Application of the octacarbonyldicobalt-catalyzed carbonylation of ethyl diazoacetate for the one-pot synthesis of n-tert-butyl-trans-α- ethoxycmbonyl- β-phenyl-β-lactam

Article abstract of DOI:10.1002/ejoc.200801247

N-tert-Butyl-trans-α-ethoxycarbonyl-β-phenyl-β-lactam has been prepared in 95% yield (GC) by the octacarbonyldicobalt-catalyzed carbonylation of ethyl diazoacetate in dichloromethane in the presence of ZV-tert-butylbenzaldimine at 10 °C and 75 bar pressur

Full text of DOI:10.1002/ejoc.200801247

FULL PAPER
DOI: 10.1002/ejoc.200801247
Application of the Octacarbonyldicobalt-Catalyzed Carbonylation of Ethyl
Diazoacetate for the One-Pot Synthesis of N-tert-Butyl-trans-α-ethoxycarbonyl-
β-phenyl-β-lactam
Eszter Fördo˝s,[a] Róbert Tuba,[b] László Párkányi,[c] Tamás Kégl,[a] and Ferenc Ungváry*[a,b]
Dedicated to Professor László Markó on the occasion of his 80th birthday
Keywords: Cobalt / Carbene ligands / Carbonyl ligands / C–C coupling / Lactams / Density functional calculations
N-tert-Butyl-trans-α-ethoxycarbonyl-β-phenyl-β-lactam has
been prepared in 95% yield (GC) by the octacarbonyldico-
balt-catalyzed carbonylation of ethyl diazoacetate in dichlo-
romethane in the presence of N-tert-butylbenzaldimine at
10 °C and 75 bar pressure of carbon monoxide. The key step
of the reaction is the catalytic formation of the highly reactive
(ethoxycarbonyl)ketene from both of the intermediary com-
plexes [Co2(CO)7(CHCO2Et)] and [Co2(CO)6(CHCO2Et)2],
which is in situ scavenged by the imine in a [2+2] cycload-
dition reaction. DFT (PBEPBE/6-31G**) calculations re-
vealed that the reaction follows a two-step mechanism via a
noncyclic intermediate with
a reaction free energy of
–15.9 kcal/mol and a free-energy barrier of 24.7 kcal/mol for
the second rate-limiting step. The computation also shows
that the formation of the trans isomer is preferred both kinet-
ically and thermodynamically.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
pounds.[6,7] We found that imines are also suitable scaven-
gers for the in situ formed unstable ketene leading to β-
lactams. Herein we report the selective one-pot synthesis of
N-tert-butyl-trans-α-ethoxycarbonyl-β-phenyl-β-lactam by
the octacarbonyldicobalt-catalyzed carbonylation of ethyl
diazoacetate in the presence of N-tert-butylbenzaldimine.
It is generally assumed[8] that the [2+2] ketene/imine cy-
cloaddition is a stepwise reaction involving a zwitterionic
intermediate formed after a stereoselective attack by the ni-
trogen lone pair of the imine on the sp-carbon atom of the
ketene. In the second rate-determining step, the intermedi-
ate undergoes an electrocyclic conrotatory ring-closure to
give the final product, the β-lactam. The existence of zwit-
terionic intermediates was proved experimentally in the
thermal reaction of ketenes with imidazoles by using IR
spectroscopy at low temperature.[9] Some ab initio studies,
however, predict that the mechanism for the reaction be-
tween formaldimine and ketene takes place by a concerted
mechanism.[10] The two possible pathways of the Staudinger
reaction are outlined in Scheme 1.
Introduction
β-Lactams have found broad medical applications in the
form of penicillin and cephalosporin antibiotics. On the
other hand, enantiopure β-lactams have become important
as versatile building blocks in the asymmetric synthesis of
proteinogenic and non-proteinogenic amino acids, peptido-
mimetics, heterocycles, and other types of compounds of
biological importance.[1] To prepare β-lactams the Staud-
inger [2+2] cycloaddition reaction between an imine and a
ketene[2,3] and its variants has been widely used.[4,5] Appli-
cation of the Staudinger reaction with (ethoxycarbonyl)ke-
tene, EtO2CCH=C=O, however, is impeded by the fact that
this highly reactive ketene cannot be isolated under ambient
conditions.
The cobalt-catalyzed carbonylation of ethyl diazoacetate
results in the formation of (ethoxycarbonyl)ketene, which
can be scavenged by OH, NH, and suitable CH com-
[a] Department of Organic Chemistry, University of Pannonia
Egyetem u. 10, 8201 Veszprém, Hungary
Fax: +36-88-624-469
E-mail address: ungvary@almos.vein.hu
[b] Research Group for Petrochemistry, Hungarian Academy of
Sciences,
Egyetem u. 10, 8201 Veszprém, Hungary
[c] Institute of Structural Chemistry, Chemical Research Center,
Hungarian Academy of Sciences,
In the two-step mechanism, close similarity was found
between the second transition state, corresponding to the
electrocyclic conrotatory ring-closure of the zwitterionic in-
termediate, and the transition-state structures of the electro-
cyclic ring-opening of cyclobutenes described by Houk and
co-workers.[11] The special stereoselectivity associated with
such reactions is termed as torquoselectivity. The influence
of substituents governing the torquoselectivity has been ex-
P. O. Box 17, 1525 Budapest, Hungary
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
1994
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 1994–2002

Octacarbonyldicobalt-Catalyzed Carbonylation Reactions
Scheme 1. Possible pathways for the [2+2] Staudinger reaction.
amined in various theoretical studies.[12] It was found that
donor groups prefer outward rotation in the transition
state, whereas strong acceptors prefer inward rotation.
The existence of a zwitterionic intermediate would sug-
gest that the stabilization energy of the solvent plays an
important role, especially if the inward–outward energy dif-
ference of the intermediates and transition-state structures
are small.[13] Other studies have shown, however, that the
introduction of solvation did not influence the diastereo-
selectivity or the overall reaction energetics.[14]
Results and Discussion
Figure 1. ORTEP drawing of N-tert-butyl-trans-α-ethoxycarbonyl-
β-phenyl-β-lactam.
Catalytic Syntheses
We found that a stoichiometric mixture of ethyl diazo- of formation of TBL between 1 and 3 h of reaction time
acetate (EDA) and N-tert-butylbenzaldimine (BTB) in can be estimated as rTBL[1–3 h; 10 °C; P(CO) = 50 bar] =
CH2Cl2 solution in the presence of a catalytic amount of 0.47ϫ10–5 mol/dm3 s.
[Co2(CO)8] can be converted under carbon monoxide pres-
To see the effect of the concentrations of [Co2(CO)8],
sure at room temperature into N-tert-butyl-trans-α-ethoxy- EDA, and BTB, we performed experiments at 10 °C and
carbonyl-β-phenyl-β-lactam (TBL) in up to 95% yield, as 50 bar CO pressure over 3 h with various initial concentra-
determined by quantitative IR spectroscopy and gas tions (Table 1). The data in Table 1 show that the amount
chromatography. The formation of this product can be of TBL formed is nearly linear with the initial concentra-
monitored by its characteristic absorptions at 1756 and tions of [Co2(CO)8] and EDA, and independent of the BTB
1728 cm–1 in the IR spectra of the reaction mixture. Isola- concentrations.
tion by column chromatography resulted in a white crystal-
The effect of CO pressure on the TBL formation was
line product with a melting point of 82 °C. The literature investigated at 10 °C in experiments started with different
has reported the trans isomer as a colorless oil at room tem- CO pressures between 1 and 170 bar by using [EDA]0 =
perature.[15] The 1H NMR spectrum of our product re- [BTB]0 = 0.50 mol/dm3 and [Co2(CO)8]0 = 0.025 mol/dm3
vealed clearly the trans structure in solution (JHH = 2.2 Hz and 3 h of reaction time. The data in Figure 3 show a maxi-
for the trans methine protons), which we confirmed by X- mum TBL yield at around 85 bar. Before this maximum the
ray crystallography of the crystalline product (see Figure 1 CO dependence is nearly linear between 10 and 75 bar CO
and Tables S1 and S2 of the Supporting Information). Most pressure. Beyond the maximum the effect of rising CO pres-
remarkable is the small torsion angle (4.2°) of C13–N1– sure is slightly negative.
C1–O1, which indicates that the hybridization of the lactam
The composition of the cobalt complexes in the reaction
nitrogen atom is sp2 rather than sp3. Consequently, there is mixture checked by IR spectroscopy after 3 h of reaction
a strong overlap between N1 and C1, which is reflected in time shows the presence of three different cobalt complexes:
the observed short N1–C1 bond [1.350(2) Å].
[Co2(CO)8], [Co2(CO)7(CHCO2Et)] (1), and [Co2(CO)6-
By monitoring the yield of TBL with time in the carbon- (CHCO2Et)2] (2), which can be recognized in the mixtures
ylation reaction (see Figure 2), a short induction period can by their characteristic ν(CO) bands at 2021, 2070, and
be observed, and from the points thereafter the initial rate 2080 cm–1, respectively. Their ratio depends on the CO pres-
Eur. J. Org. Chem. 2009, 1994–2002
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1995

E. Fördos, R. Tuba, L. Párkányi, T. Kégl, F. Ungváry
˝
FULL PAPER
Figure 3. Effect of CO pressure on the yield of N-tert-butyl-trans-
α-ethoxycarbonyl-β-phenyl-β-lactam (TBL) in experiments using
[EDA]0 = [BTB]0 = 0.50 mol/dm3 and [Co2(CO)8]0 = 0.025 mol/
dm3 and 3 h of reaction time.
Figure 2. Yield of N-tert-butyl-trans-α-ethoxycarbonyl-β-phenyl-β-
lactam (TBL) vs. reaction time in the [Co2(CO)8]-catalyzed carbon-
ylation reaction of ethyl diazoacetate (EDA) in the presence of N-
tert-butylbenzaldimine (BTB) at 10 °C and 50 bar CO pressure. Ini-
(1) and [Co2(CO)6(CHCO2Et)2] (2) depending on the molar
ratio of EDA/[Co2(CO)8], in accord with Equations (1) and
(2), respectively.[6]
tial concentrations: [Co2(CO)8]0
= =
0.025 mol/dm3; [EDA]0
[BTB]0 = 0.25 mol/dm3.
(1)
Table 1. Yield of N-tert-butyl-trans-α-ethoxycarbonyl-β-phenyl-β-
lactam (TBL) from the [Co2(CO)8]-catalyzed carbonylation reac-
tion of ethyl diazoacetate (EDA) in the presence of N-tert-bu-
tylbenzaldimine (BTB) at 10 °C and 50 bar CO pressure in 3 h of
reaction time by using various initial concentrations of the reac-
tants.
(2)
Under carbon monoxide the (ethoxycarbonyl)carbene li-
gand(s) of these complexes couple(s) with CO to give
(ethoxycarbonyl)ketene, which is replaced under carbon
monoxide by CO [see Equations (3) and (4)].[7]
Entry [Co2(CO)8]0
[mol/dm3]
[EDA]0
[BTB]0
Yield of TBL[a]
[%]
[mol/dm3] [mol/dm3]
1
2
3
4
5
6
7
8
9
0.003
0.006
0.013
0.025
0.050
0.025
0.025
0.025
0.025
0.025
0.025
0.025
0.25
0.25
0.25
0.25
0.25
0.13
0.25
0.50
0.75
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.12
0.25
0.50
2.4
4.3
10.8
19.7
25.0
3.0
16.6
37.9
52.1
15.2
16.6
16.1
(3)
(4)
10
11
12
Complex 2 reacts faster with carbon monoxide than
complex 1.[16] The highly reactive (ethoxycarbonyl)ketene
formed as a short-living organic product in the above reac-
tions either dimerizes or reacts with suitable scavengers
such as alcohols, phenols, and amines to give the corre-
sponding malonic ester derivatives in excellent yields [Equa-
tion (5)].[6,7]
[a] Determined by quantitative IR spectroscopy.
sure used in the experiment. At 1 bar CO pressure complex
2 prevails with Ͼ90% accompanied by Ͻ10% of complex
1. At 50 bar CO pressure the reaction mixture contains
Ͻ2% of complex 2, around 80% of complex 1, and Ͻ20%
of [Co2(CO)8]. At 150 bar CO pressure Ͼ90% of the cobalt
is in the form of [Co2(CO)8], the rest is in the form of com-
plex 1.
(5)
Our earlier investigations have shown that under ambient
conditions the reaction of ethyl diazoacetate (EDA) with
(Ethoxycarbonyl)ketene may react with the CH acid
[Co2(CO)8] gives dinitrogen and (ethoxycarbonyl)carbene- ethyl diazoacetate to give diethyl 2-diazo-3-oxoglutarate
bridged carbonyldicobalt complexes [Co2(CO)7(CHCO2Et)] [Equation (6)].[6]
1996
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Octacarbonyldicobalt-Catalyzed Carbonylation Reactions
(6)
various pressures of carbon monoxide depicted in Figure 3.
The bottleneck in the catalytic reaction in the low-pressure
range might be the rate-determining reaction of the inter-
mediary complex 2 with carbon monoxide, whereas in the
high-pressure range the formation of the intermediary com-
plex 1 might be rate-determining.
We found that among various imines PhCH=NtBu is
also an excellent scavenger of the in situ formed unstable
(ethoxycarbonyl)ketene [Equation (7)]. Thus, the reaction
of either complex 1 or complex 2 with carbon monoxide in
the presence of PhCH=NtBu gives the β-lactam TBL as a
result of the 2+2 cycloaddition reaction in Equation (7).
To identify which step in the catalytic cycles is the real
bottleneck under various reaction conditions a detailed ki-
netic investigation of all the assumed steps in Scheme 2 is
underway.
(7)
Theoretical Results
We found that not only PhCH=NtBu but other imines of
The structures of the two possible β-lactam isomers pos-
the type PhCH=NR (R = Me and CH2Ph) are also suitable sessing the ethoxycarbonyl group with the most favorable
scavengers for the in situ formed unstable (ethoxycarbonyl)- conformation were computed at the PBEPBE/6-31G(d,p)
ketene leading to β-lactams (see Exp. Sect.). On the other level of theory and are depicted in Figure 4. The trans iso-
hand, diphenyl ketimine Ph2C=NH, having an N–H bond, mer is designated as TBL1 and the cis isomer is designated
does not give as scavenger β-lactam, but affords the malonic as TBL2. The bond lengths in TBL1 are in reasonable
ester derivative EtO2CCH2C(=O)N=CPh2 in excellent yield agreement with the corresponding X-ray structure (see
(see Exp. Sect.).
Table S1 and Figure 1). However, the difference between the
Because the intermediary (ethoxycarbonyl)ketene can be experimental and computed C13–N1–C1–O1 dihedral
formed from both complexes 1 and 2 by the reaction with angles is notable as the former is 4.2°, whereas the latter is
carbon monoxide,[6,7] two different catalytic cycles (see 16.2°. Thus the N-tert-butyl substituent is somewhat bent
Scheme 2) can serve to produce the β-lactam in the subse- out of the lactam plane.
quent fast reaction with the imine. In accord with the ob-
TBL1 is 2.5 kcal/mol more stable than TBL2 in terms of
served composition of the complexes in the reaction mix- free energy, which may be attributed to the greater repulsion
ture, at a high pressure of carbon monoxide the operating of the ethoxycarbonyl and the phenyl groups in the latter.
catalytic cycle involves most probably [Co2(CO)7] and This is also reflected in the longer C2–C3 distance in TBL2.
[Co2(CO)7(CHCO2Et)] (1), whereas at a low pressure of The topological analysis of TBL1 (see Figure 5) reveals that
carbon monoxide [Co2(CO)6(CHCO2Et)] and [Co2(CO)6- the electron density is unevenly distributed inside the ring.
(CHCO2Et)2] (2) are the working catalytic species. This Interestingly, the distortion of the density distribution only
might explain the experimental observation obtained at slightly influences the position of the ring critical point.
Scheme 2. Assumed steps in the cobalt-catalyzed carbonylation of ethyl diazoacetate in the presence of N-tert-butylbenzaldimine.
Eur. J. Org. Chem. 2009, 1994–2002
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E. Fördos, R. Tuba, L. Párkányi, T. Kégl, F. Ungváry
˝
FULL PAPER
Figure 4. Computed structure of N-tert-butyl-trans-α-ethoxycarbonyl-β-phenyl-β-lactam (TBL1) and N-tert-butyl-cis-α-ethoxycarbonyl-
β-phenyl-β-lactam (TBL2). Selected bond lengths are given in Å.
Within the framework of the atoms in molecules (AIM)
analysis the bond ellipticity at the BCP can be determined,
which can be used as a quantitative index of the π character
of a bond. The analysis of TBL1 shows that the ellipticity
of the N1–C1 bond in the bond critical point is 0.178; thus,
the charge density distribution is not cylindrical, predicting
a double bond character. The electronic structure of the β-
lactam ring has also been investigated within the framework
of the natural bond orbital (NBO) analysis. The short N1–
C1 bond is rationalized by the strong interaction of the N1
lone pair with the π* antibonding orbital between C1 and
O1. For this donor–acceptor interaction the second-order
perturbation energy is 45.3 kcal/mol; the nN1 Ǟ π*N1–C1
overlap is depicted in Figure 6a. The occupancy of nN1 is
reduced from 2 (the theoretical limit) to 1.65, whereas the
occupancy of π*N1–C1 is increased from 0 to 0.31. Owing to
the hyperconjugative interaction of the O1 lone pair both
σC1–N1 and σC1–C2 are weakened with perturbation energies
of 22.1 and 23.6 kcal/mol, respectively (see Figure 7b and
Figure 5. Contour line diagram of the Laplacian distribution ٌ2ρ(r)
c).
of TBL1 in the plane of the lactam ring. Solid lines indicate charge
The NMR parameters of TBL1 and TBL2 were pre-
dicted by using the GIAO methodology. The 13C NMR
chemical shifts are in accord with experimental values (see
concentration [ٌ2ρ(r) Ͻ 0], dashed lines indicate charge depletion
[ٌ2ρ(r) Ͼ 0]. The grey dot indicates the ring critical point (RCP)
in the lactam ring.
Figure 6. Second-order perturbation interactions of the natural bond orbitals of TBL1. (a) Interaction between the lone pair of N and
the π*C–N antibonding orbital; (b) hyperconjugation between one of the lone pairs of O and the σ*C–N antibonding orbital; (c) hyperconju-
gation between one of the lone pairs of O and the σ*C–C antibonding orbital.
1998
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Octacarbonyldicobalt-Catalyzed Carbonylation Reactions
Figure 7. Gibbs free-energy profiles for the possible mechanisms of the reaction of N-tert-butylbenzaldimine with (ethoxycarbonyl)ketene.
Table 2); however, the shifts of the carbonyl carbon signals
In the first step of the two-step pathways new σC–N
are underestimated by 8–10 ppm. Not surprisingly, compar- bonds are formed that result in noncyclic intermediates
ing TBL1 and TBL2, the biggest difference in chemical INT1 and INT2 via transition states TS1 and TS2, respec-
shifts is shown for the methine carbon atoms C2 and C3 as tively, with free energy barriers of about 14 kcal/mol. The
well as for the ipso carbon atom C7. The computed spin– computed geometry of INT1 is shown in Figure 8. The
spin coupling for the two methine protons in TBL1 is analogous intermediates are usually described in the litera-
2.28 Hz, in excellent agreement with the experimental value ture to be of zwitterionic character; however, natural pop-
of 2.23 Hz. For TBL2 the corresponding value is J = ulation analysis (NPA) revealed a rather covalent character
0.76 Hz.
for INT1 with a partial charge of –0.284 for the N1 atom
and –0.599 for the O1 atom. The corresponding partial
charges in the product TBL1 are –0.462 and –0.556, respec-
tively, which indicate that N1 becomes more negative after
ring closure, whereas the charge on O1 does not change
significantly. Also notable is the difference in the charges
on the C2 and C3 atoms in the cyclic and noncyclic com-
pounds as the partial charge on C2 is more negative and
the charge on C3 is more positive than those in TBL1 or in
TBL2. The NPA charges for TBL1 or TBL2 as well as those
for INT1 are summarized in Table 3.
Table 2. Computed 13C NMR chemical shifts for TBL1 and TBL2.
δ [ppm]
C1
C2
C3
C4
C7
C13
trans (experimental) 162.1 62.4 56.4 167.1 139.1 55.1
trans (computed)
cis (computed)
152.3 66.3 59.9 159.2 134.9 58.6
151.9 61.9 61.8 159.0 131.2 58.5
The pathways of the [2+2] cycloaddition reaction of N-
tert-butylbenzaldimine and (ethoxycarbonyl)ketene show
close similarity to analogous reactions reported in the lit-
erature. The three possible pathways are (i) a two-step
mechanism via a noncyclic intermediate and a subsequent
conrotatory ring-closure resulting in the trans isomer TBL1,
(ii) the analogous reaction resulting in the cis isomer TBL2,
and (iii) a one-step reaction resulting in the trans isomer.
We found no path to the cis isomer by a concerted pathway,
probably for steric reasons. Note that the one-step pathway
can be ruled out as a viable pathway leading to TBL1 due
to the high free-energy barrier associated with the transition
state TS5. The proposed mechanistic pathways are depicted
in Figure 7. Both isomers are formed in an exothermic reac-
tion. The reaction free energy for the formation of TBL1 is
higher by 2.5 kcal/mol than that of TBL2, in accord with
the higher thermodynamic stability of the former.
Figure 8. Computed structure of the formally zwitterionic interme-
diate INT1. Selected bond lengths are given in Å.
Eur. J. Org. Chem. 2009, 1994–2002
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1999

E. Fördos, R. Tuba, L. Párkányi, T. Kégl, F. Ungváry
˝
FULL PAPER
Table 3. Natural population analysis (NPA) charges of TBL1, TBL2, and INT1.
O1
N1
C1
C2
C3
C4
O2
O3
C7
C13
TBL1
TBL2
INT1
–0.556
–0.559
–0.599
–0.462
–0.461
–0.284
0.684
0.684
0.535
–0.440
–0.439
–0.553
–0.065
–0.051
0.166
0.789
0.788
0.720
–0.577
–0.562
–0.655
–0.515
–0.520
–0.534
–0.067
–0.081
–0.126
0.125
0.125
0.130
with an Agilent 6890N instrument equipped with a mass-selective
detector working at 70 eV and by using a 30 m, 0.25 mm i.d.,
0.25 µm SPB 5 column. TLC tests were performed on Silica 60F254
plates (Merck, Fluka), and the Rf values refer to tests with ethyl
acetate/hexanes (1:3) or dichloromethane. Flash chromatography[20]
was carried out by using Kieselgel (200–400 mesh, 60 Å, Sigma–
Aldrich) with ethyl acetate/hexanes (1:3) or dichloromethane as the
eluent. 1H NMR spectra were recorded with a Bruker 400 MHz
spectrometer by using CDCl3 as the solvent. Chemical shifts δ are
reported in ppm relative to CHCl3 (δ =5.24 ppm). 13C NMR spec-
In the second rate-limiting step the conrotatory ring-clo-
sure via transition states TS3 and TS4 results in TBL1 and
TBL2, respectively. The overall free-energy barrier is
smaller for the trans isomer by 0.9 kcal/mol, which indicates
that the formation of TBL1 is also preferred kinetically over
TBL2.
Conclusions
tra were recorded with
a Bruker 400 MHz spectrometer at
The present results have proved that N-tert-butyl-benz-
aldimine (BTB) is an effective scavenger of the intermediary
(ethoxycarbonyl)ketene in the cobalt-catalyzed carbon-
ylation of ethyl diazoacetate (EDA) and affords N-tert-bu-
tyl-trans-α-ethoxycarbonyl-β-phenyl-β-lactam (TBL) selec-
tively, which can be isolated in good yields. Investigation of
the mechanism of the catalysis has shown that the origin of
the TBL product might be the result of two different cata-
lytic cycles, both producing the intermediary (ethoxycar-
bonyl)ketene. In accord with the observed composition of
the complexes in the reaction mixture, at a high pressure of
carbon monoxide the operating catalytic cycle involves
most probably [Co2(CO)7] and [Co2(CO)7(CHCO2Et)] (1),
whereas at a low pressure of carbon monoxide [Co2(CO)6-
(CHCO2Et)] and [Co2(CO)6(CHCO2Et)2] (2) are the work-
ing catalytic species. In accord with the observed CO depen-
dence of the catalytic reaction, the bottleneck in the cata-
lytic reaction in the low-pressure range might be the rate-
determining reaction of the intermediary complex 2 with
carbon monoxide, whereas in the high-pressure range the
formation of the intermediary complex 1 might be the rate-
determining step. In agreement with experiments, computa-
tional studies revealed that the trans isomer of TBL (TBL1)
is the preferred product both kinetically and thermodynam-
ically. In contrast with the analogous reactions described in
the literature it can be concluded that in the case of (ethoxy-
carbonyl)ketene the noncyclic intermediate of the two-step
reaction is of a covalent rather than a zwitterionic charac-
ter.
100 MHz by using CD2Cl2 as the solvent. Chemical shifts δ are
reported in ppm relative to CH2Cl2 (δ =53.10 ppm). Microanalyses
were performed by using a CHNS-O EA1108 Elemental Analyser
(Carlo Erba). Octacarbonyldicobalt was prepared according to a
literature procedure[23] and was twice recrystallized under carbon
monoxide, first from dichloromethane and then from n-heptane. X-
ray crystal structure determination: Intensity data were collected
with a Rigaku R-axis Rapid IP diffractometer at ambient tempera-
ture with Mo-Kα radiation (λ = 0.7107 Å); the structure was solved
by direct methods[21] and refined by full-matrix least squares[22]
against F2. CCDC-713051 contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Preparation of N-tert-Butyl-trans-α-ethoxycarbonyl-β-phenyl-β-lac-
tam: A solution of ethyl diazoacetate (0.106 mL, 1.0 mmol) and
N-tert-butylbenzaldimine (0178 mL, 1.0 mmol) in CH2Cl2 (5.0 mL)
and an open glass insert loaded with [Co2(CO)8] (17.1 mg,
0.05 mmol) was placed under carbon monoxide into a stainless-
steel autoclave (total capacity 20 mL) and pressurized at room tem-
perature with CO to 75 bar pressure. After shaking at 10 °C for
24 h, the pressure was slowly released. The IR spectrum of the
brown solution showed weak bands of various carbonylcobalt com-
plexes in the range of 1800–2100 cm–1, very strong bands of N-tert-
butyl-trans-α-ethoxycarbonyl-β-phenyl-β-lactam at 1756 and
1728 cm–1 (corresponding to 90% yield) and very weak bands of
unreacted N-tert-butylbenzaldimine at 1640 and 1580 cm–1. Gas
chromatographic analyses with n-octane and n-hexadecane as in-
ternal references showed the presence of benzaldehyde (2%), N-
tert-butylbenzaldimine (4%), and N-tert-butyl-trans-α-ethoxycar-
bonyl-β-phenyl-β-lactam (95%, based on the starting N-tert-bu-
tylbenzaldimine). TLC analyses showed that the N-tert-butyl-trans-
α-ethoxycarbonyl-β-phenyl-β-lactam product separates well giving
an isolated spot at Rf = 0.51 with ethyl acetate/hexanes (1:3) as
eluent. The solvent from the crude reaction mixture was removed
under vacuum, and the brown oily residue was subjected to flash
chromatography on Kieselgel (200–400 mesh, 60 Å, i.d. 1 cm,
height 45 cm) with ethyl acetate/hexanes (1:3) (60 mL) as the elu-
ent. N-tert-Butyl-trans-α-ethoxycarbonyl-β-phenyl-β-lactam was
obtained from the fractions after concentration in vacuo as a white
crystalline solid (95.1 mg, 0.345 mmol, 34.5% isolated yield). M.p.
82 °C. C16H21NO3 (275.34): calcd. C 69.79, H 7.69, N 5.09; found
Experimental Section
General: Handling of the carbonylcobalt complexes was carried out
in dry (P4O10) and deoxygenated (BTS contact, room temp.) argon
or carbon monoxide by utilizing standard Schlenk techniques.[17]
Solvents were dried and distilled under argon according to stan-
dard procedures.[18] IR spectra were recorded with a Thermo Nico-
let Avatar 330 FTIR spectrometer by using 0.00265, 0.00765,
0.02095, or 0.05097 cm CaF2 solution cells calibrated by the inter-
ference method.[19] Gas chromatographic analyses were performed
with an HP 5890D instrument with FID by using a 30 m, 0.32 mm
i.d., 0.25 µm SPB 1 column. The GC/MS analyses were performed
C 68.76, H 8.34, N 5.21. IR (CH Cl ): ν (ε ) = 1756 (1295),
˜
2
2
M
1728 cm–1 (645 cm2/mmol). 1H NMR (CDCl3): δ = 1.27 (s, 9 H,
2000
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Eur. J. Org. Chem. 2009, 1994–2002

Octacarbonyldicobalt-Catalyzed Carbonylation Reactions
CH3), 1.29 (t, JHH = 7.1 Hz, 3 H, CH3), 3.67 (d, JHH = 2.2 Hz, 1
spectra are similar to the spectra of the known N-methyl-trans-α-
methoxycarbonyl-β-phenyl-β-lactam.[25]
H, CH), 4.21 (dq, JHH = 2.2, 7.1 Hz, 2 H, CH2), 4.82 (d, JHH
=
2.2 Hz, 1 H, CH), 7.3–7.42 (m, 5 H, Ph) ppm. 13C NMR (CDCl3):
δ = 14.1 (CH3), 28.0 [C(CH3)3], 55.1 [C(CH3)3], 56.4 (C6H5CH),
61.7 (CH2), 62.4 (EtO2CCH), 126.6 (o-C6H5), 128.7 (p-C6H5),
128.9 (m-C6H5), 139.1 (ipso-C6H5), 162.1 (N-CO), 167.1 (EtO-CO)
ppm. The NMR spectra are identical to those in the literature.[15]
GC/MS: m/z (%) = 275 (0.28) [M]+, 176 (65), 148 (26), 131 (100),
103 (25).
Preparation of Ethyl 3-[(Diphenylmethylene)amino]-3-oxopropano-
ate (EtO2CCH2C(=O)N=CPh2): By using diphenyl ketimine
(0.502 mL, 3.0 mmol), ethyl diazoacetate (0.315 mL, 3.0 mmol),
and [Co2(CO)8] (10.3 mg, 0.03 mmol) in the above procedure the
IR spectrum of the crude reaction product showed strong bands of
EtO2CCH2C(=O)N=CPh2 at 1740, 1691, and 1635 cm–1 and weak
bands at 1599 and 1579 cm–1. TLC analyses showed that the
EtO2CCH2C(=O)N=CPh2 product separates well giving an iso-
lated spot at Rf = 0.40 with ethyl acetate/hexanes (1:3) as eluent.
Separation of 1/10 of the crude reaction mixture on preparative
plates gave EtO2CCH2C(=O)N=CPh2 (47.3, 0.16 mmol, 53%
yield) as a yellow oil. The IR spectrum in CH2Cl2 is identical to
Preparation of N-Benzyl-trans-α-ethoxycarbonyl-β-phenyl-β-lactam:
By using N-benzylbenzaldimine (0190 mL, 1.0 mmol) in the above
procedure the IR spectrum of the crude reaction product showed
weak bands of various carbonylcobalt complexes in the range of
1800–2100 cm–1, strong bands of N-benzyl-trans-α-ethoxycarbonyl-
β-phenyl-β-lactam at 1767 and 1731 cm–1 (corresponding to a 32%
yield), and very weak bands of unreacted N-benzylbenzaldimine at
1644, 1600, and 1580 cm–1. Gas chromatographic analyses with n-
hexadecane as the internal reference showed the presence of benzal-
dehyde (9%), N-benzylbenzaldimine (14%), and N-benzyl-trans-α-
ethoxycarbonyl-β-phenyl-β-lactam (37%, based on the starting N-
tert-butylbenzaldimine). TLC analyses showed that the N-benzyl-
trans-α-ethoxycarbonyl-β-phenyl-β-lactam product separates well
giving an isolated spot at Rf = 0.23 with dichloromethane. Flash
chromatography was performed on Kieselgel (200–400 mesh, 60 Å,
i.d. 1 cm, height 45 cm) with dichloromethane (190 mL) as the elu-
ent. N-Benzyl-trans-α-ethoxycarbonyl-β-phenyl-β-lactam was ob-
tained from the fractions after concentration in vacuo as a colorless
that of the crude reaction mixture: ν (ε ) = 1740 (411), 1691 (273),
˜
M
1635 (260) 1599 (49) 1579 cm–1 (79 cm2/mmol). C18H17NO3
(295.33): calcd. C 73.20, H 5.80, N 4.74; found C 72.11, H 5.89, N
4.34. 1H NMR (CDCl3): δ = 1.17 (t, JHH = 7.0 Hz, 3 H, CH3),
3.25 (s, CH2), 4.10 (q, JHH = 7.0 Hz, 2 H, CH2), 7.4–7.6 (m, 10 H,
Ph) ppm. 13C NMR (CDCl3): δ = 14.0 (CH3), 48.2 (CH2), 61.3
(CH2), 62.4 (EtO2CCH), 128.2, 128.4, 129.4, 130.0 131.3, 136.0,
166.4, 166.5, 179.0 ppm.
Computational Details: All the geometries were calculated without
any symmetry constraints by using the gradient-corrected exchange
functional developed by Perdew, Burke and Ernzerhof in combina-
tion with a correlation functional also developed by the same au-
thors and denoted as PBEPBE.[26] The 6-31G(d,p) basis set[27] was
employed throughout this study. For all stationary points the Hess-
ian was evaluated to characterize the genuine minima (no imagi-
nary frequency) and the transition states (1 imaginary frequency).
Thermal correction for the Gibbs free energy (at 298 K) has been
estimated on the basis of the frequency calculations at the optimi-
zation level. Intrinsic reaction coordinate (IRC) analyses[28] were
carried out throughout the reaction pathways to confirm that the
stationary points are smoothly connected to each other. Natural
population and natural bond orbital (NBO) analyses[29] were per-
formed at the same level of theory as that used for geometry opti-
mization. For the calculations the PC GAMESS 7.1.C[30] software
was used. QTAIM (quantum theory of atoms in molecules) analy-
ses of the wavefunctions were carried out with the XAIM software
to investigate the structures of the electron densities of the opti-
mized structures.[31]
oil (38.4 mg, 0.124 mmol, 13% isolated yield). IR (CH Cl ): ν (ε )
˜
2
2
M
1
= 1767 (856), 1731 cm–1 (365 cm2/mmol). H NMR (CDCl3): δ =
1.28 (t, JHH = 7.1 Hz, 3 H, CH3), 3.80 (d, JHH = 15.3 Hz, 1 H,
CH2Ph), 3.89 (d, JHH = 1.7 Hz, 1 H, CH), 4.22 (dq, JHH = 2.1,
7.1 Hz, 2 H, CH2), 4.68 (d, JHH = 2.0 Hz, 1 H, CH), 4.85 (d, JHH
= 15.3 Hz, 1 H, CH2Ph), 7.1–7.4 (m, 10 H, Ph) ppm. 13C NMR
(CDCl3): δ = 14.1 (CH3), 44.7 (CH2Ph), 56.9 (CH), 61.7, (CH2),
63.4 (CH), 126.7 and 127.8 (o-C6H5), 128.2 and 128.7 (p-C6H5),
129.0, 129.1 (m-C6H5), 134.6, 135.9 (ipso-C6H5), 162.3 (N-CO),
1
166.7 (EtO-CO) ppm. Both the H and the 13C NMR spectra are
in accord with the spectra of the known N-benzyl-trans-α-ethoxy-
carbonyl-β-phenyl-β-lactam.[24]
Preparation of N-Methyl-trans-α-ethoxycarbonyl-β-phenyl-β-lactam:
By using N-methylbenzaldimine (0.124 mL, 1.0 mmol) in the above
procedure the IR spectrum of the crude reaction product showed
weak bands of [Co2(CO)8] at 2112, 2072, 2042, 2021, and
1843 cm–1, weak bands of benzaldehyde at 1702, 1597, and
1583 cm–1, and strong bands of N-methyl-trans-α-ethoxycarbonyl-
β-phenyl-β-lactam at 1738 and 1652 cm–1 (corresponding to Ͼ70%
yield). TLC analyses showed that the N-methyl-trans-α-ethoxycar-
bonyl-β-phenyl-β-lactam product separates well giving an isolated
spot at Rf = 0.62 with dichloromethane/ethyl acetate (1:1) on
Al2O3. Flash chromatography was performed on Al2O3 (Brockman
I, neutral, i.d. 1 cm, height 45 cm) with dichloromethane/ethyl ace-
tate (1:1) (130 mL) as the eluent. N-Methyl-trans-α-ethoxycar-
bonyl-β-phenyl-β-lactam was obtained from the fractions after
concentration in vacuo as a colorless oil (25.1 mg, 0.108 mmol,
Supporting Information (see footnote on the first page of this arti-
cle): Bond lengths and bond and torsion angles for N-tert-butyl-
trans-α-ethoxycarbonyl-β-phenyl-β-lactam.
Acknowledgments
The authors thank the Hungarian Academy of Sciences and the
Hungarian Scientific Research Fund for financial support under
Grant Nos. OTKA NK 71906 and F046959 and also thank the Su-
percomputer Center of the National Information Infrastructure
Development (NIIF) Program. R. T. thanks the Humboldt Foun-
dation for support, and K. T. is grateful for the support of Bolyai
Grant of the Hungarian Academy of Sciences.
11% isolated yield). IR (CH Cl ): ν (ε ) = 1733 (270), 1648 cm–1
˜
2
2
M
1
(493 cm2/mmol). H NMR (CDCl3): δ = 1.16 (t, JHH = 7.1 Hz, 3
H, CH3), 2.20 (s, 3 H, NCH3), 3.98 (d, JHH = 1.2 Hz, 1 H, CH),
4.14 (dq, JHH = 2.1, 7.1 Hz, 2 H, CH2), 4.45 (d, JHH = 1.2 Hz, 1
H, CH), 7.15–7.42 (m, 5 H, Ph) ppm. 13C NMR (CDCl3): δ = 14.0
(CH3CH2), 36.5 (CH3N), 50.2 (CH), 58.1 (CH), 61.7, (CH2), 127.9
(o-C6H5), 128.0 (p-C6H5), 128.5 (m-C6H5), 137.1 (ipso-C6H5), 165.0
(N-CO), 169.6 (EtO-CO) ppm. Both the 1H and the 13C NMR
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Received: December 16, 2008
Published Online: March 3, 2009
2002
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 1994–2002