One-pot synthesis of n-aryl-nicotinamides and diarylamines based on a tunable smiles rearrangement

Article abstract of DOI:10.1002/ejoc.201500222

A one-pot Smiles rearrangement has been developed as a useful protocol for the straightforward synthesis of diverse N-aryl-nicotinamides. This method also provides chemoselective access toward diarylamines based on the different substitutions of the amide group. The potential application of the transformation is exemplified by the synthesis of an on-market succinate dehydrogenase inhibitor, boscalid. A substituent-mediated Smiles rearrangement to N-aryl-nicotinamides and diarylamines has been developed. In addition to the wide range of heterocyclic building blocks, the one-pot process also provides an efficient access to an on-market fungicide, boscalid.

Full text of DOI:10.1002/ejoc.201500222

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201500222
One-Pot Synthesis of N-Aryl-Nicotinamides and Diarylamines Based on a
Tunable Smiles Rearrangement
Shihui Liu,[a] Shaofan Zhu,[b] Ying Wu,[a] Jiayu Gao,[a] Pengfei Qian,[a] Yanwei Hu,*[a]
Linsen Shi,[a] Shaohua Chen,[a] Shilei Zhang,*[a] and Yinan Zhang*[a,c]
Keywords: Rearrangement / Amines / Amides / Synthetic methods / Heterocycles
A one-pot Smiles rearrangement has been developed as a
useful protocol for the straightforward synthesis of diverse N-
aryl-nicotinamides. This method also provides chemoselec-
tive access toward diarylamines based on the different sub-
stitutions of the amide group. The potential application of
the transformation is exemplified by the synthesis of an on-
market succinate dehydrogenase inhibitor, boscalid.
have provided complementary ways to access heterocycles
with a C(sp2)–C(sp3) bond. These transformations together
Introduction
Among many organic rearrangement reactions, the
Smiles reaction represents a useful tool for aromatic substi-
tution bond formation to construct common and syntheti-
cally useful building blocks, especially in heterocyclic chem-
istry.[1] In this context, a wide range of heterocycles that
contain a C(sp2)–X bond have been developed.[2] On the
other hand, the variants of Smiles reactions, such as radi-
cal–Smiles,[3] Truce–Smiles,[4] and Ugi–Smiles reactions,[5]
Figure 1. Representative biologically active N-aryl-nicotinamides.
Figure 2. General methods to N-aryl-nicotinamides.
have greatly diversified structurally limited but readily avail-
able building blocks particularly in medicinal chemistry.
N-aryl-nicotinamide derivatives constitute a valuable
class of biologically active compounds (Figure 1), including
natural products[6] and medicinal substrates.[7] For example,
they serve as succinate dehydrogenase inhibitors that belong
to a significant category of fungicides and pesticides in ag-
rochemical application.[8] Considering the broad interest of
this heterocyclic building block, three general synthetic
methods were taken into consideration (Figure 2): 1) amid-
ation of nicotinic acid/nicotinyl chloride with aniline;[7e,9]
2) transamidation of primary nicotinamides with amines;[10]
[a] Jiangsu Key Laboratory of Translational Research and Therapy
for Neuro-Psycho-Diseases & Department of Medicinal
Chemistry, College of Pharmaceutical Sciences, Soochow
University,
199 Ren’ai Road, Suzhou 215123, China
E-mail: huyanwei@suda.edu.cn
zhangshilei@suda.edu.cn
ynzhang@sibs.ac.cn
http://yxx.suda.edu.cn/
[b] Novo Nordisk (China) Pharmaceuticals Co., Ltd. Shanghai
Branch,
3 Hongqiao Road, Shanghai 200030, China
[c] College of pharmacy, University of Kentucky,
789 South Limestone Street, Lexington, Kentucky 40536, USA
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500222.
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One-Pot Synthesis of N-Aryl-Nicotinamides and Diarylamines
and 3) transition metal-catalyzed coupling reactions be- Table 1. Condition screening.[a]
tween aryl halides/pseudohalides and nicotinamide.[11]
However, from a practical perspective, environmentally
benign, atom-economical, and metal-free conditions, are
still needed to fulfil the high demand for synthesizing this
N-aryl-nicotinamide scaffold. Herein, we described our
efforts, which utilized a one-pot Smiles rearrangement,[12]
to synthesize N-aryl-nicotinamides and diarylamines based
on the different substituents on amides.
Entry Base
Temp [°C] Solvent
Time [h]
Yield [%][b]
1
2
3
4
5
6
7
8
NaH
tBuOK 120
KOH
NaOH
EtONa 120
Cs2CO3 120
K3PO4
K2CO3 120
tBuOLi 120
tBuOK 120
tBuOK 120
tBuOK 120
tBuOK 120
tBuOK 120
tBuOK 100
tBuOK 110
tBuOK 130
120
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMA
DMSO
NMP
DMF
DMF
DMF
DMF
DMF
1.5
1.5
2
2
4
4
4
4
4
1.5
1.5
1.5
1.5
1.5
5
70
84
78
76
30
26
30
0
53
76
65
81
88
81
64
80
79
120
120
Results and Discussion
Our initial studies were guided by the result that nicotin-
amide 1a and phenol 2a heated in a basic medium formed
a Smiles rearrangement product 3a, rather than the desired
aromatic nucleophilic product 4a (Scheme 1). Since sub-
strate 4a can be obtained by employing a weak base in a
short time period,[13] we shifted our focus onto the develop-
ment of conditions for the Smiles rearrangement. Firstly,
we found that higher temperature increased the yield be-
cause of the thermally favorable reaction mechanism
(Table 1, entry 1).[14] An extensive survey of bases and apro-
tic polar solvents was performed at 120 °C and the results
indicated that tBuOK in DMF had the best yield (Table 1,
entries 2–12). Screening of base loading showed that
2.5 equiv. tBuOK gave a better result (Table 1, entry 13 vs.
entry 2). Further investigation of the reaction temperature
revealed that marginal temperature changes failed to im-
prove the yield, although a shorter reaction time was
needed at higher temperature (Table 1, entries 15–17).
120
9
10
11
12
13[c]
14[d]
15
16
17
2
0.5[e]
[a] Reaction conditions: 4a (0.4 mmol) and base (0.8 mmol) in sol-
vent (2 mL) with heating. [b] Isolated yields. [c] 2.5 equiv. base. [d]
3 equiv. base. [e] Product began to decompose with extended reac-
tion time.
Scheme 1. Initial reaction with substrates 1a and 2a.
Scheme 2. Proposed reaction mechanism.
The proposed reaction mechanism is shown in Scheme 2.
Deprotonation of 4 in the presence of tBuOK produces in-
termediate A, which undergoes intramolecular nucleophilic electron-neutral and withdrawing groups at different posi-
attack of amide anion to the aromatic nucleus. Considering tions gave the desired products in comparable yields to the
the formation of spiro-ring intermediate B as the rate- optimized conditions (3a–3i, Table 2). However, with elec-
determining step in this rearrangement, the steric hindrance tron-donating groups the yields varied with substitution at
of R1 and R2 and the electronic properties of R2 have sub- different positions. The para- and ortho-methoxy substitu-
stantial influences on the formation of B. Therefore, large ents did not work well in the rearrangement reaction giving
R1 and R2 substituents are detrimental to the reaction, lower yields of 17 and 37% respectively, even with extended
whereas electron-withdrawing R2 groups are beneficial to reaction times; whereas the meta-methoxy substituent led
the yield. Finally, breaking of the C–O bond in the transi- to a satisfied yield of 71% (3j–3l, Table 2). Steric hindrance
tion state affords intermediate C and final protonation gives is another factor that may be detrimental to the yield, since
the product 3.
the 2,6-dimethyl substrate produced a moderate yield of
With these optimized conditions in hand, we proceeded 50% (3m, Table 2). The differences in yield observed here
to test the generality of the rearrangement with substrates are consistent with the reaction mechanism discussed in
derived from phenols 2 (Table 2). Replacing p-chloro with Scheme 2.
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Y. Hu, S. Zhang, Y. Zhang et al.
SHORT COMMUNICATION
Table 2. Scope of substrates.[a]
Table 3. Scope of amide motifs.[a]
[a] Reaction conditions: substrates
(2.0 mmol) in solvent (2 mL) with heating for 1 h, isolated yields.
4 (0.4 mmol) and base
Scheme 3. One-pot procedure on gram scale.
The one-pot procedure also allowed us to utilize a new
route to obtain the succinate dehydrogenase inhibitor, bos-
calid (Scheme 4).[16] Starting from nicotinamide 1a and bi-
aryl phenol 6, the intermediate 7 can be generated following
the above conditions. Chlorination of the 2-hydroxy pyr-
idine with phosphoryl chloride gave the desired product in
a 21% total yield under unoptimized conditions. Thus, this
conversion based on a Smiles rearrangement has proved to
be the shortest one reported so far to obtain this important
agrochemical, as well as being an adaptable one that can
include a range of starting materials with a view to combi-
natorial synthesis.
[a] Reaction conditions: substrates
(1.0 mmol) in solvent (2 mL) with heating for 1 h or specific time
indicated, isolated yields. [b] Reaction time: 12 h. [c] Reaction time:
4 h.
4 (0.4 mmol) and base
Continuing the studies on the amide motif, we broadened
the substrate scope to include substituted amides (Table 3).
Unfortunately, the alkyl-substituted amides failed to par-
ticipate in the Smiles reaction, which resulted in a complex
mixture of products under our optimized conditions (3n–
3o, Table 3). This can be explained by the difficulty to form
intermediate B (Scheme 2) due to the steric hindrance effect
of these alkyl groups. However, the phenyl group was toler-
ated in the reaction and directly delivered diarylamine
products 5 instead of the desired nicotinamide 3, probably
due to the decomposition of N-carbonyl diarylamines in the
presence of a strong base.[15] Further investigation of the
generality of the substrate scope demonstrated that the re-
action could be applied successfully to a series of substi-
tuted phenyl amides in yields ranging from 42–80%, provid-
ing selective access to different building blocks under one
set of reaction conditions (5p–5s, Table 3).
Scheme 4. One-pot procedure to boscalid. Reagents and condi-
tions: a) K2CO3 (2.5 equiv.), DMF, 100 °C; b) tBuOK (2.5 equiv.),
120 °C, 1 h, 35% for two steps; c) POCl3, 100 °C, 10 h, 60%.
To demonstrate the robustness of this newly developed
reaction and render it practicable, we tested the one-pot
procedure to give nicotinamides 3 on a gram scale
(Scheme 3). The initial reaction between amides 1 and
phenols 2 was heated with K2CO3 overnight. Without isol-
Conclusions
In conclusion, we have developed a tunable Smiles re-
ating the intermediate, tBuOK was then added directly to arrangement based on the different substituents on the
the reaction mixture and heated at 120 °C for a further hour amide, which provides a one-pot procedure for the prepara-
to give the Smiles products with good yields after simple tion of N-aryl-nicotinamides and diarylamines. This proto-
recrystallization.
col would be a useful way for the rapid synthesis of bio-
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One-Pot Synthesis of N-Aryl-Nicotinamides and Diarylamines
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[5]
Experimental Section
General Procedure for the Synthesis of 3: tBuOK (112 mg,
1.0 mmol) was added to a solution of 4a–4m (0.4 mmol) in DMF
(2 mL), and the mixture was stirred at 120 °C for 1–12 h. After
completion of the reaction monitored by TLC, H2O (10 mL) was
added and the mixture was extracted with EtOAc (3ϫ 10 mL). The
combined organic layers were washed with brine, dried with
Na2SO4, filtered, and evaporated in vacuo. The crude product was
purified by column chromatography on silica gel to get the desired
product 3.
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One-pot Procedure on a Gram Scale for the Synthesis of 3d, 3g, and
3k: K2CO3 (3.45 g, 25 mmol) was added to a solution of 1a (1.57 g,
10 mmol) and 2 (12 mmol) in DMF (50 mL), and the mixture was
stirred at 80 °C for 12 h. tBuOK (2.8 g, 25 mmol) was added and
the mixture was stirred at 120 °C for a further 1 h. After comple-
tion of the reaction monitored by TLC, H2O (150 mL) was added
and the mixture was extracted with EtOAc (3ϫ 150 mL). The com-
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filtered, and evaporated in vacuo. The crude product was purified
by recrystallization from petroleum ether/ethyl acetate to get the
desired product 3 d, 3g or 3k.
[8]
Acknowledgments
The work was supported by National Natural Science Foundation
of China (Grant No. 21202112), Ph. D. Programs Foundation of
Ministry of Education of China (20123201120019) and PAPD (A
Project Funded by the Priority Academic Program Development
of Jiangsu Higher Education Institutions).
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Received: February 13, 2015
Published Online: April 7, 2015
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