One-pot synthesis of dihydrobenzo[4,5][1,3]oxazino[2,3-A] isoquinolines via a silver(I)-catalyzed cascade approach

Article abstract of DOI:10.3390/molecules18010814

An efficient approach for the synthesis of biologically interesting fused tetracyclic isoquinolines in high yields and with a broad substrate scope has been developed. The strategy features an AgNO₃ catalyzed 'one-pot' cascade process involving formation of two new C-N bonds and one new C-O bond.

Full text of DOI:10.3390/molecules18010814

Molecules 2013, 18, 814-831; doi:10.3390/molecules18010814
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
‘One-pot’ Synthesis of Dihydrobenzo[4,5][1,3]oxazino[2,3-a]
isoquinolines via a Silver(I)-Catalyzed Cascade Approach
Baifeng Jiang 1, Yu Zhou 2,*, Qingya Kong 1, Hualiang Jiang 1,2, Hong Liu 2 and Jian Li 1,*
1
Shanghai Key Laboratory of New Drug Design, School of Pharmacy,
East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China
2
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica,
Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China
* Authors to whom correspondence should be addressed; E-Mails: zhouyu@mail.shcnc.ac.cn (Y.Z.);
jianli@ecust.edu.cn (J.L.); Tel./Fax: +86-21-5080-7042 (Y.Z.); +86-21-6425-2584 (J.L.).
Received: 26 November 2012; in revised form: 4 January 2013 / Accepted: 5 January 2013 /
Published: 11 January 2013
Abstract: An efficient approach for the synthesis of biologically interesting fused
tetracyclic isoquinolines in high yields and with a broad substrate scope has been
developed. The strategy features an AgNO3 catalyzed ‘one-pot’ cascade process involving
formation of two new C–N bonds and one new C–O bond.
Keywords: silver; one-pot; cascade transformation; isoquinolines; heterocyclic molecule
1. Introduction
Fused isoquinolines are widely distributed in alkaloids and biologically important synthetic
substances. They exhibit a broad spectrum of biological properties, such as antitumor activity [1,2],
TC-PTP and PTP1B inhibitory activities [3], and HIV inhibitory potencies [4,5]. Therefore, the
development of new synthetic strategies for the efficient preparation of fused isoquinolines is in
considerable demand. Compared to the stepwise approach, cascade reactions represent an attractive
strategy in synthesis because multiple bond-forming and -cleaving events can be combined into a
single reaction operation. Recently, transition-metal-catalyzed cascade processes have received
significant attention [6–19]. Among these transition metals, silver salts have long been believed to
have low catalytic efficiency, and most commonly served as either co-catalysts or weak Lewis acids [20].

Molecules 2013, 18
815
However, in recent years they have been extensively employed to activate alkyne, alkene, and allene
functionalities under mild conditions and at low catalyst loadings [21–34].
In our ongoing efforts for the development of the efficient synthetic methods for the construction of
potential bioactive fused polycyclic compounds through exploration of new catalytic cascade
strategies [35–41], we envisioned that the direct assembly of nitrogen-containing tetracyclic
isoquinoline structures 3 could be realized in a ‘one-pot’ operation from readily available and
functional 2-substituted-ethynyl benzaldehydes 1 with 2-aminoarylmethanols 2 (Scheme 1). In this
design, the condensation of the starting materials 1 and 2 would be primed for the formation of the
Ag-complex (B or B') in the presence of Ag salts as catalyst. The resulting species would be subject to
a cascade nucleophilic attack to give the target scaffold 3. Successful execution of the proposal would
lead to highly functionalized isoquinolines, which are particularly attractive for further elaboration in
diversity oriented synthesis. Recently, some progress has been made via tandem nucleophilic addition
and cyclization to give fused tetracyclic isoquinolines by using o-alkynylbenzaldehyde as the starting
material in the presence of various Lewis acid catalysts, such as AuCl [17], In(OTf)3 [18], Yb(OTf)3 [13],
CuI [16], AgNO3 [28,29], and Ph3PAuMe/chiral Brønsted acids [15]. However, to the best of our
knowledge, there is no report involving the synthesis of dihydrobenzo[4,5][1,3]oxazino[2,3-a]
isoquinolines 3 via a AgNO3-catalyzed one-pot domino process. Herein, we wish to disclose our recent
results in this area.
Scheme 1. A plausible mechanism.
2. Results and Discussion
To fulfill the hypothesis, we carried out the experiments using 2-(phenylethynyl)benzaldehyde (1a)
and (2-aminophenyl)methanol (2a) as model substrates (as shown in Table 1). In our previous studies,
we found that some gold-complex and/or silver salts were highly efficient catalysts for cascade reactions
involving the activation of alkynyl groups [35–41]. Therefore, several gold catalysts, including
AuCl(PPh3), AuCl, (acetonitrile)[(2-biphenyl)di-tert-butylphosphine]gold(I) hexafluoro-antimonate

Molecules 2013, 18
(Au catalyst
816
I),
and
2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-biphenyl
gold(I)
bis(trifluoromethanesulfonyl)imide (Au catalyst II) were firstly investigated in a sealed tube using dry
toluene as the solvent at 100 °C for 3 h. Disappointingly, the desirable cascade products were obtained
in only 28%–75% yields (Table 1, entries 1–4). Different silver salts, such as AgOOCCF3, AgNO3,
AgBF4 and AgOTf, were also subsequently screened, and AgNO3 was proved to be the most effective
one for this transformation (Table 1, entries 5–8), and the product 3Aa could be obtained in 93% yield
(Table 1, entry 6). It is apparent that the solvent has a significant influence on the yield of this reaction
(Table 1, entries 9–14). Toluene was found to be the optimal solvent for this transformation (Table 1,
entries 6, 9–14), although when DMSO, CH3CN and 1,4-dioxane were used instead of toluene, the
desired product 3Aa can also obtained with good yields (Table 1, entries 12–14). The yield of the
product has no significant difference when we decrease the reaction temperature to 80 °C in toluene
(Table 1, entry 15). However, when DMSO, CH3CN and 1,4-dioxane were used, decreasing
temperature appears to have a negative impact on the yield of product (Table 1, entries 16–18). We
further decreased reaction temperature to 50 °C and room temperature, but these changes adversely
affected the product yield, and product 3Aa was obtained in only 65% and 30% yield, respectively
(Table 1, entries 19–20).
Table 1. Optimization of the reaction conditions a.
Entry Catalyst system b
Solvent
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
MeOH
Temp (°C)
100
100
100
100
100
100
100
100
reflux
reflux
100
100
reflux
100
80
Yield (%)
75
49
58
28
60
93
57
92
77
60
71
92
87
83
94
75
1
2
AuCl(PPh3)
AuCl
3
4
5
6
Au catalyst I
Au catalyst II
AgOOCCF3
AgNO3
AgBF4
7
8
AgOTf
9
AgNO3
10
11
12
13
14
15
16
17
18
19
20
21
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
THF
DMF
DMSO
CH3CN
Dioxane
Toluene
DMSO
CH3CN
Dioxane
Toluene
Toluene
Toluene
80
80
80
50
RT
80
78
77
65
AgNO3
AgNO3
AgNO3
30
94 c
a
1A (0.1 mmol), 2a (0.2 mmol) and catalyst (5 mol%) in the specified solvent (2 mL) were reacted in a
sealed vial; b Au catalyst I = (acetonitrile)[(2-biphenyl)di-tert-butylphosphine]gold (I) hexafluoroantimonate;
Au catalyst II = 2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-biphenyl gold(I) bis(trifluoromethane-sulfonyl)imide;
c 1.2 eqv. of 2a was used.

Molecules 2013, 18
817
Furthermore, the amount of starting material 2a was also screened, and the results demonstrated
that the same excellent yield for desired product 3Aa were observed in toluene at 80 °C for 3 h when
1.2 equiv. of 2a was used (Table 1, entry 21).
To explore the scope and limitation of this cascade reaction, we surveyed the diversity of the
starting materials by the structural variations of both 2-substituted-ethynyl benzaldehydes (1A–H) and
2-aminoarylmethanols (2a–j). As shown in Table 2, notably, the corresponding fused tetracyclic
isoquinolines products 3Aa–Bj were efficiently produced in moderate to excellent yields (45%–94%).
The nature of the 2-aminoarylmethanol and the substituents attached to the triple bond of
benzaldehydes has a major impact on the yield of the transformation. When 2-phenylethynyl-
benzaldehyde (1A) was treated with different substituted 2-aminoarylmethanols 2a–e, excellent yields
were achieved (Table 2, entries 1–5). Moreover, when introducing substituent groups such as fluoro,
chloro, or methyl groups onto the phenyl ring in the 2-phenylethynylbenzaldehydes, most of the
desired products were obtained with high yields (Table 2, entries 6–22). Nevertheless, some
substituted 2-aminoarylmethanols with bromo or methyl groups (Table 2, entries 8–10, 17–18 and 22),
especially 6-methyl-2-aminophenylmethanol (Table 2, entry 10), result in a decrease in the yield of the
target products, presumably due to the influence of electronic and/or steric effects. Subsequently, we
prepared substrates 1F and 1G by introducing methyl and fluoro groups in the 4-position and
5-postion of 2-phenylethynylbenzaldehyde (1A), respectively. Results of further investigations
demonstrated that all tested substrates were tolerated in this cascade transformation, giving good to
excellent yields (Table 2, entries 23–30). However, a relatively lower 55% yield of product 3Gh was
obtained in the reaction of 2-phenylethynyl-4-methylbenzaldehyde (1G) with 3-aminonaphthalenylmethanol
(2h). We speculate that the electronic effect of naphthalene ring was responsible for the decrease in the
yield. Furthermore, an alkyl (n-hexyl) group at the R1 position was also tolerated, and excellent yields
were obtained (Table 2, entries 31–32). Finally, a N-containing heterocyclic substrate (2-amino-
pyridinylmethanol, 2j) was investigated in this cascade transformation, but only moderate yields were
obtained (Table 2, entries 33–34). In view of these findings, this cascade strategy could serve as a
general approach for the preparation of fused tetracyclic isoquinoline complex molecular architectures.
Table 2. Silver-mediated one-pot domino synthesis of target compounds 3 a.
Entry
Product
Yield (%) Entry
Product
Yield (%)
1
3Aa
3Ab
94
92
18
19
3Df
65
2
3Dh
70

Molecules 2013, 18
818
Table 2. Cont.
Entry
Product
O
Yield (%) Entry
Product
Yield (%)
Cl
3
3Ac
3Ad
3Ae
85
81
77
20
21
22
3Ea
3Ec
3Ee
87
N
Ph
4
5
6
85
68
90
F
F
O
N
3Bb
3Bd
3Be
3Bf
85
82
69
68
65
88
23
24
25
26
27
28
3Fa
3Fc
3Fe
7
8
70
85
45
90
77
9
3Ff
O
N
10
11
3Bg
3Ca
3Ga
3Gc

Molecules 2013, 18
819
Table 2. Cont.
Entry
Product
Yield (%) Entry
Product
Yield (%)
12
3Cc
82
29
3Gf
85
13
14
15
16
17
3Cd
3Da
3Dc
3Dd
3De
80
97
76
80
75
30
31
32
33
34
3Gh
3Ha
3Hi
3Aj
3Bj
55
82
80
47
45
O
O
N
N
a 1A (0.1 mmol), 2a (0.12 mmol) and catalyst (5 mol%) in toluene (2 mL) were perfomed in a sealed vial.
Scheme 1 depicts a plausible mechanism for this cascade transformation. The condensation of the
starting materials 1 and 2 generates the key imine intermediate A, which subsequently can be
converted into the final product 3 via two possible catalytic pathways (I and II). In pathway I [17,42],
the imine intermediate A is activated by AgNO3 to form the π-Ag complex B, and futher generates the
N-aryl imine cation C through an intramolecular nucleophilic addition, which is subject to a subsequent
nucleophilic attack and proton transformation to afford the target scaffold 3. In the conceivable
alternative pathway II [17,28], the aminal intermediate C' is probably formed by an intramolecular
nucleophilic addition of iminoalkyne Ag-complex B'. Then, the Ag-mediated intramolecular
hydroamination reaction of C' and subsequent protonation results in the formation of the target product
3. The target product 3Aa was further characterized by X-ray crystallography (Figure 1, see
Supporting Information for details).

Molecules 2013, 18
820
Figure 1. X-ray crystallographic structure of 3Aa.
3. Experimental
3.1. General
2-Aminoarylmethanols 2a–j and the two 2-substituted-ethynyl benzaldehydes 1A and 2B are
commercially available starting materials. The five remaining 2-substituted-ethynyl benzaldehydes
1C–H were prepared as indicated in the following methods. Commercially available reagents and
solvents were used without further purification. Column chromatography was carried out on silica gel.
13
1H and C-NMR spectra were obtained on Varian Mercury-300, Varian Mercury-400 and Varian
Mercury-500 spectrometers (TMS as IS). Chemical shifts were reported in parts per million (ppm, δ)
downfield from tetramethylsilane. Proton coupling patterns are described as singlet (s), doublet (d),
triplet (t), quartet (q), multipet (m) and broad (br). Low- and high-resolution mass spectra (LRMS and
HRMS) were measured on a Finnigan MAT 95 spectrometer.
3.2. General Procedure for Synthesis of 2-Substituted-ethynyl Benzaldehyde Derivatives 1C–H
(1C as an Example)
To a solution of 2-bromobenzaldehyde (0.37 g), PdCl2(PPh3)2 (28 mg), and CuI (3.8 mg) in of Et3N
(20 mL) was added phenylacetylene (0.2 g). The resulting mixture was heated under a nitrogen
atmosphere at 60 °C for 4 h. After the reaction was completed, the reaction mixture was concentrated
under reduced pressure, and the resulting residue was purified by flash column chromatography
(PE/EA = 50/1, v/v, as an eluent) to give 2-((4-chlorophenyl)ethynyl)benzaldehyde (1C) in 90% yield.
1H-NMR (500 MHz, CDCl3) δ 10.61 (s, 1H), 7.94 (d, J = 7.8 Hz, 1H), 7.63 (d, J = 7.6 Hz, 1H), 7.58
13
(t, J = 7.5 Hz, 1H), 7.47 (m, 3H), 7.35 (d, J = 8.4 Hz, 2H). C-NMR (125 MHz, CDCl3) δ 191.47,
135.84, 135.19, 133.84, 133.25, 132.91, 128.93, 128.86, 127.46, 126.41, 120.83, 95.09, 85.91. LRMS
(ESI) m/z 241 [M+H]+; HRMS (ESI) m/z calcd C15H9ClONa [M+Na]+ 263.0240, found 263.0243.

Molecules 2013, 18
821
2-(p-Tolylethynyl)benzaldehyde (1D). 1H-NMR (400 MHz, CDCl3) δ 10.68 (s, 1H), 7.97 (d, J = 7.2 Hz,
1H), 7.66 (d, J = 7.2 Hz, 1H), 7.62 (m, 1H), 7.49 (m, 3H), 7.23 (d, J = 8.0 Hz, 2H), 2.42 (s, 3H).
13C-NMR (125 MHz, CDCl3) δ 191.87, 139.42, 135.77, 133.81, 133.17, 131.62, 129.34, 128.45,
127.21, 119.27, 96.69, 84.35, 21.63. LRMS (ESI) m/z 221 [M+H]+; HRMS (ESI) m/z calcd
C16H12ONa [M+Na]+ 243.0786, found 243.0784.
2-(m-Tolylethynyl)benzaldehyde (1E). 1H-NMR (500 MHz, CDCl3) δ 10.66 (s, 1H), 7.95 (d, J = 7.8 Hz,
1H), 7.91 (d, J = 9.7 Hz, 1H), 7.64 (d, J = 7.5 Hz, 1H), 7.59 (td, J = 7.6, 1.1 Hz, 1H), 7.45 (t, J = 7.6 Hz,
13
1H), 7.44–7.35 (m, 3H), 7.29 (d, J = 7.6 Hz, 1H), 7.21 (d, J = 7.7 Hz, 1H), 2.38 (s, 3H). C-NMR
(125 MHz, CDCl3) δ 191.78, 138.19, 135.70, 133.73, 133.11, 132.16, 129.92, 128.67, 128.45, 128.34,
127.15, 126.96, 122.02, 96.52, 84.44, 21.15. LRMS (ESI) m/z 221 [M+H]+; HRMS (ESI) m/z calcd
C16H12ONa [M+Na]+ 243.0786, found 243.0791.
5-Fluoro-2-(phenylethynyl)benzaldehyde (1F). 1H-NMR (400 MHz, CDCl3) δ 10.63 (s, 1H), 7.71–7.62
13
(m, 2H), 7.61–7.53 (m, 2H), 7.43–7.41 (m, 3H), 7.38–7.28 (m, 1H). C-NMR (125 MHz, CDCl3) δ
190.52, 162.41 (d, J = 252.7 Hz), 137.78 (d, J = 6.6 Hz), 135.28 (d, J = 7.6 Hz), 131.67, 129.21,
128.60, 123.04 (d, J = 3.3 Hz), 122.13, 121.42 (d, J = 22.8 Hz), 113.73 (d, J = 23.0 Hz), 96.06, 83.84.
LRMS (ESI) m/z 225 [M+H]+; HRMS (ESI) m/z calcd C15H9ONaF [M+Na]+ 247.0535, found
247.0529.
1
4-Methyl-2-(phenylethynyl)benzaldehyde (1G). H-NMR (400 MHz, CDCl3) δ 10.62 (s, 1H), 7.88 (d,
J = 8.0 Hz, 1H), 7.64–7.55 (m, 2H), 7.49 (s, 1H), 7.46–7.36 (m, 3H), 7.30 (s, 1H), 2.45 (s, 3H).
13C-NMR (125 MHz, CDCl3) δ 191.43, 144.91, 133.69, 133.62, 131.70, 129.72, 129.03, 128.55,
127.36, 126.91, 122.45, 95.87, 85.13, 21.67. LRMS (ESI) m/z 221 [M+H]+; HRMS (ESI) m/z calcd
C16H12ONa [M+Na]+ 243.0786, found 243.0786.
2-(Oct-1-yn-1-yl)benzaldehyde (1H). 1H-NMR (400 MHz, CDCl3) δ 10.56 (s, 1H), 7.91 (d, J = 8.0 Hz,
1H), 7.65–7.47 (m, 2H), 7.47–7.33 (m, 1H), 2.50 (t, J = 7.1 Hz, 2H), 1.73–1.59 (m, 2H), 1.54–1.44 (m,
13
2H), 1.42–1.31 (m, 4H), 0.93 (t, J = 6.8 Hz, 3H). C-NMR (125 MHz, CDCl3) δ 192.21, 135.96,
133.70, 133.29, 127.99, 127.84, 126.88, 98.24, 76.32, 31.32, 28.67, 28.50, 22.56, 19.61, 14.07. LRMS
(ESI) m/z 215 [M+H]+; HRMS (ESI) m/z calcd C15H18ONa [M+Na]+ 237.1255, found 237.1259.
3.3. General Procedure for Synthesis of Dihydrobenzo [4,5][1,3]oxazino[2,3-a]isoquinolines
(3Aa as an Example)
To a solution of 2-(phenylethynyl)benzaldehyde (1A, 0.1 mmol) in dry toluene (2 mL) were added
(2-aminophenyl)methanol (2a, 0.12 mmol) and AgNO3 catalyst (5 mol%). Then, the reaction vial was
sealed and the mixture was heated to 80 °C for 3 h. Afterwards, the cooled mixture was concentrated
under reduced pressure, and the resulting reside was purified by flash column chromatography
1
(PE/EA = 30/1, v/v, as an eluent) to afford the desired product 3Aa [17] in 94% yield. H-NMR
(400 MHz, CDCl3) δ 7.43 (d, J = 7.6 Hz, 1H), 7.34 (t, J = 7.2 Hz, 1H), 7.25–7.19 (m, 7H), 7.06
(d, J =7.6 Hz, 1H), 6.93 (t, J = 7.6 Hz, 1H), 6.80 (t, J = 8.4 Hz, 1H), 6.24 (d, J = 8.0 Hz, 1H), 6.10
13
(s, 1H), 5.97 (s, 1H), 5.27 (d, J = 14.4 Hz, 1H), 5.11 (d, J = 14.8 Hz, 1H). C-NMR (100 MHz,

Molecules 2013, 18
822
CDCl3) δ 140.75, 139.82, 136.90, 132.32, 128.96, 128.56, 128.41, 127.95, 127.82, 126.75, 125.97,
125.73, 124.66, 124.29, 123.74, 122.51, 105.63, 84.96, 69.99. LRMS (EI) m/z 311 (M+); HRMS (EI)
m/z calcd C22H17NO (M+) 311.1310, found 311.1303.
1
8-Fluoro-12-phenyl-4b,6-dihydrobenzo[4,5][1,3]oxazino[2,3-a]isoquinoline (3Ab). H-NMR (400 MHz,
CDCl3) δ 7.40 (d, J = 7.2 Hz, 1H), 7.34 (t, J = 7.6Hz, 1H), 7.26–7.22 (m, 4H), 7.20–7.17 (m, 3H), 6.77
(dd, J = 8.4, 2.4 Hz, 1H), 6.51 (td, J = 8.8, 2.8 Hz, 1H), 6.19 (dd, J = 8.8, 4.8 Hz, 1H), 6.04 (s, 1H),
13
5.91 (s, 1H), 5.24 (d, J = 15.2 Hz, 1H), 5.07 (d, J = 15.2 Hz, 1H). C-NMR (100 MHz, CDCl3) δ
158.60 (d, J = 242.0 Hz), 140.87, 136.70, 136.01, 132.17, 130.13 (d, J = 7.4 Hz), 129.17, 128.74,
127.98, 127.89, 127.15, 125.93, 125.60 (d, J = 7.8 Hz), 124.34, 112.81 (d, J = 22.8 Hz), 111.15 (d,
J = 22.9 Hz), 104.87, 84.98, 67.69. LRMS (EI) m/z 329 (M+); HRMS (EI) m/z calcd C22H16FNO (M+)
329.1216, found 329.1213.
1
8-Chloro-12-phenyl-4b,6-dihydrobenzo[4,5][1,3]oxazino[2,3-a]isoquinoline (3Ac). H-NMR (400 MHz,
CDCl3) δ 7.41 (d, J = 7.6 Hz, 1H), 7.33 (td, J = 7.6, 1.2 Hz, 1H), 7.29–7.17 (m, 6H), 7.04 (d, J = 2.4 Hz,
1H), 6.75 (dd, J = 8.8, 2.4 Hz, 1H), 6.13 (d, J = 8.8 Hz, 1H), 6.05 (s, 1H), 6.0 (s, 1H), 5.19 (d, J = 14.4 Hz,
13
1H), 5.04 (d, J = 14.4 Hz, 1H). C-NMR (100 MHz, CDCl3) δ 140.19, 138.24, 136.43, 132.10,
129.55, 129.05, 128.46, 128.16, 128.05, 127.54, 126.80, 126.50, 126.24, 126.00, 124.61, 124.51,
124.40, 106.49, 85.05, 67.44. LRMS (EI) m/z 345 (M+); HRMS (EI) m/z calcd C22H16ClNO (M+)
345.0920, found 345.0919.
1
9-Chloro-12-phenyl-4b,6-dihydrobenzo[4,5][1,3] oxazino[2,3-a]isoquinoline (3Ad). H-NMR (300 MHz,
CDCl3) δ 7.43 (d, J = 7.2 Hz, 1H), 7.36–7.26 (m, 6H), 7.23–7.18 (m, 2H), 6.97 (d, J = 8.1 Hz, 1H),
6.84 (dd, J = 8.1, 1.8 Hz, 1H), 6.16 (d, J =1.5 Hz, 1H), 6.11 (s, 1H), 6.07 (s, 1H), 5.16 (d, J = 14.1 Hz, 1H),
13
5.04 (d, J = 14.1 Hz, 1H). C-NMR (100 MHz, CDCl3) δ 139.88, 139.37, 135.60, 131.61, 131.20,
128.49, 127.85, 127.78, 127.29, 125.99, 125.70, 125.50, 125.06, 123.94, 122.11, 121.49, 107.48,
84.64, 66.85. LRMS (EI) m/z 345 (M+); HRMS (EI) m/z calcd C22H16ClNO (M+) 345.0920, found
345.0916.
1
8-Bromo-12-phenyl-4b,6-dihydrobenzo[4,5][1,3] oxazino[2,3-a]isoquinoline (3Ae). H-NMR (400 MHz,
CDCl3) δ 7.41 (d, J = 8.0 Hz, 1H), 7.32 (td, J = 7.6, 1.2 Hz, 1H), 7.21–7.28 (m, 6H), 7.19–7.17 (m,
2H), 6.88 (dd, J = 8.4, 2.0 Hz,1H), 6.07 (s, 1H), 6.05 (s, 1H), 6.01(s, 1H), 5.18 (d, J = 14.8 Hz, 1H),
13
5.03 (d, J = 14.8 Hz, 1H). C-NMR (100 MHz, CDCl3) δ 140.07, 138.69, 136.38, 132.11, 129.89,
129.04, 128.93, 128.42, 128.21, 128.09, 127.55, 126.98, 126.39, 126.32, 124.71, 124.43, 115.04,
106.83, 85.07, 67.33. LRMS (EI) m/z 389 (M+); HRMS (EI) m/z calcd C22H16BrNO (M+) 389.0415,
found 389.0410.
1
8-Fluoro-12-(4-fluorophenyl)-4b,6-dihydrobenzo[4,5][1,3]oxazino[2,3-a]isoquinoline (3Bb). H-NMR
(400 MHz, CDCl3) δ 7.43 (d, J = 7.6 Hz, 1H), 7.37 (t, J = 7.2 Hz, 1H), 7.25–7.30 (m, 1H), 7.15–7.23
(m, 3H), 6.97 (t, J = 8.4 Hz, 2H), 6.8 (dd, J = 8.4, 2.4 Hz, 1H), 6.57 (td, J = 8.8, 2.4 Hz, 1H), 6.21 (dd,
J = 8.8, 4.8 Hz, 1H), 6.05 (s, 1H), 5.90 (s, 1H), 5.27 (d, J = 15.2 Hz, 1H), 5.09 (d, J = 15.2 Hz, 1H).
13C-NMR (100 MHz, CDCl3) δ 162.39 (d, J = 246.6 Hz), 158.75 (d, J = 242.7 Hz), 139.96, 135.91,
132.84, 132.09, 130.57 (d, J = 8.0 Hz), 130.36 (d, J = 7.1 Hz), 129.27, 127.22, 126.11, 126.04, 125.71

Molecules 2013, 18
823
(d, J = 8.1 Hz), 124.40, 115.09 (d, J = 21.4 Hz), 113.00 (d, J = 23.0 Hz), 111.34(d, J = 22.8 Hz),
105.09, 85.07, 67.74. LRMS (EI) m/z 347 (M+); HRMS (EI) m/z calcd C22H15F2NO (M+) 347.1122,
found 347.1116.
1
9-Chloro-12-(4-fluorophenyl)-4b,6-dihydrobenzo[4,5][1,3]oxazino[2,3-a]isoquinoline (3Bd). H-NMR
(400 MHz, CDCl3) δ 7.45 (d, J = 7.6 Hz, 1H), 7.36 (td, J = 7.6, 1.2 Hz,1H), 731–7.25 (m, 3H), 7.22 (d,
J = 7.6 Hz, 1H), 7.05–6.98 (m, 3H), 6.89 (dd, J = 8.0, 2.0 Hz, 1H), 6.18 (d, J = 1.6 Hz, 1H), 6.10 (s,
1H), 6.07 (s, 1H), 5.16 (d, J = 14.4 Hz, 1H), 5.05 (d, J = 14.4 Hz, 1H). 13C-NMR (100 MHz, CDCl3) δ
162.63 (d, J = 246.8 Hz), 140.26, 138.91, 132.24 (d, J = 3.4 Hz), 132.00, 131.88, 130.05 (d, J = 8.2 Hz),
129.02, 127.76, 126.66, 126.26, 126.01, 125.75, 124.52, 122.67, 122.10, 115.40 (d, J = 21.6 Hz),
108.06, 85.08, 67.37. LRMS (EI) m/z 363 (M+); HRMS (EI) m/z calcd C22H15ClFNO (M+) 363.0826,
found 363.0831.
1
8-Bromo-12-(4-fluorophenyl)-4b,6-dihydrobenzo[4,5][1,3]oxazino[2,3-a]isoquinoline (3Be). H-NMR
(400 MHz, CDCl3) δ 7.45 (d, J = 7.6 Hz, 1H), 7.36 (td, J = 7.6, 1.2 Hz, 1H), 7.31–7.25 (m, 3H), 7.22
(d, J = 7.6 Hz, 1H), 7.05–6.98 (m, 3H), 6.89 (dd, J = 8.0, 2.0 Hz,1H), 6.18 (d, J = 1.6 Hz, 1H), 6.10 (s,
1H), 6.07 (s, 1H), 5.16 (d, J = 14.4 Hz, 1H), 5.05 (d, J = 14.4Hz, 1H). 13C-NMR (100 MHz, CDCl3) δ
162.49 (d, J = 246.8 Hz), 139.13, 138.57, 132.51 (d, J = 3.2 Hz), 132.01, 130.27, 130.19, 130.1,
129.09 (d, J = 6.4 Hz), 127.72, 126.99, 126.49, 126.46, 124.80, 124.47, 115.42 115.26 (d, J = 21.6 Hz),
106.91, 85.11, 67.35. LRMS (EI) m/z 407 (M+); HRMS (EI) m/z calcd C22H15BrFNO (M+) 407.0321,
found 407.0320.
1
12-(4-Fluorophenyl)-8-methyl-4b,6-dihydrobenzo[4,5][1,3]oxazino[2,3-a]isoquinoline (3Bf). H-NMR
(400 MHz, CDCl3) δ 7.40 (d, J = 7.6 Hz, 1H), 7.33 (t, J = 7.2 Hz, 1H), 7.26–7.14 (m, 4H), 6.93 (t,
J = 8.8 Hz, 2H), 6.86 (s, 1H), 6.63 (d, J = 8.0 Hz, 1H), 6.12 (d, J = 8.4 Hz, 1H), 6.05 (s, 1H), 5.84 (s,
1H), 5.25 (d, J = 14.8 Hz, 1H), 5.06 (d, J = 14.8 Hz, 1H), 2.25 (s, 3H). 13C-NMR (100 MHz, CDCl3) δ
162.26 (d, J = 246.1 Hz), 140.12, 137.29, 133.14 (d, J = 3.7 Hz), 132.69, 132.20, 130.48 (d, J = 8.3 Hz),
129.06, 128.55, 127.19, 126.48, 126.10, 125.84, 125.16, 124.21, 124.07, 114.88 (d, J = 21.4 Hz),
104.47, 84.93, 68.05, 20.81. LRMS (EI) m/z 343 (M+); HRMS (EI) m/z calcd C23H18FNO (M+)
343.1372, found 343.1375.
12-(4-Fluorophenyl)-10-methyl-4b,6-dihydrobenzo[4,5][1,3]oxazino[2,3-a]isoquinoline (3Bg). 1H-NMR
(400 MHz, CDCl3) δ 7.38–7.36 (m, 2H), 7.26–7.20 (m, 2H), 7.10–6.92 (m, 4H), 6.87–6.77 (m, 3H),
5.91–5.90 (m, 2H), 5.30–5.17 (m, 2H), 1.67 (s, 3H). 13C-NMR (125 MHz, CDCl3) δ 162.21 (d,
J = 246.3 Hz), 141.92, 140.45, 133.85, 133.35, 132.50, 130.99, 130.16 (d, J = 8.0 Hz), 129.36, 128.50,
127.80, 125.66 (d, J = 33.1 Hz), 125.67, 124.41, 122.70, 114.53, 114.36, 104.47, 85.02, 67.75, 17.34.
LRMS (EI) m/z 343 (M+); HRMS (EI) m/z calcd C23H18FNO (M+) 343.1372, found 343.1368.
1
12-(4-Chlorophenyl)-4b,6-dihydrobenzo[4,5][1,3]oxazino[2,3-a]isoquinoline (3Ca). H-NMR (400 MHz,
CDCl3) δ 7.42 (d, J = 7.6 Hz, 1H), 7.33 (t, J = 7.2 Hz, 1H), 7.27–7.14 (m, 6H), 7.06 (d, J = 7.2 Hz,
1H), 6.95 (t, J = 7.6 Hz, 1H), 6.84 (t, J = 7.6 Hz, 1H), 6.22 (d, J = 8.4 Hz, 1H), 6.08 (s, 1H), 5.95 (s,
13
1H), 5.26 (d, J = 14.4 Hz, 1H), 5.09 (d, J = 14.8 Hz, 1H). C-NMR (100 MHz, CDCl3) δ 139.52,
135.38, 133.71, 132.04, 129.81, 129.02, 128.44, 128.22, 126.76, 126.23, 125.95, 124.81, 124.37,

Molecules 2013, 18
824
123.67, 122.73, 106.07, 84.91, 67.97. LRMS (EI) m/z 345 (M+); HRMS (EI) m/z calcd C22H16ClNO
(M+) 345.0920, found 345.0890.
1
8-Chloro-12-(4-chlorophenyl)-4b,6-dihydrobenzo[4,5][1,3]oxazino[2,3-a]isoquinoline (3Cc). H-NMR
(400 MHz, CDCl3) δ 7.41 (d, J = 7.6 Hz, 1H), 7.34 (td, J = 7.2, 1.2 Hz, 1H), 7.28–7.23 (m, 3H),
7.20–7.14 (m, 3H), 7.06 (d, J = 2.0 Hz, 1H), 6.80 (dd, J = 8.8, 2.4 Hz, 1H), 6.12 (d, J = 8.4 Hz, 1H),
6.04 (s, 1H), 5.99 (s, 1H), 5.18 (d, J = 14.8 Hz, 1H), 5.04 (d, J = 14.8 Hz, 1H). 13C-NMR (100 MHz,
CDCl3) δ138.99, 137.96, 134.93, 133.99, 131.85, 129.71, 129.62, 129.12, 128.45, 127.80, 126.92,
126.54, 126.51, 126.24, 124.79, 124.51, 124.42, 107.02, 85.05, 67.45. LRMS (EI) m/z 379 (M+);
HRMS (EI) m/z calcd C22H15Cl2NO (M+) 379.0531, found 379.0503.
1
9-Chloro-12-(4-chlorophenyl)-4b,6-dihydrobenzo[4,5][1,3]oxazino[2,3-a]isoquinoline (3Cd). H-NMR
(400 MHz, CDCl3) δ 7.42 (d, J = 7.6 Hz, 1H), 7.33 (td, J = 7.2, 1.2 Hz, 1H), 7.29–7.25 (m, 3H),
7.23–7.17 (m, 3H), 6.97 (d, J = 8.0 Hz, 1H), 6.86 (dd, J = 8.0, 2.0 Hz, 1H), 6.15 (d, J = 1.6 Hz, 1H),
13
6.11 (s, 1H), 6.04 (s, 1H), 5.12 (d, J = 14.4 Hz, 1H), 5.02 (d, J = 14.4 Hz, 1H). C-NMR (100 MHz,
CDCl3) δ 140.08, 138.61, 134.56, 134.15, 131.96 131.82, 129.37, 128.96, 128.57, 127.94, 126.82,
126.08, 125.83, 125.74, 124.57, 122.35, 122.00, 108.72, 84.99, 67.26. LRMS (EI) m/z 379 (M+);
HRMS (EI) m/z calcd C22H15Cl2NO (M+) 379.0531, found 379.0508.
12-(p-Tolyl)-4b,6-dihydrobenzo[4,5][1,3]oxazino[2,3-a]isoquinoline (3Da). 1H-NMR (400 MHz,
CDCl3) δ 7.41 (d, J = 7.6, 1H), 7.31 (td, J = 7.6, 1.2 Hz, 1H), 7.23 (td, J = 7.2, 1.2 Hz, 1H), 7.17 (d,
J = 7.6 Hz, 1H), 7.12 (d, J = 8.0, 2H), 7.05 (m, 3H), 6.92 (td, J = 7.6, 1.2 Hz, 1H), 6.81 (td, J = 8.4, 1.2 Hz,
1H), 6.25 (d, J = 8.0, 1H), 6.08 (s, 1H), 5.94 (s, 1H), 5.25 (d, J = 14.8, 1H), 5.09 (d, J = 14.8, 1H), 2.33
(s, 3H). 13C-NMR (100 MHz, CDCl3) δ 140.77, 139.87, 137.69, 133.96, 132.44, 128.91, 128.66,
128.41, 128.35, 126.71, 126.63, 125.85, 125.77, 124.62, 124.20, 123.74, 122.37, 105.42, 84.98, 67.96,
21.26. LRMS (EI) m/z 325 (M+); HRMS (EI) m/z calcd C23H19NO (M+) 325.1467, found 325.1472.
8-Chloro-12-(p-tolyl)-4b,6-dihydrobenzo[4,5][1,3]oxazino[2,3-a]isoquinoline (3Dc). 1H-NMR (300 MHz,
CDCl3) δ 7.41 (d, J = 10.0 Hz, 1H), 7.32 (td, J = 10.0, 1.6 Hz, 1H), 7.26–7.04 (m, 7H), 6.77 (dd,
J = 10.6, 3.2 Hz, 1H), 6.16 (d, J = 10.6 Hz, 1H), 6.05 (s, 1H), 5.99 (s, 1H), 5.18 (d, J = 19.6 Hz, 1H),
13
5.04 (d, J = 19.2 Hz, 1H), 2.35 (s, 3H). C-NMR (100 MHz, CDCl3) δ 140.27, 138.36, 138.04,
133.56, 132.31, 129.53, 129.03, 128.92, 128.36, 127.42, 127.00, 126.41, 126.17, 126.11, 124.61,
124.53, 124.37, 106.37, 85.17, 67.45, 21.30. LRMS (EI) m/z 359 (M+); HRMS (EI) m/z calcd
C23H18ClNO (M+) 359.1077, found 359.1078.
9-Chloro-12-(p-tolyl)-4b,6-dihydrobenzo[4,5][1,3]oxazino[2,3-a]isoquinoline (3Dd). 1H-NMR (400 MHz,
CDCl3) δ 7.42 (dd, J = 8.8, 0.8 Hz, 1H), 7.32 (td, J = 7.6, 1.2 Hz, 1H), 7.25 (td, J = 7.2, 1.2 Hz, 1H),
7.20–7.16 (m, 3H), 7.10 (d, J = 8.0 Hz, 2H), 6.96 (d, J = 8.0 Hz, 1H), 6.83 (dd, J = 8.0, 1.6 Hz, 1H),
6.18 (d, J = 2.0 Hz, 1H), 6.11 (s, 1H), 6.05 (s, 1H), 5.13 (d, J = 14.0 Hz, 1H), 5.02 (d, J = 14.0 Hz,
13
1H), 2.35 (s, 3H). C-NMR (100 MHz, CDCl3) δ 140.42, 139.90, 138.22, 133.13, 132.25, 131.75,
129.00, 128.85, 128.03, 127.90, 126.38, 125.98, 125.74, 125.52, 124.38, 122.49, 121.64, 107.79,
85.04, 67.25, 21.27. LRMS (EI) m/z 359 (M+); HRMS (EI) m/z calcd C23H18ClNO (M+) 359.1077,
found 359.1053.

Molecules 2013, 18
825
1
8-Bromo-12-(p-tolyl)-4b,6-dihydrobenzo[4,5][1,3]oxazino[2,3-a]isoquinoline (3De). H-NMR (400 MHz,
CDCl3) δ 7.42 (d, J = 7.6 Hz, 1H), 7.32 (td, J = 7.6, 1.2 Hz, 1H), 7.24 (td, J = 7.2, 1.2 Hz, 1H), 7.86 (d,
J = 8.0 Hz, 2H), 7.14 (d, J = 8.0 Hz, 2H), 7.08 (d, J = 8.0 Hz, 2H), 6.91 (dd, J = 8.4, 2.0 Hz, 1H), 6.10
(d, J = 8.8 Hz, 1H), 6.04 (s, 1H), 6.02 (s, 1H), 5.17 (d, J = 14.4 Hz, 1H), 5.03 (d, J = 14.8 Hz, 1H),
13
2.35 (s, 3H). C-NMR (100 MHz, CDCl3) δ 140.07, 138.72, 138.00, 133.44, 132.25, 129.80, 128.95,
128.91, 128.25, 127.47, 127.10, 126.23, 126.17, 124.66, 124.32, 114.83, 106.64, 85.09, 67.25, 21.25.
LRMS (EI) m/z 403 (M+); HRMS (EI) m/z calcd C23H18BrNO (M+) 403.0572, found 403.0558.
1
8-Methyl-12-(p-tolyl)-4b,6-dihydrobenzo[4,5][1,3]oxazino[2,3-a]isoquinoline (3Df). H-NMR (400 MHz,
CDCl3) δ 7.40 (d, J = 7.6 Hz, 1H), 7.32 (td, J = 7.6, 0.8 Hz, 1H), 7.22 (td, J = 7.6, 1.2 Hz, 1H), 7.17 (d,
J = 7.6 Hz, 1H), 7.11 (d, J = 7.6 Hz, 2H), 7.05 (d, J = 8.0 Hz, 2H), 6.86 (s, 1H), 6.62 (d, J = 7.2 Hz,
1H), 6.17 (d, J = 8.0 Hz, 1H), 6.06 (s, 1H), 5.87 (s, 1H), 5.25 (d, J = 14.8 Hz, 1H), 5.07 (d, J = 14.8 Hz,
1H), 2.34 (s, 3H), 2.25 (s, 3H). 13C-NMR (100 MHz, CDCl3) δ 141.07, 137.56, 137.53, 134.15,
132.48, 132.24, 128.93, 128.56, 128.36, 127.01, 126.43, 126.23, 125.58, 125.01, 124.12, 123.95,
104.29, 84.98, 68.01, 21.25, 20.83. LRMS (EI) m/z 339 (M+); HRMS (EI) m/z calcd C24H21NO (M+)
339.1623, found 339.1609.
1
14-(p-Tolyl)-4b,6-dihydronaphtho[2',3':4,5][1,3]oxazino[2,3-a]isoquinoline (3Dh). H-NMR (400 MHz,
CDCl3) δ 7.70–7.66 (m, 1H), 7.54 (s, 1H), 7.47 (d, J = 7.6 Hz, 1H), 7.34–7.30 (m, 3H), 7.28–7.21 (m,
5H), 7.06 (d, J = 7.6 Hz, 2H), 6.53 (s, 1H), 6.36 (s, 1H), 6.20 (s, 1H), 5.25 (d, J = 13.6 Hz, 1H), 5.23
13
(d, J = 13.6 Hz, 1H), 2.30 (s, 3H). C-NMR (100 MHz, CDCl3) δ 140.13, 137.98, 136.77, 133.25,
132.84, 132.49, 129.39, 129.02, 128.59, 128.45, 128.07, 127.74, 127.15 , 126.80, 126.61, 125.61,
124.50, 124.20, 123.94, 123.06, 117.77, 109.94, 85.75, 67.43, 21.20. LRMS (EI) m/z 375 (M+); HRMS
(EI) m/z calcd C27H21NO (M+) 375.1623, found 375.1621.
12-(m-Tolyl)-4b,6-dihydrobenzo[4,5][1,3]oxazino[2,3-a]isoquinoline (3Ea). 1H-NMR (400 MHz,
CDCl3) δ 7.43 (d, J = 7.2 Hz, 1H), 7.34 (t, J = 7.2 Hz, 1H), 7.26–7.18 (m, 2H), 7.14–7.04 (m, 4H),
6.99–6.91 (m, 2H), 6.82 (t, J = 7.6 Hz, 1H), 6.26 (d, J = 8.0 Hz, 1H), 6.10 (s, 1H), 5.97 (s, 1H), 5.27
13
(d, J = 14.4 Hz, 1H), 5.11 (d, J = 14.4 Hz, 1H), 2.30 (s, 3H). C-NMR (100 MHz, CDCl3) δ 140.89,
139.82, 137.60, 136.77, 132.36, 129.12, 128.90, 128.54, 128.28, 127.69, 126.70, 125.85, 125.72,
125.65, 124.58, 124.21, 123.69, 122.42, 105.44, 84.93, 67.93, 21.34. LRMS (EI) m/z 325 (M+); HRMS
(EI) m/z calcd C23H19NO (M+) 325.1467, found 325.1468.
8-Chloro-12-(m-tolyl)-4b,6-dihydrobenzo[4,5][1,3]oxazino[2,3-a]isoquinoline (3Ec). 1H-NMR (400 MHz,
CDCl3) δ 7.41 (d, J = 7.6 Hz, 1H), 7.33 (t, J = 7.2 Hz, 1H), 7.26–7.10 (m, 5H), 7.04 (s, 1H), 6.96 (d,
J = 6.8 Hz, 1H), 6.76 (dd, J = 8.4, 1.2 Hz, 1H), 6.15 (d, J = 8.8 Hz, 1H), 6.05 (s, 1H), 5.99 (s, 1H),
13
5.19 (d, J = 14.4 Hz, 1H), 5.04 (d, J = 14.8 Hz, 1H), 2.31 (s, 3H). C-NMR (100 MHz, CDCl3) δ
140.35, 138.30, 137.90, 136.37, 132.19, 129.42, 129.00, 128.82, 127.94, 127.40, 126.90, 126.43,
126.18, 125.99, 125.65, 124.55, 124.43, 124.36, 106.46, 85.09, 67.42, 21.41. LRMS (EI) m/z 359
(M+); HRMS (EI) m/z calcd C23H18ClNO (M+) 359.1077, found 359.1063.

Molecules 2013, 18
826
8-Bromo-12-(m-tolyl)-4b,6-dihydrobenzo[4,5][1,3]oxazino[2,3-a]isoquinoline (3Ee). 1H-NMR (400 MHz,
CDCl3) δ 7.41 (d, J = 7.6 Hz, 1H), 7.33 (td, J = 7.2, 1.2 Hz,1H), 7.25 (td, J = 7.6, 1.2 Hz,1H),
7.20–7.08 (m, 5H), 6.97 (d, J = 7.2Hz, 1H), 6.90 (dd, J = 8.8, 2.0 Hz, 1H), 6.09 (d, J = 8.8 Hz, 1H),
6.05 (s, 1H), 6.02 (s, 1H), 5.18 (d, J = 14.8 Hz, 1H), 5.04 (d, J = 15.6 Hz, 1H), 2.3 (s, 3H). 13C-NMR
(100 MHz, CDCl3) δ 140.20, 138.73, 137.93, 136.31, 132.18, 129.71, 128.98, 128.91, 128.85, 127.94,
127.48, 127.08, 126.30, 126.23, 125.59, 24.60, 124.37, 114.87, 106.80, 85.08, 67.27, 21.42. LRMS
(EI) m/z 403 (M+); HRMS (EI) m/z calcd C23H18BrNO (M+) 403.0572, found 403.0576.
1
3-Fluoro-12-phenyl-4b,6-dihydrobenzo[4,5][1,3]oxazino[2,3-a]isoquinoline (3Fa). H-NMR (400 MHz,
CDCl3) δ 7.29–7.27 (m, 5H), 7.20–7.16 (m, 2H), 7.10–7.02 (m, 2H), 6.93 (t, J = 7.6 Hz, 1H), 6.82 (t,
J = 7.6 Hz, 1H), 6.24 (d, J = 8.0 Hz, 1H), 6.09 (s, 1H), 6.04 (s, 1H), 5.24 (d, J = 14.4 Hz, 1H), 5.10 (d,
13
J = 14.4 Hz, 1H). C-NMR (100 MHz, CDCl3) δ 161.49 (d, J = 243.5 Hz), 140.01, 139.38, 136.64,
129.23, 129.13 (d, J = 7.6 Hz), 128.73, 128.38, 128.11, 127.99, 126.13, 125. 86 (d, J = 7.9 Hz),
124.70, 123.18, 122.24, 116.09 (d, J = 22.0 Hz), 113.16 (d, J = 22.6 Hz), 105.86, 84.67, 67.86. LRMS
(EI) m/z 329 (M+); HRMS (EI) m/z calcd C22H16FNO (M+) 329.1216, found 329.1210.
1
8-Chloro-3-fluoro-12-phenyl-4b,6-dihydrobenzo[4,5][1,3]oxazino[2,3-a]isoquinoline (3Fc). H-NMR
(400 MHz, CDCl3) δ 7.30–7.23 (m, 5H), 7.18–7.13 (m, 2H), 7.06–7.00 (m, 2H), 6.76 (dd, J = 8.8, 2.4 Hz,
1H), 6.11 (d, J = 8.8 Hz,1H), 6.06 (s, 1H), 6.02 (s, 1H), 5.14 (d, J = 14.4 Hz, 1H), 5.02 (d, J = 14.4 Hz,
13
1H). C-NMR (100 MHz, CDCl3) δ 162.80 (d, J = 244.2 Hz), 139.40, 137.77, 136.13, 129.25 (d,
J = 7.5 Hz), 129.06, 128.48, 128.45, 128.28, 128.22, 127.20, 126.34, 125.98 (d, J = 7.7 Hz), 124.64,
123.85, 116.12 (d, J = 21.9 Hz), 112.96 (d, J = 22.9 Hz), 106.75, 84.71, 67.25. LRMS (EI) m/z 363
(M+); HRMS (EI) m/z calcd C22H15ClFNO (M+) 363.0826, found 363.0808.
1
8-Bromo-3-fluoro-12-phenyl-4b,6-dihydrobenzo[4,5][1,3]oxazino[2,3-a]isoquinoline (3Fe). H-NMR
(400 MHz, CDCl3) δ 7.30–7.24 (m, 5H), 7.20 (d, J = 2.4Hz, 1H), 7.17–7.13 (m, 2H), 7.04 (td, J = 8.4,
2.4 Hz,1H), 6.90 (dd, J = 8.8, 2.4 Hz, 1H), 6.09 (s, 1H), 6.05 (d, J = 8.8 Hz, 1H), 6.02 (s, 1H), 5.13 (d,
J = 14.0 Hz, 1H), 5.08–4.96 (d, J = 14.4 Hz, 1H). 13C-NMR (100 MHz, CDCl3) δ 161.64 (d, J = 244.1 Hz),
139.25, 138. 19, 136.06, 129.46 (d, J = 7.2 Hz), 129.38, 129.26, 128.42, 128.32, 128.22, 128.16,
127.54, 125.98 (d, J = 7.9 Hz), 124.02, 116.07 (d, J = 22.0 Hz), 114.62, 112.85 (d, J = 23.0 Hz),
107.12, 84.71, 67.10. LRMS (EI) m/z 407 (M+); HRMS (EI) m/z calcd C22H15BrFNO (M+) 407.0321,
found 407.0316.
1
3-Fluoro-8-methyl-12-phenyl-4b,6-dihydrobenzo[4,5][1,3]oxazino[2,3-a]isoquinoline (3Ff). H-NMR
(400 MHz, CDCl3) δ 7.26–7.19 (m, 5H), 7.16–7.11 (m, 2H), 7.02 (td, J = 8.4, 2.4 Hz, 1H), 6.86 (s,
1H), 6.60 (d, J = 8.4 Hz, 1H), 6.11 (d, J = 8.4 Hz, 1H), 6.03 (s, 1H), 5.91 (s, 1H), 5.21 (d, J =14.8 Hz,
1H), 5.05 (d, J = 14.8 Hz, 1H), 2.23 (s, 3H). 13C-NMR (100 MHz, CDCl3) δ 160.78 (d, J = 243.8 Hz),
140.30, 137.07, 136.80, 132.22, 128.86, 128.74, 128.54, 128.29 (d, J = 7.8 Hz), 127.97, 127.84,
126.66, 125.77 (d, J = 7.7 Hz), 125.10, 123.50, 116.18 (d, J = 22.8 Hz), 113.48 (d, J = 22.3 Hz),
104.42, 84.59, 67.94, 20.80. LRMS (EI) m/z 343 (M+); HRMS (EI) m/z calcd C23H18FNO (M+)
343.1372, found 343.1375.

Molecules 2013, 18
827
1
2-Methyl-12-phenyl-4b,6-dihydrobenzo[4,5][1,3]oxazino[2,3-a]isoquinoline (3Ga). H-NMR (400 MHz,
CDCl3) δ 7.31 (d, J = 8.0 Hz, 1H), 7.26–7.19 (m, 5H), 7.07–7.03 (m, 2H), 7.00 (s, 1H), 6.92 (t,
J = 7.6Hz, 1H), 6.78 (t, J = 7.6Hz, 1H), 6.22 (d, J = 8.4 Hz, 1H), 6.07 (s, 1H), 5.90 (s, 1H), 5.26 (d,
J =14.8 Hz,1H), 5.09 (d, J =14.4 Hz,1H), 2.36 (s, 3H). 13C-NMR (125 MHz, CDCl3) δ 140.81, 140.05,
138.74, 137.11, 132.24, 128.65, 128.52, 127.97, 127.79, 126.94, 126.78, 125.69, 124.79, 124.70,
124.12, 123.88, 122.54, 105.59, 85.00, 68.00, 21.40. LRMS (EI) m/z 325 (M+); HRMS (EI) m/z calcd
C23H19NO (M+) 325.1467, found 325.1463
8-Chloro-2-methyl-12-phenyl-4b,6-dihydrobenzo[4,5][1,3]oxazino[2,3-a]isoquinoline (3Gc). 1H-NMR
(400 MHz, CDCl3) δ 7.32–7.25 (m, 4H), 7.23–7.21 (m, 2H), 7.08 (d, J = 8.0 Hz, 1H), 7.04 (d, J = 1.6 Hz,
1H), 7.01 (s, 1H), 6.75 (dd, J = 8.8, 2.4 Hz, 1H), 6.13 (d, J = 8.8 Hz, 1H), 6.02 (s, 1H), 5.95 (s, 1H),
5.18 (d, J =14.8 Hz,1H), 5.04 (d, J =14.8 Hz,1H), 2.34 (s, 3H). 13C-NMR (125 MHz, CDCl3) δ 140.27,
138.87, 138.51, 136.68, 132.07, 129.69, 128.56, 128.21, 128.05, 127.60, 127.21, 126.58, 125.99,
124.95, 124.67, 124.23, 106.49, 85.14, 67.49, 21.41. LRMS (EI) m/z 359 (M+); HRMS (EI) m/z calcd
C23H18ClNO (M+) 359.1077, found 359.1058.
2,8-Dimethyl-12-phenyl-4b,6-dihydrobenzo[4,5][1,3]oxazino[2,3-a]isoquinoline (3Gf). 1H-NMR
(400 MHz, CDCl3) δ 7.31–7.28 (d, J = 8.0 Hz, 1H), 7.26–7.18 (m, 5H), 7.04 (d, J = 7.6 Hz, 1H), 6.99
(s, 1H), 6.85 (s, 1H), 6.59 (d, J = 7.6 Hz, 1H), 6.12 (d, J = 8.0 Hz, 1H), 6.04 (s, 1H), 5.81 (s, 1H), 5.25
(d, J = 14.8 Hz,1H), 5.06 (d, J = 14.8 Hz,1H), 2.36 (s, 3H), 2.24(s, 3H). 13C-NMR (125 MHz, CDCl3)
δ 141.11, 138.76, 137.73, 137.30, 132.43, 132.29, 128.82, 128.52, 127.89, 127.69, 127.14, 126.73,
126.36, 125.10, 124.69, 124.08, 123.59, 104.46, 84.99, 68.06, 21.42, 20.87. LRMS (EI) m/z 339 (M+);
HRMS (EI) m/z calcd C24H21NO (M+) 339.1623, found 339.1617.
1
2-Methyl-14-phenyl-4b,6-dihydronaphtho[2',3':4,5][1,3]oxazino[2,3-a]isoquinoline (3Gh). H-NMR
(400 MHz, CDCl3) δ 7.68 (d, J = 8.4 Hz,1H), 7.54 (s, 1H), 7.42–7.36 (m, 3H), 7.27–7.25 (m, 6H), 7.10
(d, J = 7.6 Hz, 1H), 7.07 (s, 1H), 6.51 (s, 1H), 6.31 (s, 1H), 6.21 (s, 1H), 5.28 (d, J = 13.6 Hz, 1H),
13
5.22 (d, J = 14.0 Hz, 1H), 2.39 (s, 3H). C-NMR (125 MHz, CDCl3) δ 140.27, 138.34, 137.00,
136.43, 132.78, 132.32, 128.77, 128.33, 128.17, 128.10, 128.03, 127.60, 127.20, 126.88, 126.53,
125.76, 124.98, 124.87, 124.12, 123.19, 118.14, 109.99, 85.88, 67.63, 21.39. LRMS (EI) m/z 375
(M+); HRMS (EI) m/z calcd C27H21NO (M+) 375.1623, found 375.1617.
12-Hexyl-4b,6-dihydrobenzo[4,5][1,3]oxazino[2,3-a]isoquinoline (3Ha). 1H-NMR (400 MHz, CDCl3)
δ 7.35– 7.31 (m, 3H), 7.27–7.09 (m, 5H), 5.83(s, 1H), 5.75(s, 1H), 5.23 (d, J = 15.6 Hz, 1H), 5.00 (d,
J = 15.2 Hz, 1H), 2.57–2.36 (m, 2H), 1.46–1.31 (m, 2H), 1.25–1.13 (m, 6H), 0.85 (t, J = 6.4 Hz, 3H).
13C-NMR (100 MHz, CDCl3) δ 142.63, 140.91, 132.49, 130.91, 129.23, 127.63, 125.91, 125.31,
125.15, 125.00, 124.92, 124.85, 123.62, 100.42, 84.85, 67.74, 32.88, 31.52, 28.75, 27.57, 22.43, 14.02.
LRMS (EI) m/z 319 (M+); HRMS (EI) m/z calcd C22H25NO (M+) 319.1936, found 319.1935.
1
12-Hexyl-8-iodo-4b,6-dihydrobenzo[4,5][1,3]oxa-zino[2,3-a]isoquinoline (3Hi). H-NMR (300 MHz,
CDCl3) δ 7.54 (d, J =8.7 Hz, 1H), 7.43 (s, 1H), 7.34–7.27 (m, 2H), 7.19–7.10 (m, 2H), 6.92 (d, J = 8.4 Hz,
1H), 5.74 (s, 2H), 5.14 (d, J = 15.3 Hz,1H), 4.91 (d, J =15.9 Hz, 1H), 2.43–2.40 (m, 2H), 1.30–1.17
13
(m, 8H), 0.88–0.84 (m, 3H). C-NMR (125 MHz, CDCl3) δ 141.92, 140.66, 134.94, 134.27, 133.07,

Molecules 2013, 18
828
132.26, 129.39, 127.60, 126.78, 125.19, 124.88, 123.77, 101.09, 84.83, 67.02, 32.73, 31.51, 28.74,
27.59, 22.46, 14.07. LRMS (EI) m/z 445 (M+); HRMS (EI) m/z calcd C22H24INO (M+) 445.0903,
found 445.0905.
6-Phenyl-11b,13-dihydropyrido[2',3':4,5][1,3]oxa-zino[2,3-a]isoquinoline (3Aj). 1H-NMR (500 MHz,
CDCl3) δ 7.81 (d, J = 5.5 Hz, 1H), 7.46 (d, J = 7.5 Hz, 1H), 7.36–7.28 (m, 6H), 7.26–7.19 (m, 3H),
6.71 (m, 1H), 6.34 (s, 1H), 6.23 (s, 1H), 5.09 (d, J = 14.0 Hz, 1H), 5.03 (d, J = 13.5 Hz, 1H). 13C-NMR
(125 MHz, CDCl3) δ 150.45, 146.85, 139.24, 137.51, 132.44, 132.28, 129.63, 128.69, 128.04, 127.49,
127.06, 126.87, 124.91, 124.52, 121.24, 116.31, 111.25, 85.88, 66.45. LRMS (EI) m/z 312 (M+);
HRMS (EI) m/z calcd C21H16N2O (M+) 312.1263, found 312.1260.
1
6-(4-Fluorophenyl)-11b,13-dihydropyrido[2',3':4,5][1,3]oxazino[2,3-a]isoquinoline (3Bj). H-NMR
(400 MHz, CDCl3) δ 7.81 (dd, J = 4.8, 1.6 Hz, 1H), 7.44 (d, J = 7.2 Hz, 1H), 7.34–7.26 (m, 4H),
7.25–7.22 (m, 1H), 7.18 (dd, J = 7.6, 1.2 Hz, 1H), 6.94 (t, J = 8.8 Hz, 2H), 6.74–6.70 (q, 1H), 6.26 (s,
13
1H), 6.20 (s, 1H), 5.06 (d, J = 14.0 Hz, 1H), 5.04–4.98 (d, J = 14.0 Hz, 1H). C-NMR (100 MHz,
CDCl3) δ 150.19, 146.75, 138.22, 133.53, 132.39, 132.20, 129.38, 128.72, 128.65, 126.89, 124.70 (d,
J = 25.6 Hz), 121.32, 116.46, 114.94 (d, J = 21.5 Hz), 110.90, 85.78, 66.37. LRMS (EI) m/z 330 (M+);
HRMS (EI) m/z calcd C21H15FN2O (M+) 330.1168, found 330.1162.
4. Conclusions
In summary, an efficient strategy for the one-pot construction of dihydrobenzo[4,5][1,3]oxazino-
[2,3-a]isoquinolines from simple starting substrates has been developed via an unprecedented
Ag(I)-catalyzed N-aryliminium ion cyclization cascade. On the basis of a large assortment of
bioactivities of fused isoquinolines, we believe that the new synthetic method will serve as valuable
tool to efficiently construct new members fused isoquinoline derivatives in drug discovery, and will
have potential biological applications.
Supplementary Materials
Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/18/1/814/s1.
Acknowledgments
We gratefully acknowledge financial support from the National Natural Science Foundation of
China (Grants 20902022, 81102307, 21222211), the Natural Science Foundation of Shanghai, China
(Grant 11ZR1444600), National S&T Major Project, China (Grant 2011ZX09102-005-02), the
Shanghai Committee of Science and Technology (Grant 11DZ2260600), and the Fundamental
Research Funds for the Central Universities.
References
1. Parenty, A.D.; Smith, L.V.; Guthrie, K.M.; Long, D.L.; Plumb, J.; Brown, R.; Cronin, L. Highly
stable phenanthridinium frameworks as a new class of tunable DNA binding agents with cytotoxic
properties. J. Med. Chem. 2005, 48, 4504–4506.

Molecules 2013, 18
829
2. Weinkauf, R.L.; Chen, A.Y.; Yu, C.; Liu, L.; Barrows, L.; LaVoie, E.J. Antineoplastic activity of
benzimidazo[1,2-b]-isoquinolines, indolo[2,3-b]quinolines, and pyridocarbazoles. Bioorg. Med. Chem.
1994, 2, 781–786.
3. Chen, Z.; Wu, J. Efficient generation of biologically active H-pyrazolo[5,1-a]isoquinolines via
multicomponent reaction. Org. Lett. 2010, 12, 4856–4859.
4. Iwasa, K.; Moriyasu, M.; Tachibana, Y.; Kim, H.S.; Wataya, Y.; Wiegrebe, W.; Bastow, K.F.;
Cosentino, L.M.; Kozuka, M.; Lee, K.H. Simple isoquinoline and benzylisoquinoline alkaloids as
potential antimicrobial, antimalarial, cytotoxic, and anti-HIV agents. Bioorg. Med. Chem. 2001, 9,
2871–2884.
5. Reddy, M.V.; Rao, M.R.; Rhodes, D.; Hansen, M.S.; Rubins, K.; Bushman, F.D.; Venkateswarlu, Y.;
Faulkner, D.J. Lamellarin alpha 20-sulfate, an inhibitor of HIV-1 integrase active against HIV-1
virus in cell culture. J. Med. Chem. 1999, 42, 1901–1907.
6. Petrignet, J.; Boudhar, A.; Blond, G.; Suffert, J. Step-economical synthesis of taxol-like tricycles
through a palladium-catalyzed domino reaction. Angew. Chem. Int. Ed. 2011, 50, 3285–3289.
7. Chen, J.R.; Li, C.F.; An, X.L.; Zhang, J.J.; Zhu, X.Y.; Xiao, W.J. Ru-catalyzed tandem cross-
metathesis/intramolecular-hydroarylation sequence. Angew. Chem. Int. Ed. 2008, 47, 2489–2492.
8. Wasilke, J.C.; Obrey, S.J.; Baker, R.T.; Bazan, G.C. Concurrent tandem catalysis. Chem. Rev.
2005, 105, 1001–1020.
9. Velcicky, J.; Soicke, A.; Steiner, R.; Schmalz, H.G. Palladium-catalyzed cyanomethylation of aryl
halides through domino Suzuki coupling-isoxazole fragmentation. J. Am. Chem. Soc. 2011, 133,
6948–6951.
10. Malakar, C.C.; Schmidt, D.; Conrad, J.; Beifuss, U. Cu(I)-catalyzed domino reactions: efficient
and selective synthesis of 4H-chromenes and naphthalenes. Org. Lett. 2011, 13, 1972–1975.
11. Nanjo, T.; Tsukano, C.; Takemoto, Y. Palladium-catalyzed cascade process consisting of
isocyanide insertion and benzylic C(sp3)-H activation: concise synthesis of indole derivatives.
Org. Lett. 2012, 14, 4270–4273.
12. Magano, J.; Dunetz, J.R. Large-scale applications of transition metal-catalyzed couplings for the
synthesis of pharmaceuticals. Chem. Rev. 2011, 111, 2177–2250.
13. Kumar, K.S.; Kumar, P.M.; Reddy, M.A.; Ferozuddin, M.; Sreenivasulu, M.; Jafar, A.A.;
Krishna, G.R.; Reddy, C.M.; Rambabu, D.; Kumar, K.S.; et al. Yb(OTf)3 catalyzed new cascade
reaction: A facile assembly of fused quinazolinones. Chem. Commun. 2011, 47, 10263–10265.
14. Gigant, N.; Gillaizeau, I. Palladium(II)-catalyzed direct alkenylation of nonaromatic enamides.
Org. Lett. 2012, 14, 3304–3307.
15. Patil, N.T.; Mutyala, A.K.; Konala, A.; Tella, R.B. Tuning the reactivity of Au-complexes in an
Au(I)/chiral Bronsted acid cooperative catalytic system: an approach to optically active fused
1,2-dihydroisoquinolines. Chem. Commun. 2012, 48, 3094–3096.
16. Ouyang, H.C.; Tang, R.Y.; Zhong, P.; Zhang, X.G.; Li, J.H. CuI/I2-promoted electrophilic
tandem cyclization of 2-ethynylbenzaldehydes with ortho-benzenediamines: Synthesis of
iodoisoquinoline-fused benzimidazoles. J. Org. Chem. 2011, 76, 223–228.

Molecules 2013, 18
830
17. Patil, N.T.; Mutyala, A.K.; Lakshmi, P.G.V.V.; Raju, P.V.K.; Sridhar, B. Facile Assembly of
Fused Isoquinolines by Gold(I)-Catalyzed-Coupling Cyclization Reactions between
o-Alkynylbenzaldehydes and Aromatic Amines Containing Tethered Nucleophiles. Eur. J. Org.
Chem. 2010, 1999–2007.
18. Yanada, R.; Hashimoto, K.; Tokizane, R.; Miwa, Y.; Minami, H.; Yanada, K.; Ishikura, M.;
Takemoto, Y. Indium(III)-catalyzed tandem reaction with alkynylbenzaldehydes and
alkynylanilines to heteroaromatic compounds. J. Org. Chem. 2008, 73, 5135–5138.
19. Yanada, R.; Obika, S.; Kono, H.; Takemoto, Y. In(OTf)3-catalyzed tandem nucleophilic addition
and cyclization of ortho-alkynylarylaldimines to 1,2-dihydroisoquinolines. Angew. Chem. Int. Ed.
2006, 45, 3822–3825.
20. Liu, G.; Zhou, Y.; Ye, D.; Zhang, D.; Ding, X.; Jiang, H.; Liu, H. Silver-Catalyzed Intramolecular
Cyclization of o-(1-Alkynyl)benzamides: Efficient Synthesis of (1H)-Isochromen-1-imines.
Adv. Synth. Catal. 2009, 351, 2605–2610.
21. Patil, N.T.; Pahadi, N.K.; Yamamoto, Y. Silver(I)-catalyzed novel cascade cyclization reactions:
incorporation of allenes into the isochromenes. J. Org. Chem. 2005, 70, 10096–10098.
22. Blanc, A.; Tenbrink, K.; Weibel, J.M.; Pale, P. Silver(I)-catalyzed cascade: Direct access to furans
from alkynyloxiranes. J. Org. Chem. 2009, 74, 4360–4363.
23. Su, S.; Porco, J.A., Jr. Synthesis of pyrrolo-isoquinolines related to the lamellarins using silver-
catalyzed cycloisomerization/dipolar cycloaddition. J. Am. Chem. Soc. 2007, 129, 7744–7745.
24. Weibel, J.M.; Blanc, A.; Pale, P. Ag-mediated reactions: Coupling and heterocyclization
reactions. Chem. Rev. 2008, 108, 3149–3173.
25. Huple, D.B.; Chen, C.H.; Das, A.; Liu, R.S. Silver-catalyzed exo-dig-azacyclization/[3+2]
cycloaddition cascades on 1-tosylhydrazon-4-oxy-5-yne substrates: Applicability to diverse
alkenes. Adv. Synth. Catal. 2011, 353, 1877–1882.
26. Li, W.; Wang, Y.; Lu, T. Facile synthesis of 1-aminoisoquinolines via the tandem reactions of
2-alkynylbenzaldoximes with isothiocyanates. Tetrahedron 2012, 68, 6843–6848.
27. Huang, P.; Yang, Q.; Chen, Z.; Ding, Q.; Xu, J.; Peng, Y. Metal cocatalyzed tandem alkynylative
cyclization reaction of in situ formed N-iminoisoquinolinium ylides with bromoalkynes via C–H
bond activation. J. Org. Chem. 2012, 77, 8092–8098.
28. Rustagi, V.; Aggarwal, T.; Verma, A.K. Highly efficient Ag(I)-catalyzed regioselective tandem
synthesis of diversely substituted quinoxalines and benzimidazoles in water. Green Chem. 2011,
13, 1640–1643.
29. Rustagi, V.; Tiwari, R.; Verma, A.K. AgI-Catalyzed Cascade Strategy: Regioselective Access to
Diversely Substituted Fused Benzimidazo[2,1-a]isoquinolines, Naphthyridines, Thienopyridines,
and Quinoxalines in Water. Eur. J. Org. Chem. 2012, 4590–4602.
30. Yu, X.X.; Yang, Q.; Lou, H.L.; Peng, Y.Y.; Wu, J. An efficient approach to
pyrazolo[5,1-a]isoquinolin-2-amines via a silver(I)-catalyzed three-component reaction of
2-alkynylbenzaldehyde, sulfonohydrazide, and nitrile. Org. Biomol. Chem. 2011, 9, 7033–7037.
31. Markina, N.A.; Mancuso, R.; Neuenswander, B.; Lushington, G.H.; Larock, R.C. Solution-Phase
Parallel Synthesis of a Diverse Library of 1,2-Dihydroisoquinolines. ACS Comb. Sci. 2011, 13,
265–271.

Molecules 2013, 18
831
32. Ding, Q.P.; Wu, J. Lewis acid- and organocatalyst-cocatalyzed multicomponent reactions of
2-alkynylbenzaldehydes, amines, and ketones. Org. Lett. 2007, 9, 4959–4962.
33. Yu, X.X.; Wu, J. Synthesis of 1-(1H-Indol-3-yl)-1,2-dihydroisoquinolines via AgOTf-Catalyzed
Three-Component Reactions of 2-Alkynylbenzaldehydes, Amines, and Indoles. J. Comb. Chem.
2010, 12, 238–244.
34. Asao, N.; Yudha, S.S.; Nogami, T.; Yamamoto, Y. Direct Mannich and nitro-Mannich reactions
with non-activated imines: AgOTf-catalyzed addition of pronucleophiles to ortho-alkynylaryl
aldimines leading to 1,2-dihydroisoquinolines. Angew. Chem. Int. Ed. 2005, 44, 5526–5528.
35. Liu, G.N.; Zhou, Y.; Lin, D.Z.; Wang, J.F.; Zhang, L.; Jiang, H.L.; Liu, H. Synthesis of
Pyrrolo[1,2-a]quinoxalines via Gold(I)-Mediated Cascade Reactions. ACS Comb. Sci. 2011, 13,
209–213.
36. Zhou, Y.; Li, J.; Ji, X.; Zhou, W.; Zhang, X.; Qian, W.; Jiang, H.; Liu, H. Silver- and
gold-mediated domino transformation: A strategy for synthesizing benzo[e]indolo[1,2-
a]pyrrolo/pyrido[2,1-c][1,4]diazepine-3,9-diones. J. Org. Chem. 2011, 76, 1239–1249.
37. Feng, E.; Zhou, Y.; Zhang, D.; Zhang, L.; Sun, H.; Jiang, H.; Liu, H. Gold(I)-catalyzed tandem
transformation: A simple approach for the synthesis of pyrrolo/pyrido[2,1-a][1,3]benzoxazinones
and pyrrolo/pyrido[2,1-a]quinazolinones. J. Org. Chem. 2010, 75, 3274–3282.
38. Feng, E.G.; Zhou, Y.; Zhao, F.; Chen, X.J.; Zhang, L.; Jiang, H.L.; Liu, H. Gold-catalyzed
tandem reaction in water: An efficient and convenient synthesis of fused polycyclic indoles.
Green Chem. 2012, 14, 1888–1895.
39. Zhou, Y.; Feng, E.G.; Liu, G.N.; Ye, D.J.; Li, J.; Jiang, H.L.; Liu, H., Liu, G. Gold-Catalyzed
One-Pot Cascade Construction of Highly Functionalized Pyrrolo[1,2-a]quinolin-1(2H)-ones.
J. Org. Chem. 2009, 74, 7344–7348.
40. Zhou, Y.; Zhai, Y.; Ji, X.; Liu, G.N.; Feng, E.G.; Ye, D.J.; Zhao, L.X.; Jiang, H.L.; Liu, H.
Gold(I)-Catalyzed One-Pot Tandem Coupling/Cyclization: An Efficient Synthesis of Pyrrolo-
/Pyrido[2,1-b]benzo[d][1,3]oxazin-1-ones. Adv. Synth. Catal. 2010, 352, 373–378.
41. Zhou, Y.; Ji, X.; Liu, G.N.; Zhang, D.Y.; Zhao, L.X.; Jiang, H.L.; Liu, H. Gold(I)-Catalyzed
Cascade for Synthesis of Pyrrolo[1,2-a:2',1'-c]-/Pyrido[2,1-c]pyrrolo[1,2-a]quinoxalinones.
Adv. Synth. Catal. 2010, 352, 1711–1717.
42. Waldmann, H.; Eberhardt, L.; Wittstein, K.; Kumar, K. Silver catalyzed cascade synthesis of
alkaloid ring systems: Concise total synthesis of fascaplysin, homofascaplysin C and analogues.
Chem. Commun. 2010, 46, 4622–4624.
Sample Availability: Samples of all target compounds are available from the authors.
© 2013 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article
distributed under the terms and conditions of the Creative Commons Attribution license
(http://creativecommons.org/licenses/by/3.0/).