A simple highly regioselective or regiospecific substitution method of aromatic isoquinoline

Article abstract of DOI:10.2174/157017809788681266

A novel simple version for highly regioselective or regiospecific substitution method of aromatic isoquinoline has been developed by utilizing the reaction condition of Bischler-Napieralski cyclization. The proposed reaction mechanism was successfully ind

Full text of DOI:10.2174/157017809788681266

404
Letters in Organic Chemistry, 2009, 6, 404-408
A Simple Highly Regioselective or Regiospecific Substitution Method of
Aromatic Isoquinoline
Yu-An Chang*,a and Hsiang Changb
aDepartment of Biotechnology, Chung-Chou Institute of Technology, Yuanlin, Changhua 51003, Taiwan
bDivision of Biotechnology, Agricultural Research Institute, Council of Agriculture, Wufong Township, Taichung County
41357, Taiwan
Received July 17, 2008: Revised February 13, 2009: Accepted April 29, 2009
Abstract: A novel simple version for highly regioselective or regiospecific substitution method of aromatic isoquinoline
has been developed by utilizing the reaction condition of Bischler-Napieralski cyclization. The proposed reaction
mechanism was successfully indirect confirmed. In this method, chloroiminium intermedium A was formed from the
amide compound with phosphoryl chloride, and intramolecular cyclized was preceded. The final structure of aromatic
isoquinoline was obtained through removing the acidic hydrogen atom by sodium borohydride served as a base rather than
reductive agent as expected.
Keywords: Regioselective substitution, regiospecific substitution, Bischler-Napieralski cyclization, aromatic isoquinoline.
INTRODUCTION
backbone. Hibino et al. carried out synthesis for aromatic
isoquinolines derivatives using the thermal electrocyclic
reaction of 1-azahexa-1,3,5-triene system [11]. Molina’s
method [12] utilized a tandem electrocyclic ring closure/
Claisen rearrangement/intramolecular amination process that
iminophosphorane being treated with aromatic isocyanates in
toluene at high temperature leading to corresponding
isoquinoline derivatives.
The nitrogen heterocyclic ring can be easily found in
many nature compounds. The biologically active scaffold
derivatives from isoquinoline [1], isoquinolone [2], benzo-
isoquinoline [3], naphthoisoquinoline [4] and tetrahydro-
benzyl isoquinoline [5] have been valuable subjects for many
synthetic chemists (Fig. 1).
In this report,
a simple highly regioselective or
regiospecific substitutions method of aromatic isoquinoline
was successfully developed through the Bischler-Napieralski
cyclization reaction. Even similar reactions were studied,
however, only few discussions on substitution of 2-
phenethylamine affects the reactions have been revealed [13].
Moreover, taking into account that the activity of amide, or a
substituted 2-phenethylamine, with various alkyl cyanide as
solvent was not been investigated elsewhere.
N
N
NH
O
isoquinoline
benzo[g]isoquinoline
NH
isoquinolone
N
RESULTS AND DISCUSSION
The synthesis of aromatic ketones by the electrophilic
substitution reaction of benzene derivatives and nitrile group
under Lewis acid based on Houben-Hoesch reaction [14] has
been reported (Scheme 1).
naphtho[2,1-f]isoquinoline
tetrahydrobenzyl ispquinoline
Fig. (1). The nitrogen heterocyclic ring compounds.
Miller [6] published the synthesis of isoquinolines by
ozonolysis substituting indenes reductive reaction. Inter-
mediate homophthalaldehydes were then treated with
ammonium hydroxide to obtain aromatic isoquinolines.
Previous methods, Bischler-Napieralski [7], Pictet-Spengler
[8], Pomeranz-Fritsh [9], and Schlittler-Muller [10], have
also been frequently employed in synthesis of isoquinoline
NH2Cl
H
HCl
R
X
+ R-CN
X
ZnCl2
O
H3O
R
X
*Address correspondence to this author at the Department of Biotechnology,
Chung-Chou Institute of Technology, Yuanlin, Changhua 51003, Taiwan;
Tel: 886-4-8311498 ext. 4215; Fax: 886-4-8394070;
Scheme 1. Houben-Hoesch reaction.
E-mail: cya0520@dragon.ccut.edu.tw
1570-1786/09 $55.00+.00
© 2009 Bentham Science Publishers Ltd.

A Simple Highly Regioselective or Regiospecific Substitution Method
Letters in Organic Chemistry, 2009, Vol. 6, No. 5 405
1
3
2
NH
1) POCl3/ MeCN/ reflux
2) NaBH4/ MeOH
NH
O
2
1
3
MeO
OMe
1) POCl3/ MeCN/ reflux
2) NaBH4/ MeOH
OMe
MeO
1
3
N
OMe
H
N
OMe
2
Me
Scheme 2. Synthesis of aromatic isoquinoline by mixing amide 1 and phosphoryl chloride in dry alkyl cyanide.
According to the mechanism, synthesis of aromatic
isoquinoline has been approached through the intermolecular
cyclization of nitrilium salt intermediate. The amide 1 and
phosphoryl chloride were mixed in dry alkylnitrile served as
solvent. Interestingly, the recrystallized products from
hexane/ethyl acetate were aromatic isoquinoline 2, but not
tetrahydrobenzyl isoquinoline 3 that is the expected product
for Bischler-Napieralski reaction (Scheme 2).
Houben-Hoesch reaction. Intermediate B was further
established through intramolecular cyclized. The structure of
aromatic isoquinoline was obtained by removing the acidic
hydrogen atom with base (Scheme 3). Of particular interest
was found in this particular reaction that sodium borohydride
served as a base rather than reductive agent as expected. In
order to confirm this special reaction, other bases were
investigated, such as sodium methoxide or potassium
carbonate. The results were consistent and identical results
were obtained.
Under the condition for Bischler-Napieralski reaction,
amide 1 reacted with phosphorus oxychloride to give the
intermediate nitrilium salt. There was no electron donating
group (e.g. methoxy group) at ortho-para position of
phenethylamine. The intermediate A was then yielded by the
Based on this mechanism, preliminary studies the
reaction of amide 1 against various alkyl cyanides as solvent.
Compound 4 was obtained in lower yield (57%) when the
O
O
POCl3
N
N
O
P
Cl
Cl
H
HN
O
Cl
P
Cl
Cl
H
O
N
OMe
OMe
Me
MeO
1
OMe
OMe
OMe
R
N
N
OMe
OMe
R
H
H
N
N
MeO
H
Me
Me
MeO
A
H
N
OMe
R
N
H
N
OMe
OMe
H
N
OMe
Me
B
CH3
2
Scheme 3. Proposed mechanism for product 2.

406 Letters in Organic Chemistry, 2009, Vol. 6, No. 5
Chang and Chang
Table 1. Synthesis of Aromatic Isoquinolines
R
R
1
3
2
1) POCl3/ R'CN/ reflux
2) Base
NH
O
N
OMe
OMe
H
N
1
2
3
R'
MeO
2, R, R'= H, Me
4, R, R'=OMe, Me
5, R, R'= OMe, Et
6, R, R'= H, Et
MeO
7, R, R'= OMe, i-Pr
8, R, R'= H, i-Pr
9, R, R'= OMe, t-Bu
10, R, R'= H, t-Bu
Compound
R
R’
Yield (%)
2
4
H
OMe
OMe
H
Me
Me
Et
74
57
27
77
19
35
0
5
6
Et
7
OMe
H
i-Pr
i-Pr
t-Bu
t-Bu
8
9
OMe
H
10
0
substituted R was methoxy group as electron donor group.
Moreover, the yield of aromatic isoquinoline became lower
when substituted R’ of alkyl cyanide became larger. No
product was obtained when the quaternary carbon structure
of alkyl cyanide existed. The results were summarized in
(Table 1).
tometer. 1H and 13C NMR spectra were recorded on a Varian
Gemini-200 MHz and VXR-300 MHz spectrometer using
CDCl3, with tetramethylsilane as the internal standard, as
solvent. Low-resolution mass and high-resolution mass
spectra were measured with a Hitachi M-52-Instrument or
JEOL JMS-HX110 mass spectrometer. Melting points were
uncorrected and were determined either using recrystallized
samples or samples, which crystallized during concentration
of the chromatography eluents.
CONCLUSION
A simple yet highly regioselective or regiospecific
substitutions method of aromatic isoquinoline has been
successfully developed and revealed with possible reaction
mechanisms. The desired products can be obtained with a
simple work-up procedure with high potential to give
valuable intermediates during synthesis of biologically active
natural products. Other related studies have been in progress
to further investigate the biological and pharmacological
activity of synthesized compounds, and to extend the
reactivity of the synthesis for various types of isoquinoline
alkaloids.
N-Phenylethyl-3,4-dimethoxyphenylacetamide(1)
Thionyl chloride (7.50 mL, 102.01 mmol) was added
dropwise to a solution of 3,4-dimethoxyphenylacetic acid
(5.00 g, 25.45 mmol) dissolved in dichloromethane 100 mL.
The mixture was refluxed for 1 h. The reaction mixture was
concentrated under vacuum after cooling to rt. 20 mL water
was added to the mixture and then discarded, repeated once.
2-phenylethanamine (3.34 g, 25.45 mmol) was dissolved in
solution of dichloromethane 80 mL and triethyl amine 4.24
mL. Dichloromethane 15 mL was then added dropwise to
this solution and stirred for 1 h at rt. The mixture was
dissolved in CH2Cl2, washed with saturated aqueous
NaHCO3 and saturated aqueous NaCl. Further being dried
over Na2SO4(s), filtered and concentrated under vacuum.
The crude product was purified by recrystallization
(hexane/EtOAc) to afford compound 1 (6.72 g, 88.3% yield)
ACKNOWLEDGEMENTS
The authors are grateful to the National Center for
technical support of High Performance Computing.
o
as a white solid. mp 105-107 C. IR (CHCl3): 3433, 1653,
EXPERIMENTAL
1263 cm-1. 1H NMR (300 MHz, CDCl3): ꢀ7.24-7.18(m, 3H),
7.04-7.01(m, 2H), 6.80(d, J=7.8 Hz, 1H), 6.71-6.66(m, 2H),
5.45(s, 1H), 3.88(s, 3H), 3.82(s, 3H), 3.47(s, 2H), 3.46-
All reactions were performed under dry nitrogen. IR
spectra were measured with a Bio-Rad FTS-40 spectropho-

A Simple Highly Regioselective or Regiospecific Substitution Method
Letters in Organic Chemistry, 2009, Vol. 6, No. 5 407
3.40(m, 2H), 2.73(t, J=6.6 Hz, 2H). 13C NMR (75 MHz,
CDCl3): ꢀ171.17, 149.24, 148.28, 138.60, 128.62, 128.50,
127.19, 126.39, 121.57, 112.38, 111.50, 55.90, 55.82, 43.42,
40.55, 35.38. LRMS m/z (%): 299(M+, 10.3%), 151(M+-
C9H10NO, 37.1%), 91(M+-C9H10NO-2xOMe, 100%).
Hz, 2H), 1.37 (t, J=7.8 Hz, 3H). 13C NMR (75 MHz, CDCl3):
ꢀ159.97, 157.67, 154.07, 152.75, 146.59, 136.59, 130.48,
127.83, 127.65, 120.56, 116.24, 110.37, 104.09, 104.2,
94.15, 55.89, 55.76, 55.26, 43.23, 30.35, 28.22, 13.41.
LRMS m/z (%): 366 (M+, 19.8%), 245 (M+-C6H5CH2-OMe,
100%). HRMS: calcd For C22H26N2O3, 366.1945, found
366.1943.
General Procedure for Preparation of Aromatic
Isoquinoline from Phenylacetamide (Table 1)
3-(N-Phenylethyl)amino-6,7-dimethoxy-1-ethyl-isoquino-
line (6)
Phosphoryl chloride (132.42 mmol) was added dropwise
to the solution of corresponding acetamide (22.07 mmol)
dissolved in alkyl cyanide 100 mL. The mixture was
refluxed in an oil bath and stirred for 4 h. The mixture was
concentrated under vacuum after cooling to rt. Further
dissolved in EtOAc 80 mL and washed with saturated
aqueous NaHCO3 and saturated aqueous NaCl. Samples
were then dried over anhydrous Na2SO4(s), under reduced
pressure. The mixture was dissolved in methanol 80 mL and
sodium borohydride (55.18 mmol) was added slowly. The
resulting mixture was stirred at rt for 12 h and concentrated
under vacuum. Further being dissolved in CH2Cl2 and
washed with saturated aqueous NH4Cl and saturated aqueous
NaCl. The mixture was dried with Na2SO4(s) and
concentrated under vacuum. The crude product was purified
by chromatography on a silica gel column.
o
Yellowish solid; mp 86-87 C. IR (CHCl3): 3422, 1675
cm-1. 1H NMR (300 MHz, CDCl3): ꢀ7.35-7.23(m, 5H),
7.16(s, 1H), 6.84(s, 1H), 6.34(s, 1H), 4.50(br., 1H), 3.97(s,
3H), 3.96(s, 3H), 3.51(d, J=7.9 Hz, 6.3Hz, 2H), 3.08(q, J=7.8
Hz, 2H), 2.98(t, J=6.9 Hz, 2H), 1. 37 (t, J=7.8 Hz, 3H). 13C
NMR (75 MHz, CDCl3): ꢀ160.10, 153.81, 152.77, 146.68,
139.36, 136.49, 128.75, 128.53, 126.33, 116.36, 103.99,
94.35, 55.87, 55.77, 44.48, 35.64, 28.26, 13.43.LRMS
m/z(%): 366 (M+, 21.7%), 245 (M+-C6H5CH2, 100%).
HRMS: calcd For C21H24N2O2, 366.1839, found 366.1837.
3-(N-(2-Methoxy)phenylethyl)amino-6,7-dimethoxy-1-iso-
propylisoquinoline (7)
Light brown solid; mp 65-66 oC. IR (CHCl3): 3413, 1632
cm-1. 1H NMR (300 MHz, CDCl3): ꢀ7.23-7.19 (m, 2H), 7.21
(s, 1H), 6.94-6.87(m, 2H), 6.82(s, 1H), 6.35(s, 1H), 4.80-
4.40(br., 1H), 3.97(s, 3H), 3.96(s, 3H), 3.86(s, 3H), 3.60(q,
J=6.6 Hz, 1H), 3.47(q, J=7.2 Hz, 2H), 3.01(t, J=7.2 Hz, 2H),
1. 37 (d, J=6.6 Hz, 6H). 13C NMR (75 MHz, CDCl3):
ꢀ163.12, 157.66, 154.06, 152.49, 146.45, 136.60, 130.51,
128.03, 127.61, 120.55, 115.72, 110.35, 104.06, 103.74,
94.06, 55.89, 55.75, 55.34, 43.25, 30.80, 30.44, 21.97.
LRMS m/z(%): 380 (M+, 32.7%), 259 (M+-C6H5CH2-OMe,
100%).HRMS: calcd For C23H28N2O3, 380.2101, found
380.2100.
3-(N-Phenylethyl)amino-6,7-dimethoxy-1-methyl-isoqui-
noline (2)
Yellowish solid; mp129-130 oC. IR (CHCl3): 3421, 1633
cm-1. 1H NMR (300 MHz, CDCl3): ꢀ7.33-7.28(m, 5H),
7.10(s, 1H), 6.83(s, 1H), 6.35(s, 1H), 4.50(s, 1H), 3.98(s,
3H), 3.97(s, 3H), 3.55-3.45(m, 2H), 2.98(t, J=7.2 Hz, 2H),
2.73(s, 3H). 13C NMR (75MHz, CDCl3): ꢀ157.03, 149.20,
147.85, 140.05, 138.23, 128.71, 128.60, 126.62, 115.23,
103.33, 102.72, 97.17, 56.38, 56.06, 44.43, 35.14, 17.33.
LRMS m/z(%): 322(M+, 16.1%), 231(M+-C6H5CH2, 92.5%),
151(M+- C6H5CH2-2xOMe, 100%). HRMS: calcd For
C20H22N2O2, 322.1683, found 322.1680.
3-(N-Phenylethyl)amino-6,7-dimethoxy-1-isopropyl-iso-
quinoline (8)
3-(N-(2-Methoxy)phenylethyl)amino-6,7-dimethoxy-1-
methylisoquinoline (4)
o
Yellowish solid; mp 95-96 C. IR (CHCl3): 3422, 1632
cm-1. 1H NMR (300 MHz, CDCl3): ꢀ7.35-7.24(m, 6H),
6.83(s, 1H), 6.33(s, 1H), 4.80-4.60(br., 1H), 3.97(s, 6H),
3.67(q, J=6.9 Hz, 1H), 3.53(q, J=7.5 Hz, 2H), 2.99(t, J=7.5
Hz, 2H), 1. 37 (d, J=6.9 Hz, 6H). 13C NMR (75 MHz,
CDCl3): ꢀ163.17, 153.76, 152.53, 146.59, 139.56, 136.54,
128.78, 128.49, 126.26, 115.84, 104.01, 103.64, 94.47,
55.84, 55.75, 44.48, 35.76, 30.81, 21.97. LRMS m/z (%):
350 (M+, 26.3%), 259 (M+-C6H5CH2, 100%), 91 (C6H5CH2,
48.9%). HRMS: calcd For C22H26N2O2, 350.2000, found
350.1996.
Yellowish solid; mp 130-132 oC. IR (CHCl3): 3418, 1600
cm-1. 1H NMR (300 MHz, CDCl3): ꢀ7.25-7.19(m, 2H),
7.09(s, 1H), 6.94-6.87(m, 2H), 6.83(s, 1H), 6.38(s, 1H),
4.64(s, 1H), 3.98(s, 3H), 3.97(s, 3H), 3.86(s, 3H), 3.45-
3.40(m, 2H), 3.00(t, J=7.2 Hz, 2H), 2.73(s, 3H). 13C NMR
(75 MHz, CDCl3): ꢀ157.63, 155.23, 155.99, 152.83, 146.52,
136.18, 130.44, 127.73, 127.65, 120.55, 117.11, 110.35,
104.36, 103.83, 94.10, 55.83, 55.74, 55.24, 43.18, 30.27,
22.00. LRMS m/z (%): 352 (M+, 10.9%), 231 (M+-
CH3OC6H5CH2, 100%), 91 (M+- C6H5CH2, 15.3%).
REFERENCES
3-(N-(2-Methoxy)phenylethyl)amino-6,7-dimethoxy-1-
ethylisoquinoline (5)
[1]
a) Kashdan, D. S.; Schwartz, J. A.; Rapoport, H. J. Org. Chem.,
1982, 47, 2638; b) Venkov, A. P.; Ivanov, I. I. Tetrahedron, 1996,
52, 12299; c) Roesch, K. R.; Larock, R. C. Org. Lett., 1998, 1, 553;
d) Roesch, K. R.; Larock, R. C. J. Org. Chem., 1998, 63, 5306; e)
Roesch, K. R.; Zhang, H.; Larock, R. C. J. Org. Chem., 2001, 66,
5306; f) Dai, G.; Larock, R. C. Org. Lett., 2001, 3, 4035; g) Roesch,
K. R.; Larock, R. C. J. Org. Chem., 2002, 67, 86; h) Huang, Q.;
Hunter, J. A.; Larock, R. C. J. Org. Chem., 2002, 67, 3437.
o
Yellowish solid; mp 99-101 C. IR (CHCl3): 3410, 1614
cm-1. H NMR (300 MHz, CDCl3): ꢀ7.20(d, J= 7.5 Hz, 2H),
7.16(s, 1H), 6.93-6.87(m, 2H), 6.83(s, 1H), 6.37(s, 1H),
4.70-4.50(br., 1H), 3.97(s, 3H), 3.96(s, 3H), 3.86(s, 3H),
3.46(t, J=7.2 Hz, 2H), 3.08(q, J=7.8 Hz, 2H), 3.00(t, J=7.2
1

408 Letters in Organic Chemistry, 2009, Vol. 6, No. 5
Chang and Chang
[2]
[3]
[4]
a) Wang, X.-J.; Grozinger, K. Tetrahedron Lett., 1998, 39, 6609; b)
Ryu, I.; Matsu, K.; Minakata, S.; Komatsu, M. J. Am. Chem. Soc.,
1998, 120, 5838; c) Briet, N.; Brookes, M. H.; Davenport, R. J.;
Galvin, F. C. A.; Gilbert, P. J.; Mack, S. R.; Sabin, V. Tetrahedron,
2002, 58, 5761.
a) Kametani, T.; Fukumoto, K. J. Chem. Soc., Perkin Trans. 1,
1972, 394; b) Beaumont, D.; Waigh, R. J. Chem. Res., Miniprint,
1980, 3864; c) Young, S. D.; Wiggins, J. M.; Huff, J. R. J. Org.
Chem., 1988, 53, 1114; d) Cesati, R. R.; Katzenellenbogen, J. A.
Org. Lett., 2000, 2, 3635.
a) Wu, Y.-C.; Liou, J.-Y.; Duh, C.-Y.; Lee, S.-S.; Lu, S.-T.
Tetrahedron Lett., 1991, 32, 4169; b) Lee, S.-S.; Lin, Y.-J.; Chen,
M.-Z.; Wu, Y.-C.; Chen, C.-H. Tetrahedron Lett., 1992, 33, 6309;
c) Hara, H.; Kaneko, K.-I.; Endoh, M.; Uchida, H.; Hoshino, O.
Tetrahedron, 1995, 51, 10189; d) Martinez, E.; Estevez, J. C.;
Estevez, R. J.; Villaverde, M. C.; Castedo, L. Tetrahedron Lett.,
1998, 39, 1231; e) Pampin, M. C.; Estevez, J. C.; Castedo, L.;
Estevez, R. J. Tetrahedron Lett., 2001, 42, 2307.
[5]
a) Feldman, H. S.; Takman, B. H.; Tenthorey, P. A. J. Med. Chem.,
1977, 20, 894; b) Chrzanowska, M.; Rozwadowska, M. D. Chem.
Rev., 2004, 104, 3341.
Miller, R. B.; Frincke, J. M. J. Org. Chem., 1980, 45, 5312.
Whaley, W. M.; Govindachari, T. R. Org. React., 1951, 6, 74.
Whaley, W. M.; Govindachari, T. R. Org. React., 1951, 6, 151.
Gensler, W. J. Org. React., 1951, 6, 191.
Schlittler, E.; Muller, J. Helv. Chim. Acta, 1948, 31, 1119.
Hibino, S.; Sugino, E.; Adachi, Y.; Nomi, K. Heterocycles, 1989,
28, 275.
Molina, P.; Alajarin, M.; Vidal, A. J. Org. Chem., 1990, 55, 6140.
Markovich, K. M.; Hamada, A.; Miller, D. D. J. Hetreocycl. Chem.,
1990, 27, 1665.
a) Spoerri, P. E.; DuBois, A. S. Org. React., 1949, 5, 387; b) Amer,
M. I.; Booth, B. L.; Noori, G. F. M.; Fernanda, M. J.; Proença, R.
P. J. Chem. Soc., Perkin Trans. 1, 1983, 1075; c) Arkhipov, V. V.;
Smirnov, M. N.; Khilya, V. P. Chem. Heterocycl. Comp., 1997, 33,
515; d) Kawecki, R.; Mazurek, A. P.; Kozerski, L.; Maurin, J. K.
Synthesis, 1999, 751.
[6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]