Tandem superelectrophilic hydroarylation of CC bond and carbonyl reduction in cinnamides: Synthetic rout to 3,3-diarylpropylamines, valuable pharmaceuticals

Article abstract of DOI:10.1016/j.tet.2014.11.033

Cinnamides ArCHCHCONRR′ in reactions with arenes Ar′H under the action of Bronsted (TfOH, FSO₃H) or Lewis (AlBr₃) superacids at rt for 1-2 h give CC bond hydroarylation products ArAr′CHCH₂CONRR′ in yields of 63-98%. Reduction (LiAlH₄/Et₂O) of carbonyl group in the latter results in the formation of 3,3-diarylpropylamines ArAr′CHCH₂CH₂NRR′, valuable drugs. The reaction intermediates, superelectrophilic dications ArC⁺H-CH₂C(OH⁺)NRR′, have been characterized by DFT calculations in terms of global electrophilicity index, natural charges, and atomic orbitals contributions.

Full text of DOI:10.1016/j.tet.2014.11.033

Accepted Manuscript
Tandem Superelectrophilic Hydroarylation of C=C Bond and Carbonyl Reduction in
Cinnamides: Synthetic Rout to 3,3-Diarylpropylamines, Valuable Pharmaceuticals
Dmitry N. Zakusilo , Dmitry S. Ryabukhin , Irina A. Boyarskaya , Oleg S. Yuzikhin ,
Aleksander V. Vasilyev
PII:
S0040-4020(14)01605-6
10.1016/j.tet.2014.11.033
TET 26182
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 10 September 2014
Revised Date: 25 October 2014
Accepted Date: 10 November 2014
Please cite this article as: Zakusilo DN, Ryabukhin DS, Boyarskaya IA, Yuzikhin OS, Vasilyev AV,
Tandem Superelectrophilic Hydroarylation of C=C Bond and Carbonyl Reduction in Cinnamides:
Synthetic Rout to 3,3-Diarylpropylamines, Valuable Pharmaceuticals, Tetrahedron (2014), doi: 10.1016/
j.tet.2014.11.033.
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ACCEPTED MANUSCRIPT
Tandem Superelectrophilic Hydroarylation of C=C Bond and Carbonyl
Reduction in Cinnamides: Synthetic Rout to 3,3-Diarylpropylamines,
Valuable Pharmaceuticals
a
b
b
a
Dmitry N. Zakusilo, Dmitry S. Ryabukhin, Irina A. Boyarskaya, Oleg S. Yuzikhin, and
a,b
Aleksander V. Vasilyev *
a
Department of Organic Chemistry, Saint Petersburg State Forest Technical University, Institutsky
per., 5, Saint Petersburg, 194021, Russia. Fax: +07-812-670-93-90. E-mail: aleksvasil@mail.ru
b
Department of Organic Chemistry, Institute of Chemistry, Saint Petersburg State University,
Universitetsky pr., 26, Saint-Petersburg, Petrodvoretz, 198504, Russia.
*
Corresponding author: A.V. Vasilyev
Keywords: hydroarylation, superacids, cinnamides, 3,3-diarylpropylamines, DFT calculations
Abstract:
Cinnamides ArCH=CHCONRR′ in reactions with arenes Ar′H under the action of Bronsted (TfOH,
FSO H) or Lewis (AlBr ) superacids at r.t. for 1-2 h give C=C bond hydroarylation products
3
3
ArAr′CHCH CONRR′ in yields of 63-98%. Reduction (LiAlH -Et O) of carbonyl group in the
2
4
2
latter results in the formation of 3,3-diarylpropylamines ArAr′CHCH CH NRR′, valuable drugs.
2
2
+
+
The reaction intermediates, superelectrophilic dications ArC H–CH C(OH )NRR′, have been
2
characterized by DFT calculations in terms of global electrophilicity index, natural charges, and
atomic orbitals contributions.
Graphical Abstract:
O
OH
NRR'
Ar'
Ar'
O
H+
Ar'H
[H]
NRR'
Ar
NRR'
Ar
NRR'
Ar
Ar
superelectrophiles:
DFT calculations
63-98%
61-90%
+
H - Bronsted or
Lewis superacids
1

ACCEPTED MANUSCRIPT
Introduction
3,3-Diaryl(hetaryl)propylamines are of a great importance due to their biological activity as
1
,2
3
H -antihistaminic agents.
1
These substances represent different pharmaceuticals: Drixoral,
pheniramine, fenpiprane, tussionex (antiallergic drugs), diisopropamine, prozapine (choleretic
drugs), fendiline (coronardilatic drug), detrol LA (antimuscarinic drug) (Figure 1).
R
Ph
Pheniramine (R = H)
Tussionex (R = Cl)
Drixoral (R = Br)
1
2
Ph
NR R
1
2
Diisopropamine (R = R = i-Pr)
1
2
Fenpiprane (R = R = -(CH ) -)
2
5
NMe2
1
2
Prozapine (R = R = -(CH ) -)
2
6
1
2
N
Fendiline (R = H, R = CHMePh)
Figure 1. 3,3-Diaryl(hetaryl)propylamine core based drugs.
Various synthetic methods have been developed to access these compounds: nucleophilic
4
5
substitution of 3,3-diarylhalides, Rh-catalyzed hydroaminomethylation of 1,1-diarylethylenes,
6
tandem Pd-Heck reaction - catalytic hydrogenation of cinnamides, Cu-catalyzed addition of aryl
7
Grignard reagents to cinnamides. Several methods are based on arene alkylation by carbocations
8
9
10
generated from β-amino alcohols, β-amino acetals, and α-amino alkenes in Bronsted superacid
TfOH. Similar superelectrophilic activation of cinnamides in Bronsted and Lewis superacids was
1
1
used for alkylation of benzene and 1,2-dichlorobenzene only, but no other arenes.
Based on our previous work on superelectrophilic activation of amides of acetylene
1
2
13
carboxylic acids, and other acetylene compounds, in this study we have examined the activation
of cinnamides 1 in superacids to generate reactive dications B, that are enable to alkylate arenes,
leading to amides 2, products of hydroarylation of C=C bond of cinnamides 1. Reduction of the
carbonyl group in the latter then results in the formation of 3,3-diarylpropylamines 3 (Scheme 1).
This simple tandem two step method gives access to a variety of amines 3, bearing various
substituents on the aromatic rings and on the nitrogen atom.
O
OH
NR R
Ar'
Ar'
O
H+
Ar'H
[H]
1
2
1
2
1 2
Ar
NR R
Ar
1
2
Ar
NR R
Ar
NR R
1
B
2
3
Scheme 1. Tandem superelectrophilic hydroarylation-carbonyl reduction of cinnamides 1.
The aim of this work is to study the reactions of cinnamides (amides of 3-arylpropenoic acids)
with arenes under the action of Bronsted (TfOH, FSO H) and Lewis (AlBr ) superacids, to
3
3
characterize the cationic intermediates by quantum chemical calculations (DFT), and elaborate a
two stage synthesis of 3,3-diarylpropylamines based on readily available cinnamides.
2

ACCEPTED MANUSCRIPT
Results and discussion
Initial cinnamides 1a-j used in this study are shown in Figure 2. Their reactions with arenes
1
are presented in Tables 1-3. Structures of reaction products 2a-v, 3a-c, 4a were determined by H,
1
3
C NMR, and HRMS methods. In some cases we were unable to separate isomeric amides which
have very close retention parameters, by usual preparative column chromatography on silica gel.
These compounds were detected with the use of UPLC-MS, and HRMS (see Experimental part).
CONHMe
CONR2
CONHPh
Ph
Ph
R
1
a-f
1g-i
R = Et (g), i-Pr (h),
1j
R = H (a), 4-Me (b), 3,4-Me (c),
2
2
-F (d), 4-MeO (e), 3,4-MeO (f)
(CH (i)
2 5
)
2
Figure 2. Initial cinnamides 1a-j used in this study.
First we carried out transformations of N-alkyl amides of cinnamic acid 1a,g-i, having no
substituents in phenyl ring, with alkyl-, methoxy-, and halogen- arenes (Table 1). In TfOH or with
AlBr (Table 1, entries 2, 12) at room temperature for 1-2 h these cinnamides are smoothly
3
converted into corresponding amides 2a-m in almost quantitative yields. In case of toluene and m-
xylene two regioisomers are formed 2b,c and 2e,f correspondingly (Table 1, entries 3, 5), due to
electrophilic substitution in different positions of aromatic ring.
Table 1. Reactions of amides of cinnamic acid 1a,g-i with arenes under the action of TfOH or
AlBr3.
R3
R3
+
CONR1R2
H
+
Ph
o
CONR1R2
2
0 C
Ph
1a,g-i
2a-m
Entry
Starting materials
Reaction
Reaction product
conditions
1
2
3
Cinnamide
Arene
benzene
benzene
toluene
Acid
TfOH
AlBr3
TfOH
Time, h no.
R
R
R
Yield, %
98
1
2
3
1a
1a
1a
2
2
1
2a
2a
2b
H
H
H
H
H
H
H
H
H
H
H
Et
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
H
H
93
90
4-Me
2-Me
3,4-Me2
2,4-Me2
2,6-Me
2,5-Me2
4-MeO
3,4-MeO2
3,4-Cl2
2c
7
4
5
1a
1a
o-xylene
m-xylene
TfOH
TfOH
1
1
2d
2e
96
82
2f
2
16
6
7
8
9
1a
1a
1a
1a
1g
1h
1h
1i
p-xylene
anisole
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
AlBr3
TfOH
1
1
1
1
2
2
2
2
2g
2h
2i
2j
2k
2l
82
95
98
68
90
94
98
97
veratrole
1,2-Cl C H
2
6
4
1
1
1
1
0
1
2
3
benzene
benzene
benzene
benzene
H
H
H
H
i-Pr
i-Pr
-(CH ) -
i-Pr
i-Pr
2l
2m
2
5
3

ACCEPTED MANUSCRIPT
Selected cinnamides 2a,l,m were reacted with LiAlH in ether solution at room temperature
4
for 4 h, that gave 3,3-diarylpropylamines 3a-c. Two of them are the known drugs diisopropamine
and fenpiprane (Scheme 2).
Ph
O
Ph
LiAlH , Et O
4
2
1
2
1 2
Ph
NR R
o
Ph
NR R
2
0 C, 4 h
3
a-c
2
a,l,m
Initial
Reaction products
1
2
3
a
R
R
Yield, %
2
2
2
a
l
m
H
Me
66
61
90
b (diisopropamine)
c (fenpiprane)
i-Pr
-(CH ) -
2 5
i-Pr
Scheme 2. Reduction of carbonyl group in amides 2a,j,k.
Table 2. Reactions of substituted N-methyl cinnamides 1b-f with arenes in TfOH, FSO H.
3
R2
R2
H+
CONHMe
+
CONHMe
R1
R1
1
b-f
2a,b,d,h,n-r
Entry
Initials
Cinnamide
Reaction conditions
Acid Temp., Time, no.
Reaction product
1
2
Arene
R
R
Yield,
%
17
47
60
°
C
h
1
1
2
3
4
5
6
7
8
9
1b
1b
1b
1b
1b
1b
1c
1c
benzene
benzene
benzene
TfOH
20
-35
0
2a
H
4-Me
4-Me
H
H
H
2b
TfOH-
CH Cl
1
1
2
5
2
1
1
2b
2b
2b
2b
2n
2a
2
2
TfOH-
CH Cl
4-Me
4-Me
4-Me
H
H
H
H
83
2
2
a
benzene FSO H-
-75
-75
-40
20
0
30
3
CH Cl
2
2
benzene FSO H-
85
82
3
CH Cl
2
2
benzene FSO H-
4-Me-
3-SO2F
H
3,4-Me
2
3,4-Me2
3
SO2
TfOH
benzene
benzene
H
H
H
10
79
90
2d
TfOH-
CH Cl
2d
2
2
1d
1e
1e
1f
benzene
benzene
anisole
anisole
TfOH
20
20
20
20
1
1
0.5
0.5
2o
2h
2p
2p
2-F
H
H
98
63
75
27
40
15
65
1
1
1
0
1
2
TfOH
TfOH
TfOH
4-MeO
4-MeO
4-MeO
3,4-MeO
3,4-MeO
4-MeO
4-MeO
4-MeO
3,4-MeO
4-MeO
2q
2
2
2r
2
13
1f
anisole
FSO H
-75
1
2q 3,4-MeO2
3
a
Incomplete conversion of initial 1a.
4

ACCEPTED MANUSCRIPT
Reactions of N-methyl cinnamides 1b-f, bearing various substituents in aromatic ring, are
shown in Table 2. In TfOH at room temperature cinnamides 1b,c,f, having electron donating methyl
or methoxy substituents, gave additionally products of aryl group exchange 2a, 2p, and 2r, apart
from expected amides 2b, 2d, and 2q (Table 2, entries 1, 7, 12). Similar exchange of aryl
substituents was previously observed in transformations of cinnamides under the action of strong
1
1b,14
Lewis acid AlCl3.
To overcome this synthetic obstacle we lowered the reaction temperature to
suppress aryl groups exchange. Indeed, in TfOH at -35 and 0 °C (Table 2, entries 2, 3, 8), or in
FSO H at -75°C (Table 2, entries 4, 5, 13) this exchange was completely excluded. Carrying out
3
reaction in FSO H at higher temperature -40 °C resulted in the formation of fluorosulfonation
3
product 2n derived from compound 2b at this temperature (Table 2, entry 6, compare with entry 5).
Amide of 4-fluoro cinnamic acid 1d gives only compound 2o, no aryl group exchange products
have been observed (Table 2, entry 9).
Then we considered reactions of N-phenyl cinnamide 1j in TfOH (Table 3) without and with
arenes in order to estimate concurrent inter- and intramolecular transformations of the
corresponding intermediate dication. Without added arenes, amide 1j furnishes to intramolecular
cyclization product 4a (Table 3, entry 1), analogously previously observed reaction under the action
1
1a,b,14
of AlCl3.
In the presence of benzene, two compounds have been isolated, 4a and 2s (in a ratio
~1 : 5), with a predominant formation of the latter as a result of an intermolecular process (Table 3,
entry 2). The use of more electron donating aromatic substrates, anisole and veratrole, gives a very
small increase in the ratio of intermolecular reaction products 2t-v (Table 3, entries 3,4). Thus, in
TfOH even in reactions with rather electron donating arenes it was not possible to suppress
completely the intramolecular transformation of cinnamide1j into dihydroquinolinone 4a.
Table 3. Reactions of N-phenyl cinnamide 1j with arenes in TfOH.
R
Ph
R
TfOH
CONHPh
+
+
Ph
o
2
0 C, 1 h
CONHPh
N
H
O
Ph
1j
2
s-v
4a
Entry
Arene
Reaction products
no.
4a
4a
R
-
-
H
-
Yield, %
Ratio, 4a : 2
1
2
no arene
benzene
60
14
68
13
67
13
12
69
-
~ 1 : 5
2s
3
4
anisole
4a
~ 1 : 6
~ 1 : 6
2t
4-MeO
2-MeO
-
2u
veratrole
4a
2v
3,4-MeO
2
5

ACCEPTED MANUSCRIPT
In the theoretical part of the study we have characterized the reaction intermediates in terms
of their orbital energies, atom charges, contribution of atomic orbitals into the molecular orbital,
1
5
and global electrophilicity index to estimate the reactivity of these species. The data of DFT
calculations are presented in Table 4.
1
1b
It has been shown previously by NMR that cinnamides undergo two stage protonation in
superacids, leading consequently to unreactive O-protonated and reactive O,C-diprotonated forms.
For amide 1a first protonation takes place at carbonyl oxygen, giving O-protonated form A1, then
2
atom C of the double bond is protonated, leading to dication B1 (Table 4). Selected electronic
characteristics of the initial 1a, and the resulting cations A1, B1 are presented in Table 4. Also
characteristics of mono the C-protonated species C1 are given for comparison. Among these three
species A1, B1, and C1, the dication B1 has the biggest electrophilicity index value ω, supporting
its high observed reactivity.
Table 4. Selected electronic characteristics of initial 1a, and cations A1, C1, and dications B1-B3.
O
1
O
OH
OH
H+
H+
H+
Ph
3
NHMe
Ph
3
1
NHMe
Ph
3
1
NHMe
Ph
3
1
NHMe
2
2
2
2
C1
1a
A1
B1
OH
OH
3
1
NHMe
3
1
NHMe
2
2
B2
MeO
B3
Me
a
1
b
3
b
1
3
Species EHOMO
eV
,
ELUMO
eV
,
ω,
q(C ),
e
q(C ),
e
k(C )
k(C )
LUMO,
%
c
c
eV
LUMO,
%
1
a
-6.53
-1.89
-8.19
-6.48
-11.62
-11.14
-10.58
1.9
17.1
9.3
25.6
22.7
20.4
0.64
0.67
0.68
0.74
0.74
0.75
-0.12
-0.01
0.15
0.12
0.08
0.03
4.8
24.6
0.8
12.3
16.5
22.6
19.5
27.5
50.6
31.8
22.3
A1
C1
B1
B2
B3
-10.84
-10.26
-15.11
-14.86
-14.41
a
2
b
24.7c
Global electrophilicity index ω = (EHOMO + ELUMO) /8(E
- EHOMO). Natural charges. Contribution of
LUMO
atomic orbitals into the molecular orbital
.
Substituted dications B2, and B3, derived from cinnamides 1b, and 1e, respectively, exhibit
the decreasing of ω value on substitution with the electron-donating methyl and methoxy groups,
compare to unsubstituted species B1 (Table 4). In the same range B1 → B2 → B3, positive charge
3
on reactive center, carbon atom C , is decreased. Apart from that, in the dications B1-B3, this
6

ACCEPTED MANUSCRIPT
3
carbon C gives a rather big contribution in LUMO ~22-32%, which indicates a substantial orbital
control in the reactions of these electrophiles. Also, it is worth noting that despite a big positive
1
charge on carbonyl carbon C (0.67-0.75 e), this cataionic center is not reactive and no electrophilic
reaction occurs on it.
Conclusion
Efficient two stage synthesis of 3,3-diarylpropylamines has been developed on the basis of
superelectrophilic hydroarylation (in Bronsted and Lewis superacids) followed by carbonyl
reduction (LiAlH ) of cinnamides. Reactivity of superelectrophilic intermediate dications derived
4
from cinnamides in superacids has been estimated by DFT calculations.
Experimental part
General.
The NMR spectra of compounds solutions in CDCl were recorded on a Bruker AM-500
3
1
19
13
spectrometer at 25°C (at 500, 476, and 125 MHz for H, F, and C NMR spectra respectively).
1
The residual proton-solvent peak CDCl (δ 7.26 ppm) for H NMR spectra, the signal of CF Cl (δ
3
3
1
9
13
0
.00 ppm) for F NMR spectra, and the carbon signal of CDCl (δ 77.0 ppm) for C NMR spectra
3
were used as references. HRMS was carried out at an instrument Bruker MicroTOF (ESI). GC-MS
data were obtained at a machine G2570A GC/MSD Agilent Technologies 6850c with a column HP-
5
MS (3m×0.25mm), a thickness of the stationary phase 0.25ꢀm. UPLC-MS was done on a Waters
Acuity H-class chromatograph, column UPLC BEH18 1.7 ꢀm 2.1*10 mm, eluents – acetonitrile-
+
formic acid, detector Xevo-TQD (ES ). The preparative reactions were monitored by thin-layer
chromatography carried out on silica gel plates (Silufol UV-254) using UV light for detection.
Column chromatography was performed on silica gel Chemapol 40/100 (0.04-0.10 mm) with
hexanes-ethyl acetate mixture eluation.
DFT calculations.
All computations has been carried out at the DFT/HF hybrid level of theory using Becke’s
three-parameter hybrid exchange functional in combination with the gradient-corrected correlation
1
6
functional of Lee, Yang, and Parr (B3LYP) by using GAUSSIAN 2003 program packages. The
geometries optimization were performed using the 6-311+G(2d,2p) basis set. The Hessian matrix
was calculated analytically for the optimized structures in order to prove the location of correct
minima (no imaginary frequencies) and to estimate the thermodynamic parameters. Enthalpies and
Gibbs free energies were calculated for 25 °С.
7

ACCEPTED MANUSCRIPT
General procedure for the synthesis of initial cinnamides (amides of 3-arylpropenoic
acids) 1a-j.
Chloro anhydride of the corresponding cinnamic acid (10 mmol), preliminary prepared by
heating of acid with SOCl , was quenched with solution of amine (30 mmol) in dioxane (10 mL) at
2
room temperature with vigorous stirring for 10 min. Then reaction mixture was diluted with water
(50 mL), acidified by concentrated aqueous hyhrochloric acid. Reaction product was extracted with
chloroform (3 × 50 mL). The extracts were combined, washed with water (3×20 mL), and dried
over Na SO . The solvent was distilled off under reduced pressure. The residue was purified by
2
4
recrystallization from ethanol.
N-Methylamide of 3-phenylpropenoic acid 1a. Colorless solid (yield 98%), mp 114-116 °C
17
1
(
lit. 117-118 °C). Н NMR (500 МHz, CDCl ) δ 7.63 (1H, d, J 15.6 Hz, Ar-СН=СН-), 7.50-7.49
3
(2Нarom., m), 7.36-7.35 (3Нarom., m), 6.39 (1H, d, J 15.6 Hz, Ar-СН=СН-), 5.72 (1Н, br.s, N-H),
+
+
2
1
.95 (3H, d, J 5.0 Hz, N-Me). HRMS (ES ) calcd for C H NO (M+H ) 162.0913, found
10 12
62.0917.
N-Methylamide of 3-(4-methylphenyl)propenoic acid 1b. Colorless solid (yield 96%), mp
1
8
1
1
7
32-134 °C (lit. 133 °C). Н NMR (500 МHz, CDCl ) δ 7.59 (1H, d, J 15.6 Hz, Ar-СН=СН-),
3
.38 (2Нarom., d, J 7.8 Hz,), 7.16 (2Нarom., d, J 7.8 Hz), 6.33 (1H, d, J 15.6 Hz, Ar-СН=СН-), 5.59
+
(
1Н, br.s, N-H), 2.93 (3H, d, J 3.4 Hz, N-Me), 2.35 (3Н, s, 4-MeC H ). MS (EI) m/z (%): 175 (М ,
6
4
+
+
5
1
5), 145 (100), 155 (49), 91 (20); HRMS (ES ) calcd for C H NO (M+H ) 176.1070, found
11 14
76.1076.
N-Methylamide of 3-(3,4-dimethylphenyl)propenoic acid 1c. Colorless solid (yield 61%), mp
1
1
59-161 °C. Н NMR (500 МHz, CDCl ) δ 7.56 (1H, d, J 15.6 Hz, Ar-СН=СН-), 7.25-7.21
3
(2Нarom., m), 7.09 (2Нarom., d, J 7.6 Hz), 6.36 (1H, d, J 15.6 Hz, Ar-СН=СН-), 5.89 (br.s, 1Н, N-H),
1
3
2
1
.93 (3H, d, J 8.7 Hz, N-Me), 2.24 (6H, s, 3,4-(Me) C H ); С NMR (125 МHz, CDCl ) δ 167.0,
2 6 3 3
+
40.7, 138.5, 136.9, 132.5, 130.0, 129.0, 125.2, 119.4, 26.4, 19.7. HRMS (ES ) calcd for C H NO
1
2
16
+
(
M+H ) 190.1226, found 190.1228.
N-Methylamide of 3-(2-fluorophenyl)propenoic acid 1d. Colorless solid (yield 98%), mp 125-
1
1
27 °C. Н NMR (500 МHz, CDCl ) δ 7.68 (1H, d, J 15.8 Hz, Ar-СН=СН-), 7.50-7.46 (1Нarom., m),
3
7
.32-7.30 (1Нarom., m), 7.15-7.12 (1Нarom., m), 7.10-7.06 (1Нarom., m), 6.54 (1H, d, J 15.8 Hz, Ar-
1
3
СН=СН-), 5.76 (1Н, br.s, N-H), 2.95 (3H, d, J 5.0 Hz, N-Me); С NMR (125 МHz, CDCl ) δ
3
1
1
1
7
66.5, 161.3 (d, J 251.6 Hz), 133.9, 130.8 (d, J 8.9 Hz), 129.7 (d, J 3.3 Hz), 124.3 (d, J 3.5 Hz),
1
9
23.5 (d, J 7.5 Hz), 122.9 (d, J 11.6 Hz), 116.1 (d, J 22.0 Hz), 26.5; F NMR (470 МHz, CDCl ): -
3
+
15.06 to -115.11 (1F, m). MS (EI) m/z (%): 179 (М , 49), 160 (12), 149 (100), 121 (45), 101 (49),
+
+
5 (12); HRMS (ES ) calcd for C H FNO (M+H ) 180.0819, found 180.0824.
1
0
11
8

ACCEPTED MANUSCRIPT
N-Methylamide of 3-(4-methoxyphenyl)propenoic acid 1e. Colorless solid (yield 71%), mp
1
1
8
39-141 °C. Н NMR (500 МHz, CDCl ) δ 7.57 (1H, d, J 15.6 Hz, Ar-СН=СН-), 7.42 (2Нarom., d, J
3
.5 Hz), 6.87 (2Нarom., d, J 8.5 Hz), 6.25 (1H, d, J 15.6 Hz, Ar-СН=СН-), 5.65 (br.s, 1Н, N-H), 3.81
+
(
3Н, s, 4-OMeC H ), 2.92 (3H, d, J 4.9 Hz, N-Me). MS (EI) m/z (%): 166 (М , 39), 148 (29), 133
6
4
+
+
(
98), 107 (100), 94 (15), 77 (24); HRMS (ES ) calcd for C H NO (M+H ) 192.1019, found
11 14 2
1
92.1022.
N-Methylamide of 3-(3,4-dimethoxyphenyl)propenoic acid 1f. Colorless solid (yield 59%),
1
mp 186-188 °C. Н NMR (500 МHz, CDCl ) δ 7.56 (1H, d, J 15.6 Hz, Ar-СН=СН-), 7.07 (1Нarom.,
3
d, J 8.2 Hz), 7.01 (1Нarom., s), 6.83 (1Нarom., d, J 8.2 Hz), 6.27 (1H, d, J 15.6 Hz, Ar-СН=СН-), 5.72
+
(
1Н, br.s, N-H), 3.89 (6Н, s, 3,4-(OMe) C H ), 2.94 (3H, d, J 3.6 Hz, N-Me). HRMS (ES ) calcd
2
6
3
+
for C H NO (M+H ) 222.1125, found 222.1130.
1
2
16
3
N,N-Diethylamide of 3-phenylpropenoic acid 1g. Colorless solid (yield 82%), mp 73-75 °C
19
1
(
lit. 66.5-67.5 °C). Н NMR (500 МHz, CDCl ) δ 7.66 (1H, d, J 15.5 Hz, Ar-СН=СН-), 7.48
3
(2Нarom., dd, J 8.5, 1.5 Hz), 7.34-7.29 (3Нarom., m), 6.79 (1H, d, J 15.5 Hz, Ar-СН=СН-), 3.43 (4Н,
+
q, J 7.3 Hz, N(CH Me) ), 1.18 (6Н, dt, J 35.0, 5.9 Hz, N(CH Me) ). MS (EI) m/z (%):203 (М , 36),
2
2
2
2
+
+
1
88 (11), 131 (100), 103 (35), 77 (17); HRMS (ES ) calcd for C H NO (M+H ) 204.1383, found
13 18
2
04.1387.
N,N-Diisopropylamide of 3-phenylpropenoic acid 1h. Colorless oil (yield 66%). Н NMR
500 МHz, CDCl ) δ 7.59 (1H, d, J 15.5 Hz, Ar-СН=СН-), 7.61-7.32 (5Нarom., m), 6.83 (1H, d, J
1
(
3
1
5.5 Hz, Ar-СН=СН-), 4.11 (1H, br.s, N(CHMe ) ), 3.85 (1H, br.s, N(CHMe ) ), 1.39-1.31 (12H,
2 2 2 2
13
m, N(CHMe ) ); С NMR (125 МHz, CDCl ) δ 166.4, 141.0, 135.8, 129.3, 128.9, 127.7, 120.8,
2
2
3
+
+
4
8.1, 46.0, 21.8, 20.8. HRMS (ES ) calcd for C H NO (M+H ) 232.1696, found 232.1702.
15 22
N-(Penthyliden-1,5)amide of 3-phenylpropenoic acid 1i. Colorless solid (yield 81%), mp 119-
1
9
1
1
21 °C (lit. 114-116 °C). Н NMR (500 МHz, CDCl ) δ 7.63 (1H, d, J 15.4 Hz, Ar-СН=СН-),
3
7
.51 (2Нarom., d, J 7.5 Hz), 7.38-7.31 (3Нarom., m), 6.90 d (1H, d, J 15.4 Hz, Ar-СН=СН-), 3.62 (4H,
br.s, N(CH ) (CH ) CH ), 1.69-1.65 (2Н, m, N(CH ) (CH ) CH ), 1.62-1.58 (4Н, m,
2
2
2 2
2
2 2
2 2
2
13
N(CH ) (CH ) CH ); С NMR (125 МHz, CDCl ) δ 165.3, 142.3, 142.0, 135.5, 129.3, 128.7,
2
2
2 2
2
3
+
1
27.6, 117.7, 29.6, 24.6. MS (EI) m/z (%): 215 (М , 64), 138 (40), 131 (100), 103 (55), 84 (29), 77
+
+
(
26); HRMS (ES ) calcd for C H NO (M+H ) 216.1383, found 216.1385.
14 18
N-Phenylamide of 3-phenylpropenoic acid 1j. Colorless solid (yield 98%), mp 171-173 °C
19
1
(
lit. 168-172 °C). Н NMR (500 МHz, CDCl ) δ 7.77 (1H, d, J 15.5 Hz, Ar-СН=СН-), 7.64 (1H,
3
br.s, N-H), 7.61-7.53 (3Нarom., m), 7.40-7.34 (6Нarom., m), 7.17 (1Harom., t, J 7.0 Hz), 6.55 (1H, d, J
+
+
1
5.5 Hz, Ar-СН=СН-). MS (EI) m/z (%): 223 (М , 29), 131 (100), 103 (38), 77 (23); HRMS (ES )
+
calcd for C H NO (M+H ) 224.1070, found 224.1076.
1
5
14
9

ACCEPTED MANUSCRIPT
General procedure for synthesis of amides 2a-v,4a by reactions of cinnamides 1a-j with
arenes under the action of Bronsted (TfOH, FSO H) or Lewis (AlBr ) superacids (Tables 1-3).
3
3
Amide 1 (1 mmol) was added to the mixture of TfOH (1 mL), or TfOH–CH Cl (1 mL – 0.5
2
2
mL), or AlBr – benzene (5 mmol – 3 mL) and arene (1.2 mmol). The reaction mixture was stirred
3
at –35, 0 or 20 °C for the time as indicated in Table 1–3. The mixture was poured into ice water (30
mL) and extracted with chloroform (3 × 30 mL). The extracts were combined, washed with water, a
saturated aqueous solution of NaHCO , water again, and dried over Na SO , the solvent was
3
2
4
distilled off under reduced pressure. The residue was purified by column chromatography.
Analogously reactions were carried out in FSO H (1 mL), FSO H–CH Cl (2 mL – 0.5 mL)
3
3
2
2
or FSO H–SO (2 mL – 2 mL) at –75, or –40 °C for 2-5 h (Table 2). Reaction mixture was
3
2
quenched with concentrated aqueous hyhrochloric acid frozen down to –80 °C (30 mL), diluted
with water, extracted ,and worked-up as described above.
N-Methylamide of 3,3-diphenylpropanoic acid 2a (Table 1, entries 1,2). Colorless solid, mp
1
1f
1
8
8-90 °C (lit. 76-77 °C). Н NMR (500 МHz, CDCl ) δ 7.28-7.16 (10Нarom., m), 5.43 (1H, br.s,
3
N-H), 4.58 (1Н, t, J 7.5 Hz, Ar CH-), 2.88 (2H, d, J 7.5 Hz, CH ), 2.62 (3H, d, J 3.9 Hz, N-CH );
2
2
3
1
3
С NMR (125 МHz, CDCl ) δ 171.7, 143.7, 128.5, 127.7, 126.5, 47.3, 43.2, 26.2. MS (EI) m/z
3
+
+
(
%): 239 (М , 90), 208 (15), 180 (35), 167 (100), 152 (28); HRMS (ES ) calcd for C H NO
16 18
+
(
M+H ) 240.1383, found 240.1386.
N-Methylamide of 3-(4-methylphenyl)-3-phenylpropanoic acid 2b (Table 1, entries 3; Table
1
2
, entries 1-5). Oily compound. Н NMR (500 МHz, CDCl ) δ 7.25 (2Нarom., t, J 7.5 Hz), 7.21
3
(
2Нarom., d, J 7.5 Hz), 7.17 (1Нarom., t, J 7.5 Hz), 7.12-7.07 (4Нarom., m,), 5.21 (1H, br.s, N-H), 4.53
1Н, t, J 7.5 Hz, Ar CH-), 2.86 (2H, d, J 7.5 Hz, CH ), 2.64 (3H, d, J 4.7 Hz, 4-MeC H ), 2.29 (3Н,
(
2
2
6
4
13
s, N-CH ); С NMR (125 МHz, CDCl ) δ 171.8, 144.0, 140.8, 136.0, 129.3, 128.5, 127.7, 127.6,
3
3
+
+
1
26.4, 47.0, 43.4, 26.3, 21.0. HRMS (ES ) calcd for C H NO (M+H ) 254.1539, found 254.1542.
17 20
N-Methylamide of 3-(2-methylphenyl)-3-phenylpropanoic acid 2c (Table 1, entries 3) was
obtained as a mixture with compound 2b. Colorless solid, mp 114-116 °C (for the ration ~ 10:1
1
[
2b:2c]). Н NMR (500 МHz, CDCl , from the spectrum of the mixture) δ 7.28-7.16 (9Нarom., m),
3
5
.21 (1H, br.s, N-H), 4.77 (1Н, t, J 7.5 Hz, Ar CH-), 2.86 (2H, d, J 7.5 Hz, CH ), 2.64 (3H, d, J 4.7
2 2
+
Hz, 2-MeC H ), 2.27 (3Н, s, N-CH ). For the mixture of compounds 2b,c: HRMS (ES ) calcd for
6
4
3
+
C H NO (M+H ) 254.1539, found 254.1545.
17
20
N-Methylamide of 3-(3,4-dimethylphenyl)-3-phenylpropanoic acid 2d (Table 1, entries 4;
1
Table 2, entries 7,8). Oily compound. Н NMR (500 МHz, CDCl ) δ 7.28-7.22 (4Нarom., m), 7.17
3
(
1Нarom., t, J 5.6 Hz), 7.05-6.95 (3Нarom., m), 5.30 (1H, br.s, N-H), 4.50 (1Н, t, J 7.9 Hz, Ar CH-),
2
1
3
2
.87 (2H, dd, J 7.9, 1.6 Hz, CH ), 2.65 (3H, d, J 4.8 Hz, N-CH ), 2.20 (6Н, s, 3,4-(Me) C H ); С
2 3 2 6 4
1
0

ACCEPTED MANUSCRIPT
NMR (125 МHz, CDCl ) δ 171.9, 144.1, 141.1, 136.7, 134.7, 129.8, 129.1, 128.5, 127.6, 126.4,
3
+
+
1
24.8, 47.0, 43.4, 26.3, 19.8, 19.3. HRMS (ES ) calcd for C H NO (M+H ) 268.1696, found
18 22
2
68.1702.
N-Methylamide of 3-(2,4-dimethylphenyl)-3-phenylpropanoic acid 2e and N-methylamide of
3
-(2,6-dimethylphenyl)-3-phenylpropanoic acid 2f (Table 1, entries 5) were obtained as a mixture.
1
Compound 2e: Н NMR (500 МHz, CDCl , from the spectrum of the mixture) δ 7.28-6.82 (8Нarom.,
3
m), 5.50 (1H, br.s, N-H), 4.72 (1Н, t, J 7.7 Hz, Ar CH-), 2.88-2.78 (2H, m, CH ), 2.62 (3H, d, J 4.7
2
2
Hz, N-CH ), 2.27 (3Н, s, 2,4-(Me) C H ), 2.22 (3Н, s, 2,4-(Me) C H ) в двух последних пиках
3
2
6
3
2
6
3
1
исправил 6Н на 3Н. Compound 2f: Н NMR (500 МHz, CDCl , from the spectrum of the mixture)
3
7
.28-6.82 (8Нarom., m), 5.50 (1H, br.s, N-H),4.49 (1Н, t, J 7.7 Hz, Ar CH-), 2.88-2.78 (2H, m, CH ),
2 2
2
.58 (3H, d, J 4.6 Hz, N-CH ), 2.58 (3H, d, J 4.7 Hz, N-CH ) (этот сигнал исправил
3
3
+
полностью), 2.25 (6Н, s, 2,6-(Me) C H ). For the mixture of compounds 2e,f: HRMS (ES ) calcd
2
6
3
+
for C H NO (M+H ) 268.1696, found 268.1705.
1
8
22
N-Methylamide of 3-(2,5-dimethylphenyl)-3-phenylpropanoic acid 2g (Table 1, entries 6).
1
Colorless solid, mp 139-141 °C. Н NMR (500 МHz, CDCl ) δ 7.22 (2Нarom., d, J 7.6 Hz), 7.18-7.14
3
(3Нarom., m), 7.04-7.00 (2Нarom., m), 6.94 (1Нarom., d, J 7.6 Hz), 5.21 (1H, br.s, N-H), 4.73 (1Н, t, J
7
.6 Hz, Ar CH-), 2.89-2.78 (2H, m, CH ), 2.65 (3H, d, J 4.6 Hz, N-CH ), 2.32 (3Н, s, 2,5-
2
2
3
1
3
(
Me) C H ), 2.22 (3Н, s, 2,5-(Me) C H ); С NMR (125 МHz, CDCl ) δ 172.0, 143.7, 141.5,
2 6 4 2 6 3 3
+
1
35.4, 133.6, 130.8, 128.6, 128.1, 127.3, 127.1, 126.4, 43.8, 43.4, 26.5, 21.4, 19.5. HRMS (ES )
+
calcd for C H NO (M+H ) 268.1696, found 268.1699.
1
8
22
N-Methylamide of 3-(4-methoxylphenyl)-3-phenylpropanoic acid 2h (Table 1, entries 7;
1
Table 2, entries 10). Colorless solid, mp 139-141 °C. Н NMR (500 МHz, CDCl ) δ 7.26 (1Нarom., t,
3
J 7.0 Hz), 7.21 (2Нarom., d, J 7.0 Hz), 7.17 (2Нarom., t, J 7.0 Hz), 7.14 (2Нarom., d, J 7.0 Hz), 6.81
(
2Нarom., d, J 7.0 Hz), 5.49 (1H, br.s, N-H), 4.52 (1Н, t, J 7.7 Hz, Ar CH-), 3.75 (3Н, s, 4-
2
1
3
OMeC H ), 2.85 (2H, d, J 7.7 Hz, CH ), 2.62 (3H, d, J 4.9 Hz, N-CH ); С NMR (125 МHz,
6
4
2
3
CDCl ) δ 182.5, 171.8, 158.0, 144.1, 135.8, 128.6, 128.5, 127.5, 126.3, 113.9, 55.1, 46.5, 43.4,
3
+
+
2
6.2. MS (EI) m/z (%): 269 (М , 37), 210 (14), 197 (100), 165 (17), 152 (14); HRMS (ES ) calcd
+
for C H NO (M+H ) 270.1489, found 270.1493.
1
7
20
2
N-Methylamide of 3-(3,4-dimethoxylphenyl)-3-phenylpropanoic acid 2i (Table 1, entries 8).
1
Colorless solid, mp 110-112 °C. Н NMR (500 МHz, CDCl ) δ 7.30-7.27 (2Нarom., m), 7.23-7.18
3
(
3Нarom., m), 6.79-6.73 (3Нarom., m), 5.22 (1H, br.s, N-H), 4.52 (1Н, t, J 7.7 Hz, Ar CH-), 3.84 (3Н,
2
s, 3,4-(OMe) C H ), 3.81 (3Н, s, 3,4-(OMe) C H ) (этот сигнал исправил), 2.85 (2H, d, J 7.7 Hz,
2
6
3
2
6
3
13
CH ), 2.66 (3H, d, J 4.9 Hz, N-CH ); С NMR (125 МHz, CDCl ) δ 171.7, 149.0, 147.7, 143.9,
2
3
3
1
1

ACCEPTED MANUSCRIPT
+
1
36.4, 128.6, 127.6, 126.5, 119.3, 111.6, 111.2, 55.9, 46.9, 43.6, 26.3. HRMS (ES ) calcd for
+
C H NO (M+H ) 300.1594, found 300.1598.
18
22
3
N-Methylamide of 3-(3,4-dichlorophenyl)-3-phenylpropanoic acid 2j (Table 1, entries 9).
1
Oily compound. Н NMR (500 МHz, CDCl ) δ 7.28-7.22 (2Нarom., m), 7.17-7.15 (3Нarom., m), 7.03-
3
6
2
.97 (2Нarom., m), 6.93 (1Нarom., d, J 7.0 Hz), 5.27 (1H, br.s, N-H), 4.72 (1Н, t, J 7.7 Hz, Ar CH-),
2
+
.89-2.78 (2H, m, CH ), 2.65 (3H, br.s, N-CH ). MS (EI) m/z (%): 307 (М , 88), 248 (34), 235
2
3
+
(
68), 199 (33), 178 (33), 165 (100), 107 (19), 91 (23), 58 (39); HRMS (ES ) calcd for C H Cl NO
16 16 2
+
(
M+H ) 308.0603, found 308.0609.
N,N-Diethylamide of 3,3-diphenylpropanoic acid 2k (Table 1, entries 10). Colorless solid, mp
1
1b
1
7
9-81 °C (lit. 77-78 °C). Н NMR (500 МHz, CDCl ) δ 7.26-7.24 (8Нarom., m), 7.18-7.16 (2Нarom.,
3
m), 4.75 (1Н, t, J 7.0 Hz, Ar CH-), 3.26-3.19 (4H, m, N(CH CH ) ), 3.05 (2H, d, J 7.0 Hz, CH ),
2
2
3 2
2
+
1
.02 (6H, br.s, N(CH CH ) ). MS (EI) m/z (%): 281 (М , 100), 167 (69), 152 (26), 114 (60), 72
2 3 2
+
+
(
33); HRMS (ES ) calcd for C H NO (M+H ) 282.1852, found 282.1856.
19 24
N,N-Diisopropylamide of 3,3-diphenylpropanoic acid 2l (Table 1, entries 11,12). Oily
1
compound. Н NMR (500 МHz, CDCl ) δ 7.29-7.15 (8Нarom., m), 7.18 (2Нarom., t, J 5.0 Hz), 4.72
3
(
1Н, t, J 7.4 Hz, Ar CH-), 3.98-3.95 (1H, m, N(CH(CH ) ) ), 3.44-3.32 (1H, m, N(CH(CH ) ) ),
2 3 2 2 3 2 2
3
.01 (2H, d, J 7.4 Hz, CH ), 1.29 (6H, d, J 6.6 Hz, N(CH(CH ) ) ), 1.04 (6H, d, J 6.6 Hz,
2 3 2 2
13
N(CH(CH ) ) ); С NMR (125 МHz, CDCl ) δ 170.0, 144.6, 128.5, 128.1, 126.3, 48.7, 47.4, 45.9,
3
2 2
3
+
+
4
0.8, 21.0, 20.7. HRMS (ES ) calcd for C H NO (M+H ) 310.2165, found 310.2169.
21 28
N-Piperidinylamide of 3,3-diphenylpropanoic acid 2m (Table 1, entries 13). Oily compound
11c
1
(
lit. 122-124 °C). Н NMR (500 МHz, CDCl ) δ 7.28-7.23 (8Нarom., m,), 7.18-7.15 (2Нarom., m),
3
4
.67 (1Н, t, J 7.4 Hz, Ar CH-), 3.47-3.29 (4H, m, N(CH ) (CH ) CH ), 3.04 (2H, d, J 7.4 Hz, CH ),
2 2 2 2 2 2 2
13
1
.54-1.53 (4H, m, N(CH ) (CH ) CH ), 1.41-1.31 (4H, m, N(CH ) (CH ) CH ); С NMR (125
2
2
2 2
2
2 2
2 2
2
МHz, CDCl ) δ 169.3, 144.2, 128.4, 127.8, 126.2, 47.3, 46.7, 38.8, 29.6, 24.4. MS (EI) m/z (%):
3
+
+
+
2
93 (М , 53), 165 (30), 126 (100); HRMS (ES ) calcd for C H NO (M+H ) 294.1852, found
20 24
2
94.1857.
N-Methylamide of 3-(4-methyl-3-sulfonylfluoridephenyl)-3-phenylpropanoic acid 2n (Table
1
2
, entries 6). Oily compound. Н NMR (500 МHz, CDCl ) δ 7.89 (1Harom., s), 7.50 (1Нarom., d, J 7.8
3
Hz), 7.18-7.33 (6Нarom., m,), 5.31 (1H, br.s, N-H), 4.69 (1Н, t, J 7.4 Hz, Ar CH-), 2.90 (2H, d, J 7.8
2
13
Hz, CH ), 2.70 (3H, d, J 4.8 Hz, N-CH ), 2.63 (3H, s, 4-MeC H ); С NMR (125 МHz, CDCl ) δ
2
3
6
4
3
1
9
1
70.7, 143.0, 142.4, 137.0, 135.2, 133.1, 128.9, 128.5, 127.6, 127.1, 46.4, 42.6, 26.3, 19.8; F
+
NMR (470 MHz, CDCl ) δ -193.88 to -194.20 (m, 1F). MS (EI) m/z (%): 335 (М , 100), 263 (50),
3
+
+
1
94 (75), 165(60), 58 (25); HRMS (ES ) calcd for C H FNO S (M+H ) 335.0991, found
17 18 3
3
35.0997.
1
2

ACCEPTED MANUSCRIPT
N-Methylamide of 3-(2-fluorophenyl)-3-phenylpropanoic acid 2o (Table 2, entries 9).
1
Colorless solid, mp 79-81 °C. Н NMR (500 МHz, CDCl ) δ 7.29-7.25 (5Нarom., m,), 7.20-7.18
3
(2Нarom., m), 7.07 (1Нarom., t, J 7.8 Hz), 6.99 (1Нarom., t, J 7.8 Hz), 5.44 (1H, br.s, N-H), 4.83 (1Н, t,
13
J 7.8 Hz, Ar CH-), 2.93 (2H, dd, J 7.8, 4.8 Hz, CH ), 2.66 (3H, d, J 4.8 Hz, N-CH ); С NMR (125
2
2
3
МHz, CDCl ) δ 171.3, 160.7 (d, J 224.9 Hz), 142.6, 130.5 (d, J 13.8 Hz), 129.0, 128.6, 128.3,
3
1
9
1
27.6, 126.6, 124.2 (d, J 3.6 Hz), 115.8 (d, J 89.2 Hz), 41.8, 41.5, 26.3; F NMR (470 MHz,
+
CDCl ) δ -117.17 to -117.22 (1F, m). MS (EI) m/z (%): 257 (М , 100), 198 (26), 185 (83), 165
3
+
+
(
32), 121 (18), 91 (16), 58 (17); HRMS (ES ) calcd for C H FNO (M+H ) 258.1289, found
16 17
2
58.1294.
N-Methylamide of 3,3-(4-methoxyphenyl)propanoic acid 2p (Table 2, entries 11,12).
1
Colorless solid, mp 104-106 °C. Н NMR (500 МHz, CDCl ) δ 7.11 (4Нarom., d, J 8.4 Hz), 6.79
3
(
4Нarom., d, J 8.4 Hz), 5.36 (1H, br.s, N-H), 4.46 (1Н, t, J 7.6 Hz, Ar CH-), 3.75 (6H, s (4-
2
13
OMeC H ) ), 2.80 (2H, d, J 7.6 Hz, CH ), 2.63 (3H, d, J 4.8 Hz, N-CH ); С NMR (125 МHz,
6
4 2
2
3
+
CDCl ) δ 171.9, 158.1, 136.3, 128.5, 113.9, 55.2, 45.8, 43.7, 26.2. MS (EI) m/z (%): 299 (М , 16),
3
+
+
2
27 (100); HRMS (ES ) calcd for C H NO (M+H ) 300.1594, found 300.1598.
18 22 3
N-Methylamide of 3-(3,4-dimethoxyphenyl)-3-(4-methoxyphenyl)propanoic acid 2q (Table 2,
1
entries 12,13). Oily compound. Н NMR (500 МHz, CDCl ) δ 7.10-6.60 (7Нarom., m), 5.56 (1H,
3
br.s, N-H), 4.45 (1Н, t, J 7.6 Hz, Ar CH-), 3.80 (3H, s, 3,4-OMe C H ), 3.77 (3H, s, 3,4-
2
2
6
3
OMe C H ), 3.74 (3H, s, 4-OMeC H ), 2.80 (2H, d, J 7.6 Hz, CH ), 2.63 (3H, d, J 4.8 Hz, N-CH ).
2
6
3
6
4
2
3
+
+
HRMS (ES ) calcd for C H NO (M+H ) 330.1700, found 330.1703.
1
9
24
4
N-Methylamide of 3,3-(3,4-dimethoxyphenyl)propanoic acid 2r. Compound 2r was obtained
1
in a mixture with compounds 2p,q (Table 2, entries 12). Oily compound. Н NMR (500 МHz,
CDCl , from the spectrum of the mixture) δ 7.13-6.71 (6Н
, m), 4.45 (1Н, t, J 7.5 Hz, Ar CH-),
2
3
arom.
3
3
.87 (3H, s, 3,4-OMe C H ), 3.83 (3H, s, 3,4-OMe C H ), 3.80 (3H, s, 3,4-OMe C H ), 3.76 (3H, s,
2 6 3 2 6 3 2 6 3
,4-OMe C H ), 2.81 (2H, d, J 7.5 Hz, CH ), 2.63 (3H, d, J 4.8 Hz, N-CH ). MS (EI) m/z (%): 359
2
6
3
2
3
+
+
+
(
М , 19), 287 (100), 207 (44), 73 (9); HRMS (ES ) calcd for C H NO (M+H ) 360.1805, found
20 26 5
3
60.1807.
N-Phenylamide of 3,3-diphenylpropanoic acid 2s (Table 3, entries 2). Compound 2s was
1
obtained in a mixture with compound 4a (for the ration ~ 5:1 [2s:4a]). Oily compound. Н NMR
(
500 МHz, CDCl , from the spectrum of the mixture) δ 7.28-6.94 (15Нarom., m), 4.62 (1Н, t, J 7.5
3
+
+
Hz, Ar CH-), 3.06 (2H, d, J 7.5 Hz, CH ). HRMS (ES ) calcd for C H NO (M+H ) 301.1467,
2
2
21 19
found 301.1472.
N-Phenylamide of 3-(4-methoxyphenyl)-3-phenylpropanoic acid 2t and N-phenylamide of 3-
2-methoxyphenyl)-3-phenylpropanoic acid 2u were obtained as a oily mixture with compound 4a
(
1
3

ACCEPTED MANUSCRIPT
1
(
Table 3, entries 3). Compound 2t: Н NMR (500 МHz, CDCl , from the spectrum of the mixture)
3
δ 7.21-6.80 (14Нarom., m), 4.59 (1Н, t, J 7.6 Hz, Ar CH-), 3.76 (3H, s, 4-OMeC H ), 3.05 (2H, d, J
2
6
4
1
7
.6 Hz, CH ). Compound 2u: Н NMR (500 МHz, CDCl , from the spectrum of the mixture) δ
2 3
7
.21-6.80 (14Нarom., m), 5.00 (1Н, t, J 7.6 Hz, Ar CH-), 3.77 (3H, s, 2-OMeC H ), 3.05 (2H, d, J 7.6
2
6
4
+
+
Hz, CH ). For the mixture of compounds 2t,u: HRMS (ES ) calcd for C H NO (M+H )
2
22 21
2
3
31.1572, found 331.1576.
N-Phenylamide of 3-(3,4-dimethoxyphenyl)-3-phenylpropanoic acid 2v. Compound 2v was
1
obtained as a oily mixture with compound 4a (Table 3, entries 4). Н NMR (500 МHz, CDCl , from
3
the spectrum of the mixture) δ 7.42 (1H, br.s, N-H), 7.35-7.18 (9Нarom., m), 7.05 (1Нarom., t, J 9.7
Hz), 6.83-6.76 (3Нarom., m), 4.60 (1Н, t, J 9.7 Hz, Ar CH-), 3.81 (3H, s, 3-OMeC H ), 3.75 (3H, s,
2
6
4
+
+
4
-OMeC H ), 3.04 (2H, d, J 9,7 Hz, CH ). HRMS (ES ) calcd for C H NO (M+H ) 361.1678,
6 4 2 23 23 3
found 361.1684.
1
1h
3,4-Dihydro-4-phenyl-quinolin-2(1H)-one 4a (Table 3, entries 1-4). Oily compound (lit.
1
1
77-178 °C). Н NMR (500 МHz, CDCl ) δ 8.92 (1H, br.s, N-H), 7.35-7.19 (6Нarom., m), 6.98-6.88
3
+
(
3Harom., m), 4.30 (1Н, t, J 7.5 Hz, C4-H), 2.95-2.89 (2H, m, C3-H ). HRMS (ES ) calcd for
2
+
C H NO (M+H ) 223.0997, found 223.1004.
15
13
General procedure for reduction of cinnamides 2a,l,m into 3,3-diphenylpropylamines
a-c (Scheme 2). Mixture of LiAlH (0.5 mmol) with solution of cinnamide (0.5 mmol) in
3
4
anhydrous ether (10 mL) was refluxed with magnetic stirring for 4 h. Then reaction mixture was
cooled down to room temperature, quenched with water (50 mL), and extracted with chloroform
(3×30 mL). The extracts were combined, washed with water, a saturated aqueous solution of
NaHCO , water again, and dried over Na SO , the solvent was distilled off under reduced pressure.
3
2
4
The residue was purified by column chromatography.
N-Methyl-3,3-diphenylpropylamine 3a. Oily compound (yield 66%). Н NMR (500 МHz,
CDCl ) δ 7.39-7.17 (10Н , m), 4.01 (1Н, t, J 7.8 Hz, Ar CH-), 3.39 (1H, br.s, N-H), 2.57 (2Н, t,
1
3
arom.
2
J 7.8 Hz, CHCH CH N), 2.38 (3H, s, N-CH ), 2.29 (2Н, q, J 7.8 Hz, CHCH CH N). MS (EI) m/z
2
2
3
2
2
+
+
+
(
%): 225 (М , 100), 193 (65), 179 (34), 165 (75), 152 (33); HRMS (ES ) calcd for C H N (M+H )
16 20
2
26.1590, found 226.1594.
N,N-Diisopropyl-3,3-diphenylpropylamine 3b. Oily compound (yield 61%). Н NMR (500
МHz, CDCl ) δ 7.29-7.25 (8Нarom., m), 7.16-7.14 (2Нarom., m), 3.93 (1Н, t, J 7.5 Hz, Ar CH-), 3.02-
5
d 1
3
2
2
.98 (2H, m, N((CH) (Me) ) ), 2.38-2.32 (2H, m, CHCH CH N), 2.22-2.16 (2H, m,
2 2 2 2 2
13
CHCH CH NH), 0.94-0.93 (12H, m, N((CH) (Me) ) ); С NMR (125 МHz, CDCl ) δ 145.0,
2
2
2
2 2
3
+
+
1
28.4, 127.8, 126.1, 49.2, 48.3, 47.2, 44.2, 20.3. HRMS (ES ) calcd for C H N (M+H ) 295.2300,
16 20
found 295.2306.
1
4

ACCEPTED MANUSCRIPT
2
0
1
1
-(3,3-Diphenylpropyl)piperidine 3c. Oily compound (yield 90%) (lit. 40-41 °C). Н NMR
(
500 МHz, CDCl ) δ 7.29-7.25 (8Нarom., m), 7.19-7.15 (2Нarom., m), 3.97 (1Н, t, J 7.7 Hz, Ar CH-),
3
2
2
.40-2.30 (4H, m, N(CH CH ) CH ), 2.28-2.25 (Ar -CHCH CH N), 1.61-1.57 (4H, m,
2 2 2 2 2 2 2
13
N(CH CH ) CH ), 1.44-1.40 (2H, m, N(CH CH) CH ); С NMR (125 МHz, CDCl ) δ 144.1,
2
2 2
2
2
2
2
3
+
+
1
28.5, 127.7, 126.4, 57.2, 54.1, 49.2, 31.3, 24.6, 23.6. HRMS (ES ) calcd for C H N (M+H )
20 26
2
80.2060, found 280.2064.
Acknowledgments
This project was supported by the Russian Scientific Foundation, grant no. 14-13-00448
Natural lingo-carbohydrate materials for organic synthesis”.
“
Supplementary data
1
19
13
These data include H, F, C NMR spectra of the obtained compounds, and details of
computational quantum chemical calculations of carbocations.
References
1
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Andersson, P. G.; Schink, H. E.; Osterlund, K. J. Org. Chem., 1998, 63, 8067-8070.
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67, 5028-5031.
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0. Zhang, Y.; McElria, A.; Sanches, G. V.; Do, D.; Gomez, A.; Aguirre, S. L.; Rendy, R.;
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1. (a) Koltunov, K. Yu.; Walspurger, S.; Sommer, J. Chem. Comm., 2004, 1754-1755; (b)
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Yu.; Surya Prakash, G. K.; Rasul, G.; Olah, G. A. Heterocycles, 2004, 62, 757-772.
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2. Ryabukhin, D. S.; Gurskaya, L. Yu.; Fukin, G. K.; Vasilyev, A. V. Tetrahedron, 2014, 70,
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1
3. Vasilyev, A.V. Russ. Chem. Rev., 2013, 82, 187-204.
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5. (a) Parr, R. G.; Szentpaly, L. v.; Liu, S. J. Am. Chem. Soc., 1999, 121, 1922-1924; (b)
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Cui, Q.; Baboul, A.G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.;
Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.;
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20. Adamson, D.W. J. Chem. Soc., 1949, 144-155.
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Supporting Information
Tandem Superelectrophilic Hydroarylation of C=C Bond and Carbonyl
Reduction in Cinnamides: Synthetic Rout to 3,3-Diarylpropylamines,
Valuable Pharmaceuticals
a
b
b
Dmitry N. Zakusilo, Dmitry S. Ryabukhin, Irina A. Boyarskaya,
a
a,b
Oleg S. Yuzikhin, and Aleksander V. Vasilyev *
a
Department of Organic Chemistry, Saint Petersburg State Forest Technical University,
Institutsky per., 5, Saint Petersburg, 194021, Russia. Fax: +07-812-670-93-90.
*
Corresponding author: A.V. Vasilyev, e-mail: aleksvasil@mail.ru
b
Department of Organic Chemistry, Institute of Chemistry, Saint Petersburg State University,
Universitetsky pr., 26, Saint-Petersburg, Petrodvoretz, 198504, Russia.
Table of contents
1
13
19
H, C, F Spectra of compounds………………………………………………………S2-S29
DFT Quantum chemical calculations of carbocations……………………………………S30-S48
1

ACCEPTED MANUSCRIPT
O
1
a
HN
CH3
7
.35
2.95
ppm)
(
(ppm)
(ppm)
8
.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
(ppm)
1
Figure 1. Н NMR spectrum of the compound 1a (CDCl , 500 МHz).
3
H C
3
O
HN
1
b
CH3
7
.6
7.4
ppm)
7.2
7.0
(
8
.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
(ppm)
1
Figure 2. Н NMR spectrum of the compound 1b (CDCl , 500 МHz).
3
2

ACCEPTED MANUSCRIPT
H C
3
O
H C
3
HN
1
c
CH3
7
.25
7.20
7.15
ppm)
7.10
7.05
(
8
.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
(ppm)
1
Figure 3. Н NMR spectrum of the compound 1c (CDCl , 500 МHz).
3
H C
3
O
H C
3
HN
1
c
CH3
1
90
180
170
160
150
140
130
120
110
100
90
80
70
60
50
40
30
20
10
(ppm)
1
3
Figure 4. С NMR spectrum of the compound 1c (CDCl , 125 МHz).
3
3

ACCEPTED MANUSCRIPT
F
O
HN
1d
CH3
1
Figure 5. Н NMR spectrum of the compound 1d (CDCl , 500 МHz).
3
F
O
HN
1d
CH3
1
3
Figure 6. С NMR spectrum of the compound 1d (CDCl , 125 МHz).
3
4

ACCEPTED MANUSCRIPT
F
O
HN
1d
CH3
1
9
Figure 7. F NMR spectrum of the compound 1d (CDCl , 470 МHz).
3
O
H C
3
O
HN
1e
CH3
1
Figure 8. Н NMR spectrum of the compound 1e (CDCl , 500 МHz).
3
5

ACCEPTED MANUSCRIPT
O
O
H C
3
H C
O
3
HN
CH3
1f
7
.10
7.05
7.00
6.95
6.90
6.85
6.80
(ppm)
3
.92
3.88
ppm)
3.84
2.95
(ppm)
2.90
(
8
.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
(ppm)
1
Figure 9. Н NMR spectrum of the compound 1f (CDCl , 500 МHz).
3
O
dioxane
NEt2
1g
7
.6
7.4
7.2
ppm)
7.0
6.8
(
3
.4
1.2
(ppm)
(ppm)
1
0.0
9.5
9.0
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
ppm)
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
(
1
Figure 10. Н NMR spectrum of the compound 1g (CDCl , 500 МHz).
3
6

ACCEPTED MANUSCRIPT
O
N
1
h
7
.60
7.50
7.40
7.30
(ppm)
(ppm)
8
.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
ppm)
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
(
1
Figure 11. Н NMR spectrum of the compound 1h (CDCl , 500 МHz).
3
O
N
1
h
2
0
1
29.0
128.0
(ppm)
(
ppm)
(ppm)
1
90
180
170
160
150
140
130
120
110
100
90
80
70
60
50
40
30
20
10
(ppm)
1
3
Figure 12. С NMR spectrum of the compound 1h (CDCl , 125 МHz).
3
7

ACCEPTED MANUSCRIPT
O
N
1
i
7
.52
6.90
1
.70
1.65
ppm)
1.60
(ppm)
(ppm)
(ppm)
(ppm)
(
8
.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
(ppm)
1
Figure 13. Н NMR spectrum of the compound 1i (CDCl , 500 МHz).
3
O
N
1i
1
3
Figure 14. С NMR spectrum of the compound 1i (CDCl , 125 МHz).
3
8

ACCEPTED MANUSCRIPT
O
N
H
1j
7
.60
7.50
7.40
ppm)
7.30
7.20
(
8
.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
(ppm)
1
Figure 15. Н NMR spectrum of the compound 1j (CDCl , 500 МHz).
3
O
NH CH3
2a
1
Figure 16. Н NMR spectrum of the compound 2a (CDCl , 500 МHz).
3
9

ACCEPTED MANUSCRIPT
O
NH CH3
2a
1
3
Figure 17. С NMR spectrum of the compound 2a (CDCl , 125 МHz).
3
O
NH CH3
2
b
CH3
H
N
(ppm)
CH3
H C
O
3
7
.28
7.24
7.20
7.16
ppm)
7.12
7.08
2
c
(
(ppm)
2
.32
2.28
(ppm)
8
.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
ppm)
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
(
1
Figure 18. Н NMR spectrum of mixture of the compounds 2b and 2c (CDCl , 500 МHz).
3
1
0

ACCEPTED MANUSCRIPT
O
NH CH3
2b
CH3
1
29.0
128.0
ppm)
127.0
126.0
(
1
90
180
170
160
150
140
130
120
110
100
ppm)
90
80
70
60
50
40
30
20
10
(
1
3
Figure 19. С NMR spectrum of the compound 2b (CDCl , 125 МHz).
3
O
NH CH3
H C
3
CH3
2
d
7
.20
7.0
4
.5
(
ppm)
(ppm)
(ppm)
(ppm)
(ppm)
7
.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
(ppm)
1
Figure 20. Н NMR spectrum of the compound 2d (CDCl , 500 МHz).
3
1
1

ACCEPTED MANUSCRIPT
O
NH CH3
H C
3
CH3
2d
1
28
126
(ppm)
1
90
180
170
160
150
140
130
120
110
100
90
80
70
60
50
40
30
20
10
(ppm)
1
3
Figure 21. С NMR spectrum of the compound 2d (CDCl , 125 МHz).
3
O
H C
NH CH3
3
2e
CH3
CH3
O
CH3
NH CH3
2f
4
.7 4.50
(ppm)
(ppm)
2.90
2.80
(ppm)
7
.0
6.9
(ppm)
7
.20
2
.60
2.25
(ppm)
(ppm)
(
ppm)
8
.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
ppm)
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
(
1
Figure 22. Н NMR spectrum of mixture of the compounds 2e and 2f (CDCl , 500 МHz).
3
1
2