[Ag(PcL)]-Catalysed Domino Approach to 6-Substituted Benzoxazino Isoquinolines

Article abstract of DOI:10.1002/ejoc.202000341

In this paper, we describe a new silver catalysed domino approach to 6-substituted benzoxazino isoquinolines starting from 2-alkynylbenzaldehydes and 1-substituted-(2-aminophenyl)methanols. The strategy is characterized by good reaction yields, and can be performed at room temperature as well as under heating (conventional or dielectric) in different reaction times. Best results have been obtained by using silver complexes of macrocyclic pyridine-containing ligands (PcL) as catalysts. The stereoselectivity of the transformation has been investigated by using chiral reaction partners and chiral catalysts, but unfortunately, modest stereoselectivities have been achieved. On the other hand, this approach represents an alternative synthetic strategy for the preparation of 6-substituted benzoxazino isoquinolines, which are the key scaffold of some compounds endowed of biological activity.

Full text of DOI:10.1002/ejoc.202000341

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: [Ag(PcL)]-Catalysed Domino Approach to 6-Substituted
Benzoxazino Isoquinolines
Authors: Davide Garanzini, Valentina Pirovano, Ilaria Menghi,
Giuseppe Celentano, Silvia Rizzato, Elisabetta Rossi,
Alessandro Caselli, and Giorgio Abbiati
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000341
Link to VoR: https://doi.org/10.1002/ejoc.202000341
01/2020

10.1002/ejoc.202000341
European Journal of Organic Chemistry
[Ag(PcL)]-Catalysed Domino Approach to
6-Substituted Benzoxazino Isoquinolines
Davide Garanzini,a Valentina Pirovano,a Ilaria Menghi,a,b Giuseppe Celentano,a
Silvia Rizzato,b Elisabetta Rossi,a Alessandro Caselli,b,c and Giorgio Abbiati*,a
a Dipartimento di Scienze Farmaceutiche, Sezione di Chimica Generale e Organica “A. Marchesini”,
Università degli Studi di Milano, Via Venezian, 21–20133 Milano–Italy
b Dipartimento di Chimica, Università degli Studi di Milano and CNR-SCITEC, Via Golgi, 19–20133
Milano–Italy
c CNR-SCITEC, Via Golgi, 19–20133 Milano–Italy
E-mail: giorgio.abbiati@unimi.it
Corresponding author homepage url: https://www.unimi.it/en/ugov/person/giorgio-abbiati
Abstract
In this paper, we describe a new silver catalysed domino approach to 6-substituted benzoxazino
isoquinolines starting from 2-alkynylbenzaldehydes and 1-substituted-(2-aminophenyl)methanols.
The strategy is characterized by good reaction yields, and can be performed at room temperature as
well as under heating (conventional or dielectric) in different reaction times. Best results have been
obtained by using silver complexes of macrocyclic pyridine-containing ligands (PcL) as catalysts.
The stereoselectivity of the transformation has been investigated by using chiral reaction partners and
chiral catalyst, but unfortunately, modest stereoselectivities has been achieved. On the other hand,
this approach represents an alternative synthetic strategy for the preparation of 6-substituted
benzoxazino isoquinolines, which are the key scaffold of some compounds endowed of biological
activity.
1
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10.1002/ejoc.202000341
European Journal of Organic Chemistry
Introduction
The “domino effect” is defined as the cumulative effect produced when one event triggers a chain of
related events.1 In analogy, in chemistry a domino reaction2 is a sequence of reactions in which
subsequent transformations are a consequence of the functionalities formed in the previous steps. In
a typical domino reaction, a number of bond-forming transformations take place without change
reaction conditions or add reagents and catalysts. Everything fall–almost magically–in its place. It is
not surprising that in the last twenty-five years such approach fascinating many synthetic organic
chemists. Domino transformations demonstrated to be especially useful and reliable strategies for the
synthesis of heterocyclic compounds,3 including polycyclic fused isoquinolines which display a broad
spectrum of potential pharmacological applications against cancer,4,5 for diabetes and obesity
treatment,5 as inhibitors of HIV-1,6 and as PAF-receptor (Platelet Activating Factor receptor)
antagonists,7 just to cite some representative examples. In particular, 6-aryl-substituted 4bH,6H-
benzo[4,5][1,3]oxazino[2,3-a]isoquinolines display interesting activities as antimalarial agents.8
One effective method to obtain benzoxazino isoquinolines is the domino reaction between a 2-
alkynylbenzaldehyde and a 2-(hydroxymetyl)anilines in the presence of a suitable electrophilic
reagent or catalyst. The very first example was reported in 2010 by Patil and co-workers. Within a
more general study on cascade reaction of o-alkynylbenzaldehydes and aromatic amines containing
tethered nucleophiles, the authors reported a single example of gold(I) chloride catalysed synthesis
of 12-phenyl-benzoxazino isoquinoline at 80 °C in DCE9 (Scheme 1, a). Li and co-workers in early
201310 widened the scope of the approach performing the reaction with silver nitrate as catalyst at
80°C in toluene, yielding the desired adducts in fair to very good yields (Scheme 1, b). A couple of
month after, Verma and co-workers, independently reported a very similar AgNO3-based approach,
enhanced by the use of water as solvent, which needed a higher catalyst loading at the same
temperature11 (80 °C) (Scheme 1, c). In the same year, within a more extensive work on Electrophile
Induced Branching Cascade approach (EIBC), Patil and co-workers prepared three benzoxazino
isoquinolines at rt by using stoichiometric iodine as electrophile in the presence of K2CO3 in
acetonitrile12 (Scheme 1, d). More recently, a copper(I) iodide catalysed method under microwave
irradiation (70 °C) has been also proposed13 (Scheme 1, e).
2
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10.1002/ejoc.202000341
European Journal of Organic Chemistry
Scheme 1: Previous approaches to benzoxazino isoquinolines by domino reaction between a 2-
alkynylbenzaldehydes and a 2-(hydroxymetyl)anilines.
3
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10.1002/ejoc.202000341
European Journal of Organic Chemistry
All these methods are valuable, yields ranging from moderate to very good, but in general suffer for
a relatively high catalyst loading (5-10 mol%) and none of them seems to well tolerate the presence
of EW groups on the alkyne terminus. Moreover, no enantioselective examples of this transformation
have been already reported, neither reactions involving the bidentate nucleophile partner (namely the
(2-aminophenyl)methanol) substituted on benzylic carbon to obtain 6-substituted benzoxazino
isoquinolines. This can be of particular interest, because, as mentioned above, some 6-aryl-substituted
benzoxazino isoquinolines displayed an interesting antimalarial activity.8 Usually this kind of
benzoxazino isoquinolines are prepared by a different way, that is a multicomponent approach
involving arynes, isoquinolines, and aldehydes that involves the formation of a 1,4-zwitterionic
intermediate.14 A similar approach allowed the synthesis of 6,6-spirobenzoxazino isoquinolines by
using substituted isatins instead of aldehydes as carbonyl partner15 (Scheme 2).
Scheme 2: Multicomponent approach to 6-substituted benzoxazino isoquinolines
Among the research interests of our group, the development of new and effective domino approaches
for the synthesis of isoquinoline derivatives starting from -ketoalkynes16 represent a topic since ever
fascinated and attracted us.17 Thus, in connection with our recent interest in silver catalysis,18 and in
the use of original PcL (pyridine containing ligands) as efficient metal ligands19 we report here the
results of our studies on [Ag(I)(PcL)] catalysed domino approach to 6-substituted benzoxazino
isoquinolines, starting from 2-alkynylbenzaldehydes and 1-substituted (2-aminophenyl)methanols
(Scheme 3).
4
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10.1002/ejoc.202000341
European Journal of Organic Chemistry
Scheme 3: New domino approach to 6-substituted benzoxazino isoquinolines.
Results and discussion
The reaction between 2-[(4-tolyl)-ethynyl]benzaldehyde 1a and 2-(hydroxymetyl)aniline 2a was
chosen to a preliminary study with the aim to optimize the reaction conditions. In particular we tested
the activity of some [Ag(PcL)] complexes characterized by different electronic and steric properties
(Figure 1). The result are summarized in Table 1.
Figure 1: [Ag(PcL)] complexes involved in the preliminary study.
5
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10.1002/ejoc.202000341
European Journal of Organic Chemistry
Table 1: Optimization of the reaction conditions.
T
(°C)
1
[Ag]+
X-
Solvent
t (h)
1
2
Ag+
TfO-
10
10
5
DMF
DMF
DMF
DMF
DMF
DMF
60
60
60
80
60
60
3
3
a: 32
a: 55
a: 82
a: 56
a: 36
a: 80
a: 35
a: 64
9b
a
a
a
a
a
a
a
a
a
a
a
a
b
c
[Ag(PcL1)]+ BF4
-
-
b
3
[Ag(PcL2)]+ TfO-
21
7.5
72
44
7.5
48
48
48
48
120
25
19
-
-
b
4
[Ag(PcL2)]+ BF4
5
-
-
b
5
[Ag(PcL3)]+ BF4
5
-
-
6
[Ag(PcL4)]+ BF4
5
-
-
b
7
[Ag(PcL2)]+ BF4
5
Toluene 80
Toluene 40
-
8
[Ag(PcL2)]+ TfO-
[Ag(PcL2)]+ TfO-
[Ag(PcL2)]+ TfO-
[Ag(PcL2)]+ TfO-
5
10
9
5
DCE
40
a: (22)c (58)c
a: (18)c (62)c
a: (18)c (45)c
10
11
12
13
14
5
Dioxane 40
5
Me-CN
Toluene
DMF
40
rt
[Ag(PcL2)]+ BF4
5
a: 77
b: 63
c: 35
-
-
[Ag(PcL2)]+ TfO-
[Ag(PcL2)]+ TfO-
5
60
60
5
b
5
DMF
-
a Isolated yields. b The NMR of the crude display the signals of unidentified by-products. c Yields estimated via 1H NMR.
We chose DMF as solvent and 60 °C as starting reaction conditions; after a control experiment with
a simple silver salt such as AgOTf (Table 1, entry 1), we started to test the activity of [Ag(PcL)]+
6
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10.1002/ejoc.202000341
European Journal of Organic Chemistry
complexes. Among them, the complex [Ag(PcL2)]+ has already demonstrated to be effective in our
previous study on silver catalysed A3-coupling MCR.18b The reactions were normally stopped when
the TLC analysis seemed to display the disappearance of the limiting starting material 2a. [Ag(PcL1)]+
catalyst, characterized by the presence of a propionic acid pendant linked to the amino group of the
1
macrocycle, gave promising result, although the H NMR of the reaction crude displayed also the
signals of unidentified by-products (Table 1, entry 2). A great improvement was observed when the
reaction was performed with 5 mol% of [Ag(PcL2)]+ catalyst for a prolonged time (Table 1, entry 3),
but an increase of temperature of 20 degrees and a reduction of reaction time gave slightly worse
results (Table 1, entry 4). Electron-poor [Ag(PcL3)]+ complex gave worse results (Table 1, entry 5),
while electron-rich [Ag(PcL4)] complex gave yields comparable to [Ag(PcL2)]+ (Table 1, entry 6).
Then, we test some other solvents (Table 1, entries 7-12). When the reaction was performed at high
temperature (80 °C for 7.5 h), toluene gave worse results compared to DMF (Table 1, compare entry
4 and entry 7). With in mind the idea to study also the stereoselective version of the approach, we
performed the solvents screening at lower temperature. Under these conditions, only toluene gave
results of a certain interest in terms of reaction yields, but only after prolonged reaction times (Table
1, entries 8 and 12).
Finally, under the best reaction condition (Table 1, entry 3), the reaction was performed on three
different substrates (Table 1, entries 13-15). We were pleased to observed that an aromatic electron
donating group on the alkyne end is well tolerated (Table 1, entry 13), whereas alkyl groups gave
worse results (Table 1, entry 14), probably due to a low stability of the starting material.
This preliminary screening revealed some interesting features. First, electron-rich [Ag(PcL)]+
complexes seem to be able to catalyse the reaction under conventional heating better than a simple
silver salt such as AgOTf. Second, at rt and under conventional heating reaction times are long, also
at relatively high temperatures. Third, DMF and toluene demonstrate to be the solvents of choice, in
spite of their deep polarity differences.
To reduce reaction times and improve the efficiency of the approach we decided to switch from
conventional to dielectric heating. The ability of microwaves to promote this kind of reaction has
been already documented.13 It is well known that the efficiency of dielectric heating is strongly related
to the nature of the solvent,20 so the highly polar DMF was selected as the solvent of choice to be
used in these experiments, together with [Ag(PcL2)] + complex as catalyst. The results are reported in
Table 2.
7
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10.1002/ejoc.202000341
European Journal of Organic Chemistry
Table 2: Optimization of the reaction conditions under microwave heating.
t
3
Entry
1
a
a
a
a
a
a
a
a
a
a
d
d
[Ag]+
X-
(mol%)
Solvent
DMF
DMF
DMF
DMF
DMF
DMF
DMF
Toluene
DMF
DMF
DMF
DMF
T (°C)
90
(h) (yield%)a
1
2
[Ag(PcL2)]+ TfO-
5
5
2
2
5
5
5
5
5
5
5
5
1
1
1
2
1
2
a: 69
a: 78
a: 62
a: 52
a: 53
a: 35
a: 65
a: 45
a: 76
a: 75
d: 64
d: 70
[Ag(PcL2)]+ BF4
100
100
100
80
-
-
3
[Ag(PcL2)]+ BF4
-
4
[Ag(PcL2)]+ BF4
-
5
[Ag(PcL2)]+ BF4
-
6
[Ag(PcL2)]+ BF4
80
-
7
[Ag(PcL2)]+ BF4
100 0.75
-
8
[Ag(PcL2)]+ BF4
100
100
100
100
100
1
1
1
1
1
-
9
Ag+
Ag+
BF4
-
10
11
12
NO3
[Ag(PcL2)]+ BF4
-
Ag+
BF4
-
a Isolated yields.
When the model reaction was heated at 90° C for one hour under dielectric heating, the desired
product was obtained in fair yields (Table 2, entry 1). Tetrafluoborate as counter-ion at 100° C for
one hour seemed to be the best arrangement to our goal (Table 2, entry 2), as testified by the
subsequent experiments (Table 2, entries 3-8). A halving of the catalyst loading (Table 2, entries 3
and 4), or a slight decrease of temperature, also under double reaction times (Table 2, entries 5 and
8
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10.1002/ejoc.202000341
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6) gave worse results, as well as a simple reduction of times under the best conditions (Table 2, entry
7). As expected, also the change of the solvent to less polar toluene, gave poor results (Table 2, entry
8). However, differently from what observed under conventional heating, two control experiments
under the best microwave reaction conditions with simple silver salts, gave results comparable to
those obtained with [Ag(PcL2)]+ complex (Table 2, entries 9 and 10) and a comparable behaviour
was observed changing the nature of the substitution on alkynylbenzaldehyde (Table 2, entries 11 and
12).
In connection with the growing interest in the development of asymmetric silver catalysed
transformation,21 we decide to investigate also the possibility to induce enantioselectivity in this
transformation by using some chiral [Ag(PcL)*]+ complexes (Figure 2).
Figure 2: Chiral [Ag(PcL)*]+ complexes tested in the study.
We test two chiral silver complexes characterized by different stereospecific arrangements on the
pyridine-containing macrocycle. One of them, i.e. (PcL6)*, has only a chiral pendant linked to the
amine group in position 6, a (1-naphtalenyl)ethyl group in (S) configuration. The other, (PcL5)* beside
the chiral (1-naphtalenyl)ethyl group on the N-6 has two isopropyl group in (S)-configuration on the
macrocycle in the positions 4 and 8, respectively (Figure 2).
The reaction with the chiral catalyst [Ag(PcL5)*]+ at 60 °C gave good results in terms of yields but
scarce enantioselectivity (Table 3, entry 1). The reduction of reaction temperature to 30 °C, beside a
poor enantioselectivity, gave also low yield (Table 3, entry 2). The simplest catalyst [Ag(PcL6)*]+
demonstrated to give comparable results to [Ag(PcL5)*]+ in terms of yield and selectivity (Table 3,
entry 3), so it was chosen for the prosecution of the study.
9
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European Journal of Organic Chemistry
Table 3: Screening of the activity chiral [Ag(PcL)*] complexes on the model reaction.
Entry
[Ag(PcL)*]+
[Ag(PcL5)*]+
[Ag(PcL5)*]+
[Ag(PcL6)*]+
T (°C)
60
t (h)
26
3a (yield%)a
erb
1
2
3
80
57
78
53 : 47b
54 : 46b
52 : 48c
30
48
rt
120
a Isolated yields. b Determined by Chiral HPLC (Column: Phenomenex, Lux Amylose-2; eluent: n-
hexane/isopropanol/diethylamine = 90:10:0.1). c Determined by Chiral HPLC (Column: Daicel, Chiracel AD,
amylose; eluent: n-hexane/isopropanol/diethylamine = 75:25:0.1)
Due to above mentioned importance of 6-substituted benzoxazino isoquinolines,8 we next focused
our efforts to the synthesis of these interesting scaffolds, starting from 1-(2-aminophenyl)ethan-1-ol
as racemate ((±)-2b) or as pure enantiomer ((R)-2b). The first was prepared by simple reduction of
the corresponding 1-(2-aminophenyl)ethan-1-one with sodium borohydride in methanol in almost
quantitative yields.22 Enantiomeric pure (R)-1-(2-aminophenyl)ethan-1-one (R)-2b was prepared
starting from the same starting material by enzymatic kinetic resolution of the corresponding tert-
butyl 2-(1-hydroxyethyl)phenylcarbamate through a lipase-catalysed transesterification, as reported
in the literature.23 Reactions were conducted under the optimized reaction conditions under
microwave heating using both racemic and enantiomeric pure 2b and testing achiral and chiral
[Ag(PcL)]+ complexes. Moreover, control reactions were also performed in the presence of simple
silver salts. The results are reported in Table 4.
10
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Table 4: Reactions with 1-(2-aminophenyl)ethan-1-ol 2b.
Entry
2
[Ag]+
Yielda
80%
88%
98%
85%
82%
84%
dr 3e:3’eb
70 : 30
71 : 29
70 : 30
76 : 34
72 : 28
72 : 28
er 3ec
50 : 50
50 : 50
50 : 50
1 : 99
er 3’ec
50 : 50
48 : 52
47 : 53
10 : 90
9 : 91
1
2
3
4
5
6
(±)-2b
Ag+
(±)-2b [Ag(PcL2)] +
(±)-2b [Ag(PcL6)*]+
Ag+
(R)-2b
[Ag(PcL2)] +
1 : 99
(R)-2b
[Ag(PcL6)*]+
1 : 99
9 : 91
(R)-2b
a Isolated yield by flash silica gel column chromatography n-hexane/AcOEt. b Calculated via 1H NMR of the crude.
c Determined by Chiral HPLC (Column: Kromasil AmyCoat; eluent: n-hexane/isopropanol = 9:1).
In all the tests performed with 1-(2-aminophenyl)ethan-1-ol 2b, the yields were comparable and
slightly higher than those obtained in the previous experiments with 2-(hydroxymetyl)aniline 2a
(Table 4, entries 1-6). Irrespective to the catalyst used, the reactions performed with racemic 2b, gave
ever a mixture of the two possible diastereoisomers 3f (cis) and 3’f (trans) in a ratio of 70:30, both
as racemates (Table 4, entries 1-3). This unequal distribution among cis and trans isomers reveals the
existence of an energetic gap between the diastereoisomers and/or the corresponding transition states.
Interestingly, the [Ag(PcL)]+ complex gave higher yields than simple silver tetrafluoborate (Table 4,
cfr entries 1 with 2,3), and in particular the chiral catalyst [Ag(PcL6)*]+ gave the couple of
diastereoisomers almost in quantitative yield (Table 4, entry 3).
When enantiopure (R)-2b was used, a comparable diastereoselectivity was observed (Table 4, entries
4-6), whereas the activity of the different catalysts in terms of yields was more homogeneous.
Surprisingly, while the majority diastereoisomer 3e was obtained in almost enantiopure form (ee =
99%), the minority ones 3’e was obtained in 80% ee. This suggests that a partial racemization occurs
specifically at the level of the high-energy transition state that bring to the formation of the minority
diastereoisomer 3’e.
11
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1
13
All new compounds have been fully characterized by H and C NMR spectroscopies, and MS
spectrometry. The stereochemistry of diastereoisomeric products 3e (cis) and 3’e (trans) was assigned
by NOESY experiments (see Supporting Information). Moreover, the structure of 3e was confirmed
by single crystal X-ray crystallography (Figure 3).
Figure 3: The molecular structure of compound 3e showing the numbering schemes for some non-
hydrogen atoms. Displacement ellipsoids are plotted at the 40% probability level.
Since in the experiments discussed above, the chiral catalyst failed to induce stereoselectivity, we
decided to try the reactions at a lower temperature, with the aim to exclude and prevent whichever
negative effect of the heat on diastereo- and enantio-selection. Thus, the reactions were repeated at rt
for 60 hours. The results are reported in Table 5.
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Table 5: Reactions with 1-(2-aminophenyl)ethan-1-ol 2b at rt.
Entry
2
[Ag]+
Yielda
95%
91%
93%
99%
dr 3e:3’eb
77 : 23
88 : 12
74 : 26
85 : 15
er 3ec
49 : 51
1 : 99
1 : 99
1 : 99
er 3’ec
53 : 47
15 : 85
15 : 85
26 : 74
1
2
3
4
(±)-2b [Ag(PcL6)*]+
Ag+
(R)-2b
[Ag(PcL2)]+
(R)-2b
[Ag(PcL6)*]+
(R)-2b
a Isolated yield by flash silica gel column chromatography n-hexane/AcOEt; b Calculated via 1H NMR of the crude; c
Determined by Chiral HPLC (Column: Kromasil AmyCoat; eluent: n-hexane/isopropanol = 9:1).
As already observed (see Table 4), in terms of yields [Ag(PcL)]+ complexes gave in general slightly
better results than simple silver salts, and in particular the chiral complex [Ag(PcL6)*]+ demonstrated
once again to be the most effective (Table 5, entries 1 and 4). Unfortunately, the reduction of the
reaction temperature did not give the desired improvement in terms of stereoselectivity. Interestingly,
at room temperature, the formation of unfavoured diastereoisomers 3’e seems to be a bit depressed
(cfr. drs in Tables 4 and 5). This is in agreement with the previous observation that the energy of
transition states of 3’e is higher than for 3e.
In the introduction, it has been underlined that 6-aryl-substituted oxazino isoquinolines displayed
interesting activities as therapeutic agents, in particular versus malaria.8 Thus, we performed our
domino reaction with a new bidentate nucleophile partner, i.e. the (2-aminophenyl)(phenyl)methanol
2c, prepared by conventional reduction of (2-aminophenyl)(phenyl)methanone with sodium
borohydride.21 Moreover, we reasoned that a bulkier group on the aminoalcohol could have a positive
effect on the stereoselectivity of the transformation.
The results of domino condensation of 1a with 2c are reported in Table 6.
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Table 6: Reactions with (2-aminophenyl)(phenyl)methanol 2c.
Entry
2
Catalyst
Yielda
85%
dr 3f:3’fb
69 : 31
er 3fc
50 : 50
50 : 50
50 : 50
er 3’f c
50 : 50
50 : 50
49 : 51
1
2
3
(±)-2c
Ag+
(±)-2c [Ag(PcL2)]+
83%
68 : 32
(±)-2c [Ag(PcL6)*]+
90%
69 : 31
a Isolated yield by flash silica gel column chromatography n-hexane/AcOEt; b Calculated via 1H NMR of the crude;
c Determined by Chiral HPLC (Column: Kromasil AmyCoat; eluent: n-hexane/isopropanol = 9:1).
With all the silver catalysts tested, the reactions under microwave heating gave the mixture of the two
expected diastereoisomeric products in very good yields with a diastereoisomeric ratio near to 7 : 3.
In agreement with the previous observations, the chiral [Ag(PcL)]+ complex [Ag(PcL6)*]+ gave the
highest yield (Table 6, entry 3). However, the presence of the bulkier phenyl group on the nucleophile
reaction partner, did not give any improvement in terms of diastereo- or enantio-selectivity. Also in
this case the stereochemistry of diastereoisomeric products 3f (cis) and 3’f (trans) was assigned by
NOESY experiments (see Supporting Information).
Finally, with the aim to briefly investigate the effect of the substitution at the alkyne terminus, we
prepared four 2-alkynylbenzaldehydes characterized by the presence of EW, ED, and alkyl groups on
the alkyne terminus. As for 1a, 2-alkynylbenzaldehydes 1d-g were synthesized by means of a typical
Sonogashira coupling24 in good to excellent yields starting from 2-bromobenzaldehyde and suitable
terminal acetylenes. The results are described in Table 7. As expected, different substitution on alkyne
terminus are well tolerated and the corresponding 6-substitued benzoxazino isoquinolines (3g-j and
3’g-j) were obtained in very yield with diastereoisomeric ratios in agreement with the previous
findings.
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Table 7: Brief scope or the domino reaction.
Entry
1
d
e
f
R
Yielda
78%
66%
73%
80%
3
g
h
i
dr 3:3’b
72 : 28
70 : 30
73 : 27
59 : 41
1
2
3
4
m-CF3-Ph
p-MeO-Ph
p-Cl-Ph
cyclopropyl
g
j
a Isolated yield by flash silica gel column chromatography n-hexane/AcOEt; b Calculated via 1H NMR
of the crude.
The stereochemistry of diastereoisomeric products 3g-j (cis) and 3’g-j (trans) was assigned by
analogy with compounds 3e and 3’e.
According to literature findings10,11,13 and based on our results, a plausible reaction mechanism is
proposed as depicted in Scheme 1. The very first step is the condensation between the benzaldehydes
1 and -aminoalcohols 2 to give the imine intermediate I. This reaction is probably very fast due to
the strong nucleophilicity of the electron-rich anilines. The transformation of the imine intermediate
I into the final product 3 could occur through two different pathway-that are the real driving force of
the transformation-involving two subsequent intramolecular cascade nucleophilic attacks,
respectively pathway A and B (Scheme 1).
In path A, silver activates the triple bond, forming the intermediate II, which undergo the
intramolecular nucleophilic attack from the nitrogen atom of the imine to give isoquinolines
intermediate III. Then, the subsequent intramolecular attack of alcoholic oxygen on activated
iminium group gave the final product 3, whereas the protodemetallation restore the silver catalyst.
Alternatively, path B involves the direct intramolecular addition of the alcoholic oxygen nucleophile
to silver activated imine (intermediate IV) to give the benzoxazino intermediate V. The following
intramolecular reaction of the nitrogen of the oxazine moiety to the silver activated triple bond
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10.1002/ejoc.202000341
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resulted in the formation of the product 3, always after protodemetallation and regeneration of the
catalyst (Scheme 4).
Scheme 4: Proposed mechanism.
Although path B cannot be ruled out, among the two possible pathways Path A seems to be more
reliable on the basis of the following considerations: i) nitrogen is in general more nucleophile than
oxygen; ii) a Path like A, in which the catalytic complex is far from the incoming stereocentre,
justifies the absence of enantioselectivity observed also in the presence of hindered chiral silver
catalysts such as [Ag(PcL6)*]+ iii) under the optimized reaction conditions, intermediate V was never
isolated or identified in the reaction crude.
Conclusions
A new efficient synthetic [Ag(PcL)]-catalysed domino strategy has been developed which leads to
the formation of 6-substituted benzoxazino isoquinolines with excellent yields starting from 2-
alkynylbenzaldehydes and 1-substituted (2-aminophenyl)methanols. The approach has been
optimized by a preliminary in-depth screening of the reaction conditions with 2-(p-
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10.1002/ejoc.202000341
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tolylethynyl)benzaldehyde and (2-aminophenyl)methanol as achiral model compounds. Best results
have been obtained by using original silver complexes of macrocyclic pyridine-containing ligands
(PcL) as catalysts. The reactions can be performed under conventional heating, under microwave
irradiation, or at room temperature with comparable results in term of yields but very different
reaction times. The use of a -substituted o-aminobenzyl alcohol bring to the formation of two
diastereoisomers characterized by different stability. In particular, the diastereoisomer in which the
hydrogen in positions 4b and 6 are in a cis conformation (confirmed by NOE 1H NMR experiments
and single crystal X-ray crystallography) is the more stable and it is always isolated as major isomer.
The formation of the disfavoured trans-diastereoisomer is improved by the reaction temperature, and
this suggests the involvement of a higher-energy transition state. When the 1-substituted (2-
aminophenyl)methanol is used as a racemate, the two diastereoisomeric products are obtained-as
expected-in racemic form. Instead, when the starting material is enantiomerically pure, the cis
diastereoisomer is obtained as almost pure enantiomer (ee = 99%), while the trans ones does not fully
retain its configuration such as a sort of racemization occurred, most probably at the high energy
transition state level. Unfortunately, in this transformation an adequate degree of enantioselection was
not achieved in any case.
Nevertheless, this approach represents a new and alternative path for the synthesis of 6-substituted
benzoxazino isoquinolines, which are important scaffolds in medicinal chemistry. The use of silver
PcL complexes as catalysts bring some interesting improvements compared to the use of the simple
silver salts. First, (PcL) ligands increase the solubility and the stability of the silver. Second, in some
cases they improved reaction yields, as in the case of the chiral complex [Ag(PcL6)]*. Further studies
will be now devoted to the elucidation of the reaction mechanism to gain some insight for a more
accurate design of new chiral silver (PcL) complexes as effective stereoselective catalysts.
Experimental section
General experimental details
All the reactions, that involve the use of reagents sensitive to oxygen or hydrolysis, were carried out
under a nitrogen atmosphere. The glassware was previously dried in an oven at 110 °C and set with
cycles of vacuum and nitrogen. Syringes used to transfer reagents and solvents, were previously set
under nitrogen atmosphere. All chemicals and solvents are commercially available and were used
without further purification. The chromatographic column separations were performed by flash
technique, using silica gel (pore size 60Å, particle size 230-400 mesh, Merck Grade 9385). For thin-
layer chromatography (TLC), Silica on TLC Alu foils with fluorescent indicator (254 nm) was
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employed and the detection was performed by irradiation with UV light (λ = 254 nm and/or 366 nm).
Chiral HPLC analyses were performed with the following chiral columns: Phenomenex, Lux
Amylose-2; (eluent: n-hexane/isopropanol/diethylamine = 90:10:0.1) or Column: Daicel, Chiracel
AD, amylose; (eluent: n-hexane/isopropanol/diethylamine = 75:25:0.1) for 3a and Kromasil,
1
AmyCoat (eluent: n-hexane/isopropanol = 9:1) for 3e, 3’e, 3f and 3’f. H NMR analysis were
performed with 300 MHz spectrometers at room temperature. The coupling constants (J) are
expressed in Hertz (Hz), the chemical shifts (δ) in ppm. The multiplicity of the proton spectra were
described by the following abbreviations: s (singlet), d (doublet), t (triplet), q (quartet), dt (double
13
triplet), dd (double doublet), td (triple doublet), m (multiplet), br (broad), ps (pseudo). C NMR
analysis were performed with the same instruments at 74.45 MHz; APT sequence was used to
distinguish the methine and methyl carbon signals from those arising from methylene and quaternary
carbon atoms. All 13C NMR spectra were recorded with complete proton decoupling.
Low resolution MS spectra were recorded with electron impact source and electrospray/ion trap
instruments, using a syringe pump device to inject directly the sample solutions. The values are
expressed as mass-charge ratio and the relative intensities of the most significant peaks are shown in
brackets. Melting points are uncorrected. Alkynylbenzaldehydes 1a-f,18d 1-(2-aminophenyl)ethan-1-
one (±)-2b21 and its enantiomeric pure form (R)-(2-aminophenyl)ethan-1-one (R)-2b22 and (2-
aminophenyl)(phenyl)methanol (±)-2c21 are known compounds and have been prepared as described
in the literature. The synthesis of complexes [Ag(PcL1)],18c [Ag(PcL2)],18b [Ag(PcL3)],18e
[Ag(PcL4)],18e [Ag(PcL5)],19b [Ag(PcL6)],19b have been already described.
General procedure for the synthesis of benzoxazino isoquinolines 3. Method A–rt or thermal.
To a N2-flushed solution of the selected 2-alkynylbenzaldehyde 1 (0.317 mmol) and 2-
aminobenzylalcohol 2 (0.380) in anhydrous DMF (1 mL), the [Ag(PcL)]+X- catalyst (5 mol%) was
added. The mixture was stirred at room temperature or at 60 °C. The reaction mixture was poured
into water (50 mL) and extracted twice with ethyl acetate (2 × 30 mL). The organic phase was washed
twice with brine (30 mL) and water (30 mL). The organic phase was dried over sodium sulphate,
filtered and concentrated to dryness to afford the reaction crude. This was purified by flash column
chromatography over silica gel with mixtures of n-hexane/AcOEt/TEA as eluent. Some spectra show
traces of the corresponding diastereoisomer, because they are very difficult to separate by column
chromatography. For times, temperature and yields see the Table 1 in the main text.
Method B–microwave heating. In a microwave test tube, the selected 2-alkynylbenzaldehyde 1
(0.317 mmol) and 2-aminobenzylalcohol 2 (0.380) were dissolved in anhydrous DMF (1 mL), then
the [Ag(PcL)]+X- catalyst (5 mol%) was added. The mixture was stirred at 100 °C under microwave
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heating for 1 h. The reaction mixture was poured into water (50 mL) and extracted twice with ethyl
acetate (2 × 30 mL). The organic phase was washed twice with brine (30 mL) and water (30 mL).
The organic phase was dried over sodium sulphate, filtered and concentrated to dryness to afford the
reaction crude. This was purified by flash column chromatography over silica gel with mixtures of
n-hexane/AcOEt/TEA as eluent. Some spectra show traces of the corresponding diastereoisomer,
because they are very difficult to separate by column chromatography.
12-(p-tolyl)-4bH,6H-benzo[4,5][1,3]oxazino[2,3-a]isoquinoline (3a): Method A (Table 1, entry 3).
Reaction temperature: 60 °C. Eluent for chromatography: Hexane/EtOAc/TEA = 96:4:2.5. Yellow
solid. Yield: 82% (84 mg); mp 152.3-154.4 °C. 1H NMR (300 MHz, CDCl3): δ 7.41 (d, J = 7.4 Hz,
1H), 7.32 (t, J = 7.4 Hz, 1H), 7.20 (m, 2H), 7.08 (m, 5H), 6.92 (t, J = 7.1 Hz, 1H), 6.81 (t, J = 7.7 Hz,
1H), 6.25 (d, J = 8.0 Hz, 1H), 6.08 (s, 1H), 5.95 (s, 1H), 5.25 (d, J = 14.6 Hz, 1H), 5.09 (d, J = 14.6
Hz, 1H), 2.33 (s, 3H). The spectral data are in agreement with literature findings.10
12-(4-methoxyphenyl)-4bH,6H-benzo[4,5][1,3]oxazino[2,3-a]isoquinoline (3b): Method A (Table 1,
entry 13). Reaction temperature: 60 °C. Eluent for chromatography: Hexane/EtOAc = 85:15. Yellow
solid. Yield: 63% (68 mg); mp 158.1-162.9 °C. 1H NMR (300 MHz, CDCl3): δ 7.40 (dd, J = 7.5, 0.6
Hz, 1H), 7.32 (td, J = 7.4, 1.1 Hz, 1H), 7.23 (dd, J = 7.4, 1.3 Hz, 1H), 7.19 (d, J = 3.4 Hz, 1H), 7.15
(d, J = 8.2 Hz, 2H), 7.05 (d, J = 7.5 Hz, 1H), 6.92 (td, J = 7.4, 1.0 Hz, 1H), 6.83 (dd, J = 8.1, 0.7 Hz,
1H), 6.78 (d, J = 8.9 Hz, 2H), 6.25 (d, J = 8.1 Hz, 1H), 6.07 (s, 1H), 5.93 (s, 1H), 5.24 (d, J = 14.5
Hz, 1H), 5.08 (d, J = 14.5 Hz, 1H), 3.79 (s, 3H). 13C NMR (75.45 MHz, CDCl3): δ 159.4 (C), 140.6
(C), 139.9 (C), 132.9 (C), 129.8 (CH), 129.4 (C), 128.9 (CH), 128.4 (C), 127.0 (C), 126.6 (CH), 125.9
(CH), 125.8 (CH), 124.6 (CH), 124.2 (CH), 123.8 (CH), 122.3 (CH), 113.4 (CH), 105.3 (CH), 85.9
(CH), 67.9 (CH2), 55.2 (CH3). MS ESI(+): m/z (%) = 342.29 (100) [M+H]+. Anal. Calcd for
C23H19NO2: C, 80.92; H, 5.61; N, 4.10. Found: C, 81.24; H, 5.68; N, 4.21.
12-propyl-4bH,6H-benzo[4,5][1,3]oxazino[2,3-a]isoquinoline (3c): Method A (Table 1, entry 15).
Reaction temperature: 60 °C. Eluent for chromatography: Hexane/EtOAc/TEA = 95:5:2.5. Yellow
oil. Yield: 35% (31 mg). 1H NMR (300 MHz, CDCl3): δ 7.35–7.07 (m, 8H), 5.82 (s, 1H), 5.74 (s,
1H), 5.21 (d, J = 15.3 Hz, 1H), 4.99 (d, J = 15.3 Hz, 1H), 2.52 (ddd, J = 14.9, 8.9, 5.8 Hz, 1H), 2.37
(ddd, J = 15.4, 9.1, 6.8 Hz, 1H), 1.41–1.25 (m, 2H), 0.85 (t, J = 7.4 Hz, 3H). 13C NMR (75.45 MHz,
CDCl3): δ 142.3 (C), 140.9 (C), 132.5 (C), 130.9 (C), 129.3 (CH), 127.7 (CH), 126.0 (CH), 125.4
(CH), 125.12 (CH), 125.07 (C), 124.97 (CH), 124.8 (CH), 123.7 (CH), 100.6 (CH), 84.9 (CH), 67.7
(CH2), 34.9 (CH2), 20.9 (CH2), 13.7 (CH3). MS ESI(+): m/z (%) = 278.25 (100) [M+H]+. Anal. Calcd
for C19H19NO: C, 82.28; H, 6.90; N, 5.05. Found: C, 82.39; H, 6.81; N, 4.99.
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12-(3-(trifluoromethyl)phenyl)-4bH,6H-benzo[4,5][1,3]oxazino[2,3-a]isoquinoline (3d): Method B
(Table 2, entry 11). Reaction temperature: 100 °C. Eluent for chromatography: Hexane/EtOAc/TEA
= 96:4:1. Yellow solid. Yield: 64% (90 mg); mp 145.6-146.2 °C. 1H NMR (300 MHz, CDCl3): δ 7.52
(m, 2H), 7.44 (dd, J = 7.5, 0.6 Hz, 1H), 7.32 (m, 4H), 7.22 (d, J = 7.6 Hz, 1H), 7.08 (d, J = 7.5 Hz,
1H), 6.96 (td, J = 7.5, 1.0 Hz, 1H), 6.81 (t, J = 7.7 Hz, 1H), 6.16 (d, J = 8.1 Hz, 1H), 6.10 (s, 1H),
6.00 (s, 1H), 5.29 (d, J = 14.8 Hz, 1H), 5.12 (d, J = 14.8 Hz, 1H). 13C NMR (75.45 MHz, CDCl3): δ
139.40 (C), 139.36 (C), 137.8 (C), 131.92 (C), 131.88 (CH), 130.6 (q, J2 = 32.4 Hz, C-CF3), 129.1
(CH), 128.7 (C), 128.4 (CH), 126.91 (CH), 126.89 (C), 126.5 (CH), 125.9 (CH), 125.3 (q, J3 = 3.8
Hz, CH), 124.9 (CH), 124.71 (CH) overlapping with 124.66 (q, J3 = 3.8 Hz, CH), 124.05 (q, J1 =
272.5 Hz, CF3) 123.7 (CH), 123.0 (CH), 106.6 (CH), 84.9 (CH), 68.0 (CH2). MS ESI(+): m/z (%) =
380.28 (100) [M+H]+. Anal. Calcd for C23H16F3NO: C, 72.82; H, 4.25; N, 3.69. Found: C, 72.99; H,
4.28; N, 3.61.
(Cis)-6-methyl-12-(p-tolyl)-4bH,6H-benzo[4,5][1,3]oxazino[2,3-a]isoquinoline (3e): Method A
(Table 5, entry 4). Reaction temperature: 25 °C. Eluent for chromatography: Hexane/EtOAc/TEA =
95:5:1. Yellow solid. Yield: 85% (91 mg); mp 148.4-149.7 °C. 1H NMR (300 MHz, CDCl3): δ 7.41
(d, J = 7.5 Hz, 1H), 7.34–7.20 (m, 2H), 7.20–7.03 (m, 6H), 6.93 (td, J = 7.5, 1.1 Hz, 1H), 6.81 (td, J
= 7.8, 1.5 Hz, 1H), 6.24 (dd, J = 8.1, 0.9 Hz, 1H), 6.14 (s, 1H), 5.96 (s, 1H), 5.39 (q, J = 6.5 Hz, 1H),
2.33 (s, 3H), 1.71 (d, J = 6.5 Hz, 3H). 13C NMR (75.45 MHz, CDCl3): δ 140.9 (C), 139.7 (C), 137.8
(C), 134.3 (C), 133.5 (C), 132.7 (C), 129.0 (CH), 128.9 (CH), 128.6 (CH), 127.3 (C), 126.7 (CH),
126.02 (CH), 125.99 (CH), 124.5 (CH), 124.4 (CH), 123.9 (CH), 122.5 (CH), 105.7 (CH), 85.2 (CH),
73.8 (CH), 22.0 (CH3), 21.4 (CH3). MS ESI(+): m/z (%) = 338.07 (100), 340.06 (96) [M+H]+. Anal.
Calcd for C24H21NO: C, 84.92; H, 6.24; N, 4.13 Found: C, 84.24; H, 6.41; N, 4.08. Crystal data:
C24H21NO, M = 1212.85, monoclinic a = 14.0503(6), b = 5.6227(3), c = 22.727(1) Å, β = 97.907(1)°,
V = 1778.38(14) Å3, T = 180 K, space group P21/c (no. 14), Z = 4, 16557 reflections measured, 4171
unique (Rint = 0.0164), which were used in all calculations. The final agreement indices R1 and wR2
were 0.0406 and 0.1103 respectively for 3707 independent observed [I > 2σ(I)] absorption corrected
data.
(Trans)-6-methyl-12-(p-tolyl)-4bH,6H-benzo[4,5][1,3]oxazino[2,3-a]isoquinoline (3’e): Method A
(Table 5, entry 4). Reaction temperature: 25 °C. Eluent for chromatography: Hexane/EtOAc/TEA =
95:5:1. Yellow solid. Yield: 14% (16 mg); mp 68.5-69.2 °C. 1H NMR (300 MHz, CDCl3): δ 7.38 (d,
J = 7.5 Hz, 1H), 7.34–7.21 (m, 2H), 7.20–7.02 (m, 6H), 6.93 (td, J = 7.5, 1.1 Hz, 1H), 6.80 (td, J =
7.9, 1.0 Hz, 1H), 6.28 (d, J = 8.1 Hz, 1H), 6.06 (s, 1H), 5.90 (s, 1H), 5.20 (q, J = 6.5 Hz, 1H), 2.32
(s, 3H), 1.79 (d, J = 6.7 Hz, 3H). 13C NMR (75.45 MHz, CDCl3): δ 140.9 (C), 139.6 (C), 137.8 (C),
134.3 (C), 132.8 (C), 132.7 (C), 129.0 (CH), 128.8 (CH), 128.6 (CH), 127.1 (CH), 126.9 (C), 125.9
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(CH), 125.8 (CH), 125.6 (CH), 124.4 (CH), 124.1 (CH), 122.6 (CH), 105.1 (CH), 80.6 (CH), 72.1
(CH), 22.2 (CH3), 21.4 (CH3). MS ESI(+): m/z (%) = 338.04 (25), 340.06 (100) [M+H]+. Anal. Calcd
for C24H21NO: C, 84.92; H, 6.24; N, 4.13 Found: C, 84.72; H, 6.35; N, 4.15.
(Cis)-6-phenyl-12-(p-tolyl)-4bH,6H-benzo[4,5][1,3]oxazino[2,3-a]isoquinoline (3f): Method B
(Table 6, entry 3). Reaction temperature: 100 °C. Eluent for chromatography: Hexane/EtOAc = from
98:2 to 90:10. Yellow solid. Yield: 62% (79 mg); mp 94.9-96.7 °C. 1H NMR (300 MHz, CDCl3): δ
7.59 (d, J = 6.8 Hz, 2H), 7.51 (d, J = 7.4 Hz, 1H), 7.48–7.30 (m, 5H), 7.30–7.20 (m, 2H) overlapping
with 7.26 (d, J = 7.6 Hz, 1H), 7.11 (d, J = 7.6 Hz, 2H), 6.88–6.80 (m, 3H), 6.40 (s, 1H), 6.30 (s, 1H),
6.11 (s, 1H), 2.38 (s, 3H). 13C NMR (75.45 MHz, CDCl3): δ 141.1 (C), 140.6 (C), 139.7 (C), 138.0
(C), 134.0 (C), 132.8 (C), 132.2 (C), 129.0 (CH), 128.7 (CH), 128.6 (CH), 128.3 (CH), 128.1 (CH),
127.5 (C), 126.7 (CH), 126.3 (CH), 126.2 (CH), 126.2 (CH), 124.3 (CH), 123.5 (CH), 122.2 (CH),
106.5 (CH), 85.6 (CH), 80.5 (CH), 21.4 (CH3). MS ESI(+): m/z (%) = 402.40 (100) [M+H]+. Anal.
Calcd for C29H23NO: C, 86.75; H, 5.77; N, 3.49 Found: C, 86.86; H, 5.85; N, 3.44.
(Trans)-6-phenyl-12-(p-tolyl)-4bH,6H-benzo[4,5][1,3]oxazino[2,3-a]isoquinoline (3’f): Method B
(Table 6, entry 3). Reaction temperature: 100 °C. Eluent for chromatography: Hexane/EtOAc = from
98:2 to 90:10. Yellow solid. Yield: 28% (35 mg); mp 101.2-102.7 °C. 1H NMR (300 MHz, CDCl3):
δ 7.53–7.38 (m, 6H), 7.29 (dd, J = 6.5, 1.2 Hz, 2H), 7.17 (m, 6H), 6.94–6.87 (m, 2H), 6.35 (dd, J =
5.6, 3.7 Hz, 1H), 6.14 (s, 1H), 6.06 (s, 1H), 6.04 (s, 1H), 2.36 (s, 3H). 13C NMR (75.45 MHz, CDCl3):
δ 141.1 (C), 140.4 (C), 139.6 (C), 137.9 (C), 134.2 (C), 132.7 (C), 129.0 (CH), 128.7 (CH), 128.7
(CH), 128.5 (C), 128.4 (CH), 128.3 (CH), 127.3 (CH), 126.8 (CH), 126.2 (CH), 126.0 (CH), 124.3
(CH), 122.9 (CH), 121.4 (CH), 107.3 (CH), 81.1 (CH), 77.7 (CH), 21.4 (CH3), one C overlapped. MS
ESI(+): m/z (%) = 402.45 (100) [M+H]+. Anal. Calcd for C29H23NO: C, 86.75; H, 5.77; N, 3.49
Found: C, 86.92; H, 5.65; N, 3.56.
(Cis)-6-methyl-12-(3-(trifluoromethyl)phenyl)-4bH,6H-benzo[4,5][1,3]oxazino[2,3-a]isoquinoline
(3g): Method B (Table 7, entry 1). Reaction temperature: 100 °C. Eluent for chromatography:
Hexane/EtOAc = 95:5. Yellow solid. Yield: 56% (70 mg); mp 54.2-56.1 °C. 1H NMR (300 MHz,
CDCl3): δ 7.57–7.48 (m, 2H), 7.43 (d, J = 7.3 Hz, 1H), 7.38–7.23 (m, 5H), 7.21 (d, J = 7.4 Hz, 1H),
7.13 (dd, J = 7.6, 0.7 Hz, 1H), 6.97 (td, J = 7.5, 1.1 Hz, 1H), 6.81 (td, J = 7.7, 1.5 Hz, 1H), 6.16 (s,
1H), 6.01 (s, 1H), 5.43 (q, J = 6.2 Hz, 1H), 1.72 (d, J = 6.5 Hz, 3H).13C NMR (75.45 MHz, CDCl3):
δ 139.4 (C), 139.2 (C), 138.0 (C), 133.7 (C), 132.1 (C), 131.9 (CH), 130.7 (q, J2 = 32.3 Hz, C-CF3),
129.2 (CH), 128.6 (CH), 127.3 (C), 127.0 (CH), 126.7 (CH), 126.2 (CH), 125.5 (q, J3 = 3.8 Hz, CH),
124.9 (CH), 124.7 (CH) overlapping with 124.6 (q, J3 = 3.8 Hz, CH), 124.1 (q, J1 = 272.3 Hz, CF3),
123.8 (CH), 123.2 (CH), 106.8 (CH), 85.1 (CH), 74.0 (CH), 22.0 (CH3). MS ESI(+): m/z (%) = 394.28
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(100) [M+H]+. Anal. Calcd for C24H18F3NO: C, 73.27; H, 4.61; N, 3.56 Found: C, 73.05; H, 4.74; N,
3.64.
(Trans)-6-methyl-12-(3-(trifluoromethyl)phenyl)-4bH,6H-benzo[4,5][1,3]oxazino[2,3-
a]isoquinoline (3’g): Method B (Table 7, entry 2). Reaction temperature: 100 °C. Eluent for
chromatography: Hexane/EtOAc = 95:5. Yellow solid. Yield: 22% (27 mg); mp 56.1-57.8 °C. 1H
NMR (300 MHz, CDCl3): δ 7.54–7.46 (m, 2H), 7.39 (d, J = 8.1 Hz, 1H), 7.36–7.18 (m, 5H), 7.15 (d,
J = 7.7 Hz, 1H), 6.97 (td, J = 7.6, 1.1 Hz, 1H), 6.80 (t, J = 8.2 Hz, 1H), 6.18 (d, J = 8.1 Hz, 1H), 6.08
13
(s, 1H), 5.93 (s, 1H), 5.23 (q, J = 6.6 Hz, 1H), 1.79 (d, J = 6.7 Hz, 3H). C NMR (75.45 MHz,
CDCl3): δ 139.5 (C), 139.2 (C), 138.1 (C), 133.2 (C), 132.2 (C), 132.0 (CH), 129.2 (CH), 128.5 (CH),
127.4 (CH), 126.9 (C), 126.5 (CH), 125.97 (CH), 125.95 (CH), 125.5 (q, J3 = 3.8 Hz, CH), 124.7
(CH), 124.6 (q, J3 = 3.8 Hz, CH), 124.1 (CH), 123.3 (CH), 106.1 (CH), 80.5 (CH), 72.1 (CH), 22.4
(CH3), two C (C-CF3 and CF3) are not attributable. MS ESI(+): m/z (%) = 394.20 (100) [M+H]+.
Anal. Calcd for C24H18F3NO: C, 73.27; H, 4.61; N, 3.56 Found: C, 73.11; H, 4.69; N, 3.68.
(Cis)-12-(4-methoxyphenyl)-6-methyl-4bH,6H-benzo[4,5][1,3]oxazino[2,3-a]isoquinoline
(3h):
Method B (Table 7, entry 2). Reaction temperature: 100 °C. Eluent for chromatography:
Hexane/EtOAc = 90:10. Yellow solid. Yield: 46% (52 mg); mp 150-152 °C. 1H NMR (300 MHz,
CDCl3) δ 7.45 – 7.38 (m, 1H), 7.31 (td, J = 7.4, 1.4 Hz, 1H), 7.23 (dd, J = 7.4, 1.4 Hz, 1H), 7.18 (d,
J = 8.6 Hz, 3H), 7.11 (d, J = 7.6 Hz, 1H), 6.94 (td, J = 7.5, 1.1 Hz, 1H), 6.84 (dd, J = 8.1, 1.0 Hz,
1H), 6.79 (d, J = 8.9 Hz, 2H), 6.26 (dd, J = 8.1, 1.0 Hz, 1H), 6.14 (s, 1H), 5.95 (s, 1H), 5.39 (q, J =
6.5 Hz, 1H, 3.80 (s, 2H), 1.72 (d, J = 6.5 Hz, 3H).13C NMR (75 MHz, CDCl3) δ 159.3 (C), 140.5 (C),
139.5 (C), 133.3 (C), 132.6 (C), 129.7 (CH), 129.5 (C), 128.8 (CH), 127.2 (C), 126.5 (CH), 125.9
(CH), 125.8 (CH), 124.3 (CH), 124.1 (CH), 123.7 (CH), 122.3 (CH), 113.5 (CH), 105.3 (CH), 85.1
(CH), 73.6 (CH), 55.2 (CH3), 21.8 (CH3). MS ESI(+): m/z (%) = 356.45 (100) [M+H]+. Anal. Calcd
for C24H21NO2: C, 81.10; H, 5.96; N, 3.94 Found: C, 80.88; H, 5.79; N, 3.81.
(Trans)-12-(4-methoxyphenyl)-6-methyl-4bH,6H-benzo[4,5][1,3]oxazino[2,3-a]isoquinoline (3’h):
Method B (Table 7, entry 2). Reaction temperature: 100 °C. Eluent for chromatography:
1
Hexane/EtOAc = 90:10. Yellow solid. Yield: 19% (21 mg). mp 98-101°C. H NMR (300 MHz,
CDCl3) δ 7.38 (d, J = 7.4 Hz, 1H), 7.31 (dt, J = 7.5, 3.7 Hz, 1H), 7.25 – 7.20 (m, 1H), 7.20 – 7.05 (m,
5H), 6.93 (t, J = 8.0 Hz, 1H), 6.83 (d, J = 8.2 Hz, 1H), 6.77 (d, J = 8.9 Hz, 2H), 6.28 (d, J = 8.2 Hz,
1H), 6.06 (s, 1H), 5.89 (s, 1H), 5.20 (q, J = 6.6 Hz, 1H), 3.79 (s, 3H), 1.78 (d, J = 6.6 Hz, 3H). 13C
NMR (75 MHz, CDCl3) δ 159.3 (C), 140.5 (C), 139.5 (C), 132.7 (C), 132.6 (C), 129.8 (CH), 129.6
(C), 128.7 (CH), 126.9 (C), 126.8 (CH), 125.7 (CH), 125.6 (CH), 125.3 (CH), 124.1 (CH), 123.8
(CH), 122.3 (CH), 113.4 (CH), 104.8 (CH), 80.6 (CH), 71.8 (CH), 55.2 (CH3), 21.9 (CH3). MS
22
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10.1002/ejoc.202000341
European Journal of Organic Chemistry
ESI(+): m/z (%) = 356.32 (100) [M+H]+. Anal. Calcd for C24H21NO2: C, 81.10; H, 5.96; N, 3.94
Found: C, 81.24; H, 5.90; N, 4.09.
(Cis)-12-(4-chlorophenyl)-6-methyl-4bH,6H-benzo[4,5][1,3]oxazino[2,3-a]isoquinoline
(3i):
Method B (Table 7, entry 2). Reaction temperature: 100 °C. Eluent for chromatography:
1
Hexane/EtOAc = from 100:0 to 70:30. Brownish wax. Yield: 53% (60 mg). H NMR (300 MHz,
CDCl3) δ 7.41 (d, J = 7.5 Hz, 1H), 7.32 (td, J = 7.4, 1.4 Hz, 1H), 7.24 (d, J = 1.4 Hz, 1H), 7.20 (d, J
= 9.0 Hz, 3H), 7.16 (s, 1H), 7.12 (d, J = 7.6 Hz, 1H), 6.95 (td, J = 7.5, 1.0 Hz, 1H), 6.84 (dd, J = 11.2,
4.2 Hz, 1H), 6.20 (d, J = 8.1 Hz, 1H), 6.13 (s, 1H), 5.96 (s, 1H), 5.39 (q, J = 6.5 Hz, 1H), 1.70 (d, J
= 6.5 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 139.5 (C), 139.2 (C), 135.5 (C), 133.7 (C), 133.4 (C),
132.1 (C), 129.7 (2CH), 128.9 (CH), 128.3 (2CH), 127.3 (C), 126.6 (CH), 126.3 (CH), 126.0 (CH),
124.5 (CH), 124.4 (CH), 123.6 (CH), 122.6 (CH), 106.3 (CH), 85.0 (CH), 73.7 (CH), 21.7 (CH3). MS
ESI(+): m/z (%) = 360.64 (100) [M+H]+. Anal. Calcd for C23H18ClNO: C, 76.77; H, 5.04; N, 3.89
Found: C, 76.94; H, 5.12; N, 3.75.
(Trans)-12-(4-chlorophenyl)-6-methyl-4bH,6H-benzo[4,5][1,3]oxazino[2,3-a]isoquinoline (3’i):
Method B (Table 7, entry 2). Reaction temperature: 100 °C. Eluent for chromatography:
Hexane/EtOAc = from 10:0 to 7:3. Brownish wax. Yield: 20 % (23 mg).1H NMR (300 MHz, CDCl3)
δ 7.38 (d, J = 7.5 Hz, 1H), 7.31 (dd, J = 7.4, 1.5 Hz, 1H), 7.26 (dd, J = 7.4, 1.5 Hz, 1H), 7.19 (m, 3H),
7.13 (m, 3H), 6.96 (td, J = 7.5, 1.2 Hz, 1H), 6.83 (td, J = 7.9, 1.1 Hz, 1H), 6.24 (dd, J = 8.1, 0.9 Hz,
1H), 6.06 (s, 1H), 5.89 (s, 1H), 5.20 (q, J = 6.7 Hz, 1H), 1.78 (d, J = 6.7 Hz, 3H). 13C NMR, MS and
elemental analysis have not been performed because the product contains a not negligible amount of
the diastereoisomer 3i.
(Cis)-12-cyclopropyl-6-methyl-4bH,6H-benzo[4,5][1,3]oxazino[2,3-a]isoquinoline (3j): Method B
(Table 7, entry 4). Reaction temperature: 100 °C. Eluent for chromatography: Hexane/EtOAc = from
9:1 to 7:3. Yellow oil. Yield: 47% (43 mg). 1H NMR (300 MHz, CDCl3): δ 7.44–7.39 (m, 1H), 7.34–
7.25 (m, 2H), 7.25–7.08 (m, 5H), 5.91 (s, 1H), 5.67 (s, 1H), 5.40 (q, J = 6.5 Hz, 1H), 1.66–1.43 (m,
13
2H) overlapping with 1.51 (d, J = 6.5 Hz, 3H), 0.98–0.77 (m, 2H), 0.65–0.57 (m, 1H). C NMR
(75.45 MHz, CDCl3): δ 144.0 (C), 140.7 (C), 135.8 (C), 132.6 (C), 129.2 (CH), 127.8 (CH), 126.2
(CH), 125.9 (CH), 125.7 (CH), 125.4 (C), 125.2 (CH), 124.8 (CH), 123.9 (CH), 98.2 (CH), 85.2 (CH),
74.2 (CH), 23.9 (CH), 14.6 (CH3), 9.9 (CH2), 6.2 (CH2). MS ESI(+): m/z (%) = 290.15 (100) [M+H]+.
Anal. Calcd for C20H19NO: C, 83.01; H, 6.62; N, 4.84 Found: C, 82.88; H, 6.60; N, 4.91.
(Trans)-12-cyclopropyl-6-methyl-4bH,6H-benzo[4,5][1,3]oxazino[2,3-a]isoquinoline (3’j): Method
B (Table 7, entry 4). Reaction temperature: 100 °C. Eluent for chromatography: Hexane/EtOAc =
from 9:1 to 7:3. Yellow oil. Yield: 33% (30 mg). 1H NMR (300 MHz, CDCl3): δ 7.45 (d, J = 7.5 Hz,
23
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10.1002/ejoc.202000341
European Journal of Organic Chemistry
1H), 7.34–7.13 (m, 6H), 7.10 (d, J = 7.6 Hz, 1H), 5.86 (s, 1H), 5.63 (s, 1H), 5.03 (q, J = 6.6 Hz, 1H),
13
1.70 (d, J = 6.6 Hz, 3H), 1.52 (tt, J = 5.8, 4.7 Hz, 1H), 0.97–0.74 (m, 2H), 0.66–0.51 (m, 2H). C
NMR (75.45 MHz, CDCl3): δ 143.7 (C), 140.8 (C), 135.2 (C), 132.7 (C), 129.2 (CH), 127.9 (CH),
126.2 (CH), 126.0 (CH), 125.9 (CH), 125.2 (C), 125.2 (CH), 124.6 (CH), 123.9 (CH), 97.9 (CH),
80.9 (CH), 71.6 (CH), 23.0 (CH), 14.7 (CH3), 10.3 (CH2), 6.1 (CH2). MS ESI(+): m/z (%) = 290.15
(100) [M+H]+. Anal. Calcd for C20H19NO: C, 83.01; H, 6.62; N, 4.84 Found: C, 82.95; H, 6.51; N,
4.88.
Chrystal data: Full crystallographic data have been deposited with the Cambridge Crystallographic
Data Centre (CCDC No. 1989682). A copy of the data can be obtained free of charge on application
to CCDC, 12 Union Road, Cambridge CB2 IEZ, UK (Fax: +44 1223 336 033; e-mail:
deposit@ccdc.cam.ac.uk).
Acknowledgements
This research was supported by a grant from Università degli Studi di Milano, Linea 2 “Dotazione
Annuale per Attività Istituzionali” 2017.
Keywords
Alkynes, Pyridine containing ligands, Silver, Domino reactions, Microwaves, Polycyclic N-O
Heterocycles
Notes and references
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European Journal of Organic Chemistry
Table of contents graphic
6-Substituted benzoxazino isoquinoline nucleus, a key skeleton in some biological active molecules,
can be prepared by a silver catalysed domino approach starting from 2-alkynylbenzaldehydes and 1-
substituted (2-aminophenyl)methanols. The silver(I) complexes of macrocyclic pyridine-containing
ligands (PcL) demonstrated to be the catalysts of choice.
Key Topic
Domino Addition/Cycloisomerization
26
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