Asymmetric N-allylation of indoles through the iridium-catalyzed allylic alkylation/oxidation of indolines

Article abstract of DOI:10.1002/anie.201200649

Two steps can be better than one: An efficient synthesis of enantioenriched N-allylindoles by a one-pot Ir-catalyzed asymmetric allylic alkylation/oxidation reaction of indolines has been realized. The current method features high regioselectivity and enantioselectivity together with a broad range of indoles with varying electronic properties. The utility of this method was demonstrated by the synthesis of dihydropyrrolo[1,2-a]indole derivatives. Copyright

Full text of DOI:10.1002/anie.201200649

Angewandte
Chemie
DOI: 10.1002/anie.201200649
Asymmetric Catalysis
Asymmetric N-Allylation of Indoles Through the Iridium-Catalyzed
Allylic Alkylation/Oxidation of Indolines**
Wen-Bo Liu, Xiao Zhang, Li-Xin Dai, and Shu-Li You*
The synthesis of enantiopure indole derivatives is of signifi-
cant importance because optically active indole moieties are
a common occurrence in bioactive natural products and
pharmaceuticals.[1] To this end, enormous efforts have been
devoted to the development of catalytic asymmetric reactions
of indoles in the past decade.[2] It has been well documented
that the C3-position of an indole is the most reactive one
among the three positions (N1, C2, C3) under the conditions
of the Friedel–Crafts reaction.[3] Recently, the enantioselec-
tive C2 alkylation of indoles was realized through variations
of the Pictet–Spengler reaction,[4] alkylation of 2-indolyl
trifluoroborate salts,[5] and alkylation/oxidation of 4,7-dihy-
droindoles.[6] However, the enantioselective N-substitution[7]
Scheme 1. The synthesis of allylindoles by Ir-catalyzed allylic substitu-
tion reactions. EDG=electron donating group, EWG=electron with-
drawing group, L* =chiral ligand, LG=leaving group.
of indoles has rarely been explored due to the weak acidity of
À
the N H group, despite the fact that the products are
privileged structural motifs in natural alkaloids and biolog-
ically active compounds (Figure 1).[8]
tures the introduction of electron-withdrawing groups on the
indole ring or substituent at the C3-position, which limits the
scope of indole substrates. Herein, we report a general
synthesis of N-allylindoles through a one-pot reaction involv-
ing an iridium-catalyzed allylic alkylation[11] of indolines
followed by oxidation[12] [Scheme 1, Eq. (3)]. Notably, indo-
lines are commercially available and can also be easily
prepared by the reduction of indoles, which allows access to
a broad range of enantioenriched N-allylindoles in excellent
enantionselectivity without the limitation on substituents
found in previous work.
Figure 1. Biologically active N-alkylated indole derivatives.
With a catalyst derived from [{Ir(cod)Cl}2]/1a,[13b] (cod =
cyclooctadiene) indoline 3a smoothly reacted with carbonate
2a, affording the alkylation product 4aa in 82% yield and
95% ee (Table 1, entry 1).[13] Different chiral ligands
(Figure 2) were next examined, and the results are summar-
ized in Table 1. Phosphoramidite ligand 1b, containing an
ortho-methoxy substituent on the aryl group of the amine
moiety, developed by Alexakis and Polet,[14] led to the
formation of product 4aa in a higher yield and ee (90%
yield, 99% ee, entry 2), while ligand 1c afforded the product
in a decreased yield (entry 3). The catalyst derived from 1d,
which is the diastereoisomer of 1a, could catalyze the
reaction, but gave lower selectivities (4aa/5aa 87:13, 84%
ee; entry 4). This result indicates that there is a match of
chiralities within 1a. The use of either ligand 1e or 1 f resulted
in reduced yields and moderate enantioselectivity (entries 5
and 6). Ligands 1g, 1h, 1i, and 1j were also suitable for this
reaction, but gave slightly poorer ratios of branched to linear
products (entries 7–10). Ligands 1k and 1l[13g,o] resulted in
lower yields, enantioselectivity, and regioselectivity
(entries 11 and 12). Fortunately, with the catalyst derived
In the last decade, the transition-metal-catalyzed allylic
alkylation reaction has proven suitable for direct functional-
ization of indoles at the C3 position [Scheme 1, Eq. (1)].[9]
Recent work by Stanley and Hartwig[10] elegantly realized the
enantioselective N1 allylic alkylation of indoles with an
iridium catalyst [Scheme 1, Eq. (2)].[11] Their reaction fea-
[*] Dr. W.-B. Liu, X. Zhang, Prof. Dr. L.-X. Dai, Prof. Dr. S.-L. You
State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences
345 Lingling Lu, Shanghai 200032 (China)
E-mail: slyou@sioc.ac.cn
Homepage: http://shuliyou.sioc.ac.cn
[**] We thank the National Basic Research Program of China (973
Program 2010CB833300) and the NSFC (20923005, 20932008,
21025209, and 21121062) for financial support. We also thank
Prof. Dr. G. Helmchen of Univ. Heidelberg for generously offering
dbcot.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201200649.
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
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Table 1: Screening of chiral ligands for the Ir-catalyzed allylic alkylation of
indoline.
To test our hypothesis for the synthesis of N-allylated
indoles, 1.5 equivalents of 2,6-dichloro-3,5-dicyano-p-benzo-
quinone (DDQ) were added to the reaction mixture upon
completion of the Ir-catalyzed allylic amination. After stirring
for 30 min, the N-allylated indoles were obtained in good
yields without loss of enantiomeric purity.
Under the optimal reaction conditions, the one-pot allylic
alkylation/oxidation reaction was investigated with a wide
range of indolines and allyl carbonates. As summarized in
Table 2, the method was general for both indolines and allyl
carbonates. Aryl allyl carbonates 2b–e, with either an
electron-donating group (4-Me, 4-OMe) or an electron-
withdrawing group (4-Br, 3-CF3) on the phenyl ring, all
gave their corresponding indole products in excellent yields
with 96–98% ee (Table 2, entries 2–5). The reaction of 2-
thienyl allyl carbonate 2g led to 6ag in 84% yield and 99% ee
(entry 15). Aliphatic allyl carbonates 2h and 2i were both
well tolerated and gave their desired products in slightly lower
regioselectivity and enantioselectivity (6ah, 6/7 90:10, 92%
ee, and 6ai, 6/7 91:9, 82% ee; entries 16 and 17). As for the
nucleophiles, indolines having different substitution patterns
(4-Me, 5-OMe, 6-Br) worked well to afford the products in
81–92% yields with 96–99% ee (entries 6–8,11). Notably, the
2-methyl and 3-methyl indolines were also suitable substrates,
leading to excellent enantioselectivity (entries 9, 10, and 12).
The enantiopure bromo-containing product 6da was easily
obtained after recrystallization from n-hexane/isopropanol.
An X-ray crystallographic analysis to determine the absolute
configuration of the enatiopure product revealed it to be
(S)-6da.[17]
Entry[a]
Ligand
t [h]
4aa/5aa[b]
Yield [%][c]
ee [%][d]
1
2
3
4
5
6
1a
1b
1c
1d
1e
1 f
1g
1h
1i
17
17
17
24
36
36
36
6
95:5
95:5
96:4
87:13
99:1
87:13
77:23
78:22
80:20
83:17
57:43
67:33
97:3
82
90
74
93
24
27
70
93
92
61
49
50
95
95
99
95
84
88
71
89
90
87
7[e]
8
9
2
10
11[e]
12[e]
13[f]
1j
1k
1l
36
36
36
6
97
À15
43
1b
99
[a] 3a/2a/[{Ir(cod)Cl}2]/ligand, 1.5:1.0:0.02:0.04; 2a (0.25 mmol) was
used in THF (2.5 mL) at 508C. [b] Determined by H NMR of the crude
reaction mixture. [c] Yields of isolated 4aa and 5aa. [d] The ee of 4aa was
determined by HPLC analysis (Chiralcel OD-H). [e] Yield determined by
1H NMR spectroscopy. [f] [{Ir(dbcot)Cl}2] was used. Cod=cycloocta-
diene, dbcot=dibenzo[a,e]cyclooctatetraene.
1
As depicted in Scheme 2, several diverse transformations
were carried out to further test the utility of the current
methodology. Allylindole 6ad was readily converted into a,b-
unsaturated ester 8 in 53% yield through an olefin cross-
metathesis reaction. Primary alcohols 9a and 9b were
obtained in quantitative yields through hydroboration of
terminal alkenes with 9-borabicyclo[3.3.1]nonane (9-BBN)
followed by oxidation. A monoamine reuptake inhibitor
analogue,[8c] 3-(1H-indol-1-yl)-3-arylpropan-1-amine (11),
was synthesized in 78% yield over two straightforward steps.
Reactions with 3,4,5-trimethoxyphenyl allyl carbonate
were carried out on a gram scale to smoothly afford 6gf and
6hf in 94 and 98% ee, respectively (Table 2, entries 13 and
14). Both of these products are potentially valuable synthons
of yuremamine, a new phytoindole recently isolated from the
stem bark of Mimosa hostilis.[18] The diastereoisomer of
methylyuremamine 15 was synthesized as shown in Scheme 3.
Compound 6hf was converted into a diol with a 3:1 d.r.
through a dihydroxylation reaction. Protection/deprotection
of the diols afforded product 12 in 68% yield (three steps).
Oxidation of 12 with Dess–Martin periodinane and subse-
quent treatment with (2,4-dimethoxyphenyl)lithium gave 13,
which was treated with an excess of trifluoroacetic acid
(TFA), a process which required a carefully controlled
reaction time.[19] The resulting cascade sequence, featuring
cation generation, stereoselective cyclization, and deprotec-
tion, afforded dihydropyrrolo[1,2-a]indole 14 in 57% yield
after 2 h. The relative stereochemistry of compound 14 was
confirmed by X-ray diffraction analysis.[17] Compound 15 was
Figure 2. Chiral ligands 1a–1l.
from [{Ir(dbcot)Cl}2]/1b (dbcot = dibenzo[a,e]cycloocta-
tetraene), developed in the Helmchen group,[13h,15] the allylic
alkylation reaction proceeded in 95% yield and 99% ee
(entry 13). Various temperatures, substrate concentrations,
and solvents, including CH2Cl2, dioxane, Et2O, and toluene,
were found to be well tolerated.[16] Taking multiple factors
into consideration, the optimal reaction conditions were
determined to be: [{Ir(dbcot)Cl}2]/1b as catalyst in THF at
508C.
2
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Table 2: Substrate scope.
Entry[a] Product
t [h] 6/7[b]
Yield [%][c] ee [%][d]
1
2
3
4
5
6aa: Ar=Ph
6
6
6
12
6
97:3
88
85
88
92
87
98
98
98
96
97
6ab: Ar=4-MeC6H4
6ac: Ar=4-MeOC6H4
6ad: Ar=4-BrC6H4
6ae: Ar=3-CF3C6H4
98:2
>99:1
>99:1
97:3
Scheme 2. Transformations of products. Reaction conditions: a) Zhan-
=
1B (5 mol%), CH2 CH2CO2Et, CH2Cl2, reflux, 24 h; b) 9-BBN, THF,
À788C–RT, 8 h, then NaOH (3m), H2O2 (30%), RT, 6 h; c) PPh3, CCl4,
CH2Cl2, reflux, 24 h; d) MeNH2, EtOH, 908C, sealed tube, 6 h.
9-BBN=9-borabicyclo[3.3.1]nonane, Mes=2,4,6-Me3C6H2.
6
7
8
6ba: R1 =4-Me
6ca: R1 =5-OMe
6da: R1 =6-Br
6ea: R1 =3-Me
6 fa: R1 =2-Me
10
4
12
8
96:4
98:2
>99:1
>99:1
97:3
82
92
88
82
76
98
96
96
92
97
9[e]
10[e]
12
11
11
97:3
81
86
99
95
12[e]
8
>99:1
Scheme 3. Synthesis of a diastereomer of a yuremamine derivative.
Reaction conditions: a) 7 mol% of K2OsO4·2H2O, K3Fe(CN)6, K2CO3,
DABCO, tBuOH/H2O, RT, 5 h, 3:1 d.r.; b) TBSOTf, 2,6-lutidine, CH2Cl2,
08C–RT, 12 h; c) THF/H2O/TFA (4:1:1), 08C–RT, 1 h, 68% yield over
three steps; d) DMP, CH2Cl2, RT, 30 min; e) THF, 2,4-(MeO)2-C6H3Li,
À788C–RT, 10 h, 70% yield over two steps; f) TFA (500 mol%),
CH2Cl2, 08C–RT, 3 h, 57% yield; g) Raney-Ni, H2 (1 atm), MeOH,
508C, 12 h; h) TEA, MsCl, CH2Cl2, 08C, 1 h; i) Me2NH (2m in THF),
THF, 908C, sealed tube, 12 h, 78% yield over three steps. Bn=benzyl,
DABCO=1,4-diazabicyclo[2.2.2]octane, DMP=Dess–Martin periodi-
nane, Ms=methanesulfonyl, OTf=trifluoromethanesulfonate,
TBS=tert-butyldimethylsilyl, TEA=triethylamine, TFA=trifluoroacetic
acid.
13[e,f]
14[e,f]
6gf: R=NMe2
6hf: R=OBn
8
10
>99:1
>99:1
77
85
94
98
15
16
17
6ag: R2 =2-thienyl
6ah: R2 =n-propyl
6ai: R2 =Me
20
18
5
97:3
90:10
91:9
84
76
81
99
92
82
[a] 3a/2a/[{Ir(dbcot)Cl}2]/1b, 1.1–1.5:1:0.02:0.04; 2a (0.25 mmol) in
THF (2.5 mL) at 508C for the indicated time. DDQ was then added and
the reaction was stirred at RT for another 30 min. [b] Determined by
1H NMR spectroscopy of the crude reaction mixture. [c] Yield of isolated
product. [d] The ee of 6 was determined by HPLC analysis. [e] The DDQ
oxidation takes 2 h. [f] Gram scale at RT with [{Ir(cod)Cl}2]/(R,R,Ra)-1a.
Cod =cyclooctadiene, dbcot=dibenzo[a,e]cyclooctatetraene,
DDQ=2,6-dichloro-3,5-dicyano-p-benzoquinone.
obtained after removal of the benzyl group,[20] formation of
the primary methanesulfonate, and substitution with dime-
thylamine in 78% yield over three steps from 14.
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
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In conclusion, we have developed a general and practical
synthesis of enantioenriched N-allylindoles by a one-pot
strategy involving the Ir-catalyzed asymmetric allylic alkyla-
tion and subsequent oxidation of indolines. Starting from
readily available indolines and allylic carbonates, various N-
alkylated indoles were obtained in good yields and with
excellent regioselectivity and enantioselectivity. The potential
for diverse transformation of the N-allylindole products
makes this protocol potentially useful in organic synthesis.
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Received: January 24, 2012
Published online: && &&, &&&&
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Keywords: allylic substitution · asymmetric catalysis · indoles ·
iridium · oxidation
.
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U. Kazmaier, S. Fçrster, in Catalytic Asymmetric Synthesis, 3rd
ed. (Ed: I. Ojima), Wiley-VCH, New York, 2010, p. 497; e) J. F.
Hartwig, M. J. Pouy, Top. Organomet. Chem. 2011, 34, 169; f) W.-
B. Liu, J.-B. Xia, S.-L. You, Top. Organomet. Chem. 2012, 38, 155.
[12] For a recent synthesis of N1-substituted indoles from indolines,
see: S. Bayindir, E. Erdogan, H. Kilic, N. Saracoglu, Synlett 2010,
1455, and references therein.
[13] For selected examples of Ir-catalyzed asymmetric allylic amina-
tion reactions, see: a) T. Ohmura, J. F. Hartwig, J. Am. Chem.
Soc. 2002, 124, 15164; b) C. Shu, A. Leitner, J. F. Hartwig,
Angew. Chem. 2004, 116, 4901; Angew. Chem. Int. Ed. 2004, 43,
4
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Angewandte
Chemie
4797; c) K. Tissot-Croset, D. Polet, A. Alexakis, Angew. Chem.
2004, 116, 2480; Angew. Chem. Int. Ed. 2004, 43, 2426; d) R.
Weihofen, A. Dahnz, O. Tverskoy, G. Helmchen, Chem.
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chen, Angew. Chem. 2006, 118, 5673; Angew. Chem. Int. Ed.
2006, 45, 5546; f) O. V. Singh, H. Han, J. Am. Chem. Soc. 2007,
129, 774; g) C. Defieber, M. A. Ariger, P. Moriel, E. M. Carreira,
Angew. Chem. 2007, 119, 3200; Angew. Chem. Int. Ed. 2007, 46,
3139; h) S. Spiess, C. Welter, G. Franck, J.-P. Taquet, G.
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[16] See the Supporting Information for details.
[17] See the Supporting Information for details on the crystal
structures of 6da and 14.
[18] a) J. J. Vepsꢃlꢃinen, S. Auriola, M. Tukiainen, N. Ropponen, J. C.
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[19] Extended reaction times led to the detection of the elimination
product.
[20] Pd/C and Pd(OH)2/C were found to be ineffective in removing
the benzyl group, even under high pressure.
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
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.
Angewandte
Communications
Communications
Asymmetric Catalysis
W.-B. Liu, X. Zhang, L.-X. Dai,
S.-L. You*
&&&& — &&&&
Asymmetric N-Allylation of Indoles
Through the Iridium-Catalyzed Allylic
Alkylation/Oxidation of Indolines
Two steps can be better than one: An
efficient synthesis of enantioenriched N-
allylindoles by a one-pot Ir-catalyzed
asymmetric allylic alkylation/oxidation
reaction of indolines has been realized.
The current method features high regio-
selectivity and enantioselectivity together
with a broad range of indoles with varying
electronic properties. The utility of this
method was demonstrated by the syn-
thesis of dihydropyrrolo[1,2-a]indole
derivatives.
6
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Angew. Chem. Int. Ed. 2012, 51, 1 – 6
These are not the final page numbers!