Nucleophilic addition of Lewis acid complexed α-amino carbanions to arynes: Synthesis of 1-aryl- N -methyl-1,2,3,4-tetrahydroisoquinolines

Article abstract of DOI:10.1055/s-0033-1341239

The direct C-1 arylation of N-methyl-1,2,3,4-tetrahydroisoquinolines via coupling of α-amino carbanions derived from Lewis acid complexed tetrahydroisoquinolines and in situ generated arynes is described. This process provides an easy access to the title compounds and a new synthetic route to (±)-cryptostyline alkaloids. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1341239

PAPER
▌1739
paper
Nucleophilic Addition of Lewis Acid Complexed α-Amino Carbanions to
Arynes: Synthesis of 1-Aryl-N-methyl-1,2,3,4-tetrahydroisoquinolines
1-Aryl-N-methyl-1,2,3,4-tetrahydroisoquinolines
Kamal Nain Singh,* Paramjit Singh, Esha Sharma, Yadwinder Singh Deol
Department of Chemistry and Centre of Advanced Studies in Chemistry, Panjab University, Chandigarh 160014, India
Fax +91(172)2545074; E-mail: kns@pu.ac.in
Received: 13.02.2014; Accepted after revision: 28.03.2014
imines9 and the Pictet–Spengler condensation2,10 of elec-
tron-rich phenethylamines with aldehydes. Methods uti-
lizing addition of carbon nucleophiles to iminium ions
generated via Bischler–Napieralski cyclization9a,11 and
Abstract: The direct C-1 arylation of N-methyl-1,2,3,4-tetrahy-
droisoquinolines via coupling of α-amino carbanions derived from
Lewis acid complexed tetrahydroisoquinolines and in situ generated
arynes is described. This process provides an easy access to the title
compounds and a new synthetic route to (±)-cryptostyline alkaloids. addition of Grignard reagents to 3,4-dihydroisoquinolini-
um tetrafluoroborate salt12 have also been reported.
Key words: arylation, arynes, tetrahydroisoquinolines, cryptosty-
line alkaloids, Lewis acid complexation
R1
N
R2
Me
R5
cryptostyline I (2f); R1 = R2 = OMe
The 1-aryltetrahydroisoquinoline moiety is an important
structural motif present in many alkaloids and compounds
of pharmaceutical interest. A variety of these compounds
show potent anti-HIV,1 antibacterial,2 and antitumor ac-
tivities.3 Various 1-aryl-THIQ (THIQ: tetrahydroisoquin-
oline) antagonists4 have been studied as neuroprotective
agents, which can be useful in treating ischemia, epilepsy,
Huntington, Alzheimer, and Parkinson type diseases. The
1-aryl-N-methyl-1,2,3,4-tetrahydroisoquinolines 1 (Fig-
ure 1) are also known to modulate glutamate neurotrans-
mission in the CNS.5 Cryptostyline I–III (2f, 2d, 2e)
(Figure 2) have been isolated from Cryptostylis fulva6 and
belong to 1-aryl-N-methyl-THIQ alkaloids. These have
been studied as pharmacological probes for the D1 dopa-
mine receptor,5b and other analogues of the cryptostylines
act as bladder-selective muscarinic M3 receptor antago-
nists.7
R
3 = R4 = OCH2O, R5 = H
cryptostyline II (2d); R1 = R2 = OMe
R
3 = R4 = OMe, R5 = H
R3
cryptostyline III (2e); R1 = R2 = OMe
R4
R
3 = R4 = R5 = OMe
Figure 2 Cryptostyline alkaloids
Furthermore, Saitoh et al. reported the synthesis of 1-aryl-
N-methyl-THIQs using sulfoxide-mediated electrophilic
cyclization via modified Pummerer reaction.13 Other
methods include double cyclization process using o-vi-
nylbenzaldehyde and amino alcohols,14 reaction of vari-
ous nucleophiles with α-siloxyamines prepared by
Polonovsky reaction of tertiary amine N-oxides with trial-
kylsilyltrifluoromethane sulfonates,15 and radical cycliza-
tion method.16 Recently, Miyaura and co-workers
reported rhodium-catalyzed asymmetric addition of aryl
boronic acids to N-sulfonylarylaldimines for the synthesis
of cryptostyline alkaloids.17
4
5
4a
8a
3
6
7
2
N
1
Lewis acid (BF3·OEt2) complexation of tertiary amines
followed by treatment with sec-butyllithium in tetrahy-
drofuran at –78 °C has been established as an effective
method for the generation of α-amino carbanions 5 by our
research group.18 The α-amino carbanions can be subse-
quently reacted with various electrophiles to give α-sub-
stituted products19 (Scheme 1, equation 1). Using this
procedure, many N-methyltetrahydroisoquinoline alka-
loids were synthesized.19 Recently, we reported our find-
ings involving reactions of β-amino carbanions 6 and
arynes, which led to the synthesis of 4-aryl-N-methyl-
1,2,3,4-tetrahydroisoquinolines20 (Scheme 1, equation 2).
It was of obvious interest to investigate whether the Lewis
acid complexed α-amino carbanions 5 can also participate
in a similar manner with the in situ generated aryne. If
successful, it can lead to a direct one-pot synthesis of 1-
aryl-N-methyl-1,2,3,4-tetrahydroisoquinolines(Scheme2).
Me
C8a–C1: Bischler–Napieralski cyclization
or Pictet–Spengler condensation
8
1'
6'
5'
C1–C1': nucleophilic or electrophilic addition
C4a–C4: Pomeranz–Fritsch cyclization
2'
3'
4'
R
1
Figure 1 The disconnection approaches to the synthesis of 1-aryl-N-
methyl-THIQs
Many reports on the syntheses of 1-aryl-N-methyl-THIQs
including cryptostylines I–III are available in the litera-
ture.8 Most commonly employed procedures are the
Bischler–Napieralski cyclization of amides derived by
condensation of acid chlorides with 2-arylethylamines
and subsequent reduction of 3,4-dihydroisoquinoline
SYNTHESIS 2014, 46, 1739–1750
Advanced online publication: 12.05.2014
As outlined in our earlier publication,20 many methods are
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1341239; Art ID: ss-2014-t0106-op
© Georg Thieme Verlag Stuttgart · New York
available for aryne generation.21 Further, intermolecu-

1740
K. N. Singh et al.
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s-BuLi
E+
BF3•OEt2
–
–
BF3
BF3
+
+
N
N
N
(1)
N
0 °C
–78 °C
Me
Me
Me
Me
4
3
Li
E
5
E = CH(OH)Ph, Me, SiMe3
R
Li
H
H
Bu
s-BuLi
Li
(2)
–78 °C to .r.t
N
N
N
–78 °C
N
Me
Me
–78 °C
s-BuLi
Me
Me
6a
3
6
8
X
(X = F, Cl)
R
7
Scheme 1 Lithiation substitution of N-methyl-1,2,3,4-THIQ 3
conditions
a or b
–78 °C to r.t.
Lewis acid
–
–
LA
LA
N
N
N
N
solvent
0 °C
+
+
Me
Me
Me
Me
3
4
Li
5
conditions a: LA = BF3; –78 °C, s-BuLi, 30 min
Cl
conditions b: LA = BH3; –78 °C, n-BuLi, –78 °C to r.t., 1 h, r.t. to –78 °C
s-BuLi
1a
–78 °C
7a
Scheme 2 Aryne-mediated arylation at C-1 position in 3
lar/intramolecular reactions of these intermediates are ran as solvent, BF3·OEt2 as the Lewis acid and using 3
known with a variety of nucleophiles including carban- equivalents of base (second instalment) and 3 equivalents
ions.22 In the present work also we chose ortho-lithiation of aryl halide (Table 1, entry 7). Use of a different base,
of aryl chlorides or fluorides with alkyllithium at low tem- lithium tetramethylpiperidide, instead of sec-butyllithi-
perature followed by elimination of lithium halide for um, in the first addition also resulted in a lower yield of
aryne generation23 as the temperature required for this the product (Table 1, entry 10). When a solution of 4- bro-
process is compatible with generation and reactions of α- moanisole and lithium diisopropylamide was used for
lithiated species 5.
benzyne generation and subsequently transferred to 5 via
cannula, only the starting amine was recovered (Table1,
entry 11). Thus, the yield of the product 1a could not be
increased beyond 40%.
In a model reaction, the amine-BF3 complex 4 was gener-
ated by taking THIQ 3 (1.36 mmol) in tetrahydrofuran (10
mL) and adding BF3·OEt2 (1.63 mmol) at 0 °C. After an
interval of 30 minutes, the reaction mixture was cooled to After establishing the optimized reaction conditions, var-
–78 °C and sec-butyllithium (1.36 mmol) was added. It ious substituted aryne precursors were used to check the
was then stirred for 30 minutes at the same temperature scope of aryne mediated C-1 arylation of N-methyl-
and sec-butyllithium (1.63 mmol) was added once again 1,2,3,4-THIQ (3) and the results are summarized in Table
followed by chlorobenzene (7a) (1.36 mmol). The reac- 2. All the selected aryne precursors 7a–f20 underwent
tion mixture was stirred at –78 °C for another 45 minutes smooth reaction with 3 to furnish products 1a–f in moder-
and then allowed to warm to room temperature where it ate yields (Table 2).
was quenched with aqueous 10% HCl. Workup and puri-
To explore the substrate scope with respect to the starting
fication by column chromatography afforded the C-1 ary-
amine, differently substituted tetrahydroisoquinolines 9a–
lated product 1a in a low yield of 28% (Table 1, entry 1).24
d were synthesized according to the known procedures.26
For optimization of the yield, the reaction was carried out
These were reacted with aryne precursors 7a–f using sim-
ilar conditions as for the reactions with 3 to give the cor-
responding C-1 arylated products 2a–x (Table 3, entries
1–24), which were obtained in moderate yields. All three
by changing various parameters like solvent, amount of
the base or of the aryl halide, Lewis acid (BH3)25 (Table 1,
entries 2–9). Best result was obtained with tetrahydrofu-
Synthesis 2014, 46, 1739–1750
© Georg Thieme Verlag Stuttgart · New York

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1-Aryl-N-methyl-1,2,3,4-tetrahydroisoquinolines
1741
Table 1 Optimizaton of Reaction Conditions for C-1 Arylation of 3
Entry
Solvent
Base (equiv)
1st addition
7a (equiv)
1a (yield %)a
2nd addition
LA = BF3
LA = BH3
(n-BuLi or s-BuLi) (s-BuLi)
conditions a
conditions b
1
THF
1
1.2
1.2
1.2
1.2
1.2
2
1
1
1
1
1
2
3
4
6
3
3e
28b
–
22c
–
2
Et2O
1
3
toluene–Et2O (1:1)
1
20
19
32
35
40
36
35
30
–
–
4
THF–pentane (6:4)
1
–
5
THF
THF
THF
THF
THF
THF
THF
2
27
29
31
30
–
6
2
7
2.2
2.2
2.2
2.2d
2.2
3
8
4
9
6
10
3
11
3e
–
a Isolated yield.
b Reaction conditions: 3 (1.36 mmol), 0 °C, BF3·OEt2 (1.63 mmol), 30 min, 0 °C to –78 °C, s-BuLi (1.36 mmol), 30 min, s-BuLi (1.63 mmol),
7a (1.36 mmol), –78 °C (45 min), –78 °C to r.t.
c Reaction conditions: 3 (1.36 mmol), 0 °C, BH3·SMe2 (1.63 mmol), –78 °C, n-BuLi (1.36 mmol), –78 °C to r.t., 1 h, r.t. to –78 °C, s-BuLi (1.63
mmol), 7a (1.36 mmol), –78 °C (45 min), –78 °C to r.t.
d LTMP was used as base instead of s-BuLi.
e Reaction conditions: {3 (1.36 mmol), 0 °C, BF3·OEt2 (1.63 mmol), 30 min, 0 °C to –78 °C, s-BuLi (2.99 mmol), 30 min} + {4-bromoanisole
(4.08 mmol), –78 °C, LDA (4.08 mmol), 30 min}, transferred via cannula, –78 °C to r.t.
alkaloids of Cryptostylis fulva, namely cryptostyline I ther allowed to come to room temperature and aqueous
(2f), cryptostyline II (2d), and cryptostyline III (2e) were 10% HCl was added. Usual workup and chromatographic
synthesized in yields of 41, 39 and 45%, respectively (Ta- separation afforded products 12 (14%) and 13 (41%) (Fig-
ble 3, entries 6, 4, and 5).
ure 3) indicating that once the phenylated product 1a is
formed in the reaction, it does not transfer a proton to 5.
In the above reaction, when acetic acid-d1 was added at
room temperature, instead of –10 °C, the products 12 and
13 were obtained in 15% and 39% yield, respectively.
Formation of product 13 can be rationalized as shown in
Scheme 3.27 Addition of 5 to the benzyne generates an in-
termediate carbanion 16 in which the negative charge is
located at ortho-position of the introduced phenyl substit-
uent. Intramolecular benzylic proton abstraction in 16
gives the rearranged carbanion 17 which upon reaction
with acetic acid-d1 furnishes 13.
In all the above reactions, some unreacted starting amine
3 or 9 was always recovered. This could be due to (i) in-
complete formation of the lithiated intermediate 5 or 11,
or (ii) because the lithiated intermediate gets partially
quenched by another proton source (e.g., C-1 benzylic
proton of arylated products 1 or 2, or from the solvent), or
(iii) the generated aryne intermediate is partially con-
sumed by other side reactions. To get some insight on
these aspects, two experiments were carried out: (1) To a
solution of the amine-BF3 complex 4 (1.36 mmol) in tet-
rahydrofuran (10 mL) at –78 °C, containing sec-butyllith-
ium (2.99 mmol), was added acetic acid-d1 (2.99 mmol) in
tetrahydrofuran (2 mL) at the same temperature. The reac-
tion mixture was allowed to come to room temperature
and aqueous 10% HCl was added. The 1H NMR spectrum
of the material obtained after workup revealed 100% deu-
terium incorporation at C-1 (12) (Figure 3). (2) The reac-
tion of 4 and 7a was carried out in the normal manner, but
after allowing the reaction mixture to warm from –78 °C
to –10 °C, acetic acid-d1 (in THF) was added. It was fur-
Cl
N
N
Me
Me
D
14
H
D
12
15
13
Figure 3 Results of deuterium labeling experiments
© Georg Thieme Verlag Stuttgart · New York
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K. N. Singh et al.
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Table 2 Synthesis of 1 Using Different Aryne Substratesa
s-BuLi
BF3•OEt2
–
–
–78 °C to r.t.
BF3
BF3
Me
N
+
N
R
N
N
–78 °C
0 °C
THF
+
Me
Me
Me
–78 °C
s-BuLi
4
3
Li
5
X
1
(X = F, Cl)
R
7
Entry
1
7
1
Yield (%)b,c
40 (50)
Cl
N
N
Me
Me
7a
1a
OMe
2
3
4
7b
7c
7d
1b
1c
1d
35 (47)
50 (61)
32 (45)
F
OMe
N
OMe
Me
Cl
OMe
Me
OMe
Cl
N
OMe
OMe
OMe
OMe
Cl
N
Me
MeO
OMe
5
6
7e
1e
45 (56)
MeO
OMe
OMe
N
O
O
Me
O
7f
1f
40 (52)
Cl
O
a Reaction conditions: N-methyl-1,2,3,4-tetrahydroisoquinoline (1 equiv), BF3·OEt2 (1.2 equiv), s-BuLi (2.2 equiv, 1st addition), s-BuLi (3
equiv, 2nd addition), aryl halide (3 equiv), and THF (4 mL/mmol).
b Isolated yield.
c Yields shown in parentheses are calculated on the basis of recovered starting amine.
Synthesis 2014, 46, 1739–1750
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1-Aryl-N-methyl-1,2,3,4-tetrahydroisoquinolines
1743
Table 3 C-1 Arylation of Tetrahydroisoquinolines 9a
R1
R1
R1
R2
R1
R2
BF3•OEt2
–
s-BuLi
–
–78 °C to r.t.
BF3
BF3
N
N
N
N
0 °C
R2
Me
R2
+ Me
–78 °C
+
Me
Me
R5
–78 °C
s-BuLi
9
10
Li
9a R1 = R2 = OMe
11
9b R1–R2 = OCH2O
X
R3
9c R1 = OMe, R2 = H
9d R1 = OMe, R2 = OEt
R4
(X = F, Cl)
2
R
7
Entry
9
7
2
Yield (%)b,c
1
2
9a
9a
9a
9a
9a
9a
9b
9b
9b
9b
9b
9b
9c
9c
9c
9c
9c
9c
9d
9d
9d
9d
9d
9d
7a
7b
7c
7d
7e
7f
2a (R1 = R2 = OMe; R3 = R4 = R5 = H)
35 (49)
32 (47)
45 (59)
39 (58)
45 (52)
41 (50)
39 (56)
33 (49)
41 (55)
35 (50)
44 (59)
32 (46)
32 (48)
33 (50)
45 (59)
36 (48)
41 (57)
40 (52)
36 (48)
32 (49)
47 (61)
39 (52)
43 (58)
39 (54)
2b (R1 = R2 = OMe; R3 = R5 = H, R4 = OMe)
2c (R1 = R2 = OMe; R3 = R4 = H, R5 = OMe)
2d (R1 = R2 = OMe; R3 = H, R4 = R5 = OMe)
2e (R1 = R2 = OMe; R3 = R4 = R5 = OMe)
3
4
5
6
2f (R1 = R2 = OMe; R3 = H, R4 = R5 = OCH2O)
2g (R1 + R2 = OCH2O; R3 = R4 = R5 = H)
7
7a
7b
7c
7d
7e
7f
8
2h (R1 + R2 = OCH2O; R3 = R5 = H, R4 = OMe)
2i (R1 + R2 = OCH2O; R3 = R4 = H, R5 = OMe)
2j (R1 + R2 = OCH2O; R3 = H, R4 = R5 = OMe)
2k (R1 + R2 = OCH2O; R3 = R4 = R5 = OMe)
2l (R1 + R2 = OCH2O; R3 = H, R4 = R5 = OCH2O)
2m (R1 = OMe, R2 = H; R3 = R4 = R5 = H)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
7a
7b
7c
7d
7e
7f
2n (R1 = OMe, R2 = H; R3 = R5 = H, R4 = OMe)
2o (R1 = OMe, R2 = H; R3 = R4 = H, R5 = OMe)
2p (R1 = OMe, R2 = H; R3 = H, R4 = R5 = OMe)
2q (R1 = OMe, R2 = H; R3 = R4 = R5 = OMe)
2r (R1 = OMe, R2 = H; R3 = H, R4 = R5 = OCH2O)
2s (R1 = OMe, R2 = OEt; R3 = R4 = R5 = H)
2t (R1 = OMe, R2 = OEt; R3 = R5 = H, R4 = OMe)
2u (R1 = OMe, R2 = OEt; R3 = R4 = H, R5 = OMe)
2v (R1 = OMe, R2 = OEt; R3 = H, R4 = R5 = OMe)
2w (R1 = OMe, R2 = OEt; R3 = R4 = R5 = OMe)
2x (R1 = OMe, R2 = OEt; R3 = H, R4 = R5 = OCH2O)
7a
7b
7c
7d
7e
7f
a Reaction conditions: 9 (1 equiv), BF3·OEt2 (1.2 equiv), s-BuLi (2.2 equiv, 1st addition), s-BuLi (3 equiv, 2nd addition), aryl halide (3 equiv),
and THF (4 mL/mmol).
b Isolated yield.
c Yields shown in parentheses are calculated on the basis of recovered starting amine.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1739–1750

1744
K. N. Singh et al.
PAPER
prevents its coordination with lithium atom of the base.
Furthermore, the positive charge on the nitrogen atom
now inductively facilitates α-deprotonation (Scheme 1,
5).18,19
–BF3
–BF3
Me
+N
+N
H
Me
–
H
5
–
In conclusion, direct C-1 arylation of N-methyl-1,2,3,4-
tetrahydroisoquinolines involving nucleophilic addition
of α-amino carbanions derived from Lewis acid com-
plexed THIQ to arynes has been demonstrated with appli-
cations in synthesis of cryptostyline alkaloids. The modest
yields of the products are counter-balanced by the fact that
this one-pot arylation procedure does not involve the use
of any transition metal32 and has good substrate generali-
ty. Further applications of this procedure for the synthesis
of 1-aryl-2-methylisoindolines33 and 1-aryl-2-methyl-
2,3,4,5-tetrahydro-2-benz[c]azepines34 are being ex-
plored.
16
–BF3
Me
CH3COOD
workup
+N
N
–
Me
D
13
17
Scheme 3 Proposed mechanism
1H NMR spectra were recorded on a 400 MHz NMR spectrometer.
Chemical shifts δ are reported in ppm using TMS as an internal
standard. Data are reported as follows: chemical shift, multiplicity
In this reaction, the nonbasic material, obtained after
workup, was also investigated and found to contain 14
(7%), which results from the dimerization of the benzyne
intermediate,28 and 15 (9%) which is a result of reaction
of the ortho-anion of chlorobenzene with benzyne (Figure
3).29 Thus, it may be possible that side reactions of aryne
(standard abbreviations), coupling constant (J), and integration. 13
C
NMR spectra were recorded on 75 MHz NMR spectrometer. The
chemical shifts are reported on the δ-scale relative to CDCl3 (δ =
77.0 ppm). IR spectra were carried out on neat samples using a Ni-
colet iS50 FT-IR. The wavenumbers of maximum absorption peaks
intermediates occur at about the same temperature range of IR spectroscopy are presented in cm–1. MS data (APCI) was ob-
tained on Q-Tof MicroTM mass spectrometer. Elemental analyses
where the lithiated intermediates 5 or 11 react with arynes.
were performed with a Flash 2000 (organic elemental analyzer).
As far as the difference in regioselectivity in lithiation/
substitution reactions of N-methyl-1,2,3,4-tetrahydroiso-
quinoline – at C-4 position (using strong basic conditions)
and at C-1 position (under Lewis acid complexation) – is
concerned it has been shown earlier that the heteroatom
plays a pivotal role. In the case of the uncomplexed amine,
the nitrogen atom coordinates with lithium in the transi-
tion state 20 or in a prelithiation complex 19 and promotes
‘distal lithiation’ through space (Scheme 1, 6, and Scheme
4).30
Melting points were obtained on a Thomas-Hoover apparatus in
open capillary tubes and are uncorrected. Flash column chromatog-
raphy was performed using 230–400 mesh silica gel and hexane–
EtOAc or MeOH–CHCl3 mixture as an eluent.
All lithiation reactions were carried out under N2 atmosphere. An-
hydrous solvents were transferred via syringe to flame-dried glass-
ware. THF, Et2O, and toluene were dried and distilled from sodium
benzophenone ketyl. BF3·OEt2 was freshly distilled from CaH2 un-
der reduced pressure. Pentane was purified and dried according to a
known procedure.35 Alkyllithiums were estimated by using 1,10-
phenanthroline as an indicator according to a reported procedure.36
n-BuLi was used as a 1.9 M solution in hexane. s-BuLi was used as
a 2.6 M solution in pentane. Amine 3 was prepared from isoquino-
line according to the reported procedure.37 Amine 9a was prepared
from homoveratrylamine by a known procedure.26a Tetrahydroiso-
quinoline 9b was synthesized starting from homopiperonyl-
amine.26b Amine 9c was prepared from 3-methoxybenzaldehyde via
a known route.26b,c Tetrahydroisoquinoline 9d was synthesized
from vanillin according to a reported procedure.26c Chlorobenzene
(7a) was commercially available. Substrate 7d,38a 7e,38b and 7f38c
were prepared according to known procedures. Substrate 7b and 7c
were prepared from p-fluorophenol and m-chlorophenol, respec-
tively.39 All aryne precursors and starting THIQs were dried and
distilled from CaH2, under reduced pressure, before use.
N
C
(LiR)n
N
C
N
C
Li
H
R
+
(RLi)n
H
H
H
H
H
H
H H
19
20
18
– RH
N
N
C
E+
C
E
Li
1-Aryl-N-methyl-1,2,3,4-tetrahydroisoquinolines; General Pro-
cedure
H
H
H
H
Into a flame-dried two-necked round-bottomed flask, equipped with
a magnetic stirrer bar, septum cap and a bubbler, was taken a solu-
tion of N-methyl-1,2,3,4-tetrahydroisoquinoline (3; 200 mg, 1.36
mmol, 1 equiv) or the substituted analogue 9 (1.36 mmol, 1 equiv)
in anhydrous THF (10 mL) under an inert N2 atmosphere. It was
cooled to 0 °C and BF3·OEt2 (0.25 mL, 1.63 mmol, 1.2 equiv) was
added dropwise. The turbid white solution was stirred at 0 °C for 30
min. It was then cooled to –78 °C and s-BuLi [1.43 mL (2.6 M in
pentane), 2.99 mmol, 2.2 equiv] was added dropwise. A deep red
color (indicative of benzylic carbanion formation) appeared imme-
22
21
Scheme 4 Nitrogen-assisted deprotonation, E+ = electrophile
On the other hand, the nitrogen lone pair, unlike P, O, or
S, is also known to generate a relatively strong repulsive
interaction with an adjoining negative charge thus pre-
venting α-deprotonation.31 Prior complexation of the ni-
trogen atom with a strong Lewis acid (Scheme 1, 4)
Synthesis 2014, 46, 1739–1750
© Georg Thieme Verlag Stuttgart · New York

PAPER
1-Aryl-N-methyl-1,2,3,4-tetrahydroisoquinolines
MS (APCI): m/z = 284.17 [M + H]+.
1745
diately. The solution was stirred at the same temperature for 30 min.
The second instalment of s-BuLi [1.96 mL (2.6 M in pentane), 4.08
mmol, 3 equiv] was added followed by the addition of a solution of
aryl halide 7 (4.08 mmol, 3 equiv) in THF (1–2 mL). The reaction
mixture was stirred at –78 °C for 45 min and was allowed to warm
to r.t. slowly over a period of 4–5 h. The reaction was quenched with
aq 10% HCl (15 mL) and the contents were poured into Et2O (25
mL). The aqueous layer was separated and the organic layer was
further extracted with aq 10% HCl (2 × 15 mL). The combined
aqueous layers were washed with Et2O (2 × 20 mL) to remove non-
basic impurities, made alkaline with solid Na2CO3, and extracted
with CHCl3 (4 × 15 mL). The combined organic layers were washed
with brine (20 mL) and dried (Na2SO4). The solvent was evaporated
in vacuo to afford the crude product, which was purified by flash
column chromatography using 230–400 mesh silica gel. Elution
with EtOAc–hexane (3:7) or MeOH–CHCl3 (2:98) afforded the 1-
aryl substituted product. Further elution of the column with same
solvent afforded the unreacted starting material (Tables 2 and 3).
Anal. Calcd for C18H21NO2: C, 76.29; H, 7.47; N, 4.94. Found: C,
76.34; H, 7.38; N, 4.93.
1-(3,4,5-Trimethoxyphenyl)-2-methyl-1,2,3,4-tetrahydroiso-
quinoline (1e)
Yield: 191 mg (45%); pale yellow solid; mp 135–138 °C.
IR (neat): 2939, 2836, 1478, 1254, 1008 cm–1.
1H NMR (400 MHz, CDCl3): δ = 6.98–6.97 (m, 2 H, ArH), 6.90–
6.86 (m, 1 H, Ar–H), 6.56 (d, J = 7.8 Hz, 1 H, ArH), 6.39 (s, 2 H,
ArH), 3.98 (s, 1 H, C1-H), 3.75 (s, 3 H, OCH3), 3.74 (s, 6 H, 2 ×
OCH3), 3.17–3.13 (m, 1 H, C3-H), 3.06–3.01 (m, 1 H, C3-H), 2.67
(br d, J = 16.0 Hz, 1 H, C4-H), 2.48 (td, J = 11.4, 3.6 Hz, 1 H, C4-
H), 2.14 (s, 3 H, NCH3).
13C NMR (75 MHz, CDCl3): δ = 153.2, 139.4, 138.3, 133.8, 131.3,
128.2, 128.2, 126.0, 125.7, 106.5, 72.2, 60.5, 56.0, 52.8, 44.6, 29.5.
MS (APCI): m/z = 314.13 [M + H]+.
2-Methyl-1-phenyl-1,2,3,4-tetrahydroisoquinoline (1a)40
Yield: 121 mg (40%); yellow oil.
Anal. Calcd for C19H23NO3: C, 72.82; H, 7.40; N, 4.47. Found: C,
72.54; H, 7.34; N, 4.53.
1H NMR (400 MHz, CDCl3): δ = 7.19–7.10 (m, 5 H, ArH), 6.97–
6.91 (m, 2 H, ArH), 6.81 (t, J = 8.1 Hz, 1 H, ArH), 6.48 (d, J = 7.8
Hz, 1 H, ArH), 4.09 (s, 1 H, C1-H), 3.18–3.12 (m, 1 H, C3-H), 3.02–
2.97 (m, 1 H, C3-H), 2.66 (dt, J = 16.1, 3.1 Hz, 1 H, C4-H), 2.48 (td,
J = 11.3, 3.7 Hz, 1 H, C4-H), 2.11 (s, 3 H, NCH3).
2-Methyl-1-(3,4-methylenedioxyphenyl)-1,2,3,4-tetrahydroiso-
quinoline (1f)
Yield: 145 mg (40%); colorless oil.
IR (neat): 2904, 2843, 1550, 1235, 1082 cm–1.
1H NMR (400 MHz, CDCl3): δ = 6.98–6.93 (m, 2 H, ArH), 6.88–
6.84 (m, 1 H, ArH), 6.66 (dd, J = 7.8, 1.4 Hz, 1 H, ArH), 6.63–6.61
(m, 2 H, ArH), 6.55 (d, J = 7.8 Hz, 1 H, ArH), 5.83 (d, J = 1.4 Hz,
1 H, OCH2O), 5.81 (d, J = 1.4 Hz, 1 H, OCH2O), 4.01 (s, 1 H, C1-
H), 3.18–3.10 (m, 1 H, C3-H), 3.02–2.97 (m, 1 H, C3-H), 2.65 (dt,
J = 15.8, 2.8 Hz, 1 H, C4-H), 2.47 (td, J = 11.3, 3.7 Hz, 1 H, C4-H),
2.13 (s, 3 H, NCH3).
13C NMR (75 MHz, CDCl3): δ = 147.9, 146.9, 138.1, 138.1, 134.0,
128.0, 127.9, 126.0, 125.9, 122.9, 109.8, 107.4, 100.7, 71.3, 52.5,
44.4, 29.8.
1-(4-Methoxyphenyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline
(1b)
Yield: 119 mg (35%); yellow solid; mp 78–80 °C.
IR (neat): 2935, 2840, 1497, 1263, 1028 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.04 (d, J = 8.6 Hz, 2 H, ArH),
6.97–6.92 (m, 2 H, ArH), 6.82 (t, J = 8.1 Hz, 1 H, ArH), 6.69 (d, J =
8.6 Hz, 2 H, ArH), 6.49 (d, J = 7.8 Hz, 1 H, ArH), 4.04 (s, 1 H, C1-
H), 3.69 (s, 3 H, OCH3), 3.15–3.11 (m, 1 H, C3-H), 3.02–2.97 (m, 1
H, C3-H), 2.66 (dt, J = 16.0, 3.0 Hz, 1 H, C4-H), 2.47 (td, J = 11.2,
3.7 Hz, 1 H, C4-H), 2.11 (s, 3 H, NCH3).
13C NMR (75 MHz, CDCl3): δ = 158.8, 138.9, 136.1, 134.1, 130.5,
128.6, 128.2, 125.8, 125.6, 113.6, 70.9, 54.9, 52.4, 44.4, 29.6.
MS (APCI): m/z = 254.08 [M + H]+.
MS (APCI): m/z = 268.44 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C17H18NO2: 268.1332; found:
268.1331.
HRMS (ESI): m/z [M + H]+ calcd for C17H20NO: 254.1539; found:
254.1543.
6,7-Dimethoxy-2-methyl-1-phenyl-1,2,3,4-tetrahydroisoquino-
line (2a)42
Yield: 96 mg (35%); light yellow solid; mp 76–78 °C (Lit.42 mp 77–
79 °C).
1H NMR (400 MHz, CDCl3): δ = 7.23–7.13 (m, 5 H, ArH), 6.48 (s,
1 H, ArH), 5.97 (s, 1 H, ArH), 4.06 (s, 1 H, C1-H), 3.75 (s, 3 H,
OCH3), 3.47 (s, 3 H, OCH3), 3.12–3.05 (m, 1 H, C3-H), 3.02–2.97
(m, 1 H, C3-H), 2.60 (dt, J = 15.7, 3.3 Hz, 1 H, C4-H), 2.48 (td, J =
10.9, 3.7 Hz, 1 H, C4-H), 2.14 (s, 3 H, NCH3).
1-(3-Methoxyphenyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline
(1c)41
Yield: 172 mg (50%); light yellow oil.
1H NMR (400 MHz, CDCl3): δ = 7.08 (t, J = 7.8 Hz, 1 H, ArH),
6.99–6.93 (m, 2 H, ArH), 6.84 (t, J = 8.1 Hz, 1 H, ArH), 6.76 (d, J =
7.5 Hz, 1 H, ArH), 6.71–6.66 (m, 2 H, ArH), 6.53 (d, J = 7.8 Hz, 1
H, ArH), 4.07 (s, 1 H, C1-H), 3.67 (s, 3 H, OCH3), 3.20–3.13 (m, 1
H, C3-H), 3.04–2.99 (m, 1 H, C3-H), 2.67 (dt, J = 16.1, 2.9 Hz, 1 H,
C4-H), 2.49 (td, J = 11.3, 3.7 Hz, 1 H, C4-H), 2.14 (s, 3 H, NCH3).
6,7-Dimethoxy-1-(4-methoxyphenyl)-2-methyl-1,2,3,4-tetrahy-
droisoquinoline (2b)43
Yield: 97 mg (32%); light brown solid; mp 93–95 °C (Lit.43 mp 96–
97 °C).
1-(3,4-Dimethoxyphenyl)-2-methyl-1,2,3,4-tetrahydroisoquino-
line (1d)
Yield: 123 mg (32%); white solid; mp 86–87 °C.
IR (neat): 2940, 2843, 1505, 1253, 1028 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.05 (d, J = 8.7 Hz, 2 H, ArH),
6.71 (d, J = 8.6 Hz, 2 H, ArH), 6.46 (s, 1 H, ArH), 5.98 (s, 1 H,
ArH), 4.02 (s, 1 H, C1-H), 3.74 (s, 3 H, OCH3), 3.70 (s, 3 H, OCH3),
3.49 (s, 3 H, OCH3), 3.09–3.02 (m, 1 H, C3-H), 3.00–2.96 (m, 1 H,
C3-H), 2.59 (dt, J = 15.7, 3.4 Hz, 1 H, C4-H), 2.46 (td, J = 10.7, 3.7
Hz, 1 H, C4-H), 2.12 (s, 3 H, NCH3).
1H NMR (400 MHz, CDCl3): δ = 6.99–6.94 (m, 2 H, ArH), 6.83 (t,
J = 8.1 Hz, 1 H, ArH), 6.72 (dd, J = 8.1, 1.8 Hz, 1 H, ArH), 6.67 (d,
J = 8.1 Hz, 1 H, ArH), 6.63 (d, J = 1.8 Hz, 1 H, ArH), 6.52 (d, J =
7.8 Hz, 1 H, ArH), 4.01 (s, 1 H, C1-H), 3.78 (s, 3 H, OCH3), 3.71 (s,
3 H, OCH3), 3.21–3.13 (m, 1 H, C3-H), 3.05–3.00 (m, 1 H, C3-H),
2.67 (br d, J = 16.0 Hz, 1 H, C4-H), 2.48 (td, J = 11.4, 3.68 Hz, 1 H,
C4-H), 2.12 (s, 3 H, NCH3).
13C NMR (75 MHz, CDCl3): δ = 149.4, 148.5, 138.6, 136.5, 133.9,
128.4, 128.2, 125.8, 125.6, 122.1, 112.0, 110.5, 71.5, 55.7, 52.7,
44.5, 29.5.
6,7-Dimethoxy-1-(3-methoxyphenyl)-2-methyl-1,2,3,4-tetrahy-
droisoquinoline (2c)
Yield: 136 mg (45%); yellow pasty mass.
IR (neat): 2946, 2849, 1504, 1260, 1037 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.09 (t, J = 7.6 Hz, 1 H, ArH), 6.75
(d, J = 7.6 Hz, 1 H, ArH), 6.70–6.67 (m, 2 H, ArH), 6.47 (s, 1 H,
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1739–1750

1746
K. N. Singh et al.
PAPER
ArH), 6.01 (s, 1 H, ArH), 4.02 (s, 1 H, C1-H), 3.76 (s, 3 H, OCH3),
3.69 (s, 3 H, OCH3), 3.50 (s, 3 H, OCH3), 3.08–3.01 (m, 1 H, C3-H),
3.00–2.97 (m, 1 H, C3-H), 2.59 (dd, J = 15.8, 3.1 Hz, 1 H, C4-H),
2.46 (td, J = 10.9, 3.6 Hz, 1 H, C4-H), 2.14 (s, 3 H, NCH3).
13C NMR (75 MHz, CDCl3): δ = 159.6, 147.5, 147.2, 145.5, 130.3,
128.9, 126.2, 122.0, 114.6, 112.9, 111.5, 110.8, 71.1, 55.7, 55.6,
54.9, 52.4, 44.4, 29.0.
13C NMR (75 MHz, CDCl3): δ = 158.9, 145.8, 145.7, 135.8, 131.7,
130.4, 127.3, 113.6, 108.4, 107.7, 100.4, 70.8, 55.0, 52.3, 44.2,
29.5.
MS (APCI): m/z = 298.11 [M + H]+.
Anal. Calcd for C18H19NO3: C, 72.71; H, 6.44; N, 4.71. Found: C,
72.59; H, 6.34; N, 4.70.
MS (APCI): m/z = 314.10 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C19H24NO3: 314.1750; found:
1-(3-Methoxyphenyl)-2-methyl-6,7-methylenedioxy-1,2,3,4-tet-
rahydroisoquinoline (2i)
Yield: 127 mg (41%); light brown oil.
314.1754.
IR (neat): 2949, 2841, 1493, 1245, 1040 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.17 (t, J = 7.4 Hz, 1 H, ArH), 6.82
(d, J = 7.6 Hz, 1 H, ArH), 6.77–6.75 (m, 2 H, ArH), 6.52 (s, 1 H,
ArH), 6.08 (s, 1 H, ArH), 5.82 (d, J = 1.4 Hz, 1 H, OCH2O), 5.79 (d,
J = 1.4 Hz, 1 H, OCH2O), 4.06 (s, 1 H, C1-H), 3.77 (s, 3 H, OCH3),
3.15–3.07 (m, 1 H, C3-H), 3.05–3.03 (m, 1 H, C3-H), 2.65 (br d, J =
15.8 Hz, 1 H, C4-H), 2.54 (td, J = 11.0, 3.6 Hz, 1 H, C4-H), 2.20 (s,
3 H, NCH3).
13C NMR (75 MHz, CDCl3): δ = 159.8, 145.8, 145.6, 132.9, 131.4,
129.0, 127.1, 122.0, 114.5, 113.1, 108.3, 107.7, 100.3, 71.6, 54.8,
52.5, 44.5, 29.7.
6,7-Dimethoxy-1-(3,4-dimethoxyphenyl)-2-methyl-1,2,3,4-tet-
rahydroisoquinoline [(±)-Cryptostyline II, 2d]14
Yield: 129 mg (39%); pale yellow solid; mp 95–96 °C (Lit.14 mp
94 °C).
1H NMR (400 MHz, CDCl3): δ = 6.73 (dd, J = 8.1, 1.8 Hz, 1 H,
ArH), 6.69 (d, J = 8.1 Hz, 1 H, ArH), 6.65 (d, J = 1.6 Hz, 1 H, ArH),
6.48 (s, 1 H, ArH), 6.02 (s, 1 H, ArH), 3.97 (s, 1 H, C1-H), 3.81 (s,
3 H, OCH3), 3.77 (s, 3 H, OCH3), 3.74 (s, 3 H, OCH3), 3.50 (s, 3 H,
OCH3), 3.09–3.03 (m, 1 H, C3-H), 3.02–2.99 (m, 1 H, C3-H), 2.60
(br d, J = 15.6 Hz, 1 H, C4-H), 2.47 (td, J = 10.8, 3.5 Hz, 1 H, C4-
H), 2.13 (s, 3 H, NCH3).
MS (APCI): m/z = 298.13 [M + H]+.
6,7-Dimethoxy-1-(3,4,5-trimethoxyphenyl)-2-methyl-1,2,3,4-
tetrahydroisoquinoline [(±)-Cryptostyline III, 2e]44
Yield: 162 mg (45%); light brown solid; mp 138–140 °C (Lit.44 mp
140–141 °C).
1H NMR (400 MHz, CDCl3): δ = 6.47 (s, 1 H, ArH), 6.40 (s, 2 H,
ArH), 6.05 (s, 1 H, ArH), 3.93 (s, 1 H, C1-H), 3.78 (s, 6 H, 2 ×
OCH3), 3.76 (s, 6 H, 2 × OCH3), 3.52 (s, 3 H, OCH3), 3.07–3.03 (m,
1 H, C3-H), 3.01–2.98 (m, 1 H, C3-H), 2.59 (br d, J = 15.6 Hz, 1 H,
C4-H), 2.45 (td, J = 10.5, 3.2 Hz, 1 H, C4-H), 2.15 (s, 3 H, NCH3).
HRMS (ESI): m/z [M + H]+ calcd for C18H20NO3: 298.1437; found:
298.1437.
1-(3,4-Dimethoxyphenyl)-2-methyl-6,7-methylenedioxy-1,2,3,4-
tetrahydroisoquinoline (2j)
Yield: 119 mg (35%); pale yellow solid; mp 126–128 °C.
IR (neat): 2945, 2826, 1472, 1253, 1028 cm–1.
1H NMR (400 MHz, CDCl3): δ = 6.78 (dd, J = 8.1, 1.7 Hz, 1 H,
ArH), 6.75 (d, J = 8.1 Hz, 1 H, ArH), 6.71 (d, J = 1.6 Hz, 1 H, ArH),
6.52 (s, 1 H, ArH), 6.06 (s, 1 H, ArH), 5.81 (d, J = 1.4 Hz, 1 H,
OCH2O), 5.79 (d, J = 1.4 Hz, 1 H, OCH2O), 4.00 (s, 1 H, C1-H),
3.86 (s, 3 H, OCH3), 3.81 (s, 3 H, OCH3), 3.15–3.07 (m, 1 H, C3-H),
3.06–3.04 (m, 1 H, C3-H), 2.64 (br d, J = 15.8 Hz, 1 H, C4-H), 2.51
(td, J = 11.1, 3.6 Hz, 1 H, C4-H), 2.18 (s, 3 H, NCH3).
13C NMR (75 MHz, CDCl3): δ = 149.2, 148.4, 145.8, 145.6, 135.9,
131.3, 127.0, 121.9, 111.6, 110.3, 108.1, 107.6, 100.3, 71.3, 55.6,
55.6, 52.4, 44.1, 29.2.
6,7-Dimethoxy-2-methyl-1-(3,4-methylenedioxyphenyl)-1,2,3,4-
tetrahydroisoquinoline [(±)-Cryptostyline I, 2f]11
Yield: 129 mg (41%); yellow solid; mp 116–117 °C (Lit.11 mp 117–
118 °C).
1H NMR (400 MHz, CDCl3): δ = 6.65 (dd, J = 7.9, 1.4 Hz, 1 H,
ArH), 6.62 (d, J = 7.8 Hz, 1 H, ArH), 6.61 (d, J = 1.2 Hz, 1 H, ArH),
6.46 (s, 1 H, ArH), 6.04 (s, 1 H, ArH), 5.84 (d, J = 1.1 Hz, 1 H,
OCH2O), 5.83 (d, J = 1.2 Hz, 1 H, OCH2O), 3.98 (s, 1 H, C1-H),
3.75 (s, 3 H, OCH3), 3.53 (s, 3 H, OCH3), 3.09–3.02 (m, 1 H, C3-H),
3.00–2.95 (m, 1 H, C3-H), 2.58 (dd, J = 15.7, 3.0 Hz, 1 H, C4-H),
2.45 (td, J = 10.8, 3.5 Hz, 1 H, C4-H), 2.14 (s, 3 H, NCH3).
MS (APCI): m/z = 328.27 [M + H]+.
Anal. Calcd for C19H21NO4: C, 69.71; H, 6.47; N, 4.28. Found: C,
69.69; H, 6.34; N, 4.10.
2-Methyl-6,7-methylenedioxy-1-phenyl-1,2,3,4-tetrahydroiso-
quinoline (2g)45
1-(3,4,5-Trimethoxyphenyl)-2-methyl-6,7-methylenedioxy-
1,2,3,4-tetrahydroisoquinoline (2k)9d
Yield: 109 mg (39%); light yellow oil.
Yield: 164 mg (44%); white solid; mp 130–133 °C (Lit.9d mp 133–
134 °C).
1H NMR (400 MHz, CDCl3): δ = 7.28–7.24 (m, 2 H, ArH), 7.22–
7.19 (m, 3 H, ArH), 6.51 (s, 1 H, ArH), 6.03 (s, 1 H, ArH), 5.78 (d,
J = 1.4 Hz, 1 H, OCH2O), 5.75 (d, J = 1.4 Hz, 1 H, OCH2O), 4.07
(s, 1 H, C1-H), 3.13–3.09 (m, 1 H, C3-H), 3.05–3.01 (m, 1 H, C3-H),
2.63 (dt, J = 15.7, 3.2 Hz, 1 H, C4-H), 2.51 (td, J = 11.0, 3.7 Hz, 1
H, C4-H), 2.17 (s, 3 H, NCH3).
1H NMR (400 MHz, CDCl3): δ = 6.53 (s, 1 H, ArH), 6.47 (s, 2 H,
ArH), 6.11 (s, 1 H, ArH), 5.84 (d, J = 1.4 Hz, 1 H, OCH2O), 5.82 (d,
J = 1.4 Hz, 1 H, OCH2O), 3.98 (s, 1 H, C1-H), 3.83 (s, 6 H, 2 ×
OCH3), 3.82 (s, 3 H, OCH3), 3.17–3.10 (m, 1 H, C3-H), 3.08–3.07
(m, 1 H, C3-H), 2.65 (br d, J = 15.8 Hz, 1 H, C4-H), 2.50 (br t, J =
11.1 Hz, 1 H, C4-H), 2.21 (s, 3 H, NCH3).
1-(4-Methoxyphenyl)-2-methyl-6,7-methylenedioxy-1,2,3,4-tet-
rahydroisoquinoline (2h)
Yield: 102 mg (33%); light brown solid; mp 86–88 °C.
IR (neat): 2943, 2833, 1497, 1247, 1040 cm–1.
2-Methyl-6,7-methylenedioxy-1-(3,4-methylenedioxyphenyl)-
1,2,3,4- tetrahydroisoquinoline (2l)
Yield: 102 mg (32%); yellow solid; mp 164–165 °C.
1H NMR (400 MHz, CDCl3): δ = 7.11 (d, J = 8.6 Hz, 2 H, ArH),
6.79 (d, J = 8.7 Hz, 2 H, ArH), 6.51 (s, 1 H, ArH), 6.04 (s, 1 H,
ArH), 5.80 (d, J = 1.48 Hz, 1 H, OCH2O), 5.78 (d, J = 1.4 Hz, 1 H,
OCH2O), 4.04 (s, 1 H, C1-H), 3.78 (s, 3 H, OCH3), 3.17–3.09 (m, 1
H, C3-H), 3.06–3.01 (m, 1 H, C3-H), 2.64 (dt, J = 15.8, 2.8 Hz, 1 H,
C4-H), 2.51 (td, J = 10.9, 3.6 Hz, 1 H, C4-H), 2.18 (s, 3 H, NCH3).
IR (neat): 2981, 2896, 1478, 1236, 1039 cm–1.
1H NMR (400 MHz, CDCl3): δ = 6.72 (dd, J = 7.9, 1.4 Hz, 1 H,
ArH), 6.69 (d, J = 7.7 Hz, 1 H, ArH), 6.67 (d, J = 1.1 Hz, 1 H, ArH),
6.51 (s, 1 H, ArH), 6.09 (s, 1 H, ArH), 5.92 (d, J = 1.5 Hz, 1 H,
OCH2O), 5.90 (d, J = 1.5 Hz, 1 H, OCH2O), 5.81 (d, J = 1.4 Hz, 1
H, OCH2O), 5.79 (d, J = 1.4 Hz, 1 H, OCH2O), 4.00 (s, 1 H, C1-H),
3.16–3.08 (m, 1 H, C3-H), 3.05–3.01 (m, 1 H, C3-H), 2.62 (dt, J =
Synthesis 2014, 46, 1739–1750
© Georg Thieme Verlag Stuttgart · New York

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1-Aryl-N-methyl-1,2,3,4-tetrahydroisoquinolines
1747
15.8, 3.1 Hz, 1 H, C4-H), 2.50 (td, J = 11.0, 3.6 Hz, 1 H, C4-H), 2.19
(s, 3 H, NCH3).
13C NMR (75 MHz, CDCl3): δ = 147.9, 146.9, 145.9, 145.8, 138.0,
131.6, 127.3, 122.8, 109.3, 108.3, 107.8, 107.5, 100.8, 100.5, 71.3,
52.4, 44.3, 29.6.
6-Methoxy-1-(3,4,5-trimethoxyphenyl)-2-methyl-1,2,3,4-tetra-
hydroisoquinoline (2q)47
Yield: 158 mg (41%); pale brown solid; mp 96–97 °C (Lit.47 mp
94–95 °C).
1H NMR (400 MHz, CDCl3): δ = 6.50–6.48 (m, 1 H, ArH), 6.46–
6.42 (m, 2 H, ArH), 6.39 (s, 2 H, ArH), 3.92 (s, 1 H, C1-H), 3.74 (s,
3 H, OCH3), 3.72 (s, 6 H, 2 × OCH3), 3.65 (s, 3 H, OCH3), 3.15–
3.11 (m, 1 H, C3-H), 3.03–2.99 (m, 1 H, C3-H), 2.63 (br d, J = 16.0
Hz, 1 H, C4-H), 2.46 (td, J = 11.4, 3.7 Hz, 1 H, C4-H), 2.13 (s, 3 H,
NCH3).
MS (APCI): m/z = 312.41 [M + H]+.
Anal. Calcd for C18H17NO4: C, 69.44; H, 5.50; N, 4.50. Found: C,
69.12; H, 5.62; N, 4.59.
6-Methoxy-2-methyl-1-phenyl-1,2,3,4-tetrahydroisoquinoline
(2m)5b
6-Methoxy-2-methyl-1-(3,4-methylenedioxyphenyl)-1,2,3,4-tet-
rahydroisoquinoline (2r)
Yield: 134 mg (40%); white solid; mp 110–113 °C.
IR (neat): 2963, 2810, 1490, 1276, 1079 cm–1.
Yield: 91 mg (32%); yellow oil.
1H NMR (400 MHz, CDCl3): δ = 7.21–7.13 (m, 5 H, ArH), 6.50 (d,
J = 2.0 Hz, 1 H, ArH), 6.41 (d, J = 2.4 Hz, 1 H, ArH), 6.38 (d, J =
8.6 Hz, 1 H, ArH), 4.04 (s, 1 H, C1-H), 3.65 (s, 3 H, OCH3), 3.15–
2.97 (m, 2 H, C3-H), 2.65 (br d, J = 16.0 Hz, 1 H, C4-H), 2.48 (td,
J = 11.3, 3.8 Hz, 1 H, C4-H), 2.12 (s, 3 H, NCH3).
1H NMR (400 MHz, CDCl3): δ = 6.65 (dd, J = 7.8, 1.4 Hz, 1 H,
ArH), 6.61 (d, J = 7.8 Hz, 1 H, ArH), 6.60 (d, J = 1.4 Hz, 1 H, ArH),
6.48 (d, J = 1.7 Hz, 1 H, ArH), 6.45–6.42 (m, 2 H, ArH), 5.82 (d,
J = 1.4 Hz, 1 H, OCH2O), 5.81 (d, J = 1.4 Hz, 1 H, OCH2O), 3.96
(s, 1 H, C1-H), 3.65 (s, 3 H, OCH3), 3.15–3.08 (m, 1 H, C3-H), 3.00–
2.95 (m, 1 H, C3-H), 2.66–2.62 (m, 1 H, C4-H), 2.45 (td, J = 11.3,
3.7 Hz, 1 H, C4-H), 2.12 (s, 3 H, NCH3).
13C NMR (75 MHz, CDCl3): δ = 157.7, 147.9, 146.8, 138.3, 135.2,
130.9, 129.5, 122.8, 112.5, 112.2, 109.3, 107.4, 100.7, 70.9, 54.8,
52.5, 44.3, 29.9.
6-Methoxy-1-(4-methoxyphenyl)-2-methyl-1,2,3,4-tetrahy-
droisoquinoline (2n)
Yield: 105 mg (33%); light yellow solid; mp 94–96 °C.
IR (neat): 2941, 2834, 1505, 1253, 1029 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.04 (d, J = 8.6 Hz, 2 H, ArH),
6.70 (d, J = 8.7 Hz, 2 H, ArH), 6.49 (s, 1 H, ArH), 6.44–6.39 (m, 2
H, ArH), 4.00 (s, 1 H, C1-H), 3.70 (s, 3 H, OCH3), 3.64 (s, 3 H,
OCH3), 3.18–3.09 (m, 1 H, C3-H), 3.01–2.96 (m, 1 H, C3-H), 2.63
(dt, J = 16.1, 3.0 Hz, 1 H, C4-H), 2.47 (td, J = 11.2, 3.8 Hz, 1 H, C4-
H), 2.11 (s, 3 H, NCH3).
MS (APCI): m/z = 298.53 [M + H]+.
Anal. Calcd for C18H19NO3: C, 72.71; H, 6.44; N, 4.71. Found: C,
72.59; H, 6.35; N, 4.65.
13C NMR (75 MHz, CDCl3): δ = 158.8, 157.6, 136.2, 135.2, 131.3,
130.4, 129.6, 113.5, 112.4, 112.1, 70.5, 55.0, 54.9, 52.5, 44.3, 29.8.
MS (APCI): m/z = 284.09 [M + H]+.
7-Ethoxy-6-methoxy-2-methyl-1-phenyl-1,2,3,4-tetrahydroiso-
quinoline (2s)
Yield: 96 mg (36%); yellow oil.
Anal. Calcd for C18H21NO2: C, 76.29; H, 7.47; N, 4.94. Found: C,
76.44; H, 7.29; N, 4.88.
IR (neat): 2927, 2773, 1476, 1227, 1138 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.19–7.10 (m, 5 H, ArH), 6.44 (s,
1 H, ArH), 5.93 (s, 1 H, ArH), 4.02 (s, 1 H, C1-H), 3.70 (s, 3 H,
OCH3), 3.69–3.55 (m, 2 H, OCH2CH3), 3.10–3.02 (m, 1 H, C3-H),
2.99–2.94 (m, 1 H, C3-H), 2.62–2.57 (m, 1 H, C4-H), 2.45 (td, J =
11.0, 3.8 Hz, 1 H, C4-H), 2.10 (s, 3 H, NCH3), 1.13 (t, J = 7.0 Hz, 3
H, OCH2CH3).
6-Methoxy-1-(3-methoxyphenyl)-2-methyl-1,2,3,4-tetrahy-
droisoquinoline (2o)
Yield: 143 mg (45%); yellow viscous oil.
IR (neat): 2914, 2843, 1550, 1235, 1092 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.08 (t, J = 7.7 Hz, 1 H, ArH), 6.75
(d, J = 7.6 Hz, 1 H, ArH), 6.70–6.66 (m, 2 H, ArH), 6.49 (s, 1 H,
ArH), 6.45–6.43 (m, 2 H, ArH), 4.01 (s, 1 H, C1-H), 3.67 (s, 3 H,
OCH3), 3.65 (s, 3 H, OCH3), 3.18–3.11 (m, 1 H, C3-H), 3.02–2.97
(m, 1 H, C3-H), 2.63 (dt, J = 16.0, 3.1 Hz, 1 H, C4-H), 2.47 (td, J =
11.3, 3.7 Hz, 1 H, C4-H), 2.13 (s, 3 H, NCH3).
13C NMR (75 MHz, CDCl3): δ = 147.7, 146.3, 143.9, 130.3, 129.3,
127.9, 127.1, 126.1, 113.2, 111.0, 70.9, 63.9, 55.5, 52.2, 44.2, 28.9,
14.5.
MS (APCI): m/z = 298.93 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C19H24NO2: 298.1801; found:
13C NMR (75 MHz, CDCl3): δ = 159.7, 157.6, 145.8, 135.1, 130.8,
129.5, 129.0, 122.0, 114.6, 112.9, 112.5, 112.2, 71.3, 54.9, 54.9,
52.6, 44.5, 29.9.
298.1804.
7-Ethoxy-6-methoxy-1-(4-methoxyphenyl)-2-methyl-1,2,3,4-
tetrahydroisoquinoline (2t)
Yield: 94 mg (32%); yellow solid; mp 87–89 °C.
MS (APCI): m/z = 284.21 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C18H22NO2: 284.1645; found:
IR (neat): 2945, 2838, 1494, 1247, 1038 cm–1.
284.1645.
1H NMR (400 MHz, CDCl3): δ = 7.02 (d, J = 8.6 Hz, 2 H, ArH),
6.68 (d, J = 8.6 Hz, 2 H, ArH), 6.43 (s, 1 H, ArH), 5.96 (s, 1 H,
ArH), 3.98 (s, 1 H, C1-H), 3.71 (s, 3 H, OCH3), 3.67 (s, 3 H, OCH3),
3.66–3.59 (m, 2 H, OCH2CH3), 3.07–2.99 (m, 1 H, C3-H), 2.98–
2.93 (m, 1 H, C3-H), 2.56 (br d, J = 15.6 Hz, 1 H, C4-H), 2.44 (td,
J = 10.8, 3.7 Hz, 1 H, C4-H), 2.09 (s, 3 H, NCH3), 1.16 (t, J = 7.0
Hz, 3 H, OCH2CH3).
13C NMR (75 MHz, CDCl3): δ = 158.6, 147.7, 146.2, 135.7, 130.6,
130.2, 126.2, 113.3, 111.0, 70.2, 63.9, 55.5, 54.7, 52.1, 44.0, 28.8,
14.6.
6-Methoxy-1-(3,4-dimethoxyphenyl)-2-methyl-1,2,3,4-tetrahy-
droisoquinoline (2p)46
Yield: 127 mg (36%); light brown solid; mp 70–72 °C.
1H NMR (400 MHz, CDCl3): δ = 6.71 (dd, J = 8.1, 1.8 Hz, 1 H,
ArH), 6.67 (d, J = 8.1 Hz, 1 H, ArH), 6.63 (d, J = 1.7 Hz, 1 H, ArH),
6.50 (s, 1 H, ArH), 6.44–6.42 (m, 2 H, ArH), 3.95 (s, 1 H, C1-H),
3.79 (s, 3 H, OCH3), 3.72 (s, 3 H, OCH3), 3.66 (s, 3 H, OCH3), 3.19–
3.11 (m, 1 H, C3-H), 3.03–2.98 (m, 1 H, C3-H), 2.64 (br d, J = 16.1
Hz, 1 H, C4-H), 2.46 (td, J = 11.4, 3.7 Hz, 1 H, C4-H), 2.11 (s, 3 H,
NCH3).
MS (APCI): m/z = 328.24 [M + H]+.
Anal. Calcd for C20H25NO3: C, 73.37; H, 7.70; N, 4.28. Found: C,
73.61; H, 7.52; N, 4.19.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1739–1750

1748
K. N. Singh et al.
PAPER
7-Ethoxy-6-methoxy-1-(3-methoxyphenyl)-2-methyl-1,2,3,4-
tetrahydroisoquinoline (2u)
H, C4-H), 2.44 (td, J = 10.8, 3.5 Hz, 1 H, C4-H), 2.13 (s, 3 H, NCH3),
1.21 (t, J = 7 Hz, 3 H, OCH2CH3).
13C NMR (75 MHz, CDCl3): δ = 147.9, 147.8, 146.8, 146.5, 138.0,
130.4, 126.4, 122.7, 113.3, 111.1, 109.3, 107.3, 100.7, 70.8, 64.2,
55.6, 52.3, 44.3, 29.0, 14.7.
Yield: 139 mg (47%); colorless oil.
IR (neat): 2944, 2836, 1497, 1247, 1040 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.15 (t, J = 7.7 Hz, 1 H, ArH), 6.81
(d, J = 7.6 Hz, 1 H, ArH), 6.77–6.74 (m, 2 H, ArH), 6.53 (s, 1 H,
ArH), 6.07 (s, 1 H, ArH), 4.08 (s, 1 H, C1-H), 3.81 (s, 3 H, OCH3),
3.75 (s, 3 H, OCH3), 3.74–3.68 (m, 2 H, OCH2CH3), 3.15–3.09 (m,
1 H, C3-H), 3.08–3.05 (m, 1 H, C3-H), 2.66 (br d, J = 15.6 Hz, 1 H,
C4-H), 2.54 (td, J = 10.9, 3.6 Hz, 1 H, C4-H), 2.21 (s, 3 H, NCH3),
1.25 (t, J = 7.0 Hz, 3 H, OCH2CH3).
MS (APCI): m/z = 342.39 [M + H]+.
Anal. Calcd for C20H23NO4: C, 70.36; H, 6.79; N, 4.10. Found: C,
70.59; H, 6.52; N, 4.29.
Deuterium Labeling Experiments
(1) Into a flame-dried two-necked round-bottomed flask, equipped
with a magnetic stirrer bar, septum cap and a bubbler, was taken a
solution of N-methyl-1,2,3,4-tetrahydroisoquinoline (3, 200 mg,
1.36 mmol, 1 equiv) in anhydrous THF (10 mL) under an inert N2
atmosphere. It was cooled to 0 °C and BF3·OEt2 (0.25 mL, 1.63
mmol, 1.2 equiv) was added dropwise. The turbid white solution
was stirred at 0 °C for 30 min. It was then cooled to –78 °C and s-
BuLi [1.43 mL (2.6 M in pentane), 2.99 mmol, 2.2 equiv] was added
dropwise. A deep red color (indicative of benzylic carbanion forma-
tion) appeared immediately. The solution was stirred at the same
temperature for 30 min and then a solution of MeCO2D (182 mg, 0.2
mL, 2.99 mmol, 2.2 equiv) in THF (2 mL) was added. After the ad-
dition, the reaction mixture was stirred and warmed to r.t. over a pe-
riod of 4–5 h, whence aq 10% HCl (15 mL) was added. The contents
were poured into Et2O (25 mL). The aqueous layer was separated
and the organic layer was further extracted with aq 10% HCl (2 ×
15 mL). The combined aqueous layers were washed with Et2O (2 ×
20 mL) to remove nonbasic impurities, made alkaline with solid
Na2CO3, and extracted with CHCl3 (4 × 15 mL). The combined or-
ganic layers were washed with brine (20 mL) and dried (Na2SO4).
The solvent was evaporated in vacuo to afford the crude product,
which was purified by flash column chromatography using 230–
400 mesh silica gel. Elution with EtOAc–hexane (1:1) afforded 2-
methyl-1,2,3,4-tetrahydro(1-2H1)isoquinoline (12) as a yellow oil;
yield: 184 mg (92%).
13C NMR (75 MHz, CDCl3): δ = 159.6, 146.4, 145.5, 130.2, 128.9,
126.2, 122.0, 114.5, 113.2, 113.0, 111.2, 109.4, 71.1, 64.1, 55.6,
54.9, 52.4, 44.4, 29.0, 14.7.
MS (APCI): m/z = 328.29 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C20H26NO3: 328.1907; found:
328.1906.
7-Ethoxy-6-methoxy-1-(3,4-dimethoxyphenyl)-2-methyl-
1,2,3,4-tetrahydroisoquinoline (2v)
Yield: 126 mg (39%); pale yellow solid; mp 93–95 °C.
IR (neat): 2944, 2835, 1464, 1253, 1028 cm–1.
1H NMR (400 MHz, CDCl3): δ = 6.69 (dd, J = 8.1, 1.7 Hz, 1 H,
ArH), 6.65 (d, J = 8.1 Hz, 1 H, ArH), 6.64 (d, J = 1.5 Hz, 1 H, ArH),
6.44 (s, 1 H, ArH), 5.98 (s, 1 H, ArH), 3.96 (s, 1 H, C1-H), 3.76 (s,
3 H, OCH3), 3.71 (s, 3 H, OCH3), 3.70 (s, 3 H, OCH3), 3.68–3.56
(m, 2 H, OCH2CH3), 3.10–3.04 (m, 1 H, C3-H), 3.01–2.96 (m, 1 H,
C3-H), 2.56 (br d, J = 15.8 Hz, 1 H, C4-H), 2.46 (td, J = 10.9, 3.6 Hz,
1 H, C4-H), 2.11 (s, 3 H, NCH3), 1.17 (t, J = 7.0 Hz, 3 H, OCH2CH3).
13C NMR (75 MHz, CDCl3): δ = 149.1, 148.2, 147.7, 146.2, 136.1,
130.2, 125.9, 121.7, 113.1, 111.6, 110.9, 110.1, 70.8, 63.8, 55.3,
52.4, 44.1, 28.6, 14.5.
MS (APCI): m/z = 358.41 [M + H]+.
(2) Into a flame-dried two-necked round-bottomed flask, equipped
with a magnetic stirrer bar, septum cap and a bubbler, was taken a
solution of N-methyl-1,2,3,4-tetrahydroisoquinoline (3; 200 mg,
1.36 mmol, 1 equiv) in anhydrous THF (10 mL) under an inert N2
atmosphere. It was cooled to 0 °C and BF3·OEt2 (0.25 mL, 1.63
mmol, 1.2 equiv) was added dropwise. The turbid white solution
was stirred at 0 °C for 30 min. It was then cooled to –78 °C and s-
BuLi [1.43 mL (2.6 M in pentane), 2.99 mmol, 2.2 equiv] was added
dropwise. A deep red color (indicative of benzylic carbanion forma-
tion) appeared immediately. The solution was stirred at the same
temperature for 30 min. The second instalment of s-BuLi [1.96 mL
(2.6 M in pentane), 4.08 mmol, 3 equiv] was added followed by the
addition of a solution of chlorobenzene (450 mg, 0.41 mL, 4.08
mmol, 3 equiv) in THF (1–2 mL). The reaction mixture was stirred
at –78 °C for 45 min and was allowed to warm to –10 °C over a pe-
riod of 3–4 h. It was then quenched with a solution of MeCO2D (430
mg, 0.4 mL, 7.07 mmol, 5.2 equiv) in THF (2 mL). After the addi-
tion, the mixture was stirred and warmed to r.t. and aq 10% HCl (15
mL) was added. The contents were poured into Et2O (25 mL). The
aqueous layer was separated and the organic layer was further ex-
tracted with aq 10% HCl (2 × 15 mL). The combined aqueous layers
were washed with Et2O (2 × 20 mL) to remove nonbasic impurities,
made alkaline with solid Na2CO3, and extracted with CHCl3 (4 × 15
mL). The combined organic layers were washed with brine (20 mL)
and dried (Na2SO4). The solvent was evaporated in vacuo to afford
the crude product, which was purified by flash column chromatog-
raphy using 230–400 mesh silica gel. Elution with EtOAc–hexane
(3:7) afforded 2-methyl-1-phenyl-1,2,3,4-tetrahydro(1-2H1)iso-
quinoline (13) as a light yellow oil (123 mg, 41%). Further elution
with same solvent gave 12 as a yellow oil (28 mg, 14%).
Anal. Calcd for C21H27NO4: C, 70.56; H, 7.61; N, 3.92. Found: C,
70.24; H, 7.52; N, 3.88.
7-Ethoxy-6-methoxy-1-(3,4,5-trimethoxyphenyl)-2-methyl-
1,2,3,4-tetrahydroisoquinoline (2w)
Yield: 150 mg (43%); white solid; mp 123–125 °C.
IR (neat): 2939, 2841, 1483, 1236, 1030 cm–1.
1H NMR (400 MHz, CDCl3): δ = 6.53 (s, 1 H, ArH), 6.45 (s, 2 H,
ArH), 6.09 (s, 1 H, ArH), 3.98 (s, 1 H, C1-H), 3.81 (s, 3 H, OCH3),
3.80 (s, 9 H, 3 × OCH3), 3.79–3.71 (m, 2 H, OCH2CH3), 3.14–3.09
(m, 1 H, C3-H), 3.07–3.04 (m, 1 H, C3-H), 2.64 (br d, J = 15.6 Hz,
1 H, C4-H), 2.53 (td, J = 10.7, 3.3 Hz, 1 H, C4-H), 2.20 (s, 3 H,
NCH3), 1.26 (t, J = 7.0 Hz, 3 H, OCH2CH3).
13C NMR (75 MHz, CDCl3): δ = 152.9, 147.9, 146.2, 139.2, 137.2,
130.0, 126.1, 113.2, 111.1, 106.3, 71.5, 64.1, 60.4, 55.9, 55.5, 52.5,
44.4, 28.7, 14.6.
MS (APCI): m/z = 388.74 [M + H]+.
Anal. Calcd for C22H29NO5: C, 68.20; H, 7.54; N, 3.61. Found: C,
68.55; H, 7.42; N, 3.69.
7-Ethoxy-6-methoxy-2-methyl-1-(3,4-methylenedioxyphenyl)-
1,2,3,4-tetrahydroisoquinoline (2x)
Yield: 120 mg (39%); white solid; mp 88–90 °C.
IR (neat): 2974, 2899, 1477, 1236, 1039 cm–1.
1H NMR (400 MHz, CDCl3): δ = 6.64 (dd, J = 7.9, 1.4 Hz, 1 H,
ArH), 6.61 (d, J = 7.7 Hz, 1 H, ArH), 6.60 (d, J = 1.0 Hz, 1 H, ArH),
6.44 (s, 1 H, ArH), 6.02 (s, 1 H, ArH), 5.84 (d, J = 1.3 Hz, 1 H,
OCH2O), 5.83 (d, J = 1.4 Hz, 1 H, OCH2O), 3.95 (s, 1 H, C1-H),
3.73 (s, 3 H, OCH3), 3.72–3.65 (m, 2 H, OCH2CH3), 3.07–3.01 (m,
1 H, C3-H), 2.99–2.94 (m, 1 H, C3-H), 2.56 (dd, J = 15.7, 3.1 Hz, 1
The same procedure was repeated, with the only difference that
MeCO2D was added at r.t. instead of –10 °C. Workup and purifica-
Synthesis 2014, 46, 1739–1750
© Georg Thieme Verlag Stuttgart · New York

PAPER
1-Aryl-N-methyl-1,2,3,4-tetrahydroisoquinolines
1749
tion in the similar fashion as described above gave 13 as a light yel-
low oil (117 mg, 39%) and 12 as a yellow oil (30 mg, 15%).
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To investigate the nonbasic material, the Et2O layer was washed
with brine (20 mL) and dried (Na2SO4). The solvent was evaporated
in vacuo to afford the crude product, which was again purified by
flash column chromatography using 230–400 mesh silica gel. Elu-
tion with EtOAc–hexane (2:98) afforded biphenylene (14) as a yel-
low solid; yield: 42 mg (7%). Further elution with the same solvent
gave 1-chloro-2-phenylbenzene (15) as a white solid; yield: 67 mg
(9%).
2-Methyl-1,2,3,4-tetrahydro(1-2H1)isoquinoline (12)
Yield: 28 mg (14%); yellow oil.
1H NMR (400 MHz, CDCl3): δ = 6.72 (dd, J = 8.08, 1.84 Hz, 1 H,
ArH), 6.67 (d, J = 8.08 Hz, 1 H, ArH), 6.63 (d, J = 1.76 Hz, 1 H,
ArH), 6.52 (d, J = 7.84 Hz, 1 H, ArH), 3.44 (br s, 1 H, C1-H), 2.80
(t, J = 8.28 Hz, 2 H, C3-H), 2.56 (t, J = 7.84 Hz, 2 H, C4-H), 2.20 (s,
3 H, NCH3).
13C NMR (75 MHz, CDCl3): δ = 138.4, 133.9, 129.0, 128.4, 127.2,
125.9, 68.7, 52.6, 44.6, 29.7.
2-Methyl-1-phenyl-1,2,3,4-tetrahydro(1-2H1)isoquinoline (13)
Yield: 123 mg (41%); light yellow oil.
1H NMR (400 MHz, CDCl3): δ = 7.18–7.11 (m, 5 H, ArH), 6.96–
6.90 (m, 2 H, ArH), 6.81 (t, J = 8.08 Hz, 1 H, ArH), 6.47 (d, J = 7.8
Hz, 1 H, ArH), 3.18–3.10 (m, 1 H, C3-H), 3.02–2.97 (m, 1 H, C3-H),
2.65 (dt, J = 15.84, 2.84 Hz, 1 H, C4-H), 2.47 (td, J = 11.32, 3.68
Hz, 1 H, C4-H), 2.13 (s, 3 H, NCH3).
13C NMR (75 MHz, CDCl3): δ = 144.4, 138.4, 134.1, 129.5, 128.6,
128.3, 128.2, 127.3, 125.7, 125.5, 72.2, 52.0, 44.2, 29.4.
Biphenylene (14)27
Yield: 42 mg (7%); yellow solid; mp 106–108 °C (Lit.27 mp
109 °C).
1H NMR (400 MHz, CDCl3): δ = 6.68–6.61 (m, 3 H, ArH), 6.57–
6.50 (m, 1 H, ArH), 6.48–6.31 (m, 3 H, ArH), 6.27–6.20 (m, 1 H,
ArH).
1-Chloro-2-phenylbenzene (15)48
Yield: 67 mg (9%); white solid; mp 33 °C (Lit.48 mp 35 °C).
1H NMR (400 MHz, CDCl3): δ = 7.78–7.75 (m, 2 H, ArH), 7.69–
7.68 (m, 1 H, ArH), 7.57–7.28 (m, 4 H, ArH), 7.27–7.12 (m, 2 H,
ArH).
Acknowledgment
We acknowledge financial support through Scheme No.
02(0131)/13/EMR-II sponsored by CSIR, New Delhi. Y. S. Deol
thanks UGC, New Delhi, for the award of a research fellowship.
(22) (a) Khanapure, S. P.; Biehl, E. R. J. Org. Chem. 1990, 55,
1471. (b) Hofmann, R. W. Dehydrobenzene and
Cycloalkynes; Academic Press: New York, 1967, 134.
(23) (a) Adejare, A.; Miller, D. D. Tetrahedron Lett. 1984, 25,
5597. (b) Kress, T. H.; Leanna, M. R. Synthesis 1988, 803.
(24) All new products were characterized by 1H NMR, 13C NMR,
IR spectroscopy, and mass spectrometry (APCI-MS and
HRMS).
Supporting Information for this article is available online
at
http://www.thieme-connect.com/products/ejournals/journal/
10.1055/s-00000084.SunpfgIpi
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