Nucleophilic addition of β-amino carbanions to arynes: One-pot synthesis of 4-aryl-N-methyl-1,2,3,4-tetrahydroisoquinolines

Article abstract of DOI:10.1021/ol300360r

A novel approach for the direct C-4 arylation of N-methyl-1,2,3,4- tetrahydroisoquinolines by nucleophilic addition of β-aminocarbanions to benzynes is described which provides a one-pot procedure for synthesis of the title compounds.

Full text of DOI:10.1021/ol300360r

ORGANIC
LETTERS
2012
Vol. 14, No. 9
2202–2205
Nucleophilic Addition of β-Amino
Carbanions to Arynes: One-Pot Synthesis
of 4-Aryl-N-methyl-1,2,3,4-
tetrahydroisoquinolines
Kamal Nain Singh,* Paramjit Singh, Pushpinder Singh, and Yadwinder Singh Deol
Department of Chemistry, Panjab University, Chandigarh-160014, India
kns@pu.ac.in
Received February 14, 2012
ABSTRACT
A novel approach for the direct C-4 arylation of N-methyl-1,2,3,4-tetrahydroisoquinolines by nucleophilic addition of β-aminocarbanions to
benzynes is described which provides a one-pot procedure for synthesis of the title compounds.
Tetrahydroisoquinoline is a common structural motif
present in a large number of natural products1 and syn-
theticcompounds of biological importance.2 The 4-aryl-N-
methyl-1,2,3,4-tetrahydroisoquinolines have attracted at-
tention because of their wide range of physiological
activities.3 This basic skelton 1a (Figure 1) is present in
many natural products and drugs; cherylline (1b) and
latifine (1c) are isolated from Amaryllidaceae plants,4 and
nomifensine5 (1d) and diclofensine6 (1e) exhibit CNS activ-
ity and inhibit the serotonine and dopamine uptake mechan-
ism. Many approaches for the synthesis of 4-aryl-N-methyl-
1,2,3,4-tetrahydroisoquinolines have been developed,7 and
most of these involve the construction of a nitrogen-contain-
ing ring.8 More recently, a two-step process which involves a
palladium-catalyzed R-arylation between dihydroisoquino-
linones and aryl halides followed by BH3 reduction of the
carbonyl group has been reported.9
(1) (a) Higuchi, K.; Kawasaki, T. Nat. Prod. Rep. 2007, 24, 843.
(b) Chrzanowska, M.; Rozwadowska, M. D. Chem. Rev. 2004, 104,
3341. (c) Ozturk, T. The Alkaloids; Cordell, G. A., Ed.; Academic Press:
New York, 2000; Vol. 53, p 120. (d) Bentley, K. W. Nat. Prod. Rep. 2005,
22, 249.
ꢀ
(2) (a) Dalence-Guzman, M. F.; Toftered, J.; Oltner, V. T.; Wensbo,
Our research group has been actively engaged in the
generation and reactions of amino carbanions derived
D.; Johansson, M. H. Bioorg. Med. Chem. Lett. 2010, 20, 4999. (b)
€
Ludwig, M.; Hoesl, C. E.; Hoefner, G.; Wanner, K. T. Eur. J. Med.
Chem. 2006, 41, 1003. (c) 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. (d) Shamma, M. In Isoquinoline Alkaloids,
Chemistry and Pharmacology; Academic Press: New York, 1972.
(3) (a) Tateyama, M.; Nagao, T.; Ohta, S.; Hirobe, M.; Hideki, O.
Eur. J. Pharmacol. 1993, 240, 51. (b) Tateyama, M.; Ohta, S.; Nagao, T.;
Hirobe, M.; Hideki, O. Neuropharmacology 1993, 32, 761. (c) Kihara,
M.; Ikeuchi, M.; Adachi, S.; Nagao, Y.; Moritoki, H.; Yamaguchi, M.;
Taira, Z. Chem. Pharm. Bull. 1995, 43, 1543.
(4) (a) Brossi, A.; Grethe, G.; Teitel, S.; Wildman, W. C.; Bailey,
D. T. J. Org. Chem. 1970, 35, 1100. (b) Kobayashi, S.; Tokumoto, T.;
Taira, Z. J. Chem. Soc., Chem. Commun. 1984, 1043. (c) Katakawa, J.;
Yoshimatsu, H.; Yoshida, M.; Zhang, Y.; Irie, H.; Yasima, H. Chem.
Pharm. Bull. 1988, 36, 3928.
(6) Cherpillod, C.; Omer, L. M. J. Int. Med. Res. 1981, 9, 324.
(7) (a) Jacob, J. N.; Nichols, D. E.; Kohli, J. D.; Glock, D. J. Med.
Chem. 1981, 24, 1013. (b) Fodor, G.; Nagubandi, S. Tetrahedron 1980,
36, 1279. (c) Miller, R. B.; Svoboda, J. J. Synth. Commun. 1994, 24, 1187.
(d) Seijas, J. A.; V-Tato, M. P.; Martinez, M. M.; Pizzolatti, M. G.
Tetrahedron Lett. 2005, 46, 5827.
(8) (a) Brossi, A.; Teitel, S. Tetrahedron Lett. 1970, 11, 417. (b)
Ruchirawat, S.; Tontoolarug, S.; Sahakitpichan, P. Heterocycles 2001,
55, 635. (c) Philippe, N.; Denivet, F.; Vasse, J.-L.; Sopkova-de Olivera
Santos, J.; Levacher, V.; Dupas, G. Tetrahedron 2003, 59, 8049.
(d) Venkov, A. P.; Vodenicharov, D. M. Synthesis 1990, 253. (e) Toda,
J.; Sonobe, A.; Ichikawa, T.; Saitoh, T.; Horiguchi, Y.; Sano, T.
ARKIVOC 2000, 2, 165.
(5) (a) Hunt, P.; Kannengiesser, M. H.; Raynand, J. P. J. Pharm.
€
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Pharmacol. 1974, 26, 370. (b) Zara-Kaczian, E.; Gyorgy, L.; Deak, G.;
(9) Hu, M.; Guzzo, P. R.; Zha, C.; Nacro, K.; Yang, Y.-L.; Hassler,
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r
10.1021/ol300360r
Published on Web 04/16/2012
2012 American Chemical Society

with electrophiles occurred at
a distant position
(Scheme 1, eq 2).13 The nitrogen atom had a definitive role
in these reactions as in the corresponding carbocyclic
compounds; no reaction was observed under these
conditions (Scheme 1, eq 3).13a
Aryne chemistry has been extensively reviewed.14 One
of the methods of aryne generation involves treating
aryl fluorides or chlorides with alkyllithium at low tem-
peratures.15 Detailed studies with these and their methoxy-
substituted analogues have been carried out to delineate
the temperature range of formation of o-halolithiated
species and subsequent benzyne generation.16 These inter-
mediates undergo efficient intermolecular/intramolecular
reactions with many nucleophiles including carbanions
derived with the help of suitably placed electron-with-
drawing substituents.17
Figure 1. 4-Aryl-N-methyl-1,2,3,4-tetrahydroisoquinolines.
from tertiary amines.10 It was established that addition of
1 equiv of a strong Lewis acid (BF3 OEt2) to the tertiary
3
amine followed by treatment with s-BuLi in THF at
ꢀ78 °C results in carbanion formation at a position R to
the nitrogen atom. Subsequent reaction with electrophiles
furnished the R-substituted products in excellent yields
(Scheme 1, eq 1).11 This procedure was utilized for
the synthesis of many N-methyltetrahydroisoquinoline
To the best of our knowledge, the nucleophilic coupling
of amino carbanions derived from tertiary amines with
arynes has not been investigated. We reasoned that the
nucleophilic addition of the C-4-lithiated N-methyl-
1,2,3,4-tetrahydroisoquinoline (2a Li) to the in situ gen-
3
erated benzyne could be a valuable strategy for direct
access to C-4-arylated products. In this paper, we describe
our results on the basis of this novel approach.
Scheme 1. Lithiation/Substitution of Tertiary Amines
In the initial studies, the C-4-lithiated species 2a Li
3
was generated by taking tetrahydroisoquinoline 2a
(1.36 mmol) in THF (4 mL) at ꢀ78 °C and adding s-BuLi
(1 equiv). After an interval of 30 min, a second installment
of s-BuLi (1.2 equiv) was addedfollowed by chlorobenzene
(3a) (1 equiv). The reaction mixture was stirred at ꢀ78 °C
for another 45 min and then allowed to warm to ambient
temperature (Scheme 2). It was quenched with 10% HCl.
Workup and purification by column chromatography
afforded the C-4 arylated product 1a in a low yield of
22%.18 In an effort to improve the yield, the quantities of
the base and chlorobenzene were increased, and the results
are summarized in Table 1. A maximum yield of 38% was
obtained by using 2.2 equiv of s-BuLi in the first install-
ment, 3 equiv in the second installment, and addition of
3 equiv of chlorobenzene (Table 1, entry 4). A further
increase in these quantities did not have the desired result
(Table 1, entry 6). Changing the benzyne precursor from
alkaloids.12 Furthermore, it was observed that in absence
of the Lewis acid the carbanion formation and reaction
(10) (a) Kessar, S. V.; Singh, P.; Singh, K. N.; Kaur, A.; Venugopalan,
P.; Bharatam, P. V.; Sharma, A. K. J. Am. Chem. Soc. 2007, 129, 4506.
(b)Kessar, S. V.; Singh, P.; Singh, K. N.; Bharatam, P. V.; Sharma, A. K.;
Lata, S.;Kaur, A. Angew. Chem., Int. Ed. 2008, 47, 4703. (c) Kessar, S. V.;
Singh, P.; Singh, K. N.; Dutt, M. J. Chem. Soc.,Chem. Commun. 1991,
570. (d) Kessar, S. V.; Vohra, R.; Kaur, N. P.; Singh, K. N.; Singh, P.
J. Chem. Soc., Chem. Commun. 1994, 1327. (e) Kessar, S. V.; Singh, P.;
Singh, K. N.; Kaul, V. K.; Kumar, G. Tetrahedron Lett. 1995, 36,
8481.
(17) Khanapure, S. P.; Biehl, E. R. J. Org. Chem. 1990, 55, 1471.
(18) (a) All new products were characterized by 1H NMR, 13C NMR,
and IR spectroscopy and mass spectrometery (APCI-MS and HRMS).
(b) In all of the reactions reported in this paper, some unreacted starting
amine was always recovered. This could be (i) due to incomplete
formation of the lithiated intermediate of 2a or (ii) because the lithiated
intermediate of 2a gets partially quenched by another proton source
(e.g., C-4 benzylic proton of arylated product 1a or from the solvent). To
get some information on these aspects the following two experiments
were carried out: (I) A solution of the amine 2a (1mmol) in THF (3 mL),
at ꢀ78 °C, containing s-BuLi (2.2 mmol) was quenched with MeOD
after 30 min. The 1H NMR spectrum of the material obtained after
workup revealed 100% deuterium incorporation at C-4 position, in-
dicating that complete C-4 carbanion formation had occured. (II) The
reaction of 2a and 3a was carried out in the normal manner, but in the
(11) Kessar, S. V.; Singh., P.; Vohra, R.; Kaur, N. P.; Singh, K. N.
J. Chem. Soc., Chem. Commun. 1991, 568.
(12) Kessar, S. V.; Singh, P. Chem. Rev. 1997, 97, 721.
(13) (a) Kessar, S. V.; Singh, P.; Singh, K. N.; Venugopalan, P.;
Kaur, A.; Mahendru, M.; Kapoor, R. Tetrahedron Lett. 2005, 46, 6753.
(b) Ito, Y.; Nakatsuka, M.; Saegusa, T. J. Am. Chem. Soc. 1982, 104,
7609. (c) Blagg, J.; Coote, S. J.; Davies, S. G. J. Chem. Soc., Perkin
Trans. 1 1987, 689.
(14) (a) Hofmann, R. W. Dehydrobenzene and Cycloalkynes;
Academic Press: New York, 1967. (b) Yoshida, H.; Fukushima, H.; Ohshita,
J.; Kunai, A. Angew. Chem., Int. Ed. 2004, 43, 3935. (c) Reinecke, M. G.
Tetrahedron 1982, 38, 427.
(15) (a) Adejare, A.; Miller, D. D. Tetrahedron Lett. 1984, 25, 5597.
(b) Kress, T. H.; Leanna, M. R. Synthesis 1988, 803. (c) Zieger, H. E.;
Wittig, G. J. Org. Chem. 1962, 27, 3270. (d) Meyers, A. I.; Rieker, W.
Tetrahedron Lett. 1982, 23, 2091.
(16) (a) Furlano, D. C.; Calderon, S. N.; Chen, G.; Kirk, K. L. J. Org.
Chem. 1988, 53, 3145. (b) Iwao, M. J. Org. Chem. 1990, 55, 3622. (c)
Jones, E. P.; Jones, P.; Barrett, A. G. M. Org. Lett. 2011, 13, 1012.
1
end, it was quenched with MeOD instead of 10% HCl. The H NMR
spectrum of the isolated C-4 arylated product 1a did not show any
deuterium incorporation, indicating that once 1a is formed in the
reaction mixture it does not transfer the C-4 benzylic proton to 2a Li.
3
(We are grateful to a reviewer for suggesting these two experiments.)
Org. Lett., Vol. 14, No. 9, 2012
2203

group, reacted to furnish 4eꢀg (Table 2, entries 3ꢀ5). In
fact, a maximum yield of 51% was obtained from 3e. The
formation of products 4hꢀj in which the substituent “R”
appears at a different position from the corresponding
reactants 3hꢀj is along expected lines for benzyne-
mediated reactions.19
Scheme 2. C-4 Arylation of N-Methyl-1,2,3,4- tetrahydroiso-
quinoline
Table 2. Synthesis of 4 Using Different Benzyne Precursorsa
chlorobenzene (3a) to fluorobenzene (3b) gave similar
results (Table 1, entry 5).
Table 1. Optimization of Reaction Conditions for C-4 Arylation
of N-Methyl-1,2,3,4-tetrahydroisoquinoline (2a)
base (s-BuLi in equiv)
entry
3
4
yieldb (%)
entry first installment second installment 3 (in equiv) 1a (% yield)a
1
2
3
4
5
6
7
8
3c (X = Cl; R = 4-OMe)
3d (X = F; R = 4-OMe)
3e (X = Cl; R = 3-OMe)
3f [X = Cl; R = 3,4-(OMe)2]
1
2
3
4
5
6
1
1.2
1.2
2
3a (1)
3a (1)
3a (2)
3a (3)
3b (3)
3a (4)
22
4d (R = 4-OMe)
4e (R = 3-OMe)
4f [R = 3,4-(OMe)2]
42 (57)c
51 (62)
42 (56)
2
28
2
33
38 (55)b
2.2
2.2
2.2
3
3g [X = Cl; R = 3,4,5-(OMe)3] 4g [R = 3,4,5-(OMe)3] 30 (47)
3
38
3h (X = Cl; R = 2-OMe 3-Cl) 4h (R = 3-OMe 4-Cl)
38 (53)
29 (46)
31 (55)
4
35
3i (X = Cl; R = 2-Cl)
4i (R = 3-Cl)
a Isolated yield. b Yield calculated on the basis of recovered starting
amine.
3j (X = Cl; R = 2-CH3)
4j (R = 2- or 3-CH3)
a N-Methyl-1,2,3,4-tetrahydroisoquinoline (1 equiv), s-BuLi (2.2
equiv, first installment), s-BuLi (3 equiv, second installment), aryl halide
(3 equiv) and THF (3 mL/mmol). b Isolated yield. c Yields shown in
parentheses are calculated on the basis of recovered starting amine.
After establishing the optimized conditions,18 differently
substituted benzyne precursors were used to synthesize a
variety of C-4-arylated N-methyl-1,2,3,4-tetrahydroiso-
quinolines (Table 2). It is noteworthy to mention here that
whereas p-methoxyfluorobenzene (3d) reacted to give the
product 4d (Table 2, entry 2), p-methoxychlorobenzene
(3c) failed to react under these conditions (Table 2,
entry 1). This failure can be attributed to the preferential
lithiation at a position ortho to the methoxy group rather
than ortho to the chloro group in 3c. In 3d, the lithiation
occurs to an extent of 25% ortho to fluoro group besides
ortho to the methoxy group.16 However, other methoxy-
substituted chlorobenzenes 3eꢀg, which have a site for
preferential lithiation between the methoxy and chloro
The 6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisoqui-
noline (5a) was next examined for C-4 arylation. When the
reaction was performed using identical conditions as for
2a, the C-4-arylated product 6a was not obtained.20 Use of
toluene/ether (1:1) as solvent, instead of THF, and mod-
ification of temperature for C-4 carbanion generation20 led
to the desired products 6, and the results are summarized
in Table 3. In the process, we were able to synthesize
(()-cherylline dimethyl ether8a,e (6b) in a modest yield of
33% (Table 3, entry 2). Other benzyne precursors 3a,eꢀj
also reacted with 5a to give 6a,cꢀh (Table 3, entries 1 and
3ꢀ8). To further evaluate the substrate scope, differently
substituted tetrahydroisoquinolines (5bꢀd) were also re-
acted under similar conditions as for 5a, and the corre-
sponding products 6iꢀn were obtained in moderate yields
(Table 3, entries 9ꢀ14).
(19) Hofmann, R. W. Dehydrobenzene and Cycloalkynes; Academic
Press: New York, 1967; pp 134ꢀ150.
(20) Appearance of deep red color on addition of alkyllithium to
solutions of N-methyltetrahydroisoquinolines in THF is an indication of
formation of C-4 anion. In the case of 2a, a deep red color appeared at
ꢀ78 °C and persisted up to 0 °C. However, in the case of 5, the color
disappeared upon warming the solution from ꢀ78 f ꢀ60 °C. This is
probably due to proton abstraction from THF by C-4 anion; see ref 13a
and:Stanetty, P.; Koller, H.; Mihovilovic, M. J. Org. Chem. 1992, 57,
6833. When a solution of 5 in toluene/ether (1:1) is treated with s-BuLi
the color does not appear at ꢀ78 °C, but as the solution is warmed to 0 °C
the deep red color appears and persists, indicating that in this solvent
system, the C-4 anion is stable up to 0 °C. On the other hand, the benzyne
generation from 3 occurs at ca. ꢀ40 °C as inferred by trapping experi-
ments with furan:Friedman, L; Logullo, F. M. J. Org. Chem. 1969, 34,
3089.
In summary, we have developed a novel one-pot proce-
dure for direct C-4 arylation of N-methyl-1,2,3,4-tetra-
hydroisoquinolines involving nucleophilic addition of β-amino
carbanions to arynes. Although the yields are modest, its
utility in the synthesis of (()-cherylline dimethyl ether
has been demonstrated. Regioselective arylation at C-1
position in N-methyl-1,2,3,4-tetrahydroisoquinolines by
nucleophilic addition of R-amino carbanions, generated
2204
Org. Lett., Vol. 14, No. 9, 2012

Table 3. C-4 Arylation of Tetrahydroisoquinolines 5a
entry
5
3
6
yieldb (%)
1
5a
5a
5a
5a
5a
5a
5a
5a
5b
5b
5c
5c
5d
5d
3a (X = Cl; R = H)
6a (R1 = R2 = OMe, R = H)
41 (56)c
33 (47)
38 (56)
32 (51)
35 (53)
35 (55)
31 (48)
30 (45)
35 (48)
39 (52)
46 (54)
42 (60)
42 (56)
44 (57)
2
3d (X = F; R = 4-OMe)
3e (X = Cl; R = 3-OMe)
3f [X = Cl; R = 3,4-(OMe)2]
3g [X = Cl; R = 3,4,5-(OMe)3]
3h (X = Cl; R = 2-OMe-3-Cl)
3i (X = Cl; R = 2-Cl)
6b (R1 = R2 = OMe, R = 4-OMe)
6c (R1 = R2 = OMe, R = 3-OMe)
6d [R1 = R2 = OMe, R = 3,4-(OMe)2]
6e [R1 = R2 = OMe, R = 3,4,5-(OMe)3]
6f (R1 = R2 = OMe, R = 3-OMe-4-Cl)
6g (R1 = R2 = OMe, R = 3-Cl)
3
4
5
6
7
8
3j (X = Cl; R = 2-CH3)
3a (X = Cl; R = H)
6h (R1 = R2 = OMe, R = 2- or 3-CH3)
6i (R1 þ R2 = OCH2O, R = H)
9
10
11
12
13
14
3e (X = Cl; R = 3-OMe)
3a (X = Cl; R = H)
6j (R1 þ R2 = OCH2O, R = 3-OMe)
6k (R1 = OMe, R2 = H, R = H)
3e (X = Cl; R = 3-OMe)
3a (X = Cl; R = H)
6l (R1 = OMe,R2 = H, R = 3-OMe)
6m (R1 = OMe, R2 = OEt, R = H)
6n (R1 = OMe,R2 = OEt, R = 3-OMe)
3e (X = Cl; R = 3-OMe)
a 5 (1 equiv), s-BuLi (2.2 equiv, first installment), s-BuLi (3 equiv, second installment), aryl halide 3 (3 equiv) and T:E (1:1) (6 mL/mmol). b Isolated
yield. c Yields shown in parentheses are calculated on the basis of recovered starting amine.
through reaction of Lewis acid complexed amines and
s-BuLi (Scheme 1, eq 1), to arynes for synthesis of 1-aryl-
N-methyl-1,2,3,4-tetrahydroisoquinolines21 is currently
being investigated. Furthermore, application of this
methodology to obtain 1-aryl-2,3,4,5-tetrahydro-3-
benzoazepines13a,22 will be explored.
Acknowledgment. We acknowledge financial sup-
port through Scheme Nos. DST/SR/S1/OC-3/2007
and 01(2138)/07/EMR-II-CSIR sponsored by DST
and CSIR, New Delhi. Y.S.D. and P.S. thank UGC
and CSIR, New Delhi, for the award of research
fellowships.
(21) (a) Munchhof, M. J.; Meyers, A. I. J. Org. Chem. 1995, 60, 7086.
(b) Minor, D. L.; Wyrick, S. D.; Charifson, P. S.; Watts, V. J.; Nichols,
D. E.; Mailman, R. B. J. Med. Chem. 1994, 37, 4317.
Supporting Information Available. Experimental pro-
cedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
ꢀ
(22) (a) Crecente-Campo, J.; Vazquez-Tato, M. P.; Seijas, J. A.
Tetrahedron 2009, 65, 2655. (b) Neumeyer, J. L.; Baindur, N.; Yuan,
J.; Booth, G.; Seeman, P.; Niznik, H. B. J. Med. Chem. 1990, 33, 521. (c)
Chumpradit, S.; Kung, H. F.; Billings, J.; Kung, M.-P.; Pan, S. J. Med.
Chem. 1989, 32, 1431.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 9, 2012
2205