Pd-catalyzed assembly of spirooxindole natural products: A short synthesis of horsfiline

Article abstract of DOI:10.1021/jo101401z

The Pd-catalyzed intramolecular α-arylation of amides is applied to the synthesis of functionalized spirooxindoles. The substrate scope is evaluated, and the reaction is demonstrated to be useful for the assembly of spirooxindole natural products and derivatives thereof. As an application, a new synthesis of horsfiline 1 is presented, giving the natural product in only 4 steps from commercially available amino acid 12.

Full text of DOI:10.1021/jo101401z

pubs.acs.org/joc
Pd-Catalyzed Assembly of Spirooxindole Natural Products:
A Short Synthesis of Horsfiline
Nina Deppermann,† Heike Thomanek,‡ Alexander H. G. P. Prenzel,§ and
Wolfgang Maison*,‡
†Dr. Knoell Consult GmbH, Dynamostrasse 19, 68165 Mannheim, Germany, ‡Institute of Organic
Chemistry, Justus-Liebig-University Giessen, Heinrich-Buff-Ring 58, 35392 Giessen, Germany, and
§tesa SE, Research & Development, Quickbornstrasse 24, 20253 Hamburg, Germany
wolfgang.maison@org.chemie.uni-giessen.de
Received July 16, 2010
The Pd-catalyzed intramolecular R-arylation of amides is applied to the synthesis of functionalized
spirooxindoles. The substrate scope is evaluated, and the reaction is demonstrated to be useful for the
assembly of spirooxindole natural products and derivatives thereof. As an application, a new syn-
thesis of horsfiline 1 is presented, giving the natural product in only 4 steps from commercially
available amino acid 12.
Introduction
reported. The 3,30-pyrrolidinyl-spirooxindole scaffold is
therefore a privileged structural element with respect to pharma-
ceutical applications. In our efforts toward targeted antic-
ancer agents,6 we have been attracted by these natural pro-
ducts because some members of the spirooxindole family show
pronounced and cell-type-specific anticancer properties.3
A large number of synthetic methodologies have been
developed for the preparation of spirooxindole natural
products, and the reader is referred to some recent reviews
to get an overview.7 A key point in each synthesis is the con-
struction of the spirocyclic scaffold with its quarternary
carbon center. Most strategies rely on indole precursors for
the construction of the key structural element, and only a
limited number of procedures construct the indole itself.
Elegant examples of the latter approach are Overman’s Heck
cyclizations of unsaturated anilides.8 This approach allows
the synthesis of many derivatives with high structural diversity
Spirocyclic structures are abundant in many natural pro-
ducts and have always been a challenge for synthetic organic
chemists.1 In particular the 3,30-pyrrolidinyl-spirooxindoles
(some prominent examples are depicted in Figure 1) consti-
tute a pharmaceutically valuable class of biologically active
compounds, which can be isolated from plants and fungi.2
These natural products have a fascinating architecture, and
various biological activities such as anticancer properties,3
contraceptive action,4 and antimigraine activity5 have been
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(b) Rosenberg, S.; Leino, R. Synthesis 2009, 2651.
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Melenski, E. G.; McComas, C. C.; Mugford, C. A.; Slayden, O. D.; Yudt, M.;
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Gallicchio, S. N.; Johnston, V. K.; Moore, E. L.; Mosser, S. D.; Quigley,
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2009, 19, 214.
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4726. (b) Humblet, V.; Misra, P.; Bhushan, K. R.; Nasr, K.; Ko, Y. S.;
Tsukamoto, T.; Pannier, N.; Frangioni, J. V.; Maison, W. J. Med. Chem.
2009, 52, 544. (c) Pavet, V.; Beyrath, J.; Pardin, C.; Morizot, A.; Lechner, M.-
C.; Briand, J.-P.; Wendland, M.; Maison, W.; Fournel, S.; Micheau, O.;
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5994 J. Org. Chem. 2010, 75, 5994–6000
Published on Web 08/05/2010
DOI: 10.1021/jo101401z
r
2010 American Chemical Society

Deppermann et al.
JOCArticle
SCHEME 1. Synthesis of Cyclization Precursors
FIGURE 1. Some examples for bioactive natural products contain-
ing the 3,30-pyrrolidinyl-spirooxindole scaffold (highlighted in red).
The key step of this concept is the Pd-catalyzed R-aryla-
tion of an appropriate amide precursor 3. This reaction has
first been reported by Hartwig for inter- and intramolecular
variants.11
However, the method has rarely been used for the synth-
esis of spiro compounds, nor has it been applied to the
synthesis of densely functionalized natural products.
In consequence, we first focused on some model reactions
to evaluate the substrate scope and optimal conditions for
the attempted R-arylation. The key questions to be addressed
were (1) What are the right conditions for the arylation of
carboxamides 3 containing nitrogen heterocycles? (2) What
kind of protecting groups (particularly for the anilide
nitrogen) are compatible? (3) Are sterically hindered and fun-
ctionalized (particularly ’’competing’’ carboxyl derivatives)
anilides suitable substrates?
The synthesis of the required cyclization precursors is
shown for two examples, 9a and 9b (Scheme 1). All other
anilides 9c-9f were synthesized similarly in one or two steps
(see Supporting Information for details).
The first cyclizations of anilides 9a, 9c, and 9d using con-
ditions reported by Hartwig (Pd(PCy3)2 in dioxane, 55 °C)11
proceeded smoothly and gave the desired spirooxindoles
10a, 10c, and 10d in reasonable yields (Table 1). The con-
version of educts 9a, 9c, and 9d was quantitative, and the
only detectable byproducts are the dehalogenated anilides
FIGURE 2. Retrosynthesis of the spirooxindole scaffold 2.
in the indole moiety, making it particularly attractive for the
preparation of compound libraries for biological screenings.9
Results and Discussion
Our approach is depicted in Figure 2. We planned to con-
struct the spirooxindole 2 by an intramolecular R-arylation
of the intermediate o-haloanilide 3. This intermediate would
be prepared from carboxylic acids 4 and anilines 5 by amide
formation. This method is particularly attractive, because
many derivatives of both educts (anilines 5 and carboxylic
acids 4) are commercially available or can be synthesized
with limited efforts for more complex derivatives.10
(8) (a) Dounay, A. B.; Overman, L. E. Chem. Rev. 2003, 103, 2945.
(b) Madin, A.; O’Donnell, C. J.; Oh, T.; Old, D. W.; Overman, L. E.; Sharp,
M. J. J. Am. Chem. Soc. 2005, 127, 18054.
(9) Overman, L. E.; Rosen, M. D. Angew. Chem., Int. Ed. 2000, 39, 4596.
For recent alternative diversity-oriented approaches to spirooxindoles see:
(a) Wang, H.; Ganesan, A. J. Org. Chem. 2000, 65, 4685. (b) Lo, M. M. C.;
Neumann, C. S.; Nagayama, S.; Perlstein, E. O.; Schreiber, S. L. J. Am.
Chem. Soc. 2004, 126, 16077. (c) Onishi, T.; Sebahar, P. R.; Williams, R. M.
Tetrahedron 2004, 60, 9503. (d) Murphy, J. A.; Tripoli, R.; Khan, T. A.; Mali,
U. W. Org. Lett. 2005, 7, 3287. (e) Trost, B. M.; Brennan, M. K. Org. Lett.
2006, 8, 2027. (f) Marsden, S. P.; Watson, E. L.; Raw, S. A. Org. Lett. 2008,
10, 2905. (g) Ruck, R. T.; Huffman, M. A.; Kim, M. M.; Shevlin, M.;
Kandur, W. V.; Davies, I. W. Angew. Chem., Int. Ed. 2008, 47, 4711.
(h) Chen, X. H.; Wei, Q.; Luo, S. W.; Xiao, H.; Gong, L. Z. J. Am. Chem.
Soc. 2009, 131, 13819. (i) Liang, B.; Kalidindi, S.; Porco, J. A.; Stephenson,
C. R. J. Org. Lett. 2010, 12, 572. (j) Hari, G. S.; Lee, Y. R. Synthesis 2010, 453.
(k) Jiang, K.; Jia, Z.-J.; Yin, X.; Wu, L.; Chen, Y.-C. Org. Lett. 2010, 12,
2766.
(11) Shaughnessy, K. H.; Hamann, B. C.; Hartwig, J. F. J. Org. Chem.
1998, 63, 6546. Review: Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res. 2003,
36, 234. For pioneering studies on Pd-catalyzed arylations of carbonyl
compounds, see: Khan, F. A.; Czerwonka, R.; Reissig, H.-U. Synlett 1996,
533. For recent applications, see: (a) Lee, S.; Hartwig, J. F. J. Org. Chem.
2001, 66, 3402. (b) Glorius, F.; Altenhoff, G.; Goddard, R.; Lehmann, C.
Chem. Commun. 2002, 2704. (c) Zhang, T. Y.; Zhang, H. B. Tetrahedron Lett.
€
2002, 43, 193. (d) Kundig, E. P.; Seidel, T. M.; Jia, Y.-X.; Bernardinelli, G.
Angew. Chem., Int. Ed. 2007, 46, 8484. (e) Hillgren, J. M.; Marsden, S. P.
J. Org. Chem. 2008, 73, 6459. (f) Jia, Y.-X.; Hillgren, J. M.; Watson, E. L.;
€
Marsden, S. P.; Kundig, E. P. Chem. Commun. 2008, 4040. (g) Wurtz, S.;
Lohre, C.; Frohlich, R.; Bergander, K.; Glorius, F. J. Am. Chem. Soc. 2009,
€
€
(10) Deppermann, N.; Prenzel, A. H. G. P.; Beitat, A.; Maison, W. J. Org.
Chem. 2009, 74, 4267.
131, 8344.
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TABLE 1. Evaluation of Reaction Scope and Conditions
methyl in 9c, 9d, and 9f) here. N-Alkyl and N-benzyl groups
are generally well tolerated, but the conversion of the SEM-
protected anilide 9a using the above-mentioned conditions
(Pd(PCy3)2 in dioxane, 55 °C) did not give the desired
spirooxindole 10a.12 The same is true for conversions of
nipecotic acid derivatives like 9e or cyclohexyl carboxamides
like 9f under the same conditions.
However, switching the solvent to toluene and increasing
the temperature improves the situation, and a good yield of
spirooxindole 10a was obtained upon conversion of anilide
9a with Pd(PCy3)2. The best results gave the [Pd]-PEPPSI-
catalyst13 in toluene at 110 °C. This catalytic system has been
reported previously to give excellent results for the R-aryla-
tion of sterically hindered substrates by Hartwig and Lee.11a
Using these improved conditions, even SEM-protected ani-
lides like 9a, sterically hindered and functionalized deriva-
tives of cyclohexane carboxamides like 9f, or heterocycles
like 9e gave the corresponding spirooxindoles 10 in good
yields.
According to the retrosynthesis in Figure 2, the R-aryla-
tion of anilides was applied to a short total synthesis of (()-
horsfiline 1. This spirooxindole was first isolated from the
malaysian tree Horsfieldia superba in 1991 by Bodo and co-
workers.14 It has been used frequently as a model compound
to demonstrate the power of novel methodology in natural
product synthesis, and a number of syntheses have been
reported.15
We started with the commercially available Cbz-protected
pyrollidine-2-carboxylic acid 12, which was coupled to the
anilide 7c with PCl5 to give 13 in good yield (Scheme 2).16 The
R-arylation of 13 with the [Pd]-PEPPSI-catalyst system at
110 °C gave spirooxindole 14 in excellent yield. Conversion
of the starting material was complete, and no dehalogenation
was observed. Spirooxindole 14 is a known precursor for
horsfiline.15 With a slight modification of a known pro-
cedure15e we have been able to convert Cbz-protected 14 to
(13) Shore, G.; Morin, S.; Mallik, D.; Organ, M. G. Chem.-Eur. J. 2008,
14, 1351.
(14) Jossang, A.; Jossang, P.; Hadi, H. A.; Sevenet, T.; Bodo, B. J. Org.
Chem. 1991, 56, 6527.
(15) (a) Jones, K.; Wilkinson, J. J. Chem. Soc., Chem. Commun. 1992,
1767. (b) Bascop, S. I.; Sapi, J.; Laronze, J. Y.; Levy, J. Heterocycles 1994, 38,
725. (c) Pellegrini, C.; Strassler, C.; Weber, M.; Borschberg, H. J. Tetrahe-
dron: Asymmetry 1994, 5, 1979. (d) Palmisano, G.; Annunziata, R.; Papeo,
G.; Sisti, M. Tetrahedron: Asymmetry 1996, 7, 1. (e) Lakshmaiah, G.;
Kawabata, T.; Shang, M. H.; Fuji, K. J. Org. Chem. 1999, 64, 1699.
(f) Fischer, C.; Meyers, C.; Carreira, E. M. Helv. Chim. Acta 2000, 83, 1175.
(g) Cravotto, G.; Giovenzani, G. B.; Pilati, T.; Sisti, M.; Palmisano, G. J.
Org. Chem. 2001, 66, 8447. (h) Kumar, U. K. S.; Illa, H.; Junjappa, H. Org.
Lett. 2001, 3, 4193. (i) Lizos, D.; Tripoli, R.; Murphy, J. A. Chem. Commun.
2001, 2732. (j) Selvakumar, N.; Azhagan, A. M.; Srinivas, D.; Krishna, G. G.
Tetrahedron Lett. 2002, 43, 9175. (k) Lizos, D. E.; Murphy, J. A. Org. Biomol.
Chem. 2003, 1, 117. (l) Chang, M. Y.; Pai, C.-L.; Kung, Y.-H. Tetrahedron
Lett. 2005, 46, 8463. (m) Murphy, J. A.; Tripoli, R.; Khan, T. A.; Mali, U. W.
Org. Lett. 2005, 7, 3287. (n) Trost, B. M.; Brennan, M. K. Org. Lett. 2006, 8,
2027. (o) Jaegli, S.; Vors, J. P.; Neuville, L.; Zhu, J. P. Synlett 2009, 2997.
(p) Reddy, V. J.; Douglas, C. J. Org. Lett. 2010, 12, 952. (q) Thomson, J. E.;
Kyle, A. F.; Ling, K. B.; Smith, S. R.; Slawin, A. M. Z.; Smith, A. D.
Tetrahedron 2010, 66, 3801.
aEstimated amount, determined from the 1H NMR of the crude
product. b1:1 mixture of two diastereomers.
11. The reaction works for aryliodides like I-9c and arylbro-
mides like Br-9c or 9d, the latter giving less debromination as
a side reaction. In consequence, we have used arylbromides
for following conversions.
The nature of the second nitrogen substituent of the
anilide is of crucial importance, because for most natural
products this position is unsubstituted, and it would thus be
necessary to introduce suitable protecting groups (instead of
(16) It is remarkable that anilide 13 shows a double set of signals in 1H and
13C NMR spectra due to the presence of two diastereomers. The barrier to
rotation around the aryl-N-bond is unusually high for an o-bromoanilide.
No coalescence was observed in DMSO up to 120 °C by NMR. For
comparison to similar substances, see: (a) Siddall, T. H.; Stewart, W. E.
J. Org. Chem. 1968, 34, 2927. (b) Curran, D. P.; Hale, G. R.; Geib, S. J.;
Balog, A.; Cass, Q. B.; Degani, A. L. G.; Hernandes, M. Z.; Freitas, L. C. G.
Tetrahedron: Asymmetry 1997, 8, 3955. (c) Ahmed, A.; Bragg, R. A.;
Clayden, J.; Lai, L. W.; McCarthy, C.; Pink, J. H.; Westlund, N.; Yasin,
S. A. Tetrahedron 1998, 54, 13277.
(12) The reason for the slow and sluggish reactions with SEM-protected
anilides like 9a under these conditions is unclear. In contrast to methyl- and
benzyl-substituted anilides (nearly exclusively syn), we noticed a high per-
centage of the anti-anilide rotamer (∼30%) for compound 9a. This rotamer is
unproductive for the cyclization. In addition, a number of side products were
observed for the conversions of SEM-protected substrates. This might be due
to a high reactivity of the aminal CH2 group in the SEM protecting group.
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SCHEME 2. Total Synthesis of Horsfiline 1
HCl or satd NaHSO4 solution, satd Na2CO3 or NaHCO3
solution, and brine, dried over Na2SO4 ,and filtered. The solvent
was distilled off, and the crude product was purified by flash
chromatography.
General Procedure B: Amide Formation from Acid Chlorides.
To a cooled solution of 1 equiv of the carboxylic acid chloride in
abs THF was added dropwise 1 equiv of DIEA followed by a
solution of 1 equiv of the aniline derivative in abs THF. The mix-
ture was stirred at rt while the reaction was monitored via TLC.
After completion, the reaction was quenched with water and
extracted with CH2Cl2 three times. The combined organic
phases were washed with brine, then dried over Na2SO4, and
filtered. The solvent was distilled off, and the crude product was
purified by flash chromatography.
General Procedure C: Preparation of N-Methyl-anilides. To a
cooled solution of 1 equiv of the anilide in abs THF was added
1.5 equiv of NaH (60% in mineral oil) under nitrogen atmo-
sphere. After 1 h approximately 10 equiv of MeI was added
dropwise. The mixture was stirred at rt while the reaction was
monitored via TLC. After completion, the reaction was quenc-
hed with water and extracted with CH2Cl2 three times. The
combined organic phases were washed with brine, then dried
over Na2SO4, and filtered. The solvent was distilled off, and the
crude product was purified by flash chromatography.
General Procedure D: Preparation of N-SEM Protected Ani-
lides. To a cooled solution of 1 equiv of the anilide in abs THF
was added 1.5 equiv of NaH (60% in mineral oil) under nitrogen
atmosphere. After 1 h approximately 1.5-3.0 equiv of SEM-
chloride was added dropwise. The mixture was stirred at rt while
the reaction was monitored via TLC. After completion, the re-
action was quenched with water and extracted with CH2Cl2
three times. The combined organic phases were washed with
brine, then dried over Na2SO4, and filtered. The solvent was
distilled off, and the crude product was purified by flash
chromatography.
General Procedure E: Pd-Catalyzed r-Arylation. Catalyst (10
mol %) and 3 equiv freshly prepared NaOt-Bu were dissolved
in freshly dried solvent under argon in a Schlenck flask. The
o-haloanilide was dissolved in a second flask in dry solvent and
was added to the catalyst solution through a syringe. The flask
was sealed carefully, and the solution was stirred at the denoted
temperature and time. It was quenched with saturated aqueous
NH4Cl solution and extracted with CH2Cl2 three times. The
combined organic phases were washed with brine, then dried
over Na2SO4, and filtered. The solvent was distilled off, and the
crude product was purified by flash chromatography.
o-Bromoanilide 8a. According to general procedure B, 0.33 g
(2.49 mmol) of cyclopentane carboxylic acid chloride 6 was
treated with 0.43 mL of DIEA and 0.50 g of o-bromoaniline 7a
(2.49 mmol) in 10 mL of abs THF. The title compound was
obtained as a colorless oil after flash chromatography (EtOAc/
Cyclohexane 1:15) in 0.66 g (89%) yield. 1H NMR (CDCl3, 400
MHz, δ) 8.13 (d, J = 2.8 Hz, 1H), 7.68 (broad, 1H), 7.37 (d, J =
8.9 Hz, 1H), 6.54 (dd, J = 8.8 Hz, 4.0 Hz, 1H), 3.80 (s, 3H), 2.78
(quin., J = 8.1 Hz, 1H), 1.95-2.04 (m, 2H), 1.84-1.94 (m, 2H),
1.74-1.84 (m, 2H), 1.60-1.70 (m, 2H); 13C NMR (CDCl3, 100
MHz, δ) 174.9, 159.8, 136.8, 132.3, 112.0, 106.4, 103.4, 55.7,
47.4, 30.6, 26.1 ppm; mp 95 °C; HRMS-EI (m/z) [M]þ calcd for
C13H16BrNO2 297.0359, found 297.0367.
o-Iodoanilide I-8c. To a cooled solution of 0.40 g (3.50 mmol)
of cyclopentane carboxylic acid in abs Et2O was added 0.73 g
(3.50 mmol) of PCl5 under nitrogen atmosphere. After 1 h the
solvent was distilled off, and the residue was dissolved in
benzene. A solution of 0.77 g (3.50 mmol) of o-iodoaniline in
abs Et2O was added dropwise. The mixture was stirred at rt
while the reaction was monitored via TLC. After completion,
the reaction was quenched with water and extracted with
CH2Cl2 three times. The combined organic phases were washed
N-Bn-horsfiline 15 by Cbz-deprotection and reductive ami-
nation with paraformaldehyde in one step. We have not been
able to deprotect Cbz and Bn in 14 simultaneously as sug-
gested by Kung.15l Even increasing the hydrogen pressure up
to 20 bar does not permit the cleavage of the N-benzyl amide.
Instead, unwanted side reactions such as ring opening of the
spirocycle 14 were observed.
However, a two-step procedure with a final deprotection
of 15 with Li/NH3 following a protocol of Fuji15e gave
horsfiline 1. The overall yield for the four-step total synthesis
of the natural product 1 is 58%. To the best of our knowledge
this is the shortest synthesis of horsfiline 1 reported.
Conclusion
In summary, we have applied the intramolecular Pd-
catalyzed R-arylation of anilides to the synthesis of 3,30-
pyrrolidinyl-spirooxindoles. The [Pd]-PEPPSI-catalyst sys-
tem was found to be the best choice for conversion of
functionalized heterocyclic derivatives. The methodology is
valuable for the synthesis of spirooxindole natural products
as has been demonstrated with the synthesis of (()-horsfiline
1. More complex spirooxindoles should also be accessible,
and these applications are under investigation in our group.
In addition, we are currently using this approach for the
construction of solid-supported spirooxindole libraries for
screening purposes.
Experimental Section
General Procedure A: Amide Formation with PCl5. To a
cooled solution of 1 equiv of the carboxylic acid in abs THF
was added 0.9-1.0 equiv of PCl5 under nitrogen atmosphere.
After 1 h the solvent was distilled off, and the residue was
coevaporated twice with abs THF. Solvent was added again,
and first 1.0-1.2 equiv of DIEA or TEA followed by a solution
of 1.0-1.2 equiv of the aniline derivative in abs THF was added
dropwise. The mixture was stirred at rt while the reaction was
monitored via TLC. After completion, the reaction was
quenched with water and extracted with CH2Cl2 three times.
The combined organic phases were washed with aqueous 1 M
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JOCArticle
with brine, dried over Na2SO4, and filtered. Evaporation of the
solvent gave 0.56 g of o-iodoanilide I-8c (1.78 mmol) as a color-
less foam. The crude product was used in the next step without
further purification.
N-Methyl-o-iodoanilide I-9c. According to general procedure
A, 0.20 g (0.68 mmol) of the title compound was obtained from
0.48 g (1.51 mmol) of o-iodoanilide I-8c, 0.06 g of NaH (1.50
mmol, dispersion in mineral oil), and 0.14 mL of MeI (2.24
mmol) in 40% yield as a colorless solid that was purified by flash
chromatography (MeOH/CH2Cl2 1:15). 1H NMR (CDCl3, 400
MHz, δ)7.93 (dd, J = 1.5 Hz, 1.5 Hz, 1H), 7.41 (dddd, J = 7.9
Hz, 7.6 Hz, 1.5 Hz, 1.2 Hz, 1H), 7.24 (dd, J = 7.8 Hz, 1.3 Hz,
1H), 7.07 (ddd, J = 7,0 Hz, 7.6 Hz, 1.5 Hz, 1H), 3.17 (s, 3H), 2.30
(quin., J = 8.4 Hz, 1H), 1.91-1.99 (m, 1H), 1.63-1.75 (m, 4H),
1.52-1.59 (m, 1H) 1.36-1.44 (m, 2H); 13C NMR (CDCl3, 100
MHz, δ) 176.8, 146.6, 140.2, 129.9, 129.7, 129.4, 100.3, 42.7,
36.2, 31.8, 30.9, 26.3 ppm; mp 108 °C; HRMS-ES (m/z) [M þ
Na]þ calcd for C13H16INONa 352.0169, found 352.0165. Ele-
mental analysis: calcd C 47.43%, H 4.90%, N 4.26%, found C
47.48%, H 4.99%, N 4.32%.
N-Methyl-o-bromoanilide 9d. According to general procedure
B, 0.30 g (0.95 mmol) of N-methyl-o-bromoanilide 9d was
obtained from 0.41 g (1.38 mmol) of o-bromoanilide 8a, 0.08 g
of NaH (2.8 mmol, dispersion in mineral oil), and 2.0 g of MeI
(13.8 mmol) in 69% yield as a colorless solid that was purified by
flash chromatography (EtOAc/Cyclohexane 1:10). Mp 57 °C;
1H NMR (CDCl3, 400 MHz, δ) 7.52-7.55 (m, 1, J = 7.6 Hz);
13C NMR (CDCl3, 100 MHz, δ) 176.9, 159.9, 143.8, 134.1,
115.8, 115.4, 113.9, 55.8, 42.4, 36.0, 31.6, 30.8, 26.3 ppm;
HRMS-EI (m/z) [M þ Na]þ calcd for C14H18BrNO2Na
334.0413, found 334.0406.
N-Benzyl-o-bromoanilide 9e. The title compound was pre-
pared according to general procedure A from 0.30 g of Boc-
nipecotic acid (1.31 mmol) and 0.46 g of aniline 7b. The crude
product was purified by column chromatography (PE/EtOAc
3:1) to give 0.30 g of 9e (45% yield). 1H NMR (CDCl3, 400 MHz,
δ) 7.56 (d, J = 6.8 Hz, 1H), 7.17-7.23 (m, 5H), 6.79 (dd, J = 3.0
Hz, 9.2 Hz, 1H), 6.24 (d, J = 3.4 Hz, 1H), 5.64 (d, J = 13.9 Hz,
1H), 4.01-4.12 (m, 2H), 3.96 (d, J = 15.0 Hz 1H), 3.58 (s, 3H),
2.54 (dt, J = 2.8 Hz, 13.2 Hz, 1H), 2.43 (dt, J = 3.0 Hz, 13.6 Hz,
1H), 2.13 (tt, J = 3.0 Hz, 11.2 Hz, 1H), 1.82-1.93 (m, 2H),
1.63-1.78 (m, 2H), 1.44 (s, 9H). 13C NMR (CDCl3, 100 MHz, δ)
174.6, 159.3, 154.8, 141.2, 137.2, 34.1, 129.4, 128.5, 127.7, 116.7,
115.9, 114.3, 79.6, 55.6, 51.5, 43.1, 40.4, 29.2, 28.6, 28.0 ppm;
HRMS-EI (m/z) [M þ Na]þ calcd for C25H31BrN2O4 525.1365,
found 525.1366.
N-Methyl-o-bromoanilide 9f. According to general procedure
B, 0.67 g (2.05 mmol) of o-bromoanilide 8f was treated with 180
mg of NaH (14.5 mmol, 60% dispersion in mineral oil) and 1.3
mL (20.8 mmol) of MeI. The resulting crude product was stirred
in 20 mL of 2 N aqueous NaOH/THF at rt for 2 h, and the
solution was acidified to pH 1 and extracted three times with
CH2Cl2. The combined organics were washed with H2O and
dried, and the solvent was distilled off in vacuo to give a crude
product that was crystallized from EtOAc/PE to give 0.59 g
(1.73 mmol) of the carboxylic acid (84% yield). 1H NMR
(DMSO-d6, 400 MHz, mixture of rotamers and conformers, δ)
7.27-7.92 (m, 4H), 2.61-2.62 (m, 3H), 2.04-2.51 (m, 2H),
1.07-1.89 (m, 8H); 13C NMR (CDCl3, 100 MHz, δ) 175.2,
173.2, 172.8, 142.5, 142.1, 133.8, 132.8, 130.6, 129.9, 129.3, 129.1,
122.3, 42.5, 37.8, 37.7, 35.8, 26.0, 24.2, 21.2 ppm; mp 120 °C;
HRMS-ES (m/z) [M]- calcd for C15H18BrNO3 338.0397, found
338.0395.
o-Bromoanilide Br-8c. According to general procedure A,
0.39 g (1.46 mmol) of o-bromoanilide Br-8c was obtained from
0.73 g (6.40 mmol) of cyclopentane carboxylic acid, 0.74 mL of
TEA (6.73 mmol), and 1.16 g (6.74 mmol) of o-bromoaniline in
23% yield as a colorless wax that was purified by flash chroma-
tography (EtOAc/Cyclohexane 1:15). 1H NMR (CDCl3, 600
MHz, δ) 8.38 (d, J = 8.0 Hz, 1H), 7.68 (broad, 1H), 7.52 (d, J =
7.9 Hz, 1H), 7.30 (t, J = 7.7 Hz, 1H), 6.96 (t, J = 7.7 Hz, 1H),
2.78 (quin., J = 8.1 Hz, 1H), 1.97-2.03 (m, 2H), 1.89-1.95 (m,
2H), 1.77-1.83 (m, 2H), 1.62-1.69 (m, 2H); 13C NMR (CDCl3,
100 MHz, δ) 174.4, 136.1, 132.4, 128.5, 125.0, 122.0, 113.4, 47.4,
30.7, 26.2 ppm; HRMS-EI (m/z) [M]þ calcd for C12H14BrNO
267.0259 found 267.0256.
o-Bromoanilide 8f. In a round-bottom flask, 0.50 g (9.23 mmol)
of cyclohexane dicarboxylic acid anhydride and 1.60 g (9.23 mmol)
of o-bromoaniline were stirred in 20 mL of toluene for 48 h. The
reaction mixture was filtered, and the precipitated product was
washed with toluene and dried in vacuo. o-Bromoanilide 8f was
obtained in 71% yield (0.75 g, 2.30 mmol) as a colorless solid. 1H
NMR (DMSO-d6, 400 MHz, δ) 12.1 (s, 1H), 9.31 (broad, 1H),
7.74 (d, J = 8.1 Hz, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.44 (t, J =
7.8 Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H), 3.12 (broad, 1H), 2.78
(broad, 1H), 2.12-2.24 (m, 2H), 1.45-1.88 (m, 6H); 13C NMR
(CDCl3, 100 MHz, δ) 175.1, 172.6, 136.4, 132.5, 127.8, 126.9,
126.7, 117.9, 42.9, 41.9, 27.3, 25.4, 23.8, 22.6 ppm; mp 172 °C;
HRMS-ES (m/z) [M]- calcd for C14H15BrNO2, 324.0241, found
324.0248.
N-SEM-Protected o-Bromoanilide 9a. According to general
procedure D, 0.25 g (0.57 mmol) of o-bromoanilide 9a was
obtained from 0.32 g (1.07 mmol) of o-bromoanilide 8a in 53%
yield as a colorless oil that was purified by flash chromatogra-
phy (EtOAc/Cyclohexane 1:10). 1H NMR (CDCl3, 400 MHz, δ)
7.52-7.54 (m, 1H), 6.81-6.83 (m, 2H), 5.62 (d, J = 10.4 Hz,
1H), 4.41 (d, J = 10.4 Hz, 1H), 3.80 (s, 3H), 3.60-3.69 (m, 2H),
2.37-2.41 (m, 1H), 1.89-1.96 (m, 1H), 1.60-1.73 (m, 5H),
1.37-1.43 (m, 2H), 0.90-0.99 (m, 2H), 0.00 (s, 9H); 13C NMR
(CDCl3, 100 MHz, δ) 177.8, 159.6, 141.3, 133.7, 117.7, 115.3,
114.3, 76.0, 66.2, 55.8, 42.7, 32.0, 30.4, 26.4, 18.3, -1.4 ppm;
HRMS-EI (m/z) [M]þ calcd for C19H30BrNO3Si 427.1178,
found 427.1177.
N-Benzyl-o-bromoanilide 9b. According to general procedure
B, 0.33 g (2.49 mmol) of cyclopentane carboxylic acid chloride 6
was treated with 0.43 mL of DIEA and 0.72 g of o-bromoaniline
7b (2.49 mmol) in 10 mL of abs THF. The title compound was
obtained as a colorless oil after flash chromatography (EtOAc/
1
PE 1:8) in 0.81 g (84%) yield. H NMR (CDCl3, 400 MHz, δ)
7.52 (d, J = 8.3 Hz, 1J = 9.1 Hz, 3.3 Hz, J = 14.0 Hz, J = 14.4
Hz); 13C NMR (CDCl3, 100 MHz, δ) 176.8, 159.2, 141.7 ppm;
HRMS-ES (m/z) [M þ Na]þ calcd for C20H22BrNO2Na
410.0726, found 410.0727.
N-Methyl-o-bromoanilide Br-9c. According to general proce-
dure B, 0.18 g (0.64 mmol) of N-methyl-o-bromoanilide 9c was
obtained from 0.24 g (0.90 mmol) of o-bromoanilide Br-8c, 0.04
g of NaH (1.80 mmol, dispersion in mineral oil), and 0.13 mL of
MeI (2.08 mmol) in 71% yield as a colorless solid that was
purified by flash chromatography (EtOAc/Cyclohexane 1:10).
1H NMR (CDCl3, 400 MHz, δ) 7.67 (dd, J = 7.9 Hz, 1.3 Hz,
1H), 7.37 (dt, J = 7.5 Hz, 1.4 Hz, 1H), 7.21-7.27 (m, 2H), 3.18
(s, 3H), 2.33 (quin., J = 8.2 Hz, 1H), 1.85-1.91 (m, 1H),
1.61-1.75 (m, 4H), 1.53-1.60 (m, 1H), 1.34-1.42 (m, 2H);
13C NMR (CDCl3, 100 MHz, δ) 176.9, 143.2, 133.9, 130.3,
129.7, 128.9, 123.9, 42.4, 36.1, 31.5, 30.7, 26.3, 26.2 ppm; mp 71
°C; HRMS-ES (m/z) [M þ Na]þ calcd for C13H16BrNONa
304.0307, found 304.0309.
Under nitrogen atmosphere, 0.42 g (1.23 mmol) of this
carboxylic acid was stirred with 0.35 g (1.62 mmol) of Boc2O
and 46 mg (0.37 mmol) of DMAP in 30 mL of t-BuOH at rt.
After 12 h the mixture was diluted with EtOAc and washed with
1 M NaOH and 1 M HCl each three times. After flash chroma-
tography with EtOAc/PE 1:5, 150 mg (0.38 mmol) of the title
compound 9f was obtained as a colorless wax in 31% yield. 1H
NMR (CDCl3, 400 MHz, mixture of isomers, δ) 7.00-7.70
(m, 4H), 2.14-3.37 (m, 5H), 0.75-2.00 (m, 17H); HRMS-ES
5998 J. Org. Chem. Vol. 75, No. 17, 2010

Deppermann et al.
JOCArticle
(m/z) [M þ Na]þ calcd for C19H26BrNO3Na 418.0994, found
418.0985.
Spirooxindole 10e. The title compound was prepared accord-
ing to general procedure E, from 50 mg (0.10 mmol) of o-bromo-
anilide 9e; 71% of the spirooxindole 10e and 17% of the deha-
N-Benzyl-o-bromoanilide 9g. According to general procedure
B, 0.59 g (1.47 mmol) of o-bromoanilide 9g was obtained from
0.30 g (2.05 mmol) of cyclohexane carboxylic acid chloride, 0.60 g
(2.05 mmol) of N-benzyl-o-bromo-aniline 7b, and 0.36 mL of
DIEA (2.12 mmol) in 72% yield as a colorless solid that was
purified by flash chromatography (EtOAc/PE 1:10). 1H NMR
(CDCl3, 400 MHz, δ) 7.54 (d, J = 8.8 Hz, 1H), 7.16-7.27 (m,
5H), 6.76 (dd, J = 8.8 Hz, 2.8 Hz, 1H), 6.23 (d, J = 2.8 Hz, 1H),
5.65 (d, J = 14.4 Hz, 1H), 3.91 (d, J = 14.4 Hz, 1H), 3.56 (s, 3H),
1
logenated side product 11e were obtained. H NMR (CDCl3,
400 MHz, δ) 7.18-7.32 (m, 6H), 6.51 (dd, J = 2.4 Hz, 8.2 Hz,
1H), 6.33 (d, J = 2.4, 1H), 4.87 (s, 2H), 3.86-3.93 (m, 2H), 3.72
(s, 3H), 1.72-1.79 (m, 4H), 1.50 (s, 9H); 13C NMR (CDCl3, 101
MHz, δ) 180.4, 160.1, 155.2, 143.3, 135.9, 129.0, 127.8, 127.3,
126.0, 124.0, 106.1, 97.6, 79.8, 55.5, 43.6, 39.5, 38.8, 33.1, 28.6
ppm; HRMS-EI (m/z) [M þ Na]þ calcd for C25H30N2O4
445.2098, found 445.2091.
1.94-2.00 (m, 1H), 1.42-1.85 (m, 6H), 0.89-1.22 (m, 2H); 13
C
Dehalogenated Side Product 11e. 1H NMR (CDCl3, 400 MHz,
δ) 7.15-7.27 (m, 6H), 6.85 (dd, J = 2.3 Hz, 8.4 Hz, 1H), 6.55 (d,
J = 6.9 Hz, 1H), 6.46 (t, J = 2.3 Hz, 1H), 4.84 (s, 2H), 4.03 (d,
J = 13.5 Hz, 2H), 3.71 (s, 3H), 2.45 (t, J = 12.7 Hz, 2H), 2.35 (tt,
J = 3.6 Hz, 1H), 1.76 (dddd, J = 6.5 Hz, 12.7 Hz, 2H), 1.57-
1.61 (m, 2H), 1.43 (s, 9H).; 13C NMR (CDCl3, 101 MHz, δ)
174.6, 160.5, 154.8, 143.4, 137.8, 130.4, 128.9, 128.5, 127.5, 120.6,
114.3, 113.7, 79.6, 55.5, 53.1, 43.1, 39.8, 28.7, 28.5 ppm; HRMS-
EI (m/z) [M þ Na]þ calcd for C25H32N2O4 447.2254, found
447.2232.
NMR (CDCl3, 100 MHz, δ) 176.4, 159.4, 141.5, 137.8, 133.9,
129.5, 128.5, 127.5, 116.7, 115.7, 114.3, 55.5, 51.1, 42.4, 30.5,
28.9, 25.9, 25.3 ppm; mp 119 °C; HRMS-ES (m/z) [M þ Na]þ
calcd for C21H24BrNO2Na 424.0883, found 424.0880. Elemen-
tal analysis: calcd C 62.69%, H 6.01%, N 3.48%, found C
62.33%, H 5.86%, N 3.41%.
Spirooxindole 10c. According to general procedure E, 45 mg
(0.14 mmol) of N-methyl-o-iodoanilide I-9c was treated with
Pd(PCy3)2 and NaOt-Bu in dioxane for 4 d at 55 °C; 66% of
spirooxindole 10c and 34% dehalogenated side product 11c
were isolated. 1H NMR (CDCl3, 400 MHz, δ) 7.24 (dt, J = 7.5 Hz,
1.2 Hz, 1; 13CNMR (CDCl3, 100 MHz, δ) 182.1, 143.1, 137.0 ppm;
HRMS-EI (m/z) [M]þ calcd for C13H15NO 201.1154, found
201.1152.
Spirooxindole 10f. According to general procedure E, 40 mg
(0.10 mmol) of N-methyl-o-bromoanilide 9f was reacted with
i-Pr-PEPPSI and NaOt-Bu in toluene for 12 h at 77 °C. The
crude product was purified by HPLC (chromolith RP18, 3 mm ꢀ
100 mm, MeCN 20% to 60% in H2O over 30 min). A fast and a
slow fraction corresponding to the two diastereomers of 10f
Dehalogenated Side Product 11c. 1H NMR (CDCl3, 400 MHz,
δ) 7.36-7.43(m, 2H), 7.31-7.33 (m, 1H), 7.17-7.20 (m, 2H), 3.26
(s, 3H), 2.54 (quin, J = 8.1 Hz, 1H), 1.55-1.83 (m, 7H), 1.34-
1.42 (m, 1H); 13C NMR (CDCl3, 100 MHz, δ) 144.6, 129.8, 127.7,
127.6, 42.0, 37.7, 31.3, 26.3 ppm.
Spirocyclization of N-Methyl-o-bromoanilide Br-9c. Accord-
ing to general procedure E, 45 mg (0.16 mmol) of N-methyl-o-
bromoanilide Br-9c was treated with Pd(PCy3)2 and NaOt-Bu in
dioxane for 4 d at 55 °C; 77% of the spirooxindole 10c and 23%
of the dehalogenated product 11c were isolated.
Spirooxindole 10d. According to general procedure E, 70 mg
(0.22 mmol) of N-methyl-o-bromoanilide 9d was treated with
Pd(PCy3)2 and NaOt-Bu in dioxane for 4 d at 55 °C; 80% of
spirooxindole 10d was isolated after column chromatography.
The crude product contained ∼20% dehalogenated side product
11d, which was not isolated in pure form. 1H NMR (CDCl3, 400
MHz, δ) 7.08 (d, J = 8.4 Hz, 1J = 2.4 Hz, 8.4 Hz, J = 2.0 Hz,
1H), 3.82 (s, 3H), 3.18 (s, 3H), 2.01-2.17 (m, 4H), 1.91-1.99 (m,
2H), 1.76-1.82 (m, 2H); 13C NMR (CDCl3, 101 MHz, δ) 182.7,
159.8, 144.2, 128.9, 123.2, 106.2, 96.1, 55.7, 53.6, 38.7, 26.6, 26.4
ppm; HRMS-EI (m/z) [M þ Na]þ calcd for C14H17NO4 321.1259,
found 321.1243.
Spirooxindole 10a. According to general procedure E, 23 mg
(54 μmol) N-SEM-protected o-bromo-anilide 9a was reacted
with i-Pr-PEPPSI and NaOt-Bu in toluene for 12 h at 110 °C;
83% of spirooxindole 10a and 17% dehalogenated product 11a
were isolated. 1H NMR (CDCl3, 400 MHz, δ) 7.09 (d, J = 8.0
Hz, 1H), 6.63 (d, J = 2.4 Hz, 1H), 6.58 (dd, J = 8.0 Hz, 2.4 Hz,
1H), 5.13 (s, 2H), 3.81 (s, 3H), 3.53-3.57 (m, 2H), 2.09-2.16 (m,
2H), 2.01-2.08 (m, 2H), 1.93-2.00 (m, 2H), 1.79-1.85 (m, 2H),
0.89-0.97 (m, 2H), -0.04 (s, 9H); 13C NMR (CDCl3, 100 MHz,
δ) 183.3, 159.8, 142.5, 128.4, 123.0, 107.7, 96.9, 69.5, 66.0, 55.5,
53.8, 38.9, 26.5, 17.9, -1.3 ppm; HRMS-EI (m/z) [M]þ calcd for
C19H29NO3Si 347.1917, found 347.1925.
1
were collected. Fast fraction (19.3 min, 34% yield): H NMR
(CDCl3, 400 MHz, δ) 7.22 (dt, J = 7.6 Hz, 1.2 Hz, 1H), 7.12 (dd,
J = 7.2 Hz, 1.3 Hz, 1H), 7.02 (dt, J = 7.5 Hz, 0.9 Hz, 1H), 6.78
(d, J = 6.7 Hz, 1H), 3.19 (s, 3H), 2.77 (dd, J = 13.0 Hz, 3.6 Hz,
1H), 2.47-2.58 (m, 1H), 2.20-2.30 (m, 1H), 1.85-2.20 (m, 2H),
1.53-1.70 (m, 4H), 1.07 (s, 9H); 13C NMR (CDCl3, 100 MHz, δ)
178.9, 172.3, 143.5, 134.0, 127.8, 122.2, 121.8, 107.6, 80.4, 51.9,
47.5, 35.8, 28.2, 27.7, 26.1, 25.6, 24.4, 19.9, 18.6 ppm; HRMS-ES
(m/z) [M þ Na]þ calcd for C19H25NO3Na 338.1727, found
338.1729. Slow fraction (19.8 min, 41% yield): 1H NMR
(CDCl3, 400 MHz, δ) 7.71 (dd, J = 7.9 Hz, 1.6 Hz, 1H), 7.65
(dd, J = 8.0 Hz, 1.4 Hz, 1H), 7.42 (dt, J = 7.7 Hz, 1.5 Hz, 1H),
7.21-7.25 (m, 1H), 3.16 (s, 3H), 2.69-2.74 (m, 1H), 2.35-2.42
(m, 1H), 1.78-1.83 (m, 1H), 1.58-1.64 (m, 1H), 1.44 (s, 9H),
1.21-1.26 (m, 4H); 13C NMR (CDCl3, 100 MHz, δ) 175.2,
142.8, 133.8,131.6, 129.6, 128.9, 122.8, 80.0, 46.4, 43.1, 36.4,
29.2, 28.4, 28.2, 25.5 ppm; HRMS-ES (m/z) [M þ Na]þ calcd for
C19H25NO3Na 338.1727, found 338.1731.
N-Benzyl-o-bromoanilide 13. To a cooled solution of 0.30 g
(1.20 mmol) of carboxylic acid 12 in 10 mL of abs THF was
added 0.25 g (1.20 mmol) of PCl5 under nitrogen atmosphere.
After 1 h the solvent was distilled off, and the residue coevapo-
rated twice with 10 mL of abs THF. The resulting solid was dis-
solved in 10 mL of abs THF, and first 0.16 g (1.20 mmol) of
DIEA followed by a solution of 0.34 g (1.20 mmol) of o-
bromoaniline 7c in 10 mL of abs THF was added dropwise.
The mixture was stirred at rt while the reaction was monitored
via TLC. After completion, the reaction was quenched with
water and extracted with CH2Cl2 three times. The combined
organic layers were washed with each 10 mL of aqueous 1 M
HCl, satd Na2CO3 solution, and brine, dried over Na2SO4, and
filtered. The solvent was distilled off, and the crude product was
purified by flash chromatography (hexane/EtOAc 6:4) to give
0.54 g (1 mmol) of o-bromoanilide 13 in 86% yield as a colorless
oil. 1H NMR (CDCl3, 400 MHz, δ) 7.06-7.28 (m, 11H),
6.52-6.638 (m, 2H), 5.39 (dd, J = 15.5 Hz, 1H), 5.00 (m, 2H),
3.89 (dd, J = 12.4 Hz, 1H), 3.72 (s, 3H), 3.50-3.67 (m, 2H),
3.31-3.59 (m, 1H), 3.10-3.20 (m, 1H), 2.62-2.69 (m, 1H),
1.87-1.97 (m, 2H); 13C NMR (CDCl3, 100 MHz, δ) 172.7,
159.9, 154.5, 136.9, 136.8, 136.7, 131.4, 129.3, 128.4, 127.9,
127.6, 124.4, 119.0, 114.1, 66.7, 55.8, 51.9, 49.9, 45.7, 41.9,
Dehalogenated Side Product 11a. 1H NMR (CDCl3, 400 MHz,
δ) 7.30 (t, J = 8.0 Hz, 1H), 6.89 (dd, J = 8.0 Hz, 2.0 Hz, 1H),
6.79-6.83 (m, 1H), 6.75-6.76 (m, 1H), 5.06 (s, 2H), 3.82 (s, 3H),
3.63 (t, J = 8.8 Hz, 2H), 2.59 (quint, J = 7.6 Hz, 1H), 1.62-1.85
(m, 8H), 0.92-0.97 (m, 2H), 0.00 (s, 9H); 13C NMR (CDCl3, 100
MHz, δ) 178.0, 160.4, 143.4, 130.2, 120.9, 114.6, 113.4, 77.5, 65.8,
55.5, 42.4, 31.5, 26.5, 18.3, -1.3 ppm; HRMS-EI (m/z) [M]þ calcd
for C19H31NO3Si 349.2073, found 349.2049.
J. Org. Chem. Vol. 75, No. 17, 2010 5999

Deppermann et al.
JOCArticle
29.2 ppm; HRMS-ES (m/z) [M þ H]þ calcd for C27H26BrN2O4
atmosphere (1 atm). After filtration through Celite and purifi-
cation of the crude product by flash chromatography (CH2Cl2/
MeOH 20:1), 10 mg (0.03 mmol, quant.) of the title compound
15 was obtained as a colorless oil. 1H NMR (CDCl3, 400 MHz,
δ) 7.24-7.38 (m, 5H), 7.08 (d, J= 2.7 Hz, 1H), 6.65 (dd, J=2.6Hz,
6.1 Hz, 1H), 6.57 (d, J = 8.8 Hz, 1H), 4.88 (s, 2H), 3.76 (s, 3H),
3.06-3.11 (m, 1H), 2.86-2.96 (m, 2H), 2.76 (dd, J =7.7 Hz, 8.8 Hz
1H), 2.47 (s, 3H), 2.39-2.44 (m, 1H), 2.08-2.16 (m, 1H); 13C
NMR (CDCl3, 100 MHz, δ); 180.3, 156.5, 137.4, 136.2, 135.5,
128.9, 127.7, 127.4, 112.3, 110.5, 109.2, 66.5, 56.8, 56.1, 53.9,
44.0, 42.0, 38.4 ppm; HRMS-ES (m/z) [MH]þ calcd for C20H23-
N2O2, 323.1754, found 323.1751.
523.1232, found 523.1233.
N-Bn-N-Cbz-Horsfiline 14. i-Pr-PEPPSI (2.6 mg, 0.004 mmol)
and 9.2 mg of freshly prepared NaOt-Bu (0.1 mmol) were
dissolved in 2 mL of abs toluene under argon in a Schlenck flask.
Next, 20 mg (0.04 mmol) of anilide 13 was dissolved in a second
flaskin2 mLof abstoluene and was added tothe catalystsolution
through a syringe. The flask was sealed carefully, and the solution
was stirred for 12 h at reflux. After cooling, the reaction was trea-
ted with saturated aqueous NH4Cl solution and extracted with
CH2Cl2 three times. The combined organic layers were washed
with 10 mL of brine, then dried over Na2SO4, and filtered. The
solvent was distilled off, and the crude product was purified by
flash chromatography (hexane/EtOAc 6:4) to give 13 mg (0.03
(()-Horsfiline 1. According to a literature procedure5 17 mg
(0.05 mmol) of the spirooxindole 15 was added to a solution of
lithium in liquid ammonia at -70 °C. The title compound was
characterized by 1H NMR and 13C NMR and the spectra were
found to be in accordance to the literature data. The molecular
formula was proven by HRMS (ES).
1
mmol, 81%) of the title compound 14. H NMR (CDCl3, 400
MHz, δ) 7.24-7.44 (m, 10H), 6.79 (d, J = 6.2 Hz, 1H), 6.69 (dd,
J = 2.5 Hz, 2.3 Hz, 1H), 6.63 (d, J = 8.6 Hz, 1H), 5.18 (d, J =
16.1 Hz, 2H), 4.90 (s, 2H), 3.78-4.01 (m, 4H), 3.73 (s, 3H),
2.45-2.54 (m, 1H), 2.04-2.17 (m, 1H); 13C NMR (CDCl3, 100
MHz, δ); 177.2, 156.4, 154.8, 135.8, 135.4, 128.9, 128.6, 128.1,
128.0, 127.8, 127.3, 112.5, 110.3, 109.8, 67.1, 55.9, 54.7, 54.3, 45.9,
45.4, 44.0, 36.4, 35.8 ppm; HRMS-ES (m/z) [M þ Na]þ calcd for
C27H26N2O4Na 465.1785, found 465.1773.
Acknowledgment. Support by the DFG is gratefully
acknowledged.
N-Bn-Horsfiline 15. Spirooxindole 14 (13 mg, 0.03 mmol) and
9 mg (0.30 mmol) of paraformaldehyde were treated with a
catalytic amount of 10% Pd/C and stirred under a hydrogen
Supporting Information Available: General experimental
data and NMR spectra for compounds 8-15. This material is
available free of charge via the Internet at http://pubs.acs.org.
6000 J. Org. Chem. Vol. 75, No. 17, 2010