Copper-Catalyzed Asymmetric Synthesis of Borylated cis-Disubstituted Indolines

Article abstract of DOI:10.1002/asia.201800121

A copper-catalyzed, intramolecular borylative cyclization of vinyl arenes with imines is reported, which affords enantio-enriched indolines as a single diastereomer under mild conditions. A benzylcopper species is generated by Cu-Bpin addition to the alkene, which then acts as a nucleophile for intramolecular imine addition. The reaction is applicable to various vinyl arenes with an imine moiety at the ortho-position, including heterocycles, for formation of borylated indolines in good yields and ee values up to 90 %.

Full text of DOI:10.1002/asia.201800121

CHEMISTRY
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Accepted Article
Title: Copper-Catalyzed Asymmetric Synthesis of Borylated cis-
Disubstituted Indolines
Authors: Jaesook Yun, DingXi Li, Jiwon Kim, and Jung Woon Yang
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Copper-Catalyzed Asymmetric Synthesis of Borylated cis-
Disubstituted Indolines
DingXi Li,[a] Jiwon Kim,[a] Jung Woon Yang,[b] and Jaesook Yun*[a]
Dedication ((optional))
Abstract: A copper-catalyzed, intramolecular borylative cyclization
of vinyl arenes with imines is reported, which affords enantio-
enriched indolines as a single diastereomer under mild conditions. A
benzylcopper species is generated by Cu−Bpin addition to the
alkene, which then acts as a nucleophile for intramolecular imine
addition. The reaction is applicable to various vinyl arenes with an
imine moiety at the ortho-position, including heterocycles, for
formation of borylated indolines in good yields and ee up to 90%.
Chiral indolines are important structural motifs that are
frequently found in biologically active natural products and
pharmaceuticals.[1] In addition, they have been widely applied in
a variety of asymmetric transformations as chiral auxiliaries or
organocatalysts.[2] Diverse methodologies have been developed
to obtain these molecules based on kinetic resolution,[3]
asymmetric catalytic reduction of functionalized indoles,[4] [3+2]
Scheme 1. Cu-catalyzed asymmetric borylative coupling of vinyl arenes and
imines.
cycloaddition,[5a,b] asymmetric allylation of indole boronates,[5c]
and intramolecular cyclization of various precursors.[1c,6]
Over the last decade, the copper-catalyzed borylative
We initially examined various chiral bidentate phosphine
ligands, as summarized in Table 1. In all cases, a single
diastereomer of indoline 2a[13] was obtained by reacting N-
benzylidene-2-vinylaniline 1a with bis(pinacolato)diboron in the
presence of a catalytic copper chloride, LiOtBu, and phosphine
ligands. With the C2-symmetric bisphosphine ligands L1–L3, low
enantioselectivities or poor yields were obtained (entries 1–3). In
particular, the bulky L3 ligand was not efficient for product
formation. The short-tethered bisphosphine ligands L4−L6 gave
high yields of 2a with moderate ee values (entries 4–6).
Ferrocene-based bidentate phosphine ligands (L7 and L8) were
not beneficial, with only slightly increased ee values (entries 7
and 8). However, the (S,S)-Ph-BPE ligand (L9) showed
promising reactivity and enantioselectivity (entry 9). Decreasing
the reaction temperature to 0 °C led to a slight increase in
enantioselectivity and reduced yield (entry 10). Solvent
screening demonstrated diethyl ether to be the best choice.
Finally, we obtained the corresponding indoline in good yield
and high enantioselectivity (entry 13).
coupling reactions of unsaturated carbon–carbon bonds have
been developed with various electrophiles, including
aldehydes,[7] ketones,[7b] acyl halides,[8] alkyl halides,[9] and
allylphosphates.[10] Meanwhile, borylative coupling with imines
has only been reported for allenes, dienes, and azaarenes,[11]
forming copper–allyl intermediates or their equivalents after
copper–boron addition to the unsaturated substrates (Scheme 1
a). Thus, a six-membered-ring chair transition state could easily
be adopted during the reaction of the C–C unsaturated
substrates, diboranes, and imines. However, an efficient
asymmetric borylative intramolecular cyclization has not yet
been reported.[12] We envisioned that the generated L*Cu–Bpin
catalyst could react with styrene tethered to an imine group (1)
to afford the desired indolines (Scheme 1 b). Herein, we report
an efficient methodology for the synthesis of indolines via
copper-catalyzed borylative intramolecular cyclization of vinyl
arenes (1).
[a]
[b]
D. Li, J. Kim, Prof. Dr. J. Yun
Department of Chemistry
Sungkyunkwan University
Suwon16419 (Korea)
E-mail: jaesook@skku.edu
Prof. Dr. J. W. Yang
Department of Energy Science
Sungkyunkwan University
Suwon16419 (Korea)
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
Figure 1. Ligand structures.
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Table 1. Optimization of copper-catalyzed borylative cyclization.
methoxy substituent at the paraꢀposition (1m) and a methyl
substituent at the orthoꢀposition (1n) to the vinyl arenes resulted
in low yields even at higher temperatures.
Entry
L
Solvent
NMR yield
[%][a]
ee [%][b]
1
L1
L2
L3
L4
L5
L6
L7
L8
L9
L9
L9
L9
L9
THF
68
-8
2
THF
81
14
ND[c]
52
50
-52
54
59
84
86
87
88
90
3
THF
13
4
THF
80
5
THF
90
6
THF
92
7
THF
87
8
THF
51
9
THF
90
10[d]
11
12
13
THF
85
toluene
MTBE
diethyl ether
82
79
85 (73)
[a] Yields were determined by 1H NMR analysis of the crude reaction mixture
using DMF as an internal standard. The isolated yield of 2a is shown in
parentheses. [b] The ee values were determined by chiral HPLC analysis. [c]
Not determined. [d] Reaction temperature was 0 °C.
Using these optimal reaction conditions, we investigated a
variety of vinyl arenes with a tethered imine group (Scheme 2).
The electron-donating methoxy group at the para-position of the
imine moiety gave the corresponding borylated indoline (2b)
with high yield and enantioselectivity. However, an electron-
withdrawing substituent on the aromatic ring of the imine
affected the enantioselectivity and slightly decreased ee values
of the desired indoline products (2c–2g). Substrates with an
electron-withdrawing substituent such as -Br, -CF3, or -CN at
Scheme 2. Substrate scope of the copper-catalyzed borylative cyclization.
Reaction conditions: 1 (0.3 mmol), B2pin2 (1.1 equiv), CuCl (5 mol%), L9 (5
mol%), and LiOtBu (1.05 equiv) in diethyl ether at 30 °C. Yields of isolated
product are shown. The ee values were determined by HPLC analysis.
Reactions of 1h, 1m, and 1n were carried out at 50 °C.
the
para-position
resulted
in
slightly
decreased
Organic transformations of borylated indoline 3 were then
briefly studied. The protected indoline (3) could be prepared in
high yield in a one-pot synthesis by adding trifluoroacetic
enantioselectivities (2c–2e). Both meta-methoxy and nitrile
substituents on the imine phenyl ring gave moderate
enantioselectivity (2f and 2g). With increased steric hindrance
at the ortho-position, a higher temperature was required for
complete conversion and the desired indoline (2h) was
produced in 78% ee. The reaction of imines containing
thiophene afforded the corresponding indoline (2i) in 90% yield
and 90% ee. Next, different substituents on the phenyl ring of
vinyl arene were examined. Substrates with electron-donating
or electron-withdrawing substituents at the 4-position to the
imine moiety produced 2j and 2k, but a substrate with a F-
anhydride after catalytic cyclization with
1 mol% catalyst
(Scheme 3). Hydroxylation (NaBO3•4H2O/THF/H2O) of
3
afforded the corresponding hydroxyl-substituted indoline 5[13] at
excellent yield (94%), with conservation of the ee. Moreover,
amination[14] of 3 was performed with BCl3 and BnN3 in
dichloromethane to yield the conforming indoline 4 in 67% yield
with the same ee.
substituent
at
the
5-position
showed
decreased
enantioselectivity (2l). Unfortunately, an electron-donating
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1) B2pin2 (1.1 equiv)
LiOtBu (1.05 equiv)
CuCl (1 mol%)
L9 (1 mol%)
Et2O, 30 °C, 24 h
Experimental Section
OH
Ph
Bpin
Ph
NaBO3 4H2O
(4 equiv)
A mixture of CuCl (0.015 mmol, 1.5 mg), LiOtBu (0.315 mmol, 25.2 mg),
(S,S)-Ph-BPE (0.015 mmol, 7.6 mg), and bis(pinacolato)diboron (0.33
mmol, 83.8 mg) in anhydrous diethyl ether (1 mL) was stirred for 5 min in
a Schlenk tube under an atmosphere of N2. Starting material 1 (0.3
mmol) dissolved in anhydrous diethyl ether (1 mL) was added. The
reaction tube was washed with anhydrous diethyl ether (1 mL), sealed,
moved to an oil bath of 30 °C, and stirred for 24 h, until the reaction was
completed as indicated by TLC. The reaction mixture was quenched with
H2O (5 mL), extracted with ethyl acetate (3 x 10 mL), dried with MgSO4,
filtered, and concentrated. The resulting crude sample was purified by
flash column chromatography on silica gel to obtain the product 2.
N
2) TFAA (5 equiv), 1 h
THF, H2O
RT, 4 h
N
N
Ph
TFA
TFA
5
3
94% yield, 90% ee
93% yield, 90% ee
1) BCl3 (5 equiv), CH2Cl2, RT, 1 h
2) BnN3 (3 equiv), CH2Cl2, RT, 12 h
NHBn
Ph
N
TFA
4
67% yield, 90% ee
Scheme 3. Functionalization of borylated cis-2,3-disubstituted indolines.
Acknowledgements ((optional))
This research was supported by National Research Foundation
of Korea (NRF) grants (NRF-2016R1A2B4011719 and NRF-
2016R1A4A1011451), funded by the Korean government
(MEST). D. Li thanks the China Scholarship Council
(201508260066).
Keywords: asymmetric catalysis • borylative coupling • copper •
indolines • intramolecular cyclization
[1]
For reviews, see: a) F. Gueritte, J. Fahy in Anticancer Agents from
Natural Products, (Eds.: G. M. Cragg, D. G. I. Kingston, D. J. Newman),
CRC Press, Boca Raton, FL, 2005, p. 123; b) N. Neuss, M. N. Neuss in
The Alkaloids, (Eds.: H. A. Brossi, M. Suffness), Academic Press, San
Diego, 1990; p. 145; c) S. P. Roche, J.-J. Y. Tendoung, B. Tréguier,
Tetrahedron 2015, 71, 3549.
[2] a) S. W. Youn, J. Y. Choi, Y. H. Kim, Chirality 2000, 12, 404; b) F.
Andersson, E. Hedenström, Tetrahedron: Asymmetry 2006, 17, 1952;
c) R. K. Kunz, D. W. C. MacMillan, J. Am. Chem. Soc. 2005, 127, 3240;
d) J. Pietruszka, R. C. Simon, ChemCatChem 2010, 2, 505.
[3]
a) K. Saito, Y. Shibata, M. Yamanaka, T. Akiyama, J. Am. Chem. Soc.
2013, 135, 11740; b) C. Min, D. Seidel, Chem. Eur. J. 2016, 22, 10817;
c) J. I. Murray, N. J. Flodén, A. Bauer, N. D. Fessner, D. L.
Dunklemann, O. Bob-Egbe, H. S. Rzepa, T. Bürgi, J. Richardson, A. C.
Spivey, Angew. Chem. Int. Ed. 2017, 56, 5760.
Scheme 4. Proposed catalytic cycle.
The proposed catalytic cycle is shown in Scheme 4. The
L*CuOtBu species (A) is generated from the reaction of CuCl,
ligand (L*), and a base, which subsequently reacts with B2pin2
to afford the L*Cu–Bpin species (B). This species then
undergoes addition to the styrene in an anti-Markovnikov
fashion to produce a chiral β-boryl benzylcopper intermediate
C,[15] which could epimerize to C’ in solution.[16] Electron-
withdrawing groups at the orthoꢀ or paraꢀposition of the vinyl
arene have been reported to lead to facile epimerization,[17]
which could explain the variable enantioselectivities observed in
our study. The chiral benzylcopper C adds to the imine
intramolecularly to form a cyclized indoline D. Finally, the
catalytic cycle is closed by ligand exchange with LiOtBu.
[4]
a) D.-S. Wang, J. Tang, Y.-G. Zhou, M.-W. Chen, C.-B. Yu, Y. Duan,
G.-F. Jiang, Chem. Sci. 2011, 2, 803; b) A. D. Lackner, A. V. Samant, F.
D. Toste, J. Am. Chem. Soc. 2013, 135, 14090; c) Y. Duan, L. Li, M.-W.
Chen, C.-B. Yu, H.-J. Fan, Y.-G. Zhou, J. Am. Chem. Soc. 2014, 136,
7688; d) L. Chen, C. Wang, L. Zhou, J. Sun, Adv. Synth. Catal. 2014,
356, 2224; e) T. Touge, T. Arai, J. Am. Chem. Soc. 2016, 138, 11299;
f) R. Borrmann, N. Knop, M. Rueping, Chem. Eur. J. 2017, 23, 798.
a) Y. Yang, H.-X. Ren, F. Chen, Z.-B. Zhang, Y. Zou, C. Chen, X.-J.
Song, F. Tian, L. Peng, L.-X. Wang, Org. Lett. 2017, 19, 2805; b) R. D.
Aher, G. M. Suryavanshi, A. Sudalai, J. Org. Chem. 2017, 82, 5940; c)
S. Panda, J. M. Ready, J. Am. Chem. Soc. 2017, 139, 6038.
[5]
[6]
a) J. L. García Ruano, A. Parra, V. Marcos, C. del Pozo, S. Catalán, S.
Monteagudo, S. Fustero, A. Poveda, J. Am. Chem. Soc. 2009, 131,
9432; b) D. Liu, G. Zhao, L. Xiang, Eur. J. Org. Chem. 2010, 21, 3975;
c) D. Katayev, M. Nakanishi, T. Bürgi, E. P. Kündig, Chem. Sci. 2012, 3,
1422; d) S. K. Manna, G. Panda, Org. Biomol. Chem. 2014, 12, 8318;
e) K. Sharma, J. R. Wolstenhulme, P. P. Painter, D. Yeo, F. Grande-
Carmona, C. P. Johnston, D. J. Tantillo, M. D. Smith, J. Am. Chem. Soc.
2015, 137, 13414; f) T. Torigoe, T. Ohmura, M. Suginome, Angew.
Chem. Int. Ed. 2017, 56, 14272; g) J. Lee, K. M. Ko, S.-G. Kim, RSC
Adv. 2017, 7, 56457; h) M. Santi, S. T. R. Müller, A. A. Folgueiras-
Amador, A. Uttry, P. Hellier, T. Wirth, Eur. J. Org. Chem. 2017, 14,
1889.
In summary, we have developed
a copper-catalyzed
borylative cyclization method of alkenes with imines, leading to
enantio-enriched borylated cis-indolines in good to high yields.
This methodology accommodates a range of functionalized vinyl
arenes with an imine group including a heterocycle. Further
studies on this class of reactions are ongoing.
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[7]
a) A. Welle, V. Cirriez, O. Riant, Tetrahedron 2012, 68, 3435; b) F.
Int. Ed. 2016, 55, 13854; c) K. Yeung, R. E. Ruscoe, J. Rae, A. P. Pulis,
D. J. Procter, Angew. Chem. Int. Ed. 2016, 55, 11912; d) H. Jang, F.
Romiti, S. Torker, A. H. Hoveyda, Nat. Chem. 2017, 9, 1269.
[12] CuH-catalyzed reductive intramolecular cyclization of alkenes and
imines has recently been reported; E. Ascic, S. L. Buchwald, J. Am.
Chem. Soc. 2015, 137, 4666.
Meng, H. Jang, B. Jung, A. H. Hoveyda, Angew. Chem. Int. Ed. 2013,
52, 5046; c) F. Meng, F. Haeffner, A. H. Hoveyda, J. Am. Chem. Soc.
2014, 136, 11304; d) J. C. Green, M. V. Joannou, S. A. Murray, J. M.
Zanghi, S. J. Meek, ACS Catal. 2017, 7, 4441.
[8]
[9]
a) A. Boreux, K. Indukuri, F. Gagosz, O. Riant, ACS Catal. 2017, 7,
8200; b) Y. Huang, K. B. Smith, M. K. Brown, Angew. Chem. Int. Ed.
2017, 56, 13314.
[13] The absolute configuration was determined by comparing the NMR and
optical rotation data of deborylated derivative of 2a with reported data.
See the Supporting Information for details.
a) K. Kubota, E. Yamamoto, H. Ito, J. Am. Chem. Soc. 2013, 135,
2635; b) I. Kageyuki, H. Yoshida, K. Takaki, Synthesis 2014, 46, 1924;
c) H. Iwamoto, S. Akiyama, K. Hayama, H. Ito, Org. Lett. 2017, 19,
2614; d) I. Kageyuki, I. Osaka, K. Takaki, H. Yoshida, Org. Lett. 2017,
19, 830.
[14] W. J. Jang, S. M. Song, J. H. Moon, J. Y. Lee, J. Yun, J. Am. Chem.
Soc. 2017, 139, 13660.
[15] a) D. S. Laitar, E. Y. Tsui, J. P. Sadighi, Organometallics 2006, 25,
2405; b) L. Dang, H. Zhao, Z. Lin, T. B. Marder, Organometallics 2007,
26, 2824; c) Y. Lee, A. H. Hoveyda, J. Am. Chem. Soc. 2009, 131,
3160.
[10] a) K. Semba, N. Bessho, T. Fujihara, J. Terao, Y. Tsuji, Angew. Chem. Int.
Ed. 2014, 53, 9007; b) F. Meng, K. P. McGrath, A. H. Hoveyda, Nature
2014, 513, 367; c) N. Kim, J. T. Han, D. H. Ryu, J. Yun, Org. Lett. 2017,
19, 6144.
[16] Y. Xi, J. F. Hartwig, J. Am. Chem. Soc. 2017, 139, 12758.
[17] a) J. S. Bandar, M. T. Pirnot, S. L. Buchwald, J. Am. Chem. Soc. 2015,
137, 14812; b) J. Lee, S. Radomkit, S. Torker, J. del Pozo, A. H.
Hoveyda, Nat. Chem. 2018, 10, 99.
[11] a) J. J. Smith, D. Best, H. W. Lam, Chem. Commun. 2016, 52, 3770; b)
L. Jiang, P. Cao, M. Wang, B. Chen, B. Wang, J. Liao, Angew. Chem.
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DingXi Li, Jiwon Kim, Jung Woon Yang,
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Copper-Catalyzed Asymmetric
Synthesis of Borylated cis-
Disubstituted Indolines
Let’s cyclize: A copper-catalyzed, intramolecular borylative cyclization of vinyl
arenes with imines has been developed, which affords enantio-enriched indolines
as a single diastereomer under mild conditions. A benzylcopper intermediate,
generated by Cu–Bpin addition to the alkene, acts as
a nucleophile for
intramolecular imine addition.
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