Indium-catalyzed hydroamination/hydrosilylation of terminal alkynes and aromatic amines through a one-pot, two-step protocol

Article abstract of DOI:10.1002/ejoc.201402544

We demonstrated that indium tribromide effectively functioned as a single catalyst for two successive steps in a one-pot procedure. First, the hydroamination of alkynes with anilines took place to give the Markovnikov product. Then, hydrosilylation of the imine intermediates by treatment with a hydrosilane substrate afforded the corresponding secondary amines.

Full text of DOI:10.1002/ejoc.201402544

FULL PAPER
DOI: 10.1002/ejoc.201402544
Indium-Catalyzed Hydroamination/Hydrosilylation of Terminal Alkynes and
Aromatic Amines through a One-Pot, Two-Step Protocol
Norio Sakai,*[a] Nobuaki Takahashi,[a] and Yohei Ogiwara[a]
Keywords: Indium / Hydroamination / Hydrosilylation / Alkynes / Reduction
We demonstrated that indium tribromide effectively func-
tioned as a single catalyst for two successive steps in a one-
pot procedure. First, the hydroamination of alkynes with anil-
ines took place to give the Markovnikov product. Then,
hydrosilylation of the imine intermediates by treatment with
a hydrosilane substrate afforded the corresponding second-
ary amines.
catalyzed the hydroamination/hydrosilylation of terminal
aromatic alkynes and anilines by using the mild reducing
agent Et3SiH.[9] Several groups have reported that iridium
complexes in the presence of Et3SiH will undergo a one-pot
hydroamination/hydrosilylation in an inter- or intramolec-
ular manner.[10] Also reported was the tandem inter-
molecular hydroamination/transfer hydrogenation of alk-
ynes by using a combination of a gold(I) complex and a
Hantzsch ester as the reducing source.[11] Thus, we began to
develop the reductive hydroamination of alkynes by using a
single catalyst that contained a group 13 metal, particularly
an indium compound, as the combination of indium cata-
lysts and a hydrosilane have shown high functional-group
tolerance and interesting functional-group interconversion
(FGI).[12,13] Examples of employing group 13 metals in-
clude the breakthrough work of Barluenga et al. who re-
ported the Tl-catalyzed hydroamination of alkynes and re-
ports from the Huang and Loh or Prajapati groups who
found that an indium(III) compound could catalyze the hy-
droamination of either alkenes or alkynes.[14] The gallium-
catalyzed hydroamination of alkynes has also been reported
by Li et al.[7b] Herein, we report the indium-catalyzed one-
pot hydroamination/hydrosilylation of terminal alkynes and
anilines in the presence of a hydrosilane. This is the first
example of a one-pot reductive hydroamination by em-
ploying a main group metal, an indium(III) compound,
which effectively functions as a single catalyst for successive
hydroamination and hydrosilylation reactions.
Introduction
Carbon–nitrogen bond formation is important to indus-
trial chemistry because of the various uses of the resulting
secondary or tertiary amine. Central to these reactions is
the catalytic hydroamination of alkynes and anilines, which
shows high atom economy (100%).[1] Thus far, this molecu-
lar transformation has been consistently performed by
using a number of early[2] or late transition metals,[3] main
group metals,[4] and lanthanides.[5] Among them, a report
by Doye et al. attracted our attention. In this case, a Ti
complex functioned as a single catalyst and promoted both
hydroamination and hydrosilylation reactions for the ad-
dition of terminal alkynes and anilines.[6] In a typical re-
ductive hydroamination reaction, the second reduction (hy-
drogenation) step is generally achieved by using either a
separate catalyst system, such as ZnCl2/NaBH3CN,[2a] or a
strong reducing agent, such as LiAlH4.[7] These procedures
can create troublesome experimental procedures and re-
quire extra chemicals and solvents, and the strong reducing
reagents can lead to a decrease in the chemoselectivity to-
ward functional groups that are sensitive to reducing condi-
tions. Therefore, the development of a one-pot method that
uses a single catalyst for a reductive hydroamination reac-
tion that occurs under mild reaction conditions would be
highly worthwhile.
As an extension of these procedures, Beller et al. reported
an efficient method for the reductive hydroamination of an-
ilines and alkynes by using Zn(OTf)2 (OTf = trifluorometh-
anesulfonate) under hydrogen.[8] Djukic and co-workers
disclosed that a chromium-iridium complex successfully
Results and Discussion
[a] Department of Pure and Applied Chemistry, Faculty of Science
and Technology, Tokyo University of Science (RIKADAI),
Noda, Chiba 278-8510, Japan
Phenylacetylene and p-toluidine were initially treated
with InBr3 (10 mol-%) in toluene at 110 °C for 3 h followed
by the addition of Et3SiH (Si–H: 4 equiv.) and further
heated to produce the expected secondary amine 1 in 97%
E-mail: sakachem@rs.noda.tus.ac.jp
http://www.rs.tus.ac.jp/sakaigroup
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402544.
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Indium-Catalyzed Hydroamination/Hydrosilylation of Alkynes and Amines
yield (see Table 1, Entry 1). This reaction showed a high temperature (Ͼ110 °C) to complete the hydroamination
degree of selectivity for the Markovnikov product. During step (see Table 1, Entries 15 and 16).
the series of reactions, it is noteworthy that the indium com-
With optimal conditions, the scope of the reductive hy-
pound showed high catalytic activity for the two steps, that droamination was examined by using phenylacetylene and
is, the hydroamination and then the subsequent hydro- a variety of anilines (see Table 2). In most cases, with anil-
silylation. Of the screened hydrosilanes, 1,1,3,3-tetramethyl- ines that had either an electron-donating or weakly elec-
disiloxane (TMDS), polymethylhydrosiloxane (PMHS), tron-withdrawing group, the reductive hydroamination pro-
phenylsilane (PhSiH3), and methyldiphenylsilane (Ph2Me- cess proceeded cleanly to produce the corresponding sec-
SiH), none had the same effect with regard to the reductive ondary aromatic amines 2–10 in good to excellent yields. In
hydroamination (see Table 1, Entries 2–5). In contrast, di- addition, the location of the substituent on the benzene ring
methyl(phenyl)silane (PhMe2SiH) was an outstanding re- had almost no effect on the yield of the hydroamination
ducing agent (see Table 1, Entry 6). When the amount of product. The trifluoromethyl, cyano, and nitro groups,
the indium compound or the hydrosilane was decreased to which are generally sensitive to conventional reducing con-
5 mol-% or 3 equiv. (Si–H), respectively, the product was ditions, were exceptions and had a high tolerance to the
afforded in low yield (see Table 1, Entries 7 and 8). Al- InBr3/PhMe2SiH reducing system. Unlike the In(OTf)3/
though 1 equiv. of the hydrosilane is sufficient stoichiomet- Et3SiH system in N,N-dimethylformamide (DMF),[13h] our
rically for the reduction of the imine, there is no clear system in toluene would not reduce the nitro group on a
reason for the remarkable decrease in yield. Conducting the benzene ring. These strong electron-withdrawing substitu-
hydroamination with InCl3, In(OTf)3, and In2O3 led to a ents required a longer reaction time to consume the alkyne
reduced product yield, but in the case of InI3, the reaction in the first addition step, which may have led to the de-
proceeded in nearly quantitative yield (see Table 1, En- creased total yield. Compared with using other metal cata-
[7b]
tries 9–12). Consequently, the system that employed lysts such as GaCl3
or Zn(OTf)2,[4d] the employment of
In(OTf)3, as reported by Prajapati et al., could not be ap- InBr3 was successfully applied to the reductive hydroamin-
plied to this sequence.[14b] Other group 13 metal com- ation of an aromatic secondary amine. For example, when
pounds, such as AlCl3 and GaCl3, did not show high cata- the reaction was carried out with N-methylaniline, N,N-di-
lytic activity (see Table 1, Entries 13 and 14). To compare phenylamine, and N-methylbenzylamine, the corresponding
the results in which Zn(OTf)2 promoted the reductive
hydroamination of alkynes with anilines under hydrogen,[8]
a similar reaction was carried out with Zn(OTf)2 and
PhMe2SiH. This reducing system, however, required high
Table 2. Reductive hydroamination of phenylacetylene with
amines.[a]
Table 1. Optimization of the reaction conditions.[a]
Entry
Catalyst
Hydrosilane
Yield [%][b]
1
2
3
InBr3
InBr3
InBr3
Et3SiH
TMDS
PMHS
97
64
26
4
5
6
InBr3
InBr3
InBr3
InBr3
InBr3
InCl3
In(OTf)3
In2O3
InI3
PhSiH3
76
Ph2MeSiH
PhMe2SiH
PhMe2SiH
PhMe2SiH
PhMe2SiH
PhMe2SiH
PhMe2SiH
PhMe2SiH
PhMe2SiH
PhMe2SiH
PhMe2SiH
PhMe2SiH
n.d.[c]
98[d]
20
7[e]
8[f]
9
42
6
56
10
10
11
12
13
14
15
16[g]
98
AlCl3
n.d.[c]
25
GaCl3
Zn(OTf)2
Zn(OTf)2
30
90
[a] Alkyne (0.30 mmol), p-methylaniline (0.45 mmol), catalyst
(0.030 mmol), hydrosilane (1.2 mmol), and toluene (0.60 mL).
[b] NMR yield. [c] n.d. = not determined. [d] Isolated yield.
[e] InBr3 (5 mol-%) was employed. [f] PhMe2SiH (3 equiv.).
[g] Temperature of 110 °C in the second step.
[a] Alkyne (0.30 mmol), amine (0.45 mmol), InBr3 (0.030 mmol),
hydrosilane (Si–H: 1.2 mmol), toluene (0.60 mL), 3 h for the first
step, 20 h for the second step. [b] InI3 was employed as the catalyst.
[c] 6 h for the first step. [d] 24 h for the first step. [e] 30 h for the
second step. [f] n.r. = no reaction.
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N. Sakai, N. Takahashi, Y. Ogiwara
FULL PAPER
tertiary amines 14–16, respectively, were obtained in rela- rated deuterium atoms into the methyl moiety, was ob-
tively good yields. Unfortunately, the reductive hydroamin- tained after a common workup [see Scheme 1, Equa-
2
ation with a primary aliphatic amine did not produce the tion (2)]. The 1H and D NMR spectroscopic data of prod-
expected secondary amine.
uct 26 showed the incorporation of deuterium atoms into
Then, the reductive hydroamination of other alkynes, be- the benzene ring as a result of the starting aniline (incorpo-
sides phenylacetylene, with either 4-methylaniline or 4- ration ratio of deuterium Dortho/Dpara/CD3: 2:3:10).[15]
chloroaniline was conducted under the optimal conditions
(see Table 3). The employment of a terminal alkyne with an
aliphatic substituent, such as 1-octyne and 1-hexyne, pro-
duced the corresponding secondary amines 19–22 in rela-
tively good yields. When the reaction was carried out with
a chloro-substituted phenylacetylene derivative, the corre-
sponding amine 23 was obtained in good yield. Dimethyl
acetylenedicarboxylate (DMAD) was then used in this re-
ductive hydroamination reaction to lead to aspartic acid de-
rivative 24 in a practical yield. Unlike our previous system
that involved InBr3/Et3SiH in chloroform, this reducing
system, which consisted of an indium(III) compound/
PhMe2SiH in toluene, would not reduce an ester moiety.
When the reductive hydroamination method was applied to
an alkyne with a monoester moiety, such as ethyl propiolate
Scheme 1. Deuterium-labeling experiments with PhMe2SiD and
PhND2.
or ethyl phenylpropiolate, the first hydroamination step did
On the basis of these deuterium-labeling experiments, we
suggest a plausible reaction path for the reductive hydro-
amination (see Scheme 2). First, the alkyne coordinates
with the indium compound to form activated alkyne A,
which facilitates a subsequent nucleophilic attack of the an-
iline[16] to give enamine intermediate B. Intermediate B can
rapidly transform into its more stable tautomer, imine inter-
mediate C. Then, intermediate C, which is activated by the
indium compound, is smoothly hydrosilylated to produce
the reduced product D. Finally, product D is hydrolyzed by
a common workup procedure to produce the corresponding
amine derivative. During the reductive hydroamination
series, it has been inferred that the indium compound
mainly promotes the initial hydroamination step,[17] and ex-
cess amounts (0.5 equiv.) of the amine do not result in an
undesired side reaction.[18]
not occur, and the starting amine and alkyne were reco-
vered. Therefore, this reducing system does not have an ef-
fect on monoester groups. Unfortunately, this method could
not be applied to a terminal alkyne with bulky substituents
such as 3,3-dimethyl-1-butyne and internal alkynes such as
5-decyne and diphenylacetylene. On the basis of these re-
sults, it seems that the hydroamination step was influenced
by the steric factors of the alkyne.
Table 3. Reductive hydroamination of alkynes with anilines.[a]
[a] Alkyne (0.30 mmol), amine (0.45 mmol), InBr3 (0.030 mmol),
hydrosilane (Si–H, 1.2 mmol), toluene (0.60 mL), 3 h for the first
step, 20 h for the second step. [b] InI3 was employed as the catalyst.
The hydroamination of phenylacetylene with p-toluidine
was then conducted with PhMe2SiD under the optimal con-
ditions, and amine 25, which showed a high H/D exchange
ratio at the benzyl position, was obtained in a good yield
[see Scheme 1, Equation (1)]. When the reaction was carried
Scheme 2. Plausible reaction path for hydroamination and hydro-
out with PhND2, the secondary amine 26, which incorpo- silylation.
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Eur. J. Org. Chem. 2014, 5078–5082

Indium-Catalyzed Hydroamination/Hydrosilylation of Alkynes and Amines
N-([α-D]α-Phenylethyl)-p-toluidine (25): Yellow solid (63 mg, 99%
yield); m.p. 68–69 °C. H NMR (300 MHz, CDCl3): δ = 1.48 (s, 3
Conclusions
1
We have demonstrated that indium tribromide effectively
catalyzes the reductive hydroamination of terminal alkynes
and aromatic amines to produce the corresponding second-
ary and tertiary amines in good yields. Also, compared with
a sequential reaction protocol, this one-pot reductive hy-
droamination method avoids troublesome experimental
procedures and the isolation an intermediate. As a result,
there is a reduced need for extra chemicals and solvents.
H), 2.18 (s, 3 H), 3.88 (br. s, 1 H), 6.42 (d, J = 7.5 Hz, 2 H), 6.89
(d, J = 7.5 Hz, 2 H), 7.20 (t, J = 7.0 Hz, 1 H), 7.28 (t, J = 7.0 Hz,
2 H), 7.35 (d, J = 7.0 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 18.6, 23.2, 51.5 (t, J = 21.0 Hz), 111.7, 124.1, 124.6, 125.1,
126.9, 127.9, 143.3, 143.6 ppm. HRMS (FAB): calcd. for
C15H16DN 212.1424; found 212.1447.
[D2]N-(α-Phenylethyl)aniline (26): Yellow liquid (59 mg, 99% yield).
1H NMR (500 MHz, CDCl3): δ = 1.45 (m, 1.8 H), 4.00 (br. s, 1
H), 4.46 (m, 1 H), 6.49 (d, J = 7.5 Hz, 1.6 H), 6.63 (t, J = 7.5 Hz,
0.8 H), 7.08 (m, 2 H), 7.20 (t, J = 7.5 Hz, 1 H), 7.30 (t, J = 7.5 Hz,
2 H), 7.35 (d, J = 7.5 Hz, 2 H) ppm. 13C NMR (125 MHz, CDCl3):
δ = 22.9 (q, J = 19.1 Hz), 51.6 (q, J = 7.6 Hz), 115.6, 115.5, 124.1,
125.1, 126.9, 127.4 (m), 143.5, 145.6 (m) ppm. HRMS (EI): calcd.
for C14H13D2N 199.1330; found 199.1322.
Experimental Section
1
General Methods: The H NMR spectroscopic data were recorded
at 500 or 300 MHz by using tetramethylsilane (TMS) as the in-
ternal standard. The 13C NMR spectroscopic data were measured
at 125 or 75 MHz by using the resonances of the residual solvent
as the internal standard. High-resolution mass spectra (FAB or
ESI) were measured by using p-nitrobenzyl alcohol (for FAB) as a
matrix. Thin-layer chromatography was conducted on silica gel 60
Supporting Information (see footnote on the first page of this arti-
cle): Detailed experimental procedures and characterization data of
the products that were obtained by this method as well as copies
1
of the H and 13C NMR spectra of the all products.
F254
. Column chromatography was performed with silica
gel 60 F254. Manipulations were carried out under nitrogen, unless
otherwise noted. Toluene was distilled from CaH2 and then kept
dry over molecular sieves (3 Å). The indium compounds, hydro-
silanes, alkynes, and anilines were commercially available. The
indium compounds and hydrosilanes were used without further pu-
rification. The anilines and alkynes were purified by using a com-
mon purification procedure.
Acknowledgments
This work was partially supported by a Grant-in-Aid for Scientific
Research (C) from the Ministry of Education, Culture, Sports, Sci-
ence and Technology (MEXT) (No. 25410120). The authors deeply
thank Shin-Etsu Chemical Co., Ltd. for the gift of the hydrosilanes.
General Procedure for the Indium-Catalyzed Reductive Hydroamin-
ation: In a glove box, InBr3 (10.6 mg, 0.0300 mmol) was weighed
directly into a glass vial with a screw cap. The vial was sealed with
a PTFE-sealed (PTFE = polytetrafluoroethylene) screw cap under
N2 and then removed from the glove box. Into the vial were suc-
cessively added distilled toluene (0.6 mL), the alkyne (0.30 mmol),
and the aniline (0.45 mmol). The solution was stirred at 110 °C for
3 h. Then, PhMe2SiH (163.5 mg, 1.200 mmol) was added by sy-
ringe, and the resultant mixture was further heated at 60 °C for the
appropriate reaction time (see Tables 1 and 2 as well as Scheme 1).
The reaction was quenched with aqueous Na2CO3 (1 mL), and the
aqueous layer was extracted with AcOEt (3ϫ 5 mL). The com-
bined organic phases were dried with Na2CO3, filtered, and then
concentrated under reduced pressure. The crude product was puri-
fied by silica gel chromatography (hexane/AcOEt, 9:1) to give the
corresponding amine derivative.
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N-Benzyl-N-(α-phenylethyl)-p-toluidine (16): Orange oil (47 mg,
1
52% yield). H NMR (500 MHz, CDCl3): δ = 1.56 (d, J = 7.0 Hz,
3 H), 2.20 (s, 3 H), 4.36 (d, J = 17.5 Hz, 1 H), 4.45 (d, J = 17.5 Hz,
1 H), 5.20 (q, J = 7.0 Hz, 1 H), 6.67 (d, J = 8.0 Hz, 2 H), 6.95 (d,
J = 8.0 Hz, 2 H), 7.17–7.32 (m, 10 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 16.9, 18.6, 48.8, 55.7, 113.0, 124.6, 124.7, 124.8, 125.1,
125.3, 126.6, 126.8, 127.9, 138.6, 141.4, 145.3 ppm. MS (FAB): m/z
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NMR (300 MHz, CDCl3): δ = 0.90 (t, J = 6.9 Hz, 3 H), 1.15 (d, J
= 6.0 Hz, 3 H), 1.29–1.54 (m, 6 H), 3.40 (sept, J = 6.0 Hz, 1 H),
3.43 (br. s, 1 H), 6.48 (d, J = 8.7 Hz, 2 H), 7.09 (d, J = 8.7 Hz, 2
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36.7, 48.6, 114.0, 121.1, 129.0, 146.2 ppm. MS (FAB): m/z = 212
[M + H]. HRMS (FAB): calcd. for C12H19ClN 212.1206; found
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our optimal conditions, the former reaction proceeded
smoothly to give the corresponding imine product, whereas the
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pot protocol for the indium-catalyzed hydroamination/hydro-
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most cases, the unreacted starting amine was recovered.
Received: May 7, 2014
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Published Online: July 7, 2014
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