Synthesis of functionalized tetrahydroisoquinolines via palladium-catalyzed 6-exo-dig carbocyclization of 2-bromo-N-propargylbenzylamines

Article abstract of DOI:10.1016/j.tetlet.2011.01.127

An efficient twostep synthetic strategy for tetrahydroisoquinolines has been described. The first step involves CuI catalyzed three-component coupling reaction of terminal alkyne, aldehyde and amine that provides the requisite propargyl amine. Regio- and

Full text of DOI:10.1016/j.tetlet.2011.01.127

Tetrahedron Letters 52 (2011) 1644–1648
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Tetrahedron Letters
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Synthesis of functionalized tetrahydroisoquinolines via palladium-catalyzed
6-exo-dig carbocyclization of 2-bromo-N-propargylbenzylamines
⇑
A. Nandakumar, D. Muralidharan, P. T. Perumal
Organic Chemistry Division, Central Leather Research Institute (CSIR), Adyar, Chennai 600 020, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient twostep synthetic strategy for tetrahydroisoquinolines has been described. The first step
involves CuI catalyzed three-component coupling reaction of terminal alkyne, aldehyde and amine that
provides the requisite propargyl amine. Regio- and stereoselective palladium-catalyzed 6-exo-dig carbo-
cyclization of propargyl amine, which provides a concise access to functionalized tetrahydroisoquinolines
in good yields has been developed.
Received 13 December 2010
Revised 18 January 2011
Accepted 27 January 2011
Available online 1 February 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
A3 coupling
Carbocyclization
Palladium
6-exo-dig regiochemistry
Tetrahydroisoquinolines
Tetrahydroisoquinolines are an important class of heterocyclic
compounds found in a wide range of natural products. They com-
prise the largest family of alkaloids (Fig. 1),1 that exhibit important
biological activities including antiarrhythmic, angiotensin-con-
verting enzyme inhibition, antihypertensive, antitumor, antimicro-
bial, antiplasmodial, noncompetitive inhibition to AMPA receptor
and antidepression activities2,3f furthermore, they are used as syn-
thetic intermediates for an array of substances.3 The wide range of
biological and pharmacological importance of tetrahydroisoquin-
olinones prompted us to synthesize these heterocycles utilizing a
simple and efficient method.
In general, tetrahydroisoquinolines have been constructed
through various methods like Bischler–Napieralski reactions which
involves cyclization of a b-arylethylamide to a 1-substituted 3,4-
dihydroisoquinoline or a corresponding isoquinolinium salt, which
is then reduced in the next step,3h Pictet–Spengler reaction, which
includes the acid-catalyzed cyclization of a b-arylethylamine with
an aldehyde,3h intramolecular Friedel–Crafts alkylation,4 acid-cata-
lyzed cyclization of benzalamino acetals in C4–C4a bond forma-
tion,5 C1–N2 connectivity approach by Meyers and Munchhof
reaction,6 transition metal catalyzed C–C bond formation7 etc.
Among various synthetic strategies, catalytic transformation by
means of transition-metal catalysts is one of the modern approaches
for the synthesis of substituted tetrahydroisoquinoline derivatives.
Due to our interest in developing novel routes to common heterocy-
cles,8 herein we report a new and efficient two-step protocol for the
synthesis of tetrahydroisoquinolines, which involves CuI-catalyzed
three component coupling of aldehyde, alkyne and amine (A3 cou-
pling)9 providing the required propargylamines, followed by a
regio- and stereoselective Pd-catalyzed intramolecular acetylene
hydroarylation.
We first investigated the coupling reactions of N-(2-bromoben-
zyl)(phenyl)methanamine 1 (R1 = H, 1 equiv), aldehyde 2 (R2 = 4-
MePh, 1.2 equiv) and acetylene 3 (R3 = Ph, 1.5 equiv) using 10
mol % of CuI as catalyst (Scheme 1). It was found that the propargyl
amine 4 (R1 = H, R2 = 4-MePh, R3 = Ph) was formed in 76% yield by
stirring at 100 °C for 3 h in toluene (Table 1, entry 1). Similarly, when
the reaction was run with CuBr, the same propargylic amine was
obtained in 70% yield (Table 1, entry 2). It was found that the amount
of catalyst also affects the yield of the product. Increasing the cata-
lyst amount to 15 mol % CuI and CuBr resulted in very good yields
of 85% and 78%, respectively (Table 1, entries 3 and 4). Further incre-
ment of catalyst amount did not alter the reaction yield (Table 1,
CH3
HO
CH3
N
N
H3CO
H3CO
OH
OH
Latifine
OH
Cherylline
⇑
Corresponding author. Tel.: +91 44 24913289; fax: +91 44 24911589.
E-mail address: ptperumal@gmail.com (P.T. Perumal).
Figure 1. Representative structures of tetrahydroisoquinolines.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.01.127

A. Nandakumar et al. / Tetrahedron Letters 52 (2011) 1644–1648
1645
R3
Br
R2
Bn
Br
CuI salt catalyst
R1
R1
R2CHO
H
N
N
R3
Bn
1
2
3
4
Scheme 1. Optimization of three component coupling reaction.
Table 1
Optimization of three component coupling reaction
Table 2
Synthesis of propargylamines (4a–l)
Entry
Catalyst
mol %
Temperature (°C)
Yielda,b (%)
Entry
Substrate
Product (4)
Yielda,b (%)
1
2
3
4
5
6
7
CuI
CuBr
CuI
CuBr
CuI
CuI
10
10
15
15
20
15
15
100
100
100
100
100
70
76
70
85
78
84
60
0c
R1
R2
R3
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4a
4b
4c
4d
4e
4f
4g
4h
4i
84
85
87
80
84
90
82
86
83
85
84
83
4-CH3C6H4
4-ClC6H4
4-OMeC6H4
2-FC6H4
iso-Propyl
H
CuI
rt
a
The reactions were performed with amine 1 (R1 = H, 0.5 mmol), p-tolualdehyde
2 (0.55 mmol) and phenylacetylene (0.75 mmol).
Isolated yields.
Ph
4-OMeC6H4
n-Butyl
n-Butyl
Ph
b
c
9
H
4-CH3C6H4
4-ClC6H4
H
10
11
12
4,5-OMe
4,5-OMe
4,5-OMe
4j
4k
4l
Amine 1 remains unconsumed.
4-CH3C6H4
4-OMeC6H4
a
entry 5). When the reaction was carried out at a lower temperature
of 70 °C, the yield decreased to 60% (Table 1, entry 6). However the
reaction atambient temperaturefor prolonged timemet withfailure
(Table 1, entry 7).
Isolated yields.
All the compounds were characterized by IR, 1H and 13C NMR and mass spec-
b
troscopic techniques.
To generalize the reaction,11 the coupling of amine with various
aldehydes and alkynes, was carried out under optimal conditions
(Scheme 2). The results are summarized in Table 2. The results
indicated that aromatic aldehydes bearing such functional groups
as fluoro, chloro, methyl and methoxy were able to effect the A3
coupling. Aliphatic aldehydes also displayed clean reactions under
this standard condition. Various terminal alkynes were also exam-
ined. Both aromatic and aliphatic alkynes reacted smoothly with
aldehyde and amine to give the corresponding products in good
yields. To expand the scope of amine substrates, we used a substi-
tuted aryl amine. The coupling proceeded smoothly to afford the
corresponding propargylamines in good yields under standard con-
ditions. Formation of propargylamine derivatives was confirmed by
1H and 13C NMR spectroscopic techniques. The 1H NMR spectra of
compound 4d in CDCl3 consisted of a characteristic singlet due to
the methine proton (N–CH–) in the region of 4.92 ppm. In the 13C
NMR spectra, the appearance of two distinguishable peaks at 85.1
and 88.7 ppm corresponded to two acetylenic carbons. These
observations confirmed the formation of propargyl amine (4d).12
We then investigated the intramolecular cyclization of propar-
Table 3
Optimization of carbocyclization reaction using different Pd catalysts
Entry
Solvent (v/v)
Catalyst
Time (h)
Yielda (%)
1
2
3
4
5
6
7
DMF/H2O (1:0)
DMF/H2O (3:1)
DMF/H2O (4:1)
DMF/H2O (3:1)
DMF/H2O (3:1)
DMF/H2O (3:1)
DMF/H2O (3:1)
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(OAc)2 + 2PPh3
PdCl2 + 2PPh3
Pd(PPh3)4
3
3
3
3
3
55
78
68
76
70
3
12
65b
62b
Pd(PPh3)4
a
The reactions were carried out with propargylamine 4 (R1 = H, R2 = 4-MePh,
R3 = Ph, 0.4 mmol) in the presence of HCOONa (0.6 mmol) and Pd(PPh3)4
(3 mol %) in DMF/H2O (3:1) (6 mL) at 100 °C (oil bath temperature) in 70 mM
concentration.
b
The reactions were run in 140 mM concentration.
the intramolecular carbocyclisation reaction proceeded smoothly
and generated the desired product
5
(R1 = H, R2 = 4-MePh,
R3 = Ph) in 78% yield, representing one of the best results when
3 mol % of Pd(PPh3)4 was used as the catalyst (Table 3, entry 2).
Higher yields for cyclization were generated when a higher dilu-
tion (70 mM) was employed (Scheme 3 and Table 3).
gylamine
4
(R1 = H, R2 = 4-MePh, R3 = Ph) using 3 mol % of
Pd(PPh3)4 as catalyst and sodium formate as a reducing agent un-
der conventional heating condition. The optimal solvent system for
the cyclization was found to be a DMF/water mixture (3:1). Water
was essential to activate the reducing agent in this reaction.10 The
catalytic activity of various palladium catalysts were examined in a
model reaction of propargylamine 4 (R1 = H, R2 = 4-MePh, R3 = Ph)
in DMF/H2O solvent system under nitrogen atmosphere at 100 °C
for 3 h and the results are summarized in Table 3. To our delight,
Having the optimized conditions in hand,13 the analogs of tetra-
hydroisoquinoline 5 were synthesized in good yields and are pre-
sented in Table 4 and Scheme 4. The high stereo- and regio-
selectivity of the cyclization step leading to one isomer exclusively
was confirmed with the aid of 1H NMR data. In 1H NMR spectrum,
the compound 5d exhibited two sharp singlets at 4.98 and
R3
R2
Br
CuI (15 mol-%)
R1
H
R1
R2CHO
N
Toluene, 100 oC, 3 h
N
R3
Bn
Bn
Br
1
2
3
4a-l
Scheme 2. Synthesis of substituted propargylamines.

1646
A. Nandakumar et al. / Tetrahedron Letters 52 (2011) 1644–1648
Bn
not adjacent to each other which ruled out the possibility of forma-
N
tion of a seven-membered ring(Scheme 3). All these findings con-
firmed the formation of the exo-cyclic six-membered ring. The
exclusive formation of the Z-isomer was attributed to the syn-addi-
tion of the Pd on to the triple bond. The (Z)-stereochemistry of
compound has been assigned using a 1-D NOE experiment.
Selective irradiation of the vinylic proton effected the enhance-
ment of the signals of C5–H (11%; Fig. 2a). Irradiation of C3–H ef-
fected the enhancement of ortho-anisyl proton (9%) and ortho-
phenyl proton (15%). There is no enhancement of vinylic proton
(Fig. 2b). This observation confirmed that the vinylic proton is cis
to C5–H, thus compound 5d is Z configured.14 A possible pathway
of the Pd-catalyzed intramolecular carbocylization is shown in
Scheme 5.
R1
R2
Bn
[Pd] (3 mol-%)
N
R1
R2
R3
5'
HCOONa (1.5 eq.)
100 oC
Br
Bn
N
R1
R3
R2
R3
4
5
Scheme 3. Optimization of palladium catalyzed carbocyclization reaction.
7.45 ppm indicated the presence of methine and vinylic protons,
respectively. This observation showed that these two protons are
In summary, we have developed a new and efficient two-step
protocol for the synthesis of tetrahydroisoquinolines. The first step
Table 4
Synthesis of tetrahydroisoquinoline derivatives (5a–l)
Entry
Substrate (4)
Product (5)
Yielda,b (%)
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
N
N
Br
1
76
5a
4a
N
N
Br
2
3
4
5
6
78
75
73
76
79
5b
4b
N
N
N
N
N
Br
Cl
Cl
5c
5d
5e
5f
4c
N
Br
OMe
OMe
4d
F
N
Br
F
4e
N
Br
4f

A. Nandakumar et al. / Tetrahedron Letters 52 (2011) 1644–1648
1647
Table 4 (continued)
Entry
Substrate (4)
Product (5)
Yielda,b (%)
Bn
Bn
N
N
Br
7
70
5g
4g
Bn
Bn
N
N
Br
8
77
OMe
5h
MeO
4h
Bn
Bn
N
N
Br
9
70
71
4i
5i
MeO
MeO
Bn
Bn
Bn
N
N
N
Br
MeO
MeO
Cl
10
Cl
4j
5j
MeO
MeO
Bn
N
Br
MeO
MeO
11
68
5k
4k
MeO
Bn
MeO
MeO
Bn
N
N
Br
MeO
12
76
OMe
5l
MeO
4l
a
Isolated yields.
b
All the compounds were characterized by IR, 1H and 13C NMR and mass spectroscopic techniques.
9 %
Bn
8
1
Bn
R2
H
Bn
R2
2
9
Bn
Pd(PPh3)4 (3 mol-%)
N
N
N
R1
7
6
N
R1
H
H
HCOONa (1.5 equiv.)
DMF/H2O (3:1), 100 o
Br
10
H
3
OMe
5
4
OMe
C
H
15 %
H
H
R3
H
R3
4a-l
5a-l
Scheme 4. Synthesis of tetrahydroisoquinoline derivatives.
11 %
(a)
(b)
Figure 2. 1-D NOE enhancement of compound 5d.
is a CuI-catalyzed three-component coupling of an aldehyde, an
alkyne and an amine leading to propargylamines, which are the
key intermediates for the regio- and stereoselective Pd-catalyzed
intramolecular acetylene hydroarylation that generates the tetra-
hydroisoquinolines. The scope of this reaction and its application
for the bioactive compounds is currently under investigation in
our laboratory.

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A. Nandakumar et al. / Tetrahedron Letters 52 (2011) 1644–1648
Bn
N
Bn
Bn
N
Br
R2
R1
N
R2
Pd
Br
R1
R1
R2
Pd
Br
R3
4
Pd(0)
R3
R3
Bn
R2
Bn
Bn
Bn
R2
N
N
N
N
R1
R1
HCOONa
R1
R1
HCOO
R2
R2
Br
H
Pd R3
R3
Pd R3
CO2
Pd R3
5
NaBr
Scheme 5. A possible pathway for the formation of product 5.
10. (a) Donets, P. A.; Van der Eycken, E. V. Org.Lett. 2007, 9, 3017; (b) Ma, T.; Chen,
W.; Zhang, G.; Yu, Y. J. Comb. Chem. 2010, 12, 488.
Acknowledgment
11. General procedure for the synthesis of propargylamine (4): A mixture of CuI
(15 mol %), amine (0.50 mmol), aldehyde (0.55 mmol) and phenylacetylene
(0.75 mmol) in toluene (3 mL) was heated at 100 °C for 3 h. Then the reaction
mixture was filtered through Celite and washed with ethyl acetate. After
removal of the solvent, the residue was purified by column chromatography on
silica gel using petroleum ether/ethyl acetate as eluent, affording compound in
good yield (shown in Table 2).
One of the authors, A.N. thanks to the Council of Scientific and
Industrial Research (CSIR), New Delhi, India for the research
fellowship.
Supplementary data
12. Spectral data of compound (4d): N-(2-bromobenzyl)-N-benzyl-1-(4-methoxy-
phenyl)-3-phenylprop-2-yn-1-amine; yellow oil; Rf 0.80 (5% AcOEt/petroleum
ether); IR (KBr): 1020, 1242, 1593, 2363, 2928 cmÀ1 1H NMR (500 MHz,
;
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.01.127.
CDCl3): d 3.63 (d, J = 13.75 Hz, 1H, –CH2-Ar), 3.72 (d, J = 14.50 Hz, 1H, –CH2-Ar),
3.81 (s, 3H, –OCH3), 3.82 (d, J = 13.75 Hz, 1H, –CH2-Ar), 4.00 (d, J = 14.55 Hz, 1H,
–CH2-Ar), 4.92 (s, 1H, –CH), 6.92 (d, J = 8.4 Hz, 2H, Ar-H), 7.10 (t, J = 7.65 Hz, 1H,
Ar-H), 7.26 (t, J = 7.65 Hz, 1H, Ar-H), 7.31–7.35 (m, 3H, Ar-H), 7.40–7.42
(m, 3H, Ar-H), 7.46 (d, J = 7.65 Hz, 2H, Ar-H), 7.52 (d, J = 7.65 Hz, 1H, Ar-H),
7.66–7.69 (m, 5H, Ar-H); 13C NMR (125 MHz, CDCl3): d 53.9, 55.0, 55.4, 55.9,
85.1, 88.7, 113.6, 123.4, 124.8, 127.2, 127.5, 128.4, 128.5, 129.1, 129.6, 130.8,
131.1, 132.1, 132.8, 138.7, 139.4, 159.1; MS (EI): m/z 496.58 [M+H]+; Anal.
Calcd for C30H26BrNO: C, 72.58; H, 5.28; N, 2.82. Found: C, 72.62; H, 5.26; N,
2.85.
References and notes
1. Phillipson, J. D.; Roberts, M. F.; Zenk, M. H. The Chemistry and Biology of
Isoquinoline Alkaloids; Springer: New York, 1985.
2. (a) Yakoyama, A.; Ohwada, T.; Shudo, K. J. Org. Chem. 1999, 64, 611; (b) Manini,
P.; d’Ischia, M.; Prota, G. J. Org. Chem. 2001, 66, 5048; (c) Urverg-
Ratsimamanaga, S.; Rasoanaivo, P.; Rafatro, H.; Robijaona, B.; Rakato-
Ratsimamanga, A. Ann. Trop. Med. Parasitol. 1994, 88, 271; (d) Gitto, R.;
Barreca, M. L.; De Luca, L.; de Sarro, G.; Ferreri, G.; Quartarone, S.; Russo, E.;
Constanti, A.; Chimirri, A. J. Med. Chem. 2003, 46, 197.
3. (a) Chen, J.; Chen, X.; Bois-Choussy, M.; Zhu, J. J. Am. Chem. Soc. 2006, 128, 87;
(b) Kwon, S.; Myers, A. G. J. Am. Chem. Soc. 2005, 127, 16796; (c) Magnus, P.;
Matthews, K. S.; Lynch, V. Org. Lett. 2003, 5, 2181; (d) Magnus, P.; Matthews, K.
S. J. Am. Chem. Soc. 2005, 127, 12476; (e) Scott, J. D.; Williams, R. M. Angew.
Chem., Int. Ed. 2001, 40, 1463; (f) Scott, J. D.; Williams, R. M. J. Am. Chem. Soc.
2002, 124, 2951; (g) Scott, J. D.; Williams, R. M. Chem. Rev. 2002, 102, 1669; (h)
Chrzanowska, M.; Rozwadowska, M. D. Chem. Rev. 2004, 104, 3341.
4. Chandrasekhar, S.; Ramakrishna Reddy, N.; Venkat Reddy, M.; Jagannadh, B.;
Nagaraju, A.; Ravi Sankar, A.; Kunwar, A. C. Tetrahedron Lett. 2002, 43, 1885.
5. Boger, D. L.; Brotherton, C. E.; Kelley, M. D. Tetrahedron 1981, 37, 3977.
6. Munchhof, J. M.; Meyers, A. I. J. Org. Chem. 1996, 61, 4607.
7. (a) Mori, M.; Chiba, K.; Ban, Y. Tetrahedron Lett. 1977, 12, 1037; (b) Huang, W.;
Shen, Q.; Wang, J.; Zhou, X. J. Org. Chem. 2008, 73, 1586; (c) Chapman, L. M.;
Adams, B.; Kliman, L. T.; Makriyannis, A.; Hamblett, C. L. Tetrahedron Lett. 2010,
51, 1517.
8. (a) Thirumurugan, P.; Nandakumar, A.; Priya, N. S.; Muralidharan, D.; Perumal,
P. T. Tetrahedron Lett. 2010, 51, 5708; (b) Praveen, C.; Iyyappan, C.; Perumal, P.
T. Tetrahedron Lett. 2010, 51, 4767; (c) Praveen, C.; Kiruthiga, P.; Perumal, P. T.
Synlett 2009, 1990; (d) Karthikeyan, K.; Perumal, P. T. Synlett 2009, 2366.
9. (a) Wei, C.; Li, Z.; Li, C. J. Org. Lett. 2003, 5, 4473; (b) Shi, L.; Tu, Q. Y.; Wang, M.;
Zhang, M. F.; Fan, A. C. Org. Lett. 2004, 6, 1001.
13. General procedure for the synthesis of compound (5): Pd(PPh3)4 (3 mol %) and
HCOONa (1.5 equiv) were added into a two-neck round bottom flask. The flask
was evacuated and flushed with nitrogen. Propargylamine (0.4 mmol)
dissolved in DMF (4.5 ml) was added, followed by distilled water (1.5 ml).
The flask was heated to 100 °C in an oil bath for 3 h under N2 atmosphere.
Upon completion of the reaction the mixture was diluted with CH2Cl2. The
organic phase was washed several times with brine, dried (anhydrous Na2SO4)
and concentrated under reduced pressure. The crude product was
chromatographed (petroleum ether/ethyl acetate as eluent) and its
appropriate yield is shown in Table 4.
14. Spectral data of compound (5d): (Z)-2-benzyl-4-benzylidene-1,2,3,4-
tetrahydro-3-(4-methoxyphenyl)isoquinoline; yellow oil; Rf 0.71 (5% AcOEt/
petroleum ether); IR (KBr): 1024, 1237, 1564, 1645, 2369, 2938 cmÀ1 1H NMR
;
(500 MHz, CDCl3): d 3.54 (d, J = 13.75 Hz, 1H, –CH2-Ar), 3.60 (d, J = 14.50 Hz,
1H, –CH2-Ar), 3.73 (d, J = 13.75 Hz, 1H, –CH2-Ar), 3.77 (s, 3H –OCH3), 3.84 (d,
J = 14.55 Hz, 1H, –CH2-Ar), 4.98 (s, 1H, –CH), 6.83 (d, J = 8.4 Hz, 2H, Ar-H), 6.89
(d, J = 7.65 Hz, 1H, Ar-H), 7.12–7.14 (m, 5H, Ar-H), 7.16–7.22 (m, 6H, Ar-H), 7.29
(t, J = 7.85 Hz, 1H, Ar-H), 7.37 (d, J = 9.15 Hz, 2H, Ar-H), 7.45 (s, 1H, @CH), 7.83
(d, J = 7.65 Hz, 1H, Ar-H); 13C NMR (125 MHz, CDCl3): d 48.6, 55.2, 58.2, 60.9,
113.8, 124.2, 126.7, 126.8, 126.9, 127.1, 127.8, 128.0, 128.3, 128.6, 128.7, 129.0,
129.6, 132.4, 132.9, 133.8, 134.3, 137.0, 139.2, 158.7, 163.1; MS (EI): m/z
418.60 [M+H]+; Anal. Calcd for C30H27NO: C, 86.30; H, 6.52; N, 3.35. Found: C,
86.33; H, 6.55; N, 3.33.