Ferrocenylalkylation of 2-mercaptobenzoxazoles

Article abstract of DOI:10.1007/s11172-016-1670-y

Regioselectivity of the HBF₄-catalyzed ferrocenylalkylation of 2-mercaptobenzoxazole in two phase aqueous organic solvent mixture was studied. The reaction proceeds regioselectively at the heterocyclic nitrogen atom. Structures of the synthesiz

Full text of DOI:10.1007/s11172-016-1670-y

Russian Chemical Bulletin, International Edition, Vol. 65, No. 12, pp. 2868—2872, December, 2016
2868
Ferrocenylalkylation of 2ꢀmercaptobenzoxazoles
E. Yu. Osipova,a A. S. Ivanova,a A. N. Rodionov,a,b A. A. Korlyukov,a
D. E. Arkhipov,a and A. A. Simenela,c
aA. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
28 ul. Vavilova, 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 6549. Eꢀmail: jdyotvet@yandex.ru
bState Environmental Agency "Mosekomonitoring",
Build. 1, 2 Dal´niy per., 115419 Moscow, Russian Federation.
Fax: +7 (495) 954 1525. Eꢀmail: ecolaboratory@yandex.ru
cThe National University of Science and Technology "MISiS",
2 Leninsky prosp., 119049 Moscow, Russian Federation.
Fax: +7 (499) 236 2105
Regioselectivity of the HBF4ꢀcatalyzed ferrocenylalkylation of 2ꢀmercaptobenzoxazole in two
phase aqueous organic solvent mixture was studied. The reaction proceeds regioselectively at the
heterocyclic nitrogen atom. Structures of the synthesized compounds were established by 2D NMR
technique. Structure of 3ꢀ(1ꢀferrocenylbenzyl)benz[d]oxazolꢀ2ꢀthione was elucidated by Xꢀray
diffraction.
Key words: ferrocene, 2ꢀmercaptobenzoxazole, regioselectivity, ferrocenylalkylation.
Benzoxazole is an aromatic benzeneꢀfused oxazole ring
ing the DNA synthesis30 and damaging the DNA moleꢀ
cule.31 Ferroceneꢀcontaining heterocycles are effective
against murine solid tumor17,32 and human tumor cells.17
Recently, a cytotoxic cooperative effect of cyclophosꢀ
phamide, a known antitumor drug, and ferrocenylmethyl
thymine against the Ca755 solid tumor model was deꢀ
monstrated.32 Therefore, the development of new effiꢀ
cient synthetic approaches towards ferroceneꢀcontaining
heterocycles for the design of new low toxic antitumor
agents is still an ongoing challenge to organic chemists.
Introduction of ferrocenylalkyl moiety into different
structures can be achieved by ferrocenylalkylation;33—41
however, regioselectivity of this reaction is still poorly
studied. Earlier, we have described phaseꢀtransferꢀcataꢀ
lyzed alkylation of unsymmetrically substituted heterocyꢀ
cles with ferrocenyl carbinols. It has been shown that the
reaction is regioselective if the substituents exert different
electronic effects.42
structure. Despite the fact that unsubstituted benzoxazole
is of low practical value, its numerous derivatives found
application in industry (e.g., as optical brighteners for
detergents1). Heterocyclic core of benzoxazole is an inꢀ
teresting starting ring system for the synthesis of biologiꢀ
cally active substances. Aromaticity is a reason of the
relative stability of benzoxazole, at the same time it has
active sites for functionalization.2 It should be emphaꢀ
sized that benzoxazole derivatives of both natural and
synthetic origin possess a wide range of biological activiꢀ
ty.3 For instance, they show antibacterial,4 antiꢀinflamꢀ
matory,5 cyclooxigenaseꢀ2 inhibitory,6 antiviral,7 antiꢀalꢀ
lergic,8 antifungal,9,10 and antihelmintic activities.11 The
benzoxazole moiety is a constitutive part of flunoxaproꢀ
fen, a nonꢀsteroidal antiꢀinflammatory drug. Recent studꢀ
ies indicated that substituted benzoxazoles and related
heterocycles combine low toxicity and high chemotheraꢀ
peutic efficiency.12 It was also found that
2ꢀmercaptobenzoxazole is a promising candidate for biꢀ
ological13 and medicinal applications.14
Results and Discussion
It is also known that introduction of the ferrocene
fragment into different organic substances,15—19 mediꢀ
cines,20 and vitamins significantly decreases their toxiciꢀ
ty. Moreover, in vitro and in vivo antitumor activities of
ferrocene were extensively studied.17,21—27 It has been
found that ferrocenium salts exhibit not only antiprolifꢀ
erative activity28,29 but also are capable of both inhibitꢀ
Ferrocenylalkylated thiobenzoxazoles 1a—e were synꢀ
thesized by the reaction of 2ꢀmercaptobenzoxazole (2)
with different ferrocenyl carbinols 3 in dichloromethane
catalyzed by 48% tetrafluoroboric acid (Scheme 1). Reꢀ
action was carried out with equimolar amounts of ferroꢀ
cenyl carbinol and 2ꢀmercaptobenzoxazole at room temꢀ
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 12, pp. 2868—2872, December, 2016.
1066ꢀ5285/16/6512ꢀ2868 © 2016 Springer Science+Business Media, Inc.

Ferrocenylalkylated 2ꢀmercaptobenzoxazoles
Russ.Chem.Bull., Int.Ed., Vol. 65, No. 12, December, 2016 2869
perature under vigorous stirring. The reaction products
were purified by column chromatography, if necessary.
C(4)
C(3)
C(2)
O(1)
C(5)
Scheme 1
C(6)
C(1)
C(7)
N(1)
S(1)
C(16)
C(10)
C(15)
C(17)
C(18)
C(8)
C(11)
C(13)
C(9)
C(19)
C(12)
Fe(1)
C(14)
C(23)
C(22)
C(24)
C(20)
C(21)
Fig. 1. Geometry of compound 1f. The thermal displacement ellipꢀ
soids were drawn at 50% probability level.
1: R = H (a), Me (b), Et (c), Pr (d), Pri (e), Ph (f)
It is found that all reactions proceed regioselectively
at the heterocyclic nitrogen atom. Structures of the reacꢀ
1
tion products were established by H—13C heteronuclear
correlation experiments. Thus, HMBC NMR spectra of
compounds 1 exhibit characteristic correlations of the
bridging alkyl group protons of the ferrocenylalkyl moiꢀ
eties with the C atoms of the C=S group of oxazole
fragment (at about δ 180) and with the C(9) atom (in the
range of δ 129.8—131.5). This is evidence in support of
the substitution at the benzoxazole ring nitrogen.
Structure of 3ꢀ(ferrocenylbenzyl)benz[d]oxazoleꢀ
2ꢀthione (1f) was examined by Xꢀray diffraction analysis
(Fig. 1). The bond lengths and bond angles of compound
1f are nearly the same as those found for substituted
ferrocenes and benzoxazoles.
Regioselectivity of the substitution in 2ꢀmercaptoꢀ
benzoxazole agrees with our previous observations.43 We
have found43 that acidꢀcatalyzed ferrocenylalkylation of
2ꢀmercaptobenzimidazole and 2ꢀmercaptobenzothiazꢀ
ole occurred at the nitrogen atoms. Ferrocenylalkylation
proceeds via thermodynamically stable αꢀferrocenium
carbocation, which is relatively hard Lewis acid efficiently
reacting with somewhat harder basic center, in our case,
with the benzoxazole nitrogen atom. Furthermore, quanꢀ
tum chemical calculations show that Nꢀisomers 1, 5, and
7 are more thermodynamically stable than the correꢀ
sponding Sꢀisomers 4, 6, and 8 (Table 1).
lated and solvated (CH2Cl2) molecules 1 and 4—8. For
benzimidazole and benzoxazole derivatives, the ΔG valꢀ
ues are generally higher than for benzothiazole derivaꢀ
tives with the exception of calculations for the isolated
molecules 1b and 1f. Under solvation conditions, substiꢀ
tution at the nitrogen atom is always more favorable than
substitution at the sulfur atom. Moreover, solvation reꢀ
sults in an increase in the ΔG value between Nꢀ and
Sꢀisomers.
Table 1 shows the differences between the energies of
formation (ΔG) of Nꢀ and Sꢀalkylation products for isoꢀ

2870 Russ.Chem.Bull., Int.Ed., Vol. 65, No. 12, December, 2016
Osipova et al.
Table 1. ΔG values for isolated and solvated molecules of
ferrocenylated heterocyclic compounds 1, and 4—8
N, 4.01; Fe, 15.99. Rf 0.6 (petroleum ether—ethyl acetate, 3 : 1).
MS, m/z (Irel(%)): 349 [M]+ (100). 1H NMR, δ: 4.18 (s, 2 H,
C5H4); 4.27 (s, 5 H, C5H5); 4.48 (s, 2 H, C5H4); 5.21 (s, 2 H,
CH2); 7.15 (d, 1 H, Het, J = 7.6 Hz); 7.22—7.31 (m, 2 H, Het);
7.32 (d, 1 H, Het, J = 7.6 Hz). 13C NMR, δ: 45.66 (CH2), 68.74
(C5H4), 68.96 (C5H5), 69.69 (C5H4), 80.29 (ipsoꢀC5H4), 109.81
(Het), 110.34 (Het), 124.17 (Het), 124.75 (Het), 131.51 (Het),
147.05 (Het), 180.06 (C=S).
3ꢀ(1ꢀFerrocenylethyl)benz[d]oxazoleꢀ2ꢀthione (1b). Yield
65%. Orange oil. Rf 0.6 (petroleum ether—ethyl acetate, 3 : 1).
MS, m/z (Irel(%)): 364 [M]+ (80). 1H NMR, δ: 1.86 (d, 3 H, CH3,
J = 7.0 Hz); 4.20 (s, 1 H, C5H4); 4.27 (m, 6 H, C5H4); 4.31 (s, 1 H,
C5H4); 4.52 (s, 1 H, C5H4); 6.37 (q, 1 H, CH, J = 7.1 Hz); 6.92
(d, 1 H, Het, J = 8.0 Hz); 7.06 (t, 1 H, Het, J = 7.8 Hz); 7.15 (t, 1 H,
Het, J = 7.8 Hz); 7.31 (d, 1 H, Het, J = 8.0 Hz). 13C NMR, δ:
16.29 (CH3), 54.30 (CH), 66.78 (C5H4), 67.78 (C5H4), 69.17
(C5H4), 69.29 (C5H5), 69.43 (C5H4), 84.89 (ipsoꢀC5H4), 110.27
(Het), 111.42 (Het), 123.78 (Het), 124.37 (Het), 129.81 (Het),
147.14 (Het), 179.48 (C=S).
3ꢀ(1ꢀFerrocenylpropyl)benz[d]oxazoleꢀ2ꢀthione (1c). Yield
70%. Orange powder. M.p. 117.2—118.8 °C. Found (%): C, 61.70;
H, 5.10; N, 3.74; Fe, 14.84. Calculated (%): C, 61.67; H, 5.05;
N, 3.71; Fe, 14.80. Rf 0.6 (petroleum ether—ethyl acetate, 3 : 1).
MS, m/z (Irel(%)): 378 (100). 1H NMR, δ: 1.04 (t, 3 H, CH3,
J = 7.4 Hz); 2.35 (m, 1 H, CH2); 2.43 (m, 1 H, CH2); 4.15 (s, 1 H,
C5H4); 4.22 (s, 1 H, C5H4); 4.26 (s, 5 H, C5H5); 4.29 (s, 1 H,
C5H4); 4.47 (s, 1 H, C5H4); 6.28 (m, 1 H, CH); 7.01 (d, 1 H, Het,
J = 8.0 Hz); 7.07 (t, 1 H, Het, J = 7.8 Hz); 7.15 (t, 1 H, Het, J =
= 7.8 Hz); 7.30 (d, 1 H, Het, J = 8.0 Hz). 13C NMR, δ: 11.07
(CH3), 24.56 (CH2), 59.88 (CH), 66.63 (C5H4), 67.67 (C5H4),
68.70 (C5H4), 68.88 (C5H4), 69.29 (C5H5), 85.06 (ipsoꢀC5H4),
110.32 (Het), 111.28 (Het), 123.83 (Het), 124.37 (Het), 129.79
(Het), 147.03 (Het), 180.84 (C=S).
3ꢀ(1ꢀFerrocenylbutyl)benz[d]oxazoleꢀ2ꢀthione (1d). Yield
75%. Orange powder. M.p. 116—118 °C. Found (%): C, 64.49;
H, 5.44; N, 3.56; Fe, 14.31. Calculated (%): C, 64.46; H, 5.40;
N, 3.50; Fe, 14.27. Rf 0.8 (petroleum ether—ethyl acetate, 3 : 1).
MS, m/z (Irel(%)): 391 (100). 1H NMR, δ: 1.05 (t, 3 H, CH3, J =
= 7.3 Hz); 1.33 (m, 2 H, CH2); 1.53 (m, 2 H, CH2); 4.15 (s, 1 H,
C5H4); 4.22 (s, 1 H, C5H4); 4.26 (s, 5 H, C5H5); 4.30 (s, 1 H,
C5H4); 4.46 (s, 1 H, C5H4); 6.34 (s, 1 H, CH); 7.04 (d, 1 H, C6H5,
J = 7.7 Hz); 7.10 (t, 1 H, C6H5, J = 7.6 Hz); 7.17 (t, 1 H, C6H5,
J = 7.7 Hz); 7.32 (d, 1 H, C6H5, J = 7.9 Hz). 13C NMR, δ: 14.07
(CH3), 19.47 (CH2), 33.28 (CH2), 58.06 (CH), 66.65 (C5H4),
67.65 (C5H4), 68.71 (C5H4), 68.90 (C5H4), 69.27 (C5H4), 85.26
(ipsoꢀC5H4), 110.30 (Het), 111.29 (Het), 123.80 (Het), 124.36
(Het), 129.81 (Het), 147.05 (Het), 180.66 (C=S).
Possible
isomers
R
ΔG/kcal mol–1
Gas
Solution (CH2Cl2)
1, 4
5, 6
7, 8
H
Me
Et
Pri
Ph
H
Me
Et
Pri
Ph
H
Me
Et
Pri
Ph
5.1
1.6
7.4
4.3
2.3
6.5
2.9
10.3
10.6
11.0
9.4
8.6
4.8
5.1
–1.1
3.8
0.6
9.3
9.9
9.8
8.7
8.1
3.9
4.0
3.6
2.7
1.8
4.8
3.9
2.6
Experimental
Solvents were dried following the standard procedures and disꢀ
tilled under argon prior to use. EI mass spectra were taken on a
FINNIGAN POLARIS Q spectrometer at 70 eV and the temperaꢀ
1
ture of the ion chamber 250 °C. H and 13C NMR spectra were
obtained on a Bruker Advance 400 spectrometer (at 400 and 100
MHz, respectively) in CDCl3 at 30 °C. The chemical shifts are
given in the δ scale relative to the residual solvent signal. All signals
in the NMR spectra were attributed using gradient HSQC and
HMBC heteronuclear correlation techniques. Melting points were
determined with a Stuart SMP30 apparatus (Bibby Scientific).
Commercially available 2ꢀmercaptobenzoxazole (Acros Organics)
was used as purchased. Ferrocenylmethanol (3a) was synthesized
from trimethylferrocenylmethylammonium iodide by the known
procedure.44 Ferrocenyl carbinols 3b—e were accessed from ferꢀ
rocene by the Friedel—Crafts acylation with the corresponding acid
chlorides and subsequent reduction with lithium aluminum hydride
in diethyl ether or THF.45
Quantum chemical calculations were performed with a Gaussꢀ
ian09 program package. Full geometry optimization of the isolated
molecules were done with PBE0 exchangeꢀcorrelation functional
and 6ꢀ311G(d,p) basis set followed by oscillator vibrational freꢀ
quency calculations. Effects of nonꢀspecific solvation from CH2Cl2
was accounted for by the PCM model.
Synthesis of ferrocenylalkylꢀ2ꢀmercaptobenzoxazoles (general
procedure). A 48% aqueous solution of tetrafluoroboric acid (0.21 mL,
1.2 mmol) was added to a suspension of ferrocenyl carbinol (1 mmol)
and 2ꢀmercaptobenzoxazole (1 mmol) in dichloromethane (1 mL)
under vigorous stirring. The stirring was continued for 5—15 mL.
Then water (10 mL) and diethyl ether (10 mL) were added to the
reaction mixture. The resulting mixture was washed with water
(2×20 mL), the organic layer was separated and dried with Na2SO4.
The solvent was removed under water pump vacuum.
3ꢀ(1ꢀFerrocenylꢀ2ꢀmethylpropyl)benz[d]oxazoleꢀ2ꢀthione
(1e). Yield 60%. Yellow powder. M.p. 146—148 °C. Found (%):
C, 64.40; H, 5.40; N, 3.56; Fe, 14.35. Calculated (%): C, 64.46;
H, 5.41; N, 3.58; Fe, 14.27. Rf 0.6 (petroleum ether—ethyl acetate,
3 : 1). MS, m/z (Irel(%)): 391 [M]+ (55). 1H NMR, δ: 0.88 (d, 3 H,
J = 6.6 Hz); 1.36 (d, 3 H, J = 6.6 Hz); 2.61 (m, 1 H, CH); 4.13
(m, 6 H, Fc); 4.15 (s, 1 H, C5H4); 4.23 (s, 1 H, C5H4); 4.43 (s, 1 H,
C5H4); 5.92 (d, 1 H, J = 10.5 Hz); 7.07 (d, 1 H, J = 7.7 Hz); 7.15
(t, 1 H, J = 7.7 Hz); 7.21 (t, 1 H, J = 7.7 Hz); 7.36 (d, 1 H, J =
= 7.7 Hz). 13C NMR, δ: 20.03 (CH3), 21.89 (CH3), 31.49 (CH2),
64.39 (CH), 67.26 (C5H4), 67.41 (C5H4), 68.47 (C5H4), 68.74
(C5H4), 69.28 (C5H4), 86.04 (ipsoꢀC5H4), 110.38 (Het), 111.69
(Het), 123.96 (Het), 124.40 (Het), 130.40 (Het), 146.82 (Het),
180.83 (C=S).
3ꢀ(Ferrocenylmethyl)benz[d]oxazoleꢀ2ꢀthione (1a). Yield 72%.
Yellow powder. M.p. 166.8—167.2 °C. Found (%): C, 61.97;
H, 4.32; N, 4.04; Fe, 15.96. Calculated (%): C, 61.91; H, 4.33;

Ferrocenylalkylated 2ꢀmercaptobenzoxazoles
Russ.Chem.Bull., Int.Ed., Vol. 65, No. 12, December, 2016 2871
Table 2. Main crystallographic data and refinement paꢀ
rameters for compound 1f
Science Foundation for the financial support (Project
No. 14ꢀ13ꢀ00884; quantum chemical calculations).
Parameters
Values
References
Molecular formula
Molecular weight
T/K
C24H19FeNOS
425.31
120
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Space group
Z
a/Å
b/Å
c/Å
Cc
4
16.6720(11)
10.4091(7)
13.0438(7)
122.445(2)
1910.3(2)
1.479
9.13
880
52
12940
5838
5468
253
0.0291
0.0630
0.986
b/deg
3
V/Å
dcalc/g cm–3
μ/cm–1
F(000)
2 θmax/deg
Number of measured reflections
Number of independent reflections
Number reflections with I > 2σ(I)
Number of refined parameters
R1
wR2
GOOF
Residual electron
density (ρmax/ρmin)/e Å
–3
0.384/–0.205
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59%. Orange powder. M.p. 146—148 °C. Found (%): C, 67.80;
H, 4.58; N, 3.33; Fe, 13.15. Calculated (%): C, 67.77; H, 4.50;
N, 3.29; Fe, 13.13. Rf 0.6 (petroleum ether—ethyl acetate, 3 : 1).
MS, m/z (Irel(%)): 425 [M]+ (29). 1H NMR, δ: 4.20 (s, 2 H,
C5H4); 4.25 (s, 5 H, C5H5); 4.27 (s, 1 H, C5H4); 4.29 (s, 1 H,
C5H4); 6.71 (d, 1 H, CH, J = 7.9 Hz); 7.03 (t, 1 H, Het, J = 7.9 Hz);
7.17 (t, 1 H, Het, J = 8.1 Hz); 7.37 (m, 7 H, CH). 13C NMR, δ:
61.96 (CH), 68.10 (C5H4), 68.42 (C5H4), 69.04(C5H4), 69.46
(C5H5), 69.81 (C5H4), 84.68 (ipsoꢀC5H4), 110.30 (Het), 112.50
(Het), 123.85 (Het), 124.34 (Het), 128.08 (C6H5), 128.27 (ipsoꢀ
C6H5), 128.54 (C6H5), 130.90 (Het), 137.31 (C6H5), 147.05
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This work was financially supported by the Russian
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Received August 16, 2016;
in revised form October 4, 2016