Diastereo- and Enantioselective Assembly of Spirooxindole Tetrahydroquinoline Skeletons through Asymmetric Binary Acid Catalyzed Hydride Transfer-Cyclization

Article abstract of DOI:10.1055/s-0035-1560198

An efficient binary acid catalyzed asymmetric intramolecular tandem 1,5-hydride transfer/ring-closure reaction was achieved. The process is catalyzed by the combination of a chiral spirocyclic phosphoric acid and magnesium chloride to afford structurally diverse spirooxindole tetrahydroquinolines in good yields with high diastereo- and enantioselectivities.

Full text of DOI:10.1055/s-0035-1560198

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© Georg Thieme Verlag Stuttgart · New York
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Diastereo- and Enantioselective Assembly of Spirooxindole Tetra-
hydroquinoline Skeletons through Asymmetric Binary Acid Cata-
lyzed Hydride Transfer–Cyclization
Zhenjun Mao
R3
Fan Mo
Ar
N
R2
SPA (10 mol%)
MgCl2 (2.5 mol%)
Xufeng Lin*
R3
O
N
O
P
Department of Chemistry, Zhejiang University,
Hangzhou 310027, P. R. of China
lxfok@zju.edu.cn
R2
4 Å MS
OH
O
R1
R1
O
O
toluene, 80 °C
N
Ar
N
CO2Me
CO2Me
SPA
Ar = 9-phenanthryl
up to 95% yield
up to >20:1 dr
up to 97% ee
Received: 05.06.2015
Accepted after revision: 30.07.2015
Published online: 08.09.2015
enantioselectivity (54% ee) was obtained by using 20 mol%
chiral BINOL-derived phosphoric acid5 as the catalyst. More
recently, the group of Feng showed that a chiral scandium
complex of N,N′-dioxide promoted the asymmetric reac-
tions with high levels of stereocontrol.6 In the meantime,
we also achieved an efficient asymmetric binary acid catal-
ysis7 for the enantioselective synthesis of spirooxindole tet-
rahydroquinolines through intramolecular tandem 1,5-hy-
dride transfer/ring-closure reaction (Scheme 1). Herein, we
wish to report details of the process, which was catalyzed
by the combination of a chiral spirocyclic phosphoric acid8
(Figure 1) and MgCl2 to afford structurally diverse spiro-
oxindole tetrahydroquinolines in good yields with high dia-
stereo- and enantioselectivities.
DOI: 10.1055/s-0035-1560198; Art ID: st-2015-b0417-c
Abstract An efficient binary acid catalyzed asymmetric intramolecular
tandem 1,5-hydride transfer/ring-closure reaction was achieved. The
process is catalyzed by the combination of a chiral spirocyclic phospho-
ric acid and magnesium chloride to afford structurally diverse spirooxin-
dole tetrahydroquinolines in good yields with high diastereo- and enan-
tioselectivities.
Key words asymmetric catalysis, phosphoric acid, Lewis acid, spiro-
oxindoles, quaternary stereocenter
The spirocyclic-3,3′-oxindoles as well as their analogues
are important structural units that are found in natural
products and a number of drug candidates.1 Consequently,
significant efforts have been devoted to the synthesis of op-
tically enriched highly functionalized spirocyclic-3,3′-oxin-
doles.2 In this context, the development of catalytic enantio-
selective and atom-economical methods for the efficient
construction of such skeletons with all-carbon-substituted
quaternary stereocenters, is a particularly compelling ob-
jective.
R4
N
R3
R4
N
asymmetric binary-acid catalysis
*
R3
*
R2
R2
O
O
N
N
R1
R1
Scheme 1 Proposed asymmetric binary acid catalysis
The intramolecular tandem 1,5-hydride transfer/ring-
closure reaction represents an efficient approach to cleav-
age of a C(sp3)–H bond and research in this area has made
great progress.3 Recently, the group of Yuan reported an ef-
ficient stereoselective construction of spirooxindole tetra-
hydroquinolines with contiguous quaternary or tertiary
stereogenic carbon centers through FeCl3-catalyzed intra-
molecular tandem 1,5-hydride shift/ring-closure.4 They in-
vestigated an asymmetric version of this process and found
that the use of many chiral ligands such as diamine, salen,
bisoxazoline, and diphosphine, in combination with a num-
ber of metal salts, gave no more than 11% ee, and moderate
Ar
1a: Ar = Ph
1f: Ar = 3,5-(CH3)2C6H3
1g: Ar = 3,5-(CF3)2C6H3
1h: Ar = 1-naphthyl
1i: Ar = 9-phenanthryl
1j: Ar = 9-anthracenyl
1b: Ar = 4-ClC6H4
1c: Ar = 4-FC6H4
1d: Ar = 4-O2NC6H4
1e: Ar = 4-biphenyl
O
O
O
P
OH
Ar
(S)-1
Figure 1 Chiral spirocyclic phosphoric acids (SPAs)
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, A–E

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Z. Mao et al.
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We selected oxindole derivative 2a as a model substrate
to examine the asymmetric intramolecular hydride trans-
fer–cyclization reaction. Previously, the groups of Akiyama
and Gong reported that the reaction of acyclic tertiary
amines could be achieved with good enantioselectivity
through the sole use of chiral phosphoric acid as the cata-
lyst.9 Thus, we started with chiral phosphoric acid 1a alone
to catalyze the reaction. Unfortunately, almost no reaction
occurred (Table 1, entry 1). The combination of MgCl2 and
chiral spirocyclic phosphoric acid 1 was then examined in
1,2-dichloroethane at 80 °C, and we were pleased to find
that all reactions proceeded quite smoothly (entries 2–11).
To our delight, The combination of MgCl2 and 1i, with
6,6′-bis(9-phenanthryl) moieties, gave the desired prod-
uct 3a in quantitative conversion with an encouraging 71%
ee (entry 10). In addition, the reaction using the combina-
tion of 1i and other Lewis acids, such as MgF2, Mg(SO3CF3)2,
or FeCl3 also proceeded well to afford the corresponding
product 3a, albeit in slightly reduced enantioselectivity,
without compromising the conversion (entries 12–14).
A survey of solvents was then conducted in the presence
of 2.5 mol% MgCl2 and 10 mol% 1i (Table 2, entries 1–7).
Toluene turned out to be the best solvent for this process,
and the spirooxindole tetrahydroquinoline product 3a was
obtained in quantitative conversion and 90% ee at 80 °C for
5 h (entry 7). The enantioselectivity declined slightly when
the reaction was conducted at reduced temperature (entry
8). Different molar ratios of 1i/MgCl2 were also examined,
and the optimal ratio in terms of enantioselectivity was
found to be 4:1 (entries 9 and 10 versus 7). Thus, the most
suitable reaction conditions for the model reaction were es-
tablished (entry 7).
Table 2 Optimization of the Reaction Conditionsa
N
1i (10 mol%)
N
MgCl2 (2.5 mol%)
solvent, 4 Å MS
O
O
N
N
Table 1 Catalyst Optimizationa
CO2Me
3a
CO2Me
2a
Entry
Solvent
Temp. (°C)
Conv. (%)b
ee (%)c,d
N
1 (10 mol%)
Lewis acid (2.5 mol%)
1
2
ClCH2CH2Cl
CH2Cl2
80
quant.
50
71
58
67
85
66
85
90
85
87
83
N
4 Å MS
reflux
reflux
reflux
80
ClCH2CH2Cl, 80 °C, 5 h
O
3
CHCl3
80
O
N
N
4
CCl4
95
CO2Me
3a
CO2Me
5
MeCN
90
2a
6
benzene
toluene
toluene
toluene
toluene
80
quant.
quant.
quant.
quant.
quant.
Entry
Phosphoric acid Lewis acid
Conv. (%)b
ee (%)c,d
7
80
1
2
1a
1a
1b
1c
1d
1e
1f
–
trace
quant.
quant.
quant.
80
–
2
8
60
9e
10f
80
MgCl2
MgCl2
MgCl2
MgCl2
MgCl2
MgCl2
MgCl2
MgCl2
MgCl2
MgCl2
MgF2
3
24
8
80
a Reaction conditions: 2a (0.05 mmol), phosphoric acid 1i (10 mol%, 0.005
mmol), MgCl2 (2.5 mol%, 0.00125 mmol), MS 4Å (15 mg), solvent (0.7
mL), 5 h under Ar.
4
5
13
2
b Conversions were determined by 1H NMR spectroscopic analysis.
c Up to 20:1 d.r. was obtained in all cases as determined by 1H NMR spec-
troscopic analysis.
6
60
7
quant.
80
13
40
6
d Determined by chiral HPLC analysis.
8
1g
1h
1i
e Molar ratio of 1i/MgCl2 was 3:1.
f Molar ratio of 1i/MgCl2 was 2:1.
9
85
10
11
12
13
14
quant.
90
71
55
65
54
65
With the optimized reaction conditions in hand, we
next turned our attention to assessing the substrate scope;
the results are summarized in Scheme 2. In all cases, the ex-
pected intramolecular tandem 1,5-hydride transfer/ring-
closure reaction proceeded smoothly to afford the corre-
sponding products with excellent diastereoselectivities
(90:10 to > 20:1 d.r.). The nature of the substituent on the
oxindole aromatic ring had a dramatic effect on enantiose-
lectivity, although the yields remained good (3a–f; Scheme 2).
The reaction involving a substrate with a strong electron-
withdrawing group, such as NO2, proceeded smoothly to
1j
1i
quant.
quant.
quant.
1i
Mg(SO3CF3)2
FeCl3
1i
a Reaction conditions: 2a (0.05 mmol), phosphoric acid 1 (10 mol%, 0.005
mmol), Lewis acid (2.5 mol%, 0.00125 mmol), MS 4Å (15 mg), ClCH2CH2Cl
(0.7 mL), 80 °C under Ar.
b Conversions were determined by 1H NMR spectroscopic analysis.
c Up to 20:1 d.r. was obtained in all cases as determined by 1H NMR spec-
troscopic analysis.
d Determined by chiral HPLC analysis.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, A–E

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give the corresponding product 3b in 90% yield with 97% ee
and up to >20:1 d.r. The incorporation of an electron-rich
substituent, such as CH3, on the oxindole aromatic ring ap-
peared to have a remarkably negative effect on the enantio-
selectivity of the reaction (3f; Scheme 2). The method was
not limited to pyrrolidine-derived substrates 2a–f: the re-
actions with piperidine-derived substrates also occurred
smoothly to afford the desired products 3g–k in good yields
with high diastereo- and enantioselectivities under the op-
timal conditions. Subsequently, an acyclic tertiary amine
derived substrate was examined and the reaction was also
found to proceed efficiently to produce 3l in 86% yield with
Scheme 2 Scope of the reaction. Reagents and conditions: 2 (0.05 mmol), 1i (10 mol%, 0.005 mmol), MgCl2 (2.5 mol%, 0.00125 mmol), MS 4Å (15
mg), toluene (0.7 mL), 80 °C under Ar. Yields given are of the isolated major isomer. Diastereomeric ratios were determined by 1H NMR spectroscopic
analysis. The ee values were determined by chiral HPLC analysis.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, A–E

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90% ee and >20:1 d.r. In addition, the tetrahydroisoquino-
line-derived oxindole also furnished the desired prodct 3m
in high yield with good diastereo- and enantioselectivity. A
single-crystal X-ray analysis of 3b determined its absolute
configuration as (3S, 3a′S).10
In summary, we have developed an efficient enantiose-
lective intramolecular tandem 1,5-hydride transfer/ring-
closure reaction through the application of chiral phos-
phoric acid-MgCl2 combined binary acid catalysis.11 By fol-
lowing this methodology, a series of structurally diverse
spirooxindole tetrahydroquinolines were obtained in good
yields with high diastereo- and enantioselectivities. Further
application of this method for the preparation of new bio-
active heterocycles is underway.
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Acknowledgment
Financial support was provided by National Natural Foundation of
China (21272202, 21572200 and J1210042).
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Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560198.
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p
p
ortiInfogrmoaitn
S
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p
p
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References and Notes
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Chem. Soc. Rev. 2012, 41, 7247. (f) Hong, L.; Wang, R. Adv. Synth.
Catal. 2013, 355, 1023.
(3) For pioneering work on the intramolecular tandem 1,5-hydride
transfer/ring-closure reaction, see: (a) Verboom, W.; Reinhoudt,
D. N.; Visser, R.; Harkema, S. J. Org. Chem. 1984, 49, 269.
(b) Nijhuis, W. H. N.; Verboom, W.; Reinhoudt, D. N. J. Am. Chem.
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, A–E

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(9) (a) Mori, K.; Ehara, K.; Kurihara, K.; Akiyama, T. J. Am. Chem. Soc.
2011, 133, 6166. (b) He, Y.-P.; Wu, H.; Chen, D.-F.; Yu, J.; Gong,
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(10) CCDC-1059197 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html [or from the Cam-
bridge Crystallographic Data Centre, 12, Union Road,
peared. The product was purified by silica gel column chroma-
tography (EtOAc–PE, 1:4) to afford the desired product 3.
Compound 3a: Yield: 92%; off-white solid; m.p. 149–150 °C;
HPLC analysis: 90% ee {Chiralpak AD-H (hexane–i-PrOH, 90:10;
0.8 mL/min): tR = 12.4 (major), 16.8 (minor) min}; [α]D20 42.9
(c = 1.2, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 7.96 (d,
J = 8.0 Hz, 1 H), 7.29–7.20 (m, 2 H), 7.02 (d, J = 7.6 Hz, 1 H),
6.96–6.92 (m, 1 H), 6.67–6.63 (m, 1 H), 6.59 (d, J = 8.0 Hz, 1 H),
6.45 (dd, J = 7.6, 1.2 Hz, 1 H), 4.05 (s, 3 H), 3.77 (q, J = 9.6 Hz,
1 H), 3.54–3.44 (m, 1 H), 3.26–3.20 (m, 1 H), 2.75 (d, J = 15.6 Hz,
1 H), 1.92–1.81 (m, 3 H), 0.93–0.88 (m, 1 H). 13C NMR (100 MHz,
CDCl3): δ = 177.26, 151.34, 143.46, 139.02, 129.64, 128.39,
128.11, 127.99, 124.95, 124.51, 117.83, 115.90, 114.51, 110.26,
62.88, 53.94, 47.09, 46.79, 37.76, 27.04, 23.24. IR (film): 2965,
1760, 1738, 1604, 1479, 1462, 1360, 1287, 1243, 1160, 1072,
746 cm–1. HRMS (EI-TOF): m/z calcd for C21H20N2O3: 348.1474;
found: 348.1476.
Cambridge CB21EZ,
UK;
fax:
+44(1223)336033;
or
deposit@ccdc.cam.ac.uk].
(11) General Procedure for the Synthesis of 3: Phosphoric acid cat-
alyst 1i (10 mol%, 3.3 mg), a solution of MgCl2 in EtOH (2.5
mol%, 0.12 mg, 0.1 mL, 1.2 mg/mL), and 4 Å molecular sieves (15
mg) were added to a Schlenk-type flask and the mixture was
dried under vacuum. Toluene (0.3 mL) was then added and the
resulting mixture was stirred for 1 h under Ar. A solution of 2 in
toluene (0.05 mmol, 0.4 mL) was added and the resulting
mixture was heated to 80 °C until the starting material disap-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, A–E