Synthesis of isoquinoline alkaloids via oxidative amidation-bischler- napieralski reaction

Article abstract of DOI:10.1055/s-0031-1290655

A straightforward synthesis of -keto amides by coupling primary amines with aryl dibromoethanones under oxidative amidation conditions has been developed. The -keto amides were then subjected to heterocyclodehydration reaction under Bischler-Napieralski conditions followed by aromatization with DBU provided 1-benzoyl isoquinolines in a two-stage process. Utilizing this methodology, isoquinoline alkaloids such as thalmicrinone, papavaraldine, and pulcheotine A were synthesized in excellent yields. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290655

LETTER
1013
Synthesis of Isoquinoline Alkaloids via Oxidative Amidation–Bischler–
Napieralski Reaction
S
ynthesis of Isoq
.uinoline
AlkS
aloids hankar,a Satish S. More,a M. V. Madhubabu,a N. Vembu,b U. K. Syam Kumar*a
a
Technology Development Centre, Custom Pharmaceutical Services, Dr. Reddy’s Laboratories Ltd., Miyapur, Hyderabad 500 049, India
Urumu Dhanalakshmi College, Tiruchirappalli 620 019, India
Fax +91(40)23045439; E-mail: syam_kmr@yahoo.com
b
Received 23 January 2012
This letter is dedicated to the Department of Chemistry, S. N. College, Nattika, Kerala, India
Numerous strategies have been reported in the literature
Abstract: A straightforward synthesis of a-keto amides by cou-
pling primary amines with aryl dibromoethanones under oxidative
amidation conditions has been developed. The a-keto amides were
then subjected to heterocyclodehydration reaction under Bischler–
for the synthesis of 1-benzoylisoquinoline alkaloids.
These synthetic protocols involve three stages, 1) con-
struction of 1-benzyl dihydroisoquinoline framework
Napieralski conditions followed by aromatization with DBU pro- from open-chain precursor, 2) oxidation of 1-benzyl dihy-
vided 1-benzoyl isoquinolines in a two-stage process. Utilizing this
droisoquinoline to the corresponding 1-benzoyl dihy-
methodology, isoquinoline alkaloids such as thalmicrinone, papa-
droisoquinoline, and 3) the aromatization of 1-benzoyl
varaldine, and pulcheotine A were synthesized in excellent yields.
dihydroisoquinoline to isoquinoline. The most prominent
approach for the synthesis of 1-benzyl dihydroisoquino-
line is via the intramolecular cyclodehydration of N-phen-
Key words: oxidative amidation, Bischler–Napieralski cyclization,
aromatization, isoquinoline alkaloids, thalmicrinone, papavaral-
dine, pulcheotine A
ethyl-2-phenylacetamide under Bischler–Napieralski
reaction conditions.4 The conversion of 1-benzyl dihy-
droisoquinoline to 1-benzoyl dihydroisoquinoline is re-
ported with several oxidizing agents.5 Whereas
aromatization is carried out with oxidants such as chromi-
um trioxide, manganese dioxide, and also with sulfur.6
Some reports are also known in literature for direct con-
version of 1-benzyldihydroisoquinoline to the corre-
sponding 1-benzoyl isoqunoline.7 Most of these oxidants
are either toxic or hazardous metal materials, which create
environmental problems during their disposal. The appar-
ent difficulty in the synthesis of appropriately substituted
alkoxy phenyl acetic acid coupled with the toxic nature of
oxidants makes this three-stage synthesis of isoquinolines
less attractive.
The synthesis of isoquinoline alkaloids and their conge-
ners has received considerable attention because of their
widespread presence in numerous biologically active nat-
ural products and pharmaceuticals. Broadly there are two
types of isoquinoline alkaloids exist in nature, 1-benzoyl-
isoquinoline as well as 1-benzylisoquinoline alkaloids.
Isoquinoline alkaloids exhibits antimicrobial, antimalari-
al, antitumor, anti-HIV activities, and also have antioxi-
dant capacity.1 They also have shown affinity for
dopamine receptors from striatal membranes.2 Isoquino-
lines also act as antitumor agents as inhibitors of the mito-
chondrial electron-transport chains.3
In the context of our ongoing research project on the total
synthesis of biologically active natural products and its
derivatives,8 we wish to develop an efficient and general
strategy for the synthesis of 1-benzoyl isoquinolines via
oxidative amidation–Bischler–Napieralski reaction. 3,4-
Dihydropapaveraldine (1, Figure 1),9 papavaraldine (xan-
thaline) (2),10 thalmicrinone (3),11 and pulcheotine A (4)12
were chosen as the target isoquinoline alkaloids because
of their unique structural features and important biologi-
cal activities.
MeO
MeO
N
N
MeO
MeO
OMe
OMe
OMe
OMe
O
O
3,4-dihydropapaveraldine (1)
papaveraldine (xanthaline) (2)
OMe
MeO
O
N
N
O
MeO
Recently we have disclosed a straightforward synthesis of
a-keto amides by coupling secondary amines with aryl
and heteroaryl dibromoethanones under aerial oxidation
conditions.13 With anticipation that the oxidative amida-
tion methodology could be used as key step in isoquino-
line synthesis, we have designed an efficient synthetic
route for the isoquinoline synthesis as shown in the ret-
rosynthetic scheme (Scheme 1). 1-Benzoylisoquinoline
(5a) could efficiently be synthesized from the correspond-
ing 1-benzoyl-3,4-dihydroisoquinoline (6a) by aromatiza-
O
O
OMe
OMe
thalmicrinone (3)
pulcheotine A (4)
Figure 1
SYNLETT 2012, 23, 1013–1020
Advanced online publication: 28.03.2012
DOI: 10.1055/s-0031-1290655; Art ID: D06512ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.
2
0
1
2

1014
R. Shankar et al.
LETTER
tion. The cyclodehydration of a-keto amide 7a under In a prototype experiment, a mixture of 2,2-dibromo-1-
Bischler–Napieralski conditions would construct 1-ben- phenylethanone (8a, 6.0 g, 21.6 mmol) and sodium iodide
zoyl-3,4-dihydroisoquinoline (6a) in good yields. The 2- (6.48 g, 43.2 mmol) in sulfolane (30.0 mL) at 20–25 °C
oxo-N-phenethyl-2-phenylacetamide (7a) required for was stirred for 40–50 minutes. Powdered tripotassium
isoquinoline synthesis in turn could be prepared by cou- phosphate (11.46 g, 54 mmol) and 2-phenyl ethylamine
pling of 2,2-dibromo-1-phenylethanone 8a with 2-phenyl (9a, 3.15 g, 25.8 mol) were then added into the reaction
ethylamine (9a) under oxidative amidation reaction con- mixture under a nitrogen atmosphere and was stirred for
ditions (Scheme 1).
about two hours at room temperature (30–35 °C). tert-
Butyl hydroperoxide solution (5.5 M in decane, 4.89 mL,
27 mmol) was then added into the reaction mixture over a
period of five minutes, and the reaction mixture was
stirred for another 4–6 hours at room temperature. After
completion of the reaction (TLC) and usual organic ex-
tractive workup followed by column chromatographic pu-
N
N
O
O
6a
5a
rification,
the
expected
2-oxo-N-phenethyl-2-
phenylacetamide (7a) was isolated in 50% yield (2.76 g).
The isolated product was then well characterized by H
NMR spectroscopy, mass spectrometry, and by other
1
O
Br
spectral and analytical methods.
NH2
Br
NH
O
O
9a
A tentative mechanism for the oxidative amidation reac-
tion is proposed in Scheme 3. The reaction sequence
begins with the displacement of bromine in 2,2-dibromo-
ethanone 8a by 2-phenyl ethylamine (9a). The nucleo-
philic displacement of halogen in 8a by amine 9a is
accelerated by the presence of potassium iodide, probably
due to halogen-exchange reaction. Thus the reaction of 8a
with phenyl ethylamine (9a) leads to the formation of 2-
halo-2-(phenethylamino)-1-phenylethanone 10. Further
elimination of hydrogen halide from 10 generates the im-
ine (Schiff base) 11.14 The Schiff base 11 under in situ ox-
idation with tert-butyl hydroperoxide can result in the
unstable oxaziridine 12. The ring opening of oxaziridine
12 in the presence of a base yields 13 which after ketoim-
inal tautomerism provides the expected a-keto amide
7a.15 Nucleophilic displacement of the dibromomethylene
unit by an amine in 8a produced benzamide 14 in up to
20% yield. The formation of benzamide 14 in the reaction
though was able to control below 20%, it was not possible
to avoid its formation during this oxidative amidation pro-
cess.
8a
7a
Scheme 1
We initiated our investigation on the synthesis of 2-oxo-
N-phenethyl-2-phenylacetamide (7a) by coupling of 2,2-
dibromo-1-phenylethanone (8a) with 2-phenyl ethy-
lamine (9a) under our earlier reported aerial oxidative
amidation reaction conditions.13 However, oxidative ami-
dation under these reaction conditions yielded N-pheneth-
ylbenzamide (14) as the major product instead of the
required keto amide 7a. We speculated that less reactivity
of the dibromomethylene unit in 2,2-dibromoethanone 8a
in comparison to the carbonyl carbon and the absence of a
strong oxidizing agent could be the probably cause for
low yield formation of the required a-keto amide 7a in
this oxidative amidation reaction. Different types of reac-
tion conditions were then screened, and finally, alternate
oxidative amidation reaction conditions have been devel-
oped which resulted in the required a-keto amide, 2-oxo-
N-phenethyl-2-phenylacetamide (7a) in 50% yield
(Scheme 2).
The substrate scope of the oxidative amidation reaction of
substituted aryl dibromoethanones16 8a–c with various
primary amines 9a–e was then explored. As can be seen,
O
O
H
N
a
N
+
+
H
O
O
Br
+
7a (7%)
14 (49%)
NH2
Br
O
O
H
N
8a
9a
N
H
b
O
7a (50%)
14 (20%)
Scheme 2 Reagents and conditions: THF, O2, Et3N, 70 °C, 48 h; (b) NaI, K3PO4, sulfolane, t-BuOOH, 30 °C, 5–8 h.
© Thieme Stuttgart · New York
© Thieme Stuttgart · New York

LETTER
Synthesis of Isoquinoline Alkaloids
1015
O
O
O
H
Br
N
N
K3PO4
NaI,K3PO4
– HBr
+
NH2
Br
O
X
– HX
11
X = I or Br
8a
9a
10
O
t-BuOOH
O
O
H
K3PO4
N
N
N
O
H
O
H
O
12
13
7a
Scheme 3
a series of substrates could be converted into the corre- Under these oxidative amidation reaction conditions, the
sponding a-keto amide 7a–g under the optimized condi- a-keto amides 7a–g were isolated in almost consistent
tion in less than eight hours (Table 1, entries 1–7).17
Table 1 Synthesis of Keto Amides 7a–g
Entry Dibromoethanone
Amine
Keto amide
Yield (%)a mp (°C)
O
O
H
Br
N
1
50
48
51
liquid
liquid
86–88
NH2
Br
O
9a
8a
7a
O
O
MeO
H
MeO
N
Br
2
NH2
MeO
O
Br
MeO
9b
8a
7b
O
O
H
O
N
Br
Br
O
3
NH2
O
O
Br
O
OMe
MeO
8b
9c
7c
O
OMe
OMe
O
O
H
MeO
MeO
N
4
53
50
liquid
85–87
Br
Br
NH2
NH2
O
O
MeO
MeO
MeO
OMe
8b
7d
9d
O
MeO
H
N
MeO
Br
5
MeO
MeO
7e
OMe
MeO
OMe
OMe
OMe
8b
9e
O
MeO
O
O
H
N
MeO
OMe
OMe
MeO
Br
Br
NH2
6
7
48
53
96–98
MeO
O
MeO
7f
Br
Br
MeO
OMe
8c
9e
O
MeO
H
N
MeO
MeO
OMe
OMe
NH2
MeO
O
MeO
MeO
9b
8c
7g
a The yields based on the isolated 99% analytically pure compounds and not on the reaction conversion or on the crude weight.
© Thieme Stuttgart · New York © Thieme Stuttgart · New York

1016
R. Shankar et al.
LETTER
O
H
N
POCl3
N
NH
+
12 h, 80 °C
O
O
O
7a
6a
14
70%
Scheme 4
yields (48–53%). In all these reactions, the corresponding neat phosphorous oxychloride assisted intramolecular cy-
benzamide impurities were isolated in 15–20% yields.
clodehydration reaction were generally higher than those
previously reported with modified Pictet or Bischler–
Napieralski cyclization conditions.
Having demonstrated that a-keto amide could be synthe-
sized by the reaction of various primary amines 9a–e with
aryl dibromoethanones 8a–c, we decided to exploit the a- The aromatization of 1-benzoyl-3,4-dihydroisoquinoline
keto amide for the synthesis of 1-benzoyl dihydroisoquin- (6a), synthesized via oxidative amidation Bischler–Napi-
olines 6a–f by carrying out the cyclodehydration reaction eralski approach, was then carried out. Initially, aromati-
under Bischler–Napieralski conditions (Scheme 4). Thus, zation of 1-benzoyl dihydroisoquinoline (6a) reaction was
2-oxo-N-phenethyl-2-phenylacetamide (7a) was subject- performed with dichlorodicyanoquinone (DDQ); howev-
ed for the cyclodehydration reaction with freshly distilled er, the required transformation did not proceed very
phosphorous oxychloride (ten volumes) over a period of smoothly, and the aromatized product was isolated in poor
12–14 hours at 80 °C. After workup and column chro- yield. When the aromatization of 1-benzoyl-3,4-dihy-
matographic purification, 1-benzoyl dihydroisoquinolines droisoquinoline (6a) was attempted via a regioselective
6a and 14 were isolated in 70% yield as an isomeric mix- base-catalyzed air oxidation using 1,8-diazabicycloun-
ture (Scheme 4).
dec-7-ene (DBU), 1-benzoyl isoquinoline (5a) was isolat-
ed in excellent yield (80%, Scheme 5).20
All the a-keto amides 7a–g thus synthesized were then
subjected to the Bischler–Napieralski cyclodehydration
reaction (Table 2) and highly substituted 1-benzoyl dihy-
droisoquinolines 6a–f were obtained in very high yields.
In this alkoxy-substituted dihydroisoquinoline synthesis,
no isomerization of double bonds was observed, and the
reaction has been completed in almost 12 hours at 80–
85 °C using ten volumes of phosphorous oxychloride.18
The 3,4-dihydropapaveraldine (1), the dihydro derivative
of papaveraldine (2) was synthesized in 85% yield under
these reaction conditions and was characterized by spec-
tral and analytical methods. The isolated yields of substi-
tuted 1-benzoyl dihydroisoquinolines 6b–f19 under the
DBU
N
NH
N
+
CH2Cl2, r.t., 14 h
80%
O
O
O
6a
14
5a
Scheme 5
Table 2 Synthesis of Isoquinolines via Oxidative Amidation Approach
Entry a-Keto amides
Dihydroisoquinoline
Yield mp
(%) (°C)
Isoquinoline
Yield mp
(%)a (°C)
N
O
O
N
H
low
melting
solid
6a
N
1
76
80
75–7721
O
O
7a
NH
5a
O
14
© Thieme Stuttgart · New York
© Thieme Stuttgart · New York

LETTER
Synthesis of Isoquinoline Alkaloids
1017
Table 2 Synthesis of Isoquinolines via Oxidative Amidation Approach (continued)
Entry a-Keto amides
Dihydroisoquinoline
Yield mp
Isoquinoline
Yield mp
(%)a (°C)
(%)
(°C)
MeO
MeO
O
H
N
N
low
melting
solid
MeO
N
MeO
MeO
2
87
78
80
80
131–133
156–158
146–148
O
O
O
MeO
7b
6b
5b
O
O
O
O
O
N
N
H
O
N
O
3
90
88
139–141
143–145
O
O
O
OMe
OMe
OMe
7c
6c
pulcheotine A (4)
OMe
MeO
OMe
MeO
OMe
O
O
O
H
MeO
N
N
N
MeO
MeO
4
O
O
O
MeO
OMe
O
O
7d
OMe
OMe
6d
thalmicrinone (3)
MeO
MeO
H
N
MeO
N
N
MeO
MeO
5
88
86
85
175–177
165–167
188–190
82
77
79
118–120
216–218
203–205
OMe
O
OMe
O
MeO
OMe
OMe
OMe
OMe
7e
6e
5c
MeO
MeO
H
N
N
MeO
OMe
OMe
N
MeO
MeO
6
OMe
O
OMe
O
OMe
OMe
OMe
OMe
MeO
OMe
7f
6f
5d
MeO
MeO
O
H
N
N
N
MeO
MeO
OMe
OMe
MeO
7
OMe
OMe
OMe
OMe
O
O
O
MeO
7g
dihydropapveraldine (1)
papaveraldine (2)
a The yields based on the isolated 99% analytically pure compounds and not on the reaction conversion or on the crude weight.
Aromatization of other 1-benzoyl dihydroisoquinolines isoquinoline alkaloids via oxidative amidation–Bischler–
6b–f and 1 were then carried out under DBU-assisted ar- Napieralski approach. The oxidative amidation–Bischler–
omatization conditions. The alkaloids, papavaraldine (2), Napieralski reaction developed for the synthesis of 1-ben-
thalmicrinone (3), as well as pulcheotine A (4) were syn- zoyl isoquinolines provides a direct access to the 1-ben-
thesized in 79%, 80%, and 80% yields, respectively, by zoyl dihydroisoquinolines from open-chain precursors
the aromatization reaction of its corresponding dihy- other than reported by Wasserman and coworkers.23 The
droisoquinoline derivatives 1, 6d, and 6c (Table 2). The modified aromatization conditions resulted in highly sub-
spectral and analytical data of all synthetic alkaloids were stituted 1-benzoyl isoquinoline in good yields from the
found to be in conformity with the reported literature val- corresponding dihydroisoquinoline derivatives. The
ues.22 Other substituted 1-benzoyl isoquinolines such as scope and limitation of this unique oxidative amidation–
5a–d were also synthesized in very high yields in similar Bischler–Napieralski approach for the synthesis of sever-
ways.
al other isoquinoline and carboline alkaloids are in
progress and will be reported in due course.
In summary, we have successfully developed a simple but
highly useful and practical method for the synthesis of
© Thieme Stuttgart · New York
© Thieme Stuttgart · New York

1018
R. Shankar et al.
LETTER
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
The authors would like to thank Dr. Vilas H. Dahanukar, Dr.
Reddy’s Laboratories for the useful discussions and constant encou-
ragement. We also thank the analytical department, Dr. Reddy’s
Laboratories, for providing the analytical supports.
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(17) 2-Oxo-N-phenethyl-2-phenylacetamide (7a)
Pale yellow liquid; yield 2.76 g (50.0%). IR(neat): 1216,
1282, 1318, 1364, 1449, 1497, 1520, 1579, 1597, 1668,
2857, 2930 cm–1. 1H NMR (400 MHz, CDCl3): d = 2.92 (t,
J = 7.0 Hz, 2 H), 3.66 (q, J = 6.8 Hz, 2 H), 7.10 (br s, 1 H,
NH), 7.23–7.27 (m, 5 H), 7.33 (t, J = 7.2 Hz, 2 H), 7.47 (t,
J = 7.8 Hz, 2 H), 7.62 (t, J = 7.4 Hz, 1 H) 8.31 (d, J = 7.6 Hz,
2 H). 13C NMR (400MHz, CDCl3): d = 40.5, 35.4, 126.6,
128.6, 128.4, 131.0, 134.0, 138.2, 161.7, 187.6. MS: m/z
(%) = 254.10 [M + 1].
(2) (a) Protais, P.; Arbaoui, J.; Bakkali, E. H.; Bermejo, A.;
Cortes, D. J. Nat. Prod. 1995, 58, 1475. (b) Cabedo, N.;
Protais, P.; Cassels, B. K.; Cortes, D. J. Nat. Prod. 1998, 61,
709. (c) Andreu, I.; Cortes, D.; Protais, P.; Cassels, B. K.;
Chagraoui, A.; Cabedo, N. Bioorg. Med. Chem. 2000, 8,
889. (d) Cabedo, N.; Andreu, I.; Ramírez de Arellano, M.
C.; Chagraoui, A.; Serrano, A.; Bermejo, A.; Protais, P.;
Cortes, D. J. Med. Chem. 2001, 44, 1794.
(3) (a) Woo, S. H.; Reynolds, M. C.; Sun, N. J.; Cassady, J. M.;
Snapka, R. M. Biochem. Pharmacol. 1997, 54, 467.
(b) Hsieh, T. J.; Liu, T. Z.; Chen, C. L.; Tsao, D. A.; Lu, F.
J.; Syu, Y. H.; Hsieh, P. Y.; Hu, H. S.; Chang, T. T.; Chen,
C. H. Food Chem. Toxicol. 2005, 43, 1117. (c) Chang, W.
L.; Chung, C. H.; Wu, Y. C.; Su, M. J. Nitric Oxide 2004, 11,
307.
(4) (a) Gan, H.; Lu, Y.; Huang, Y.; Ni, L.; Xu, J.; Yao, H.; Wu,
X. Tetrahedron Lett. 2011, 52, 1320. (b) Leboeuf, M.;
Ranaivo, A.; Cave, A.; Moskowitz, H. J. Nat. Prod. 1989,
52, 516. (c) Cave, A.; Leboeuf, M.; Moskowitz, H.;
Ranaivo, A.; Bick, I. R. C.; Sinchai, W.; Nieto, M.; Sevenet,
T. Aust. J. Chem. 1989, 42, 2243. (d) Silveira, C. C.;
Bernardi, C. R.; Braga, A. L.; Kaufman, T. S. Tetrahedron
Lett. 2001, 42, 8947.
N-(3,4-Dimethoxyphenethyl)-2-oxo-2-phenylacetamide
(7b)
Yellow oil; yield 1.83 g (48.0%). IR(neat): 665, 846, 964,
1005, 1123, 1232, 1317, 1508, 1599, 1644, 2952, 3277 cm–
1. 1H NMR (400 MHz, CDCl3): d = 2.84 (t, 2 H, J = 6.8 Hz),
3.60 (q, 2 H, J = 6.8 Hz), 3.84 (s, 3 H), 3.86 (s, 3 H), 6.76–
6.82 (m, 2 H), 6.95 (m,1 H), 7.2 (br, NH), 7.40–7.60 (m, 3
H) 8.28 (m, 2 H). 13C NMR (200 MHz, CDCl3): d = 34.9,
40.5, 55.7, 55.8, 111.3, 111.8, 120.5, 128.3, 130.7, 130.9,
133.1, 134.2, 147.7, 148.9, 161.8, 187.7. MS: m/z
(%) = 314.2 [M + 1].
(5) Awuah, E.; Capretta, A. J. Org. Chem. 2010, 75, 5627.
N-(2-{Benzo[d][1,3]dioxol-5-yl}ethyl)-2-(4-methoxy-
© Thieme Stuttgart · New York
© Thieme Stuttgart · New York

LETTER
phenyl)-2-oxoacetamide (7c)
Synthesis of Isoquinoline Alkaloids
1019
mixture was filtered to obtain the product as a pale yellow
color solid (1.36 g, 88%); mp 143–145 °C.
(19) 6,7-Dimethoxy-3,4-dihydroisoquinolin-1-yl)(phenyl)-
methanone (6b)
Yellow solid; yield 2.64 g (51.0%); mp 86–88 °C. IR (KBr):
517, 620, 722, 803, 849, 1038, 1171, 1265, 1296, 1357,
1527, 1598, 1638, 1683, 2939, 3376 cm–1. 1H NMR (400
MHz, CDCl3): d = 2.82 (t, 2 H, J = 6.8 Hz), 3.60 (q, 2 H,
J = 6.8 Hz), 3.88 (s, 3 H), 5.93 (s, 2 H), 6.66–6.76 (m, 3 H),
Yellow color low melting solid; yield 1.05 g (87.0%).
IR(neat): 609, 756, 844, 921, 1010, 1173, 1319, 1421, 1572,
1597, 1668, 1847, 2367, 2944, 3735 cm–1. 1H NMR (400
MHz, CDCl3): d = 2.82 (t, 2 H, J = 7.6 Hz), 3.78 (s, 3 H),
3.90 (t, 2 H, J = 7.6 Hz), 3.93 (s, 3 H), 6.76 (s, 1 H), 6.95 (s,
1 H), 7.28–7.46 (m, 2 H), 7.58 (m, 1 H), 8.00 (t, 2 H, J = 7.2
Hz). 13C NMR (200 MHz, CDCl3): d = 25.3, 47.1, 55.9, 56.0,
109.6, 110.4, 119.2, 128.4, 130.3, 131.0, 133.7, 135.4,
147.5, 151.6, 164.3, 193.7. MS: m/z (%) = 296.3 [M + 1].
6.92–6.95 (m, 2 H), 7.2 (br, NH), 8.37–8.40 (m, 2 H). 13
C
NMR (200 MHz, CDCl3): d = 35.1, 40.6, 55.4, 100.8, 108.3,
108.9, 113.7, 121.6, 126.2, 132.0, 133.8, 146.2, 147.8,
162.2, 164.6, 185.6. MS: m/z (%) = 328.2 [M + 1].
2-(4-Methoxyphenyl)-2-oxo-N-(2,3,4-trimethoxy-
phenethyl)acetamide (7d)
Yellow oil; yield 2.85 g (53.0%). IR(neat): 669, 850, 1169,
1215, 1420, 1598, 1660, 2400, 3019 cm–1. 1H NMR (400
MHz, CDCl3): d = 2.84 (t, 2 H, J = 6.8 Hz), 3.57 (q, 2 H,
J = 6.8 Hz), 3.84 (s, 3 H), 3.85 (s, 3 H), 3.88 (s, 3 H), 3.97 (s,
3 H), 6.61 (d, 1 H, J = 8.4 Hz), 6.85 (d, 1 H, J = 8.4 Hz), 6.92
{7,8-Dihydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl}(4-
methoxyphenyl)methanone (6c)
Yellow solid; yield 1.26 g (90.0%); mp 139–141 °C. IR
(KBr): 509, 607, 768, 932, 1039, 1172, 1255, 1387, 1505,
1600, 1650, 2912, 3376 cm–1. 1H NMR (400 MHz, CDCl3):
d = 2.78 (t, 2 H, J = 7.6 Hz), 3.87 (s, 3 H), 3.89 (t, 2 H,
J = 6.4 Hz), 5.95 (s, 2 H), 6.76 (s, 1 H), 6.84 (s, 1 H), 6.93–
6.95 (m, 2 H), 7.99–8.02 (m, 2 H). 13C NMR (200 MHz,
CDCl3): d = 25.8, 47.0, 55.4, 101.3, 106.9, 108.1, 113.7,
120.4, 128.2, 132.6, 132.8, 146.3, 149.7, 164.1, 164.5,
192.4. MS: m/z (%) = 310.1 [M + 1].
(d, 2 H, J = 8.8 Hz), 7.35 (br, NH), 8.35–8.38 (m, 2 H). 13
C
NMR (200 MHz, CDCl3): d = 29.5, 40.2, 55.4, 55.9, 60.6,
60.8, 107.3, 113.7, 124.3, 126.4, 133.7, 142.2, 151.9, 152.7,
162.4, 164.5, 185.8. MS: m/z (%) = 374.2 [M + 1].
2-(4-Methoxyphenyl)-2-oxo-N-(3,4,5-trimethoxy-
phenethyl)acetamide (7e)
Yellow solid; yield 2.95 g (50.0%); mp 85–87 °C. IR (KBr):
665, 846, 1005, 1123, 1232, 1444, 1599, 1644, 1925, 2120,
2925, 2969, 3276 cm–1. 1H NMR (400 MHz, CDCl3): d =
2.84 (t, 2 H, J = 6.8 Hz), 3.60 (q, 2 H, J = 6.8 Hz), 3.83 (s,
3 H), 3.85 (s, 6 H), 3.89 (s, 3 H), 6.40 (s, 2 H), 6.74–6.95 (m,
2 H), 7.20 (br, NH), 8.23–8.40 (m, 2 H). 13C NMR (200
MHz, CDCl3): d = 35.8, 40.4, 55.4, 56.0, 60.7, 105.5, 113.7,
126.1, 133.7, 134.0, 136.6, 153.2, 162.3, 164.6, 185.6. MS:
m/z (%) = 374.2 [M + 1].
(4-Methoxyphenyl)(5,6,7-trimethoxy-3,4-dihydroiso-
quinolin-1-yl)methanone (6d)
Pale yellow solid; yield 1.36 g (88.0%); mp 143–145 °C. IR
(KBr): 634, 724, 881, 983, 1018, 1133, 1264, 1316, 1417,
1595, 167, 2840, 2937 cm–1. 1H NMR (400 MHz, CDCl3):
d = 2.81 (t, 2 H, J = 7.6 Hz), 3.76 (s, 3 H), 3.88 (s, 3 H), 3.89
(s, 3 H), 3.92 (s, 3 H), 3.93 (br s, 2 H), 6.70 (s, 1 H), 6.95 (d,
1 H, J = 8.8 Hz), 8.01–8.03 (m, 2 H). 13C NMR (200 MHz,
CDCl3): d = 18.7, 47.0, 55.5, 56.1, 60.9, 61.0, 106.4, 113.8,
123.8, 128.4, 132.0, 132.8, 145.0, 150.1, 151.9, 164.2,
192.4. MS: m/z (%) = 356.2 [M + 1].
2-(3,4-Dimethoxyphenyl)-2-oxo-N-(3,4,5-trimethoxy-
phenethyl)acetamide (7f)
Off white solid; yield 3.19 g (48.0%); mp 96–98 °C. IR
(KBr): 666, 872, 1015, 1126, 1276, 1421, 1514, 1591, 1648,
2025, 2836, 2935, 3311 cm–1. 1H NMR (400 MHz, CDCl3):
d = 2.85 (br, 2 H), 3.60 (br, 2 H), 3.83 (s, 3 H), 3.85 (s, 6 H),
3.94 (s, 3 H), 3.97 (s, 3 H), 6.45 (s, 2 H), 6.91 (d, 1 H, J = 8.4
Hz), 7.20 (br, NH), 7.86 (s, 1 H), 8.20 (d, 1 H, J = 7.6 Hz).
13C NMR (200 MHz, CDCl3): d = 35.8, 40.4, 55.9, 56.0,
60.7, 105.5, 110.1, 112.5, 126.2, 127.2, 133.9, 136.6, 148.7,
153.2, 154.6, 162.2, 185.4. MS: m/z (%) = 404.2 [M + 1].
N-(3,4-Dimethoxyphenethyl)-2-(3,4-dimethoxyphenyl)-
2-oxoacetamide (7g)
Yellow solid; yield 2.93 g (53.0%); mp 78–79 °C. IR (KBr):
657, 766, 868, 1029, 1141, 1267, 1416, 1513, 1591, 1651,
2835, 2935, 3332 cm–1. 1H NMR (400 MHz, CDCl3): d =
2.85 (t, 2 H, J = 7.2 Hz), 3.64 (q, 2 H, J = 6.0 Hz), 3.86 (s,
3 H), 3.88 (s, 3 H), 3.94 (s, 3 H), 3.97 (s, 3 H), 6.75 (s, 1 H),
6.78–6.93 (m, 3 H), 7.20 (br, NH), 7.86 (d, 1 H, J = 2.0 Hz),
8.23 (dd, 1 H, J = 8.8, 2.0 Hz). 13C NMR (200 MHz, CDCl3):
d = 34.9, 40.5, 55.8, 55.9, 56.0, 110.0, 111.3, 111.8, 112.4,
120.5, 126.2, 127.1, 130.7, 374.2 [M + 1].
(4-Methoxyphenyl)(6,7,8-trimethoxy-3,4-dihydroiso-
quinolin-1-yl)methanone (6e)
Pale yellow solid; yield 1.72 g (88.0%); mp 175–177 °C. IR
(KBr): 669, 928, 1008, 1174, 1215, 1436, 1598, 1691, 1740,
2853, 2925 cm–1. 1H NMR (400 MHz, CDCl3): d = 3.12 (br
s, 2 H), 3.58 (s, 3 H), 3.76 (s, 3 H), 3.89 (s, 3 H), 4.01 (s, 3
H), 4.20 (br, 2 H), 6.70 (s, 1 H), 6.99 (d, 2 H, J = 8.8 Hz),
7.87 (d, 2 H, J = 8.8 Hz). 13C NMR (200 MHz, CDCl3): d =
26.4, 42.6, 56.4, 57.7, 61.4, 61.6, 109.5, 112.2, 115.9, 127.2,
133.0, 138.9, 141.4, 156.0, 165.0, 167.0, 171.1, 187.1. MS:
m/z (%) = 356.2 [M + 1].
(3,4-Dimethoxyphenyl)(6,7,8-trimethoxy-3,4-dihydro-
isoquinolin-1-yl)methanone (6f)
Cream color solid; yield 1.23 g (86.0%); mp 165–167 °C. IR
(KBr): 609, 724, 801, 983, 1107, 1132, 1264, 1361, 1405,
1595, 1668, 2840, 2937 cm–1. 1H NMR (400 MHz, CDCl3):
d = 2.74 (t, 2 H, J = 7.6 Hz), 3.58 (s, 3 H), 3.77 (s, 3 H), 3.84
(br, 2 H), 3.91 (s, 3 H), 3.94 (s, 3 H), 3.95 (s, 3 H), 6.55 (s, 1
H), 6.88 (d, 1 H, J = 8.4 Hz, 2.0 Hz), 7.54 (dd, 1 H, J = 8.2
Hz), 7.66 (d, 1 H, J = 1.6 Hz). 13C NMR (200 MHz, CDCl3):
d = 25.9, 46.8, 55.9, 56.0, 60.2, 60.5, 106.2, 109.9, 110.8,
115.2, 125.5, 128.3, 134.7, 140.1, 148.9, 150.8, 153.3,
156.4, 163.7, 192.4. MS: m/z (%) = 386.2 [M + 1].
(6,7-Dimethoxy-3,4-dihydroisoquinolin-1-yl)(3,4-
dimethoxyphenyl)methanone (1)
Brown color solid; yield 1.08 g (85.0%); mp 188–190 °C. IR
(KBr): 631, 866, 1024, 1134, 1269, 1278, 1361, 1460, 1515,
1583, 1660, 2833, 2969 cm–1. 1H NMR (400 MHz, CDCl3):
d = 2.82 (t, 2 H, J = 8.0 Hz), 3.78 (s, 3 H), 3.92 (br, 2 H), 3.93
(s, 3 H), 3.94 (s, 3 H), 3.95 (s, 3 H), 6.75 (s, 1 H), 6.88 (d, 1
H, J = 8.4 Hz), 6.91 (s, 1 H), 7.60 (dd, 1 H, J = 8.4, 1.6 Hz),
(18) (4-Methoxyphenyl)(5,6,7-trimethoxy-3,4-dihydroiso-
quinolin-1-yl)methanone (6d)
2-(4-Methoxyphenyl)-2-oxo-N-(2,3,4-trimethoxyphenethyl)-
acetamide (7d, 1.62 g, 4.34 mmol) in POCl3 (16 mL) was
taken in the round-bottom flask under nitrogen atmosphere,
and the mixture was heated at 80 °C for 12 h under N2. The
mixture was then cooled to 0 °C and quenched into sat.
NaHCO3 solution (160 mL) below 10 °C. The product was
then extracted with CH2Cl2 (25 mL). The organic layer was
washed with 10% NaHCO3 solution (25 mL) and dried over
anhyd Na2SO4. The organic layer was distilled off under
vacuum. Hexane was added hexane (10 mL), and the
© Thieme Stuttgart · New York
© Thieme Stuttgart · New York

1020
R. Shankar et al.
LETTER
7.67 (d, 1 H, J = 1.6 Hz). 13C NMR (200 MHz, CDCl3): d =
25.3, 47.1, 55.9, 56.0, 109.6, 109.9, 110.4, 111.2, 119.4,
126.4, 128.5, 130.9, 147.5, 149.0, 151.5, 154.0, 164.5,
192.6. MS: m/z (%) = 356.2 [M + 1].
(d, 1 H, J = 5.2 Hz). 13C NMR (400 MHz, CDCl3): d = 55.4,
56.0, 61.1, 61.5, 100.3, 113.6, 116.4, 123.7, 129.1, 129.7,
133.2, 139.5, 114.1, 146.6, 154.0, 154.4, 163.9, 193.7. MS:
m/z (%) = 354.2 [M + 1].
(20) 1-Benzoyl Isoquinoline (5a)
(4-Methoxyphenyl)(6,7,8-trimethoxyisoquinolin-1-yl)-
methanone (5c)
To a stirred solution of 1-benzoyl dihydroisoquinoline (6a,
14, 1.15 g, 4.89 mmol) in CH2Cl2 (12 mL) was added DBU
(2.2 mL, 14.6 mmol), and the mixture was stirred at 25 °C
for 12 h. The mixture was concentrated in vacuo, and the
obtained residue was purified by column chromatography
(silica gel, PE–EtOAc = 7:3) to give 5a as a light yellow
color solid (0.91 g, 80%); mp 75–77 °C.
Ash color solid; yield 0.88 g (82.0%); mp 118–120 °C. IR
(KBr): 669, 928, 1008, 1174, 1215, 1436, 1598, 1691, 1740,
2853, 2925 cm–1. 1H NMR (400 MHz, CDCl3): d = 3.67 (s,
3 H), 3.83 (s, 3 H), 3.86 (s, 3 H), 4.01 (s, 3 H), 6.63–6.92 (m,
3 H), 7.54 (d, 1 H, J = 4.8 Hz), 7.72 (d, 2 H, J = 7.6 Hz),
8.43 (d, 1 H, J = 4.4 Hz). 13C NMR (400 MHz, CDCl3): d =
55.3, 56.1, 60.5, 60.9, 100.9, 113.7, 117.7, 119.3, 129.6,
131.8, 134.7, 141.7, 141.9, 148.2, 155.8, 157.3, 163.5,
193.7. MS: m/z (%) = 354.2 [M + 1].
(21) Popp, F. D.; Wefer, J. M. J. Heterocycl. Chem. 1967, 4, 183.
(22) (6,7-Dimethoxyisoquinolin-1-yl)(phenyl)methanone (5b)
Light brown color solid; yield 0.54 g (78.0%); mp 131–
133 °C. IR (KBr): 637, 866, 1140, 1231, 1421, 1675, 2838,
2936, 3077 cm–1. 1H NMR (400 MHz, CDCl3): d = 3.97 (s,
3 H), 4.06 (s, 3 H), 7.15 (s, 1 H), 7.48 (t, 2 H, J = 7.6 Hz),
7.58–7.66 (m, 3 H), 7.96 (d, 2 H, J = 7.6 Hz,), 8.47 (d, 1 H,
J = 5.5 Hz). 13C NMR (75 MHz, CDCl3): d = 56.0, 56.1,
104.2, 104.9, 105.0, 121.5, 123.0, 128.3, 130.8, 133.3,
134.1, 137.2, 140.0, 151.3, 153.1, 153.4, 195.2. MS:
m/z (%) = 294.1 [M + 1].
(3,4-Dimethoxyphenyl)(6,7,8-trimethoxyisoquinolin-1-
yl)methanone (5d)
Light brown color solid; yield 0.58 g (77.0%); mp 216–
218 °C. IR (KBr): 635, 722, 756, 991, 1018, 1116, 1271,
1348, 1420, 1584, 1667, 2837, 2936, 3078 cm–1. 1H NMR
(400 MHz, DMSO-d6): d = 3.51 (s, 3 H), 3.78 (s, 3 H), 3.81
(s, 3 H), 3.82 (s, 3 H), 3.99 (s, 3 H), 6.95 (q, 2 H, J = 8.4 Hz),
7.34 (s, 1 H), 7.40 (s, 1 H), 7.79 (d, 1 H, J = 5.6 Hz) 8.40 (d,
1 H, J = 5.6 Hz). 13C NMR (400 MHz, CDCl3): d = 55.5,
55.7, 56.2, 60.3, 60.6, 101.8, 109.8, 110.7, 116.7, 119.5,
125.0, 129.1, 134.1, 141.3, 147.2, 148.8, 153.1, 154.8,
157.0, 192.6. MS: m/z (%) = 384.2 [M + 1].
[1,3]-Dioxolo[4,5-g]isoquinolin-5-yl(4-methoxy-
phenyl)methanone (4)
Off white color solid; yield 0.71 g (80.0%); mp 156–158 °C.
IR (KBr): 518, 605, 843, 950, 1263, 1463, 1596, 1652, 1920,
2913 cm–1. 1H NMR (400 MHz, CDCl3): d = 3.87 (s, 3 H),
6.09 (s, 2 H), 6.92–6.96 (m, 2 H), 7.14 (s, 1 H), 7.48 (s, 1 H),
7.60 (d, 1 H, J = 5.6 Hz), 7.92–7.95 (m, 2 H), 8.43 (d, 1 H,
J = 5.2 Hz). 13C NMR (200 MHz, CDCl3): d = 55.5, 101.7,
102.2, 102.6, 113.6, 121.7, 123.8, 129.5, 133.1, 135.4,
140.3, 149.2, 151.0, 154.7, 163.9, 193.5. MS: m/z
(%) = 308.1 [M + 1].
(4-Methoxyphenyl)(5,6,7-trimethoxyisoquinolin-1-yl)-
methanone (3)
Cream color solid; yield 0.72 g (80.0%); mp 146–148 °C. IR
(KBr): 647, 740, 832, 934, 1030, 1053, 1127, 1257, 1479,
1601, 2944, 3735 cm–1. 1H NMR (400 MHz, CDCl3): d =
3.88 (s, 3 H), 3.93 (s, 3 H), 4.02 (s, 3 H), 4.07 (s, 3 H), 6.95
(d, 2 H, J = 8.8 Hz), 7.36 (s, 1 H), 7.93–7.99 (m, 2 H), 8.48
(6,7-Dimethoxyisoquinolin-1-yl)(3,4-dimethoxyphenyl)-
methanone (2)
Yellow color solid; yield 0.48 g (79.0%); mp 203–205 °C.
IR (KBr): 631, 860, 1024, 1140, 1269, 1324, 1512, 1584,
1656, 2836, 2934, 3070, 3403 cm–1. 1H NMR (400 MHz,
CDCl3): d = 3.95 (s, 3 H), 3.96 (s, 6 H), 4.00 (s, 3 H), 6.87
(d, 1 H, J = 8.4 Hz), 7.14 (s, 1 H), 7.43 (dd, 1 H, J = 8.4, 1.6
Hz), 7.54 (s, 1 H), 7.65 (d, 1 H, J = 5.2 Hz), 7.71 (d, 1 H,
J = 2.0 Hz), 8.45 (d, 1 H, J = 5.2 Hz). 13C NMR (400 MHz,
CDCl3): d = 56.0, 56.1, 104.1, 104.8, 109.9, 112.0, 121.2,
122.8, 126.8, 129.9, 133.9, 140.0,149.0, 151.0, 153.2, 153.7,
153.8, 193.9. MS: m/z (%) = 354.4 [M + 1].
(23) Wasserman, H. H.; Amici, R.; Frechette, R.; van Duzer, J. H.
Tetrahedron Lett. 1980, 30, 869.
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