Tandem synthesis of 1-(alkylamino)-2,4-diarylpyrimido[6,1-a]isoquinolin-5-ium chlorides from isoquinoline, N-alkyl-benzimidoyl chlorides, and isocyanides

Article abstract of DOI:10.1016/j.tetlet.2009.12.097

1-(Alkylamino)-2,4-diarylpyrimido[6,1-a]isoquinolin-5-ium chlorides are obtained in good yields via a tandem reaction between isoquinoline, N-alkyl-benzimidoyl chlorides and alkyl isocyanides in anhydrous acetonitrile.

Full text of DOI:10.1016/j.tetlet.2009.12.097

Tetrahedron Letters 51 (2010) 1190–1192
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Tetrahedron Letters
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Tandem synthesis of 1-(alkylamino)-2,4-diarylpyrimido[6,1-a]isoquinolin-
5-ium chlorides from isoquinoline, N-alkyl-benzimidoyl chlorides, and
isocyanides
*
Issa Yavari , Gholamhossein Khalili, Anvar Mirzaei
Chemistry Department, Tarbiat Modares University, PO Box 14115-175, Tehran, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
1-(Alkylamino)-2,4-diarylpyrimido[6,1-a]isoquinolin-5-ium chlorides are obtained in good yields via a
tandem reaction between isoquinoline, N-alkyl-benzimidoyl chlorides and alkyl isocyanides in anhy-
drous acetonitrile.
Received 27 June 2009
Revised 9 December 2009
Accepted 16 December 2009
Available online 4 January 2010
Ó 2010 Published by Elsevier Ltd.
Keywords:
Isoquinoline
Isocyanide
Pyrimido[6,1-a]isoquinolinium chloride
N-Alkyl-benzimidoyl chloride
Tandem reaction
Tandem reactions (TRs) that require in situ generation of reac-
tive species are a special type of organic reaction in which the
products are formed by sequential reactions.1–5 Numerous organic
transformations are the result of TRs. In fact, tandem processes
lead to skeletal changes rather than merely functional group trans-
formations. The secondary reaction for which the structural prere-
quisite is absent in the initial substrate must be triggered by the
first reaction. TRs have become an increasingly active area of re-
search yielding novel chemical scaffolds for drug discovery efforts.
Isoquinoline-fused pyrimidines are interesting as physiologi-
cally active compounds. In spite of investigations, there has been
no report on the addition of isoquinoline to imidoyl chlorides.6 In
view of our continued interest in the chemistry of pyrimido[6,1-
a]isoquinolinium salts, we have explored the reaction of isocya-
nides 3 with the reactive intermediates generated from isoquino-
line (2), and N-alkyl-benzimidoyl chlorides 1 (prepared in situ
from the corresponding amides, triphenylphosphine and CCl4)
to give 1-(alkylamino)-2,4-diarylpyrimido[6,1-a]isoquinolin-5-ium
chlorides 4. Our results are described in this Letter (Scheme 1).7
The structures of compounds 4 were assigned on the basis of
spectroscopic data. The 1H and 13C NMR spectra of the crude prod-
ucts clearly indicated the formation of 1-(alkylamino)-2,4-diary-
lpyrimido[6,1-a]isoquinolin-5-ium chlorides 4. Any product other
than isoquinolinium salts 4 could not be detected by 1H NMR
spectroscopy.
The 1H NMR spectrum of 4a exhibited four sharp singlets readily
recognized as arising from t-butyl (d = 1.30), methyl (d = 2.19 and
2.41), and NH (d = 5.63) protons along with characteristic reso-
nances for the aromatic systems. The 13C NMR spectrum of 4a
showed 20 distinct resonances in the aromatic region in agreement
with the proposed structure. The mass spectra of these compounds
displayed molecular ion peaks corresponding to the loss of chloride.
Mechanistically, the reaction may proceed via the initial
formation of N-alkyl-benzimidoyl chloride 1, generated from the
corresponding N-alkyl-benzamides and CCl4/PPh3, followed by
trapping with isoquinoline (2) to give the intermediate 5 (see
Scheme 2). Nucleophilic attack of the isocyanide8–10 3 on interme-
diate 5 leads to an adduct 6, which is deprotonated by a second
molecule of isoquinoline to generate zwitterion 7. Intermediate 7
undergoes cyclization and a 1,3-H shift to produce the dihydro
intermediate 9. This intermediate is converted into the pyrimi-
do[6,1-a]isoquinolinium chloride 4 in the presence of isoquinolin-
ium chloride, which acts as an oxidizing agent.
In summary, we have reported the synthesis of 1-(alkylamino)-
2,4-diarylpyrimido[6,1-a]isoquinolin-5-ium chlorides via a tandem
reaction between isoquinoline, N-alkyl-benzimidoyl chlorides, and
alkyl isocyanides in anhydrous MeCN. The present procedure has
the advantage that the reactants can be mixed without any prior
activation or modification. The tandem nature of the present proce-
dure makes it an interesting alternative to multi-step approaches
* Corresponding author. Tel.: +98 21 82883465; fax: +98 21 82883455.
E-mail address: yavarisa@modares.ac.ir (I. Yavari).
0040-4039/$ - see front matter Ó 2010 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2009.12.097

I. Yavari et al. / Tetrahedron Letters 51 (2010) 1190–1192
1191
Cl
N
Ar
Cl
CH3CN
+
R
N
C
N
+
Ar'
Ar
Ar
N
r.t.; 20 h
RHN
Ar'
N
Ar'
Ar'
Ar
1
3
Yield (%)
R
4
2
R
a
b
t-Bu
cyclohexyl
4-MeC6H4
4-MeC6H4
Ph
4-ClC6H4
Ph
4-MeC6H4
4-MeC6H4
Ph
4-MeC6H4
Ph
Ph
4-MeC6H4
4-MeC6H4
Ph
4-ClC6H4
Ph
4-MeC6H4
4-ClC6H4
4-MeC6H4
a
b
c
d
e
f
t
t
t
t
t
-Bu
-Bu
-Bu
-Bu
-Bu
73
75
80
72
77
78
a
b
c
d
e
Ph
4-MeC6H4
Ph
Ph
Ph
cyclohexyl
cyclohexyl
cyclohexyl
70
74
Ph
g
h
4-MeC6H4
Scheme 1.
C9H7N
O
Cl
-Ph3PO
-CHCl3
PPh3
+
+
CCl4
Ar
N
Ar'
Ar
N
Ar'
H
1
Cl
3
+
2
2
1 +
+
H
N
Ar
N
Ar
_
C9H7NHCl
N
C
N
NR
Ar'
Cl
Ar'
5
6
H
N
+ C9H7NHCl
Ar
1,3-H shift
H
4
+ C9H9N
N
Ar
N
Ar
C
N
N
N
NR
RN
RHN
Ar'
H
Ar'
Ar'
8
7
9
Scheme 2.
5. Smith, W. A.; Bochkov, A. F.; Caple, R. Organic Synthesis: The Science behind the
Art; Royal Society of Chemistry: Cambridge, UK, 1998.
and it may be considered as a practical route for the synthesis of
pyrimido[6,1-a]isoquinolinium salts. Further investigations on the
present method will be required to establish its scope and
limitations.
6. Appel, R.; Warning, K.; Ziehn, D.-K. Chem. Ber. 1973, 106, 3450.
7. General procedure for the preparation of 1-(alkylamino)-2,4-diarylpyrimido[6,1-
a]isoquinolinium chlorides 4: carbon tetrachloride (0.17 g, 1.1 mmol) was added
to a mixture of Ph3P (0.31 g, 1.2 mmol) and N-alkyl-benzamide (1 mmol) in
anhydrous MeCN. The resulting solution was stirred at rt for 3 h. After the
addition of isoquinoline (0.13 g, 1 mmol), stirring was continued for 2 h. This
was followed by the addition of isocyanide 3 (1 mmol), and isoquinoline
(0.13 g, 1 mmol) and stirring for an additional 15 h. The solvent was then
evaporated under vacuum and the residue was washed with hot AcOEt and
AcOEt–MeOH (10:1) to give 4.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tetlet.2009.12.097.
1-(tert-Butylamino)-2,4-di-p-tolylpyrimido[6,1-a]isoquinolin-5-ium chloride (4a):
yellow powder, mp (decomp.): 210–212 °C. IR (KBr) (m
max/cmÀ1): 3405 (NH),
References and notes
1645, 1609, 1577, 1491, 1463, 1388, 1358, 1217, 831, 802, 771, 696. 1H NMR
(500 MHz, DMSO-d6): d 1.30 (9H, s, CMe3), 2.19 (3H, s, Me), 2.41 (3H, s, Me),
5.63 (1H, s, NH), 6.73 (2H, d, 3J = 7.9 Hz, CH), 6.96 (2H, d, 3J = 8.1 Hz, CH), 7.37
(1H, d, 3J = 7.5 Hz, CH), 7.40–7.46 (2H, m, CH), 7.63–7.79 (5H, m, CH), 7.89 (1H,
d, 3J = 7.9 Hz, CH), 8.95 (1H, d, 3J = 7.9 Hz, CH). 13C NMR (125.7 MHz, DMSO-d6):
d 30.80 (CMe3), 48.4 (C), 57.7 (Me), 58.6 (Me), 118.3 (CH), 118.5 (CH), 119.5 (2
CH), 120.9 (CH), 122.4 (C), 123.6 (C), 125.1 (CH), 127.6 (2 CH), 128.6 (C), 128.7
(CH), 129.7 (2 CH), 129.8 (C), 130.1 (C), 130.2 (C), 130.8 (2 CH), 131.5 (C), 132.7
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Oxford, 1990.
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Synthesis; Elsevier: New York, 1996.

1192
I. Yavari et al. / Tetrahedron Letters 51 (2010) 1190–1192
(CH), 135.4 (C), 137.7 (C), 143.2 (C). MS (EI), m/z (%): 433 [MÀCl+H]+ (25), 376
8. Yavari, I.; Sabbaghan, M.; Hossaini, Z. Monatsh. Chem. 2008, 139, 625.
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2003, 59, 6083.
(50), 329 (28), 273 (30), 155 (100), 129 (50), 105 (65), 77 (20), 41 (23). Anal.
Calcd for C30H30N3Cl (468.02): C, 76.98; H, 6.46; N, 8.98. Found: C, 76.85; H,
6.34; N, 8.93.
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