On water: Silver-catalyzed domino approach for the synthesis of benzoxazine/oxazine-fused isoquinolines and naphthyridines from o-alkynyl aldehydes

Article abstract of DOI:10.1021/jo4009639

An operationally simple domino approach for the silver-catalyzed synthesis of oxazine/benzoxazine-fused isoquinolines 5a-q and naphthyridines 6a-v by the reaction of o-alkynyl aldehydes 3a-aa with amines having embedded nucleophiles 4a-d under mild reacti

Full text of DOI:10.1021/jo4009639

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Article
On Water: Silver-Catalyzed Domino Approach for the
Synthesis of Benzoxazine/Oxazine Fused Isoquinolines
and Naphthyridines from ortho-Alkynylaldehydes
Akhilesh K. Verma, Deepak Choudhary, Rakesh K. Saunthwal,
Vineeta Rustagi, Monika Patel, and Rakesh Kumar Tiwari
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo4009639 • Publication Date (Web): 12 Jun 2013
Downloaded from http://pubs.acs.org on June 14, 2013
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On Water: SilverꢀCatalyzed Domino Approach for the
Synthesis of Benzoxazine/Oxazine Fused Isoquinolines
and Naphthyridines from orthoꢀAlkynylaldehydes
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Akhilesh K. Verma,†* Deepak Choudhary,† Rakesh K. Saunthwal, † Vineeta Rustagi, † Monika
Patel† and Rakesh K. Tiwari‡
† Synthetic Organic Chemistry Research Laboratory, Department of Chemistry, University of
Delhi, Delhi, 110007, India
‡ Department of Life Sciences, School of Natural Sciences, Shiv Nadar University, Gautam
Budh Nagar 203207, India
averma@acbr.du.ac.in
ABSTRACT: An operationally simple domino approach for the silverꢀcatalyzed synthesis
of oxazine/benzoxazine fused isoquinolines 5a–q and naphthyridines 6a–v by the reaction of
orthoꢀalkynylaldehydes 3a–aa with amines having embedded nucleophiles 4a–d under mild
reaction condition in water is described. The reaction showed selective CꢀN bond formation
on more electrophilic alkynyl carbon resulting in the formation of 6ꢀendoꢀdig cyclised
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product. The competitive experiments showed the viability of intramolecular nucleophilic
attack over intermolecular attack of external nucleophile. This methodology accommodates
wide functional group variation which proves to be useful for structural and biological
assessment.
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INTRODUCTION
The increasing significance of synthetic organic chemistry in pharmaceutical sciences
demands the development of new strategies to synthesize a collection of natural product-like
compounds.1 For several decades; a large effort has been devoted for the development of
new, efficient catalytic transformations to achieve high molecular complexity from simple
starting materials. Domino reactions are one of such attractive processes that enhance the
synthetic efficiency by using more than two reactants to create complex products with an
optimal number of new bonds and functionalities.1a,2a Among various catalysts used,
transition metalꢀcatalyzed domino processes have shown to affect the efficient conversion
using simple starting materials to complex molecules in a stepwise manner.2bꢀf Particularly
silverꢀcatalyzed cyclizations have acquired tremendous success due to their cost and
capability to activate alkyne, alkene and allene functionalities at lowꢀcatalyst loading under
mild reaction condition.3
As a privileged fragment, 1,2ꢀdihydroisoquinoline skeleton is an important substructure
occur in both natural products and therapeutic agents having wide applications in
pharmaceutical research.4 Functionalized benzoxazines have attracted considerable attention
due to their prominent biological activities. They are known to act as antidepressant, antiꢀ
inflammatory, antitumor5aꢀd and antimalarial agents6 (Figure 1, A). They also act as
phosphatidylinositolꢀ3ꢀkinase (PI3K) inhibitor,7 neuroprotective antioxidants,8 5ꢀHT1A/B/D
receptor antagonists,9 antiarrhythmics against ischemiaꢀreperfusion injury10 and act as
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intermediate for the synthesis of various natural product such as glyantrypine,
fumiquinazoline F, fumiquinazoline G, and fiscalin B.11 Their analogues exhibit high
selectivity as competitive antagonist for the M4 receptor and parkinsonism.12 Their
derivatives have shown thrombin inhibitory and glycoprotein IIb/IIIa receptor antagonistic
activity13 and were evaluated as progesterone receptor (PR) antagonists14 (Figure 1, B).
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Figure 1. Significant examples of biologically active benzoxazine core
Substituted benzoxazines such as levofloxacin are known to act as antibacterial agent
(Figure 1, C).15 1,3ꢀBenzoxazines have been used as herbicides and agricultural
microbiocides as well as bactericide and fungicide.5aꢀd,16a Further, Nꢀhaloacetyl derivatives of
benzoxazines inhibit methane production in ruminants.16b As a privileged fragment, oxazine
core is also found in many natural products exhibiting remarkable biological activities17aꢀf and
also acts as synthetic intermediates in synthesis as well.18 Because of such enriched biological
profile, significant efforts are being continued and are still required for the development of
efficient ecoꢀfriendly methods for their construction.
Using cascade addition of nucleophiles19a and cyclization,19bꢀl various reports are
present in the literature showing the syntheses of fused 1,2ꢀdihydroisoquinolines20ꢀ22
/
isoquinolines,23 naphthyridines23gꢀh,24 in the presence of various transitionꢀmetal catalysts or
even in their absence.25 Moreover, 1,3ꢀbenzoxazines were synthesized using 2ꢀ
(allyloxy)benzylamines with syngas in the presence of rhodium(I) catalyst.26aꢀb Their
26d
synthesis have been reported using metal catalysts such as Au,26c Cu(OTf)2 and also in the
absence of metal.26eꢀf Along this, some polymeric 1,3ꢀbenzoxazines were also synthesized
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without using catalyst.26gꢀh Similarly, synthesis of substituted 1,3ꢀoxazine have been reported
by both metal26eꢀf and nonꢀmetal catalyst.26j
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Development of new and efficient synthetic strategies is as important as offering its
reduced environmental impacts. Therefore, many reactions are being carried out in ecoꢀ
friendly condition. Thus, reactions of water insoluble organic compounds taking place in
aqueous suspension are becoming prominent, proceeding with high efficiency and possess
feasible synthetic protocol.27 Water is an ideal solvent since it fulfils many criteria; it is
nontoxic, nonꢀflammable, and abundantly available and inexpensive.27 Use of water imparts
often a significant effect on the both rate and selectivity of organic reactions through
hydrophobic interactions and enrichment of organic substrates in local hydrophobic
environment.28
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Scheme 1. Heterocycles Synthesized in our Laboratory Using o-Alkynylaldehydes
Motivated by importance of biological activity and as a part of our ongoing efforts to
synthesize Nꢀheterocycles by activation of alkyne (Scheme 1),29 and also on the basis of our
recent preliminary reports regarding the synthesis of fused polyheterocyclic quinoxalines and
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benzimidazoles,23gꢀh we thought that oꢀalkynylaldehydes could further be used to synthesize
fused isoquinolines/naphthyridines with new heterocyclic frame. We thereby envisaged that
reactions of orthoꢀalkynylaldehyde 3a–aa and amines having embedded nucleophiles 4a–d
through intermolecular condensation would provide the corresponding imines, which in the
presence of appropriate alkyne activators would afford fused isoquinolines/naphthyridines in
an apparently simple way. Designed retrosynthetic pathway is shown in Scheme 2. This
cascade strategy would involve the formation of two new C–N bonds and one new C–Y bond
thereby leading to the formation of two heterocyclic rings in oneꢀpot. This has prompted us to
explore and develop a convergent domino strategy for the divergent preparation of fused array
of isoquinolines, keeping in mind the environmental considerations. Herein, we present our
recent efforts for the silverꢀcatalyzed regioselective domino synthesis of benzoxazine/oxazine
fused isoquinolines and naphthyridines in water.
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Scheme 2. Designed Reterosythetic Pathway for the Synthesis of Oxazine/Benzoxazine
Fused Isoquinolines and Naphthyridines
RESULTS AND DISCUSSION
Preparation of ortho-alkynylaldehydes. To probe the viability of the designed domino
strategy, orthoꢀalkynylaldehydes 3a–aa were readily prepared by standard Sonogashira crossꢀ
coupling reaction of commercially available and readily accessible orthoꢀhaloaldehydes 1a–d
with terminal alkynes 2a–n (Scheme 3).29b This coupling procedure has readily
accommodated a large variety of functional groups and provided the coupling products 3a–aa
in good to excellent yields.
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Scheme 3. Preparation of ortho-Alkynylaldehydes
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Table 1. Optimization of Reaction Conditionsa
entry
catalyst (mol %)
conditions
t °C
yield (%)
solvent
CH2Cl2
time (h)
4
1
2
3
4
5
6
7
AgNO3 (5)
AgNO3 (10)
AgNO3 (10)
AgNO3 (10)
AgNO3 (10)
AgNO3 (10)
AgNO3 (10)
25
38
60
62
73
70
40
64
CH2Cl2
THF
25
50
4
1
1
1
1
1
EDC
70
DMF
110
70
Toulene
EtOH
70
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8
AgNO3 (10)
AgOAc (10)
AgOTf (10)
AgI (10)
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
80
80
80
80
80
80
80
80
80
1
1
1
1
1
2
2
3
6
81
71
76
74
ꢀ
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ꢀ
PdCl2 (10)
Pd(OAc)2 (10)
CuI (10)
55
55
70
trace
AlCl3 (10)
aThe reactions were performed using 0.5 mmol of oꢀalkynylaldehyde 3a, 1.1
equiv of amine 4a in 2.0 mL of solvent.
In order to find an optimal reaction condition, we selected 2ꢀphenylethynyl benzaldehyde (3a)
and (2ꢀaminophenyl)methanol (4a) as model substrates (Table 1). Reaction of alkyne 3a (0.5
mmol) with amine 4a (1.1 equiv.) using 5 mol % of AgNO3 in 2.0 mL of CH2Cl2 at 25 °C for
4 h afforded the formation of desired product 5a in 38% yield (Table 1, entry 1). Increasing
the amount of AgNO3 from 5 to 10 mol % in CH2Cl2 afforded the product 5a in 60% yield
(entry 2). Different solvents such as THF, EDC, DMF, toluene, ethanol were examined at
elevated temperatures, it was observed that the respective reaction did not attain the desired
levels of reactivity and provided the formation of product 5a in 40–73% yield (entries 3–7).
When water was employed as a solvent, reaction proceeded to completion and it provided the
formation of desired product 5a in 81% yield in 1 h at 80 °C (entry 8). Other silver catalysts
with different counter anions like AgOAc, AgOTf, AgI resulted in 71–76% yield of the
desired product 5a (entries 9–11). However, in the absence of catalyst, reactants remained
almost unchanged during the course of reaction (entry 12). Transitionꢀmetalꢀcatalysts other
than silver like PdCl2, Pd(OAc)2 and CuI afforded the formation of desired product 5a in
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lower yields (entries 13–15). Reaction with Lewis acid AlCl3 fails to afford the desired
product (entry 16). The formation of regioselective 6ꢀendoꢀdig cyclized product 5a was
characterized by 1H, 13C NMR and mass spectroscopic data. Appearence of peaks at 5.95 ppm
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as a singlet & 5.26, 5.09 ppm as a diastereotopic doublets in H NMR of 5a and
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disappearance of the two peaks of alkynyl carbons in its characteristic region in 13C NMR
spectrum suggested the formation of desired cyclized product 5a. Xꢀray crystallographic
analysis of 5a confirmed the formation of 6ꢀendoꢀdig cyclized product (see supporting
information).
Synthesis of benzoxazine/oxazine fused isoquinolines. Having demonstrated the viability of
this domino strategy, we then investigated the generality and scope of the transformation
under the optimized condition (Table 2). As shown in Table 2, the reaction is tolerant towards
a variety of oꢀalkynylaldehydes 3 bearing different alkynyl substituents. We commenced our
study by the reaction of amines having embedded nucleophiles 4a–d with substrate 3. The
results of this study are summarized in table 2 showing that use of amine 4a gave better yield
of respective product than the use of 4b, 4c, 4d and also reaction was a bit faster in the case of
former amine. When electronically neutral, moderately donating groups such as Ph, 4ꢀEtꢀ
C6H4 3a–b were used, reaction preceded well and afforded products 5a–b in 81 and 83%
yields respectively (Table 2, entries 1–2). When strong donating group such as thienyl was
used, reaction proceeded well and afforded the product 5c in 85% yield (entry 3). With
aliphatic groups such as cyclohexyl and nꢀbutyl, the reaction provided the respective desired
products 5d–e in 77 and 75% yields respectively (entries 4–5). Alkynes 3f bearing two
methoxy group at meta position of the phenyl ring afforded the cyclized products 5f in
comparatively lower yield (entry 6), which may be the result of the reduced electrophilicity at
the proximal end of alkyne which thereby reduced the efficiency of the desired
transformation. Encouraged by above results, we further extended the same protocol with 3ꢀ
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aminopropanꢀ1ꢀol 4b. Reaction of substrates 3a–c, 3g–i with 3ꢀaminopropanꢀ1ꢀol proceeded
well and afforded the desired products 5g–l in 75–82% yields (Table 2, entries 7–12).
Alkynes 3j, bearing a cyclopropyl group provided the desired products 5m in 71% yields,
(entry 13). Reaction of amine 4b with 2ꢀ((4ꢀnitrophenyl)ethynyl)ꢀquinolineꢀ3ꢀcarbaldehyde
(3m) bearing an electronꢀwithdrawing nitro group at para position of the phenyl ring fails to
afford the desired product 5o (entry 15). Reaction of 3a with ethaneꢀ1,2ꢀdiamine (4c) afforded
the desired product 5p in 68% yield (entry 16); however an inseparable complex mixture was
obtained when Nꢀmethylpropaneꢀ1,3ꢀdiamine (4d) was reacted with 3a (entry 17).
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Table 2. Domino Synthesis of Benzoxazine/Oxazine Fused Isoquinolinesa
substrate
amine
product
entry
1
yield (%)
81
3a
5a
4a
2
3
83
85
3b
3c
4a
4a
5b
5c
4
5
77
75
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3e
4a
4a
5d
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70
3f
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7
8
75
79
3a
3b
4b
4b
5g
5h
9
78
3g
4b
5i
3c
10
11
82
77
4b
4b
5j
3h
5k
3i
12
76
4b
5l
13
14
71
67
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5n
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b
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_
3k
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4b
5o
5p
68
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4c
4d
b
Me
17
_
3a
5q
N
N
aThe reactions were performed using oꢀalkynylaldehyde 3 (0.5 mmol), amine 4a–d (1.1
equiv), 10 mol % of AgNO3 in 2.0 mL of H2O at 80 °C for 1–1.5 h. bAn inseparable mixture
of products.
Synthesis of benzoxazine/oxazine fused naphthyridines. To gain further insight into
the reaction, we continued our study by examining various nitrogen containing substrates 3l–
aa furnished differently substituted benzoxazino/oxazinoꢀnaphthyridines 6a–v (Table 3) and a
similar kind of observation can be inferred. Alkynes 3l–o with electronꢀdonating groups
provided the respective desired products 6a–d in 88–92% yields (entries 1–4) whereas alkyne
3p bearing methoxy groups at meta position of the phenyl ring afforded the product 6e in 75%
yield (entry 5). Switching from aromatic amine (2ꢀaminophenyl)methanol (4a) to aliphatic
amine 3ꢀaminopropanꢀ1ꢀol (4b), the reaction proceeded with comparatively lower levels of
reactivity (entries 6–16). We have also explored the reaction of 3ꢀ
(substitutedethynyl)isonicotinaldehydes 3q–v with amines 4a–b (entries 11–16). The desired
products 6k–o was obtained in good yields (entries 11–15). Presence of electronꢀwithdrawing
–CF3 group at para position retarded the reaction and product was obtained in 62% yield
(entries 16).
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We further switched our strategy to two ring system in order to explore more diversity
and complexity. So we reacted 2ꢀ(substituted)quinolineꢀ3ꢀcarbaldehydes 3w–aa with amines
4a and 4b. We observed that reaction was slightly sluggish than in the case of substituted
pyridine alkynylaldehydes 3l–v. The substituted benzoxazino fused naphthyridines 6q–u were
obtained in 72–87% yields (entries 17–21). Reaction of alkyne 3w with 3ꢀaminopropanꢀ1ꢀol
proceeded well and provided the oxazinoꢀnaphthyridine 6v in 81% yield (entry 22). All the
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1
synthesized products were fully characterized by the H NMR, 13CꢀNMR, HRMS and Xꢀray
crystallographic analysis (Figure 2). Products were obtained as racemic mixtures as no optical
rotation was observed.
Table 3. Domino Synthesis of Fused Benzoxazino/Oxazino-Naphthyridinesa
substrate
amine
product
entry
yield (%)
88
3l
6a
6b
1
2
4a
4a
3m
90
89
3n
3
4a
6c
3o
3p
4
5
92
75
4a
4a
6d
6e
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4b
4b
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3m
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4b
4b
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O
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3v
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3w
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aThe reactions were performed using oꢀalkynylaldehyde 3 (0.5 mmol), amine 4a–b (1.1 equiv),
10 mol % of AgNO3 in 2.0 mL of H2O at 80 °C for 0.5–1 h.
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Competitive study. In order to see the comparative studies of different nucleophiles such as
(2ꢀaminophenyl)methanol (4a), 3ꢀaminopropanꢀ1ꢀol (4b) and methanol, we carried out
different sets of reactions (Scheme 4). Firstly, we studied the relative reactivity between
aromatic and aliphatic nucleophiles by choosing 2ꢀ(phenylethynyl)benzaldehyde 3a, amines 4a
and 4b (1.1 equiv) in H2O using 10 mol % AgNO3 as a catalyst (Scheme 4, A). We observed
the product 5a was obtained in 52% yield and product 5g in 26% yield. The reason can be
attributed that the second intramolecular attack in case of amine 4a is more favourable due to
rigid and optimum conformation imparted by aryl ring for faster trapping of imine formed than
in case of amine 4b. Formation of compound 5p was not at all observed.
Scheme 4. Competitive Study
OH
OMe
O
OMe
N
AgNO3 (10%)
3a
4a
5a
MeOH
B)
AgNO3 (10%)
EDC, 70 C
EDC, 70 C, 0.5 h
Ph
Ph
7 (trace)
68%
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We also studied the comparison of the reactivity between an intramolecular and an
intermolecular reaction. We carried out the reaction of alkynylaldehyde 3a, amine 4a and
MeOH (1.1 equiv) in EDC using 10 mol% AgNO3 (Scheme 4, B). It was found that fused
benzoxazine 5a was formed as a major product in 68% yield whereas 1ꢀmethoxyꢀ1Hꢀ
isochromene 723g was formed in trace amount. Formation of 2ꢀ(2ꢀ(1Hꢀpyrrolꢀ1ꢀyl)phenyl)ꢀ1ꢀ
methoxyꢀ3ꢀphenylꢀ1,2ꢀdihydroisoquinoline 8 was not at all observed. This clearly shows that
intramolecular reaction is favoured over intermolecular reaction as amine 4a with attached
nucleophile is in close proximity to attack onto imine carbon as compared to distal methanol
molecules.
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Scheme 5. Probable Mechanism
O
O
X
A
R1
N
HO
H2N
3
X
R1
intermolecular
imine formation
5, 6
AgNO3
4
H2O
H
O
A
HO
N
O
B
A
R'
X
R1
N
N
B
P
X
X
R1
R1
S
HO
N
B
1st intramolecular
nucleophilic attack
2nd intramolecular
nucleophilic attack
X
R1
Q'
O
H
A
O
N
H
A
N
X
R
R1
Q
X
intramolecular
proton transfer
R1
In the light of these above preliminary results, a catalytic cycle for this domino transformation
was proposed as shown in Scheme 5. Initially reaction of oꢀalkynyl aldehyde 3 with
nucleophilic amine 4 produced condensation species P. After this, two possibilities exit for
the formation of compound 5, 6 i.e. either ring A forms first than ring B or vice versa. Ring A
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could be formed prior as P on activation by silver would undergo first intramolecular
nucleophilic attack of OH group onto imine carbon to afford Q. Intramolecuar proton transfer
would then produce R which upon πꢀactivation by AgNO3 would undergo second
intramolecular nucleophic attack of NH onto the triple bond to afford S to give desired
compound 5, 6. Alternatively, ring B could be formed initially by the activation of triple bond
by silver to give Q' followed by second intramolecular nucleophilic attack to furnish R'
which after subsequent deprotonation would give compound 5, 6.
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CONCLUSIONS
In summary, we have developed Ag(I)ꢀcatalyzed domino protocol in water which
allowed a facile access to an impressive variety of benzoxazines/oxazines fused isoquinolines
and naphthyridines using readily available starting materials in good yields with high
regioselectivity under mild reaction conditions. The reaction proceeded with high 6ꢀendoꢀdig
regioselectivity and confirmed by Xꢀray crystallographic studies. The competitive
experiments demonstrated the practicality of intramolecular nucleophilic attack over
intermolecular attack. The product formation was also found to be higher in case of aromatic
amine over aliphatic amine. The method appeared to be very general and compatible with
differently substituted starting materials having different electronic properties increasing its
applicability to various functional groups. From a synthetic point of view, the net
transformation involves a oneꢀstep conversion of simple, inexpensive and readily available
starting materials into an interesting class of fused heterocyclic scaffolds. It is likely that the
efficiency of this environment friendly method combined with its operational simplicity will
make it attractive for the construction of variety of heterocyclic compounds.
EXPERIMENTAL SECTION
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General Information. H NMR (400 MHz) and 13C NMR (100 MHz) spectra were recorded
in CDCl3. Chemical shifts for protons are reported in ppm from tetramethylsilane with the
residual CHCl3 resonance as internal reference. Chemical shifts for carbons are reported in
ppm from tetramethylsilane and are referenced to the carbon resonance of the solvent. Data
are reported as follows: chemical shift, multiplicity (s=singlet, d=doublet, t=triplet, q=quartet,
m=multiplet), coupling constants in Hertz, and integration. Highꢀresolution mass spectra were
recorded on QqTOF mass analyzer. TLC analysis was performed on commercially prepared
60 F254 silica gel plates and visualized by either UV irradiation or by staining with I2.
Anhydrous forms of all reagents such as diethyl ether, hexanes, ethyl acetate, EDC, Et3N, 2ꢀ
bromobenzaldehyde, 3ꢀbromoisonicotinaldehyde, 2ꢀbromonicotinaldehyde, 2ꢀchloroquinoline
ꢀ3ꢀcarbaldehyde, 3ꢀbromobenzo[b]thiopheneꢀ2ꢀcarbaldehyde, Silver nitrate, palladium salts
and copper salts were used directly as obtained commercially unless otherwise noted.
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Procedure for the Synthesis of Compound 5 and 6. To a solution of 0.5 mmol of oꢀalkynyl
aldehyde 3 in 2.0 mL H2O, was added 1.1 equiv of amine 4 followed by the addition of 10
mol % of AgNO3. The reaction mixture was allowed to stir at 80 °C for 0.5–1.5 h. The
disappearance of the starting material was determined by TLC. The reaction mixture was then
washed with brine solution and was extracted with ethyl acetate (2 x 10 mL). The combined
organic fractions were dried over anhydrous Na2SO4 and concentrated under vacuum to yield
the crude product. The crude product was purified by column chromatography on neutral
alumina using hexane/ethyl acetate as the eluent.
The structure and purity of the known starting materials 3a, 3c, 3o–q, 23g 3d, 3l, 3aa, 29c 3m,
3r, 3w–z,24b 3f, 3h, 3k,30a 3e, 3j,30b 3s,29e 3i,23h 3g30c were confirmed by comparison of their
physical and spectral data (1H NMR and 13C NMR) with those reported in literature.
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2-((4-ethylphenyl)ethynyl)benzaldehyde (3b). The product was obtained as orange semi
solid (90.2 mg, 77%): 1H NMR (400 MHz, CDCl3) δ 10.67 (s, 1H), 7.96 (dd, J = 7.8, 0.92 Hz,
1H), 7.65–7.63 (m, 1H), 7.59 (td, J = 7.3, 1.8 Hz, 1H), 7.50 (d, J = 8.3 Hz, 2H), 7.44 (t, J =
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7.3 Hz, 1H), 7.23 (d, J = 8.2 Hz, 2H), 2.69 (q, J = 7.8 Hz, 2H), 1.27 (t, J = 7.4 Hz, 3H); C
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NMR (100 MHz, CDCl3) δ 191.7, 145.6, 135.7, 133.7, 133.1, 131.6, 128.3, 128.0, 127.9,
127.1, 119.4, 96.6, 84.2, 28.8, 15.2; HRMS (ESI) [M]+ Calcd for [C17H14O] 234.1045, found
234.1046.
3-((4-Ethylphenyl)ethynyl)isonicotinaldehyde (3t). The product was obtained as pale
yellow needle crystals (92.9 mg, 79%): mp 72–76 °C; 1H NMR (400 MHz, CDCl3) δ 10.62 (s,
1H), 8.95 (s, 1H), 8.71 (d, J = 5.1 Hz, 1H), 7.71 (d, J = 5.1 Hz, 1H), 7.48 (d, J = 8.1 Hz,
2H),7.22 (d, J = 8.0 Hz, 2H), 2.61 (q, J = 7.3 Hz, 2H), 1.17 (t, J = 7.8 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 190.8, 154.5,149.0, 140.2, 140.0, 131.7, 129.3, 121.6, 119.1, 118.5, 99.4,
81.3, 32.8, 19.1; HRMS (ESI) [M]+ Calcd for [C16H13NO] 235.0997, found 235.0998.
3-(Thiophen-3-ylethynyl)isonicotinaldehyde (3u). The product was obtained as orange
1
needle crystals (89.6 mg, 84%): mp 66–70 °C; H NMR (400 MHz, CDCl3): δ 10.50 (s,
1H),8.86 (s, 1H), 8.63 (d, J = 5.2 Hz, 1H), 7.63 (d, J = 5.1 Hz, 1H), 7.58 (d, J = 2.2 Hz,
1H),7.30–7.28 (m, 1H), 7.17 (d, J = 3.6 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 190.6,
154.3,149.0, 140.3, 130.5, 129.6, 126.0, 121.4, 120.6, 119.2, 94.3, 81.5; HRMS (ESI) [M]+
Calcd for [C12H7NOS] 213.0248, found 213.0248.
3-((4-(Trifluoromethyl)phenyl)ethynyl)isonicotinaldehyde (3v). The product was obtained
1
as yellow crystals (96.3 mg, 70%): mp 80–86 °C; H NMR (400 MHz, CDCl3) δ 10.53 (s,
1H), 8.93 (s, 1H), 8.72 (d, J = 5.1 Hz, 1H), 7.70 (d, J = 5.1 Hz, 1H), 7.62 (q, J = 8.0 Hz, 4H);
13C NMR (100 MHz, CDCl3) δ 190.3, 154.6, 149.9, 140.6, 132.1, 125.6 (q, J = 3.8 Hz),
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125.4, 125.0, 120.4, 119.6, 97.1, 84.1; HRMS (ESI) [M]+ Calcd for [C15H8F3NO] 275.0558,
found 275.0558.
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12-Phenyl-4b,6-dihydrobenzo[4,5][1,3]oxazino[2,3-a]isoquinoline (5a). The product was
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obtained as pale yellow crystals (126.1 mg, 81%): mp 176–180 °C; H NMR (400 MHz,
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CDCl3) δ 7.42 (d, J = 7.3 Hz, 1H), 7.34–7.30 (m, 1H), 7.25–7.23 (m, 6H), 7.18 (d, J = 8.1
Hz, 1H), 7.05 (d, J = 7.4 Hz, 1H), 6.91 (t, J = 8.0 Hz, 1H), 6.78 (t, J = 8.1 Hz, 1H), 6.22 (d, J
= 8.1 Hz, 1H), 6.09 (s, 1H), 5.95 (s, 1H), 5.26 (d, J = 18.1 Hz, 1H), 5.09 (d, J = 14.6 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 140.8, 139.8, 136.9, 132.3, 129.0, 128.6, 128.4, 128.0,
127.8, 126.8, 126.0, 125.8, 124.7, 124.3, 123.8, 122.5, 105.7, 85.0, 68.0; HRMS (ESI) [M]+
Calcd for [C22H17NO] 311.1310, found 311.1309.
Compound 5a was crystallized in the triclinic crystal system with space group P 21. The
singleꢀcrystal Xꢀray data were collected using graphite monochromated Mo Kα radiation (λ=
0.71073 Å). The structures were solved using SIRꢀ92 and refined by the full matrix leastꢀ
squares technique on F2 using the SHELXLꢀ97 program within the WinGX v1.80.05 software
package. Crystal data for 5a: C22H17NO, M= 311.37, Monoclinic, space group P 21, a=
11.3784(19) Å, b= 5.7382(8) Å, c= 13.148(3) Å, α = 90, β = 114.27(2), γ = 90, V = 782.6(2)
Å3, Z= 2, T= 296 K, D calcd= 1.321 Mg/m3, R(int) = 0.0203, R1 = 0.0503, wR2 = 0.1050 [I
> 2σ(I)], R1 = 0.0664, wR2 = 0.1157 (all data), GOF = 1.058. Crystallographic data for 5a
have been deposited with the Cambridge Crystallographic Data Centre. CCDC 932014,
contain all crystallographic details of this publication and is available free of charge at
www.ccdc.cam.ac.uk/conts/retrieving.html. For further details on the crystal structure of
compound 5a, see the CIF file (Supporting Information).
12-(4-Ethylphenyl)-4b,6-dihydrobenzo[4,5][1,3]oxazino[2,3-a]isoquinoline (5b). The
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product was obtained as a pale yellow semiꢀsolid (140.9 mg, 83%): H NMR (400 MHz,
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CDCl3) δ 7.39 (d, J = 8.2 Hz, 1H), 7.31–7.27 (m, 1H), 7.21–7.18 (m, 1H), 7.16–7.10 (m, 3H),
7.05–7.02 (m, 3H), 6.91–6.87 (m, 1H), 6.77 (t, J = 7.8 Hz, 1H), 6.22 (d, J = 8.7 Hz, 1H), 6.06
(s, 1H), 5.93 (s, 1H), 5.23 (d, J = 14.2 Hz, 1H), 5.07 (d, J = 15.1 Hz, 1H ), 2.60 (q, J = 7.4
Hz, 2H), 1.21–1.17 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 144.0, 140.8, 139.9, 134.2,
132.5, 128.9, 128.5, 128.3, 127.4, 126.6, 125.9, 125.8, 124.6, 124.2, 123.7, 122.3, 105.4,
85.0, 68.0, 26.9, 15.4; HRMS (ESI) [M]+ Calcd for [C24H21NO] 339.1623, found 339.1623
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12-(Thiophen-3-yl)-4b,6-dihydrobenzo[4,5][1,3]oxazino[2,3-a]isoquinoline (5c). The
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product was obtained as brown needles (134.9 mg, 85%): mp 104–108 °C; H NMR (400
MHz, CDCl3) δ 7.55 (d, J = 8.1 Hz, 1H), 7.18–7.17 (m, 1H), 7.06–7.04 (m, 1H), 7.02–6.97
(m, 3H), 6.92 (t, J = 7.3 Hz, 2H), 6.80 (t, J = 7.3 Hz, 1H), 6.63–6.61 (m, 1H), 6.29 (d, J = 8.8
Hz, 1H), 6.15 (s, 1H), 5.96 (s, 1H), 5.13 (d, J = 14.6 Hz, 1H), 4.99 (d, J = 14.6 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 151.0, 150.2, 140.4, 139.1, 137.1, 134.4, 128.4, 127.6, 125.9,
125.1, 124.8, 124.71, 124.68, 123.6, 123.4, 121.9, 120.4, 105.6, 84.5, 67.9; HRMS (ESI)
[M]+ Calcd for [C20H15NOS] 317.0874, found 317.0875.
12-Cyclohexyl-4b,6-dihydrobenzo[4,5][1,3]oxazino[2,3-a]isoquinoline (5d). The product
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was obtained as a pale yellow semiꢀsolid (122.2 mg, 77%): H NMR (400 MHz, CDCl3) δ
7.23–7.17 (m, 2H), 7.16–7.09 (m, 2H), 7.07–7.00 (m, 4H), 5.71–5.69 (m, 2H), 5.09 (d, J =
15.1 Hz, 1H), 4.88 (d, J = 15.1 Hz, 1H), 2.58–2.51 (m, 1H), 1.98–1.95 (m, 1H) 1.78–1.75 (m,
1H), 1.57–1.47 (m, 4H), 1.45–1.36 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 147.5, 140.7,
132.4, 131.0, 129.1, 127.4, 125.8, 125.4, 124.93, 124.89, 124.7, 124.6, 123.8, 98.1, 84.8,
67.7, 38.4, 26.7, 26.5, 26.1; HRMS (ESI) [M]+ Calcd for [C22H23NO] 317.1780, found
317.1781.
12-Butyl-4b,6-dihydrobenzo[4,5][1,3]oxazino[2,3-a]isoquinoline (5e). The product was
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obtained as a brown oil (109.3 mg, 75%): H NMR (400 MHz, CDCl3) δ 7.33–7.29 (m, 2H),
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7.24–7.18 (m, 3H), 7.17–7.12 (m, 2H), 7.08 (d, J = 7.4 Hz, 1H), 5.81 (s, 1H), 5.74 (s, 1H),
5.20 (d, J = 15.1 Hz, 1H), 4.98 (d, J = 15.1 Hz, 1H ), 1.47–1.43 (m, 2H), 0.93–0.87 (m, 4H),
0.80 (t, J = 9.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 142.4, 140.8, 132.4, 130.8, 129.1,
127.6, 125.8, 125.2, 125.0, 124.9, 124.8, 124.7, 123.5, 100.3, 84.8, 67.6, 32.5, 29.6, 22.1,
13.7; HRMS (ESI) [M]+ Calcd for [C20H21NO] 291.1623, found 291.1623.
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12-(3,5-Dimethoxyphenyl)-4b,6-dihydrobenzo[4,5][1,3]oxazino[2,3-a]isoquinoline (5f).
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The product was obtained as a yellow semi-solid (130.0 mg, 70%): H NMR (400 MHz,
CDCl3) δ 7.39 (d, J = 6.9 Hz, 1H), 7.33–7.29 (m, 1H), 7.24–7.16 (m, 3H), 7.02 (d, J = 7.4
Hz, 1H), 6.92 (t, J = 8.2 Hz, 1H), 6.83 (t, J = 7.8 Hz, 1H), 6.34–6.31 (m, 3H), 6.07 (s, 1H),
5.95 (s, 1H), 5.24 (d, J = 14.6 Hz, 1H), 5.07 (d, J = 14.7 Hz,1H ), 3.62 (s, 6H); 13C NMR
(100 MHz, CDCl3) δ 160.2, 140.7, 139.9, 138.8, 132.1, 129.0, 126.9, 126.0, 125.9, 124.6,
124.4, 123.7, 122.7, 106.8, 105.2, 100.2, 96.4, 84.9, 68.0, 55.3; HRMS (ESI) [M]+ Calcd for
[C24H21NO3] 371.1521, found 371.1520.
6-Phenyl-2,3,4,11b-tetrahydro-[1,3]oxazino[2,3-a]isoquinoline (5g). The product was
obtained as a brown semiꢀsolid (98.8 mg, 75%): 1H NMR (400 MHz, CDCl3) δ 7.33−7.30 (m,
5H), 7.23–7.18 (m, 2H), 7.08 (t, J = 8.1 Hz, 1H), 6.96 (d, J = 8.1 Hz, 1H), 5.97 (s, 1H), 5.51
(s, 1H), 4.07–4.01 (m, 2H), 3.74–3.70 (m, 1H), 3.30–3.22 (m, 1H), 2.03–1.93 (m, 1H), 1.88–
1.77 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 145.1, 137.6, 132.7, 129.1, 128.3, 128.2, 127.9,
127.4, 125.0, 124.8, 123.7, 101.8, 88.7, 68.1, 47.7, 26.8; HRMS (ESI) [M]+ Calcd for
[C18H17NO] 263.1310, found 263.1310.
6-(4-Ethylphenyl)-2,3,4,11b-tetrahydro-[1,3]oxazino[2,3-a]isoquinoline (5h). The product
was obtained as a brown semiꢀsolid (115.1 mg, 79%): 1H NMR (400 MHz, CDCl3) δ 7.30 (t,
J = 8.0 Hz, 3H), 7.24 (t, J = 10.2 Hz, 3H), 7.14 (t, J = 9.1 Hz, 1H), 7.05 (d, J = 7.3 Hz, 1H),
6.04 (s, 1H), 5.58 (s, 1H), 4.15–4.05 (m, 2H), 3.84–3.81 (m, 1H), 3.36–3.29 (m, 1H), 2.70–
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2.68 (m, 2H), 2.05–1.88 (m, 2H), 1.37–1.26 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 145.2,
143.9, 139.2, 134.9, 132.1, 129.4, 128.2, 127.6, 124.9, 123.5, 114.0, 101.6, 87.7, 68.0, 47.6,
26.8, 22.6, 14.1; HRMS (ESI) [M]+ Calcd for [C20H21NO] 291.1623, found 291.1624.
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6-(4-Butylphenyl)-2,3,4,11b-tetrahydro-[1,3]oxazino[2,3-a]isoquinoline (5i). The product
was obtained as a red oil (124.6 mg, 78%): 1H NMR (400 MHz, CDCl3) δ 7.31–7.23 (m, 4H),
7.23–7.19 (m, 2H), 7.14 (t, J = 6.8, 1H), 7.05 (d, J = 10.1 Hz, 1H), 6.04 (s, 1H), 5.57 (s, 1H),
4.15–4.05 (m, 2H), 2.60–2.57 (m, 4H), 1.73–1.59 (m, 4H), 1.42–1.34 (m, 2H), 0.95 (t, J = 8.2
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 145.1, 142.5, 134.7, 132.7, 128.9, 128.1, 127.3,
124.8, 124.7, 101.6, 88.7, 68.0, 47.6, 35.3, 33.4, 26.8, 22.3, 13.9; HRMS (ESI) [M]+ Calcd
for [C22H25NO] 319.1936, found 319.1937.
6-(Thiophen-3-yl)-2,3,4,11b-tetrahydro-[1,3]oxazino[2,3-a]isoquinoline (5j). The product
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was obtained as a red semiꢀsolid (113.1 mg, 84%): H NMR (400 MHz, CDCl3) δ 7.34–7.33
(m, 2H), 7.28–7.23 (m, 2H), 7.15–7.12 (m, 1H), 7.09–7.08 (m, 1H), 7.04 (d, J = 8.8 Hz, 1H),
6.00 (s, 1H), 5.66 (s, 1H), 4.16–4.05 (m, 2H), 3.85–3.80 (m, 1H), 3.33 (t, J=13.0 Hz, 1H),
2.07–1.93 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 140.1, 137.8, 132.4, 129.1, 127.9, 127.4,
125.4, 125.1, 124.9, 123.6, 123.5, 102.0, 88.6, 68.1, 47.7, 26.8; HRMS (ESI) [M]+ Calcd for
[C16H15NOS] 269.0874, found 269.0874.
2,3,4,11b-Tetrahydro-6-m-tolyl-[1,3]oxazino[2,3-a]isoquinoline (5k). The product was
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obtained as a dark yellow semiꢀsolid (112.6 mg, 77%): H NMR (400 MHz, CDCl3) δ 7.22–
7.16 (m, 3H), 7.13–7.04 (m, 4H), 6.97 (d, J = 7.3 Hz, 1H), 5.96 (s, 1H), 5.49 (s, 1H), 4.08–
3.97 (m, 2H), 3.76–3.71 (m, 1H), 3.28–3.20 (m, 1H), 2.31 (s, 3H), 1.98–1.76 (m, 2H); 13C
NMR (100 MHz, CDCl3) δ 145.2, 137.9,137.5, 132.7, 129.1, 129.0, 128.6, 128.0, 127.4,
125.4, 124.9, 124.8, 123.6, 101.6, 88.7, 68.0, 47.7, 26.9, 21.4; HRMS (ESI) [M]+ Calcd for
[C19H19NO] 277.1467, found 277.1467.
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6-(4-(tert-Butyl)phenyl)-2,3,4,11b-tetrahydro-[1,3]oxazino[2,3-a]isoquinoline (5l). The
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product was obtained as orange crystals (121.4 mg, 76%): mp 96–100°C; H NMR (400
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MHz, CDCl3) δ 7.32–7.30 (m, 2H), 7.24–7.21 (m, 2H), 7.19–7.14 (m, 2H), 7.04 (t, J = 8.8
Hz, 1H), 6.95 (d, J = 8.0 Hz, 1H), 5.95 (s, 1H), 5.48 (s, 1H), 4.07–3.96 (m, 2H), 3.85–3.72
(m, 2H), 1.97–1.92 (m, 1H), 1.87–1.74 (m, 1H), 1.25 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
150.8, 145.2, 134.6, 132.7, 129.0, 127.9, 127.4, 125.1, 124.8, 124.7, 123.5, 101.6, 88.7, 68.0,
47.6, 34.6, 31.3, 26.9; HRMS (ESI) [M]+ Calcd for [C22H25NO] 319.1936, found 319.1935.
6-Cyclopropyl-2,3,4,11b-tetrahydro-[1,3]oxazino[2,3-a]isoquinoline (5m). The product
was obtained as a red yellow semiꢀsolid(80.7 mg, 71%): 1H NMR (400 MHz, CDCl3) δ 7.19–
7.16 (m, 2H), 7.06–7.02 (m, 1H), 6.96–6.94 (m, 1H), 5.91 (s, 1H), 5.45 (s, 1H), 4.15–4.03 (m,
2H), 3.40–3.35 (m, 2H), 1.59–1.45 (m, 2H), 0.92–0.77 (m, 5H); 13C NMR (100 MHz, CDCl3)
δ 144.6, 133.0, 128.8, 127.4, 124.4, 123.1, 114.0, 97.3, 88.9, 68.7, 46.4, 27.1, 13.1, 5.6, 5.5;
HRMS (ESI) [M]+ Calcd for [C15H17NO] 227.1310, found 227.1310.
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6-(3,5-Dimethoxyphenyl)-2,3,4,11b-tetrahydro-[1,3]oxazino[2,3-a]isoquinoline (5n). The
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product was obtained as a pale yellow semiꢀsolid (108.3 mg, 67%): H NMR (400 MHz,
CDCl3) δ 7.29–7.24 (m, 2H), 7.15–7.11 (m, 1H), 7.06–7.02 (m, 1H), 6.54 (s, 2H), 6.45–6.44
(m, 1H), 6.01 (s, 1H), 5.61 (s, 1H), 4.12–4.02 (m, 2H), 3.79 (s, 6H), 3.35–3.28 (m, 2H), 2.07–
1.89 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 160.6, 145.1, 139.5, 132.5, 129.1, 127.4, 125.1,
124.8, 123.7, 106.5, 101.5, 100.1, 88.7, 68.1, 55.4, 47.7, 27.1; HRMS (ESI) [M]+ Calcd for
[C20H21NO3] 323.1521, found 323.1520.
5-Phenyl-1,2,3,10b-tetrahydroimidazo[2,1-a]isoquinoline (5p). The product was obtained
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as a brown semiꢀsolid (84.4 mg, 68%): H NMR (400 MHz, CDCl3) δ 7.55 (t, J = 8.1 Hz,
1H), 7.47–7.41 (m, 4H), 7.40–7.38 (m, 1H), 7.28–7.27 (m, 1H), 7.03–7.00 (m, 1H), 6.70 (d, J
= 8.0 Hz, 1H), 6.19 (s, 1H), 5.00 (s, 1H), 4.08–4.03 (m, 4H); 13C NMR (100 MHz, CDCl3) δ
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158.1, 141.6, 136.5, 132.6, 129.3, 128.7, 128.2, 127.3, 127.0, 126.1, 123.3, 119.9, 114.0,
113.1, 106.3, 49.8, 49.7; HRMS (ESI) [M]+ Calcd for [C17H16N2] 248.1313, found 248.1313.
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12-Phenyl-4b,6-dihydrobenzo[4,5][1,3]oxazino[2,3-f][1,6]naphthyridine
(6a).
The
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product was obtained as yellow needles (137.4 mg, 88%): mp 154–158 °C; H NMR (400
MHz, CDCl3) δ 8.43–8.41 (m, 1H), 7.55 (d, J = 7.3 Hz, 1H), 7.19–7.15 (m, 5H), 7.02–6.98
(m, 1H), 6.95 (d, J = 7.3 Hz, 1H), 6.84 (t, J = 7.3 Hz, 1H), 6.69 (t, J = 8.1 Hz, 1H), 6.12 (d, J
= 8.1 Hz, 1H), 6.08 (s, 1H), 5.98 (s, 1H), 5.13 (d, J = 16.8 Hz, 1H), 4.99 (d, J = 14.6 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 151.1, 150.1, 145.0, 139.1, 136.2, 134.4, 128.5, 128.3, 128.1,
125.9, 124.7, 123.7, 123.0, 122.0, 120.4, 106.2, 84.7, 68.0; HRMS (ESI) [M]+ Calcd for
[C21H16N2O] 312.1263, found 312.1263.
12-(p-Tolyl)-4b,6-dihydrobenzo[4,5][1,3]oxazino[2,3-f][1,6]naphthyridine (6b). The
1
product was obtained as yellow crystals (146.9 mg, 90%): mp 166–170 °C; H NMR (400
MHz, CDCl3) δ 8.44–8.43 (m, 1H), 7.57 (d, J = 7.4 Hz, 1H), 7.08–7.06 (m, 2H), 7.03–6.97
(m, 4H), 6.87 (t, J = 14.6 Hz, 1H), 6.74 (t, J = 7.3 Hz, 1H), 6.18 (d, J = 13.3 Hz, 1H), 6.09 (s,
1H), 6.00 (s, 1H), 5.15 (d, J = 14.6 Hz, 1H), 5.01 (d, J = 14.6 Hz, 1H), 2.25 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 151.3, 150.2, 145.2, 139.2, 138.4, 134.3, 133.3, 128.8, 128.4,
128.3, 126.0, 124.7, 123.8, 122.9, 122.2, 120.4, 106.2, 84.8, 68.0, 21.3; HRMS (ESI) [M]+
Calcd for [C22H18N2O] 326.1419, found 326.1420.
12-(4-Ethylphenyl)-4b,6-dihydrobenzo[4,5][1,3]oxazino[2,3-f][1,6]naphthyridine
(6c).
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The product was obtained as yellow crystals (151.5 mg, 89%): mp 162–166 °C; H NMR
(400 MHz, CDCl3) δ 8.45–8.44 (m, 1H), 7.59 (d, J = 7.3 Hz, 1H), 7.11–7.09 (m, 2H), 7.06–
6.98 (m, 3H), 6.96–6.93 (m, 2H), 6.78–6.73 (m, 2H), 6.18 (d, J = 8.0 Hz, 1H), 6.11 (s, 1H),
6.02 (s, 1H), 5.17 (d, J = 13.9 Hz, 1H), 5.02 (d, J = 13.9 Hz, 1H), 2.56 (q, J = 7.3 Hz, 2H),
1.08 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 151.3, 150.0, 145.3, 139.2, 138.5,
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134.3, 133.4, 128.7, 128.5, 126.0, 124.7, 123.8, 122.9, 122.0, 120.4, 106.1, 84.8, 68.0, 28.6,
15.3; HRMS (ESI) [M]+ Calcd for [C23H20N2O] 340.1576, found 340.1576.
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12-(Thiophen-3-yl)-4b,6-dihydrobenzo[4,5][1,3]oxazino[2,3-f][1,6]naphthyridine
(6d).
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The product was obtained as brown needles (146.5 mg, 92%): mp 100–104 °C; 1H NMR (400
MHz, CDCl3) δ 8.43–8.42 (m, 1H), 7.55 (d, J = 8.1 Hz, 1H), 7.18–7.17 (m, 1H), 7.06–7.04
(m, 1H), 7.02–6.97 (m, 2H), 6.92 (t, J = 7.3 Hz, 1H), 6.80 (t, J = 7.3 Hz, 1H), 6.63–6.61 (m,
1H), 6.29 (d, J = 8.8 Hz, 1H), 6.15 (s, 1H), 5.96 (s, 1H), 5.13 (d, J = 14.6 Hz, 1H), 4.99 (d, J
= 14.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 151.0, 150.2, 140.4, 139.1, 137.1, 134.4,
128.4, 127.6, 125.9, 125.1, 124.8, 124.7, 123.6, 123.4, 121.9, 120.4, 105.6, 84.5, 67.9;
HRMS (ESI) [M]+ Calcd for [C19H14N2OS] 318.0827, found 318.0828.
12-(3,5-Dimethoxyphenyl)-4b,6-dihydrobenzo[4,5][1,3]oxazino[2,3-f][1,6]naphthyridine
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(6e). The product was obtained as pale yellow needles (139.6 mg, 75%): mp 80–86 °C; H
NMR (400 MHz, CDCl3) δ 8.47–8.45 (m, 1H), 7.60 (d, J = 7.3 Hz, 1H), 7.06 (m, 1H), 6.99
(d, J = 7.4 Hz, 1H), 6.92–6.88 (m, 1H), 6.80 (t, J = 8.1 Hz, 1H), 6.32 (s, 2H), 6.28 (d, J = 8.0
Hz, 1H), 6.22–6.20 (m, 1H), 6.14 (s, 1H), 6.03 (s, 1H), 5.18 (d, J = 13.9 Hz, 1H), 5.02 (d, J =
13
13.9 Hz, 1H), 3.58 (s, 6H); C NMR (100 MHz, CDCl3) δ 160.4, 151.0, 150.1,145.1, 139.2,
138.0, 134.6, 128.1, 126.1, 124.7, 123.7, 123.2, 122.2, 120.6, 107.1, 106.7, 105.9, 101.0,
84.7, 68.1, 55.3; HRMS (ESI) [M]+ Calcd for [C23H20N2O3] 372.1474, found 372.1474.
6-Phenyl-2,3,4,11b-tetrahydro-[1,3]oxazino[2,3-f][1,6]naphthyridine (6f). The product
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was obtained as a brown oil (108.4 mg, 82%): H NMR (400 MHz, CDCl3) δ 8.36–8.35 (m,
1H), 7.47–7.45 (m, 1H), 7.32–7.27 (m, 5H), 6.94–6.91 (m, 1H), 6.01 (s, 1H), 5.66 (s, 1H),
4.09–3.95 (m, 2H), 3.72–3.67 (m, 1H), 3.37–3.19 (m, 2H), 1.88–1.82 (m, 1H); 13C NMR
(100 MHz, CDCl3) δ 151.7, 150.7, 150.2, 137.1, 135.5, 129.2, 128.7, 128.4, 120.4, 119.9,
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102.1, 88.9, 68.5, 47.9, 27.6; HRMS (ESI) [M]+ Calcd for [C17H16N2O] 264.1263, found
264.1263.
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6-(p-Tolyl)-2,3,4,11b-tetrahydro-[1,3]oxazino[2,3-f][1,6]naphthyridine (6g). The product
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was obtained as brown crystals (119.7 mg, 86%): mp 110–114 °C; H NMR (400 MHz,
CDCl3) δ 8.39–8.38 (m, 1H), 7.47 (d, J = 6.6 Hz, 1H), 7.22–7.14 (m, 4H), 6.96–6.93 (m, 1H),
6.03 (s, 1H), 5.66 (s, 1H), 4.08–4.01 (m, 2H), 3.77–3.73 (m, 1H), 3.27–3.20 (m, 1H), 2.32 (s,
3H), 2.09–1.84 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 151.4, 150.3, 149.9, 138.2, 135.2,
133.9, 129.0, 128.0, 120.0, 119.5, 101.7, 88.6, 68.2, 47.6, 27.2, 21.3; HRMS (ESI) [M]+
Calcd for [C18H18N2O] 278.1419, found 278.1419.
6-(4-Ethylphenyl)-2,3,4,11b-tetrahydro-[1,3]oxazino[2,3-f][1,6]naphthyridine (6h). The
1
product was obtained as a brown oil (122.8 mg, 84%): H NMR (400 MHz, CDCl3) δ 8.39–
8.38 (m, 1H), 7.48–7.46 (m, 1H), 7.23 (d, J = 9.5 Hz, 2H), 7.19–7.16 (m, 2H), 6.95–6.92 (m,
1H), 6.03 (s, 1H), 5.66 (s, 1H), 4.11–4.04 (m, 1H), 4.01–3.98 (m,1H), 3.37–3.73 (m, 1H),
3.27–3.20 (m, 1H), 2.61 (q, J = 8.0 Hz, 2H), 1.91–1.83 (m, 2H), 1.21 (t, J = 8.0 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 151.6, 150.5, 149.8, 144.4, 135.0, 134.1, 128.1, 127.8, 120.0,
119.4, 101.9, 88.7, 68.2, 47.6, 28.6, 27.2, 15.3; HRMS (ESI) [M]+ Calcd for [C19H20N2O]
292.1576, found 292.1576.
6-(Thiophen-3-yl)-2,3,4,11b-tetrahydro-[1,3]oxazino[2,3-f][1,6]naphthyridine (6i). The
1
product was obtained as a brown oil (118.9 mg, 88%): H NMR (400 MHz, CDCl3) δ 8.36
(dd, J = 5.1, 1.4 Hz, 1H), 7.45 (dd, J = 7.3, 1.4 Hz, 1H), 7.31–7.27 (m, 2H), 7.02–7.00 (m,
1H), 6.95–6.92 (m, 1H), 5.99 (s, 1H), 5.74 (s, 1H), 4.11–4.04 (m, 1H), 4.01ꢀ3.98 (m, 1H)
3.81–3.76 (m, 1H), 3.28–3.21 (m, 1H), 1.95–1.85 (m, 1H), 1.30–1.27 (m, 1H); 13C NMR
(100 MHz, CDCl3) δ 153.1, 152.0, 151.1, 145.5, 137.8, 135.8, 128.3, 126.5, 124.9, 120.8,
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120.4, 102.9, 89.2, 69.0, 48.3, 27.9; HRMS (ESI) [M]+ Calcd for [C15H14N2OS] 270.0827,
found 270.0827.
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(6j). The product was obtained as a pale yellow semiꢀsolid (111.9 mg, 69%): H NMR (400
MHz, CDCl3) δ 8.45–8.44 (m, 1H), 7.52 (d, J = 7.3 Hz, 1H), 7.02–6.99 (m, 1H), 6.52 (s, 2H),
6.47–6.46 (m, 1H), 6.07 (s, 1H), 5.76 (s, 1H), 4.14–4.13 (m, 1H), 4.06 (td, J = 12.8, 3.2 Hz,
1H), 3.88–3.81 (m, 2H), 3.79 (s, 6H), 3.29 (td, J = 13.8, 2.8 Hz, 1H), 2.03–1.92 (m, 1H); 13C
NMR (100 MHz, CDCl3) δ 160.7, 151.4, 150.5, 149.7, 139.3, 138.6, 135.1, 119.6, 106.3,
101.6, 100.5, 88.7, 68.3, 55.5, 47.6, 27.4; HRMS (ESI) [M]+ Calcd for [C19H20N2O3]
324.1474, found 324.1475.
6-Phenyl-2,3,4,11b-tetrahydro-[1,3]oxazino[2,3-a][2,6]naphthyridine (6k). The product
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was obtained as a brown oil (105.7 mg, 80%): H NMR (400 MHz, CDCl3) δ 8.39 (s, 2H),
7.43– 7.41 (m, 5H), 7.23 (d, J = 5.1 Hz, 1H), 6.10 (s, 1H), 5.57 (s, 1H), 4.22–4.08 (m, 2H),
3.83–3.79 (m, 1H), 3.36–3.29 (m, 1H), 2.01–1.91 (m, 1H), 1.46–1.45 (m, 1H); 13C NMR
(100 MHz, CDCl3) δ 145.8, 145.4, 142.0, 137.2, 130.9, 128.3, 127.7, 125.9, 124.0, 121.5,
97.7, 87.2, 68.5, 47.6, 27.0; HRMS (ESI) [M]+ Calcd for [C17H16N2O] 264.1263, found
264.1263.
6-(4-Methoxyphenyl)-2,3,4,11b-tetrahydro-[1,3]oxazino[2,3-a][2,6]naphthyridine
(6l).
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The product was obtained as a brown semiꢀsolid (126.6 mg, 86%): H NMR (400 MHz,
CDCl3) δ 8.33 (s, 2H), 7.27 (d, J = 8.8 Hz, 2H), 7.14 (d, J = 5.1 Hz, 1H), 6.91 (d, J = 8.8 Hz,
2H), 6.03 (s, 1H), 5.50 (s, 1H), 4.16–4.03 (m, 2H), 3.82–3.80 (m, 3H), 3.77–3.76 (m, 1H)
3.30–3.23 (m, 1H), 1.30–1.22 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 159.5, 146.8, 145.5,
145.3, 130.7, 129.4, 129.2, 128.6, 121.5, 113.7, 97.2, 87.3, 68.4, 55.3, 47.4, 27.0; HRMS
(ESI) [M]+ Calcd for [C18H18N2O2] 294.1368, found 294.1367.
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Page 29 of 39
The Journal of Organic Chemistry
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6-(p-Tolyl)-2,3,4,11b-tetrahydro-[1,3]oxazino[2,3-a][2,6]naphthyridine (6m). The product
was obtained as brown crystals (114.1 mg, 82%): mp 95–98 °C; 1H NMR (400 MHz, CDCl3)
δ 8.36 (s, 2H), 7.27–7.17 (m, 5H), 6.06 (s, 1H), 5.53 (s, 1H), 4.19–4.15 (m, 1H), 4.08 (td, J =
11.7, 2.2 Hz, 1H), 3.83–3.79 (m, 1H), 3.33–3.25 (m, 1H), 2.40 (s, 3H), 1.98–1.84 (m, 2H);
13C NMR (100 MHz, CDCl3) δ 147.1, 145.5, 145.3, 138.2, 134.0, 130.8, 129.0, 128.1, 121.5,
97.2, 87.3, 68.4, 47.5, 27.0, 21.3; HRMS (ESI) [M]+ Calcd for [C18H18N2O] 278.1419, found:
278.1420.
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6-(4-Ethylphenyl)-2,3,4,11b-tetrahydro-[1,3]oxazino[2,3-a][2,6]naphthyridine (6n). The
product was obtained as a brown semiꢀsolid (118.4 mg, 81%): 1H NMR (400 MHz, CDCl3) δ
8.28 (s, 2H), 7.24–7.16 (m, 4H), 7.10 (d, J = 5.1 Hz, 1H), 5.99 (s, 1H), 5.46 (s, 1H), 4.12–
4.08 (m, 1H), 4.04–3.98 (m, 1H), 3.77–3.73 (m, 1H), 3.22 (td, J = 14.6, 2.2 Hz, 1H), 2.62 (q,
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J = 8.0 Hz, 2H), 2.54 (d, J = 1.4 Hz, 1H), 1.88–1.82 (m, 1H), 1.23–1.18 (m, 3H); C NMR
(100 MHz, CDCl3) δ 147.2, 145.5, 145.3, 144.4, 134.1, 130.7, 128.6, 128.1, 127.8, 121.5,
97.1, 87.2, 68.4, 47.4, 28.6, 27.0, 15.4; HRMS (ESI) [M]+ Calcd for [C19H20N2O] 292.1576,
found 292.1575.
6-(Thiophen-3-yl)-2,3,4,11b-tetrahydro-[1,3]oxazino[2,3-a][2,6]naphthyridine (6o). The
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product was obtained as yellow brown needles (116.2 mg, 86%): mp 100–104 °C; H NMR
(400 MHz, CDCl3) δ 8.30–8.29 (m, 2H), 7.30 (d, J = 2.7 Hz, 2H), 7.09 (d, J = 5.0 Hz, 1H),
7.02–7.00 (m, 1H), 5.97 (s, 1H), 5.56 (s, 1H), 4.13–4.08 (m, 1H), 4.01 (td, J = 11.9, 2.3 Hz,
1H), 3.79–3.75 (m, 1H), 3.28–3.21 (m, 1H), 1.96–1.86 (m, 1H), 1.30–1.18 (m, 1H); 13C
NMR (100 MHz, CDCl3) δ 145.8, 145.4, 142.0, 137.2, 130.9, 128.3, 127.6, 125.9, 124.0,
121.5, 97.7, 87.2, 68.5, 47.6, 27.0; HRMS (ESI) [M]+ Calcd for [C15H14N2OS] 270.0827,
found 270.0827.
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