Synthesis of isoquinoline derivatives through rhodium(III)-catalyzed reactions of benzylamines with non-terminal alkynes

Article abstract of DOI:10.1002/adsc.201300377

A new rhodium(III)-catalyzed N-annulation reaction of benzylamines with internal alkynes has been developed. Observations made during these efforts suggest that the mechanistic pathway followed in this process involves direct participation of benzylamines without their preliminary oxidative dehydrogenation. Moreover, N-annulation reactions of primary benzylamines result in the formation of mixtures of isoquinolines and 8-vinylisoquinolines. Finally, secondary and tertiary benzylamines undergo rhodium(III)-catalyzed N-annulation reactions to generate the respective isoquinolinium and hydroisoquinolinium salt products. Copyright

Full text of DOI:10.1002/adsc.201300377

FULL PAPERS
DOI: 10.1002/adsc.201300377
Synthesis of Isoquinoline Derivatives through Rhodium(III)-
G
Catalyzed Reactions of Benzylamines with Non-Terminal Alkynes
Dong-Su Kim,a Jung-Woo Park,a and Chul-Ho Juna,*
a
Department of Chemistry, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-749, Korea
Fax : (+82)-2-3147-2644; e-mail: junch@yonsei.ac.kr
Received: May 2, 2013; Revised: July 15, 2013; Published online: September 10, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300377.
Abstract: A new rhodium
tion reaction of benzylamines with internal alkynes ly, secondary and tertiary benzylamines undergo
has been developed. Observations made during these rhodium(III)-catalyzed N-annulation reactions to
ACHTUNGTRNE(NUNG III)-catalyzed N-annula- tures of isoquinolines and 8-vinylisoquinolines. Final-
AHCTUNGTRENNUNG
efforts suggest that the mechanistic pathway fol- generate the respective isoquinolinium and hydroiso-
lowed in this process involves direct participation of quinolinium salt products.
benzylamines without their preliminary oxidative de-
À
hydrogenation. Moreover, N-annulation reactions of Keywords: alkynes; amines; annulation; C H activa-
primary benzylamines result in the formation of mix- tion; heterocycles
Introduction
In a related study, Miura et al. also observed that
isoquinolines are generated in reactions of benzyla-
New synthetic processes that rely on transition metal- mine with aryl-substituted alkynes promoted by
À
catalyzed C H bond activation are of current inter- [Cp*RhCl2]2 (4b), Cu
(OAc)2·H2O (6, 2 equiv.) and
ests because they have the potential for forming DABCO in o-xylene.[7] However, these workers noted
carbon-carbon bonds in an atom economical that isoquinolines are formed only in reactions of
manner.[1] Recent advances made in transition-metal aryl-substituted alkynes and that aliphatic alkynes
À
catalyzed C H bond activation reactions have led to react to generate isoindole derivatives 8a
the development of novel approaches to the prepara- (Scheme 1c). In a recent effort, we found that isoqui-
tion of N-heterocyclic compounds.[2] In particular, sev- nolines are also generated even when aliphatic al-
eral recent studies have led to the development of kynes are used as substrates when a modified catalytic
methods for the synthesis of isoquinolines starting system is employed. In addition, we observed that this
with a variety of different substances such as imines,[3] N-annulation reaction is highly sensitive to the condi-
oximes[4] and azides.[5] In 2003, we described a Rh(I)- tions employed, such as the nature of the solvent and
catalyzed one-pot method for the synthesis of isoqui- additives. In the study described below, we have dem-
nolines that involves sequential ortho-alkenylation of onstrated that by utilizing proper conditions, reactions
in situ generated aromatic ketimines with alkynes fol- of benzylamines with a variety of non-terminal al-
lowed by cyclization of the resulting ortho-vinyl aryl kynes serve as an ideal method for the preparation of
ketimines (Scheme 1a).[6] For example, p-methoxyace- isoquinoline derivatives. In addition, the studies have
tophenone (1), benzylamine (2a) and alkynes 3a were led to the proposal of a plausible mechanism for the
found to react in the presence of (Ph3P)3RhCl (4a) to N-annulation reaction, which can also be employed to
afford isoquinolines 5a and 5b in a nearly 1:1 ratio. transform sec- and tert-benzylamines to respective iso-
Interestingly, when the same starting materials are quinolinium and dihydroisoquinolinium salts.
treated with a different catalyst mixture comprised of
(Cp*RhCl2)2 (4b, 10 mol% [Rh]) and Cu
(6, 2 equiv.), the reaction proceeds to produce isoqui-
noline 7a along with trace amount of 5c
ACHTUNGTERN(NUNG OAc)2·H2O
a
(Scheme 1b). These findings suggest that reactions of
benzylamines with alkynes can be used for the synthe-
sis of N-containing heterocyclic compounds.
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Scheme 1. Comparison of two sets of conditions for the preparation of isoquinolines by using (a) Rh(I) and (b) RhACHTUNGTRENNUNG(III)/
Cu(II) catalysis. (c) Isoindole synthesis reported by Miura and Satoh.
Results and Discussion
6 did not increase the yield of the reaction. Moreover,
this reaction does not occur when other oxidants such
as CuSO4·5H2O, CuCl2, K2S2O8, oxone and benzoqui-
none are used (entries 6–10). In contrast to the effi-
N-Annulation Reaction of Primary Benzylamines
with Alkynes: Optimization and Substrate Scope
cient process promoted by the cationic Rh
ACHTUNGTRENN(UNG III) spe-
The initial phase of this investigation focused on opti- cies Cp*Rh(MeCN)3A(SbF6)2 (4c) (entry 11), the reac-
A
CHTUNGTRENNUNG
mization of the N-heterocyclic annulation reaction tion did not take place when (Ph3P)3RhCl (4a) was
using o-methoxybenzylamine (2b) and 4-octyne (3b) employed as the catalyst (entry 12).[8] A survey dem-
as substrates (Table 1). The reaction of 2b with 3b, onstrated that MeOH is a superior solvent for this re-
carried out using (Cp*RhCl2)2 (4b) as the catalyst and action in contrast to others including t-BuOH, o-
CuACHTUNGTRENNUNG(OAc)2·H2O (6) as the oxidant, was observed to xylene, DMF, AcOH, and 1,2-DCE (entries 1, 13–19).
give rise to isoquinoline 7b. An exploration to deter- In addition, reactions performed using t-BuOH and o-
mine the optimal amount of 6 required for this pro- xylene as solvents produce mixtures of isoindole 8b
cess, in which 0.5, 1.0, 1.5 and 2.0 equivalents of the and isoquinoline 7b (entries 13 and 14). The presence
oxidant were utilized (entries 1-4), showed that of DABCO (1 equiv.) in the reaction mixture does
2.0 equivalents led to the highest yielding reaction not lead to any improvement in the reaction efficien-
(entry 1), and the use of more than 2.0 equivalents of cy (entry 15).[7] Finally, the reaction, performed with
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Synthesis of Isoquinoline Derivatives through RhodiumACTHNUTRGNE(NUG III)-Catalyzed Reactions of Benzylamines
Table 1. Optimization of the reaction conditions.
Entry
Metal catalyst
Oxidant
Solvent
MeOH
Isolated yield of 7b [%][a]
1
2
3
4
5
6
7
8
4b
4b
4b
4b
4b
4b
4b
4b
4b
4b
4c
4a
4b
4b
4b
4b
4b
4b
4b
6 (2.0 equiv.)
6 (1.5 equiv.)
6 (1.0 equiv.)
6 (0.5 equiv.)
92
54
51
32
0
9
trace
trace
trace
trace
80
–
CuSO4·5H2O
CuCl2
K2S2O8
oxone
BQ
6 (2.0 equiv.)
6 (2.0 equiv.)
6
6
6
6
6
6
6
9
10
11
12
13
14
15[b]
16[b]
17
18
19
0
t-BuOH
o-xylene
o-xylene
MeOH
16 (2)[c]
9 (10)[c]
7 (3)[c]
87
DMF
14
24
51
AcOH
1,2-DCE[c]
[a]
Unless otherwise stated, the reactions give isoquinoline 7b exclusively.
The reaction was performed with DABCO (1 equiv.).
Isolated yields of isoindole 8b are given in parenthesis.
1,2-DCE=1,2-dichloroethane.
[b]
[c]
[d]
DABCO in methanol as solvent, gave isoquinoline 7b tron-withdrawing substituents (e.g., fluorine) (en-
exclusively without forming isoindole 8b (entry 16). tries 1, 5–7). As expected, aniline and 2-phenethyla-
The benzylamine 2 and alkyne 3 substrate scope of mine do not undergo the N-annulation reactions
the N-annulation reaction was explored next owing presumably to difficulties associated with form-
(Table 2). Under the optimized conditions described ing stable, intermediate 5-membered ring metallacy-
above, reactions of o-methoxybenzylamine (2b) with clic complexes.
a variety of internal alkynes take place smoothly to
produce the corresponding isoquinoline products (en- benzylamine 2a with 4-octyne (3b) promoted by
tries 1–3). Interestingly, reaction of 2b with the un- Cp*Rh(MeCN)3A(SbF6)2 (4c) and Cu(OAc)2·H2O (6)
In further studies, we observed that reaction of
A
N
ACHTUNGTRENNUNG
symmetrically alkyl-substituted alkyne 3e generates at 1008C for 4 h generates a 83:17 mixture of isoqui-
the single isoquinoline regioisomer 7e exclusively in noline 7a and 8-vinylisoquinoline 9a in 84% isolated
a 51% isolated yield (entry 4). Analysis of NOESY yield (Figure 1a). Interestingly, the 7/9 ratio is influ-
NMR spectroscopic data showed that 7e has the enced by the nature of the substituents at the a-posi-
structure in which the bulky tert-butyl group is posi- tion of the benzylamine substrate.[9] For example, in
tioned adjacent to the isoquinoline ring to nitrogen contrast to the annulation reaction of 2a which produ-
(see the Supporting Information). Benzylamine sub- ces a minor amount of 9a, reactions of benzylamines
strates possessing electron-donating aryl substituents, bearing methyl (2g), cyclohexyl (2h), n-hexyl (2i), and
such as methoxy, methyl and amino, were observed to phenyl (2j) a-substituents generate major amounts of
react more efficiently than those that contain elec- the corresponding 8-vinylisoquinolines 9 as reflected
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Table 2. Substrate scope.
10, a trend that is also followed in the reaction of a-
substituted benzylamine 2g with alkyne 3b (the 7i/9b
ratio changes from 9/91 to 35/65 with a temperature
change from 80 to 1508C). These results suggest that
the N-annulation reaction favours the formation of
the ortho-vinyl product at low temperatures while
production of the isoquinoline products is favoured at
high temperatures.
Mechanism of the N-Annulation Reaction of Primary
Benzylamines with Alkynes
Two plausible mechanistic routes for this N-annula-
tion reaction of primary benzylamines with alkynes
are depicted in Scheme 2. In route A, benzylamine 2j
undergoes initial Cu
genation to form the benzophenone imine 10a. In the
absence of water, imine 10a participates in a Rh(III)-
ACHTUNGRTEN(NUNG OAc)2 (6) promoted dehydro-
ACHTUNGTRENNUNG
catalyzed N-annulation reaction. In the other possible
pathway (route B), 2j undergoes direct N-annulation
to form the dihydroisoquinoline 12a, which upon oxi-
dative dehydrogenation affords isoquinoline 7l.
Several experiments were carried out in order to
gain information that would enable a distinction be-
tween the two mechanistic pathways. To test whether
the benzylamine substrate is first oxidized to afford
the corresponding imine,[7] reaction of N-diphenylme-
thylamine (2j) with 6 (2 equiv.) at 1008C was conduct-
ed in the presence of H2O. This process was observed
to form benzophenone (11) in 31% yield
(Scheme 3a), and this result suggests that 2j can be
oxidized by 6 to give corresponding imine 10a, which
is readily hydrolyzed in H2O to give 11. In addition,
we found that in contrast with the N-annulation of
imine 10a with alkyne 3b promoted by 4c and 6 in
MeOH, which produces isoquinoline 7l in 94% isolat-
ed yield, the same process conducted in H2O gener-
ates a mixture of 7l and benzophenone 11 in a 23:34
ratio (Scheme 3b). Moreover, reaction of benzylamine
2j with 3b in H2O under otherwise identical condi-
tions does not yield the hydrolysis product 11 but in-
stead forms the vinylisoquinoline 9e along with 7l in
a 73:21 ratio (Scheme 3c). Importantly, 9e is not pro-
duced in the reaction of imine 10a with 3b. These ob-
servations suggest that reaction of 2j with 3b does not
proceed through the intermediacy of imine 10a and,
[a]
Less than 3% of 8-vinylisoquinoline was observed.
in the finding that 2g, 2h, 2i and 2j produce 7 and 9 in as a result, the N-annulation process likely takes
respective ratios of 18/82 (7i/9b), 28/72 (7j/9c), 15/85 place through the mechanistic pathway portrayed in
(7k/9d), and 7/93 (7l/9e) (Figure 1a). Thus, although route B (Scheme 2).
not well understood at this point, the formation of 8-
Another interesting feature of the N-annulation re-
vinylisoquinolines 9 seems to become increasingly action is the formation of 8-vinylisoquinoline products
favoured as the steric bulk of the a-substituent on the 9, as exemplified by the observation that diphenylme-
benzylamine substrates increases. The 7/9 ratio is also thylamine (2j) reacts with 3b under the optimized
influenced by reaction temperature (Figure 1b). Spe- conditions to afford 8-vinylisoquinoline 9e predomi-
cifically, as the temperature is increased from 80 to nantly (Figure 1a). To explore this feature, the N-an-
1508C the ratio of 7a/9a increases from 77/23 to 90/ nulation reaction of diphenylmethylamine-d (2j-d)
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Synthesis of Isoquinoline Derivatives through RhodiumACTHNUTRGNE(NUG III)-Catalyzed Reactions of Benzylamines
Figure 1. (a) Substituent effect of a-position on the formation of isoquinoline 7 and 8-vinylisoquinoline 9. The reactions
were performed at 1008C. (b) Temperature dependence on the formation of 7 and 9.
cyclic intermediate 13a to the rhodium center in rho-
dium intermediate 14a, followed by reductive elimina-
tion of rhodium in 14a to produce the alkenyl-benzo-
phenone imine 10b (Scheme 4). Importantly, if the re-
action were to have proceeded via a route involving
oxidative transformation of benzylamine to the corre-
sponding imine, the deuterium atom present in 2j-d
would not be transferred to the vinylic position of 9e.
Based on the evidence gained in the experiments
described above, it is possible to propose the mecha-
nistic pathway shown in Scheme 5 for N-annulation
reactions of benzylamines and alkynes that produce
isoquinoline derivatives. The catalytic cycle is initiated
À
by Rh insertion into the N H bond of the benzyla-
mine 2j to form the Rh-complex 15a, which does not
undergo elimination to form the corresponding imine.
À
Scheme 2. Possible routes for N-annulation reaction of pri-
mary benzylamine 2j with internal alkyne 3b.
Subsequent C H bond activation at the ortho-posi-
tion of phenyl group in 15a gives rise to the 5-mem-
bered rhodacycle 16a, which then participates in
alkyne coordination followed by carbometallation to
with 3b was carried out in the presence of the typical afford the 7-membered rhodacycle 13a. Reductive
catalytic system (Scheme 4). 8-Vinylisoquinoline 9e elimination in 13a leads to formation of dihydroiso-
formed in this process was found to have 90% deute- quinoline 12a, which is then dehydrogenated by 6 to
rium enrichment in the exocyclic vinyl moiety. This generate isoquinoline 7l. In the pathway for produc-
result suggests that deuterium in the benzylic position tion of 8-vinylisoquinoline 9e, b-hydride elimination
of the amine is transferred to the vinyl position of the in rhodacycle 13a followed by reductive elimination
product by a pathway involving b-hydride elimination of the formed vinyl rhodium intermediate 14a takes
À
through migration of the benzylic hydrogen in rhoda- place to generate imine 10b. N H bond cleavage in
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Scheme 3. (a) Experimental evidence for oxidation of benzylamine by CuACTHNURTGNENG(U OAc)2 (6). (b) N-Annulation reaction of benzo-
phenone imine (10a) and 3b in MeOH (up) or H2O solvent (down). (c) N-Annulation reaction of diphenylmethanamine (2j)
and 3b in H2O solvent.
Scheme 4. Possible routes for N-annulation reaction of primary benzylamine 2j-d with internal alkyne 3b.
10b promoted by 4d affords the imino-Rh intermedi- dacyclic 13b, which participates in reductive elimina-
À
ate 15b, which then undergoes chelation-assisted C H tion to form the 8-vinylisoquinoline product 9e along
bond cleavage at ortho-phenyl position to give rhoda- with a Rh(I) species. Oxidation of the formed Rh(I)
cyclic 16b. Alkyne coordination and subsequent car- complex by 6 regenerates the active Rh
ACHTUNGTREN(NUNG III) catalyst
bometallation gives rise to the seven-membered rho- 4d.[3a]
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Synthesis of Isoquinoline Derivatives through RhodiumACTHNUTRGNE(NUG III)-Catalyzed Reactions of Benzylamines
Scheme 5. Proposed mechanistic pathway of N-annulation reaction using benzylamine and alkyne to produce isoquinoline 7l
and 8-vinylisoquinoline 9e.
N-Annulation Reactions of Secondary Benzylamines
with Alkynes to Produce Isoquinolinium Salts
quinolinium salts 18b–f in high to moderate yields
(entries 2–6).
The mechanism for the N-annulation reaction of
N-Alkylisoquinolinium salts are important building secondary benzylamines is similar to that operating in
blocks in the synthesis of natural product.[10] Earlier, reactions of primary benzylamines (Scheme 6). In the
À
Cheng et al. described a procedure for the synthesis pathway, initial N H bond cleavage of the secondary
of isoquinolinium salts that involved a one-pot 3-com- benzylamine 17a by 4d forms intermediate 15c. ortho-
À
ponent N-annulation reaction of aldehydes, primary C H bond insertion then gives rise to 5-membered
amines and alkynes.[10a] In our effort, we observed rhodacycle 16c, which undergoes alkyne coordination
that N-annulation reactions of secondary benzyla- followed by carbometallation to afford the 7-mem-
mines and non-terminal alkynes using the optimized bered rhodacycle 13b. Reductive elimination in 13b
catalyst system were not successful. However, the ad- results in the formation of dihydroisoquinoline 12b.
dition of HBF4 to the reaction mixtures results in effi- Finally, CuACHTNURGTENUNG(OAc)2 (6)/HBF4-promoted aromatization
cient reactions that produce N-alkylisoquinolinium of 12b affords the isoquinolinium salt 18a.
salts. For example, reaction of N-methylbenzylamine
(17a) with alkyne 3a in the presence of a mixture of
4b and 6, and HBF4 (1 equiv.) produces the N-methyl- N-Annulation Reactions of Tertiary Benzylamines
isoquinolinium BF4 salt 18a in a 93% isolated yield with Alkynes to Produce Dihydroisoquinolinium Salts
(Table 3, entry 1). Various secondary amines (17b–d)
were found to react with aliphatic and aromatic al- The possible participation of tertiary benzylamines in
kynes 3a, 3b and 3f to produce the corresponding iso- the N-annulation reaction was explored because these
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Table 3. The reaction of secondary benzylamine 17 with
alkyne 3.[a]
Conclusions
The investigation described above has led to the de-
velopment of a Rh(III)-catalyzed N-annulation pro-
AHCTUNGTRENNUNG
cess that serves as a method for the facile and direct
synthesis of isoquinoline derivatives from benzyl-
AHCTUNGTREGUNaNN mines and internal alkynes. Observations made in
this effort show that the benzylamine substrate direct-
ly participates in the N-annulation reaction without
undergoing initial dehydrogenation to form an imine.
À
Instead, the reaction proceeds through initial N H
bond insertion by the Rh
G
À
ortho-C H bond activation to generate an ortho-vinyl
rhodium
(III) intermediate. Carbometallation of inter-
nal alkyne and reductive elimination of carbometal-
lated rhodium(III) complex produces the correspond-
AHCTUNGTRENNUNG
ing dihydroisoquinoline and Rh(I) species. In this re-
action, the oxidant Cu(II) serves the dual role of pro-
moting aromatization of the dihydroisoquinoline and
oxidizing Rh(I) to regenerate the catalytically active
RhACTHNUGRTENUNG(III) species.
Importantly, N-annulation reactions of primary
benzylamines result in the formation of mixtures of
isoquinolines and 8-vinylisoquinolines. Furthermore,
secondary and tertiary benzylamines also participate
in the N-annulation process to generate isoquinolini-
um and hydroisoquinolinium salts, respectively.
Experimental Section
General Remarks
Flash column chromatography was performed using E.
Merck 230–400 mesh silica gel and column chromatography
was monitored by using analytical thin-layer chromatogra-
phy (TLC) carried out on 0.25 Merck silica gel plates (60F-
254) using UV light as a visualizing agent, p-anisaldehyde,
ninhydrin and KMnO4 solution as staining solutions, and
heat as developing agent. Gas chromatographic analyses
were performed using an Agilent 7890A instrument with an
FID detector and an Agilent HP-5 capillary column. GC/
MS analyses were performed on an Agilent 5975C instru-
ment with an Agilent HP-5MS column. IR spectra were re-
corded using a Bruker Vertex 70 FT-IR spectrometer.
1H NMR and 13C NMR were recorded on Bruker Advance
[a]
Isolated yield. Conversion yields, determined by
1H NMR with using mesitylene as an internal standard,
are given in parentheses.
À
substrates are unique in that they do not contain N
H bonds. Interestingly, when subjected to the opti-
mized reaction conditions N,N-dimethylbenzylamine
(19a) and 3-hexyne (3d) react to form 2,2-dimethyl-
3,4-dipropyl-1,2-dihydroisoquinolin-2-ium hexafluoro-
phosphate (20a) in
a
69% isolated yield
(Scheme 7a).[11,12] The mechanism for the generation
of the hydroisoquinolinium salt (Scheme 7b) is similar
1
II/DPX 400 (400 MHz H, 100 MHz 13C) spectrometers with
to that followed in reactions of primary and secon- chemical shifts reported relative to residual deuterated sol-
1
vent peaks. H NMR spectra are referenced to CDCl3 (for
dary benzylamines. It is interesting to note that reac-
tion of N,N-dibenzylmethylamine (19b) with 3d under
the optimized catalytic conditions produces N-methyl-
isoquinolinium salt (18g, 27% yield, Scheme 8), which
lacks the benzyl group present in the amine substrate.
The formation of 18g in this process suggests that the
initially formed tetraalkylammonium cation 20b un-
dergoes dehydrobenzylation promoted by 6 and KPF6
as a consequence of stabilization offered by the for-
mation of the aromatic isoquinolium ring system.
1H, d=7.26), CD2Cl2 (for H, d=5.34) as internal standard,
1
and are reported as follows: chemical shift multiplicity (br=
broad, s=singlet, d=doublet, t=triplet, q=quartet, m=
multiplet). 13C NMR spectra are referenced to the residual
CDCl3 (for 13C, d=77.26), CD2Cl2 (for 13C, d=54.00) as in-
ternal standard. 11B NMR spectra were referenced to exter-
.
nal BF3 OEt2 (0.0 ppm) with a negative sign indicating an
up-field shift. 19F NMR spectra are referenced to external
CFCl3 (0.0 ppm). High-resolution mass spectrometric analy-
ses were carried out at the NCIRF Seoul National Universi-
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Synthesis of Isoquinoline Derivatives through RhodiumACTHNUTRGNE(NUG III)-Catalyzed Reactions of Benzylamines
Scheme 6. Proposed mechanism for N-annulation reaction of secondary benzylamine 17a with internal alkyne 3b.
Scheme 7. (a) N-Annulation reaction of tertiary benzylamine 19a and 3d in the presence of 4b, 6 and KPF6. (b) Proposed
mechanism for N-annulation reaction of tertiary benzylamine 19a with internal alkyne 3d.
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14.8, 14.5; IR (CDCl3): n=3073, 2959, 2871, 1620, 1574,
1489, 1388, 1263, 1060, 792 cmÀ1; HR-MS (EI+): m/z=
243.1622, calcd. for C16H21NO [M]+: 243.1623.
8-Methoxy-3,4-dipentylisoquinoline
(7c):
1H NMR
(400 MHz, CDCl3): d=9.46 (s, 1H), 7.56–7.47 (m, 2H), 6.78
(d, J=7.44 Hz, 1H), 3.98 (s, 3H), 2.99–2.92 (m, 4H), 1.80–
1.72 (m, 2H), 1.66–1.59 (m, 2H), 1.51–1.33 (m, 8H), 0.94–
0.89 (m, 6H); 13C NMR (100 MHz, CDCl3): d=157.2, 153.9,
145.1, 136.8, 130.5, 127.8, 119.5, 115.2, 103.8, 55.7, 35.6, 32.6,
32.3, 30.7, 30.4, 28.3, 22.9, 22.7, 14.3, 14.2; IR (CDCl3): n=
3073, 2956, 2929, 2870, 2858, 1775, 1621, 1574, 1488, 1414,
1262, 1063, 756 cmÀ1; HR-MS (EI+): m/z=299.2247, calcd.
for C20H29NO [M]+: 299.2249.
Scheme 8. N-Annulation reaction of tertiary benzylamine
19b and 3d in the presence of 4b, 6 and KPF6.
3,4-Diethyl-8-methoxyisoquinoline
(7d):
1H NMR
(400 MHz, CDCl3): d=9.47 (s, 1H), 7.56–7.49 (m, 2H), 6.77
(d, J=6.8 Hz, 1H), 3.98 (s, 3H), 3.05–2.96 (m, 4H), 1.35 (t,
J=7.5 Hz, 3H), 1.27 (t, J=7.4 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=157.2, 154.6, 145.3, 136.5, 130.5,
128.7, 119.6, 115.0, 103.8, 55.7, 28.6, 21.2, 15.2, 15.8; IR
(CDCl3): n=3073, 2935, 1873, 1722, 1492, 1414, 1197, 1154,
965, 719 cmÀ1; HR-MS (FAB+): m/z=216.1388, calcd. for
C14H17NO [M+H]+: 216.1310.
ty. Most commercially available reagent grade chemicals (1,
2a, 2b, 2d–g, 2j, 3a–f, 6, 10a, 17a–d and 19a) were purchased
from Aldrich Chemical Company, TCI, ACROS and Bur-
dick & Jackson, and used as received unless otherwise
stated. Reagents (2h and 2i,[13] 2j-d,[14] and 19b[15]) were pre-
pared according to the literature procedures. Complexes
[Cp*RhCl2]2 (4b)[16] and Cp*Rh (SbF6)2 (4c)[17] were
ACTHNUTRGENNUG(MeCN)3ACHTUNGTRENNUGN
3-tert-Butyl-8-methoxy-4-methylisoquinoline
(7e):
1H NMR (400 MHz, CDCl3): d=9.47 (s, 1H), 7.54 (d, J=
4.3 Hz, 2H), 6.80 (t, J=4.2 Hz, 1H), 4.00 (s, 3H), 2.77 (s,
3H), 1.56 (s, 9H); 13C NMR (100 MHz, CDCl3): d=159.4,
157.0, 143.5, 138.6, 130.2, 123.4, 119.1, 115.1, 103.8, 55.8,
38.8, 31.1, 16.7; IR (CDCl3): n=3049, 2955, 1775, 1703, 1577,
1456, 1364, 1224, 1167, 1052, 754 cmÀ1; HR-MS (EI+): m/z=
229.1470, calcd. for C15H19NO [M]+: 229.1467.
prepared using literature procedures and stored in a refriger-
ator under an N2 atmosphere.
6-Methoxy-1-methyl-3,4-dipropylisoquinoline
(5c):
1H NMR (400 MHz, CDCl3): d=7.98 (d, J=9.1 Hz, 1H),
7.18 (d, J=2.3 Hz, 1H), 7.12 (dd, J=9.1 Hz, 2.4 Hz, 1H),
3.94 (s, 3H), 2.94–2.87 (m, 4H), 2.85 (s, 3H), 1.81–1.72 (m,
2H), 1.72–1.62 (m, 2H), 1.08 (t, J=7.3 Hz, 3H), 1.04 (t, J=
7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=160.5, 155.2,
152.3, 137.5, 128.2, 125.7, 121.9, 117.4, 102.4, 55.4, 37.6, 30.1,
24.0, 23.8, 22.2, 14.8, 14.6; IR (CDCl3): n=3099, 2959, 2871,
1925, 1678, 1573, 1506, 1463, 1263, 1235, 1157, 1029, 779,
8-Methyl-3,4-dipropylisoquinoline
(7f):
1H NMR
(400 MHz, CDCl3): d=9.29 (s, 1H), 7.81 (d, J=8.6 Hz, 1H),
7.52 (t, J=7.2 Hz, 1H), 7.26 (d, J=7.0 Hz, 1H), 3.02–2.93
(m, 4H), 2.74 (s, 3H), 1.87–1.77 (m, 2H), 1.72–1.62 (m, 2H),
1.09 (t, J=7.3 Hz, 3H), 1.04 (t, J=7.4 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=152.9, 146.9, 135.9, 135.7, 129.8,
128.4, 126.7, 126.3, 121.5, 37.5, 30.2, 24.3, 23.7, 18.9, 14.8,
14.5; IR (CDCl3): n=3070, 3043, 2959, 2871, 1721, 1614,
1580, 1454, 1380, 1341, 1088, 973, 756 cmÀ1; HR-MS (EI+):
m/z=227.1675, calcd. for C16H21N [M]+: 227.1674.
703 cmÀ1; HR-MS
[M]+ 257.1780.
ACHTUNGTRENNUNG(EI+): m/z=257.1780, calcd for C17H23NO
Typical Procedure for Preparing Isoquinoline 7b in
the Presence of 4b/6 (Table 2)
8-Fluoro-3,4-dipropylisoquinoline
(7g):
1H NMR
To a 1 mL pressure vial was added o-methoxybenzylamine
(2b, 68.6 mg, 0.5 mmol), 4-octyne (3b, 66.1 mg, 0.6 mmol),
[Cp*RhCl2]2 (4b, 3.7 mg, 0.00625 mmol), CuACHTNURGTNE(UNG OAc)2·H2O (6,
200 mg, 1.0 mmol) and methanol (500 mL). The mixture was
stirred at 1008C for 4 h. After cooling, the mixture was sub-
jected to column chromatography (n-hexane:ethyl acetate=
2:1) on silica gel to give 8-methoxy-3,4-dipropylisoquinoline
(7b) as a pale yellow oil; yield: 112.0 mg (92%).
(400 MHz, CDCl3): d=9.35 (s, 1H), 7.71 (d, J=8.6 Hz, 1H),
7.59–7.54 (m, 1H), 7.10 (t, J=8.9 Hz, 1H), 3.00–2,92 (m,
4H), 1.84–1,75 (m, 2H), 1.70–1.61 (m, 2H) 1.08 (t, J=
7.3 Hz, 3H), 1.03 (t, J=7.3 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=159.9 (d, J=254.0 Hz), 154.3 143.7 (d, J=
6.0 Hz), 137.1 (d, J=4.0 Hz), 130.2 (d, J=9.0 Hz), 127.9 (d,
J=2.0 Hz), 119.2 (d, J=5.0 Hz), 117.9 (d, J=5.0 Hz), 109.5
(d, J=19.0 Hz), 37.6, 30.3, 24.2, 23.7, 14.8, 14.5; IR (CDCl3):
n=3078, 3045, 2961,2931, 2872, 1633, 1580, 1454, 1415, 1389,
1089, 767 cmÀ1; HR-MS (EI+): m/z=231.1423, calcd for
C15H18FN [M]+: 231.1423.
3,4-Dipropylisoquinoline (7a) [CAS No. 1185276-02-1]:
1H NMR (400 MHz, CDCl3): d=9.08 (s, 1H), 7.96 (d, J=
8.5 Hz, 1H), 7.90 (d, J=8.0 Hz, 1H), 7.66 (t, J=7.5 Hz,
1H), 7.50 (t, J=7.5 Hz, 1H), 3.01 (t, J=7.8 Hz, 2H), 2.95 (t,
J=7.5 Hz, 2H), 1.86–1.77 (m, 2H), 1.73–1.63 (m, 2H), 1.09
(t, J=7.2 Hz, 3H), 1.04 (t, J=7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=153.0, 150.2, 135.5, 130.1, 128.3,
128.2, 127.3, 125.8, 123.1, 37.4, 30.0, 24.2, 23.8, 14.8, 14.5.
3,4-Dipropylisoquinolin-6-amine
(7h):
1H NMR
(400 MHz, CDCl3): d=8.83 (s, 1H), 7.64 (d, J=8.6 Hz, 1H),
6.92 (s, 1H), 6.88 (dd, J=8.6 Hz, 2.0 Hz, 1H), 2.90–2.81 (m,
4H), 2.12 (br s, 2H), 1.81–1.71 (m, 2H), 1.66–1.57 (m, 2H),
1.04 (t, J=7.3 HZ, 3H), 1.01 (t, J=7.3 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=151.7, 148.9, 148.3, 137.9, 130.4,
126.6, 121.8, 118.0, 102.8, 36.7, 30.0, 23.8, 23.6, 14.7, 14.4; IR
(CDCl3): n=3328, 3191, 3052, 2960, 2930, 2871, 1619, 1504,
1380, 1246, 1088, 1012, 725 cmÀ1; HR-MS (EI+): m/z=
228.1626, calcd. for C15H20N2 [M]+: 228.1626.
8-Methoxy-3,4-dipropylisoquinoline
(7b):
1H NMR
(400 MHz, CDCl3): d=9.46 (s, 1H), 7.55–7.47 (m, 2H), 6.77
(d, J=7.3 Hz, 1H), 3.98 (s, 3H), 2.98–2.91 (m, 4H), 1.84–
1.75 (m, 2H), 1.70–1.61 (m, 2H), 1.09–1.01 (m, 6H);
13C NMR (100 MHz, CDCl3): d=157.1, 153.7, 145.1, 136.8,
130.4, 127.7, 119.5, 115.3, 103.8, 55.7, 37.6, 30.3, 24.2, 23.8,
2676
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Adv. Synth. Catal. 2013, 355, 2667 – 2679

Synthesis of Isoquinoline Derivatives through RhodiumACTHNUTRGNE(NUG III)-Catalyzed Reactions of Benzylamines
1-Methyl-3,4-dipropylisoquinoline (7i) [CAS No. 362061-
46-9]: 1H NMR (400 MHz, CDCl3): d=8.07 (d, J=8.3 Hz,
1H), 7.96 (d, J=8.5 Hz, 1H), 7.64 (t, J=7.0 Hz, 1H), 7.48
(t, J=7.9 Hz), 1H), 3.00–2.96 (m, 2H), 2.93–2.89 (m, 2H),
2.91 (s, 3H), 1.84–1.74 (m, 2H), 1.72–1.62 (m, 2H), 1.09 (t,
J=7.3 Hz, 3H), 1.05 (t, J=7.3 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=155.8, 151.9, 135.6, 129.6, 126.37,
126.31, 126.2, 125.4, 123.8, 37.7, 30.0, 24.4, 24.0, 22.6, 14.8,
14.6.
128.1, 125.8, 125.4, 121.6, 37.5, 35.1, 30.6, 30.3, 24.3, 23.7,
23.2, 21.9, 14.9, 14.6, 14.3, 14.2; IR (CDCl3): n=3069, 2959,
2931, 2872, 1771, 1715, 1605, 1575, 1463, 1378, 1259, 1125,
897, 802, 718 cmÀ1; HR-MS (EI+): m/z=323.2610, calcd. for
C23H33N [M]+: 323.2613.
1-Methyl-8-(oct-4-en-4-yl)-3,4-dipropylisoquinoline (9b):
1H NMR (400 MHz, CDCl3): d=7.86 (dd, J=8.6 Hz, 0.9 Hz,
1H), 7.52–7.48 (m, 1H), 7.16 (dd, J=6.8 Hz, 0.9 Hz, 1H),
5.51 (t, J=7.1 Hz, 1H), 2.99–2.88 (m, 4H), 2.96 (s, 3H),
2.75–2.67 (m, 1H), 2.32–2.15 (m, 2H), 2.11–2.04 (m, 1H),
1.85–1.75 (m, 2H), 1.73–1.64 (m, 2H), 1.59–1.46 (m, 2H),
1.38–1.20 (m, 2H), 1.10 (t, J=7.3 Hz, 3H), 1.06 (t, J=
7.3 Hz, 3H), 1.01 (t, J=7.3 Hz, 3H), 0.85 (t, J=7.3 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=155.9, 151.1, 144.19,
144.13, 137.1, 129.7, 128.5, 128.4, 126.1, 124.8, 122.7, 37.6,
36.4, 30.6, 30.4, 27.2, 24.3, 23.9, 22.8, 21.6, 14.8, 14.6, 14.3; IR
(CDCl3): n=3071, 2960, 2872, 2732, 1699, 1597, 1462, 1377,
1089, 807 cmÀ1; HR-MS (FAB+): m/z=338.2856, calcd. for
C24H35N [M+H]+: 338.2842.
1-Cyclohexyl-3,4-dipropylisoquinoline
(7j):
1H NMR
(400 MHz, CDCl3): d=8.16 (d, J=8.4 Hz, 1H), 7.94 (d, J=
8.4 Hz, 1H), 7.57 (t, J=7.2 Hz, 1H), 7.43 (t, J=7.6 Hz, 1H),
3.50–3.45 (m, 1H), 2.97–2.88 (m, 4H), 1.94–1.77 (m, 9H),
1.70–1.61 (m, 2H), 1.55–1.46 (m, 2H), 1.42–1.35 (m, 1H),
1.08 (t, J=7.2 Hz, 3H), 1.01 (t, J=7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=162.3, 151.7, 135.9, 128.9, 125.4,
125.2, 125.0, 124.7, 123.9, 41.6, 37.3, 32.8, 30.0, 27.1, 26.6,
24.2, 23.3, 12.9, 14.5; IR (CDCl3): n=3071, 2958, 2929, 2870,
2853, 1615, 1565, 1504, 1449, 1377, 1323, 985, 761 cmÀ1; HR-
MS (FAB+): m/z=296.2383, calcd. for C21H29N [M+H]+:
296.2373.
1-Cyclohexyl-8-(oct-4-en-4-yl)-3,4-dipropylisoquinoline
(9c): 1H NMR (400 MHz, CDCl3): d=7.85 (d, J=8.4 Hz,
1H), 7.45 (t, J=7.7 Hz, 1H), 7.11 (dd, J=6.8 Hz, 0.7 Hz,
1H), 5.52 (t, J=7.0 Hz, 1H), 3.86–3.81 (m, 1H), 2.96–2.82
(m, 4H), 2.71–2.64 (m, 1H), 2.25 (q, J=7.3 Hz, 2H), 2.18–
2.08 (m, 2H), 1.90–1.81 (m, 4H), 1.70–1.62 (m, 4H), 1.60–
1.47 (m, 3H), 1.42–1.18 (m, 6H), 1.09 (t, J=7.3 Hz, 3H),
1.02 (td, J=7.3 Hz, 1.0 Hz, 6H), 0.83 (t, J=7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=163.1, 151.0, 144.5, 143.2,
137.3, 128.6, 128.1, 127.8, 125.2, 123.1, 122.9, 42.9, 37.2, 35.9,
34.7, 31.9, 30.8, 30.5, 27.3, 27.2, 26.6, 24.1, 23.1, 23.0, 21.7,
15.0, 14.6, 14.49, 14.47; IR (CDCl3): n=3075, 2958, 2927,
1-Hexyl-3,4-dipropylisoquinoline
(7k):
1H NMR
(400 MHz, CDCl3): d=8.11 (d, J=8.3 Hz, 1H), 7.96 (d, J=
8.5 Hz, 1H), 7.65–7.61 (m, 1H), 7.50–7.46 (m, 1H), 3.23 (t,
J=7.9 Hz, 2H), 2.99–2.95 (m, 2H), 2.93–2.89 (m, 2H), 1.85–
1.74 (m, 4H), 1.72–1.62 (m, 2H), 1.50–1.43 (m, 2H), 1.37–
1.29 (m, 2H), 1.09 (t, J=7.2 Hz, 3H), 1.03 (t, J=7.2 Hz,
3H), 0.88 (t, J=6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d=159.7, 151.9, 135.9, 129.4, 126.16, 126.10, 125.4, 125.3,
123.9, 37.6, 35.9, 32.0, 30.5, 30.0, 29.8, 24.3, 24.0, 22.9, 14.9,
14.5, 14.3; IR (CDCl3): n=3071, 2957, 2929, 2871, 1616,
1566, 1504, 1463, 1378, 1260,1028, 759 cmÀ1
; HR-MS
2870, 2851, 1597, 1557, 1450, 1378, 1225, 982, 891, 771 cmÀ1
;
(FAB+): m/z=298.2540, calcd. for C21H31N [M+H]+:
298.2529.
HR-MS (EI+): m/z=405.3389, calcd. for C29H43N [M]+:
405.3396.
1-Phenyl-3,4-dipropylisoquinoline (7l) [CAS No.387862-
1-Hexyl-8-(oct-4-en-4-yl)-3,4-dipropylisoquinoline
(9d):
1
67-1]: H NMR (400 MHz, CDCl3): d=8.03 (dd, J=8.5 Hz,
1H NMR (400 MHz, CDCl3): d=7.85 (d, J=8.4 Hz, 1H),
7.50–7.46 (m, 1H), 7.13 (d, J=6.7 Hz, 1H), 5.60 (t, J=
7.0 Hz, 1H), 3.60–3.53 (m, 1H), 3.01–2.81 (m, 5H), 2.71–
2.64 (m, 1H), 2.23 (q, J=7.5 Hz, 2H), 2.11–2.04 (m, 1H),
1.86–1.77 (m, 2H), 1.73–1.63 (m, 2H), 1.57–1.47 (m, 4H),
1.25–1.15 (m, 8H), 1.09 (t, J=7.2 Hz, 3H), 1.05–1.00 (m,
6H), 0.85–0.78 (m, 6H); 13C NMR (100 MHz, CDCl3): d=
159.9, 151.2, 144.2, 143.7, 137.3, 128.8, 128.7, 128.2, 125.7,
123.8, 122.9, 38.2, 37.5, 36.3, 32.2, 31.4, 30.8, 30.5, 29.7, 24.3,
23.7, 23.0, 22.9, 21.7, 14.9, 14.6, 14.4, 14.33, 14.31; IR
(CDCl3): n=3068, 2959, 2932, 2872, 1710, 1463, 1378, 1179,
1089, 772 cmÀ1; HR-MS (FAB+): m/z=408.3622, calcd. for
C29H45N [M+H]+: 408.3625.
2.8 Hz, 2H), 7.68–7.64 (m, 3H), 7.53–7.40 (m, 4H), 3.10–
3.00 (m, 4H), 1.91–1.82 (m, 2H), 1.80–1.71 (m, 2H), 1.15 (t,
J=7.3 Hz, 3H), 1.06 (t, J=7.3 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=258.3, 152.4, 140.4, 136.3, 130.2,
129.6, 128.4, 128.38, 128.30, 127.3, 125.5, 125.4, 123.5, 37.6,
30.2, 24.3, 23.9, 14.9, 14.5.
1-(But-1-en-1-yl)-1-propyl-1H-isoindole (8): 1H NMR
(400 MHz, CDCl3): d=8.58 (s, 1H), 7.33 (t, J=7.7 Hz, 1H),
6.99 (d, J=7.4 Hz, 1H), 6.79 (d, J=8.0 Hz, 1H), 5.71 (d, J=
15.5 Hz, 1H), 5.63–5.56 (m, 1H), 3.91 (s, 3H), 2.05–1.95 (m,
3H), 1.84–1.77 (m, 1H), 1.14–1.04 (m, 1H), 0.93 (t, J=
7.4 Hz, 3H), 0.88–0.76 (m, 4H); 13C NMR (100 MHz,
CDCl3): d=158.28, 158.24, 154.5, 131.4, 130.5, 129.4, 127.8,
115.2, 109.2, 84.1, 55.6, 40.6, 25.8, 17.2, 14.5, 13.7; IR
(CDCl3): n=3087, 3006, 2959, 2934, 2911, 2872, 1702, 1612,
1547, 1269, 1029, 970, 788 cmÀ1; HR-MS (FAB+): m/z=
243.1626, calcd. for C16H21NO [M]+: 243.1623.
8-(Oct-4-en-4-yl)-1-phenyl-3,4-dipropylisoquinoline (9e):
1H NMR (400 MHz, CDCl3): d=7.96 (d, J=8.6 Hz, 1H),
7.60–7.57 (m, 2H), 7.40–7.28 (m, 5H), 5.29 (t, J=7.2 Hz,
1H), 3.07–3.03 (m, 2H), 3.01–2.89 (m, 2H), 1.84–1.60 (m,
8H), 1.27–1.05 (m, 2H), 1.12 (t, J=7.3 Hz, 3H), 1.03–0.92
(m, 2H), 1.01 (t, J=7.3 Hz, 3H), 0.63 (t, J=7.3 Hz, 3H),
0.56 (t, J=7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=
159.4, 152.1, 144.7, 140.7, 138.4, 135.8, 131.8, 130.4, 129.7,
129.5, 128.9, 128.1, 127.1, 126.5, 126.2, 125.0, 123.1, 37.6,
33.0, 30.3, 30.2, 24.4, 24.1, 22.7, 21.8, 14.8, 14.5, 14.1, 13.8; IR
(CDCl3): n=3067, 2960, 2872, 1690, 1614, 1557,1461, 1381,
1086, 761 cmÀ1; HR-MS (EI+): m/z=399.2923, calcd. for
C29H37N [M]+: 399.2926
8-(Oct-4-en-4-yl)-3,4-dipropylisoquinoline (9a): 1H NMR
(400 MHz, CDCl3): d=9.26 (s, 1H), 7.84 (d, J=8.6 Hz, 1H),
7.60–7.56 (m, 1H), 7.24 (d, J=7.0 Hz, 1H), 5.48 (t, J=
7.3 Hz, 1H), 3.02–2.98 (m, 2H), 2.95–2.91 (m, 2H), 2.51 (t,
J=7.6 Hz, 2H), 2.27 (q, J=7.3 Hz, 2H), 1.86–1.77 (m, 2H),
1.74–1.64 (m, 2H), 1.54–1.45 (m, 2H), 1.35–1.25 (m, 2H),
1.10 (t, J=7.3 Hz, 3H), 1.04 (t, J=7.3 Hz, 3H), 0.99 (t, J=
7.3 Hz, 3H), 0.87 (t, J=7.3 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=152.3, 149.0, 144.5, 138.2, 135.9, 132.8, 129.5,
Adv. Synth. Catal. 2013, 355, 2667 – 2679
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FULL PAPERS
139.8, 138.2, 137.5, 133.2, 133.0, 131.7, 131.2, 130.8, 130.7,
130.2, 130.0, 129.26, 129.20, 128.7, 128.6, 128.6, 128.5, 127.4,
126.3, 63.6.
Typical Procedure for Preparing Isoquinolinium Salt
18a by Reaction of Secondary Benzylamine 19a and
Alkyne 3a in the Presence of 4b/6/HBF4 (Table 3)
To a 1 mL pressure vial was added N-methylbenzylamine
(19a, 60.6 mg, 0.5 mmol), diphenylacetylene (3a, 106.9 mg,
0.6 mmol), [Cp*RhCl2]2 (4b, 3.7 mg, 0.00625 mmol), Cu-
General Procedure for the Preparation of
Dihydroisoquinolinium Salt by the Reaction of
Tertiary Benzylamines in the Presence of 4b/6/KPF6
(Table 3)
ACHTUNGTRENNUNG(OAc)2·H2O (6, 200 mg, 1.0 mmol), 48% of HBF4 soluion in
H2O (67 mL, 0.5 mmol) and methanol (500 mL). The mixture
was stirred at 1008C for 4 h. After cooling and dilution with
CH2Cl2, the mixture was filtered through a celite pad. The
filtrate was concentrated under vacuum and the residue was
carefully washed with ethyl acetate and hexane to give 2-
methyl-3,4-diphenylisoquinolinium tetrafluoroborate (18a)
as a white solid; yield: 178.2 mg (93%).
To a 1 mL pressure vial was added N,N-dimethylbenzyla-
mine (19a, 67.6 mg. 0.5 mmol), 3-hexyne (3d, 49.2 mg,
0.6 mmol), [Cp*RhCl2]2 (4b, 3.7 mg, 0.00625 mmol), Cu-
AHCTUNGRTEG(NNUN OAc)2·H2O (6, 200 mg, 1.0 mmol), KPF6 (110.4 mg,
0.6 mmol) and methanol (700 mL). The reaction mixture was
stirred at 1008C in a preheated oil-bath for 8 h. After cool-
ing the vessel to room temperature the mixture was diluted
with CH2Cl2. The reaction mixture was filtered through
a celite pad and the celite pad was washed with CH2Cl2. The
combined filtrate was concentrated under vacuum and the
residue was diluted with a small amount of CH2Cl2 again.
Addition of Et2O led to precipitation of 3,4-diethyl-2,2-di-
methyl-1,2-dihydroisoquinolin-2-ium hexafluorophosphate
(20a) as an off-white solid; yield: 125.3 mg (69%).
3,4-Diethyl-2,2-dimethyl-1,2-dihydroisoquinolin-2-ium
hexafluorophosphate (20a) [CAS No. 151655-55-5]:
1H NMR (400 MHz, CD2Cl2): d=7.56–7.41 (m, 4H), 4.60 (s,
2H), 3.23 (s, 6H), 2.66 (q, J=7.5 Hz, 4H), 1.34 (t, J=
7.5 Hz, 3H), 1.18 (t, J=7.5 Hz, 3H); 13C NMR (100 MHz,
CD2Cl2): d=141.1, 134.8, 130.9, 130.6, 129.4, 128.2, 126.1,
124.8, 66.7, 51.4, 22.3, 20.4, 14.8, 13.8; anal. calcd. for
C15H22F6NP: C 49.86, H 6.14, N 3.88; found: C 49.45, H
6.18, N 4.07.
2-Methyl-3,4-diphenylisoquinolinium
tetrafluoroborate
1
(18a) [CAS No. 114943-84-9]: H NMR (400 MHz, CDCl3):
d=10.05 (s, 1H), 8.60 (d, J=8.0 Hz, 1H), 7.96 (t, J=7.9 Hz,
1H), 7.88 (t, J=7.5 Hz, 1H), 7.63 (d, J=8.2 Hz, 1H), 7.34–
7.26 (m, 8H), 7.16–7.13 (m, 2H), 4.24 (s, 3H); 13C NMR
(100 MHz, CDCl3): d=151.8, 144.4, 139.1, 138.1, 137.0,
133.4, 131.6, 131.3, 131.0, 130.3, 130.2, 129.1, 128.8, 128.6,
127.6, 126.4, 48.6; 11B NMR (96 MHz, CDCl3): d=À0.91;
19F NMR (282 MHz, CDCl3): d=À152.13, À152.18.
2-Methyl-3,4-dipropylisoquinolinium
tetrafluoroborate
1
(18b) [CAS No. 1356496-71-3]: H NMR (400 MHz, CDCl3):
d=9.75 (s, 1H), 8.41 (d, J=8.1 Hz, 1H), 8.10–8.03 (m, 2H),
7.77 (t, J=7.3 Hz, 1H), 4.52 (s, 3H), 3.09 (q, J=7.8 Hz,
4H), 1.73–1.66 (m, 4H), 1.14 (q, J=7.0 Hz, 6H); 13C NMR
(100 MHz, CDCl3): d=150.5, 145.3, 137.6, 136.96, 136.93,
131.8, 130.2, 126.8, 123.6, 46.8, 13.1, 30.7, 24.1, 22.6, 14.7,
14.4.
3,4-Diethyl-2-methylisoquinolin-2-ium
hexafluorophos-
2,4-Dimethyl-3-phenylisoquinolinium
tetrafluoroborate
1
(18c) [CAS No. 1356496-74-6]: 1H NMR (400 MHz,
CD2Cl2): d=9.80 (s, 1H), 8.53 (d, J=8.2 Hz, 1H), 8.28–8.20
(m, 2H), 8.02–7.99 (m, 1H), 7.68–7.67 (m, 3H), 7.41–7.39
(m, 2H), 4.13 (s, 3H), 2.51 (s, 3H); 13C NMR (100 MHz,
CD2Cl2): d=150.1, 144.2, 138.1, 137.6, 134.5, 131.8, 131.7,
131.4, 131.2, 130.2, 129.5, 127.1, 124.6, 48.7, 16.3.
phate (18g): H NMR (400 MHz, CD2Cl2): d=9.43 (s, 1H),
8.34 (d, J=8.2 Hz, 1H), 8.23 (d, J=8.6 Hz, 1H), 8.16 (t, J=
7.2 Hz, 1H), 7.92 (t, J=7.5 Hz, 1H); 13C NMR (100 MHz,
CD2Cl2): d=149.9, 146.6, 139.2, 138.1, 137.7, 131.6, 131.0,
127.1, 124.2, 47.2, 23.0, 22.2, 15.0, 13.3; IR (CDCl3): n=
3087, 2988, 2942, 2881, 1635,1452, 1392, 1281,1184, 1119,
925, 836, 557 cmÀ1; HR-MS (FAB+): m/z=200.1437, calcd.
2,3,4-Triphenylisoquinolinium tetrafluoroborate (18d)
À
for C14H18N [MÀPF6 ]+: 200.1439.
1
[CAS No. 1356496-80-4]: H NMR (400 MHz, CDCl3): d=
9.72 (s, 1H), 8.57 (d, J=8.2 Hz, 1H), 8.03 (t, J=8.0 Hz,
1H), 7.91 (t, J=7.7 Hz, 1H), 7.74 (d, J=8.5 Hz, 1H), 7.52–
7.50 (m, 2H), 7.36–7.28 (m, 8H), 7.11–7.01 (m, 5H);
13C NMR (100 MHz, CDCl3): d=150.7, 144.6, 142.3, 139.5,
139.0, 137.9, 133.5, 132.0, 131.47, 131.10, 130.6, 130.5, 129.6,
129.3, 128.8, 128.6, 128.0, 127.1, 127.0, 126.7.
Acknowledgements
This study was supported by Mid-career Research Program
(Grant 2011-0016830) through NRF grant funded by the
MEST.
2-(4-Methoxyphenyl)-3,4-diphenylisoquinolinium
tetra-
fluoroborate (18e) [CAS No. 1356496-82-6]: 1H NMR
(400 MHz, CDCl3): d=9.65 (s, 1H), 8.50 (d, J=8.1 Hz, 1H),
7.97 (t, J=7.5 Hz, 1H), 7.85 (t, J=7.5 Hz, 1H), 7.67 (d, J=
8.4 Hz, 1H), 7.36 (d, J=8.8 Hz, 2H), 7.26–7.21 (m, 7H),
7.04–6.96 (m, 5H), 6.73 (d, J=8.8 Hz, 2H), 3.68 (s, 3H);
13C NMR (100 MHz, CDCl3): d=160.3, 150.7, 144.6, 139.1,
138.6, 137.4, 135.0, 133.3, 131.6, 131.2, 131.1, 131.0, 130.2,
128.9, 128.5, 128.3, 127.9, 127.8, 126.9, 126.3, 114.3, 55.4.
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