Synthesis of Acrylonitriles via Mild Base Promoted Tandem Nucleophilic Substitution-Isomerization of α-Cyanohydrin Methanesulfonates

Article abstract of DOI:10.1002/cjoc.202000579

Main observation and conclusion: We have developed an efficient synthesis of acrylonitriles via mild base promoted tandem nucleophilic substitution-isomerization of α-cyanohydrin methanesulfonates with alkenylboronic acids. This transition metal-free protocol works under simple and mild conditions and offers good chemical yields for a wide range of substrates and demonstrates good functional group tolerance. (Figure presented.).

Full text of DOI:10.1002/cjoc.202000579

Chinese Journal
of Chemistry
CJC 中 国 化 学 - An International Journal
Accepted Article
Title: Synthesis of Acrylonitriles via Mild Base Promoted Tandem Nucleophilic
Substitution-Isomerization of α-Cyanohydrin Methanesulfonates
Authors: Shiwen Liu, Lingling Meng, Xiaojun Zeng, Gerald, B. Hammond,* Bo Xu*
This manuscript has been accepted and appears as an Accepted Article online.
This work may now be cited as: Chin. J. Chem. 2020, 38, 10.1002/cjoc.202000579.
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Synthesis of Acrylonitriles via Mild Base Promoted Tandem Nucleophilic
Substitution-Isomerization of α-Cyanohydrin Methanesulfonates
a
a
b
c
b
Shiwen Liu, Lingling Meng, Xiaojun Zeng, Gerald, B. Hammond, * Bo Xu *
a
College of Textiles and Clothing & Key Laboratory for Advanced Technology in Environmental Protection of Jiangsu Province, Yancheng Institute of
Technology, Jiangsu, 224003, China.
b
Key Laboratory of Science and Technology of Eco-Textiles, Ministry of Education, College of Chemistry, Chemical Engineering and Biotechnology, Donghua
University, Shanghai 201620, China.
c
Department of Chemistry, University of Louisville, Louisville, Kentucky 40292, United States.
Cite this paper: Chin. J. Chem. 2019, 37, XXX—XXX. DOI: 10.1002/cjoc.201900XXX
We have developed an efficient synthesis of acrylonitriles via mild base promoted tandem nucleophilic substitution-isomerization of α-cyanohydrin
methanesulfonates with alkenylboronic acids. This transition metal-free protocol works under simple and mild conditions and offers good chemical yields
for a wide range of substrates and demonstrates good functional group tolerance.
Background and Originality Content
couplings[18] of alkenyl or aryl boronic acids have been well
[
19]
[20]
[21]
[22]
explored by groups of Tang, Wang, Huang, Ryu and
Nitriles are important targets and highly useful building blocks
which can be transformed to many functionalities such as
us[ (Scheme 1h).
23]
[1]
[2]
[3]
carboxylic acids , amines
and aldehydes . More
Scheme 1 Literature background.
specifically, acrylonitriles involved in various transformations,
Literature methods for synthesis of acrylonitriles
[
4]
[5]
such as Michael addition , Diels−Alder cycloadditions and
NSO
2
R
CN
Cat.
CN
CN
CN
Wittig-type
reactions
[6]
+
Ar
Ar
cross-couplings . Besides, acrylonitriles remain one of
a) Ar
b) Ar
H
Ph P
3
commonly used monomers for preparation of plastics, acrylic
fibers and polyacrylonitrile.[7] Moreover, the acrylonitrile
Cat.
Heck-type reactions
X
+
CN
motif represents a common structural motif frequently found
in many pharmaceuticals and natural products such as
Entacapone (agent for Pakinson's disease), CC-5079
Cat.
of
CONH
2
C=N-OH
Cat.
Dehydration acrylamides
c)
d)
e)
or
or
oximes
conjugated
+
CN
Cyanation
of alkenyl halides
X
[CN]
(
antitumor agent), Rilpivirine (reverse transcriptase inhibitor)
[
8]
.
Thus, their efficient synthesis has been a longstanding goal
R'
R
R
CN
Cat.
of organic synthesis.
+
R
R' CN
of
Cyanation alkynes
Traditional methods for the synthesis of acrylonitriles are
CN
Ar
Literature methods for cross-coupling of -cyanohydrin sulfonates
tBuOK
[
9]
addition
based on the classical Knoevenagel condensations, Wittig-
f)
R
+
Alkyne
Ar
CN
[
10]
type reactions (Scheme 1a), Heck or oxidative Heck-type
[
11]
α
reactions
conjugated oximes (Scheme 1c),
(Scheme 1b), dehydration of acrylamides or
[
12]
CN
CN
cyanation of alkenyl
Pd cat.
+
Ar B(OH)
[
13]
[11c,
g)
R
OTf
2
H2
O,
KF, toluene
R
Ar
halides (Scheme 1d), cyanation of alkynes (Scheme 1e
)
14]
[15]
and allylic cyanation. However, these methods usually
B(OH)
2
R
h) R-X
+
base or acid
suffer from poor substrate scope and/or low E/Z selectivity.
Recently, Jiang and coworkers reported an efficient base
promoted addition of arylacetonitriles to terminal alkynes[
X = leaving groups
e.g. -Br, -OMs,
-OTf
16]
This work
(Scheme 1f), providing a straightforward and transition metal-
Synthesis of acrylonitriles via tandem nucleophilic substitution-isomerization
mild
free protocol for the preparation of acrylonitriles although
strong base (KOtBu) was needed. On the other hand, Pd
catalyzed Suzuki cross-coupling of organoboronic acids with α-
cyanohydrin triflates has been reported by Falck and
CN
CN
CN
base
i)
+
base
B(OH)
2
R
Ar
R
Ar
OMs
Ar
R
1
2
H
A
3
Based on these pioneering works, we envisioned a new
synthesis of acrylonitriles via tandem nucleophilic
[17]
coworkers (Scheme 1g). Also metal-free Suzuki type cross-
a
Chin. J. Chem. 2018, 36, 587－593© 2018 SIOC, CAS, Shanghai,
&
WILEY-VCH Verlag GmbH
&
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substitution-isomerization protocol (Scheme 1i). First, a mild Diverse alkenylboronic acids could couple with α-cyanohydrin
base promoted nucleophilic substitution of α-cyanohydrin methanesulfonate 1a smoothly in moderate to excellent yields
methanesulfonates by alkenylboronic acids generates (Table 2, 3a
intermediate , then a base promoted isomerization leads positions of the phenyl ring in
to the formation of acrylonitriles . Due to only mild bases are (Table 2, 3c 3d 3h), alkyl (Table 2, 3b), high yields were
needed, this tandem protocol may offer wide substrates scope obtained regardless. Besides, alkenyl boronic acids
–
3l). For substituents at the ortho, meta or para
, including halides (F, Cl and Br)
A
A
2
3
–
,
2
and good functional group tolerance.
containing a thiophene, benzothiophene, benzofuran or
fluorene moieties (Table 2, 3e 3k 3l 3ad) all are suitable
substrates. For electron-donating substituents at the phenyl
ring in (Table 2, 3j 3ae), good yields were obtained while
electron-withdrawing substituents like COOMe or CF led to
sluggish reactions due to their low nucleophilicity (Table 2, 3f
).
,
,
,
Results and Discussion
As shown in Table 1, firstly, we investigated the reactions of α-
CN benzyl electrophiles (1a-1c) containing various leaving
groups with alkenylboronic acid 2a in the presence of weak
2
,
3
,
3
g
3 4
base K PO at room temperature. Both bromide 1a and
Table 2. Scope for synthesis of acrylonitriles. a
tosylate 1b did not give any product. To our delight, the
coupling product 3a was obtained in 89% yield when α-
cyanohydrin methanesulfonate 1c was used. On the other
hand, no reaction occurred when less reactive alkenylboronic
ester 2b or potassium alkenyltrifluoroborate 2c was used.
Screening of bases of different strength revealed that weaker
CN
PO4, Tol
3
CN
K
+
B(OH)
2
R
60 oC, 12 air
h,
Ar
OMs
Ar
R
1
2
3
CN
Br
CN
CN
CN
CN
Cl
S
Ph
Ph
Ph
Ph
Ph
Ph
3e, 73 %
3
a, 83 %a
3b, 82 %
3c, 78 %
3d, 80 %
2 3 3 4
bases (K CO , NaF, KF, K PO ) could give moderate to good
yields and were better than stronger bases (tBuOK, NaOMe)
probably due to the strong binding effect to the cation.
Besides, comparison of different cations showed that the
transformation hardly proceeded when using LiF as base.
Moreover, changing the solvent from low polar solvents to
more polar solvents such as DMF, THF resulted in significant
CN
CN
CN
R = COOMe, 0, 3f
R = CF
, 16 %, 3g
R = F, 74 %, 3h
R = Me, 86 %, 3i
R = OMe, 89 %, 3j
3
O
S
Ph
Ph
Ph
R
3
k, 66 %
3l, 59 %
CN
CN
CN
R = F, 79%, 3m
R
=
Cl, 82 %,
3n
R = Br, 81 %, 3o
decrease of the chemical yields.
Table 1. Optimization of reaction conditions. a
R
O
O
N
3
3p,
83 %
3q, 79 %
CN
CN
CN
R = Me, 87%, 3r
R = OBn, 72%, 3s
Ph
CN
CN
=
+
base
=
2, 2a
[B] B(OH)
R
OTBS, 67 %, 3t
Ph
R = OBz, 51 %, 3u
F
=
2b
Ph
X
[B]
[B] Bpin,
BF2
K,
solvent,
60 oC, air,12 h
Ph
Ph
R
O
O
N3
3w, 76 %
=
2c
OTs
[B]
1
2
3a
3v, 69 %
CN
Cl
CN
Cl
CN
Br
yield(%)b
Cl
entry
X
2
base
solvent
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DCE
Cl
OMe
F
1
Br
2a
2a
2a
2b
2c
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
K
3
K
3
K
3
K
3
K
3
K
2
PO
PO
PO
PO
PO
4
4
4
4
4
0
0
3x, 89 %
y,
58 %
3
3z, 76 %
2
3
4
5
6
7
8
9
OTs
OMs
OMs
OMs
OMs
OMs
OMs
OMs
OMs
OMs
OMs
OMs
OMs
OMs
OMs
CN
CN
CN
89
0
MeO
MeO
MeO
S
OMe
OMe
OMe
0
OMe
3
aa, 71 %
3ab, 75 %
3ac, 81 %
CN
CO
3
76
8
CN
CN
LiF
Ph
Ph
3
af, 0
NaF
KF
59
79
44
65
53
45
67
32
0
OEt
Cl
Br
O
3ad, 88 %
3ae, 69 %
O
NC
1
0
CsF
O
O
CN
1
1
NaOH
NaOMe
KOtBu
O
a
O
Ph
1
2
3
O
3
ag, 54 %
3ah, 0
1
o
Conditions: 1 (0.1 mmol), 2 (0.15 mmol), K PO (0.2 mmol) in toluene (1 mL), 60 C,
3
4
1
2 h. All yields are isolated yields.
1
4
K
K
K
3
3
3
PO
PO
PO
4
4
4
1
5
THF
1
6
DMF
Next, we aimed to investigate the scope of α-cyanohydrin
methanesulfonate . For halogen substituents (F, Cl and Br) at
para positions of the phenyl ring in (Table 2, 3m 3o), good
a
Conditions: 1 (0.1 mmol), 2 (0.15 mmol), base (0.2 mmol) in solvent (1 mL), 60℃,
1
b
1
2 h. All yields are determined by GC-MS.
1
–
With the optimized reaction conditions in hand, we examined
the substrate scope of acrylonitrile synthesis (Table 2).
Firstly, we investigated the scope of alkenylboronic acids.
yield was obtained. Besides, the reaction system tolerated
diverse functional groups including methyl, allyl, benzyl, azide,
tosylate, benzoyl and silyl groups (Table 2, 3p–3w).
3
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Running title
Chin. J. Chem.
Additionally, disubstituted α-cyanohydrin methanesulfonates transformation. Besides, under the optimized conditions,
were also suitable substrates (Table 2, 3y–3ac). Moreover, compound 4a can be converted into 3a in 60% yield, which
even for
1 containing complex natural product like skeleton suggested that nucleophilic substitution product 4a was
(Table 2, 3ag), this protocol also worked very well. However, formed firstly in this transformation, and then was
aliphatic α-cyanohydrin methanesulfonates (Table 2, 3af) and transformed into more stable acrylonitriles 3a
alkyl alkenylboronic acid (Table 2, 3ah) did not work under
.
same conditions due to less reactivity.
Table 3. Scope for synthesis of α-alkenyl nitriles. a
Based on above experimental results, we propose a possible
mechanism (Scheme 3). Firstly, the base (K PO ) attacks the
3
4
organoboronic acid 2a to form an ate type complex
A
, whose
In this
CN
CN
3
K PO
4
+
Ar2
B(OH)
2
[24]
anionic nature leads to enhanced nucleophilicity.
Ar1
OMs
Ar1
Ar2
rt, 12 air
h,
1
2
4
+
process, K plays an important role in the formation of ion pair
CN
CN
CN
organic compound intermediate
A. On the other hand,
MeO
Ph
Ph
formation of ion pair organic compound intermediate
A
could
a, 56 %a
F
4c, 57 %
OMe
4
4b, 51 %
enhance the nucleophilicity of alkenyl boronic acids. Then
3
complex
intermediate
base, a deprotonation/isomerization/protonation of
A
reacting with the sp -carbon electrophile 1a to give
CN
CN
CN
4
via a S
N
2 pathway. Then, in the presence of
gives
Cl
4
Br
Br
F
4
d, 48 %
4e, 43 %
the thermodynamic product 3a. Remarkably, only (Z)-2, 3-
disubstituted acrylonitriles could be obtained without any (E)-
isomers, probably due to the steric effect of aromatics.
4
f, 45 %
a
Conditions: 1 (0.1 mmol), 2 (0.15 mmol), K PO4 (0.2 mmol) in toluene (1 mL), rt,
2 h. All yields are isolated yields.
3
1
Scheme 3 Proposed mechanism.
Remarkably, diverse coupling products
room temperature (Table 3). These results indicated that
acrylonitriles were probably transformed from coupling
products . It should be also noted that our metal-free
4 were obtained at
CN
OMs
K
Ph
3
K PO
4
1a
3
Ph
Ph
O
B(OH)
2
B
PO K
3
2
2a
HO
4
OH
protocol is orthogonal towards the classic transitional metal
catalyzed Suzuki reaction. For example, reactive aryl bromides
A
(
Table 3, 4d, 4e) showed no reactivity towards alkenylboronic
CN
H
CN
CN
CN
proton
acids in our conditions.
Ar
R
Ph
Ph
Ar
R
Ar
R
3a
4
3
K PO
4
Scheme 2. Investigation of reaction pathways.
NC
Additionally, our methodology can be used in larger scale
synthesis without complications (Scheme 4). Also the obtained
Ph
CN
CN
N
PO
+
Ph
+
a) Ph
OMs
B(OH)
2
Ph
Ph
3a can be selective reduced to give 6a in 79% yield using the
N
1a
2a
toluene, K
o
3
4
3a, 88%
[25]
60
C, 12 h
5, 0%
simple reductant - NaBH
4
.
Moreover, the epoxidation of 3a
led to the formation of an epoxide 5a in 65% yield.[
26]
CN
OMs
CN
+
Ph
Ph
TEMPO, K PO4
3
b) Ph
B(OH)
2
Ph
Ph
Ph
Ph
Scheme 4 Gram-scale synthesis and further synthetic manipulations.
toluene, 60 oC, 12 h
3a, 84%
1a
2a
2a
CN
+
Ph
B(OH)2
Ph
OMs
CN
OMs
CN
+
1a 5 mmol, 1.06 g) 2a 7.5 mmol, 1.11 g)
1
8-Crown-6, K
3
PO
4
(
(
c) Ph
d) Ph
B(OH)
2
toluene, 60 oC, 12 h
1a
3
a, trace
K PO toluene, 60 oC, 12 h
,
3
4
CN
CN
CN
CN
m-CPBA
K PO
CN
3
4
Ph
Ph
NaBH4
Ph
toluene, 60 oC, 12 h
Ph
Ph
Ph
Ph
75 %)
Ph
Ph
4a
3a, 60%
O
3
a
(0.82 g,
5
a, 65 %
6a, 79 %
Then, we moved our focus to the investigation of possible
reaction pathway (Scheme 2). The reaction was not affected
by both TEMPO (a radical quencher) and N-methylindole (an
(Scheme 2, a-b). These
results indicated that both radical intermediate or cationic
intermediate were not likely and the reaction may not go
Conclusions
In conclusion, we have developed an efficient cross-coupling
between alkenylboronic acids and α-cyanohydrin
methanesulfonate. Acrylonitriles can be accessed under
simple and mild conditions with good chemical yields and
good functional group tolerance for a wide range of
substrates. Other transition metal-free systems are currently
electron-rich aromatic) [
19a,
20, 22a]
through a radical mechanism or a S
Furthermore, only trace product was detected when using K
chelator (18-crown-6) (Scheme 2, c), which indicated that K
N
1 like mechanism.
+
+
played an extremely important role, even participating in this
Chin. J. Chem. 2019, 37, XXX－XXX
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First author et al.
being investigated in our laboratory and will be communicated
in due course.
[4]
a) F. F. Fleming, Q. Wang, Unsaturated Nitriles:ꢀ Conjugate
Additions of Carbon Nucleophiles to a Recalcitrant Class
of Acceptors, Chemical Reviews 2003, 103, 2035-2078; b)
A. P. Prakasham, M. K. Gangwar, P. Ghosh, Michael
addition of cyclic β-oxo ester and α-methyl cyano ester
substrates with activated olefins by iron complexes of
benzimidazole derived N-heterocyclic carbene ligands,
Journal of Organometallic Chemistry 2018, 859, 106-116;
c) A. Kowalkowska, A. Jończyk, J. K. Maurin, Domino
Reaction of Pyrrolidinium Ylides: Michael Addition/[1,2]-
Stevens Rearrangement, The Journal of Organic
Chemistry 2018, 83, 4105-4110.
Experimental
Procedure for cross-coupling reaction: An oven-dried vial was
charged with α-cyano methanesulfonate (0.1 mmol),
3 4
alkenylboronic acids (0.15 mmol), K PO (0.2 mmol). Tol (1 mL)
was added and the mixture was stirred at 60 centigrade for 12
h under air. After that, water were added and the aqueous
phase was extracted with ethyl acetate (3 x 3 mL). The
combined organic layers were dried over Na SO and then
2 4
concentrated. The crude product was purified by silica gel
column chromatography.
Acknowledgement
[
[
5]
6]
S. K. Chittimalla, C.-C. Liao, Diels–Alder reactions of
masked o-benzoquinones with acrylonitrile, Tetrahedron
We are grateful to the Scientific Research Foundation of
Yancheng Institute of Technology (No. 1542036), the National
Science Foundation of China for financial support (NSFC-21472018)
and the National Science Foundation (NSF, Grant CHE-1401700) and
Open Fund of Jiangsu Collaborative Innovation Center for Ecological
Building Material and Environmental Protection Equipments and
Key Laboratory for Advanced Technology in Environmental
Protection of Jiangsu Province (No.JH201832) and Funding for
School-Level Research Projects of Yancheng Institute of Technology
2
003, 59, 4039-4046.
N. Kise, Y. Hamada, T. Sakurai, Electroreductive coupling
of aromatic ketones, aldehydes, and aldimines with α,β-
unsaturated esters: Synthesis of 5-aryl substituted γ-
butyrolactones and lactams, Tetrahedron 2017, 73, 1143-
(1542036).
1
156.
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Manuscript received: XXXX, 2019
Manuscript revised: XXXX, 2019
Manuscript accepted: XXXX, 2019
Accepted manuscript online: XXXX, 2019
Version of record online: XXXX, 2019
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© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2019, 37, XXX－XXX

Running title
Chin. J. Chem.
Entry for the Table of Contents
Page No.
Synthesis of acrylonitriles via mild base
promoted tandem nucleophilic substitution-
isomerization
of
α-cyanohydrin
methanesulfonates
mild
base
CN
OMs
CN
H
CN
base
+
B(OH)
2
R
Ar
Ar
R
Ar
R
3
Synthesis of acrylonitriles via tandem nucleophilic substitution-isomerization.
Shiwen Liu, Lingling Meng, Xiaojun Zeng, Gerald,
B. Hammond, * Bo Xu *.
Chin. J. Chem. 2019, 37, XXX－XXX
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de