Multicomponent strategy to indeno[2,1- C ]pyridine and hydroisoquinoline derivatives through cleavage of carbon-carbon bond

Article abstract of DOI:10.1021/jo5025199

A concise and efficient three-component domino reaction has been developed for the synthesis of polyfunctionalized indenopyridine and hydroisoquinoline derivatives via the cleavage of a C-C bond under transition-metal-free conditions. This reaction provides facile access to complex nitrogen-containing heterocycles by simply mixing three common starting materials in EtOH in the presence of 20 mol % NaOH under microwave irradiation conditions.

Full text of DOI:10.1021/jo5025199

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Article
Multicomponent Strategy to Indeno[2,1-c]pyridine and Hydroisoquinoline
Derivatives through Cleavage of Carbon-Carbon Bond
Xian Feng, Jian-Jun Wang, Zhan Xun, Zhi-Bin Huang, and Da-Qing Shi
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo5025199 • Publication Date (Web): 18 Dec 2014
Downloaded from http://pubs.acs.org on December 25, 2014
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Multicomponent Strategy to Indeno[2,1-c]pyridine and
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Hydroisoquinoline Derivatives through Cleavage of
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Carbon-Carbon Bond
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Xian Feng, Jian-Jun Wang, Zhan Xun, Zhi-Bin Huang and Da-Qing Shi*
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical
Engineering and Materials Science, Soochow University, Suzhou 215123, China
Corresponding Author: dqshi@suda.edu.cn (Da-Qing Shi)
ABSTRACT: A concise and efficient three-component domino reaction has been developed for
the synthesis of polyfunctionalized indenopyridine and hydroisoquinoline derivatives via the
cleavage of a C–C bond under transition-metal-free conditions. This reaction provides facile
access to complex nitrogen-containing heterocycles by simply mixing three common starting
materials in EtOH in the presence of 20 mol% NaOH under microwave irradiation conditions.
INTRODUCTION
Nitrogen-containing heterocyclic skeletons can be found in a broad range of natural products
and synthetic molecules, and many of these compounds have been reported to exhibit important
biological activities.1 Indenopyridines, for example, represent an important structural class of
nitrogen-containing compounds, with numerous applications in biological and medicinal
chemistry.2 The 4-azafluorenone (5H-indeno[1,2-b]pyridine-5-one) alkaloids (Figure 1, structure
A), which were originally isolated from plants belonging to the Annonaceae family, are a small
group of alkaloids with interesting biological properties.3 For example, 4-azafluorenone
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derivatives have been reported to exhibit cytotoxic, phosphodiesterase inhibitory, adenosine A2a
receptor antagonistic, coronary dilating, anti-inflammatory and calcium modulating activities.4 It
has also been reported that the pharmacological profiles of B and C are both similar to that of the
antidepressant desmethylimipramine.5 In 2003, Garrido et al.6 identified haouamine A (Figure 1,
structure D) during their chemical study of the ascidian Aplidium haouarianum. The cytotoxic
activity of this compound was tested against several human tumor cell lines, where it was found it
to be highly cytotoxic towards HT-29 cells, with an IC50 value of 0.1 mg/mL.6 Although several
studies have been published pertaining to the synthesis of indenopyridine derivatives,7 the overall
applicability of these methods has been limited by their use for toxic catalysts and solvents,
narrow substrate scope, harsh reaction conditions and operational complexity. The development of
new methods for the concise and efficient construction of haouamine A and its analogues is
therefore highly desired.8
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Figure 1. Naturally occurring and medicinally important indenopyridine derivatives
The development of concise and effective one-pot transformations for the construction of
complex molecule libraries represents a major challenge in modern organic synthetic chemistry.9
Several novel strategies have been developed to meet this challenge, and multicomponent domino
reactions (MDRs), in particular, have received considerable attention. MDRs eliminate the need
for the isolation and purification of multiple reaction intermediates, which can lead to an increase
in the overall yield of the desired product and a reduction in the amount of waste, making MDRs
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ideal candidates for the construction of complex molecules from readily available starting
materials.10 For these reasons, MDRs have been used as synthetic tools to deliver high levels of
diversity in the construction of targeted compound libraries.11 We recently reported the
development of several new MDRs that provided rapid access to a variety of nitrogen-containing
heterocyclic skeletons of chemical and pharmaceutical interest.12 In this study, we have developed
a novel three-component domino reaction for the synthesis of polyfunctionalized indenopyridine
and hydroisoquinoline derivatives under transition-metal-free and microwave irradiation
conditions. There are several attractive features to this newly developed MDR, including the novel
strategy used for the construction of the indenopyridine skeleton and the direct C–C bond cleavage
of a β-ketoamide, both of which were easily achieved without the need for multistep operations.
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RESULTS AND DISCUSSION
3-Oxo-3-phenyl-N-(p-tolyl)-propanamide (1a), phthalaldehyde (2) and malononitrile (3a) were
selected as model substrates for this MDR to establish the feasibility of the strategy and to
optimize the reaction conditions (Table 1). Initial optimization experiments revealed that the
desired reaction did not proceed in ethanol under catalyst-free conditions (Table 1, entry 1).
Pleasingly, however, the desired indeno[2,1-c]pyridine product 4a was formed in 55% yield when
the reaction was conducted in the presence of NaOH (10 mol%) in ethanol (Table 1, entry 2). The
effect of different solvents on the yield of the reaction was investigated, and the results showed
that the use of ethanol gave a much better yield than dimethylformamide, acetonitrile, toluene or
tetrahydrofuran (Table 1, entries 2–6). Several bases were evaluated in the reaction, including
NaOH, Cs2CO3, piperidine and pyridine, which were all added in catalytic quantities (10 mol%),
and the reactions themselves were conducted in ethanol at 100 °C under microwave irradiation
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conditions. The results of these screening experiments revealed that NaOH provided superior
catalytic efficiency compared with all of the other catalysts tested (Table 1, entries 2 and 7–9).
Having identified NaOH as the best catalyst for the transformation, we proceeded to evaluate
the amount of catalyst required for this reaction. The results of these screening experiments
revealed that increasing the amount of NaOH from 10 to 20 mol% led to an increase in the yield
from 55 to 85% (Table 1, entries 2 and 10). The use of a 20 mol% charge of NaOH in ethanol was
determined to be most effective way of pushing this reaction towards completion, with the
addition of even larger amounts of this catalyst failing to provide any further improvements in the
yield. Last, the reaction was conducted at a variety of temperatures to identify the optimum
reaction temperature, The reaction was carried out with 20 mol% NaOH in EtOH at 80, 90, and
100 °C, with the desired product 4a being formed in yields of 70, 79, and 85% (Table 1, entries
12–13 and 10), respectively. These results therefore revealed that the best reaction temperature
was 100 °C.
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Taken together, the results of these screening experiments have shown that the optimum
reaction conditions for this transformation are 20 mol% NaOH in EtOH at 100 °C under
microwave irradiation conditions. It is noteworthy that the desired product was only formed in
71% yield when the same reaction was carried out in EtOH under refluxing conditions for 3 h
without microwave irradiation (Table 1, entry 14). This result clearly shows that this reaction was
occurring at a faster rate under microwave irradiation conditions.
Table 1. Optimization of the Reaction Conditions for the Synthesis of 4a
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entry
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solvent
EtOH
EtOH
DMF
catalyst (mol%) temp (oC)
time (min)
isolated yield (%)
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No
100
100
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100
100
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80
15
Trace
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2
NaOH (10)
NaOH (10)
NaOH (10)
NaOH (10)
NaOH (10)
Cs2CO3(10)
Piperidine (10)
Pyridine (10)
NaOH (20)
NaOH (30)
NaOH (20)
NaOH (20)
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Trace
24
4
CH3CN
toluene
THF
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Trace
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EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
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48
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Trace
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82
70
90
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79
180 (without
MWI)
14
EtOH
NaOH (20)
reflux
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With the optimal reaction conditions in hand, we proceeded to evaluate the scope of this novel
strategy using a variety of different β-ketoamides. As shown in Table 2, a variety of mono- and
disubstituted phenyl rings bearing either electron-withdrawing or electron-donating substituents
were well tolerated on the amide nitrogen of the β-ketoamide (i.e., R2), with the corresponding
products being formed in satisfactory yields. Furthermore, the replacement of malononitrile with
ethyl cyanoacetate gave the corresponding ester substituted products in good yields (Table 2,
entries 15–19).
Table 2. Synthesis of 1H-Indeno[2,1-c]pyridine-1-one Derivatives 4a-v
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entry
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product
4a
4b
4c
R1
R2
R3
CN
isolated yield (%)
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
4-CH3C6H4
4-(CH3)3CC6H4
4-(CH3)2CHC6H4
4-CH3OC6H4
C6H5
85
83
79
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66
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71
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2
CN
3
CN
4
4d
4e
CN
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5
CN
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4f
4-FC6H4
CN
7
4g
4h
4i
4-ClC6H4
CN
8
4-BrC6H4
CN
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4-CF3C6H4
3,5-(CH3)2C6H3
3-Cl-4-CH3C6H3
CH3CH2CH2CH2
4-CH3OC6H4CH2
C6H5CH2
CN
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4j
CN
4k
4l
CN
CN
4m
4n
4o
4p
4q
4r
CN
Ph
CN
Me
Me
Me
Me
Me
4-CH3OC6H4
4-CH3C6H4
4-FC6H4
COOEt
COOEt
COOEt
COOEt
COOEt
4-ClC6H4
4v
4-BrC6H4
β-Ketothioamide (5) was also investigated as a substrate for this reaction, to further expand the
scope of this transformation. Pleasingly, the desired 1H-indeno[2,1-c]pyridine-1-thione
derivatives (6a–g) were obtained in satisfactory yields under the optimal reaction conditions.
Table 3. Synthesis of 1H-Indeno[2,1-c]pyridine-1-thione Derivatives 6a–g
entry
product
6a
R1
Ph
Ph
Ph
Ph
Ph
Ph
Ph
R2
R3
CN
isolated yield (%)
1
2
3
4
5
6
7
C6H5
78
75
72
67
66
60
58
6b
4-CH3C6H4
3-CH3C6H4
C6H5
CN
6c
CN
6d
COOEt
COOEt
COOMe
COOMe
6e
4-CH3C6H4
C6H5
6f
6g
4-CH3C6H4
Interestingly, the replacement of phthalaldehyde (2) with glutaraldehyde (7) gave the
corresponding hydroisoquinolines (8a–i) in good yields when it was reacted with a series of
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β-ketoamides (1) and malononitrile (3) under the optimal conditions (Table 4). In this particular
case, the C–C double bond formed in a different position. However, none of the desired product
was formed when β-ketothioamide (5) and ethyl cyanoacetate were used as the starting materials
in this reaction.
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Table 4. Synthesis of Hydroisoquinoline Derivatives 8a–i
entry
product
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R1
Ph
Ph
Ph
Ph
Me
Ph
Ph
Ph
Ph
R2
isolated yield (%)
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9
4-(CH3)3CC6H4
4-(CH3)2CHC6H4
4-CH3CH2OC6H4
4-CH3OC6H4
4-CH3C6H4
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60
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3,5-(CH3)2C6H3
3-Cl-4-CH3C6H3
4-FC6H4
8g
8h
8i
4-ClC6H4
The structures of these products were determined from their IR, 1H NMR, 13C NMR and HRMS
spectra. The structures of compounds 4h, 6a and 8a were further confirmed by X-ray diffraction
analysis (see Supporting Information).
Based on the results of this study, we have proposed mechanism for the synthesis of compound
4, which is shown in Scheme 1. The initial NaOH-catalyzed Knoevenagel condensation of
phthalaldehyde (2) with malononitrile (3) or β-ketoamide (1) would give intermediate A or A’.
The subsequent Michael addition of β-ketoamide (1) or malononitrile (3) to intermediate A or A’
would give intermediate B, which could undergo an intramolecular nucleophilic addition reaction
catalyzed by NaOH to form intermediate C. The cyclization and subsequent isomerization of
Intermediate C would give intermediate E, which would undergo a NaOH-catalyzed C-C bond
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cleavage reaction to give intermediate G via the loss of its R1COO– (intermediate H) and hydroxy
groups. In the last step, intermediate G would undergo a NaOH-catalyzed isomerization reaction
to generate the desired product 4. Notably, it would not be possible for the final isomerization
reaction to occur when phthalaldehyde (2) was replaced by glutaraldehyde (7), which explains
why intermediate G was obtained as the final product in these cases. Intermediate H could be
detected by HPLC-MS in the reaction mixture after aciding with HCl to pH 1~2.
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Scheme 1. Proposed Mechanism for the Synthesis of Compound 4
Density functional theory calculations were carried out at the B3LYP/6-31G level to determine
the energy associated with the different conformations of intermediate G and product 4e and
evaluate the energy barrier associated with the final isomerization in this system. The geometries
of the two possible configurations were initially optimized and their lowest energy minima were
then calculated (Figure 2). The results revealed that the most stable configuration of 4e was 98.22
kJ/mol lower in energy than that of intermediate G. This result therefore suggested that
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intermediate G could be readily transformed to the more stable product 4.
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Intermediate G: E = –970.758832 hartree
Product 4e: E = –970.796244 hartree
Figure 2. Lowest energy minimum of intermediate G and product 4e
CONCLUSION
In conclusion, we have developed a facile and efficient method for the synthesis of
indenopyridine and hydroisoquinoline derivatives using a novel three-component domino reaction.
This method allowed for the rapid construction of a diverse collection of polyfunctionalized
indenopyridine and hydroisoquinoline derivatives in good yields by simply heating a mixture of a
β-ketoamide, a phthalaldehyde (or glutaraldehyde) and a malononitrile (or alkyl 2-cyanoacetate) in
EtOH under microwave irradiation conditions in the presence of 20 mol% NaOH.
EXPERIMENTAL SECTION
General Methods. Microwave irradiation was carried out with Initiator 2.5 Microwave
Synthesizers from Biotage, Uppsala, Sweden. The reaction temperatures were measured by
infrared detector (external sensor type) during microwave heating.
General Experimental Procedures for the Synthesis of Compounds 1. Compounds 1 were
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synthesized according to the procedure reported in the literature13. A mixture of ethyl acetoacetate
(10 mmol), an appropriate amine (10 mmol) and a catalytic amount of potassium tert-butoxide
was taken into a 250 mL Pyrex beaker with an inverted glass funnel and irradiated in a domestic
microwave oven for 3-5 min with 30 s pulses at 480 W while monitoring the progress of the
reaction by TLC. On completion of the reaction, the reaction mixture was cooled and triturated
with ice-cold ether. The product separated was filtered, washed with small portions of ice-cold
ether and dried. Purification by recrystallization from ethanol afforded a colorless crystalline solid.
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1
3-Oxo-N-(p-tolyl)butanamide (1a): white solid, yield 60%; mp 95-96 °C (Lit.14 95 C); H
NMR (400 MHz, CDCl3, δ, ppm) 9.10 (s, 1H), 7.43 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 8.0 Hz, 2H),
3.54 (s, 2H), 2.90-2.83 (m, 1H), 2.27 (s, 3H), 1.22 (s, 3H) , 1.21 (s, 3H); 13C NMR (100 MHz,
CDCl3, δ, ppm) 204.9, 163.9, 135.0, 134.2, 129.5, 120.3, 50.2, 31.0, 20.9; HRMS (ESI-TOF) m/z
calcd for C11H13NNaO2 214.0844 [M+Na]+, found 214.0840.
1
N-(4-(tert-butyl)phenyl)-3-oxobutanamide (1b): colourless oil, yield 63%; H NMR (400
MHz, CDCl3, δ, ppm) 9.08 (s, 1H), 7.45 (d, J = 8.8 Hz, 2H), 7.32 (d, J = 8.8 Hz, 2H), 3.56 (s, 2H),
2.29 (s, 3H), 1.29 (s, 9H); 13C NMR (100 MHz, CDCl3, δ, ppm) 205.0, 163.7, 147.6, 134.9, 125.8,
120.1, 50.1, 34.4, 31.4; HRMS (ESI-TOF) m/z calcd for C14H19NNaO2 256.1313 [M+Na]+, found
256.1290.
N-(4-isopropylphenyl)-3-oxobutanamide (1c): white solid, yield 53%; mp 86-87 °C ; 1H NMR
(400 MHz, CDCl3, δ, ppm) 9.10 (s, 1H), 7.39 (d, J = 8.4 Hz, 2H), 7.08 (d, J = 8.0 Hz, 2H), 3.52 (s,
2H), 2.29 (s, 3H), 2.26 (s, 3H); 13C NMR (100 MHz, CDCl3, δ, ppm) 205.0, 163.8, 145.3, 135.2,
126.9, 120.4, 50.2, 33.6, 31.0, 24.0; HRMS (ESI-TOF) m/z calcd for C13H17NNaO2 242.1157
[M+Na]+, found 242.1155.
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N-(4-methoxyphenyl)-3-oxobutanamide (1d): gray solid, yield 66%; mp 118-119 °C (Lit.14
6
7
1
118C); H NMR (400 MHz, CDCl3, δ, ppm) 9.00 (s, 1H), 7.41 (d, J = 8.8 Hz, 2H), 6.83 (d, J =
8
9
8.8 Hz, 2H), 3.76 (s, 3H), 3.53 (s, 2H), 2.28 (s, 3H); 13C NMR (100 MHz, CDCl3, δ, ppm) 205.2,
163.6, 156.6, 130.6, 122.0, 114.1, 55.5, 49.9, 31.1; HRMS (ESI-TOF) m/z calcd for C11H13NNaO3
230.0793 [M+Na]+, found 230.0796.
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3-Oxo-N-phenylbutanamide (1e): white solid, yield 57%; mp 86-87 °C (Lit.15 86C); H
NMR (400 MHz, CDCl3, δ, ppm) 9.23 (s, 1H), 7.53 (d, J = 7.6 Hz, 2H), 7.32-7.28 (m, 2H),
7.13-7.09 (m, 1H), 3.55 (s, 2H), 2.27 (s, 3H); 13C NMR (100 MHz, CDCl3, δ, ppm) 204.9, 164.2,
137.6, 129.0, 124.7, 120.3, 50.3, 31.0; HRMS (ESI-TOF) m/z calcd for C10H11NNaO2 200.0687
[M+Na]+, found 200.0687.
N-(4-fluorophenyl)-3-oxobutanamide (1f): white solid, yield 64%; mp 110-111 °C (Lit.16
110C); 1H NMR (400 MHz, CDCl3, δ, ppm) 9.21 (s, 1H), 7.46-7.43 (m, 2H), 6.97-6.92 (m, 2H),
3.52 (s, 2H), 2.26 (s, 3H); 13C NMR (100 MHz, CDCl3, δ, ppm) 204.9, 164.1, 159.5 (d, JCF
=
242.3 Hz), 133.6, 133.5, 122.1 (d, JCF = 7.9 Hz), 115.6 (d, JCF = 22.3 Hz), 50.0, 31.0; HRMS
(ESI-TOF) m/z calcd for C10H10FNNaO2 218.0593 [M+Na]+, found 218.0595.
N-(4-chlorophenyl)-3-oxobutanamide (1g): white solid, yield 55%; mp 133-134 °C (Lit.17
132-133C); 1H NMR (400 MHz, CDCl3, δ, ppm) 9.26 (s, 1H), 7.50 (d, J = 8.8 Hz, 2H), 7.28 (d, J
= 8.8 Hz, 2H), 3.59 (s, 2H), 2.32 (s, 3H); 13C NMR (100 MHz, CDCl3, δ, ppm) 205.3, 163.7,
136.1, 129.5, 129.0, 121.4, 49.6, 31.3; HRMS (ESI-TOF) m/z calcd for C10H10ClNNaO2 234.0298
[M+Na]+, found 234.0296.
N-(4-bromophenyl)-3-oxobutanamide (1h): white solid, yield 61%; mp 132-133 °C (Lit.18
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132-135C); H NMR (400 MHz, CDCl3, δ, ppm) 9.26 (s, 1H), 7.52-7.50 (m, 2H), 7.30-7.28 (m,
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2H), 3.59 (s, 2H), 2.33 (s, 3H); 13C NMR (100 MHz, CDCl3, δ, ppm) 205.3, 163.6, 136.1, 129.5,
129.0, 121.4, 49.5, 31.3; HRMS (ESI-TOF) m/z calcd for C10H10BrNNaO2 277.9793 [M+Na]+,
found 277.9795.
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3-Oxo-N-(4-(trifluoromethyl)phenyl)butanamide (1i): white solid, yield 51%; mp 155-156 °C
(Lit.19 157C); 1H NMR (400 MHz, CDCl3, δ, ppm) 9.46 (s, 1H), 7.68 (d, J = 8.4 Hz, 2H), 7.57 (d,
J = 8.4 Hz, 2H), 3.62 (s, 2H), 2.34 (s, 3H); 13C NMR (100 MHz, CDCl3, δ, ppm) 205.4, 163.7,
140.5, 130.6, 130.4, 126.5, 126.3, 126.2, 126.1, 122.7, 119.8, 114.5, 49.2, 31.4; HRMS (ESI-TOF)
m/z calcd for C11H10F3NNaO2 268.0561 [M+Na]+, found 268.0557
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N-(3,5-dimethylphenyl)-3-oxobutanamide (1j): white solid, yield 64%; mp 81-82 °C ; H
NMR (400 MHz, CDCl3, δ, ppm) 9.02 (s, 1H), 7.16 (s, 2H), 6.75 (s, 1H), 3.54 (s, 2H), 2.29-2.27
(m, 9H); 13C NMR (100 MHz, CDCl3, δ, ppm) 205.0, 163.8, 138.7, 137.4, 126.4, 118.0, 50.2, 31.1,
21.3; HRMS (ESI-TOF) m/z calcd for C12H15NNaO2 228.1000 [M+Na]+, found 228.0998.
N-(3-chloro-4-methylphenyl)-3-oxobutanamide (1k): white solid, yield 53%; mp 116-117 °C ;
1H NMR (400 MHz, CDCl3, δ, ppm) 9.17 (s, 1H), 7.63 (s, 1H), 7.28 (s, 1H), 7.13 (d, J = 8.0 Hz,
1H), 3.56 (s, 2H), 2.31 (s, 3H); 13C NMR (100 MHz, CDCl3, δ, ppm) 205.2, 163.6, 136.2, 134.4,
132.1, 131.0, 120.8, 118.5, 49.6, 31.2, 19.5; HRMS (ESI-TOF) m/z calcd for C11H12ClNNaO2
248.0454 [M+Na]+, found 248.0451.
N-butyl-3-oxobutanamide (1l): colourless oil, yield 48%; 1H NMR (400 MHz, CDCl3, δ, ppm)
8.46 (s, 1H), 4.30(s, 2H), 3.11-3.06 (m, 2H), 1.80 (s, 3H), 1.46-1.40 (m, 2H), 1.32-1.27 (m, 2H),
0.83 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3, δ, ppm) 170.5, 161.7, 81.7, 58.0, 42.5, 32.4,
19.9, 13.6; HRMS (ESI-TOF) m/z calcd for C8H15NNaO2 180.1000 [M+Na]+, found 180.0996.
N-(4-methoxybenzyl)-3-oxo-3-phenylpropanamide (1m): white solid, yield 66%; mp 86-87 °C ;
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1H NMR (400 MHz, CDCl3, δ, ppm) 7.96 (d, J = 8.4 Hz, 2H), 7.61-7.58 (m, 1H), 7.48-7.44 (m,
3H), 7.19 (d, J = 8.4 Hz, 2H), 6.83 (d, J = 8.4 Hz, 2H), 4.40-4.38 (m, 2H), 3.94 (s, 2H), 3.76 (s,
3H); 13C NMR (100 MHz, CDCl3, δ, ppm) 195.9, 165.8, 159.0, 136.2, 134.0, 130.0, 129.1, 128.9,
128.6, 114.1, 55.3, 45.4, 43.1; HRMS (ESI-TOF) m/z calcd for C17H17NNaO3 306.1106 [M+Na]+,
found 306.1099.
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N-benzyl-3-oxo-3-phenylpropanamide (1n): white solid, yield 60%; mp 84-85 °C (Lit.20
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85-86C); H NMR (400 MHz, CDCl3, δ, ppm) 7.99 (d, J = 8.8 Hz, 2H), 7.65-7.63 (m, 1H),
7.52-7.48 (m, 2H), 7.35-7.26 (m, 6H), 4.51-4.49 (m, 2H), 3.98 (s, 2H), 3.76 (s, 3H); 13C NMR
(100 MHz, CDCl3, δ, ppm) 195.9, 165.9, 138.0, 136.2, 134.1, 128.9, 128.7, 128.6, 127.7, 127.5,
45.4, 43.6; HRMS (ESI-TOF) m/z calcd for C16H15NNaO2 276.1000 [M+Na]+, found 276.0984.
N-(4-(tert-butyl)phenyl)-3-oxo-3-phenylpropanamide (1o): white solid, yield 64%; mp
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132-133 °C ; H NMR (400 MHz, CDCl3, δ, ppm) 9.32 (s, 1H), 8.01-7.98 (m, 2H), 7.61-7.58 (m,
1H), 7.51-7.44 (m, 4H), 7.35-7.26 (m, 2H), 4.09 (s, 2H), 1.30 (s, 9H); 13C NMR (100 MHz,
CDCl3, δ, ppm) 196.2, 164.2, 147.6, 136.1, 135.0, 134.2, 128.9, 128.6, 125.8, 120.1, 45.9, 34.4,
31.4; HRMS (ESI-TOF) m/z calcd for C12H21NNaO2 334.1242 [M+Na]+, found 334.1235.
N-(4-isopropylphenyl)-3-oxo-3-phenylpropanamide (1p): white solid, yield 68%; mp
1
130-131 °C ; H NMR (400 MHz, CDCl3, δ, ppm) 9.28 (s, 1H), 8.01-7.98 (m, 2H), 7.63-7.60 (m,
1H), 7.50-7.48 (m, 4H), 7.18-7.16 (m, 2H), 4.09 (s, 2H), 2.89-2.86 (m, 1H), 1.24 (s, 3H), 1.22 (s,
3H); 13C NMR (100 MHz, CDCl3, δ, ppm) 196.4, 163.9, 145.3, 136.1, 135.3, 134.2, 128.9, 128.6,
126.9, 120.4, 45.7, 33.6, 24.0; HRMS (ESI-TOF) m/z calcd for C18H19NNaO2 320.1085 [M+Na]+,
found 320.1080.
N-(4-ethoxyphenyl)-3-oxo-3-phenylpropanamide (1q): white solid, yield 59%; mp
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139-140 °C ; H NMR (400 MHz, CDCl3, δ, ppm) 9.18 (s, 1H), 8.00-7.98 (m, 2H), 7.61-7.59 (m,
1H), 7.50-7.44 (m, 4H), 6.84-6.81 (m, 2H), 4.07 (s, 2H), 4.01-3.96 (m, 2H), 1.39 (t, J = 6.8 Hz,
3H); 13C NMR (100 MHz, CDCl3, δ, ppm) 196.4, 163.8, 155.9, 136.1, 134.2, 130.6, 128.9, 128.6,
122.0, 114.7, 63.7, 45.6, 14.8; HRMS (ESI-TOF) m/z calcd for C17H17NNaO3 306.1106 [M+Na]+,
found 306.1098.
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N-(4-methoxyphenyl)-3-oxo-3-phenylpropanamide (1r): white solid, yield 62%; mp
123-124 °C (Lit.21 123C); 1H NMR (400 MHz, DMSO-d6, δ, ppm) 10.1 (s, 1H), 8.039 (d, J = 7.2
Hz, 2H), 7.67-7.64 (m, 2H), 7.57-7.52 (m, 4H), 6.94-6.88 (m, 2H), 4.14 (s, 2H), 3.72 (s, 3H); 13
C
NMR (100 MHz, DMSO-d6, δ, ppm) 195.1, 165.3, 155.8, 136.8, 134.0, 132.7, 129.2, 128.9, 125.7,
121.1, 55.6, 48.4; HRMS (ESI-TOF) m/z calcd for C16H15NNaO3 308.0721 [M+Na]+, found
308.0734.
N-(3,5-dimethylphenyl)-3-oxo-3-phenylpropanamide (1s): white solid, yield 56%; mp
1
113-114 °C ; H NMR (400 MHz, CDCl3, δ, ppm) 9.30 (s, 1H), 7.97-7.94 (m, 2H), 7.59-7.55 (m,
1H), 7.45-7.41 (m, 2H), 7.21-7.18 (m, 2H), 6.74 (s, 1H), 4.04 (s, 2H), 2.26 (s, 3H), 2.24 (s, 3H);
13C NMR (100 MHz, CDCl3, δ, ppm) 195.9, 164.6, 138.6, 137.5, 136.1, 134.1, 128.9, 128.6, 126.4,
118.1, 46.2, 21.3; HRMS (ESI-TOF) m/z calcd for C17H17NNaO2 306.0929 [M+Na]+, found
306.0911.
N-(3-chloro-4-methylphenyl)-3-oxo-3-phenylpropanamide (1t): white solid, yield 58%; mp
141-142 °C ; 1H NMR (400 MHz, CDCl3, δ, ppm) 9.36 (s, 1H), 8.01 (d, J = 7.2 Hz, 2H), 7.68-7.62
(m, 2H), 7.53-7.49 (m, 2H), 7.34-7.32 (m, 1H), 7.16-7.14 (m, 1H), 4.10 (s, 2H), 2.32 (s, 3H); 13
C
NMR (100 MHz, CDCl3, δ, ppm) 196.5, 163.8, 136.3, 136.0, 134.5, 132.1, 131.0, 129.0, 128.6,
120.8, 118.4, 45.2, 19.5; HRMS (ESI-TOF) m/z calcd for C16H14NNaO2 326.0382 [M+Na]+, found
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N-(4-fluorophenyl)-3-oxo-3-phenylpropanamide (1u): white solid, yield 63%; mp 153-154 °C
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(Lit.22 153C); H NMR (400 MHz, DMSO-d6, δ, ppm) 10.28 (s, 1H), 8.02 (d, J = 7.6 Hz, 2H),
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7.67-7.60 (m, 3H), 7.57-7.51 (m, 2H), 7.17-7.13 (m, 2H), 4.16 (s, 2H); 13C NMR (100 MHz,
DMSO-d6, δ, ppm) 195.0, 165.7, 158.5 (J = 238Hz), 136.7, 134.1, 129.3, 128.8, 125.8, 121.3,
121.2, 115.8 (J = 22Hz), 48.4; HRMS (ESI-TOF) m/z calcd for C15H12FNNaO2 296.0521
[M+Na]+, found 296.0510.
N-(4-chlorophenyl)-3-oxo-3-phenylpropanamide (1v): white solid, yield 66%; mp
158-159 °C (Lit.23 157-158C); 1H NMR (400 MHz, DMSO-d6, δ, ppm) 10.35 (s, 1H), 8.01 (d, J =
7.2 Hz, 2H), 7.67 (t, J = 7.2 Hz, 1H), 7.58-7.56 (m, 3H), 7.52-7.48 (m, 3H), 4.17 (s, 2H); 13C
NMR (100 MHz, DMSO-d6, δ, ppm) 194.9, 166.0, 138.8, 136.7, 134.1, 132.1, 129.3, 128.8, 125.8,
121.4, 48.6; HRMS (ESI-TOF) m/z calcd for C15H12ClNNaO2 312.0226 [M+Na]+, found
312.0214.
Representative Synthesis of 4: 3-Amino-1-oxo-2-(p-tolyl)-2,9-dihydro-1H-indeno[2,1-c]
pyridine-4-carbonitrile (4a). 3-Oxo-3-phenyl-N-(p-tolyl)propanamide 1a (1.0 mmol),
phthalaldehyde 2 (1.0 mmol) and malononitrile 3a (1.0 mmol) were placed in a 5 mL Initiator
reaction vial, followed by NaOH (0.2 mmol) and EtOH ( 2 mL). The reaction vial was then sealed
and prestirred for 20 s before being irradiated in the microwave (time, 15 min; temperature,
100 °C; absorption level, high; fixed hold time) until TLC (2:1 mixture of petroleum ether and
ethyl acetate) revealed the complete consumption of the starting materials. The reaction mixture
was then cooled to room temperature to give a precipitate, which was collected by Büchner
filtration. The solid material was then purified by recrystallization from 95% EtOH to afford the
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desired product 4a as a gray solid, 0.266 g, yield 85%; mp 242-243 °C; IR (KBr, ν, cm-1) 3433,
3173, 2922, 2199, 1669, 1586, 1511, 1423, 1314, 1294, 1197, 1102, 822, 778, 753, 645; 1H NMR
(400 MHz, DMSO-d6, δ, ppm) 8.21-8.18 (m, 1H), 7.66-7.64 (m, 1H), 7.51-7.48 (m, 2H),
7.39-7.37 (m, 2H), 7.21-7.19 (m, 2H), 6.74 (s, 2H), 3.65 (s, 2H), 2.40 (s, 3H); 13C NMR (100
MHz, DMSO-d6, δ, ppm) 159.3, 157.7, 148.5, 146.1, 139.4, 139.0, 132.8, 131.2, 129.5, 129.1,
127.5, 125.8, 122.3, 118.0, 116.9, 64.7, 35.0, 21.3; HRMS (ESI-TOF) m/z calcd for C20H16N3O
314.1293 [M+H]+, found 314.1297.
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3-Amino-2-(4-(tert-butyl)phenyl)-1-oxo-2,9-dihydro-1H-indeno[2,1-c]pyridine-4-carbonitrile
(4b): Yellow solid, 0.295 g, yield 83%; mp 206-208 °C; IR (KBr, ν, cm-1) 3412, 3316, 3235, 2963,
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2196, 1675, 1618, 1521, 1400, 1385, 1112, 1051, 748, 715. H NMR (400 MHz, DMSO-d6, δ,
ppm) 8.21-8.19 (m, 1H), 7.67-7.65 (m, 1H), 7.60-7.58(m, 2H), 7.51-7.49 (m, 2H), 7.24-7.22 (m,
2H), 6.73 (s, 2H), 3.66 (s, 2H), 1.35 (s, 9H); 13C NMR (100 MHz, DMSO-d6, δ, ppm) 159.2, 157.5,
148.5, 146.1, 139.9, 139.0, 135.2, 131.3, 129.5, 127.5, 126.7, 125.8, 122.3, 118.0, 116.9, 64.6,
56.5, 35.0, 21.2, 19.0; HRMS (ESI-TOF) m/z calcd for C23H22N3O 356.1763 [M+H] +, found
356.1792.
3-Amino-2-(4-isopropylphenyl)-1-oxo-2,9-dihydro-1H-indeno[2,1-c]pyridine-4-carbonitrile
(4c): Brown solid, 0.270 g, yield 79%; mp 235-236 °C; IR (KBr, ν, cm-1) 3459, 3316, 3210, 2946,
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2869, 2201, 1682, 1621, 1568, 1528, 1153, 1126, 1018, 828, 747, 716; H NMR (400 MHz,
DMSO-d6, δ, ppm) 8.22-8.19 (m, 1H), 7.66-7.64 (m, 1H), 7.52-7.49(m, 2H), 7.46-7.43 (m, 2H),
7.24-7.21 (m, 2H), 6.72 (s, 2H), 3.65 (s, 2H), 3.00-2.97 (m, 1H) , 1.29-1.26 (m, 6H); 13C NMR
(100 MHz, DMSO-d6, δ, ppm) 159.3, 157.7, 149.9,148.5, 146.1, 138.9, 133.0, 129.4, 129.1, 128.5,
127.5, 125.7, 122.3, 118.0, 116.9, 64.8, 35.0, 33.7, 24.2; HRMS (ESI-TOF) m/z calcd for
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3-Amino-2-(4-methoxyphenyl)-1-oxo-2,9-dihydro-1H-indeno[2,1-c]pyridine-4-carbonitrile (4d):
Gray solid, 0.266 g, yield 81%; mp 208-209 °C ; IR (KBr, ν, cm-1) 3430, 3014, 2972, 2936, 2840,
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2203, 1672, 1503, 1439, 1422, 1304, 1251, 1176, 1102, 1027, 832, 778, 754, 640; H NMR (400
MHz, DMSO-d6, δ, ppm) 8.20-8.18 (m, 1H), 7.66-7.64 (m, 1H), 7.51-7.48(m, 2H), 7.24-7.22 (m,
2H), 7.12-7.10 (m, 2H), 6.80 (s, 2H) , 3.83 (s, 3H), 3.65 (s, 2H); 13C NMR (100 MHz, DMSO-d6,
δ, ppm) 160.2, 159.5, 157.9, 148.5, 146.1, 139.0, 130.5, 129.5, 127.8, 127.5, 125.8, 122.3, 118.0,
116.8, 115.8, 64.6, 55.9, 35.0; HRMS (ESI-TOF) m/z calcd for C20H15N3O2 328.1086 [M-H]-,
found 328.1085.
3-Amino-1-oxo-2-phenyl-2,9-dihydro-1H-indeno[2,1-c]pyridine-4-carbonitrile (4e): Yellow
solid, 0.197 g, yield 66%; mp 257-259 °C (Lit.24 263-265 C); IR (KBr, ν, cm-1) 3451, 3307, 2945,
2845, 2344, 2208, 1674, 1629, 1525, 1450, 1384, 1290, 1126, 1074, 959, 753; 1H NMR (400 MHz,
DMSO-d6, δ, ppm) 8.21-8.19 (m, 1H), 7.67-7.65 (m, 1H), 7.61-7.49 (m, 5H), 7.34-7.32 (m, 2H),
6.80 (s, 2H), 3.66 (s, 2H); 13C NMR (100 MHz, DMSO-d6, δ, ppm) 159.3, 157.6, 148.6, 146.1,
138.9, 135.5, 130.6, 129.9, 129.5, 129.5, 127.5, 125.8, 122.3, 118.0, 116.9, 64.8, 35.0; HRMS
(ESI-TOF) m/z calcd for C19H12N3O 298.0980 [M-H]-, found 298.0990.
3-Amino-2-(4-fluorophenyl)-1-oxo-2,9-dihydro-1H-indeno[2,1-c]pyridine-4-carbonitrile (4f):
Yellow solid, 0.222 g, yield 70%; mp 244-246 °C ; IR (KBr, ν, cm-1) 3453, 3340, 2897, 2201, 1667,
1618, 1508, 1295, 1227, 1155, 1094, 1050, 844, 752, 717, 663; 1H NMR (400 MHz, DMSO-d6, δ,
ppm) 8.20-8.18 (m, 1H), 7.66-7.64 (m, 1H), 7.52-7.47(m, 2H), 7.40-7.39 (m, 4H), 6.97 (s, 2H),
3.64 (s, 2H); 13C NMR (100 MHz, DMSO-d6, δ, ppm) 163.0 (J = 243 Hz), 159.3, 157.8, 148.8,
146.1, 138.9, 131.8 (J = 9 Hz), 131.7, 129.5, 127.5, 125.8, 122.3, 118.0, 117.5 (J = 23 Hz), 116.6,
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64.7, 34.9; HRMS (ESI-TOF) m/z calcd for C19H12FN3O 316.0886 [M-H]-, found 316.0900.
3-Amino-2-(4-chlorophenyl)-1-oxo-2,9-dihydro-1H-indeno[2,1-c]pyridine-4-carbonitrile (4g):
Green solid, 0.243 g, yield 73%; mp 270-272 °C (Lit.24 275-278 C); IR (KBr, ν, cm-1) 3455, 3309,
3207, 2205, 1683, 1621, 1530, 1490, 1399, 1296, 1198, 1154, 1089, 1016, 940, 836, 792, 748, 716,
661; 1H NMR (400 MHz, DMSO-d6, δ, ppm) 8.21-8.19 (m, 1H), 7.66-7.61 (m, 3H), 7.51-7.49 (m,
2H), 7.38-7.36 (m, 2H), 7.00 (s, 2H), 3.64 (s, 2H); 13C NMR (100 MHz, DMSO-d6, δ, ppm) 159.2,
157.7, 148.9, 146/1, 138.9, 134.6, 134.5, 131.5, 130.7, 129.5, 127.5, 125.8, 122.4, 118.0, 116.6,
64.8, 34.9; HRMS (ESI-TOF) m/z calcd for C19H13ClN3O 334,0747 [M+H]+, found 334.0756.
3-Amino-2-(4-bromophenyl)-1-oxo-2,9-dihydro-1H-indeno[2,1-c]pyridine-4-carbonitrile (4h):
Brown solid, 0.294 g, yield 78%; mp 252-253 °C; IR (KBr, ν, cm-1) 3449, 3314, 3211, 2202, 1677,
1628, 1525, 1488, 1396, 1296, 1263, 1153, 1068, 1013, 826, 790, 748, 716; 1H NMR (400 MHz,
DMSO-d6, δ, ppm) 8.21-8.18 (m, 1H), 7.76-7.74 (m, 2H), 7.66-7.64 (m, 1H), 7.51-7.47 (m, 2H),
7.31-7.29 (m, 2H), 7.01 (s, 2H), 3.64 (s, 2H2); 13C NMR (100 MHz, DMSO-d6, δ, ppm) 159.1,
157.6, 148.9, 146.1, 138.9, 135.0, 133.6, 131.8, 129.5, 127.5, 125.8, 123.3, 122.3, 117.9, 116.6,
64.8, 34.9; HRMS (ESI-TOF) m/z calcd for C19H13BrN3O 378.0242 [M+H]+, found 378.0270.
3-Amino-1-oxo-2-(4-(trifluoromethyl)phenyl)-2,9-dihydro-1H-indeno[2,1-c]pyridine-4-carbonit
rile (4i): Yellow solid, 0.283 g, yield 77%; mp 255-256 °C ; IR (KBr, ν, cm-1) 3451, 2207, 1676,
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1632, 1529, 1400, 1330, 1296, 1163, 1101, 1068, 1020, 771, 747, 658; H NMR (400 MHz,
DMSO-d6, δ, ppm) 8.23-8.20 (m, 1H), 7.95-7.93 (m, 2H), 7.67-7.63(m, 1H), 7.61-7.60 (m, 2H),
7.54-7.48 (m, 2H), 7.07 (s, 2H), 3.65 (s, 2H); 13C NMR (100 MHz, DMSO-d6, δ, ppm) 159.1,
157.5, 149.1, 146.1, 139.5, 138.8, 130.8, 130.3 (J = 32 Hz), 129.5, 128.6, 127.7 (J = 4 Hz), 127.5,
126.1, 125.7, 124.5 (J = 271 Hz), 122.4, 120.1, 117.9, 116.5, 65.0, 34.9; HRMS (ESI-TOF) m/z
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calcd for 367.0932 C20H12F3N3O [M] +, found 367.0946.
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3-Amino-2-(3,5-dimethylphenyl)-1-oxo-2,9-dihydro-1H-indeno[2,1-c]pyridine-4-carbonitrile
8
9
(4j): Brown solid, 0.328 g, yield 73%; mp 218-219 °C; IR (KBr, ν, cm-1) 3316, 3210, 2918, 2201,
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1678, 1611, 1587, 1523, 1466, 1272, 1153, 1043, 852, 751, 714, 689; H NMR (400 MHz,
DMSO-d6, δ, ppm) 8.20-8.18 (m, 1H), 7.66-7.64 (m, 1H), 7.51-7.48(m, 2H), 7.16 (s, 1H), 6.92 (s,
2H), 6.75 (s, 2H) , 3.64 (s, 2H), 3.33 (s, 6H); 13C NMR (100 MHz, DMSO-d6, δ, ppm) 159.4,
157.7, 152.2, 148.5, 146.1, 138.9, 132.7, 129.5, 128.8, 127.5, 127.4, 125.8, 122.3, 118.0, 117.0,
64.7, 35.0, 31.6; HRMS (ESI-TOF) m/z calcd for C21H17N3O 326.1293 [M-H]-, found 326.1299.
3-Amino-2-(3-chloro-4-methylphenyl)-1-oxo-2,9-dihydro-1H-indeno[2,1-c]pyridine-4-carbonitr
ile (4k): Brown solid, 0.238 g, yield 69%, mp 223-225 °C ; IR (KBr, ν, cm-1) 3465, 3314, 3203,
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2202, 1681, 1567, 1520, 1444, 1389, 1342, 1268, 1153, 1053, 870, 752, 718, 700; H NMR (400
MHz, DMSO-d6, δ, ppm) 8.21-8.19 (m, 1H), 7.65-7.64 (m, 1H), 7.55-7.48 (m, 4H), 7.22-7.20 (m,
1H), 7.00 (s, 2H), 3.64 (s, 2H), 2.41 (s, 3H); 13C NMR (100 MHz, DMSO-d6, δ, ppm) 159.2, 157.7,
148.8, 146.1, 138.9, 137.3, 134.6, 134.4, 132.9, 129.9, 129.5, 128.2, 127.5, 125.8, 122.4, 118.0,
116.6, 64.7, 34.9, 19.9; HRMS (ESI-TOF) m/z calcd for C20H14ClN3O 348.0904 [M+H]+, found
348.0915.
3-Amino-2-butyl-1-oxo-2,9-dihydro-1H-indeno[2,1-c]pyridine-4-carbonitrile (4l): Yellow solid,
0.178 g, yield 64%; mp 230-231 °C ; IR (KBr, ν, cm-1) 3396, 3152, 2956, 2931, 2868, 2198, 1743,
1666, 1641, 1585, 1520, 1440, 1184, 1101, 1060, 777, 752, 717; 1H NMR (400 MHz, DMSO-d6, δ,
ppm) 8.13-8.11 (m, 1H), 7.63-7.60 (m, 1H), 7.51 (s, 2H), 7.47-7.44 (m, 2H), 4.03 (t, J = 7.6 Hz,
2H), 3.65(s, 2H), 1.52-1.46(m, 2H), 1.37-1.28(m, 2H), 0.89 (t, J = 7.2 Hz, 3H); 13C NMR (100
MHz, DMSO-d6, δ, ppm) 158.9, 156.9, 147.8, 146.0, 138.9, 129.3, 127.4, 125.7, 122.2, 118.3,
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116.0, 64.8, 41.3, 34.9, 29.5, 19.8, 14.2; HRMS (ESI-TOF) m/z calcd for C17H17N3O 278.1293
[M-H]-, found 278.1285.
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3-Amino-2-(4-methoxybenzyl)-1-oxo-2,9-dihydro-1H-indeno[2,1-c]pyridine-4-carbonitrile (4m):
Yellow solid 0.258 g, yield 75%; mp 248-249 °C ; IR (KBr, ν, cm-1) 3388, 3220, 3179, 2897, 2835,
2344, 2209, 2158, 1662, 1629, 1612, 1526, 1518, 1439, 1251, 1179, 1030, 984, 818, 755, 745; 1H
NMR (400 MHz, DMSO-d6, δ, ppm) 8.15-8.13 (m, 1H), 7.63-7.61 (m, 1H), 7.47-7.45(m, 4H),
7.17 (d, J = 8.4 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 5.31 (s, 2H), 3.70 (s, 3H), 3.65 (s, 2H); 13C
NMR (100 MHz, DMSO-d6, δ, ppm) 159.1, 158.9, 157.1, 148.2, 146.1, 138.9, 129.4, 128.6, 128.1,
127.4, 125.7, 122.3, 118.1, 116.1, 114.3, 65.1, 55.5, 43.5, 35.0; HRMS (ESI-TOF) m/z calcd for
C21H16N3O2 342.1243 [M-H]-, found 342.1251.
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3-Amino-2-benzyl-1-oxo-2,9-dihydro-1H-indeno[2,1-c]pyridine-4-carbonitrile (4n): Gray solid,
0.210 g, yield 67%; mp 257-258 °C ; IR (KBr, ν, cm-1) 3420, 3026, 2202, 1663, 1619, 1566, 1519,
1455, 1384, 1068, 748, 693; 1H NMR (400 MHz, DMSO-d6, δ, ppm) 8.17-8.15 (m, 1H), 7.64-7.63
(m, 1H), 7.51-7.46(m, 4H), 7.34-7.31 (m, 2H), 7.27-7.23 (m, 1H), 7.19-7.17 (m, 2H), 5.38 (s, 2H),
3.66 (s, 2H); 13C NMR (100 MHz, DMSO-d6, δ, ppm) 159.0, 157.2, 148.3, 146.1, 138.9, 136.2,
129.4, 128.9, 127.5, 127.4, 126.9, 125.7, 122.3, 118.1, 116.0, 65.1, 44.1, 35.0; HRMS (ESI-TOF)
m/z calcd for C20H14N3O 312.1137 [M-H]-, found 312.1140.
Ethyl
3-amino-2-(4-methoxyphenyl)-1-oxo-2,9-dihydro-1H-indeno
[2,1-c]pyridine-4-
carboxylate (4o): Yellow solid, 0.255 g, yield 68%; mp 191-193 °C ; IR (KBr, ν, cm-1) 3367, 2971,
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2835, 1890, 1736, 1676, 1483, 1368, 1301, 1166, 1028, 1109, 866, 837, 752, 716; H NMR (400
MHz, DMSO-d6, δ, ppm) 7.97-7.95 (m, 1H), 7.60-7.58 (m, 1H), 7.41-7.38(m, 2H), 7.27-7.25(m,
2H), 7.15-7.12(m, 2H), 7.02 (s, 2H), 4.39-4.34 (m, 2H), 3.84 (s, 3H), 3.66 (s, 2H), 1.29 (t, J = 7.2
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Hz, 3H); 13C NMR (100 MHz, DMSO-d6, δ, ppm) 167.8, 160.1, 159.7, 155.9, 149.8, 146.2, 140.9,
130.6, 128.4, 128.0, 126.5, 126.4, 125.1, 119.2, 115.8, 85.0, 60.7, 55.9, 35.5, 14.5; HRMS
(ESI-TOF) m/z calcd for C22H20N2O4 375.1345 [M-H]-, found 375.1334.
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Ethyl 3-amino-1-oxo-2-(p-tolyl)-2,9-dihydro-1H-indeno [2,1-c] pyridine-4-carboxylate (4p):
Yellow solid, 0.224 g, yield 62%; mp 186-188 °C ; IR (KBr, ν, cm-1) 3378, 3253, 2973, 2922, 1677,
1638, 1548, 1513, 1484, 1401, 1366, 1315, 1301, 1239, 1108, 1019, 817, 792, 753; 1H NMR (400
MHz, DMSO-d6, δ, ppm) 7.96-7.94 (m, 1H), 7.59-7.58 (m, 1H), 7.41-7.39(m, 4H), 7.22-7.20 (m,
2H), 6.95 (s, 2H), 4.39-4.33 (m, 2H), 3.66 (s, 2H), 2.41 (s, 3H) , 1.29 (t, J = 7.2 Hz, 3H); 13C
NMR (100 MHz, DMSO-d6, δ, ppm) 167.8, 159.6, 155.6, 149.9, 146.2, 140.9, 139.2, 133.1, 131.2,
129.2, 128.4, 126.5, 126.4, 125.1, 119.2, 85.1, 60.7, 35.5, 21.3, 14.5; HRMS (ESI-TOF) m/z calcd
for C22H21N2O3 361.1552 [M+H]+, found 361.1562.
Ethyl 3-amino-2-(4-fluorophenyl)-1-oxo-2,9-dihydro -1H-indeno[2,1-c]pyridine-4-carboxylate
(4q): Yellow solid, 0.278 g, yield 76%; mp 206-208 °C ; IR (KBr, ν, cm-1) 3239, 3123, 3073, 2978,
2929, 1680, 1548, 1506, 1395, 1369, 1314, 1245, 1217, 1110, 1016, 843, 757, 716; 1H NMR (400
MHz, DMSO-d6, δ, ppm) 7.96-7.94 (m, 1H), 7.59-7.58 (m, 1H), 7.43-7.39(m, 6H), 7.12 (s, 2H),
4.39-4.34 (m, 2H), 3.66 (s, 2H), 1.28 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, DMSO-d6, δ, ppm)
167.8, 166.9, 162.8 (J = 244 Hz), 159.6, 158.1, 155.7, 150.1, 146.2, 140.8, 132.1, 132.0, 131.9 (J
= 9 Hz), 128.5, 126.5, 126.4, 125.1, 121.8, 119.1, 117.5 (J = 23 Hz), 117.1, 85.2, 61.8, 60.7, 35.4,
14.5; HRMS (ESI-TOF) m/z calcd for C21H17FN2O3 363.1145 [M-H]-, found 363.1161.
Ethyl 3-amino-2-(4-chlorophenyl)-1-oxo-2,9-dihydro -1H-indeno[2,1-c]pyridine-4-carboxylate
(4r): Yellow solid, 0.270 g, yield 71%; mp 220-222 °C ; IR (KBr, ν, cm-1) 3412, 2973, 2922, 1674,
1631, 1542, 1488, 1391, 1368, 1301, 1150, 1111, 1099, 1059, 837, 747, 713; 1H NMR (400 MHz,
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DMSO-d6, δ, ppm) 7.96-7.94 (m, 1H), 7.68-7.64 (m, 2H), 7.61-7.59(m, 1H), 7.43-7.39 (m, 4H),
7.15 (s, 2H), 4.39-4.34 (m, 2H), 3.66 (s, 2H), 1.29 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
DMSO-d6, δ, ppm) 167.8, 159.4, 155.5, 150.1, 146.2, 140.8, 134.7, 134.5, 131.6, 130.7, 128.5,
126.6, 126.4, 125.1, 119.0, 85.2, 60.7, 35.4, 14.5; HRMS (ESI-TOF) m/z calcd for C21H17ClN2O3
379.0849 [M-H]-, found 379.0838.
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Ethyl 3-amino-2-(4-bromophenyl)-1-oxo-2,9-dihydro -1H-indeno[2,1-c]pyridine-4-carboxylate
(4s): Yellow solid, 0.302 g, yield 71%; mp 220-221 °C ; IR (KBr, ν, cm-1) 3411, 3124, 2975, 1671,
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1662, 1595, 1558, 1543, 1486, 1393, 1301, 1112, 1012, 877, 748, 712; H NMR (400 MHz,
DMSO-d6, δ, ppm) 7.96-7.94 (m, 1H), 7.80-7.78 (m, 2H), 7.60-7.58(m, 1H), 7.41-7.39(m, 2H),
7.34-7.32(m, 2H), 7.14 (s, 2H), 4.39-4.33 (m, 2H), 3.66 (s, 2H2), 1.28 (t, J = 7.2 Hz, 3H); 13C
NMR (100 MHz, DMSO-d6, δ, ppm) 167.8, 159.4, 155.5, 150.2, 146.2, 140.8, 135.2, 133.6, 131.9,
128.5, 126.6, 126.4, 125.1, 123.2, 119.0, 85.2, 60.7, 35.4, 14.5; HRMS (ESI-TOF) m/z calcd for
C21H17BrN2O3 423.0344 [M-H]-, found 423.0351.
General Experimental Procedures for Compounds 5. A mixture of 40 mmol NaH, 30 mL
1,4-dioxane, 40 mmol acetophenone was stirred at RT. 40 mmol isothiocyanatobenzene was
added dropwise and stirring was continued at RT for 2 h. The solids were collected by filtration,
washed with 1,4-dioxane. The solids were dissolved with water then slowly neutraliazed under
stirring with HCl. After filtration , the filter cake was dried to yield product as a light yellow solid.
3-Oxo-N,3-diphenylpropanethioamide (5a): yellow solid, yield 47%; mp 79-80 °C (Lit.25
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79-81C); H NMR (400 MHz, CDCl3, δ, ppm) 10.98 (s, 1H), 8.06-8.02 (m, 2H), 7.80-7.78 (m,
3H), 7.42-7.40 (m, 5H), 4.64 (s, 2H); 13C NMR (100 MHz, CDCl3, δ, ppm) 197.0, 190.8, 137.8,
135.8, 134.5, 129.0, 128.9, 128.8, 128.7, 123.6, 54.3; HRMS (ESI-TOF) m/z calcd for
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C15H13NNaOS 278.0616 [M+Na]+, found 278.0606.
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3-Oxo-3-phenyl-N-(p-tolyl)propanethioamide (5b): yellow solid, yield 50%; mp 99-100 °C
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(Lit.25 102-103C); H NMR (400 MHz, CDCl3, δ, ppm) 10.93 (s, 1H), 7.08 (d, J = 7.6 Hz, 2H),
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7.55-7.51 (m, 1H), 7.47-7.40 (m, 4H), 7.22-7.20 (m, 2H), 4.65 (s, 2H), 2.37 (s, 3H); 13C NMR
(100 MHz, CDCl3, δ, ppm) 197.1, 191.0, 137.0, 134.5, 129.5, 129.0, 128.8, 128.6, 123.6, 54.0,
21.2; HRMS (ESI-TOF) m/z calcd for C16H15NNaOS 292.0772 [M+Na]+, found 292.0768.
3-Oxo-3-phenyl-N-(m-tolyl)propanethioamide (5c): yellow oil, yield 43%; 1H NMR (400 MHz,
CDCl3, δ, ppm) 10.93 (s, 1H), 8.06-8.04 (m, 2H), 7.53-7.49 (m, 2H), 7.42-7.38 (m, 3H), 7.31-7.27
(m, 2H), 4.64 (s, 2H), 2.36 (s, 3H); 13C NMR (100 MHz, CDCl3, δ, ppm) 196.8, 190.8, 138.9,
137.8, 135.9, 134.4, 129.0, 128.9, 128.7, 127.9, 126.3, 124.1, 54.5, 21.4; HRMS (ESI-TOF) m/z
calcd for C16H15NNaOS 292.0772 [M+Na]+, found 292.0767.
Representative Synthesis of 6: 3-Amino-2-phenyl-1-thioxo-2,9-dihydro-1H-indeno[2,1-c]
pyridine-4-carbonitril (6a). 3-Oxo-N,3-diphenylpropanethioamide 5a (1.0 mmol),
phthalaldehyde 2 (1.0 mmol) and malononitrile 3a (1.0 mmol) were placed in a 5 mL Initiator
reaction vial, followed by NaOH (0.2 mmol) and EtOH (2 mL). The reaction vial was then sealed
and prestirred for 20 s before being irradiated in the microwave (time, 15 min; temperature, 100
oC; absorption level, high; fixed hold time) until TLC (2:1 mixture of petroleum ether and ethyl
acetate) revealed the complete consumption of the starting materals. The reaction mixture was
then cooled to room temperature to give a precipitate, which was collected by Büchner filtration.
The solid material was then purified by recrystallization from 95% EtOH to afford the desired
product 6a as a yellow solid, 0.247 g, yield 78%; mp 274-275 °C (Lit.24 277-278 C); IR (KBr, ν,
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cm-1) 3461, 2205, 1631, 1566, 1473, 1361, 1276, 1186, 104, 743, 710; H NMR (400 MHz,
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DMSO-d6, δ, ppm) 8.24-8.22 (m, 1H), 7.68-7.67 (m, 1H), 7.62-7.58 (m, 2H), 7.56-7.51 (m, 3H),
7.30-7.28 (m, 2H), 7.03 (s, 2H), 3.76 (s, 2H); 13C NMR (100 MHz, DMSO-d6, δ, ppm) 178.4,
156.9, 146.8, 143.8, 139.0, 138.3, 131.9, 130.9, 130.4, 130.0, 129.1, 127.9, 125.7, 123.4, 117.1,
72.0; HRMS (ESI-TOF) m/z calcd for C19H13N3NaS 338.0728 [M+Na]+, found 338.0716.
Methyl 3-amino-1-thioxo-2-(p-tolyl)-2,9-dihydro-1H- indeno[2,1-c] pyridine-4-carboxylate (6b):
Brown solid, 0.246 g, yield 75%; mp 240-241 °C (Lit.24 245 C); IR (KBr, ν, cm-1) 3318, 2203,
1542, 1464, 1404, 1359, 1312, 1185, 1106, 1037, 886, 774, 737; 1H NMR (400 MHz, DMSO-d6, δ,
ppm) 8.18 (d, J = 7.2 Hz, 1H), 7.64-7.62 (m, 1H), 7.51-7.47 (m, 2H), 7.40-7.38 (m, 2H), 7.15 (d, J
= 7.6 Hz, 2H), 6.97 (s, 2H), 3.70 (s, 2H), 2.4 (s, 3H); 13C NMR (100 MHz, DMSO-d6, δ, ppm)
178.5, 157.1, 146.8, 143.7, 139.4, 138.3, 136.4, 131.9, 131.4, 130.4, 128.7, 127.9, 125.7, 123.4,
117.1, 71.9, 21.4; HRMS (ESI-TOF) m/z calcd for C20H16N3S 330.1065 [M+H]+, found 330.1042.
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3-Amino-1-thioxo-2-(m-tolyl)-2,9-dihydro-1H-indeno[2,1-c]pyridine-4-carbonitrile
(6c):
Yellow solid, 0.237 g, yield 72%; mp 236-238 °C ; IR (KBr, ν, cm-1) 3304, 3214, 2212, 1719, 1637,
1542, 1475, 1359, 1276, 1185, 1062, 791, 737, 684; 1H NMR (400 MHz, DMSO-d6, δ, ppm) 8.14
(d, J = 7.2 Hz, 1H), 7.61-7.59 (m, 1H), 7.50-7.44 (m, 3H), 7.34-7.32 (m, 1H), 7.09-7.07 (m, 2H),
6.91 (s, 2H), 3.67 (s, 2H), 2.37 (s, 3H); 13C NMR (100 MHz, DMSO-d6, δ, ppm) 178.3, 157.0,
146.9, 146.8, 143.8, 140.7, 139.0, 138.3, 132.1, 131.0, 130.9, 130.6, 129.4, 128.0, 126.1, 125.8,
123.5, 117.2, 72.2, 21.6; HRMS (ESI-TOF) m/z calcd for C20H15N3SNa 352.0884 [M+Na]+, found
352,0877.
Ethyl 3-amino-2-phenyl-1-thioxo-2,9-dihydro-1H-indeno [2,1-c]pyridine-4-carboxylate (6d):
Yellow solid, 0.244 g, yield 67%; mp 184-185 °C ; IR (KBr, ν, cm-1) 3431, 2968, 2876, 1659, 1590,
1349, 1309, 1275, 1205, 1118, 1014, 763, 732, 696; 1H NMR (400 MHz, DMSO-d6, δ, ppm) 7.94
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(d, J = 7.6 Hz, 1H), 7.64-7.60 (m, 3H), 7.56-7.52 (m, 1H), 7.46-7.37 (m, 2H), 7.30 (d, J = 7.2 Hz,
2H), 6.87 (s, 2H), 4.44-4.39 (m, 2H), 3.81 (s, 2H), 1.30 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
DMSO-d6, δ, ppm) 194.6, 167.6, 154.8, 147.2, 144.8, 139.9, 139.5, 133.1, 131.1, 130.1, 129.7,
129.2, 127.2, 127.1, 125.3, 92.7, 61.8, 14.5; HRMS (ESI-TOF) m/z calcd for C21H18N2O2S
362.1089 [M]+, found 362.1089.
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Ethyl 3-amino-1-thioxo-2-(p-tolyl)-2,9-dihydro-1H- indeno[2,1-c]pyridine-4-carboxylate (6e):
Brown solid, 0.248 g, yield 66%; mp 159-161 °C ; IR (KBr, ν, cm-1) 3415, 1719, 1659, 1589, 1537,
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1349, 1273, 1241, 1099, 1014, 868, 820, 767, 735; H NMR (300 MHz, DMSO-d6, δ, ppm) 7.94
(d, J = 7.5 Hz, 1H), 7.62-7.59 (m, 1H), 7.46-7.36 (m, 4H), 7.17-7.14 (m, 2H), 6.87 (s, 2H),
4.45-4.38 (m, 2H), 3.80 (s, 2H), 2.41 (s, 3H), 1.30 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
DMSO-d6, δ, ppm) 177.5, 167.4, 154.7, 147.0, 144.6, 139.7, 139.3, 136.8, 132.8, 131.4, 129.5,
129.0, 128.7, 127.0, 126.9, 125.1, 92.5, 61.6, 21.4, 14.3; HRMS (ESI-TOF) m/z calcd for
C22H21N2O2S 377.1324 [M+H]+, found 377.1312.
Methyl 3-amino-2-phenyl-1-thioxo-2,9-dihydro-1H- indeno[2,1-c] pyridine-4-carboxylate (6f):
Brown solid, 0.210 g, yield 60%; mp 184-185 °C ; IR (KBr, ν, cm-1) 3454, 1656, 1581, 1535, 1316,
1246, 1216, 1154, 1120, 948, 783, 767, 706; 1H NMR (400 MHz, DMSO-d6, δ, ppm) 7.94 (d, J =
7.6 Hz, 1H), 7.64-7.60 (m, 3H), 7.56-7.52 (m, 1H), 7.46-7.37 (m, 2H), 7.30 (d, J = 7.2 Hz, 2H),
6.87 (s, 2H), 3.91 (s, 3H), 3.80 (s, 2H); 13C NMR (100 MHz, DMSO-d6, δ, ppm) 177.6, 167.9,
154.7, 147.2, 144.8, 139.9, 139.5, 133.1, 131.1, 129.7, 129.2, 127.4, 127.0, 125.3, 92.6, 52.5, 52.4;
HRMS (ESI-TOF) m/z calcd for C20H17N2O2S 349.1011 [M+H]+, found 349,0998.
Methyl 3-amino-1-thioxo-2-(p-tolyl)-2,9-dihydro-1H- indeno[2,1-c]pyridine-4-carboxylate (6g):
Brown solid, 0.211 g, yield 58%; mp 148-150 °C ; IR (KBr, ν, cm-1) 3415, 1719, 1656, 1587, 1535,
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1316, 1276, 1216, 1154, 1199, 948, 820, 767, 736;1H NMR (400 MHz, DMSO-d6, δ, ppm)
7.87-7.85 (m, 1H), 7.63-7.61 (m, 1H), 7.47-7.40 (m, 4H), 7.16-7.14 (m, 2H), 6.85 (s, 2H), 3.91 (s,
3H), 3.79 (s, 2H), 2.41 (s, 3H); 13C NMR (100 MHz, DMSO-d6, δ, ppm) 177.6, 167.7, 154.6,
147.0, 144.5, 139.7, 139.3, 136.8, 132.8, 131.4, 129.7, 129.5, 128.7, 127.2, 126.8, 125.1, 92.3,
52.3, 21.4; HRMS (ESI-TOF) m/z calcd for C21H17N2O2S 361.1011 [M-H]-, found 361.1012.
Representative Synthesis of 8: 3-Amino-2-(4-(tert-butyl)phenyl)-1-oxo-1,2,4a,5,6,7-
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hexahydroisoquinoline-4-carbonitrile
(8a).
3-(4-(tert-Butyl)phenyl)-3-oxo-N-phenyl
propanamide 1b (1.0 mmol), glutaraldehyde 7 (1.0 mmol) and malononitrile 3a (1.0 mmol) were
placed in a 5 mL Initiator reaction vial, followed by NaOH (0.2 mmol) and EtOH (2 mL). The
reaction vial was then sealed and prestirred for 20 s before being irradiated in the microwave (time,
o
15 min; temperature, 100 C; absorption level, high; fixed hold time) until TLC (2:1 mixture of
petroleum ether and ethyl acetate) revealed the complete consumption of the starting materials.
The reaction mixture was then cooled to room temperature to give a precipitate, which was
collected by Büchner filtration. The solid material was then purified by recrystallization from 95%
EtOH to afford the desired product 8a as a yellow solid, 0.240 g, yield 75%; mp 209-210 °C; IR
(KBr, ν, cm-1) 3452, 3307, 3199, 2964, 2183, 1696, 1641, 1592, 1414, 1310, 1255, 1128, 821, 753;
1H NMR (400 MHz, DMSO-d6, δ, ppm) 7.51 (d, J = 8.4 Hz, 2H), 7.16 (d, J = 8.4 Hz, 2H),
6.84-6.83(m, 1H), 5.38(s, 2H), 3.33-3.32(m, 1H), 2.29-2.27 (m, 2H), 2.16-2.13 (m, 1H), 1.87-1.84
(m, 1H), 1.59-1.54 (m, 1H), 1.42-1.39 (m, 1H), 1.33 (s, 9H); 13C NMR (100 MHz, DMSO-d6, δ,
ppm) 164.0, 153.3, 151.7, 139.0, 132.9, 129.8, 129.6, 126.7, 120.6, 100.0, 59.7, 34.9, 31.5, 30.2,
28.5, 25.8, 20.7; HRMS (ESI-TOF) m/z calcd for C20H22N3O 320.1763 [M-H]-, found 320.1771.
3-Amino-2-(4-isopropylphenyl)-1-oxo-1,2,4a,5,6,7-hexahydroisoquinoline-4-carbonitrile (8b):
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Yellow solid, 0.228 g, yield 74%; mp 190-192 °C ; IR (KBr, ν, cm-1) 3463, 3306, 3197, 2962, 2869,
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2813, 2217, 2186, 1693, 1643, 1592, 1527, 1413, 1310, 1257, 1202, 1129, 823, 759, 719; H
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NMR (400 MHz, DMSO-d6, δ, ppm) 7.36 (d, J = 8.4 Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H),
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6.84-6.83(m, 1H), 5.38(s, 2H), 3.33-3.32(m, 1H), 3.00-2.93 (m, 1H), 2.29-2.24 (m, 2H), 2.17-2.13
(m, 1H), 1.87-1.84 (m, 1H), 1.60-1.53 (m, 1H), 1.41-1.35 (m, 1H), 1.26 (s, 3H), 1.24 (s, 3H); 13
C
NMR (100 MHz, DMSO-d6, δ, ppm) 164.0, 153.3, 149.4, 139.0, 133.1, 129.9, 129.8, 127.7, 120.6,
59.6, 33.6, 30.3, 28.5, 25.8, 24.2, 20.7; HRMS (ESI-TOF) m/z calcd for C19H20N3O 306.1606
[M-H]-, found 306.1600.
3-Amino-2-(4-ethoxyphenyl)-1-oxo-1,2,4a,5,6,7-hexahydroisoquinoline-4-carbonitrile
(8c):
White solid, 0.206 g, yield 67%; mp 250-251 °C ; IR (KBr, ν, cm-1) 3469, 3325, 2981, 2938, 2183,
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1690, 1647, 1591, 1510, 1410, 1313, 1257, 1176, 1114, 1043, 920, 839, 806, 746; H NMR (400
MHz, DMSO-d6, δ, ppm) 7.14 (d, J = 8.8 Hz, 2H), 7.00 (d, J = 8.8 Hz, 2H), 6.83-6.82(m, 1H),
5.43(s, 2H), 4.10-4.04(m, 2H), 3.35-3.30 (m, 1H), 2.28-2.26 (m, 2H), 2.16-2.12 (m, 1H),
1.86-1.83 (m, 1H), 1.61-1.51 (m, 1H), 1.40-1.32 (m, 4H); 13C NMR (100 MHz, DMSO-d6, δ, ppm)
164.1, 159.1, 153.5, 138.9, 131.2, 129.8, 127.7, 120.7, 115.5, 63.8, 59.3, 30.3, 28.5, 25.8, 20.7,
15.1; HRMS (ESI-TOF) m/z calcd for C18H18N3O2 308.1399 [M-H]-, found 308.1417.
3-amino-2-(4-methoxyphenyl)-1-oxo-1,2,4a,5,6,7-hexahydroisoquinoline-4-carbonitrile
(8d):
Brown solid, 0.210 g, yield 71%; mp 217-218 °C ; IR (KBr, ν, cm-1) 3461, 3316, 3244, 3201, 2933,
2859, 2836, 2361, 2182, 1688, 1645, 1591, 1509, 1414, 1314, 1254, 1131, 1023, 967, 826, 761; 1H
NMR (400 MHz, DMSO-d6, δ, ppm) 7.16 (d, J = 8.8 Hz, 1H), 7.02 (d, J = 8.8 Hz, 1H),
6.83-6.82(m, 1H), 5.44(s, 2H), 3.81(s, 3H), 3.34-3.30 (m, 1H), 2.28-2.27 (m, 2H), 2.17-2.13 (m,
1H), 1.87-1.84 (m, 1H), 1.60-1.54 (m, 1H), 1.41-1.32 (m, 1H); 13C NMR (100 MHz, DMSO-d6, δ,
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ppm) 164.1, 159.8, 153.5, 138.9, 131.2, 129.8, 127.8, 120.7, 115.0, 59.3, 55.8, 30.3, 28.5, 25.8,
20.7; HRMS (ESI-TOF) m/z calcd for C17H16N3O2 294.1243 [M-H]-, found 294.1257.
3-Amino-1-oxo-2-(p-tolyl)-1,2,4a,5,6,7-hexahydroisoquinoline-4-carbonitrile (8e): Yellow solid,
0.193 g, yield 69%; mp 269-270 °C ; IR (KBr, ν, cm-1) 3447, 3329, 2934, 2863, 2804, 2365, 2180,
1680, 1643, 1583, 1416, 1314, 1261, 1203, 1136, 1080, 806, 743; 1H NMR (400 MHz, DMSO-d6,
δ, ppm) 7.28 (d, J = 7.2 Hz, 2H), 7.11 (d, J = 7.2 Hz, 2H), 6,82(s, 1H), 5.41(S, 2H), 3.32-3.30(m,
1H), 2.35 (s, 3H), 2.26 (s, 2H), 2.14-2.11 (m, 1H), 1.86-1.82 (m, 1H), 1.57-1.50 (m, 1H) ,
1.39-1.33 (m, 1H); 13C NMR (100 MHz, DMSO-d6, δ, ppm) 164.0, 153.3, 138.9, 138.8, 132.9,
130.4, 129.8, 129.7, 120.6, 59.5, 30.3, 28.5, 25.8, 21.2, 20.7; HRMS (ESI-TOF) m/z calcd for
C17H16N3O 278.1293 [M-H]-, found 278.1300.
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3-Amino-2-(3,5-dimethylphenyl)-1-oxo-1,2,4a,5,6,7-hexahydroisoquinoline-4-carbonitrile (8f):
White solid, 0.199 g, yield 68%; mp 203-205 °C; IR (KBr, ν, cm-1) 3368, 2938, 2182, 1692, 1649,
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1591, 1412, 1323, 1260, 1128, 841, 745; H NMR (400 MHz, DMSO-d6, δ, ppm) 7.09 (s, 1H),
6.86 (s, 2H), 6.82-6.81(m, 1H), 5.42(s, 2H), 3.33-3.30(m, 1H), 2.30 (s, 6H), 2.28-2.26 (m, 2H),
2.16-2.12 (m, 2H), 1.86-1.83 (m, 1H), 1.59-1.53 (m, 1H), 1.41-1.31 (m, 1H); 13C NMR (100 MHz,
DMSO-d6, δ, ppm) 163.9, 153.2, 139.8, 139.1, 138.8, 135.3, 130.8, 129.8, 127.5, 120.6, 59.4, 30.2,
28.5, 25.8, 21.2, 20.7; HRMS (ESI-TOF) m/z calcd for C18H18N3O 292.1450 [M-H]-, found
292.1445.
3-Amino-2-(3-chloro-4-methylphenyl)-1-oxo-1,2,4a,5,6,7-hexahydroisoquinoline-4-carbonitrile
(8g): Yellow solid, 0.189 g, yield 60%; mp 144-145 °C ; IR (KBr, ν, cm-1) 3508, 3387, 2892, 2841,
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2218, 2162, 1714, 1673, 1614, 1557, 1508, 1368, 1337, 1288, 1279, 1216, 1182, 956, 867; H
NMR (400 MHz, DMSO-d6, δ, ppm) 7.45-7.36 (m, 2H), 7.12 (d, J = 8.0 Hz, 1H),6,82(s, 1H),
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5.62(S, 2H), 3.31-3.29(m, 1H), 2.37 (s, 3H), 2.26 (s, 2H), 2.14-2.11 (m, 1H), 1.85-1.82 (m, 1H),
1.60-1.50 (m, 1H), 1.40-1.30 (m, 1H); 13C NMR (100 MHz, DMSO-d6, δ, ppm) 164.0, 153.2,
139.2, 136.8, 134.5, 133.8, 132.1, 130.6, 129.7, 128.9, 120.6, 59.7, 30.2, 28.4, 25.9, 20.7, 19.8;
HRMS (ESI-TOF) m/z calcd for C17H15ClN3O 312.0904 [M-H]-, found 312.0893.
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3-Amino-2-(4-fluorophenyl)-1-oxo-1,2,4a,5,6,7-hexahydroisoquinoline-4-carbonitrile
(8h):
Yellow solid, 0.148 g, yield 52%; mp 156-158 °C ; IR (KBr, ν, cm-1) 3379,3316, 3213, 3076, 2936,
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2808, 2178, 1689, 1650, 1579, 1506, 1420, 1313, 1258, 1152, 833, 762; H NMR (400 MHz,
DMSO-d6, δ, ppm) 7.29 (d, J = 7.2 Hz, 4H), 6.83-6.82(m, 1H), 5.57(s, 2H), 3.33-3.30 (m, 1H),
2.28-2.26 (m, 2H), 2.15-2.11 (m, 1H), 1.86-1.83 (m, 1H), 1.58-1.52 (m, 1H), 1.40-1.34 (m, 1H);
13C NMR (100 MHz, DMSO-d6, δ, ppm) 164.0, 162.4 (J = 244 Hz), 153.3, 139.1, 132.4 (J = 9
Hz), 131.8, 131.7, 129.7, 120.6, 116.6 (J = 23 Hz), 59.5, 30.2, 28.5, 25.8, 20.7; HRMS (ESI-TOF)
m/z calcd for C16H13FN3O 282.1043 [M-H]-, found 282.1050.
3-Amino-2-(4-chlorophenyl)-1-oxo-1,2,4a,5,6,7-hexahydroisoquinoline-4-carbonitrile
(8i):
White solid, 0.150 g, yield 50%; mp 180-181 °C ; IR (KBr, ν, cm-1) 3386, 3310, 3210, 2923, 2864,
2816, 2175, 1688, 1650, 1597, 1490, 1309, 1257, 1199, 1089, 812; 1H NMR (400 MHz, DMSO-d6,
δ, ppm) 7.52 (d, J = 8.4 Hz, 2H), 7.27 (d, J = 8.8 Hz, 2H),6.83-6.82(m, 1H), 5.63(s, 2H),
3.33-3.30 (m, 1H), 2.28-2.24 (m, 2H), 2.15-2.11 (m, 1H), 1.86-1.83 (m, 1H), 1.58-1.52 (m, 1H),
1.40-1.30 (m, 1H); 13C NMR (100 MHz, DMSO-d6, δ, ppm) 163.9, 153.2, 139.2, 134.6, 133.9,
132.1, 129.8, 129.7, 120.6, 59.6, 30.2, 28.5, 25.9, 20.7; HRMS (ESI-TOF) m/z calcd for
C16H13ClN3O 298.0747 [M-H]-, found 298.0744.
ACKNOWLEDGMENTS
We are grateful for financial support from the Natural Science Foundation of Jiangsu Province
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