NH4OAc-Promoted Domino Route to Hydroxyarylated Unsymmetrical Pyridines under Neat Conditions

Article abstract of DOI:10.1021/acs.joc.9b02896

A new metal-, oxidant-, and solvent-free ecofriendly domino method has been established for modular synthesis of a diverse range of medicinally promising hydroxyarylated unsymmetrical pyridines in good to high chemical yields with an excellent regioselect

Full text of DOI:10.1021/acs.joc.9b02896

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Article
NH4OAc-Promoted Domino Route to Hydroxyarylated
Unsymmetrical Pyridines Under Neat Conditions
Meher Prakash, Santosh Kumar Gudimella, Rajni Lodhi, Soumitra Guin, and Sampak Samanta
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02896 • Publication Date (Web): 25 Dec 2019
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NH OAc-Promoted Domino Route to Hydroxyarylated Unsymmetrical
4
Pyridines Under Neat Conditions
Meher Prakash, Santosh K. Gudimella, Rajni Lodhi, Soumitra Guin and Sampak Samanta*
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Discipline of Chemistry, Indian Institute of Technology Indore, Simrol, Indore-453552, Madhya
Pradesh, India.
*
Corresponding author. Tel +91-731-2438753
Email: sampaks@iiti.ac.in
O
O
O
O
S
NH OAc
4
N
C/N/O-
cycles
neat, 80 °C
C/N/O-
cycles
6-18h
Me
N
O
Neutral conditions
OH
8 Examples
H
Yields 85%
6
Broad substrate scope
Excellent functional group
tolerance
Excellent regioselectivity
Large scale synthesis
ABSTRACT: A new metal-oxidant-and solvent-free based eco-friendly domino method for the
modular synthesis of a diverse range of medicinally promising hydroxyarylated unsymmetrical
pyridines in good to high chemical yields with an excellent regioselectivity has been established.
This domino process involves a range of N-sulfonyl ketimines as C,N-binucleophiles, enolizable
ketones and aromatic/heteroaromatic aldehydes using ammonium acetate as an ideal promoter
under neat conditions which creates new two C-C and one C-N bonds. Notably, the neutral
reaction conditions are mild enough to tolerate a range of functionalities and cover a variety of
substrates, thus bestowing a powerful avenue to access tri-and tetra-substituted pyridines including
carbo-and heterocyclic-fused ones. Interestingly, a practical, scalable and high yielding synthesis
of pyridylphenol derivative was successfully accomplished by our unique method.
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KEYWORDS: N-Sulfonyl ketimines, ammonium acetate, hydroxyarylated pyridines, neat
conditions, green method.
INTRODUCTION:
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Pyridine ring systems are certainly one of the most explored heterocyclic molecules which are
profoundly present in a plethora of natural alkaloids including an essential subunit of vitamins (B6
and B3) and enzymes that regulate many therapeutic actions in our metabolic systems. 1-2 Besides,
the substituted pyridines have impressive applications in a variety of research fields such as drug
discovery program,3 pharmaceutical chemistry,4 agrochemicals,5 functional materials,6
7
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coordination chemistry, supramolecular chemistry, catalysis etc. Consequently, efficient
synthesis of pyridine skeletons with biologically prevalent functionalities is a lucrative target for
1
0
th
chemists. In this context, massive efforts have been paid by chemists since 19 century to
establish many concise synthetic routes for the facile access to a diverse set of functionalized
pyridine frameworks with unprecedentedly high molecular complexity.1-10 Traditionally, several
hallmark methods to prepare substituted pyridines via a condensation-cyclization reaction
employing amines (or ammonia) and active carbonyl compounds/alkyl aldehydes were effectively
established by Hantzsch, Chichibabin and other groups independently.11-12 Similarly, Bohlmann-
1
3
14
15
Rahtz, Bagely and Tsuda groups also synthesized functionalized pyridines from isolated or
in situ produced enamines and enones/ynones in AcOH medium. During past decades, many
elegant and powerful approaches have been also discovered for the predominant synthesis of
1
6
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pyridine building blocks which comprise [4+2] /[2+2+2] cycloaddition reactions of α,β-
unsaturated oximes/enamides/nitriles with alkynes catalyzed by different kinds of transition metal-
1
8
19
salts, 6π-electrocyclization, C-H functionalization on the pyridine rings etc. Most importantly,
the multicomponent reaction (MCR) has been greatly exercised as one of the most atom-and step-
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economical routes to functionalized pyridines.20-23 For example, Kröhnke et al. designed a three-
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component reaction of N-phenacylpyridinium salts, α,β-unsaturated ketones with NH OAc in
4
AcOH medium at 100-140°C to produce 2,4,6-trisubstituted pyridines. However, both the non-
commercial starting materials must be prepared before executing the reaction. So, this approach is
usually considered to be a relatively expensive, less atom-economical and with harsher conditions.
Alternatively, an improved solvent-free method was nicely developed via a domino MCR of
arylaldehydes, acetophenones and large excess amounts of ammonium acetate as a N-sourcing
agent using several acid-catalysts/heterogeneous LPSF-nanocatalyst under heating conditions,
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establishing a general access to tri-arylsubstituted symmetrical pyridines only. Furthermore, Cui,
Jiang and Yoshikai groups have documented novel Cu(I)-and base-catalyzed domino reaction
between oxime esters, aldehydes and active methylene compounds under heating conditions to
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serve unsymmetrical pyridine frameworks. Even though these are magnificent advancements,
the one-pot synthesis of hydroxyarylated unsymmetrical pyridines (especially fused ones) 24,25 has
not been studied in a systematic manner despite their potential applications in bioactive
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6
27
substances and light-emitting materials. The common synthetic approach to pyridylphenol
derivatives is based on the direct C-H hydroxylation at specific site (i.e. C2-position) of the phenyl
ring of 2-arylpyridines in the presence of a variety of oxidants such as TBHP, H O , K S O ,
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2
2
2
8
oxone, PIDA and NHPI catalyzed by precious transition-metal-salts (e.g. Pd(II),24a-d Rh(III)24e-f
and Ru(II)24g ) at heating conditions (Scheme 1a). However, the above C-H functionalization
technique has several serious weaknesses such as necessity of a large excess amount of powerful
oxidants or additives, high temperature, longer reaction time, poor functional group tolerance,
use of costly metal-salts, unsatisfactory yields, the use of hazardous and volatile organic solvents,
the need for tedious extraction procedures to eliminate the toxic metals from the reaction mixtures
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etc. In addition to the above complications, the described technique in general does not tolerate
substitution on the pyridine ring, leading to the less practical utility of the method. Towards our
efforts, we also recently documented organobase-promoted a number of promising domino
techniques to build functionalized pyridines including 2-pyridylphenol derivatives from cyclic
sulfamidate imines as C-nucleophiles and different kinds of 1,3-bielectrophiles including α-
arylacetylenyl-β-aryl-nitroolefins,28a MBH adducts28b and β,γ-unsaturated α-keto carbonyls28c
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(
Scheme 1b-c). However, they always need high loading of base and prefunctionalization of both
the starting materials which interferes with the further growth of synthetic process.
Therefore, we are highly focused on the development a new, eco-friendly, convenient, acid-base-
oxidant-solvent-and metal-free based reliable one-pot synthetic strategy for preparing
unsymmetrical substituted pyridines and fused ones with one or more hydroxyaryl moieties from
Scheme 1. One-Pot Approach to the Synthesis of Hydroxylated Arylpyridine Frameworks
Rh(II)/Ru(II)/Pd(II)
OH
Other reports:
oxidant/additive
high temperature
N
R
N
(
a)
N
X
C-H hydroxylation
X
Our previous work:
O
O
R1
S
One-pot Two-step
(i) DABCO (20 mol%)
60 °C, toluene
O
N
OH
OH
OBoc
R1
(b)
Me
+
X
X
R
+
(ii) DBU (1.2 equiv)
60 °C, toluene
Our previous work:
R1
O
O
R2
S
O
N
NO2
DABCO
R2
Me
2-MeTHF
N
(c)
X
R1
X
MW, 60 C, 150 psi
O
Present work:
R1
O
O
acid-base-oxidant-solvent-free
NH OAc
S
O
N
4
O
O
promoter
X
Me
R1
N
R
(d)
R
H
neat, 80 °C
OH
Metal-free
X
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easily accessible starting substances under neutral conditions, which is still a thought-provoking
exercise for organic chemists. Enthused by these precedents as well as a part of our research
program related to the development of new synthetic routes for the synthesis of unsymmetrical
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substituted pyridines, herein, we further demonstrate a solvent-free three-component chemical
transformation that delivers different kinds of pyridyl-substituted phenols by taking N-sulfonyl
ketimines, enolizable ketones and aldehydes promoted by ammonium acetate under neutral
conditions (Scheme 1d).
RESULTS AND DISCUSSION: Our initial attempt was to synthesize 2-(4,6-diphenylpyrdin-2-
yl)phenol (4aaa) by taking an equimolecular mixture of 2-hydroxyacetophenone (2t),
acetophenone (2a) and benzaldehyde (3a) with ammonium acetate at 80 °C in toluene or a neat
condition for 12h as shown in Scheme 2. Surprisingly, instead of targeted pyridine 4aaa, a
trisubstituted symmetrical pyridine (4aa) was isolated in 41% yield. The above result clearly
showed that a less nucleophilic 2-hydroxyacetophenone (2t) did not participate in this [2+2+1+1]
Scheme 2. Multicomponent Reaction for the Construction of Substituted Pyridines
Ph
NH OAc (1.0 equiv)
4
N
Ph
Ph
OH
O
O
O
80 C, 12h
neat or toluene
4
aaa
OH
(
not observed)
Me Ph
Me
Ph
H
targeted
Ph
N
Ph+
+
Ph
2t
2a
3a
4aa
4
1%
isolated
OH
OH
N
4ata
(not observed)
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cyclization process at all and recovered it fully. Therefore, we envisaged that a more reactive N-
sulfonyl ketimine 1a as a powerful C/N-binucleophile in the place of its unmasked form (2t, less
reactive) may react with aldehyde 3a faster than acetophenone in the presence of ammonium
acetate which inhibits the formation of unwanted 4aa. To verify our proposed idea, we performed
this reaction by employing the suitable reactants N-sulfonyl ketimine 1a, 2a and 3a using
ammonium acetate in toluene at 80 °C. To our delight, after 12h, the cyclization reaction gave an
astonishing result that provided good yield (71%) of expected phenolic-substituted pyridine 4aaa
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(entry 1, Table 1). This interesting outcome inspired us to examine this three-component reaction
in detail. In this connection, other organic solvents like 2-MeTHF, EtOH, PEG-400 and DMF were
screened and led to the desired pyridine 4aaa in mediocre to good yields (41-73%, entries 2-5).
Pleasantly, when the reaction was carried out in a neat condition, a high yield (81%) of 4aaa was
observed after 10h. However, marginally dropped yields were observed when the reaction was
conducted either at lower (70 °C) or higher temperature (90 °C, slight decomposition of 1a) than
8
0 °C. In order to find out the best promoter for this transformation, a range of commercially
accessible ammonium salts [NH CO H, NH HCO , (NH ) CO , NH Cl and (NH ) SO ] and
4
2
4
3
4 2
3
4
4 2
4
amino-acids (glycine and L-proline) were tested under solvent-free conditions at 80 °C. Results
indicated that ammonium format was found to be an equipotent with ammonium acetate, giving a
comparable yield 79% (entry 10). However, other ammonium salts including amino-acids were
not capable of promoting this reaction effectively, providing inferior yields (5-36%, entries 11-
16). It should be noted that 2.0 equiv of ammonium acetate provided 82% yield of 4aaa (entry 9).
Furthermore, under microwave heating at 80 ˚C, the reaction furnished a mediocre yield (57%) of
4
aaa along with undesired pyridine derivative 4aa in 15% yield (entry 18).
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Table 1. Optimization of Reaction Conditionsa,b
Ph
N
O
O
O
N
S
O
OH
O
Ammonium salt
Me Ph
Me
Ph
Ph
H
Conditions
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4
aaa
1a
2a
3a
Temp (°C) Time (h) Yield (%)b
Entry
1d
2d
3d
4d
5d
6
Solvent
toluene
salt
NH OAc
80
80
80
80
80
80
90
70
80
80
80
80
80
80
12
12
12
12
12
10
10
10
10
12
12
12
12
12
12
12
12
71
68
51
41
73
81
75
70
82
79
36
35
<5
<5
31
<5
48
4
2-MeTHF
EtOH
PEG-400
DMF
neat
NH OAc
4
NH OAc
4
NH OAc
4
NH OAc
4
NH OAc
4
7
neat
NH OAc
4
8
neat
NH OAc
4
9e
neat
NH OAc
4
1
1
0
1
neat
HCO NH
2
4
3
neat
NH HCO
4
12
neat
(NH ) CO
4 2 3
1
1
1
1
3
4
5
6
neat
NH Cl
4
neat
(NH ) SO
4 2 4
neat
NH CH CO H 80
2 2 2
neat
L-Proline
80
80
17c
neat
NH OAc
4
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2
2
2
2
2
2
2
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3
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3
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4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
8f,g
neat
NH OAc
MW
1h
57
4
aReaction conditions: 1a (0.15 mmol), 2a (0.18 mmol), benzaldehyde 3a (0.18 mmol) and
b
c
0
1
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ammonium salt (0.15 mmol) in a neat condition at 90 °C. Isolated yield. 50 mol% NH4OAc was
d
e
f
used. 1.0 mL dry solvent was used. 2.0 equivalent of NH OAc was used. Microwave (MW)
4
g
heating at 80 °C. 15% yield of compound 4aa was isolated.
To gain deeper insight of the mechanism, several control experiments were conducted as shown
in Scheme 3. First, a mixture of compound 1a, 2a and 3a was heated at 80 °C for 12h without
using ammonium acetate. Reaction did not occur which suggested that ammonium acetate was
inevitable for this conversion (Scheme 3a). Next, N-sulfonyl ketimine 1a has been shown as a
potential C-nucleophile in the condensation reaction with a benzaldehyde (3a) promoted by
ammonium acetate to form condensation product 5 in 90% yield (Scheme 3b). Furthermore,
acetophenone (2a) efficiently reacted with ketimine 5 under standard conditions, leading to the
desired pyridine 4aaa in 86% yield (Scheme 3c). However, in the absence of ammonium acetate,
pyridine 4aaa was not observed (Scheme 3d). These results indicated that ammonium acetate may
involve in the condensation reaction with acetophenone (2a) to form a more nucleophilic species
enamine (increasing HOMO energy) which facilitates the cyclization process. Alternatively, the
chalcone (6) could react with 1a in the established conditions, capable of forming 4aaa in 30%
yield only. Therefore, the originating of 4aaa from the combination of chalcone (6) and 1a is very
unlikely. Furthermore, under present conditions, the condensation of benzaldehyde (3a) with
acetophenone (2a, 2.0 equiv) provided only 2,4,6-triphenylpyridine (4aa) in 77% yield in Scheme
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f. Thus, the conjugate addition of 2a to unsaturated imine 5 is a preferential route for making
product 4aaa in Scheme 3c.
Scheme 3. Control Experiments
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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0
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5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Ph
O
O
O
N
OH
S
O
O
neat, 80 C
(a)
N
Ph
+
Me
+
Ph
H
X
Ph
Me
12h
4aaa
Not observed
1a
2a
3a
O
O
N
O
O
O
N
S
S
O
NH OAc
neat, 80 C
12h
4
O
(b)
(c)
Ph
90% yield
Ph
Me
+
+
Ph
H
1a
3a
5
O
O
O
N
S
S
OH
NH OAc
4
O
neat, 80 C
N
Ph
Ph
Ph
Ph
Me
4aaa
2a
10h
86% yield
5
Ph
O
O
O
N
OH
O
(d)
neat, 80 C
N
Ph
+
+
+
Ph
Me
X
12h
5
2a
No conversion
O
O
N
Ph
S
O
NH4OAc
neat, 80 C
12h
O
OH
(e)
Ph
Ph
Ph
N
Ph
1a
6
4aaa
0% yield
Ph
3
O
O
NH OAc
4
neat, 80 C
(f)
Me
a (2.0 equiv)
Ph
H
Ph
N
Ph
4aa: 77%
2
3
a
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Scheme 4. Plausible Mechanism
O
O
O
O
O
O
N
S
S
NH
O
O
O
N
Me
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1a
OAc
S
1a
NH OAc
3
H
H
O
N
imine-enamine
tautomerism
NH OAc
4
Ph
Ph
H
Ph
H
-
H O
3a
2
7
3a
C-C bond formation
NH OAc
O
O
O
N
O
O
2
H-OAc
NH
2 NH OAc
O
S
S
4
O
NH
Ph
Ph
elimination
NH OAc
Ph
Ph
Me
2a
2a
Ph
-
4
Michael addition
C-C bond
formation
5
8
NH OAc
Ph
N
O
O
N
3
Ph
Ph
O
O
O
N
S
S
O
OH
C-N bond
creation
aromatization
elimination
NH OAc
Ph
-SO2
Ph
-
Ph
4
9
4aaa
1
0
Based on the above experimental results, we proposed a plausible reaction mechanism as depicted
in Scheme 4. At the beginning, ammonium acetate may react with a benzaldehyde to form a very
reactive iminium ion 3aʹ (lowering LUMO activation energy). The latter involves in C-C bond
formation reaction with enamine intermediate 1aʹ to generate an adduct 7 which is subsequently
liberated ammonium acetate, resulting in unsaturated imine 5. Afterwards, the conjugate addition
of enamine 2aʹ [in situ generated from the combination of 2a and ammonium salt] to aza-diene 5
leads to the intermediate 8 which in turn converts into cyclic intermediate 9 via an intramolecular
C-N bond making process. Finally, it eliminates ammonium acetate to form sulfamate-fused-
dihydropyridine 10 which undergoes aromatization by releasing SO in the present conditions that
2
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would eventually lead to the 4aaa. However, the detailed mechanism for the conversion from 10
to 4aaa is not clear to us.
With the established reaction conditions in hand, we examined the generality and scope of this
three-component reaction by altering a group of 4-methyl N-sulfonyl ketimines as 2C1N (two
carbon one nitrogen source) units for pyridine synthesis, C-H activated acyclic ketones (2C
synthons) and aromatic/heteroaromatic aldehydes (1C sources) using ammonium acetate as a
promoter under solvent-free conditions. The obtained results are summarized in Table 2. It was
found that not only a benzaldehyde but also a wide range of aromatic aldehydes bearing electron
donating ( MeO) and electron withdrawing (F, Cl, Br, CN, NO and CF ) functionalities underwent
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
3
C-C and C-N bonds forming reaction with N-sulfonyl ketimine 1a and 2a to produce uniformly
good to high yields (76-83%) of the corresponding trisubstituted unsymmetrical pyridines (4aad-
4
aak). Next we turned our attention to apply aldehydes bearing a heteroaryl moiety such as
pyridine, furan or thiophene in this cyclization process. All the heterocycles easily coupled with
1a and 2a by this method, leading to the 4-heteroaryl-substituted pyridine scaffolds 4aak, 4aam
and 4aan in 75%, 77% and 79% yields respectively. Moreover, incorporation of electron poor
substituents such as F, Br, and NO on the aryl rings of acetophenones afforded relatively lesser
2
yields of the products (4aeb-4afb; 70-75%) as compared to electron donating ones (4abm-4acf;
7
6-82%). Furthermore, heteroaryl methyl ketone (2h) also afforded desired pyridine derivative
(4ahm-4ahc) in 75-82% yields; Interestingly, by using an unsymmetrical ketone (ethyl methyl
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Table 2. MCR Approach to Hydroxylarylated Tri-and Tetra-Substituted Pyridines (4aad-
4
faa)a,b,c
R2
N
O
O
O
N
R1
S
OH
O
O
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
NH OAc (1.0 equiv)
4
R1
R
Me
R
R2
H
neat, 80 °C
2
3
4aad-4faa
2
b:R=4-MeC H4
X
6
2
2
3
b:R =4-MeC H ;3j:R = 4-NCC H
6
4
6
4
X
2
c:R=4-MeOC H4
6
R1 = H
2
2
1
1
1
1
1
1
a: X = H
3c: R = 4-MeOC H ; 3k: R =4-CF C H
6 4 3 6
4
b: X= Me
6
2d:R =4-FC H4
2
2
3
d:R = 2,5-(MeO) C H ;3l:R = 4-pyridyl
2 6 3
c: X = MeO 2e:R=3-FC H4
d: X = Cl 2f:R=
6
2
2
3
e:R = 3-BrC H ; 3m:R = 2-furyl
6
4
4
-BrC H4
2
2
6
3f:R = 4-ClC H ; 3n:R = 2-thiophenyl
e: X = Br
f:naphthyl
6
4
2g:R=4-NO C H
2 6 4
2
3g:R = 4-FC6H4;
2h:R =2-thiophenyl
2
core
3h:R = 2-FC H
1
6
4
2i:R = Me,R = cyclopropyl
2j:R=Me,R =Et;2k:R=Me,R =Ph
2
3
i:R = 4-NO C H
1
1
2 6 4
N
X
N
X
4aad:X=2,5-(MeO) ; 76%
4aae:X = 3-Br; 80%
X
2
X
4
4
aaf:X= 4-Cl;81%
aah:X = 2-F; 77%
OH
OH
OH
OH
N
OH
N
Ph4aai:X = 4-NO2;83%
4aaj:X= 4-CN; 80%
N
Ph
N
Ph
Me
4
aal: 75%
4aam: X = O; 77%4abm:X = O; 78%
4aan: X = S. 79% 4abn:X = S; 82%
4
aak:X = 4-CF ; 81%
3
Me
F
Me
OMe
4acc: X=MeO,76%
4acf: X =Cl, 79%
S
X
OH
OH
OH
OH
OH
S
N
N
N
N
4aeg: 75%
N
X
4
aeb: 73%
4afn:X = Br; 74%
4ahm:X = O; 80%
4
afb:75%
Br
4agn:X = NO ; 70%
4ahn:X =S; 82%
2
F
F
OMe
OMe
OMe
S
O
OH
Me
Me
OH
OH
OH
OH
S
N
N
N
N
Ph
N
4ajc:
Me
76%
4
akc:71%
aim: 55%c
4ain:59%c
4
4
ahc:75%
Cl
OMe
Ph
N
Ph
Ph
Me
R
OH
OH
OH
OH
Me
OH
Ph
N
Ph
N
N
N
Ph
4
bfc:67%
4bka:R = Me;72%
4baa: R =H; 83%
Cl
4caa: 84%
4cka:74%
4
bbf:80%
Br
Me
OMe
OH
OMe
Me
Me
OMe
Ph
N
Ph
Ph
Me
Me
OH
OH
OH
OH
Cl
N
Ph
N
Ph
N
N
4
cja:78%
4faa: 75%
4
daa:X = Cl; 70%
X 4eaa;X = Br; 72%
4ddc:65%
F
4dcf:68%
OMe
OMe
Cl
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aReaction conditions: 1a-f (0.15 mmol), ketone (2a-k, 0.18 mmol), aldehyde (3a-n, 0.18 mmol)
b
c
and NH OAc (0.15 mmol) at 80 °C in a neat condition for 10-18h. Isolated yield. ketones 2i
4
and 2j were used 0.3 mmol (2.0 equiv.).
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
ketone, 2j), a regioselective C-C bond formation occurred quantitively at the CH position to
2
produce only one regioisomer 4ajc in 76% yield. Pleasantly, propiophenone (2k) also actively
participated in this cyclization process, leading to the tetrasubstituted pyridine 4akc in a
satisfactory chemical yield (71%). It should be mentioned that using cyclopropyl methyl ketone
(2i) as a 2C reaction partner, C-C bond formation was happened at the methyl site to afford the
corresponding 4aim and 4ain in moderate yields (55-59%). Expectedly, the presence of halide
atoms (Cl, Br) at the aryl-rings of N-sulfonyl ketimines (1d and 1e) diminished their
nucleophilicities which resulted in 5-10% lower yields as compared to donating ones (65-75% vs
6
7-84%). Moreover, they needed additional times (14-16h) to complete the cyclization process.
Gratifyingly, N-sulfonyl ketimine 1f with a naphthyl group was witnessed to be an appropriate
nucleophile for this cyclization reaction to afford 75% yield of 4faa with an interesting class of α-
naphthol moiety. Importantly, the neutral reaction conditions are mild in nature which protect
successfully several chemically sensitive functionalities including Me, MeO, Br, Cl, F, NO , CN,
2
CF , OH, furan, thiophene, phenol and cyclopropane ring.
3
Next, the application of our designed protocol was further expanded towards the construction of
an important class of carbo-and heterocyclic fused pyridine building blocks involving different
kinds of cyclic C-H activated carbonyls as donors (Table 3). For instance, when 5-, 6-and 7-
membered alicyclic ketones (2l, 2m and 2n) were employed as 2C units for pyridine access, all
the annulation reactions proceeded efficiently with 1a and 1C sources such as 3f and 3h in a
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Table 3: Pot-Economy Approach to Carbo-and Heterocyclic Fused Pyridine Scaffolds (4alf-
4
eoa)a, b,c
R
O
O
O
N
S
O
O
OH
X
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
NH OAc (1.0 equiv)
4
Me
a-e
R
H
N
neat, 80 C
4alf-4eoa
1
2l-s
3
X
Cl
Cl
N
F
Ph
N
OH
OH
OH
OH
N
N
4
alf: 83%c
4amf: 85%
4anh: 78%
4aoa:
79%
NO2
Me
Me
S
H
F
Me
H
Me
OH
OH
OH
Me
H
H
N
N
N
CO2Et
N
4
apn: 81%
H
4ari: 79%
4
aqh: 74%
OMe
S
Ph
Ph
N
OH
OH
O
OH
OH
OH
O
N
N
N
4bla: 82%c
4cna: 79%
4asn: 84%
4
asc: 77%
Ph
Ph
Ph
Me
OH
OMe
Ph
OH
OH
N
N
N
CO Et
N
2
N
4dna:73%
4dra: 70%
4coa: 80%
4cpa: 79%
Cl
Cl
OMe
OH
OMe
OH
Ph
Ph
Ph
O
OH
N
N
N
4dsa: 69%
4
ela: 74%c
4eoa: 72%
Cl
Br
Br
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a
Reaction conditions: 1a-e (0.15 mmol), 2l-s (0.18 mmol), aldehyde 3(0.18 mmol) and NH OAc
4
b
c
(0.15 mmol) at 80 °C in a solvent-free condition for 8-12h. Isolated yield. 1.5 equiv. of 2l was
used.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
spotless manner. Consequently, they delivered the corresponding 5-, 6-and 7-membered
carbocyclic rings-fused-pyridine frameworks 4alf, 4amf and 4anh in 83%, 85% and 78% yields
respectively. Furthermore, by taking α-tetralone (2o) and 1-indanone (2p) as reactants, the targeted
tricyclic-fused-pyridines 4aoa and 4apn were successfully isolated in 79% and 81% yields
respectively, while reacting with 1a and aldehydes (3a and 3n). In order to synthesize a
pharmacologically as well as synthetically interesting pyridine fused steroid scaffold, a steroidal
ketone 2q derived from a cholesterol has been used in the domino reaction with 1a and 2-
fluorobenzaldehyde (3h). We were pleased to find that the above combination gave steroidal-A-
ring fused pyridine (4aqh, enantiomerically pure pyridine) as a single regio-and stereoisomer in
7
4% yield after 12h. Notably, we did not detect other possible regioisomeric product.
Furthermore, six-membered heterocyclic ketones namely N-protected piperidin-4-one (2r) and
tetrahydro-4H-pyran-4-one (2s) were subjected to cyclize with a number of aldehydes and
ketimine 1a to give 77-84% yields of 6-membered heterocyclic fused pyridines (4ari-4asn) which
are usually difficult to synthesize by reported methods. Moreover, this modular approach was not
limited only for N-sulfonyl imine 1a as a 2C1N unit, but it could also be tolerant to several aryl-
substituted N-sulfonyl ketimines (1b-1e) with Me, MeO, Cl or Br substituents on the aryl rings
and delivered a wide array of carbo-and heterocyclic fused pyridines (4bla-4eoa) in 69-82%
yields.
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Scheme 5. Synthesis of Di-and Tri-hydroxyarylated Pyridines (4ata-4etp)a,b,c
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
R
O
O
O
N
S
OH
O
X
O
NH OAc (1.0 equiv)
N
4
+
Me
Me
R
H
neat, 80 C
OH HO
3
o: R= 2-HOC H
4ata-4etp
6
4
1
2t
X
3p: R = 4-HOC H
6
4
OH
OH
Ph
N
OH
Br
N
N
N
OH HO
4ata: 73%
OH HO
ato: 76%
OH HO
OH HO
4etp: 70%
4
4atp: 78%
IC50 = >50 M (HCT15)
c
IC = 0.14 M (HEK 293)
c
50
c
=
=
2.18 M (HCT15)
2.51M (T47D)
= 5.04 M (Du 145)
c
=
18.3 M (T47D)
c
c
a
Reaction conditions: 1a (0.15 mmol), 2t (0.18 mmol), aldehyde 3(0.18 mmol) and NH OAc (0.15
4
b
c
30a.
mmol) at 80 °C in neat conditions for 9-12h. Isolated yield. Reported data, see reference
After efficiently synthesizing pyridine scaffolds bearing a one phenolic moiety, we are now greatly
interested to construct two or more hydroxylated 2,4,6-triarylpyridine derivatives. Because these
novel building blocks displayed highly potent selective topoisomerase II inhibitors and
3
0
cytotoxicity against human cancer cell lines (HEK 293, HCT15, T47D and DU 145). However,
the reported chemical method has a number of shortcoming such as the use of strong base, acidic
solvent, excess amounts of N-sourcing agent, two step methods, lower yields, less atom-
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economical, higher temperature etc which obstacle the efficacy of the method. Therefore, an
alternative one-pot metal-and oxidant-solvent-free based benign method is demanded for their
efficient access. Towards this aim, a chemically challenging 2-hydroxyacetophenone (2t) has been
selected as 2C unit for pyridine synthesis. Surprisingly, it nicely made C-C and C-N bonds with
N-sulfonyl ketimines 1a-1e and several aldehydes (3a, 3o and 3p) in neutral reaction conditions,
affording the corresponding biologically active di or trihydoxylated-2,4,6-pyridines (4ata-4etp) in
good 70-78% yields (Scheme 5).
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
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2
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8
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2
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0
1
2
3
4
5
6
7
8
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1
2
3
4
5
6
7
8
9
0
Scheme 6: Synthesis of 6-Hydroxyayl-2,3,4-Trisubstituted Pyridines from 1,3-Dicarbonyls
a,b
R1
N
O
O
O
O
N
S
O
O
NH OAc (1.0 equiv)
4
X
Me +
+
R1
H
neat, 80 C
O
OH
3
4
1
2u-w
X
X
R1
N
O
F
Me
O
OEt
Ph OEt
O
OH
O
Me
Me
N
Me
N
Me
N
Me
OH
awc: R =4-MeOC H ; 79%
OH
auh: 81%
OH
X = 3-Br; 74%
avf: X = 4-Cl; 77%
4cva: 70%
OMe
4
4
4ave:
4
6 4
4awn: R = 2-thiophenyl; 84%
a
Reaction conditions: 1a-c (0.15 mmol), 2u-w (0.18 mmol), aldehyde 3(0.18 mmol) and NH OAc
4
b
(
0.15 mmol) at 80 °C in neat conditions for 12h. Isolated yield.
Furthermore, switching mono ketones by more reactive diketone compounds such as acetyl
acetone (2u), ethyl acetoacetate (2v) and dimedone (2w), the domino reaction took place
exclusively at the C-3 position of 1,3-dicarbonyls due to the presence of an activated methylene
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4
4
4
4
4
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5
5
5
5
5
5
5
6
group. Consequently, the corresponding tetra-substituted pyridines (4auh-4awn, nicotinic acid
derivatives) possessing a special class of carbonyl group at C-3 position were obtained in 70-84%
yields with great regioselectivities (Scheme 6).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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7
8
9
0
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2
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7
8
9
0
Next, we deliberated to employ 4-ethyl N-sulfonyl ketimine as a poor enamine donor in this aza-
cyclization reaction with acetophenone (2a) and benzaldehyde (3a) under standard conditions
(method A, Scheme 7). Surprisingly, the substrate 1g could not participate in the cyclization
process due to its poor nucleophilicity in neutral conditions. Therefore, we contemplated that base
may necessitate for abstracting a proton from 1g which triggers the condensation reaction with
aldehyde that may produce desired scaffold. To our delight, by using method B, a moderate yield
(
47%) of 4gaa was isolated. However, without NH OAc, only triethyl amine did not afford the
4
desired product (method C). Similarly, the desired product 4gaf was obtained in 44% yield while
using aldehyde 3f and ketone 2a.
Scheme 7. MCR Approach to Tetra-Substituted Pyridine Scaffolds
method A: NH OAc, neat, 80 C
4
R1
method B:NH OAc, Et N (1.0 equiv)
O
O
O
N
4
3
Me
neat, 80 C, 10h
S
O
O
method C: Et N (50 mol%), neat, 80 °C
3
N
Ph
Ph
Me
R1
+
+
H
Me
OH
4gaa-4gaf
gaa: R = Ph; 47%(method B)
1g
2a
3
1
4
1
4gaf: R = 4-ClC H ; 44%(method B)
6
4
method A = no desired product
method C = no desired product
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CONCLUSIONS
In the current manuscript, we have established a unique modular synthetic strategy for the de novo
synthesis of a diverse set of a biologically relevant tri-and tetra-substituted unsymmetrical
pyridines including ring annulated building blocks bearing an interesting class of phenol, α-
naphthol, acetyl and ester moieties at the C-6 and C-3 positions. Notably, many of our synthesized
pyridines (especially fused ones) are otherwise tedious to prepare or not capable of being prepared
by traditional techniques. This eco-friendly technique is simple that proceeds under acid-base-
solvent-and metal-free conditions via a condensation-addition-cyclization-aromatization (two C-
C and one C-N bonds) sequence reaction between a group of N-sulfonyl ketimines, a wide range
of acyclic and cyclic ketones/1,3-dicarbonyls and aromatic/heteroaromatic aldehydes using
ammonium acetate as a cheap, non-toxic and biodegradable promoter. In addition, our logical
design method has significant merits such as good to high yields, a broad substrate scope, excellent
functional group tolerance, great regioselectivity, neutral reaction conditions, operational
simplicity, no need for organic solvents as well as toxic transition metal-salts, no stochiometric
oxidants etc. Thus, we believe that this modular approach will find potential applications in
heterocyclic chemistry, medicinal chemistry and material sciences. Moreover, additional works
towards the biological study of prepared scaffolds are in progress. The fruitful results will be
documented in due course of time.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
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8
9
0
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8
9
0
1
2
3
4
5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
EXPERIMENTAL SECTION
3
1
General Information: All the N-sulfonyl ketimines (1a-1g), ketones (2a-2w) and aldehydes
(3a-3n) were synthesized by literature known procedures or purchased from commercial sources.
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All the reactions were carried out either under inert atmosphere or air and monitored by TLC using
Merck 60 F254 pre coated silica gel plates and the products were visualized by UV detection. Flash
1
13
chromatography was carried out using silica gel (200-300 mesh). H and C NMR spectra were
0
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4
5
6
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8
9
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9
0
1
recorded on a 400 MHz spectrometer. Data for H NMR are reported as a chemical shift (δ ppm),
multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constant J
1
3
(
Hz), integration, and assignment, data for C are reported as a chemical shift. High resolutions
mass spectral analyses (HRMS) were carried out using ESI-TOF-MS. Melting points were
recorded on an Electro thermal melting points apparatus and are uncorrected.
General Procedure for the Synthesis of Pyridines: A mixture of N-sulfonyl ketimine 1 (0.15
mmol), ketone 2 (0.18 mmol), aldehyde 3 (0.18 mmol) and ammonium acetate (0.15 mmol) was
heated in oil bath at 80 °C. The progress of the reaction was judged by TLC. After completion of
the reaction, the crude product was directly purified by silica-gel column chromatography using
ethyl acetate/hexane as eluent to yield the corresponding substituted pyridine derivative in a pure
1
form. All the obtained products in Tables 2-3 and Schemes 4-7 were characterized by H NMR,
13C NMR and HRMS data.
2
-(4,6-Diphenylpyridin-2-yl)phenol (4aaa):25a Following the general procedure, the reaction of
N-sulfonyl ketimine 1a (29.6 mg, 0.15 mmol), acetophenone (2a; 21.6 mg, 0.18 mmol),
benzaldehyde (3a; 18.9 mg, 0.18 mmol) and ammonium acetate (11.55 mg, 0.15 mmol) gave 4aaa
o
as a pale yellow solid; yield 81% (39.3 mg); mp 156 - 158 C; R = 0.8 (ethyl acetate/hexane =
f
1
1:20); H NMR (400 MHz, CDCl ) δ 14.82 (s, 1H), 8.06 (s, 1H), 8.01 (d, J = 7.2 Hz, 2H), 7.95 (d,
3
J = 7.4 Hz, 1H), 7.85 (s, 1H), 7.75 (d, J = 7.0 Hz, 2H), 7.61-7.46 (m, 6H), 7.39-7.31 (m, 1H), 7.08
1
3
1
(
d, J = 8.1 Hz, 1H), 6.96 (t, J = 7.5 Hz, 1H) ppm; C{ H} NMR (100 MHz, CDCl ) δ 160.1,
3
1
58.1, 155.2, 151.2, 138.5, 138.3, 131.6, 129.6, 129.4, 129.2, 129.1, 127.6, 127.4, 127.1, 126.4,
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18.9, 118.6, 117.2, 115.8 ppm; HRMS (ESI-TOF): m/z [M + H] calcd for C H NO 324.1383,
23 18
found 324.1411.
Large Scale Preparation of Compound 4aaa: Following the procedure, the reaction of N-
sulfonyl ketimine 1a (1.97 g, 10 mmol), acetophenone (2a; 1.44 g, 12 mmol), benzaldehyde (3a;
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
.272 g, 12 mmol) and ammonium acetate (0.77 gm,10.0 mmol) at 80 °C for 12h afforded 4aaa;
After usual work-up and purification, the product yielded in 78% (2.52 g).
-(4-(2,5-Dimethoxyphenyl)-6-phenyl)pyridin-2-yl)phenol (4aad): Following the general
2
procedure, the reaction of N-sulfonyl ketimine 1a (29.6 mg, 0.15 mmol), acetophenone (2a; 21.6
mg, 0.18 mmol), aldehyde 3d (29.9 mg, 0.18 mmol) and ammonium acetate (11.55 mg, 0.15
o
mmol) gave 4aad as a pale yellow solid; yield 76% (43.7 mg); mp 164 - 167 C; R = 0.60 (ethyl
f
1
acetate/hexane = 1:15); H NMR (400 MHz, CDCl ) δ 14.87 (s, 1H), 8.04 (s, 1H), 7.99 (d, J = 7.3
3
Hz, 2H), 7.89 (d, J = 7.6 Hz, 1H), 7.82 (s, 1H), 7.54-7.45 (m, 3H), 7.34 (t, J = 7.2 Hz, 1H), 7.07
1
3
1
(d, J = 8.1 Hz, 1H), 7.01-6.98 (m, 3H), 6.95-6.91 (m, 1H), 3.85 (s, 3H), 3.82 (s, 3H) ppm; C{ H}
NMR (100 MHz, CDCl ) δ 160.1, 157.4, 154.5, 153.9, 150.8, 148.9, 138.3, 131.4, 129.4, 129.0,
3
1
28.8, 127.0, 126.4, 119.8, 119.2, 118.5, 118.4, 118.3, 116.3, 114.9, 112.9, 56.4, 55.9 ppm; HRMS
+
(
ESI-TOF): m/z [M + H] calcd for C H NO 384.1594, found 384.1598.
25 22
3
2
-(4-(3-Bromophenyl)-6-phenyl)pyridin-2-yl)phenol (4aae): Following the general procedure,
the reaction of N-sulfonyl ketimine 1a (29.6 mg, 0.15 mmol), acetophenone (2a; 21.6 mg, 0.18
mmol), aldehyde 3e (33.3 mg, 0.18 mmol) and ammonium acetate (11.55 mg, 0.15 mmol) gave
o
4aae as a pale yellow solid; yield 80% (48.2 mg); mp 136 - 138 C; R = 0.82 (ethyl acetate/hexane
f
1
=
1:20); H NMR (400 MHz, CDCl ) δ 14.68 (s, 1H), 7.99 (d, J = 6.0 Hz, 3H), 7.93 (d, J = 7.8
3
Hz, 1H), 7.87 (s, 1H), 7.77 (s, 1H), 7.64 (t, J = 8.1 Hz, 2H), 7.59-7.46 (m, 3H), 7.41 (t, J = 7.8 Hz,
1
3
1
1H), 7.36 (t, J = 7.6 Hz, 1H), 7.07 (d, J = 8.1 Hz, 1H), 6.96 (t, J = 7.4 Hz, 1H) ppm; C{ H} NMR
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2
2
2
2
2
2
2
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3
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3
3
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4
4
4
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(
100 MHz, CDCl ) δ 160.1, 158.3, 155.6, 149.7, 140.6, 137.9, 132.3, 131.8, 130.7, 130.3, 129.8,
3
1
29.1, 127.0, 126.4, 125.9, 123.4, 118.9, 118.9, 118.6, 117.0, 115.6 ppm; HRMS (ESI-TOF): m/z
+
79
+
[M + H] calcd for C H NO Br 402.0488, found 402.0486; HRMS (ESI-TOF): m/z [M + H]
2
3
17
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
81
calcd for C H NO Br 404.0469, found 404.0460.
2
3
17
2
-(4-(4-Chlorophenyl)-6-phenyl)pyridin-2-yl)phenol (4aaf): Following the general procedure,
the reaction of N-sulfonyl ketimine 1a (29.6 mg, 0.15 mmol), acetophenone (2a; 21.6 mg, 0.18
mmol), aldehyde 3f (25.3 mg, 0.18 mmol) and ammonium acetate (11.55 mg, 0.15 mmol) gave
o
4
aaf as a pale yellow solid; yield 81% (43.4 mg); mp 152 - 155 C; R = 0.82 (ethyl acetate/hexane
f
1
=
1:20); H NMR (400 MHz, CDCl ) δ 14.70 (s, 1H), 7.99 (d, J = 8.1 Hz, 3H), 7.93 (d, J = 7.8
3
Hz, 1H), 7.79 (s, 1H), 7.68 (d, J = 8.3 Hz, 2H), 7.60-7.46 (m, 5H), 7.36 (t, J = 7.5 Hz, 1H), 7.07
13
1
(d, J = 8.2 Hz, 1H), 6.96 (t, J = 7.4 Hz, 1H) ppm; C{ H} NMR (100 MHz, CDCl ) δ 160.1,
3
1
58.3, 155.5(2C), 150.0, 137.9, 136.9, 135.7, 131.8, 129.8, 129.5, 129.1, 128.5, 127.0, 126.4,
+
118.9, 118.6, 116.9, 115.5 ppm; HRMS (ESI-TOF): m/z [M + H] calcd for C H NOCl 358.0993,
2
3
17
found 358.0989.
-(4-(2-Fluorophenyl)-6-phenyl)pyridin-2-yl)phenol (4aah): Following the general procedure,
2
the reaction of N-sulfonyl ketimine 1a (29.6 mg, 0.15 mmol), acetophenone (2a; 21.6 mg, 0.18
mmol), aldehyde 3h (22.34 mg, 0.18 mmol) and ammonium acetate (11.55 mg, 0.15 mmol) gave
o
4
aah as a pale yellow solid; yield 77% (39.4 mg); mp 100 - 102 C; R = 0.81 (ethyl
f
1
acetate/hexane = 1:20); H NMR (400 MHz, CDCl ) δ 14.64 (s, 1H), 7.97 (s, 1H), 7.92 (d, J =
3
7.4 Hz, 2H), 7.84 (d, J = 7.9 Hz, 1H), 7.76 (s, 1H), 7.55-7.39 (m, 4H), 7.29-7.23 (m, 2H), 7.22-
13
1
7
.16 (m, 2H), 7.00 (d, J = 8.2 Hz, 1H), 6.88 (t, J = 7.5 Hz, 1H) ppm; C{ H} NMR (100 MHz,
CDCl ) δ 160.1, 159.6 (d, J = 248.6 Hz), 157.9, 155.0, 146.2, 138.0, 131.7, 131.1 (d, J = 8.4
3
C-F
Hz), 130.4 (d, J = 2.8 Hz), 129.7, 129.1, 127.0, 126.5, 124.9 (d, J = 3.7 Hz), 119.1, 118.8, 118.6,
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17.6, 116.7, 116.5; HRMS (ESI-TOF): m/z [M + H] calcd for C H NOF 342.1289, found
2
3
17
42.1284.
2-(4-(4-Nitrophenyl)-6-phenylpyridin-2-yl)phenol (4aai): Following the general procedure, the
reaction of N-sulfonyl ketimine 1a (29.6 mg, 0.15 mmol), acetophenone (2a; 21.6 mg, 0.18
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
mmol), aldehyde 3i (27.2 mg, 0.18 mmol) and ammonium acetate (11.55 mg, 0.15 mmol) gave
o
4
aai as a pale yellow solid; yield 83% (45.8 mg); mp 210-212 C; R = 0.65 (ethyl acetate/hexane
f
1
=
1:15); H NMR (400 MHz, CDCl ) δ 14.51 (s, 1H), 8.41 (d, J = 8.6 Hz, 2H), 8.04 (s, 1H), 8.00
3
(
d, J = 6.9 Hz, 2H), 7.97.89 (m, 3H), 7.83 (s, 1H), 7.65-7.47 (m, 3H), 7.38 (t, J = 7.3 Hz, 1H), 7.09
1
3
1
(
d, J = 8.1 Hz, 1H), 6.98 (t, J = 7.5 Hz, 1H) ppm; C{ H} NMR (100 MHz, CDCl ) δ 160.1,
3
158.6, 155.9, 148.9, 148.4, 144.8, 137.6, 132.1, 130.0, 129.2, 128.3, 127.0, 126.4, 124.4, 119.0,
+
1
18.7, 118.6, 117.1, 115.8 ppm; HRMS (ESI-TOF): m/z [M + H] calcd for C H N O 369.1234,
2
3
17
2
3
found 369.1230.
2-(4-(4-Cyanophenyl)-6-phenylpyridin-2-yl)phenol (4aaj): Following the general procedure,
the reaction of N-sulfonyl ketimine 1a (29.6 mg, 0.15 mmol), acetophenone (2a; 21.6 mg, 0.18
mmol), aldehyde 3j (23.6 mg, 0.18 mmol) and ammonium acetate (11.55 mg, 0.15 mmol) gave
o
4
aaj as a pale yellow solid; yield 80% (41.7 mg); mp 185-187 C; R = 0.7 (ethyl acetate/hexane
f
1
=
1:15); H NMR (400 MHz, DMSO-d ) δ 14.20 (s, 1H), 8.52 (s, 1H), 8.32-8.29 (m, 4H), 8.15 (d,
6
J = 7.2 Hz, 2H), 8.08 (d, J = 8.3 Hz, 2H), 7.60-7.55 (m, 3H), 7.38 (t, J = 7.2 Hz, 1H), 7.00-6.98
1
3
1
(
m, 2H) ppm; C{ H} NMR (100 MHz, DMSO-d ) δ 164.3, 162.9, 160.1, 154.0, 146.9 142.7,
6
138.2, 137.0, 135.2, 134.5, 133.9, 133.2, 132.1, 124.4, 124.3, 123.9, 123.1, 122.5, 122.0, 117.4
+
ppm; HRMS (ESI-TOF): m/z [M + H] calcd for C H N O 349.1335, found 349.1337.
2
4
17
2
2
-(4-(4-Trifluoromethylphenyl)-6-phenylpyridin-2-yl)phenol (4aak): Following the general
procedure, the reaction of N-sulfonyl ketimine 1a (29.6 mg, 0.15 mmol), acetophenone (2a; 21.6
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1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
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3
3
3
4
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4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
mg, 0.18 mmol), aldehyde 3k (31.3 mg, 0.18 mmol) and ammonium acetate (11.55 mg, 0.15
o
mmol) gave 4aak as a pale yellow solid; yield 81% (47.5 mg); mp 162 - 164 C; R = 0.77 (ethyl
f
1
acetate/hexane = 1:20); H NMR (400 MHz, CDCl ) δ 14.63 (s, 1H), 8.04 (s, 1H), 8.00 (d, J = 7.0
3
0
1
2
3
4
5
6
7
8
9
0
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6
7
8
9
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3
4
5
6
7
8
9
0
Hz, 2H), 7.94 (d, J = 7.3 Hz, 1H), 7.84-7.80 (m, 5H), 7.53-7.48 (m, 3H), 7.37-7.35 (m, 1H), 7.08
1
3
1
(
d, J = 7.9 Hz, 1H), 6.97 (t, J = 7.5 Hz, 1H) ppm; C{ H} NMR (100 MHz, CDCl ) δ 160.1,
3
1
1
58.4, 155.7, 149.8, 142.1, 137.8, 131.9, 131.6, 131.2, 129.9, 129.2, 127.7, 127.0, 126.4, 126.3,
+
26.2, 126.2, 126.1, 118.9, 118.8, 118.7, 117.2, 115.8 ppm; HRMS (ESI-TOF): m/z [M + H] calcd
for C H F NO 392.1257, found 392.1283.
2
4
17 3
2
-(6-Phenyl-[4,4'-bipyridin]-2-yl)phenol (4aal): Following the general procedure, the reaction
of N-sulfonyl ketimine 1a (29.6 mg, 0.15 mmol), acetophenone (2a; 21.6 mg, 0.18 mmol),
aldehyde 3l (19.3 mg, 0.18 mmol) and ammonium acetate (11.55 mg, 0.15 mmol) gave 4aal as a
o
1
pale yellow solid; yield 75% (36.5 mg); mp 165 - 167 C; R = 0.5 (ethyl acetate/hexane = 1:15); H
f
NMR (400 MHz, CDCl ) δ 14.62 (s, 1H), 9.02 (s, 1H), 8.76 (d, J = 4.0 Hz, 1H), 8.09-8.03 (m,
3
2
4
H), 8.01 (d, J = 7.0 Hz, 2H), 7.94 (d, J = 7.1 Hz, 1H), 7.83 (d, J = 0.8 Hz, 1H), 7.60-7.47 (m,
1
3
1
H), 7.41-7.33 (m, 1H), 7.08 (d, J = 7.9 Hz, 1H), 6.98 (t, J = 7.6 Hz, 1H) ppm; C{ H} NMR
(
100 MHz, CDCl ) δ 160.1, 158.5, 155.8, 150.5, 148.2, 148.1, 137.8, 134.6, 131.9, 129.9, 129.2,
3
+
1
27.0, 126.4, 123.9, 119.0, 118.7, 117.0, 115.6 ppm; HRMS (ESI-TOF): m/z [M + H] calcd for
C H N O 325.1335, found 325.1345.
2
2
17
2
2
-(4-(Furan-2-yl)-6-phenyl)pyridin-2-yl)phenol (4aam): Following the general procedure, the
reaction of N-sulfonyl ketimine 1a (29.6 mg, 0.15 mmol), acetophenone (2a; 21.6 mg, 0.18
mmol), aldehyde 3m ( 17.3 mg, 0.18 mmol) and ammonium acetate (11.55 mg, 0.15 mmol) gave
o
4
aam as a pale yellow solid; yield 77% (36.1 mg); mp 157 - 159 C; R = 0.8 (ethyl acetate/hexane
f
1
= 1:20); H NMR (400 MHz, CDCl ) δ 14.79 (s, 1H), 8.11 (s, 1H), 8.02-7.92 (m, 3H), 7.88 (d, J
3
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=
0.9 Hz, 1H), 7.63 (d, J = 1.2 Hz, 1H), 7.55-7.46 (m, 3H), 7.40-7.31 (m, 1H), 7.06-7.06 (m, 2H),
1
3
1
7
.00 – 6.93 (m, 1H), 6.61-6.60 (m, 1H) ppm; C{ H} NMR (100 MHz, CDCl ) δ 160.1, 158.2,
3
155.3, 151.3, 144.2, 139.8, 138.0, 131.6, 129.7, 129.1, 126.9, 126.4, 118.9, 118.8, 118.5, 113.0,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
1
12.3, 111.5, 109.5 ppm; HRMS (ESI-TOF): m/z [M + Na] calcd for C H NO Na 336.0995,
2
1
15
2
found 336.0982.
2
-(4-(Thiophen-2-yl)-6-phenyl)pyridin-2-yl)phenol (4aan): Following the general procedure,
the reaction of N-sulfonyl ketimine 1a (29.6 mg, 0.15 mmol), acetophenone (2a; 21.6 mg, 0.18
mmol), aldehyde 3n (20.17 mg, 0.18 mmol) and ammonium acetate (11.55 mg, 0.15 mmol) gave
o
4
aan as a pale yellow solid; yield 79% (39.0 mg); mp 175 - 178 C; R = 0.8 (ethyl acetate/hexane
f
1
= 1:20); H NMR (400 MHz, CDCl ) δ 14.72 (s, 1H), 8.02 (s, 1H), 7.98 (d, J = 7.1 Hz, 2H), 7.91
3
(d, J = 7.5 Hz, 1H), 7.81 (s, 1H), 7.64 (d, J = 3.2 Hz, 1H), 7.59-7.45 (m, 4H), 7.37-7.33 (m, 1H),
.23-7.16 (m, 1H), 7.07 (d, J = 8.1 Hz, 1H), 6.97 (t, J = 7.5 Hz, 1H) ppm; 13C{ H} NMR (100
1
7
MHz, CDCl ) δ 160.1, 158.3, 155.5(2C), 144.0, 141.2, 137.9, 131.7, 129.7, 129.1, 128.6, 127.7,
3
+
1
26.9, 126.3, 125.9, 118.8, 118.6, 115.4, 113.8 ppm; HRMS (ESI-TOF): m/z [M + H] calcd for
C H NSO 330.0947, found 330.0949.
2
1
16
2
-(6-(4-Methylphenyl)-4-(furan-2-yl)pyridin-2-yl)phenol (4abm): Following the general
procedure, the reaction of N-sulfonyl ketimine 1a (29.6 mg, 0.15 mmol), ketone 2b(24.14 mg,
0
.18 mmol), aldehyde 3m (17.3 mg, 0.18 mmol) and ammonium acetate (11.55 mg, 0.15 mmol)
o
gave 4abm as a pale yellow solid; yield 78% (38.3 mg); mp 157 - 159 C; R = 0.8 (ethyl
f
1
acetate/hexane = 1:20); H NMR (400 MHz, CDCl ) δ 14.87 (s, 1H), 8.08 (s, 1H), 7.94 (d, J = 7.9
3
Hz, 1H), 7.89 (d, J = 7.8 Hz, 2H), 7.85 (s, 1H), 7.62 (s, 1H), 7.36-7.32 (m, 3H), 7.11-7.01 (m, 2H),
1
3
1
6
.96 (t, J = 7.5 Hz, 1H), 6.60 (s, 1H), 2.44 (s, 3H) ppm; C{ H} NMR (100 MHz, CDCl ) δ 160.2,
3
158.1, 155.3, 151.4, 144.1, 139.8, 135.2, 131.6, 129.8, 126.8, 126.4, 119.0, 118.7, 118.5, 112.7,
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2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
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4
5
5
5
5
5
5
5
5
5
5
6
+
1
12.7, 112.3, 111.2, 109.4, 21.3 ppm; HRMS (ESI-TOF): m/z [M + H] calcd for C H NO
22 18 2
3
28.1332, found 328.1339.
2-(6-(4-Methylphenyl)-4-(thiophen-2-yl)pyridin-2-yl)phenol (4abn): Following the general
procedure, the reaction of N-sulfonyl ketimine 1a (29.6 mg, 0.15 mmol), ketone 2b (24.14 mg,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
0
.18 mmol), aldehyde 3n (20.17 mg, 0.18 mmol) and ammonium acetate (11.55 mg, 0.15 mmol)
o
gave 4abn as a pale yellow solid; yield 82% (42.2 mg); mp 145-147 C; R = 0.8 (ethyl
f
1
acetate/hexane = 1:20); H NMR (400 MHz, CDCl ) δ 14.79 (s, 1H), 8.01 (s, 1H), 7.92-7.87 (m,
3
3
H), 7.80 (s, 1H), 7.65 (d, J = 2.8 Hz, 1H), 7.49 (d, J = 4.8 Hz, 1H), 7.36-7.33 (m, 3H), 7.21-7.91
1
3
1
(
m, 1H), 7.06 (d, J = 8.2 Hz, 1H), 6.97 (t, J = 7.5 Hz, 1H), 2.44 (s, 3H) ppm; C{ H} NMR (100
MHz, CDCl ) δ 160.2, 158.2, 155.5, 143.9, 141.4, 139.9, 135.1, 131.6, 129.8, 128.5, 127.6, 126.8,
3
+
1
26.3, 125.9, 118.9, 118.8, 118.6, 115.1, 113.5, 21.3 ppm; HRMS (ESI-TOF): m/z [M + H] calcd
for C H NOS 344.1104, found 344.1118.
2
2
18
2-(4,6-Di(4-methoxyphenyl)pyridin-2-yl)phenol (4acc):25a Following the general procedure, the
reaction of N-sulfonyl ketimine 1a (29.6 mg, 0.15 mmol), ketone 2c (27.01 mg, 0.18 mmol),
aldehyde 3c (24.5 mg, 0.18 mmol) and ammonium acetate (11.55 mg, 0.15 mmol) gave 4acc as a
o
pale yellow solid; yield 76% (43.6 mg); mp 128 - 130 C; R = 0.6 (ethyl acetate/hexane = 1:20);
f
1
H NMR (400 MHz, CDCl ) δ 15.03 (s, 1H), 7.92-7.90 (m, 4H), 7.74-7.64 (m, 3H), 7.33 (t, J =
3
1
3
1
7
.2 Hz, 1H), 7.10-7.00 (m, 5H), 6.94 (t, J = 7.4 Hz, 1H), 3.88 (s, 3H), 3.87 (s, 3H) ppm; C{ H}
NMR (100 MHz, CDCl ) δ 160.9, 160.8, 160.2, 157.8(2C), 154.8, 150.6, 131.4, 130.8, 130.7,
3
128.4, 128.3, 126.3, 119.2, 118.7, 118.5, 115.9, 114.6, 114.4, 55.4 ppm; HRMS (ESI-TOF): m/z
+
[M + H] calcd for C H NO 384.1594, found 384.1606.
2
5
22
3
2
-(4-(4-Chlorophenyl)-6-(4-methoxyphenyl)pyridin-2-yl)phenol (4acf): Following the general
procedure, the reaction of N-sulfonyl ketimine 1a (29.6 mg, 0.15 mmol), ketone 2c (27.01 mg,
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.18 mmol), aldehyde 3f (25.3 mg, 0.18 mmol) and ammonium acetate (11.55 mg, 0.15 mmol)
o
gave 4acf as a pale yellow solid; yield 79% (40.6 mg); mp 135 - 137 C; R = 0.7 (ethyl
f
1
acetate/hexane = 1:20); H NMR (400 MHz, CDCl ) δ 14.82 (s, 1H), 7.94-7.90 (m, 4H), 7.73 (s,
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
H), 7.67 (d, J = 8.3 Hz, 2H), 7.52 (d, J = 8.3 Hz, 2H), 7.35 (t, J = 7.5 Hz, 1H), 7.06-7.04 (m, 3H),
1
3
1
6
.95 (t, J = 7.5 Hz, 1H), 3.89 (s, 3H) ppm; C{ H} NMR (100 MHz, CDCl ) δ 161.0, 160.1,
3
1
58.0, 155.0, 149.8, 137.0, 135.6, 131.6, 130.3, 129.4, 128.4, 128.2, 126.3, 118.9, 118.8, 118.5,
+
1
16.0, 114.7, 114.5, 55.4 ppm; HRMS (ESI-TOF): m/z [M + H] calcd for C H ClNO 388.1099,
2
4
19
2
found 388.1118.
2
-(6-(3-Fluorphenyl)-4-(4-methylphenyl)pyridin-2-yl)phenol (4aeb): Following the general
procedure, the reaction of N-sulfonyl ketimine 1a (29.6 mg, 0.15 mmol), ketone 2e (22.33 mg,
0
.18 mmol), aldehyde 3b (21.62 mg, 0.18 mmol) and ammonium acetate (11.55 mg, 0.15 mmol)
o
gave 4aeb as a pale yellow solid; yield 73% (38.9 mg); mp 129 - 131 C; R = 0.8 (ethyl
f
1
acetate/hexane = 1:20); H NMR (400 MHz, CDCl ) δ 14.55 (s, 1H), 8.07 (s, 1H), 7.94 (d, J = 7.9
3
Hz, 1H), 7.79 (d, J = 7.9 Hz, 2H), 7.67-7.64 (m, 3H), 7.53-7.47 (m, 1H), 7.36 (t, J = 7.0 Hz, 3H),
7
.18 (t, J = 8.1 Hz, 1H), 7.07 (d, J = 8.2 Hz, 1H), 6.96 (t, J = 7.5 Hz, 1H), 2.46 (s, 3H) ppm;
1
3
1
C{ H} NMR (100 MHz, CDCl ) δ 163.3 (d, J = 245.1 Hz), 160.0, 158.2, 154.0, 153.9, 151.3,
3
C-F
1
40.6, 140.5, 139.8, 135.2, 131.7, 130.7 (d, JC-F = 8.2 Hz), 130.0, 127.0, 126.4, 122.7 , 118.9 (d,
JC-F = 2.9 Hz), 118.5, 117.1, 116.4 (d, JC-F = 21.1 Hz), 116.0, 114.0, 113.8, 21.3 ppm; HRMS (ESI-
+
TOF): m/z [M + H] calcd for C H FNO 356.1445, found 356.1448.
24 19
2-(6-(3-Fluorphenyl)-4-(4-fluorophenyl)pyridin-2-yl)phenol (4aeg): Following the general
procedure, the reaction of N-sulfonyl ketimine 1a (29.6 mg, 0.15 mmol), ketone 2e (22.33 mg,
0
.18 mmol), aldehyde 3g (22.33 mg, 0.18 mmol) and ammonium acetate (11.55 mg, 0.15 mmol)
o
gave 4aeg as a pale yellow solid; yield 75% (40.4 mg); mp 176 - 178 C; R = 0.76 (ethyl
f
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2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
acetate/hexane = 1:20); H NMR (400 MHz, CDCl ) δ 14.44 (s, 1H), 8.03 (s, 1H), 7.93 (d, J = 7.8
3
Hz, 1H), 7.79-7.71 (m, 4H), 7.67 (d, J = 9.8 Hz, 1H), 7.53-7.48 (m, 1H), 7.36 (t, J = 7.6 Hz, 1H),
1
3
1
7.27-7.16 (m, 3H), 7.08 (d, J = 8.2 Hz, 1H), 6.97 (t, J = 7.5 Hz, 1H) ppm; C{ H} NMR (100
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
MHz, CDCl ) δ 163.7 (d, J = 248.6 Hz), 163.3 (d, JC-F = 245.3 Hz), 160.0, 158.3, 154.2, 154.1,
3
C-F
1
1
50.3, 140.3, 140.2, 134.4, 134.3, 131.8, 130.7 (d, JC-F = 8.2 Hz), 129.1 (d, JC-F = 8.3 Hz), 126.4,
22.6 (d, JC-F = 2.9 Hz), 119.1, 118.6, 118.5, 117.1, 116.6 (d, JC-F = 21.1 Hz), 116.5 (d, JC-F = 3.2
+
Hz), 116.3 (d, JC-F = 21.6 Hz) 114.0, 113.8 ppm; HRMS (ESI-TOF): m/z [M + H] calcd for
C H F NO 360.1194, found 360.1185.
2
3
16 2
2
-(6-(4-Bromophenyl)-4-(thiophenyl-2-yl)pyridin-2-yl)phenol (4afn): Following the general
procedure, the reaction of N-sulfonyl ketimine 1a (29.6 mg, 0.15 mmol), ketone 2f (35.83 mg,
0
.18 mmol), aldehyde 3n (20.17 mg, 0.18 mmol) and ammonium acetate (11.55 mg, 0.15 mmol)
o
gave 4afn as a pale yellow solid; yield 74% (45.3 mg); mp 160 - 163 C; R = 0.75 (ethyl
f
1
1
acetate/hexane = 1:20); H NMR (400 MHz, CDCl ) δ 14.45 (s, 1H), 8.04 (s, 1H), 7.91 (d, J = 7.9
3
Hz, 1H), 7.84 (d, J = 8.3 Hz, 2H), 7.77 (s, 1H), 7.66 (d, J = 8.0 Hz, 3H), 7.51 (d, J = 5.0 Hz, 1H),
7
.36 (t, J = 7.6 Hz, 1H), 7.21 (t, J = 4.2 Hz, 1H), 7.06 (d, J = 8.2 Hz, 1H), 6.98 (t, J = 7.6 Hz, 1H)
1
3
1
ppm; C{ H} NMR (100 MHz, CDCl ) δ 160.0, 158.5, 154.5, 144.2, 141.0, 136.9, 132.3, 131.9,
3
1
28.6, 128.4, 127.9, 126.4, 126.1, 124.2, 119.1, 118.8, 118.6, 115.2, 114.2 ppm; HRMS (ESI-
TOF): m/z [M + H] calcd for C H1579BrNOS 408.0052, found 408.0029; HRMS (ESI-TOF): m/z
+
2
1
+
[
M + H] calcd for C H1581BrNOS 410.0032, found 410.0011.
21
2-(6-(4-Nitrophenyl)-4-(thiophenyl-2-yl)pyridin-2-yl)phenol (4ago): Following the general
procedure, the reaction of N-sulfonyl ketimine 1a (29.6 mg, 0.15 mmol), ketone 2g (29.72 mg,
0
.18 mmol), aldehyde 3o (20.18 mg, 0.18 mmol) and ammonium acetate (11.55 mg, 0.15 mmol)
o
gave 4ago as a pale yellow solid;yield 70% (39.3 mg); mp 210 - 213 C; R = 0.65 (ethyl
f
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acetate/hexane = 1:15); H NMR (400 MHz, CDCl ) δ 14.10 (s, 1H), 8.40 (d, J = 8.5 Hz, 2H), 8.19-
3
8
.09 (m, 3H), 7.93 (d, J = 7.9 Hz, 1H), 7.86 (s, 1H), 7.69 (d, J = 3.0 Hz, 1H), 7.54 (d, J = 4.8 Hz,
1H), 7.39 (t, J = 7.6 Hz, 1H), 7.26-7.18 (m, 1H), 7.08 (d, J = 8.2 Hz, 1H), 7.00 (t, J = 7.5 Hz, 1H)
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
1
ppm; C{ H} NMR (100 MHz, CDCl ) δ 159.8, 158.9, 153.2, 148.5, 144.4, 143.9, 140.5, 132.2,
3
1
28.8, 128.3, 127.8, 126.5, 126.4, 124.3, 119.2, 118.7, 118.6, 116.1, 115.2 ppm; HRMS (ESI-
+
TOF): m/z [M + H] calcd for C H N O S 375.0798, found 375.0806.
21 15
2
3
2
-(4-(4-Methylphenyl)-6-(4-bromophenyl)pyridin-2-yl)phenol (4afb): Following the general
procedure, the reaction of 1a (29.6 mg, 0.15 mmol), ketone 2f (35.83 mg, 0.18 mmol), aldehyde
b (21.62 mg, 0.18 mmol) and ammonium acetate (11.55 mg, 0.15 mmol) gave 4afb as a pale
3
o
1
yellow solid; yield 75% (46.8 mg); mp 180 - 185 C; R = 0.75 (ethyl acetate/hexane = 1:20); H
f
NMR (400 MHz, CDCl ) δ 14.59 (s, 1H), 8.06 (s, 1H), 7.94 (d, J = 7.9 Hz, 1H), 7.87 (d, J = 8.2
3
Hz, 2H), 7.79 (s, 1H), 7.71-7.61 (m, 4H), 7.35-7.33 (m, 3H), 7.07 (d, J = 8.2 Hz, 1H), 6.96 (t, J =
1
3
1
7.5 Hz, 1H), 2.46 (s, 3H) ppm; C{ H} NMR (100 MHz, CDCl ) δ 160.0, 158.2, 154.1, 151.3,
3
1
1
4
2
39.8, 137.1, 135.3, 132.2, 131.7, 130.0, 128.5, 127.0, 126.4, 124.1, 119.0, 118.9, 118.5, 116.8,
15.9, 21.3 ppm; HRMS (ESI-TOF): m/z [M + H] calcd for C H1979BrNO 416.0645, found
+
2
4
16.0656; HRMS (ESI-TOF): m/z [M + H] calcd for C H1981BrNO 418.0625, found 418.0641.
+
24
-(4-(Furan-2-yl)-6-(thiophen-2-yl)pyridin-2-yl)phenol (4ahm): Following the general
procedure, the reaction of 1a (29.6 mg, 0.15 mmol), ketone 2h (22.7 mg, 0.18 mmol), aldehyde
m (17.3 mg, 0.18 mmol) and ammonium acetate (11.55 mg, 0.15 mmol) gave 4ahm as a pale
3
o
1
yellow solid; yield 80% (38.3 mg); mp 158 - 160 C; R = 0.75 (ethyl acetate/hexane = 1:20); H
f
NMR (400 MHz, CDCl ) δ 14.05 (s, 1H), 7.97 (s, 1H), 7.88 (d, J = 7.9 Hz, 1H), 7.77 (s, 1H), 7.68
3
(
d, J = 2.0 Hz, 1H), 7.60 (s, 1H), 7.45 (d, J = 4.7 Hz, 1H), 7.34 (t, J = 7.6 Hz, 1H), 7.15 (s, 1H),
1
3
1
7.06 (d, J = 8.2 Hz, 1H), 7.01 (s, 1H), 6.94 (t, J = 7.5 Hz, 1H), 6.58 (s, 1H) ppm; C{ H} NMR
29
ACS Paragon Plus Environment