N-substituted-3(10H)-acridones as visible-light photosensitizers for organic photoredox catalysis

Article abstract of DOI:10.1016/j.tet.2017.12.019

N-Substituted-3(10H)-acridones have been established as visible-light organic photocatalyst. These photosensitizers are efficient for oxidative coupling reaction of N-aryl tetrahydroisoquinolines with various nucleophiles. Notably, N-methyl-3(10H)-acridon

Full text of DOI:10.1016/j.tet.2017.12.019

Accepted Manuscript
N-substituted-3(10H)-acridones as visible-light photosensitizers for organic
photoredox catalysis
Kun Chen, Yong Cheng, Yongzhi Chang, Enqin Li, Qing-Long Xu, Can Zhang, Xiaoan
Wen, Hongbin Sun
PII:
S0040-4020(17)31270-X
10.1016/j.tet.2017.12.019
TET 29175
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 27 October 2017
Revised Date: 2 December 2017
Accepted Date: 8 December 2017
Please cite this article as: Chen K, Cheng Y, Chang Y, Li E, Xu Q-L, Zhang C, Wen X, Sun H, N-
substituted-3(10H)-acridones as visible-light photosensitizers for organic photoredox catalysis,
Tetrahedron (2018), doi: 10.1016/j.tet.2017.12.019.
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N-Substituted-3(10H)-acridones as Visible-
Light Photosensitizers for Organic Photoredox
Catalysis
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Kun Chen,‡ Yong Cheng,‡ Yongzhi Chang, Enqin Li, Qing-Long Xu, Can Zhang, Xiaoan Wen* and Hongbin
Sun*
State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Discovery for Metabolic
Disease, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China

1
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Tetrahedron
journal homepage: www.elsevier.com
N-Substituted-3(10H)-acridones as Visible-Light Photosensitizers for Organic
Photoredox Catalysis
Kun Chen,‡ Yong Cheng,‡ Yongzhi Chang, Enqin Li, Qing-Long Xu, Can Zhang, Xiaoan Wen* and Hongbin Sun*
State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, 24
Tongjiaxiang, Nanjing 210009, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
N-Substituted-3(10H)-acridones have been established as visible-light organic photocatalyst.
These photosensitizers are efficient for oxidative coupling reaction of N-aryl
tetrahydroisoquinolines with various nucleophiles. Notably, N-methyl-3(10H)-acridone (Ia) is
stable and can be effectively prepared. It is a water-soluble and atom-economic catalyst, and
thus holds promise for green chemical applications. Mechanistic studies confirm a single
electron transfer (SET)-induced radical process and a rate-limiting step. Analysis of the
photocatalytic reactivity−structure relationship reveals that the acridones are robust and tunable
photosensitizers for photoredox catalysis.
Available online
Keywords:
Acridone
Photoredox catalysis
Tetrahydroquinoline
Cross-dehydrogenative-coupling
2009 Elsevier Ltd. All rights reserved
.
Introduction
Figure 1. Visible-light photosensitizers for organic photoredox
catalysis.
Visible light constitutes the major part of sunlight, which
provides clean and renewable energy for the nature. Application
of solar photocatalysts on an industrial scale has been an
aspiration since a century ago.1 Photocatalysts mainly include
transition metal chromophores and organic chromophores.
[Ru(bpy)3]Cl2 and iridium polypyridyl complexes are among the
best organometallic photoredox catalysts with well demonstrated
versatility in organic synthesis.2 On the other hand, “metal-free”
organic chromophores have long been recognized for their ability
to initiate photoredox catalysis.3 Despite the significant advances
in the field of photoredox catalysis, development of robust,
versatile and eco-friendly organic photocatalysts is still highly
desirable. In this study, N-substituted-3(10H)-acridones Ia~f
(Figure 1) are prepared as visible-light photosensitizers for
organic photoredox catalysis.
As part of our program to develop inhibitors of epigenetic
Result and Discussion
enzymes,
we
became
interested
in
3-hydroxy-N-
methylacridinium ion (Ac+OH) and its derivatives.4 This
compound could be synthesized according to the literature
To test this hypothesis, photocatalytic oxidative coupling
reaction of N-phenyl tetrahydroisoquinoline (1a) with
nitromethane was chosen as the model reaction (Table 1). Firstly,
different types of light sources were examined (entries 1~5,
Table 1). To our delight, the desired product 3a was obtained in
77% yield after 7 h of irradiation with blue LED at room
temperature (entry 2, Table 1). It was found that the reaction was
significantly affected by the volume of nitromethane (entries 8,
11, Table 1). A screening of solvents revealed that MeOH was
the best solvent allowing for production of 3a in 82% yield (see
5
procedures. Interestingly, N-methyl-3(10H)-acridone (Ia) was
obtained as an orange red solid whose structure was confirmed
by X-ray crystallography (see Supporting Information (SI):
Figure S6). Given its unique chromophore structure and
photophysical properties (see SI: Figures S2~5, Tables S1~2), we
reasoned that Ia might find its utility as a visible-light organic
photocatalyst. To the best of our knowledge, there are no any
reports concerning its applications in organic photoredox
catalysis.6

2
Tetrahedron
26
If (1)
blue
1
5
100
85
in the supporting information). The catalyst loading also had a
ACCEPTED MANUSCRIPT
a Conditions: 1a (0.25 mmol), 2a, catalyst Ia, solvent (total solution
volume 2.5 mL), air, r.t., blue LED irradiation (6W, λ= 450±10 nm).
significant impact on the reaction. While 1~5 mol % catalyst
loading afforded good product yields and appropriate reaction
speed (entries 8, 12, 13, Table 1), 0.01~0.001 mol % catalyst
loading resulted in decreased reaction speed and conversion rate
(entries 15, 16, Table 1). Surprisingly, TON (turnover number)
and TOF (turn over frequency) of Ia could reach approximately
79000 and 3950 h-1, respectively (entry 16, Table 1). The reaction
proceeded very poorly in the absence of air (entry 18, Table 1),
indicating the critical role of oxygen. When the reaction was run
under an oxygen atmosphere, the reaction proceeded very fast at
the early stage, however, the overall conversion rate was not as
good as with using air (entries 8, 19, Table 1). Notably, the
reaction did not take place at all in the dark (entry 20, Table 1).
The photocatalyst was also required for efficient conversion
(entry 17, Table 1). To investigate the photocatalytic
b
Conversion rate was determined by 1H-NMR, 1,1,2,2-
c
tetrachloroethane as internal standard. Isolated yields after column
chromatography. Reaction was run under nitrogen atmosphere.e
d
f
Reaction was run under oxygen atmosphere. Reaction was run in
the dark. g One equivalent of TEMPO was added.
Next, we wanted to compare acridone Ia with the common
photoredox catalysts, including Eosin Y (II),6a Rose Bengal
(III),6b Acr+-Mes (IV),6c TPP (V),6d and [Ru(bpy)3]Cl2.2a,7 As
shown in Table 2, photocatalytic reaction of N-phenyl
tetrahydroisoquinoline with nitromethane was run in the presence
of various photocatalysts. LED with different color was used to
match the maximum absorption wavelength of each catalyst. To
our delight, under the same reaction condition, Ia (1 mol%)
showed the best photocatalytic capability, enabling an almost
complete conversion after 6 h (entry 1, Table 2), while Acr+-Mes
(IV) induced only 81% conversion (entry 4, Table 2). Eosin Y (II)
and Rose Bengal (III) showed moderate activity for
photocatalysis (entries 2 and 3, Table 2). TPP (V) was a weak
catalyst for this reaction with only 46% conversion (entry 5,
Table 2). Notably, Ia had a slightly higher conversion rate than
[Ru(bpy)3]Cl2 (entry 6, Table 2). Together, in this context,
acridone Ia was more efficient than the common photocatalyst
such as [Ru(bpy)3]Cl2 and Acr+-Mes (IV). It is worth noting that
Ia has a very good water-solubility, thus allowing for green
chemical applications with using water as a solvent.
reactivity−structure relationship of acridones,
acridones Ia~f (Figure 1) were synthesized following the
literature procedures
a series of
4,11
(see SI: Scheme S1 and experimental
section). To compare the photocatalytic efficiency of Ia~f, the
CDC reaction of 1a with nitromethane was carried out (Table 1).
Notably, all the acridones tested were efficient photocatalyts for
this CDC reaction, leading to a complete conversion within 7.5 h.
Acridone Ia exhibited almost the same reactivity with Ib (entries
8 and 22, Table 1), indicating the negligible effect caused by
different N-substituted groups. Acridones Ic and Id with 6-Cl or
7-Cl substitution showed obviously decreased reaction rate
(entries 23 and 24, Table 1), implying that electron-withdrawing
groups might have negative effect on the photocatalytic activity.
On the other hand, the introduction of a methoxy or benzyloxy
group at the 6 position of Ie or If resulted in an increase in
photocatalytic efficiency (entries 25 and 26, Table 1), indicating
that electron-donating substituents on the benzene ring may be
favorable for the photocatalytic activity. Together, various
acridones represent a new class of robust and tunable organic
photoredox catalysts. Finally, acridone Ia was found to be a
novel and highly efficient organic photoredox catalyst.
Table 2. Comparison of Acridone Ia with Common
Photocatalysts a
LED
color
blue
green
green
blue
time
(h)
6
conversion
yield
(%)c
97
54
56
74
41
95
entry
catalyst
(%)b
99
Table
1.
Photocatalytic
Reaction
of
N-phenyl
1
2
3
4
5
6
Ia
II
III
IV
V
Tetrahydroisoquinoline with Nitromethane a
6
6
6
6
56
58
81
46
blue
blue
[Ru(bpy)3]Cl2
6
95
a
Conditions: 1a (0.25 mmol), 2a (1 mL), catalyst (1 mol%), MeOH
b,c
(1.5 mL), air, r.t., LED irradiation.
were determined by H-NMR, 1,1,2,2-tetrachloroethane as internal
standard.
Conversion rate and yields
Ia
(mol%)
1
1
1
1
1
1
1
1
1
1
1
LED
Color
white
blue
green
red
2a
(mL)
0.5
0.5
0.5
0.5
0.5
0.1
0.5
1
1.5
2
2.4
1
1
1
time
(h)
7
7
7
7
7
6
6
6
6
6
6
4.5
5
conv.
yield
(%)c
70
77
56
8
entry
(%)b
96
1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18 d
19 e
20 f
21g
22
23
24
25
99
82
<10
<10
91
94
100
96
97
88
100
100
100
94
79
56
31
93
0
Scheme 1. The Substrate Scope of Coupling Reaction between N-
Aryl Tetrahydroisoquinolines with Various Nucleophiles.
yellow
blue
blue
blue
blue
blue
blue
blue
blue
blue
blue
blue
blue
blue
blue
-
6
61
72
82
68
66
58
79
74
-
-
-
-
-
5
2
0.1
0.01
0.001
0
1
1
11
20
20
20
6
1
1
1
1
1
1
6
6
-
-
1
1
blue
blue
blue
blue
blue
1
1
1
1
6
6
7
7.5
5
24
-
Ib (1)
Ic (1)
Id (1)
Ie (1)
100
100
100
100
80
82
77
78
1

3
R2
R2
R2
R2
ACCEPTED MANUSCRIPT
Radical anion B is then oxidized by O2 to allow for
NuH (2a~g, 1 mL), Ia (1 mol%)
N
regeneration of Ia for the next catalytic cycle. Meanwhile,
N
MeOH, rt, air, blue LED
Nu
3a~p
superoxide radical anion O2
is formed, which abstracts
R1
R1
1a~f
hydrogen radical from A to afford iminium cation C together
with hydroperoxide anion HOO-. Deprotonation of nitromethane
by hydroperoxide anion yields nitromethane anion, which
undergoes nucleophilic attack at C to give 3a.
N
N
N
N
O2N
O2N
Cl
O2N
Br
O2N
F
3a (6h, 82%)
3b (6.5h, 46%)
(6.5h, 57%)
N
3c
3d (9h, 73%)
To validate the reaction mechanism, one equivalent of
(2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) was added to
the reaction, leading to only 24% conversion rate (entry 30ꢀ
Table 1). This suggests that the reaction should proceed through
a radical process. Furthermore, to identify if hydrogen abstraction
was a rate-limiting step, we carried out deuterium experiments
with using deuterated N-phenyl tetrahydroisoquinoline (1a’) 10 as
a substrate (Scheme 4). Thus, three reactions (equations i~iii)
were performed with using 1a (0.25 mmol), 1a’ (0.25 mmol), and
1a (0.125 mmol) plus 1a’ (0.125 mmol) as the substrates,
respectively. As expected, reaction of 1a with nitromethane
(equation i) proceeded quickly and smoothly to achieve
completion in 6 h. Reaction of 1a’ with nitromethane (equation
ii), however, underwent much slowly to take 12 h for a complete
conversion. Reaction of 1a plus 1a’ with nitromethane (equation
iii) was stopped after 5 h, and after removal of the solvents, fast
column chromatography provided a mixture of products 3a and
3a’. 1H-NMR analysis of this product mixture revealed that
production of 3a from 1a was much more than production of 3a’
from 1a’, and the calculated KH/KD value was 1.65 (see SI:
Figure S7). This demonstrates that the reaction rate of 1a’ was
much slower than that of 1a under the same condition, implying
that hydrogen abstraction of the radical cation A to form iminium
cation C should be a rate-limiting step (Scheme 3).
O
O
N
N
N
O2N
O2N
O2N
O2N
3f (15h, 80%)
3g (8h, 26%)
3h (7h, 43%)
3e (6.5h, 45%)
N
N
N
O
N
O
O
O
P
O
O
P
O
O
F
O
O
O
O
O
O
3i (8h, 68%)
3l
(8h, 57%)
3k (6h, 79%)
3j (8h, 57%)
N
O
N
O
N
N
O
O
O
P
P
P
O
P
O
O
O
Cl
O
Br
O
O
3p (6h,81%)
3o (10h, 45%)
3m (7h, 86%)
3n
(11h, 78%)
NuH (2a~g): CH3NO2 (2a); CH3CH2NO2 (2b); CH3(CH2)2NO2 (2c);
Dimethyl malonate (2d); Diethyl malonate (2e); Dimethyl
phosphonate (2f); Diethyl phosphonate (2g).
aConditions: 1 (0.25 mmol), 2 (1 mL), catalyst Ia (1 mol%), MeOH
(1.5 mL), air, r.t., blue LED irradiation. b Isolated yields after column
chromatography.
With the optimal reaction conditions established, we further
examined the substrate scope of the oxidative coupling reaction
of N-aryl tetrahydroisoquinolines 1a~f with various nucleophiles
2a~g in the presence of photocatalyst Ia. Various N-aryl
tetrahydroisoquinolines underwent smooth reactions with
nitromethane to afford the corresponding products 3a~f in
45~82% yields (Scheme 1). It seems that electron-donating
groups are favorable for this reaction (3f), while electron-
withdrawing groups are not (3b, 3c). Reaction of 1a with
nitroethane or 1-nitro-propane gave 3g (26%) or 3h (43 %) in
low yields, respectively. To further explore the substrate scope,
other nucleophiles such as dimethyl malonate (2d), diethyl
malonate (2e), dimethyl phosphonate (2f) and diethyl
phosphonate (2g) were examined. Reaction of 1a with 2d or 2e
afforded 3i or 3j in moderate yields, respectively. Reaction of N-
aryl-tetrahydroisoquinolines 1a~e with dialkylphosphonates 2f~g
yielded α-amino phosphonates 3k~3p in moderate to good yields.
Scheme 3. Proposed Mechanism
Scheme 2. Gram-Scale Reaction
To demonstrate the practical utility of photocatalyst Ia, a
gram-scale reaction (1.0 g) was carried out (Scheme 2). Thus,
under the irradiation with blue LED, reaction of 1a with
nitromethane in the presence of Ia (1 mol%) in methanol for 15 h
gave 3a in 73% yield and 100% conversion.
On the basis of our experimental results and the literature
reports,6a,7,8,9
a plausible mechanism for acridone-mediated
photocatalytic cross-dehydrogenative-coupling (CDC) reaction is
proposed (Scheme 3). Blue LED irradiation of acridone Ia
provides the excited intermediate Ia* with enhanced oxidative
ability. Oxidation of 1a by Ia* via a single electron transfer (SET)
process yields radical cation A together with radical anion B.
Scheme 4. Deuterium Experiment for Determination of a
Rate-Limiting Step

4
Tetrahedron
ACCEPTED MANUSCRIPT
(i)
MeNO2, Ia (1 mol%)
N
N
1a (0.25 mmol)
N
MeOH, rt, air, blue LED
6 h, 82% yield
O2N
3a
MeNO2, Ia (1 mol%)
(ii)
N
D
MeOH, rt, air, blue LED
12 h
D
D
O2N
2-((3-methoxyphenyl)amino)benzoic acid (6a)
1a'
3a'
(0.25 mmol)
An oven-dried Schlenk tube equipped with a magnetic stirring
bar was charged with 4a (20 g, 128 mmol), Cu powder (0.658 g,
10.3 mmol), K2CO3 (20 g, 145 mmol), and 5 (16.8 mL, 135
mmol). The tube was evacuated and backfilled with argon three
times, and then anhydrous degassed pentanol (170 mL) was
added under a stream of nitrogen by syringe at room temperature.
The tube was sealed, stirred, and heated to 140 ºC for 24 h. After
being cooled to room temperature, the mixture was diluted with
100 mL water and acidfied with 2N HCl to pH = 3. The aqueous
phase was extracted 200 mL CH2Cl2 (DCM) three times. The
combined organic phase was washed with water (20 mL × 3) and
dried over Na2SO4, filtered, and concentrated under vacuum. The
residue was purified by flash chromatography on silica gel using
petroleum ether/EtOAc/AcOH (200:10:0.2) as the eluent to
(iii)
N
N
D
D
D
O2N
3a'
1a'
(0.125 mmol)
+
MeNO2, Ia (1 mol%)
+
MeOH, rt, air, blue LED
5 h
N
N
KH/KD=1.65
O2N
1a (0.125 mmol)
3a
Conclusion
1
In conclusion, we demonstrate that N-substituted-3(10H)-
acridones represent as visible-light photosensitizers for organic
photoredox catalysis. These acridones are highly efficient for
photocatalytic CDC reaction of N-aryl tetrahydroisoquinolines
with various nucleophiles. This catalyst is stable and can be cost-
effectively prepared. It has a high atom-economy and a good
water-solubility, and thus holds promise for green chemical
applications. Mechanistic study results support a single electron
transfer (SET)-induced radical process, during which hydrogen
abstraction of the radical cation by superoxide radical anion
might be a rate-limiting step. Preliminary analysis of the
photocatalytic reactivity−structure relationship shows that the
acridones are robust and tunable photocatalysts. Further
development of the acridone class of photosensitizers and
exploration their applications in organic synthesis and
photodynamic therapy (PDT) are undergoing in our laboratory.
afford the product as a brown solid (27 g, 87% yield). H NMR
(500 MHz, CDCl3) δ 9.30 (s, 1H), 8.04 (d, J = 7.9 Hz, 1H), 7.36
(t, J = 7.7 Hz, 1H), 7.27 (m, 1H), 6.87 (d, J = 7.9 Hz, 1H), 6.82 (s,
1H), 6.77 (t, J = 7.5 Hz, 1H), 6.68 (d, J = 8.2 Hz, 1H), 3.82 (s,
3H); ESI MS m/z 242.1 [M-H]-.
3-methoxyacridin-9(10H)-one (7a) and 1-methoxy-9-oxo-
9,10-dihydroacridin-2-ylium (isomer)
An oven dried flask was charged with PPA (111 g, 329 mmol)
and 6a (20 g, 82.2 mmol). The flask was evacuated and
backfilled with argon three times. The mixture was heated to 110
ºC for 3 h. After being cooled to room temperature, the mixture
was diluted with 100 mL water and stirred for 30 min. The
solution was neutralized with NaOH to pH = 8 and then filtered.
The combined solid was washed with water and ethyl ether to
afford a pale yellow solid (7a and its isomer, 18 g, 97% yield).
isomer: 1H NMR (300 MHz, DMSO-d6) δ 11.59 (s, 1H), 8.16 (dd,
J = 18.0, 8.5 Hz, 2H), 7.68 (t, J = 7.6 Hz, 1H), 7.48 (d, J = 8.3 Hz,
1H), 7.22 (t, J = 7.5 Hz, 1H), 6.95-6.58 (m, 2H), 3.89 (s, 3H); 7a:
1H NMR (300 MHz, DMSO-d6) δ 11.41 (s, 1H), 8.12 (d, J = 7.7
Hz, 1H), 7.64 (t, J = 7.1 Hz, 1H), 7.56 (t, J = 8.2 Hz, 1H), 7.42 (d,
J = 8.2 Hz, 1H), 7.18 (t, J = 7.5 Hz, 1H), 7.02 (d, J = 8.3 Hz, 1H),
6.68 (d, J = 8.1 Hz, 1H), 3.85 (s, 3H); ESI MS m/z 224.1 [M-H]-.
Experimental Section
1H and 13C NMR spectra were recorded on an ACF* 300Q
Bruker or ACF* 500Q Bruker spectrometer. Low- and high-
resolution mass spectra (LRMS and HRMS) were recorded in
electron impact mode. The mass analyzer type used for the
HRMS measurements was TOF. Reactions were monitored by
TLC on silica gel 60 F254 plates (Qingdao Ocean Chemical
Company, China). Column chromatography was carried out on
silica gel (200-300 mesh, Qingdao Ocean Chemical Company,
China). Data for 1H NMR are recorded as follows: chemical shift
(δ, ppm), multiplicity (s = singlet, d = doublet, t = triplet, m =
multiplet or unresolved, br = broad singlet, coupling constant (s)
in Hz, integration). Data for 13C NMR are reported in terms of
chemical shift (δ, ppm). Commercially available reagents and
solvents were used without further purification. Irradiation with
blue light was performed using high-power LEDs (6W, λ =
450±10 nm, 1 m).
3-methoxyacridine (8a)
7a and its isomer (18 g, 80 mmol) was dissolved in 180 mL
ethyl ether and cooled to 0 ºC. LiAlH4 (12.5 g, 400 mmol) was
added slowly to the solution. After stirring for 3 h, the mixture
was diluted with 180 mL toluene and heated to 113 ºC for 12 h.
After cooling to 0 ºC, the mixture was diluted with water and
then filtered. The filtrate was collected and extracted with 5
portions of 100 mL DCM. The combined organic phase was
washed with brine, dried with Na2SO4 and concentrated in vacuo.
The residue was dissolved in 300 mL ethanol and 60 mL water
and anhydrous FeCl3 (39 g, 240 mmol) was added. The mixture
was heated to 50 ºC for 30 min and then the solvent was
evaporated. The residue was neutralized with 10% NaHCO3
solution and then filtered. The solid was washed with DCM and
the organic phase was collected. The aqueous phase was
extracted with three portions of 100 mL DCM. The combined
organic phase was washed with brine, dried with Na2SO4 and
concentrated in vacuo. The residue was purified by flash
Synthesis of N-methyl-3(10H)-acridone (Ia)

5
chromatography on silica gel usingpetroleum ether/EtOAc (50:1)
as the eluent to afford the product as a yellow solid (4.0 g, 24%
yield). H NMR (300 MHz, CDCl3) δ 8.64 (s, 1H), 8.18 (d, J =
133.29, 132.85, 131.35, 128.90, 126.54, 124.84, 122.33, 117.71,
ACCEPTED MANUSCRIPT
100.63, 35.05; ESI MS m/z 244.1 [M+H]+; HRMS (ESI) for
C14H11ClNO [M+H]+ calcd 244.0529, found 244.0533.
1
8.7 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.84 (d, J = 9.2 Hz, 1H),
7.76 (t, J = 7.6 Hz, 1H), 7.48 (t, J = 7.2 Hz, 2H), 7.20 (dd, J = 9.2,
1.9 Hz, 1H), 4.00 (s, 3H); ESI MS m/z 232.1 [M+Na]+.
Synthesis of 6-Methoxy-N-methyl-3(10H)-acridone (Ie)
A mixture of 9c (3.5 g, 9.08 mmol), pyridine (17 mL) and acetic
o
acid (50 mL) was stirred at 100 C for 24 h. After cooling to
3-methoxy-10-methylacridin-10-ium iodide (9a)
room temperature, the excessive solvents were evaporated under
reduced pressure. The residue was basified slowly with an
aqueous saturated sodium bicarbonate solution (40 mL) to pH =
7-8, then MeOH (100 mL) was added and filtered. The filter was
concentrated in vacuo. The crude product was subjected to
column chromatography (CH2Cl2: MeOH = 25: 1) to give Ie as
8a (1.5 g, 7.2 mmol) and CH3I (2.68 mL, 43 mmol) was
dissolved in 50 mL DMF. The mixture was heated to 50 ºC for
28 h. After cooling to room temperature, the mixture was filtered.
The solid was collected and washed with DCM and ethyl ether.
The residue was dried to afford the product as a yellow solid (1.6
1
1
g, 64% yield). H NMR (300 MHz, DMSO-d6) δ 9.89 (s, 1H),
an orange yellow solid (2.0 g, 92% yield). H NMR (300 MHz,
8.66 (d, J = 9.3 Hz, 1H), 8.51 (t, J = 8.9 Hz, 2H), 8.40-8.28 (m,
1H), 7.94 (t, J = 7.5 Hz, 1H), 7.78 (s, 1H), 7.66 (d, J = 9.2 Hz,
1H), 4.71 (s, 3H), 4.21 (s, 3H); ESI MS m/z 224.1 [M-I]+;
CD3OD) δ 8.21 (s, 1H), 7.67 (d, J = 8.9 Hz, 1H), 7.48 (d, J = 9.2
Hz, 1H), 6.98 (d, J = 7.9 Hz, 2H), 6.74 (d, J = 9.0 Hz, 1H), 6.39
(s, 1H), 3.97 (s, 3H), 3.77 (s, 3H); 13C NMR (75 MHz, CD3OD) δ
180.55, 164.78, 144.97, 141.18, 140.51, 132.66, 131.71, 126.05,
119.40, 116.22, 114.10, 98.85, 96.25, 54.85, 33.85; ESI MS m/z
240.1 [M+H]+; HRMS (ESI) for C15H14NO2 [M+H]+ calcd
240.1025, found 240.1026.
10-methylacridin-3(10H)-one (Ia)
9a (1.4 g, 4.0 mmol) and HI (45% aqueous solution, 41 mL)
were heated to 125 ºC for 24 h. After cooling to room
temperature, NaHCO3 solid was added to neutralize the solution
to pH = 8. The aqueous solution was extracted with 6 portions of
50 mL DCM. The combined organic phase was washed with
brine, dried with Na2SO4 and concentrated in vacuo. The residue
was purified by flash chromatography on silica gel using
DCM/MeOH (50:1) as the eluent to afford the product as an
orange solid (0.61 g, 63% yield).1H NMR (300 MHz, CD3OD) δ
8.44 (s, 1H), 8.05-7.78 (m, 3H), 7.64 (d, J = 9.3 Hz, 1H), 7.52-
7.38 (m, 1H), 6.83 (d, J = 9.3 Hz, 1H), 6.42 (s, 1H), 3.91 (s, 3H);
13C NMR (75 MHz, CD3OD) δ 182.43, 146.07, 141.02, 139.48,
134.11, 133.26, 130.48, 128.34, 123.33, 122.77, 121.71, 115.19,
99.03, 34.19; ESI MS m/z 210.1 [M+H]+; HRMS for C14H11NO
[M+H]+ cacld 210.0919, found 210.0912;
Synthesis of 6-Benzyloxy-N-methyl-3(10H)-acridone (If)
Compound Ie (1.1 g, 4.43 mmol) was dissolved in 45% aqueous
HI (45 mL, 274.67 mmol) and the resulting mixture was stirred at
reflux for 24 h. After cooling to room temperature, the reaction
mixture was basified slowly with an aqueous saturated sodium
bicarbonate solution to pH = 7-8 and extracted with butyl alcohol
(5 x 100 mL). The organic layer was washed with water and
brine, dried over anhydrous Na2SO4, and concentrated in vacuo.
The crude product was subjected to column chromatography
(CH2Cl2:MeOH = 25:1) to give the crude intermediate 10 (about
900 mg). To a stirred mixture of 10 (90 mg, 0.40 mmol) and
K2CO3 (165 mg, 1.20 mmol) in DMF (4 mL) was added slowly
benzyl bromide (82 mg, 0.48 mmol). The reaction mixture was
stirred at room temperature for 5 h. Then water (5 mL) was
added and the mixture was extracted with CH2Cl2 (5 x 10 mL).
The organic layer was washed with water and brine, dried over
anhydrous Na2SO4, and concentrated in vacuo. The crude product
was subjected to column chromatography (CH2Cl2:MeOH = 30:
1) to give If (64 mg, 46% yield). 1H NMR (300 MHz, CD3OD) δ
8.26 (s, 1H), 7.73 (d, J = 8.9 Hz, 1H), 7.57-7.46 (m, 3H), 7.45-
7.28 (m, 3H), 7.16 (s, 1H), 7.09 (dd, J = 8.9, 2.0 Hz, 1H), 6.77
(dd, J = 9.2, 1.6 Hz, 1H), 6.41 (s, 1H), 5.26 (s, 2H), 3.80 (s, 3H);
13C NMR (75 MHz, CD3OD) δ 181.98, 164.08, 145.76, 141.61,
140.76, 136.05, 133.18, 132.25, 128.28, 127.95, 127.47, 127.07,
120.15, 116.74, 114.65, 99.41, 98.11, 70.36, 34.27; ESI MS m/z
316.1 [M+H]+; HRMS (ESI) for C21H18NO2 [M+H]+ calcd
316.1338, found 316.1345.
Synthesis of N-benzyl-3(10H)-acridone (Ib)
Following the procedure described for preparation of Ia, Ib
was obtained as an orange red solid (60 mg, 22% yield). 1H NMR
(300 MHz, CD3OD) δ 8.64 (s, 1H), 7.98 (d, J = 7.9 Hz, 1H), 7.74
(dd, J = 11.6, 8.3 Hz, 3H), 7.43 (t, J = 7.2 Hz, 1H), 7.33-7.15 (m,
3H), 7.06 (d, J = 7.1 Hz, 2H), 6.84 (d, J = 9.2 Hz, 1H), 6.38 (s,
1H), 5.72 (s, 2H); 13C NMR (75 MHz, CD3OD) δ 182.71, 146.05,
141.79, 139.57, 134.44, 134.13, 133.69, 130.74, 128.80, 128.54,
127.50, 125.67, 123.69, 123.21, 121.90, 115.48, 99.84, 51.01;
ESI MS m/z 286.1 [M+H]+; HRMS (ESI) for C20H16NO [M+H]+
calcd 286.1232, found 286.1238.
6-Chloro-N-methyl-3(10H)-acridone (Ic)
Following the procedure described for preparation of Ia, Ic
1
was obtained as an orange red solid (114 mg, 82% yield). H
The typical procedure for synthesis and characterization of
NMR (300 MHz, CD3OD) δ 8.31 (s, 1H), 7.92-7.67 (m, 2H),
7.57 (d, J = 9.3 Hz, 1H), 7.33 (d, J = 8.3 Hz, 1H), 6.76 (d, J = 9.1
Hz, 1H), 6.32 (s, 1H), 3.81 (s, 3H); 13C NMR (75 MHz, CD3OD)
δ 182.85, 152.45, 145.32, 139.50, 133.00, 131.29, 128.27, 123.29,
122.57, 119.65, 114.53, 99.08, 33.85; ESI MS m/z 244.1 [M+H]+;
HRMS (ESI) for C14H11ClNO [M+H]+ calcd 244.0529, found
244.0524.
β-nitro amine derivatives 3a~h
In a 5 mL open snap vial equipped with magnetic stirring bar
the tetrahydroisoquinoline derivative 1 (0.25 mmol, 1.0 eq.) and
N-methyl-3(10H)-acridone (Ia, 0.01 eq.) were dissolved in
nitroalkane 2 (1 mL) and methanol (1.5 mL). The resulting
mixture was irradiated with blue LEDs until the reaction was
completed (monitored by TLC). The solvent was evaporated
under reduced pressure and the residue was purified by flash
chromatography (petroleum ether/ethyl acetate 200: 1~100:1) to
give β-nitro amine derivative 3 (43-82% yields).
7-Chloro-N-methyl-3(10H)-acridone (Id)
Following the procedure described for preparation of Ia, Id
was obtained as an orange red solid (84 mg, 73% yield).1H NMR
(300 MHz, DMSO-d6) δ 8.26 (s, 1H), 7.93 (d, J = 2.2 Hz, 1H),
7.83 (d, J = 9.3 Hz, 1H), 7.70 (dd, J = 9.2, 2.3 Hz, 1H), 7.57 (d, J
= 9.5 Hz, 1H), 6.60 (d, J = 9.4 Hz, 1H), 6.10 (s, 1H), 3.75 (s, 3H);
13C NMR (75 MHz, DMSO-d6) δ 182.85, 145.56, 138.43, 136.64,
13
1-Nitromethyl-2-phenyl-1,2,3,4-tetrahydroisoquinoline (3a)
55 mg, 82% yield; Yellow oil; H NMR (300 MHz, CDCl3): δ
7.39-7.08 (m, 6H), 7.00 (d, J = 7.8 Hz, 2H), 6.87 (t, J = 7.1 Hz,
1H), 5.57 (t, J = 7.0 Hz, 1H), 4.89 (dd, J = 11.3, 8.1 Hz, 1H),
1

6
Tetrahedron
4.58 (dd, J = 11.6, 6.6 Hz, 1H), 3.88-3.39 (m, 2H), 3.27-2.96
88.96*, 85.47, 62.77, 61.19*, 43.56*, 42.70, 26.75*, 26.41,
ACCEPTED MANUSCRIPT
(m, 1H), 2.91-2.66 (m, J = 16.3 Hz, 1H); 13C NMR (75 MHz,
CDCl3): δ 148.48, 135.31, 133.00, 129.54, 129.22, 128.15,
127.04, 126.74, 119.50, 115.19, 78.84, 58.23, 42.16, 26.53.
17.42*, 16.40.
1-(1-Nitro-propyl)-2-phenyl-1,2,3,4–tetrahydroisoquinoline
(3h)13 A mixture of two diastereoisomers: 32 mg, 43% yield,
1
2-(4-Fluorophenyl)-1-nitromethyl-1,2,3,4-tetrahydroisoquino
2.0:1 dr; Yellow oil; H NMR (300 MHz, CDCl3): δ 7.39-7.10
line (3b)14 33 mg, 46% yield; Yellow oil; H NMR (300 MHz,
(m, 5H), 7.06-6.92 (m, 2H), 6.90-6.78 (m, 1H), 5.27 (d, J = 9.2
Hz, 0.3H, minor isomer), 5.17 (d, J = 9.5 Hz, 0.6H, major
isomer), 5.01-4.80 (m, 0.6H, major isomer), 4.80-4.57 (m, 0.3H,
minor isomer), 4.08-3.43 (m, 2H), 3.26-2.75 (m, 2H), 2.48-1.70
(m, 2H), 1.09-0.87 (m, 3H); 13C NMR (75 MHz, CDCl3, minor
isomer marked*): δ 149.09, 149.01*, 135.55, 134.69*, 133.91*,
132.57, 129.41, 129.31, 129.17 (major and minor isomers),
128.66, 128.59*, 128.21*, 128.16, 127.22*, 126.61*, 125.89
(major and minor isomers), 119.39, 118.59*, 115.84, 114.16*,
96.14*, 93.05, 62.18, 60.70*, 43.53*, 42.34, 26.81*, 25.74,
24.98*, 24.60, 10.66 (major and minor isomers).
1
CDCl3) δ 7.35-7.11 (m, 4H), 7.03-6.83 (m, J = 14.2, 6.8 Hz, 4H),
5.44 (dd, J = 8.1, 6.2 Hz, 1H), 4.84 (dd, J = 11.9, 8.6 Hz, 1H),
4.57 (dd, J = 12.0, 5.9 Hz, 1H), 3.72-3.48 (m, 2H), 3.11-2.96 (m,
J = 15.8, 7.8 Hz, 1H), 2.73 (dt, J = 16.5, 4.1 Hz, 1H); 13C NMR
(75 MHz, CDCl3) δ 157.21 (d, J = 239.2 Hz), 145.32, 135.24,
132.62, 129.43, 128.09, 126.94, 126.76, 117.99 (d, J = 7.6 Hz),
115.86 (d, J = 22.3 Hz), 78.88, 58.73, 42.90, 25.85; 19F NMR
(282 MHz, CDCl3) δ -98.16.
2-(4-Chlorophenyl)-1-nitromethyl-1,2,3,4-tetrahydroiso
quinoline (3c)14 43 mg, 57% yield; Yellow oil; H NMR (300
1
MHz, CDCl3) δ 7.35-7.04 (m, 6H), 6.90 (d, J = 9.0 Hz, 2H), 5.49
(t, J = 7.2 Hz, 1H), 4.85 (dd, J = 11.9, 8.1 Hz, 1H), 4.57 (dd, J =
11.9, 6.3 Hz, 1H), 3.73-3.55 (m, 2H), 3.19-2.96 (m, 1H), 2.95-
2.57 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 147.15, 135.06,
132.54, 129.33, 129.30, 128.25, 126.97, 126.83, 124.41, 116.56,
78.69, 58.21, 42.26, 26.21.
The typical procedure forsynthesis and Characterization of
β-diester Amine Derivatives 3i and 3j
In a 5 mL open snap vial equipped with magnetic stirring bar 2-
phenyl tetrahydroisoquinoline 1a (0.25 mmol, 1.0 eq), dialkyl
malonates 2d~e (5 equiv.), and N-methyl-3(10H)-acridone (Ia,
0.01 equiv.) were dissolved in methanol (2.5 mL). The resulting
mixture was irradiated with blue LED until the reaction was
completed (monitored by TLC). The solvent was evaporated
under reduced pressure and the residue was purified by flash
chromatography (petroleum ether/ethyl acetate 200: 1~100:1) to
give β-diester amine derivatives 3i~j (57-68% yields).
2-(4-Bromophenyl)-1-nitromethyl-1,2,3,4-tetrahydroiso
1
quinoline (3d)13 63 mg, 73% yield; Brown yellow oil; H NMR
(300 MHz, CDCl3) δ 7.35 (d, J = 9.0 Hz, 2H), 7.30-7.08 (m, 4H),
6.85 (d, J = 9.0 Hz, 2H), 5.49 (t, J = 7.2 Hz, 1H), 4.84 (dd, J =
11.9, 8.0 Hz, 1H), 4.57 (dd, J = 11.9, 6.4 Hz, 1H), 3.75-3.50 (m,
2H), 3.21-2.94 (m, J = 14.8, 7.2 Hz, 1H), 2.88-2.62 (m, J = 16.4,
4.8 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 147.52, 135.04,
132.49, 132.25, 129.29, 128.29, 126.98, 126.85, 116.82, 111.61,
78.64, 58.12, 42.14, 26.23.
2-(2-Phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)-malonic acid
dimethyl ester (3i)13
58 mg, 68% yield; Pale yellow oil;1H NMR (300 MHz, CDCl3) δ
7.32-7.07 (m, 6H), 6.99 (d, J = 8.1 Hz, 2H), 6.77 (t, J = 7.2 Hz,
1H), 5.71 (d, J = 9.3 Hz, 1H), 3.95 (d, J = 9.3 Hz, 1H), 3.81-3.60
(m, 5H), 3.55 (s, 3H), 3.08 (ddd, J = 15.5, 8.7, 6.5 Hz, 1H), 2.88
(dt, J = 16.5, 5.1 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 168.24,
167.37, 148.76, 135.65, 134.75, 129.07, 128.93, 127.59, 127.02,
126.00, 118.60, 115.19, 59.08, 58.14, 52.48, 42.17, 26.04.
2-(4-Methylphenyl)-1-nitromethyl-1,2,3,4-tetrahydroiso
1
quinoline (3e)14 32 mg, 45% yield; Yellow oil; H NMR (300
MHz, CDCl3) δ 7.31-7.12 (m, 4H), 7.09 (d, J = 8.3 Hz, 2H), 6.90
(d, J = 8.5 Hz, 2H), 5.51 (t, J = 7.1 Hz, 1H), 4.86 (dd, J = 11.8,
8.0 Hz, 1H), 4.56 (dd, J = 11.8, 6.4 Hz, 1H), 3.84-3.46 (m, 2H),
3.20-2.97 (m, 1H), 2.76 (dt, J = 16.4, 4.4 Hz, 1H), 2.27 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 146.42, 135.35, 133.03, 129.98,
129.27, 129.16, 128.00, 126.97, 126.63, 115.98, 78.87, 58.40,
42.39, 26.30, 20.33.
2-(2-Phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)-malonic acid
diethyl ester (3j)13
1
51 mg, 57% yield; Light brown oil; H NMR (300 MHz, CDCl3)
6,7-Dimethoxy-1-nitromethyl-2-phenyl-1,2,3,4–tetrahydroiso
δ 7.35-7.10 (m, 6H), 7.01 (d, J = 8.3 Hz, 2H), 6.86-6.68 (m, 1H),
5.76 (d, J = 9.1 Hz, 1H), 4.30-3.98 (m, 4H), 3.93 (d, J = 9.1 Hz,
1H), 3.79-3.59 (m, 2H), 3.19-3.00 (m, 1H), 2.99-2.80 (m, 1H),
1.20 (t, J = 7.1 Hz, 3H), 1.12 (t, J = 7.1 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 167.88, 167.07, 148.82, 135.92, 134.77, 129.00,
128.81, 127.44, 127.12, 125.93, 118.39, 115.04, 61.48, 59.50,
57.82, 42.24, 26.10, 13.85, 13.80.
1
quinoline (3f)13 66 mg, 80% yield; Yellow oil; H NMR (300
MHz, CDCl3) δ 7.27 (t, J = 8.0 Hz, 2H), 6.98 (d, J = 8.2 Hz, 2H),
6.85 (t, J = 7.3 Hz, 1H), 6.63 (d, J = 12.4 Hz, 2H), 5.47 (t, J = 7.1
Hz, 1H), 4.85 (dd, J = 11.8, 8.0 Hz, 1H), 4.57 (dd, J = 11.8, 6.4
Hz, 1H), 3.86 (s, 3H), 3.85 (s, 3H), 3.75-3.63 (m, 1H), 3.62-3.47
(m, 1H), 3.16-2.81 (m, 1H), 2.68 (dt, J = 16.1, 4.5 Hz, 1H); 13C
NMR (75 MHz, CDCl3) δ 148.81, 148.61, 147.77, 129.44,
127.43, 124.60, 119.58, 115.55, 111.78, 109.69, 78.79, 57.97,
56.08, 55.91, 42.08, 25.83.
The typical procedure for synthesis and characterization of
α-amino Phosphonates 3k~p.
In a 5 mL open snap vial equipped with magnetic stirring bar
tetrahydroisoquinoline derivative 1 (0.25 mmol, 1.0 equiv.) and
N-methyl-3(10H)-acridone (Ia, 0.01 equiv.) were dissolved in
dialkylphosphonate 2 (1 mL) and methanol (1.5 mL). The
resulting mixture was irradiated with blue LEDs until the
reaction was completed (monitored by TLC). The solvent was
evaporated under reduced pressure and the residue was purified
by flash chromatography (petroleum ether/ethyl acetate 50:
1~5:1) to give α-amino phosphonates 3k~p (45-86% yields).
1-(1-Nitro-ethyl)-2-phenyl-1,2,3,4-tetrahydroisoquinoline
(3g)13 A mixture of the two diastereoisomers. 18 mg, 26% yield,
1.5:1 dr; Yellow oil; 1H NMR (300 MHz, CDCl3) δ 7.35-7.10 (m,
5.2H), 7.09-6.97 (m, 2.4H), 6.90-6.82 (m, 0.8H), 5.33-5.24 (m,
1H), 5.14-5.01 (m, 0.6H, major isomer), 4.98-4.86 (m, 0.4H,
minor isomer), 3.93-3.80 (m, 0.7H), 3.68-3.51 (m, 1.5H), 3.15-
3.01 (m, 1.1H), 3.00-2.84 (m, 1.1H), 1.73 (d, J = 6.8 Hz, 1.2H,
minor isomer), 1.57 (d, J = 6.6 Hz, 2.1H, major isomer); 13C
NMR (75 MHz, CDCl3, minor isomer marked*): δ 149.21*,
148.93, 135.65, 134.83*, 133.86*, 132.07, 129.45*, 129.33
(major and minor isomers), 129.13*, 128.75*, 128.37, 128.22,
127.28*, 126.60*, 126.15, 119.35, 118.82*, 115.46, 114.55*,
1-Phenyl-2-dimethylphosphonate-1,2,3,4-tetrahydroiso
quinoline (3k)15

7
1
1
63 mg, 79% yield; White solid; H NMR (300 MHz, CDCl3) δ
70 mg, 81% yield; Clear oil; H NMR (300 MHz, CDCl3) δ
ACCEPTED MANUSCRIPT
7.37 (d, J = 6.2 Hz, 1H), 7.27 (t, J = 7.9 Hz, 2H), 7.22-7.12 (m,
3H), 6.98 (d, J = 8.3 Hz, 2H), 6.82 (t, J = 7.2 Hz, 1H), 5.21 (d, J
= 20.0 Hz, 1H), 4.03 (ddd, J = 13.1, 8.4, 5.0 Hz, 1H), 3.71-3.59
(m, 7H), 3.15-2.92 (m, 2H); 13C NMR (75 MHz, CDCl3) δ
149.24 (d, J = 5.9 Hz), 136.40 (d, J = 5.6 Hz), 130.41, 129.23,
128.82 (d, J = 2.6 Hz), 127.93 (d, J = 4.7 Hz), 127.52 (d, J = 3.5
Hz), 126.03 (d, J = 2.9 Hz), 118.66, 114.77, 58.73 (d, J = 159.3
Hz), 53.88 (d, J = 7.1 Hz), 52.90 (d, J = 7.7 Hz), 43.54, 26.66;
31P NMR (121 MHz, CDCl3) δ 24.50.
7.38 (d, J = 6.0 Hz, 1H), 7.32-7.08 (m, 5H), 6.98 (d, J = 8.2 Hz,
2H), 6.79 (t, J = 7.2 Hz, 1H), 5.19 (d, J = 20.0 Hz, 1H), 4.17–
3.82 (m, 5H), 3.74-3.53 (m, 1H), 3.16-2.90 (m, 2H), 1.25 (t, J =
7.0 Hz, 3H), 1.14 (t, J = 7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3)
δ 149.34 (d, J = 12.7 Hz), 136.41 (d, J = 5.6 Hz), 130.66, 129.09,
128.70 (d, J = 2.5 Hz), 128.10 (d, J = 4.7 Hz), 127.38 (d, J = 3.5
Hz), 125.82 (d, J = 2.8 Hz), 118.42, 114.76, 63.24 (d, J = 7.2
Hz), 62.27 (d, J = 7.7 Hz), 59.83, 57.72, 43.45, 26.73, 16.36 (t, J
= 5.9 Hz); 31P NMR (121 MHz, CDCl3) δ 22.28.
1-(4-Fluorophenyl)-2-dimethylphosphonate-1,2,3,4–
tetrahydroisoquinoline (3l)
THE ASSOCIATED CONTENT
Supporting Information
1
48 mg, 57% yield; White solid; H NMR (300 MHz, CDCl3) δ
Experimental procedures, characterization data (PDF)
AUTHOR INFORMATION
Corresponding Author
7.38-7.31 (m, 1H), 7.28-7.09 (m, 3H), 7.01-6.84 (m, 4H), 5.07 (d,
J = 20.3 Hz, 1H), 4.08-3.92 (m, 1H), 3.65 (d, J = 10.5 Hz, 6H),
3.59-3.48 (m, 1H), 3.06-2.93 (m, 2H); 13C NMR (75 MHz,
CDCl3) δ 156.57 (d, J = 238.2 Hz), 146.02 (dd, J = 7.0, 2.0 Hz),
136.23 (d, J = 5.8 Hz), 130.49 (d, J = 52.0 Hz), 128.87 (d, J = 2.6
Hz), 127.95 (d, J = 4.6 Hz), 127.55 (d, J = 3.6 Hz), 126.07 (d, J =
2.8 Hz), 116.68 (d, J = 7.5 Hz), 115.72, 115.43, 59.28 (d, J =
159.0 Hz), 53.79 (d, J = 7.2 Hz), 52.89 (d, J = 7.6 Hz), 44.38,
26.41; 19F NMR (282 MHz, CDCl3) δ -99.72; 31P NMR (121
MHz, CDCl3) δ 24.34; HRMS (ESI) for C17H19FNNaO3P
[M+Na]+ calcd 358.0979, found 358.0983.
*wxagj@126.com
*hbsun2000@yahoo.com
Author Contributions
‡These authors contributed equally.
Notes
The authors declare no competing financial interest.
1-(4-Chlorophenyl)-2-dimethylphosphonate-1,2,3,4–
tetrahydroisoquinoline (3m)16
ACKNOWLEDGMENT
1
76 mg, 86% yield; white solid; H NMR (300 MHz, CDCl3) δ
Financial support from National Natural Science Foundation
of China (grants 81473080, 81573299, 21502230 and
31501182) is gratefully acknowledged. This project was also
supported by the Jiangsu Province Natural Science
Foundation (BK20150688), the “111 Project” from the
Ministry of Education of China, the State Administration of
Foreign Expert Affairs of China (No. 111-2-07) and
program for Changjiang Scholars and Innovative Research
Team in University (IRT1193), Project Program of State
7.45-7.31 (m, 1H), 7.29-7.10 (m, 5H), 6.91 (d, J = 9.0 Hz, 2H),
5.14 (d, J = 19.3 Hz, 1H), 4.05-3.89 (m, 1H), 3.72-3.49 (m, 7H),
3.23-3.08 (m, 1H), 3.07-2.91 (m, 1H); 13C NMR (75 MHz,
CDCl3) δ 147.75 (d, J = 5.2 Hz), 136.23 (d, J = 5.6 Hz), 130.14,
129.00, 128.74 (d, J = 2.6 Hz), 127.93 (d, J = 4.8 Hz), 127.71 (d,
J = 3.6 Hz), 126.16 (d, J = 2.8 Hz), 123.38, 115.71, 58.72 (d, J =
159.7 Hz), 53.78 (d, J = 7.2 Hz), 52.98 (d, J = 7.7 Hz), 43.77,
26.79; 31P NMR (121 MHz, CDCl3) δ 24.16.
Key
Laboratory
of
Natural
Medicines,
China
1-(4-Bromophenyl)-2-dimethylphosphonate-1,2,3,4–
tetrahydroisoquinoline (3n)16
Pharmaceutical University (No. SKLNMZZYQ201607), the
Program for Jiangsu Province Innovative Research Team.
1
77 mg, 78% yield; white solid; H NMR (300 MHz, CDCl3) δ
References
7.39-7.28 (m, 3H), 7.29-7.13 (m, 3H), 6.86 (d, J = 9.0 Hz, 2H),
5.14 (d, J = 19.1 Hz, 1H), 4.06-3.88 (m, 1H), 3.72-3.47 (m, 7H),
3.24-3.07 (m, 1H), 3.07-2.90 (m, 1H); 13C NMR (75 MHz,
CDCl3) δ 148.13 (d, J = 5.1 Hz), 136.22 (d, J = 5.5 Hz), 131.89,
130.13, 128.72 (d, J = 2.7 Hz), 127.92 (d, J = 4.8 Hz), 127.74 (d,
J = 3.5 Hz), 126.18 (d, J = 2.7 Hz), 116.08, 110.52, 58.61 (d, J =
159.7 Hz), 53.78 (d, J = 7.2 Hz), 53.00 (d, J = 7.7 Hz), 43.67,
26.83; 31P NMR (121 MHz, CDCl3) δ 24.10.
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tetrahydroisoquinoline (3o)16
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1
37 mg, 45% yield; white solid; H NMR (300 MHz, CDCl3) δ
7.43-7.32 (m, 1H), 7.30-7.13 (m, 3H), 7.09 (d, J = 8.3 Hz, 2H),
6.90 (d, J = 8.5 Hz, 2H), 5.17 (d, J = 20.7 Hz, 1H), 4.11-3.95 (m,
1H), 3.76-3.55 (m, 7H), 3.08-2.92 (m, 2H), 2.28 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 147.25 (d, J = 7.1 Hz), 136.43 (d, J =
5.6 Hz), 130.38, 129.75, 128.89 (d, J = 2.5 Hz), 128.21, 127.95
(d, J = 4.5 Hz), 127.43 (d, J = 3.5 Hz), 125.99 (d, J = 2.8 Hz),
115.33, 58.95 (d, J = 159.4 Hz), 53.97 (d, J = 7.2 Hz), 52.88 (d, J
= 7.7 Hz), 43.90, 26.38, 20.27; 31P NMR (121 MHz, CDCl3) δ
24.54.
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tetrahydroisoquinoline (3p)13,15

8
Tetrahedron
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