Synthesis of ferrocene tethered open and macrocyclic bis-β-lactams and bis-β-amino acid derivatives

Article abstract of DOI:10.1039/b911450e

New bioorganometallic ferrocene derivatives are synthesized through a Diversity Oriented Synthesis strategy. Easily available ferrocene bisimines have been transformed into open ferrocenyl bis-β-lactams. These compounds have demonstrated to be versatile s

Full text of DOI:10.1039/b911450e

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www.rsc.org/dalton | Dalton Transactions
Synthesis of ferrocene tethered open and macrocyclic bis-b-lactams and
bis-b-amino acid derivatives†
Miguel A. Sierra,* Mamen Rodr´ıguez-Ferna´ndez, Luis Casarrubios, Mar Go´mez-Gallego, Charles P. Allen and
Mar´ıa Jose´ Manchen˜o*
Received 12th June 2009, Accepted 11th August 2009
First published as an Advance Article on the web 2nd September 2009
DOI: 10.1039/b911450e
New bioorganometallic ferrocene derivatives are synthesized through a Diversity Oriented Synthesis
strategy. Easily available ferrocene bisimines have been transformed into open ferrocenyl bis-b-lactams.
These compounds have demonstrated to be versatile synthons used in further transformations into new
ferrocene bis-b-amino acids. Carefully selected substituents submitted to ring closing metathesis (RCM)
and Cu-catalyzed oxidative alkyne coupling conditions have also allowed the conversion of open
substrates into ferrocenic macrocyclic bis-b-lactams.
penicillin and cephalosporin derivatives having 6- and 7-positions
Introduction
acylated with ferrocenyl fragments have been prepared (Chart 1).4,5
Ferrocene plays a pivotal role in bio-organometallic chemistry.1
Our research group has described a method to easily incor-
The stability of the ferrocene moiety in aqueous or aerobic media,
porate the ferrocene unit at the N1 and/or C4 positions of the
its electrochemical properties together with a well established
2-azetidinone ring by reacting a photogenerated ketene derived
chemistry that allows the preparation of a wide variety of
from a chromium(0) carbene with the adequate ferrocenylimines
(Scheme 1).3a
derivatives, make ferrocenes interesting starting points for the
development of new properties in already bioactive compounds.2
Ferrocene derived b-lactams are good candidates for the construc-
tion of new bio-organometallic structures and also as intermedi-
ates to prepare new types of metalla amino acids and peptides.
Nevertheless, compounds having a ferrocene fragment incorpo-
rated into a b-lactam nucleus are scarce,3 and among them some
The access to bis-b-lactams 2 from the easily available ferrocene
diimines 1 will allow the preparation of different compounds
(Chart 2). Thus, the ring opening of both 2-azetidinone rings will
yield bis-b-amino acids 3 tethered by a ferrocene nucleus, while
the metathesis or the intramolecular alkyne coupling in suitably
functionalized 2 would yield new bis-b-lactam macrocyles 4 and
5.6 Reported here is the development of the synthesis of ferrocenyl
bis-b-lactams 2 and their use in the preparation of unusual bis-
aminoacid derivatives and strained macrocycles 4–5. Therefore,
access from diimines 1 to the final products can be gained in three
or four steps, being an archetypical example of diversity oriented
organic synthesis (DOS).7
Departamento de Qu´ımica Orga´nica I. Universidad Complutense de
Madrid. Avda, Complutense s/n. 28040, Madrid, Spain. E-mail: sierraor@
quim.ucm.es, mjmreal@quim.ucm.es; Fax: +34 91 394 43 10; Tel: +34 91
394 43 10
† Electronic supplementary information (ESI) available: Copies of the
NMR spectra for the synthesized compounds. See DOI: 10.1039/b911450e
Chart 1
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Scheme 2
Scheme 1
Scheme 3
data.9 Thus, the two azetidinone rings in bis-b-lactams 2a have a cis
relative stereochemistry with a coupling constant of J = 5.1 Hz for
the lactamic protons (d = 5.40–5.17 ppm). However, bis-b-lactams
2b showed a characteristic trans-coupling constant (J = 2.1 Hz)
for the C3–C4 hydrogens (d = 5.46-4.77 ppm). 13C-NMR spectra
of the diastereomeric mixtures clearly showed the azetidinone C3
and C4 signals for each isomer (2a: 80.6, 80.4 ppm (C3), 58.6,
58.4 ppm (C4) and 2b: 86.8, 86.7 ppm (C3), 59.6, 59.4 ppm (C4)).
Since the reaction at low temperature gave better yields, these
conditions were followed to prepare bis-b-lactams 2c–e. The
reaction between imines 1b–d and phenoxyacetyl chloride gave
the expected cis,cis-isomers of bis-b-lactams 2c–d in all cases
as 1:1 syn/anti mixtures and in good to excellent yields. The
syn/anti isomers of 2c were efficiently separated and isolated by
trituration with Et2O and sonication (29% isolated yield for each
isomer) while mixtures of 2d and 2e were inseparable (Scheme 4).
The structure of compounds 2c–e was established on the basis
of their spectroscopic data. In all cases, the characteristic sig-
nals for the 2-azetidinone ring C3–C4 hydrogens were observed
Chart 2
Results and discussion
1,1¢-ferrocenedicarbaldehyde was reacted with different substi-
tuted amines in the presence of MgSO4 to obtain diimines 1 in good
yields (Scheme 2). Diimine 1a was reacted with phenoxyacetyl
chloride at -78 ◦C in dichloromethane (DCM) and in the presence
of triethylamine (TEA) yielding a mixture of cis-cis-2-azetidinones
2a as 2:1 syn/anti mixture of diastereomers in 76% yield.
Subsequently, the reaction of diimine 1a and phenoxyacetyl
chloride in the presence of TEA, in boiling toluene, yielded a
mixture of syn/anti trans-trans-2-azetidinones 2b in 34% yield
(Scheme 3).8 The mixture of syn/anti diastereomers was insep-
arable in both cases. The structures and relative stereochemistries
of bis-b-lactams 2 were established based on their spectroscopic
8400 | Dalton Trans., 2009, 8399–8405
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amide structure of these compounds (the corresponding azetidi-
none CO appeared at 165.9 and 165.8 ppm, respectively).
Formation of macrocyclic ferrocene-linked b-lactam structures
by either metathesis or diyne coupling of compounds 2 was
next pursued. The ring closing metathesis (RCM) reaction was
effected by using the diastereomeric mixture of the cis,cis-b-
lactam 2c. The best conditions implied the reaction of 2c with a
second generation Grubbs’ catalyst (10 mol%) in anhydrous DCM
(1 mM) under reflux for 48 h to quantitatively yield macrocycles
4. The crude macrocyclic cis,cis-bis-b-lactams 4 were isolated as
1:1 mixtures of syn/anti diastereomers that were separated by
SiO2 chromatography (Scheme 6). To unambiguously determine
whether the metathesis reaction was an intra- or intermolecular
reaction, FAB experiments were performed for each isomer. A
detected [M + H]+ ion of 589 amu clearly discarded the formation
of open dimers and confirmed the formation of the macrocycle 4.
NMR signals were again in good agreement with the expected
structure, showing the characteristic signals for the lactamic
protons at 4.75, 3.70 ppm and 4.89, 4.14 ppm respectively with
coupling constants of 4.5 and 4.7 Hz, which clearly indicated a
cis relationship. E stereochemistry for the newly formed double
bond was assigned according to the observed coupling constants
(J = 17.2 and 17.8 Hz, respectively) of the olefinic protons, whose
signals were found between 5.55 and 5.86 ppm for both isomers.
Finally, the preparation of strained macrocycles 5 was achieved
by the intramolecular Cu-catalyzed oxidative alkyne coupling
in compounds 2e. We first tested the standard Hay’s10 coupling
conditions (TMEDA–CuCl/O2). The procedure is a modification
of the original Glaser’s11 that increases the solubility of the reactive
species. However, none of them afforded positive results. Other
methods like Eglinton–Galbraith12 (Cu(II) salts in py/MeOH
solution), or Eglington13 modified methods (Cu(AcO)2/DMF or
CuCl/Cu(AcO)2/py) were also unsuccessful. Macrocyclization
was finally achieved by using Cu(AcO)2·H2O (20 mmol) in the
presence of MeCN at 50 ◦C for 16 h. The highly strained
Scheme 4
(5.42–5.33 ppm for H3, 4.96–4.74 ppm for H4) with clear H3–H4
cis coupling constants (J = 4.6–4.8 Hz).
The use of ferrocene bis-b-lactams 2 as precursors of ferrocene-
linked bis-b-amino acids was pursued next. Heating separately
the syn and anti diasteromers 2c with aqueous MeNH2 in a sealed
tube at 70 ◦C yielded ferrocene linked bis-b-aminoacid derivatives
3a–b in excellent yields. Compounds 3 are C–C ferrocene tethered
dipeptides and it is worth mentioning that no isomerization of the
four preexisting chiral centers was observed during this process
(Scheme 5).
Characteristic signals for the newly developed stereogenic cen-
ters (CH hydrogens) were observed in all cases (4.94, 4.12 ppm for
3a, 4.11, 3.86 ppm for 3b) together with the signals corresponding
to the N–Me groups (2.70 and 2.78 ppm respectively). Signal
broadening precluded the measurement of coupling constants.
=
The amide C O group appeared at 170.8 and 171.8 ppm in the
13C-NMR spectra of compounds 3, which confirmed the open
Scheme 5
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Scheme 6
macrocycle 5 was isolated as an inseparable 1:1 mixture of syn/anti
Avance AVIII-700 (1H: 700.1733 MHz) spectrometers. Chemical
shifts are given in parts per million relative to TMS (1H, 0.0 ppm)
or the specified solvent. IR spectra were taken on a Perkin-Elmer
781 or a Bruker Tensor 27 spectrometer. Anhydrous solvents were
obtained by distillation over adequate drying agents. Flame-dried
glassware and standard Schlenk techniques were used for moisture
sensitive reactions. Merck silica gel (230–400 mesh) was used as
the stationary phase for purification of crude reaction mixtures
by flash column chromatography. Identification of products was
made by TLC (kiesegel 60F254). UV light (l = 254 nm) and
5% phosphomolybdic acid solution in 95% EtOH were used to
develop the plates. All commercially available compounds were
used without further purification. 1,1¢-ferrocenedicarbaldehyde16
was prepared according to literature procedures.
diastereomers in 30% yield (Scheme 7). Analysis of the NMR
1
≡
spectra showed absence of the terminal CH signal in the H-
NMR. 13C-NMR C C signals of 5 were also compared with those
≡
of the open chain precursor 2e. A displacement to higher field (2e:
73.5, 73.4 ppm and 5: 72.5, 72.2, 60.3) indicates a higher degree of
conjugation due to the coupling of the two triple bonds. FABMS
experiments ([M + H]+, 583 amu) unambiguously confirmed the
intramolecular oxidative coupling. To the best of our knowledge,
examples of macrocyles having embedded bis-b-lactam rings are
scarce,6 the first example of these kinds of compounds was
reported from our laboratories a few years ago.6c Furthermore,
macrocylic embedded bis-b-lactams having a ferrocene moiety are
unknown. The preparation of these compounds is a straight entry
to a new family of bio-organometallic compounds.14,15
General method for the synthesis of diimines 1
Experimental
A solution of 1,1¢-ferrocenedicarbaldehyde (1.00 mmol) in anhy-
drous DCM (6 mL) was treated with (2.01 mmol) of p-anisidine
in the presence of anhydrous MgSO4 (2.0 g) and under Ar
atmosphere. The reaction was stirred at r.t. for 48 h, filtered
General
NMR experiments were performed at 22 ◦C on Bruker Avance
300 (300.1 and 75.4 MHz), Bruker 200-AC (200.1 and 50 MHz),
Bruker Avance AV-500 (500.1330 and 125.7722 MHz), or Bruker
R
through Celiteꢀ and the solvent eliminated under vacuum to
Scheme 7
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obtain crude imines 1 which were purified by Et2O trituration or
used without further purification.
Method B. To a solution of imine 1 (1.00 mmol) in dry toluene
(19 mL), TEA (4.00 mmol) was added dropwise. The mixture was
heated to reflux and the corresponding acid chloride (2.40 mmol)
in dry toluene (6.0 mL) was then added dropwise. Reflux was
maintained overnight and after cooling to r.t., the reaction was
extracted with DCM (3 ¥ 20 mL). The combined organic layers
were washed with 10% NaHCO3 (2 ¥ 20 mL), brine (2 ¥ 30 mL),
dried over MgSO4 and evaporated. Crude bis-b-lactams 2 were
purified by chromatography (SiO2, Hex/EtOAc/DCM mixtures).
Diimine 1a. Following the general procedure, from 4.00 g
(16.52 mmol) of 1,1¢-ferrocenedicarbaldehyde, 4.17 g (33.87 mmol)
of p-anisidine and after trituration with Et2O, 5.50 g (75%) of pure
1
1a were obtained as a red solid. H NMR (300 MHz, CDCl3) d
8.28 (s, 2H), 7.09 (d, J = 8.7 Hz, 4H), 6.85 (d, J = 8.7 Hz, 4H),
4.86 (t, J = 1.9 Hz, 4H), 4.51 (t, J = 1.9 Hz, 4H), 3.83 (s, 6H). 13
C
NMR (75 MHz, CDCl3) d 158.4, 157.8, 145.3, 121.8, 114.8, 82.0,
71.8, 69.8, 55.3. IR (CHCl3) n 1622, 1578, 1470, 1244, 1032 cm-1.
C26H24FeN2O2 (452.33): calcd. C, 69.04; H, 5.35; found C, 69.21;
H, 5.39. MS (ESI): 453 [M + H].+
Ferrocene bis-b-lactam 2a. Following method A, from 3.00 g
(6.63 mmol) of imine 1a, 3.10 g (18.20 mmol) of phenoxyacetyl
chloride and 4.00 g (39.80 mmol) of TEA and after overnight
Et2O trituration, 3.70 g (76%) of pure cis,cis-2a were obtained
as an inseparable 2:1 syn/anti diastereomeric mixture as a light
brown solid. 1H NMR (300 MHz, CDCl3) d 7.45–7.28 (m, 16H),
7.06–6.99 (m, 12H), 6.92–6.87 (m, 8H), 5.40 (d, J = 5.1 Hz, 2H),
5.31 (d, J = 5.1 Hz, 2H), 5.17 (d, J = 5.1 Hz, 4H), 4.25–4.01
(m, 16H), 3.79 (s, 12H). 13C NMR (50 MHz, CDCl3) d 163.6,
157.4, 157.1, 157.0, 129.8, 129.6, 122.3, 120.7, 120.5, 115.7, 115.6,
114.6, 114.4, 82.4, 82.1, 80.6, 80.4, 70.0, 69.8, 69.6, 69.0, 68.9, 58.6,
58.4, 55.5. IR (KBr) n 2934, 1747, 1597, 1514, 1495, 1387, 1240,
1111 cm-1. C42H36FeN2O6 (720.19): calcd. C, 70.01; H, 5.04; found
C, 70.12; H, 5.10.
Diimine 1b. Following the general procedure, from 4.00 g
(16.52 mmol) of 1,1¢-ferrocenedicarbaldehyde and 3.70
g
(64.48 mmol) of allylamine, 4.66 g (90%) of pure 1b were obtained
as a red oil. The product was used without further purification.
1H NMR (300 MHz, CDCl3) d 8.08 (s, 2H), 6.03 (ddt, J = 17.1,
10.3, 5.6 Hz, 2H), 5.22 (dq, J = 17.1, 1.7 Hz, 2H), 5.15 (dq, J =
10.3, 1.7 Hz, 2H), 4.68 (t, J = 1.9 Hz, 4H), 4.38 (t, J = 1.9 Hz,
4H), 4.09 (dq, J = 5.6, 1.5 Hz, 4H).13C NMR (75 MHz, CDCl3)
d 161.3, 136.1, 115.8, 81.5, 74.0, 71.6, 71.4, 70.5, 69.7, 69.3, 63.8.
IR (CHCl3) n 3077, 2927, 2831, 1643, 1435, 1368, 1327, 1243,
1019 cm-1.
Ferrocene bis-b-lactam 2b. Following method B, from 1.50 g
(3.31 mmol) of imine 1a, 1.23 g (7.20 mmol) of phenoxyacetyl
chloride and 1.34 g (13.26 mmol) of TEA and after purification by
chromatography (SiO2, Hex/EtOAc/DCM 10:2:3), 0.82 g (34%)
of pure trans,trans-2b were obtained as an inseparable 1:1 syn/anti
diastereomeric mixture as a light brown solid. 1H NMR (300 MHz,
CDCl3) d 7.41-7.25 (m, 16H), 7.19–6.89 (m, 12H), 6.81–6.75 (m,
8H), 5.46 (d, J = 2.1 Hz, 2H), 5.40 (d, J = 2.1 Hz, 2H), 5.00 (d, J =
2.1 Hz, 2H), 4.77 (d, J = 2.1 Hz, 2H), 4.46–4.42 (m, 4H), 4.32–4.20
(m, 12H), 3.75 (s, 6H), 3.75 (s, 6H). 13C NMR (75 MHz, CDCl3) d
163.1, 157.3, 157.2, 156.6, 156.5, 129.9, 122.8, 122.4, 122.0, 119.2,
119.2, 116.2, 116.2, 114.8, 114.2, 86.8, 86.7, 82.6, 82.6, 71.6, 71.4,
70.7, 70.5, 69.4, 69.1, 67.5, 67.3, 59.6, 59.4, 55.4, 55.4. IR (KBr)
n 1747, 1512, 1493, 1387, 1298, 1238, 1113 cm-1. C42H36FeN2O6
(720.19): calcd. C, 70.01; H, 5.04. found C, 70.21; H, 5.13.
Diimine 1c. Following the general procedure, from 1.45 g
(5.99 mmol) of 1,1¢-ferrocenedicarbaldehyde, 1.12 mL
(12.28 mmol) of 3-buten-1-amine and after trituration with
Et2O, 2.07 g, (99%) of pure 1c were obtained as a reddish solid.
1H NMR (300 MHz, CDCl3) d 8.05 (s, 2H), 5.89–5.77 (m, 2H),
5.15–5.04 (m, 4H), 4.63 (t, J = 1.9 Hz, 4H), 4.36 (t, J = 1.9 Hz,
4H), 3.52 (td, J = 7.1, 1.2 Hz, 4H), 2.42 (dq, J = 7.0, 1.2 Hz, 4H).
13C NMR (75 MHz, CDCl3) d 160.5, 136.3, 116.1, 81.6, 71.4,
69.3, 61.4, 35.2. IR (CHCl3) n 3077, 2927, 2831, 1643, 1435, 1368,
1327, 1243, 1019 cm-1. C20H24FeN2 (348.26): calcd. C, 68.97; H,
6.95; found C, 69.08; H, 7.04.
Diimine 1d. Following the general procedure, from 2.00 g
(8.25 mmol) of 1,1¢-ferrocenedicarbaldehyde and 1.00
g
(18.15 mmol) of propargylamine, 1.85 g, (71%) of pure 1d were
obtained as a red oil. The product was used without further
purification. H NMR (300 MHz, CDCl3) d 8.25 (s, 1H), 8.25
(s, 1H), 4.62 (s, 2H), 4.61 (s, 2H), 4.31 (s, 2H), 4.30 (s, 2H), 4.25
(s, 2H), 4.25 (s, 2H), 2.48 (t, J = 2.5 Hz, 2H). 13C NMR (75 MHz,
CDCl3) d 161.9, 81.1, 79.2, 75.3, 71.4, 69.4, 47.2. IR (CHCl3) n
3301, 2897, 1930, 1642, 1248 cm.-1
Ferrocene bis-b-lactam 2c. Following method A, from 4.66 g
(14.55 mmol) of imine 1b, 6.20 g (36.40 mmol) of phenoxyacetyl
chloride and 7.76 g (76.84 mmol) of TEA, 5.00 g (58%) of a 1:1
syn/anti diastereomeric mixture of cis,cis-bis-b-lactams 2c. Both
isomers were separated by Et2O trituration. Yield: 2.50 g (29%)
of syn-2c as a brown solid and 2.5◦ 0 g (29%) of anti-2c as a dark
brown solid. syn-2c: m. p. 198–200 C.1H NMR (300 MHz, CDCl3)
d 7.30–7.22 (m, 3H), 7.02–6.92 (m, 7H), 5.80 (ddt, J = 15.1, 10.9,
6.3 Hz, 2H), 5.38 (d, J = 4.6 Hz, 2H), 5.30–5.21 (m, 4H), 4.80 (d,
J = 4.6 Hz, 2H), 4.34–4.23 (m, 2H), 4.21–4.11 (m, 8H), 3.72–3.62
(m, 2H). 13C NMR (75 MHz, CDCl3) d 165.9, 157.2, 131.5, 129.4,
122.1, 118.2, 115.5, 81.3, 81.2, 69.9, 68.8, 68.3, 68.3, 57.8, 42.2.
IR (CHCl3) n 3488, 2483, 2335, 1758, 1248 cm-1. An. Calcd. for
C34H32FeN2O4 (%): C, ◦69.39; H, 5.48; found: C, 69.12; H, 5.71.
1
Synthesis of ferrocenyl bis-b-lactams 2
Method A. To a -78 ◦C solution of phenoxyacetyl chloride
(3.00 mmol) in 5 mL of anhydrous DCM and under Ar atmo-
sphere, TEA (6.00 mmol) was added dropwise. The mixture was
stirred for 30 min and the corresponding imine 1 (1.0 mmol)
in DCM (30 mL) was added slowly dropwise. The reaction
temperature was raised to 0 ◦C and maintained for 30 min and then
allowed to reach r.t. overnight. The reaction was extracted with
DCM (3 ¥ 20 mL) and the combined organics layers were washed
with 10% NaHCO3 (2 ¥ 20 mL), brine (2 ¥ 30 ml), dried over
MgSO4 and evaporated. Crude bis-b-lactams 2 were purified by
chromatography (SiO2, Hex/EtOAc mixtures) or Et2O trituration.
1
anti-2c: m. p. 129–131 C. H NMR (300 MHz, CDCl3) d 7.30–
7.23 (m, 3H), 7.02–6.94 (m, 7H), 5.84–5.72 (m, 2H), 5.42 (d, J =
4.7 Hz, 2H), 5.29–5.21 (m, 4H), 4.81 (d, J = 4.7 Hz, 2H), 4.31–
4.09 (m, 10H), 3.65 (dd, J = 16.0, 6.8 Hz, 2H).13C NMR (75 MHz,
CDCl3) d 165.8, 157.2, 131.5, 129.4, 122.1, 118.2, 115.4, 81.2, 81.1,
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70.0, 68.8, 68.6, 68.2, 57.7, 42.1. IR (CHCl3) n 3369, 2358, 2252,
1757, 1238 cm-1. C34H32FeN2O4 (588.17): calcd. C, 69.39; H, 5.48;
found C, 69.55; H, 5.63.
purification (SiO2, Hex/EtOAc 1:1), 1.1 g (92%) of 3b as a dark
◦
1
brown solid. m. p. 160–162 C. H NMR (300 MHz, CDCl3) d
7.36–7.26 (m, 4H), 7.06-6.93 (m, 6H), 6.54 (c, J = 4.9 Hz, 2H),
5.80 (ddt, J = 16.9, 10.7, 6.9 Hz, 2H), 5.18–5.02 (m, 4H), 4.11
(bs, 2H), 4.04–4.02 (m, 2H), 3.86 (bs, 2H), 3.75–3.72 (m, 2H),
3.56–3.47 (m, 4H), 3.32–3.13 (m, 4H), 2.78 (d, J = 4.9 Hz, 6H).
13C NMR (75 MHz, CDCl3) d 171.8, 157.3, 136.8, 129.8, 122.0,
116.0, 115.1, 89.2, 82.2, 69.4, 68.7, 68.3, 67.2, 57.5, 50.1, 25.8. IR
(CHCl3) n 3498, 2400, 2385, 1716, 1512, 1225 cm-1. C36H42FeN4O4
(650.26): calcd. C, 66.46; H, 6.51; found C, 66.63; H, 6.71.
Ferrocene bis-b-lactam 2d. Following method A, from 2.18 g
(6.26 mmol) of imine 1c, 2.14 g (12.52 mmol) of phenoxyacetyl
chloride and 1.92 g (18.78 mmol) of TEA and after purification
by chromatography (SiO2, Hex/EtOAc 2:1), 3.60 g (93%) of
pure cis,cis bis-b-lactams 2d were obtained as an inseparable 1:1
syn/anti diastereomeric mixture as a light brown solid. 1H NMR
(300 MHz, CDCl3) d 7.29–7.23 (m, 8H), 7.01–6.95 (m, 12H), 5.83–
5.74 (m, 4H), 5.34 (d, J = 4.7 Hz, 2H), 5.33 (d, J = 4.7 Hz, 2H),
5.18–5.10 (m, 8H), 4.77 (d, J = 4.7 Hz, 2H), 4.74 (d, J = 4.7 Hz,
2H), 4.22–4.09 (m, 16 H), 3.63 (dt, J = 14.3, 7.2 Hz, 4H), 3.20 (dt,
J = 13.8, 6.8 Hz, 4H), 2.47–2.27 (m, 8H). 13C NMR (125 MHz,
CDCl3) d 165.7, 165.7, 157.0, 134.2, 129.2, 129.1, 121.8, 117.3,
117.3, 115.3, 115.2, 81.5, 81.4, 80.8, 80.8, 69.7, 69.7, 68.6, 68.5,
57.8, 57.3, 39.2, 39.1, 31.8, 31.8. IR (CHCl3) n 2924, 1754, 1641,
1598, 1494, 1235, 1048 cm-1. C36H36FeN2O4 (616.20): calcd. C,
70.13; H, 5.89; found C, 70.35; H, 5.02.
Synthesis of ferrocenic macrocycles
Lactamic ferrocenic macrocycle 4. A solution of 2c (0.11 g,
0.18 mmol) in 20 mL of anhydrous DCM was added over a
2 h period using a syringe pump to a refluxing deoxygenated
solution of Grubbs 2nd Gen. catalyst (10 mol%) in 180 mL of
anhyd. DCM. The reaction was monitored by T.L.C. until total
disappearance of the starting material (48 h), filtered through a
short pad of SiO2 and evaporated. The crude thus obtained was
purified by flash chromatography (SiO2, Hex/EtOAc 1:1) to obtain
40 mg (36%) of isomer syn-E-4, 40 mg (36%) of isomer anti-E-
Ferrocene bis-b-lactams 2e. Following method A, from 1.00 g
(3.16 mmol) of imine 1d, 1.08 g (6.32 mmol) of phenoxyacetyl
chloride and 0.98 g (9.48 mmol) of TEA and after overnight
Et2O trituration, 1.79 g (97%) of an inseparable 1:1 syn/anti
diastereomeric mixture of cis,cis-bis-b-lactams 2e were obtained
as a light brown solid. 1H NMR (500 MHz, CDCl3) d 7.23 (t, J =
7.3 Hz, 8H), 6.97 (t, J = 7.3 Hz, 4H), 6.88 (d, J = 7.8 Hz, 8H),
5.36 (d, J = 4.8 Hz, 2H), 5.34 (d, J = 4.8 Hz, 2H), 4.96–4.95 (m,
4H), 4.60 (dd, J = 17.6, 2.5 Hz, 2H), 4.59 (dd, J = 17.7, 2.9 Hz,
2H), 4.26–4.19 (m, 16H), 3.90 (d, J = 17.6 Hz, 2H), 3.89 (d, J =
17.7 Hz, 2H), 2.41 (d, J = 2.5 Hz, 2H), 2.40 (d, J = 2.9 Hz, 2H).
13C NMR (125 MHz, CDCl3) d 165.2, 165.2, 157.1, 129.4, 129.3,
122.2, 122.2, 115.6, 115.5, 81.6, 81.6, 81.0, 81.0, 73.5, 73.4, 69.9,
69.9, 69.1, 68.9, 68.3, 68.3, 67.7, 67.7, 57.6, 57.6, 29.5, 29.5. IR
(CHCl3) n 3288, 1761, 1590, 1494, 1234, 1047 cm-1. C34H28FeN2O4
(584.14): calcd. C, 69.87; H, 4.83; found C, 69.94; H, 4.97.
◦
1
4 as orange solids. Syn-E-4. m. p. 219–221 C (dec). H NMR
(500 MHz, C6D6) d 6.99 (dd, J = 8.5, 7.4 Hz, 4H), 6.81 (d, J =
8.5 Hz, 4H), 6.75 (t, J = 7.4 Hz, 2H), 5.86 (m, 1H), 5.83 (m, 1H),
4.75 (d, J = 4.5 Hz, 2H), 4.18 (s, 2H), 3.76 (td, J = 2.4, 1.3 Hz,
2H), 3.70 (d, J = 4.5 Hz, 2H), 3.67 (s, 2H), 3.56 (s, 2H), 3.21 (t, J =
12.5 Hz, 2H), 3.06–3.01 (m, 2H), 2.99 (qd, J = 12.5, 3.9 Hz, 2H),
1.85–1.79 (m, 2H). 13C NMR (75 MHz, CDCl3) d 166.6, 157.0,
131.1, 129.1, 121.9, 115.4, 82.0, 80.9, 69.2, 68.9, 68.5, 68.2, 59.4,
43.2, 30.2. IR (KBr) n 2924, 1755, 1599, 1496, 1358, 1237, 1145,
1030, 804, 755 cm-1. C34H32FeN2O4 (588.17): calcd. C, 69.39; H,
5.48; found C, 69.54; H,◦5.63. MS (FAB) m/z 589 [M + H]+ (12).
1
anti-E-4. m.p. 213–215 C (dec). H NMR (500 MHz, C6D6) d
7.04–6.97 (m, 4H), 6.87 (dd, J = 8.7, 0.9 Hz, 4H), 6.76 (t, J =
7.3 Hz, 2H), 5.60 (m, 1H), 5.55 (m, 1H), 4.89 (d, J = 4.7 Hz, 2H),
4.14 (d, J = 4.7 Hz, 2H), 4.13 (s, 2H), 3.80–3.76 (m,4H), 3.55-3.53
(m, 2H), 3.39–3.30 (m, 2H), 3.14 (ddd, J = 13.3, 8.2, 3.7 Hz, 2H),
2.60–2.50 (m, 2H, 2.17–2.07 (m, 2H). 13C NMR (75 MHz, C6D6) d
166.0, 158.2, 131.9, 129.6, 122.3, 116.2, 82.7, 82.5, 69.0, 68.7, 67.7,
67.6, 58.1, 40.5, 25.9. IR (KBr) n 2924, 1753, 1598, 1494, 1415,
1236, 754 cm-1. MS (FAB) m/z 589 [M + H]+ (43). C34H32FeN2O4
(588.17): calcd. C, 69.39; H, 5.48; found C, 69.48; H, 5.54
Compound 3a. 0.50 g (0.85 mmol) of syn-2c were placed in a
sealed tube and treated with 40% aq. MeNH2 (5 mL, 57.00 mmol).
The tube was sealed and the mixture was heated to 70 ◦C for
48 h until total disappearance of the starting material (T.L.C.).
The crude was then extracted with DCM (2 ¥ 5 mL), dried
(anhyd. MgSO4) and evaporated to yield, after chromatography
purification (SiO2, Hex/EtOAc 1:1), 0.48 g (88%) of 3a as a dark
◦
brown solid. m. p. 138–140 C.1H NMR (300 MHz, CDCl3) d
Lactamic ferrocenic macrocycle 5. A solution of 2e (0.10 g,
0.17 mmol) in 36 mL of anhyd. MeCN was treated with 0.68 g
(3.42◦mmol) of Cu(OAc)2 monohydrate. The mixture was heated
7.25–7.19 (m, 4H), 6.92–6.82 (m, 6H), 6.46 (c, J = 4.9 Hz, 2H),
5.75 (ddt, J = 14.1, 10.0, 6.8 Hz, 2H), 5.14–5.01 (m, 4H), 4.94
(bs, 2H), 4.12 (bs, 2H), 3.98–3.80 (m, 8H), 3.23–3.12 (m, 4H),
2.70 (d, J = 4.9 Hz, 6H). 13C NMR (75 MHz, CDCl3) d 170.8,
157.2, 136.6, 129.6, 121.8, 115.9, 114.9, 89.2, 81.8, 69.2, 68.6, 68.1,
66.8, 57.4, 49.9, 25.6. IR (CHCl3) n 3502, 2400, 1714, 1219 cm-1.
C36H42FeN4O4 (650.26): calcd. C, 66.46; H, 6.51; found C, 66.67;
H, 6.73.
R
to 50 C for 16 h. The reaction was filtrated through Celiteꢀ, evap-
orated and purified by flash chromatography (SiO2, DCM/EtOAc
10:1) to obtain 30.00 mg (30%) of 5 as a 1:1 inseparable mixture of
syn/anti diastereomers as a dark red solid. 1H NMR (300 MHz,
CDCl3) d 7.32–7.23 (m, 10H), 7.05–6.97 (m, 6H), 6.91 (d, J =
8.0, Hz, 4H), 5.39 (bs, 2H), 5.32 (d, J = 4.2 Hz, 2H), 5.17 (bs, 2H),
5.02 (bs, 2H), 4.68 (d, J = 18.6 Hz, 2H), 4.64 (d, J = 18.2, Hz, 2H),
4.44–4.34 (m, 6H), 4.19–4.11 (m, 10H), 4.04 (d, J = 18.2 Hz, 2H),
3.98 (d, J = 18.6 Hz, 2H). 13C NMR (75 MHz, CDCl3) d 166.4,
166.0, 157.5, 157.3, 129.6, 129.4, 122.3, 122.2, 115.8, 115.7, 83.2,
83.0, 81.7, 81.5, 72.5, 72.2, 69.4, 69.1, 68.8, 68.7, 62.5, 61.2, 60.3,
32.6, 32.4. IR (KBr) n 2926, 1759, 1596, 1493, 1415, 1234, 1174,
Compound 3b. 1.00 g (1.70 mmol) of anti-2c were placed
in a sealed tube and treated with 40% aq. MeNH2 (10 mL,
115.00 mmol). The tube was sealed and the mixture was heated to
◦
70 C for 24 h until total disappearance of the starting material
(T.L.C.). The crude was then extracted with DCM (2 ¥ 10 mL),
dried over MgSO4 and evaporated to yield, after chromatography
8404 | Dalton Trans., 2009, 8399–8405
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1094, 828, 752 cm-1. C34H26FeN2O4 (582.12): calcd. C, 70.11; H,
4.50; found C, 70.24; H, 4.72. MS (FAB) m/z 583 [M + H]+ (12).
Asymmetry, 1994, 5, 809–812; (f) C. Baldoli, P. Del Buttero, E. Licandro
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6 (a) Y. A. Ibrahim, T. A. Al-Azemi, M. D. Abd El-Halim and E.
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Conclusions
This study has demonstrated the possibility of obtaining new ferro-
cenyl derivatives using azetidinone rings as versatile synthons. New
ferrocenyl bis-b-lactams, peptides and macrocyclic derivatives can
be easily obtained and these molecules are a new group of bio-
organometallic derivatives with potential bioactivity.
7 (a) M. D. Burke and S. L. Schreiber, Angew. Chem., Int. Ed., 2004, 43,
46–58; (b) For other examples from these laboratories of DOS applied
to the preparation of bio-organometallic compounds, see: M. C. de la
Torre, I. Garc´ıa and M. A. Sierra, Chem.–Eur. J., 2005, 11, 3659–3667;
Acknowledgements
Support for this work under grants CTQ2007-67730-C02-
01/BQU and CSD2007-0006 (Programa Consolider-Ingenio
2010) from the MEC (Spain) and CCG07-UCM/PPQ-2596
CAM, is gratefully acknowledged. M. Rodr´ıguez-Ferna´ndez was
a FPU-MEC fellow.
´
(c) E. Alvaro, M. A. Sierra and M. C. de la Torre, Chem. Commun.,
´
2006, 985–987; (d) M. C. de la Torre, A. M. Deometrio, E. Alvaro, I.
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Garc´ıa and M. A. Sierra, Org. Lett., 2006, 8, 593–596; (e) E. Alvaro,
M. C. de la Torre and M. A. Sierra, Chem.–Eur. J., 2006, 12, 6403–6411;
´
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Notes and references
8 The stereochemical outcome of the reaction between ketenes or their
precursors and imines (the Staudinger reaction) depends on different
factors, among others the reaction temperature, the order of addition
of the reagents, and the structure of both the imine and the ketene.
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1
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