Iridium-catalyzed annulation between 1,2-diarylethanone and 3-aminopropanol toward site-specific 2,3-diaryl pyridines

Article abstract of DOI:10.1016/j.tetlet.2017.07.061

An iridium-catalyzed annulation between 1,2-diarylethanone and 3-aminopropanol was developed, leading to site specific 2,3-diarylpyridines in moderate yields. 3-Aminopropanol served as both a four-atom component and solvent during this procedure, releasing water as a clean by-product. The reaction may proceed with sequential imine formation, alcohol oxidation and intramolecular cyclization by Knoevenagel reaction.

Full text of DOI:10.1016/j.tetlet.2017.07.061

Accepted Manuscript
Iridium-Catalyzed Annulation between 1,2-Diarylethanone and 3-Aminopro-
panol toward Site-Specific 2,3-Diaryl Pyridines
Ning Gu, Miaochang Liu, Hepan Wang, Song Sun, Zhen Zhou, Weiming Hu,
Jin-Tao Yu, Jiang Cheng
PII:
S0040-4039(17)30916-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.07.061
TETL 49143
Reference:
Tetrahedron Letters
To appear in:
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Revised Date:
Accepted Date:
13 June 2017
14 July 2017
17 July 2017
Please cite this article as: Gu, N., Liu, M., Wang, H., Sun, S., Zhou, Z., Hu, W., Yu, J-T., Cheng, J., Iridium-Catalyzed
Annulation between 1,2-Diarylethanone and 3-Aminopropanol toward Site-Specific 2,3-Diaryl Pyridines,
Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.07.061
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Iridium-Catalyzed Annulation between 1,2-
Diarylethanone and 3-Aminopropanol
toward Site-Specific 2,3-Diaryl Pyridines
Ning Gu,a Miaochang Liu,b Hepan Wang,a Song Sun,a Zhen Zhou,a Weiming Hu,a Jin-Tao Yua and
Jiang Chenga,*

1
Tetrahedron Letters
journal homepage: www.els evier.com
Iridium-Catalyzed Annulation between 1,2-Diarylethanone and 3-Aminopropanol
toward Site-Specific 2,3-Diaryl Pyridines
Ning Gu,a Miaochang Liu,b Hepan Wang,a Song Sun,a Zhen Zhou,a Weiming Hu,a Jin-Tao Yua and
Jiang Chenga,*
aSchool of Petrochemical Engineering, Jiangsu Key Laboratory of Advanced Catalytic Materials & Technology, Jiangsu Province Key Laboratory of
Fine Petrochemical Engineering, Changzhou University, Changzhou, 213164, P. R. China.
bCollege of Chemistry & Materials Engineering, Wenzhou University, Wenzhou 325000, P. R. China.
†E-mail: jiangcheng@cczu.edu.cn
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An iridium-catalyzed annulation between 1,2-diarylethanone and 3-aminopropanol was
developed, leading to site specific 2,3-diarylpyridines in moderate yields. 3-Aminopropanol
served as both a four-atom component and solvent during this procedure, releasing water as a
clean by-product. The reaction may proceed with sequential imine formation, alcohol oxidation
and intramolecular cyclization by Knoevenagel reaction.
Available online
Keywords:
.
Iridium-catalyzed
intramolecular cyclization
2,3-diarylpyridines
Knoevenagel reaction
Recently, the transformation of alcohols for the C-hetero and
C-C bonds formation have drawn much attention not only
because generally only water was released as the sole clean
byproduct,1 but also comparing with starting materials bearing C-
X and C-H groups, some diols, polyols and amino alcohols may
be derived from biomass.2 With this regard, much progress has
been made in the construction of hetero- cyclic compounds.3 For
example, Kempe,4 Milstein,5 and Saito,6 respectively reported the
annulation of amino alcohols leading to pyrroles. Meanwhile,
Beller demonstrated Ru-catalyzed three-component coupling
protocol using ketones, 1,2-diols, and amines generate pyrroles.7
Afterwards, Kempe developed a sustainable multicomponent
reaction of primary, sec-alcohols and amidines to access
pyrimidines.8 We also described sustainable procedures toward
2,3-disubstituted furans by diethylene glycol and N-(2-
hydroxyethyl)pyrroles by diethanolamine, respectively.9
structures in phosphodiesterase 10A (PDE10A)15 and served
as potent medicines.16
Table 1. Screening the optimized reaction condition.a
entry catalyst
oxidant
TBHP
additive
--
yield (%)b
54
1
[Cp*IrCl2]
2
IrBr3·H2O
IrCl3·3CH3CN
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
--
TBHP
TBHP
TBHP
DTBP
BQ
--
38
3
--
17
4
CaO
CaO
CaO
CaO
CaCl2
4Å MS
DCC
CaO
CaO
CaO
72, 46c, 33d
5
51
6
42
Substituted pyridines are among the ubiquitous scaffolds
in medical chemistry.10 Yu,11 Bharate,12 and Zhang13
respectively reported the cyclization of acetophenones with
diamines toward such frameworks. However, being a
sustainable starting material, amino alcohol was rarely
demonstrated in such a transformation. To date, only few
examples were reported to access pyridines and
quinolones.14 Herein, we wish to report an iridium-catalyzed
annulation reaction between 1,2-diarylethanone and 3-
aminopropanol, allowing site-specific access to 2,3-
diarylpyridines in moderate to good yields, along with water
as the clean byproduct. 2,3-Diarylpyridines were core
7
K2S2O8
TBHP
TBHP
TBHP
TBHP
--
33
8
57
9
64
10
11
12
13
59
<1
[Cp*IrCl2]2
[Cp*IrCl2]2
46
73e, 65f
TBHP
a Reaction conditions: 1a (0.1 mmol), 2 (0.25 mL), catalyst (5 mol%), oxidant
(4.0 equiv), additive (2.0 equiv) at 140 oC under N2 for 48 h, in a sealed
Schlenk tube, unless otherwise noted. b Isolated yield. c Under air. d Under O2.
e 150 oC . f 130 oC. DCC = dicyclohexylcarbodiimide.

2
Tetrahedron
Initially, we tested the combination of 1,2-
substituted aryl all worked well, site-specifically providing 2-
aryl-3-phenyl pyridines in moderate to good yields (40-62%, 13-
17). Notably, the heteroaryl, such as 2-furanyl- and 2-thiophenyl
were efficiently introduced to 2- position of 3-phenyl pyridine,
providing corresponding annulation products 20 and 21 in 66%
and 57% yields, respectively.
diarylethanone (1.0 equiv) in the presence of [Cp*IrCl2] (5
mol %), tert-butyl hydroperoxide (TBHP, 5.5 M in nonane,
4.0 equiv) in neat 3-aminopropanol (0.25 mL) under 140 oC
as the model reaction. To our delight, the annulated product
2,3-diphenyl pyridine
3 was isolated in 54% yield (Table 1,
entry 1). IrBr3·H2O and IrCl3·3CH3CN also worked to some
extent (38% and 17%, Table 1, entries 2 and 3). Pleasingly,
the yield dramatically increased to 72% in the presence of
2.0 equivalent of CaO as dehydrating reagent (Table 1, entry
4). Some other tested oxidant, such as di-tert-butyl peroxide
(DTBP, 51%), benzoquinone (BQ, 42%) and K2S2O8 (33%)
were all inferior to TBHP (Table 1, entries 5-7). Among the
dehydrating reagents screened, CaO was the best (Table 1,
entries 8-10). The reaction did not work in the absence of
Tabel 3 The Scope of 1-Aryl in Acetophenones. a
iridium (Table 1, entry 11); while
3 was isolated in 46%
yield without TBHP (Table 1, entry 12). Elevating reaction
temperature had no positive effect on the reaction efficiency
o
and the yield dropped to 65% under 130 C (Table 1, entry
13). A 1 mmol scale reaction provided
63% yield.
3 in a comparable
Tabel 2 The Variety of 2-Aryl in Acetophenonesa
a
Reaction conditions: 1 (0.1 mmol), 2 (0.25 mL), [Cp*IrCl2]2 (5 mol%),
TBHP (5.5 M in nonane, 4.0 equiv), CaO (2.0 equiv) at 140 oC under N2 for
48 h, in a sealed Schlenk tube, unless otherwise noted.
Scheme 1 Chelating-assited ortho- C-H functionalization of 2-aryl in
2,3-diaryl pyridine 3.
Reaction conditions: (22) 3 (0.2 mmol), K3[Fe(CN)6] (0.04 mmol), Pd(OAc)2
(5 mol %), CuBr2 (1.0 equiv), dry DMF (1 mL), 130oC, 4 h; (23) 3 (0.2
mmol), MeBF3K (0.60 mmol), AgF(0.56 mmol), [RhCp*Cl2]2 (0.008 mmol),
a
Reaction conditions: 1 (0.1 mmol), 2 (0.25 mL), [Cp*IrCl2]2 (5 mol%),
o
AgSbF6 (0.032 mmol), ClCH2CH2Cl (3.0 mL), 100 C, under nitrogen, 24 h;
TBHP (5.5 M in nonane, 4.0 equiv), CaO (2.0 equiv) at 140 oC under N2 for
48 h, in a sealed Schlenk tube, unless otherwise noted.
(24) 3 (0.2 mmol), NaCl (0.6 mmol), [Cp*RhCl2]2 (0.008 mmol), PhI(OAc)2
(0.3 mmol), CF3CO2H (0.3 mmol), acetone (2 mL), 50 oC, 12 h; (25) 3 (0.2
mmol), DCE (1 mL), Pd(OAc)2, TBHP, 115 oC , 20 h.
After the establishment of the optimized reaction
conditions, the variety of 2-aryl in acetophenones was
tested, as shown in Tabel. 2. As expected, this procedure
showed good diversity in the final product since it allowed
The further transformation of 2,3-diphenyl pyridine 3 was
studied. The pyridine ring could be oxidized by m-CPBA to 1-
oxide, which may be transformed into 3-nitro-2,3-diphenyl
pyridine in the presence of POCl3.16 Moreover, the
functionalization of 2-aryl allowed introducing a series of groups
whereby a chelating-assisted ortho- C-H bond cleavage (Scheme
1).17,18
rapidly site-specefic introduction of both para-
ortho-substituted aryl to 3-position of 2,3-diarylpyridine
(47-61%, ). Notably, α-(2-thiophenyl)acetophenone also
, meta- and
4-8
ran smoothly under the procedure, affording 2-phenyl-3-(2-
thiophenyhl)pyridine 12 in 54% yield. Meanwhile, chloro
and bromo survived well as
6 and 11 were isolated in 53%
and 46% yields, respectively. This provided facile handle for
potentially further functionalization.
Scheme 2 A tentative mechanism.
Next, the scope of 1-aryl in acetophenones was studied (Tabel.
3). Once again, all substrates bearing para-, meta- and ortho-

3
3
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9
A tentative pathway of this reaction is outlined in Scheme 2.
First, the imine intermediate A was formed by the annulation
between 1,2-diarylethanone 1 and 3-aminopropanol 2. Then, the
primary hydroxyl group was oxidized by Ir(III) to aldehyde
intermediate B.19 Meanwhile, Ir(III) was regenerated by the
oxidation of TBHP. Second, in the presence of base, the
intramolecular Knoevenagel reaction took place to access the
cyclized intermediate C, which released one equivalent of H2O
leading to intermediate D. Finally, the aromatization of D
afforded 2,3-diphenyl pyridine.
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Vicente, A.; Medarde, M.; Pelaez, R. Curr. Med. Chem. 2016, 23,
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In conclusion, we have developed an iridium-catalyzed
,
annulation
between
1,2-diarylethanone
and
3-
,
aminopropanol toward 2,3-diaryl pyridine with chemical
diversity and complexity in moderate yields. In this
procedure, the sequential imine formation, alcohol oxidation
and intramolecular cyclization by Knoevenagel reaction may
be involved.
,
,
,
6
.
2013
Acknowledgments
49, 6632; (b) Hille, T.; Irrgang, T.; Kempe, R. Angew. Chem. Int. Ed.
We thank the National Natural Science Foundation of China
(nos. 21572025, 21372177, 21672028), “Innovation &
Entrepreneurship Talents” Introduction Plan of Jiangsu
Province, the Key University Science Research Project of
Jiangsu Province (15KJA150001), and Advanced Catalysis
and Green Manufacturing Collaborative Innovation Center
for financial supports. Sun thanks the National Natural
Science Foundation of China (no. 21602019) and Young
Natural Science Foundation of Jiangsu Province
(BK20150263) for financial support.
2017
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5
1. 3-Aminopropanol served as both a four-atom subunit
and solvent in this reaction.
2. Imine formation, alcohol oxidation and cyclization
may involve in this reaction.
3. This strategy features with good yields and good
functional group compatibility.