Exploitation of differential reactivity of the carbon-chlorine bonds in 1,3-dichloroisoquinoline. Routes to new N,N-chelate ligands and 1,3-disubstituted isoquinolines

Article abstract of DOI:10.1039/a605827b

Under Pd(PPh₃)₄ catalysis, coupling of arylboronic acids to the 1-position of 1,3-dichloroisoquinoline takes place, leading exclusively to 1-aryl-3-chloroisoquinolines. This regiochemistry is demonstrated by the crystal structure of

Full text of DOI:10.1039/a605827b

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Exploitation of differential reactivity of the carbon–chlorine bonds in
1,3-dichloroisoquinoline. Routes to new N,N-chelate ligands and 1,3-
disubstituted isoquinolines
Alan Ford, Ekkehard Sinn and Simon Woodward*
School of Chemistry, University of Hull, Kingston-upon-Hull HU6 7RX, UK
U nder Pd(PPh3)4 catalysis, coupling of arylboronic acids to the 1-position of 1,3-dichloroisoquinoline
takes place, leading exclusively to 1-aryl-3-chloroisoquinolines. This regiochemistry is demonstrated by
the crystal structure of 3-chloro-1-(8-methoxy-1-naphthyl)isoquinoline. The 3-chloro group may be
modified by nickel-catalysed reaction with G rignard reagents or direct nucleophilic displacement with
LiSCH 2Ph. Attempted lithiation of the 3-position is not successful (either deprotonation or complex
reactivity results). U nder zinc reduction in the presence of N iCl2–PPh3 and N aI, the 1-aryl-3-
chloroisoquinolines furnish 3,3Ј-biisoquinolines in good yield.
Introduction
Cl
Ar
Cl
i
N,N-Chelates, especially 2,2Ј-bipyridyl (bpy) and its analogues,
are ubiquitous ligands as additives and modifiers in organic
reactions mediated by transition metals.1 For example, al-
though the combination of RuCl3–NaIO4 is normally a power-
N
N
N
Ar
Cl
Cl
not formed
1
ful system for the cleavage of C᎐C bonds,2 in the presence of
᎐
2 Ar = Ph
bpy the nature of the oxidant is moderated and useful epoxi-
dation chemistry results.3,4 We are interested in the preparation
of new bpy-analogues for use in a wide range of transition
metal promoted chemistry, including related ruthenium-
catalysed oxidations.5,6 This paper addresses the synthesis of
new N,N-chelates based on isoquinolines, whereby the steric
and electronic environment about a coordinated transition
metal can be easily perturbed by simple substitutions to the
basic core structure. Such approaches are useful as they allow
the ‘tuning’ of rates and selectivities of metal catalysts when
optimising the efficiency of individual catalytic systems. In add-
ition a number of different approaches to the synthesis of 1,3-
diarylisoquinolines have been developed.
3 Ar = 4-C6H4Me
4 Ar = 2-C6H4Me
5 Ar = 2-C6H4(OMe)
6 Ar = 1-(2-C10H6OMe)
7 Ar = 1-C10H7
8 Ar = 1-(8-C10H6OMe)
Scheme 1 Reagents and conditions: i, ArB(OH)2, CsF, Pd(PPh3)4 (3
mol%), DME, 6 h
isoquinoline racemises freely.11 This 1,3-isoquinoline coupling
selectivity appears not to have been demonstrated before.
Selective mono-coupling reactions normally rely on the pres-
ence of C–I/C–Br or C–Br/C–OSO3CF3 bonds for differential
reactivity.12 Molecules similar to 2–8 are known but in these
cases there are no regiochemical issues to be addressed.13,14 Two
reports of rate differences in the oxidative addition of poly-
halogenoheterocycles have appeared very recently during the
course of our studies. Reactions at the 6-position of 2,6-
dichloropurines with organotin or organozinc reagents under
catalysis by [Pd(PPh3)2] sources are known.15 2,4-Dichloro-
quinazoline is electronically different at the 2- and 4-positions;
the 4-position is more electrophilic. Under Pd(PPh3)4 catalysis,
AlR3 (R = Me, Bui) couples first to the benzylic 4-position in
refluxing THF or 1,2-dichloroethane. Subsequent addition of
more AlR3 results in coupling to the 2-position.16
Results and discussion
1,3-Selective cross-coupling reactions
Simple canonical structure arguments indicate that the 1-chloro
substituent of 1,3-dichloroisoquinoline7–9 should be signifi-
cantly more reactive than its 3-position counterpart. This
differential reactivity may be exploited in palladium-
catalysed cross-coupling of 1,3-dichloroisoquinoline with aryl-
boronic acids (Suzuki reactions). Regiochemistry in palladium-
catalysed reactions of polyhalo substrates is determined at the
moment of oxidative addition. We reasoned that the rate of
oxidative addition of the isoquinoline’s benzylic 1-chloro group
would greatly exceed that of the 3-chloro group, leading to high
regioselectivity regardless of the steric requirements of the
nucleophilic coupling partner. When 1,3-dichloroisoquinoline 1
reacts with phenylboronic acid only the 1-substituted product 2
is formed, none of the 3-substituted regioisomer is isolated
from the reaction mixture (Scheme 1). Optimal conditions for
this reaction are attained if 3 equiv. of CsF promoter are
used.10 In these cases the reactions are faster and cleaner than
those with other bases [5–6 h with CsF vs. overnight with
Na2CO3 or Ba(OH)2]. Under fluoride promotion even the high-
ly hindered 8-methoxy-1-naphthylboronic acid couples in good
yield (80%). It is noteworthy that a reasonable barrier to
racemisation is expected in atropisomeric 8, whereas 1-naphthyl-
The regiochemistry of the isoquinoline in Scheme 1 is con-
firmed by a number of techniques. Complete assignment of the
isoquinoline protons of all compounds is possible at 600 MHz.
In particular, the 2D NOESY spectrum of 3 shows a clear
cross-peak for the o-tolyl proton signal and that due to H-C(8)
on the isoquinoline. Degradation of 6 by stoichiometric
1
amounts of PdCl2–NaBH4 results in material with H NMR
spectra identical to the known 1-(2-methoxynaphthyl)iso-
quinoline.13 In the case of 8 the atom connectivity was further
confirmed by the results of a crystallographic study (Fig. 1).
Although all the arylboronic acids tried were successful, there is
one limitation on this selective coupling strategy: vinylboronic
acids do not participate in the reactions, as Me C᎐CHB(OH)
fails to couple with 1 when the coupling is promoted with
᎐
2
2
J. Chem. Soc., Perkin Trans. 1, 1997
927

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Na2CO3. Analogous reactions using CsF have not been carried
out.
disubstituted species. This chemistry is summarised in Scheme
2. The 3-chloro substituent is resistant to transmetallation with
BuLi or ButLi; only deprotonation at H-C(4) results. This may
be achieved cleanly with LiNPri2 at 0 ЊC, or with BuLiؒTMEDA
or lithium 2,2,6,6-tetramethylpiperidine at Ϫ78 ЊC in THF.
Deuteriation of the resulting anion leads to 9 or 10. Partial
transmetallation of the 3-chloro group may be effected in some
cases with LiC10H8, followed by a proton quench. For example,
rapid addition of 8 to 2.5 equiv. of LiC10H8 at Ϫ70 ЊC yields
some 11, after D2O quench. However, this reaction is not syn-
thetically useful as variable quantities of uncharacterised reduc-
tion products are also formed; use of electrophiles other than
Hϩ led only to 11.
Disubstituted isoquinolines
Despite their simple constitution, 1,3-disubstituted isoquino-
lines are not always easily prepared by traditional methods.
Often several steps are required to reach the desired target.
Several modifications of the new 1-aryl-3-chloroisoquinolines
are possible leading to efficient syntheses of new 1,3-
Reaction of the 1-aryl-3-chloroisoquinolines with Grignard
reagents at room temperature affords entry to the mixed isoqui-
nolines 12–15. These reactions are best carried out using cata-
lysis with 10 mol% NiCl2(dppf) [dppf = 1,1Ј-bis(diphenyl-
phosphino)ferrocene], as far higher reaction rates are attained
than with other chelate phosphine nickel catalysts. For example,
compound 12 is isolated in 78% within 1 h using NiCl2(dppf),
while 70 h are required for equivalent preparations of 13–14
using NiCl2(dppp) [dppf = 1,3-bis(diphenylphosphino)pro-
pane] (84 and 75% yield respectively). As an alternative to
nickel catalysis, Pd(PPh3)4 (5 mol%) may be used to promote a
second ArB(OH)2 coupling, as in the synthesis of 16–18. For-
cing conditions are necessary as the 3-chloro substituent is only
reactive in DMF at 100 ЊC. The heterocyclic systems 19 (61%),
20 (94%) and 21 (80%) are accessible via Stille-type coupling
with 2-(Me3Sn)C5H4N. These reactions are rather sluggish and
a rather large catalyst loading [Pd(PPh3)4, 28 mol%] at elevated
temperature is required. Competitive product binding to the
catalyst necessitates these conditions. In a final catalytic reac-
tion with organoborates it proved possible to introduce an ethyl
substituent at the 3-position. Under NiCl2(dppf) catalysis, in
the presence of excess zinc dust, reaction of 8 with Li[BEt3(O-
Pri)] led to smooth formation of 22 in 70% yield. This efficient
Fig. 1 An ORTEP view of one of the two identical 8 molecules in the
unit cell. Selected bond distances: Cl(1)–C(2) 1.742(4), N(1)–C(1)
1.318(5), N(1)–C(2) 1.343(4), O(1)–C(19) 1.367 Å; dihedral angle:
N(1)–C(1)–C(10)–C(11) 94.8Њ
Scheme 2 Reagents and conditions: i, LiNPri2, THF, 0 ЊC; or LiTMP, THF, 0 ЊC; or BuLiؒTMEDA, THF, Ϫ78 ЊC; ii, D2O; iii, LiC10H8, THF,
Ϫ70 ЊC, then D2O or H2O; iv, Ar2MgBr, NiCl2(dppf) (5 mol%), THF 0 ЊC to room temp., 1 h; or Ar2B(OH)2, Cs2CO3, Pd(PPh3)4 (5 mol%), DMF,
100 ЊC, 18 h; or 2-(Me3Sn)C5H5N, Pd(PPh3)4 (28 mol%), DMF, 100 ЊC, 18 h; v, LiBEt3(OPri), NiCl2(dppf) (6.5 mol%), THF, reflux, 3 h; vi,
LiSCH2Ph, DMF, 120 ЊC, 6 h; vii, BBr3, CH2Cl2, Ϫ78 ЊC to room temp., 18 h
928
J. Chem. Soc., Perkin Trans. 1, 1997

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transfer of the ethyl functionality is of note as reductive elimin-
ation of the Ni(Et)(Ar)(dppf) intermediate must be rapid to
avoid competing β-hydride elimination. Similar effects have
been noted by Miyaura et al.17
major product in addition to smaller amounts of 25. Given
that stoichiometric amounts of ZnCl2 are produced in zinc-
promoted pyridyl dimerisations, loss of product as insoluble
zinc complexes is not unexpected. We find that reproducibly
high yields of free ligand are attained if aqueous Na3PO4 or 6 
HCl is added to the reaction mixture prior to work-up to remove
the ZnCl2.
In conclusion we have demonstrated that by exploiting the
differential reactivity of the two carbon–chlorine bonds in 1,3-
dichloroisoquinoline, a wide range of novel isoquinolines and
N,N-chelate ligands are easily accessible. The metal complexes
and use of these ligands in various transition metal mediated
reactions is currently being explored.
In the absence of catalytic activation, the 3-chloro function is
rather reluctant to participate in nucleophilic substitution reac-
tions. Reaction of 8 with LiSCH2Ph is only achieved in DMF at
high temperatures (120 ЊC). Under these conditions the desired
product 23 is attained but some dealkylation of the methoxy-
ether occurs as a low yield competing side reaction. The iso-
lation of 23 allows an estimation of the barrier to rotation
about the atropisomeric 1,1Ј-axis. At room temperature in
1
CDCl3 or [2H8]toluene the H NMR spectrum of 23 shows a
typical AB pattern for the diastereotopic benzyl protons. The
appearance of the spectrum is identical in the temperature
range Ϫ20 to ϩ100Њ C. The signals do not broaden or coalesce
and only a slight reduction in the chemical shift difference
between the AB-pair is observed. Based on the unchanging
nature of the spectrum, compound 23 must have an appreciable
barrier to rotation (∆G‡ > 100 kJ molϪ1) and similar barriers are
likely in the related 8-methoxynaphthyl compounds 8 and 22.
The 8-methoxy function significantly increases the barrier to
racemisation, as this value for 1-naphthylisoquinoline is 78.3
kJ molϪ1 at 298 K.11 To assess the effect of the 8-methoxy group
on the rotational barriers in 8, 22 and 23 a simple model of the
transition state was investigated using the atomic coordinates
of 8. Rotation about the 1,1Ј-bond indicates that anti transition
states (i.e. those in structures 22–23) constitute the lowest
energy pathway to racemisation for these compounds.18 Simple
Chem 3D modelling using the coordinates of 8 indicates that as
the dihedral angle falls from 90 to 72Њ the separation of the
isoquinoline nitrogen and the 8-OMe ether oxygen falls to 2.71
Å; the sum of the N,O van der Waals radii. At a dihedral angle
of 0Њ the N–O distance is only 1.76 Å corresponding to about
two thirds of the sum of N,O van der Waals radii. It is likely
that these strong interactions lead to significant barriers to 1,1Ј-
rotation.
Experimental
All reactions involving air sensitive reagents were carried out
under argon or nitrogen atmospheres using standard Schlenk
techniques. Tetrahydrofuran (THF) and 1,2-dimethoxyethane
(DME) were distilled from sodium–benzophenone immediately
prior to use. Toluene and acetonitrile were distilled from cal-
cium hydride, dimethylformamide (DMF) was dried over 4 Å
molecular sieves. POCl3 was distilled before use. All other
reagents were used as supplied. The light petroleum used had
bp 40–60 ЊC. Flash chromatography was carried out on acti-
vated silica gel (Rhône-Poulenc Sorbsil C60 40/60H) or alu-
mina (BDH, Brockmann Grade I). Thin layer chromatography
(TLC) analyses used Merck Kieselgel 60 HF254ϩ366 plates. Infra-
red spectra were recorded using a Perkin-Elmer 983G instru-
ment. Proton NMR spectra (270 MHz) and 13C NMR spectra
(67.8 MHz) were recorded on a JEOL-270 spectrometer at
ambient temperature in CDCl3. High field proton NMR spectra
were obtained on a Bruker VXR600S (600 MHz). For all NMR
spectra tetramethylsilane was used as the internal standard;
J values are given in Hz. Finnigan 1020 (electron impact ionis-
ation, EI) and VG-ZAB (EI and fast atom bombardment ion-
isation, FAB) machines were employed for mass spectrometry
studies. The arylboronic acids (except 8-methoxy-1-naphthyl-
boronic acid) and 2-(Me3Sn)C5H4N 21 used were literature
compounds. General routes to 1,3-dichloroisoquinoline were
employed.7–9
For those compounds possessing methoxyether functional-
ity, deliberate dealkylation can be effected by use of BBr3. For
example, reaction of 6 with BBr3 at Ϫ78 ЊC followed by warming
to room temperature yields the substituted naphthol 24 in
reasonable yield (78%).
8-Methoxy-1-naphthylboronic acid
A solution of ButLi (1.7  in pentane; 50 cm3, 0.085 mol) was
added dropwise to 1-methoxynaphthalene (12.18 g, 11.2 cm3,
0.077 mol) in cyclohexane (50 cm3) and the mixture was stirred
at room temperature for 24 h. The resulting pale orange–brown
suspension was added slowly, using a wide-bore cannula, to a
stirred solution of B(OMe)3 (16 g, 17.5 cm3, 0.154 mmol) in
THF (100 cm3), keeping the temperature below Ϫ60 ЊC. The
reaction mixture was allowed to warm to room temperature
overnight, then quenched with 10% HCl and stirred under
argon for 1 h. The mixture was extracted with Et2O and the
combined extracts dried over MgSO4. Removal of the solvents
furnished the crude product which was washed with hexane to
give a fine white powder (6.2 g, 40%); mp 134–136 ЊC; νmax(KBr
disc)/cmϪ1 3390br s (OH), 3045w, 2940w (CH), 1611m, 1500s,
1462m (CC), 1348br s (BO), 1250s (CO), 819s, 773s, 759m
(CH); δH [270 MHz, (CD3)2SO] 7.77 (dd, 1 H, J 8.06 and 1.22,
Ar-H), 7.6 [br s, 2 H, B(OH)2], 7.48–7.32 (m, 4 H, Ar-H), 6.93
(dd, 1 H, J 7.08 and 1.47, Ar-H), 3.89 (s, 3 H, OCH3); δC[68
MHz, (CD3)2SO] 155.7, 133.5, 127.8, 126.8, 126.4, 125.8, 125.7,
120.3, 104.5, 55.5. This material was used as obtained.
Colon reactions
Compounds 2–8 also engage in nickel-catalysed reductive
dimerisations (zinc-based Colon reactions19,20) to furnish the
3,3Ј-biisoquinolines 25–31 (69–88%, Scheme 3). These reac-
Cl
N
N
N
Ar
Ar
Ar
2 Ar = Ph
3 Ar = 4-C6H4Me
4 Ar = 2-C6H4Me
5 Ar = 2-C6H4(OMe)
6 Ar = 1-(2-C10H6OMe)
7 Ar = 1-C10H7
25 Ar = Ph
26 Ar = 4-C6H4Me
27 Ar = 2-C6H4Me
28 Ar = 2-C6H4(OMe)
29 Ar = 1-(2-C10H6OMe)
30 Ar = 1-C10H7
8 Ar = 1-(8-C10H6OMe)
31 Ar = 1-(8-C10H6OMe)
Scheme 3 Reagents and conditions: i, NaI, Zn, NiCl2 (10 mol%), PPh3
(30 mol%), THF, reflux, 3 h
tions allowed us to improve the procedure for the preparation
of 2,2Ј-bipyridyl-type compounds. Investigation of the primary
literature reveals that the isolated yields reported by many dif-
ferent groups for the Colon procedure span a wide range of
yields (ca. 30–90%) even for very similar molecules. Analysis of
the crude reaction mixture containing 25 by FAB mass spec-
trometry revealed the presence of insoluble ZnCl2(25) as the
Representative preparation of the 1-aryl-3-chloroisoquinolines:
3-chloro-1-phenylisoquinoline 2
A mixture of 1,3-dichloroisoquinoline 1 (0.99 g, 5 mmol) and
Pd(PPh3)4 (0.17 g, 0.15 mmol) in DME (25 cm3) was warmed to
form a yellow solution. Phenylboronic acid (0.67 g, 5.5 mmol)
and CsF (1.75 g, 11 mmol) were added and the mixture heated
J. Chem. Soc., Perkin Trans. 1, 1997
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under reflux for 6 h. Water and Et2O were added, the organic
layer separated and the aqueous layer extracted twice with
Et2O. The combined organic layers were washed with brine,
dried (MgSO4) and evaporated to yield the crude product which
was purified by dry flash chromatography (1:4 CH2Cl2–light
petroleum changing to neat CH2Cl2). Yield 1.08 g (90%); mp
81–82 ЊC (Found: C, 75.0; H, 4.2; N, 5.8. Calc. for C15H10ClN:
C, 75.1; H, 4.2; N, 5.8%); νmax(KBr disc)/cmϪ1 3050w, 3030w
(CH), 1610m (CN), 1565m, 1540s, 1485m (CC), 855s, 760s, 700s
(CH); δH (600 MHz, CDCl3) 8.09 (m, 1 H, H-8), 7.81 (d with
unresolved splitting, J5,6 8.4, 1 H, H-5), 7.71 (apparent d, 1 H,
J4,5 1.0, H-4), 7.71–7.68 (m, 3 H, H-2Ј, H-6Ј and H-6), 7.52–7.49
(m, 4 H, Ar-H); δC(68 MHz, CDCl3) 161.5, 144.8, 139.0, 138.2,
130.9, 130.1, 129.1, 128.5, 127.9, 127.4, 126.3, 125.5, 118.9; m/z
(EI) 239, 241 (Mϩ).
3-Chloro-1-(4-tolyl)isoquinoline 3. The same procedure was
used as for the preparation of compound 2. Yield 87%; mp
116–117 ЊC (Found: C, 75.6; H, 4.7; N, 5.5. Calc. for
C16H12ClN: C, 75.7; H, 4.8; N, 5.5%); νmax(KBr disc)/cmϪ1
3060w, 2920w (CH), 1610m (CN), 1570m, 1540s, 1482m (CC),
860s, 835s (CH); δH (600 MHz, CDCl3) 8.11 (m, 1 H, H-8), 7.79
(m, 1 H, H-5), 7.68 (s, 1 H, H-4), 7.67 (m, 1 H, H-6), 7.60–7.58
(m, 2 H, H-3Ј and H-5Ј), 7.51 (ddd, 1 H, J 8.6, 6.8 and 1.1, H-7),
7.34–7.32 (m, 2 H, H-2Ј and H-6Ј), 2.45 (s, 3 H, Ar-CH3); δC(68
MHz, CDCl3) 161.6, 144.8, 139.1, 139.0, 135.4, 130.8, 130.1,
129.1, 128.0, 127.2, 126.3, 125.6, 118.6, 21.4; m/z (EI) 253, 255
(Mϩ).
3-Chloro-1-(2-tolyl)isoquinoline 4. The same procedure was
used as for the preparation of compound 2. Yield 67%; mp 43–
44 ЊC (Found: C, 75.7; H, 5.0; N, 5.4. Calc. for C16H12ClN: C,
75.7; H, 4.8; N, 5.5%); νmax(KBr disc)/cmϪ1 3060w, 2920w
(CH), 1613m (CN), 1572m, 1545s, 1480m (CC), 855s, 730s
(CH); δH (600 MHz, CDCl3) 7.81 (m, 1 H, H-5), 7.74 (appar-
ent d, 1 H, J 0.75, H-4), 7.69 (ddd, 1 H, J 8.1, 6.7 and 1.2,
H-6), 7.63 (m, 1 H, H-8), 7.46 (ddd, 1 H, J 8.1, 6.8 and 1.2,
H-7), 7.4–7.3 (m, 4 H, Ar-H), 2.08 (s, 3 H, Ar-CH3); δC(68
MHz, CDCl3) 162.3, 144.7, 138.5, 137.7, 136.5, 131.1, 130.4,
129.7, 128.9, 127.6, 127.4, 126.2, 125.7, 119.0, 19.9; m/z (EI)
253, 255 (Mϩ).
1-(2-Methoxyphenyl)-3-chloroisoquinoline 5. The same pro-
cedure was used as for the preparation of compound 2. Yield
65%; mp 96–96.5 ЊC (Found: C, 70.9; H, 4.4; N, 5.1. Calc. for
C16H12ClNO: C, 71.25; H, 4.5; N, 5.2%); νmax(KBr disc)/cmϪ1
3060w, 2940w (CH), 1615m (CN), 1600m, 1580m, 1540m,
1480s (CC), 1242s (CO), 855s, 745s (CH); δH (600 MHz, CDCl3)
7.78 (m, 1 H, H-5), 7.72 (apparent d, 1 H, J 0.86, H-4), 7.68 (m,
1 H, H-8), 7.66 (ddd, 1 H, J 8.1, 6.7 and 1.2, H-6), 7.48–7.44 (m,
2 H, H-5Ј and H-7), 7.38 (dd with unresolved splitting, 1 H,
J 7.4 and 1.75, H-3Ј), 7.10 (ddd, 1 H, J 8.4, 7.4 and 1.0, H-4Ј),
7.03 (dd, 1 H, J 8.3 and 1.0, H-6Ј), 3.69 (s, 3 H, OCH3); δC(68
MHz, CDCl3) 160.0, 157.1, 144.8, 138.2, 131.3, 130.8, 130.5,
128.2, 127.5, 127.0, 126.7, 126.0, 120.9, 119.2, 111.2, 55.6; m/z
(EI) 269, 271 (Mϩ).
3-Chloro-1-(1-naphthyl)isoquinoline 7. The same procedure
was used as for the preparation of compound 2. Yield 69%;
mp 113–114 ЊC (Found: C, 78.4; H, 4.1; N, 4.8. Calc. for
C19H12ClN: C, 78.8; H, 4.2; N, 4.8%); νmax(KBr disc)/cmϪ1
3050w (CH), 1613m (CN), 1570m, 1545s, 1485m (CC), 870s,
855s, 775s (CH); δH (600 MHz, CDCl3) 8.00–7.99 (m, 1 H,
H-4Ј), 7.93 (d with unresolved splitting, 1 H, J5Ј,6Ј 8.1, H-5Ј),
7.86–7.84 (m, 1 H, H-5), 7.83 (apparent d, 1 H, J 0.98, H-4),
7.69 (ddd, 1 H, J6,5 8.3, J6,7 6.8 and J6,8 1.1, H-6), 7.60 (dd, 1 H,
J3Ј,4Ј 8.1 and J3Ј,2Ј 6.9, H-3Ј), 7.59–7.57 (m, 1 H, H-8), 7.57 (dd, 1
H, J2Ј,3Ј 6.9 and J2Ј,4Ј 1.5, H-2Ј), 7.48 (ddd, 1 H, J6Ј,5Ј 8.1, J6Ј,7Ј 6.5
and J6Ј,8Ј 1.4, H-6Ј), 7.38 (ddd, 1 H, J7,8 8.5, J7,6 6.8 and J7,5 1.2,
H-7), 7.38–7.36 (m, 1 H, H-8Ј), 7.34 (ddd, 1 H, J7Ј,8Ј 8.5, J7Ј,6Ј 6.5
and J7Ј,5Ј 1.3, H-7Ј); δC(68 MHz, CDCl3) 161.3, 144.9, 138.5,
135.6, 133.7, 132.1, 131.2, 129.3, 128.3, 128.1, 127.9, 127.4,
127.2, 126.6, 126.2, 126.1, 125.8, 125.2, 119.4; m/z (EI) 289, 291
(Mϩ).
3-Chloro-1-(8-methoxy-1-naphthyl)isoquinoline 8. The same
procedure was used as for the preparation of compound 2.
Yield 80%; mp 144 ЊC (Found: C, 74.9; H, 4.4; N, 4.4. Calc. for
C20H14ClNO: C, 75.1; H, 4.4; N, 4.4%); νmax(KBr disc)/cmϪ1
3060w, 2940w (CH), 1610m (CN), 1573m, 1545m, 1460m (CC),
1257s (CO), 853m, 820s, 760m (CH); δH (600 MHz, CDCl3) 7.94
(dd, 1 H, J4Ј,3Ј 8.2 and J4Ј,2Ј 1.3, H-4Ј), 7.79 (d with unresolved
splitting, 1 H, J5,6 8.3, H-5), 7.72 (apparent d, 1 H, J 0.8, H-4),
7.62 (ddd, 1 H, J6,5 8.3, J6,7 6.7 and J6,8 1.2, H-6), 7.56 (dd, 1 H,
J3Ј,4Ј 8.2 and J3Ј,2Ј 7.0, H-3Ј), 7.54 (dd, 1 H, J5Ј,6Ј 8.2 and J5Ј,7Ј 0.9,
H-5Ј), 7.42 (dd, 1 H, J2Ј,3Ј 7.0 and J2Ј,4Ј 1.3, H-2Ј), 7.42–7.39 (m,
2 H, H-8 and H-6Ј), 7.31 (ddd, 1 H, J7,8 8.1, J7,6 6.7 and J7,5
1.2, H-7), 6.88 (dd, 1 H, J7Ј,6Ј 7.1 and J7Ј,5Ј 0.9, H-7Ј), 3.12 (s,
3 H, OCH3); δC(68 MHz, CDCl3) 165.2, 155.7, 143.9, 137.3,
135.3, 134.0, 130.5, 129.0, 128.3, 127.8, 127.3, 126.7, 126.4,
125.7, 125.6, 124.2, 121.2, 117.9, 106.4, 55.5; m/z (EI) 319,
321 (Mϩ).
Lithiation of 3-chloro-1-(1-naphthyl)isoquinoline 7 and D2O
quench
A solution of BuLi (1.6  in hexanes; 800 mm3 0.125 mmol)
was added dropwise to 2,2,6,6-tetramethylpiperidine (17 mg, 21
mm3, 0.125 mmol) in THF (2.5 cm3) at 0 ЊC. The mixture was
stirred for 5 min then a solution of the 3-chloro-1-(1-naphthyl)-
isoquinoline 7 (28 mg, 0.11 mmol) in THF (2.5 cm3) was added
dropwise. The mixture was stirred for 15 min then quenched
with D2O. After the reaction had reached room temperature,
the solvents were removed in vacuo and CH2Cl2 added. The
solution was dried over MgSO4 and evaporated to give the
1
crude product, the H NMR spectrum of which was identical
to the starting material, save for the absence of the 4-isoquino-
line signal. All other data were in accord with the formation of
10.
Lithiation using lithium naphthalenide: radical anion reduction of
8
3-Chloro-1-(2-methoxy-1-naphthyl)isoquinoline 6. The same
procedure was used as for the preparation of compound 2.
Yield 85%; mp 159–160 ЊC; νmax(KBr disc)/cmϪ1 3060w, 2950w
(CH), 1615m (CN), 1590m, 1575m, 1540m, 1505m (CC), 1260s,
1245s (CO), 810m, 750s (CH); δH (600 MHz, CDCl3) 8.01
(apparent dd, 1 H, J4Ј,3Ј 9.1 and J4Ј,5Ј 0.6, H-4Ј), 7.85 (d with
unresolved splitting, 1 H, J5Ј,6Ј 8.1, H-5Ј), 7.84 (d with
unresolved splitting, 1 H, J5,6 8.2, H-5), 7.81 (s, 1 H, H-4), 7.67
(ddd, 1 H, J6,5 8.2, J6,7 6.7 and J6,8 1.2, H-6), 7.48 (m, 1 H, H-8),
7.41 (d, 1 H, J3Ј,4Ј 9.1, H-3Ј), 7.32 (ddd, 1 H, J7,8 8.5, J7.6 6.7 and
J7,5 1.1, H-7), 7.37 (ddd, 1 H, J6Ј,5Ј 8.1, J6Ј,7Ј 6.7 and J6Ј,8Ј 1.1,
H-6Ј), 7.26 (ddd, 1 H, J7Ј,8Ј 8.4, J7Ј,6Ј 6.7 and J7Ј,5Ј 1.4, H-7Ј), 7.03
(m, 1 H, H-8Ј), 3.12 (s, 3 H, OCH3); δC(68 MHz, CDCl3) 159.2,
155.0, 145.2, 138.4, 133.7, 131.1, 131.0, 129.1, 128.0, 127.8,
127.4, 127.1, 126.2, 125.0, 123.9, 120.7, 119.3, 113.4, 56.6; m/z
(EI) 319, 321 (Mϩ) [Found (HRMS): 319.0764. C20H14ClNO
requires 319.0764].
A solution of 3-chloro-1-(8-methoxy-1-naphthyl)isoquinoline 8
(50 mg, 0.156 mmol) in THF (2.5 cm3) was cooled to Ϫ72 ЊC
(CO2–EtOH) and stirred while a solution of LiC10H8 (0.23  in
THF; 2.4 cm3, 0.546 mmol) was added rapidly. The mixture was
stirred at Ϫ72 ЊC for 5 min then quenched with H2O (0.1 cm3).
After warming to room temperature, the solvent was evapor-
ated and CH2Cl2 added. The solution was dried (MgSO4) and
concentrated to give the crude product which was washed two
or three times with pentane; δH (270 MHz, CDCl3) 8.56 (d, 1 H,
J 5.5, H-3), 7.95 (dd, 1 H, J 8.5 and 1.5, H-4Ј), 7.90–7.86 (m, 1
H, H-5), 7.64 (d with unresolved splitting, 1 H, J 5.5, H-4),
7.66–7.54 (m, 3 H, Ar-H), 7.46–7.40 (m, 3 H, Ar-H), 7.34 (ddd,
1 H, J 8.0, 6.5 and 1.3, H-7), 6.69 (dd, 1 H, J 7.8 and 1.0, H-7Ј),
3.10 (s, 3 H, OCH3). When the reaction was carried out as above
and quenched with D2O the intensities of the H-3 and H-4Ј
signals were in the ratio 0.28:1, indicating 60% deuterium
incorporation.
930
J. Chem. Soc., Perkin Trans. 1, 1997

View Article Online
Representative preparation of 1,3-diarylisoquinolines via NiCl2-
(dppf) catalysed Grignard coupling of 1,3-diphenylisoquinoline
12
mmol) and Pd(PPh3)4 (58 mg, 0.05 mmol) in degassed DMF
(5 cm3) was warmed to give a bright yellow solution. Solid
2-methoxyphenylboronic acid (1.1 mmol) and Cs2CO3 (488.7
mg, 1.5 mmol) were added and the mixture was heated at
100 ЊC (18 h). Water and Et2O were added to the cooled mix-
ture, the organic phase separated and the aqueous layer
extracted twice with Et2O. The combined organic layers were
washed with 1  HCl and brine and then dried over Mg4SO and
concentrated. The residue was purified by flash chrom-
atography (SiO2, 3:2 light petroleum–CH2Cl2) to yield 3-(2-
methoxyphenyl)-1-(4-tolyl)isoquinoline 16 as a white solid, 200
mg (61%); mp 130–131 ЊC; νmax(KBr disc)/cmϪ1 3045w, 2943w
(CH), 1612m (CN), 1597w, 1566m, 1549m (CC), 1240 (CO),
825m, 756s (CH); δH (270 MHz, CDCl3) 8.24 (s, 1 H, H-4), 8.12
(dd, 1 H, J8,7 8.5 and J8,6 1.0, H-8), 8.07 [dd, 1 H, J3Ј,4Ј 7.6 and
J3Ј,5Ј 1.9, 2-C6H4(OMe) H-3], 7.91–7.88 (m, 1 H, H-5), 7.70–7.67
(m, 2 H, tolyl H-3 and H-5), 7.65 (ddd, 1 H, J6,5 8.1, J6,7 6.8 and
J6,8 1.2, H-6), 7.49 (ddd, 1 H, J7,8 8.5, J7,6 6.8 and J7,5 1.4, H-7),
7.38–7.32 [m, 3 H, tolyl H-2 and H-6, 2-C6H4(OMe) H-5], 7.10
[dt, 1 H, J4Ј,3Ј ≈ J4Ј,5Ј ≈ 7.6 and J4Ј,6Ј 1.2, 2-C6H4(OMe) H-4],
7.05–7.02 [m, 1 H, 2-C6H4(OMe) H-6], 3.93 (s, 3 H, OCH3),
2.46 (s, 3 H, Ar-CH3); δC(68 MHz, CDCl3) 160.1, 157.3, 148.1,
138.3, 137.2, 137.2, 131.8, 130.1, 129.7, 129.3, 129.0, 127.6,
127.5, 126.7, 125.5, 121.1, 120.4, 111.5, 55.8, 21.4; m/z (EI)
325 (Mϩ) [Found (HRMS): 325.1467. C23H19NO requires
325.1467].
A mixture of NiCl2 (6.5 mg, 0.05 mmol) and dppf (28 mg, 0.05
mmol) in THF (5 cm3) was warmed to give a dark green solu-
tion. Solid 3-chloro-1-phenylisoquinoline 2 (240 mg, 1.00
mmol) was added and the mixture cooled to 0 ЊC then treated
dropwise with a solution of PhMgBr (3.0  in Et2O; 0.4 cm3, 1.2
mmol). The mixture was stirred at 0 ЊC for 30 min then at room
temperature for 30 min. Water and Et2O were added, the
organic layer separated and the aqueous layer extracted twice
with Et2O. The combined organic extracts were washed with
water and brine, dried over MgSO4 and concentrated. Flash
chromatography (SiO2, 2:3 CH2Cl2–light petroleum) gave 1,3-
diphenylisoquinoline as a colourless oil which solidified slowly.
Yield 219 mg (78%); mp 71–73 ЊC; νmax(KBr disc)/cmϪ1 3045w
(CH), 1615m (CN), 1585w, 1552m, 1490m (CC), 770s, 765s,
690s, 682s (CH); δH (270 MHz, CDCl3) 8.22 (m, 2 H, 3-phenyl
H-2 and H-6), 8.13 (m, 1 H, H-8), 8.08 (s, 1 H, H-4), 7.94 (m, 1
H, H-5), 7.82 (m, 2 H, 1-phenyl H-2 and H-6), 7.68 (ddd, 1 H,
J 1.2, 6.8 and 8.2, H-6), 7.60–7.48 (m, 6 H, Ar-H), 7.40 (m, 1 H,
3-phenyl H-4); δC(68 MHz, CDCl3) 160.4, 150.2, 139.9, 139.6,
137.9, 130.3, 130.1, 128.7, 128.6, 128.5, 128.3, 127.6, 127.5,
127.1, 126.9, 125.8, 115.8; m/z (EI) 281 (Mϩ) [Found (HRMS):
281.1204. C21H15N requires 281.1204].
3-Phenyl-1-(4-tolyl)isoquinoline 13. The same procedure was
used as for the preparation of compound 12. Yield 84%; mp
56–57 ЊC; νmax(KBr disc)/cmϪ1 3050w, 2910w (CH), 1615m
(CN), 1585w, 1550m, 1490m (CC), 825s, 770s, 685s (CH);
δH (270 MHz, CDCl3) 8.22 (m, 2 H, phenyl H-2 and H-6), 8.15
(m, 1 H, H-8), 8.05 (apparent d, 1 H, J 0.97, H-4), 7.92 (m, 1 H,
H-5), 7.72 (m, 2 H, tolyl H-3 and H-5), 7.67 (ddd, 1 H, J 1.23,
6.84 and 8.18, H-6), 7.50 (m, 1 H, H-7), 7.48 (m, 2 H, phenyl
H-3 and H-5), 7.39 (m, 1 H, phenyl H-4), 7.36 (m, 2 H, tolyl
H-2 and H-6), 2.48 (s, 3 H, Ar-CH3); δC(68 MHz, CDCl3) 160.4,
150.2, 139.7, 138.5, 137.9, 137.1, 130.2, 130.0, 129.0, 128.7,
128.5, 127.7, 127.5, 127.1, 126.8, 125.9, 115.5, 21.4; m/z (EI) 295
(Mϩ) [Found (HRMS): 295.1361. C22H17N requires 295.1361].
1,3-Di(4-tolyl)isoquinoline 14. The same procedure was used
as for the preparation of compound 12. Yield 73%; mp 89–
90 ЊC; νmax(KBr disc)/cmϪ1 3050w, 2920w (CH), 1615m (CN),
1605m, 1580m, 1550s, 1520m (CC), 825br s (CH); δH (600 MHz,
CDCl3) 8.14–8.12 (m, 1 H, H-8), 8.12–8.10 (m, 2 H, 3-tolyl H-3
and H-5), 8.02 (s, 1 H, H-4), 7.91–7.89 (m, 1 H, H-5), 7.72–7.69
(m, 2 H, 1-tolyl H-3 and H-5), 7.65 (ddd, 1 H, J 8.1, 6.6 and 1.1,
H-6), 7.47 (ddd, 1 H, J 8.1, 6.8 and 1.1, H-7), 7.37–7.35 (m, 2
H, 1-tolyl H-2 and H-6), 7.30–7.28 (m, 2 H, 3-tolyl H-2 and
H-6), 2.47 (s, 3 H, 1-tolyl CH3), 2.41 (s, 3 H, 3-tolyl CH3); δC(68
MHz, CDCl3) 153.9, 143.7, 132.0, 131.9, 131.5, 130.7, 130.4,
123.7, 123.5, 123.0, 122.5, 121.2, 120.9, 120.5, 120.2, 119.3,
108.5, 15.0, 14.9; m/z (EI) 309 (Mϩ) [Found (HRMS):
309.1517. C23H19N requires 309.1517].
1-(4-Tolyl)-3-(2-tolyl)isoquinoline 17. The same procedure was
used as for the preparation of compound 16. Yield 77%; mp
109–110 ЊC; νmax(KBr disc)/cmϪ1 3050w, 3022w (CH), 1610m
(CN), 1583w, 1549m, 1490m (CC), 802s, 799s, 762s (CH);
δH (270 MHz, CDCl3) 8.19–8.15 (m, 1 H, H-8), 7.92–7.88 (m, 1
H, H-5), 7.73 (s, 1 H, H-4), 7.69 (ddd, 1 H, J 8.2, 6.7 and 1.2,
H-6), 7.68–7.64 (m, 2 H, p-tolyl H-3 and H-5), 7.59–7.54 (m, 1
H, Ar-H), 7.53 (ddd, 1 H, J 8.2, 6.7 and 1.5, H-7), 7.36–7.32
(m, 2 H, p-tolyl H-2 and H-6), 7.32–7.26 (m, 3 H, Ar-H), 2.49
(s, 3 H, CH3), 2.45 (s, 3 H, CH3); δC(68 MHz, CDCl3) 160.0,
153.0, 138.4, 137.5, 136.4, 130.8, 130.2, 130.1, 129.0, 128.0,
127.7, 127.2, 126.9, 125.9, 125.3, 119.3, 21.4, 20.8; m/z (EI)
309 (Mϩ) [Found (HRMS): 309.1517. C23H19N requires
309.171 75].
1-(1-Naphthyl)-3-(2-naphthyl)isoquinoline 18. The same pro-
cedure was used as for the preparation of compound 16. Yield
68%; mp 174–175 ЊC; νmax(KBr disc)/cmϪ1 3043w (CH), 1612w
(CN), 1580w, 1557s, 1501w (CC), 812s, 808s, 775s, 747s (CH);
δH (270 MHz, CDCl3) 8.71 (s with unresolved splitting, 1 H,
Ar-H), 8.33–8.29 (m, 2 H, Ar-H), 8.05–7.92 (m, 5 H, Ar-H),
7.88–7.83 (m, 1 H, Ar-H), 7.72–7.48 (m, 8 H, Ar-H), 7.41–7.32
(m, 2 H, Ar-H); δC(68 MHz, CDCl3) 160.4, 150.4, 137.5, 137.3,
137.0, 133.8, 133.7, 133.5, 132.5, 130.4, 128.9, 128.8, 128.4,
128.3, 128.0, 127.9, 127.7, 127.5, 127.4, 127.0, 126.6, 126.3,
126.3, 126.2, 126.0, 125.3, 125.0, 116.5; m/z (EI) 381 (Mϩ)
[Found (HRMS): 381.1518. C29H19N requires 381.1518].
1-(2-Methoxyphenyl)-3-phenylisoquinoline 15. The same pro-
cedure was used as for the preparation of compound 12. Yield
58%; mp 113–114 ЊC; νmax(KBr disc)/cmϪ1 3050w, 2922w (CH),
1612m (CN), 1592m, 1574m, 1557s (CC), 1242 (CO), 758s, 695s
(CH); δH (270 MHz, CDCl3) 8.18–8.14 (m, 2 H, phenyl H-2 and
H-6), 8.06 (s, 1 H, H-4), 7.91–7.89 (m, 1 H, H-5), 7.71–7.69 (m,
1 H, H-8), 7.64 (ddd, 1 H, J 8.1, 6.8 and 1.2, H-6), 7.53–7.36 (m,
6 H, Ar-H), 7.18–7.12 [m, 1 H, 2-C6H4(OMe) H-4], 7.09–7.05
[m, 1 H, 2-C6H4(OMe) H-6], 3.71 (s, 3 H, OCH3); δC(68 MHz,
CDCl3) 159.1, 157.5, 150.6, 139.9, 137.0, 131.6, 130.0, 129.95,
128.7, 128.3, 128.0, 127.25, 127.2, 126.6, 120.9, 116.2, 111.2,
55.6; m/z (EI) 311 (Mϩ) [Found (HRMS): 311.1310. C22H17NO
requires 311.1310].
Representative preparation of 1,3-diarylisoquinolines via
catalytic Stille coupling of 1-(4-tolyl)-3-(2-pyridyl)isoquinoline
19
A mixture of 3-chloro-1-(4-tolyl)isoquinoline 3 (127 mg, 0.5
mmol), 2-pyridyltrimethylstannane (145 mg, 0.60 mmol) and
Pd(PPh3)4 (192 mg, 0.167 mmol) in DMF (5 cm3) was heated at
100 ЊC for 18 h. Water and Et2O were added, the organic phase
separated and the aqueous phase extracted twice with Et2O.
The combined organic layers were washed with brine, dried
over MgSO4 and concentrated. The residue was purified by
flash chromatography (SiO2, 1:4 EtOAc–light petroleum) to
yield 1-(4-tolyl)-3-(2-pyridyl)isoquinoline 19 as a white solid (90
mg, 61%); mp 109–110 ЊC (Found: C, 84.8; H, 5.4; N, 9.5. Calc.
for C21H16N2: C, 85.1; H, 5.4; N, 9.45%); νmax(KBr disc)/cmϪ1
3050w, 2920w (CH), 1610m, 1575s (CN), 1555m, 1490m, 1470s
(CC), 825s, 788s, 740s (CH); δH (270 MHz, CDCl3) 8.77 (s, 1 H,
H-4), 8.73 (ddd, 1 H, J6Ј,5Ј 4.7, J6Ј,4Ј 1.7 and J6Ј,3Ј 1.0, pyridyl
Representative preparation of 1,3-diarylisoquinolines via
catalytic Suzuki coupling of 3-(2-methoxyphenyl)-1-(4-tolyl)-
isoquinoline 16
A mixture of 3-chloro-1-(4-tolyl)isoquinoline 3 (253 mg, 1
J. Chem. Soc., Perkin Trans. 1, 1997
931

View Article Online
H-6), 8.64 (ddd, 1 H, J3Ј,4Ј 8.1 and J3Ј,5Ј ≈ J3Ј,6Ј ≈ 1.0, pyridyl
H-3), 8.16 (dd, 1 H, J8,7 8.4 and J8,6 1.1, H-8), 8.03–8.00 (m, 1 H,
H-5), 7.81 (ddd, 1 H, J4Ј,3Ј 8.1, J4Ј,5Ј 7.5 and J4Ј,6Ј 1.8, pyridyl
H-4), 7.73–7.70 (m, 2 H, tolyl H-3 and H-5), 7.68 (ddd, 1 H, J6,5
8.1, J6,7 6.9 and J6,8 1.1, H-6), 7.53 (ddd, 1 H, J7,8 8.4, J7,6 6.9 and
J7,5 1.5, H-7), 7.39–7.36 (m, 2 H, tolyl H-2 and H-6), 7.29 (ddd,
1 H, J5Ј,4Ј 7.4, J5Ј,6Ј 4.7 and J5Ј,3Ј 1.1, H-5), 2.48 (s, 3 H, Ar-CH3);
δC(68 MHz, CDCl3) 160.1, 156.7, 149.2, 148.8, 138.6, 137.8,
137.0, 136.9, 130.2, 130.0, 129.0, 128.3, 127.6, 127.4, 126.8,
123.3, 121.6, 116.6, 21.2; m/z (EI) 296 (Mϩ).
1-(8-Methoxy-1-naphthyl)-3-(2-pyridyl)isoquinoline 20. The
same procedure was used for the preparation of compound 19.
Yield 94%; mp 186–188 ЊC; νmax(KBr disc)/cmϪ1 3050w, 2930w
(CH), 1610m, 1575s (CN), 1560s, 1450m, 1460m (CC), 1260s
(CO), 825s, 795m, 690m (CO); δH (600 MHz, CDCl3) 8.77
(apparent d, 1 H, J 0.6, H-4), 8.73 (ddd, 1 H, J6Љ,5Љ 4.8, J6Љ,4Љ 1.8
and J6Љ,3Љ 0.9, pyridyl H-6), 8.53 (ddd, 1 H, J3Љ,4Љ 8.0 and
J3Љ,5Љ ≈ J3Љ,6Љ ≈ 1.0, pyridyl H-3), 8.00 (apparent d, 1 H, J 8.2,
H-5), 7.97 (dd, 1 H, J4Ј,3Ј 8.2 and J4Ј,2Ј 1.3, naphthyl H-4), 7.75
(ddd, 1 H, J4Љ,3Љ 8.0, J4Љ,5Љ 7.4 and J4Љ,6Љ 1.8, pyridyl H-4), 7.62 (dd,
1 H, J3Ј,4Ј 8.2 and J3Ј,2Ј 6.9, naphthyl H-3), 7.61 (ddd, 1 H, J6,5
8.1, J6,7 6.7 and J6,8 1.2, H-6), 7.57 (dd, 1 H, J5Ј,6Ј 8.3 and J5Ј,7Ј
1.0, naphthyl H-5), 7.53 (dd, 1 H, J2Ј,3Ј 6.9, J2Ј,4Ј 1.3, naphthyl
H-2), 7.41 (apparent t, 1 H, J 7.8, naphthyl H-6), 7.39–7.37 (m,
1 H, H-8), 7.31 (ddd, 1 H, J7,8 8.0, J7,6 6.7 and J7,5 1.2, H-7), 7.27
(ddd, 1 H, J5Љ,4Љ 7.4, J5Љ,6Љ 4.8 and J5Љ,3Љ 1.2, pyridyl H-5), 6.68
(apparent d, 1 H, J 7.1, naphthyl H-7), 3.03 (s, 3 H, OCH3);
δC(68 MHz, CDCl3) 163.9, 157.1, 156.1, 149.2, 148.1, 136.9,
136.0, 135.9, 135.3, 129.6, 128.6, 128.4, 127.6, 127.4, 126.9,
126.3, 125.8, 124.6, 123.1, 121.9, 121.2, 116.3, 106.4, 55.4; m/z
(EI) 362 (Mϩ) [Found (HRMS): 362.1419. C25H18N2O requires
362.1419].
1-(2-Methoxy-1-naphthyl)-3-(2-pyridyl)isoquinoline 21. The
same procedure was used as for the preparation of compound
19. Yield 80%; mp 155–156 ЊC (Found: C, 69.8; H, 4.4; N,
6.2. Calc. for C25H18N2OؒCH2Cl2: C, 69.8; H, 4.5; N, 6.3%);
νmax(KBr disc)/cmϪ1 3050w, 2930w (CH), 1615m (CN), 1590m,
1575s, 1557m (CC), 1212s, 1198s (CO), 807m, 795m, 690s (CH);
δH (270 MHz, CDCl3) 8.88 (s, 1 H, H-4), 8.74 (ddd, 1 H, J6Љ,5Љ 4.9,
J6Љ,4Љ 1.9 and J6Љ,3Љ 1.0, pyridyl H-6), 8.50 (ddd, 1 H, J3Љ,4Љ 7.0 and
J3Љ,5Љ ≈ J3Љ,6Љ 1.0, pyridyl H-3), 8.07–8.02 (m, 2 H, naphthyl H-4
and H-5), 7.90–7.87 (m, 1 H, H-5), 7.76–7.70 (m, 1 H, pyridyl
H-4), 7.69–7.63 (ddd, J6,5 8.1, J6,7 6.6 and J6,8 1.21 H, H-6),
7.51–7.16 (m, 7 H, Ar-H), 3.78 (s, 3 H, OCH3); δC(68 MHz,
CDCl3) 157.7, 156.9, 154.9, 149.5, 149.2, 137.1, 136.9, 134.0,
130.4, 130.2, 129.3, 128.9, 128.1, 128.0, 127.5, 127.4, 126.8, 125.1,
123.8, 123.2, 122.5, 122.0, 117.3, 113.9, 56.8; m/z (EI) 362 (Mϩ).
135.7, 135.5, 129.4, 128.5, 128.2, 127.5, 126.9, 126.2, 126.0,
125.7, 125.5, 121.1, 115.4, 106.3, 55.5, 31.3, 14.6; m/z (EI)
313 (Mϩ).
3-(Benzylthio)-1-(8-methoxy-1-naphthyl)isoquinoline 23
A solution of Super-Hydride (1.0  LiBHEt3 in THF; 1.0
cm3, 1.0 mmol) was added slowly to dibenzyl disulfide (123 mg,
0.50 mmol). When gas evolution had ceased, the solvent
was removed in vacuo and 3-chloro-1-(8-methoxy-1-naphthyl)-
isoquinoline 8 and DMF (5 cm3) were added. The mixture was
heated for 6 h at 120 ЊC then cooled and diluted with Et2O and
1  HCl. Sufficient CH2Cl2 was added to just dissolve the dark
solid, the organic layer was separated and the aqueous phase
extracted with Et2O. The combined organic extracts were
washed with 1  HCl (×5), water (×2), then brine (×2) and dried
over MgSO4. The solution was evaporated and the residue
purified by flash chromatography (SiO2, 4:1 light petroleum–
Et2O) to afford 246 mg (60%) of product; mp 127–129 ЊC;
νmax(KBr)/cmϪ1 3052w, 2930w (CH), 1612m (CN), 1572m,
1547m, 1502m (CC), 1259s (CO), 821s, 771s, 762s, 750s (CH);
δH (270 MHz, CDCl3) 7.92 (dd, 1 H, J 8.3, 1.2, Ar-H), 7.69–7.64
(m, 1 H, Ar-H), 7.61–7.48 (m, 4 H, Ar-H), 7.44–7.41 (m, 2
H, Ar-H), 7.39–7.30 (m, 3 H, Ar-H), 7.23–7.17 (m, 4 H,
Ar-H), 6.72–6.68 (m, 1 H, Ar-H), 4.52–4.36 (m, 2 H, CH2), 3.04
(s, 3 H, OCH3); δC(68 MHz, CDCl3) 164.2, 160.0, 149.4, 138.8,
136.1, 135.3, 132.4, 132.2, 129.9, 129.0, 128.6, 128.3, 128.2,
127.6, 126.8, 126.6, 126.3, 125.7, 125.5, 124.4, 121.1, 116.9,
106.2, 55.4, 35.8; m/z (EI) 407 (Mϩ) [Found (HRMS): 407.1344.
C27H21NOS requires 407.1344].
3-Chloro-1-(2-hydroxy-1-naphthyl)isoquinoline 24
A solution of 3-chloro-1-(2-methoxy-1-naphthyl)isoquinoline 6
(1.00 g, 3.13 mmol) in CH2Cl2 (10 cm3) was cooled to Ϫ78 ЊC
and treated dropwise with BBr3 (1.6 g, 0.6 cm3, 6.3 mmol). The
mixture was allowed to warm to room temperature overnight,
then quenched with H2O and made basic with concentrated
ammonia. The organic layer was separated and the aqueous
layer extracted twice with CH2Cl2. The combined organic
extracts were washed with water and brine, then passed through
a short plug of SiO2 and evaporated to afford the crude product
which was washed with a little Et2O. Yield 0.75 g (78%); mp
212–215 ЊC; νmax(KBr disc)/cmϪ1 3100br s (OH), 3062s (CH),
1613m (CN), 1575m, 1547m, 1503m (CC), 1340s (OH), 1261s
(CO), 871s, 818m, 742s (CH); δH (270 MHz, CDCl3) 7.93–7.90
(m, 1 H, Ar-H), 7.88–7.83 (m, 3 H, Ar-H), 7.73 (ddd, 1 H, J 8.3,
6.7 and 1.2, Ar-H), 7.59–7.55 (m, 1 H, Ar-H), 7.39 (ddd, 1 H, J
8.2, 6.7 and 1.4, Ar-H), 7.35–7.22 (m, 3 H, Ar-H), 7.12–7.08
(m, 1 H, Ar-H); δC(68 MHz, CDCl3) 159.0, 152.8, 144.0, 138.1,
133.4, 131.4, 130.4, 128.0, 127.95, 127.7, 127.1, 127.05, 126.8,
126.5, 123.5, 122.8, 119.2, 116.8; m/z (EI) 305, 307 (Mϩ) [Found
(HRMS): 305.0590. C19H12ClNO requires 305.0607].
3-Ethyl-(8-methoxy-1-naphthyl)isoquinoline 22
A mixture of NiCl2(dppf) (21 mg, 0.031 mmol) and Zn (31 mg,
0.47 mmol) in THF (2.5 cm3) was warmed at 50 ЊC for 30 min
to give a pale yellow–green solution and then 3-chloro-1-
(8-methoxy-1-naphthyl)isoquinoline 8 (100 mg, 0.313 mmol)
was added. Super-Hydride LiBHEt3 (1.0  in THF; 0.5 cm3,
0.5 mmol) was added to PriOH (30 mg, 38 mm3, 1 mmol) and
when evolution of gas had ceased, the solution was added via
cannula to the catalyst–substrate mix. The mixture was heated
under reflux for 3 h, filtered and evaporated. The residue was
purified by flash chromatography (SiO2, 4:1 light petroleum–
Et2O) to afford 3-ethyl-(8-methoxy-1-naphthyl)isoquinoline as
a white solid (69 mg, 70%); mp 114–115 ЊC (Found: C, 84.0;
H, 6.15; N, 4.4. Calc. for C22H19NO: C, 84.3; H, 6.1; N,
4.4%); νmax(KBr)/cmϪ1 3045w, 2960w, 2922w (CH), 1613m
(CN), 1578m, 1553s, 1501w (CC), 1260s (CO), 820s, 767s;
δH (270 MHz, CDCl3) 7.93 (dd, 1 H, J 8.1 and 1.2, H-4Ј),
7.82–7.77 (m, 1 H, H-5), 7.60–7.52 (m, 3 H, Ar-H), 7.48 (s, 1
H, H-4), 7.45–7.33 (m, 3 H, Ar-H), 7.24 (ddd, 1 H, J 8.1,
6.6 and 1.2, H-7), 6.60–6.66 (m, 1 H, H-7Ј), 3.08 (s, 3 H,
OCH3), 3.03 (q, 2 H, J 7.5, CH2CH3), 1.41 (t, 3 H, J 7.5,
CH2CH3); δC(68 MHz, CDCl3) 163.8, 156.2, 155.4, 136.2,
Representative Colon reaction: preparation of 1,1Ј-diphenyl-3,3Ј-
biisoquinoline 25
A mixture of NiCl2 (13 mg, 0.10 mmol), PPh3 (80 mg, 0.30
mmol), Zn dust (100 mg, 1.5 mmol) and NaI (150 mg, 1.0
mmol) in THF (5 cm3) was warmed to 50 ЊC for 30 min, result-
ing in a blood-red solution. To this was added a solution of
3-chloro-1-phenylisoquinoline 2 (239 mg, 1.00 mmol) in THF
(2.5 cm3) and the mixture heated for a further 3 h. The mixture
was quenched with 6  HCl, made basic with concentrated
ammonia solution, filtered and extracted three times with
CH2Cl2. The combined organic layers were washed with brine,
dried (MgSO4) and evaporated. Column chromatography
(activity II Al2O3, 3:2 light petroleum–CH2Cl2) afforded 1,1Ј-
diphenyl-3,3Ј-biisoquinoline 25 as a white solid (190 mg, 93%);
mp 280 ЊC (decomp.); νmax(KBr disc)/cmϪ1 3050w (CH), 1612m
(CN), 1560m, 1550m, 1480w (CC), 760m, 750s, 695m (CH);
δH (270 MHz, CDCl3) 9.00 (s, 2 H, H-4), 8.15 (m, 2 H, H-8),
8.04–8.01 (m, 2 H, H-5), 7.91–7.87 (m, 4 H, phenyl H-2 and
H-6), 7.68 (ddd, 2 H, J 8.1, 6.8 and 1.0, H-6), 7.61–7.59 (m, 4 H,
932
J. Chem. Soc., Perkin Trans. 1, 1997

View Article Online
phenyl H-3 and H-5), 7.64–7.58 (m, 2 H, phenyl H-4), 7.52
(ddd, 2 H, J 8.3, 6.8 and 1.2, H-7); δC(68 MHz, CDCl3) 160.2,
149.3, 140.1, 137.9, 130.3, 130.0, 128.7, 128.4, 128.3, 127.6,
127.2, 126.7, 117.1; m/z (EI) 408 (Mϩ) [Found (HRMS):
408.1626. C30H20N2 requires 408.1626].
1,1Ј-Di(4-tolyl)-3,3Ј-biisoquinoline 26. The same procedure
was used as for the preparation of compound 25. Yield 73%;
mp 220 ЊC (decomp.); νmax(KBr disc)/cmϪ1 3050w, 2920w (CH),
1612s (CN), 1565m, 1550m, 1480m (CC), 820s, 750s (CH);
δH (270 MHz, CDCl3) 8.99 (s, 2 H, H-4), 8.15 (m, 2 H, H-8),
8.03–8.00 (m, 2 H, H-5), 7.8–7.77 (m, 4 H, tolyl H-3 and H-5),
7.67 (ddd, 2 H, J 8.1, 6.8 and 1.0, H-6), 7.51 (ddd, 2 H, J 8.3, 6.8
and 1.2, H-7), 7.43–7.41 (m, 4 H, tolyl H-2 and H-6), 2.51 (s, 6
H, Ar-CH3); δC(68 MHz, CDCl3) 160.2, 149.2, 138.6, 137.9,
137.2, 130.3, 129.9, 129.1, 128.2, 127.7, 127.0, 126.7, 116.9,
21.5; m/z (EI) 436 (Mϩ) [Found (HRMS): 436.1939. C32H24N2
requires 436.1939].
1,1Ј-Di(2-tolyl)-3,3Ј-biisoquinoline 27. The same procedure
was used as for the preparation of compound 25. Yield 75%;
mp 200 ЊC (decomp.); νmax(KBr disc)/cmϪ1 3060w, 2950w (CH),
1610m (CN), 1560br m, 1480w (CC), 750s, 730s (CH); δH (600
MHz, CDCl3) 8.94 (s, 2 H, H-4), 7.98 (d with unresolved split-
ting, 2 H, J 8.2, H-5), 7.66 (m, 2 H, H-8), 7.64 (ddd, 2 H, J 8.0,
6.7 and 1.2, H-6), 7.48–7.38 (m, 10 H, Ar-H), 2.21 (s, 3 H,
Ar-CH3), 2.20 (s, 3 H, Ar-CH3); δC(68 MHz, CDCl3) 160.9,
149.4, 139.5, 137.4, 136.8, 130.5, 130.0, 129.9, 128.5, 128.1,
127.5, 127.4, 127.1, 125.6, 117.2, 20.1; m/z (EI) 436 (Mϩ)
[Found (HRMS): 436.1939. C32H24N2 requires 436.1939].
1,1Ј-Bis(2-methoxyphenyl)-3,3Ј-biisoquinoline 28. The same
procedure was used as for the preparation of compound 25.
Yield 81%; mp 290 ЊC (decomp.); νmax(KBr disc)/cmϪ1 3060w,
2930w (CH), 1615m (CN), 1597m, 1575m, 1562m (CC), 1240s
(CO), 756s, 752s (CH); δH (270 MHz, CDCl3) 8.96 (s, 2 H, H-4),
7.98–7.93 (m, 2 H, H-8), 7.71–7.66 (m, 2 H, H-5), 7.65–7.58 (m,
2 H, H-6), 7.56–7.49 (m, 4 H, H-3Ј and H-5Ј), 7.43 (m, 2 H,
H-7), 7.20 (t with unresolved splitting, J 7.5, 2 H, H-4Ј), 7.11
(m, 2 H, H-6Ј), 3.54 (s, 6 H, OCH3); δC(68 MHz, CDCl3) 158.6,
157.6, 149.8, 137.1, 131.7, 130.0, 129.8, 129.5, 127.9, 127.6,
126.6, 120.9, 117.5, 111.4, 55.6; m/z (EI) 468 (Mϩ) [Found
(HRMS): 468.1838. C32H24N2O2 requires 468.1838].
1,1Ј-Bis(2-methoxy-1-naphthyl)-3,3Ј-biisoquinoline 29. The
same procedure was used as for the preparation of compound
25. Yield 73%; mp 280 ЊC (decomp.); νmax(KBr disc)/cmϪ1
3060w, 2939w (CH), 1615m (CN), 1590m, 1560m, 1505m (CC),
1265s, 1250s (CO), 815s, 750s (CH); δH (270 MHz) 8.99 (br s, 2
H, Ar-H), 8.79–8.11 (m, 2 H, Ar-H), 7.96–7.91 (m, 2 H, Ar-H),
7.62–7.55 (m, 2 H, Ar-H), 7.54–7.49 (m, 2 H, Ar-H), 7.50–7.43
(m, 4 H, Ar-H), 7.41–7.27 (m, 8 H, Ar-H), 3.83 (s, 3 H, OCH3),
3.81 (s, 3 H, OCH3); δC[68 MHz, CDCl3–(CD3)2SO] 161.0,
157.4, 154.7, 149.8, 136.9, 133.8, 130.2, 129.8, 129.0, 128.4,
127.8, 127.0, 126.8, 126.5, 124.9, 123.5, 117.3, 113.9, 56.5; m/z
(EI) 568 (Mϩ) [Found (HRMS): 568.2150. C40H28N2O2 requires
568.2151].
129.25, 128.6, 128.4, 127.5, 127.2, 127.1, 126.2, 125.8, 124.6,
121.1, 121.0, 116.5, 106.2, 55.2; m/z (EI) 568 (Mϩ) [Found
(HRMS): 568.2150. C40H28N2O2 requires 568.2151].
Crystallographic data for 3-chloro-1-(8-methoxy-1-naphthyl)-
isoquinoline 8
Crystals were grown by slow diffusion of hexane into a di-
chloromethane solution of 8 and were mounted on a glass fibre
for the analysis.
Crystal data. The crystal was a colourless plate of approxi-
mate dimensions 0.40 × 0.60 × 0.50 mm, C20H14ClNO, Mw
=
¯
319.8, triclinic, space group P1, a = 11.814(5), b = 14.227(5),
³
c = 11.704(4) Å, α = 90.62(3), β = 115.91(3), γ = 112.56(3)Њ,
V = 1596(3) Å3, Z = 4, Dc = 1.33 g cmϪ3, µ(Mo-Kα) = 2.40 cmϪ1
F(000) = 664.
,
Data collection and processing. All measurements were made
as previously described 22 using a Rigaku AFC6S diffractometer
with graphite monochromated Mo-Kα radiation. Cell con-
stants and an orientation matrix for data collection were
obtained from a least-squares refinement using the setting
angles of 25 carefully centred reflections (2θ ranges 16.2–28.7Њ
for cell parameters and orientation matrix determination; ca. 2–
57.1Њ for full data collection). Data were collected at 25 ЊC using
the ω–2θ scan technique. Scans of range (1.68 ϩ 0.30 tan θ)Њ
were made at a speed of 8.0Њ minϪ1 (in omega). Stationary
background counts were recorded on each side of the reflection.
Of the 8506 reflections collected, 7427 were unique
(Rint = 0.038); equivalent reflections were averaged. Of these,
2
2
2637 reflections had [Fo2 > 3σ(Fo )], where σ(Fo ) was esti-
mated from the counting statistics.22,23 Lorentz-polarisation
and absorption corrections were applied (transmision factors
0.71, Ϫ1.20). The intensitites of three standard reflections
measured after every 150 reflections showed no greater fluctu-
ations than expected from Poisson statistics.
Structure solution and refinement. The structure was solved
by direct methods.24 The non-hydrogen atoms were refined
either anisotropically or isotropically. Full-matrix least-squares
refinement was carried out using the TEXRAY programme set,
as previously described.22 The unweighted and weighted agree-
ment factors converged at R = 0.046 and Rw = 0.046 respect-
ively. The standard deviation of an observation of unit weight
was 1.95. The weighting scheme was based on counting
statistics and included a factor (p = 0.02) to downweight intense
reflections. Plots of Σw(|Fo| Ϫ |Fc|)2 vs. |Fo|, reflection order in
data collection, sin θ/λ, and various classes of indices showed
no unusual trends. While the first molecule in the unit cell is well
behaved, molecule 2 demonstrates slight thermal flexing about
the 1,1Ј-binaphthyl bond. Attempts to model this disorder with
partial atom fragments produced poorer agreement.
Atomic coordinates, thermal parameters and bond lengths
and angles have been deposited at the Cambridge Crystallo-
graphic Data Centre (CCDC). See Instructions for Authors,
J. Chem. Soc., Perkin Trans. 1, 1997, Issue 1. Any request to the
CCDC for this material should quote the full literature citation
and the reference number 207/88.
1,1Ј-Di(1-naphthyl)-3,3Ј-biisoquinoline 30. The same pro-
cedure was used as for the preparation of compound 25. Yield
82%; mp 270 ЊC (decomp.); νmax(KBr disc)/cmϪ1 3050w (CH),
1612m (CN), 1552m, 1483m (CC), 802m, 792s, 773s, 750s (CH);
δH (270 MHz, CDCl3) 9.08 (s, 2 H, H-4), 8.09–8.06 (m, 2 H,
Ar-H), 8.03–7.99 (m, 2 H, Ar-H), 7.99–7.95 (m, 2 H, Ar-H),
7.76–7.33 (m, 16 H, Ar-H); m/z (EI) 508 (Mϩ) [Found
(HRMS): 509.1939. C38H24N2 requires 508.1939].
1,1Ј-Bis(8-methoxy-1-naphthyl)-3,3Ј-biisoquinoline 31. The
same procedure was used as for the preparation of compound
25. Yield 64%; mp 320 ЊC (decomp.); νmax(KBr disc)/cmϪ1
3050w, 2960w (CH), 1610m (CN), 1580m, 1560m, 1500m (CC),
1255s (CO), 820s, 765s, 755s (CH); δH (270 MHz) 8.86 (s, 2 H,
H-4), 8.03 (dd, 2 H, J 8.3 and 1.5, H-4Ј), 7.96–7.92 (m, 2 H,
H-8), 7.70–7.54 (m, 8 H, Ar-H), 7.45 (2 H, t, J 7.8, Ar-H),
7.39–7.25 (m, 4 H, Ar-H), 6.74 (m, 2 H, H-7Ј), 3.06 (s, 6 H,
OCH3); δC(68 MHz) 163.8, 156.1, 148.8, 136.1, 135.9, 135.2,
Acknowledgements
We are grateful to the EPSRC for access to their Ultra High
Field NMR (Dr Ian H. Sadler, University of Edinburgh) and
FAB Mass spectrometry (Dr J. A. Ballantine, University of
Wales) services and for a project studentship (A. F.). We thank
Johnson Matthey for a generous loan of PdCl2 and Professor
Brian E. Mann (University of Sheffield) and Dr John M. Brown
(University of Oxford) for much advice and help.
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Paper 6/05827B
Received 21st August 1996
Accepted 6th November 1996
934
J. Chem. Soc., Perkin Trans. 1, 1997