Synthesis of new ferrocenyl aminoalcohols and aminonitriles and catalytic properties of the aminoalcohols in the ethylation of benzaldehyde

Article abstract of DOI:10.1016/S0957-4166(98)00478-9

Chiral ferrocenyl aminoalcohols possessing either OH or NR₂ functionality α to the ferrocenyl ring were prepared and exhibit modest enantioselectivities for the addition of diethylzinc to benzaldehyde. Chiral ferrocenyl aminonitriles exhibit a facile inversion process in protonic solvents.

Full text of DOI:10.1016/S0957-4166(98)00478-9

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 4381–4394
Synthesis of new ferrocenyl aminoalcohols and aminonitriles and
catalytic properties of the aminoalcohols in the ethylation of
benzaldehyde
Angela Patti,a Giovanni Nicolosi,a,∗ James A. S. Howell b,∗ and Kristina Humphries b
aIstituto CNR per lo Studio delle Sostanze Naturali di Interesse Alimentare e Chimico-Farmaceutico, via del Santuario 110,
I-95028 Valverde CT, Italy
bChemistry Department, Keele University, Keele, Staffordshire, ST5 5BG, UK
Received 15 October 1998; accepted 24 November 1998
Abstract
Chiral ferrocenyl aminoalcohols possessing either OH or NR2 functionality α to the ferrocenyl ring were
prepared and exhibit modest enantioselectivities for the addition of diethylzinc to benzaldehyde. Chiral ferrocenyl
aminonitriles exhibit a facile inversion process in protonic solvents. © 1998 Elsevier Science Ltd. All rights
reserved.
1. Introduction
Chiral ferrocenes are well known as effective auxiliaries in a number of stereoselective syntheses,1
and in this context, hydroxyaminoferrocenes were reported as able to catalyse the asymmetric addition
of dialkylzinc reagents to aldehydes to yield optically active secondary alcohols.2 These catalysts can
be structurally grouped into three classes. Norephedrine derivatives 1 and 2 (generated in situ from
the corresponding α-iodo complex)3 containing central and central/planar chirality provide a modest
enhancement (85–95% e.e.) of the already strong (80–90% e.e.) directing effect of the ephedrine
framework in the ethylation of benzaldehyde.4 Aminoalcohols of structure 3 possessing both planar
and central chirality provide effective induction (up to 99% e.e.) for the ethylation of both aromatic
and aliphatic aldehydes,5 while the aminoalcohols 4 and 5 possessing only planar chirality provide more
modest degrees of induction (83% and 51%, respectively).6,7
∗
Corresponding authors: E-mail: nicolosi@issn.ct.cnr.it and j.a.s.howell@chem.keele.ac.uk
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00478-9

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Surprisingly, hydroxyaminoferrocenes containing only single stereogenic centres alpha to the ferro-
cenyl nucleus have not been investigated. We report here our full results8 on the synthesis and catalytic
properties for asymmetric ethylation of benzaldehyde of aminoalcohols of structures 6 and 7.
The methods used for the synthesis of aminoalcohols of structure 7 also lend themselves to the potential
synthesis of optically active ferrocenyl aminonitriles. These latter compounds have exhibited a facile
inversion process in protonic solvents which is described in detail in this paper.
2. Results and discussion
2.1. Synthesis of ferrocenyl aminoalcohols
The new β-aminoalcohols (R)-(−)-6a,b were obtained by reaction of (R)-(−)-1-acetoxyethylferrocene
8 (>95% e.e. from the lipase catalysed kinetic resolution of 1-hydroxyethylferrocene)9 with ethanolamine
or N-methylethanolamine under conditions of nucleophilic substitution with retention of configuration.10
Alkylation of (R)-(−)-6a with n-BuI or benzyl bromide gave (R)-(−)-6c,d, respectively. (1R,R)-(−)-6e
was prepared by diastereoselective lithiation of (R)-(+)-N,N-dimethylaminoethylferrocene 711 to give
10, followed by stereoselective conversion to the acetate 11 and reaction with N-methylethanolamine.
The aminoalcohols (R)-(+)-7b, (S)-(−)-7b and (R)-(+)-7c were obtained via lipase catalysed acylation
of ferrocene cyanohydrin 1212 followed by reduction and alkylation. Optimal results for the kinetic
resolution were obtained using Pseudomonas cepacia lipase and neat vinyl acetate as acyl donor and
solvent. At 50% conversion to the acetate 13, NMR analysis also indicated formation of the acyl cyanide
1413 as a by-product (10%) resulting from the solution instability of the cyanohydrin 12. Conversion
of 12 to 14 is particularly enhanced in chlorinated solvents in the presence of oxygen, although the
mechanism of the formal oxidation has not been investigated. Complexes 12 and 13 are unstable towards
chromatography on active silica or alumina, decomposing to a mixture of ferrocene carboxaldehyde
and 14. The acetate 13 may be isolated from the crude products of the lipase catalysed acylation by
chromatography on 15% deactivated alumina (during which decomposition of 12 occurs). Use of the

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4383
more expensive silica diol as support enables separation and isolation of both 12 and 13 in optical purities
of 81% e.e. and 85% e.e., respectively. The enantiomeric excess of the acetate may be increased to >95%
e.e. by recrystallisation. Stability towards chromatography is much enhanced in the easily prepared O-
protected derivatives 15a–c.
The (R)-configuration of the acetate (+)-13 was confirmed by a single crystal structure determination8
and is consistent with other results on the lipase catalysed resolution of organic cyanohydrins.14 Use of
other lipases for acylation of 12 (lipase AY from Candida cylindracea) or alcoholysis of rac-13 (lipase PS
from Pseudomonas cepacia) either proceed too slowly or provide products of lower enantiomeric excess.
Use of supported enzymes (lipase PS from Pseudomonas cepacia, Chirozyme from Mucor miehei) results
in more extensive conversion to 14.
Both 12 and 13 are cleanly reduced15 to the aminoalcohol 7a which may be methylated under mild
conditions16 to give 7b without loss of enantiomeric excess. The vigorous conditions required for
alkylation of 7a to give the piperidino derivative 7c17 result in some loss of enantiomeric excess.

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2.2. Catalytic alkylation of benzaldehyde
The new ferrocenyl aminoalcohols were examined as catalysts for the asymmetric addition of Et2Zn
to benzaldehyde to give enantiomerically enriched 1-phenyl-1-propanol. The results are summarised in
Table 1, together with relevant literature results. The observed product chirality is in agreement with the
results obtained using other aromatic and aliphatic β-aminoalcohols containing only a single stereogenic
centre.18 Several points of interest may be noted:
(i) Enantioselectivities in both the 6 and 7 series are modest. In view of the demonstrated influence of
the bulkiness of substituents alpha to hydroxy, the slightly better enantioselection in the 6 series is
surprising. As observed for complexes of structure 3,5a an increase in the steric bulk of the nitrogen
substituent in 6b–d (entries 2, 8 and 9) results in a decrease in activity and enantioselection. The
dramatic decrease in activity and enantioselection of the piperidino derivative 7c (entries 10 and 11)
is, however, surprising in view of the demonstrated efficacy of the piperidino moiety in 3 and in the
related phenyl analogue 16b.19
(ii) Increasing catalyst concentration (entries 2, 4 and 5) to effect higher conversion results in a subs-
tantial loss of enantiomeric excess. This most likely arises from a non-stereoselective ethyl transfer

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4385
Table 1
Enantioselective addition of Et2Zn to benzaldehyde catalysed by ferrocenyl aminoalcohols
to benzaldehyde, promoted by zinc co-ordination to only the amino group of the catalyst. In the pre-
sence of enantiopure (R)-(+)-N,N-dimethylaminoethylferrocene 9, catalysis affords high conversion
to racemic product (entry 7). Pretreatment of the catalyst with one equivalent of Et2Zn at 85°C20
provided no alteration in the enantiomeric excess of the product (entry 6). The conversion may be
increased by increasing the temperature without loss of enantiomeric excess (entries 2 and 3).
(iii) Given the interest in the ferrocenyl moiety as a three-dimensional phenyl equivalent,21 the lower
enantioselection of 7b compared to its phenyl equivalent 16a (entries 10 and 16) is intriguing.

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Compound 17, the phenyl equivalent of 6b has not been used as a catalyst for alkylation, but
provides only a 10% e.e when used as an auxiliary in the LiAlH4 reduction of acetophenone.22
(iv) Introduction of planar chirality, though not containing a donor atom, provides a substantial
increase in enantioselectivity (entries 2 and 12). Taken together, the results in Table 1 demonstrate
decreasing enantioselection as a function of type(s) of chirality in the order (planar+central)>(planar
only)>(central only) but with planar chirality providing the dominant influence on enantioselection,
particularly when chelation sites are contained in both ferrocenyl substituents.
2.3. Configurational stability of ferrocenyl aminonitriles
Aminonitriles constitute valuable precursors to a variety of chiral compounds, including amino acids
(via hydrolysis) and diamines (via reduction).23 We have therefore investigated access to enantiomer-
ically pure ferrocenyl aminonitriles via nucleophilic displacement of acetate from resolved 13. In view
of the well-established stereospecific retention of configuration on reaction of 5 with methanolic Me2NH
at ambient temperature,10 it was surprising to find that reaction of (+)-13 under these conditions provides
only racemic 16. No reaction occurs in aprotic solvents such as benzene or dimethylformamide.
Though configurational instability of cyanohydrins has previously been noted,24 the facility of the

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4387
Table 2
Data for epimerisation of aminonitriles 17–20
presumed racemisation of 16 was unexpected. We have therefore carried out more detailed studies of
this inversion process via diastereoisomer interconversion in the ferrocenyl derivatives 17a,b and 18a,b
and compared the results to the analogous inversion process in the organic aminonitriles 19a,b and 20a,b
containing electron releasing aromatic and sterically demanding aliphatic substituents, respectively.
Reaction of (+)-13 with (S)-(−)-PhCH(Me)NH(R) (R_Me, H) or a Strecker reaction using ferrocene
carboxaldehyde25 both yield thermodynamic equilibrium mixtures of 17a,b and 18a,b. The minor
diastereoisomer 17a may be isolated by crystallisation and shown to have the (S,S)-configuration by
X-ray crystal structure determination.26 A pure sample of the major diastereoisomer 18b was obtained
by chromatography. Diastereoisomerically pure and enriched samples of 19b and 20a were obtained by
modification of literature procedures.24a,b
1
Epimerisation studies were monitored by integration of appropriate H NMR resonances; the results
are displayed in Table 2. The much reduced rate of epimerisation of 17a in benzene at elevated
temperature and the lack of epimerisation of 19a at 30°C in the less acidic t-amyl alcohol are consistent
with a mechanism involving reversible, acid-catalysed dissociation of HCN to generate the iminium
cation as intermediate.
Indeed, thermolysis of 18a or 19a in benzene at 70°C results in clean loss of HCN without epimeri-
sation, to give the imines 21 and 22. The similarity of the rates of epimerisation of 18 and 19 indicates
a similar ability of the electron releasing ferrocenyl and p-anisyl groups to stabilise charge at the α-
position. The similarity of the Keq for 18a and 19a is consistent with an equal steric demand for the
ferrocenyl and p-anisyl groups in this system. N-Methyl substitution as in 17 has only a minor effect
on the diastereoselection and a negligible effect on the rate of epimerisation. A comparison of the rates
of epimerisation of 17–19 with 20 indicates that electronic stabilisation of the transition state is more
efficient than steric acceleration. The sterically demanding t-Bu group is, however, more efficient at
promoting higher diastereoselection. Loss of stereochemical integrity is also evident in the reaction of
diastereomerically pure 17a with MeMgI to give 23a,b as an inseparable 1:1 mixture of diastereoisomers.
3. Experimental
1H and 13C NMR spectra were recorded at 250 or 270 MHz and 62.9 or 68.0 MHz, respectively;

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A. Patti et al. / Tetrahedron: Asymmetry 9 (1998) 4381–4394
chemical shifts are reported in ppm relative to tetramethylsilane. Optical rotations were measured on
Perkin–Elmer 141 polarimeter and JASCO DIP135 instruments.
3.1. Synthesis of (R)-(−)-2-(1-ferrocenylethylamino)ethanol 6a
To a solution of (R)-acetoxyethylferrocene (−)-8 (150 mg, 0.55 mmol) in MeOH was added ethanol-
amine (830 µl, 13.77 mmol) and the reaction was stirred at room temperature for 3 days. The solution
was partitioned between H2O and diethyl ether and the separated organic layer was extracted with 10%
citric acid solution. After basifying with 1 N NaOH, the aqueous layer was extracted with diethyl ether
and the organic phase dried over Na2SO4. Removal of solvent gave (R)-(−)-6a as a brown oil (110 mg,
71%). Analysis: calcd for C14H19FeNO: C, 61.6; H, 7.01; N, 5.13%; found C, 61.4; H, 7.11; N, 5.04%.
1H NMR (CDCl3): 1.39 (3H, d, J=6.3 Hz, CH3CH), 2.74 (2H, m, CH2N), 3.54 (1H, q, CH3CH), 3.61
(2H, m, CH2OH), 4.13–4.19 (9H, m, Cp, Cp0). 13C NMR (CDCl3): 21.5 (Me), 48.7, 52.1, 61.0 (CH,
CH2CH2), 65.7, 67.2, 67.4 (Cp2–5), 68.4 (Cp0), 93.1 (Cp1). [α]25 −21.0 (c 1.5, CHCl3).
D
3.2. 2-[(1-Ferrocenylethyl)methylamino]ethanol 6b
This was prepared in the same way using N-methylethanolamine. Analysis: calcd for C15H21FeNO:
C, 62.7; H, 7.37; N, 4.88%; found C, 62.6; H, 7.50; N, 4.75%. 1H NMR (CDCl3): 1.41 (3H, d, J=6.9 Hz,
CH3CH), 2.06 (3H, s, CH3N), 2.37, 2.48 (2H, dd, J=12.9 and 5.3 Hz, CHaHbN), 3.48 (2H, m, CH2OH),
3.76 (1H, q, CHCH3), 4.10–4.17 (9H, m, Cp, Cp0). 13C NMR (CDCl3): 15.3 (Me), 36.0 (NMe), 54.2,
57.8, 58.5 (CH, CH2CH2), 66.8, 67.2, 68.6, 68.7 (Cp2–5), 67.8 (Cp0), 87.8 (Cp1). [α]25 −25.1 (c 1.1,
D
CHCl3).
3.3. Synthesis of (R)-(−)-2-[(1-ferrocenylethyl)butylamino]ethanol 6c
To a solution of (−)-6a (180 mg, 0.66 mmol) in EtOH (10 ml) was added n-BuI (113 µl, 1.00 mmol)
and Na2CO3 (105 mg, 1.00 mmol). The mixture was refluxed for 5 h and the solvent was removed.
Chromatography on basic alumina (hexane:ethyl acetate) provided (R)-(−)-6c as a brown oil (109 mg,
50%). Analysis: calcd for C18H27FeNO: C, 65.7; H, 8.27; N, 4.25%; found C, 65.5; H, 8.40; N, 4.15%.
1H NMR (CDCl3): 0.88 (3H, t, J=7.3 Hz, CH3CH2), 1.27 (4H, m, CH3CH2CH2), 1.38 (3H, d, J=6.9 Hz,
CH3CH), 2.30 (2H, m, CH3(CH2)2CH2N), 2.38, 2.50 (2H, dd, J=12.8 and 5.2 Hz, CHaHbN), 3.41 (2H,
m, CH2OH), 3.86 (1H, q, CHCH3), 4.08–4.16 (9H, m, Cp, Cp0). 13C NMR (CDCl3): 14.0, 15.2, 20.4,
31.2 (Me, NCH2CH2CH2CH3), 49.7, 50.9, 54.1, 58.2 (CH, NCH2CH2OH, NCH2CH2CH2CH3), 66.8,
67.2, 67.9 (Cp), 68.6 (Cp0), (Cp1). [α]25 −24.7 (c 1.3, CHCl3).
D
3.4. Synthesis of (R)-(−)-2-[benzyl(1-ferrocenylethyl)amino]ethanol 6d
To a solution of (−)-6a (130 mg, 0.48 mmol) in EtOH (7 ml) were added PhCH2Br (86 µl, 0.72
mmol) and Na2CO3 (76 mg, 0.72 mmol). The mixture was refluxed for 3 h, cooled, and partitioned
between aqueous 10% citric acid and diethyl ether. After basifying, the aqueous layer was extracted
with diethyl ether. After drying over Na2SO4 and removal of solvent, the residue was chromatographed
on basic alumina (hexane:acetone) to give (R)-(−)-6d as a brown oil (98 mg, 56%). Analysis: calcd for
1
C21H25FeNO: C, 69.4; H, 6.94; N, 3.86%; found C, 69.3; H, 7.10; N, 3.70%. H NMR (CDCl3): 1.48
(3H, d, J=6.8 Hz, CHCH3), 2.48, 2.65 (2H, m, CHaHbN), 3.43 (2H, m, CH2OH), 3.59 (2H, m, CH2Ph),
3.90 (1H, q, CHCH3), 4.10 (5H, s, Cp0), 4.14–4.20 (4H, m, Cp), 7.33 (5H, m, Ph). 13C NMR (CDCl3):

A. Patti et al. / Tetrahedron: Asymmetry 9 (1998) 4381–4394
4389
16.8 (Me), 52.4, 55.8, 56.1, 59.5 (CH2CH2OH, NCH2Ph, CH), 68.9, 69.2, 70.1, 70.2 (Cp2–5), 69.5 (Cp0),
88.4 (Cp1), 128.7, 129.9, 130.2, 130.4, 140.2 (Ph). [α]25 −23.2 (c 1.3, CHCl3).
D
3.5. Synthesis of (1R,R)-(−)-1-trimethylsilyl-2-(N-methyl,N-hydroxyethyl)aminoethylferrocene 6e
To a solution of (+)-N,N-dimethylaminoethylferrocene (200 mg, 0.78 mmol, Aldrich) in anhydrous
tetrahydrofuran (4 ml) cooled to 0°C was added t-BuLi (1.17 mmol, 686 µl of a 1.7 M solution
in pentane). After 30 min, (CH3)3SiCl (198 µl, 1.56 mmol) was added at room temperature. The
mixture was stirred for 5 h and refluxed for a further 3 h. After cooling and partitioning between
H2O and diethyl ether, solvent was removed from the organic phase and the residue was purified by
chromatography on basic alumina (petroleum ether:diethyl ether) to give (1R,R)-1-trimethylsilyl-2-N,N-
dimethylaminoethylferrocene (+)-10 as a brown oil (117 mg, 46%) identified by a comparison of its
optical and NMR data with the literature.11
(+)-10 was quantitatively converted into the ester 11 by treatment with acetic anhydride in tetra-
hydrofuran under reflux for 2 h. After removal of solvent, 11 was dissolved in MeOH and treated with
N-methylethanolamine (711 µl, 8.85 mmol). After stirring for 4 days at room temperature, the mixture
was partitioned between H2O and diethyl ether. After drying over Na2SO4, the organic layer was taken
to dryness and the residue purified by chromatography on silica gel (hexane:diethyl ether) to give (1R,R)-
(−)-6e as a brown oil (61 mg, 48%). Analysis: calcd for C18H29FeNOSi: C, 60.2; H, 8.13; N, 3.90%;
1
found C, 60.0; H, 8.26; N, 3.75%. H NMR (CDCl3): 0.32 (9H, s, (CH3)3Si), 1.33 (3H, d, J=6.8 Hz,
CH3CH), 2.11 (3H, s, CH3N), 2.45, 2.59 (2H, dd, J=12.6 and 7.0 Hz, CHaHbN), 3.49 (2H, m, CH2OH),
3.88 (1H, q, CHCH3), 4.10 (5H, s, Cp0), 4.33 (3H, m, C5H3). [α]25 −22.8 (c 1.0, CHCl3).
D
3.6. Synthesis of rac-1-acetoxyferrocenylacetonitrile 13
To rac-ferrocene cyanohydrin 1212a [(500 mg, 2.07 mmol); 1H NMR (C6D6): 1.68 (1H, d, J=7.9 Hz,
OH), 3.97 (5H, s, Cp0), 3.80 (2H, m, Cp), 3.93, 4.14 (each 1H, m, Cp), 4.50 (1H, d, CH)] dissolved in dry
diethyl ether (75 ml) was added freshly distilled acetyl chloride (160 mg, 2.07 mmol) and dry pyridine
(160 mg, 2.07 mmol). After stirring overnight at room temperature, the solvent was removed and the
residue purified by chromatography using 15% deactivated alumina (1:1, petroleum ether:CH2Cl2) to
give rac-12 as a yellow solid (390 mg, 67%) which was recrystallised from petroleum ether (60–80).
Mp: 88–90°C. Analysis: calcd for C14H13FeNO2: C, 59.4; H, 4.59; N, 4.95%; found C, 59.6; H, 4.49;
1
N, 4.67%. H NMR (C6D6): 1.35 (3H, s, COCH3), 3.97 (5H, s, Cp0), 3.81, 3.86, 4.03, 4.39 (each 1H,
m, Cp), 6.17 (1H, s, CH). 13C NMR (CDCl3): 20.5 (Me), 60.6 (CH), 69.6 (Cp0), 67.9, 69.7, 70.0, 70.1
(Cp2–5), 78.0 (Cp1), 116.0 (CN), 169.1 (CO). The 1H COCH3 resonance is resolved into two on addition
of tris[(heptafluoropropylhydroxymethylene)-(+)-camphorato]Eu(III).
3.7. Synthesis of rac-1-benzoyloxyferrocenylacetonitrile 15a
To rac-12 (100 mg, 0.42 mmol) dissolved in dry pyridine (1.5 ml) was added benzoyl chloride (0.07 ml,
0.63 mmol). After stirring for 3 h at room temperature, the solvent was removed and the residue purified
by chromatography on 15% deactivated alumina to give 15a (70 mg, 49%) which was recrystallised
from petroleum ether (60–80). Mp: 124–127°C. Analysis: calcd for C19H15FeNO2: C, 66.1; H, 4.35; N,
1
4.06%; found C, 65.9; H, 4.48; N, 3.96%. H NMR (C6D6): 3.99 (5H, s, Cp0), 3.82, 3.88, 4.11, 4.46
(each 1H, m, Cp), 6.42 (1H, s, CH), 6.8–7.1, 7.92 (5H, m, Ph).

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3.8. Synthesis of rac-ferrocenyltrimethylsiloxyacetonitrile 15b
Imidazole (450 mg, 6.6 mmol) and (CH3)3SiCl (430 mg, 4.0 mmol) were dissolved in dry dimethyl-
formamide (10 ml) and rac-12 (200 mg, 0.83 mmol) was added with stirring. After heating at 40°C
for 2 h, the solution was cooled and poured into ice water (50 ml). After extraction with diethyl ether,
washing with H2O and drying over MgSO4, the solvent was removed and the crude product recrystallised
from hexane to give rac-15b as brown crystals (130 mg, 53%). Mp: 80–82°C (lit.27 80–82°C). 1H NMR
(C6D6): 0.05 (9H, s, (CH3)3Si), 4.07 (5H, s, Cp0), 3.83, 3.87, 3.94, 4.36 (each 1H, m, Cp), 5.03 (1H, s,
CH).
Compound rac-15c was prepared similarly as a brown oil using t-BuMe2SiCl and purified by chro-
matography on 15% deactivated alumina (1:1, petroleum ether:CH2Cl2). Mass spectrum: calcd for
1
C18H25FeNOSi 355.3341; found 355.3325. H NMR (C6D6): 0.01 (6H, 2s, Si(CH3)2), 0.88 (9H, s, t-
Bu), 4.10 (5H, s, Cp0), 3.87 (2H, m, Cp), 4.02, 4.31 (each 1H, m, Cp), 5.01 (1H, s, CH).
3.9. Enzymatic resolution of ferrocenylhydroxyacetonitrile
Compound rac-12 (100 mg, 0.42 mmol) and Pseudomonas cepacia lipase (100 mg, Amano lipase PS)
were added to distilled vinyl acetate (2.3 ml) under nitrogen and shaken gently at room temperature.
The reaction was monitored by NMR until the integrated ratio of the CH resonances due to 12 and
13 had reached 1:1. At this point, resonances assignable to 14 [1H NMR (CDCl3): 4.37 (5H, s, Cp0),
4.86, 4.98 (each 2H, t, Cp)] accounted for 10% of the integrated intensity. The enzyme was removed by
filtration, washed with diethyl ether and the residue evaporated to dryness. The reaction may be carried
out successfully on a scale of up to 1 g of 12. Purification was accomplished in two ways:
(i) Careful chromatography on 15% deactivated alumina (1:1, petroleum ether:CH2Cl2) eluted first
the acetate 13 (40%, 84% e.e.) followed by ferrocene carboxaldehyde. Recrystallisation provided
(R)-(+)-13 (>95% e.e., [α]25 +73.8 (c 0.2, CH3CN)).
D
(ii) Chromatography on silica gel under N2 pressure using 1:4, ethyl acetate:petroleum ether (40–60)
eluted first the (S)-cyanohydrin 12 (34% yield, 81% e.e. by NMR analysis of the derived acetate),
followed by a purplish yellow band which was further purified by chromatography on 15%
deactivated alumina (see earlier) to give (R)-(−)-acetate 13 (40% yield, 84% e.e. by NMR analysis).
3.10. Synthesis of 2-amino-1-ferrocenylethanol 7a
A quantity of rac-13 (200 mg, 0.71 mmol) was added to a suspension of LiAlH4 (60 mg, 2.5 mmol)
in dry diethyl ether (20 ml) under nitrogen and refluxed for 90 min. After cooling, ice water (20 ml) was
added and the yellow precipitate collected and dried over P2O5. The crude precipitate was extracted with
boiling toluene. After concentration and cooling, the product rac-7a was collected as golden plates (220
mg, 92%). Mp: 148–150°C. Analysis: calcd for C12H15FeNO: C, 58.8; H, 6.12; N, 5.71%; found C, 58.5;
H, 6.20; N, 5.48%. 1H NMR (CDCl3): 2.73 (1H, dd, J=7.4, 12.8 Hz, CHaHb), 2.92 (1H, dd, J=4.1, 12.8
Hz, CHaHb), 4.17 (5H, s, Cp0), 4.14 (3H, m, Cp), 4.22 (1H, m, Cp), 4.29 (1H, dd, CH).
LiAlH4 reduction of rac-12 provides rac-7a in similar yield. Reduction of (R)-(+)-13 or (S)-12
provides (R)-(−)-7a ([α]25 −14.7 (c 0.09, CH3CN)) or (S)-(+)-7a, respectively, without loss of optical
D
purity, established using Pirkle’s alcohol after conversion to 7b.

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3.11. Synthesis of 2-dimethylamino-1-ferrocenylethanol 7b
To a solution of rac-7a (500 mg, 2.04 mmol) in MeOH (15 ml) was added HCHO (0.8 ml of 37%
solution) followed by a suspension of ZnCl2 (144 mg, 1.02 mmol) and NaBH3CN (133 mg, 2.04 mmol)
in MeOH (15 ml). After stirring for 7 h at room temperature, 1 M NaOH (30 ml) was added and MeOH
removed by evaporation under reduced pressure. Extraction with ethyl acetate, drying over MgSO4 and
removal of solvent gave a residue which was purified by chromatography on 15% deactivated alumina
(1:9, methanol:ethyl acetate) to give rac-7b as a brown oil (280 mg, 59%) which was crystallised from
petroleum ether (60–80). Mp: 56–58°C. Analysis: calcd for C14H19FeNO: C, 61.5; H, 6.96; N, 5.13%;
1
found C, 61.6; H, 7.23; N, 5.18%. H NMR (C6D6): 1.96 (6H, s, NMe2), 2.13 (1H, dd, J=3.2, 12.0 Hz,
CHaHb), 2.37 (1H, dd, J=11.1, 12.0 Hz, CHaHb), 4.19 (5H, s, Cp0), 4.00 (2H, m, Cp), 4.07, 4.42 (each 1H,
m, Cp), 4.47 (1H, dd, CH). 13C NMR (CDCl3): 45.5 (NMe2), 65.8, 66.1, 66.3, 66.4, 67.7, 67.8 (Cp2–5
,
CH, CH2), 68.5 (Cp0), 89.7 (Cp1). Reaction of (R)-(+)-7a in the same way provides (R)-(+)-7b ([α]25
D
+42.1 (c 0.3, CH3CN)). Optical purity may be determined by the resolution of the 1H Cp0 resonance in
the presence of (R)-(9-anthryl)-2,2,2-trifluoroethanol (Pirkle’s alcohol).
3.12. Synthesis of 1-ferrocenyl-2-piperidin-1-ylethanol 7c
To rac-7a (100 mg, 0.40 mmol) in dry toluene (20 ml) were added i-Pr2NH (0.16 ml, 0.9 mmol) and
1,5-dibromopentane (0.06 ml, 0.40 mmol). The reaction mixture was refluxed gently until TLC indicated
disappearance of starting material. After cooling and evaporation of solvent, the residue was purified
by chromatotron (1:1, ethyl acetate:petroleum ether) to give 7c as a brown solid, recrystallised from
petroleum ether (60–80) (80 mg, 63%). Mp: 98–99°C. Analysis: calcd for C17H23FeNO: C, 65.1; H, 7.35;
1
N, 4.47%; found C, 65.1; H, 7.11; N, 4.41%. H NMR (C6D6): 1.22 (2H, m, NCHcHdCH2CH2), 1.33
(4H, m, NCHcHdCH2CH2), 2.06 (2H, m, NCHcHdCH2CH2), 2.36 (4H, m, NCHcHdCH2CH2, CHaHb),
4.20 (5H, s, Cp0), 4.03 (2H, m, Cp), 4.11, 4.45 (each 1H, m, Cp), 4.52 (1H, dd, J=4.2, 9.6 Hz, CH). 13
C
NMR (CDCl3): 25.6, 27.5, 55.9 (piperidinyl), 66.3, 67.0, 67.4, 67.8, 68.9, 69.1 (Cp2–5, CH, CH2), 69.1
(Cp0), 91.0 (Cp1).
Reaction of (R)-(+)-7a in the same way provides (R)-(+)-7c. Optical purity may be determined by
resolution of the 1H Cp0 NMR resonance in the presence of Pirkle’s alcohol. Some loss of optical purity
is evident during reaction. (+)-7a of 85% e.e. is converted into crude (+)-7c of 60% e.e. which may be
enriched to 75% e.e. on recrystallisation. [α]25 +42.1 (c 0.1, CH3CN).
D
3.13. Standard procedure for alkylation of benzaldehyde with ZnEt2
ZnEt2 (1.02 mmol, 927 µl of a 1.1 M solution in toluene) was added under argon at room temperature
to a degassed solution of benzaldehyde (0.51 mmol, 52 µl) and catalyst (0.025 mmol) in dry toluene
(1.3 ml). Progress of the reaction was monitored by gas chromatography. On completion, the reaction
was quenched by addition of saturated NH4Cl solution, followed by extraction with diethyl ether, drying
over Na2SO4 and removal of solvent. The enantiomeric excess of the (S)-(−)-1-phenyl-1-propanol was
determined by acetylation or derivatisation to the methoxy(trifluoromethyl)phenylacetyl ester followed
by gas chromatographic analysis on chiral (Chiraldex γ-DA) or achiral (HP-5) columns, respectively.

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A. Patti et al. / Tetrahedron: Asymmetry 9 (1998) 4381–4394
3.14. Synthesis of ferrocenyl[methyl(1-phenylethyl)amino]acetonitrile 17a,b
3.14.1. From ferrocene carboxaldehyde
To a stirred solution of NaHSO3 (240 mg, 2.3 mmol) in water (15 ml) was added a solution of
ferrocene carboxaldehyde (500 mg, 2.34 mmol) in methanol (12.5 ml). The resulting brown slurry
was cooled to 0°C and a solution of (S)-(−)-HN(Me)CHMePh28 (0.49 ml, 3.28 mmol) in methanol
(5 ml) was added dropwise, followed by a solution of NaCN (120 mg, 2.34 mmol) in water (10 ml)
and diethyl ether (7.5 ml). After separation, the organic layer was extracted with diethyl ether. The
combined organic layers were washed with brine, dried over MgSO4 and evaporated to give a brown oil
containing diastereoisomers 17a,b in a 1:4.2 ratio. Crystallisation from petroleum ether (60–80) provided
the pure minor diastereoisomer 17a as yellow needles (130 mg, 16%). Mp: 129–131°C. Analysis: calcd
1
for C21H22FeN2: C, 70.4; H, 6.14; N, 7.82%; found C, 70.6; H, 6.13; N, 7.67%. H NMR (C6D6):
1.34 (3H, d, J=6.9 Hz, CHMePh), 2.08 (3H, s, NMe), 3.55 (1H, q, CHMePh), 3.88, 4.05, 4.36 (2H,
1H, 1H, m, Cp), 4.01 (5H, s, Cp0), 4.87 (1H, s, CHN(Me)CH(Me)Ph), 7.0–7.4 (5H, m, Ph). 13C NMR
(CDCl3): 19.3 (CHMe), 35.2 (NMe), 53.8 (NCH(Me)Ph), 61.8 (CHCN), 68.3, 68.8, 69.0, 69.2 (Cp2–5),
69.3 (Cp0), 82.0 (Cp1), 116.9 (CN), 127.3, 127.4, 127.5, 144.0 (Ph). [α]20 −85.2 (c 0.2, CH3CN). The
D
residue was purified to remove traces of aldehyde by chromatography on 15% deactivated alumina (1:4,
ethyl acetate:petroleum ether (40–60)) to give a 7.9:1 enriched mixture of the major diastereoisomer
1
17b (180 mg, 22%) as a brown oil. H NMR (CDCl3): 1.36 (3H, d, J=6.9 Hz, CHMePh), 2.26 (3H, s,
NMe), 4.55 (1H, q, CHMePh), 4.07, 4.13, 4.16, 4.37 (each 1H, m, Cp), 4.02 (5H, s, Cp0), 4.50 (1H, s,
CHN(Me)CH(Me)Ph), 7.2–7.4 (5H, m, Ph). Ferrocenyl(1-phenylethyl)aminoacetonitrile was similarly
prepared from ferrocene carboxaldehyde and (S)-(−)-1-phenylethylamine as a 1:2.8 mixture of 18a,b
which would not crystallise. Collection of the front-running part of the single yellow band obtained
on chromatography (15% deactivated alumina, 1:9, ethyl acetate:petroleum ether (40–60)) gave a pure
sample of the major diastereoisomer 18b as a yellow oil. The configuration of 18b is assigned as shown
by analogy with the determined configuration of 17b. Mass spectrum: calcd for C19H19FeN (M+−HCN):
317.2128; found 317.2120. 1H NMR (C6D6): 1.05 (3H, d, J=6.3, CH(Me)Ph), 3.88, 4.05, 4.32 (2H, 1H,
1H, m, Cp), 3.96 (5H, s, Cp0), 4.06 (1H, s (br), CHNHCH(Me)Ph), 4.16, (1H, q, CH(Me)Ph), 7.05–7.40
(5H, m, Ph). [α]25 −9.5 (c 0.2, CH3CN).
D
3.14.2. From 13
To a stirred solution of rac-13 (330 mg, 1.17 mmol) in dry methanol (7 ml) was added (−)-(S)-
NH(Me)CH(Me)Ph (0.38 ml, 2.56 mmol) at room temperature. After stirring for 24 h, solvent was evapo-
rated and the crude product chromatographed on 15% deactivated alumina (1:4, ethyl acetate:petroleum
ether (40–60)) to give a mixture of 17a,b as a brown oil in a 1:4.1 ratio by NMR (340 mg, 81%). Use of
optically pure (+)-13 provides 17a,b in the same diastereoisomeric ratio.
Reaction of optically pure (+)-13 with HNMe2 under the same conditions provides racemic dimethyl-
aminoferrocenylacetonitrile 16 in 81% yield. Mp: 86–88°C (lit.25 86–88°C). NMR (C6D6): 2.03 (6H, s,
NMe2), 3.85, 3.87, 3.98, 4.32 (each 1H, m, Cp), 4.02 (5H, s, Cp0), 4.27 (1H, s, CH).
3.15. Synthesis of 2-ferrocenyl-2-[methyl(1-phenylethyl)amino]ethane 23a,b
MgMeI (0.11 ml of a 3 M solution in diethyl ether) was added to a solution of 17a (20 mg, 0.21 mmol)
in diethyl ether (10 ml) at 0°C with stirring. After warming to room temperature and stirring for 1 h,
the solution was hydrolysed with saturated NH4Cl (10 ml) and the aqueous phase extracted with diethyl
ether. The combined organic extracts were dried over MgSO4 and evaporated to give an inseparable

A. Patti et al. / Tetrahedron: Asymmetry 9 (1998) 4381–4394
4393
mixture of 23a,b as a yellow oil (20 mg, 27%) in a 1:1 ratio. Mass spectrum: calcd for C21H25FeN:
347.2882; found 347.2792. 1H NMR (CDCl3): 1.15–1.24 (6H, m, CH(Me)N(Me)CH(Me)Ph), 1.89, 1.96
(each 3H, s, NMe), 3.47, 3.54 (each 1H, q, J=6.9 Hz, CH(Me)N(Me)CH(Me)Ph), 3.76, 3.83 (each 1H,
q, J=6.8 Hz, CH(Me)N(Me)CH(Me)Ph), 4.03–4.20 (4H, m, Cp), 3.93, 3.99 (each 5H, s, Cp0), 7.20–7.35
(10H, m, Ph).
3.16. Synthesis of 4-methoxyphenyl(1-phenylethylamino)acetonitrile 19 and 3,3-dimethyl-2-(1-phenyl-
ethylamino)butyronitrile 20
Reaction of [(S)-(−)-NH3CH(Me)Ph]Cl with p-anisaldehyde according to the literature24b provided [4-
MeOC6H4CH(CN)NH2CH(Me)Ph]Cl as a diastereoisomer mixture. A single fractional recrystallisation
from CH2Cl2:diethyl ether gave the optically pure (S,S)-diastereoisomer in 46% yield. 1H NMR (CDCl3):
1.40 (3H, d, J=6.8 Hz, CH(Me)Ph), 3.67 (3H, s, MeO), 4.33 (1H, q, CH(Me)Ph), 4.36 (1H, s, CHCN),
6.8–7.7 (9H, m, Ph). Diastereomerically pure 19b was generated by neutralisation of the above with
1
NaHCO3 solution, followed by extraction with CH2Cl2. H NMR (CDCl3): 1.38 (3H, d, J=7.2 Hz,
CH(Me)Ph), 3.78 (3H, s, MeO), 4.19 (1H, q, CH(Me)Ph), 4.30 (1H, s, CHCN), 6.85–7.50 (9H, m, Ph).
13C NMR (CDCl3): 24.8 (CH(Me)Ph), 51.8, 55.3, 56.7 (MeO, NCH(Me)PhCHCN), 119.1 (CN), 114.2,
126.9, 127.3, 127.8, 128.4, 128.8, 143.1, 159.9 (Ph).
A 1:3.8 diastereoisomeric mixture of 20a,b was prepared according to the literature.24a Collection
of the front-running part of a broad band from the chromatotron (1:4, ethyl acetate:petroleum ether)
provided a 1:1.2 mixture of 20a,b enriched in the minor (R,S)-diastereoisomer which was suitable for
epimerisation studies. NMR (CDCl3): 20a 0.92 (9H, s, t-Bu), 1.28 (3H, d, J=6.8 Hz, CH(Me)Ph), 3.96
(1H, q, CH(Me)Ph), 7.1–7.3 (5H, m, Ph); 20b 0.97 (9H, s, t-Bu), 1.34 (3H, d, J=6.8 Hz, CH(Me)Ph),
4.03 (1H, q, CH(Me)Ph), 3.97 (1H, s, CHCN), 7.1–7.3 (5H, m, Ph).
3.17. Epimerisation studies of aminonitriles
A solution of the aminonitrile in either dry, N2 degassed MeOH or C6D6 was heated in a constant
temperature bath (ꢀ0.5°C). For studies in MeOH, samples were periodically withdrawn and the solvent
removed immediately at 0°C; NMR spectra of the residues were run in CDCl3. Spectra of samples in
C6D6 were run directly. Values of k1+k−1 were obtained from plots of ln(P −t)/(Pt+1) versus time,
∞
where P is the diastereoisomer ratio obtained by integration using CHCN resonances at 4.85, 4.49 ppm
for 17a,b, NCH(Me)Ph resonances at 1.31, 1.39 ppm for 18a,b, CHCN resonances at 4.40, 4.29 ppm for
19a,b and t-Bu resonances at 0.92, 0.97 ppm for 20a,b. All plots gave correlation coefficients of >0.98.
The imines 2129 and 2230 were identified spectroscopically in situ. 21 (C6D6): 1.52 (3H, d, CHMe,
J=6.8 Hz), 4.25 (1H, q, CHMe), 3.92 (5H, s, Cp0), 4.05, 4.59, 4.66 (4H, m, Cp), 7.96 (1H, s, CHN),
7.1–7.5 (5H, m, Ph); 22 (C6D6): 1.56 (3H, d, CHMe, J=6.9 Hz), 4.33 (1H, q, CHMe), 6.7–7.7 (9H, m,
Ph), 8.05 (1H, s, CHN).
Acknowledgements
We thank the Amano Chemical Corporation for the gift of enzymes, the EPSRC Mass Spectroscopy
and Chiroptical Spectroscopy facilities for services, and CNR and the European Union COST Programme
for financial support.

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