Co2(CO)8-induced domino reactions of ethyl diazoacetate, carbon monoxide and ferrocenylimines leading to 2-(1-ferrocenyl-methylidene)-malonic acid derivatives

Article abstract of DOI:10.1016/j.tetlet.2009.06.035

Novel 2-(1-ferrocenyl-methylidene)-malonic acid derivatives are obtained upon reacting ethyl diazoacetate, carbon monoxide and ferrocenylimines in the presence of Co₂(CO)₈ as catalyst under mild conditions. Presumably, the reaction involves three steps taking place in a domino fashion, (i) carbonylation of ethyl diazoacetate leading to a ketene derivative, (ii) [2+2] cycloaddition of the ketene with the ferrocenylimine present in the reaction mixture resulting in the formation of a β-lactam and (iii) N(1)-C(4) cleavage of the β-lactam ring. In most cases, 2-(1-ferrocenyl-methylidene)-malonic acid derivatives are obtained as a separable mixture of E- and Z-isomers in ratios depending on the structure of the imine component.

Full text of DOI:10.1016/j.tetlet.2009.06.035

Tetrahedron Letters 50 (2009) 4727–4730
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Co2(CO)8-induced domino reactions of ethyl diazoacetate, carbon monoxide
and ferrocenylimines leading to 2-(1-ferrocenyl-methylidene)-malonic
acid derivatives
*
János Balogh, Tamás Kégl, Ferenc Ungváry, Rita Skoda-Földes
University of Pannonia, Institute of Chemistry, Department of Organic Chemistry, H-8201 Veszprém, PO Box 158, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel 2-(1-ferrocenyl-methylidene)-malonic acid derivatives are obtained upon reacting ethyl diazoace-
tate, carbon monoxide and ferrocenylimines in the presence of Co2(CO)8 as catalyst under mild condi-
tions. Presumably, the reaction involves three steps taking place in a domino fashion, (i) carbonylation
of ethyl diazoacetate leading to a ketene derivative, (ii) [2+2] cycloaddition of the ketene with the ferr-
ocenylimine present in the reaction mixture resulting in the formation of a b-lactam and (iii) N(1)-C(4)
cleavage of the b-lactam ring. In most cases, 2-(1-ferrocenyl-methylidene)-malonic acid derivatives are
obtained as a separable mixture of E- and Z-isomers in ratios depending on the structure of the imine
component.
Received 5 May 2009
Revised 22 May 2009
Accepted 5 June 2009
Available online 11 June 2009
Keywords:
Domino reactions, b-Lactams
Cobalt-catalysis
Carbonylation
Ó 2009 Elsevier Ltd. All rights reserved.
As part of our ongoing research towards the synthesis of ferro-
cene bioconjugates via transition metal-catalyzed carbonylation
reactions,1 we decided to investigate the possibility of the synthe-
sis of ferrocenyl b-lactams. The special properties of ferrocene,
such as high stability, reversible change of the valency state,
non-benzoic aromatic structure, low toxicity towards mammals
and potential as an iron source, make its derivatives ideal candi-
dates for drug design. In some cases, the introduction of a ferroce-
nyl moiety has been found to enhance the biological activity of the
original compound.2 It was shown that ferrocene-substituted pen-
icillin had improved stability to b-lactamase attack without a
reduction in antibiotic activity.3 Hence, it is no surprise that several
ferrocene-substituted b-lactam derivatives have been synthesized
and their antibiotic activity has been tested.4–9
Recently, a new domino reaction, comprising the cobalt-cata-
lyzed carbonylation of ethyl diazoacetate in the presence of nucle-
ophilic reagents leading to various malonic acid derivatives was
developed.10–12 The carbonylation step results in the formation of
ethoxycarbonylketene which can be scavenged by alcohols or sec-
ondary amines (Scheme 1).10,11 Also, the reaction has been shown
to produce N-alkyl-trans-1-ethoxycarbonyl-4-phenyl-b-lactams
using N-alkyl-benzaldimines as the nucleophiles.12
catalyst,13 we found that instead of the expected b-lactam, a mix-
ture of two isomeric 2-(1-ferrocenyl-methylidene)-malonic acid
derivatives, 2a and 3a, was produced (Scheme 2). As the one-step
synthesis of such compounds can also be of interest, we decided
to investigate this domino reaction in the presence of various ferr-
ocenylimines 1a–h (Scheme 2, Table 1).
The reaction conditions were determined based on the results
of a detailed investigation of a similar reaction of N-tert-butyl-
benzaldimine.12 The reaction of an equimolar amount of ferroce-
nylimine and ethyl diazoacetate in the presence of 5 mol % of
Co2(CO)8 under 80 bar CO pressure resulted in the selective forma-
tion of 2-(1-ferrocenyl-methylidene)-malonic acid derivatives. An
earlier study showed that, under ambient conditions, the reaction
of ethyl diazoacetate (EDA) with Co2(CO)8 gave dinitrogen and
ethoxycarbonylcarbene-bridged dicobalt carbonyl complexes
Co2(CO)7(CHCO2Et) and Co2(CO)6(CHCO2Et)2 depending on the
molar ratio of EDA and Co2(CO)8.10 Under an atmosphere of carbon
monoxide, the ethoxycarbonylcarbene ligand of these complexes
couples with CO to give ethoxycarbonylketene which is replaced
by CO. The highly reactive ethoxycarbonylketene either dimerizes
or reacts with ferrocenylimines 1a–h leading to b-lactam
derivatives.
However, upon reacting ferrocenylimine 1a with ethyl diazo-
acetate and carbon monoxide in the presence of Co2(CO)8 as the
The formation of 2-(1-ferrocenyl-methylidene)-malonic acid
derivatives can be rationalized by the N(1)-C(4) cleavage of the ini-
tially formed b-lactams. It should be mentioned that no lactam
products could be isolated or could be detected by GC–MS in the
reaction mixtures which show that the ferrocenyl lactam structure
is highly unstable under the present reaction conditions.
* Corresponding author. Tel.: +36 88 624719; fax: +36 88 624469.
E-mail address: skodane@almos.uni-pannon.hu (R. Skoda-Földes).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.06.035

4728
J. Balogh et al. / Tetrahedron Letters 50 (2009) 4727–4730
O
O
HC C O
O
Co2(CO)8
O
Nu
EtO
CHN2
+ CO + NuH
EtO
EtO
+ NuH
Nu = OMe, OEt, OtBu, OPh, NEt2
Scheme 1. Cobalt-catalyzed carbonylation of ethyl diazoacetate in the presence of nucleophilic reagents.
O
NR
RN
H
O
CO2Et
Co2(CO)8
CHN2
+ CO +
Fe
Fe
EtO
1a R = n-Bu
1b R = i-Pr
RHN
1c R = c-Hex
1d R = t-Bu
H
CO2Et
O
RHN
H
O
1e R = CH2Ph
CO2Et
1f R = 4-MeOC6H4CH2
1g R = CH3(CH)Ph
1h R = 4-MeC6H4
+
Fe
Fe
3a-g (E-isomer)
2a-c, e-h (Z-isomer)
Scheme 2. Domino reaction of ethyl diazoacetate, carbon monoxide and ferrocenylimines 1a–h in the presence of Co2(CO)8.
Table 1
Synthesis of 2-(1-ferrocenyl-methylidene)-malonic acid derivatives 2 and 3 via the domino reaction of ethyl diazoacetate, carbon monoxide and ferrocenylimines 1a–ha
Entry
Imine
Ratio of productsb
Combined yields of products 2 and 3 (%)
2
3
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
18
38
16
0
15
13
11
82
62
84
100
85
87
89
0
48
34
50
33
54
39
82
26
1g
1h
100
a
Reaction conditions: 5 mol % Co2(CO)8, imine/ethyl diazoacetate = 1/1, in CH2Cl2, 80 bar CO, room temperature, 24 h.
Determined from the yields of 2 and 3.
b
N(1)-C(4) cleavage of b-lactams is not unprecedented, but until
although both isomers were detected in the reaction mixture by
GC–MS.17
now, similar reactions were shown to proceed by palladium-cata-
lyzed hydrogenolysis14 or in the presence of either an excess of a
base (NaH15 or LDA7) or an excess of an acid (p-TsOH).9 To the best
of our knowledge, complete N(1)-C(4) cleavage under neutral con-
ditions has not been reported before.
Both the conversion of ferrocenylimines and the selectivities of
the reactions depend greatly on the properties of the substituent
on the imine nitrogen. With the exception of the reaction of 1d,
the use of N-alkyl or N-arylalkylimines as reaction partners led to
a mixture of two isomeric products16 in moderate to good yields.
In contrast, reactions of 1d and the N-arylimine 1h resulted in a
single E or Z isomeric product.
The structures of the two isomers 2a and 3a were proved
unequivocally by NOESY experiments. Cross peaks were observed
between the protons of the substituted cyclopentadienyl ring (at
4.51 ppm) and the amide NH proton (at 5.76 ppm) in the spectrum
of 3a as well as between the same ferrocenyl protons and the NCH2
protons at 3.31 ppm. No such cross peaks were observed in the
NOESY spectrum of 2a.
The structure, as well as the relative energies of 2-(1-ferrocenyl-
methylidene)-malonic acid derivatives has been computed within
the framework of the density functional formalism.18 The B3LYP
functional was employed19 in combination with the 6-31G(d,p) ba-
sis set.20 For preliminary calculations the N-n-butyl derivatives
were chosen, that is, 2a and 3a (Z- and E-isomers, respectively).
For both isomers, both the s-trans (designated as 2a1 and 3a1)
and s-cis (2a2 and 3a2) conformers were considered and are de-
picted in Figure 1. The species 3a1 is lowest in energy among the
four isomers, whilst the relative energies of the other unsaturated
amides are in a small range between 2.3 kcal/mol (2a1) and
2.8 kcal/mol (2a2). The s-cis conformer 3a2 is higher in energy by
The latter results are in accordance with the previous findings
of Bonini9 and Brown17 concerning the synthesis of N-aryl- and
N-t-butylamido malonates, respectively. Bonini and co-workers
synthesized various
a,b-unsaturated amides by acidic cleavage of
4-ferrocenyl-N-aryl-b-lactams and they observed the exclusive for-
mation of the Z-isomers.9 In contrast, only the more stable E-ethyl
tert-butylamido-benzylmalonate was isolated from the Knoevena-
gel condensation of benzaldehyde with ethyl t-butylamidoacetate,

J. Balogh et al. / Tetrahedron Letters 50 (2009) 4727–4730
4729
Figure 2. Electron delocalization between carbon–carbon
p-bonds and a one-
centre natural bond orbital of d-character of the iron of isomer 3a1.
positive hydrogen, and less negative oxygen compared to the other
isomers.
In order to shed some light on the electron delocalization of the
ferrocene-substituted unsaturated amides, the natural bond–bond
polarizability indices (NBBP)21 were examined. The NBBP indices
are indicative of how perturbation of one bond will affect the oth-
ers through conjugative or hyperconjugative couplings. The ole-
finic carbon–carbon bond shows a fairly high NBBP value (0.369)
with one of the one-centre natural bond orbitals (NBOs) of iron,
as well as with one of the NBOs of p-symmetry of the cyclopenta-
dienyl ring (0.261). The NBO analysis reveals that the dxy orbital of
Fe has the highest contribution in the one-centre NBO involved in
the conjugated system. The extended electron delocalization in
3a1 is depicted in Figure 2.
In summary, the domino reaction presented herein can serve as
an efficient method for the synthesis of 2-(1-ferrocenyl-methyli-
dene)-malonic acid derivatives from ferrocenylimines in a single
operation and under relatively mild conditions. Research towards
optimization of the reaction conditions and clarification of the
influence of the structure of the imine on the selectivity of the
reaction is in progress.
Acknowledgements
The authors thank the Hungarian National Science Foundation
for financial support (OTKA NK71906). The support of Bolyai Grant
of the Hungarian Academy of Sciences for T.K. is also
acknowledged.
References and notes
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Varchi, G. Synlett 2001, 1092–1096.
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Figure 1. Computed structures of the N-n-butyl unsaturated amides 2a and 3a.
Bond lengths are given in Å, ZPVE-corrected relative energies are given in kcal/mol.
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ˇ
ˇ
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2.6 kcal/mol than 3a1, thus for both the E- and Z-isomers, the s-
trans conformers are predicted to be more stable.
The higher stability of 3a1 can be rationalized by a weak hydro-
gen bond between the olefinic hydrogen and the sp3 oxygen of the
ester group. Natural population analysis reveals a somewhat less
}
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}
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1994–2002.

4730
J. Balogh et al. / Tetrahedron Letters 50 (2009) 4727–4730
13. In
a
typical reaction 0.3 mmol of ferrocenylimine, 0.3 mmol of ethyl
3.31 (q, J = 7.0 Hz, 2H, NHCH2); 1.48 (quin, J = 7.0 Hz, 2H, CH2); 1.31 (sext,
J = 7.0 Hz, 2H, CH2); 1.25 (t, J = 7.3 Hz, 3H, CH3); 0.86 (t, J = 7.0 Hz, 3H, CH3). 13
NMR (d): 166.6; 165.4; 143.6; 124.1; 75.9; 71.7; 70.7; 69.9; 61.1; 39.4; 31.3;
20.0; 14.2; 13.7. MS (m/z/rel. int.): 383 (M+) (100); 318 (69); 274 (21); 121
(18); 56 (6).
diazoacetate and 0.015 mmol of Co2(CO)8 were reacted in a stainless steel
autoclave in 3 ml of CH2Cl2 as solvent under 80 bar CO pressure at room
temperature for 24 h. The solvent was removed in vacuo and the residue was
purified by column chromatography (silica gel, eluent: n-hexane/EtOAc = 3/1).
14. Ojima, I.; Qiu, X. J. Am. Chem. Soc. 1987, 109, 6537–6538.
C
17. Brown, J. M.; Guiry, P. J.; Laing, J. C. P.; Hursthouse, M. B.; Malik, K M. A.
Tetrahedron 1995, 51, 7423–7434.
18. For all calculations the PC GAMESS/Firefly software was applied (Alex A.
15. Alcaide, B.; Domínguez, G.; Martín-Domenech, A.; Plumet, J.; Monge, A.; Pérez-
García, V. Heterocycles 1987, 26, 1461–1466.
16. Selected spectroscopic data for 2a: 1H NMR (d):7.91 (s, 1H, =CH); 7.39 (t,
J = 7.3 Hz, 1H, NH); 4.43 (t, J = 1.8 Hz, 2H, Cp); 4.40 (t, J = 1.8 Hz, 2H, Cp); 4.21
(q, J = 7.2 Hz, 2H, OCH2); 4.12 (s, 5H, Cp); 3.29 (q, J = 7.3 Hz, 2H, NHCH2); 1.49
(quin, J = 7.3 Hz, 2H, CH2); 1.32 (sext, J = 7.3 Hz, 2H, CH2); 1.23 (t, J = 7.2 Hz, 3H,
CH3); 0.88 (t, J = 7.3 Hz, 3H, CH3). 13C NMR (d): 170.3; 169.3; 147.0; 120.4; 77.2;
71.5; 71.3; 69.8; 61.2; 39.7; 31.5; 20.2; 13.9; 13.8. MS (m/z/rel. int.): 383 (M+)
(100); 318 (68); 274 (22); 121 (14); 56 (7). Selected spectroscopic data for 3a: 1H
NMR (d): 7.48 (s, 1H, =CH); 5.76 (t, J = 7.0 Hz, 1H, NH); 4.51 (t, J = 1.8 Hz, 2H,
Cp); 4.38 (t, J = 1.8 Hz, 2H, Cp); 4.18 (q, J = 7.3 Hz, 2H, OCH2); 4.14 (s, 5H, Cp);
Granovsky,
http://classic.chem.msu.su/gran/gamess/index.html).
Natural
Population Analyses were completed with the NBO program (NBO 5.G.
Glendening, E. D.; Badenhoop, J. K.; Reed, A. E.; Carpenter, J. E.; Bohmann, J.
A.; Morales, C. M.; Weinhold, F. Theoretical Chemistry Institute, University of
Wisconsin, Madison, WI, 2004) implemented in the Firefly package.
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20. Hehre, W. J.; Ditchfield, R.; Pople, J. A. J. Chem. Phys. 1972, 56, 2257.
21. Zimmerman, H. E.; Weinhold, F. J. Am. Chem. Soc. 1994, 116, 1579–
1580.