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Letter
Organocatalytic Enantioselective Friedel-Crafts Aminoalkylation of Indoles in the Carbocyclic Ring Marc Montesinos-Magraner, Carlos Vila, Alejandra Rendón-Patiño, Gonzalo Blay, Isabel Fernández, M. Carmen Muñoz, and José R. Pedro ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b00260 • Publication Date (Web): 21 Mar 2016 Downloaded from http://pubs.acs.org on March 22, 2016
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Organocatalytic Enantioselective Friedel-Crafts Aminoalkylation of Indoles in the Carbocyclic Ring Marc Montesinos-Magraner,† Carlos Vila,† Alejandra Rendón-Patiño,† Gonzalo Blay,† Isabel Fernández,† M. Carmen Muñoz‡ and José R. Pedro†* †
Departament de Química Orgànica, Facultat de Química, Universitat de València, C/Dr. Moliner, 50, E-46100, Burjassot, València, Spain. ‡Departament de Física Aplicada, Universitat Politècnica de València, C/Camí de Vera, s/n, E-46022, València, Spain. *e-mail:
[email protected] ABSTRACT: The first general catalytic method for the,
so far elusive, enantioselective Friedel-Crafts functionalization of indoles in the carbocyclic ring is presented. This transformation contrasts with the usual tendency of these heterocycles to react at the azole ring. For this purpose, the four regioisomeric hydroxy carbocyclicsubstituted indoles were reacted with several isatinderived ketimines, using a Cinchona alkaloid-based squaramide, in a low 0.5-5 mol% catalyst loading, as a bifunctional catalyst. This methodology allows the functionalization of indoles in every position of the carbocyclic ring in a regio- and enantioselective fashion, by just switching the position of the hydroxy group in the starting material. Furthermore, several transformations were carried out, including the reductive elimination of the hydroxy group. KEYWORDS: Asymmetric catalysis, Organocatalysis, Friedel-Crafts reaction, Indoles, Phenols, Isatin-derived ketimines The indole scaffold is a privileged structure not only in medicinal chemistry but also in materials science and technology. In fact, over 10000 indole derivatives with biological activity have been reported to date and the number of drugs, either commercialized or in clinical trial stage, containing this scaffold is increasing.1 The indole framework is also present in a multitude of natural products.2 On account of this, the synthesis and modification of indoles has been intensively studied since the 19th century. Indoles are excellent nucleophiles prone to react by electrophilic aromatic substitution at the C-3 position of the azole ring including enantioselective transformations. Positions C-2 and N-1 can also be functionalized selectively using different strategies.3 However, general methods to carry out selectively the functionalization of indoles in the carbocyclic ring are scarce. Generally, this functionalization requires the presence of deactivating or blocking substituents in the 5-membered ring, the appropriate choice of a directing group on the N-atom and the use of a transition metal catalyst.4-6 Alternatively, the enantioselective functional-
ization of indolines, followed by oxidation,7 can provide functionalized indoles in the carbocyclic ring, although just at the C-5 position.8
Figure 1. Biologically active indoles and oxindoles.
Undoubtedly, there is a demand for a general method for the enantioselective electrophilic functionalization of the carbocyclic ring of indoles lacking a substituent in the azole system. On the basis of our recent work on the addition of naphthols and electron-rich phenols to isatinderived ketimines,9,10 we envisioned that the functionalization of the carbocyclic ring of indoles could be attained by introducing an activating/directing hydroxy group in the carbocyclic ring of the indole. This represents a diametrically opposed approach to the commonly applied methods, focused on the electronic or sterical deactivation of the 5-membered ring. Moreover, the hydroxyindole moiety is of high importance in medicinal chemistry as it is present in serotonine and other biologically active compounds (Figure 1). However, although the activating/directing ability of the OH group in hydroxyindoles is known for nearly 50 years,11 this effect has not been exploited in enantioselective Friedel-Crafts reactions and all the asymmetric reactions with hydroxyindoles have been reported occurring at the C-3 position (Scheme 1).12 Only very recently, Jørgensen and coworkers have described just one example of Friedel-Crafts/oxa-Michael reaction of 4-
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(98% ee). To our delight, quinine-derived thiourea IV gave excellent results in terms of yield and enantioselectivity for compound 3aa (Table 1, entry 4). Further improvement was achieved using squaramide V (Table 1, entry 5).16 This catalyst also allowed us to reduce the catalyst loading as low as 1 mol%, keeping the enantiomeric excess in 99% (Table 1, entry 6). It should be pointed out that the reaction affords just one product as observed by HPLC and 1H-NMR analysis of the crude mixture, demonstrating the high selectivity of the method. Finally, we also could access the opposite enantiomer by using squaramide VI as catalyst, which is based on the quinidine skeleton (Table 1, entry 7).
OH
O
NBoc O
+ N H
N Bn
1a
2a
OH
N H
Ph
OH Ar
+
Ar'
HO
+ F C 3
N
Ar'
H N
Ref. 11b MeO
OH
Ref. 11c-d
HO
NMe2
H N
MeO
N
F3C OH COOEt
IV (Ar=3,5-(CF3)2-C6H3)
O
Ar
N
NH
H N
Ar
S
III (Ar=3,5-(CF3)2-C6H3)
Ar
N
O
N H
O N H
Ar
NH
II (R=4-Me-C6H4CH2)
N H
Ar NH
S R
N
I
NHAc
3aa'
HO N
OH
N H
O
MeO
Ref. 11a +
OH
3aa
N
a) Previous work
HN
N H
OH
Ph NHAc
O BnN
Toluene, 25ºC
N
OH
OH
BnN
cat. (x mol%)
NH Bo c
Table 1. Optimization of the reaction conditions.a NH Bo c
hydroxyindole occurring at the C-5 position of the carbocyclic ring, leading to an interesting chiral chroman.13 In this communication we present the first regio- and enantioselective functionalization of each position of the carbocyclic ring in indoles. Our strategy involved three actions: a) switching the reacting ring by activating the carbocyclic ring with a hydroxy group; b) directing the regioselectivity by changing the position of the hydroxy group, and c) removal of the OH group in the resulting products. Accordingly, we carried out the Friedel-Crafts reaction of the four regioisomeric hydroxyindoles, unsubstituted in the azole ring, using a bifunctional organocatalyst based on the quinine skeleton.14 The electrophiles of choice were Boc-protected isatin-derived ketimines.15 The catalyst activates both nucleophile and electrophile at the same time, providing an exquisite enantioselectivity and complete regioselectivity, to give highly enantioenriched tetrasubstituted 3aminooxindoles. Interestingly, this motif is present in several biologically active compounds (Figure 1).
NH
H N
MeO O
O
N
N
VI (Ar=3,5-(CF3)2-C6H3)
V (Ar=3,5-(CF3)2-C6H3)
COOEt
Catalyst (mol%)
Time (h)
Yield (%)b
ee (%)c
1
I (10 mol%)
5
38
18
2
II (10 mol%)
24
72
14d
3
III (10 mol%)
16
32
93d
4
IV (10 mol%)
5
91
98
Scheme 1. Asymmetric Friedel-Crafts reactions of hydroxyindoles.
5
V (10 mol%)
2
95
>99
6
V (1 mol%)
12
98
99
We started our study by testing the reaction of 4hydroxyindole (1a) and N-Boc-protected ketimine 2a with different bifunctional organocatalysts in toluene at 25 °C. First, we carried out the reaction with simple quinine (I) as a chiral base, obtaining a complex mixture of products. The desired product 3aa was isolated in low yield (38%) and with low enantioselectivity (18% ee) (Table 1, entry 1). We also observed the formation of compound 3aa' in comparable yield (35%) and low enantioselectivity (35% ee). Cupreine derivative II gave product 3aa with good yield, but still low enantiocontrol (Table 1, entry 2). With Takemoto’s catalyst III we reached excellent enantioselectivity (93% ee), but low yield (Table 1, entry 3). Interestingly, in this case the major product of the reaction (65% yield) was product 3aa’, which was isolated in excellent enantioselectivity
7
VI (10 mol%)
12
93
92d
b) This work O
OH
NBoc
+ N H
Four regioisomers
O
OH
O N H
Regioselective Enantioselective
H
BnN
BnN
N Bn
NH Bo c
N H NH Bo c
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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N H
Four regioisomers available
a Reaction conditions: catalyst (x mol%), 1a (0.2 mmol), 2a (0.21 mmol) and dry toluene (2 mL) at 25 °C. b Isolated yields are reported. c Enantiomeric excess (ee) was determined by chiral HPLC. d Opposite enantiomer.
Then, we examined the generality of our methodology by reacting 4-hydroxyindole (1a) with different isatinderived ketimines (Scheme 2). Different protecting groups at isatin N-1, such as methoxymethyl, allyl and methyl, were well tolerated, the corresponding products 3ab-3ad being obtained with high yields and excellent enantioselectivities (Scheme 1). Unfortunately, the unprotected ketimine 2e gave the expected product 3ae in low yield (41%) and moderate enantioselectivity (72% ee). We attribute this result to the formation of nonproductive hydrogen bonds caused by the presence of
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the free NH group and the poor solubility of 2e in the reaction solvent. High yields and excellent enantioselectivities (97-99% ee) were also obtained with isatinderived ketimines having different substituents in the carbocyclic ring, independently of their position or electronic nature (3af-3al and 3ba, Scheme 1). Remarkably, good yield and enantioselectivity were reached even with just a 0.1 mol % of catalyst V in a gram-scale reaction between 4-hydroxyindole (1a) and ketimine 2a.
NBoc
N R2
R1
N R
O V (0.1-5 mol%)
O
+
NH
OH
Bo
c
Enantioselective aminoalkylation of 4-hydroxyindoles (1a-b)a
R2 N
NR
2
NH Bo
O
O
OH
BnN
3af, R1=OMe, 72 %, 99% ee 3ag, R1=Br 80%, 99% ee 3ah, R1=Cl, 90 %, 98% ee 3ai, R1=NO2, 90 %, 97% ee O
OH
OH
BnN
BnN N H
NH
N H R1
c
c
NR
NH Bo
R2 N
OH
BnN
NH Bo c
c Bo NH
OH
3aa, R=H, R2=Bn, 98 %, 99% ee 88 %, 89% eeb 3ab, R=H, R2=MOM, 82 %, 96% ee 2 3ac, R=H, R =allyl, 99 %, 98% ee 3ad, R=H, R2=Me, 96 %, 98% ee 3ae, R=H, R2=H, 41 %, 72% ee 3ba, R=Me,R2=Bn 80%, 99% ee
Bo c
3 O
O
OH
Toluene, rt R1
1a, R1=H 1b, R1=Me
N H
Me
N H
F
Cl
Me 3al, 99%, 98% ee
3ak, 95%, 98% ee
3aj, 98%, 99% ee
Enantioselective aminoalkylation of 5-hydroxyindole (1c)c
Me
Cl NBn
NBn
Cl
O
BocHN HO
NBn
NBn
O
BocHN HO
N H 3ca, 80%, 96% ee
O
BocHN HO
N H 3ch, 98%, 95% ee
O
BocHN HO
N H 3cm, 99%, 94% ee
N H 3cj, 93%, 98% ee
After having proved the efficiency of our method for the enantioselective aminoalkylation of 4hydroxyindoles at the C-5 position, we examined the scope of the reaction with indoles bearing a hydroxy group in other positions of the carbocyclic ring (Scheme 2). Our aim was to achieve the functionalization of every position in this ring by simply changing the position of the directing group. Delightfully, 5-hydroxyindole (1c) reacted with ketimine 2a to give product 3ca substituted at C-4 with very good regioselectivity and high enantiocontrol (96% ee), although we had to increase the catalyst loading to 5 mol%. Excellent results (3ch, 3cj, 3cm) were obtained also with different ketimines. In a similar manner, 6-hydroxyindole (1d) was functionalized selectively in the C-7 position using this method. Distinct ketimines were also introduced with outstanding selectivity leading to the corresponding products (3da, 3df, 3dg, 3dl). Furthermore, 7-hydroxyindole (1e) reacted with several ketimines 2, which yielded the desired 6substituted 7-hydroxyindoles (3ea, 3eh, 3ek and 3el) with good enantioselectivities (85-96% ee). In this latter case, a slight decrease of enantioselectivity was observed, probably due to the presence of the vicinal NH. Finally, when 4-hydroxycarbazole (1f) was used as a nucleophile the product 3fa was obtained with excellent yield and enantiomeric excess. It is interesting to note that hydroxyindoles 1c and 1d are specially challenging substrates, as they have two available ortho positions for the substitution reaction. Our method allows the regioselective aminoalkylation in only one ortho position, leading to the desired product. O
N Bn
N H
N Bn
3da, 99%, 99% ee
N H
HO BocHN O
OMe
Br
N Bn
N Bn 3dg, 70%, 98% ee
3df, 75%, 98% ee
OH
BnN
N H BnN
O
3ea, 99%, 92% ee
OH
N H
F
O
R1
N H
R
3dl,72%, 98% ee
3eh, 72%, 96% ee
Me
OH
N H
O
3ek, 53%, 96% ee
Me
BnN
R2
Me 3
OH
N H
MeOH N H R4 2 3 4a, R =OTf, R =X, R =R4=H 4c, R1=X, R2=OTf, R3=R4=H 4d, R1=R2=H, R3=OTf, R4=X 4e, R1=R2=H, R3=X, R4=OTf
CH2Cl2
2
3
N H
H2 (1 atm) 10% Pd/C Et2NH
R1
Tf2NPh 4-DMAP
R2
1
BnN
O BocHN H
Me
R4 Enantioselective aminoalkylation of 7-hydroxyindole (1e)c Cl
NBn
H
BnN
5c, 83%
R3
1
4
3aa, R =OH, R =X, R =R =H 3ca, R1=X, R2=OH, R3=R4=H 3da, R1=R2=H, R3=OH, R4=X 3ea, R1=R2=H, R3=X, R4=OH
H BocHN O
X=
N H BnN
O
N Bn 5d, 88%
BocHN
O
N H
5a, 79%
Bo c
HO BocHN O
N H
NH
N H
HO BocHN O
HO BocHN O
NH Bo c
Enantioselective aminoalkylation of 6-hydroxyindole (1d)c
H
N H
5e, 74%
O
3el, 99%, 85% ee
N Bn
O
Scheme 2. Substrate Scope
Bo c
OH
O
BnN NaCNBH3 N H
OH
BnN
AcOH, 0ºC quantitative
N H
3aa
9 MVK, BPA CH2Cl2 98%
N H 8
O
O oc
Reaction with 4-hydroxyindole: V (1 mol %), 4hydroxyindole (1a, 0.2 mmol), imine 2 (0.21 mmol), toluene (2 mL), 25 °C, 12 h. b Gram scale reaction: V (0.1 mol %), 4hydroxyindole (1a, 3.0 mmol), imine 2a (3.05 mmol), toluene (16 mL), 25 °C, 36 h. c Reaction with hydroxyindoles 1c-f: V (5 mol %), hydroxyindole 1 (0.1 mmol), imine 2 (0.105 mmol), toluene (1 mL), 25 °C, 12 h.
CH2Cl2 80%, two steps
NH B
a
NH
O
3fa, 97%, 98% ee
N H 7
OMe
BnN
NH Bo c
Me-I K2CO3 CH3CN
NH
TFA
2
OMe
BnN
NH
OH
NH B
O
Bo c
O Bn N
oc
Enantioselective aminoalkylation of 4-hydroxycarbazole (1f)c NH
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OH
BnN N H 10
a
See Supporting Information for details.
Scheme 3. Removal of the hydroxy group and other synthetic transformations.a
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HB oc
Although hydroxyindoles are interesting targets per se, it is important that the activating/directing hydroxy group could also be removed or used in further transformations (Scheme 3). After some optimization, compounds 3aa, 3ca, 3da and 3ea were transformed into their corresponding triflates 4a, 4c, 4d and 4e, respectively, which were catalytically hydrogenated at 1 atm to give hydroxy group-free products 5a, 5c, 5d and 5e respectively, in high overall yields. All of these four aminoalkylated indoles exhibit distinct chromatographic behavior and spectroscopic properties (See SI), demonstrating we had accessed every aminoalkylated regioisomer. Moreover, triflates 4c, 4e and mesylate 6 (prepared from product 3aa, see SI) were successfully crystallized and their structures established by X-ray crystal analysis (see SI), unambiguously confirming the structures of their precursors 3ca, 3ea and 3aa, and hence, that of 3da. The X-ray analysis of crystals from 6 and 4c also revealed the R configuration for the stereogenic center in both compounds. For the rest of the compounds 3 we assumed a uniform stereochemical mechanism. Interestingly, when compoundaa' was subjected to the triflation/hydrogenation sequence, ent-5d was isolated (see SI). Furthermore, different synthetic transformations were conducted with product 3aa proving the utility of the method (Scheme 3). Thus, compound 3aa was selectively methylated to compound 7, which was deprotected with trifluroacetic acid, obtaining the corresponding free amine 8. Hydroxyindole 3aa was also easily transformed into hydroxyindoline 9 by reduction with NaCNBH3 in the presence of acetic acid. Moreover, compound 3aa reacted with methylvinylketone under acidic catalysis to give product 10, following a classical Friedel-Crafts reaction at C-3 position of the indole nucleus.
N
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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tained by the fact that the 5-methoxyindole does no react under the optimized reaction conditions. In summary, we have developed the first general method for the enantioselective Friedel-Crafts reaction of hydroxyindoles with isatin-derived ketimines, using an squaramide based on the quinine skeleton as bifunctional organocatalyst (catalyst loading 0.1-5 mol%). Under our reaction conditions, hydroxyindoles react in the carbocyclic ring rather than in the azole system to give the desired aminoalkylated products with high enantioselectivity. Unlike conventional Friedel-Crafts reactions, this approach enables the introduction of substituents in every position of the carbocyclic ring of indole in a regioselective manner, by just switching the position of the activating/directing hydroxy group. Besides the importance of the hydroxyindole moiety in medicinal chemistry, the hydroxy group could be removed under mild reductive elimination conditions in high overall yield. We envision this procedure provides a general strategy for the less explored enantioselective functionalization of indoles in the carbocyclic ring. ASSOCIATED CONTENT Experimental procedures, spectroscopic data and X-ray data (CIF). This material is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION Corresponding Author
*
[email protected] Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT Financial support from MINECO (Gobierno de España; CTQ2013-47494-P) and from Generalitat Valenciana (ISIC2012/001) is gratefully acknowledged. M.M-M. thanks Universitat de València for a pre-doctoral grant and C.V. thanks MINECO for a JdC contract. Access to NMR, X-ray and MS facilities from SCSIE-UV is also acknowledged.
REFERENCES Figure 2. Proposed stereochemical model.
In order to rationalize the observed regio- and stereochemistry, we propose a tentative transition state (Figure 2). As a model, we have followed the activation mode proposed by Khan, Ganguly and co-workers for the thiourea-catalyzed reaction between 1-naphthols and isatin-derived ketimines.10a This model explains the ortho-regioselectivity for the nucleophiles and the R absolute configuration of the final products. The influence of the catalyst/OH-group interaction can be ascer-
(1) (a) Sundberg, R. J. Indoles; Academic Press: San Diego, 1996; p. 1-175. (b) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003, 103, 893-930. (c) Zhou, G.; Wu, D.; Snyder, B.; Ptak, R. G.; Kaur, H.; Gochin, M. J. Med. Chem. 2011, 54, 7220-7231. (d) Zhang, M. Z.; Chen, Q.; Yang, G.-F. Eur. J. Med. Chem. 2015, 89, 421-441. (e) Sherer, C.; Snape, T. J. Eur. J. Med. Chem. 2015, 97, 552-560. (2) (a) Lancianesi, S.; Palmieri, A.; Petrini, M., Chem. Rev. 2014, 114, 7108-7149. (b) Ishikura, M.; Abe, T.; Choshi, T.; Hibino, S. Nat. Prod. Rep. 2015, 32, 1389-1471. (3) For selected reviews see: (a) Bandini, M.; Eichholzer, A. Angew. Chem. Int. Ed. 2009, 48, 9608-9644. (b) Bartoli, G.; Bencivenni, G.; Dalpozzo, R. Chem. Soc. Rev. 2010, 39, 4449-4465. (c) Zeng, M.; You, S.-L. Synlett 2010, 1289-1301. (d) Dalpozzo, R. Chem. Soc. Rev. 2015, 44, 742-778. (e) Wu, H.; He, Y.-P.; Shi, F. Synthesis 2015, 47, 1990-2016. For some recent examples of enantioselective FriedelCrafts reactions of indoles see: (f) Bi, B.; Lou, Q.-X.; Ding, Y.-Y.;
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Chen, S.-W.; Zhang, S.-S.; Hu, W.-H.; Zhao, J.-L. Org. Lett. 2015, 17, 540-543. (g) Li, M.-L.; Chen, D.-F-; Luo. S.-W.; Wu, X. Tetrahedron: Asymmetry 2015, 26, 219-224. (h) Fang, F.; Hua, G.; Shi, F.; Li, P. Org. Biomol. Chem. 2015, 13, 4395-4398. (i) Frías, M.; Padrón, J. M.; Alemán, J. Chem. Eur. J. 2015, 21, 8237-8241. (j) Liu, R.-R.; Ye, S.-C.; Lu, C.-J.; Zhuang, G.-L.; Gao, J.-R.; Jia, Y.-X. Angew. Chem. Int. Ed. 2015, 54, 11205-11208. (k) Romanini, S.; Galletti, E.; Caruana, L.; Mazzanti, A.; Himo, F.; Santoro, S.; Fochi, M; Bernardi, L. Chem. Eur. J. 2015, 21, 17578-17582. (l) Kato, M.; Hirao, S.; Nakano, K.; Sato, M.; Yamanaka, M.; Sohtome, Y.; Nagasawa, K. Chem. Eur. J. 2015, 21, 18606-18612. (m) Pan, J.; Wanga, Y.; Chena, S.; Zhanga, X.; Wang, Y.; Zhou, Z. Tetrahedron 2016, 72, 240-246. (4) For functionalization of indoles by lithiation see: a) Iwao, M.; Ishibashi, F. Tetrahedron 1997, 53, 51-58. (b) Fukuda, T.; Maeda, R.; Iwao, M. Tetrahedron 1999, 55, 9151-9162. (c) Hartung, C. G.; Fecher, A.; Chapell, B.; Snieckus, V. Org. Lett. 2003, 5, 1899-1902. (5) For a review about C-H activation with indoles see (a) Sandtorv, A. H. Adv. Synth. Catal. 2015, 357, 2403-2435. For selected examples see: (b) Lanke, V.; Prabhu, K. R. Org. Lett. 2013, 15, 6262-6265. (c) Liu, Q.; Li, Q.; Ma, Y.; Jia, Y. Org. Lett. 2013, 15, 4528-4531. (d) Paul, S.; Chotana, G. A.; Holmes, D.; Reichle, R. C.; Maleczka, Robert E.; Smith, M. R. J. Am. Chem. Soc. 2006, 128, 15552-15553. (e) Feng, Y.; Holte, D.; Zoller, J.; Umemiya, S.; Simke, L. R.; Baran, P. S. J. Am. Chem. Soc. 2015, 137, 10160-10163. (f) Robbins, D. W.; Boebel, T. A.; Hartwig, J. F. J. Am. Chem. Soc. 2010, 132, 4068-4069. (g) Yang, Y.; Qiu, X.; Zhao, Y.; Mu, Y.; Shi, Z. J. Am. Chem. Soc. 2016, 138, 495-498. (6) For F-C reactions of substituted indoles see (a) Xu, Q.-L.; Dai, L.-X.; You, S.-L. Chem. Sci. 2013, 4, 97-102. (b) Liu, H.; Zheng, C.; You, S.-L. J. Org. Chem. 2014, 79, 1047-1054. (c) Zhou, L.-J.; Zhang, Y.-C.; Zhao, J.-J.; Shi, F.; Tu, S.-J. J. Org. Chem. 2014, 79, 10390-10398. (7) Nicolaou, K. C.; Baran, P. S.; Zhong, Y.-L.; Fong, K. C.; He, Y.; Yoon, W. H.; Choi, H.-S. Angew. Chem. Int. Ed. 1999, 38, 16761678. (8) For enantioselective F-C reactions of indolines see (a) Gathergood, N.; Zhuang, W.; Jørgensen, K. A. J. Am. Chem. Soc. 2000, 122, 12517-12522. (b) Saaby, S.; Fang, X.; Gathergood, N.; Jørgensen, K. A. Angew. Chem. Int. Ed. 2000, 39, 4114-4116. c) Paras, N. A.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 7894-7895. d) Yuan, Y.; Wang, X.; Li, X.; Ding, K. J. Org. Chem., 2004, 69, 146– 149. For selected C-H activation processes of indolines see: (e) Talwar, D.; Gonzalez-de-Castro, A.; Li, H. Y.; Xiao, J. Angew. Chem. Int. Ed. 2015, 54, 5223-5227. (f) Yang, X.-F.; Hu, X.-H.; Feng, C.; Loh, T.-P. Chem. Commun. 2015, 51, 2532-2535. (g) Yang, G.; Lindovska, P.; Zhu, D.; Kim, J.; Wang, P.; Tang, R.-Y.; Movassaghi, M.; Yu, J.-Q. J. Am. Chem. Soc. 2014, 136, 10807-10813. (h) Wang, X.; Tang, H.; Feng, H.; Li, Y.; Yang, Y.; Zhou, B. J. Org. Chem. 2015, 80, 6238-6249. (9) (a) Montesinos-Magraner, M.; Vila, C.; Cantón, R.; Blay, G.; Fernández, I.; Muñoz, M. C.; Pedro, J. R. Angew. Chem. Int. Ed. 2015, 54, 6320-6324. (10) For more examples of enantioselective F-C reactions with hydroxyarenes and ketimines see: (a) Kumari, P.; Barik, S.; Khan, N. H.; Ganguly, B.; Kureshy, R. I.; Abdi, S. H. R.; Bajaj, H. C. RSC Adv. 2015, 5, 69493-69-501. (b) Zhou, D.; Huang, Z.; Yu, X.; Wang, Y.; Li, J.; Wang, W.; Xie, H. Org. Lett. 2015, 17, 5554-5557. For a review on enantioselective F-C reactions with naphthols and phenols, see: (c) M. Montesinos-Magraner, C. Vila, G. Blay, J. R. Pedro, Synthesis 2016, manuscript accepted. (11) (a) Monti, S. A.; Johnson, W. O.; White, D. H. Tetrahedron Lett. 1966, 37, 4459-4464. (b) Troxler, F.; Bormann, G.; Seemann, F. Helv. Chim. Acta 1968, 51, 1203-1213. (12) (a) Jia, Y.-X.; Zhong, J.; Zhu, S.-F.; Zhang, C.-M.; Zhou, Q.L. Angew. Chem. Int. Ed. 2007, 46, 5565-5567. (b) Saha, S.; Alamsetti, S. K.; Schneider, C. Chem. Commun. 2015, 51, 1461-1464. c) Han, X.; Ouyang, W.; Liu, B.; Wang, W.; Tien, P.; Wu, S.; Zhou, H.-B. Org. Biomol. Chem. 2013, 11, 8463-8475. d) Wolf, C.; Zhang, P. Adv. Synth. Catal. 2011, 353, 760-766. (13) During our investigation, Jørgensen and coworkers reported a very stimulating 1,6-Friedel-Crafts/1,4-oxa-Michael reaction, in
which they described a single example with 4-hydroxyindole (7 days; 43% yield, 97% ee). Poulsen, P. H.; Feu, K. S.; Paz, B. M.; Jensen, F.; Jørgensen, K. A. Angew. Chem. Int. Ed. 2015, 54, 8203-8207. (14) For selected reviews: a) Alemán, J.; Parra, A.; Jiang, H.; Jørgensen, K. A. Chem. Eur. J. 2011, 17, 6890-6899. b) Chauhan, P.; Mahajan, S.; Kaya, U.; Hack, D.; Enders, D. Adv. Synth. Catal. 2015, 357, 253-281. (15) For recent reviews see: a) Kaur, J.; Chimni, S. S.; Mahajan, S.; Kumar, A. RSC Adv 2015, 5, 52481-52496. b) Yu, J.-S.; Zhou, F.; Liu, Y.-L.; Zhou, J. Synlett 2015, 26, 2491-2504. For stereoselective F-C reaction of indoles see: c) Feng, J.; Yang, W.; Wang, D.; Li, P.; Sun, Q.; Wang, R. Chem. Commun. 2012, 48, 8003-8005. d) Chen, J.P. Chen, W.-W.; Li, Y.; Xu, M.-H. Org. Biomol. Chem. 2015, 13, 3363-3370. For recent examples see: e) Bao, X.; Wang, B.; Cui, L.; Zhu, G.; He, Y.; Qu, J. ; Song, Y. Org. Lett. 2015, 17, 5168-5171. f) Arai, T.; Tsuchiya, K.; Matsumura, E. Org. Lett. 2015, 17, 24162419. g) Holmquist, M.; Blay, G.; Muñoz, M. C.; Pedro, J. R. Adv. Synth. Catal. 2015, 357, 3857-3862. h) Engl, O. D.; Fritz, S. P.; Wennemers, H Angew. Chem. Int. Ed. 2015, 54, 8193-8197. i) Zheng, H.; Liu, X.; Xu, C.; Xia, Y.; Lin, L.; Feng, X Angew. Chem. Int. Ed. 2015, 54, 10958-10962. j) He, Q.; Wu, L.; Kou, X.; Butt, N.; Yang, G.; Zhang, W. Org. Lett. 2016, 18, 288-291. k) Beceño, C.; Chauhan, P.; Rembiak, A.; Wang, A.; Enders, D. Adv. Synth. Catal. 2015, 357, 672-676. l) Zhao, J.; Fang, B.; Luo, W.; Hao, X.; Liu, X.; Lin, L.; Feng, X. Angew. Chem. Int. Ed. 2015, 54, 241-244. (16) For seminal examples: (a) Malerich, J. P.; Hagihara, K.; Rawal V. H. J. Am. Chem. Soc. 2008, 130, 14416-14417. (b) Yang, W.; Du, D.-M. Org. Lett. 2010, 12, 5450-5453.
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NH Bo c
oc
TOC
NH Bo
c
NH B
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