Nickel-catalyzed regioselective hydrocyanation of terminal alkynes by assistance of a tosyl group

Article abstract of DOI:10.1016/j.tet.2019.03.019

Nickel-catalyzed regioselective hydrocyanation of terminal alkynes is described. A tosylamide functionality at the propargyl position was the most suitable group for controlling the regiochemistry for C–CN bond formation as well as rate enhancement. A gram-scale synthesis was achieved by minimizing the catalyst loading to 2 mol%. The major HCN adduct could be transformed to the corresponding indoline through construction of a benzylic quaternary carbon under iron catalysis.

Full text of DOI:10.1016/j.tet.2019.03.019

Accepted Manuscript
Nickel-catalyzed regioselective hydrocyanation of terminal alkynes by assistance of a
tosyl group
Shigeru Arai, Koichi Nakazawa, Xiao-fei Yang, Atsushi Nishida
PII:
S0040-4020(19)30294-7
https://doi.org/10.1016/j.tet.2019.03.019
TET 30205
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 21 January 2019
Revised Date: 9 March 2019
Accepted Date: 11 March 2019
Please cite this article as: Arai S, Nakazawa K, Yang X-f, Nishida A, Nickel-catalyzed regioselective
hydrocyanation of terminal alkynes by assistance of a tosyl group, Tetrahedron (2019), doi: https://
doi.org/10.1016/j.tet.2019.03.019.
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ACCEPTED MANUSCRIPT
Nickel-catalyzed regioselective hydrocyanation of terminal alkynes by
assistance of a tosyl group
Shigeru Arai,*a,b Koichi Nakazawa,a Xiao-fei Yanga and Atsushi Nishidaa,b
a Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana,
Chuo-ku, 260-8675 Chiba, Japan
b Molecular Chirality Research Center, Chiba University, 1-33 Yayoi-cho, 263-8522
Chiba, Japan
Abstract: Nickel-catalyzed regioselective hydrocyanation of terminal alkynes is
described. A tosylamide functionality at the propargyl position was the most
suitable group for controlling the regiochemistry for C−CN bond formation as well
as rate enhancement. A gram-scale synthesis was achieved by minimizing the
catalyst loading to 2 mol%. The major HCN adduct could be transformed to the
corresponding indoline through construction of a benzylic quaternary carbon
under iron catalysis.
Keywords: Alkynes, Hydrocyanation, Iron, Nickel, Sulfonamide
1. Introduction
A cyano group is equivalent to aminomethyl and formyl groups and carboxylic
acids. Therefore, its introduction has been recognized as a key reaction for
creation of biologically important compounds.1 Nickel-catalyzed hydrocyanation2,3
using various substrates such as olefins,4 styrene derivatives,5 conjugated dienes,6
allenes7,8 and alkynes,9 is one of the most powerful cyanation protocols, although
limited C−C multiple bonds have been shown to give high regioselectivity. Among
terminal alkynes, neighboring functional groups such as silyl9b and oxygen
functionalities9c,d have been influential for controlling the regioselectivity
(Scheme 1). Recently, Liu and co-workers reported the hydrocyanation of terminal
alkynes under Ni/Mn catalysis.10a In this article, we report the effect of
sulfonamides on both regiocontrol and rate enhancement using inexpensive HCN
precursors in a nickel-catalyzed hydrocyanation reaction.
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Scheme 1. Ni-catalyzed hydrocyanation of terminal alkynes
2. Result and discussion
Since sulfonamides are effective for stabilizing the organonickel (II) species,11 we
expected that chelation of the Ni(II) center in the hydronickelation step would
control its regioselectivity. First, 1a with a tosylamide at the propargylic position
was chosen as a substrate and the reaction was performed in the presence of Ni(0)
(10 mol%) with various HCN sources in toluene (Table 1). As expected, the sp
alkynyl carbons were discriminable, and the reaction using acetonecyanohydrin
(AC) (5 eq) at 100 °C for 2 h proceeded to give the corresponding HCN adducts in
37% yield as an inseparable mixture (2a:3a = 10:1) (entry 1). Since the efficacy of
HCN release from AC seems to be lower, in-situ generation of HCN from TMSCN
with alcohols was examined next. The use of MeOH increased the yield and the
selectivity was 12.5:1. Trifluoroethanol (TFE) improved the conversion to 90%
yield with 10:1 selectivity. With t-BuOH, the yield slightly decreased. Water also
acted as a proton source instead of alcohols, however both the yield and selectivity
decreased (entries 2-5). A shorter reaction time gave similar results and lower
temperature gave slight improvement of the product ratio (entries 6 and 7).
Solvent effect was examined at 100 °C, and 1,2-dichloroethane and THF gave
similar results to toluene however CH3CN gave no reaction even after 3 h (entries
8-10). Further optimization using TFE with TMSCN in toluene at 100 °C revealed
that the external ligand such as PPh3 and bipyridine was quite ineffective.
4b
10a
Cheaper Ni(0) source such as NiCl2•6H2O
and Ni(acac)2
with metal
reductants did not work at all (entries 11-14). These results indicate that TFE
with TMSCN is the best HCN source and optimum condition (toluene, 100 °C) was
adopted for further investigation.
Table 1. Optimization
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To optimize the suitable functional groups, the effect of acyl groups on nitrogen
was examined (Table 2, entries 2-4). An acetyl instead of a Ts group gave lower
conversion to give 2b in 26% yield even after 3 h (entry 1 vs 2). Methyl carbamate
(1c) gave lower conversion to give 2c in 57% yield (entry 3). A methoxy instead of a
methyl group on the ArSO2 functionality slightly decreased the chemical yield to
give 2d in 82% yield (entry 4). When the amide functionality was replaced by
methylene such as 1e, both the product ratio and the yield decreased to give the
corresponding adducts in 35% yield (5:1) (entry 5). An amine such as 1f was found
to be an unsuitable substrate, and no any HCN adducts were identified with
recovery of 1f in 50% yield (entry 6). This result suggests that NH function might
have enough nucleophilicity to deactivate the Ni catalyst. In the case of
phenylether (1g), the reaction proceeded smoothly, however its efficacy and
selectivity (2g/3g) were both lower than those for 1a (entry 7). These results
suggest that SO2N at the propargylic position is the most effective for regiocontrol
and rate enhancement for Ni-catalyzed hydrocyanation.
Alkyl and acyl groups as well as hydrogen on tosylamide (R in 1h-k) did not
affect regioselective hydrocyanation and the major products 2h-k were obtained at
up to 10:1 within 2 h (entries 8-11). Aryl groups on tosylamide did not affect the
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selectivity in 2l-n (entries 12-14). However, an ortho methyl group in 1o
dramatically decreased the reactivity and only a trace amount of 2o was obtained
even after 9 h (entry 15). To clarify the effect of an SO2 group, 1p with two
methylenes next to a triple bond was examined (entry 16). Although the reaction
proceeded smoothly, the decreased selectivity in 2p (6:1) suggests that the
distance between a sulfonamide and a C−C triple bond is important for controlling
the regiochemistry in the hydrometallation step. This reaction was sensitive to
the steric environment around a C−C triple bond because an NTs2 functionality in
1q and a quaternary carbon in 1r prevented the reactions (entries 17 and 18). As
we assumed, simple terminal alkynes (1s,t) were unsuitable for regiocontrol
because the lack of sulfonamide would be disfavored to discriminate sp carbons in
the hydrometallation step (entries 19 and 20). Finally, internal alkynes with a
PhNTs group (1u-w) were examined. They were reactive enough to promote
hydrocyanation and their selectivity was up to 6:1 (entries 21-23).9d
Table 2. Substrate scope
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Based on the above observations, we propose plausible reaction pathways
(Scheme 2). The initial step is the oxidative addition of HCN to Ni(0). The
resulting H−NiIICN species promotes hydronickelation to a terminal alkyne by
controlling chelation between an SO2 group and the Ni(II) center (path A).11 As
observed in 1f vs. 1a, this effect would be essential to enhance the efficacy of the
reaction. This proposal is also consistent with the finding that steric bulkiness
around the triple bond could prevent the hydronickelation step (1o,q,r vs 1a). The
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resulting alkenylnickel intermediate (Ia) would be smoothly transformed to 2a via
reductive elimination with the release of Ni(0) catalyst. In path B, chelation
between the Ni center and an SO2 group would be unlikely in Ib, and therefore
this catalytic cycle does not act as a major pathway.
Scheme 2. Plausible reaction pathways
Since we realized the effect of a tosylamide group, two applications using 1a and
2a were next investigated. First, we investigated minimization of the catalyst
loading and HCN source. When the reaction (toluene, 1.0 M) was carried out in
the presence of 2 mol% of Ni(0) species, a longer reaction time was required to
give the corresponding HCN adducts in 58% yield (2a:3a = 20:1) (entry 2). The
HCN source could also be reduced to 2 eq. in a gram-scale reaction and 2a was
obtained in 60% yield after 22 h (entry 3). In contrast, with the use of inexpensive
MeOH, the conversion was unfortunately lower to give 2a in 30% yield (entry 4).
These results are summarized in Table 3.
Table 3. Application to gram-scale synthesis
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The second application was the synthetic transformation of 2 to indoline skeleton
(Scheme 3). Olefinic and aromatic carbons in 2a can be connected by radical
cyclization through aromatic CH bond cleavage.12 Therefore, we focused on the
construction of a quaternary carbon through iron-catalyzed indoline formation.12b
The reaction using 2a, FeCl2 (10 mol%), PhCHO and (t-BuO)2 effectively
proceeded to give 4a in 48% yield and its structure was confirmed by X-ray
crystallographic analysis.13
Scheme 3. Fe-catalyzed indoline formation
In conclusion, we have found that sulfonamides at the propargylic position play
key roles in the reactivity and selectivity in Ni-catalyzed hydrocyanation. This
finding provides new insight into metal-catalyzed cyanation and could lead to
further applications including the synthesis of biologically important compounds.
Experimental section
:
Typical procedure for Ni-catalyzed hydrocyanation, synthesis of 2a: A mixture of
TMSCN (0.19 mL, 1.5 mmol) and trifluoroethanol (0.11 mL, 1.5 mmol) was stirred
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for 10 min at room temperature and then toluene (0.6 mL), 1a (85.5 mg, 0.3 mmol)
and Ni[P(OPh)3]4 (39.0 mg, 0.03 mmol, 10 mol%) were added. After being stirred
for 0.5 h at 100 °C under argon, the reaction mixture was filtrated by celite pad to
1
remove metallic salts and regioselectivity of the product was determined by H
NMR. The resulting crude mixture was charged on a silica gel pad to purify
column chromatography (hexane:AcOEt = 5:1) and an inseparable mixture of 2a
and 3a (83.8 mg, 0.27 mmol, 90%, 10:1) was obtained. Recrystallization of the
mixture from hexane-AcOEt gave 2a as a sole product.
Synthesis of 4a: To a solution of 2a (46.7 mg, 0.15 mmol) in PhCl (0.5 mL, 0.3 M)
were added FeCl2 (3.0 mg, 0.015 mmol, 10 mol%), benzaldehyde (0.08 mL, 0.75
mmol) and di-tert-butylperoxide (0.07 mL, 0.375 mmol), and the reaction mixture
was stirred for 21 h at 120 °C. After being cooled to room temperature, the
reaction mixture was poured onto a silica gel pad to purify by flash column
chromatography (hexane:AcOEt = 5:1) to give 4a as a colorless solid (30.2 mg,
0.073 mmol, 48%).
This research was supported by a JSPS KAKENHI Grant (17K08205) and The
Naito Foundation (to S.A.).
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