Ammonium iodide-promoted cyclization of ketones with DMSO and ammonium acetate for synthesis of substituted pyridines

Article abstract of DOI:10.1039/c5ra07584j

A simple and efficient method has been developed for the synthesis of symmetrical and unsymmetrical pyridines via NH₄I-promoted cyclization of ketones with DMSO and NH₄OAc. It was found that methyl ketones always gave selective forma

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Ammonium iodide-promoted cyclization of ketones with DMSO and
ammonium acetate for synthesis of substituted pyridines
Xiaojun Pan, Qiao Liu, Liming Chang and Gaoqing Yuan*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
A simple and efficient method has been developed for
the synthesis of symmetrical and unsymmetrical
pyridines via NH4I-promoted cyclization of ketones
with DMSO and NH4OAc. It was found that methyl
10 ketones always gave selective formation of the
unsymmetrical pyridine, while non-methyl ketones
gave unpredictable results (symmetrical or non-
symmetrical product only, or a mixture of the two). In
addition, the deuterium-labeling experiments indicated
15 that the C4 or C6 of the target product pyridine rings
resulted from DMSO.
As an important class of nitrogenꢀcontaining heterocyclic
compounds, substituted pyridines are found in numerous
natural products and extensively used in functional materials,
20 synthetic pharmaceuticals and various valuable ligands.1
Consequently, diverse synthetic approaches toward substituted
pyridines have been developed in the past few decades.2
Among them, condensation of carbonyl compounds with
amines is a traditional method for the synthesis of pyridine
25 rings.3 As modern synthetic methodologies, transitionꢀmetalꢀ
catalyzed cycloaddition, cycloisomerization and C−H
functionalization reactions promote the construction of
pyridine rings greatly.4 Although a number of synthetic
methods have been established, simple and flexible strategies
30 for the synthesis of symmetrical and unsymmetrical pyridines
are still highly needed. Exploring new carbon sources to
construct pyridine ring is a critical issue.
Recently, Guan and coꢀworkers reported a rutheniumꢀ
catalyzed cyclization of ketoxime acetates with DMF for the
35 synthesis of symmetrical pyridine, in which DMF acts as both
C4 source and reaction medium (Scheme 1a).5 Different from
Guan’s work, Deng and coꢀworkers developed a method for
construction of unsymmetrical pyridines by employing DMF
as C6 source (Scheme 1b).6 DMSO, a cheap and lowꢀtoxic
40 solvent, has been widely used in organic synthesis. In addition,
DMSO can be used as a multipurpose precursor for the
formation of −Me,7 −SMe,8 −SO2Me,9 −CHO,10 −CN,11 and
50
Scheme 1 Various methods for the synthesis of pyridines.
–OH.12 Based on DMSO playing multiple roles in the organic
synthesis, we have reported an efficient ammonium iodideꢀ
55 induced sulfonylation of alkenes for the synthesis of vinyl
methyl sulfones by using DMSO and H2O as the source of
13
−SO2Me,
and the coupling of alkenes with DMSO and
alcohols for the synthesis of β-alkoxy methyl sulfides by
employing DMSO as the source of −SMe.14 In the
60 experimental process, we found that DMSO was easily
subjected to decomposition to produce MeSH and HCHO. The
formation of formaldehyde makes the utilization of DMSO as
a new carbon source for the synthesis of substituted pyridines
become possible. Herein, we report an efficient ammonium
65 iodideꢀpromoted cyclization of ketones with DMSO and
ammonium acetate for synthesis of unsymmetrical and
symmetrical pyridines by employing DMSO as C4 or C6
source, respectively (Scheme 1c).
We initially employed acetophenone (1a) as model
70 substrate to optimize the reaction conditions. In the presence
of NH4I, acetophenone 1a was converted to 2,4ꢀ
diarylpyridines (2a) in 22% yield without ammonium acetate
in DMSO at 130 °C for 14 h (Table 1, entry 1). Instead of
NH4I, 33% yield of 2a was obtained when equal amount of
75 ammonium acetate was added into this reaction system (Table
School of Chemistry and Chemical Engineering, South China University
45 of Technology, Guangzhou, 510640, P. R. China
Eꢀmail: gqyuan@scut.edu.cn
† Electronic Supplementary Information (ESI) available: Detailed
experimental procedures, characterization of products, and NMR spectral
charts. See DOI: 10.1039/b000000x/
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Table 1 Optimization of reaction conditions.a
Table 2 Synthesis of unsymmetrical pyridines from methyl
ketones.a,b
Halide (equiv.) Ammonia source Solvent Yield (%) b
35
Entry
Substrate
Yield
Entry
1
2
3
4
5
6
7
8
9
Product
1
NH4I (1)
—
—
DMSO 22
DMSO 33
DMSO 87
DMSO 23
2
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
(NH4)2CO3
NH4HCO3
NH4Cl
R =H
R =F
R =Cl
R =Br
2a, 81%
2b, 78%
2c, 72%
3
4c
NH4I (0.5)
NH4I (0.5)
NH4I (0.5)
NH4I (0.5)
NH4I (0.5)
NH4I (0.5)
NH4I (0.5)
NH4I (0.5)
NH4Br (0.5)
NH4Cl (0.5)
NaI (0.5)
N
O
2d
2e
, 77%
, 80%
, 83%
5
DMF
DMA
6
5
R =I
R
R
6
R
2f
2g
R =CH3
R =OCH3
R =n-butyl
, 76%
2h
7
CH3CN trace
DMSO 16
, 60%
8
O
N
N
Cl
2i
R =isopropyl , 75%
9
DMSO
DMSO
6
5
10
11
2j
, 40%
10
11
12
13
14
15
16
17d
18
19
20e
Cl
O
Cl
NH4OAc
NH4OAc
NH4OAc
DMSO 53
DMSO 60
DMSO 38
DMSO 36
DMSO 25
DMSO 50
DMSO 61
DMSO 42
DMSO 30
DMSO 75
2k
, 65%
nꢀBu4NI (0.5) NH4OAc
O
12
13
2l
,
R =F
R =Cl
R =Br
R =OCH3
85%
I2 (0.25)
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
N
R
2m, 80%
R
R
HI (0.5)
14
15
2n
, 70%
2o
, 75%
HI/I2 = 2:1
HI/I2 = 1:1
HI/I2 = 1:1.5
NH4I (0.5)
O
O
N
N
16
17
2p
, 45%
, 45%
a Reaction conditions: 1a (1 mmol), solvent (2.0 mL), ammonia source (1
equiv.), 130 °C, 14 h under air in a sealed tube. Determined by GC
b
S
S
2q
2r
c
d
5
based on 1a. Reaction temperature 120 °C. I2 (0.125 equiv.), HI (0.25
S
equiv.). e Under N2 in a sealed tube.
N
N
O
1, entry 2). To our delight, the yield of 2a could be increased
from 33% to 87% when the reaction was performed in the
presence of 0.5 equiv. of NH4I and 1.0 equiv. of NH4OAc
18
19
, 52%
O
10 (Table 1, entry 3). However, the efficiency of this
transformation decreased significantly when the reaction was
carried out at 120 °C (Table 1, entry 4). Subsequently, the
effect of solvents on the reaction was also investigated.
Unfortunately, only a little or even trace amount of 2a was
15 detected in DMF, DMA and acetonitrile (Table 1, entries 5–7).
These results indicated that the solvent was probably involved
in this transformation. In addition, the source of ammonia was
also varied and it was observed that ammonium acetate was
the most suitable ammonia source for this reaction (Table 1,
20 entries 8–10). Compared to NH4I, a similar ammonium salt
NH4Br or NH4Cl resulted in a lower yield (Table 1, entries 11
and 12). Neither NaI nor tetrabutylammonium iodide (nꢀ
Bu4NI) could be used to facilitate this reaction (Table 1,
entries 13 and 14). When employing 0.25 equiv. of I2 instead
25 of 0.5 equiv. of NH4I, only 25% yield of 2a was obtained
(Table 1, entry 15). Compared to I2, HI could afford a higher
yield of 2a (Table 1, entry 16). In addition, different ratios of
HI and I2 have a great effect on this reaction (Table 1, entries
17–19). Obviously, a high initial concentration of I2 is
30 unfavorable to this reaction (Table 1, entry 15). Based on
these results, it was proposed that inꢀsitu generated I2 from
NH4I was an active promoter in this reaction.
2s
, 0%
, 0%
N
N
N
O
N
2t
20
21
O
N
c
2u
, 21%
a
Reaction conditions: 1 (1 mmol), NH4I (0.5 equiv.), NH4OAc (1 equiv.),
DMSO (2.0 mL), 130 °C, 14 h. b Isolated yield. c GC yield.
40
With the optimal reaction conditions established, a number
of ketones (1) were investigated to evaluate the generality and
scope of this reaction. Very interestingly, methyl ketones
always afforded unsymmetrical pyridines, as shown in Table
2. Using various methyl aryl ketones with electronꢀ
45 withdrawing and electronꢀdonating groups as the substrates,
the reaction could give the corresponding unsymmetrical
products in moderate to good yields (Table 2, entries 1–9). In
addition, functional group at the meta positions of the
aromatic ring was also applicable for this transformation
50 (Table 2, entries 12–15). However, when orthoꢀsubstituted of
acetophenone was involved in this reaction, only 40% yield of
the desired product was obtained (Table 2, entry 10). The
2
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similar results
3ꢀenꢀ2ꢀone was employed as the substrate (Table 2, entries 19
20 and 20).
Table 3 Synthesis of symmetrical and unsymmetrical pyridines
from nonꢀmethyl ketones.a,b
For nonꢀmethyl ketone substrates, the reaction gave
unpredictable results (symmetrical or nonꢀsymmetrical
pyridine only, or a mixture of the two), as shown in Table 3.
For example, the reactions utilizing propiophenone and
25 valerophenone as the substrates gave a mixture of two
regioisomers in a ratio of 1:1.3 and 2.3:1, respectively (Table
3, entries 1 and 2). The same phenomenon occurred when 3,4ꢀ
dihydronaphthalenꢀ1(2H)ꢀone and cyclooctanone were used
as the substrates (Table 3, entries 3 and 4). Surprisingly, only
30 one desired product was obtained when the substrate above
was
replaced
by
2,3ꢀdihydroꢀ1Hꢀindenꢀ1ꢀone
or
cycloheptanone (Table 3, entries 7 and 8). It was worth noting
that the corresponding product was symmetrical pyridine for
2,3ꢀdihydroꢀ1Hꢀindenꢀ1ꢀone and unsymmetrical pyridine for
35 cycloheptanone. No desired products could be observed if 3ꢀ
chloroꢀ1ꢀphenylpropanꢀ1ꢀone
and
2ꢀhydroxyꢀ1ꢀ
phenylethanone were employed as the substrates (Table 3,
entries 5 and 6).
Several deuteriumꢀlabeling experiments were carried out
40 to gain a preliminary insight into the reaction mechanism
(Scheme 2). The reaction was carried out successfully under
N2 to afford the corresponding product in 75% yield, which
indicated that oxygen was not an important factor in this
reaction system (Table 1, entry 20). Instead of DMSO, when
45 DMSOꢀD6 was subjected to the procedure under the standard
conditions, 6ꢀdeuterated pyridine 2c' was obtained in 80%
yield (Scheme 2, eqn (1)). This result confirmed that the C6 in
the pyridine ring was provided by DMSO. In addition, the
reaction occurred as well to give 6ꢀdeuterated unsymmetrical
50 pyridine 2d' and 4ꢀdeuterated symmetrical pyridine 3f when
propiophenone was used, which could also provide the
evidence of the source of C6 or C4 (Scheme 2, eqn (2)).
Scheme 2 Deuteriumꢀlabeling experiments.
5
55
Based on the above experimental results and literature
reports,6,15 two possible reaction pathways are proposed in
Scheme 3. Initially, the intermediate 2 is formed by the
a
Reaction conditions: 1 (1 mmol), NH4I (0.5 equiv.), NH4OAc (1 equiv.),
b
c
DMSO (2.0 mL), 130 °C, 14 h. Isolated yield. 1.5 equiv. of NH4OAc
was used. A small amount of the corresponding regioisomer was
detected by GC.
d
condensation of ketone
1 itself, which can react with
ammonium acetate to give imine intermediate 3. Then,
10 were observed when employing 1ꢀ(naphthalenꢀ1ꢀyl)ethanone
and 1ꢀ(thiophenꢀ2ꢀyl)ethanone as the substrates (Table 2,
entries 16 and 17). Besides, 3,4ꢀdimethylacetophenone and 4ꢀ
phenylbutanꢀ2ꢀone could smoothly perform in this process
(Table 2, entries 11 and 18). However, only 21% yield of
15 desired product was detected by GC when employing heptanꢀ
2ꢀone as the substrate (Table 2, entry 21). Also, the product
was difficult to be separated. No desired products could be
obtained when 1ꢀ(pyridinꢀ3ꢀ yl)ethanone or (E)ꢀ4ꢀphenylbutꢀ
60 intermediate 3 easily undergoes tautomerization leading to an
intermediate 4. Meanwhile, the formaldehyde is generated via
decomposition of DMSO (eqn (5)), followed by the reaction
with 4 to afford intermediate 5. Subsequently, 5 is oxidized to
intermediate 6 by I2 resulting from the reaction of DMSO with
65 HI (eqn (4)). The final product
7 is formed by the
intramolecular condensation of intermediate 6 (path a).
According to the experimental results (Table 2), methyl
ketones seem to exclusively follow path a. It is also possible
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that ketone 1 has priority to react with ammonium acetate to 30 synthesis of symmetrical and unsymmetrical pyridines.
afford imine intermediate 8, which is easily converted to
intermediate
9
via tautomerization. Subsequently, the
Acknowledgements
intermediate 9 combines with formaldehyde provided by
DMSO to give intermediate 10. With the help of I2,
intermediate 10 is oxidized into intermediate 11. Addition of 1
to 11 generates intermediate 12, which gives intermediate 13
via a intramolecular condensation. Finally, losing a molecule
of water, intermediate 13 is transformed into the desired
We are grateful to the National Natural Science Foundation of
China (21172079), the Science and Technology Planning Project
of Guangdong Province (2011B090400031), and Guangdong
35 Natural Science Foundation (10351064101000000).
5
10 product 14 (path b). For nonꢀmethyl ketones, the reaction
may undergo path a and/or path b. In addition, it should be
pointed out that if the imine intermediate 8 was formed from a
methyl ketone it would be less likely to tautomerize to
enamine 9 due to the lower stability of lessꢀalkyl substituted
15 C=C bonds. So methyl ketones do not follow path b.
Notes and references
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40
45
50
55
60
65
NH4I
NH3 + HI
(3)
(4)
(5)
O
S
S
+
I2
+
H2O
2
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+
2 HI
(CH3)2SO
CH3SH
+
HCHO
path a:
O
R2
R1
R2
R1
R2
R2
1
3
4
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NH
O
NH2
NH4OAc
-AcOH
O
R1
R1
R1
R1
R1
R1
R2
R2
R2
R2
-H2O
-H2O
4
1
3
2
O
C
H
H
OH
O
R2
R1
R2
R1
R2
-H2O
N
I2
NH2
NH2
R1
R1
R1
R1
R2
R2
R2
2HI
7
6
5
path b:
5
6
7
O
R2
R1
Y. Bai, L. C. Tang, H. W. Huang and G. J. Deng, Org. Biomol. Chem.,
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-H2O
NH4OAc
-AcOH
O
2HI
H
C H
R2
R1
R2
R1
R2
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NH2
NH
OH
O
R2
R2
R1
R1
NH2
I2
NH2
9
8
10
11
O
R1
9
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1
OH
75
80
85
O
R2
R1
R2
R1
R2
R1
R2
R1
-H2O
-H2O
HO
R1
H2N
R1
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R2
N
N
R2
14
13
12
Scheme 3 Proposed reaction mechanism.
In conclusion, a convenient and efficient method has been
20 developed for the preparation of symmetrical and
unsymmetrical pyridines via ammonium iodideꢀpromoted
cyclization of ketones with DMSO and ammonium acetate. In
this reaction system, DMSO is used not only as an effective
reaction medium, but also as the source of C4 or C6 for the
25 formation of pyridines. It is worth mentioning that a mixture
of two regioisomers, or only symmetrical or unsymmetrical
product is obtained when nonꢀmethyl ketones are used as
substrates, while methyl ketones alwalys gives unsymmetrical
pyridines. The present work provides a new strategy for the
90 13 X. F. Gao, X. J. Pan, J. Gao, H. W. Huang, G. Q. Yuan and Y. W. Li,
Chem. Commun., 2015, 51, 210.
14 X. F. Gao, X. J. Pan, J. Gao, H. F. Jiang, G. Q. Yuan and Y. W. Li,
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4
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