Sodium Salts of Anionic Chiral Cobalt(III) Complexes as Catalysts of the Enantioselective Povarov Reaction

Article abstract of DOI:10.1002/anie.201504790

The sodium salts of anionic chiral cobalt(III) complexes (CCC^?Na⁺) have been found to be efficient catalysts of the asymmetric Povarov reaction of easily accessible dienophiles, such as 2,3-dihydrofuran, ethyl vinyl ether, and an N-protected 2,3-dihydropyrrole, with 2-azadienes. Ring-fused tetrahydroquinolines with up to three contiguous stereogenic centers were thus obtained in high yields, excellent diastereoselectivities (endo/exo up to >20:1), and high enantioselectivities (up to 95:5 e.r.).

Full text of DOI:10.1002/anie.201504790

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201504790
German Edition: DOI: 10.1002/ange.201504790
Chiral Anion Catalysis
Sodium Salts of Anionic Chiral Cobalt(III) Complexes as Catalysts of
the Enantioselective Povarov Reaction
Jie Yu, Hua-Jie Jiang, Ya Zhou, Shi-Wei Luo, and Liu-Zhu Gong*
Abstract: The sodium salts of anionic chiral cobalt(III)
À
+
complexes (CCC Na ) have been found to be efficient
catalysts of the asymmetric Povarov reaction of easily acces-
sible dienophiles, such as 2,3-dihydrofuran, ethyl vinyl ether,
and an N-protected 2,3-dihydropyrrole, with 2-azadienes.
Ring-fused tetrahydroquinolines with up to three contiguous
stereogenic centers were thus obtained in high yields, excellent
diastereoselectivities (endo/exo up to > 20:1), and high enan-
tioselectivities (up to 95:5 e.r.).
T
he use of chiral anions as stereoinductors in the field of
asymmetric catalysis has received increasing attention.
[1]
Whereas organic molecular anion catalysts have been
widely employed, the potential of chiral metal complexes as
counteranions in asymmetric catalysis has hardly been
explored. Belokon et al. recently showed that salicylalde-
À
+
Scheme 1. CCC M catalysts used for the Povarov reaction.
III
hyde-derived chiral Co complexes can be employed to
accelerate a few CÀC bond formation reactions by asymmet-
The catalytic enantioselective Povarov reaction has been
[2b-d]
[5–7]
ric counterion catalysis.
However, these transformations
intensively investigated
since the pioneering work by
[2a–d]
proceeded with low to moderate enantioselectivities
owing to the limitations of unsubstituted salicylaldehydes
Ishitani and Kobayashi, who employed a chiral ytterbium
[6a]
complex as the catalyst. In these cases, classical chiral Lewis
[2e–f]
[6]
[7]
and the meridional stereoisomers of these complexes.
We
acids or chiral Brønsted acids have generally been the
catalysts of choice to promote asymmetric versions. Thus, the
development of new chiral catalyst motifs that are principally
distinct from traditional ones is still highly desirable. Herein,
envisioned that easily prepared, structurally tunable, and
[
2g]
III
stereochemically stable metal salts of anionic chiral Co
À
+
complexes (CCC M ) that are derived from salicylaldehydes
with bulky substituents and l-amino acids would be more
applicable to asymmetric catalysis than anticipated by
common sense (Scheme 1). We hypothesized that the achiral
cation can activate a substrate while the chiral counteranion
might be applied to control the stereoselectivity of the
transformation. Thus, we decided to test these catalysts in the
challenging Povarov reaction of simple 2-azadienes and
dienophiles to generate structurally diverse 1,2,3,4-tetrahy-
droquinoline (THQ) derivatives with contiguous stereogenic
centers, which are key structural motifs of numerous natural
III
we show that the sodium salts of anionic chiral Co
À
+
complexes (CCC Na ) are able to act as promising chiral
catalysts for the asymmetric Povarov reaction of a wide
variety of simple 2-azadienes and dienophiles, such as 2,3-
dihydrofuran, ethyl vinyl ether, and an N-protected 2,3-
dihydropyrrole, giving rise to multiply substituted THQ
derivatives in high yields and with excellent stereoselectivities
(Scheme 1).
[
3]
Our initial investigation started with the reaction of
N-phenyl benzaldimine (1a) with 2,3-dihydrofuran (2a) in the
[
4]
III
products and pharmacologically relevant molecules.
presence of the Brønsted acids of various anionic chiral Co
À
+
complexes (CCC H , 4a–4e; 5 mol%), which are all derived
from salicylaldehydes and l-amino acids (Table 1, entries 1–
7). Among them, L-4e, which bears a 3,5-di-tert-butyl-
[
2d]
[8]
[
*] Dr. J. Yu
Department of Applied Chemistry
Anhui Agricultural University (China)
1
2
substituted (R , R ) salicylaldehyde and a tert-butyl group
3
(
R ) on the amino acid moiety, gave the highest enantiomeric
H.-J. Jiang, Y. Zhou, Prof. Dr. S.-W. Luo, Prof. Dr. L.-Z. Gong
Hefei National Laboratory for Physical Sciences at the Microscale
and Department of Chemistry
University of Science and Technology of China (China)
E-mail: gonglz@ustc.edu.cn
ratio of 75:25 (entry 7). Interestingly, the use of sodium salt
L-4 f to replace its acidic form L-4e improved both the
diastereo- and enantioselectivities (entry 8 vs. entry 7). The
stereoselectivity could be enhanced by introducing a larger
substituent, such as a trimethylsilyl, triethylsilyl, or triisopro-
Prof. Dr. L.-Z. Gong
Collaborative Innovation Centre of Chemical Science and Engineer-
ing, Tianjin (China)
2
pylsilyl group, at the C3 position (R ) of the salicylaldehyde
À
+
moiety (entries 9–11). In particular, CCC Na catalyst L-4i,
which bears a triisopropylsilyl moiety at the C3 position, gave
3aa in 91% yield, 20:1 d.r., and 87.5:12.5 e.r. (entry 11),
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201504790.
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11209

.
Angewandte
Communications
[
a]
Table 1: Optimization of the reaction conditions.
reaction did not work when the tetra-n-butylammonium salt
L-4l, which is derived from chiral Co complex L-4e and
III
tetra-n-butylammonium hydroxide, was used (entry 14).
These results (entries 7–8, 11, 13, and 14) indicated that the
alkali cations act as Lewis acids to accelerate the reaction
III
while the coordinatively saturated anionic Co complexes
[
b]
[c]
[c]
[2b,c]
Entry
4
Yield [%]
endo/exo
e.r.
only control the stereoselectivity.
Various additives were
then tested (entries 15–18), and 5Š molecular sieves turned
out to be the optimal additive for this transformation; the
THQ product 3aa was thus obtained in 92% yield and
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
D-4a
L-4a
L-4b
L-4c
D-4d
L-4d
L-4e
L-4 f
L-4g
L-4h
L-4i
L-4j
L-4k
L-4l
L-4i
L-4i
L-4i
L-4i
L-4i
L-4i
L-4i
15
39
75
42
61
12
74
73
86
88
91
69
74
N.R.
87
92
49
55
96
93
89
6:1
4:1
8:1
8:1
3:1
51.5:48.5
52.5:47.5
50:50
52:48
56:44
55:45
75:25
80:20
81.5:18.5
82.5:17.5
87.5:12.5
58.5:41.5
83.5:16.5
N.D.
8
8.5:11.5 e.r. at ambient temperature (entry 16). Lowering the
temperature resulted in enhanced enantioselectivity
entries 19 and 20), and the reaction proceeded well at
3:2
(
6.5:1
10:1
15:1
15:1
20:1
10:1
15:1
N.D.
>20:1
>20:1
9:1
À408C, providing product 3aa in 92:8 e.r. (entry 20). Increas-
ing the catalyst loading from 5 mol% to 10 mol% led to
a further small enhancement of the enantioselectivity
(entry 21).
With an optimized procedure established (Table 1,
entry 20), we next explored the scope of the enantioselective
Povarov reaction with respect to the 2-azadienes 1 (Table 2).
1
1
1
1
1
1
1
1
1
1
2
2
[
[
[
[
[
[
[
d]
88:12
e]
88.5:11.5
82.5:17.5
82.5:17.5
89:11
92:8
93.5:6.5
f]
[a]
Table 2: Variation of the 2-azadiene.
g]
8:1
e,h]
e,i]
e,i,j]
>20:1
>20:1
>20:1
[
(
a] Unless otherwise noted, the reaction was performed with 1a
0.2 mmol), 2a (0.4 mmol), catalyst 4 (0.01 mmol), and 3Š M.S. (20 mg)
in n-hexane (2 mL) at room temperature for 6 h. [b] Yield of isolated
1
2
[b]
[c]
[c]
Entry
1
R
R
Yield [%] endo/exo
e.r.
product. [c] Determined by HPLC analysis on a chiral stationary phase;
1
the relative configuration of the endo isomer was confirmed by H NMR
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1 f
H
H
H
H
H
4-Me
H
89 (3aa)
85 (3ba)
84 (3ca)
93 (3da)
>20:1
>20:1
>20:1
>20:1
15:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
93.5:6.5
95:5
92:8
93:7
94:6
spectroscopy, and the e.r. values refer to the endo isomer. [d] 4Š M.S.
4-Me
4-Cl
4-Br
4-CO Et 37 (3ea)
4-Me
were used. [e] 5Š M.S. were used. [f] Anhydrous Na SO was used.
2
4
[
g] Anhydrous MgSO was used. [h] The reaction was performed at
4
À208C for 24 h. [i] The reaction was performed at À408C for 72 h. [j] L-4i
2
(10 mol%). M.S.=molecular sieves, N.D.=not determined, N.R.=no
[d]
81 (3 fa)
89 (3ga)
60 (3ha)
86 (3ia)
88 (3ja)
40 (3ka)
88:12
reaction, TBDMS=tert-butyldimethylsilyl, TES=triethylsilyl, TIPS=tri-
isopropylsilyl, TMS=trimethylsilyl.
[d]
1g 4-NO2 4-Me
1h 4-CN
93.5:6.5
92.5:7.5
93.5:6.5
92.5:7.5
61.5:38.5
[d]
4-Me
4-Me
4-Me
[
[
[
d]
d]
d]
9
0
1
1i
1j
4-Br
4-Cl
1
1
1k 2,4-Cl2 4-Me
[
a] Unless otherwise noted, the reaction was performed with
1
(0.2 mmol), 2a (0.4 mmol), catalyst L-4i (0.02 mmol), and 5Š M.S.
(
20 mg) in n-hexane (2 mL) at À408C for 72 h. [b] Yield of isolated
product. [c] Determined by HPLC analysis on a chiral stationary phase;
the e.r. values refer to the endo isomer. [d] The reaction was performed at
0
8C for 72 h, and n-hexane/CH Cl (20:1 v/v) was used as the solvent.
2 2
Various substituents on the aniline moiety of the N-aryl imine
were nicely tolerated (1a–1e), and the corresponding endo
tetrahydroquinolines were obtained in up to 93% yield,
>
20:1 d.r., and up to 95:5 e.r. (entries 1–5). The electronic
nature of the substituent on the para position of the N-aryl
ring did not exert an obvious influence on the stereoselectivity
(
entries 2–5), and the best enantiomeric ratio of 95:5 was
À
+
whereas the use of a CCC Na catalyst with tert-butyldime-
thylsilyl substituents (L-4j) resulted in much poorer results
(
obtained for product 3ba, which features a 4-methyl sub-
stituent on the N-aryl ring (entry 2). However, the poor
solubility of imines derived from substituted aldehydes in
n-hexane at À408C always led to incomplete conversion.
Therefore, a series of other solvents, such as CH Cl , CHCl ,
entry 12). A comparison of potassium salt L-4k with L-4i
suggested that the size of the cation has a subtle influence on
the stereoselectivity (entry 13 vs. entry 11). Interestingly, the
2
2
3
1
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and toluene, were then screened as co-solvents. Fortunately,
when the reactions of these substrates were carried out in
a CH Cl /n-hexane solvent mixture (1:20 v/v) at 08C, better
results were obtained. Thus, the N-aryl imines 1 f–1j, which
bear either electron-donating, electron-withdrawing, or hal-
ogen substituents, furnished the corresponding products
with stereoselectivities similar to those observed for the
corresponding reactions with preformed aldimines [Eq. (1)].
2
2
[
9]
(3 fa–3ja) with good stereoselectivities (entries 6–10). How-
ever, the introduction of a 2,4-disubstituted aryl ring (1k) led
to a significantly diminished enantioselectivity (entry 11).
The scope of the Povarov reaction with regard to the
dienophiles 2 was also evaluated (Table 3). Remarkably, the
[
a]
À
+
Table 3: Variation of the dienophile.
During our studies on the CCC Na catalyzed Povarov
reaction, we found a positive nonlinear effect for the reaction
of benzaldimine 1a with 2,3-dihydrofuran (2a) in the
presence of 10 mol% of scalemic catalyst 4i in n-hexane at
À408C (Figure 1). Kinetic studies revealed that optically pure
À
+
CCC Na showed a higher catalytic activity than a racemic
catalyst sample (Figure S2), which might be the possible
reason for the positive nonlinear effect.
[
9]
[
10]
[
b]
[c]
[c]
Entry
1
2
Yield [%]
endo/exo
e.r.
[
[
d]
d]
1
2
3
4
5
6
7
1a
1b
1a
1g
1a
1a
1a
2b
2b
2c
2c
2d
2e
2 f
64 (3ab)
44 (3bb)
94 (3ac)
99 (3gc)
63 (3ad)
36 (3ae)
70 (3af)
>20:1
>20:1
>20:1
12:1
2:1
4:1
>20:1
94:6
94.5:5.5
93:7
[
e]
91:9
77.5:22.5
78:22
76:24
[
1
a] Unless otherwise noted, the reaction was performed with
(0.2 mmol), 2 (0.4 mmol), catalyst L-4i (0.02 mmol), and 5Š M.S.
(
20 mg) in n-hexane (2 mL) at À408C for 72 h. [b] Yield of isolated
product. [c] Determined by HPLC analysis on a chiral stationary phase;
the e.r. values refer to the endo isomer. [d] The 1/2 ratio was 1:4, and the
reaction was run for 5 days. [e] The reaction was performed at 08C, and
À
+
n-hexane/CH Cl (20:1 v/v) was used as the solvent.
2
2
Figure 1. The CCC Na catalyzed asymmetric Povarov reaction dis-
plays a nonlinear effect.
simple vinyl ether 2b was able to undergo a Povarov reaction
with the N-aryl imines 1a and 1b to smoothly generate THQ
products with high levels of enantioselectivity (up to 94.5:5.5
e.r., entries 1 and 2). Furthermore, N-protected 2,3-dihydro-
pyrrole 2c was also a good substrate, generating the
corresponding tetrahydroquinolines in excellent yields and
with good stereoselectivities (entries 3 and 4). However, the
use of either 2-hydroxystyrene (2d) or 3-vinylindole (2e),
which contain acidic functional groups, as the dienophiles led
to significantly reduced diastereo- and enantioselectivities
According to these experimental data and the crystal
À
+
[11]
structures of CCC Na L-4h and the products 3aa and
[12]
3ia, we propose a transition state to explain the observed
stereochemistry (Scheme 2). The sodium cation, in combina-
tion with the weakly coordinating chiral anion, is considered
to act as a Lewis acid to activate 2-azadiene 1a, leading to the
possible transition state TS-I, as suggested by preliminary
[13]
DFT calculations. The [4+2] cycloaddition with 2,3-dihy-
drofuran (2a) should then preferentially occur on the Si face
of 2-azadiene 1a, because in the proposed TS-I structure, the
Re face of the imine might be shielded by both the triisopro-
pylsilyl and tert-butyl groups of the catalyst, which leads to the
formation of (3aS,4S,9bS)-3aa as the major enantiomer.
In summary, we have demonstrated that the sodium salts
(
entries 5 and 6). N-Methyl-3-vinylindole (2 f) gave the
corresponding product in excellent diastereoselectivity and
good yield, albeit with moderate enantioselectivity
entry 7).
The one-pot three-component asymmetric Povarov reac-
a
(
III
of anionic chiral Co complexes are highly promising
tion of 2,3-dihydrofuran (2a) and para-toluidine (6) with
various aromatic aldehydes 5 catalyzed by L-4i (10 mol%)
was also successful, furnishing the products 3 in good yields
catalysts for the asymmetric Povarov reaction of 2-azadienes
with various dienophiles, such as 2,3-dihydrofuran, ethyl vinyl
ether, and an N-protected 2,3-dihydropyrrole, furnishing
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.
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Communications
Schreiner, Chem. Soc. Rev. 2009, 38,
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1
Gale, Chem. Soc. Rev. 2012, 41, 480;
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Brak, E. N. Jacobsen, Angew. Chem.
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013, 125, 558; for pioneering work on
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Fletcher, A. Nelson, Tetrahedron:
Asymmetry 2003, 14, 1995.
Scheme 2. Proposed transition state.
[
2] For a recent review, see: a) L. Gong, L.-
A. Chen, E. Meggers, Angew. Chem.
Int. Ed. 2014, 53, 10868; Angew. Chem.
2
014, 126, 11046, and references therein; for selected examples
structurally diverse endo tetrahydroquinolines with excellent
diastereoselectivities (up to > 20:1 d.r.) and high enantiose-
lectivities (up to 95:5 e.r.). In this reaction, the N-aryl imines
were probably activated by the sodium cation in combination
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Belokonꢀ, V. I. Maleev, D. A. Kataev, I. L. Malꢀfanov, A. G.
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T. V. Skrupskaya, L. V. Yashkina, A. F. Mkrtchyan, A. S.
III
with the weakly coordinating anionic chiral Co complex.
More importantly, these findings might inspire the develop-
III
ment of anionic Co complexes as alternative stereocontrol
elements for enantioselective transformations. Further stud-
ies will focus on the elucidation of the exact reaction
mechanism and the development of other asymmetric coun-
Saghyan, M. M. Ilꢀin, D. A. Chusov, Tetrahedron: Asymmetry
2
III
013, 24, 178. Chiral Co complexes with two perpendicular
tridentate ligands, such as the Schiff bases of salicylaldehydes
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which correspond to a left- and right-helical arrangement of the
ligands in relation to the C2 axis of the complexes; see: e) J. I.
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Burrows, J. C. Bailar, J. Am. Chem. Soc. 1966, 88, 4150; the chiral
Co complex can retain its chiral integrity during the amino acid
III
teranion-directed reactions with chiral Co complexes.
Experimental Section
III
N-Aryl imine 1 (0.20 mmol), catalyst L-4i (19.5 mg, 0.02 mmol),
activated 5Š M.S. (20 mg), and n-hexane (2 mL) were added to
a 10 mL oven-dried vial at room temperature. The mixture was cooled
down to À408C and stirred for 15 min. The dienophile 2 (0.40 mmol)
was then added, and the resultant solution was stirred vigorously until
the reaction was complete (monitored by TLC). The reaction was
III
synthesis, see: g) Y. N. Belokonꢀ, V. M. Belikov, S. V. Vitt, T. F.
Savelꢀeva, V. M. Burbelo, V. I. Bakhmutov, G. G. Aleksandrov,
Y. T. Struchkov, Tetrahedron 1977, 33, 2551.
quenched with pre-cooled NEt (À408C, 140 mL, 1.0 mmol); and the
[3] L. S. Povarov, B. M. Mikhailov, Izv. Akad. Nauk SSSR Ser. Khim.
1963, 955.
3
crude reaction mixture was purified by flash column chromatography
on silica gel (petroleum ether/EtOAc = 10:1) to give the enantioen-
riched THQ derivative 3.
[4] For reviews, see: a) A. R. Katritzky, S. Rachwal, B. Rachwal,
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[5] For reviews on the Povarov reaction, see: a) H. Waldmann,
Synthesis 1994, 535; b) K. A. Jørgensen, Angew. Chem. Int. Ed.
Acknowledgements
We are grateful for financial support from the NSFC
(
21202155, 21232007), the Anhui Provincial Natural Science
Foundation (1408085QB24), Anhui Agricultural University
Yj2013-9), and the Ministry of Education. We thank Dr. Shi-
(
2
000, 39, 3558; Angew. Chem. 2000, 112, 3702; c) J. S. Johnson,
Ming Zhou for the determination of the absolute configu-
ration.
D. A. Evans, Acc. Chem. Res. 2000, 33, 325; d) P. Buonora, J.-C.
Olsen, T. Oh, Tetrahedron 2001, 57, 6099; e) S. Kobayashi, K. A.
Jørgensen, Cycloaddition Reactions in Organic Synthesis, Wiley-
VCH, Weinheim, 2002; f) V. A. Glushkov, A. G. Tolstikov, Russ.
Chem. Rev. 2008, 77, 137; g) V. V. Kouznetsov, Tetrahedron 2009,
Keywords: asymmetric catalysis · 2-azadienes ·
cobalt complexes · Povarov reaction · tetrahydroquinolines
6
5, 2721; h) G. Masson, C. Lalli, M. Benohoud, G. Dagousset,
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1
1212 www.angewandte.org
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Angewandte
Chemie
III
2
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[8] For the syntheses of the chiral Co complexes 4e–4k using
l-tert-leucine, only the L-(S,S) isomers were obtained; see the
Supporting Information for details.
3
X. Zhao, Y. Xia, L. Lin, X. Feng, Chem. Eur. J. 2011, 17, 13800.
7] For examples of chiral Brønsted acid catalyzed Povarov
reactions, see: a) T. Akiyama, H. Morita, K. Fuchibe, J. Am.
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[9] See the Supporting Information for details.
[
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[11] CCDC 1025164 (L-4h) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre. The
absolute configurations of other catalysts were assigned by
comparison of their CD spectra with those of D-4a, L-4a, and
L-4h; see the Supporting information for details.
9
1
86; e) G. Dagousset, J. Zhu, G. Masson, J. Am. Chem. Soc. 2011,
33, 14804; f) G. Dagousset, P. Retailleau, G. Masson, J. Zhu,
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i) F. Shi, G.-J. Xing, R.-Y. Zhu, W. Tan, S. Tu, Org. Lett. 2013, 15,
[12] CCDC 1021263 (3aa) and 1054919 (3ia) contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic
Data Centre.
1
28; j) L. Caruana, M. Fochi, S. Ranieri, A. Mazzanti, L.
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[13] To obtain insights into the role of the sodium salt of the anionic
III
chiral Co complex in the asymmetric Povarov reaction,
preliminary DFT calculations were carried out on the reactant
complexes formed by catalyst L-4i with imine 1a and 2,3-
dihydrofuran (2a), respectively; see the Supporting Information
for details.
2
013, 125, 14334; n) J. Brioche, T. Courant, L. Alcaraz, M.
Stocks, M. Furber, J. Zhu, G. Masson, Adv. Synth. Catal. 2014,
56, 1719; for examples of relay catalytic Povarov reactions using
3
chiral Brønsted acids, see: o) C. Wang, Z.-Y. Han, H.-W. Luo, L.-
Z. Gong, Org. Lett. 2010, 12, 2266; p) J. Calleja, A. B. Gonzµlez-
PØrez, . R. de Lera, R. lvarez, F. J. FaÇanµs, F. Rodríguez,
Chem. Sci. 2014, 5, 996.
Received: May 27, 2015
Revised: June 30, 2015
Published online: July 31, 2015
Angew. Chem. Int. Ed. 2015, 54, 11209 –11213
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