One-pot tandem hydrophenylation and ionic hydrogenation of 3-phenylpropynoic acid derivatives under superelectrophilic activation

Article abstract of DOI:10.1016/j.tetlet.2015.09.026

The reactions of esters and amides of 3-phenylpropynoic acid with strong Lewis acids AlX₃ (X = Cl, Br) or conjugate Br?nsted-Lewis superacids HX-AlX₃ (X = Cl, Br) in benzene and cyclohexane at room temperature afforded 3,3-diphenylpropanoic acid derivatives in up to 94% yield. This tandem reaction of the acetylene bond proceeded by hydrophenylation followed by ionic hydrogenation.

Full text of DOI:10.1016/j.tetlet.2015.09.026

Accepted Manuscript
One-pot tandem hydrophenylation and ionic hydrogenation of 3-phenylpropy-
noic acid derivatives under superelectrophilic activation
Denis I. Nilov, Aleksander V. Vasilyev
PII:
S0040-4039(15)30068-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.09.026
TETL 46698
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
11 June 2015
25 August 2015
7 September 2015
Please cite this article as: Nilov, D.I., Vasilyev, A.V., One-pot tandem hydrophenylation and ionic hydrogenation
of 3-phenylpropynoic acid derivatives under superelectrophilic activation, Tetrahedron Letters (2015), doi: http://
dx.doi.org/10.1016/j.tetlet.2015.09.026
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One-pot tandem hydrophenylation and ionic hydrogenation of 3-phenylpropynoic acid
derivatives under superelectrophilic activation
Denis I. Nilova and Aleksander V. Vasilyev*a,b
aInstitute of Chemistry, Saint Petersburg State University, Universitetskaya nab., 7/9, Saint
Petersburg, 199034, Russia.
bDepartment of Chemistry, Saint Petersburg State Forest Technical University, Institutsky per., 5,
Saint Petersburg, 194021, Russia. E-mails: aleksvasil@mail.ru; a.vasilyev@spbu.ru
*Corresponding author: A.V. Vasilyev
Keywords: alkynes, hydrophenylation, ionic hydrogenation, phenylpropynoic acid derivatives,
Brønsted and Lewis superacids
Graphical Abstract:
Abstract:
The reactions of esters and amides of 3-phenylpropynoic acid with strong Lewis acids AlX3
(X = Cl, Br) or conjugate Brønsted-Lewis superacids HX-AlX3 (X = Cl, Br) in benzene and
cyclohexane at room temperature afforded 3,3-diphenylpropanoic acid derivatives in up to 94%
yield. This tandem reaction of the acetylene bond proceeded by hydrophenylation followed by ionic
hydrogenation.
Introduction:
The acetylene bond is a highly reactive functional group that is capable of undergoing various
transformations via their reactions with electrophiles, nucleophiles, and radicals.1,2 Activation of the
triple carbon-carbon bond in superelectrophilic (superacidic) systems is widely used in organic
synthesis,3,4 and is an effective means to achieve various transformations of alkynes where the triple
bond is conjugated with an electron withdrawing group (carbonyl, alkoxycarbonyl, cyano).4
1

However, there are no examples of the involvement of such conjugated alkynes in ionic
hydrogenation reactions.
Ionic hydrogenation is used for the reduction of alkene and carbonyl bonds. This process
includes formation of a carbocationic species followed by abstraction of a hydride ion from a
suitable donor. Different combinations of electrophile/hydride ion sources: trifluoroacetic
acid/silicon hydride,5-7 metal halide/silicon hydride,8 and trialkylboron/aryl tin hydride have been
reported.9 However, the ionic hydrogenation of alkenes under mild conditions is not a versatile
reaction and suitable starting materials are limited. Thus, reduction of alkene bonds in deactivated
conjugated enones requires the use of superacids HF-SbF5 or AlX3 (X = Cl, Br) to generate the
O,C-diprotonated enone form (dications),3 which are reactive enough to abstract a hydride ion from
cycloalkane donors.10-24
Based on our research on the chemistry of alkynes in superacids,4 in this work, we describe
the reactions of 3-phenylpropynoic acid derivatives (esters and amides) with various Brønsted and
Lewis superacids in cycloalkanes (as the hydride ion source) and arenes.
Scheme 1. Possible transformations of conjugated ynone 1 under superelectrophilic activation, in
the presence of arenes and alkanes (as the hydride ion source).
Protonation of the carbonyl oxygen and acetylene carbon of conjugated ynone 1 in Brønsted
superacids (or coordination of these basic centers with Lewis acid) leads to formation of the
reactive dication A (or its complex with a Lewis acid) (Scheme 1).4 This species may abstract a
hydride ion from an alkane, leading to enone B (path a). On the other hand, dication A in the
presence of an arene, results in alkenylation of the aromatic molecule affording aryl enone C.
Protonation of the latter gives dication D, which in turn may abstract a hydride ion to form structure
E (path b). It should be noted that -aryl substituted vinyl cations are linear according to DFT
2

calculation.25 Moreover, experimental X-ray data on the structure of the -tert-butyl substituted
vinyl cation clearly demonstrate its linear structure.26
In order to examine the different potential reactions of ynones 1 (paths a and b, Scheme 1) we
undertook the study reported herein. Initially, we examined the reaction of methyl 3-
phenylpropynoate 1a with various Lewis and Brønsted superacids in cyclohexane or
methylcyclohexane, as hydride ion sources (Table 1). In the reactions with AlCl3 or AlBr3 in low
coordinating solvent such as CH2Cl2, CH2Br2, or CS2 (Entries 1, 2, 4) the corresponding vinyl
halogenides E-,Z-2a or E-,Z-2b were obtained resulting from the addition of HCl or HBr to the
triple bond. In the same manner, vinyl triflates E-,Z-2c were formed in TfOH (Entry 5). The use of
AlCl3 in CS2 afforded oligomeric material, presumably due to the partial solubility of the Lewis
acid in this solvent (Entry 3). These data showed that the corresponding vinyl dication A does not
abstract a hydride ion from cycloalkanes (path a, Scheme 1), but prefers to react with other
nucleophiles, such as counter ions from the reaction medium ([AlnX3n+1]- or TfO-). Increasing the
acidity of the reaction medium using conjugate Brønsted-Lewis systems TfOH-SbF5 or HX-AlX3
(X = Cl, Br) gave unsatisfactory results, and only complex mixtures of oligomeric materials were
obtained (Entries 6-9).
Table 1. Reaction of methyl 3-phenylpropynoate 1a with various Lewis and Brønsted superacids in
cycloalkanes.
Reaction product
AlkH
yield
Entry
Acida
Solvent
ratio
no.
E- : Z- (%)
1
2
3
4
5
6
7
8
9
AlCl3 (5 eq.)
AlBr3 (5 eq.)
AlCl3 (5 eq.)
CH2Cl2
CH2Br2
CS2
c-C6H12
c-C6H12
c-C6H12
c-C6H12
c-C6H12
c-C6H12
Me-c-C6H11
c-C6H12
c-C6H12
1.7 : 1
2.3 : 1
90
80
-
88
82
-
-
-
-
2a
2b
oligomers
2b
-
AlBr3 (5 eq.)
CS2
1 : 1
19 : 1
TfOH (H0 -14)a (30 eq.)
TfOH-SbF5 (H0 -18)a (30 eq.)
TfOH-SbF5 (H0 -18)a (30 eq.)
HCl-AlCl3 (H0 < -13)a (5 eq.)
HBr-AlBr3 (H0 < -13)a (5 eq.)
2c
oligomers
oligomers
oligomers
oligomers
-
-
-
-
CS2
CS2
Note. aValues of the Hammett acidity function H0 are taken from ref. 3a.
The same reactions of compound 1a were then carried out in mixtures of benzene and various
cycloalkanes (Table 2). The reactions with Lewis acids AlX3 (X = Cl, Br) at room temperature for
15 h led smoothly to ester 3a in high yields 83-90% (Entries 1-5). Compound 3a was formed by
3

tandem hydrophenylation of the acetylene bond of substrate 1a followed by ionic hydrogenation
(path b, Scheme 1). The same result was achieved using HX-AlX3 (X = Cl, Br) (Entries 6, 7), but
took less time (3 h). In the TfOH-SbF5 system, the yield of compound 3a was significantly lower
(20%), and large amounts of the benzene cycloalkylation products were formed (Entry 8).
Additionally, acidic zeolite CBV-720 was explored as an activator of substrate 1a. Running the
reaction in a high pressure glass tube at 120 C for 30 h gave target compound 3a in 29% yield
(Entry 9).
Table 2. Transformation of methyl 3-phenylpropynoate 1a into methyl 3,3-diphenylpropanoate 3a
using various Lewis and Brønsted superacids in various mixtures of benzene and cycloalkanes.
Entry
Acida
AlCl3 (5 eq.)
AlCl3 (5 eq.)
AlCl3 (5 eq.)
AlCl3 (5 eq.)
AlBr3 (5 eq.)
AlkH
c-C6H12
Me-c-C6H11
Me-c-C5H9
adamantane
c-C6H12
Reaction time, (h)b
Yield (%)
1
2
3
4
5
6
7
8
9
15
15
15
15
15
3
85
83
88
86
90
92
70
20c
29
HCl-AlCl3 (H0 < -13)a (5 eq.)
HBr-AlBr3 (H0 < -13)a (5 eq.)
TfOH-SbF5 (H0 -18)a (30 eq.)
Zeolite CBV-720 (30 eq.)
c-C6H12
c-C6H12
c-C6H12
c-C6H12
3
1
30
a
b
Notes. Values of Hammett acidity function H0 are from ref. 3a. Entries 1-8 were performed at rt,
Entry 9 was performed at 120 °C. cLarge amounts of benzene cycloalkylation product formed.
In comparison with TfOH-SbF5 or HX-AlX3 (X = Cl, Br) (Table 2, Entries 6-8), the reaction
of esters 1a and 1b in TfOH resulted in the formation of indanone 4a (Scheme 2), which was not a
product of ionic hydrogenation. Compound 4a was formed by double hydrophenylation of the
acetylene bond, followed by intramolecular acylation (without the participation of cyclohexane),
analogous to the same transformation of 3-phenylpropynoic acid in benzene.27
Scheme 2. Transformation of esters 1a,b into indanone 4a.
4

As part of further optimization, different cycloalkanes (cyclohexane, methylcyclohexane,
methylcyclopentane and adamantane), which may be used as hydride ion sources, were examined in
this reaction (Table 2, Entries 1-4). Various Lewis acids AlX3 (X = Cl, Br) and conjugate Brønsted-
Lewis acids HX-AlX3 (X = Cl, Br) (Table 2, Entries 1-7) were effective for the activation of ester
1a. However, among these acids, aluminum chloride AlCl3 was the most convenient and easy to
handle, because it was not as hygroscopic as AlBr3. Thus, for further reactions we chose the
following convenient conditions: AlCl3 (5 eq.) in a mixture of benzene and cyclohexane at room
temperature for 15 h. Under these conditions ethyl 3-phenylpropynoate 1b was converted into ethyl
3,3-diphenylpropanoate 3b in 92% yield (Scheme 3).
Scheme 3. Transformation of ester 1b into compound 3b using AlCl3 in benzene and cyclohexane.
Finally, a series of phenylpropynoic acid amides 1c-g was transformed into the corresponding
amides of 3,3-diphenylpropanoic acid 3c-g in 45-94% yield (Scheme 4). Amides such as 3 are in
great demand and are used for the synthesis of 3,3-diphenylprop-1-ylamines, such as
diphenylpropylamines, diisopropamine, and fenpiprane, which are valuable antiallergic drugs.28
Scheme 4. Transformation of amides 1c-g into compounds 3c-g using AlCl3 in benzene and
cyclohexane.
The formation of compounds 3a-g from acetylene substrates 1a-g proceeded via a sequence of
two reactions: hydrophenylation of the acetylene bond (see examples in the literature3,4), followed
by ionic hydrogenation of the formed alkene bond (path b, Scheme 1).
To gain additional proof for the proposed reaction mechanism, we carried out the
transformation of methyl 3,3-diphenylpropenoate, which may lie on the reaction pathway
(analogous to structure C in Scheme 1). Indeed, this ester quantitatively gave ester 3a under the
optimal reaction conditions (AlCl3, benzene, cyclohexane, room temperature, 15 h).
The data obtained indicated that dication A (Scheme 1), generated from compound 1, does not
abstract a hydride ion from cycloalkanes (Table 1). Conversely, dication D (Scheme 1) can easily
abstract a hydride ion. Although vinyl cations are strongly disfavored relative to alkyl cations,3,4,29
vinyl dication A was observed to be extremely reactive compared to alkyl dications D. Upon
5

formation, species A immediately reacts with the surrounding nucleophilic counter anions of the
acid to give vinyl derivatives 2 (Table 1). On the contrary, the more stable dication D may slowly
abstract a hydride ion from cycloalkanes. Additionally, the interaction of dication D with a further
benzene molecule may be sterically unfavorable.
The effect of Brønsted acidity on the reaction can be noted. Thus, the reaction of ester 1a in
TfOH (H0 -14) gives indanone 4a without ionic hydrogenation (Scheme2). In stronger acidic
systems TfOH-SbF5 (H0 -18) or HX-AlX3 (X = Cl, Br) (H0 < -13) (Table 2, Entries 6-8), ionic
hydrogenation takes place. Increasing the acidity and decreasing the nucleophilicity of the reaction
medium promoted the reaction of dication D with the hydride ion (Scheme 1).
The source of the original protons in the reactions promoted by AlX3 (X = Cl, Br) should be
noted. Protons are formed in the reaction system after the deprotonation of benzene; additionally, a
catalytic amount of protic superacids HX-AlX3 (X = Cl, Br) or H2O-AlX3 (X = Cl, Br) is normally
present due to trace of water in the starting materials.
In conclusion, we have demonstrated for the first time an effective one-pot tandem
hydrophenylation - ionic hydrogenation reaction sequence for the transformation of esters or amides
of 3-phenylpropynoic acid in benzene and cyclohexane to give the corresponding
3,3-diphenylpropanoic acid derivatives under superelectrophilic activation. Studies on the reactions
of other acetylene substrates and arenes in this tandem process are under current investigation.
1
Supplementary Information: Supplementary data associated with this article (general remarks, H
and 13C NMR spectra of compounds, experimental procedures) can be found in the online version at
http://www.sciencedirect.com/science/journal/00404039.
Acknowledgements
This work was supported by Saint Petersburg State University (grant no 12.50.1187.2014 and no
12.38.195.2014) and the Russian Scientific Foundation (grant no 14-13-00448). Spectral studies
were performed at the Center for Magnetic Resonance, the Center for Chemical Analysis and
Materials Research of Saint Petersburg State University.
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