Branch-selective synthesis of oxindole and indene scaffolds: Transition metal-controlled intramolecular aryl amidation leading to C3 reverse-prenylated oxindoles

Article abstract of DOI:10.1021/ol1012372

In an effort to access biologically important scaffolds, a concise branch-selective synthesis of C3 tertiary oxindoles by Cu(I)-catalyzed aryl amidation and 2,2-dimethyl indene by Pd(0)-catalyzed Heck cyclization has been accomplished from acyclic reverse-prenylated intermediates. Oxindole C3-enolate generation using NaH followed by alkylation in the presence of appropriate electrophiles provides a novel route to quaternary C3 reverse-prenylated oxindoles.

Full text of DOI:10.1021/ol1012372

ORGANIC
LETTERS
2010
Vol. 12, No. 16
3594-3597
Branch-Selective Synthesis of Oxindole
and Indene Scaffolds: Transition
Metal-Controlled Intramolecular Aryl
Amidation Leading to C3
Reverse-Prenylated Oxindoles
Vasily A. Ignatenko, Nihal Deligonul, and Rajesh Viswanathan*
Department of Chemistry, Case Western ReserVe UniVersity, CleVeland, Ohio 44106
rajesh.Viswanathan@case.edu
Received May 28, 2010
ABSTRACT
In an effort to access biologically important scaffolds, a concise branch-selective synthesis of C3 tertiary oxindoles by Cu(I)-catalyzed aryl
amidation and 2,2-dimethyl indene by Pd(0)-catalyzed Heck cyclization has been accomplished from acyclic reverse-prenylated intermediates.
Oxindole C3-enolate generation using NaH followed by alkylation in the presence of appropriate electrophiles provides a novel route to quaternary
C3 reverse-prenylated oxindoles.
Direct synthetic access to privileged scaffolds is of crucial
importance in the discovery and development of new drug
candidates. Indole and oxindole scaffolds are common
structural motifs in many therapeutic agents.1-3 Indole
alkaloids, which contain a reverse prenyl group at the C3
position, such as notoamide, roquefortine, amauromine, and
ardeemin, have attracted the attention of the scientific
community because of their significant biological activity.
Nature has produced the welwitindolinone family of alkaloids
that has challenged synthetic chemists by presenting this C3
reverse-prenyl signature embedded in addition to a highly
dense arrangement of rings and functionalities (see Figure
1, reverse prenyl group highlighted).4 Concurrently, the
(4) For ardeemins as a representative example, see: (a) Chou, T.-C.;
Depew, K. M.; Zheng, Y.-H.; Safer, M. L.; Chan, D.; Helfrich, B.; Zatorska,
D.; Zatorski, A.; Bornmann, W.; Danishefsky, S. J. Proc. Natl. Acad. Sci.
U.S.A. 1998, 95, 8369. For selected recent reports on synthetic approaches
towards welwitindolinones, see: (b) Heidebrecht, R. W., Jr.; Gulledge, B.;
Martin, S. F. Org. Lett. 2010, 12, 2492. (c) Brailsford, J. A.; Lauchli, R.;
Shea, K. J. Org. Lett. 2009, 11, 5330. (d) Trost, B. M.; McDougall, P. J.
Org. Lett. 2009, 11, 3782. (e) Tian, X.; Huters, A. D.; Douglas, G. J.; Garg,
N. K. Org. Lett. 2009, 11, 2349. (f) For a potentially biomimetic approach,
see: Richter, J. M.; Ishihara, Y.; Masuda, T.; Whitefield, B. W.; Llamas,
T.; Pohjakallio, A.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 17938. (g)
Brown, L. E.; Konopelski, J. P. Org. Prep. Proced. Int. 2008, 40, 411. (h)
Baran, P. S.; Maimone, T. J.; Richter, J. M. Nature 2007, 446, 404. (I)
MacKay, J. A.; Bishop, R. L.; Rawal, V. H. Org. Lett. 2005, 7, 3421. (j)
For an example of early seminal report, see: Ready, J. M.; Reisman, S. E.;
Hirata, M.; Weiss, M. M.; Tamaki, K.; Ovasaka, T. V.; Wood, J. L. Angew.
Chem., Int. Ed. 2004, 43, 1270. (k) For a recent review, see Gademann,
K.; Portmann, C. Curr. Org. Chem. 2008, 12, 326.
(1) Kochanowska-Karamyan, A. J.; Hamann, M. T. Chem. ReV. 2010,
published ASAP April 9, 2010; DOI: 10.1021/cr900211p
.
(2) de Sa Alves, F. R.; Barreiro, E. J.; Manssour Fraga, C. A. Mini-
ReV.Med. Chem. 2009, 9, 782
.
(3) Galliford, C. V.; Scheidt, K. A. Angew. Chem., Int. Ed. 2007, 46,
8748
.
10.1021/ol1012372  2010 American Chemical Society
Published on Web 07/27/2010

strategies are limited by a narrow substrate scope, low-
yielding protocols, arduous routes, or the use of highly toxic
reagents (e.g., tin or selenium). Few methods exist for the
synthesis of tertiary C3 reverse-prenylated oxindole scaf-
folds.8 Although the corresponding C3 hydroxy product has
been obtained in good yields, additional steps are required
for the construction of complex and diverse C3 quaternary
centers.
With the broad goal of synthesis and evaluation of
biological activity for a series of C3 reverse-prenylated
oxindoles and 2,2-dimethyl indenes, herein we report an
elegant branch-selective syntheses of C3 tertiary oxindoles
6a-e and indene 7 from the key intermediates 5a-l simply
by switching the transition metal catalyst for the correspond-
ing coupling reactions (Scheme 1). Furthermore, the repre-
Figure 1. Representative examples with the highlighted portion
showing a C3 reverse-prenyl scaffold in a prominent or in a cryptic
fashion.
Scheme 1. Divergent Synthetic Route to Reverse-Prenylated
Oxindole (6a-e) and Indene (7) Scaffolds
indene scaffold has been found in selective inhibitors of
aldosterone synthase5 and a series of serotonin receptor
agonists.6
Oxindole derivatives containing a reverse prenyl group at
C3 are challenging synthetic targets. Several approaches have
been developed for the construction of reverse-prenylated
quaternary C3 centers.7 Despite the fact that some of them
were applied to the syntheses of natural products, these
(5) Uimschneider, S.; Muller-Vieira, U.; Klein, C. D.; Antes, I.;
Lengauer, T.; Hartmann, R. W. J. Med. Chem. 2005, 48, 1563.
(6) Alcalde, E.; Mesquida, N.; Lopez-Perez, S.; Frigola, J.; Merce, R.
J. Med. Chem. 2009, 52, 675.
(7) For the construction of reverse-prenylated quaternary C3 centers,
see the following. (a) Olefination followed by a tandem isomerization-Claisen
rearrangement process: Kawasaki, T.; Terashima, R.; Sakaguchi, K.;
Sekiguchi, H.; Sakamoto, M. Tetrahedron Lett. 1996, 37, 7525. (b)
Kawasaki, T.; Nagaoka, M.; Satoh, T.; Okamoto, A.; Ukon, R.; Ogawa, A.
Tetrahedron 2004, 60, 3493. (c) Kawasaki, T.; Shinada, M.; Kamimura,
D.; Ohzono, M.; Ogawa, A. Chem.Commun. 2006, 420. (d) Kawasaki, T.;
Shinada, M.; Kamimura, D.; Ohzono, M.; Ogawa, A.; Terashima, R.;
Sakamoto, M. J. Org. Chem. 2008, 73, 5959. (e) Preactivation of
C3-substituted indoles with N-(phenylseleno)phthalimide followed by
reaction with prenyl tributylstannane: Marsden, S.; Depew, K.; Danishefsky,
S. J. J. Am. Chem. Soc. 1994, 116, 11143. (f) Depew, K.; Marsden, S.;
Zatorska, D.; Zatorski, A.; Bornmann, W.; Danishefsky, S. J. J. Am. Chem.
Soc. 1999, 121, 11953. (g) Chen, W.-C.; Joulie, M. M. Tetrahedron Lett.
1998, 39, 8401. (h) Schiavi, B.; Richard, D. J.; Joulie, M. M. J. Org. Chem.
2002, 67, 620. (i) Richard, D. J.; Schiavi, B.; Joulie, M. M. Proc. Natl.
Acad. Sci. U.S.A. 2004, 101, 11971. (j) Shangguan, N.; Hehre, W. J.;
Ohlinger, W. S.; Beavers, M. P.; Joulie, M. M. J. Am. Chem. Soc. 2008,
130, 6281. (k) Preactivation of C3-substituted indoles with NBS followed
by reaction with prenyl tributylstannane: Fuchs, J. R.; Funk, R. L. Org.
Lett. 2005, 7, 677. (l) Thio-Claisen rearrangement of 2-prenyl thioindole:
Bycroft, B.; Landon, W. Chem.Commun. 1970, 168. (m) Takase, S.; Iwami,
M.; Ando, T.; Okamoto, M.; Yoshida, K.; Horiai, H.; Kohsaka, M.; Aoki,
H.; Imanaka, H. J. Antibiot. 1984, 37, 1320. (n) Takase, S.; Itoh, Y.; Uchida,
I.; Tanaka, H.; Aoki, H. Tetrahedron Lett. 1985, 847. (o) Takase, S.; Itoh,
Y.; Uchida, I.; Tanaka, H.; Aoki, H. Tetrahedron 1986, 42, 5887. (p) Takase,
S.; Uchida, I.; Tanaka, H.; Aoki, H. Tetrahedron 1986, 42, 5879. (q) Bhat,
B.; Harrison, D. Tetrahedron Lett. 1986, 27, 5873. (r) Bhat, B.; Harrison,
D.; Lamony, H. Tetrahedron 1993, 49, 10663. (s) Bhat, B.; Harrison, D.
Tetrahedron 1993, 49, 10655. (t) Grignard reaction of an activated indoline
with prenyl magnesium bromide: Morales-Rios, M.; Suarez-Castillo, O.;
Joseph-Nathan, P. J. Org. Chem. 1999, 64, 1086. (u) Morales-Rios, M.;
Suarez-Castillo, O.; Trujillo-Serrato, J.; Joseph-Nathan, P. J. Org. Chem.
2001, 66, 1186. (v) Addition of prenyl alcohol to 3-chloro iminium ion
followed by Claisen rearrangement: Booker-Milburn, K.; Fedouloff, M.;
Paknoham, S.; Strachan, J.; Melville, J.; Voyle, M. Tetrahedron Lett. 2000,
41, 4657. (w) For the singular report on catalytic enantioselective variant,
see: Linton, E. C.; Kozlowski, M. C. J. Am. Chem. Soc. 2008, 130, 16162.
sentative tertiary C3 reverse-prenylated oxindole 6a has been
shown to easily undergo the amide-enolate alkylation reaction
to furnish quaternary C3 reverse-prenylated oxindoles 8 and
9 (Vide infra).
Substituted phenylacetamides 3a-l were obtained in a
straightforward fashion from commercially available acids,
in good yields by the reaction of the corresponding acid
chlorides (X ) H, Br [1] or I [2]) with an amine in the
presence of DMAP (20 mol %) as a nucleophilic catalyst in
DCM. Use of either pyridine (for 3a-e) or triethylamine
(for 3f-l) as a base proved equally efficacious, while
triethylamine proving superior with aliphatic amine sub-
strates.
(8) For C3 reverse prenylation leading to isatin derivatives, see the
following. (a) Enolate-Claisen rearrangement: Malapel-Andrieu, B.; Piroelle,
S.; Merour, J.-Y. Chem. Res., Synop. 1998, 594. (b) Barbier reaction of
prenylindium reagents with isatin: Nair, V.; Ros, S.; Jayan, C.; Viji, S.
Synthesis 2003, 16, 2542. (c) Transfer hydrogenation reaction of isatin with
1,1-dimethylallene as the prenyl donor: Skucas, E.; Bower, J.; Krische, M.
J. Am. Chem. Soc. 2007, 129, 12678. (d) Grant, C. D.; Krische, M. J. Org.
Lett. 2009, 11, 4485. (e) Itoh, J.; Han, S. B.; Krische, M. J. Angew. Chem.,
Int. Ed. 2009, 48, 6313. (f) For a review on the importance of this structural
scaffold, see: Peddibhotla, S. Curr. Bioact. Compd. 2009, 5, 20.
Org. Lett., Vol. 12, No. 16, 2010
3595

4b-l, however these imidates proved sensitive to storage
and/or to further spectroscopic characterization. The
Meerwein-Eschenmoser Claisen rearrangement under the
contitions attempted caused a deprenylation event as a minor
side reaction that led to formation of amides 3b-l. Amides
3b-l could be isolated from the reaction mixture and
recycled as the starting material for the preparation of
allylimidates 4b-l, thereby rendering further efficiency to
this sequence (Scheme 1). On our way to tertiary C3 reverse-
prenylated oxindoles 6a-e, we focused on copper(I)-
catalyzed intramolecular Goldberg N-arylation reaction10,11
of amides 5b,c,e-j,l.
Table 1. Meerwein-Eschenmoser Claisen Rearrangement
Leading to Major (5b-l) and Minor (3b-l) Product Formation
ratioa
yieldb of
entry
R
X
time, h
5:3
5, %
In order to avoid the standard protocol, which implies the
use of high temperatures, highly polar solvents, and large
amounts of copper(I) reagents, we have applied recent
advances in aryl amidation chemistry to our substrates. For
compound 6a, we explored a set of two distinct conditions
operating under Cu(I) catalysis. First, 5a was subjected to
the Aryl C-N bond-forming reaction according to the
approach reported by Buchwald.12 Use of copper(I) iodide
as the source of transition metal, K3PO4 as a base, and
N,N′-dimethylethylenediamine (DMEDA) as a ligand in
toluene gave the desired product 6a in only 55% yield
(Table 2). Alternatively, substituting the amidation condi-
1
2
3
4
5
6
7
8
benzyl
benzyl
propyl
propyl
propyl
pentyl
Br
I
H
Br
I
Br
I
Br
I
2.5
2
3
1
1
1
0.5
3
0.5
1
0.5
6:1
1:1
5:1
3:1
6:1
5:1
3:1
8:1
3:1
1:1
1:2
71 (5b)
45 (5c)
64 (5d)
66 (5e)
71 (5f)
76 (5g)
59 (5h)
68 (5i)
54 (5j)
41 (5k)
33 (5l)
pentyl
isopropyl
isopropyl
phenyl
Phenyl
9
10
11
H
I
a Determined by 1H NMR. b Isolated yield after flash chromatography.
Indene scaffold 7 was synthesized from reverse-prenylated
amide 5b by a palladium (0)-catalyzed intramolecular 5-exo-
trig Heck cyclization process. The use of tris(dibenzylide-
neacetone)dipalladium (0) with tri-o-tolyl phosphine as a
ligand in toluene at 100 °C gave the desired product 7 in
69% yield after 24 h. Alternatively the use of bis(triph-
enylphosphine)palladium(II) chloride in toluene at 100 °C
gave 2,2-dimethyl indene 7 in 82% yield after 15 h.
Structurally rigid terminal olefin functionality was identified
Table 2. Goldberg Aryl Amidation Reaction Leading to Tertiary
C3 Reverse Prenylated Oxindoles 6a-e
1
through distinct H NMR signals at 4.92 and 5.41 ppm in
addition to a characteristic 13C NMR signal at 102.9 ppm
that showed large coupling to the chemically distinct terminal
olefinic protons (data not shown). The discovery of this
synthetic route leading to 7 is important as it allows for
derivatization of indene scaffold in previously intractable
positions.
In midcourse to reverse-prenylated amides 5b-l, the key
intermediates in the synthesis of both target scaffolds, we
applied the Meerwein-Eschenmoser Claisen rearrangement
of allyl imidates9 to substrates 4b-l. Following this se-
quence, the amides 3b-l were converted to intermediate
imidochlorides by the means of phosphorus pentachloride
in refluxing benzene. The crude imidochlorides were treated
with lithium prenyloxide to form allyl imidates 4b-l, which
proved sufficiently pure for subsequent transformations. 1H
NMR signatures were observed for all of the precursors
(9) (a) For a general discussion on this variant of the Claisen rearrange-
ment, see: Gradl, S. N.; Trauner, D. In Claisen Rearrangement; Hiersemann,
M., Nubbemeyer, U., Eds.; Wiley-VCH: Weinheim, 2007; pp 367-396.
(b) Metz, P.; Mues, C. Tetrahedron 1988, 44, 6841. (c) Metz, P.; Mues,
C.; Schoop, A. Tetrahedron 1992, 48, 1071. (d) Metz, P.; Linz, C.
Tetrahedron 1994, 50, 3951. (e) For chiral auxiliary-based enantioselection,
see: Metz, P.; Hungerhoff, B. J. Org. Chem. 1997, 62, 4442. Hungerhoff,
B.; Metz, P. Tetrahedron 1999, 55, 14941.
a Except for entry 2. b Isolated yield after flash chromatography.
tions with structurally defined, air-stable copper(I) complex
Cu(phen)(PPh3)Br as reported by Venkataraman’s group for
3596
Org. Lett., Vol. 12, No. 16, 2010

aryl-nitrogen bond formation proved superior.13 Following
this method, 10% Cu(phen)(PPh3)Br, reverse-prenylated
amide 5c, and Cs2CO3 as a base in toluene gave desired
cyclization product 6a in 87% yield (Table 2) after 72 h.
Using 6a as a prototypical case, this amidation protocol was
optimized for the catalyst, base, and duration of reaction (see
Supporting Information). The use of K3PO4 as a base proved
to be superior for the synthesis of the products 6b-e, which
were obtained in moderate to good yields following the same
approach14 (Table 2).
Scheme 2
.
Enolate Alkylation of 6a; Direct Access to C3
Quaternary Oxindoles
To illustrate the applicability of the developed synthetic
method for the further derivatization of tertiary C3 reverse-
prenylated oxindoles, we attempted an oxindole alkylation
at the neopentyl C3 center. Because of the steric conge-
stability caused by the C3 substitution, we anticipated this
transformation to be challenging. Gratifyingly, formation
of the corresponding enolate proved feasible upon treat-
ment of 6a with sodium hydride in DMF at room
temperature, and the alkylation of the enolate with
bromoacetonitrile and ethyl bromoacetate proceeded to
completion at room temperature within 30 min to give
the products 8 and 9 in 98% and 97% yield, respectively
(Scheme 2). Oxindole 8 crystallized upon dissolving the
purified compound in minimum amount of THF followed
by vapor phase trituration with hexanes. The structure of
oxindole 8 deduced from the X-ray diffraction data is
shown below (Scheme 2). It is interesting to note that the
C-N portion of the nitrile aligns, at least in the solid state,
in an antiperiplanar orientation with the CdO π bond of
the oxindole carbonyl group, understandably due to
possible minimization of the dipole moment. As reverse-
prenylated oxindoles occupy a significant chemical space
in medicine, we anticipate the ease of crystallizability
shown by oxindole 8 to bode well for ensuing ligand-
receptor docking studies.
intermediate 5b by a 5-exo-trig Heck cyclization reaction.
Conditions were studied for the conversion of acyclic reverse-
prenylated amides 5 to tertiary C3 reverse-prenylated oxin-
doles 6a-e via Cu(I)-catalyzed intramolecular aryl amida-
tion. Finally, oxindole 6a underwent enolate alkylation with
corresponding electrophiles to give quaternary C3 reverse-
prenylated adducts 8 and 9. In addition to accessing
stereodivergent ring skeletons from readily available precur-
sors, the development of stereocontrolled syntheses of tertiary
and quaternary C3 reverse-prenylated natural products is
currently ongoing and will be reported in due course.
Acknowledgment. Authors thank NSF (CHE 0541766)
for funding provided for support of X-ray diffractometer.
R.V. and V.A.I. deeply thank Prof. Gregory P. Tochtrop
(CWRU) for highly insightful comments during the prepara-
tion of this work. R.V. thanks Dr. Jonathan Karty (IU) and
Ms. Angela Hansen (IU) for ESI-MS data collection. Authors
thank Ms. Deepti Sharma (CWRU) for efforts to collect
X-ray of 8 and ESI-MS data collection and analysis. R.V.
thanks Dr. Karthikeyan Thandavamurthy (CWRU) for proof-
ing and editorial support. N.D. thanks the Republic of Turkey
for a graduate fellowship.
In conclusion, we have developed a novel, elegant branch-
selective synthesis of oxindole and indene privileged scaf-
folds. 2,2-Dimethyl indene 7 has been obtained from
(10) Goldberg, I. Ber. Dtsch. Chem. Ges. 1906, 39, 1691.
(11) For a review, se: e Evano, G.; Blanchard, N.; Toumi, M. Chem.
ReV. 2008, 108, 3054.
(12) (a) Klapars, A.; Antila, J. C.; Huang, X.; Buchwald, S. L. J. Am.
Chem. Soc. 2001, 123, 7727. (b) Klapars, A.; Huang, X.; Buchwald, S. L.
J. Am. Chem. Soc. 2002, 124, 7421. (c) Strieter, E. R.; Blackmond, D. G.;
Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 4120. (d) Strieter, E. R.;
Bhayana, B.; Buchwald, S. L. J. Am. Chem. Soc. 2009, 131, 78.
(13) (a) Gujadhur, R.; Bates, C.; Venkataraman, D. Org. Lett. 2001, 3,
4315. (b) Gujadhur, R.; Venkataraman, D.; Kintigh, J. T. Tetrahedron Lett.
2001, 42, 4791 The complex could be easily synthesized in good yield by
a reported protocol (ref 15a) in two steps from copper (II) bromide,
triphenylphosphine and 1,10-phenanthroline.
Supporting Information Available: Detailed experimen-
tal procedures and spectral data for all new compounds (1H
NMR, 13C NMR, IR, HRMS). This material is available free
of charge via the Internet at http://pubs.acs.org.
(14) Moriwaki, K.; Satoh, K.; Takada, M.; Ishino, Y.; Ohno, T.
Tetrahedron Lett. 2005, 46, 7559.
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