Fe(II)/Au(I) Relay Catalyzed Propargylisoxazole to Pyridine Isomerization: Access to 6-Halonicotinates

Article abstract of DOI:10.1021/acs.joc.7b00736

An efficient synthesis of methyl nicotinates/6-halonicotinates by the domino isomerization of 4-propargyl/(3-halopropargyl)-5-methoxyisoxazoles under Fe(II)/Au(I) relay catalysis was developed. It was found that FeNTf₂ is an effective catalyst

Full text of DOI:10.1021/acs.joc.7b00736

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Article
Fe(II)/Au(I) Relay Catalyzed Propargylisoxazole to
Pyridine Isomerization: Access to 6-Halonicotinates
Alexey V. Galenko, Firuza M. Shakirova, Ekaterina E. Galenko,
Mikhail Sergeevich Novikov, and Alexander F. Khlebnikov
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 28 Apr 2017
Downloaded from http://pubs.acs.org on April 28, 2017
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Fe(II)/Au(I) Relay Catalyzed Propargylisoxazole to
Pyridine Isomerization: Access to 6ꢀHalonicotinates
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Alexey V. Galenko, Firuza M. Shakirova, Ekaterina E. Galenko, Mikhail S. Novikov and
Alexander F. Khlebnikov*
Saint Petersburg State University, Institute of Chemistry, 7/9 Universitetskaya nab.,
St. Petersburg, 199034 Russia.
KEYWORDS: gold, homogeneous catalysis, iron, isoxazole, pyridine.
ABSTRACT: An efficient synthesis of methyl nicotynates/6ꢀhalonicotinates by the domino
isomerization of 4ꢀpropargyl/(3ꢀhalopropargyl)ꢀ5ꢀmethoxyisoxazoles under Fe(II)/Au(I) relay
catalysis was developed. It was found that FeNTf is effective catalyst for first step of the domino
2
isomerization, transformation of isoxazole to 2Hꢀazirine, which is compatible with Ph PAuNTf ,
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catalyzing the second step.
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INTRODUCTION
Pyridine is one of the most important nitrogen heterocycles found in natural products, is widely
exploited in pharmaceutical and agrochemistry, and industry. This has led to the development a
plethora of methods for their preparation. Nevertheless new synthetic strategies, based on recent
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developments in organic synthesis, still need to be explored due to, in particular, all increasing use
2
of pyridine derivatives as ligands. 2ꢀHalopyridines are important building blocks for synthesis of
both pyridine derivatives and diverse pyridineꢀcontaining heterocycles via crossꢀcoupling
3
, 4
reactions. Preparation of 2ꢀhalopyridines by direct halogenation of substituted pyridines suffers
5
from poor regioselectivity and low reactivity of pyridine core. Halogenation of pyridine Nꢀoxides
with phosgene, POX , SOX and other halogenating agents is used more successfully; however the
3
2
problem of selectivity and using harsh reaction conditions are often characteristic of this approach
6
too. The examples of the formation of 2ꢀhalopyridine derivative from acyclic precursor, which are
rare and very specific, are represented by the cyclization of 3ꢀaminoꢀ5ꢀarylꢀ2,4ꢀdicyanopentaꢀ2,4ꢀ
dienimidoyl
bromide/chloride
and
1ꢀalkylꢀ4ꢀaminoꢀ4ꢀbromo/chloroꢀ1ꢀoxobutꢀ3ꢀeneꢀ2,2,3ꢀ
tricarbonitrile providing 6ꢀarylꢀ4ꢀaminoꢀ2ꢀhalopyridineꢀ3,5ꢀdicarbonitriles and methyl 6ꢀalkylꢀ3ꢀ
7
cyanoꢀ2ꢀhalopyridineꢀ4ꢀcarboxylates. Three approaches to 2ꢀhalopyridines involving the formation
of two bonds of the pyridine ring were also reported. In the first two, the C2ꢀC3 and C4ꢀC5 bonds of
the pyridine system were formed via a twoꢀstep procedure involving DielsꢀAlder reaction of
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8f, 9
halogenated 1,2,4ꢀtriazines or 2Hꢀ1,4ꢀoxazineꢀ2ꢀones
with unsaturated compounds followed by
nitrogen or carbon dioxide extrusion. The complementary approach via DielsꢀAlder reaction of
chlorophenylacetylene with methyl 3ꢀ((trimethylsilyl)oxy)ꢀ2ꢀ(((trimethylsilyl)oxy)imino)butꢀ3ꢀ
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enoate is not effective, leading to the mixture of the corresponding 2ꢀ and 3ꢀchloropyridines.
Coupling of acetylenes, nitriles, and Ti(OꢀiꢀPr) /2 iꢀPrMgCl leads to azatitanacyclopentadienes
4
reacting with sulfonylacetylenes with formation of pyridyltitanium compounds, which give 2ꢀiodoꢀ
11
substituted pyridines in moderate yield by reaction with iodine.
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One of the most promising contemporary technics for the construction of molecular frameworks in
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a resourceꢀefficient and sustainable manner is relay multicatalysis. Despite the incredible potential
of this synthetic approach it still has rare been utilized for the formation a pyridine nucleus. Possible
reasons for this are necessity of orthogonal reactivity of catalysts and compatibility of every reaction
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component with a specific set of reaction conditions. The following works, where pyridine
13ꢀ16
derivatives were obtained under relay catalytic conditions, were published.
Tetrahydropyridine
derivatives were prepared utilizing an asymmetric organocatalytic nitroꢀMannich reaction of 5ꢀ
nitropentꢀ1ꢀynes with protected aldimines followed by
a
goldꢀcatalyzed alkyne
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hydroamination/isomerization sequence.
Functionalized 1,2ꢀdihydroisoquinolines were
synthesized by reaction of 2ꢀalkynylbenzaldehyde, aniline and α,βꢀunsaturated ketone under metal
1
4
(AgOTf) and organo (PPh ) catalysis. Enantioselective [4+2]ꢀcycloaddition reaction catalyzed by
3
chiral phosphoric acid and a subsequent catalytic intramolecular hydroamination by gold(I) complex
1
5
provides access to julolidine derivatives starting from 2ꢀpropargylanilines, aldehydes and enamine.
4ꢀSubstituted 1,2ꢀdihydroquinoline derivatives were prepared via indiumꢀcatalyzed intramolecular
hydroarylation of 2ꢀ(bromopropargyl)anilines followed by palladiumꢀcatalyzed crossꢀcoupling
16
reaction using triorganoindium reagents.
Recently Gagosz et al. discovered the effective goldꢀcatalyzed transformation of alkyl
1
7
2
ꢀpropargylꢀ2Hꢀazirineꢀ2ꢀcarboxylates to functionalized pyridines. Isoxazoles under certain
conditions can be transformed into 2ꢀcarbonylꢀsubstituted 2Нꢀazirines, and this isomerization can
serve as a reactivity switch that enables easier manipulation with substituents in an isoxazole, which
1
8
is usually much less reactive than an azirine counterpart. Taking all this into account and based on
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our experience in use of isoxazoles as synthetic equivalent of 2Нꢀazirines, we postulated that the
use of propargylꢀsubstituted isoxazoles in combination with an appropriate catalytic system could
allow easy direct access to pyridine derivatives, and in particular, highly synthetically useful 2ꢀ
halopyridines. Retrosynthetic scheme for the synthesis of nicotynates/6ꢀhalonicotinates from Cꢀ
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propargylated keto esters involves isoxazoleꢀazirine/azirineꢀpyridine isomerization cascade as the
key step of the synthetic sequence (Scheme 1). The advantages of this scheme are that it allows (a)
the lateꢀstage functionalization of the acetylenic moiety, and (b) avoiding working with unstable
azirines when implementing a domino variant of the isoxazoleꢀpyridine isomerization.
In this communication, we wish to report the synthesis of pyridines, including 2ꢀhalopyridines, by
the domino reaction of isoxazoles under Fe(II)/Au(I) relay catalysis (Scheme 1).
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Scheme 1. Retrosynthetic scheme for the synthesis of nicotinates from isoxazoles.
RESULTS AND DISCUSSION
At first we examined whether isoxazole 1a can undergo thermal conversion into pyridine 3a, but
only the starting material was found in the reaction mixture even after heating at high temperature
(Table 1, Entry 1). We decided, therefore, to check the ability of some metal salts and complexes,
1
8
which catalyze isomerization of 5ꢀalkoxyisoxazole to 2Hꢀazirineꢀ2ꢀcarboxylate, to induce the
subsequent conversion of azirine 2a to nicotinate 3a. Iron(II) chloride is well known to promote the
1
8ꢀ20
isoxazoleꢀazirine transformation,
and it was, therefore, not unexpected to obtain azirine 2a in a
nearly quantitative yield under reaction of isoxazole 1a at ambient temperature for 2 h (Table 1,
Entry 2), no other products were, however, detected in the reaction mixture even upon longer
heating at elevated temperature (Table 1, Entry 3). The similar result was obtained with
molybdenum hexacarbonyl, which was used as promoter of the 2Hꢀazirine–isoxazole
1
8, 21
interconversion (Table 1, Entry 4).
Copper(I) NHC complex (IPrCuCl), which was reported as
2
2
catalyst for NꢀC(2) azirine bond cleavage, showed ability to catalyze both the isomerization of
isoxazole 1a to azirine 2a, and the formation of nicotinate 3a, although in lesser extent (Table 1,
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Entry 5). We observed only a resignification of isoxazole 1a under the reaction conditions, which
were used for transformation of 2ꢀallylꢀ2Hꢀazirines to pyridines promoted by 1,8ꢀ
2
3
diazabicyclo[5.4.0]undecꢀ7ꢀene (DBU) (Table 1, Entry 6). However addition of DBU to the
reaction mixtures containing azirine 2a, which was formed from isoxazole 1a under metal catalysis,
afforded nicotinate 3a in moderate yields (Table 1, Entries 7ꢀ9). Isoxazole 1a remained intact under
heating in the presence of Auꢀcomplexes (Table 1, Entries 10ꢀ12), although it was reported that
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isoxazoles react under goldꢀcatalysis with ynamides giving substituted pyrroles. Refluxing azirine
2
a in 1,2ꢀdichloroethane (DCE) in the presence of catalytic amount of Rh (OAc) , AgOTf,
2
4
Ph PAuCl showed no reaction, whereas in the presence of ZnBr and Ph PAuNTf 32 and 90%,
3
2
3
2
respectively, of nicotinate 3a was formed. These experiments revealed that two different catalysts
are required to transform isoxazole 1a to nicotinate 3a: (1) for isomerization of isoxazole 1a to
azirine 2a, most probably derivatives of Fe(II) and (2) for isomerization of azirine 2a to nicotinate
3
a, most probably derivatives of Au(I). Addition of PhPAuNTf to the reaction mixture containing
2
azirine 2a, formed under the FeCl ·4H O catalyzed isomerization of 1a, gave 55/26 mixture of
2
2
2
a/3a before catalytic system became inactive due to gold reduction under the reaction conditions to
form “gold mirror” (Table 1, Entry 13). Our assumption, that the chloride ion is responsible for
decreasing of catalytic activity of the gold(I) complex was confirmed by the experiment where
AgOTf was used as additive to precipitate off chloride ion: 3a was obtained in high yield and only
2
3% of 2a left intact (Table 1, Entry 14). Use of silver AgNTf instead of AgOTf in 1,2ꢀ
2
dichloroethane gave even better result (Table 1, Entries 15, 16). Elimination of chloride ions from
the reaction mixture by use of airꢀstable non hydroscopic bis((trifluoromethyl)sulfonyl)amide
iron(II), which has not earlier been reported as a catalyst for isomerization of 5ꢀalkoxyisoxazole to
2
Hꢀazirineꢀ2ꢀcarboxylate, gave the best result (Table 1, Entry 17). The reaction was then performed
under the conditions of domino relay catalysis, affording practically the same isolated yield of
nicotinate 3a (Table 1, Entry 18).
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Table 1. Optimization of catalytic system.
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a
b
Entry Catalyst or additive A/B
Solvent Temperature, Time,
Yield
1
2
1
2
T /T [°C]
Dioxane 155
MeCN 24
t / t [h] of 2/3 [%]
1
2
3
4
5
6
7
8
9
1
1
1
1
1
ꢀ
6
0/0
FeCl ·4H O
2
98/0
89/0
95/0
75/15
0/0
2
2
FeCl ·4H O
Dioxane 155
Dioxane 85
Dioxane 85
6
2
2
Mo(CO)6
36
CuIPrCl
36
d
DBU
PhCl
130
6
d
FeCl ·4H O/DBU
Dioxane 155/155
Dioxane 85/155
Dioxane 85/155
6/6
36/24
36/24
18
0/28
0/26
0/38
ꢀ
2
2
d
Mo(CO) /DBU
6
d
IPrCuCl/DBU
0
1
2
3
4
Ph PAuCl+AgOTf
DCE
DCE
DCE
DCE
DCE
MeCN
DCE
DCE
DCE
85
3
IPrAuCl+AgOTf
Ph PAuNTf
85
18
ꢀ
85
18
ꢀ
3
2
FeCl ·4H O/Ph PAuNTf
2
85/85
85/85
85/85
85/85
85/85
85
1/12
1/12
1/24
1/24
1/24
24
55/26
23/75
68/27
16/82
2
2
3
e
FeCl ·4H O+AgOTf /Ph PAuNTf
2
2
2
3
e
15
FeCl ·4H O+AgNTf /Ph PAuNTf
2 2 2 3
2
e
1
6
FeCl ·4H O+AgNTf /Ph PAuNTf
2 2 2 3
2
c
17
FeNTf /Ph PAuNTf
2
5/93 (71 )
2
3
c
1
8
FeNTf +Ph PAuNTf
2
ꢀ/72
2
3
a
Catalyst or additive loading was 5 mol% unless otherwise stated.
Yields were determined by H NMR spectroscopy with 2ꢀmethylnaphthalene as internal
b
1
standard.
Isolated yield.
300 mol%.
c
d
e
1
0 mol%.
With optimal reaction conditions in hand, we performed isomerizations of isoxazoles 1a-i, with
various substituents in position 3, into nicotinates 3a-i. 3ꢀAryl and 3ꢀalkyl substituted 5ꢀmethoxyꢀ4ꢀ
(propꢀ2ꢀynꢀ1ꢀyl)isoxazoles 1a-i upon heating in 1,2ꢀdichloroethane in the presence of Fe(NTf ) and
2
2
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Au(PPh )NTf afforded 2ꢀsubstituted nicotinates in high yields with the exception for 3ꢀ
3
2
cyclopropylisoxazole (Table 2). 3ꢀBromophenylꢀ, 4ꢀnitrophenyl, cyclopropyl and tertꢀbytyl
substituted isoxazoles needed longer time for the isomerization. Besides, 3ꢀalkyl substituted
isoxazoles required higher gold(I) catalyst loading for the reaction to complete.
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Table 2. Synthesis of 2ꢀsubstituted methyl nicotinates from 4ꢀpropargylisoxazoles under
a
Fe(II)/Au(I) relay catalysis.
N O
CO Me
2
Fe(NTf ) , AuPPh NTf
2
2 2
3
R
OMe
o
DCE, 85 C
N
R
1
a-i
3a-i
b
Entry R
Time, [h]
Yield, [%]
1
2
3
4
5
6
7
8
9
a, Ph
b, 4ꢀMeC H
20
20
18
22
24
30
32
38
46
72
82
94
91
90
67
90
61
93
6
4
c, 4ꢀMeOC H
6
4
d, 4ꢀClC H
6
4
e, 4ꢀBrC H
6
4
f, 3ꢀBrC H
6
4
g, 4ꢀNO C H
4
2
6
c
h, cꢀC H
3
5
c
i, tꢀC H
4
9
a
A mixture of 0.5 mmol of 1, 25 ꢁmol (5 mol%) of Fe(NTf ) and 25 ꢁmol (5 mol%) of
2 2
Ph PAuNTf in 2 mL of DCE was heated at 85°C in a screwꢀcap tube.
3
2
b
c
Yield after column chromatography on silica deactivated by Et N.
3
5
0 ꢁmol (10 mol%) of Ph PAuNTf was used.
3 2
Bromine or iodine can be readily introduced to terminal acetylene carbon atom by reaction with
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Nꢀbromoꢀ or Nꢀiodosuccinimide in the presence of silver(I). This reaction can be used for the
preparation of 4ꢀ(3ꢀhalopropargyl)isoxazoles from the corresponding 4ꢀpropargylisoxazoles, but it is
useless for the synthesis of 2ꢀ(3ꢀhalopropargyl)ꢀ2Hꢀazirines from the corresponding 2ꢀpropargylꢀ
2
Hꢀazirines due to their instability under the halogenation conditions. Because of this, the discussed
transformation of isoxazoles could be potentially a useful method for the preparation of highly
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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
sought 2ꢀhalopyridines. 4ꢀ(3ꢀHalopropargyl)isoxazoles 4a-i,5a-c,6 were prepared from isoxazoles
a-i and Nꢀhalosuccinimides. To our delight all isoxazoles 4-6 obtained underwent the isomerization
3
under our standard Fe(II)/Au(I) relay catalysis conditions providing 6ꢀhalonicotinates in generally
good yields that were only a bit lower than for the corresponding nonꢀhalogenated nicotinates (Table
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
3
).
Table 3. Synthesis of 2ꢀsubstituted methyl 6ꢀhalonicotinates from 4ꢀ(3ꢀhalopropꢀ2ꢀynꢀ1ꢀ
a
yl)isoxazoles under Fe(II)/Au(I) relay catalysis.
b
Entry Isoxazole
R
Time, [h]
24
Yield, [%]
7a, 70
7b, 72
7c, 53
7d, 80
7e, 75
7f, 80
1
2
3
4
5
6
7
8
9
1
1
4a
4b
4c
4d
4e
4f
Ph
4ꢀMeC H
19
6
4
4ꢀMeOC H
30
6
4
4ꢀClC H
22
6
4
4ꢀBrC H
25
6
4
4ꢀNO C H
4
45
2
6
c
4g
4h
4i
Me
48
7g, 40
7h, 45
7i, 83
c
cꢀC H
44
3
5
c
tꢀC H
40
4
9
0
1
5a
5b
5c
6
Ph
23
8a, 88
8b, 67
8c, 71
9, 63
4ꢀMeOC H
23
6
4
12
4ꢀBrC H
24
6
4
1
3
Ph
21
a
A mixture of 1 mMol of 4-6, 50 ꢁmol (5 mol %) of Fe(NTf ) and 50 ꢁmol (5 mol%) of
2
2
Ph PAuNTf in 5 mL of DCE was heated at 85°C in a screwꢀcap tube.
3
2
b
Yield after column chromatography on silica deactivated by Et N.
3
c 25 ꢁmol (2.5 mol%) of Ph PAuNTf were added after first 24 hours of the reaction.
3
2
3
ꢀAlkylꢀsubstituted isoxazoles (4g-i) again required longer reaction times and bigger gold(I)
catalyst loads for the full conversion. The yields of 2ꢀmethylꢀ and 2ꢀcyclopropylꢀsubstituted methyl
6
ꢀbromonicotinates 7g,h are the lowest among of the investigated substrates. We suppose that the
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low yields of bromonicotinates 7g,h are caused by the relatively lower stability of the corresponding
starting isoxazoles and intermediate azirines.
It is worth mentioning that TMSꢀgroup of 4ꢀ(3ꢀ(trimethylsilyl)propꢀ2ꢀynꢀ1ꢀyl)isoxazoles is lost
partly or even completely under the transformation into nicotinates under the Fe(II)/Au(I) relay
catalysis conditions. Thus, only 15% of 6ꢀ(trimethylsilyl)nicotinate 11a, together with the main
product, nicotinate 3b, was isolated, when isoxazole 10a was used as the starting material. Isoxazole
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
1b gave only the desilylation product (3i) (Scheme 2).
Scheme 2. Isomerization of 4ꢀ(3ꢀ(trimethylsilyl)propꢀ2ꢀynꢀ1ꢀyl)isoxazoles to nicotinates under
Fe(II)/Au(I) relay catalysis.
Electronꢀdeficient aryl groups can be introduced to acetylene moiety of 4ꢀpropargylisoxazole by
copperꢀfree Sonogashira crossꢀcoupling protocol, e.g. 12. Diarylnicotinate 13 was prepared in
quantitative yield by domino isomerization of propargylisoxazole 12 under the relay catalysis
conditions (Scheme 3). Sonogashira reaction of 1b with electronꢀrich aryl iodides did not, however,
proceed in copperꢀfree conditions, while the standard crossꢀcoupling procedure gave low yields of
target products due to side reactions in the presence of copper catalyst.
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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
Scheme 3. Synthesis of 2,6ꢀdiarylated nicotinate under relay catalysis conditions.
A proposed mechanism for the formation of pyridines J, based on literature analysis of the
18ꢀ20, 26
transformations of 5ꢀalkoxyisoxazoles A under Fe(II)ꢀcatalysis
and the transformations of 2ꢀ
1
7, 27
propargylꢀ2Hꢀazirines E under Au(I)ꢀcatalysis,
is presented in Scheme 4. It involves the
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
isoxazole ring opening in isoxazole complex B with the formation of Feꢀnitrene complex C, the
cyclization of C into Feꢀazirine complex D, formation of Auꢀacetylene complex F, 5ꢀendoꢀdig
cyclization by nucleophilic attack into complex G followed by the azirine ring expansion in G and
proton transfer in H.
Scheme 4. Proposed mechanism of nicotinate formation under Fe(II)/Au(I) relay catalysis.
Finally, we tried some substitution and crossꢀcoupling reactions of 6ꢀhalonicotinates obtained
(Scheme 5). Reactions of 6ꢀbromonicotynates 7f and 7e with sodium 4ꢀchlorobenzenethiolate and
pyrrolidine proceeded smoothly to give products of nucleophilic aromatic substitution 14 and 15 in
excellent yields. Sonogashira crossꢀcoupling of 7c with hexꢀ1ꢀyn provided 6ꢀ(alkꢀ1ꢀynꢀ1ꢀ
yl)nicotinate 16 in quantitative yield under standard reaction conditions. Suzuki crossꢀcoupling
reaction of phenylboronic acid with methyl 6ꢀbromoꢀ2ꢀ(4ꢀchlorophenyl)nicotinate 7d proceeds
selectively affording 2,6ꢀdiarylnicotinate 17 in nearly quantitative yield. In contrast, methyl 6ꢀ
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bromoꢀ2ꢀ(4ꢀbromophenyl)nicotinate 7e gives bisꢀcrossꢀcoupling product, azaquaterphenyl 18, as the
result of substitution of both bromines in the starting material. These high yield reactions
demonstrate a high synthetic potential of 6ꢀhalonicotinates, which are available via the developed
method, for the preparation of variously substituted 2,6ꢀdisubstituted pyridines.
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. Synthesis of 2,6ꢀsubstituted nicotinates from 6ꢀhalonicotinates by SN ꢀ and crossꢀ
Ar
coupling reactions.
CONCLUSION
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5
5
5
6
In conclusion, an efficient synthesis of nicotynates by the domino isomerization of
propargylisoxazoles under Fe(II)/Au(I) relay catalysis was developed. Easy modification of
propargylisoxazoles into halopropargylisoxazoles provides direct approach to highly sought
6ꢀhalonicotinates. Use of bis((trifluoromethyl)sulfonyl)amide iron(II) as an airꢀstable non
hygroscopic catalyst for first step of the tandem isomerization, the transformation of isoxazole into
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
Hꢀazirine, allows realization of Fe(II)/Au(I) relay catalytic scheme due to that FeNTf does not
2
inhibit catalytic activity of gold(I) complexes. A high synthetic potential of 6ꢀhalonicotinates, which
are available via the developed method, for the preparation of variously substituted 2,6ꢀdisubstituted
pyridines by substitution and metalꢀcatalyzed crossꢀcoupling reactions was also demonstrated.
EXPERIMENTAL SECTION
General Information and Methods
1
Melting points were determined on a capillary melting point apparatus using unsealed capillary. H
13
(
400 MHz) and C (100 MHz) NMR spectra were recorded in CDCl with NMRꢀspectrometer.
3
Chemical shifts (δ) are reported in parts per million downfield from tetramethylsilane (TMS δ 0.00).
1
H NMR spectra were calibrated according to the residual peak of CHCl (7.26 ppm). For all new
3
1
3
1
13
nicotinates and isoxazoles C{ H} and C DEPT135 were recorded and calibrated according to the
peak of CDCl (77.00 ppm). Mass spectra were recorded on a HRMSꢀESIꢀQTOF massꢀanalyzer,
3
electrospray ionization, positive mode. Thinꢀlayer chromatography (TLC) was conducted on
aluminium sheets with 0.2 mm silica gel with fluorescent indicator, silica 60 M was used for column
chromatography.
Acetonitrile and 1,2ꢀdichloroethane were distilled successively over phosphorous pentoxide and
calcined potassium carbonate under argon atmosphere prior before use. Tetrahydrofuran,
1
,4ꢀdioxane and toluene were distilled from sodium benzophenoneꢀketyl. Triethylamine was
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distilled from sodium. Acetone was distilled from calcined potassium carbonate under argon
atmosphere. Commercial N,Nꢀdimethylformamide of HPLCꢀgrade was used without purification.
Synthesis of Starting Materials
Synthesis of Catalysts and Precursors
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
2
8
Synthesis of 3ꢀsubstitutedꢀ3ꢀoxopropanoates was performed according to the published procedure
with exception for commercial ethyl benzoylacetate and ethyl 3ꢀ(4ꢀnitrophenyl)ꢀ3ꢀoxopropanoate
that
were
used
without
was
purification.
synthesized by
Bis((trifluoromethyl)sulfonyl)amide
29
[
triphenylphosphane]gold(I)
V.
A. Rassadin
procedure.
3
0
Bis((trifluoromethyl)sulfonyl)amide iron(II) was synthesized by M. P. Sibi procedure.
General procedure I for the synthesis of alkyl 2-aroylpent-4-ynoates 19 (corresponds to slightly
31
modified procedure of B. Kirschleger et al). Alkyl 3ꢀarylꢀ3ꢀoxopropanoate (10 mmol) and
propargylbromide (1.31 g, 11 mmol) were dissolved in dry acetone (10 mL), calcined and mortarꢀ
grounded potassium carbonate (2.07 g, 15 mmol) and dry NaI (0.37 g, 2.5 mmol) were then added
and the mixture was stirred at room temperature until complete consumption of the starting ester
(monitored by TLC). The mixture was diluted with water, extracted with ether, the organic phase
was washed with water and brine, dried over sodium sulfate and all volatiles were removed in
vacuo. The product could be purified by column chromatography or vacuum distillation, but
generally it was used in further steps without any purification.
Ethyl 2-benzoylpent-4-ynoate 19a was obtained following the general procedure I from ethyl
3
ꢀoxoꢀ3ꢀphenylpropanoate (9.60 g, 50 mmol) in 9.50 g (83%) yield as a colorless oil, bp 130ꢀ5 °C
32
(
1.0 Torr) (lit. bp 130 °C (0.9 Torr) ). Spectral data were in agreement with previously reported
3
3
values.
Ethyl 2-(4-methoxybenzoyl)pent-4-ynoate 19c was obtained following the general procedure I
from ethyl 3ꢀ(4ꢀmethoxyphenyl)ꢀ3ꢀoxopropanoate (5.60 g, 25.0 mmol) in 6.60 g yield as a lightꢀ
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1
1
1
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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
yellow oil and used without any purification. Spectral data were in agreement with previously
34
reported values.
Ethyl 2-(4-bromobenzoyl)pent-4-ynoate 19e was obtained following the general procedure I from
ethyl 3ꢀ(4ꢀbromophenyl)ꢀ3ꢀoxopropanoate (1.00g, 3.7 mmol), in 1.34 g yield as a lightꢀbrown oil
and used without any purification. Spectral data were in agreement with previously reported
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
34
values.
Ethyl 2-(4-nitrobenzoyl)pent-4-ynoate 19g was obtained following the general procedure I from
ethyl 3ꢀ(4ꢀnitrophenyl)ꢀ3ꢀoxopropanoate (3.00 g, 12.6 mmol) in 3.22 g yield as a darkꢀbrown oil and
35
used without any purification. Spectral data were in agreement with previously reported values.
General procedure II for the synthesis of 3-aryl-4-(prop-2-yn-1-yl)isoxazol-5(4H)-ones 20.
Alkyl 2ꢀaroylpentꢀ4ꢀynoate 19 (10 mmol) was dissolved in ethanol (25 mL) and hydroxylamine
hydrochloride was then added (1.75 g, 25 mmol). The mixture was stirred at room temperature for
several days until TLC showed absence either of the starting ester or of any further changes. The
mixture was concentrated in vacuo and the residue was portioned between water and ether, the
layers were separated and the aqueous one was extracted with ether. The combined organic phases
were washed with water and extracted with 5% aqueous potassium hydroxide solution and the
combined basic extracts were washed with small portion of ether prior to acidification with
concentrated hydrochloric acid. If the product solidified it was separated by filtration, washed with
water and dried in air, otherwise it was extracted with ether. The ether solution was washed with
water, brine and dried over sodium sulfate. The solvent was removed in vacuo and the residue was
forced to crystallize by ultrasound sonification from hexanes/ether mixture. The compounds
obtained were used in further steps without additional purification, though could be purified by
recrystallization.
3-Phenyl-4-(prop-2-yn-1-yl)isoxazol-5(4H)-one 20a was obtained following the general procedure
II from ethyl 2ꢀbenzoylpentꢀ4ꢀynoate 19a (9.41 g, 41 mmol) in 6.02 g (74%) yield as a peachꢀ
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1
colored solid, mp 130.5ꢀ131.5 °C (heptane/dichloromethane). H NMR (CDCl , 400 MHz): δ 2.05
3
(
t, J = 2.6 Hz, 1H), 2.85 (ddd, J = 17.1, 5.3, 2.6 Hz, 1H), 3.01 (ddd, J = 17.1, 4.4, 2.6 Hz, 1H), 3.98
(
t, J = 4.9 Hz, 1H), 7.49ꢀ7.58 (m, 3H), 7.66ꢀ7.68 (m, 2H). Spectra shows ~16% of 5ꢀ
1
hydroxyisoxazol form. H NMR (CDCl , 400 MHz): δ 2.06 (t, J = 2.7 Hz, 1H), 3.32 (d, J = 2.7 Hz,
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
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
13
2
H), 7.49ꢀ7.58 (m, 3H), 7.66ꢀ7.69 (m, 2H), 8.34 (br. s, 1H). C NMR (CDCl , 100 MHz): δ 19.1
3
(
CH ), 44.3 (CH), 72.7 (CH), 76.3 (C), 127.0 (CH), 127.3 (C), 129.3 (CH), 132.0 (CH), 165.0 (C),
2
1
76.4 (C) (only major isoxazoleꢀ5(4H)ꢀone form signals are reported). HRMS (ESIꢀTOF) m/z: [M +
+
+
Na] Calcd for C H NNaO 222.0525; Found 222.0530.
12
9
2
3
-(4-Methylphenyl)-4-(prop-2-yn-1-yl)isoxazol-5(4H)-one 20b. Ethyl 2ꢀ(4ꢀmethylbenzoyl)pentꢀ4ꢀ
ynoate 19b was first obtained following the general procedure I from ethyl 3ꢀ(4ꢀmethylphenyl)ꢀ3ꢀ
oxopropanoate (8.25 g, 40 mmol) in 7.81 g (80%) yield as a colorless oil with bp 160ꢀ2 °C (0.5
1
Torr) [ H NMR (CDCl , 400 MHz): δ 1.18 (t, J = 7.1 Hz, 3H), 1.98 (t, J = 2.6 Hz, 1H), 2.42 (s, 3H),
3
2
.83 (ddd, J = 17.0, 7.1, 2.6 Hz, 1H), 2.98 (ddd, J = 17.0, 7.7, 2.6 Hz, 1H) 4.16 (qd, J = 7.1, 1.7 Hz,
2H), 4.54 (t, J = 7.4 Hz, 1H), 7.28 (d, J = 8.1 Hz, 2H), 7.94 (d, J = 8.1 Hz, 2H)]. Compound 19b
5.98g, 24 mmol) was then treated with hydroxylamine hydrochloride in accordance with the
(
general procedure II to provide the title isoxazolone 20b in 3.50 g (67%) yield as a lightꢀbeige solid,
1
mp 109ꢀ111 °C (heptane). H NMR (CDCl , 400 MHz): δ 2.04 (t, J = 2.6 Hz, 1H), 2.42 (s, 3H),
3
2
.84 (ddd, J = 17.1, 5.4, 2.6 Hz, 1H), 2.99 (ddd, J = 17.1, 4.4, 2.6 Hz, 1H), 3.94ꢀ3.96 (m, 1H), 7.30
1
(
d, J = 8.0 Hz, 2H), 7.56 (d, J = 8.0 Hz, 2H). Spectra shows ~15% of 5ꢀhydroxyisoxazol form. H
NMR (CDCl , 400 MHz): δ 2.06 (t, J = 2.6 Hz, 1H), 2.44 (s, 3H), 3.31 (d, J = 2.6 Hz, 2H), 7.34 (d,
3
1
3
J = 8.0 Hz, 2H), 7.57 (d, J = 8.0 Hz, 2H), 8.28 (d, J = 7.8 Hz, 1H). C NMR (CDCl , 100 MHz): δ
3
1
9.2 (CH ), 21.6 (CH ), 44.3 (CH), 72.7 (CH), 76.3 (C), 124.3 (C), 126.8 (CH), 130.0 (CH), 142.7
2 3
(
C), 164.9 (C), 176.6 (C) (only major isoxazoleꢀ5(4H)ꢀone form signals are reported). HRMS (ESIꢀ
+
+
TOF) m/z: [M + Na] Calcd for C H NNaO 236.0682; Found 236.0684.
1
3
11
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6
3-(4-Methoxyphenyl)-4-(prop-2-yn-1-yl)isoxazol-5(4H)-one 20c was obtained following the
general procedure II from ethyl 2ꢀ(4ꢀmethoxybenzoyl)pentꢀ4ꢀynoate 19c (2.95 g, 11 mmol) in 1.92 g
1
(
73%) yield as a light roseꢀcolored solid, mp 126ꢀ127 °C (water). H NMR (CDCl , 400 MHz): δ
3
2.05 (t, J = 2.6 Hz, 1H), 2.84 (ddd, J = 17.1, 5.4, 2.6 Hz, 1H), 2.99 (ddd, J = 17.1, 4.5, 2.6 Hz, 1H),
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
3
3
.87 (s, 3H), 3.93 (t, J = 4.9 Hz, 1H), 6.98ꢀ7.02 (m, 2H), 7.60ꢀ7.63 (m, 2H). C NMR (CDCl , 100
3
MHz): δ 19.3 (CH ), 44.3 (CH), 55.5 (CH ), 72.6 (CH), 76.4 (C), 114.8 (CH), 119.4 (C), 128.6
2
3
1
(
CH), 162.5 (C), 164.5 (C), 176.7 (C). Spectra shows ~14% of 5ꢀhydroxyisoxazol form. H NMR
(
CDCl , 400 MHz): δ 2.06 (t, J = 2.7 Hz, 1H), 3.31 (d, J = 2.7 Hz, 2H), 3.88 (s, 3H), 7.04ꢀ7.06 (m,
3
13
2
H), 7.63ꢀ7.66 (m, 2H), 8.14 (br. s, 1H). C NMR (CDCl , 100 MHz): δ 12.6 (CH ), 55.5 (CH ),
3
2
3
6
9.3 (CH), 80.3 (C), 97.8 (C), 114.8 (CH), 119.0 (C), 129.3 (CH), 162.3 (C), 162.6 (C), 172.6 (C).
+
+
HRMS (ESIꢀTOF) m/z: [M + H] Calcd for C H NO 230.0812; Found 230.0817.
13
12
3
3
-(4-Chlorophenyl)-4-(prop-2-yn-1-yl)isoxazol-5(4H)-one 20d. Ethyl 2ꢀ(4ꢀchlorobenzoyl)pentꢀ4ꢀ
ynoate 19d was first obtained following the general procedure I from ethyl 3ꢀ(4ꢀchlorophenyl)ꢀ3ꢀ
1
oxopropanoate (4.53 g, 20.0 mmol) in 5.33 g yield as a lightꢀbrown oil. [ H NMR (CDCl , 400
3
MHz): δ 1.17 (t, J = 7.1 Hz, 3H), 1.98 (t, J = 2.7 Hz, 1H), 2.85 (ddd, J = 17.0, 7.4, 2.7 Hz, 1H),
2
7
.92 (ddd, J = 17.0, 7.4, 2.7 Hz, 1H), 4.16 (qd, J = 7.1, 1.3 Hz, 2H), 4.51 (t, J = 7.4 Hz, 1H), 7.43ꢀ
.48(m, 2H), 7.96ꢀ7.99 (m, 2H) (spectra shows ~ 5% of enol form and ~ 15% of dipropargylated
product δ 1.16 (t, J = 7.3 Hz, 3H), 2.02 (t, J = 2.7 Hz, 2H), 3.12 (qd, J = 17.4, 2.7 Hz, 4H), 4.19ꢀ
.25 (m, 2H), 7.40ꢀ7.42 (m, 2H), 7.77ꢀ7.79 (m, 2H)]. The entire crude compound 19d obtained was
4
used in further steps without any purification. It was treated with hydroxylamine hydrochloride in
accordance with the general procedure II to provide the title isoxazolone 20d in 3.14 g yield (67%
yield on two steps based on the starting ethyl 3ꢀ(4ꢀchlorophenyl)ꢀ3ꢀoxopropanoate) as a sandꢀ
1
colored solid, mp 134ꢀ135 °C (light petroleum/dichloromethane). H NMR (CDCl , 400 MHz): δ
3
2.05 (t, J = 2.7 Hz, 1H), 2.84 (ddd, J = 17.2, 5.3, 2.7 Hz, 1H), 3.00 (ddd, J = 17.2, 4.5, 2.7 Hz, 1H),
1
3
3
.95 (t, J = 4.9 Hz, 1H), 7.48ꢀ7.50 (m, 2H), 7.61ꢀ7.63 (m, 2H). C NMR (CDCl , 100 MHz): δ 19.1
3
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(CH ), 44.1 (CH), 72.9 (CH), 76.1 (C), 125.6 (C), 128.2 (CH), 129.7 (CH), 138.4 (C), 164.1 (C),
2
1
1
76.2 (C). Spectra shows ~15% of 5ꢀhydroxyisoxazol form. H NMR (CDCl , 400 MHz): δ 2.06 (t,
3
J = 2.6 Hz, 1H), 3.30 (d, J = 2.7 Hz, 2H), 7.52ꢀ7.54 (m, 2H), 7.63ꢀ7.65 (m, 2H), 8.44 (br. s, 1H).
1
3
C NMR (CDCl , 100 MHz): δ 12.5 (CH ), 69.7 (CH), 79.8 (C), 99.0 (C), 125.1 (C), 129.1 (CH),
3
2
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
29.8 (CH), 138.2 (C), 161.5 (C), 172.3 (C). HRMS (ESIꢀTOF) m/z: [M + Na] Calcd for
35
8
+
C H ClNNaO 258.0136; Found 258.0141.
12
2
3
-(4-Bromophenyl)-4-(prop-2-yn-1-yl)isoxazol-5(4H)-one 20e was obtained following the general
procedure II from crude ethyl 2ꢀ(4ꢀbromobenzoyl)pentꢀ4ꢀynoate 19e (2.88 g) in 1.84 g yield as a
1
yellowish solid, mp 137ꢀ138 °C (water). H NMR (CDCl , 400 MHz): δ 2.05 (t, J = 2.7 Hz, 1H),
3
2
.84 (ddd, J = 17.2, 5.2, 2.7 Hz, 1H), 3.00 (ddd, J = 17.2, 4.3, 2.7 Hz, 1H), 3.95 (t, J = 4.9 Hz, 1H),
13
7.69 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 8.4 Hz, 2H). C NMR (CDCl , 100 MHz): δ 19.1 (CH ), 44.0
3
2
(CH), 73.0 (CH), 76.1 (C), 126.1 (C), 126.8 (C), 128.3 (CH), 132.7 (CH), 164.2 (C), 176.1 (C).
1
Spectra shows ~14% of 5ꢀhydroxyisoxazol form. H NMR (CDCl , 400 MHz): δ 2.05 (t, J = 2.5 Hz,
3
1H), 3.30 (d, J = 2.5 Hz, 2H), 7.57 (d, J = 8.5 Hz, 2H), 7.69 (d, J = 8.4 Hz, 2H), 8.43 (br. s, 1H).
+
+
HRMS (ESIꢀTOF) m/z: [M + H] Calcd for C H BrNO 277.9811; Found 277.9803.
1
2
9
2
3
-(3-Bromophenyl)-4-(prop-2-yn-1-yl)isoxazol-5(4H)-one 20f. Ethyl 2ꢀ(3ꢀbromobenzoyl)pentꢀ4ꢀ
ynoate 19f was first obtained following the general procedure I from ethyl 3ꢀ(3ꢀbromophenyl)ꢀ3ꢀ
1
oxopropanoate (2.00 g, 7.4 mmol) in 2.23 yield as a lightꢀbrown oil. [ H NMR (CDCl , 400 MHz): δ
3
1
.19 (t, J = 7.2 Hz, 3H), 1.99 (t, J = 2.6 Hz, 1H), 2.86 (ddd, J = 17.0, 7.4, 2.6 Hz, 1H), 2.92 (ddd, J
17.0, 7.2, 2.6 Hz, 1H), 4.17 (qd, J = 7.2, 3.4 Hz, 2H), 4.50 (t, J = 7.4 Hz, 1H), 7.38 (td, J = 7.9,
0.8 Hz, 1H), 7.73 (ddd, J = 7.9, 1.8, 0.8 Hz, 1H), 7.95 (d, J = 7.9 Hz, 1H), 8.17 (t, J = 1.8 Hz, 1H)
spectra shows ~ 13% of enol form and ~14% of dipropargylated product δ 1.17 (t, J = 7.1 Hz, 3H),
.03 (t, J = 2.7 Hz, 2H), 3.12 (qd, J = 17.3, 2.7 Hz, 4H), 4.18ꢀ4.24 (m, 2H), 7.47ꢀ7.54 (m, 1H),
=
(
2
7.59ꢀ7.63 (m, 1H), 8.02ꢀ8.04 (m, 1H)]. It was used in further steps without any purification. The
entire compound 19f obtained was treated with hydroxylamine hydrochloride in accordance with the
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Page 18 of 44
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2
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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
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4
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4
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5
5
5
5
5
5
5
5
5
6
general procedure II to provide the title isoxazolone 20f in 0.732 g yield (36% yield on two steps
based on the starting ethyl 3ꢀ(3ꢀbromophenyl)ꢀ3ꢀoxopropanoate) as a yellowish solid, mp 126ꢀ128
1
°
C (water). H NMR (CDCl , 400 MHz): δ 2.08 (m, 1H), 2.84ꢀ2.88 (m, 1H), 2.98ꢀ3.02 (m, 1H), 3.93
3
1
3
(t, J = 4.8 Hz, 1H), 7.27ꢀ7.41 (m, 1H), 7.59ꢀ7.63 (m, 1H), 7.68ꢀ7.70 (m, 1H), 7.84 (s, 1H). C NMR
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
(
CDCl , 100 MHz): δ 19.0 (CH ), 44.0 (CH), 73.0 (CH), 76.1 (C), 123.4 (C), 125.5 (CH), 129.0 (C),
3 2
1
29.8 (CH), 130.8 (CH), 135.0 (CH), 163.9 (C), 176.0 (C). Spectra shows ~13% of 5ꢀ
1
hydroxyisoxazol form. H NMR (CDCl , 400 MHz): δ 2.05 (M, 1H), 3.32 (m, 2H), 8.11 (br. s, 1H)
3
+
(
only wellꢀresolved characteristic signals are given). HRMS (ESIꢀTOF) m/z: [M + H] Calcd for
+
C H BrNO 277.9811; Found 277.9809.
12
9
2
3
-(4-Nitrophenyl)-4-(prop-2-yn-1-yl)isoxazol-5(4H)-one 20g was obtained following the general
procedure II from crude ethyl 2ꢀ(4ꢀnitrobenzoyl)pentꢀ4ꢀynoate 19g (3.10 g) in 1.91 g yield as a
1
brickꢀcolored solid, mp 123ꢀ127 °C (water). H NMR (CDCl , 400 MHz): δ 2.07 (t, J = 2.7 Hz, 1H),
3
2
.88 (ddd, J = 17.3, 5.3, 2.7 Hz, 1H), 3.04 (ddd, J = 17.3, 4.6, 2.7 Hz, 1H), 4.01 (t, J = 4.9 Hz, 1H),
1
3
7.88ꢀ7.90 (m, 2H), 8.36ꢀ8.38 (m, 2H). C NMR (CDCl , 100 MHz): δ 19.0 (CH ), 44.0 (CH), 73.3
3
2
(CH), 75.9 (C), 124.5 (CH), 128.0 (CH), 133.0 (C), 149.8 (C), 163.5 (C), 175.6 (C). Spectra shows
1
~
9% of 5ꢀhydroxyisoxazol form. H NMR (CDCl , 400 MHz): δ 2.08 (t, J = 2.7 Hz, 1H), 3.35 (d, J
3
+
=
2.7 Hz, 2H), 7.89ꢀ7.92 (m, 2H), 8.40ꢀ8.42 (m, 2H). HRMS (ESIꢀTOF) m/z: [M + H] Calcd for
+
C H N O 245.0557; Found 245.0553.
12
9
2
4
Synthesis of Isoxazoles
General procedure III for the synthesis of 3-substituted 5-methoxy-4-(prop-2-yn-1-yl)isoxazoles 1,
10.
3
ꢀSubstituted 4ꢀ(propꢀ2ꢀynꢀ1ꢀyl)isoxazolꢀ5(4H)ꢀone 20 (or 22) was worked up with excess of
ethereal diazomethane solution and 3ꢀsubstituted 5ꢀmethoxyꢀ4ꢀ(propꢀ2ꢀynꢀ1ꢀyl)isoxazole 1 (or
5ꢀmethoxyꢀ4ꢀ(3ꢀ(trimethylsilyl)propꢀ2ꢀynꢀ1ꢀyl)isoxazole 10b-d) were isolated by chromatography
1
9a
according to the previously reported procedure.
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5-Methoxy-3-phenyl-4-(prop-2-yn-1-yl)isoxazole 1a was obtained following the general procedure
III from 3ꢀphenylꢀ4ꢀ(propꢀ2ꢀynꢀ1ꢀyl)isoxazolꢀ5(4H)ꢀone (1.08 g, 5.4 mmol) 20a in 0.86 g (74%)
1
yield as a sandꢀcolored solid, mp 56ꢀ58 °C (hexaneꢀEtOAc). H NMR (CDCl , 400 MHz): δ 2.04 (t,
3
1
3
J = 2.7 Hz, 1H), 3.26 (d, J = 2.7 Hz, 2H), 4.17 (s, 3H), 7.46ꢀ7.49 (m, 3H), 7.72ꢀ7.74 (m, 2H). C
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
NMR (CDCl , 100 MHz): δ 11.5 (CH ), 58.0 (CH ), 68.9 (CH), 81.2 (C), 86.9 (C), 128.0 (CH),
3
2
3
+
1
28.8 (CH), 129.5 (C), 129.8 (CH), 164.3 (C), 169.6 (C). HRMS (ESIꢀTOF) m/z: [M + Na] Calcd
+
for C H NNaO 236.0682; Found 236.0680.
13 11
2
5
-Methoxy-3-(4-methylphenyl)-4-(prop-2-yn-1-yl)isoxazole 1b was obtained following the
general procedure III from 3ꢀ(4ꢀmethylphenyl)ꢀ4ꢀ(propꢀ2ꢀynꢀ1ꢀyl)isoxazolꢀ5(4H)ꢀone 20b (1.52 g,
1
7
.1 mmol) in 1.09 g (67%) yield as an yellow solid, mp 70.5ꢀ72.0°C (hexaneꢀEtOAc). H NMR
(CDCl , 400 MHz): δ 2.04 (t, J = 2.7 Hz, 1H), 2.41 (s, 3H), 3.25 (d, J = 2.7 Hz, 2H), 4.16 (s, 3H),
3
13
7
.29 (d, J = 8.0 Hz, 2H), 7.63 (d, J = 8.0 Hz, 2H). C NMR (CDCl , 100 MHz): δ 11.6 (CH ), 21.4
3
2
(
CH ), 57.9 (CH ), 68.8 (CH), 81.3 (C), 86.8 (C), 126.6 (C), 127.8 (CH), 129.5 (CH), 139.8 (C),
3 3
+
+
2
164.2 (C), 169.5 (C). HRMS (ESIꢀTOF) m/z: [M + H] Calcd for C H NO 228.1019; Found
1
4
14
2
28.1026.
-Methoxy-3-(4-methoxyphenyl)-4-(prop-2-yn-1-yl)isoxazole 1c was obtained following the
5
general procedure III from 3ꢀ(4ꢀmethoxyphenyl)ꢀ4ꢀ(propꢀ2ꢀynꢀ1ꢀyl)isoxazolꢀ5(4H)ꢀone 20c (1.00 g,
4
.40 mmol) in 0.83 g (77%) yield as a colorless solid, mp 73ꢀ74 °C (light petroleum/ethyl acetate).
1
H NMR (CDCl , 400 MHz): δ 2.04 (t, J = 2.7 Hz, 1H), 3.25 (d, J = 2.7 Hz, 2H), 3.85 (s, 3H), 4.15
3
1
3
(
s, 3H), 6.99 (d, J = 8.8 Hz, 2H), 7.68 (d, J = 8.8 Hz, 2H). C NMR (CDCl , 100 MHz): δ 11.6
3
(CH ), 55.3 (CH ), 57.9 (CH ), 68.8 (CH), 81.4 (C), 86.7 (C), 114.2 (CH), 121.9 (C), 129.3 (CH),
2
3
3
+
+
1
60.8 (C), 163.9 (C), 169.5 (C). HRMS (ESIꢀTOF) m/z: [M + H] Calcd for C H NO 244.0968;
14 14 3
Found 244.0969.
3-(4-Chlorophenyl)-5-methoxy-4-(prop-2-yn-1-yl)isoxazole 1d was obtained following the
general procedure III (with exception that the product was purified by recrystallization from
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1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
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4
4
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5
5
5
5
5
5
5
6
methanol instead of column chromatography) from 3ꢀ(4ꢀchlorophenyl)ꢀ4ꢀ(propꢀ2ꢀynꢀ1ꢀyl)isoxazolꢀ
5
(4H)ꢀone 20d (3.00 g, 12.8 mmol) in 2.10 g (66%) yield as an yellow solid, mp 107ꢀ108 °C
1
(
methanol). H NMR (CDCl , 400 MHz): δ 2.04 (t, J = 2.7 Hz, 1H), 3.24 (d, J = 2.7 Hz, 2H), 4.17
3
1
3
(s, 3H), 7.44ꢀ7.47 (m, 2H), 7.67ꢀ7.71 (m, 2H). C NMR (CDCl , 100 MHz): δ 11.5 (CH ), 58.1
3
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
(
CH ), 69.1 (CH), 81.0 (C), 86.9 (C), 127.9 (C), 129.1 (CH), 129.3 (CH), 136.0 (C), 163.3 (C),
3
+
+
1
3
69.7 (C). HRMS (ESIꢀTOF) m/z: [M + H] Calcd for C H ClNO 248.0473; Found 248.0477.
13 11 2
-(4-Bromophenyl)-5-methoxy-4-(prop-2-yn-1-yl)isoxazole 1e was obtained following the
general procedure III from 3ꢀ(4ꢀbromophenyl)ꢀ4ꢀ(propꢀ2ꢀynꢀ1ꢀyl)isoxazolꢀ5(4H)ꢀone 20e (1.00 g,
3
.60 mmol) in 0.88 g (84%) yield as a colorless solid, mp 107ꢀ108 °C (light petroleum/ethyl
1
acetate). H NMR (CDCl , 400 MHz): δ 2.04 (t, J = 2.7 Hz, 1H), 3.24 (d, J = 2.7 Hz, 2H), 4.17 (s,
3
1
3
3H), 7.62 (pseudoꢀs, 4H). C NMR (CDCl , 100 MHz): δ 11.5 (CH ), 58.1 (CH ), 69.2 (CH), 81.0
3
2
3
(C), 86.8 (C), 124.3 (C), 128.4 (C), 129.5 (CH), 132.0 (CH), 163.3 (C), 169.7 (C). HRMS (ESIꢀ
+
+
TOF) m/z: [M + H] Calcd for C H BrNO 291.9968; Found 291.9967.
1
3
11
2
3-(3-Bromophenyl)-5-methoxy-4-(prop-2-yn-1-yl)isoxazole 1f was obtained following the general
procedure III from 3ꢀ(3ꢀbromophenyl)ꢀ4ꢀ(propꢀ2ꢀynꢀ1ꢀyl)isoxazolꢀ5(4H)ꢀone 20f (0.63 g, 2.27
1
mmol) in 0.46 g (69%) yield as a light yellow oil. H NMR (CDCl , 400 MHz): δ 2.06 (t, J = 2.7
3
Hz, 1H), 3.25 (d, J = 2.7 Hz, 2H), 4.17 (s, 3H), 7.33ꢀ7.37 (m, 1H), 7.59ꢀ7.61 (m, 1H), 7.67ꢀ7.69 (m,
1
3
1
8
H), 7.92 (m, 1H). C NMR (CDCl , 100 MHz): δ 11.5 (CH ), 58.1 (CH ), 69.2 (CH), 80.9 (C),
3 2 3
7.0 (C), 122.8 (C), 126.6 (CH), 130.3 (CH), 131.0 (CH), 131.4 (C), 132.8 (CH), 163.1 (C), 169.8
+
+
(
C). HRMS (ESIꢀTOF) m/z: [M + H] Calcd for C H BrNO 291.9968; Found 291.9962.
13 11 2
5-Methoxy-3-(4-nitrophenyl)-4-(prop-2-yn-1-yl)isoxazole 1g was obtained following the general
procedure III from 3ꢀ(4ꢀnitrophenyl)ꢀ4ꢀ(propꢀ2ꢀynꢀ1ꢀyl)isoxazolꢀ5(4H)ꢀone 20g (1.00 g, 4.00 mmol)
1
in 0.72 g (69%) yield as an yellow solid, mp 115ꢀ116 °C (light petroleum/ethyl acetate). H NMR
(CDCl , 400 MHz): δ 2.05 (t, J = 2.7 Hz, 1H), 3.28 (d, J = 2.7 Hz, 2H), 4.20 (s, 3H), 7.96 (d, J =
3
1
3
8
.8 Hz, 2H), 8.34 (d, J = 8.8 Hz, 2H). C NMR (CDCl , 100 MHz): δ 11.5 (CH ), 58.3 (CH ), 69.6
3
2
3
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(CH), 80.6 (C), 87.2 (C), 124.0 (CH), 129.0 (CH), 135.8 (C), 148.6 (C), 162.4 (C), 170.1 (C).
+
+
HRMS (ESIꢀTOF) m/z: [M + H] Calcd for C H N O 259.0713; Found 259.0710.
13
11
2
4
3
-Cyclopropyl-5-methoxy-4-(prop-2-yn-1-yl)isoxazole
1h.
To
a
solution
of
3
6
3ꢀcyclopropylisoxazolꢀ5(4H)ꢀone (626 mg, 5 mmol) in dry toluene (5 mL) ethylenediamine
1
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diacetate (45 mg, 0.25 mmol) was added under argon atmosphere upon cooling with ice bath
38
followed by addition of 3ꢀ(trimethylsilyl)propiolaldehyde (1.26 g, 10 mmol) solution in toluene
(5 mL). The mixture was stirred with 4 Å molecular sieves for 2 hours at 0 °C under argon and then
was subjected to flash chromatography on silica eluting with dichloromethane. The solvents were
removed under vacuum at external heater temperature below 30 °C to provide 3ꢀcyclopropylꢀ4ꢀ(3ꢀ
(trimethylsilyl)propꢀ2ꢀynꢀ1ꢀylidene)isoxazolꢀ5(4H)ꢀone 21b in 712 mg (61%) yield as a brown oil.
Because of instability of the substance, NMR spectra of appropriate quality were not recorded. The
substance should be used in further steps as soon as possible due to the low stability even when
stored below ꢀ18 °C under inert atmosphere. The solution of 3ꢀcyclopropylꢀ4ꢀ(3ꢀ
(trimethylsilyl)propꢀ2ꢀynꢀ1ꢀylidene)isoxazolꢀ5(4H)ꢀone 21b (562 mg, 2.41 mmol) in 15 mL of 1,4ꢀ
dioxane was added dropwise to the suspension of sodium borohydride (365 mg, 9.65 mmol) in
aqueous dioxane (1.5 mL of water and 3.0 mL of 1,4ꢀdioxane) under ice cooling and vigorous
stirring. Stirring was continued for 10 min. at 0 °C and for additional 30 min. at room temperature.
Water (10 mL) was added and the mixture was carefully acidified with concentrated hydrochloric
acid. The product was extracted three times with benzene and combined organic layers were washed
with water and brine prior to drying over sodium sulfate. The volatiles were removed in vacuo to
provide 3ꢀcyclopropylꢀ4ꢀ(3ꢀ(trimethylsilyl)propꢀ2ꢀynꢀ1ꢀyl)isoxazolꢀ5(4H)ꢀone 22b in 539 mg (95%)
1
yield as a brown viscous oil. H NMR (CDCl , 400 MHz): δ 0.13 (s, 9H), 0.91ꢀ1.21 (m, 4H), 1.64
3
(tt, J = 8.2, 5.1 Hz, 1H), 2.82 (dd, J = 17.3, 6.0 Hz, 1H), 2.88 (dd, J = 17.3, 5.0 Hz, 1H), 3.50 (dd, J
1
= 6.0, 5.0 Hz, 1H). Spectra shows ~11% of 5ꢀhydroxyisoxazol form. H NMR (CDCl , 400 MHz): δ
3
0
.13 (s, 9H), 0.91ꢀ1.21 (m, 4H), 1.62ꢀ1.66 (m, 1H), 3.27 (s, 2H), 7.37 (s, 1H). The compound was
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used without further purification. 3ꢀCyclopropylꢀ4ꢀ(3ꢀ(trimethylsilyl)propꢀ2ꢀynꢀ1ꢀyl)isoxazolꢀ
(4H)ꢀone 22b (530 mg, 2.25 mmol) was treated with ethereal diazomethane solution in accordance
5
with the general procedure III to provide 3ꢀcyclopropylꢀ5ꢀmethoxyꢀ4ꢀ(3ꢀ(trimethylsilyl)propꢀ2ꢀynꢀ1ꢀ
1
yl)isoxazole 10d in 303 mg (54%) yield as a darkꢀyellow oil. H NMR (CDCl , 400 MHz): δ 0.14 (s,
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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1
1
H), 0.90ꢀ1.01 (m, 4H), 1.85 (tt, J = 8.3, 5.2 Hz, 1H), 3.24 (s, 2H), 4.04 (s, 3H). C NMR (CDCl ,
3
00 MHz): δ 0.1 (CH ), 6.6 (CH), 6.7 (CH ), 12.2 (CH ), 57.7 (CH ), 84.8 (C), 87.8 (C), 103.1 (C),
3
2
2
3
67.1 (C), 168.4 (C). The compound was used without further purification. 3ꢀCyclopropylꢀ5ꢀ
methoxyꢀ4ꢀ(3ꢀ(trimethylsilyl)propꢀ2ꢀynꢀ1ꢀyl)isoxazole 10d (128 mg, 0.51 mmol) was stirred with 5
mL of saturated potassium carbonate solution in methanol upon cooling with ice bath for four hours.
Concentrated hydrochloric acid (2 mL) was added dropwise followed with water (10 mL) and the
resulting mixture was extracted 3 times with ether. The combined organic layers were washed with
saturated aqueous sodium bicarbonate, brine and dried over anhydrous sodium sulfate. The volatiles
were removed in vacuo and the residue was subjected to flash chromatography on silica eluting with
light petroleum/ethyl acetate mixture (10/1) to provide the title compound 1h (72 mg, 79%) as a
1
paleꢀyellow oil. The substance darkens upon storage even in a freezer. H NMR (CDCl , 400 MHz):
3
δ 0.91ꢀ0.99 (m, 4H), 1.82 (tt, J = 8.1, 5.3 Hz, 1H), 2.00 (t, J = 2.7 Hz, 1H), 3.20 (d, J = 2.7 Hz, 2H),
13
4
.04 (s, 3H). C NMR (CDCl , 100 MHz): δ 6.5 (CH ), 6.7 (CH ), 10.7 (CH ), 57.7 (CH ), 68.4
3 3 2 2 3
+
(
CH), 80.9 (C), 87.5 (C), 166.9 (C), 168.5 (C). HRMS (ESIꢀTOF) m/z: [M + H] Calcd for
+
C H NO 178.0863; Found 178.0857.
10
12
2
3
-(tert-Butyl)-5-methoxy-4-(prop-2-yn-1-yl)isoxazole 1i. 3ꢀ(tertꢀButyl)ꢀ4ꢀ(3ꢀ(trimethylsilyl)propꢀ
3
9
2ꢀynꢀ1ꢀylidene)isoxazolꢀ5(4H)ꢀone 21c was obtained from 3ꢀ(tertꢀbutyl)isoxazolꢀ5(4H)ꢀone
(426 mg,
3.02
mmol)
analogously to
3ꢀcyclopropylꢀ4ꢀ(3ꢀ(trimethylsilyl)propꢀ2ꢀynꢀ1ꢀ
ylidene)isoxazolꢀ5(4H)ꢀone 21b in quantitative yield (755 mg) as an yellow oil. Spectra shows two
1
(E/Z)ꢀisomers in ~ 1:0.65 ratio. Major isomer: H NMR (CDCl , 400 MHz): δ 0.28 (s, 9H), 1.45 (s,
3
1
9
H), 6.89 (s, 1H). Minor isomer: H NMR (CDCl , 400 MHz): δ 0.30 (s, 9H), 1.36 (s, 9H), 6.91 (s,
3
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1H). The compound was used without further purification (in the procedure analogous for
compound 22b) to provide 3ꢀ(tertꢀbutyl)ꢀ4ꢀ(3ꢀ(trimethylsilyl)propꢀ2ꢀynꢀ1ꢀyl)isoxazolꢀ5(4H)ꢀone
2
2c in quantitative yield (750 mg) as a lightꢀbrown oil that solidified upon standing, mp 55ꢀ58 °C
1
(benzene). H NMR (CDCl , 400 MHz): δ 0.13 (s, 9H), 1.33 (s, 9H), 2.91 (d, J = 4.8 Hz, 2H), 3.48
3
1
1
1
1
1
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9
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1
3
(
t, J = 4.8 Hz, 1H). C NMR (CDCl , 100 MHz): δ ꢀ0.3 (CH ), 20.8 (CH ), 28.1 (CH ), 35.3 (C),
3 3 2 3
4
5.6 (CH), 90.2 (C), 99.2 (C), 173.7 (C), 177.4 (C). The compound 22c (740 mg, 2.97 mmol) was
used without further purification to give after work up in accordance with the general procedure III
3
ꢀ(tertꢀbutyl)ꢀ5ꢀmethoxyꢀ4ꢀ(3ꢀ(trimethylsilyl)propꢀ2ꢀynꢀ1ꢀyl)isoxazole 10b in 552 mg (70%) yield
1
as a lightꢀyellow oil. H NMR (CDCl , 400 MHz): δ 0.12 (s, 9H), 1.38 (s, 9H), 3.27 (s, 2H), 4.05 (s,
3
1
3
3
H). C NMR (CDCl , 100 MHz): δ 0.1 (CH ), 13.5 (CH ), 28.6 (CH ), 33.6 (C), 57.7 (CH ), 85.0
3 3 2 3 3
(C), 86.6 (C), 104.2 (C), 169.5 (C), 171.6 (C). The compound 10b (200 mg, 0.75 mmol) without
further purification was treated with methanol potassium carbonate solution analogously to 3ꢀ
cyclopropylꢀ5ꢀmethoxyꢀ4ꢀ(3ꢀ(trimethylsilyl)propꢀ2ꢀynꢀ1ꢀyl)isoxazole 10d to provide the title
1
compound 1i in 96 mg (66%) yield as a paleꢀyellow oil. H NMR (CDCl , 400 MHz): δ 1.38 (s, 9H),
3
1
3
2
.00 (t, J = 2.7 Hz, 1H), 3.25 (d, J = 2.7 Hz, 2H), 4.07 (s, 3H). C NMR (CDCl , 100 MHz): δ 12.1
3
(CH ), 28.6 (CH ), 33.6 (C), 57.7 (CH ), 68.5 (CH), 81.7 (C), 86.2 (C), 169.7 (C), 171.4 (C). HRMS
2 3 3
+
+
2
(
ESIꢀTOF) m/z: [M + H] Calcd for C H NO 194.1176; Found 194.1185.
11 16
General procedure IVA for the synthesis of 3-substituted 4-(3-bromoprop-2-yn-1-yl)-5-
methoxyisoxazoles 4. 3ꢀSubstituted 5ꢀmethoxyꢀ4ꢀ(propꢀ2ꢀynꢀ1ꢀyl)isoxazoles 1 were brominated
with Nꢀbromosuccinimide in acetone in presence of 25~30 mol% of silver nitrate according to the
4
0
published procedure.
General procedure IVB for the synthesis of 3-substituted 4-(3-iodoprop-2-yn-1-yl)-
-methoxyisoxazoles 5. 3ꢀSubstituted 5ꢀmethoxyꢀ4ꢀ(propꢀ2ꢀynꢀ1ꢀyl)isoxazoles 1 were iodinated
with Nꢀiodosuccinimide in dry DMF in presence of 25~30 mol% of silver nitrate according to the
5
4
1
published procedure with the exception of procedure of product isolation. After the completion the
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reaction the mixture was poured into the mixture of saturated aqueous sodium thiosulfate (25 mL)
and aqueous ammonia (10 mL) and stirred for an hour in the dark. The precipitate deposited was
filtered off washed thoroughly with saturated sodium bicarbonate solution and water, dissolved in
ether and worked up with activated charcoal and anhydrous sodium sulfate. Then solids were
filtered off, all volatiles were removed in vacuo and the residue was vacuum dried to provide the
title compound.
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General procedure IVC for the synthesis of 3-substituted 4-(3-bromoprop-2-yn-1-yl)-
5
-methoxyisoxazoles 4. Exchange of trimethylsilylꢀgroup with bromine in 3ꢀsubstituted 5ꢀmethoxyꢀ
4
ꢀ(3ꢀ(trimethylsilyl)propꢀ2ꢀynꢀ1ꢀyl)isoxazoles 10 was performed with Nꢀbromosuccinimide in
4
2
acetone in presence of 10 mol% of silver nitrate according to the published procedure.
4-(3-Bromoprop-2-yn-1-yl)-5-methoxy-3-phenylisoxazole 4a was obtained following the general
procedure IVA from 5ꢀmethoxyꢀ3ꢀphenylꢀ4ꢀ(propꢀ2ꢀynꢀ1ꢀyl)isoxazole 1a (213 mg, 1.00 mmol) in
1
2
53 mg (87%) yield as a brown viscous oil. H NMR (CDCl , 400 MHz): δ 3.27 (s, 2H), 4.17 (s,
3
1
3
3H), 7.46ꢀ7.50 (m, 3H), 7.68ꢀ7.70 (m, 2H). C NMR (CDCl , 100 MHz): δ 12.8 (CH ), 39.5 (C),
3
2
5
8.0 (CH ), 76.9 (C), 86.5 (C), 128.0 (CH), 128.8 (CH), 129.4 (C), 129.8 (CH), 164.3 (C), 169.4
3
+
+
(
C). HRMS (ESIꢀTOF) m/z: [M + H] Calcd for C H BrNO 291.9968; Found 291.9969.
13 11 2
4
-(3-Bromoprop-2-yn-1-yl)-5-methoxy-3-(4-methylphenyl)isoxazole 4b was obtained following
the general procedure IVA from 5ꢀmethoxyꢀ3ꢀ(4ꢀmethylphenyl)ꢀ4ꢀ(propꢀ2ꢀynꢀ1ꢀyl)isoxazole 1b
(114 mg, 0.50 mmol) in 136 mg (89%) yield as a brown viscous oil, that crystallized in a freezer to
1
an yellowish solid with mp 57ꢀ8 °C (light petroleum). H NMR (CDCl , 400 MHz): δ 2.41 (s, 3H),
3
1
3
3.26 (s, 2H), 4.16 (s, 3H), 7.29 (d, J = 8.0 Hz, 2H), 7.58 (d, J = 8.0 Hz, 2H). C NMR (CDCl , 100
3
MHz): δ 12.8 (CH ), 21.4 (CH ), 39.4 (C), 58.0 (CH ), 77.1 (C), 86.4 (C), 126.5 (C), 127.8 (CH),
2
3
3
+
1
29.5 (CH), 139.9 (C), 164.3 (C), 169.6 (C). HRMS (ESIꢀTOF) m/z: [M + Na] Calcd for
+
C H BrNNaO 327.9944; Found 327.9947.
14
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4-(3-Bromoprop-2-yn-1-yl)-5-methoxy-3-(4-methoxyphenyl)isoxazole 4c was obtained following
the general procedure IVA from 5ꢀmethoxyꢀ3ꢀ(4ꢀmethoxyphenyl)ꢀ4ꢀ(propꢀ2ꢀynꢀ1ꢀyl)isoxazole 1c
1
(
300 mg, 1.23 mmol) in 283 mg (71%) yield as a lightꢀbrown solid, mp 71ꢀ72 °C (water). H NMR
(CDCl , 400 MHz): δ 3.26 (s, 2H), 3.86 (s, 3H), 4.15 (s, 3H), 6.99ꢀ7.02 (m, 2H), 7.63ꢀ7.66 (m, 2H).
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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3
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3
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5
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0
1
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0
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0
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2
3
4
5
6
7
8
9
0
1
2
3
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1
3
C NMR (CDCl , 100 MHz): δ 12.9 (CH ), 39.4 (C), 55.3 (CH ), 57.9 (CH ), 77.1 (C), 86.3 (C),
3
2
3
3
1
14.3 (CH), 121.8 (C), 129.3 (CH), 160.8 (C), 163.9 (C), 169.5 (C). HRMS (ESIꢀTOF) m/z: [M +
+
+
H] Calcd for C H BrNO 322.0073; Found 322.0066.
14 13
3
4
-(3-Bromoprop-2-yn-1-yl)-3-(4-chlorophenyl)-5-methoxyisoxazole 4d was obtained following
the general procedure IVA from 3ꢀ(4ꢀchlorophenyl)ꢀ5ꢀmethoxyꢀ4ꢀ(propꢀ2ꢀynꢀ1ꢀyl)isoxazole 1d
1
(
743 mg, 3.00 mmol) in 850 mg (87%) yield as a lightꢀyellow solid, mp 83ꢀ85 °C (CH Cl ). H
2
2
1
3
NMR (CDCl , 400 MHz): δ 3.25 (s, 2H), 4.17 (s, 3H), 7.45ꢀ7.48 (m, 2H), 7.63ꢀ7.66 (m, 2H). C
3
NMR (CDCl , 100 MHz): δ 12.7 (CH ), 39.9 (C), 58.1 (CH ), 76.8 (C), 86.5 (C), 127.8 (C), 129.1
3
2
3
+
(
CH), 129.3 (CH), 136.0 (C), 163.3 (C), 169.7 (C). HRMS (ESIꢀTOF) m/z: [M + Ag] Calcd for
+
C H AgBrClNO 431.8551; Found 431.8558.
13
9
2
3
-(4-Bromophenyl)-4-(3-bromoprop-2-yn-1-yl)-5-methoxyisoxazole 4e was obtained following
the general procedure IVA from 3ꢀ(4ꢀbromophenyl)ꢀ5ꢀmethoxyꢀ4ꢀ(propꢀ2ꢀynꢀ1ꢀyl)isoxazole 1e
1
(
300 mg, 1.03 mmol) in 300 mg (79%) yield as a yellowish solid, mp 88ꢀ89 °C (water). H NMR
1
3
(
CDCl , 400 MHz): δ 3.25 (s, 2H), 4.17 (s, 3H), 7.57ꢀ7.59 (m, 2H), 7.62ꢀ7.64 (m, 2H). C NMR
3
(
CDCl , 100 MHz): δ 12.7 (CH ), 39.9 (C), 58.1 (CH ), 76.8 (C), 86.4 (C), 124.3 (C), 128.3 (C),
3
2
3
+
1
29.5 (CH), 132.1 (CH), 163.3 (C), 169.7 (C). HRMS (ESIꢀTOF) m/z: [M + H] Calcd for
+
C H Br NO 369.9073; Found 369.9066.
13
10
2
2
4
-(3-Bromoprop-2-yn-1-yl)-5-methoxy-3-(4-nitrophenyl)isoxazole 4f was obtained following the
general procedure IVA from 5ꢀmethoxyꢀ3ꢀ(4ꢀnitrophenyl)ꢀ4ꢀ(propꢀ2ꢀynꢀ1ꢀyl)isoxazole 1g (300 mg,
1
1.17 mmol) in 325 mg (83%) yield as an yellowish solid, mp 125ꢀ127 °C (water). H NMR (CDCl ,
3
1
3
4
00 MHz): δ 3.30 (s, 2H), 4.20 (s, 3H), 7.91 (d, J = 8.5 Hz, 2H), 8.35 (d, J = 8.5 Hz, 2H). C NMR
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(CDCl , 100 MHz): δ 12.7 (CH ), 40.5 (C), 58.3 (CH ), 76.4 (C), 86.8 (C), 124.0 (CH), 128.9 (CH),
3
2
3
+
1
35.7 (C), 148.6 (C), 162.4 (C), 170.1 (C). HRMS (ESIꢀTOF) m/z: [M + Na] Calcd for
+
C H BrN NaO 358.9638; Found 358.9654.
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4-(3-Bromoprop-2-yn-1-yl)-5-methoxy-3-methylisoxazole 4g. 3ꢀMethylꢀ4ꢀ(3ꢀ(trimethylsilyl)propꢀ
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5
ꢀynꢀ1ꢀylidene)isoxazolꢀ5(4H)ꢀone 21a was obtained from 3ꢀmethylisoxazolꢀ5(4H)ꢀone (500 mg,
.00 mmol) as a brown liquid that solidified in a freezer in a 500 mg (48%) yield by the procedure
used for the preparation of isoxazole 21b. Spectra shows (E/Z)ꢀisomers mixture in ~ 1:0.25 ratio.
1
Major isomer: H NMR (CDCl , 400 MHz): δ 0.28 (s, 9H), 2.43 (s, 3H), 6.84 (s, 1H). Minor isomer:
3
1
H NMR (CDCl , 400 MHz): δ 0.30 (s, 9H), 2.21 (s, 3H), 6.60 (s, 1H). The substance was used in
3
further steps without purification due to the low stability even when stored below ꢀ18 °C under inert
atmosphere. It was reduced into 3ꢀmethylꢀ4ꢀ(3ꢀ(trimethylsilyl)propꢀ2ꢀynꢀ1ꢀyl)isoxazolꢀ5(4H)ꢀone
2
2a in quantitative yield (505 mg) by the procedure used for the preparation of isoxazole 22b.
1
Yellow oil that solidified upon standing, mp 68ꢀ70 °C (benzene). H NMR (CDCl , 400 MHz): δ
3
0.14 (s, 9H), 2.19 (d, J = 0.8 Hz, 3H), 2.75 (dd, J = 17.4, 6.8 Hz, 1H), 2.83 (dd, J = 17.4, 5.0 Hz,
1
1
H), 3.40 (ddd, J = 6.7, 5.0, 0.8 Hz, 1H). Spectra shows ~16% of 5ꢀhydroxyisoxazol form. H NMR
(
CDCl , 400 MHz): δ 0.15 (s, 9H), 2.30 (s, 3H), 3.23 (s, 2H), 7.36 (s, 1H). The compound was used
3
without further purification. 5ꢀMethoxyꢀ3ꢀmethylꢀ4ꢀ(3ꢀ(trimethylsilyl)propꢀ2ꢀynꢀ1ꢀyl)isoxazole 10c
was obtained following the general procedure III from isoxazole 22a (430 mg, 2.00 mmol) in 177
mg (39%) yield as a darkꢀyellow oil that solidified upon cooling in refrigerator at yellow solid, mp
1
2
2ꢀ25 °C (hexaneꢀEtOAc). H NMR (CDCl , 400 MHz): δ 0.14 (s, 9H), 2.24 (s, 3H), 3.17 (s, 2H),
3
13
4.05 (s, 3H). C NMR (CDCl , 100 MHz): δ 0.1 (CH ), 11.2 (CH ), 12.3 (CH ), 57.7 (CH ), 85.1
3
3
3
2
3
(C), 87.1 (C), 102.6 (C), 162.6 (C), 168.3 (C). The compound 10c (165 mg, 0.74 mmol) was used
without further purification to provide following the general procedure IVC the title compound in
1
139 mg (82%) yield as a sandꢀcolored solid, mp 51ꢀ2 °C (hexaneꢀEtOAc). H NMR (CDCl , 400
3
1
3
MHz): δ 2.23 (s, 3H), 3.15 (s, 2H), 4.06 (s, 3H). C NMR (CDCl , 100 MHz): δ 11.0 (CH ), 12.0
3
3
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(CH ), 39.0 (C), 57.8 (CH ), 76.3 (C), 86.5 (C), 162.3 (C), 168.5 (C). HRMS (ESIꢀTOF) m/z: [M +
2
3
+
+
H] Calcd for C H BrNO 229,9811; Found 229,9819.
8
9
2
4
-(3-Bromoprop-2-yn-1-yl)-3-cyclopropyl-5-methoxyisoxazole 4h was obtained following the
general procedure IVC from 3ꢀcyclopropylꢀ5ꢀmethoxyꢀ4ꢀ(3ꢀ(trimethylsilyl)propꢀ2ꢀynꢀ1ꢀyl)isoxazole
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
1
0d (250 mg, 1.00 mmol) in 227 mg (88%) yield as a paleꢀyellow viscous oil. H NMR (CDCl , 400
3
13
MHz): δ 0.93ꢀ0.98 (m, 4H), 1.78 (tt, J = 8.2, 5.4 Hz, 1H), 3.22 (s, 2H), 4.04 (s, 3H). C NMR
(
CDCl , 100 MHz): δ 6.5 (CH ), 6.6 (CH ), 12.0 (CH ), 38.9 (C), 57.7 (CH ), 76.7 (C), 87.1 (C),
3 3 2 2 3
+
+
1
66.9 (C), 168.5 (C). HRMS (ESIꢀTOF) m/z: [M + Ag] Calcd for C H AgBrNO 361,8940;
10 10 2
Found 361,8930.
4
-(3-Bromoprop-2-yn-1-yl)-3-(tert-butyl)-5-methoxyisoxazole 4i was obtained following the
general procedure IVC from 3ꢀ(tertꢀbutyl)ꢀ5ꢀmethoxyꢀ4ꢀ(3ꢀ(trimethylsilyl)propꢀ2ꢀynꢀ1ꢀyl)isoxazole
0b (130 mg, 0.49 mmol) in 94 mg (71%) yield as a paleꢀyellow solid mp 68ꢀ70 °C (hexaneꢀ
1
1
13
EtOAc). H NMR (CDCl , 400 MHz): δ 1.37 (s, 9H), 3.26 (s, 2H), 4.06 (s, 3H). C NMR (CDCl ,
3
3
100 MHz): δ 13.4 (CH ), 28.6 (CH ), 33.6 (C), 39.1 (C), 57.7 (CH ), 77.5 (C), 85.8 (C), 169.6 (C),
2
3
3
+
+
1
71.4 (C). HRMS (ESIꢀTOF) m/z: [M + H] Calcd for C H BrNO 272,0281; Found 272,0279.
11 15 2
4
-(3-Iodoprop-2-yn-1-yl)-5-methoxy-3-phenylisoxazole 5a was obtained following the general
procedure IVB from 5ꢀmethoxyꢀ3ꢀphenylꢀ4ꢀ(propꢀ2ꢀynꢀ1ꢀyl)isoxazole 1a (106 mg, 0.50 mmol) in
1
1
3
4
20 mg (71%) as offꢀwhite solid, mp 102ꢀ103.5 °C (diethyl ether). H NMR (CDCl , 400 MHz): δ
3
13
.41 (s, 2H), 4.16 (s, 3H), 7.47ꢀ7.51 (m, 3H), 7.68ꢀ7.70 (m, 2H). C NMR (CDCl , 100 MHz): δ ꢀ
3
.7 (C), 13.9 (CH ), 58.0 (CH ), 86.7 (C), 91.0 (C), 128.0 (CH), 128.8 (CH), 129.4 (C), 129.8 (CH),
2
3
+
+
164.3 (C), 169.6 (C). HRMS (ESIꢀTOF) m/z: [M + Na] Calcd for C H INNaO 361.9648; Found
1
3
10
2
3
61.9657.
-(3-Iodoprop-2-yn-1-yl)-5-methoxy-3-(4-methoxyphenyl)isoxazole 5b was obtained following
4
the general procedure IVB from 5ꢀmethoxyꢀ3ꢀ(4ꢀmethoxyphenyl)ꢀ4ꢀ(propꢀ2ꢀynꢀ1ꢀyl)isoxazole 1c
(100 mg, 0.40 mmol) in 80 mg (54%) yield as a lightꢀbrown solid, mp 109ꢀ112 °C (ethyl acetate).
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1
1
1
1
1
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1
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2
2
2
2
2
2
2
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3
3
3
3
3
3
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4
4
4
4
4
4
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5
5
5
5
5
5
5
5
5
5
6
1
H NMR (CDCl , 400 MHz): δ 3.40 (s, 2H), 3.86 (s, 3H), 4.15 (s, 3H), 6.99ꢀ7.01 (m, 2H), 7.64ꢀ7.66
3
13
(m, 2H). C NMR (CDCl , 100 MHz): δ ꢀ4.8 (C), 14.0 (CH ), 55.3 (CH ), 58.0 (CH ), 86.5 (C),
3
2
3
3
9
1.1 (C), 114.3 (CH), 121.8 (C), 129.4 (CH), 160.8 (C), 164.0 (C), 169.5 (C). HRMS (ESIꢀTOF)
+
+
m/z: [M + H] Calcd for C H INO 369.9935; Found 369.9929.
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13
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
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6
7
8
9
0
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9
0
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2
3
4
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6
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9
0
3
-(4-Bromophenyl)-4-(3-iodoprop-2-yn-1-yl)-5-methoxyisoxazole 5c was obtained following the
general procedure IVB from 3ꢀ(4ꢀbromophenyl)ꢀ5ꢀmethoxyꢀ4ꢀ(propꢀ2ꢀynꢀ1ꢀyl)isoxazole 1e (212
1
mg, 0.73 mmol) in 249 mg (82%) yield as a lightꢀbrown solid, mp 110ꢀ112 °C (water). H NMR
(CDCl , 400 MHz): δ 3.39 (s, 2H), 4.16 (s, 3H), 7.58 (d, J = 8.6 Hz, 2H), 7.62 (d, J = 8.6 Hz, 2H).
3
13
C NMR (CDCl , 100 MHz): δ ꢀ4.2 (C), 13.8 (CH ), 58.1 (CH ), 86.7 (C), 90.7 (C), 124.3 (C),
3
2
3
+
1
28.3 (C), 129.6 (CH), 132.1 (CH), 163.4 (C), 169.7 (C). HRMS (ESIꢀTOF) m/z: [M + H] Calcd
+
for C H BrINO 417.8934; Found 417.8949.
1
3
10
2
4
-(3-Cloroprop-2-yn-1-yl)-5-methoxy-3-phenylisoxazole 6. The solution of 5ꢀmethoxyꢀ3ꢀphenylꢀ
4
ꢀ(propꢀ2ꢀynꢀ1ꢀyl)isoxazole 1a (320 mg, 1.5 mmol) in dry THF (10 mL) was treated with nꢀbutyl
lithium solution (2.5 M solution in hexane, 1.2 mL, 3.0 mmol) with stirring under argon atmosphere
at ꢀ78 °C during 0.5 h. A Nꢀchlorosuccinimide (268 mg, 3.0 mmol) solution in dry (THF 5.0 mL)
was then added dropwise upon cooling, and stirring was continued allowing slow warming up to
0
°C. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted
with ethyl acetate. Combined organic phases were washed with water, saturated aqueous sodium
bicarbonate and brine and dried over anhydrous sodium sulfate. The volatiles were removed in
vacuo and the residue was subjected to column chromatography on silica eluting with light
petroleum/ethyl acetate (8/1) mixture to provide the product 6 in 136 mg (55 %) yield as a lightꢀ
1
yellow oil. H NMR (CDCl , 400 MHz): δ 3.25 (s, 2H), 4.17 (s, 3H), 7.46ꢀ7.50 (m, 3H), 7.66ꢀ7.71
3
13
(m, 2H). C NMR (CDCl , 100 MHz): δ 11.9 (CH ), 58.0 (CH ), 66.5 (C), 86.6 (C), 128.0 (CH),
3 2 3
+
128.8 (CH), 129.4 (C), 129.8 (CH), 164.3 (C), 169.6 (C). HRMS (ESIꢀTOF) m/z: [M + Na] Calcd
+
for C H ClNNaO 270.0292; Found 270.0297.
1
3
10
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5-Methoxy-3-(4-methylphenyl)-4-(3-(trimethylsilyl)prop-2-yn-1-yl)isoxazole 10a. The solution
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of 5ꢀmethoxyꢀ3ꢀ(4ꢀmethylphenyl)isoxazole (380 mg, 2.0 mmol) in dry THF (10 mL) was treated
dropwise with nꢀbutyl lithium solution (2.5 M solution in hexane, 1.0 mL, 2.5 mmol) under argon
atmosphere upon cooling at ꢀ78 °C with stirring and the mixture was stirred for 0.5 h at ꢀ70~ꢀ60 °C.
Copper(I) cyanide (197 mg, 2.2 mmol) and triphenylphosphane (577 mg, 2.2 mmol) were added in
one portion and the resulting mixture was stirred for further 15 minutes at ꢀ60 °C. (3ꢀBromopropꢀ1ꢀ
1
1
1
1
1
1
1
1
1
1
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4
4
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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
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8
9
0
1
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9
0
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9
0
4
5
ynꢀ1ꢀyl)trimethylsilane (478 mg, 2.5 mmol) solution in dry THF (2 mL) was then added by syringe
in one portion and the mixture was allowed to warm up gradually to 0 °C for 1.5 h and agitated at
that temperature for one hour more. The reaction mixture was quenched with iceꢀcold aqueous
ammonium chloride with aqueous ammonia addition and extracted with ethyl acetate. The organic
phase was washed with aqueous ammonia, water and brine and dried over anhydrous sodium
sulfate. All volatiles were removed in vacuo and the residue was subjected to column
chromatography on silica eluting with light petroleum/ethyl acetate (10/1) mixture to provide the
title product 10a in 180 mg (30%) yield as an yellow oil along with 145 mg (38% recovery) of
1
unreacted starting isoxazole. H NMR (CDCl , 400 MHz): δ 0.10 (s, 9H), 2.41 (s, 3H), 3.28 (s, 2H),
3
13
4
.14 (s, 3H), 7.27 (d, J = 8.1 Hz, 2H), 7.65 (d, J = 8.1 Hz, 2H). C NMR (CDCl , 100 MHz): δ ꢀ
3
0
.16 (CH ), 13.0 (CH ), 21.4 (CH ), 57.9 (CH ), 85.4 (C), 87.3 (C), 103.5 (C), 126.7 (C), 128.0
3
2
3
3
+
(
CH), 129.3 (CH), 139.7 (C), 164.5 (C), 169.4 (C). HRMS (ESIꢀTOF) m/z: [M + Na] Calcd for
+
C H NNaO Si 322.1234; Found 322.1250.
17
21
2
4
-(3-(5-Methoxy-3-(4-methylphenyl)isoxazol-4-yl)prop-1-yn-1-yl)benzonitrile 12. 5ꢀMethoxyꢀ3ꢀ
(4ꢀmethylphenyl)ꢀ4ꢀ(propꢀ2ꢀynꢀ1ꢀyl)isoxazole 1b (227 mg, 1.0 mmol), 4ꢀiodobenzonitrile (229 mg,
.0 mmol), triphenylphosphane (53 mg, 0.2 mmol), calcined potassium carbonate (166 mg, 1.2
1
mmol), dry tetrabutylammonium iodide (37 mg, 0.1 mmol) and magnetic stirring bar were placed in
a Schlenk flask and purged with argon. Degassed absolute DMF (5 mL) was added followed after 5
min. stirring with palladium acetate (11 mg, 0.05 mmol) and the mixture was heated under argon
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