AgOTf-catalyzed cycloisomerization of alkynyl oxiranes for dihydro-1,4-oxazine synthesis

Article abstract of DOI:10.1055/s-0031-1290466

The efficient AgOTf-catalyzed isomerization reactions of various alkynyl oxiranes and alkynyl allyl alcohols were carried out at room temperature with moderate to good yields. This is an economical and mild method for the construction of O-heterocyclic co

Full text of DOI:10.1055/s-0031-1290466

LETTER
▌2481
lAettgerOTf-Catalyzed Cycloisomerization of Alkynyl Oxiranes for Dihydro-
1,4-oxazine Synthesis
Silver-Catalyzed Cycloisomerization to O-Heterocycles
Muchchintala Maheswara, Yun Yeong Lee, Eun Joo Kang*
Department of Applied Chemistry, Kyung Hee University, Yongin, Gyeonggi, 446-701, Korea
Fax +82(31)2012340; E-mail: ejkang24@khu.ac.kr
Received: 20.07.2012; Accepted after revision: 26.08.2012
of 2,3-epoxy alcohol functionality, and Gansäuer and co-
workers reported the [Cp2TiCl]-catalyzed five-membered
carbocycle synthesis by reductive opening to titanoxy rad-
icals.5 In addition, tungsten-mediated [3+2] or [3+3] cy-
cloaddition for bicyclic lactone or pyrane synthesis was
reported by Liu and co-workers, and nickel-catalyzed re-
ductive cyclization via disfavored endo epoxide opening
was reported by Jamison and co-workers.6 Gold and plat-
inum were also used in this cycloisomerization, however
new C–O bonds were introduced; Shi and co-workers re-
ported gold(I)-catalyzed cascade reactions that provided
bicyclic ketals through the use of alcohol, and Fang and
co-workers reported platinum(II)-catalyzed dihydro-1,4-
oxazine formation reactions.7 Our interest in metal-cata-
lyzed domino reactions prompted us to investigate this
kind of reaction. Herein, we disclose a silver-catalyzed
cycloisomerization that proceeded in a distinct way to af-
ford the dihydro-1,4-oxazines under milder conditions
than those used in the first report on platinum-catalyzed
reactions.
Abstract: The efficient AgOTf-catalyzed isomerization reactions
of various alkynyl oxiranes and alkynyl allyl alcohols were carried
out at room temperature with moderate to good yields. This is an
economical and mild method for the construction of O-heterocyclic
compounds.
Key words: cyclization, isomerization, alkynes, epoxides, Lewis
acids, silver, heterocycles, domino reaction
The activation of functional groups such as carbonyls, im-
ines, alkenes and alkynes, through coordination with
Lewis acids is a useful and important method for facilitat-
ing many different types of organic transformations. In re-
cent years, alkyne activation with gold and platinum
complexes has attracted keen interest from a number of
organic chemists, because the activation brings about im-
portant molecular transformations, such as cyclization,
cycloisomerization, and cycloaddition, for the synthesis
of carbocyclic and heterocyclic compounds.1 Moreover,
alkynes having additional functional groups such as epox-
ides and aziridines2 could be great precursors for the direct
and efficient synthesis of more complex heterocycles. In
order to develop this kind of intramolecular tandem cycli-
zation, the selective reactivity of the Lewis acid to activate
the alkynyl group and other groups, as well as the subse-
quently formed alkenyl group should be taken into consid-
eration. Indeed, various Lewis acids can build numerous
types of ring frameworks, and the outcome can depend on
subtle changes in the reaction conditions.3
Alk-4-ynyl oxirane 1a was chosen as the substrate for the
screening of catalyst systems (Table 1). The cycloisomer-
ization reactions were carried out at room temperature for
1 h at a concentration of 0.2 M in solvent unless otherwise
specified. Employing oxophilic Lewis acid catalysts such
as BF3·OEt2, Sc(OTf)3 or Fe(OTf)3 afforded a mixture of
allyl alcohol 3a by E2-type ring opening and isopropyl ke-
tone 4a by pinacolic rearrangement,8 indicating that these
catalysts showed lower reactivities as π-activators (entries
1–3). Next, we examined silver(I) salts displaying both
π-electrophilic Lewis acid character to activate the C–C
multiple bond, and σ-electrophilic Lewis acid character to
activate the C=X bond in the various tandem catalyses.9
When AgOTf was used as catalyst at room temperature
for 1 h (entry 4), the cycloisomerization reaction proceed-
ed smoothly to afford dihydro-1,4-oxazine 2a in 54%
yield, and a trace amount of ketone 4a was obtained. It is
noteworthy that the dihydro-1,4-oxazine framework is
found in many biologically active compounds,10 and the
previous report on the PtCl2 and PPh3AuCl-catalyzed syn-
thesis featured reflux conditions for 24 h to afford 2a in 62
and 50% yield, respectively.7c Encouraged by this result,
we then screened other silver salts. Reactions with AgOTs
and AgTFA having lower cationic character on Ag re-
quired elevated reaction temperature and extended reac-
tion time (2 h; entries 5 and 6), however, the isolated yield
of 2a decreased owing to the formation of a mixture of by-
products. No progress was observed in the reaction using
Looking through the previous results regarding the reac-
tions of alkynyl oxiranes, cycloisomerization of alk-1-
ynyl oxiranes have been the subject of intense study for
highly substituted furan synthesis. There are several re-
ports for such transformations: the KH or t-BuOK-
catalyzed reaction via a cumulene anion,4a molybdenum
[Mo(CO)5] or ruthenium [TpRuPPh3(CH3CN)Cl]-
catalyzed reaction via vinylidene intermediates,4b,c and
gold (AuCl3), platinum (PtCl2) or silver (AgOTf)-cata-
lyzed reaction via vinyl metal species.4d–f Among the oth-
er types of alkynyl oxiranes, alk-4-ynyl oxiranes attracted
the attention of chemists because their use resulted the
generation of various cyclization patterns with a wide
range of metal salts. Marson et al. reported the TiCl4-in-
duced seven-membered carbocycle synthesis with the aid
SYNLETT 2012, 23, 2481–2484
Advanced online publication: 28.09.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0031-1290466; Art ID: ST-2012-U0609-L
© Georg Thieme Verlag Stuttgart · New York

2482
M. Maheswara et al.
LETTER
Table 2 Silver(I)-Catalyzed Dihydro-1,4-oxazine Synthesis; Sub-
Table 1 Optimization of the Cycloisomerization of 1a
strate Scopea
10 mol%
catalyst
..
TsN
TsN
OH
TsN
O
TsN
O
R2
R2
X
+
R2
X
R1
+
O
R1
R1
solvent
10 mol% AgOTf
CH2Cl2, r.t. 1 h
X
O
O
+
1a
3a
4a
2a
O
Entry
Catalyst
Solvent
Temp (°C)
Yield (%)b
R3
R3
R3
1
2
4
2a
3a 4a
14 11
46 20
32 20
Entry X
R1
R2
R3 Product Yield
(%)b
1
BF3·OEt2
Sc(OTf)3
Fe(OTf)3
AgOTf
AgOTs
AgTFA
AgOBz
AgSbF6
AgBF4
DCE
25
25
25
25
45
45
25
25
25
25
25
25
0
2
DCE
0
1
NTs
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
2a
2b
2c
2d
2e
2f
54
42
55
47
48
0
3
DCE
0
2
NSO2Mes
4
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DCE
54
44
12
0
0
<5
0
3
NSO2(4-PhC6H4)
5c
6c
7
36
4
NSO2(4-MeOC6H4)
10 36
5
NSO2(2-NO2C6H4)
0
0
6
NBoc
NCbz
NTs
8
<5
<5
40
0
26 21
22
<5 19
7
2g
2h
2i
0
9
0
8
CO2Et
Ph
Me
H
55
20
33
61
48
56
0
10
11
12
13
14
15c
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
pTsOH
9c
10d
11e
12e
13e
14
15
NTs
MeCN
MeNO2
0
<5
29
0
NTs
2j
9
0
NTs
Me
H
2k
benzene 25
21
17
0
10
NTs
H
Me 2l
toluene
toluene
25
14 17
0 37
NTs
H
H
iPr 2m
120
C(CO2Et)2
O
H
H
H
H
2n
2o
a Reactions and conditions: alkynyl oxirane 1a (0.25 mmol), catalyst
(10 mol%), solvent (0.2 M), 1 h under N2, unless otherwise specified.
b Isolated yield after chromatographic purification.
c Reaction ran for 2 h.
H
H
0
a Reactions and conditions: alkynyl oxirane (1; 0.25 mmol), catalyst
(10 mol%), solvent (0.2 M), 1 h under N2, unless otherwise specified.
b Isolated yield of 2 after chromatographic purification.
c Reaction in benzene at 80 °C for 12 h.
AgOBz, and AgSbF6 and AgBF4 gave only trace amounts
of product 2a, demonstrating that AgOTf was the most ef-
fective (entries 7–9). During solvent optimization studies
(entries 10–14), other chlorinated solvents, polar solvents,
and aromatic solvents were shown to provide little benefit
relative to dichloroethane (DCE). On the basis of these re-
sults, we performed an acid-catalyzed control experiment
with pTsOH, which resulted in 37% yield of 4a even with
a prolonged reaction time (2 h) under reflux conditions
(entry 15).
d Reaction in DCE at 50 °C for 6 h.
e Reaction with AgOTs in DCE at 50 °C for 12 h.
(2,4,6-trimethylphenyl) group depleted the yield to 42%.
Unlike sulfonyl amide, carbamate derivatives with a Boc
or Cbz group did not demonstrate any reactivity in the cy-
cloisomerization reactions (entries 6 and 7). Next, a vari-
ety of substituents, R1, R2 and R3 were evaluated. The
electron-withdrawing group on the alkyne facilitated the
reaction, affording compound 2h in 55% yield, by making
the β-position of the ester more electrophilic (entry 8).
Other substrates possessing Ph or Me substituents on the
alkyne participated in the reaction, but yielded ketone by-
products to a similar extent (4i, 27%; 4j, 26%), even under
heating to promote the cyclization pathway. Ketones 4i
and 4j, which showed a more polar character than the ox-
azine products, could be isolated by column chromatogra-
phy, and seemed not to be the assumed reaction
intermediates by TLC analysis of the cycloisomerization
reactions. In addition, when alkynyl oxirane 1k, having
With these optimal conditions in hand, we explored the
generality of this process (Table 2). Various alkynyl oxi-
ranes were easily prepared by epoxidation of the corre-
sponding enynes, which were synthesized by Mitsunobu
reactions with propargyl amides and allyl alcohols. The
substituents on the amine group subtly affected the reac-
tivity; several sulfonyl amides afforded the desired prod-
ucts 2a–e in good yield (entries 1–5), regardless of having
electron-withdrawing or electron-donating substituents
on its phenyl ring, although the sterically hindered mesityl
Synlett 2012, 23, 2481–2484
© Georg Thieme Verlag Stuttgart · New York

LETTER
Silver-Catalyzed Cycloisomerization to O-Heterocycles
2483
the methyl substituent on the propargyl position (R2), was
treated with 15 mol% AgOTs under heating, cyclized ox-
azine 2k was obtained in 61% yield (entry 11), whereas
treatment with AgOTf did not furnish any product, result-
ing in a complex mixture containing ketone 4k as a major
product. When one methyl substituent (R3) of oxirane was
changed into either an ethyl or isobutyl group (entries 12
and 13), the anticipated epoxide opening took place to af-
ford products 2l and 2m in good yield under heating with
AgOTs in DCE. Removing one alkyl substituent of oxi-
rane to generate a disubstituted substrate eliminated the
reactivity towards the Ag catalyst (data not shown).
Switching the NTs group to C(CO2Et)2 or using an oxygen
atom as a linker also led to no progress in the cycloisomer-
ization reactions (entries 14 and 15).
R1
R1
R1
10 mol% AgOTf
TsN
O
TsN
OH
TsN
O
+
CH2Cl2
3a R1 = H
3i R1 = Ph
25 °C, 1 h
2a 79%
2i 16%
4a 0%
4i 28%
50 °C, 12 h
Scheme 2 Cyclization reactions of alkynyl allyl alcohols
Subsequently, two proposed pathways are possible de-
pending on the electrophilic C–C multiple bonds that at-
tend the cyclization; one route proceeds through allene
formation from the propargyl unit followed by cyclization
of allenol C, whereas the second route proceeds through
direct cyclization to the alkyne and sequential double
bond isomerization reactions. The mechanism involving
allenol C is considered more likely than the alternative on
the basis of the following results:7c,11b (1) no exo-methy-
lene intermediate E in reactions of 1h and 1i was ob-
served, even though this would increase the conjugated
system, and (2) the methyl substituent in 1k did not in-
crease the rate of cyclization.
We wondered whether this interesting Ag(I)-catalyzed re-
action could be successfully extended to a nucleophilic al-
cohol addition followed by a cyclization reaction. To test
this, the reaction of alkynyl oxirane 1a with MeOH cata-
lyzed by 5 mol% AgOTf was carried out (Scheme 1). The
formation of ring-opened alkynol 5 by selective oxirane
activation followed by alcohol addition was observed to
take place in high yield and subsequent cyclization by the
newly formed hydroxyl group proceeded smoothly to af-
ford dihydro-1,4-oxazine 6. Treatment of 1a with isopro-
pyl or benzyl alcohol instead of methanol gave complex
mixtures, and reaction with tBuOH resulted in the forma-
tion of 2a (43%) without any participation of alcohol.
AgI
AgI
•
allene
formation
oxirane
opening
TsN
TsN
OH
OH
TsN
AgI
H
O
A
B
C
allene
formation
cyclization
cyclization
10 mol% AgOTf
10 mol% AgOTf
5 equiv MeOH
TsN
O
TsN
TsN
CH2Cl2, r.t. 1 h
OH
CH2Cl2, r.t. 1 h
88%
OMe
•
isomer-
ization
O
TsN
O
TsN
TsN
O
97%
OMe
O
1a
5
6
F
D
E
Scheme 1 AgOTf-catalyzed addition of alcohol nucleophile and
cyclization reaction
Scheme 3 Proposed mechanism of the silver-catalyzed cycloisomer-
ization of alkynyl oxiranes
To provide insight into the cycloisomerization mecha-
nism, we examined the Ag-catalyzed cyclization reactions
of alkynyl allyl alcohols, which were supposed to be the
reaction intermediates of the cycloisomerization reactions
(Scheme 2).11 Alkynyl allyl alcohol 3a, prepared from the
Sc(OTf)3-catalyzed reaction of 1a, was transformed into
In conclusion, we have developed a simple and economi-
cal synthetic method that can be used to obtain a range of
dihydro-1,4-oxazines from alkynyl oxiranes and alkynyl
allyl alcohols.12 The cycloisomerization reactions were
the corresponding product 2a in high yield within one performed with the AgOTf catalyst under mild conditions
hour under the same reaction conditions in the presence of
10 mol% AgOTf catalyst. The cyclization reaction of 3i
resulted in the formation of 2i (16%) with a significant
amount of 4i, which is a similar result to that obtained
with the tandem cyclization reaction of 1i shown in Table
2. The result indicates that ketone 4, derived from allyl al-
cohol, does not participate in the cyclization pathway.
and were successfully extended to the addition of alcohol
followed by cyclization. Efficient domino reactions using
various functional groups such as C–C multiple bonds and
versatile three-membered heterocycles are currently being
investigated.
Acknowledgment
Based on the above experimental results, this reaction
might proceed through a tandem sequence involving the
first step of ring opening of oxirane (Scheme 3). Selective
activation of the epoxy group in A by Ag(I) followed by
ring opening afforded the allyl alcohol intermediate B.
This work was supported by a post-doctoral fellowship grant from
the Kyung Hee University in 2011 (KHU-20110218).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SupInpfioomgrattr
o
nSupprigI
o
tnnofrmat
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2481–2484

2484
M. Maheswara et al.
LETTER
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Synlett 2012, 23, 2481–2484
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