Rhodium-Catalyzed Enantioselective Hydroamination of Alkynes with Indolines

Article abstract of DOI:10.1021/jacs.5b05200

The hydroamination of internal alkynes via tandem rhodium catalysis gives branched N-allylic indolines with high regio- and enantioselectivity. An acid switch provides access to the linear isomer in preference to the branched isomer by an isomerization me

Full text of DOI:10.1021/jacs.5b05200

Communication
pubs.acs.org/JACS
Rhodium-Catalyzed Enantioselective Hydroamination of Alkynes
with Indolines
Qing-An Chen, Zhiwei Chen, and Vy M. Dong*
Department of Chemistry, University of California, Irvine, 4403 Natural Sciences 1, Irvine, California 92697, United States
S
* Supporting Information
amines, with preference for the linear isomers (Figure 1c).3
ABSTRACT: The hydroamination of internal alkynes via
tandem rhodium catalysis gives branched N-allylic indo-
lines with high regio- and enantioselectivity. An acid switch
provides access to the linear isomer in preference to the
branched isomer by an isomerization mechanism.
Mechanistic studies suggest formation of an allene
intermediate, which undergoes hydroamination to gen-
erate allylic amines instead of the enamine or imine
products typically observed in alkyne hydroaminations.
While a promising approach, no intermolecular variants have
been shown to access the corresponding branched isomers.
Herein, we demonstrate a Rh-catalyzed alkyne hydroamination4
that allows access to either the branched or linear isomers, with
high regiocontrol by the choice of carboxylic acid additive used
(Figure 1d). This communication showcases the first enantio-
selective intermolecular hydroamination of alkynes.
Late transition-metal hydrides (e.g., Ru, Rh, Ir, Pd) are known
to convert alkynes to π-allyl metal intermediates. Since
Yamamoto’s report,3 Ishii,5 Krische,6 and our group7 have used
metal-hydride catalysis to couple internal alkynes with alcohols
or aldehydes to generate C−C bonds. The Breit group pioneered
the use of terminal alkynes to form allylrhodium intermediates
that undergo C−O and C−S bond formations.8 Encouraged by
this emerging concept, we focused on the functionalization of
alkynes to generate C−N bonds with both regio- and
enantiocontrol.
To test our hypothesis, we chose the coupling of indoline 1a
and 1-phenyl-1-propyne 2a as model substrates (Table 1).
Commercially available metal hydride complexes (e.g., RuHCl-
(CO)(PPh3)3, RhH(CO)(PPh3)3, or IrH(CO)(PPh3)3) did not
promote hydroamination. In contrast, a mix of [Rh(COE)2Cl]2/
L1 and benzoic acid8 afforded the desired branched indoline 3aa
in trace amounts (4% yield, entry 1).9 More electron-rich and
bulky ligands L2 and L3 improved the reactivity and gave high
regioselectivities (3aa/4aa) and moderate enantioselectivities
(47−55% ee, entries 2−3). Among the bidentate phosphines
bearing point chirality that we studied, (S,S)-BDPP L6 gave the
most promising regio- and enantioselectivity (87% ee, entry 6).
We assume this ligand shows enhanced reactivity and selectivity
due to its ability to promote isomerization and hydroamination
in parallel. In the absence of acid, no hydroamination was
observed. By investigating other acid additives, we found higher
enantioselectivity using m-xylylic acid (90% ee, entry 7).
With this protocol in hand, we explored the hydroamination of
alkyne 2a with various amines 1 (Table 2). Good yields (72% and
81%) and high enantioselectivities (90% ee) were obtained using
indolines with varying substituents at the 4-position (3ba and
3ca). Substrates bearing fluoro, chloro, and bromo at the 5-
position were transformed into allylic amines with similar
efficiency (3da−3fa). A slight decrease in enantioselectivity was
observed with indolines containing electron-donating substitu-
ents at the 5- or 6-position (3ga vs 3ha, 3ia). In contrast, an
aliphatic amine, such as morpholine, showed poor reactivity
onstructing C−N bonds with high regio- and enantiocon-
Ctrol represents an important challenge given the
occurrence of amines in agrochemicals, fine chemicals, and
pharmaceuticals. Transition-metal catalysis has enabled the
coupling of amines with allylic electrophiles to provide either
the branched or linear isomers (Figure 1a).1 The hydroamination
of alkynes has emerged as an attractive approach for C−N bond
formation because of its high atom economy.2 The majority of
metal catalysts investigated provide enamine or imine products
(Figure 1b). In contrast, Yamamoto demonstrated a Pd-
catalyzed hydroamination of internal alkynes to yield allylic
Received: May 19, 2015
Figure 1. Allylic aminations versus alkyne hydroaminations.
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.5b05200
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Journal of the American Chemical Society
Communication
a
Table 1. Ligand Effects on Hydroamination of Alkyne
Table 2. Branched-Selective Hydroamination with Various
Amines
a
a
1 (0.20 mmol), 2a (0.30 mmol), [Rh(COE)2Cl]2 (4.0 mol %), (S,S)-
BDPP (8.8 mol %), m-xylylic acid (15 mol %), 60 °C. The ratio of (3/
b
1
4) was determined by H NMR analysis of reaction mixture. At 70
a
c
1a (0.10 mmol), 2a (0.12 mmol), [Rh(COE)2Cl]2 (2 mol %), Ligand
(4.4 mol %), PhCO2H (30 mol %), THF (0.25 mL), 70 °C, 18 h.
°C. m-Xylylic acid (50 mol %).
b
1
Determined by H NMR or GC-FID with 1,3,5-trimethoxybenzene
Table 3. Branched-Selective Hydroamination of Various
c
a
as the internal standard; ND = not determined. Determined by chiral
SFC. 1a (0.20 mmol), 2a (0.30 mmol), [Rh(COE)2Cl]2 (4 mol %),
(S,S)-BDPP (8.8 mol %), m-xylylic acid (15 mol %). Isolated yield.
Alkynes
d
e
under this protocol (8% yield, 3ja). An improved yield (47%,
3ja) could be obtained by using more m-xylylic acid (50 mol %).
Aniline 1k was coupled with alkyne 2a in good selectivity (>20:1
b/l, 76% ee, 3ka) without bisallylation. In all cases, we observed
excellent regioselectivity for the branched isomers in preference
to the linear isomers.
b
b
entry
1
R1/R2 in 2
3/4
yield (%)
ee (%)
4-MeC6H4/Me (2b)
4-MeOC6H4/Me (2c)
4-FC6H4/Me (2d)
4-ClC6H4/Me (2e)
4-BrC6H4/Me (2f)
4-CF3C6H4/Me (2g)
3-MeC6H4/Me (2h)
3-FC6H4/Me (2i)
3-ClC6H4/Me (2j)
3-Thienyl/Me (2k)
Cy/Me (2l)
>20:1
>20:1
20:1
11:1
5:1
73
70
87
83
69
70
79
82
81
80
15
37
29
91 (3ab)
82 (3ac)
90 (3ad)
92 (3ae)
86 (3af)
91 (3ag)
90 (3ah)
94 (3ai)
93 (3aj)
65 (3ak)
27 (3al)
89 (3aa)
7 (3an)
c
2
3
Next, we examined the scope of alkynes (Table 3). The use of
electron-rich 1-aryl-1-propynes 2b−c gave branched allylic
amines in >20:1 regioselectivities, 70−73% yields, and 82−91%
ee (entries 1−2). Although a decrease in regioselectivity (from
20:1 to 3:1) was observed with electron-deficient alkynes 2d−g,
high enantioselectivities (86−92%) were still achieved (entries
3−6). The coupling of indoline with meta-substituted 1-phenyl-
1-propynes 2h−j gave a slight increase in enantioselectivity (90−
94%, entries 7−9). This protocol tolerated a heterocycle-
substituted alkyne 2k (80% yield, entry 10). However, low
reactivity (15% yield) and selectivity (27% ee) were obtained
using the internal alkyne 2l bearing an aliphatic group (entry 11).
The hydroamination of terminal alkyne 2m gave the same
product as that of 2a, with similar regio- and enantioselectivity
but lower reactivity (entry 12). Poor enantioselectivity (7%) was
observed in the hydroamination of 1-octyne 2n (entry 13).10
These results suggest that an aromatic substituent on alkyne 2 is
critical for high yield and selectivity.
4
5
6
3:1
7
>20:1
11:1
8:1
8
9
10
7:1
c
11
2:1
c
12
Bn/H (2m)
19:1
7:1
c
13
n-C6H13/H (2n)
a
1a (0.20 mmol), 2 (0.30 mmol), [Rh(COE)2Cl]2 (4.0 mol %), (S,S)-
BDPP (8.8 mol %), m-xylylic acid (15 mol %), THF (0.25 mL), 60 °C.
The ratio of 3/4 was determined by H NMR analysis of reaction
1
b
c
mixture. Isolated yield and ee of 3. At 70 °C.
droaromatization of indolines 3, to provide facile access to N-
allylic indoles11 5aa (90% ee) and 5ba (85% ee) (eq 1). The
absolute configuration of 5aa was determined to be (S) by
comparison of its optical rotation with literature data.11c,d,12
A one-pot protocol was developed, using Rh-catalyzed
asymmetric hydroamination and subsequent oxidative dehy-
B
DOI: 10.1021/jacs.5b05200
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Journal of the American Chemical Society
Communication
To support the proposed allene intermediate, phenylallene 6
was prepared and then subjected to coupling with indoline 1a
under otherwise standard conditions (eq 2).15 Only a trace
During our optimization studies, we found that using phthalic
acid (benzene-1,2-dicarboxylic acid)13 instead of m-xylylic acid
gave linear allylic amines with high regioselectivity (>20:1). A
number of amines are suitable coupling partners (4aa, 4la−4oa,
Table 4). By tuning the stoichiometry of aniline 1k (PhNH2) and
amount of the expected allylic amine was generated using a high
concentration (∼1.20 M) of allene 6. However, the allene was
transformed into the expected allylic amine when using a lower
concentration (∼0.16 M). Our results support the feasibility of
allene 6 as the intermediate and suggest that high concentrations
of allene inhibit catalysis. Using alkynes as allene surrogates can
enable transformations that would be sluggish with allene
precursors.6a,7
Table 4. Linear-Selective Hydroamination of Alkynes
When the hydroamination was performed with deuterated
alkyne 2a-d3, the deuterium label was scrambled into the α-, β-,
and γ-positions of amine 3aa-dn (eq 3). The observed
incorporation of hydrogen at the γ-position of amine 3aa-dn
indicates the reversibility of β-hydride elimination during allene
formation.
To better understand the regioselective switch (Table 2 vs 4),
we isolated and subjected racemic 3aa to various conditions
(Figure 3). No isomerization was observed in the absence of
alkyne 2a, either monoallylated product 4ka or bisallylated
product 4ka′ could be formed exclusively. This protocol can be
applied to 1-phenyl-1-butyne 2n, which bears an ethyl group, to
generate allylic amine 4ao.
On the basis of literature1,8 and our observations, we propose a
pathway involving tandem Rh-catalysis (Figure 2). The oxidative
addition of carboxylic acid with a Rh(I) precursor generates a
rhodium(III)-hydride species. The insertion of alkyne 2a into the
Rh(III)−H gives Rh-vinyl intermediate A, which subsequently
undergoes β-hydride elimination to form intermediate allene 6
and regenerate the Rh(III)−H species. Reinsertion of the
terminal allene 6 into Rh(III)−H yields chiral π-allyl rhodium
complex B. Two competing pathways can be considered for
formation of product 3.14 For path A, a ligand exchange of amine
1 with the benzoate (X) on complex B will give π-allyl rhodium
species C, which can undergo reductive elimination to yield
allylic amine 3. In path B, amine 1 undergoes nucleophilic attack
at the carbon center to deliver allylic amine 3.
Figure 3. Acid-promoted isomerization study.
Figure 2. Tandem Rh-catalysis: proposed mechanism for hydroamination of alkynes.
C
DOI: 10.1021/jacs.5b05200
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Journal of the American Chemical Society
Communication
Curr. Chem. 2014, 343, 191. (j) Huang, L.; Arndt, M.; Gooβen, K.;
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either Rh or acid. However, the branched isomer 3aa underwent
isomerization to the linear product 4aa faster in the presence of a
more acidic additive (e.g., m-xylylic vs phthalic acid). Thus, the
branched isomer is the kinetic product, which can be generated in
high yield using m-xylylic acid. In contrast, our phthalic acid
protocol generates linear products by a thermodynamically
controlled isomerization. Indeed, when we monitored the
reaction profile for our linear-selective hydroamination, we
observed formation of the branched isomer at early time points
followed by its conversion to the linear. Yudin observed a related
isomerization of allylic amines under Pd-catalysis, whereby the
kinetic (branched) product was favored by addition of DBU.16
Our Rh-catalyzed hydroamination provides an atom econom-
ical synthesis of allylic amines that complements traditional
allylic aminations, which require the use of leaving groups.
Mechanistic studies support the in situ formation of an allene
which undergoes hydroamination to provide allylic amines,
rather than the typically observed products of alkyne hydro-
amination (e.g., imines and enamines). Phthalic acid promotes
isomerization of the kinetically favored isomers to yield the more
stable linear isomers. Future studies will focus on catalyst design
to extend substrate scope and develop other variants.
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ASSOCIATED CONTENT
* Supporting Information
■
Kahny, M.; Drexler, H.-J.; Heller, D.; Plattner, D. A.; Breit, B. J. Am.
̈
S
Chem. Soc. 2014, 136, 1097. (d) Xu, K.; Khakyzadeh, V.; Bury, T.; Breit,
Experimental procedures and spectral data for all new
compounds. The Supporting Information is available free of
charge on the ACS Publications website at DOI: 10.1021/
jacs.5b05200.
B. J. Am. Chem. Soc. 2014, 136, 16124. (e) Koschker, P.; Kahny, M.;
̈
Breit, B. J. Am. Chem. Soc. 2015, 137, 3131.
(9) For the synthesis of 3aa by Ir-catalyzed allylic amination, see: Shu,
C. T.; Leitner, A.; Hartwig, J. F. Angew. Chem., Int. Ed. 2004, 43, 4797.
(10) For alkyne 2l, no decomposition of starting materials was
observed after 18 h. For alkyne 2m, competitive alkyne decomposition
(dimerization and trimerization) was observed by GC/MS. The use of
other internal alkynes (e.g., 1-phenyl-1-butyne) gave trace amounts of
product.
AUTHOR INFORMATION
Corresponding Author
*dongv@uci.edu
■
(11) For the asymmetric synthesis of N-allylic indoles, see: (a) Stanley,
L. M.; Hartwig, J. F. Angew. Chem., Int. Ed. 2009, 48, 7841. (b) Cui, H.-
L.; Feng, X.; Peng, J.; Lei, J.; Jiang, K.; Chen, Y.-C. Angew. Chem., Int. Ed.
2009, 48, 5737. (c) Liu, W.-B.; Zhang, X.; Dai, L.-X.; You, S.-L. Angew.
Chem., Int. Ed. 2012, 51, 5183. (d) Ye, K.-Y.; Dai, L.-X.; You, S.-L.
Chem.Eur. J. 2014, 20, 3040. (e) Chen, L.-Y.; Yu, X.-Y.; Chen, J.-R.;
Feng, B.; Zhang, H.; Qi, Y.-H.; Xiao, W.-J. Org. Lett. 2015, 17, 1381.
(12) The absolute configurations of all other amines 3 were assigned by
analogy.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Funding provided by UC Irvine and the National Institutes of
Health (GM105938).
■
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