Thiol-Catalyzed Radical Decyanation of Aliphatic Nitriles with Sodium Borohydride

Article abstract of DOI:10.1021/acs.orglett.8b00626

Radical decyanation of aliphatic nitriles was achieved in the presence of NaBH₄ and a thiol. The reaction proceeds via a radical mechanism involving borane radical anion addition to nitrile to form an iminyl radical, which undergoes carbon-carbon cleavage. Reductive radical addition to acrylonitrile is followed by decyanation to give a two-carbon homologated product in a net radical ethylation reaction.

Full text of DOI:10.1021/acs.orglett.8b00626

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Thiol-Catalyzed Radical Decyanation of Aliphatic Nitriles with
Sodium Borohydride
Takuji Kawamoto,*,† Kyohei Oritani,† Dennis P. Curran,‡ and Akio Kamimura†
†Department of Applied Chemistry, Yamaguchi University, Ube, Yamaguchi 755-8611, Japan
‡Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States
S
* Supporting Information
ABSTRACT: Radical decyanation of aliphatic nitriles was achieved in the
presence of NaBH4 and a thiol. The reaction proceeds via a radical mechanism
involving borane radical anion addition to nitrile to form an iminyl radical,
which undergoes carbon−carbon cleavage. Reductive radical addition to
acrylonitrile is followed by decyanation to give a two-carbon homologated
product in a net radical ethylation reaction.
he utility of nitriles as functional handles and activating
groups is crucial to the strategic deployment of carbon−
crossover methods require exceptionally powerful reducing
agents to remove the nitrile. Classical methods include Na/
EtOH,6 Na/NH3, and Li/EtNH2.7 Modern methods include K/
crown-ether,8 potassium-graphite,9 K/HMPA/t-BuOH,10 and
organic super electron donors.11 These conditions are harsh on
functional groups, and the intermediate radicals are difficult to
trap because they are rapidly reduced to anions. On the upside,
the anions can be trapped with other electrophiles besides
protons.
Reductive decyanation by the radical hydrogen atom transfer
method were first reported with Bu3SnH.12 In this reaction, the
cyano group functions as a radical precursor and is abstracted by
Bu3Sn•. Recently, we have introduced tris(trimethylsilyl)silane
((TMS)3SiH)13 and N-heterocyclic carbene boranes (NHC-
BH3)14 as easily separable and more environmentally friendly
reagents. These conditions are mild, and the intermediate
radicals can be trapped in other processes. However, the scope is
narrow because suitable substrates are restricted to geminal
dinitriles (malononitriles) and closely related molecules. Simple
primary alkanenitriles are essentially inert to these reagents.
Here, we report that decyanation of unactivated primary and
secondary alkyl nitriles can be accomplished with sodium
borohydride (NaBH4)15 and methyl thiosalicylate as a polarity
reversal catalyst (Scheme 1, eq 3).16
T
carbon bond-forming reactions.1,2 Though nitriles are valuable
for their ability to facilitate carbon−carbon bond formation, the
nitrile functionality is not always desired in downstream adducts.
Excising a nitrile group by a reductive decyanation allows for the
use of nitriles as traceless functional handles for assembling
molecular complexity.3 In the past decade, several methods for
transition-metal-catalyzed reductive decyanation reaction have
been developed.4 In 2016, Hirao, Chiba, and co-workers
reported reductive decyanation of alkyl nitrile with NaH/NaI
or NaH/LiI.5 However, these systems are limited to tertiary alkyl
nitriles and benzylic nitriles.
Many reductive decyanation methods involve radical inter-
mediates. There are two distinct approaches: (a) radical/anion
cross over methods (Scheme 1, eq 1) and (b) radical hydrogen
atom transfer methods (Scheme 1, eq 2). Radical/anion
Scheme 1. Radical Reductive Decyanation Methods
Our studies commenced with the decyanation of pentadeca-
nenitrile 1a (Table 1). A t-BuOH solution of 1a, NaBH4 (2.4
equiv), PhSSPh 3a, and t-BuOOt-Bu (0.8 equiv) was heated at
120 °C in a sealed tube. Under these conditions, PhSSPh is
reduced by NaBH4 to PhSH. After 48 h, n-tetradecane 2a was
obtained in 84% yield (GC-MS) (Table 1, entry 1). In contrast,
1,3-dimethylimidazol-2-ylidene borane (diMeImd-BH3) ex-
hibited poor reactivity under the same conditions (10% yield,
Table 1, entry 2). Notably, the conversion of 1a to 2a did not
occur effectively in the absence of either PhSSPh 3a (10%, Table
1, entry 3) or t-BuOOt-Bu (0%, Table 1, entry 4). When the
Received: February 21, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00626
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Table 1. Screening of Reaction Conditions
Table 2. Substrate Scope for Reductive Decyanation
entry
1
variation from the standard conditions
none
yield (%)
b
1
2
3
4
5
6
1a
1a
1a
1a
1b
1b
1b
1a
84
b
diMeImd-BH3 instead of NaBH4
without PhSSPh
10
b
10
b
without t-BuOOt-Bu
0
c
none
40
d
3b (0.4 equiv) instead of PhSSPh
3b (0.4 equiv) instead of PhSSPh, 1 mmol scale
3b (0.4 equiv) instead of PhSSPh
71
e
d
7
68
b
8
77
a
Standard conditions: 1 (0.5 mmol), NaBH4 (2.4 equiv), PhSSPh (0.2
equiv), t-BuOOt-Bu (0.8 equiv), t-BuOH (2 mL), 120 °C, 48 h.
b
Determined by GC using n-decane as an internal standard.
c
Determined by 1H NMR using CHCl2CHCl2 as an internal standard.
d
e
Isolated yield after silica gel column chromatography. 1 mmol scale.
secondary nitrile 2-(4-methoxybenzyl)-hexanenitrile (1b) was
reduced under the standard conditions with PhSSPh, the yield of
2b was only 40% (Table 1, entry 5). A further screening of
polarity reversal catalysts revealed that methyl thiosalicylate 3b,17
which is commercially available and has inoffensive odor,
afforded 2b in 71% yield after silica gel column chromatography
(Table 1, entry 6). The reaction at 1 mmol scale of 1b gave 2b in
68% yield (Table 1, entry 7). The reaction of 1a with methyl
thiosalicylate 3b gave decyanation product 2a in 77% yield
(Table 1, entry 8).
To learn about the scope, we then applied the reaction
conditions of Table 1, entries 6 and 7, to preparative decyanation
reactions of various aliphatic nitriles. These results are shown in
Table 2. Decyanation of 5-(4-methoxy-phenoxy)pentane-nitrile
(1c) gave reduced product 2c and bicyclic ether 2c′ in a
combined yield of 77% with a ratio of 83/17 (Table 2, entry 1).
Ether 2c′ is a homolytic aromatic substitution product that
results from radical cyclization to the arene ring, followed by
oxidative rearomatization.18 Substrate 1d with a mesityl(2,4,6-
trimethylphenyl) ring gave only the direct reduction product 2d
in 63% yield (Table 2, entry 2). Here, the 2-methyl substituents
block radical cyclization to the arene. The reaction of 2-
methyltridecanenitrile (1e) with methyl thiosalicylate gave n-
tridecane 2e in 59% yield (Table 2, entry 3). When PhSSPh was
used, instead of methyl thiosalicylate, the yield of 2e was
improved to 72% (Table 2, entry 4). The yields of the target
products 2f−2j (Table 2, entries 5−9) from the secondary alkyl
nitriles 1f−1j were moderate to good, ranging from 42% for 2h
(Table 2, entry 7) up to 78% for 2f (Table 2, entry 5). However,
secondary alkyl nitrile 1k having a cyanide substituent on the
benzene ring gave a poor yield of 2k (3%) with recovery of 1k
(95%) (Table 2, entry 10). No decyanation product was
observed with typical tertiary alkyl nitrile 1l (Table 2, entry 11).
a
Standard conditions: 1 (0.5 mmol), NaBH4 (2.4 equiv), methyl
thiosalicylate (0.4 equiv), t-BuOOt-Bu (0.8 equiv), t-BuOH (2 mL),
b
120 °C, 48 h. Isolated yield after silica gel column chromatography.
c
The ratio was determined by 1H NMR analysis after silica gel column
d
chromatography. Determined by GC-MS using n-decane as an
internal standard. PhSSPh 3a was used instead of methyl
thiosalicylate 3b. Determined by H NMR using CHCl2CHCl2 as
an internal standard. Without methyl thiosalicylate 3b. Bu4NBH4
e
f
1
g
h
was used instead of NaBH4.
B
DOI: 10.1021/acs.orglett.8b00626
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
In contrast, 1-adamantane-carbonitrile 1m afforded adamantane
2m in 45% yield (Table 2, entry 12). Interestingly, the reaction of
1l in the absence of catalyst 3b and with Bu4NBH4, which has a
higher solubility than NaBH4, and in place of NaBH4 gave
adamantane in 80% yield (Table 2, entry 13). Though we
reinvestigated Bu4NBH4-mediated decyanation of other nitriles
(e.g., 1a) in the presence of thiols or disulfides, we could not
obtain better results due to the formation of aryl butyl sulfides in
situ. Since the dehydration or detosylation19 proceeded, β-
hydroxy nitriles or nitrile bearing tosylamides are not suitable for
the present decyanation.
Scheme 3. Proposed Mechanism for Reductive Decyanation
Reaction
Ethylation is an important transformation in organic syn-
thesis.20 Radical addition to ethene (ethylene) is an attractive
route to ethylated products that is rarely reported.21 This is
because rate constants for addition of alkyl radicals to ethene are
low. High concentrations of ethene are needed, and polymer-
ization competes. In contrast, acrylonitrile reacts with alkyl
radicals selectively and with high rate constants.22 We envisioned
that a one-pot reaction from an alkyl iodide and acrylonitrile via
borohydride-mediated reductive radical addition reaction,23
followed by reductive decyanation reaction would afford an
ethylation product. In this reaction, acrylonitrile behaves as an
ethene equivalent.
The formation of radical cyclization product 2c′ supports the
intermediacy of alkyl radicals C. In addition, the inertness of 3°-
nitrile 1k (Table 2, entry 11) suggests that the borohydride
radical anion A adds to the carbon atom of the nitrile (to give B)
rather than to the nitrogen atom. This addition is subject to steric
hindrance. Finally, the presence of an aryl nitrile suppresses the
reaction because radical A can add to aryl nitriles in competition
with (and perhaps faster than) addition to alkyl nitriles. However,
To demonstrate this principle, a room temperature t-BuOH
solution of 1-iodododecane (3a), acrylonitrile, NaBH3CN, and
2,2′-azobis(2-methylpropionitrile) (AIBN) was photoirradiated
with two black lights to form adduct 1a (Scheme 2). Then,
Scheme 2. One-Pot Synthesis of Alkane from 1-Iododecane
(3a) and Acrylonitrile
−
the resulting adduct [ArC(N•)BH3 ] does not fragment
because aryl radicals are less stable than alkyl radicals. In essence,
aryl nitriles inhibit the chain reaction. Indeed, when 1-
napthonitrile was added to a standard reduction with 1a, hardly
any 2a was formed with recovery of 1a and 1-napthonitrile.
In summary, we have discovered that primary and secondary
alkyl nitriles can be reductively decyanated with inexpensive
NaBH4 in the presence of a thiol and t-BuOOt-Bu (an initiator).
The reaction proceeds via an iminyl radical intermediate, which
then fragments to an alkyl radical. The thiol acts on this radical as
a polarity reversal catalyst. We also achieved one-pot radical
ethylation by reductive addition, followed by reductive
decyanation. Here, the common radical acceptor acrylonitrile
acts as an ethene equivalent.
NaBH4, methyl thiosalicylate 3b, and t-BuOOt-Bu were directly
added to the reaction mixture, which was heated for 48 h.
Reductive ethylation product 2a was generated in 60% yield,
which was determined by GC-MS using decane as an internal
standard.
ASSOCIATED CONTENT
■
S
* Supporting Information
A plausible radical chain mechanism for the reductive
decyanation reaction is shown in Scheme 3. Initiation occurs
by homolytic cleavage of t-BuOOt-Bu to produce a tert-butoxy
radical, which abstracts a hydride hydrogen from borohydride
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b00626.
Experimental procedures, compound characterization
data, and copies of NMR spectra (PDF)
anion to give borane radical anion A (and tert-butylalcohol).24
A
adds to the nitrile carbon of 1 to form an iminyl radical B,
followed by β-fragmentation to give cyanoborohydride anion
and an alkyl radical C.24 The radical C can potentially abstract a
hydrogen atom from borohydride anion to form 2, but this
reaction is sluggish due to polarity mismatching.16,23 Instead,
hydrogen transfer from the thiol (ArSH) to C predominates,
forming 2 and ArS•. The chain cycle is closed by reaction of ArS•
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: tak102@yamaguchi-u.ac.jp.
ORCID
Takuji Kawamoto: 0000-0002-1845-4700
Dennis P. Curran: 0000-0001-9644-7728
Akio Kamimura: 0000-0002-3060-4265
−
with BH4 to give back the thiol and the radical anion A of
borohydride. An alternative mechanism is also illustrated in
Scheme 3. The generating thiyl radicals dimerize to from a
disulfide, which is reduced by NaBH4 to give thiol. Thus, an
excess amount of initiator is possibly needed.
Notes
The authors declare no competing financial interest.
C
DOI: 10.1021/acs.orglett.8b00626
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ACKNOWLEDGMENTS
■
This work was partially supported by a JSPS Grant-in-Aid for
Young Scientists (B) (16K17869), the Tokuyama Science
Foundation, the Naito Foundation, the YU project for formation
of the core research center (Yamaguchi University), the Yazaki
Memorial Foundation for Science and Technology, the Inamori
Foundation, and the Yamaguchi University Foundation. D.P.C.
thanks the US National Science Foundation for support.
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D
DOI: 10.1021/acs.orglett.8b00626
Org. Lett. XXXX, XXX, XXX−XXX