Functionalization and rearrangement of spirocyclohexadienyl oxindoles: Experimental and theoretical investigations

Article abstract of DOI:10.1002/chem.200901434

The preparation and functionalization of spirocyclohexa-2,5diene oxindoles is described. The spirocyclic core of the title compounds was installed by using a SmI₂-mediated cyclization of aryl iodobenzamides. Epoxidation with CF₃CO

Full text of DOI:10.1002/chem.200901434

DOI: 10.1002/chem.200901434
Functionalization and Rearrangement of Spirocyclohexadienyl Oxindoles:
Experimental and Theoretical Investigations
Gꢀraldine Rousseau, Frꢀdꢀric Robert,* and Yannick Landais*[a]
Abstract: The preparation and func-
tionalization of spirocyclohexa-2,5-
diene oxindoles is described. The spiro-
cyclic core of the title compounds was
installed by using a SmI2-mediated cyc-
lization of aryl iodobenzamides. Epoxi-
dation with CF3CO3H was then carried
out and was shown to occur with a
high level of diastereocontrol: the re-
agent approaches the diene moiety syn
to the amide group, which is likely to
be as a consequence of hydrogen bond-
ing between the amide C=O bond and
the peracid hydrogen. Carbanionic
functionalization of the spirocyclohexa-
2,5-diene oxindoles was then examined,
leading to an unprecedented rearrange-
ment of the strained spiro system into
was trapped by electrophiles including
alkyl halides and aldehydes. Interest-
ingly, alkylation and hydroxyalkylation
occurred with different regiocontrol.
DFT calculations were performed that
rationalize the observed skeleton rear-
rangement, emphasizing the role of
LDA/diisopropylamine in this rear-
rangement. The proposed mechanism
dearomatized
phenanthridinones.
Upon treatment with lithium diisopro-
pylamide (LDA) at ꢀ408C, the dienes
rearranged to provide a phenanthridi-
none lithium enolate intermediate that
thus relies on
a thermodynamically
driven diisopropylamine-mediated
Keywords: density functional calcu-
lations · enolates · epoxidation ·
lithium amides · rearrangement
proton transfer with the cleavage of
the diene–amide C=O bond as the key
step.
Introduction
Spirocyclic oxindoles such as I constitute the key fragment
of relevant alkaloids, including gelsemine 1,[1] the main com-
ponent of Gelsemium sempervirens, but also of several im-
portant synthetic targets that exhibit attractive biological ac-
tivities, amongst them the ketone 2 (active against Mycobac-
terium tuberculosis H37Rv[2]) and SR 121463 A 3, an antago-
nist of vasopressin receptors (Scheme 1).[3] Spirocyclic oxin-
doles are also versatile intermediates, as illustrated in the
synthesis of complex Alstonia oxindole alkaloids.[4] The func-
tionalized spirooxindole core is accessible through a wide
range of methods, including Pummerer[5a] and Claisen[5b] re-
arrangements of tryptophan precursors, [3,3]-sigmatropic re-
arrangements,[5c] but also radical processes,[5d–i] or through
oxidation of indoles.[5j] The challenging installation of the
Scheme 1. The spirocyclic oxindole skeleton in natural and synthetic com-
pounds of biological interest.
[a] Dr. G. Rousseau, Dr. F. Robert, Prof. Dr. Y. Landais
Universitꢀ de Bordeaux, Institut des Sciences Molꢀculaires
UMR-CNRS 5255, 351 cours de la libꢀration
33405 Talence (France)
stereogenic spiro center in gelsemine 1 has also garnered a
lot of attention.[1] This has led to the development of general
approaches for the elaboration of spirooxindoles,[6] which in-
clude the intramolecular Heck reaction that provides the re-
quired spirocyclic skeleton with a high level of stereoselec-
tivity.[7] In the course of our ongoing research on desymmet-
rization,[8] it was envisioned that spirocyclohexa-2,5-dienes
Fax : (+33)540-00-62-86
E-mail: f.robert@ism.u-bordeaux1.fr
y.landais@ism.u-bordeaux1.fr
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200901434.
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FULL PAPER
of type II might be valuable precursors for chiral spirocyclic
oxindoles using symmetry-breaking transformations, includ-
ing enantioselective electrophilic (epoxidation, dihydroxyla-
tion) and carbanionic processes. These simple functionaliza-
tions of precursor II would thus offer a rapid approach to
such attractive synthons that would be complementary to
those described before.
Enantioselective desymmetrization of II implies that one
is able to differentiate between the diastereo- and enantio-
topic faces of the cyclohexadienyl system, a difficult task to
achieve.[9] We showed previously that both faces could be ef-
ficiently distinguished providing that a large substituent
(e.g., SiR3) is present on the prochiral allylic center to shield
one diastereotopic face.[8a,b,9a] We envisaged in this study
that discrimination of the two faces of the dienyl system
might also be carried out through electronic effects by using
a polar group on one face and an apolar group on the other
face (Scheme 2). Spirocyclic oxindoles II exhibit electroni-
dides. They showed that spiro compounds were formed pre-
dominantly, providing that an ortho substituent was located
on the aromatic amide. In the absence of such a substituent,
the reaction led to the corresponding phenanthridinones.
Based on this premise, we tested the reaction on aryl amides
4a–d, which have various alkoxy substituents (OR) in the
ortho position that can then be removed to afford the de-
sired cyclohexa-1,4-dienes (Scheme 3).
Scheme 3. SmI2-mediated cyclization of aryliodoamides 4a–e.
The results are summarized in Table 1. Phenol amide 4a
cyclizes to give the phenanthridinone 6a as the sole product,
albeit in modest yield (Table 1, entry 1). Surprisingly, the
same compound was obtained starting from the triflate 4b
Table 1. Synthesis of spirocyclohexadienyl oxindoles 5a–d (Scheme 3).
Entry Amide
R
R’
Cpd 5 Cpd 6 Ratio 5/6[a] Yield
[%][b]
Scheme 2. Diastereotopic face differentiation in spirocyclohexadienyl ox-
indoles using electrophilic and organometallic reagents.
1
2
3
4
4a
4b
4c
4d
H
Tf
H
H
H
5a
5b
5c
6a
6a
6b
6c
0:100
0:100
100:0
100:0
55
20
SiMe2tBu
SiMe2tBu OMe 5d
99
49[c]
cally well-differentiated diastereotopic faces with a polar
amide function and an apolar aryl group, respectively,
shielding each face. One can then envisage the approach of
a given reagent A on the top face though hydrogen bonding
(e.g., III) or complexation (A=metal, IV) by the strongly
polar amide group. Conversely, p stacking might favor ap-
proach from the bottom face (III).
We describe below our study on functionalization of these
dienes, using both electrophilic and organometallic process-
es. In the course of these studies, we discovered a new rear-
rangement mediated by lithium amide bases that provides
useful and highly functionalized phenanthridinones, which
are valuable intermediates for organic synthesis. We report
a full account on these investigations,8d including our at-
tempts at desymmetrizing dienes II and disclose our efforts
to understand the mechanism of the above rearrangement.
Ab initio calculations that support the mechanism of amide–
base-mediated rearrangement of these compounds are also
provided.
[a] Estimated by 1H NMR spectroscopy of the crude reaction mixture.
[b] Isolated yields of 5 and 6. [c] 60% based on recovered starting mate-
rial (brsm).
(Table 1, entry 2), a direct precursor of the desired diene
(see below). Finally, the OSiMe2tBu group in amides 4c and
4d gave the best results with the expected spirooxindole 5c
and 5d formed in quantitative and modest yields, respective-
ly (Table 1, entries 3 and 4). The siloxycyclohexadienes 5c
and 5d were then transformed into the desired nonsubstitut-
ed dienes 7a and 7b using a two-step sequence (Scheme 4).
Compounds 5c and 5d were first converted, by treatment
with PhNTf2, into the corresponding triflates,[11] which were
not isolated but directly transformed into the desired dienes
through
a
palladium-mediated hydrogenation.[12] Com-
pounds 7a and 7b were isolated in satisfying 87 and 81%
overall yields, respectively.
Results and Discussion
Synthesis of spirocyclic oxindole precursors: The spirocylic
precursors were prepared by using methodology based on a
SmI2-mediated aryl cyclization of arylamides 4a–d. Tanaka
et al.[10] recently described a rapid access to spirooxindoles
using a radical-mediated 5-exo-trig cyclization of aryl io-
Scheme 4. Preparation of spirocyclic oxindoles 7a and 7b.
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F. Robert, Y. Landais, and G. Rousseau
Epoxidation of cyclohexadienes 7a and 7b: The epoxidation
reaction was first tested, since it is a well-documented pro-
cess,[13] which should be helpful to reveal the electronic and
steric effects at play during the functionalization of these
dienes as depicted in Scheme 2. Various conditions were
tested on spirocyclohexadiene 7a (Table 2), indicating that
Figure 1. X-ray crystal structures of epoxides 8b and 9.
Table 2. Epoxidation of spirooxindole 7a.
to the polar amide group, which is likely to be as a result of
hydrogen bonding between the reagent and the amide C=O
bond, following
a
transition state such as TS-A
(Scheme 5).[17] The Lewis basic carbonyl group thus plays
Entry Conditions[a]
Product Yield[b] d.r.[c]
ee[d]
[%]
[%]
[%]
1
2
mCPBA, CH2Cl2, 208C, 24 h
(CF3CO)2O (2 equiv), H2O2,
(1.3 equiv) CH2Cl2, 208C, 12 h
(CF3CO)2O (13 equiv), H2O2
ACHTUNGTRENNUNG(13 equiv), CH2Cl2, 08C, 4 h
10, Na2EDTA, Oxone, 08C,
24 h
10, Na2EDTA, Oxone, 208C,
24 h
8a/8b
8a/8b
33
50:50
–
–
G
19 (59) >95:<5
Scheme 5. Transition state for the epoxidation of spirooxindoles.
3
4
5
R
9
78 >95:<5
–
8a/8b
8a/8b
43 (78) <5:>95 10
33 (50) <5:>95
the role of the proton acceptor and directs the epoxidation
reagent, in good agreement with previous results by Ganem
and McKittrick,[14b] who showed that CF3CO3H was able to
hydrogen bond to chiral allylic and homoallylic ethers, but
also to urethanes and amides. In contrast, the less acidic
mCPBA is not able to hydrogen bond efficiently to the
oxygen of the amide group, thus leading to no diastereofa-
cial selectivity. It is interesting to notice the difference in di-
recting effect between mCPBA and CF3CO3H, the former
generally providing good level of diastereocontrol with
chiral allylic and homoallylic alcohols through TS-B
(Scheme 5). In this case, the epoxidizing reagent plays the
role of the proton acceptor.[18]
Finally, epoxidation using the Shi reagent 10/Oxone led to
complementary diastereocontrol, showing that when the het-
eroatom directing effect cannot operate, the face anti to the
amide group is the more accessible. As suggested by
Fehr,[14a] it was envisaged that the preference for syn selec-
tivity with CF3CO3H, could also be ascribed to electrostatic
interactions. CF3CO3H possesses a high electrostatic poten-
tial and coulombic interactions with the p face of the olefin
with the highest electron density should be favored. The es-
timation of electrostatic potential of each of the diastereo-
topic faces (carried out through semi-empirical calculations
using PM6)[19a] effectively showed that the diene double
bonds exhibit a more negative electrostatic field on the car-
bonyl face (red area in Figure 2).
3
[a] EDTA=ethylenediaminetetraacetic acid. [b] Isolated yield (brsm
yield). [c] Estimated from 1H NMR spectroscopic analysis of the crude
reaction mixture. [d] Estimated from HPLC analysis on WHELK-O 2
(REGIS technologies INC).
spirooxindoles are poorly reactive toward most epoxidation
reagents. However, we were pleased to observe that comple-
mentary stereochemical outcomes may be obtained by
changing the nature of the reagents. For instance, meta-
chloroperbenzoic acid (mCPBA) was shown to be nonselec-
tive (Table 2, entry 1), whereas the much more reactive
CF3CO3H[14] (generated in situ from (CF3CO)2O and H2O2)
led to a low yield of a single isomer, 8a (Table 2, entry 2).
Increasing the reaction time had a deleterious effect and led
to product degradation, along with unreacted starting mate-
rial. When a large excess of (CF3CO)2O (13 equiv) was used
at 08C, the syn-diepoxide 9 was formed as a single diaste-
reomer (Table 2, entry 3), the structure of which was unam-
biguously determined through X-ray diffraction studies. In
contrast, the chiral Shi reagent (e.g., 10/Oxone)[15] afforded
the other diastereomer, 8b, with complete diastereocontrol,
albeit with low enantioselectivity (Table 2, entries 4 and 5).
The structures of both diastereomers 8a and 8b were also
confirmed through X-ray diffraction analysis (Figure 1). Fi-
nally, Sharpless epoxidation conditions[16] (not shown) did
not provide the desired epoxides.
Furthermore, DFT calculations were run to estimate the
energy of the spirocyclic system when approaching (or not)
an added positive charge (0.2 unit) on the two p faces.[19a]
The charge was placed 2.0 ꢂ from the alkene center, per-
pendicular to the alkene plane. Then, B3LYP 6-31G(d)
These results were tentatively rationalized as follows: In
the presence of the acidic CF3CO3H, the reaction occurs syn
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Rearrangement of Spirooxindoles
FULL PAPER
interesting observations were made when treating 7a with
tBuOK in THF. Under these conditions, isomerization of 7a
provided 1,3-diene 11 in moderate yield, through deprotona-
tion of 7a with the strong base, followed by reprotonation
with tBuOH (Scheme 6). Addition of benzaldehyde shortly
after deprotonation gave rise to olefin 12 as a single Z
isomer along with isomerized 11.[21]
Figure 2. Optimized geometry of 7a and electron density surface encoded
by the electrostatic potential at the PM6 level.
energy calculations were performed, which showed
a
6.4 kcalmolꢀ1 stabilization on the carbonyl face and a
3.29 kcalmolꢀ1 stabilization on the aryl face. These results
are consistent with the ability of the spirocycle to stabilize a
transition state close to TS-A (Scheme 5), in which positive-
ly charged electrophiles like CF3CO3H approach the face
syn to the carbonyl group. This shows that electrostatic ef-
fects also significantly influence the stereoselectivity of the
epoxidation reaction onto spirocyclohexa-2,5-diene oxin-
doles II. Such an effect was also put forward to explain the
anti selectivity during electrophilic reactions of chiral allylsi-
lanes.[19b] In summary, the results of these series of experi-
ments support our assumption that highly diastereoselective
reactions may be performed using the directing effect of the
Lewis basic amide bond. They also show that the face anti
to the C=O bond is accessible to bulky reagents and pro-
vides a general trend for further electrophilic functionaliza-
tion of these spirocyclic oxindoles.
Scheme 6. Metalation of spirocyclohexadienyl oxindole 7a with tBuOK.
More surprising results were obtained when treating
diene 7a with lithium diisopropylamide (LDA), followed by
quenching the reaction mixture with MeI. Whereas 7a did
not react at ꢀ788C, a conversion was observed at ꢀ408C,
with the formation of a rearranged product 13a, which pos-
sesses a new 1,4-cyclohexadienyl system and a phenanthridi-
none skeleton. When the alkylating agent (MeI) was added
after 1 h at ꢀ408C, about 50% (1H NMR spectroscopic
analysis) of 13a was formed along with phenanthridinone 14
and recovered starting material (Table 3, entry 1). A larger
amount of 14 was obtained when MeI was added after 2 h at
ꢀ408C (Table 3, entry 2) or at higher temperature (Table 3,
entry 3), indicating that 14 is probably formed through oxi-
dative aromatization of a lithium intermediate. Optimal
yields of 13a were obtained by adding freshly prepared
LDA to the diene 7a at ꢀ408C, and allowing the resulting
purple solution to stir for 10 min before the addition of the
alkylating agent (Table 3, entry 4). Finally, THF was shown
Rearrangement of spirooxindoles 7a and 7b: We then
turned our attention to the desymmetrization of our sub-
strates through metalation of the cyclohexadienyl system.
Recent studies by Studer et al.[9b–d] have demonstrated that
metalation of 1,4-cyclohexadiene with a strong base, fol-
lowed by transmetalation using chiral titanium or boron re-
agents led to the corresponding useful chiral enantiopure di-
enylmetals, which, upon addition to aldehydes and imines,
provided addition products with high levels of diastereo-
and enantioselectivity. It was envisioned that extension of
this strategy to our spirooxindoles should afford a chiral
metal complex closely related to IV (Scheme 2), in which
the C=O bond of the amide would coordinate to the
metal[20] and thus help in the control of the diastereofacial
selectivity. Various attempts at metallating precursor 7a
were thus made, leading first to disappointing results. nBuLi
and tBuLi at ꢀ788C in THF gave complex mixtures of prod-
ucts, whereas lithium hexamethyldisilazide (LiHMDS),
tBuOLi, and NaH led to recovered starting material. More
Table 3. Optimization of rearrangement of spirooxindole 7a with LDA.
Entry Conditions
13a[a] [%] 14[a] [%] 7a[b] [%]
1
2
3
4
5
THF, ꢀ408C, 1 h
64
48
–
>90
–
15
41
75
–
21
11
25
–
>95
THF, ꢀ408C, 2 h
THF, ꢀ208C, 1 h
THF, ꢀ408C, 10 min
diethyl ether, ꢀ408C, 10 min
1
–
[a] Estimated yields through H NMR spectroscopy of the crude reaction
mixture. [b] Yield of recovered material.
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F. Robert, Y. Landais, and G. Rousseau
Table 5. Rearrangement of spirooxindole 7a followed by addition of al-
dehydes.
to be the best solvent because no reaction occurred in dieth-
yl ether (Table 3, entry 5).
With these conditions in hand, the process was extended
to other dienes and electrophiles. Thus, spirooxindole 7b led
to rearranged product 13d in modest yield (Table 4,
Table 4. Rearrangement of spirooxindole 7a and 7b in the presence of
LDA, followed by the addition of alkylating agents.
Entry
R
Product
d.r.[a]
Yield [%][b]
1
2
3
4
Ph
iPr
tBu
4-OMePh
16a
16b
16c
16d
>95:<5
85:15
>95:<5
>95:<5
60
63
61
30
[a] Estimated from the 1H NMR spectroscopy of the crude reaction mix-
ture. [b] Isolated yield after chromatography.
Entry
Spirooxindole
R’
RX
Product
Yield [%][a]
1
2
3
4
7a
7a
7a
7b
H
H
H
OMe
MeI
13a
13b
13c
13d
67
48
30
42
AllylBr
MeOCH2Cl
MeI
[a] Isolated yield after chromatography.
entry 4). A range of electrophiles was also tested, providing
alkylated products 13b and 13c in modest to good yields
(Table 4, entries 2 and 3). These dienes are obtained as
single regioisomers and as indicated in Table 3, the isolated
yields do not reflect the real efficiency of the process be-
cause compounds 13a–d tend to rearomatize.
The structure of dienes 13a–d was confirmed through X-
ray crystallography of 15, which was obtained from the
regio- and diastereoselective epoxidation of diene 13a; the
epoxide formed anti relative to the resident methyl substitu-
ent (Scheme 7).
Scheme 8. Addition of cinnamaldehyde and synthesis of 17.
kyllithiums generally react in a 1,2-fashion, which suggests
that the anionic intermediate generated through LDA rear-
rangement of 7a is a soft species, likely an enolate (see
below). Our attempts to obtain crystals of the oxime and hy-
drazone derivatives of 17 unfortunately failed, and there-
fore, the relative configuration of 17 was assigned based on
the assumption that the topicity of the 1,4-addition was the
same as that of the 1,2-addition described above.
The various phenanthridinones obtained previously were
also functionalized, demonstrating that despite their tenden-
cy to aromatize, they constitute valuable intermediates for
organic synthesis. For instance, methylated diene 13a was
regioselectively hydrogenated into compound 18, or epoxi-
dized into 15 (Scheme 7), but also dihydroxylated to afford,
after protection of the diol, acetonide 19 (Scheme 9). In the
dihydroxylation experiment, the reaction occurred anti rela-
tive to the resident methyl substituent, as indicated by NMR
spectroscopy. The 1,3-dienyl system of these phenanthridi-
nones was also engaged in a Diels–Alder reaction. The
highly stereoselective [4+2] cycloaddition between 16a and
maleimide afforded the complex polycyclic compound 20,
the structure of which was determined through NOESY ex-
periments and confirmed by X-ray diffraction studies. The
endo adduct 20 results from an approach of the dienophile
anti relative to the benzyl alcohol moiety of 16a.
Scheme 7. Epoxidation of dearomatized phenanthridinone 13a.
Other electrophiles, such as aldehydes, were found to
react with the intermediate resulting from the rearrange-
ment of diene 7a (Table 5). Surprisingly, the regioselectivity
was different from that observed for the alkylation and oc-
curred at the C-5 center on the putative carbanionic inter-
mediate. The reaction was also highly stereoselective to give
the anti-isomer, as indicated by the structure of alcohol 16a,
which was confirmed through X-ray diffraction analysis. We
assume that analogues 16b–d possess the same relative con-
figuration (see below).
Rearrangement mechanism: theoretical and experimental
aspects: To draw a plausible picture of the whole rearrange-
ment mechanism, a quantum chemical study, using DFT cal-
culations, was performed along with some additional experi-
ments, which are described as follows: First, we assumed
Interestingly, when cinnamaldehyde was added, a new al-
dehyde 17 was formed, resulting from a 1,4-addition of the
putative carbanion species that is generated in the rear-
rangement onto the unsaturated aldehyde (Scheme 8). Al-
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Rearrangement of Spirooxindoles
FULL PAPER
hexadienyl radical to form a highly strained norcaradiene-
type species, which upon fragmentation led to the phenan-
thridinone skeleton. Such a highly energetic species was not
envisaged in our rearrangement, due to excessive ring
strain, a hypothesis supported by DFT calculations.
The possible pathways depicted in Scheme 10 were exam-
ined by performing two sets of experiments (Scheme 11). Io-
dodiarylamide 21 was first submitted to iodine–lithium ex-
Scheme 9. Functionalization of phenanthridinones 13a and 16a.
that the rearrangement of the spirocycle takes place before
the reaction with electrophiles (RX or RCHO). Because de-
protonation of 7a in the presence of tBuOK provides iso-
merization product 11 and addition product 12, it was as-
sumed that abstraction of the bis-allylic proton by LDA,[22]
would provide a pentadienyllithium species i,[23] which
would rearrange at ꢀ408C into a phenanthridinyl anion in-
termediate ii (Scheme 10).
Scheme 11. Attempts at establishing the intermediate involved in the re-
arrangement of spirooxindoles.
change in the presence of tBuLi to generate in situ the lithi-
um species i’’, then MeI was added. No trace of phenanthri-
dinone 13a was observed, but instead product 22 issued
from a Fries rearrangement was obtained, thus ruling out
the participation of an aryllithium species in the conversion
i!ii under the rearrangement conditions.[24b] The genera-
tion of an acyl anion such as i’ proved to be more trouble-
ꢀ
some. Insertion of carbon monoxide into an N Li bond has
been described,[26] but was unsuccessful in our hands even
under forcing conditions. For instance, carbonylation of lithi-
ated amine 23 with CO (1 atm), followed by methylation led
to the corresponding dimethylamine 24 and no trace of the
expected phenanthridinone 13a. Other methods, including
the deprotonation of the N-formyl arylamine 25[27] using
LDA and even bulky lithium tetramethylpiperidide
(LiTMP) led to the loss of the formyl group, probably
through a nucleophilic attack of the lithium amide base.
Therefore, these experiments did not allow us to establish or
unambiguously rule out the formation of an acylanion inter-
mediate. It is worth noting that in comparison, the corre-
sponding acyl radical (generated from selenylated precursor
26 using Bu3SnH, azobisisobutyronitrile (AIBN), benzene,
reflux) led to phenanthridinone 14, albeit in a modest 24%
yield (60% brsm).
Scheme 10. Bond breaking during the rearrangement process of 7a.
The amide group is essential here because it probably co-
ordinates the lithium ion and influences the regioselectivity
of the whole process. Two different routes starting from pen-
tadienyl lithium species i may be envisioned; the first in
ꢀ
which the C1 C2=O bond is broken (route a) to provide a
putative acyllithium i’ and the second (route b) where the
C1–aryl bond is cleaved to give an aryllithium i’’
(Scheme 10). A third route might also be envisioned that
would involve a concerted process without the formation of
one of the lithiated intermediate species above. Although
closely related pentadienyllithiums have been proposed re-
cently as intermediates in rearrangements,[24] the ring expan-
sion to phenanthridinones is unprecedented. A recent report
by Robertson and co-workers described some radical cycli-
zations of aryl amides and the formation of phenanthridi-
nones, involving a spirocyclohexadienyl radical intermediate
closely related to i.[25] The radical ring expansion was as-
sumed to involve a 3-exo-trig cyclization of the spirocyclo-
To validate rearrangement through an anionic pathway,
DFT calculations were conducted at the B3LYP 6-31++G-
AHCTUNGTREG(NNNU d,p) level starting from the pentadienyl lithium A. The
effect of the solvent (THF) was accounted for, by assuming
two dimethyl ether (DME) ligands coordinated to the lithi-
um[28] to keep the pentadienyl lithium coordinated to the
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F. Robert, Y. Landais, and G. Rousseau
carbonyl group in a tetrahedral environment.[29] This com-
plex is a plausible starting point because allyllithium species
are monomeric.[30] We did not consider, at that stage, the in-
volvement of LDA or diisopropylamine as potential ligands
for Li (see below). Rearrangement through route b was rap-
idly ruled out, because the migration of the aryl moiety
went through a single but highly energetic (31.6 kcalmolꢀ1)
transition state. Exploring route a, the minimum-energy
ꢀ
pathway was found to be stepwise. The cleavage of the C1
C2 bond through a first transition state (TS1) revealed an
unexpectedly stable acyl anion B, which could reattack the
aryl ring through TS2 to give the phenanthridinyl anion in-
termediate C with reasonable energy barriers (Figure 3).
Scheme 12. Possible pathways for the generation of the reactive inter-
mediate iv and rearrangement of 7a in the presence of chiral amide 27.
chiral LDA equivalent,[32] the reaction provided, under the
conditions reported above for LDA and after the addition
of MeI, phenanthridinone 13a in low to moderate yield but
with significant enantiomeric excess (ee) (Scheme 12). A
lower ee value was measured after 1 h, probably due to a
partial racemization of 13a in the strongly basic medium.
Several other chiral bases were also tested but led to lower
yields of 13a and no enantioselectivity. Similarly, the use of
(ꢀ)-sparteine to bind to the lithium enolate prior to alkyla-
tion led to 13a in 84% yield but with no enantioselectivity.
This enantioselective alkylation indicates that the lithium
amide and its conjugate amine are likely to be in close prox-
imity with the lithium enolate.[33] It was thus envisioned that
the proton transfer could be mediated by the diisopropyla-
mine present in the medium. The crucial role of the latter
would also explain the failure of the anionic rearrangement
with other bases such as nBuLi, NaH, or tBuOK, which led
instead to isomerization of 7a into the 1,3-diene 11. Proto-
nation of ii’ would thus give iii, which upon treatment with
the regenerated LDA would lead to the thermodynamically
more stable enolate iv, through abstraction of the acidic
proton at C1 (Scheme 12). Diisopropylamine would thus
serve to shift the equilibrium towards the thermodynamic
species iv. The latter would then react with alkylating agents
and aldehydes at C3 or C5, respectively, to provide 13, 16,
and 17. The origin of the regioselectivity remains unclear to
date, but follows some precedent in the literature.[34] The rel-
ative configuration of aldehydes 16a–d thus results from a
ul addition, in which the Re face of the aldehydes ap-
proaches the Si face of the enolate intermediate.[35]
Figure 3. Energy profile [kcalmolꢀ1] reaction path at B3LYP 6-31++G-
ACHTUNGTRENNUNG(d,p) level in gas phase (black) and with single-point calculation in THF
(blue).
Single-point calculations in THF, using IEFPCM as the con-
tinuum solvation model, showed a slight decrease of the re-
action energetic profile (Figure 3, blue) indicating that a full
optimization in THF and with two molecules of THF as li-
gands[31] could lower the barrier around 12–15 kcalmolꢀ1,
which are more reasonable values for a rearrangement
taking place at ꢀ408C.
Given the nature of products 13 and 16 and the 1,4-addi-
tion product 17, a soft nucleophile, such as enolate iv, is
likely to be involved in the late stage of the anionic rear-
rangement (Scheme 12). This would then imply a conversion
of ii’ into iv through a simple proton transfer. However, a
direct 1,2-hydrogen transfer is forbidden by symmetry rules
and a calculated pathway for this transformation showed a
highly energetic transition state (around 55 kcalmolꢀ1).
However, an additional experiment led to a key observation,
which eventually enabled us to rationalize the hydrogen
transfer from ii’ to iv. When an enantioselective version of
the rearrangement was attempted using chiral base 27 as a
Following these observations, a complete reaction path-
way was then computed at the B3LYP 6-31+GACTHNUTRGENU(GN d,p) level,
replacing one DME ether ligand around the lithium atom
by a dimethylamine or the corresponding amide (DMA) to
mimic LDA/diisopropylamine behavior.[36] The enantioselec-
tive rearrangement above led us to rule out a possible inter-
molecular hydrogen transfer from diisopropylamine to ii’,
which therefore was not computed. The reaction would start
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Rearrangement of Spirooxindoles
FULL PAPER
with the complexation of LDA to the amide carbonyl group
and was thus modeled by the DMA equivalent D (Figure 4).
Deprotonation and loss of a DME ligand in E led to the spi-
rocycle F. It is interesting to notice the low energy barrier
for the deprotonation of D (through TS3) as a result of a
chelation-induced proximity effect (CIPE), supporting our
assumption in Scheme 2.[37] However, it turned out that re-
placing a dimethyl ether ligand by dimethylamine rendered
the lithium atom of F chiral. As the migration also generates
a chiral center, both combinations had therefore to be com-
puted. Chirality around the lithium was noted R and S by
following the priority order: 1) carbonyl oxygen; 2) DME
oxygen; 3) nitrogen atom; 4) carbanion center, and the mi-
gration studied on the same side for both complexes. Thus
TSR corresponds to a migration on the DMA side (Figure 4,
green) and TSS to a migration on the DME side (Figure 4,
blue). Interestingly, the reaction pathways were quite similar
and also very close to the former reaction with two DME li-
gands (Figure 3). The migration (from F to H) computed at
But again, the two reaction pathways were found to be
almost isoenergetic. This proton transfer regenerated a com-
plex J, in which the lithium amide partner is in close proxim-
ity with the acidic proton a to the amide carbonyl group
(Figure 4, red). This could explain the very low energy barri-
er to reach the final enolate K through TS7. The replace-
ment of a DME ligand by a DMA did not modify the rear-
rangement profile, but as ligand exchanges are easier than
the migration, the rearrangement could also take place with
two DME ligands (A!C, Figure 3), followed by the addi-
tion of one DMA (I!K) that would finally promote the
proton transfer. Additional single-point calculations in THF
(using IEFPCM as the continuum solvation model and the
UFF parameter for proton nucleus radius in proton transfer)
were run at the B3LYP 6-31+GACTHNUTRGNEUGN(d,p) level to confirm the
relative stability of the different complexes. Results were
almost identical, in a 1–1.5 kcalmolꢀ1 range (see the Sup-
porting Information).
The picture in Figure 4 was supported further by a final
experiment as depicted in Scheme 13. During the rearrange-
ment of 7a mediated by chiral amide base 27, when a
second equivalent of nBuLi was added 10 min after the ad-
dition of 27, but prior to MeI, a dialkylated product 28 with
syn-stereochemistry was formed, as shown by X-ray diffrac-
tion studies. Following the calculations outlined above, this
can be rationalized by the removal of the secondary amine
(NR*2H) from the solution by the addition of the second
equivalent of nBuLi. In the absence of this secondary
amine, ii’ cannot provide the protonated species iii
(Scheme 12). In the energy profile depicted in Figure 4, the
the high B3LYP 6-311++GACTHNUTRGNEU(GN d,p) level showed almost iden-
tical energy values, in a 1 kcalmolꢀ1 range (see the Support-
ing Information). The proton transfer was then studied start-
ing from I, obtained by addition of a DME ligand to either
complex HR or HS (the lithium atom is no longer chiral in
I). This addition was found to be necessary to keep the lithi-
um constantly in a tetrahedral environment. At this stage,
two transition states (TS6) could be drawn, depending on
which side the proton is transferred (sup, shown in green
(Figure 4), is noted for the proton transfer on the carbonyl
face and inf, shown in red, for the transfer on the aryl face).
Figure 4. Computed energy profile [kcalmolꢀ1] relative to F at the B3LYP 6-31+G
ACTHNUTRGNEUNG(d,p) level for a complete reaction pathway with one amino ligand
and one or two ethers.
Chem. Eur. J. 2009, 15, 11160 – 11173
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
11167

F. Robert, Y. Landais, and G. Rousseau
Experimental Section and Computational Details
General: 1H and 13C NMR spectra were recorded on Brꢃker DPX-200
FT (1H: 200 MHz, 13C: 50.2 MHz), Brꢃker AC-250 FT (1H: 250 MHz,
13C: 62.5 MHz), Brꢃker Avance-300 FT (1H: 300 MHz, 13C: 75.4 MHz),
and Brꢃker DPX-400 FT (1H: 400 MHz, 13C: 100.2 MHz) instruments.
The chemical shifts (d) and coupling constants (J) are expressed in ppm
and Hz, respectively. The following abbreviations were used to explain
the multiplicities: s=singlet, d=doublet, t=triplet, q=quartet, m=mul-
tiplet, br=broad. IR spectra were recorded on a Perkin–Elmer Paragon
1000 FTIR spectrophotometer as neat films on NaCl windows or as KBr
pellets. Mass spectra were recorded on a Nermag R10-10C instrument
and high-resolution mass spectra were recorded on a Micromass ZAB-
Spec TOF apparatus (for ESI). Melting points were not corrected and de-
termined by using a Stuart Scientific apparatus (SMP3). Macherey–Nagel
silica gel 60M (230–400 mesh ASTM) was used for flash chromatography.
Dichloromethane,
dimethoxyethane,
hexamethylphosphoramide
(HMPA), (iPr)2NH, and iPrOH were distilled from CaH2. THF and Et2O
were distilled from sodium and benzophenone. Commercial anhydrous
DMF was used without further purification. THF was degassed by bub-
bling nitrogen gas through the solvent for 30 min to 1 hour or by three
successive freeze–thaw–pump cycles.
Scheme 13. Rearrangement of 7a in the presence of chiral amide 27-
nBuLi.
Radical spirocyclization of amide (General procedure A): SmI2 was
freshly prepared from samarium powder (1.2 equiv) and iodine
(1 equiv).[39] SmI2 (5 equiv, 0.1m in THF) was added by cannula to a
stirred, degassed solution of amide (1 equiv), HMPA (16 equiv), and
iPrOH (2 equiv) in THF (0.04m) at ꢀ358C. After complete addition, a
10% aqueous solution of Na2S2O3 was added until the blue mixture
turned to a milky solution. The reaction mixture was then allowed to
reach room temperature and the layers were separated. The aqueous
layer was extracted three times with EtOAc. The combined organic ex-
tracts were washed with brine, dried over MgSO4, filtered, and concen-
trated in vacuo. Purification by flash chromatography yielded the desired
spirooxindoles 5 and phenanthridinones 6.
pathway I!J!K would thus be interrupted (due to remov-
ꢀ
al of the N H proton in I). Intermediate ii’ would then be
methylated regioselectively at C6 by MeI to afford inter-
mediate v. The latter would finally be deprotonated by the
remaining NR*2Li to give the enolate vi, which upon meth-
ylation would lead to 28. These few experiments along with
DFT calculations strongly support the mechanism proposed
above. The complete pathway displays realistic activation
barriers consistent with all of the experimental observations.
Rearrangement using chiral bases also suggests that further
optimization of the process with suitable chiral bases may
lead to enantioenriched phenanthridinones.
Reduction of vinyl TBDMS ether (General procedure B): CsF (8 equiv)
(previously dried for 12 h. at 3008C in vacuo) and PhN(Tf)2 (5 equiv)
were added quickly (to prevent the escape of gaseous CF3SO2F formed
during the reaction) to
a solution of vinyl tert-butyldimethylsilyl
(TBDMS) ether 5c and 5d (1 equiv) in dimethoxyethane (0.1m), in a
flask equipped with a screw cap (previously evacuated and flushed with
nitrogen). The flask was closed and the reaction mixture was stirred at
RT overnight. The flask was cooled to 08C and opened carefully. A phos-
phate buffer solution (pH 7) and Et2O were added and the layers were
separated. The aqueous layer was extracted twice with Et2O. The com-
bined organic extracts were dried over MgSO4, filtered and the solvents
Conclusion
concentrated in vacuo. PdACHTUNGTRNEUG(N OAc)2 (10 mol%), PPh3 (20 mol%), iPr2NEt
We have described a short synthesis and the functionaliza-
tion of a new class of spirocyclohexadienyl oxindoles. Epoxi-
dation of these systems occurs diastereoselectively, depend-
ing on the nature of the oxidizing reagent. An unprecedent-
ed rearrangement of these spirooxindoles, mediated by lithi-
um amide bases, was also observed, which led to dearomat-
ized phenanthridinones that proved to be valuable synthons
for organic synthesis. An enantioselective version of this re-
arrangement is possible by using chiral amide bases and is
currently under study in our laboratory. During these differ-
ent functionalizations, the polar amide bond plays a crucial
role, notably by directing the reagents through hydrogen
bonding or coordinating metal ions in anionic processes.
DFT calculations were performed that rationalized the ob-
served selectivities and established the full pathway for the
spirooxindole rearrangement.
(6 equiv), and HCO2H (8 equiv) were added to a solution of the crude
vinyl triflate (1 equiv) in DMF (0.13m) and the reaction mixture was
stirred at 608C for 1 h. EtOAc and H2O were added and the layers were
separated. The aqueous layer was extracted twice with EtOAc. The com-
bined organic extracts were washed with brine, dried over MgSO4, fil-
tered, and the solvents concentrated in vacuo. Purification by flash chro-
matography yielded the desired dienes 7.
Base-induced spirocyclic oxindole rearrangement (General procedure C):
Freshly prepared LDA (1.1 equiv, 0.1m in THF) was added dropwise to a
solution of spirocyclic diene 7a and 7b (1 equiv) in THF (0.1m) at
ꢀ408C (temperature inside flask <ꢀ388C). The reaction mixture was
stirred at this temperature for 10 min. The electrophile (2 equiv) was
added dropwise and stirring was continued for 10 min. H2O (2.5 mL) was
added by syringe at ꢀ408C and the mixture was allowed to reach room
temperature. Et2O was added and the layers were separated. The aque-
ous layer was extracted twice with Et2O. The combined organic extracts
were washed with brine, dried over MgSO4, filtered, and the solvents
concentrated in vacuo. Purification by flash chromatography yielded the
desired dienes.
Compound 5c: Synthesized according to general procedure A from 4c
(1.75 g, 3.74 mmol, 1 equiv), HMPA (10.5 mL, 59.84 mmol, 16 equiv),
iPrOH (0.58 mL, 7.48 mmol, 2 equiv), and SmI2 (187 mL, 18.72 mmol,
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Rearrangement of Spirooxindoles
FULL PAPER
5 equiv) in THF (90 mL). Purification by flash chromatography (silica
gel, CH2Cl2: 100%) afforded 5c as a pale yellow solid (1.27 g, 99%).
M.p. 63–648C; 1H NMR (250 MHz, CDCl3): d=7.25 (td, J=7.6, 1.6 Hz,
1H), 7.12–6.99 (m, 2H), 6.78 (d, J=7.9 Hz, 1H), 6.04 (td, J=9.8, 3.4 Hz,
1H), 5.34 (td, J=9.8, 2.1 Hz, 1H), 5.08 (t, J=3.5 Hz, 1H), 3.20 (s, 3H),
3.04–2.99 (m, 2H), 0.54 (s, 9H), 0.08 (s, 3H), ꢀ0.16 ppm (s, 3H);
13C NMR (62.5 MHz, CDCl3): d=177.1, 146.9, 144.2, 133.0, 128.3, 126.9,
124.1, 123.9, 122.5, 107.6, 101.7, 55.6, 26.9, 26.4, 25.0, 17.4, 4.5, ꢀ5.4 ppm;
IR (KBr): n=2930, 2857, 1723, 1611, 1491, 1471, 1345, 1242 cmꢀ1; HRMS
(ESI): m/z calcd for C20H28NO2Si [M+H]+: 342.1883; found: 342.1887.
Compound 8a: At 08C, a 35% aqueous solution of H2O2 (24 mL,
0.27 mmol, 1.35 equiv) was added to a solution of trifluoroacetic anhy-
dride (56 mL, 0.4 mmol, 2 equiv) in CH2Cl2 (0.2 mL). The reaction mix-
ture was stirred at 08C for 30 min. At ꢀ508C, this mixture was added to
a
solution of 7a (42 mg, 0.2 mmol, 1 equiv) and Na2CO3 (57 mg,
0.54 mmol, 2.7 equiv) in CH2Cl2 (0.24 mL). The reaction mixture was
stirred at ꢀ508C for 3 h, at ꢀ108C for 2 h, and overnight at RT. The reac-
tion mixture was then poured into a saturated aqueous solution of
Na2SO3. The aqueous layer was extracted three times with Et2O. The
combined organic extracts were washed with brine, dried over MgSO4,
filtered, and concentrated in vacuo. Purification by flash chromatography
(silica gel, petroleum ether/EtOAc 9:3) yielded 8a as a yellow solid
(9 mg, 19%; 59% yield brsm). M.p. 143–1498C; 1H NMR (300 MHz,
CDCl3): d=7.37–7.30 (m, 1H), 7.13–7.03 (m, 2H), 6.88 (d, J=7.9 Hz,
1H), 5.87–5.80 (m, 1H), 5.36–5.30 (m, 1H), 3.40–3.36 (m, 1H), 3.27 (s,
3H), 3.08–3.04 (m, 1H), 2.92–2.81 (m, 1H), 2.75–2.65 ppm (m, 1H);
13C NMR (75.4 MHz, CDCl3): d=176.3, 143.8, 129.7, 124.8, 124.2, 122.8,
122.4, 108.4, 55.2, 50.2, 48.7, 26.5, 25.1 ppm; IR (neat, NaCl): n=2919,
1708, 1605, 1467, 1345 cmꢀ1; HRMS (ESI): m/z calcd for C14H13NO2Na
[M+Na]+: 250.0838; found: 250.0839.
Compound 8b: An aqueous solution of Na2EDTA (2.5 mL, 1ꢄ10ꢀ4 m in
H2O, 2.5ꢄ10ꢀ4 mmol) and an aqueous solution of tetrabutylammonium
hydroxide (0.08 mL, 40% in H2O, 0.05 mmol, 5 mol%) were added to a
solution of 7a (53 mg, 0.25 mmol, 1 equiv) in CH3CN (3.8 mL) at 08C
with vigorous stirring. A mixture of Oxone (770 mg, 1.25 mmol, 5 equiv)
and NaHCO3 (326 mg, 3.86 mmol, 15.5 equiv) was pulverized. A small
portion of this mixture was added to the reaction mixture to adjust the
pH>7. After 5 min, ketone 10 (194 mg, 0.75 mmol, 3 equiv) was added
portionwise over 1 h. Simultaneously, the rest of the Oxone and NaHCO3
mixture was added portionwise over 50 min. After completion of the ad-
dition of 10, the reaction mixture was stirred at 08C for 24 h, diluted with
water (8 mL), and extracted four times with Et2O. The combined organic
extracts were washed with brine, dried over MgSO4, filtered, and concen-
trated in vacuo. Purification by flash chromatography (silica gel, petrole-
um ether/EtOAc 8:2 to 6:4) yielded 8b as a yellow solid (25 mg, 43%;
78% yield brsm). M.p. 100–1118C; 1H NMR (300 MHz, CDCl3): d=
7.41–7.32 (m, 2H), 7.11 (t, J=7.5 Hz, 1H), 6.89 (d, J=7.9 Hz, 1H), 5.88–
5.81 (m, 1H), 5.17–5.10 (m, 1H), 3.48–3.46 (m, 1H), 3.25 (s, 3H), 3.16–
3.14 (m, 1H), 2.83 (dq, J=19.6, 2.6 Hz, 1H), 2.73 ppm (dd, J=19.6,
4.9 Hz, 1H); 13C NMR (75.4 MHz, CDCl3): d=175.8, 143.1, 131.3, 128.9,
126.1, 125.3, 123.2, 122.5, 108.1, 55.7, 51.4, 50.8, 26.6, 24.9 ppm; IR (neat,
NaCl): n=1702, 1610, 1347, 1260 cmꢀ1; HRMS (ESI): m/z calcd for
C14H14NO2 [M+H]+: 228.1019; found: 228.1018.
Compound 5d: Synthesized according to general procedure A from 4d
(764 mg, 1.54 mmol, 1 equiv), HMPA (4.47 mL, 10.01 mmol, 16 equiv),
iPrOH (0.24 mL, 3.08 mmol, 2 equiv), and SmI2 (77 mL, 7.70 mmol,
5 equiv) in THF (36 mL). Purification by flash chromatography (silica
gel, petroleum ether/EtOAc 9:1) afforded 5d as a pale yellow solid
(280 mg, 49%; 60% brsm). M.p. 122–1258C; 1H NMR (200 MHz,
CDCl3): d=6.98 (d, J=8.3 Hz, 1H), 6.52 (dd, J=8.1, 2.2 Hz, 1H), 6.37
(d, J=2.4 Hz, 1H), 6.01 (td, J=9.7, 3.4 Hz, 1H), 5.29 (m, 1H), 5.06 (t,
J=3.6 Hz, 1H), 3.81 (s, 3H), 3.16 (s, 3H), 3.01–2.96 (m, 2H), 0.57 (s,
9H), 0.08 (s, 3H), ꢀ0.14 ppm (s, 3H); 13C NMR (50 MHz, CDCl3): d=
177.4, 160.4, 147.0, 145.3, 126.4, 124.5, 124.3, 106.2, 101.5, 95.7, 55.4, 55.0,
26.8, 26.3, 25.0, 17.4, ꢀ4.7, ꢀ5.4 ppm; IR (KBr): n=2930, 2857, 1724,
1686, 1625, 1505, 1471, 1371, 1325, 1260, 1182 cmꢀ1; HRMS (ESI): m/z
calcd for C21H30NO3Si [M+H+]: 372.1989; found: 372.1992.
Compound 6a: Synthesized according to general procedure A from 4a
(83 mg, 0.24 mmol, 1 equiv), HMPA (0.67 mL, 3.84 mmol, 16 equiv),
iPrOH (36 mL, 0.47 mmol, 2 equiv), and SmI2 (11.8 mL, 1.18 mmol,
5 equiv) in THF (6 mL). Purification by flash chromatography (silica gel,
CH2Cl2: 100%) afforded 6a as a pale yellow solid (30 mg, 55% yield).
1
M.p. 109–1138C; H NMR (250 MHz, CDCl3): d=13.33 (s, 1H), 8.22 (dd,
J=8.2, 1.2 Hz, 1H), 7.70–7.51 (m, 2H), 7.41–7.30 (m, 2H), 7.01 (dd, J=
7.6, 1.2 Hz, 1H), 3.75 ppm (s, 3H); 13C NMR (62.5 MHz, CDCl3): d=
165.3, 162.0, 137.0, 134.6, 134.5, 129.7, 123.8, 123.3, 119.7, 115.1, 115.0,
111.5, 110.34, 29.2 ppm; IR (neat, NaCl): n=2925, 1640, 1420, 1213,
1141 cmꢀ1; HRMS (ESI): m/z calcd for C14H12NO2 [M+H]+: 226.0862;
found: 226.0860.
Compound 7a: Synthesized according to general procedure B from 5c
(3.6 g, 10.56 mmol, 1 equiv), CsF (12.75 g, 84.48 mmol, 8 equiv), and
PhN(Tf)2 (18.84 g, 52.80 mmol, 5 equiv) in dimethoxyethane (30 mL) for
the first step, and PdACTHNUGTRNE(UNG OAc)2 (236 mg, 1.10 mmol, 10 mol%), PPh3
(552 mg, 2.20 mmol, 20 mol%), iPr2NEt (11 mL, 63.36 mmol, 6 equiv),
and HCO2H (3.2 mL, 84.48 mmol, 8 equiv) in DMF (85 mL) for the
second step. Purification by flash chromatography (silica gel, petroleum
ether/EtOAc 8:2) yielded 7a as a yellow solid (1.95 g, 87% over 2 steps).
M.p. 98–1018C; 1H NMR (250 MHz, CDCl3): d=7.32–7.26 (m, 1H),
7.14–7.03 (m, 2H), 6.84 (d, J=7.6 Hz, 1H), 6.02–6.01 (m, 2H), 5.41–5.36
(m, 2H), 3.23 (s, 3H), 2.96–2.88 ppm (m, 2H); 13C NMR (62.5 MHz,
CDCl3): d=177.7, 142.8, 134.0, 128.3, 127.1, 124.6, 123.7, 122.8, 107.9,
51.6, 26.5, 25.6 ppm; IR (KBr): n=3032, 2863, 1716, 1608, 1491, 1470,
1338 cmꢀ1; MS (ESI): m/z (%) 234 (98) [M+Na]+, 212 (100) [M+H]+;
HRMS (ESI): ): m/z calcd for C14H13NONa [M+Na]+: 234.0889; found:
234.0886.
Compound 9: A 35% aqueous solution of H2O2 (0.25 mL, 2.6 mmol,
13 equiv) was added to a solution of trifluoroacetic anhydride (0.56 mL,
4 mmol, 20 equiv) in CH2Cl2 (4 mL) at 08C. The reaction mixture was
stirred for 30 min at 08C and a solution of 7a (42 mg, 0.2 mmol, 1 equiv)
in CH2Cl2 (0.4 mL) was added dropwise. The resulting reaction mixture
was stirred at 08C for 4 h and poured into a saturated aqueous solution
of Na2SO3. The aqueous layer was extracted three times with CH2Cl2.
The combined organic layers were washed with brine, dried over MgSO4,
filtered, and concentrated in vacuo to afford 9 as yellow crystals (38 mg,
78% yield). M.p. 217–2238C; 1H NMR (250 MHz, CDCl3): d=7.40 (td,
J=7.6, 1.1 Hz, 1H), 7.24–7.20 (m, 1H), 7.12 (td, J=7.5, 0.8 Hz, 1H), 6.93
(d, J=7.9 Hz, 1H), 3.30 (s, 3H), 3.21–3.17 (m, 2H), 3.02 (d, J=17.0 Hz,
1H), 2.90 (d, J=3.8 Hz, 1H), 2.46 ppm (dt, J=17.0, 2.6 Hz, 1H);
13C NMR (62.5 MHz, CDCl3): d=174.3, 143.9, 130.0, 126.5, 124.1, 122.8,
108.7, 52.4, 47.8, 47.1, 29.6, 23.1 ppm; IR (neat): n=1717, 1609, 1493,
1471, 1344, 1256, 2092 cmꢀ1; MS (EI): m/z: 243 (100) [M]+; HRMS
(ESI): m/z calcd for C14H13NO3Na [M+Na]+: 266.0787; found: 266.0788.
Compound 7b: Synthesized according to general procedure B from 5d
(280 mg, 0.75 mmol, 1 equiv), CsF (0.91 g, 6 mmol, 8 equiv), and
PhN(Tf)2 (1.34 g, 3.75 mmol, 5 equiv) in dimethoxyethane (9 mL) for the
first step, and PdACHTUNGTRENNUNG(OAc)2 (17 mg, 0.08 mmol, 10 mol%), PPh3 (42 mg,
0.16 mmol, 20 mol%), iPr2NEt (0.8 mL, 4.50 mmol, 6 equiv), and
HCO2H (0.23 mL, 6 mmol, 8 equiv) in DMF (6 mL) for the second step.
Purification by flash chromatography (silica gel, petroleum ether/EtOAc
8:2) yielded 7b as colorless crystals (147 mg, 81% over 2 steps). M.p.
133–1358C; 1H NMR (300 MHz, CDCl3): d=7.00 (d, J=8.1 Hz, 1H),
6.55 (dd, J=8.1, 2.2 Hz, 1H), 6.42 (dd, J=8.1, 2.4 Hz, 1H), 6.10 (td, J=
9.7, 3.4 Hz, 2H), 5.35 (td, J=10.0, 1.7 Hz, 2H), 3.82 (s, 3H), 3.20 (s, 3H),
3.01–2.76 ppm (m, 2H); 13C NMR (75.4 MHz, CDCl3): d=178.3, 160.3,
144.1, 126.9, 126.2, 125.2, 124.1, 106.5, 95.9, 55.4, 51.1, 26.5, 25.6 ppm; IR
(neat, NaCl): n=3037, 1720, 1627, 1371, 1258, 1086 cmꢀ1; HRMS (ESI):
m/z calcd for C15H15NO2Na [M+Na]+: 264.0995; found: 264.0995.
Compounds 11 and 12: tBuOK (19 mg, 0.17 mmol, 1.1 equiv) was added
to a solution of 7a (32 mg, 0.15 mmol, 1 equiv) in THF (1.5 mL) at
ꢀ408C. The reaction mixture was stirred at ꢀ408C for 10 min. PhCHO
(30 mL, 0.30 mmol, 2 equiv) was added and the mixture was allowed to
reach RT. H2O and Et2O were added and the layers were separated. The
aqueous layer was extracted twice with Et2O. The combined organic ex-
tracts were washed with brine, dried over MgSO4, filtered, and concen-
trated in vacuo. Purification by flash chromatography (silica gel, petrole-
Chem. Eur. J. 2009, 15, 11160 – 11173
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
11169

F. Robert, Y. Landais, and G. Rousseau
um ether/EtOAc 9:1) yielded 11 (5 mg, 14% yield) as a yellow oil and 12
(24 mg, 54% yield) as a yellow oil. 11: 1H NMR (300 MHz, CDCl3): d=
7.44 (d, J=7.5 Hz, 1H), 7.41–7.24 (td, J=7.9, 1.5 Hz, 1H), 6.98 (t, J=
7.5 Hz, 1H), 6.83 (d, J=7.5 Hz, 1H), 6.20 (dd, J=9.4, 5.3 Hz, 1H), 6.14–
6.08 (m, 1H), 5.91–5.85 (m, 1H), 5.46 (d, J=9.4 Hz, 1H), 3.22 (s, 3H),
3.07–3.01 (td, J=7.7, 2.6 Hz, 1H), 2.36 ppm (dd, J=7.7, 5.6 Hz, 1H);
13C NMR (75.4 MHz, CDCl3): d=180.6, 141.7, 133.1, 128.5, 125.5, 124.7,
124.2, 123.6, 123.4, 122.7, 108.1, 48.5, 32.3, 26.5 ppm; IR (neat, NaCl): n=
3042, 2932, 1713, 1610, 1490, 1470, 1372, 1345 cmꢀ1; MS (EI): m/z: 211
(26) [M]+, 210 (100) [MꢀH]+; HRMS (ESI): m/z calcd for C14H13NONa
[M+Na]+: 234.0889; found: 234.0898. 12: 1H NMR (250 MHz, CDCl3):
d=7.41–7.22 (m, 6H), 7.15–7.04 (m, 3H), 6.87 (d, J=7.9 Hz, 1H), 6.61
(d, J=9.8 Hz, 1H), 6.53 (s, 1H), 5.62–5.52 (m, 2H), 3.26 ppm (s, 3H);
13C NMR (62.5 MHz, CDCl3): d=143.0, 136.7, 132.2, 131.7, 130.0, 129.4,
129.2, 128.7, 128.3, 127.9, 127.1, 125.5 125.3, 125.0, 123.1, 108.2, 55.0,
26.8 ppm; IR (neat, NaCl): n=3418, 3055, 2928, 1714, 1608, 1488, 1470,
1421 cmꢀ1; MS (EI): m/z: 299 (100) [M]+, 284 (10) [MꢀCH3]+; HRMS
(ESI): m/z calcd for C21H18NO [M+H]+: 300.1382; found: 300.1382.
113.6, 109.0, 104.5, 98.9, 55.5, 30.4, 29.7, 25.7, 22.8 ppm; IR (neat, NaCl):
n=3563, 2969, 1679, 1567 cmꢀ1; HRMS (ESI): m/z calcd for C16H18NO2
[M+H]+: 256.1332; found: 256.1330.
Compound 15: mCPBA (54 mg, 0.31 mmol, 1.5 equiv) was added to a so-
lution of 13a (45 mg, 0.2 mmol, 1 equiv) in CH2Cl2 (2 mL) at 08C. After
4 h at 08C, the reaction mixture was stirred for 16 h at RT. A saturated
aqueous solution of NaHCO3 was added and the mixture was extracted
three times with CH2Cl2.The combined organic extracts were washed
with brine, dried over MgSO4, and the solvent concentrated in vacuo. Pu-
rification by flash chromatography (silica gel, CH2Cl2/EtOAc 8:2) yielded
10 as a white solid (35 mg, 72%). M.p. 181–1838C; 1H NMR (300 MHz,
CDCl3): d=7.72 (d, J=8.3 Hz, 1H), 7.52 (t, J=7.9 Hz, 1H), 7.36 (d, J=
8.6 Hz, 1H), 7.25 (t, J=7.7 Hz, 1H), 3.90–3.83 (m, 1H), 3.72 (s, 3H), 3.60
(d, J=16.3 Hz, 1H), 3.54 (brs, 1H), 3.40 (brs, 1H), 2.80 (d, J=16.3 Hz,
1H), 1.34 ppm (d, J=7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=161.7,
142.5, 138.9, 129.5, 123.3, 122.0, 121.7, 119.5, 114.5, 56.2, 50.5, 29.8, 29.7,
24.6, 17.4 ppm; IR (KBr): n=2922, 1638, 1596, 1457, 1339, 1312,
1098 cmꢀ1; MS (EI): m/z (%): 241 (34) [M]+, 226 (29) [MꢀCH3]+, 212
(100) [MꢀNCH3]+, 198 (54) [MꢀCOCH3]+; HRMS (ESI): m/z calcd for
C15H16NO2 [M+H]+: 242.1175; found: 242.1178.
Compound 13a: Synthesized according to general procedure C from 7a
(211 mg, 1 mmol, 1 equiv), methyl iodide (0.3 mL, 2 mmol, 2 equiv), and
THF (10 mL). Purification by flash chromatography (silica gel, CH2Cl2/
EtOAc 97:3) afforded the 13a as a yellow viscous oil (150 mg, 67%).
1H NMR (250 MHz, CDCl3): d=7.76 (d, J=7.9 Hz, 1H), 7.54–7.52 (m,
1H), 7.40–7.38 (m, 1H), 7.28–7.24 (m, 1H), 5.95 (brs, 2H), 3.87–3.84 (m,
1H), 3.75 (s, 3H), 3.46–3.38 (m, 1H), 3.17–3.10 (m, 1H), 1.32 ppm (d, J=
7.0 Hz, 3H); 13C NMR (65 MHz, CDCl3): d=161.8, 144.7, 139.1, 129.3,
125.8, 124.5, 123.7, 122.0, 119.7, 114.7, 30.6, 29.9, 26.2, 22.9 ppm; IR
(neat, NaCl): n=3053, 2930, 1644, 1584, 1455, 1417, 1356, 1311 cmꢀ1; MS
(EI): m/z: 225 (10) [M]+, 210 (100) [M-CH3]+, 195 (23); HRMS (ESI):
m/z calcd for C15H16NO [M+H]+: 226.1231; found: 226.1230.
Compound 16a: Synthesized according to general procedure C from 7a
(42 mg, 0.2 mmol, 1 equiv) and benzaldehyde (50 mL, 0.40 mmol, 2 equiv)
in THF (2 mL). Purification by flash chromatography (silica gel, CH2Cl2/
EtOAc 6:4) afforded 16a as a pale yellow solid (38 mg, 60%). M.p. 182–
1838C; 1H NMR (300 MHz, CDCl3): d=7.81 (d, J=8.3 Hz, 1H), 7.56–
7.50 (m, 1H), 7.40–7.23 (m, 7H), 6.97 (dd, J=9.8, 1.5 Hz, 1H), 6.11 (dd,
J=10.0, 4.3 Hz, 1H), 4.65 (d, J=10.3 Hz, 1H), 3.76 (s, 3H), 3.16–
2.88 ppm (m, 3H); 13C NMR (75.4 MHz, CDCl3): d=162.0, 142.4, 138.8,
136.7, 136.1, 129.5, 128.3, 127.7, 126.8, 123.4, 123.3, 121.9, 121.6, 118.3,
114.4, 75.2, 40.9, 29.8, 23.0 ppm; IR (KBr): n=3386, 1643, 1597, 1454,
1093 cmꢀ1; MS (ESI): m/z: 340 (100) [M+Na]+, 318 (23) [M+H]+, 300
(15) [M+HꢀH2O]+; HRMS (ESI): m/z calcd for C21H19NO2Na
[M+Na]+: 340.1313; found: 340.1309.
By using (+)-bis[(R)-a-methylbenzyl]amine instead of diisopropylamine
led to enantioenriched 13a. Enantiomeric excess was measured by HPLC
analysis using a Chiralcel AD-H column (MeOH/EtOH/Et2NH 70:30:0.1,
flow rate 0.8 mLminꢀ1, l=276 nm): tminor =14.3 min, tmajor =30.1 min).
Compound 16b: Synthesized according to general procedure C from 7a
(42 mg, 0.2 mmol, 1 equiv) and isobutyraldehyde (35 mL, 0.40 mmol,
2 equiv) in THF (2 mL). Purification by flash chromatography (silica gel,
petroleum ether/EtOAc 1:1) afforded 16b (36 mg, 63%) as a yellow oil
(85:15 mixture of diastereomers that were assigned M for the major and
Compound 13b: Synthesized according to general procedure C from 7a
(42 mg, 0.2 mmol, 1 equiv) and allyl bromide (35 mL, 0.4 mmol, 2 equiv)
in THF (2 mL). Purification by flash chromatography (silica gel, CH2Cl2/
EtOAc 98:2) afforded 13b as a yellow oil (24 mg, 48%). 1H NMR
(300 MHz, CDCl3): d=7.75 (d, J=8.3 Hz, 1H), 7.57–7.50 (m, 1H), 7.42–
7.39 (m, 1H), 7.30–7.25 (m, 1H), 6.10–5.94 (m, 2H), 5.81–5.71 (m, 1H),
4.97 (m, 2H), 3.98–3.89 (m, 1H), 3.77 (s, 3H), 3.47–3.37 (m, 1H), 3.14–
3.03 (m, 1H), 2.61–2.30 ppm (m, 2H); 13C NMR (75.4 MHz, CDCl3): d=
161.4, 142.6, 138.9, 134.5, 129.2, 126.9, 126.8, 125.1, 124.0, 121.9, 119.4,
117.3, 114.6, 40.6, 35.3, 29.7, 26.4 ppm; IR (neat, NaCl): n=3415, 2928,
1633, 1588, 1462, 1416, 1316 cmꢀ1; MS (EI): m/z: 251 (5) [M]+, 210 (100)
[MꢀC3H5]+, 195 (42) [MꢀC4H8]+; HRMS (ESI): m/z calcd for C17H18NO
[M+H]+: 252.1382; found: 252.1389.
1
m for the minor one in the NMR data). H NMR (300 MHz, CDCl3): d=
7.71 (d, J=8.3 Hz , 1HM), 7.59 (d, J=8.3 Hz, 1Hm), 7.45–7.40 (m, 1HM+m),
7.27–7.24 (m, 1HM+m), 7.18–7.12 (m, 1HM+m), 6.90 (dd, J=10.0, 1.3 Hz,
1HM), 6.26 (dd, J=9.8, 4.1 Hz, 1HM+m), 5.87–5.81 (m, 1Hm), 4.17 (m,
1Hm), 3.65 (s, 3HM), 3.60 (s, 3Hm), 3.45–3.39 (m, 1Hm), 3.32 (t, J=6.0 Hz,
1HM+m), 3.16–3.07 (m, 1Hm), 2.99–2.80 (m, 2HM+m), 2.66–2.60 (m, 1HM),
1.85–1.74 (m, 1HM+m), 1.14 (d, J=6.8 Hz, 3Hm), 0.96 (d, J=6.8 Hz, 3Hm),
0.92 (d, J=6.8 Hz, 3HM), 0.85 ppm (d, J=6.8 Hz, 3HM); 13C NMR
(75.4 MHz, CDCl3): d=162.0 (M), 161.1 (m), 141.1 (m), 139.0 (m), 138.8
(M), 137.4 (M),136.6 (M), 129.6 (m), 129.4 (M+m), 129.2 (m), 128.3 (m),
123.6 (m), 123.4 (M), 121.8 (M), 121.5 (M), 121.4 (M+m), 119.2 (m),
118.3 (M), 114.7 (m), 114.4 (M), 80.3 (m), 77.4 (M), 38.6 (m), 36.8 (M),
32.4 (m), 30.4 (M), 29.8 (M), 29.6 (m), 27.0 (m), 21.4 (M), 20.2 (m), 19.8
(M), 19.4 (m), 17.0 (M); IR (neat, NaCl): n=3416, 2959, 1642, 1618,
1597, 1460 cmꢀ1; MS (ESI): m/z: 306 (100) [M+Na]+, 284 (63) [M+H]+;
HRMS (ESI): m/z calcd for C18H21NO2Na [M+Na]+: 306.1470; found:
310.1476.
Compound 13c: Synthesized according to general procedure C from 7a
(42 mg, 0.2 mmol, 1 equiv) and methoxymethyl chloride (MOMCl; 30 mL,
0.4 mmol, 2 equiv) in THF (2 mL). Purification by flash chromatography
(silica gel, petroleum ether/EtOAc 1:1) afforded 13c as a yellow oil
(15 mg, 30%). 1H NMR (250 MHz, CDCl3): d=7.83 (d, J=8.3 Hz, 1H),
7.56–7.51 (m, 1H), 7.41–7.26 (m, 2H), 6.11 (brs, 2H), 4.15–4.06 (m, 1H),
3.76 (s, 3H), 3.68 (dd, J=9.0, 4.1 Hz, 1H), 3.53–3.44 (m, 2H), 3.32 (s,
3H), 3.19–3.09 ppm (m, 1H); 13C NMR (62.5 MHz, CDCl3): d=161.4,
140.2, 138.8, 129.3, 127.6, 126.0, 125.7, 124.1, 121.9, 119.7, 114.5, 77.0,
59.2, 36.7, 29.7, 26.3 ppm; IR (neat, NaCl): n=2926, 1633, 1596, 1461,
1417, 1314, 1192, 1110 cmꢀ1; MS (ESI): m/z: 256 (100) [M+H]+, 239 (14)
[MꢀCH3]+; HRMS (ESI): m/z calcd for C16H18NO2 [M+H]+: 256.1338;
found: 256.1341.
Compound 16c: Synthesized according to general procedure C from 7a
(42 mg, 0.2 mmol, 1 equiv) and pivaladehyde (44 mL, 0.4 mmol, 2 equiv)
in THF (2 mL). Purification by flash chromatography (silica gel, petrole-
um ether/EtOAc 1:1) afforded 16c as a pale yellow solid (36 mg, 61%).
M.p. 96–988C; 1H NMR (250 MHz, CDCl3): d=7.77 (d, J=8.3 Hz, 1H),
7.51 (t, J=8.3 Hz, 1H), 7.36–7.33 (m, 1H), 7.25–7.20 (m, 1H), 6.93 (dd,
J=9.8, 2.3 Hz, 1H), 6.30 (dd, J=9.8, 3.8 Hz, 1H), 3.74 (s, 3H), 3.47 (d,
J=3.8 Hz, 1H), 3.10–2.91 (m, 2H), 2.83–2.75 (m, 1H), 1.01 ppm (s, 9H);
13C NMR (62.5 MHz, CDCl3): d=161.9, 139.9, 138.8, 136.4, 129.4, 123.9,
123.3, 121.8, 121.0, 118.2, 114.3, 81.4, 36.1, 35.7, 29.8, 27.0, 21.9 ppm; IR
(KBr): n=3424, 2954, 2868, 1645, 1616, 1598, 1460, 1414, 1364,
1315 cmꢀ1; MS (ESI): m/z: 320 (100) [M+Na]+, 298 (77) [M+H]+, 210
Compound 13d: Synthesized according to general procedure C from 7b
(48 mg, 0.2 mmol, 1 equiv) and methyl iodide (25 mL, 0.4 mmol, 2 equiv)
in THF (2 mL). Purification by flash chromatography (silica gel, petrole-
um ether/EtOAc 8:2) afforded 13d as
a yellow oil (21 mg, 42%).
1H NMR (200 MHz, CDCl3): d=7.66 (d, J=8.6 Hz, 1H), 6.87–6.81 (m,
2H), 5.94 (brs, 2H), 3.91 (s, 3H), 3.84–3.75 (m, 1H), 3.71 (s, 3H), 3.42–
3.31 (m, 1H), 3.14–3.03 (m, 1H), 1.30 ppm (d, J=7.0 Hz, 3H); 13C NMR
(50 MHz, CDCl3): d=162.0, 160.4, 144.5, 140.5, 129.0, 125.6, 123.6, 122.5,
11170
www.chemeurj.org
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 11160 – 11173

Rearrangement of Spirooxindoles
FULL PAPER
(17) [M+HꢀC5H12O]+; HRMS (ESI): m/z calcd for C19H23NO2Na
[M+Na]+: 320.1626; found: 320.1624.
[MꢀC3H6O2]+; HRMS (ESI): m/z calcd for C18H22NO3 [M+H]+:
300.1594; found: 300.1597.
Compound 16d: Synthesized according to general procedure C from 7a
(42 mg, 0.2 mmol, 1 equiv) and p-anisaldehyde (49 mL, 0.4 mmol, 2 equiv)
in THF (2 mL). Purification by flash chromatography (silica gel, petrole-
um ether/EtOAc 8:2 to 2:8) afforded 16d as a yellow viscous oil (21 mg,
30%). 1H NMR (300 MHz, CDCl3): d=7.72 (d, J=7.9 Hz, 1H), 7.46 (t,
J=7.9 Hz, 1H), 7.31–7.27 (m, 1H), 7.20–7.15 (m, 3H), 6.87 (dd, J=10.0,
1.3 Hz, 1H), 6.76 (d, J=8.7 Hz, 2H), 6.03 (dd, J=9.8, 4.1 Hz, 1H), 4.51
(d, J=7.5 Hz, 1H), 3.69 (s, 3H), 3.66 (s, 3H), 3.05–2.88 (m, 2H), 2.85–
2.75 ppm (m, 1H); 13C NMR (75.4 MHz, CDCl3): d=161.9, 159.1, 138.9,
136.7, 136.0, 134.5, 129.5, 127.9, 123.4, 121.9, 121.7, 118.3, 114.4, 113.7,
75.0, 55.2, 40.9, 29.8, 23.2 ppm; IR (neat, NaCl): n=3317, 1640, 1574,
1513, 1248 cmꢀ1; MS (EI): m/z: 329 (34) [M+HꢀH2O]+, 210 (100)
[MꢀC8H10O2]+, 137 (73) [C8H10O2]+; HRMS (ESI): m/z calcd for
C22H21NO3Na [M+Na]+: 370.1419; found: 370.1414.
Cycloadduct 20: Maleimide (240 mg, 2.4 mmol, 24 equiv) was added to a
solution of conjugated diene 16a (32 mg, 0.1 mmol, 1 equiv) in toluene
(2.5 mL). The reaction mixture was heated at reflux overnight and the
solvent evaporated in vacuo. Flash chromatography (silica gel, CH2Cl2/
EtOAc: 6/4) afforded the cycloadduct 20 (29 mg, 71% yield) as a white
powder, m.p. 254–2568C; 1H NMR (400 MHz, [D6]DMSO): d=11.08 (s,
1H), 7.98 (d, J=7.9 Hz, 1H), 7.52–7.44 (m, 5H), 7.32 (d, J=8.4 Hz ,1H),
7.19 (t, J=7.9 Hz, 1H), 7.03 (d, J=6.5 Hz, 1H), 5.32 (d, J=3.9 Hz, 1H),
3.93–3.90 (m, 1H), 3.63 (d, J=8.4 Hz, 1H), 3.53 (s, 3H), 3.09 (dd, J=8.4,
2.0 Hz, 1H), 2.74–2.72 (m, 1H), 2.39–2.29 (m, 2H), 1.63 ppm (dd, J=
12.8, 3.2 Hz, 1H); 13C NMR (75.4 MHz, [D6]DMSO): d=179.3, 178.1,
170.2, 144.7, 137.1, 135.1, 129.5, 128.2, 127.3, 126.6, 122.7, 122.6, 120.7,
117.7, 115.4, 76.6, 48.5, 44.7, 44.5, 44.2, 35.4, 34.6, 29.3 ppm; IR (neat,
NaCl): n=3379, 1715, 1649, 1598, 1472, 1374 cmꢀ1; HRMS (ESI): m/z
calcd for C25H22N2O4Na [M+Na]+: 437.1471; found: 437.1453.
Compound 17: Synthesized according to general procedure C from 7a
(42 mg, 0.2 mmol, 1 equiv) and cinnamaldehyde (50 mL, 0.4 mmol,
2 equiv) in THF (2 mL). Purification by flash chromatography (silica gel,
CH2Cl2/EtOAc 9:1) afforded 17 as a pale yellow solid (34 mg, 50%).
Compound 22: tBuLi (0.32 mL, 0.42 mmol, 2.1 equiv) was added to a so-
lution of benzamide 21 (68 mg, 0.2 mmol, 1 equiv) in THF (2 mL) at
ꢀ788C. The reaction mixture was stirred at ꢀ788C for 2 h and MeI
(0.08 mL, 1.2 mmol, 6 equiv) was added. A saturated aqueous solution of
NH4Cl was added after an additional hour at ꢀ788C, and the resulting
reaction mixture was allowed to reach RT. H2O was added and the aque-
ous layer was extracted three times with Et2O. The combined organic ex-
tracts were washed with brine, dried over MgSO4, filtered and concen-
trated in vacuo. Purification by flash chromatography (silica gel, petrole-
1
M.p. 99–1038C; H NMR (300 MHz, CDCl3): d=9.35 (s, 1H), 8.01 (d, J=
7.9 Hz, 1H), 7.60–7.57 (m, 1H), 7.47–7.28 (m, 1H), 6.26–6.21 (m, 1H),
5.72–5.66 (m, 1H), 4.23–4.13 (m, 1H), 3.96–3.89 (m, 1H), 3.79 (s, 3H),
3.52–3.47 (m, 1H), 3.21–3.15 (m, 1H), 3.00–2.87 (m, 1H), 2.44–2.36 ppm
(m, 1H); 13C NMR (50 MHz, CDCl3): d=201.5, 161.3, 141.5, 141.3, 139.4,
129.9, 129.1, 128.3, 128.1, 128.0, 127.5, 124.2, 123.5, 122.5, 119.3, 115.2,
44.4, 42.5, 41.9, 30.0, 27.3 ppm; IR (KBr): n=3411, 2958, 1721, 1631,
1593, 1460, 1416, 1316, 1265 cmꢀ1; MS (EI): m/z: 344 (8) [M+H]+, 209
(100) [MꢀC9H10O]+; HRMS (ESI): m/z calcd for C23H22NO2 [M+H]+:
344.1645; found: 344.1650.
1
um ether/EtOAc 95:5) yielded 22 (27 mg, 64%) as a yellow oil, H NMR
(300 MHz, CDCl3): d=8.56 (brs, 1H), 7.61–7.39 (m, 5H), 6.76 (d, J=
8.7 Hz, 1H), 6.54 (t, J=7.5 Hz, 1H), 2.98 ppm (s, 3H); 13C NMR
(62.5 MHz, CDCl3): d=199.3, 152.7, 140.6, 135.4, 135.0, 130.6, 128.9,
128.0, 117.1, 113.6, 111.0, 29.4 ppm; IR (neat, NaCl): n=3339, 2962, 2816,
1619, 1572, 1520, 1445, 1425, 1261 cmꢀ1; HRMS (ESI): m/z calcd for
C14H14NO [M+H]+: 212.1069; found: 212.1073.
Compound 18: H2 gas was introduced with a balloon to a mixture of 13a
(45 mg, 0.2 mmol, 1 equiv) and palladium (10% on charcoal, 42 mg,
0.04 mmol, 20 mol%) in EtOH (5 mL) at RT. The reaction mixture was
stirred at RT overnight, filtered through Celite, then the solvent was
evaporated under vacuum. Purification by flash chromatography (silica
gel, CH2Cl2/EtOAc 95:5) yielded 18 as a white solid (34 mg, 75%). M.p.
Compound 24: A 2.34m solution of nBuLi in hexane (0.47 mL, 1.1 mmol,
1.1 equiv) was added dropwise to
a solution of amine 23 (0.183 g,
1 mmol) in dry THF (2 mL) at ꢀ788C. The yellow reaction mixture was
allowed to reach ꢀ408C. The solution was then degassed by three succes-
sive freeze–thaw–pump cycles and dry CO was bubbled through the sol-
vent for 0.5 h. The reaction mixture under a CO atmosphere was then
stirred for 10 min at ꢀ408C then H2O was added. CO was carefully elimi-
nated by bubbling N2 into the reaction vessel, and the reaction mixture
was extracted twice with Et2O. The combined organic extracts were
washed with brine, dried over MgSO4, filtered and the solvents concen-
trated in vacuo. Purification by flash chromatography (silica gel, petrole-
um ether/EtOAc: 9/1) afforded amine 24 as a colorless oil (0.107 g,
54%). Spectroscopic data were identical with those reported in the litera-
ture.[40]
1
88–908C; IR (neat): n=3050, 2935, 1637, 1594, 1461, 1414 cmꢀ1; H NMR
(300 MHz, CDCl3): d=7.79 (d, J=7.9 Hz, 1H), 7.51–7.45 (m, 1H), 7.37–
7.34 (m, 1H), 7.27–7.21 (m, 1H), 3.73 (s, 3H), 3.41–3.31 (m, 1H), 2.91–
2.83 (m, 1H), 2.50–2.40 (m, 1H), 1.91–1.80 (m, 4H), 1.32 ppm (d, J=
7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=162.2, 146.5, 138.5, 128.8,
127.5, 124.0, 121.6, 120.2, 114.3, 29.6, 28.9, 27.8, 24.6, 21.0, 16.7 ppm; MS
(EI): m/z: 227 (81) [M]+, 212 (100) [MꢀCH3]+, 198 (32) [MꢀNCH3]+;
HRMS (ESI): m/z calcd for C15H18NO [M+H]+: 228.1382; found:
228.1384.
Compound 19: N-methylmorpholine N-oxide (28 mg, 0.21 mmol,
1.05 equiv) and OsO4 (90 mL, 2.5 wt% in tBuOH) were added sequential-
ly to a solution of 13a (45 mg, 0.2 mmol, 1 equiv) in THF/tBuOH (1:1;
3 mL) and H2O (0.3 mL). The reaction mixture was stirred overnight at
RT. Then, Na2SO3 (152 mg, 1.2 mmol, 6 equiv) and H2O (1.5 mL) were
added at 08C and stirring was continued for 30 min at RT. EtOAc and
brine were added. The aqueous layer was extracted five times with
EtOAc. The combined organic extracts were dried over MgSO4, filtered,
and the solvent concentrated in vacuo. p-Toluenesulfonic acid monohy-
drate (cat.) was added to a solution of the crude diol (0.2 mmol, 1 equiv)
and 4 ꢂ molecular sieves (100 mg) in acetone (4 mL). The reaction mix-
ture was stirred at RT overnight, filtered over basic alumina, washed with
EtOAc, and the solvent evaporated. Purification by flash chromatogra-
phy (silica gel, petroleum ether/EtOAc 6:4) yielded 19 as a white solid
Compound 26: Phosgene (0.07 mL, 20% in toluene 0.68 mmol, 2.5 equiv)
was added dropwise to a solution of N-methylbiphenyl-2-amine (50 mg,
0.27 mmol, 1 equiv) in toluene (4 mL). The reaction mixture was heated
for 2 h under reflux then cooled to RT. Toluene was then removed
through distillation under a well-ventilated fume hood and CH2Cl2 was
added. The organic extracts were washed with H2O, dried over MgSO4,
filtered, and concentrated in vacuo. NaBH4 (55 mg, 0.59 mmol,
2.02 equiv) was added portionwise to a suspension of diphenyldiselenide
(84 mg, 0.27 mmol, 1 equiv) in EtOH (3.5 mL). The reaction mixture was
stirred for 15 min and a solution of the above crude carbamoyl chloride
(0.27 mmol) in THF (3 mL) was added dropwise. The reaction mixture
was stirred for 1 h at RT. EtOAc and brine were added, the layers were
separated and the aqueous layer was extracted twice with EtOAc. The
combined organic extracts were dried over MgSO4, filtered and concen-
trated in vacuo. Purification by flash chromatography (silica gel, petrole-
um ether/EtOAc 9:1) yielded 26 as a yellow oil (74 mg, 75% yield over 2
steps). 1H NMR (250 MHz, CDCl3): d=7.60–7.37 (m, 14H), 2.96 ppm (s,
3H); 13C NMR (62.5 MHz, CDCl3): d=165.2, 140.9, 138.6, 138.3, 136.2,
131.6, 130.4, 129.8, 128.9, 128.6, 128.5, 128.4, 127.8, 37.6 ppm; IR (neat,
NaCl): n=3059, 2930, 1682, 1479, 1276 cmꢀ1; MS (EI): m/z: 210 (100)
1
(35 mg, 59%). M.p. 173–1758C; H NMR (300 MHz, CDCl3): d=7.77 (d,
J=8.3 Hz, 1H); 7.51 (t, J=7.9 Hz, 1H); 7.39 (d, J=8.3 Hz, 1H); 7.26 (t,
J=7.2 Hz, 1H); 4.79 (t, J=6.0 Hz, 1H); 4.53 (d, J=6.4 Hz, 1H); 3.76 (s,
3H); 3.67 (q, J=7.5 Hz, 1H); 3.58 (d, J=14.8 Hz, 1H), 2.46 (dd, J=17.7,
4.9 Hz, 1H), 1.31 (s, 3H), 1.57 (d, J=7.9 Hz, 3H), 1.10 ppm (s, 3H);
13C NMR (75 MHz, CDCl3): d=161.7, 145.3, 138.9, 129.5, 124.0, 123.3,
122.0, 119.9, 114.5, 107.8, 78.4, 72.1, 32.9, 29.8, 26.4, 25.9, 24.4, 15.4 ppm;
IR (neat, NaCl): n=2970, 2925, 2889, 1640, 1595, 1568, 1460, 1382,
1310 cmꢀ1; MS (EI): m/z: 299 (30) [M]+, 284 (29) [MꢀCH3]+, 224 (100)
Chem. Eur. J. 2009, 15, 11160 – 11173
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F. Robert, Y. Landais, and G. Rousseau
[M-C6H5Se]+; HRMS (ESI): m/z calcd for C20H18NOSe [M+H]+:
368.0548; found: 368.0555.
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Compound 28: nBuLi (0.11 mL, 0.44 mmol, 2 equiv) was added to a solu-
tion of (+)-bis[(R)-a-methylbenzyl]amine hydrochloride (58 mg,
0.22 mmol, 1 equiv) in THF (2.1 mL) at ꢀ788C. The reaction mixture
was allowed to reach RT and cooled again to ꢀ788C. The resulting fresh-
ly prepared solution of chiral base 27 was added dropwise to a solution
of 7a (42 mg, 0.2 mmol, 1 equiv) in THF (2 mL) at ꢀ408C (temperature
inside flask <ꢀ388C). The reaction mixture was stirred at ꢀ408C for
10 min. nBuLi (0.11 mL, 0.22 mmol, 1.1 equiv) was added and the reac-
tion mixture was stirred for an additional 10 min at ꢀ408C. Methyl
iodide (25 mL, 0.44 mmol, 2 equiv) was then added dropwise and stirring
was continued for another 10 min. H2O (0.55 mL) was added by syringe
at ꢀ408C and the mixture was allowed to reach RT. Et2O was added and
the layers were separated. The aqueous layer was extracted twice with
Et2O. The combined organic layers were washed with brine, dried over
MgSO4, filtered, and concentrated in vacuo. Purification by flash chroma-
tography (silica gel, petroleum ether/EtOAc 8:2) afforded 28 as yellow
crystals (19 mg, 40%). M.p. 132–1348C; Rf =0.4 (petroleum ether/EtOAc
8:2); 1H NMR (250 MHz, CDCl3): d=7.75 (dd, J=8.2, 1.22 Hz, 1H),
7.54–7.47 (m, 1H), 7.38–7.34 (m, 1H), 7.28–7.21 (m, 1H), 6.02–5.89 (m,
2H), 3.81–3.76 (m, 1H), 3.74 (s, 3H), 3.67–3.62 (m, 1H), 1.38 (d, J=
7.0 Hz, 3H), 1.32 ppm (d, J=7.0 Hz, 3H); 13C NMR (62.5 MHz, CDCl3):
d=161.2, 144.9, 139.0, 131.1, 131.0, 129.1, 128.3, 124.3, 121.8, 119.5, 114.4,
31.2, 30.9, 29.6, 23.8, 21.9 ppm; IR (neat, NaCl): n=2961, 1926, 1673,
1629, 1595, 1456, 1312, 1078, 1051, 743 cmꢀ1; HRMS (ESI): m/z calcd for
C16H18NO [M+H]+: 240.1382; found: 240.1383.
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X-ray crystallography: CCDC 731966 (8b), CCDC 731967 (9), CCDC
710659 (15), CCDC 710658 (16a), CCDC 710660 (20) and CCDC 710661
(28) contain the crystallographic data for this paper. These data can be
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Computational details: All geometries of intermediates and transition
states were optimized fully using the Gaussian 03 program.[38] Geometry
optimizations were performed in vacuum using DFT with the three-pa-
rameter hybrid functional B3LYP as implemented in Gaussian. Frequen-
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points and to obtain zero-point energies (ZPE). The connectivity be-
tween stationary points was established by intrinsic reaction coordinate
computations (IRC). Every transition structure was characterized by a
single imaginary frequency in the diagonalized mass-weighted Hessian
matrix. The geometries of all the stationary points and TS are provided
in the Supporting Information. Single-point calculations in THF were run
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Acknowledgements
MNERT (grant to G.R.) and the CNRS are thanked for financial sup-
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Chem. Eur. J. 2009, 15, 11160 – 11173

Rearrangement of Spirooxindoles
FULL PAPER
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Received: May 28, 2009
Published online: September 16, 2009
Chem. Eur. J. 2009, 15, 11160 – 11173
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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