Total synthesis of (±)-armepavines and (±)-nuciferines from (2-nitroethenyl)benzene derivatives

Article abstract of DOI:10.1080/00397910903435411

A concise route to armepavine 1 and nuciferine 2 and 3, which can be isolated from the leaves of Nelumbo nucifera (Nymphaceae), has been achieved in which the longest linear sequence is only six steps from commercially available benzaldehyde in 28%, 21%, and 20% overall yield, respectively. The key transformations in the synthesis are the radical cyclization of aryl bromide with Bu3SnH and the Pictet-Spengler reaction of N-substituted amine with aldehyde. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910903435411

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Total Synthesis of (±)-Armepavines
and (±)-Nuciferines From (2-
Nitroethenyl)benzene Derivatives
Chia-Fu Chang a , Chu-Yun Huang a , Yu-Chao Huang a , Kuan-Yu Lin a
, Yean-Jang Lee a & Chau-Jong Wang b
a Department of Chemistry, National Changhua University of
Education, Changhua, Taiwan
b Institute of Biochemistry, Chung Shan Medical University, Taichung,
Taiwan
Available online: 05 Nov 2010
To cite this article: Chia-Fu Chang, Chu-Yun Huang, Yu-Chao Huang, Kuan-Yu Lin, Yean-Jang
Lee & Chau-Jong Wang (2010): Total Synthesis of (±)-Armepavines and (±)-Nuciferines From (2-
Nitroethenyl)benzene Derivatives, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 40:23, 3452-3466
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Synthetic Communications1, 40: 3452–3466, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903435411
TOTAL SYNTHESIS OF (ꢀ)-ARMEPAVINES AND
(ꢀ)-NUCIFERINES FROM (2-NITROETHENYL)BENZENE
DERIVATIVES
Chia-Fu Chang,1 Chu-Yun Huang,1 Yu-Chao Huang,1
Kuan-Yu Lin,1 Yean-Jang Lee,1 and Chau-Jong Wang2
1Department of Chemistry, National Changhua University of Education,
Changhua, Taiwan
2Institute of Biochemistry, Chung Shan Medical University,
Taichung, Taiwan
A concise route to armepavine 1 and nuciferine 2 and 3, which can be isolated from the
leaves of Nelumbo nucifera (Nymphaceae), has been achieved in which the longest linear
sequence is only six steps from commercially available benzaldehyde in 28%, 21%, and 20%
overall yield, respectively. The key transformations in the synthesis are the radical cycliza-
tion of aryl bromide with Bu3SnH and the Pictet–Spengler reaction of N-substituted amine
with aldehyde.
Keywords: Armepavine; Nef; nuciferines; Pictet–Spengler
INTRODUCTION
As part of our research aiming to uncover new natural products with improved
biological activities, including antioxidant, anti-human immunodeficiency virus
(HIV), and tumor growth inhibition activities, we attended to the flavonoid, coume-
stan, and maleimide family.[1] Recently, several structurally interesting alkaloids with
substituted isoquinoline[2] have been isolated from the leaves of Nelumbo nucifera
(Nymphaceae) and show significant anti-HIV activity (EC50 value of 0.8 mg=mL,
TI > 125)[3] and also inhibit platelet aggregation[3] (Fig. 1). Although armepavine
(1) and nuciferine (2) have been synthesized by several groups,[2c,4] they were
achieved with very time-consuming and complicated synthetic approaches. To over-
come these technical difficulties, we report our studies on the synthesis of nuciferine
analogs from the readily available (2-nitroethenyl)benzene derivatives by sequential
Pictet–Spengler and radical cyclization.
Retrosynthetic analysis (Scheme 1) suggested that 2 and 3 can be secured by Heck
coupling or radical cyclization[4i] of 4. The latter should be accessible from 5 and 6
with Pictet–Spengler[5] or Bischler–Napieralski[6] reactions. In addition, commercially
Received August 25, 2009.
Address correspondence to Yean-Jang Lee, Department of Chemistry, National Changhua
University of Education, Changhua 50058, Taiwan. E-mail: leeyj@cc.ncue.edu.tw
3452

TOTAL SYNTHESIS OF (ꢀ)-NUCIFERINES
3453
Figure 1. Armepavine and nuciferines from the leaves of Nelumbo nucifera (Nymphaceae).
Scheme 1. Retrosynthesis of (ꢀ)-nuciferines.
available ketones and aldehydes would allow facile introduction of a wide range of
different substituents of 5 and 6 by Nef[7] or Willgerodt–Kindler[8] reactions.
RESULTS AND DISCUSSION
With the aim of developing a concise route to synthesize aryl acetaldehyde and
amine with diverse substituents, the commercially available 7a–c were used to pre-
pare the corresponding aldehydes 10a–c and amines 11a–c from this compound
(Scheme 2). In the beginning of our synthesis, aldehydes 7a–c were transformed
by aldol condensation with CH3NO2=NH4OAc under acetic acid to obtain the cor-
responding nitro compounds 8a–c in excellent yield. Subsequently, selective
1,4-reduction of conjugated 8a–c proceeded with NaBH4 to provide the saturated
nitro product 9a–c. According to the Nef-type reaction, the nitro group of 9a–c
was readily changed to the carbonyl group under acidic conditions to give the desired
10a and 10b in quantitative yield, respectively, as well as 10c in 96% yield. At the
same time, compounds 11a–c were prepared by direct reduction of 8a–c with LiAlH4
in tetrahydrofuran (THF) at 0 ꢁC. With 10a and 11b in hand, we tried to synthesize
tetrahydroisoquinoline 13 through the coupling of 10a and 11b using the Pictet–
Spengler reaction. However, the acid-catalyzed reaction using different Lewis acids,
such as trifluoroacetic acid (TFA), HCl, p-toluenesulfonic acid (p-TSA), and BF3-
OEt2, to give 13 was unsuccessful. The major product was the recovered starting
material or amine hydrochloride salt. This problem could be due to the need for
anhydrous conditions, because the iminium salt is readily hydrolyzed under

3454
C.-F. CHANG ET AL.
Scheme 2. Synthesis of aryl amines and aryl aldehydes.
acid-catalyzed reactions. Therefore, we sought to overcome this problem by convert-
ing the primary amine into the secondary amine. Amine 11b was protected with
the electron-withdrawing groups CO2Me and Boc to provide 12a, b, respectively
(Scheme 2). Subsequently, the N-methoxycarbonyl hydroisoquinoline obtained
under BF3-OEt2 catalysis by condensation-cyclization of N-methoxycarbonyl amine
12a with aldehyde 10a may be used without further purification, and then the process
proceeded smoothly using the reductive reaction with LiAlH4 to provide the desired
product 13 (67%) in three steps (Scheme 3). Finally, the isopropyl group in 13 was
removed with BCl3 in CH2Cl2 at 0 ꢁC to afford armepavine 1 in 69% yield. The struc-
ture of 1 was confirmed by x-ray crystallography.[9] With the success of achieving
12a, b, we employed the same Lewis acid BF3-OEt2–catalyzed Pictet–Spengler reac-
tion in nuciferines 2 and 3 syntheses. Coupling of 12a, b respectively with aldehyde
10c proceeded readily in mixed solvent (CH2Cl2=CHCl3 1:1) under BF3-OEt2 cataly-
sis to give the bromoarmepavine 14a, b, which can then undergo the radical cycliza-
tion with azobisisobutyronitrile (AIBN)=Bu3SnH to accomplish 15a, b in 52% and
56% yield, respectively. Trying to obtain 15a, b via palladium-catalyzed cou-
pling[2c,4g] proved unsuccessful. With precursor 15a, b in hand, completion of the
final steps in the nuciferine syntheses was straightforward, requiring either reduction
or deprotection. Previous reduction of the methoxycarbonyl group in compound 15a
with LiAlH4 provided the N-methyl nuciferine 2 in 66% yield. Also, direct
acid-catalyzed deprotection of the t-butoxycarbonyl group in compound 15b with
AcCl=MeOH furnished the expected product 3 in 59% yield. 1H and 13C NMR spec-
tra of the synthetic products are in agreement with those of reported natural product
derivatives.
It is worth noting that an alternative construction[4g] of armepavine 1 was
created by Willgerodt–Kindler and Bischler–Napieralski reactions (Scheme 4). Using
the Willgerodt–Kindler and hydrolysis procedures, the phenylacetic acid 17 can be
readily prepared from the commercially available hydroxyacetophenone in excellent

TOTAL SYNTHESIS OF (ꢀ)-NUCIFERINES
3455
Scheme 3. Synthesis of (þ=ꢂ)-armepavines and (þ=ꢂ)-nuciferines.
yield (three steps, 67%). First, the protection of hydroxyacetophenone was employed
with i-PrBr and K2CO3 to obtain 16 in 95% yield, and then the acetophenone 16 was
readily transformed by sulfur and morpholine with catalyst p-TSA under refluxing
conditions to afford the expected thioacetomorpholide, which could directly be used
by hydrolysis with 20% NaOH and catalyst tetrabutylammonium bromide (TBAB)
to provide the desired acid 17. The acetic acid 17 was treated with oxalyl chloride,
followed by reaction with the readily available phenylethamine 11b to obtain the
Scheme 4. Synthesis of isoquinoline 13.

3456
C.-F. CHANG ET AL.
desired amide 18 in 82% yield. With the required amide 18 in hand, the Bischler–
Napieralski cyclization with POCl3 in acetonitrile gave the isoquinimium ion, which
can undergo the reduction with NaBH4 to afford isoquinoline 19 in 60% yield (two
steps). Sequential condensation and reduction of 19 with formaldehyde and NaBH4,
respectively, provided the isopropyl armepavine 13 in 83% yield.
CONCLUSION
In summary, a concise route to armepavine 1 and nuciferine 2 and 3 has been
achieved in which the longest linear sequence is only six steps from commercially
available benzaldehyde in 28%, 21%, and 20% overall yield, respectively. Alterna-
tively, 1 was also accomplished in 19% overall yield from commercially available
4-hydroxyacetophenone by a route in which the longest linear sequence is only eight
steps. Thus, it is demonstrated that using the Lewis acid BF3-OEt2-catalyzed Pictet–
Spengler reaction gives a good yield and is easily modified to give access to a variety
of different armepavine and nuciferine analogs. The preparation of these compounds
is currently under way, and their biological activities will be investigated to evaluate
the efficacy of these compounds as antitumor agents.
EXPERIMENTAL
Melting points were determined on a Mel Temp II melting-point apparatus and
1
are uncorrected. H NMR and 13C NMR spectra were measured with a Bruker 300
spectrometer. Chemical shifts are reported in parts per million (d, ppm) using CHCl3
(dH 7.26) as an internal standard. Low-resolution mass spectra (MS) and
high-resolution mass spectra (HRMS) were determined on a Jeol JMS-HX 110 mass
spectrometer from National Chung-Tsing University, Taichung. Elemental analyses
were performed on a Heracus CHN-OS Rapid spectrometer in the Taichung Instru-
mentation Center, National Science Council, Taiwan. Solvents were freshly distilled
prior to use from phosphorus pentoxide or CaH2. THF was distilled from sodium
diphenyl ketyl. All reactions were carried out under a nitrogen atmosphere unless
otherwise stated. Silica gel (silica gel 60, 230–400 mesh, Merck) was used for chro-
matography. Organic extracts were dried over anhydrous MgSO4.
1-Isopropoxy-4-(2-nitrovinyl)benzene (8a)[10]
A solution of 4-isopropoxy benzaldehyde (7a) (1.51 g, 9.2 mmol) in NH4OAC
(1.40 g) = AcOH (20.0 mL) was stirred for 10 min at 25 ꢁC, followed by slow addition
of CH3NO2 (2.0 mL, 36.9 mmol) with stirring for 5 min. The resulting mixture was
heated to reflux at 120 ꢁC for 4 h, then quenched by addition of ice water
(10.0 mL) and extracted with CH2Cl2 (3 ꢃ 30.0 mL). The combined organic layers
was concentrated in vacuo, and the residue was subjected to flash chromatography
(SiO2, hexane-CH2Cl2 2:1) to obtain the desired 8a (1.62 g, 85%) as an orange solid:
1
mp 50–51 ꢁC, H NMR d: 1.21 (d, J ¼ 6.0 Hz, 6H), 4.48 (hept, J ¼ 6.0 Hz, 1H), 6.77
(d, J ¼ 8.7 Hz, 2H), 7.32 (d, J ¼ 8.7 Hz, 2H), 7.36 (d, J ¼ 13.5 Hz, 1H), 7.80
(d, J ¼ 13.5 Hz, 1H); 13C NMR :d 21.7, 70.1, 116.1, 121.9, 131.1, 134.6, 139.0, 161.4.

TOTAL SYNTHESIS OF (ꢀ)-NUCIFERINES
3457
1,2-Dimethoxy-4-(2-nitrovinyl)benzene (8b)
According to previous procedures, 3,4-dimethoxy benzaldehyde (7b) (1.73 g,
10.4 mmol) in NH4OAC (1.58 g) = AcOH (20.0 mL) was stirred for 10 min at
25 ꢁC, followed by slow addition of CH3NO2 (2.3 mL, 41.7 mmol) with stirring for
5 min. The resulting mixture was heated to reflux at 120 ꢁC for 4 h, then quenched
by addition of ice water (10.0 mL) and extracted with CH2Cl2 (3 ꢃ 30.0 mL). The
combined organic layers was concentrated in vacuo, and the residue was subjected
to flash chromatography (SiO2, hexane-CH2Cl2 2:1) to provide the expected 8b
1
(1.70 g, 78%) as an orange solid: mp 131–132 ꢁC (lit.[11] mp 140–142 ꢁC), H NMR
d :3.84 (s, 3H), 3.85 (s, 3H), 6.83 (d, J ¼ 8.4 Hz, 1H), 6.94 (d, J ¼ 1.8 Hz, 1H), 7.09
(dd, J ¼ 8.4, 1.8 Hz, 1H), 7.46 (d, J ¼ 13.5 Hz, 1H), 7.87 (d, J ¼ 13.5 Hz, 1H); 13C
NMR :d 55.8, 55.9, 110.2, 111.2, 122.7, 124.5, 135.0, 139.2, 149.4, 152.7.
1-Bromo-2-(2-nitrovinyl)benzene (8c)
Compound 8c was prepared, using the previous procedure, from 2-bromo
benzaldehyde (7c) (1.00 g, 5.4 mmol) in NH4OAC (0.73 g)=AcOH (15.0 mL),
followed by slow addition of CH3NO2 (1.0 mL, 19.2 mmol) with stirring for 5 min.
The resulting mixture was heated to reflux at 120 ꢁC for 4 h, then quenched by
addition of ice water (10.0 mL) and extracted with CH2Cl2 (3 ꢃ 20.0 mL). The
combined organic layers was concentrated in vacuo, and the residue was subjected
to flash chromatography (SiO2, hexane-CH2Cl2 2:1) to provide the expected 8c
1
(0.94 g, 76%) as a light yellow solid: mp 87–88 ꢁC (lit.[11] mp 86–87 ꢁC); H NMR
d 7.21–7.32 (m, 2H), 7.44 (d, J ¼ 13.8 Hz, 1H), 7.48 (dd, J ¼ 7.5, 1.8 Hz, 1H), 7.58
(dd, J ¼ 7.5, 1.8 Hz, 1H), 8.26 (d, J ¼ 13.8 Hz, 1H); 13C NMR :d 126.2, 128.0,
128.4, 130.1, 132.9, 133.8, 137.4, 138.7.
1-Isopropoxy-4-(2-nitroethyl)benzene (9a)
To a solution of 8a (0.71 g, 3.4 mmol) in MeOH=CH2Cl2 (15.0=15.0 mL) was
cooled for 10 min at 0 ꢁC. One portion of NaBH4 (0.19 g, 5.1 mmol) the solution
was added to and stirred for 20 min, followed by the other portion of NaBH4
(0.19 g, 5.1 mmol) at 0 ꢁC. The mixture was allowed to stir for 30 min and then
quenched with distilled H2O, which was extracted with CH2Cl2 (3 ꢃ 20.0 mL). After
removal of solvent, the residue was subjected to column chromatography (SiO2,
1
hexane–ethyl acetate 8:1) to provide 9a (0.54 g, 75%) as an oil. H NMR d :1.24
(d, J ¼ 6.0 Hz, 6H), 3.14 (t, J ¼ 7.2 Hz, 2H), 4.42 (hept, J ¼ 6.0 Hz, 1H), 4.46 (t,
J ¼ 7.2 Hz, 2H), 6.74 (d, J ¼ 8.7 Hz, 2H), 7.00 (d, J ¼ 8.7 Hz, 2H); 13C NMR :d
21.9, 32.6, 69.8, 76.5, 116.1, 127.3, 129.5, 157.1; HRMS (EI) calcd. for C11H15NO3
(Mþ) 209.1052; found 209.1048.
1,2-Dimethoxy-4-(2-nitroethyl)benzene (9b)
Compound 9b was prepared, using the previous procedure, from 8b (0.59 g,
2.9 mmol) in MeOH=CH2Cl2 (10.0=10.0 mL), cooled for 10 min at 0 ꢁC. One portion
of NaBH4 (0.16 g, 4.3 mmol) was added, followed by the other portion of NaBH4

3458
C.-F. CHANG ET AL.
(0.16 g, 4.3 mmol) with stirring for 30 min at 0 ꢁC. The resulting mixture was then
quenched by addition of distilled H2O (5.0 mL) and extracted with CH2Cl2
(3 ꢃ 20.0 mL). The combined organic layers were concentrated in vacuo, and the resi-
due was subjected to flash chromatography (SiO2, hexane–ethyl acetate 8:1) to give
the expected 9b (0.42 g, 70%) as a yellow oil (lit.[12] mp 53–54 ꢁC);1H NMR d :3.19 (t,
J ¼ 7.2 Hz, 2H), 3.80 (s, 3H), 3.82 (s, 3H), 4.51 (t, J ¼ 7.2 Hz, 2H), 6.63 (d, J ¼ 1.8 Hz,
1H), 6.67 (dd, J ¼ 8.1,1.8 Hz, 1H), 6.74 (d, J ¼ 8.1 Hz, 1H); 13C NMR :d 33.1, 55.9,
55.9, 76.5, 111.5, 111.7, 120.6, 128.0, 148.3, 149.2.
1-Bromo-2-(2-nitroethyl)benzene (9c)
According to previous procedures, 8c (0.45 g, 2.0 mmol) in MeOH=CH2Cl2
(10.0=10.0 mL) was cooled down to 0 ꢁC, and one portion of NaBH4 (0.19 g,
5.1 mmol) was added with stirring for 10 min, followed by the other portion of
NaBH4 (0.19 g, 5.1 mmol) at 0 ꢁC. The mixture was allowed to stir for 20 min and
then quenched with distilled H2O, which was extracted with CH2Cl2 (3 ꢃ 15.0 mL).
After removal of solvent, the residue was subjected to column chromatography
(SiO2, hexane–ethyl acetate 8:1) to obtain 9c (0.30 g, 67%) as an oil.1H NMR d
3.34 (t, J ¼ 7.5 Hz, 2H), 4.54 (t, J ¼ 7.5 Hz, 2H), 7.04–7.20 (m, 3H), 7.46 (d,
J ¼ 7.5 Hz, 1H); 13C NMR d 33.7, 74.2, 124.2, 127.9, 129.2, 131.0, 133.1, 134.9.
4-Isopropoxyphenylacetaldehyde (10a)
A mixture of 9a (0.51 g, 2.4 mmol) and NaOH (0.39 g, 9.8 mmol) in ethanol
(5.0 mL) was stirred for 10 min at 25 ꢁC, and then the solvent was evaporated in
vacuo to give the desired sodium nitronate, which was dissolved in distilled H2O
(5.0 mL). The solution was added into the two-layer mixture of concentrated
H2SO4=H2O (2.5=5.0 mL) and pentane (20.0 mL) for 1 h at 0 ꢁC and then warmed
to 25 ꢁC. After stirring for 4 h, the resulting suspension was extracted with CH2Cl2
(3 ꢃ 20.0 mL). The combined organic layers was concentrated in vacou, and the
residue was subjected to flash chromatography (SiO2, hexane–ethyl acetate 5:1) to
1
provide the expected 10a (0.43 g, 100%) as an oil. H NMR d :1.31 (d, J ¼ 6.3 Hz,
6H), 3.57 (d, J ¼ 2.4 Hz, 2H), 4.51 (hept, J ¼ 6.3 Hz, 1H), 6.85 (d, J ¼ 8.4 Hz, 2H),
7.08 (d, J ¼ 8.4 Hz, 2H), 9.67 (t, J ¼ 2.4 Hz, 1H); 13C NMR :d 22.0, 49.7, 69.9,
116.3, 123.4, 130.6, 157.2, 199.8, HRMS (EI) calcd. for C11H14O2 (Mþ) 178.0994;
found 178.0988.
3,4-Dimethoxyphenylacetaldehyde (10b)[13]
A solution of 9b (0.49 g, 2.3 mmol) and NaOH (0.37 g, 9.2 mmol) in ethanol
(5.0 mL) was stirred for 10 min at 25 ꢁC, and then the removal of solvent in vacuo
gave the intermediate sodium nitronate, which was dissolved in distilled H2O
(5.0 mL). The solution was introduced into the two-layer mixture of concentrated
H2SO4=H2O (2.5=5.0 mL) and pentane (20.0 mL) for 1 h at 0 ꢁC and then warmed
to 25 ꢁC. After stirring for 5 h, the resulting suspension was extracted with CH2Cl2
(3 ꢃ 20.0 mL). The combined organic layers was concentrated in vacuo, and the
residue was subjected to flash chromatography (SiO2, hexane-CH2Cl2 1:1) to provide

TOTAL SYNTHESIS OF (ꢀ)-NUCIFERINES
3459
the expected 10b (0.42 g, 100%) as an oil.1H NMR d 3.56 (d, J ¼ 2.4 Hz, 2H), 3.81 (s,
6H), 6.64 (d, J ¼ 1.8 Hz, 1H), 6.70 (dd, J ¼ 8.1,1.8 Hz, 1H), 6.80 (d, J ¼ 8.1 Hz, 1H),
9.66 (t, J ¼ 2.4 Hz, 1H); 13C NMR d 50.1, 55.8, 55.9, 111.6, 112.6, 121.8, 124.1, 148.4,
149.3, 199.5.
2-Bromophenylacetaldehyde (10c)[14]
Compound 10c was prepared, using the previous procedure, from 9c (0.30 g,
1.3 mmol) and NaOH (0.21 g, 5.2 mmol) in ethanol (5.0 mL) and stirred for 10 min
at 25 ꢁC, and then the solvent was evaporated in vacuo to give the desired sodium
nitronate, which was dissolved in distilled H2O (3.0 mL). The solution was added
into the two-layer mixture of concentrated H2SO4=H2O (2.0=4.0 mL) and pentane
(15.0 mL) for 1 h at 0 ꢁC and then warmed to 25 ꢁC. After stirring for 3 h, the result-
ing suspension was extracted with CH2Cl2 (3 ꢃ 15.0 mL). The combined organic
layers were concentrated in vacuo, and the residue was subjected to flash chromato-
graphy (SiO2, hexane–ethyl acetate 10:1) to obtain the aldehyde 10c (0.25 g, 96%) as
an oil.1H NMR [(CD3)2CO] d :3.92 (d, J ¼ 1.2 Hz, 2H), 7.19–7.37 (m, 3H), 7.62
(d, J ¼ 8.1 Hz, 1H), 9.74 (t, J ¼ 1.2 Hz, 1H); 13C NMR [(CD3)2CO] d 50.0, 124.6,
127.8, 129.1, 132.2, 132.6, 133.6, 197.6.
2-(4-Isopropoxyphenyl)ethylamine (11a)[15]
LiAlH4 (0.22 g, 5.8 mmol) was added to a solution of 8a (0.40 g, 1.9 mmol) in
dried THF (10.0 mL) at 0 ꢁC and then stirred under N2 overnight at room tempera-
ture. The reaction was quenched with distilled H2O (5.0 mL), which was extracted
with CH2Cl2 (3 ꢃ 10.0 mL). After the removal of solvent, the residue was subjected
to flash chromatography (SiO2, hexane–ethyl–acetate–MeOH 8:2:1) to provide
the desired 11a (0.25 g, 73%) as an oil.1H NMR d :1.25 (d, J ¼ 6.0 Hz, 6H), 1.66
(brs, 2H), 2.61 (t, J ¼ 6.9 Hz, 2H), 2.85 (t, J ¼ 6.9 Hz, 2H), 4.43 (hept, J ¼ 6.0 Hz,
1H), 6.75 (d, J ¼ 8.4 Hz, 2H), 7.02 (d, J ¼ 8.4 Hz, 2H); 13C NMR :d 22.0, 38.9,
43.5, 69.9, 115.9, 129.7, 131.5, 156.3.
2-(3,4-Dimethoxyphenyl)ethylamine (11b)[16]
A mixture of 8b (0.30 g, 1.4 mmol) and LiAlH4 (0.16 g, 4.3 mmol) in dried
THF (10.0 mL) was stirred at 25 ꢁC and then heated to reflux under N2 for 3 h.
The reaction was quenched with distilled H2O (5.0 mL), which was extracted with
CH2Cl2 (3 ꢃ 10.0 mL). After the removal of solvent, the residue was subjected to
flash chromatography (SiO2, ethyl acetate-MeOH 19:1) to provide the desired 11b
(0.21 g, 83%) as an oil (lit.[17] mp 155–156 ꢁC);1H NMR d :1.30 (brs, 2H), 2.58
(t, J ¼ 6.9 Hz, 2H), 2.81 (t, J ¼ 6.9 Hz, 2H), 3.80 (s, 3H), 3.87 (s, 3H), 6.60–6.66
(m, 3H); 13C NMR d 39.2, 43.2, 55.4, 55.5, 111.0, 111.7, 120.3, 132.0, 147.1, 148.5.
2-(2-Bromophenyl)ethylamine (11c)[18]
LiAlH4 (0.22 g, 5.8 mmol) was added to a solution of 8c (0.44 g, 1.9 mmol)
in dried THF (10.0 mL) at 0 ꢁC, and then stirred under N2 overnight at room

3460
C.-F. CHANG ET AL.
temperature. The reaction was quenched with distilled H2O (5.0 mL), which was
extracted with CH2Cl2 (3 ꢃ 10.0 mL). The combined organic layers was concentrated
in vacuo, and the residue was subjected to flash chromatography (SiO2, hexane–
1
ethyl–acetate–MeOH 8:2:1) to provide the expected 11c (0.20 g, 56%) as a oil. H
NMR d :1.55 (brs, 2H), 2.80–2.93 (m, 4H), 6.99–7.03 (m, 1H), 7.16–7.20 (m, 2H),
7.47 (d, J ¼ 7.8 Hz, 1H); 13C NMR d 40.1, 42.0, 124.6, 127.4, 128.0, 130.9, 132.9,
139.0.
Methyl N-[2-(3,4-Dimethoxyphenyl)ethyl]carbamate (12a)[19]
A solution of 11b (1.00 g, 5.5 mmol) in dried THF (30.0 mL) was dissolved,
followed by dropwise addition of methyl chloroformate (0.5 mL, 6.6 mmol) under
N2 at 0 ꢁC. The resulting solution was stirred at room temperature, and the reaction
was monitored by thin-layer chromatography (TLC). The reaction was quenched
with distilled H2O (20.0 mL), which was extracted with CH2Cl2 (3 ꢃ 50.0 mL). After
the removal of solvent, the residue was subjected to flash chromatography (SiO2,
1
hexane–ethyl-acetate 1:1) to provide the desired 12a (1.25 g, 95%) as an oil. H
NMR d 2.69 (t, J ¼ 6.9 Hz, 2H), 3.35 (q, J ¼ 6.9 Hz, 2H), 3.60 (s, 3H), 3.80 (s,
3H), 3.87 (s, 3H), 4.80 (brs, 1H), 6.65–6.68 (m, 2H), 6.75 (d, J ¼ 8.4 Hz, 1H); 13C
NMR d 35.6, 42.3, 52.0, 55.7, 55.8, 111.3, 111.9, 120.6, 131.2, 147.6, 148.9, 157.0.
tert-Butyl N-[2-(3,4-Dimethoxyphenyl)ethyl]carbamate (12b)
According to the procedure of Toste and Still,[20] a mixture of 11b (1.40 g,
7.7 mmol), dimethylaminopyradine (DMAP; 0.05 g, 0.4 mmol), and N,N-diisopro-
pylethylamine (DIEA; 2.00 g, 15.5 mmol) in dried CH2Cl2 (30.0 mL) was added to
Boc2O (2.00 g, 9.2 mmol) with dropwise at 0 ꢁC. Stirring continued at 0 ꢁC for
30 min and at room temperature for 2 h. The reaction was quenched with saturated
aqueous solution of NH4Cl (10.0 mL), which was extracted with CH2Cl2
(3 ꢃ 30.0 mL). Evaporation and chromatography (SiO2, hexane–ethyl–acetate–
1
CH2Cl2 1:1:1) gave 12b (2.02 g, 93%) as a white solid: mp 61–62 ꢁC. H NMR d
1.21 (s, 9H), 2.50 (t, J ¼ 6.9 Hz, 2H), 3.10 (t, J ¼ 6.9 Hz, 2H), 3.61 (s, 3H), 3.63 (s,
3H), 4.60 (brs, 1H), 6.49–6.60 (m, 3H); 13C NMR d 28.3, 35.7, 42.0, 55.6, 55.7,
78.9, 111.3, 111.9, 120.6, 131.5, 147.5, 148.8, 155.8.
1-(4-Isopropoxybenzyl)-6,7-dimethoxy-2-methyl-
1,2,3,4-tetrahydroisoquinoline (13)
A mixture of 12a (0.51 g, 2.1 mmol) and 10a (0.75 g, 4.2 mmol) in mixed sol-
vents of CH2Cl2 and CHCl3 (20.0=20.0 mL) was introduced by dropwise addition
of BF3-OEt2 (0.5 mL, 3.9 mmol) at ꢂ78 ꢁC for 1 h. The resulting solution was stirred
at room temperature, and the reaction was monitored by TLC. The reaction was
quenched with saturated aqueous solution of NaHCO3 (10.0 mL), which was
extracted with CH2Cl2 (3 ꢃ 50.0 mL). After the removal of solvent, the crude product
was directly used with no further purification. To a solution of the crude product in
dried THF (40.0 mL), LiAlH4 (0.24 g, 6.3 mmol) was added at 0 ꢁC under N2. The
reaction was quenched with distilled H2O (10.0 mL), which was extracted with

TOTAL SYNTHESIS OF (ꢀ)-NUCIFERINES
3461
CH2Cl2 (3 ꢃ 50.0 mL). After the removal of solvent, the residue was subjected to
flash chromatography (SiO2, CH2Cl2-ethyl acetate–MeOH 10:2:1) to provide the
1
desired 13 (0.50 g, 67%) as an oil. H NMR [(CD3)2CO] d :1.45 (d, J ¼ 6.0 Hz,
6H), 2.42 (s, 3H), 2.44–2.81 (m, 4H), 2.99–3.15 (m, 2H), 3.56 (s, 3H), 3.63 (t,
J ¼ 6.0 Hz, 1H), 3.82 (s, 3H), 4.52 (hept, J ¼ 6.0 Hz, 1H), 6.32 (s, 1H), 6.57 (s,
1H), 6.74 (d, J ¼ 8.4 Hz, 2H), 7.01 (d, J ¼ 8.4 Hz, 2H); 13C NMR [(CD3)2CO] :d
21.4, 25.3, 39.9, 42.1, 47.0, 54.9, 55.0, 64.7, 69.1, 111.5, 111.7, 115.1, 126.4, 129.6,
130.7, 132.0, 147.0, 147.6, 156.1; HRMS (EI) calcd. for C22H29NO3 (Mþ)
355.2147; found 355.2142.
1,2-Dimethoxy-4,5,6a,7-tetrahydrodibenzo[de,g]
quinoline-6-carboxylic Acid Methyl Ester (15a)[2c]
Compound 15a was prepared, using the previous procedure, from 12a (0.30 g,
1.3 mmol) and 10c (0.50 g, 2.5 mmol) in mixed solvents of CH2Cl2 and CHCl3 (20.0=
20.0 mL), followed by dropwise addition of BF3-OEt2 (0.3 mL, 2.5 mmol) at ꢂ 78 ꢁC
for 1 h by TLC monitoring. The reaction was quenched with saturated aqueous sol-
ution of NaHCO3 (10.0 mL), which was extracted with CH2Cl2 (3 ꢃ 50.0 mL). After
the removal of solvent, the crude 14a was directly used no further purification. A
mixture of 14a (0.53 g, 1.3 mmol), AIBN (0.01 g, 63.2 mmol), and Bu3SnH (0.37 g,
1.3 mmol) in dried toluene (35.0 mL) was heated to reflux under N2. The reaction
was monitored by TLC and quenched with addition of cyclohexane (10.0 mL),
which was extracted with CH2Cl2 (3 ꢃ 35.0 mL). After the removal of solvent, the
residue was subjected to flash chromatography (SiO2, hexane–ethyl acetate 5:1) to
obtain the desired 15a (0.22 g, 52%) as an oil.1H NMR d 2.51 (d, J ¼ 15.0 Hz, 1H),
2.66–2.89 (m, 4H), 3.52 (s, 3H), 3.62 (s, 3H), 3.74 (s, 3H), 4.31 (d, J ¼ 10.5 Hz,
1H), 4.61 (d, J ¼ 12.9 Hz, 1H), 6.53 (s, 1H), 7.10–7.20 (m, 3H), 8.31 (d, J ¼ 7.8 Hz,
1H); 13C NMR d 30.2, 35.2, 38.9, 51.6, 52.6, 55.9, 59.9, 111.5, 126.0, 127.0, 127.5,
127.6, 128.3, 128.4, 129.6, 131.7, 136.7, 145.6, 152.0, 155.9.
1,2-Dimethoxy-4,5,6a,7-tetrahydrodibenzo[de,g]
quinoline-6-carboxylic Acid tert-Butyl Ester (15b)[2c]
A mixture of 12b (0.28 g, 1.0 mmol) and 10c (0.39 g, 2.0 mmol) in mixed sol-
vents of CH2Cl2 and CHCl3 (20.0=20.0 mL) was stirred and followed by dropwise
addition of BF3-OEt2 (0.3 mL, 2.5 mmol) at ꢂ 78 ꢁC for 1 h by TLC monitoring.
The reaction was quenched with saturated aqueous solution of NaHCO3
(10.0 mL), which was extracted with CH2Cl2 (3 ꢃ 50.0 mL). After the removal of sol-
vent, the crude 14b was directly used no further purification. A mixture of 14b
(0.46 g, 1.0 mmol), AIBN (0.01 g, 63.2 lmol), and Bu3SnH (0.29 g, 1.0 mmol) in dried
toluene (30.0 mL) was heated to reflux under N2. The reaction was monitored by
TLC and quenched with addition of cyclohexane (10.0 mL), which was extracted
with CH2Cl2 (3 ꢃ 30.0 mL). After the removal of solvent, the residue was subjected
to flash chromatography (SiO2, hexane–ethyl acetate 4:1) to obtain the desired 15b
1
(0.21 g, 56%) as a white solid: mp 184–185 ꢁC, H NMR d 1.41 (s, 9H), :2.56 (d,
J ¼ 14.4 Hz, 1H), 2.70–2.90 (m, 4H), 3.64 (s, 3H), 3.81 (s, 3H), 4.34 (d, J ¼ 9.9 Hz,
1H), 4.58 (d, J ¼ 12.9 Hz, 1H), 6.59 (s, 1H), 7.12–7.25 (m, 3H), 8.35 (d, J ¼ 7.8 Hz,

3462
C.-F. CHANG ET AL.
1H); 13C NMR d 28.5, 30.4, 35.4, 38.4, 51.6, 55.9, 60.0, 79.8, 111.4, 126.5, 126.9,
127.5, 127.6, 128.1, 128.4, 129.8, 131.7, 137.0, 145.5, 151.9, 154.6; HRMS (EI) calcd.
for C23H27NO4 (Mþ) 381.1940; found 381.1943.
4-(6,7-Dimethoxy-2-methyl-1,2,3,4-tetrahydro-isoquinolin-
1-ylmethyl)phenol (1)
BCl3 (1.6 mL, 1 M) was added dropwise to a solution of 13 (0.58 g, 1.6 mmol) in
CH2Cl2 (50.0 mL) at 0 ꢁC. The reaction was stirred at room temperature and mon-
itored by TLC. The resulting reaction was quenched by treatment with saturated
aqueous solution of NaHCO3 (5.0 mL), which was extracted with CH2Cl2
(3 ꢃ 50.0 mL). After the removal of solvent, the residue was subjected to flash chro-
matography (SiO2, hexane–ethyl acetate 7:1) to afford 1 (0.35 g, 69%) as a white
1
solid: mp 155–156 ꢁC (lit.[4b] mp 166 ꢁC); H NMR d :2.54 (s, 3H), 2.59–2.96 (m,
4H), 3.13–3.28 (m, 2H), 3.53 (s, 3H), 3.71 (s, 1H), 3.74 (t, J ¼ 7.5 Hz, 1H), 3.83 (s,
3H), 5.97 (s, 1H), 6.56 (s, 1H), 6.63 (d, J ¼ 8.1 Hz, 2H), 6.90 (d, J ¼ 8.1 Hz, 2H);
13C NMR d 24.3, 40.3, 41.9, 45.8, 55.4, 55.7, 64.8, 111.1, 111.2, 115.5, 124.9,
128.3, 130.4, 130.7, 146.2, 147.3, 155.0; HRMS (FABþH) calcd. for C19H24NO3
[(MþH)þ] 314.1756; found 314.1766.
1,2-Dimethoxy-6-methyl-5,6,6a,7-tetrahydro-4H-
dibenzo[de,g]quinoline (2)
A solution of 15a (0.14 g, 0.4 mmol) in THF (10.0 mL) was treated by dropwise
addition of LiAlH4 (1.6 mL of 1 M in THF, 1.6 mmol) at 0 ꢁC for 1 h. The resulting
reaction was quenched with distilled H2O (5.0 mL) and allowed to warm to room
temperature. When a gelatinous mixture formed, it was diluted with CH2Cl2
(20.0 mL). The mixture was filtered, washing with CH2Cl2 and MeOH. The solvent
was evaporated, and the residue was subjected to flash chromatography (SiO2, hex-
ane–ethyl acetate 1:6) to afford 2 (80 mg, 66%) as a colorless oil (lit.[21] mp
165 ꢁC).1H NMR d :2.38–2.62 (m, 3H), 2.47 (s, 3H), 2.93–3.15 (m, 4H), 3.76 (s,
3H), 3.85 (s, 3H), 6.55 (s, 1H), 7.12–7.25 (m, 3H), 8.29 (d, J ¼ 7.5 Hz, 1H); 13C
NMR d 29.1, 35.0, 43.9, 53.2, 55.8, 60.2, 62.3, 111.2, 126.8, 127.0, 127.3, 127.7,
127.8, 128.3, 128.6, 132.1, 136.4, 145.1, 152.0; HRMS (EI) calcd. for C19H21NO2
(Mþ) 295.1572; found 295.1568.
1,2-Dimethoxy-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline (3)
Compound 15b (0.10 g, 0.3 mmol) was dissolved in MeOH (5.0 mL) and fol-
lowed by dropwise addition of AcCl (30.0 lL, 0.4 mmol) at room temperature.
The reaction was stirred at room temperature and monitored by TLC for 3 h. The
resulting reaction was quenched by treatment with saturated aqueous solution of
NaHCO3 (3.0 mL), which was extracted with CH2Cl2 (3 ꢃ 10.0 mL). After the
removal of solvent, the residue was subjected to flash chromatography (SiO2,
CH2Cl2–ethyl acetate–MeOH 8:4:1) to provide the desired 3 (44 mg, 59%) as a yellow
solid: mp 208–209 ꢁC (lit.[4a] mp 136–137 ꢁC);1H NMR d :2.56–2.79 (m, 3H),
2.89–2.96 (m, 2H), 3.28–3.30 (m, 1H), 3.54 (s, 3H), 3.72–3.78 (m, 1H), 3.76 (s, 3H),

TOTAL SYNTHESIS OF (ꢀ)-NUCIFERINES
3463
6.52 (s, 1H), 7.09–7.19 (m, 3H), 7.13 (s, 1H), 8.26 (d, J ¼ 8.1 Hz, 1H); 13C NMR d
28.6, 37.0, 42.9, 53.4, 55.9, 60.2, 111.7, 126.6, 127.1, 127.4, 127.7, 127.8, 128.3,
128.4, 132.0, 135.7, 145.3, 152.3; HRMS (EI) calcd. for C18H19NO2 (Mþ)
281.1416; found 281.1410.
(4-Isopropoxyphenyl)acetic Acid (17)
i-PrBr (3.3 mL, 35.1 mmol) was added to a mixture of 4-hydroxyacetophenone
(3.31 g, 24.3 mmol) and K2CO3 (4.15 g, 30.1 mmol) in acetone (50.0 mL) at 50 ꢁC and
then refluxed at 70 ꢁC for 8 h by TLC monitoring. After cooling, the solution was
evaporated in vacuo, and the brown residue was subjected to flash chromatography
(SiO2, hexane–CH2Cl2 10:1) to give 16 (4.12 g, 95%) as a colorless oil.1H NMR d :
1.30 (d, J ¼ 6.0 Hz, 6H), 2.48 (s, 3H), 4.58 (hept, J ¼ 6.0 Hz, 1H), 6.84 (d, J ¼ 8.7 Hz,
Hz, 2H), 7.86 (d, J ¼ 8.7 Hz, 2H); 13C NMR :d 21.8, 26.2, 70.0, 115.0, 129.7, 130.6,
162.0, 198.0. A mixture of 16 (3.01 g, 16.9 mmol), sulfur (1.08 g, 33.8 mmol), morph-
oline (4.4 mL, 50.3 mmol), and p-toluenesulfonic acid (97 mg, 0.5 mmol) was refluxed
at 120 ꢁC for 4 h. After completion of the reaction, the mixture was allowed to cool,
and 20% NaOH (20.0 mL) and tetrabutylammonium bromide (27 mg, 85.0 lmol)
were added. Hydrolysis continued for further 8 h at 100 ꢁC. The cooled reaction mix-
ture was filtered and the filtrate was acidified with HCl to pH 2, which was extracted
with ethyl acetate (3 ꢃ 50.0 mL). After the removal of solvent, the residue was sub-
jected to flash chromatography (SiO2, hexane–ethyl acetate 10:1) to afford 17
(2.33 g, 71%) as a white solid: mp 56–57 ꢁC (lit.[22] mp 57–61 ꢁC),1H NMR d :1.32
(d, J ¼ 6.0 Hz, 6H), 3.56 (s, 2H), 4.51 (hept, J ¼ 6.0 Hz, 1H), 6.85 (d, J ¼ 8.7 Hz,
2H), 7.17 (d, J ¼ 8.7 Hz, 2H), 11.98 (brs, 1H); 13C NMR d 22.0, 40.1, 69.9, 115.9,
125.1, 130.4, 157.1, 178.3.
N-[2-(3,4-Dimethoxyphenyl)-ethyl]-2-(4-isopropoxyphenyl)-
acetamide (18)
Oxalyl chloride (0.2 mL, 2.4 mmol) was added to a solution of 17 (0.39 g,
2.0 mmol) in dried CH2Cl2 (15.0 mL) dropwise at room temperature with stirring
for 30 min, followed by evaporation to give the residue, which was directly used with
no further purification. A solution of the crude product in dried CH2Cl2 (20.0 mL)
was cooled to 0 ꢁC, followed by dropwise addition of 11b (0.36 g, 2.0 mmol) in
CH2Cl2 (10.0 mL) for 1 h. The resulting reaction was quenched by treatment with
saturated aqueous solution of NaHCO3 (5.0 mL), which was extracted with CH2Cl2
(3 ꢃ 30.0 mL). After the removal of solvent, the residue was subjected to flash chro-
matography (SiO2, hexane–CH2Cl2–ethyl acetate 5:1:1) to provide the desired 18
(0.59 g, 82%) as a white solid: mp 80–81 ꢁC; 1H NMR [(CD3)2CO] d 1.26 (d,
J ¼ 6.0 Hz, 6H), 2.66 (t, J ¼ 7.2 Hz, 2H), 3.35 (s, 2H), 3.36 (q, J ¼ 7.2 Hz, 2H), 3.73
(s, 3H), 3.80 (s, 3H), 4.55 (hept, J ¼ 6.0 Hz, 1H), 6.62–6.65 (m, 1H), 6.76–6.81 (m,
4H), 7.01 (brs, 1H), 7.13 (d, J ¼ 8.4 Hz, 2H); 13C NMR [(CD3)2CO] :d 21.4, 35.0,
40.7, 42.1, 55.0, 55.2, 69.2, 111.9, 112.6, 115.5, 120.6, 128.1, 130.1, 132.1, 147.9,
149.3, 156.7, 170.3; HRMS (EI) calcd. for C21H27NO4 (Mþ) 357.1940; found
357.1939.

3464
C.-F. CHANG ET AL.
1-(4-Isopropoxybenzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-
isoquinoline (19)
POCl3 (0.1 mL, 1.1 mmol) was added to a solution of 18 (0.26 g, 0.7 mmol) in
dried acetonitrile (10.0 mL) at room temperature, and the resulting solution was
refluxed for 2 h. The reaction was quenched with saturated aqueous solution of
NaHCO3 (3.0 mL), which was extracted with CH2Cl2 (3 ꢃ 10.0 mL). After the
removal of solvent, the crude product was directly used no further purification.
The crude reaction mixture was dissolved in MeOH (10.0 mL) at room temperature
for 5 min. NaBH4 (0.11 g, 2.9 mmol) was added at room temperature, and the sol-
ution was stirred and monitored by TLC for 1 h. The solvent was evaporated and
the residue was subjected to flash chromatography (SiO2, CH2Cl2–ethyl acetate
1:15) to obtain 19 (0.15 g, 60%) as a colorless oil.1H NMR d :1.33 (d, J ¼ 6.0 Hz,
6H), 2.18 (brs, 1H), 2.70–2.95 (m, 4H), 3.11–3.25 (m, 2H), 3.81 (s, 3H), 3.85 (s,
3H), 4.08–4.12 (m, 1H), 4.52 (hept, J ¼ 6.0 Hz, 1H), 6.59 (s, 1H), 6.62 (s, 1H), 6.85
(d, J ¼ 8.4 Hz, 2H), 7.14 (d, J ¼ 8.4 Hz, 2H); 13C NMR d 22.1, 29.4, 40.6, 41.7,
55.8, 55.9, 56.8, 69.8, 109.4, 111.7, 116.0, 127.2, 130.3, 130.4, 130.7, 146.9, 147.3,
156.5.
Compound 13 from 19
To a solution of 19 (0.14 g, 0.4 mmol) in MeOH (5.0 mL), 37% aqueous
solution of formaldehyde (0.06 mL, 0.8 mmol) was added at room temperature with
stirring for 1 h. NaBH4 (23 mg, 0.6 mmol) was added at room temperature, and the
solution was stirred and monitored by TLC for 1 h. The solvent was evaporated and
the residue was subjected to flash chromatography (SiO2, CH2Cl2–ethyl acetate 1:7)
to obtain 13 (0.12 g, 83%) as a yellow oil.
ACKNOWLEDGMENTS
We thank the National Science Council (NSC) of the Republic of China
for financial support (Research Grant NSC 96–2113-M-018–001-MY2). We also
acknowledge with appreciation the NSC-supported HRMS spectrometry facility
for providing HRMS.
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