Selective [5 + 1] and [5 + 2] Cycloaddition of Ynamides or Propargyl Esters with Benzo[ d]isoxazoles via Gold Catalysis

Article abstract of DOI:10.1021/acs.joc.8b02935

Benzo[d]isoxazoles are found to act as novel nucleophiles to undergo gold-catalyzed [5 + 1] or [5 + 2] cycloaddition reactions with ynamides. The reaction provides a concise and chemoselective access to polysubstituted 2H-benzo[e][1,3]oxazines or benzo[f][1,4]oxazepines. In addition, benzo[d]isoxazoles can also react with gold-carbene intermediates derived from propargyl esters to afford [5 + 1] annulation products.

Full text of DOI:10.1021/acs.joc.8b02935

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Article
Selective [5+1] and [5+2] Cycloaddition of Ynamides or
Propargyl Esters with Benzo[d]isoxazoles via Gold Catalysis
Wei Xu, Jidong Zhao, Xiangdong Li, and Yuanhong Liu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02935 • Publication Date (Web): 30 Nov 2018
Downloaded from http://pubs.acs.org on December 1, 2018
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Selective [5+1] and [5+2] Cycloaddition of Ynamides or Propargyl Esters with
Benzo[d]isoxazoles via Gold Catalysis
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Wei Xu, Jidong Zhao, Xiangdong Li and Yuanhong Liu*
State Key Laboratory of Organometallic Chemistry,
Center for Excellence in Molecular Synthesis,
Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences,
Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, People’s Republic of
China
Fax: (+86) 21-64166128, E-mail: yhliu@sioc.ac.cn
R2
N
PG
N
O
Me
R2
OBz
PG
R2
N
R1
R1
N
R3
N
[5+1] Annulations
Me
Catalyst
controlled
R3
O
[
Au]
O
[Au]
R2
OBz
5+1] Annulations
[
N
PG
novel nucleophiles
N
high chemoselectivity
broad substrate scope
Me
O
R1
5+2] Annulations
[
Abstract: Benzo[d]isoxazoles are found to act as novel nucleophiles to undergo
gold-catalyzed [5+1] or [5+2] cycloaddition reactions with ynamides. The reaction
provides
a
concise and chemoselective access to polysubstituted
2H-benzo[e][1,3]oxazines
or
benzo[f][1,4]oxazepines.
In
addition,
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benzo[d]isoxazoles can also react with gold-carbene intermediates derived from
propargyl esters to afford [5+1] annulation products.
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INTRODUCTION
In recent years, gold-catalyzed reactions involving α-imino gold carbenes 1-5 have
attracted extensive attention because of their high efficiency in constructing
nitrogen-containing heterocyclic compounds. Up to now, many substrates (so called
nucleophilic nitrenoids) which could initiate the generation of α-imino gold carbenes have
1
2
3
4
been developed, including isoxazoles, anthranils, 2H-azirines, N-iminopyridium ylides
5
and triazapentalene, et al. Among them, isoxazoles and anthranils were two significant
kinds of nucleophilic reagents since they could react with ynamides or propiolates to
1
a
1b
trigger efficient cycloaddition reactions. For example, Ye and Liu et al reported various
catalytic annulations between isoxazoles and ynamides/propiolates to afford
4
-carbonly-2-aminopyrroles or 2,4-dicarbonylpyrroles via [3+2] or [4+1] annulations,
2
a
2b
respectively (Scheme 1, eq 1). Hashmi and Liu et al found that anthranils could also
cycloisomerize with ynamides/propiolates via [3+2] or [4+2] cycloaddition reactions
(Scheme 1, eq 2). Of particular note is that isoxazoles and anthranils usually serve as
three-atom or four-atom synthons in these reactions, affording the corresponding five- or
six-membered nitrogen heterocycles. However, substrates which could act as more than
four-atom building blocks in the cycloaddition reactions have rarely been reported.6
Benzo[d]isoxazoles are easily available heterocyclic substrates, which have been
7
applied in a number of metal-catalyzed transformation reactions, such as the
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a
Rh-catalyzed [4+2] annulations with alkynes and Lewis acid-catalyzed [4+2]
annulations with propargylic alcohols.7b However, to the best of our knowledge,
benzo[d]isoxazoles have not been studied in gold-catalyzed reactions. We recently found
1
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that 1,4,2-dioxazoles and 4,5-dihydro-1,2,4-oxadiazoles could be used as three-atom
synthons to oxazoles and imidazoles. As our continuous interests in oxazole chemistry,
herein, we report our success on gold-catalyzed cyclization of benzo[d]isoxazoles and
ynamides, which provided an efficient and controllable synthesis of
2
H-benzo[e][1,3]oxazines or benzo[f][1,4]oxazepines through [5+1] or [5+2] cycloaddition
9
reactions. Remarkably, a novel 1,2-amino migration of the ynamide substrate was
observed during the [5+1] process. During the preparation of this paper, a gold-catalyzed
cycloaddition reaction of ynamides and 1,2-benzisoxazoles without substituents on the
isoxazole ring was reported by Liu’s group.10 Compared with their work, our method
accomodates with diversely benzo[d]isoxazoles bearing substituents on the isoxazole ring,
and proceeds with generally higher chemoselectivity in the course of [5+1] annulation.
Furthermore, we found that these substrates could also trap gold-carbene intermediates
1
1
derived from propargyl esters, leading to [5+1] cycloaddition products.
Scheme 1. Gold-catalyzed cycloaddition reactions with isoxazoles, anthranils and
benzo[d]isoxazoles
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Previous work : annulations of isoxazoles and anthranils
Ye and Liu's work :
PG
R2
O
O
R4
O
R1
R1
R4
R3
N
R4
R5
R5
6
CO R
2
PG
(1)
[
Au]
[Au]
[4+1] Annulations
6
R3
N
[3+2] Annulations R3
N
R O2C
N
H
0
1
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0
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0
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0
N
R2
H
Hashmi and Liu's work :
R1
PG
PG
R2
R7
R1
N
H
O
R5
6
CO R
R5
2
N
O
(2)
R2
7
N
[Au]
3+2] Annulations
[Au], R = H
4+2] Annulations
N
6
H
N
CO R
2
[
[
R7
O
Previous nucleophiles
Our previous works
This work
R
R
R
X
N
R
O
O
O
N
R
N
N
O
X = O, N
three-atom synthons
three/four-atom synthons
five-atom synthons
OBz
R3
R2
R2
R2
N
PG
N
Me
R1
R3
[Au]
N
PG
N
N
OBz
O
[Au]
O
O
via
R3
1
Me
OBz
R
[
Au]
path a
6 electrocyclization
1,2-amino migration
[
Au]+
electrocyclization
path b
O attack
6

Catalyst controlled
R2
O
R2
N
R2
N
PG
N
PG
N
N
R3
Me
O
Me
O
OBz
5+1] Annulations
R1
R1
[
[5+1] Annulations
[5+2] Annulations
RESULTS AND DISCUSSION
To test the feasibility of our hypothesis, we initially investigated the cyclization reaction
of 3-phenylbenzo[d]isoxazole 2a with ynamide 1a bearing a p-methoxyphenylsulfonyl
protecting group. To our delight, the use of common gold catalysts such as PPh AuNTf
3
2
and PPh AuSbF formed in situ afforded 2H-benzo[e][1,3]oxazine 3a in 75-79% yields as
3
6
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a mixture of E/Z isomers (E/Z = 3.9:1-4:1), along with seven-membered heterocycle
benzo[f][1,4]oxazepine 4a in 13-14% yields (Table 1, entries 1-2). Apparently,
benzo[d]isoxazole 2a was served as distinctive five-atom synthons in this reaction to
deliver the products 3 or 4 via [5+1] or [5+2] annulations, respectively. Interestingly, a
1,2-amino group migration9,10 was also observed in the formation of product 3.
Considering the steric and electronic effects of ligands could influence the reaction greatly,
1
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we then chose JohnphosAu(MeCN)SbF (catalyst A) as the catalyst. It was found that 3a
6
could be formed in 93% yield (E/Z = 7.5:1) within 6 h (Table 1, entry 3). Under this
t
condition, 4a was formed in only 3% yield. When gold catalyst B with a bulky BuXphos
as the ligand was used, the reaction was suppressed greatly, affording E-3a in 15% yield
after 24 h (Table 1, entry 4). When N-heterocyclic carbene gold(I) complex C was
employed as the catalyst, the yield of 3a was increased to 91%, along with 4a in 3% yield
(Table 1, entry 5). The reaction also proceeded smoothly in various solvents like THF,
DCM, MeCN and toluene, with the yields of 3a in the range of 55-87% and 4a in < 6%
yields (Table 1, entries 6-9). The catalytic activity of gold(III) complex such as
pyridine-ligated AuCl was also tested and only 14% yield of 4a was obtained (Table 1,
3
o
entry 10). When PicAuCl (catalyst E) was used as the catalyst at 50 C, the yield of 4a
2
could be increased to 58% without the formation of 3a (Table 1, entry 11). Switching the
catalyst to simple gold(III) salt of AuBr gave 3a in a higher yield of 66% (Table 1, entry
3
12). We fould that substrate 1a could slowly decompose in the presence of AuBr3.
To improve the yield of 4a, 2.0 equiv of 2a was added under the dilute reaction
conditions (0.033 M). However, the yield of 4a was improved slightly (Table 1,
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entry 13). After turning the ratio of 1a: 2a to 1.2: 1, the yield of 4a could be
increased to 79% (Table 1, entry 14). Employing AgSbF alone or Brønsted acid of
6
HNTf as the catalyst did not afford desired products, with recovered 1a in 99% and
2
0
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5% yields, respectively (Table 1, entries 15-16). The reaction could not proceed
o
without any catalyst, even at 50 C for 24 h (Table 1, entry 17). Then the effects of
the protecting groups on nitrogen were examined. In the presence of catalyst A,
mesyl-protected substrate 1b and tosyl-protected substrate 1c gave the
corresponding product 3b and 3c in 82% and 92% yields, respectively (Table 1,
entries 18-19). In addition, when substrate 1c was tested under the catalysis of
AuBr , 4c could be isolated in 80% yield (Table 1, entry 20). After careful
3
separation of isomers through recrystallization or column chromatography, the
structure of benzo[e][1,3]oxazines 3 was confirmed by X-ray crystallographic
analyses of the analogous products of E-3b, Z-3i, E-3m, Z-3m, E-3r, and product 4
was also confirmed by X-ray crystallographic analysis of 4a.12
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Table 1. Optimization of the Reaction Conditions
Ph
Ph
O
Ph
PG
N
PG
Me
catalyst
N
PG
N
Ph
N
+
N
+
N
solvent, rt.
Me
O
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
O
Me
1
2a (1.2 equiv)
Ph
Ph
4
3 (E+Z isomers)
+
tBu tBu
Au NCMe
SbF6
P
N
N
Ar
Ar
O
R
N
N
R
Au
Cl Au Cl
Cl Au
Cl
O
NTf2
R
Cl
D
i
A: R = H
C: Ar = 2,6- Pr C H
E
2
6
3
i
B: R = Pr
yields (%)a
entry
PG
catalyst (mol %)
solvent
time(h)
3
(E:Z)
4
1a
1
2
3
4
5
6
7
SO2PMP (1a)
PPh3AuNTf2 (5)
DCE
DCE
DCE
DCE
DCE
THF
3
75 (4:1)
13
-
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
PPh3AuCl/AgSbF6 (5)
8
79 (3.9:1)
93 (7.5:1)
15 (1:0)
14
3
-
A (5)
B (5)
C (5)
A (5)
A (5)
6
-
24
3.5
5
-
60
-
91 (5.1:1)
55 (8.2:1)
87 (8.7:1)
3
-
-
DCM
MeCN
9
4
-
8
A (5)
A (5)
D (5)
24
11
24
77 (6:1)
70 (6:1)
-
6
-
9
toluene
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
-
-
10
14
72
1
1
1b
E (5)
3
-
-
-
-
-
-
-
58
66
70
-
2
1a
1a
1a
1a
1a
AuBr3 (5)
AuBr3 (5)
AuBr3 (5)
AgSbF6 (10)
1
-
1
1
3c
4d
1
-
1
-
79
-
1
5
24
24
24
6
99
1
17b
6
HNTf (10)
-
-
-
-
45
99
-
2
1a
none
A (5)
1
1
2
8
Ms (1b)
Ts (1c)
Ts (1c)
82 (6.5:1)
92 (7.7:1)e
-
9
0d
A (5)
6
-
AuBr3 (5)
1
80e
-
a
All the reactions were carried out on 0.3 mmol scale (0.1 M). PMP = p-methoxyphenyl.
1
b
o
c
H NMR yields using 1,3,5-trimethoxybenzene as an internal standard. 50 C. 0.033 M in
d
DCE. 2.0 equiv of 2a was used. 0.033 M in DCE.1.2 equiv of 1a and 1.0 equiv of 2a were
e
used. Isolated yields.
With optimized reaction conditions established (Table 1, entry 19), we first paid our
attention to investigate the substrate scope of [5+1] cycloaddition reactions (Scheme 2).
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The scope of ynamides with the aryl substituents on R group was first studied.
Electron-donating groups such as p-methyl and p-methoxy on the aryl ring gave 3d and 3e
in lower yields of 63-67%, along with the formation of 4 in 20-25% yields. The results
indicated that the chemoselectivity was decreased between [5+1] and [5+2] cycloaddition
0
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0
mode in these cases. Electron-withdrawing groups such as p-F, p-Cl and p-CO Et on the
2
aryl ring tolerated well in the reaction, giving 3f-3h in 49-93% yields.
Heteroaryl-substituted ynamides such as 2-thienyl-containing substrate reacted efficiently
to furnish 3i in 78% yield. According to the above results, it was noted that the
stereoselectivity was decreased (3d) or opposite (3e and 3i) when ynamides bearing
electron-rich aryl groups were employed as the substrates. Besides, ynamide with an
1
,3,5(10)-estratrien-3-ol-17-one derivative was also compatible, giving 3j in a yield of
65%. The reaction can be extended to alkyl-substituted ynamides such as
cyclopropyl-substituted 1k, with the formation of 3k in an excellent yield of 95%.
Subsequently, we investigated the scope of benzo[d]isoxazoles using 1c as the reaction
partner. It was found that both electron-donating groups (p-OMe) and
electron-withdrawing groups (p-Cl) on aryl ring were suitable for this reaction, leading to
3l and 3m in high yields. Sterically encumbered o-OMe substituted aryl benzo[d]isoxazole
reacted efficiently to afford 3n in 94% yield. Alkyl-substituted benzo[d]isoxazoles with
methyl or 2-phenethyl groups turned out to be perfect substrates, giving 3o and 3p in yields
2
of 91% and 85%, respectively. In addition, when the R substituent is a methoxy group, 3q
could be formed in 88% yield. The parent phenyl ring substituted with a methyl group was
also suitable for this transformation, furnishing the single isomer E-3r in 87% yield. This
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result indicated that the steric effect of the methyl group may also have great influence on
2
the double bond configuration of the products. When R is a hydrogen, a mixture of
inseparatable compounds of 3s (60%) and 4q (23%) were obtained, indicating that the
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
chemoselectivity was not good in this case.13
Scheme 2. Scope of Gold-Catalyzed [5+1] Annulations with Ynamides
R2
R2 5 mol%
Ts
JohnphosAu(MeCN)SbF6
N
R1
N
Me
N
+
DCE, rt
NMeTs
O
O
R1
1
R
R
2
(1.2 equiv)
3 (E isomer)
Ph
O
Ph
3
3
3
3
3
c, X = H, 6 h, 92%, E/Z = 7.7:1
d, X = Me, 7 h, 67%, E/Z = 3.7:1b
e, X = OMe, 7 h, 63%, E/Z = 0.74:1c
f, X = F, 5.5 h, 89%, E/Z = 9.1:1
g, X = Cl, 9 h, 93%, E/Z = 10:1
N
N
O
S
NMeTs
NMeTs
3
i, 1 h, 78%, E/Z = 0.1:1
d
3h, X = CO Et, 30 h, 49%, E/Z = 6.7:1
2
R
Ph
X
N
Ph
O
NMeTs
O
N
H
N
NMeTs
NMeTs
O
3
k, 1 h, 95%, E/Z = 1.54:1
Ph
3l, R = OMe, 5 h, 86%, E/Z = 11.1:1
3m, R = Cl, 5 h, 91%, E/Z = 7.7:1
R2
OMe
N
H
H
N
NMeTs
O
NMeTs
O
O
3
j, 6 h, 65%,
E/Z = 2.1:1
Ph
Ph
2
e
3o, R = Me, 2 h, 91%, E/Z = 7.7:1
3n, 8 h, 94%, E/Z = 12.5:1
2
e
3
p, R = (CH ) Ph, 4 h, 85%, E/Z = 9.1:1
2
2
OMe
N
Ph
N
N
NMeTs
O
Ph
Ph
O
O
Me
3r, 9 h, 87%, E/Z = 1:0
Ph
NMeTs
s, 4 h, 60%, E/Z = 0.79:1f
NMeTs
q, 3.5 h, 88%, E/Z = 0.38:1
3
3
a
b
Only the structure of the major isomer was shown in most cases. 4d was also isolated in 20%
c
d
e
yield. 4e was also isolated in 25% yield. 7.5 mol% IPrAuNTf was used as the catalyst. 2.0
2
f
equiv 2 was used. As a mixture of 3s and 4q (23%).
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1
1
1
1
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1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Next, the scope of [5+2] cycloaddition reaction was tested by using 5 mol% AuBr as
3
the catalyst in DCE at room temperature (Scheme 3). We first examined the electronic
0
1
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4
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
effect of R substituents on ynamides. Substrates bearing both electron-donating groups
(p-Me and p-OMe) and electron-withdrawing groups (p-F, p-Cl and p-CO Et) on the aryl
2
ring were compatible in the reactions, furnishing 4d-4h in 63-82% yields. In the case of
2-thienyl-substituted ynamides, 4i could be formed in 57% yield, along with the formation
of Z-3i in 14% yield. Ynamide with an 1,3,5(10)-estratrien-3-ol-17-one derivative or
2
formononetin moiety also reacted efficiently (4j and 4k). Then the effect of R substituents
on benzo[d]isoxazoles were examined. Substrates bearing p-OMe, p-Cl and o-OMe groups
on the aryl ring resulted in 4l-4n in 68-77% yields. Benzo[d]isoxazoles with alkyl
2
substituents such as methyl and 2-phenethyl on R group could also react with 1c smoothly
2
(
4o and 4p). When the R substituent is a hydrogen group, the chemoselectivity was
decreased, affording a mixture of 3s (35%) and 4q (47%).14
Scheme 3. Scope of Gold-Catalyzed [5+2] Annulations with Ynamides
1
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R2
O
R2
Ts
N
Me
Ts
5 mol% AuBr3
N
R1
N
+
N
DCE, rt
O
Me
R1
1 (1.2 equiv)
2
4
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Ph
Ph
4c, X = H, 1 h, 80%
N
Me
N
Ts
N
Me
Ts
4
d, X = Me, 1 h, 80%
N
4
4
e, X = OMe, 1 h, 63%
f, X = F, 1 h, 82%
4g, X = Cl, 1 h, 81%
O
O
4
h, X = CO Et, 1 h, 73%
2
X
R
H
H
Ph
O
H
N
Me
Ts
O
N
4
j, 1.5 h, 65%
N
Me
Ts
S
N
Ph
O
Ph
4l, R = OMe, 1 h, 74%
N
Me
Ts
4
i, 1.5 h, 57%a
N
4
m, R = Cl, 1 h, 77%
O
R2
O
N
Me
N
Ts
OMe
N
Me
Ts
O
O
Ph
4o , R = Me, 2 h, 61%
N
b
2
O
b
OMe
b
2
4k , 1 h, 60%
Ph
4p , R = (CH ) Ph, 2 h, 61%
4q, R = H, 1 h, 47%c
2 2
2
4n, 1 h, 68%
a
b
c
Z-3i was also isolated in 14% yield. 1.0 equiv of 1 and 2.0 equiv of 2 were used. As a
mixture of 3s (35%, E/Z = 0.33:1) and 4q.
Interestingly, when Me SAuCl was used as the catalyst in the reaction of ynamide 1c
2
with benzo[d]isoxazole 2a or 2h, benzo[f][1,4]oxazepine 4c or 4r could be obtained in the
same yield of 79%, along with the formation of the unexpected spiro products 5 in 10-18%
yields (Scheme 4). The results indicated that the use of less hindered gold catalyst favoured
the formation of seven-membered products 4. The yield of 5 could be increased to 41% by
1
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1
1
1
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1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
using methoxy-substituted 2g as the reaction partner under the catalysis of AuBr , which
3
indicated that the electronic effect of the substrates played an important role in the
formation of the spiro product. The structure of spiro product was confirmed by X-ray
crystallographic analysis of 5b.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 4. Formation of Spiro Products
Ph
Ph
Ph
Ts
N
Me
N
Ts
5
mol% Me SAuCl
N
2
N
Ph
N
+
+
O
R
DCE, rt
Me
O
O
R
Ph
NMeTs
Ph
R
1c
2a or 2h
1.2 equiv)
R = H, 21.5 h
R = Me, 7 h
4c, 79%
4r, 79%
5a,10%
5b,18%
(
OMe
N
OMe
N
OMe
5
mol% AuBr3
1c
(1.2 equiv)
+
N
+
DCE, rt
NMeTs
O
O
8
h
O
2g
Ph
NMeTs
c, 41%
Ph
3q, 26%, E/Z = 0.56:1
5
In order to extend the application scope of this reaction, propargyl esters were used as
the reaction partner instead of ynamides (Scheme 5). It was found that
benzo[e][1,3]oxazine analogues 7 were formed through an entirely different pathway. We
found that benzoyl-protected substrate 6a could react with benzo[d]isoxazole 2a to form 7a
o
in 52% yield by using 5 mol% JohnphosAu(MeCN)SbF (catalyst A) in DCE at 80 C for
6
2
4 h. After a brief screening on reaction conditions, it was found that the use of IPrAuNTf2
could increase the yield of 7a to 75%. Changing the protecting group to acetyl group
decreased the yield of 7b to 43%. Propargyl esters bearing substituted aryl groups were
compatible (7c and 7d), while dimethyl-substituted 6e resulted in 7e in a lower yield of
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7%. For aryl-substituted benzo[d]isoxazoles, the corresponding products 7f-7i were
formed in 38-86% yields. The structure of 7c was confirmed by X-ray crystallographic
analysis.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 5. Scope of Gold-Catalyzed [5+1] Annulations with Propargyl Esters
R2
R2
OR1
5 mol % IPrAuNTf2
R3
N
3
+
N
R
o
R4
DCE, 80 C
R4
O
2
O
24 h
6
(1.5 equiv)
OR1
7
Ph
N
Ph
O
Ph
O
N
N
OMe
OMe
O
Ph
Ph
OBz
OAc
OBz
7c, 91%
7
a, 75% (52%a)
7b, 43%
OMe
Ph
Ph
p-OMe-C H4
6
N
N
O
N
O
O
Ph
OBz
OBz
7e, 47%b,c
OBz
7f, 52%b
Cl
7
d, 65%
p-Cl-C H4
o-OMe-C H4
Ph
6
6
N
N
N
O
O
Ph
O
Ph
Ph
OBz
g, 86%
OBz
7h, 38%
Me
OBz
7i, 61%
7
a5 mol % catalyst A was used as the catalyst. 3 equiv of 6 was used. 65 C for 9 h.
b
c
o
On the basis of the above results and our previous work, a possible reaction mechanism
is given in Scheme 6. Attack of the imino nitrogen to ynamide activated by gold affords
vinyl gold intermediate 9, which fragmentizes into the α-imino gold- carbene 10. Then
there are three possible pathways: In path a, with a bulky ligand, 11 is formed through 6π
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1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
electrocyclization. 1,2-amino group migration followed by elimination of the catalyst
affords the products 3. In path b, O-attack to gold-carbene occurs to furnish intermediate
1
3. This is followed by elimination of the gold catalyst to give the product 4. It is
0
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2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
suggested that the O-attack process could be facilitated through the decrease of the steric
interaction between the gold-carbene and the carbonyl group caused by the less hindered
ligand on gold or increasing the electrophilic reactivity of gold-carbene by the use of
gold(III) salts with stronger Lewis acidity. In path c, C-attack to the carbene center occurs
due to the nucleophilicity of the exocyclic double bond, especially when OMe-substituted
benzo[d]isoxazole 2g is used. Elimination of the gold catalyst gives the spiro product 5
(Scheme 6). When propargyl esters are used as the substrates, gold-carbene intermediate 15
1
1
is generated through 1,2-acyloxy migration. This is followed by the nucleophilic attack of
nitrogen on benzo[d]isoxazole to deliver intermediate 16. Elimination of the gold catalyst
followed by 6π electrocyclization affords the products 7 (Scheme 6).
Scheme 6. Possible Reaction Mechanism
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path a:
6 electro-
cyclization
R2
R2
R2
R2
N O 2
NMeTs
Ph
O
N O
N
Ph
O
N
L = bulky
ligand
Ph
NMeTs
Ph
LAu
NMeTs
9
LAu
NMeTs
LAu
Au+L
10
11
8
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
path c: C attack
path b: O attack
L = less hindered ligand
or gold(III) salts
2
R = OMe
R2
O
OMe
N
OMe
N
R2
N
LAu
Ph NMeTs
12
O
N
LAu+
O
O
NMeTs
Ph AuL
NMeTs
Ph
LAu
5
Ph NMeTs
14
13
LAu+
LAu+
R2
R2
N
O
N
NMeTs
O
Ph
Ph
NMeTs
4
3
R2
R2
N
R2
N
AuL
6
 electro-
cyclization
OBz
O
LAu+
N
2
Ph
6a
O
7
15 AuL+
BzO
Ph
LAu+
O
1
Ph
16
7
OBz
CONCLUSION
In summary, we have disclosed that benzo[d]isoxazoles can be used as novel substrates
to undergo gold-catalyzed [5+1] or [5+2] cycloaddition reactions with ynamides. The
reaction provides
a
concise and chemoselective access to polysubstituted
2H-benzo[e][1,3]oxazines or benzo[f][1,4]oxazepines. Interestingly, a novel 1,2-amino
group migration is observed during the [5+1] process. In addition, benzo[d]isoxazoles can
also react with gold-carbene intermediates derived from propargyl esters to afford [5+1]
annulation products. Further extensions of the reactions with benzo[d]isoxazoles are
currently underway in our laboratory.
1
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1
1
1
1
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1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
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3
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4
4
4
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4
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5
5
5
5
5
5
5
5
6
EXPERIMENTAL SECTION
General Methods. All reactions were carried out under Argon unless noted. DCM, DCE
were distilled from CaH . Toluene was distilled from sodium and benzophenone. THF was
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
distilled from sodium and benzophenone or purified using Innovative Technology Solvent
Purifier (for the synthesis of substrates). MeCN was purified using Innovative Technology
Solvent Purifier. Unless noted, all commercial reagents were used without further
purification.
(Acetonitrile)[(2-biphenyl)di-tert-butylphosphine]gold(I)
hexafluoroantimonate (catalyst A), Gold complex D and AgSbF were purchased from
6
Stream Chemicals. Gold complexe B was prepared by stirring the [Au(L)Cl] complex and
1
5
16
17
AgSbF in MeCN at room temperature overnight. Gold complex C, PPh AuCl and
6
3
1
8
PPh AuNTf were prepared according to the published methods. PicAuCl (catalyst E)
3
2
2
and HNTf were purchased from Aldrich Chemical Company. AuBr was purchased from
2
3
Alfa Aesar. Beznzo[d]isoxazole 2i was purchased from Tokyo Chemical Industry and
further purified by column chromatography on silica gel before use.
1H and 13C NMR spectra were recorded at room temperature in CDCl (containing
3
0
.03% TMS) or CDCl (containing 0.03% TMS), on Varian XL-400 MHz spectrometer,
3
1
Agilent 400 MHz NMR spectrometer or Bruker 400 MHz NMR spectrometer. H NMR
1
3
1
spectra was recorded at 400 MHz, C NMR spectra was recorded at 100 MHz. H NMR
spectra was recorded with tetramethylsilane (δ = 0.00 ppm) as internal reference in CDCl3;
1
3
C NMR spectra was recorded with CDCl (δ = 77.00 ppm) as internal reference.
3
High-resolution mass spectra were obtained by using Agilent Technologies 5973N.
Elemental analyses were performed on an Italian Carlo-Erba 1106 analyzer. IR spectra
1
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were obtained by using a Nicolet iS10 spectrometer. Melting points were measured using a
SGW-4 microscopic melting point apparatus and were uncorrected. Single crystal X-ray
diffraction data were collected at 296(2) K for E-3b, E-3m, 4a, 7c and 173(2) for Z-3i,
Z-3m, E-3r, 5b on a Bruker APEX-II diffractometer or Bruker SMART diffractometer
with graphite-monochromated Mo-Kα radiation (λ = 0.71073 Å).
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Ynamides 1 were synthesized according to published methods.16
For the characterization of new ynamide substrates, see following:
Ethyl 4-(((N,4-dimethylphenyl)sulfonamido)ethynyl)benzoate (1h). 3 mmol scale.
Column chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 5:1)
1
afforded the title product as a white solid in 86% (925.3 mg) yield. H NMR (400 MHz,
CDCl ) δ 7.96 (d, J = 8.4 Hz, 2H), 7.84 (d, J = 8.0 Hz, 2H), 7.40-7.27 (m, 4H), 4.37 (q, J =
3
13
1
7
.2 Hz, 2H), 3.18 (s, 3H), 2.46 (s, 3H), 1.39 (t, J = 7.2 Hz, 3H). C{ H} NMR (100 MHz,
CDCl ) δ 166.0, 145.0, 133.1, 130.6, 129.9, 129.4, 129.1, 127.7, 127.5, 87.0, 69.0, 61.0,
3
-1
3
9.1, 21.6, 14.2. IR (neat): 2979, 2945, 2901, 2228, 1712, 1604, 1359, 1164 cm . HRMS
+
(ESI-TOF) calcd for C H NO S [M+H] : 358.1108, found 358.1102.
1
9
20
4
Synthesis of 1j.
To a solution of 1,3,5(10)-estratrien-3-ol-17-one (5.407 g, 20 mmol) in DCM (80 mL)
was added pyridine (3.2 mL, 40 mmol). Then Tf O (4.0 mL, 24 mmol, diluted with 40 mL
2
o
DCM) was added dropwise to the mixture at 0 C. The resulting solution was warmed up
1
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to room temperature and stirred for 3 h. Then the mixture was quenched with saturated
ammonium chloride solution, extracted with dichloromethane, and dried over anhydrous
Na SO . The solvent was evaporated under the reduced pressure and the residue was
2
4
0
1
2
3
4
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4
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purified by column chromatography on silica gel (eluent: petroleum ether: ethyl acetate =
5:1) to afford (8R,9S,13S,14S)-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-
6
H-cyclopenta[a]phenanthren-3-yl trifluoromethanesulfonate (s1-1j) in 94% yield (7.535
g) as a white solid.
To a solution of the above s1-1j (7.445 g, 18.5 mmol) in triethylamine (16 mL) and
DMF (40 mL) were added ethynyltrimethylsilane (2.18 g, 22.2 mmol) and Pd(PPh ) Cl
2
3
2
o
(779.1 mg, 1.11 mmol) at room temperature. Then the mixture was stirred at 50 C for 5 h.
After the starting material was consumed, the reaction mixture was quenched with 3 N HCl
solution, extracted with dichloromethane, washed with water and brine followed by drying
over anhydrous Na SO . The solvent was evaporated under the reduced pressure and the
2
4
residue was purified by column chromatography on silica gel (eluent: petroleum ether:
ethyl acetate 8:1 to 5:1) to afford compound
8R,9S,13S,14S)-13-methyl-3-((trimethylsilyl)ethynyl)-6,7,8,9,11,12,13,14,15,16-decahydr
o-17H-cyclopenta[a]phenanthren-17-one (s2-1j) (4.9 g, 76%) as a yellow solid.
=
(
To a solution of the above s2-1j (4.9 g, 14 mmol) in THF (45 mL) was added TBAF
o
(
15.4 mL, 1M in THF, 15.4 mmol) at 0 C. The resulting solution was warmed up to room
temperature and stirred for 1 h. Then the mixture was quenched with water, extracted with
dichloromethane, and dried over anhydrous Na SO . The solvent was evaporated under the
2
4
reduced pressure and the residue was purified by chromatography on silica gel (eluent:
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petroleum ether: ethyl acetate: dichloromethane
=
10:1:1) to afford
(8R,9S,13S,14S)-3-ethynyl-13-methyl-6,7,8,9,11,12,13,14,15,16-decahydro-17H-cyclopent
a[a]phenanthren-17-one (s3-1j) in 46% yield (1.792 g) as a white solid.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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8
9
0
To a solution of s3-1j (1.058 g, 3.8 mmol) in acetone (20 mL) were added
N-bromosuccinimide (811.6 mg, 4.56 mmol) and AgNO (32.3 mg, 0.19 mmol) at room
3
temperature. The mixture was stirred at the same temperature for 12 h. The reaction
mixture was diluted with hexane and filtered through a pad of celite using dichloromethane
as an eluent. The filtrate was collected and evaporated under the reduced pressure, the
residue was purified by column chromatography on silica gel (eluent: petroleum
ether/ethyl
8R,9S,13S,14S)-3-(bromoethynyl)-13-methyl-6,7,8,9,11,12,13,14,15,16-decahydro-17H-c
yclopenta[a]phenanthren-17-one (s4-1j) (1.053 g, 78%) as a white solid.
acetate/dichloromethane
=
5:1:1)
to
afford
compound
(
To a dry flask were added N,4-dimethylbenzenesulfonamide (222.3 mg, 1.2 mmol),
anhydrous toluene (10 mL), CuSO ·5H O (25.0 mg, 0.1 mmol), 1,10-phenanthroline (36.0
4
2
mg, 0.2 mmol) and K CO (276.4 mg, 2 mmol). Then s4-1j (357.3 mg, 1 mmol) was
2
3
o
added, and the resulting mixture was stirred at 80 C for 48 h under an atmosphere of
argon. When the reaction was complete, the crude mixture was cooled down to room
temperature, filtered through celite and washed with ethyl acetate. After solvent
evaporation, the residue was purified by column chromatography on silica gel (eluent:
petroleum ether: ethyl acetate: dichloromethane = 10:1:1) to afford compound 1j (323.4
mg, 70%) as a white solid.
1
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N,4-Dimethyl-N-(((8R,9S,13S,14S)-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decah
ydro-6H-cyclopenta[a]phenanthren-3-yl)ethynyl)benzenesulfonamide
(1j).
M.p.
o
1
1
77-179 C. H NMR (400 MHz, CDCl ) δ 7.83 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 8.0 Hz,
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
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5
6
7
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2
H), 7.22-7.20 (m, 1H), 7.15-7.12 (m, 2H), 3.13 (s, 3H), 2.89-2.86 (m, 2H), 2.54-2.38 (m,
1
3
1
5H), 2.30-2.26 (m, 1H), 2.19-1.95 (m, 4H), 1.66-1.38 (m, 6H), 0.91 (s, 3H).; C{ H}
NMR (100 MHz, CDCl ) δ 220.7, 144.7, 139.8, 136.5, 133.1, 131.9, 129.7, 128.7, 127.8,
3
125.2, 119.8, 83.2, 68.8, 50.3, 47.8, 44.3, 39.3, 37.9, 35.7, 31.4, 29.0, 26.2, 25.5, 21.6,
-1
2
1.5, 13.7. IR (neat): 2961, 2932, 2875, 2236, 1731, 1597, 1456, 1365, 1168, 721 cm .
+
HRMS (ESI-TOF) calcd for C H NO S [M+H] : 462.2097, found 462.2096.
2
8
32
3
Synthesis of 1l.
To a solution of 7-hydroxy-3-(4-methoxyphenyl)-4H-chromen-4-one (4.292 g, 16
mmol) in DCM (60 mL) was added pyridine (2.6 mL, 32 mmol). Then Tf O (3.2 mL, 19.2
2
o
mmol, diluted with 30 mL DCM) was added dropwise to the mixture at 0 C. The resulting
solution was warmed up to room temperature and stirred for 1 h. Then the mixture was
quenched with saturated ammonium chloride solution, extracted with dichloromethane,
washed with saturated CuSO solution, brine and dried over anhydrous Na SO . The
4
2
4
solvent was evaporated under the reduced pressure and the residue was purified by column
chromatography on silica gel (eluent: petroleum ether: dichloromethane = 1:1) to afford
3-(4-methoxyphenyl)-4-oxo-4H-chromen-7-yl trifluoromethanesulfonate (s2-1l) which was
directly used in the following reaction.
To a solution of the above s2-1l in triethylamine (16 mL) and DMF (40 mL) were
2
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added ethynyltrimethylsilane (1.886 g, 19.2 mmol) and Pd(PPh ) Cl (673.8 mg, 0.96
3
2
2
o
mmol) at room temperature under Agron. Then the mixture was stirred at 50 C for 3.5 h.
After the starting material was consumed, the reaction mixture was quenched with 3 N HCl
solution, extracted with dichloromethane, washed with water and brine followed by drying
over anhydrous Na SO . The solvent was evaporated under the reduced pressure and the
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
4
residue was purified by column chromatography on silica gel (eluent: petroleum ether:
ethyl acetate: dichloromethane 10:1:1) to afford compound
-(4-methoxyphenyl)-7-((trimethylsilyl)ethynyl)-4H-chromen-4-one (s3-1l) which was
=
3
directly used in the following reaction.
To a solution of the above s3-1l in MeOH (100 mL) was added K CO (663.4 mg, 4.8
2
3
mmol) at room temperature and stirred for 2 h. Then the mixture was quenched with water
and MeOH was evaporated under the reduced pressure. The residue was extracted with
dichloromethane, washed with brine and dried over anhydrous Na SO . The solvent was
2
4
evaporated under the reduced pressure and the residue was purified by chromatography on
silica gel (eluent: petroleum ether: dichloromethane 2:1) to afford
-ethynyl-3-(4-methoxyphenyl)-4H-chromen-4-one (s4-1l) in 38% (3 steps) yield (1.68 g)
as a white solid.
=
7
To a solution of s4-1l (663.1 mg, 2.4 mmol) in acetone (15 mL) were added
N-bromosuccinimide (469.9 mg, 2.64 mmol) and AgNO (40.8 mg, 0.24 mmol) at room
3
temperature. The mixture was stirred at the same temperature for 8 h. The solution was
evaporated under the reduced pressure and the residue was quenched with saturated NH Cl
4
solution, extracted with dichloromethane, washed with brine and dried over anhydrous
2
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Na SO . The solution was evaporated under the reduced pressure and the residue was
2
4
filtered
-(bromoethynyl)-3-(4-methoxyphenyl)-4H-chromen-4-one (s5-1l) was used directly
without further purification.
through
a
pad
of
silica
gel.
The
crude
product
7
0
1
2
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4
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To a dry flask were added N,4-dimethylbenzenesulfonamide (533.5 mg, 2.88 mmol),
anhydrous toluene (20 mL), CuSO ·5H O (59.9 mg, 0.24 mmol), 1,10-phenanthroline
4
2
(86.5 mg, 0.48 mmol) and K CO (663.4 mg, 4.8 mmol). Then s5-1l was added, and the
2
3
o
resulting mixture was stirred at 80 C for 14 h under an atmosphere of argon. When the
reaction was complete, the crude mixture was cooled down to room temperature, filtered
through celite and washed with ethyl acetate. The mixture was washed with 10% NaOH
solution, brine and dried over anhydrous Na SO . After solvent evaporation, the residue
2
4
was purified by column chromatography on silica gel (eluent: petroleum ether: ethyl
acetate: dichloromethane = 10:1:1 to dichloromethane) to afford compound 1l (522.7 mg,
4
7% for 2 steps) as a light yellow solid.
N-((3-(4-Methoxyphenyl)-4-oxo-4H-chromen-7-yl)ethynyl)-N,4-dimethylbenzenesulfo
o
1
namide (1l). M.p. 158-160 C. H NMR (400 MHz, CDCl ) δ 8.17 (d, J = 8.4 Hz, 1H),
3
7
.95 (s, 1H), 7.85 (d, J = 7.6 Hz, 2H), 7.49 (d, J = 8.0 Hz, 2H), 7.40-7.38 (m, 3H), 7.31 (d,
13
1
J = 8.0 Hz, 1H), 6.95 (d, J = 8.0 Hz, 2H), 3.82 (s, 3H), 3.19 (s, 3H), 2.45 (s, 3H); C{ H}
NMR (100 MHz, CDCl ) δ 175.6, 159.5, 155.7, 152.4, 145.1, 132.9, 129.9, 128.3, 127.6,
3
1
27.2, 126.1, 124.9, 123.7, 123.1, 119.4, 113.8, 88.0, 68.6, 55.1, 39.0, 21.5. IR (neat):
-1
3066, 2937, 2841, 2239, 1637, 1619, 1358, 1165 cm . HRMS (ESI-TOF) calcd for
2
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C H NO S [M+H] : 460.1213, found 460.1210.
2
6
22
5
General procedure for the synthesis of benzo[d]isoxazoles 2.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
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5
6
0
1
2
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Method A : For 2a-2d19
Typical procedure for the synthesis of 3-phenylbenzo[d]isoxazole 2a.
To a solution of 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (2.984 g, 10 mmol)
in MeCN (60 mL) was added CsF (4.56 g, 30 mmol). Then N-hydroxybenzimidoyl
chloride (777.9 mg, 5 mmol) in MeCN (60 mL) was added slowly to the reaction mixture
at room temperature within 4 h and stirred for another 2 h. After the reaction was
completed, the solvent was evaporated under the reduced pressure and the residue was
quenched with brine, extracted with dichloromethane, washed with brine and dried over
anhydrous Na SO . The solvent was evaporated under the reduced pressure and the residue
2
4
was purified by column chromatography on silica gel (eluent: petroleum ether: ethyl
acetate = 40:1) to obtain a light yellow solid. The product was washed with a small amount
of pentane to afford 2a (630.7 mg, 65%) as a white solid. This compound can also be
synthesized by method B.
Method B : For 2e, 2f, 2h20
Typical procedure for the synthesis of 3-methylbenzo[d]isoxazole 2e.
To
-(2-hydroxyphenyl)ethan-1-one (1.362 g, 10 mmol) and stirred at room temperature for 2
h. Then MeOH was evaporated under the reduced pressure to afford a yellow solid.
a
solution of NH3 in MeOH (7 mL,
7
M) was added
1
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5
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6
Subsequently, to a solution of the above product in THF (30 mL) was added
N-chlorosuccinimide (2.003 g, 15 mmol) and K CO (2.764 g, 20 mmol) and stirred at
2
3
room temperature for 15 h. The mixture was quenched with H O, extracted with ethyl
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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2
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2
3
4
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8
9
0
acetate, washed with brine and dried over anhydrous Na SO . The solvent was evaporated
2
4
under the reduced pressure and the residue was purified by column chromatography on
silica gel (eluent: petroleum ether: ethyl acetate = 100:1) to afford 2e (487.2 mg, 37%) as
light yellow oil.
1
3
-Phenylbenzo[d]isoxazole (2a). Method A was used. H NMR (400 MHz, CDCl ) δ
3
7.97-7.95 (m, 2H), 7.92 (d, J = 8.0 Hz, 1H), 7.64-7.52 (m, 5H), 7.38-7.34 (m, 1H).
1
3
1
C{ H} NMR (100 MHz, CDCl ) δ 163.8, 157.2, 130.2, 129.7, 129.1, 128.9, 128.0, 123.8,
3
122.1, 120.4, 110.1. The spectroscopic data is in agreement with that previously reported.21
3
-(4-Methoxyphenyl)benzo[d]isoxazole (2b). Method A was used. 4 mmol scale. Column
chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 40:1) followed by
washing with pentane afforded the title product in 73% yield (660.5 mg) as a white solid).
1
H NMR (400 MHz, CDCl ) δ 7.92-7.89 (m, 3H), 7.63-7.54 (m, 2H), 7.37-7.33 (m, 1H),
3
1
3
1
7
1
.08-7.05 (m, 2H), 3.87 (s, 3H). C{ H} NMR (100 MHz, CDCl ) δ 163.6, 161.1, 156.7,
3
29.6, 129.3, 123.6, 122.2, 121.2, 120.5, 114.5, 110.0, 55.3. The spectroscopic data is in
agreement with that previously reported.21
3-(4-Chlorophenyl)benzo[d]isoxazole (2c). Method A was used. 4 mmol scale. Column
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chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 20:1) followed by
washing with pentane afforded the title product in 53% yield (484.5 mg) as a light yellow
1
solid). H NMR (400 MHz, CDCl ) δ 7.91-7.86 (m, 3H), 7.65-7.57 (m, 2H), 7.53-7.51 (m,
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
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5
6
7
8
9
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1
2
3
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5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
1
2
H), 7.39-7.35 (m, 1H). C{ H} NMR (100 MHz, CDCl ) δ 163.8, 156.2, 136.3, 129.9,
3
129.4, 129.2, 127.3, 124.0, 121.8, 120.1, 110.2. The spectroscopic data is in agreement
with that previously reported.22
3
-(2-Methoxyphenyl)benzo[d]isoxazole (2d). Method A was used. 4 mmol scale. Column
chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 20:1) afforded the
1
title product in 85% yield (761.7 mg) as light yellow oil). H NMR (400 MHz, CDCl ) δ
3
7
.67-7.62 (m, 2H), 7.57-7.55 (m, 1H), 7.50-7.43 (m, 2H), 7.25 (t, J = 7.6 Hz, 1H),
1
3
1
7.08-7.01 (m, 2H), 3.78 (s, 3H). C{ H} NMR (100 MHz, CDCl ) δ 163.0, 157.2, 156.3,
3
1
31.5, 131.0, 129.3, 123.3, 123.0, 121.6, 120.7, 117.3, 111.2, 109.5, 55.2. The
spectroscopic data is in agreement with that previously reported.21
1
3
-Methylbenzo[d]isoxazole (2e). Method B was used. H NMR (400 MHz, CDCl ) δ 7.63
3
1
3
1
(d, J = 8.0 Hz, 1H), 7.54-7.51 (m, 2H), 7.32-7.27 (m, 1H), 2.58 (s, 3H). C{ H} NMR
(
100 MHz, CDCl ) δ 162.7, 154.9, 129.6, 123.1, 122.1, 121.1, 109.7, 10.0. The
3
spectroscopic data is in agreement with that previously reported.23
3
-Phenethylbenzo[d]isoxazole (2f). Method B was used. 5 mmol scale. Column
chromatography on basic aluminum oxide (eluent: petroleum ether: ethyl acetate = 20:1 to
2
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2
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7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
5
:1) afforded the title product in 55% yield (613.3 mg) as colorless oil). H NMR (400
MHz, CDCl ) δ 7.53-7.47 (m, 3H), 7.30-7.19 (m, 6H), 3.29-3.25 (m, 2H), 3.18-3.14 (m,
3
1
3
1
2
H). C{ H} NMR (100 MHz, CDCl ) δ 162.8, 157.8, 140.5, 129.6, 128.5, 128.3, 126.3,
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
23.0, 121.5, 121.1, 109.8, 33.7, 27.3. The spectroscopic data is in agreement with that
previously reported.20
7-Methyl-3-phenylbenzo[d]isoxazole (2h). Method B was used. 5 mmol scale. Column
chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 100:1) afforded the
1
title product in 43% yield (450.7 mg) as a yellow solid). H NMR (400 MHz, CDCl ) δ
3
7.97-7.95 (m, 2H), 7.73 (d, J = 8.0 Hz, 1H), 7.58-7.52 (m, 3H), 7.35 (d, J = 7.2 Hz, 1H),
1
3
1
7
.26 (t, J = 7.6 Hz, 1H), 2.62 (s, 3H). C{ H} NMR (100 MHz, CDCl ) δ 163.1, 157.5,
3
130.1, 130.1, 129.2, 129.0, 128.0, 124.1, 120.9, 119.9, 119.4, 15.2. IR (neat): 3053, 2977,
-1
+
2
2
917, 1603, 1382, 902, 742, 695 cm . HRMS (ESI-TOF) calcd for C H NO [M+H] :
14 12
10.0913, found 210.0912.
The procedure for the synthesis of 3-methoxybenzo[d]isoxazole 2g.24
To a solution of benzo[d]isoxazol-3-ol (405.4 mg, 3 mmol) in DMSO (5 mL) was
added K CO (1.244 g, 9 mmol), MeI (0.37 mL, 6 mmol) and stirred at room temperature
2
3
for 3 h. The mixture was quenched with H O, extracted with ethyl ether, washed with brine
2
and dried over anhydrous Na SO . The solvent was evaporated under the reduced pressure
2
4
and the residue was purified by column chromatography on silica gel (eluent: petroleum
1
ether: ethyl acetate = 7.5:1 to 5:1 to 3:1) to afford 2g (214.1 mg, 48%) as colorless oil. H
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7
8
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NMR (400 MHz, CDCl ) δ 7.60 (d, J = 8.0 Hz, 1H), 7.51-7.47 (m, 1H), 7.41-7.39 (m, 1H),
3
1
3
1
7.23 (t, J = 7.6 Hz, 1H), 4.15 (s, 3H). C{ H} NMR (100 MHz, CDCl ) δ 166.9, 163.8,
3
1
1
30.2, 122.8, 120.6, 113.9, 110.0, 57.1. IR (neat): 2987, 2943, 1613, 1541, 1453, 1390,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
-1
+
235, 746 cm . HRMS (EI-TOF) calcd for C H NO [M] : 149.0477, found 149.0479.
8
7
2
Propargyl esters 6 were synthesized by the protection of corresponding propargyl
alcohols.25,26
For the characterization of new propargyl esters, see following:
1-(3,4,5-Trimethoxyphenyl)prop-2-yn-1-yl benzoate (6c). 10 mmol scale. Column
chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 5:1) to afford the
1
title compound (2.985 g, 91%) as light yellow oil. H NMR (400 MHz, CDCl ) δ 7.95 (d, J
3
=
7.6 Hz, 2H), 7.41 (t, J = 7.6 Hz, 1H), 7.29 (t, J = 8.0 Hz, 2H), 6.76 (s, 2H), 6.54 (d, J =
13
1
2
.0 Hz, 1H), 3.75 (s, 6H), 3.73 (s, 3H), 2.66 (d, J = 2.4 Hz, 1H). C{ H} NMR (100 MHz,
CDCl ) δ 165.0, 153.1, 138.3, 133.1, 131.7, 129.5, 129.2, 128.2, 104.7, 79.9, 75.7, 65.7,
3
-1
6
0.5, 55.8. IR (neat): 3291, 3000, 2940, 2835, 2252, 1719, 1593, 1151 cm . HRMS
+
(EI-TOF) calcd for C H O [M] : 326.1154, found 326.1155.
1
9
18
5
1
-(4-Chlorophenyl)prop-2-yn-1-yl benzoate (6d).
5
mmol scale. Column
chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 20:1) afforded the
1
title product (1.14 g, 84%) as yellow oil). H NMR (400 MHz, CDCl ) δ 7.97 (d, J = 7.6
3
Hz, 2H), 7.48-7.46 (m, 3H), 7.36-7.28 (m, 4H), 6.58 (d, J = 1.6 Hz, 1H), 2.62 (d, J = 2.4
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4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
3
1
Hz, 1H). C{ H} NMR (100 MHz, CDCl ) δ 165.2, 135.0, 133.4, 129.8, 129.3, 129.1,
3
128.9, 128.4, 79.8, 76.0, 65.0. IR (neat): 3260, 3079, 2932, 2121, 1721, 1491, 1247, 1067
-1
+
cm . HRMS (EI-TOF) calcd for C H O Cl [M] : 270.0448, found 270.0453.
1
6
11
2
0
1
2
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6
7
8
9
0
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6
7
8
9
0
General procedure for the synthesis of 2H-benzo[e][1,3]oxazine 3.
Typical procedure for the synthesis of 3a.
To a Schlenk tube were added ynamide 1a (90.4 mg, 0.3 mmol), DCE (3 mL),
benzo[d]isoxazole 2a (70.3 mg, 0.36 mmol) and JohnphosAu(MeCN)SbF (catalyst A)
6
(
11.6 mg, 0.015 mmol) under Argon. After the reaction mixture was stirred at room
temperature for 6 h as monitored by thin-layer chromatography, the solvent was
evaporated under the reduced pressure and the residue was purified by column
chromatography on silica gel (eluent: petroleum ether: ethyl acetate: dichloromethane =
2
0:2:1 to 10:1:1 to 10:1:2) to afford 3a in 92% yield (137.1 mg, E/Z = 7.1:1) as a red solid.
4-Methoxy-N-methyl-N-(phenyl(4-phenyl-2H-benzo[e][1,3]oxazin-2-ylidene)methyl)b
1
enzenesulfonamide (3a). E-isomer: H NMR (400 MHz, CDCl ) δ 7.92 (d, J = 7.6 Hz,
3
2H), 7.71 (d, J = 8.8 Hz, 2H), 7.47-7.30 (m, 9H), 7.26-7.21 (m, 1H), 6.98 (d, J = 8.8 Hz,
1
3
1
2
H), 6.55 (d, J = 8.4 Hz, 2H), 3.60 (s, 3H), 3.28 (s, 3H). C{ H} NMR (100 MHz, CDCl )
3
δ 162.0, 159.8, 154.8, 150.0, 136.6, 135.2, 134.2, 131.6, 130.0, 129.7, 128.6, 127.9, 127.9,
127.4, 127.1, 126.8, 123.0, 116.4, 116.2, 115.8, 113.0, 55.0, 38.1. Partial NMR for
1
Z-isomer: H NMR (400 MHz, CDCl ) δ 7.84 (d, J = 7.6 Hz, 2H), 7.80 (d, J = 8.8 Hz, 2H),
3
1
3
1
7.67-7.65 (m, 2H), 6.85 (d, J = 8.8 Hz, 2H), 6.29 (d, J = 8.4 Hz, 1H), 3.73 (s, 3H). C{ H}
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NMR (100 MHz, CDCl ) δ 162.4, 161.2, 155.0, 149.2, 136.4, 135.5, 133.8, 131.9, 130.3,
3
129.4, 128.9, 128.5, 128.3, 127.5, 126.6, 122.8, 116.5, 115.8, 115.5, 113.6, 55.4, 37.1. IR
-1
(
neat): 3053, 2924, 2851, 1595, 1577, 1336, 1145, 1020 cm . HRMS (ESI-TOF) calcd for
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
C H N O S [M+H] : 497.1530, found 497.1523.
2
9
25
2
4
N-Methyl-N-(phenyl(4-phenyl-2H-benzo[e][1,3]oxazin-2-ylidene)methyl)methanesulfo
namide (3b). Following the typical procedure, 0.3 mmol scale, 1b (62.8 mg, 0.3 mmol), 3
mL DCE, 2a (70.3 mg, 0.36 mmol), catalyst A (11.6 mg, 0.015 mmol) were stirred at room
temperature for 6 h. Column chromatography on silica gel (eluent: petroleum ether: ethyl
acetate: dichloromethane = 20:1:1 to 10:1:1 to 5:1:1) afforded the Z-3b in 11% (13.5 mg)
yield as a red solid and E-3b which was further purified by Recycling Preparative HPLC in
o
1
57% (69.1 mg) yield as a red solid. E-isomer: m.p. 211-213 C. H NMR (400 MHz,
CDCl ) δ 7.90 (d, J = 8.0 Hz, 2H), 7.69-7.67 (m, 2H), 7.54-7.51 (m, 3H), 7.46-7.39 (m,
3
13
1
4
H), 7.26 (t, J = 7.6 Hz, 1H), 7.05-7.02 (m, 2H), 3.26 (s, 3H), 2.95 (s, 3H). C{ H} NMR
(100 MHz, CDCl ) δ 161.2, 154.9, 150.2, 135.8, 135.5, 134.6, 130.5, 128.5, 128.1, 127.5,
3
1
27.1, 123.3, 116.6, 116.2, 115.9, 38.9, 37.6. IR (neat): 3058, 3032, 2934, 1576, 1532,
-1
+
1324, 1138 cm . HRMS (ESI-TOF) calcd for C H N O S [M+H] : 405.1267, found
2
3
21
2
3
o
1
4
2
05.1255. Z-isomer: m.p. 198-200 C. H NMR (400 MHz, CDCl ) δ 7.83 (d, J = 8.0 Hz,
3
H), 7.72-7.69 (m, 2H), 7.51-7.45 (m, 5H), 7.35 (t, J = 7.6 Hz, 2H), 7.22 (t, J = 7.6 Hz,
1
3
1
1H), 7.09-7.02 (m, 2H), 3.31 (s, 3H), 3.07 (s, 3H). C{ H} NMR (100 MHz, CDCl ) δ
3
1
61.5, 155.5, 149.5, 135.7, 135.7, 134.5, 130.5, 129.0, 128.6, 128.5, 127.8, 127.8, 127.0,
123.3, 117.1, 115.7, 115.5, 39.2, 37.0. IR (neat): 3055, 2932, 1579, 1538, 1322, 1139, 963
2
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