Quinone methide initiated cyclization reaction: Synthesis of 4-aryl-1,2,3,4-tetrahydroisoquinolines

Article abstract of DOI:10.1016/j.tetlet.2004.08.053

4-Aryl-1,2,3,4-tetrahydroisoquinolines were synthesized in very good yields by in situ generation of p-quinone methides resulting in a novel C-C bond cyclization. 4-Aryl-1,2,3,4-tetrahydroisoquinolines were synthesized in very good yields by in situ gener

Full text of DOI:10.1016/j.tetlet.2004.08.053

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 7487–7489
Quinone methide initiated cyclization reaction: synthesis of
4-aryl-1,2,3,4-tetrahydroisoquinolines
,
B. China Raju,* Parvathi Neelakantan and U. T. Bhalerao*
Organic Chemistry Division, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 24 May 2004; revised 30 July 2004; accepted 6 August 2004
Available online 26 August 2004
Abstract—4-Aryl-1,2,3,4-tetrahydroisoquinolines were synthesized in very good yields by in situ generation of p-quinone methides
resulting in a novel C–C bond formation.
Ó 2004 Elsevier Ltd. All rights reserved.
Tetrahydroisoquinolines are an important class of natu-
ral and synthetic compounds, which exhibit a vast range
of biological activities1 such as antitumor,2 antibacte-
rial,3 antiplasmodial,4 and b-adrenergic receptor anta-
gonism.5 Tetrahydroisoquinolines arylated at C-4 dis-
play prominent pharmaceutical activities.6 Cherylline is
a naturally occurring optically active, 4-aryl-1,2,3,4-
tetrahydroisoquinoline alkaloid, isolated from an Ama-
ryllidaceae plant7 and several synthesis have been
reported.8
of p-quinone methides. 2,6-Disubstitution imparts in-
creased stability to a quinone methide,14 so a subsequent
cyclization would require an internal nucleophile (cycli-
zation terminator) that is stable under the conditions
used to generate the quinone methide yet reactive
enough to attack the carbon terminus. N-(3,5-Dimethyl-
4-hydroxyphenethyl)-N-tosyl-3,4-dimethoxybenzyl-amine
7a is required to generate the quinone methide and
allow a subsequent cyclization to give the tetrahydroiso-
quinoline (Scheme 2). Accordingly 4-benzyloxy-3,5-
dimethylphenylacetic acid13a,15 1 was esterified giving
2. The ester 2 on reduction with LAH gave alcohol 3
and bromination16 with CBr4/PPh3 gave 4-benzyloxy-
3,5-dimethylphenethyl bromide 4 (Scheme 1).
Quinone methides are interesting compounds and play
an important role in biosynthesis and in the biological
activity of many quinonoid antitumor compounds.9
However, synthetic methodologies to produce such quin-
one methides and their applications are limited because
in situ generated o-quinone methides acting as hetero-
dienes in Diels–Alder reactions.10 p-Quinone methides
are involved as transition intermediates in a synthesis
of picropodophylline.11
The substituted N-tosylated benzylamine 5a was treated
with NaH17 followed by the addition of phenethyl bro-
mide 4 and gave N-(4-benzyloxy-3,5-dimethylphen-
ethyl)-N-tosyl-3,4-dimethoxybenzylamine 6a (Scheme
2). Compound 6a on debenzylation with palladium
charcoal under hydrogen in ethyl acetate gave N-(3,5-
dimethyl-4-hydroxyphenethyl)-N-tosyl-3,4-dimethoxy-
benzylamine 7a, which, on oxidation14 with Ag2O in dry
DCM at room temperature gave quinone methide 8a as
a yellow viscous liquid. The quinone methide was iso-
lated and characterized by its 1H NMR spectrum, which
clearly indicated the formation of quinone methide 8a
by the appearance of methine proton as a triplet at d
5.78 (J = 7.8Hz) and the disappearance of the singlet
at d 4.40 of the phenolic proton and the triplet at d
2.42 (J = 5.6Hz) of 7a. Due to restricted rotation, the
two methyl groups resonated as two separate singlets
at d 1.86 and 1.90 in 8a where as they appeared as a sin-
glet at d 2.08 in 7a. The yellow viscous 8a was dissolved
We have reported the stereospecific synthesis of
dihydroindenyl and tetrahydronaphthalene12 derivatives
by novel C–C bond formation via in situ generated of p-
quinone methides. Herein, we report13 the synthesis of
4-aryl-1,2,3,4-tetrahydroisoquinolines and derivatives
of the cherylline alkaloid series, via in situ generated
Keywords: 4-Aryl-1,2,3,4-tetrahydroisoquinolines; p-Quinone met-
hides; C–C bond formation; Cherylline analogues.
*
Corresponding author. E-mail: chinaraju@iict.res.in
Former Director, IICT, Hyderabad 500 007, India, IICT Commu-
nication No. 040210.
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.08.053

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B. China Raju et al. / Tetrahedron Letters 45 (2004) 7487–7489
OBn
OBn
OBn
OBn
H3C
CH3
H3C
CH3
H3C
CH3
H3C
CH3
MeOH/ H+
85%
LAH
75%
CBr4/PPh3
76%
COOH
COOMe
CH2OH
CH2Br
1
2
3
4
Scheme 1.
OH
References and notes
OBn
H3C
Pd/C/ H2
CH3
H3C
CH3
1. (a) Herbert, R. B. In The Chemistry and Biology of
Isoquinoline Alkaloids; Philipson, J. D., Roberts, M. F.,
Zenk, M. H., Eds.; Springer: Berlin, 1985; p 213; (b)
Shamma, M. In Isoquinoline Alkaloids, Chemistry and
Pharmacology; Academic: New York, 1972.
2. Capilla, A. S.; Romero, M.; Pujol, M. D.; Caignard, D.
H.; Renard, P. Tetrahedron 2001, 57, 8297.
3. Bernan, V. S.; Montenegro, D. A.; Korshalla, J. D.;
Maiese, W. M.; Steinberg, D. A.; Greenstein, M. J.
Antibiot. 1994, 47, 1417.
R1
1
3
1
1) NaH/DMF
R
2
R
R
NHR
2) Compound 4
R2
3
R
3 N
R
N
R2
a-c
5
7a-c
6a-c
Ag2O
DCM
OH
O
H3C
CH3
H3C
CH3
4. Urverg-Ratsigmamanga, S.; Rasoanairo, P.; Rafatro, H.;
Robijana, B.; Rokato-Ratsimamanga, A. Ann. Trop. Med.
Parasitol. 1994, 88, 271.
5. Dong, H.; Sheng, J. Z.; Lee, C. M.; Wong, T. M. Br. J.
Pharmacol. 1993, 109, 113.
6. (a) Dandridge, P. A.; Kaiser, C.; Brenner, M.; Gaitanop-
oulos, D.; Davis, L. D.; Webb, R. L.; Foley, J. J.; Sarau, H.
M. J. Med. Chem. 1984, 27, 28; (b) Kihara, M.; Ikeuchi,
M.; Adachi, S.; Nagao, Y.; Moritoki, H.; Yamaguchi, M.;
Taira, Z. Chem. Pharm. Bull. 1995, 43, 1543.
ZnCl2
DCM
R1
R1
R2
3
3
R
N
N
R
R2
9a-c
8a-c
R1=R2=OMe, R3=Ts
,
yield
86%
9 a
9 b
9 c
1
2
3
yield
yield
R =OMe, R =H, R =Ts,
85%
78%
1
2
3
R =H, R =OMe, R =Ts,
,
Scheme 2.
7. Brossi, A.; Grethe, G.; Teitel, S.; Wildman, W. C.; Bailey,
D. T. J. Org. Chem. 1970, 35, 1100.
8. (a) Schwartz, M. A.; Scott, S. W. J. Org. Chem. 1971, 36,
1827; (b) Kametani, T.; Takahashi, K.; Lock, C. V.
Tetrahedron 1975, 31, 235; (c) Hart, D. J.; Cain, P. A.;
Evans, D. A. J. Am. Chem. Soc. 1978, 100, 1548; (d)
Kametani, T.; Higashiyama, K.; Honda, T.; Otomasu, H.
J. Chem. Soc., Perkin Trans. 1 1982, 2935; (e) Katakawa,
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in dry DCM and ZnCl2 was added with stirring at room
temperature affording 4-(3,5-dimethyl-4-hydroxyphe-
nyl)-N-tosyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquin-
oline 9a as a thick viscous liquid in 86% yield (Scheme
2).18 The cyclization was indicated by the appearance
of a methine proton (C-4) as a triplet at d 4.10
1
(J = 6.2Hz) in the H NMR spectrum. Similarly, the
compounds 4-(3,5-dimethyl-4-hydroxyphenyl)-N-tosyl-
6-methoxy-1,2,3,4-tetrahydroisoquinoline 9b and 4-
(3,5-dimethyl-4-hydroxyphenyl)-N-tosyl-7-methoxy-1,2,
3,4-tetrahydroisoquinoline 9c were also prepared and all
1
the new products were characterized by H NMR, IR,
10. (a) Turner, A. B. Quart. Rev. 1965, 18, 347; (b) Wagner,
H. U.; Gompper, R. Quinone Methides. In The Chemistry
of the Quinonoid Compounds; Patai, S., Ed.; Wiley: New
York, 1974; p 1145; (c) Mariano, J. P.; Dax, S. L. J. Org.
Chem. 1984, 49, 3671.
MS, and CHN analysis. The results confirm the novel
C–C bond formation in this synthesis of 4-aryl-1,2,3,4-
tetrahydroisoquinolines, in very good yields, with simple
and mild procedures. We are currently exploring the
application of this methodology to the synthesis of nat-
ural products.
11. Kende, A. S.; Liebeskind, L. S.; Mills, J. E.; Rutledge, P. S.;
Curran, D. P. J. Am. Chem. Soc. 1977, 99, 7082.
12. Bhalerao, U. T.; Murali Krishna, C.; Pandey, G. J. Chem.
Soc., Chem. Commun. 1992, 17, 1176.
In conclusion, we have demonstrated a new and conven-
ient synthesis of 4-aryl-1,2,3,4-tetrahydroisoquinolines
via a novel C–C bond formation by in situ generation
of p-quinone methides in very good yields.
13. (a) Bhalerao, U. T.; China Raju, B.; Neelakantan, P.
Synth. Commun. 1995, 25, 1433; (b) Bhalerao, U. T.;
China Raju, B.; Neelakantan, P. Ind. J. Chem. 1994, 31B,
1197; (c) Bhalerao, U. T.; China Raju, B.; Neelakantan, P.
Ind. J. Chem. 1996, 35B, 530; (d) China Raju, B.;
Jayathirtha Rao, V. U.S. Patent 2003, 6566528; (e) Ganga
Dasu, B.; China Raju, B.; Jayathirtha Rao, V. U.S. Patent
2002, 6479664; (f) China Raju, B.; Jayathirtha Rao, V.
Ind. J. Chem. 2002, 41B, 2180.
Acknowledgements
One of the authors B.C.R. thanks the Director, IICT
and Dr. V. Jayathirtha Rao for their constant
encouragement.
14. (a) Angle, S. R.; Turnbell, K. D. J. Am. Chem. Soc. 1989,
111, 1136; (b) Angle, S. R.; Louie, M. S.; Mattson, H. L.
Yang, W. Tetrahedron Lett. 1989, 30, 1193; (c) Angle, S.

B. China Raju et al. / Tetrahedron Letters 45 (2004) 7487–7489
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J = 7.6Hz), 7.69 (d, 2H, aromatic, J = 7.6Hz).
To the quinone methide 8a in dry DCM (5mL), ZnCl2
(0.22g, 1.6mmol) was added and the mixture stirred for
30min at room temperature. The organic layer was
washed with water, dried over sodium sulfate, the solvent
removed under reduced pressure and the residue purified
by column chromatography using silica gel giving 4-(3,5-
dimethyl-4-hydroxyphenyl)-N-tosyl-6,7-dimethoxy-1,2,3,
4-tetrahydroisoquinoline 9a (0.12g, 86%) as a thick viscous
liquid. 1H NMR (CDCl3, 200MHz): d 2.20 (s, 6H, 2CH3),
2.42 (s, 3H, CH3), 2.84, 2.92 (dd, 1H, C3–H, J = 7.2 and
11.2Hz), 3.66 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 3.72,
3.78 (dd, 1H, C3–H, J = 6.4 and 11.2Hz), 4.02 (d, 1H, C1–
H, J = 5.8Hz), 4.10 (t, 1H, C–4H, J = 6.2Hz), 4.42 (d, 1H,
C–1H, J = 5.8Hz), 4.61 (s, 1H, OH, D2O exchangeable),
6.35 (s, 1H, aromatic), 6.56 (s, 1H, aromatic), 6.68 (s, 1H,
aromatic), 7.29 (d, 2H, aromatic, J = 7.4Hz), 7.64 (d, 2H,
aromatic, J = 7.4Hz). IR (KBr): 3475, 2940, 1590, 1510,
1265, 1220, 1150 and 1125cmÀ1. Mass (EI): m/e 467 (M+),
311, 309, 284, 269, 253, 190, 166, 135, 92, 83, 43. Anal.
Calcd for C26H29NSO5: C, 66.80; H; 6.20; N, 2.99. Found:
C, 66.82; H; 6.24; N, 2.96.
15. Krapcho, A. P.; Larson, J. R.; Eldride, M. J. J. Org.
Chem. 1977, 42, 3749.
16. Hooz, J.; Gilani, S. S. H. Can. J. Chem. 1968, 46, 86.
17. Tietze, L. F.; Schimpt, R. Chem. Ber. 1994, 127, 2235.
18. Typical experimental procedure. 4-(3,5-Dimethyl-4-
hydroxyphenyl)-N-tosyl-6,7-dimethoxy-1,2,3,4-tetrahydro-
isoquinoline 9a: to
a solution of N-(3,5-dimethyl-4-
hydroxyphenethyl)-N-tosyl-3,4-dimethoxybenzylamine 7a
(0.15g, 0.3mmol) in dry DCM (6mL), Ag2O (0.37g,
1.6mmol) was added and the mixture stirred at room
temperature for 6h. The contents were filtered using Celite
as filter aid and the solvent was removed under reduced
pressure below 40°C to give the quinone methide 8a as a
yellow viscous liquid. 1H NMR (CDCl3, 200MHz): d 1.86
(s, 3H, CH3), 1.90 (s, 3H, CH3), 2.41 (s, 3H, CH3), 3.70 (s,
3H, OCH3), 3.78 (s, 3H, OCH3), 4.02 (d, 2H, CH2,
J = 6.2Hz), 4.18 (s, 2H, CH2), 5.78 (t, 1H, methine,
J = 7.8Hz), 6.58 (s, 2H, dienone), 6.62–6.8 (m, 2H,
aromatic), 6.75 (s, 1H, aromatic), 7.29 (d, 2H, aromatic,