A simple and efficient preparation of 3,4-dialkylsubstituted tetrahydroisoquinoline using cyclopropylethyliden benzylamine

Article abstract of DOI:10.1081/SCC-120012985

Intramolecular Friedel-Crafts alkylation of N-benzyl-N-(1-cyclopropylethyl)acetamide to 3,4-dialkyl substituted tetrahydroisoquinoline by reaction of the acetamide with an excess of PPA is described. The conformational study of intermediates by high resol

Full text of DOI:10.1081/SCC-120012985

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A SIMPLE AND EFFICIENT PREPARATION OF 3,4-
DIALKYLSUBSTITUTED TETRAHYDROISOQUINOLINE
USING CYCLOPROPYLETHYLIDEN BENZYLAMINE
Vladimir Kouznetsov a , Alirio Palma a , Wilson Rozo a , Elena Stashenko a , Alí Bahsas b &
Juan Amaro-Luis b
a Research Center for Biomolecules, Laboratory of Fine Organic Synthesis, School of
Chemistry, Industrial University of Santander, Bucaramanga, A.A. 678, Colombia
b Laboratorio de RMN, Grupo de Productos Naturales, Departamento de Química,
Universidad de los Andes, Mérida, 5101, Venezuela
Published online: 16 Aug 2006.
To cite this article: Vladimir Kouznetsov , Alirio Palma , Wilson Rozo , Elena Stashenko , Alí Bahsas & Juan Amaro-
Luis (2002): A SIMPLE AND EFFICIENT PREPARATION OF 3,4-DIALKYLSUBSTITUTED TETRAHYDROISOQUINOLINE USING
CYCLOPROPYLETHYLIDEN BENZYLAMINE, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 32:19, 2965-2971
To link to this article: http://dx.doi.org/10.1081/SCC-120012985
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SYNTHETIC COMMUNICATIONS
Vol. 32, No. 19, pp. 2965–2971, 2002
A SIMPLE AND EFFICIENT
PREPARATION OF
3,4-DIALKYLSUBSTITUTED
TETRAHYDROISOQUINOLINE
USING CYCLOPROPYLETHYLIDEN
BENZYLAMINE
Vladimir Kouznetsov,1, Alirio Palma,1 Wilson Rozo,1
*
Elena Stashenko,1 Alı Bahsas,2 and Juan Amaro-Luis2
1Research Center for Biomolecules, Laboratory of
Fine Organic Synthesis, School of Chemistry,
Industrial University of Santander, A.A. 678,
Bucaramanga, Colombia
2Laboratorio de RMN, Grupo de Productos Naturales,
Departamento de Quımica, Universidad de los Andes,
Merida, Venezuela, 5101
ABSTRACT
Intramolecular Friedel–Crafts alkylation of N-benzyl-N-
(1-cyclopropylethyl)acetamide to 3,4-dialkyl substituted
tetrahydroisoquinoline by reaction of the acetamide with an
excess of PPAis described. The conformational study of inter-
mediates by high resolution NMR analysis is also reported.
*Corresponding author. Fax: (57)-6349069; E-mail:kouznet@uis.edu.co
2965
DOI: 10.1081/SCC-120012985
Copyright & 2002 by Marcel Dekker, Inc.
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2966
KOUZNETSOV ET AL.
Figure 1.
Isoquinolines as well as 2,3,4,5-tetrahydroisoquinolines have received
considerable attention from both theoretical and practical points of view.[1]
Tetrahydroisoquinoline core occurs in a large number of alkaloids.[2]
Although their methods of preparation have been well-documented,
organic and medicinal chemists still continue to develop new approaches
to obtain them.
As part of our research program on the preparation of potentially
bioactive N-heterocycles.[3,4] we recently synthesized new series of 2-benz-
azepine,[5] quinoline[6] and acridine[7] derivatives using allyl cationic cycliza-
tion and now addressed the chemistry of N-cyclopropylethyl benzylamine
under acidic conditions. Keeping in our minds that cyclopropylimines have
proven to be useful building blocks in synthesis of several alkaloids contain-
ing pyrrolidine skeleton using, as key step, the intramolecular cyclization
process promoted by acids or halide salts,[8] we believed that this type of
imines and their derivatives could serve as starting materials in the synthesis
of important medicinally 3,4-dialkylsubstituted tetrahydroisoquinolines.
Asimple retrosynthetic analysis of disubstituted tetrahydroisoquino-
line structure shows that its construction could be realized by electrophilic
ring-opening of appropriated cyclopropyl moiety using Bronsted acids
(Fig. 1). We report here that reduction of N-cyclopropylethyliden benzyl-
amine followed by N-acetylation and subsequent intramolecular Friedel–
Crafts ring closure of the corresponding acetamide can be an useful and
easy alternative for the preparation of 3,4-dialkylsubstituted tetrahydroiso-
quinolines. Surprisingly enough, this obvious synthetic strategy has not been
used before.
RESULTS AND DISCUSSION
As shown in Sch. 1, the starting imine 1 was obtained by condensation
of benzylamine with methyl cyclopropyl ketone in anhydrous benzene at
reflux overnight. After distillation in vacuo, the imine 1 immediately was
reduced (NaBH4/MeOH/25ꢀC) to secondary benzylamine 2,[9] that was
obtained by silica gel column chromatography as viscous yellow oil with

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3,4-DIALKYLSUBSTITUTED TETRAHYDROISOQUINOLINE
2967
high yield (92%). To avoid possible decomposition of 2 which can occur
under drastic acidic conditions employed, the latter was first reacted with
an excess of the acetic anhydride to give the corresponding acetamide 3 in a
quantitative yield (96%) as maroon viscous oil after the workup
of the reaction mixture with saturated Na2CO3 solution, the IR spec-
trum of which showed a single carbonyl stretching band at 1641 cmꢁ1
but no adsorption in the region 3317 cmꢁ1 which would be expected for
precursor amine.
1
The structures of compounds 2 and 3 were also confirmed by H and
13C NMR spectroscopy, GC-MS and elemental analysis. The mass spectra
of compounds 2 and 3 exhibit low intensity signals of parent ions (3 and 5%,
respectively), which agree with the expected molecular mass. High resolu-
1
tion H NMR analysis of both compounds revealed that benzylamine 2
exists as unique conformer 2a, while acetamide 3 exists as two conformers
in 1.8 : 1 ratio (Fig. 2). Major conformationally no restricted acetamide was
assigned as conformer 3a and minor restricted acetamide as conformer 3b.
The results of this analysis are summarized in the Table 1.
Scheme 1.
Figure 2.

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2968
KOUZNETSOV ET AL.
Because the rotation of benzyl fragment around C–N bond in con-
former 3a is free, the signal of benzylic protons appears as singlet at
4.54 ppm. In contrast, in conformer 3b the steric effect of cyclopropyl
moiety is enough great and hindered the free rotation of benzyl fragment,
and by this reason the signal of these protons appears as two doublets at
4.62 and 4.70 ppm with a coupling constant J ¼ 15.7 Hz. The 1H NMR
spectrum of acetamide also showed that the singlet at 2.26 ppm associated
with the NH protons was absent and, instead, a three-proton singlets at 2.01
and 2.14 ppm, and an one-proton multiplets at 3.14 and 3.99 ppm and 0.49
1
Table 1. The H and 13C-NMR Spectral Data of Compounds 2–4
No.
1H NMR (CDCl3), ꢀ (ppm)
13C NMR (CDCl3), ꢀ (ppm)
2
7.33–7.21 (5H, m, arom.-H), 3.84 (2H, 141.0–128.16 (arom.-C), 58.29
s, benzylic-H), 2.26 (1H, s, N–H), (1-C), 51.54 (benzylic-C), 20.35
1.92 (1H, m, 1-CH), 1.20 (3H, d, (2-C), 17.76 (10-C), 4.54 (30-C),
J ¼ 6.4 Hz, 2-CH3), 0.79 (1H, m, 1.93 (20-C)
10-H), 0.50 (1H, m, 30-Hpseudoeq.), 0.43
(1H, m, 30-Hpseudoax.), 0.16 (1H, m,
20-Hpseudoeq.), 0.07 (1H, m, 20-Hpseudoax.
)
3
3a: 7.34–7.20 (5H, m, arom.-H), 4.54 171.40 (C¼O), 138.49 (quatern-
(2H, s, benzylic-H), 3.99 (1H, m, ary-C), 128.53 (meta-C), 127.01
1-CH), 2.01 (3H, s, CH3–CO), 1.16 (ortho-C), 126.04 ( para-C), 54.98
(3H, d, J ¼ 6.8 Hz, 2-CH3), 0.49 (1H, (1-C), 47.73 (benzylic-C), 22.38
m, 10-H), 0.33–0.21 (4H, m, 20-H-30-H)
(C–CO), 18.22 (2-C), 15.48 (10-
C), 4.48–5.35 (20-C-30-C)
3b: 7.34–7.20 (5H, m, arom.-H), 4.70 170.31 (C¼O), 139.62 (quatern-
(1H, d, J ¼ 15.6 Hz, benzylic-HA), 4.62 ary-C), 128.03 (meta-C), 127.21
(1H, d, J ¼ 15.7 Hz, benzylic-HB), 3.14 (ortho-C), 126.43 ( para-C), 59.66
(1H, m, 1-CH), 2.14 (3H, s, CH3–CO), (1-C), 44.67 (benzylic-C), 21.89
1.16 (3H, d, J ¼ 6.8 Hz, 2-CH3), 1.16 (C–CO), 19.16 (2-C), 16.19 (10-
(1H, m, 10-H), 0.33–021 (4H, m, 20-H- C), 5.35–4.48 (20-C-30-C)
30-H)
4
7.37–7.18 (4H, m, arom.-H), 4.56 (1H, 170.42 (C¼O), 138.44–126.56
d, J ¼ 16.7 Hz, 1-HA), 4.46 (1H, d, (arom.-C), 75.80 (4-C), 59.48
J ¼ 17.0 Hz, 1-HB), 3.64 (1H, td, (3-C), 53.35 (1-C), 27.77 (C–CO),
J ¼ 6.8 and 1.4 Hz, 4-H), 3.51 (1H, q, 22.99 (–C–CH3), 10.75 (3-CH3),
J ¼ 7.1 Hz, 3-H), 1.96 (3H, s, CH3–CO), 10–42 (CH2–C)
1.40 (2H, m, CH2–CH3), 1.18 (3H, d,
J ¼ 7.1 Hz, 3-CH3), 0.76 (3H, t,
J ¼ 7.4 Hz, CH2–CH3)

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3,4-DIALKYLSUBSTITUTED TETRAHYDROISOQUINOLINE
2969
and 1.16 ppm were observed. These data confirmed that the obtained acet-
amide exists as a mixture of two conformers.
Finally, easily available acetamide 3 underwent an intramolecular elec-
trophilic aromatic alkylation promoted by PPA, in which the cyclopropyl
fragment of the acetamide acts as the electrophilic component, giving the
tetrahydroisoquinoline 4, that was obtained by silica gel column chromatog-
raphy in 80% yield as maroon viscous oil.
The involvement of carbocations in the electrophilic opening of cyclo-
propyl ring under appropriate acidic conditions has been well established.[10]
By this reason, we suppose that under these strongly acidic conditions,
initially occurs the cleavage of cyclopropyl ring with the formation of
cationic species A as unique probably precursor of the formed 2,4-dialkyl-
substituted tetrahydroisoquinoline 4 since it corresponds to a secondary,
sufficiently stable in situ generated carbocation, which then undergoes intra-
molecular alkylation by the benzene ring. Other cyclization products have
not been detected.
IR spectrum of 4 had carbonyl adsorption band at 1625 cmꢁ1. The mass
spectrum of this compound showed a very low intensity (<1%) molecular ion
at m/z 217, and as main fragments the loss of the hydrogen atom, and the
subsequent loss of the C3H5 (m/z 176), C5H7O (m/z 134), C7H11O (m/z 106)
1
and C7H12NO (m/z 91) groups. The H and 13C NMR data allowed us to
1
confirm the expected structure (Table 1). Thus, the presence in H NMR
spectrum of one triplet at 0.76 ppm and one multiplet at 1.40 ppm integrated
for three methyl and two methylene protons, as well as one triplet of doublets
at 3.64 ppm and one quartet at 3.51 ppm integrated for two methyne protons
are the best evidences that the cyclization of acetamide take place. Benzylic
protons resonated as two doublets at 4.56 and 4.46 ppm.
CONCLUSION
The fast and easy procedure and good yields of the products make our
approach a useful addition to the current methodologies. Both building
blocks benzylamine and methylcyclopropyl ketone used in this approach
as starting materials are commercially available.
EXPERIMENTAL
IR spectra were obtained on a Nicolet Avatar 360-FTIR spectro-
1
photometer as KBr pellets. The H NMR spectra were recorded in CDCl3
solution with TMS as internal standard on Bruker AM-400 spectrometer

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2970
KOUZNETSOV ET AL.
(400 MHz 1H NMR and 100 MHz 13C NMR). GC-MS spectra were obtained
on a HP-5890ASeries II gas chromatograph interfaced to an HP-5972 mass
selective detector (MSD) with an HP MS ChemStation Data. The electron
beam energy was 70 eV. Elemental analyses were performed on a Leco
CHN-600 analyzer. Column chromatography and TLC were carried out
using Merck Kieselgel 60 (230–400 mesh) and Silufol UV54 chromatoplates.
All reagents were purchased from Merck and Aldrich Chemical Co. (p.a.
quality). All solvents were used without further purification.
Compounds 1–3 were synthesized according to known methods (5a, 9).
N-(1-Cyclopropylethyl)benzylamine, 2: Viscous oil, n2D5 1.5707; MS m/z
(relative intensity) 175 (Mþ., 3), 160 (55), 146 (3), 134 (17), 106 (5), 91 (100);
Anal. Calcd. for C12H17N: C, 82.29; H, 9.71; N, 8.0%. Found: C, 82.10;
H, 9.60; N, 8.13%.
N-(1-Cyclopropylethyl)benzylacetamide, 3: Viscous oil, n2D5 1.5208; MS
m/z (relative intensity) 217 (Mþ, 5), 202 (1), 188 (18), 174 (9), 160 (21), 148
(35), 134 (9), 126 (8), 106 (55), 91 (100); Anal. Calcd. for C14H19NO:
C, 77.42; H, 8.76; N, 6.45%. Found: C, 77.51; H, 8.62; N, 6.32%.
Synthesis of N-acetyl-4-ethyl-3-methyl-1,2,3,4-tetrahydroisoquinoline 4:
Amixture of the acetamide 3 (0.5 g, 2.3 mmol), and PPA(5.0 g) was heated
at 70ꢀC for 6 h. After cooling, the reaction mixture was poured into ice (50 g)
and neutralized with saturated Na2CO3 solution. The organic phase was
extracted with dichloromethane (3 ꢂ 30 mL) and dried on anhydrous
Na2SO4. Evaporation of the solvent leads to a viscous black oil, which is
purified by silica gel column chromatography using ethylacetate–heptane
(1 : 20) as eluent to give 0.4 g (80% yield) of a viscous maroon oil.
n2D5 1.5209; MS m/z (relative intensity) 217 (Mþ, <1), 216 (<1), 177
(15), 176 (17), 150 (2), 134 (63), 118 (<1), 106 (6), 91 (100); Anal. Calcd.
for C14H19NO: C, 77.42; H, 8.76; N, 6.45%. Found: C, 77.27; H, 8.90;
N, 6.53%.
ACKNOWLEDGMENTS
Financial support from Colciencias (grants No. 1115-05-353-96 and
1102-05-110-97) is gratefully acknowledged.
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3,4-DIALKYLSUBSTITUTED TETRAHYDROISOQUINOLINE
2971
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Received in the USASeptember 14, 2001

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