Scaffold Diversity through a Branching Double-Annulation Cascade Strategy: Iminium-Induced One-Pot Synthesis of Diverse Fused Tetrahydroisoquinoline Scaffolds

Article abstract of DOI:10.1021/acs.joc.6b01096

A branching double-annulation cascade (BDAC) strategy for diverse and complex fused THIQ scaffolds via a highly reactive iminium-induced one-pot double-cyclization sequence involving Pictect-Spengler-type cyclization has been developed for the first time. The salient features of this protocol are that it allows direct and rapid access to unprecedented diverse fused THIQ skeletons, is metal/catalyst free, has a cleaner reaction profile, provides good to excellent yields, and is a convenient approach. This catalyst-free domino process facilitates the double annulation with a variety of scaffold building agents via two C-N and one C-X (X = C, N, O) bond formation in a single step under uniform reaction conditions. Furthermore, we reveal an unusual dual BDAC sequence leading to N-N-linked isoquinoline dimer.

Full text of DOI:10.1021/acs.joc.6b01096

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Article
Scaffold Diversity through a Branching Double Annulation
Cascade Strategy: An Iminium Induced One-pot Synthesis
of Diverse Fused Tetrahydroisoquinoline (THIQ) Scaffolds
Duddu S. Sharada, Anand H Shinde, Srilaxmi M. Patel, and Shinde Vidyacharan
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 11 Jul 2016
Downloaded from http://pubs.acs.org on July 11, 2016
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Scaffold Diversity through a Branching Double Annulation Cascade
Strategy: An Iminium Induced One-pot Synthesis of Diverse Fused
Tetrahydroisoquinoline (THIQ) Scaffolds
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Duddu S. Sharada,* Anand H. Shinde,† Srilaxmi M. Patel† and Shinde Vidyacharan
Department of Chemistry, Indian Institute of Technology Hyderabad (IITH), Kandi, Sangareddy, 502 285,
Telangana, India. Eꢀmail: sharada@iith.ac.in
Abstract: A branching double annulation cascade (BDAC) strategy for diverse and complex fused
THIQ scaffolds via a highly reactive iminium induced one-pot double cyclization sequence
involving Pictect-Spengler type cyclization has been developed for the first time. The salient
features of this protocol are direct and rapid access to unprecedented diverse fused THIQ
skeletons, metal/catalyst free, cleaner reaction profile, good to excellent yields and convenient
approach. This catalyst-free domino process facilitates the double annulation with variety of
scaffold building agents via two C-N and one C-X (X = C, N, O) bonds formation in a single step,
under uniform reaction conditions. Furthermore, we reveal an unusual dual BDAC sequence
leading to N-N linked isoquinoline dimer.
Introduction
The pursuit of identification of new small molecule modulators for chemical genetics and drug
discovery has led to synthesis of natural product based compounds, combinatorial synthesis of libraries1
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and cascade strategies.2 Awestruck by the nature’s ability to create structurally and functionally diverse
preꢀvalidated natural product libraries from a limited pool of simple building blocks and the demand for
compound libraries with structural complexity and stereogenic centers3 has led synthetic organic chemist
to explore chemical space paradigm by taking the leads from natural products, which is highly
challenging.4 To meet this challenge, diversity oriented synthesis (DOS)5 has emerged as an important
tool which entails efficient synthesis of skeletally, stereochemically and functionally diverse libraries.6
DOS by employing folding7/branching pathways,8 build/couple/pair (B/C/P) strategies,9 structural
variations in common substrates/building blocks10 and branching cascade approaches11 have successfully
demonstrated in creating diverse molecular scaffolds, which serve as biological probes and potential leads
for drug discovery.
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In connection with our broader interests in developing synthetic strategies for diverse and complex
polyheterocycles involving cascade annulations12 in a oneꢀpot manner, herein, we are pleased to disclose
a cascade sequence involving a highly reactive iminium intermediate and further PictetꢀSpengler13 type
cyclization for accessing three dimensional privileged THIQ compounds as branching double annulation
cascade (BDAC).
Numerous strategies have been reported for the synthesis of THIQ such as Strecker
lactamization/alkylations,14 allylationꢀlactamization cascade,15 MukaiyamaꢀMannich lactamization/
alkylations,16 1,3ꢀdipolar cycloaddition reaction of azomethine imine17 and Grignard18 as well as
allyltrimethoxysilane19 addition to imine as shown in Scheme 1a. Latest approaches to substituted THIQ
involve metal catalysed ortho CꢀH allylation/cyclization (Scheme 1b),20 crossꢀdehydrogenative coupling
(CDC) reactions (Scheme 1c),21 and redoxꢀneutral reactions.22 Recently, we have developed cascade
strategies for the synthesis of THIQ in oneꢀpot fashion.12c,d However, many of the previous reported
approaches to construct complex THIQ derivatives often have limited skeletal diversity and require
several steps, and hence there lies a need to develop efficient strategies for THIQ compounds. To address
this challenge, we envisioned that the concept of branching cascade could be utilized, involving the
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reaction of a common substrate with different scaffoldꢀbuilding agents (SBAs) and Scheme 1d illustrates
the general concept of substrateꢀbased approach to scaffold diversity, which we have utilized in the
present strategy. To the best of our knowledge the branching cascade pathway has not yet been reported
for the synthesis of diverse and complex THIQ molecules. With this in mind, we have identified 2ꢀ(2ꢀ
bromoethyl)benzaldehyde 1a as a common substrate to generate highly reactive and versatile iminium
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Scheme 1. Different approaches for the synthesis of fused THIQ skeletons and our designed BDAC
strategy.
Previous reports:
(Ref. 13-21)
Br
N
(a)
R
NuH
NH2
N
O
R
Nu
R
O
O
O
Ortho
Ph
R
Ph cyclization
R
N
CH-allylation
(b)
N
NHR
H
metal-catalysts
CDC
NuH
(c)
N
N
R
N
R
R
Nu
General concept of substrate-based approach to scaffold diversity (SD):
Br
P1
P3
A =
N
CHO
A
P =
(d)
Nu
Nu
SBA =
Scaffold Building agent
Common substrate
Product
SBA
A
P
=
=
=
P2
NH2
Our present BDAC approach:
Br
N
Nu
H2N
DCE, 90 o
C
(e)
+
Nu
30-60 min
CHO
metal-free
approach
1a
2
3
library of 29-diverse
compounds
intermediate for further diversification with wide range of SBAs 2 (Scheme 1e). THIQ with a stereogenic
center at the C1 position occupy an important place among natural and unnatural compounds possessing
valuable biological activities23 and are precursors for synthesis of complex alkaloids.14ꢀ16
Herein, we report a novel BDAC strategy for rapid access to diverse molecular library containing
unprecedented THIQ fused skeletons by using 2ꢀ(2ꢀbromoethyl)benzaldehyde 1a as a common substrate
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and variety of N,Cꢀ, N,Oꢀ and N,Nꢀ1,5ꢀbisnucleophiles as SBAs. The synthesized molecules contain
multiple privileged structures such as tetrahydroisoquinoline (coralydine I and (+) cripsin A II),
imidazoquinoxaline (PPQꢀ102 III),24 pyrroloquinoxaline (IV),25 tetrazolo[1,5ꢀc]quinoxaline (V),26
quinazolinone (rutaecapine VI),27 and benzothiadiazinedioxide (IDRAꢀ21 VII),28 which form part of
natural products and biological important molecules (Figure 1).
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Figure 1. Naturally occurring THIQ alkaloids and representative examples of bioactive molecules
containing our privileged motifs.
Results and Discussion:
To this end, initially to check the feasibility of our branching cascade strategy we performed a model
reaction of 2ꢀ(2ꢀbromoethyl)benzaldehyde (1a) with 2ꢀ(2ꢀaminophenyl)imidazole (2a) under polar protic
solvents such as MeOH and EtOH at various temperatures (Table 1, entries 1ꢀ4), of which under reflux
temperature in MeOH gave the desired product 3a albeit in 47% yield (Table 1, entry 2). Inspired by this
result, in order to increase the yield further, we screened the reaction under polar aprotic solvents such as
acetonitrile and 1,4 dioxane, which afforded the moderate yields of the products (20ꢀ53%, Table 1, entries
5ꢀ7). We continued our attempts to optimize the yield by performing the reaction in chlorinated solvents
(Table 1, entries 8ꢀ10) and to our delight, DCE at reflux temperature provided the desired product in good
yield (Table 1, entry10). After having screened various solvents, we have chosen DCE as a solvent for
o
further optimization studies. The increase in reaction temperature to 90 C resulted in better yield of the
o
product 3a (75%) (Table 1, entry 11), however, further increase in temperature to 100 C as well as the
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unconventional microwave heating could not improve the yield of the product further (Table 1, entries 12
and 13). Our attempts to use additives like DBU, PTSA and Et3N have failed to improve the yield of the
product (Table 1, entries 14ꢀ16). Similarly, employing dehydrating agents like 4Å molecular sieves and
Na2SO4 did not aid in enhancing the yields (Table 1, entries 17 and 18).
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Table 1. Optimization conditions for the synthesis of fused tetrahydroisoquinoline compound 3a
through BDAC a
Entry Solvent
Additive Tempt oC Time (min) Yield (%)b
1
2
3
4
5
6
7
8
MeOH
MeOH
EtOH
EtOH
CH3CN
CH3CN
1,4ꢀDioxane
DCM
DCE
DCE
DCE
DCE
DCE
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
rt
reflux
rt
reflux
rt
reflux
reflux
rt
rt
reflux
90
100
90
120
60
120
60
90
60
60
90
90
60
30
30
30
60
60
60
60
60
45
47
40
42
20
53
45
42
56
66
75c
65
66d
0
9
10
11
12
13
14
15
16
17
18
ꢀ
DCE
DCE
DCE
DCE
DBU
PTSA
Et3N
M.S.
90
90
90
90
70
68
70e
69
DCE
Na2SO4 90
a Reaction conditions: 1a (0.23 mmol), 2a (0.23 mmol) and 1 mL of solvent; b Isolated yields after column
c
chromatography; No detrimental effect observed on reaction outcome by varying the concentration of
e
reaction. d Unconventional microwave heating was used; 4Å molecular sieves was used.
At the outset of this study, our efforts were directed towards design and synthesis of different N,Cꢀ,
N,Oꢀ, and N,Nꢀ1,5ꢀbisnucleophiles (Figure 2). With this pool of compounds (2aꢀ2h) in hand, a series of
annulation reactions were envisaged in order to achieve skeletal diversity. With the standard reaction
conditions in hand, we first subjected substituted imidazole based N,Cꢀbisnucleophiles 2a(I) and 2a(II)
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leading to corresponding products 3b and 3c in 67% and 68% yields. In addition, we have also employed
2ꢀ(1Hꢀpyrrolꢀ1ꢀyl)aniline (2b) in our cascade annulation resulting in pyrroloquinoxalineꢀTHIQs (3dꢀ3f) in
good yields (71ꢀ73%). The fact that the more nucleophilic pyrrole substituted SBA 2b gave better yield
than imidazole substituted SBA 2a is in agreement with our proposed concept. In our efforts to diversify
the skeleton, we investigated azole based N,Nꢀbisnucleophiles such as 2c and 2d, which resulted in the
corresponding products tetrazoloquinozalinoꢀTHIQs (3g-3i, 75ꢀ87%) and benzimidazoquinazolinoꢀ
THIQs (3j and 3k, 48% and 65%). Tetrazole based SBA 2c was the best nucleophile, which afforded the
excellent yields of the corresponding products among all heterocyclic SBAs. With an aim to functionally
diversify the skeleton and for comparative study, we evaluated the reactivity of the amide as N,Nꢀ
bisnucleophile, in our present strategy. To our surprise the reaction of variety of 2ꢀaminobenzamides 2e
with 1a-1c under standard conditions, afforded the corresponding products (3lꢀ3s) in good to high yields
(48ꢀ70%). It is to be noted that these products could be diversified further for various applications. The
successful employment of 2ꢀaminobenzamides 2e (I-V), prompted us to examine the 2ꢀ
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aminobenzenesulfonamides (2f) as
a
scaffold building agent for the synthesis of
tetrahydrobenzothiadiazinoisoquinolinoꢀ6,6ꢀdioxide which is a privileged scaffold present in several
natural products of biological interest.28 Accordingly, when we have reacted variety of 2ꢀ
aminosulphonamides (2f) with 1a-1c, afforded the products 3t-3z in good to excellent yields (62ꢀ90%).
Encouraged by the results, we envisioned to explore the nucleophilicity of oxygen in our present
strategy, by treatment of 2ꢀaminobenzyl alcohol 2g(I) and 2ꢀaminobenzoic acid 2g(II) with 1a, which
afforded 3aa and 3ab in 60 and 72% yields, respectively. Due to the ubiquity of THIQ based natural
products containing C1 stereocenter, many research groups have focused on the introduction of a
substituent at C1 position in a stereogenic fashion and also on natural products containing two contiguous
and 1,3 stereocenters. Our aim to introduce stereochemical diversity in our present strategy, prompted us
to examine the possibility of diastereoselectivity by employing the 1,3 stereocenter inducing SBAs. With
this idea in mind, we selected the phenyl substituted secondary alcohol 2g(III) as N,Oꢀ1,5 bisnucleophile,
which afforded the expected product 3ac although in low stereoselectivity (cis/trans = 4:3) as a mixture
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N
Br
R1
Nu
NH2
DCE
+
90 o
C
Nu
R2
R1
CHO
1 (a-c)
30-60 min
3 (a-ac)a
29 examples
48-90% yields
R2
2 (a-g)b
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3aa, X = CH2, R1 = H, R2 = H, 60%
3ab, X = CO, R1 = H, R2 = H, 72%
3ac, X = CHPh, R1 = H, R2 = H, 52%, cis/trans= 4:3 drc
N
N
N
R1
3a
3b
, R1 = H, R2 = H, 72%
, R1 = H, R2 = CH3, 67%
, R1 = Br, R2 = H, 68%
R1
O
X
R2
R2
3c
N
N
S
R1
, R1 = H, R2 = H, 70%
HN
O
Br
2f
3t
3u
R2
N
N
O
R1
, R1 = H, R2 = Cl, 90%
, R1 = H, R2 = Br, 82%
R1
CHO
, R1 = H
, R1 = CH3
, R1 = Br
3v
3w
R2
1a
1b
, R1 = H, R2 =I, 79%
3x
, R1 = CH3, R2 = H, 62%
1c
3d
, R1 = H, R2 = H, 71%
, R1 = CH3, R2 = H, 60%
, R1= Br, R2 = H, 73%
3y
3z
, R1 = CH3, R2 = I, 68%
3e
N
O
R1
3f
, R1 = Br, R2 = H, 65%
N
R3
R2
N
R1
N
3l
, R1 = H, R2 = H, R3 = PhNH, 62%
N
N
R2
N
R1
3m
, R1 = H, R2 = Cl, R3 = PhNH, 55%
N
N
3n
3o
R2
, R1 = H, R2 = H, R3 = Ph, 70%
N
3g
3h
, R1 = H, R2 = H, 87%
, R1 =CH3, R2 = H, 68%
, R1 = Br, R2 = H, 75%
, R1 = H, R2 = H, R3 = Bn, 65%
1 gm scale = 0.79 gm, 56%
3p
, R1 = H, R2 = Cl, R3 = Bn, 55%
3i
3j
, R1 = H, R2 = H, 65%
3q
3r
3s
, R1 = CH3, R2 = H, R3 = Bn, 60%
3k
, R1 = CH3, R2 = H, 48%
R1 = CH3, R2 = Cl, R3 = Bn, 48%
, R1 = Br, R2 = H, R3 = Bn, 62%
NH2
NH2
NH2
N
N
N
N
N
H
N
H
N
H2N
N
N
R2
2c
2a(I)
2a(II)
2b
R2 = H
R2 = CH3
2d
NH2
NH2
NH2
NH2
H
OH
N
X
R2
S
R2
R3
O
O
O
2e(I)= R2 = H, R3 = Ph-NH
2f(I)
2f(II)
2g(I)
2g(II)
R2 = H
R2 = Cl
X = CH2
X = CO
2e(II)
= R2 = Cl, R3 = Ph-NH
2f(III)
2f(IV)
R2 = Br
R2 = I
2g(III)
X = CHPh
2e(III)
2e(IV)
= R2 = H, Ph
= R2 = H, R3 = Bn
2e(V)
= R2 = Cl, R3 = Bn
a Reactions were performed in DCE (1mL) with 1 (0.23 mmol), 2 (0.23 mmol) at 90 oC for 30ꢀ60 min.
b
2aꢀ2g represent various N,Cꢀ, N,Oꢀ and N,Nꢀ1,5ꢀbisnucleophiles as SBAs. c dr was determined by H
1
NMR spectroscopy.
Figure 2. Synthesis of various diverse fused tetrahydroisoquinoline compounds 3a-3ac through
branching double annulation cascade (BDAC) strategy.
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of inseparable diastereomers in 52% yield. The relative configuration of the major diastereomers was
assigned to be cis based on NOE experiment. Our attempts to improve the diastereoselectivity by varying
temperature, solvent system and concentration went in vein (see ESI). All the compounds were confirmed
9
1
by H and 13C spectroscopy and high resolution mass spectrometry. Although, the NMR spectroscopic
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data support the formation of fused privileged tetrahydroisoquinoline scaffolds 3, the structures of 3p and
3t were unambiguously secured by Xꢀray crystal analyses (see ESI for Xꢀray data of 3p and 3t).
In our present BDAC strategy, several diverse haloꢀsubstituted compounds have been synthesized,
which could be utilized as versatile synthons for further diversification. The present BDAC strategy was
proved to be very general and versatile by enabling variety of SBAs with distinct nucleophilic centers to
react with common precursor under unified reaction conditions. Overall, it was found that the N,Nꢀ
bisnucleophiles afforded excellent yields compared to N,C and N,Oꢀbisnucleophiles, and 2ꢀ
aminobenzenesulfonamides (2f) though being weak nucleophile comparatively were the best among all
1,5ꢀbisnucleophiles in terms of the reactivity and yield. The substituents such as Me and Br on common
substrate 1 was non detrimental on reaction outcome and yield of the products (3aꢀ3ac).
Scheme 2. Scope of BDAC strategy with 2-aminobenzohydrazide (2h).
Further aiming to expand the diversity in the BDAC strategy, we envisioned that by using 2ꢀ
aminobenzohydrazide
(2h)
as
1,6ꢀbisnucleophile
can
result
in
7ꢀmembered
fused
tetrahydrobenzotriazepino isoquinolinone skeleton. To our surprise, when we used 2ꢀ
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aminobenzohydrazide (2h) as N,Nꢀbisnucleophile, resulted in the dimer product 3ae instead of expected
compound 3ad (Scheme 2), which was confirmed by spectral and Xꢀray crystal structure analyses (CCDC
1478494, see ESI for Xꢀray data of 3ae). The formation of 3ae can be explained by dual BDAC reactions
involving transamination of 2h with intermediate A with the elimination of hydrazine hydrobromide.
After having developed the BDAC strategy for the synthesis of diverse heterocyclic scaffolds, we
envisaged that it would be appropriate to check the scalability of our BDAC strategy for the synthesis of
fused tetrahydroisoquinoline compounds 3. Accordingly, we performed the scaleꢀup (1g scale) reaction
for the synthesis of the product 3o, resulting in 0.79 gm, 56% yield (Figure 2).
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Based on the literature reports12c,d, 29 and experimental studies (see ESI for experimental studies), we
have formulated a plausible reaction mechanism for the synthesis of diverse fused tetrahydroisoquinoline
derivatives as shown in scheme 3. Initially, 2ꢀ(2ꢀbromoethyl)benzaldehydes (1a) and scaffoldꢀbuilding
agents (SBAs) 2 react to give an imine intermediate I, followed by an intramolecular alkylative
cyclization leading to reactive Mannich base II which on further PictetꢀSpengler13 type annulation affords
the desired product 3 (Scheme 3).
Scheme 3. Plausible reaction mechanism for the synthesis of THIQ fused compound 3.
In summary, we have successfully developed an advanced metalꢀfree double annulation branching
cascade (BDAC) strategy for the synthesis of library of 29 new, complex and diverse
tetrahydroisoquinoline fused derivatives by using a variety of N,Cꢀ, N,Oꢀ and N,Nꢀ1,5ꢀbisnucleophiles as
a SBAs and 2ꢀ(2ꢀbromoethyl)benzaldehydes as a common precursor under uniform reaction conditions.
The important features of the present protocol are metal and catalystꢀfree, operational simplicity, use of
simple starting materials and moderate to excellent yields. Moreover, the success of gramꢀscale synthesis
of fused THIQ make this process useful for industrial applications. Undoubtedly, this protocol which
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affords three dimensional THIQ derivatives which are diverse in its coverage of chemical space, should
prove useful for further scaffold innovation in drug discovery program. Further, studies on
enantioselective synthesis of these scaffolds are currently under way.
9
We gratefully acknowledge Council of Scientific and Industrial Research (CSIR), New Delhi, India
and Indian Institute of Technology Hyderabad (IITH) for financial support. AHS, SMP and SV thank to
UGC, New Delhi, India for the award of research fellowship.
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Experimental Section
General Considerations
IR spectra were recorded on a FTIR spectrophotometer. 1H NMR spectra were recorded on 400 MHz
spectrometer at 295 K in CDCl3; chemical shifts (δ ppm) and coupling constants (Hz) are reported in
standard fashion with reference to either internal standard tetramethylsilane (TMS) (δH = 0.00 ppm) or
CHCl3 (δH = 7.25 ppm). 13C NMR spectra were recorded on 100 MHz spectrometer at RT in CDCl3;
chemical shifts (δ ppm) are reported relative to CHCl3 [δC = 77.00 ppm (central line of triplet)]. In the
1HNMR, the following abbreviations were used throughout: s = singlet, d = doublet, t = triplet, q =
quartet, qui = quintet, m = multiplet and br s. = broad singlet. The assignments of signals were confirmed
13
by 1H, C CPD, and DEPT spectra. Highꢀresolution mass spectra (HRꢀMS) were recorded using QꢀTOF
multimode source. Melting points were determined on an electro thermal melting point apparatus and are
uncorrected. 2ꢀ(2ꢀbromoethyl)benzaldehyde (1aꢀ1c) were prepared by using known procedures. All the
bisnucleophiles such as N,Cꢀ, N,Oꢀ and N,Nꢀ1,5ꢀbisnucleophiles as a SBAs (2aꢀ2h) which were either
prepared in the laboratory or purchased from commercial sources. All the dry solvents such as, MeOH,
EtOH and 1,4ꢀDioxane were dried over sodium metal and CH3CN, DCM and DCE were dried over
calcium hydride.
All small scale dry reactions were carried out using standard syringeꢀseptum technique. Reactions
were monitored by TLC on silica gel using a combination of petroleum ether and ethyl acetate as eluents.
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Reactions were generally run under argon atmosphere. Solvents were distilled prior to use; petroleum
ether with a boiling range of 40 to 60 ˚C was used.
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(I) General Procedure 1: Preparation of isochromans.30
9
A mixture of the substituted phenylethyl alcohol (i) (4.97 mmol), chloromethylmethyl ether (7.046
mmol) and N,Nꢀdiisopropylethylamine (9.95 mmol) in dry dichloromethane (15 mL) was stirred under
nitrogen atmosphere for 2.5 h at rt. The reaction mixture was then washed with water, dried (Na2SO4) and
the solvent was removed in vaccuo. The crude MOM acetal (ii) was dissolved in dried acetonitrile and
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o
added to cooled (0 C) solution of trimethylsilyl trifluoromethanesulfonate (TMSOTf) (4.97 mmol). The
reaction was carried out under nitrogen atmosphere for 3h. Then the mixture was quenched by the
addition of l M NaHCO3. The organic phase was washed with brine, dried with anhydrous sodium
sulphate and evaporated under reduced pressure. Purification by column chromatography afforded
corresponding substituted isochromans (see ESI).
(II) General procedure 2: Preparation of 2-(2-bromoethyl)benzaldehydes (1a-1c).30
To a solution of the substituted isochroman iii (7.46 mmol) derivatives in acetonitrile (15 mL), CuBr2
(8.95 mmol) was added under nitrogen atmosphere. The solution was refluxed for about 2h and then
cooled to room temperature. The reaction mixture was added water, extracted with ethyl acetate. The
combined organic extracts were washed with brine and dried with anhydrous Na2SO4, filtered and
concentrated and then purified by silica gel column chromatography to afford the products (1a-1c) in 68ꢀ
74% yield (see ESI).
(III) General procedure 3: Synthesis of diverse scaffold containing fused tetrahydroisoquinolines
(3a-3ae) through BDAC strategy: 2ꢀ(2ꢀBromoethyl)benzaldehydes (1a-c) (50 mg, 0.23 mmol) and
variety of bisnucleophiles 2 (0.23 mmol) were taken in a 5 mL round bottom flask and added 1 mL of
o
DCE heated at 90 C. After completion of the reaction (monitored by TLC), the DCE solvent was
completely evaporated under reduced pressure. The reaction mixture was quenched by aq. NaHCO3 and
extracted with ethyl acetate (2 × 20 mL). The combined organic layer was washed with brine solution and
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allowed to dry over anhydrous Na2SO4. The crude extract was purified by filtration through a silica gel
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(100ꢀ200 mesh) column using hexane and ethyl acetate as eluents to yield the desired product 3a-3ae.
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(IV) General procedure 4: Large scale synthesis of isoquinolinoquinazolinone 3o through BDAC
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strategy.
2ꢀ(2ꢀBromoethyl)benzaldehyde (1a) (1000 mg, 4.69 mmol) and N,Nꢀbisnucleophile 2e(IV) (790 mg, 4.69
o
mmol) were taken in a 25 mL round bottom flask and added 10 mL of DCE heated at 90 C. After
completion of the reaction (monitored by TLC), the DCE solvent was completely evaporated under
reduced pressure. The reaction mixture was quenched by aq. NaHCO3 and extracted with ethyl acetate (2
× 20 mL). The combined organic layer was washed with brine solution and allowed to dry over
anhydrous Na2SO4. The crude extract was purified by filtration through a silica gel (100ꢀ200 mesh)
column using hexane and ethyl acetate as eluents to yield the desired product 3o in 56%, 790 mg.
Spectroscopic data of all unknown compounds: 7,11b-Dihydro-6H-imidazo-6H-imidazo[1,5-
o
a]isoquinolino[1,2-c]quinoxaline (3a): Brown solid (46 mg, 72%); mp 198−200 C; IR (MIRꢀATR,
4000−600 cmꢀ1): νmax = 3112, 2923, 2854, 1710, 1600, 1507, 1462, 1351, 1109, 746, 653; H NMR (400
1
MHz, CDCl3) δ ppm = 2.86 (d, J = 16.1 Hz, 1H), 3.21−3.28 (m, 1H), 3.36−3.40 (m, 1H), 3.97 (ddd, Ja =
12.5, Jb = 5.4 and Jc = 2.2 Hz, 1H), 5.53 (s, 1H), 6.92−6.97 (m, 2H), 7.05 (d, J = 7.8 Hz, 1H), 7.17−7.23
(m, 4H), 7.26−7.32 (m, 1H), 7.43 (dd, Ja = 7.8 and Jb = 1 Hz, 1H), 8.0 (s, 1H); 13C NMR (100 MHz,
CDCl3) δ ppm = 27.1, 43.7, 54.7, 114.7, 115.7, 119.7, 124.6, 124.7, 126.3, 126.9, 127.4, 127.52, 129.3,
131.5, 133.1, 133.9, 137.6; HRꢀMS (ESI+) m/z calculated for C18H16N3 = [M+H+]: 274.1339; found:
+
274.1326.
2-Methyl-7,11b-dihydro-6H-imidazo[1,5-a]isoquinolino[1,2-c]quinoxaline (3b): Brown solid (45 mg,
67%); mp 177−180 oC; IR (MIRꢀATR, 4000−600 cmꢀ1): νmax = 3055, 2924, 2858, 1705, 1513, 1360, 816,
1
736, 651; H NMR (400 MHz, CDCl3) δ ppm = 2.32 (s, 3H), 2.82−2.87 (m, 1H), 3.19−3.24 (m, 1H),
3.28− 3.35 (m, 1H), 3.87−3.92 (m, 1H), 5.45 (s, 1H), 6.94−6.96 (m, 2H), 7.01 (d, J = 1.5 Hz, 1H),
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7.13−7.16 (m, 1H), 7.19−7.22 (m, 2H), 7.24−7.25 (m, 1H), 7.30−7.33 (m, 1H), 7.97 (d, J = 1 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ ppm = 20.7, 27.1, 43.9, 54.9, 115.2, 116.3, 124.7, 124.8, 126.2, 126.9,
7
8
+
127.3, 127.4, 127.7, 129.3, 129.8, 131.5, 133.1, 134.0, 135.4; HRꢀMS (ESI+) m/z calculated for C19H18N3
9
= [M+H+]: 288.1495; found: 288.1482.
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10-Bromo-7,11b-dihydro-6H-imidazo[1,5-a]isoquinolino[1,2-c]quinoxaline (3c): Brown solid (56 mg,
o
68%); 168−170 C; IR (MIRꢀATR, 4000−600 cmꢀ1): νmax = 3049, 2922, 1718, 1604, 1509, 1475, 1347,
1
1273, 813, 739, 651; H NMR (400 MHz, CDCl3) δ ppm = 2.78−2.82 (m, 1H), 3.2 (ddd, Ja = 16.9, Jb =
11.5 and Jc = 5.9 Hz, 1H), 3.42 (ddd, Ja = 13.2, Jb = 11.7 and Jc = 4.4 Hz, 1H), 4.02−4.07 (m, 1H), 5.56 (s,
1H), 6.92 (td, Ja = 7.7 and Jb = 1.2 Hz, 1H), 7.00−7.05 (m, 3H), 7.17−7.20 (m, 1H), 7.32 (dd, Ja = 8.3 and
Jb = 1.5 Hz, 1H), 7.41−7.45 (m, 2H), 8.03 (d, J = 1 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ ppm = 25.8,
43.9, 54.6, 114.8, 115.8, 119.8, 119.9, 124.4, 125.2, 126.1, 127.0, 129.7, 130.6, 131.0, 131.7, 132.9,
+
135.8, 136.7; HRꢀMS (ESI+) m/z calculated for C18H15BrN3 = [M+H+]: 352.0444; found: 352.0430.
7,11b-Dihydro-6H-isoquinolino[2,1-a]pyrrolo[2,1-c]quinoxaline (3d): Brown solid (45 mg, 71%) mp
120−122 oC; IR (MIRꢀATR, 4000−600 cmꢀ1): νmax = 3052, 2902, 2829, 1506, 1337, 1288, 1221, 738, 701,
1
643; H NMR (400 MHz, CDCl3) δ ppm = 2.8 (d, J = 16.1 Hz, 1H), 3.19−3.27 (m, 1H), 3.31−3.38 (m,
1H), 3.90−3.95 (m, 1H), 5.46 (s, 1H), 6.07−6.08 (m, 1H), 6.32−6.34 (m, 1H), 6.84−6.88 (m, 1H),
13
6.97−6.99 (m, 1H), 7.05−7.20 (m, 5H), 7.31−7.34 (m, 2H); C NMR (100 MHz, CDCl3) δ ppm = 27.1,
44.0, 56.2, 105.7, 110.0, 114.5, 115.1, 115.1, 119.7, 125.0, 126.0, 127.0, 127.5, 127.7, 128.5, 129.2,
+
134.2, 134.4, 137.6; HRꢀMS (ESI+) m/z calculated for C19H17N2 = [M+H+]: 273.1386; found: 273.1382.
10-Methyl-7,11b-dihydro-6H-isoquinolino[2,1-a]pyrrolo[2,1-c]quinoxaline (3e): Brown solid (38 mg,
60%); mp 130−132 oC; IR (MIRꢀATR, 4000−600 cmꢀ1): νmax = 3044, 2918, 2847, 1505, 1337, 1289, 1164,
1
741, 701, 610, 549; H NMR (400 MHz, CDCl3) δ ppm = 2.29 (s, 3H), 2.78 (d, J = 15.7 Hz, 1H),
3.17−3.25 (m, 1H), 3.34 (td, Ja = 12 and Jb = 3.9 Hz, 1H), 3.9−3.96 (m, 1H), 5.44 (s, 1H), 6.09 (d, J = 2.9
Hz, 1H), 6.34 (t, J = 3.2 Hz, 1H), 6.85−6.89 (m, 1H), 6.98−7.03 (m, 2H), 7.05−7.09 (m, 1H), 7.14 (s, 1H),
7.17 (dd, Ja = 2.7 and Jb = 1.7 Hz, 1H), 7.23 (s, 1H), 7.33 (dd, J = 7.8 Hz, 1H). 13C NMR (100 MHz,
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CDCl3) δ ppm = 21.3, 26.6, 44.1, 56.14, 105.7, 110.0, 114.4, 115.0, 115.1, 119.6, 124.9, 127.6, 127.8,
5
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128.5, 129.0, 131.0, 134.1, 135.5, 137.6; HRꢀMS (ESI+) m/z calculated for C20H19N2 = [M+H+]:
+
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287.1543; found: 287.1539.
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10-Bromo-7,11b-dihydro-6H-isoquinolino[2,1-a]pyrrolo[2,1-c]quinoxaline (3f): Brown solid (44 mg,
73%); m.p. 148−150 oC; IR (MIRꢀATR, 4000−600 cmꢀ1): νmax = 3048, 2919, 2833, 1508, 1340, 1165, 741,
1
703, 657, 538; H NMR (400 MHz, CDCl3) δ ppm = 2.75 (d, J = 17.6, 1H), 3.16−3.24 (m, 1H), 3.38
(ddd, Ja = 13.1, Jb = 11.6 and Jc = 4.2 Hz, 1H), 3.99 (ddd, Ja= 13.2, Jb = 5.6 and Jc = 2.2 Hz, 1H), 5.47 (s,
1H), 6.13 (dd, Ja = 3.2 and Jb = 1.2 Hz, 1H), 6.36 (t, J = 3.2 Hz, 1H), 6.87 (td, Ja = 7.6 and Jb = 1.5 Hz,
1H), 6.96−6.99 (m, 2H), 7.05−7.09 (m, 1H), 7.18 (dd, Ja = 2.9 and Jb = 1.5 Hz, 1H), 7.26−7.29 (m, 1H),
7.32 (dd, Ja = 7.8 and Jb = 1.5 Hz, 1H), 7.42 (d, J = 1 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ ppm =
25.9, 44.1, 56.0, 106.2, 110.2, 114.5, 115.1, 115.2, 119.5, 119.8, 125.0, 127.0, 127.5, 130.1, 130.2, 130.8,
+
133.0, 136.7, 137.1; HRꢀMS (ESI+) m/z calculated for C19H16BrN2 = [M+H+]: 351.0491; found:
351.0477.
7, 11b-Dihydro-6H-isoquinolino[2,1-a]tetrazolo[1,5-c]quinazoline (3g): White solid (56 mg, 87%); mp
88−90 oC; IR (MIRꢀATR, 4000−600 cmꢀ1) νmax = 3067, 2922, 2854, 1720, 1655, 1614, 1489, 1387, 1295,
1
1238, 1119, 1031, 749, 697, 649; H NMR (400 MHz, CDCl3) δ ppm = 2.94 (dt, Ja = 16.6 and Jb = 4.4
Hz, 1H), 3.19−3.27 (m, 1H), 3.53−3.61 (m, 1H), 3.92−3.98 (m, 1H), 6.88 (s, 1H), 7.08 (td, J = 7.6 Hz,
1H), 7.14−7.17 (t, J = 7.6 Hz, 2H), 7.20−7.22 (m, 1H), 7.28−7.35 (m, 2H ), 7.47 (ddd, Ja = 8.4, Jb = 7.2
and Jc = 1.5 Hz, 1H), 8.03 (dd, Ja = 7.6 and Jb = 1.7 Hz, 1H ); 13C NMR (100 MHz, CDCl3) δ ppm = 25.8,
44.8, 72.0, 111.5, 116.2, 121.9, 126.3, 126.8, 127.7, 129.3, 129.4, 129.8, 133.4, 134.5, 143.7, 148.8; HRꢀ
+
MS (ESI+) m/z calculated for C16H14N5 = [M+H+]: 276.1244; found: 276.1239.
10-Methyl-7,11b-dihydro-6H-isoquinolino[2,1-a]tetrazolo[1,5-c]quinazoline (3h): White solid (43 mg,
68%); mp 170−172 oC; IR (MIRꢀATR, 4000−600 cmꢀ1): νmax = 2920, 1618, 1494, 1303, 1214, 1144, 1064,
1
747, 612; H NMR (400 MHz, CDCl3) δ ppm = 2.28 (s, 3H), 2.89 (dt, Ja = 16.9 and Jb = 4 Hz, 1H),
3.22(ddd, Ja = 16.5, Jb = 10.6 and Jc = 5.6 Hz, 1H), 3.54−3.61 (m, 1H), 3.95−4.01 (m, 1H), 6.89 (s, 1H),
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7.04−7.15 (m, 5H), 7.45−7.49 (m, 1H), 8.04 (dd, Ja = 7.8 and Jb = 1.5 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ ppm = 21.1, 25.3, 44.9, 72.1, 111.4, 115.9, 121.7, 126.4, 127.9, 129.2, 129.8, 130.3, 131.2,
6
7
8
+
133.4, 136.6, 143.6, 148.8; HRꢀMS (ESI+) m/z calculated for C17H16N5 = [M+H+]: 290.1400; found:
9
290.1395.
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10-Bromo-7,11b-dihydro-6H-isoquinolino[2,1-a]tetrazolo[1,5-c]quinazoline (3i): white solid (46 mg,
75%); 192−195 oC; IR (MIRꢀATR, 4000−600 cmꢀ1): νmax = 1618, 1580, 1488, 1304, 1220, 1139, 816, 739;
1H NMR (400 MHz, CDCl3) δ ppm = 2.91 (dt, Ja = 17.1 and Jb = 3.9 Hz, 1H), 3.21 (ddd, Ja = 16.6, Jb =
10.5 and Jc = 5.6 Hz, 1H), 3.59 (ddd, Ja = 14.4, Jb = 10 and Jc = 4.9 Hz, 1H), 3.99−4.05 (m, 1H), 6.91 (s,
1H), 7.05 (d, J = 8.3, 1H), 7.09−7.16 (m, 2H), 7.41−7.52 (m, 3H), 8.06 (dd, Ja = 7.6 and Jb = 1.2 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ ppm = 25.1, 44.6, 71.4, 111.3, 116.0, 120.3, 122.1, 126.5, 130.4, 131.0,
+
132.1, 132.6, 133.3, 133.6, 143.1, 148.7; HRꢀMS (ESI+) m/z calculated for C16H13BrN5 = [M+H+]:
354.0349; found: 354.0343.
6,17a-Dihydro-5H-benzo[4,5]imidazo[1,2-c]isoquinolino[2,1-a]quinazoline (3j): White solid (49 mg,
o
65%); m.p. 188−190 C; IR (MIRꢀATR, 4000−600 cmꢀ1): νmax = 3054, 2921, 2851, 1613, 1479, 1449,
1226, 736, 642, 546; 1H NMR (400 MHz, CDCl3) δ ppm = 2.86 (d, J = 17.1 Hz, 1H), 3.45−3.62 (m, 1H),
3.76−3.81 (m, 1H), 4.32−4.45 (m, 1H), 7.16−6.74 (m, 7H), 7.47−7.25 (m, 4H), 7.88−7.86 (m, 1H), 8.14
13
(d, J = 7.3 Hz, 1H); C NMR (100 MHz, CDCl3) δ ppm = 23.8, 44.9, 69.5, 109.3, 119.7, 123.0, 123.2,
125.6, 126.2, 126.6, 128.7, 129.5, 131.9, 134.3, 134.2, 134.5, 135.45, 143.8; HRꢀMS (ESI+) m/z
+
calculated for C22H18N3 = [M+H+]: 324.1495; found: 324.1494.
2-Methyl-6,17a-dihydro-5H-benzo[4,5]imidazo[1,2-c]isoquinolino[2,1-a]quinazoline (3k): White solid
o
(36 mg, 48%); m.p. 178−180 C; IR (MIRꢀATR, 4000−600 cmꢀ1): νmax = 3049, 2920, 2851, 1613, 1479,
1
1267, 1218, 736, 699, 641, 543; H NMR (400 MHz, CDCl3) δ ppm = 2.04 (s, 3H), 2.83 (d, J = 14.7 Hz,
1H), 3.44−3.46 (m, 1H), 3.78−3.82 (m, 1H), 4.27−4.31 (m, 1H), 6.51−6.54 (m, 1H), 6.84−7.05 (m, 5H),
7.32−7.42 (m, 4H), 7.88 (d, J = 7.3 Hz, 1H), 8.14 (d, J = 7.3 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
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ppm = 21.1, 23.5, 44.8, 69.3, 108.0, 109.1, 113.1, 119.5, 122.8, 123.0, 126.1, 129.3, 129.4, 131.8, 134.5,
5
6
136.3, 143.7; HRꢀMS (ESI+) m/z calculated for C23H20N3 = [M+H+]: 338.1652; found: 338.1650.
+
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8
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5-(Phenylamino)-12,13-dihydro-4bH-isoquinolino[2,1-a]quinazolin-6(5H)-one (3l): White solid (50
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o
mg, 62%); mp 196−198 C; IR (MIRꢀATR, 4000−600 cmꢀ1): νmax = 3260, 3032, 2922, 2853, 1655, 1599,
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1472, 1267, 741, 697; H NMR (400 MHz, CDCl3) δ ppm = 2.75 (dd, Ja = 16.9 and Jb = 4.6, 1H),
3.26−3.35 (m, 1H), 3.65 (ddd, Ja = 14.4, Jb = 12 and Jc = 5.4 Hz, 1H), 4.25 (dd, Ja = 14.4 and Jb = 5.1 Hz,
1H), 5.98 (s, 1H), 6.84−6.87 (m, 1H), 6.92 (t, J = 7.3 Hz, 1H), 7.01−7.04 (m, 4H), 7.09−7.15 (m, 2H),
7.22−7.26 (m, 2H), 7.31 (s, 1H), 7.38−7.42 (m, 1H), 7.53 (d, J = 7.3 Hz, 1H), 7.9 (dd, Ja = 7.8 and Jb =
1.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ ppm = 24.4, 44.8, 75.1, 113.6, 114.2, 117.2, 119.5, 121.8,
126.2, 126.4, 128.2, 129.0, 129.3, 129.4, 134.0, 134.2, 135.3, 146.7, 147.5, 163.1; HRꢀMS (ESI+) m/z
calculated for C22H20N3O+ = [M+H+]: 342.1601; found: 342.1595.
8-Chloro-5-(phenylamino)-12, 13-dihydro-4bH-isoquinolino[2, 1-a]quinazolin-6(5H)-one (3m): White
solid (48 mg, 55%); mp 125−127 C; IR (MIRꢀATR, 4000−600 cmꢀ1): νmax = 3263, 2916, 2754, 1657,
o
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1488, 1248, 1099, 900, 739, 691, 643, 591; H NMR (400 MHz, CDCl3) δ ppm = 2.74 (dd, Ja = 16.9 and
Jb = 4.6 Hz, 1H), 2.72−2.77 (m, 1H), 3.22−3.31 (m, 1H), 3.61−3.68 (m, 1H), 4.17−4.22 (m, 1H), 5.96 (s,
1H), 6.92−6.93 (m, 2H), 6.99−7.02 (m, 2H), 7.11−7.22 (m, 2H), 7.23−7.25 (m, 2H), 7.31−7.34 (m, 1H),
7.44 (br. s, 1H), 7.53 (d, J = 7.3 Hz, 1H), 7.86−7.87 (m, 1H); 13C NMR (100 MHz, CDCl3) δ ppm = 24.3,
45.0, 75.2, 114.1, 115.1, 118.4, 121.8, 124.8, 126.3, 126.4, 128.4, 128.9, 129.0, 129.4, 133.8, 133.9,
135.0, 146.1, 146.5, 162.1; HRꢀMS (ESI+) m/z calculated for C22H19ClN3O+ = [M+H+]: 376.1211; found:
376.1204.
5-Phenyl-12,13-dihydro-4bH-isoquinolino[2,1-a]quinazolin-6(5H)-one (3n): White solid (54 mg, 70%);
mp 92−94 C; IR (MIRꢀATR, 4000−600 cmꢀ1): νmax = 3065, 1667, 1598, 1462, 1378, 1326, 1275, 755,
o
695, 662; 1H NMR (400 MHz, CDCl3) δ ppm = 2.83 (dd, Ja = 17.1 and Jb = 4.4, 1H), 3.26−3.29 (m, 1H),
3.72 (ddd, Ja = 14.7, Jb = 11.2 and Jc = 5.9 Hz, 1H), 4.20−4.26 (m, 1H), 6.16 (s, 1H), 6.85−6.89 (m, 1H),
6.98 (d, J = 8.3 Hz, 1H), 7.03−7.08 (m, 2H), 7.13−7.16 (m, 1H), 7.19−7.23 (m, 1H), 7.32−7.40 (m, 4H),
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7.48−7.50 (m, 2H), 7.99 (dd, Ja = 7.8 and Jb = 2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ ppm = 24.6,
45.1, 75.3, 114.1, 119.2, 119.7, 125.1, 125.9, 126.2, 127.2, 128.2, 128.9, 129.1, 129.9, 133.8, 134.4,
135.6, 141.7, 147.4, 162.8; HRꢀMS (ESI+) m/z calculated for C22H19N2O+ = [M+H+]: 327.1492; found:
327.1486.
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5-Benzyl-12, 13-dihydro-4bH-isoquinolino[2,1-a]quinazolin-6(5H)- one (3o): White solid (52 mg,
65%); mp 158−160 oC; IR (MIRꢀATR, 4000−600 cmꢀ1): νmax = 3030, 2917, 1648, 1601, 1475, 1261, 744,
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697; H NMR (400 MHz, CDCl3) δ ppm = 2.29 (dd, Ja = 16.9 and Jb = 3.7 Hz, 1H), 3.13−3.04 (m, 1H),
3.48 (ddd, Ja = 14.1, Jb = 11.1 and Jc = 5.6 Hz, 1H), 3.98 (dd, Ja = 13.7 and Jb = 5.4 Hz, 1H), 4.36 (d, J =
15.2 Hz, 1H), 5.72−5.85 (m, 2H), 6.82−6.88 (m, 2H), 6.99−7.01 (m, 1H), 7.13−7.19 (m, 2H), 7.22−7.35
(m, 7H), 7.95 (dd, Ja = 7.8 and Jb = 1.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ ppm = 24.5, 44.6, 49.7,
71.7, 113.7, 118.5, 119.4, 119.8, 125.9, 126.2, 127.5, 127.7, 128.3, 128.7, 129.3, 129.5, 133.4, 134.8,
137.3, 147.5, 163.5; HRꢀMS (ESI+) m/z calculated for C23H21N2O+ = [M+H+]: 341.1648; found: 341.1644.
5-Benzyl-8-chloro-12,13-dihydro-4bH-isoquinolino[2,1-a]quinazolin-6(5H)-one (3p): White solid (48
o
mg, 55%); mp 210−212 C; IR (MIRꢀATR, 4000−600 cmꢀ1): νmax = 3062, 2920, 1652, 1476, 1259, 737,
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699, 639; H NMR (400 MHz, CDCl3) δ ppm = 2.71 (dd, Ja = 17.1 and Jb = 3.9 Hz, 1H), 3.03−3.11 (m,
1H), 3.5 ( ddd, Ja = 14.2, Jb = 11 and Jc = 5.6 Hz, 1H), 3.95 (dd, Ja = 13.7 and Jb = 5.4 Hz, 1H), 4.35 (d, J
= 15.2 Hz, 1H), 5.64−5.68 (m, 2H), 6.82 (d, J = 8.8 Hz, 1H), 7.02 (d, J = 6.8 Hz, 1H), 7.15−7.21 (m, 2H),
7.23−7.32 (m, 7H), 7.91 (d, J = 2.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ ppm = 24.4, 44.7, 49.8, 71.7,
104.9, 109.8, 115.2, 124.7, 125.8, 126.4, 127.6, 127.7, 128.5, 128.7, 129.1, 129.3, 133.3, 134.5, 136.9,
146.0, 162.4; HRꢀMS (ESI+) m/z calculated for C23H20ClN2O+ = [M+H+]: 375.1259; found: 375.1250.
5-Benzyl-3-methyl-12,13-dihydro-4bH-isoquinolino[2,1-a]quinazolin-6(5H)-one (3q): White solid (47
o
mg, 60%); mp 158−160 C; IR (MIRꢀATR, 4000−600 cmꢀ1): νmax = 3032, 2917, 1647, 1603, 1476, 1384,
1264, 1169, 818, 738, 698; 1H NMR (400 MHz, CDCl3) δ ppm = 2.27 (s, 3H), 2.66 (dd, Ja = 16.6 and Jb =
4.4 Hz, 1H), 3.08 (d, J = 6.4 Hz, 1H), 3.49 (ddd, Ja = 14.2, Jb = 11.2 and Jc = 5.9 Hz, 1H), 4.01 (dd, Ja =
13.9 and Jb = 5.6 Hz, 1H), 4.34 (d, J = 15.7 Hz, 1H), 5.64 (s, 1H), 5.74 (s, 1H), 6.83−6.92 (m, 3H), 6.99−
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7.02 (m, 2H), 7.27−7.34 (m, 6H), 7.97 (dd, Ja = 7.8 and Jb = 1.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
ppm = 21.2, 24.1, 44.7, 49.9, 71.8, 113.6, 118.4, 119.3, 126.4, 127.5, 127.7, 128.7, 129.0, 129.1, 129.5,
131.6, 133.4, 135.8, 137.3, 147.5, 163.5; HRꢀMS (ESI+) m/z calculated for C24H23N2O+ = [M+H+]:
355.1805; found: 355.1799.
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5-Benzyl-8-chloro-3-methyl-12,13-dihydro-4bH-isoquinolino[2,1-a]quinazolin-6(5H)-one (3r): White
o
solid (41 mg, 48%); mp 152−155 C; 48% yield; IR (MIRꢀATR, 4000−600 cmꢀ1): νmax = 2912, 2753,
1649, 1454, 1255, 1103, 889, 809, 732, 698, 640, 589, 539; 1H NMR (400 MHz, CDCl3) δ ppm = 2.27 (s,
3H), 2.66 (dd, J = 16.9 and 4.6, 1H), 3.01−3.09 (m, 1H), 3.48 (ddd, Ja = 14.2, Jb = 11.2 and Jc = 5.9 Hz,
1H), 3.94 (dd, Ja = 13.7 and Jb = 5.9 Hz, 1H), 4.32 (d, J = 15.2 Hz, 1H), 5.61 (s, 1H), 5.72 (d, J = 12.2
Hz, 1H), 6.8 (d, J = 8.8 Hz, 1H), 6.9−6.92 (m, 1H), 6.99−7.01 (m, 2H), 7.24−7.33 (m, 6H), 7.91 (d, J =
2.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ ppm = 21.2, 24.0, 44.8, 50.0, 71.8, 115.1, 119.6, 124.6,
126.3, 127.6, 127.7, 128.7, 129.1, 129.2, 129.3, 131.3, 133.2, 136.0, 137.0, 146.0, 162.4; HRꢀMS (ESI+)
m/z calculated for C24H22ClN2O+ = [M+H+]: 389.1415; found: 389.1408.
5-Benzyl-3-bromo-12,13-dihydro-4bH-isoquinolino[2,1-a]quinazolin-6(5H)-one (3s): White solid (43
mg, 62%); 128−130 oC; IR (MIRꢀATR, 4000−600 cmꢀ1) νmax = 3340, 3057, 2919, 1647, 1603, 1477, 1260,
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1167, 816, 734, 697, 629, 546; H NMR (400 MHz, CDCl3) δ ppm = 2.64 (dd, Ja = 17.1 and Jb = 4.9 Hz,
1H), 3.07−3.11 (m, 1H), 3.5 (ddd, Ja = 14.4, Jb = 11.5 and Jc = 5.9 Hz, 1H), 4.07 (dd, Ja = 14.2 and Jb =
5.9 Hz, 1H), 4.3 (d, J = 15.7 Hz, 1H), 5.6 (s, 1H), 5.81 (d, J = 15.2 Hz, 1H), 6.86−6.89 (m, 3H),
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7.26−7.36 (m, 8H), 7.96 (dd, Ja = 7.8 and Jb = 1.5 Hz, 1H); C NMR (100 MHz, CDCl3) δ ppm = 23.6,
44.3, 50.1, 71.4, 113.4, 118.2, 119.6, 119.9, 127.6, 127.7, 128.6, 128.8, 129.62, 130.9, 131.4, 133.5,
133.6, 136.9, 146.9, 163.1; HRꢀMS (ESI+) m/z calculated for C23H20BrN2O+ = [M+H+]: 419.0754; found:
419.0746.
4b,5,12,13-Tetrahydrobenzo[5,6]thiadiazino[3,4-a]isoquinoline 6,6-dioxide (3t): White solid (47 mg,
70%); mp 218−220 oC; 70% yield; IR (MIRꢀATR, 4000−600 cmꢀ1): νmax = 3231, 2922, 2853, 1597, 1481,
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1449, 1318, 1274, 1158, 748, 662, 610, 556; H NMR (400 MHz, CDCl3) δ ppm = 2.98−3.14 (m, 2H),
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3.46 (ddd, Ja = 12.3, Jb = 8.2 and Jc = 4.4 Hz, 1H), 3.86 (dt, Ja = 12.5 and Jb = 5.3 Hz, 1H), 4.77 (d, J =
12.7 Hz, 1H), 5.98 (d, J = 13.2 Hz, 1H), 6.97 (t, J = 7.6 Hz, 1H), 7.03 (d, J = 8.3 Hz, 1H), 7.20−7.23 (m,
1H), 7.30−7.33 (m, 2H), 7.45 (ddd, Ja = 8.6, Jb = 7.1 and Jc = 1.5 Hz, 1H), 7.6 (dd, Ja = 5.4 and Jb = 3.9
Hz, 1H), 7.78 (dd, Ja = 7.8 and Jb = 1.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ ppm = 29.0, 43.8, 68.5,
116.1, 119.4, 125.3, 125.4, 127.1, 127.7, 128.3, 128.7, 131.7, 133.5, 135.0, 144.5; HRꢀMS (ESI+) m/z
calculated for C15H15N2O2S+ = [M+H+]: 287.0849; found: 287.0845.
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8-Chloro-4b,5,12,13-tetrahydrobenzo[5,6][1,2,4]thiadiazino[3,4-a]isoquinoline 6,6-dioxide (3u): White
o
solid (69 mg, 90%); mp 198−200 C; IR (MIRꢀATR, 4000−600 cmꢀ1): νmax = 3222, 3065, 2925, 2849,
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1597, 1478, 1322, 1160, 734, 666, 621, 554; H NMR (400 MHz, CDCl3) δ ppm = 3.0−3.1 (m, 2H), 3.46
(ddd, Ja = 12.2, Jb = 8.1 and Jc = 4.6 Hz, 1H), 3.78−3.84 (m, 1H), 4.93 (d, J = 12.7 Hz, 1H), 5.95 (d, J =
12.7 Hz, 1H), 7.0 (d, J = 8.8 Hz, 1H), 7.21−7.23 (m, 1H), 7.31−7.38 (m, 3H), 7.57 (dd, Ja = 5.1 and Jb =
3.7 Hz, 1H), 7.7 (d, J = 2.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ ppm = 28.9, 44.0, 68.3, 117.8,
124.3, 124.7, 125.9 , 127.2, 127.7, 128.3, 128.8, 131.2, 133.6, 134.8, 143.1; HRꢀMS (ESI+) m/z calculated
for C15H14ClN2O2S+ = [M+H+]: 321.0459; found: 321.0454.
8-Bromo-4b,5,12,13-tetrahydrobenzo[5,6][1,2,4]thiadiazino[3,4-a]isoquinoline 6,6-dioxide (3v): White
o
solid (70 mg, 82%); mp 200−202 C; IR (MIRꢀATR, 4000−600 cmꢀ1): νmax = 3411, 3027, 2837, 2720,
2253, 2128, 1644, 1593, 1476, 1322, 1164, 1005, 820, 758, 617, 561; 1H NMR (400 MHz, CDCl3) δ ppm
= 2.98−3.10 (m, 2H), 3.43−3.47 (td, Ja = 8.2 and Jb = 4.2 Hz, 1H), 3.78−3.83 (m, 1H), 4.95 (d, J = 12.7
Hz, 1H), 5.93 (d, J = 12.7 Hz, 1H), 6.93 (d, J = 9.3 Hz, 1H), 7.21−7.24 (m, 1H), 7.30−7.35 (m, 2H),
7.47−7.5 (m, 1H), 7.54−7.57 (m, 1H), 7.82 (d, J = 2.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ ppm =
28.9, 43.9, 68.4, 111.2, 117.8, 126.3, 127.3, 127.6, 127.8, 128.3, 128.9, 131.2, 134.8, 136.4, 143.4; HRꢀ
MS (ESI+) m/z calculated for C15H14BrN2O2S+ = [M+H+]: 364.9954; found: 364.9948.
8-Iodo-4b,5,12,13-tetrahydrobenzo[5,6][1,2,4]thiadiazino[3,4-a]isoquinoline 6,6-dioxide (3w): White
o
solid (76 mg, 79%); mp 210−212 C; IR (MIRꢀATR, 4000−600 cmꢀ1): νmax = 3419, 1649, 1402, 1175,
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1006, 821, 759, 618, 568; H NMR (400 MHz, CDCl3) δ ppm = 2.55−2.61 (m, 1H), 2.96−3.13 (m, 1H),
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3.47 (ddd, Ja = 12.1, Jb = 7.5 and Jc = 4.4 Hz, 1H), 3.77−3.83 (m, 1H), 5.9 (d, J = 12.2 Hz, 1H), 6.84 (d, J
= 8.8 Hz, 1H), 7.20−2.22 (m, 1H), 7.29−7.38 (m, 2H), 7.55−7.57 (m, 1H), 7.64 (dd, Ja = 8.8 and Jb = 2
Hz, 1H), 7.98 (d, J = 2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ ppm = 28.9, 43.8, 68.3, 79.9, 117.9,
126.7, 127.3, 127.6, 128.3, 128.9, 131.3, 133.4, 134.8, 142.0, 143.9; HRꢀMS (ESI+) m/z calculated for
C15H14IN2O2S+ = [M+H+]: 412.9815; found: 412.9809.
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3-Methyl-4b,5,12,13-tetrahydrobenzo[5,6][1,2,4]thiadiazino[3,4-a]isoquinoline 6,6-dioxide (3x): White
o
solid (41 mg, 62%); mp 228−230 C; IR (MIRꢀATR, 4000−600 cmꢀ1): νmax = 3205, 2918, 2851, 1715,
1594, 1450, 1319, 1156, 741, 664, 559; 1H NMR (400 MHz, CDCl3) δ ppm = 2.36 (s, 3H), 2.96−3.04 (m,
2H), 3.42 (ddd, Ja = 12.3, Jb = 8.2 and Jc = 4.2 Hz, 1H), 3.83 (dt, Ja = 12.1 and Jb = 5.2 Hz, 1H), 4.78 (d, J
= 12.7 Hz, 1H), 5.92 (d, J = 13.2 Hz, 1H), 6.94−6.96 (m, 1H), 7.05−7.14 (m, 3H), 7.40−7.46 (m, 2H),
7.76 (dd, Ja = 7.8 and Jb = 1.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ ppm = 21.1, 28.6, 43.9, 68.6,
116.1, 119.4, 125.3, 125.4, 128.2, 129.6, 131.4, 131.8, 133.5, 136.9, 144.6; HRꢀMS (ESI+) m/z calculated
for C16H17N2O2S+ = [M+H+]: 301.1005; found: 301.1001.
8-Iodo-3-methyl-4b,5,12,13-tetrahydrobenzo[5,6][1,2,4]thiadiazino[3,4-a]isoquinoline 6,6-dioxide (3y):
o
White solid (64 mg, 68%); mp 218−220 C; IR (MIRꢀATR, 4000−600 cmꢀ1): νmax = 3217, 2921, 2854,
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1469, 1322, 1273, 1160, 929, 798, 730, 665; H NMR (400 MHz, CDCl3) δ ppm = 2.36 (s, 3H), 2.92−
3.05 (m, 2H), 3.41 (ddd, Ja = 12.3, Jb = 8.4 and Jc = 4.2 Hz, 1H), 3.78−3.83 (m, 1H), 4.88 (d, J = 12.7 Hz,
1H), 5.9 (d, J = 12.7 Hz, 1H), 6.81 (d, J = 9.3 Hz, 1H), 7.09−7.14 (m, 2H), 7.38 (s, 1H), 7.66 (dd, Ja = 8.8
and Jb = 2 Hz, 1H), 7.99 (d, J = 2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ ppm = 21.1, 28.5, 43.9, 68.4,
79.9, 117.9, 126.7, 128.0, 128.2, 129.7, 131.0, 131.7, 133.5, 137.1, 142.0, 143.9; HRꢀMS (ESI+) m/z
calculated for C16H16IN2O2S+ = [M+H+]: 426.9972; found: 426.9962.
3-Bromo-4b,5,12,13-tetrahydrobenzo[5,6][1,2,4]thiadiazino[3,4-a]isoquinoline 6,6-dioxide (3z): White
o
solid (54 mg, 65%); mp 228−230 C; IR (MIRꢀATR, 4000−600 cmꢀ1): νmax = 3213, 2924, 2852, 1706,
1598, 1478, 1319, 1161, 738, 548; 1H NMR (400 MHz, CDCl3) δ ppm = 2.90−2.96 (m, 2H), 3.36 (ddd, Ja
= 12.5, Jb = 7.8 and Jc = 4.6 Hz, 1H), 3.74−3.79 (m, 1H), 4.83 (d, J = 12.7 Hz, 1H), 5.81 (d, J = 13.2 Hz,
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1H), 6.87−6.92 (m, 1H), 7.01 (dd, Ja = 10.3 and Jb = 8.8 Hz, 2H), 7.34−7.40 (m, 2H), 7.64−7.67 (m, 2H);
13C NMR (100 MHz, CDCl3) δ ppm = 28.6, 43.7, 67.9, 116.4, 119.8, 120.7, 125.4, 125.5, 130.0, 130.7,
131.9, 133.6, 133.9, 144.2; HRꢀMS (ESI+) m/z calculated for C15H14BrN2O2S+ = [M+H+]: 364.9954;
found: 364.9951.
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4b,6,12,13-Tetrahydrobenzo[4,5][1,3]oxazino[2,3-a]isoquinoline (3aa): White solid (33 mg, 60%); mp
o
115−117 C; IR (MIRꢀATR, 4000−600 cmꢀ1): νmax = 3035, 2933, 2897, 2838, 1602, 1491, 1455, 1389,
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1287, 1228, 1193, 1154, 1056, 1029, 946, 749, 664; H NMR (400 MHz, CDCl3) δ ppm = 2.91 (dt, Ja =
15.9 and Jb = 3.5 Hz, 1H), 3.14 (ddd, Ja = 16, Jb = 10.6 and Jc = 5.1 Hz, 1H), 3.44−3.58 (m, 2H), 4.96 (d,
J = 15.2 Hz, 1H), 5.22 (d, J = 14.7 Hz, 1H), 5.41 (s, 1H), 6.95−7.02 (m, 2H), 7.11 (d, J = 7.8 Hz, 1H),
13
7.17−7.28 (m, 4H), 7.45 (dd, Ja= 5.4 and Jb = 3.9 Hz, 1H). C NMR (100 MHz, CDCl3) δ ppm = 29.8,
46.2, 68.3, 84.4, 121.2, 121.7, 1245.0, 126.3, 126.4, 127.3, 128.3, 128.7, 133.4, 135.3, 146.0; HRꢀMS
(ESI+) m/z calculated for C16H14N+ = [[M+H+]ꢀH2O]: 220.1120; found: 220.1113.
12,13-Dihydrobenzo[4,5][1,3]oxazino[2,3-a]isoquinolin-6(4bH)-one (3ab): White solid (43 mg, 72%);
mp 115−117 oC; IR (MIRꢀATR, 4000−600 cmꢀ1): νmax = 1720, 1607, 1484, 1467, 1399, 1331, 1292, 1229,
1
752; H NMR (400 MHz, CDCl3) δ ppm = 3.1 (t, Ja = 5.9, Jb = 5.9 Hz, 2H), 3.46−3.52 (m, 1H), 3.71−
3.76 (m, 1H), 6.14 (s, 1H), 7.11−7.13 (m, 2H), 7.26−7.24 (m, 1H), 7.33−7.36 (m, 2H), 7.55−7.59 (m,
2H), 8.11 (dd, J = 7.8 Hz, 1.5, 1H); 13C NMR (100 MHz, CDCl3) δ ppm = 29.0, 43.6, 85.7, 117.0, 117.2,
122.0, 127.0, 128.4, 128.6, 129.3, 130.0, 131.0, 134.7, 135.1, 150.0, 165.1; HRꢀMS (ESI+) m/z calculated
+
for C16H14NO2 = [M+H+]: 252.1019; found: 252.1008.
6-Phenyl-4b,6,12,13-tetrahydrobenzo[4,5][1,3]oxazino[2,3-a]isoquinoline (3ac): brown solid (35 mg,
o
52%); mp 60−62 C ; IR (MIRꢀATR, 4000ꢀ600 cmꢀ1): νmax = 3029, 2925, 2834, 1659, 1601, 1487.44,
1
1455, 1391, 1221, 1146, 939, 747, 699, 644; H NMR (400 MHz, CDCl3) δ ppm = 2.85−2.99 (m, 2H),
3.18−3.23 (m, 2H), 3.55−3.60 (m, 2H), 3.71−3.72 (m, 1H), 3.98 (t, J = 5.9 Hz, 1H), 5.36 (s, 1H), 5.68 (s,
1H), 6.04 (s, 1H), 6.21 (s, 1H), 6.74 (d, J = 7.8 Hz, 1H), 6.85−6.88 (m, 1H), 6.97−7.05 (m, 3H),
7.15−7.16 (m, 4H), 7.21−7.25 (m, 4H), 7.29−7.32 (m, 2H), 7.33−7.43 (m, 4H), 7.43−7.51 (m, 7H); 13C,
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HMBC, HSQC NMR (100 MHz, CDCl3) δ ppm = 29.7 (t, ꢀCH2ꢀ), 29.9 (t, ꢀCH2ꢀ), 46.1 (t, ꢀCH2ꢀ), 47.0 (t,
ꢀCH2ꢀ), 77.07 (d, ꢀCHꢀ), 78.2 (d, ꢀCHꢀ), 81.5 (d, ꢀCHꢀ), 84.4 (d, ꢀCHꢀ), 120.9 (d, ArꢀCH), 121.0 (d, Arꢀ
CH), 121.7 (s, ArꢀC), 121.8 (d, ArꢀCH), 122.0 (d, ArꢀCH), 125.8 (s, ArꢀC), 126.3 (d, ArꢀCH), 126.4 (d,
ArꢀCH), 127.3 (d, ArꢀCH), 127.6 (d, ArꢀCH), 127.9 (d, ArꢀCH), 128.0 (d, 2C, ArꢀCH), 128.0 (d, 2C, Arꢀ
CH), 128.1 (d, ArꢀCH), 128.2 (d, 2C, ArꢀCH), 128.3 (s, ArꢀC), 128.4 (d, 2C, ArꢀCH), 128.5 (d, ArꢀCH),
128.5 (d, 2C, ArꢀCH), 128.8 (d, 2C, ArꢀCH), 129.1 (d, ArꢀCH), 129.4 (d, 2C, ArꢀCH), 130.3 (s, ArꢀC),
133.4 (s, ArꢀC), 135.1 (s, ArꢀC), 135.4 (s, ArꢀC), 141.8 (s, ArꢀC), 142.4 (s, ArꢀC), 146.4 (s, ArꢀC).
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12,12',13,13'-Tetrahydro-[5,5'-biisoquinolino[2,1-a]quinazoline]-6,6'(4bH,4'bH)-dione (3ae): White
o
solid (45 mg, 38%); mp 230−232 C; IR (MIRꢀATR, 4000−600 cmꢀ1): νmax = 2903, 1722, 1606, 1466,
1398, 1294, 1241, 1160, 1119, 1032, 951, 750, 697, 639; 1H NMR (400 MHz, CDCl3) δ ppm = 2.90−2.93
(m, 2H), 3.45−3.62 (m, 2H), 6.48 (s, 1H), 7.32−7.49 (m, 1H), 7.50−7.53 (m, 3H), 7.81−7.91 (m, 3H),
8.33−8.35 (m, 1H); 13C NMR (100 MHz, CDCl3) δ ppm = 29.0, 45.0, 72.7, 118.7, 120.3, 121.7, 125.9,
127.7, 128.1, 128.9, 129.6, 130.6, 133.9, 136.4, 150.0, 166.6; HRꢀMS (ESI+) m/z calculated for
+
C32H27N4O2 = [M+H+]: 499.2129; found: 499.2127.
Supporting Information
Experimental procedures and characterization for all new compounds, copies of NMR spectra, and CIF
files (for 3p, 3t and 3ae) provided. This material is available free of charge via the Internet at
http://pubs.acs.org.
Author Contributions
†AHS and SMP contributed equally.
References
1) (a) Walsh, D. P.; Chang, Y. T. Chem. Rev. 2006, 106, 2476ꢀ2530. (b) Ahn, Y. H.; Chang, Y. T.
Acc. Chem. Res. 2007, 40, 1025–1033. (c) Cragg G. M.; Grothaus P. G.; Newman, D. L. Chem.
Rev. 2009, 109, 3012–3043. (d) Newman D. J.; Cragg, G. M. J. Nat. Prod. 2007, 70, 461–477.
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The Journal of Organic Chemistry
1
2
3
4
2) (a) Zhou, L.; Li, Z.; Zou, Y.; Wang, Q.; Sanhueza, I. A.; Schoenebeck, F.; Goeke, A. J. Am.
5
6
7
8
Chem. Soc. 2012
,
134, 20009ꢀ20012. (b) Cruz, F. A.; Chen, Z.; Kurtoic, S. I.; Dong, V.
52, 5836ꢀ5839. (c) Jiao, Z. W.; Tu, Y. Q.; Zhang Q.; Liu,
M. Chem. Commun. 2016
,
9
W.X.; Zhang, S. Y.; Wang, S. H.; Zhang, F. M.; Jiang, S. Nat. Commun. 2015, doi:
10.1038/ncomms8332. (d) Bakthadoss, M.; Kannan, D.; Srinivasan, J.; Vinayagam, V. Org.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Biomol. Chem. 2015, 13, 2870ꢀ2874. (e) Bakthadoss, M.; Kannan, D. RSC Adv. 2014, 4,
11723ꢀ11731. (f) Bakthadoss, M.; Devaraj, A.; Kannan, D. Eur. J. Org. Chem. 2014, 1505ꢀ
1513.
3) Teague, S. J.; Davis, A. M.; Leeson, P. D.; Oprea, T. Angew. Chem., Int. Ed. 1999, 38, 3743–
3748.
4) (a) Renner, S.; Otterlo, W. V.; Seoane, M. D.; Möcklinghoff, S.; Hofmann, B.; Wetzel, S.;
Schuffenhauer, A.; Ertl, P.; Oprea, T. A.; Steinhilber, D.; Brunsveld, L.; Rauh, D.; Waldmann, H.
Nat. Chem. Biol. 2009, 5, 585ꢀ592. (b) Burke, M. D.; Berger, E. M.; Schreiber, S. L. Science
2003, 302, 613–618. (c) Galloway W. R. J. D.; Spring, D. R. Expert Opin Drug Discov. 2009, 4,
467–472.
5) Schreiber, S. L.; Science 2000, 287, 1964–1969.
6) (a) Morton, D.; Leach, S.; Cordier, C.; Warriner, S.; Nelson, A. Angew. Chem. Int. Ed. 2009, 48,
104–109. (b) Kumagai, N.; Muncipinto, G.; Schreiber, S. L. Angew. Chem. Int. Ed. 2006, 45,
3635–3638. (c) Burke, M. D.; Schreiber, S. L. Angew. Chem. Int. Ed. 2004, 43, 46–58. (d)
O'Connor, C. J.; Beckmann, H. S.; Spring, D. R. Chem. Soc. Rev. 2012, 41, 4444–4456.
7) (a) Oguri H.; Schreiber, S.L. Org. Lett. 2005
Kinderman, S. S.; Argueta, C. E.; Beshir, A. B.; Fenteany, G.; Kwon, O. Chem. Eur. J. 2011
17, 649 654.
, 7, 47–50. (b) Wang, Z.; Castellano, S.;
,
–
8) (a) Robbins, D.; Newton, A. F.; Gignoux, C.; Legeay, J. C.; Sinclair, A.; Rejzek, M.; Stockman,
R. A. Chem. Sci. 2011, 2, 2232–2235. (b) Schreiber, S. L. Nature 2009, 457, 153 –154
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The Journal of Organic Chemistry
Page 24 of 26
1
2
3
4
5
6
7
8
9
9) (a) Marcaurelle, L. A.; Comer, E.; Dandapani, S.; Duvall, J. R.; Gerard, B.; Kesavan, S.;
Mulrooney, C. A. J. Am. Chem. Soc. 2010, 132, 16962–16976. (b) Morton, D.; Leach, S.;
Cordier, C.; Warriner, S.; Nelson, A. Angew. Chem. Int. Ed. 2009, 48, 104–109. (c) Kwon, O.;
Park, S. B.; Schreiber, S. L. J. Am. Chem. Soc. 2002, 124, 13402–13404.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
10) (a) Patil, N. T.; Mutyala, A. K.; Lakshmi, P. G.; Raju, P. V.; Sridhar, B. Eur. J. Org. Chem. 2010,
1999–2007. (b) Kumar K.; Waldmann, H. Angew. Chem. Int. Ed. 2009, 48, 1740–1752.
11) (a) Patil, N. T.; Shinde, V. S.; Sridhar, B. Angew. Chem. Int. Ed. 2013, 52, 2251–2255. (b) Liu,
W.; Khedkar, V.; Baskar, B.; Schürmann, M.; Kumar, K. Angew. Chem. Int. Ed. 2011, 50, 6900–
6905. (c) GarciaꢀCastro, M.; Kremer, L.; Reinkemeier, C. D.; Unkelbach, C.; Strohmann, C.;
Ziegler, S.; Kumar, K. Nat. Commun. 2015, doi: 10.1038/ncomms7516.
12) (a) Vidyacharan, S.; Murugan, A.; Sharada, D. S. J. Org. Chem., 2016, 81, 2837–2848. (b)
Vidyacharan, S.; Shinde, A. H.; Satpathi, B.; Sharada, D. S. Green Chem. 2014, 16, 1168–1175.
(c) Vidyacharan, S.; Sagar, A.; Sharada, D. S. Org. Biomol. Chem. 2015, 13, 7614–7618. (d)
Shinde, A. H.; Archith, N.; Malipatel, S.; Sharada, D. S. Tetrahedron Lett. 2014, 55, 6821–6826.
(e) Shinde, A. H.; Vidyacharan, S.; Sharada, D. S. Org. Biomol. Chem. 2016, 14, 3207–3211. (f)
Sagar, A.; Babu, V. N.; Sharada, D. S. RSC Adv. 2015, 5, 29066–29071. (g) Shinde, A. H.;
Vidyacharan, S.; Sharada, D. S. Tetrahedron Lett. 2014, 55, 3064–3069.
13) Pictet, A.; Spengler, T. Chem. Ber. 1911, 44, 2030ꢀ2036.
14) Dhanasekaran, S.; Suneja, A.; Bisai, V.; Singh, V. K. Org. Lett. 2016
15) Dhanasekaran, S.; Bisai, V.; Unhale, R. A.; Suneja A.; Singh, V. K. Org. Lett. 2014
6068 6071.
, 18, 634–637.
,
16
,
–
16) Dhanasekaran, S.; Kayet, A.; Suneja, A.; Bisai V.; Singh, V. K. Org. Lett. 2015
,
17, 2780
–
2783.
17) (a) Hashimoto, T.; Kimura, H.; Kawamata, Y.; Maruoka, K. Nat. Chem. 2011, 3, 642–646.
(b) Hashimoto, T.; Maeda, Y.; Omote, M.; Nakatsu, H.; Maruoka, K. J. Am. Chem. Soc.
ACS Paragon Plus Environment

Page 25 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
2010
2011
,
,
132, 4076
50, 3489
–
4077. (c) Hashimoto, T.; Omote, M.; Maruoka, K. Angew. Chem. Int. Ed.
–
3492.
7
8
9
18) (a) Davis, F. A.; Mohanty, P. K.; Burns, D. M.; Andemichael, Y. W. Org. Lett. 2000
3901 3903. (b) Amat, M.; Elias, V.; Llor, N.; Subrizi, F.; Molins, E.; Bosch, J. Eur. J. Org.
Chem. 2010, 4017 4026.
19) Itoh, T.; Miyazaki, M.; Fukuoka, H.; Nagata, K.; Ohsawa, A. Org. Lett. 2006
20) Li, J. J.; Mei, T. S.; Yu, J. Q. Angew. Chem. 2008 120, 6552 6555.
21) For selected CDC methods see: (a) SchweitzerꢀChaput, B.; Klussmann, M. Eur. J. Org.
Chem. 2013 2013, 666ꢀ671. (b) Ueda, H.; Yoshida, K.; Tokuyama, H. Org. Lett. 2014 16
4194 4197. (c) Baslé, O.; Li, C.ꢀJ. Org. Lett. 2008 3663. (d) Dhineshkumar, J.;
Lamani, M.; Alagiri, K.; Prabhu, K. R. Org. Lett. 2013
Devadig, P.; Prabhu, K. R. Chem. Eur. J. 2012
Wang, Y.; Wang, C.; Liu, X.; Xu, Z.; Lin, L.; Wang, R. Org. Lett. 2015
Huo, C.; Xie, H.; Wu, M.; Jia, X.; Wang, X.; Chen, F.; Tang, J. Chem. Eur. J. 2015
5723 5726.
22) (a) Zhang, C.; De, C. K.; Mal, R.; Seidel, D. J. Am. Chem. Soc. 2008
Murarka, S.; Zhang, C.; Konieczynska, M. D.; Seidel, D. Org. Lett. 2009
Murarka, S.; Deb, I.; Zhang, C.; Seidel, D. J. Am. Chem. Soc. 2009 131, 13226
23) (a) Aalla, S.; Gilla, G.; Bojja, Y.; Anumula, R. R.; Vummenthala, P. R.; Padi, P. R. Org.
Process Res. Dev. 2012 16, 682 686. (b) Breschi, M. C.; Calderone, V.; Digiacomo, M.;
Martelli, A.; Martinotti, E.; Minutolo, S. F.; Rapposelli, S.; Balsamo, A. J. Med. Chem.
2004 47, 5597 5600. (c) Jin, Y. C., Lee, Y. S., Kim, Y. M., Seo, H. G., Lee, J. H., Kim, H.
J.; Chang, K. C. J. Pharmacol. Exp. Ther. 2009 330, 440 448. (d) Liu, W.; Liu, S.; Jin, R.;
Guo, H.; Zhao, J. Org. Chem. Front 2015 , 288 299. (e) Wright, A. E.; Forleo, D. A.;
Gunawardana, G. P.; Gunasekera, S. P.; Koehn F. E.; McConnell, O. J. J. Org. Chem. 1990
55, 4508 4512. (f) Möcklinghoff, S.; Otterlo, W. V.; Rose, R.; Fuchs, S.; Zimmermann, T.
, 2,
–
10
11
12
13
14
15
16
17
18
19
20
21
22
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31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
–
, 8, 1295–1297.
,
–
,
,
,
–
,
10, 3661
–
,
15, 1092–1095. (e) Alagiri, K.;
,
18, 5160
–
5164. (f) Chen, Q.; Zhou, J.;
17, 4212 4215. (g)
21
,
–
,
,
–
,
130, 416
11, 129
13227.
–
417. (b)
,
–
132. (c)
,
–
,
–
,
–
,
–
.
,
2
–
,
–
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Page 26 of 26
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3
4
J.; Seoane, M. D.; Waldmann, H.; Ottmann, C.; Brunsveld, L. J. Med. Chem. 2011, 54, 2005ꢀ
5
6
2011.
7
8
9
24) Malamas, M. S.; Stange, H.; Schindler, R.; Lankau, H. J.; Grunwald, C.; Langen, B.; Fan, K.
Y. Bioorg. Med. Chem. Lett. 2012 22, 5876 5884.
25) Sharma, M.; Pandey Snyder, D. S.; Tradtrantip, L.; Yao, C.; Kurth, M. J.; Verkman, A. S. J.
Med. Chem. 2011 54, 5468 5477.
26) Yanagihara, Y.; Kasai, H.; Kawashima, T.; Shida, T. Jpn. J. Pharmacol. 1988
10
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27
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47
48
49
50
51
52
53
54
55
56
57
58
59
60
,
–
,
–
,
48, 91–101.
27) (a) Sharma, M.; Pandey, S.; Chauhan, K.; Sharma, D.; Kumar, B.; Chauhan, P. M. J. Org. Chem.
2012, 77, 929–937. (b) Ghosh, S. K.; Nagarajan, R. RSC Adv. 2016, 6, 27378ꢀ27387.
28) Phillips, D.; Sonnenberg, J.; Arai, A. C.; Vaswani, R.; Krutzik, P. O.; Kleisli, T.;
Chamberlin, A. R. Bioorg. Med. Chem. 2002
29) (a) For iminium ion formation see: Yang, R.; Gao, Z.ꢀF.; Zhao, J. Y.; Li, W.ꢀB.; Zhou, L.;
Miao, F. J. Agric. Food Chem. 2015 63, 1906ꢀ1914. (b) We have performed the reaction of
, 10, 1229–1248.
,
2ꢀ(2ꢀbromoethyl)benzaldehyde (1a) with aniline under DCE solvent to give the 2ꢀphenylꢀ
1
3,4ꢀdihydroisoquinolinꢀ2ꢀium bromide salt, which was characterised by the H and 13C
NMR, thus supporting the proposed mechanism.
30) Zhou, M. Y.; Kong, S. S.; Zhang, L. Q.; Zhao, M.; Duan, J. A.; Ouꢀyang, Z.; Wang, M.
Tetrahedron Lett., 2013, 54, 3962–3964.
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