Ru(ii)-Catalyzed annulation of benzamidines and alkynes by C-H/N-H activation: a facile synthesis of 1-aminoisoquinolines

Article abstract of DOI:10.1039/c7ob00389g

An inexpensive Ru(ii) complex catalyzes the oxidative annulation reaction of disubstituted alkynes with benzamidines to provide highly valuable 1-aminoisoquinolines in high yields. The reaction also features excellent regioselectivity with some unsymmetrical alkynes.

Full text of DOI:10.1039/c7ob00389g

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DOI: 10.1039/C7OB00389G
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Ru(II)-Catalyzed Annulation of Benzamidines and Alkynes by C-
H/N-H Activation: A Facile Synthesis of 1-Aminoisoquinolines
P. P. Kaishapa, G.Duaraha, D. Chetiab and S. Gogoia*
Received 00th January 20xx,
Accepted 00th January 20xx
An inexpensive Ru(II) complex catalyzes the oxidative annulation reaction of disubstituted alkynes with benzamidines to
provide highly valuable 1-aminoisoquinolines in high yields. The reaction also features excellent regioselectivity with some
unsymmetrical alkynes.
DOI: 10.1039/x0xx00000x
www.rsc.org/
Introduction
(eqn 2, Scheme 1).5 In continuation of our work on transition-
metal-catalyzed C-C/C-H activation and functionalization
1-Aminoisoquinolines are very important compounds due to
the wide range of biological activities exhibited by them. For
example, they are the inhibitors of thrombin, factor Xa, rho
kinase-I and they display antitumor and antimalarial activities.1
Because of the high biological profile, there is a continued
strong demand for efficient and selective synthesis of 1-
aminoisoquinolines for highthroughput drug screening. The
most common methods to prepare 1-aminoisoquinoline
derivatives are through nucleophilic aromatic substitution
reactions of an existing 1-haloisoquinoline with amino
compounds.1
reactions,6 herein, we report a C−H activation and annulation
reaction of readily available benzamidines with disubstituted
alkynes catalyzed by inexpensive and readily available
ruthenium catalyst [RuCl2(p-cymene)]2, for the synthesis of a
wide range of 1-aminoisoquinolines (eqn 3, Scheme 1).
Notably, the annulation reaction of benzamidine with some
alkynes were highly regioselective in this Ru(II)-catalyzed
reaction.
In the last two decades, the transition-metal-catalyzed
organic reactions via C-H activation have evolved as a powerful
tool to construct functional molecules.2 The C-H activation and
functionalization reactions could be used effectively for the
synthesis of isoquinolines substituted with a secondary amino
group at 1-position, which needs to be removed to obtain the
more biologically important primary amine counterparts.3 The
first use of C-H bond activation and annulation reaction to
synthesize N-unsubstituted 1-aminoisoquinoline was reported
by
Cheng
and
co-workers
using
N'-hydroxy-4-
methylbenzimidamide and diphenyl acetylene as the starting
materials and [Cp*Rh(CH3CN)3](SbF6)2 as the catalyst to afford
6-methyl-3,4-diphenylisoquinolin-1-amine (eqn 1, Scheme 1).4
However, they reported the synthesis of only one derivative of
1-aminoisoquinoline and the high cost of the used rhodium(III)
catalyst are the main limitations of this approach. Very
recently, Zhu and co-workers developed a Co(III)-catalyzed C-H
activation and annulation reaction of oxadiazolones and
disubstituted alkynes for the synthesis of 1-aminoisoquinolines
Scheme 1. Synthetic routes for N-unsubstituted 1-aminoisoquinolines
Results and discussion
Initially, we studied the Ru(II)-catalyzed oxidative annulation
reaction of benzamidine hydrochloride (1a) with diphenyl
acetylene (2a) in the presence of different oxidants using
tAmOH as the solvent for the synthesis of 1-aminoisoquinoline
3aa7 (entries 1-6, Table 1). Among the oxidants screened for
this annulations reaction, Cu(OAc)2 provided the highest yield
of 3aa (entry 4). In the absence of oxidant, the reaction did not
work (entry 7). Further screening of solvents and additives
could not provide better yield of 3aa (entries 8-13).
a.Applied Organic Chemistry, Chemical Sciences & Technology Division, CSIR-North
East Institute of Science and Technology, Jorhat-785006, AcSIR, India, Fax:
+913762370011 Tel.: +91 3762372948; skgogoi1@gmail.com.
b.Department of Pharm. Sciences, Dibrugarh University, Dibrugarh Address here.
Electronic Supplementary Information (ESI) available: Experimental procedures,
characterization
data,
spectra
of
synthesized
compounds.
See
DOI: 10.1039/x0xx00000x
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Table 1. Optimization study for 1-aminoisoquinoline synthesisa
Journal Name
a
Table 2. Scope with substituted alkynes (2a-r)
View Article Online
DOI: 10.1039/C7OB00389G
entry
1
oxidant
NaOAc
additive
solvent
tAmOH
tAmOH
tAmOH
tAmOH
tAmOH
tAmOH
tAmOH
MeOH
H2O
yield (%)b
-
63
78
76
90
80
23
0
-
-
-
-
-
-
2
KOAc
3
AgOAc
4
Cu(OAc)2.H2O
CsOAc
5
6
CuBr2
7
8c
-
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
-
65
46
53
27
64
57
9
-
10
11
12
13
-
-
MeCN
PhMe
AgSbF6
KPF6
tAmOH
tAmOH
aReaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), catalyst (2.5 mol %),
K2CO3 (0.5 mmol), oxidant (0.5 mmol), solvent (6 mL), 85 °C, 12 h; unless
otherwise mentioned. bIsolated yields. cTemperature 64 oC.
The scope of the oxidative annulation reaction of
benzamidine
disubstituted alkynes 2a
substituted symmetrical alkynes, substituted with electron-
donating and electron-withdrawing groups (2b ) were found
to be good substrates to afford 1-aminoisoquinolines 3aa ad in
(1a
)
was then tested with representative
-
r
(Table 2). All the tested diaryl-
-
d
-
good yields. Similarly, the diaryl-substituted unsymmetrical
alkynes substituted with electron-donating and electron-
withdrawing groups on the phenyl rings (2e
mixture of isomers with 1a, which were easily separated by
silica gel column chromatography to afford 3ae 3ae′ (~2:1),
3af 3af′ (~6:1) and 3ah 3ah′ (~1:1). In contrast, the annulation
-f,2h) provided a
,
,
,
reaction of 1a with unsymmetrical alkyne 2g was highly
regioselective to provide only one isomer 3ag. The alkyne
substituted with an aryl and heteroaryl rings 2i, was well
tolerated to afford a 1:1 mixture of 1-aminoisoquinolines 3ai
.
Dialkyne 2j also turned out to be a very good substrate for this
annulation reaction and it provided alkyne substituted
aminoisoquinoline 3aj in high yield, which could be used for
further functional group transformations. Dialkyl-substituted
symmetrical alkynes 2k
substrates for this reaction to provide compounds 3ak
-
m
were also found to be good
am. The
-
alkyne ethyl 3-phenylpropiolate (2n) afforded a mixture of the
product 3an (2:1). The reactions of aryl alkyl substituted
alkynes 2o-q with 1a were highly regioselective to afford 3ao-
aq. The regioselectivity of the products were determined by
their 1H, 13C, HMQC, HMBC and NOE spectra studies. The
annulated products obtained with unsymmetrical alkynes were aReaction conditions: 1a (0.5 mmol), 2 (0.5 mmol), K2CO3 (0.5 mmol), catalyst
t
(2.5 mol %), Cu(OAc)2.H2O (0.5 mmol), AmOH (6.0 mL), 85 °C, 12 h; unless
similar to the reported transition-metal-catalyzed annulation
reactions, where the electon rich group occupy the position
otherwise mentioned. bTemperature 50 oC.
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closer to the heteroatom of the heterocycle.7 The and 1c was studied with diester containing alkyne
View Article On2linse
.
unsymmetrical low boiling alkyne 2-pentyne (2r) was also Interestingly, these reactions afDfoOrId: 1e0d.1039i/mC7iOdaBz0o0[328,91G-
found to be a good annulating partner with 1a to afford a a]isoquinolines 3as and 3cs as the only products, though with
1:1 mixture of 3ar. Similarly, the annulation reaction of some low yields (Table 4). Imidazo[2,1-a]isoquinoline is the key motif
representative benzamidines (1b-i
) were also tested (Table 3). of wide range of natural and biologically important molecules.8
The electron releasing group containing benzamidines 1b-c
The intermolecular competition experiments performed with
differently substituted alkynes revealed the preferential
conversion of aryl substituted alkynes and electron poor
alkyne to their corresponding isoquinoline derivatives 3aa and
3ad (Scheme 2). In contrast, the competition experiment
performed with benzimidines substituted with electron-
donating and electron-withdrawing substituents indicated
electron-withdrawing substituent on the phenyl ring to be
Table 3. Scope with substituted benzamidines 1b-ia
favourable (3ca, Scheme 2). The isocoumarin 3aa-D obtained
by the reaction of 1a and 2a in CD3OD under standard
conditions, resulted in a significant D/H exchange in the eight
aromatic proton of the isoquinoline ring (Scheme 2), indicating
a reversible C-H bond ruthenation step.
aReaction conditions: 1 (0.5 mmol), 2 (0.5 mmol), K2CO3 (0.5 mmol), catalyst
t
(2.5 mol %), Cu(OAc)2.H2O (0.5 mmol), AmOH (6.0 mL), 85 °C, 12 h; unless
otherwise mentioned.
Table 4. Synthesis of imidazo[2,1-a]isoquinolinea
Scheme 2. Intermolecular competition and isotopically labelled
reactions
On the basis of our studies and previous studies on
aReaction conditions: 1 (0.5 mmol), 2s (0.5 mmol), K2CO3 (0.5 mmol), catalyst
ruthenium
functionalization reactions,9 a mechanism is proposed for the
formation of , which is shown in Scheme 3. The active Ru(II)
species 4a first reacts with benzamidine 1a irreversibly to form
the Ru-benzamidine complex 4b In the competition
experiment between 1b 1c and 2a (Scheme 2), preferential
metal
catalyzed
C-H
activation
and
(2.5 mol %), Cu(OAc)2.H2O (1.0 mmol), tAmOH (6.0 mL), 85 °C, 18 h.
afforded moderate yield of the corresponding products 3ba
ca. However, the electron withdrawing group containing
benzamidines 1d 1f provided good yields of 1-
aminoisoquinolines 3da 3fa ia 3el, irrespective of the position
-
3
,
-i
.
,
- ,
,
of the substituent present on the aromatic ring. Notably, the
reactions of 1g-h and 2a were highly regioselective to afford
3ga-ha. Surprisingly, the ortho-substituted benzamidine 1e
could not afford the desired product 3ea under the optimized
condition. Then, the annulation reaction of benzamidines 1a
formation of 3ca supports the formation of 4b, as the
formation of the intermediate 4b would be easier for more
acidic benzamidine 1c. This intermediate 4b on reversible
cycloruthenation affords the complex 4c. Migratory insertion
of alkyne
2
with 4c, followed by reductive elimination in the
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presence of Cu(OAc)2 provides compound
the active Ru(II) catalyst.
3 and regenerates General procedure for the synthesis of imidazo[2,1-
View Article Online
DOI: 10.1039/C7OB00389G
a]isoquinolines:
A solution of benzamidine hydrochloride (0.5 mmol), diethyl
acetylenedicarboxylate (0.5 mmol), [RuCl2(p-cymene)]2 (2.5
mol %), Cu(OAc)2.H2O (0.5 mmol) and K2CO3 (0.5 mmol) in
o
tAmOH (6.0 mL) was stirred at 85 C for 18 hours. The solvent
was removed under vacuo and the crude reaction mixture was
poured into water and extracted with ethylacetate (25 mL x 3).
The ethylacetate layer was then washed with brine. Finally, it
was dried over anhydrous Na2SO4 and the solvent was
removed under vacuo. The crude product obtained was
purified by silica gel (100-200 mesh) column chromatography
using EtOAc/Hexane (1:4) as the eluant to afford imidazo[2,1-
a]isoquinoline.
3,4-Diphenylisoquinolin-1-amine (3aa). Yield 90% (133 mg).
o
1
M.p.: 188 C. H NMR (500 MHz, CDCl3) δ 7.85 (d, J = 8.1 Hz,
1H), 7.59–7.46 (m, 3H), 7.34–7.26 (m, 5H), 7.21–7.14 (m, 5H),
5.39 (bs, 2H). 13C NMR (125 MHz, CDCl3) δ 155.2, 148.7, 141.0,
137.9, 137.5, 131.8, 130.1, 130.0, 128.04, 127.4, 126.8, 126.6,
126.1, 125.7, 122.7, 122.4, 116.4. IR (CHCl3, cm-1): 3294, 2933,
1632, 1505, 1342, 701. MS (EI, m/z): 296. Anal. calcd. for
C21H16N2: C, 85.11; H, 5.44; N, 9.45; Found: C, 85.03; H, 5.49; N,
9.37.
Scheme 3. Proposed mechanism
Conclusions
In summary, we have developed one new method for the
synthesis of highly valuable 1-amino isocoumarins using Ru(II)-
catalyzed C-H/N-H activation and functionalization reaction of
benzamidines and disubstituted alkynes. Owing to the
importance of the products, simplicity in the experimental
procedure, high regioselectivity and high yield, this oxidative
coupling reaction would be of synthetic utility.
3,4-di-p-Tolylisoquinolin-1-amine (3ab). Yield 85% (137 mg).
o
1
M.p.: 110 C. H NMR (500 MHz, CDCl3) δ 7.75 (d, J = 7.8 Hz,
1H), 7.49–7.31 (m, 3H), 7.14 (d, J = 6.2 Hz, 2H), 7.04 (d, J = 7.8
Hz, 2H), 6.98 (d, J = 7.9 Hz, 2H), 6.89 (d, J = 7.1 Hz, 2H), 5.48
(bs, 2H), 2.27 (s, 3H), 2.17 (s, 3H). 13C NMR (125 MHz, CDCl3) δ
154.9, 148.1, 137.7, 136.4, 136.1, 134.9, 131.6, 130.9, 130.1,
129.9, 129.6, 129.0, 128.8, 128.3, 128.2, 126.1, 125.6, 122.6,
21.2, 21.1. IR (CHCl3, cm-1): 3364, 2924, 1614, 1515, 1439,
1220, 771. MS (EI, m/z): 324. Anal. calcd. for C23H20N2: C,
85.15; H, 6.21; N, 8.63; Found: C, 85.48; H, 6.44; N, 8.52.
Experimental
General information
Melting points were measured with a Buchi B-540 melting
point apparatus and are uncorrected. IR spectra were
recorded on Elmer FT-IR-2000 spectrometer on a thin film
using chloroform. NMR spectra were recorded on Bruker
Avance III 500 MHz FTNMR spectrometer using
tetramethylsilane (TMS) as an internal standard. Mass spectra
were recorded on Trace DSQ GCMS instrument. All the
commercially available regents were used as received. All
experiments were monitored by thin layer chromatography
(TLC). TLC was performed on pre-coated silica gel plates
(Merck). Column chromatography was performed on silica gel
(100-200 mesh, Merck). The benzamidine hydrochlorides were
synthesized using known procedure.10
3,4-bis(4-Methoxyphenyl)isoquinolin-1-amine (3ac). Yield
o
87% (155 mg). M.p.: 205 C. 1H NMR (500 MHz, CDCl3) δ 7.82
(d, J = 8.2 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.51 (t, J = 7.5 Hz,
1H), 7.44 (t, J = 7.5 Hz, 1H), 7.28 (d, J = 8.7 Hz, 2H), 7.11 (d, J =
8.5 Hz, 2H), 6.88 (d, J = 8.5 Hz, 2H), 6.73 (d, J = 8.7 Hz, 2H), 5.36
(bs, 2H), 3.82 (s, 3H), 3.75 (s, 3H). 13C NMR (125 MHz, CDCl3) δ
158.3, 158.2, 154.9, 148.3, 137.9, 133.6, 132.7, 131.2, 130.2,
129.9, 126.1, 125.4, 122.4, 121.9, 116.3, 113.6, 112.9, 55.1,
55.0. IR (CHCl3, cm-1): 3307, 2925, 1606, 1515, 1248, 771. MS
(EI, m/z): 356. Anal. calcd. for C23H20N2O2: C, 77.51; H, 5.66; N,
7.86; Found: C, 77.38; H, 5.79; N, 7.70.
3,4-bis(4-Fluorophenyl)isoquinolin-1-amine (3ad). Yield
General procedure for the synthesis of 1-aminoisoquinolines:
A solution of benzamidine hydrochloride (0.5 mmol), alkyne
(0.5 mmol), [RuCl2(p-cymene)]2 (2.5 mol %), Cu(OAc)2.H2O (0.5
o
1
91% (151 mg). M.p.: 190 C. H NMR (500 MHz, CDCl3) δ 7.86
(d, J = 8.3 Hz, 1H), 7.60–7.46 (m, 3H), 7.32–7.22 (m, 2H), 7.17–
7.10 (m, 2H), 7.03 (t, J = 8.5 Hz, 2H), 6.87 (t, J = 8.5 Hz, 2H).
5.74 (bs, 2H) 13C NMR (125 MHz, CDCl3) δ 162.6 (d, J = 245 Hz),
155.3, 147.9, 137.4, 133.2 (d, J = 7.5 Hz), 131.6 (d, J = 7.5 Hz),
130.3, 125.9, 125.8, 122.5, 116.4, 115.2 (d, J = 21.3 Hz), 114.5
(d, J = 21.3 Hz). IR (CHCl3, cm-1): 3300, 2926, 1635, 1509, 1209,
1157, 834, 768. MS (EI, m/z): 332. Anal. calcd. for C21H14F2N2:
C, 75.89; H, 4.25; N, 8.43; Found: C, 75.75; H, 4.39; N, 8.27.
t
mmol) and K2CO3 (0.5 mmol) in AmOH (6.0 mL) was stirred at
o
85 C for 12 hours. The solvent was removed under vacuo and
the crude reaction mixture was poured into water and
extracted with ethylacetate (25 mL x 3). The ethylacetate layer
was then washed with brine. Finally, it was dried over
anhydrous Na2SO4 and the solvent was removed under vacuo.
The crude product obtained was purified by silica gel (100-200
mesh) column chromatography using EtOAc/Hexane (7:3) as
the eluant to afford 1-aminoisoquinolines.
4-(4-Fluorophenyl)-3-(p-tolyl)isoquinolin-1-amine
Yield 54% (88 mg) M.p.: 162 C. H NMR (500 MHz, CDCl3) δ
7.85 (d, J = 8.2 Hz, 1H), 7.56–7.46 (m, 3H), 7.23–7.12 (m, 4H),
(3ae).
o
1
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7.07–6.97 (m, 4H), 5.31(bs, 2H) 2.28 (s, 3H). 13C NMR (125 7.53 (d, J = 8.3 Hz, 1H), 7.50–7.46 (m, 1H), 7.27 (Vdie,wJA=rtic8le.3OnHlinze,
DOI: 10.1039/C7OB00389G
MHz, CDCl3) δ 161.7 (d, J = 243.8 Hz), 155.1, 149.0, 137.9, 2H), 7.14 (d, J = 7.7 Hz, 2H), 7.10 (d, J = 8.0 Hz, 2H), 6.71 (d, J =
137.5, 136.5, 133.2 (d, J = 7.5 Hz), 130.1, 129.8, 128.3, 125.8, 8.4 Hz, 2H), 5.50 (bs, 2H), 3.75 (s, 3H), 2.65–2.58 (m, 2H), 1.70–
125.6, 122.4, 121.4, 116.3, 115.1 (d, J = 21.3 Hz), 21.1. IR 1.63 (m, 2H), 0.98–0.91 (m, 3H). 13C NMR (125 MHz, CDCl3) δ
(CHCl3, cm-1): 3343, 3924, 1621, 1507, 1221, 765. MS (EI, m/z): 158.4, 154.8, 141.0, 137.7, 135.0, 131.5, 131.2, 130.2, 128.3,
328. Anal. calcd. for C22H17FN2: C, 80.47; H, 5.22; N, 8.53; 126.2, 125.6, 122.5, 112.9, 55.1, 37.6, 24.3, 13.6. IR (CHCl3, cm-
Found: C, 80.65; H, 5.41; N, 8.68.
1): 3378, 3138, 2959, 1618, 1567, 1426, 1343, 763. MS (EI,
3-(4-fluorophenyl)-4-(p-tolyl)isoquinolin-1-amine
Yield 25% (41 mg). M.p.: 171 C. H NMR (500 MHz, CDCl3) δ Found: C, 81.31; H, 6.71; N, 7.49.
7.85 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 8.3 Hz, 1H), 7.53 (t, J = 7.5 4-(4-Methoxyphenyl)-3-(4-propylphenyl)isoquinolin-1-
(3aeʹ). m/z): 368. Anal. calcd. for C25H24N2O: C, 81.49; H, 6.57; N, 7.60;
o
1
o
1
Hz, 1H), 7.51–7.46 (m, 1H), 7.31 (dd, J = 8.1 Hz, 5.7 Hz, 2H), amine (3ahʹ). Yield 43% (79 mg). M.p.: 190 C. H NMR (500
7.14 (d, J = 7.8 Hz, 2H), 7.06 (d, J = 7.8 Hz, 2H), 6.87 (t, J = 8.6 MHz, CDCl3) δ 7.86 (d, J = 8.1 Hz, 1H), 7.59 (d, J = 8.3 Hz, 1H),
Hz, 2H), 5.28 (bs, 2H), 2.38 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 7.53 (dd, J = 7.6, 6.7 Hz, 1H), 7.47 (dd, J = 10.9 Hz, 4.0 Hz, 1H),
161.7 (d, J = 245 Hz), 154.9, 147.6, 137.6, 136.3, 134.6, 131.6 7.26–7.21 (m, 2H), 7.10 (d, J = 8.3 Hz, 2H), 6.99 (d, J = 7.9 Hz,
(d, J = 8.0 Hz), 131.5, 130.1, 128.9, 128.5, 126.2, 125.7, 122.3, 2H), 6.86 (d, J = 8.4 Hz, 2H), 5.42 (s, 2H), 3.82 (s, 3H), 2.54–2.48
116.4, 114.2 (d, J = 21.0 Hz), 21.2. IR (CHCl3, cm-1): 3312, 3935, (m, 2H), 1.61–1.54 (m, 2H), 0.91–0.86 (m, 3H). 13C NMR (125
1607, 1533, 1234, 771. MS (EI, m/z): 328. Anal. calcd. for MHz, CDCl3) δ 158.2, 154.8, 148.4, 141.1, 138.1, 137.8, 132.7,
C22H17FN2: C, 80.47; H, 5.22; N, 8.53; Found: C, 80.19; H, 5.20; 130.1, 129.8, 127.7, 126.1, 125.5, 122.4, 122.1, 116.4, 113.5,
N, 8.63.
3-(3,5-Difluorophenyl)-4-(p-tolyl)isoquinolin-1-amine (3af). 1255, 763. MS (EI, m/z): 368. Anal. calcd. for C25H24N2O: C,
55.1, 37.6, 24.3, 13.7. IR (CHCl3, cm-1): 3338, 2983, 1656, 1569,
o
1
Yield 73% (126 mg). M.p.: 210 C. H NMR (500 MHz, CDCl3) δ 81.49; H, 6.57; N, 7.60; Found: C, 81.37; H, 6.75; N, 7.43.
7.86 (d, J = 8.0 Hz, 1H), 7.60–7.49 (m, 3H), 7.17 (d, J = 7.8 Hz, 4-(Thiophen-2-yl)-3-(p-tolyl)isoquinolin-1-amine and 3-
2H), 7.07 (d, J = 8.1 Hz, 2H), 6.91–6.84 (m, 2H), 6.58–6.62 (m, (thiophen-2-yl)-4-(p-tolyl)isoquinolin-1-amine (3ai, 1:1). Yield
o
1H), 5.29 (bs, 2H) 2.39 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 78% (123 mg). M.p.: 184 C. 1H NMR (500 MHz, CDCl3) δ 7.94–
163.2 (d, J = 245.0 Hz), 162.1 (d, J = 246.3 Hz), 154.9, 144.5, 7.80 (m, 1H), 7.64–7.44 (m, 3H), 7.35–7.28 (m, 1H), 7.20–7.12
137.5, 136.8, 133.9, 131.26, 130.2, 129.1, 126.4, 126.2, 123.2, (m, 2H), 7.09–6.98 (m, 2.5H), 6.92–6.82 (m, 1H), 6.92–6.81 (m,
122.3, 113.0 (d, J = 26.3 Hz), 112.9 (d, J = 25.8 Hz), 102.3 (d, J = 0.5H), 5.3 (bs, 1H), 5.30 (bs, 1H), 2.37 (s, 1.5H), 2.28 (s, 1.5H).
25.0 Hz), 102.1 (d, J = 25.0 Hz), 21.2. IR (CHCl3, cm-1): 3294, 13C NMR (125 MHz, CDCl3) δ 162.7, 155.1, 154.9, 149.0, 137.5,
2988, 1639, 1512, 1469, 1217, 1184, 755. MS (EI, m/z): 346. 136.5, 136.3, 133.3, 133.2, 131.7, 131.6, 131.5, 130.1, 130.0,
Anal. calcd. For C22H16F2N2: C, 76.29; H, 4.66; N, 8.09; Found: C, 129.8, 128.9, 128.3, 126.2, 125.8, 125.7, 125.6, 122.4, 122.3,
76.10; H, 4.83; N, 8.24.
121.4, 115.2, 115.0, 114.4, 114.2, 21.2, 21.1. IR (CHCl3, cm-1):
3-(3,5-Difluorophenyl)-3-(p-tolyl)isoquinolin-1-amine 3afʹ. 3376, 3025, 1611, 1515, 1498, 1426, 1218, 768. MS (EI, m/z):
o
Yield 12% (21 mg). M.p.: 225 C. 1H NMR (500 MHz, CDCl3) δ 316. Anal. calcd. for C20H16N2S: C, 75.92; H, 5.10; N, 8.85;
7.88 (dd, J = 11.3 Hz, 8.4 Hz, 1H), 7.64–7.50 (m, 3H), 7.24–7.01 Found: C, 75.95; H, 5.26; N, 8.71.
(m, 4H), 6.86–6.72 (m, 3H), 5.40 (S, 2H), 2.30 (s, 3H). 13C NMR
3-(4-Fluorophenyl)-4-{(4-fluorophenyl)ethynyl}isoquinolin-
o
1
(125 MHz, CDCl3) δ 162.7 (d, J = 247.5 Hz), 162.6 (d, J = 247.5 1-amine (3aj). Yield 88% (157 mg). M.p.: 221 C. H NMR (500
Hz), 155.4, 148.9, 139.0, 137.3, 137.0, 136.8, 132.5, 130.8, MHz, CDCl3) δ 8.38 (d, J = 8.3 Hz, 1H), 8.05 (dd, J = 8.4, 5.4 Hz,
129.5, 128.4, 127.1, 126.2, 125.9, 125.4, 122.5 (d, J = 10.0 Hz), 2H), 7.83 (d, J = 8.3 Hz, 1H), 7.77 (t, J = 7.6 Hz, 1H), 7.56 (t, J =
114.8 (d, J = 19.0 Hz), 114.7 (d, J = 18.8 Hz), 102.4 (d, J = 25.0 7.5 Hz, 1H), 7.45–7.41 (m, 2H), 7.17 (t, J = 8.5 Hz, 2H), 7.05 (t, J
Hz), 102.2 (d, J = 25.0 Hz), 21.2. IR (CHCl3, cm-1): 3324, 2961, = 8.8 Hz, 2H), 5.46 (bs, 2H). 13C NMR (125 MHz, CDCl3) δ 162.8
1622, 1236, 767. MS (EI, m/z): 346. Anal. calcd. for C22H16F2N2: (d, J = 246.3 Hz), 162.2 (d, J = 247.5 Hz), 154.9, 152.8, 137.8,
C, 76.29; H, 4.66; N, 8.09; Found: C, 76.01; H, 4.57; N, 7.87.
136.2, 132.7 (d, J = 7.5 Hz), 131.5 (d, J = 8.8 Hz), 131.0, 126.5,
126.2, 122.5, 119.8, 118.1, 115.8, 115.6 (d, J = 21.3 Hz), 114.6
3-(2-Chlorophenyl)-4-(4-fluorophenyl)isoquinolin-1-amine
o
1
(3ag). Yield 76% (132 mg). M.p.: 256 C. H NMR (500 MHz, (d, J = 21.3 Hz), 103.6, 95.3, 86.1. IR (CHCl3, cm-1): 3356, 3031,
CDCl3) δ 7.87 (d, J = 8.3 Hz, 1H), 7.59–7.54 (m, 1H), 7.53–7.49 1617, 1523, 1488, 1433, 1203, 771. MS (EI, m/z): 356. Anal.
(m, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.34 (dd, J = 8.3 Hz, 5.9 Hz, calcd. for C23H14F2N2: C, 77.52; H, 3.96; N, 7.86; Found: C,
2H), 7.31–7.26 (m, 2H), 7.22–7.17 (m, 1H), 7.12 (dd, J = 7.5 Hz, 77.39; H, 3.87; N, 7.68.
1.2 Hz, 1H), 6.88 (t, J = 8.8 Hz, 2H), 5.37 (s, 2H). 13C NMR (125
3,4-Diethylisoquinolin-1-amine (3ak). Yield 79% (79 mg).
MHz, CDCl3) δ 161.9 (d, J = 245 Hz), 155.5, 148.3, 136.8, 136.8, M.p.: 83 oC. 1H NMR (500 MHz, CDCl3) δ 7.85 (d, J = 8.5 Hz, 1H),
135.5, 133.4, 131.0, 130.8 (d, J = 7.5 Hz), 129.37, 128.8, 126.7, 7.79 (d, J = 8.3 Hz, 1H), 7.59 (t, J = 7.6 Hz, 1H), 7.36 (t, J = 7.6
125.9, 125.7, 122.5, 120.1, 116.3, 114.4 (d, J = 21.3 Hz). IR Hz, 1H), 5.35 (s, 2H), 2.91 (q, J = 7.5 Hz, 2H), 2.79 (q, J = 7.6 Hz,
(CHCl3, cm-1): 3296, 2991, 1637, 1509, 1441, 1345, 1217, 1155, 2H), 1.29 (t, J = 7.5 Hz, 3H), 1.22 (t, J = 7.5 Hz, 3H). 13C NMR
839, 766. MS (EI, m/z): 348. Anal. calcd. for C21H14ClFN2: C, (125 MHz, CDCl3) δ 154.2, 151.2, 136.6, 129.8, 124.5, 123.3,
72.31; H, 4.05; N, 8.03; Found: C, 72.19; H, 4.21; N, 7.81.
123.1, 120.0, 116.7, 28.0, 20.2, 15.3, 14.6. IR (CHCl3, cm-1):
3372, 2955, 1615, 1563, 1426, 1343, 764. MS (EI, m/z): 200.
3-(4-Methoxyphenyl)-4-(4-propylphenyl)isoquinolin-1-
o
1
amine (3ah). Yield 45% (83 mg) M.p.: 163 C. H NMR (500 Anal. calcd. for C13H16N2: C, 77.96; H, 8.05; N, 13.99; Found: C,
MHz, CDCl3) δ 7.88 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 77.85; H, 8.26; N, 13.80.
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Organic & Biomolecular Chemistry
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ARTICLE
Journal Name
3,4-Dipropylisoquinolin-1-amine (3al). Yield 82% (93 mg). 3251, 2962, 1606, 1570, 1272, 771. MS (EI, m/z): 264. Anal.
View Article Online
M.p.: 45 oC. 1H NMR (500 MHz, CDCl3) δ 7.85 (d, J = 8.5 Hz, 1H), calcd. for C17H16N2O: C, 77.25; H, 6.10; N, 10.60; Found: C,
DOI: 10.1039/C7OB00389G
7.78 (d, J = 8.0 Hz, 1H), 7.61 (t, J = 7.5 Hz, 1H), 7.40 (t, J = 7.5 77.26; H, 6.17; N, 10.32.
Hz, 1H), 5.15 (bs, 2H), 2.90–2.83 (m, 2H), 2.78–2.71 (m, 2H),
3-Ethyl-4-methylisoquinolin-1-amine
and
4-ethyl-3-
1.78–1.71 (m, 2H), 1.66–1.59 (m, 2H), 1.09–0.99 (m, 6H). 13C methylisoquinolin-1-amine (3ar, 1:1). Yield 64% (59 mg).
o
1
NMR (125 MHz, CDCl3) δ 153.9, 150.3, 136.9, 129.7, 124.5, M.p.: 90 C. H NMR (500 MHz, CDCl3) δ 7.87 (dd, J = 8.5 Hz,
123.6, 123.0, 119.3, 116.6, 37.0, 29.4, 24.1, 23.5, 14.4, 14.3. IR 3.4 Hz, 1H), 7.80 (d, J = 8.3 Hz, 1H), 7.64 (t, J = 8.3 Hz, 1H),
(CHCl3, cm-1): 3376, 2957, 1617, 1566, 1425, 1278, 763. MS (EI, 7.45–7.40 (m, 1H), 5.20 (bs, 2H), 2.91 (q, J = 7.5 Hz, 1H), 2.83
m/z): 228. Anal. calcd. for C15H20N2: C, 78.90; H, 8.83; N, 12.27; (q, J = 7.5 Hz, 1H), 2.51 (s, 1.5H), 2.45 (s, 1.5H), 1.28–1.19 (m,
Found: C, 78.97; H, 8.94; N, 12.06.
3H). 13C NMR (125 MHz, CDCl3) δ 153.9, 153.6, 151.3, 145.5,
3,4-Dibutylisoquinolin-1-amine (3am). Yield 81% (103 mg). 137.5, 136.4, 130.0, 129.9, 124.6, 124.5, 123.5, 123.2, 123.1,
o
M.p.: 37 C. 1H NMR (500 MHz, CDCl3) δ 7.90–7.81 (m, 2H), 122.9, 121.0, 116.5, 116.4, 113.8, 28.7, 21.3, 20.6, 14.3, 14.0,
7.63 (m, J = 7.5 Hz, 1H), 7.41 (t, J = 7.5 Hz, 1H), 5.77 (bs, 2H), 12.9. IR (CHCl3, cm-1): 3244, 2965, 1647, 1249, 741 MS (EI,
2.90–2.83 (m, 2H), 2.81–2.73 (m, 2H), 1.73–1.65 (m, 2H), 1.60– m/z): 186. Anal. calcd. for C12H14N2: C, 77.38; H, 7.58; N, 15.04;
1.55 (m, 2H), 1.53–1.43 (m, 4H), 1.01–0.94 (m, 6H). 13C NMR Found: C, 77.23; H, 7.69; N, 15.01.
(125 MHz, CDCl3) δ 154.0, 149.1, 136.9, 130.2, 124.7, 123.6,
6-Methyl-3,4-diphenylisoquinolin-1-amine (3ba). Yield 64%
o
123.3, 119.0, 116.7, 34.2, 33.0, 32.4, 26.9, 23.1, 22.9, 14.0, (99 mg). M.p.: 182 C. 1H NMR (500 MHz, CDCl3) δ 7.82 (d, J =
13.9. IR (CHCl3, cm-1): 3356, 2969, 1631, 1547, 1251, 766. MS 8.3 Hz, 1H), 7.37–7.29 (m, 7H), 7.20–7.14 (m, 5H), 5.80 (s, 2H),
(EI, m/z): 256. Anal. calcd. for C17H24N2: C, 79.64; H, 9.44; N, 2.41 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 154.9, 144.5, 139.9,
10.93; Found: C, 79.44; H, 9.69; N, 10.69.
137.7, 137.5, 136.2, 131.8, 129.9, 128.0, 127.9, 127.4, 126.9,
Ethyl 1-amino-3-phenylisoquinoline-4-carboxylate and 126.7, 125.3, 122.5, 114.6, 22.0. IR (CHCl3, cm-1): 3257, 2924,
ethyl 1-amino-4-phenylisoquinoline-3-carboxylate (2:1, 3an). 1623, 1591, 1280, 696. MS (EI, m/z): 310. Anal. calcd. for
o
Yield 72% (105 mg). M.p.: 155 C 1H NMR (500 MHz, CDCl3) δ C22H18N2: C, 85.13; H, 5.85; N, 9.03; Found: C, 85.07; H, 5.92; N,
8.31 (d, J = 8.5 Hz, 0.33H) 8.08 (d, J = 8.5 Hz, 0.67H), 7.87–7.58 9.31.
(m, 4H), 7.56–7.35 (m, 3.67H), 7.33–7.29 (m, 0.33H) 5.87 (bs,
6-Methoxy-3,4-diphenylisoquinolin-1-amine (3ca). Yield
o
1
0.67H), 5.69 (bs, 1.3H), 4.30–3.98 (m, 2H), 1.06–0.76 (m, 3H). 69% (112 mg). M.p.: 201 C. H NMR (500 MHz, CDCl3) δ 7.79
13C NMR (125 MHz, CDCl3) δ 169.2, 167.6, 156.7, 156.5, 151.6, (d, J = 9.0 Hz, 1H), 7.33–7.26 (m, 5H), 7.24–7.13 (m, 5H), 7.12
151.0, 141.0, 139.8, 135.1, 132.7, 131.3, 131.2, 130.2, 129.2, (dd, J = 9.0 Hz, 2.5 Hz, 1H), 6.87 (d, J = 2.5 Hz, 1H), 5.24 (s, 2H),
128.9, 128.1, 128.0, 126.6, 126.3, 126.2, 125.5, 124.8, 122.5, 3.71 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 160.7, 154.8, 149.4,
122.4, 116.0, 115.5, 114.8, 61.0, 60.7, 13.5, 13.3. IR (CHCl3, cm- 141.0, 139.5, 138.1, 131.7, 129.9, 128.1, 127.4, 126.7, 126.6,
1): 3271, 2931, 1685, 1601, 1506, 1471, 1277, 1171, 1023, 823. 124.3, 122.5, 117.2, 111.5, 105.1, 55.1. IR (CHCl3, cm-1): 3262,
MS (EI, m/z): 292. Anal. calcd. For C18H16N2O2: C, 73.95; H, 2925, 1627, 1596, 1279. MS (EI, m/z): 326. Anal. calcd. for
5.52; N, 9.58; Found: C, 74.01; H, 5.59; N, 9.39.
C22H18N2O: C, 80.96; H, 5.56; N, 8.58; Found: C, 80.78; H, 5.71;
4-Methyl-3-phenylisoquinolin-1-amine (3ao). Yield 72% (84 N, 8. 80.
o
1
mg). M.p.: 159 C. H NMR (500 MHz, CDCl3) δ 7.94 (d, J = 8.4
6-Fluoro-3,4-diphenylisoquinolin-1-amine (3da). Yield 82%
Hz, 1H), 7.86 (d, J = 8.3 Hz, 1H), 7.71 (t, J = 8.3 Hz, 1H), 7.54– (129 mg). M.p.: 191 oC. 1H NMR (500 MHz, CDCl3) δ 7.95 (d, J =
7.49 (m, 3H), 7.46–7.42 (m, 2H), 7.37 (t, J = 7.4 Hz, 1H), 5.38 9.1 Hz, 1H), 7.34–7.26 (m, 5H), 7.23–7.14 (m, 7H), 5.96 (s, 2H).
(bs, 2H), 2.45 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 153.9, 148.8, 13C NMR (125 MHz, CDCl3) δ 164.4 (d, J = 251.3 Hz), 155.2,
141.1, 137.6, 130.3, 129.5, 127.9, 127.3, 125.5, 124.2, 123.0, 145.6, 140.1 (d, J = 10.0 Hz), 137.2, 136.1, 131.5, 129.9, 128.4,
117.0, 115.0, 14.8. IR (CHCl3, cm-1): 3353, 2947, 1611, 1532, 127.8, 127.6, 127.3, 126.8 (d, J = 8.8 Hz), 121.8, 116.0 (d, J =
1243, 733. MS (EI, m/z): 234. Anal. calcd. for C16H14N2: C, 25.0 Hz), 113.8, 110.6 (d, J = 22.5 Hz). IR (CHCl3, cm-1): 3286,
82.02; H, 6.02; N, 11.96; Found: C, 81.32; H, 6.23; N, 11.88.
2979, 1631, 1447, 1235, 753. MS (EI, m/z): 314. Anal. calcd. for
3-Ethyl-4-phenylisoquinolin-1-amine (3ap). Yield 75% (93 C21H15FN2: C, 80.24; H, 4.81; N, 8.91; Found: C, 80.07; H, 4.97;
mg). M.p.: 113 oC. 1H NMR (500 MHz, CDCl3) δ 7.99 (d, J = 8.5 N, 8.78.
Hz, 1H), 7.89 (d, J = 8.2 Hz, 1H), 7.72 (t, J = 7.5 Hz, 1H), 7.47-
6-Chloro-3,4-diphenylisoquinolin-1-amine (3fa). Yield 85%
750 (m, 5H), 7.39 (d, J = 6.9 Hz, 1H), 5.34 (s, 2H), 2.86 (q, J = 7.5 (140 mg). M.p.: 240 oC. 1H NMR (500 MHz, CDCl3) δ 7.70 (d, J =
Hz, 2H), 1.22 (t, J = 7.4 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 8.8 Hz, 1H), 7.46 (s, 1H), 7.34 (d, J = 8.8 Hz, 1H), 7.27–7.19 (m,
153.7, 149.1, 136.6, 130.2, 128.8, 128.0, 127.3, 125.5, 124.2, 5H), 7.09 (dd, J = 4.6 Hz, 3.1 Hz, 5H), 5.28 (bs, 2H). 13C NMR
123.2, 21.2, 15.6. IR (CHCl3, cm-1): 3233, 2961, 1656, 1233, 731. (125 MHz, CDCl3) δ 154.9, 150.2, 140.6, 138.7, 137.2, 136.5,
MS (EI, m/z): 248. Anal. calcd. for C17H16N2: C, 82.22; H, 6.49; 131.7, 129.9, 128.3, 127.5, 127.0, 126.9, 126.4, 125.1, 124.2,
N, 11.28; Found: C, 82.16; H, 6.64; N, 11.06.
122.0, 114.6. IR (CHCl3, cm-1): 3246, 2999, 1602, 1417, 1232,
4-(Methoxymethyl)-3-phenylisoquinolin-1-amine
Yield 72% (95 mg). M.p.: 112 C. H NMR (500 MHz, CDCl3) δ 4.57; N, 8.47; Found: C, 76.38; H, 4.75; N, 8.38.
(3aq). 753. MS (EI, m/z): 330. Anal. calcd. for C21H15ClN2: C, 76.24; H,
o
1
8.06 (d, J = 8.4 Hz, 1H), 7.80–7.62 (m, 4H), 7.50–7.39 (m, 4H),
5-Chloro-3,4-diphenylisoquinolin-1-amine (3ga). Yield 83%
o
5.42 (s, 2H), 4.60 (s, 2H), 3.42 (s, 3H). 13C NMR (125 MHz, (137 mg). M.p.: 183 C. 1H NMR (500 MHz, CDCl3) δ 7.87 (d, J
CDCl3) δ 155.5, 152.0, 140.5, 137.6, 130.6, 129.4, 127.9, 127.7, = 8.3 Hz, 1H), 7.66 (d, J = 7.5 Hz, 1H), 7.42 (t, J = 8.0 Hz, 1H),
125.7, 124.50, 122.6, 116.8, 115.2, 69.0, 57.9. IR (CHCl3, cm-1): 7.20–7.07 (m, 10H), 5.66 (s, 2H). 13C NMR (125 MHz, CDCl3) δ
6 | J. Name., 2012, 00, 1-3
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155.1, 152.2, 141.2, 139.1, 133.9, 133.7, 132.2, 131.9, 129.6,
127.2, 126.9, 126.6, 126.4, 125.8, 122.0, 121.5, 118.5. IR
(CHCl3, cm-1): 3285, 2966, 1637, 1451, 1241, 771. MS (EI, m/z):
330. Anal. calcd. for C21H15ClN2: C, 76.24; H, 4.57; N, 8.47;
Found: C, 76.21; H, 4.81; N, 8.69.
Acknowledgements
View Article Online
DOI: 10.1039/C7OB00389G
Authors thank SERB, New Delhi, for financially supporting us with
GPP-0303 (YSS/2014/001018) project. P. P. Kaishap thanks
UGC for the fellowship. We are grateful to the Director, CSIR-
NEIST for his keen interests.
5-Bromo-3,4-diphenylisoquinolin-1-amine (3ha). Yield 58%
(108 mg). M.p.: 189 oC. 1H NMR (500 MHz, CDCl3) δ 7.94 (dd, J
= 7.5 Hz, 1.0 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.34 (t, J = 7.5 Hz,
1H), 7.20-7.07 (m, 10H), 5.28 (bs, 2H). 13C NMR (125 MHz,
CDCl3) δ 155.1, 141.4, 138.4, 138.2, 134.6, 132.9, 129.3, 127.2,
127.0, 126.6, 126.5, 126.1, 122.6, 122.3, 120.3, 118.5. IR
(CHCl3, cm-1): 3248, 2995, 1600, 1231. MS (EI, m/z): 374. Anal.
calcd. for C21H15BrN2: C, 67.21; H, 4.03; N, 7.47; Found: C,
67.20; H, 4.17; N, 7.18.
3,4-Diphenyl-6-(trifluoromethyl)isoquinolin-1-amine (3ia).
Yield 73% (133 mg). 1H NMR (500 MHz, CDCl3) δ 7.79 (d, J = 8.7
Hz, 1H), 7.66–7.58 (m, 2H), 7.36–7.29 (m, 7H), 7.22–7.16 (m,
3H), 5.16 (s, 2H). 13C NMR (125 MHz, CDCl3) δ 156.1, 153.9,
149.5, 140.1, 139.7, 139.2, 138.2, 137.1, 136.8, 135.7, 131.8,
131.7, 131.4, 131.2, 130.4, 129.8, 128.2 (q, J = 31.3 Hz), 127.6
(q, J = 31.6 Hz), 123.8, 123.4 (q, J = 271.3 Hz), 116.8. IR (CHCl3,
cm-1): 3397, 2915, 1643, 1501, 1207, 1163, 761. MS (EI, m/z):
364. Anal. calcd. for C22H15F3N2: C, 72.52; H, 4.15; N, 7.69;
Found: C, 72.39; H, 4.31; N, 7.57.
Notes and references
1
(a) Y. Song, L. Clizbe, C. Bhakta, W. Teng, W. Li, P. Wong, B.
Huang, U. Sinha, G. Park, A. Reed, R. M. Scarborough and B.
Zhu, Bioorg. Med. Chem. Lett., 2002, 12, 2043; (b) A. L.
Smith, F. F. De Morin, N. A. Paras, Q. Huang, J. K. Petkus, E.
M. Doherty, T. Nixey, J. L. Kim, D. A. Whittington, L. F.
Epstein, M. R. Lee, M. J. Rose, C. Babij, M. Fernando, K. Hess,
Q. Le, P. Beltran and J. Carnahan, J. Med. Chem., 2009, 52
,
6189; (c) C. E. Gutteridge, M. M. Hoffman, A. K.
Bhattacharjee, W. K. Milhous and L. Gerena, Bioorg. Med.
Chem. Lett., 2011, 21, 786; (d) H. Van der Goot, J. G.
Oostendorp and W. T. Nauta, Eur. J. Med. Chem., 1975, 10
,
603.
2
3
For recent reviews on C-H activation, see: (a) W. Liu and L.
Ackermann, ACS Catal., 2016, 6, 3743; (b) P. L. Arnold, M. W.
McMullon, J. Rieb and F. E. Kühn, Angew. Chem. Int. Ed.,
2015, 54, 82; Angew. Chem., 2015, 127, 84; (c) J. Wencel-
Delord and F. Glorius, Nat. Chem., 2013,
5, 369; (d) L.
Ackermann, Chem. Rev., 2011, 111, 1315; (e) N. Kuhl, M. N.
Hopkinson, J. Wencel-Delord and F. Glorius, Angew. Chem.
Int. Ed., 2012, 51, 10236; Angew. Chem., 2012, 124, 10382;
6-Chloro-3,4-dipropylisoquinolin-1-amine (3el). Yield 79%
(f) W.-H. Rao and B.-F. Shi, Org. Chem. Front., 2016, 3, 1028.
o
(103 mg). M.p.: 91 C. 1H NMR (500 MHz, CDCl3) δ 7.80 (d, J =
For the utility of azaaromatic compounds with a primary
amino group and for the synthesis of N-substituted 1-
aminoisoquinoline, see (a) N. Chernyak and V. Gevorgyan,
Angew. Chem. Int. Ed., 2010, 49, 2743; (b) S. Ueda and H.
Nagasawa, J. Am. Chem. Soc., 2009, 131, 15080; (c) J. Zeng,
Y. Tan, M. L. Leow and X.-W. Liu, Org. Lett., 2012, 14, 4386;
(d) J. B. M. Rewinkel, H. Lucas, P. J. M. van Galen, A. B. J.
Noach, T. G. van Dinther, A. M. M. Rood, A. J. S. Jenneboer
2.1 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.35 (dd, J = 8.8 Hz, 2.1 Hz,
1H), 5.00 (s, 2H), 2.83–2.78 (m, 2H), 2.75–2.70 (m, 2H), 1.76–
1.70 (m, 2H), 1.64–1.57 (m, 2H), 1.07 (t, J = 7.3 Hz, 3H), 1.02 (t,
J = 7.4 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 153.6, 152.1,
138.0, 136.0, 125.1, 124.7, 122.8, 118.8, 114.8, 37.1, 29.3,
24.0, 23.3, 14.4, 14.3. IR (CHCl3, cm-1): 3311, 2997, 1646, 1256,
1058, 779. MS (EI, m/z): 262. Anal. calcd. for C15H19ClN2: C,
68.56; H, 7.29; N, 10.66; Found: C, 68.47; H, 7.08; N, 10.41.
Tetraethylimidazo[2,1-a]isoquinoline-2,3,5,6-
and C. A. A. van Boeckel, Bioorg. Med. Chem. Lett., 1999,
685; (e) X. Wei, M. Zhao, Z. Du and X. Li, Org. Lett., 2011, 13
9
,
,
4636; (f) J. Li, M. John and L. Ackermann, Chem. Eur. J., 2014,
20, 5403.
1
tetracarboxylate (3as). Yield 43% (98 mg). Gum. H NMR (500
4
J. Jayakumar, K. Parthasarathy, Y.-H. Chen, T.-H. Lee, S.-C.
Chuang and C.-H. Cheng, Angew. Chem., Int. Ed., 2014, 53
,
,
MHz, CDCl3) δ 8.86 (d, J = 7.9 Hz, 1H), 7.87 (d, J = 8.2 Hz, 1H),
7.83–7.78 (m, 1H), 7.78–7.73 (m, 1H), 4.54–4.47 (m, 4H), 4.45–
4.38 (m, 4H), 1.48–1.39 (m, 12H). 13C NMR (125 MHz, CDCl3) δ
165.1, 162.3, 161.2, 160.5, 143.7, 137.5, 130.6, 130.5, 125.9,
125.5, 124.9, 123.8, 123.6, 62.9, 62.6, 62.2, 61.8, 14.2, 13.9,
13.8, 13.7. IR (CHCl3, cm-1): 3270, 2930, 1686, 1603, 1508,
1470, 1282, 1179, 1033, 817. MS (EI, m/z): 456. Anal. calcd. for
C23H24N2O8: C, 60.52; H, 5.30; N, 6.14; Found: C, 60.70; H, 5.43;
N, 6.09.
9889.
5
6
X. Yu, K. Chen, F. Yang, S. Zha and J. Zhu, Org. Lett., 2016, 18
5412.
(a) P. P. Kaishap, B. Sarma and S. Gogoi, Chem. Commun.,
2016, 52, 9809; (b) R. Prakash and S. Gogoi, Adv. Synth.
Catal., 2016, 358, 3046; (c) R. Prakash, K. Shekarrao and S.
Gogoi, Org. Lett., 2015, 17, 5264.
7
(a) A. Seoane, N. Casanova, N. Quiñones, J. L. Mascareñas,
and M. Gulías, J. Am. Chem. Soc., 2014, 136, 834; (b) L.
Ackermann, A. V. Lygin and N. Hofmann, Angew. Chem., Int.
Ed., 2011, 50, 6379; (c) H. Shiota, Y. Ano, Y. Aihara, Y.
Fukumoto and N. Chatani, J. Am. Chem. Soc., 2011, 133
14952.
Tetraethyl
8-fluoroimidazo[2,1-a]isoquinoline-2,3,5,6-
1
,
tetracarboxylate (3cs). Yield 36% (85 mg). Gum. H NMR (500
MHz, CDCl3) δ 8.88 (dd, J = 9.0 Hz, 5.4 Hz, 1H), 7.59 (dd, J = 9.7
Hz, 2.5 Hz, 1H), 7.53 (td, J = 8.5 Hz, 2.5 Hz, 1H), 4.53–4.47 (m,
4H), 4.44–4.39 (m, 4H), 1.47–1.40 (m, 12H). 13C NMR (125
MHz, CDCl3) δ 164.7, 164.6, 162.2, 161.4 (d, J = 245.2 Hz),
160.4, 143.2 (d, J = 8.8 Hz), 133.7, 127.8 (d, J = 8.8 Hz), 127.3,
122.4, 119.5 (d, J = 23.8 Hz), 111.2 (d, J = 23.8 Hz), 63.1, 62.8,
62.3, 61.86, 14.2, 13.9, 13.9, 13.7. IR (CHCl3, cm-1): 3265, 2926,
1679, 1603, 1501, 1473, 1275, 1169, 1031, 801. MS (EI, m/z):
474. Anal. calcd. for C23H23FN2O8: C, 58.23; H, 4.89; N, 5.90;
Found: C, 58.12; H, 4.97; N, 5.79.
8
9
(a) M. Sun, H. Wu, J. Zheng and W. Bao, Adv. Synth. Catal.,
2012, 354, 835; (b) V. P. Reddy, T. Iwasaki and N. Kambe,
Org. Biomol. Chem., 2013, 11, 2249; (c) A. D. C. Parenty, Y.-F.
Song, C. J. Richmond and L. Cronin, Org. Lett., 2007,
9, 2253.
(a) S. I. Kozhushkov and L. Ackermann, Chem. Sci., 2013,
4
,
886; (b) V. S. Thirunavukkarasu, M. Donati and L. Ackermann,
Org. Lett., 2012, 14, 3416; (c) P. B. Arockiam, C. Bruneau and
P. H. Dixneuf, Chem. Rev., 2012, 112, 5879.
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