Efficient entry to diversely functionalized spirocyclic oxindoles from isatins through carbonyl-addition/cyclization reaction sequences

Article abstract of DOI:10.1021/jo0525027

A novel approach to diversely functionalized spirocyclic oxindoles has been developed by using different metal-mediated carbonyl-addition/cyclization reaction sequences. Spirocyclization precursors, 2-indolinonetethered homoallylic alcohols, (buta-1,3-die

Full text of DOI:10.1021/jo0525027

Efficient Entry to Diversely Functionalized Spirocyclic Oxindoles
from Isatins through Carbonyl-Addition/Cyclization Reaction
Sequences
Benito Alcaide,† Pedro Almendros,*,‡ and Raquel Rodr´ıguez-Acebes†
Departamento de Qu´ımica Orga´nica I, Facultad de Qu´ımica, UniVersidad Complutense de Madrid,
28040-Madrid, Spain, and Instituto de Qu´ımica Orga´nica General, CSIC, Juan de la CierVa 3,
28006-Madrid, Spain
alcaideb@quim.ucm.es; iqoa392@iqog.csic.es
ReceiVed December 5, 2005
A novel approach to diversely functionalized spirocyclic oxindoles has been developed by using different
metal-mediated carbonyl-addition/cyclization reaction sequences. Spirocyclization precursors, 2-indolinone-
tethered homoallylic alcohols, (buta-1,3-dien-2-yl)methanols, and R-allenols have been obtained by
regioselective addition of stabilized organoindium reagents to isatins in aqueous environment. Ruthenium-,
silver-, and palladium-catalyzed reactions of the above unsaturated alcohol derivatives provided oxaspiro
oxindoles.
Introduction
describe metal-mediated carbonyl-addition/cyclization reaction
sequences as a novel entry to diversely functionalized spirocyclic
oxindoles from commercially available isatins.
Spirocyclic compounds, which are systems containing one
carbon atom common to two rings, are structurally quite
interesting.1 Among them, the heterocyclic spiro-oxindole
framework is an important structural motif in biologically
relevant compounds as natural products and pharmaceuticals.2
Azaspiro derivatives are well-known,3 but the preparation of
the corresponding oxa analogues has evolved at a relatively slow
pace.4 In this context, we became aware that more of these
syntheses were performed via cycloaddition or condensation
reactions. In contrast to this literature scenario, we thought that
the highly selective properties of metals would seem to
recommend their application to the preparation of spirocycles.
In connection with our current research interest in the prepara-
tion of biologically relevant nitrogenated compounds,5 we now
Results and Discussion
Starting substrates, homoallyl alcohol 2, (buta-1,3-dien-2-yl)
alcohol 3, and R-allenyl alcohols 4a-c were regiospecifically
prepared using our recently developed metal-mediated Barbier-
type carbonyl-allylation, -1,3-butadien-2-ylation, or -allenylation
reactions of isatins 1 in aqueous media (Scheme 1).6
(3) For selected examples, see: (a) Ding, K.; Lu, Y.; Nikolovska-Coleska,
Z.; Qiu, S.; Ding, Y.; Gao, W.; Stuckey, J.; Krajewski, K.; Roller, P. P.;
Tomita, Y.; Parrish, D. A.; Deschamps, J. R.; Wang, S. J. Am. Chem. Soc.
2005, 127, 10130. (b) Chen, C.; Li, X.; Neumann, C. S.; Lo, M. M.-C.;
Schreiber, S. L. Angew. Chem., Int. Ed. 2005, 44, 2249. (c) Bella, M.;
Kobbelgaard, S.; JØrgensen, K. A. J. Am. Chem. Soc. 2005, 127, 3670. (d)
Ready, J. M.; Reisman, S. E.; Hirata, M.; Weiss, M. M.; Tamaki, K.; Ovaska,
T. V.; Wood, J. L. Angew. Chem., Int. Ed. 2004, 43, 1270. (e) Lo, M.
M.-C.; Neumann, C. S.; Nagayama, S.; Perlstein, E. O.; Schreiber, S. L. J.
Am. Chem. Soc. 2004, 126, 16077. (f) Rehn, S.; Bergman, J.; Stensland, B.
Eur. J. Org. Chem. 2004, 413. (g) Nishikawa, T.; Kajii, S.; Isobe, M. Synlett
2004, 2025. (h) Williams, R. M.; Cao, J.; Tsujishima, H.; Cox, R. J. J. Am.
Chem. Soc. 2003, 125, 12172. (i) Bagul, T. D.; Lakshmaiah, G.; Kawabat,
T.; Fuji, K. Org. Lett. 2002, 4, 249. (j) Lerchner, A.; Carreira, E. M. J. Am.
Chem. Soc. 2002, 124, 14826. (k) Lin, X.; Weinreb, S. M. Tetrahedron
Lett. 2001, 42, 2631. (l) Edmondson, S.; Danishefsky, S. J. Angew. Chem.,
Int. Ed. 1998, 37, 1138.
† Universidad Complutense de Madrid.
‡ Instituto de Qu´ımica Orga´nica General.
(1) For selected reviews, see: (a) Sannigrahi, M. Tetrahedron 1999, 55,
9007. (b) Heathcock, C. H.; Graham, S. L.; Pirrung, M. C.; Plavac, F.;
White, C. T. Spirocyclic Systems. In The Total Synthesis of Natural
Products; ApSimon, J., Ed.; John Wiley and Sons: New York, 1983; Vol.
5, pp 264-313.
(2) For reviews, see: (a) Williams, R. M.; Cox, R. J. Acc. Chem. Res.
2003, 36, 127. (b) Da Silva, J. F. M.; Garden, S. J.; Pinto, A. C. J. Braz.
Chem. Soc. 2001, 273.
10.1021/jo0525027 CCC: $33.50 © 2006 American Chemical Society
Published on Web 02/10/2006
2346
J. Org. Chem. 2006, 71, 2346-2351

Entry to DiVersely Functionalized Spirocyclic Oxindoles from Isatins
SCHEME 1
SCHEME 2 a
With the advent of well-defined, practically air-stable, and
functional-group-tolerant metathesis catalysts, e.g., the first,
[Cl2(PCy3)2RudCHPh], and second, [Cl2(Im)(Cy3P)RudCHPh],
generation of Grubbs’ ruthenium-based catalysts, ring-closing
metathesis (RCM) has become one of the most powerful and
reliable approaches to construct a ring system.7 Our first task
was to develop a method for the synthesis of appropriately
substituted metathesis precursors. The treatment of homoallyl
alcohol 2 either with allyl bromide or methyl propiolate, under
different basic conditions, gave dienes 5 and 6, respectively
(Scheme 2). Sodium hydride-promoted O-acylation of alcohol
2 with acryloyl chloride provides dienic substrate 7 (Scheme
2). To further expand the scope of substrates to submit to RCM,
we thought of the buta-1,3-dien-2-yl moiety, bearing an extra
a Key: (i) TBAI (cat.), CH2Cl2, NaOH (aq 50%) (1:1), rt, 16 h; (ii)
CH2Cl2, Et3N (2 equiv), 0 °C, 1 h; (iii) NaH (2 equiv), THF, rt, 1 h.
alkene group. Following the same alkylation strategy used to
obtain diene 5, the required triene 8 was smoothly achieved
from buta-1,3-dien-2-yl alcohol 3 (Scheme 2).
In view of the particular disposition of a variety of dienes to
undergo spiro-forming RCM reaction, we sought to apply this
methodology to our novel 2-indolinone-tethered diene substrates
5-8 for the synthesis of unusual oxindoles bearing a spiranic
center substituted with a oxygen atom. The use of this approach
in the synthesis of spirocyclic oxindoles has not been hitherto
applied. Our objective was the synthesis of oxaspiro-oxindole
structures containing five- and six-membered rings. Treatment
of dienes 5-8 having a quaternary atom with first-generation
Grubbs’ carbene under smooth ring-closing metathesis condi-
tions (5 mol %, CH2Cl2, 25 °C) did not furnish the desired
spirocycles. The majority of the reaction mixture was composed
of unreacted dienes. While the reasons for this lack of cyclization
were not definitively established, we attributed the low reactivity
of the structures 5-8 to either the ring strain inherent to the
spirocyclic products or kinetic problems associated with its
formation. Fortunately, we found that dienic substrates 5-8
require more vigorous conditions for ring closure. Under
optimized conditions, we found that toluene at reflux temper-
ature gave the best yields of oxindoles containing dihydrofuran,
dyhydropyran, and dyhydropyranone spiranic rings. More active
second-generation Grubbs’ carbene was required for the spiro-
cyclization taking place on terminally monosubstituted diene
6. Exposure of dienes 5-8 to the Grubbs’ ruthenium-based
catalysts under our standard cyclization conditions (5 mol %
of catalyst, 0.03 M, toluene, 110 °C) resulted in clean formation
of the spirocycles 9-12 in good to excellent yields (57-89%)
(Scheme 3). Grubbs’ catalysts are known to be moderately
thermally unstable, and the decomposition would inhibit pro-
ductive metathesis.8 To circumvent this problem, Grubbs’
carbene was added in small portions (up to five) every 20 min
(4) (a) Nair, V.; Biju, A. T.; Vinod, A. U.; Suresh, E. Org. Lett. 2005,
7, 5139. (b) Basavaiah, D.; Rao, J. S.; Reddy, R. J.; Rao, A. J. Chem.
Commun. 2005, 2621. (c) Nair, V.; Mathai, S.; Mathew, S. C.; Rath, N. P.
Tetrahedron 2005, 61, 2849. (d) Zhang, Y.; Wang, L.; Zhang, M.; Fun,
H.-K.; Xu, J.-H. Org. Lett. 2004, 6, 4893. (e) Nair, V.; Mathai, S.; Augustine,
A.; Radhakrishnan, S. V. K. V. Synthesis 2004, 2617. (f) Muthusamy, S.;
Gunanathan, C.; Nethaji, M. J. Org. Chem. 2004, 69, 5631. (g) Smet, M.;
Van Oosterwijck, C.; Van Hecke, K.; Van Meervelt, L.; Vandendriessche,
A.; Dehaen, W. Synlett 2004, 2388. (h) Nair, V.; Rajesh, C.; Dhanya, R.;
Rath, N. P. Tetrahedron Lett. 2002, 43, 5349. (i) Lee, S.; Hartwig, J. J.
Org. Chem. 2001, 66, 3402. (j) Tobisu, M.; Chatani, N.; Asaumi, T.; Amako,
K.; Ie, Y.; Fukumoto, Y.; Murai, S. J. Am. Chem. Soc. 2000, 122, 12663.
(5) See, for instance: (a) Alcaide, B.; Almendros, P.; Aragoncillo, C.;
Redondo, M. C.; Torres, M. R. Chem. Eur. J. 2006, 12, in press. (b) Alcaide,
B.; Almendros, P.; Redondo, M. C.; Ruiz, M. P. J. Org. Chem. 2005, 70,
8890. (c) Alcaide, B.; Almendros, P.; Rodr´ıguez-Acebes, R. Chem. Eur. J.
2005, 11, 5708. (d) Alcaide, B.; Almendros, P.; Cabrero, G.; Ruiz, M. P.
Org. Lett. 2005, 7, 3981. (e) Alcaide, B.; Almendros, P.; Rodr´ıguez-Acebes,
R. J. Org. Chem. 2005, 70, 2713. (f) Alcaide, B.; Almendros, P.; Alonso,
J. M. J. Org. Chem. 2004, 69, 993. (g) Alcaide, B.; Almendros, P.; Redondo,
M. C. Org. Lett. 2004, 6, 1765.
(6) Alcaide, B.; Almendros, P.; Rodr´ıguez-Acebes, R. J. Org. Chem.
2005, 70, 3198.
(7) For some reviews on olefin metathesis, see: (a) Deiters, A.; Martin,
S. F. Chem. ReV. 2004, 104, 2199. (b) Handbook of Metathesis; Grubbs,
R. H., Ed.; Wiley-VCH: Weinheim, 2003; Vols. 1-3. (c) Schrock, R. R.;
Hoveyda, A. H. Angew. Chem., Int. Ed. 2003, 42, 4592. (d) Grubbs, R. H.;
Trnka, T. M. Acc. Chem. Res. 2001, 34, 18. (e) Fu¨rstner, A. Angew. Chem.,
Int. Ed. 2000, 39, 3012. (f) Schrock, R. R.; Hoveyda, A. H. Chem. Eur. J.
2001, 7, 945. (g) Fu¨rstner, A. Synlett 1999, 1523. (h) Wright, D. L. Curr.
Org. Chem. 1999, 3, 211. (i) Grubbs, R. H.; Chang, S. Tetrahedron 1998,
54, 4413. (j) Armstrong, S. K. J. Chem. Soc., Perkin Trans. 1 1998, 371.
(k) Schuster, M.; Blechert, S. Angew. Chem., Int. Ed. Engl. 1997, 36, 2036.
(8) (d) Hong, S. H.; Day, M. W.; Grubbs, R. H. J. Am. Chem. Soc. 2004,
126, 7414. (b) Ulman, M.; Grubbs, R. H. J. Org. Chem. 1999, 64, 7202.
J. Org. Chem, Vol. 71, No. 6, 2006 2347

Alcaide et al.
SCHEME 3 a
SCHEME 4 a
a Key: (i) Ag2O (1.5 equiv), I2 (1.5 equiv), dioxane/water (7:1), rt, 5
days.
SCHEME 5 a
a Key: (i) 5 mol % of [Cl2(PCy3)2RudCHPh], toluene, reflux; 9, 1 h;
11, 38 h; 12, 18 h; (ii) 5 mol % of [Cl2(Im)(Cy3P)RudCHPh], toluene,
reflux, 13 h.
a Key: (i) AgNO3 (1 equiv), acetone/water (1:1), reflux, 1 h; (ii) 5 mol
% of Pd(PPh3)4, PhI (1.1 equiv), K2CO3 (4 equiv), toluene, reflux, 80 h;
(iii) 5 mol % PdCl2, allyl bromide (5 equiv), DMF, rt; 17a, 2 h; 17b, 1.5
h.
(5 mol % is the overall amount of all the portions). Thus, the
catalytic species is continuously being renewed by fresh Grubbs’
carbene. The exposure of triene 8 to Grubbs’ catalyst gave the
six-membered spiro compound 12, which bears an exocyclic
methylene. No traces of the five-membered regioisomer 13 could
be detected because only the least substituted double bond of
the 1,3-diene system reacted (Scheme 3).
Having in hand the unsaturated alcohols 2-4, our next target
was to perform metal-mediated reactions in order to directly
convert them to novel oxaspirocyclic oxindoles. For instance,
homoallyl alcohol 2 was treated with iodine and silver(I) oxide
in a 7:1 mixture of dioxetane-water at room temperature for 5
days9 to give the corresponding iodotetrahydrofuran derivative
14 (Scheme 4).
different spiranic dihydrofuran oxindole derivatives was
explored starting from allenylcarbinols 4. When treated with
silver(I) nitrate, R-allenols 4 gave rise to spirocyclic dihydro-
furans 15 in quantitative yields (Scheme 5).11 Next, we focused
our efforts on the palladium-catalyzed coupling-cyclization
reaction of R-allenols 4 with organic halides.12 After some trial
and error, it was observed that the Pd(PPh3)4-catalyzed reaction
of R-allenol 4b and iodobenzene afforded as main product the
spiranic dihydrofuran oxindole 15b, together with the oxirane
γ-amino acid 16 (Scheme 5). The formation of epoxide 16
involves concomitant ring opening of the γ-lactam nucleus,
probably because of the ring strain of the intermediate spiro-
cyclic epoxyoxindole which cannot survive under the reaction
conditions. The transformation of the allenols 4a and 4b into
the spirocyclic disubstituted dihydrofuran indolones 17a and
17b was readily achieved in quantitative and 75% yields by
treatment with allyl bromide in the presence of palladium(II)
chloride (5 mol %) (Scheme 5).
The combination of an allene moiety and a functional group
in the same molecule provides many opportunities in metal-
catalyzed processes.10 However, allenes are still under utilized
in heterocyclic synthesis. Application of this concept to install
Scheme 6 outlines a mechanistic hypothesis for the formation
of compound 16. The Pd(0)-catalyzed insertion of iodobenzene
(9) Alonso, F.; Mele´ndez, J.; Yus, M. Tetrahedron Lett. 2004, 45, 1717.
(10) For reviews on transition metal catalyzed cyclizations of allenes,
see: (a) Hashmi, A. S. K. Angew. Chem., Int. Ed. 2000, 39, 3590. (b) Bates,
R. W.; Satcharoen, V. Chem. Soc. ReV. 2002, 31, 12. (c) Ma, S. Acc. Chem.
Res. 2003, 36, 701. (d) Modern Allene Chemistry; Krause, N., Hashmi, A.
S. K., Eds.; Wiley-VCH: Weinheim, 2004; Vol. 2. (e) Hoffmann-Ro¨der,
A.; Krause, N. Org. Biomol. Chem. 2005, 3, 387. (f) Ma, S. Chem. ReV.
2005, 105, 2829.
(11) For the Ag(I)-catalyzed cyclization of 2,3-allenols, see: (a) Marshall,
J. A.; Yu, R. H.; Perkins, J. F. J. Org. Chem. 1995, 60, 5550. (b) Marshall,
J. A.; Pinney, K. G. J. Org. Chem. 1993, 58, 7180.
(12) Xu, D.; Li, Z.; Ma, S. Chem. Eur. J. 2002, 8, 5012.
2348 J. Org. Chem., Vol. 71, No. 6, 2006

Entry to DiVersely Functionalized Spirocyclic Oxindoles from Isatins
SCHEME 6
SCHEME 8 a
a Key: (i) 9 mol % of Pd(OAc)2, LiBr (5 equiv), Cu(OAc)2 (2.1 equiv),
K2CO3 (1.2 equiv), O2, MeCN, rt; 22a, 20 h; 22b, 120 h.
SCHEME 9
SCHEME 7
formation of a (π-allyl)palladium species. The allenepalladium
complex 23 is formed initially and suffers a nucleophilic attack
by the bromide to produce a σ-allylpalladium species, which
rapidly equilibrates to the corresponding (π-allyl)palladium
intermediate 24. Then, an intramolecular cycloetherification
reaction on the (π-allyl)palladium complex must account for
the formation of bromodihydrofuran intermediates 22 (Scheme
9).
generated the corresponding (π-allyl)palladium intermediate 18.
Then, an intramolecular oxycyclization reaction on the (π-allyl)-
palladium complex must account for the formation of the
spiranic oxirane intermediate 19. Subsequent γ-lactam ring
opening of the spirocyclic epoxyoxindole 19 under the reaction
conditions, afforded the oxirane γ-amino acid 16. Compound
15b should be formed without the intervention of PhI, via an
allenepalladium complex which undergoes an intramolecular
attack by the hydroxyl group (hydroalkoxylation).
The formation of spirocyclic allylmethyldihydrofuran indo-
lones 17 could be explained following a Pd(II)-catalyzed
mechanism.13 Initial Pd(II) coordination followed by an in-
tramolecular cycloetherification reaction gave the palladadihy-
drofuran species 20. Intermediate 20 reacted with allyl bromide
to form intermediate 21, which after dehalopalladation generated
spirooxindoles 17 with concomitant regeneration of the Pd(II)
species (Scheme 7).
Conclusions
In conclusion, the present study provides the first general
methodology for the preparation of the oxacyclic spiro-oxindole
framework, which is an important structural motif in some
biologically relevant compounds. We have shown that combina-
tion of Barbier-type carbonyl-addition reactions and metal-
mediated cyclizations is an useful methodology for the prepa-
ration of a variety of diversely functionalized oxaspirocyclic
oxindoles from isatins.
Experimental Section
We next investigated the feasibility of synthesizing spirocyclic
bromodihydrofuran-containing oxindoles by employing palla-
dium(II)-induced intramolecular 2,3-oxybromination of R-alle-
nols 4. As shown in Scheme 8, the bromo-functionalized
spirodihydrofuranoxindole derivatives 22 can be prepared as
single isomers in reasonable yields. As far as we know, this is
the first preparation of a furan derivative containing the
bromovinyl moiety starting from allenols.14 A likely mechanism
for the generation of spirocycles 22 should involve the initial
General Methods. The same experimental techniques were used
as previously reported.5
General Procedure for the Ring-Closing Metathesis (RCM)
Reaction of Diolefin Precursors 5-8. Preparation of Spirocyclic
Oxindoles 9-12. To a solution protected from the sunlight of the
appropriate diene (0.20 mmol) in anhydrous toluene (6 mL) was
added in portions [Cl2(Cy3P)2RudCHPh] or [Cl2(Im)(Cy3P)Rud
(14) The palladium-catalyzed intramolecular cyclization of simple γ-al-
lenic alcohols has been recently reported by Ba¨ckvall and co-workers.
However, it should be noted the dramatic change on the regioselectivity by
the effect of the tether length. They obtained the 1,2-addition products,
while we obtained the 2,3-addition products. See: Jonasson, C.; Horva´th,
A.; Ba¨ckvall, J.-E. J. Am. Chem. Soc. 2000, 122, 9600.
(13) Ma, S.; Gao, W. J. Org. Chem. 2002, 67, 6104. One of the reviewers
has suggested that compounds 17 might also arise from a π-allyl Pd
intermediate similar to that involved in Scheme 6, which undergoes
cyclization by nucleophilic attack to the distal allyl carbon atom.
J. Org. Chem, Vol. 71, No. 6, 2006 2349

Alcaide et al.
1
CHPh] (0.01 mmol) under argon. The resulting mixture was heated
at reflux until complete disappearance of the starting material (TLC)
and was concentrated under reduced pressure. Chromatography of
the residue eluting with ethyl acetate/hexanes or ethyl acetate/
dichloromethane mixtures gave analytically pure compounds 9-12.
Spectroscopic and analytical data for some representative pure forms
of 9-12 follow.15
colorless oil. H NMR: δ 8.49 (br s, 1H), 7.24 (m, 2H), 7.06 (t,
1H, J ) 7.3 Hz), 6.89 (d, 1H, J ) 7.6 Hz), 5.99 (d, 1H, J ) 1.5
Hz), 5.04 and 4.94 (dq, each 1H, J ) 12.2, 2.0 Hz), 1.50 (d, 3H,
J ) 1.7 Hz). 13C NMR: δ 178.1, 141.0, 135.9, 130.1, 128.8, 124.9,
124.8, 123.3, 110.3, 93.0, 76.6, 11.2. IR (CHCl3, cm-1): ν 3420,
1714. MS (EI), m/z: 202 (M+ + 1, 5), 201 (M+, 100). Anal. Calcd
for C12H11NO2: C, 71.63; H, 5.51; N, 6.96. Found: C, 71.51; H,
5.53; N, 6.99.
Spirocyclic Oxindole 11. From 49 mg (0.191 mmol) of diene
7, 39 mg (89%) of compound 11 was obtained as a colorless oil
after chromatography eluting with ethyl acetate/dichloromethane
Pd(0)-Catalyzed Coupling Cyclization of R-Allenol 4b with
PhI. Preparation of Spirocyclic Oxindole 15b and Oxirane
γ-Amino Acid 16. [Pd(PPh3)4] (15 mg, 0.013 mmol) was added
to a mixture of R-allenol 4b (50 mg, 0.25 mmol), iodobenzene (54
mg, 0.27 mmol), and potassium carbonate (138 mg, 1.0 mmol) in
DMF (2 mL) under Ar, and the resulting mixture was heated at
115 °C for 80 h. The reaction was then quenched with brine (2.5
mL), the mixture was extracted with ethyl acetate (4 × 5 mL), and
the combined extracts were washed twice with brine and dried
(MgSO4). Removal of solvent under reduced pressure yielded 16
mg (32%) of the less polar compound 15b and 17 mg (23%) of
the more polar compound 16 after chromatography eluting with
ethyl acetate/dichloromethane (1:15).
1
(1:30). H NMR: δ 7.45 (d, 1H, J ) 7.2 Hz), 7.37 (dd, 1H, J )
7.8, 1.2 Hz), 7.08 (td, 1H, J ) 7.6, 1.1 Hz), 6.95 (dt, 1H, J ) 9.9,
4.3 Hz), 6.86 (d, 1H, J ) 7.8 Hz), 6.26 (dt, 1H, J ) 9.9, 2.1 Hz),
3.19 (s, 3H), 2.93 and 2.75 (ddd, each 1H, J ) 18.9, 4.2, 2.0 Hz).
13C NMR: δ 172.6, 161.9, 143.1, 142.0, 131.1, 127.6, 124.0, 123.4,
121.4, 108.9, 80.0, 30.3, 26.4. IR (CHCl3, cm-1): ν 1720, 1710.
MS (ES), m/z: 230 (M+ + 1, 100), 229 (M+, 25). Anal. Calcd for
C13H11NO3: C, 68.11; H, 4.84; N, 6.11. Found: C, 68.00; H, 4.86;
N, 6.14.
Spirocyclic Oxindole 12. From 40 mg (0.157 mmol) of triene
8, 21 mg (57%) of compound 12 was obtained as a colorless oil
1
after chromatography eluting with ethyl acetate/hexanes (1:3). H
1
Oxirane γ-Amino Acid 16. H NMR: δ 9.03 (br s, 1H), 7.96
NMR: δ 7.36 (td, 1H, J ) 7.7, 1.3 Hz), 7.31 (d, 1H, J ) 6.9 Hz),
7.09 (td, 1H, J ) 7.4, 1.1 Hz), 6.85 (d, 1H, J ) 7.6 Hz), 6.48 (dt,
1H, J ) 10.2, 2.2 Hz), 6.11 (d, 1H, J ) 10.5 Hz), 4.98 (s, 1H),
4.91 (dm, 1H, J ) 17.6 Hz), 4.55 (s, 1H), 4.42 (d, 1H, J ) 17.6
Hz), 3.19 (s, 3H). 13C NMR: δ 174.0, 144.2, 138.5, 130.1, 129.1,
128.0, 125.1, 125.0, 123.1, 113.4, 108.3, 77.2, 62.4, 26.0. IR
(CHCl3, cm-1): ν 1707. MS (EI), m/z: 228 (M+ + 1, 7), 227 (M+,
100). Anal. Calcd for C14H13NO2: C, 73.99; H, 5.77; N, 6.16.
Found: C, 73.86; H, 5.80; N, 6.14.
Procedure for the Silver-Induced Reaction of Homoallyl
Alcohol 2. Preparation of Spirocyclic Oxindole 14. Silver(I) oxide
(108 mg, 0.465 mmol) and iodine (118 mg, 0.465 mmol) were
sequentially added to a stirred solution of alkenol 2 (63 mg, 0.31
mmol) in dioxane/water (7:1) (4 mL). The reaction was stirred at
room temperature for 120 h, before water (2 mL) was added. Then,
the mixture was extracted with ethyl acetate (3 × 7 mL). The
organic extract was washed with brine and dried (MgSO4). Removal
of solvent under reduced pressure yielded 38 mg (37%) of the
spiranic iodotetrahydrofuran adduct 14 after chromatography eluting
with ethyl acetate/dichloromethane (1:10).
(dd, 1H, J ) 7.8, 1.5 Hz), 7.54 (ddd, 1H, J ) 8.1, 7.3, 1.5 Hz),
7.13 (m, 6H), 6.86 (dd, 1H, J ) 8.3, 0.7 Hz), 5.68 and 5.61 (s,
each 1H), 1.77 (s, 3H). 13C NMR: δ 173.7, 146.2, 140.3, 140.0,
136.1, 128.3, 128.1, 127.5, 127.1, 123.7, 118.8, 118.4, 116.2, 77.2,
62.4, 23.4. IR (CHCl3, cm-1): ν 3420, 3390, 1712. MS (ES), m/z:
296 (M+ + 1, 100), 295 (M+, 11). Anal. Calcd for C18H17NO3: C,
73.20; H, 5.80; N, 4.74. Found: C, 73.07; H, 5.82; N, 4.76.
General Procedure for the Palladium(II)-Catalyzed Coupling
Reaction of R-Allenols 4 with Allyl Bromide. Preparation of
Spirocyclic Oxindoles 17. Palladium(II) chloride (0.005 mmol) was
added to a stirred solution of the corresponding R-allenol 4 (0.10
mmol) and allyl bromide (0.50 mmol) in N,N-dimethylformamide
(0.6 mL). The reaction was stirred under argon atmosphere until
disappearance of the starting material (TLC). Water (0.5 mL) was
added before the mixture was extracted with ethyl acetate (3 × 4
mL). The organic phase was washed with water (2 × 2 mL), dried
(MgSO4), and concentrated under reduced pressure. Chromatog-
raphy of the residue eluting with hexanes/ethyl acetate mixtures
gave analytically pure spiranic oxindoles 17. Spectroscopic and
analytical data for some representative pure forms of 17 follow.
Spirocyclic Oxindole 17a. From 48 mg (0.223 mmol) of
R-allenol 4a, 57 mg (100%) of compound 17a was obtained as a
colorless oil. 1H NMR: δ 7.33 (td, 1H, J ) 7.6, 1.5 Hz), 7.19 (dd,
1H, J ) 7.2, 1.4 Hz), 7.07 (td, 1H, J ) 7.5, 1.0 Hz), 6.83 (d, 1H,
J ) 7.6 Hz), 5.85 (ddt, 1H, J ) 17.1, 10.0, 6.2 Hz), 5.19 (dq, 1H,
J ) 17.1, 1.5 Hz), 5.10 (dq, 1H, J ) 10.0, 1.5 Hz), 4.97 and 4.86
(dd, each 1H, J ) 12.0, 2.0 Hz), 3.20 (s, 3H), 2.99 (dt, 2H, J )
6.2, 1.5 Hz), 1.32 (t, 3H, J ) 2.0 Hz). 13C NMR: δ 175.9, 144.0,
134.5, 134.1, 130.0, 128.7, 128.6, 124.5, 123.1, 116.3, 108.2, 93.9,
78.5, 29.7, 26.3, 8.8. IR (CHCl3, cm-1): ν 1714. MS (EI), m/z:
256 (M+ + 1, 7), 255 (M+, 100). Anal. Calcd for C16H17NO2: C,
75.27; H, 6.71; N, 5.49. Found: C, 75.39; H, 6.68; N, 5.47.
General Procedure for the Palladium(II)-Catalyzed Oxybro-
mination of R-Allenols 4. Preparation of Spirocyclic Oxindoles
22. Palladium(II) acetate (0.012 mmol), lithium bromide (0.656
mmol), potassium carbonate (0.16 mmol), and copper(II) acetate
(0.28 mmol) were sequentially added to a stirred solution of the
corresponding R-allenol 4 (0.134 mmol) in acetonitrile (7 mL). The
resulting suspension was stirred at room temperature under an
oxygen atmosphere for 24 h at room temperature. The organic phase
was diluted with brine (2 mL), extracted with ethyl acetate (3 × 5
mL), washed with brine (2 mL), dried (MgSO4), and concentrated
under reduced pressure. Chromatography of the residue eluting with
hexanes/ethyl acetate mixtures gave analytically pure spiranic
oxindoles 22. Spectroscopic and analytical data for some repre-
sentative pure forms of 22 follow.
Spirocyclic Oxindole 14. Colorless solid. Mp: 109-111 °C
1
(hexanes/ethyl acetate). H NMR: δ 7.60 (dd, 1H, J ) 7.4, 1.2
Hz), 7.31 and 7.08 (td, each 1H, J ) 7.5, 1.0 Hz), 6.80 (d, 1H, J
) 7.7 Hz), 4.87 (m, 1H), 4.39 (dd, 1H, J ) 9.7, 3.8 Hz), 4.16 (dd,
1H, J ) 9.7, 1.5 Hz), 3.17 (s, 3H), 2.67 (dd, 1H, J ) 13.7, 5.5
Hz), 2.20 (dt, 1H, J ) 13.7, 1.8 Hz). 13C NMR: δ 177.8, 143.8,
130.2, 129.9, 125.3, 123.4, 108.3, 82.9, 77.6, 73.2, 44.0, 26.2. IR
(CHCl3, cm-1): ν 1711. MS (EI), m/z: 329 (M+, 7), 160 (M+,
100). Anal. Calcd for C12H12INO2: C, 43.79; H, 3.67; N, 4.26.
Found: C, 43.93; H, 3.64; N, 4.23.
General Procedure for the Silver-Induced Reaction of R-Al-
lenols (+)-4. Preparation of Spirocyclic Oxindoles 15. Silver
nitrate (0.20 mmol) was added to a stirred solution of the
corresponding R-allenol 4 (0.20 mmol) in acetone/water (1:1) (0.4
mL). The reaction was refluxed until disappearance of the starting
material (TLC). The mixture was allowed to reach room temperature
before brine (2 mL) was added, and then it was extracted with ethyl
acetate (4 × 5 mL). The organic extract was washed with brine
and dried (MgSO4). Removal of solvent under reduced pressure
yielded the corresponding spiranic dihydrofuran adducts 15 in
analytically pure form. Spectroscopic and analytical data for some
representative pure forms of 15 follow.
Spirocyclic Oxindole 15b. From 26 mg (0.129 mmol) of
R-allenol 4b, 26 mg (100%) of compound 15b was obtained as a
(15) Full spectroscopic and analytical data for compounds not included
in this Experimental Section are described in the Supporting Information.
2350 J. Org. Chem., Vol. 71, No. 6, 2006

Entry to DiVersely Functionalized Spirocyclic Oxindoles from Isatins
Spirocyclic Oxindole 22a. From 39 mg (0.18 mmol) of R-allenol
4a was obtained 27 mg (52%) of compound 22a as a colorless
solid after chromatography eluting with ethyl acetate/hexanes
(1:1). Mp: 230-231 °C (hexanes/ethyl acetate). 1H NMR: δ 7.36
(td, 1H, J ) 7.7, 1.5 Hz), 7.24 (ddd, 1H, J ) 7.3, 1.5, 0.5 Hz),
7.10 (td, 1H, J ) 7.4, 1.0 Hz), 6.85 (d, 1H, J ) 7.8 Hz), 5.15 and
5.05 (dq, each 1H, J ) 11.5, 2.0 Hz), 3.22 (s, 3H), 1.41 (t, 3H, J
) 2.0 Hz). 13C NMR: δ 175.3, 144.1, 133.3, 130.4, 129.3, 128.1,
124.5, 123.3, 108.4, 93.7, 77.2, 26.3, 10.8. IR (CHCl3, cm-1): ν
1712. MS (ES), m/z: 295 (M+ + 2 + H, 100), 293 (M+ + H, 98).
Anal. Calcd for C13H12BrNO2: C, 53.08; H, 4.11; N, 4.76. Found:
C, 53.19; H, 4.09; N, 4.73.
Acknowledgment. We thank the DGI-MEC (Project
BQU2003-07793-C02-01) for financial support. R.R.-A. thanks
the MEC for a predoctoral grant.
Supporting Information Available: Compound characterization
data and experimental procedures for compounds 2, 3, 4a-c, 5-8,
9, 10, 15a, 17b, and 22b. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO0525027
J. Org. Chem, Vol. 71, No. 6, 2006 2351