Nickel-Catalyzed Cyanation of Unactivated Alkyl Sulfonates with Zn(CN)2

Article abstract of DOI:10.1021/acs.orglett.0c02722

Cyanation of unactivated primary and secondary alkyl mesylates with Zn(CN)2 catalyzed by nickel has been developed. The reaction provides an efficient route for the synthesis of alkyl nitriles with wide substrate scope, good functional group tolerance, and compatibility with heterocyclic compounds. Mechanistic studies indicate that alkyl iodide generated in situ serves as the reactive intermediate and the gradual release of alkyl iodide is crucial for the success of the reaction.

Full text of DOI:10.1021/acs.orglett.0c02722

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Letter
Nickel-Catalyzed Cyanation of Unactivated Alkyl Sulfonates with
Zn(CN)2
Aiyou Xia, Peizhuo Lv, Xin Xie, and Yuanhong Liu*
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ABSTRACT: Cyanation of unactivated primary and secondary
alkyl mesylates with Zn(CN)2 catalyzed by nickel has been
developed. The reaction provides an efficient route for the synthesis
of alkyl nitriles with wide substrate scope, good functional group
tolerance, and compatibility with heterocyclic compounds. Mecha-
nistic studies indicate that alkyl iodide generated in situ serves as the
reactive intermediate and the gradual release of alkyl iodide is crucial
for the success of the reaction.
Scheme 1. Transition-Metal Catalyzed Coupling Reactions
of Unactivated Alkyl Electrophiles
ransition-metal-catalyzed cross-coupling reactions have
attracted great attention owing to their high selectivity
T
and efficiency in the construction of carbon−carbon and
carbon−heteroatom bonds under environmentally friendly
conditions.1 Usually, aryl electrophiles such as aryl halides
and phenol derivatives, including sulfonates, phosphates,
ethers, carbamates, carbonates, etc., have been employed as
the electrophiles. Compared with aryl electrophiles, the
coupling reactions of alkyl electrophiles are generally more
challenging due to the low tendency of oxidative addition and
the facile β-hydride elimination from alkylmetal intermediates.2
In recent years, great progress has been achieved in metal-
catalyzed cross-coupling reactions with alkyl halides. For
example, alkyl halides have been found to couple well with
Grignard reagents,3a,b organoboranes,3c,d organozinc,3e,f orga-
nosilicon,3g3h organotin,3i,j organozirconium reagents,3k
B2pin2,3l,m etc. under transition metal catalysis (Scheme 1a).3
On the other hand, nitriles are versatile and efficient building
blocks in organic chemistry as well as in medicinal chemistry.4
Transition-metal-catalyzed cyanation of alkyl electrophiles
would be one of the most promising methods for the synthesis
of alkyl nitriles. However, such reports are quite limited. To
the best of our knowledge, there are only two examples
involving the metal-catalyzed cyanation of unactivated alkyl
electrophiles.5,6,7a Fu and coworkers developed a copper-
catalyzed and photoinduced cyanation of unactivated alkyl
halides using TBACN (tetrabutylammonium cyanide) as the
cyanide source (Scheme 1b).6 Recently, we found that nickel
could catalyze the cyanation7 of unactivated secondary alkyl
halides with Zn(CN)2 in the presence of DMAP and n-Bu4NCl
under thermal conditions (Scheme 1b).7a Reactions of primary
alkyl chlorides or bromides with Zn(CN)2 were found to occur
at generally high temperature (140 °C) without the need for
nickel catalyst.7a Although these reactions are effective,
methods for the preparation of alkyl halides are not always
satisfactory. Alkyl halides are usually prepared through
halogenation of the corresponding alcohols; however, in
some cases, it suffers from low yields of the products and
difficulty in separating the desired products from the
Received: August 14, 2020
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© XXXX American Chemical Society
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A

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byproducts.8 In this context, alkyl sulfonates are more
attractive than alkyl halides for cross-coupling reactions
because these compounds can be readily prepared from the
easily available alcohols in generally high yields. Inspired by
our previous work, we expected that alkyl sulfonates might also
serve as efficient electrophiles for cyanation reactions. It was
noted that alkyl sulfonates have rarely been used in nickel-
catalyzed cross-coupling reactions,9 possibly due to their low
tendency to engage in a SET process that usually operate with
alkyl halides. In this paper, we report the first example of
nickel-catalyzed cyanation of alkyl sulfonates using Zn(CN)2 as
the cyanide source owing to its relatively lower toxicity
(intraperitoneal, LD50 = 100 mg kg−1,10a compared with
NaCN, KCN,10b intraperitoneal, LD50 = 4.72−5.55 mg kg−1)10
and low solubility in organic solvents which was beneficial to
mitigate catalyst poisoning by cyanide ions (Scheme 1c). The
method also avoids the use of highly toxic reagents such as
MCN (M = Na, K) as the cyanide source.11 Although these
reagents could be used for cyanation of alkyl sulfonates, the
systematic studies on these reactions are quite rare. In some
cases, the reactions suffer from an excess of cyanide,11a,b
serious side reactions,11c and low yields.11d,e
Table 1. Optimization of the Reaction Conditions
Our investigation commenced with the nickel-catalyzed
cyanation of 1-tosylpiperidin-4-yl methanesulfonate 1a as the
model substrate. Initially, the reactions were examined under
the conditions for cyanation of alkyl chlorides or bromides
(NiCl2·6H2O/Xantphos/Zn/DMAP/n-Bu4NCl or Ni(acac)2/-
Xantphos/DMAP/Zn) reported in our previous paper.7a
However, trace or no desired cyanation products were
observed. The effects of nickel catalysts, ligands, reductants,
additives, solvents, substrate concentration, etc. on the reaction
were then studied, and the detailed results are shown in the
Supporting Information. Finally, we were pleased to find that
the desired reaction took place smoothly to give the alkyl
nitrile 2a in 88% yield at 100 °C using NiCl2·6H2O/Xantphos
as the catalyst system in the presence of 40 mol % zinc powder
(Adamas, 325 mesh), 1.0 equiv DMAP, and 3.0 equiv n-Bu4NI
(Table 1, entry 1). Zinc acts as a reductant to reduce Ni(II). It
was found that the additive of n-Bu4NI played a key role in this
reaction because, without n-Bu4NI, no desired product was
observed (entry 2). The use of n-Bu4NBr as the additive
afforded 2a in low yield, along with the formation of 4-bromo-
1-tosylpiperidine, alkene 4a, and dehalogenated product 6a as
the byproducts (entry 3). The results indicated that alkyl
bromide might act as the active intermediate under this
condition. When n-Bu4NCl was added, the corresponding alkyl
chloride was formed in 84% yield (entry 4). No product was
found in this case, possibly due to the lower reactivity of the
alkyl chloride toward cyanation compared with alkyl bromide.
Based on these results, we assumed that alkyl iodide might be
produced in the presence of n-Bu4NI,9d,12 which should be
more reactive than alkyl bromides or alkyl chlorides. n-Bu4NI
might also act as a phase transfer reagent to promote the
cyanide ion entering into the organic phase. When KI was
employed instead of n-Bu4NI, the yield of 2a decreased to 41%
(entry 5). Reducing the amount of n-Bu4NI to 2.0 equiv
caused an erosion in yield (entry 6). Without DMAP, 2a was
formed in 67% yield, along with the formation of alkene 5a and
dehalogenated product 6a, indicating that DMAP could
effectively reduce the side reactions (entry 7 vs entry 1).
DMAP may also promote cyanide ion dissociation through the
formation of a DMAP-Zn(CN)2 complex and acts as a
coligand as well.7b The use of 4-aminopyridine or Cs2CO3
a
Determined by 1H NMR using 1,3,5-trimethoxybenzene as an
b
c
internal standard. Isolated yield. 4-Bromo-1-tosylpiperidine was
formed in 28% yield. 4-Chloro-1-tosylpiperidine was formed in 84%
yield.
d
instead of DMAP afforded 2a in similar yields (82−85%,
entries 8−9). NiCl2(DME) or NiCl2 could also catalyze this
reaction, albeit with lower yields of 60−72% (entries 10 and
11). Other bidentate phosphine ligands such as dppf gave 2a in
74% yield, while the use of PCy3 or 2,2′-bpy was not effective
(entries 12−14). Control experiments indicated that NiCl2·
6H2O, Xantphos, and Zn were indispensable (entries 17−19).
Alkyl tosylate was also compatible for this reaction, while no
desired products were observed using alkyl acetate or benzoate
as the substrates (entries 20 and 21).
We next studied the substrate scope of this new cyanation
reaction under the best reaction conditions (Table 1, entry 1).
The results are shown in Scheme 2. Boc- or CO2Et-protected
piperidin-4-yl methanesulfonates could be cyanated efficiently
in 88−90% yields (2b−2c). Cyclic substrates bearing benzene-
fused five- or six-membered rings coupled smoothly with
Zn(CN)2 (2d−2e). Substrate 1f containing a ketal moiety
could be successfully converted to 2f in 82% yield. Cyanation
of 1g bearing a large-sized ring afforded 2g in low yield (24%).
When the optically pure alkyl sulfonate 1h derived from the
nature product was used as the substrate, a mixture of two
diastereomers (2h) was produced. The results revealed that
the radical species might be generated during the reaction.
Next, the reactivity of acyclic alkyl mesylates was investigated.
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the standard conditions for 2a, the nitrile 9a was formed in
only 39% yield (Scheme 3, eq 2). Further optimization,
including the change of the catalyst, ligands, and additives,
could not improve the yield of 9a,13 possibly due to the low
efficiency of the radical production from the primary alkyl
iodide intermediates. To our delight, lowering the reaction
temperature to 80 °C increased the yield of 9a to 54%.
Possibly, at the lower reaction temperature, the side reactions
such as dehydroiodination could be reduced.
Scheme 2. Nickel Catalyzed Cyanation of Secondary Alkyl
Mesylates
a
Under the best reaction conditions for 9a, the scope of
various primary alkyl mesylates was examined (Scheme 4).
Scheme 4. Nickel Catalyzed Cyanation of Primary Alkyl
a
Mesylates
a
b
Isolated yields. [Substrate] = 0.2 M. β-Cholestanol methanesulfo-
c
nate was used as the substrate. 1-(4-Bromophenyl)propan-2-yl
methanesulfonate was used. 80 °C, 24 h.
d
Linear alkyl mesylates bearing aryl rings were well-suited for
this reaction (2i−2l). The functionalities on the aryl rings such
as −OMe or −CF3 were tolerated. Mesylate 1m (1-(4-
bromophenyl)propan-2-yl methanesulfonate) containing an
aryl bromide moiety converted to alkene 7 in 31% yield,
indicating that dehydromesylation and cyanation of the
C(sp2)−Br bond occurred in this case. Alkyl ethers with an
OTBS or a benzyl group also worked well, affording 2n−2o in
68−70% yields. Under the standard conditions, substrate 1p
bearing an indole substituent afforded 2p in only 27% yield. By
lowering the reaction temperature to 80 °C, the yield of 2p
could be improved to 53%. Substrate 1q with an amino group
afforded 2q in 31% yield at 80 °C.
Encouraged by the above results, we next examined the
reactivity of primary alkyl mesylates. We have found that
primary alkyl halides could be cyanated directly without the
need for nickel catalyst.7a However, when 8a was subjected to
our previous reaction conditions,7a only 26% of 9a was
obtained (Scheme 3, eq 1, with n-Bu4NCl). Changing the n-
Bu4NCl to n-Bu4NI could not improve the yield of the
product. After treatment of mesylate 8a with Zn(CN)2 under
a
b
Isolated yields. Determined by 1H NMR using 1,3,5-trimethox-
c
ybenzene as an internal standard. 2.0 equiv of NaHCO3 instead of
d
e
DMAP was used. 100 °C, 19 h. Ten mol % NiCl2·6H2O and 12 mol
% Xantphos instead of 5 mol % NiCl2·6H2O and 6 mol % Xantphos
f
were used. 60 °C, 26 h.
Substrates tethered with an aryl ring such as methylenedioxy-
substituted phenyl or 1-naphthyl group transformed to 9b and
9c in higher yields of 72−75%. In the case of 9d with an amide
functionality, better yield was obtained (72%) using 2.0 equiv
NaHCO3 instead of DMAP. Adamantine-bearing alkyl
mesylate gave the desired 9e in 79% yield. 8f derived from
(−)-Corey lactone benzoate containing an ester substituent
afforded 9f in 67% yield, while the -OBz group remained
unchanged. When substrate 8g with a pyridyl ring was
employed, the nitrile 9g was formed in 58% yield. Raising
the temperature from 80 to 100 °C did not improve the
product yield. To our delight, through increasing the amounts
of catalyst and ligand, 9g could be formed in 66% yield. A
furanyl-substituted alkyl mesylate was also cyanated smoothly
(9h). Substrates tethered with various functional groups such
as -OPh, -indolyl, and amide groups also worked well (9j−9l).
To gain insight into the reaction mechanism, various control
experiments were carried out (Scheme 5).13 The reaction of 1a
with n-Bu4NI afforded 59% of alkyl iodide 3a and 25% of
alkene 4a after 5 h (Scheme 5, eq 1). In the presence of
Scheme 3. Cyanation Reaction of 8a
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diphenylethylene) inhibited the reaction, suggesting that a
radical process might be involved (Scheme 5, eq 4). The above
investigation suggests that the present reaction may proceed
through the first formation of an alkyl iodide followed by
nickel-catalyzed cyanation reaction through the Ni(I)/Ni(III)
catalytic cycle proposed in our previous work.7a
Scheme 5. Mechanistic Studies
In summary, we developed a facile approach for the
synthesis of alkyl nitriles via nickel-catalyzed cyanation of
unactivated alkyl sulfonates. Given the importance of the nitrile
compounds in chemistry and biology, the method might find
wide utility in pharmaceutical preparations and drug develop-
ment. Mechanistic studies indicate that the in situ-generated
alkyl iodide serves as the reactive intermediate, and the gradual
release of alkyl iodide plays an important role for the success of
the reaction. Further investigations on the detailed reaction
mechanism and application of this chemistry are in progress.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02722.
Experimental details and spectroscopic characterization
of all new compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Yuanhong Liu − State Key Laboratory of Organometallic
Chemistry, Center for Excellence in Molecular Synthesis,
Shanghai Institute of Organic Chemistry, University of Chinese
Academy of Sciences, Chinese Academy of Sciences, Shanghai
200032, People’s Republic of China; orcid.org/0000-0003-
1153-5695; Email: yhliu@sioc.ac.cn
Zn(CN)2, 3a was observed in 49% yield after 10 h, along with
43% of 4a, while cyanation product 2a was not formed
(Scheme 5, eq 2). 4a was not observed without n-Bu4NI,
indicating that 4a should be formed during the iodination
process. The results implied that alkyl iodide might be the
active intermediate of the cyanation reaction. However, the
nickel-catalyzed reaction of alkyl iodide 3a with Zn(CN)2
under the standard conditions gave 2a only in low yield, along
with the formation of 4a and 6a (Scheme 5, eq 3). We initially
speculated that the excessive iodide ions in the reaction
mixture might deactivate the nickel catalyst, thus lowering the
reaction efficiency. To verify this point, the effect of the
amount of n-Bu4NI was investigated. Similar yield was
observed by reducing the amount of n-Bu4NI to 0.5 equiv,
while the yield was slightly improved without n-Bu4NI (2a,
17%), and in both cases, cyanation product 2a′ could also be
observed. 2a′ might be formed via hydrocyanation of 4a. A
large amount of side products were observed in the above
reactions. These results indicated that in the presence of
stoichiometric amount of alkyl iodide, the side reactions such
as dehydroiodination or hydrodeiodination reactions were
significant increased. Interestingly, when the iodide 3a was
added in four portions to the reaction mixture, the yield of 2a
could be improved to 75%. Thus, it was concluded that the low
concentration of the alkyl iodide is crucial for the success of
the cyanation reactions due to the reduced side reactions. To
maintain the low concentration of the alkyl iodide, it is possible
that alkyl iodide participates the cyanation rapidly once it was
generated. In fact, the alkyl iodide was not detected after
stirring the mixture at 100 °C for 1 h under the standard
reaction conditions for 2a. Addition of a radical scavenger
TEMPO (2,2,6,6-tetramethylpiperidinooxy) or BPE (1,1-
Authors
Aiyou Xia − State Key Laboratory of Organometallic Chemistry,
Center for Excellence in Molecular Synthesis, Shanghai Institute
of Organic Chemistry, University of Chinese Academy of
Sciences, Chinese Academy of Sciences, Shanghai 200032,
People’s Republic of China
Peizhuo Lv − State Key Laboratory of Organometallic
Chemistry, Center for Excellence in Molecular Synthesis,
Shanghai Institute of Organic Chemistry, University of Chinese
Academy of Sciences, Chinese Academy of Sciences, Shanghai
200032, People’s Republic of China
Xin Xie − State Key Laboratory of Organometallic Chemistry,
Center for Excellence in Molecular Synthesis, Shanghai Institute
of Organic Chemistry, University of Chinese Academy of
Sciences, Chinese Academy of Sciences, Shanghai 200032,
People’s Republic of China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02722
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Key Research and Development
Program (2016YFA0202900), the National Natural Science
Foundation of China (21772217), the Science and Technology
Commission of Shanghai Municipality (18XD1405000), and
D
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the Strategic Priority Research Program of the Chinese
Academy of Sciences (XDB20000000) for financial support.
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