Novel total syntheses of oxoaporphine alkaloids enabled by mild Cu-catalyzed tandem oxidation/aromatization of 1-Bn-DHIQs

Article abstract of DOI:10.1039/c8ra05338c

Novel total syntheses of oxoaporphine alkaloids such as liriodenine, dicentrinone, cassameridine, lysicamine, oxoglaucine and O-methylmoschatoline were developed. The key step of these total syntheses is Cu-catalyzed conversion of 1-benzyl-3,4-dihydro-isoquinolines (1-Bn-DHIQs) to 1-benzoyl-isoquinolines (1-Bz-IQs) via tandem oxidation/aromatization. This novel Cu-catalyzed conversion has been studied in detail, and was successfully used for constructing the 1-Bz-IQ core.

Full text of DOI:10.1039/c8ra05338c

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Novel total syntheses of oxoaporphine alkaloids
enabled by mild Cu-catalyzed tandem oxidation/
aromatization of 1-Bn-DHIQs†
Cite this: RSC Adv., 2018, 8, 28997
Bo Zheng, Hui-Ya Qu, Tian-Zhuo Meng, Xia Lu, Jie Zheng, Yun-Gang He, Qi-Qi Fan
*
and Xiao-Xin Shi
Novel total syntheses of oxoaporphine alkaloids such as liriodenine, dicentrinone, cassameridine,
lysicamine, oxoglaucine and O-methylmoschatoline were developed. The key step of these total
syntheses is Cu-catalyzed conversion of 1-benzyl-3,4-dihydro-isoquinolines (1-Bn-DHIQs) to 1-benzoyl-
isoquinolines (1-Bz-IQs) via tandem oxidation/aromatization. This novel Cu-catalyzed conversion has
been studied in detail, and was successfully used for constructing the 1-Bz-IQ core.
Received 21st June 2018
Accepted 6th August 2018
DOI: 10.1039/c8ra05338c
rsc.li/rsc-advances
Results and discussion
Introduction
According to the above general retrosynthetic analysis, novel
total syntheses of the six targeted oxoaporphine alkaloids 1a–f
are depicted in Scheme 2. As can be seen from the Scheme 2,
EDA (ethylenediamine)-catalyzed condensation of aryl alde-
hydes with nitromethane13 rst produced nitroalkenes 2a–c in
high yields. Next, when compounds 2a–c were treated with 6.0
equiv. of LiAlH4 in tetrahydrofuran at reux, simultaneous
reduction of both nitro group and double bond occurred in
one-pot to furnish 2-aryl ethanamines 3a–c, which then
immediately exposed to 1.1 equiv. of 2-arylacetyl chlorides and
3.0 equiv. of K2CO3 at 0 ꢀC in a mixed solvent of dichloro-
methane and water (3 : 1) to afford amides 4a–f. Subsequently,
treatment of compounds 4a–f with 3.0 equiv. of POCl3 in
anhydrous acetonitrile at reux gave 1-Bn-DHIQs 5a–f via
Bischler–Napieralski cyclization.14 It was observed that
compounds 5a–f and compounds 50a–f were interchangeable
Oxoaporphines, which have a characteristic carbonyl junction
between aromatic B and D rings (see Fig. 1), are a sub-class of
aporphinoid alkaloids.1 Oxoaporphine alkaloids are widespread
in the kingdom of plants.1,2 For example, liriodenine 1a,3
dicentrinone 1b,4 cassameridine 1c,5 lysicamine 1d,6 oxoglau-
cine 1e7 and O-methylmoschatoline 1f8 (also referred to as lir-
idine9 and homomoschatoline10) have been isolated from
various botanic natural resources.3–10 Since oxoaporphine alka-
loids 1a–f have shown a broad spectrum of interesting biolog-
ical activities,11 so the total syntheses of them have aroused
much interest from chemists.12 However, efficient, benign and
practical total syntheses of these alkaloids remained highly
desirable. Therefore, we herein report novel total syntheses
of oxoaporphine alkaloids 1a–f via a key Cu-catalyzed conver-
sion of 1-benzyl-3,4-dihydro-isoquinolines (1-Bn-DHIQs) to
1-benzoyl-isoquinolines (1-Bz-IQs).
A general retrosynthetic analysis of the above several oxoa-
porphine alkaloids 1a–f is depicted in Scheme 1. As can be seen
from the Scheme 1, C-ring could be constructed via Pschorr
cyclization of anilines A, which could be obtained from the
reduction of nitro groups of compounds B. The 1-Bz-IQ core of
compounds B could be constructed via Cu-catalyzed tandem
oxidation/aromatization of 1-Bn-DHIQs C. B-ring of compounds
C could be constructed via Bischler–Napieralski cyclization of
amides D, which could be derived from amines E and acyl
chlorides F. Amines E could be prepared from aryl aldehydes G.
Shanghai Key Laboratory of Chemical Biology and Department of Pharmaceutical
Engineering, School of Pharmacy, East China University of Science and Technology,
130 Mei-Long Road, Shanghai 200237, P. R. China. E-mail: xxshi@ecust.edu.cn
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c8ra05338c
Fig. 1 The targeted oxoaporphine alkaloids 1a–f.
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Scheme 1 A novel general retrosynthetic analysis of oxoaporphine alkaloids 1a–f.
at room temperature, we failed to separate them by chroma- N2 atmosphere in aqueous ethanol (EtOH/H2O ¼ 9 : 1),
tography due to rapid tautomerization between imines (5a–f) reduction of nitro groups took place smoothly to produce
and enamines (50a–f), so they were used as such for the next anilines 7a–f in high yields. Finally, compounds 7a–f were rst
ꢀ
step without separation; when the tautomeric mixture of 5a–f treated with 1.0 equiv. of NaNO2 at 0–8 C to produce diazo-
and 50a–f were treated with 0.1 equiv. (10 mol%) of anhydrous nium intermediates, which were then immediately treated
CuBr2 and 1.0 equiv. of 1,8-diazabicyclo[5.4.0]undec-7-ene with 10 equiv. of copper powder at 60 ꢀC in an aqueous H2SO4
(DBU) in dimethyl sulfoxide (DMSO) at 35 C under an open (10% w/w) solution, Pschorr cyclization16 happened rapidly to
ꢀ
air (O2) atmosphere, Cu-catalyzed tandem benzylic oxidation afford oxoaporphines 1a–f in good yields. Thus, the targeted
and aromatization occurred smoothly in one-pot to afford 1- oxoaporphine alkaloids liriodenine 1a, dicentrinone 1b, cas-
Bz-IQs 6a–f in good yields over two steps (from 4a–f). Nitro sameridine 1c, lysicamine 1d, oxoglaucine 1e and O-methyl-
(NO2) groups of compounds 6a–f could be rapidly reduced by moschatoline 1f were synthesized from aryl aldehydes via 7
acid-activated iron;15 when compounds 6a–f were treated with steps in 39%, 26%, 29%, 38%, 31% and 41% overall yields,
10 equiv. of iron powder and 30 equiv. of HOAc at 70 ꢀC under respectively.
Scheme 2 Total syntheses of the targeted oxoaporphine alkaloids 1a–f starting from aryl aldehydes.
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In the above-described total syntheses of oxoaporphine as the catalyst, and air (O2) was used as the clean oxidant. So
alkaloids 1a–f, the key step is Cu-catalyzed conversion of 1-Bn- this Cu-catalyzed method might be much more benign, eco-
THIQs 5a–f to 1-Bz-IQs 6a–f. This key conversion can be ach- friendly and practical than the previous known methods.17–21
ieved by some known methods.17–21 However, these known Advantages such as mildness (at 35 ꢀC), high efficiency and eco-
methods oen suffered from drawbacks such as use of friendliness prompted us to investigate the details of this
poisonous and hazardous strong oxidants including SeO2,17 potential green chemical method.
Pb(OAc)4,18 and CAN,19 inconvenient use of the photoactivated
singlet O2,20 or need of high reaction temperature21 (120 ꢀC). more variously substituted 1-Bn-DHIQs 5 were prepared via
Therefore, development of an efficient and benign method for Bischler–Napieralski cyclization, and total of twenty
this particular conversion might be very helpful for total substrates 5a–t have been tested for the CuBr2-catalyzed aerobic
syntheses of oxoaporphine alkaloids. oxidation under the standard reaction conditions (see footnote
In order to know the scope and limitation of the method,
a
Copper is a cheap transition metal with low toxicity; and air of Table 1); the results are summarized in Table 1 (20 examples).
(O2) is an eco-friendly clean oxidant. Hence, an increasing As can be seen from the Table 1, the scope of the reaction is
amount of copper-catalyzed aerobic oxidations of various wide, it could be applicable to all the tested substrates, and
compounds have been recently developed.22 For the above afforded the desired 1-Bz-IQs 6a–t in good to high yields. We
conversion of 1-Bn-THIQs 5a–f to 1-Bz-IQs 6a–f, CuBr2 was used have found that 1-benzyl-3,4-dihydro-b-carbolines could
Table 1 CuBr2-catalyzed conversion of variously substituted 1-Bn-DHIQs 5 to 1-Bz-IQs 6a
a
Standard reaction conditions: 1-Bn-DHIQs 5 (2 mmol), CuBr2 (0.2 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (2 mmol), DMSO (6 mL), 35 ꢀC
(inner temperature), air (O2). Reaction time. c Isolated yields.
b
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In addition, a novel practical Cu-catalyzed conversion of
1-Bn-DHIQs 5 to 1-Bz-IQs 6, which was used as the key step in
the above total syntheses, has also been investigated in detail;
this Cu-catalyzed method has some advantages such as mild-
ness, eco-friendliness, wide scope, ease of experimental proce-
dure and high yields. It would provide a new general basic
approach towards the total syntheses of oxoaporphine alkaloids
and their derivatives.
Experimental
General
1H NMR and 13C NMR spectra were acquired on a Bruker AM
400 instrument, chemical shis are given on the d scale as parts
per million (ppm) with tetramethylsilane (TMS) as the internal
standard. IR spectra were recorded on a Nicolet Magna IR-550
instrument. Mass spectra were performed with a HP1100 LC-
MS spectrometer. Melting points were measured on a Mei-
TEMP II melting point apparatus. Column chromatography
was performed on silica gel (Qingdao Chemical Factory). All
reagents and solvents were analytically pure, and were used as
such as received from the chemical suppliers.
Scheme 3 A possible mechanism for the CuBr2-catalyzed conversion
of 1-Bn-DHIQs 5 to 1-Bz-IQs 6.
undergo aerobic oxidation in DMSO to afford 1-benzoyl-b-car-
bolines without a copper catalyst,23 but herein we found that
a copper catalyst is necessary for this one-pot aerobic oxidation,
it was sluggish in the absence of copper catalyst. Several copper
salts have been tested as the catalyst, CuBr2 obviously worked
better than CuCl2, Cu(OAc)2, CuSO4, Cu2(OH)2CO3, CuO and
CuI. Moreover, a base is also necessary for the reaction, DBU
worked obviously better than Et3N, diisopropylethylamine,
pyridine, N,N-dimethylaminopyridine (DMAP), 1,5-diazabicyclo
[4,3,0]non-5-ene (DBN), Na2CO3 and K2CO3; DMSO as the
solvent is better than DMF, CH3CN, THF, EtOH, Me2CO, CH2Cl2
and 1,4-dioxane.
A possible mechanism for the CuBr2-catalyzed conversion of
1-Bn-DHIQs 5 to 1-Bz-IQs 6 was proposed in Scheme 3. 1-Bn-
DHIQs 5 would rst react with CuBr2 and a base (B ¼ DBU,
etc.) to form enamine-CuBr complexes 50-CuBr, which would
then undergo Jenkins-like aerobic oxidation24 to produce
peroxide-CuBr complexes I-A. The intermediate Cu-complexes
I-A would be unstable enough to decompose immediately to
furnish 1-Bz-DHIQs 8. Compounds 8 would nally undergo
DBU-promoted oxidation by O2 to produce 1-Bz-IQs 6 according
to Kumar's reports.25 The intermediate compounds 8 could be
detected by TLC during the reaction, and could also be isolated
if the reaction was stopped at a middle point. For example,
when CuBr2-catalyzed conversion of compound 5a to
compound 6a was stopped at 3 h, the intermediate compound
8a was isolated in 38% yield.
Preparation of nitroalkenes 2a–c
An aryl aldehyde (ꢁ40 mmol) was dissolved in nitromethane
(30 mL), and then ethylenediamine (0.025 g, 0.416 mmol) was
added. The resulting solution was then heated and stirred at
reux for 5 h. Aer the reaction was complete (checked by TLC,
eluent: CH2Cl2/hexane ¼ 3 : 2), the solution was concentrated
under vacuum to give crude product as yellow solid, which was
triturated in aqueous methanol (MeOH/H2O ¼ 9 : 1), and was
then ltered by suction. Compounds 2a–c were thus obtained in
89%, 90% and 91% yields, respectively. Characterization data of
compounds 2a–c are as follows:
(E)-5-(2-Nitrovinyl)benzo[d][1,3]dioxole (2a). Yellow crystals,
mp 158–159 ꢀC. 1H NMR (400 MHz, CDCl3) d 7.93 (d, J ¼
13.5 Hz, 1H), 7.48 (d, J ¼ 13.5 Hz, 1H), 7.09 (d, J ¼ 7.8 Hz, 1H),
7.00 (s, 1H), 6.88 (d, J ¼ 7.8 Hz, 1H), 6.07 (s, 2H); 13C NMR (100
MHz, CDCl3) d 151.39, 148.77, 139.13, 135.37, 126.69, 124.18,
109.08, 106.98, 102.10.
(E)-1,2-Dimethoxy-4-(2-nitrovinyl)benzene (2b). Pale yellow
crystals, mp 141–142 ꢀC. 1H NMR (400 MHz, CDCl3) d 7.97 (d, J
¼ 13.6 Hz, 1H), 7.56 (d, J ¼ 13.6 Hz, 1H), 7.19 (d, J ¼ 8.2 Hz, 1H),
7.02 (s, 1H), 6.92 (d, J ¼ 8.2 Hz, 1H), 3.95 (s, 3H), 3.93 (s, 3H); 13
C
NMR (100 MHz, CDCl3) d 152.78, 149.51, 139.39, 135.13, 124.71,
122.78, 111.30, 110.18, 56.10, 56.02.
(E)-1,2,3-Trimethoxy-4-(2-nitrovinyl)benzene (2c). Pale yellow
crystals, mp 192–193 ꢀC. 1H NMR (400 MHz, CDCl3) d 8.09 (d, J
¼ 13.6 Hz, 1H), 7.77 (d, J ¼ 13.6 Hz, 1H), 7.21 (d, J ¼ 8.8 Hz, 1H),
Conclusions
6.73 (d, J ¼ 8.8 Hz, 1H), 4.00 (s, 3H), 3.93 (s, 3H), 3.88 (s, 3H); 13
C
In conclusion, novel total syntheses of oxoaporphine alkaloids
including liriodenine 1a, dicentrinone 1b, cassameridine 1c,
lysicamine 1d, oxoglaucine 1e and O-methyl-moschatoline 1e
were achieved via a benign and ecofriendly Cu-catalyzed general
approach. They were synthesized from the cheap and
NMR (100 MHz, CDCl3) d 157.36, 154.27, 142.39, 136.52, 135.37,
126.65, 117.02, 107.68, 61.19, 60.94, 56.20.
Preparation of 2-aryl ethanamines 3a–c
commercially available aryl aldehydes via seven steps in 39%, A solution of compound 2 (ꢁ18 mmol) in THF (40 mL) was
26%, 29%, 38%, 31% and 41% overall yields, respectively.
dropwise added into a stirred suspension of LiAlH4 (4.102 g,
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108.1 mmol) in THF (100 mL) at 0 ꢀC over 20 min. Aer the were thus obtained in 85%, 62%, 63%, 83%, 71% and 84%
addition was nished, the mixture was then heated and stirred yields, respectively. Characterization data of compounds 4a–f
at reux for 7–9 h. The mixture was cooled to 0 ꢀC by an ice-bath. are as follows:
While the mixture was vigorously stirred, water (5 mL) was
N-(2-(Benzo[d][1,3]dioxol-5-yl)ethyl)-2-(2-nitrophenyl)aceta-
1
ꢀ
dropwise added into the reaction mixture over 30 min, and an mide (4a). White crystals, mp 125–126 C. H NMR (400 MHz,
aqueous solution of NaOH (28 mL, 15% w/w) was then slowly CDCl3) d 8.03 (d, J ¼ 8.2 Hz, 1H), 7.60 (dd, J1 ¼ 8.0 Hz, J2 ¼
added into the mixture at 0 ꢀC. The ice-bath was removed, and 7.8 Hz, 1H), 7.48–7.42 (m, 2H), 6.69 (d, J ¼ 7.9 Hz, 1H), 6.60 (s,
the mixture was further stirred at room temperature for 3 h. The 1H), 6.55 (d, J ¼ 7.9 Hz, 1H), 5.92 (s, 2H), 5.84 (br. s, 1H, CONH),
mixture was ltered through a thin layer of celite, and the lter 3.79 (s, 2H), 3.49–3.42 (m, 2H), 2.69 (t, J ¼ 6.8 Hz, 2H); 13C NMR
cake was washed twice with THF (2 ꢂ 30 mL). The ltrates were (100 MHz, CDCl3) d 168.93, 148.80, 147.72, 146.11, 133.57,
combined and dried over anhydrous MgSO4. The solution was 133.33, 132.44, 130.41, 128.37, 125.12, 121.61, 109.03, 108.30,
concentrated under vacuum to give crude product as yellow oil, 100.87, 41.06, 40.89, 35.24; IR (KBr lm) 3280, 3070, 2921, 1640,
which was puried by formation of hydrochloride ammonium 1552, 1521, 1492, 1350, 1247, 1192, 1034, 923, 809, 790,
salt. Pure 2-aryl ethanamines 3a–c were obtained aer neutral- 715 cmꢃ1
.
ization in 87%, 76% and 82% yields, respectively. Character-
ization data of compounds 3a–c are as follows:
N-(2-(Benzo[d][1,3]dioxol-5-yl)ethyl)-2-(4,5-dimethoxy-2-
nitrophenyl)acetamide (4b). White crystals, mp 206–207 ꢀC. 1H
2-(Benzo[d][1,3]dioxol-5-yl)ethanamine (3a). 1H NMR (400 NMR (400 MHz, DMSO-d6) d 7.97 (t, J ¼ 5.8 Hz, 1H, CONH), 7.64
MHz, CDCl3) d 6.74 (d, J ¼ 7.8 Hz, 1H), 6.69 (s, 1H), 6.64 (d, J ¼ (s, 1H), 7.05 (s, 1H), 6.81 (d, J ¼ 7.9 Hz, 1H), 6.79 (s, 1H), 6.65 (d,
7.8 Hz, 1H), 5.92 (s, 2H), 2.91 (t, J ¼ 6.9 Hz, 2H), 2.67 (t, J ¼ J ¼ 7.9 Hz, 1H), 5.96 (s, 2H), 3.87 (s, 3H), 3.85 (s, 3H), 3.82 (s,
6.9 Hz, 2H), 1.56 (br. s, 3H, NH2); 13C NMR (100 MHz, CDCl3) 2H), 3.25–3.17 (m, 2H), 2.61 (t, J ¼ 7.2 Hz, 2H); 13C NMR (100
d 147.57, 145.80, 133.46, 121.55, 109.02, 108.09, 100.71, 43.49, MHz, DMSO-d6) d 168.62, 152.57, 147.16, 147.10, 145.42, 140.92,
39.49.
133.25, 126.01, 121.43, 115.36, 108.98, 108.02, 107.94, 100.58,
2-(3,4-Dimethoxyphenyl)ethanamine (3b). 1H NMR (400 56.10, 55.90, 40.78, 40.00, 34.84; IR (KBr lm) 3270, 3092, 2933,
MHz, CDCl3) d 6.79 (d, J ¼ 7.9 Hz, 1H), 6.76 (d, J ¼ 7.9 Hz, 1H), 1641, 1580, 1525, 1502, 1420, 1330, 1274, 1239, 1186, 1063,
6.73 (s, 1H), 3.87 (s, 3H), 3.85 (s, 3H), 2.93 (t, J ¼ 6.9 Hz, 2H), 2.68 1034, 923, 875, 804, 748 cmꢃ1
.
(t, J ¼ 6.9 Hz, 2H), 1.43 (br. s, 2H, NH2); 13C NMR (100 MHz,
N-(2-(Benzo[d][1,3]dioxol-5-yl)ethyl)-2-(6-nitrobenzo[d][1,3]
1
CDCl3) d 148.81, 147.34, 132.35, 120.65, 111.96, 111.22, 55.83, dioxol-5-yl)acetamide (4c). White crystals, mp 208–209 ꢀC. H
55.73, 43.58, 39.51.
NMR (400 MHz, DMSO-d6) d 8.02 (t, J ¼ 5.7 Hz, 1H, CONH), 7.63
2-(2,3,4-Trimethoxyphenyl)ethanamine (3c). 1H NMR (400 (s, 1H), 7.01 (s, 1H), 6.82 (d, J ¼ 7.9 Hz, 1H), 6.79 (s, 1H), 6.65 (d,
MHz, CDCl3) d 6.84 (d, J ¼ 8.5 Hz, 1H), 6.62 (d, J ¼ 8.5 Hz, 1H), J ¼ 7.9 Hz, 1H), 6.22 (s, 2H), 5.96 (s, 2H), 3.76 (s, 2H), 3.26–3.18
3.88 (s, 3H), 3.87 (s, 3H), 3.84 (s, 3H), 2.91 (t, J ¼ 7.0 Hz, 2H), 2.71 (m, 2H), 2.61 (t, J ¼ 7.2 Hz, 2H);13C NMR (100 MHz, DMSO-d6)
(t, J ¼ 7.0 Hz, 2H), 2.32 (br. s, 2H, NH2); 13C NMR (100 MHz, d 168.40, 151.26, 147.11, 146.53, 145.43, 142.63, 133.20, 128.10,
CDCl3) d 152.31, 152.08, 142.29, 125.46, 124.35, 107.16, 60.92, 121.45, 111.87, 108.99, 108.03, 105.08, 103.20, 100.58, 40.61,
60.69, 55.97, 42.81, 33.84.
39.95, 34.82; IR (KBr lm) 3280, 3064, 2920, 1637, 1548, 1524,
1504, 1480, 1442, 1378, 1328, 1249, 1192, 1032, 924, 877, 816,
722 cmꢃ1
.
Preparation of amides 4a–f
N-(3,4-Dimethoxyphenethyl)-2-(2-nitrophenyl)acetamide
2-Aryl acetic acid (ꢁ11 mmol) was dissolved in CH2Cl2 (20 mL), (4d). White crystals, mp 129–130 ꢀC. 1H NMR (400 MHz, CDCl3)
and SOCl2 (1.790 g, 15.05 mmol) was added. The resulting d 8.01 (d, J ¼ 8.2 Hz, 1H), 7.58 (dd, J1 ¼ 8.0 Hz, J2 ¼ 8.2 Hz, 1H),
solution was then heated and stirred at reux for 4 h. The 7.46–7.40 (m, 2H), 6.75 (d, J ¼ 8.1 Hz, 1H), 6.69 (s, 1H), 6.67 (d, J
reaction solution was concentrated under vacuum to dryness, ¼ 8.1 Hz, 1H), 3.85 (s, 3H), 3.84 (s, 3H), 3.78 (s, 2H), 3.52–3.45
oily residue was then dissolved in dry CH2Cl2 (10 mL), the (m, 2H), 2.73 (t, J ¼ 7.0 Hz, 2H); 13C NMR (100 MHz, CDCl3)
solution was immediately used bellow. 2-Aryl ethanamine 3 d 168.88, 148.98, 148.76, 147.62, 133.58, 133.37, 131.20, 130.38,
(10 mmol) was dissolved in 40 mL CH2Cl2, and an aqueous 128.39, 125.12, 120.60, 111.90, 111.32, 55.92, 55.84, 40.94,
solution of K2CO3 (4.150 g, 30.03 mmol) in water (30 mL) was 40.85, 35.10; IR (KBr lm) 3424, 3065, 2944, 2839, 1651, 1602,
added. The biphasic mixture was cooled by an ice-bath, and was 1479, 1280, 1256, 1163, 1125, 1028, 935, 823, 718 cmꢃ1; HRMS
stirred at 0 to 5 ꢀC. The above freshly prepared solution of 2-aryl (ESI) m/z calcd for C18H21N2O5 [M + H]+: 345.1450, found:
acetyl chloride was added dropwise into the reaction mixture 345.1451.
over 2 min. Aer the addition was nished, stirring was
N-(3,4-Dimethoxyphenethyl)-2-(4,5-dimethoxy-2-nitrophenyl)-
continued at 0 to 5 ꢀC for 2 h. When the reaction was complete acetamide (4e). White crystals, mp 131–132 ꢀC. 1H NMR (400
(checked by TLC, eluent: EtOAc/hexane ¼ 1 : 3), the reaction MHz, CDCl3) d 7.60 (s, 1H), 6.83 (s, 1H), 6.74 (d, J ¼ 8.1 Hz, 1H),
mixture was transferred into a separatory funnel. Two phases 6.67 (s, 1H), 6.65 (d, J ¼ 8.1 Hz, 1H), 5.96 (br. s, 1H, CONH), 3.96
were separated, and the aqueous phase was extracted again with (s, 3H), 3.94 (s, 3H), 3.85 (s, 3H), 3.84 (s, 3H), 3.77 (s, 2H), 3.53–
CH2Cl2 (20 mL). The organic extracts were combined, dried over 3.44 (m, 2H), 2.73 (t, J ¼ 6.8 Hz, 2H); 13C NMR (100 MHz, CDCl3)
anhydrous MgSO4, and then concentrated under vacuum to give d 168.90, 153.35, 148.96, 148.07, 147.59, 140.80, 131.14, 125.48,
crude product as pale yellow solid, which was puried by ash 120.56, 114.44, 111.88, 111.23, 108.15, 56.57, 56.35, 55.87, 55.82,
chromatography (eluent: EtOAc/hexane ¼ 1 : 4). Amides 4a–f 41.39, 40.90, 35.09; IR (KBr lm) 3467, 3072, 2945, 2832, 1653,
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1600, 1475, 1282, 1251, 1168, 1125, 1018, 925, 827, 724 cmꢃ1
;
7.8 Hz, 1H), 7.92–7.84 (m, 2H), 7.40 (s, 1H), 6.40 (s, 2H); 13C NMR
HRMS (ESI) m/z calcd for C20H25N2O7 [M + H]+: 405.1662, found: (100 MHz, CDCl3-TFA) d 186.14, 156.93, 154.17, 146.24, 142.08,
405.1665.
141.68, 135.87, 134.04, 131.80, 131.08, 130.20, 126.47, 125.39,
N-(2,3,4-Trimethoxyphenethyl)-2-(2-nitrophenyl)acetamide 124.52, 104.36, 103.78, 103.16; IR (KBr, lm) 3077, 2917, 1684,
(4f). White crystals, mp 106–107 ꢀC. 1H NMR (400 MHz, CDCl3) 1576, 1518, 1460, 1348, 1275, 1214, 1036, 1017, 946, 867, 788,
d 8.02 (d, J ¼ 7.8 Hz, 1H), 7.57 (d, J ¼ 7.2 Hz, 1H), 7.48–7.41 (m, 706 cmꢃ1; HRMS (ESI) m/z calcd for C17H11N2O5 [M + H]+:
2H), 6.78 (d, J ¼ 8.2 Hz, 1H), 6.58 (d, J ¼ 8.2 Hz, 1H), 6.21 (br. s, 323.0668, found: 323.0665.
1H, CONH), 3.85 (s, 3H), 3.845 (s, 3H), 3.843 (s, 3H), 3.80 (s, 2H),
(4,5-Dimethoxy-2-nitro-phenyl)([1,3]dioxolo[4,5-g]isoquino-
3.47–3.41 (m, 2H), 2.73 (t, J ¼ 6.8 Hz, 2H); 13C NMR (100 MHz, lin-5-yl)methanone (6b). Pale yellow crystals, mp 258–259 ꢀC. 1H
CDCl3) d 168.94, 152.58, 151.80, 148.89, 142.19, 133.49, 133.42, NMR (400 MHz, CDCl3-TFA) d 8.37 (s, 1H), 8.16 (d, J ¼ 6.3 Hz,
130.53, 128.28, 125.06, 124.74, 124.51, 107.43, 60.98, 60.74, 1H), 8.06 (d, J ¼ 6.3 Hz, 1H), 7.70 (s, 1H), 7.38 (s, 1H), 7.27 (s,
56.00, 40.95, 40.94, 29.63; IR (KBr, lm) 3420, 3293, 2958, 2939, 1H), 6.40 (s, 2H), 4.07 (s, 3H), 4.05 (s, 3H); 13C NMR (100 MHz,
1644, 1548, 1524, 1495, 1467, 1417, 1349, 1240, 1101, 933, 792, CDCl3-TFA) d 187.14, 155.78, 154.82, 153.24, 152.19, 144.56,
716 cmꢃ1; HRMS (ESI) m/z calcd for C19H23N2O6 [M + H]+: 140.54, 139.96, 131.12, 126.75, 125.71, 124.55, 112.93, 107.34,
375.1556, found: 375.1537.
103.84, 103.81, 103.35, 56.88, 56.73; IR (KBr, lm) 3096, 2916,
1682, 1579, 1520, 1500, 1463, 1397, 1326, 1282, 1261, 1228,
1210, 1077, 1034, 942, 863, 778, 758 cmꢃ1; HRMS (ESI) m/z calcd
for C19H15N2O7 [M + H]+: 383.0879, found: 383.0881.
Preparation of 1-benzyl-3,4-dihydroisoquinolines 5
A corresponding amide 4 (ꢁ5 mmol) was dissolved in anhy-
drous acetonitrile (40 mL), and phosphorus oxychloride
(2.350 g, 15.33 mmol) was slowly added into the mixture. The
resulting solution was then heated and stirred at reux for 2 h.
Aer the reaction was complete (checked by TLC, eluent:
CH2Cl2/hexane ¼ 2 : 1), the solution was concentrated under
vacuum to dryness, the residue was dissolved in CH2Cl2
(50 mL). An aqueous solution of K2CO3 (20 mL, 15% w/w) was
added. Aer the mixture was vigorously stirred for 5 min, two
phases were separated, and the aqueous phase was extracted
again with CH2Cl2 (20 mL). The organic extracts were combined,
dried over anhydrous MgSO4, and then concentrated under
vacuum to give crude solid product as a tautomeric mixture of
1-benzyl-3,4-dihydroisoquinoline 5 and enamine 50, which was
used as such for the next step.
([1,3]Dioxolo[4,5-g]isoquinolin-5-yl)(6-nitrobenzo[d][1,3]
dioxol-5-yl)methanone (6c). Pale yellow crystals, mp 229–230 ꢀC.
1H NMR (400 MHz, CDCl3-TFA) d 8.38 (s, 1H), 8.21 (d, J ¼ 6.3 Hz,
1H), 8.07 (d, J ¼ 6.3 Hz, 1H), 7.64 (s, 1H), 7.38 (s, 1H), 7.16 (s,
1H), 6.39 (s, 2H), 6.30 (s, 2H); 13C NMR (100 MHz, CDCl3-TFA)
d 185.29, 156.70, 154.12, 153.93, 151.96, 142.54, 141.76, 141.62,
130.04, 128.24, 126.18, 124.54, 109.97, 105.43, 104.87, 104.22,
103.62, 103.61; IR (KBr, lm) 3065, 2917, 1677, 1609, 1577, 1519,
1500, 1464, 1424, 1398, 1326, 1273, 1237, 1203, 1031, 988, 920,
871, 764 cmꢃ1; HRMS (ESI) m/z calcd for C18H11N2O7 [M + H]+:
367.0566, found: 367.0565.
(6,7-Dimethoxyisoquinolin-1-yl)(2-nitrophenyl)methanone
1
ꢀ
(6d). Pale yellow crystals, mp 195–196 C. H NMR (400 MHz,
CDCl3) d 8.75 (s, 1H), 8.24 (d, J ¼ 5.6 Hz, 1H), 8.15 (d, J ¼ 5.6 Hz,
1H), 7.80 (dd, J1 ¼ 8.0 Hz, J2 ¼ 7.7 Hz, 1H), 7.73–7.58 (m, 3H),
7.10 (s, 1H), 4.14 (s, 3H), 4.05 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 195.63, 153.08, 152.47, 148.35, 147.59, 140.15, 137.94, 134.54,
134.02, 130.29, 129.66, 123.67, 123.66, 123.55, 104.74, 104.53,
General procedure for the CuBr2-catalyzed conversion of 1-
benzyl-3,4-dihydroisoquinolines 5 to 1-benzoyl-isoquinolines 6
The above tautomeric mixture of 1-benzyl-3,4-dihydro- 56.26, 56.07; IR (KBr lm) 2945, 2835, 1650, 1600, 1477, 1329,
isoquinoline 5 and enamine 50 were dissolved in DMSO 1282, 1255, 1168, 1125, 1020, 915, 809 cmꢃ1; HRMS (ESI) m/z
(10 mL), DBU (0.755 g, 4.959 mmol) and CuBr2 (0.113 g, calcd for C18H15N2O5 [M + H]+: 339.0981, found: 339.0985.
0.506 mmol) were added. The resulting solution was then stir-
(6,7-Dimethoxyisoquinolin-1-yl)(4,5-dimethoxy-2-nitrophenyl)-
1
ꢀ
red at 35 ꢀC for 6–10 h (see Table 1) under an atmosphere of air. methanone (6e). Pale yellow crystals, mp 212–213 C. H NMR
Aer the reaction was complete (checked by TLC, eluent: EtOAc/ (400 MHz, CDCl3) d 8.65 (s, 1H), 8.24 (d, J ¼ 5.4 Hz, 1H), 7.65 (s,
hexane ¼ 1 : 4), a dilute ammonia aqueous solution (5% w/w, 50 1H), 7.61 (d, J ¼ 5.4 Hz, 1H), 7.12 (s, 1H), 7.09 (s, 1H), 4.13 (s, 3H),
mL) and CH2Cl2 (40 mL) were added into the mixture. Two 4.04 (s, 3H), 4.02 (s, 3H), 4.01 (S, 3H); 13C NMR (100 MHz, CDCl3)
phases were separated, and the aqueous phase was twice d 195.33, 153.69, 153.06, 152.30, 149.68, 149.06, 140.57, 140.01,
extracted again with CH2Cl2 (2 ꢂ 30 mL). The organic extracts 134.44, 132.05, 123.54, 111.05, 106.46, 104.72, 104.71, 104.61,
were combined, and dried over anhydrous MgSO4. Removal of 56.64, 56.57, 56.22, 56.07; IR (KBr lm) 2981, 2845, 1652, 1603,
solvent by vacuum distillation gave crude product as pale yellow 1473, 1328, 1282, 1255, 1166, 1123, 1021, 934, 865, 812 cmꢃ1
;
solid, which was puried by ash chromatography (eluent: HRMS (ESI) m/z calcd for C20H19N2O7 [M + H]+: 399.1192, found:
EtOAc/CH2Cl2 ¼ 1 : 10) to afford pure 1-benzoyl-isoquinoline 6 399.1190.
as crystals in a yield (over two steps) as indicated in Table 1.
(2-Nitrophenyl)(5,6,7-trimethoxyisoquinolin-1-yl)methanone
1
Characterization data of 1-benzoyl-isoquinolines 6a–t are as (6f). Pale yellow crystals, mp 113–114 ꢀC. H NMR (400 MHz,
follows:
CDCl3) d 8.56 (s, 1H), 8.26 (d, J ¼ 5.2 Hz, 1H), 8.15 (d, J ¼ 8.0 Hz,
([1,3]Dioxolo[4,5-g]isoquinolin-5-yl)(2-nitrophenyl)metha-none 1H), 8.00 (d, J ¼ 5.2 Hz, 1H), 7.80 (dd, J1 ¼ 8.0 Hz, J2 ¼ 7.7 Hz,
(6a). Pale yellow crystals, mp 244–245 ꢀC. 1H NMR (400 MHz, 1H), 7.70 (d, J ¼ 7.5 Hz, 1H), 7.65 (dd, J1 ¼ 7.7 Hz, J2 ¼ 7.5 Hz,
CDCl3-TFA) d 8.42 (s, 1H), 8.30 (d, J ¼ 8.2 Hz, 1H), 8.19 (d, J ¼ 1H), 4.12 (s, 3H), 4.05 (s, 3H), 4.04 (s, 3H); 13C NMR (100 MHz,
6.4 Hz, 1H), 8.09 (d, J ¼ 6.4 Hz, 1H), 7.98 (dd, J1 ¼ 7.5 Hz, J1 ¼ CDCl3) d 195.45, 156.02, 148.63, 147.48, 146.51, 144.13, 139.55,
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137.92, 134.07, 130.33, 129.84, 129.69, 124.45, 123.58, 119.13,
100.86, 61.70, 61.23, 56.26; IR (KBr, lm) 2938, 1687, 1612, 1577,
1528, 1476, 1353, 1274, 1243, 1124, 1048, 941, 855, 758,
637 cmꢃ1; HRMS (ESI) m/z calcd for C19H17N2O6 [M + H]+:
369.1087, found: 369.1085.
(6,7-Dimethoxyisoquinolin-1-yl)(3-methoxyphenyl)methanone
(6g). White crystals, mp 168–169 ꢀC. 1H NMR (400 MHz, CDCl3)
d 8.47 (d, J ¼ 5.5 Hz, 1H), 7.66 (d, J ¼ 5.5 Hz, 1H), 7.60 (s, 1H), 7.56
(s, 1H), 7.44 (d, J ¼ 7.6 Hz, 1H), 7.37 (dd, J ¼ 7.9 Hz, J ¼ 7.6 Hz,
1H), 7.17 (d, J ¼ 7.9 Hz, 1H), 7.14 (s, 1H), 4.05 (s, 3H), 3.96 (s, 3H),
3.85 (s, 3H); 13C NMR (100 MHz, CDCl3) d 195.18, 159.62, 153.22,
153.02, 151.21, 140.05, 138.40, 134.05, 129.37, 123.99, 122.95,
121.64, 120.13, 114.55, 104.88, 103.95, 56.14, 56.08, 55.47. IR (KBr
lm) 2937, 2834, 1660, 1591, 1485, 1439, 1310, 1270, 1259, 1148,
1036, 746, 634 cmꢃ1; HRMS (ESI) m/z calcd for C19H18NO4 [M +
H]+: 324.1236, found: 324.1219.
(7-Methoxyisoquinolin-1-yl)(4-methoxyphenyl)methanone (6l).
White crystals, mp 101–103 ꢀC. 1H NMR (400 MHz, CDCl3) d 8.49
(d, J ¼ 5.5 Hz, 1H), 7.96 (d, J ¼ 8.9 Hz, 2H), 7.81 (d, J ¼ 9.0 Hz, 1H),
7.73 (d, J ¼ 5.5 Hz, 1H), 7.54 (s, 1H), 7.38 (d, J ¼ 9.0 Hz, 1H), 6.96
(d, J ¼ 8.9 Hz, 2H), 3.88 (s, 3H), 3.87 (s, 3H); 13C NMR (100 MHz,
CDCl3) d 193.74, 164.02, 159.15, 154.69, 139.33, 133.27 (2C),
132.58, 129.76, 128.60, 127.82, 124.19, 122.35, 113.76 (2C), 103.35,
55.56, 55.51. IR (KBr lm) 2926, 2837, 1652, 1622, 1601, 1506,
1427, 1251, 1215, 1185, 1166, 1044, 843, 613 cmꢃ1. HRMS (ESI) m/
z calcd for C18H16NO3 [M + H]+: 294.1130, found: 294.1127.
(3,4-Dimethoxyphenyl)(7-methoxyisoquinolin-1-yl)methanone
(6m). White crystals, mp 150–152 ꢀC. 1H NMR (400 MHz, CDCl3)
d 8.49 (d, J ¼ 5.4 Hz, 1H), 7.82 (d, J ¼ 9.0 Hz, 1H), 7.74 (d, J ¼
5.4 Hz, 1H), 7.72 (s, 1H), 7.52 (s, 1H), 7.44–7.38 (m, 2H), 6.87 (d, J
¼ 8.5 Hz, 1H), 3.97 (s, 3H), 3.95 (s, 3H), 3.88 (s, 3H); 13C NMR (100
MHz, CDCl3) d 193.76, 159.17, 154.68, 153.92, 149.11, 139.27,
132.57, 129.87, 128.60, 127.86, 126.92, 124.23, 122.35, 111.89,
109.99, 103.37, 56.14, 56.04, 55.52; IR (KBr lm) 2998, 2931, 1653,
(6,7-Dimethoxyisoquinolin-1-yl)(4-methoxyphenyl)methanone
(6h). White crystals, mp 157–158 ꢀC (lit. 21 150–152 ꢀC). 1H NMR
(400 MHz, CDCl3) d 8.46 (d, J ¼ 5.5 Hz, 1H),7.96 (d, J ¼ 8.9 Hz,
2H), 7.65 (d, J ¼ 5.5 Hz), 7.57 (s, 1H), 7.15 (s, 1H), 6.96 (d, J ¼
8.9 Hz, 2H), 4.06 (s, 3H), 3.96 (s, 3H), 3.88 (s, 3H); 13C NMR (101
MHz, CDCl3) d 193.92, 163.95, 153.69, 153.15, 151.00, 140.02,
133.98, 133.28 (2C), 129.81, 122.80, 121.29, 113.71 (2C), 104.86,
104.06, 56.12, 56.07, 55.55; IR (KBr lm) 2961, 2940, 2836, 1650,
1597, 1585, 1516, 1265, 1232, 1143, 1027, 847, 762, 641 cmꢃ1
.
HRMS (ESI) m/z calcd for C19H18NO4 [M + H]+: 324.1236, found:
324.1233.
(7-Methoxyisoquinolin-1-yl)(phenyl)methanone (6n). White
crystals, mp 120–122 ꢀC. 1H NMR (400 MHz, CDCl3) d 8.50 (d, J
¼ 5.4 Hz, 1H), 7.96 (d, J ¼ 8.4 Hz, 2H), 7.82 (d, J ¼ 9.0 Hz, 1H),
7.75 (d, J ¼ 5.4 Hz, 1H), 7.62 (t, J ¼ 8.0 Hz, 1H), 7.61 (s, 1H), 7.49
(dd, J1 ¼ 8.0 Hz, J2 ¼ 8.4 Hz, 2H), 7.40 (d, J ¼ 9.0 Hz, 1H), 3.89 (s,
3H); 13C NMR (100 MHz, CDCl3) d 195.13, 159.37, 153.95,
139.32, 137.04, 133.50, 132.68, 130.85 (2C), 128.65 (2C), 128.42,
128.00, 124.31, 122.75, 103.29, 55.53; IR (KBr lm) 2978, 2923,
1661, 1624, 1502, 1455, 1317, 1247, 1216, 1168, 851, 715,
646 cmꢃ1. HRMS (ESI) m/z calcd for C17H14NO2 [M + H]+:
264.1025, found: 264.1018.
(Isoquinolin-1-yl)(3-methoxyphenyl)methanone (6o). White
crystals, mp 62–63 ꢀC. 1H NMR (400 MHz, CDCl3) d 8.60 (d, J ¼
5.6 Hz, 1H), 8.19 (d, J ¼ 8.5 Hz, 1H), 7.93 (d, J ¼ 8.4 Hz, 1H), 7.82
(d, J ¼ 5.6 Hz, 1H), 7.75 (dd, J1 ¼ 8.2 Hz, J2 ¼ 8.4 Hz, 1H), 7.63
(dd, J1 ¼ 8.2 Hz, J2 ¼ 8.5 Hz, 1H), 7.58 (s, 1H), 7.41 (d, J ¼ 7.6 Hz,
1H), 7.35 (dd, J1 ¼ 7.6 Hz, J2 ¼ 8.0 Hz, 1H), 7.16 (d, J ¼ 8.0 Hz,
1H), 3.86 (s, 3H); 13C NMR (100 MHz, CDCl3) d 194.61, 159.73,
156.49, 141.16, 137.93, 136.67, 130.78, 129.50, 128.36, 127.14,
126.35, 126.12, 123.99, 122.63, 120.44, 114.33, 55.50; IR (KBr
lm) 3005, 2937, 1665, 1594, 1463, 1281, 1266, 1147, 1039, 834,
769, 637 cmꢃ1; HRMS (ESI) m/z calcd for C17H14NO2 [M + H]+:
264.1025, found: 264.1030.
1607, 1511, 1442, 1321, 1264, 1156, 1054, 916, 862, 836, 613 cmꢃ1
.
(6,7-Dimethoxyisoquinolin-1-yl)(3,4-dimethoxyphenyl)metha-
1
ꢀ
none (6i). White crystals, mp 209–210 C. H NMR (400 MHz,
CDCl3) d 8.47 (d, J ¼ 5.5 Hz, 1H), 7.72 (s, 1H), 7.69 (d, J ¼ 5.5 Hz,
1H), 7.55 (s, 1H), 7.42 (d, J ¼ 8.4 Hz, 1H), 7.15 (s, 1H), 6.87 (d, J ¼
8.4 Hz, 1H), 4.06 (s, 3H), 3.97 (s, 3H), 3,96 (s, 3H), 3.95 (s, 3H); 13
C
NMR (100 MHz, CDCl3) d 193.94, 153.79, 153.68, 153.15, 150.98,
149.00, 140.01, 133.93, 129.89, 126.91, 122.80, 121.26, 111.88,
109.94, 104.85, 104.01, 56.11, 56.09, 56.04, 55.99; IR (KBr lm)
2970, 2934, 1657, 1505, 1460, 1270, 1227, 1140, 1025, 860,
749 cmꢃ1; HRMS (ESI) m/z calcd for C20H20NO5 [M + H]+:
354.1341, found: 354.1343.
(6,7-Dimethoxyisoquinolin-1-yl)(phenyl)methanone
(6j).
White crystals, mp 130–131 ꢀC (lit. 21 131–132 ꢀC). 1H NMR (400
MHz, CDCl3) d 8.47 (d, J ¼ 5.5 Hz, 1H), 7.96 (d, J ¼ 8.0 Hz, 2H),
7.67 (d, J ¼ 5.5 Hz, 1H), 7.65 (s, 1H), 7.63 (t, J ¼ 7.8 Hz, 1H), 7.50
(dd, J1 ¼ 7.8 Hz, J2 ¼ 8.0 Hz, 2H), 7.15 (s, 1H), 4.06 (s, 3H), 3.97
(s, 3H); 13C NMR (100 MHz, CDCl3) d 195.39, 153.20, 152.96,
151.22, 140.07, 137.11, 134.07, 133.42, 130.87 (2C), 128.38 (2C),
123.03, 121.66, 104.88, 103.99, 56.13, 56.08; IR (KBr lm) 2971,
2841, 1657, 1510, 1456, 1260, 1232, 1154, 1052, 864, 709,
(Isoquinolin-1-yl)(4-methoxyphenyl)methanone (6p). White
crystals, mp 67–69 ꢀC. 1H NMR (400 MHz, CDCl3) d 8.60 (d, J ¼
5.7 Hz, 1H), 8.17 (d, J ¼ 8.5 Hz, 1H), 7.95 (d, J ¼ 8.8 Hz, 2H), 7.94
(d, J ¼ 8.0 Hz, 1H), 7.81 (d, J ¼ 5.7 Hz, 1H), 7.75 (dd, J1 ¼ 8.3 Hz,
J2 ¼ 8.5 Hz, 1H), 7.61 (dd, J1 ¼ 8.0 Hz, J2 ¼ 8.3 Hz, 1H), 6.95 (d, J
¼ 8.8 Hz, 2H), 3.88 (s, 3H); 13C NMR (100 MHz, CDCl3) d 193.40,
164.16, 157.08, 141.16, 136.67, 133.19 (2C), 130.72, 129.52,
128.19, 127.08, 126.32, 126.30, 122.30, 113.83 (2C), 55.58; IR
(KBr lm) 3008, 2936, 1651, 1600, 1576, 1412, 1249, 1154, 1022,
649 cmꢃ1
.
(7-Methoxyisoquinolin-1-yl)(3-methoxyphenyl)methanone
(6k). White crystals, mp 106–107 ꢀC. 1H NMR (400 MHz, CDCl3)
d 8.50 (d, J ¼ 5.5 Hz, 1H), 7.82 (d, J ¼ 8.5 Hz, 1H), 7.75 (d, J ¼
5.5 Hz, 1H), 7.58 (s, 1H), 7.57 (s, 1H), 7.45–7.34 (m, 3H), 7.16 (d, J
¼ 8.2 Hz, 1H), 3.89 (s, 3H), 3.86 (s, 3H); 13C NMR (100 MHz,
CDCl3) d 194.98, 159.68, 159.33, 154.03, 139.35, 138.32, 132.64,
129.41, 128.66, 127.93, 124.31, 124.00, 122.73, 120.26, 114.48,
103.22, 55.53, 55.50; IR (KBr lm) 3448, 2923, 1660, 1622, 1593,
1452, 1315, 1283, 1263, 1235, 1038, 869, 848, 646 cmꢃ1; HRMS
(ESI) m/z calcd for C18H16NO3 [M + H]+: 294.1130, found:
294.1136.
828, 745 cmꢃ1
(3,4-Dimethoxyphenyl)(isoquinolin-1-yl)methanone
.
(6q).
White crystals, mp 145–146 ꢀC. 1H NMR (400 MHz, CDCl3)
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d 8.60 (d, J ¼ 5.7 Hz, 1H), 8.16 (d, J ¼ 8.5 Hz, 1H), 7.93 (d, J ¼ removed under vacuum to give crude product as pale yellow
8.1 Hz, 1H), 7.81 (d, J ¼ 5.7 Hz, 1H), 7.76 (dd, J1 ¼ 8.3 Hz, J2 ¼ solid, which was puried by ash chromatography (eluent:
8.5 Hz, 1H), 7.74 (s, 1H), 7.62 (dd, J1 ¼ 8.1 Hz, J2 ¼ 8.3 Hz, 1H), EtOAc/hexane ¼ 1 : 2). Anilines 7a–f were thus obtained in 85%,
7.36 (d, J ¼ 8.4 Hz, 1H), 6.84 (d, J ¼ 8.4 Hz, 1H), 3.97 (s, 3H), 3.94 85%, 86%, 93%, 90% and 91% yields, respectively. Character-
(s, 3H); 13C NMR (100 MHz, CDCl3) d 193.45, 157.03, 154.04, ization data of compounds 7a–f are as follows:
149.18, 141.12, 136.66, 130.76, 129.62, 128.20, 127.08, 127.02,
(2-Aminophenyl)([1,3]dioxolo[4,5-g]isoquinolin-5-yl)metha-
1
126.36, 126.29, 122.31, 111.52, 109.97, 56.17, 56.08; IR (KBr none (7a). Pale yellow crystals, mp 246–247 ꢀC. H NMR (400
lm) 3002, 2938, 1660, 1582, 1510, 1410, 1266, 1150, 1134, 1019, MHz, DMSO-d6) d 8.37 (d, J ¼ 5.6 Hz, 1H), 7.78 (d, J ¼ 5.6 Hz,
825, 752 cmꢃ1; HRMS (ESI) m/z calcd for C18H16NO3 [M + H]+: 1H), 7.56 (br. s, 2H, NH2), 7.47 (s, 1H), 7.29 (dd, J1 ¼ 8.2 Hz, J2 ¼
294.1130, found: 294.1131.
8.5 Hz, 1H), 7.03 (s, 1H), 6.92–6.87 (m, 2H), 6.37 (dd, J1 ¼ 8.0 Hz,
(Isoquinolin-1-yl)(phenyl)methanone (6r). White crystals, J2 ¼ 8.3 Hz, 1H), 6.22 (s, 2H); 13C NMR (100 MHz, DMSO-d6)
1
ꢀ
mp 74–75 C. H NMR (400 MHz, CDCl3) d 8.61 (d, J ¼ 5.6 Hz, d 196.49, 156.03, 152.65, 150.85, 148.81, 140.43, 135.06, 134.73,
1H), 8.22 (d, J ¼ 8.5 Hz, 1H), 8.00–7.91 (m, 3H), 7.81 (d, J ¼ 134.12, 122.04, 120.89, 116.90, 115.83, 114.16, 102.77, 102.21,
5.6 Hz, 1H), 7.74 (dd, J1 ¼ 8.2 Hz, J2 ¼ 8.5 Hz, 1H), 7.64–7.58 (m, 100.59; IR (KBr lm) 3421, 3124, 3078, 2918, 1684, 1576, 1518,
2H), 7.48 (dd, J1 ¼ 7.8 Hz, J2 ¼ 8.0 Hz, 2H); 13C NMR (100 MHz, 1460, 1348, 1314, 1275, 1260, 1214, 1036, 946, 867, 788, 706,
CDCl3) d 194.81, 156.44, 141.18, 136.71, 136.63, 133.73, 130.78 636 cmꢃ1; HRMS (ESI) m/z calcd for C17H13N2O3 [M + H]+:
(2C), 130.74, 128.51, 128.37 (2C), 127.15, 126.42, 126.16, 122.65; 293.0926, found: 293.0919.
IR (KBr lm) 2978, 2922, 1663, 1596, 1449, 1402, 1335, 1317,
(2-Amino-4,5-dimethoxy-phenyl)([1,3]dioxolo[4,5-g]isoqui-
nolin-5-yl)methanone (7b). Pale yellow crystals, mp 182–183 ꢀC.
1279, 1252, 1153, 924, 709, 678, 639 cmꢃ1
.
(2-Bromophenyl)([1,3]dioxolo[4,5-g]isoquinolin-5-yl)metha- 1H NMR (400 MHz, DMSO-d6) d 8.37 (d, J ¼ 5.6 Hz, 1H), 7.74 (d, J
1
ꢀ
none (6s). White crystals, mp 180–181 C. H NMR (400 MHz, ¼ 5.6 Hz, 1H), 7.56 (br. s, 2H, NH2), 7.41 (s, 1H), 7.05 (s, 1H),
CDCl3) d 8.38 (d, J ¼ 5.4 Hz, 1H), 8.20 (s, 1H), 7.65–7.57 (m, 3H), 6.48 (s, 1H), 6.40 (s, 1H), 6.19 (s, 2H), 3.80 (s, 3H), 3.43 (s, 3H);
7.46 (dd, J1 ¼ 7.7 Hz, J2 ¼ 7.9 Hz, 1H), 7.36 (dd, J1 ¼ 7.9 Hz, J2 ¼ 13C NMR (100 MHz, DMSO-d6) d 193.52, 156.42, 156.34, 150.85,
8.1 Hz, 1H), 7.15 (s, 1H), 6.15 (s, 2H); 13C NMR (100 MHz, CDCl3) 150.76, 148.67, 140.36, 138.72, 134.74, 122.05, 120.74, 115.72,
d 197.22, 151.43, 151.04, 150.38, 141.64, 140.61, 135.97, 133.08, 108.04, 102.75, 102.17, 100.79, 98.61, 56.07, 55.41; IR (KBr lm)
131.88, 130.72, 127.35, 124.68, 123.63, 120.46, 102.78, 102.53, 3415, 3310, 2916, 1645, 1585, 1545, 1507, 1465, 1403, 1264,
102.00; IR (KBr lm) 2975, 2908, 1679, 1576, 1497, 1460, 1317, 1221, 1204, 1150, 1110, 1037, 948, 873, 854, 734, 675 cmꢃ1
;
1261, 1208, 1037, 951, 867, 723, 631 cmꢃ1; HRMS (ESI) m/z calcd HRMS (ESI) m/z calcd for C19H17N2O5 [M + H]+: 353.1137, found:
for C17H11NO3Br [M + H]+: 355.9922, found: 355.9917.
353.1142.
(6-Aminobenzo[d][1,3]dioxol-5-yl)([1,3]dioxolo[4,5-g]iso-
(4-Methoxyphenyl)(5,6,7-trimethoxyisoquinolin-1-yl)methan-
one (6t). White crystals, mp 154–156 ꢀC. 1H NMR (400 MHz, quinolin-5-yl)methanone (7c). Pale yellow crystals, mp 240–
CDCl3) d 8.48 (d, J ¼ 5.5 Hz, 1H), 8.01 (d, J ¼ 5.5 Hz, 1H), 7.94 (d, 241 ꢀC. 1H NMR (400 MHz, DMSO-d6) d 8.37 (d, J ¼ 5.6 Hz, 1H),
J ¼ 8.3 Hz, 2H), 7.36 (s, 1H), 6.96 (d, J ¼ 8.3 Hz, 2H), 4.08 (s, 3H), 7.84 (br. s, 2H, NH2), 7.75 (d, J ¼ 5.6 Hz, 1H), 7.44 (s, 1H), 7.02 (s,
4.03 (s, 3H), 3.93 (s, 3H), 3.88 (s, 3H); 13C NMR (100 MHz, CDCl3) 1H), 6.46 (s, 1H), 6.21 (s, 2H), 6.19 (s, 1H), 5.91 (s, 2H); 13C NMR
d 193.72, 164.04, 154.58, 154.01, 146.71, 144.30, 139.44, 133.26 (100 MHz, DMSO-d6) d 193.22, 156.33, 153.63, 152.51, 150.77,
(2C), 129.73, 129.21, 123.77, 116.58, 113.75 (2C), 100.36, 61.64, 148.66, 140.41, 137.27, 134.70, 121.90, 120.70, 109.29, 108.08,
61.23, 56.10, 55.55; IR (KBr lm) 2944, 2839, 1651, 1602, 1479, 102.75, 102.17, 101.29, 100.70, 95.69; IR (KBr lm) 3393, 3286,
1327, 1280, 1256, 1163, 1125, 1028, 935, 823, 702 cmꢃ1. HRMS 2890, 1684, 1648, 1565, 1500, 1462, 1421, 1392, 1270, 1230,
(ESI) m/z calcd for C20H20NO5 [M + H]+: 354.1341, found: 1207, 1091, 1035, 944, 855, 839, 778, 669 cmꢃ1; HRMS (ESI) m/z
354.1336.
calcd for C18H13N2O5 [M + H]+: 337.0824, found: 337.0826.
(2-Aminophenyl)(6,7-dimethoxyisoquinolin-1-yl)methanone
1
ꢀ
(7d). Pale yellow crystals, mp 170–171 C. H NMR (400 MHz,
CDCl3) d 8.42 (d, J ¼ 5.6 Hz, 1H), 7.57 (d, J ¼ 5.6 Hz, 1H), 7.25 (s,
Preparation of anilines 7a–f
Nitro compound 6 (ꢁ2 mmol) was dissolved in a mixed solvent 1H), 7.25–7.18 (m, 2H), 7.10 (s, 1H), 6.72 (d, J ¼ 8.2 Hz, 1H), 6.60
of EtOH (18 mL) and H2O (2 mL). Iron powder (1.130 g, (br. s, 2H, NH2), 6.46 (dd, J1 ¼ 8.0 Hz, J2 ¼ 8.2 Hz, 1H), 3.99 (s,
20.23 mmol) and acetic acid (3.610 g, 60.12 mmol) were added 3H), 3.88 (s, 3H); 13C NMR (100 MHz, CDCl3) d 197.64, 155.57,
into the solution. The mixture was then heated and stirred 153.14, 152.11, 150.72, 140.34, 135.20, 134.79, 133.77, 122.06,
under N2 at 70 ꢀC for 3–5 h. Aer the reaction was complete 120.45, 117.46, 117.06, 115.57, 104.95, 103.94, 56.10, 56.04; IR
(checked by TLC, eluent: EtOAc/hexane ¼ 1 : 2), the mixture was (KBr lm) 3412, 3302, 2967, 2844, 1672, 1645, 1477, 1282, 1212,
cooled down to room temperature and then ltered. The cake 1127, 1090, 938, 854, 735, 674 cmꢃ1; HRMS (ESI) m/z calcd for
was washed twice with EtOH (2 ꢂ 10 mL). The ltrate was
C
18H17N2O3 [M + H]+: 309.1239, found: 309.1236.
(2-Amino-4,5-dimethoxyphenyl)(6,7-dimethoxyisoquinolin-
concentrated under vacuum to give a residue, which was dis-
solved in CH2Cl2 (30 mL). An aqueous solution of Na3PO4 1-yl)methanone (7e). Pale yellow crystals, mp 156–157 ꢀC. 1H
(20 mL, 10% w/w) was added, the mixture was vigorously stirred NMR (400 MHz, CDCl3) d 8.44 (d, J ¼ 5.5 Hz, 1H), 7.59 (d, J ¼
for 5 min. Two phases were separated, and the aqueous phase 5.5 Hz, 1H), 7.33 (s, 1H), 7.13 (s, 1H), 6.68 (s, 1H), 6.56 (br. s, 2H,
was extracted again with CH2Cl2 (30 mL). The organic extracts NH2), 6.20 (s, 1H), 4.04 (s, 3H), 3.93 (s, 3H), 3.89 (s, 3H), 3.50 (s,
were combined, and dried over anhydrous MgSO4. Solvent was 3H); 13C NMR (100 MHz, CDCl3) d 195.00, 156.42, 155.80,
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153.14, 150.65, 149.96, 140.32, 140.01, 133.86, 122.09, 120.34, 5.6 Hz, 1H), 8.33 (d, J ¼ 5.6 Hz, 1H), 8.05 (s, 1H), 7.82 (s, 1H),
115.97, 109.84, 104.88, 104.21, 98.82, 56.38, 56.12, 56.10, 55.93; 7.43 (s, 1H), 6.63 (s, 2H), 4.10 (s, 3H), 4.04 (s, 3H); 13C NMR (100
IR (KBr lm) 3421, 3312, 2982, 2834, 1658, 1601, 1470, 1285, MHz, CDCl3-TFA) d 174.96, 158.63, 157.13, 152.03, 150.56,
1252, 1203, 1143, 1027, 937, 828, 689 cmꢃ1; HRMS (ESI) m/z 143.27, 135.07, 133.57, 129.04, 126.63, 122.59, 121.78, 109.71,
calcd for C20H21N2O5 [M + H]+: 369.1450, found: 369.1449.
109.64, 108.06, 105.40, 103.58, 56.46, 56.16; IR (KBr lm) 3002,
(2-Aminophenyl)(5,6,7-trimethoxyisoquinolin-1-yl)methanone 2918, 2839, 1640, 1593, 1577, 1513, 1476, 1453, 1425, 1368,
(7f). Pale yellow crystals, mp 105–106 ꢀC. 1H NMR (400 MHz, 1344, 1307, 1276, 1253, 1217, 1136, 1056, 1001, 966, 855, 777,
CDCl3) d 8.47 (d, J ¼ 5.7 Hz, 1H), 7.94 (d, J ¼ 5.7 Hz, 1H), 7.27 (dd, 676, 636, 577 cmꢃ1; HRMS (ESI) m/z calcd for C19H14NO5 [M +
J1 ¼ 8.1 Hz, J2 ¼ 7.8 Hz, 1H), 7.20 (d, J ¼ 8.1 Hz, 1H), 7.10 (s, 1H), H]+: 336.0872, found: 336.0870.
6.73 (d, J ¼ 8.2 Hz, 1H), 6.55 (br. s, 2H, NH2), 6.50 (dd, J1 ¼ 8.2 Hz,
Cassameridine (1c). Pale yellow crystals, mp 301–302 ꢀC
J2 ¼ 7.8 Hz, 1H), 4.07 (s, 3H), 4.02 (s, 3H), 3.89 (s, 3H); 13C NMR (lit.5a mp 300 ꢀC). 1H NMR (400 MHz, CDCl3-TFA) d 8.72 (d, J ¼
(100 MHz, CDCl3) d 197.48, 155.80, 154.30, 152.05, 146.79, 144.28, 6.2 Hz, 1H), 8.35 (d, J ¼ 6.2 Hz, 1H), 8.11 (s, 1H), 7.76 (s, 1H),
139.82, 135.27, 134.87, 129.00, 123.14, 117.48, 117.04, 115.73, 7.45 (s, 1H), 6.61 (s, 2H), 6.23 (s, 2H); 13C NMR (100 MHz, CDCl3-
115.69, 100.23, 61.62, 61.23, 56.10; IR (KBr, lm) 3457, 3310, TFA) d 174.76, 158.64, 156.46, 152.30, 150.01, 143.18, 134.79,
2958, 2922, 2851, 1668, 1619, 1584, 1547, 1475, 1262, 1203, 1157, 133.71, 130.79, 126.58, 124.25, 121.60, 108.03, 107.52, 107.12,
1122, 1049, 940, 749, 657 cmꢃ1; HRMS (ESI): calcd for 105.34, 103.55, 103.54; IR (KBr lm) 3029, 2917, 2848, 1648,
C19H19N2O4 [M + H]+: 339.1345, found: 339.1337.
1611, 1572, 1503, 1482, 1467, 1444, 1376, 1294, 1268, 1240,
1123, 1101, 1079, 1040, 965, 899, 818, 604; HRMS (ESI) m/z calcd
for C18H10NO5 [M + H]+: 320.0559, found: 320.0560.
Preparation of oxoaporphines 1a–f
Lysicamine (1d). Pale yellow crystals, mp 206–207 ꢀC (lit.26
Aniline 7 (ꢁ1 mmol) was dissolved in an aqueous solution mp 207–208 ꢀC). 1H NMR (400 MHz, CDCl3) d 9.17 (d, J ¼ 8.2 Hz,
(5 mL, 10% w/w) of sulfuric acid. The solution was cooled to 0– 1H), 8.90 (d, J ¼ 5.3 Hz, 1H), 8.59 (d, J ¼ 7.8 Hz, 1H), 7.80 (d, J ¼
8
ꢀC with an ice bath. A freshly prepared aqueous solution 5.3 Hz, 1H), 7.78 (dd, J1 ¼ 7.8 Hz, J2 ¼ 8.0 Hz, 1H), 7.57 (dd, J1 ¼
(1 mL, 1 M) of sodium nitrite was dropwise added over 5 min. 8.0 Hz, J2 ¼ 8.2 Hz, 1H), 7.22 (s, 1H), 4.10 (s, 3H), 4.02 (s, 3H);
Stirring was continued at 0–8 ꢀC for 15 min to give a clear pale 13C NMR (100 MHz, CDCl3) d 182.71, 156.85, 152.08, 152.05,
orange aqueous solution of diazonium salt, which was 145.39, 145.05, 135.50, 134.34, 132.11, 128.90, 128.80, 128.45,
immediately used below. Copper powder (0.640 g, 10.07 mmol) 123.58, 122.11, 119.84, 106.48, 60.67, 56.23; IR (KBr lm) 2968,
was added into an aqueous solution (5 mL, 10% w/w) of 2920, 2837, 1662, 1610, 1552, 1512, 1465, 1415, 1375, 1260,
sulfuric acid. The suspension was warmed and stirred at 60 ꢀC. 1235, 1110, 1079, 1041, 962, 887, 792, 605; HRMS (ESI) m/z calcd
The above aqueous solution of diazonium salt was dropwise for C18H14NO3 [M + H]+: 292.0974, found: 292.0970.
added over 10 min. The mixture was further stirred at 60 ꢀC for
Oxoglaucine (1e). Pale yellow crystals, mp 225–226 C (lit.27
ꢀ
2–4 h. Aer the reaction was complete (checked by TLC, mp 227–229 ꢀC). 1H NMR (400 MHz, CDCl3) d 8.82 (d, J ¼ 5.2 Hz,
eluent: EtOAc/hexane ¼ 2 : 1), the mixture was cooled to room 1H), 8.72 (s, 1H), 7.95 (s, 1H), 7.69 (d, J ¼ 5.2 Hz, 1H), 7.11 (s,
temperature. CH2Cl2 (30 mL) and concentrated ammonia 1H), 4.06 (s, 3H), 4.04 (s, 3H), 4.03 (s, 3H), 3.99 (s, 3H); 13C NMR
(10 mL, 25% w/w) were added, and the mixture was then (100 MHz, CDCl3) d 181.28, 156.60, 153.65, 150.91, 149.39,
vigorously stirred for 5 min. Two phases were separated, and 145.38, 144.81, 135.25, 129.05, 126.76, 123.30, 121.53, 119.73,
the aqueous phase was extracted again with CH2Cl2 (30 mL). 110.13, 109.67, 105.98, 60.57, 56.18, 56.17, 55.98; IR (KBr lm)
The organic extracts were combined, and dried over anhydrous 2979, 2924, 2841, 1662, 1600, 1554, 1501, 1463, 1403, 1378,
MgSO4. The organic solution was concentrated under vacuum 1292, 1266, 1246, 1217, 1100, 1081, 1037, 975, 890, 827, 739,
to give crude product, which was puried by ash chroma- 624; HRMS (ESI) m/z calcd for C20H18NO5 [M + H]+: 352.1185,
tography (eluent: EtOAc/CH2Cl2 ¼ 1 : 4). Compounds 1a–f found: 352.1187.
were thus obtained in 86%, 77%, 82%, 80%, 79% and 81%
yields, respectively. Characterization data of oxoaporphines 185 ꢀC (lit.10b mp 186–188 ꢀC). 1H NMR (400 MHz, CDCl3) d 9.00
1a–f are as follows:
O-Methylmoschatoline (1f). Pale yellow crystals, mp 184–
(d, J ¼ 8.2 Hz, 1H), 8.86 (d, J ¼ 5.2 Hz, 1H), 8.46 (d, J ¼ 7.7 Hz,
Liriodenine (1a). Pale yellow crystals, mp 283–284 C (lit.3d 1H), 8.11 (d, J ¼ 5.2 Hz, 1H), 7.64 (dd, J1 ¼ 8.2 Hz, J2 ¼ 7.9 Hz,
mp 282 ꢀC). 1H NMR (400 MHz, CDCl3-TFA) d 8.78 (d, J ¼ 5.9 Hz, 1H), 7.42 (dd, J1 ¼ 7.7 Hz, J2 ¼ 7.9 Hz, 1H), 4.11 (s, 3H), 4.03 (s,
1H), 8.66 (d, J ¼ 8.1 Hz, 1H), 8.43 (d, J ¼ 8.0 Hz, 1H), 8.36 (d, J ¼ 3H), 4.00 (s, 3H); 13C NMR (100 MHz, CDCl3) d 182.59, 156.48,
5.9 Hz, 1H), 7.93 (dd, J1 ¼ 7.8 Hz, J2 ¼ 8.1 Hz, 1H), 7.67 (dd, J1 ¼ 148.45, 147.25, 145.43, 144.52, 134.51, 134.34, 131.38, 131.01,
7.8 Hz, J2 ¼ 8.0 Hz, 1H), 7.48 (s, 1H), 6.63 (s, 2H); 13C NMR (100 128.85, 128.08, 127.64, 122.77, 119.12, 115.56, 61.81, 61.46,
MHz, CDCl3-TFA) d 176.51, 158.50, 152.03, 143.26, 137.16, 60.99; IR (KBr, lm) 2956, 2923, 2853, 1660, 1579, 1466, 1393,
134.99, 133.94, 132.15, 130.37, 129.11, 128.27, 128.08, 126.79, 1311, 1261, 1205, 1092, 970, 800, 723, 612 cmꢃ1; HRMS (ESI):
122.36, 108.14, 105.20, 103.66; IR (KBr lm) 3034, 2920, 1660, calcd for C19H16NO4 [M + H]+: 322.1079, found: 322.1072.
1597, 1575, 1469, 1486, 1421, 1309, 1260, 1229, 1206, 1125,
ꢀ
1041, 1014, 958, 869, 778, 689, 568 cmꢃ1; HRMS (ESI) m/z calcd
for C17H10NO3 [M + H]+: 276.0661, found: 276.0665.
Conflicts of interest
Dicentrinone (1b). Pale yellow crystals, mp 292–293 ꢀC (lit.4b
1
ꢀ
mp 293–295 C). H NMR (400 MHz, CDCl3-TFA) d 8.74 (d, J ¼ There are no conicts to declare.
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Prod., 2010, 73, 1180; (c) M. D. Menachery and
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Acknowledgements
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We are grateful to the National Natural Science Foundation of
China (No. 20972048, 20172015) for the nancial support of this
work.
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