Chiral indoline synthesis via enantioselective intramolecular copper-catalyzed alkene hydroamination

Article abstract of DOI:10.1021/om300744m

An enantioselective copper-catalyzed hydroamination/cyclization of N-sulfonyl-2-allylanilines for the synthesis of chiral 2-methylindolines is reported. Chiral 2-methylindolines are important subunits in drugs and bioactive compounds. This method provides

Full text of DOI:10.1021/om300744m

Communication
pubs.acs.org/Organometallics
Chiral Indoline Synthesis via Enantioselective Intramolecular Copper-
Catalyzed Alkene Hydroamination
Benjamin W. Turnpenny,† Kiante L. Hyman,† and Sherry R. Chemler*
Department of Chemistry, State University of New York at Buffalo, Buffalo, New York 14260, United States
S
* Supporting Information
ABSTRACT: An enantioselective copper-catalyzed hydro-
amination/cyclization of N-sulfonyl-2-allylanilines for the
synthesis of chiral 2-methylindolines is reported. Chiral 2-
methylindolines are important subunits in drugs and bioactive
compounds. This method provides chiral N-sulfonyl-2-
methylindolines in up to 90% ee.
he enantioselective hydroamination/cyclization of amino-
appeared.4 Copper(II) triflate catalyzed intra- and intermolec-
Talkenes is an active topic of interest to organic and ular hydroamination of alkenes with sulfonamides have been
organometallic chemists.1 The nitrogen heterocyclic products
reported by Komeyama, Chan, and Hii, respectively, but these
reactions are generally thought to be promoted by trace
amounts of Brønsted acid generated under the reaction
conditions.4a−c A Cu(O-t-Bu)·Xantphos catalyzed hydroamina-
tion/cyclization of electron-rich amines has been reported
where copper(I) is thought to directly activate the alkene (via
aminocupration), but no enantioselective variant of this
reaction has yet appeared.4d The enantioselective copper(II)-
catalyzed hydroamination/cyclization reaction reported herein
is based on a family of alkene aminofunctionalization reactions
we have recently developed.5 In these reactions, addition of the
nitrogen and copper(II) across the alkene is thought to occur
via a cis aminocupration transition state (Scheme 1).5b,c The
obtained in these reactions are commonly found as
components of bioactive natural products and pharmaceutical
agents. While a number of highly selective methods for the
metal-catalyzed enantioselective hydroamination/cyclization of
4-pentenylamines have been developed,1 few methods report
use of 2-allylaniline-based substrates,1f−h and the highest
enantioselectivity reported for the synthesis of a 2-methylindo-
line via alkene hydroamination is 70% ee.1g 2-Methylindolines
can be found in bioactive molecules with diverse biological
activities (e.g., Figure 1).2
Scheme 1. Proposed Copper-Catalyzed Enantioselective
Hydroamination
Figure 1. Bioactive compounds containing the 2-methylindoline core.
The synthesis of chiral 2-methylindolines has been actively
pursued,3 and resolutions are frequently used to obtain these
compounds in optically enriched form.3b,c The enantioselective
hydrogenation of indoles has also been reported as a
straightforward method for synthesizing chiral indolines, but
the procedures often suffer from long reaction times, harsh
reaction conditions, or limited substrate scope.3d,e Herein is
reported a complementary method for the synthesis of
variously substituted chiral 2-methylindolines 2 from N-
sulfonyl-2-allylanilines 1 with up to 90% ee, the highest
selectivity yet reported for the enantioselective alkene hydro-
amination/cyclization of 2-allylaniline derivatives (Scheme 1,
vide infra).
resulting organocopper(II) intermediate is unstable and suffers
homolysis under the reaction conditions, generating a primary
organic radical and copper(I). We have shown that the carbon
radical can be trapped with (2,2,6,6-tetramethylpiperidin-1-
yl)oxyl radical (TEMPO) or undergo addition to various
alkenes and arenes.5 We reasoned that atom transfer via H
Special Issue: Copper Organometallic Chemistry
Reports of copper(I) and copper(II) complexes catalyzing
the racemic hydroamination of alkenes have previously
Received: August 3, 2012
Published: August 27, 2012
© 2012 American Chemical Society
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Organometallics
Communication
a
atom abstraction from a good H atom donor, e.g. 1,4-
cyclohexadiene,5d would provide a net hydroamination product
(Scheme 1).5c
Table 1. Optimization of the Hydroamination
The enantioselectivity would be determined by the cis-
aminocupration step, and we have previously shown that the
ligand (4R)-(+)-2,2′-isopropylidinebis(4-phenyl-2-oxazoline)
((R,R)-Ph-box) provides very good levels of asymmetric
induction in such reactions.5 N-Tosyl-2-allylaniline (1a) was
subjected to [Cu(R,R)-Ph-box](OTf)2-catalyzed (20 mol %)
cyclization in the presence of 1,4-cyclohexadiene (3 equiv)
using MnO2 (3 equiv) as the stoichiometric oxidant in toluene
at 110 °C (eq 1). (The MnO2 used in all reactions described
entry
substrate temp (°C) time (h)
yield (%)
ee (%)
bc
d
d
d
,
1
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1c
1c
1c
1c
110
110
120
110
100
90
24
24
8
>95
>95
>95
nd
nd
nd
81
80
77
nd
73
76
nd
77
nd
nd
nd
86
nd
c
2
3
4
5
6
7
d
8
77 (>95 )
8
77
77
8
d
80
8
61
c
8
e
90
8
74
d
9
90
8
56 (89 )
f
d
10
90
8
90
f
d
11
100
90
8
73 (>95 )
g
d
12
8
50
d
h
h
13
14
110
100
110
110
8
>90 (70:30)
d
h
8
80 (81:19)
b
h
15
bf
,
8
72 (94:6)
d
16
8
>90 (77:23)
a
Conditions: Cu(OTf)2 (20 mol %) and (R,R)-Ph-box (25 mol %)
were stirred for 2 h at 60 °C in dry toluene in a sealed tube under Ar.
The cooled solution was diluted with dry toluene (0.1 M total
concentration with respect to 1) and was treated with sulfonamide 1b
(0.237 mmol) or 1c (0.120 mmol), 2,6-di-tert-butyl-4-methylpyridine
(1 equiv), MnO2 (3 equiv), 1,4-cyclohexadiene (3 equiv), and 4 Å
flame-dried molecular sieves (20 mg/mL) under Ar and was heated in
the sealed tube for 8 h unless otherwise noted. Filtration through
Celite and flash chromatography on SiO2 afforded the isolated product
unless otherwise noted. The percent ee was determined by chiral
herein is activated, ca. 85%, <5 μm, as supplied by a commercial
vendor.) This reaction provided a 43:57 mixture of the desired
hydroamination product 2a along with the intramolecular
carboamination product 3a.5e Chiral HPLC analysis of 2-
methylindoline 2a indicated it had been formed in 90% ee.
Increasing the amount of 1,4-cyclohexadiene to 9 equiv resulted
in only a slight decrease in the relative amount of
carboamination product 3a (result not shown).
b
c
HPLC. 5 equiv of 1,4-cyclohexadiene was used. No molecular sieves
d
e
were used. Percent conversion (NMR) given. K2CO3 (1 equiv) was
f
used instead of 2,6-di-tert-butyl-4-methylpyridine. 15 mol % Cu-
(OTf)2 and 19 mol % (R,R)-Ph-box were used. γ-Terpinine was used
instead of 1,4-cyclohexadiene. Ratio of hydroamination (2c) to
carboamination (3c) as determined by analysis of the crude H NMR
g
h
We next explored the hydroamination reactions of N-mesyl-
2-allylaniline (1b), which cannot undergo the intramolecular
carboamination reaction, and N-(3,5-di-tert-butyl-4-methoxy-
benzenesulfonyl)-2-allylaniline (1c), where intramolecular
carboamination is minimized due to steric hindrance on the
arylsulfonyl group (Table 1). The data in Table 1 indicate that
the N-mesyl substrate 1b readily converts to the indoline
product 2b in good yield (Table 1, entries 1−12). A number of
reaction conditions such as temperature, time, amount of 1,4-
cyclohexadiene, the presence or absence of 4 Å molecular
sieves, and catalyst loading were examined. We found that the
reaction time could be reduced from 24 to 8 h (Table 1,
compare entries 1 and 2 to entries 3 and 4) and the reaction
temperature could be lowered to 90 °C at 20 mol % [Cu(R,R)-
Ph-box](OTf)2 loading (Table 1, entries 4−6). We found that
flame-dried 4 Å molecular sieves were beneficial to the reaction
selectivity and reproducibility (Table 1, compare entries 6 and
8 and additional trials not shown), and 2,6-di-tert-butyl-4-
methylpyridine was a better base than K2CO3 (Table 1,
compare entries 6 and 9). We were able to reduce the catalyst
loading to 15 mol % [Cu(R,R)-Ph-box](OTf)2, but the
temperature had to be increased to 100 °C for optimal
conversion at 8 h (Table 1, compare entries 10 and 11). Thus,
the optimal conditions are 15 mol % [Cu(R,R)-Ph-box](OTf)2,
2,6-di-tert-butyl-4-methylpyridine (1 equiv) as base, and 3 equiv
of 1,4-cyclohexadiene at 100 °C for 8 h to give a 73% yield of 2-
1
spectrum. nd = not determined.
methylindoline 2b in 77% ee (Table 1, entry 11). We
attempted to use γ-terpinene as a hydrogen atom source
(Table 1, entry 12) under conditions otherwise identical with
those of Table 1, entry 6, and found that this commonly
available natural product could transfer a hydrogen atom but
was less efficient than 1,4-cyclohexadiene.
The hydroamination reaction of N-arylsulfonyl-2-allylaniline
1c, a hindered analogue of N-tosyl-2-allylaniline (1a), was next
investigated. The hope was the enantioselectivity could be
increased, relative to the reaction of 1b (note that the
hydroamination of 1a occurs with 90% ee, eq 1, vide supra)
without reducing the hydroamination yield due to competing
carboamination. When substrate 1c was subjected to the
reaction conditions (110 °C, 20 mol % Cu[(R,R)-Ph-box]OTf2,
and 3 equiv 1,4-cyclohexadiene; Table 1, entry 13), >90%
conversion was achieved but the hydroamination reaction was
accompanied by formation of the corresponding carboamina-
tion product 3c (hydroamination/carboamination 70/30).
When the temperature was decreased, the ratio improved but
the reaction did not go to completion (Table 1, entry 14).
Increasing the amount of 1,4-cyclohexadiene to 5 equiv and
running the reaction at 110 °C provided a tolerable
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Communication
a
hydroamination/carboamination ratio of 94/6, where the
reaction went to completion (Table 1, entry 15). This reaction
provided the highest isolated yield (72%) of 2c, which was
formed in 86% ee. Reduction of the catalyst loading to 15 mol
% led to an increased formation of the undesired carboami-
nation product (Table 1, entry 16).
Scheme 2. Scope of the Enantioselective Indoline Synthesis
The reaction enantioselectivity as a function of time was
briefly examined (not shown) to ascertain if enantioenrichment
could be lost due to reversible hydroamination.4c In such a
scenario, the reaction enantioselectivity could be higher in the
initial hours of the reaction. Running substrate 1b under the
same conditions as in Table 1, entry 11 but for only 3 h led to a
30% isolated yield of 2b (the rest being substrate 1b) in 67%
ee. This indicates that the reaction is not more selective in its
early stages and the observed enantioselectivity is nearly within
experimental error of Table 1, entry 11 for the detection
method ( 5% ee for chiral HPLC). We also ran a control
experiment using the same conditions as Table 1, entry 11 but
without Cu[(R,R)-Ph-box]OTf2 (not shown). This control
reaction gave 8% conversion of 1b to 2b, indicating there is a
degree of uncatalyzed background reaction that can lead to
racemic product.
a
Ar = 3,5-di-tert-butyl-4-methoxybenzene, Ms = methanesulfonyl, SES
= 2-trimethylsilylethylsulfonyl. The percent yield refers to amount of
pure isolated indoline 2. HA = hydroamination product (2), and CA =
carboamination product (3); the ratio was obtained by analysis of the
crude 1H NMR spectrum. Reactions of R2NMs substrates were
performed at 100 °C with 15 mol % [Cu]; reactions of R2NSO2Ar and
R2NSES substrates were performed at 110 °C with 20 mol % [Cu]. nd
= not determined. Enantiomers could not be separated by chiral
HPLC.
The absolute stereochemistry of N-mesyl-2-methylindoline
(2b; 77% ee), initially assigned R by analogy to other
Cu[(R,R)-Ph-box]OTf2 catalyzed reactions we have reported
with substrates 1,5 was confirmed by removal of the mesyl
group by treatment with sodium bisaluminumhydride (Red-Al)
in refluxing xylenes (eq 2). (Removal of the arylsulfonyl group
to carboamination (3, Figure 2) than did the anilines 2f−h,j
(functionalized with MeO, Cl, Br, and CN aniline substituents).
of 2c is best performed as previously described.5f) The optical
rotation of the 2-methylindoline was compared to the known
value for (S)-2-methylindoline (4)3b and found to be of the
opposite sign, establishing the configuration of our major
product as R. 2-Methylindoline (4) is a key intermediate in the
synthesis of the clinically used diuretic indapamide; thus,
methods for the enantioselective synthesis of this compound
and analogues thereof are useful.2a
The hydroamination reactions of various N-sulfonyl-2-
allylanilines 1 were examined under the optimal reaction
conditions (Table 1, entry 11 for N-mesyl substrates 1d,e and
Table 1, entry 15 for N-arylsulfonyl substrates 1f−j and N-SES
substrate 1k), as illustrated in Scheme 2. Yields of the isolated
hydroamination products are given along with the hydro-
amination (HA) to carboamination (CA) ratios (based on
analysis of the crude 1H NMR) of substrates with N-
arylsulfonyl groups. The hydroaminations of substrates 1f,g
were run for 24 h, and the reaction of 1g was run with 3 equiv
of 1,4-cyclohexadiene (reactions performed prior to reaction
time optimization). The N-mesyl-2-allylanilines 1d,e gave the
respective indolines in 76% and 73% ee, while the N-SES
substrate 1k gave indoline 2k in 72% ee. The N-arylsulfonyl-2-
allylanilines 1c,f−j gave higher levels of enantioselectivity, but
the yields were somewhat eroded by formation of the
competing carboamination products 3. We observed that
anilines 1c (Table 1) and 1i (containing H and Me aniline
substituents, respectively) gave higher ratios of hydroamination
Figure 2. Carboamination side products.
Nevertheless, moderately good yields of the hydroamination
products can be obtained in all cases and the enantioselectiv-
ities of the N-arylsulfonyl hydroamination products range from
84 to 89%. Indoline products 2c,g−j were isolated as solids;
therefore, further enantiomeric enrichment of these compounds
via recrystallization can in principle be achieved.5g,i
In summary, we have developed the first copper-catalyzed
enantioselective alkene hydroamination/cyclization. The meth-
od provides an expedient route to enantioenriched 2-
methylindolines, compounds of value in medicinal chemistry
and drug design. This chiral 2-methylindoline synthesis method
is competitive with other reported methods.3 The N-sulfonyl-2-
allylaniline substrates 1 can be synthesized in two to three
steps,5 and the hydroamination reaction uses a commercially
available, amino acid derived chiral ligand and a widely available
copper(II) salt. The hydrogen atom source, 1,4-cyclohexadiene,
has a low molecular weight, is relatively inexpensive, and
produces a volatile byproduct. This enantioselective intra-
molecular alkene hydroamination provides the highest
enantioselectivity yet reported for the hydroamination of 2-
allylaniline-derived substrates, and several of the products are
crystalline; thus, the enantiomeric excesses of such products can
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Communication
Chemler, S. R. Chem. Eur. J. 2012, 18, 1711−1726. (c) Sherman, E. S.;
Fuller, P. H.; Kasi, D.; Chemler, S. R. J. Org. Chem. 2007, 72, 3896−
3905. (d) Miller, Y.; Miao, L.; Hosseini, A. S.; Chemler, S. R. J. Am.
Chem. Soc. 2012, 134, 12149−12156. (e) Zeng, W.; Chemler, S. R. J.
Am. Chem. Soc. 2007, 129, 12948−12949. (f) Fuller, P. H.; Kim, J.-W.;
Chemler, S. R. J. Am. Chem. Soc. 2008, 130, 17638−17639. (g) Bovino,
M. T.; Chemler, S. R. Angew. Chem., Int. Ed. 2012, 51, 3923−3927.
(h) Liwosz, T. W.; Chemler, S. R. J. Am. Chem. Soc. 2012, 134, 2020−
2023. (i) Sequeira, F. C.; Bovino, M. T.; Chipre, A. J.; Chemler, S. R.
Synthesis 2012, 44, 1481−1484.
in principle be even further enhanced. Further reaction
optimization and expansion of the substrate scope are
underway and will be reported in due course.
ASSOCIATED CONTENT
* Supporting Information
■
S
Text and figures giving full experimental details, character-
ization data, and NMR spectra for all new compounds and
chiral HPLC traces for all chiral products. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: schemler@buffalo.edu.
■
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Author Contributions
†Both authors contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the National Institutes of Health (GM078383) for
support of this work.
■
REFERENCES
■
(1) Reviews: (a) Mueller, T. E.; Hultzsch, K. C.; Yus, M.; Foubelo,
F.; Tada, M. Chem. Rev. 2008, 3795−3892. (b) Zi, G. F. J. Organomet.
Chem. 2011, 696, 68−75. (c) Chemler, S. R. Org. Biomol. Chem. 2009,
7, 3009−3019. (d) Allaud, I.; Collin, J.; Hannedouche, J.; Schulz, E.
Dalton Trans. 2007, 5105−5118. (e) Hultzsch, K. C. Org. Biomol.
Chem. 2005, 3, 1819−1824. Enantioselective hydroamination of 2-
allylanilines: (f) Knight, P. D.; Munslow, I.; O’Shaughnessy, P. N.;
Scott, P. Chem. Commun. 2004, 894−895. (g) Watson, D. A.; Chiu,
M.; Bergman, R. G. Organometallics 2006, 25, 4731−4733. (h) Shen,
X.; Buchwald, S. L. Angew. Chem., Int. Ed. 2010, 49, 564−567.
(2) (a) Temperini, C.; Cecchi, A.; Scozzafava, A.; Supuran, C. T. J.
Med. Chem. 2009, 52, 322−328. (b) Khan, P. M.; Correa, R. G.;
Divlianska, D. B.; Peddibhotla, S.; Sessions, E. H.; Magnuson, G.;
Brown, B.; Suyama, E.; Yuan, H.; Mangravita-Novo, A.; Vicchiarelli,
M.; Su, Y.; Vasile, S.; Smith, L. H.; Diaz, P. W.; Reed, J. C.; Roth, G. P.
ACS Med. Chem. Lett. 2011, 2, 780−785. (c) Yoon, S. J.; Chung, Y. H.;
Lee, M. S.; Choi, D. R.; Lee, J. A.; Lee, H. S.; Yun, H. R.; Lee, D. K.;
Moon, E. Y.; Hwang, H. S.; Choi, C. H.; Jung, S. H.
Arylsulfonylimidazoline derivatives as a antitumor agent. U.S. Patent
5,932,742, Aug. 3, 1999.
(3) (a) Anas, S.; Kagan, H. B. Tetrahedron: Asymmetry 2009, 2193−
2199. (b) Arp, F. O.; Fu, G. C. J. Am. Chem. Soc. 2006, 128, 14264−
14265. (c) Hou, X. L.; Zheng, B. H. Org. Lett. 2009, 111, 1789−1791.
(d) Xiao, Y.-C.; Wang, C.; Yao, Y.; Sun, J.; Chen, Y.-C. Angew. Chem.,
Int. Ed. 2011, 50, 10661−10664. (e) Wang, D.-S.; Chen, Q.-A.; Li, W.;
Yu, C.-B.; Zhou, Y.-G.; Zhang, X. J. Am. Chem. Soc. 2010, 132, 8909−
8911.
(4) Copper-catalyzed hydroaminations: (a) Komeyama, K.;
Morimoto, T.; Takaki, K. Angew. Chem., Int. Ed. 2006, 45, 2938−
2941. (b) Rao, W.; Kothandaraman, P.; Koh, C. B.; Chan, P. W. H.
Adv. Synth. Catal. 2010, 352, 2521−2530. (c) Taylor, J. G.; Whittall,
N.; Hii, K. K. Org. Lett. 2006, 8, 3561−3564. (d) Ohmiya, H.; Moriya,
T.; Sawamura, M. Org. Lett. 2009, 11, 2145−2147. (e) Munro-
Leighton, C.; Delp, S. A.; Alsop, N. M.; Blue, E. D.; Gunnoe, T. B.
Chem. Commun. 2008, 111−113.
(5) (a) Chemler, S. R. J. Organomet. Chem. 2011, 696, 150−158.
(b) Paderes, M. C.; Belding, L.; Fanovic, B.; Dudding, T.; Keister, J. B.;
7822
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