Synthesis of versatile intermediates of the ferrocene series: Reductive amination of ferrocenecarbaldehyde

Article abstract of DOI:10.1023/B:RUCB.0000037851.47573.4b

Reductive amination of ferrocenecarbaldehyde with several primary and secondary amines in the presence of sodium triacetoxyborohydride was studied. This method was used for the synthesis of new ferrocenylmethylamines, viz., N-(ferrocenylmethyl)isoleucine methyl ester, N,N-bis(ferrocenylmethyl)glycine ethyl ester, and N-(3,5-dibenzyloxybenzyl)-N-(ferrocenylmethyl)methylamine. The latter is a potential precursor of a dendrimer with the chiral ferrocenyl plane in the core.

Full text of DOI:10.1023/B:RUCB.0000037851.47573.4b

830
Russian Chemical Bulletin, International Edition, Vol. 53, No. 4, pp. 830—833, April, 2004
Synthesis of versatile intermediates of the ferrocene series:
reductive amination of ferrocenecarbaldehyde
N. S. Khrushchevaꢀ and V. I. Sokolov
A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
28 ul. Vavilova, 119991 Moscow, Russian Federation.
Fax: +7 (095) 135 5085. Eꢀmail: stemos@ineos.ac.ru
Reductive amination of ferrocenecarbaldehyde with several primary and secondary amines
in the presence of sodium triacetoxyborohydride was studied. This method was used for the
synthesis of new ferrocenylmethylamines, viz., Nꢀ(ferrocenylmethyl)isoleucine methyl ester,
N,Nꢀbis(ferrocenylmethyl)glycine ethyl ester, and Nꢀ(3,5ꢀdibenzyloxybenzyl)ꢀNꢀ(ferroꢀ
cenylmethyl)methylamine. The latter is a potential precursor of a dendrimer with the chiral
ferrocenyl plane in the core.
Key words: reductive amination, ferrocenecarbaldehyde, sodium triacetoxyborohydride,
amines, dendrimers.
Reductive amination of aldehydes and ketones with
to both secondary amines (the reaction products with one
sodium triacetoxyborohydride is often used in organic
synthesis and allows one to prepare alkylated amines unꢀ
der mild conditions in high yields.1 However, to our
knowledge, the use of this reaction for the synthesis
of organometallic amines, in particular, (ferrocenylꢀ
methyl)amines, is not documented. The latter compounds
attract interest as important intermediates in the ferrocene
synthesis due to their coordination ability, which enables
one to perform regioꢀ and sometimes stereoselective inꢀ
troduction of a second substituent into ferrocene. At the
same time, dimethylaminomethylferrocene is one of the
most popular building blocks. In our study on the use of
reductive amination in the ferrocene series, we syntheꢀ
sized this well known compound as the first example
(Scheme 1).
molecule of the aldehyde) and tertiary amines (due to the
repeated reaction with the aldehyde). Reductive amination
of aldehyde 1 with Lꢀisoleucine methyl ester afforded exꢀ
clusively monoalkylated product 3 (Scheme 2).
Scheme 2
The high yield of this compound (~92% after chroꢀ
matographic purification) suggests the virtually complete
absence of the repeated reaction. Reductive amination of
aldehyde 1 with glycine ethyl ester proceeded differently
to give tertiary amine 4 as the major reaction product
(Scheme 3).
Scheme 1
Fc = C5H5FeC5H4
The reaction of ferrocenecarbaldehyde (1) with diꢀ
methylamine hydrochloride and sodium triacetoxyꢀ
borohydride in the presence of triethylamine in diꢀ
chloromethane afforded amine 2 as the only product
(yield >90%).
Scheme 3
Reductive amination of ferrocenecarbaldehyde with
primary amines, viz., derivatives of amino acids, such as
glycine, Lꢀisoleucine, and Lꢀlysine esters, could give rise
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 4, pp. 794—797, April, 2004.
1066ꢀ5285/04/5304ꢀ0830 © 2004 Plenum Publishing Corporation

Reductive amination of ferrocenecarbaldehyde
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 4, April, 2004
831
Scheme 4
According to the published data,1 this result is not
unexpected for the reaction of an aldehyde with primary
amines (in particular, with amino acid esters). The use of
a ~10% excess of primary amine in reductive amination
often suppresses the reaction of the secondary amine that
formed with the aldehyde. However, in the case under
consideration, an excess of glycine ester did not prevent
the formation of compound 4. This can be attributable to
an insufficient amount of the free amine in the reaction
mixture because of its slow elimination from the salt unꢀ
der the reaction conditions. On the other hand, it is not
inconceivable that the replacement of one hydrogen atom
at the nitrogen atom in glycine with the electronꢀdonatꢀ
ing ferrocenylmethyl group increases the basicity of the
secondary amine to an extent that it becomes more reacꢀ
tive than the primary amine.
Scheme 5
R = H (a), OBn (b)
The reaction of Lꢀlysine was performed with the use of
2 equiv. of aldehyde 1 with an idea to achieve complete
alkylation of both amino groups. Unfortunately, this reꢀ
action gave ferrocenylmethanol as the only identified
product.
Our investigation on reductive amination of ferroceneꢀ
carbaldehyde is aimed at the synthesis of the optically
active core of a dendrimer containing planarꢀchiral disꢀ
ubstituted ferrocene. We intend to construct such a comꢀ
pound using well known and studied asymmetric cycloꢀ
palladation of appropriate (ferrocenylmethyl)amines.2
Amine (A) containing a fragment of Fréchet's dendron3
seems to be the most convenient precursor (Scheme 4).
We chose amine A as the starting compound primarily
because it can be synthesized from commercially availꢀ
able and relatively inexpensive 3,5ꢀdihydroxybenzoic acid.
The further replacement of the Pd atom in the ferrocene
moiety of intermediate B leads to the introduction of one
Scheme 6
Reagents: i. MeOH, H2SO4, ∆; ii. BnCl, K2CO3, MeCOMe; iii. LiAlH4, THF; iv. MnO2, CHCl3; v. MeNH2•HCl, NaBH(OAc)3, Et3N, CH2Cl2.

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Russ.Chem.Bull., Int.Ed., Vol. 53, No. 4, April, 2004
Khrushcheva and Sokolov
compound 5a was prepared in 92% yield as orange crystals,
m.p. 37—39 °C. Found (%): C, 70.56; H, 6.45; N, 4.25.
more 3,5ꢀdihydroxybenzyl fragment into the molecule.
The drawback of this approach is possible competitive
cyclopalladation at the benzene ring.
C
19H21FeN•0.1 H2CO3. Calculated (%): C, 70.47; H, 6.60;
1
N, 4.30. H NMR (C6D6), δ: 2.18 (s, 3 H, Me); 3.42 and 3.49
(both s, 2 H each, CH2); 4.00 (s, 5 H, C5H5); 4.04 and 4.16
(both m, 2 H each, C5H4); 7.18 (m, 1 H, Ph); 7.29 and 7.47
(both m, 2 H each, Ph).
To examine the possibility of the synthesis of the reꢀ
quired starting (ferrocenylmethyl)amine by reductive
amination, we stuided this process using the synthesis of
known4 model compound 5a as an example (Scheme 5).
Reductive amination of ferrocenecarbaldehyde 1 with
benzylmethylamine 6a was carried out under standard
conditions to give the target product in high yield.
The required amine 6b was synthesized according to
Scheme 6.
Compounds 9 and 10 serve as important synthons in
numerous syntheses of Fréchet's dendrimers described in
the literature. Various procedures for their synthesis are
available. We developed a new procedure for the synthesis
of these compounds.
Nꢀ(3,5ꢀDibenzyloxybenzyl)ꢀNꢀ(ferrocenylmethyl)methylꢀ
amine (5b). Sodium triacetoxyborohydride (15.26 g, 0.072 mol)
was added portionwise to a stirred solution of amine 6b (8 g,
0.024 mol) and aldehyde 1 (5.14 g, 0.024 mol) in CH2C12
(150 mL). The reaction mixture was stirred for 6 h, poured onto
ice, alkalified with 10 M NaOH to pH 12, extracted with CHC13,
and dried with Na2SO4. The solvent was evaporated and
the residue was chromatographed on SiO2 (CHCl3—MeOH,
100 : 1—80 : 20). Compound 5b was obtained in a yield of 8 g
(63%) as orange crystals, m.p. 67—70 °C (hexane—AcOEt, 4 : 1).
Found (%): C, 74.79; H, 5.86; N, 2.59. C33H33FeNO2. Calcuꢀ
lated (%): C, 74.58; H, 6.26; N, 2.64. 1H NMR (CDCl3), δ: 2.17
(s, 3 H, Me); 3.40 and 3.44 (both s, 2 H each, CH2); 4.11 (s,
5 H, C5H5); 4.13 and 4.17 (both m, 2 H each, C5H4); 5.05 (s,
4 H, 2 CH2); 6.55 (s, 1 H, C6H3); 6.62 (s, 2 H, C6H3); 7.34—7.46
(m, 10 H, 2 Ph).
Reductive amination of aldehyde 1 with amine 6b afꢀ
forded secondary amine 5b, which is the starting comꢀ
pound for the further synthesis of a dendrimer based on
planarꢀchiral ferrocene.
Methyl 3,5ꢀdihydroxybenzoate (7). Sulfuric acid (2 mL)
was added to a solution of 3,5ꢀdihydroxybenzoic acid (10 g,
0.064 mol) in MeOH (70 mL). The reaction mixture was reꢀ
fluxed for 10 h and concentrated. The residue was dissolved in
water, extracted with a 1 : 1 CHC13—ButOH mixture, and dried
with Na2SO4. The solvent was evaporated and the residue was
crystallized from water. Ester 7 (8.9 g, 82%) was obtained as
colorless crystals, m.p. 164—166 °C. 1H NMR (CD3OD), δ:
4.07 (s, 3 H, Me); 6.67 (s, 1 H, C6H3); 6.91 (s, 2 H, C6H3).
Methyl 3,5ꢀdibenzyloxybenzoate (8). A mixture of ester 7
(20 g, 0.12 mol), BnCl (29.2 mL, 0.25 mol), and К2CO3 (18.4 g
0.13 mol) in Me2CO (100 mL) was refluxed with stirring for
5 days, diluted with water, extracted with CHC13, washed with
water and brine, and dried with Na2SO4. The solvent was
evaporated and the residue was chromatographed on SiO2
(CHCl3—MeOH, 100 : 1—98 : 2). Ester 8 was obtained in a
yield of 37 g (93%) as colorless crystals, m.p. 68—69 °C (cf. lit.
data7: m.p. 69—71 °C). 1H NMR (CDCl3), δ: 3.93 (s, 3 H, Me);
5.09 (s, 4 H, 2 CH2); 6.82 (s, 1 H, C6H3); 7.29—7.49 (m, 12 H,
C6H3 and 2 Ph).
3,5ꢀDibenzyloxybenzyl alcohol (9). A solution of ester 8 (37 g,
0.111 mol) in anhydrous THF (200 mL) was added dropwise to a
suspension of LiAlH4 (2.1 g, 0.055 mol) in anhydrous THF
(200 mL) at 5 °C. The reaction mixture was allowed to warm,
stirred for 6 h, and cooled with ice. Water (5 mL) was added
dropwise and then 5% H2SO4 (100 mL) was added. The mixture
was extracted with diethyl ether and the extract was dried with
Na2SO4. The solvent was evaporated and the residue was crysꢀ
tallized from CC14. Alcohol 9 was obtained in a yield of 27 g
(80%) as colorless crystals, m.p. 78—80 °C (cf. lit. data7: m.p.
78—80 °C). 1H NMR (CDCl3), δ: 4.65 (s, 2 H, CH2); 5.05 (s,
4 H, 2 CH2); 6.57 (s, 1 H, C6H3); 6.65 (s, 2 H, C6H3); 7.32—7.49
(m, 10 H, 2 Ph).
Experimental
The 1H NMR spectra were recorded on
a Bruker
AMXꢀ400ꢀST instrument. Ferrocenecarbaldehyde5 and MnO2
were synthesized according to known procedures. Analytiꢀ
cal data for dimethylaminomethylferrocene 2 are in complete
agreement with the parameters of the commercial reagent
(Aldrich). The melting point of methyl 3,5ꢀdihydroxybenzoate 7
is identical to m.p. of the commercially available compound
(Lancaster).
6
Nꢀ(Ferrocenylmethyl)isoleucine methyl ester (3). Isoleucine
methyl ester hydrochloride (2 g, 0.011 mol) and Et3N (1.6 mL,
0.011 mol) were added to a stirred solution of aldehyde 1 (2.14 g
0.01 mol) in THF (50 mL) and then NaBH(OAc)3 (5.3 g,
0.025 mol) was added portionwise. The reaction mixture was
stirred for 4 h, poured onto ice, alkalified with 10 M NaOH to
pH 12, extracted with diethyl ether, and dried with Na2SO4.
The solvent was evaporated and the residue was chromatographed
on SiO2 (CHCl3—MeOH, 100 : 1—98 : 2). Ester 3 was obtained
as an orange oil in a yield of 3.15 g (91.8%). Found (%): C, 63.21;
H, 7.45; Fe, 16.36. C18H25FeNO2. Calculated (%): C, 62.99;
1
H, 7.34; Fe, 16.27. H NMR (CDCl3), δ: 0.92 (m, 6 H, 2 Me);
1.21 and 1.57 (both m, 1 H each, CH2); 1.70 (m, 2 H, CH
and NH); 3.17 (d, 1 H, CH, J = 6.3 Hz); 3.36 and 3.47 (both d,
1 H each, CH2, J = 12.7 Hz); 3.74 (s, 3 H, MeO); 4.10 (m, 2 H,
C5H4); 4.16 (m, 6 H, C5H4 and C5H5); 4.24 (m, 1 H, C5H4).
N,NꢀBis(ferrocenylmethyl)glycine ethyl ester (4) was prepared
analogously in 64% yield as orange crystals, m.p. 76—78 °C
(hexane). Found (%): C, 62.57; H, 5.81; N, 2.85.
C26H29Fe2NO2. Calculated (%): C, 62.56; H, 5.86; N, 2.81.
1H NMR (CDCl3), δ: 1.27 (m, 3 H, Me); 3.16 (s, 2 H, CH2N);
3.60 (s, 4 H, 2 CH2N); 4.06—4.21 (m, 20 H, 2 C5H4, 2 C5H5
and OCH2).
3,5ꢀDibenzyloxybenzaldehyde (10). Manganese oxide (11.4 g
0.131 mol) was added to a solution of alcohol 9 (20 g, 0.065 mol)
in CHC13 (400 mL). The reaction mixture was stirred for 5 days,
MnO2 being added portionwise (10 g per day; a total amount
NꢀBenzylꢀNꢀ(ferrocenylmethyl)methylamine (5a). Under the
aboveꢀdescribed conditions (in CH2Cl2 in the absence of Et3N),

Reductive amination of ferrocenecarbaldehyde
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 4, April, 2004
833
was ~51 g, 0.58 mol). The precipitate was filtered off and washed
with CHC13. The solvent was evaporated and the residue was
crystallized from a 1 : 4 hexane—AcOEt mixture. Aldehyde 10
was obtained in a yield of 15 g (75%) as colorless crystals,
m.p. 78—79 °C (hexane—AcOEt, 1 : 4) (cf. lit. data7: m.p.
This study was financially supported by the
ChemBridge Corporation and the Russian Foundation
for Basic Research (Project No. 02ꢀ03ꢀ33355).
References
1
80.5—81 °C). H NMR (CDCl3), δ: 5.00 (s, 4 H, 2 CH2); 6.88
(s, 1 H, C6H3); 7.14 (s, 2 H, C6H3); 7.30—7.49 (m, 10 H, 2 Ph);
9.91 (s, 1 H, CHO).
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Nꢀ(3,5ꢀDibenzyloxybenzyl)ꢀNꢀmethylamine (6b). Methylꢀ
amine hydrochloride (8.9 g, 0.132 mol) and Et3N (18.4 mL,
0.132 mol) were added to a stirred solution of aldehyde 10 (8 g,
0.026 mol) in CH2C12 (100 mL) and then NaBH(OAc)3 (16.7 g,
0.079 mol) was added portionwise. The reaction mixture was
stirred for 6 h, poured onto ice, alkalified with 10 M NaOH to
pH 12, and extracted with CHC13. The extract was dried with
Na2SO4, the solvent was evaporated, and the residue was
chromatographed on SiO2 (CHCl3—MeOH, 100 : 1—80 : 20).
Amine 6b was obtained in a yield of 8 g (91%) as a colorless oil.
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Found (%): C, 77.56; H, 6.89; N, 4.10.
C22H23NO2•
•0.15 H2CO3. Calculated (%): C, 77.62; H, 6.85; N, 4.09.
1H NMR (CDCl3), δ: 2.46 (s, 3 H, Me); 3.73 (s, 2 H, CH2);
5.05 (s, 4 H, 2 CH2); 6.55 (s, 1 H, C6H3); 6.64 (s, 2 H, C6H3);
7.30—7.49 (m, 10 H, 2 Ph).
Received September 29, 2003;
in revised form December 17, 2003