Efficient One-Pot Synthesis of Tetrahydronaphtho[2,1-f]isoquinolines by Using Domino Pictet–Spengler/Friedel–Crafts-Type Reactions

Article abstract of DOI:10.1002/ejoc.201701243

This study describes a facile and efficient one-pot method for the synthesis of a tetrahydronaphtho[2,1-f]isoquinoline alkaloid. An N-protected amino aldehyde biaryl substrate underwent domino Pictet–Spengler/Friedel–Crafts-type cyclization reactions to p

Full text of DOI:10.1002/ejoc.201701243

A Journal of
Accepted Article
Title: Efficient one-pot synthesis of tetrahydronaphtho[2,1-f]isoquinoline
under domino Pictet-Spengler/Friedel-Crafts type reactions
Authors: Nisachon Khunnawutmanotham, Poolsak Sahakitpichan,
Nitirat Chimnoi, and Supanna Techasakul
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201701243
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10.1002/ejoc.201701243
European Journal of Organic Chemistry
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Efficient one-pot synthesis of tetrahydronaphtho[2,1-
f]isoquinoline under domino PictetSpenglerFriedelCrafts type
reactions
Nisachon Khunnawutmanotham,[a] Poolsak Sahakitpichan,[b] Nitirat Chimnoi,[b] and Supanna
Techasakul*[a]
Abstract: This study described a facile and efficient one-pot method
for the synthesis of tetrahydronaphtho[2,1-f]isoquinoline alkaloid. N-
protected amino aldehyde biaryl underwent domino cyclization under
PictetSpengler/FriedelCrafts type reactions to produce
tetrahydronaphtho[2,1-f]isoquinoline skeleton. Litebamine,
a
a
naturally occurring compound, was prepared using the proposed
method to exemplify its utility.
Introduction
Figure 1. Structures of annoretine, litebamine and boldine.
Our previous report presented the utilization of N-
sulfonamoyl-protected amino aldehyde biaryl to construct two
scaffolds of the natural product of alkaloids, namely,
azafluoranthene and dehydroaporphine (Scheme 1).[1] In the
course of our continuing study, we further investigated the use of
this N-protected amino aldehyde biaryl as a precursor for the
synthesis of tetrahydronaphtho[2,1-f]isoquinoline alkaloid. Only
two natural products that contain tetrahydronaphtho[2,1-
f]isoquinoline skeleton, namely, litebamine and annoretine, have
been reported (Figure 1). Litebamine was isolated from the
wood of Litsea cubeba[2] and was reported to be an antiplatelet
aggregation agent.[3] Recently, the anti-acetylcholinesterase
activity of litebamine and its N-homologues has been
described.[4] Annoretine was isolated from the leaves of Annona
montana, and its cytotoxicity against KB, P-388, A-548, and HT-
29 cells was reported.[5]
Many
published
reports
on
the
syntheses
have
of
tetrahydronaphtho[2,1-f]isoquinoline
scaffold
been
released from the Estévez’s group. The key steps involved the
use of BischlerNapieralski reaction to form an isoquinoline unit
and photocyclization to install the tetrahydronaphthoisoquinoline
skeleton[6], these procedures were later adopted to complete the
total syntheses of annoretine and litebamine.[7,8] Alternatively, 1-
methyl
tetrahydronaphtho[2,1-f]isoquinolines
has
been
successfully prepared by the same group in reverse order of
either photochemical[9] or free radical cyclization[10] to construct
the corresponding phenanthrene ring system followed by the
BischlerNapieralski reaction. A few biomimetic syntheses of
litebamine from its plausible biogenetic precursor, boldine, have
also been reported.[4,11,12]
We aimed to develop a facile strategy for reaching the
tetrahydronaphtho[2,1-f]isoquinoline scaffold from an N-
protected amino aldehyde biaryl. A retrosynthetic analysis was
proposed in Scheme 2. A phenanthrene ring system was
constructed by an acid-mediated cyclization of the aldehyde
whereas the isoquinoline unit could be constructed by the
PictetSpengler reaction. In addition, two key steps could occur
successively in one step under appropriate reaction condition.
As such, this strategy could be considered as a novel domino
PictetSpengler/FriedelCrafts type reaction sequence. This
anticipated facile synthesis will give us access to structurally
diverse derivatives for further biological studies.
Scheme 1. Synthesis of azafluoranthene and dehydroaporphine alkaloids
from N-sulfonamoyl-protected amino aldehyde biaryl.
[a]
[b]
N. Khunnawutmanotham, S. Techasakul
Laboratory of Organic Synthesis, Chulabhorn Research Institute, 54
Kamphaeng Phet 6, Talat Bang Khen, Lak Si, Bangkok 10210,
Thailand
E-mail: supanna@cri.or.th
P. Sahakitpichan, N. Chimnoi
Laboratory of Natural Products, Chulabhorn Research Institute, 54
Kamphaeng Phet 6, Talat Bang Khen, Lak Si, Bangkok 10210,
Thailand
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
Scheme 2. Retrosynthetic analysis of tetrahydronaphtho[2,1-f]isoquinoline.
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10.1002/ejoc.201701243
European Journal of Organic Chemistry
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When considering the precursor for the cyclization (A), the
PictetSpengler reaction could provide two different
regioisomers depending on the position on the aromatic ring that
undergoes cyclization (a or a, as shown in Scheme 2). By
contrast, the formation of phenanthrene unit could take place
only at the position a of the aromatic ring. Thus, the
phenanthrene formation at the position a must precede the
PictetSpengler cyclization at the position a to achieve the
synthesis of the desired tetrahydronaphtho[2,1-f]isoquinoline
framework. If the PictetSpengler reaction occurred first,
cyclization on position a is possible, and this phenomenon
would not result in the formation of the desired product.
Table 1. Percentage yields of products obtained under various conditions.
Entry
Compound
RCHO
Condition
Time
(h)
Product
(isolated yield)
Results and Discussion
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
HCHO
CH3CHO
CH3CHO
C6H5CHO
C6H5CHO
HCHO
A[a]
A
1
24
2
2a (88%)
2b (89%)
2b (89%)
On the basis of our hypothesis, we prepared the
corresponding onecarbon homologated analog of the N-
protected amino aldehyde biaryl as the precursor. Wittig reaction
of the N-sulfonamoyl-protected amino aldehyde biaryl with
(methoxymethyl)triphenylphosphonium chloride provided the
corresponding inseparable mixture of (E)- and (Z)-enol ether 1a
(Scheme 3).[1] Then, 1a was treated successively with a solution
of trifluoroacetic acid (TFA) in dichloromethane (1:9 v/v) and
formaldehyde. With stirring at room temperature for 1 h, 1a
smoothly underwent the anticipated double cyclizations, and
high yield of tetrahydronaphtho[2,1-f]isoquinoline 2a was
obtained (Table 1, entry 1). The result suggested that the rate of
the phenanthrene formation for enol ther 1a (a masked form of
twocarbon aldehyde) is faster than that of the PictetSpengler
B[b]
A
2c (10%) +
3 (82%)
24
48
1
2c (50%) +
3 (33%)
1a
1b
B
A
2d (76%)
2e (65%)
2e (72%)
1b
1b
CH3CHO
CH3CHO
HCHO
A
24
4
B
2f (30%) +
2g (8.5%)
1c
1c
A
1
Provided a
complex
mixture of
polar
cyclization,
thereby
leading
to
tetrahydronaphtho[2,1-
10
HCHO
B
0.5
f]isoquinoline. To achieve the purpose of this method, enol
ethers with different amino protecting groups (1b and 1c) were
prepared and subjected to acids using different aldehydes.
Table 1 summarizes the results.
compounds
[a] Condition A: TFA/CH2Cl2(1:9 v/v), rt. [b] Condition B: BF3.OEt2, CH2Cl2, rt.
achieved when boron trifluoride diethyl etherate (BF3OEt2) was
used (entry 3). With benzaldehyde, the conversion of 1a to the
corresponding product 2c was very slow. After 24 h of using
TFA in CH2Cl2, product 2c was isolated in only 10% yield along
with phenanthrene 3 in 82% yield (entry 4). When BF3OEt2
condition was used, product 2c yield increased to 50% together
with 3 at 33% yield after 48 h (entry 5). The results suggested
that phenanthrene was an intermediate during this reaction.
Following the phenanthrene formation, PictetSpengler
cyclization took place, thereby furnishing the desired
tetrahydronaphtho[2,1-f]isoquinoline. For the methylcarbamoyl-
protected amino enol ether biaryl substrate 1b (entries 68), the
results were similar to those of the sulfonamide substrate 1a,
except that slightly lower yields were obtained. Treatment of the
carbamate 1b with formaldehyde in a 1:9 TFA-CH2Cl2 solution
for 1 h yielded product 2d at 76% yield (entry 6). When
acetaldehyde was used instead of formaldehyde, a 24 h-reaction
Scheme 3. Preparation of the substrates for one-pot cyclization study.
For the N-nitrosulfonamoyl-protected amino enol ether biaryl
substrate 1a, a high yield of product 2a was obtained within 1 h
after treatment with a 1:9 solution of TFA in dichloromethane
and formaldehyde (entry 1). The completion of treatment of 1a
with acetaldehyde in a 1:9 TFA-CH2Cl2 solution required a
longer reaction time (24 h) and a high yield of product 2b was
obtained (entry 2). Shorter reaction time (2h) of 2a with
acetaldehyde to furnish 2b, which gave a comparable yield, was
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10.1002/ejoc.201701243
European Journal of Organic Chemistry
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time was need for complete the conversion of 1b to the
corresponding product 2e, which was produced as a pair of
amide rotamers in a 1:1 ratio (entry 7). BF3OEt2 was used as an
acid, and the reaction of 1b with acetaldehyde was completed in
4 h to provide 2e at a comparable yield (entry 8). Then,
substrate 1c was designed to process the Boc group. Both
cyclization and deprotection were expectedly affected in the
same step under acidic conditions. However, treatment of the
tert-butylcarbamoyl-protected amino enol ether biaryl substrate
1c with formaldehyde in a 1:9 TFA-CH2Cl2 solution provided the
isolated product 2f at only 30% yield, together with a small
amount of the hydrolyzed product 2g at 8.5% yield (entry 9). A
complex mixture of polar compounds was obtained (entry 10)
using BF3OEt2 as the acid. The results demonstrated a
Scheme 5. Reagents and conditions: (a) Br2, KOAc, AcOH, rt (90%); (b) AlCl3,
pyridine, CH2Cl2, reflux, 6 h (92%); (c) Li2CO3, DMF, 45 C, 1 h then MeI, 45
C, 5 h (55%); (d) 2-bromopropane, K2CO3, DMF, rt, 24 h (99%); (e) CH3NO2,
successful
one-pot
reaction
to
construct
from
the
the
.
tetrahydronaphtho[2,1-f]isoquinoline
scaffold
NH4OAc, AcOH, 90 C, 7 h (91%); (f) NaBH4, BF3 OEt2, THF, reflux, 4 h; (g)
ClCOOMe, CH2Cl2, Na2CO3, H2O, rt, 24 h (41%, 2 steps).
corresponding amino aldehyde biaryl. The method was facile
and resulted in a high product yield.
Moreover, the total synthesis of the natural product
litebamine was contemplated and pursued to illustrate the
utilization of this approach. The corresponding boronic acid 7
and aryl bromide 13 were the requisite precursors for the
preparation of the amino aldehyde biaryl. Boronic acid 7 could
be prepared in a straightforward manner in four steps from
isovanillin (4) at 27% overall yield (Scheme 4). Aryl bromide 13
could be prepared from vanillin (8) in seven steps at 17% overall
yield (Scheme 5). The key steps involved AlCl3-mediated
demethylation of bromovanillin (9) in pyridine followed by
selective methylation with Li2CO3 and MeI in N,N-
dimethylformamide.[13] Subsequent isopropylation of the
remaining phenolic group furnished the corresponding aldehyde
11. Bromonitrostyrene 12, which was obtained from the Henry
nitroaldol reaction of 11, was then reduced by NaBH4 in the
.
presence of BF3 OEt2 in tetrahydrofuran at reflux to afford the
corresponding phenethylamine, which was converted to
carbamate 13. Methylcarbamate was chosen as the amino
protecting group for functionalization purpose at a later stage.
Suzuki cross-coupling reaction of boronic acid 7 with aryl
bromide 13 was carried out smoothly to yield the N-carbamoyl-
protected amino aldehyde biaryl 14 (Scheme 6). C-
Homologation
reaction
of
14
by
treatment
with
(methoxymethyl)triphenylphosphonium chloride gave a mixture
Scheme 4. Reagents and conditions: (a) 2-bromopropane, K2CO3, DMF, rt, 24
h (91%); (b) NBS, DMF, 80 C, 24 h (64%, 74%BRSM); (c) HOCH2CH2OH, p-
TsOH, toluene, reflux, 7 h; (d) (i) nBuLi, THF, 78 C, 1 h (ii) then B(iPrO)3, 0
C to rt, 2.5 h (iii) then 2M HCl, rt, 2 h (40% from 6).
Scheme
6. Reagents and conditions: (a) Pd(PPh3)4, K2CO3,
toluene:EtOH:H2O (3:3:2), reflux, 24h (88%); (b) ClPPh3CH2OCH3, LiHMDS,
THF, 0 C, 1 h (88%); (c) CF3COOH:CH2Cl2 (1:9 V/V), HCHO, rt, 1 h (76%);
(d) LiAlH4, THF, reflux, 4 h (83%); (e) AlCl3, CH2Cl2, rt, 3 h (71%); f) BCl3,
CH2Cl2, 78 C for 1 h then 0 C for 2 h (83%).
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10.1002/ejoc.201701243
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of (E)- and (Z)-enol ether 15, which smoothly underwent
cyclization under acidic conditions in the presence of
formaldehyde to yield tetrahydronaphtho[2,1-f]isoquinoline 16 in
76% isolated yield. Then, the methyl carbamate group of 16 was
reduced by LiAlH4 in refluxing tetrahydrofuran to provide the
methylamino group of compound 17. Attempted removal of both
isopropoxy groups using AlCl3 in dichloromethane at room
temperature led to the formation of the undesired C-
isopropylated litebamine 18 at 71% yield. 1H and 13C NMR
supported the existence of one isopropyl group in the molecule,
but its methine proton was shifted to high field at 3.5 ppm,
thereby indicating the attachment of the isopropyl group to a
carbon atom rather than to an oxygen atom. In addition, HMBC
correlation between Ha signal (H 7.49) and an aromatic carbon
connected to the isopropyl group (C 138.0), NOESY
correlations between Ha signal and the methine proton of the
isopropyl group (H 3.5), and between Hb signal (H 7.52) and
CH2 protons (H 3.2) confirmed the position of the isopropyl
moiety of compound 18. Thus, we turned to use BCl3 for the
deprotection and found that both isopropoxy groups could be
smoothly removed to furnish the desired litebamine in 83% yield.
added to the reaction mixture, and tetrahydrofuran was removed under
reduced pressure. The residue was extracted with dichloromethane. The
combined organic layers were washed with water, dried with anhydrous
sodium sulfate, and concentrated under reduced pressure. The residue
was purified by column chromatography to provide enol ether 1a,[1] at a
4:5 mixture of E/Z isomers, as a yellow gum (345 mg, 65%).
Compound 1b: This compound was prepared from methylcarbamoyl-
protected amino aldehyde biaryl (646 mg, 1.88 mmol) by the same
method as described for 1a. Compound 1b has a 1:1.3 mixture of E/Z
epimers, in the form of a colorless gum (630 mg, 90%). 1H-NMR (CDCl3,
300 MHz), : 8.13 (d, J  7.8 Hz, 1H, Z), 7.41 (d, J = 7.5 Hz, 1H, E),
7.337.23 (m, 2H, E and Z), 7.197.16 (m, 4H, E and Z), 6.88 (d, J 
12.9 Hz, 1H, E), 6.74 (s, 2H, E and Z), 6.59 (s, 2H, E and Z), 6.02 (d, J 
7.2 Hz, 1H, Z), 5.65 (d, J  12.9 Hz, 1H, E), 5.02 (d, J  7.2 Hz, 1H, Z),
4.78 (br s, 2H, E and Z), 3.89 (s, 3H, E), 3.88 (s, 3H, Z), 3.72 (s, 3H, Z),
3.66 (s, 3H, E), 3.51 (s, 3H, E), 3.50 (s, 3H, E), 3.49 (s, 6H, Z), 3.44 (q, J
 6.6 Hz, 4H, E and Z), 2.77 (t, J  6.6 Hz, 4H, E and Z); 13C-NMR
(CDCl3, 75 MHz), δ: 156.9 (E and Z), 152.7 (E), 152.6 (Z), 148.9 (E),
147.8 (Z), 145.3 (E and Z), 136.4 (Z), 136.2 (E), 135.8 (Z), 135.5 (E),
134.6 (E and Z), 134.0 (E), 133.9 (Z), 130.3 (E), 129.8 (Z), 128.7 (Z),
127.5 (E), 127.2 (Z), 125.3 (E), 125.2 (Z), 124.1 (E), 123.5 (Z), 123.4 (E),
112.0 (E), 111.8 (Z), 104.2 (E), 103.5 (Z), 60.5 (E), 60.4 (Z), 56.5 (E and
Z), 55.9 (E), 55.8 (Z), 52.0 (E and Z), 42.2 (E and Z), 35.9 (E and Z); FT-
IR, νmax (cm 1): 3355, 1701, 1638, 1520, 1463, 1251, 1230, 1137, 1006;
MS (EI), m/z (relative intensity): 339 ([M-MeOH]+, 8), 251 (7), 225 (3),
178 (3), 149 (4), 75 (100); HRMS (ESI-POS), m/z calculated for
C21H25NO5Na[M + Na]+: 394.1625, measured: 394.1622.
Conclusions
The one-pot domino PictetSpengler/FriedelCrafts type
reaction sequence reported in this work provided a facile and
effective method for the construction of a tetrahydronaphtho[2,1-
f]isoquinoline skeleton. The key feature involved a sequence of
successive cyclizations of the N-protected amino enol ether
biaryls under acid-catalyzed PictetSpengler conditions. The
developed strategy could be utilized for the synthesis of natural
tetrahydronaphtho[2,1-f]isoquinoline alkaloid litebamine which
was obtained in 46% overall yield from 14 in four steps.
Compound 1c: This compound was prepared from tert-butylcarbamoyl-
protected amino aldehyde biaryl (1.39 g, 3.61 mmol) by the same method
as described for 1a. Compound 1c has a 1:1 mixture of E/Z epimers as a
colorless gum (1.09 g, 73%). 1H-NMR (CDCl3, 300 MHz), : 8.13 (d, J 
7.8 Hz, 1H, Z), 7.41 (d, J = 7.5 Hz, 1H, E), 7.357.23 (m, 2H, E and Z),
7.207.15 (m, 4H, E and Z), 6.89 (d, J  12.9 Hz, 1H, E), 6.75 (d, J  1.8
Hz, 2H, E and Z), 6.59 (d, J  1.8 Hz, 2H, E and Z), 6.02 (d, J  7.2 Hz,
1H, Z), 5.65 (d, J  12.9 Hz, 1H, E), 5.03 (d, J  7.2 Hz, 1H, Z), 4.62 (br
s, 2H, E and Z), 3.89 (s, 3H, E), 3.88 (s, 3H, Z), 3.72 (s, 3H, Z), 3.51 (s,
3H, Z), 3.50 (s, 3H, E), 3.49 (s, 3H, E), 3.37 (q, J  6.9 Hz, 4H, E and Z),
2.75 (t, J  6.9 Hz, 4H, E and Z), 1.43 (s, 18H); 13C-NMR (CDCl3,
75 MHz), δ: 155.9 (E and Z), 152.7 (E), 152.6 (Z), 148.9 (E), 147.8 (Z),
145.2 (E and Z), 136.5 (Z), 136.3 (E), 135.8 (Z), 135.4 (E), 134.6 (E),
134.3 (Z), 134.2 (E), 133.9 (Z), 130.4 (E), 129.9 (Z), 128.7 (Z), 127.5 (E),
127.3 (Z), 125.3 (E), 125.2 (Z), 124.1 (E), 123.7 (Z), 123.5 (E), 112.0 (E),
111.8 (Z), 104.2 (E), 103.6 (Z), 79.3 (E and Z), 60.6 (E), 60.5 (Z), 56.6 (E
and Z), 55.9 (E), 55.8 (Z), 41.8 (E and Z), 36.0 (E and Z), 28.4 (3C, E
and Z); FT-IR, νmax (cm1): 3374, 1698, 1480, 1250, 1231, 1164, 1138,
735; MS (EI), m/z (relative intensity): 381 ([M-MeOH]+, 5), 325 (3), 251
(9), 239 (4), 225 (5), 75 (100); HRMS (ESI-POS), m/z calculated for
C24H31NO5Na[M + Na]+: 436.2094, measured: 436.2092.
Experimental Section
General: 1H and 13C NMR spectra were recorded with the Bruker Avance
300 and Bruker Avance IIIHD400 spectrometers. Chemical shifts were
reported relative to tetramethylsilane. Mass spectra were obtained with a
Finnigan Polaris ion-trap mass spectrometer, and HRMS data were
recorded with a Bruker MicroTOF mass spectrometer. Infrared spectra
were determined with a PerkinElmer Spectrum One FTIR spectrometer.
Column chromatography was performed on Merck silica gel 60 (70–230
mesh).
Compound 1a: Lithium bis(trimethylsilyl)amide (LiHMDS, 1.0 M in
tetrahydrofuran; 3.83 mL, 3.83 mmol) was added dropwise to a 0 C
cooled suspension of (methoxymethyl)triphenylphosphonium chloride
(1.09 g, 3.18 mmol) in anhydrous tetrahydrofuran (15 mL). The deep red
mixture was stirred at 0 C under argon for 20 min. Then solution of N-
nitrosulfonamoyl-protected amino aldehyde biaryl (500 mg, 1.06 mmol) in
anhydrous tetrahydrofuran (15 mL) was added dropwise to the solution,
and the mixture was stirred at 0 C for another 1 h. Then, water was
General procedure for one-pot cyclization to tetrahydronaphtho[2,1-
f]isoquinoline
Condition A: The compound (0.3 mmol) was dissolved in a solution of
trifluoroacetic acid in dichloromethane (1:9 v/v, 5 mL), and aldehyde (1.5
mmol) was added. After stirring at room temperature at the indicated time,
the reaction mixture was added to water, washed with saturated aqueous
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10.1002/ejoc.201701243
European Journal of Organic Chemistry
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sodium hydrogen carbonate, and extracted with dichloromethane. The
combined organic layers were washed with water, dried with anhydrous
sodium sulfate, filtered, and concentrated under reduced pressure. The
residue was purified by column chromatography to yield the product.
Condition B: The compound (0.3 mmol) was dissolved in
dichloromethane (5 mL). Borontrifluoride etherate (1.5 mmol) and
aldehyde (1.5 mmol) were successively added. After stirring at room
temperature for the indicated time, the reaction mixture was added to
water, washed with saturated aqueous sodium hydrogen carbonate, and
extracted with dichloromethane. The combined organic layers were
washed with water, dried with anhydrous sodium sulfate, filtered, and
concentrated under reduced pressure. The residue was purified by
column chromatography to yield the product.
1445, 1393, 1237, 1117, 1035, 973, 734; MS (EI), m/z (relative intensity):
351 (M+, 100), 336 (98), 320 (15), 304 (10), 276 (12), 264 (13), 249 (22),
221 (39); HRMS (ESI-POS), m/z calculated for C21H21NO4Na[M + Na]+:
374.1363, measured: 374.1374.
Compound 2e: This compound was obtained as a white solid at a 1:1
mixture of two rotamers (1H-NMR temperature course study of compound
2e at 25 C60 C in benzene-d6 was shown in the supporting
information). 1H-NMR (CDCl3, 300 MHz), : 9.62 (d, J  8.4 Hz, 1H),
7.877.79 (m, 2H), 7.707.55 (m, 3H), 5.63 (q, J  6.3 Hz, 0.5H), 5.50 (q,
J  6.3 Hz, 0.5H), 4.504.43 (m, 0.5H), 4.304.24 (m, 0.5H), 4.11 (s,
1.5H), 4.09 (s, 1.5H), 3.92 (s, 3H), 3.78 (s, 1.5H), 3.76 (s, 1.5H),
3.523.35 (m, 1H), 3.233.18 (m, 2H), 1.601.53 (m, 3H),; 13C-NMR
(CDCl3, 75 MHz), δ: 155.7, 155.4, 149.7, 149.5, 148.9, 148.7, 132.8,
132.3, 132.2, 129.8, 128.2, 127.7, 126.8, 126.7, 126.6, 126.3, 125.9,
123.9, 121.3, 60.8, 59.5, 52.7, 52.5, 46.9, 36.8, 36.4, 25.7, 25.5, 20.4,
20.1; FT-IR, νmax (cm1): 1696, 1443, 1389, 1207, 1117, 1035, 974, 766;
MS (EI), m/z (relative intensity): 365 (M+, 25), 350 (100), 334 (20), 320
(3), 292 (5), 248 (4); HRMS (ESI-POS), m/z calculated for
C22H23NO4Na[M + Na]+: 388.1519, measured: 388.1517.
Compound 2f: This compound was obtained as a yellow solid. 1H-NMR
(CDCl3, 300 MHz), : 9.63 (d, J  8.4 Hz, 1H), 7.86 (dd, J = 7.7, 1.8 Hz,
1H), 7.82 (d, J = 9.0 Hz, 1H), 7.70 (d, J  9.0 Hz, 1H), 7.667.57 (m, 2H),
4.75 (s, 2H), 4.06 (s, 3H), 3.95 (s, 3H), 3.80 (t, J  6.0 Hz, 2H), 3.19 (t, J
 6.0 Hz, 2H); 13C-NMR (CDCl3, 75 MHz), δ: 154.9, 149.4, 148.9, 132.3,
130.0, 128.4, 128.3, 127.9, 127.7, 127.0, 126.8, 126.7, 126.3, 123.6,
121.3, 79.9, 60.6, 59.7, 42.3, 40.9, 28.5(3C), 26.1; FT-IR, νmax (cm1):
1693, 1421, 1393, 1240, 1163, 1117, 1035, 974, 754; MS (EI), m/z
(relative intensity): 393 (M+, 16), 336 (100), 249 (19), 221 (21), 178 (29),
149 (37); HRMS (ESI-POS), m/z calculated for C24H27NO4Na[M + Na]+:
416.1832, measured: 416.1832.
Compound 2g: This compound was obtained as a yellow solid. 1H-NMR
(CDCl3, 300 MHz), : 9.63 (dd, J  8.3, 0.9 Hz, 1H), 7.87 (dd, J = 7.8, 1.8
Hz, 1H), 7.83 (d, J = 9.0 Hz, 1H), 7.70 (d, J  9.0 Hz, 1H), 7.667.58 (m,
2H), 4.24 (s, 2H), 4.03 (s, 3H), 3.94 (s, 3H), 3.33 (t, J  5.7 Hz, 2H), 3.18
(t, J  5.7 Hz, 2H), 2.65 (bs, 1H); 13C-NMR (CDCl3, 75 MHz), δ: 149.3,
148.9, 132.3, 130.0, 129.0, 128.7, 128.3, 127.7, 126.9, 126.8, 126.6,
126.2, 123.6, 121.2, 60.6, 59.7, 43.9, 43.3, 26.0; FT-IR, νmax (cm1): 1445,
1386, 1338, 1201, 1102, 1037, 976, 753, 733; MS (EI), m/z (relative
intensity): 293 (M+, 90), 276 (26), 264 (86), 249 (100), 221 (73), 206 (23),
178 (25); HRMS (ESI-POS), m/z calculated for C19H20NO2[M + H]+:
294.1489, measured: 294.1481.
1
Compound 2a: This compound was obtained as a pale yellow solid. H-
NMR (CDCl3, 300 MHz), : 9.60 (dd, J  8.1, 1.5 Hz, 1H), 8.38 (d, J = 9.0
Hz, 2H), 8.09 (d, J = 9.0 Hz, 2H), 7.87 (dd, J  7.2, 2.1 Hz, 1H), 7.73 (d, J
 2.4 Hz, 2H), 7.687.57 (m, 2H), 4.47 (s, 3H), 4.06 (s, 3H), 3.90 (s, 3H),
3.57 (t, J  6.0 Hz, 2H), 3.31 (t, J  6.0 Hz, 2H); 13C-NMR (CDCl3,
75 MHz), δ: 150.2, 149.5, 148.4, 142.7, 132.4, 129.8, 128.8(2C), 128.4,
128.1, 127.7, 127.3, 126.9, 126.6, 125.4, 125.2, 124.4(2C), 124.1, 120.9,
60.8, 59.7, 44.0, 43.5, 26.3; FT-IR, νmax (cm1): 1529, 1342, 1164, 1091,
1024, 969, 753, 740; MS (EI), m/z (relative intensity): 478 (M+, 69), 291
(36), 265 (22), 249 (23), 221 (34), 149 (29), 104 (63); HRMS (ESI-POS),
m/z calculated for C25H23N2O6S[M + H]+: 479.1271, measured: 479.1266.
Compound 2b: This compound was obtained as a yellow solid. 1H-NMR
(CDCl3, 300 MHz), : 9.57 (d, J  8.0 Hz, 1H), 8.15 (d, J = 8.7 Hz, 2H),
7.98 (d, J = 8.7 Hz, 2H), 7.84 (dd, J  7.5, 1.8 Hz, 1H), 7.697.56 (m, 4H),
5.48 (q, J  6.6 Hz, 1H), 4.19 (dd, J  14.0, 6.0 Hz, 1H), 4.11 (s, 3H),
3.89 (s, 3H), 3.723.61 (m, 1H), 3.182.99 (m, 2H), 1.55 (d, J  6.6 Hz,
3H); 13C-NMR (CDCl3, 75 MHz), δ: 149.6, 148.1, 146.7, 132.3, 131.0,
129.6, 128.3, 128.0(2C), 127.7, 127.2, 126.9, 126.6, 124.3, 124.2,
124.0(2C), 120.7, 61.0, 59.6, 48.7, 38.3, 24.7, 21.3; FT-IR, νmax (cm1):
1528, 1347, 1159, 1032, 972, 738; MS (EI), m/z (relative intensity): 492
(M+, 40), 477 (100), 447 (10), 291 (43), 276 (27), 249 (12); HRMS (ESI-
POS), m/z calculated for C26H24N2O6SNa[M + Na]+: 515.1247, measured:
515.1254.
1
Compound 2c: This compound was obtained as a yellow solid. H-NMR
(CDCl3, 400 MHz), : 9.59 (d, J  8.0 Hz, 1H), 8.03 (d, J = 8.0 Hz, 2H),
7.927.86 (m, 3H), 7.717.59 (m, 4H), 7.287.20 (m, 5H), 6.65 (s, 1H),
4.10 (dd, J  12.0, 8.0 Hz, 1H), 3.86 (s, 3H), 3.57 (s, 3H), 3.543.43 (m,
1H), 3.153.00 (m, 2H); 13C-NMR (CDCl3, 100 MHz), δ: 149.8, 149.5,
148.5, 146.6, 140.1, 132.4, 129.7, 128.6(2C), 128.4(2C), 128.1,
128.0(3C), 127.8, 127.7, 127.4, 127.0, 126.8, 125.5, 124.8, 123.7(2C),
120.6, 60.4, 59.6, 55.5, 38.7, 24.1; FT-IR, νmax (cm1): 1528, 1347, 1163,
1106, 1033, 966, 737; MS (EI), m/z (relative intensity): 554 (M+, 100),
477 (75), 366 (18), 291 (35), 276 (20), 264 (40); HRMS (ESI-POS), m/z
calculated for C31H27N2O6S[M + H]+: 555.1584, measured: 555.1571.
Compound 2d: This compound was obtained as a colorless gum. 1H-
NMR (CDCl3, 300 MHz), : 9.63 (d, J  8.1 Hz, 1H), 7.87 (dd, J = 7.8, 1.2
Hz, 1H), 7.82 (d, J = 9.0 Hz, 1H), 7.71 (d, J  9.0 Hz, 1H), 7.727.56 (m,
2H), 4.79 (s, 2H), 4.07 (s, 3H), 3.94 (s, 3H), 3.85 (t, J  5.7 Hz, 2H), 3.21
(t, J  5.7 Hz, 2H); 13C-NMR (CDCl3, 75 MHz), δ: 156.1, 149.5, 148.8,
132.3, 129.9, 128.4, 128.3, 128.0, 127.7, 127.2, 126.9, 126.7, 126.3,
123.7, 121.3, 60.6, 59.7, 52.7, 42.4, 41.1, 25.9; FT-IR, νmax (cm1): 1699,
Compound 11: 2-Bromopropane (0.9 ml, 9.6 mmol) was added to a
mixture of 10 (1.53 g, 6.6 mmol) and potassium carbonate (2.76 g, 20.0
mol) in N,N-dimethylformamide (30 ml). The mixture was stirred at room
temperature under argon for 24 h. Next, the reaction mixture was added
to water and extracted with ethyl acetate. The combined organic layers
were washed with water, dried with anhydrous sodium sulfate, filtered,
and concentrated under reduced pressure to give a quantitative yield of
compound 11 as pale yellow oil, which was used in the next step without
purification. 1H-NMR (CDCl3, 300MHz), : 9.83 (s, 1H), 7.63 (d, J = 1.5
Hz, 1H), 7.38 (d, J = 1.5 Hz, 1H), 4.704.62 (m, 1H), 3.95 (s, 3H), 1.40 (d,
J  6.0 Hz, 6H); 13C-NMR (CDCl3, 75 MHz), δ: 189.8, 152.7, 152.2, 132.9,
128.2, 118.1, 113.0, 71.7, 60.6, 21.9 (2C); FT-IR, νmax (cm1): 1695, 1586,
1564, 1481, 1423, 1385, 1274, 1127, 1107, 996; MS (EI), m/z (relative
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701243
European Journal of Organic Chemistry
FULL PAPER
intensity): 272 (M+, 20), 230 (100), 215 (22), 187 (14), 178 (6); HRMS
(ESI-POS), m/z calculated for C11H14O3Br[M + H]+: 273.0121, measured:
273.0120.
After cooling down to room temperature, the reaction mixture was mixed
with water and extracted with ethyl acetate. The combined organic layers
were washed with water, dried with anhydrous sodium sulfate, filtered,
and concentrated under reduced pressure. The residue was purified by
column chromatography to yield compound 14 as a yellow gum (708 mg,
88%). 1H-NMR (CDCl3, 300 MHz), δ: 9.70 (s, 1H), 7.53 (s, 1H), 6.83 (s,
1H), 6.82 (d, J = 1.8 Hz, 1H), 6.67 (d, J = 1.8 Hz, 1H), 4.78 (br s, 1H),
4.754.67 (m, 1H), 4.644.56 (m, 1H), 3.93 (s, 3H), 3.67 (s, 3H), 3.52 (s,
3H), 3.45 (q, J  6.9 Hz, 2H), 2.79 (t, J  6.9 Hz, 2H), 1.441.40 (m,
12H); 13C-NMR (CDCl3, 75 MHz), δ: 191.1, 157.0, 154.3, 150.9, 147.0,
146.5, 136.5, 134.3, 132.1, 127.0, 123.7, 116.4, 113.5, 111.3, 71.3, 71.2,
60.3, 56.2, 52.1, 42.2, 35.9, 22.2, 22.1, 22.0, 21.9; FT-IR, νmax (cm1):
1702, 1681, 1594, 1509, 1265, 1111, 1093, 1012; MS (EI), m/z (relative
intensity): 459 (M+, 35), 428 (100), 396 (29), 386 (31), 354 (25), 312 (53),
269 (45); HRMS (ESI-POS), m/z calculated for C27H33NO6Na[M + Na]+:
482.2149, measured: 482.2165.
Compound 12: A solution of 11 (4.0 g, 16.5 mmol), nitromethane (4.0 ml,
73.5 mmol), and ammonium acetate (3.4 g, 44.1 mmol) in acetic acid (40
ml) was heated at 90 C for 7 h. After cooling down to room temperature,
the reaction mixture was poured to ice-water and stirred for an additional
0.5 h. The precipitates were collected, washed with water, and dried to
yield 12 as a yellow solid (4.1 g, 90%). The product was used in the next
1
step without purification. H-NMR (CDCl3, 300 MHz), : 7.86 (d, J = 13.5
Hz, 1H), 7.49 (d, J = 13.5 Hz, 1H), 7.36 (d, J = 1.8 Hz, 1H), 7.00 (d, J =
1.8 Hz, 1H), 4.644.56 (m, 1H), 3.92 (s, 3H), 1.40 (d, J  6.0 Hz, 6H);
13C-NMR (CDCl3, 75 MHz), δ: 152.1, 150.9, 137.6, 137.0, 126.7, 126.1,
118.7, 115.1, 72.1, 60.7, 21.9 (2C); FT-IR, νmax (cm1): 1544, 1484, 1429,
1281, 1136, 1107, 994; MS (EI), m/z (relative intensity): 315 (M+, 85),
273 (72), 226 (43), 211 (50), 194 (100), 178 (48), 149 (66); HRMS (ESI-
POS), m/z calculated for C12H15NO4Br[M + H]+: 316.0179, measured:
316.0167.
Compound 15: This compound was obtained from compound 14 (708
mg, 1.54 mmol) by using the same method described for 1a. This
compound has a 1:1 mixture of E/Z epimers in a form of pale yellow gum
(662 mg, 88%). 1H-NMR (CDCl3, 300 MHz), δ: 7.78 (s, 1H), 6.93 (s, 1H),
6.786.70 (m, 5H), 6.626.58 (m, 2H), 5.94 (d, J = 7.2 Hz, 1H), 5.60 (d, J
= 12.9 Hz, 1H), 4.98 (d, J = 7.2 Hz, 1H), 4.784.70 (m, 1H), 4.634.58 (m,
5H), 3.81 (s, 6H), 3.72 (s, 3H), 3.66 (s, 6H), 3.54 (s, 3H), 3.52 (s, 3H),
3.50 (s, 3H), 3.38 (q, J = 6.3 Hz, 4H), 2.75 (t, J = 6.3 Hz, 4H), 1.451.37
(m, 24H); 13C-NMR (CDCl3, 75 MHz), δ: 156.9, 151.0, 148.4, 147.7,
147.6, 146.8, 146.7, 146.5, 146.2, 146.0, 135.8, 135.5, 133.7, 133.6,
129.5, 129.2, 126.9, 126.5, 124.2, 124.1, 115.8, 115.6, 115.2, 114.3,
113.6, 112.0, 104.3, 103.7, 71.5, 71.2, 71.1, 71.0, 60.4, 60.3, 56.5, 56.0,
55.9, 52.0, 42.2, 35.8, 22.2; FT-IR, νmax (cm1): 3362, 1716, 1593, 1509,
1464, 1264, 1237, 1108; MS (EI), m/z (relative intensity): 455 [(M-
MeOH)+, 100], 423 (27), 413 (24), 367 (22), 325 (34), 283 (50), 269 (26);
HRMS (ESI-POS), m/z calculated for C27H37NO7Na[M + Na]+: 510.2462,
measured: 510.2480.
Compound 13: Boron trifluoride diethyl etherate (5.67 ml) was added
dropwise to a suspension of sodium borohydride (1.25 g, 33.0 mmol) in
tetrahydrofuran (40 ml), and the reaction was stirred at room temperature
under argon atmosphere for 15 min. Then a solution of 12 (2.2 g, 7.0
mmol) in tetrahydrofuran (50 ml) was added dropwise, and the reaction
was refluxed for 4 h. Then, the reaction mixture was cooled down in ice
bath, and water was added dropwise until gas evolution had ceased. The
reaction was then acidified with 10% aqueous hydrochloric acid, the ice
bath was removed, and the solution was heated at 8085 C for 2 h.
After cooling down to room temperature, the reaction mixture was
washed twice with diethyl ether. The aqueous layer was basified with
10% aqueous sodium hydroxide and extracted with dichloromethane.
The organic layer was combined and washed with water, dried over
anhydrous sodium sulfate, filtered, and concentrated under reduced
pressure to give 2-(3-bromo-4-methoxy-5-isopropoxyphenyl)ethanamine
as a colorless oil. The compound was redissolved in dichloromethane (40
ml), and the solution was then added with methyl chloroformate (1.1 ml,
14.3 mmol) followed by a solution of sodium carbonate (1.85 g, 17.45
mol) in water (3 ml). After stirring at room temperature for 24 h, the
reaction mixture was added to water and extracted with dichloromethane.
The combined organic layers were washed with water, dried with
anhydrous sodium sulfate, filtered, and concentrated under reduced
pressure. The residue was purified by column chromatography to yield
compound 13 as colorless oil (980 mg, 41% from 12). 1H-NMR (CDCl3,
300 MHz), δ: 6.95 (d, J = 1.8 Hz, 1H), 6.68 (d, J = 1.8 Hz, 1H), 4.79 (br s,
1H), 4.584.50 (m, 1H), 3.83 (s, 3H), 3.67 (s, 3H), 3.39 (q, J = 6.6 Hz,
2H), 2.71 (t, J = 6.6 Hz, 2H), 1.35 (d, J = 6.3 Hz, 6H); 13C-NMR (CDCl3,
75 MHz), δ: 156.9, 151.8, 146.3, 135.7, 124.9, 117.7, 116.0, 71.6, 60.3,
52.0, 42.0, 35.6, 22.0 (2C); FT-IR, νmax (cm1): 3338, 1701, 1524, 1485,
1270, 1234, 1136, 1109, 1003; MS (EI), m/z (relative intensity): 345 (M+,
25), 228 (97), 215 (37), 149 (7), 88 (81); HRMS (ESI-POS), m/z
calculated for C14H20BrNO4Na [M + Na]+: 368.0468, measured: 368.0475.
Compound 14. A mixture of 7 (504 mg, 2.12 mmol), 13 (608 mg, 1.76
mmol), tetrakis(triphenylphosphine)palladium(0) (81.7 mg, 0.07 mmol),
and potassium carbonate (487 mg, 3.52 mmol) in tolueneethanolwater
(3:3:2) (80 ml) was heated at 120 C under argon atmosphere for 24 h.
Compound 16: Compound 15 (662 mg, 1.36 mmol) was dissolved in a
solution of trifluoroacetic acid in dichloromethane (1:9, 15 mL), and 38%
formaldehyde (0.5 ml, 6.9 mmol) was added. After stirring at room
temperature for 1 h, the reaction mixture was added to water, washed
with saturated aqueous sodium hydrogen carbonate, and extracted with
dichloromethane. The combined organic layers were washed with water,
dried with anhydrous sodium sulfate, filtered, and concentrated under
reduced pressure. The residue was purified by column chromatography
to yield compound 16 as a white solid (480 mg, 76%). 1H-NMR (CDCl3,
300 MHz), δ: 9.20 (s, 1H), 7.71 (d, J = 9.0 Hz, 1H), 7.58 (d, J = 9.0 Hz,
1H), 7.24 (s, 1H), 5.004.92 (m, 1H), 4.824.74 (m, 3H), 4.07 (s, 3H),
3.91 (s, 3H), 3.903.80 (q, J = 5.7 Hz, 2H), 3.77 (s, 3H), 3.19 (t, J = 5.7
Hz, 2H), 1.48 (d, J  6.0 Hz, 6H), 1.39 (d, J  6.0 Hz, 6H); 13C-NMR
(CDCl3, 75 MHz), δ: 156.1, 149.8, 148.7, 147.0, 146.0, 127.9 (2C), 127.5,
126.6, 125.6, 124.4, 123.2, 119.5, 111.1, 109.1, 74.9, 70.8, 59.4, 55.9,
52.6, 42.9, 41.2, 25.8, 22.9 (2C), 22.0 (2C); FT-IR, νmax (cm1): 1701,
1512, 1465, 1442, 1402, 1236, 1104 ; MS (EI), m/z (relative intensity):
467 (M+, 100), 425 (94), 383 (48), 368 (88), 350 (22), 309 (30) ; HRMS
(ESI-POS), m/z calculated for C27H33NO6Na[M + Na]+: 490.2200,
measured: 490.2212.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701243
European Journal of Organic Chemistry
FULL PAPER
Compound 17: A suspension of 16 (280 mg, 0.6 mmol) and lithium
aluminiumhydride (341 mg, 9.0 mmol) in tetrahydrofuran (30 ml) was
heated at reflux for 4 h. After cooling down in ice-water, saturated
aqueous sodium sulfate was added dropwise to the reaction mixture to
destroy lithium aluminiumhydride. The mixture was filtered, and the
filtrate was extracted with ethyl acetate. The combined organic layers
were washed with water, dried with anhydrous sodium sulfate, filtered,
and concentrated under reduced pressure. The residue was purified by
column chromatography to yield compound 17 as a yellow solid (206 mg,
83%). 1H-NMR (CDCl3, 300 MHz), δ: 9.21 (s, 1H), 7.72 (d, J = 9.0 Hz,
1H), 7.56 (d, J = 9.0 Hz, 1H), 7.23 (s, 1H), 4.954.87 (m, 1H), 4.804.72
(m, 1H), 4.06 (s, 3H), 3.90 (s, 3H), 3.72 (s, 2H), 3.25 (t, J = 6.0 Hz, 2H),
2.81(t, J = 6.0 Hz, 2H), 2.55 (s, 3H), 1.48 (d, J  6.0 Hz, 6H), 1.36 (d, J 
6.0 Hz, 6H); 13C-NMR (CDCl3, 75 MHz), δ: 149.7, 148.5, 146.8, 146.1,
128.9, 127.8, 127.6, 126.4, 125.3, 124.5, 122.9, 119.9, 111.2, 109.1,
74.7, 70.8, 59.4, 55.9, 54.2, 52.8, 46.2, 27.0, 22.9 (2C), 22.0 (2C); FT-IR,
νmax (cm1): 1613, 1591, 1513, 1464, 1372, 1263, 1243, 1106; MS (EI),
m/z (relative intensity): 423 (M+, 77), 380 (77), 337 (100), 323 (26), 309
(23), 178 (18), 149(27); HRMS (ESI-POS), m/z calculated for C26H34NO4
[M + H]+: 424.2482, measured: 424.2480.
column chromatography to yield litebamine as a white solid (20 mg, 83%).
1H-NMR (DMSO-d6, 300 MHz), δ: 8.95 (s, 1H), 7.62 (d, J = 9.3 Hz, 1H),
7.46 (d, J = 9.3 Hz, 1H), 7.23 (s, 1H), 3.96 (s, 3H), 3.74 (s, 3H), 3.69 (s,
2H), 3.14 (br t, 2H), 2.84 (br t, 2H), 2.52 (s, 3H); 13C-NMR (DMSO-d6,
75 MHz), δ: 147.9, 146.4, 144.9, 141.1, 127.9, 126.2, 123.4, 123.3, 122.4,
122.2, 121.8, 119.8, 111.6, 107.9, 59.6, 55.2, 52.7, 51.7, 45.2, 25.9; FT-
IR, νmax (cm1): 3146, 1603, 1466, 1442, 1411, 1248, 1114; MS (EI), m/z
(relative intensity): 339 (M+, 39), 296 (43), 281 (31), 178 (89), 167 (41),
149 (70), 71 (83), 52 (100); HRMS (ESI-POS), m/z calculated for
C20H22NO4 [M + H]+: 340.1543, measured: 340.1541.
Acknowledgements
We gratefully acknowledged Dr. Poonsakdi Ploypradith at the
Chulabhorn Research Institute for critical reading of the
manuscript. We also thank Miss Kittiporn Trisupphakant for
recording EI-MS and IR spectra data.
Keywords: One-pot synthesis • PictetSpengler/FriedelCrafts
type reactions • Cyclization • Isoquinoline • Alkaloid
Reaction of 17 with aluminum (III) chloride. AlCl3 (126 mg, 0.94 mmol)
was added to a solution of 17 (100 mg, 0.23 mmol) in dichloromethane
(10 ml) and the reaction was stirred at room temperature for 3 h. Then,
the reaction was mixed with water and stirred for an additional 0.5 h. The
mixture was extracted with dichloromethane several times, and the
combined organic layers were washed with water, dried with anhydrous
sodium sulfate, filtered, and concentrated under reduced pressure. The
residue was purified by column chromatography to yield compound 18 as
a gray solid (46 mg, 71%). 1H-NMR (DMSO-d6, 300 MHz), δ: 9.07 (s, 1H),
7.53 (s, 1H), 7.49 (s, 1H), 3.96 (s, 3H), 3.71 (s, 3H), 3.57 (s, 2H),
3.543.45 (m, 1H), 3.13 (t, J  5.7 Hz, 2H), 2.73 (t, J  5.7 Hz, 2H), 2.44
(s, 3H), 1.37 (d, J  6.9 Hz, 6H); 13C-NMR (DMSO-d6, 75 MHz), δ: 147.2,
146.2, 144.5, 140.7, 138.0, 126.3, 126.1, 123.3, 123.2, 123.0, 120.5,
115.1, 108.5, 107.5, 59.6, 55.2, 53.2, 52.1, 45.7, 28.5, 26.3, 23.1 (2C);
FT-IR, νmax (cm1): 3149, 1602, 1530, 1462, 1414, 1246, 1132, 1102; MS
(EI), m/z (relative intensity): 381 (M+, 92), 338 (100), 323 (58), 295 (39),
178 (85), 97 (68); HRMS (ESI-POS), m/z calculated for C23H28NO4
[M + H]+: 382.2013, measured: 382.2009.
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Reaction of 17 with boron trichloride. BCl3 (1.0 M in dichloromethane;
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10% ethanol/ethyl acetate. The combined organic layers were
concentrated under reduced pressure. The residue was purified by
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10.1002/ejoc.201701243
European Journal of Organic Chemistry
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One-pot strategy
Me
N
iPr O
iPr O
Nisachon Khunnawutmanotham,
Poolsak Sahakitpichan, Nitirat Chimnoi,
Supanna Techasakul*
HO
NHCOOMe
OMe
NHCOOMe
CHO
MeO
MeO
MeO
MeO
MeO
14
OiPr
MeO
OiPr
litebamine
14
(46%, 4 steps from
)
OH
Page No. – Page No.
N-Protected amino aldehyde biaryl
A facile and efficient one-pot method for the synthesis of tetrahydronaphtho [2,1-
f]isoquinoline alkaloid using domino PictetSpengler/FriedelCrafts type cyclizations has
been reported. The natural litebamine was prepared by using the proposed method to
exemplify its utility.
Efficient one-pot synthesis of
tetrahydronaphtho[2,1-f]isoquinoline
under domino
PictetSpengler/FriedelCrafts type
reactions
*one or two words that highlight the emphasis of the paper or the field of the study
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