One-pot synthesis of Fluorinated 1-benzoyl-3,4-dihydroisoquinolines from [2-(o-alkynylphenyl)ethyl]amines by a hydroamination/oxidation sequence

Article abstract of DOI:10.1002/ejoc.200901034

Fluorinated 1-benzoyl-3,4-dihydroisoquinolines can easily be synthesized by a new one-pot procedure from corresponding fluorinated [2-(o-alkynylphenyl) ethyl]amines in high yields. The one-pot process consists of an initial [Ind₂TiMe₂]-catalyzed intramolecular alkyne hydroamination and a subsequent Pd-catalyzed oxidation of the benzyl side chain of the resulting hydroamination product. The process tolerates electron-donating and-withdrawing substituents on the benzene ring that is converted into the benzoyl side chain of the products as well as ortho-substitution.

Full text of DOI:10.1002/ejoc.200901034

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200901034
One-Pot Synthesis of Fluorinated 1-Benzoyl-3,4-dihydroisoquinolines from
[2-(o-Alkynylphenyl)ethyl]amines by a Hydroamination/Oxidation Sequence
René Severin,[a] Jessica Reimer,[a] and Sven Doye*[a]
Keywords: Antitumor agents / Nitrogen heterocycles / Hydroamination / Palladium / Oxidation / Titanium
Fluorinated 1-benzoyl-3,4-dihydroisoquinolines can easily
be synthesized by a new one-pot procedure from correspond-
ing fluorinated [2-(o-alkynylphenyl)ethyl]amines in high
yields. The one-pot process consists of an initial [Ind2TiMe2]-
catalyzed intramolecular alkyne hydroamination and a sub-
sequent Pd-catalyzed oxidation of the benzyl side chain of
the resulting hydroamination product. The process tolerates
electron-donating and -withdrawing substituents on the ben-
zene ring that is converted into the benzoyl side chain of the
products as well as ortho-substitution.
During the past 10 years we have developed a number of
protocols for the catalytic hydroamination of alkenes and
alkynes[6–8] which have already been used for the synthesis
of biologically interesting target molecules.[9] Based on our
initial synthetic strategy towards the enantioselective syn-
thesis of the benzylisoquinoline alkaloid (S)-laudanosine[10]
we also synthesized a number of norlaudanosine derivatives
possessing electron-withdrawing substituents on the ben-
zene ring of the isoquinoline skeleton.[11] In both cases, a
Ti-catalyzed intramolecular hydroamination of aminoal-
kynes (Scheme 1)[12] which takes place in the presence of
catalytic amounts of [Cp2TiMe2] (Cp = η5-cyclopen-
tadienyl) or [Ind2TiMe2] (Ind = η5-indenyl) is the key syn-
thetic step. While in the past, the resulting imines were usu-
ally reduced to give the envisioned corresponding amine
target molecules, we recently decided to directly use the hy-
droamination products for a subsequent oxidation of the
Introduction
Benzylisoquinolines are regarded as a class of com-
pounds with a wide range of interesting pharmacological
properties, including analgetic, sedative, anesthetic, antitus-
sive, spasmolytic, and sympathomimetic activity.[1] In ad-
dition, it was recently reported that a number of 1-benzoyl-
3,4-dihydroisoquinolines possess significant antitumor ac-
tivity at micromolar concentration (IC50 Ͻ 5 µ).[2] While
it was found that a hydrophobic group at the C-6 position
(e.g. benzyloxy, alkyloxy or allyloxy) seems to be relevant
for cytotoxicity,[2] to the best of our knowledge no infor-
mation is available about the antitumor activity of corre-
sponding 6-fluoro- or 6-trifluoromethyl-substituted or even
more halogenated derivatives. At first sight, this is surpris-
ing because it is a widely accepted strategy in pharmaceuti-
cal research to synthesize fluorinated derivatives of biolo-
gically active compounds to improve their pharmacological
properties (e.g. metabolic stability and/or lipophilicity).[3]
On the other hand, 1-benzoyl-3,4-dihydroisoquinolines are
usually synthesized from the corresponding 1-benzyl-3,4-di-
hydroisoquinolines by selective oxidation of the benzylic
carbon[2,4] which means that corresponding fluorinated 1-
benzyl-3,4-dihydroisoquinolines are needed as starting ma-
terials for the final oxidation step. However, because of the
electron-withdrawing nature of the fluoro-substituents these
fluorinated imines are not easily accessible by simple elec-
trophilic aromatic substitution reactions (e.g. Bischler–Nap-
ieralski reaction).[5]
[a] Institut für Reine und Angewandte Chemie,
Universität Oldenburg,
Carl-von-Ossietzky-Str. 9-11, 26111 Oldenburg, Germany
Fax: +49-441-798-3329
E-mail: doye@uni-oldenburg.de
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200901034.
Scheme 1. Synthetic approach towards the synthesis of fluorinated
1-benzoyl-3,4-dihydroisoquinolines.
Eur. J. Org. Chem. 2010, 51–54
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51

R. Severin, J. Reimer, S. Doye
SHORT COMMUNICATION
benzylic carbon atom which should lead to the formation Table 1. One-pot synthesis of fluorinated 1-benzoyl-3,4-dihydroiso-
quinolines from [2-(o-alkynylphenyl)ethyl]amines.
of antitumor-active 1-benzoyl-3,4-dihydroisoquinolines. As
the result, we now describe a one-pot synthesis of 6-fluoro-
and 6-trifluoromethyl-substituted 1-benzoyl-3,4-dihydroiso-
quinolines from corresponding fluorinated [2-(o-alk-
ynylphenyl)ethyl]amines (Scheme 1). An obvious advantage
of the envisioned strategy is the fact that these aminoalk-
ynes are easily accessible with high diversity from commer-
cially available starting materials by a Sonogashira-coupling
strategy, as described before.[11]
Results and Discussion
Initial experiments were performed with the fluoro-sub-
stituted aminoalkyne 1 (Table 1, entry 1) and it was found
that the intramolecular hydroamination could easily be
achieved in the presence of 5 mol-% [Ind2TiMe2] in toluene
at 105 °C. In agreement with the accepted mechanism of the
Ti-catalyzed hydroamination of alkynes,[8c] the cyclization
reaction takes place with complete regioselectivity.[12] After
a reaction time of 12 h, it was not possible by TLC analysis
to detect the aminoalkyne 1 anymore. The resulting solu-
tion of the hydroamination product was then allowed to
cool to room temperature and 10 mol-% Pd/C and CH3CN
were added for the subsequent oxidation step.[2] After this
mixture had been stirred under an atmosphere of oxygen
for 24 h at room temperature TLC analysis showed the for-
mation of a new product which indeed turned out to be the
desired 6-fluoro-substituted 1-benzoyl-3,4-dihydroisoquin-
oline 17. Final purification by column chromatography gave
17 in 67% yield. In this context it is worth to mention that
the oxidation step does not require the use of pure oxygen,
it can also be performed in air. However, in this case the
rate of the oxidation reaction is significantly reduced and
complete conversion is not achieved within 3 days.
Encouraged by this result, we turned our attention
towards the synthesis of related 6-fluoro-substituted 1-ben-
zoyl-3,4-dihydroisoquinolines with differently substituted
benzoyl side chains. For that reason, the new one-pot pro-
cedure was applied to the aminoalkynes 2–8 (Table 1, en-
tries 2–8) and it turned out that the process tolerates elec-
tron-donating (entries 2, 7) and electron-withdrawing sub-
stituents (entries 3, 8) as well as ortho-substitution (entries
6–8) of the benzene ring that is converted into the benzoyl
side chain. In all cases, the desired keto imines (18–24) were
obtained in good yields (59–77%). Fortunately, quite sim-
ilar results were obtained during the synthesis of the 6-tri-
fluoromethyl-substituted 1-benzoyl-3,4-dihydroisoquinol-
ines 25–32 (Table 1, entries 9–16) from the corresponding
aminoalkynes 9–16. Because most of the yields are again
good to very good (49–84%) the new one-pot process obvi-
ously does not imply any significant limitations with regard
to the substituents on the benzene rings of the aminoalk-
ynes. Especially interesting is the fact that even the bis(tri-
fluoromethyl)-substituted products 27 and 32 are obtained
in very good yields.
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Eur. J. Org. Chem. 2010, 51–54

One-Pot Synthesis of Fluorinated Isoquinolines
3
3
(q, JF,C = 4 Hz, CH), 124.7 (q, JF,C = 4 Hz, CH), 126.9 (CH),
Table 1. (Continued)
4
2
129.0 (C), 131.6 (d, JF,C = 2 Hz, C), 133.0 (q, JF,C = 33 Hz, C),
3
1
133.2 (d, JF,C = 10 Hz, CH), 138.1 (C), 163.6 (C), 166.3 (d, JF,C
= 257 Hz, CF), 191.2 (C) ppm. IR (neat): 1/λ = 2963, 2857, 1671,
1596, 1505, 1318, 1213, 1169, 1144, 1112, 1078, 1060, 1016, 908,
845 cm–1. MS (CI): m/z (%) = 322 (100) [M + H]+, 293 (4), 123 (7).
HRMS: (CI) calcd. (C17H12F4NO) 322.0855; found 322.0860.
Supporting Information (see also the footnote on the first page of
this article): Experimental details and complete characterization
1
data of all products, H and 13C NMR spectra.
Acknowledgments
We thank the Deutsche Forschungsgemeinschaft (DFG) and the
Fonds der Chemischen Industrie for financial support of our re-
search.
[a] Typical reaction conditions: (a) aminoalkyne (1.00 mmol),
[Ind2TiMe2] (0.05 mmol, 5 mol-%), toluene (1 mL), 105 °C, 12–
16 h; (b) Pd/C (0.10 mmol Pd, 10 mol-%), CH3CN (3 mL), O2
(1 atm), 25 °C, 24 h. Yields refer to isolated pure compounds.
[1] a) The Chemistry and Biology of Isoquinoline Alkaloids (Eds.:
J. D. Phillipson, M. F. Roberts, M. H. Zenk), Springer, Berlin,
1985; b) The Isoquinoline Alkaloids (Ed.: M. Shamma), Aca-
demic Press, Inc., New York, 1972.
[2] A. Bermejo, I. Andreu, F. Suvire, S. Léonce, D. H. Caignard,
P. Renard, A. Pierré, R. D. Enriz, D. Cortes, N. Cabedo, J.
Med. Chem. 2002, 45, 5058–5068.
Conclusions
[3] a) T. Hiyama, M. Shimizu, Angew. Chem. 2005, 117, 218–234;
Angew. Chem. Int. Ed. 2005, 44, 214–231; b) H.-J. Böhm, D.
Banner, S. Bendels, M. Kansy, B. Kuhn, K. Müller, U. Obst-
Sander, M. Stahl, ChemBioChem 2004, 5, 637–643.
[4] R.-Y. Kuo, F.-R. Chang, C.-C. Wu, R. Patnam, W.-Y. Wang,
Y.-C. Du, Y.-C. Wu, Bioorg. Med. Chem. Lett. 2003, 13, 2789–
2793.
[5] Strategic Applications of Named Reactions in Organic Synthesis
(Eds.: L. Kürti, B. Czakó), Elsevier Academic Press, Burl-
ington, 2005, pp. 62–63.
[6] For general reviews on hydroamination, see: a) T. E. Müller,
M. Beller, Chem. Rev. 1998, 98, 675–703; b) J. J. Brunet, D.
Neibecker, in: Catalytic Heterofunctionalization (Eds.: A.
Togni, H. Grützmacher), Wiley-VCH, Weinheim, 2001, pp. 91–
141; c) P. W. Roesky, T. E. Müller, Angew. Chem. 2003, 115,
2812–2815; Angew. Chem. Int. Ed. 2003, 42, 2708–2710; d)
K. C. Hultzsch, Adv. Synth. Catal. 2005, 347, 367–391; e) K. C.
Hultzsch, Org. Biomol. Chem. 2005, 3, 1819–1824; f) J.-J. Bru-
net, N.-C. Chu, M. Rodriguez-Zubiri, Eur. J. Inorg. Chem.
2007, 4711–4722; g) I. Aillaud, J. Collin, J. Hannedouche, E.
Schulz, Dalton Trans. 2007, 5105–5118; h) A. V. Lee, L. L.
Schafer, Eur. J. Inorg. Chem. 2007, 2243–2255; i) J.-J. Brunet,
N.-C. Chu, M. Rodriguez-Zubiri, Eur. J. Inorg. Chem. 2007,
4711–4722; j) T. E. Müller, K. C. Hultzsch, M. Yus, F. Foubelo,
M. Tada, Chem. Rev. 2008, 108, 3795–3892; k) S. Doye, in:
Science of Synthesis, vol. 40a, Thieme, Stuttgart, 2009, pp. 241–
304.
[7] For reviews on hydroamination of alkynes, see: a) F. Pohlki, S.
Doye, Chem. Soc. Rev. 2003, 32, 104–114; b) I. Bytschkov, S.
Doye, Eur. J. Org. Chem. 2003, 935–946; c) S. Doye, Synlett
2004, 1653–1672; d) F. Alonso, I. Beletskaya, M. Yus, Chem.
Rev. 2004, 104, 3079–3160; e) A. Odom, Dalton Trans. 2005,
225–233; f) R. Severin, S. Doye, Chem. Soc. Rev. 2007, 36,
1407–1420.
In summary, we have shown that potentially antitumor-
active fluorinated 1-benzoyl-3,4-dihydroisoquinolines can
easily be synthesized by a new one-pot procedure from cor-
responding fluorinated [2-(o-alkynylphenyl)ethyl]amines in
high yields. The one-pot process consists of an initial
[Ind2TiMe2]-catalyzed intramolecular alkyne hydroamin-
ation and a subsequent Pd-catalyzed oxidation of the ben-
zyl side chain of the resulting hydroamination product. The
process tolerates electron-donating and -withdrawing sub-
stituents on the benzene ring that is converted into the ben-
zoyl side chain of the products as well as ortho-substitution.
Experimental Section
[Ind2TiMe2][8e] and the aminoalkynes 1–16[11] were synthesized ac-
cording to literature procedures.
Typical Procedure Exemplified by the Reaction of Aminoalkyne 12:
(Table 1, entry 12) In an Argon-filled Schlenk tube, a mixture of
aminoalkyne 12 (307 mg, 1.00 mmol) and [Ind2TiMe2] (15 mg,
0.05 mmol, 5 mol-%) in toluene (1 mL) was stirred at 105 °C for
16 h. The resulting dark brown solution was cooled to room tem-
perature and treated with CH3CN (3 mL) and Pd/C (10% Pd on
C, 106 mg, 0.10 mmol Pd, 10 mol-%). After this had been stirred
at 25 °C under an atmosphere of O2 for 24 h, the reaction mixture
was filtered through Celite and concentrated under vacuum. After
purification by flash chromatography (SiO2, 22 g, light petroleum
ether/EtOAc, 4:1), compound 28 (266 mg, 0.83 mmol, 83%, Rf =
0.51) was isolated as a yellow solid; m.p. 70 °C. 1H NMR
(500 MHz, CDCl3, 24 °C): δ = 2.94 (br. t, 3JH,H = 7.7 Hz, 1 H, Ar-
[8] For selected examples, see: a) E. Haak, I. Bytschkov, S. Doye,
Angew. Chem. 1999, 111, 3584–3586; Angew. Chem. Int. Ed.
1999, 38, 3389–3391; b) F. Pohlki, A. Heutling, I. Bytschkov,
T. Hotopp, S. Doye, Synlett 2002, 799–801; c) A. Heutling,
F. Pohlki, S. Doye, Chem. Eur. J. 2004, 10, 3059–3071; d) K.
Marcseková, B. Wegener, S. Doye, Eur. J. Org. Chem. 2005,
4843–4851; e) A. Heutling, R. Severin, S. Doye, Synthesis 2005,
1200–1204; f) C. Müller, C. Loos, N. Schulenberg, S. Doye,
3
3
CH2), 4.03 (br. t, JH,H = 7.7 Hz, 1 H, CH2-N), 7.16 (dt, JH,H
=
4
8.6, JF,H = 1.7 Hz, 2 H, Ar-H), 7.50–7.55 (m, 3 H, Ar-H), 8.10
(dd, JH,H = 8.6, JF,H = 5.6 Hz, 2 H, Ar-H) ppm. 13C NMR
(126 MHz, DEPT, CDCl3, 24 °C): δ = 25.3 (CH2), 47.1 (CH2),
115.8 (d, 2JF,C = 22 Hz, CH), 123.5 (q, 1JF,C = 273 Hz, CF3), 124.2
3
3
Eur. J. Org. Chem. 2010, 51–54
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53

R. Severin, J. Reimer, S. Doye
SHORT COMMUNICATION
Eur. J. Org. Chem. 2006, 2499–2503; g) C. Müller, W. Saak, S.
Doye, Eur. J. Org. Chem. 2008, 2731–2739.
[9] a) H. Siebeneicher, S. Doye, Eur. J. Org. Chem. 2002, 1213–
1220; b) I. Bytschkov, H. Siebeneicher, S. Doye, Eur. J. Org.
Chem. 2003, 2888–2902; c) H. Siebeneicher, I. Bytschkov, S.
Doye, Angew. Chem. 2003, 115, 3151–3153; Angew. Chem. Int.
Ed. 2003, 42, 3042–3044.
[10]
[11]
D. Mujahidin, S. Doye, Eur. J. Org. Chem. 2005, 2689–2693.
R. Severin, D. Mujahidin, J. Reimer, S. Doye, Heterocycles
2007, 74, 683–700.
[12] I. Bytschkov, S. Doye, Tetrahedron Lett. 2002, 43, 3715–3718.
Received: September 9, 2009
Published Online: November 20, 2009
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Eur. J. Org. Chem. 2010, 51–54