An Efficient Synthesis of Polysubstituted Pyridines via C sp 3 -H Oxidation and C-S Cleavage of Dimethyl Sulfoxide

Article abstract of DOI:10.1002/adsc.201500683

An expedient cleavage of the C-S bond of dimethyl sulfoxide (DMSO) has been developed for the preparation of substituted pyridines from ketones. In this transformation, the co-product formic acid was formed from ammonium formate, which acted as an important catalyst for the reaction. Notably, this transformation exhibited a broad substrate scope towards a wide variety of different ketones to give the corresponding substituted pyridines in high yields. Mechanistic studies suggested that dimethyl sulfoxide delivered a methylene fragment, which was subsequently captured in situ to give a pyridine.

Full text of DOI:10.1002/adsc.201500683

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DOI: 10.1002/adsc.201500683
À
An Efficient Synthesis of Polysubstituted Pyridines via Csp3 H
À
Oxidation and C S Cleavage of Dimethyl Sulfoxide
Xia Wu,a Jingjing Zhang,a Shan Liu,a Qinghe Gao,a,* and Anxin Wua,*
a
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal
University, Wuhan 430079, Peopleꢀs Republic of China
Fax: (+86)-027-6786-7773; phone: (+86)-027-6786-7773; e-mail: chwuax@mail.ccnu.edu.cn or
gao_qinghe@mails.ccnu.edu.cn
Received: July 17, 2015; Revised: October 29, 2015; Published online: January 5, 2016
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500683.
À
À
Abstract: An expedient cleavage of the C S bond
H and N H bonds, is one of the most important
of dimethyl sulfoxide (DMSO) has been developed
for the preparation of substituted pyridines from
ketones. In this transformation, the co-product
formic acid was formed from ammonium formate,
which acted as an important catalyst for the reac-
tion. Notably, this transformation exhibited a broad
substrate scope towards a wide variety of different
ketones to give the corresponding substituted pyri-
dines in high yields. Mechanistic studies suggested
that dimethyl sulfoxide delivered a methylene frag-
ment, which was subsequently captured in situ to
give a pyridine.
transformations in organic chemistry.[1] Transforma-
tions of this type are especially important because the
introduction of a methylene or methyl group to
a target molecule can have a significant impact on its
pharmacological properties.[2] Therefore, significant
research efforts have been directed towards the devel-
opment of new methods for the methylenation or
methylation of Csp3 H and N H bonds.
[3,4]
À
À
However,
there have been very few reports to date pertaining
to the in situ trapping of Csp3 -methylenation or N-
methylenation intermediates to construct heterocyclic
systems.[5] The rare reports in this area have been at-
tributed to difficulties associated with the over reduc-
tion of the Csp3 - or N-methylation products,[4] as well
as the lack of suitable methods or reagents to capture
these intermediates in situ. The first novel Cu-cata-
lyzed synthesis of quinazolines from amidines via the
intramolecular capture of an N-methylene intermedi-
ate was presented by Zhang in 2011 (Scheme 1a).[6]
À
À
Keywords: C H oxidation; C S cleavage; methyla-
tion; pyridine methylenation
À
The direct methylenation or methylation of C H and Wang and co-workers recently reported the develop-
heteroatom H bonds, especially those involving Csp3
À
À
ment of a facile method for the construction of quina-
Scheme 1. The capture of the in situ-generated methylenation intermediate.
218
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An Efficient Synthesis of Polysubstituted Pyridines
Table 1. Optimization of the reaction conditions.[a]
zolinones via the intramolecular nucleophilic attack
of an N-methylene intermediate (Scheme 1b).[7] More
recently, an iodine-catalyzed method for the prepara-
tion quinazolines and quinazolinones using N,N,N’,N’-
tetramethylethylenediamine (TMEDA) as methylene
reagent has been realized by Liu and Yan
(Scheme 1c).[8] Reviewing these important examples,
it is seen that their success is mainly due to the intra-
molecular nucleophilic attack which can greatly in-
crease the speed of capturing N-methylene intermedi-
ates. Despite these advances, the capture of in situ-
generated Csp3 - or N-methylene intermediates for the
direct construction of heterocycles is still a young and
constant challenging theme. In particular, the inter-
molecular capture of in situ-generated Csp3 -methylene
intermediates to build nitrogen-containing heterocy-
cles has not been reported to date. Herein, we report
the first examples of the ammonium formate-mediat-
ed intermolecular and intramolecular trapping of in
situ-generated Csp3 - and N-methylene intermediates
for the preparation of 2,3,5,6- and 2,4-substituted pyri-
dines from methyl ketones and a-substituted ketones,
respectively. This method was successfully applied to
pyridines involving the capture of in situ-generated
Csp3 - and N-methylene intermediates using DMSO
served as a source of the methylene unit.
Our initial efforts focused on the reaction of aceto-
phenone 1a with ammonium formate 2a in the pres-
ence of a copper salt and molecular iodine as a model
reaction. Pleasingly, this reaction afforded the corre-
sponding annulation product 3a in 49% yield when
acetophenone (1a, 1.0 mmol) was reacted with ammo-
nium formate (2a, 10.0 mmol) in the presence of I2,
CuCl2 and K2CO3 in DMSO at 1308C (Table 1,
entry 1). The structure of compound 3 was unambigu-
ously confirmed by X-ray crystallography (see the
Supporting Information).[9] It is noteworthy that pyri-
dine and its derivatives have found numerous applica-
tions in a wide range of different areas, such as orga-
nocatalysis,[10] natural products,[11] biologically active
substances[12] and others.[13] The simple and direct syn-
thesis of substituted pyridine systems has therefore re-
ceived considerable interest from numerous research-
ers.[14,15] However, there have been no reports in the
literature to date describing the capture of in situ-gen-
erated methylene intermediates for the construction
of pyridines using DMSO as a source of the methyl-
ene unit. This result therefore encouraged us to fur-
ther examine the feasibility of using this method for
Entry 2a
[equiv.]
Iodine
[equiv,]
Temperture
[8C]
Yield
[%][b]
1[c]
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
10.0
10.0
10.0
10.0
10.0
10.0
10.0
10.0
10.0
10.0
10.0
10.0
10.0
1.0
1.6
1.6
1.6
1.6
1.6
1.6
1.6
1.6
1.6
0.5
0.8
1.2
2.0
1.6
1.6
1.6
1.6
1.6
1.6
1.6
1.6
1.6
1.6
1.6
130
130
60
49
74
trace
5
80
100
120
140
150
160
130
130
130
130
130
130
130
130
130
130
130
130
130
130
130
25
60
70
59
30
37
40
62
69
0
3.0
6.0
15.0
0
65
73
55
57
62
40
0
18[d] 10.0
19[e] 10.0
20[f]
10.0
21[g] 10.0
22[h] 10.0
23[i]
24[j]
10.0
10.0
0
<5%
[a]
Reaction
conditions:
1a
(1.0 mmol),
2a,
I2,
Cu(NO3)2·3H2O (1.0 mmol) heated in 3 mL of DMSO
within 6 h unless otherwise noted.
Isolated yield.
0.1 mmol of K2CO3 was used and 1.0 mmol of CuCl2 was
used instead of Cu(NO3)2·3H2O.
Cu(NO3)2·3H2O (0.1 mmol).
Cu(NO3)2·3H2O (0.3 mmol).
Cu(NO3)2·3H2O (0.5 mmol).
Cu(NO3)2·3H2O (1.5 mmol).
N,N-Dimethylformamide (DMF) was used as solvent in-
stead of DMSO.
Toluene was used as solvent instead of DMSO.
N,N-Dimethylacetamide (DMA) was used as solvent in-
stead of DMSO.
[b]
[c]
[d]
[e]
[f]
[g]
[h]
[i]
[j]
the direct formation of pyridines via the capture of in tones and Kornblum oxidation by-products were ob-
situ-generated methylene intermediates.
served.[16] Subsequently, various temperatures were
After many efforts, the employment of scanned to improve the yield, increasing or decreasing
.
Cu(NO3)2 3H2O was found to be the best copper salt the temperature did not improve the yield for this re-
(see the Supporting Information) for this reaction action (Table 1, entries 3–9). Moreover, 1.6 equiv. of
(Table 1, entry 2). Importantly, the reaction displayed iodine was determined as being optimal for this trans-
high selectivity. Even though all the substrates and formations (Table 1, entries 10–13). Under these con-
catalysts were added in one pot, no a-iodomethyl ke- ditions, different equivalents of ammonium formate
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Xia Wu et al.
Scheme 2. Scope of aryl methyl ketones.
and copper salt were screened, which indicated that tones were well tolerated, with the corresponding pyr-
10.0 and 1.0 equiv. were optimal for the total process idines (3a–m) being isolated in moderate to good
of the reaction, respectively (Table 1, entries 14–21). yields (58–80%). The electronic and steric nature of
Various solvents, such as N,N-dimethylformamide, the substituent on the aromatic ketones had little in-
DMA and toluene were also examined, but only the fluence on the efficiency of the reaction. Furthermore,
DMSO can perform this reaction smoothly (Table 1, it was found that the phenyl ring could also be effec-
entries 22–24).
tively replaced by the naphthalene moiety (59%, 3n).
With the optimized conditions in hand, we proceed- Moreover, several heteroaryl methyl ketones were
ed to investigate the scope of the reaction using a vari- also evaluated under the optimal conditions, including
ety of aromatic methyl ketones (Scheme 2). The re- thiophenyl and benzofuryl methyl ketones, which
sults revealed that aryl methyl ketones bearing a varie- gave the corresponding products 3o–q in good yields
ty of functional groups and substitution patterns af- (64–73%).
forded the desired products in moderate to good
Next, we carried out an investigation on the sub-
yields (58–80%). The presence of electron neutral (4- strate scope of the a-substituent on the ketones, and
H, 2-Me, 4-Me), electron-donating (2-OMe, 3-OMe, the results are displayed in Scheme 3. Surprisingly,
4-OMe, 4-OEt, 3,4-OCH2O, 3,4-OCH2CH2O), elec- the substitution patterns of the pyridine ring changed
tron-deficient (3-NO2) and halogen (4-Cl, 4-F, 3,4-Cl2) when 1,3-diphenylpropane-1,3-dione was used as
substituents on the phenyl rings of the aryl methyl ke- a substrate instead of an aryl methyl ketone. The
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An Efficient Synthesis of Polysubstituted Pyridines
Scheme 3. Scope of a-substituted ketones.
structure of compound 5a was further confirmed by substrates were not intermediates in the reaction. The
X-ray crystallography (see the Supporting Informa- reaction of acetophenone (1a) with ammonium ace-
tion).[17] Based on this result, we proceeded to investi- tate (2b) and paraformaldehyde (2ab) instead of am-
gate a variety of other 1,3-dicarbonyl compounds. As monium formate (2a) under the standard conditions,
expected, the electronic nature of the phenyl ring on also failed to afford any of the desired product 3a
the 1,3-dicarbonyl compound had little impact on the (Scheme 4c). However, the reaction proceeded
efficiency of the reaction (69–88% yields for 5a–f). smoothly in the presence of formic acid (2aa)
Moreover, the use of propiophenone or 1-(4-ethylphe- (Scheme 4d). These results therefore suggested that
nyl)propan-1-one as a substrate under the optimized HCHO was not generated as an intermediate and em-
conditions also gave the corresponding products 5g phasized that the formic acid generated in situ was
and 5h in moderate to good yields (63–71%). The playing a critical role in the subsequent domino pro-
scope of the reaction was further extended to a-cya- cess. To lend further support to this mechanism, we
noacetophenone, which gave the corresponding prod- investigated the preparation and subsequent reaction
uct 5i in moderate yield (72%). Surprisingly, an unex- of substrate 1ad. The results revealed that 1ad could
À
pected C S bond cleavage occurred to give the 2,3,6- be converted to the desired product, albeit in a lower
trisubstituted pyridine 5j in 75% yield when 1-phenyl- yield (Scheme 4e), which clearly confirmed that 1ad
2-(phenylsulfonyl)ethanone was used as a substrate was not a key intermediate in the transformation. The
instead of a 1,3-dicarbonyl compound. However, the use of DMSO-d6 in the reaction showed that DMSO
use of benzocyclohexanone as a substrate under the was behaving as a source of methylene units, follow-
standard conditions resulted in a mixture of re- ing the isolation of the partially deuterated product
gioisomers (5k and 5l), which implied that reaction 3a-d1 (Scheme 4f), which further confirmed that
could proceed via two different pathways simultane- DMSO was a source of methylene units. Moreover,
ously.
the H-D exchange experiment between DMSO-d6
To develop a deeper insight into the reaction mech- and the product was also carried out. The result ex-
anism of this transformation, a series of control ex- cludes the possibility of H-D exchange between
periments was performed (Scheme 4). The reaction of DMSO-d6 and the product (see the Supporting Infor-
a-iodoacetophenone (1ab) or hydrated hemiacetal mation).
(1ac) with ammonium formate (2a) under the stan-
Based on our preliminary results, we propose a pos-
dard conditions, did not lead to the desired product sible mechanism for this transformation using aceto-
3a (Scheme 4a and b), which suggested that these two phenone (1a) and ammonium formate (2a) as the sub-
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Scheme 4. Control experiments.
Scheme 5. Proposed reaction mechanism.
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An Efficient Synthesis of Polysubstituted Pyridines
Scheme 6. Control experiments.
strates (Scheme 5). The initial reaction of carbonyl
Based on the results described above, we propose
group of acetophenone (1a) with ammonia (2ac) from a possible mechanism for this reaction, which is
ammonium formate would give intermediate A, shown in Scheme 7. Briefly, 1,3-diphenylpropane-1,3-
which would undergo an imine tautomerization reac- dione 4a would undergo an enolization which is fol-
tion to give isomer B. Intermediate B would then un- lowed by the nucleophilic attack of intermediate
dergo a rapid nucleophilic attack on acetophenone to E[4b,18] to give intermediate J. Subsequently, the reac-
afford C, which would be converted to D through tion of the carbonyl group of J with ammonia (2ac)
a dehydration reaction. DMSO could be protonated would form intermediate K (path 1), which would un-
or acylated by formic acid which was formed in-situ dergo a rapid nucleophilic attack by 1,3-diphenylpro-
from ammonium formate to give an activated species, pane-1,3-dione (4a) to give intermediate L. Finally,
which would be converted to the methylene source annulation and aromatization of L would then give
E.[4b,18] The subsequent nucleophilic attack of E by the the desired product 5a. Alternatively, intermediate A
nitrogen atom of D would lead to the formation of in- could undergo a rapid nucleophilic addition reaction
termediate F. The elimination of methanethiol, fol- with 4a to form intermediate L’ (path 2), which would
lowed by the tautomerization of the double bonds undergo sequential dehydration, condensation, annu-
would give the N-methylene intermediate G, which lation and aromatization[19] reactions to give the de-
would undergo sequential 6p electrocyclization and sired product 5a.
aromatization[19] reactions to provide the desired
product 3a.
In order to further confirm our proposed mecha-
nism, we investigated the cross-coupling reaction be-
To develop a deeper understanding of the mecha- tween two representative substrates 4-methoxyaceto-
nism responsible for the formation of product 5, we phenone 1d and 3-nitroacetophenone 1j or ethyl 3-(4-
conducted an additional series of control experiments methoxyphenyl)-3-oxopropanoate 4d and ethyl 3-(3-
(Scheme 6). When substrate 4aa was prepared in ad- nitrophenyl)-3-oxopropanoate 4e under the standard
vance, its subsequent reaction with formic acid and conditions. According to our proposed reaction mech-
a copper salt as catalyst in DMSO at 1308C did not anism, the reaction of equimolar amounts of 1d and
provide access to any of the expected intermediates 1j or of 4d and 4e would give four or three pyridine
4aa-a, although the desired product 5a was obtained products, respectively. Fortunately, all the products
in a low yield. Surprisingly, benzil (4aa-b) and 1,3-di- were successfully identified by HR-MS analysis of the
phenylpropane-1,3-dione (4aa-c) were obtained in crude reaction extract, which clearly confirmed our
55% and 10% yields, respectively. These results indi- proposed mechanism (see the Supporting Informa-
cated that 4aa was not generated as a key intermedi- tion).
À
À
ate (Scheme 6a). Subsequently, the desired product 5a
In summary, a squential Csp3 H oxidation and C S
was obtained in low yield when 4aa was reacted with cleavage of dimethyl sulfoxide have been developed
4a in DMSO at 1308C. This reaction also led to the to build pyridines from ketones. This reaction demon-
formation of benzil (4aa-b) and 1,3-diphenylpropane- strates a broad substrate scope, as well as good func-
1,3-dione (4aa-c) (Scheme 6b). This result provided tional group tolerance towards a variety of functional
further confirmation that 4aa was not generated as groups on the pyridine rings. This method represents
a key intermediate and suggested that 4a was directly a new practical strategy for capturing in situ-generat-
converted to the corresponding methylene intermedi- ed methylene intermediates using DMSO as a source
ate via an enolization followed by the nucleophilic of methylene units. Furthermore, these reactions can
attack of intermediate E (Scheme 7).
be conducted under simple conditions with high re-
gioselectivity. Further studies to elucidate a detailed
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Scheme 7. Proposed reaction mechanism.
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A
sealed tuble was charged with acetophenone 1a
(1.0 mmol), ammonium formate 2a (10.0 mmol), iodine
(1.6 mmol), Cu(NO3)2·3H2O (1.0 mmol) in DMSO (3 mL)
and the mixture was stirred at 1308C for 3 h until almost
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