Cinnamonitrile as a precursor of a bi-centered electrophile in reactions with arenes in triflic acid

Article abstract of DOI:10.1016/j.tetlet.2019.02.047

The reaction of cinnamonitrile [PhCH = CHCN] with arenes in the superacid TfOH at room temperature for 1 h gave two types of compounds, 3-aryl-3-phenyl propionitriles [Ar(Ph)CHCH₂CN] and/or 3-phenylindanones in 28–76% yield. The formation of these two reaction products depends on the nucleophilicity of the arene. In these reactions, carbocations generated upon the protonation of cinnamonitrile in TfOH behave as bi-centered electrophiles possessing reactive centers on the C3 carbon of the double bond and on the C1 carbon of the nitrile group.

Full text of DOI:10.1016/j.tetlet.2019.02.047

Accepted Manuscript
Cinnamonitrile as a precursor of a bi-centered electrophile in reactions with
arenes in triflic acid
Yelizaveta Gorbunova, Dmitriy N. Zakusilo, Aleksander V. Vasilyev
PII:
S0040-4039(19)30201-1
https://doi.org/10.1016/j.tetlet.2019.02.047
TETL 50641
DOI:
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
6 February 2019
23 February 2019
28 February 2019
Please cite this article as: Gorbunova, Y., Zakusilo, D.N., Vasilyev, A.V., Cinnamonitrile as a precursor of a bi-
centered electrophile in reactions with arenes in triflic acid, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/
j.tetlet.2019.02.047
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Cinnamonitrile as a precursor of a bi-centered electrophile
in reactions with arenes in triflic acid
Yelizaveta Gorbunova,a Dmitriy N. Zakusilo,a,b Aleksander V. Vasilyev*a,b
a Department of Organic Chemistry, Institute of Chemistry, Saint Petersburg State University,
Universitetskaya nab., 7/9, Saint Petersburg, 199034, Russia
b Department of Chemistry, Saint Petersburg State Forest Technical University, Institutsky per., 5,
Saint Petersburg, 194021, Russia
*Corresponding author: A.V. Vasilyev; e-mail: aleksvasil@mail.ru, a.vasilyev@spbu.ru
Keywords: nitriles; indanones; superacids; electrophilic substitution
Graphical Abstract
O
H+
(TfOH)
ArH,
TfOH
NH
N
1.TfOH
2. H2O
Ar
Ph
Ph
N
Ph
R
Ph
9 examples (28-76%)
Abstract
The reaction of cinnamonitrile [PhCH=CHCN] with arenes in the superacid TfOH at room
temperature for 1 h gave two types of compounds, 3-aryl-3-phenyl propionitriles
[Ar(Ph)CHCH2CN] and/or 3-phenylindanones in 28-76% yield. The formation of these two
reaction products depends on the nucleophilicity of the arene. In these reactions, carbocations
generated upon the protonation of cinnamonitrile in TfOH behave as bi-centered electrophiles
possessing reactive centers on the C3 carbon of the double bond and on the C1 carbon of the nitrile
group.
1

Nitriles are an important and useful class of organic compounds. Significant attention has
been paid to the synthesis of these substances1-4 and investigation of their chemical properties.5-16
Among the various chemical transformations of nitriles, are their use as acylation reagents in
electrophilic aromatic substitution under the action of Brønsted or Lewis acids in the Houben-
Hoesch reaction.17,18 Shudo and Ohwada,19-21 and Klumpp22-24 described the effective acylation of
arenes by various nitriles in the Brønsted superacid CF3SO3H (triflic acid, TfOH). However, such
reactions for unsaturated nitriles, for instance, cinnamonitrile (nitrile of 3-phenylpropenoic acid),
have not yet been studied.
Protonation of the nitrile group nitrogen and the C2 carbon of the double bond of
cinnamonitrile in Brønsted superacids may give rise to the corresponding dication A having two
reactive electrophilic centers on the C1 and C3 atoms (Scheme 1). Both of the cationic centers may
participate in reactions with arenes. Thus, cinnamonitrile is a precursor of the highly reactive bi-
centered electrophilic species. Similar dicationic species were generated via the protonation of
various alkenes conjugated with electron-withdrawing groups (enones and other relative structures)
in Brønsted superacids, and were thoroughly studied by NMR.25
NH
H+
N
2
1
3
Ph
Ph
A
Scheme 1. Protonation of cinnamonitrile in Brønsted superacids with the formation of dication A.
Based on our previous work on the electrophilic activation of organic compounds,26,27 we
undertook a study on the superacid-promoted transformations of unsaturated nitriles. This study
focused on investigation of the regioselectivity in transformations of electrophiles generated upon
protonation of this nitrile in the superacid.
The reactions of cinnamonitrile with various arenes under the action of TfOH or AlX3 (X =
Cl, Br) are presented in Table 1. It was found that two types of reaction products were obtained, 3-
aryl-3-phenyl propionitriles 1a-i and/or 3-phenylindanones 2a-g, in TfOH at room temperature for 1
h in 28-76% yield.28 The reactions with benzene, methoxybenzene (anisole), 1,2-dimethoxybenzene
(veratrole), and 1,2-dichlorobenzene only gave propionitriles 1 (Entries 1, 8, 9, 11). π-Nucleophilic
methyl substituted aromatic substrates, methylbenzene (toluene), dimethylbenzenes (o-, m-, p-
xylenes), and 1,2,4-trimethylbenzene (pseudocumene), additionally formed indanones 2 (Entries 4,
6, 7, 10). In the cases of donating arenes such as p-xylene and pseudocumene, the corresponding
indanones 2d and 2f,g were solely obtained (Entries 6, 10). In some cases regioisomers of aromatic
substitution were isolated: 2a,b (Entry 4), 1f,g (Entry 9), 2f,g (Entry 10), 1h,i (Entry 11). It should
2

be noted, that the structures of compounds 1a, 2a,d,g were additionally confirmed by single crystal
X-ray analysis (see X-ray structures in Table 1 and data in the ESI).
Table 1. Reactions of cinnamonitrile with arenes in TfOH leading to nitriles 1 and/or indanones 2.
O
N
Ar
acid
ArH
+
+
Ph
N
Ph
R
Ph
1
2
Entry ArH
Acida Reaction product, yield (%)
TfOH
1
benzene
Ph
N
Ph
1a (76%)
X-rayb of 1a
2
3
4
benzene
benzene
1,2-dimethylbenzene
AlBr3 1a (63%)
AlCl3 1a (93%)
Me
O
TfOH
O
Me
Me
Me
Me
+
+
Me
N
Ph
Ph
Ph
1b (16 %)
2b (16%)
2a (16%)
X-rayb of 2a
O
5
6
1,3-dimethylbenzene
1,4-dimethylbenzene
TfOH
TfOH
Me
Me
Me
+
N
Ph
Ph
Me
1c (12%)
2c (21%)
Me
O
Ph
Me
2d
(5
7%
)
X-rayb of 2d
O
7
methylbenzene
TfOH
Me
Me
+
N
Ph
Ph
1d (46%)
2e (3%)
3

MeO
8
9
methoxybenzene
TfOH
TfOH
N
Ph
Ph
1e (30%)
MeO
1,2-dimethoxybenzene
+
MeO
MeO
N
N
OMe Ph
1g (15%)
1f (43%)
Me
Me
10
1,2,4-trimethylbenzene TfOH
O
O
Me
+
Me
Ph
Ph
Me
Me
2g (32%)
2f (43%)
X-rayb of 2g
Cl
Cl
11
1,2-dichlorobenzene
TfOH
+
Cl
N
N
Ph
Cl
Ph
1i (10%)
1h (18%)
a Reagents and conditions: cinnamonitrile (100 mg, 0.78 mmol), arene [benzene – 1 mL, other
arenes – 0.94 mmol (1.2 equiv.)], TfOH (2 mL), room temperature, 1 h. Reactions with AlX3 (X =
Cl, Br) (5 equiv.) were carried out in excess benzene at 80 °C for 1 h. bCCDC numbers for X-ray
structures: 1a – 1895300, 2a – 1895301, 2d – 1895302, 2g – 1559532.
A plausible mechanism for the reaction of cinnamonitrile with arenes in TfOH is presented in
Scheme 2. Firstly, interaction of N,C-diprotonated species A with the arene proceeds at the
electrophilic center C3 giving rise to the N-protonated form of propionitrile B, the hydrolysis of
which gives nitrile 1. Cation B possessing a reactive electrophilic center at C1 may also undergo
cyclization, if the aromatic ring is sufficiently nucleophilic. This leads to species C, which is the N-
protonated form of the corresponding imine. Hydrolysis of the superacidic reaction mixture finally
gives indanone 2.
Thus, nitriles 1 are the initial reaction products of cinnamonitrile with arenes in TfOH. Under
the superacidic reaction conditions, compounds 1 may be further cyclized into indanones 2. Indeed,
for instance, in the reaction with toluene, increasing the reaction time to 10 h at room temperature
led to an increase in the yield of indanone 2e (18%) and a decrease in the yield of nitrile 1d (23%)
(compare with entry 7). We also attempted to achieve the transformation of nitrile 1a into 3-
phenylindanone by heating a solution of compound 1a in TfOH at an elevated temperature (80 °C)
4

for 1 h. However, in this particular case, a complex mixture of oligomeric materials was formed. It
should be noted that nitriles may give dimeric, trimeric and oligomeric compounds in TfOH due to
involvement of the nitrile group in various transformations, as it has been recently shown for
acetonitrile.29 Therefore, in the case of the reactions of cinnamonitrile, prolongation of the reaction
time or increasing the reaction temperature may also lead to secondary transformations of the
obtained reaction products 1.
R
NH
Ar
ArH
-H+
H2O
-H+
2
1
3
Ph
N
NH
Ph
A
B
1
Ph
H+ -H+
H+
O
N
NH2
Ph
H2O
+
-NH4
R
R
Ph
2
C
Ph
Scheme 2. Plausible mechanism for the reaction of cinnamonitrile with arenes in TfOH.
Apart from TfOH, aluminum halides AlX3 (X = Cl, Br) were found to be good activators for
the transformation of cinnamonitrile and benzene into compound 1a in high yields at 80 °C for 1 h
(Entries 2, 3). However, the reactions of methylated arenes (toluene and xylenes) was more
complex and gave the target reaction products in low yields with a large amount of oligomeric
materials.
It should be emphasized, that reduction of the cyano group in 3,3-diaryl propionitriles 1
furnishes 3,3-diarylpropylamines [Ar(Ar')CH(CH2)2NH2], which are in demand due to a variety of
biologically active properties.30-35
In conclusion, we have studied the reactions of cinnamonitrile with arenes under
superelectrophilic activation conditions in TfOH. These reactions may proceed through
intermediate formation of highly reactive the N,C-diprotonated form of cinnamonitrile. The
reactions afford 3-aryl-3-phenyl propionitriles, which may be further cyclized into 3-
phenylindanones.
Acknowledgements
This work was supported by the Russian Foundation for Basic Research (RFBR, grant no. 18-33-
0017\18). Spectral studies were performed at the Center for Magnetic Resonance, the Center for
Chemical Analysis and Materials Research, and Research Center for X-ray Diffraction Studies of
Saint Petersburg State University, Saint Petersburg, Russia.
5

Supplementary data
Experimental procedures, compound characterization, 1H, 13C NMR spectra, X-Ray data.
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room temperature for 1 h, and quenched with water (30 mL). The reaction products were extracted
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7

Highlights
-
-
-
Reactive N,C-diprotonated form of cinnamonitrile
Synthesis of 3-aryl-3-phenyl propionitriles
Synthesis of 3-phenylindanones
8