Chiral phosphanylferrocenecarboxamides with amino acid pendant groups as ligands for Cu-mediated asymmetric conjugate additions of diethylzinc to chalcones - Structural characterisation of precursors to the Cu catalyst

Article abstract of DOI:10.1002/ejoc.201000480

A series of chiral phosphanylferrocenecarboxamides was prepared by treatment of either l'-(diphenylphosphanyl)ferrocene-1-carboxylic acid (Hdpf) or its planar-chiral 1,2isomers with amino acid methyl esters in the presence of peptide coupling agents. The compounds were characterised by spectroscopic methods, and the crystal structure of one representative was determined by X-ray diffraction. Catalytic testing of these donors in Cu-catalysed asymmetric conjugate additions of diethylzinc to chalcones revealed that the reaction outcomes were highly sensitive to the ligand structure and the reaction conditions (copper source and solvent), whereas the chalcone substituents (Me, MeO, or Cl in positions 4 or 4') had a less pronounced influence. Compounds based on Hdpf proved to be better ligands than their planarchiral analogues. Under optimised conditions, the reaction with L-valine-Hdpf conjugate, (S)-Ph₂PfcCONHCH(CHMe₂)CO₂Me (fc = ferrocene-1,1'-diyl) and unsubstituted chalcone gave the alkylation product with complete conversion (20 °C/ 4 h) and in 87 % ee. The catalytic behaviour of the amidophosphane ligands was correlated to the results of a model coordination study and the crystal structure of [Cu(Ph₂PfcCONHCH ₂CO₂Me)₂](CF₃SO₃) ·2CHCl₃.

Full text of DOI:10.1002/ejoc.201000480

FULL PAPER
DOI: 10.1002/ejoc.201000480
Chiral Phosphanylferrocenecarboxamides with Amino Acid Pendant Groups as
Ligands for Cu-Mediated Asymmetric Conjugate Additions of Diethylzinc to
Chalcones – Structural Characterisation of Precursors to the Cu Catalyst
[a]
[a]
ˇ
[a]
Ji rˇ í Tauchman, Ivana Císa rˇ ová, and Petr St eˇ pni cˇ ka*
Keywords: Phosphanylferrocene ligands / Amino acids / Amides / Copper / Asymmetric synthesis / Conjugate addition
A series of chiral phosphanylferrocenecarboxamides was
prepared by treatment of either 1Ј-(diphenylphosphanyl)-
ferrocene-1-carboxylic acid (Hdpf) or its planar-chiral 1,2-
isomers with amino acid methyl esters in the presence of
peptide coupling agents. The compounds were characterised
by spectroscopic methods, and the crystal structure of one
representative was determined by X-ray diffraction. Cata-
lytic testing of these donors in Cu-catalysed asymmetric con-
jugate additions of diethylzinc to chalcones revealed that the
reaction outcomes were highly sensitive to the ligand struc-
ture and the reaction conditions (copper source and solvent),
whereas the chalcone substituents (Me, MeO, or Cl in posi-
tions 4 or 4Ј) had a less pronounced influence. Compounds
based on Hdpf proved to be better ligands than their planar-
chiral analogues. Under optimised conditions, the reaction
with
2 2
L-valine–Hdpf conjugate, (S)-Ph PfcCONHCH(CHMe )-
CO Me (fc = ferrocene-1,1Ј-diyl) and unsubstituted chalcone
2
gave the alkylation product with complete conversion (20 °C/
4 h) and in 87% ee. The catalytic behaviour of the amido-
phosphane ligands was correlated to the results of
model coordination study and the crystal structure of
[Cu(Ph PfcCONHCH CO Me) ](CF SO )·2CHCl
a
2
2
2
2
3
3
3
.
Introduction
During our studies on phosphanylferrocenecarboxam-
Asymmetric conjugate additions of carbon nucleophiles ides,[ we noticed that these donors have a structural simi-
to acceptor-activated double bonds represent an attractive larity with some ligands utilised (though with varying suc-
tool for the stereoselective formation of C–C bonds. Their cess) in conjugate additions of organometals. Prominent ex-
practical implementation was recently facilitated by the dis- amples of such ligands, combining phosphane and carbox-
covery of metal-catalysed processes that allow for con- amide moieties, are Trost’s chiral bis(amide) (A in
4,5]
[
6]
trolled use of highly reactive organometals and require the Scheme 1), some C- and axial-chiral amidophosphanes
presence of only catalytic amounts of a metal precursor and
[
1]
a chiral ligand.
In this regard, copper-mediated conjugate additions of
diorganozinc reagents to α,β-unsaturated ketones have at-
tracted particular synthetic interest and have dominated the
[2]
field since their discovery in the 1990s. This is very proba-
bly due to the efficient acceleration of this reaction through
the use of Cu/L* catalysts (typically generated in situ), al-
lowing in turn for fine-tuning of the course of the reaction.
In addition, organozinc reagents react rather selectively and
tolerate a variety of functional groups,[ which further
broadens the field of application of these reactions. On the
other hand, careful attention has to be paid to the design
of chiral donors for any enantioselective variant of these
reactions because the chiral ligands are the only source of
chirality in this process and thus have crucial impact on the
3]
[
1]
reaction outcomes.
[
a] Department of Inorganic Chemistry, Faculty of Science,
Charles University in Prague,
Hlavova 2030, 12840 Prague, Czech Republic
Fax: +420-221-951-253
E-mail: stepnic@natur.cuni.cz
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000480.
Scheme 1.
4276
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 4276–4287

Chiral Phosphanylferrocenecarboxamides with Amino Acid Pendant Groups
(
e.g., B and C),[7] phosphanyloxazolines (D and E)[8] and, carboxyl group, were generated in situ from the correspond-
mainly, the highly versatile amino-acid- and peptide-based ing hydrochlorides – [H NCH(R)CO Me]Cl (R = H, Me,
3
2
phosphanes [F; R and chirality depend on the amino acid(s) iPr, and CH Ph) – and triethylamine.
2
[
9,10]
used].
All amides were obtained by standard amide coupling in
In view of this similarity and of the successful applica- the presence of 1-hydroxybenzotriazole and a carbodiimide
[
14]
tions of phosphanylferrocene ligands in asymmetric conju- reagent
gate additions,
and were isolated by column chromatography,
[
1,6,11]
we decided to extend our work directed typically in the forms of orange amorphous solids. It should
towards the design, coordination properties and catalytic be noted that, whereas the reactions with -amino acids
utilisation of phosphanylferrocene–glycine donors Ph P- proceeded with excellent yields for all phosphanylcarboxylic
2
fcC(O)NHCH C(O)Y (fc = ferrocene-1,1Ј-diyl; Y = OH, acids, those involving (S )-1 and -amino acids did not
2
4a]
p
[
OMe, NH2)
to their chiral analogues. Here we describe reach completion, with limited amounts of the intermediate
the preparation of a library of phosphanylferrocenecarbox- active ester 1-hydroxybenzotriazolyl (S )-2-(diphenylphos-
p
amides with stereogenic carbon atoms in their amide side phanyl)ferrocene-1-carboxylate [(S )-10] also being isolated.
p
chains and/or planar chirality at their ferrocene units, to- This can be explained by a chirality mismatch, resulting in
gether with the results of their testing as ligands for copper- steric crowding and making the coupling reaction more dif-
catalysed asymmetric conjugate additions of diethylzinc to ficult.
chalcones.
Results and Discussion
Synthesis and Characterisation of the Ligands
The series of amino acid amides (Scheme 2) was designed
to incorporate compounds featuring either a chirality centre
in the amino acid or a chirality plane, as well as their ana-
The presence of amide and ester moieties in 3–9 is mani-
fested in their IR spectra through the strong bands due to
logues with combined chirality. Accordingly, the amides
–
1
–1
νC=O (ester; 1740–1751 cm ), amide I (1624–1656 cm )
were prepared from 1Ј-(diphenylphosphanyl)ferrocene-1-
–
1
[
12]
and amide II (1517–1532 cm ) vibrations. In addition to
signals attributable to the functional substituents, H NMR
carboxylic acid (Hdpf) or its planar-chiral isomers (S )-
p
1
[
13]
and (R )-1, and from glycine or C-chiral (- or -)amino
p
spectra of the Hdpf-based amides each displayed eight reso-
nances due to diastereotopic ferrocene protons, whereas
compounds derived from the acid 1 each showed a sharp
singlet and three characteristic multiplets of the unsubsti-
tuted C H ring and the C H protons, respectively. No-
acids. Amino acid methyl esters, which were used through-
out this study in order to avoid undesired reactions at the
5
5
5
3
tably, the signals of the amide protons and the CH (or CH2)
groups bonding to the amide nitrogen atom in the planar-
31
chiral amides were observed as P-coupled multiplets (con-
1
31
firmed by H{ P} NMR). This interaction, resulting in rel-
atively high coupling constants (ca. 13 Hz for the NH pro-
tons), seems to reflect the mutual orientation of the inter-
acting moieties and possible N–H···P contacts (vide infra).
The 13C{ H} NMR spectra confirmed the formulation
1
by combining the signals of the PPh -substituted ferrocene
2
units and the amide pendants, with two C=O resonances
being of particular diagnostic value (Hdpf-based com-
pounds: δC ≈ 170 ppm for CONH and δC ≈ 173 ppm for
CO Me; compounds based on 1: δ = 170.6–173.7 ppm for
2
C
31
CO Me, and a P-coupled doublet at δ ≈ 170 ppm for
2
C
CONH). Finally, the 31P{ H} NMR spectra displayed sin-
1
gle resonances at δ ≈ –17 ppm for the Hdpf derivatives and
P
at δ ≈ –20 ppm for their planar-chiral analogues.
P
Circular dichroism (CD) spectra of isomeric amides
bearing alanine pendants (Figure 1) show several Cotton
effects in the regions of ferrocene d–d and CT transi-
Scheme 2. Preparation of the amidophosphane ligands 2–9. Rea-
gents and conditions: (i) 1-hydroxybenzotriazole and N-[3-(dimeth-
ylamino)propyl]-NЈ-ethylcarbodiimide in dry dichloromethane
[15]
tions. The spectra of (R)- and (S)-3 demonstrate the ex-
pected enantiomeric relationship. Those of the planar-chiral
isomers suggest a dominant contribution of planar chirality
to the CD response.
(0 °C/30 min); then addition of an [H
3 2 3
NCH(R)CO Me]Cl/NEt /
CH Cl mixture and stirring at room temp. overnight.
2
2
Eur. J. Org. Chem. 2010, 4276–4287
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ˇ
J. Tauchman, I. Císa rˇ ová, P. St eˇ pni cˇ ka
FULL PAPER
C3 angles differ by less than 2°, the difference in the C11–
C1–C2/C5 angles is 10.5°, because the C1–C11 bond is bent
away from the PPh group. This bending occurs without
2
any notable torsion, however, as indicated by the P–C2–C1–
C11 angle of 2.5(2)°. The amide group (C11,O1,N) is nearly
coplanar with its parent Cp ring [dihedral angle 5.4(2)°] and
is oriented with the N–H bond pointing towards the phos-
[
16]
phorus atom.
Catalytic Tests
The catalytic potential of the amidophosphane ligands
was examined in the copper-catalysed conjugate addition of
diethylzinc to trans-chalcone (11a) to give the ketone 12a
Figure 1. CD spectra of the isomeric compounds (S)-3 (dotted
(Scheme 3). The initial screening reactions were performed
p p
line), (R)-3, (S,S )-7 (dashed line) and (R,S )-7 (c ≈ 1 m in
with (S)-3, possessing only central chirality. Particular at-
tention was paid to finding the optimal reaction conditions
MeOH).
(Table 1).
In addition to the spectroscopic characterisation, the
crystal structure of (S,S )-9 (Figure 2) was determined, cor-
p
roborating both the expected connectivity and chirality. The
geometric data for (S,S )-9 compare well with those for the
p
[
4a]
achiral donor 2
and for amides prepared from the acid
The ferrocene cyclopentadienyl rings (Cp) in
S,S )-9 are practically coplanar and assume a near-to-
[
4g]
(
(
Sp)-1.
p
eclipsed conformation. However, the substituents are Scheme 3. Conjugate addition of diethylzinc to chalcone (11a) to
give 12a.
bonded somewhat asymmetrically. Whereas the P–C2–C1/
All reactions proceeded cleanly, affording either pure al-
kylation product or, in cases of incomplete conversion, its
mixtures with unreacted chalcone. No 1,3-diphenylpent-1-
en-3-ol, the product of direct attack of diethylzinc on the
carbonyl group, was detected. However, the crude reaction
mixtures typically contained traces of 1,3,5-triphenyl-2-(1-
phenylpropyl)pentane-1,5-dione (13). This compound, pre-
sumably arising from a side-reaction of an intermediate zinc
[
18]
enolate (Scheme 4),
was found to crystallise preferen-
tially from the product mixture and was structurally charac-
terised (see the Supporting Information). The amounts of
isolated pure alkylation products were always high: a 91%
yield of analytically pure 12a, for instance, was isolated by
flash column chromatography from the reaction presented
as Entry 1 in Table 1 (conversion 98%).
The results summarised in Table 1 demonstrate that the
reaction course (conversion and ee) changes strongly both
with the metal source and with the solvent. In donor media
the reaction became slow (in MeCN it stopped entirely) and
less selective. However, even the similar halogenated sol-
vents proved to give different results (cf. Entries 1, 10, 11).
On the other hand, the initial oxidation state of copper did
Figure 2. PLATON[17] plot of the molecular structure of (S,S
showing displacement ellipsoids with 30% probability. Selected
distances [Å] and angles [°]: Fe–Cg1 1.6421(7), Fe–Cg2
.6527(7), ЄCp1,Cp2 2.84(9); C1–C11 1.492(2), C11–O1 1.228(2),
)-
p
9
1
C11–N 1.350(2), N–C24 1.449(2), C24–C25 1.520(2), C25–O2 not play any important role, whereas the counterions (En-
1
.196(2), C25–O3 1.342(2), O3–C26 1.451(3), C24–C27 1.537(2), tries 1, 3–8), possibly influencing the solubility (etc.) of the
C27–C28 1.512(3), C2–P 1.817(2), P–C12 1.830(1), P–C18 1.833(2);
O1–C11–N 121.8(1), C11–N–C24 120.5(1), O2–C25–O3 124.3(2),
C25–O3–C26 115.7(1), C–P–C angles 101.84(7)–103.13(7). Defini-
tions: Cp1 = C(1–5), Cp2 = C(6–10); Cg1 and Cg2 are the corre-
sponding ring centroids.
copper source, had a pronounced impact. The selectivity
was also strongly affected by the Cu/L ratio (Entries 1 and
2). Out of the conditions tested, the combination of a cata-
lyst prepared in situ from (CuOTf) ·PhMe (3 mol-% Cu)
2
4278
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Eur. J. Org. Chem. 2010, 4276–4287

Chiral Phosphanylferrocenecarboxamides with Amino Acid Pendant Groups
Table 1. Initial optimisation of the reaction conditions with the ligand (S)-3.[a]
Entry
Metal salt
Solvent
T [°C] (t [h])
Conversion [%]
ee [%][c]
1
2
3
4
5
6
7
8
9
(CuOTf)
(CuOTf)
2
·PhMe
CH
CH
CH
CH
CH
CH
CH
CH
PhMe
CHCl
(ClCH
tBuOMe
Et
2
2
2
2
2
2
2
2
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
2
2
2
2
2
2
2
2
0 (4)
0 (4)
0 (4)
0 (4)
0 (4)
0 (4)
0 (4)
0 (4)
0 (4)
0 (4)
0 (4)
0 (4)
0 (4)
0 (4)
0 (4)
0 (4)
98
92
94
91
87
79
40
93
98
81
75
100
100
57
10
0
+70
+20
+57
+39
+40
+35
+33
+35
+38
+64
+48
+49
+42
+13
+8
[
b]
2
·PhMe
Cu(OTf)
CuCl
CuBr
CuI
2
CuBr·SMe
2
Cu (OAc) ·2H O
2
4
2
(CuOTf)
(CuOTf)
(CuOTf)
(CuOTf)
(CuOTf)
(CuOTf)
(CuOTf)
(CuOTf)
2
2
2
2
2
2
2
2
·PhMe
·PhMe
·PhMe
·PhMe
·PhMe
·PhMe
·PhMe
·PhMe
10
11
12
13
14
15
16
3
2
)
2
2
O
THF
(MeOCH
MeCN
2 2
)
–
[
“
a] All reactions were carried out with 11a (0.50 mmol) and diethylzinc (0.75 mmol, 1  heptane solution) in the presence of 15 µmol of
copper” (3.0 mol-%) and 18 µmol of ligand (S)-3 (3.6 mol-%), in 3 mL of the solvent stated. The results are averages of two independent
runs. [b] Reaction performed at Cu/L = 1:2.4 (molar ratio). [c] ee = {[(R)] – [(S)]}/{[(R)] + [(S)]}; positive values indicate that the (R)
isomer dominates.
Table 2. Survey of the ligands.[a]
Entry
Ligand
T [°C] (t [h])
Conversion [%]
ee [%][c]
1
2
3
4
5
6
7
8
9
(S)-3
(R)-3
(S)-4
(R)-4
(S)-5
(R)-5
0 (4)
0 (4)
0 (4)
0 (4)
0 (4)
0 (4)
0 (4)
0 (4)
0 (4)
0 (4)
0 (4)
0 (4)
0 (4)
0 (4)
0 (4)
98
97
100
100
92
91
86
87
20
14
13
10
32
16
23
+70
–68
+83
–84
+79
–80
–72
–59
–39
–12
+11
–9
(S
p
)-6[
)-6
b]
(S
p
p
(S,S )-7
10
11
12
13
14
15
(R,S
(S,R
p
)-7
)-7
)-8
)-8
)-9
)-9
p
(S,S
(R,S
p
p
–13
–8
–3
(S,S
(R,S
p
p
[
a] All reactions were carried out with 11a (0.50 mmol) and dieth-
ylzinc (0.75 mmol, 1  heptane solution) in the presence of (Cu-
OTf) ·PhMe (7.5 µmol, 3.0 mol-% Cu) and ligand (S)-3 (18 µmol,
.6 mol-%) in CH Cl (3 mL). The results are averages of two runs.
Scheme 4. Plausible reaction pathway leading to the side-product
3.
2
1
3
2
2
[
[
b] Reaction performed at Cu/L molar ratio = 1:2.4. [c] ee = {[(R)] –
(S)]}/{[(R)] + [(S)]}.
and 1.2 equiv. of ligand in dichloromethane as the solvent
gave the best results and was therefore used in all subse-
quent reactions.
Quite unexpectedly, the planar chiral amides proved to
Having established the optimal reaction conditions, we be rather poor ligands, with the single exception of the steri-
continued with the assessment of the influence of the ligand cally least congested (S )-6 (Entry 7). No improvement was
p
structure on the reaction course (Table 2). The application observed when the amount of ligand was increased to
of all of the Hdpf-based ligands (Entries 1–6) resulted in 2.4 equiv. (Entry 8). This is rather surprising in view of the
good levels of conversion and enantioselectivity. However, high efficiency of the related (non-amino acid) ligands in
[
4g,5]
a distinct positive effect of the size of the amino acid sub- Pd-catalysed asymmetric allylic alkylations
and of the
stituent on the ee was noted: ligands bearing bulkier groups successful application of C- and planar-chiral ferrocenediyl-
gave better results. Accordingly, the best results were ob- diphosphanes in Cu-catalysed conjugate additions of Grig-
[
1f,1j]
tained with the valine-based donors (S)-4 and (R)-4, which nard reagents to enones.
gave rise to active catalysts affording the alkylation prod- Another series of catalytic tests was performed with li-
ucts with complete conversion at 0 °C within 4 h and with gand (S)-4 in order to establish possible effects of the reac-
ee values of +83 or –84% depending on the configurations tion temperature and chalcone substituents. The former pa-
of the amino acid chirality centres.
rameter was varied in the model system involving 11a. For
Eur. J. Org. Chem. 2010, 4276–4287
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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4279

ˇ
J. Tauchman, I. Císa rˇ ová, P. St eˇ pni cˇ ka
FULL PAPER
the latter purpose, six additional substituted chalcones 11b– Coordination Study
g were included in the testing, each bearing a substituent
In attempts to interpret the catalytic results, the interac-
(
Cl, Me, or MeO) in the 4- or 4Ј-position, where its influ-
tion of copper(I) triflate with 2 as a model donor in solu-
ence can be expected to be limited mainly to electronic ef-
fects (Scheme 5).
1
31
1
tion and in the solid state was studied. H and P{ H}
NMR spectra recorded in CD Cl for a mixture of 2 and
2
2
(
CuOTf) ·PhMe at a Cu/L molar ratio of 1:0.9 indicated
2
the presence of two species with chemical shifts δ = –10.8
P
and –4.2 ppm (Figure 3). The signal due to free ligand (δP
=
–17.1 ppm) was not observed. With a change in the Cu/
L ratio to 1:2 the high-field signal became dominant (δ =
P
–
11.0 ppm), and a minor resonance tentatively attributed
[
4a]
to ligand phosphane oxide
appeared (δ = +32.2 ppm).
P
Electrospray mass spectra of both mixtures revealed the
+
Scheme 5. Conjugate additions of diethylzinc to ring-substituted presence of ions attributable to [2 + H] (m/z = 486), [2 +
+
+
+
chalcones.
Na] (m/z = 508), [2 + K] (m/z = 524), [2 + Cu] (m/z =
+
5
48) and [(2) + Cu] (m/z = 1033).
2
As indicated by the results in Table 3, the lowering of the
reaction temperature to –20 °C did not decrease the reac-
tion rates (conversion) considerably but, surprisingly, had a
[19]
negative effect on enantioselectivity. At –40 °C the reac-
tions became not only rather slow but also even less selec-
tive (Entries 5 and 6). On the other hand, the alkylation
performed at 20 °C was complete within 4 h and produced
12a with 87% ee (Entry 2). An increase in the reaction tem-
perature by another 20 °C (Entry 1) finally led to a lower
ee value.
Table 3. Influence of the reaction temperature and remote substitu-
ents.[
a]
Entry Substrate
T [°C] (t [h]]
Conversion [%]
ee [%][c]
1
2
3
4
5
6
7
8
9
11a
11a
11a
11a
11a
11a
11b
11c
11d
11e
11f
+40 (4)
+20 (4)
0 (4)
–20 (4)
–40 (4)
–40 (23)
0 (4)
0 (4)
0 (4)
0 (4)
0 (4)
100
100
100
100
41
100
100
100
100
100
100
100
+82
+87
+83
+79
+70
+64
(90)[
(87)[
[
b]
Figure 3. 31P{ H} NMR spectra of (CuOTf)
1
·PhMe/2 mixtures as
2 2
Cl at 25 °C and (a) 1:0.9, or (b) 1:2 Cu/L molar
2
recorded in CD
ratios.
d]
d]
[
d]
d]
d]
d]
(90)
Addition of hexane to a solution of (CuOTf)
·PhMe and
2
1
1
1
0
1
2
(89)[
(83)[
(85)[
2 (Cu/L = 1:1, sic!) in CH Cl afforded yellow crystals of
2
2
the solvated complex [Cu(2) ](TfO). Unfortunately, these
2
11g
0 (4)
crystals readily decomposed by desolvation, and the deter-
mined structure suffered from severe disorder. With a
[
(
a] The reactions were performed with the corresponding chalcone
0.50 mmol) and diethylzinc (0.75 mmol, 1  heptane solution) in
the presence of (CuOTf) ·PhMe (7.5 µmol, 3.0 mol-% Cu) and li-
gand (S)-4 (18 µmol, 3.6 mol-%) in dry CH Cl (3 mL). The results
change in the solvent to CHCl , the same complex was iso-
3
2
lated as a slightly more stable CHCl solvate, [Cu(2) ](TfO)·
3
2
2
2
are averages of two independent runs. [b] This entry from Table 2 2CHCl
(14). Even in this case, the solvent and the counter-
3
is included for comparison. [c] ee = {[(R)] – [(S)]}/{[(R)] + [(S)]}.
ion are disordered in the solid state, but the better quality
and higher stability of the crystals allowed for the collection
of good-quality diffraction data and, consequently, for ob-
[d] The configuration was not determined.
Previous studies on the influence of remote substituents taining a reliable structural model.
in conjugate additions to chalcones had given diverse re- A view of the cation in the structure of 14 is shown in
[
20]
sults. In the present case, the introduction of a substitu- Figure 4 (for a “full” view, see the Supporting Information).
ent at the 4- or 4Ј-position in the substrate (Table 3, En- Selected geometric data are presented in Table 4. The cop-
tries 3 and 7–12) influenced the stereoselectivity only mar- per(I) ion is surrounded by two phosphorus atoms and two
ginally, irrespective of the point of attachment. Nonetheless, amide oxygen atoms making up a distorted tetrahedron.
the substrates with electron-donating groups (Me and The Cu–donor distances are quite uniform and somewhat
I
MeO) consistently afforded better results than those bear- longer than those reported for a Cu complex with a doubly
ing chlorine as an electron-withdrawing substituent.
(2-Ph PC H )NHCOCH -functionalised
calix[4]arene
2
6
4
2
4280
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 4276–4287

Chiral Phosphanylferrocenecarboxamides with Amino Acid Pendant Groups
forming an identical donor set.[21] On the other hand, the (see φ angles). Notably, the amide C=O distances in 14 are
interligand angles span a rather wide range (ca. 85–124°) only very slightly elongated in relation to that found for
[4a]
and clearly reflect steric demands of the donor moieties: the uncoordinated Ph PfcCONHCH CO tBu [1.235(2) Å].
2
2
2
O11–Cu–O21 angle is the most acute, whereas the P1–Cu–
The complex was also characterised in solution. The
P2 angle represents the maximum.
NMR spectra recorded for [Cu(2) ](OTf) generated in situ
2
indicate that the O,P-coordination remains intact, showing
the 31P NMR signal (∆δ ≈ +6 ppm) and the amide reso-
P
nance [∆δ (CONH) ≈ +2 ppm] shifted to lower fields.
C
Furthermore, IR spectra of a solid sample suggest a coordi-
nated C=O group (the amide ν
4
band is shifted by ca.
C=O
0 cm–1 to lower energies vs. that of free 2; the ester νC=O
band remains practically unaffected) and corroborate the
presence of the triflate anion (strong bands at 1165–1295
–
1 [22]
and 1029 cm ).
Electrospray mass spectra confirm the
+
formulation, showing the [Cu(2) ] ion at m/z = 1033 with
2
the corresponding accurate mass and isotopic patterns.
Conclusions
Phosphanylferrocenecarboxamides with amino acid pen-
dant groups, readily available in extensive libraries from
phosphanylferrocenecarboxylic acids and amino acids as a
common chiral pool, were shown to be efficient ligands for
copper-catalysed asymmetric conjugate additions of dieth-
Figure 4. PLATON[17] plot of the cation in the structure of 14
showing atom labelling. (Note: The ligand “molecules” are labelled
analogously. Atomic labels for “ligand 2” are obtained by adding ylzinc to chalcones. In the series of ligands tested, the do-
0 for the carbon atoms or by changing the first digit to 2 for other nors based on Hdpf proved to be superior to their planar-
5
heavy atoms.) Displacement ellipsoids correspond to 20% prob-
ability level. For clarity, only pivotal carbon atoms in the phenyl
rings and one orientation of the disordered phenyl ring C(62–67)
are shown. Carbon atoms that are stereogenic (i.e., substituted) in
chiral ligands are circled (C24 and C74).
chiral 1,2-counterparts, providing both high reactivity and
enantioselectivity under convenient reaction conditions.
The alkylation of unsubstituted chalcone (11a) in the pres-
ence of -valine–Hdpf conjugate (S)-4, for instance, af-
forded the alkylation product with 100% conversion (20 °C/
4
h; 3 mol-% Cu) and 87% ee. With 11d as the substrate,
the same catalytic system also achieved the highest selectiv-
ity (er 95:5 at 0 °C/4 h).
Table 4. Selected distances [Å] and angles [°] for the cation in the
structure of complex 14.[
a]
The particular combination of hard and soft donor
atoms allows the phosphanyl amides to bind (principally)
to both metal atoms involved in the reaction (Cu and Zn)
and to act as O,P-chelate ligands. It is the chelate coordina-
tion that plays a key role in determining catalytic efficacy,
because it results in the formation of rigid structures and
brings the ligand’s chirality into proximity to the catalyti-
cally active metal centre. Furthermore, the data suggest that
the addition of the phosphanyl amide ligands to copper(I)
Cu–P1
Cu–O11
P1–Cu–P2
P1–Cu–O11
P1–Cu–O21
C11–O11
C11–N1
2.244(1) Cu–P2
2.201(2) Cu–O21
124.38(4) O11–Cu–O21
113.74(8) P2–Cu–O21
113.52(8) P2–Cu–O11
1.251(4) C61–O21
1.332(5) C61–N2
2.275(1)
2.135(2)
84.72(9)
115.77(8)
94.98(7)
1.248(3)
1.326(3)
122.0(2)
1.198(5)
1.337(5)
1.640(2)
1.642(2)
1.5(2)
O11–C11–N1
C25–O12
C25–O13
120.7(4) O21–C61–N2
1.197(6) C75–O22
1.327(5) C75–O23
P
P
Fe–Cg (1)
1.642(2) Fe–Cg (2)
C
C
triflate affords an equilibrium mixture of cationic species of
Fe–Cg (1)
1.646(2) Fe–Cg (2)
+
P
C
P
C
the type [CuL ] (n = 0–2), the exact composition of which
ѯCp (1),Cp (1)
4.2(2)
69.5
16.0(5)
ѯCp (2),Cp (2)
τ(2)
φ(2)
n
+
τ(1)
φ(1)
68.4
15.0(3)
changes with the Cu/L molar ratio. Whereas the [CuL ]
2
+
cation is probably the most stable (isolable), the [CuL] spe-
a] Definitions: CpP and Cp are PPh
C
- and amide-substituted Cp cies appears to be a likely precursor to the catalytically
[
2
P
C
rings, respectively; Cg and Cg denote their ring centroids; τ(1/2)
active species. On the other hand, the available data do not
allow for any conclusion with regard to the nature of the
true catalytic species or substrate–catalyst interactions.
P
C
=
torsion angles C(1/51)–Cg (1/2)–Cg (1/2)–C(6/56); φ = dihedral
C
angles of the Cp and amide planes (N1–C11–O11 and N2–C61–
O21).
The geometry of the ferrocene units in 14 is regular (cf.
Fe–Cg distances and tilt angles). The chelate coordination
Experimental Section
of 2 is facilitated by a synclinal eclipsed orientation of the
Materials and Methods: All syntheses were performed under argon
[12a]
[13a]
donor substituents (cf. ideal value: τ = 72°) and by an incli- and with exclusion of direct daylight. Hdpf,
(S )-1,
p
(R )-
p
nation of the amide oxygen atom towards the copper atom 1,[
13b] [4a]
2
and 11b–g
[23]
were prepared by literature procedures.
Eur. J. Org. Chem. 2010, 4276–4287
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4281

ˇ
J. Tauchman, I. Císa rˇ ová, P. St eˇ pni cˇ ka
FULL PAPER
Amino acid methyl ester hydrochlorides – [H
3
NCH(R)CO
2
Me]Cl
(CH
3
CH), 52.42 (OMe), 69.50 (CH fc), 71.76 (d, JP,C = 1 Hz, CH
(
R = H, Me, iPr, CH
2
Ph) – were obtained by treatment of the
fc), 71.82 (d, JP,C = 1 Hz, CH fc), 72.90 (d, JP,C = 4 Hz, CH fc),
amino acid in question with methanol and thionyl chloride (see the
Supporting Information).[ The racemic ketones 12a–g used for
optimisation of the HPLC conditions were synthesised as described
in the literature. Anhydrous acetonitrile and tBuOMe were pur-
chased from Fluka. Other solvents (Lach-Ner) were dried by stand-
73.05 (d, JP,C = 4 Hz, CH fc), 74.30 (d, JP,C = 13 Hz, CH fc), 74.44
24]
3
(d, JP,C = 15 Hz, CH fc), 75.97 (CCONH fc), 128.26 (d, JP,C
=
7 Hz, CH PPh
2
), 128.70 (CH PPh
2
), 128.72 (CH PPh
2
), 133.36 (d,
), 133.55 (d, JP,C = 3 Hz, CH PPh ), 138.35
), 138.49 (d, JP,C = 10 Hz, Cipso PPh ),
169.53 (CONH), 173.65 (CO Me) ppm; the signal due to CP of fc
; diethyl ether, 1,2-dimethoxyethane, THF, was not found. P{ H} NMR (CDCl ): δ = –17.0 (s) ppm. IR
[
25]
2
2
J
P,C = 3 Hz, CH PPh
2
2
1
1
(d, JP,C = 10 Hz, Cipso PPh
2
2
ing over appropriate drying agents (CH
ClCH CH Cl: K CO
2
Cl
2
,
CHCl
3
,
and
2
3
1
1
2
2
2
3
3
and toluene: sodium) and distilled under argon. Other chemicals
were obtained from commercial sources (Fluka, Aldrich, Alfa) and
were used as received. NMR spectra were measured with a Varian
(Nujol): ν˜ max = 3325 (s, νNH), 1743 (vs., νCO), 1632 (vs., amide I),
1530 (vs., amide II), 1305 (s), 1266 (w), 1214 (m), 1193 (m), 1175
(m), 1161 (m), 1055 (w), 1027 (m), 834 (w), 743 (s), 697 (s), 569
1
13
31
–1
+·
UNITY Inova 400 spectrometer ( H, 399.95; C, 100.58; P, (w), 488 (m), 451 (w) cm . EI MS: m/z (%) = 499 (15) [M] , 412
+
1
61.90 MHz) at 298 K. Chemical shifts (δ/ppm) are given relative to
(5) [M – CH(Me)CO
(9), 256 (5), 201 (9) [Ph
(30), 129 (5), 111 (5), 105 (11), 83 (100), 73 (10) [CH
2
Me] , 321 (4) [Fe(C
5
H
4
PPh
2
)O], 305 (2), 279
1
13
+
+
internal tetramethylsilane ( H and C) or to external 85% aqueous
H
spectrometer (Thermo Fisher Scientific) in the 400–4000 cm
PO] , 183 (5) [Ph P – 2 H] , 167 (8), 149
2 2
31
+
3
PO
4
( P). IR spectra were recorded with a Nicolet 7600 FTIR
2
CO
2
Me] , 69
–
1
(24), 57 (32). HR MS: calcd. for C27
499.1008.
H26NO PFe 499.0999; found
3
range. Electron impact mass spectra (EI MS), including high-reso-
lution (HR) measurements, were performed with a GCT Premier
1
-(Diphenylphosphanyl)-1Ј-{N-[(R)-1-(methoxycarbonyl)ethyl]carb-
amoyl}ferrocene [(R)-3]: The above procedure, starting with Hdpf
207 mg, 0.50 mmol), HOBt (82 mg, 0.60 mmol), EDC (0.11 mL,
.60 mmol), (R)-[H NCH(CH )CO Me]Cl (97 mg, 0.69 mmol) and
Et N (0.11 mL, 0.80 mmol), gave the amide (R)-3 as an orange
solid (225 mg, 90%). The NMR spectroscopic data for (R)-3 were
identical to those of the corresponding (S) isomer. [α] = –9 (c =
(Waters) spectrometer. Electrospray mass spectra (ESI MS) were
obtained with an Esquire 3000 (Bruker; low resolution) or an LTQ
Orbitrap XL instrument (Thermo Fisher Scientific; high resolu-
tion). CD spectra were recorded with a JASCO J-815 spectrometer
(
0
3
3
2
3
(ca. 1 m solutions in methanol, d = 1 mm). Optical rotations were
determined with an Autopol III (Rudolph Research) automatic po-
larimeter at room temperature.
D
0.5, CHCl
3
).
Preparation of the Ligands
1
-(Diphenylphosphanyl)-1Ј-{N-[(S)-1-(methoxycarbonyl)-2-methyl-
General Procedure for the Preparation of Amides 2–9: A two-necked
flask fitted with a gas inlet and containing a stirrer bar was charged
with the appropriate acid (1.0 equiv.) and 1-hydroxybenzotriazole
prop-1-yl]carbamoyl}ferrocene [(S)-4]: The General Procedure,
starting with Hdpf (414 mg, 1.0 mmol), HOBt (170 mg,
1.26 mmol), EDC (0.22 mL, 1.20 mmol), (S)-[H
CO Me]Cl (203 mg, 1.21 mmol) and Et N (0.21 mL, 1.49 mmol),
= –5 (c =
): δ = 0.97 (d, JH,H = 6.8 Hz, 3 H,
), 2.24 (d of sept,
), 3.72 (s, 3 H, OMe), 4.11 (dq, J
3 2
NCH(CHMe )
(HOBt, 1.2 equiv.). The reaction vessel was flushed with argon and
2
3
sealed with a septum. Dry dichloromethane (10 mL per 1.0 mmol
of the acid) was introduced, and the mixture was stirred for 5 min
in an ice bath. Neat N-[3-(dimethylamino)propyl]-NЈ-ethylcarbodii-
mide (EDC, 1.2 equiv.) was added, and the reaction mixture was
stirred in an ice bath for another 30 min. Another mixture, pre-
pared separately by mixing the corresponding amino acid methyl
ester hydrochloride (1.2 equiv.), dry triethylamine (ca. 1.4 equiv.)
and dichloromethane (10 mL per 1.0 mmol of the hydrochloride),
was then introduced. After stirring at room temperature overnight,
the reaction mixture was washed successively with aqueous citric
provided (S)-4 as an orange solid (496 mg, 94%). [α]
D
1
3
0.5, CHCl
CHMe
3
). H NMR (CDCl
3
3
2
), 1.0 (d,
JH,H = 6.8 Hz, 3 H, CHMe
2
3
JH,H = 4.9, 6.8 Hz, 1 H, CHMe
2
= 1.2, 3.1 Hz, 1 H, fc), 4.22 (m, 2 H, fc), 4.25 (dq, J = 1.2, 3.1 Hz,
1 H, fc), 4.43 (dt, J = 1.2, 2.4 Hz, 1 H, fc), 4.47 (dt, J = 1.2, 2.4 Hz,
1 H, fc), 4.55 (dt, J = 1.5, 2.2 Hz, 1 H, fc), 4.60 (dt, J = 1.5, 2.3 Hz,
3
3
1 H, fc), 4.66 (dd, JH,H = 4.9, 8.8 Hz, 1 H, NHCH), 6.25 (d, JH,H
1
3
1
= 8.7 Hz, 1 H, NH), 7.29–7.41 (m, 10 H, PPh
NMR (CDCl ): δ = 17.99 (CHMe ), 19.21 (CHMe
(CHMe ), 52.15 (OMe), 56.98 (NHCH), 69.25 (CH fc), 69.69 (d,
P,C = 1 Hz, CH fc), 71.79 (d, JP,C = 1 Hz, CH fc), 71.83 (d, JP,C =
2
) ppm. C{ H}
3
2
2
), 31.17
acid (10%), saturated NaHCO
3
and brine. The organic layer was
2
dried with MgSO , and the solvents were removed under vacuum.
4
J
The residue was purified by column chromatography on silica gel
with dichloromethane/methanol (20:1) as the eluent. In the cases
1 Hz, CH fc), 72.92 (d, JP,C = 3 Hz, CH fc), 73.12 (d, JP,C = 4 Hz,
CH fc), 74.13 (d, JP,C = 13 Hz, CH fc), 74.43 (d, JP,C = 15 Hz, CH
3
of (R,S
p
)-6, (R,S
p
)-7 and (R,S
p
)-8, the crude reaction product was
)-10. This ester was easily sepa-
fc), 76.25 (CCONH fc), 128.24 (2ϫd,
128.68 (CH PPh ), 128.74 (CH PPh
2
JP,C = 7 Hz, CH PPh ),
2
contaminated with unreacted (S
p
2
2
), 133.34 (d, JP,C = 7 Hz, CH
2
1
rated from the amide (major component) by column chromatog-
raphy on silica gel (dichloromethane/methanol, 50:1).
PPh
2
), 133.54 (d, JP,C = 7 Hz, CH PPh
2
), 138.30 (d, JP,C = 9 Hz,
), 138.49 (d, JP,C = 9 Hz, Cipso PPh ), 169.99 (CONH),
72.72 (CO Me) ppm; the CP of fc was not found. P{ H} NMR
CDCl ): δ = –17.1 (s) ppm. IR (neat): ν˜ max = 3335 (m, νNH), 1742
vs., νCO), 1652 (vs., amide I), 1521 (vs., amide II), 1434 (s), 1309
m), 1259 (w), 1193 (m), 1163 (s), 1093 (w), 1067 (w), 1027 (m),
1
Cipso PPh
2
2
3
1
1
1
2
1
-(Diphenylphosphanyl)-1Ј-{N-[(S)-1-(methoxycarbonyl)ethyl]carb-
amoyl}ferrocene [(S)-3]: The General Procedure, starting with Hdpf
414 mg, 1.0 mmol), HOBt (165 mg, 1.20 mmol), EDC (0.21 mL,
.20 mmol), (S)-[H NCH(CH )CO Me]Cl (170 mg, 1.20 mmol)
and Et N (0.20 mL, 1.42 mmol), afforded the amide (S)-3 as an
orange solid (474 mg, 95%). [α]
(
(
(
3
(
1
3
3
2
–1
9
99 (w), 833 (m), 744 (s), 697 (s), 492 (m), 451 (w) cm . EI MS:
m/z (%) = 527 (26) [M] , 496 (3) [M – OMe] , 412 (41) [M –
3
+·
+
1
D
= +10 (c = 0.5, CHCl
): δ = 1.47 (d, JH,H = 7.2 Hz, 3 H, CH CH), 3.75 (s, 3 H,
OMe), 4.09 (dq, J = 1.2, 3.2 Hz, 1 H, fc), 4.21 (m, 2 H, fc), 4.24
dq, J = 1.2, 3.2 Hz, 1 H, fc), 4.44 (dt, J = 1.2, 2.4 Hz, 1 H, fc),
.47 (dt, J = 1.2, 2.4 Hz, 1 H, fc), 4.55 (dt, J = 1.3, 2.6 Hz, 1 H,
3
). H NMR
+
+
CH(CHMe
2
)CO
2
Me] , 397 (4) [M – NHCH(CHMe
PPh )O], 305 (6), 250 (4), 226 (4), 201 (29)
PO] , 183 (7) [Ph P – 2 H] , 171 (9), 121 (5) [Fe(C
100). HR MS: calcd. for C29 PFe 527.1313; found
27.1300.
2 2
)CO Me] ,
3
(
CDCl
3
3
3
21 (20) [Fe(C
5
H
4
2
+
+
+
[Ph
2
2
5 5
H )] , 83
(
4
(
5
H30NO
3
3
fc), 4.62 (dt, J = 1.3, 2.6 Hz, 1 H, fc), 4.69 (p, JH,H = 7.3 Hz, 1
H, CH CH), 6.31 (d, JH,H = 7.4 Hz, 1 H, NH), 7.30–7.41 (m, 10 1-(Diphenylphosphanyl)-1Ј-{N-[(R)-1-(methoxycarbonyl)-2-methyl-
3
3
1
H, PPh
2
) ppm. 13C{ H} NMR (CDCl
3 3
): δ = 18.57 (CH CH), 48.01 prop-1-yl]carbamoyl}ferrocene [(R)-4]: When treated according to
4282
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 4276–4287

Chiral Phosphanylferrocenecarboxamides with Amino Acid Pendant Groups
the General Procedure, Hdpf (207 mg, 0.50 mmol), HOBt (81 mg,
.60 mmol), EDC (0.10 mL, 0.60 mmol), (R)-[H NCH(CHMe )- 71.75 (CH C
CO Me]Cl (117 mg, 0.70 mmol) and Et N (0.11 mL, 0.80 mmol) = 4 Hz, CH C
afforded (R)-4 as an orange solid (251 mg, 95%). The NMR spec-
troscopic data for (R)-4 were identical with those for (S)-4. [α]
4 (c = 0.5, CHCl ).
(CDCl
3
): δ = 41.31 (NHCH
2
), 52.22 (OMe), 70.97 (CH C
), 74.61 (d, JP,C
), 75.48 (d, JP,C = 11 Hz, CP C ), 79.82 (d,
P,C = 20 Hz, CCONH C ), 128.21 (CH PPh ), 128.24 (d, JP,C
= 7 Hz, CH PPh ), 128.37 (d, JP,C = 7 Hz, CH PPh
5 5
H ),
0
3
2
5
H
3
), 73.41 (d, JP,C = 2 Hz, CH C H
5 3
1
2
3
5
H
3
5 3
H
2
3
J
5
H
3
2
3
D
=
2
2
2
2
), 129.71 (CH
+
3
PPh
CH PPh
Hz, Cipso PPh
2
), 131.98 (d, JP,C = 17 Hz, CH PPh
2
), 135.22 (d, JP,C = 21 Hz,
1
1
2
), 136.15 (d, JP,C = 6 Hz, Cipso PPh
), 170.61 (CO Me), 170.73 (d,
CONH) ppm. P{ H} NMR (CDCl ): δ = –20.2 (s) ppm. IR (Nu-
jol): ν˜ max = 3330 (m, νNH), 1750 (vs., νCO), 1640 (vs., amide I), 1532
vs., amide II), 1434 (vs), 1410 (w), 1366 (s), 1279 (m), 1199 (s),
2
), 138.18 (d, JP,C
=
1
-(Diphenylphosphanyl)-1Ј-{N-[(S)-1-(methoxycarbonyl)-2-phenyl-
3
7
2
2
JP, C = 4 Hz,
ethyl]carbamoyl}ferrocene [(S)-5]: The amide (S)-5 was prepared ac-
cording to the General Procedure from Hdpf (414 mg, 1.0 mmol),
HOBt (169 mg, 1.25 mmol), EDC (0.22 mL, 1.25 mmol), (S)-
31
1
3
(
[
H
3
NCH(CH
2 2 3
Ph)CO Me]Cl (262 mg, 1.21 mmol) and Et N
1
8
178 (s), 1107 (m), 1094 (w), 1019 (m), 1003 (m), 987 (w), 940 (w),
44 (w), 821 (m), 744 (s), 698 (s), 563 (w), 486 (s), 463 (w) cm .
(0.20 mL, 1.42 mmol), and was isolated as an orange solid (541 mg,
–1
1
9
4%). [α]
D
= –3 (c = 0.5, CHCl
H,H = 7.1, 2JH,H = 14.0 Hz, 1 H, CH
2JH,H = 14.0 Hz, 1 H, CH
Ph), 3.72 (s, 3 H, OMe), 3.96 (dq, J =
.2, 3.1 Hz, 1 H, fc), 4.15 (dq, J = 1.2, 3.2 Hz, 1 H, fc), 4.17 (m, 2
H, fc), 4.28 (dt, J = 1.2, 2.4 Hz, 1 H, fc), 4.34 (dt, J = 1.2, 2.4 Hz,
3
). H NMR (CDCl
3
): δ = 3.13 (dd,
+·
+
EI MS: m/z (%) = 485 (40) [M] , 454 (5) [M – OMe] , 420 (100)
3
3
J
2
Ph), 3.22 (dd, JH,H = 5.6,
+
+
[
M – C
5
H
5
] , 412 (58) [M – CH
2
CO
2
Me] , 397 (8) [M –
2
+
NHCH
2
CO
2
Me] , 362 (35), 346 (26), 291 (14), 226 (13), 201 (90)
1
+
+
[
[
Ph
Fe(C
2
PO] , 183 (21) [Ph
2
P – 2 H] , 170 (38), 152 (11), 121 (45)
+
2
6
5
H
5
)
]
,
5
5
(
1
5
)
.
H
R
M
S
:
c
a
l
c
d
.
f
o
r
C
H24NO PFe 485.0843;
3
1
1
H, fc), 4.45 (dt, J = 1.3, 2.6 Hz, 1 H, fc), 4.54 (dt, J = 1.3, 2.6 Hz,
found 485.0834.
3
H, fc), 4.99 (ddd, JH,H = 5.5, 7.1, 7.9 Hz, 1 H, NHCH), 6.18 (d,
3
J
H,H = 7.9 Hz, 1 H, NHCH), 7.18–7.35 (m, 15 H, CH
2
Ph + PPh
Ph), 52.33 (OMe),
2.91 (NHCH), 64.06 (CH fc), 69.68 (d, JP,C = 1 Hz, CH fc), 71.80
d, JP,C = 1 Hz, CH fc), 71.82 (d, JP,C = 1 Hz, CH fc), 72.84 (d,
2
)
(
S
p
)-1-(Diphenylphosphanyl)-2-{N-[(S)-1-(methoxycarbonyl)ethyl]-
carbamoyl}ferrocene [(S,S )-7]: The General Procedure, starting
with (S )-1 (414 mg, 1.0 mmol), HOBt (163 mg, 1.20 mmol), EDC
0.21 mL, 1.20 mmol), (S)-[H NCH(CH )CO Me]Cl (170 mg,
N (0.20 mL, 1.42 mmol), afforded the amide
)-7 (orange solid; 379 mg, 76%). [α] = –176 (c = 0.5, CHCl ).
): δ = 1.29 (d, JH,H = 7.3 Hz, 3 H, CH CH), 3.80
), 4.21 (s, 5 H,
ppm. 13C{ H} NMR (CDCl
5
(
1
): δ = 37.96 (CH
3 2
p
p
(
3
3
2
J
1
P,C = 4 Hz, CH fc), 73.07 (d, JP,C = 4 Hz, CH fc), 74.07 (d, JP,C
3 Hz, CH fc), 74.41 (d, JP,C = 15 Hz, CH fc), 75.96 (CCONH fc),
27.18 (CH CH ), 128.26 (d,
Ph), 128.19 (d, 3JP,C = 1 Hz, CH PPh
P,C = 2 Hz, CH PPh ), 128.66 (CH PPh ), 128.67 (CH CH Ph),
28.71 (CH PPh ), 129.21 (CH CH Ph), 133.34 (d, JP,C = 10 Hz,
CH PPh P,C = 10 Hz, CH PPh ), 136.11 (Cipso
), 133.53 (d, 2
CH P,C = 9 Hz, Cipso PPh ), 138.47 (d,
Ph), 138.30 (d, 1
Hz, Cipso PPh ), 169.70 (CONH), 172.28 (CO Me) ppm; the sig-
nal due to CP of fc was not found. P{ H} NMR (CDCl ): δ =
17.2 (s) ppm. IR (Nujol): ν˜ max = 3325 (s, νNH), 1743 (vs., νCO),
633 (vs., amide I), 1532 (vs., amide II), 1305 (m), 1216 (m), 1196
=
1.20 mmol) and Et
3
(
S,S
p
D
3
1
2
2
1
3
H NMR (CDCl
3
3
3
J
2
2
2
(
C
J
7
s, 3 H, OMe), 3.80 (dt, J = 1.2, 2.8 Hz, 1 H, C
), 4.46 (dt, J = 0.5, 2.6 Hz, 1 H, C ), 4.63 (dp, JH,H = 7.3,
P,H = 2.1 Hz, 1 H, CH CH), 5.14 (dt, J = 1.6, 2.6 Hz, 1 H, C ),
.13–7.60 (m, 10 H, PPh ), 7.82 (dd, JH,H = 7.7, JP,C = 12.9 Hz, 1
): δ = 17.87 (CH CH), 48.04
), 71.51 (CH C ), 73.41
), 74.55 (d, JP,C = 2 Hz, CH C ), 75.57
P,C = 20 Hz, CCONH
5 3
H
2
1
2
2
3
5
H
5
5 3
H
2
J
2
3
5 3
H
1
2
J
2
J
P,C
=
3
2
9
2
2
13
1
H, NH) ppm. C{ H} NMR (CDCl
3
3
31
1
3
(
(
(
CH
3
CH), 52.35 (OMe), 70.96 (CH C
5
H
5
5 3
H
–
1
d, JP,C = 2 Hz, CH C
5
H
3
5 3
H
d, 1JP,C = 10 Hz, CP C
2
5
3
H ), 79.83 (d, J
(m), 1161 (m), 1094 (w), 1027 (s), 834 (m), 743 (vs), 698 (vs), 491
3
3
C
5
H
3
), 128.33 (d, JP,C = 6 Hz, CH PPh
2
), 128.41 (d, JP,C = 5 Hz,
–1
+·
+
(s) cm . EI MS: m/z (%) = 575 (48) [M] , 544 (5) [M – OMe] ,
), 132.20 (d, 2JP,C
CH PPh
18 Hz, CH PPh
2 2 2
), 128.47 (CH PPh ), 129.71 (CH PPh
+
+
5
16 (5) [M – CO
2
Me] , 412 (100) [M – CH(CH
2
Ph)CO
2
Me] , 397
), 135.07 (d, 2JP,C = 21 Hz, CH PPh
=
(
2
2
), 135.77
), 137.65 (d, 1JP,C = 7 Hz, Cipso PPh
2 2
),
+
+
(
(
[
12) [M – NHCH(CH
69) [Fe(C
Ph
Fe(C H
5 5
2
Ph)CO
2
Me] , 374 (37) [M – Ph
2
PO] , 321
1
d, JP,C = 6 Hz, Cipso PPh
70.00 (d, 3JP,C = 4 Hz, CONH), 173.78 (CO
2
Me) ppm. P{ H}
+
5
H
4
PPh
2
)O] , 305 (28), 264 (27), 226 (14), 201 (81)
31
1
1
+
+
2
PO] , 183 (20) [Ph
2
P – 2H] , 171 (33), 133 (13), 121 (32)
)] , 109 (15), 93 (33), 65 (25). HR MS: calcd. for
PFe 575.1313; found 575.1319.
NMR (CDCl ): δ = –20.0 (s) ppm. IR (Nujol): ν˜ max = 3290 (w,
NH), 1742 (vs., νCO), 1652 (vs., amide I), 1521 (vs., amide II), 1434
vs), 1340 (w), 1309 (w), 1264 (m), 1215 (m), 1195 (s), 1165 (m),
3
+
[
C
ν
(
33
H30NO
3
1
7
107 (m), 1094 (w), 1069 (w), 1001 (m), 985 (w), 845 (w), 819 (m),
1
-(Diphenylphosphanyl)-1Ј-{N-[(R)-1-(methoxycarbonyl)-2-
phenylethyl]carbamoyl}ferrocene [(R)-5]: Treatment of Hdpf
207 mg, 0.50 mmol), HOBt (81 mg, 0.60 mmol), EDC (0.10 mL,
.60 mmol), (R)-[H NCH(CH Ph)CO Me]Cl (151 mg, 0.70 mmol)
and Et N (0.11 mL, 0.80 mmol) according to the General Pro-
cedure provided (R)-5 as an orange solid (280 mg, 97%). The NMR
spectroscopic data for (R)-5 were identical to those for (S)-5. [α]
+3 (c = 0.5, CHCl ).
–
1
44 (vs), 697 (vs), 545 (w), 498 (s), 484 (s), 456 (m) cm . EI MS:
+
·
+
m/z (%) = 499 (26) [M] , 468 (4) [M – OMe] , 434 (66) [M –
C
(
0
+
+
5
H
5
] , 412 (73) [M – CH(Me)CO
2
Me] , 397 (8) [M – NHCH-
3
2
2
+
(
Me)CO
2
+
Me] , 374 (42), 346 (43), 291 (10), 226 (10), 201 (100)
3
+
[Ph
2
PO] , 183 (18) [Ph
2
P – 2 H] , 170 (37), 152 (6), 133 (8), 121
)] , 115 (6), 100 (6), 83 (38), 77 (8), 56 (17). HR MS:
+
(
38) [Fe(C
5
H
5
D
3
calcd. for C27H26NO PFe 499.0999; found 499.0981.
=
3
(
S
p
)-1-(Diphenylphosphanyl)-2-{N-[(methoxycarbonyl)methyl]carb-
amoyl}ferrocene [(S )-6]: The above procedure, starting with (S )-
Hpfc (414 mg, 1.0 mmol), HOBt (163 mg, 1.20 mmol), EDC
0.21 mL, 1.20 mmol), (H NCH CO Me)Cl (151 mg, 1.20 mmol) 0.60 mmol), EDC (0.11 mL, 0.60 mmol), (R)-[H
and Et N (0.20 mL, 1.42 mmol), yielded the amide (S )-6 as an CO Me]Cl (84 mg, 0.60 mmol) and Et N (0.10 mL, 0.71 mmol).
orange solid (354 mg, 73 %). [α] = –177 (c = 0.5, CHCl Isolation by column chromatography afforded (R,S )-7 as an
NMR (CDCl ): δ = 3.75 (s, 3 H, OMe), 3.87 (m, 1 H, C ), 3.95 orange solid (170 mg, 68%). Some (S )-10 was also isolated. Ana-
), 4.18 lytical data for (R,S )-7. [α] = –153 (c = 0.5, CHCl
): δ = 1.46 (d, JH,H = 7.2 Hz, 3 H, CH CH), 3.60 (s, 3 H,
), 5.16 (dt, J = OMe), 3.81 (m, 1 H, C ), 4.16 (s, 5 H, C ), 4.45 (dt, J = 0.5,
), 7.73 (apparent 2.6 Hz, 1 H, C ), 4.71 (dp, H,H = 7.3, JP,H = 1.5 Hz, 1 H,
CH), 5.06 (dt, J = 1.4, 2.8 Hz, 1 H, C ), 7.14–7.60 (m, 11
(S
carbamoyl}ferrocene [(R,S
described above, from (S
p
)-1-(Diphenylphosphanyl)-2-{N-[(R)-1-(methoxycarbonyl)ethyl]-
)-7]: The amide (R,S )-7 was prepared as
)-1 (207 mg, 0.50 mmol), HOBt (81 mg,
NCH(CH )-
p
p
p
p
p
(
3
2
2
3
3
3
p
2
3
1
D
3
). H
p
3
5
H
3
p
ddd, JP,H = 0.8, 3JH,H = 4.9, JH,H = 18.2 Hz, 1 H, NHCH
2
1
(
(
2
p
D
3
). H NMR
), 4.30 (ddd, JP,H = 1.3, 3JH,H = 6.2, JH,H = 18.2 Hz, (CDCl
), 4.49 (dt, J = 0.5, 2.6 Hz, 1 H, C
.6, 2.6 Hz, 1 H, C ), 7.10–7.65 (m, 10 H, PPh
H,H ≈ 6 Hz, 1 H, NH) ppm. C{ H} NMR CH
2
3
s, 5 H, C
5
H
5
3
3
1
1
H, NHCH
2
5
H
3
5
H
3
5 5
H
3
5
H
3
2
13
5
H
3
J
dt, JP,C ≈ 12, 3
J
1
3
5 3
H
Eur. J. Org. Chem. 2010, 4276–4287
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4283

ˇ
J. Tauchman, I. Císa rˇ ová, P. St eˇ pni cˇ ka
FULL PAPER
) ppm. 13C{ H} NMR (CDCl
1
): δ = 18.75 (CH
), 71.42 (CH C
), 74.53 (d, JP,C = 5 Hz, CH C
CH), 0.60 mmol), EDC (0.11 mL, 0.60 mmol), (R)-[H
NCH(CHMe
N (0.10 mL, 0.71 mmol),
p
)-8 (orange solid; 169 mg, 64%). Some unre-
H, NH + PPh
2
3
3
3
2
)-
4
7
7
8.19 (CH
3.05 (d, JP,C = 2 Hz, CH C
6.25 (d, 1
P, C = 12 Hz, CP C
), 128.18 (CH PPh
3
CH), 52.21 (OMe), 70.92 (CH C
5
H
5
5
H
H
3
),
), afforded amide (R,S
p
acted (S )-10 was also isolated. Analytical data for (R,S )-8. [α]
2 3
CO Me]Cl (101 mg, 0.60 mmol) and Et
5
H
3
5
3
J
5
H
3
), 80.24 (d, 2
J
P,C = 18 Hz,
p
D
3
1
3
CCONH C
PPh ), 128.31 (d, JP,C = 7 Hz, CH PPh
32.18 (d, JP,C = 18 Hz, CH PPh
PPh
5
H
3
2
), 128.21 (d, JP,C = 6 Hz, CH = –151 (c = 0.5, CHCl
3
). H NMR (CDCl
3
): δ = 1.03 (d, JH,H
), 1.06 (d, JH,H = 6.9 Hz, 3 H, CHMe
(dsept, JH,H = 4.8, 6.8 Hz, 1 H, CHMe ), 3.43 (s, 3 H, OMe), 3.85
(m, 1 H, C ), 4.13 (s, 5 H, C ), 4.46 (dt, J = 0.5, 2.6 Hz, 1 H,
), 4.63 (ddd, JP,H = 2.0, JH,H = 4.8, 8.6 Hz, 1 H, NHCH),
5.15 (dt, J = 1.6, 3.0 Hz, 1 H, C ), 7.12–7.60 (m, 11 H, NH +
): δ = 18.10 (CHMe ), 19.31
), 51.71 (OMe), 57.56 (NHCH), 70.80
=
3
3
2
2
), 129.54 (CH PPh
2
), 6.9 Hz, 3 H, CHMe
2
2
), 2.27
2
), 135.19 (d, 2JP,C = 21 Hz, CH
3
1
2
2
), 136.65 (d, 1JP,C = 9 Hz, Cipso PPh
), 138.50 (d, JP,C = 7 Hz,
1
H
2
2
5
3
5 5
H
C
ipso PPh
2
1
), 169.71 (d, 3JP,C = 4 Hz, CONH), 173.33 (CO
2
Me)
5 3
C H
3
ppm. 31P{ H} NMR (CDCl
): δ = –20.0 (s) ppm. IR (Nujol): ν˜ max
3
5 3
H
1
3
1
=
3325 (w, νNH), 1746 (vs., νCO), 1624 (vs., amide I), 1521 (vs., PPh
2
) ppm. C{ H} NMR (CDCl
), 30.88 (CHMe
), 71.59 (CH C
74.50 (d, JP,C = 4 Hz, CH C
3
2
amide II), 1265 (w), 1193 (m), 1155 (s), 1106 (w), 1050 (w), 1002 (CHMe
2
2
–
1
(w), 909 (w), 819 (m), 743 (vs), 698 (vs), 489 (s), 466 (w) cm . EI (CH C
5
H
5
5
H
3
), 73.64 (d, JP,C = 2 Hz, CH C
), 75.45 (d, JP,C = 11 Hz, CP C
5
H
H
3
),
),
+
·
+
1
MS: m/z (%) = 499 (21) [M] , 468 (5) [M – OMe] , 434 (69) [M –
5
H
3
5
3
+
+
2
C
(
(
5
H
5
] , 412 (64) [M – CH(Me)CO
2
Me] , 397 (8) [M – NHCH- 80.72 (d, JP,C = 20 Hz, CCONH C ), 128.16 (CH PPh
5
H
3
2
), 128.19
P,C = 9 Hz, CH PPh ),
), 132.06 (d, JP,C = 17 Hz, CH PPh ), 135.24 (d,
P,C = 21 Hz, CH PPh ),
), 136.26 (d, 1JP,C = 7 Hz, Cipso PPh
P,C = 7 Hz, Cipso PPh P, C = 4 Hz,
), 170.24 (d, 3
): δ = –20.0
s) ppm. IR (neat): ν˜ max = 3305 (m, νNH), 1745 (vs., νCO), 1656 (vs.,
amide I), 1525 (vs., amide II), 1435 (vs), 1311 (m), 1267 (m), 1206
m), 1161 (m), 1107 (w), 1093 (w), 1069 (w), 1027 (m), 1003 (m),
23 (s), 752 (vs), 699 (vs), 666 (w), 646 (w), 613 (w), 501 (s), 485
+
3
3
Me)CO
84) [Ph
2
Me] , 374 (38), 346 (33), 291 (8), 247 (8), 226 (8), 201
(d,
J
P,C = 6 Hz, CH PPh
129.68 (CH PPh
2
), 128.33 (d,
J
2
+
+
2
2
PO] , 183 (14) [Ph
2
P – 2 H] , 170 (25), 149 (21), 121 (36)
)] , 111 (19), 97 (34), 81 (44), 69 (95), 57 (100). HR MS:
calcd. for C27 PFe 499.0999; found 499.1010.
2
2
+
2
[Fe(C
5
H
5
J
2
2
1
H26NO
3
138.26 (d,
J
2
1
J
3
1
2 3
CONH), 172.01 (CO Me) ppm. P{ H} NMR (CDCl
(
R
p
)-1-(Diphenylphosphanyl)-2-{N-[(S)-1-(methoxycarbonyl)ethyl]-
carbamoyl}ferrocene [(S,R )-7]: The amide (R,S )-7 was prepared
as described above, from (R )-1 (69 mg, 0.17 mmol), HOBt (27 mg,
.20 mmol), EDC (0.03 mL, 0.20 mmol), (S)-[H NCH(CH
CO Me]Cl (30 mg, 0.22 mmol) and Et N (0.03 mL, 0.25 mmol).
Yield: 52 mg (63%) of an orange solid. The NMR spectroscopic
data were identical to those for (R,S )-7. [α] = +156 (c = 0.5,
CHCl ).
(
p
p
p
(
8
(
0
3
3
)
2
3
–1
+·
s), 461 (m) cm . EI MS: m/z (%) = 527 (26) [M] , 496 (10) [M –
+
+
OMe] , 481 (10), 462 (27) [M – C
5
H
5
] , 412 (18) [M – CH(CHMe
2
)-
p
D
+
+
CO
2
Me] , 402 (16), 397 (4) [M – NHCH(CHMe
2
)CO
2
Me] , 346
3
+
+
(
1
11), 201 (23) [Ph
2
PO] , 183 (7) [Ph
2
P – 2 H] , 170 (8), 165 (16),
)] , 97 (22), 83 (100), 69 (53), 57 (81).
PFe 527.1313; found 527.1321.
+
5 5
49 (13), 121 (12) [Fe(C H
(S
p
)-1-(Diphenylphosphanyl)-2-{N-[(S)-1-(methoxycarbonyl)-2-meth-
ylprop-1-yl]carbamoyl}ferrocene [(S,S )-8]: The General Procedure,
with (S )-1 (207 mg, 0.50 mmol), HOBt (81 mg, 0.60 mmol), EDC
0.11 mL, 0.60 mmol), (S)-[H NCH(CHMe )CO Me]Cl (101 mg,
N (0.10 mL, 0.71 mmol), yielded the amide
)-8 as an orange solid (198 mg, 75%). [α] = –195 (c = 0.5,
): δ = 0.64 (d, JH,H = 6.9 Hz, 3 H,
HR MS: calcd. for C29
H
30NO
3
p
p
(
S
p
)-1-(Diphenylphosphanyl)-2-{N-[(S)-1-(methoxycarbonyl)-2-
phenylethyl]carbamoyl}ferrocene [(S,S )-9]: Treatment of (S )-1
207 mg, 0.50 mmol), HOBt (81 mg, 0.60 mmol), EDC (0.11 mL,
0.60 mmol), (S)-[H NCH(CH Ph)CO Me]Cl (131 mg, 0.61 mmol)
and Et N (0.10 mL, 0.71 mmol) according to the General Pro-
cedure gave (S,S )-9 as an orange solid (204 mg, 71%). Single crys-
tals suitable for X-ray diffraction analysis were grown from ace-
(
3
2
2
p
p
0
.60 mmol) and Et
3
(
(
S,S
CHCl
CHMe
4.5, 6.9 Hz, 1 H, CHMe
OMe), 4.22 (s, 5 H, C ), 4.47 (t, J = 2.6 Hz, 1 H, C
ddd, JP,H = 2.2, JH,H = 4.9, 8.8 Hz, 1 H, NHCH), 5.20 (dt, J =
.5, 2.7 Hz, 1 H, C ), 7.11–7.60 (m, 10 H, PPh ), 7.88 (dd, JP,H
13.6, JH,H = 8.7 Hz, 1 H, NH) ppm. C{ H} NMR (CDCl ):
), 30.66
), 71.63
p
D
1
3
3
2
2
3
). H NMR (CDCl
3
3
3
3
2
), 0.83 (d, JH,H = 6.9 Hz, 3 H, CHMe
2
), 2.17 (dsept, JH,H
), 3.80 (s, 3 H,
), 4.63
p
=
2
), 3.77 (m, 1 H, C H
5 3
5
H
5
5 3
H
1
3
tone/diethyl ether at +4 °C. [α]
D
= –198 (c = 0.5, CHCl
3
). H NMR
): δ = 3.02 (dd, JH,H = 7.6, JH,H = 14.0 Hz, 1 H, CH Ph),
Ph), 3.78 (s, 3 H,
), 4.46 (dt, J = 1.0,
), 4.95 (dddd, JP,H = 2.3, JH,H = 5.3, 7.7, 7.7 Hz,
H, NHCH), 5.14 (dt, J = 1.6, 2.7 Hz, 1 H, C ), 6.96–7.61 (m,
), 7.91 (dd, JH,H = 7.8, JP,H = 12.8 Hz, 1 H,
(
1
=
3
2
(
CDCl
3.12 (dd, JH,H = 5.2, JH,H = 14.0 Hz, 1 H, CH
OMe), 3.86 (m, 1 H, C ), 4.09 (s, 5 H, C
3
2
5
H
3
2
3
2
3
13
1
2
3
7
5
H
3
5 5
H
δ = 17.60 (d,
J
P,C = 2 Hz, CHMe
2
), 18.85 (CHMe
2
3
2
1
5 3
.6 Hz, 1 H, C H
(
(
CHMe
CH C
2
), 52.11 (OMe), 57.43 (NHCH), 70.91 (CH C
5
H
5
5
H
3
5
H
3
), 73.83 (d, JP,C = 2 Hz, CH C
5
H
3
), 74.57 (d, JP,C = 4 Hz,
3
), 74.83 (d, 1
2
15 H, CH
NHCH) ppm. C{ H} NMR (CDCl
(OMe), 53.86 (NHCH), 70.90 (CH C
(d, JP,C = 2 Hz, CH C ), 74.62 (d, JP,C = 4 Hz, CH C
(d, 1JP,C = 11 Hz, CP C
), 126.77 (CH CH Ph), 128.08 (CH PPh
5 Hz, CH PPh ), 128.35 (CH CH Ph), 128.35 (d, JP,C = 9 Hz, CH
PPh ), 129.16 (CH CH Ph), 129.81 (CH PPh
), 131.85 (d, 2JP,C
7 Hz, CH PPh ), 136.14 (d,
), 135.36 (d, 2JP,C = 21 Hz, CH PPh
P,C = 6 Hz, Cipso PPh ), 136.17 (Cipso CH
Ph), 138.36 (d, 1JP,C
P,C = 4 Hz, CONH), 172.54
): δ = –20.6 (s) ppm. IR
2 2
Ph + PPh
CH C
5
H
3
JP,C = 9 Hz, CP C
5
H
3
), 80.08 (d,
), 128.36
), 129.81 (CH PPh ),
2
), 135.22 (d, JP,C = 21 Hz, CH
P,C
J =
1
3
1
3
3
): δ = 37.97 (CH
), 71.89 (CH C
2
Ph), 52.27
H
H
1
8 Hz, CCONH C
5 3 2
H ), 128.31 (d, JP,C = 6 Hz, CH PPh
3
5
H
5
5
3
), 73.64
), 75.02
(CH PPh ), 128.41 (d, JP,C = 9 Hz, CH PPh
2
2
2
2
2
5
H
3
5
3
132.07 (d, JP,C = 17 Hz, CH PPh
2
), 135.56 (d, 1JP,C = 6 Hz, Cipso PPh
1
5 3
H ), 79.97 (d, JP,C = 20 Hz, CCONH
PPh
C
2
2
), 137.40 (d, JP,C = 6 Hz,
), 170.70 (d, 3JP,C = 4 Hz, CONH), 172.86 (CO
3
C
5
H
3
2
2
), 128.24 (d, JP,C =
ipso PPh
2
1
2
Me)
3
): δ = –20.0 (s) ppm. IR (neat): ν˜ max
3
ppm. 3 P{ H} NMR (CDCl
1
2
2
2
2
2
=
=
3315 (m, νNH), 1740 (vs., νCO), 1653 (vs., amide I), 1517 (vs.,
amide II), 1310 (m), 1274 (w), 1193 (m), 1160 (m), 1107 (w), 1028
m), 1001 (m), 845 (w), 820 (m), 743 (s), 697 (s), 543 (w), 484 (s)
1
2
2
1
J
2
2
=
(
3
–1
+·
+
6 Hz, Cipso PPh
(CO
2
1
), 170.34 (d, J
cm . EI MS: m/z (%) = 527 (31) [M] , 496 (3) [M – OMe] , 462
Me) ppm. 3 P{ H} NMR (CDCl
1
+
+
2
3
(100) [M – C
5
H
5
] , 412 (64) [M – CH(CHMe
2
)CO
2
Me] , 402 (51),
+
(Nujol): ν˜ max = 3290 (w, νNH), 1751 (vs., νCO), 1647 (vs., amide I),
1524 (s, amide II), 1410 (w), 1308 (m), 1269 (m), 1217 (m), 1203
(w), 1193 (m), 1153 (m), 1106 (m), 1090 (w), 1034 (w), 999 (w), 985
w), 845 (w), 818 (w), 747 (s), 699 (s), 502 (m), 484 (s), 457 (w)
cm . EI MS: m/z (%) = 575 (23) [M] , 544 (5) [M – OMe] , 510
Ph)CO
Me] , 374 (12) [M – Ph
2 2
346 (44), 291 (14), 226 (12), 201 (100) [Ph PO] , 183 (20) [Ph P –
397 (10) [M – NHCH(CHMe
2
)CO
2
Me] , 346 (43), 303 (7), 291 (6),
+
+
247 (6), 226 (10), 201 (85) [Ph
2
PO] , 183 (15) [Ph
2
P – 2 H] , 170
)] , 97 (10), 83 (14), 73 (20), 55
3
30NO PFe 527.1313; found 527.1306.
+
(28), 149 (11), 121 (30) [Fe(C
5 5
H
(
(39). HR MS: calcd. for C29
H
–
1
+·
+
+
+
(
S
p
)-1-(Diphenylphosphanyl)-2-{N-[(R)-1-(methoxycarbonyl)-2-meth- (27) [M – C
)-8]: The General Procedure,
)-1 (207 mg, 0.50 mmol), HOBt (81 mg,
5
H
5
] , 450 (31), 412 (74) [M – CH(CH
2
2
Me] ,
+
+
ylprop-1-yl]carbamoyl}ferrocene [(R,S
starting with (S
p
397 (11) [M – NHCH(CH
2
Ph)CO
2
2
PO] ,
+
p
4284
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 4276–4287

Chiral Phosphanylferrocenecarboxamides with Amino Acid Pendant Groups
+
)]+, 91 (25), 69 (9), 57
PFe 575.1313; found 575.1295.
+
+
2
(
H] , 170 (35), 133 (8), 121 (42) [Fe(C
5
H
5
= 554 [M + Na] , 570 [M + K] . HR MS (FAB): calcd. for
PFe [M + H]+ 532.0877; found 532.0888.
14). HR MS: calcd. for C33
H30NO
3
29 23 3 2
C H N O
Catalytic Tests: The ligand (18 µmol) and the copper salt (15 µmol
of Cu) were mixed with dry dichloromethane (3 mL) and stirred at
room temperature for 20 min. The mixture was cooled in ice, and
(
S
p
)-1-(Diphenylphosphanyl)-2-{N-[(R)-1-(methoxycarbonyl)-2-
)-9]: Treatment of (S )-1
207 mg, 0.50 mmol), HOBt (81 mg, 0.60 mmol), EDC (0.11 mL,
.60 mmol), (R)-[H NCH(CH Ph)CO Me]Cl (129 mg, 0.60 mmol)
and Et N (0.10 mL, 0.71 mmol) according to the General Pro-
cedure gave the amide (R,S )-9 (orange solid; 178 mg, 62%) and
also some (S )-10. [α] = –125 (c = 0.5, CHCl
phenylethyl]carbamoyl}ferrocene [(R,S
(
0
p
p
(
E)-1,3-diphenylprop-2-en-1-one (11a; 104 mg, 0.50 mmol) was
added. After the mixture had been stirred for another 10 min, a
solution of Et Zn in heptane (0.75 mL of 1  solution, 0.75 mmol)
was introduced, and the stirring was continued at 0 °C for 4 h. The
reaction mixture was washed with saturated aqueous NH Cl
2ϫ5 mL) and extracted with diethyl ether. The organic layers were
3
2
2
3
2
p
1
p
D
3
). H NMR (CDCl
δ = 3.10 (dd, JH,H = 8.3, JH,H = 14.1 Hz, 1 H, CH Ph), 3.27 (dd,
Ph), 3.45 (s, 3 H, OMe),
), 4.41 (dt, J = 0.5, 2.6 Hz,
), 5.01 (m, 2 H, NHCH + C ), 7.11–7.56 (m, 16 H,
) ppm. 13C{ H} NMR (CDCl
): δ = 37.97
Ph), 52.05 (OMe), 53.57 (NHCH), 70.80 (CH C ), 71.58
CH C ), 73.04 (d, JP,C = 4 Hz, CH C ), 74.44 (d, JP,C = 4 Hz,
), 75.82 (d, 1
P,C = 11 Hz, CP C
0 Hz, CCONH C ), 127.17 (CH CH Ph), 128.12 (CH PPh
28.14 (d, JP,C = 10 Hz, CH PPh
), 128.32 (d, 3JP,C = 7 Hz, CH
), 128.73 (CH CH Ph), 129.32 (CH CH Ph), 129.65 (CH
), 132.05 (d, JP,C = 17 Hz, CH PPh
), 135.21 (d, 2JP,C = 22 Hz,
P,C = 7 Hz, Cipso PPh ), 136.70 (Cipso
3
):
3
2
4
2
(
3
2
J
H,H = 5.2, JH,H = 14.1 Hz, 1 H, CH
.81 (m, 1 H, C ), 3.90 (s, 5 H, C
5 3
H, C H
2
4
dried (MgSO ) and concentrated under vacuum. Subsequent purifi-
3
1
5
H
3
5 5
H
cation by column chromatography (silica gel; hexane/diethyl ether,
:1) afforded the alkylation product 12a or, in cases of incomplete
5
H
3
1
1
NHCH + CH
(
(
2
Ph + PPh
2
3
conversion, its mixture with unreacted substrate. Levels of conver-
CH
2
5 5
H
1
sion were determined from H NMR spectra. Enantiomeric ex-
5
H
3
5 3
H
cesses were established by HPLC analysis: Daicel Chiralcel OD-H
2
CH C
2
1
5
H
3
J
5 3 P,C
H ), 80.04 (d, J =
column (250 mmϫ4.6 mm), hexane/iPrOH (99:1), flow rate
5
H
3
2
2
),
–
1
0
R R
.75 mLmin ; t [(R)-12a] = 20.3, t [(S)-12a] = 23.0 min. Spectro-
3
2
scopic data for the alkylation product were in accordance with lit-
erature. The configuration was assigned on the basis of optical ro-
tation.[ Reactions with the substituted chalcones 11b–g were per-
PPh
PPh
CH PPh
CH
Ph), 138.42 (d, 1
2
2
2
2
2
2
26]
1
2
), 136.38 (d,
J
2
formed similarly. The products were analysed by NMR spec-
3
2
J
P,C = 7 Hz, Cipso PPh
2
), 170.22 (d,
J
P,C
=
troscopy and HPLC[
20b,20e]
(see the Supporting Information).
Me) ppm. 31P{ H} NMR (CDCl
1
): δ =
4
–
1
(
(
5
4
(
2
(
Hz, CONH), 172.05 (CO
20.5 (s) ppm. IR (neat): ν˜ max = 3300 (w, νNH), 1743 (vs., νCO),
651 (vs., amide I), 1522 (vs., amide II), 1436 (s), 1276 (m), 1218
m), 1178 (m), 1107 (w), 1028 (w), 1002 (w), 911 (w), 822 (m), 748
vs), 699 (vs), 666 (w), 548 (w), 485 (s) cm . FAB MS : m/z (%) =
76 (100) [M + H] , 544 (4) [M – OMe] , 510 (14) [M – C
2 2
98 (9), 481 (7), 450 (5), 412 (13) [M – CH(CH Ph)CO
29) [M – NHCH(CH
2
3
Model Complexation Experiments: Ligand 2 (6.6 mg/13.5 µmol or
4.6 mg/30 µmol) and (CuOTf) ·PhMe (3.9 mg, 15 µmol Cu) were
mixed with CD Cl (1 mL). The mixture was sonicated for ca.
1
2
2
2
–1
5 min and filtered through a pad of Celite to eliminate traces of
II
+
·
+
+
paramagnetic Cu , and the filtrate was analysed by NMR spec-
5
+
H
5
] ,
Me] , 397
Me] , 346 (9), 277 (15), 226 (11),
troscopy. The crystalline complex 14 resulted when the reagents
+
[15 µmol of 2 and 7.5 µmol of (CuOTf) ·PhMe] were mixed in chlo-
Ph)CO
2
2
2
+
+
roform (ca. 1 mL), and the solution was layered with hexane. Ana-
lytical data for 14 are available in the Supporting Information.
01 (6) [Ph
21), 121 (18) [Fe(C
2
PO] , 183 (24) [Ph
2
P – 2 H] , 170 (12), 154 (17), 136
)] , 105 (9), 91 (19), 77 (16), 69 (13), 55 (24).
+
5
H
5
+
HR MS (FAB): calcd. for C33
found 576.1401.
3
H31NO PFe [M + H] 576.1391;
X-ray Crystallography
Crystallographic Data for (S,S
orange prism, 0.40ϫ0.55ϫ0.55 mm; orthorhombic, space group
P2 , a = 11.6754(1), b = 11.7822(1), c = 20.1930(2) Å; V =
777.79(4) Å , Z = 4. Diffraction data were collected with a Nonius
KappaCCD instrument (Mo-K radiation, λ = 0.71073 Å) at
50(2) K and were corrected for absorption [µ(Mo-K
p 3
)-9: C33H30FeNO P, M = 575.40,
(
S
p
)-1-({[2-(Diphenylphosphanyl)-1-ferrocenyl]carbonyl}oxy)-1H-
benzotriazole [(S )-10]: The active ester (S )-10 was isolated from
amidation reactions between (S )-1 and (R)-amino acid methyl es-
1 1 1
2 2
p
p
3
2
p
α
ters in the presence of HOBt/EDC as an orange solid after column
chromatography on silica gel with dichloromethane/methanol
1
α
) =
–
1
1
0.636 mm ; transmission factors: 0.718–0.835]. A total of 48591
diffractions was measured (θmax = 27.5°), of which 6361 were
unique (Rint = 4.2%) and 6068 observed with IϾ2σ(I). The struc-
(
(
50:1) as the eluent. [α]
CDCl ): δ = 4.02 (ddd, J = 0.9, 1.6, 2.5 Hz, 1 H, C
), 4.73 (dt, J = 0.6, 2.7 Hz, 1 H, C ), 5.36 (ddd, J = 0.9,
.6, 2.6 Hz, 1 H, C ), 6.96 (dt, J = 1.1, 8.1 Hz, 1 H, C ), 7.20–
.55 (m, 10 H, PPh ), 7.35–7.40 (m, 2 H, C ), 8.02 (dt, J = 1.0,
) ppm. 1 C{ H} NMR (CDCl
.3 Hz, 1 H, C ): δ = 68.08 (d,
P,C = 16 Hz, CCONH C ), 72.04 (CH C ), 73.76 (CH
), 74.60 (CH C ), 77.24 (d, JP,C = 5 Hz, CH C ), 81.90
), 108.32 (CH C ), 120.27 (CH C ),
), 128.40 (CH C ), 128.42 (2ϫd, JP,C = 5 Hz,
), 128.47 (CH PPh ), 128.74 (C C ), 129.42 (CH PPh ),
32.44 (d, JP,C = 20 Hz, CH PPh ), 134.85 (d, JP,C = 21 Hz, CH
D
= –209 (c = 0.5, CHCl
3
). H NMR
3
5 3
H ), 4.46 (s, 5
H, C
1
7
5
H
5
5 3
H
[
27]
ture was solved by direct methods (SIR97 ) and refined by full-
5
H
3
6 4
H
2
[28]
matrix least squares on F (SHELXL97 ). Non-hydrogen atoms
were refined with anisotropic displacement parameters. Hydrogen
atoms, except for the amide hydrogen atom, were placed in their
calculated positions and refined as riding atoms with Uiso(H) as-
signed to a multiple of Ueq of their bonding carbon atom. The
amide hydrogen atom, H1N, was identified on a difference Fourier
2
6 4
H
3
1
8
6
H
4
3
2
J
5
H
3
5 5
H
C
5
H
3
5
H
3
5 3
H
1
(
1
d, JP,C = 20 Hz, CP C
24.54 (CH C
CH PPh
5
H
3
6
H
4
6 4
H
3
6
H
4
6 4
H
map and refined similarly. The refinement converged (∆/σmax
Յ
2
2
6
H
4
2
2
2
0.001, 354 parameters) to R = 2.37% for observed, and R = 2.61%,
wR = 6.21%, GOF = 1.053 for all diffractions; ∆ρ = 0.51,
1
2
), 137.03 (d, 1JP,C = 13 Hz, Cipso PPh
), 143.41 (C C ), 167.97 (d, JP,C = 4 Hz, CO)
ppm. P{ H} NMR (CDCl ): δ = –17.5 (s) ppm. IR (Nujol): ν˜ max
1777 (vs., νCO), 1321 (w), 1247 (m), 1237 (m), 1155 (w), 1107
w), 1086 (s), 1019 (m), 926 (m), 905 (m), 829 (w), 741 (vs), 697 (s), 1421.91, yellow prism, 0.20ϫ0.23ϫ0.35 mm; triclinic, space group
1
PPh
1
2
2
), 138.61 (d, JP, C =
–
3
[29]
3
–0.23 e·Å . The Flack enantiomorph parameter was determined
to be –0.012(8).
3 Hz, Cipso PPh
2
6 4
H
31
1
3
=
(
5
+
6 3 2 2 9 2
Crystallographic Data for 14: C55H50Cl CuF Fe N O P S, M =
–1
¯
00 (m), 484 (m), 464 (m) cm . FAB MS: m/z (%) = 532 (20) [M P1, a = 13.0920(3), b = 14.4847(3), c = 17.6069(4) Å; α = 97.023(1),
+
·
+
3
H] , 521 (5), 446 (5), 429 (15), 414 (12), 397 (25) [M – OBt] , β = 97.085(1), γ = 112.233(1)°; V = 3014.2(1) Å , Z = 2. Diffraction
+
3
69 (3) [M – CO
Ph
2
Bt] , 277 (11), 257 (6), 226 (5), 215 (12), 201 (18)
data were collected as described above; absorption was neglected
+
+
–1
[
[
2
PO] , 185 (55), 183 (9) [Ph
2
P – 2 H] , 149 (5), 121 (5) [µ(Mo-K
α
) = 1.243 mm ]. A total of 59208 diffractions was mea-
Fe(C
5
H
5
)]+, 110 (27), 93 (100), 75 (22), 57 (25). ESI MS: m/z (%)
sured (θmax = 27.5°), of which 13796 were unique (Rint = 4.2%)
Eur. J. Org. Chem. 2010, 4276–4287
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4285

ˇ
J. Tauchman, I. Císa rˇ ová, P. St eˇ pni cˇ ka
FULL PAPER
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[
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Received: April 8, 2010
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Published Online: June 11, 2010
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