Electrophilic cyanation of allylic boranes: Synthesis of β,γ-unsaturated nitriles containing allylic quaternary carbon centers

Article abstract of DOI:10.1039/c8cc09229j

The electrophilic cyanation of allylic boranes, a process that is applicable to the construction of allylic quaternary carbon centers, is reported. The reaction has a broad substrate scope with a high functional group tolerance. The results represent an u

Full text of DOI:10.1039/c8cc09229j

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Electrophilic cyanation of allylic boranes:
synthesis of b,c-unsaturated nitriles containing
allylic quaternary carbon centers†
Cite this: Chem. Commun., 2019,
55, 458
Received 20th November 2018,
Accepted 5th December 2018
Kensuke Kiyokawa, * Shotaro Hata, Shunpei Kainuma and Satoshi Minakata
*
DOI: 10.1039/c8cc09229j
rsc.li/chemcomm
The electrophilic cyanation of allylic boranes, a process that is found to proceed via an activation process that involved the
applicable to the construction of allylic quaternary carbon centers, formation of a six-membered ring transition state, in which a
is reported. The reaction has a broad substrate scope with a high cyano group of the cyanating reagent coordinates to the Lewis
functional group tolerance. The results represent an unprecedented acidic boron center of the boron enolate.7b This finding prompted
and powerful tool for preparing synthetically useful b,c-unsaturated us to explore the synthetic potential of the electrophilic cyanation
nitriles, including derivatives that have been difficult to access using of organoboron nucleophiles in more detail. Herein, we report
existing methods. The synthetic utility of the method was further that the electrophilic cyanation of allylic boranes leads to the
demonstrated by functional group interconversions of the cyano formation of b,g-unsaturated nitriles. The reaction proceeds with
group of the products.
complete allylic transposition, thus permitting allylic quaternary
carbon centers to be constructed by employing g,g-disubstituted
Introducing a cyano group into an organic molecule is one allylic boranes (Scheme 1B). Although allylic boranes have found
of the most fundamental methods for preparing nitriles, an countless applications in the field of organic synthesis,8,9 the
important class of compounds that have wide applications present study appears to be the first example of their use
in organic synthesis, pharmaceuticals, and material science.1 in cyanation and provides a powerful tool for the synthesis of
Over the past few decades, considerable efforts have been b,g-unsaturated nitriles.10
expended in attempts to develop efficient and selective cyana-
We began our investigation by examining the electrophilic
tion methods.2 Reactions that permit a cyano group to be cyanation of an allylic borane that was prepared by the hydro-
introduced at allylic positions provide a straightforward access boration of an allene with 9-BBN.11 Allene 1a as a model
to synthetically versatile b,g-unsaturated nitriles. Although substrate was treated with 9-BBN at room temperature for
several methods, such as nucleophilic allylic cyanation3 and 4 h, and the resulting allylic borane 3a was subsequently
the carbo- and hydrocyanation of dienes,4,5 have been reported, subjected to cyanation with NCTS at the same temperature,
these reactions often suffer from site selectivity and limited affording the desired b,g-unsaturated nitrile 2a in 78% yield as
substrate scope. It is particularly noteworthy that a reaction a single isomer (Table 1, entry 1). This result indicates that an
that allows the construction of an allylic quaternary carbon in situ generated g,g-disubstituted allylic borane 3a underwent
center remains largely undeveloped.
cyanation with complete allylic transposition, which would be
Electrophilic cyanation has emerged as a promising tool for
nitrile synthesis.6 Our group recently reported that dialkylboron
enolates could be used in electrophilic cyanation reactions using
readily available cyanating reagents, such as N-cyano-N-phenyl-
p-toluenesulfonamide (NCTS) and p-toluenesulfonyl cyanide
(TsCN), providing efficient access to b-ketonitriles containing
an a-quaternary carbon center (Scheme 1A).7 The cyanation was
Department of Applied Chemistry, Graduate School of Engineering,
Osaka University, Yamadaoka 2-1, Suita, Osaka 565-0871, Japan.
E-mail: kiyokawa@chem.eng.osaka-u.ac.jp, minakata@chem.eng.osaka-u.ac.jp
† Electronic supplementary information (ESI) available: Experimental details,
characterization data, and spectra. See DOI: 10.1039/c8cc09229j
Scheme 1 Electrophilic cyanation of boron nucleophiles.
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Table 1 Optimization of reaction conditionsa
Entry R2BH
Conditions
Cyanating reagent Yield of 2ab [%]
1
2
3
4
5
6
7
9-BBN r.t., 4 h
Cy2BH r.t., 4 h
CatBH r.t., 4 h
9-BBN 40 1C, 30 min NCTS
9-BBN 40 1C, 30 min TsCN
9-BBN 40 1C, 30 min BrCN
9-BBN 40 1C, 30 min BnSCN
NCTS
NCTS
NCTS
78
59
0
91
495
88
59
a
b
Reactions were performed on a 0.6 mmol scale. Determined by
1H NMR analysis of the crude product using mesitylene as an internal
standard.
predicted to proceed via a six-membered ring transition state.
The use of dicyclohexylborane (Cy2BH) resulted in the formation
of 2a in a lower yield than that with 9-BBN (entry 2). Meanwhile,
when catecholborane (CatBH) was used (entry 3), the desired
product was not obtained and most of the starting material 1a was
recovered. A key to the success of this cyanation method is the use
of 9-BBN, leading to the formation of a reactive allylic borane, the
boron center of which is sufficiently Lewis acidic to permit a
cyanating reagent to be activated.12 Screening of the reaction
conditions, including the reaction temperature and time, revealed
that conducting the hydroboration with 9-BBN at 40 1C for
30 min, followed by cyanation, increased the yield of 2a to 91%
(entry 4). It should also be noted that, in addition to NCTS, several
commercially available cyanating reagents were found to be
applicable for use in this reaction (entries 5–7). TsCN was
particularly reactive, leading to the quantitative formation of 2a.
With the optimized reaction conditions identified, we next
investigated the substrate scope of the method (Scheme 2).
Scheme 2 Scope of terminal allenes. Reactions were performed on a
0.6 mmol scale. Yields are isolated yields. a The reaction was conducted on
b
c
a 6 mmol scale. NCTS was used instead of TsCN. 9-BBN, 1, THF, and
NCTS were added in succession, and the mixture was stirred at 40 1C for
d
1.5 h. The reaction was conducted on a 10 mmol scale.
A number of 1,1-disubstituted allenes were subjected to the Allylic boranes prepared from allenes bearing aromatic
hydroboration/cyanation sequence, and all of the reactions substituents also participated in the selective electrophilic
proceeded with complete regioselectivity, affording the corres- cyanation. The reaction appears to be insensitive to electronic
ponding b,g-unsaturated nitriles bearing an allylic quaternary and steric effects of the aryl substituents (2l–q). The substrate
carbon center. Such compounds are difficult to access using containing a 2-naphthyl group reacted well also on a larger
existing methods.3–5,13 The synthetic utility of this cyanation scale reaction, providing 2r highly efficiently (1.85 g, 89%). The
was demonstrated by a gram-scale reaction using 1a, which replacement of a methyl group with ethyl (2s), cyclopropyl (2t),
resulted in the formation of 2a in excellent yield (1.60 g, 93%). and more sterically hindered cyclohexyl (2u) groups at the
In addition to a tosyl-protected alcohol moiety, a tert-butyl- reaction site had a slight effect on the reaction. Although the
dimethylsilyl (TBS)-protected one was also well tolerated under yield of 2t was moderate, no product was produced as a result
the reaction conditions (2b). This cyanation was also found to of the ring-opening of the cyclopropyl group, indicating that
be compatible with various functional groups, which include the cyanation does not involve a radical process. Using this
carbamoyl (2c), chloro (2d), iodo (2e), nitro (2f), cyano (2g), protocol, it was possible to install a cyano group on a cyclo-
ester (2h), phthaloyl (2i), and indolyl (2j) groups. It should be hexane framework (2v). 1,1-Diphenyl allene underwent smooth
noted here that reactions of 1g–i were conducted with NCTS cyanation to provide 2w. Moreover, mono-substituted allenes
instead of TsCN, and that all of the reagents were added in could also be used in this cyanation, affording 2x and 2y in
succession to avoid side reactions that were observed when good yields.
the standard stepwise protocol was used, in which in situ
A trisubstituted allene was also found to be a suitable
generated allylic boranes were thought to react with function- substrate for this cyanation (Scheme 3). When allene 1z was
alities of those substrates prior to adding a cyanating reagent. subjected to the standard reaction conditions using 9-BBN,
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potential bioactive compounds.13l The treatment of 1-phenyl
cyclohexa-1,3-diene (4a) with 9-BBN at 40 1C for 1 h, followed by
cyanation with NCTS at room temperature, afforded the desired
5a in 81% yield as a single product. This result clearly indicates
that the site-selective hydroboration at the sterically less hindered
alkene moiety of 4 provided the allylic borane 6 that then under-
went cyanation. This reaction system was successfully applied
to various 1-substituted cyclohexa-1,3-dienes. The electronic and
steric effects of aryl substituents at the 1-position had no notice-
able effect on the yield (5a–f). The cyanation proceeded well even
in the presence of a Lewis-basic pyridine moiety (5g). An alkyne
functionality was incompatible with the standard stepwise protocol,
leading to a complex mixture, while the method, in which all of
the reagents are added in succession, provided 5h and 5i in low
yields along with several unidentified byproducts and the recovered
starting materials. A sterically hindered (triisopropylsilyl)ethynyl
group remained intact to afford the desired product 5j in high
yields. A phenyl substituent at the 5-position did not affect the
reactivity and regioselectivity, and a diastereomeric mixture of
nitrile 5k was obtained in a 78% combined yield. In addition
to cyclohexa-1,3-dienes, a cyclohepta-1,3-diene derivative was
also a suitable substrate for this cyanation process (5l). Using
this method, cyclohexa-1,3-diene was converted to 5m in a
moderate yield.
The synthesized b,g-unsaturated nitriles could be readily
converted into other useful compounds through functional
group interconversions, as shown in Scheme 5. For example,
the hydrolysis of 2r and 5a using hydrogen peroxide in the
presence of a catalytic amount of a base proceeded effectively to
afford amides 7 and 8, respectively. In addition, the nitriles
were readily partially reduced by DIBAL-H leading to aldehydes
(9 and 10) and full reduction by LiAlH4 led to the formation of
amines (11 and 12). These products can also serve as platforms
for further chemical elaborations, illustrating the synthetic
utility of this cyanation.
Scheme 3 Reaction using a trisubstituted allene.
the corresponding product 2z was obtained in good yield but as
a mixture of geometric isomers (E/Z = 1 : 5). After a brief
screening of boranes, we were pleased to find that the use of
Cy2BH instead of 9-BBN led to (E)-2z being produced as a single
isomer. These stereoselectivities can be explained by the for-
mation of a chair-like six-membered ring transition state in the
cyanation step.7b,10 The reaction using Cy2BH would proceed
through TS-1, in which a methyl group at the a-position of the
allylic borane 3z adopts an equatorial position, leading to the
formation of the (E)-isomer, while the methyl group would be
expected to adopt an axial position to minimize steric repulsion
between the methyl group and the 9-BBN backbone when
9-BBN is employed.14,15
To expand the scope of this electrophilic cyanation, allylic
boranes prepared from cyclic 1,3-dienes by hydroboration with
9-BBN were next examined (Scheme 4).16 Cyclic alk-1-enecarbo-
nitrile derivatives, which can be synthesized by the present
reaction, are also attractive synthetic intermediates for preparing
Finally, the enantioselective version of this electrophilic
cyanation was investigated by employing a chiral allylic borane
Scheme 4 Scope of cyclic 1,3-dienes. Reactions were performed on a
0.6 mmol scale. Yields are isolated yields. a The reaction was conducted on
a 10 mmol scale. b The reaction was conducted on a 1 mmol scale. 9-BBN,
4, THF, and NCTS were added in succession, and the mixture was stirred at
40 1C for 2 h. c Recovered starting materials. d Determined by the 1H NMR
analysis of the crude product. e Cy2BH was used instead of 9-BBN, and the
hydroboration was conducted at r.t. for 4 h.
Scheme 5 Functional group interconversions of b,g-unsaturated nitrile
products. (a) For 2r: H2O2 (aq., 2.2 equiv.), NaOH (aq., 0.3 equiv.), DMSO,
0 1C to r.t., 5 h. For 5a: H2O2 (aq., 2.2 equiv.), K2CO3 (0.16 equiv.), DMSO,
0 1C to r.t., 16 h. (b) DIBAL-H (1.2 equiv.), toluene, 0 1C, 24 h. (c) LiAlH4
(1 equiv. for 2r and 2 equiv. for 5a), Et2O, 0 1C to r.t., 3 h.
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¨
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in acyclic systems, which is an important research topic in
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In conclusion, we report the electrophilic cyanation of allylic
boranes, which can be readily prepared by the hydroboration of
allenes and cyclic 1,3-dienes, for the selective and efficient
formation of synthetically useful b,g-unsaturated nitriles. This
process is operationally simple, easily scalable, and displays
a broad substrate scope with a high functional group tolerance.
The present method represents a new entry into synthetic
applications of allylic boranes. Further investigations of this
method in organic synthesis including enantioselective reactions
based on this preliminary result are currently in progress.
This work was supported by the JSPS KAKENHI Grant
Number 18K14217.
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reaction. See the ESI† for details.
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