Synthesis of Bi- and tricyclic 1,2-dihydroquinoline derivatives from arylamines and alkynes by a consecutive zinc-ammonium salt catalysis

Article abstract of DOI:10.1002/adsc.201200155

A relay catalysis of a cationic zinc complex and N,N-dimethylaniline hydrotrifluoromethyl sulphonate induces a multiple C-C bond and C-N bond formation. The one-step synthesis make highly substituted bi- and tricyclic 1,2-dihydroquinoline derivatives easily available from simple starting materials. The high yielding process consists of several simultaneous operating steps. Copyright

Full text of DOI:10.1002/adsc.201200155

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DOI: 10.1002/adsc.201200155
Synthesis of Bi- and Tricyclic 1,2-Dihydroquinoline Derivatives
from Arylamines and Alkynes by a Consecutive Zinc-Ammonium
Salt Catalysis
a
a,
Nibadita Purkait and Siegfried Blechert *
a
Institute of Chemistry, TU Berlin - Berlin Institute of Technology, Str. d. 17. Juni 135, 10623 Berlin, Germany
Fax : (+49)-30-3142-23619; e-mail: blechert@chem.tu-berlin.de
Received: February 23, 2012; Revised: May 2, 2012; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200155.
Abstract: A relay catalysis of a cationic zinc com-
plex and N,N-dimethylaniline hydrotrifluoromethyl
sulphonate induces a multiple CꢀC bond and CꢀN
ACHTUNGTRENNGNUa mination–hydroarylation with 5 mol% of an Au(I)-
NHC 1c6]omplex under microwave conditions at
[
1508C.
bond formation. The one-step synthesis make
highly substituted bi- and tricyclic 1,2-dihydroquino-
line derivatives easily available from simple starting
materials. The high yielding process consists of sev-
eral simultaneous operating steps.
Herein we present a new domino process using
a consecutive catalysis with 5 mol% of a Zn complex
(3) as a cheap metal together with 15 mol% of an ani-
linium salt (4) as proton source. Domino reactions are
highly attractive because several individual reactions
[17]
are coupled yielding a product in a single process.
Another advantage of such cascade reactions in or-
Keywords:
1,2-dihydroquinoline
derivatives;
[18]
domino reaction; hydroamination; sigmatropic rear-
rangement; zinc
ganic synthesis is often a high atom economy.
In
context of our work on Zn-catalyzed hydroamination,
we reported recently a new domino hydroamination–
alkyne addition reaction giving access to functional-
[
19]
ized propargylic amines. The regioselective hydro-
amination of an alkyne with a cationic Zn complex
AHCTUNGTRENNUNG
Substituted hydroquinoline derivatives are important led to an iminium salt followed by the Zn-catalyzed
structural units in various natural products and phar- addition of monosubstituted acetylenes. In continua-
[1]
maceuticals.
Many heterocycles containing such tion of this work we observed in the case of aryla-
units show biological activity and have potential ther- mines, like N-methylaniline, at elevated temperatures
[
2]
apeutic uses such as antibacterial, anti-inflammato- as by-product the hydroquinoline derivative
6
[3]
[4]
ry, inhibitors for lipid peroxidation, HMG-CoA re- (Scheme 1). The importance of such a type of hetero-
ductase, and progesterone agonists and antago- cycles motivated us to unertake further studies on this
[5]
[6]
[7]
nists.
reaction. A mixture of 1 with 2.5 equivalents of 1-
Many synthesis of hydroquinolines starting with hexyne was heated in toluene together with 5 mol%
[
8]
aniline derivatives have been reported such as of a 1:1 mixture of precatalyst 3 and activator 4 for
[
9]
Brønsted acid-catalyzed tandem reactions, modified 24 h at 708C yielding 99% of the expected propargylic
[
10]
[11]
Skraup reactions, Michael-aldol reactions, meta- amine 5. The same reaction at 1308C gave under de-
[12]
thesis
with alkynes.
and tandem reactions of aromatic amines composition as only product which could be isolated
[13]
by chromatography on silica gel the wanted 1,2-dihy-
Hydroaminations of alkynes with aromatic amines droquinoline 6 in a yield of 28%. Similar results were
followed by metal-catalyzed formation of the hetero- obtained by heating the isolated 5 with 5 mol% of the
cycles have also been described. In 2005, Li and co- 1:1 mixture of Zn complex and activator at 1308C,
workers reported a domino route using 5 mol% thus indicating 5 as a precursor for the formation of 6.
AgBF4 in diethyl ether at temperatures between However, the pure thermal reaction of 5 led only to
[
14]
1
408C and 1908C,
at the same time Yi and co- decomposition, which demonstrates a catalytic reac-
workers used 5 mol% of a ruthenium complex com- tion. The CꢀC bond formation between the arene and
bining hydroamination and CꢀH bond activation in the triple bond could go via a direct metal-catalyzed
[
15]
benzene at 958C. Later Che et al. prepared 1,2-di- cyclization. A similar copper-promoted reaction has
[
20]
hydroquinolines and quinolones by a tandem hydro- been described.
Another pathway is the aromatic
Adv. Synth. Catal. 0000, 000, 0 – 0
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1
ÞÞ
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Nibadita Purkait and Siegfried Blechert
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Scheme 1.
aza-Claisen rearrangement followed by cyclization of gylic rearrangement at least as the predominant path-
[
21]
the resulting allene. The thermal rearrangement of way. A by-product resulting from an allyl rearrange-
N-propargylanilines requires high temperatures which ment could not be found, but such a reaction cannot
[
22]
led to decomposition of the products.
The Lewis be excluded, in particular in view of the different
acid- or proton-catalyzed process is significantly yields of 14 and 6.
[9]
milder. Consequently we tested the influence of the
In order to extend the methodology also for the
anilinium salt 4 on the reaction 5!6. We were synthesis of tricyclic 1,2-dihydroquinoline derivatives
pleased to see a complete conversion after 6 h at we tested 2,3-dihydroindole and 1,2,3,4-tetrahydroqui-
1
308C yielding 98% of the wanted dihydroquinoline. noline. The results are presented in Table 2. The reac-
We supposed that the low yield formation of 6 during tivity of the tetrahydroquinoline is comparable with
the first attempt was caused by a small excess of the that of N-methylaniline. The overall yields using
activator 4. Thus heating N-methylaniline and alkyl- and aryl-substituted acetylenes are mostly ex-
2.5 equivalents of 1-hexyne with 5 mol% Zn complex cellent. Phenylacetylene gave a moderate yield of 17,
and 15 mol% 4 at 1308C gave a clean formation of like in the case of 11, whereas methyl- or methoxy-
the wanted 1,2-dihydroquinoline with an excellent substituted phenylacetylenes worked much better. Di-
yield of 97%.
hydroindole is also a suitable substrate. The yields for
With these conditions in hand we tested the scope the fused heterocycles 21–23 are in the range 53–
of this method. We synthesized first a series of substi- 61%. This means an average of 85–88% for each step
tuted 1,2-dihydroquinolines starting from N-methyl- of the domino process consisting of hydroamination,
or N-allylaniline. The results are presented in Table 1. alkyne addition, rearrangement and cyclization.
Besides 1-hexyne we used also 1-pentyne and 1-hept- Our hypothesis for the mechanism is summarized
ACHTUNGTRENNUNGy ne giving similar yields (7 and 8). Not surprisingly in Scheme 2. The reaction of the Zn complex 3 with
olefins are also tolerated (see 9). Due to the weak the anilinium salt 4 gives the catalytically active cat-
Brønsted acid 4 the method tolerates the trityl-pro- ionic Zn species, which leads via Markovnikov hydro-
tected 4-pentynol, yielding 10 with an excellent over- amination, protonation of the enamine, addition of
all yield of 92%. In this case the isolation of the prod- the Zn acetylide and protonation to the propargylic
uct by chromatography on silica failed due to the la- ammonium salt C. This should undergo a proton-cata-
bility of the trityl groups under such slightly acidic lyzed 3,3-sigmatropic rearrangement. The resulting
conditions. Using neutral alumina we could purify 10 allene D can be trapped by protonation to an allyl
without problems. We used also arylacetylenes. The cation which cyclizes to the final product F. A direct
simple phenyl-substituted case gave only moderate proton-catalyzed cyclization of this type of propargyl-
yields whereas the donor-substituted arenes yields ic amines seems less likely to us, because such a syn-
8
6% and 88% (see 11–13). We tested also N-allylani- thesis of a 2,2-disubstituted 1,2-dihydroquinolines has
line. This substrate would give an N,N-allyl-propargyl- to the best of our knowledge not been described.
ACHTUNGTRENNUNGa niline as an intermediate which could undergo two However, a clear proof of our proposal was not possi-
different N-aryl-Claisen rearrangements. The sole ble, since we could not obtain our propargylic amines
product which could be isolated with 64% yield was with a quaternary carbon in an enantioenriched form.
again a quinoline derivative 14, indicating the propar- The yields of the sequence C!F are remarkable,
2
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Synthesis of Bi- and Tricyclic 1,2-Dihydroquinoline Derivatives from Arylamines and Alkynes
Table 1. Synthesis of bicyclic 1,2-dihydroquinoline deriva-
tives.
Table 2. Synthesis of tricyclic 1,2-dihydroquinoline deriva-
tives.
In summary, we have developed an efficient consec-
utive process with two different catalysts working co-
since many described propargylic aromatic N-Claisen existent under the same reaction conditions, allowing
rearrangements proceed less efficiently. Our studies a short synthesis of bi- and tricyclic substituted quino-
clearly indicated the importance of the suitable line derivatives from simple starting materials.
proton source. The use of the catalyst 4 is not only
crucial for the activation of the Zn catalyst, but also
for the last proton-catalyzed steps. The reaction of
Experimental Section
propargylic amines with stronger acids like HCl gave
no quinoline derivatives. Instead we observed elimi-
nation of the aniline substituent. A weak acid like
BINOL-derived phosphoric acid, (R)-3,3’-bis(9-an-
thracenyl)-1,1’-binaphthyl-2,2’-diyl hydrogen phos-
phate also works, but it cannot be used in combina- prepared in an inert atmosphere. The precatalyst
tion with 3.
Typical Procedure for the Synthesis of 1,2-
Dihydroquinoline Derivatives
Reactions were typically performed in reaction vials and
3
4
(24.90 mg,
0.05 mmol)
and
the
cocatalyst
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Nibadita Purkait and Siegfried Blechert
COMMUNICATIONS
[
3] I. V. Ukrainets, L. V. Sidorenko, O. V. Gorokhova,
N. A. Jaradat, Chemistry of Heterocyclic Compounds,
2
006, 42, 475.
[4] B. Lockhart, N. Bonhomme, A. Roger, G. Dorey, P.
Casara, P. Lestage, Eur. J. Pharmacol. 2001, 416, 59.
[5] T. K. Jones, D. T. Winn, L. Zhi, L. G. Hamann, C. M.
Tegley, C. L. F. Pooley, U.S. Patent 5,688,808, 1997.
[6] L. Zhi, Tegley, M. Christopher, K. B. Marschke, D. E.
Mais, Jones, K. Todd, J. Med. Chem. 1999, 42, 1466.
[7] M. J. Coughlan, S. W. Elmore, M. E. Kort, P. R. Kym,
J. L. Moore, J. K. Pratt, A. X. Wang, J. P. Edwards,
T. K. Jones, Patent WO 9941256, 1999.
[
8] Microreview: T. Kitamura, Eur. J. Org. Chem. 2009,
1
111–1125; a) X. Y. Liu, C. M. Che, Angew. Chem.
2
008, 120, 3865; Angew. Chem. Int. Ed. 2008, 47, 3805;
b) M. Arisawa, C. Theeraladanon, A. Nishida, M. Na-
kagawa, Tetrahedron Lett. 2001, 42, 8029; c) K. A.
Parker, T. L. Mindt, Org. Lett. 2002, 4, 4265; d) C. S.
Yi, S. Y. Yun, I. A. Guzei, J. Am. Chem. Soc. 2005, 127,
5
782; e) G. L. Lu, J. L. Portscheller, H. C. Malinakova,
Organometallics 2005, 24, 945; f) R. Kamakshi, B. S. R.
Reddy, Catal. Commun. 2007, 8, 825.
[
9] X.-Y. Hua, J.-C. Zhang, W. Wie, J.-X. Ji, Tetrahedron
Lett. 2011, 52, 2903–2905.
Scheme 2. Proposed mechanism.
[10] a) S. Kamiguchi, I. Takahshi, H. Kurokawa, H. Miura,
T. Chihara, Appl. Catal. A 2006, 309, 70; b) M. E. The-
oclitou, L. A. Robinson, Tetrahedron Lett. 2002, 43,
[
PhNMe H][OTf] (40.20 mg, 0.15 mmol) were dissolved in
2
3
907.
11] a) B. C. Ranu, A. Hajra, S. S. Dey, U. Jana, Tetrahedron
003, 59, 813; b) K. Makino, O. Hara, Y. Takiguchi, T.
Katano, Y. Asakawa, K. Hatano, Y. Hamada, Tetrahe-
dron Lett. 2003, 44, 8925.
12] a) P. Evans, R. Grigg, M. Monteith, Tetrahedron Lett.
toluene (2 mL). The substrate N-methylaniline (107 mg,
mmol) and n-hexyne (246.42 mg, 3 mmol) were added in
[
[
[
1
2
the mixture. Subsequently, the mixture was injected into the
reaction vial. The reaction mixture was then heated in an oil
bath at 1308C for 24 h. The reaction mixture was then
cooled to room temperature and solvent was removed by
evaporation. The crude mixture was purified by column
chromatography with cyclohexane-DCM on silica giving 6;
yield: 97%.
1
999, 40, 5247; b) M. Arisawa, C. Theeraladanon, A.
Nishida, M. Nakagawa, Tetrahedron Lett. 2001, 42,
029–8033.
8
13] a) Y. M. Luo, Z. G. Li, C. J. Li, Org. Lett. 2005, 7, 2675;
b) X. Y. Liu, P. Ding, J. S. Huang, C. M. Che, Org. Lett.
Procedures and analytical data for all compounds are
given in the Supporting Information.
2
007, 9, 2645; c) Y. Zhou, E. Feng, G. Liu, D. Ye, J. Li,
H. Jiang, H. Liu, J. Org. Chem. 2009, 74, 7344–7348.
14] Y. Luo, Z. Li, C-J. Li, Org. Lett. 2005, 7, 2675–2678.
15] C.-S. Yi, S.-Y. Yun, I.-A. Guzei, J. Am. Chem. Soc.
[
[
2
005, 127, 5782–5783.
16] a) X.-Y. Liu, P. Ding, J.-S. Huang, C.-M. Che, Org. Lett.
007, 9, 2645–2648; b) X.-Y. Liu, C.-M. Che, Angew.
Chem. 2008, 120, 3865–3870; Angew. Chem. Int. Ed.
008, 47, 3805–3810.
Acknowledgements
[
2
We are thankful to the Berlin International Graduate School
of Natural Science and Engineering (BIG-NSE) and Cluster
of Excellence “Unifying Concepts in Catalysis” coordinated
by the TU Berlin – Berlin Institute of Technology for the fi-
nancial support.
2
[
17] For recent examples of relay domino sequences, see:
a) Y. Wang, R.-G. Han, Y.-L. Zhao, S. Yang, P.-F. Xu,
D. J. Dixon, Angew. Chem. 2009, 121, 10018–10022;
Angew. Chem. Int. Ed. 2009, 48, 9834–9838; b) Z.-Y.
Han, H. Xiao, X.-H. Chen, L.-Z. Gong, J. Am. Chem.
Soc. 2009, 131, 14452–14453; c) S. Chercheja, T. Roth-
enbꢁcher, P. Eilbracht, Adv. Synth. Catal. 2009, 351,
339–344; d) S. P. Lathrop, T. Rovis, J. Am. Chem. Soc.
2009, 131, 13628–13630; e) H. Rahaman, ꢂ. Madarꢃsz,
I. Pꢃpai, P. M. Pihko, Angew. Chem. 2011, 123, 6247–
6251; Angew. Chem. Int. Ed. 2011, 50, 6123–6127; f) P.
Julien, B. Aicha, B. Gaelle, S. Jean, Angew. Chem.
2011, 123, 3343–3347; Angew. Chem. Int. Ed. 2011, 50,
3285–3289; g) B. M. Trost, N. Maulide, R. C. Living-
ston, J. Am. Chem. Soc. 2008, 130, 16502–16503;
References
[
1] a) H. Takahash, Y. Bekkali, A. J. Capolino, T. Gilmore,
S. E. Goldrick, P. V. Kaplita, L. Liu, R. M. Nelson, D.
Terenzio, J. Wang, L. Zuvela-Jelaska, J. Proudfoot, G.
Nabozny, D. Thomson, Bioorg. Med. Chem. Lett. 2007,
1
7, 5091; b) L. Zhi, C. M. Tegley, B. Pio, S. J. West,
K. B. Marschke, D. E. Mais, T. K. Jones, Bioorg. Med.
Chem. Lett. 2000, 10, 415.
2] J. V. Johnson, J. Med. Chem. 1989, 32, 1942.
[
4
asc.wiley-vch.de
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

Synthesis of Bi- and Tricyclic 1,2-Dihydroquinoline Derivatives from Arylamines and Alkynes
h) L. F. Tietze, K. M. Sommer, J. Zinngrebe, F. Stecker,
Angew. Chem. 2005, 117, 262–264; Angew. Chem. Int.
Ed. 2005, 44, 257–259; i) S. A. A. El Bialy, H. Braun,
L. F. Tietze, Angew. Chem. 2004, 116, 5505–5507;
Angew. Chem. Int. Ed. 2004, 43, 5391–5393; j) K. C.
Nicolaou, T. R. Wu, Q. Kang, D. Y.-K. Chen, Angew.
Chem. 2009, 121, 3492–3495; Angew. Chem. Int. Ed.
Hudson, G. Song, A. R. Moores, C. J. Li, Org. Lett.
2011, 13, 442–445; c) S. Zhu, W. Yan, B. Mao, X. Jiang,
R. Wang, J. Org. Chem. 2009, 74, 6980.
[20] a) R. D. Dillard, D. E. Pavey, D. N. Benslay, J. Med.
Chem. 1973, 16, 251; b) U. K. Pomeranz, H. J. Hansen,
H. Schmid, Helv. Chim. Acta 1973, 56, 2981; c) S. Joli-
don, H.-J. Hansen, Helv. Chim. Acta 1977, 60, 978;
d) R. D. Dillard, D. E. Pavey, D. N. Bensley, J. Med.
Chem. 1973, 16, 251; e) M. A. Holman, N. M. William-
son, A. D. Ward, Aust. J. Chem. 2005, 58, 368.
2
009, 48, 3440–3443; k) E. R. Strieter, A. Koglin, Z. D.
Aron, C. T. Walsh, J. Am. Chem. Soc. 2009, 131, 2113–
115.
2
[
[
18] T. K.-Y. Desmond, T.-G. Foo, F.-W. Yip, Organometal-
lics 2011, 30, 4136–4143; B. Klaus, P. Oliver, Angew.
Chem. 2011, 123, 6295–6298; Angew. Chem. Int. Ed.
[
21] A. Saito, A. Kanno, Y. Hanzawa, Angew. Chem. 2007,
19, 4005; Angew. Chem. Int. Ed. 2007, 46, 3931. For
1
further examples of aromatic Aza-Claisen rearrange-
ments, see: M. Hiersemann, U. Nubbemeyer, The Clais-
en Rearrangement: Methods and Applications, Wiley-
VCH, Weinheim, 2007.
2
011, 50, 6171–6174; B. Amadeu, P.-U. Cristina, B.
Carles, G. Henrik, F. Elena, Angew. Chem. 2011, 123,
296–7299; Angew. Chem. Int. Ed. 2011, 50, 7158–7161.
7
19] a) M. Biyikal, M. Porta, P. W. Roesky, S. Blechert, Adv.
Synth. Catal. 2010, 352, 1870–1875. For other alkyne-
imine addition reaction see: b) T. Zeng, L. Yang, R.
[
22] H. Scheurer, J. Zsindely, H. Schmid, Helv. Chim. Acta
1
973, 56, 478.
Adv. Synth. Catal. 0000, 000, 0 – 0
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asc.wiley-vch.de
5
ÞÞ
These are not the final page numbers!

COMMUNICATIONS
6
Synthesis of Bi- and Tricyclic 1,2-Dihydroquinoline
Derivatives from Arylamines and Alkynes by a Consecutive
Zinc-Ammonium Salt Catalysis
Adv. Synth. Catal. 2012, 354, 1 – 6
Nibadita Purkait, Siegfried Blechert*
6
asc.wiley-vch.de
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!