Controlled rearrangement of lactam-tethered allenols with brominating reagents: A combined experimental and theoretical study on α-versus β-keto lactam formation

Article abstract of DOI:10.1002/chem.201101160

N-Bromosuccinimide (NBS) smoothly promotes the ring expansion of lactam-tethered allenols to efficiently afford cyclic α- or β-ketoamides with good yields and high chemo-, regio-, and diastereoselectivity, through controlled C-C bond cleavage of the β- or

Full text of DOI:10.1002/chem.201101160

FULL PAPER
DOI: 10.1002/chem.201101160
Controlled Rearrangement of Lactam-Tethered Allenols with Brominating
Reagents: A Combined Experimental and Theoretical Study on a- versus
b-Keto Lactam Formation
Benito Alcaide,*[a] Pedro Almendros,*[b] Amparo Luna,[a] Sara Cembellꢀn,[a, b]
Manuel Arnꢁ,[c] and Luis R. Domingo[c]
Dedicated to Professor Francisco Palacios on the occasion of his 60th birthday
Abstract: N-Bromosuccinimide (NBS)
smoothly promotes the ring expansion
of lactam-tethered allenols to efficient-
ly afford cyclic a- or b-ketoamides with
good yields and high chemo-, regio-,
and diastereoselectivity, through con-
trast to the rearrangement reactions of
2-azetidinone-tethered allenols, which
lead to the corresponding tetramic acid
derivatives (b-keto lactam adducts) as
the sole products, the reactions of 2-in-
dolinone-tethered allenols under simi-
lar conditions give quinoline-2,3-diones
(a-keto lactam adducts) as the exclu-
sive or major products. To rationalize
the experimental observations, theoret-
ical studies have been performed.
Keywords: allenes · chemoselectivi-
ty · lactams · reaction mechanisms ·
rearrangement
À
trolled C C bond cleavage of the b- or
g-lactam nucleus. Interestingly, in con-
Introduction
biological activities demonstrated.[2,3] On the other hand, the
discovery of new reactivity and principles for controlling
chemo-, regio-, and stereoselectivity is a fundamental task
for organic synthesis. The enormous potential for confront-
ing two different groups that are either reactive or inert
(chemoselectivity) and preferential reaction with one direc-
tion of bond making (regioselectivity) combined with the
possibility of stereocontrol can all be encountered in reac-
tions of lactam-tethered allenols with electrophilic reagents.
Recently, we discovered that dual reactivity of 2-azetidi-
none-tethered allenols may occur by judicious choice of the
electrophilic reagent.[4] In our continuing efforts on the con-
struction of potentially bioactive heterocycles,[5] we were de-
lighted to find that brominating reagents were also very ef-
fective reagents for the ring-expansion reaction of 3-allenyl
3-hydroxyindolin-2-ones, but exhibited different chemoselec-
tivity. Herein, we report these results on the regio-, chemo-,
and stereocontrolled preparation of pyrrolidine-2,4-diones
(tetramic acids) and quinoline-2,3-diones. Additionally, the
mechanisms of these chemodivergent rearrangement reac-
tions have been theoretically investigated.
The emergence in organic synthesis of allenes, which are a
class of compounds with two p orbitals perpendicular to
each other, has allowed chemists to prepare a variety of
compounds of chemical and biological interest.[1] Demands
for facile and efficient generation of complex and diverse
druglike small molecules continue to stimulate the design
and development of conceptually innovative strategies in
the synthetic community. The abundance of nitrogen-con-
taining heterocycles in biologically active molecules has pro-
pelled many efforts for their synthesis and functionalization.
In particular, tetramic acids and quinolin-2-one derivatives
have attracted a great deal of attention due to the range of
[a] Prof. Dr. B. Alcaide, Dr. A. Luna, Dipl.-Chem. S. Cembellꢀn
Grupo de Lactamas y Heterociclos Bioactivos
Departamento de Quꢀmica Orgꢁnica I,
Unidad Asociada al CSIC, Facultad de Quꢀmica,
Universidad Complutense de Madrid,
28040 Madrid (Spain)
Fax : (+34)91-3944103
E-mail: alcaideb@quim.ucm.es
[b] Dr. P. Almendros, Dipl.-Chem. S. Cembellꢀn
Instituto de Quꢀmica Orgꢁnica General
Consejo Superior de Investigaciones Cientꢀficas, CSIC
Juan de la Cierva 3, 28006 Madrid (Spain)
Fax : (+34)91-5644853
Results and Discussion
Starting substrates, 2-azetidinone-tethered allenols 1a–j and
2-indolinone-tethered allenols 2a–i, were prepared accord-
ing to literature protocols by indium-mediated Barbier-type
allenylation reactions of the corresponding a-oxo lactams in
aqueous media.[6] The ring-expansion reaction from allenols
1 to tetramic acid derivatives 3 was conducted using our op-
timized protocol with stoichiometric amounts of N-bromo-
succinimide (NBS). Moderate to good yields were obtained.
E-mail: Palmendros@iqog.csic.es
[c] Prof. Dr. M. Arnꢂ, Prof. Dr. L. R. Domingo
Departamento de Quꢀmica Orgꢁnica
Universidad de Valencia, C/Dr. Moliner 50
46100 Burjassot, Valencia (Spain)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201101160.
Chem. Eur. J. 2011, 17, 11559 – 11566
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Interestingly, the smooth skeletal reorganization of allene-b-
lactam precursors 1 into tetramic acids 3 occurs in a com-
pletely chemo- and regioselective fashion and with high dia-
stereoselectivity (Scheme 1).[7] Of particular interest is the
exclusive formation of tetramic acid derivative 3i,[8] which
showed selective bond breaking of the b-lactam nucleus
with an allene moiety, allowing differentiation between two
chemically equivalent azetidinone rings. The controlled con-
version of 1j into either the tetramic acid/b-lactam hybrid
3j or the bis(tetramic acid) 3k is also worthy of note. While
substrate 1j underwent clean double expansion to 3k,
mono-ring expansion, yielding hybrid 3j, was the preferred
pathway when employing one equivalent of NBS.
The bromoalkene moiety of 3 is a good handle for further
functionalization at the alkene. For example, coupling of
bromoalkenyl adducts 3a and 3d with arylboronic acids
(Suzuki–Miyaura reaction) successfully produced 5a and 5b
(Scheme 2).
The skeletal reorganization of 2a was selected as our ini-
tial test reaction. Three widely used brominating reagents,
namely, NBS, tribromoisocyanuric acid (TBCA), and bro-
modimethylsulfonium bromide (BDMS) were screened in
the model reaction at 208C in dichloromethane. To our de-
light, all of the reagents exhibited high activities and the
ring-expansion product 6a was isolated as the sole isomer in
good yields (Table 1, entries 1–7). Interestingly, cyclic a-
versus b-ketoamide formation was observed; adduct 6a was
exclusively obtained. Thus, the rearrangement reaction of 2-
indolinone-tethered allenols exhibited different chemoselec-
tivity to that previously observed for 2-azetidinone-tethered
allenols (Scheme 1). Among the brominating reagents exam-
ined, NBS gave the best yield (Table 1, entry 4). The reac-
tion was next optimized by screening the solvent, tempera-
ture, and additive. It was found that the reaction in the ini-
tially selected solvent dichloromethane gave the best results
(Table 1, entries 1, 4, and 7). Next, we investigated the sub-
strate scope in this interesting ring-expansion reaction. An
excellent yield was achieved for carbon–carbon bond cleav-
age in the electrophilic ring-opening reaction of allenic 2b
to afford 6b, but the reaction was considerably slower
Scheme 1. Rearrangement reaction of 1a–j into 3a–k and 4e–g by NBS
treatment. Reagents and conditions: i) NBS (1.3 equiv), dichloromethane,
RT, 3a: 1.5 h; 3b: 45 min; 3c: 30 min; 3d: 45 min; 3e: 30 min; 3 f: 3 h;
3g: 1 h; 3h: 1 h; 3i: 45 min; ii) NBS (1.0 equiv), dichloromethane, RT,
24 h; iii) NBS (3.0 equiv), dichloromethane, RT, 24 h. PMP=4-
MeOC6H4, Bn=benzyl.
Abstract in Spanish: La N-bromosuccinimida (NBS) pro-
mueve de forma suave la expansion de anillo de alenoles
lactꢀmicos para generar eficientemente a-cetolactamas y b-ce-
tolactamas con buenos rendimientos y excelentes quimio-,
regio-, y diastereoselectividades, a travꢁs de roturas controla-
À
das del enlace C C en los nfflcleos de b- o g-lactama. Es
digno de destacar, que al contrario del reagrupamiento en
alenoles b-lactꢀmicos que fflnicamente da lugar a ꢀcidos tetrꢀ-
micos (aductos b-cetolactꢀmicos), la reacción de alenoles
oxindólicos en las mismas condiciones de reacción genera
quinolin-2,3-dionas (aductos a-cetolactꢀmicos) como produc-
tos mayoritarios o exclusivos. Ademꢀs, los mecanismos de
estas reacciones promovidas por NBS se han estudiado teóri-
camente.
Scheme 2. Suzuki–Miyaura reaction of 3a and 3d. Reagents and condi-
tions: i) 2.5 mol% [PdACHTUNGTERN(NNUG PPh3)4], NaHCO3, toluene/EtOH/H2O (18:1:1),
reflux, 4 h.
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Lactam-Tethered Allenols
FULL PAPER
Table 1. Controlled ring-expansion reactions of 2 to 6 under modified
bromination conditions.
Entry Reagent Solvent
Time R1, R2, R3
[h]
Product
(Yield
[%])[a]
AHCTUNGTRENNUNG
1
2
3
NBS
MeCN/H2O
(15:1)
MeCN/H2O
(15:1)
0.4
0.5
144
Me, H, H (2a) 6a (80)
Me, H, H (2a) 6a (68)
Me, H, H (2a) 6a (74)
TBCA
BDMS MeCN/H2O
(15:1)
4
5
6
7
8
NBS
TBCA
BDMS CH2Cl2
NBS
NBS
CH2Cl2
CH2Cl2
1
Me, H, H (2a) 6a (86)
Me, H, H (2a) 6a (72)
Me, H, H (2a) 6a (74)
Me, H, H (2a) 6a (70)
1.5
24
2
THF/H2O (15:1)
CH2Cl2
48
Me, Cl, H
(2b)
6b (80)
9
NBS[b]
CH2Cl2
40
Me, Cl, H
(2b)
6b (80)
10
11
NBS
NBS
CH2Cl2
CH2Cl2
60
144
Me, H, Cl (2c) 6c (47)
PMP, H, H
6d (–)
(2d)
[a] Yield of pure, isolated product with correct analytical and spectral
data. [b] The reaction was run in the presence of 3 ꢄ molecular sieves.
(Table 1, entry 8). The addition of 3 ꢄ molecular sieves to
the reaction mixture slightly decreased the reaction time,
but did not affect the yield or chemoselectivity (Table 1,
entry 9).[9] Compound 2c was also amenable to these condi-
tions, although it showed decreased reactivity and required
a prolonged reaction time (60 h) for complete conversion to
product 6c (Table 1, entry 10). Chloride substitution in prod-
ucts 2b and 2c may be synthetically valuable, offering new
opportunities for selective functionalization through cross-
coupling strategies. Unfortunately, compound 2d, with an ar-
omatic substituent at the allenic moiety, remained unreac-
tive in the ring-expansion reaction upon treatment with
NBS and only led to multiple products after extended reac-
tion times (Table 1, entry 11).
Figure 1. ORTEP drawing of b-keto lactam 3a (top) and a-keto lactam
6a (bottom). Ellipsoids are drawn at the 50% probability level.
Ring-expansion adducts are supported by the C=O stretch
detected by FTIR analysis (generally, 1785 cmÀ1 is a C=O
stretch in a four-membered ring, 1750 cmÀ1 is a C=O stretch
in a five-membered ring, and 1730 cmÀ1 is a C=O stretch in
a six-membered ring). Moreover, the structural and configu-
rational assignments of b- and a-keto lactams 3 and 6 were
confirmed by means of X-ray diffraction analysis of 3a and
6a (Figure 1).[10,11]
Scheme 3. Rearrangement reaction of 2e–h into 6e–h and 7 f–h by NBS
treatment. Reagents and conditions: i) NBS (1.3 equiv), CH2Cl2, RT, 2e:
45 min; 2 f: 40 min; 2g: 24 h; 2h: 72 h.
Under the optimized reaction conditions, we investigated
the generality of the protocol for 2e–h. The ring-enlarge-
ment reaction of 3-hydroxyindolin-2-ones potentially results
in the formation of a mixture of regioisomeric products.
Methyl-substituted 2e smoothly provided 6e as the sole
product (Scheme 3). Although substitution at the nitrogen
atom of the heterocycle should have little effect upon the
reactivity of the allenol moiety, in contrast to 2d, the related
compound 2 f underwent
a
rearrangement reaction
(Scheme 3). Hence, despite the presence of halide substitu-
ents at the benzenoid ring, which was anticipated to provide
the same reactivity pattern, we tested the validity of the
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11561

B. Alcaide, P. Almendros et al.
Figure 2. Geometries of the TSs involved in the NBS-catalyzed ring ex-
pansion of 1l and 2e. Distances are given in ꢄ.
above postulation with 2g and 2h. To our surprise, the
major product for the reaction of 2g was ring-expanded b-
keto 7g;[12] the expected compound 6g was the minor com-
ponent (Scheme 3). Although the chemoselectivity was poor
under these conditions and efforts for further improvements
were in vain, it should be noted that isomers 6 f–h and 7 f–h
were easily separated, thus readily providing two structural-
ly complex and valuable quinolin-2-one-type products.
To understand the mechanism of the ring expansion pro-
moted by NBS, the mechanism for the reactions of 1l and
2e was investigated using DFT methods at the B3LYP/6-
31G** level (see Scheme 4). We selected allenols 1l and 2e
as theoretical models because they were very closely related
structures to the parent precursors; indeed, oxindole 2e was
actually an experimentally used substrate. Since some spe-
cies involved in the reaction had a large ionic character, ge-
ometry optimizations were performed in dichloromethane.
In addition, due to the free bond rotation of the allenyl sub-
stituent and the bromination on both faces of the allenic
C5=C6 bond, several stereoisomeric reaction pathways are
feasible. We present herein the most favorable ones.
For the NBS-catalyzed ring expansion of azetidinone 1l,
two stereoisomeric reaction pathways were studied: path 1-I
and path 1-II in Scheme 4. They are related to the approach
of NBS to both faces of the allenic C5=C6 bond. It should
be noted that for the ring expansion of azetidinone 1l, only
migration of the carbonyl group is feasible. For the NBS-cat-
alyzed ring expansion of oxindole 2e, two regioisomeric re-
action pathways were considered. They were related to the
Scheme 4. Structure of allenols 1l and 2e (oxindole 2e corresponds to
the experimental substrate) as the selected theoretical models for compu-
tational studies.
migration of the carbonyl group, path 2-I, or the migration
of aryl group, path 2-II, during ring expansion.
These NBS-promoted ring expansions involve two distinct
processes: 1) addition of Br+ cation from NBS to the allenic
C5=C6 bond and 2) ring expansion. In dichloromethane, the
four reaction pathways present one-step mechanisms. There-
fore, two stereoisomeric transitions states (TSs) for the reac-
tion of azetidinone 1l, TS1-I and TS1-II, and two regioiso-
meric TSs for the reaction of oxindole 2e, TS2-I and TS2-II,
and the corresponding products were located and character-
ized (see Scheme 4). The total and relative energies in di-
chloromethane are given in Table 2. Noteworthy that in the
gas phase, azetidinone 1l has one-step mechanisms similar
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Lactam-Tethered Allenols
FULL PAPER
Table 2. Total (E) and relative energies (DE) calculated in dichlorome-
thane at the B3LYP/6-31G** level of theory for the stationary points in-
volved in NBS-promoted ring expansions of 1l and 2e.
path 2-I, is slightly favored over formation of isomer 7e as-
sociated with the migration of the carbonyl C2 carbon
À
through breaking of the C2 C3 bond, path 2-II. These re-
E [A.u.]
DE [kcalmolÀ1
]
sults are in reasonable agreement with experimental results.
It should be noted that the structure of oxindole 2e corre-
sponds to that of the experimental one.
1l
À555.9441285
À2931.749286
À3487.666187
À3487.667553
À3487.780489
À3487.778604
À669.0873928
À3600.807236
À3600. 806684
À3600.890528
À3600.912078
NBS
TS1-I
TS1-II
3l
4l
2e
TS2-I
TS2-II
6e
17.1
16.2
The geometries of the TSs involved in the NBS-promoted
ring expansion of 1l and 2e are depicted in Figure 2. The
more relevant geometrical parameters that allow for charac-
terization of bond formation and bond breaking at these
À54.6
À53.5
18.5
18.8
À
À
TSs are 1) the Br C6 bond lengths and the Br N distances,
which yield a measure of the evolution of the Br+ addition
À33.8
À
À
7e
À47.3
process; 2) the O7 H8 bond lengths and the H8 O distance,
which yield a measure of the proton abstraction by the suc-
À
À
cinimidate anion; and 3) the C2 C3 or C3 C4 lengths,
which yield a measure of the ring-expansion processes.
Analysis of these geometrical parameters given in
Figure 2 indicates that the four TSs present similar asyn-
chronicity in the Br+ addition/ring-expansion processes. At
to those found in dichloromethane, but for oxindole 2e
some paths have stepwise mechanisms via very unstable cat-
ionic intermediates. However, in the gas phase these cation-
ic intermediates undergo, without any appreciable barrier,
acid/base reactions or nucleophilic attacks by the succinimi-
date anion, making it unfeasible to characterize the step as-
sociated with the ring-expansion process. This behavior does
not allow the NBS-catalyzed ring expansion of 2e to be
studied in the gas phase.
Analysis of the geometries of the four TSs, associated
with these one-step mechanisms, shows that they present
have behavior: 1) the addition of the Br+ cation to the C6
carbon of the allenic C5=C6 bond is very advanced; 2) this
addition allows the formation of a carbocationic C5 center
instead of a three-membered bromonium ion structure;
3) formation, in an early step of the reaction, of a hydrogen
bond between one oxygen atom of NBS and the hydroxyl
hydrogen atom, which remains along the reactions, and fi-
À
the four TSs, the lengths of the Br C6 bonds (in the narrow
À
range of 1.91–1.94 ꢄ) and the Br N distances (in the range
of 2.69–3.05 ꢄ) indicate that at these TSs the Br+ cation is
essentially transferred from NBS to the C6 carbon atom of
À
the allenic substituents. On the other hand, the O7 H8
lengths (in the narrow range of 1.01–1.05 ꢄ) together with
the C2 C3 bond lengths (1.650 ꢄ at TS1-I, 1.631 ꢄ at TS1-
À
À
II, 1.755 ꢄ at TS2-II), or the C3 C4 bond length at TS2-I
(1.545 ꢄ) indicate that the ring-expansion process is de-
layed.
Analysis of the geometries of the four TSs shows that the
three carbon atoms attached to the carbocationic C5 center
formed with the addition of the Br+ ion at the C6 carbon
are in a planar rearrangement, in agreement with sp2 hybrid-
ization for the C5 carbon atom. On the other hand, at these
À
nally; 4) C C breaking bond associated with the ring expan-
À
À
sion is very delayed.
TSs the breaking C2 C3 or C3 C4 bonds adopt a near per-
pendicular rearrangement, which is required for subsequent
C2 or C4 carbon migration. At TS1-I and TS1-II, the C2-
C3-C5-C6 dihedral angles are 84.2 and 122.68. For TS2-I and
TS2-II, the corresponding C2(4)-C3-C5-C6 dihedral angles
are 106.6 and 102.68, respectively. Finally, the C2(4)-C3-C5
bond angles can be taken as a measure of the evolution of
the ring expansion. These values at the TSs are 103.98 at
TS1-I, 113.98 at TS1-II, 79.98 at TS2-I, and 96.28 at TS2-II.
The four TSs have very low imaginary frequencies, be-
tween À19 and À63 cmÀ1. Analysis of the atomic movement
associated with these unique imaginary frequencies shows
the participation of a large number of atoms in these TSs, in
clear agreement with the participation, in a different exten-
sion, of several forming and breaking bonds in these bromi-
nation/ring-expansion processes.
The extent of bond cleavage or formation along a reaction
pathway is provided by the concept of bond order (BO).[13]
The BO values of the forming and breaking bonds involved
in these NBS-promoted ring expansions are listed in
Table 3. For the NBS promoted-ring expansion of azetidi-
none 1l, analysis of the BO values given in Table 3 indicates
that they are associated with similar processes. While the ad-
For azetidinone 1l, the activation energies associated with
TS1-I and TS1-II are 17.1 and 16.2 kcalmolÀ1, respectively.
These reactions are strongly exothermic, À54.6 (3l) and
À53.5 (4l) kcalmolÀ1, since these processes are irreversible.
Therefore, for 1l the formation of stereoisomer 4l, via TS1-
II, is slightly preferred over the formation of 3l, via TS1-I;
this is in disagreement with experimental results. The pres-
ence of a p-methoxyphenyl substituent at the N1 nitrogen or
a bulky 2,2-dimethyl-1,3-dioxolane substituent at the C4 po-
sition in the experimental substrates are able to modify this
low energy difference. The difficulty found in the search for
these TSs together with the large number of feasible confor-
mations associated with the presence of the p-methoxyphen-
yl and the 2,2-dimethyl-1,3-dioxolane substituents render
the search for the stereoisomeric TSs associated with the ex-
perimental model inadequate.
For oxindole 2e, the activation energies associated with
TS2-I and TS2-II are 18.5 and 18.8 kcalmolÀ1. These reac-
tions are strongly exothermic, À33.8 (6e) and À47.3 (7e)
kcalmolÀ1, since these processes are also irreversible. There-
fore, formation of isomer 6e associated with the migration
À
of the aryl C4 carbon through breaking the C3 C4 bond,
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B. Alcaide, P. Almendros et al.
Table 3. BO values of the bonds formed and broken at the TSs.
Experimental Section
TS1-I
TS1-II
TS2-I
TS2-II
General: 1H and 13C NMR spectra were recorded on Bruker AMX-500,
Bruker Avance-300, Varian VRX-300S, or Bruker AC-200 spectrometers.
NMR spectra were recorded in CDCl3, unless otherwise stated. Chemical
shifts are given in ppm relative to tetramethylsilane (TMS; 1H, d=
0.0 ppm) or CDCl3 (13C, d=77.0 ppm). Low- and high-resolution mass
spectra were recorded on an AGILENT 6520 Accurate-Mass QTOF LC/
MS spectrometer using the electronic impact (EI) or electrospray (ES)
modes unless otherwise stated. IR spectra were recorded on a Bruker
Tensor 27 spectrometer. Specific rotation [a]D is given in 10À18cm2 gÀ1 at
208C, and the concentration (c) is expressed in g per 100 mL. All com-
mercially available compounds were used without further purification.
À
C6 Br
À
Br N
0.91
0.04
0.54
0.16
0.72
0.06
0.96
0.09
0.56
0.13
0.77
0.04
0.95
0.07
0.55
0.14
0.85
0.41
1.01
0.03
0.50
0.20
0.63
0.10
À
O7 H
À
H O
À
À
C2 C3 (C4 C3)
À
C3 C7
dition of the Br+ cation is advanced (C6 Br BOs are 0.91
(TS1-I) and 0.96 (TS1-II)), ring expansion is delayed (C2
C3 BOs are 0.72 (TS1-I) and 0.77 (TS1-II)). TS TS2-II, asso-
ciated with NBS-promoted ring expansion of oxindole 2e,
has a slightly more advanced character; the C6 Br and C2
C3 BOs are 1.01 and 0.63, respectively. TS TS2-I, associated
with phenyl migration, has different behavior; along ring ex-
pansion, C3 C7 bond formation (C3 C7 BO is 0.41) is
more advanced than the breaking C3 C4 bonds (C3 C4 BO
is 0.85).
À
À
General procedure for NBS-promoted lactam ring expansion
Preparation of tetramic acids 3 and 4 and quinolinedione derivatives 6
and 7: The appropriate amount of NBS (1–3 equiv) was added to a solu-
tion of 1 or 2 (0.50mmol) in dichloromethane (20mL). The reaction mix-
ture was stirred at RT until the starting material disappeared, as indicated
by TLC. A saturated aqueous solution of sodium hydrogen carbonate
(5mL) was added, before the reaction mixture was partitioned between
dichloromethane and water. The organic extract was washed with brine,
dried (MgSO4), concentrated under vacuum, and purified by flash
column chromatography using ethyl acetate/hexanes or dichloromethane/
ethyl acetate mixtures as the eluents.[14]
À
À
À
À
À
À
From this DFT study, some interesting conclusions on
these NBS-catalyzed ring expansions can be deduced:
1) These NBS-promoted ring expansions have one-step
mechanisms. 2) At the corresponding TSs, while the Br+
cation is essentially transferred to the central sp carbon
atom of the allene group, ring expansion is delayed. 3) The
four TSs have similar behavior. The addition of the Br+
cation to the central sp carbon atom of the allene group
leads to the formation of a carbocationic sp2 C5 center,
which induces concomitant ring expansion. 4) For 1l, the
two stereoisomeric TSs have similar energies. The presence
of a bulky substituent can control the stereochemistry of the
reaction. Finally, 5) for 2e, migration of the phenyl group is
favored over migration of the carbonyl group.
Compound (À)-3a: Starting from (+)-1a (50 mg, 0.15 mmol), and after
chromatography of the residue using hexanes/ethyl acetate (2:1) as the
eluent, gave (À)-3a as a colorless solid (61 mg, 96%). M.p. 137–1398C;
[a]D =À12.5 (c=0.6 in CHCl3); 1H NMR (300 MHz, CDCl3, 258C): d=
7.32 and 6.95 (d, J=8.8 Hz, each 2H), 6.03 and 5.85 (d, J=3.0 Hz, each
1H), 4.65 (d, J=2.3 Hz, 1H), 4.51 (td, J=6.6, 2.2 Hz, 1H), 3.81 (m, 4H),
3.42 (dd, J=8.9, 6.1 Hz, 1H), 1.60 and 1.42 (s, each 3H), 1.26 ppm (s,
3H); 13C NMR (75 MHz, CDCl3, 258C): d=206.1, 171.7, 158.6, 129.8,
126.5, 125.7, 121.2, 114.4, 109.8, 75.1, 68.4, 64.5, 59.7, 55.4, 26.1, 24.6,
17.6 ppm; IR (CHCl3): n˜ =1760, 1703, 1513, 1251 cmÀ1; HRMS (EI): m/z
calcd for C19H23BrNO5 [M+H]+: 424.0760; found: 424.0756.
Compound 6a: Starting from 2a (30 mg, 0.14 mmol), and after chroma-
tography of the residue using hexane/ethyl acetate (2:1) as the eluent,
gave 6a as a colorless solid (36 mg, 86%). M.p. 93–958C; 1H NMR
(300 MHz, CDCl3, 258C): d=7.36 (m, 4H), 5.85 and 5.82 (d, J=3.2 Hz,
each 1H), 3.41 (s, 3H), 1.67 ppm (s, 3H); 13C NMR (75 MHz, CDCl3,
258C): d=190.9, 155.0, 137.1, 131.7, 129.6, 127.4, 126.1, 124.4, 121.6,
116.5, 60.4, 30.0, 21.9 ppm; IR (CHCl3): n˜ =1743, 1684cmÀ1; HRMS (ES):
m/z calcd for C13H13BrNO2 [M+H]+: 294.0130; found: 294.0123.
Conclusion
Computational methods: DFT calculations were carried out by using the
B3LYP[15] exchange-correlation functional, together with the standard 6-
31G** basis set.[16] Since TSs and intermediates have a large zwitterionic
character and polar solvents can modify gas-phase energies and geome-
tries, the effects of dichloromethane were considered for the geometrical
optimizations by using the polarizable continuum model (PCM) of Toma-
siꢅs group.[17] The optimizations were carried out by using the Berny ana-
lytical gradient optimization method.[18] Stationary points were character-
ized by frequency calculations. The intrinsic reaction coordinate (IRC)[19]
paths were traced by using the second-order Gonzꢁlez–Schlegel integra-
tion method.[20] The electronic structures of stationary points were ana-
lyzed by the natural bond orbital (NBO) method.[21] All calculations
were carried out with the Gaussian 03 suite of programs.[22]
This is the first single-step approach to tetramic acid or qui-
nolinedione cores through brominating-reagent-promoted
ring-expansion reactions of the b-lactam or oxindole nu-
cleus. This mild protocol uses NBS, which is a highly useful
halogenating reagent in laboratories in terms of its inexpen-
siveness, ease of handling, as well as the generation of rela-
tively inert succinimide as the byproduct. Additionally, the
method allows polysubstitution at the heterocyclic dione
ring. On the other hand, divergent chemoselectivity, namely,
cyclic a- versus b-ketoamide formation was encountered. In
addition, DFT calculations were performed to obtain an in-
sight into various aspects of the controlled reactivity of 2-
azetidinone- and 2-indolinone-tethered allenols under NBS
treatment.
Acknowledgements
Support for this work by the DGI-MICINN (projects CTQ2009-09318
and CTQ2009-11027), Comunidad Autꢂnoma de Madrid (project S2009/
PPQ-1752), and UCM-Santander (grant GR35/10A) are gratefully ac-
knowledged. S.C. thanks the CSIC and MEC for studentships (JAE-intro
and beca de colaboraciꢂn).
11564
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Chem. Eur. J. 2011, 17, 11559 – 11566

Lactam-Tethered Allenols
FULL PAPER
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[7] Diastereoselectivity is due to the exclusive or preferential formation
of a diastereomer. Chemoselectivity arises from the exclusive cleav-
À
age of the C2 C3 bond of the b-lactam ring, whereas regioselectivity
comes from sole attack to the proximal allene carbon atom with
concomitant placement of the bromine to the central allene posi-
tion.
[8] Attached ring adduct 3i can be regarded as a hybrid of the pharma-
cologically relevant subunits of b-lactam and tetramic acid.
[9] The mild basicity of molecular sieves should be responsible for this
slight catalytic activity by deprotonation of the hydroxyl moiety to
provide a nucleophilic alcoxide which facilitates the rearrangement.
[10] X-ray data for 3a: crystallized from ethyl acetate/n-hexane at 208C;
C19H22BrNO5
P2(1)2(1)2(1); a=7.7011(7), b=9.4066(9); c=27.809(3) ꢄ; b=908;
V=2014.5(3) ꢄ3; Z=4; 1calcd =1.399 mgmÀ3 m=2.068 mmÀ1
F-
(000)=872. A transparent crystal of 0.313ꢇ0.424ꢇ0.460 mm3 was
used. 4380 [R(int)=0.0422] independent reflections were collected
(Mr =424.29);
orthorhombic;
space
group=
;
;
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
on a Bruker Smart CCD diffractomer using graphite-monochromat-
ed MoKa radiation (l=0.71073 ꢄ) operating at 50 kV and 30 mA.
Data were collected over a hemisphere of the reciprocal space by
combination of three exposure sets. Each exposure of 20 s covered
0.3 in w. The cell parameters were determined and refined by a
least-squares fit of all reflections. The first 100 frames were re-col-
lected at the end of the data collection to monitor crystal decay, and
no appreciable decay was observed. The structure was solved by
direct methods and Fourier synthesis. It was refined by full-matrix
least-squares procedures on F2 (SHELXL-97). All non-hydrogen
atoms were refined anisotropically. All hydrogen atoms were includ-
ed in calculated positions and refined riding on the respective
carbon atoms. Final R(wR) values were R1=0.0433 and wR2=
0.1082. CCDC-711362 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.a-
c.uk/data_request/cif.
[11] X-ray data of 6a: crystallized from ethyl acetate/n-hexane at 208C;
C13H12BrNO2 (Mr =294.15); monoclinic; space group=P21/n; a=
11.3440(10), b=9.1381(8); c=12.2424(11) ꢄ; a=90; b=105.830(2);
g=908; V=1220.95(19) ꢄ3; Z=4; 1calcd =1.600 mgmÀ3
;
m=
3.355 mmÀ1
transparent crystal of 0.19ꢇ0.13ꢇ
0.06 mm3 was used. 2916 [R
ACHTUNGTERNN(UNG int)=0.0511] independent reflections
; FACHTUNRTGENN(GUN 000)=592. A
were collected on a Bruker Smart CCD diffractomer using graphite-
monochromated MoKa radiation (l=0.71073 ꢄ) operating at 50 kV
and 30 mA. Data were collected over a hemisphere of the reciprocal
space by combination of three exposure sets. Each exposure of 20 s
covered 0.3 in w. The cell parameter were determined and refined
by a least-squares fit of all reflections. The first 100 frames were re-
collected at the end of the data collection to monitor crystal decay,
Chem. Eur. J. 2011, 17, 11559 – 11566
ꢃ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
11565

B. Alcaide, P. Almendros et al.
and no appreciable decay was observed. The structure was solved by
direct methods and Fourier synthesis. It was refined by full-matrix
least-squares procedures on F2 (SHELXL-97). All non-hydrogen
atoms were refined anisotropically. All hydrogen atoms were includ-
ed in calculated positions and refined riding on the respective
carbon atoms. Final R(wR) values were R1=0.0460 and wR2=
0.1071. CCDC-765452 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.a-
c.uk/data_request/cif.
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[14] Experimental procedures as well as full spectroscopic and analytical
data for compounds not included in the Experimental Section are
described in the Supporting Information. It also contains copies of
NMR spectra for all new compounds.
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Received: April 15, 2011
Published online: August 31, 2011
11566
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Chem. Eur. J. 2011, 17, 11559 – 11566