Novel ruthenium-catalyzed cleavage of allyl protecting group in lactams

Article abstract of DOI:10.1016/j.tetlet.2003.09.165

A convenient and general method of synthesis of NH-lactams via Grubbs' carbene promoted isomerization of the respective N-allyl lactams followed by RuCl₃-catalyzed enamide cleavage has been developed.

Full text of DOI:10.1016/j.tetlet.2003.09.165

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8693–8695
Novel ruthenium-catalyzed cleavage of allyl protecting group in
lactams
Benito Alcaide,a,* Pedro Almendrosb,* and Jose´ M. Alonsoa
aDepartamento de Qu´ımica Orga´nica I, Facultad de Ciencias Qu´ımicas, Universidad Complutense de Madrid,
28040 Madrid, Spain
bInstituto de Qu´ımica Orga´nica General, CSIC, Juan de la Cierva 3, 28006 Madrid, Spain
Received 2 April 2003; revised 9 June 2003; accepted 6 September 2003
Abstract—A convenient and general method of synthesis of NH-lactams via Grubbs’ carbene promoted isomerization of the
respective N-allyl lactams followed by RuCl3-catalyzed enamide cleavage has been developed.
© 2003 Elsevier Ltd. All rights reserved.
NH-Lactams are nitrogen-containing heterocycles
which have long attracted synthetic interest due to their
relatively simple structural features and wide range of
pharmacologic activity coupled with serving as crucial
intermediates for numerous natural products. In partic-
ular, N-unsubstituted b-lactams play a central role as
key intermediates in the synthesis of several biologically
active antibiotics,1 and the anti-cancer agents paclitaxel
and docetaxel.2 There are relatively few methods avail-
able for the deprotection of an amide group.3 Oxidative
cleavage by ceric ammonium nitrate of an activated
aromatic moiety attached to the nitrogen of the lactam
ring offers the most direct synthesis of NH-lactams.4
However, conditions used are quite harsh and in many
cases the yields are poor, making such procedure hardly
suitable for the synthesis of highly functionalized
molecules. There are many other methods known in the
literature, but less frequently used.5,6 Despite that the
allyl protecting group cleavage in ethers and amines is
a well documented methodology, specially using palla-
dium chemistry,7 its extension to the deprotection of
allylic lactams has been scarcely documented. As far a
we know the N-allyl deprotections of a 4-unsubstituted-
b-lactam as well as a 2-hydroxy-g-lactam, both induced
by rhodium(III) followed by KMnO4 or acidic treat-
ments, respectively, are the only available examples.8
To overcome these problems, we reported some time
ago a stoichiometric cobalt induced cleavage of N-
propargyl b-lactams.9 In continuation of these efforts to
prepare N-unsubstituted lactams, herein we report an
efficient strategy for the catalytic deprotection of N-
allyl lactams via ruthenium complexes in mild
conditions.
A growing number of newly discovered catalytic pro-
cesses mediated by Grubbs’ carbene complex broaden
its synthetic utility beyond olefin metathesis.10 In partic-
ular, we recently described the first examples account-
ing for the catalytic cleavage of allylic amines by using
reagents different from palladium catalysts.11 The
higher stability of enamides comparing with enamines
favours the double bond isomerization, preventing from
(CO)N-allyl cleavage. On the basis of these principles,
it was to be expected that successful catalytic CꢀN
deprotection in N-allyl lactams would require and addi-
tional step (Scheme 1). We thought in ruthenium(III)
chloride which has been probed as an excellent catalyst
for the oxidative cleavage of olefins to aldehydes,12
because it has been reported that N-formyl lactams
smoothly loss CO under slightly basic conditions to
give the corresponding NH-amides.13
Keywords: lactams; ruthenium; catalytic; allyl cleavage.
* Corresponding authors. E-mail: alcaideb@quim.ucm.es; iqoa392@
iqog.csic.es
Scheme 1.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.09.165

8694
B. Alcaide et al. / Tetrahedron Letters 44 (2003) 8693–8695
Table 1. N-Allyl cleavage of different-sized lactams
Starting substrates, N-allyl lactams 1a–h, were prepared
using standard methodology. N-Allyl lactams 1a–c
were obtained via reaction of the corresponding NH-
lactams with allyl bromide in the presence of sodium
hydride,14 while 2-azetidinones 1d–h were obtained
from the corresponding allyl imine, through Staudinger
reaction with the appropriate alkoxyacetyl chloride in
the presence of Et3N.15
Firstly, we tested as a model reaction the deprotection
of N-allyl l-valerolactam 1a. Treatment of allylic
amide 1a with Grubbs’ carbene Cl2(Cy3P)2RuꢁCHPh
under optimised reaction conditions (5 mol% catalyst,
0.03 M, toluene, 110°C)16 resulted in clean formation of
the corresponding enamide as an isomeric mixture (1:1)
E/Z in good isolated yield (71%) after chromatographic
purification. The catalytic scission of the internal CꢁC
was attained by using the system of RuCl3–NaIO4 in
1,2-dichloroethane–H2O (1:1), followed by an aqueous
work-up in slightly basic conditions (sat. aq. NaHCO3
containing a catalytic amount of Na2CO3). Thus, the
N-unsubstituted 2-piperidone 2a was obtained in a 70%
yield. Exposure of N-allyl g-butyrolactam 1b and N-
allyl -pyroglutamic acid ethyl ester (+)-1c to the above
L
sequential catalytic conditions smoothly afforded the
NH-lactams 2b and (+)-2c. Next, we decide to test the
N-allyl cleavage protocol in the strained four-mem-
bered lactam series. Racemic as well as enantiopure
allylic b-lactams 2d–h were conveniently deprotected to
the corresponding NH-b-lactams by using both ruthe-
nium catalysts (Table 1). Under the reaction conditions,
the intermediate N-formyl lactams accumulate in the
reaction mixture immediately after the RuCl3–NaIO4
system is added over the enamide, and can be isolated
under a neutral work-up. Importantly, the stereochemi-
cal integrity of the stereogenic centres at the lactam
rings, when applicable, remained unaltered during the
transformation of N-allyl compounds 1 into NH-prod-
ucts 2.
References
1. For pertinent reviews, see: (a) Kant, J.; Walker, D. G. In
the Organic Chemistry of i-Lactams; Georg, G. I., Ed.;
Wiley-VCH: New York, 1993; p. 121; (b) Durckheimer,
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In conclusion, we have presented a new convenient
methodology for the catalytic deprotection of N-allylic
lactams. This protocol is tolerant towards different
functionalities as well as the stereocentres present in the
ring.
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Acknowledgements
We would like to thank the DGI-MCYT (Project
BQU2000-0645) for financial support. J.M.A. thanks
the UCM for a predoctoral grant.

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8695
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