Bifunctional cinchona alkaloid-squaramide-catalyzed highly enantioselective aza-Michael addition of indolines to α,β-unsaturated ketones

Article abstract of DOI:10.1016/j.tetlet.2013.04.080

An enantioselective aza-Michael addition of indolines to α,β-unsaturated ketones was achieved using a bifunctional cinchona alkaloid-derived chiral squaramide derivative. Various β-indolinyl ketone derivatives were obtained in good to excellent yields and

Full text of DOI:10.1016/j.tetlet.2013.04.080

Tetrahedron Letters xxx (2013) xxx–xxx
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Bifunctional cinchona alkaloid-squaramide-catalyzed highly enantioselective
aza-Michael addition of indolines to a,b-unsaturated ketones
⇑
Arun K. Ghosh , Bing Zhou
Department of Chemistry and Medicinal Chemistry, Purdue University, 560 Oval Drive, West Lafayette, IN 47907, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
An enantioselective aza-Michael addition of indolines to a,b-unsaturated ketones was achieved using a
Received 2 April 2013
Revised 16 April 2013
Accepted 19 April 2013
Available online xxxx
bifunctional cinchona alkaloid-derived chiral squaramide derivative. Various b-indolinyl ketone deriva-
tives were obtained in good to excellent yields and with high enantioselectivity. DDQ or MnO2 oxidation
of indoline derivatives provided convenient access to various enantioenriched N-substituted indole
derivatives.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Aza-Michael reaction
Organocatalysis
Indoline
b-Keto indoline
Cinchona alkaloid
Enantioselective
The indole nucleus is a common structural feature in many bio-
active alkaloids.1 These subunits are also widely utilized in medic-
inal chemistry. Thus, enantioselective functionalization of indole
ring is important. Over the years, a number of methods were devel-
oped which involved enantioselective alkylation of indoles at the
C-3 position.2 Recently, enantioselective alkylation of indoles at
the C-2 has been carried out through the Pictet–Spengler reaction
or alkylation/oxidation of 4,7-dihydroindoles.3 However, enantio-
selective derivatization of indoles utilizing indole nitrogen atom
has rarely been explored possibly due to its low nucleophilicity.4
Interestingly, such N-functionalized indole derivatives are impor-
tant structural elements of numerous biologically active natural
products and synthetic medicinal agents.5,6
additions catalyzed by secondary amines were investigated.9 The
scope of these protocols was extended to ,b-unsaturated aliphatic
ketones using primary amines and ,b-unsaturated aromatic ke-
a
a
tones using chiral phosphoric acids as the catalyst.10,11 Recently,
bifunctional urea derived catalysts were employed for aza-Michael
addition, however low enantioselectivity of products and high cat-
alyst loading were some of the drawbacks of these methodolo-
gies.12 Enantioselective aza-Michael addition of indole or indoline
has been limited. Recent report of enantioselective aza-Michael
addition of indoline to b-nitro styrene only provided 28% ee.13
Herein, we describe an enantioselective intermolecular aza-Mi-
chael reaction of indolines with a,b-unsaturated aromatic ketones
catalyzed by a bifunctional cinchona alkaloid-squaramide catalyst.
The resulting indoline derivative can be converted into indole
derivative by a mild oxidation protocol. The current methodology
provides access to a range of enantioenriched N-substituted in-
doles with good to excellent enantioselectivity.
Our studies were focused on the aza-Michael reaction between
chalcone 1a and indoline 2a catalyzed by various quinine thiourea
derivatives. Initially, we performed all reactions with 20 mol % cat-
alyst in toluene at À20 °C. The results are shown in Table 1. As can
be seen, when thiourea catalyst A14 was used, the addition product
3a showed moderate enantioselectivity (55% ee) and the conver-
sion was excellent (90%, entry 1). We examined various other thio-
urea catalysts B–E.15 However, these catalysts showed moderate
enantioselectivity for the product 3a (entries 2–5). Subsequently,
we investigated squaramide derivatives of quinine F–J (entries
Asymmetric Michael addition of nitrogen to
a,b-unsaturated
carbonyl derivatives represents a straightforward, logical ap-
proach. A number of methods have been developed relying upon
the use of chiral auxiliaries, chiral starting materials, or stoichiom-
etric amounts of chiral ligands. However, the catalytic enantiose-
lective aza-Michael addition to
a,b-unsaturated carbonyl
compounds is quite challenging and remained relatively unex-
plored until recently.7 In 2006, MacMillian and co-workers8 re-
ported
intermolecular aza-Michael addition of N-silyloxycarbamates to
,b-unsaturated aldehydes. Subsequently, several other conjugate
an
enantioselective
secondary
amine-catalyzed
a
⇑
Corresponding author. Tel.: +1 765 494 5323.
E-mail address: akghosh@purdue.edu (A.K. Ghosh).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.04.080
Please cite this article in press as: Ghosh, A. K.; Zhou, B. Tetrahedron Lett. (2013), http://dx.doi.org/10.1016/j.tetlet.2013.04.080

2
A. K. Ghosh, B. Zhou / Tetrahedron Letters xxx (2013) xxx–xxx
Table 1
Table 2
Screening of the reaction conditionsa
Asymmetric aza-Michael reaction of indolines and a
,b-unsaturated ketonesa
R3
Catalyst
R3
+
O
Catalyst J
O
(20 mol%)
O
N
(20 mol%)
O
N
R2
+
Ph
solvent,-20°C
Ph
N
H
xylene
-20°C
Ph
S
Ph
N
H
R2
1a
2a
3a
D
R1
1
2
3
R1
CF3
R1, R2, R3
Product
Yieldb (%)
eec (%)
OMe
Entry
N
N
H
N
H
CF3
1
2
3
4
5
6
7
8
H, Ph, H
CH3, Ph, H
Br, Ph, H
3a
3b
3c
3d
3e
3f
3g
3h
3i
74 (89)
54 (85)
60 (88)
55 (83)
84
81
84
83
86
95
96
92
90
90
80
84
80
80
99
95
99
S
Ar
N
H
NMe2
N
N
H
H, 4-CH3-Ph, H
H, 4-CF3-Ph, H
H, 4-Br-Ph, H
H, 4-Cl-Ph, H
H, 3-Cl-Ph, H
H, 4-CN-Ph, H
H, 2-furyl, H
H, Me, H
H, 4-Br-Ph, Br
H, 4-CF3-Ph, Cl
H, 4-CF3-Ph, Me
H, 4-CF3-Ph, MeO
H, 4-Br-Ph, Me
A: Ar = 3,5-(CF3)2-Ph
B: Ar = 4-NO2-Ph
C: Ar = Ph
OMe
N
86
83
84
N
O
CF3
9
40 (87)
55 (84)
57
54 (84)
53 (90)
93
N
H
O
10
11
12
13
14
15
16
3j
S
3k
3l
3m
3n
3o
3p
HN
F: Ar = 4-CF3-Ph
G: Ar = 4-MeO-Ph
Ar
F3C
N
H
N
H
N
E
H: Ar = 3,5-(CF3)2-Ph
I: Ar = 3,5-Cl2-Ph
J: Ar = 3,5-Me2-Ph
94
94
Convb (%)
eec (%)
a
Entry
Catalyst
Solvent
Unless otherwise noted, reactions were performed with 0.1 mmol of 1,
0.2 mmol of 2, and 20 mol % of catalyst J in 1 mL xylene at À20 °C for 7 days.
1
2
3
4
5
6
7
8
A
B
C
D
E
F
G
H
I
J
J
J
J
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
CH2Cl2
Et2O
90
70
34
20
82
56
20
88
25
76
94
60
50
83
92
60
55
52
45
25
50
60
40
69
70
78
70
76
45
81
72
80
b
Yield of isolated product. Yields in parentheses are based upon recovered
starting material.
c
Determined by HPLC analysis.
on the benzoyl ring (R1) have little effect on the enantioselectivity
and isolated yields were moderate because of significantly low
conversion (entries 2 and 3). Incorporation of an electron-donating
group on the phenyl ring (R2) did not improve conversion (entry 4).
Electron-withdrawing substituents on the phenyl ring resulted in
both improvement in enantioselectivity and yield of addition prod-
ucts (entries 5–8). Interestingly, p-nitrile group on the phenyl ring
provided low isolated yield of the product possibly due to hydro-
gen bonding interaction of a CN-group with the squaramide
catalyst (entry 9). Significantly, furyl and methyl b-substituted
9
10
11
12
13
14
15d
16e
CH3CN
Xylene
Xylene
Xylene
J
J
J
a
Unless otherwise noted, reactions were performed with 0.1 mmol of 1a,
0.2 mmol of 2a, and 20 mol % of catalysts in 1 mL solvent at À20 °C for 7 days.
Determined by 1H NMR analysis.
b
a,b-unsaturated ketones were also shown to be compatible with
c
Determined by HPLC analysis.
the reaction conditions. The corresponding products 3j and 3k
were isolated in moderate yields but with good enantioselectivity
(entries 10 and 11). We have explored substituted indolines con-
taining either an electron-withdrawing group or electron-donating
group (5-Br, 5-Cl, 5-Me, and 5-OMe, respectively), for these aza-
Michael reactions (entries 12–16). Indolines with electron-donat-
ing groups were much more reactive toward conjugate addition
and gave Michael adducts in higher yields, and with higher enanti-
oselectivity (entries 14–16). The absolute configuration of products
was determined to be R as depicted based upon stereochemical
outcome of previous 1,4-addition reactions catalyzed by quinine-
derived squaramide catalysts.16b,18
We have converted a number of aza-Michael indoline products
into the corresponding N-substituted indole derivatives by mild
oxidation.13b As shown in Table 3, oxidation of various Michael ad-
ducts with DDQ (1.05 equiv) in THF at 23 °C for 15 min afforded
the N-substituted indole derivatives in excellent yields without
loss of enantioselectivity (entries 1–4). Similarly, oxidation of Mi-
chael adducts with MnO2 (10 equiv) in CH2Cl2 also provided enan-
tioenriched N-substituted indole derivatives in excellent yields
without any loss of optical purity (entry 5).
d
Reaction was conducted at À10 °C.
e
Reaction was conducted at À30 °C.
6–10).16 Interestingly, squaramide catalyst
J showed much
improvement in enantioselectivity (78% ee, entry 10), however,
conversion (76%) was less satisfactory. In an effort to improve con-
version, we examined various solvents for catalyst J (entries 10–
14). As it turned out, nonpolar solvents were more suitable for
optimal conversion and product enantioselectivity. Aza-Michael
reaction of 1a and 2a catalyzed by squaramide derivative J
(20 mol %) provided the best result with 83% conversion and
81% ee for the addition product 3a (entry 14). Raising the reaction
temperature to À10 °C resulted in improvement of conversion
(92%) however, enantioselectivity was reduced to 72% ee (entry
15). Also, lowering of reaction temperature to À30 °C did not im-
prove enantioselectivity and a relatively low conversion (60%)
was observed (entry 16). From the above studies, we concluded
that squaramide catalyst J (20 mol %) in xylene at À20 °C would
be the optimum condition for best enantioinduction and
conversion.
We then explored aza-Michael reactions with a variety of
a,b-
In summary, we have developed an enantioselective protocol
unsaturated ketones 1 and indolines 2 using catalyst J in xylene
at À20 °C. The results are shown in Table 2. First, we examined var-
ious electron-donating and electron-withdrawing substituents on
the phenyl and benzoyl rings (1a–i).17 As can be seen, substituents
for aza-Michael additions of indolines to a,b-unsaturated ketones
by utilizing bifunctional cinchona alkaloid–squaramide derivatives
as catalysts. This asymmetric reaction provided excellent yields
and good to excellent enantioselectivity for a variety of substituted
Please cite this article in press as: Ghosh, A. K.; Zhou, B. Tetrahedron Lett. (2013), http://dx.doi.org/10.1016/j.tetlet.2013.04.080

A. K. Ghosh, B. Zhou / Tetrahedron Letters xxx (2013) xxx–xxx
3
Table 3
Li, G.-Q.; Kang, Q.; Zhang, A.-J.; You, S.-L. Chem. Eur. J. 2009, 15, 3351; (d) Hong,
L.; Liu, C.; Sun, W.; Wang, L.; Wong, K.; Wang, R. Org. Lett. 2009, 11, 2177; (e)
Hong, L.; Sun, W.; Liu, C.; Wang, L.; Wong, K.; Wang, R. Chem. Eur. J. 2009, 15,
11105; (f) Schipper, D. J.; Hutchinson, M.; Fagnou, K. J. Am. Chem. Soc. 2010, 132,
6910. and references cited therein.
Synthesis of N-substituted indolesa
Entry
Indoline
Product
Yieldb (%)
eec (%)
4. (a) Trost, B. M.; Krische, M. J.; Berl, V.; Grenzer, E. M. Org. Lett. 2002, 4, 2005; (b)
Bandini, M.; Eichholzer, A.; Tragni, M.; Umani-Ronchi, A. Angew. Chem., Int. Ed.
2008, 47, 3238; (c) Cui, H.-L.; Feng, X.; Peng, J.; Lei, J.; Jiang, K.; Chen, Y.-C.
Angew. Chem., Int. Ed. 2009, 48, 5737; (d) Enders, D.; Wang, C.; Raabe, G.
Synthesis 2009, 5, 4119; (e) Hong, L.; Sun, W.; Liu, C.; Wang, L.; Wang, R. Chem.
Eur. J. 2010, 16, 440; (f) Trost, B. M.; Osipov, M.; Dong, G. J. Am. Chem. Soc. 2010,
132, 15800; (g) Cai, Q.; Zheng, C.; You, S.-L. Angew. Chem., Int. Ed. 2010, 49,
8666; (h) Stanley, L. M.; Hartwig, J. F. Angew. Chem., Int. Ed. 2009, 48, 7841; (i)
Liu, W.-B.; Zhang, X.; Dai, L.-X.; You, S.-L. Angew. Chem., Int. Ed. 2012, 51, 5183.
5. (a) Tillequin, F.; Koch, M.; Bert, M.; Sevenet, T. J. Nat. Prod. 1979, 42, 92; (b)
Orlemans, E. O. M.; Verboom, W.; Scheltinga, M. W.; Reinhoudt, D. N.; Lelieveld,
P.; Fiebig, H. H.; Winterhalter, B. R.; Double, J. A.; Bibby, M. C. J. Med. Chem.
1989, 32, 1612; (c) Paris, D.; Cottin, M.; Demonchaux, P.; Augert, G.;
Dupassieux, P.; Lenoir, P.; Peck, M. J.; Jasserand, D. J. Med. Chem. 1995, 38,
669; (d) Mahaney, P. E.; Vu, A. T.; McComas, C. C.; Zhang, P.; Nogle, L. M.; Watts,
W. L.; Sarkahian, A.; Leventhal, L.; Sullivan, N. R.; Uveges, A. J.; Trybulski, E. J.
Bioorg. Med. Chem. 2006, 14, 8455; (e) Fernandez, L. S.; Buchanan, M. S.; Carroll,
A. R.; Feng, Y. J.; Quinn, R. J.; Avery, V. M. Org. Lett. 2009, 11, 329.
N
N
O
4a
1
3a
92
80
O
4f
2
3
3f
93
95
94
92
Br
N
N
O
O
4h
3h
Cl
Br
6. Cardillo, G.; Tomasini, C. Chem. Soc. Rev. 1996, 25, 117.
7. For recent reviews on asymmetric aza-Michael reactions, see: (a) Wang, J.; Li,
P.; Choy, P. Y.; Chan, A. S. C.; Kwong, F. Y. ChemCatChem 2012, 4, 917; (b)
Enders, D.; Wang, C.; Liebich, J. X. Chem. Eur. J. 2009, 15, 11058.
4l
4
3l
93
94
80
99
8. Chen, Y. K.; Yoshida, M.; MacMillan, D. W. C. J. Am. Chem. Soc. 2006, 128, 9328.
9. (a) Diner, P.; Nielsen, M.; Marigo, M.; Jørgensen, K. A. Angew. Chem. Int. Ed.
2007, 46, 1983; (b) Lin, Q.-Y.; Meloni, D.; Pan, Y.-C.; Xia, M.; Rodgers, J.;
Shepard, S.; Li, M.; Galya, L.; Metcalf, B.; Yue, T.-Y.; Liu, P.-L.; Zhou, J. Org. Lett.
2009, 11, 1999; (c) Fustero, S.; Moscardo, J.; Jimenez, D.; Perez-Carrion, M. D.;
Sanchez-Rosello, M.; del Pozo, C. Chem. Eur. J. 2008, 14, 9868; (d) Vesely, J.;
Ibrahem, I.; Zhao, G.-L.; Rios, R.; Cordova, A. Angew. Chem. Int. Ed. 2007, 46, 778;
(e) Li, H.; Zu, L.-S.; Xie, H. X.; Wang, J.; Wang, W. Chem. Commun. 2008, 5636; (f)
Zhao, G.-L.; Rios, R.; Vesely, J.; Eriksson, L.; Cordova, A. Angew. Chem. Int. Ed.
2008, 47, 8468; (g) Uria, U.; Reyes, E.; Vicario, J. L.; Badia, D.; Carrillo, L. Org.
Lett. 2011, 13, 336; (h) Guo, H.-M.; Yuan, T.-F.; Niu, H.-Y.; Liu, J.-Y.; Mao, R.-Z.;
Li, D.-Y.; Qu, G.-R. Chem. Eur. J. 2011, 17, 4095; (i) Li, H.; Zhao, J.; Zeng, L.; Hu, W.
J. Org. Chem. 2011, 76, 8064.
10. (a) Lu, X.; Deng, L. Angew. Chem. Int. Ed. 2008, 47, 7710; (b) Pesciaioli, F.; De
Vincentiis, F.; Galzerano, P.; Bencivenni, G.; Bartoli, G.; Mazzanti, A.;
Melchiorre, P. Angew. Chem. Int. Ed. 2008, 47, 8703; (c) Luo, G.; Zhang, S.;
Duan, W.; Wang, W. Synthesis 2009, 1564; (d) Gogoi, S.; Zhao, C.-G.; Ding, D.
Org. Lett. 2009, 11, 2249; (e) Lv, J.; Wu, H.; Wang, Y. Eur. J. Org. Chem. 2010,
2073; (f) Liu, J.-D.; Chen, Y.-C.; Zhang, G.-B.; Li, Z.-Q.; Chen, P.; Du, J.-Y.; Tu, Y.-
Q.; Fan, C.-A. Adv. Synth. Catal. 2011, 353, 2721.
Br
Me
N
O
5d
3p
4p
Br
a
Unless otherwise noted, reactions were performed with 0.1 mmol of 3 and
0.105 mmol of DDQ in 1 mL THF at 23 °C for 15 min.
b
Yield of isolated product.
c
Determined by HPLC analysis.
d
Using MnO2 (10 equiv) as oxidizing agent.
chalcones. The indoline derivatives can be oxidized to indoles
conveniently without loss of enantioselectivity. The present
aza-Michael reaction provides access to highly enantiopure
N-substituted indole and indoline derivatives. Further applications
of this methodology are in progress in our laboratories.
11. (a) Enders, D.; Narine, A.; Toulgoat, F.; Bisschops, T. Angew. Chem. Int. Ed. 2008,
47, 5661; (b) Yang, L.; Xia, C.; Huang, H. Chin. J. Catal. 2011, 32, 1573; (c) Feng,
Z.; Xu, Q.-L.; Dai, L.-X.; You, S. L. Heterocycles 2010, 80, 765.
12. (a) Wang, J.; Zu, L.; Li, H.; Xie, H.; Wang, W. Synthesis 2007, 2576; (b) Pettersen,
D.; Piana, F.; Bernardi, L.; Fini, F.; Fochi, M.; Sgarzani, V.; Ricci, A. Tetrahedron
Lett. 2007, 48, 7805; (c) Sibi, M. P.; Itoh, K. J. Am. Chem. Soc. 2007, 129, 8064; (d)
Lykke, L.; Monge, D.; Nielsen, M.; Jorgensen, K. A. Chem. Eur. J. 2010, 16, 13330;
(e) Gu, Q.; You, S. L. Chem. Sci. 2011, 2, 1519.
Acknowledgments
13. (a) Kilic, H.; Bayindir, S.; Erdogan, E.; Saracoglu, N. Tetrahedron 2012, 68, 5619;
(b) Bayindir, S.; Erdogan, E.; Kilic, H.; Saracoglu, N. Synlett 2010, 1455.
14. Vakulya, B.; Varga, S.; Csámpai, A.; Soós, T. Org. Lett. 2005, 7, 1967.
15. (a) Song, J.; Wang, Y.; Deng, L. J. Am. Chem. Soc. 2006, 128, 6048; (b) Galzerano,
P.; Bencivenni, G.; Pesciaioli, F.; Mazzanti, A.; Giannichi, B.; Sambri, L.; Bartoli,
G.; Melchiorre, P. Chem. Eur. J. 2009, 15, 7846; (c) Okino, T.; Hoashi, Y.;
Takemoto, T. J. Am. Chem. Soc. 2003, 125, 12672; (d) Okino, T.; Hoashi, Y.;
Furukawa, T.; Xu, X.; Takemoto, T. J. Am. Chem. Soc. 2005, 127, 119.
16. (a) Malerich, J. P.; Hagihara, K.; Rawal, V. H. J. Am. Chem. Soc. 2008, 130, 14416;
(b) Yang, W.; Du, D.-M. Org. Lett. 2010, 12, 5450.
Financial support of this work was provided by the National
Institutes of Health and Purdue University. We thank Mr. Siddhar-
tha Akasapu (Purdue University) for helpful discussions.
References and notes
1. (a) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003, 103, 893; (b)
Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006, 106, 2875; (c) Higuchi, K.;
Kawasaki, T. Nat. Prod. Rep. 2007, 24, 843; (d) Kochanowska-Karamyan, A. J.;
Hamann, M. T. Chem. Rev. 2010, 110, 4489.
2. (a) Bandini, M.; Melloni, A.; Umani-Ronchi, A. Angew. Chem., Int. Ed. 2004, 43,
550; (b) Bandini, M.; Melloni, A.; Tommasi, S.; Umani-Ronchi, A. Synlett 2005,
1199; (c) You, S.-L.; Cai, Q.; Zeng, M. Chem. Soc. Rev. 2009, 38, 2190; (d)
Terrasson, V.; Figueiredo, R. M.; Campagne, J. M. Eur. J. Org. Chem. 2010, 2635.
3. (a) Kang, Q.; Zheng, X.-J.; You, S.-L. Chem. Eur. J. 2008, 14, 3539; (b) Zeng, M.;
Kang, Q.; He, Q.-L.; You, S.-L. Adv. Synth. Catal. 2008, 350, 2169; (c) Sheng, Y.-F.;
17. For details, please see supplementary data.
18. Selected examples of squaramide catalyzed 1,4-additions: (a) Dai, L.; Wang, S.-
X.; Chen, F.-E. Adv. Synth. Catal. 2010, 352, 2137; (b) Yang, W.; Du, D.-M. Chem.
Commun. 2011, 47, 12706; (c) Yang, W.; Du, D.-M. Org. Biomol. Chem. 2012, 10,
6876; (d) Ling, J.-B.; Su, Y.; Zhu, H.-L.; Wang, G. Y.; Xu, P. F. Org. Lett. 2012, 14,
1090; (e) Kasaplar, P.; Riente, P.; Hartmann, C.; Pericas, M. A. Adv. Synth. Catal.
2012, 354, 2905.
Please cite this article in press as: Ghosh, A. K.; Zhou, B. Tetrahedron Lett. (2013), http://dx.doi.org/10.1016/j.tetlet.2013.04.080