A catalytic asymmetric ring-expansion reaction of isatins and α-alkyl-α-diazoesters: Highly efficient synthesis of functionalized 2-quinolone derivatives

Article abstract of DOI:10.1002/anie.201204594

Asymmetric expansion: A catalytic asymmetric ring-expansion reaction of the title compounds occurs in the presence of a Sc(OTf)3 catalyst bearing an N,N?-dioxide-based ligand. Highly functionalized 2-quinolone derivatives containing a chiral C4-quaternary stereocenter were obtained in high yields and high levels of selectivity under mild reaction conditions (see scheme; Tf=trifluoromethanesulfonyl).

Full text of DOI:10.1002/anie.201204594

Angewandte
Chemie
DOI: 10.1002/anie.201204594
Asymmetric Catalysis
A Catalytic Asymmetric Ring-Expansion Reaction of Isatins and
a-Alkyl-a-Diazoesters: Highly Efficient Synthesis of Functionalized
2-Quinolone Derivatives**
Wei Li, Xiaohua Liu, Xiaoyu Hao, Yunfei Cai, Lili Lin, and Xiaoming Feng*
The ring-expansion reaction of cyclic ketones and diazo
compounds is a classical way to expand the ring size of cyclic
carbonyl compounds by one-carbon unit.[1] The ring expan-
sion of isatin and other ketones with diazomethane was
reported early in the last century.[2] Since then, a number of
advances have been made, such as the development of
variants that use a-diazoesters, which are more stable and less
reactive than a-diazoalkanes.[3] However, the development of
Scheme 1. Regiochemistry in the ring expansion of unsymmetrical
substrates.
catalytic asymmetric variants seems particularly difficult.
Innovative approaches have recently been reported by
Kingsbury and co-workers[4] and by Maruoka and co-work-
ers.[5] However, the catalytic reactions developed by these
research groups involved the ring expansion of symmetric
aliphatic cyclic ketones through 1,2-alkyl migration.
Extremely low reaction temperatures and high catalyst
loadings were required, especially when a-alkyl-a-diazoesters
were used to incorporate all-carbon quaternary centers. To
the best of our knowledge, asymmetric ring expansion of
prochiral cyclic carbonyl compounds, which usually suffer
from complicated regiochemical problems,[1a,2c] has not been
documented to date. Although isatin was chosen as the
substrate in the first example of a ring-expansion reaction
with diazomethane, a reaction that was reported in the year
1919,[2a] an asymmetric ring expansion of isatins has not been
reported. In this reaction multiple products are possible
because of competitive 1,2-aryl migration and 1,2-carbonyl
migration reaction pathways (Scheme 1).[2c,6] Thus, the devel-
opment of a suitable catalyst for the ring expansion of
unsymmetric substrates with high regio- and enantiocontrol is
particularly desirable, albeit challenging. In a continuation of
our research with diazo compounds,[7] we report herein
a highly enantioselective ring-expansion reaction of isatins
and a-alkyl-a-diazoesters involving 1,2-aryl migration.[8]
Quinolone scaffolds,[9] particularly functionalized 2-qui-
nolones that contain a chiral quaternary center at C4, are
common in natural products and medicinal molecules, such as
the Melodinus alkaloids (scandine,[10] meloscine,[11] and melo-
scandonine),[12] melicodenine G,[13] and yaequinolone A1.[14]
Efficient asymmetric approaches to incorporate this impor-
tant molecular scaffold are limited,[15] as are the formations of
chiral quaternary centers.[16] The asymmetric ring-expansion
reaction of isatins and a-substituted a-diazoesters would be
a straightforward method for preparing this quinolone com-
pounds. In the presence of a Sc(OTf)3 catalyst containing
a N,N’-dioxide-based ligand,[17] we found that the asymmetric
ring-expansion reaction of isatins and a-alkyl-a-diazoesters
performed well with a catalyst loading as low as 0.05 mol%,
thus providing highly functionalized C4-quaternary 2-quino-
lone derivatives with ee values as high as 99%. Moreover, the
catalytic reaction shows high functional-group tolerance,
which facilitates the further transformation of products into
other useful synthetic intermediates.
We screened an array of chiral ligands and metal ions (see
the Supporting Information) for their reactivity and ability to
induce asymmetry in the ring-expansion reaction of N-benzyl
isatin 2a and a-benzyl-a-diazoacetate 1a. This survey led to
the following optimized reaction conditions: 0.2 mol% of
a scandium(III) complex with the N,N’-dioxide ligand L,
which was prepared from l-ramipril, CH2Cl2 as the solvent,
and 308C as the reaction temperature. The desired quinoline-
2,3(1H,4H)-dione derivative 3a was obtained in 91% yield
with an ee value of 99% (Scheme 2); a byproduct derived
from the 1,2-carbonyl migration pathway was obtained in 8%
yield. This result shows that in this reaction the aryl group has
a higher migratory aptitude than the carbonyl group.[2c]
We then explored the scope of this reaction with a range
of a-alkyl-a-diazoesters (Scheme 2). Varying the ester group
of the a-diazoester (1a–1d) had no adverse effect on yield
and selectivity. The rate and enantioselectivity of the ring-
[*] W. Li, Prof. Dr. X. H. Liu, X. Y. Hao, Y. F. Cai, Dr. L. L. Lin,
Prof. Dr. X. M. Feng
Key Laboratory of Green Chemistry & Technology
Ministry of Education, College of Chemistry
Sichuan University, Chengdu 610064 (China)
E-mail: xmfeng@scu.edu.cn
Prof. Dr. X. M. Feng
State Key Laboratory of Applied Organic Chemistry
Lanzhou University, Lanzhou 730000 (China)
[**] We acknowledge the National Natural Science Foundation of China
(Nos. 21021001 and 21172151), National Basic Research Program
of China (973 Program: No. 2010CB833300), and the Ministry of
Education (No. 20110181130014) for financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201204594.
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although the yields of the products 3r–3t were lower owing to
deleterious side reactions. Further exploration of the scope of
the reaction with respect to the diazoester focused on the
those containing substituents bearing functional groups (1u–
1w). Cinnamyl, allyl, and alkynyl moieties proved to be well
tolerated by the reaction, thus giving a-allylic and a-alkynylic
ketone derivatives, respectively. Other a-alkyl diazoesters,
which contained a terminal substituent, such as an ester,
a nitrile, and a silyl ether group (1x–1z) were also trans-
formed in this reaction with low catalyst loading. Generally,
the levels of enantioselectivity in the reactions of all
substrates were very high, ranging from 93% to 99% ee.
We then investigated the scope of the reaction with
respect to the isatin substrate (Table 1). The position and
electronic nature of substituents of the isatin had significant
effects on both enantioselectivity and reactivity (Table 1,
entries 1–10). Isatins 2b–2e, which have substituents at the C5
position, gave lower levels of enantioselectivity and were less
reactive than isatins with substituents at the C6 and C7
positions. For 5-halo-substituted isatins, both the reactivity
and the enantioselectivity decreased in the order 5-F > 5-Cl >
5-Br> 5-I (Table 1, entries 1–4). The presence of a halo-
substituent either at the C6 or the C7 positions of isatins did
Table 1: Scope of isatins in the catalytic asymmetric ring expansion.[a]
Entry R3 (2)
x [mol%] t [h] Yield [%][b] (3) ee [%][c]
1
2
3
4
5
6
7
8
9
10
5-F (2b)
0.2
0.5
0.5
0.5
0.2
0.2
0.2
0.2
0.2
0.2
16
21
32
48
15
30
8
20
20
32
88 (3ab)
84 (3ac)
84 (3ad)
76 (3ae)
90 (3af)
89 (3ag)
80 (3ah)
82 (3ai)
80 (3aj)
82 (3ak)
93 (S)
90 (S)
87 (S)
80 (S)
99
98
98
97
98
5-Cl (2c)
5-Br (2d)
5-I (2e)
6-F (2 f)
6-Br (2g)
7-F (2h)
7-Cl (2i)
7-Br (2j)
7-Me (2k)
Scheme 2. Scope of a-alkyl-a-diazoesters in the catalytic asymmetric
ring expansion. The reactions were performed with L/Sc(OTf)3 (0.05–
0.2 mol%, 1:1.2), 2a (0.20 mmol), 1 (0.30 mmol), CH2Cl2 (0.2 mL) in
308C for 5–50 h (for details, see the Supporting Information). Yields of
isolated products are reported. The ee values were determined by
HPLC using a chiral stationary phase. The absolute configuration of
3a was determined to be S by X-ray crystallographic analysis, and
those of 3b–3m were assigned by comparing their circular-dichroism
spectra with that of 3a. TBS=tert-butyldimethylsilyl, Tf=trifluorome-
thanesulfonyl.
96
11
12
0.5
0.5
40
40
80 (3al)
95
97
(2l)
82 (3am)
expansion reactions of a series of substituted a-benzyl
diazoacetates (1e–1p) were uniformly high. The electronic
properties, bulkiness, or positions of the substituents on the
benzyl group of diazoacetates had very little effect on the
reaction outcome. 2-Naphthylmethyl-substituted a-diazo-
ester 1q was also well tolerated in this reaction. The reactions
of diazoesters containing an ethylphenyl substituent or an
alkyl substituent at the a position (1r–1t) were relatively fast.
For these reactions, the catalyst loading was reduced to
0.05 mol%; the levels of enantioselectivity remained high,
(2m)
H (2n)
H (2o)
13
0.2
0.5
10
52
91 (3an)
78 (3ao)
96 (S)
96 (S)
14[d]
[a] Unless specified otherwise, all reactions were performed with 1a
(0.30 mmol), 2 (0.20 mmol), L/Sc(OTf)3 (0.2–0.5 mol%, 1:1.2), CH2Cl2
(0.2 mL) at 308C. [b] Yield of isolated product. [c] Determined by HPLC
using a chiral stationary phase. The absolute configurations of the
products 3ab–3ae, 3an, and 3ao were determined by comparing their
circular-dichroism spectra with that of 3a. [d] 0.15 mL of CH2Cl2 was
used. Bn=benzyl.
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not have an adverse effect on enantioselectivity (97–99% ee).
Isatin 2k, which has a methyl group at the C7 position, gave
the corresponding product 3ak in 82% yield and 96% ee.
Isatins containing either a fused saturated or a fused unsatu-
rated ring were good substrates, albeit the catalyst loading
and the reaction time had to be increased a little (Table 1,
entries 11 and 12). N-Methyl-protected isatin 2n also gave the
corresponding product in high yield and with a high ee value
(Table 1, entry 13). Moreover, N-unprotected isatin 2o was
found to be a suitable substrate and gave the corresponding
product 3ao in 78% yield and 96% ee, albeit after a prolonged
reaction time (Table 1, entry 14).
To gain information about how the catalyst induces
asymmetry, the catalyst was analyzed by X-ray diffraction
and high resolution mass spectrometry (HRMS). In the X-ray
structure of the chiral metal—ligand complex L/Sc(OTf)3
(Scheme 3), the two oxygen atoms of the amide moieties
catalyst and the product 3a,[18] intermediates I and II are
possible. The a-diazoester should preferentially approaches
isatin 2a from the Si face, because the Re face is shielded by
one of the bulky 2,6-diisopropylaniline groups of the ligand.
The prochiral faces of the a-alkyl a-diazoester 1a are
probably discriminated by the repulsive interaction between
the ester group of the diazoester and the amide moiety of the
ligand (Scheme 3, I versus II). We believe that as the electron-
rich diazo-bearing carbon atom of 1a, attacks, through its Re
face, the isatin 2a, the resulting complex would also exhibit
the antiperiplanar relationship between the diazo moiety and
the aryl ring that is necessary for the 1,2 aryl shift/dinitrogen
extrusion process.[2c,6] If the reaction proceeds in this way, the
product will be obtained with the observed S configuration.
The results of the reactions using the various isatin and
diazoester substrates support this proposed model (see the
Supporting Information). When 4-bromoisatin 2p was used,
lower reactivity and reduced enantioselectivity were
obtained. This result might be due to the fact that the
C4 position of isatin is closer to the octahydrocyclopentapyr-
role unit of the ligand than the other positions. The resulting
repulsion would put the 4-substituted isatin at a disadvantage
regarding activation. Similarly, the a-isopropyl substituent of
diazoester 1aa would incur steric hindrance in the arrange-
ment depicted in Scheme 3, a fact that may explain its
conversion into product in low yield and relatively low
ee value (see the Supporting Information).
Next, the synthetic value of the reaction was investigated.
The reaction of isatin 2a was carried out on a gram scale
(1.19 g, 5.0 mmol) to show the scalability of this method and
gave the product 3a in 89% yield and 99% ee (Scheme 4a).
The product 3a could be efficiently converted, through
reduction using NaBH4, into useful 3-hydroxyl 2-quinolone
5.[14] The absolute stereochemistry of the secondary hydroxy
group of 5 was determined to be R by using the modified
Mosher-ester analysis. TiCl4-catalyzed allylation of 3v gave
highly functionalized compound 6, which contains two con-
Scheme 3. Proposed mechanism of the catalytic asymmetric ring
expansion.
and the two oxygen atoms of the N-oxide moieties of the
ligand L, together with the OTfÀ ion and a molecule of H2O
form bonds with the scandium(III) center. HRMS analysis of
a mixture of isatin 2a and the catalyst, which was prepared
in situ from Sc(OTf)3, L, and 2a (1:1:1) in CH2Cl2, confirmed
that isatin interacts with the catalyst. A peak at m/z 490.7509
was detected and corresponds to the complex [Sc3+ + 2a +
(LÀH+)]2+ (calc. m/z 490.7599). This result suggests that isatin
2a could be activated upon coordination of the 1,2-dicarbonyl
group with the ScIII center in a bidentate fashion. To achieve
high enantioselectivity, simultaneously discrimination of the
prochiral faces of both the isatin and the approaching a-alkyl-
a-diazoesters is crucial. In light of the structures of the
Scheme 4. Applications of the catalytic asymmetric ring expansion.
Reaction conditions: (i) L/Sc(OTf)3 (0.2 mol%, 1:1.2), CH2Cl2, 308C,
=
12 h; (ii) NaBH4, CH3OH, À208C, 15 min; (iii) H2C CHCH2Si(CH3)3,
TiCl4, CH2Cl2, À208C, 15 min; (iv) Grubbs II (10 mol%), CH2Cl2, 24 h.
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Hashimoto, Y. Naganawa, K. Maruoka, Chem. Commun. 2010,
46, 6810 – 6812; f) B. Morandi, E. M. Carreira, Angew. Chem.
2011, 123, 9251 – 9254; Angew. Chem. Int. Ed. 2011, 50, 9085 –
9088.
tiguous chiral quaternary stereocenters (Scheme 4b). Olefin
metathesis of 6 using Grubbsꢀ second generation catalyst
afforded tricyclic compound 7 in 99% yield and 98% ee.
Interestingly, when hydroxy-group-containing diazoester 1ab
was used, a cascade reaction occurred, thus affording product
8 with 73% yield and 93% ee (Scheme 4c).
In summary, we have described the first catalytic asym-
metric ring-expansion reaction of isatins and a-alkyl-a-
diazoesters, a reaction that gives the 1,2-aryl migration
product preferentially. In the presence of 0.05–0.5 mol% of
a Sc(OTf)3 catalyst bearing an N,N’-dioxide ligand, a series of
substrates underwent the reaction smoothly, providing highly
functionalized C4-quaternary 2-quinolones in high yields (up
to 94%) and with high levels of enantioselectivity (up to
99% ee). A range of functional groups was also tolerated
under the mild reaction conditions. Based on an X-ray crystal
structure of the catalyst, a reasonable model that explains the
asymmetric induction was proposed. Further transformations
of the highly functionalized products into useful molecules
are underway.
[4] V. L. Rendina, D. C. Moebius, J. S. Kingsbury, Org. Lett. 2011,
13, 2004 – 2007.
[5] T. Hashimoto, Y. Naganawa, K. Maruoka, J. Am. Chem. Soc.
2011, 133, 8834 – 8837.
[6] a) A. Gioiello, F. Venturoni, M. Marinozzi, B. Natalini, R.
Pellicciari, J. Org. Chem. 2011, 76, 7431 – 7437; b) B. Alcaide, P.
Almendros, C. Aragoncillo, G. Gꢁmez-Campillos, M. Arnꢁ,
L. R. Domingo, ChemPlusChem 2012, 77, 563 – 569.
[7] a) W. Li, J. Wang, X. L. Hu, K. Shen, W. T. Wang, Y. Y. Chu,
L. L. Lin, X. H. Liu, X. M. Feng, J. Am. Chem. Soc. 2010, 132,
8532 – 8533; b) A. Hassner, I. Namboothiri in Organic Syntheses
Based on Name Reactions, 3th ed., Elsevier, Oxford, 2011,
p. 408; c) W. Li, X. H. Liu, X. Y. Hao, X. L. Hu, Y. Y. Chu, W. D.
Cao, S. Qin, C. W. Hu, L. L. Lin, X. M. Feng, J. Am. Chem. Soc.
2011, 133, 15268 – 15271.
[8] T. Hashimoto, Y. Naganawa, K. Maruoka, J. Am. Chem. Soc.
2008, 130, 2434 – 2435.
[9] For recent reviews, see: a) J. P. Michael, Nat. Prod. Rep. 2008, 25,
166 – 187; b) V. Sridharan, P. A. Suryavanshi, J. C. Menꢂndez,
Chem. Rev. 2011, 111, 7157 – 7259.
[10] a) S. E. Denmark, J. J. Cottell, Adv. Synth. Catal. 2006, 348,
2397 – 2402; b) A. F. G. Goldberg, B. M. Stoltz, Org. Lett. 2011,
13, 4474 – 4476.
[11] a) L. E. Overman, G. M. Robertson, A. J. Robichaud, J. Am.
Chem. Soc. 1991, 113, 2598 – 2610; b) P. Selig, T. Bach, Angew.
Chem. 2008, 120, 5160 – 5162; Angew. Chem. Int. Ed. 2008, 47,
5082 – 5084.
[12] M. Plat, M. Hachem-Mehri, M. Koch, U. Scheidegger, P. Potier,
Tetrahedron Lett. 1970, 11, 3395 – 3398.
[13] K. Nakashima, M. Oyama, T. Ito, Y. Akao, J. R. Witono, D.
Darnaedi, T. Tanaka, J. Murata, M. Iinuma, Tetrahedron 2012,
68, 2421 – 2428.
Experimental Section
10–100 mL of L/Sc(OTf)3 catalyst solution (0.01m in THF) was added
to a dry reaction tube. After removing THF from the tube under
vacuum and then filling the tube with N2, isatin 2 (0.20 mmol) and
CH2Cl2 (0.2 mL) were added at 308C. After stirring the mixture for
0.5 h, a-diazoester 1 (0.30 mmol) was added, and the resulting
mixture was stirred at 308C for the indicated time. The crude mixture
was purified by flash chromatography on silica gel (dichloromethane
to 50:1 dichloromethane/acetone) to afford the desired product 3.
Received: June 13, 2012
Published online: && &&, &&&&
[14] R. Uchida, R. Imasato, Y. Yamaguchi, R. Masuma, K. Shiomi, H.
¯
Tomoda, S. Omura, J. Antibiot. 2006, 59, 646 – 651.
[15] a) L. Yin, M. Kanai, M. Shibasaki, Angew. Chem. 2011, 123,
7762 – 7765; Angew. Chem. Int. Ed. 2011, 50, 7620 – 7623; b) C.
Mꢃller, A. Bauer, M. M. Maturi, M. C. Cuquerella, M. A.
Miranda, T. Bach, J. Am. Chem. Soc. 2011, 133, 16689 – 16697.
[16] a) K. Fuji, Chem. Rev. 1993, 93, 2037 – 2066; b) E. J. Corey, A.
Guzman-Perez, Angew. Chem. 1998, 110, 402 – 415; Angew.
Chem. Int. Ed. 1998, 37, 388 – 401; c) B. Tan, N. R. Candeias, C. F.
Barbas III, Nat. Chem. 2011, 3, 473 – 477.
Keywords: diazo compounds · isatins · quinolones ·
ring expansion · scandium
.
[1] For recent reviews, see: a) T. Ye, M. A. McKervey, Chem. Rev.
1994, 94, 1091 – 1160; b) M. P. Doyle, M. A. McKervey, T. Ye,
Modern Catalytic Methods for Organic Synthesis with Diazo
Compounds, Wiley, New York, 1998; c) Z. Zhang, J. Wang,
Tetrahedron 2008, 64, 6577 – 6605.
[2] a) G. Heller, Ber. Dtsch. Chem. Ges. 1919, 52, 741 – 745; b) E.
Mosettig, A. Burger, J. Am. Chem. Soc. 1930, 52, 3456 – 3463;
c) C. D. Gutsche, Org. React. 1954, 8, 364 – 429; d) J. J. Li in
Name Reactions: A Collection of Detailed Reaction Mechanism,
Springer, Berlin, 2003, p. 58.
[3] For recent examples, see: a) Y. Zhang, J. Wang, Chem. Commun.
2009, 5350 – 5361; b) D. C. Moebius, J. S. Kingsbury, J. Am.
Chem. Soc. 2009, 131, 878 – 879; c) J. A. Dabrowski, D. C.
Moebius, A. J. Wommack, A. F. Kornahrens, J. S. Kingsbury,
Org. Lett. 2010, 12, 3598 – 3601; d) T. Hashimoto, Y. Naganawa,
K. Maruoka, J. Am. Chem. Soc. 2009, 131, 6614 – 6617; e) T.
[17] For reviews, see: a) X. H. Liu, L. L. Lin, X. M. Feng, Acc. Chem.
ˇ
´
Res. 2011, 44, 574 – 587; b) A. V. Malkov, P. Kocovsky, Eur. J.
Org. Chem. 2007, 29 – 36; for a Highlight, see: c) S.-X. Huang,
K. L. Ding, Angew. Chem. 2011, 123, 7878 – 7880; Angew. Chem.
Int. Ed. 2011, 50, 7734 – 7736; for recent examples see: d) Y. F.
Cai, X. H. Liu, J. Jiang, W. L. Chen, L. L. Lin, X. M. Feng, J. Am.
Chem. Soc. 2011, 133, 5636 – 5639; e) K. Shen, X. H. Liu, G.
Wang, L. L. Lin, X. M. Feng, Angew. Chem. 2011, 123, 4780 –
4784; Angew. Chem. Int. Ed. 2011, 50, 4684 – 4688.
[18] CCDC 882157 (3a) and CCDC 882608 (the catalyst) 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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Communications
Asymmetric Catalysis
W. Li, X. H. Liu, X. Y. Hao, Y. F. Cai,
L. L. Lin, X. M. Feng*
&&&& — &&&&
A Catalytic Asymmetric Ring-Expansion
Reaction of Isatins and a-Alkyl-a-
Diazoesters: Highly Efficient Synthesis of
Functionalized 2-Quinolone Derivatives
Asymmetric expansion: A catalytic asym-
metric ring-expansion reaction of the title
compounds occurs in the presence of
a Sc(OTf)3 catalyst bearing an N,N’-
dioxide-based ligand. Highly functional-
ized 2-quinolone derivatives containing
a chiral C4-quaternary stereocenter were
obtained in high yields and high levels of
selectivity under mild reaction conditions
(see scheme; Tf=trifluoromethanesul-
fonyl).
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