A convergent rhodium-catalysed asymmetric synthesis of tetrahydroquinolines

Article abstract of DOI:10.1039/c4cc04940c

Rh-catalysed conjugate additions of 2-aminophenyl boronic acid derivatives were exploited in diastereoselective and asymmetric syntheses of tetrahydroquinolines. In both cases, combinatorial variation of the substitution of the tetrahydroquinoline ring system was possible. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc04940c

ChemComm
View Article Online
View Journal | View Issue
COMMUNICATION
A convergent rhodium-catalysed asymmetric
synthesis of tetrahydroquinolines†
Cite this: Chem. Commun., 2014,
50, 10222
Ho Yin Li,a Joachim Horn,a Amanda Campbell,b David House,b Adam Nelson*ac
and Stephen P. Marsden*a
Received 27th June 2014,
Accepted 18th July 2014
DOI: 10.1039/c4cc04940c
www.rsc.org/chemcomm
Rh-catalysed conjugate additions of 2-aminophenyl boronic acid
derivatives were exploited in diastereoselective and asymmetric
syntheses of tetrahydroquinolines. In both cases, combinatorial
variation of the substitution of the tetrahydroquinoline ring system
was possible.
The tetrahydroquinoline ring system is an important synthetic
target1 that is found in many bioactive compounds including natural
products (e.g. dynemicin A2) and drugs (e.g. the thrombin inhibitor
argatroban3a 1 and the antiarrhythmic agent nicainoprol3b 2).
Established catalytic asymmetric synthetic approaches to tetrahydro-
quinolines include transition metal-catalysed hydrogenation and
transfer-hydrogenation of quinolines,4 organocatalytic reduction of
quinolines5 and dihydroquinolines,6 hetero-Diels–Alder reactions
of aniline-derived imines with electron-rich dienophiles
(Povarov reactions)7 and catalysed intramolecular hydride transfer/
Mannich condensations.8
Scheme 1 Stereoselective synthesis of tetrahydroquinolines. Diastereomeric
ratios (dr) are reported for the purified products. Ar = p-methoxyphenyl;
Ar0 = p-nitrophenyl.
As part of a programme focused on the synthesis of diverse
small molecule scaffolds,9 we have exploited Rh-catalysed con-
jugate additions10 in convergent heterocycle syntheses.9a,b For
example, Rh-catalysed conjugate addition of 2-aminophenyl
boronic acids 3 to enones 4 was followed by cyclisation‡ (-5)
and oxidation to give quinolines 6 in good yield (Scheme 1).9a
The reaction presumably proceeds by intramolecular condensation
of the initial conjugate addition adduct to yield a 3,4-dihydro-
quinoline 5 and, hence, the corresponding quinoline 6.
a School of Chemistry, University of Leeds, Leeds, LS2 9JT, UK.
E-mail: a.s.nelson@leeds.ac.uk, s.p.marsden@leeds.ac.uk
b GlaxoSmithKline Medicines Research Centre, Stevenage, SG1 2NY, UK
c Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds,
LS2 9JT, UK
Although the general approach might, in principle, be exploited
in asymmetric heterocycle synthesis, it had only been demonstrated
in the synthesis of achiral9a,b or racemic9b heterocycles. We recog-
nized that Rh-catalysed conjugate addition chemistry might enable a
new convergent, and potentially asymmetric,11 synthesis of substi-
tuted tetrahydroquinolines 7 (Scheme 1). Initial studies focused on
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4cc04940c
10222 | Chem. Commun., 2014, 50, 10222--10224
This journal is ©The Royal Society of Chemistry 2014

View Article Online
Communication
ChemComm
the convergent synthesis of the racemic tetrahydroquinoline 7a. were obtained in good yield and with high diastereoselectivity.
Thus, after completion of the Rh-catalysed conjugate addition reac- The accessibility of substituted 2-aminophenyl pinacolboro-
tion, the reaction mixture was diluted with toluene and treated with nates enabled the synthesis of tetrahydroquinolines 7j–m in
an excess of sodium triacetoxyborohydride: the tetrahydroquinoline which the benzenoid ring had been substituted.
7a was obtained in 94% yield with 88 : 12 diastereoselectivity.
The syntheses of the 2,4-disubstituted tetrahydroquinolines
Our initial studies into the scope of the convergent synthesis of 7 were all highly diastereoselective in favour of the cis diastereo-
racemic tetrahydroquinolines 7 are summarised in Scheme 1. The isomer. The 1,3-diaxial orientations of H-2 and H-4 were determined
synthesis of the 2-substituted tetrahydroquinoline 7b was lower by careful analysis of vicinal coupling constants13 and, for 3h and 3l,
yielding that that of the 2,4-disubstituted analogue 7a. However, observation of strong mutual nOe interactions; in addition, the cis
with all of the a,b-disubstituted enones 4 studied, the reaction diastereoisomer of 3d is a known compound.14 The stereoselectivity
yielded the corresponding 2,4-disubstituted tetrahydroquinolines may be explained in terms of axial attack15 of the reducing agent on
7c–f in reasonable to excellent yield with both aliphatic and aromatic the 3,4-dihydroquinoline intermediate.
R1 and R2 substituents. In each case, the products were obtained
Extension to the synthesis of a 2,3-disubstituted tetrahydro-
with good to excellent diastereoselectivity in favour of the cis isomer. quinoline was also possible (Scheme 2). Thus, with 2-methyl-1-
To enable substitution of the benzenoid ring, we investigated the phenyl prop-2-en-one, the known16 tetrahydroquinoline 9
use of 2-aminophenylpinacolboronates 8, which may be prepared (3JH2,H3 = 3.5 Hz) was obtained in 67% yield as a 495 : o5 mixture
easily from the corresponding 2-bromoanilines (Scheme 2).12 The of diastereoisomers. As previously observed with the b-unsubstituted
reaction between the parent pinacolboronate 8 (R3 = H) with chalcone enone (-7b; compare Scheme 1 with Scheme 2), the yield was
was slower than that of the corresponding boronic acid 3. However, higher with the pinacolboronate 8 (R3 = H) as the reactant (67%)
by increasing the catalyst loading (to 6 mol%), and the amount than with the corresponding boronic acid 3 (58%).
of base (to 2.5 eq.), the reaction was complete in a similar time,
We next focused on the development of an asymmetric
and a comparable yield of the tetrahydroquinoline 7c was obtained tetrahydroquinoline synthesis. In studies directed towards an
(compare Scheme 1 with Scheme 2). Remarkably, the synthesis of the asymmetric synthesis of tetrahydroquinolones, we had found that
2-substituted tetrahydroquinoline 7b was much more effective with addition of the pinacolboronate 8 (R3 = H) to methyl cinnamate gave
the pinacolboronate 8 (R3 = H) as the reactant, and a much improved racemic products with a wide range of chiral ligands; however, the
77% yield was observed (compare Scheme 1 with Scheme 2). In corresponding Boc-protected substrate 10 (R3 = H) gave, with (R,R,S,S)-
a similar vein, the 2,4-disubstituted tetrahydroquinolines 7g–i Duanphos as ligand,17,18 a low yield of the corresponding tetrahydro-
quinolone in 498% ee (ESI†). These initial results prompted us to
investigate the addition of the Boc-protected pinacolboronates 10
to unsaturated ketones. In each case, the intermediate conjugate
addition products were treated with triethylsilane in TFA to effect
deprotection, cyclisation and reduction, and the enantiomeric
excess of the corresponding tetrahydroquinolines 8 was deter-
mined by chiral HPLC (Table 1).
The reactions of the Boc-protected pinacolboronate 10
(R3 = H) with a range of a,b-unsaturated ketones, catalysed by
6 mol% (R,R,S,S)-Duanphos[Rh(nbd)][BF4], were successful with both
aromatic and aliphatic R1 and R2 groups (entries 1–4, Table 1). The
use of the Boc-protected pinacolboronate 10 (R3 = CF3) was also
successful, and allowed variation of the substitution of the benzenoid
ring (entries 5–7). The stereoselectivity of the reactions was remark-
able: the products 7 were obtained with very high cis diastereoselec-
tivity and with good to excellent enantiomeric excess. The absolute
configuration of the tetrahydroquinolines 7c and 7l was determined
by comparison of their experimental and simulated vibrational
circular dichroism spectra.19 This outcome is consistent with the
observed sense of induction in reported asymmetric conjugate
addition reactions using this catalyst system.18
We also investigated the effect of generating the chiral
catalyst in situ. Thus, the enantiomerically-enriched tetra-
hydroquinolines ent-7c and 7g could be prepared using the
combination of 3 mol% [Rh(nbd)Cl]2 and 6 mol% of either
(S,S,R,R) or (R,R,S,S)-Duanphos (entries 8 and 9, Table 1). The
Scheme 2 Stereoselective synthesis of tetrahydroquinolines. Diastereo-
yield of the tetrahydroquinoline 7c was higher under these
conditions than with 6 mol% (R,R,S,S)-Duanphos[Rh(nbd)][BF4]
(compare entries 2 and 8).
meric ratios (dr) for purified products. a Performed at 50 1C. b Performed at
40 1C with 2-methyl-1-phenylprop-2-en-one; reduction conditions:
LiAlH4, toluene, r.t. Ar00 = p-chlorophenyl.
This journal is ©The Royal Society of Chemistry 2014
Chem. Commun., 2014, 50, 10222--10224 | 10223

View Article Online
ChemComm
Communication
Table 1 Asymmetric synthesis of tetrahydroquinolines
and A. S. C. Chan, J. Am. Chem. Soc., 2011, 133, 9878; ( f ) H. Zhou,
Z. Li, Z. Wang, T. Wang, L. Xu, Y. He, Q.-H. Fan, J. Pan, L. Gu and
A. S. C. Chan, Angew. Chem., Int. Ed., 2008, 47, 8464.
5 (a) M. Rueping, A. P. Antonchick and T. Theissmann, Angew. Chem.,
Int. Ed., 2006, 45, 3683; (b) Q.-S. Guo, D.-M. Du and J. Xu, Angew.
Chem., Int. Ed., 2008, 47, 759; (c) M. Rueping, T. Theissman, S. Raja
and J. W. Bats, Adv. Synth. Catal., 2008, 350, 1001; (d) M. Rueping
and T. Theissman, Chem. Sci., 2010, 1, 473; (e) M. Rueping,
T. Theissman, M. Stoeckel and A. P. Antonchick, Org. Biomol. Chem.,
2011, 9, 6844; ( f ) Q. A. Chen, K. Gao, Y. Duan, Z. S. Ye, L. Shi, Y. Yang
and Y.-G. Zhou, J. Am. Chem. Soc., 2012, 134, 2442; (g) X.-F. Tu and
L.-Z. Gong, Angew. Chem., Int. Ed., 2012, 51, 11346.
6 Z.-Y. Han, H. Xiao, X.-H. Chen and L.-Z. Gong, J. Am. Chem. Soc.,
2009, 131, 9182.
7 (a) H. Ishitani and S. Kobayashi, Tetrahedron Lett., 1996, 37, 1973.
For select recent examples, see: (b) T. Akiyama, H. Morita and
K. Fuchibe, J. Am. Chem. Soc., 2006, 128, 13070; (c) H. Liu,
G. Dagousset, G. Masson, P. Retailleau and J. Zhu, J. Am. Chem.
Soc., 2009, 131, 4598; (d) G. Bergonzini, L. Gramigna, A. Mazzanti,
M. Fochi, L. Bernardi and A. Ricci, Chem. Commun., 2010, 46, 327;
(e) M.-S. Xie, X.-H. Chen, Y. Zhu, B. Gao, L.-L. Lin, X.-H. Liu and
X.-M. Feng, Angew. Chem., Int. Ed., 2010, 49, 3799; ( f ) H. Xu,
S. J. Zuend, M. G. Woll, Y. Tao and E. N. Jacobsen, Science, 2010,
327, 986; (g) G. Dagousset, J. P. Zhu and G. Masson, J. Am. Chem.
Soc., 2011, 133, 14804; (h) C. Min, N. Mittal, D. X. Sun and D. Seidel,
Angew. Chem., Int. Ed., 2013, 52, 14084; (i) C. S. Luo and Y. Huang,
J. Am. Chem. Soc., 2013, 135, 8193; ( j) J. Calleja, A. B. Gonzalez-
Perez, A. R. de Lera, R. Alvarez, F. J. Fananas and F. Rodriguez,
Chem. Sci., 2014, 5, 996.
Entry
Product
Yield/%
dr
eea/%
1
2
3
4
5
6
7a
7c
7h
7i
7k
76
60
45
65
72
65
72
78
62
94 : 6
498b
498
498b
498
498
92
498
98
87
495 : 5
495 : 5
495 : 5
495 : 5
92 : 8
495 : 5
495 : 5
495 : 5
7l
7
7m
ent-7c
7g
8c
9d
a
b
Determined by chiral analytical HPLC. The ee of the corresponding
c
8 (a) S. Murarka, I. Deb, C. Zhang and D. Seidel, J. Am. Chem. Soc.,
2009, 131, 13226; (b) K. Mori, K. Ehara, K. Kurihara and T. Akiyama,
J. Am. Chem. Soc., 2011, 133, 6166; (c) Y.-K. Kang, S. M. Kim and
D. Y. Kim, J. Am. Chem. Soc., 2010, 132, 11847.
3,5-dinitrobenzamide derivative was determined. 3 mol% [Rh(nbd)Cl]2
and 6 mol% (S,S,R,R)-Duanphos were used. 3 mol% [Rh(nbd)Cl]2 and
6 mol% (R,R,S,S)-Duanphos were used.
d
9 (a) J. Horn, S. P. Marsden, A. Nelson, D. House and
G. G. Weingarten, Org. Lett., 2008, 10, 4117; (b) J. Horn, H. Y. Li,
S. P. Marsden, A. Nelson, R. J. Shearer, A. J. Campbell, D. House and
G. G. Weingarten, Tetrahedron, 2009, 65, 9002; (c) P. Tosatti, J. Horn,
A. J. Campbell, D. House, A. Nelson and S. P. Marsden, Adv. Synth.
Catal., 2010, 352, 3153; (d) P. Tosatti, A. J. Campbell, D. House,
A. Nelson and S. P. Marsden, J. Org. Chem., 2011, 76, 5495.
10 (a) M. Sakai, H. Hayashi and N. Miyaura, Organometallics, 1997,
16, 4229. For reviews, see: (b) T. Hayashi, Synlett, 2001, 879;
(c) K. Fagnou and M. Lautens, Chem. Rev., 2003, 103, 169;
(d) H. J. Edwards, J. D. Hargrave, S. D. Penrose and C. G. Frost,
Chem. Soc. Rev., 2010, 39, 2093.
A novel convergent and stereoselective synthesis of tetra-
hydroquinolines exploited the Rh-catalysed addition of 2-amino-
phenyl boronate derivatives to a,b-unsaturated ketones as the
key step. Remarkably, it was possible to develop a highly
enantioselective variant of the reaction that exploited the
specific combination of Duanphos as the chiral ligand and
Boc-protected pinacolboronates as the reactants. The synthetic
approach was modular, and will likely be adapted to synthesis
of a range of other benzo-fused heterocyclic ring systems. We
thank EPSRC and GlaxoSmithKline for funding, Douglas Minick
for conducting VCD experiments, and Amgen and ChiralQuest
for generous gifts of metal complexes.
11 (a) Y. Takaya, M. Ogasawara, T. Hayashi, M. Sakai and N. Miyaura,
J. Am. Chem. Soc., 1998, 120, 5579. For reviews, see ref. 10c,d and:
(b) T. Hayashi and K. Yamasaki, Chem. Rev., 2003, 103, 2829;
(c) D. Mueller and A. Alexakis, Chem. Commun., 2012, 48, 12037.
´
´
12 O. Baudoin, D. Guenard and F. Gueritte, J. Org. Chem., 2000,
65, 9268.
13 M. Karplus, J. Am. Chem. Soc., 1963, 85, 2870.
14 M. Ueda, S. Kawai, M. Hayashi, T. Naito and O. Miyata, J. Org. Chem.,
2010, 75, 914.
15 R. V. Stevens, in Strategies and Tactics in Organic Synthesis, ed.
T. Lindberg, Academic Press, 1984, vol. 1.
16 S.-I. Murahashi, Y. Imada and Y. Hirai, Bull. Chem. Soc. Jpn., 1989,
62, 2968.
17 (a) D. Liu and X. Zhang, Eur. J. Org. Chem., 2005, 646; (b) I. C. Lennon,
Chim. Oggi, 2010, 28, 46.
Notes and references
‡ See ref. 9a for evidence for the formation of 5 (R1 = Me; R2 = C5H11).
1 A. R. Katritzky, S. Rachwal and B. Rachwal, Tetrahedron, 1996,
52, 15031.
2 M. Konishi, H. Ohkuma, K. Matsumoto, T. Tsuno, H. Kamei,
T. Miyaki, T. Oki, H. Kawaguchi, G. D. VanDuyne and J. Clardy,
J. Antibiot., 1989, 42, 1449.
18 For an example of a Rh-catalysed conjugate addition with Duanphos
as ligand, see: J. L. Zigterman, J. C. S. Woo, S. D. Walker,
J. S. Tedrow, C. J. Borths, E. E. Bunel and M. M. Faul, J. Org. Chem.,
2007, 72, 8870.
19 (a) P. J. Stephens, in Computational Medicinal Chemistry for Drug
Discovery, ed. P. Bultinick, H. de Winter, W. Langenaeker and
J. P. Tollenare, Marcel Dekker, New York, 2004, pp. 699–725;
(b) T. Kuppens, P. Bultinick and W. Langenaeker, Drug Discovery
Today: Technol., 2004, 1, 269.
3 (a) L. R. Bush, Cardiovasc. Drug Rev., 1991, 9, 247; (b) S. Imanishi,
T. Kimura and M. Arita, Cardiovasc. Drug Rev., 1991, 9, 223.
4 For examples, see: (a) W.-B. Wang, S.-M. Lu, P.-Y. Yang, X.-W. Han
and Y.-G. Zhou, J. Am. Chem. Soc., 2003, 125, 10536; (b) M. T. Reetz
and X. Li, Chem. Commun., 2006, 2159; (c) W.-J. Tang, S.-F. Zhu,
L.-J. Xu, Q.-L. Zhou, Q.-H. Fan, H.-F. Zhou, K. Lam and A. S. C. Chan,
Chem. Commun., 2007, 613; (d) C. Wang, C. Li, X. Wu, A. Pettman
and J. Xiao, Angew. Chem., Int. Ed., 2009, 48, 6524; (e) T. Wang,
L.-G. Zhuo, Z. Li, F. Chen, Z. Ding, Y. He, Q.-H. Fan, J. Xiang, Z.-X. Yu
10224 | Chem. Commun., 2014, 50, 10222--10224
This journal is ©The Royal Society of Chemistry 2014