Synthesis of β-lactams from a N-rhenaimine: Effect of the transition metal on the energetic profile of the Staudinger reaction

Article abstract of DOI:10.1021/ja034070s

As depicted in the scheme, the alkylidenamido complex 1, a N-rhenaimine, reacts with ketenes to afford the β-lactams 2-4, which possess a {Re(CO)₃(bpy)} fragment as substituent at nitrogen. Clean demetalations using HOTf or MeOTf yield the free β-lactams or N-methyl-β-lactams along with [Re(OTf)(CO)₃(bpy)]. DFT calculations help to rationalize why the reaction is faster than those of non transition metal N-substituted imines. Copyright

Full text of DOI:10.1021/ja034070s

Published on Web 03/05/2003
Synthesis of â-Lactams from a N-Rhenaimine: Effect of the Transition Metal
on the Energetic Profile of the Staudinger Reaction
Eva Hevia,† Julio Pe´rez,*,† V´ıctor Riera,† Daniel Miguel,§ Pablo Campomanes,‡ M. Isabel Mene´ndez,‡
Toma´s L. Sordo,‡ and Santiago Garc´ıa-Granda‡
Departamentos de Qu´ımica Orga´nica e Inorga´nica-IUQOEM y de Qu´ımica F´ısica y Anal´ıtica,
UniVersidad de OViedo, 33071 OViedo, Spain, and Departamento de Qu´ımica Inorga´nica, Facultad de Ciencias,
UniVersidad de Valladolid, 47071 Valladolid, Spain
Received January 8, 2003; E-mail: japm@sauron.quimica.uniovi.es
The synthesis of â-lactams attracts considerable interest due to
the presence of the 2-azetidinone ring in several types of natural
and unnatural antibiotics.1 The formal [2 + 2] cycloaddition of
imines and ketenes, termed Staudinger reaction, is one of the most
employed synthetic methods because of its simplicity and wide
availability of substrates. Its mechanism has been extensively
studied from experimental2 and theoretical3 perspectives, and the
most generally accepted model consists of an initial imine attack
to the ketene carbonyl carbon to afford a zwitterionic intermediate,
followed by a conrotatory [2 + 2] cycloaddition to form the final
product (see Scheme 1).4
Figure 1. Molecular structure and numbering scheme of 2.
We have recently found that the alkylideneamido complex [Re-
Scheme 1
(NdCPh2)(CO)3(bpy)] (1) (bpy) 2, 2′-bipyridine), whose structure
allows it to be considered as a N-rhenaimine,5 reacts with alkyl
and aryl isocyanates to afford products related to those obtained
using N-silylimines. However, the reaction takes place at consider-
ably lower temperatures, indicating that the presence of the
transition metal fragment reduces the reaction kinetic barrier. We
have extended now these studies to the reaction of 1 with ketenes,
and here we report our results.
Scheme 2
Complex 1 reacts with diphenylketene to afford, as single
product, complex 2 (see Scheme 2), which could be isolated in
good yield by crystallization and was characterized by elemental
(C, H, N) analysis, IR and NMR (1H and 13C) and single-crystal
X-ray diffraction. The IR spectrum shows three intense νCO stretches
diagnostic of a fac-Re(CO)3 fragment, which occur at wavenumber
values some 15 cm-1 higher than those of the precursor 1, as
expected for the reaction of 1 with an electrophile. In addition, the
carbonyl group within the â-lactam ring gives rise to a medium
intensity band at 1668 cm-1. The 13C NMR spectrum of 2 contains
two sets of signals for the bpy, carbonyl and â-lactam groups (in
an approximate 1:1 ratio), a fact attributed to the presence of two
rotamers resulting from hindered rotation around the Re-N(â-
lactam) bond. Each rotamer features three 13C NMR signals due to
the three carbons which, along with nitrogen, constitute the four-
membered cycle. The solid-state structure of 2, shown in Figure 1,
consists of a [Re(CO)3(bpy)] fragment acting as a substituent on
the nitrogen atom of a â-lactam ring. No previous examples of
transition metal N-substituted â-lactams are known. This nitrogen,
N(3), along with C(6), has its origin on the alkylideneamido ligand
of complex 1, whereas C(4) and C(5), which complete the â-lactam
ring, result from diphenylketene. The sum of angles around N(3),
358.4°, reveals a nearly planar geometry, attributable to delocal-
ization of the nitrogen lone pair involving the carbonyl group.6
Accordingly, the C(4)-N(3) distance (1.338(7) Å) is appreciably
shorter than C(6)-N(3) (1.523(6) Å). The distances and angles
within the â-lactam ring are comparable with those found in the
â-lactams whose structures have been determined by X-ray dif-
fraction.7
Although transition metal complexes have been previously
employed for the stoichiometric8 or catalytic synthesis9 of â-lactams,
the reaction leading to 2 is, to the best of our knowledge, the only
example of a â-lactam synthesis in which the N-C moiety
originates from a transition metal complex. Using complexes with
chiral chelates instead of the bpy ligand could lead to asymmetric
induction in the synthesis of chiral â-lactams.
† Departamento de Qu´ımica Orga´nica e Inorga´nica-IUQOEM, Universidad de
Oviedo.
2 reacts with methyl triflate, affording the free N-methyl-â-lactam
and the complex [Re(OTf)(CO)3(bpy)] (which has been the precur-
sor of complex 1).5 The fact that a single â-lactam is obtained
‡ Departamento de Qu´ımica F´ısica y Anal´ıtica, Universidad de Oviedo.
§ Universidad de Valladolid.
9
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J. AM. CHEM. SOC. 2003, 125, 3706-3707
10.1021/ja034070s CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
nucleophilicity of the imine N atom due to the presence of the
metallic substituent causes the first TS to occur at a larger distance
between the reactants (2.427 Å in TS1 versus 1.745 Å in the
corresponding TS for the ketene-formaldimine reaction13) and,
consequently, with a smaller charge transfer from the imine (0.15e
compared to 0.21e). The formation of the C-N bond at I produces
a larger charge transfer (0.40e) than in the absence of the metallic
substituent (0.29e). As a result, the difference in charge between
the two remaining C atoms of the â-lactam ring increases and the
conrotatory electrocyclic closure leading to the final â-lactam has
a much lower energetic cost than for the ketene-formaldimine
reaction.
To conclude, we have reported the first Staudinger reaction of a
transition metal N-metallaimine, which is considerably faster than
related reactions of nonmetal-substituted or N-silylimines. This
diference was rationalized in terms of the different location of the
intermediates and transition states in the reaction profile using the
results of DFT calculations.
Figure 2. B3LYP/6-31+G*(LANL2DZ effective core potential for Re)
relative electronic energy profile including ZPVE for the reaction between
ketene and [Re(NdCH2)(CO)3(N2C2H4).
strongly supports that the presence of two sets of signals in the 13
C
NMR spectrum of 2 is due to two rotamers (vide supra). 1 also
reacts with ethylphenylketene and cycloheptylketene to afford 3
and 4, respectively (see Scheme 2), which could be demetalated
by treatment with MeOTf to give the corresponding N-methyl-â-
lactams and the rhenium triflate complex. Triflic acid can also be
used as demetallating agent; thus, its reaction with 2 produces the
N-H â-lactam as shown in Scheme 2.
The closer precedent of the reaction of diphenylketene with 1 is
the reaction with the imine Ph2CdN(SiMe3).10 Despite the enhanced
reactivity against electrophiles shown by N-silylimines, the reaction
of Ph2CdCdO with Ph2CdN(SiMe3) requires 2 equiv of the ketene
to obtain the â-lactam via reaction of 1 equiv to give an intermediate
azabutadiene which subsequently reacts with a second equivalent
to afford a N-acylated â-lactam.11 The formation of â-lactams from
N-silylimines and a single equivalent of ketene requires forcing
conditions (T ) 100 °C) to achieve ring closure;12 in contrast, the
reaction of 1 with diphenylketene takes place instantaneously at
-78 °C.
A theoretical analysis has been carried out to gain information
on the causes of the difference. DFT calculations (see details in
Supporting Information) on the model reaction between ketene and
[Re(NdCH2)(CO)3(N2C2H4)] render an electronic energy profile
(including the zero-point vibrational energy correction (ZPVE)) that
corresponds to a two-step mechanism (see Figure 2). Ketene and
the N-metallaimine interact through a first transition state (TS), TS1,
with an energy barrier of 3.1 kcal/mol, to yield the intermediate I,
6.4 kcal/mol more stable than the separate reactants. Finally, I
transforms into the â-lactam product after surmounting a second
TS, TS2, 8.8 kcal/mol less stable than reactants. This energy profile
allows us to rationalize the behavior of the system experimentally
observed. Thus, TS1 is earlier and more stable than the corre-
sponding TS found for the reaction between ketene and formaldi-
mine.13 On the other hand, the rate limiting TS2, presents a much
greater relative stability than the corresponding TS when form-
aldimine is used (21.3 kcal/mol),13 in accordance with the fast
reaction between 1 and diphenylketene. The enhancement of the
Acknowledgment. We thank Dr. Francisco J. Gonza´lez for
helpful comments and Ministerios de Ciencia y Tecnolog´ıa, y de
Educacio´n, and Principado de Asturias for funding (Grants BQU2000-
0220, BQU2000-0219, PR-01-GE-7, PR-01-GE-4, PB97-0470-
C02-01, and SAF2001-3596) and a predoctoral fellowship (to E.H.).
Note Added after ASAP Publication: The title contained a
misspelling in the version published on the Web 3/5/2003. The final
Web version published 3/10/2003 and the print version are correct.
Supporting Information Available: Complete details for the
synthesis of all compounds and spectroscopic data for 2 (PDF); X-ray
crystallographic data for 2 (CIF). This material is available free of
charge via the Internet at http://pubs.acs.org.
References
(1) (a) Chemistry and Biology of â-Lactam Antibiotics; Morin, R. B., Gorman,
M., Eds.; Academic Press: New York, 1982; Vol. 1-3. (b) The Chemistry
of â-Lactams; Page, M. I., Ed.; Chapman and Hall: London, 1997.
(2) (a) Palomo, C.; Coss´ıo, F. P.; Cuevas, C.; Lecea, B.; Mielgo, A.; Roma´n,
P.; Luque, A.; Martinez-Ripoll, M. J. Am. Chem. Soc. 1992, 114, 9360.
(b) Birchler, A. G.; Liu, F.; Liebeskind, L. S. J. Org. Chem. 1994, 59,
7737. (c) Hafez, A. M.; Taggi, A. E.; Wack, H.; Drury, W. J., III; Lectka,
J.; Marshall, G. R.; Almqvist, F. Org. Lett. 2000, 2, 2065.
(3) (a) Coss´ıo, F. P.; Ugalde, J. M.; Lopez, X.; Lecea, B.; Palomo, C. J. Am.
Chem. Soc. 1993, 115, 995. (b) Lo´pez, R.; Sordo, T. L.; Sordo, J. A.;
Gonza´lez, J. J. J. Org. Chem. 1993, 58, 7036. (c) Lo´pez, R.; Ruiz-Lo´pez,
M. F.; Rinaldi, D.; Sordo, J. A.; Sordo, T. J. J. Phys. Chem. 1996, 100,
10600.
(4) Taggi, A. E.; Hafez, A. M.; Wack, H.; Young, B.; Ferraris, D.; Lectka,
T. J. Am. Chem. Soc. 2002, 124, 6626.
(5) Hevia, E.; Pe´rez, J.; Riera, V.; Miguel, D. Angew. Chem., Int. Ed. 2002,
41, 3858.
(6) Hevia, E.; Pe´rez, J.; Riera, V.; Miguel, D. Chem. Commun. 2002, 1814.
(7) See for instance: Hodous, B. L.; Fu, G. C. J. Am. Chem. Soc. 2002, 124,
1578.
(8) Hegedus, L. S.; Weck, G. de; D’Andrea, S. J. Am. Chem. Soc. 1988, 110,
2122.
(9) Piotti, M. E.; Alper, H. J. Am. Chem. Soc. 1996, 118, 111.
(10) Birkofer, L.; Schramm, J. Justus Liebigs Ann. Chem. 1977, 760.
(11) Panunzio, M.; Zarantonello, P. Org. Process Res. DeV. 1998, 2, 49.
(12) Martelli, G.; Spunta, G.; Panunzio, M. Tetrahedron Lett. 1998, 39, 6257.
(13) Sordo, J. A.; Gonza´lez, J.; Sordo, T. L. J. Am. Chem. Soc. 1992, 114,
6249.
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