Synthesis of planar chiral ferrocene alcohols as potential dendrimer cores

Article abstract of DOI:10.1007/s11172-006-0393-x

Planar chiral compounds, 1-hydroxymethyl-2-methylferrocene and new 3-(2-hydroxymethylferrocenyl)propanol, were synthesized to be used as dendrimer cores. The ethers of these compounds, namely, 1-(benzyloxymethyl)-2- methylferrocene and 2-(benzyloxymethyl)

Full text of DOI:10.1007/s11172-006-0393-x

Russian Chemical Bulletin, International Edition, Vol. 55, No. 7, pp. 1159—1162, July, 2006
1159
Synthesis of planar chiral ferrocene alcohols
as potential dendrimer cores
N. S. Khrushchevaꢀ and V. I. Sokolov
A. N. Nesmeyanov Institute of Organoelement Compounds of the Russian Academy of Sciences,
28 ul. Vavilova, 119991 Moscow, Russian Federation.
Fax: +7 (495) 135 5085. Eꢀmail: stemos@ineos.ac.ru
Planar chiral compounds, 1ꢀhydroxymethylꢀ2ꢀmethylferrocene and new 3ꢀ(2ꢀhydroxyꢀ
methylferrocenyl)propanol, were synthesized to be used as dendrimer cores. The ethers of
these compounds, namely, 1ꢀ(benzyloxymethyl)ꢀ2ꢀmethylferrocene and 2ꢀ(benzyloxymethyl)ꢀ
1ꢀ(benzyloxypropyl)ferrocene, can be regarded as zeroꢀgeneration Freche type dendrimers.
Key words: ferrocenes, planar chirality, Freche type dendrimers, palladacycles.
In the previous study,1 we described the synthesis of
ferrocenic amine 1 (Scheme 1), which was meant for the
preparation of the optically active core of dendrimer 3
containing a planar chiral 1,2ꢀdisubstituted ferrocene.
The cyclopalladation of amine 1, which already conꢀ
tains a Freche dendrone fragment, was planned as the key
stage of this synthesis. However, we could not obtain the
desired cyclopalladation product 2 in a sufficiently pure
state. The reaction gave mixtures containing apparently
both cyclopalladation products of the ferrocene and aryl
rings and L2PdCl4 type complexes, and further work along
this line was considered inappropriate.
Scheme 1
In this work we propose a different route to dendrimers
based on 1,2ꢀdisubstituted planar chiral ferrocenes with
one (4) or two (5) hydroxy groups, which can be conꢀ
verted into ethers.
The reactions of these compounds with the bromides
of Freche dendrones of different generations2 in the presꢀ
ence of sodium hydride should result in dendrimers with
one or two branches and with a planarꢀchiral ferrocene as
the core. To evaluate this possibility and to determine the
stability of the resulting ethers, we carried out the model
reaction between ferrocenylmethanol and 2ꢀfluorobenzyl
chloride (Scheme 2).
Ether 6 was formed in a high yield (82%) and was
fairly stable. A 3 : 1 THF—DMF mixture proved to be the
solvent of choice.
The favorable outcome of the test reaction allowed us
to proceed to the synthesis of target compounds 4 and 5.
The palladium dimer 7, whose synthesis is well developed
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1116—1119, July, 2006.
1066ꢀ5285/06/5507ꢀ1159 © 2006 Springer Science+Business Media, Inc.

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Khrushcheva and Sokolov
Scheme 2
reaction of 7 with methyl acrylate followed by the reducꢀ
tion of, first, the double bond and, second, the ester group
gave amino alcohol 12 and, after hydrolysis of the interꢀ
mediate ammonium salt, diol 5 (Scheme 4).
Scheme 4
for both racemic and scalemic forms,3 served as the key
compound in the synthesis. Alcohol 4 has been known
previously;4 however, in this study we prepared it by a
different method (Scheme 3).
Scheme 3
Reagents: a. CH2=CHCOOMe, Et3N, C6H5Me; b. H2,
5% Pd/C, MeOH; c. LiAlH4, THF; d. 1) MeI, 2) NaOH, H2O.
The double bond in compound 10 was reduced in two
ways: by catalytic hydrogenation at room temperature at a
moderate hydrogen pressure and by catalytic reduction
with heating using ammonium formate as the source of
hydrogen.5 Both methods furnish the desired product 11
in a high yield; however, the possibility of addition of two
H atoms in the autoclaveꢀfree version seems fairly atꢀ
tractive.
Scheme 5
Reagents and conditions: a. CO, MeOH, C6H6; b. LiAlH4, THF;
c. 1) MeI, 2) NaBH4, MeCN, 80 °C.
It should be emphasized that, according to our synꢀ
thetic route, compound 4 is formed upon the transformaꢀ
tion of the dimethylaminomethyl group into methyl, while
in the method developed previously,4 palladium was reꢀ
placed by a methyl group. Thus, when working with optiꢀ
cally active material, both enantiomers 4 and then two
enantiomeric series of dendrimers can be obtained from
the same precursor 7.
Unlike alcohol 4, diol 5 has not been prepared previꢀ
ously. We synthesized it from the same dimer 7. The

Ferrocene based dendrimers
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 7, July, 2006
1161
late (2.8 mL, 31 mmol), and triethylamine (5.4 mL, 39 mmol)
in toluene (100 mL) was refluxed for 6 h and filtered. The filtrate
was washed with water and a solution of NaHCO3, dried
with Na2SO4, concentrated, chromatographed on SiO2 (hexꢀ
ane : AcOEt = (100 : 0)—(50 : 50), then hexane : triethylamine =
(80 : 20)—(50 : 50)), and concentrated to give 5 g (59%) of ester
10 as a darkꢀcherry oil. Found (%): C, 62.84; H, 6.22; Fe, 16.63.
C17H21FeNO2. Calculated (%): C, 62.40; H, 6.47; Fe, 17.07.
1H NMR (CDCl3), δ: 2.16 (s, 6 H, NMe2); 3.26, 3.52 (dd,
1 H each, CH2N, J1 = 1.29 Hz, J2 = 7.56 Hz); 3.76 (s, 3 H, Me);
4.08 (s, 5 H, C5H5); 4.38, 4.42, 4.55 (all m, 1 H each, C5H3);
6.10 and 7.69 (both d, 1 H each, =CH, J = 15.6 Hz).
Methyl 3ꢀ(2ꢀdimethylaminomethylferrocenyl)propionate (11).
А. A mixture of ester 10 (5 g, 15.3 mmol) and 5% Рd/C (1 g) in
МеOH (50 mL) was hydrogenated in an autoclave for 6 h
(10 atm, 20 °C), filtered, concentrated, and chromatographed
on SiO2 (toluene : AcOEt = (100 : 0)—(50 : 50), then toluꢀ
ene : triethylamine = (100 : 0)—(80 : 20)) to give compound 11
(4.7 g, 93%) as an orange oil.
B. To a solution of ester 10 (2.11 g, 6.5 mmol) and ammoꢀ
nium formate (1.6 g, 25.4 mmol) in МеOH (50 mL), was added
5% Pd/C (0.4 g). The mixture was refluxed with stirring for 6 h,
filtered, concentrated, and chromatographed on SiO2 (hexꢀ
ane : triethylamine = (100 : 0)—(80 : 20)) to give 1.6 g (75%) of
compound 11. Found (%): C, 62.50; H, 7.06; N, 4.21; Fe, 16.95.
C17H23FeNO2. Calculated (%): C, 62.02; H, 7.04; N, 4.25;
Fe, 16.96. 1H NMR (CDCl3), δ: 2.14 (s, 6 H, NMe2); 2.50—2.75
(m, 4 H, 2 CH2); 3.10, 3.52 (dd, 1 H each, CH2N, J1 = 1.34 Hz,
J2 = 9.32 Hz); 3.69 (s, 3 H, Me); 4.02 (m, 7 H, C5H5 + C5H3);
4.13 (m, 1 H, C5H3).
In this work both planarꢀchiral alcohols 4 and 5
were obtained as racemates. In attempted synthesis of
dendrimers based on them, they were made to react
with benzyl bromide in the presence of NaH (Scheme 5).
This gave ethers 13 and 14, which are zeroꢀgeneration
dendrimers. This result suggests that higherꢀgeneration
dendrimers, including optically active ones, could be preꢀ
pared in the future based on ferrocene alcohols 4 and 5.
Experimental
1H NMR spectra were recorded on a Bruker AMXꢀ400ꢀST
instrument.
Dimer 73 and ferrocenylmethanol6 were synthesized by
known procedures. The solvents were preliminarily dehydrated
by standard procedures.
(2ꢀFluorobenzyloxy)methylferrocene (6). Sodium hydride
(0.18 g, 4.5 mmol) as a 60% dispersion in mineral oil was added
to a solution of ferrocenylmethanol (0.70 g, 3.2 mmol) and
2ꢀfluorobenzyl chloride (0.54 mL, 4.5 mmol) in THF (30 mL)
and DMF (5 mL). The mixture was stirred for ~24 h, carefully
diluted with water, extracted with ether, dried with Na2SO4,
concentrated, and chromatographed on SiO2 (hexane : AcOEt =
(100 : 0)—(90 : 10)) to give 0.85 g (82%) of ether 6, yellow oil.
Found (%): C, 66.69; H, 5.29. C18H17FFeO. Calculated (%):
1
C, 66.95; H, 5.21. H NMR (CDCl3), δ: 4.19 (s, 5 H, C5H5);
4.21, 4.31 (both m, 2 H each, C5H4); 4.34, 4.58 (both s, 2 H each,
2 CH2); 7.04, 7.12, 7.27, 7.42 (all m, 1 H each, C6H4).
2ꢀMethylferrocenylmethanol (4) (see Ref. 4). Carbon monoxꢀ
ide was passed for 3 h through a stirred solution of palladium
dimer 7 (3.44 g, 9 mmol) in a benzene—МеOH mixture (4 : 1)
(60 mL), and the mixture was filtered and concentrated. The
residue was dissolved in AcOEt, washed with water and a
NaHCO3 solution, dried with Na2SO4, and concentrated to give
ester 8 (2.16 g, 7.2 mmol, 80%) as an orange oil. The product
was dissolved in THF (30 mL) and added dropwise to a suspenꢀ
sion of LiAlH4 (0.22 g, 5.8 mmol) in THF (30 mL) stirred
at 0 °C. The cooling was removed, the mixture was stirred at
room temperature for 4 h and cooled with ice. Water (20 mL)
and then 15 N aqueous NaOH (20 mL) were added, the organic
layer was separated, the aqueous layer was extracted with ether,
and the combined organic fractions were washed with water,
dried with Na2SO4, and concentrated to give amino alcohol 9
(1.8 g, 6.8 mmol, 92%) as a yellow oil. At 0 °C, MeI (1 mL) was
added dropwise to its solution in acetone (5 mL), the mixture
was stirred for 30 min, ether (50 mL) was added, and the preꢀ
cipitate was filtered off, washed with ether, dried, and dissolved
in MeCN (30 mL). Sodium tetrafluoroborate (1 g, 13.5 mmol)
was added, the mixture was refluxed for 4 h, diluted with water,
and extracted with ether, and the extract was washed with water,
dried with Na2SO4, and concentrated. The residue was chromaꢀ
tographed on SiO2 (hexane : AcOEt = 100 : 1→50 : 50→0 : 100)
to give compound 4 (1 g, 66%) as a yellow powder, m.p.
44—46 °C. Found (%): C, 63.11; H, 6.42; Fe, 23.92. C12H14FeO.
Calculated (%): C, 62.64; H, 6.13; Fe, 24.27. 1H NMR (CDCl3),
δ: 1.62 (br.s, 1 H, OH); 2.07 (s, 3 H, CH3); 4.09 (m, 1 H, C5H3);
4.14 (s, 5 H, C5H5); 4.19, 4.21 (both m, 1 H each, C5H3); 4.44
(dd, 2 H, CH2, J1 = 1.18 Hz, J2 = 2.60 Hz).
3ꢀ(2ꢀDimethylaminomethylferrocenyl)propanol (12). A soluꢀ
tion of ester 11 (4.7 g, 14.3 mmol) in THF (30 mL) was added
dropwise with stirring at 0 °C to a suspension of LiAlH4 (0.46 g,
12.2 mmol) in THF (30 mL), cooling was removed, and the
mixture was stirred at room temperature for 4 h and cooled with
ice. Water (25 mL) and 15 N aqueous NaOH (25 mL) were
successively added dropwise, the organic layer was separated,
the aqueous layer was extracted with ether, and the combined
organic fractions were washed with water, dried with Na2SO4,
and concentrated to give compound 12 (4.26 g, 90%) as a
yellow oil. Found (%): C, 63.96; H, 7.64; N, 4.43; Fe, 18.59.
C16H23FeNO. Calculated (%): C, 63.80; H, 7.70; N, 4.65;
Fe, 18.54. 1H NMR (CDCl3), δ: 1.40 (m, 1 H, CH); 1.50—2.00
(m + br.s, 2 H, CH + OH); 2.19 (s, 6 H, NMe2); 2.59 (m,
2 H, 2 CH); 2.73 (dd, 1 H, CH2N, J1 = 1.26 Hz, J2 =
31.44 Hz); 3.05, 3.34 (both m, 1 H each, 2 CH); 3.78 (dd, 1 H,
CH2N, J1 = 1.26 Hz, J2 = 31.44 Hz); 4.00—4.10 (s + m, 8 H,
C5H5 + C5H3).
3ꢀ(2ꢀHydroxymethylferrocenyl)propanol (5). Methyl iodide
(4 mL) was added dropwise with stirring at 0 °C to a solution of
alcohol 12 (4.26 g, 14.1 mmol) in acetone (10 mL), the mixture
was stirred for 30 min, ether (100 mL) was added, and the
precipitate was filtered off, washed with ether, dried, and disꢀ
solved in 4% NaOH (50 mL). The solution was refluxed
for 6 h, extracted with ether, dried with Na2SO4, concenꢀ
trated, and chromatographed on SiO2 (hexane : AcOEt =
100 : 1→50 : 50→0 : 100) to give compound 5 (2.7 g, 70%)
as a yellow oil. Found (%): C, 62.53; H, 6.89; Fe, 19.07.
C14H18FeO2•0.2C6H14. Calculated (%): C, 62.66; H, 7.20;
Fe, 19.17. 1H NMR (CDCl3), δ: 1.58 (m, 1 H, CH); 1.67—1.90,
2.33—2.90 (m + br.s, 2 H each, CH + OH); 3.38—3.62 (m, 2 H,
Methyl 3ꢀ(2ꢀdimethylaminomethylferrocenyl)acrylate (10).
A solution of palladium dimer 7 (10 g, 26 mmol), methyl acryꢀ

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Khrushcheva and Sokolov
CH2); 4.04—4.20 (s + m, 8 H, C5H5 + C5H3); 4.26, 4.50 (dd,
1 H each, FcCH2O, J1 = 1.20 Hz, J2 = 7.32 Hz).
1H NMR (CDCl3), δ: 1.73—1.98 (m, 2 H, CH2); 2.46 (t, 2 H,
CH2, J = 0.78 Hz); 3.51 (t, 2 H, CH2, J = 0.65 Hz); 4.05 (s + m,
6 H, C5H5 + C5H3); 4.12 (m, 1 H, C5H3); 4.17—4.27 (m, 2 H,
C5H3 + FcCH3); 4.43—4.60 (m, 5 H, 2 PhCH2O + FcCH3);
7.24—7.42 (m, 10 H, Ph).
1ꢀ(Benzyloxymethyl)ꢀ2ꢀmethylferrocene (13). Sodium hyꢀ
dride (0.1 g, 2.5 mmol) in mineral oil (60%) was added to a
solution of alcohol 1 (0.23 g, 1 mmol) and benzyl bromide
(0.17 g, 1 mmol) in anhydrous THF (6 mL) and anhydrous
DMF (2 mL), the mixture was stirred for 24 h, more alcohol 1
(0.05 g) and NaH (0.03 g) were added, and the mixture
was stirred for an additional 2 h, carefully diluted with water,
and extracted with ether. The extract was dried with Na2SO4,
concentrated, chromatographed on SiO2 (hexane : AcOEt =
(100 : 0)—(90 : 10)), and concentrated to give ether 13 (0.26 g,
81%) as a yellow oil. Found (%): C, 71.30; H, 6.23; Fe, 17.26.
C19H20FeO. Calculated (%): C, 71.27; H, 6.30; Fe, 17.44.
1H NMR (CDCl3), δ: 2.01 (s, 3 H, CH3); 4.02 (s + m, 6 H,
C5H5 + C5H3); 4.11, 4.16 (both m, 1 H each, C5H3); 4.26 (dd,
1 H, CH2, J1 = 1.11 Hz, J2 = 6.66 Hz); 4.47 (dd, 1 H, CH2, J1 =
1.17 Hz, J2 = 2.11 Hz); 4.48 (dd, 1 H, CH2, J1 = 1.11 Hz, J2 =
6.66 Hz); 4.54 (dd, 1 H, CH2, J1 = 1.17 Hz, J2 = 2.11 Hz);
7.25—7.39 (m, 5 H, Ph).
2ꢀ(Benzyloxymethyl)ꢀ1ꢀ(3ꢀbenzyloxypropyl)ferrocene (14).
Sodium hydride (0.20 g, 5 mmol) in mineral oil (60%) was
added to a solution of diol 5 (0.27 g, 1 mmol) and benzyl broꢀ
mide (0.34 g, 2 mmol) in THF (9 mL) and DMF (3 mL). The
mixture was stirred for 24 h, more diol 5 (0.05 g) and NaH
(0.05 g) were added, and the mixture was stirred for 2 h, careꢀ
fully diluted with water, extracted with ether, dried with Na2SO4,
concentrated, chromatographed on SiO2 (hexane : AcOEt =
(100 : 0)—(90 : 10)), and concentrated to give diether 14 (0.28 g,
62%) as a yellow oil. Found (%): C, 74.23; H, 6.54; Fe, 11.49.
C28H30FeO2. Calculated (%): C, 74.01; H, 6.65; Fe, 12.29.
The authors are grateful to the ChemBridge corporaꢀ
tion for the support of this work.
This work was financially supported by the Russian
Foundation for Basic Research (Project No. 05ꢀ03ꢀ
33031).
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Received February 20, 2006;
in revised form April 26, 2006