Reactions of enaminones and related compounds with N,N-dimethylacetamide dimethyl acetal. A simple one-pot metal-free synthesis of polysubstituted benzene derivatives

Article abstract of DOI:10.1016/j.tet.2014.02.039

Herein a simple one-pot metal-free synthesis of alkyl-, aryl-, heteroaryl- and alkoxycarbonyl substituted 1,3-bis(dimethylamino)benzene derivatives is described. The products were prepared from the corresponding methyl ketones or compounds with an α-methylene group in regard to the carbonyl group, using N,N-dimethylacetamide dimethyl acetal (DMADMA) as the reagent.

Full text of DOI:10.1016/j.tet.2014.02.039

Tetrahedron 70 (2014) 2359e2369
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Reactions of enaminones and related compounds with
N,N-dimethylacetamide dimethyl acetal. A simple one-pot
metal-free synthesis of polysubstituted benzene derivatives
b
a
a
a,b
ꢀ
ꢀ a
ꢀ
ꢀ
Benjamin Prek , Jure Bezensek , Marta Kasunic , Uros Groselj , Jurij Svete
,
Branko Stanovnik a
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Askerceva 5, PO Box 537, SI-1000 Ljubljana, Slovenia
b EN-FIST Centre of Excellence, Dunajska 156, SI-1000 Ljubljana, Slovenia
,b,
*
a
ꢀ
ꢀ
a r t i c l e i n f o
a b s t r a c t
Article history:
Herein a simple one-pot metal-free synthesis of alkyl-, aryl-, heteroaryl- and alkoxycarbonyl substituted
1,3-bis(dimethylamino)benzene derivatives is described. The products were prepared from the corre-
Received 18 November 2013
Received in revised form 4 February 2014
Accepted 17 February 2014
Available online 21 February 2014
sponding methyl ketones or compounds with an
using N,N-dimethylacetamide dimethyl acetal (DMADMA) as the reagent.
Ó 2014 Published by Elsevier Ltd.
a-methylene group in regard to the carbonyl group,
Keywords:
Methyl ketones
1,3-Dicarbonyl compounds
Enaminones
Polysubstituted benzene derivatives
Cyclocondensations
Microwave assisted reactions
1. Introduction
Aromatic compounds play an important role in organic chem-
istry as functional materials and bioactive compounds. Many
methods leading to benzene derivatives via cyclization of un-
saturated compounds are described in the literature. These are: the
DielseAlder reaction, which due to its broad scope and simplicity of
operation, is the most powerful and versatile synthetic method for
construction of six-membered rings ever since its discovery in
1928,8 Bergmann cyclization,9 Meyers,10 Saito,11 and Schmittel12
reactions.
Transition metal-catalyzed cycloadditions of alkynes provide an
efficient method for constructing aromatic derivatives.13 Recently,
a cobalt-catalyzed neutral DielseAlder reaction,14 an AuCl-catalyzed
[3þ3] cycloaddition,15 which allows excellent control of substitution
at the benzene ring, and a cationic rhodium(I)/BINAP complex-
catalyzed decarboxylative [2þ2þ2] cycloaddition16 as a new route
to substituted phenols, have been described. Additionally, Bronsted
acid activated chiral oxazaborolidine complexes,17 diarylprolinol
silyl ethers as catalysts,18a,b chiral Indium(III) complex,18c
[AlCl3þ2THF],18d cationic silicon Lewis acids,18e and also rhenium
and manganese-catalyzed syntheses18f of aromatic compounds
have also been reported. Ring-closure metathesis is also an impor-
tant method. In this manner, various substituted phenol and other
benzene derivatives were prepared.19 Because of the limitations of
Recently, alkyl-, aryl-, and heteroaryl methyl ketones 1 have been
transformed by treatment with N,N-dimethylformamide dimethyl
acetal (DMFDMA) or tert-butoxy bis(dimethylamino)methane
(Bredereck’s reagent) into the corresponding 3-(dimethylamino)-1-
substituted-prop-2-enones 2, which afforded, via regiospecific
microwave assisted [2þ2] cycloaddition to dimethyl acetylenedi-
carboxylate (DMAD), highly functionalized buta-1,3-dienes, i.e.,
dimethyl 2-[(dimethylamino)methylene]-3-(2-substituted)-succi-
nates 3.1e7 These highly functionalized buta-1,3-dienes proved to be
useful and versatile reagents in the formation of highly substituted
pyridines,2 pyridine N-oxides,2 pyrroles,2 pyrido[3,4-c]pyridazine
derivatives,2 6-substituted pyridine-3,4-dicarboxylates and their N-
oxides,7 as well as triazafulvalene derivatives4 (Scheme 1).
However, when we tried to prepare 4-(dimethylamino)pent-3-
en-2-one (4a) by treatment of acetone (1a) with N,N-dimethyla-
cetamide dimethyl acetal (DMADMA) under microwave irradiation,
we observed that N1,N1,N3,N3,5-pentamethylbenzene-1,3-diamine
(9a) was formed.
* Corresponding author. E-mail address: branko.stanovnik@fkkt.uni-lj.si
(B. Stanovnik).
0040-4020/$ e see front matter Ó 2014 Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.tet.2014.02.039

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B. Prek et al. / Tetrahedron 70 (2014) 2359e2369
Scheme 1.
the synthetic methods most of the diaminobenzene derivatives are
1-substituted-2,4-diaminobenzene derivatives.20 1-Alkyl-3,5-
diaminobenzene derivatives with various alkyl chain lengths have
been prepared from commercially available di-tert-butylmalonate
and 3,5-dinitrobenzyl chloride.21
3,5-bis(dimethylamino)toluene (9a) was isolated as the main
product in a one-pot procedure (Scheme 2). Since the formation of
3,5-bis(dimethylamino)toluene is a simple one-pot procedure, we
decided to examine the scope and limitations of this methodology
for the construction of polysubstituted benzene derivatives. In this
connection we selected several types of methyl ketones (acetyl
compounds).
3,5-Bis(dimethylamino)toluene was previously prepared from
acetylacetone and dimethylamine via 4-N,N-dimethylamino-3-
Scheme 2. Synthesis of N1,N1,N3,N3-tetramethyl-5-(substituted)benzene-1,3-diamines 9aej.
penten-2-one, which was converted with tetrakis(dimethylamino)-
titanium into N,N,N0,N0-tetramethyl-1,3-pentadiene-2,4-diamine,
followed by treatment with acetyl chloride and potassium tert-but-
oxide. When propionyl chloride was used, 3,5-bis(dimethylamino)-
1-ethylbenzene was obtained.22 The formation of 3,5-
bis(dimethylamino)toluene was also observed in the photochemical
heterolysis of 3,5-bis(dimethylamino)benzyl alcohols and esters in
connection with the studies of aryl carbenium ions substituted with
The first group represents simple methyl ketones, such as ace-
tone (1a), pentan-2-one (1b), acetophenone (1c), 2-acetylpyridine
(1d), 2-acetylpyrazine (1e), 3-acetyl-1-methylpyrrole (1f), 2-
acetylthiophene (1g), 3-acetylthiophene (1h), 2-acetylfuran (1i)
and 4-nitroacetophenone (1j). They were treated with DMADMA in
2.5 M ratio in a closed vessel under microwave conditions at tem-
peratures between 130 and 170 ꢀC for 12e35 min. After isolation
and purification of the crude products we obtained 1-substituted
3,5-bis(dimethylamino)benzene derivatives 9aej (Scheme 2,
Table 1).
meta-p
-donors.23,24
In this communication we report on a simple one-pot metal-free
synthesis of polysubstituted aromatic compounds from poly-
substituted enaminones prepared from alkyl ketones or com-
pounds with an a-methylene group next to the carbonyl group, and
N,N-dimethylacetamide dimethyl acetal (DMADMA).
Table 1
The N1,N1,N3,N3-tetramethyl-5-(substituted)benzene-1,3-diamines
Compound 9
R
Yield [%]
Mp [ꢀC]
a
b
c
d
e
f
g
h
i
Me
Pr
Ph
30
10
16
19
19
8
30
21
49
30
Oil
Oil
40e43a
76e80
96e101
90e96
Oil
2. Results and discussion
Pyridyl-2
Pyrazinyl-2
1-Methyl- pyrrolyl-3
Thienyl-2
Thienyl-3
Furyl-2
When we treated acetone (1a) with DMADMA instead of
DMFDMA a mixture of (E)-4-(dimethylamino)pent-3-en-2-one (4a)
and 9a were formed. Compound 4a did not react with dimethyl
acetylenedicarboxylate (DMAD) to give the corresponding 5a via
[2þ2] cycloaddition reaction. When we tried to improve the yield
of 4a by using excess DMADMA at elevated temperature;
83e89
Oil
112e117
j
40eO2NeC6H4
a
The starting acetophenone (1c) was incorporated in the crystal structure.

B. Prek et al. / Tetrahedron 70 (2014) 2359e2369
2361
The formation of the final products can be explained in the
following way: the methyl group of the methyl ketones 1aej reacts
with DMADMA to give the N,N-dimethylaminomethylene in-
termediates 4aej. The methyl group of 4aej reacts further with
DMADMA to give polysubstituted butadienes 6aej, from which the
corresponding anions 7aej are formed followed by rapid cycliza-
tion into 8aei and elimination of water to give the final products
9aej. The only exception is 1j where the reaction under these
conditions stops at 4j. In order to carry out the reaction to the
desired product 9j the intermediate 4j was heated with a large
excess of DMADMA (Scheme 2).
In the case of phenylacetone (10) the more reactive methylene
group at position 1 reacts with DMADMA to form firstly 4-(dime-
thylamino)-3-phenylpent-3-en-2-one (11). The methyl group at
position 4 reacts further with DMADMA to give 12. In the next step,
substitution of one dimethylamino group with a methoxy group
takes place to form 14, followed by cyclization into 15 and elimi-
nation of water to form 2-methoxy-N,N,6-trimethylbiphenyl-4-
amine (16) as the final product (Scheme 3).
to 30a,b. Intermediates 25a,b can than be transformed under re-
action conditions in a retro-Claisen reaction into 4a,c, which react
further with DMADMA to form 6a,c. The latter intermediates can
alsobe formed from30a,bin a retro-Claisen reaction. Intermediate6a
cyclizes into 9a. On the other hand, intermediate 6c cyclizes in the
reaction sequence 26/27/28 into 29. The reaction path
30a,b/31a,b/9a (and 29) seems to be less plausible (Scheme 5).
Ethyl acetoacetate (32) reacts analogously via intermediates 33
and 34 to form ethyl 2,4-bis(dimethylamino)-6-methylbenzoate
(35) (Scheme 6).
The reaction of dimethyl malonate (36) proceeds via in-
termediates 37e39 to afford the corresponding methyl 2,4-
bis(dimethylamino)-6-methoxybenzoate (40). The reaction with
diethyl malonate (41) proceeds analogously, thus leading to the
corresponding ethyl 2,4-bis(dimethylamino)-6-methoxybenzoate
(42) (Scheme 7).
Methyl hippurate (43) produced N-[2,4-bis(dimethylamino)-6-
methoxyphenyl]benzamide (47) via intermediates 44ꢁ46
(Scheme 8).
Scheme 3. Synthesis of 2-methoxy-N,N,6-trimethylbiphenyl-4-amine (16).
In the case of propiophenone (17) the reaction took place at
the methylene group to form in the reaction sequence
18/19/20/21/22 the isomeric biphenyl derivative 5-methoxy-
N,N,6-trimethylbiphenyl-3-amine (23) (Scheme 4).
In some instances, intermediates were isolated and charac-
terized, such as (E)-3-(dimethylamino)-1-phenylbut-2-ene-1-one
(4c)
and
3-(dimethylamino)-1-(4-nitrophenyl)but-2-ene-1-
one (4j).
Scheme 4. Synthesis of 5-methoxy-N,N,6-trimethylbiphenyl-3-amine (23).
The 1,3-diketone representatives acetylacetone (24a) and ben-
zoylacetone (24b) react with DMADMA first at the methylene group
to form intermediates 25a,b. These can react further with DMADMA
Methyl cyanoacetate (48) afforded, via intermediate 49, (2Z,4Z)-
methyl 2-cyano-3,5-bis(dimethylamino)hexa-2,4-dienoate (50),
which did not cyclize into the benzene derivative due to

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B. Prek et al. / Tetrahedron 70 (2014) 2359e2369
Scheme 5. Cyclization of 1,3-diketones 24a,b into N1,N1,N3,N3,5-pentamethylbenzene-1,3-diamine (9a) and 5-methoxy-N,N-dimethylbiphenyl-3-amine (29).
Scheme 6. Synthesis of ethyl 2,4-bis(dimethylamino)-6-methylbenzoate (35).
inappropriate orientation of the methyl group in respect to the
ester group (Scheme 9).
showed a triplet with a meta coupling constant for the 4-H proton
in the range between 5.95 (R¼methyl) and 6.19 (R¼pyrazinyl-2)
and a doublet integrated for 2 for the 2-H and 6-H protons in the
range between 6.03 (R¼methyl) and 6.78 (R¼pyrazinyl-2) (Fig. 1).
In the case of the reaction between phenylacetone (10) and
DMADMA, more than one product could be formed. Besides the
reaction path i that leads to the actual product via intermediates
11e15 (Scheme 3), reaction path ii could also be probable, thus five
different products could be formed (Scheme 10). After careful
evaluation of the information derived from the 1Hꢁ13C HSQC and
1Hꢁ13C HMBC NMR spectra, we were able to confirm, without
a doubt that the structure of the product is 16.
3. Structure determination
The structures of the new compounds were determined by 1H
and 13C NMR spectroscopy, HRMS and microanalyses for C, H, and
N.
In many cases the structure of the final product was not
straightforward, therefore additional methods for determination of
the structures had to be applied. Two-dimensional nuclear mag-
netic resonance spectroscopy (2D NMR), mainly 1He13C HSQC and
1He13C HMBC, were the means of gathering the missing in-
formation, to correctly determine the structures. In the case of
products 9aej the structure determination was straightforward.
Because of the symmetry of the products, the 1H NMR spectra
The absence of the benzyl CH2 group signal in the 1H NMR
spectrum meant that structures 16c and 16d were not those of the
product. The characteristic lower chemical shifts for the protons on
the diamine bearing benzene ring, made it easy to distinguish the

B. Prek et al. / Tetrahedron 70 (2014) 2359e2369
2363
Scheme 7. Synthesis of methyl 2,4-bis(dimethylamino)-6-methoxybenzoate (40) and ethyl 2,4-bis(dimethylamino)-6-methoxybenzoate (42).
Scheme 8. Synthesis of N-(2,4-bis(dimethylamino)-6-methoxyphenyl)benzamide (47).
Scheme 9. (2Z,4Z)-methyl 2-cyano-3,5-bis(dimethylaminohexa-2,4-dienoate (50).
H3 and H5 protons from other aromatic protons, which were at
higher chemical shifts. The meta coupling constant J¼2.5 Hz was in
accordance with the expected structure (Fig. 2). The information
that was needed to correctly position the substituents was col-
lected with the before mentioned 2D NMR experiments. From
1Hꢁ13C HMBC NMR we could see the correlation of 3-H and 5-H
with 1-C. The same correlation with 1-C was seen for the methyl
protons and for 20-H. The correlation of 5-H with the methyl group
carbon made it possible to distinguish between 3-H and 5-H, be-
cause 3-H did not correlate with the methyl carbon. Both 3-H and
5-H showed a weak correlation through two bonds with 4-C, which
was also correlated with the methyl protons of the dimethylamino
Fig. 1. Chemical shifts and coupling constants of the benzene protons of products 9aej.

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B. Prek et al. / Tetrahedron 70 (2014) 2359e2369
Scheme 10. Possible products of the reaction between phenylacetone (10) and DMADMA.
Fig. 2. 1H NMR spectrum of 16.

B. Prek et al. / Tetrahedron 70 (2014) 2359e2369
2365
group. The protons on the methoxy group correlated with 2-C, and
a weak correlation through two bonds between 3-H and 2-C meant
that the methoxy group is positioned next to the 3-H proton. The
NOESY experiment also showed the appropriate correlations. The
correlation between 5-H and the methyl group carbon and the
correlation between 3-H and methoxy carbon meant that these
groups are closely related through space, thus confirming the
structure of 16 (Fig. 3).
5.2.1. N1,N1,N3,N3,5-Pentamethylbenzene-1,3-diamine (9a).
(a) From acetone: The product was prepared from acetone (1a;
174 mg, 3 mmol), 140 ꢀC, 20 min; column chromatography (ethyl
acetate/petroleum ether¼1:7). Yield: 10% (54 mg), yellow oil. The
product was identified only with 1H NMR spectroscopy. 1H NMR
(CDCl3, 500 MHz):
d
2.28 (3H, s, CH3); 2.91 (12H, s, 2ꢂ N(CH3)2);
5.94 (1H, t, J¼2.2 Hz, 2-CH); 6.03 (2H, d, J¼2.2 Hz, 4-CH in 6-CH).
(b) From pentane-2,4-dione (acetylacetone): The product was pre-
pared from pentane-2,4-dione (24a; 300 mg, 3 mmol), 140 ꢀC,
30 min; column chromatography (ethyl acetate/petroleum
ether¼1:5). Yield: 30% (160 mg), black oil.22,24 1H NMR (CDCl3,
300 MHz):
d
2.28 (3H, s, CH3); 2.92 (12H, s, 2ꢂ N(CH3)2); 5.95
(1H, t, J¼2.2 Hz, 2-CH); 6.03 (2H, d, J¼2.2 Hz, 4-CH and 6-CH).
13C NMR (CDCl3, 75.5 MHz):
d 22.7, 41.3, 95.9,104.1,139.5,152.3.
EI-HRMS: m/z¼179.153 (MHþ) found; C11H19N2 calculated: m/
z¼179.153. nmax 3068, 2915, 2790, 1698, 1670, 1586, 1487, 1438,
1380, 1365, 1154, 803.
5.2.2. N1,N1,N3,N3-Tetramethyl-5-propylbenzene-1,3-diamine
(9b). The product was prepared from 2-pentanone (1b; 258 mg,
3 mmol), 140 ꢀC, 60 min; column chromatography (ethyl acetate/
petroleum ether¼1:10). The isolated yellow oil was found to be
a mixture of the aromatic product and the starting 2-pentanone in
approximately 1.5:1 ratio in favour of the product. The longer re-
action time is a consequence of the non-polar character of the re-
action mixture, which leads to longer reaction times to reach the
high temperature that is needed for the reaction to proceed. With
the help of HSQC and HMBC 2D NMR techniques, we were able to
assign the signals, corresponding to the aromatic product. 1H NMR
Fig. 3. Key 2D NMR correlations for compound 16.
Other products, whose structure could be ambiguous, had their
structure determined in the same manner as shown in the case of
16. The structures of compounds 4c, 9c, 9d, 9e, 9h, 40 and 50 were
confirmed by X-ray analyses (Fig. 4).
4. Conclusion
In conclusion, this paper reports a one-pot metal-free synthesis
of polyfunctional benzene derivatives, based simply on the reaction
of methyl ketones or compounds with an a-methylene group next
(CDCl3, 500 MHz):
d
0.96 (3H, t, J¼7.5 Hz, CH3); 1.62e1.68 (2H, m,
20-CH2); 2.50 (2H, t, J¼7.5 Hz, 10-CH2); 2.92 (12H, s, 2ꢂ N(CH3)2);
5.96 (1H, t, J¼2.3 Hz, 2-CH); 6.04 (2H, J¼2.3 Hz, 4-CH and 6-CH). 13
C
to the carbonyl group and N,N-dimethylacetamide dimethyl acetal.
NMR (CDCl3, 125 MHz):
d 14.2, 24.9, 39.3, 40.9, 95.8, 103.2, 144.1,
151.74. EI-HRMS: m/z¼206.1857 (MHþ) found; C13H23N2 calculated
m/z¼207.1856 (MHþ). nmax 2954, 2928, 2867, 2790, 1586, 1485,
1374, 1305, 1155, 1126, 1012, 806, 692.
5. Experimental
5.1. General
5.2.3. N3,N3,N5,N5-Tetramethylbiphenyl-3,5-diamine
(9c). The
Melting points were determined on a Stanford Research Sys-
tems MPA100 OptiMelt automated melting point system. The NMR
spectra were obtained on a Bruker Avance DPX 300 at 300 MHz for
1H and 75.5 MHz for 13C and on a Bruker Avance III UltraShield 500
plus at 500 MHz for 1H and 126 MHz for 13C, using CDCl3 and
DMSO-d6 with Me4Si as the internal standard, as solvents. Mass
spectra were recorded on an Agilent 6224 Accurate Mass TOF LC/
MS spectrometer, IR spectra on a Perkin Elmer Spectrum BX FTIR
spectrophotometer. Microanalyses were performed on a Per-
kineElmer CHN Analyzer 2400 II. Column chromatography (CC)
was performed on silica gel (Fluka, Silica gel 60, particle size
product was prepared from acetophenone (1c; 360 mg, 3 mmol),
140 ꢀC, 15 min; column chromatography (ethyl acetate/petroleum
ether¼1:5), crystallization from ethyl acetate/heptane afforded
brown crystals. Although the structure was determined by single
crystal X-ray analysis, the 1H and 13C NMR spectrum showed the
presence of the starting acetophenone. Using 1H NMR we evaluated
that the ratio between the starting compound and the product is
approximately 1:1. The corresponding product signals in 1H and 13
C
NMR spectrums were assigned by subtracting the peaks of aceto-
phenone. The determined melting point for the mixture: 40e43 ꢀC.
1H NMR (CDCl3, 500 MHz):
d
2.99 (12H, s, 2ꢂ N(CH3)2); 6.12 (1H, br
35e70 mm). Starting compounds 1aej, 10, 17, 24a,b, 32, 36, 41 and
43 are commercially available.
s, 4-CH); 6.38 (2H, d, J¼2.2 Hz, 2-CH and 6-CH); 7.43e7.47 (2H, m,
Ph); 7.49e7.54 (1H, m, Ph); 7.86e7.90 (2H, m, Ph). 13C NMR (CDCl3,
125 MHz):
d 41.2, 96.9, 102.2, 127.2, 128.8, 132.5, 143.2, 183.5.
5.2. General procedure for the preparation of N1,N1,N3,N3-
tetramethyl 5-(substituted)benzene-1,3-diamines and related
compounds
EI-HRMS: m/z¼241.1817 (MHþ) found; C16H21N2 calculated m/
z¼241.1699 (MHþ). nmax 2876, 2848, 2787, 1586, 1572, 1485, 1425,
1304, 1160, 1062, 1023, 812, 685.
To the starting compound (3 mmol), being methyl ketones or
compounds with an active methylene group, 2.5 equiv of DMADMA
(N,N-dimethylacetamide dimethyl acetal) (7.5 mmol) were added.
The resulting mixture was heated and stirred in a closed vessel at
an automatically-controlled constant temperature (300 W) in
a CEM Corporation Discover microwave unit. The reaction tem-
perature varied from 130 ꢀC to 170 ꢀC, depending on the progress of
the reaction, and the irradiation times were typically short-
dbetween 12 and 35 min.
5.2.4. N1,N1,N3,N3-Tetramethyl-5-(pyridin-2-yl)benzene-1,3-diamine
(9d). The product was prepared from 2-acetylpyridine
(1d; 363 mg, 3 mmol), 160 ꢀC, 20 min; column chromatography
(ethyl acetate/petroleum ether¼1:2). Yield: 19% (82 mg), yellow-
green solid; mp¼76e80 ꢀC. 1H NMR (CDCl3, 500 MHz):
d 3.02
(12H, s, 2ꢂ N(CH3)2); 6.18 (1H, t, J¼2.3 Hz, 2-CH); 6.78
(2H, d, J¼2.2 Hz, 4-CH and 6-CH); 7.18e7.22 (1H, m, Py); 7.68e7.74
(2H, m, Py); 8.68 (1H, dt, J1¼4.9 Hz, J2¼1.4 Hz, 40-CH). 13C NMR
(CDCl3, 125 MHz): d 41.0, 98.5, 101.6, 121.0, 121.8, 136.4, 140.9, 149.3,

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B. Prek et al. / Tetrahedron 70 (2014) 2359e2369
Fig. 4. ORTEP view of compounds 9c, 9d, 9e, 9h, 40, 4c, 50.

B. Prek et al. / Tetrahedron 70 (2014) 2359e2369
2367
152.1, 159.1. EA C15H19N3 requires: C 74.65; H 7.94; N 17.41. Found: C
(CDCl3, 500 MHz):
d
2.99 (12H, s, 2ꢂ N(CH3)2); 6.06 (1H, t, J¼2.2 Hz,
74.42; H 7.78; N 17.07. EI-HRMS: m/z¼242.1652 (MHþ) found;
2-CH); 6.45 (1H, dd, J1¼3.2 Hz, J2¼1.8 Hz, 30-CH); 6.54
(2H, d, J¼2.2 Hz, 4-CH and 6-CH); 6.60e6.62 (1H, m, 40-CH); 7.45
(1H, dd, J1¼1.8 Hz, J2¼0.9 Hz, 50-CH). 13C NMR (CDCl3,125 MHz):
C
15H20N3 calculated: m/z¼242.1652 (MHþ). nmax 3049, 2977, 2875,
2789, 1721, 1662, 1578, 1561, 1377, 1278, 1237, 1057.
d
41.1, 97.4, 98.7, 104.6, 111.5, 132.0, 141.6, 152.0, 155.5. EI-HRMS: m/
5.2.5. N1,N1,N3,N3-Tetramethyl-5-(pyrazin-2-yl)benzene-1,3-diamine
(9e). The product was prepared from 2-acetylpyrazine (1e; 366 mg,
3 mmol), 160 ꢀC, 20 min; column chromatography (ethyl acetate/
petroleum ether¼1:2), crystallization from ethyl acetate/heptane.
Yield: 19% (138 mg), yellow-brown crystals; mp¼96e101 ꢀC. 1H
z¼231.1494 (MHþ) found; C14H19N2O calculated: m/z¼231.1492
(MHþ). nmax 3139, 3108, 2981, 2847, 2794, 1582, 1562, 1498, 1308,
1152, 982, 794.
5.2.10. N3,N3,N5,N5-Tetramethyl-40-nitrobiphenyl-3,5-diamine
(9j). The product was prepared from 3-(dimethylamino)-1-(4-
nitrophenyl)but-2-en-1-one (4j; 151 mg, 0.65 mmol) and a larger
amount of DMADMA (6.3 equiv, 0.6 mL), 140 ꢀC, 30 min; column
chromatography (ethyl acetate/petroleum ether¼1:5). Yield: 30%
(57 mg), red wax; mp¼112e117 ꢀC. 1H NMR (CDCl3, 500 MHz):
NMR (CDCl3, 500 MHz):
d
3.03 (12H, s, 2ꢂ N(CH3)2); 6.19 (1H, t,
J¼2.2 Hz, 2-CH); 6.78 (2H, d, J¼2.2 Hz, 4-CH and 6-CH); 8.47 (1H, d,
J¼2.2 Hz, 30-CH); 8.61 (1H, dd, J1¼2.5 Hz, J2¼1.5 Hz, 50-CH); 9.00
(1H, s, 60-CH). 13C NMR (CDCl3, 125 MHz):
d 40.9, 98.7, 101.0, 137.7,
142.5, 142.7, 143.8, 152.2, 154.5. EA C14H18N4 requires: C 69.39; H
7.49; N 23.12. Found: C 69.23; H 7.47; N 22.87. EI-HRMS: m/
z¼243.1608 (MHþ) found; C14H19N4 calculated: m/z¼243.1604
(MHþ). nmax 3046, 2880, 2848, 2797, 1747, 1589, 1571, 1393, 1304,
1141, 1013, 813.
d
3.01 (12H, s, 2ꢂ N(CH3)2); 6.13 (1H, t, J¼2.2 Hz, 4-CH); 6.33 (2H, d,
J¼2.2 Hz, 2-CH and 6-CH); 7.73 (2H, d, J¼8.8 Hz, 20-CH and 60-CH);
8.25 (2H, d, J¼8.8 Hz, 30-CH and 50-CH). 13C NMR (CDCl3, 125 MHz):
d
40.9, 97.4, 101.4, 123.8, 128.1, 140.6, 146.8, 149.8, 152.1. EI-HRMS:
m/z¼286.155 (MHþ) found; C16H20N3O2 calculated: m/z¼286.155
(MHþ). nmax 2916, 2849, 2799, 1576, 1510, 1482, 1441, 1383, 1336,
1315, 1277, 1240, 1159, 1107, 1023, 983, 857, 814, 751.
5.2.6. N1,N1,N3,N3-Tetramethyl-5-(1-methyl-1H-pyrrol-3-yl)benzene-
1,3-diamine (9f). The product was prepared from 3-acetyl-1-
methylpyrrole (1f; 369 mg, 3 mmol), 170 ꢀC, 25 min; column
chromatography (ethyl acetate/petroleum ether¼1:1). Yield: 8%
(58 mg), white solid; mp¼90e96 ꢀC. 1H NMR (CDCl3, 500 MHz):
5.2.11. 2-Methoxy-N,N,6-trimethylbiphenyl-4-amine
(16). The
product was prepared from phenylacetone (10; 402 mg, 3 mmol),
160 ꢀC, 35 min; column chromatography (ethyl acetate/petroleum
ether¼1:10). Yield: 27% (195 mg), brown oil. 1H NMR (CDCl3,
d
2.96 (12H, s, 2ꢂ N(CH3)2); 3.67 (3H, s, CH3); 6.01 (1H, t, J¼2.2 Hz,
2-CH); 6.36 (2H, d, J¼2.2 Hz, 4-CH and 6-CH); 6.41 (1H, t, J¼2.2 Hz,
40-CH); 6.60 (1H, t, J¼2.5 Hz, 50-CH); 6.87 (1H, t, J¼2.0 Hz, 20-CH). 13C
300 MHz):
d 2.10 (3H, s, CH3); 3.02 (6H, s, N(CH3)2); 3.73 (3H, s,
NMR (CDCl3, 125 MHz):
d
36.3, 41.1, 96.2, 100.8, 106.8, 118.7, 122.2,
OCH3); 6.26 (1H, d, J¼2.4 Hz, 3-CH); 6.31 (1H, d, J¼2.5 Hz, 5-CH);
126.8, 137.2, 152.0. EA C15H21N3*1/5 MeOH requires: C 73.10; H
8.80; N 16.82. Found: C 73.31; H 8.43; N 16.41. EI-HRMS: m/
z¼244.1809 (MHþ) found; C15H22N3 calculated: m/z¼244.1808
(MHþ). nmax 3114, 3077, 2979, 2872, 2788, 1715, 1649, 1571, 1505,
1389, 1310, 1154, 786.
7.21e7.27 (2H, m, Ph); 7.30e7.35 (1H, m, Ph); 7.37e7.44 (2H, m, Ph).
13C NMR (CDCl3, 75.5 MHz):
d
21.4, 41.1, 56.1, 94.7, 107.0, 120.5,
126.6, 128.2, 129.8, 131.2, 151.1, 158.2. EA 16H19NO*1/2H2O
C
requires: C 76.77; H 8.05; N 5.60. Found: C 76.87; H 7.71; N 5.25. EI-
HRMS: m/z¼242.1542 (MHþ) found; C16H20NO calculated:
242.1539 (MHþ). nmax 3052, 3004, 2986, 2918, 2838, 1711, 1608,
1559, 1487, 1469, 1364, 1240, 1156, 1092, 936.
5.2.7. N1,N1,N3,N3-Tetramethyl-5-(thiophen-2-yl)benzene-1,3-
diamine (9g). The product was prepared from 2-acetylthiophene
(1g; 441 mg, 3.5 mmol), 150 ꢀC, 20 min; column chromatography
(ethyl acetate/petroleum ether¼1:5). Yield: 30% (258 mg), yellow
5.2.12. 5-Methoxy-N,N,6-trimethylbiphenyl-3-amine
(23). The
product was prepared from propiophenone (17; 402 mg,
3 mmol), 140 ꢀC, 15 min; column chromatography (ethyl acetate :
petroleum ether¼1:10). Yield: 17% (126 mg), yellow oil. 1H NMR
oil. 1H NMR (CDCl3, 300 MHz):
d
3.02 (12H, s, 2ꢂ N(CH3)2); 6.09
(1H, t, J¼2.2 Hz, 2-CH); 6.46 (2H, d, J¼2.2 Hz, 4-CH and 6-CH); 7.08
(1H, dd, J1¼5.1 Hz, J2¼3.5 Hz, 40-CH); 7.26 (1H, dd, J1¼5.1 Hz,
J2¼1.2 Hz, 30-CH); 7.31 (1H, dd, J1¼3.6 Hz, J2¼1.2 Hz, 50-CH). 13C NMR
(CDCl3, 500 MHz):
d 2.02 (3H, s, Ph-CH3); 2.93 (6H, s, N(CH3)2);
3.86 (3H, s, OCH3); 6.26 (1H, d, J¼2.5 Hz, 2-CH); 6.32 (1H, d,
(CDCl3, 75.5 MHz): d 41.3, 97.5,101.3,123.2,124.4,127.9,136.0,146.8,
J¼2.5 Hz, 4-CH); 7.31e7.40 (5H, m, Ph). 13C NMR (CDCl3,
152.4. EI-HRMS: m/z¼247.1267 (MHþ) found; C14H19N2S calculated:
m/z¼247.1263 (MHþ). nmax 3098, 3070, 2979, 2796,1578,1481,1307,
1210, 1126, 804.
125 MHz): d 12.5, 41.1, 55.6, 95.7, 107.0, 112.9, 126.7, 128.0, 129.4,
142.9, 143.6, 149.5, 158.7. EI-HRMS: m/z¼242.1541 (MHþ) found;
C
16H20NO calculated m/z¼242.1539 (MHþ). nmax 2988, 2933,
2863, 2791, 1604, 1567, 1491, 1438, 1381, 1361, 1250, 1164, 1123,
1096, 1047, 1001, 809, 701.
5.2.8. N1,N1,N3,N3-Tetramethyl-5-(thiophen-3-yl)benzene-1,3-
diamine (9h). The product was prepared from 3-acetylthiophene
(1h; 428 mg, 3.4 mmol), 140 ꢀC, 12 min; column chromatography
(ethyl acetate/petroleum ether¼1:5). Yield: 21% (174 mg), brown
5.2.13. 5-Methoxy-N,N-dimethylbiphenyl-3-amine (29). The prod-
uct was prepared from 1-phenyl-1,3-butanedione (24b; 486 mg,
3 mmol), 140 ꢀC, 20 min; column chromatography (ethyl acetate/
petroleum ether¼1:15). Yield: 13% (90 mg), yellow oil. 1H NMR
crystalline solid; mp¼83e89 ꢀC. 1H NMR (CDCl3, 300 MHz):
d 3.01
(12H, s, 2ꢂ N(CH3)2); 6.10 (1H, t, J¼2.2 Hz, 2-CH); 6.43 (2H, d,
J¼2.2 Hz, 4-CH and 6-CH); 7.34e7.42 (2H, m, 20-CH and 50-CH); 7.43
(1H, dd, J1¼2.8 Hz, J2¼1.5 Hz, 40-CH). 13C NMR (CDCl3, 75.5 MHz):
(CDCl3, 300 MHz):
d 2.97 (6H, s, N(CH3)2); 3.83 (3H, s, OCH3); 6.28
(1H, t, J¼2.3 Hz, 4-CH); 6.50 (1H, dd, J1¼2.2 Hz, J2¼1.4 Hz, 2-CH);
6.54 (1H, dd, J1¼2.2 Hz, J2¼1.4 Hz, 6-CH); 7.37e7.44 (3H, m, Ph);
7.55e7.60 (2H, m, Ph). 13C NMR (CDCl3, 75.5 MHz): 40.8, 55.3, 98.1,
101.2, 105.1, 127.3, 127.4, 128.6, 142.4, 143.4, 152.2, 161.1. EI-HRMS:
m/z¼228.1383 (MHþ) found; C15H18NO calculated m/z¼228.1383
(MHþ). nmax 2992, 2935, 2838, 2803, 1684, 1586, 1573, 1490, 1440,
1367, 1269, 1207, 1147, 1062, 999, 825, 758.
d
41.3, 97.3, 100.4, 101.9, 120.4, 125.8, 127.45, 137.8, 152.4. EA
14H18N2S requires: C 68.25; H 7.36; 11.37. Found: C 68.02; H 7.47; N
C
11.24. EI-HRMS: m/z¼247.1267 (MHþ) found; C14H19N2S calculated:
m/z¼247.1263 (MHþ). nmax 3100, 3084, 2874, 2798, 1578, 1486,
1439, 1373, 1292, 1249, 1156, 1062, 1020, 776.
5.2.9. 5-(Furan-2-yl)-N1,N1,N3,N3-tetramethylbenzene-1,3-diamine
(9i). The product was prepared from 2-acetylfuran (1i; 235 mg,
2.14 mmol), 140 ꢀC, 15 min; column chromatography (ethyl acetate/
petroleum ether¼1:1). Yield: 49% (241 mg), yellow oil. 1H NMR
5.2.14. Ethyl 2,4-bis(dimethylamino)-6-methylbenzoate (35). The
product was prepared from ethyl acetoacetate (32; 390 mg,
3 mmol), 130 ꢀC, 10 min; column chromatography (ethyl acetate/

2368
B. Prek et al. / Tetrahedron 70 (2014) 2359e2369
petroleum ether¼1:7). Yield: 8.8% (66 mg), yellow oil. 1H NMR
2188, 1686, 1557, 1433, 1400, 1277, 1263, 1185, 1113, 1073, 1054,
1013, 936, 765.
(CDCl3, 500 MHz):
d
1.36 (3H, t, J¼7.1 Hz, EteCH3); 2.28
(3H, s, PheCH3); 2.77 (6H, s, N(CH3)2); 2.94 (6H, s, N(CH3)2); 4.34
(2H, q, J¼7.1 Hz, EteCH2); 6.13 (1H, d, J¼2.9 Hz, 3-CH); 6.14
5.2.19. (E)-3-(Dimethylamino)-1-phenylbut-2-en-1-one
(4c). The
(1H, d, J¼2.9 Hz, 5-CH). 13C NMR (CDCl3, 125 MHz):
d
14.4, 20.9,
product was prepared from a solution of acetophenone (1c; 12 g,
100 mmol) in anhydrous toluene, and 1.4 equiv of DMADMA
(18.62 g, 140 mmol). The reaction mixture was heated to reflux
temperature and stirred vigorously for 24 h. The solvent was re-
moved under reduced pressure, thus affording brown crystals of
the product. Yield: 46.6% (8.81 g); mp¼68e70 ꢀC. 1H NMR (CDCl3,
40.4, 44.4, 60.5, 99.6, 107.4, 116.0, 137.6, 151.7152.9, 170.6. EI-HRMS:
m/z¼251.1753 (MHþ) found; C14H23N2O2 calculated m/z¼251.1754
(MHþ). nmax 2976, 2933, 2791, 1713, 1596, 1560, 1477, 1365, 1253,
115, 1081, 814.
5.2.15. Methyl 2,4-bis(dimethylamino)-6-methoxybenzoate
(40). The product was prepared from dimethyl malonate (36;
396 mg, 3 mmol), 160 ꢀC, 35 min; column chromatography (ethyl
acetate/petroleum ether¼1:2). Yield: 40% (302 mg), brown solid;
300 MHz): d 2.66 (3H, s, CH3); 3.07 (6H, s, N(CH3)2); 5.68 (1H, s, CH);
7.30e7.51 (3H, m, Ph); 7.79e7.94 (2H, m, Ph). 13C NMR (CDCl3,
75.5 MHz): 16.5, 40.1, 92.7, 127.3, 128.0, 130.3, 143.2, 163.9, 188.3. EI-
HRMS: m/z¼190.1226 (MHþ) found; C12H16NO calculated m/
z¼190.1226 (MHþ). nmax 3042, 2951, 2873, 1533, 1480, 1419, 1382,
1358, 1223, 1178, 1153, 1063, 1027, 917, 861, 771, 705.
mp¼84e86 ꢀC. 1H NMR (CDCl3, 300 MHz):
d 2.81 (6H, s, N(CH3)2);
2.99 (6H, s, N(CH3)2); 3.82 (3H, s, OCH3); 3.88 (3H, s, OCH3); 5.84
(1H, d, J¼2.1 Hz, CH); 5.86 (1H, d, J¼2.1 Hz, CH). 13C NMR (CDCl3,
75.5 MHz):
d
40.6, 43.8, 52.2, 56.0, 88.9, 94.2, 104.6, 152.8, 153.2,
5.2.20. 3-(Dimethylamino)-1-(4-nitrophenyl)but-2-en-1-one
(4j). The product was prepared from 40-nitroacetophenone
(1j; 495 mg, 3 mmol), 140 ꢀC, 10 min; column chromatography
(ethyl acetate/petroleum ether¼1:1), crystallization from ethyl
acetate. Yield: 8% (50 mg), brown-orange solid; mp¼183e185 ꢀC.
159.3, 169.6. EA C13H20N2O3 requires: C 61.88; H 7.99; N 11.10.
Found: C 61.88; H 8.17; N 10.89. EI-HRMS: m/z¼253.1547 (MHþ)
found; C13H21N2O3 calculated: m/z¼253.1547 (MHþ). nmax (KBr)
2945, 2838, 2795, 1704, 1595, 1558, 1504, 1451, 1428, 1270, 1249,
1159, 1077, 1015, 978, 803.
1H NMR (DMSO-d6, 300 MHz):
d 2.61 (3H, s, CH3); 3.10 (6H, s,
N(CH3)2); 5.65 (1H, s, CH); 8.02 (1H, d, J1¼2.2 Hz, CH); 8.04 (1H, d,
J1¼2.2 Hz, CH); 8.22 (1H, d, J1¼2.1 Hz, CH); 8.24 (1H, d, J1¼2.1 Hz,
CH). 13C NMR (DMSO-d6, 75.5 MHz): 17.0, 29.3, 91.9, 124.2, 129.0,
149.0, 149.5, 166.0, 183.9. EI-HRMS: m/z¼235.1079 (MHþ) found;
5.2.16. Ethyl 2,4-bis(dimethylamino)-6-methoxybenzoate (42). The
product was prepared from diethyl malonate (41; 480 mg,
3 mmol), 130 ꢀC, 30 min; column chromatography (ethyl acetate/
petroleum ether¼1:5). Yield: 42%, brown solid; mp¼38e44 ꢀC.
C
12H15N2O3 calculated m/z¼235.1077 (MHþ). nmax 3107, 2955, 2916,
1H NMR (CDCl3, 500 MHz):
d
1.35 (3H, t, J¼7.1 Hz, EteCH3); 2.79
1585, 1555, 1523, 1511, 1342, 1317, 1238, 1207, 1064, 742.
(6H, s, N(CH3)2); 2.96 (6H, s, N(CH3)2); 3.79 (3H, s, OCH3); 4.34
(2H, q, J¼7.1 Hz, EteCH2); 5.83 (1H, d, J¼2.2 Hz, CH); 5.85 (1H, d,
5.2.21. (2Z,4Z)-Methyl 2-cyano-3,5-bis(dimethylamino)hexa-2,4-
dienoate (50). The product was prepared from methyl cyanoace-
tate (48; 297 mg, 3 mmol), 100 ꢀC, 10 min; column chromatography
(ethyl acetate). Yield: 28% (201 mg), brown crystalline solid;
J¼2.2 Hz, CH). 13C NMR (CDCl3, 125 MHz):
d 14.4, 40.6, 43.9, 55.9,
60.8, 89.1, 34.4, 105.2, 152.7, 153.1, 159.1, 169.2. EA C14H22N2O3
requires: C 63.13; H 8.33; N 10.52. Found: C 62.92; H 8.18; N
10.26. EI-HRMS: m/z¼555.3149 (2MþNa)þ found; C28H44N4NaO6
calculated: m/z¼555.3153 (2MþNa)þ. nmax (KBr) 2979, 2941,
2837, 2800, 1709, 1598, 1559, 1506, 1452, 1428, 1303, 1249, 1156,
1090, 1016, 977, 806.
mp¼104e109 ꢀC. 1H NMR (CDCl3, 300 MHz):
d 2.26 (3H, s, CH3);
3.05 (6H, s, N(CH3)2); 3.09 (6H, s, N(CH3)2); 3.71 (3H, s, OCH3); 4.56
(1H, s, CH). 13C NMR (CDCl3, 75.5 MHz): 17.9, 40.8, 43.2, 51.2, 92.0,
124.3, 162.3, 167.1, 170.5. EI-HRMS: m/z¼238.1572 (MHþ) found;
C
12H20N3O2 calculated m/z¼238.1550 (MHþ). nmax 2949, 2935,
5.2.17. N-(2,4-Bis(dimethylamino)-6-methoxyphenyl)benzamide
(47). The product was prepared from methyl hippurate
(43; 328 mg, 1.7 mmol), 140 ꢀC, 12 min; column chromatography
(ethyl acetate/petroleum ether¼1:1). Yield: 21% (112 mg), brown-
2176, 1657, 1548, 1528, 1395, 1265, 1181, 1071, 1016, 787, 764.
5.3. X-ray structure analysis for compounds 4c, 9c, 9d, 9e, 9h,
40 and 50
white solid; mp¼137e142 ꢀC. 1H NMR (CDCl3, 500 MHz):
d 2.68
(6H, s, N(CH3)2); 2.96 (6H, s, N(CH3)2); 3.82 (3H, s, OCH3); 6.03
(1H, d, J¼2.6 Hz, 30-CH); 6.05 (1H, d, J¼2.6 Hz, 50-CH); 7.30 (1H, br s,
NH); 7.42e7.54 (3H, m, Ph); 7.90e7.97 (2H, m, Ph). 13C NMR (CDCl3,
Diffraction data for the above mentioned compounds were
collected on a SuperNova X-ray single crystal diffractometer
equipped with an Atlas detector using monochromated Mo Ka ra-
125 MHz):
d
41.0, 43.8, 56.0, 92.0, 95.8, 109.2, 127.6, 128.6, 131.4,
diation at 150 K (for 9c and 9e) or ambient temperature for the
other five structures. Data reduction and integration were per-
formed with the software package CrysAlis PRO.25 The coordinates
of all of the nonhydrogen atoms were found via direct methods
using the SIR97 or Supeflip or Olex2 structure solution pro-
grams.26e28 A full-matrix least-squares refinement on F2 magni-
tudes with anisotropic displacement parameters for all non-
hydrogen atoms using SHELXL-97 was employed.29 All hydrogen
atoms were initially located in difference Fourier maps. All H atoms
attached to carbon were subsequently treated as riding atoms in
geometrically idealized positions with bond lengths CeH of 0.96/
0.98 A for methyl and 0.93/0.95 A for aromatic CeH bonds (the first
number refers to ambient and the second to low temperature). The
corresponding displacement parameters Uiso(H) were 1.5-times
higher than those of the carrier methyl carbons and 1.2-times
higher than all other hydrogen bearing carbon atoms. Figures
depicting the structures were prepared by ORTEP3.30 CCDC
967245ꢁ967251 contain the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
135.3, 150.7, 151.2, 156.4, 166.8. EA C18H23N3O2 requires: C 68.98; H
7.40; N 13.41. Found: C 68.33; H 6.93; N 13.02. EI-HRMS: m/
z¼314.1865 (MHþ) found; C18H24N3O2 calculated: m/z¼314.1863
(MHþ). nmax 3202, 3063, 2987, 2954, 2820, 2766, 1720, 1637, 1590,
1509, 1446, 1256, 1084, 981.
5.2.18. Methyl 2-cyano-3-(dimethylamino)but-2-enoate (49). To
a solution of methyl cyanoacetate (48; 297 mg, 3 mmol) in toluene
(5 mL), DMADMA (1.1 equiv, 0.482 mL) was added. The reaction
was stirred at ambient temperature for 2 h. The reaction progress
was monitored with thin-layer chromatography. Volatile com-
pounds were removed under reduced pressure and the product
was isolated via column chromatography (ethyl acetate/petro-
leum ether¼1:1). Yield: 74% (373 mg), yellow oil. 1H NMR (DMSO-
ꢁ
ꢁ
d6, 500 MHz):
d 2.41 (3H, br s, CH3); 3.16 (6H, br s, N(CH3)2); 3.59
(3H, s, OCH3). 13C NMR (DMSO-d6, 125 MHz): 19.3, 43.0, 50.8, 69.0,
120.2, 166.4, 173.3. EI-HRMS: m/z¼169.0973 (MHþ) found;
C8H12N2O2 calculated m/z¼169.0972 (MHþ). nmax 2984, 2838,

B. Prek et al. / Tetrahedron 70 (2014) 2359e2369
2369
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Acknowledgements
Financial support from the Slovenian Research Agency through
grants P0-0502-0103, P1-0179 and J1-6689-0103-04 are gratefully
acknowledged. We also thank the Krka d.d. (Novo mesto, Slovenia)
and Lek d.d., a Sandoz Company (Ljubljana, Slovenia) for financial
support.
References and notes
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