Organo-catalyzed Michael addition of 2-fluoro-2-arylacetonitriles

Article abstract of DOI:10.1016/j.tetlet.2021.152919

An efficient synthesis of a variety of 2-arylacetonitriles containing a fluorinated stereogenic center through organo-catalyzed Michael addition reaction of 2-fluoro-2-arylacetonitriles has been developed. This protocol uses a cheap organocatalyst (DBU) and has a broad substrate scope: α, β-unsaturated ketones, esters, nitriles and sulfones were all successfully reacted. Importantly, water proved to be a good solvent for this reaction.

Full text of DOI:10.1016/j.tetlet.2021.152919

Tetrahedron Letters 68 (2021) 152919
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Organo-catalyzed Michael addition of 2-fluoro-2-arylacetonitriles
⇑
De-Yin Chen, Shuai Song, Ling-Yan Chen, Xinfeng Ren, Ya Li
School of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, 333 Longteng Road, Shanghai 201620, China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthesis of a variety of 2-arylacetonitriles containing a fluorinated stereogenic center
through organo-catalyzed Michael addition reaction of 2-fluoro-2-arylacetonitriles has been developed.
Received 21 December 2020
Revised 4 February 2021
Accepted 8 February 2021
Available online 16 February 2021
This protocol uses a cheap organocatalyst (DBU) and has a broad substrate scope:
a, b-unsaturated
ketones, esters, nitriles and sulfones were all successfully reacted. Importantly, water proved to be a good
solvent for this reaction.
Ó 2021 Elsevier Ltd. All rights reserved.
Keywords:
Fluorine
Fluoroalkylation
Conjugate addition
Organocatalysis
Fluorocarbon nucleophile
The introduction of fluorine into organic molecules can often
result in unique physical, chemical, and biological properties [1].
Not surprisingly, fluorine is highly valued in the synthetic and
medicinal communities. Organic molecules that contain a fluori-
nated stereogenic center have attracted a lot of attention because
they are present in many biologically active compounds and phar-
maceuticals [2]. A large number of synthetic methods have been
developed for the synthesis of such compounds bearing a fluori-
nated stereogenic center [1,2]. Among these, the 1,4-addition of
fluorinated Z- and E-enamines was required (Scheme 1b) [6].
Finally, nitro proved to be a good activating group, and the Michael
addition of 2-fluoronitroalkanes to a, b-unsaturated carbonyl com-
pounds, acrylonitrile and nitroalkenes has been reported using an
organic base or RuH2(PPh3)4 as a catalyst (Scheme 1c) [7].
The cyano is an important one-carbon functional group. It can
undergo a multitude of transformations to produce synthetically
important carboxylic acids, amides, amines, aldehydes, and
ketones. Also, the cyano is a strong electron-withdrawing group
and has been frequently used to stabilize a carbanion. Not surpris-
ingly, the use of 2-fluoronitriles as fluorocarbon nucleophiles to
produce fluorinated stereogenic centers has received considerable
attention [8]. For example, an elegant catalytic asymmetric Man-
nich reaction of 2-fluoro-2-phenylacetonitrile with ketimines has
been recently reported [9]. To the best of our knowledge, the use
of 2-fluoro-2-arylacetonitriles in the Michael addition has not been
disclosed. As a continuation of our own interest in the reactivity
and application of fluorocarbon nucleophiles [10], we herein report
the first general use of 2-fluoro-2-arylacetonitriles in the Michael
addition reaction. This reaction uses 1,8-diazabicyclo [5.4.0]
undec-7-ene (DBU) as a catalyst and has a broad substrate scope:
monofluorinated carbanions to a, b-unsaturated Michael acceptors
represents a straightforward and simple approach. Because a fluo-
rinated carbanion is significantly destabilized by the electronic
repulsion between the electron pairs on the small fluorine atom
and the electron lone pair occupying the p-orbital of the carbanion
[3],
a-functionalization of monofluorinated nucleophiles with
strong electron-withdrawing groups has commonly been used to
overcome the problem. To date, many monofluorinated nucle-
ophiles featuring two strong electron-withdrawing groups (such
as nitro, cyano, sulfonyl and carbonyl group) at the germinal posi-
tion to fluorine have been commonly used in the Michael addition
[4]. However, the use of monofluorinated nucleophiles functional-
ized with only one electron-withdrawing group in the Michael
addition reaction is still challenging. For example, the 1,4-addition
of PhSO2CH2F to chalcones using LHMDS at À78 °C gave a mixture
a,b-unsaturated ketones, esters, nitriles, and sulfones are all
suitable substrates (Scheme 1d). In addition, water proved to be
a good solvent for this reaction.
of 1,2- and 1,4-adducts (Scheme 1a) [5].
a-Fluoroacetophenone has
Using 2-fluoro-2-phenylacetonitrile 1a as the Michael donor
and (E)-chalcone 2a as the Michael acceptor, we carried out our
study by the examination of several commercially available
organic bases (Table 1). Using DMAP or DABCO as an organocata-
lyst and DMSO as the reaction solvent, no reaction occurred, with
the starting materials completely recovered (entries 1–2). This
also been successfully used as a Michael donor in the Michael addi-
tion. However, the preactivation of a-fluoroacetophenone to form
⇑
Corresponding author.
E-mail address: ya.li@sues.edu.cn (Y. Li).
https://doi.org/10.1016/j.tetlet.2021.152919
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.

De-Yin Chen, S. Song, Ling-Yan Chen et al.
Tetrahedron Letters 68 (2021) 152919
Scheme 1. The Michael addition of monofluorinated nucleophiles bearing an electron-withdrawing activating group.
Table 1
Optimization of the Michael addition between 2-fluorophenylnitrile 1a and chalcone 2a.a
Entry
Base
Solvent
Time
Yieldd (%)
d.r.e
1
2
3
4
5
6
DMAP
DABCO
K2CO3
TBD
TMG
DBU
DBU
DBU
DBU
DBU
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
Toluene
DMF
24 h
24 h
24 h
0
0
–
–
10
95
90
97
82
95
13
94
83
95
88
97
77:23
70:30
70:30
71:29
72:28
72:28
61:39
69:31
68:32
69:31
70:30
70:30
45 min
60 min
25 min
3 h
60 min
25 min
25 min
25 min
25 min
25 min
25 min
7b
8c
9
10
11
12
13
14
DBU
DBU
DBU
DBU
DCM
THF
MeCN
H2O
a
b
c
The reaction was perfomed with 0.45 mmol of 1a, 0.45 mmol of 2a, and 0.09 mmol of organocatalyst (20 mol %) in 3.0 mL solvent.
10 mol % DBU was used in the reaction, and other reaction conditions remain unchanged.
The reaction was carried out at 5 °C.
Isolated yield.
d
e
d.r. was determined by 19F NMR.
2

De-Yin Chen, S. Song, Ling-Yan Chen et al.
Tetrahedron Letters 68 (2021) 152919
Table 2
Scope of the Michael addition of 1a with respect to the Michael acceptor 2.a
aThe reaction was performed with 0.45 mmol of 1a, 0.45 mmol of 2a, 20 mol % of catalyst and solvent (3.0 mL).
Condition A: DMSO was used as the sole solvent. Condition B: water was used as the sole solvent.
b20 mol % of TMG was used as the base.
indicated that the strength of the bases used was not strong
enough to deprotonate the -H of 1a. The use of inorganic base
albeit with a low diastereoselectivity (around 70:30). Further
a
examination revealed that lowering the catalyst loading to
10 mol % resulted in a decrease of the yield (82%, entry 7). Using
20 mol % DBU, further screening of the reaction variables to
improve the reaction was investigated. Lowering the reaction tem-
perature to 5 °C gave a comparable diastereoselectivity, although
the yield remained high (95%, entry 8). Evaluation of other solvents
including toluene, DMF, DCM, THF and CH3CN demonstrated no
improvements with respect to both the yield and diastereoselectiv-
K2CO3 enabled the reaction to proceed, giving the desired product
3aa in only 10% yield after a 24 h reaction (entry 3). Stronger bases
including 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), 1,1,3,3-
tetramethylguanidine (TMG) and DBU were found to be active (en-
tries 4–6): in the presence of 20 mol % catalyst, the current trans-
formation could be finished in 25–60 min and gave exclusively the
Michael addition product 3aa in an excellent yield (90–97% yield),
3

De-Yin Chen, S. Song, Ling-Yan Chen et al.
Tetrahedron Letters 68 (2021) 152919
Table 3
Scope of the Michael addition reaction with respect to 2-fluoro-2-arylacetonitrile 1.a
a
The reaction was performed with 0.45 mmol of 1a, 0.45 mmol of 2a, 20 mol % of catalyst and solvent (3.0 mL).
Condition A: DMSO was used as the sole solvent. Condition B: water was used as the sole solvent.
Scheme 2. The Michael reaction of a-fluorocarboxylates and a-fluoroketones with acrylonitrile. Condition A: DMSO was used as the sole solvent. Condition B: water was
used as the sole solvent.
ity (entries 9–13). Finally, water proved to be a suitable solvent,
and the use of water gave product 3aa in an excellent yield of
97% with a diastereoselectivity of 70:30 (entry 14).
With two sets of optimized reaction conditions in hand (entries
6 and 14), we then checked the substrate scope of the reaction with
rated ketones (2a–2e), esters (2f–2j), nitriles (2k and 2l) and sul-
fones (2m and 2n) all reacted with 1a to give the desired
product 3 in good to excellent yields. For the chalcones, the intro-
duction of either an electron-donating (2b and 2d) or electron-
withdrawing substituent (2c) at the aromatic rings gave
a
regard to the Michael acceptors. As shown (Table 2),
a,b-unsatu-
decreased yield (3ab, 58–61% yield; 3ac, 50–74% yield; 3ad, 72–
4

De-Yin Chen, S. Song, Ling-Yan Chen et al.
Tetrahedron Letters 68 (2021) 152919
Scheme 3. Gram-scale synthesis and the transformations of compound 3.
74% yield), indicating that steric hindrance played an important
role in determining the outcome of the reaction. The relative con-
figuration of the major diasteromer of product 3ac was determined
through X-ray crystallography [11]. In the crystal structure, the
vicinal phenyl groups adopt an anti orientation. Vinyl phenyl
ketone 2e also reacted as expected to give product 3ae in a good
3cm, 45% yield). Additionally, the reaction of 2-alkylated 2-fluo-
roacetonitrile 1h was also tried, but failed to give the desired pro-
duct 3hm, with the starting materials left intact. Raising the
reaction temperature to 70 °C resulted in the decomposition of
compound 1h, and this may be caused by the thermal unstable
nature of the corresponding fluorinated carbanion. Based on the
above experiments, we have reason to believe that a synergistic
stabilizing effect of the cyano and phenyl groups in fluorocarbon
nucleophile 1 was important in promoting the Michael addition
of 2-fluoro-2-arylacetonitriles to activated alkenes.
The current protocol can be extended to other fluorocarbon
nucleophiles bearing an acyl group (Scheme 2). Under the same
reaction conditions (Table 3), 2-fluoro-2-phenylacetate (1i), 2-flu-
oro-2-(4-nitrophenyl)acetate (1j), 2-fluoro-2-phenylacetophenone
(1k) and cyclic 2-fluoro-1-tetralone (1l) were all successfully
reacted to give product 3im–3lm in a moderate to good yield
(40–74% yield). In contrast, methyl fluoroacetate (1m) and 2-fluo-
roacetophenone (1n) were unreactive under the reaction condi-
tions, further demonstrating that the stability of the
corresponding fluoroenolates played a vital role in facilitating the
Michael reaction.
yield (55–60% yield). For the above
a,b-enones (except 2c), the
use of DMSO as the reaction solvent (condition A) gave a yield
comparable to that of water (condition B). It is worth noting that
only the 1,4-addition products were observed in the above addi-
tion reactions. In addition, acrylates were found to be good Michael
acceptors (2f–2j), although a longer reaction time was required (2–
5 h). As shown, methyl (2f), phenyl (2g), and benzyl (2h) acrylates
as well as acrylates bearing an ether structural unit (2i and 2j)
were all successfully reacted and gave the corresponding products
3af–3aj in 68–85% yield (Condition A). For the acrylates we exam-
ined, the use of DMSO as the reaction solvent generally gave better
results than the use of water (condition B: 3af–3aj, 46–71% yield).
Additionally, vinyl alkyl sulfones participated in the reaction,
affording products 3ak and 3al in very good yields (61–78% yield).
Finally, acrylonitrile 2m and crotononitrile 2n proved to be compe-
tent substrates, giving the expected products 3am and 3an in mod-
erate to very good yield (condition A: 65–80% yield; condition B:
48–83% yield).
To further investigate the generality of this reaction, acryloni-
trile 2m was used as the Michael acceptor and its addition with
structural diverse 2-fluoro-2-arylacetonitriles were examined
(Table 3). 2-Fluoroarylacetonitriles bearing a methoxyl (1b and
1c), bromo (1d), chloro (1e), cyano (1f), or nitro group (1g) were
all tolerated, leading to the target products 3am–3gm in good to
excellent yields. Substrates bearing an electron-withdrawing
group (such as bromo, chloro and cyano) at the aromatic ring gave
a higher yield (condition A: 3dm–3fm, 80–94% yield) than those
bearing an electron-donating group such as methoxy group (condi-
tion A: 3bm and 3cm, 60–65% yield). A nitro-functionalized 2-flu-
oronitrile 2g also reacted and gave product 3gm in a good yield
(condition A: 67%; condition B: 58%)). For 2-fluoro-2-arylnitriles
bearing a methoxy group (2b and 2c), water proved to be an inap-
propriate solvent and a low yield was obtained (3bm, 35% yield;
To demonstrate the utility of our method for preparing useful
organofluorine compounds, a gram-scale reaction and the diverse
transformations of product 3 were conducted. Using water as the
sole solvent, the Michael addition was carried out with 1.0 g 2-flu-
oro-2-phenylacetonitrile 1a to give 1.18 g of the addition product
3am (85% yield) (Scheme 3a) [12]. Treatment of the thus obtained
compound 3am with H2O2/K2CO3 led to selective oxidation of the
cyano
a to fluorine to deliver the corresponding amide 4 in a very
good yield (86%) (Scheme 3b). The carbonyl group in the addition
product also allows for useful transformations. For instance, com-
pound 3ae was reduced with NaBH4 to give 5-hydroxyl-2-fluoroni-
trile 5 in an excellent yield (92%). When compound 5 was
subjected to HCl/MeOH, a process involving hydrolysis of the
nitrile along with intramolecular dehydration occurred and the
corresponding
a-fluorinated carbonyl ester 6 was obtained in
60% yield (Scheme 3c). Finally, compound 3af could be hydrolyzed
to give 4-fluoro-butanoic acid 7 in a good yield of 62%, with the
cyano group left intact (Scheme 3d).
5

De-Yin Chen, S. Song, Ling-Yan Chen et al.
Tetrahedron Letters 68 (2021) 152919
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In conclusion, we have developed the first organo-catalyzed
Michael addition of 2-fluoro-2-arylacetonitriles to activated alke-
nes, which allows an efficient synthesis of a variety of arylacetoni-
triles containing a fluorinated stereogenic center. This protocol
uses DBU as an organocatalyst and has a broad substrate scope:
a, b-unsaturated ketones, esters, nitriles and sulfones were all
proved to be competent. Besides, water proved to be a good solvent
for this addition reaction.
Declaration of Competing Interest
ˇ
´
bjoc.4.17; (n) M. Urban, M. Franc, M. Hofmanová, I. Císarová, J. Vesely, Org.
Biomol. Chem. 15 (2017) 9071–9076; (o) G.K. Prakash, F. Wang, T. Stewart, T.
Mathew, G.A. Olah, Proc. Natl. Acad. Sci. U.S.A. 106 (2009) 4090–4094; (p) S.
Zhang, Y. Zhang, Y. Ji, H. Li, W. Wang, Chem. Commun. 28 (2009) 4886–4888;
(q) T. Furukawa, N. Shibata, S. Mizuta, S. Nakamura, T. Toru, M. Shiro, Angew.
Chem., Int. Ed. Engl. 47 (2008) 8051–8054.
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
Acknowledgments
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Support of our work by the Natural Science Foundation of
Shanghai (16ZR1413800).
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2021.152919.
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6