Nature of the Nucleophilic Oxygenation Reagent Is Key to Acid-Free Gold-Catalyzed Conversion of Terminal and Internal Alkynes to 1,2-Dicarbonyls

Article abstract of DOI:10.1021/acs.joc.9b02785

2,3-Dichloropyridine N-oxide, a novel oxygen transfer reagent, allows the conductance of the gold(I)-catalyzed oxidation of alkynes to 1,2-dicarbonyls in the absence of any acid additives and under mild conditions to furnish the target species, including those derivatized by highly acid-sensitive groups. The developed strategy is effective for a wide range of alkyne substrates such as terminal- and internal alkynes, ynamides, alkynyl ethers/thioethers, and even unsubstituted acetylene (40 examples; yields up to 99%). The oxidation was successfully integrated into the trapping of reactive dicarbonyls by one-pot heterocyclization and into the synthesis of six-membered azaheterocycles. This synthetic acid-free route was also successfully applied for the total synthesis of a natural 1,2-diketone.

Full text of DOI:10.1021/acs.joc.9b02785

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Article
Nature of the Nucleophilic Oxygenation Reagent is Key to Acid-Free Gold-
Catalyzed Conversion of Terminal and Internal Alkynes to 1,2-Dicarbonyls
Alexey Yu. Dubovtsev, Nikolay V. Shcherbakov, Dmitry V. Dar'in, and Vadim Yu. Kukushkin
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02785 • Publication Date (Web): 18 Dec 2019
Downloaded from pubs.acs.org on December 18, 2019
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Nature of the Nucleophilic Oxygenation Reagent is Key to Acid-Free
Gold-Catalyzed Conversion of Terminal and Internal Alkynes to
1,2-Dicarbonyls
Alexey Yu. Dubovtsev,* Nikolay V. Shcherbakov, Dmitry V. Dar’in, Vadim Yu. Kukushkin*
Saint Petersburg State University, Universitetskaya Nab. 7/9, 199034 Saint Petersburg,
Russian Federation
E-mails: a.dubovtsev@spbu.ru (A.Yu.D.), v.kukushkin@spbu.ru (V.Yu.K.)
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GRAPHICAL ABSTRACT
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Au+
Cl
Cl
O
R2
R1
R2
+
R1
N
O
40 examples
up to 99%
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O
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Novel efficient oxidant
Glyoxal,
mono- and di-
substituted dicarbonyls
Acid-free mild conditions
Trapping of reactive dicarbonyls by
one-pot heterocyclization
ABSTRACT: 2,3-Dichloropyridine N-oxide, a novel oxygen transfer reagent, allows the
conductance of the gold(I)-catalyzed oxidation of alkynes to 1,2-dicarbonyls in the absence of any
acid additives and under mild conditions to furnish the target species including those derivatized
by highly acid-sensitive groups. The developed strategy is effective for a wide range of alkyne
substrates such as terminal- and internal alkynes, ynamides, alkynyl ethers/thioethers, and even
unsubstituted acetylene (40 examples; yields up to 99%). The oxidation was successfully
integrated into the trapping of reactive dicarbonyls by one-pot heterocyclization and into the
synthesis of six-membered azaheterocycles. This synthetic acid-free route was also successfully
applied for the total synthesis of a natural 1,2-diketone.
INTRODUCTION
In the past two decades, the avalanche-like growth in the number of publications devoted to gold
catalysis, the so-called “new gold rush”,1,2 allowed the discoveries of advanced methodologies to
achieve libraries of diverse classes of organic compounds. Owing the unique ability of cationic
gold species to activate triple C≡C bonds, Au-catalyzed transformations of alkynes have become
a powerful tool for increasing molecular complexity.3–9 Among such reactions, the gold-catalyzed
oxygenation of alkynes by N–O10 or S–O11 nucleophilic oxygenation reagents draw significant
attention because of the possibility of generation of highly reactive intermediates – gold α-oxo12
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and α-imino13 carbenes, what makes alkynes an excellent safe alternative for hazardous and
potentially explosive α-diazo carbonyls.14
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As far as the N–O reagents for the Au-catalyzed nucleophilic oxygenation of alkynes are
concerned, various pyridine N-oxides represent the most common choice (Scheme 1).15 An
inherent feature of these reactions is the formation of pyridines as non-target products; their
appearance in the reaction mixture poisons gold catalysts and, consequently, inhibits the oxidation.
Conventionally the addition of strong acids (e.g., MsOH, TfOH, Tf2NH) is required to bind the
formed pyridine and to increase TONs of appropriate catalytic reactions.16–19 As a consequence,
the employment of acids to trap and deactivate pyridines limits the possibility of application of
acid-sensitive molecular fragments in the gold-catalyzed reactions of alkynes.
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Scheme 1. Gold-catalyzed oxygenation of alkynes by pyridine N-oxides
R
R
O
[Au]
R2
R1
R2
+
+
R1
N
O
N
[Au]
It is well documented that structural features of an N-oxide, employed as a nucleophilic
oxygenation reagent in gold-catalyzed transformations, could dramatically affect the efficiency of
these processes.15,20 A pyridine N-oxide should be sufficiently nucleophilic to interact with a
gold(I)-activated alkyne substrate. On the other hand, the nucleophilicity/basicity of the N-oxide
and of the resulting unavoidable pyridine should not be too high to prevent deactivation of the gold
catalyst by coordination of these donor species. Thus, the occurrence of the reaction is determined
by a fine balance between steric and electronic properties of the N–O oxygenation reagent and in
the vast majority of cases choice of the latter becomes more empirical than rational.
CAS SciFinder search indicates that a total of about 50 N-oxides of various structures were
tested in gold-catalyzed oxygenations. Among these N-oxides, three compounds (pyridine-, 3,5-
dichloropyridine-, 8-methylquinoline-N-oxides) were employed in approximately a half of the
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studies.15 Analysis of the available data indicates that selection of certain N-oxide is required for
each specific reaction and when the known N-oxides are ineffective, the search for new reagents
might give a successful solution.20,21 In view of our interest in Au-catalyzed diketonization of
alkynes briefly reviewed in the next section, we found that the choice of appropriate pyridine N-
oxide is as important as the choice of gold catalysts. Thus, 2,3-dichloropyridine N-oxide, a novel
nucleophilic oxygenation reagent, allows the conductance of the Au-catalyzed conversion of
alkynes to 1,2-dicarbonyls in the absence of any acid additives under mild conditions to furnish
the target species including those derivatized by highly acid-sensitive groups. All our results are
consistently disclosed in sections that follow.
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RESULTS AND DISCUSSION
1,2-Dicarbonyls are widespread in nature22–25 and, moreover, these compounds exhibit various
types of biological activity.26–29 These species are commonly applied as convenient building
blocks in the synthesis of numerous acyclic, carbo- and heterocyclic structures for medicinal30–33
and materials chemistry.34,35 Vicinal dicarbonyls were also employed as precursors to many
valuable ligands (e.g., 1,2-diols,36 1,2-diimines,37 or NHCs38). In view of the importance of 1,2-
dicarbonyls, synthetic methods to achieve these compounds are constantly being improved.39–44
Often the formation of 1,2-diketones or α-ketoamides is a side process in the gold-catalyzed
oxygenation of alkynes.11,45–49 An important work in the study of these secondary reactions was
the development by Hashmi and coworkers of the Au-catalyzed oxidation of terminal acetylenes
to substituted glyoxals involving pyridine N-oxides as the nucleophilic oxygenation reagents
(Scheme 2, a).50 However, this method has proven to be inapplicable for the oxidation of internal
alkynes. In continuation of our project on homogeneous Au-catalyzed organic transformations,51–
54
we previously reported the extension of the Hashmi’s method to diketonization of internal
diarylalkynes to 1,2-diketones (b).55 It is noteworthy that both methods are specific for any
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particular type of substrate and they were developed either for terminal (a) or internal (b) alkynes.
Moreover, their serious drawback is the need of the usage of equivalent amounts of strong acids
as an auxiliary reagent to quench pyridines formed and to retain the activity of the gold catalysts.
This substantially limits the range of used substrates and, consequently, possible products. We
envisioned that a screening of a new range of the oxygen donors and discovery of a pyridine N-
oxide with appropriate balance of electronic and steric properties might open up a possibility to
overcome these limitations. The scenario of this work was as the following. We started with the
oxidant screening for Au-catalyzed dicarbonylation of terminal alkynes, whereupon we tested the
reactions of varieties of internal alkynes and also unsubstituted acetylene; an especially important
point was the examination of acid-sensitive substrates. Finally, we applied this method for
combined one-pot dicarbonylation–heterocyclization reactions and also showed its significance
for the total synthesis of a natural 1,2-diketone. Our experiments are given in sections i–iv.
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Scheme 2. Gold-catalyzed dicarbonylation of alkynes
Cl
Cl
N
O
O
O
O
R
H
(a)
(b)
Hashmi's work Ref. 50:
only terminal alkynes
H
R
Ar1
R1
[Au] 5 mol %
Tf2NH 1 equiv
R = Alk, Ar
O
O
O
N
O
Me
Ar1
Ar2
Ar2
Our work Ref. 55:
only internal alkynes
[Au] 5 mol %
TfOH 2 equiv
Cl
N
O
Cl
(c)
R1
R2
R2
THIS WORK:
versatile alkynes
Ph3PAuNTf2 3–5
R1 = H, Alk, Ar
R1 = H, Ar, NRR',
OMe, SMe
NO ACID!
mol %,
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(i) Oxidant Screening for Gold-catalyzed Dicarbonylation of Terminal Alkynes. In the Hashmi’s
work,50 only three N-oxides were tested for the oxidation of terminal alkynes. Two of them (3,5-
dichloropyridine-, 6-methoxyquinoline-N-oxides) acted as the oxidants only upon additional
treatment with an equimolar amount of TfOH, whereas the third reagent (4-picoline N-oxide) was
totally inactive in these reactions. Other reports on transformations of terminal alkynes to vicinal
dicarbonyls are rare and the development of a general and convenient approach to 1,2-dicarbonyls
is still a challenging task.41,50
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We began our study with the oxidant screening for the Au-catalyzed dicarbonylation of
phenylacetylene (1) to phenylglyoxal (3). Glyoxal itself and substituted glyoxals are reversibly
hydrated and easily polymerized and these reactions complicate their identification and
chromatographic isolation.50 Therefore, the oxidation of phenylacetylene (1) followed by
heterocyclization with o-phenylenediamine to achieve 2-phenylquinoxaline (5) was chosen as a
model reaction (Table 1); this reaction was conducted sequentially to avoid the interplay between
the alkyne and o-phenylenediamine 4.56
Table 1. Optimization of the gold(I)-catalyzed model reaction involving phenylacetylenea
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NH2
O
5 mol % catalyst
N
N
H
2
N-oxide 2.5 equiv
NH2
1.5 equiv
80 °C, 2 h
t, Time
4
O
1
3
5
7
8
9
Cl
Cl
Cl
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N
O
N
O
Me Me
N
O
Me
N
O
Bn
Br
N
O
Cl
N
O
N
O
Cl
2a
2b
2c
2d
2e
2f
2g
Cl
OMe
Cl
Me
Cl
Cl
Cl
N
O
Cl
N
N
N
O
N
O
O
O
2h
2i
2j
2k
2l
Br
Me
N
N
O
N
O
O
Me
2m
2n
2o
Entry
1
N-oxide
Catalyst
Solvent
t, °C
60
60
60
60
60
60
60
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60
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60
60
60
60
60
60
60
60
40
60
60
rt
Time, h
Yield,b %
48
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2f
2f
2f
2f
2f
2f
2f
2f
2f
Ph3PAuNTf2
Ph3PAuNTf2
Ph3PAuNTf2
Ph3PAuNTf2
Ph3PAuNTf2
Ph3PAuNTf2
Ph3PAuNTf2
Ph3PAuNTf2
Ph3PAuNTf2
Ph3PAuNTf2
Ph3PAuNTf2
Ph3PAuNTf2
Ph3PAuNTf2
Ph3PAuNTf2
Ph3PAuNTf2
IPrAuNTf2
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
PhCl
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
72
1
2
6
6
2
3
4
5
6
7
8
9
20
8
33
44
54
49
11
33
25
10
traces
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50
43
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35
51
30
11
27
39
55
60
62
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25
Ph3PAuCl/AgOTf
PicAuCl2
Ph3PAuNTf2
Ph3PAuNTf2
Ph3PAuNTf2
DCM
THF
Ph3PAuNTf2, 3 mol %
Ph3PAuNTf2
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
Ph3PAuNTf2
Ph3PAuNTf2
Ph3PAuNTf2
Ph3PAuNTf2
80
80
80
80
2f
2f
2f, 3 equiv
62
aAll reactions were carried out on a 0.1 mmol scale (0.2 M). bEstimated by 1H NMR spectroscopy
using durene as an internal standard.
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Initially, Ph3PAuNTf2 (5 mol %) was chosen as the catalyst, and the reaction was carried
out in PhCF3 at 60 °C for 2 h. A series of fifteen pyridine N-oxides (2a–o, 2.5 equiv) exhibiting
various electronic and steric effects of substituents have been tested in Au-catalyzed oxidative
transformations of alkynes; 2a–o include the previously studied (2a–c,e,g,h,n) and not yet
examined (2d,f,i–m,o) species. The introduction of electron-withdrawing groups and bulky
substituents in the α-positions of pyridines reduces their ability to bind metal centers (e.g.,
gold(I),15 rhodium(II)57) and this contributes to the preservation of the catalytic activity of the gold
catalysts. At the same time, a significant decrease in the nucleophilicity of the α-substituted
pyridine N-oxides can lead to reduction of their activity in the nucleophilic oxygenation of
alkynes.58 Indeed, the experimental data (Entries 1–15) follow the indicated reactivity trends. The
best yield was achieved for 2,3-dichloropyridine-N-oxide (2f) that, although the known
compound,59 has never been used as an oxidant in any synthetic transformation. This oxide is shelf-
stable, easy to handle, and it can be obtained via the facile and almost quantitative oxidation of
2,3-dichloropyridine (1f) by the urea hydrogen peroxide complex.59 Pyridine 1f, formed upon
reduction of 2f, can be easily separated from the reaction mixture by sublimation and thus
recovered as pure compound for its further usage.
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Next, we studied the effect of the catalytic system on the reaction by the variation of the
ligand (replacement of Ph3P by the NHC-ligand IPr60) and counterion (NTf2/OTf). The gold(III)
PicAuCl2 complex was also tested and the best results were achieved with the Gagosz catalyst
(Entry 6). Reducing the amount of Ph3PAuNTf2 to 3 mol % led to a significant reduction of the
yield. A blank experiment without any gold catalyst indicates that Tf2NH (5 mol %) alone does
not catalyze the oxidation. Different solvents were then examined and inert nonpolar solvents (e.g.,
PhCF3, PhCl) gave the best results (Entries 6, 19). Most likely these rather inert solvents are
efficient in view of the high reactivity of gold carbene intermediates; when toluene, reactive in the
CH-insertion, was used as a solvent, the yield was only 19%.
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Experiments on temperature and reaction time variations (Entries 23–26) demonstrate that
the best yield was achieved when the reaction was conducted at 80 °C for 6 h. Finally, increase of
the amount of the oxidant to 3 equiv. does not lead to the increase in the efficiency of the gold-
catalyzed process. Thus, the optimal results were obtained in the model reaction conducted at 80
°C for 6 h in PhCF3 as the solvent and 2.5 equiv. of 2,3-dichloropyridine N-oxide and 5 mol % of
Ph3PAuNTf2 were employed.
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With the optimal conditions at hand, the substrate scope and limitations of the model
reaction were examined (Table 2). Arylacetylenes featuring both electron-donating and electron-
withdrawing groups at the para-, meta-, and ortho-positions of the aryl ring all delivered the
corresponding quinoxalines in good to moderate yields (8a–g; 84–48%). Heteryl (5-
benzo[d][1,3]dioxolyl, 3-quinolinyl, 2-thienyl) and alkyl (2-hexyl, 1-adamantyl) substituted
acetylenes can also be successfully used as the alkyne component (8g–k). Furthermore, the
reaction conditions were applied for the synthesis of diquinoxaline 8l from 1,4-diethynylbenzene
7l; in this case, the by-product of monooxidation/heterocyclization 8l' was also detected by NMR.
It is noteworthy that only mono-product 8l' (30%) was obtained from 7l by the Hashmi’s method.50
Table 2. Gold-catalyzed dicarbonylation of terminal alkynes. Synthesis of 2-substituted
quinoxalinesa,b
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2
NH2
3
4
5
6
O
Ph3PAuNTf2 5 mol %
2f
N
N
R
NH2
1.5 equiv
80 °C, 2 h
H
R
H
2.5 equiv
PhCF3, 80 °C
R
4
O
1 6
,
7
5 8
,
7
8
9
Me
Bu-t
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N
N
N
N
N
8b
,
53%
N
8a
5
, 60%
, 69%
, 76%
, 71%
OMe
NO2
CN
N
N
N
N
N
8d
N
8e
,
84%
8c
, 63%
N
O
O
N
N
N
F
S
N
N
8g
N
8h
55%
,
8f
, 48%
N
N
N
Hex-n
N
N
N
8i
8j
8k
,
57%
, 46%
, 41%
N
N
N
N
N
N
c
8l
8l'
, 16%
, 48%
aAll reactions were carried out on a 0.2 mmol scale (0.2 M). bIsolated yield. c 1H NMR yield.
(ii) Gold-catalyzed Dicarbonylation of Internal Alkynes. Motivated by the successful results of the
dicarbonylation of terminal alkynes, we decided to extend this acid-free dicarbonylation method
to internal alkynes. Compared to terminal spices, internal alkynes display different
steric/electronic properties and their regioselective oxidation is worthwhile in view of the
availability of two potential sites for nucleophilic attack at asymmetric internal alkynes.21 4-
Fluorosubstituted tolan 9 was chosen as a model substrate because its diketonization can be easily
monitored by 19F NMR (Table 3). Initial screening of the most effective reagents for the oxidation
of phenylacetylene (Table 1) showed that 2f is again the best choice and the almost complete
conversion of 9 was achieved with 5 mol % of Ph3PAuNTf2 in PhCF3 at 60 °C for 6 h (Entry 2).
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8
9
As in the cases of terminal alkynes, the oxidation of 9 in polar solvents (for example, in MeCN
and DMSO) was less efficient than in non-polar, but to our surprise, application of rather polar
THF (Entry 8) gave as excellent results as those with PhCF3. Further optimization demonstrated
that the highest product yield can be achieved with only 3 mol % of the Ph3PAuNTf2 catalyst when
the reaction was conducted at 60 °C for 6 h (Entry 11). The transformation of 9 can also be carried
out at room temperature but the reaction time in this case is substantially larger (72 h; Entry 14).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
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60
Table 3. Optimization of the gold(I)-catalyzed dicarbonylation of 1-fluoro-4-
(phenylethynyl)benzene (9)a
O
Ph3PAuNTf2
F
2
N-oxide 2.5 equiv
O
F
9
10
Cl
Cl
N
O
Cl
Cl
N
O
Cl
N
O
N
O
Me
2e
2f
2h
2n
Catalyst,
mol %
Yield,b
%
Entry
N-oxide
Solvent
t, °C
Time, h
1
2
3
4
5
6
8
9
10
11
12
13
14
2e
2f
2h
2n
2f
2f
2f
2f
2f
2f
2f
2f
2f
5
5
5
5
5
5
5
5
3
3
2
3
3
PhCF3
PhCF3
PhCF3
PhCF3
DCM
60
60
60
60
40
60
60
60
60
60
60
80
rt
3
3
3
3
3
3
3
3
3
97
99
84
86
87
78
99
38
89
99
93
89
MeCN
THF
DMSO
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
6
12
3
72
96
aAll reactions were carried out on a 0.1 mmol scale (0.2 M). b 19F NMR yield.
Then we examined the scope of this acid-free procedure for the preparation of various
disubstituted dicarbonyls including those that cannot be prepared using our previous protocol55
(Table 4). Good-to-excellent yields of 10 and 12 were obtained from unsubstituted tolane 11a and
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monosubstituted diarylalkynes 9,11b,c,f,g bearing either electron-donating (Me, OMe) or
electron-withdrawing (F, Br, Ac) groups. Asymmetrically disubstituted (MeO, CN) diketone 12h
was also generated and isolated in almost quantitative yield. The yield of m-MeO substituted
diketone 12d is slightly lower than those for the o- and p-substituted isomers (12c,e), probably due
to the electron-withdrawing effect of the methoxy group in the meta position. 1-Nitro-4-
(phenylethynyl) benzene (11i) is a problematic55 substrate for the diketonization due to its
electron-deficient nature that determines poor coordination of the alkyne to the cationic metal
center. However, the corresponding diketone 11i was still obtained in 56% yield. When we
increased the catalyst load to 5 mol %, the yield of the corresponding diketone was reached 76%.
The usage of the acid-free conditions significantly expands the range of possible products
of the gold-catalyzed diketonization. Various functional groups were tolerated well, including an
oxidizable aldehyde fragment (12j) and acid- or hydrolysis-sensitive groups such as an ester
moiety (12k), 1,3-dioxalane (12l) or Boc-protected amino group (12m). In the latter two cases,
traces of unprotected 1,2-diketones were detected in the reaction mixtures. This is probably
associated with the formation of minor amounts of an acid as a result of uncontrolled
decomposition of the catalyst. The reaction conditions were also found applicable to the synthesis
of heteroaryl (acidophobic α-furyl (12n), α-thienyl (12o)), or even ferrocenyl (12p) substituted
1,2-diketones. Moreover, tetraketone 12q was obtained (74%) as a result of the bidirectional
diketonization of dialkynyl-substituted benzene 11q. In addition, our methodology was efficiently
applied to ynamides 11r,s, alkynyl-ether 11t and thioether 11u that were converted to the
corresponding α-ketoamides 12r,s α-ketoester 12t, and α-ketothioester 12u, respectively.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 4. Gold-catalyzed dicarbonylation of internal alkynesa,b
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O
Ph3PAuNTf2 3 mol %
R2
R1
R2
R1
2f
2.5 equiv
PhCF3, 60 °C
O
5
6
10 12
,
9 11
,
7
8
9
F
Me
OMe
O
O
O
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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60
O
O
O
O
10
12a
12b
12c
, 95%
, 96%
, 99%
, 95%
Br
Ac
O
O
O
O
OMe
O
O
OMe
O
O
12d
12e
12f
12g
, 80%
, 83%
, 95%
, 82%
OMe
NO2
CHO
O
O
O
O
CO2Me
O
O
O
O
NC
c
12h
12i
12j
12k
, 95%
, 56(76)%
, 94%
, 87%
O
NHBoc
O
O
O
O
O
O
S
O
O
O
O
12l
12m
12n
12o
, 89%
, 76%
, 96%
, 94%
O
O
Ts-4
N
O
O
Me
Fe
O
O
O
O
12p
12q
12r
, 94%
, 90%
, 74%
O
O
O
O
N
OMe
SMe
O
O
O
O
d
12s
12t
12u
, 69%
, 99%
, 95%
aAll reactions were carried out on a 0.2 mmol scale (0.2 M). bIsolated yield. c5 mol % of Ph3PAuNTf2 was used. drt,
10 min.
We also tested some alkyl-substituted internal alkynes as substrates for the diketonization.
However, in this case, we observed the side 1,2-migrations61 of the gold α-oxo carbene
intermediates. Under the optimized conditions, 1-methyl-2-phenylacetylene (13a), in addition to
target diketone 14a, gave α,β-unsaturated ketone 15a as a minor product (Scheme 3). For tert-
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butyl substituted acetylene 13b, the ratio of the formed products, on the contrary, shifted to
rearrangement product 15b.
6
7
8
9
Scheme 3. Gold-catalyzed oxidation of alkyl-substituted internal alkynesa
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
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51
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53
54
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58
59
60
O
O
Me
+
Me
O
13a
15a
, 27%
14a
, 35%
O
O
Me
Me
Bu-t
+
Bu-t
O
Me
13b
14b
, 12%
15b
, 78%
aPh3PAuNTf2 3 mol %, 2f 2.5 equiv, PhCF3, 60 °C.
(iii) The Acid-free Gold-catalyzed Dicarbonylation of Acetylene. Although acetylene is one of the
most important building blocks in industrial chemistry,62 its application in laboratory practice is
severely limited by the high fire hazard and substantial risk of explosion. The use of compressed
acetylene requires special facilities and techniques as well as strict safety precautions.63 To
overcome these restrictions calcium carbide was suggested as a convenient and rather safe source
of acetylene64,65 and we decided to explore this CaC2-based method in our experiments.
Gratefully, by passing acetylene gas 16 – generated from calcium carbide in a two-chamber
reactor66 – to a solution of 2,3-dichloropyridine N-oxide in PhCF3 containing Ph3PAuNTf2 (5 mol
%) at rt, we achieved the almost complete conversion of 2f. The generation of glyoxal was
confirmed by the formation of the corresponding dihydrazone upon treatment of the reaction
mixture with 2,4-dinitrophenylhydrazine.67 Then we synthesized quinoxaline 19 and triazine 21
directly from acetylene by the oxidation–heterocyclization sequence (Scheme 4), thus linking
these important heterocyclic motifs68,69 to the alkyne reagent space.
Scheme 4. The oxidation–heterocyclization of unsubstituted acetylene
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N
3
4
5
6
NH2
NH2
Me
N
Me
19
, 60%
7
8
9
18
O
H
O
H
Ph3PAuNTf2, 5 mol %
2f
H
H
1.5 equiv
, 2.5 equiv
PhCF3, rt
50 °C, 5 h
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
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42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
16
17
NH2
NH2
N
N
MeO
N
20
MeO
21
, 65%
(iv) The Acid-free Gold-catalyzed Dicarbonylation in the Total Synthesis. Owing to the high
prevalence in natural compounds and drug candidates, 2-hydroxybenzil motif are the desired target
for synthesis.24,70,71 To demonstrate the synthetic possibilities of the developed method for acid-
free dicarbonylation of alkynes, we carried out a total synthesis of 2-hydroxybenzil 28, isolated
from the heartwood of Dalbergia latifolia,72 starting from vanillin 22 (Scheme 5). The key step is
the diketonization of acid-sensitive MOM-protected acetylene 26, obtained by the gold-
supported73 Sonogashira coupling from 25. As with the protected compounds 12l,m, the
methoxymethyl groups of 27 are preserved upon the oxidation. Notably that earlier we were unable
to obtain diketone 28 by the oxidation of 26 following our previous protocol55 that requires the
presence of TfOH.
Scheme 5. Total synthesis of 2,5-dihydroxy-4-methoxyphenyl)-2-phenylethane-1,2-dione (28)
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7
8
OH
OH
OH
OMOM
Br
CHO
OH
Br
a)
b)
c)
80%
MeO
MeO
MeO
68%
MeO
8
2
OH
24
OMOM
25
%
22
23
d)
62%
9
OH
OMOM
OMe
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
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59
60
MOMO
OMe
f)
e)
O
O
OMe
OMOM
56%
6
O
OH
O
OMOM
28
27
26
Reaction conditions
Pd(PPh3)2Cl2, Ph3PAuCl, DMF, 80 °C; e) , Ph3PAuNTf2, PhCF3, rt; f) HCl, THF, rt
: a) H2O2, NaHCO3, H2O, rt; b) Br2, AcOH, 10 °C; c) MOMCl, NaH, THF, 0-20 °C; d) PhCCH, Et3N,
2f
CONCLUSIONS
Summarizing, we found a novel effective reagent, 2,3-dichloropyridine N-oxide, for the
nucleophilic oxygenation of gold(I)-activated alkynes to furnish 1,2-dicarbonyls. The application
of this N-oxide as an O-transfer reagent allows the conductance of the dicarbonylation in the
absence of any acid additives and this acid-free approach significantly expands the range of the
obtained products in comparison with the previously described H+-involving methods. Our
approach combines terminal and internal alkynes, ynamides, and alkynyl ethers/thioethers into a
single substrate pool for the production of vicinal dicarbonyls of highly diverse nature (α-
ketoaldehydes, 1,2-diketones, α-ketoamides, and α-ketoesters/thioesters). A significant advantage
of the developed method is the possibility of using unsubstituted acetylene as a synthetic precursor
of glyoxal. To the best of our knowledge, this is the first example of a gold-catalyzed oxygen-
transfer involving acetylene. Acid-sensitive molecular fragments, including protecting groups,
survive the reaction conditions, which made it possible to apply this route to 1,2-dicarbonyls in
the total synthesis. The utility of this oxidation method was also demonstrated by facile one-pot
synthesis of important azaheterocyclic systems.
EXPERIMENTAL SECTION
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General Information. NMR spectra were recorded at ambient temperature with a Bruker Avance III 400 instrument
at 400.13 MHz (1H NMR) and 100.61 MHz (13C NMR) in CDCl3 or DMSO-d6. Chemical shifts (δ) are given in ppm
relative to resonances of the solvents (1H: δ = 7.26 for residual CHCl3 peak, δ = 2.50 for residual DMSO peak; 13C: δ
= 77.2 for CDCl3, δ = 39.5 for DMSO-d6). Mass-spectra were recorded on Bruker MicroTOF (ESI) and Bruker maXis
HRMS-ESI-QTOF instruments. Chromatographic separation was carried out on Macherey–Nagel silica gel 60 M
(0.04–0.063 mm). Analytical TLC was performed on unmodified Merck ready-to-use plates (TLC silica gel 60 F254);
detection was achieved with a UV lamp. Melting points were measured with Stuart smp30 apparatus. Gold complexes
(Ph3PAuNTf2,51 IPrAuNTf2,74 PicAuCl275) and N-oxides 2a-e,k-o76 and 2h59 were synthesized accordingly to the
published protocols. Terminal alkynes 6b,d,e,f,52 internal alkynes 9, 11b-i,o,55 11k,77 11n,78 11p,79 13a52 , 13b80
ynamides 11r,s, alkynyl ether 11t81 and alkynyl thioether 11u82 were prepared by the literature procedures. The
solvents were purified using standard techniques and stored over activated 4 Å molecular sieves before use. Other
reagents were purchased from commercial vendors and were used as received.
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11
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22
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59
60
General procedure for the oxidation-heterocyclization of terminal alkynes. Synthesis of 2-substituted
quinoxalines 5,8. Ph3PAuNTf2 (7.4 mg, 10.0 μmol, 5 mol %) was added to the solution of terminal alkyne (1,6, 0.2
mmol) and 2,3-dichloropyridine N-oxide 2f (82.0 mg, 0.5 mmol, 2.5 equiv) in PhCF3 (1.0 mL). The resulting solution
was stirred at 80 °C in an oil bath for 6 h. Then o-phenylenediamine 4 (32.4 mg, 0.3 mmol, 1.5 equiv) was added and
the mixture was stirred at 80 °C for another 2 h. Upon cooling to r.t., all volatile components were removed in vacuo
and the residue was purified by silica gel chromatography eluting with hexane/EtOAc (gradient from 12:1 to 1:1) to
afford quinoxalines 5,8.
1
2-Phenylquinoxaline (5)83: yellow solid (24.8 mg, 60%); Rf 0.50 (hexane/ethyl acetate 4:1); H NMR (400 MHz,
CDCl3) δ 9.33 (s, 1H), 8.22–8.19 (m, 2H), 8.18–8.11 (m, 2H), 7.81–7.73 (m, 2H), 7.60–7.50 (m, 3H); 13C{1H} NMR
(100 MHz, CDCl3) δ 152.0, 143.5, 142.5, 141.8, 137.0, 130.4, 130.3, 129.8, 129.7, 129.29, 129.28, 127.7; HRMS
+
(ESI): m/z [M + H]+ calcd. for C14H11N2 : 207.0922; found: 207.0925.
2-(4-Tolyl)quinoxaline (8a)83: orange solid (30.4 mg, 69%); Rf 0.50 (hexane/ethyl acetate 4:1); 1H NMR (400 MHz,
CDCl3) δ 9.31 (s, 1H), 8.14 (dd, J = 8.1, 1.7 Hz, 1H), 8.12–8.10 (m, 3H), 7.79–7.71 (m, 2H), 7.37 (t, J = 7.9 Hz, 2H),
2.45 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 152.0, 143.4, 142.5, 141.6, 140.6, 134.1, 130.3, 130.0, 129.7, 129.4,
+
129.2, 127.6, 21.6; HRMS (ESI): m/z [M + H]+ calcd. for C15H13N2 : 221.1079; found: 221.1075.
2-(4-(tert-Butyl)phenyl)quinoxaline (8b)50: yellow oil (27.2 mg, 52%); Rf 0.45 (hexane/ethyl acetate 8:1); 1H NMR
(400 MHz, CDCl3) δ 9.32 (s, 1H), 8.16–8.11 (m, 4H), 7.80–7.71 (m, 2H), 7.60 (d, J = 8.5 Hz, 2H), 1.40 (s, 9H);
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13C{1H} NMR (100 MHz, CDCl3) δ 153.8, 152.0, 143.5, 142.5, 141.6, 134.2, 130.3, 129.7, 129.4, 129.2, 127.5, 126.3,
3
4
+
35.0, 31.4; HRMS (ESI): m/z [M + H]+ calcd. for C18H19N2 : 263.1548; found: 263.1553.
5
6
7
8
2-(4-Methoxyphenyl)quinoxaline (8c)83: orange solid (29.8 mg, 63%); Rf 0.50 (hexane/ethyl acetate 2:1); 1H NMR
(400 MHz, CDCl3) δ 9.29 (s, 1H), 8.17 (d, J = 8.8 Hz, 2H), 8.10 (t, J = 8.2 Hz, 2H), 7.77–7.69 (m, 2H), 7.08 (t, J =
8.8 Hz, 2H), 3.90 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 161.6, 151.6, 143.2, 142.5, 141.4, 130.3, 129.53,
129.46, 129.21, 129.17, 129.1, 114.7, 55.6; HRMS (ESI): m/z [M + H]+ calcd. for C15H13N2O+: 237.1028; found:
237.1028.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
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45
46
47
48
49
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59
60
2-(4-Nitrophenyl)quinoxaline (8d)84: yellow solid (38.2 mg, 76%); Rf 0.50 (hexane/ethyl acetate 2:1); 1H NMR (400
MHz, CDCl3) δ 9.38 (s, 1H), 8.42–8.38 (m, 4H), 8.20–8.15 (m, 2H), 7.86–7.80 (m, 2H); 13C{1H} NMR (100 MHz,
CDCl3) δ 149.4, 149.0, 142.9, 142.7, 142.34, 142.26, 131.0, 130.8, 130.0, 129.4, 128.5, 124.4; HRMS (ESI): m/z [M
+
+ H]+ calcd. for C14H10N3O2 : 252.0773; found: 252.0774.
1
4-(Quinoxalin-2-yl)benzonitrile (8e)84: yellow solid (38.9 mg, 84%); Rf 0.50 (hexane/ethyl acetate 2:1); H NMR
(400 MHz, CDCl3) δ 9.35 (s, 1H), 8.34 (d, J = 8.4 Hz, 2H), 8.17 (ddd, J = 8.4, 6.8, 2.4 Hz, 2H), 7.87–7.79 (m, 4H);
13C{1H} NMR (100 MHz, CDCl3) δ 149.7, 142.9, 142.4, 142.2, 141.0, 133.0, 131.0, 130.7, 130.0, 129.4, 128.2, 118.6,
+
113.9; HRMS (ESI): m/z [M + H]+ calcd. for C15H10N3 : 232.0875; found: 232.0875.
1
2-(2-Fluorophenyl)quinoxaline (8f)85: yellow solid (21.5 mg, 48%); Rf 0.40 (hexane/ethyl acetate 4:1); H NMR
(400 MHz, CDCl3) δ 9.33 (d, JF = 3.0 Hz, 1H), 8.19–8.10 (m, 3H), 7.82–7.76 (m, 2H), 7.53–7.47 (m, 1H), 7.36 (t, J
= 7.6 Hz, 1H), 7.28–7.23 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 161.0 (d, JF = 250.6 Hz), 149.4 (d, JF = 3.2
Hz, C), 146.1 (d, JF = 11.0 Hz), 142.6, 141.7, 132.0 (d, JF = 8.5 Hz), 131.6 (d, JF = 2.9 Hz), 130.4, 130.1, 129.8, 129.4,
+
125.2 (m, JF = 3.5 Hz), 116.6 (d, JF = 22.7 Hz); HRMS (ESI): m/z [M + H]+ calcd. for C14H10FN2 : 225.0828; found:
225.0831.
2-(Benzo[d][1,3]dioxol-5-yl)quinoxaline (8g)86: yellow solid (35.5 mg, 71%); Rf 0.40 (hexane/ethyl acetate 4:1); 1H
NMR (400 MHz, CDCl3) δ 9.25 (s, 1H), 8.10 (ddd, J = 7.8, 5.9, 1.6 Hz, 2H), 7.78–7.69 (m, 4H), 6.98 (d, J = 8.1 Hz,
1H), 6.06 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 151.4, 149.8, 148.9, 143.2, 142.3, 141.5, 131.3, 130.4, 129.6,
+
129.3, 129.2, 122.2, 108.9, 107.8, 101.7; HRMS (ESI): m/z [M + H]+ calcd. for C15H11N2O2 : 251.0821; found:
251.0825.
2-(Quinolin-3-yl)quinoxaline (8h): white solid (28.3 mg, 55%); mp 118.0–119.5 °C (hexane/ethyl acetate); Rf 0.40
(hexane/ethyl acetate 1:1); 1H NMR (400 MHz, CDCl3) δ 9.78 (d, J = 2.3 Hz, 1H), 9.49 (s, 1H), 8.95 (d, J = 2.2 Hz,
1H), 8.24–8.16 (m, 3H), 8.01 (d, J = 8.2 Hz, 1H), 7.87–7.78 (m, 3H), 7.65 (d, J = 7.0 Hz, 1H); 13C{1H} NMR (100
MHz, CDCl3) δ 149.6, 149.4, 148.8, 143.1, 142.6, 142.0, 134.9, 130.9, 130.8, 130.3, 129.9, 129.64, 129.60, 129.4,
+
128.8, 127.8, 127.6; HRMS (ESI): m/z [M + H]+ calcd. for C17H12N3 : 258.1031; found: 258.1038.
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2-(Thiophen-2-yl)quinoxaline (8i)83: orange solid (19.5 mg, 46%); Rf 0.40 (hexane/ethyl acetate 4:1); 1H NMR (400
MHz, CDCl3) δ 9.24 (s, 1H), 8.09–8.05 (m, 2H), 7.87 (d, J = 2.6 Hz, 1H), 7.77–7.67 (m, 2H), 7.55 (dd, J = 5.1, 1.0
Hz, 1H), 7.21 (dd, J = 5.1, 3.7 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 147.5, 142.4, 142.3, 142.2, 141.5, 130.6,
130.0, 129.34, 129.28 (×2), 128.6, 127.1; HRMS (ESI): m/z [M + H]+ calcd. for C12H9N2S+: 213.0486; found:
213.0481.
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2-Hexylquinoxaline (8j)50: orange oil (17.6 mg, 41%); Rf 0.40 (hexane/ethyl acetate 8:1); H NMR (400 MHz,
CDCl3) δ 8.74 (s, 1H), 8.06–8.03 (m, 2H), 7.75–7.68 (m, 2H), 3.03–2.99 (m, 2H), 1.85 (p, J = 7.6 Hz, 2H), 1.47–1.40
(m, 2H), 1.38–1.25 (m, 4H), 0.89 (t, J = 6.9 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 157.9, 146.0, 142.4, 141.4,
130.0, 129.3, 129.0 (×2), 36.7, 31.8, 29.7, 29.3, 27.7, 14.2; HRMS (ESI): m/z [M + H]+ calcd. for C14H19N2 :
+
215.1548; found: 215.1551.
2-(Adamantan-1-yl)quinoxaline (8k): white solid (30.1 mg, 57%); mp 115.0–117.0 °C (hexane/ethyl acetate); Rf
0.30 (hexane/ethyl acetate 8:1); 1H NMR (400 MHz, CDCl3) δ 8.95 (s, 1H), 8.06 (dd, J = 7.5, 2.0 Hz, 2H), 7.71 (td,
J = 7.9, 1.5 Hz, 2H), 2.19–2.15 (m, 9H), 1.85 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 163.4, 143.3, 142.1, 141.1,
129.7, 129.4, 129.1, 129.0, 41.5, 39.1, 36.8, 28.7; HRMS (ESI): m/z [M + H]+ calcd. for C18H21N2 : 265.1705; found:
+
265.1709.
1,4-Di(quinoxalin-2-yl)benzene (8l)87: yellow solid (32.1 mg, 48%); Rf 0.40 (hexane/ethyl acetate 2:1); H NMR
1
(400 MHz, CDCl3) δ 9.43 (s, 2H), 8.44 (s, 4H), 8.21 (d, J = 7.1 Hz, 2H), 8.16 (d, J = 7.6 Hz, 2H), 7.84–7.77 (m, 4H);
13C{1H} NMR (100 MHz, CDCl3) δ 151.1, 143.4, 142.5, 142.0, 138.4, 130.6, 130.0, 129.9, 129.3, 128.4; HRMS
+
(ESI): m/z [M + H]+ calcd. for C22H15N4 : 335.1297; found: 335.1292.
General procedure for the oxidation of internal alkynes. Ph3PAuNTf2 (4.4 mg, 10.0 μmol, 3 mol %) was added to
the solution of internal alkyne (9,11,13, 0.2 mmol) and 2,3-dichloropyridine N-oxide 2f (82.0 mg, 0.5 mmol, 2.5 equiv)
in PhCF3 (1.0 mL). The resulting solution was stirred at 60 °C in an oil bath for 6 h. Then all volatile components
were removed in vacuo and the residue was purified by silica gel chromatography eluting with hexane/EtOAc
(gradient from 12:1 to 1:1) to afford corresponding 1,2-dicarbonyls 10,12,14.
1-(4-Fluorophenyl)-2-phenylethane-1,2-dione (10)55: yellow solid (39.2 mg, 97%); Rf 0.65 (hexane/ethyl acetate
8:1); 1H NMR (400 MHz, CDCl3) δ 8.04–8.00 (m, 2H), 7.97 (d, J = 7.1 Hz, 2H), 7.67 (t, J = 7.4 Hz, 1H), 7.52 (t, J =
7.8 Hz, 2H), 7.19 (t, J = 8.6 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 194.2, 192.8, 166.9 (d, JF = 258.2 Hz, CF),
135.1, 133.0, 132.9 (d, JF = 9.8 Hz, CH), 130.1, 129.7 (d, JF = 2.9 Hz, C), 129.2, 116.5 (d, JF = 22.2 Hz, CH); HRMS
+
(ESI): m/z [M + Na]+ calcd. for C14H9FNaO2 : 251.0479, found 251.0471.
1,2-Diphenylethane-1,2-dione (12a)55: yellow solid (42.2 mg, 99%); Rf 0.30 (hexane/ethyl acetate 12:1); 1H NMR
(400 MHz, CDCl3) δ 7.98 (d, J = 7.2 Hz, 4H), 7.65 (t, J = 7.4 Hz, 2H), 7.51 (t, J = 7.7 Hz, 4H); 13C{1H} NMR (100
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MHz, CDCl3) δ 194.7, 135.0, 133.1, 130.0, 129.2; HRMS (ESI): m/z [M + Na]+ calcd. for C14H10NaO2 : 233.0573,
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found 233.0578.
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1-Phenyl-2-(4-tolyl)ethane-1,2-dione (12b)55: yellow solid (33.4 mg, 95%); Rf 0.65 (hexane/ethyl acetate 8:1); H
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NMR (400 MHz, CDCl3) δ 7.97 (d, J = 7.1 Hz, 2H), 7.87 (d, J = 8.2 Hz, 2H), 7.64 (t, J = 7.4 Hz, 1H), 7.50 (t, J = 7.7
Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 2.43 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 194.9, 194.4, 146.3, 134.9, 133.2,
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130.7, 130.1, 130.0, 129.9, 129.1, 22.0; HRMS (ESI): m/z [M + Na]+ calcd. for C15H12NaO2 : 247.0730, found
247.0742.
1-(4-Methoxyphenyl)-2-phenylethane-1,2-dione (12c)55: yellow solid (38.2 mg, 95%); Rf 0.35 (hexane/ethyl acetate
4:1); 1H NMR (400 MHz, CDCl3) δ 7.97–7.92 (m, 4H), 7.64 (t, J = 7.4 Hz, 1H), 7.49 (t, J = 7.7 Hz, 2H), 6.97 (d, J =
9.0 Hz, 2H), 3.87 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 195.0, 193.3, 165.1, 134.8, 133.3, 132.5, 130.0, 129.1,
126.2, 114.5, 55.8; HRMS (ESI): m/z [M + Na]+ calcd. for C15H12NaO3 : 263.0679, found 263.0676.
+
1-(3-Methoxyphenyl)-2-phenylethane-1,2-dione (12d)55: yellow solid (33.5 mg, 83%); Rf 0.45 (hexane/ethyl acetate
8:1); 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 7.1 Hz, 2H), 7.66 (t, J = 7.4 Hz, 1H), 7.56–7.46 (m, 4H), 7.39 (t, J =
7.9 Hz, 1H), 7.20 (ddd, J = 8.2, 2.7, 1.0 Hz, 1H), 3.86 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 194.6 (×2), 160.3,
135.0, 134.4, 133.2, 130.2, 130.0, 129.2, 123.4, 122.0, 113.0, 55.7; HRMS (ESI): m/z [M + Na]+ calcd. for
+
C15H12NaO3 : 263.0679, found 263.0691.
1-(2-Methoxyphenyl)-2-phenylethane-1,2-dione (12e)55: yellow solid (35.1 mg, 95%), Rf 0.30 (hexane/ethyl acetate
4:1); 1H NMR (400 MHz, CDCl3) δ 8.02 (dd, J = 7.8, 1.8 Hz, 1H), 7.92 (d, J = 7.1 Hz, 2H), 7.63–7.56 (m, 2H), 7.49
(t, J = 7.7 Hz, 2H), 7.13 (t, J = 7.5 Hz, 1H), 6.94 (d, J = 8.4 Hz, 1H), 3.56 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3)
δ 194.8, 193.6, 160.6, 136.6, 133.9, 133.1, 130.7, 129.5, 128.8, 124.0, 121.7, 112.5, 55.8; HRMS (ESI): m/z [M +
+
Na]+ calcd. for C15H12NaO3 : 263.0679, found 263.0673.
1-(4-Bromophenyl)-2-phenylethane-1,2-dione (12f)55: yellow solid (32 mg, 82%); Rf 0.60 (hexane/ethyl acetate
8:1); 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 7.2 Hz, 2H), 7.84 (d, J = 8.6 Hz, 2H), 7.69–7.65 (m, 3H), 7.52 (t, J
= 7.8 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 194.0, 193.4, 135.2, 132.9, 132.6, 131.9, 131.4, 130.6, 130.1,
+
129.2; HRMS (ESI): m/z [M + Na]+ calcd. for C14H9BrNaO2 : 310.9678, found 310.9682.
1-(4-Acetylphenyl)-2-phenylethane-1,2-dione (12g)55: yellow solid (31.5 mg, 80%); Rf 0.30 (hexane/ethyl acetate
4:1); 1H NMR (400 MHz, CDCl3) δ 8.06 (s, 4H), 7.97 (d, J = 7.1 Hz, 2H), 7.68 (t, J = 7.5 Hz, 1H), 7.52 (t, J = 7.8
Hz, 2H), 2.64 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 197.3, 193.9, 193.7, 141.5, 136.1, 135.3, 132.9, 130.2,
130.1, 129.3, 128.8, 27.1; HRMS (ESI): m/z [M + Na]+ calcd. for C16H12NaO3 : 275.0679, found 275.0677.
+
4-(2-(4-Methoxyphenyl)-2-oxoacetyl)benzonitrile (12h)55: yellow solid (38.5 mg, 95 %); Rf 0.50 (hexane/ethyl
acetate 2:1); 1H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 8.4 Hz, 2H), 7.95 (d, J = 8.9 Hz, 2H), 7.80 (d, J = 8.4 Hz,
2H), 7.00 (d, J = 8.9 Hz, 2H), 3.90 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 192.8, 191.6, 165.6, 136.3, 132.8,
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132.7, 130.3, 125.7, 117.9, 117.8, 114.7, 55.9; HRMS (ESI): m/z [M + Na]+ calcd. for C16H11NNaO3 : 288.0631,
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found 288.0637.
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1-(4-Nitrophenyl)-2-phenylethane-1,2-dione (12i)55: yellow solid (29.8 mg, 76%); Rf 0.40 (hexane/ethyl acetate
4:1); 1H NMR (400 MHz, CDCl3) δ 8.36 (d, J = 8.8 Hz, 2H), 8.17 (d, J = 8.8 Hz, 2H), 8.00–7.98 (m, 2H), 7.71 (t, J
= 7.5 Hz, 1H), 7.55 (t, J = 7.8 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 193.0, 192.2, 151.3, 137.5, 135.6, 132.6,
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131.1, 130.2, 129.4, 124.3; HRMS (ESI): m/z [M + H]+ calcd. for C14H10NO4 : 256.0604, found 256.0603.
4-(2-Oxo-2-phenylacetyl)benzaldehyde (12j)88: yellow solid (36.7 mg, 88%); Rf 0.40 (hexane/ethyl acetate 4:1); 1H
NMR (400 MHz, CDCl3) δ 10.12 (s, 1H), 8.13 (d, J = 8.2 Hz, 2H), 8.02–7.96 (m, 4H), 7.68 (t, J = 7.4 Hz, 1H), 7.53
(t, J = 7.8 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 193.7, 193.6, 191.4, 140.2, 137.2, 135.4, 132.7, 130.5,
+
130.1(×2), 129.3; HRMS (ESI): m/z [M + Na] + calcd. for C15H10NaO3 : 261.0528, found 261.0525.
Methyl 3-(2-oxo-2-phenylacetyl)benzoate (12k)89: yellow oil (46.7 mg, 87%); Rf 0.50 (hexane/ethyl acetate 4:1);
1H NMR (400 MHz, CDCl3) δ 8.61 (td, J = 1.7, 0.6 Hz, 1H), 8.33 (dt, J = 7.8, 1.5 Hz, 1H), 8.19 (dt, J = 7.8, 1.3 Hz,
1H), 8.01–7.98 (m, 2H), 7.70–7.67 (m, 1H), 7.62 (t, J = 7.8 Hz, 1H), 7.53 (t, J = 7.8 Hz, 2H), 3.94 (s, 3H); 13C{1H}
NMR (100 MHz, CDCl3) δ 193.9, 193.5, 165.9, 135.7, 135.2, 133.9, 133.5, 132.9, 131.4, 131.1, 130.2, 129.4, 129.2,
52.7; HRMS (ESI): m/z [M + Na]+ calcd. for C16H12NaO4 : 291.0633; found: 291.0633.
+
1-(4-(1,3-Dioxolan-2-yl)phenyl)-2-phenylethane-1,2-dione (12l): yellow oil (33 mg, 84%), Rf 0.31 (hexane/ethyl
1
acetate 1:1); H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 8.5 Hz, 2H), 8.03 (d, J = 8.5 Hz, 2H), 7.98–7.95 (m, 2H),
7.68 (t, J = 7.5 Hz, 1H), 7.52 (t, J = 7.8 Hz, 2H), 4.50–4.48 (m, 2H), 3.98–3.96 (m, 2H), 2.03 (br. s, 1H); 13C{1H}
NMR (100 MHz, CDCl3) δ 193.9, 193.7, 165.8, 136.3, 135.3, 135.2, 132.8, 130.3, 130.1, 129.9, 129.3, 67.3, 61.3;
HRMS (ESI): m/z [M + Na]+ calcd. for C17H14NaO4 : 305.0784, found 305.0789.
+
tert-Butyl (4-(2-oxo-2-phenylacetyl)phenyl)carbamate (12m): yellow oil (49.5 mg, 76%); Rf 0.35 (hexane/ethyl
acetate 4:1); 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 7.0 Hz, 2H), 7.91 (d, J = 8.8 Hz, 2H), 7.64 (t, J = 7.5 Hz, 1H),
7.53–7.47 (m, 4H), 6.88 (br. s, 1H), 1.52 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 194.9, 193.3, 152.1, 144.8,
134.9, 133.3, 131.7, 130.0, 129.1, 127.6, 117.9, 81.8, 28.4; HRMS (ESI): m/z [M + Na]+ calcd. for C19H19NNaO4 :
+
348.1212; found: 348.1222.
1-(Furan-2-yl)-2-phenylethane-1,2-dione (12n)90: yellow solid (38.4 mg, 96%), Rf 0.35 (hexane/ethyl acetate 4:1);
1H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 7.2 Hz, 2H), 7.75 (s, 1H), 7.65 (t, J = 7.4 Hz, 1H), 7.50 (t, J = 7.8 Hz, 2H),
7.37 (d, J = 3.6 Hz, 1H), 6.61 (dd, J = 3.6, 1.6 Hz 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 191.7, 180.6, 150.1, 149.3,
135.0, 132.7, 130.3, 129.0, 123.4, 113.1; HRMS (ESI): m/z [M + Na]+ calcd. for C12H8NaO3 : 223.0371, found
+
223.0371.
1-Phenyl-2-(thiophen-2-yl)ethane-1,2-dione (12o)55: brown solid (40.7 mg, 94%), Rf 0.30 (hexane/ethyl acetate
8:1); 1H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 7.2 Hz, 2H), 7.82 (dd, J = 12.0, 4.4 Hz, 2H), 7.66 (t, J = 7.4 Hz, 1H),
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7.51 (t, J = 7.8 Hz, 2H), 7.18 (dd, J = 4.7, 4.1 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 192.2, 185.7, 139.9, 137.0,
136.8, 134.9, 132.7, 130.3, 129.0, 128.9 (×2); HRMS (ESI): m/z [M + Na]+ calcd. for C12H8NaO2S+: 239.0137, found
239.0142.
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acetate); Rf 0.30 (hexane/ethyl acetate 8:1); H NMR (400 MHz, CDCl3) δ 8.07–8.05 (m, 2H), 7.64 (t, J = 7.4 Hz,
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1H), 7.52 (t, J = 7.7 Hz, 2H), 4.88 (t, J = 2.0 Hz, 2H), 4.68–4.67 (m, 2H), 4.27 (s, 5H); 13C{1H} NMR (100 MHz,
CDCl3) δ 199.1, 193.0, 134.6, 133.2, 130.1, 129.0, 74.7, 74.1, 70.7, 70.6; HRMS (ESI): m/z [M + Na]+ calcd. for
+
C18H14FeNaO2 : 341.0241; found: 341.0251.
2,2'-(1,4-Phenylene)bis(1-phenylethane-1,2-dione) (12q)88: yellow solid (27.8 mg, 74%), Rf 0.45 (hexane/ethyl
acetate 4:1); 1H NMR (400 MHz, CDCl3) δ 8.11 (s, 4H), 7.97 (d, J = 7.1 Hz, 4H), 7.69 (t, J = 7.5 Hz, 2H), 7.53 (t, J
= 7.8 Hz, 4H); 13C{1H} NMR (100 MHz, CDCl3) δ 193.6, 193.4, 137.3, 135.4, 132.7, 130.4, 130.1, 129.3; HRMS
+
(ESI): m/z [M + Na]+ calcd. for C22H14NaO4 : 365.0790, found 365.0791.
N-Methyl-2-oxo-2-phenyl-N-tosylacetamide (12r)91: white solid (49 mg, 94%), Rf 0.30 (hexane/ethyl acetate 4:1);
1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 7.1 Hz, 2H), 7.89 (d, J = 8.4 Hz, 2H), 7.64 (t, J = 7.4 Hz, 1H), 7.53 (t, J =
7.6 Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H), 3.24 (s, 3H), 2.46 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 188.2, 167.4,
146.0, 134.6, 133.6, 132.9, 130.2, 129.8, 129.0, 128.5, 30.8, 21.8; HRMS (ESI): m/z [M + Na]+ calcd. for
C16H15NNaO4S+: 340.0614; found: 340.0609.
1-(2-Oxooxazolidin-3-yl)-2-phenylethane-1,2-dione (12s)91: white solid (33.1 mg, 99%), Rf 0.35 (hexane/ethyl
acetate 1:1); 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 7.2 Hz, 2H), 7.64 (t, J = 7.4 Hz, 1H), 7.51 (t, J = 7.7 Hz, 2H),
4.57 (t, J = 8.0 Hz, 2H), 4.14 (t, J = 8.0 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 188.0, 166.6, 153.3, 134.9,
+
132.5, 129.5, 129.2, 64.2, 41.1; HRMS (ESI): m/z [M + Na]+ calcd. for C11H9NNaO4 : 242.0429, found 242.0432.
Methyl 2-oxo-2-phenylacetate (12t)92: yellow oil (31.2 mg, 95%); Rf 0.50 (hexane/ethyl acetate 4:1); 1H NMR (400
MHz, CDCl3) δ 8.02 (d, J = 7.1 Hz, 2H), 7.66 (t, J = 7.5 Hz, 1H), 7.52 (t, J = 7.9 Hz, 2H), 3.98 (s, 3H); 13C{1H} NMR
+
(100 MHz, CDCl3) δ 186.2, 164.2, 135.1, 132.6, 130.2, 129.0, 52.9; HRMS (ESI): m/z [M + Na]+ calcd. for C9H8O3 :
187.0371; found: 187.0371.
S-Methyl 2-oxo-2-phenylethanethioate (12u)93: yellow oil (24.9 mg, 69%); Rf 0.50 (hexane/ethyl acetate 8:1); 1H
NMR (400 MHz, CDCl3) δ 8.15–8.13 (m, 2H), 7.65 (t, J = 7.4 Hz, 1H), 7.50 (t, J = 7.8 Hz, 2H), 2.46 (s, 3H); 13C{1H}
NMR (100 MHz, CDCl3) δ 193.4, 186.2, 135.0, 131.8, 130.9, 129.0, 11.6; HRMS (ESI): m/z [M + Na]+ calcd. for
C9H8NaO2S+: 203.0143; found: 203.0144.
1-Phenylpropane-1,2-dione (14a)94 and 1-phenylprop-2-en-1-one (15a)95: yellow oil (17.5 mg, 62 %); Rf 0.30
(hexane/ethyl acetate 8:1); mixture 35:27; 1H NMR for 14a (400 MHz, CDCl3) δ 8.01 (d, J = 7.2 Hz, 2H), 7.63 (t, J
= 7.4 Hz, 1H), 7.52–7.45 (m, 2H), 2.52 (s, 3H); 13C{1H} NMR for 14a (100 MHz, CDCl3) δ 200.7, 191.5, 134.7,
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131.8, 132.6, 129.0, 26.5; HRMS (ESI) for 14a: m/z [M + H]+ calcd. for C9H9O2 : 149.0603; found: 149.0607; H
NMR for 15a (400 MHz, CDCl3) δ 7.94 (d, J = 7.1 Hz, 2H), 7.57 (t, J = 7.4 Hz, 1H), 7.52–7.45 (m, 2H), 7.15 (dd, J
= 17.1, 10.6 Hz, 1H), 6.43 (dd, J = 17.1, 1.7 Hz, 1H), 5.93 (dd, J = 10.6, 1.7 Hz, 1H); 13C{1H} NMR for 15a (100
MHz, CDCl3) δ 191.2, 137.4, 133.1, 132.6, 130.3, 129.0, 128.8; HRMS (ESI) for 14b: m/z [M + H]+ calcd. for C9H9O+:
133.0653; found: 133.0653.
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3,3-Dimethyl-1-phenylbutane-1,2-dione (14b)96 and 2,3-dimethyl-1-phenylbut-2-en-1-one (15b)97: yellow oil
(28.6 mg, 90%); Rf 0.50 (hexane/ethyl acetate 8:1); mixture 12:78; 1H NMR for 14b (400 MHz, CDCl3) δ 7.83–7.81
(m, 2H), 7.63 (t, J = 7.5 Hz, 1H), 7.49 (t, J = 7.8 Hz, 2H), 1.30 (s, 9H); 13C{1H} NMR for 14b (100 MHz, CDCl3) δ
+
211.0, 195.6, 134.6, 133.0, 129.6, 129.1, 42.8, 26.4; HRMS (ESI) for 14b: m/z [M + Na]+ calcd. for C12H14NaO2 :
213.0891; found: 213.0886; 1H NMR for 15b (400 MHz, CDCl3) δ 7.88–7.86 (m, 2H), 7.54 (t, J = 7.3 Hz, 1H), 7.45
(t, J = 7.5 Hz, 2H), 1.88 (s, 3H), 1.83 (s, 3H), 1.61 (s, 3H); 13C{1H} NMR for 15b (100 MHz, CDCl3) δ 201.7, 137.0,
133.7, 133.1, 129.9, 129.4, 128.7, 22.5, 22.3, 16.7; HRMS (ESI) for 15b: m/z [M + Na]+ calcd. for C12H14NaO+:
197.0942; found: 197.0937.
General procedure for the oxidation-heterocyclization of acetylene. Synthesis of 19 and 21. The first vessel of
the two-chamber reactor was loaded with the calcium carbide (128 mg). Ph3PAuNTf2 (7.4 mg, 10.0 μmol, 5 mol %)
and 2,3-dichloropyridine N-oxide 2f (65.6 mg, 0.4 mmol, 2.0 equiv) were loaded to the second vessel and 1.0 mL of
PhCl was added to each part. Then 0.1 mL of water was poured to the carbide vessel over a layer of PhCl. The reactor
was immediately sealed and the both vessels were vigorously stirred at room temperature for 24 h. Next 0.3 mmol
(1.5 equiv) of 4-methylbenzene-1,2-diamine (18) or 4-methoxybenzohydrazonamide (20) was added to the second
vessel and the mixture was stirred at 50 °C for another 5 h. After completing the reaction, the content of the second
vessel was collected by a syringe, all volatile components were removed in vacuo and the residue was purified by
silica gel chromatography eluting with hexane/EtOAc (2:1) to afford 19 or 21.
1
6-Methylquinoxaline (19)98: orange oil (17.3 mg, 60%); Rf 0.35 (hexane/ethyl acetate 2:1); H NMR (400 MHz,
CDCl3) δ 8.78–8.75 (m, 2H), 7.98 (d, J = 8.5 Hz, 1H), 7.85 (s, 1H), 7.58 (dd, J = 8.6, 1.9 Hz, 1H), 2.58 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 145.0, 144.2, 143.2, 141.6, 140.7, 132.5, 129.1, 128.4, 21.9; HRMS (ESI): m/z
+
[M + H]+ calcd. for C9H9N2 : 145.0766; found: 145.0763.
1
3-(4-Methoxyphenyl)-1,2,4-triazine (21)99: yellow solid (24.3 mg, 65%); Rf 0.30 (hexane/ethyl acetate 2:1); H
NMR (400 MHz, CDCl3) δ 9.06 (d, J = 2.3 Hz, 1H), 8.59 (d, J = 2.4 Hz, 1H), 8.50–8.47 (m, 2H), 7.05–7.01 (m, 2H),
3.88 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 164.1, 162.9, 148.7, 147.1, 130.2, 127.3, 114.4, 55.5; HRMS (ESI):
m/z [M + H]+ calcd. for C10H10N3O+: 188.0824; found: 188.0821.
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Total synthesis of 28.
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2-Methoxybenzene-1,4-diol (23):100 Aqueous solution of H2O2 (30%, 0.1 mol, 10.2 ml) was added to the mixture of
vanillin (50 mmol, 7.61 g), NaHCO3 (50 mmol, 4.20 g), ethyl acetate (50 mL) and water (25 mL). The resulting
mixture was stirred at room temperature for 2 h. After the completion, the mixture was diluted with ethyl acetate (100
mL), washed with a saturated sodium bisulfite solution (3×50 mL) and the organic phase was separated. The aqueous
phase was extracted with ethyl acetate (3×50 mL) and the combined organic phase was dried over anhydrous Na2SO4.
After filtration, the solvent was removed in vacuo to afford 23 as a colorless solid (5.61 g, 80%), which was used in
the next step without additional purification. 1H NMR (400 MHz, CDCl3) δ 6.76 (d, J = 8.4 Hz, 1H), 6.45 (d, J = 2.7
Hz, 1H), 6.31 (dd, J = 8.5, 2.7 Hz, 1H), 5.15 (br.s, 1H), 4.61 (br.s, 1H), 3.84 (s, 3H).
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2-Bromo-5-methoxybenzene-1,4-diol (24): Solution of Br2 (5.03 g, 31.5 mmol) in glacial AcOH was added (20 mL)
dropwise to a stirred water bath-cooled (10 °C) solution of 2-methoxybenzene-1,4-diol (23; 4.20 g, 30 mmol) in glacial
AcOH (80 mL) over 1 h. Then the solvent was removed to give a dark brown oil. The oil was dissolved in boiling
CHCl3 (200 mL) and filtered through a pad of silica gel. The solvent was removed in vacuo and the residue was
recrystallized from benzene to afford 24 as a sandy solid (4.47 g, 68%); mp 127.5–129.0 °C (benzene); 1H NMR (400
MHz, CDCl3) δ 7.00 (s, 1H), 6.60 (s, 1H), 5.21 (s, 1H), 5.10 (s, 1H), 3.86 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3)
+
δ 147.2, 146.0, 140.1, 116.8. 99.75, 99.65, 56.3; HRMS (ESI): m/z [M + Na]+ calcd. for C7H7BrNaO3 : 240.9476;
found: 240.9463.
1-Bromo-4-methoxy-2,5-bis(methoxymethoxy)benzene (25): NaH (1.24 g, 58% in mineral oil, 30 mmol) was added
portionwise to a solution of 24 (2.19 g, 10 mmol) in THF (30 mL) at 0 °C. The suspension was stirred and a solution
of MOMCl (2.42 g, 30 mmol) in THF (10 mL) was added dropwise. The reaction mixture was stirred for 24 h at room
temperature, then quenched by the dropwise addition of water (10 mL) and extracted with Et2O (3×30 mL). The
combined organic extracts were dried over anhydrous Na2SO4. After filtration, the solvent was removed in vacuo and
the residue was purified by silica gel chromatography eluting with hexane/ ethyl acetate (4:1) to afford 25 as a colorless
oil (2.52 g, 82%); 1H NMR (400 MHz, CDCl3) δ 7.30 (s, 1H), 6.78 (s, 1H), 5.16 (s, 2H), 5.12 (s, 2H), 3.84 (s, 3H),
3.52 (s, 3H), 3.49 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 150.1, 149.5, 142.1, 121.5, 102.7, 102.5, 96.3, 96.2,
+
56.5, 56.3 (×2); HRMS (ESI): m/z [M + Na]+ calcd. for C11H15BrNaO5 : 329.0001; found: 329.0011.
1-Methoxy-2,5-bis(methoxymethoxy)-4-(phenylethynyl)benzene (26): A mixture of 25 (1.54 g, 5.0 mmol), Et3N
(2.1 g, 15 mmol), Pd(PPh3)2Cl2 (175.5 mg, 0.25 mmol, 5 mol %)3PAuCl (123.7 mg, 0.25 mmol, 5 mol %) in DMF
(15 mL) was stirred at room temperature under argon for 5 min. Then phenylacetylene (562 g, 5.5 mmol) was added.
The reaction flask was sealed, and the mixture was stirred at 80 °C in an oil bath for 16 h. After cooling, the reaction
mixture was dried in vacuo, diluted with CH2Cl2 (50 mL), washed with water (3×20 mL), and the organic phase was
dried over anhydrous Na2SO4. After filtration, the solvent was removed in vacuo. The residue was purified by silica
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gel chromatography eluting with hexane/ ethyl acetate (4:1) to afford 26 as an orange oil (1.02 g, 62%); Rf 0.50
(hexane/ethyl acetate 2:1); 1H NMR (400 MHz, CDCl3) δ 7.52 (dd, J = 7.8, 1.9 Hz, 2H), 7.35–7.30 (m, 3H), 7.28 (s,
1H), 6.75 (s, 1H), 5.25 (s, 2H), 5.18 (s, 2H), 3.88 (s, 3H), 3.57 (s, 3H), 3.53 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3)
δ 154.2, 151.3, 141.6, 131.5, 128.4, 128.0, 123.8, 121.1, 105.9, 101.9, 96.4, 96.2, 92.2, 85.8, 56.5, 56.3, 56.1; HRMS
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(ESI): m/z [M + Na]+ calcd. for C19H20NaO5 : 351.1208; found: 351.1208.
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1-(4-Methoxy-2,5-bis(methoxymethoxy)phenyl)-2-phenylethane-1,2-dione (27): Ph3PAuNTf2 (22.2 mg, 50.0
μmol, 3 mol %) was added to the solution of 26 (328.4 mg, 1.0 mmol) and 2f (410.0 mg, 2.5 mmol) in PhCF3 (5.0
mL). The resulting mixture was stirred at room temperature for 5 h. The solvent was then removed in vacuo and the
residue was purified by silica gel chromatography eluting with hexane/ ethyl acetate (gradient from 4:1 to 1:1) to
afford 27 as an yellow oil (201.8 mg, 56%); Rf 0.40 (hexane/ethyl acetate 1:1); 1H NMR (400 MHz, CDCl3) δ 7.91
(d, J = 7.0 Hz, 2H), 7.81 (s, 1H), 7.59 (t, J = 7.4 Hz, 1H), 7.48 (t, J = 7.7 Hz, 2H), 6.66 (s, 1H), 5.23 (s, 2H), 4.80 (s,
2H), 3.92 (s, 3H), 3.54 (s, 3H), 3.09 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 194.0, 193.2, 157.5, 155.8, 142.1,
133.8, 133.4, 129.3, 128.8, 117.0, 116.3, 98.8, 96.1, 94.7, 56.5, 56.4, 56.3; HRMS (ESI): m/z [M + Na]+ calcd. for
+
C19H21O7 : 361.1287; found: 361.1301.
1-(2,5-Dihydroxy-4-methoxyphenyl)-2-phenylethane-1,2-dione (28):72 Concentrated aqueous HCl (10.0 μL) was
added to the solution of 27 (180.2 mg, 0.5 mmol) in THF (2.0 mL). The resulting mixture was stirred at room
temperature for 12 h. The solvent was then removed in vacuo and the residue was purified by silica gel
chromatography eluting with hexane/ ethyl acetate (gradient from 4:1 to 1:1) to afford 28 as an yellow solid (129.3
mg, 95%); Rf 0.45 (hexane/ethyl acetate 1:1); 1H NMR (400 MHz, CDCl3) δ 11.69 (s, 1H), 7.98–7.96 (m, 2H), 7.66
(t, J = 7.4 Hz, 1H), 7.51 (t, J = 7.8 Hz, 2H), 6.92 (s, 1H), 6.53 (s, 1H), 5.23 (s, 1H), 3.97 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 197.1, 192.3, 160.8, 155.6, 138.9, 135.1, 133.0, 130.2, 129.2, 114.8, 109.8, 100.1, 56.6; HRMS (ESI):
+
m/z [M + Na]+ calcd. for C15H12NaO5 : 295.0582; found: 295.0581.
Preparation of starting compounds.
General procedure for preparation of pyridine N-oxides 2f,g,j: Triflic anhydride (20 mml) was added dropwise to
a stirred water bath-cooled (10 °C) mixture of substituted pyridine (10 mmol), and urea hydrogen peroxide (22 mmol)
in DCM (50 mL). The mixture was allowed to reach rt and stirred overnight. After the completion, the mixture was
diluted with DCM (100 mL), washed with a saturated sodium carbonate solution (3×50 mL) and the organic phase
was dried over anhydrous Na2SO4. After filtration, the solvent was removed in vacuo to afford pure 2f,g,j.
2,3-Dichloropyridine N-oxide (2f): colorless solid (1.57 g, 96%); mp 123.0–124.0 °C (dichloromethane); 1H NMR
(400 MHz, CDCl3) δ 8.27 (dd, J = 6.6, 1.4 Hz, 1H), 7.35 (dd, J = 8.4, 1.3 Hz, 1H), 7.14 (dd, J = 8.3, 6.6 Hz, 1H);
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13C{1H} NMR (100 MHz, CDCl3) δ 142.6, 139.0, 133.2, 126.5, 122.5; HRMS (ESI): m/z [M + Na]+ calcd. for
C5H3Cl2NNaO+: 185.9484; found: 185.9484.
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2,4-Dichloropyridine N-oxide (2g)101: colorless solid (1.50 g, 94%); 1H NMR (400 MHz, CDCl3) δ 8.22 (d, J = 7.1
Hz, 1H), 7.47 (d, J = 2.7 Hz, 1H), 7.17 (dd, J = 7.1, 2.9 Hz, 1H);
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3,4,5-Trichloropyridine N-oxide (2i): colorless solid (2.02 g, 97%); mp 157.0–159.0 °C (dichloromethane); H
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NMR (400 MHz, CDCl3) δ 8.22 (s, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 138.4, 132.7, 130.0; HRMS (ESI): m/z
[M + Na]+ calcd. for C5H2Cl3NNaO+: 219.9094; found: 219.9091.
1
3-Bromo-5-chloropyridine N-oxide (2j): colorless solid (2.02 g, 97%); mp 88.0–89.5 °C (dichloromethane); H
NMR (400 MHz, CDCl3) δ 8.26 (t, J = 1.5 Hz, 1H), 8.19 (t, J = 1.6 Hz, 1H), 7.45 (t, J = 1.5 Hz, 1H); 13C{1H} NMR
(100 MHz, CDCl3) δ 139.5, 137.9, 133.6, 129.3, 120.3; HRMS (ESI): m/z [M + Na]+ calcd. for C5H3BrClNNaO+:
229.8979; found: 229.8979.
2-(4-(Phenylethynyl)phenyl)-1,3-dioxolane (11l): 4-(Phenylethynyl)-benzaldehyde (11j) (206.2 mg, 1.0 mmol),
ethylene glycol (186.2 g, 3.0 mmol) and methanesulfonic acid (9.6 mg, 0.1 mmol) were dissolved in toluene (30
mL). After being heated in an oil bath at reflux for 12 h using a Dean-Stark trap, the mixture was then allowed to
cool, diluted with dichloromethane (20 ml) and washed with saturated aqueous solution of NaHCO3. The separated
organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by
silica gel chromatography eluting with hexane/EtOAc (8:1) to afford 11l as a yellow solid (130.1 mg, 52%); mp
79.0–80.0 °C (hexane/ethyl acetate); Rf 0.30 (hexane/ethyl acetate 8:1); 1H NMR (400 MHz, CDCl3) δ 7.58–7.54
(m, 4H), 7.49–7.47 (m, 2H), 7.39–7.35 (m, 3H), 5.83 (s, 1H), 4.15–4.09 (m, 2H), 4.08–4.02 (m, 2H); 13C{1H} NMR
(100 MHz, CDCl3) δ 138.1, 131.75, 131.71, 128.5 (×2), 126.6, 124.2, 123.3, 103.4, 90.0, 89.2, 65.4; HRMS (ESI):
+
m/z [M + Na]+ calcd. for C17H14NaO2 : 273.0891; found: 273.0893.
For compounds 2g, 5, 8a–g,i,j,l, 10, 12a–k,n,o,q–u, 14a,b, 15a,b, 19, 21, 23 and 28 the 1H, 13C and HRMS spectra
are consistent with previously reported literature.
SUPPORTING INFORMATION
Copies of 1H and 13C{1H} spectra.
ORCIDs:
0000-0001-6576-814X (A. Yu. D.)
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0000-0002-4918-2162 (N. V. S.)
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0000-0002-0413-7413 (D. V. D.)
0000-0002-2253-085X (V. Yu. K.)
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ACKNOWLEDGEMENTS
AYuD thanks the Russian Science Foundation for support of these studies (grant 18-73-00026)
and also Dr. K. S. Rodygin (Saint Petersburg State University) for valuable comments and the kind
loan of calcium carbide. We are much obliged to the Center for Magnetic Resonance, Center for
Chemical Analysis and Material Research (both belonging to Saint Petersburg State University)
for physicochemical measurements.
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