Catalytic sp3C-CN Bond Cleavage: Ni-Mediated Phosphorylation of Alkylnitriles

Article abstract of DOI:10.1021/acs.orglett.8b02854

A direct phosphorylation of the sp³C-CN bond catalyzed by a nickel catalyst is disclosed. A wide range of primary nitriles readily coupled with secondary phosphine oxides to produce the corresponding phosphorylated products in high yields. As a key step, this new method was applied to the synthesis of anticancer drug Combretastatin-A4, significantly shortening its synthetic path.

Full text of DOI:10.1021/acs.orglett.8b02854

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Catalytic sp3C−CN Bond Cleavage: Ni-Mediated Phosphorylation of
Alkylnitriles
Ji-Shu Zhang,† Tieqiao Chen,*,†,‡ Yongbo Zhou,† Shuang-Feng Yin,† and Li-Biao Han*,§
†State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan
University, Changsha, Hunan 410082, China
‡Key Laboratory of Ministry of Education for Advanced Materials in Tropical Island Resources, College of Materials and Chemical
Engineering, Hainan University, Haikou, Hainan 570228, China
§National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki 305-8565, Japan
S
* Supporting Information
ABSTRACT: A direct phosphorylation of the sp3C−CN bond
catalyzed by a nickel catalyst is disclosed. A wide range of
primary nitriles readily coupled with secondary phosphine
oxides to produce the corresponding phosphorylated products
in high yields. As a key step, this new method was applied to
the synthesis of anticancer drug Combretastatin-A4, signifi-
cantly shortening its synthetic path.
Scheme 1. Carbon−Carbon/Carbon−Heteroatom Bond
Formation via C−CN Bond Cleavage
elective activation of nonstrained carbon−carbon single
Sbonds by a transition metal catalyst is one of the most
challenging topics in organic chemistry.1 This is not only
because it constitutes fundamental academic value but also
because it holds significant potential application in industrial
manufacturing.2 The successful carbon−carbon bond cleavages
reported so far are usually accompanied by either the release of
ring strain or aromatization; thus, they lack generality.1b The
activation of the strong C−CN bonds (∼550 kJ mol−1) is a hot
topic that has been extensively studied in recent years.3,4 In
2001, Miller et al. reported a nickel-catalyzed cross-coupling
reaction of benzonitriles with ArMgX that affords biaryl
compounds (Scheme 1a, path 1).5 Later, similar cross-coupling
reactions were successfully developed to construct sp2C−Z
bonds (e.g., sp2C−Si, sp2C−B, and sp2C−P bonds) (Scheme
1a, path 2).6 In addition, the direct decyanation of nitriles was
also achieved using a transition metal catalyst with a reductant
(Scheme 1a, path 3).7 Although only being limited to electron-
deficient (heteroatom)aryl nitriles, a novel photoredox/
organic-cocatalyzed C−CN/C−H cross-coupling was achieved
(Scheme 1a, path 4).8 Moreover, C−CN bond transfer
insertion into alkynes and olefins mediated by nickel/Lewis
acid cocatalyst was also disclosed (Scheme 1a, path 5).9,10
Recently, Morandi et al. reported an elegant protocol for
catalytic reversible alkene-nitrile interconversion through
controllable transfer hydrocyanation to form a new nitrile
and a new alkene in which HCN was a shuttle reagent
(Scheme 1b).11 Likewise, a Rh-catalyzed anti-Markovnikov
hydrocyanation of terminal alkynes using 2-hydroxy-2-methyl-
propanenitrile as CN source was reported.12
reported.11 Therefore, a general catalytic transformation of an
inert sp3C−CN bond by a low-price metal catalyst is still
highly challenging.1,9,10b,11
Despite these advances, the substrates were usually limited
to sp2C−CN compounds or active benzylic nitriles.5−10,13
Only limited examples on inactive sp3C−CN activation were
Received: September 7, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02854
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Herein, we communicate a new phosphorylation reaction of
nonstrained alkylnitriles sp3C−CN with [P]-H compounds
under mild conditions catalyzed by a nickel catalyst (Scheme
1c). Organophosphorous compounds play a vital role in
organic synthesis, catalysis, pharmaceutical chemistry, agro-
chemistry, material science, and coordination chemistry, and
their synthesis is of current interest.14,15
Scheme 2. Substrate Scope
This reaction was accidently found during extensive studies
on the nickel-catalyzed phosphorylation of aryl nitriles.6h
When 4-(2-cyanoethyl)benzonitrile was allowed to couple with
Ph2P(O)H in the presence of 2.5 mol % NiCl2 and 1.5 equiv of
t-BuOK in dioxane at 120 °C for 16 h, a new phosphorylated
product via sp3C−CN cleavage was produced in 41% yield.
Encouraged by the result, we attempted to achieve the novel
phosphorylation of sp3C−CN bonds by optimizing the
reaction conditions and chose the reaction of 3-phenyl
propanenitrile with Ph2P(O)H as a model. It was found that
nickel catalyst was essential to this reaction. When the reaction
was conducted at 100 °C in the absence of nickel catalyst, only
a trace amount of 3a was detected by GC (Table 1, entry 1).
a
Table 1. Optimization of the Reaction Conditions
temp
yield
b
entry
cat. Ni
base
solvent
dioxane
(°C)
(%)
1
2
3
4
5
6
7
8
−
Ni(cod)2
Ni(cod)2
NiCl2 glyme
NiCl2
NiCl2
NiCl2
NiCl2
NiCl2
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuONa
t-BuOLi
Cs2CO3
t-BuOK
t-BuOK
t-BuOK
t-BuOK
100
100
120
120
120
120
120
120
120
120
120
120
<5
43
99
99
99
23
9
trace
80
93
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
toluene
DMF
a
Reaction conditions: 1 (0.4 mmol), 2 (1.3 equiv 0.52 mmol), 2.5
mol % NiCl2. Unless otherwise noted, all reactions used 1.5 equiv of t-
BuOK as base and dioxane (3.0 mL) as solvent at 16 h for 120 °C;
9
10
11
12
NiCl2
NiCl2
NiCl2
b
isolated yield. Using 2.5 mol % NiCl2·glyme instead of 2.5 mol %
NMP
cyclohexane
53
17
c
d
e
NiCl2. Charging 5.0 mol % IMes·HCl. Using 1.1 equiv of 1. Using
f
3.5 equiv of t-BuOLi instead of 1.5 equiv of t-BuOK. At 140 °C.
Using 10.0 mol % Ni(cod)2, 10.0 mol % 8-hydroxyquinoline (8-
a
Reaction conditions: 1a (0.4 mmol), 2a (1.3 equiv, 0.52 mmol),
g
b
nickel catalyst (2.5 mol %), solvent (3.0 mL), 16 h. GC yields using
dodecane as an internal standard.
HQ), 26 h.
With 2.5 mol % Ni(cod)2, the yield of 3a was dramatically
increased to 43% (Table 1, entry 2). By elevating the reaction
temperature to 120 °C, almost quantitative yield of 3a was
obtained (Table 1, entry 3). Ni(II) salts also served as an
effective catalyst for this reaction (Table 1, entries 4 and 5).
The bases were also screened. When t-BuONa, t-BuOLi, or
Cs2CO3 were used, low yields were obtained under similar
reaction conditions (Table 1, entries 6−8). This reaction also
took place in other solvents with dioxane being the best choice
(Table 1, entries 9−12).
progressed sluggishly under the current conditions (3c). It is
worth noting that phosphorylated product 3j was a key
intermediate for the synthesis of Combretastatin-A4 (CA-4), a
natural cis-stilbene isolated from the bark of African willow tree
Combretum caffrum (Scheme 3).16 Pettit et al. synthesized 3j
via two steps involving (1) formation of benzyl chloride 5 by
Scheme 3. Synthesis of (Z)-Combretastatins A-4
With the optimal conditions in hand, we then investigated
the substrate scope. As shown in Scheme 2, benzylic nitriles, 3-
aryl propanenitriles, 4-phenyl butanenitrile, and even 6-phenyl
hexanenitrile could readily couple with H-phosphine oxides
under the reaction conditions. Thus, benzyl nitriles including
those bearing functional groups were phosphorylated by
diphenyl phosphine oxide to produce the corresponding
organophosphorus compounds 3b−3j. Plausibly due to the
steric hindrance, the reaction of 2-(o-tolyl)acetonitrile
B
DOI: 10.1021/acs.orglett.8b02854
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
the reaction of an expensive aldehyde 4 with moisture sensitive
Ph2PCl and (2) reduction of compound 5 with NaBH4 or
Bu3SnH (Scheme 3).17−19 The overall yield of 3j was less than
50%. By using our method, 3j could be obtained in a high yield
from the commercially available starting materials in one pot.
In addition to the benzylic nitriles, the inert 3-aryl
propanenitriles were also phosphorylated under the current
nickel catalytic conditions. 3-Phenyl propanenitriles and those
with electron-donating groups on the benzene ring served well
to produce the expected phosphine oxides in high yields.
Polycyclic 3-aryl propanenitriles were also applicable to this
reaction. Under the reaction conditions, substrates with
valuable functional moieties such as indole, pyridine, carbazole,
and fluorine were also found to couple readily with H-
phosphine oxides, generating the corresponding organo-
phosphorus compounds in high yields. These results show
potential application of the current reaction in pharmaceutical
and material synthesis. Notably, 4-phenyl butanenitrile and 6-
phenyl hexanenitrile were also successfully phosphorylated by
Ph2P(O)H under the reaction conditions.
Scheme 5. Proposed Mechanism for the Nickel-Catalyzed
Phosphorylation of Inert sp3C−CN Bonds
Combretastatin-A4 as a key step demonstrating well the
potential synthetic value of this new reaction in organic
synthesis.
As for the hydrogen phosphoryl compounds, both aromatic
and aliphatic H-phosphine oxides were applicable to this
reaction. Thus, di(4-methylphenyl)phosphine oxides and di(2-
naphthyl)phosphine oxides coupled with 3-phenyl propane-
nitrile smoothly to produce the corresponding products 3y and
3z in excellent yields, respectively. Dibutylphosphine oxide and
dicyclohexylphosphine oxide also served as highly effective
coupling partners under the reaction conditions.
To our delight, this reaction could be easily conducted at
gram scale without decreasing the reaction efficiency, showing
its practical usefulness of this new reaction. For example, a
mixture of 3-phenyl propanenitrile (10 mmol, 1.3 mL),
diphenylphosphine oxide (13.0 mmol, 2.66 g), NiCl2 (0.25
mmol, 32.5 mg), and t-BuOK (15.0 mmol, 1.67 g) was heated
in dioxane at 120 °C for 16 h (Scheme 4). After removal of the
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02854.
■
S
General information, detailed experimental procedures,
characterization data of products, and copies of H, 31P,
1
19F, and 13C spectroscopies (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: chentieqiao@hnu.edu.cn
*E-mail: libiao-han@aist.go.jp
ORCID
Scheme 4. Gram-Scale Synthesis of 3a
Ji-Shu Zhang: 0000-0002-5497-4455
Tieqiao Chen: 0000-0002-9787-9538
Yongbo Zhou: 0000-0002-3540-8618
Shuang-Feng Yin: 0000-0001-9857-9804
Li-Biao Han: 0000-0001-5566-9017
Notes
The authors declare no competing financial interest.
volatiles in a vacuum, the residues were passed through a short
silica column (eluent: petroleum ether/ethyl acetate) to give
the analytically pure product 3a in 99% yield.
ACKNOWLEDGMENTS
■
On the basis of the literature,6h,9,10b,11 a plausible
mechanism is proposed, as shown in Scheme 5. The precatalyst
NiCl2 is first reduced by a hydrogen phosphoryl compound to
generate the Ni(0) species, which is then oxidatively added to
the sp3C−CN bond, producing intermediate A. With the aid of
a base, compound A subsequently undergoes ligand exchange
with hydrogen phosphoryl compounds to give intermediate B
followed by reductive elimination to produce the desired
products and regenerate the Ni(0) species.
We are grateful for the financial support from NSFC (Nos.
21573064, 21403062, and 21373080), HNNSF 2015JJ3039,
and Fundamental Research Funds for the Central Universities
(Hunan University).
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DOI: 10.1021/acs.orglett.8b02854
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D
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