Product-selectivity control by the nature of the catalyst: Lewis acid-catalyzed selective formation of ring-fused tetrahydroquinolines and tetrahydroazepines via intramolecular redox reaction

Article abstract of DOI:10.1039/c0cc01946a

Selective synthesis of ring-fused tetrahydroquinolines and tetrahydroazepines from the same starting materials was achieved by subtle use of the oxophilic Sc(OTf)₃ or carbophilic IPrAuOTf as the catalyst.

Full text of DOI:10.1039/c0cc01946a

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Product-selectivity control by the nature of the catalyst: Lewis
acid-catalyzed selective formation of ring-fused tetrahydroquinolines
and tetrahydroazepines via intramolecular redox reactionw
Guanghua Zhoua and Junliang Zhang*ab
Received 18th June 2010, Accepted 2nd July 2010
DOI: 10.1039/c0cc01946a
Selective synthesis of ring-fused tetrahydroquinolines and tetra-
hydroazepines from the same starting materials was achieved by
subtle use of the oxophilic Sc(OTf)3 or carbophilic IPrAuOTf as
the catalyst.
The development of methodology for the direct functionaliza-
tion of relatively unactive C–H bonds has now become a
rapidly growing topic of research,1 which offers an intriguing
opportunity for the rapid buildup of molecular complexity.
However, the functionalization of inert and sterically hindered
sp3 C–H bonds2–4 is still a particularly difficult challenge,
owing to the strength of sp3 C–H bonds and the metal cannot
reach to a C–H bond to be activated. Recently, Sames and
co-workers4a–e have developed an alternative and efficient
redox-neutral strategy to address this issue, wherein a suitable
unsaturated moiety is introduced and activated by an electro-
philic metal, which in turn induces a selective C–H bond
cleavage via a 1,5-hydride shift. On the other hand, construc-
tion of distinct types of complex molecules from identical
starting materials simply by subtle choice of the catalyst is
an interesting but often very challenging issue in modern
organic synthesis.5 Here we report a Lewis acid-catalyzed
Scheme 1 (a) Seidel’s work and (b) proposed working hypothesis in
intramolecular redox reaction for selective synthesis of fused
this work.
tetrahydroquinolines and tetrahydroazepines, and show the
of Lewis acid (Scheme 1(b)). We speculated that two distinctly
different compounds (e.g. tetrahydroquinolines 2 and tetra-
hydroazepines 3) might be produced, the selectivity of which
may be controllable by subtle choice of different Lewis acids.
Under the catalysis of oxophilic Lewis acid (Scheme 1(b),
Cycle A), the reaction would proceed through a zwitterionic
intermediate IA via a 1,5-hydride shift, which in turn
would undergo cyclization to give tetrahydroquinolines 2.
In this case, the alkyne moiety plays a role as a substituent.
In contrast, carbophilic Lewis acid would trigger a hetero-
cyclization (first cyclization) by activation of the alkyne
moiety to generate the furanyl intermediate IB with a reactive
carbocation;8a,9e,f,10 after 1,5-hydride shift to produce the
intermediate IC and subsequent ring closure (second cyclization),
polycyclic tetrahydroazepines 3 may be produced. It is obvious
that cycle B is a novel and alternative strategy to generate a
more active hydrogen acceptor IB, which is quite different
from the direct activation of the acceptor by metal.
selectivity of the product can be controlled by the nature of the
catalyst.
Seidel and co-workers4f,g recently reported an intriguing
Lewis acid-catalyzed redox domino6 1,5-hydride shift/cyclization
reaction for an efficient synthesis of tetrahydroquinolines, in
which a C–H bond a to the tertiary amine nitrogen (tert-amine
effect7) is replaced by a C–C bond that becomes part of the
newly formed tetrahydroquinoline ring system (Scheme 1(a)).
Meanwhile, others8 and our group9 have showed that con-
jugated yne-enones undergo cyclization readily in the presence
of a transition metal complex (such as a gold complex), in
which a carbocationic furanyl gold intermediate8a,9e,f,10 was
involved for those gold-catalyzed reactions.11 During these
studies, we envisaged that yne-enones 1 might undergo
novel intramolecular redox domino reaction in the presence
a Shanghai Key Laboratory of Green Chemistry and Chemical
Processes, Department of Chemistry, East China Normal University,
3663 N. Zhongshan Road, Shanghai 200062, P.R. China.
E-mail: jlzhang@chem.ecnu.edu.cn; Fax: (+86) 21-6223-5039
b State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, Shanghai 200032, P.R. China
This hypothesis was initially tested with yne-enone 1a under
the catalysis of a series of Lewis acids.12 After numerous
attempts, we were pleased to find that the reaction gave ring-
fused tetrahydroquinoline 2a with high diastereoselectivity
(15 : 1) in 86% combined isolated yield in refluxing 1,2-di-
chloroethane (DCE) under the catalysis of oxophilic
w Electronic supplementary information (ESI) available: Experimental
details. CCDC 772731–772732. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/c0cc01946a
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Lewis acid, 10 mol% of Sc(OTf)3 (eqn (1): Conditions A).13
In contrast, 92% yield of fused tetracyclic 3a can be isolated
under the catalysis of carbophilic IPrAuOTf (5 mol%, generated
in situ from 1 : 1 ratio of IPrAuCl and AgOTf) in CH3CN
(eqn (1): Conditions B) at room temperature.
ð1Þ
Using the optimized conditions, the scope of the Sc(OTf)3-
catalyzed domino 1,5-hydride shift/cyclization reaction was
explored (Scheme 2). Polycyclic 2b and 2d containing a
morpholine ring can be obtained with high diastereoselectivity
in 68% and 79% yields, respectively. The piperidine derived
compounds 1g–h also give reasonable yields of the desired
products 2g–h with good diastereoselectivities. Gratifyingly,
the corresponding eight-membered amine and acyclic diethyl
amine starting materials (1k and 1m) can readily rearrange to
produce the corresponding products 2k and 2m, respectively,
in good to high yields, albeit the diastereoselectivities are not
high. Substrate 1n with a convertible group (Br) worked well
under conditions A to give the expected product 2n in 72%
yield with high diastereoselectivity (12 : 1); the structure of the
major isomer was further confirmed by X-ray diffraction
analysis.14
Scheme 3 Carbophilic Au(I)-catalyzed domino cyclization/1,5-hydride
shift/cyclization reaction.
For example, the reactions of aryl substituted substrates 1b–d
gave higher yield (70–99%) than alkyl or alkenyl substituted
ones (53–64%), since the aryl substituted alkyne is more active
to undergo heterocyclization and in turn give the cationic
furanyl gold intermediate. Similar results were obtained
for piperidine derived ones (3g–j) and the structure of 3g
was further determined by X-ray diffraction analysis.14 The
cyclic eight-membered amine starting material 1k can readily
undergo the domino process to yield the corresponding
product 3k in 94% yield. Starting materials derived from
noncyclic amines such as dibenzyl or diethyl amine can give
rise to the expected products upon rearrangement (1l–m). The
reactions of 1n–o with a convertible group (Br) on the phenyl
ring can also proceed smoothly to afford the desired products
3n–o in high yields.
Next, we focused on the carbophilic Au(I)-catalyzed domino
cyclization/1,5-hydride shift/cyclization reaction for synthesis
of ring-fused tetrahydroazepines, and the results are summarized
in Scheme 3. The Au(I)-catalyzed domino reactions of the
morpholine derived compounds 1b–f afford the corresponding
products 3b–f in moderate to excellent yields. The substituent
(R2) on the alkyne moiety also plays a significant role in yields.
The synthetic utility of ring-fused benzazepines was then
showcased by the selective additional transformation of the
representative product 3a (eqn (2)).15 The furan moiety of
compound 3a can readily undergo oxidative ring opening by
3-chlorobenzoperoxoic acid (m-CPBA) in dichloromethane
(DCM) at 0 1C to produce tricyclic benzazepine 4 with
convertible functional groups.16
ð2Þ
In summary, we have developed a novel Lewis acid-catalyzed
intramolecular redox domino reaction, in which the product
Scheme 2 Oxophilic Sc(OTf)3-catalyzed domino 1,5-hydride shift/
cyclization reaction.
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selectivity could be efficiently tuned by the nature of the Lewis
acid. In the presence of oxophilic scandium(III) triflate, the
reaction undergoes domino 1,5-hydride shift/cyclization to
afford highly substituted multifunctionalized ring-fused tetra-
hydroquinolines in moderate to excellent yields with high
diastereoselectivity, whereas ring-fused tetrahydroazepines
could be obtained in moderate to excellent yields via the
carbophilic gold(I)-catalyzed domino reaction under the mild
conditions; this is a new alternative strategy to generate active
hydrogen acceptor by a metal-mediated cyclization instead of
the direct activation of the acceptor. Further studies including
mechanism, scope and asymmetric catalysis are ongoing in our
laboratories and will be reported in due course.
7 (a) W. D. Verboom, N. Reinhoudt, R. Visser and S. Harkema,
J. Org. Chem., 1984, 49, 269; (b) W. H. N. Nijhuis, W. Verboom
and D. N. Reinhoudt, J. Am. Chem. Soc., 1987, 109, 3136; (c) W.
H. N. Nijhuis, W. Verboom, A. A. El-Fadl, S. Harkema and
D. N. Reinhoudt, J. Org. Chem., 1989, 54, 199; (d) W. H.
N. Nijhuis, W. Verboom, A. A. El-Fadl, G. J. van Humme1 and
D. N. Reinhoudt, J. Org. Chem., 1989, 54, 209; (e) K. Mori,
Y. Ohshima, K. Ehara and T. Akiyama, Chem. Lett., 2009, 38,
524.
8 (a) T. Yao, X. Zhang and R. C. Larock, J. Am. Chem. Soc., 2004,
126, 11164; (b) T. Yao, X. Zhang and R. C. Larock, J. Org. Chem.,
2005, 70, 7679; (c) N. T. Patil, H. Wu and Y. Yamamoto, J. Org.
Chem., 2005, 70, 4531.
9 (a) Y. Xiao and J. Zhang, Angew. Chem., Int. Ed., 2008, 47,
1903; (b) Y. Xiao and J. Zhang, Adv. Synth. Catal., 2009, 351,
617; (c) Y. Xiao and J. Zhang, Chem. Commun., 2009, 3594;
(d) R. Liu and J. Zhang, Chem.–Eur. J., 2009, 15, 9303;
(e) F. Liu and J. Zhang, Angew. Chem., Int. Ed., 2009, 48,
5505; (f) H. Gao, X. Zhao, Y. Yu and J. Zhang, Chem.–Eur. J.,
2010, 16, 456.
We are grateful to the National Natural Science Foundation
of China (20972054) and the Ministry of Education of PRC
(NCET) for financial support. This work was also sponsored
by 973 program (2009CB825300).
10 For selected reviews dealing with the synthesis of furans, see:
(a) R. C. D. Brown, Angew. Chem., Int. Ed., 2005, 44, 850;
(b) D. M. D’Souza and T. J. J. Muller, Chem. Soc. Rev., 2007,
¨
Notes and references
36, 1095; (c) X. L. Hou, Z. Yang, K.-S. Yu and H. N. C. Wong, in
Progress in Heterocyclic Chemistry, ed. G. W. Gribble and
J. A. Joule, Pergamon, Oxford, 2008, vol. 19, p. 176. For recent
examples of synthesis of ring-fused furans, see: (d) G. Zhang,
X. Huang, G. Li and L Zhang, J. Am. Chem. Soc., 2008, 130,
1814; (e) Y. Zhang, Z. Chen, Y. Xiao and J. Zhang, Chem.–Eur. J.,
2009, 15, 5208.
1 For recent reviews on C–H bond activation, see: (a) D. Alberico,
M. E. Scott and M. Lautens, Chem. Rev., 2007, 107, 174;
(b) R. G. Bergman, Nature, 2007, 446, 391; (c) K. Godula and
D. Sames, Science, 2006, 312, 67; (d) H. M. L. Davies, Angew.
Chem., Int. Ed., 2006, 45, 6422.
2 For reviews on sp3 C–H activation, see: (a) M. Tobisu and
N. Chatani, Angew. Chem., Int. Ed., 2006, 45, 1683;
(b) K. R. Campos, Chem. Soc. Rev., 2007, 36, 1069.
11 For selected reviews on gold-catalyzed reactions published since
2008, see: (a) Z. Li, C. Brouwer and C. He, Chem. Rev., 2008, 108,
3239; (b) D. J. Gorin, B. D. Sherry and F. D. Toste, Chem. Rev.,
2008, 108, 3351; (c) N. Marion and S. P. Nolan, Chem. Soc. Rev.,
2008, 37, 1776; (d) A. S. K. Hashmi and M. Rudolph, Chem. Soc.
Rev., 2008, 37, 1766.
12 More reaction conditions were screened, please see details in
Table 1 in the Supporting Information.
13 For selected Sc(OTf)3-catalyzed reactions, see: (a) S. Suarez-Pantiga,
´
3 For transition metal-catalyzed sp3 C–H activation, see:
(a) S. Yang, Z. Li, X. Jian and C. He, Angew. Chem., Int. Ed.,
2009, 48, 3999; (b) K. Mori, T. Kawasaki, S. Sueoka and
T. Akiyama, Org. Lett., 2010, 12, 1732; (c) D. Shikanai,
H. Murase, T. Hata and H. Urabe, J. Am. Chem. Soc., 2009,
131, 3166; (d) I. D. Jurberg, Y. Odabachian and F. Gagosz, J. Am.
Chem. Soc., 2010, 132, 3543.
4 For selected redox-neutral reactions containing sp3 C–H activation,
see: (a) S. J. Pastine, K. M. McQuaid and D. Sames, J. Am. Chem.
Soc., 2005, 127, 12180; (b) K. M. McQuaid and D. Sames, J. Am.
Chem. Soc., 2009, 131, 402; (c) P. A. Vadola and D. Sames, J. Am.
Chem. Soc., 2009, 131, 16525; (d) K. M. McQuaid, J. Z. Long and
D. Sames, Org. Lett., 2009, 11, 2972; (e) C. Zhang, C. K. De,
R. Mal and D. Seidel, J. Am. Chem. Soc., 2008, 130, 416;
(f) S. Murarka, C. Zhang, M. D. Konieczynska and D. Seidel,
Org. Lett., 2009, 11, 129; (g) S. Murarka, I. Deb, C. Zhang and
D. Seidel, J. Am. Chem. Soc., 2009, 131, 13226.
5 For selected recent examples, see: (a) S. Kamijo, C. Kanazawa and
Y. Yamamoto, J. Am. Chem. Soc., 2005, 127, 9260; (b) B. Alcaide,
´
P. Almendros and T. Martınez del Campo, Angew. Chem., Int. Ed.,
2007, 46, 6684; (c) A. S. Dudnik, A. W. Sromek, M. Rubina,
J. T. Kim, A. V. Kel’in and V. Gevorgyan, J. Am. Chem. Soc.,
2008, 130, 1440; (d) S. Ma and J. Zhang, J. Am. Chem. Soc., 2003,
125, 12386; (e) X. Jiang, X. Ma, Z. Zheng and S. Ma, Chem.–Eur.
J., 2008, 14, 8572; (f) L. Liu and J. Zhang, Angew. Chem., Int. Ed.,
2009, 48, 6093.
D. Palomas, E. Rubio and J. M. Gonzalez, Angew. Chem., Int. Ed.,
´
2009, 48, 7857; (b) G. Desimoni, G. Faita, M. Toscanini and
M. Boiocchi, Chem.–Eur. J., 2007, 13, 9478; (c) G. Desimoni,
G. Faita, M. Toscanini and M. Boiocchi, Chem.–Eur. J., 2008, 14,
3630; (d) W. Wang, X. Liu, W. Cao, J. Wang, L. Lin and X. Feng,
Chem.–Eur. J., 2010, 16, 1664.
14 CCDC 772731 (2n) and CCDC 772732 (3g) contain the supple-
mentary crystallographic data for this paper.
15 Y. Kobayashi, H. Katsuno and F. Sato, Chem. Lett., 1983, 1771.
16 For recent reviews of azepine synthesis, see: (a) J. B. Bremner, in
Progress in Heterocyclic Chemistry, 2005, vol. 17, p. 389;
(b) Chemistry of Heterocyclic Compounds: Azepines, ed.
A. Rosowsky, Part 2, 2008, vol. 43; (c) D. O’Hagan, Nat. Prod.
Rep., 1997, 14, 637. Selected recent examples see: (d) L. Cui, L. Ye
and L. Zhang, Chem. Commun., 2010, 46, 3351; (e) H. He,
W.-B. Liu, L.-X. Dai and S.-L. You, Angew. Chem., Int. Ed.,
2010, 49, 1496; (f) S. Sakami, M. Maeda, K. Kawai, T. Aoki,
K. Kawamura, H. Fujii, K. Hasebe, M. Nakajima, T. Endo,
S. Ueno, T. Ito, J. Kamei and H. Nagase, J. Med. Chem., 2008,
51, 4404; (g) C. M. Yea, C. E. Allan, D. M. Ashworth and
J. Barnett, et al., J. Med. Chem., 2008, 51, 8124;
(h) W. H. Pearson and W.-K. Fang, J. Org. Chem., 2000, 65,
7158; (i) N. D. Shapiro and F. D. Toste, J. Am. Chem. Soc., 2008,
130, 9244.
6 For selected reviews of domino reactions, please see:
(a) A. Dondoni and A. Massi, Acc. Chem. Res., 2006, 39, 451;
(b) A. Domling, Chem. Rev., 2006, 106, 17; (c) D. M. D’Souza and
¨
T. J. J. Muller, Chem. Soc. Rev., 2007, 36, 1095; (d) L. F. Tietze,
¨
Chem. Rev., 1996, 96, 115.
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This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 6593–6595 6595