Synthesis of polysubstituted pyridines from oxime acetates using NH4I as a dual-function promoter

Article abstract of DOI:10.1039/c7ob02471a

Pyridine formation with oxime acetates as the building blocks under metal-free conditions is described. Ammonium iodide has proved to be a highly efficient promoter for oxime N-O bond reduction and subsequent condensation reactions, whereby it played a dual-function role in the transformation. While the three-component reaction of oxime acetates, benzaldehydes, and 1,3-dicarbonyls proceeded well with the assistance of a stoichiometric amount of ammonium iodide, the condensation of oximes and acroleins was enabled by using a catalytic initiator to afford substituted pyridines. By this protocol, substituted pyridine products were generated in moderate to excellent yields with tolerance towards a broad range of functional groups.

Full text of DOI:10.1039/c7ob02471a

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Synthesis of polysubstituted pyridines from oxime acetates using
NH4I as dual-function promoter
Yujia Xia,† Jinhui Cai,† Huawen Huang* and Guo-Jun Deng*
Received 00th January 20xx,
Accepted 00th January 20xx
Pyridine formation with oxime acetates as the building blocks under metal-free conditions is described. Ammonium iodide
has proved to be a highly efficient promoter for oxime N-O bond reduction and subsequent condensation reaction, whereby
it played a dual-function role in the transformation. While the three-component reaction of oxime acetates, benzaldehydes,
and 1,3-dicarbonyls proceeded well by the assistance of stoichiometric amount of ammonium iodide, the condensation of
oximes and acroleins was enabled by catalytic initiator to afford substituted pyridines. By this protocol, substituted pyridine
products were generated in moderate to excellent yields with a broad range of functional groups tolerated.
DOI: 10.1039/x0xx00000x
www.rsc.org/
Introduction
Pyridine-containing compounds have wide applications in
the fields of naturally occurring products, pharmaceuticals,
spices, and functionalized organic materials. Consequently,
beyond the classic Chichibabin and Hantzsch pyridine synthesis,
the development of methodologies for pyridine formation
remains a topic of considerable interest in modern synthetic
chemistry.1,2
Oxime derivatives provide structurally advantaged and
versatile building blocks for pyridine synthesis under transition-
metal catalysis.3 For example, vinyl ketoximes undergo formal
[4+2] cycloaddition4 with alkenes or alkynes to afford highly
substituted pyridines (Scheme 1a), in which copper-catalyzed
electrophilic amination4a or rhodium-catalyzed directing C–H
activation4b-d occurs as the initial step. Furthermore, oxime
acetates bearing α-protons have also been widely used as C2N1
units for pyridine construction. The activation of oximes by
metal salts followed by condensation of two molecules of
Scheme 1 Synthesis of pyridines from oximes under metal catalysis.
The activation of oxime N-O bond could also proceed with
non-metal initiator, which was originally applied for
intramolecular cyclization and N
-heterocycle synthesis.7 Within
oxime acetates with
a C1 source such as aldehyde,
dimethylformamide (DMF), or dimethylaniline proceeds
through formal [3+2+1] annulation to give structurally
symmetrical pyridines or 2,4-diarylpyridines (Scheme 1b).5
Furthermore, [3+3] pyridine formation has been disclosed6
independently by Youshikai,6a,e Cui,6b and Jiang6c,d groups,
wherein copper-catalyzed oxime activation initiates subsequent
condensation with acroleins, α,β-unsaturated ketimines, or α,β-
unsaturated nitriles and ketones in situ generated by three-
component assembly (Scheme 1c).
our own program on sustainable metal-free synthesis,8 recently,
we developed an efficient I2/Et3N-mediated pyridine synthesis
from ketoximes and acroleins (Scheme 2a).8a Thereafter, the
construction of trifluoromethyl pyridines was enabled by NH4I-
based system combined with Na2S2O4 as the reducing agent
(Scheme 2b).8b The experimental results of these works
encouraged us to explore broader generality of
N-heterocycle
synthesis from oximes under metal-free systems. Herein, we
disclose NH4I-initiated effective formation of polysubstituted
pyridines through [3+3] annulation of oxime acetates and α,β-
unsaturated carbonyls (Scheme 2c). The present work provides
alternative entry to oxime-based pyridine synthesis in a reaction
complementary to previous copper-catalyzed methods.6a,6c
Moreover, the dual-function iodide catalysis would inspire
other cases of iodine-based synthetic chemistry.9
Key Laboratory for Green Organic Synthesis and Application of Hunan Province, Key
Laboratory of Environmentally Friendly Chemistry and Application of Ministry of
Education, College of Chemistry, Xiangtan University, Xiangtan 411105, China. E‐
mail: hwhuang@xtu.edu.cn; gjdeng@xtu.edu.cn
† The authors contributed equally to this work.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information]. See DOI: 10.1039/x0xx00000x
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DOI: 10.1039/C7OB02471A
2
NH4I (20)
PhCl
120
0
3
NH4I (20)
NH4I (20)
NH4Cl (20)
NH4Br (20)
KI (20)
DMSO
120
120
120
120
120
120
120
120
120
120
120
100
130
0
4
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
17
0
5
6
0
7
0
8
NaI (20)
0
9
Bu4NI (20)
I2 (20)
0
10
11
12
13
14
15
10
12
53
87
51
78
NIS (20)
NH4I (50)
NH4I (100)
NH4I (100)
NH4I (100)
Scheme 2 Synthesis of pyridines from oximes under metal-free
conditions.
a The reactions were performed with 0.2 mmol of 1a, 0.3 mmol of 2a, 0.4
mmol of 3a in 1 mL of solvent, 12 h. b Yields of isolated product 4aa were
given.
Results and discussion
In a reaction complementary to our previous synthesis of
fluorinated pyridines, the three-component reaction of
ketoximes, benzaldehydes, and trifluoromethyldiketones had
been preliminarily investigated, and moderate yields were
generally obtained in the NH4I/Et3N/toluene system.8b We
suspected that more efficient reaction system could be explored
for the three-component assembly of pyridines. Thereby
ketoxime acetate 1a, benzaldehyde 2a, and acetylacetone 3a
were chosen as the model system to screen the reaction
conditions of the pyridine formation (Table 1). When catalytic
amount of NH4I was used, solvent screening indicated 1,4-
dioxane was superior to previously used toluene and others
(entries 1-4). Other ammonium halides such as NH4Cl and
NH4Br featured no catalytic activity for this reaction (entries
5,6), as did other iodides such as KI, NaI and Bu4NI (entries 7-
9). These results revealed that NH4I might play a dual-function
role, which, as previously proposed, served as electron-donor to
enable oxime N–O bond cleavage and as an acid to promote the
condensation process. Notably, elemental iodine and NIS gave
lower yield of 4a compared with NH4I (entry 10,11). To our
delight, in the 1,4-dioxane media, the reaction yield increased
with the amount of NH4I increased (entries 12,13), and
excellent yield of 4a (87%) was afforded with 1 equiv of
With the optimized reaction conditions in hand, we explored
the generality of the three-component pyridine formation by
employment of a broad range of substrates (Scheme 3). First,
acetophenone oxime acetates bearing various functionalities at
the benzene ring were subjected to this system and proved to be
effective, affording the corresponding pyridine products in
moderate to good yields (4a-4k). Among them, alkyl, methoxyl,
chloro, and bromo functional groups were well tolerated.
Naphthyl and thienyl ketoximes were also compatible with this
reaction (4l and 4m, respectively). Then, a series of substituted
benzaldehydes attached with alkyl, methoxyl, halo (F, Cl, Br),
nitro, and amino substuents worked smoothly to give the
respected tetrasubstituted pyridines in good yields (5a
-5o)).
Thereafter, we studied the scope of viable 1,3-dicarbonyls
3
.
Thereby, among others 1,3-diketone was successfully coupled
with oxime 1a and benzaldehyde 2a to afford the target
pyridines 6a in moderate yields. Then various β-ketone esters
bearing functional groups (6b-6e) including allyl ester (6d)
were all accommodated with the present NH4I system.
Moreover, β-ketoamide furnished the desired nicotinamide
product 6f in modest yield.
o
o
initiator. Finally, the reaction performed at 100 C or 130 C
gave inferior results (entries 14,15).
Table 1 Optimization of the reaction conditionsa
Entry Add. (mol %)
NH4I (20)
Solvent
toluene
Temp.
(°C)
Yield
(%)b
1
120
6
2 | J. Name., 2012, 00, 1‐3
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toluene was the best media for this pyridine formation, giving
Ar2
O
View Article Online
DOI: 10.1039/C7OB02471A
NOAc
8a in 85% yield.
NH4I (1 equiv)
O
O
R2
Ar2CHO
+
+
Ar1
R1
R2
1,4-dioxane
120 oC, 12 h
Ar1
N
R1
Table 2 Optimization of the reaction conditionsa
2
1
3
4, 5, 6
(a) oximes
Ph
N
O
4f, R = 4-Br, 69%
4g, R = 3-OMe, 73%
4h, R = 3-Br, 60%
4i, R = 2-Me, 66%
4j, R = 2-Cl, 61%
4a, R = H, 87%
4b, R = 4-Me, 75%
4c, R = 4-t-Bu, 72%
4d, R = 4-OMe, 51%
4e, R = 4-Cl, 80%
R
Entry
Cat. (mol %)
Add. (mol %) Solvent
Yield
(%)b
Ph
O
Ph
O
Ph
O
Cl
1
NH4I (100)
NH4I (20)
NH4Br (20)
KI (20)
--
1,4-dioxane
22
19
0
N
N
N
2
--
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
toluene
S
Cl
3
--
4k, 88%
4l, 48%
4m, 49%
4
--
0
(b) benzaldehydes
R
5
NaI (20)
--
0
R
6
I2 (20)
--
9
R
O
O
O
7
Bu4NI (20)
NIS (20)
NH4I (20)
NH4I (20)
NH4I (20)
NH4I (20)
NH4I (20)
--
0
8
--
7
Ph
N
Ph
N
Ph
N
9
Et3N (50)
Et3N (25)
Et3N (25)
Et3N (25)
Et3N (25)
68
70
85
26
35
5a, R = t-Bu, 77%
5b, R = OMe, 56%
5c, R = Cl, 86%
5d, R = Br, 80%
5e, R = NO2, 65%
5g, R = Me, 63%
5h, R = OMe, 52%
5i, R = F, 66%
5j, R = Cl, 73%
5k, R = Br, 65%
5l, R = NO2, 70%
5m, R = 2-OMe, 59%
5n, R = 2-Cl, 71%
5o, R = 2,4-Cl2, 70%
10
11
12
13
PhCl
5f, R = N(Me)2, 74%
DMSO
(c) 1,3-dicarbonyls
a The reactions were performed with 0.2 mmol of 1a, 0.3 mmol of 7a in 1 mL
of solvent at 120 oC for 12 h. b Yields of isolated product 8a were given.
Ph
Ph
Ph
O
Ph
CO2Et
CO2All
CO2Me
Ph
N
Ph
N
Ph
N
Ph
N
Comparably, while elemental iodine could be used as soft
acid and electron-donor for oxime N–O bond reduction in
previous work,8a,10 NH4I/Et3N system featured obviously higher
dual-function catalytic activity in current observation.
Furthermore, the catalytic NH4I system allowed the reaction
handling either in pre- or late-stage much easier.
6c, 69%
6d, 70%
6a, 50%
6b, 72%
Ph
O
N
Ph
CO2Bn
O
Ph
N
Ph
N
6f, 46%
6e, 64%
Thereafter, we probed the scope of ketoximes and acroleins
for this NH4I/Et3N-catalyzed pyridine generation (Scheme 4).
In general, moderate to excellent yields were observed and
electron and steric hindrance effect of the substrates on the
yield proved not to be a strong factor on catalytic reactivity.
This catalytic system allowed a broad range of oxime acetates
Scheme 3 Three-component pyridine synthesis by NH4I
initiator
.
With the three-component pyridine formation established by
the NH4I system, we speculate that this viable dual-function
initiator could be applicable to other cases of oxime-based
condensation reactions, whereby we reexamined the pyridine
formation from ketoxime 1a and cinnamic aldehyde 7a (Table
2). Initially, we subjected them to the NH4I-mediated system
for the three-component reaction, and obtained the 2,6-diphenyl
pyridine 8a in 22% yield (entry 1). Very slightly reduced yield
of 8a was observed when using catalytic amount of NH4I (entry
2). Likewise, other ammonium salts and iodides also gave no
pyridine product and elemental iodine as well as NIS was
inferior (entries 3-8). Then we found the addition of
triethylamine in catalytic amount dramatically improved the
transformation (entries 9,10), furnishing the product in good
yield. In combination of NH4I (20 mol %) with Et3N (25
mol %), the examination of solvent (entries 11-13) revealed that
derived from acetoarenes to couple with cinnamic aldehyde 7a
with functional groups such as alkyl (8b and 8c), methoxyl (8e
and 8j), and nitro (8i 8l, and 8n) tolerated well. To our delight,
halo-functionalities such as F, Cl, Br, and I were all tolerated
well (8f 8h 8k, and 8m). And heteroaromatic ketoximes
,
,
-
,
bearing furan (8q), thiophene (8r), and pyridine (8s) were all
accommodated. Then, 2,3,4-trisubstituted pyridines 8t and 8u
were generated in good yield by the use of oxime acetates
derived from propiophenone and 1,2-diphenylethanone. The
investigation of cinnamic aldehydes indicated that both
electron-donating methoxy and electron-deficient nitro attached
to the benzene ring were compatible with this reaction,
affording the product 9a and 9b in 74% and 66% yield,
respectively. Finally, we found that (
E
)-4-phenylbut-3-en-2-one
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reacted smoothly to give 2-methyl-4,6-diphenylpyridine 9d in the assistance of iodine12 in situ generated (Scheme 5d, B’
View ArticletOonlCine).
DOI: 10.1039/C7OB02471A
modest yield.
Then, intramolecular condensation/annulation of intermediate
occurs to deliver dihydropyridine . Finally, the desired
C
D
pyridine products are given through the I2-mediated oxidative
aromatization.
Ar2
NH4I (20 mol%)
Et3N (25 mol%)
NOAc
R
CHO
Ar2
Ar1
+
toluene, 120 oC
Ar
N
R
7
8, 9
1
(a) oximes
Ph
N
8a, R = H, 85%
8h, R = 4-I, 54%
8b, R = 4-Me, 75%
8c, R = 4-t-Bu, 79%
8d, R = 4-Ph, 91%
8e, R = 4-OMe, 80%
8f, R = 4-Cl, 83%
8g, R = 4-Br, 77%
8i, R = 4-NO2, 77%
8j, R = 3-OMe, 85%
8k, R = 3-Br, 80%
8l, R = 3-NO2, 81%
8m, R = 2-Cl, 57%
8n, R = 2-NO2, 80%
R
Ph
Ph
Ph
Ph
N
Cl
Cl
N
8p, 60%
Ph
N
N
O
S
8r, 79%
8o, 93%
8q, 37%
Ph
Ph
Ph
Ph
Me
Ph
N
N
N
N
8u, 76%
8t, 80%
8s, 41%
(b) aldehydes
O
NO2
F
Ph
Ph
N
Ph
N
Ph
N
Ph
N
9a, 74%
9d, 55%
9b, 66%
9c, 80%
Scheme 4 Pyridine synthesis catalyzed by NH4I
.
Scheme 5 Mechanistic studies and proposal of pyridine
Next, a number of control experiments were performed to
gain mechanistic information of the ammonium iodide initiated
oxime reduction and annulation. The addition of a scavenger
such as 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) and
butylated hydroxytoluene (BHT) did not dramatically affect the
yields of both reaction systems (Scheme 5, reactions a and b).
Compared with the iodine-promoted oxime reduction probably
involving radical pathway,8a ammonium iodide may directly
serve as electron- and proton-donor to reduce the N–O bond of
oxime acetate to give imine and acetic acid, in which radical
intermediate would not be formed, while elemental iodine be
synthesis catalyzed by NH4I
.
Conclusions
In summary, we developed efficient ammonium iodide-
assistant N-O bond reduction of oxime acetates, which was
applied to the condensation reactions with α,β-unsaturated
carbonyls to provide alternative methods for pyridine synthesis.
In complementary with previous copper- and iodine-promoted
reactions, this protocol allows a modular generation of
multisubstituted pyridines from oxime acetates and α,β-
unsaturated carbonyls. More importantly, the present metal-free
oxime reduction by the simple and mild system with
ammonium iodide may be applied into the cleavage of oxime
linkage groups in the field of biochemistry.
generated (Scheme 5, d, 1a to
B). The viable reductive
reactivity of ammonium iodide was further demonstrated by the
experimental result of oxime acetate 1d, which furnished the
expected ketone 10 with excellent yield in the absence of any
carbonyls (Scheme 5, reaction c). Concerning about the broad
application of oximes as linkage groups in biochemistry,11 the
present simple and mild reductive system could be applied in a
Experimental
broader field of chemistry. Thereafter, the imine intermediate
B
General information
undergoes tautomerization to form enamine B’, which proceeds
through a Michael addition to α,β-unsaturated carbonyls with
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All reactions were carried out under the standard conditions
unless otherwise noted. Column chromatography was
performed using silica gel (200-300 mesh). 1H NMR and 13C
NMR spectra were recorded on a 400 MHz NMR spectrometer,
and the chemical shifts are referenced to signals at 7.26 and
77.0 ppm, respectively. Generally, chloroform was used as the
solvent with TMS as the internal standard. MS analyses were
performed on an Agilent 5975 GC-MS instrument (EI). HRMS
was carried out on a high-resolution mass spectrometer (ESI,
LCMS-IT-TOF). The structure of known compounds was
Notes and references
View Article Online
1
For reviews, see: (a) G. D. Henry, TDeOtrIa: 1h0e.d10r3o9n/,C72O0B0042,46710A
,
6043-6061; (b) M. D. Hill, Chem. Eur. J., 2010, 16, 12052–
12062; (c) C. Allais, J. M. Grassot, J. Rodriguez and T.
Constantieux, Chem. Rev., 2014, 114, 10829–10868.
2
For recent representative examples of pyridine synthesis, see:
(a) P. Kumar, S. Prescher and J. Louie, Angew. Chem., Int.
Ed., 2011, 50, 10694–10698; (b) M. Ohashi, I. Takeda, M.
Ikawa and S. Ogoshi, J. Am. Chem. Soc., 2011, 133, 18018–
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N. Kimura, J. Kobayashi, Y. Ebihara, K. Kondo, K. Sakata
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(e) N. S. Loy, A. Singh, X. Xu and C. M. Park, Angew. Chem.,
Int. Ed., 2013, 52, 2212–2216; (f) S. Michlik and R. Kempe,
Angew. Chem., Int. Ed., 2013, 52, 6326–6329; (g) Z. Shi and
T. P. Loh, Angew. Chem., Int. Ed., 2013, 52, 8584–8587; (h) J.
Wu, W. Xu, Z. X. Yu and J. Wang, J. Am. Chem. Soc., 2015,
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Sun, Angew. Chem., Int. Ed., 2016, 55, 9704–9708; (j) L. G.
Xie, S. Shaaban, X. Chen and N. Maulide, Angew. Chem., Int.
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1
further corroborated by comparing their H NMR, 13C NMR
data and MS data with those in literature. Melting points were
measured with a BÜCHI B-545 melting point instrument
without correction. All reagents were obtained from
commercial suppliers and used without further purification.
General procedure for pyridine synthesis by three-
component reaction (4, 5 and 6)
A 10 mL reaction vessel was charged with NH4I (0.2 mmol, 1.0
equiv), oxime acetate (
1
, 0.2 mmol, 1.0 equiv), aldehyde (
2, 0.3
3
4
For reviews, see: (a) M. Kitamura and K. Narasaka, Chem.
Rec., 2002, 2, 268–277; (b) K. Narasaka and M. Kitamura,
mmol, 1.5 equiv), 1,3-dicarbonyl (
3
, 0.4 mmol, 2.0 equiv). The
sealed reaction vessel was purged with argon three times. 1,4-
Dioxane (0.5 mL) was added to the sealed reaction vessel by
Eur. J. Org. Chem., 2005, 2005, 4505–4519; (c) H. Huang, X.
Ji, W. Wu and H. Jiang, Chem. Soc. Rev., 2015, 44, 1155–
1171; (d) H. Huang, J. Cai and G. J. Deng, Org. Biomol.
Chem., 2016, 14, 1519-1530, and references cited therein.
(a) S. Liu and L. S. Liebeskind, J. Am. Chem. Soc., 2008,
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C.-H. Cheng, Org. Lett., 2008, 10, 325–328; (c) I. Nakamura,
o
syringe. The resulting solution was stirred at 120 C for 12 h.
The mixture was then allowed to cool down to room
temperature and flushed through a short column of silica gel
with ethyl acetate. After rotary evaporation, the residue was
purified by column chromatography (silica gel, petroleum
D. Zhang and M. Terada, J. Am. Chem. Soc., 2010, 132
,
ether/EtOAc = 20:1 to 50:1) to give 4, 5, 6.
7884–7886; (d) T. K. Hyster and T. Rovis, Chem. Commun.
,
2011, 47, 11846–11848; (e) R. M. Martin, R. G. Bergman
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M. Neely and T. Rovis, J. Am. Chem. Soc., 2013, 135, 66–69;
General procedure for the synthesis of pyridines 8 and 9
A 10 mL reaction vessel was charged with NH4I (0.04 mmol,
(g) J. M. Neely and T. Rovis, J. Am. Chem. Soc., 2014, 136
,
20 mol%), Et3N (0.05 mmol, 25 mol%), oxime acetate (
1, 0.2
2735–2738.
mmol, 1.0 equiv), aldehyde ( , 0.3 mmol, 1.5 equiv). The
7
5
6
(a) Z.-H. Ren, Z.-Y. Zhang, B.-Q. Yang, Y.-Y. Wang and Z.-
H. Guan, Org. Lett., 2011, 13, 5394–5397; (b) M. N. Zhao, R.
sealed reaction vessel was purged with argon three times.
Toluene (0.5 mL) was added to the sealed reaction vessel by
R. Hui, Z. H. Ren, Y. Y. Wang and Z. H. Guan, Org. Lett.
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Conflicts of interest
There are no conflicts of interest to declare.
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We gratefully acknowledge National Natural Science
Foundation of China (21602187, 21572194), the Collaborative
Innovation Center of New Chemical Technologies for
Environmental Benignity and Efficient Resource Utilization,
the Hunan Provincial Innovative Foundation for Postgraduate
(CX2017B293), and Hunan Provincial Natural Science
Foundation of China (2017JJ3299).
,
9
For selective iodine-based synthesis, see: (a) S. Tang, Y. Wu,
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J. Name., 2013, 00, 1‐3 | 5
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DOI: 10.1039/C7OB02471A
O
R3
N
NH4I
EWG
R3
N
R4
CHO
R3
+
R2
R1
EWG
R4
in situ
R3 formed
R2
R1
R4
R4
NOAc
R1
R2
metal-free
59 examples
yield up to 93%
NH4I dual-function promoter enables pyridine synthesis through oxime N-O bond reduction
and subsequent condensation reactions