Divergent Syntheses of Isoquinolines and Indolo[1,2-a]quinazolines by Copper-Catalyzed Cascade Annulation from 2-Haloaryloxime Acetates with Active Methylene Compounds and Indoles

Article abstract of DOI:10.1021/acs.joc.5b02914

A convenient and reliable method for the direct construction of isoquinolines is described. A series of isoquinoline derivatives were synthesized, with high chemo- and regioselectivities, via the copper-catalyzed cascade reaction of 2-haloaryloxime acetates with β-diketones, β-keto esters, and β-keto nitriles. This tandem annulation process features inexpensive catalysts, no need for additional ligands, and excellent functional group tolerance, which makes it have potential synthetic applications. Furthermore, this strategy could also be used to enter functionalized indolo[1,2-a]quinazolines by using indoles as the counterpart of the 2-haloaryloxime acetates.

Full text of DOI:10.1021/acs.joc.5b02914

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Article
Divergent Syntheses of Isoquinolines and Indolo[1,2-a]quinazolines
by Copper-Catalyzed Cascade Annulation from 2-Haloaryloxime
Acetates with Active Methylene Compounds and Indoles
Huanfeng Jiang, Jidan Yang, Xiaodong Tang, and Wanqing Wu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02914 • Publication Date (Web): 01 Feb 2016
Downloaded from http://pubs.acs.org on February 2, 2016
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Divergent Syntheses of Isoquinolines and
Indolo[1,2-a]quinazolines by Copper-Catalyzed
Cascade Annulation from 2-Haloaryloxime Acetates
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with Active Methylene Compounds and Indoles
Huanfeng Jiang*, Jidan Yang, Xiaodong Tang, and Wanqing Wu
School of Chemistry and Chemical Engineering, South China University of Technology,
Guangzhou 510640, China
Fax: (+86) 20ꢀ8711ꢀ2906; Eꢀmail: jianghf@scut.edu.cn
Abstract: A convenient and reliable method for the direct construction of
isoquinolines is described. A series of isoquinoline derivatives were synthesized, with
high chemoꢀ and regioselectivities, via the copperꢀcatalyzed cascade reaction of
2ꢀhaloaryloxime acetates with βꢀdiketones, βꢀketo esters and βꢀketo nitriles. This
tandem annulation process features inexpensive catalysts, no need of additional
ligands, and excellent functional group tolerance, which make it have potential
synthetic applications. Furthermore, this strategy could also be used to entry to
functionalized indolo[1,2ꢀa]quinazolines by using indoles as the counterpart of the
2ꢀhaloaryloxime acetates.
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INTRODUCTION
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Nitrogenꢀcontaining heterocycles are an important subunit of alkaloidal compounds,
which widely occur in natural products and pharmaceutical compounds.1 In fact,
isoquinoline and its derivatives have recently been reported to be attractive
azaheterocyclic skeletons, with the synthetic use for inhibitors of 11βꢀHSD1,2
antiꢀHIV,3 the precursor of dopamine agonist and antagonist,4 ionꢀchannel blocker,5
chiral ligands,6 and phosphorescent emitters of OLEDs (Scheme 1).7 The classic
BischlerꢀNapieralski, PomeranzꢀFritsch, and PictetꢀSpengler reactions opened the way
to the preparation of isoquinolines.8 Similarly, indolo[1,2ꢀa]quinazoline derivatives
represent an important nitrogenꢀcontaining tetracyclic motif in a variety of bioactive
compounds,9 such as antitumor agents and Protein Kinase CK2 Inhibitor (Scheme 1).
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9a,9b
To the best of our knowledge, the synthesis of functionalized
indolo[1,2ꢀa]quinazolines is rarely reported.9,10 Vidal described pioneering work on
the synthesis of indolo[1,2ꢀa]quinazolines via intramolecular [3+2] cycloadditions of
azidoꢀketenimines.10c Recently, Liu and Perumal developed a Cu catalytic system for
the synthesis of indolo[1,2ꢀa]quinazolines.10d, 10e However, the preparation of some
practical and sensitive isoquinolines such as 4ꢀcyanoisoquinoline and
3ꢀaminoisoquinoline derivatives is one continuing challenge among general
preparative methods and the example of direct functionalization of indoles for the
synthesis of indolo[1,2ꢀa]quinazoline derivatives have not been described. Thus, the
development of efficient procedures for acquisition of isoquinolines and
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indolo[1,2ꢀa]quinazolines from easily available starting materials remains highly
desirable.
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Ketoximes and their derivatives are versatile building blocks in organic synthesis,
which provide convenient method to a broad range of functionalized Nꢀcontaining
heteropolycycles. Generally, two intramolecular cyclization strategies are typically
employed: (i) SN2ꢀtype substitution,11 (ii) iminyl radical reaction.12 In recent years,
great developments in the field of transitionꢀmetal (ruthenium,13 rhodium,14 and
palladium,15) catalyzed N–O bond oxidative cleavage of oxime derivatives provided
new promising approaches to assemble Nꢀcontaining heterocycles. Practically, a
number of elegant studies in copperꢀcatalyzed cyclization of oxime esters to prepare
various nitrogenꢀcontaining motifs have been reported.16 For example, Yoshikai
described a modular synthesis of pyridine through synergistic copper/iminium
catalysis from oximes and enals.16c Guan developed efficient synthetic protocols for
symmetrical Nꢀheterocycle compounds by copperꢀcatalyzed cyclization of oxime
esters.16b, 16d As our continuing interest in the search for Nꢀheterocycle synthesis
through copperꢀcatalyzed coupling of ketoxime esters,17 herein, we present a concise
copperꢀcatalyzed Ullmannꢀtype reaction and intramolecular condensation process to
construct functionalized isoquinolines and indolo[1,2ꢀa]quinazolines under mild
reaction conditions from 2ꢀhaloaryloxime acetates with active methylene compounds
and indoles.
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Scheme 1. Representative Examples of Bioactive Tetracyclic Compounds Containing
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the Isoquinoline and Indole Motif
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RESULTS AND DISCUSSION
The investigation was initiated by choosing the reaction of 2ꢀbromoketoxime acetate
(1a) with 1ꢀphenylbutaneꢀ1,3ꢀdione (2a) as a model system (Table 1). To our delight,
the desired product 3a was obtained in 83% yield with good regioselectivity in the
presence of CuBr and K2CO3 (entry 1). A broad range of copper salts were screened,
including CuI, CuCl, Cu(OTf)2, and Cu(OAc)2, and CuI was found to be the most
effective catalyst for the transformation (entries 2ꢀ5). Undoubtedly, no desired product
could be obtained in the absence of copper catalysts (entry 6). When we subjected
oxime acetate to diketone using Cs2CO3 or tꢀBuOK as the additives, 60% and 16% of
3a was afforded, respectively (entries 7 and 8). The organic base also decreased the
yield of 3a (entries 9 and 10). As predicted, there was no reaction occurred without
base (entry 11). This investigation indicated that the base was crucial to the interaction
between copper salts and oxime esters. In the presence of CuI and K2CO3, only trace
amount of the desired product was observed when using toluene, DCE, or CH3CN as
solvent (entries 12ꢀ14). Remarkably, the addition of 2 equiv DMF in this reaction
system gave a significant improvement (entries 15ꢀ17). Therefore, DMF was
necessary media for this Cu(I)ꢀcatalyzed cascade reaction.
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Table 1. Optimization of the reaction conditionsa
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Yield (%)b
83
Entry
1
Catalyst
CuBr
CuI
Base
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
tꢀBuOK
DBU
Solvent
DMF
2
DMF
DMF
86 (78)
77
3
CuCl
Cu(OTf)2
Cu(OAc)2
none
CuI
4
DMF
34
5
DMF
73
6
DMF
0
7
DMF
60
8
CuI
DMF
16
9
CuI
DMF
65
10
11
12
13
14
15c
16c
17c
CuI
NEt3
DMF
trace
0
CuI
none
DMF
CuI
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
toluene
DCE
trace
10
CuI
CuI
CH3CN
toluene
DCE
trace
62
CuI
CuI
19
CuI
CH3CN
73
a
Unless otherwise noted, all reactions were performed with 1a (0.5 mmol), 2a (0.6 mmol), [Cu]
b
(10 mol %), base (1.0 mmol) and solvent (2 mL) at 120 °C under N2 atmosphere for 6 h.
Determined by GC using dodecane as an internal standard. c 2 equiv. DMF of was added.
With the optimized reaction conditions in hand, we investigated the scope of the
Cu(I)ꢀcatalyzed cyclization reaction. Representative results were summarized in Table
2. A series of benzoylacetones successfully participated in this transformation,
affording the isoquinolines 3a-3f in moderate to excellent yields with high
regioselectivity. A single crystal of product 3f was obtained and its structure was
confirmed by singleꢀcrystal Xꢀray analysis.18 Symmetrical 1,3ꢀdiketones also could be
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converted to the corresponding products in good yields (3g and 3h). When
6ꢀmethylheptaneꢀ2,4ꢀdione (2i) was employed, this transformation gave a 5.5:1 ratio
of regioisomeric cycloadducts 3i and 3i’ determined by GCꢀMS, and the former could
be separated in 61% yield. Besides, the cyclohexaneꢀ1,3ꢀdione could efficiently
transfer to the desired tricyclic compound 3j. Reasonable yields were also obtained
with substituted cyclic 1,3ꢀdiketones (3k and 3l). Furthermore, different singleꢀester
dicarbonyl compounds could be converted into the desired products in moderate to
high yields (3m-3p). And under this optimized conditions, when the oximes derived
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from
1ꢀ(2ꢀbromoꢀ4ꢀfluorophenyl)ethanꢀ1ꢀone
or
1ꢀ(2ꢀbromoꢀ5ꢀfluorophenyl)ethanꢀ1ꢀone participated in this reaction, the
corresponding tetraisoquinolines were afforded in reasonable yields (3q and 3r).
Notably, the introduction of thiophene heterocycle into this system made this process
more useful (3s). Moreover, replacing 2ꢀbromoketoxime acetate with 2ꢀiodoketoxime
acetate, this transformation also performed successfully and gave the corresponding
isoquinolines in excellent yields.
Table 2. Substrate Scope of βꢀDiketones and βꢀKeto Esters for the Synthesis of
1,3,4ꢀTrisubstituted Isoquinolinesa
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Me
NOAc
Me
R3
R3
O
O
N
CuI (10 mol %), K2CO3 (2 equiv)
R1
R2
+
R1
COR2
DMF, 120 oC, N2
Br
2
1
3
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Me
Me
Me
N
1
N
R = Ph,
3a, 78%
N
R1= Tol, 3b, 77%
Ph
Me
Me
Me
R1= 4-MeO-Ph, 3c, 80%
1
R = 4-F-Ph,
3d,65%
O
Ph
O
O
R1
Me
R1= 4-Cl-Ph, 3e, 63%
3g, 85%
3h, 72%
R1= 3-MeO-Ph, 3f, 79%
Me
Me
Me
N
N
N
N
Me
Me
Me
Me
O
Me
Me
O
O
O
Me
3ib, 61%
3k, 73%
3j, 69%
3l, 70%
Me
Me
Me
Me
N
N
N
N
Me
Me
Me
OMe
O
O
O
OEt
O
OEt
O
3n, 81%
Me
3m, 84%
3o, 71%
3p, 76%
Me
Me
F
S
N
N
N
F
Me
Me
3q, 63%
Me
Me
O
O
Me
O
Me
3r, 66%
3s,42%
a
All reactions were performed with 1 (0.5 mmol), 2 (0.6 mmol), K2CO3 (1.0 mmol), CuI (10
mol %) in DMF (2 mL) at 120 °C under N2 atmosphere for 6 h. b Regioisomeric cycloadduct 3i’
was also formed in 12% GC yield.
Table 3. Substrate Scope of βꢀKeto Nitriles for the Synthesis of 4ꢀCyanoisoquinoline
Derivativesa
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a Reaction conditions: all reactions were performed with 1a (0.5 mmol), 4 (0.6 mmol), K2CO3 (1.0
mmol), CuI (10 mol %) in DMF (2 mL) at 120 °C under N2 atmosphere for 6 h.
Table 4. Substrate Scope of 2ꢀCyanoacetates for the Synthesis of
3ꢀAminoisoquinoline Derivatives a
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Me
NOAc
Me
O
N
CuI (10 mol %), K2CO3 (2 equiv)
NC
R5
+
O
NH2
R5
Br
DMF, 120 oC, N2
7
6
1a
O
O
Me
Me
Me
Me
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N
N
N
O
N
NH2
NH2
NH2
NH2
O
O
O
O
O
O
O
7a, 85%
7d, 70%
7c, 87%
7b, 77%
Me
Me
Me
N
N
N
NH2
NH2
NH2
O
O
O
O
O
O
7e, 74%
7f, 79%
7g, 76%
a
All reactions were performed with 1a (0.5 mmol), 6 (0.6 mmol), K2CO3 (1.0 mmol), CuI (10
mol %) in DMF (2 mL) at 120 °C under N2 atmosphere for 6 h.
Under the optimal reaction conditions, it is delightful that the coupling reactions of
2ꢀbromoacetophenone oxime acetate (1a) and βꢀketo nitriles 4 were found to be
favored to afford 4ꢀcyanoisoquinolines in good yields with high chemoselectivity. The
results were tabulated in Table 3. Benzoylacetonitriles with a series of functional
groups, such as methyl, methoxy and halogen, could be converted to the desired
products in satisfactory yields (5a-5e). Additionally, the reaction of
3ꢀoxopentanenitrile (4f) and 3ꢀoxoꢀ3ꢀ(thiophenꢀ2ꢀyl)propanenitrile (4g) also
proceeded smoothly under the optimized conditions, affording the corresponding
products in 72% and 78% yields, respectively (5f and 5g).
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The scope of copperꢀcatalyzed coupling reaction was further expanded to a
variety of 2ꢀcyanoacetates (Table 4). Gratifyingly, 3ꢀaminoisoquinoline derivatives
could be formed in good yields with complete chemoselectivity when a series of alkyl
2ꢀcyanoacetates were used. (7a-7e). We were pleased to find that alkenyl and benzyl
2ꢀcyanoacetate were soomthly converted into the corresponding products in 79% and
76% yields, respectively (7f and 7g).
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Table 5. Substrate Scope of Indoles for the Synthesis of Indolo[1,2ꢀa]quinazoline
Derivativesa
Cu(OAc)2 (10 mol%)
NOAc
t-KOBu (1 equiv)
N
R
Me
+
DBU (1 equiv)
N
Me
H
R
N
I
DMSO, 120 oC
MeO
H
9
1d
8
Me
N
O
Ph
N
N
N
N
N
Me
Me
N
Me
N
Me
9b, 65%
9a, 76%
9c, 75%
9d, 83%
NC
N
F
Me
N
MeO
Me
N
N
Me
N
N
Me
N
N
Me
9h, 64%
9g, 76%
9e, 77%
9f, 82%
N
N
N
N
N
Me
N
Me
N
Me
N
Me
N
F
OMe
9k, 78%
9l, 74%
9i, 68%
9j, 83%
a All reactions were performed with 1d (0.5 mmol), 8 (0.5 mmol), tꢀKOBu (1.0 equiv), DBU (1.0
equiv), Cu(OAc)2 (10 mol %) in DMSO (2 mL) at 120 °C under N2 atmosphere for 6 h.
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Encouraging by the above results, we next investigated the Cuꢀcatalyzed cascade
reaction of indole 8a with easily accessible 2ꢀiodoketoxime acetate 1d. When this
reaction was carried out in DMSO at 120°C, using 10 mol % Cu(OAc)2 as the catalyst,
in the presence of 1.0 equiv of KOtꢀBu and DBU, under N2 atmosphere for 6 h, the
indolo[1,2ꢀa]quinazoline product 9a was successfully observed (for detailed screening
of reaction conditions, see the Supporting Information). As exhibited in Table 5, the
coupling of 2ꢀiodoketoxime ester with slight steric hindered 3ꢀmethylindole gave the
desired product 9b in reasonable yield. For 4ꢀmethoxyꢀ1Hꢀindole (8c) and
4ꢀ(benzyloxy)ꢀ1Hꢀindole (8d), the corresponding products 9c and 9d were obtained in
75% and 83% yields, respectively. Both electronꢀdonating and electronꢀwithdrawing
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5ꢀsubstituted
indoles
could
also
preform
smoothly,
affording
the
indolo[1,2ꢀa]quinazoline derivatives in moderate to good yields (9e-9h). In addition,
when 6ꢀfluoroꢀ1Hꢀindole and 7ꢀmethoxyꢀ1Hꢀindole were employed, the
transformations gave 9i and 9j in 68% and 83% yields, respectively. Notably,
pyrrolo[2,3ꢀb]pyridine (8k) and pyrrole (8l) were effective substrates for this cascade
annulation to afford the good yields of 9k and 9l.
To investigate the practicality of these processes in the synthesis of isoquinoline
and indolo[1,2ꢀa]quinazoline derivatives, we carried out the reactions in a gramꢀscale
(Scheme 2). When 1.27 g of 1a was employed, methylene compounds 2g, 4a, and 6a
were tolerated under the optimized reaction conditions and gave the corresponding
products in 81, 69, and 78% yields, respectively (Scheme 2, Eqn. 1ꢀ3). To our delight,
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when running the reaction with 1.51 g of 1d, 1.25 g of product 9d was obtained in
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74% yield (Scheme 2, Eqn. 4).
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Scheme 2. Gramꢀscale Synthesis of Functionalized Isoquinolines (3g, 5a, and 7a) and
Indolo[1,2ꢀa]quinazoline 9d
Me
NOAc
O
O
CuI (10 mol %), K2CO3 (2 equiv)
DMF, 120 oC, N2, 6 h
N
Me
+
Ph
Ph
Eqn. 1
Eqn. 2
Ph
COPh
Br
1a
3g
2g
1.31 g, 81%
Me
1.27 g, 5 mmol
6 mmol
NOAc
O
CuI (10 mol %), K2CO3 (2 equiv)
DMF, 120 oC, N2, 6 h
N
Me
+ NC
Ph
Ph
Br
1a
CN
5a
4a
0.84 g, 69%
Me
1.27 g, 5 mmol
6 mmol
NOAc
Me
N
O
CuI (10 mol %), K2CO3 (2 equiv)
DMF, 120 oC, N2, 6 h
Eqn. 3
NC
Ph
NH2
+
OEt
Br
1a
O
7a
OEt
6a
6 mmol
1.27 g, 5 mmol
0.90 g, 78%
O
Ph
Cu(OAc)2 (10 mol%)
NOAc
Me
KOtBu (1 equiv)
O
N
DBU (1 equiv)
N
Me
Eqn. 4
+
H
DMSO, 120 oC, 6 h
I
N
H
8d
5 mmol
1d
9d
1.51 g, 5 mmol
1.25 g, 74%
According to the experimental results and literature precedents on oxime
derivatives,16, 17, 19 we proposed a plausible mechanism for this crossꢀcoupling
reaction (Scheme 3). In the presence of copper salt, the complex A was first obtained
through the reaction between orthoꢀhaloaryloxime ester 1 with methylene compound
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2, namely the Hurtley reaction.20a, 20c, 20d Cleavage of the N–O bond of the complex A
was initiated by CuI, generating copper enamide intermediate B and producing CuII
species.16, 17a, 17d Subsequently, the copper(II) enamide served as an intramolecular
nucleophile towards the carboxide,20c affording the corresponding intermediate C or
D. Finally, the 1,3,4ꢀpolysubstituted isoquinoline 3 was generated from elimination of
intermediate C or D. The Cu(I) species might be generated in situ via the reduction of
CuII by DMF,21 and then entered into the next catalytic cycle. Additionally, the
reactions of βꢀketo nitriles 4 or alkyl 2ꢀcyanoacetates 6 with orthoꢀhaloketoximes
esters 1 were also proposed through the similar pathway.
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With respect to indolo[1,2ꢀa]quinazolines synthesis, firstly, copperꢀcatalyzed
Ullmann condensation occured between the active orthoꢀiodoketoximes ester and
indoles 8 to form E.20b, 20d Oxidative addition of Cu(I) to E afforded the Cu(III)ꢀimino
species G,17b, 17c, 19. Then a copper ring intermediate I was generated from orthoꢀC–H
activation of intermediate G and subsequent reductive elimination would provide the
desired product 9.
Scheme 3. Proposed Mechanism
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HN
CuII
O
R2
COR1
DMF
7
8
9
D
2CuI
2CuII
CuII(OH)X
NOAc
COR1
XCuII
HN
R2OC
2 CuIX
N
N
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XCuII
O
R2OC
CuII(OAc)X
O
R2
R2
R1
O
COR1
C
COR1
2
COR1
3
A
B
R2
NOAc
X
1
H
8
NH
R
H
N
R
R
N
NOAc
N
CuIX
E
9
CulllX
N
R
N
H
R
H
N
CulX
O
R
I
CulllOAcX
N
O
N
HN
F
HOAc
H
H
R
N
N
CulllOAcX
G
CONCLUSION
In conclusion, we have developed a copperꢀcatalyzed cascade condensation for
divergent syntheses of functionalized isoquinolines and indolo[1,2ꢀa]quinazolines
from 2ꢀhaloketoxime acetates. This protocol provides a powerful method for the
construction of a series of nitrogenꢀcontaining heterocycles with high chemoꢀ and
regioselectivity. Moreover, the success of gramꢀscale synthesis of functionalized
isoquinolines and indolo[1,2ꢀa]quinazolines made this process more useful in
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synthetic and pharmaceutical chemistry.
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EXPERIMENTAL SECTION
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General Methods. Melting points were measured by a melting point instrument and
were uncorrected. 1H and 13C NMR spectra were recorded by using a 400 MHz NMR
1
spectrometer. H and 13C NMR spectra are reported in parts per million (ppm)
downfield from an internal standard, tetramethylsilane (0 ppm) and CHCl3 (77.0 ppm),
respectively. IR spectra were obtained either as potassium bromide pellets or as liquid
films between two potassium bromide pellets with an infrared spectrometer. GCꢀMS
was obtained using electron ionization. The data of HRMS were carried out on a
highꢀresolution mass spectrometer (LCMSꢀITꢀTOF). Unless otherwise noted, all
purchased chemicals were used without further purification. The ketoxime acetates
were prepared according to the literatures.19a, 22
General Procedure for the Synthesis of Isoquinolines 3, 5, and 7. The
2ꢀhaloketoxime acetates 1 (0.5 mmol), methylene compounds 2, 4, or 6 (0.6 mmol),
CuI (10 mol %), and K2CO3 (2 equiv, 1.0 mmol, 138 mg) were stirred in DMF (2.0
mL) at 120 °C, in a 20 mL tube under N2 for 6 h. When the reaction was completed
(detected by TLC), the mixture was cooled to room temperature. The reaction was
quenched with H2O (10 mL) and extracted with EtOAc (3 × 10 mL). The combined
organic layers were dried over anhydrous MgSO4 and then evaporated in vacuum. The
residue was purified by column chromatography on silica gel to afford the
corresponding isoquinolines with petroleum ether /ethyl acetate as the eluent.
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General Procedure for the Synthesis of Indolo[1,2-a]quinazolines 9. The
2ꢀiodoketoxime acetates 1d (0.5 mmol), indoles 8 (0.5 mmol), Cu(OAc)2 (10 mol %,
0.05 mmol, 9.08 mg), KOtꢀBu (1.0 equiv, 0.5 mmol, 56.1 mg), and DBU (1.0 equiv,
0.5 mmol, 76.1 mg) were stirred in DMSO (2.0 mL) at 120 °C, in a 20 mL tube under
N2 for 6 h. When the reaction was completed, the mixture was cooled to room
temperature. The reaction was quenched with H2O (10 mL) and extracted with EtOAc
(3 × 10 mL). The combined organic layers were dried over anhydrous MgSO4 and
then evaporated in vacuum. The residue was purified by column chromatography on
silica gel to afford the corresponding indolo[1,2ꢀa]quinazolines with petroleum ether
/ethyl acetate as the eluent.
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4-Benzoyl-1,3-dimethylisoquinolin (3a): Red oil (101 mg, 78 %); H NMR (400
MHz, CDCl3) δ 8.16ꢀ8.14 (m, 1H), 7.83 (d, J = 7.2 Hz, 2H), 7.59 (t, J = 8.0 Hz, 1H),
7.55ꢀ7.53 (m, 2H), 7.50ꢀ7.46 (m, 1H), 7.45ꢀ7.41 (m, 2H), 3.01 (s, 3H), 2.48 (s, 3H);
13C {1H} NMR (100 MHz, CDCl3) δ 198.6, 159.4, 146.5, 137.4, 134.1, 133.9, 130.7,
129.8, 129.0, 127.5, 126.6, 125.9, 125.2, 124.5, 22.7, 22.6; HRMSꢀESI (m/z): calcd
for C18H16NO, [M+H]+ : 262.1226; found, 262.1228; IR (KBr): 2922, 1666, 1617,
1502, 1393, 1241, 758, 712 cm−1.
1,3-Dimethyl-4-(4-methylbenzoyl)isoquinolin (3b): Yellow needles (104 mg, 77 %),
m.p. = 86.5–87.3 °C; 1H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 8.8 Hz, 1H), 7.73 (d,
J = 7.6 Hz, 2H), 7.56ꢀ7.52 (m, 2H), 7.49 (d, J = 8.8 Hz, 1H), 7.27ꢀ7.23 (m, 2H), 3.02
(s, 3H), 2.48 (s, 3H), 2.41 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3) δ 198.2, 159.2,
146.3, 145.2, 135.1, 134.0, 130.7, 129.9, 129.7, 127.7, 126.6, 125.8, 125.3, 124.6,
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22.6, 22.5, 21.8; HRMSꢀESI (m/z): calcd for C19H18NO, [M+H]+ : 276.1383; found,
276.1388; IR (KBr): 2921, 1663, 1605, 1502, 1395, 1246, 759 cm−1.
7
8
9
1
1,3-Dimethyl-4-(4-methoxybenzoyl)isoquinolin (3c): Red oil (116 mg, 80 %); H
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NMR (400 MHz, CDCl3) δ 8.15 (d, J = 6.8 Hz,, 1H), 7.80 (d, J = 8.0 Hz, 2H),
7.58ꢀ7.49 (m, 3H), 6.90 (d, J = 8.8 Hz, 2H), 3.85 (s, 3H), 3.01 (s, 3H), 2.49 (s, 3H);
13C {1H} NMR (100 MHz, CDCl3) δ 197.0, 164.4, 159.1, 146.2, 134.0, 132.2, 130.7,
127.8, 126.5, 125.8, 125.3, 124.7, 114.2, 55.6, 22.6, 22.5; HRMSꢀESI (m/z): calcd for
C19H18NO2, [M+H]+ : 292.1332; found, 292.1336; IR (KBr): 2926, 1657, 1597, 1504,
1393, 1251, 758 cm−1.
4-(4-Fluorobenzoyl)-1,3-dimethylisoquinolin (3d): Yellow needles (91 mg, 65 %),
1
m.p. = 114.3 – 115.5 °C; H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 8.4 Hz, 1H),
7.88ꢀ7.85 (m, 2H), 7.60ꢀ7.54 (m, 2H), 7.46 (d, J = 8.0 Hz, 1H), 7.11 (t, J = 8.4 Hz,
13
2H), 3.02 (s, 3H), 2.48 (s, 3H); C {1H} NMR (100 MHz, CDCl3) δ 196.9, 166.4 (J
= 255.4 Hz), 159.5, 146.4, 134.0 (J = 2.7 Hz), 133.8, 132.5 (J = 9.5 Hz), 130.9, 127.2,
126.7, 125.9, 125.3, 124.4, 116.2 (J = 21.9 Hz), 22.6, 22.5; HRMSꢀESI (m/z): calcd
for C18H15FNO, [M+H]+: 280.1132; found, 280.1138; IR (KBr): 2923, 1667, 1595,
1500, 1391, 1239, 761 cm−1.
4-(4-Chlorobenzoyl)-1,3-dimethylisoquinolin (3e): Yellow needles (93 mg, 63 %),
1
m.p. = 108.9 – 110.2 °C; H NMR (400 MHz, CDCl3) δ 8.19ꢀ8.16 (m, 1H), 7.77 (d, J
= 8.4 Hz, 2H), 7.58ꢀ7.54 (m, 2H), 7.46ꢀ7.41 (m, 3H), 3.01 (s, 3H), 2.47 (s, 3H); 13C
{1H} NMR (100 MHz, CDCl3) δ 197.4, 159.7, 146.5, 140.7, 135.8, 133.8, 131.1,
130.9, 129.4, 127.0, 126.7, 125.9, 125.3, 124.4, 22.7, 22.6; HRMSꢀESI (m/z): calcd
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for C18H15ClNO, [M+H]+ : 296.0837; found, 296.0843; IR (KBr): 2994, 1667, 1618,
1501, 1397, 756 cm−1.
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8
9
1
1,3-Dimethyl-4-(3-methoxybenzoyl)isoquinolin (3f): Red oil (114 mg, 79 %); H
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NMR (400 MHz, CDCl3) δ 8.17ꢀ8.15 (m, 1H), 7.58ꢀ7.48 (m, 4H), 7.33ꢀ7.26 (m, 2H),
7.15 (d, J = 7.6 Hz, 1H), 3.84 (s, 3H), 3.02 (s, 3H), 2.49 (s, 3H); 13C {1H} NMR (100
MHz, CDCl3) δ 198.5, 160.1, 159.4, 146.4, 138.8, 134.0, 130.8, 130.0, 127.6, 126.6,
125.8, 125.2, 124.5, 123.1, 120.7, 113.1, 55.5, 22.7, 22.5; HRMSꢀESI (m/z): calcd for
C19H18NO2, [M+H]+ : 292.1332; found, 292.1336; IR (KBr): 2925, 1666, 1573, 1393,
1262, 810, 763 cm−1.
4-Benzoyl-1-methyl-3-phenylisoquinolin (3g): Yellow needles (137 mg, 85 %), m.p.
1
= 126.4 – 127.7 °C; H NMR (400 MHz, CDCl3) δ 8.26ꢀ8.23 (m, 1H), 7.77ꢀ7.43 (m,
1H), 7.66ꢀ7.63 (m, 4H), 7.60 (d, J = 7.2 Hz, 2H), 7.40 (t, J = 7.2 Hz, 1H), 7.26ꢀ7.20
(m, 5H), 3.12 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3) δ 198.3, 159.9, 148.7,
139.7,137.8, 134.3, 133.4, 131.0, 129.6, 129.6, 128.4, 128.3, 128.2, 127.5, 127.4,
125.9, 125.8, 125.2, 22.8; HRMSꢀESI (m/z): calcd for C23H18NO, [M+H]+ : 324.1383;
found, 324.1387; IR (KBr): 2924, 1663, 1235, 758. cm−1.
4-Acetyl-1,3-dimethylisoquinolin (3h): Red oil (72 mg, 72 %); 1H NMR (400 MHz,
CDCl3) δ 8.13 (d, J = 8.4 Hz, 1H), 7.70ꢀ7.65 (m, 1H), 7.61ꢀ7.52 (m, 2H), 2.95 (s, 3H),
2.64 (s, 3H), 2.60 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3) δ 206.1, 159.2, 144.5,
132.2, 130.9, 130.1, 126.6, 126.0, 125.2, 123.6, 32.9, 22.5, 22.3; HRMSꢀESI (m/z):
calcd for C13H14NO, [M+H]+ : 200.1070; found, 200.1073; IR (KBr): 2923, 1697,
1567, 1204, 761 cm−1.
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1,3-Dimethyl-4-(3-methylbutanoyl)isoquinolin (3i): Red oil (73 mg, 61 %); H
NMR (400 MHz, CDCl3) δ 8.13 (d, J = 8.0 Hz, 1H), 7.66 (d, J = 6.8 Hz, 1H), 7.58 (d,
J = 7.6 Hz, 2H), 2.95 (s, 3H), 2.78 (d, J = 6.5 Hz, 2H), 2.59 (s, 3H), 2.43ꢀ2.36 (m, 1H),
1.06 (d, J = 6.8 Hz, 6H); 13C {1H} NMR (100 MHz, CDCl3) δ 208.1, 161.4, 147.6,
133.0, 130.9 130.3, 126.6, 126.0, 125.5, 123.6, 54.5, 29.7, 24.0, 22.7, 22.4, 22.3;
HRMSꢀESI (m/z): calcd for C16H20NO, [M+H]+ : 242.1539; found, 242.1543; IR
(KBr): 2958, 2927, 1697, 1569, 1394, 1365, 760 cm−1.
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6-Methyl-3,4-dihydrophenanthridin-1(2H)-one (3j): Yellow needles (73 mg, 69 %),
m.p. = 74.5 – 75.9 °C; 1H NMR (400 MHz, CDCl3) δ 9.42 (d, J = 8.8 Hz, 1H), 8.13 (d,
J = 8.4 Hz, 1H), 7.81ꢀ7.66 (m, 1H), 7.60ꢀ7.56 (m, 1H), 3.27 (t, J = 6.0 Hz, 2H), 2.98
(s, 3H), 2.80ꢀ2.76 (m, 2H), 2.25ꢀ2.18 (m, 2H); 13C {1H} NMR (100 MHz, CDCl3) δ
200.7, 164.0, 160.2, 133.8, 132.5, 126.8, 126.6, 126.4, 125.8, 119.7, 40.6, 33.9, 23.3,
21.9; HRMSꢀESI (m/z): calcd for C14H14NO, [M+H]+ : 212.1070; found, 212.1072;
IR
(KBr):
2945,
1670,
1562,
1498,
758
cm−1.
3,3,6-Trimethyl-3,4-dihydrophenanthridin-1(2H)-one (3k): Red oil (87 mg, 73 %);
1H NMR (400 MHz, CDCl3) δ 9.42 (d, J = 8.8 Hz, 1H), 8.12 (d, J = 8.4 Hz, 1H),
7.80ꢀ7.56 (m, 1H), 7.59ꢀ7.55 (m, 1H), 3.16 (s, 2H), 2.97 (s, 3H), 2.62 (s, 2H), 1.15 (s,
6H); 13C {1H} NMR (100 MHz, CDCl3) δ 200.9, 164.3, 158.6, 133.5, 132.5, 126.8,
126.5, 126.3, 125.8, 118.7, 54.2, 47.8, 32.8, 28.2, 23.3; HRMSꢀESI (m/z): calcd for
C16H18NO, [M+H]+ : 240.1383; found, 240.1387; IR (KBr): 2956, 1671, 1564, 761
cm−1.
3-Isopropyl-6-methyl-3,4-dihydrophenanthridin-1(2H)-one (3l): Red oil (86 mg,
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70 %); H NMR (400 MHz, CDCl3) δ 9.42 (d, J = 8.8 Hz, 1H), 8.12 (d, J = 8.4 Hz,
1H), 7.80ꢀ7.76 (m, 1H), 7.59 ꢀ 7.55 (m, 1H), 3.35ꢀ3.30 (m, 1H), 3.05ꢀ3.01 (m, 1H),
2.97 (s, 3H), 2.86ꢀ3.81 (m, 1H), 2.53ꢀ2.46 (m, 1H), 2.12ꢀ2.06 (m, 1H), 1.74ꢀ1.67 (m,
1H), 1.03 (d, J = 6.8, 3H), 1.02 (d, J = 6.8, 3H); 13C {1H} NMR (100 MHz, CDCl3) δ
201.2, 164.0, 159.9, 133.7, 132.5, 126.8, 126.5, 126.3, 125.8, 119.3, 44.7, 40.4, 37.8,
32.1, 23.3, 19.7, 19.5; HRMSꢀESI (m/z): calcd for C17H20NO, [M+H]+ : 254.1539;
found, 254.1544; IR (KBr): 2960, 1670, 1564, 1499, 1390, 1360, 761 cm−1.
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Methyl 1,3-Dimethylisoquinoline-4-carboxylate (3m): Red oil (90 mg, 84 %); H
NMR (400 MHz, CDCl3) δ 8.11 (d, J = 8.4 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H),
7.70ꢀ7.66 (m, 1H), 7.57ꢀ7.53 (m, 1H), 4.04 (s, 3H), 2.95 (s, 3H), 2.68 (s, 3H); 13C
{1H} NMR (100 MHz, CDCl3) δ 169.4, 160.0, 148.4, 133.3, 130.9, 126.6, 125.8,
125.2, 124.3, 121.7, 52.4, 23.0, 22.6; HRMSꢀESI (m/z): calcd for C13H14NO2,
[M+H]+ : 216.1019; found, 216.1023; IR (KBr): 2951, 1725, 1235, 758 cm−1.
1
Ethyl 1,3-Dimethylisoquinoline-4-carboxylate (3n): Red oil (93 mg, 81 %); H
NMR (400 MHz, CDCl3) δ 8.12 (d, J = 8.0 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H),
7.71ꢀ7.67 (m, 1H), 7.58ꢀ7.54 (m, 1H), 4.53 (q, J = 6.8 Hz, 2H), 2.96 (s, 3H), 2.70 (s,
3H), 1.46 (t, J = 7.2 Hz, 3H); 13C {1H} NMR (100 MHz, CDCl3) δ 168.9, 159.8,
148.0, 133.3, 131.0, 126.6, 125.8, 125.2, 124.3, 122.1, 61.6, 22.8, 22.5, 14.3;
HRMSꢀESI (m/z): calcd for C14H16NO2, [M+H]+ : 230.1176; found, 230.1177; IR
(KBr): 2982, 2928, 1723, 1234, 757 cm−1.
Ethyl 1-Methyl-3-phenylisoquinoline-4-carboxylate (3o): Yellow needles (103 mg,
71 %), m.p. = 87.1 – 88.3 °C; 1H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 8.4 Hz, 1H),
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8.05 (d, J = 8.4 Hz, 1H), 7.76 (t, J = 8.0 Hz, 1H), 7.70 (d, J = 7.6 Hz, 2H), 7.64 (t, J =
7.6 Hz, 1H), 7.47ꢀ7.39 (m, 3H), 4.21 (q, J = 7.2 Hz, 2H), 3.05 (s, 3H), 1.03 (t, J = 7.2
Hz, 3H); 13C {1H} NMR (100 MHz, CDCl3) δ 168.9, 160.1, 149.8, 140.4, 133.5,
131.2, 128.9, 128.4, 128.3, 127.3, 125.9, 125.7, 124.8, 122.2, 61.6, 22.8, 13.7;
HRMSꢀESI (m/z): calcd for C19H18NO2, [M+H]+ : 292.1332; found, 292.1331; IR
(KBr): 2983, 2926, 1719, 1227, 763, 701 cm−1.
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Allyl 1,3-Dimethylisoquinolin-4-carboxylate (3p): Red oil (91 mg, 76 %); 1H NMR
(400 MHz, CDCl3) δ 8.11 (d, J = 8.4 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.68 (t, J = 7.6
Hz, 1H), 7.55 (t, J = 7.6 Hz, 1H), 6.14ꢀ6.04 (m, 1H), 5.46 (d, J = 16.8 Hz, 1H), 5.34
(d, J = 10.6 Hz, 1H), 4.95 (d, J = 6.0 Hz, 2H), 2.96 (s, 3H), 2.70 (s, 3H); 13C {1H}
NMR (100 MHz, CDCl3) δ 168.6, 160.0, 148.3, 133.3, 131.7, 130.9, 126.6, 125.8,
125.2, 124.3, 121.6, 119.5, 77.3, 66.2, 23.0, 22.6; HRMSꢀESI (m/z): calcd for
C15H16NO2, [M+H]+ : 242.1176; found, 242.1178; IR (KBr): 3075, 2927, 1724, 1227,
760 cm−1.
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4-Acetyl-6-fluoro-1,3-dimethylisoquinolin (3q): Red oil (68 mg, 63 %); H NMR
(400 MHz, CDCl3) δ 8.14 (dd, J = 9.2, 5.6 Hz, 1H), 7.33ꢀ7.28 (m, 1H), 7.22 (d, J =
7.6 Hz, 1H), 2.92 (s, 3H), 2.62 (s, 3H), 2.59 (s, 3H); 13C {1H} NMR (100 MHz,
CDCl3) δ 205.62, 163.6 (d, J = 251.5 Hz), 159.0, 146.1, 133.9, 129.9, 129.1 (d, J =
9.7 Hz), 122.6, 116.8 (d, J = 24.9 Hz), 107.6 (d, J = 22.0 Hz), 32.5, 22.6, 22.5;
HRMSꢀESI (m/z): calcd for C13H13FNO, [M+H]+ : 218.0976; found, 218.0982; IR
(KBr): 2925, 1698, 1623, 1574, 1414, 1209 cm−1.
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4-Acetyl-7-fluoro-1,3-dimethylisoquinolin (3r): Red oil (71 mg, 66 %); H NMR
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(400 MHz, CDCl3) δ 7.73 (d, J = 9.6 Hz, 1H), 7.67ꢀ7.63 (m, 1H), 7.49ꢀ7.45 (m, 1H),
2.93 (s, 3H), 2.65 (s, 3H), 2.62 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3) δ 205.7,
160.4 (d, J = 248 Hz), 158.5 (d, J = 5 Hz), 144.0, 130.1, 129.3, 126.3 (d, J = 9 Hz),
126.2 (d, J = 8 Hz), 121.4 (d, J = 25 Hz), 109.7 (d, J = 21 Hz), 101.4, 32.87, 22.35,
22.06; HRMSꢀESI (m/z): calcd for C13H13FNO, [M+H]+ : 218.0976; found, 218.0980;
IR (KBr): 2925, 1698, 1570, 1508, 1394, 1205 cm−1.
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4-Acetyl-5,7-dimethylthieno[2,3-c]pyridine (3s): Red oil (43 mg, 42 %); H NMR
(400 MHz, CDCl3) δ 7.73 (d, J = 5.4 Hz, 1H), 7.37 (d, J = 5.4 Hz, 1H), 2.81 (s, 3H),
2.70 (s, 3H), 2.67 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3) δ 204.0, 153.4, 147.8,
142.3, 133.6, 132.5, 128.7, 122.4, 32.1, 23.6, 22.8; HRMSꢀESI (m/z): calcd for
C11H12NOS, [M+H]+ : 206.0634; found, 206.0633; IR (KBr): 3054, 2986, 1692, 1265,
743 cm−1.
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1-Methyl-3-phenylisoquinoline-4-carbonitrile (5a): Red oil (96 mg, 79 %); H
NMR (400 MHz, CDCl3) δ 8.29 (d, J = 8.4 Hz, 1H), 8.23 (d, J = 8.4 Hz, 1H), 8.05 (d,
J = 7.2 Hz, 2H), 7.89 (t, J = 7.6 Hz, 1H), 7.73 (t, J = 7.6 Hz, 1H), 7.58ꢀ7.51 (m, 3H),
3.09 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3) δ 163.1, 156.4, 137.9, 135.9, 132.5,
129.9, 129.5, 128.7, 128.4, 126.3, 125.3, 117.2, 100.9, 23.2; HRMSꢀESI (m/z): calcd
for C17H13N2, [M+H]+ : 245.1073; found, 245.1072; IR (KBr): 2922, 2218, 1551,
1388, 1267, 758, 697 cm−1.
1-Methyl-3-(p-tolyl)isoquinoline-4-carbonitrile (5b): Yellow needles (94 mg, 73 %),
m.p. = 152.9 – 154.0 °C; 1H NMR (400 MHz, CDCl3) δ 8.26 (d, J = 8.0 Hz, 1H), 8.20
(d, J = 8.0 Hz, 1H), 7.96 (d, J = 7.6 Hz, 2H), 7.87 (t, J = 7.6 Hz, 1H), 7.70 (t, J = 7.6
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Hz, 1H), 7.36 (d, J = 7.2 Hz, 2H), 3.07 (s, 3H), 2.45 (s, 3H); 13C {1H} NMR (100
MHz, CDCl3) δ 163.0, 156.5, 140.1, 136.0, 135.2, 132.4, 129.4, 129.4, 128.2, 126.3,
125.2, 125.1, 117.5, 100.4, 23.3, 21.5; HRMSꢀESI (m/z): calcd for C18H15N2,
[M+H]+ : 259.1230; found, 259.1224; IR (KBr): 2923, 2219, 1612, 1552, 1390, 827,
761 cm−1.
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3-(4-Methoxyphenyl)-1-methylisoquinoline-4-carbonitrile (5c): Yellow needles
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(101 mg, 74 %), m.p. = 122.9 – 124.1 °C; H NMR (400 MHz, CDCl3) δ 8.26 (d, J =
8.4 Hz, 1H), 8.20 (d, J = 8.4 Hz, 1H), 8.06 (d, J = 8.8 Hz, 2H), 7.87 (t, J = 7.6 Hz,
1H), 7.69 (t, J = 7.6 Hz, 1H), 7.07 (d, J = 8.4 Hz, 2H), 3.89 (s, 3H), 3.07 (s, 3H); 13C
{1H} NMR (100 MHz, CDCl3) δ 162.8, 161.1, 156.0, 136.1, 132.4, 131.0, 130.4,
128.1, 126.3, 125.1, 125.0, 117.6, 114.1, 99.7, 55.4, 23.2; HRMSꢀESI (m/z): calcd for
C18H15N2O, [M+H]+ : 275.1179; found, 275.1173; IR (KBr): 2928, 2218, 1606, 1513,
1254, 1178, 838, 760 cm−1.
3-(4-Fluorophenyl)-1-methylisoquinoline-4-carbonitrile (5d): Yellow needles (92
1
mg, 70 %), m.p. = 85.2 – 87.0 °C; H NMR (400 MHz, CDCl3) δ 8.26 (dd, J = 19.6,
7.2 Hz, 2H), 8.08ꢀ8.05 (m, 2H), 7.90 (t, J = 7.6 Hz, 1H), 7.73 (t, J = 7.6 Hz, 1H),
7.26ꢀ7.22 (m, 2H), 3.08 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3) δ 163.9, 163.1, (d,
J = 249 Hz), 155.25, 135.86, 134.3 (d, J = 3 Hz), 132.65, 131.5 (d, J = 9 Hz), 128.55,
126.33, 125.24, 115.7 (d, J = 22 Hz), 100.7, 23.2; HRMSꢀESI (m/z): calcd for
C17H12FN2, [M+H]+ : 263.0979; found, 263.0974; IR (KBr): 2924, 2219, 1602, 1519,
1385, 1221, 1158, 837, 757 cm−1.
3-(4-Chlorophenyl)-1-methylisoquinoline-4-carbonitrile (5e): Yellow needles (95
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mg, 68 %), m.p. = 144.5 – 146.7 °C; H NMR (400 MHz, CDCl3) δ 8.28 (d, J = 8.4
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7.74 (t, J = 7.6 Hz, 1H), 7.52 (d, J = 7.6 Hz, 2H), 3.07 (s, 3H); C {1H} NMR (100
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MHz, CDCl3) δ 163.2, 155.0, 136.3, 136.2, 135.8, 132.7, 130.8, 128.9, 128.7, 126.3,
125.4, 125.3, 117.2, 100.9, 23.2; HRMSꢀESI (m/z): calcd for C17H12ClN2, [M+H]+ :
279.0684; found, 279.0684; IR (KBr): 2920, 2220, 1649, 1499, 829, 756 cm−1.
3-Ethyl-1-methylisoquinoline-4-carbonitrile (5f): Yellow needles (70 mg, 72 %),
m.p. = 106.2 – 108.1 °C; 1H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 8.4 Hz, 1H), 8.12
(d, J = 8.4 Hz, 1H),7.83 (t, J = 7.6 Hz, 1H), 7.66 (t, J = 7.6 Hz, 1H), 3.18 (q, J = 7.6
Hz, 2H), 3.01 (s, 3H), 1.42 (t, J = 7.6 Hz, 3H); 13C {1H} NMR (100 MHz, CDCl3) δ
163.0, 162.1, 135.3, 132.3, 127.8, 126.3, 125.0, 124.6, 116.5, 101.5, 30.8, 23.0, 14.1;
HRMSꢀESI (m/z): calcd for C13H13N2, [M+H]+ : 197.1073; found, 197.1072; IR
(KBr): 2922, 2216, 1562, 1502, 764 cm−1.
1-Methyl-3-(thiophen-2-yl)isoquinoline-4-carbonitrile (5g): Yellow needles (97 mg,
1
78 %), m.p. = 169.0 – 170.8 °C; H NMR (400 MHz, CDCl3) δ 8.34 (d, J = 2.8 Hz,
1H), 8.17 (d, J = 8.4 Hz, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.81 (t, J = 7.6 Hz, 1H), 7.62
(t, J = 7.6 Hz, 1H), 7.55 (d, J = 4.8 Hz, 1H), 7.20 (t, J = 4.4 Hz, 1H), 2.99 (s, 3H); 13C
{1H} NMR (100 MHz, CDCl3) δ 163.0, 148.9, 142.7, 135.9, 132.6, 130.4, 128.6,
128.6, 128.0, 126.3, 125.1, 125.0, 117.4, 96.2, 22.9; HRMSꢀESI (m/z): calcd for
C15H11N2S, [M+H]+ : 251.0637; found, 251.0641; IR (KBr): 2921, 2212, 1610, 1497,
728 cm−1.
Ethyl 3-Amino-1-methylisoquinoline-4-carboxylate (7a): Yellow needles (98 mg,
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85 %), m.p. = 120.3 – 122.0 °C; H NMR (400 MHz, CDCl3) δ 8.55 (d, J = 8.8 Hz,
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1H), 7.86 (d, J = 8.4 Hz, 1H), 7.50 (t, J = 7.6 Hz, 1H), 7.17 (t, J = 7.6 Hz, 1H), 6.51 (s,
2H), 4.40 (q, J = 7.2 Hz, 2H), 2.74 (s, 3H), 1.40 (t, J = 7.2 Hz, 3H); 13C {1H} NMR
(100 MHz, CDCl3) δ 169.1, 164.4, 157.2, 136.9, 131.6, 126.4, 124.8, 122.5, 122.5,
94.5, 60.7, 22.9, 14.5; HRMSꢀESI (m/z): calcd for C13H15N2O2, [M+H]+ : 231.1128;
found, 231.1127; IR (KBr): 3377, 3240 1663, 1607, 1309, 1224, 743 cm−1.
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Isopropyl 3-Amino-1-methylisoquinoline-4-carboxylate (7b): Yellow needles (94
mg, 77 %), m.p. = 99.4 – 101.1 °C; 1H NMR (400 MHz, CDCl3) δ 8.63 (d, J = 8.8 Hz,
1H), 7.94 (d, J = 8.4 Hz, 1H), 7.58 (t, J = 7.6 Hz, 1H), 7.27ꢀ7.23 (m, 1H), 6.56 (s, 2H),
5.42ꢀ5.36 (m, 1H), 2.82 (s, 3H), 1.46 (d, J = 6.0 Hz, 6H); 13C {1H} NMR (100 MHz,
CDCl3) δ 168.6, 164.1, 157.0, 136.9, 131.5, 126.3, 124.7, 122.5, 97.8, 68.5, 22.9, 22.2;
HRMSꢀESI (m/z): calcd for C14H17N2O2, [M+H]+ : 245.1285; found, 245.1283; IR
(KBr): 3495, 3283, 1656, 1613, 1221, 748 cm−1.
Isobutyl 3-Amino-1-methylisoquinoline-4-carboxylate (7c): Yellow needles (112
mg, 87 %), m.p. = 92.5 – 94.6 °C; 1H NMR (400 MHz, CDCl3) δ 8.64 (d, J = 8.8 Hz,
1H), 7.94 (d, J = 8.4 Hz, 1H), 7.58 (t, J = 8.0 Hz, 1H), 7.27ꢀ7.23 (m, 1H), 6.67 (s, 2H),
4.22 (d, J = 6.8 Hz, 2H), 2.82 (s, 3H), 2.20ꢀ2.13 (m, 1H), 1.07 (d, J = 6.8 Hz, 6H); 13C
{1H} NMR (100 MHz, CDCl3) δ 169.2, 164.4, 157.3, 136.9, 131.6, 126.4, 124.9,
122.5, 122.5, 94.6, 71.2, 27.9, 22.8, 19.5; HRMSꢀESI (m/z): calcd for C15H19N2O2,
[M+H]+ : 259.1441; found, 259.1440; IR (KBr): 3402, 3285, 2958, 1666, 1611, 1219,
744 cm−1.
tert-Butyl 3-Amino-1-methylisoquinoline-4-carboxylate (7d): Yellow needles (90
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mg, 70 %), m.p. = 125.7 – 127.0 °C; H NMR (400 MHz, CDCl3) δ 8.58 (d, J = 8.8
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Hz, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.57ꢀ7.54 (m, 1H), 7.25ꢀ7.21 (m, 1H), 6.47 (s, 2H),
2.81 (s, 3H), 1.68 (s, 9H); 13C {1H} NMR (100 MHz, CDCl3) δ 168.3, 163.6, 156.7,
136.9, 131.3, 126.3, 124.7, 122.5, 122.4, 96.2, 81.8, 28.7, 22.8; HRMSꢀESI (m/z):
calcd for C15H19N2O2, [M+H]+ : 259.1441; found, 259.1444; IR (KBr): 3410, 3282,
1658, 1316, 1273, 1149 cm−1.
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Butyl 3-Amino-1-methylisoquinoline-4-carboxylate (7e): Yellow needles (95 mg,
74 %), m.p. = 77.3 – 78.9 °C; 1H NMR (400 MHz, CDCl3) δ 8.62 (d, J = 8.8 Hz, 1H),
7.94 (d, J = 8.4 Hz, 1H), 7.58 (t, J = 7.6 Hz, 1H), 7.27ꢀ7.24 (m, 1H), 6.63 (s, 2H),
4.43 (t, J = 6.8 Hz, 2H), 2.83 (s, 3H), 1.87ꢀ1.80 (m, 2H), 1.57ꢀ1.47 (m, 2H), 1.00 (t, J
= 7.2 Hz, 3H); 13C {1H} NMR (100 MHz, CDCl3) δ 169.1, 164.2, 157.1, 137.0, 131.7,
126.4, 124.8, 122.6, 122.4, 94.7, 64.8, 30.9, 22.8, 19.5, 13.8; HRMSꢀESI (m/z): calcd
for C15H19N2O2, [M+H]+ : 259.1441; found, 259.1448; IR (KBr): 3488, 3279, 1663,
1612 1234, 758 cm−1.
Allyl 3-Amino-1-methylisoquinoline-4-carboxylate (7f): Yellow needles (96 mg,
79 %), m.p. = 99.2 – 101.0 °C; 1H NMR (400 MHz, CDCl3) δ 8.61 (d, J = 8.8 Hz, 1H),
7.92 (d, J = 8.4 Hz, 1H), 7.56 (t, J = 8.0 Hz, 1H), 7.25ꢀ7.21 (m, 1H), 6.59 (s, 2H),
6.15ꢀ6.05 (m, 1H), 5.43 (d, J = 17.2 Hz, 1H), 5.30 (d, J = 10.8 Hz, 1H), 4.90 (d, J =
5.6 Hz, 2H), 2.79 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3) δ 168.7, 164.7, 157.4,
136.8, 132.4, 131.7, 126.4, 124.9, 122.6, 122.5, 118.6, 94.1, 65.4, 22.9; HRMSꢀESI
(m/z): calcd for C14H15N2O2, [M+H]+ : 243.1128; found, 243.1132; IR (KBr): 3354,
3248, 1667, 1615, 1220, 743 cm−1.
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Benzyl 3-Amino-1-methylisoquinoline-4-carboxylate (7g): Yellow needles (111 mg,
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76 %), m.p. = 115.9 – 117.1 °C; H NMR (400 MHz, CDCl3) δ 8.65 (d, J = 8.8 Hz,
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1H), 7.95 (d, J = 8.0 Hz, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.49 (d, J = 7.2 Hz, 2H),
7.42ꢀ7.33 (m, 3H), 7.27ꢀ7.23 (m, 2H), 5.47 (s, 2H), 2.83 (s, 3H); 13C {1H} NMR (100
MHz, CDCl3) δ 168.6, 164.4, 156.9, 137.1, 136.0, 132.1, 128.7, 128.3, 128.3, 126.5,
124.9, 122.8, 122.36, 94.4, 66.6, 22.6; HRMSꢀESI (m/z): calcd for C18H17N2O2,
[M+H]+ : 293.1285; found, 293.1288; IR (KBr): 3488, 3290, 1665, 1610, 1218, 740
cm−1.
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5-Methylindolo[1,2-a]quinazoline (9a): Brown needles (88 mg, 76 %), m.p. =
164.1 – 165.7 °C; 1H NMR (400 MHz, CDCl3) δ 8.43 (d, J = 8.4 Hz, 1H), 8.28 (d, J =
8.4 Hz, 1H), 7.94 (d, J = 6.8 Hz, 1H), 7.90ꢀ7.87 (m, 1H), 7.79ꢀ7.45 (m, 1H),
7.46ꢀ7.34 (m, 3H), 6.89 (s, 1H), 2.80 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3) δ
157.1, 141.8, 138.1, 133.1, 130.2, 129.7, 127.4, 122.8, 122.2, 121.5, 118.4, 114.8,
114.0, 95.6, 22.7; HRMSꢀESI (m/z): calcd for C16H13N2, [M+H]+ : 233.1073; found,
233.1078; IR (KBr): 3052, 2920, 1597, 1553, 1453, 745 cm−1.
5,7-Dimethylindolo[1,2-a]quinazoline (9b): Yellow needles (80 mg, 65 %), m.p. =
1
157.4 – 158.1 °C; H NMR (400 MHz, CDCl3) δ 8.26 (d, J = 8.4 Hz, 1H), 8.19ꢀ8.17
(m, 1H), 7.82ꢀ7.79 (m, 2H), 7.66ꢀ7.62 (m, 1H), 7.41ꢀ7.36 (m, 2H), 7.26ꢀ7.21 (m, 1H),
2.73 (s, 3H), 2.60 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3) δ 155.3, 138.4, 138.3,
132.7, 130.2, 129.3, 127.2, 122.3, 122.2, 121.5, 119.5, 118.5, 114.4, 113.7, 102.9, 22.8,
7.8; HRMSꢀESI (m/z): calcd for C17H15N2, [M+H]+ : 247.1230; found, 247.1231; IR
(KBr): 3101, 1565, 1268, 754 cm−1.
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8-Methoxy-5-methylindolo[1,2-a]quinazoline (9c): Brown needles (98 mg, 75 %),
m.p. = 178.3 – 180.1 °C; 1H NMR (400 MHz, CDCl3) δ 8.39 (d, J = 8.4 Hz, 1H), 7.90
(d, J = 8.0 Hz, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.73 (t, J = 8.0 Hz, 1H), 7.34 (t, J = 8.0
Hz, 2H), 7.00 (s, 1H), 6.79 (d, J = 7.6 Hz, 1H), 4.03 (s, 3H), 2.78 (s, 3H); 13C {1H}
NMR (100 MHz, CDCl3) δ 156.3, 153.7, 140.7, 137.9, 132.8, 131.1, 127.1, 123.0,
122.9, 120.9, 118.6, 114.9, 107.1, 101.7, 92.9, 55.5, 22.7; HRMSꢀESI (m/z): calcd for
C17H15N2O, [M+H]+ : 263.1179; found, 263.1182; IR (KBr): 2926, 1553, 1447, 1243,
752 cm−1.
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8-(Benzyloxy)-5-methylindolo[1,2-a]quinazoline (9d): Yellow needles (140 mg,
83 %), m.p. = 164.8 – 166.3 °C; 1H NMR (400 MHz, CDCl3) δ 8.33 (d, J = 8.4 Hz,
1H), 7.86ꢀ7.81 (m, 2H), 7.70ꢀ7.66 (m, 1H), 7.53 (d, J = 7.6 Hz, 2H), 7.39 (t, J = 7.6
Hz, 2H), 7.35ꢀ7.24 (m, 3H), 7.06 (s, 1H), 6.81 (d, J = 7.6 Hz, 1H), 5.29 (s, 2H), 2.75
(s, 3H); 13C {1H} NMR (100 MHz, CDCl3) δ 156.4, 152.7, 140.8, 137.9, 137.5, 132.8,
131.2, 128.6, 127.8, 127.1, 127.1, 122.9, 122.9, 121.3, 118.6, 114.8, 107.4, 103.5,
93.1, 70.1, 22.7; HRMSꢀESI (m/z): calcd for C23H19N2O, [M+H]+ : 339.1492; found,
339.1501; IR (KBr): 3034, 2923, 1551, 1446, 749 cm−1.
5,9-Dimethylindolo[1,2-a]quinazoline (9e): Brown needles (95 mg, 77 %), m.p. =
164.2 – 166.0 °C; 1H NMR (400 MHz, CDCl3) δ 8.35 (d, J = 8.4 Hz, 1H), 8.13 (d, J =
8.8 Hz, 1H), 7.89 (d, J = 7.6 Hz, 1H), 7.73 (t, J = 8.0 Hz, 1H), 7.64 (s, 1H), 7.31 (t, J
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= 7.6 Hz, 1H), 7.23 (d, J = 8.8 Hz, 1H), 6.79 (s, 1H), 2.78 (s, 3H), 2.54 (s, 3H); C
{1H} NMR (100 MHz, CDCl3) δ 156.8, 142.0, 138.0, 133.0, 131.6, 130.0, 128.5,
127.2, 123.8, 122.6, 121.1, 118.3, 114.7, 113.6, 95.1, 22.7, 21.5; HRMSꢀESI (m/z):
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calcd for C17H15N2, [M+H]+ : 247.1230; found, 247.1234; IR (KBr): 3026, 2917, 1597,
1553, 1455, 746 cm−1.
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9-Methoxy-5-methylindolo[1,2-a]quinazoline (9f): Brown needles (107 mg, 82 %),
m.p. = 168.1 – 169.4 °C; 1H NMR (400 MHz, CDCl3) δ 8.32 (t, J = 8.8 Hz, 1H), 8.15
(d, J = 8.0 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.75 (t, J = 8.0z, 1H), 7.33 (t, J = 7.6 Hz,
1H), 7.27 (d, J = 7.2 Hz, 1H), 7.04 (d, J = 9.2 Hz, 1H), 6.81 (s, 1H), 3.92 (s, 3H), 2.80
(s, 3H); 13C {1H} NMR (100 MHz, CDCl3) δ 156.8, 155.4, 142.4, 137.8, 133.1, 130.8,
127.3, 125.2, 122.6, 118.2, 114.9, 114.4, 112.4, 102.2, 95.3, 55.6, 22.7; HRMSꢀESI
(m/z): calcd for C17H15N2O, [M+H]+ : 263.1179; found, 263.1181; IR (KBr): 3072,
2936, 1594, 1454, 1218, 750 cm−1.
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9-Fluoro-5-methylindolo[1,2-a]quinazoline (9g): Brown needles (95 mg, 76 %),
m.p. = 162.7 – 163.9 °C; 1H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 8.4 Hz, 1H), 7.99
(dd, J = 9.2, 4.0 Hz, 1H), 7.77 (d, J = 7.6 Hz, 1H), 7.60 (t, J = 8.0 Hz, 1H), 7.34ꢀ7.31
(m, 1H), 7.23ꢀ7.19 (m, 1H), 7.01ꢀ7.96 (m, 1H), 6.67 (s, 1H), 2.65 (s, 3H); 13C {1H}
NMR (100 MHz, CDCl3) δ 158.5 (J = 237.7 Hz), 157.6, 142.9, 137.4, 133.1, 130.5 (J
= 10.4 Hz), 127.3, 126.6, 122.9, 118.1, 114.8 (J = 9.7 Hz), 114.23, 110.2 (J = 25.8 Hz),
105.9 (J = 23.2 Hz), 95.4 (J = 4.5 Hz), 22.6; HRMSꢀESI (m/z): calcd for C16H12FN2,
[M+H]+ : 251.0979; found, 251.1012; IR (KBr): 3067, 2924, 1595, 1554, 1452, 751
cm−1.
5-Methylindolo[1,2-a]quinazoline-9-carbonitrile (9h): Yellow needles (82 mg,
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64 %), m.p. = 233.8 – 234.4 °C; H NMR (400 MHz, CDCl3) δ 8.32 (d, J = 8.4 Hz,
1H), 8.26 (d, J = 8.8 Hz, 1H), 8.12 (s, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.83ꢀ7.79 (m,
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