Catalytic Asymmetric Conjugate Addition of Indolizines to α,β-Unsaturated Ketones

Article abstract of DOI:10.1002/anie.201700513

A catalytic enantioselective conjugate addition of indolizines to enones is described. The chiral phosphoric acid (S)-TRIP activates α,β-unsaturated ketones, thereby promoting an enantioface-differentiating attack by indolizines. Using this reaction, several alkylated indolizines were synthesized in good yields and with enantiomeric ratios of up to 98:2.

Full text of DOI:10.1002/anie.201700513

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International Edition: DOI: 10.1002/anie.201700513
German Edition: DOI: 10.1002/ange.201700513
Asymmetric Alkylation
Catalytic Asymmetric Conjugate Addition of Indolizines to a,b-
Unsaturated Ketones
Josꢀ Tiago Menezes Correia, Benjamin List,* and Fernando Coelho*
Abstract: A catalytic enantioselective conjugate addition of
indolizines to enones is described. The chiral phosphoric acid
(S)-TRIPactivates a,b-unsaturated ketones, thereby promoting
an enantioface-differentiating attack by indolizines. Using this
reaction, several alkylated indolizines were synthesized in good
yields and with enantiomeric ratios of up to 98:2.
T
he organocatalytic asymmetric conjugate addition of het-
eroarenes and electron-rich arenes to a,b-unsaturated car-
À
bonyl compounds is a highly valuable C C bond forming
reaction. Since it was first reported,[1] several strategies have
been developed, involving a large range of substrates and
catalytic activation modes.[2] Among the different catalyst
types used, chiral Brønsted acids[3] have stood out by
displaying high performance in catalyzing Friedel–Crafts-
type reactions with ketones and imines and with activated
olefins such as a,b-unsaturated oxo-esters, nitrolefins, and
a,b-unsaturated imines.[2,4] Other Friedel–Crafts-type trans-
formations, such as the asymmetric Pictet–Spengler reactions
have also been reported with excellent results under chiral
Brønsted acid catalysis.[5,6] Among the commonly used
nucleophiles in these transformations are pyrroles and
indoles. Indolizines are versatile building blocks for natural
product synthesis, possessing a large range of bioactivities and
interesting photophysical properties,[7,8] which make their
enantiopure derivatives of great interest (Figure 1). However,
while non-asymmetric metal-catalyzed Friedel–Crafts-type
conjugate additions using indolizines as nucleophiles have
been reported,[9] enantioselective versions remained
unknown. We herein report the first use of indolizines in
asymmetric organocatalysis.
Figure 1. Examples of biologically active indolizines.
Scheme 1. Asymmetric catalysis through monofunctional activation.
In most previous reports,[4] the phosphoric acid acts as
a bifunctional catalyst, activating both the electrophile
through protonation/hydrogen-bonding (LUMO lowering),
and the nucleophile (e.g., unprotected pyrroles or indoles)
through an interaction with the NH portion (HOMO raising;
Scheme 1a). The unavailability of this kind of bifunctional
activation with indolizines, which lack an available NH
moiety, represents the challenge and uniqueness of our
reaction design (Scheme 1b). By using TRIP as catalyst, we
have developed a catalytic enantioselective conjugate addi-
tion of indolizines to enones to furnish several alkylated
indolizines with good yields and in good to excellent
enantiomeric ratios.
In our preliminary studies, indolizine 1a and methylci-
nammyl ketone 2a were chosen as the model reactants. To
find suitable conditions, an extensive screening of catalysts,
solvents, temperatures, and concentrations was carried out
(Table 1; see the supporting information for complete
details). We found that a stoichiometric mixture of reactants
and 10 mol% of (S)-TRIP (3a)[10] in benzene after 7 days at
508C afforded the Friedel–Crafts-type adduct 4a in moderate
yield but with a promising enantioselectivity of 94:6 e.r.
(Table 1, entry 1). Since indolizine 1a is only a moderate
nucleophile, owing to the presence of an electron-withdraw-
ing group at C2, its stoichiometric proportion was doubled,
[*] M. Sc. J. T. M. Correia, Prof. Dr. F. Coelho
Department of Organic Chemistry
University of Campinas—Institute of Chemistry
Rua Josuꢀ de Castro, s/n—Cidade Universitꢁria Zeferino Vaz
P.O. Box 6154 13083 Campinas, SP (Brazil)
E-mail: coelho@iqm.unicamp.br
Prof. Dr. B. List
Max-Planck-Institut fꢂr Kohlenforschung
Kaiser-Wilhelm-Platz 1, 45470 Mꢂlheim an der Ruhr (Germany)
E-mail: list@kofo.mpg.de
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under https://doi.org/10.
1002/anie.201700513.
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Table 1: Reaction development and optimization.[a]
Entry Cat. Conc. of 2a
[molLÀ1]/Additive
t [days] T [8C] Yield [%][b] e.r. [%][c]
1[d]
2
3
4
5
6
7
8
9
3a 0.2
4
7
4
4
8
7
7
7
7
7
4
7
7
7
7
7
7
7
7
50
50
50
50
50
40
RT
40
40
40
80
40
40
35
35
RT
RT
RT
RT
34
76
72
73
20
93
37
37
29
40
40
42
56
70
71
32
14
53
62
94:6
94:6
58:42
75:25
82:18
3a 0.2
3b 0.2
3c 0.2
3d 0.2
3e 0.2
3e 0.2
3 f 0.2
3g 0.2
3h 0.2
79:21
91.5:8.5
78.5:21.5
75.5:29.5
5.5:94.5
70.5:29.5
95:5
95:5
94.5:5.5
94:6
10
11[e] 3i
0.2
12
13
14
15
16
3a 0.2
3a 0.5
3a 0.8
3a 1.0
3a 0.8
95:5
17[f] 3a 0.8/3 ꢃ MS
18[f] 3a 0.8/4 ꢃ MS
19[f] 3a 0.8/5 ꢀ MS
95.5:4.5
95.5:4.5
95.5:4.5
[a] Standard parameters unless otherwise indicated: 1 (0.08 mmol), 2
(0.04 mmol). [b] Yield of isolated product. [c] The e.r. were determined by
HPLC analysis. [d] 1 (0.04 mmol), 2 (0.04 mmol). [e] Side products
detected. [f] 750 mg mmolÀ1
which gave satisfactory yield (Table 1, entry 2). Other phos-
phoric acid catalysts bearing various substituents in the 3,3’-
position (3b–3i) were also tested, but none of them afforded
the desired product with enantioselectivity superior to that
obtained when using TRIP (3a, entries 3–11). Increasing the
reaction temperature led to side reactions, lowering the yield
and enantioselectivity of the desired product. Lowering the
reaction temperature instead led to a drastic decrease in yield
(Table 1, entries 12 and 13). Increasing the concentration to
0.8 molLÀ1 while lowering the reaction temperature to 358C
led to good yield and enantioselectivity (Table 1,
entries 14,15). Running the reaction at room temperature
again gave good enantioselectivity but low yield (Table 1,
entry 16). Taking advantage of the strong influence of
molecular sieves in Brønsted acid organocatalysis,[11] we
tested 4 ꢀ and 5 ꢀ molecular sieves, which further improved
both yield and enantioselectivity (Table 1, entries 17–19).
With the optimal conditions in hand, the scope and
limitations of the transformation were investigated. Initially,
a range of structurally and electronically modulated a,b-
unsaturated methyl ketones were tested (Scheme 2). The
enantioselectivity varied up to > 95:5 e.r. and, following the
expected reactivity tendency, the yields varied from 64 to as
high as 98% for substrates bearing moderate and strong
Scheme 2. Scope with respect to the a,b-unsaturated ketone. Reac-
tions were conducted on a 0.1 mmol scale. All yields are those of
isolated products, and the enantiomeric ratios (e.r.) were determined
by high-performance liquid chromatography (HPLC) with chiral sta-
tionary phases. Absolute configurations were assigned by crystallo-
graphic analysis of 4a (see the Supporting Information for details).
electron-withdrawing groups, and from 29–64%, for sub-
strates bearing strong and moderate electron-donating
groups. Comparing each pair of isomeric aromatic substrates
(4b,4c; 4d,4e and 4j,4k), is evident that there is no
significant difference between the enantioselectivity values
for the meta-substituted and para-substituted isomers. Only
moderate enantioselectivity was achieved for the heteroar-
omatic substrate 4m, as well as for the aliphatic substrates 4n
and 4o. In an attempt to expand the scope with respect to the
ketones, chalcone 2p was also tested. But despite the very
good yield, the enantioselectivity of the reaction leading to
product 4p was only moderate.
Our method was also tested using a set of different
indolizines (Scheme 3). Interestingly, almost no reactivity was
observed when C5- and C6-substituted indolizines were
tested, even at 408C. In such cases, adducts 4q and 4r,
2
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Scheme 4. Derivatization of the chiral indolizine products. a) Diphenyl
phosphate (10 mol%), Hantzsch ester, p-anisidine, toluene, 808C, 72 h
(Ref. [14]). b) K-Selectride (5 equiv), THF, 08–RT, 1,5 h. c) AcOH, PtO2
(10 mol%), 40 bar, RT, 96 h.
Scheme 3. Scope with respect to the indolizines. Reactions were
conducted on a 0.1 mmol scale. All yields are those of isolated
products, and the enantiomeric ratios (e.r.) were determined by high-
performance liquid chromatography (HPLC) with chiral stationary
phases. Absolute configurations were assigned by crystallographic
analysis of 4a. [a] Performed at 408C.
could be isolated in low yields and moderate enantioselectiv-
ity. The reaction with indolizines that are substituted at C7
and C8 (1d–1 f) afforded adducts 4s–u with very good
enantioselectivity, although yields were low. Replacement of
the methyl ester by the ethyl ester afforded 4v in good yield,
but with a slight decrease in the enantioselectivity.[12]
Apart of their broad biological activities, reduced forms of
indolizines are also known for being straightforward precur-
sors to indolizidinic alkaloids.[13] Derivatization, including
reductive amination, reductive lactonization, and partial
hydrogenation, was realized to further illustrate useful
applications (Scheme 4).[14,15]
A possible mechanistic scenario for such reactions would
involve the initially anticipated monofunctional activation
pathway, according to which the catalyst only activates the
ketone by protonation (Scheme 5). Other mechanistic possi-
bilities cannot be excluded at this point. For example,
a bifunctional activation pathway involving an additional
coordination of the basic site of the catalyst to the C3
hydrogen atom of the indolizine could be considered. Such
a pathway is reminiscent of a mechanism previously proposed
by Liu et al. for the Friedel–Crafts-type addition of N-methyl-
pyrroles to imines.[16] Future studies are underway aimed at
a deeper understanding of this intriguing reaction as well as
expanding the use of indolizines in organocatalysis.
Scheme 5. Suggested mechanism.
reading this manuscript. This work is part of the Cluster of
Excellence RESOLV (EXC 1069). J.T.M.C and F.C. thank the
FAPESP-Brazil for a research fellowship (Processes no. 2014/
02062-6, 2013/10449-5 and 2013/07600-3). FC thanks CNPq-
Brazil for research a fellowship (process no. 307840/2014-0).
The authors also thank Prof. Rodrigo Cormanich (IQ-
Unicamp) for performing the calculations for the configura-
tional assignment of product 5c.
Conflict of interest
The authors declare no conflict of interest.
Keywords: Brønsted acids · Friedel–Crafts reactions ·
indolizines · Michael addition · phosphoric acids
Acknowledgements
We thank our technician team and the members of the NMR,
MS, GC, and HPLC departments at the MPI fꢁr Kohlenfor-
schung for their excellent service. In particular, we gratefully
acknowledge the careful NMR investigation of compound 5c
by Petra Philipps. We thank Grigory Shevchenko for critically
[1] a) N. A. Paras, D. W. C. MacMillan, J. Am. Chem. Soc. 2001, 123,
4370 – 4371; b) J. F. Austin, D. W. C. MacMillan, J. Am. Chem.
Soc. 2002, 124, 1172 – 1173; c) N. A. Paras, D. W. C. MacMillan,
J. Am. Chem. Soc. 2002, 124, 7894 – 7895.
Angew. Chem. Int. Ed. 2017, 56, 1 – 5
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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[2] Reviews on asymmetric Friedel–Crafts alkylations: a) M. Ban-
dini, A. Melloni, A. Umani-Ronchi, Angew. Chem. Int. Ed. 2004,
43, 550 – 556; b) K. A. Jørgensen, Synthesis 2003, 1117 – 1125;
c) S.-L. You, Q. Cai, M. Zeng, Chem. Soc. Rev. 2009, 38, 2190 –
2201; d) E. Marquez-Lopez, A. Diez-Martinez, P. Merino, R. P.
Herrera, Curr. Org. Chem. 2009, 13, 1585 – 1609; e) T. B.
Poulsen, K. A. Jørgensen, Chem. Rev. 2008, 108, 2903 – 2915;
f) Catalytic Asymmetric Friedel – Crafts Alkylations (Eds.: M.
Bandini, A. Umani-Ronchi), Wiley-VCH, Weinheim, 2009; g) V.
Terrasson, R. M. de Figueiredo, J. M. Campagne, Eur. J. Org.
Chem. 2010, 2635 – 2655; h) M. Montesinos-Magraner, C. Vila,
G. Blay, J. R. Pedro, Synthesis 2016, 48, 2151 – 2164.
Ricci, G. Bartoli, G. Bencivenni Adv. Synth. Catal. 2011, 353,
860 – 864; e) X. Li, D. Chen, H. Gu, X. Lin, Chem. Commun.
2014, 50, 7538 – 7541.
[7] a) K. Bedjeguelal, H. Bienayme, A. Dumoulin, S. Poigny, P.
Schmitt, E. Tam, Bioorg. Med. Chem. Lett. 2006, 16, 3998 – 4001;
b) D. A. James, K. Koya, H. Li, G. Liang, Z. Xia, W. Ying, Y. Wu,
L. Sun, Bioorg. Med. Chem. Lett. 2008, 18, 1784 – 1787; c) G. S.
Singh, E. E. Mmatli, Eur. J. Med. Chem. 2011, 46, 5237 – 5257;
d) V. R. Vemula, S. Vurukonda, C. K. Bairi, Int. J. Pharm. Sci.
Rev. Res. 2011, 11, 159 – 163; e) V. Sharma, V. Kumar, Med.
Chem. Res. 2014, 23, 3593 – 3606.
[8] Photophysical properties of indolizines: a) E. J. Choi, E. Kim, Y.
Lee, A. Jo, S. B. Park, Angew. Chem. Int. Ed. 2014, 53, 1346 –
1350; Angew. Chem. 2014, 126, 1370 – 1374; b) E. Kim, Y. Lee, S.
Lee, S. B. Park, Acc. Chem. Res. 2015, 48, 538 – 547; c) M. F. Z. J.
Amaral, L. A. Deliberto, C. R. de Souza, R. M. Z. G. Naal, Z.
Naal, G. C. Clososki, Tetrahedron 2014, 70, 3249 – 3258.
[9] a) T. Matviiuk, G. Mori, C. Lherbet, F. Rodriguez, M. R. Pasca,
M. Gorichko, B. Guidetti, Z. Voitenko, M. Baltas, Eur. J. Med.
Chem. 2014, 71, 46 – 52; b) Y. Jung, I. K. Kim, Org. Biomol.
Chem. 2015, 13, 10986 – 10994; c) K. Zhang, H. Wang, J. Zheng,
L. Yub, H. Ding, Chem. Commun. 2015, 51, 6399 – 6402.
[10] a) J. T. M. Correia, Synlett 2015, 26, 416 – 417; b) G. Adair, S.
Mukherjee, B. List, Aldrichimica Acta 2008, 41, 31 – 39; c) S.
Hoffmann, A. Seayad, B. List, Angew. Chem. Int. Ed. 2005, 44,
7424 – 7427; Angew. Chem. 2005, 117, 7590 – 7593; d) T.
Akiyama, PCT Int. Appl.WO 200409675, 2004.
[11] a) J. Itoh, K. Fuchibe, T. Akiyama, Angew. Chem. Int. Ed. 2008,
47, 4016 – 4018; Angew. Chem. 2008, 120, 4080 – 4082; b) L.
Hong, W. Sun, D. Yang, G. Li, R. Wang, Chem. Rev. 2016, 116,
4006 – 4123.
[12] The enantioselectivity dropped and side products were observed
when the corresponding C1 methyl ester indolizine derivative
was used (see the Supporting Information).
[13] a) J. P. Michael, Nat. Prod. Rep. 2008, 25, 139 – 165; b) Z.-P.
Yang, Q.-F. Wu, W. Shao, S.-L. You, J. Am. Chem. Soc. 2015, 137,
15899 – 15906.
[3] a) T. Akiyama, Chem. Rev. 2007, 107, 5744 – 5758; b) M. Terada,
Synthesis 2010, 12, 1929 – 1982; c) D. Kampen, C. M. Reisinger,
B. List, Top. Curr. Chem. 2010, 291, 395 – 456; d) T. Akiyama, K.
Mori, Chem. Rev. 2015, 115, 9277 – 9306; e) D. Parmar, E.
Sugiono, S. Raja, M. Rueping, Chem. Rev. 2014, 114, 9047 – 9153.
[4] Selected recent examples of chiral Brønsted acid catalyzed
Friedel–Crafts reactions: a) Y.-S. Fan, Y. J. Jiang, D. An, D. Sha,
J. C. Antilla, S. Zhang, Org. Lett. 2014, 16, 6112 – 6115; b) K.-F.
Zhang, J. Nie, R. Guo, Y. Zheng, J.-A. Ma, Adv. Synth. Catal.
2013, 355, 3497 – 3502; c) Q. Yin, S.-L. You, Chem. Sci. 2011, 2,
1344 – 1348; d) L.-Y. Chen, H. He, W.-H. Chan, A. W. M. Lee, J.
Org. Chem. 2011, 76, 7141 – 7147; e) R. Husmann, E. Sugiono, S.
Mersmann, G. Raabe, M. Rueping, C. Bolm, Org. Lett. 2011, 13,
1044 – 1047; f) B. Bi, Q.-X. Lou, Y.-Y. Ding, S.-W. Chen, S.-S.
Zhang, W.-H. Hu, J.-L. Zhao, Org. Lett. 2015, 17, 540 – 543; g) J.-
W. Zhang, X.-W. Liu, Q. Gu, X.-X. Shi, S.-L. You, Org. Chem.
Front. 2015, 2, 476 – 480; h) C. Garcꢂa-Garcꢂa, L. Ortiz-Rojano,
S. ꢃlvarez, R. ꢃlvarez, M. Ribagorda, M. C. CarreÇo, Org. Lett.
2016, 18, 2224 – 2227; i) H.-Y. Tang, A.-D. Lu, Z.-H. Zhou, G.-F.
Zhao, L.-N. He, C.-C. Tang, Eur. J. Org. Chem. 2008, 1406 – 1410;
j) T. Sakamoto, J. Itoh, K. Mori, T. Akiyama, Org. Biomol.
Chem. 2010, 8, 5448 – 5454; k) Y. Zhou, X.-W. Liu, Q. Gu, S.-L.
You, Synlett 2016, 27, 586 – 590; l) M. Zhang, W. Sun, G. Zhu, G.
Bao, B. Zhang, L. Hong, M. Li, R. Wang, ACS Catal. 2016, 6,
5290 – 5294; m) S. Romanini, E. Galletti, L. Caruana, A.
Mazzanti, F. Himo, S. Santoro, M. Fochi, L. Bernardi, Chem.
Eur. J. 2015, 21, 17578 – 17582; n) G. B. Rowland, E. B. Rowland,
Y. Liang, J. A. Perman, J. C. Antilla, Org. Lett. 2007, 9, 2609 –
2611; o) Y. He, M. Lin, Z. Li, X. Liang, G. Li, J. C. Antilla, Org.
Lett. 2011, 13, 4490 – 4493.
[14] K.-H. Kim, C.-Y. Lee, C.-H. Cheon, J. Org. Chem. 2015, 80,
6367 – 6374. Using (S)-TRIP instead of diphenyl phosphate as
the catalyst gave a similar d.r. of 3:1. Enantiomeric (R)-TRIP
gave a d.r. of 1:3. However, conversion was lower in both cases.
[15] B. Sahoo, M. N. Hopkinson, F. Glorius, Angew. Chem. Int. Ed.
2015, 54, 15545 – 15549; Angew. Chem. 2015, 127, 15766 – 15770.
[16] a) C. Liu, P. Han, X. Wu, M. Tang, Comput. Theor. Chem. 2014,
1050, 39 – 45; b) G. L. Li, G. B. Rowland, E. B. Rowland, J. C.
Antilla, Org. Lett. 2007, 9, 4065 – 4068.
[5] a) M. S. Sigman, E. N. Jacobsen, J. Am. Chem. Soc. 1998, 120,
4901 – 4902; b) M. S. Taylor, E. N. Jacobsen, J. Am. Chem. Soc.
2004, 126, 10558 – 10559.
[6] a) J. Seayad, A. M. Seayad, B. List, J. Am. Chem. Soc. 2006, 128,
1086 – 1087; b) M. J. Wanner, R. N. S. van der Haas, K. R.
de Cuba, J. H. van Maarseveen, H. Hiemstra, Angew. Chem.
Int. Ed. 2007, 46, 7485 – 7487; Angew. Chem. 2007, 119, 7629 –
7631; c) J. J. Badillo, A. Silva-Garcꢂa, B. H. Shupe, J. C. Fet-
tinger, A. K. Franz, Tetrahedron Lett. 2011, 52, 5550 – 5553; d) S.
Duce, F. Pesciaioli, L. Gramigna, L. Bernardi, A. Mazzanti, A.
Manuscript received: January 16, 2017
Revised: March 31, 2017
Final Article published: && &&, &&&&
4
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Communications
Asymmetric Alkylation
J. T. M. Correia, B. List,*
F. Coelho*
&&&& — &&&&
Catalytic Asymmetric Conjugate Addition
of Indolizines to a,b-Unsaturated
Ketones
Alkylated indolizines: Using (S)-TRIP as
monofunctional catalyst, several alkylated
indolizines were synthesized in good
yields and with enantiomeric ratios of up
to 98:2.
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