A new protocol for nickel-catalysed regio- and stereoselective hydrocyanation of allenes

Article abstract of DOI:10.1039/c5cc01899d

Regio- and stereoselective hydrocyanation under nickel catalysis is described. This report shows that allenyl C-C double bonds are discriminated and converted to the corresponding carbonitriles as a single product. The key functionalities for achieving high regio- and stereocontrol are aryl and cyclopropyl groups in the substrates. This journal is

Full text of DOI:10.1039/c5cc01899d

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A new protocol for nickel-catalysed regio- and
stereoselective hydrocyanation of allenes
Cite this: DOI: 10.1039/x0xx00000x
Shigeru Arai,* Hiroto Hori, Yuka Amako and Atsushi Nishida
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
www.rsc.org/
Regio- and stereoselective hydrocyanation under nickel catalysis improvement is based on the unique reactivity of allenes to give a
is described. This report shows that allenyl C—C double bonds total 5 possible organonickel intermediates and a maximum of 8
are discriminated and converted to the corresponding HCN adducts that could be obtained from the starting allenes with
carbonitriles as a single product. The key functionalities for Ni(0) and HCN (Scheme 1). In this communication, we set a
achieving high regio- and stereocontrol are aryl and cyclopropyl challenging goal of highly regio- and stereocontrolled
groups in the substrates.
hydrocyanation using allenes to establish an unprecedented synthetic
method for various carbonitriles.7-9
Since a cyano group has a potential utility in pharmaceuticals and
biologically important compounds1 and equivalent to a carbonyl
group and related functionalities, its introduction has been a useful
synthetic tool in synthetic chemistry. Particularly, metal-catalysed
hydrocyanation with the use of non-activated C—C multiple bonds
has been one of the most powerful cyanation protocols. Since the
pioneering work on nickel-catalysed hydrocyanation using simple
and non-activated olefins reported in the 1970s,2 facile access to
various carbonitriles through the use of this transformation has been
very advantageous,3-5 however higher regioselectivity has been
observed only with vinylarenes.2
Initially, we investigated the substituent effect in the nickel-catalysed
hydrocyanation of allenes 1a-c using acetonecyanohydrin (AC)
(Scheme 2). The results indicate that the substituents on allenes
greatly influenced the regioselectivity and reaction efficiency. For
example, mono-substituted allene (1a) gave 2ab in 55% yield as a
major adduct within 30 min, however the product selectivity among
2aa-ad was not satisfactory. The yields are determined by 1H NMR.
In the case of 1b, which contains an alkyl chain on R, reduced
reactivity was observed, and this resulted in lower conversion of 2bb
of only 30% even after 20 h, with the recovery of 1b in 55% yield.
These observations are quite similar to those reported by Sakakibara
and co-workers.5a On the other hand, we were pleased to find that
aryl-substituted allene (1c) had much higher reactivity and was
almost exclusively converted to 2ca in 83% yield. The structures of
all the major adducts from 1a-c include newly formed C—H bonds
on allenyl sp carbons, which explains why π-allyl but not alkenyl
On the other hand, we previously reported that the allene
functionality plays a key role in cyanative cyclisation6a,c and 3-
component coupling reaction6a,d however simple allenes are
unsuitable substrates because the two C—C double bonds are not
effectively discriminated during hydrocyanation. Only one example
for this chemistry reported in 1985 shows both the chemical
reactivity and selectivity are significantly improved.5a This need for
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nickel intermediates could be generated predominantly and a phenyl
group strongly determined the regiochemistry in the reductive
elimination step (C—CN bond formation), because a trans-styryl
moiety in 2ca would be thermodynamically favoured. In this
reaction, various ligands such as PAr3 (Ar = Ph, 4-CF3Ph, 2-MePh),
P(OMe)3, dppb and xantphos instead of triphenylphosphite gave no
significant difference however dppe dramatically decreased the
reaction rate (20 h) and electron donating phosphines such as PCy3
and P(4-MeOPh)3 completely prevented the reaction.
This protocol could be applied to various 1,3-disubstituted allenes
that have aryl functionalities. Regio- and stereochemistry in products
are predictable to be achieved in good to excellent yields (Scheme
3). For example, primary, secondary and tertiary alkyl groups in 2d-f
were all suitable, and the aromatic ring including indole (2g-k) could
contain a wide variety of functional groups to be transformed to the
corresponding adducts in 74-78% yield.
A plausible reaction pathway is outlined in Scheme 5. The initial
step would be the regioselective hydronickelation of 3 to form π-
allyl nickel species I. Sequential C—C bond breaking via
cyclopropane cleavage gives III that would be quickly converted to
triene 5 via β-H elimination rather than reductive elimination to give
the primary carbonitrile IV. A second hydronickelation would
selectively proceed at the terminal C—C double bond of 5 to give π
-allyl nickel species V again, and the reaction could be terminated by
formation of 4 together with Ni(0) via regioselective reductive
elimination. Both a sequential formation of a C—Ni bond and V
determines the regiochemistry of the C—CN bond in the products.
Since β-C and β-H elimination from I to 5 should be quite rapid,
side products such as II and IV were not observed at all through this
reaction.
If the π -allyl nickel species have a sufficient life-time and reactivity,
an alternative transformation could be developed, since the
regiochemistry of the C—Ni bonds in the reaction intermediates are
predictable. Thus, we next examined remote cyanation via sequential
C—C bond cleavage of cyclopropanes10 through the use of 3
(Scheme 4). When 3a was used under optimum conditions,
trans,trans-4a was exclusively obtained in 72% yield as a sole HCN
adduct together with trans-trans-5a in 10% yield. The condition
survey using 3a under lower temperature (70 °C) or with the reduced
amount of AC gave lower conversion to 4a. Using arylphosphines,
alkylphosphites and bidendentate phosphines instead were all
ineffective to increase the yield of 3a and resulted in the formation
of triene as a major product. As described in the reaction of 1, ligand
screening gave no any positive effect. The substrate scope shows that
various functionalities such as methoxy, trifluoromethyl, tert-butyl
and bromo groups on the benzene ring (3b-g), 2-naphthyl (3h),
thiophene (3i), aniline moieties (3j) as well as trisubstituted allene
(3k) could all be applicable in this transformation to give 4 in
moderate to good yields. Furthermore, cyclohexyl and aminoalkyl
groups instead of an aryl moiety in 3 could both be used in this
cyanation to give 4l and 4m via cyclopropane cleavage, respectively.
Trans,trans-5a could be isolated from the reaction mixture and we
performed further investigations to confirm the above reaction
mechanism. When trans,trans- and trans,cis-trienes were
independently used under nickel catalysis, 4a was exclusively
obtained from both substrates as a single product in respective yields
of 46% and 76% (Scheme 6). These results indicate that similar π -
allyl nickel species such as V would be generated during these
reactions and a trans dienyl moiety in 4a is more favoured, as
observed in hydrocyanation starting from arylallenes.
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bond, in the plausible intermediate 8a should occur to 8b selectively
and a similar sequence as in the formation of 4, i.e., β-H elimination,
regioselective hydronickelation and reductive elimination, would
achieve regioselective cyanation to form 7. The substrate scope
indicates that various aryl functionalities (6a-g) including
bromophenyl and thiophene groups could be used to give the
corresponding stereo-defined adducts of 7a-g in 63-93% yield.
To confirm the most favoured functionality to determine the
reaction pathway and regio- and stereochemistry through this
cyanation, we next turned to use vinilydenecyclopropane 9 that
contains both allenyl and alkylidenecyclopropyl double bonds
(Scheme 9). When 9a was employed under nickel catalysis, the
corresponding single product 10a was exclusively obtained in regio-
and stereoselective fashion. Its structure suggests that the
hydrocyanation would be triggered by Csp-H bond formation
selectively, and a cyano group was regioselectively installed without
any cleavage of cyclopropane rings at all. Various functionalities in
substrates (9b-e) were applicable for this transformation and the
corresponding products 10 were obtained in 63% to quantitative
yield, exclusively, however 10f was obtained in 17% yield due to the
lower reactivity of tetrasubstituted allene 9f.
In the reaction of 3a using DCN (prepared in-situ from CD3OD with
TMSCN)11, D was effectively incorporated at both the allenyl sp
carbon and cyclopropyl methylene to give 4a-D in 60% yield. D was
also incorporated at the two sp2 carbons of the recovered triene of
5a-D, which was isolated in 19% yield (Scheme 7). The deuteration
ratio in these products is similar, which strongly suggests that the
reaction pathway includes the formation of two C—H bonds. Due to
the in-situ generation of HCN through β-H elimination (III to 5), the
100% incorporation of D in both products would be prevented even
if an excess amount of D source was used. Based on the above
results, the reaction pathway includes C—H bond formation
(hydronickelation) on specific carbons and triene formation as a
precursor of the HCN adducts. Furthermore, the reaction using 3a
with Ni(0) in the absence of cyanohydrin was examined, and was
found to result in the recovery of 3a without the observation of any
trienes 5.12 This result suggests that a hydride source is essential for
starting the reaction and a nickelacyclobutane intermediate would be
unsuitable. These results reasonably explain the above reaction
pathway
via
a
hydronickelation—β-C
elimination—β-H
elimination—hydronickelation—reductive elimination sequence
Conclusions
without the observation of any side products such as II or IV.
In conclusion, we have demonstrated a new protocol for nickel-
catalysed hydrocyanation of allenes to give a single product and
achieved the sequential transformation via regio- and stereoselective
cyclopropane cleavage. This method could be also applicable for
alkylidene- and vinylidenecyclopropanes to be converted to the
corresponding cyanoadducts in regioselective manner. We believe
that these cyanations offer a new and important synthetic tool for Ni-
catalysed transformation, and further studies are currently underway.
This research was supported by a JSPS KAKEHNHI Grant
(21590003), The Uehara Memorial Foundation (to S.A.) and
NANOHANA Competition 2014 in Chiba University (to Y.A.).
Notes and references
Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1
Inohana, Chuo-ku, Chiba, Japan. E-mail: araisgr@chiba-u.jp
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/c000000x/
For further application, we next chose alkylydenecyclopropanes13,14
as allene analogues and used them under nickel catalysis (Scheme
8). As expected, the regio- and stereoselective cyanation of 6
proceeded smoothly to give 7 as a sole product. Its structure suggests
that the initial C—H bond exclusively formed at a more substituted
sp2 carbon. Subsequent cleavage of a C—CA bond, but not C—HA
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