A feature of reaction of 1,1′-diacetylferrocene with dimethylformamide dimethyl acetal leading to a new strategy of the synthesis of asymmetrical 1,1′-disubstituted ferrocene

Article abstract of DOI:10.1134/S1070363211030145

The reaction of 1,1′-diacetylferrocene with the dimethylformamide dimethyl acetal proceeds regioselectively to afford [1-acetyl-1′-(1- dimethylamino-3-oxoprop-1-en-3-yl)]ferrocene, based on which new approaches to the synthesis of 1,1′-disubstituted unsymmetrical ferrocene derivatives via the reaction with nucleophilic reagents hydrazine hydrate, hydroxylamine, and amidines were developed.

Full text of DOI:10.1134/S1070363211030145

ISSN 1070-3632, Russian Journal of General Chemistry, 2011, Vol. 81, No. 3, pp. 529–534. © Pleiades Publishing, Ltd., 2011.
Original Russian Text © A.I. Moskalenko, A.V. Boeva, V.I. Boev, 2011, published in Zhurnal Obshchei Khimii, 2011, Vol. 81, No. 3, pp. 433–438.
A Feature of Reaction of 1,1'-Diacetylferrocene
with Dimethylformamide Dimethyl Acetal Leading
to a New Strategy of the Synthesis
of Asymmetrical 1,1'-Disubstituted Ferrocene
A. I. Moskalenko, A. V. Boeva, and V. I. Boev
Lipetsk State Pedagogical University, ul. Lenina 42, Lipetsk, 398020 Russia
e-mail: kaf_himii@lspu.lipetsk.ru
Received March 23, 2010
Abstract—The reaction of 1,1'-diacetylferrocene with the dimethylformamide dimethyl acetal proceeds
regioselectively to afford [1-acetyl-1'-(1-dimethylamino-3-oxoprop-1-en-3-yl)]ferrocene, based on which new
approaches to the synthesis of 1,1'-disubstituted unsymmetrical ferrocene derivatives via the reaction with
nucleophilic reagents hydrazine hydrate, hydroxylamine, and amidines were developed.
DOI: 10.1134/S1070363211030145
Ferrocene derivatives possessing several unique
and unusual properties [1, 2] attracted attention of
researchers in many countries [3]. Recently the
biological effects of substituted ferrocenes were exten-
sively studied [4–6], which largely depend on the
number and nature of functional groups in their
molecules. This stimulates further research in view of
new methods for synthesizing compounds of the
ferrocene series.
atoms to form the corresponding enamines, the highly
reactive chemicals in organic synthesis [12–14].
In 1,1'-diacetylferrocene the labile hydrogen atoms
belong to two methyl sustituents of acetyl groups,
which in principle could react with the acetal I.
However, we found that under prolonged reflux (30 h)
of 1,1'-diacetylferrocene in a large excess of I the
reaction occurs only with the participation of one
acetyl group to form enamine II in a yield of 74%. The
further refluxing of the reaction mixture led only to the
decomposition of the ferrocene-containing components,
while no formation of the expected bis-enamine III
was detected by TLC.
In this paper we first examined the reaction of 1,1'-
diacetylferrocene with the dimethylformamide di-
methyl acetal I, which is known [7–11] to be able to
react with compounds containing labile hydrogen
o
(
MeO) CHNMe 105 C
2
2,
I
H ССOС H FeС H СOCH
H ССOС H FeС H СOCH CH NMe
2
3
5
4
5
4
3
3
5
4
5
4
−
2 MeOH
II
(
Me N CH CH COC H ) Fe
2
5 4 2
III
The high regioselectivity of this process is
apparently due to the insufficiently strong electron-
withdrawing effect of enaminocarbonyl group of the
intermediate II, which contributes to the lability of the
hydrogen atoms in acetyl group of II. It is known [9–
substrate the more readily proceeds its condensation
with the acetal I.
The composition and the structure of compound II
are confirmed by elemental analysis, gas chromato-
1
1
1] that the higher lability of the hydrogen atoms in the
graphy-mass spectrometry (Table 1), IR and H NMR
5
29

5
30
MOSKALENKO et al.
Table 1. Yields, melting points, TLC, elemental analysis, and chromato-mass-spectral data of compounds II, IV–XIV
Mass-
Found, %
Fe
Calculated, %
Fe
Comp. Yield,
mp,
R
f
spectrum, m/z
Formula
M
calc
no.
%
°С
(system)
+
C
H
N
C
H
N
[
M + 1]
II
74
58
69
76
77
48
50
68
76
84
91
65
136–137 0.42 (A)
172–173 0.68 (B)
168–169 0.31 (А)
198–200 0.54 (C)
176–177 0.48 (А)
156–157 0.30 (А)
161–162 0.58 (А)
184–186 0.71 (C)
202–205 0.56 (C)
184–185 0.52 (B)
210–212 0.61 (C)
205–206 0.38 (B)
326
309
311
442
311
322
392
410
455
337
395
337
62.56 5.73 17.19 4.26 C17
58.27 5.06 17.93 18.31 C15
57.81 4.39 18.24 8.85 C15
59.67 4.25 12.83 15.43 C22
58.11 4.63 17.97 9.16 C15
59.75 4.28 17.26 12.87 C16
61.24 5.32 14.16 10.53 C20
67.24 4.67 13.21 10.15 C23
60.71 4.08 12.57 12.09 C23
57.35 4.63 16.48 16.30 C16
51.58 4.41 14.16 20.82 C17
56.94 4.53 16.78 16.75 C16
H
H
H
H
H
H
H
H
H
H
H
H
19FeNO
2
62.77 5.85 17.23 4.31 325
58.44 5.19 18.18 18.18 308
58.06 4.52 18.06 9.03 310
59.86 4.31 12.70 15.87 441
58.06 4.52 18.06 9.03 310
59.81 4.67 17.45 13.08 321
61.38 5.37 14.32 10.74 391
67.48 4.65 13.69 10.27 409
60.79 3.96 12.33 12.33 454
57.14 4.76 16.67 16.67 336
51.78 4.57 14.21 21.32 394
57.14 4.76 16.67 16.67 336
IV
16FeN
14FeN
19FeN
14FeN
15FeN
21FeN
19FeN
18FeN
16FeN
18FeN
16FeN
4
2
5
2
3
3
3
4
4
6
4
V
O
O
O
O
O
O
O
O
S
2
2
2
VI
VII
VIII
IX
2
3
X
XI
XII
XIII
XIV
O
1
Table 2. IR and Н NMR spectral data for compounds II, IV–XIV
–
1
IR spectrum, ν, cm
Aromatic system
Comp.
no.
1
Н NMR spectrum, δ, ppm
Ferrocene core
Functional groups
II
3110, 2998, 1601, 1461,
1682, 1668 (C=O),
1626 (C=C)
2.38 s (3H, COCH
), 4.76 m (4H, C
.70 d (1H, C=СН–N, J 16.5 Hz)
2.05 s (3H, CH ), 4.28 m (4H, C
), 6.45 d (1Н, Het), 7.56 d (1Н, Het)
2.12 s (3H, CH ), 4.28 m (4H, C ), 4.75 m (4H,
5 4
C H ), 6.12 d (1Н, Het), 7.96 d (1Н, Het), 12.04 s (1H,
3
), 2.98 s (6H, 2 CH
3
), 4.37 m (4H,
1
336, 809
C
7
5
H
4
5 4
H ), 5.38 d (1H, C=СН, J 16.5 Hz),
IV
V
3101, 2997, 1597, 1462, 1601, 1505, 1430 3448, 3398 (N–H),
332, 812
1618 (C=N)
3100, 2998, 1600, 1460, 1593, 1506, 1431 3426 (OH),
334, 810
1621 (C=N)
3
5 4
H ), 4.72 m (4H,
1
5 4
C H
3
5 4
H
1
OH)
2.08 s (3H, CH
VI
3101, 2998, 1598, 1462, 1602, 1564, 1510, 3428, 3386 (NH),
332, 811 1500, 1430
1624, 1614 (C=N),
340 (NO
3100, 2997, 1601, 1460, 1594, 1506, 1430 3442 (NH),
332, 810
1658 (C=O)
3
), 4.29 m (4H, C
), 6.46 d (1Н, Het), 7.58 d (1Н, Het), 7.83 d (2Н,
), 8.61 d (2Н, C ), 9.93 s (1H, CH)
N), 4.36 m (4H, C ), 4.76 m (4H,
), 6.14 d (1Н, Het), 7.94 d (1Н, Het), 9.86 br.s
1H, NH)
3110, 2998, 1600, 1462, 1594, 1543, 1504, 3446, 3391, 3374 (NH), 2.36 s (3H, CH
5 4
H ), 4.72 m (4H,
1
C
C
5
H
H
4
1
2
)
6
2
6 2
H
VII
2.81 d (3H, CH
3
5 4
H
1
5 4
C H
(
VIII
IX
3
), 4.32 m (4H, C
), 6.10 d (1Н, Het), 8.44 d (1Н, Het)
2.36 s (3H, CH ), 3.24–3.46 m (4H, 2NCH
3.97 m (2H, 2OCH ), 4.38 m (4H, C ), 4.78 m (4H,
), 6.19 d (1Н, Het), 8.45 d (1Н, Het)
3448, 3394, 3380 (NH), 4.34 m (4H, C ), 4.61–4.75 m (6H, C
1662 (C=O), d (1Н, =СН, J 17.4 Hz), 5.96 d (1Н, CO–CH=, J 17.4 Hz),
5 4
H ), 4.60-4.78 m (6H,
1
337, 812
3106, 2997, 1598, 1462,
338, 812
1435
1678 (C=O)
1678 (C=O)
5 4 2
C H , NH
3
2
), 3.75–
1
1588, 1541, 1506,
2
5 4
H
1
434
5 4
C H
X
3110, 2996, 1600, 1460,
337, 810
5
H
4
5
H
4
, NH
), 8.45 d (1Н,
, NH ), 5.68
2
), 5.42
1
1
1
590, 1563, 1512, 1622 (C=C)
500, 1431
6 5
6.12 d (1Н, Het), 7.44–7.58 m (5Н, С Н
Het)
XI
XII
3110, 2997, 1597, 1461, 1605, 1562, 1512, 3448, 3390 (NH),
337, 810 1500, 1431
1667 (C=O),
4.36 m (4H, C
d (1Н, =СН, J 17.6 Hz), 5.98 d (1Н, CO–CH=, J 17.6 Hz),
6.14 d (1Н, Het), 7.68 d (2Н, С ), 8.45 d (1Н, Het),
8.60 d (2Н, С
2.10 s (3H, CH ), 4.37 m (4H, C H ), 4.64–4.81 m (6H,
5
H
4
), 4.66–4.83 m (6H, C
5
H
4
2
1
1
1
631 (C=C),
332 (NO
6 2
Н
2
)
6 2
Н )
3112, 2996, 1600, 1463, 1594, 1542, 1506 3448, 3389,
334, 809
3328 (NH, OH),
621 (C=N)
3
5
4
1
C
5
H
4
2
, NH ), 6.14 d (1Н, Het), 8.46 d (1Н, Het), 12.03 s
1
(1H, OH)
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 81 No. 3 2011

A FEATURE OF REACTION OF 1,1'-DIACETYLFERROCENE
531
Table 2. (Contd.)
–
1
IR spectrum, ν, cm
Comp.
no.
1
Н NMR spectrum, δ, ppm
), 4.36 m (4H, C ), 4.65–4.78 m
Ferrocene core
3110, 2997, 1600, 1462, 1594, 1544, 1508
335, 812
Aromatic system
Functional groups
XIII
3464–3285 (NH),
1618 (C=N)
2.08 s (3H, CH
(6H, C , NH
.96 s (2Н, NH
2.83 d (3H, CH
(6H, C , NH
.87 br.s (1H, NH)
3
5 4
H
1
5
H
4
2
), 6.14 d (1Н, Het), 8.48 d (1Н, Het),
9
2
C=S), 10.84 br.s (1H, NH)
XIV
3109, 2998, 1598, 1458, 1592, 1543, 1508
336, 810
3445–3326 (NH),
1660 (C=O)
3
5 4
N), 4.35 m (4H, C H ), 4.65–4.79 m
1
5
H
4
2
), 6.15 d (1Н, Het), 8.47 d (1Н, Het),
9
spectroscopy (Table 2), as well as by chemical
transformations.
The presence of different functionalities in com-
pound II allows to develop a new strategy for the
synthesis of a number of asymmetric 1,1'-disubstituted
ferrocene derivatives.
The IR spectrum of compound II contains the absorp-
tion bands characterizing the stretching vibrations of
C–H bond of the cyclopentadienyl rings at 3110–
–
1
–1
2
998 cm , the carbonyl groups at 1682 and 1668 cm ,
In particular, refluxing enamine II with an excess
of hydrazine hydrate in ethanol or reacting it with
hydroxylamine in aqueous ethanol afford heterocyclic
compounds IV (58%) and V (69%) containing
functional groups also capable of further chemical
transformations. Thus, compound IV containing hyd-
razone group readily reacts with 4-nitrobenzaldehyde
to give the mixed azine VI. Oxime V undergoes
Beckmann rearrangement under the trichloroaceto-
nitrile action [15] to provid the corresponding N-
methylamide VII.
–
1
and the double C=C bond at 1626 cm .
1
In the H NMR spectrum of compound II the
signals of HC=CH groups appear as doublets at 5.38
and 7.70 ppm with coupling constants 16.5 Hz,
indicating trans-arrangement of substituents at the
carbon atoms relative to the double bond. Methyl
protons of СОСН and N(CH ) resonate as singlets at
3
3 2
2
.38 and 2.98 ppm, respectively. The spectrum also
contains the multiplets at 4.37 and 4.76 ppm originat-
ing from the protons (8H) of the substituted cyclo-
pentadienyl rings of the ferrocene core.
NO2
CH
N
N
C
C H FeC H
NH
5
4
5
4
N
CH3
VI
O
C
−
H O
NO
2
2
H
H NNH H O
2
2
2
H C
3
C
C H FeC H
5
4
5
4
NH
O
N
o
EtOH, 78 C
NNH2
IV
II
−
HNMe , −2 H O
2
2
H NOH HCl, NaHCO
2
3
H C
3
C
N
C H FeC H
5
4
5
4
N
OH
V
Cl CCN
3
O
C
C H FeC H
O
5
4
5
4
N
H CHN
3
VII
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 81 No. 3 2011

5
32
MOSKALENKO et al.
Unlike hydrazine hydrate and hydroxylamine, the
amidines (guanidine and morpholino-1-carboxami-
dine) react with enamine II chemoselectively involv-
ing enaminocarbonyl moiety. As a result ferrocene-
containing pyrimidines VIII and IX containing an
acetyl group were obtained in moderate yields.
NH
R
C
N
NH2
HNMe , −H O
II
H C
3
C
O
C H FeC H
5
4
5
4
R
N
−
2
2
VIII, IX
O (IX).
R = H N (VIII),
N
2
Acetyl derivatives of the ferrocene series can
participate in a variety of chemical transformations [1].
Indeed, by an example of compound VIII we showed
that it can react with aldehydes, hydroxylamine,
thiosemicarbazide to form the corresponding con-
densation products involving methyl (X, XI) as well as
carbonyl (XII, XIII) group. Oxime XII as well as the
previously described compound V is rearranged into
N-methylamide XIV under the action of trichloro-
acetonitrile.
O
R1
C
, OH
−
N
H
CH CH R1
H N
N
N
C H FeC H
5 4
C
O
2
5
4
X, XI
S
N
CH3
C
S
N H2
NH
NH2
C
VIII
H N
C H FeC H
N NH
C NH2
−
H O
2
5
4
5
4
2
XIII
H NOH HCl, NaHCO
2
3
N
N
CH3
O
C
CCl CN
3
H N
N
C H FeC H
C
N OH
H N
N
C H FeC H
5 4 5 4
2
5
4
5
4
2
NHCH3
XII
XIV
1
R = Ph (X), 4-NO
2
C
6
H
4
(XI).
The composition and structure of compounds IV–
XIV were confirmed by analytical and spectroscopic
data listed in Tables 1 and 2.
EXPERIMENTAL
Commercial reagents (Acros) were used. The IR
spectra were recorded on a UR-20 spectrometer from
1
Thus, based on [1-acetyl-1'-(1-dimethylamino-3-
oxoprop-1-en-3-yl)]ferrocene II we developed new
approaches to the synthesis of 1,1'-disubstituted
unsymmetrical ferrocene derivatives, which are of
scientific and practical interest.
KBr pellets. The H NMR spectra were registered on a
Varian Mercury Plus-400 spectrometer (400 MHz) in
CDCl with internal reference HMDS. The GC–MS
3
spectra were recorded on a Thermo Finnigan Surveyor
MSQ (USA) instrument by the method of chemical
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 81 No. 3 2011

A FEATURE OF REACTION OF 1,1'-DIACETYLFERROCENE
533
ionization at atmospheric pressure. Identity and purity
of the compounds obtained was monitored by TLC on
Silufol UV-254 plates, eluents ethyl acetate (A),
benzene–chloroform, 2:1 (B), ethyl acetate–chloro-
form, 4:1 (C).
matography eluting with ethyl acetate. Yield 0.48 g
(77%).
Compound XIV was prepared similarly.
[1-Acetyl-1'-(2-aminopyrimidin-4-yl)]ferrocene
(
VIII). A mixture of 1.07 g of compound II, 0.96 g of
[
1-Acetyl-1'-(1-dimethylamino-3-oxoprop-1-en-
guanidine hydrochloride, and 1.68 g of potassium tert-
butoxide in 20 ml of anhydrous ethanol was refluxed
for 5 h at stirring. Then the mixture was cooled, mixed
with 100 ml of water, and extracted with methylene
chloride (2×80 ml). The organic layer was washed
with water, dried over anhydrous sodium sulfate, and
concentrated. The residue was subjected to chro-
matography eluting with ethyl acetate. Yield 0.51 g
3
-yl)]ferrocene (II). A mixture of 2.7 g of 1,1'-diacetyl-
ferrocene and 50 ml of dimethylformamide dimethyl
acetal I was refluxed under argon for 30 h at stirring.
Excess of acetal I was removed in a vacuum. The
residue was dissolved in ethyl acetate and subjected to
chromatography, eluting with ethyl acetate the starting
1
,1'-diacetylferrocene (0.24 g), and then with ethyl
acetate–methanol mixture (2:1) the target product II
(
48%). The product was recrystallized from water–
(
2.4 g, 74%).
methanol mixture (2:1).
[
1-Acetyl-1'-(pyrazol-3-yl)]ferrocene hydrazone
Compound IX was prepared similarly.
(
IV). A mixture of 1.07 g of compound II, 0.8 ml of
hydrazine hydrate in 20 ml of ethanol was refluxed for
h with stirring. The solvent was removed in a
[(1-Phenyl-3-oxoprop-1-en-3-yl)-1'-(2-aminopyri-
midin-4-yl)]ferrocene (X). To a solution of 0.32 g of
compound VIII and 0.11 g of the freshly distilled
benzaldehyde was added 0.2 ml of 30% aqueous
NaOH. The mixture was kept for 3 days at room
temperature. The reddish violet precipitate formed was
filtered off, washed with water, and dried. Yield 0.28 g
(68%).
3
vacuum. The residue was dissolved in 30 ml of water
and extracted with ethyl acetate (2×50 ml). The
organic layer was washed with water, dried over
anhydrous sodium sulfate, and concentrated. The
product was purified by chromatography, eluting with
system B. Yield 0.59 g (58%).
[
1-Acetyl-1'-(oxazol-3-yl)]ferrocene oxime (V).
Compound XI was prepared similarly.
To a solution of 1.07 g of II in 15 ml of ethanol was
added hydroxylamine solution obtained from 1.26 g of
HONH ·HCl and 1.68 g of NaHCO in 10 ml of water.
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2
3
The mixture was refluxed for 4 h under stirring, then
mixed with 50 ml of water and processed as in the
previous experiment. Yield 0.71 g (69%).
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2
3
4
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