Synthesis of 3-(3-piperidyl)-isoquinoline and 3-(4-piperidyl)-isoquinoline

Article abstract of DOI:10.1007/s10593-009-0368-6

3-(3-Piperidyl)isoquinoline and 3-(4-piperidyl)isoquinoline have been synthesized from o-tolylaldehyde aldimines and the methylmethoxycarboxamides (Weinreb amides) of N-Boc-substituted nipecotic and isonipecotic acids.

Full text of DOI:10.1007/s10593-009-0368-6

Chemistry of Heterocyclic Compounds, Vol. 45, No. 8, 2009
SYNTHESIS OF 3-(3-PIPERIDYL)-
ISOQUINOLINE AND 3-(4-PIPERIDYL)-
ISOQUINOLINE
D. A. Kovalskiy1* and V. P. Perevalov2
3-(3-Piperidyl)isoquinoline and 3-(4-piperidyl)isoquinoline have been synthesized from o-tolylaldehyde
aldimines and the methylmethoxycarboxamides (Weinreb amides) of N-Boc-substituted nipecotic and
isonipecotic acids.
Keywords: Weinreb amide, isoquinoline, 3-(3-piperidyl)isoquinoline, 3-(4-piperidyl)isoquinoline.
Despite the abundance of biologically active compounds containing an isoquinoline fragment the
interest in a related structure has not diminished. At his time there has accumulated a rich volume of data
concerning isoquinolines with different substituents in all positions [1]. At the same time, the development of
methods leading to the preparation of 3-substituted isoquinolines has been given the least attention. This is
possibly related to the large number of stages or to the low availability of starting reagents.
The Bischler-Napieralski and Pictet-Gams [1] methods have been used most often. The limitation of
these routes is the mandatory presence of functional groups which activate the aromatic ring towards
electrophilic substitution. More contemporary is a method based on the palladium catalyzed reaction of
o-iodobenzaldehyde imines with different acetylenes which eventually leads to the formation of 3-substituted
isoquinolines [2]. The particular value of this reaction is that, beside variation of the substituent in the 3 position,
in certain conditions there may be introduced into the 4 position of the isoquinoline an iodine atom [3], aryl and
allyl [4], and also acyl fragments [5]. This route is of great practical interest but the scope of readily available
acetylenes is limited and the reaction course demands expensive catalysts. Another method based on the
acylation of the methyl group of o-tolylaldehyde cyclohexylimine by Weinreb amides and subsequent
cyclization in aqueous ammonia of the ketone formed to a 3-substituted isoquinoline [6] was the basis of the
route we selected for the preparation of isoquinolines with a 3-piperidyl fragment in position 3. This type of
compound is certainly of interest thanks to the combination of two known pharmacophoric heterocycles which,
in turn, opens a route to novel, potentially biologically active compounds.
The N-Boc-substituted methylmethoxycarboxamides of 4- and 3-piperidinocarboxylic acids (3 and 6
respectively) were used as the source of the piperidyl fragment. The synthesis of compound 3 was achieved by a
_______
* To whom correspondence should be addressed, e-mail: DKovalskiy@asinex.com.
1ASINEX Ltd, Moscow 125480, Russia.
2D. I. Mendeleev University of Chemical Technology of Russia, Moscow 125047, Russia; e-mail:
pvp@muctr.edu.ru.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1204-1213, August, 2009.
Original article submitted February 10, 2009.
0009-3122/09/4508-0957©2009 Springer Science+Business Media, Inc.
957

scheme including the introduction of a Boc-group into ethyl isonipecotate (1), hydrolysis of the ester, and
subsequent acylation of N,O-dimethylhydroxylamine by N-Boc-isonipecotic acid (2). Amide 6 was prepared by
a similar scheme from ethyl N-Boc-nipecotate with intermediate separation of N-Boc-nipecotic acid (5).
O
O
Me
COOH
N
1. Boc2O
2. KOH
CDI, MeNHOMe
CDI, MeNHOMe
OEt
OEt
OMe
N
N
HN
Boc
3
Boc
2
1
O
O
Me
COOH
1. Boc2O
2. KOH
N
OMe
N
N
H
N
Boc
Boc
6
4
5
CDI − N,N'-carbonyldiimidazole
2-Methylbenzaldehyde and 4-methoxy-2,3-dimethylbenzaldehyde were used as precursors of the
isoquinoline fragment. Schiff bases were prepared by a classical method.
NH2
N
O
R1
Me
R1
Me
R
R
7, 8
7 R = R1 = H; 8 R = Me, R1 = OMe
Metallation of imines 7 and 8 was carried out under conditions close to those used in the study [6]
adding compounds 7 and 8 to a solution of lithium tetramethylpiperide (LiTMP) in THF at low temperature and
then treatment with the Weinreb amide.
1) LiTMP (2 equiv.)
1) LiTMP (2 equiv.)
2) 3
2) 6
7, 8
N
N
R1
R
O
R
O
N
12a,b
N
Boc
9a,b
Boc
NH4Cl
NH4Cl
958

N
N
R1
R1
R
N
R
Boc
N
10a,b
13a,b
Boc
HCl
HCl
N
N
R1
R1
R
R
NH
N
· 2HCl
H
· 2HCl
14a,b
11a,b
9–14 a R = R1 = H; b R = Me, R1 = OMe
As found experimentally, treatment of the reaction mixture with a saturated solution of ammonium
chloride at the stage of preparation of ketones of type 9 and 12 leads to partial, or sometimes full, cyclization to
form the isoquinolines 10 and 13 but further refluxing in aqueous ammonia did not increase the yield of the
target cyclization product (Table 1).
The authors of the report [6] have shown the reaction needs, as a minimum, the addition of a further
equivalent of the lithium base for satisfactory yields. We propose that the first equivalent is most likely
consumed by deprotonation of the tertiary carbon atom of the cyclohexyl fragment (route A) or by formation of
a benzyl anion which is accompanied by migration of the double bond (route B). The second equivalent is used
for deprotonation of the methyl group.
N
LiTMP
LiTMP
Me
A
Li+
Li+
B
–
–
–
N
N
Me
Me
Li+
–
–
N
N
–
CH2
CH2
Li+
Li+
959

TABLE 1. Characteristics of the Compounds Synthesized
Found, %
Calculated, %
——————
Com-
pound
Empirical
formula
m/z
Yield,
%
mp, °C
[
M+H]+
С
H
Cl
N
С19H24N2O2
С21H28N2O3
С14H18Cl2N2
73.12 7.67
73.05 7.74
70.84 7.88
70.76 7.92
—
—
9.01
8.97
7.75
7.86
9.93
9.82
8.60
8.51
9.03
8.97
7.88
7.86
9.88
9.82
8.57
8.51
313
357
213
257
313
357
213
257
377
120-121
144-146
195-199
237-241
105-107
152-155
220-222
247-250
—
47
31
93
96
48
38
96
94
71
77
10a
10b
11a
11b
13a
13b
14a
14b
14c
14d
59.12 6.40 24.77
58.96 6.36 24.86
С16H22Сl2N2O 58.45 6.71 21.61
58.36 6.73 21.53
С19H24N2O2
С21H28N2O3
С14H18Cl2N2
73.11 7.69
73.05 7.74
70.84 7.85
70.76 7.92
—
—
59.05 6.31 24.80
58.96 6.36 24.86
С16H22Сl2N2O 58.40 6.79 21.50
58.36 6.73 21.53
С24H27N2O3
72.84 6.51
73.38 6.43
—
7.56
7.44
13.71 411
13.63
С21H27СlN4O 67.31 6.57
8.05
8.63
—
67.22 6.62
and 413
333
С22H26Сl2N2O 64.81 6.58 18.10
65.19 6.46 17.99
7.12
6.91
117-121
55
14e
TABLE 2. 1H NMR Spectra of the Compounds Synthesized
Com-
pound
Chemical shifts, δ, ppm (J, Hz)*
1
2
3
6
1.49 (9Н, s, t-Bu); 1.71 (4H, m, CH2CHCH2); 2.81 (3H, m, CH2N+CH);
3.19 (3H, s, OCH3); 3.71 (3H, s, NCH3); 4.19 (2H, m, CH2N)
1.41 (9Н, s, t-Bu); 1.51 and 1.91 (2H, m, CH2СH2CH2CH);
1.72 (2H, m, CH2СH2CH2CH); 2.71 (1H, m, CH); 2.91 (2H, m, CH2N);
3.15 (3Н, s, OCH3); 3.74 (3H, s, NCH3); 4.09 and 4.19 (2Н, m, CH2N)
8
1.15–1.80 (10Н, m, (СН2)5); 2.10 (3Н, s, 3-CH3); 2.35 (3Н, s, 2-CH3);
3.18 (1Н, m, CH2CHCH2); 3.78 (3Н, s, OCH3); 6.84 (1Н, d, J = 8.7, Н-5);
7.59 (1Н, d, J = 8.7, Н-6); 8.58 (1Н, s, HC=N)
10a
10b
11a
11b
1.49 (9H, s, t-Bu); 1.68 (2Н, m, CHCH2); 1.95 (2H, m, CHCH2);
2.89 (2Н, m, CH2N); 3.0 (1Н, m, CH2CHCH2); 4.11 (2Н, m, CH2N);
7.58 (1Н, t, J = 7.3, Н-7); 7.65 (1Н, s, Н-4); 7.72 (1Н, t, J = 7.8, Н-6);
7.87 (1H, d, J = 8.2, Н-5); 8.04 (1Н, d, J = 7.8, H-8); 9.21 (1Н, s, Н-1)
1.42 (9Н, s, C(CH3)3); 1.70 (2H, m, CH2CH), 1.86 (2H, m, CH2CH);
2.39 (3Н, s, 5-СН3); 2.81 (2Н, m, CH2N); 2.96 (1Н, m, CH2CHCH2);
3.91 (3Н, s, 6-OCH3); 4.10 (2Н, m, CH2N); 7.46 (1Н, d, J = 8.5, Н-7);
7.55 (1Н, s, Н-4); 7.93 (1Н, d, J = 8.5, Н-8); 9.09 (1Н, s, Н-1)
2.11 (2H, m, CHCH2); 2.25 (2H, m, CHCH2); 3.09 (2H, m, CH2N);
3.41 (3H, m, CH2N and CH2CHCH2); 7.82 (1Н, t, J = 7.8, Н-7);
8.05 (1Н, t, J = 7.8, Н-6); 8.09 (1Н, s, Н-4); 8.15 (1H, d, J = 7.8, Н-5);
8.35 (1Н, d, J = 7.8, H-8); 9.11 (1H, br. s, NH); 9.31 (1H, br. s, HCl); 9.61 (1Н, s, Н-1)
2.19 (2H, m, CHCH2); 2.29 (2H, m, CHCH2); 2.39 (3Н, s, CH3);
3.11 (2H, m, CH2N); 3.44 (3H, m, CH2CHCH2+CH2N);
4.11 (3Н, s, OCH3); 7.58 (1Н, br. d, H-7); 7.91 (1Н, br. d, H-8);
8.15 (1Н, s, Н-4); 9.41 (3Н, br. s, Н-1 + NH + HCl)
13a
1.41 (9Н, s, t-Bu); 1.51–2.02 (4H, m, CH2CH2); 2.81–2.91 (2H, m, CH2N);
3.09 (1H, m, CH2CHCH2); 3.95–4.21 (2H, m, CH2N); 7.61 (1H, t, J = 7.8, Н-7);
7.69 (1H, s, Н-4); 7.75 (1H, t, J = 7.3, Н-6); 7.91 (1H, d, J = 8.2, Н-5);
8.05 (1Н, d, J = 7.8, Н-8); 9.26 (1Н, s, Н-1)
960

TABLE 2 (continued)
1
2
13b
14a
1.40 (9Н, s, t-Bu); 1.57–1.89 (4H, m, CH2CH2); 2.33 (3Н, s, 5-СН3);
2.83 (2H, m, CH2N); 3.09 (1H, m, CH2CHCH2); 3.81 (3Н, s, 6-OCH3);
3.95 (1Н, m, CH2N); 4.20 (1H, m, CH2N); 7.39 (1Н, d, J = 8.5, Н-7);
7.50 (1Н, s, Н-4); 8.01 (1Н, d, J = 8.5, Н-8); 9.11 (1Н, s, Н-1)
1.91–2.19 (4H, m, CHCH2CH2N); 2.91 (1H, m, CH2CHCH2);
3.31 (2Н, m, CH2N); 3.61 (2H, m, CH2N); 7.81 (1H, t, J = 7.3, Н-7);
7.96 (1H, t, J = 7.3, Н-6); 8.09 (1H, d, J = 8.5, Н-5); 8.11 (1H, s, Н-4);
8.34 (1Н, d, J = 8.2, Н-8); 9.41 (1H, br. s, NH); 9.61 (1H, br. s, HCl);
9.63 (1Н, s, Н-1)
14b
1.95–2.11 (4H, m, CH2CH2); 2.45 (3Н, s, СН3); 2.91 (1H, m, CH2CHCH2);
3.31–3.62 (4Н, m, 2CH2N); 4.09 (3Н, s, OCH3); 7.80 (1Н, d, J = 8.9, Н-7);
8.08 (1H, s, Н-4); 8.38 (1Н, d, J = 9.1, H-8); 9.43 (1H, br. s, NH);
9.51 (1Н, s, Н-1); 9.72 (1H, br. s, HCl)
14с
1.67–2.12 (4Н, m, СНСН2СН2); 3.01 (1Н, m, CH2CHCH2);
3.39 and 3.57 (2Н, both m, CH2N); 3.73 (6Н, br. s, 2СН3О);
4.56 and 3.71 (2Н, both m, CH2N); 6.53 (2Н, m, Н-5 Ar and Н-6 Ar);
7.09 (1Н, br. s, Н-3 Ar); 7.51-8.09 (5Н, m, Н-4,5,6,7 and Н-8 isoquinoline);
9.16 and 9.25 (1Н, both br. s, Н-1 isoquinoline)
14d
14e
1.37 (3Н, d, J = 6.2, CН3); 1.80-2.16 (7Н, m, СНСН2СН2, CН3 pyrazole);
2.21 (3Н, s, CН3 pyrazole); 2.52-2.70 (1Н, m, С(О)СН);
3.10-3.40 (5Н, m, CH2CHCH2, CH2N and С(О)СНСН2N);
3.57-3.63 (2Н, m, CH2N); 7.90 (1Н, br. s, Н-7 isoquinoline);
8.08-8.30 (3Н, m, Н-4,5,6 isoquinoline); 8.45 ( 1Н, d, J = 8.2, Н-8 isoquinoline);
9.31 (1Н, s, Н-1 isoquinoline)
1.70–2.20 (4Н, m, СНСН2СН2); 2.97 (1Н, m, CH2CHCH2);
3.20-3.49 (2Н, m, CH2N); 3.65–3.72 (2Н, m, CH2N); 3.81 (3Н, s, ОСН3);
4.30 (2Н, s, ArСН2); 7.05 (2Н, br. d, Н-3,6 Ar); 7.41 (1Н, s, Н-4 isoquinoline);
7.55-8.10 (4Н, m, Н-4,5 Ar, Н-6,7 isoquinoline);
8.17 (2Н, br. d, Н-5,8 isoquinoline); 9.41 (1Н, s, Н-1 isoquinoline);
10.95 (1Н, br. s, HCl)
_______
* 1H NMR spectra recorded in CDCl3 (compounds 3 and 6) or in DMSO-d6
(remaining compounds).
According to the results of the two experiments under similar conditions but with different amounts of base
(1 and 2 equivalents) there is formed in the first case a small yield of the isoquinoline (~ 6%) and in the second an
acceptable yield (59%). It should be noted that different data is given in publications by other authors. Thus
according to [7], the Schiff base from benzaldehyde and the sterically hindered 3-amino- 2,4-dimethylpentane is
readily metallated at position 2 of the aromatic ring and does not need this excess of base.
Me
Me
Me
N
Me
R
R
Me
1) BuLi/TMEDA
2) MeI
Me
N
Me
Me
Me
TMEDA − tetramethylenediamine
Other authors [8] have revealed the possibility of using a Schiff base from tert-butylamine which does
not have the structural possibility of deprotonation under the action of base. However, the yield of the alkylation
product is very low.
R
R
Bu-t
t
Bu-
1. BuLi
2. AlkI
N
N
Alk
Me
961

The formation of a tolyl anion is accompanied by the appearance of a deep violet color but treatment
with the Weinreb agents 3, 6 causes almost complete decolorization. For analysis of the products of the
acylation stage the reaction mass was treated not with NH4Cl solution but with water. Chromato-mass
spectrometric analysis (in the example of compound 9a) showed that the acylation product of the o-tolyl-
aldehyde 15 predominates in solution.
O
O
N
Boc
15
None the less, in the studies [7, 8] there appear data supporting the formation of ketones with retention
of the cyclohexyl fragment. Moreover, the authors point to the necessity of treating with a solution of
ammonium chloride with subsequent refluxing of such a ketone in aqueous ammonia to reach completion of the
reaction, i.e. formation of the isoquinoline fragment.
In our work we have shown that the formation of isoquinolines 11 and 14 needs only short treatment
with NH4Cl solution. This fact testifies to the formation of keto aldehyde 15.
The 1H NMR spectra of the N-Boc-substituted 3-piperidylisoquinolines 10 and 13 (Table 2) show signals
for the piperidyl fragment at 1.5-4.0 ppm and a narrow singlet at 9.2 ppm corresponding to the 1-proton of the
isoquinoline. The nine protons of the tert-butoxycarbonyl group appear as a narrow singlet at 1.4-1.5 ppm.
The amines 11a,b ad 14a,b satisfy all of the demands of the Lipinski rule [9], appearing as potentially
biologically active compound. The selection criteria for the Lipinski rule are molecule weight (< 500),
calculated solubility, control value ClogP (<5), as well as the number of donor and acceptor hydrogen bonds
which should not be greater than 5 and 10 respectively.
Screening of the inhibitory activity towards protein kinases for the obtained amine derivatives 11a,b and
14a,b, obtained by reductive amination, and those derivatives obtained by acylation with carboxylic acids and
sulfochlorides revealed significant activity in compounds 14c-e (see Table 3).
Hence we have synthesized the novel isoquinolines 3-(3-piperidyl)isoquinoline and 3-(4-
piperidyl)isoquinoline. Use of this method leads to the production of isoquinolines with different amino acid
residues at position 3. The introduction and subsequent modification of the piperidyl fragment leads to the
preparation of substances inhibiting protein kinases.
EXPERIMENTAL
1H NMR spectra were recorded on a Mercury 400 (400 MHz) instrument using TMS as internal
standard. Melting points were measured on a Gallenkamp apparatus. The course of the reactions was monitored
by TLC on Silica gel/TLC card plates (Fluka) with different eluents. Chromato mass spectra were obtained on a
TABLE 3. Bioscreening Results
Compound
Type of inhibited kinase
IC50, µmol
14c
Bruton's Tyrosine Kinase [10]
0.5
Glycogen synthase Kinase 3b [11]
10.0
14d
14e
BTK
0.9
9.0
3.5
GSK 3b
Lymphocyte Kinase [12]
962

OMe
HO2C
OMe
TBTU, Et3N
HO2C
OMe
N
O
N
OMe
Me
14c
N
N
Me
N
O
Me
Cl
N
N
N
Me
14a
TBTU, Et3N
Me
Me
Cl
14d
OMe
CHO
1.
OMe
N
N
.
2HCl
2. Na(OAc)3BH
3. HCl
14e
TBTU – 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate
Thermo Finnigan Surveyor MSQ chemical ionization instrument for a solution (15 eV) with a YMC
Hydrosphere C18 column (12 nm, S-3 µm, 33×3 mm) using gradient elution (acetonitrile – 0.1% aqueous formic
acid, eluent flow rate 1.3 ml/min).
N-Boc-isonipecotic Acid Methoxymethylamide (3). A solution of di-tert-butylpyrocarbonate (480 g,
2.2 mol) in dichloromethane (400 ml) was added dropwise to a solution of the ethyl ester 1 (317 g, 2.0 mol) in
dichloromethane (500 ml) at 0ºC. The reaction mixture was stirred for 1 h. At the end of the reaction the solvent
was evaporated and the ethyl N-Boc- isonipecotate obtained was dissolved in a mixture of ethanol (100 ml) and
water (600 ml). KOH (150 g, 2.7 mol) was added portionwise at room temperature, the product was stirred at
room temperature for 6-7 h, and 5% hydrochloric acid was added to neutrality at the end of the reaction. The
precipitated acid 2 was filtered off, washed with water, and dried in vacuo to give product (420 g, 91% based on
ester 1). N,N-Carbonyl-diimidazole (171 g, 1.06 mol) was added portionwise with stirring to a suspension of
acid 2 (220 g, 0.96 mol) in acetonitrile (800 ml). After 30 min, N,O-dimethylhydroxylamine hydrochloride
(87 g, 1.25 mol) followed by a solution of triethylamine (130 g, 1.3 mol) in acetonitrile (150 ml) were added.
The product was held for 5-7 h and the triethylamine hydrochloride was filtered off and washed with cold ethyl
acetate. The mother liquor was evaporated by 2/3 from the starting volume, diluted with ethyl acetate (200 ml),
and washed with 5% NaHCO3. The organic layer was separated, dried over Na2SO4, evaporated, and purified by
flash chromatography to give an oil which was triturated with hexane. The precipitate was filtered, washed with
hexane, and dried to give N-Boc-isonipecotic acid methylmethoxycarboxamide (3) (233 g, 81%).
N-Boc-nipecotic Acid Methoxymethylamide (6). By a similar method from the ethyl nipecotate 4 (150
g, 0.95 mol) to give the N-Boc-nipecotic acid (5) (202 g, 93% based on ester 4). This material (201 g, 0.88 mol)
gave amide 6 (177 g, 74%).
2,3-Dimethyl-4-benzaldehyde Cyclohexylimine (8). A solution of 4-methoxy-2,3-dimethylbenz-
aldehyde (27.6 g, 0.17 mol), cyclohexylamine (16.7 g, 0.17 mol), and p-toluenesulfonic acid (0.01 g) was
refluxed in benzene (300 ml) using a Dean-Stark apparatus. Solvent was evaporated and the oil obtained was
triturated with hexane to give compound 8 (38.1 g, 92%).
963

o-Tolylaldehyde Cyclohexylimine (7) was prepared similarly from o-tolylaldehyde (67.3 g, 0.56 mol).
Yield of compound 7 104.7 g (93%); bp 120-125ºC (1 mm Hg [6]).
N-Boc-3-(4-piperidyl)isoquinoline (10a). BuLi (150 ml, 0.37 mol, 2.5 molar in hexane) was added to a
solution of 2,2,6,6-tetramethylpiperidine (52.3 g, 0.37 mol) in THF (750 ml) at -45ºC under an argon
atmosphere. The mixture was held for 20-30 min at -40ºC and then from -17 to -20ºC. A solution of compound 7
(35.5 g, 0.18 mol) in THF was added dropwise. The solution obtained was dark-crimson in color and was stirred
in an argon stream for 20-30 min at -20ºC. A solution of amide 3 (58 g, 0.21 mol) in THF was added in one
portion, stirred for 30 min, and treated with a saturated solution of NH4Cl (100 ml). Solvent was evaporated,
extracted with ethyl acetate, and the organic layer was separated and evaporated. The oil obtained was treated
with 20% aqueous ammonia (100 ml), several drops of acetic acid were added, and the product was stirred for 1
h at 80ºC. It was then cooled and extracted with ethyl acetate. The organic layer was washed twice with water
(2×100 ml) to weakly basic reaction, dried over Na2SO4, and evaporated. Column chromatographic purification
gave the N-Boc-isoquinoline 10a (26.1 g, 47%).
Isoquinolines 10b, 13a,b (Tables 1 and 2) were prepared similarly.
3-(4-Piperidyl)isoquinoline Hydrochloride (11a). Dioxane saturated with hydrogen chloride (20 ml)
was added to a refluxing solution of compound 10a (3.5 g, 11 mmol) in 2-propanol (40 ml). At the end of the
reaction the precipitate was filtered off, washed with 2-propanol, and dried to give compound 11a (2.9 g, 93%).
Piperidylisoquinoline Hydrochlorides 11b, 14a,b (Tables 1 and 2) were prepared similarly.
3-(3-Piperidyl)isoquinoline Amides 14c,d (General Method). Triethylamine (0.25 ml, 2.5 mmol) was
added to a suspension of amine 14a (0.28 g, 1 mmol), 2,4-dimethoxybenzoic acid (or 3-(4-chloro-
3,5-dimethylpyrazol-1-yl)-2-methylpropionic acid) (1 mmol), and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl-
uronium tetrafluoroborate (0.32 g, 1 mmol) in acetonitrile (15 ml). The solution was stirred for 2 h, treated with
saturated potassium carbonate solution (15 ml), and extracted with ethyl acetate. The organic layer was
separated and evaporated and the residue was column chromatographed.
N-(2-Methoxybenzyl)-3-(3-piperidyl)isoquinoline (14e). Triethylamine (0.15 g, 1.5 mmol) was added
to a suspension of amine 14a (0.28 g, 1 mmol) and 2-methoxybenzaldehyde (0.13 g, 1 mmol) in acetonitrile
(15 ml). After 10-15 min, sodium triacetoxyborohydride (0.42 g, 2 mmol) was added and the product was stirred
for 1 day, and treated with saturated potassium carbonate solution (15 ml). The product was extracted with ethyl
acetate and the organic layer was separated and evaporated. The amine 14e was purified on a chromatographic
column and treated with dioxane (2-3 ml) saturated with hydrogen chloride to give the amine hydrochloride 14e
(0.22 g, 55%).
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