2-Substituted-1,2,3,4-tetrahydroisoquinolines and chiral 3-carboxyl analogues from N-benzotriazolylmethyl-N-phenethylamines

Article abstract of DOI:10.1016/S0957-4166(01)00418-9

N-Benzotriazolylmethyl-N-phenethylamines 5a-5c and 11a-11c cyclize in the presence of aluminum chloride to produce 1,2,3,4-tetrahydroisoquinolines 6a-6c and 12a-12c (70-89%) via electrophilic attack of a transient iminium cation X on the tethered phenyl r

Full text of DOI:10.1016/S0957-4166(01)00418-9

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 2427–2434
2-Substituted-1,2,3,4-tetrahydroisoquinolines and chiral
3-carboxyl analogues from
N-benzotriazolylmethyl-N-phenethylamines
Alan R. Katritzky,* Hai-Ying He, Rong Jiang and Qiuhe Long
Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville, FL 32611-7200, USA
Received 9 August 2001; accepted 19 September 2001
Abstract—N-Benzotriazolylmethyl-N-phenethylamines 5a–5c and 11a–11c cyclize in the presence of aluminum chloride to
produce 1,2,3,4-tetrahydroisoquinolines 6a–6c and 12a–12c (70–89%) via electrophilic attack of a transient iminium cation X on
the tethered phenyl ring. The Bt group in 2-benzotriazolylmethyl-1,2,3,4-tetrahydroisoquinolines 6a–6b was replaced (i) with
hydrogen by sodium borohydride to afford N-methyl-1,2,3,4-tetrahydroisoquinolines 7a–7b or (ii) by nucleophiles, such as
Grignard reagents, a silyl enol ether or triethyl phosphite, to furnish novel N-substituted-1,2,3,4-tetrahydroisoquinolines 13a–13c,
14 or 15, respectively. Optically active 3-substituted-1,2,3,4-tetrahydroisoquinolines 12a–12c were similarly prepared in high yields
without racemization. © 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
3,4-tetrahydroisoquinolines7a and N - benzotriazol-1-yl-
methyl-1,2,3,4-tetrahydroisoquinolines.7b
We now
Many alkaloids possess 1,2,3,4-tetrahydroisoquinoline
(THIQ) skeletons. Derivatives of THIQ play an impor-
tant role in medicinal chemistry due to their significant
biological and physiological activities,1 e.g. in vitro
inhibition of diazepam binding to rat cerebral cortical
membranes.2 A number of selective inhibitors of
phenylethanolamine N-methyltransferase (PNMT, an
enzyme that is involved in the biosynthesis of
epinephrine in the central nervous system) contain the
THIQ nucleus 1.3 Therefore, syntheses of substituted
1,2,3,4-tetrahydroisoquinolines continues to attract
much interest.4 Many of the classical methods for the
preparation of THIQs are intermolecular cyclization
reactions involving aromatic rings with electrophilic
substituents; for example, cyclocondensation of 1-
phenyl-2-aminopropane with formaldehyde gave 3-
methyl-1,2,3,4-tetrahydroisoquinoline (43%).5
extend these methodologies to prepare THIQ deriva-
tives 1 unsubstituted at C(1), including chiral deriva-
tives without racemization.
O
R
O
N
NH
NH
O
R
Ar
2
3
1
2. Results and discussion
2.1. Preparation of N-benzotriazolylmethyl-N-phenethyl-
amines 5a–5c and their cyclizations in the presence of
AlCl3
We have investigated intensively Mannich reactions of
benzotriazole, amines and formaldehyde (as well as
other aldehydes).8 Two methods were generally used for
the condensation: (A) reactions of amines with benzo-
triazole and formaldehyde (37% aqueous solution); (B)
reactions of amines with Bt1CH2OH. Generation of
mono(benzotriazolylmethyl) products in good yields
from primary amines requires hindered amines with a
substituent at the a-position.9 Reactions of unhindered
primary amines with 2 equivalents of BtH and formal-
dehyde give bis(benzotriazolylmethyl) products.10
We previously reported the preparation of 1-aryl-1,4-
dihydro-3-(2H)-isoquinolinones 2,6a enantiopure oxa-
zolo[3,4-b]tetrahydroisoquinolin-3-ones
36b
and
substituted 1,2,3,4-tetrahydroquinolines6c,d using benzo-
triazole methodology. Locher and Peerzada recently
reported Lewis acid-promoted intramolecular Friedel–
Crafts cyclizations to synthesize N-methyl-1,2,
* Corresponding author. Tel.: +1 352 392 0554; fax: +1 352 392 9199;
e-mail: katritzky@chem.ufl.edu
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00418-9

2428
A. R. Katritzky et al. / Tetrahedron: Asymmetry 12 (2001) 2427–2434
In the present work, using
1
equivalent of 4-
furnish
2-benzotriazolylmethyl-1,2,3,4-tetrahydroiso-
methoxyphenethylamine 4a, BtH and formaldehyde
(37% aqueous solution), we obtained no p-
MeOC6H4CH2CH2NHCH2Bt; instead the crude 1H
NMR spectrum showed that bis(benzotriazolylmethyl)
derivative 5a was formed. When 2 equivalents of BtH
and HCHO were used to react with 4a, the bis(benzo-
triazolylmethyl) intermediate 5a was furnished in 92%
yield. Bis(benzotriazolylmethyl) intermediates 5b and 5c
were obtained in 95 and 97% yields, respectively, by the
reaction of the corresponding amines 4b and 4c with
quinolines 6a–6c. The ratios of Bt1 and Bt2 isomers for
6a–6c changed to 5:1, 7:1 and 4:1, respectively. This is
consistent with our previous reports that both Bt1 and
Bt2 groups are good leaving groups in the presence of
Lewis acids, such as AlCl3, ZnBr2, BF3, etc.11 For 6a
and 6b, we report the individual 1H and 13C NMR
(using attached proton test technique) data for each of
their Bt1 and Bt2 isomers. The chemical shifts of the
carbons attached to the benzotriazol-2-yl group appear
at a lower field (76.7 ppm, for both 6a and 6b) com-
pared to those of the carbons attached to the benzotri-
azol-1-yl group (68.9 ppm, for both 6a and 6b).8e
Bt1CH2OH in the presence of sodium sulfate. H NMR
1
spectral analysis showed that 5a–5b were obtained as
mixtures of Bt1 and Bt2 isomers with ratios of 22:1 and
4:1, respectively; while 5c was obtained as a sole Bt1
isomer. It is difficult to distinguish the proton and
carbon NMR peaks of the minor Bt2 isomers from the
major Bt1 isomers in 5a–5b due to their overlap with
Treatment
of
2-benzotriazolylmethyl-1,2,3,4-tetra-
hydroisoquinolines 6a–6b with 2 equivalents of sodium
borohydride in THF at room temperature readily
replaced the benzotriazolyl group with hydrogen to give
N-methyl-1,2,3,4-tetrahydroisoquinolines 7a–7b in 83
and 87% yield, respectively (Scheme 1).
each other; therefore we report only the H and 13C
1
NMR data for the major Bt1 isomers.
Treatment of 5a–5c with aluminum chloride in reflux-
ing CH2Cl2 was found to eliminate only one benzotria-
zolyl moiety to give 2-benzotriazolylmethyl-1,2,3,
4-tetrahydroisoquinolines 6a–6c in excellent yields
(Scheme 1). Elimination of the benzotriazolyl anion in
5a–5c generates the iminium cation X, which undergoes
electrophilic substitution on the tethered phenyl ring to
2.2. Preparation of optically active 3-substituted-
1,2,3,4-tetrahydroisoquinolines 12a–12c
A similar methodology was used for the syntheses of
optically active 3-substituted-1,2,3,4-tetrahydroiso-
quinolines 12a,12b starting from chiral N-Boc-
R3
R3
R2
R1
R2
R1
i
ii
N+
N
-
NH2
Bt
Bt
Bt
Bt
4a-4c
5a-5c
X
H+
R3
R2
R2
R1
NaBH4
R3 = H
N
MeO
Me
N
7a, R2 = H
7b, R2 = MeO
Bt
6a-6c
Bt = benzotriazol-1-yl and -2-yl
i) For 5a, using method A: BtH and HCHO (37%);
For 5b, 5c, using method B: Bt1CH2OH
ii) AlCl3/CH2Cl2, reflux
Compd
R1
MeO
MeO
H
R2
R3
H
Ya (%) of 5 Ya (%) of 6
a
b
c
H
92
95
97
86
89
82
MeO
H
H
Ph
a Isolated yield.
Scheme 1.

A. R. Katritzky et al. / Tetrahedron: Asymmetry 12 (2001) 2427–2434
2429
a-Phe 8. Following a recently published procedure,12
reaction of 8 with iso-butyl chloroformate in the pres-
ence of N-methylmorpholine generated the mixed anhy-
dride, which with morpholine or N,N-dibutylamine
afforded N-Boc-a-amino amides 9a,9b in 92 and 89%
yields, respectively. Treatment of crude 9a,9b with HCl
(ca. 1 M in EtOAc) readily removed the protecting
N-Boc group. a-Amino amide 10a was obtained as the
hydrochloride salt in 87% yield; while 10b was obtained
as its free base in 92% yield. Compounds 10a,10b were
used directly for subsequent reactions without further
purification. Reaction of 10a–10c (10c, R=OMe, pur-
chased from Aldrich) with 1 equivalent of benzotriazole
and formaldehyde gave benzotriazolylmethyl intermedi-
ates 11a–11c in 91, 93 and 92% yields, respectively. The
1H NMR spectra showed that 11a,11b were obtained as
a mixture of Bt1 and Bt2 isomers in 6:1 and 8:1 ratio,
respectively; while 11c was obtained as a sole Bt1
isomer.
2.3. Nucleophilic substitution of 2-benzotriazolylmethyl-
7-methoxy-1,2,3,4-tetrahydroisoquinoline 6a with Grig-
nard reagents, a silyl enol ether or triethyl phosphite
Nucleophilic substitution of 6a with 2 equivalents of
Grignard reagents (phenyl, n-pentyl or phenylethynyl
magnesium bromide) in dry THF produced novel N-
substituted-1,2,3,4-tetrahydroisoquinolines
13a–13c
(Scheme 3). The structures of 13a–13c were clearly
supported by their 1H and 13C NMR spectra and
microanalysis or HRMS results. We further investi-
gated the nucleophilic substitution reaction of 6a with a
silyl enol ether in the presence of BF3·Et2O and found
that the benzotriazolyl group in 6a can be easily substi-
tuted by such an organosilyl nucleophile to afford 14 in
63% yield. Treatment of 6a with 1.2 equivalents of
triethyl phosphite in the presence of ZnBr2 furnished
diethyl
[7-methoxy-3,4-dihydro-2(1H)-isoquinolinyl]-
methylphosphonate 15 in 80% yield.
Subsequent treatment of 11a–11c with aluminum chlo-
ride in refluxing CH2Cl2 readily eliminated the Bt anion
to generate the iminium cation, which underwent elec-
trophilic substitution on the tethered phenyl ring to
furnish optically active 3-substituted-1,2,3,4-tetra-
hydroisoquinolines 12a–12c. The optical activity of 12c
matches that reported earlier.13 This indicates that no
racemization occurred for all of the above transforma-
tions under the mild reaction conditions. An earlier
paper reported that the treatment of phenylalanine with
formaldehyde in the presence of concentrated hydro-
chloric acid afforded 1,2,3,4-tetrahydro-3-isoquinoline-
carboxylic acid; however, enantiopure phenylalanine
was partially racemized under the strongly acidic condi-
tions (Scheme 2).3
3. Conclusion
In summary, a simple and efficient approach to 1,2,3,4-
tetrahydroisoquinolines has been reported by the treat-
ment of N-benzotriazolylmethyl-N-phenethylamines
5a–5c and 11a–11c with aluminum chloride. No race-
mization was observed when chiral phenethylamines
10a–10c were used as starting materials. Reduction of
6a–6b with sodium borohydride easily replaces the ben-
zotriazolyl group with hydrogen and nucleophilic sub-
stitutions of 6a with Grignard reagents, a silyl enol
ether or triethyl phosphite furnish novel N-substituted-
1,2,3,4-tetrahydroisoquinolines 13a–13c, 14 or 15.
O
O
COOH
R
i
Ph
Boc
Ph
Boc
ii
Ph
R
N
N
NH2
H
H
8
9a-9b
10a-10b
O
O
O
R
AlCl3
Ph
Bt
R
iii
Ph
R
H
N
H
N
H
NH2
10a-10c#
11a-11c
12a-12c
a, R =
; b, R = N(C H -n) ; c, R = OMe
4 9 2
N
O
i) morpholine or HN(C4H9-n)2; N-methylmorpholine, ClCOOBu-i;
ii) HCl/EtOAc; iii) BtH, HCHO (37%)
# 10a and 10c (from Aldrich) were used as their hydrochloride salts.
Therefore, one equivalent of NaOH was used in step iii).
Scheme 2.

2430
A. R. Katritzky et al. / Tetrahedron: Asymmetry 12 (2001) 2427–2434
RMgBr
N
N
MeO
MeO
13a, R = Ph
Bt
R
6a
OTMS
Ph
13b, R = n-C5H11
13c, R = C6H5C
C
P(OEt)3
ZnBr2
.
BF3 Et2O
O
P
N
Ph
OEt
OEt
N
MeO
MeO
O
15
14
Scheme 3.
4. Experimental
3.74 (s, 3H), 3.11 (t, J=6.8 Hz, 2H), 2.75 (t, J=6.8 Hz,
2H); 13C NMR l (Bt1) 158.0, 146.0, 133.1, 130.6, 129.4,
127.7, 124.1, 119.9, 113.8, 109.8, 64.4, 55.1, 52.3, 33.0.
Anal. calcd for C23H23N7O: C, 66.81; H, 5.61; N, 23.71.
Found: C, 66.65; H, 5.63; N, 23.79%.
Melting points were determined using a Bristoline hot-
1
stage microscope and are uncorrected. H (300 MHz)
and 13C NMR (75 MHz) spectra were recorded on a
Gemini 300 NMR spectrometer in CDCl3 (with TMS
for H and chloroform-d for 13C as the internal refer-
1
4.1.2. N,N-Bis(benzotriazolylmethyl)-N-(3,4-dimethoxy-
phenethyl)amine 5b. Method B: A mixture of Bt1 and
Bt2 isomers in a 4:1 ratio; sticky oil; yield 95%; 1H
NMR l (Bt1) 8.07 (d, J=8.3 Hz, 2H), 7.55–7.36 (m,
6H), 6.65–6.52 (m, 2H), 6.43 (d, J=1.7 Hz, 1H), 5.64
(s, 4H), 3.80 (s, 3H), 3.49 (s, 3H), 3.13 (t, J=7.0 Hz,
2H), 2.73 (t, J=7.0 Hz, 2H); 13C NMR (Bt1) 148.6,
147.3, 145.8, 132.9, 131.1, 127.7, 124.1, 120.3, 119.8,
109.7, 64.6, 55.6, 55.5, 52.2, 33.5. Anal. calcd for
C24H25N7O2: C, 65.00; H, 5.68; N, 22.11. Found: C,
64.64; H, 6.04; N, 21.71%.
ence), unless otherwise stated. HRMS were measured
on an AEI-30 mass spectrometer. Optical rotation val-
ues were measured on a Perkin–Elmer 341 polarimeter
with the use of the sodium D line. Column chromatog-
raphy was performed on silica gel (200–425 mesh). All
of the reactions were carried out under N2.
4.1. General procedure for the syntheses of bis(benzo-
triazolylmethyl) intermediates 5a–5c
Method A: Benzotriazole (2.38 g, 20 mmol) and an
appropriate primary amine 4 (10 mmol) were stirred in
MeOH (30 mL)/H2O (5 mL) at 25°C for 10 min.
Formaldehyde (37% aqueous solution, 1.62 g, 20 mmol)
was added to the vigorously stirred mixture. After 4 h,
a thick suspension was filtered and the precipitate was
washed with cool MeOH to give the desired product.
4.1.3. N,N-Bis-(1H-1,2,3-benzotriazol-1-ylmethyl)-2,2-
diphenyl-1-ethanamine 5c. Method B: colorless flakes
1
(from CHCl3/hexanes); yield 97%; mp 120–121°C; H
NMR l 8.04 (d, J=8.2 Hz, 2H), 7.41–7.33 (m, 4H),
7.31–7.25 (m, 2H), 7.16–7.11 (m, 6H), 7.09–7.02 (m,
4H), 5.54 (s, 4H), 4.26 (t, J=8.1 Hz, 1H), 3.46 (d,
J=8.1 Hz, 2H); 13C NMR l 146.0, 141.5, 133.0, 128.4,
127.8, 127.7, 126.6, 124.1, 119.8, 109.8, 64.7, 55.3, 49.1.
Anal. calcd for C28H25N7: C, 73.18; H, 5.48; N, 21.34.
Found: C, 72.95; H, 5.29; N, 21.42%.
Method B: A mixture of an appropriate amine 4 (10
mmol), Bt1CH2OH (20 mmol) and Na2SO4 (anhydrous,
4 g) was stirred in MeOH (40 mL) at 25°C for 10 h.
The solid was filtered off and the solvent was evapo-
rated in vacuo to give the desired product.
4.2. Preparation of N-benzotriazolylmethyl-1,2,3,4-tetra-
hydroisoquinolines 6a–6c via annulation of bis(benzotri-
azolylmethyl) intermediates 5a–5c
Bis(benzotriazolylmethyl) intermediates 5a–5c can be
used for the subsequent cyclization without further
purification. For microanalysis purposes, the solid
formed was recrystallized from appropriate solvents or
the sticky oil was purified by column chromatography.
To a stirred solution of 5a–5c (4 mmol) in dry CH2Cl2
(30 mL), AlCl3 (2.13 g, 16 mmol) was added. The
reaction mixture was refluxed for 10 h. After cooling, 2
M NaOH (20 mL) was added. The separated aqueous
phase was extracted with CH2Cl2. The combined
organic fractions were washed with 2 M NaOH, brine
and dried over anhydrous MgSO4. Removal of solvents
in vacuo gave a solid, which was recrystallized from
appropriate solvents to afford the pure products 6a,6b.
4.1.1.
N,N-Bis(benzotriazolylmethyl)-N-(4-methoxy-
phenethyl)amine 5a. Method A: A mixture of Bt1 and
Bt2 isomers in 22:1 ratio; colorless needles (from
CHCl3/Et2O); yield 92%; mp 96–97°C; 1H NMR l (Bt1)
8.07 (d, J=8.1 Hz, 2H), 7.54–7.36 (m, 6H), 6.90 (d,
J=8.3 Hz, 2H), 6.68 (d, J=8.3 Hz, 2H), 5.61 (s, 4H),

A. R. Katritzky et al. / Tetrahedron: Asymmetry 12 (2001) 2427–2434
2431
4.2.1. 2-Benzotriazolylmethyl-7-methoxy-1,2,3,4-tetra-
hydroisoquinoline 6a. A mixture of Bt1 and Bt2 isomers
in 5:1 ratio; colorless prisms (from CH2Cl2/Et2O); yield
layers were dried over anhydrous Na2SO4. After
removal of the solvents in vacuo, the residue was
purified by column chromatography with hexanes/
EtOAc (2:1) as an eluent to give N-methyl-1,2,3,4-tetra-
hydroisoquinolines 7a–7b.
1
86%; mp 127–129°C; H NMR l (Bt1) 8.05 (d, J=8.3
Hz, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.48 (dd, J=7.2, 7.2
Hz, 1H), 7.35 (dd, J=7.6, 7.6 Hz, 1H), 6.94 (d, J=8.4
Hz, 1H), 6.66 (dd, J=8.4, 2.5 Hz, 1H), 6.50 (d, J=2.5
Hz, 1H), 5.58 (s, 2H), 3.79 (s, 2H), 3.71 (s, 3H), 2.92 (t,
J=5.3 Hz, 2H), 2.81 (t, J=5.4 Hz, 2H), [l (Bt2)
7.90–7.85 (m, 2H), 7.40–7.34 (m, 2H), 6.94 (d, J=8.4
Hz, 1H), 6.66 (dd, J=8.4, 2.5 Hz, 1H), 6.53 (d, J=2.5
Hz, 1H), 5.73 (s, 2H), 3.88 (s, 2H), 3.71 (s, 3H), 3.01 (t,
J=5.3 Hz, 2H), 2.83 (t, J=5.4 Hz, 2H)]; 13C NMR l
(Bt1): 157.5 (q), 145.8 (q), 134.5 (q), 133.7 (q), 129.5,
127.4, 125.4 (q), 123.8, 119.7, 112.7, 110.9, 109.9, 68.9
(Bt1CH2), 55.1 (OCH3), 52.3, 48.6, 28.2, [l (Bt2) 157.5
(q), 144.1 (q), 134.8 (q), 126.3, 125.5 (q), 118.1, 112.5,
110.8, 109.9, 76.7 (Bt2CH2), 55.1 (OCH3), 51.7, 48.4,
28.5]. Anal. calcd for C17H18N4O: C, 69.37; H, 6.16; N,
19.03. Found: C, 69.34; H, 6.02; N, 19.16%.
4.3.1. 7-Methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline
7a. Colorless flakes; yield 83%; mp 50–51°C (lit.14 bp
126°C/8 mmHg; mp 50–51°C); 1H NMR l 7.09 (d,
J=8.6 Hz, 1H), 6.80 (dd, J=8.4, 2.3 Hz, 1H), 6.54 (d,
J=2.0 Hz, 1H), 4.21 (d, J=12.3 Hz, 1H), 3.81 (d,
J=12.3 Hz, 1H), 3.78 (s, 3H), 3.20 (t, J=8.4 Hz, 2H),
2.93 (t, J=6.2 Hz, 2H), 2.62 (s, 3H, NCH3); 13C NMR
l 148.2, 147.9, 122.4, 121.8, 110.9, 109.1, 61.0, 56.3,
55.7, 46.6, 23.9.
4.3.2.
6,7-Dimethoxy-2-methyl-1,2,3,4-tetrahydroiso-
quinoline 7b. Colorless flakes; yield 87%; mp 83–84°C
(lit.15 mp 83–84°C); H NMR l 6.66 (s, 1H), 6.50 (s,
1
1H), 4.16 (d, J=16.0 Hz, 1H), 3.86 (s, 3H, OCH3), 3.84
(s, 3H, OCH3), 3.77 (d, J=16.0 Hz, 1H), 3.17 (t, J=6.2
Hz, 2H), 2.91 (t, J=6.1 Hz, 2H), 2.62 (s, 3H, NCH3);
13C NMR l 148.1, 147.9, 122.4, 121.8, 110.9, 109.1,
61.0, 56.3, 55.8 (OCH3), 55.7 (OCH3), 46.6, 23.9.
4.2.2.2-Benzotriazolylmethyl-6,7-dimethoxy-1,2,3,4-tetra-
hydroisoquinoline 6b. A mixture of Bt1 and Bt2 isomers
in 7:1 ratio; colorless needles (from CH2Cl2/Et2O); yield
1
89%; mp 136–137°C; H NMR l (Bt1) 8.06 (d, J=8.4
Hz, 1H), 7.69 (d, J=8.4 Hz, 1H), 7.50 (dd, J=7.2, 7.2
Hz, 1H), 7.36 (dd, J=7.5, 7.5 Hz, 1H), 6.55 (s, 1H),
6.47 (s, 1H), 5.61 (s, 2H, Bt1CH2), 3.81 (s, 3H), 3.79 (s,
3H), 3.76 (s, 2H), 2.94 (t, J=5.5 Hz, 2H), 2.82 (t,
J=5.3 Hz, 2H), [l (Bt2) 7.91–7.88 (m, 2H), 7.40–7.37
(m, 2H), 6.55 (s, 1H), 6.50 (s, 1H), 5.74 (s, 2H,
Bt2CH2), 3.84 (s, 3H), 3.83 (s, 2H), 3.81 (s, 3H), 3.03 (t,
J=5.9 Hz, 2H), 2.82 (t, J=5.3 Hz, 2H)]; 13C NMR l
(Bt1) 147.4 (q), 147.1 (q), 145.7 (q), 133.6 (q), 127.3,
125.1 (q), 125.0 (q), 123.7, 119.5, 111.1, 109.9, 109.1,
68.9 (Bt1CH2), 55.7, 51.8, 48.4, 28.6, [l (Bt2) 147.3 (q),
147.1 (q), 144.0 (q), 126.3, 125.5 (q), 125.1 (q), 118.1,
109.9, 109.1, 76.7 (Bt2CH2), 55.7, 51.1, 48.2, 28.9].
Anal. calcd for C18H20N4O2: C, 66.65; H, 6.21; N,
17.27. Found: C, 66.52; H, 6.45; N, 17.53%.
4.4. Procedure for the preparation of chiral a-amino
amides 9a,9b from N-Boc-Phe 8
Toacoldsolution(−15°C)of(2S)-2-({[(1,1-dimethylethyl)-
oxy]carbonyl}amino)-3-phenylpropanoic acid (8, 2.65 g,
10 mmol) and 4-methylmorpholine (1.01 g, 10 mmol) in
dry THF (30 mL), iso-butyl chloroformate (1.36 g, 10
mmol) in THF (5 mL) was added dropwise in 15 min.
After stirring for another 15 min, morpholine (0.87 g,
10 mmol) or N,N-dibutylamine (1.29 g, 10 mmol) was
added. Then, the reaction mixture was stirred at rt for
2 h. After evaporation of the solvent in vacuo, the
residue was diluted with EtOAc (80 mL) and the
organic phase was washed with 10% Na2CO3, 0.1 M
HCl and brine and dried over anhydrous MgSO4.
Evaporation of the solvent in vacuo gave 9a,9b, which
was used for the subsequent step without further purifi-
cation.
4.2.3.
2-(Benzotriazolylmethyl)-4-phenyl-1,2,3,4-tetra-
hydroisoquinoline 6c. A mixture of Bt1 and Bt2 isomers
1
in 4:1 ratio; sticky oil; yield 82%; H NMR l (Bt1) 8.04
(d, J=8.2 Hz, 1H), 7.51 (d, J=8.2 Hz, 1H), 7.43 (dd,
J=7.2, 7.2 Hz, 1H), 7.34 (dd, J=7.3, 7.3 Hz, 1H),
7.26–7.20 (m, 3H), 7.20–7.00 (m, 5H), 6.86 (d, J=7.5
Hz, 1H), 5.55 (s, 2H), 4.27–4.21 (m, 1H), 3.94 (d,
J=5.6 Hz, 2H), 3.25 (dd, J=11.5, 5.1 Hz, 1H), 2.98
(dd, J=11.5, 6.4 Hz, 1H). 13C NMR (Bt1) 145.9, 144.4,
136.5, 133.9, 129.6, 128.9, 128.2, 127.5, 126.5, 126.4,
126.3, 126.2, 123.9, 119.8, 118.3, 110.0, 69.2, 56.6, 52.7,
45.6. Anal. calcd for C22H20N4: C, 77.62; H, 5.92.
Found: C, 77.39; H, 6.24%.
4.4.1.
tert-Butyl
N-[(1S)-1-benzyl-2-morpholino-2-
oxoethyl]carbamate 9a12. Colorless oil; yield 92%; 1H
NMR l 7.32–7.19 (m, 5H), 5.49 (d, J=8.6 Hz, 1H),
4.84–4.76 (m, 1H), 3.67–3.38 (m, 5H), 3.33–3.25 (m,
1H), 3.06–2.84 (m, 4H), 1.43 (s, 9H); 13C NMR l 170.2,
155.0, 136.3, 129.5, 128.5, 127.0, 79.7, 66.4, 66.0, 50.7,
45.9, 42.1, 40.4, 28.3.
4.4.2. tert-Butyl N-[(1S)-1-benzyl-2-(dibutylamino)-2-
oxoethyl]carbamate 9b. Colorless oil; yield 89%; [h]2D5=
+6.0 (c 1.84, CHCl3); H NMR l 7.27–7.19 (m, 5H),
5.35 (d, J=8.9 Hz, 1H), 4.78–4.70 (m, 1H), 3.47–3.38
(m, 1H), 3.07–2.85 (m, 5H), 1.41 (s, 9H), 1.35–1.81 (m,
8H), 0.95–0.83 (m, 6H); 13C NMR l 171.0, 154.8,
136.6, 129.4, 128.2, 126.6, 79.2, 51.3, 47.3, 45.9, 40.3,
30.8, 29.4, 28.1, 20.0, 19.8, 13.7, 13.6. Anal. calcd for
C22H36N2O3: C, 70.18; H, 9.64; N, 7.44. Found: C,
69.97; H, 9.31; N, 7.62%.
1
4.3. General procedure for reduction of N-benzotria-
zolylmethyl-1,2,3,4-tetrahydroisoquinolines 6a–6b with
NaBH4
A mixture of 6a or 6b (2 mmol) and NaBH4 (0.16 g, 4
mmol) was stirred in dry THF (15 mL) at 25°C
overnight. The reaction mixture was quenched with
water and extracted with Et2O. The combined organic

2432
A. R. Katritzky et al. / Tetrahedron: Asymmetry 12 (2001) 2427–2434
To a stirred solution of 9a,9b (10 mmol) in EtOAc (30
mL), HCl in EtOAc (ca. 1 M, 20 mL) was added. The
mixture was stirred at rt until TLC showed disappear-
ance of the starting material (about 15 h). For 10a, the
precipitate formed was filtered and washed with ether
to give its hydrochloride salt. For 10b, the clear solu-
tion was washed with 1 M NaOH, brine, dried over
anhydrous K2CO3 and evaporated to give 10b.
4.5.2. (2S)-2-[(Benzotriazolylmethyl)amino]-N,N-dibutyl-
3-phenylpropanamide 11b. A mixture of Bt1 and Bt2
isomers in 8:1 ratio; light yellow oil; yield 93%; [h]2D5=
1
+47.7 (c 1.70, CHCl3); H NMR l (Bt1) 8.00 (d, J=8.2
Hz, 1H), 7.54 (d, J=8.3 Hz, 1H), 7.42 (dd, J=7.3, 7.3
Hz, 1H), 7.34 (dd, J=7.3, 7.3 Hz, 1H), 7.21–7.15 (m,
3H), 7.07 (d, J=7.5 Hz, 2H), 5.43 (br s, 2H), 3.80–3.74
(m, 1H), 3.20 (br s, 1H, NH), 3.10–3.04 (m, 1H),
3.00–2.93 (m, 1H), 2.87–2.82 (m, 2H), 2.79–2.74 (m,
2H), 1.19–1.08 (m, 4H), 0.95–0.87 (m, 4H), 0.82 (t,
J=7.7 Hz, 6H); 13C NMR l (Bt1) 172.4 (CꢀO), 146.3,
137.5, 132.4, 129.1, 128.2, 127.2, 126.5, 123.9, 119.6,
110.2, 62.1, 56.6, 47.1, 46.1, 40.6, 30.7, 29.4, 20.1, 20.0,
13.7, 13.6. Anal. calcd for C24H33N5O: C, 70.73; H,
8.16. Found: C, 70.74; H, 8.48%.
4.4.3. (2S)-1-Morpholino-1-oxo-3-phenyl-2-propanamin-
ium chloride 10a. Colorless needles (from EtOH); yield
1
87%; mp 231–233°C; [h]2D5=+69.5 (c 1.73, EtOH); H
NMR l (DMSO-d6) 8.65 (br s, 3H), 7.37–7.24 (m, 5H),
4.64–4.59 (m, 1H), 3.49–3.22 (m, 7H), 2.96–2.87 (m,
2H), 2.71–2.68 (m, 1H); 13C NMR l (DMSO-d6) 166.9,
134.7, 129.8, 128.6, 127.3, 65.6, 65.3, 49.4, 45.6, 42.0,
37.0. Anal. calcd for C13H19ClN2O2: C, 57.67; H, 7.07;
N, 10.35. Found: C, 57.28; H, 7.20; N, 10.04%.
4.5.3. Methyl (2S)-2-[(1H-1,2,3-benzotriazol-1-ylmethyl)-
amino]-3-phenylpropanoate 11c. Colorless needles (from
CHCl3); yield 92%; mp 96–97°C; [h]2D5=+18.3 (c 2.17,
1
EtOH); H NMR l 8.03 (d, J=8.3 Hz, 1H), 7.42–7.38
(m, 2H), 7.38–7.32 (m, 1H), 7.19–7.13 (m, 3H), 7.02–
7.00 (m, 2H), 5.56–5.41 (m, 2H), 3.70–3.60 (m, 1H),
3.46 (s, 3H), 2.97 (dd, J=13.7, 5.2 Hz, 1H), 2.79 (dd,
J=13.6, 8.1 Hz, 1H), 2.69 (br s, NH, 1H); 13C NMR l
173.6 (CꢀO), 146.1, 136.4, 132.4, 128.9, 128.3, 127.3,
126.7, 123.9, 119.8, 109.4, 61.4, 59.4, 51.9, 39.2. Anal.
calcd for C17H18N4O2: C, 65.79; H, 5.85; N, 18.05.
Found: C, 65.77; H, 6.22; N, 18.13%.
4.4.4. (2S)-2-Amino-N,N-dibutyl-3-phenylpropanamide
10b. Colorless oil; yield 92%; [h]2D5=+50.7 (c 1.81,
1
EtOH); H NMR l 7.32–7.18 (m, 5H), 3.81 (t, J=7.0
Hz, 1H), 3.50–3.43 (m, 1H), 3.10–2.85 (m, 4H), 2.76
(dd, J=13.2, 7.3 Hz, 1H), 1.78 (s, 2H), 1.52–1.32 (m,
4H), 1.32–1.17 (m, 4H), 0.92 (t, J=7.2 Hz, 3H), 0.89 (t,
J=7.2 Hz, 3H); 13C NMR l 174.2, 137.8, 129.2, 128.3,
126.5, 52.9, 47.0, 46.0, 42.9, 31.2, 29.6, 20.1, 19.9, 13.7,
13.6. Anal. calcd for C17H28N2O: C, 73.87; H, 10.21; N,
10.13. Found: C, 73.92; H, 10.36; N, 9.97%.
4.6. General procedure for the preparation of chiral
3-substituted-1,2,3,4-tetrahydroisoquinolines 12a–12c via
annulation of 11a–11c
4.5. General procedure for the preparation of Bt inter-
A mixture of 11a–11c (4 mmol) and AlCl3 (2.13 g, 16
mmol) was refluxed in dry CH2Cl2 (30 mL) for 10 h.
After cooling, 2 M NaOH (20 mL) was added. The
separated aqueous phase was additionally extracted
with CH2Cl2. The combined organic phase was washed
with 2 M NaOH, brine and dried over anhydrous
MgSO4. After removal of the solvent in vacuo, the
residue was purified by column chromatography with
hexanes/EtOAc/Et3N (2:1:0.005) as an eluent to give
12a–12c.
mediates 11a–11c
To a solution of benzotriazole (0.36 g, 3 mmol), hydro-
chloride salt 10a,10c (3 mmol) and NaOH (0.12 g, 3
mmol) in MeOH/H2O (20/10 mL), formaldehyde (0.24
g, 3 mmol, 37% aqueous solution) was added. The
mixture was stirred at rt for 5 h. For 11a,11c, the
precipitate formed was filtered, washed with cool H2O
and EtOH, and recrystallized from appropriate sol-
vents. For 11b, NaOH was not needed and, the clear
solution was concentrated, extracted with CH2Cl2, and
dried over anhydrous Na2SO4. Evaporation of solvents
in vacuo afforded 11b, which was used directly for the
subsequent reaction.
4.6.1.
Morpholino[(3S)-(1,2,3,4-tetrahydro-3-isoquino-
linyl)]methanone 12a. Colorless needles; yield 70%; mp
1
113–114°C; [h]2D5=−89.4 (c 2.03, EtOH); H NMR l
7.16–7.07 (m, 3H), 7.04–7.01 (m, 1H), 4.08 (s, 2H), 3.87
(dd, J=11.1, 4.4 Hz, 1H), 3.80–3.42 (m, 6H), 3.62–3.49
(m, 2H), 2.98 (dd, J=16.3, 11.2 Hz, 1H), 2.76 (dd,
J=16.4, 4.2 Hz, 1H), 1.99 (br s, 1H, NH); 13C NMR l
171.3 (CꢀO), 135.2, 133.4, 129.2, 126.2, 126.1, 125.6,
66.7, 66.6, 53.0, 47.2, 45.8, 42.1, 31.3. Anal. calcd for
C14H18N2O2: C, 68.27; H, 7.37; N, 11.37. Found: C,
68.63; H, 7.73; N, 11.37%.
4.5.1.
(2S)-2-[(Benzotriazolylmethyl)amino]-1-mor-
pholino-3-phenyl-1-propanone 11a. A mixture of Bt1 and
Bt2 isomers in 6:1 ratio; colorless flakes (from EtOAc);
1
yield 91%; mp 91–92°C; [h]2D5=+151 (c 2.39, EtOH); H
NMR l (Bt1) 8.01 (d, J=8.2 Hz, 1H), 7.60 (d, J=8.2
Hz, 1H), 7.48 (dd, J=7.2, 7.2 Hz, 1H), 7.36 (dd,
J=7.5, 7.5 Hz, 1H), 7.28–7.13 (m, 3H), 7.10–7.02 (m,
2H), 5.50 (s, 2H), 3.90–3.78 (br s, 1H, NH), 3.35–3.00
(m, 6H), 2.91–2.82 (m, 2H), 2.77–2.59 (m, 3H); 13C
NMR l (Bt1) 171.4 (CꢀO), 146.0, 136.6, 132.2, 129.2,
128.3, 127.3, 126.8, 124.0, 119.3, 109.8, 65.8, 65.4, 61.9,
55.9, 45.1, 41.6, 41.0. Anal. calcd for C20H23N5O2: C,
65.73; H, 6.34; N, 19.16. Found: C, 66.05; H, 6.48; N,
19.20%.
4.6.2. (3S)-N,N-Dibutyl-1,2,3,4-tetrahydro-3-isoquino-
linecarboxamide 12b. Colorless oil; yield 80%; [h]2D5=
1
−53.2 (c 1.76, CHCl3); H NMR l 7.18–7.03 (m, 4H),
4.11 (s, 2H), 3.83 (dd, J=10.8, 3.9 Hz, 1H), 3.40–3.25
(m, 4H), 3.01 (dd, J=16.5, 10.8 Hz, 1H), 2.74 (dd,
J=16.5, 3.6 Hz, 1H), 1.89 (br s, 1H, NH), 1.60–1.53
(m, 4H), 1.37–1.26 (m, 4H), 0.93 (t, J=7.3 Hz, 6H); 13
C

A. R. Katritzky et al. / Tetrahedron: Asymmetry 12 (2001) 2427–2434
2433
NMR l 172.4, 135.4, 133.9, 129.2, 126.1, 126.0, 125.6,
4.8. Procedure for the nucleophilic substitution of 6a
with a silyl enol ether
53.0, 47.4, 47.3, 45.8, 31.7, 31.6, 29.7, 20.1, 20.0, 13.8,
13.7. Anal. calcd for C18H28N2O: C, 74.95; H, 9.78; N,
9.71. Found: C, 74.64; H, 10.07; N, 9.61%.
To a solution of 6a (0.59 g, 2 mmol) in dry THF (30
mL) at 0°C, 1-phenylvinyl trimethylsilyl ether (0.58 g, 3
mmol) and BF3·Et2O (2 mmol, 0.28 g) were added. The
mixture was stirred at 0°C for 2 h and at room temper-
ature for a further 10 h. The reaction mixture was
washed with 2 M NaOH, brine and the aqueous phase
was extracted with Et2O. The combined organic layers
were dried over anhydrous Na2SO4. After removal of
the solvent in vacuo, the residue was purified by
column chromatography with hexanes/EtOAc (2:1) as
an eluent to afford 14.
4.6.3. Methyl (3S)-1,2,3,4-tetrahydro-3-isoquinolinecar-
boxylate 12c. Light yellow oil; yield 72%; [h]2D5=−126 (c
1
1.28, CH2Cl2), {lit.13 [h]D22=−124 (c 1.28, CH2Cl2)}; H
NMR l 7.15–7.06 (m, 3H), 7.06–6.98 (m, 1H), 4.08 (d,
J=3.3 Hz, 2H), 3.76 (s, 3H), 3.72 (dd, J=10.1, 4.8 Hz,
1H), 3.18–2.90 (m, 2H), 2.20 (br s, 1H, NH); 13C NMR
l 173.4 (CꢀO), 134.7, 132.9, 129.0, 126.1, 126.0, 125.9,
55.7, 52.0, 47.2, 31.5; MS (EI): 191 (M+, 3), 176 (M+−
CH3, 3), 132 (M+−COOMe, 100). Anal. calcd for
C11H13NO2: C, 69.09; H, 6.85. Found: C, 69.10; H,
6.69%.
4.8.1. 3-[7-Methoxy-3,4-dihydro-2(1H)-isoquinolinyl]-1-
phenyl-1-propanone 14. Pale yellow oil; yield 63%; H
1
4.7. General procedure for the nucleophilic substitution
of 6a with Grignard reagents
NMR l 7.98 (d, J=7.2 Hz, 2H), 7.55 (t, J=7.2 Hz,
1H), 7.45 (dd, J=7.6, 7.6 Hz, 2H), 7.00 (d, J=8.1 Hz,
1H), 6.70 (dd, J=8.4, 2.7 Hz, 1H), 6.56 (d, J=2.1 Hz,
1H), 3.75 (s, 3H), 3.67 (s, 2H), 3.30 (t, J=7.2 Hz, 2H),
3.00 (t, J=8.1 Hz, 2H), 2.84–2.79 (m, 4H); 13C NMR l
199.0, 157.5, 136.9, 135.5, 133.0, 129.5, 128.5, 128.0,
126.2, 112.5, 111.2, 56.2, 55.2, 52.8, 51.3, 36.7, 28.2.
Anal. calcd for C19H21NO2: N, 4.74. Found: N, 4.79%.
HRMS calcd for C19H22NO2 296.1651 (M+1), found
296.1655.
To a cold solution (−40°C) of 2-benzotriazolylmethyl-7-
methoxy-1,2,3,4-tetrahydroisoquinoline (6a, 0.88 g, 3
mmol) in dry THF (30 mL), an appropriate Grignard
reagent (6 mmol) was added and the mixture was
stirred at −40°C for 2 h and at rt for a further 10 h. The
reaction mixture was washed with 2 M NaOH, and the
aqueous phase was extracted with Et2O. The combined
organic layers were washed with brine and dried over
anhydrous Na2SO4. After removal of solvents in vacuo,
the residue was purified by column chromatography
with hexanes/EtOAc (3:1) as an eluent to afford 13a–
13c.
4.9. Procedure for the nucleophilic substitution of 6a
with triethyl phosphite
To a solution of 6a (0.59 g, 2 mmol) in dry THF (20
mL) at 0°C, ZnBr2 (0.90 g, 4 mmol) was added. The
solution was stirred for 20 min before triethyl phosphite
(0.40 g, 2.4 mmol) was added dropwise. After stirring at
room temperature for 10 h, most of the THF was
evaporated. The residue was diluted with EtOAc, and
the solution was washed with 2 M NaOH, water and
dried over Na2SO4. After removal of solvent in vacuo,
the residue was purified by column chromatography
with hexanes/EtOAc (3:1–1:1) as an eluent to afford 15.
4.7.1. 2-Benzyl-7-methoxy-1,2,3,4-tetrahydroisoquinoline
1
13a. Colorless oil; yield 63%; H NMR l 7.40–7.26 (m,
5H), 6.99 (d, J=8.4 Hz, 1H), 6.70 (d, J=8.4 Hz, 1H),
6.51 (s, 1H), 3.72 (s, 3H), 3.67 (s, 2H), 3.59 (s, 2H), 2.81
(t, J=5.3 Hz, 2H), 2.74 (t, J=5.4 Hz, 2H); 13C NMR
l 157.5, 138.3, 135.8, 129.5, 129.1, 128.3, 127.1, 126.4,
112.6, 111.1, 62.6, 56.2, 55.2, 50.8, 28.2. Anal. calcd for
C17H19NO: C, 80.59; H, 7.56; N, 5.53. Found: C, 80.65;
H, 7.74; N, 5.77%.
4.7.2. 2-Hexyl-7-methoxy-1,2,3,4-tetrahydroisoquinoline
4.9.1. Diethyl [7-methoxy-3,4-dihydro-2(1H)-isoquino-
linyl]methylphosphonate 15. Light yellow oil; yield 80%;
1H NMR l 7.00 (d, J=8.4 Hz, 1H), 6.71 (dd, J=8.4,
2.7 Hz, 1H), 6.55 (d, J=2.7 Hz, 1H), 4.22–4.15 (m,
4H), 3.82 (s, 2H), 3.76 (s, 3H), 2.98–2.94 (m, 4H), 2.82
(t, J=7.2 Hz, 2H), 1.33 (t, J=7.0 Hz, 6H); 13C NMR
l 157.5, 135.4, 129.5, 125.9, 112.6, 111.1, 62.1 (d,
J=6.8 Hz), 57.4 (d, J=10.8 Hz), 55.2, 53.5 (d, J=162.8
Hz), 52.6 (d, J=10.3 Hz), 27.9, 16.5 (J=5.7 Hz). Anal.
calcd for C15H24NO4P: C, 57.50; H, 7.72; N, 4.47.
Found: C, 57.84; H, 8.02; N, 4.68%.
1
13b. Colorless flakes; yield 59%; mp 40–41°C; H NMR
l 6.99 (d, J=8.4 Hz, 1H), 6.70 (dd, J=8.4, 2.7 Hz,
1H), 6.56 (d, J=2.4 Hz, 1H), 3.76 (s, 3H), 3.61 (s, 2H),
2.84 (t, J=5.7 Hz, 2H), 2.73 (t, J=5.7 Hz, 2H), 2.50 (t,
J=7.8 Hz, 2H), 1.63–1.52 (m, 2H), 1.40–1.22 (m, 6H),
0.89 (t, J=6.6 Hz, 3H); 13C NMR l 157.5, 135.7, 129.5,
126.4, 112.5, 111.2, 58.4, 56.3, 55.2, 51.1, 31.8, 28.0,
27.3, 27.0, 22.6, 14.0; HRMS calcd for C16H26NO
248.2014 (M+1), found 248.2006.
4.7.3. 7-Methoxy-2-(3-phenyl-2-propynyl)-1,2,3,4-tetra-
hydroisoquinoline 13c. Colorless oil; yield 74%; 1H
NMR l 7.45–7.42 (m, 2H), 7.31–7.28 (m, 3H), 7.03 (d,
J=8.4 Hz, 1H), 6.72 (dd, J=8.7, 2.7 Hz, 1H), 6.60 (d,
J=2.1 Hz, 1H), 3.82 (s, 2H), 3.77 (s, 3H), 3.73 (s, 2H),
2.90 (s, 4H); 13C NMR l 157.6, 135.6, 131.7, 129.5,
128.2, 128.1, 125.9, 123.1, 112.6, 111.3, 85.5, 84.3, 55.3,
54.7, 50.1, 47.5, 28.4. Anal. calcd for C19H19NO: N,
5.05. Found: N, 5.21%. HRMS calcd for C19H20NO
278.1545 (M+1), found 278.1542.
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