Ring expansion versus cyclization in 4-oxoazetidine-2-carbaldehydes catalyzed by molecular iodine: Experimental and theoretical study in concert

Article abstract of DOI:10.1002/adsc.201000171

Molecular iodine (10 mol%) efficiently catalyzes the ring expansion of 4-oxoazetidine-2-carbaldehydes in the presence of tert-butyldimethylsilyl cyanide, or allylic and propargylic trimethylsilanes to afford protected 5-functionalized-3,4-dihydroxypyrrolidin-2-ones with good yield and high diastereoselectivity, through a C3-C4 bond cleavage of the β-lactam nucleus. Interestingly, in contrast to the iodine-catalyzed reactions of 3-alkoxy-β-lactam aldehydes which lead to the corresponding γ-lactam derivatives (rearrangement adducts), the reactions of 3 aryloxy-β-lactam aldehydes under similar conditions gave β-lactam-fused chromanes (cyclization adducts) as the sole products, through exclusive electrophilic aromatic substitution involving the C3 aromatic ring and the carbaldehyde. In order to support the mechanistic proposals, theoretical studies have been performed.

Full text of DOI:10.1002/adsc.201000171

FULL PAPERS
DOI: 10.1002/adsc.201000171
Ring Expansion versus Cyclization in 4-Oxoazetidine-2-
carbaldehydes Catalyzed by Molecular Iodine: Experimental and
Theoretical Study in Concert
Benito Alcaide,a,* Pedro Almendros,b,* Gema Cabrero,a Ricardo Callejo ,a
M. Pilar Ruiz,a Manuel Arnꢀ,c and Luis R. Domingoc,*
a
Grupo de Lactamas y Heterociclos Bioactivos, Departamento de Quꢁmica Orgꢂnica I, Unidad Asociada al CSIC, Facultad
de Quꢁmica, Universidad Complutense de Madrid, 28040 Madrid, Spain
Fax : (+34)-91-394-4103; e-mail: alcaideb@quim.ucm.es
Instituto de Quꢁmica Orgꢂnica General, Consejo Superior de Investigaciones Cientꢁficas, CSIC, Juan de la Cierva 3, 28006
b
Madrid, Spain
Fax : (+34)-91-564-4853; e-mail: Palmendros@iqog.csic.es
Departamento de Quꢁmica Orgꢂnica, Universidad de Valencia, C/ Dr. Moliner 50, 46100 Burjassot, Valencia, Spain
c
Fax : (+34)-96-354-3880; e-mail: domingo@utopia.uv.es
Received: March 5, 2010; Revised: May 31, 2010; Published online: July 7, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000171.
Abstract: Molecular iodine (10 mol%) efficiently aryloxy-b-lactam aldehydes under similar conditions
catalyzes the ring expansion of 4-oxoazetidine-2- gave b-lactam-fused chromanes (cyclization adducts)
carbACHTUNGTRENNUNGaldehydes in the presence of tert-butyldimethyl- as the sole products, through exclusive electrophilic
silyl cyanide, or allylic and propargylic trimethylsi- aromatic substitution involving the C3 aromatic ring
lanes to afford protected 5-functionalized-3,4-dihy- and the carbaldehyde. In order to support the mech-
droxypyrrolidin-2-ones with good yield and high dia- anistic proposals, theoretical studies have been per-
À
stereoselectivity, through a C3 C4 bond cleavage of formed.
the b-lactam nucleus. Interestingly, in contrast to the
iodine-catalyzed reactions of 3-alkoxy-b-lactam alde-
hydes which lead to the corresponding g-lactam de- Keywords: aldehydes; catalysis; iodine; lactams; re-
rivatives (rearrangement adducts), the reactions of 3- action mechanisms
Introduction
On the other hand, iodine-catalyzed reactions have
captured much recent attention because of the low
b-Lactams are not only the most commonly pres- cost, ready availability, environmentally benign char-
ACHTUNGTRENNUNG
lactam nucleus as chiral building block to prepare a- lecular iodine.[4] In a preliminary study,[5] a single-step
and b-amino acids, alkaloids, heterocycles, taxoids, catalytic ring expansion approach from 4-oxoazeti-
and other types of compounds of biological and me- dine-2-carbaldehydes to enantiopure 5-cyano-3,4-di-
dicinal interest is now well established.[2] However, al- hydroxypyrrolidin-2-ones was achieved by the use of
though many efforts have been made in this field, molecular iodine in the presence of tert-butyldime-
there is a lack of information on the direct conversion thylsilyl cyanide. The reactivity observed in the above
of b-lactam aldehydes into the pharmacologically rel- reactions was substantially different from that report-
evant pyrrolidine core. In particular, iminosugars ed for related simple catalysts and suggested that it
based on polyhydroxylated pyrrolidines have attract- was strongly modulated by the nature of the cata-
ed a great deal of attention due to the range of bio- lyst.[6] Albeit starting from slightly different substrates
logical activities they show, exhibiting action as inhibi- and triggered by different reaction conditions, the
tors of the enzymes a-galactosidase, a-glucosidase, conversion of 3-alkoxy-4-(1-haloalkyl)azetidin-2-ones
and glycosidase.[3]
into 3-alkoxypyrrolidin-2-ones proceeds via a closely
related mechanistic protocol, and may be considered
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Ring Expansion versus Cyclization in 4-Oxoazetidine-2-carbaldehydes Catalyzed by Molecular Iodine
an analogue b- to g-lactam ring expansion.[7] Follow-
ing our commitment in b-lactam chemistry and cata-
lytic processes of synthetic utility,[8] in this paper we
report a systematic investigation of the iodine-cata-
lyzed ring expansion of 4-oxoazetidine-2-carbalde-
hydes that fully confirms and extends our earlier con-
clusions and establishes a regio- and stereocontrolled
versatile route to a variety of enantiopure 5-function-
alized-3,4-dihydroxypyrrolidin-2-ones, together with a
chemodivergent reactivity, namely, the Friedel–Crafts
cyclization to b-lactam fused chromanes. Besides, the
mechanisms of these iodine-catalyzed reactions have
been theoretically investigated.
Scheme 1. Reaction of 3-alkylACHTNUTRGNE(NUG aryl)-4-oxoazetidine-2-carbal-
dehydes 1a and 1b with TBSCN under iodine catalysis. Re-
agents and conditions: i) TBSCN (3 equiv.), 10 mol% I2,
MeCN, room temperature, 6 h. TBSCN=tert-butyldimethyl-
silyl cyanide, PMP=4-MeOC6H4.
Results and Discussion
Taking into account both that iodine has been identi-
fied as a mild catalyst to promote the addition of tri-
methylsilyl cyanide to aldimines and ketones,[9] as
well as our recent contribution on the Lewis acid-cat-
alyzed hydrocyanation of b-lactam aldehydes,[6] we
decide to test the mild Lewis acidity associated with
iodine for the cyanosilylation of 4-oxoazetidine-2-car-
baldehydes.
Scheme 2. Diastereoselective ring expansion of b-lactam al-
dehydes 1 to masked pyroglutamic acid derivatives 3 cata-
lyzed by molecular iodine in the presence of TBSCN.
aldehyde 1c with TBSCN under molecular iodine cat-
Starting substrates, 4-oxoazetidine-2-carbaldehydes alysis. To our delight, we obtained instead of the ex-
1a–r, were prepared both in the racemic form and in pected b-lactam cyanohydrin the enantiopure 5-
optically pure form using standard methodology. Rac- cyano-3,4-dihydroxypyrrolidin-2-one 3c in 89% yield
emic compounds 1a and 1b were obtained as single (Scheme 2, see also Supporting Information,
cis-diastereoisomers, following our one-pot method Table S1), which can be regarded as a hybrid of the
from
N,N-di-(p-methoxyphenyl)glyoxaldiimine.[10] pharmacologically relevant subunits of iminosugar
Enantiopure 2-azetidinones 1c–l, were prepared using and pyroglutamic acid.[13] This result may be ex-
À
standard methodology as single cis-enantiomers from plained through a C3 C4 bond cleavage of the 2-aze-
imines of (R)-2,3-O-isopropylideneglyceraldehyde, tidinone nucleus followed by rearrangement; the ring
through Staudinger reaction with the corresponding expansion reaction not being compatible with C3 sub-
alkoxyACHTUNGTRENNUNG(aryloxy)acetyl chloride in the presence of stituents at the b-lactam ring different from alkoxy
Et3N, followed by sequential acidic acetonide hydroly- groups (aldehydes 1a and 1b, see Scheme 1). When
sis and oxidative cleavage.[10] Enantiopure spiranic or identical conditions were applied to 4-oxoazetidine-2-
3-substituted 3-alkoxy-b-lactam aldehydes 1m and 1n carbaldehydes 1d–l, similar rearrangement reactions
were prepared from (S)-4-[(S)-2,2-dimethyl-1,3-dioxo- occurred to afford the corresponding adducts 3d–l in
lan-4-yl]-1-(4-methoxyphenyl)azetidine-2,3-dione via good yields (Scheme 2, see also Supporting Informa-
metal-mediated Barbier-type carbonyl addition reac- tion, Table S1). Gratifyingly, when the reaction was
tions in aqueous media followed by functionalization not totally stereoselective, in all cases the diastero-
reactions, as we recently described.[11] Optically pure meric adducts syn-3 and anti-3 could be easily sepa-
trans-4-oxoazetidine-2-carbaldehyde epim-1c was pre- rated by gravity flow chromatography, the isomeric
pared adopting literature methodology.[12] Initial at- products anti-3 being the less polar compounds. The
tempts to promote the cyanosilylation reaction of 4- cyclic structures and the stereochemistry of masked
oxoazetidine-2-carbaldehydes with tert-butyldimethyl- pyroglutamic acid derivatives 3 were established by
silyl cyanide (TBSCN) were performed with 3-alkyl- one- and two-dimensional NMR techniques and NOE
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
with small amounts of the O-silylated cyanohydrin 2a H4–H5 in compounds syn-3 and anti/anti in com-
when a three-fold excess of TBSCN was used pounds anti-3, in agreement with that reported in the
(Scheme 1).
literature for related products.[14]
Next, we turned our attention to 3-alkoxy-4-oxo-
At this point, we became intrigued as to whether
ACHTUNGTRENNUNGazetidine-2-carbaldehydes, and so we treated b-lactam appropriately selected silylated nucleophiles different
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from TBSCN, for instance, allylic and propargylic tri-
methylsilanes, could be used for the iodine-catalyzed
ring expansion reaction. In the event, mixtures of sep-
arable isomers were in general obtained in moderate
or good combined yields (56–80%). When the result-
ing reaction mixtures were subjected to column chro-
matography,
5-functionalized-2-pyrrolidinones
4
(major product, except for aldehyde 1h), along with
homoallylic alcohols (Sakurai products) 5 and mor-
pholinones 6, were obtained. The most significant re-
sults for different 3-alkoxy-4-oxoazetidine-2-carbalde-
hydes are summarized in Scheme 3.
In order to show the capacity of the method to pre-
pare an array of g-lactams bearing chemical diversity,
several functionalities of the 2-pyrrolidinone nucleus
in g-lactam syn-3c were selectively manipulated
(Scheme 4). Thus, the controlled reduction of the
Scheme 4. Selective manipulations of polyfunctional g-
lactam syn-3c. PMP=4-MeOC6H4, TBS=tert-butyldimethyl-
cyano group in the g-lactam cyanohydrin derivative silyl.
syn-3c with NaBH4/NiCl2 and subsequent Boc protec-
tion, chemospecifically afforded aminoalkylpyrrolidi-
none 7.[15] Chemoselective cleavage of the TBS and
We subsequently wished to expand the scope of our
PMP protecting groups under standard conditions, study to include aryloxy substituents at the C3 posi-
yielded g-lactams 8 and 9 bearing free amino and hy- tion of the b-lactam ring. Thus, several 3-aryloxy-4-
droxy functionalities.
oxo
ACHTUNGTRENaNGNU zetidine-2-carbaldehydes 1o–r, were treated with
molecular iodine. A smooth reaction took place, but
Scheme 3. Molecular iodine-catalyzed reaction in the presence of unsaturated trimethylsilanes of 4-oxoazetidine-2-carbalde-
hydes 1c, 1d, and 1h. PMP=4-MeOC6H4, TMS=trimethylsilyl.
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Ring Expansion versus Cyclization in 4-Oxoazetidine-2-carbaldehydes Catalyzed by Molecular Iodine
Scheme 5. Cyclization of 3-aryloxy-b-lactam aldehydes 1o–r to b-lactam-fused chromanes 10 and 11 catalyzed by molecular
iodine in the presence of TBSCN. Reagents and conditions: i) TBSCN (2 equiv.), 50 mol% I2, MeCN, room temperature, 10a:
1 h; 10b: 72 h; 10c: 17 h. ii) TBSCN (2 equiv.), 100 mol% I2, MeCN, reflux, 72 h. TBSCN=tert-butyldimethylsilyl cyanide,
PMP=4-MeOC6H4.
the expected g-lactams were not detected; instead the
corresponding fused tricyclic b-lactams 10a–d,[16] were
isolated in fair yields (60–100%) as mixtures of sepa-
rable epimers at the carbinolic-like carbon
(Scheme 5). We observed that increasing the amount
of iodine from 10 mol% to 50 mol% had a benefitial
impact on the overall yield of the b-lactam-fused
chromanes. Except for tricyclic 2-azetidinone 10a, the
TBS group was not incorporated into the final prod-
uct; however, the absence of TBSCN as reaction re-
agent considerably diminished the conversion. The
chloro-b-lactam 1r needed forcing conditions
(100 mol% of iodine, reflux) for the reaction to
occur; affording amide 11a as the major product,
along with b-lactam-fused chromanes 10d (Scheme 5).
The formation of amide 11a must be explained by in-
voking a Ritter reaction with the participation of the
solvent (acetonitrile) and the promotion of the mild
Lewis acid iodine.
Taking into account the formation of amide 11a, we
decided to explore the exposure of alcohols 10b
under usual Ritter reaction conditions.[17] Thus, the
use of epimeric tricycles trans-10b and cis-10b as the
Scheme 6. Selective manipulations of b-lactam-fused chro-
manols trans-10b and cis-10b. Reagents and conditions: i)
H2SO4 (10% vol), MeCN, room temperature, 17 h. ii) TBSCl
(2 equiv.), 50 mol% I2, CH2Cl2, room temperature, 22 h.
PMP=4-MeOC6H4, TBS=tert-butyldimethylsilyl.
alcoholic substrates in the presence of a catalytic epimer trans-10b was converted into the chloroadduct
amount of sulphuric acid as the proton source, result- 12 (Scheme 6).
ed in the clean formation of amide 11b as single
The tricyclic structure and the stereochemistry of b-
isomer (Scheme 6). Later on and in view of the above lactam-fused chromanes 10–12 were established by
results, it seemed to us interesting to analyze the be- one- and two-dimensional NMR techniques and
haviour of 10b under modified Ritter conditions, run- NOESY-1D experiments. It should be noted that, al-
ning the reaction in dichloromethane and replacing though considerable synthetic progress has been
acetonitrile by tert-butyldimethylsilyl chloride. In the made in the area of bicyclic b-lactam antibiotics (1,4-
event, alcohol cis-10b remained unreacted while its fused b-lactams), to date, the construction of related
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Table 1. Total (E, in a.u.) and relative[a] energies (DE, in kcal
molÀ1) in acetonitrile of the stationary points involved in the
iodine-catalyzed ring expansion of the 4-oxoazetidine-2-car-
baldehyde 13.
3,4-fused bicyclic b-lactams containing heteroatoms
like oxygen in the second heterocyclic core comprises
an interesting synthetic challenge as an alternative for
the conventional bicyclic 2-azetidinones.[18]
In order to understand these iodine-catalyzed reac-
tions, the mechanism for the iodine-catalyzed ring ex-
pansion of b-lactam aldehydes was investigated using
DFT methods (see Computational Methods). We se-
lected 4-oxoazetidine-2-carbaldehyde 13 as a theoreti-
cal model, a very closely related structure to the
parent precursors. Additionally, we also selected tri-
methylsilyl cyanide (TMSCN) to simulate the silicon
reagent. The iodine-catalyzed ring expansion has a
stepwise mechanism that comprises several consecu-
tive steps (see Scheme 7). These steps can be gathered
in two differentiated processes: i) the iodine-promot-
ed ring expansion of the 4-oxoazetidine-2-carbalde-
hyde complex 14 to yield the zwitterionic intermedi-
B3LYP/6-31G*
E
B3LYP/6-31+G*
E
DE
DE
14
15
À14486.222221
À14486.259139
À14486.226205
À14486.224685
À14486.241052
À14988.379030
À14988.339285
À14988.341087
À14486.187734 21.6
20.7
21.6
11.4
TS1 À14486.186493 22.4
16
17
À14486.203846 11.5
À14988.332917
TS2 À14988.291038 26.3
24.9
23.8
À37.5
18
19
À14988.292285 25.5
À14988.394131 À38.4 À14988.438826
Relative to 14 or 17.
[a]
ate 16, and ii) the capture of this intermediate by um ionic C3 carbon to the carbonyl C5 carbon yields
TMSCN to yield complex 19. The total and relative the zwitterionic intermediate 16. The intermediate 15
energies in acetonitrile are given in Table 1.
is 21.5 kcalmolÀ1 higher in energy than the complex
À
At the iodine molecule, the I7 I8 bond cleavage 14 as a consequence of the large zwitterionic charac-
has a large energy, 62.4 kcalmolÀ1. Consequently, we ter of this species. However, with a very low activa-
considered molecular iodine as the catalyst along the tion energy, 0.9 kcalmolÀ1, 15 is converted via TS1 in
ring expansion process. Coordination of molecular the zwitterionic intermediate 16 through the forma-
À
iodine to the aldehyde oxygen atom of 13 affords tion of the C3 C5 bond. Formation of 16 is endother-
complex 14, which is 4.8 kcalmolÀ1 more stable than mic by 11.5 kcalmolÀ1. All attempts to locate the tran-
À
À
the separated reagents. From 14, the C3 C4 bond sition state (TS) associated with the C3 C4 bond
cleavage affords the zwitterionic intermediate 15, cleavage were unsuccessful because of the large endo-
which through an electrophilic attack of the carbeni- thermic character of 15; this fact suggesting that the
corresponding TS might be energetically and geomet-
rically closer to 15.[19]
These energy results indicate that the ring expan-
sion with formation of the zwitterionic intermediate
16 is a reversible process. However, in presence of
TMSCN, intermediate 16 can be trapped to yield irre-
versibly the final pyrrolidin-2-one 20. The heterolytic
À
Si10 C11 bond cleavage at TMSCN to yield the TMS
cation and the cyanide anion was also discarded be-
cause of this process is energetically very unfavoura-
ble, 79.7 kcalmolÀ1. Due to the large negative charge
located at the O6 oxygen of 16, it is expected that this
oxygen atom could produce a nucleophilic attack to
the Si10 atom of TMSCN with displacement of the cy-
anide anion. Thus, after formation of the molecular
complex 17, the nucleophilic attack of the O6 oxygen
to the Si10 atom causes the formation of the inter-
mediate 18, via TS2. TS2 presents a large activation
energy, 26.3 kcalmolÀ1, probably due to the presence
of molecular iodine in 17 that decreases the nucleo-
philic character of the O6 oxygen atom. Formation of
18 is also strongly endothermic, 25.5 kcalmolÀ1. How-
ever, with an unappreciable barrier, the cyanide C11
carbon causes a nucleophilic attack to the carbenium
ionic C4 atom of 18 to yield irreversibly the complex
19. Formation of 19 from the intermediate 17 is exo-
thermic by 38.4 kcalmolÀ1 (see Table 1).
Scheme 7. Proposed catalytic cycle for the formation of pyr-
rolidin-2-one derivative 20 from 4-oxoazetidine-2-carbalde-
hyde 13.
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Ring Expansion versus Cyclization in 4-Oxoazetidine-2-carbaldehydes Catalyzed by Molecular Iodine
although the conformer 14 and rot-14 and even the
zwitterionic intermediates 15 and 21 could be in equi-
librium, only the reactive channel associated with the
formation of trans-16 via TS1 can be operative in the
ring expansion process. Note that although the forma-
tion of 15 is strongly endothermic, the irreversible
capture of this species by TMSCN displaces the reac-
tion towards the formation of the trans-pyrrolidin-2-
one 20.
Compound epim-1c does not suffer the ring expan-
sion in standard conditions (see Scheme 2). In order
to explain this result, the ring expansion at the molec-
ular complex epim-14 was also investigated (see
Scheme 9). Now, intermediate 22 is located 31.3 kcal
molÀ1 above the complex epim-14, while the activa-
tion energy associated with ring closure via TS4 is
31.4 kcalmolÀ1. These energy results indicate that
both 22 and TS4 are located ca. 9 kcalmolÀ1 above 15
and TS1 (Table 2). These high energies associated
Scheme 8. Reactive channel associated with the formation
of intermediates cis-16 and trans-16.
These ring expansions are diastereoselective to give with the ring expansion of the epim-14 account for
only the formation of trans-pyrrolidin-2-ones such as the experimental observation that epim-1 does not
20. The MeO–OTMS trans relationship is obtained undergo the ring expansion under standard reaction
through a stereoselective ring closure at the inter- conditions.
mediate 15 via TS1. In order to understand the diaste-
The geometries of the TS and intermediates in-
reoselectivity, the reactive channel associated with the volved in the iodine-catalyzed ring expansion are de-
formation of the intermediate cis-16 was investigated picted in Figure 1. At the zwitterionic intermediate 15
(see Scheme 8). Formation of cis-16 requires the in- the distances between the C3 and C4 and C5 atoms
tramolecular electrophilic attack of the C3 carbenium are 2.455 and 2.515 ꢄ, respectively. At 15 the distance
ionic center of intermediate 21 to the C5 carbon of between O6 and I7 atoms, 2.356 ꢄ, is shorter than
À
À
the C4 C5 O6 Z-enolate. Note that at intermediate that at the molecular complex 14, 2.699 ꢄ, as a conse-
À
À
15, the C4 C5 O6 enolate framework has the E con- quence of the larger interaction of the iodine mole-
À
figuration. Because of the C4 C5 bond rotation on in-
termediates 15 and 21 is restricted, due to the some p
Table 2. B3LYP/6-31G* Total (E, in u.a.) and relative[a] ener-
gies (DE, in kcalmolÀ1) in acetonitrile of the stationary
points involved in the iodine-catalyzed formation of the
character of this bond, the formation of the Z- and E-
enolates should take place at the ring apertures of the
b-lactams 14 and rot-14, respectively. The conformer
rot-14 is 0.3 kcalmolÀ1 more stable than that of 14. In zwitterionic intermediates cis-16 and epim-16.
À
consequence, through a free C4 C5 bond rotation
E
DE
these rotamers are in equilibrium. In addition, the
zwitterionic intermediate 21 is only 1.6 kcalmolÀ1
rot-14
21
TS3
cis-16
epim-14
22
À14486.222640
À14486.185262
À14486.171547
À14486.201376
À14486.222869
À14486.172872
À14486.172784
À14486.198585
higher in energy than 15. Although the TS associated
23.5
32.1
13.3
À
with the C3 C4 bond cleavage of rot-14 cannot be lo-
cated, it is expected that the TSs associated with the
À
C3 C4 bond cleavage at 14 and rot-14 have similar
31.4
31.4
15.2
energies. However, the formation of the intermediate
cis-16 via TS3 presents a large activation energy,
32.1 kcalmolÀ1. That is, TS3 is located 9.4 kcalmolÀ1
above TS1. This large energy difference means that,
TS4
epim-16
[a]
Relative to rot-14 or epim-14.
Scheme 9. Reactive channel associated with the formation of intermediate epim-16.
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Figure 1. Geometries of the TS and intermediates involved in the iodine-catalyzed ring expansion of 4-oxoazetidine-2-carbal-
dehyde 13. The distances are given in ꢄ.
À
cule with the enolic O6 oxygen atom of 15 than with 16 the length of the C3 C5 bond is 1.550 ꢄ; this inter-
À
the carbonyl O6 oxygen atom of 14. At TS1 the mediate presents the shorter O6 I7 distance, 2.195 ꢄ.
À
length of the C4 C5 forming-bond is 2.153 ꢄ. At this
At the complex intermediate 17, the distance be-
TS, the analysis of the atomic movement associated tween the alkoxidic O6 oxygen atom and the Si10
with the unique imaginary frequency, À151.6 cmÀ1, in- atom is 3.8 ꢄ. This intermediate opens the reactive
À
dicates that it is mainly associated with the C3 C5 channel associated with the nucleophilic attack of the
bond formation. Analysis of the eigenvalues associat- alkoxidic O6 oxygen to the Si10 atom of TMSCN. At
À
À
À
ed to the C3 C4 and C3 C5 bonds of the transition TS2, the length of the O6 Si10 forming-bond is
vector of TS1,[20] 0.0853 and 0.7368, indicates that at 1.995 ꢄ, while the length of the Si10 C11 bond,
À
À
À
this TS the C3 C4 bond cleavage and C3 C5 bond 2.046 ꢄ, is slightly larger than that at 17, 1.898 ꢄ. At
formation are not coupled. This fact justifies the step- TS2 the analysis of the atomic movement associated
wise nature of the ring expansion. At the intermediate with the unique imaginary frequency, À112.3 cmÀ1, in-
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Ring Expansion versus Cyclization in 4-Oxoazetidine-2-carbaldehydes Catalyzed by Molecular Iodine
À
dicates that it is mainly associated with the O6 Si10
bond formation. At intermediate 18, the length of the
À
O6 Si10 bond is 1.885 ꢄ, whereas the length of the
À
Si10 C11 bond remains at 2.179 ꢄ. The distance be-
tween C4 and C11 atoms is 2.677 ꢄ. At both TS2 and
À
À
18 the lengths of O6 Si10 and Si10 C11 bonds indi-
cate that the Si10 atom is pentacoordinated in these
species. Finally, at molecular complex 19, the lengths
À
À
of O6 Si10 and C4 C11 bonds are 1.715 and 1.482 ꢄ,
respectively.
The geometries of TS3 and TS4 are depicted in
À
Figure 2. At these TS, the lengths of the C3 C5 form-
ing-bond, 2.015 ꢄ (TS3) and 2.217 ꢄ (TS4), are simi-
lar to that at TS1. In order to understand the higher
activation energy associated with TS3 and TS4 than
Figure 2. Geometries of TS3 and TS4. The distances are
given in ꢄ.
À
TS1, a conformational analysis along the C3 C5
forming-bond at the three TS was performed (see
Figure 3).[21] Two geometrical parameters at these TS
are analyzed: the distance between the O6 and O9
À
À
À
oxygen atoms and the O6 C5 C3 O9 dihedral
angles. The most favourable TS1 presents the largest
À
O6 O9 distance, 3.605 ꢄ. In addition, this transition
À
À
À
state presents the largest O6 C5 C3 O9 dihedral
angle, 75.2 degrees. These geometrical parameters
suggest that the two O6 and O9 oxygen atoms, which
could present some unfavourable electronic interac-
tions at the corresponding TS, are further apart at the
most favourable TS1. In addition, while TS1 presents
À À À
À À À
one C C C C and one O C C O gauche interac-
À À À
À À
tion, TS3 and TS4 present one C C C C, one C C
À
À À À
C O and one O C C O gauche interactions. There-
fore, at the less favourable TS3 and TS4 there is an
additional C C C O gauche interaction, which is not
À À À
present at TS1 (see Figure 3).
The extent of bond cleavage or bond formation
along a reaction pathway is provided by the concept
of bond order (BO).[22] At 15, the BO values between
the C3 and C4 and C5 atoms are 0.22 and 0.14, re-
spectively. These low values, which are not null, are a
consequence of some charge delocation at this zwit-
À
terionic intermediate. The BO value of the C3 O9
bond, 1.21, points to a large delocalization of the O9
À
Figure 3. Stereoisomeric TS associated with C3 C5 bond
formation. The O6 O9 distances are given in ꢄ, while dihe-
oxygen lone pair in the carbenium ionic C3 center
formed through the heterolytic C3 C4 bond cleavage. dral angles are given in degrees.
At this intermediate the C4 C5 and C5 O6 BO
values, 1.34 and 1.35, point to a C4 C5 O6 enolate
À
À
À
À
À
À
À
À
structure. At TS1, the BO value of the C3 C5 form- Si10 forming-bond is 0.31, while the Si10 C11 value
À
ing-bond is 0.34. At 16, the BO value of the C4 C5 is 0.57. At the intermediate 18, the BO values of the
À
À
À
bond is 0.94. At this intermediate, the C3 O9 BO O6 I7 and Si10 C11 bonds are 0.40 and 0.47, while
À
value, 0.95, agrees with a single C O bond. On the the BO values between the C4 and the C11 and N12
other hand, the N1 C4 BO value, 1.55, points to a are closer to 0.0.
large delocalization of the nitrogen N1 lone pair in
À
The natural charges at the I7 and I8 atoms at 14,
the C4 carbenium ionic center of 16. At this inter- 15, TS1 and 16 are 0.04 and À0.16 e, 0.13 and À0.40 e,
mediate, the BO value between the alkoxidic O6 0.15 and À0.47 e and 0.20 and À0.62 e, respectively.
atom and the I7 iodine atom, 0.51, points to a large Along the ring expansion there is an increase of the
À
À
bonding interaction between the enolate and the charge transfer from negatively charged C4 C5 O6
À
iodine molecule. At TS2, the BO value of the O6
enolate framework to the iodide molecule, which
Adv. Synth. Catal. 2010, 352, 1688 – 1700
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1695

Benito Alcaide et al.
FULL PAPERS
presents a maximum value at 16. The large charge
transfer found at the intermediate 16, ca. À0.40 e, ac-
counts for the catalytic role of the iodine molecule to
favour, together with the presence of the C3 methoxy
À
group, the heterolytic C3 C4 bond cleavage that
takes place at these ring expansion reactions. Interest-
ingly, the non-coordinated I8 atom supports the nega-
tive charge that is being transferred at the iodine mol-
ecule catalyst.
From this DFT study we can draw some interesting
conclusions about these iodine-catalyzed ring expan-
sion reactions. i) The ring expansion process proceeds
À
by a stepwise mechanism that involves the C3 C4
bond cleavage and the subsequent C3 C5 bond for-
À
À
mation. In order to favour the heterolytic C3 C4
bond cleavage, the presence of an electron-releasing
methoxy group at the C3 carbon, and the electron-
withdrawing iodine molecule acting as a Lewis cata-
lyst are demanded. Note that these ring expansions
do not take place in the absence of the methoxy
group at the C3 position. ii) The capture of the zwit-
terionic intermediate 16 by TMSCN takes place also
through a two-step nucleophilic substitution at the Si
atom with formation of a pentacoordinated Si inter-
mediate. The subsequent transfer of the CN group
Scheme 10. Mechanistic explanation for the formation of
morpholin-3-one derivatives 6.
from the Si atom to the carbocationic C4 center takes ion in C3 due to the a oxygen atom. The formation of
place via a concerted process. This behaviour means the six-membered intermediate 23 presents large acti-
that the C3 C5 bond formation takes place by the vation energy, 6.0 kcalmolÀ1, in comparison with its
À
same face of the pyrrolidin-2-one 17 where the five-membered counterpart (intermediate 16). How-
OSiMe3 group is located. This behaviour allows us to ever, while the formation of intermediate 16 is highly
explain the cis arrangement of the OSiMe3 and CN endothermic, 11.2 kcalmolÀ1, the formation of inter-
substituents at the final pyrrolidin-2-ones. iii) The mediate 23 is slightly exothermic, À1.1 kcalmolÀ1.
À
higher energy associated with the C3 C5 bond forma- Thus, pyrrolidin-2-one derivatives 3 come from a ki-
tion at the conformer rot-14, allowing the formation netic control and morpholin-3-ones 6 should arise
of the cis-16, accounts for the diastereoselectivity of from a thermodynamic control. For the TBSCN case,
these ring expansion processes. Finally, iv) the high intermediate 16 is attacked for the sylilated reagent,
À
energy associated with the C3 C5 bond formation at irreversibly affording the final product 3. Because the
the epim-13 accounts for the observation that epim-1c addition of allyltrimethylsilane requires more energy,
does not suffer the ring expansion in standard condi- the competitive mechanism for the obtention of com-
tions.
The differences encountered for the iodine-cata-
lyzed ring expansion reaction between different sily- arylCATHNUGTRNEoGUN xy rather than alkoxy, the disponibility of the
pounds 6 via intermediate 23 is also operative.
When the C3 substituent in the b-lactam ring is
lated nucleophiles such as TBSCN and allyltrimethyl- oxygen lone pair is lower because of the delocaliza-
silane, could be explained through the different polar- tion at the aromatic ring. This fact may well explain
À
izability of the C Si bond in both reagents. TBSCN the alternative way (electrophilic aromatic substitu-
bears a more polarized C Si bond than the allylic tion) for the reaction to happen. A possible mecha-
À
silane, which implies that allyltrimethylsilane requires nism for the iodine-catalyzed Friedel–Crafts type cy-
a higher activation energy for the SN2 reaction (from
ACHTUNGTRENcNGNU lization may initially involve the formation of a com-
17 to 18 in Scheme 7). The formation of morpholin-3- plex 24 through coordination of elemental iodine to
ones 6 should proceed by a reaction course that also the aldehyde group of 3-aryloxy-4-oxoazetidine-2-car-
À
involves C3 C4 b-lactam bond breakage in the transi- baldehydes 1o–r. This increase of the carbonyl group
tion state (Scheme 10). Probably, iodine enhances the reactivity should promote an electrophilic aromatic
reactivity of the 2-azetidinone moiety through selec- substitution with the C3 aromatic ring, forming the
tive complexation to the aldehyde site. The cleavage six-membered Wheland-type intermediate 25, which
À
of the C3 C4 bond is facilitated both by the enhance- is stabilized by the electron pair of the a heteroatom.
ment of the electrophilicity of the carbonyl group as Subsequent deprotonation would form tricycles 26. Fi-
well as by the stabilization of the resulting carbocat- nally, iodine-silicon exchange liberates adducts 10
1696
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Adv. Synth. Catal. 2010, 352, 1688 – 1700

Ring Expansion versus Cyclization in 4-Oxoazetidine-2-carbaldehydes Catalyzed by Molecular Iodine
the b-lactam skeleton relies upon appropriate substi-
tution and stereochemistry at C3. This mild protocol
uses a cheap and environmentally friendly catalyst,
and can install polysubstitution at the pyrrolidin-2-
one ring. On the other hand, starting from 3-aryloxy-
4-oxoazetidine-2-carbaldehydes a divergent reactivity,
namely, the Friedel–Crafts type cyclization to b-
lactam-fused chromanes was encountered. In addi-
tion, density functional theory (DFT) calculations
were performed to obtain an insight into various as-
pects of the reactivity of 4-oxoazetidine-2-carbalde-
hydes under iodine catalysis.
Experimental Section
General methods
1H NMR and 13C NMR spectra were recorded on a Bruker
AMX-500, Bruker Avance-300, Varian VRX-300S or Bruker
AC-200. NMR spectra were recorded in CDCl3 solutions,
except where otherwise stated. Chemical shifts are given in
ppm relative to TMS (1H, 0.0 ppm), or CDCl3 (13C,
77.0 ppm). Low- and high-resolution mass spectra were
taken on an Agilent 6520 Accurate-Mass QTOF LC/MS
spectrometer using the electronic impact (EI) or electro-
spray modes (ES) unless otherwise stated. IR spectra were
recorded on a Bruker Tensor 27 spectrometer. Specific rota-
tion [a]D is given in 10À1 deg cm2 gÀ1 at 208C, and the con-
centration (c) is expressed in g per 100 mL. All commercial-
ly available compounds were used without further purifica-
tion.
Scheme 11. Mechanistic explanation for the formation of b-
lactam fused chromanes 10 under iodine catalysis.
with concomitant regeneration of the catalyst
(Scheme 11).
A rational accounting for the stereochemical out-
come of the cyclization reactions of b-lactam alde-
hydes catalyzed by iodine is depicted in Scheme 12.
Thus, a six-membered cyclic chair-like transition-state
model with minimization of interactions would ac-
count for the formation of tricyclic adducts trans-10.
General Procedure for the Iodine-Catalyzed b-
Lactam Ring Expansion Reaction. Preparation of 3,4-
Dihydroxypyrrolidin-2-one Derivatives 3 and 4
A solution of the appropriate sylilated nucleophile (1.50–
5.00 mmol) in anhydrous acetonitrile (3.4 mL) was added
dropwise via syringe to a stirred solution of the appropriate
4-oxoazetidine-2-carbaldehyde 1 (1.00 mmol) and iodine
(0.10 mmol) in the same solvent (3.4 mL) at room tempera-
ture and under an argon atmosphere. The reaction mixture
was stirred at room temperature until disappearance of
starting material (TLC). Then, brine (10 mL) was added and
the resulting mixture was extracted with dichloromethane
(DCM) (5ꢅ20 mL). The organic layer was dried (MgSO4),
Conclusions
In conclusion, this is the first single-step catalytic ap-
proach to the pyroglutamic acid core via molecular
iodine-catalyzed ring expansion reaction of the b-
À
lactam nucleus. The novel C3 C4 bond breakage of filtered and concentrated under reduced pressure. Analyti-
Scheme 12. Proposed model for iodine-catalyzed cyclization reaction of 4-oxoazetidine-2-carbaldehydes leading to b-lactam
fused chromanes.
Adv. Synth. Catal. 2010, 352, 1688 – 1700
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1697

Benito Alcaide et al.
FULL PAPERS
cally pure adducts 3 or 4 were obtained after flash chroma-
tography of the residue on silica gel eluting with hexanes/
ethyl acetate mixtures.[23]
General Procedure for the Iodine-Catalyzed
Cyclization of 3-Aryloxy b-lactam aldehydes.
Preparation of b-Lactam-Fused Chromanes 10 and 11
ACHTUNGTRENNUNG
A
solution of tert-butyldimethylsilyl cyanide (1.50–
5.00 mmol) in anhydrous acetonitrile (3.4 mL) was added
dropwise via syringe to a stirred solution of the appropriate
3-aryloxy-b-lactam aldehyde 1o–r (1.00 mmol) and iodine
(0.10 mmol) in the same solvent (3.4 mL) at room tempera-
ture and under an argon atmosphere. The reaction mixture
was stirred at room temperature until disappearance of
starting material (TLC). Then, brine (10 mL) was added and
the resulting mixture was extracted with DCM (5ꢅ20 mL).
The organic layer was dried (MgSO4), filtered and concen-
trated under reduced pressure. Analytically pure adducts 10
or 11 were obtained after flash chromatography of the resi-
due on silica gel eluting with hexanes/ethyl acetate mixtures.
b-Lactam-fused chromanes (2aR,8R,8aS)-8-hydroxy-6-me-
3c]: From 1.0 g (4.26 mmol) of 4-oxoazetidine-2-carbalde-
hyde (+)-1c, and after chromatography of the residue using
hexanes/ethyl acetate (5:1) as eluent gave compound (+)-
syn-3c as a colourless oil; yield: 1.42 g (89%); [a]D: +44.9 (c
1
0.7 in CHCl3); H NMR (300 MHz, CDCl3, 258C): d=7.43
(AA’XX’, 2H), 6.94 (AA’XX’, 2H), 4.68 (d, J=7.3 Hz, 1H),
4.47 (t, J=7.6 Hz, 1H), 4.11 (d, J=7.9 Hz, 1H), 3.81 (s,
3H), 3.75 (s, 3H), 0.97 (s, 9H), 0.20 (s, 3H), 0.19 (s, 3H);
13C NMR (75 MHz, CDCl3, 258C): d=169.3, 158.4, 129.3,
124.1, 115.1, 114.6, 82.6, 71.9, 59.7, 55.5, 53.8, 25.5, 17.9,
À4.8, À5.1; IR (CHCl3): n=1727 cmÀ1; MS (EI): m/z (%)=
376 (15) [M]+, 319 (100) [MÀ57]+; elemental analysis calcd.
(%) for C19H28N2O4Si (376.5): C 60.61, H 7.50, N 7.44;
found: C 60.51, H 7.42, N 7.54.
thoxy-1-(4-methoxyphenyl)-8,8a-dihydro-1H-chromeno
b]azet-2(2aH)-one [(+)-trans-10b] and (2aR,8S,8aS)-8-hy-
droxy-6-methoxy-1-(4-methoxyphenyl)-8,8a-dihydro-1H-
chromeno[3,2-b]azet-2(2aH)-one [(+)-cis-10b]: From
ACHTUNGTRENNUNG[3,2-
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
(0.21 mmol) of 4-oxoazetidine-2-carbaldehyde (+)-1c, and
after chromatography of the residue using hexanes/ethyl
acetate (5:1) as eluent, 40 mg (67%) of the less polar com-
pound (+)-syn-4a, 4 mg (7%) of compound (+)-5a, and
3 mg (6%) of the more polar compound (À)-6a were ob-
tained.
105 mg (0.084 mmol) of 3-aryloxy-b-lactam aldehyde (+)-1p,
and after chromatography of the residue using hexanes/ethyl
acetate (3:1) as eluent, 77 mg (73%) of the less polar com-
pound (+)-trans-10b and 28 mg (27%) of the more polar
compound (+)-cis-10b were obtained.
(2aR,8R,8aS)-8-Hydroxy-6-methoxy-1-(4-methoxyphen-
yl)-8,8a-dihydro-1H-chromenoACHTNUTRGENNUG[3,2-b]azet-2AHCTUNGTREN(NNGU 2aH)-one [(+)-
ACHTUNGTRENNUNG(3R,4S,5R)-5-Allyl-4-hydroxy-3-methoxy-1-(4-methoxy-
phenyl)pyrrolidin-2-one [(+)-syn-4a]: Colourless solid; mp
123–1258C; [a]D: +57.7 (c 0.5 in CHCl3); 1H NMR
(300 MHz, CDCl3, 258C): d=7.30 (AA’XX’, 2H), 6.92
(AA’XX’, 2H), 5.82 (m, 1H), 5.15–5.06 (m, 2H), 4.52 (t, J=
7.1 Hz, 1H), 4.26 (dt, J=7.3, 5.4 Hz, 1H), 4.08 (d, J=
6.8 Hz, 1H), 3.81 (s, 3H), 3.72 (s, 3H), 2.45 (t, J=6.1 Hz,
2H); 13C NMR (75 MHz, CDCl3, 258C): d=167.0, 157.8,
133.7, 129.8, 125.4, 118.9, 114.4, 83.4, 72.4, 60.4, 59.0, 55.4,
32.2; IR (KBr): n=3373, 1678 cmÀ1; MS (EI): m/z (%)=277
(63) [M]+, 134 (100).
trans-10b]: Colourless solid; mp 132–1338C; [a]D: +161.6 (c
1
0.5 in CHCl3); H NMR (300 MHz, CDCl3, 258C): d=7.34
(AA’XX’, 2H), 7.04 (d, J=8.9 Hz, 1H), 6.87 (AA’XX’, 2H),
6.88–6.84 (m, 1H), 6.70 (d, J=3.0 Hz, 1H), 5.40 (d, J=
5.1 Hz, 1H), 5.07 (d, J=2.0 Hz, 1H), 4.71 (dd, J=5.1,
2.1 Hz, 1H), 3.79 (s, 3H), 3.73 (s, 3H); 13C NMR (75 MHz,
CDCl3, 258C): d=162.2, 156.7, 155.6, 146.0, 129.8, 125.2,
119.9, 118.5, 116.4, 115.2, 114.6, 79.0, 66.2, 59.2, 55.6, 55.5;
IR (KBr): n=3413, 1747 cmÀ1
; HR-MS (ES): m/z=
328.1179, calcd. for C18H18NO5 [M+H]+: 328.1185.
ACHTUNGTRENNUNG(3R,4S)-4-[(R)-1-Hydroxybut-3-enyl]-3-methoxy-1-(4-me-
(2aR,8S,8aS)-8-Hydroxy-6-methoxy-1-(4-methoxyphenyl)-
8,8a-dihydro-1H-chromenoACTHNUTRGENNG[U 3,2-b]azet-2HCATUNGTRENN(UGN 2aH)-one [(+)-cis-
thoxyphenyl)azetidin-2-one [(+)-5a]: Pale yellow oil; [a]D:
1
+127.5 (c 1.7 in CHCl3); H NMR (300 MHz, CDCl3, 258C):
10b]: Colourless oil; [a]D: +147.7 (c 0.4 in CHCl3);
1H NMR (300 MHz, CDCl3, 258C): d=7.52 (AA’XX’, 2H),
7.04 (d, J=8.8 Hz, 1H), 7.00 (d, J=2.8 Hz, 1H), 6.84
(AA’XX’, 2H), 6.85–6.80 (m, 1H), 5.35 (d, J=5.4 Hz, 1H),
5.13 (br s, 1H), 5.00 (dd, J=5.4, 4.1 Hz, 1H), 3.78 (s, 3H),
3.76 (s, 3H), 2.22 (d, J=9.1 Hz, 1H); 13C NMR (75 MHz,
CDCl3, 258C): d=163.2, 156.8, 156.0, 145.2, 130.9, 127.4,
119.5, 118.9, 114.5, 114.2, 110.4, 79.2, 68.7, 61.0, 55.6, 55.5;
d=7.41 (AA’XX’, 2H), 6.87 (AA’XX’, 2H), 5.85 (ddt, J=
15.9, 11.4, 6.9 Hz, 1H), 5.16–5.07 (m, 2H), 4.64 (d, J=
5.4 Hz, 1H), 4.31 (t, J=4.8 Hz, 1H), 4.10 (m, 1H), 3.80 (s,
3H), 3.69 (s, 3H), 2.56 (d, J=3.9 Hz, 1H), 2.33 (t, J=
6.6 Hz, 2H); 13C NMR (75 MHz, CDCl3, 258C): d=165.1,
156.8, 134.3, 130.7, 120.5, 117.9, 114.2, 82.7, 70.4, 60.1, 59.7,
55.5, 38.3; IR (CHCl3): n=3468, 1743 cmÀ1; MS (EI): m/z
(%)=277 (100) [M]+.
IR (CHCl3): n=3430, 1740 cmÀ1
; HR-MS (ES): m/z=
(R)-2-Methoxy-4-(4-methoxyphenyl)-2H-1,4-oxazin-
328.1171, calcd. for C18H18NO5 [M + H]+: 328.1185.
3(4H)-one [(À)-6a]: Pale orange oil; [a]D: À166.5 (c 0.5 in
CHCl3); 1H NMR (300 MHz, CDCl3, 258C): d=7.26
(AA’XX’, 2H), 6.94 (AA’XX’, 2H), 6.20 (d, J=4.3 Hz, 1H),
5.94 (d, J=4.4 Hz, 1H), 5.27 (s, 1H), 3.83 (s, 3H), 3.60 (s,
3H); 13C NMR (75 MHz, CDCl3, 258C): d=158.8, 158.6,
131.5, 126.7, 126.5, 114.5, 112.3, 97.9, 56.5, 55.5; IR (CHCl3):
n=1696 cmÀ1; MS (EI): m/z (%)=235 (37) [M]+, 134 (100).
Computational Methods
DFT calculations have been carried out using the B3LYP[24]
exchange-correlation functional, together with the standard
6–31G* basis set.[25] For the iodine atoms, the standard 3–
21G basis set was used. Since TSs and intermediates have a
large zwitterionic character and polar solvents can modify
both gas phase energies and geometries, the effects of aceto-
nitrile was considered at the geometrical optimizations by
using the polarizable continuum model (PCM) of Tomasiꢆs
group.[26] Single point energy calculation at the 6–31+G*
1698
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ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 1688 – 1700

Ring Expansion versus Cyclization in 4-Oxoazetidine-2-carbaldehydes Catalyzed by Molecular Iodine
level using the 6–31G* geometries were performed. Minor
changes were observed because of the zwitterionic species
are already stabilized by the solvent effects. The optimiza-
tions were carried out using the Berny analytical gradient
optimization method.[27] The stationary points were charac-
terized by frequency calculations. The intrinsic reaction co-
ordinate (IRC)[28] paths were traced by using the second
order Gonzꢂlez–Schlegel integration method.[29] The elec-
tronic structures of stationary points were analyzed by the
natural bond orbital (NBO) method.[30] All calculations
were carried out with the Gaussian 03 suite of programs.[31]
as Glycosidase Inhibitors: Nojirimycin and Beyond,
(Ed.: A. E. Stꢇtz), Wiley-VCH, Weinheim, 1999.
[4] For recent reviews, see: a) S. Das, R. Borah, R. R.
Devi, A. J. Thakur, Synlett 2008, 2741; b) H. Togo, S.
Iida, Synlett 2006, 2159.
[5] a) B. Alcaide, P. Almendros, G. Cabrero, M. P. Ruiz,
Chem. Commun. 2008, 615; b) B. Alcaide, P. Almen-
dros, G. Cabrero, M. P. Ruiz, Synthesis 2008, 2835.
[6] We have recently described the hydrocyanation and cy-
anosilylation of 4-oxoazetidine-2-carbaldehydes togeth-
er with the manipulation of the corresponding b-lactam
cyanohydrins: B. Alcaide, P. Almendros, G. Cabrero,
M. P. Ruiz, J. Org. Chem. 2007, 72, 7980.
[7] a) W. Van Brabandt, N. De Kimpe, J. Org. Chem. 2005,
70, 3369; b) W. Van Brabandt, N. De Kimpe, J. Org.
Chem. 2005, 70, 8717; c) S. Dekeukeleire, M. D’hooghe,
N. De Kimpe, J. Org. Chem. 2009, 74, 1644.
Acknowledgements
Support for this work by the DGI-MICINN (Projects
CTQ2006-10292, CTQ2009-09318 and CTQ2009-11027), Co-
munidad Autꢀnoma de Madrid (Project S2009/PPQ-1752)
and UCM-BSCH (Project GR58/08) are gratefully acknowl-
edged. G. C. and R. C. thank the MEC for predoctoral
grants.
[8] See, for instance: a) B. Alcaide, P. Almendros, R. Car-
rascosa, M. R. Torres, Adv. Synth. Catal. 2010, 352,
1277; b) B. Alcaide, P. Almendros, A. Luna, M. R.
Torres, Adv. Synth. Catal. 2010, 352, 621; c) B. Alcaide,
P. Almendros, T. Martꢁnez del Campo, M. T. Quirꢀs,
Chem. Eur. J. 2009, 15, 3344; d) B. Alcaide, P. Almen-
dros, R. Carrascosa, T. Martꢁnez del Campo, Chem.
Eur. J. 2009, 15, 2496; e) B. Alcaide, P. Almendros, R.
Carrascosa, M. C. Redondo, Chem. Eur. J. 2008, 14,
637; f) B. Alcaide, P. Almendros, T. Martꢁnez del
Campo, Angew. Chem. 2007, 119, 6804; Angew. Chem.
Int. Ed. 2007, 46, 6684.
[9] a) B. Das, P. Balasubramanyam, M. Krishnaiah, B.
Veeranjaneyulu, G. C. Reddy, Synthesis 2009, 3467;
b) J. S. Yadav, B. V. S. Reddy, M. S. Reddy, A. R.
Prasad, Tetrahedron Lett. 2002, 43, 9703.
[10] B. Alcaide, P. Almendros, Chem. Soc. Rev. 2001, 30,
226.
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