Synthesis of ferrocene-containing six-membered cyclic ureas via α-ferrocenyl carbocations

Article abstract of DOI:10.1039/c5ra01383f

A series of ferrocene-containing six-membered cyclic ureas (1-aryl-4-ferrocenyl-3-phenyltetrahydropyrimidin-2(1H)-ones) was synthesized (in high-to-excellent yields) by reacting the corresponding aminopropanols with phenyl isocyanate and the subsequent intramolecular cyclization of the thus obtained β-hydroxy ureas (prompted by acetic acid), via an α-ferrocenyl carbocation. This journal is

Full text of DOI:10.1039/c5ra01383f

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Synthesis of ferrocene-containing six-membered
cyclic ureas via a-ferrocenyl carbocations†
Cite this: RSC Adv., 2015, 5, 24915
a
a
a
a
Aleksandra Minic, Dragana Stevanovic, Ivan Damljanovic, Anka Pejovic,
´
´
´
´
b
c
d
Mirjana Vukicevic, Goran A. Bogdanovic, Niko S. Radulovic
Received 23rd January 2015
Accepted 2nd March 2015
´
´
´
´
a
and Rastko D. Vukicevic*
´
´
DOI: 10.1039/c5ra01383f
www.rsc.org/advances
A series of ferrocene-containing six-membered cyclic ureas (1-aryl-4- acid derivatives (phosgene chiey, but also urea and dialkyl
ferrocenyl-3-phenyltetrahydropyrimidin-2(1H)-ones) was synthesized carbonates), carbon monoxide and carbon dioxide; recently
(
in high-to-excellent yields) by reacting the corresponding amino- published protocols mainly represent (improved) variants of
propanols with phenyl isocyanate and the subsequent intramolecular earlier ones (see, for example, ref. 9).
cyclization of the thus obtained b-hydroxy ureas (prompted by acetic
acid), via an a-ferrocenyl carbocation.
In continuation of our permanent interest in the synthesis of
ferrocene derivatives, particularly those that are potentially
bioactive, we decided to synthesize a series of new ferrocene-
containing six-membered cyclic ureas (tetrahydropyrimidin-2-
ones). The following two main motives stimulated us to
undertake this project: (i) a general notion exists that increased
lipophilicity of cyclic ureas enhances their biological activity
Six-membered cyclic ureas make up the core structure of a
number of molecules possessing interesting biological features
1
(
Fig. 1), such as action on the central nervous system (1), reti-
2
3
noidal (2) and herbicidal (3) activities, as well as dihydroor-
(
incorporation of a ferrocene unit into organic molecules, such
as six-membered cyclic ureas, will certainly cause an increase of
4
5
otase (4) and HIV protease (5) inhibiting activities.
Furthermore, while some readily accessible and re-isolable
representatives of ve-membered cyclic ureas were used as effi-
the lipophilicity of these compounds, that, in turn, could be
1b,2,10
benecial to their biological activity);
(ii) we recently
6
cient chiral auxiliaries in asymmetric organic synthesis, a six-
reported a versatile synthesis of a series of ferrocene-containing
b-aminoketones (Mannich bases, 2-ferrocenoylethyl aryl
amines) by aza-Michael addition of aryl amines to the conju-
gated ketone acryloylferrocene, catalyzed by montmorillonite
membered urea, 3-decyl-4-hydroxymethyltetrahydropyrimidin-
2
-one, was exploited in the chiral resolution of some polyfunc-
7
tional xanthone derivatives. Therefore, considerable interest
exists among synthetic and medicinal chemists in the develop-
ment of this class of compounds, and a multitude of reports
dealing with these compounds appeared in the literature.
11
K-10 and assisted by microwave or ultrasound irradiation.
Considering the known carbonyl group reactivity, we realized
that these ketones could serve as precursors of the
8
As extensively summarized ten years ago, most of the
reported methods for the synthesis of cyclic ureas refer to the
oldest method based on the reaction of diamines with carbonic
a
Department of Chemistry, Faculty of Science, University of Kragujevac, R. Domanovi ´c a
1
2, 34000 Kragujevac, Serbia. E-mail: vuk@kg.ac.rs; Fax: +381 34 335040; Tel: +381
4 300268
3
b
Department of Pharmacy, Faculty of Medicinal Sciences, University of Kragujevac,
S. Markovi ´c a 69, 34000 Kragujevac, Serbia
c
Vin ˇc a Institute of Nuclear Sciences, University of Belgrade, PO Box 522, 11001
Belgrade, Serbia
d
Department of Chemistry, Faculty of Science and Mathematics, University of Ni ˇs ,
Vi ˇs egradska 33, 18000 Ni ˇs , Serbia
†
Electronic supplementary information (ESI) available: Detailed experimental
1
13
procedures, spectral characterisation (including copies of H and C NMR
spectra) of all new compounds, crystallographic data and CIF les. CCDC
1
043324 and 1043325. For ESI and crystallographic data in CIF or other
Fig. 1 Some bioactive six-membered cyclic ureas.
electronic format see DOI: 10.1039/c5ra01383f
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11
corresponding ferrocene-containing 1,3-diamines which procedure, Scheme 2). Aer the reduction of this ketone (with
8,9
(
according to the aforementioned literature reports ) would sodium
borohydride
in
methanol),
the
obtained
represent a starting material in the synthesis of the corre- 3-(aminophenyl)-1-ferocenyl-1-propanol (9a) was treated with
15
sponding six-membered cyclic ureas.
In this communication we report on the synthesis of seven- desired
teen new ferrocene-containing six-membered cyclic ureas tetrahydroquinoline (10). Apparently, upon protonation, the
1-aryl-4-ferrocenyl-3-phenyltetrahydropyrimidin-2(1H)-ones), alcohol loses a water molecule giving a (stable) a-ferrocenyl
which were completely characterized by spectral data. carbocation electrophilic enough to undergo an intramolecular
Having a series of 2-ferrocenoylethyl aryl amines at hand, we alkylation of the benzene ring activated by the amine nitrogen.‡
performed a simple retrosynthetic analysis and envisaged a Based on this experience (and, also, being unwilling to use
aniline in the presence of acetic acid. However, instead of the
diamine, we obtained 4-ferrocenyl-1,2,3,4-
(
synthesis of the target six-membered cyclic ureas with the cor- phosgene as the most efficient reagent for the subsequent step
responding diamines as key intermediates, as depicted in of the synthesis), we envisaged an alternative approach to the
Scheme 1 (Pathway a). Among several possible approaches to target ferrocene-containing six-membered cyclic ureas, aban-
these diamines from 2-ferrocenoylethyl aryl amines – the doning the idea of 1,3-diamines as the key intermediates. In
reduction of the latter and subsequent nucleophilic substitu- fact, we opted for the “reverse order of events” – b-amino-
tion of the hydroxyl group from the obtained alcohol with an ketones / 1,3-aminoalcohols / cyclic ureas; instead of
amine seemed to be the most suitable one. The ease of forma- substituting the hydroxyl group before the introduction of the
tion of a-ferrocenyl carbocations from 1-ferrocenylalkanols and urea functionality, we chose to submit the aminoalcohols to the
their well-known stability lied at the heart of this idea. For reaction with an isocyanate. Namely, it is well known that the
example, a successful a-ferrocenylalkylation of anilines with addition of amines to isocyanates represents the most widely
8
,16
1
-ferrocenylethanol, under mild conditions, was reported used method for the synthesis of acyclic ureas, and this gives
12
recently. However, recently, following this procedure, we failed the opportunity to design the corresponding b-hydroxy ureas as
to obtain the product of substitution of the hydroxyl group from key intermediates in the target synthesis (Pathway b, Scheme 1).
1
-ferrocenyl-3-thiapentan-1-ol using diethylamine as the In this way, the role of an a-ferrocenyl carbocation was le for
13
nucleophile; an attempt with aniline as the nucleophile was the nal step, in which the hydroxyl group was to be substituted
also unsuccessful. (The successful substitution was accom- (via this cation) by an NH group from the formed urea moiety,
plished by applying an older method that included acetylation
of the starting alcohol before the substitution step ).
A recently reported successful substitution of the hydroxyl
13,14
15
group in 1-ferrocenyl-1-alkanols, promoted by acetic acid,
deemed very suitable for the synthesis of the necessary
diamines. Thus, the realization of the synthetic plan by Pathway
a (Scheme 1) began with the synthesis of the Mannich base
2-ferocenoylethyl phenyl amine (8a) (by aza-Michael addition of
aniline (7a) to acryloylferrocene (6), following the known
Scheme 1 Retrosynthetic analysis.
Scheme 2 Synthesis of tetrahydropyrimidin-2-ones 12a–q.
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assembling the six-membered ring. The idea was tested on the giving, via zwitterions I, hydroxyureas 11a–q. A key step of the
Mannich base 8a, i.e., via the aminoalcohol 9a, which reacted overall reaction is an intramolecular cyclization of these inter-
smoothly (without any particular purication) with phenyl mediates. As depicted in Scheme 3, the reaction starts with the
isocyanate affected by a short ultrasonic irradiation. Acetic acid protonation of 11a–q by acetic acid and dehydration of the
was added to the product (still in the same vessel, i.e., again resulting oxonium ions II, giving a-ferrocenyl carbocations III,
without isolation or purication) and the mixture irradiated known to be very stable due to the participation of the ferrocenyl
17
additionally to give, aer the usual workup and column chro- group in the delocalization of the positive charge. A nucleo-
matography (SiO /n-hexane–EtOAc, 8 : 2, v/v), the target six- philic attack of the carbamide nitrogen on the positive centre of
membered cyclic urea 12a in a good yield (78%). these cations affords cations IV, which are deprotonated to give
The same procedure was applied for the synthesis of a small the target compounds 12a–q.
library of cyclic ureas (see Scheme 2), and the obtained results The structures of the synthesized cyclic ureas were corrobo-
2
1
13
are summarized in Table 1. As these results show, this protocol rated by careful H, C and 2D NMR spectral analyses. Since the
allowed an easy and high yielding (up to 99%) access to structures of these compounds include only one chiral centre
ferrocene-containing tetrahydropyrimidin-2-ones 12a–q start- (C4, originating from the corresponding racemic alcohols 9a–q)
ing from the corresponding Mannich bases. These compounds they were expected to form the corresponding racemates.
were found to be stable at room temperature for a prolonged However, the spectra of some ortho-substituted derivatives
time period and could safely be handled in air, but like other revealed the existence of mixtures of two diastereoisomers.
ferrocene derivatives, should be stored in closed containers.
Namely, compared to that of 12a, the number of signals in the
C NMR spectrum of compound 12b was found to be almost
1
3
Although the reaction of alcohols 9a–q with phenyl isocya-
nate and the subsequent intramolecular cyclization of the thus doubled (some, most probably, must have overlapped). Char-
1
obtained products to cyclic ureas 12a–q proceeded in “a one acteristic signals appearing in the H NMR spectra of this
pot” manner, the existence of intermediates 11a–q was inferred compound, like those attributed to the protons of the methyl
1
13
from a careful analysis of H and C NMR spectra of an aliquot group (singlet), the C4 methylene group (pseudotriplet J ꢀ 4 Hz)
of the reaction mixture obtained with 9k, sampled before the and the unsubstituted cyclopentadiene ring (singlet) appeared
addition of acetic acid (see ESI†).
as pairs of more or less well-separated analogous pairs of
A plausible mechanism of these transformations is depicted signals (ESI, Fig. S1†). According to the integral ratios of these
in Scheme 3. In the rst reaction step, the NH group of alcohols
9a–q adds to the C]N double bond of the isocyanate group
Table 1 Synthesis of tetrahydropyrimidin-2-ones 12a–q
a
Entry
Product
Ar
Yield (%)
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
12a
12b
12c
12d
12e
12f
12g
12h
12i
12j
12k
12l
12m
12n
12o
12p
12q
C
6
H
5
78
83
86
80
78
84
91
80
80
88
83
62
68
89
99
58
64
2-CH
3-CH
4-CH
3
3
3
C
C
C
6
6
6
H
H
H
4
4
4
2,3,4-(CH
3
)
3
C
6
H
2
2-FC
3-FC
4-FC
2-ClC
3-ClC
4-ClC
2-BrC
3-BrC
4-BrC
2-CH
3-CH
4-CH
6
6
6
H
H
H
4
4
4
6
6
6
H
H
H
4
4
4
0
1
2
3
4
5
6
7
6
6
6
H
H
H
4
4
4
3
OC
OC
OC
6
6
6
H
H
H
4
4
4
3
3
a
Yields of isolated compounds, based on aminoketones 8a–q.
Scheme 3 A plausible reaction mechanism of the transformation of
alcohols 9a–q into six-membered cyclic ureas 12a–q.
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the fragment C6–N1–C2–N3–C4 lies almost in the same plane
(
2
torsion angles N1–C2–N3–C4 and N3–C2–N1–C6 were less than
). To approximately adopt a coplanar arrangement of this
ꢁ
fragment and the benzene ring (this represents the highest
0
energetic barrier to the rotation around N1–C1 bond), the
hydrogen atoms from the methyl groups have to approach the
oxygen atom or the protons of C6 methylene group to a distance
ꢀ
of less than 1 A (ESI, Fig. S2†). This molecular event would
0
certainly govern the rotation around the single N1–C1 bond in
Fig. 2 Resonance structures of 12b.
this compound, and the same should happen in the case of 12b.
As mentioned, an analogous phenomenon was observed for
all other ortho-substituted cyclic ureas (12f, 12i, 12l and 12o).
However, it seems that the rotational energetic barrier for the
protons, we estimated that the obtained product represented a
55 : 45 mixture of two diastereoisomers, even though 12b
contains only a single chiral centre.
0
N1–C1 bond in these molecules is lower than that in the case of
1
An explanation for this phenomenon was much simpler than
it looked at the rst glance. Namely, participating in the reso-
nance delocalisation, the nitrogen atoms of the urea unit take a
trigonal character, as depicted in Fig. 2, causing all atoms of the
tetrahydropyirimidin-2-one unit to lie in the same plane, except
C5. This induces a high rigidity of the six-membered ring and
1
2b, so the corresponding signals in the H NMR spectra either
overlapped or were conformationally broadened or averaged.
This interesting occurrence of diastereoisomerism caused by
conformational chirality (atropisomerism) indeed needs (and
deserves) additional study. Namely, enantiomeric forms of
alcohols 9a–q, obtained by an asymmetric reduction of Man-
nich bases 8a–q, would certainly give enantiomeric forms of
cyclic ureas 12a–q, due to the known feature of a-ferrocenyl
carbocations – to retain the conguration during nucleophilic
0
0
restricts rotation around the single N1–C1 bond when C2 bears
a bulky group (for example, a methyl group). This imparts an
additional element of (axial) chirality to the molecule, and
provides an explanation for the observed diastereoisomerism,
i.e., for the appearance of two pairs of enantiomers.
19
substitutions. If that were the case, cyclic ureas like 12c would
appear as the mixture of two diastereoisomers, and not as the
mixture of two pairs of enantiomers. The use of aminoalcohols
carrying a more sterically demanding group in the ortho posi-
tion might also be useful for such investigations.
Although we did not obtain crystals of urea 12b suitable for
single crystal X-ray analysis to conrm this claim, monocrystals
of 12c and 12e were of sufficient quality, and their molecular
18
structures are presented in Fig. 3. Thus, this analysis showed
that in 12e (containing methyl groups in both ortho positions)
Conclusions
In conclusion, herein, we presented a versatile protocol for the
synthesis of ferrocene-containing six-membered cyclic ureas –
1-aryl-4-ferrocenyl-3-phenyltetrahydropyrimidin-2(1H)-ones
–
starting from the corresponding b-(arylamino)ketones,
compounds readily available through the aza-Michael addition
of the corresponding anilines to acryloylferrocene. The forma-
tion and reactivity of an a-ferrocenyl carbocation represents the
key step in this synthesis.
Acknowledgements
This work was supported by the Ministry of Education, Science
and Technological Development of the Republic of Serbia (grant
172034).
Notes and references
‡
Although irrelevant for the current work, this reaction is certainly very inter-
esting and deserves separate investigations, which have been already initiated (the
results will be reported in the near future).
1
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Fig. 3 The molecular structures of (a) 12c and (b) 12e (hydrogen atoms
are omitted). Displacement ellipsoids are drawn at 30% probability
18
level.
Pharm. Jugosl., 1982, 32, 79.
24918 | RSC Adv., 2015, 5, 24915–24919
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R. J. K. Taylor, Elsevier, Amsterdam, 2004, vol. 6, pp. 453– 18 Crystal data for 12c:
93.
C
27
H
26FeN
ꢀ
2
O,
M
¼
356.81,
ꢀ
4
orthorhombic, a ¼ 23.4076(10) A, b ¼ 10.6422(3) A, c ¼
ꢀ
ꢁ
ꢁ
ꢁ
ꢀ
3
9
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8.9673(3) A, a ¼ 90 , b ¼ 90 , g ¼ 90 , V ¼ 2233.83(14) A ,
T ¼ 293(2) K, space group Pca2
1
, Z ¼ 4, m(MoKa) ¼ 0.696
ꢂ1
mm , 18343 reections measured, 5273 independent
reections (Rint ¼ 0.0216). The nal R values were 0.0402
1
2
(I > 2s(I)). The nal wR(F ) values were 0.0989 (I > 2s(I)).
2
2010, 75, 3037; (e) M. Tamura, K. Noro, M. Honda,
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1043324. Crystal data for 12e: C29
H
30FeN
2
O, M ¼ 356.81,
ꢀ
ꢀ
1
0 (a) D. A. Nugiel, K. Jacobs, T. Worley, M. Patel,
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R. J. McHugh, Q. Han, R. Li, J. A. Markwalder, S. P. Seitz,
triclinic, a ¼ 8.9564(4) A, b ¼ 11.9843(5) A, c ¼ 22.8058(10)
ꢀ
ꢁ
ꢁ
ꢁ
A, a ¼ 79.735(4) , b ¼ 88.568(4) , g ¼ 89.935(4) , V ¼
ꢀ
ꢁ
2407.94(18) A3, T ¼ 293(2) K, space group P1, Z ¼ 4,
ꢂ1
m(MoKa) ¼ 0.650 mm , 30636 reections measured, 8712
independent reections (R ¼ 0.0441). The nal R values
int
1
2
were 0.1094 (I > 2s(I)). The nal wR(F ) values were 0.3031
2
(I > 2s(I)). The goodness of t on F was 1.078. CCDC
number CCDC 1043325.†
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