Synthesis and properties of optically active ferrocenylethylindazoles

Article abstract of DOI:10.1023/B:RUCB.0000037868.08052.23

The stereochemistry of two processes, viz., α-ferrocenylalkylation of indazole with optically active S-(+)-1-ferrocenylethanol and the thermal rearrangement of S-(+)-2-N-(ferrocenylethyl)indazole into S-(+)-1-N- (ferrocenylethyl)indazole, was studied. Bot

Full text of DOI:10.1023/B:RUCB.0000037868.08052.23

Russian Chemical Bulletin, International Edition, Vol. 53, No. 4, pp. 939—941, April, 2004
939
Synthesis and properties of optically active ferrocenylethylindazoles
A. A. Simenel, Yu. V. Kuzmenko, M. M. Ilyin, V. V. Gumenyuk, L. V. Snegur,ꢀ and Yu. S. Nekrasov
A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
28 ul. Vavilova, 119991 Moscow, Russian Federation.
Fax: +7 (095) 135 5085. Eꢀmail: snegur@ineos.ac.ru
The stereochemistry of two processes, viz., αꢀferrocenylalkylation of indazole with optiꢀ
cally active Sꢀ(+)ꢀ1ꢀferrocenylethanol and the thermal rearrangement of Sꢀ(+)ꢀ2ꢀNꢀ(ferroꢀ
cenylethyl)indazole into Sꢀ(+)ꢀ1ꢀNꢀ(ferrocenylethyl)indazole, was studied. Both reactions
proceed stereoselectively.
Key words: ferrocenes, ferrocenylalkylation, enantiomeric resolution, highꢀperformance
liquid chromatography.
Acidꢀcatalyzed ferrocenylalkylation of nitrogenꢀconꢀ
taining heterocycles with ferrocenylcarbinols and ferroꢀ
cenyl(alkyl)amines provides a convenient procedure for
the introduction of the ferrocenylalkyl group into nucleoꢀ
philes. For example, refluxing of (R,S)ꢀdimethyl{1ꢀ[2ꢀ(diꢀ
phenylphosphino)ferrocenyl]ethyl}amine with pyrazoles
in acetic acid afforded pyrazoleꢀcontaining P,Nꢀbidentate
ligands in 30—70% yields (ee 95%).1 A very convenient
method for ferrocenylalkylation is based on reactions of
Nꢀheterocycles with ferrocenylcarbinols under conditions
of acid phaseꢀtransfer catalysis, which allows one to preꢀ
pare products in high yields (60—95%).2 After the introꢀ
duction of the ferrocene fragment into molecules of orꢀ
ganic compounds, the latter often exhibit biological acꢀ
tivity due to their ability to penetrate through lipid cell
membranes and abnormal metabolism.3,4 Earlier,5 we have
demonstrated that compounds of the ferrocenyl(alꢀ
kyl)azole series possess pronounced antitumor activity in
combination with low toxicity.
two isomeric ferrocenylethylindazoles 2 and 3 in 29 and
60% yields, respectively.8
Racemates 1—3 were resolved into enantiomers by
HPLC on columns with carbamateꢀmodified cellulose
(Chiralcel OD) and 4ꢀ(3,5ꢀdinitrobenzamido)tetrahydroꢀ
phenanthrene ((R,R)ꢀWhelkꢀ01) grafted on silica gel. The
results of the study are given in Table 1. The chromatoꢀ
gram of resolution of αꢀ(indazolꢀ2ꢀyl)ethylferrocene
enantiomers (2) is shown in Fig. 1.
To study the stereochemistry of ferrocenylalkylation
of indazole, wу prepared alcohol Sꢀ1 from N,Nꢀdimethylꢀ
aminoethylferrocene.6 This alcohol was resolved into
enantiomers with the use of (+)ꢀtartaric acid according to
a procedure described earlier.9 According to the HPLC
data, the enantiomeric excess (ee) was 97%. The reaction
a
The present study was aimed at investigating the stereꢀ
ochemistry of αꢀferrocenylalkylation of indazole with opꢀ
tically active Sꢀ(+)ꢀ1ꢀferrocenylethanol (1) as well as of
the thermal rearrangement of positional isomers, viz., of
Sꢀ(+)ꢀ(indazolꢀ2ꢀyl)ethylferrocene (2) into Sꢀ(+)ꢀ(indꢀ
azolꢀ1ꢀyl)ethylferrocene (3).
0
4
8
12
16
20 t/min
It is known6 that the singleꢀphase nucleophilic substiꢀ
tution in αꢀderivatives of ferrocene proceeds with retenꢀ
tion of the configurations of the starting reagents, which
is associated with the structural features of αꢀferrocenyl
carbocations.
b
Analytical resolution of enantiomers was carried out
and the enantiomeric excess was determined by HPLC on
chiral columns.7 To estimate the efficiency of the method,
all the compounds used were initially synthesized as raceꢀ
mates. The reaction of racemic 1ꢀferrocenylethanol 1 with
indazole in the twoꢀphase CH2Cl2—H2O system afforded
0
4
8
12
16
20 t/min
Fig. 1. Chromatographic resolution of αꢀ(indazolꢀ2ꢀyl)ethylꢀ
ferrocene enantiomers: (a) racemic mixture of 2, (b) enantioꢀ
merically enriched product 2a (a Chiracel OD column).
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 4, pp. 901—903, April, 2004.
1066ꢀ5285/04/5304ꢀ0939 © 2004 Plenum Publishing Corporation

940
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 4, April, 2004
Simenel et al.
Table 1. Chromatographic resolution of racemic compounds into enantiomers
Comꢀ
pound
HPLC data
Chiral stationary phase
(R,R)ꢀWhelkꢀ01
k´1
k´2
α
Rs
Eluent
(1)
7.06
7.93
1.12
1.02
C6H14—PriOH (99 : 1)
(2)
Chiralcel OD
Chiralcel OD
7.46
7.08
11.52
9.59
1.54
1.35
4.0
C6H14—PriOH (99 : 1)
(3)
1.33
C6H14—PriOH (100 : 4)
of 1a with indazole in the twoꢀphase CH2Cl2—H2O meꢀ
dium in the presence of HBF4 afforded two ferrocenylꢀ
alkylation products 3a and 2a (Scheme 1); ee was 91 and
90%, respectively.
fraction analysis.* A decrease in the enantiomeric excess
in the reaction products prepared under conditions of
heterophase catalysis compared to the enantiomeric exꢀ
cess achieved in the reaction in AcOH 1 is apparently
associated with the fact that the carbocation that formed
is less stabilized by solvent molecules in a nonpolar phase
and has a lower energy barrier to rotation about the
C—C bond.
Scheme 1
It is known10 that thermal stability of 2ꢀNꢀsubstituted
indazoles is much lower than that of the corresponding
1ꢀN isomers, which was exemplified by ferrocenylalkylꢀ
indazoles.8 Thermal treatment leads to isomerization of
their 2ꢀN isomers into the corresponding 1ꢀN derivatives.
To elucidate the stereochemistry of this reaction, we carꢀ
ried out the rearrangement of optically active Sꢀ(+)ꢀ2a
into Sꢀ(+)ꢀ3a.
As a result, we isolated two products, viz., 3a and
vinylferrocene (4) (Scheme 2). Study of compound 3a by
HPLC demonstrated that the thermal rearrangement proꢀ
ceeds with retention of the configuration (ee 90%). Hence,
this transformation can be assigned to 1,2ꢀsigmatropic
rearrangements.
To summarize, our investigation of the stereochemisꢀ
try of two processes, viz., αꢀferrocenylalkylation of
indazole with optically active S(+)ꢀ1ꢀferrocenylethanol
(1) and the thermal rearrangement of Sꢀ(+)ꢀ(indazolꢀ2ꢀ
yl)ethylferrocene into Sꢀ(+)ꢀ(indazolꢀ1ꢀyl)ethylferroꢀ
cene, showed that both reactions proceed stereoselectively.
Based on the data on conformational stability of
αꢀferrocenyl carbocations, the (S) configuration can be
assigned to the compounds synthesized. In particular, the
structure and absolute configuration of Sꢀ(+)ꢀαꢀ(3,5ꢀdiꢀ
methylpyrazolyl)ethylferrocene, which was prepared
by ferrocenylalkylation of 3,5ꢀdimethylpyrazole with
Sꢀ(+)ꢀ1ꢀferrocenylethanol, were established by Xꢀray difꢀ
* A. A. Simenel, Yu. V. Kuzmenko, and Z. A. Starikova, unpubꢀ
lished results.

Optically active ferrocenylethylindazoles
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 4, April, 2004
941
1
Scheme 2
(62). H NMR, δ: 1.99 (d, 3 H, Me, J = 12.0 Hz); 4.13—4.43
(m, 9 H, Fc); 5.67 (m, 1 H, CH); 6.99—7.47 (m, 4 H, ABCD
system, indazole); 7.68 (s, 1 H, C(3)H, indazole). IR, ν/cm–1
:
3110, 2919, 1653, 1481, 1459, 1160, 1110, 1014—1000, 920,
824, 618, 587, 436.
Rearrangement of Sꢀ(+)ꢀαꢀ(indazolꢀ2ꢀyl)ethylferrocene (2a)
into Sꢀ(+)ꢀαꢀ(indazolꢀ1ꢀyl)ethylferrocene (3a). Benzene (5 mL)
was added to compound 2a (0.02 g). The reaction mixture was
refluxed for 15 h, cooled, and chromatographed on Al2O3
(Brockmann II neutral). Elution with hexane afforded vinylꢀ
ferrocene 4 in a yield of 0.002 g (15%). MS, m/z (Irel (%)):
212 [M]+ (100). Elution with Et2O gave Sꢀ(+)ꢀαꢀ(indazolꢀ1ꢀ
yl)ethylferrocene (3a) in a yield of 0.015 g (75%) as a yellowꢀ
20
orange crystalline compound, [α]D +10.0 (c 0.3; benzene)
(ee 90%), m.p. 92—94 °C.
This study was in part financially supported by the
Presidium of the Russian Academy of Sciences (Program
for Support of Young Scientists, 2003).
References
Experimental
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1
The H NMR spectra were recorded on a Brukerꢀ200ꢀWP
spectrometer in CDCl3 with Me4Si as the internal standard. The
mass spectra were obtained on a Kratos MSꢀ890 spectrometer
(the energy of ionizing electrons was 70 eV; the temperature of
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Chiracel OD (Daicel Chemicel Industries, Ltd) and Whelkꢀ01
(Regis Technologies, Inc) (250×4.6 mm, 5 µm) chiral columns
and a Bruker LC 31 instrument equipped with a UV detector
(254 nm); the flow rate was 1.0 mL min–1 at a constant temperaꢀ
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Synthesis of Sꢀ(+)ꢀαꢀ(indazolꢀ1ꢀyl)ethylferrocene (3a) and
Sꢀ(+)ꢀαꢀ(indazolꢀ2ꢀyl)ethylferrocene (2a). A 48% aqueous soluꢀ
tion of HBF4 (0.18 mL, 1 mmol) was added with intense stirring
to a suspension of Sꢀ(+)ꢀ1ꢀferrocenylethanol (0.23 g, 1 mmol)
and indazole (0.118 g, 1 mmol) in CH2Cl2 (1 mL). After 5 min,
water (10 mL) and Et2O (10 mL) were added. The organic layer
was separated, washed with water (2×20 mL), and dried over
Na2SO4. The solvent was removed in vacuo using a rotary evapoꢀ
rator. The products were separated on a column (4×25 mm,
silica gel); the darkꢀyellow band was eluted with benzene
and compound 3a was obtained in a yield of 0.24 g (73%),
[α]20D +10.0 (c 0.3; benzene), as a yellow crystalline compound,
m.p. 92—94 °C, Rf 0.54 (benzene). MS, m/z (Irel (%)): 330 [M]+
(38). 1H NMR, δ: 1.89 (d, 3 H, Me, J = 7.8 Hz); 4.03—4.23 (m,
9 H, Fc); 5.65 (m, 1 H, CH); 7.04—7.48 (m, 4 H, ABCD system,
indazole); 7.98 (s, 1 H, C(3)H, indazole). IR, ν/cm–1: 3117,
2921, 1654, 1476, 1453, 1155, 1112, 1011—1000, 914, 823, 722,
615, 597, 438.
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The yellow band was eluted with chloroform and compound
2a was obtained in a yield of 0.04 g (15%), [α]20 +14.0 (c 0.3;
D
benzene), as a yellowꢀorange crystalline compound, m.p.
116—118 °C, Rf 0.46 (benzene). MS, m/z (Irel (%)): 330 [M]+
Received January 23, 2004;
in revised form March 12, 2004