 2003, No. 13, 2017–2020 © Thieme Stuttgart · New York

2020
Y.-K. Yang, J. Tae
LETTER
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(13) Spectral data for 10a: Colorless oil; Rf = 0.5 (silica gel,
hexane–EtOAc = 2:1). IR(film): 1701, 1603, 1394, 1368,
1240, 1163, 1092, 1045 cm–1. 1H NMR (250 MHz, CDCl3):
d = 6.33 (dd, J = 17.8, 10.9 Hz, 1 H), 5.81 (m, 1 H), 5.14 (d,
J = 18.7 Hz, 1 H), 5.08 (d, J = 12.0 Hz, 1 H), 4.51–4.46 (m,
2 H), 4.25–4.20 (m, 2 H), 1.51 (s, 9 H). 13C NMR (62.9 MHz,
CDCl3): d = 155.1, 135.3, 132.4, 124.0, 112.7, 81.9, 68.2,
44.7, 28.5. HRMS: m/z (M+) calcd for C11H17NO3: 211.1208;
found: 211.1206.
(14) Spectral data for 16: Colorless oil; Rf = 0.3 (silica gel,
hexane–EtOAc = 2:1). IR(film): 1731, 1655, 1434, 1368,
1265, 1158, 1071, 1035 cm–1. 1H NMR (500 MHz, CDCl3):
d = 5.70 (s, 1 H), 4.39 (d, J = 13.8 Hz, 1 H), 4.22–4.17 (m, 1
H), 3.79 (s, 3 H), 3.77 (s, 3 H), 3.67 (t, J = 10.8 Hz, 2 H),
3.61–3.57 (m, 1 H), 3.19–3.11 (m, 1 H), 3.05–2.97 (m, 1 H),
1.49 (s, 9 H). 13C NMR (125.8 MHz, CDCl3): d = 167.5,
167.4, 155.0, 133.2, 132.1, 128.5, 118.2, 82.0, 74.1, 52.7,
52.4, 38.0, 28.3, 27.7. HRMS: m/z (M+) calcd for
C17H23NO7: 353.1475; found: 353.1485.
(7) (a) Koeanig, S. G.; Leonard, K. A.; Lwe, R. S.; Austin, D. J.
Tetrahedron Lett. 2000, 41, 9393. (b) Cicchi, S.; Bonanni,
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(8) Schreiber, S. L. Science 2000, 287, 1964.
(9) Yang, Y.-K.; Tae, J. Synlett 2003, 1043.
(10) For related RCM of hydroxylamine-tethered dienes, see:
(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.
(11) We have observed spontaneous oxidation of compounds 18
and 19 to the corresponding aromatic compounds 30 and 32
within a few days after preparation under the standard
storage conditions.
Synlett 2003, No. 13, 2017–2020 © Thieme Stuttgart · New York