Regioselective synthesis of functionalized dihydroisoquinolines from: O -alkynylarylaldimines via the Reformatsky reaction

Article abstract of DOI:10.1039/c6ob01790h

A novel approach for the synthesis of functionalized 1,2-dihydroisoquinolines from o-alkynylarylaldimines via the Reformatsky reaction without the aid of an external Lewis acid has been described. The chemistry involves the dual role of the Reformatsky reagent which has been generated in situ in the reaction. We propose that one molecule of the Reformatsky reagent is being utilised for the activation of alkynes, whereas the second molecule acts as a nucleophile on the iminium carbon. This synthetic pathway has high functional group tolerance, and can be utilized on a gram scale. The proposed mechanistic pathway is well supported by the control experiments. The 1,2-dihydroisoquinoline derivatives showed up to 90% inhibition of the strand transfer activity of the HIV integrase enzyme.

Full text of DOI:10.1039/c6ob01790h

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Regioselective synthesis of functionalized
dihydroisoquinolines from o-alkynylarylaldimines
via the Reformatsky reaction†
Cite this: DOI: 10.1039/c6ob01790h
Tohasib Yusub Chaudhari,a Urvashi,b Sandeep K. Ginotra,c Pooja Yadav,b
Gulshan Kumarb and Vibha Tandon*a,b
A novel approach for the synthesis of functionalized 1,2-dihydroisoquinolines from o-alkynylarylaldimines
via the Reformatsky reaction without the aid of an external Lewis acid has been described. The chemistry
involves the dual role of the Reformatsky reagent which has been generated in situ in the reaction. We
propose that one molecule of the Reformatsky reagent is being utilised for the activation of alkynes,
whereas the second molecule acts as a nucleophile on the iminium carbon. This synthetic pathway has
high functional group tolerance, and can be utilized on a gram scale. The proposed mechanistic pathway
is well supported by the control experiments. The 1,2-dihydroisoquinoline derivatives showed up to 90%
inhibition of the strand transfer activity of the HIV integrase enzyme.
Received 16th August 2016,
Accepted 21st September 2016
DOI: 10.1039/c6ob01790h
www.rsc.org/obc
have wide utility in medicinally active scaffolds,4a natural pro-
Introduction
ducts,4b and pharmaceutically active agents having anti-HIV,4c
The C–C and C–N bond formation has emerged as a potent anti-tumour,4d topoisomerase-I inhibitors,4e and anti-cancer
tool for the generation of fused heterocycles. In the last activity (Fig. 1).4f They are also utilized in materials sciences
century, the Reformatsky reaction has found wide application owing to their positive physicochemical properties.5 Therefore,
in the construction of C–C bonds via ester-stabilized organo- divergent approaches have been reported in the last two
zinc reagents followed by addition to carbonyl compounds.1a decades for the construction of these motifs using transition
Due to the low basicity of zinc enolates, it is difficult to find metals such as silver,6a–c indium,6d gold,6e,f palladium6g and
any competition from proton transfer and the scope of carbo- copper.6h,i Larock and co-workers7a–f pioneered the synthesis
nyl addition partners is quite broad. It is noteworthy that their of isoquinolines via electrophilic iodocyclization. Later
low nucleophilic reactivity compared to other reagents Yamamoto et al.7g,h and Wu et al.7i,j have demonstrated the
becomes an advantage and involves a better chemoselectiv- synthesis of 1,2-dihydroisoquinolines by using AgOTf and
ity.1a–d It is extensively explored for the synthesis of bioactive Mg/Cu bimetallic systems respectively (Scheme 1, i and ii). In
compounds, for example αvβ3 integrin antagonists,2a tonantzi- 2013, Verma et al.8a investigated AgNO3 alongwith the proline
tlolones,2b antifungal agents,2c ansamycins2d and leustroduc- catalyzed tandem synthesis of N-heterocycles via a three com-
sin B.2e In recent years, extension of this reagent has been ponent reaction (Scheme 1, iii). Subsequently Asao8b–c and
reported with an increased substrate scope towards electro- Takemoto8d research groups have developed the synthesis of
philes such as imines, nitriles and esters.3
isoquinoline derivatives via pronucleophiles. In recent years,
The synthesis of N-containing heterocycles became a step- base promoted,9 cycloaddition10 and C–H functionalization11
ping stone in organic synthesis. Particularly, isoquinoline, tetra- reactions were also employed to obtain the isoquinoline core
hydroisoquinoline and 1,2-dihydroisoquinoline derivatives
aSpecial Centre for Molecular Medicine, Jawahar Lal Nehru University,
New Delhi-110067, India. E-mail: vtandon@mail.jnu.ac.in, vibhadelhi6@gmail.com
bDepartment of Chemistry, University of Delhi, New Delhi-110007, India
cSyngene International Ltd, Biocon Park, Plot # 2 & 3, Phase IV, Bommasandra,
Jigani Link Road, Bengaluru, Karnataka-560099, India
†Electronic supplementary information (ESI) available: Experimental procedure
characterization data, 1H & 13C NMR spectra and HRMS of all compounds.
CCDC 1062612 and 1420734. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c6ob01790h
Fig. 1 Biologically important 1,2-dihydroisoquinolines.
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Table 1 Optimization of reaction conditionsa
2a
(equiv.)
Zn
(equiv.)
T (°C)/
t (h)
Yieldb
(%)
Entry
Solvent
1
1
2
2
2
2
2
2
3
2
2
2
2
2
2
2
3
3
3
4
4
4
4
4
4
THF
THF
68/3
68/3
70/3
70/3
80/3
80/1.5
80/1.5
80/1.5
100/3
100/1.5
110/1.5
110/1.5
20
35
50
55
63
63
86
83
40
76
N.R.
N.R.
2
3c
4c
5
THF : CH3CN
THF : CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
Dioxane
Toluene
DMF
6
7
8
9
10
11
12
DMA
a Reaction conditions: 1a (0.5 mmol), solvent (3 mL) under N2.
b Isolated yield. c THF : CH3CN (3 : 1) N.R. = No reaction.
Scheme 1 Previous synthetic approaches and our designed approach.
Using THF : CH3CN in 3 : 1 ratio provided the product 3a in
50–55% yield (entries 3 and 4). The desired product 3a was
obtained in 63% yield when acetonitrile was used as the sole
solvent (entry 5). No significant change in the yield of product
3a was observed on lowering the reaction time (entry 6).
Further increasing the amount of Zn-dust to 4.0 equiv.
afforded the cyclised product 3a in 86% yield (entry 7).
A similar yield of the product 3a was obtained by increasing
the stoichiometric amount of bromoethylacetate 2a (entry 8).
Solvents such as 1,4-dioxane, toluene, DMF and DMA did not
provide the profitable results (Table 1, entries 9–12).
With the optimized reaction conditions in hand, the scope
and generality of the reaction were determined on a variety of
non-activated o-alkynylarylaldimines 1a–j and bromoesters
2a–e (Table 2). The reaction of halo-substituted imines 1a–c
with bromoester 2a afforded the desired products 3a–c in 86,
87 and 61% yields respectively. Electron-rich and electron
neutral aldimines underwent intramolecular 6-endo-dig cycliza-
tion smoothly to provide 1,2-dihydroisoquinolines 3d–f in
moderate to good yields. The substrates 1g–h bearing cyclopro-
pyl and n-propyl groups as R2 gave the desired products 3g–h
in 75–68% yields. Interestingly, the scope of the reaction can
be extended to the strong electron withdrawing group contain-
ing alkyne substrate 1i to afford product 3i in 65% yield. When
nucleus. To the best of our knowledge the synthesis of iso-
quinoline using the Reformatsky reaction is still unknown.
The research activity of our group is mainly focused on the
construction of biologically active N-heterocycles. We achieved
the synthesis of copper catalyzed indolo-isoquinolines12a and
later 1,2-dihydroisoquinolines through 6-endo dig cyclization
using a cobalt catalyst.12b Subsequently we disclosed their bio-
logical activity as potential HIV-1 integrase inhibitors.12c In
continuation of our ongoing research to explore a novel cata-
lytic system for various organic transformations,13 we were
prompted to establish a new methodology for the synthesis of
highly functionalized 1,2-dihydroisoquinolines, which are
difficult to access by other reported procedures.
Herein, we have developed a facile route for the synthesis of
1,2-dihydroisoquinoline motifs via 6-endo-dig cyclization using
the Reformatsky reagent. The developed methodology provides
an easy access to 1,2-dihydroisoquinolines from inexpensive
and readily accessible α-bromoesters in good to excellent yields.
Results and discussion
To identify the optimal conditions for the reaction, a variety of the steric hindering tert-butyl group was employed in 2c as R3,
combinations of organic solvents under varied conditions were the reaction was well implemented to form intriguing cyclized
examined in the reaction of 4-bromo-N-(2-(phenylethynyl) products 3j–o in 62–80% yields. The reaction of bromomethyl-
benzylidene)aniline 1a with bromoethylacetate 2a (Table 1). acetate 2d with electronically biased aldimines (1a, 1e, 1f, 1i
Inspired from the literature procedure, we performed the reac- and 1j) afforded the desired products 3p–t in good to excellent
tion of 1a with bromoester 2a (1.0 equiv.) using tetrahydro- yields. A comparable yield of 3u was obtained when the
furan (THF) as a solvent at 68 °C for 3 h, and only 20% of the benzylic substituted bromoester 2e was used. These results
desired product 3a was obtained (Table 1, entry 1), whereas the suggest that the electronic and steric factors of organozinc
yield was increased to 35% using 2 equivalents of 2a (entry 2). reagents do not have much influence on the reaction con-
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Table 2 Scope of o-alkynylarylaldimines and bromoestersa,b
ditions (Table 2). The reaction of aldimine 1c with ethyl 2-bro-
mopropionoate 2b provided the product 3v in 60% yield.
We then further employed the same protocol to examine its
scope for the Reformatsky reaction of substituted o-alkynyl-
arylaldimines 1k–n with functionally varied bromoesters
(Table 3). The reaction proceeded well with an electron with-
drawing fluoro R3 group, which provided the fused dihydro-
isoquinoline scaffolds 3w–za in 70–92% yields. The reaction
also accommodated the –OMe substituents at the C-3 position
of aldimine 1n to provide the desired heterocyclic product 3za
in 46% yield (Table 3). Due to the steric factor, it was a signifi-
cant challenge to achieve the Reformatsky reaction of 4-bromo-
N-(2-(phenylethynyl)benzylidene)aniline 1a–1b with ethyl
2-bromo-2-fluoroacetate 2f. The established reaction con-
ditions were appropriate for providing the desired products
3zb and 3zc in 74 and 71% yield respectively (Scheme 2).
In order to assess the utility of the developed protocol, the
reaction of 1a was performed on the gram scale (Scheme 3).
Fortunately, the reaction conditions were found to be suitable
for producing the corresponding product 3a in 70% yield.
The structures of 1,2-dihydroisoquinoline analogues 3a and
3m were unambiguously confirmed by X-ray diffraction ana-
Table 3 Scope of substituted o-alkynylarylaldiminesa,b
a Conditions: 1 (k–n) (0.5 mmol), 2 (1 mmol), Zn dust (2 mmol),
CH3CN (5 mL) at 80 °C under N2. b Isolated yields. c 2 mmol of
α-halogenated esters were used.
a Conditions: 1 (a–j) (0.5 mmol), 2 (a–e) (1 mmol), Zn dust (2 mmol),
CH3CN (5 mL) at 80 °C under N2. b Isolated yields. c 2 mmol of
α-halogenated esters were used.
Scheme 2 Scope of dihaloesters.
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Reformatsky reagent in 6-endo-dig cyclization, an isoquino-
linium salt 4a was treated with Reformatsky reagents (5) (pre-
pared via addition of 2a and Zn in 1 : 2 ratio), and the antici-
pated product 3a was obtained in 85% yield, suggesting that
the reaction proceeds via the isoquinolinium intermediate and
consequently the second molecule of the Reformatsky reagent
attacks as a nucleophile to afford the desired product 3a
(Scheme 4a). Furthermore, two sets of control experiments
were performed in the presence of 0.3 and 1.0 equiv. of zinc
bromide along with 1.0 equiv. of the Reformatsky reagent,
which gave the desired product 3a in 10% and 30% yields
respectively. This result clearly indicates that the in situ gener-
ated zinc bromide does not activate the alkyne to undergo
intramolecular 6-endo-dig cyclization (Scheme 4b).
Scheme 3 Gram scale reaction.
Interestingly, when the addition of 1a with the Reformatsky
reagent 5 was performed in an NMR tube using CD3CN as the
solvent at room temperature, we came across another crucial
reaction intermediate 4b which was confirmed by 13C NMR
(Scheme 4c; see the ESI†). In order to establish the source of
hydrogen in the cyclised product 3a, two different sets of
control experiments were performed in CD3CN and CH3CN as
solvents. The deuterated product 3ab was not observed while
using CD3CN as the solvent followed by aqueous work-up
(Scheme 4d). However, the reaction performed in CH3CN on
quenching with D2O provided the product 3ab in 75% yield
with 80% deuterium incorporation. The latter experiment con-
firms that the source of the cyclized proton is not from the
solvent but from the aqueous work-up (Scheme 4e).
On the basis of the preliminary mechanistic studies, a
plausible reaction mechanism is proposed in Scheme 5.
Initially, an ester-stabilized organozinc reagent A was formed
in the presence of zinc dust followed by the activation of the
triple bond of o-alkynylarylaldimine 1a to form species B.
Then 6-endo dig cyclization occurs to form the isoquinolinium
intermediate 4b. Subsequent attacks of nucleophile 5 would
produce an ester intermediate C. Finally, the quenching of
species C with aq. NH4Cl leads to the formation of 1,2-di-
hydroisoquinoline 3a.
Fig. 2 ORTEP drawing of compounds 3a and 3m drawn at the 50%
probability level.
lysis of high quality crystals (Fig. 2).14 It revealed that the 1,2-
dihydroisoquinoline backbone lies at 116.3° and 123.4° to the
phenyl rings attached to the nitrogen atom and alkene carbon,
respectively, producing a stable configuration.
To validate our hypothesis, various mechanistic studies and
deuterium labelling experiments were performed which are
summarized in Scheme 4. To identify the role of the
Scheme 4 Mechanistic studies.
Scheme 5 Plausible mechanism.
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Table 4 Inhibitory potency and mutation profiles of RAL and potent
compounds
CD3CN solvents using TMS as the internal standard at 25 °C.
HRMS (m/z) were recorded on an Accurate-mass Q-TOF LC/MS
mass spectrometer. Infrared (IR) spectra were recorded by
Fourier transform infrared spectroscopy. Melting points were
determined in Buchi B-540 apparatus and are uncorrected.
Zinc dust (20 g) was stirred in 100 mL of 0.1 N HCl in distilled
water for 5 min and repeatedly washed with 3 × 100 mL of dis-
tilled water followed by 100 mL of acetone and dried at 110 °C
in a vacuum for 10–12 h to obtain activated zinc.
CC50 on TZM-bl
cells (μM)
% ST inhibition at
Entry
10 μM dose in WTa
RAL
3j
3t
>200
64
67
94.7 2.3
90
90
a ST; % inhibition of the strand transfer activity of integrase enzyme.
RAL = Raltegravir.
General procedure for the synthesis of o-alkynylaryl/
acylaldimines (1a–1m)8d
Our group has earlier evaluated the nitromethane ana-
logues of 1,2-dihydroisoquinolines12b and established them as
potent HIV integrase inhibitors active against raltegravir (RAL)
resistant HIV mutant strains.12c HIV integrase is responsible
for integration of the HIV genome with the host genome. The
present analogues were also evaluated as HIV integrase inhibi-
tors using a standard method12c and they showed good thera-
peutic activity. The oxygen atoms of the acetate moiety in the
present compounds might chelate with one of the Mg2+ ions
essential for the strand transfer activity of the integrase
enzyme.15
For the preparation of o-alkynylaldehydes, the standard
Sonogashira reaction was used. To a solution of o-alkynylaryl-
aldehyde (1 mmol) and aniline (1 mmol) in DCM (10 mL), 4 Å
MS were added at room temperature and stirred for 12 to 24 h.
After completion of the reaction as indicated by TLC, the reac-
tion mixture was filtered through a Celite bed. The filtrate was
concentrated under reduced pressure and the product
obtained was used for the next reaction without further
purification.
(E)-4-Bromo-N-(2-(phenylethynyl)benzylidene)aniline (1a).
1
Yellow solid, mp: 76–78 °C. H NMR (400 MHz, CDCl3): δ 9.06
Pleasantly, all the compounds showed HIV-IN inhibition at
10 µM concentration (Table 4). Compounds 3j and 3t showed
90% inhibition of the strand transfer activity of HIV-IN, in an
in vitro assay, an activity of integrase.
(s, 1H), 8.24 (d, J = 6.8 Hz, 1H), 7.62–7.60 (m, 1H), 7.53–7.50
(m, 4H), 7.58–7.40 (m, 2H), 7.37–7.36 (m, 3H), 7.15 (d, J = 8.4
Hz, 2H); 13C NMR (100 MHz, CDCl3): δ 158.8, 152.0, 136.6,
132.7, 131.5, 130.9, 129.2, 128.7, 128.6, 128.4, 126.6, 126.1,
125.0, 122.7, 121.0, 95.3, 86.2; 1H NMR (400 MHz, CD3CN):
δ 9.07 (s, 1H), 8.19 (d, J = 7.6 Hz, 1H), 7.67–7.65 (m, 2H),
7.57–7.49 (m, 5H), 7.41–7.40 (m, 3H), 7.19 (d, J = 8.39 Hz, 2H);
13C NMR (100 MHz, CD3CN): 160.1, 152.0, 137.3, 133.7, 133.2,
132.4, 130.1, 129.9, 129.7, 127.4, 125.8, 123.9, 123.3, 120.0,
118.3, 96.3, 86.8; HRMS (ESI) m/z for C21H15BrN (M + H)+, cal-
culated 360.0387, found 360.0381.
Conclusions
In conclusion, we have designed a new approach for the syn-
thesis of biologically active 1,2-dihydroisoquinolines from
easily accessible o-alkynylarylaldimines and α-bromo esters
with high functional group tolerance. Notably, the mechanistic
studies revealed that the Reformatsky reagent acts as a Lewis
acid to activate the alkyne as well as a nucleophile. The
mechanistic pathway has been established by the control
experiments, suggesting that the reaction proceeds via the iso-
quinolinium intermediate. The deuterium labelling experi-
ments confirm that the source of the cyclized proton is
through aqueous work-up. The 1,2-dihydroisoquinolines have
shown up to 90% inhibition of the strand transfer activity of
HIV-IN.
(E)-4-Fluoro-N-(2-(phenylethynyl)benzylidene)aniline (1b).
1
Yellow solid, mp: 85–87 °C. H NMR (400 MHz, CDCl3): δ 9.07
(s, 1H), 8.24 (d, J = 7.6 Hz, 1H), 7.62–7.59 (m, 1H), 7.54–7.52
(m, 2H), 7.47–7.43 (m, 2H), 7.37–7.36 (m, 3H), 7.27–7.24 (m,
2H), 7.09 (t, J = 8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3):
δ 161.4 (d, J = 245.9 Hz, 1C), 158.6, 148.0, 136.5, 132.7, 131.5,
130.9, 128.6 (d, J = 7.6 Hz, 1C), 128.4, 126.4, 125.0, 122.6, 122.4
(d, J = 8.5 Hz, 1C), 115.9 (d, J = 22.8 Hz, 1C), 95.4, 86.2; HRMS
(ESI) m/z for C21H15FN (M + H)+, calculated 300.1188, found
300.1165.
(E)-4-Chloro-N-(2-(phenylethynyl)benzylidene)aniline (1c).
Yellow solid, mp: 98–100 °C. 1H NMR (400 MHz, CDCl3): δ 9.06
(s, 1H), 8.25–8.23 (m, 1H), 7.62–7.60 (m, 1H), 7.54–7.51 (m,
2H), 7.48–7.41 (m, 2H), 7.38–736 (m, 5H), 7.20 (d, J = 9.1 Hz,
Experimental section
General information
The reactions for all air sensitive reagents were performed 2H); 13C NMR (100 MHz, CDCl3): δ 159.2, 150.5, 136.3, 132.7,
under a dry nitrogen atmosphere using dried and distilled sol- 131.7, 131.5, 131.1, 129.3, 128.8, 128.7, 128.5, 126.6, 125.2,
vents. TLC was visualized with UV light (254 and 365 nm), 122.6, 122.3, 95.5, 86.1; HRMS (ESI) m/z for C21H15ClN (M +
iodine or by charring the plate dipped in ninhydrin solution. H)+, calculated 316.0893, found 316.0887.
The purification of the compound was performed by column
(E)-4-Methyl-N-(2-(phenylethynyl)benzylidene)aniline (1d).
1
chromatography using silica gel of 100–200 mesh size. 1H Yellow solid, mp: 67–69 °C. H NMR (400 MHz, CDCl3): δ 9.12
NMR and 13C NMR spectra were recorded at 400 or 500 MHz (s, 1H), 8.28–8.26 (m, 1H), 7.61–7.59 (m, 1H), 7.55–7.52 (m,
and 100 or 125 MHz frequency respectively in CDCl3 and 2H), 7.44–7.42 (m, 2H), 7.37–7.35 (m, 3H), 7.24–7.19 (m, 4H),
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2.38 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 158.0, 149.4, 136.8,
(E)-4-Chloro-N-(5-fluoro-2-(p-tolylethynyl)benzylidene)aniline
136.1, 132.6, 131.5, 130.7, 129.8, 128.7, 128.4, 126.5, 124.9, (1k). Yellow solid, mp: 126–128 °C. 1H NMR (400 MHz, CDCl3):
122.8, 120.9, 95.3, 86.3, 21.0; HRMS (ESI) m/z for C22H18N δ 9.01 (s, 1H), 7.94 (dd, J = 9.9, 3.0 Hz, 1H), 7.58 (dd, J = 8.4,
(M + H)+, calculated 296.1439, found 296.1456.
5.3 Hz, 1H), 7.42–7.36 (m, 4H), 7.22–7.14 (m, 5H), 2.38 (s, 3H);
(E)-4-Methoxy-N-(2-(phenylethynyl)benzylidene)aniline (1e). 13C NMR (100 MHz, CDCl3): 162.5 (d, J = 252.6 Hz, 1C), 157.9,
This compound was previously reported by Takemoto et al.8d 149.9, 139.1, 138.6 (d, J = 9.5 Hz, 1C), 134.5 (d, J = 7.6 Hz, 1C),
1
Yellow solid, mp: 76–78 °C. H NMR (400 MHz, CDCl3): δ 9.12 132.0, 131.3, 129.3, 129.2, 122.3, 121.4, 119.3, 118.6 (d, J = 22.8
(s, 1H), 8.27–8.25 (m, 1H), 7.61–7.59 (m, 1H), 7.56–7.53 Hz, 1C), 112.8 (d, J = 22.8 Hz, 1C), 95.4, 84.5, 21.6; HRMS (ESI)
(m, 2H), 7.44–7.42 (m, 2H), 7.38–7.36 (m, 3H), 7.30 (d, J = m/z for C22H16ClFN (M + H)+, calculated 348.0955, found
8.4 Hz, 2H), 6.95 (d, J = 8.4 Hz, 2H), 3.84 (s, 3H); HRMS (ESI) 348.0932.
m/z for C22H18NO (M + H)+, calculated 312.1388, found
312.1392.
(E)-N-(5-Fluoro-2-(phenylethynyl)benzylidene)aniline
Yellow solid, mp: 83–85 °C. H NMR (400 MHz, CDCl3): δ 9.05
(1l).
1
(E)-N-(2-(Phenylethynyl)benzylidene)aniline (1f). Yellow (d, J = 2.2 Hz, 1H), 7.98 (dd, J = 9.9, 3.0 Hz, 1H), 7.60 (dd, J =
solid, mp: 61–63 °C. 1H NMR (400 MHz, CDCl3): δ 9.10 (s, 1H), 9.1, 5.3 Hz, 1H), 7.45–7.41 (m, 2H), 7.43 (t, J = 7.6 Hz, 2H),
8.29–8.26 (m, 1H), 7.62–7.60 (m, 1H), 7.54–7.52 (m, 2H), 7.38–7.36 (m, 3H), 7.28–7.26 (m, 3H), 7.16 (td, J = 7.6, 2.2 Hz,
7.46–7.39 (m, 4H), 7.36–7.34 (m, 3H), 7.30–7.23 (m, 3H); 1H); 13C NMR (100 MHz, CDCl3): 162.6 (d, J = 251.7 Hz, 1C),
13C NMR (100 MHz, CDCl3): δ 158.8, 152.0, 136.6, 132.7, 131.5, 157.4, 151.4, 139.0, 138.9, 134.5 (d, J = 7.6 Hz, 1C), 131.5,
130.9, 129.2, 128.7, 128.6, 128.4, 126.6, 126.1, 125.0, 122.7, 129.2, 128.7, 128.4, 126.5, 122.5, 121.0, 118.4 (d, J = 22.8 Hz,
121.0, 95.4, 86.2; HRMS (ESI) m/z for C21H16N (M + H)+, calcu- 1C), 113.1 (d, J = 22.8 Hz, 1C), 94.9, 85.3; HRMS (ESI) m/z for
lated 282.1282, found 282.1289.
C21H15FN (M + H)+, calculated 300.1188, found 300.1168.
(E)-4-Bromo-N-(2-(cyclopropylethynyl)benzylidene)aniline (1g).
(E)-N-(5-Fluoro-2-(phenylethynyl)benzylidene)-4-methoxy-
Brown oil, 1H NMR (400 MHz, CDCl3): δ 8.91 (s, 1H), 8.21–8.14 aniline (1m). This is earlier reported by Takemoto et al.8d
1
(m, 1H), 7.52 (d, J = 8.4 Hz, 2H), 7.45–7.43 (m, 1H), 7.40–7.32 Yellow solid, mp: 97–99 °C. H NMR (400 MHz, CDCl3): δ 9.07
(m, 2H), 7.13–7.07 (m, 2H), 1.53–1.46 (m, 1H), 0.94–0.87 (m, (d, J = 2.2 Hz, 1H), 7.96 (dd, J = 9.9, 3.0 Hz, 1H), 7.60–7.52 (m,
2H), 0.85–0.79 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 159.4, 3H), 7.38–7.37 (m, 3H), 7.31 (d, J = 9.1 Hz, 2H), 7.14 (td, J = 8.4,
150.8, 136.1, 132.9, 132.4, 131.8, 130.7, 128.7, 127.5, 126.0, 3.0 Hz, 1H), 6.96 (d, J = 9.1 Hz, 2H), 3.84 (s, 3H); HRMS (ESI) m/z
122.4, 119.0, 99.8, 72.1, 8.5, 0.1; HRMS (ESI) m/z for C18H15BrN for C22H17FNO (M + H)+, calculated 330.1294, found 330.1282.
(M + H)+, calculated 324.0387, found 324.0366.
(E)-4-Fluoro-N-(2-(pent-1-yn-1-yl)benzylidene)aniline
(E)-N-(5-Methoxy-2-(phenylethynyl)benzylidene)aniline (1n).
(1h). Brown solid, mp: 93–96 °C. H NMR (400 MHz, CDCl3): δ 9.07
1
Brown oil, 1H NMR (400 MHz, CDCl3): δ 8.99 (s, 1H), 8.19–8.17 (s, 1H), 7.79–7.78 (m, 1H), 7.53–7.50 (m, 3H), 7.44–7.40 (m,
(m, 1H), 7.51–7.46 (m, 1H), 7.41–7.34 (m, 2H), 7.25–7.21 2H), 7.35–7.33 (m, 3H), 7.28–7.24 (m, 3H), 7.02 (dd, J = 9.1, 3.0
(m, 2H), 7.09 (t, J = 8.4 Hz, 2H), 2.45 (t, J = 7.2 Hz, 2H), Hz, 1H), 3.91 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 159.8,
1.70–1.62 (m, 2H), 1.06 (t, J = 10.6 Hz, 3H); 13C NMR 158.8, 151.9, 138.1, 133.9, 131.4, 129.2, 128.4, 126.2, 123.0,
(100 MHz, CDCl3): δ 160.5 (J = 244.0 Hz, 1C), 158.3, 147.5, 121.0, 119.0, 117.7, 115.0, 109.3, 94.0, 86.3, 55.6; HRMS (ESI)
135.7, 132.7 (J = 20 Hz, 1C), 131.9, 130.1, 127.2, 125.5, 121.7 m/z for C22H18NO (M + H)+, calculated 312.1388, found
(J = 10 Hz, 1C), 115.0 (J = 10 Hz, 1C), 96.0, 77.0, 21.4, 20.8, 312.1369.
12.8; HRMS (ESI) m/z for C18H17FN (M + H)+, calculated
266.1345, found 266.1347.
General experimental procedure for the synthesis of 1,2-
dihydroisoquinolines (3a–3zc)
(E)-4-Bromo-N-(2-((4-(trifluoromethyl)phenyl)ethynyl)benzyli-
dene)aniline (1i). Brown solid, mp: 92.8–95.6 °C. 1H NMR To a heterogeneous solution of Zn dust (2 mmol, 4 equiv.) in
(400 MHz, CDCl3): δ 9.02 (s, 1H), 8.27–8.25 (m, 1H), 7.62 (s, CH3CN (5 mL), α-bromoester (1–2.5 mmol, 2–5 equiv.) was
5H), 7.52 (d, J = 8.4 Hz, 2H), 7.49–7.47 (m, 2H), 7.13 (d, J = added dropwise with vigorous stirring and the reaction
8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ 158.8, 150.9, 136.5, mixture was refluxed (80 °C) for 0.5 h, followed by an addition
132.9, 132.3, 131.9, 131.7, 131.2, 130.7 (q, J = 29.5 Hz), 129.3, of o-alkynylarylaldimine (0.5 mmol) and the reaction mixture
126.8, 126.4, 125.4 (q, J = 3.8 Hz), 124.3, 122.7, 119.7, 93.9, was stirred for 1–6 h at the same temperature. After completion
88.4; HRMS (ESI) m/z for C22H14BrF3N (M + H)+, calculated of the reaction as indicated by TLC, the reaction mixture was
428.0261, found 428.0256.
cooled to room temperature and quenched with a saturated
(E)-4-Fluoro-N-(2-(p-tolylethynyl)benzylidene)aniline
(1j). solution of NH4Cl (10 mL). The organic layer was extracted with
1
Yellow solid, mp: 84–86 °C. H NMR (400 MHz, CDCl3): δ 9.08 ethyl acetate (2 × 20 mL). The combined organic layer was
(s, 1H), 8.25–8.23 (m, 1H), 7.61–7.58 (m, 1H), 7.46–7.40 (m, washed with distilled water (2 × 10 mL) and brine solution
4H), 7.27–7.24 (m, 2H), 7.17 (d, J = 7.6 Hz, 2H), 7.09 (t, J = 8.4 (10 mL), dried over anhyd. Na2SO4, filtered and concentrated
Hz, 2H), 2.38 (s, 3H); 13C NMR (100 MHz, CDCl3): 161.3 (d, J = under reduced pressure. The crude obtained was purified by
243.1), 158.7, 148.1, 139.0, 136.4, 132.6, 131.3, 130.8, 129.2, silica gel column chromatography using hexane–ethyl acetate as
128.5, 126.4, 125.2, 122.5 (d, J = 7.7 Hz, 1C), 119.6, 115.9 (d, J = an eluent (9 : 1 to 8 : 2) to obtain the desired products.
21.9 Hz, 1C), 95.7, 85.6, 21.5; HRMS (ESI) m/z for C22H17FN
Ethyl 2-(2-(4-bromophenyl)-3-phenyl-1,2-dihydroisoquinolin-
1-yl)acetate (3a). Yellow solid (193 mg, 86% yield), mp:
(M + H)+, calculated 314.1345, found 314.1325.
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137–139 °C. H NMR (400 MHz, CDCl3): δ 7.43–7.41 (m, 2H), 131.7, 131.1, 128.2, 127.9, 127.5, 127.4, 126.6, 125.2, 124.4,
7.21–7.15 (m, 6H), 7.09 (d, J = 8.4 Hz, 2H), 7.01–6.99 (m, 1H), 123.9, 113.9, 111.5, 62.8, 60.7, 55.2, 39.6, 14.3; HRMS (ESI) m/z
6.84 (d, J = 9.1 Hz, 2H), 6.70 (s, 1H), 5.36 (dd, J = 11.4, 3.8 Hz, for C26H26NO3 (M + H)+, calculated 400.1912, found 400.1914.
1H), 4.21–4.12 (m, 2H), 2.93 (dd, J = 11.4, 14.4 Hz, 1H), 2.39
Ethyl
2-(2,3-diphenyl-1,2-dihydroisoquinolin-1-yl)acetate
(dd, J = 14.4, 4.5 Hz, 1H), 1.21 (t, J = 6.8 Hz, 3H); 13C NMR (3f). Yellow solid (110 mg, 60% yield); mp: 76–79 °C. H NMR
(100 MHz, CDCl3): 171.7, 145.9, 139.8, 136.9, 131.6, 131.5, (400 MHz, CDCl3): δ 7.56–7.53 (m, 2H), 7.29–7.21 (m, 5H), 7.16
131.4, 128.4, 128.2, 127.8, 127.2, 127.0, 125.1, 124.7, 123.8, (td, J = 1.5, 1.5 Hz, 1H), 7.10–7.06 (m, 3H), 7.03–7.02 (m, 2 H),
114.8, 113.1, 62.0, 60.8, 39.3, 14.2; IR (neat): νmax 3061, 1722, 6.82 (t, J = 6.8 Hz, 1H), 6.76 (s, 1H), 5.51 (dd, J = 9.9, 4.5 Hz,
1486, 1265, 1151 cm−1; HRMS (ESI) m/z for C25H23BrNO2 1H), 4.31–4.21 (m, 2H), 3.02 (dd, J = 14.4, 9.9 Hz, 1H), 2.50 (dd,
1
(M + H)+, calculated 448.0912, found 448.0893.
J = 14.5, 4.6 Hz, 1H), 1.30 (t, J = 6.8 Hz, 3H); 13C NMR
Ethyl 2-(2-(4-fluorophenyl)-3-phenyl-1,2-dihydroisoquinolin- (100 MHz, CDCl3): δ 171.8, 146.9, 140.3, 137.4, 131.7, 131.6,
1-yl)acetate (3b). Yellow solid (167 mg, 87% yield); mp: 128.6, 128.3, 128.0, 127.6, 127.3, 126.8, 125.2, 124.6, 122.2,
97–100 °C. 1H NMR (400 MHz, CDCl3): δ 7.44 (d, J = 7.6 Hz, 122.0, 112.5, 62.1, 60.8, 39.5, 14.2; IR (neat): νmax 3021, 2926,
2H), 7.20–7.15 (m, 5H), 7.12–7.08 (m, 1H), 7.01–6.99 (m, 1H), 1727, 1597, 1491, 1218 cm−1; HRMS (ESI) m/z for C25H24NO2
6.94–6.91 (m, 2H), 6.71–6.67 (m, 3H), 5.32 (dd, J = 8.6, 4.5 Hz, (M + H)+, calculated 370.1807, found. 370.1795.
1H), 4.24–4.14 (m, 2H), 2.93 (dd, J = 14.5, 10.6 Hz, 1H), 2.38
Ethyl 2-(2-(4-bromophenyl)-3-cyclopropyl-1,2-dihydroisoqui-
(dd, J = 15.2, 4.6 Hz, 1H), 1.23 (t, J = 6.8 Hz, 3H); 13C NMR nolin-1-yl)acetate (3g). Yellow oil, (153 mg, 75% yield); 1H
(100 MHz, CDCl3): δ 171.9, 158.4 (d, J = 242.1 Hz, 1C), 143.1, NMR (400 MHz, CDCl3): δ 7.32 (d, J = 9.1 Hz, 2H), 7.18–7.15
140.4, 137.1, 131.5, 131.2, 128.3, 128.1, 127.7, 127.4, 126.9, (m, 1H), 7.07–7.04 (m, 4H), 6.97–6.95 (m, 1H), 6.09 (s, 1H),
125.2, 124.6, 123.9 (d, J = 7.6 Hz, 1C), 115.3 (d, J = 21.9 Hz, 1C), 5.18 (dd, J = 9.1, 5.3 Hz, 1H), 4.21–4.11 (m, 2H), 2.81 (dd, J =
112.4, 62.6, 60.8, 39.5, 14.3; IR (neat): νmax 3061, 2981, 2923, 14.5, 9.9 Hz, 1H), 2.41 (dd, J = 14.4, 5.3 Hz, 1H), 1.46–1.41 (m,
1727, 1502, 1221 cm−1; HRMS (ESI) m/z for C25H23FNO2 1H), 1.24 (t, J = 7.6 Hz, 3H), 0.83–0.77 (m, 1H), 0.73–0.67 (m,
(M + H)+, calculated 388.1712, found 388.1704.
1H), 0.66–0.58 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 171.6,
Ethyl 2-(2-(4-chlorophenyl)-3-phenyl-1,2-dihydroisoquinolin- 145.9, 143.5, 131.6, 131.4, 130.1, 127.6, 125.8, 124.9, 124.1,
1-yl)acetate (3c). Yellow solid (123 mg, 61% yield); mp: 123.5, 115.3, 107.5, 62.0, 60.7, 39.3, 14.1 (d, J = 20.0 Hz, 1C),
1
1
109–111 °C. H NMR (400 MHz, CDCl3): δ H NMR (400 MHz, 9.7, 7.7; IR (neat): νmax 3063, 2983, 2928, 1727, 1484, 1272,
CDCl3): δ 7.44–7.42 (m, 2H), 7.21–7.17 (m, 5H), 7.10 (td, J = 1235, 1163, 1031 cm−1; HRMS (ESI) m/z for C22H23BrNO2
2.3, 2.2 Hz, 1H), 7.01–6.99 (m, 1H), 6.96–6.93 (m, 2H), (M + H)+, calculated 412.0912, found 412.0904.
6.91–6.88 (m, 2H), 6.70 (s, 1H), 5.36 (dd, J = 10.6, 4.6 Hz, 1H),
Ethyl 2-(2-(4-fluorophenyl)-3-propyl-1,2-dihydroisoquinolin-
4.23–4.13 (m, 2H), 2.93 (dd, J = 10.7, 5.2 Hz, 1H), 2.39 (dd, J = 1-yl)acetate (3h). Yellow oil, (119 mg, 68% yield); 1H NMR
15.2, 4.5 Hz, 1H), 1.22 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, (400 MHz, CDCl3): δ 7.20–7.16 (m, 1H), 7.09–7.03 (m, 4H),
CDCl3): δ 171.8, 145.5, 139.9, 136.9, 131.6, 131.4, 128.6, 128.4, 6.96–6.89 (m, 3H), 6.17 (s, 1H), 5.10 (dd, J = 9.9, 5.3 Hz, 1H),
128.2, 127.7, 127.2, 127.0, 125.1, 124.7, 124.4, 123.4, 112.9, 4.23–4.11 (m, 2H), 2.88 (dd, J = 15.2, 9.9 Hz, 1H), 2.40 (dd, J =
62.1, 60.8, 39.3, 14.2; IR (neat): νmax 3060, 2981, 2926, 1727, 15.2, 5.3 Hz, 1H), 2.30–2.23 (m, 1H), 2.10–2.02 (m, 1H),
1488, 1266 cm−1; HRMS (ESI) m/z for C25H23ClNO2 (M + H)+, 1.50–1.41 (m, 2H), 1.25 (t, J = 7.6 Hz, 3H), 0.88 (t, J = 7.6 Hz,
calculated 404.1417, found 404.1425.
Ethyl 2-(3-phenyl-2-(p-tolyl)-1,2-dihydroisoquinolin-1-yl) Hz, 1C), 142.6 (d, J = 2.8 Hz, 1C), 142.5, 131.5, 129.7, 127.4,
3H); 13C NMR (100 MHz, CDCl3): δ 171.7, 159.1 (d, J = 237.4
acetate (3d). Yellow solid (118 mg, 62% yield); mp: 125–127 °C. 125.9, 125.0, 124.9 (d, J = 8.5 Hz, 1C), 123.5, 115.4 (d, J = 21.9
1H NMR (400 MHz, CDCl3): δ 7.47 (d, J = 6.8 Hz, 2H), 7.20–7.13 Hz, 1C), 110.7, 62.6, 60.6, 39.7, 35.2, 21.5, 14.2, 13.9; IR (neat):
(m, 5H), 7.09–7.06 (m, 1H), 6.99–6.97 (m, 1H), 6.82 (q, J = 8.4, νmax 3060, 2962, 2932, 1729, 1501, 1214, 1158 cm−1; HRMS
7.6 Hz, 4H), 6.65 (s, 1H), 5.37 (dd, J = 9.9, 4.6 Hz, 1H), (ESI) m/z for C22H25FNO2 (M + H)+, calculated 354.1869, found
4.23–4.14 (m, 2H), 2.92 (dd, J = 15.2, 10.7 Hz, 1H), 2.40 (dd, J = 354.1867.
14.4, 4.5 Hz, 1H), 2.08 (s, 3H), 1.22 (t, J = 7.6 Hz, 3H); 13C NMR
Ethyl
2-(2-(4-bromophenyl)-3-(4-(trifluoromethyl)phenyl)-
(100 MHz, CDCl3): δ 171.9, 144.5, 140.6, 137.5, 131.7, 131.6, 1,2-dihydroisoquinolin-1-yl)acetate (3i). Yellow solid, (168 mg,
131.5, 129.2, 128.2, 127.9, 127.5, 127.4, 126.7, 125.3, 124.5, 65% yield), mp: 141.1–144.9 °C. 1H NMR (400 MHz, CDCl3):
122.3, 112.0, 62.4, 60.7, 39.6, 20.6, 14.2; IR (neat): νmax 3024, δ 7.62–7.60 (m, 2H), 7.52–7.50 (m, 2H), 7.31–7.27 (m, 2H),
2981, 2923, 2858, 1727, 1506, 1260 cm−1; HRMS (ESI) m/z for 7.23–7.18 (m, 3H), 7.09–7.07 (m, 1H), 6.89 (d, J = 9.1 Hz, 2H),
C26H26NO2 (M + H)+, calculated 384.1963, found 384.1974.
6.85 (s, 1H), 5.43 (dd, J = 10.6, 3.8 Hz, 1H), 4.30–4.22 (m, 2H),
Ethyl 2-(2-(4-methoxyphenyl)-3-phenyl-1,2-dihydroisoquino- 2.96 (dd, J = 15.2, 10.6 Hz, 1H), 2.46 (dd, J = 15.2, 3.8 Hz, 1H),
lin-1yl)acetate (3e). Yellow oil, (125 mg, 63% yield); 7.46 (d, J = 1.29 (t, J = 14.4 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 171.5,
6.8 Hz, 2H) 7.17 (d, J = 6.1 Hz, 3H), 7.14–7.12 (m, 2H), 7.07 145.6, 140.6, 138.4, 131.8, 131.7, 130.9, 130.1, 129.6 (q, J = 32.4
(dd, J = 1.5, 1.5 Hz, 1H), 6.98–6.96 (m, 1H), 6.68 (d, J = 9.1 Hz, Hz), 127.9, 127.8, 127.3, 125.5 (q, J = 3.8 Hz), 125.2, 125.1,
2H), 6.62 (s, 1H), 6.53 (d, J = 9.1 Hz, 2H), 5.29 (dd, J = 10.6, 4.5 123.8, 115.4, 114.8, 62.2, 60.9, 39.4, 14.3; HRMS (ESI) m/z for
Hz, 1H) 4.24–4.14 (m, 2H), 3.56 (s, 3H), 2.91 (dd, J = 15.2, 10.6 C26H22BrF3NO2 (M + H)+, calculated 516.0786, found 516.0635.
Hz, 1H), 2.37 (dd, J = 14.5, 4.6 Hz, 1H), 1.22 (t, J = 6.8 Hz, 3H);
tert-Butyl-2-(2-(4-fluorophenyl)-3-(p-tolyl)-1,2-dihydroisoqui-
13C NMR (100 MHz, CDCl3): δ 171.9, 155.0, 140.8, 140.5, 137.5, nolin-1-yl)acetate (3j). Yellow solid (158 mg, 74% yield); mp:
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130–132 °C. H NMR (400 MHz, CDCl3): δ 7.37 (d, J = 7.6 Hz, 2949, 2923, 1731, 1503, 1218, 811 cm−1; HRMS (ESI) m/z for
2H), 7.16–7.15 (m, 2H), 7.08–7.04 (m, 1H), 6.99–6.92 (m, 5H), C28H30NO2 (M + H)+, calculated 412.2276, found 412.2276.
6.68 (t, J = 9.1 Hz, 2H), 6.61 (s, 1H), 5.27 (dd, J = 10.7 Hz,
tert-Butyl-2-(2,3-diphenyl-1,2-dihydroisoquinolin-1-yl)acetate
3.8 Hz, 1H), 2.84 (dd, J = 15.2, 10.7 Hz, 1H), 2.26 (dd, J = 16.0, (3o). Yellow solid (122 mg, 62% yield); mp: 134–136 °C. 1H
3.8 Hz, 1H), 2.21 (s, 3H), 1.44 (s, 9H); 13C NMR (100 MHz, NMR (400 MHz, CDCl3): δ 7.59–7.57 (m, 2H), 7.28–7.21 (m,
CDCl3): δ 171.3, 158.3 (d, J = 38.4 Hz, 1C), 143.4, 140.5, 138.1, 5H), 7.15 (td, J = 4.5, 1.5 Hz 1H), 7.08–7.06 (m, 5H), 6.84–6.79
134.6, 131.7, 131.6, 129.0, 127.5, 127.3, 126.7, 125.2, 124.4, (m, 1H), 6.74 (s, 1H), 5.49 (dd, J = 10.6, 5.3 Hz, 1H), 2.94 (dd,
123.8 (d, J = 8.5 Hz, 1C), 115.2 (d, J = 21.9 Hz, 1C) 111.9, 80.9, J = 17.5, 10.6 Hz, 1H), 2.40 (dd, J = 15.2, 4.6 Hz, 1H), 1.52 (s,
62.6, 40.4, 28.2, 21.2; IR (neat): νmax 3061, 2978, 2929, 1723, 9H); 13C NMR (100 MHz, CDCl3): δ 171.1, 146.9, 140.4, 137.6,
1504, 1152, 812 cm−1; HRMS (ESI) m/z for C28H29FNO2 132.0, 131.6, 128.5, 128.3, 127.9, 127.5, 127.4, 126.7, 125.3,
(M + H)+, calculated 430.2182, found 430.2194.
124.5, 122.2, 121.8, 112.7, 80.9, 62.0, 40.6, 28.2; IR (neat): νmax
tert-Butyl-2-(2-(4-bromophenyl)-3-phenyl-1,2-dihydroisoquino- 3059, 3019, 2977, 1720, 1489, 1146 cm−1; HRMS (ESI) m/z for
lin-1-yl)acetate (3k). Yellow solid (191 mg, 80% yield); mp: C27H28NO2 (M + H)+, calculated 398.2120, found 398.2116.
1
181–183 °C. H NMR (400 MHz, CDCl3): δ 7.53–7.51 (m, 2H),
Methyl 2-(2-(4-bromophenyl)-3-phenyl-1,2-dihydroisoquino-
7.26–7.22 (m, 5H), 7.16–7.14 (m, 3H), 7.06–7.04 (m, 1H), 6.94 lin-1-yl)acetate (3p). Yellow solid (194 mg, 90% yield); mp:
1
(d, J = 9.2 Hz, 2H), 6.73 (s, 1H), 5.39 (dd, J = 10.6, 4.6 Hz, 1H), 124–126 °C. H NMR (400 MHz, CDCl3): δ 7.48 (d, J = 7.6 Hz,
2.91 (dd, J = 16.8, 11.4 Hz, 1H), 2.35 (dd, J = 15.2, 3.0 Hz, 1H), 2H), 7.29–7.23 (m, 5H), 7.19–7.18 (m, 1H), 7.16 (d, J = 9.1 Hz,
1.49 (s, 9H); 13C NMR (100 MHz, CDCl3): δ 171.1, 146.1, 139.8, 2H), 7.07–7.05 (m, 1H), 6.90 (d, J = 8.4 Hz, 2H), 6.77 (s, 1H),
137.2, 131.9, 131.5, 131.4, 128.4, 128.2, 127.6, 127.3, 127.0, 5.43 (dd, J = 9.9, 4.5 Hz, 1H), 3.01 (dd, J = 15.2, 10.6 Hz, 1H),
125.1, 124.7, 123.7, 114.6, 113.3, 81.1, 61.9, 40.3, 28.1; 2.49 (dd, J = 15.2, 4.6 Hz, 1H), 3.77 (s, 3H); 13C NMR (100 MHz,
IR (neat): νmax 3062, 2977, 2929, 1722, 1560, 1263, 1178 cm−1
;
CDCl3): δ 172.1, 145.9, 139.8, 136.8, 131.6, 131.5, 131.4, 128.5,
HRMS (ESI) m/z for C27H27BrNO2 (M + H)+, calculated 128.3, 127.8, 127.2, 127.1, 125.1, 124.8, 123.8, 114.9, 112.9,
476.1225, found 476.1193.
62.0, 51.8, 39.0; IR (neat): νmax 3061, 3023, 2949, 1731, 1485,
tert-Butyl-2-(2-(4-fluorophenyl)-3-phenyl-1,2-dihydroisoquino- 1265 cm−1; HRMS (ESI) m/z for C24H21BrNO2 (M + H)+, calcu-
lin-1-yl)acetate (3l). Yellow solid (166 mg, 80% yield); mp: lated 434.0755, found 434.0737.
1
117–119 °C. H NMR (400 MHz, CDCl3): δ 7.55 (d, J = 6.1 Hz,
Methyl 2-(2-(4-methoxyphenyl)-3-phenyl-1,2-dihydroisoqui-
2H), 7.27–7.22 (m, 5H), 7.16 (td, J = 2.2, 1.5 Hz, 1H), 7.06–7.02 nolin-1-yl)acetate (3q). Yellow solid (152 mg, 80% yield); mp:
1
(m, 3H), 6.76 (t, J = 9.1 Hz, 2H), 6.73 (s, 1H), 5.36 (dd, J = 11.4, 199–201 °C. H NMR (400 MHz, CDCl3): δ 7.54–7.52 (m, 2H),
5.3 Hz, 1H), 2.92 (dd, J = 16.8, 13.0 Hz, 1H), 2.35 (dd, J = 16.0, 7.29–7.20 (m, 5H), 7.15 (td, J = 1.6, 1.5 Hz, 1H), 7.06–7.04 (m,
3.0 Hz, 1H), 1.52 (s, 9H); 13C NMR (100 MHz, CDCl3): δ 171.2, 1H), 6.95 (d, J = 9.1 Hz, 2H), 6.72 (s, 1H), 6.62 (d, J = 9.1 Hz,
159.5, 157.1, 143.2, 140.4, 137.4, 131.6, 128.3, 128.1, 127.6, 2H), 5.37 (dd, J = 10.6, 4.6 Hz, 1H), 3.79 (s, 3H), 3.64 (s, 3H),
127.4, 126.9, 125.2, 124.5, 123.8, 123.7, 115.3, 115.0, 112.6, 3.00 (dd, J = 14.4, 9.9 Hz, 1H), 2.49 (dd, J = 15.2, 4.5 Hz, 1H);
80.9, 62.5, 40.5, 28.2; IR (neat): νmax 3061, 3015, 2977, 1719, 13C NMR (100 MHz, CDCl3): δ 172.3, 155.2, 140.9, 140.5, 137.4,
1561, 1218 cm−1; HRMS (ESI) m/z for C27H27FNO2 (M + H)+, 131.7, 131.0, 128.2, 128.0, 127.6, 127.5, 126.6, 125.2, 124.4,
calculated 416.2025, found 416.2036.
124.0, 113.9, 111.4, 62.8, 55.2, 51.7, 39.4; IR (neat): νmax 3057,
tert-Butyl-2-(2-(4-chlorophenyl)-3-phenyl-1,2-dihydroisoquino- 2948, 2838, 1732, 1504, 1241 cm−1, HRMS (ESI) m/z for
lin-1-yl)acetate (3m). Yellow solid (161 mg, 75% yield); mp: C25H24NO3 (M + H)+, calculated 386.1756, found 386.1755.
1
158–160 °C. H NMR (400 MHz, CDCl3): δ 7.55–7.53 (m, 2H),
Methyl 2-(2,3-diphenyl-1,2-dihydroisoquinolin-1-yl)acetate
7.26–7.22 (m, 5H), 7.16 (td, J = 4.5, 3.8 Hz, 1H), 7.07–7.04 (m, (3r). Pale yellow solid (111 mg, 63% yield); mp: 134–136 °C. 1H
1H), 7.01 (s, 4H), 6.75 (s, 1H), 5.40 (dd, J = 9.1, 3.8 Hz, 1H), NMR (400 MHz, CDCl3): δ 7.51 (d, J = 7.6 Hz, 2H), 7.26–7.25
2.92 (dd, J = 16.0, 9.9 Hz, 1H), 2.36 (dd, J = 16.0, 6.8 Hz, 1H), (m, 3H), 7.23–7.20 (m, 2H), 7.15 (td, J = 1.5, 1.5 Hz, 1H),
1.51 (s, 9H); 13C NMR (100 MHz, CDCl3): δ 171.1, 145.6, 139.9, 7.09–7.05 (m, 3H), 7.01–6.99 (m, 2H), 6.82 (t, J = 7.6 Hz, 1H),
137.2, 131.9, 131.4, 128.6, 128.4, 128.2, 127.6, 127.3, 127.0, 6.75 (s, 1H), 5.49 (dd, J = 9.9, 4.5 Hz, 1H), 3.77 (s, 3H), 3.02 (d,
125.2, 124.7, 123.3, 113.2, 81.1, 62.1, 40.3, 28.2; IR (neat): νmax J = 14.4, 9.9 Hz, 1H), 2.52 (dd, J = 15.2, 5.3 Hz, 1H); 13C NMR
2978, 1719, 1488, 1261, 1149 cm−1; HRMS (ESI) m/z for (100 MHz, CDCl3): δ 172.1, 146.9, 140.3, 137.3, 131.6, 128.6,
C27H27ClNO2 (M + H)+, calculated 432.1730, found 432.1714.
128.3, 128.0, 127.6, 127.3, 126.8, 125.2, 124.6, 122.3, 122.1,
tert-Butyl-2-(3-phenyl-2-(p-tolyl)-1,2-dihydroisoquinolin-1-yl) 112.4, 62.1, 51.7, 39.2; IR (neat): νmax 3060, 3029, 2949, 1734,
acetate (3n). Yellow solid (148 mg, 73% yield); mp: 166–168 °C. 1491, 1265 cm−1; HRMS (ESI) m/z for C24H22NO2 (M + H)+, cal-
1H NMR (400 MHz, CDCl3): δ 7.57 (d, J = 6.8 Hz, 2H), 7.25–7.20 culated 356.1650, found 356.1649.
(m, 5H), 7.13 (td, J = 2.3, 2.2 Hz, 1H), 7.05–7.03 (m, 1H), 6.95
Methyl 2-(2-(4-bromophenyl)-3-(4-(trifluoromethyl)phenyl)-
(d, J = 8.4 Hz, 2H) 6.87 (d, J = 8.4 Hz, 2H), 6.70 (s, 1H), 5.42 1,2-dihydroisoquinolin-1-yl)acetate (3s). Yellow solid (160 mg,
(dd, J = 9.1, 3.8 Hz, 1H), 2.91 (dd, J = 15.2, 10.6 Hz, 1H), 2.37 64% yield); mp: 137.6–140.5 °C. 1H NMR (400 MHz, CDCl3):
(dd, J = 14.5, 4.6 Hz, 1H), 2.15 (s, 3H), 1.51 (s, 9H); 13C NMR δ 7.53–7.51 (m, 2H), 7.45–7.43 (m, 2H), 7.22–7.11 (m, 5H),
(100 MHz, CDCl3): δ 171.2, 144.6, 140.6, 137.8, 131.8, 131.7, 7.01–7.69 (m, 1H), 6.81 (d, J = 8.4 Hz, 2H), 6.78 (s, 1H), 5.35
131.4, 129.2, 128.2, 127.9, 127.4, 126.6, 125.3, 124.4, 122.3, (dd, J = 9.9 Hz, 1H), 3.70 (s, 3H), 2.89 (dd, J = 15.2, 10.6 Hz,
112.3, 80.8, 62.3, 40.6, 28.2, 20.6; IR (neat): νmax 3056, 3023, 1H), 2.41 (dd, J = 15.2, 4.5 Hz, 1H); 13C NMR (100 MHz,
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CDCl3): δ 171.9, 140.6, 140.5, 138.4, 131.8, 131.7, 131.6, 130.8, (ESI) m/z for C26H24ClFNO2 (M + H)+, calculated 436.1479,
130.0 (q, J = 15.2 Hz), 127.9, 127.8, 127.2, 125.5 (q, J = 3.8 Hz), found 436.1455.
125.2, 125.1, 123.8, 115.5, 114.7, 62.2, 51.8, 39.1; HRMS (ESI)
Methyl
2-(2-(4-chlorophenyl)-7-fluoro-3-(p-tolyl)-1,2-di-
m/z for C25H20BrF3NO2 (M + H)+, calculated 502.0629, found hydroisoquinolin-1-yl)acetate (3x). Yellow solid (170 mg, 81%
1
502.0446.
yield); mp: 174–176 °C. H NMR (400 MHz, CDCl3): δ 7.35 (d,
Methyl 2-(2-(4-fluorophenyl)-3-(p-tolyl)-1,2-dihydroisoquino- J = 8.4 Hz, 2H), 7.25–7.20 (m, 1H), 7.08–7.04 (m, 3H), 7.02 (s,
lin-1-yl)acetate (3t). Yellow solid (155 mg, 81% yield); mp: 1H), 6.97–6.93 (m, 3H), 6.79 (dd, J = 8.4, 2.2 Hz, 1H), 6.71 (s,
1
168–170 °C. H NMR (400 MHz, CDCl3): δ 7.38 (d, J = 7.6 Hz, 1H), 5.36 (dd, J = 10.6, 4.6 Hz, 1H), 3.77 (s, 3H), 2.99 (dd, J =
2H), 7.26–7.25 (m, 2H), 7.15 (td J = 2.28, 2.28 Hz, 1H), 15.2, 9.9 Hz, 1H), 2.48 (dd, J = 15.2, 4.6 Hz, 1H), 2.29 (s, 3H);
7.07–7.04 (m, 3H), 6.99–6.96 (m, 2H), 6.76 (t, J = 8.4 Hz, 2H), 13C NMR (100 MHz, CDCl3): δ 171.9, 161.8 (d, J = 249.8 Hz,
6.72 (s, 1H), 5.36 (dd, J = 10.6, 4.5 Hz, 1H), 3.77 (s, 3H), 3.00 1C), 145.4, 139.3, 138.3, 133.8, 133.2 (d, J = 7.6 Hz, 1C), 129.2,
(dd, J = 15.2, 10.6 Hz, 1H), 2.47 (dd, J = 15.2, 4.5 Hz, 1H), 2.29 128.7, 127.8 (d, J = 2.8 Hz, 1C), 127.4, 126.9, 126.1 (d, J =
(s, 3H); 13C NMR (100 MHz, CDCl3): δ 172.3, 158.4 (d, J = 242.2 7.6 Hz, 1C), 123.4, 114.7 (d, J = 21.9 Hz, 1C), 112.2 (d, J = 21.9
Hz, 1C), 143.2, 140.4, 138.2, 134.2, 131.7, 131.1, 129.1, 127.7, Hz, 1C), 111.2, 61.8, 51.8, 38.7, 21.2; IR (neat): νmax 3026, 2951,
127.2, 126.7, 125.1, 124.5, 123.9 (d, J = 7.6 Hz, 1C), 115.3 (d, J = 2922, 1732, 1409, 1236, 825 cm−1; HRMS (ESI) m/z for
22.8 Hz, 1C), 111.6, 62.6, 51.7, 39.1, 21.2; IR (neat): νmax 3057, C25H22ClFNO2 (M + H)+, calculated 422.1323, found 422.1316.
3023, 2949, 2924, 1733, 1504, 1221 cm−1; HRMS (ESI) m/z for
Methyl 2-(7-fluoro-2,3-diphenyl-1,2-dihydroisoquinolin-1-yl)
C25H23FNO2 (M + H)+, calculated 388.1712, found 388.1713.
acetate (3y). Yellow oil, (170 mg, 92% yield); 1H NMR
Benzyl 2-(2-(4-fluorophenyl)-3-phenyl-1,2-dihydroisoquino- (400 MHz, CDCl3): δ 7.50 (d, J = 6.8 Hz, 2H), 7.27–7.20 (m, 4H),
1
lin-1-yl)acetate (3u). Yellow oil, (168 mg, 75% yield); H NMR 7.10–7.06 (m, 2H), 7.00–6.92 (m, 3H), 6.85–6.79 (m, 2H), 6.73
(400 MHz, CDCl3): δ 7.40–7.37 (m, 2H), 7.30–7.25 (m, 5H), (s, 1H), 5.45 (dd, J = 9.9, 5.3 Hz, 1H), 3.78 (s, 3H), 3.00 (dd, J =
7.20–7.17 (m, 2H), 7.13–7.06 (m, 4H), 6.98–6.96 (m, 1H), 15.2, 9.9 Hz, 1H), 2.53 (dd, J = 15.2, 5.3 Hz, 1H); 13C NMR
6.88–6.85 (m, 2H), 6.65 (t, J = 8.4 Hz, 3H), 5.31 (dd, J = 9.9, 3.8 (100 MHz, CDCl3): δ 171.9, 161.7 (d, J = 256.5 Hz, 1C), 146.7,
Hz, 1H), 5.17 (q, J = 12.2 Hz, 2H), 2.99 (dd, J = 15.2, 9.9 Hz, 139.7, 137.1, 133.3 (d, J = 6.6 Hz, 1C), 128.7, 128.4, 128.1, 127.8
1H), 2.43 (dd, J = 15.2, 4.5 Hz, 1H); 13C NMR (100 MHz, (d, J = 2.9 Hz, 1C), 127.2, 126.1 (d, J = 7.5 Hz, 1C), 122.3, 122.2,
CDCl3): δ 171.6, 158.4 (d, J = 240.2 Hz, 1C), 143.1, 140.5, 137.1, 114.6 (d, J = 21.9 Hz, 1C), 112.2 (d, J = 21.9 Hz, 1C), 111.5, 61.8,
135.5, 131.3 (d, J = 41.9 Hz, 1C), 128.7, 128.6, 128.4, 128.3, 51.8, 38.9; IR (neat): νmax 3059, 3030, 2951, 2920, 1732, 1490,
128.2, 128.1, 127.7, 127.4, 126.9, 125.2, 124.6, 123.9 (d, J = 7.6 1234 cm−1; HRMS (ESI) m/z for C24H21FNO2 (M + H)+, calcu-
Hz, 1C), 115.2 (d, J = 21.9 Hz, 1C), 112.3, 66.7, 62.6, 39.4; lated 374.1556, found 374.1554.
IR (neat): νmax 3061, 2958, 2922, 2854, 1729, 1499, 1217 cm−1
HRMS (ESI) m/z for C30H25FNO2 (M + H)+, calculated 450.1869 quinolin-1-yl)acetate (3z). Yellow oil (166 mg, 70% yield); 1H
found 450.1869. NMR (400 MHz, CDCl3): δ 7.47–7.45 (m, 2H), 7.37–7.33 (m,
;
Benzyl-(7-fluoro-2-(4-methoxyphenyl)-3-phenyl-1,2-dihydroiso-
Ethyl 2-(2-(4-chlorophenyl)-3-phenyl 1,2-dihydroisoquinolin- 5H), 7.23–7.20 (m, 1H), 7.19–7.17 (m, 3H), 6.96–6.92 (m, 1H),
1-yl)propanoate (3v). Yellow solid (125 mg, 60% yield); mp: 6.90 (d, J = 9.1 Hz, 2H), 6.76 (d, J = 8.4, 2.2 Hz, 1H), 6.65 (s,
1
159–161 °C. H NMR (400 MHz, CDCl3): δ 7.43–7.41 (m, 2H), 1H), 6.59 (d, J = 8.4 Hz, 1H), 5.31 (dd, J = 9.9, 4.6 Hz, 1H), 5.25
7.22–7.07 (m, 6H), 6.93–6.85 (m, 5H), 6.76 (s, 1H), 4.88 (d, J = (q, J = 3.0 Hz, 2H), 3.64 (s, 3H), 3.03 (dd, J = 15.2, 10.6 Hz, 1H),
9.9 Hz, 1H), 4.28–4.15 (m, 2H), 2.90–2.86 (m, 1H), 1.18 (t, J = 2.51 (dd, J = 15.2, 4.6 Hz, 2H); 13C NMR (100 MHz, CDCl3):
6.8 Hz, 3H), 0.92 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, δ 171.4, 163.0, 160.5, 155.3, 140.4, 140.2, 137.2, 135.5, 132.7 (d,
CDCl3): δ 176.5, 145.6, 140.5, 136.7, 131.6, 129.0, 128.6, 128.3, J = 5.7 Hz, 1C), 128.6, 128.5, 128.4, 128.3, 128.0, 127.4, 125.8
128.2, 127.8, 127.4, 127.3, 127.2, 126.3, 124.7, 123.6, 113.1, (d, J = 7.6 Hz, 1C), 124.0, 114.5 (d, J = 20.9 Hz, 1C) 113.9, 112.3
67.9, 60.8, 41.6, 15.2, 14.1; IR (neat): νmax 3062, 3024, 2979, (d, J = 20.9 Hz, 1C), 110.6, 66.7, 62.5, 55.2, 39.3; HRMS (ESI)
1725, 1488, 1252, 1134 cm−1; HRMS (ESI) m/z for C26H25ClNO2 m/z for C31H27FNO3 (M + H)+, calculated 480.1975, found
(M + H)+, calculated 418.1573, found. 418.1567.
480.1965.
Ethyl 2-(2-(4-chlorophenyl)-7-fluoro-3-(p-tolyl)-1,2-dihydro-
Ethyl 2-(7-methoxy-2,3-diphenyl-1,2-dihydroisoquinolin-1-yl)
isoquinolin-1-yl)acetate (3w). Yellow solid (173 mg, 80% yield); acetate (3za). Brown solid (91 mg, 46% yield); mp: 106–109 °C.
1
mp: 146–148 °C. H NMR (400 MHz, CDCl3): δ 7.37 (d, J = 8.4 1H NMR (400 MHz, CDCl3): δ 7.52 (d, J = 7.6 Hz, 2H), 7.24–7.17
Hz, 2H), 7.21 (dd, J = 8.4, 6.1 Hz, 1H), 7.07–7.03 (m, 3H), (m, 4H), 7.09–7.05 (m, 2H), 7.03–7.01 (m, 2H), 6.82–6.78 (m,
7.02–7.01 (m, 1H), 6.97–6.92 (m, 3H), 6.80 (dd, J = 8.4, 2.2 Hz, 2H), 6.74 (s, 1H), 6.64–6.63 (m, 1H), 5.45 (dd, J = 9.9, 4.5 Hz,
1H), 6.70 (s, 1H), 5.37 (dd, J = 9.9, 3.8 Hz, 1H), 4.28–4.22 (m, 1H), 4.29–4.21 (m, 2H), 3.74 (s, 3H), 3.0 (dd, J = 14.5, 10.6 Hz,
2H), 2.98 (dd, J = 15.2, 10.6 Hz, 1H), 2.46 (dd, J = 15.2, 4.6 Hz, 1H), 2.48 (dd, J = 15.2, 4.6 Hz, 1H), 1.29 (t, J = 6.8 Hz, 3H);
1H), 2.29 (s, 3H), 1.29 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, 13C NMR (100 MHz, CDCl3): δ 171.8, 158.9, 147.0, 138.1,
CDCl3): δ 171.5, 161.7 (d, J = 257.4 Hz, 1C), 145.5, 139.3, 138.3, 137.5, 133.5, 128.6, 128.2, 127.7, 126.9, 125.9, 124.8, 121.9,
133.9, 133.3 (d, J = 7.6 Hz, 1C), 129.2, 128.7, 127.9, 127.4, 121.8, 113.6, 112.5, 110.4, 62.2, 60.8, 55.3, 39.4, 14.2; IR (neat):
127.0, 126.0 (d, J = 8.6 Hz, 1C), 123.4, 114.7 (d, J = 20.9 Hz, 1C), νmax 3058, 2980, 2925, 2848, 1729, 1495, 1250 cm−1; HRMS
112.2 (d, J = 22.8 Hz, 1C), 111.3, 61.8, 60.9, 38.9. 21.2, 14.3; (ESI) m/z for C26H26NO3 (M + H)+, calculated 400.1912, found
IR (neat): νmax 3209, 2981, 2924, 1727, 1488, 1234 cm−1; HRMS 400.1908.
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Ethyl 2-(2-(4-bromophenyl)-3-phenyl 1,2-dihydroisoquinolin- mixture was allowed to stir at 80 °C until the reaction was
1
1-yl)-2-fluoroacetate (3zb). Yellow oil, (172 mg, 74% yield); H complete.
NMR (400 MHz, CDCl3): δ 7.51 (d, J = 7.6, 2H), 7.32–7.23 (m,
Eqn (c). The Reformatsky reagent 5 (α-bromoester 2a
5H), 7.15–7.12 (m, 1H), 7.06–7.02 (m, 2H), 6.96–6.92 (m, 3H), (0.5 mmol) and Zn dust (1 mmol)) was prepared in CD3CN
6.60 (s, 1H), 5.29 (dd, J = 12.9, 8.4 Hz, 1H), 5.04 (dd, J = 49.6, and cooled to room temperature followed by its addition to an
8.4 Hz, 1H), 4.12–4.05 (m, 1H), 3.98–3.91 (m, 1H), 1.03 (t, J = NMR tube containing aldimine 1a at room temperature. The
6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 168.2 (d, J = 23.8 reaction mixture was allowed to stir for 5 min and examined
Hz, 1C), 168.0, 145.0, 140.4, 136.7, 132.7, 128.8, 128.7, 128.5, by NMR and compared with the isoquinolinium salt 4a, the
128.4, 127.8, 126.5, 126.4, 124.6, 124.2, 111.8, 87.9 (d, J = 187.8 Reformatsky reagent 5 and the starting substrate 1a in CD3CN
Hz, 1C), 66.8, 66.6, 61.6, 13.7; HRMS (ESI) m/z for solvent. The NMR spectra indicated that 1a was completely
C25H21BrFNO2 (M + Na)+, calculated 488.0637, found 488.0627. converted to the isoquinolinium salt (4a), but as 5 was used in
Ethyl 2-fluoro-2-(2-(4-fluorophenyl)-3-phenyl-1,2-dihydroiso- excess, unreacted 5 was also observed along with 4a in NMR.
quinolin-1-yl)acetate (3zc). Yellow solid (144 mg, 71% yield);
Eqn (d). The Reformatsky reagent 5 (α-bromoester 2a
1
mp: 82.4–85.2 °C. H NMR (400 MHz, CDCl3): δ 7.55–7.53 (m (0.5 mmol) and Zn dust (1 mmol)) was prepared as mentioned
2H), 7.35–7.28 (m, 2H), 7.25–7.21 (m, 4H), 7.15–7.13 (m, 1H), above, followed by addition of o-alkynylarylaldimine 1a
6.93–6.89 (m, 2H), 6.76 (t, J = 20 Hz, 2H), 6.67 (s, 1H), (0.5 mmol). The reaction mixture was quenched with 10 mL
5.30–5.25 (m, 1H), 4.92 (dd, J = 48, 7.6 Hz, 1H), 4.32–4.28 (m, H2O and extracted with ethyl acetate (2 × 10 mL) and washed
1H), 4.26–4.19 (m, 1H), 1.24 (t, J = 7.6 Hz, 3H); 13C NMR with H2O (2 × 5 mL) and separated as mentioned above in the
(100 MHz, CDCl3): δ 168.5 (d, J = 23.8 Hz), 158.8 (d, J = 225.9 general procedure for 3 to afford 3a as the desired product in
Hz), 143.0, 141.6, 136.4, 132.0, 128.7, 128.3, 128.2, 127.6, 85% yield.
127.4, 126.9, 126.2, 124.5, 124.4 (d, J = 7.6 Hz), 114.4 (d, J =
Eqn (e). The Reformatsky reagent 4a (α-bromoester 2a
21.9 Hz), 111.9, 88.3 (d, J = 184.9 Hz), 66.7 (d, J = 25.7 Hz), (1 mmol) and Zn dust (2 mmol)) was prepared as mentioned
61.9, 13.8; HRMS (ESI) m/z for C25H22F2NO2 (M + H)+, calcu- above in CH3CN, followed by the addition of o-alkynylarylaldi-
lated 406.1619, found 406.1604.
mine 1a (0.5 mmol) at 80 °C until the reaction was complete.
Synthesis of 2-(4-bromophenyl)-3-phenylisoquinolin-2-ium The solvent was evaporated and the reaction mixture was
(4a).6a To a 50 mL round bottom flask having DCM (5 mL) as shaken with 3 ml of D2O for 1 h to afford 3ab with approx.
the solvent, o-arylalkylaldimine 1a (0.5 mmol), AgOTf 80% incorporation of D as a product.
(0.5 mmol) and triflic acid (1 mmol) were added at room temp-
Ethyl 2-(2-(4-bromophenyl)-3-phenyl-1,2-dihydroisoquinolin-
erature under an N2 atmosphere and the resulting mixture was 1-yl-4-d) acetate (3ab). Yellow solid, 1H NMR (500 MHz,
stirred at 40 °C for 1 h. The solvent was evaporated under CDCl3): 7.54–7.53 (m, 2H), 7.40–7.38 (m, 1H), 7.32–7.28 (m,
reduced pressure and crystallized with hexane and ethyl 5H), 7.20 (d, J = 10.0 Hz, 2H), 7.12–7.10 (m, 1H), 6.80 (s, 0.2H),
acetate to afford 4a in 96% yield. This salt is a greyish white 6.95 (d, J = 10.0 Hz, 2H), 5.47 (dd, J = 10.0, 5.0 Hz, 1H),
solid, mp: 193–195 °C. 1H NMR (400 MHz, CD3CN): 9.74 (s, 4.33–4.23 (m, 2H), 3.03 (dd, J = 15.0, 10.0 Hz, 1H), 2.50 (dd, J =
1H), 8.51–8.48 (m, 2H), 8.33–8.28 (m, 2H), 8.11–8.07 (m, 1H), 15.0, 0.0 Hz, 1H), 1.32 (t, J = 10. 0 Hz, 3H); HRMS (ESI) m/z for
7.64–7.62 (m, 2H), 7.46–7.43 (m, 1H), 7.40–7.34 (m, 6H); 13C C25H22DBrNO2 (M + H)+, calculated 449.0974, found 449.0884.
NMR (100 MHz, CD3CN): δ 152.7, 147.0, 142.0, 139.8, 139.5,
133.7, 133.1, 132.9, 131.5, 131.2, 131.1, 129.7, 129.6, 128.7,
128.4, 127.7, 125.4, 118.2; HRMS (ESI) m/z for C21H15BrN (M)+,
calculated 360.0382, found 360.0383.
Acknowledgements
Synthesis of (2-ethoxy-2-oxoethyl)zinc(II)bromide (5). To a The authors acknowledge the Department of Science and
round bottom flask having CH3CN/CD3CN (5 mL) as the Technology, New Delhi, UPOE-II, JNU and ICMR-CAR, SCMM
solvent, Zn dust (1 mmol) and α-bromoester 2a (0.5 mmol) JNU, DST Purse, JNU for financial support. Delhi University
were added dropwise with vigorous stirring and the reaction Instrumentation Centre and AIRF, JNU are acknowledged for
1
mixture was refluxed (80 °C) for 0.5–1 h. H NMR (400 MHz, providing instrumentation facilities. TYC and Urvashi are
CD3CN): 4.16–4.00 (m, 2H), 1.95–1.92 (m, 2H), 1.23–1.16 (m, thankful to DST & UGC respectively for a fellowship.
3H); 13C NMR (100 MHz, CD3CN): 171.5, 60.9, 21.0, 14.4.
Control experiments for mechanistic studies (Scheme 4)
Notes and references
Eqn (a). The Reformatsky reagent 5 was prepared in CH3CN
and transferred to a 50 ml round bottom flask containing
o-isoquinolinium 4a at 80 °C. Then the mixture was stirred
until the formation of 3a in 85% yield.
Eqn (b). In continuation to the above the Reformatsky
reagent 5 (1 equiv.) along with zinc bromide (30 mol% and
1 equiv. respectively for two reactions) was added to a round
bottom flask containing aldimine 1a (0.5 mmol). The reaction
1 (a) S. Reformatsky, Ber. Dtsch. Chem. Ges., 1887, 20, 1210–
1211; (b) S. Choppin, L. F. Medeiros, M. Barbarotto and
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