Asymmetric tandem 1,5-hydride shift/ring closure for the synthesis of chiral spirooxindole tetrahydroquinolines

Article abstract of DOI:10.1002/chem.201404327

The direct functionalization of sp³ C-H bonds through a tandem 1,5-hydride shift/ring closure is described. Various optically active spirooxindole tetrahydroquinoline derivatives bearing contiguous quaternary or tertiary stereogenic carbon centers were readily synthesized. A chiral scandium complex of N,N'-dioxide promoted the reactions in good yields (up to 97%) with excellent diastereoselectivities (>20:1) and enantioselectivities (up to 94% ee). Kinetic isotope effect (KIE) experiments and internal redox reactions of chiral substrates were conducted, and the results provided intriguing information that helped clarify the mechanism of the reaction.

Full text of DOI:10.1002/chem.201404327

DOI: 10.1002/chem.201404327
Full Paper
&
Spiro Compounds
Asymmetric Tandem 1,5-Hydride Shift/Ring Closure for the
Synthesis of Chiral Spirooxindole Tetrahydroquinolines
Weidi Cao, Xiaohua Liu, Jing Guo, Lili Lin, and Xiaoming Feng*[a]
Abstract: The direct functionalization of sp3 CÀH bonds
through a tandem 1,5-hydride shift/ring closure is described.
Various optically active spirooxindole tetrahydroquinoline
derivatives bearing contiguous quaternary or tertiary stereo-
genic carbon centers were readily synthesized. A chiral scan-
dium complex of N,N’-dioxide promoted the reactions in
good yields (up to 97%) with excellent diastereoselectivities
(>20:1) and enantioselectivities (up to 94% ee). Kinetic iso-
tope effect (KIE) experiments and internal redox reactions of
chiral substrates were conducted, and the results provided
intriguing information that helped clarify the mechanism of
the reaction.
Introduction
asymmetric versions of the process have hitherto been far
from satisfactory. The combination of chiral diamine, salen, di-
phosphine, and bisoxazoline ligands with a number of metal
salts gave no more than 11% ee. Only moderate enantioselec-
tivity of 54% ee was achieved by using chiral phosphoric acids
as the catalysts.[8] Highly diastereo- and enantioselective as-
pects of the reaction have remained elusive. Our group
showed that chiral N,N’-dioxide–CoII complexes could be ex-
ploited in the asymmetric formation of tetrahydroquinolines
through an internal redox reaction.[6f] Furthermore, access to
the set of stereoisomers of 2-oxindole-based compounds has
also been realized through a number of strategies.[7] In this
context, we envisaged that this privileged type of chiral Lewis
acid could enable the highly stereoselective synthesis of spi-
rooxindole tetrahydroquinolines by lowering the activation
barriers of 1,5-hydride shift and controlling the stereoselectivity
of the H-transfer and subsequent ring closure. We herein pres-
ent our achievement of this goal (Figure 1).
The development of methodologies for the direct functionali-
zation of relatively unreactive CÀH bonds is of intense interest
and represents a long-standing goal in chemistry because
these reactions provide novel strategic approaches for synthe-
sis.[1] In the past decades, some promising catalytic systems for
the selective functionalization of C(sp3)ÀH bonds have been
developed. Since Reinhoudt et al.[2] provided an alternative
method of cleavage of a C(sp3)ÀH bond through an intramo-
lecular tandem 1,5-hydride shift/ring closure process in 1984,
variants of this rearrangement have been reported.[3–6] One
challenge associated with this chemistry has been to render it
enantioselective under mild reaction conditions. Chiral organo-
catalysts (e.g., chiral phosphoric acid and iminium) and chiral
Lewis acids (e.g., MgII, CoII and AuI coordinating with chiral li-
gands) are general catalysts that are used for the asymmetric
transitions. This concept has enabled the straightforward con-
struction of tetrahydroquinoline,[6a–c,f–h] furan-fused benzazepi-
nes,[6d] cyclic aminals,[6e] spiroethers,[6i] and others.
The chiral spirocyclic-3,3’-oxindole unit is encountered in
a large variety of natural products and several pharmaceutical
candidates with a wide spectrum of biological activities.[7] Ex-
tensive investigation has led to the synthesis of a series of
enantiomeric enriched spiro-fused 2-oxindole rings with differ-
ent functionality. Recently, Yuan and co-workers realized an ef-
ficient FeCl3-catalyzed 1,5-hydride shift/ring closure reaction to
form spirooxindole tetrahydroquinolines with contiguous qua-
ternary or tertiary stereogenic carbon centers. Nevertheless,
[a] W. Cao, Prof. Dr. X. Liu, J. Guo, Dr. L. Lin, Prof. Dr. X. Feng
Key Laboratory of Green Chemistry and Technology
Ministry of Education, College of Chemistry
Sichuan University, Chengdu 610064(China)
Fax: (+86)28-85418249
E-mail: xmfeng@scu.edu.cn
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201404327.
Figure 1. The synthesis of spirooxindole tetrahydroquinolines catalyzed by
N,N’-dioxide–metal complexes.
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Results and Discussion
Table 2. Optimization of the reaction conditions.
We selected oxindole derivative 1a as a representative sub-
strate to examine the intramolecular tandem 1,5-hydride shift/
ring closure reaction. Initial efforts focused on the metal pre-
cursors. A series of metal salts such as MgII, ZnII, CuII CoII, and
ScIII chelated with l-ramipril derived N,N’-dioxide L1 were used
to catalyze the reaction in CH2Cl2 at 358C (Table 1, entries 1–
Entry[a]
Solvent
Additive
Yield [%][b]
ee [%][c,d]
Table 1. Optimization of chiral N,N’-dioxide–metal complexes.
1
2
3
4
5
6
7
8
9
THF
EtOAc
toluene
CH3CN
CH2Cl2
–
–
–
–
–
–
–
–
27
19
22
NR
95
93
97
91
90
93
91
92
90
88
87
–
89
89
91
87
88
91
91
91
CHCl3
CH2ClCH2Cl
CHCl2CHCl2
PhCl
CH2ClCH2Cl
CH2ClCH2Cl
CH2ClCH2Cl
–
10[e]
11[e]
12[e]
3 ꢁ MS
4 ꢁ MS
5 ꢁ MS
Entry[a]
Metal
Ligand
Yield [%][b]
ee [%][c,d]
1
2
3
4
5
6
7
8
9
10
11
12
13
Mg(OTf)2
Zn(OTf)2
Cu(OTf)2
Co(BF4)2·6H2O
Sc(OTf)3
La(OTf)3
Y(OTf)3
Yb(OTf)3
Sm(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
L1
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
NR
NR
NR
trace
95
17
25
75
25
93
91
97
97
–
–
–
[a] Reaction conditions (unless otherwise noted): L1–Sc(OTf)3 (10 mol%,
1:1), 1a (0.10 mmol), solvent (1.0 mL), 358C, 20 h. [b] Isolated yield. [c] De-
termined by chiral HPLC analysis. [d] Up to 20:1 d.r. was obtained in all
cases determined by 1H NMR analysis. [e] Molecular sieves (10 mg) were
used.
–
89
64
73
77
70
61
29
85
83
tigated, and 91% ee could be obtained in the medium of
CH2ClCH2Cl (Table 2, entries 5–9). Molecular sieves were then
added to this reaction, but no better results were obtained
(Table 2, entries 10–12). Therefore, the optimal conditions were
established as: L1–Sc(OTf)3 complex (10 mol%; 1:1) and oxin-
dole derivative 1 (0.1 mmol) in CH2ClCH2Cl (1.0 mL) at 358C
(Table 2, entry 7).
[a] Reaction conditions (unless otherwise noted): L–metal (10 mol%, 1:1),
1a (0.10 mmol), CH2Cl2 (1.0 mL), 358C, 20 h. [b] Isolated yield. [c] Deter-
mined by chiral HPLC analysis. [d] Up to 20:1 d.r. was obtained in all
1
cases determined by H NMR analysis. NR=no reaction.
With the optimal conditions identified, we examined the
substrate scope of the reaction (Scheme 1). In all cases, the re-
action occurred smoothly to afford the products exclusively in
up to 20:1 d.r. values. Oxindole derivatives 1b and 1c with N-
Boc and N-Bn protecting groups were tolerated with no influ-
ence on the diastereo- and enantioselectivity, although the
yields decreased slightly (Scheme 1, 2a–c). We found that
a range of substrates 1d–k, with substituents at the oxindole
framework, participated effectively in the internal redox reac-
tions to yield the corresponding spirooxindole tetrahydroqui-
nolines with extremely high diastereoselectivities (>20:1 d.r.).
Compared with the 5-methyl or 5-methoxyl substituted oxin-
doles 1d and 1h, respectively, the electronically deficient halo-
substituted oxindoles 1e–g produced somewhat lower enan-
tioselectivities (82–87% ee). Substrates 1i–k, bearing halo-sub-
stituents at the 6- or 7-positions, served to generate the target
products in 80–87% yields and 85–88% ee. Substituent at the
extended aryl group of oxindole derivative 1l was also com-
patible with the reaction conditions, generating 2l in 92%
yield and 90% ee. Substrate 1m, containing the 6,7-dime-
thoxy-tetrahydroisoquinoline unit, was also tolerated (93%
yield, 94% ee). The method was not limited to the C(sp3)ÀH
bond of tetrahydroisoquinoline, with both pyrrolidine and pi-
peridine furnishing the desired products in high diastereo- and
enantioselectivities (>20:1 d.r., 91–92% ee), which served to
5).[9] Scandium(III) triflate proved to be competent for the for-
mation of the desired spirooxindole tetrahydroquinoline 2a,
with 95% yield, 89% ee and >20:1 d.r. (Table 1, entry 5),
whereas the others were found to be ineffective Lewis acid
mediators for the transformation. Other lanthanide metal salts
could furnish the product in a range of yields and enantiose-
lectivities, all of which were inferior to that obtained with scan-
dium(III) triflate (Table 1, entries 6–9). The structure of the N,N’-
dioxide ligands had a large effect on the enantioselectivity.
Neither ligand L4 derived from l-proline nor ligand L5 derived
from l-pipecolic acid were superior to l-ramipril derived L1
(Table 1, entries 12 and 13 vs. entry 5). Altering the amide sub-
stitutions from 2,6-diisopropylaniline to 2,6-diethylaniline or
2,6-dimethylaninline allowed for the formation of the products
in high yields but seriously decreased the enantioselectivity
(Table 1, entries 10–11).
Encouraged by the initial results, a range of solvents were
tested in the presence of L1–Sc(OTf)3 (10 mol%). The results in-
dicated that the reaction solvent played an important role in
governing the activity of the reaction. Low yields were ob-
tained in coordinating solvents (Table 2, entries 1–2). No reac-
tion took place in CH3CN, presumably due to the poor solubili-
ty (Table 2, entry 4). Given that CH2Cl2 was initially found to be
the optimal solvent, other chlorinated alkanes were then inves-
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Scheme 2. a) Substrate for the catalytic asymmetric intramolecular 1,5-hy-
dride transfer/closure of an acyclic compound. b) Gram-scale version of the
reaction.
phy separation of the spirooxindole tetrahydroquinoline prod-
ucts (see the Supporting Information).
To clarify the detailed reaction course, a kinetic isotope
effect (KIE) experiment[4f] was then conducted (Scheme 3). Rac-
Scheme 1. Substrate scope for spirooxindole tetrahydroquinoline derivatives.
Unless otherwise noted, all reactions were performed with L1-Sc(OTf)3
(10 mol%, 1:1), 1 (0.10 mmol) in CH2ClH2Cl (1.0 mL) at 358C for 20 h. Isolated
yields based on the amount of total E/Z isomers are reported. The ee was
1
determined by chiral HPLC analysis and the d.r. was determined by H NMR
Scheme 3. Kinetic isotope effect experiments with monodeuterated sub-
strate.
analysis. Relative and absolute stereochemical configurations were deter-
mined by X-ray analysis of the product 2l and on the circular dichroism
spectrum. [a] Mg(ClO4)2 was used instead of Sc(OTf)3. [b] CHCl3 was used in-
stead of CH2ClCH2Cl and L4 was used instead of L1. [c] The reaction was per-
formed at 608C.
emic monodeuterated substrate 1q was subjected to the intra-
molecular 1,5-hydride transfer/closure. The labeling experi-
ments showed interesting results. H-transferred product 2q-H
and d-transferred product 2q-D were obtained with kH/kD ratio
as 6.3, 5.1 and 5.2, respectively, when Sc(OTf)3, rac-L5/Sc(OTf)3,
and L5/Sc(OTf)3 were used as catalysts, indicating that the 1,5-
H transfer process in this reaction is the rate-determining step.
The phenomenon is similar to MgCl2-catalyzed tert-aminocycli-
zation proven by Luo and co-workers.[6g] As mentioned in early
reports,[2c,d] the tert-aminocyclization of 2-vinyl-N,N-dialkylani-
lines takes place in a suprafacial 1,5-H transfer manner, result-
ing in the formation of 2,4-cis configuration. In this case, based
slow the rate of reaction and required a higher reaction tem-
perature (608C) to drive the process. The absolute configura-
tion of the product 2l was determined to be (2S,3S) by X-ray
analysis (see the Supporting Information). Notably, (Z)-sub-
strates failed to be converted into the corresponding
products.[10]
Subsequently, we turned our attention to broadening the
substrate scope to include the acyclic tertiary amine unit and
found that this substrate gave only trace amounts of the 1,5-
hydride shift/ring closure product at 358C. Delightfully, apply-
ing the unique N,N’-dioxide-scandium(III)-mediated system at
higher reaction temperature (808C) enabled the redox process
to progress smoothly (57% yield, >20:1 d.r.), albeit with
a slight drop in the enantioselectivity (80% ee; Scheme 2a). In
addition, to show the synthetic utility of the catalyst system,
a gram-scale reaction with 1a was performed. As shown in
Scheme 2b, the reaction proceeded smoothly to give the de-
sired product 2a in 92% yield with 92% ee and >20:1 d.r. No-
tably, significant self-disproportionation of enantiomers
(SDE)[11] was observed during the silica column chromatogra-
1
on the H NMR spectrum of d-transferred product 2q-D, the
transferred H-2 and the bridgehead hydrogen H-1 was located
at 3.81 and 4.86 ppm. Irradiation of the bridgehead hydrogen
H-1 of 2a gave a NOE of 0.73% at H-2, which indicated that
two hydrogen atoms were located on the same face in 2a (see
the Supporting Information).
Control experiments were also conducted using chiral phe-
nylethanamine derived substrate 1r to clarify the origins of the
stereocontrol of the internal redox reaction (Scheme 4). When
optically pure oxindole derivative (S)-1r was employed in the
reaction with Sc(OTf)3 as the catalyst, the desired product was
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lent performance. A range of optically active spirooxindole tet-
rahydroquinoline derivatives bearing quaternary or tertiary ste-
reogenic carbon centers were obtained in high yields (up to
97%) with good ee values (up to 94% ee) and diastereoselec-
tivities (>20:1 d.r.). Kinetic isotope effect (KIE) and control ex-
periments were conducted. Strong chiral memory effect was
found using a chiral substrate. Further investigations explain-
ing the asymmetric mechanism of catalysis of the redox-neu-
tral sp3 CÀH functionalization are underway in our group.
Experimental Section
Typical experimental procedure for the cyclic substrate
Scheme 4. Control experiments of optically active substrate (S)-1r and (R)-
1r.
To a dry tube, L1 (0.01 mmol, 7.1 mg), Sc(OTf)3 (0.01 mmol, 4.9 mg),
and CH2ClCH2Cl (1.0 mL) were added under a N2 atmosphere and
the mixture was stirred at 358C for 0.5 h. The substrate 1a was
added and the mixture was stirred at 358C for an additional 20 h.
The residue was purified by flash chromatography on silica gel (pe-
troleum ether/Et2O=5:1) to afford the corresponding product 2a
(97% yield) as a white solid; m.p. 73–758C; 91% ee; >20:1 d.r.;
[a]2D5 +201.96 (c=0.56 in CH2Cl2). The ee was determined by HPLC
afforded in 87% ee (Scheme 4). This is consistent with Akiya-
ma’s observation that the chiral information in optically active
substrate did not completely disappear through the hydride
shift process (Figure 2).[6c] Interestingly, in the presence of cata-
analysis using
a
chiral ID column (hexane/iPrOH=80:20,
1.0 mLminÀ1, 254 nm): tr =11.39 (minor), 12.09 (major) min; the d.r.
1
1
was determined by H NMR analysis; H NMR (400 MHz, CDCl3): d=
7.29 (d, J=7.2 Hz, 1H), 7.27–7.20 (m, 1H), 7.14–7.06 (m, 2H), 7.06–
6.97 (m, 2H), 6.95–6.86 (m, 2H), 6.84–6.73 (m, 3H), 6.51 (d, J=
7.6 Hz, 1H), 4.86 (s, 1H), 7.04–3.95 (m, 1H), 3.81 (d, J=16.8 Hz, 1H),
3.21 (td, J=11.6, 3.2 Hz, 1H), 3.01 (s, 3H), 2.61–2.49 (m, 1H), 2.75
(d, J=8.4 Hz, 1H), 2.46–2.38 ppm (m, 1H); 13C NMR (101 MHz,
CDCl3): d=178.69, 145.93, 143.10, 136.03, 132.51, 130.69, 129.85,
127.97, 127.77, 127.64, 127.16, 126.76, 125.55, 125.24, 121.84,
120.29, 117.36, 111.86, 107.10, 62.19, 52.34, 42.79, 36.09, 29.82,
26.07 ppm; HRMS (ESI-TOF): m/z calcd. for C25H22N2O: 367.1810
[M+H+]; found: 367.1808.
Typical experimental procedure for the acyclic substrate
Figure 2. Possible reaction pathways.
To a dry tube, L1 (0.01 mmol, 7.1 mg), Sc(OTf)3 (0.01 mmol, 4.9 mg),
and CH2ClCH2Cl (1.0 mL) were added under a N2 atmosphere and
the mixture was stirred at 358C for 0.5 h. The substrate 1p was
added and the mixture was stirred at 808C for an additional 48 h.
The residue was purified by flash chromatography on silica gel (pe-
troleum ether/Et2O=5:1) to afford the corresponding product 2p
(57% yield) as a viscous oil; 80% ee; >20:1 d.r.; [a]2D5 +112.38 (c=
0.42 in CH2Cl2); the ee was determined by HPLC analysis using
a chiral ID column (hexane/iPrOH=80:20, 1.0 mLminÀ1, 254 nm):
tr =6.33 (major), 7.09 (minor) min; the d.r. was determined by
lyst systems L5/Sc(OTf)3, ent-L5/Sc(OTf)3, or L1/Sc(OTf)3, (S)-1r
underwent the redox reaction to give the product in compara-
bly high yields and identical configuration (Scheme 4). The ab-
solute configuration was determined to be (2S,3S) by X-ray
analysis (Figure 2). Consequently, (R)-1r furnished exclusively
(2R,3R)-2r irrespective of which chiral catalyst was used
(Scheme 4). The results differed from chiral phosphoric acid
promoted internal redox reactions of chiral benzylidene malo-
nates.[6c] One could speculate that the chiral memory effect is
extremely strong in the presence of a chiral N,N’-dioxide–
Sc(OTf)3 complex catalyst, overwhelming the stereocontrol ex-
erted by the chiral ligand (Figure 2, path 1). However, we have
no means of ruling out an enantiofacial selection of the nucle-
ophilic attack on the iminium cation when achiral substrates
were used.
1
1H NMR analysis; H NMR (400 MHz, CDCl3): d=7.31–7.21 (m, 2H),
7.16–7.03 (m, 3H), 7.02–6.91 (m, 3H), 6.89–6.68 (m, 4H), 6.50 (d,
J=8.0 Hz, 1H), 4.71 (s, 1H), 3.64 (d, J=15.6 Hz, 1H), 2.86 (s, 3H),
2.80 (s, 3H), 2.65 ppm (d, J=15.6 Hz, 1H); 13C NMR (101 MHz,
CDCl3): d=177.43, 147.51, 143.17, 137.08, 129.60, 129.50, 127.97,
127.90, 127.56, 127.20, 125.75, 122.11, 120.45, 117.53, 113.14,
107.35, 68.29, 51.59, 38.17, 35.88, 25.89 ppm; HRMS (ESI-TOF): m/z
calcd for C24H22N2O: 377.1630 [M+Na+]; found: 377.1634.
Procedure for the scale-up reaction
Conclusion
To a dry round-bottomed flask, L1 (0.3 mmol, 213.0 mg), Sc(OTf)3
(0.3 mmol, 147.0 mg), and CH2ClCH2Cl (30 mL) were added and the
mixture was stirred at 358C for 2.5 h. 1a (3.0 mmol) was added
and the mixture was stirred at 358C for 20 h. The residue was puri-
We have presented a highly diastereo- and enantioselective
1,5-hydride shift/ring closure cascade. The identified optimal
catalytic system of chiral N,N’-dioxide–Sc(OTf)3 exhibits excel-
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fied by flash chromatography on silica gel to afford the product 2a
(92% yield); 92% ee and >20:1 d.r. It was notable that the product
2a exhibited a clear self-disproportionation of enantiomers (SDE)
effect.
[4] For examples of 1,5-hydride shifts mediated by a C(sp3)ÀH bond a to
a nitrogen atom, see: a) C. Zhang, C. K. De, R. Mal, D. Seidel, J. Am.
Chem. Soc. 2008, 130, 416; b) S. Murarka, C. Zhang, M. D. Konieczynska,
D. Seidel, Org. Lett. 2009, 11, 129; c) C. Zhang, S. Murarka, D. Seidel, J.
Org. Chem. 2009, 74, 419; d) J. C. Ruble, A. R. Hurd, T. A. Johnson, D. A.
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General procedure for the kinetic isotope effect experiment
with monodeuterated 1q
To a dry tube, rac-5 (0.01 mmol, 6.5 mg), Sc(OTf)3 (0.01 mmol,
4.9 mg), and CH2ClCH2Cl (1.0 mL) were added and the mixture was
stirred at 358C for 0.5 h. 1q (0.1 mmol) was added and the mixture
was stirred at 358C for 20 h. The residue was purified by flash chro-
matography on silica gel (petroleum ether/Et2O=5:1) to afford the
corresponding product 2q as a white solid. 1H NMR (400 MHz,
CDCl3): d=7.34–7.26 (m, 1H), 7.26–7.20 (m, 1H), 7.17–6.96 (m, 4H),
6.96–6.85 (m, 2H), 6.84–6.68 (m, 3H), 6.50 (d, J=8.0 Hz, 1H), 4.85
(s, 0.23H), 4.02–3.96 (m, 1H), 3.81 (d, J=16.8 Hz, 0.77H), 3.21 (td,
J=11.6, 3.2 Hz, 1H), 3.01 (s, 3H), 2.75 (d, J=16.8 Hz, 1H), 2.61–2.49
(m, 1H), 2.47–2.37 ppm (m, 1H); 13C NMR (101 MHz, CDCl3): d=
177.62, 144.88, 142.05, 134.98, 131.38, 129.61, 128.76, 126.88,
126.68, 126.57, 126.08, 125.68, 124.47, 124.16, 120.75, 119.21,
116.26, 110.78, 106.01, 61.11, 51.26, 41.75, 35.00, 28.74, 24.98 ppm.
[6] For examples of asymmetric 1,5-hydride shifts mediated by a C(sp3)ÀH
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Crystallography
Details of the crystal structure determination are given in the Sup-
porting Information. CCDC-994332 (2l) and -1012868 (2r) contain
the supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
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We appreciate the financial support provided by the National
Natural Science Foundation of China (nos. 21290182,
21321061, and 21172151), the Ministry of Education (NCET-11–
0345), and the National Basic Research Program of China (973
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Keywords: asymmetric catalysis
hydride shift · scandium · spirooxindoles
·
CÀH functionalization
·
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Received: July 10, 2014
Published online on November 24, 2014
Chem. Eur. J. 2015, 21, 1632 – 1636
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