Substituent effects on axial chirality in 1-aryl-3,4-dihydroisoquinolines: controlling the rate of bond rotation

Article abstract of DOI:10.1016/j.tet.2016.01.037

A series of 1-aryl-3,4-dihydroisoquinolines (DHIQs) were synthesized and their barriers to bond rotation were determined by means of VT-NMR, dynamic HPLC or racemization studies. Although they all presented lower rotational stability than the related 1-ar

Full text of DOI:10.1016/j.tet.2016.01.037

Accepted Manuscript
Substituent effects on axial chirality in 1-aryl-3,4-dihydroisoquinolines: controlling the
rate of bond rotation
Josep Mas Roselló, Samantha Staniland, Nicholas J. Turner, Jonathan Clayden
PII:
S0040-4020(16)30037-0
10.1016/j.tet.2016.01.037
TET 27444
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 17 November 2015
Revised Date: 8 January 2016
Accepted Date: 19 January 2016
Please cite this article as: Roselló JM, Staniland S, Turner NJ, Clayden J, Substituent effects on axial
chirality in 1-aryl-3,4-dihydroisoquinolines: controlling the rate of bond rotation, Tetrahedron (2016), doi:
10.1016/j.tet.2016.01.037.
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Substituent effects on axial chirality in 1-
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Josep Mas Roselló, Samantha Staniland, Nicholas J. Turner and Jonathan Clayden*

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1
Tetrahedron
journal homepage: www.elsevier.com
Substituent effects on axial chirality in 1-aryl-3,4-dihydroisoquinolines: controlling
the rate of bond rotation.
Josep Mas Roselló,a,b Samantha Staniland,a Nicholas J. Turnerc and Jonathan Claydena,b
aSchool of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, UK
bSchool of Chemistry, University of Bristol, Cantock's Close, Bristol BS8 1TS, UK
cSchool of Chemistry, University of Manchester, Manchester Institute of Biotechnology, 131 Princess Street, Manchester M1 7DN, UK
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A series of 1-aryl-3,4-dihydroisoquinolines (DHIQs) were synthesized and their barriers to bond
rotation were determined by means of VT-NMR, dynamic HPLC or racemization studies.
Although they all presented lower rotational stability than the related 1-arylisoquinolines (such
as QUINAP), certain 1-aryl-DHIQ structures had a sufficiently high barrier to bond rotation to
Available online
show
axial
chirality.
These
compounds
included
1-(2-triflyl-1-naphthyl)-4,5-
dihydroisoquinoline 4h and 1-(2-diphenylphosphanyl-1-naphthyl)-4,5-dihydroisoquinoline 4i.
This discovery opens the door to the development of a new group of axially chiral N,P ligands
for asymmetric synthesis and also potentially to new strategies for the synthesis of axially chiral
1-arylisoquinolines.
Keywords:
atropisomers, axial chirality, QUINAP, biaryls,
dihydroisoquinolines
2009 Elsevier Ltd. All rights reserved.
———
Corresponding author. Tel.: +44-117-331-8054; fax: +44-117-927-7985; e-mail: j.clayden@bristol.ac.uk

ACCEPTED MANUSCRIPT
2
Tetrahedron
1. Introduction
2. Results and discussion
2.1. Starting materials
The majority of axially chiral compounds are biaryls, whether
biphenyls or binaphthyls1 or their heterocyclic counterparts.2
Particularly valuable are biaryls containing the isoquinoline ring,3
which function as atropisomeric chiral ligands because their basic
nitrogen atom allows bidentate coordination in P,N ligands4 such
as QUINAP (Figure 1). QUINAP is the ligand of choice in many
asymmetric reactions,5 including asymmetric hydroborations,
diborations, dipolar cycloadditions, conjugate additions and
additions to iminium ions.
A range of racemic 1-aryl-DHIQs halogenated at the 2-
position of the 1-aryl ring (4a-g) were readily synthesized in high
yields from the corresponding amides 3a-g by the modified
Bischler-Napieralski cyclisation reported by Movassaghi et al.14
Amide starting materials for the cyclisation were made either by
acylation of phenethylamine with available 2-halobenzoyl
chloride or 1-naphthoyl chloride (giving 3a-d). The remaining
amides 3e-f were made by halogenation of 3d by means of
rhodium15 or palladium16 catalyzed C-H activation reactions, with
the amide as a directing group for chemoselective halogenation at
the ortho position of the 1-naphthyl ring.
Configurational stability about the biaryl axis in 1-
naphthylisoquinolines depends on the substituent at the 2-
position of the naphthyl ring. The 2-unsubstituted structure 1a is
configurationally unstable at room temperature, with an
estimated half-life for racemization of 13 min at –20 °C.6 In
contrast, the amino-substituted structure 1b is configurationally
stable, with a barrier to bond rotation of 125.4 kJ mol–1.7 The
more substituted compounds 1c8 and QUINAP 1d5 showed no
sign of racemization on extended heating.
NH2
N
Tf2O, 2-ClPyr
Et3N,
X
HN
Cl
CH2Cl2, 45 °C,
16 h
CH2Cl2, rt
16 h
O
X
O
X
4a X = Cl; 5-H, 6-H 98%
4b X = Br; 5-H, 6-H 70%
4c X = I; 5-H, 6-H 83%
4d X = H; 5,6-benzo 80%
4e X = Cl; 5,6-benzo 88%
4f X = Br; 5,6-benzo 90%
4g X = I; 5,6-benzo 65%
3a X = Cl; 5-H, 6-H 99%
3b X = Br; 5-H, 6-H 91%
3c X = I; 5-H, 6-H 99%
One report of a related partially saturated structure,9 3,4-
dihydroisoquinoline 2a, suggests that its barrier to rotation is too
low to permit resolution, but the rate of bond rotation was not
3d X = H; 5,6-benzo 99%
3e X = Cl; 5,6-benzo 55%
3f X = Br; 5,6-benzo 92%
3g X = I; 5,6-benzo 34%
a
b
Scheme 1. Synthesis of 1-acyl-3,4-dihydroisoquinolines.
quantified.
A chiral derivative 2b nonetheless displayed
Reagents: (a) NCS, Pd(OAc)2 (5 mol%), TfOH, Na2S2O8, DCE, 80
°C, 32 h; (b) NBS/NIS, [RhCp*Cl2]2 (2.5 mol%), AgSbF6 (10
mol%), PivOH, DCE, 70 °C, 18 h.
separable diastereoisomeric atropisomers, but again no barrier
was reported. The diastereoisomers of the corresponding triflate
2c were not separable. Related 1-aryl-3,4-dihydroisoquinolines
are of medicinal interest as potent neuroprotectors.10
In addition, triflyl-substituted DHIQ 4h was made by the
method of Li et al.9 (Scheme 2) and converted into phosphine
oxide 4i by palladium-catalyzed coupling17 with Ph2P(O)H.
1-Naphthylisoquinolines
N
N
N
N
Ph2P(O)H, DIPEA
Pd(OAc)2 (10 mol%)
dppp (15 mol%)
3 steps
85% overall
N
N
N
NH2
PPh2
O
OH
+
DMSO, 100 °C, 22 h,
75%
PPh2
OTf
OH
method of
Li et al.9
1a
1b
1c
1d (QUINAP)
4h
4i
∆G‡ = 77.5 kJ mol–1 ∆G‡ = 125.4 kJ mol–1
No racemisation
after
24 h at 80 ˚C
No racemisation
after
24 h at 65 ˚C
at –20 ˚C
at 25 ˚C
Scheme 2. Synthesis of substituted 1-naphthyl-3,4-
(non-atropisomeric)
dihydroisoquinolines.
1-Naphthyl-3,4-dihydroisoquinolines
2.2. Determination of the barriers to bond rotation in variously
Ph
Ph
substituted DHIQs
N
N
N
PPh2
PPh2
OTf
Variable temperature NMR (VT-NMR) studies were carried
out to estimate the rate of bond rotation about the Ar-DHIQ axis
of the less hindered group of compounds 4a-d. The 1H NMR line
shapes of the signals arising from the potentially diatereotopic
protons in the –CH2–CH2– unit of the DHIQ were monitored in
CDCl3 at temperatures between –30 °C and +30 °C. The line
shapes were modelled using the commercial program gNMR.18,19
Table 1 illustrates (for one example, bromo-substituted 4b) the
modelled and observed line shapes of the two diastereotopic
methylene protons (HA, HB) α to the nitrogen atom at a series of
temperatures, and shows the estimated rate constant, k, for their
exchange.
2a
2b
Resolvable
2c
Rotationally unstable
at 25 ˚C
Diastereoisomers
interconvert
Figure 1. Bond rotations in 1-naphthylisoquinolines and their
3,4-dihydroisoquinoline analogues.
Although 1-aryl-DHIQs are more conformationally flexible
than the related fully aromatic isoquinolines, and evidently
display lower barriers to rotation, they do show potential for
atropisomerism and could provide a new class of axially chiral
compounds with potential applications as ligands or building
blocks for asymmetric synthesis or chiral ligands. QUINAP is
typically produced in enantiomerically pure form by classical
resolution.4,5,11
Methods have also been reported for its
asymmetric synthesis by dynamic resolution techniques, relying
of the control of the kinetics and thermodynamics of bond
rotation.12 Further interest arises from the possibility of using
redox interconversions between QUINAP and its partially
saturated analogues to control dynamic resolution processes. In
this paper we describe our investigation into the control of
rotational barriers in 1-aryl-3,4-dihydroisoquinolines as
a
potential new class of non-biaryl atropisomers.13

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3
interconversion of the two enantiomers of 4f were calculated.
An Eyring plot of this data revelaed that 4f was almost
Table 1. Line shape analysis in the VT NMR study of 4b
atropisomeric22 at 25 ºC (∆G‡298 = 92.6 kJ mol–1; t rac = 900 s).
½
T /
ºC
k / s–
1
Table 2. Dynamic HPLC profiles for 4f on the (R,R)-Whelk-O1
chiral stationary phase, eluting with n-hexane/isopropanol (60:40).
Experimental line shape
Modelled line shape
T
k
Observed peak shape
/ ºC
/ 103 s-1
-
1
30
20
4.5
7.1
9.9
-
20
10
30
0
57
20
30
220
550
40
Similar approximate analysis of the DHPLC trace of 4g
around 0 °C indicated that 4g had a lower barrier to rotation than
4f. The replacement of a bromine atom by a bulkier iodine atom
at the naphthyl ring's ortho position did not increase rotational
stability at the Ar-DHIQ bond. Presumably the bigger atomic
radius of iodine is countered by the longer bond length of C–I (a
similar effect is well established in A values).23
These rates were analysed using the Eyring equation, allowing
calculation of the barrier to bond rotation (∆G‡) and an estimation
the half life for racemization (t rac) of 4a-d in solution at a given
½
temperature.
It was not possible to use VT-NMR to derive a barrier to
rotation of the more sterically encumbered substrate 4e since no
line broadening or coalescences were observed even at 120 ºC in
1,2-dichlorobenzene-d4. Rotationally restricted compounds with
half lives for racemization falling into the timescale of minutes at
ambient temperature are typically difficult to analyse by VT-
NMR for this reason, but this racemization profile is ideal for
investigation by dynamic (variable temperature) HPLC (DHPLC)
on a chiral stationary phase.13a,19-21
Table 3. Summary of kinetic parameters for bond rotations in 1-
arylDHIQs
N
N
X
X
DHPLC studies were undertaken using DHIQs 4e-g. For 4e,
all the chiral stationary phases and eluents we explored showed a
single peak, even on cooling the column to 0 ºC. Although no
numerical values for the barrier to rotation of 4e were obtained,
we assume therefore that chloro-substituted 4e rotates freely (that
is, on a time scale of seconds or less) at room temperature.
4a-4c
∆H‡
4d-4i
rac
a
Cpd. X =
∆S‡
∆G‡
t1/2
298
298
/ kJ mol–1
56.6
50.7
64.0
55.1
–
/ J mol–1 K–1
/ kJ mol–1
59.2
4a
4b
4c
4d
4e
4f
Cl
Br
I
H
Cl
Br
I
–9
–26
+20
+1
–
–195
–
≈ 10-3
< 10-3
< 10-3
≈ 10-4
s
s
s
s
58.4
57.9
54.7
More information was obtained from 4f, which showed peak
shapes characteristic of racemisation on the timescale of elution
< 90b
92.6
< 5 min
15 min
34.6
–
on
a (R,R)-Whelk-O1 stationary phase, eluting with n-
4g
< 1 mind
81.9c
hexane/isopropanol (60:40). Peak profiles were monitored at 20,
30 and 40 °C (Table 2) and the parameters obtained from the
profiles were entered into the Unified Equation for Dynamic
Chromatography.19,20 From this equation, the rates of
4h
4i
OTf
P(O)Ph2
10.7
–
+14.5
–
103.1
>>100
36 days
>25 days

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4
Tetrahedron
aEstimated half life for racemization. bNot determined (achiral
Compound 3e was prepared according to the method of Rao et
al.16 N-Phenethyl-1-naphthamide 3d (100 mg, 0.36 mmol), NCS
(64 mg, 0.48 mmol), Pd(OAc)2 (6 mg, 0.018 mmol, 5 mol%) and
sodium persulfate (174 mg, 0.72 mmol) were dissolved in dry
1,2-DCE (2 mL) in a flame-dried sealed vial under argon. The
mixture was degassed under reduced pressure and the vessel
filled with argon. TfOH (110 mg, 0.72 mmol) was added
dropwise. The reaction mixture was stirred for 32 h at 80 ºC.
After cooling to room temperature, the reaction was quenched by
adding saturated aqueous NaHCO3. The reaction mixture was
diluted with dichloromethane. The organic layer was dried over
MgSO4, filtered, concentrated under reduced pressure and the
crude product was purified by flash column chromatography
(80:20 Pet. Ether:EtOAc) to afford the title compound as a
yellow oil (62 mg, 55%); 3e: Rf (70:30 Pet. Ether:EtOAc) 0.45;
by HPLC). cDetermined at 0 °C. Insufficient data to allow
calculation of ∆H‡ and ∆S‡. dAssuming ∆S‡ = 0.
In marked contrast, compound 4h bearing an O-triflyl group at
the ortho position of the naphthyl core showed no signs of
racemization on the timescale of elution from a chiral stationary
phase at room temperature. The enantiomers of 4h were therefore
separated on a small scale by semi-preparative HPLC, and their
interconversion was studied in isopropanol at three different
temperatures: 43, 50 and 58 °C. The decrease in ee over time was
monitored and plots of ln(ee) against time gave for the rate of
racemisation at each temperature. Using the Eyring equation,
values of ꢀG‡ at room temperature could be derived along with
ꢀS‡ and ꢀH‡ (Table 3). From these values we estimate 4h to
have a half life for racemization of at least one month in solution.
IR (film, cm-1): νmax = 3268, 1636 (C=O), 821; H NMR (400
1
MHz, CDCl3): δH = 7.90 (1 H, dd, J=6.2, 3.4 Hz, ArH), 7.80 (1
H, dd, J=8.2, 0.9 Hz, ArH), 7.63 (1 H, dd, J=7.6, 1.3 Hz, ArH),
7.51 - 7.47 (2 H, m, 2xArH), 7.45 - 7.42 (1 H, m, ArH), 7.34 -
7.29 (3 H, m, 3xArH), 7.23 (2 H, m, 2xArH), 5.81 (1 H, br. s.,
NH), 3.84 (2 H, dt, J=7.1, 6.3 Hz, NHCH2CH2Ph), 3.01 ppm (2
H, t, J=7.1 Hz, NHCH2CH2Ph); 13C {1H} NMR (100 MHz,
CDCl3): δC = 171.0 (C=O), 138.8 (ArC), 135.4 (ArC), 134.3
(ArC), 130.4 (ArC), 130.2 (ArC), 130.1 (ArC), 129.0 (2xArC),
128.7 (ArC), 128.6 (ArC), 127.9 (ArC), 127.7 (ArC), 126.9
(ArC), 126.5 (ArC), 126.2 (ArC), 125.5 (ArC), 41.2
(NHCH2CH2Ph), 35.2 (NHCH2CH2Ph) ppm; HRMS (ESI+) m/z
calcd for C19H16ClNONa [M+Na+]: 332.0813, found: 332.0820.
We envisaged that a phosphine oxide substituent at the
naphthyl 2-position might further increase the barrier to rotation,
and possibly provide a valuable contrast to dihydro-QUINAP
(2a, Figure 1), which was reported to be rotationally unstable at
room temperature. Indeed, chiral HPLC traces of rac-4i showed
no racemisation on-column at 50 ºC, suggesting a half life for
racemization at this temperature of at least 30 min, and hence a
barrier to bond rotation of >>100 kJ mol–1. Phosphine oxide 4i is
thus the first reported rotationally stable 1-aryl-3,4-
dihydroisoquinoline. Interestingly, tertiary phosphine oxide N,P-
ligands have been found to display higher catalytic activities in,
for example, olefin hydroformylation reactions than their tertiary
phosphine analogues,23 suggesting the possible use of 4i itself as
a chiral ligand.
4.1.2. 2-Bromo-N-phenethyl-1-naphthamide (3f)
Compound 3f was prepared according to the method of
Glorius et al.15 [RhCp*Cl2]2 (0.058 g, 0.09 mmol, 2.5 mol%),
AgSbF6 (0.127 g, 0.36 mmol, 10 mol%) and PivOH (0.5 ml, 4.00
mmol). 1,2-DCE (18 mL), N-phenethyl-1-naphthamide 3d (1.000
g, 3.63 mmol) and NBS (0.970 g, 5.45 mmol) were added under
nitrogen to a flame-dried round-bottom flask. The reaction
mixture was degassed under reduced pressure, the vessel filled
with nitrogen, and the mixture heated at 65 ºC for 18 h. The
mixture was cooled to room temperature, diluted with EtOAc and
filtered through a short pad of silica gel and eluted with EtOAc.
After removal of solvent under reduced pressure, the crude
product was purified by flash column chromatography (70:30
Pet. Ether:EtOAc) to afford the title compound as a white solid
(1.184 g, 92%); 3f: Rf (50:50 Pet. Ether:EtOAc) 0.5; m.p. 135-
137 ºC; IR (film, cm-1): νmax = 3264, 1639 (C=O), 1530, 760; 1H
NMR (400 MHz, CDCl3): δH = 7.93 - 7.81 (3 H, m, 3xArH), 7.52
(1 H, dd, J = 7.1, 1.5 Hz, ArH), 7.50 - 7.42 (1 H, m, ArH), 7.38 -
7.28 (5 H, m, 5xArH), 7.26 - 7.20 (1 H, m, ArH), 5.84 (1 H, br. t,
J = 4.8 Hz, NH), 4.07 – 3.64 (2 H, m, NHCH2CH2Ph), 3.03 ppm
(2 H, t, J = 6.9 Hz, NHCH2CH2Ph); 13C {1H} NMR (125 MHz,
CDCl3): δC = 170.7 (C=O), 138.8 (ArC), 135.7 (ArC), 135.6
(ArC), 133.3 (ArC), 131.7 (ArC), 130.7 (ArC), 130.5 (ArC),
128.8 (ArC), 128.7 (ArC), 128.6 (ArC), 128.1 (ArC), 128.1
(ArC), 126.6 (ArC), 126.5 (ArC), 125.4 (ArC), 119.3 (ArC), 41.4
(NHCH2CH2Ph), 35.1 (NHCH2CH2Ph) ppm; HRMS (ESI+) m/z
calcd for C19H16BrNONa [M+Na+]: 376.0307, found: 376.0294.
3. Conclusion
A series of rotationally restricted and axially chiral 1-aryl-3,4-
dihydroisoquinolines (1-aryl-DHIQ) were readily synthesized
using inter or intramolecular electrophilic aromatic substitution
chemistry. Their barriers to rotation about their Ar–CN bond
were determined by means of VT-NMR, dynamic HPLC and
racemization studies. Despite significantly greater molecular
flexibility than the related 1-aryl-isoquinolines, two 1-naphthyl
DHIQs showed stable axial chirality at ambient temperature.
Notably, triflate, as a pseudohalide, provided a much greater
barrier to bond rotation than the equivalent halides (Br, I). This
first report of atropisomeric 1-aryl-3,4-dihydroisoquinolines
opens the door to the development of new axially chiral 3,4-
dihydroisoquinoline-containing N,P ligands for asymmetric
synthesis.
4. Experimental
4.1. General procedure for amide (3a-d) formation from 2-
phenylethylamine and an acyl chloride.
2-Phenylethylamine (1 equiv) and Et3N (2 equiv) were added
to a solution of the acyl chloride (1 equiv) in dichloromethane
and the reaction mixture was stirred for 16 h at room
temperature. The solvent and the excess Et3N were removed
under reduced pressure. The residue was suspended in water and
extracted twice in EtOAc. The combined organic layer was
washed with brine and dried over MgSO4, filtered and
concentrated under reduced pressure. The crude product was used
without any further purification. The experimental data for 2-
4.1.3. 2-Iodo-N-phenethyl-1-naphthamide (3g)
Compound 3g was prepared according to the method of
Glorius et al.15 [RhCp*Cl2]2 (9.3 mg, 0.0014 mmol, 1 mol%),
AgSbF6 (20.4 mg, 0.058 mmol, 4 mol%), PivOH (165 mg, 1.598
mmol), 1,2-DCE (7.3 mL), N-phenethyl-1-naphthamide 3d (400
mg, 1.453 mmol) and NIS (0.360 g, 1.598 mmol). The reaction
chloro-N-phenethylbenzamide
3a,25a
2-bromo-N-
phenethylbenzamide 3b,25b 2-iodo-N-phenethylbenzamide 3c25c
and N-phenethyl-1-naphthamide 3d25d were consistent with the
literature.
o
mixture was heated at 60 C for 16 h. The crude product was
purified by flash column chromatography (70:30 Pet.
Ether:EtOAc) to afford the title compound as a yellow solid (199
4.1.1. 2-Chloro-N-phenethyl-1-naphthamide (3e)

ACCEPTED MANUSCRIPT
5
NCHAHBCH2Ar), 3.07–2.88 (2 H, m, NCH2CH2Ar) ppm; 13C
mg, 34%); 3g: Rf (60:40 Pet. Ether:EtOAc) 0.4; m.p. 138-140
ºC; IR (film, cm-1): νmax = 3297, 1632 (C=O), 1538, 532; 1H
NMR (300 MHz, CDCl3): δH = 8.24 (1 H, dd, J=7.3, 1.1 Hz,
ArH), 7.89 - 7.80 (2 H, m, 2xArH), 7.56 - 7.50 (1 H, m, ArH),
7.47 - 7.39 (1 H, m, ArH), 7.36 - 7.20 (5 H, m, 5xArH), 7.15 (1
H, t, J=7.7 Hz, ArH), 5.94 (1 H, br. t, J=5.2 Hz, NH), 3.83 (2 H,
br. m, NHCH2CH2Ph), 3.03 (2 H, t, J=7.1 Hz, NHCH2CH2Ph)
ppm; 13C {1H} NMR (100 MHz, CDCl3): δC = 169.8 (C=O),
141.9 (ArC), 139.7 (ArC), 138.8 (ArC), 137.7 (ArC), 137.4
(ArC), 135.3 (ArC), 131.3 (ArC), 130.5 (ArC), 129.7 (ArC),
128.8 (ArC), 128.7 (ArC), 128.3 (ArC), 127.1 (ArC), 126.6
(ArC), 125.2 (ArC), 92.0 (ArC-I), 41.6 (NHCH2CH2Ph), 35.0
(NHCH2CH2Ph) ppm; HRMS (ESI+) m/z calcd for
C19H16INONa [M+Na+]: 424.0169, found: 424.0155.
{1H} NMR (100 MHz, CDCl3): δC = 169.2 (C=N), 136.9 (ArC),
136.6 (ArC), 135.9 (ArC), 131.6 (ArC), 130.9 (ArC), 130.6
(ArC), 129.8 (ArC), 129.8 (ArC), 129.2 (ArC), 129.1 (ArC),
128.2 (ArC), 127.4 (ArC), 127.4 (ArC), 126.8 (ArC), 126.0
(ArC), 125.9 (ArC), 48.0 (NCH2CH2Ar), 25.6 (NCH2CH2Ar)
ppm; HRMS (ESI+) m/z calcd forC19H15NCl [M+H+]: 292.0888,
found: 292.0882
4.2.3. 1-(2-Bromonaphthalen-1-yl)-3,4-dihydroisoquinoline
(4f)
General procedure for cyclodehydration of amides was
followed:
amide
3f
(0.195
g,
0.56
mmol),
trifluoromethanesulfonic anhydride (0.13 mL, 0.62 mmol), 2-
chloropyridine (78 µL, 0.68 mmol) in dichloromethane (3 mL).
The reaction mixture was stirred at 45 ºC for 16 h. The crude
product was purified by flash column chromatography (70:30:1
Pentane:EtOAc:Et3N) to afford the title compound as a yellow oil
(0.166 g, 90%); 4f: Rf (70:30 Pet. Ether:EtOAc ) 0.3; IR (film,
cm-1): νmax = 2928, 1298, 821, 764; 1H NMR (500 MHz, CDCl3):
δH = 7.94 (1 H, dd, J=7.0, 2.5 Hz, ArH), 7.89 (1 H, dd, J=8.2, 1.3
Hz, ArH), 7.80 (1 H, dd, J=7.4, 1.2 Hz, ArH), 7.58 - 7.50 (2 H,
m, 2xArH), 7.35 (1 H, td, J=7.4, 1.3 Hz, ArH), 7.28 (2 H, m,
2xArH), 7.09 (1 H, td, J= 7.6, 1.3 Hz, ArH), 6.81 (1 H, dd, J =
7.6, 1.2 Hz, ArH), 4.07 (2 H, m, NCHAHBCH2Ar), 2.99 (2 H, m,
4.2. General procedure for cyclodehydration of amides 3a-g
to 1-aryl-3,4-dihydroisoquinolines 4a-g.
The cyclodehydration of amides 3a-g was performed
according to the method of Movassaghi et al.14b The experimental
data for 1-(2-chlorophenyl)-3,4-dihydroisoquinoline 4a,26a 1-(2-
bromophenyl)-3,4-dihydroisoquinoline
4b,26b
and
1-(2-
bromophenyl)-3,4-dihydroisoquinoline 4c26c were in accordance
with the literature.
4.2.1. 1-(Naphthalen-1-yl)-3,4-dihydroisoquinoline (4d)
NCH2CH2Ar) ppm; 13C {1H} NMR (125 MHz, CDCl3): δC
=
General procedure for cyclodehydration of amides was
followed.
Amide
3d
(1.000
g,
3.63
mmol),
168.5(C=N), 137.3 (ArC), 136.7 (ArC), 135.8 (ArC), 133.1
(ArC), 131.7 (ArC), 130.4 (ArC), 130.3 (ArC), 129.9 (ArC),
129.8 (ArC), 128.7 (ArC), 127.5 (ArC), 127.2 (ArC), 126.6
(ArC), 126.1 (ArC), 125.6 (ArC), 119.7 (ArC-Br), 47.8
(NCH2CH2Ar), 25.3 (NCH2CH2Ar) ppm; HRMS (ESI+) m/z
calcd forC19H14NBrNa [M+Na+]: 358.0202, found: 358.0206.
trifluoromethanesulfonic anhydride (0.69 mL, 4.00 mmol), 2-
chloropyridine (0.42 mL, 4.36 mmol) in dichloromethane (18
mL). The reaction mixture was refluxed for 2 h. The crude
product was purified by flash column chromatography (70:30:1
Pentane:EtOAc:Et3N) to afford the title compound as a white
solid (0.752 g, 80%); Rf (70:30 Pet. Ether:EtOAc ) 0.3; 4d: m.p.
1
135-136 ºC; IR (film, cm-1): νmax = 1613 (C=O), 759; H NMR
4.2.4. 1-(2-Iodonaphthalen-1-yl)-3,4-dihydroisoquinoline (4g)
(400 MHz, CDCl3): δH = 7.97 - 7.87 (2 H, m, 2xArH), 7.73 (1 H,
dq, J=8.4, 0.9 Hz, ArH), 7.58 – 7.52 (2 H, m, 2xArH), 7.47 (1 H,
ddd, J=8.2, 6.8, 1.3 Hz, ArH), 7.37 (2 H, tdd, J = 7.3, 4.7, 1.4 Hz,
2xArH), 7.31 (1 H, dd, J = 7.5, 1.3 Hz, ArH), 7.09 (1 H, td,
J=7.5, 1.4 Hz, ArH), 6.87 (1 H, dd, J=7.7, 1.3 Hz, ArH), 4.06 (2
H, br. m., J = 5.2 Hz, NCH2CH2Ar), 2.98 ppm (2 H, t, J = 7.5 Hz,
NCH2CH2Ar); 13C {1H} NMR (100 MHz, CDCl3): δC = 167.7
(C=N), 137.5 (ArC), 137.2 (ArC), 133.8 (ArC), 131.7 (ArC),
131.0 (ArC), 130.3 (ArC), 129.0 (ArC), 128.4 (ArC), 127.9
(ArC), 127.5 (ArC), 127.1 (ArC), 126.7 (ArC), 126.3 (ArC),
126.0 (ArC), 125.8 (ArC), 125.4 (ArC), 48.0 (NCH2CH2Ar), 26.3
(NCH2CH2Ar) ppm; HRMS (ESI+) m/z calcd for C19H16N
[M+H+]: 258.1277, found: 258.1268.
General procedure for cyclodehydration of amides was
followed:
amide
3g
(0.100
g,
0.25
mmol),
trifluoromethanesulfonic anhydride (47 µL, 0.27 mmol), 2-
chloropyridine (29 µL, 0.30 mmol) in dichloromethane (1.5 mL).
The reaction mixture was stirred at 45 ºC for 16 h. The crude was
purified by flash column chromatography (70:30:1
Pentane:EtOAc:Et3N) to afford the title compound as a yellow oil
(0.062 g, 65%); 4g: Rf (70:30 Pet. Ether:EtOAc ) 0.35; IR (film,
1
cm-1): νmax = 2934, 818, 740, 713; H NMR (400 MHz, CDCl3):
δH = 8.20 (1 H, dd, J= 7.4, 1.3 Hz, ArH), 7.96 - 7.85 (2 H, m,
2xArH), 7.54 - 7.43 (2 H, m, 2xArH), 7.36 (1 H, dd, J= 8.2, 7.0
Hz, ArH), 7.29 – 7.22 (1 H, m, ArH), 7.19 - 7.11 (2 H, m,
2xArH), 6.87 (1 H, d, J=7.7 Hz, ArH), 4.17 (1 H, dt, J=15.6, 6.2
Hz, NCHAHBCH2Ar), 4.01 (1 H, ddd, J = 15.7, 11.2, 6.9 Hz,
4.2.2. 1-(2-Chloronaphthalen-1-yl)-3,4-dihydroisoquinoline
(4e)
NCHAHBCH2Ar), 3.11 - 2.92 (2 H, m, NCHAHBCH2Ar) ppm; 13
C
{1H} NMR (100 MHz, CDCl3): δC = 167.8 (C=N), 141.8 (ArC),
138.9 (ArC), 137.1 (ArC), 135.9 (ArC), 133.1 (ArC), 132.6
(ArC), 130.8 (ArC), 130.5 (ArC), 130.2 (ArC), 129.9 (ArC),
128.3 (ArC), 127.5 (ArC), 126.9 (ArC), 126.9 (ArC), 125.5
(ArC), 92.4 (ArC-I), 48.0 (NCH2CH2Ar), 25.6 (NCH2CH2Ar)
ppm; HRMS (ESI+) m/z calcd for C19H15NI [M+H+]: 384.0244,
found: 384.0243.
General procedure for cyclodehydration of amides was
followed:
amide
3e
(440
mg,
1.42
mmol),
trifluoromethanesulfonic anhydride (0.22 mL, 1.56 mmol), 2-
chloropyridine (0.16 mL, 1.70 mmol) in dichloromethane (10
mL). The reaction mixture was refluxed for 16 h. The crude
product was purified by flash column chromatography (70:30:1
Pentane:EtOAc:Et3N) to afford the title compound as a yellow
solid (363 mg, 88%); 4e: Rf (70:30 Pet. Ether:EtOAc ) 0.3; m.p.
112-114ºC; IR (film, cm-1): νmax = 2941, 1618 (C=N), 810, 739;
1H NMR (400 MHz, CDCl3): δH = 7.95 (1 H, dd, J = 8.1, 1.4 Hz,
ArH), 7.85 (1 H, dd, J = 8.2, 1.3 Hz, ArH), 7.57 (1 H, t, J = 7.6
Hz, ArH), 7.51 (2 H, td, dd, J = 7.3, 1.3 Hz, 2xArH), 7.39 (1 H, t,
J = 7.8 Hz, ArH), 7.34 (1 H, td, J = 7.4, 1.3 Hz, ArH), 7.27 (1 H,
d, J = 7.4 Hz, ArH), 7.08 (1 H, td, J=7.6, 1.3 Hz, ArH), 6.73 (1
H, d, J=7.7 Hz, ArH), 4.07 (1 H, ddd, J=14.9, 8.3, 6.3 Hz,
NCHAHBCH2Ar), 3.96 (1 H, ddd, J = 15.6, 9.5, 6.1 Hz,
4.3. 1-(3,4-Dihydroisoquinolin-1-yl)naphthalen-2-yl
trifluoromethanesulfonate (4h)
Compound 4h was prepared from 2-naphthol (1.33 g, 9.10 mmol)
and 3,4-dihydroisoquinoline (1.19 g, 9.10 mmol) according to the
synthetic route reported by Li et al.9 The crude product was
purified by flash column chromatography to afford the title
compound as a clear oil (3.13 g, 85% overall yield); Rf (70:30:1
Pet. Ether:EtOAc:Et3N) 0.6; IR (film, cm-1): νmax = 1618 (C=N),

ACCEPTED MANUSCRIPT
6
Tetrahedron
1420, 1200, 1140; 1H NMR (500 MHz, CDCl3): δH = 8.00 (1 H,
4. (a) Guiry, P. J.; Saunders, C. P. Adv. Synth. Catal. 2004, 346, 497.
(b) McCarthy, M.; Guiry, P. J. Tetrahedron 2001, 57, 3809.
d, J=9.0 Hz, ArH), 7.95 (1 H, d, J = 8.1 Hz, ArH), 7.70 (1 H, dd,
J=8.4, 1.0 Hz, ArH), 7.56 (1 H, ddd, J = 8.2, 6.8, 1.2 Hz, ArH),
7.51 - 7.46 (2 H, m, 2xArH), 7.38 (1 H, td, J=7.5, 1.3 Hz, ArH),
7.31 (1 H, dd, J=7.5, 1.2 Hz, ArH), 7.09 (1 H, td, J=7.5, 1.2 Hz,
ArH), 6.75 (1 H, dd, J=7.6, 1.2 Hz, ArH), 4.19 - 4.05 (2 H, m,
NCHAHBCH2Ar), 3.09 - 2.93 (2 H, m, NCH2CH2Ar) ppm; 13C
{1H} NMR (125 MHz, CDCl3): δC =162.7 (C=N), 144.6 (ArC),
137.3(ArC), 132.6 (ArC), 131.6 (ArC), 131.1 (ArC), 129.7
(ArC), 129.3 (ArC), 128.4 (ArC), 128.0 (ArC), 127.8 (ArC),
127.3 (ArC), 127.3 (ArC), 127.1 (ArC), 126.3 (ArC), 119.8
(ArC), 119.4 (ArC), 117.3 (ArCSO2CF3), 48.1 (NCH2CH2Ar),
25.7 (NCH2CH2Ar); HRMS (ESI+) m/z calcd for
C20H14F3NNaO3S [M+Na+]: 428.0539, found: 428.0544. HPLC:
Chiralpak® AD-H, n-Hex:IPA = 80:20, T = 25 oC; flow = 1
mL/min, λ = 254 nm, tR,A = 4.8 min, tR,B = 8.2 min.
5. (a) Pfaltz, A. Angew. Chem. Int. Ed. Engl. 1993, 32, 566. (b) Valk,
J. M.; Whitlock, G. A.; Layzell, T. P.; Brown, J. M. Tetrahedron
Asymm. 1995, 6, 2593. (c) Doucet, H.; Fernandez, E.; Layzell, T.
P.; Brown, J. M. Chem. Eur. J. 1999, 5, 1320. (d) Fernández, E.;
Guiry, P. J.; Connole, K. P. T; Brown, J. M. J. Org. Chem. 2014,
79, 5391.
6. Pedersen, J. R. Acta Chem. Scand. 1972, 26, 929.
7. Cortright, S. B.; Yoder, R.A.; Johnston, J. N. Heterocycles 2004,
62, 223.
8. Baker, R.W.; Rea, S.O.; Sargent, M.V.; Schenkelaars, E.M.C.;
Skelon, B. W.; White, A. H. Tetrahedron Asymm 1994, 5, 45.
9. Feng, J.; Dastgir, S.; Li, C. Tetrahedron Lett. 2008, 49, 668.
10. Christopher, J. A.; Atkinson, F. L.; Bax, B. D.; Brown, M. J. B.;
Champigny, A. C.; Chuang, T. T.; Jones, E. J.; Mosley, J. E.;
Musgrave, J. R. Bioorg. Med. Chem. Lett. 2009, 19, 2230.
11. Thaler, T.; Geittner, F.; Knochel, P. Synlett 2007, 2655
12. (a) Clayden, J.; Fletcher, S. P.; McDouall, J. J. W.; Rowbottom, S.
J. M. J. Am. Chem. Soc. 2009, 131, 5331; (b) Bhat, V.; Wang, S.;
Stoltz, B. M.; Virgil, S. C. J. Am. Chem. Soc. 2013, 135, 16829.
13. (a) Clayden, J.; Senior, J.; Helliwell, M. Angew. Chem. Int. Ed.
2009, 48, 6270; (b) Clayden, J. Angew. Chemie. Int. Ed. Engl.
1997, 36, 949; (c) Kumarasamy, E.; Raghunathan, R.; Jockush, S.;
Ugrinov, A.; Sivaguru, J., J. Am. Chem. Soc. 2014, 136, 8729; (d)
Bai, X-F.; Song, T.; Xu, Z.; Xia, C-G; Huang, W-S.; Xu, L-W,
Angew. Chem. Int. Ed. 2015, 54, 5255; (e) Kumarasamy, E.;
Raghunathan, R.; Sibi, M. P.; Sivaguru, J., Chem. Rev. 2015, 115,
11239; (f) Brandes, S.; Niess, B.; Bella, M.; Prieto, A.; Overgaard,
J.; Jørgensen, K. A. Chem. Eur. J. 2006, 12, 6039; (g) Kitagawa,
O.; Kurihara, D.; Tanabe, H.; Shibuya, T.; Taguchi, T,
Tetrahedron Lett. 2008, 49, 471; (h) Clayden, J. P.; Lai, L. W;
Angew. Chem. Int. Ed. 1999, 38, 2556; (i) Clayden, J.; Helliwell,
M.; Pink, J. H.; Westlund, N. J. Am. Chem. Soc. 2001, 123, 12449;
(j) Betson, M. S.; Clayden, J.; Lam, H. K.; Helliwell, M. Angew.
Chemie Int. Ed. 2005, 44, 1241; (k) Clayden, J.; Lund, A.;
Vallverdu, L.; Helliwell, M. Nature (London) 2004, 431, 966; (l)
Yuan, B.; Page, A.; Worrall, C. P.; Escalettes, F.; Willies, S. C.;
McDouall, J. J. W.; Turner, N. J.; Clayden, J. Angew. Chemie. Int.
Ed. 2010, 49, 7010.
4.4. (1-(3,4-Dihydroisoquinolin-1-yl)naphthalen-2-
yl)diphenylphosphine oxide (4i)
Compound 4i was prepared according to the method of Mikami
et al.17 Dimethylsulfoxide (8 mL) and diisopropylethylamine
(1.29 mL, 7.4 mmol) were added to a mixture of 1-aryl-3,4-
dihydroisoquinoline 4h (600 mg, 1.48 mmol), diphenylphosphine
oxide (617 mg, 2.96 mmol), palladium diacetate (33 mg, 0.15
mmol, 10 mol%), and 1,3-bis(diphenylphosphino)propane (dppp;
94 mg, 0.22 mmol, 15 mol%), and the mixture was heated with
stirring at 100 ºC for 22 h. After cooling to room temperature, the
reaction mixture was diluted with EtOAc, washed with water,
dried over MgSO4, and concentrated again under reduced
pressure. The crude product was purified by flash column
chromatography (EtOAc:MeOH 95:5) to afford the title
compound as a yellow solid (0.508 g, 75%); 4i: Rf (95:5
EtOAc:MeOH ) 0.6; m.p. 97-98 ºC; IR (film, cm-1): νmax = 1629
1
(C=N), 1196; H NMR (400 MHz, CDCl3): δH = 7.88 (2 H, dd,
14. (a) Bischler, A.; Napieralski, B. Ber. 1893, 26, 1903 (b)
Movassaghi, M.; Hill, M. D. Org. Lett. 2008, 10, 3485.
15. Schröder, N.; Wencel-Delord, J.; Glorius, F. J. Am. Chem. Soc.
2012, 134, 8298.
16. Sun, X.; Shan, G.; Sun, Y.; Rao, Y. Angew. Chem. Int. Ed. 2013,
52, 1-6.
J=8.6, 1.3 Hz, 2xArH), 7.71 (1 H, d, J=8.8 Hz, ArH), 7.65 - 7.50
(6 H, m, 6xArH), 7.50 - 7.31 (7 H, m, 7xArH), 7.23 (1 H, td,
J=7.3, 1.0 Hz, ArH), 7.17 (1 H, dd, J=7.3, 0.5 Hz, ArH), 6.88 (1
H, td, J=7.4, 1.3 Hz, ArH), 6.59 (1 H, d, J=7.1 Hz,ArH), 3.81 (2
H, m, NCH2CH2Ar), 3.01 (1 H, dt, J=16.0, 8.0 Hz,
NCH2CHXCHYAr), 2.81 ppm (1 H, dt, J=16.0, 7.0 Hz,
17. Ding, K.; Wang, Y.; Yun, H.; Liu, J.; Wu, Y.; Terada, M.; Okubo,
Y.; Mikami, K. Chem. Eur. J. 1999, 5, 1734.
18. Adept Scientific, gNMR, version 5, Letchworth Garden City,
Herts, SG6 1ZA. UK.
19. Dynamic Stereochemistry of Chiral Compounds, Wolf, C. 2008
(pub. Royal Society of Chemistry); Wolf, C. Chem. Soc. Rev.
2005, 34, 595.
20. (a) Trapp, O.; Schurig, V. J. Chromatogr. A 2001, 911, 167; (b) O.
Trapp, V. Schurig, Chirality 2002, 14, 465; (c) Trapp, O. Anal.
Chem. 2006, 78, 189.
21. (a) Clayden, J.; Fletcher, S. P.; Senior, J.; Worrall, C. P.
Tetrahedron: Asymm 2010, 21, 1355; (b) Betson, M. S.; Clayden,
J.; Worrall, C. P.; Peace, S. Angew. Chem. Int. Ed. 2006, 45, 5803;
(c) Clayden, J., Worrall, C. P., Moran, W. J., Helliwell, M. Angew.
Chemie Int Ed. 2008, 47, 3234.
NCH2CHXCHYAr); 13C {1H} NMR (100 MHz, CDCl3): δC
=
166.3 (ArC=N, d, J(13C,31P) = 4.0 Hz), 143.3 (ArC, d, J(13C,31P))
= 8.0 Hz), 136.8, 134.6, 134.6, 134.2, 133.5, 132.2, 132.1, 132.0,
132.0, 131.9, 131.4, 131.4, 130.8, 130.4, 128.6, 128.2, 128.2,
128.1, 128.1, 128.0, 128.0, 127.9, 127.7, 127.5, 127.3, 127.2,
127.1, 126.7, 126.3, 47.5 (NCH2CH2Ar), 25.4 (NCH2CH2Ar)
ppm; 31P {1H} NMR (162 MHz, CDCl3): δP = 29.6 ppm. HRMS
(ESI+) m/z calcd for C31H24ONNaP [M+Na+]: 480.1488, found:
480.1475. HPLC: (R,R)-Whelk-O1, n-Hex:IPA = 60:40, T = 50
oC; flow = 1 mL/min, λ = 254 nm, tR,A = 6.8 min, tR,B = 10.2 min.
22. Oki, M. Top. Stereochem. 1983, 14, 1.
23. Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry of
Organic Compounds 1994 (pub Wiley)
Acknowledgments
We are grateful to the EU Erasmus programme, the BBSRC,
and Johnson Matthey Catalysts for support of this work.
24. (a) Abu-Gnim, C.; Amer, I. Chem. Soc., Chem. Commun.,
1994, 115; (b) Tolis, E. I.; Vallianatou, K. A.; Andreadaki, F. J.;
Kostas, I. D. Appl. Organometal. Chem. 2006, 20, 335.
25. (a) Janin, Y. L.; Roulland, E.; Beurdeley-Thomas, A.; Decaudin,
D.; Monneret, C.; Poupon, M. F. J. Chem. Soc., Perkin Trans. 1
2002, 529; (b) Funder, E. D.; Trads, J. B.; Gothelf, K. V. Org.
Biomol. Chem 2015, 185; (c) Gualtierotti, J-B.; Schumacher, X.;
Fontaine, P.; Masson, G.; Wang, Q.; Zhu, J. Chem. Eur. J. 2012,
14812; (d) Dumas, A. M.; Molander, G. A.; Bode, J. W. Angew.
Chem. Int. Ed. 2012, 5683.
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References and notes
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