2:1 versus 1:1 Coupling of Alkylacetylenes with Secondary Amines: Selectivity Switching in 8-Quinolinolato Rhodium Catalysis

Article abstract of DOI:10.1021/acs.orglett.1c00094

Both 2:1 and 1:1 couplings of alkylacetylenes with secondary amines were achieved using 8-quinolinolato rhodium catalysts and CsF. The 2:1/1:1 selectivity was switched by choosing the reaction solvent. In DMA, an unprecedented 2:1 coupling reaction of alkylacetylenes with amines proceeded to give 2-aminodiene products. One-pot 2:1 coupling/reduction provided rapid access to various allylamines, while one-pot coupling/hydrolysis gave enones as products. In toluene, anti-Markovnikov hydroamination occurred under relatively mild conditions to give 1:1 coupling products.

Full text of DOI:10.1021/acs.orglett.1c00094

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Letter
2:1 versus 1:1 Coupling of Alkylacetylenes with Secondary Amines:
Selectivity Switching in 8‑Quinolinolato Rhodium Catalysis
Yoshihiko Morimoto, Moe Hamada, Shotaro Takano, Katsufumi Mochizuki, Takuya Kochi,
and Fumitoshi Kakiuchi*
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ABSTRACT: Both 2:1 and 1:1 couplings of alkylacetylenes with
secondary amines were achieved using 8-quinolinolato rhodium
catalysts and CsF. The 2:1/1:1 selectivity was switched by choosing
the reaction solvent. In DMA, an unprecedented 2:1 coupling
reaction of alkylacetylenes with amines proceeded to give 2-
aminodiene products. One-pot 2:1 coupling/reduction provided
rapid access to various allylamines, while one-pot coupling/
hydrolysis gave enones as products. In toluene, anti-Markovnikov
hydroamination occurred under relatively mild conditions to give 1:1
coupling products.
ddition-type reactions constitute one of the most atom-
Aeconomical classes of organic transformations. In this
context, hydroamination of alkynes has been studied
extensively to prepare nitrogen-containing molecules with
high atom efficiency,1 but there are still limitations in the
functional group tolerance and the substrate scope. For
example, few reports have been made on anti-Markovnikov
addition of secondary amines to alkylacetylenes, which are
relatively less electrophilic than arylacetylenes.2−4
Methods for addition of three or more molecules provide
further efficient synthetic routes for organic compounds. 2:1
couplings of alkynes with heteroatom nucleophiles have also
been explored by many researchers, and several reactions using
alkylacetylenes have been reported (Scheme 1).5−8 Most of the
examples provide propargyl amines via hydroamination/alkyne
addition (Scheme 1a),5 but reactions to selectively give other
types of products are also desired. In 2004, the Jun group
reported the elegant hydrative dimerization of alkylacetylenes
via α,β-unsaturated imine intermediates (Scheme 1b),6 but the
use of 2-pyridylamines as amines were required and the
products were obtained as enones by in situ hydrolysis.
Fukumoto and co-workers also developed an interesting 2:1
coupling of alkylacetylenes with allylamine to form N-
heterocycles (Scheme 1c).7
offers rapid access to various allylamine structures, while
enones were obtained by one-pot coupling/hydrolysis. By
choosing toluene as a solvent, 1:1 coupling proceeded to give
anti-Markovnikov addition product under relatively mild
conditions. These reactions can be conducted in the presence
of polar functional groups such as hydroxy, cyano, and ester
groups. The NMR studies suggested that the 2:1/1:1
selectivity resulted from the relative easiness of forming an
aminocarbene intermediate in each solvent.
Our group has been studying transformations of terminal
alkynes using 8-quinolinolato rhodium catalysts.9 For example,
anti-Markovnikov addition of secondary amines to arylacety-
lenes proceeded at room temperature using an 8-quinolinolato
rhodium/phosphine catalyst system to form E-enamines.4c In
order to expand the scope of the hydroamination, the reactions
of alkylacetylenes were examined. The reaction of 1-octyne
(2a) with piperidine (3a) in toluene at 80 °C for 24 h using 5
mol % of Rh(Q)(cod) (1a) (Q = 8-quinolinolato; cod = 1,5-
cyclooctadiene) and 10 mol % of P(4-MeOC6H4)3 gave 23%
1
yield of anti-Markovnikov addition product 4aa, based on H
NMR analysis of the crude product, and the use of P(4-
CF3C6H4)3 as a phosphine ligand improved the yield to 69%
(Table 1, entry 1). While the use of CsF as an additive further
Here, we report that both 2:1 and 1:1 couplings of
alkylacetylenes with secondary amines were accomplished
using 8-quinolinolato rhodium catalysts and CsF. Facile
switching of the 2:1/1:1 selectivity was achieved by choosing
the solvent. The unprecedented 2:1 coupling of alkylacetylenes
with secondary amines to provide 2-aminodienes proceeded by
using DMA as a solvent. One-pot 2:1 coupling/reduction
Received: January 11, 2021
https://dx.doi.org/10.1021/acs.orglett.1c00094
© XXXX American Chemical Society
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A

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Letter
in 31% combined yield. The reaction was also investigated
using DMA as a solvent (entries 4−6). In the absence of an
additive, enamine 4aa was formed as the major product, but
the 2:1 coupling mainly proceeded in the reaction with CsF or
DBU to provide enones 6B and 6L after hydrolysis (entries 5
and 6). These results basically showed that the product
selectivity can be switched by reaction conditions, and
particularly in the presence of CsF, the 2:1/1:1 selectivity
can be readily switched by the choice of the solvent (entries 2
and 5).11 The 2:1 coupling is unprecedented for the reaction of
alkylacetylenes, but an example using phenylacetylene with
Scheme 1. Alkylacetylene/Heteroatom Nucleophile
Couplings
piperidine to form aminodiene products in moderate yield was
2c
́
reported by the Szymanska−Buzar group.
In order to investigate the intriguing product selectivity,
monitoring of the reaction was examined by 31P NMR
spectroscopy (Figure S1).12 While only weak signals except
for that of the free phosphine were detected after 2 h under the
reaction conditions for Table 1, entry 2 (in toluene), a
relatively strong doublet was observed at 47.5 ppm for the
similar reaction for 2 h in DMA (see the conditions for Table
1, entry 5). This doublet with a characteristic large JRh−P value
(223.6 Hz) is considered to be the signal of an aminocarbene
complex, as it is similar to the signal of the aminocarbene
complex bearing a phosphine-quinolinolato (PNO) tridentate
ligand (δ 51.2, JRh−P = 217.3 Hz, in toluene-d8).4g The doublet
at 47.5 ppm was similarly observed for the reactions using
DBU in either solvent (entries 3 and 6), while much smaller or
no signal was detected for other conditions (entries 1, 2, and
4). In addition, the 13C NMR spectrum measured after the
reaction of 2a with 3a using CsF in DMF-d7 for 7 h showed a
signal at 263.6 ppm (dd, J = 43.3, 16.6 Hz) (Figure S3), which
was similar to that observed for the above-mentioned (PNO)
Rh aminocarbene complex.4g These results suggest that an
aminocarbene complex generated in situ is a key intermediate
for the 2:1 coupling but not for the 1:1 coupling.
Table 1. Facile Switching of 1:1/2:1 Selectivity in Coupling
of Alkylacetylenes with Secondary Amines
a
Our proposed catalytic cycles of the 2:1 and 1:1 couplings
are shown in Figure 1. Alkyne 2 reacts with 8-quinolinolato
rhodium catalyst A to form vinylidene complex B, which is
then attacked by amine 3 to form ammonium complex C, as
often considered for anti-Markovnikov hydroamination of
b
conversions (%)
entry
additive
solvent
enamine 4aa
enone 6a (6aB, 6aL)
1
2
3
4
5
6
none
CsF
DBU
none
CsF
toluene
toluene
toluene
DMA
DMA
DMA
69
82
43
47
10
11
2 (1, 1)
4 (3, 1)
31 (18, 13)
4 (4, trace)
57 (38, 19)
59 (39, 20)
DBU
a
Reaction conditions: 2a (2 mmol), 3a (1 mmol), solvent (0.5 mL).
b
Conversions to 4 and 6 were determined by 1H NMR analysis using
1,3,5-trimethoxybenzene as an internal standard.
improved the yield of 4aa to 82% yield (entry 2),10 the
reaction in the presence of DBU decreased the yield of 4aa to
43% (entry 3), and formation of 2:1 coupling product 5aa was
suggested. Therefore, one-pot hydrolysis was conducted after
the reaction using DBU, and enones 6B and 6L were obtained
Figure 1. Proposed catalytic cycles of the 2:1 and 1:1 couplings.
B
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terminal alkynes.1,4g In the absence of a base stronger than
amines, intramolecular proton transfer to the large rhodium
center occurs to form complex D, and subsequent reductive
elimination gives 1:1 coupling product 4 with regenerating
catalyst A. In contrast, if there is a high enough concentration
of a base such as fluoride and DBU in the solution phase,
ammonium complex C is deprotonated to form alkenyl
complex E, which is protonated again at a carbon atom to
form relatively stable aminocarbene complex F. Alkyne
coordination to F to form G, followed by [2 + 2]-
cycloaddition, gives rhodacyclobutene H. Generation of
aminodienyl complex I by β-hydride elimination and
subsequent reductive elimination provides 2-aminodiene
product 5 and regenerates catalyst A. A similar [2 + 2]
cycloaddition/β-hydride elimination sequence of aminocar-
bene complexes was proposed in a hydroaminative cyclization
of enynes reported recently by our group.9c The key steps to
determine the 2:1/1:1 selectivity were the conversions of a
ammonium complex C to D and E. The low polarity of toluene
may suppress the formation of anionic intermediate E by the
intermolecular deprotonation by an additional base, while the
use of more polar DMA facilitates the deprotonation. In
particular, the low solubility of CsF in toluene may retard the
deprotonation under conditions for Table 1, entry 2, to further
decelerate the generation of E.
Scheme 2. Synthesis of Various Allylamines 7 and Enones 6
by 8-Quinolinolato Rhodium Catalysis
The 2:1 and 1:1 couplings of terminal alkynes with
secondary amines can be applied to the syntheses of a variety
of products such as allylamines, enones, enamines, and tertiary
amines (Scheme 2). After optimization of the reaction
conditions (Tables S2−S8), the use of catalyst 1b at 70 °C
for 48 h was found to be effective for the 2:1 coupling. Various
allylamines were prepared by the 2:1 coupling and subsequent
one-pot reduction with NaBH(OAc)3 (entries 1−14).13,14
High yields of allylamines 7 were obtained for the reactions
with six-membered cyclic amines such as piperidine, morpho-
line, N-methylpiperazine, and 4-hydroxypiperidine. Other
amines including pyrrolidine and acyclic amines also provided
the corresponding products, albeit in moderate yields.15 The
scope of alkynes was also examined, and allylamine products
were obtained in good yields from various alkynes including
those bearing polar functional groups such as THP-protected
alcohol, cyano, and ester groups. All of these alkynes were also
converted to enones 6 in good yields by the 2:1 coupling,
followed by hydrolysis (entries 15−21). Phenylacetylene was
also examined for the 2:1 coupling/hydrolysis, and the
corresponding enone product 6h was obtained in 19%
combined yields after conducting hydrolysis for 24 h (entry
22).
The reaction temperature for the 1:1 coupling of terminal
alkynes with secondary amines can be lowered to 50 °C (Table
S), and under this condition, the yield of enamine 4aa was
improved to 88% (Scheme 3, entry 1) . The 1:1 coupling can
be conducted using similar sets of terminal alkyne/secondary
amine substrates to give enamines regioselectively in good
yields (entries 1−15).15 It is noteworthy that the relatively low
reaction temperature enabled the first use of azetidine (bp 61−
62 °C)16 for anti-Markovnikov addition to alkynes, though the
product was obtained in low yield (entry 7). The one-pot
reduction used for the allylamine synthesis was also applicable
to the reduction of enamines formed by the 1:1 coupling, and
the corresponding amines were obtained mostly in good yields.
In conclusion, both 2:1 and 1:1 couplings of alkylacetylenes
with secondary amines were accomplished using 8-quinolino-
a
Reaction conditions: 2 (2 mmol), 3 (1 mmol), 1b (0.05 mmol),
P(4-CF3C6H4)3 (0.1 mmol), CsF (1 mmol), DMA (0.5 mL), 70 °C,
48 h, then NaBH(OAc)3 (5 mmol), AcOH (3.6 mmol), THF (10
b
mL), rt, 1 h. Conversions to 7 and branched/linear ratios were
determined by 1H NMR analysis using 1,3,5-trimethoxybenzene as an
c
internal standard. The branched products and the linear products
were isolated separately by silica gel column chromatography.
d
Reaction conditions: 2 (2 mmol), 3b (1 mmol), 1b (0.05 mmol),
P(4-CF3C6H4)3 (0.1 mmol), CsF (1 mmol), DMA (0.5 mL), 70 °C,
48 h, then AcOH (3 mmol), H2O (2 mL), rt, 1 h. Hydrolysis was
performed for 24 h.
e
lato rhodium catalysts and CsF. The 2:1/1:1 selectivity was
switched by the choice of the reaction solvent. While the
unprecedented 2:1 coupling to provide 2-aminodienes
proceeded by using DMA as a solvent, the 1:1 coupling
selectively occurred in toluene. One-pot 2:1 coupling/
reduction provided various allylamines, and enones were also
obtained by one-pot coupling/hydrolysis. The 1:1 coupling to
give anti-Markovnikov addition product proceeded under
C
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Scheme 3. Synthesis of Amines 8 by 8-Quinolinolato
Rhodium Catalysis
AUTHOR INFORMATION
Corresponding Author
■
Fumitoshi Kakiuchi − Department of Chemistry, Faculty of
Science and Technology, Keio University, Yokohama,
Kanagawa 223-8522, Japan; orcid.org/0000-0003-
2605-4675; Email: kakiuchi@chem.keio.ac.jp
Authors
Yoshihiko Morimoto − Department of Chemistry, Faculty of
Science and Technology, Keio University, Yokohama,
Kanagawa 223-8522, Japan
Moe Hamada − Department of Chemistry, Faculty of Science
and Technology, Keio University, Yokohama, Kanagawa
223-8522, Japan
Shotaro Takano − Department of Chemistry, Faculty of
Science and Technology, Keio University, Yokohama,
Kanagawa 223-8522, Japan
Katsufumi Mochizuki − Department of Chemistry, Faculty of
Science and Technology, Keio University, Yokohama,
Kanagawa 223-8522, Japan
Takuya Kochi − Department of Chemistry, Faculty of Science
and Technology, Keio University, Yokohama, Kanagawa
223-8522, Japan; orcid.org/0000-0002-5491-0566
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00094
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
F.K. acknowledges financial support, in part, by the Promotion
of Science (JSPS) KAKENHI Grant No. JP15H05839 in
Middle Molecular Strategy, Japan. Y.M. is also grateful for
support by the Research Grant of Keio Leading-edge
Laboratory of Science & Technology and Research Grant of
Keio Research Development and Sponsored Projects, Faculty
of Science & Technology.
a
Reaction conditions: 2 (2 mmol), 3 (1 mmol), 1a (0.05 mmol), P(4-
CF3C6H4)3 (0.1 mmol), CsF (1 mmol), toluene (0.5 mL), 50 °C, 48
b
1
h. Conversions to 4 was determined by H NMR analysis using
c
1,3,5-trimethoxybenzene as an internal standard. Reaction con-
ditions: 2 (2 mmol), 3 (1 mmol), 1a (0.05 mmol), P(4-CF3C6H4)3
(0.1 mmol), CsF (1 mmol), toluene (0.5 mL), 50 °C, 48 h, then
NaBH(OAc)3 (5 mmol), AcOH (3.6 mmol), THF (10 mL), rt, 1h.
DEDICATION
■
This paper is dedicated to Professor Ilhyong Ryu on the
occasion of his 70th birthday.
relatively mild conditions. Both the 2:1 and 1:1 coupling
reactions can be conducted using substrates with polar
functional groups such as hydroxy, cyano, and ester groups.
The NMR studies suggested that the 2:1/1:1 selectivity
resulted from the relative easiness of forming an aminocarbene
intermediate in each solvent. Further investigation of reaction
mechanism and exploration of the substrate scopes of the
alkyne/amine couplings are in progress.
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(12) The NMR experiments performed in DMA and DMF provided
similar results. See Figure S2.
(13) Synthesis of allylamines by hydroamination of 1,3-dienes have
been reported. For example, see: Tran, G.; Shao, W.; Mazet, C. Ni-
Catalyzed Enantioselective Intermolecular Hydroamination of
E
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Organic Letters
pubs.acs.org/OrgLett
Letter
Branched 1,3-Dienes Using Primary Aliphatic Amines. J. Am. Chem.
Soc. 2019, 141, 14814−14822. See also references cited therein.
(14) Less than 10% NMR yield of 4 was observed for the reaction
conditions described for entries 1−14 of Scheme 2. See Table S7 for
details.
(15) N-Methylaniline and dibenzylamine were tested for the 2:1
coupling/reduction and the 1:1 coupling but gave no more than trace
amounts of the desired allylamine products.
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̌
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Concise Synthesis of a Novel Insulin-Like Growth Factor I Receptor
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F
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