One-pot homolytic aromatic substitutions/HWE olefinations under microwave conditions for the formation of a small oxindole library

Article abstract of DOI:10.1021/ol048759t

(Chemical Equation Presented) An efficient one-pot sequence comprising a homolytic aromatic substitution followed by an ionic Horner Wadsworth-Emmons olefination for the preparation of a small library of α,β-unsaturated oxindoles is presented. Microwave-induced heating is used to conduct these reactions. The homolytic aromatic substitution is mediated by the persistent radical effect.

Full text of DOI:10.1021/ol048759t

ORGANIC
LETTERS
2004
Vol. 6, No. 20
3477-3480
One-Pot Homolytic Aromatic
Substitutions/HWE Olefinations under
Microwave Conditions for the Formation
of a Small Oxindole Library
Antje Teichert,† Katja Jantos,† Klaus Harms,† and Armido Studer*,†,‡
Fachbereich Chemie, Philipps-UniVersita¨t Marburg, 35032 Marburg, Germany.
Organisch-Chemisches Institut, Westfa¨lische Wilhelms-UniVersita¨t Mu¨nster,
Corrensstrasse 40, 48149 Mu¨nster, Germany
studer@uni-muenster.de
Received June 30, 2004
ABSTRACT
An efficient one-pot sequence comprising a homolytic aromatic substitution followed by an ionic Horner−Wadsworth−Emmons olefination for
the preparation of a small library of
r,â-unsaturated oxindoles is presented. Microwave-induced heating is used to conduct these reactions.
The homolytic aromatic substitution is mediated by the persistent radical effect.
The indole core occurs in many natural products and
pharmaceutically important compounds.1 Indoles are desig-
nated as privileged structures in medicinal chemistry. Ox-
indoles belong to this important class of compounds and have
therefore gained some interest during the past few years.2
We recently extended this concept to intermolecular
alkoxyamine additions onto nonactivated olefins, so-called
radical carboaminoxylation reactions.6 Moreover, we have
shown that these reactions can efficiently be conducted under
microwave conditions.7 An example is depicted in Scheme
1.
Recently, we introduced the use of TEMPO-derived
alkoxyamines (TEMPO ) 2,2,6,6-tetramethylpiperidin-N-
oxyl radical) as C-radical precursors for environmentally
benign radical cyclization reactions.3,4 These reactions are
mediated by the so-called persistent radical effect (PRE).5
Scheme 1. Intermolecular Radical Carboaminoxylation of
1-Octene under Microwave Conditions
† Philipps-Universita¨t Marburg.
‡ Westfa¨lische Wilhelms-Universita¨t Mu¨nster.
(1) Bra¨se, S.; Gil, C.; Knepper, K. Bioorg. Med. Chem. 2002, 10, 2415.
Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. ReV. 2003, 103, 893.
(2) For an example see: Froestl, W. Chimia 2004, 58, 54.
(3) Studer, A. Angew. Chem., Int. Ed. 2000, 39, 1108.
(4) For other applications of the PRE in synthesis, see: Allen, A. D.;
Fenwick, M. F.; Henry-Riyad, H.; Tidwell, T. T. J. Org. Chem. 2001, 66,
5759. Leroi, C.; Fenet, B.; Couturier, J.-L.; Guerret, O.; Ciufolini, M. A.
Org. Lett. 2003, 5, 1079. Alajar´ın, M.; Vidal, A.; Ort´ın, M.-M.; Bautista,
D. Synlett 2004, 991.
(5) Fischer, H. Chem. ReV. 2001, 101, 3581. Studer, A. Chem. Eur. J.
2001, 7, 1159. Studer, A. Chem. Soc. ReV. 2004, 33, 267.
Herein, we present a new approach to substituted oxindoles
using one-pot PRE-mediated intramolecular homolytic aro-
(6) Wetter, C.; Jantos, K.; Woithe, K.; Studer, A. Org. Lett. 2003, 5,
2899.
10.1021/ol048759t CCC: $27.50
© 2004 American Chemical Society
Published on Web 09/02/2004

matic substitutions8,9 followed by ionic Horner-Wadsworth-
Emmons (HWE)-type olefination reactions. The reaction
sequence is depicted in Scheme 2. HWE-type TEMPO
the alkoxyamines 6a-g in moderate to excellent yields.
Alkoxyamine 6d was obtained as a 1:1 mixture of diaste-
reoisomers.11
Before attempting the above sketched one-pot process, the
intramolecular homolytic aromatic substitution was studied
using alkoxyamine 6a. The reaction was conducted using
classical heating in a sealed tube at 135 °C. We were pleased
to observe that the Horner-type radical12 formed via C-O
bond homolysis of alkoxamine 6a undergoing the desired
homolytic aromatic substitution process. Unfortunately, in
THF (25%), in ClCH2CH2Cl (32%), and in DMF (18%)
unsatisfactory low yields of oxindole 7 were obtained (0.02
M). However, we found that microwave-induced heating in
DMF (0.01 M) for 2 min at 180 °C provided 7 in 81%.13 It
is important to note that there are only a few reports in the
literature on microwave-induced free radical chemistry.7,14
Scheme 2. Homolytic Aromatic Substitution/HWE Olefination
derivatives 1 should undergo homolytic aromatic substitution
upon simple heating to provide oxindoles of type 2, which
are ready to be used in olefination reactions to eventually
afford R,â-unsaturated oxindoles of type 3.
Phosphonates 5a-g were prepared from readily available
acid chloride 4 and the corresponding aniline derivatives10
(Scheme 3). Deprotonation of the phosphonates 5a-g with
We next tried to run the HWE reaction of 7 in DMF under
microwave conditions. The reaction was optimized using
benzaldehyde as the electrophile. The base and the reaction
time were systematically varied. The best results were
obtained with KOt-Bu as a base at 180 °C for 6 min (92%).
To our delight, we found that the homolytic aromatic
substitution and the ionic HWE reaction can be conducted
in a one-pot process. After extensive optimization the
following protocol was obtained: (1) microwave-induced
heating of 6a in DMF (0.03 M) for 2 min at 180 °C and (2)
addition of benzaldehyde (10 equiv) and KOt-Bu (1.2 equiv)
and renewed microwave heating at 180 °C for 6 min. The
R,â-unsaturated oxindole 8a was isolated in 75% yield as a
mixture of isomers (trans:cis ) 3.4:1, Table 1, run 1).15
Under the optimized conditions (less than 12 min is necessary
to prepare the oxindoles) various aromatic aldehydes (10-
20 equiv) were used for the one-pot radical/ionic process.
The results are summarized in Table 1.
Scheme 3. Preparation of Phosphonates 6a-g
para-Substituted aldehydes reacted with moderate to
excellent yields with low selectivities favoring the trans-
isomer (f 8b-f, 38-87%, runs 2-6). The isomers were
readily separated by chromatography. Slightly higher selec-
(10) Prepared according to: Barluenga, J.; Bayo´n, A. M.; Asensio, G.
Chem. Commun. 1983, 1109.
(11) Axial chirality in radical chemistry: Curran, D. P.; Liu, W.; Chen,
C. H.-T. J. Am. Chem. Soc. 1999, 121, 11012.
(12) Cholleton, N.; Gauthier-Gillaizeau, I.; Six, Y.; Zard, S. Z. Chem.
Commun. 2000, 535.
(13) The microwave experiments were conducted using professional
laboratory microwave equipment. A MLS-Ethos 1600 Mikrowellen System
(Milestone) was used for the present studies. The reactions were run in 40
mL MLS high-pressure reaction vessels (up to 15 bar) that contain pressure
control valves. An advanced temperature control system from MLS allowing
direct contactless temperature monitoring was used. The microwave power
is continuously and dynamically adjusted to follow the defined temperature
profile. Temperature profile for the homolytic aromatic substitution: from
25 to 100 °C in 10 s; from 100 to 150 °C in 10 s; from 150 to 180 °C in
10 s; then keep the temperature at 180 °C for 2 min.
(14) Bose, A. K.; Manhas, M. S.; Ghosh, M.; Shah, M.; Raju, V. S.;
Bari, S. S.; Newaz. S. N.; Banik, B. K.; Chaudhary, A. G.; Barakat, K. J.
J. Org. Chem. 1991, 56, 6968. Olofsson, K.; Kim, S.-Y.; Larhed, M.; Curran,
D. P.; Hallberg, A. J. Org. Chem. 1999, 64, 4539. Lamberto, M.; Corbett,
D. F.; Kilburn, J. D. Tetrahedron Lett. 2003, 44, 1347. Ericcson, C.;
Engman, L. J. Org. Chem. 2004, 69, 5143.
(15) The same selectivity was obtained upon running the HWE reaction
at 100 °C. At room temperature HWE reaction did not work as controlled
by TLC. The HWE reaction in THF at 100 °C occurred with lower
selectivity (trans:cis ) 1.9:1).
lithium diisopropyl amide (LDA) in dimethoxyethane (DME)
followed by Cu(II)-oxidation in the presence of TEMPO gave
(7) Wetter, C.; Studer, A. Chem. Commun. 2004, 174.
(8) Leroi, C.; Bertin, D.; Dufils, P.-E.; Gigmes, D.; Marque, S.; Tordo,
P.; Couturier, J.-L.; Guerret, O.; Ciufolini, M. A. Org. Lett. 2003, 5, 4943.
(9) For a review on homolytic aromatic substitutions, see: Studer, A.;
Bossart, M. In Radicals in Organic Synthesis; Renaud, P., Sibi, M. P., Eds.;
Wiley-VCH: Weinheim, 2001; Vol. 2, p 62.
3478
Org. Lett., Vol. 6, No. 20, 2004

Table 1. One-Pot Homolytic Aromatic Substitution/HWE
Olefination Using Alkoxyamine 6a
run
R
equiv oxindole ratio (trans:cis) yield (%)
1
2
3
4
5
6
7
8
Ph
1.0
1.0
1.0
1.5
1.5
2.0
1.5
1.5
8a
8b
8c
8d
8e
8f
3.4:1
1.9:1
1.4:1
2.4:1
2.3:1
1.9:1
3.6:1
6.0:1
75
87
44
38
43a
52
58b
38
4-CF3-Ph
4-NO2-Ph
4-Br-Ph
4-Me-Ph
4-MeO-Ph
2-Br-Ph
2-Me-Ph
8g
8h
a Conducted at 0.02 M. b Conducted at 0.04 M.
tivities were obtained with the ortho-substituted aldehydes
(f 8g,h, up to 6:1, runs 7 and 8). Reaction of 4-pyridine-
carboxaldehyde with 6a provided oxindole 9 in 48% yield
(trans:cis ) 2.3:1). The relative configuration of the oxin-
doles was assigned on the basis of X-ray analysis of cis-8b
and trans-8c (Figure 1).16 Furthermore, we found that during
chromatography on silia gel the cis-isomer was always eluted
faster than its trans-congener. In addition, the vinylic proton
of the trans-isomer always appears at slightly lower field in
the 1H NMR spectrum than the corresponding signal of the
cis-isomer.
Figure 1. X-ray structure of cis-8b (above) and trans-8c (below).
We could also show that the N-methyl group, which is
difficult to remove, can be replaced by a benzyl group. Thus,
one-pot reaction of 6f afforded oxindole 14 in 35% yield
We then tested whether the one-pot sequence works also
with substituted anilides. These studies were performed with
benzaldehyde as electrophile in the HWE step using the
optimized protocol. Reaction with the p-MeO-substituted
anilide 6b afforded the oxindole 10 in 65% yield (trans:cis
) 3.1:1, Figure 2). A lower yield was obtained for the
o-MeO-derivative 6d (f 11, 42%, trans:cis ) 2.6:1).
Surprisingly, for the m-MeO-compound 6c, the sterically
more hindered isomer 12a was formed as the major
compound in 51% yield (cis:trans ) 5.0:1). Interestingly,
for regioisomer 12b only the cis-isomer was isolated (36%).
The assignment of the regioisomers is based on the reduction
of 12a (Pd/C, MeOH, H2) to 13a for which an X-ray structure
was obtained (Figure 3).17 In analogy the regioisomeric
oxindole 12b was reduced to 13b.
(16) The data for the structure of cis-8b and trans-8c have been deposited
with the Cambridge Crystallographic Data Center as supplementary
publications no. CCDC 241647 (cis-8b) and CCDC 241648 (trans-8c).
(17) The data for the structure of 13a have been deposited with the
Cambridge Crystallographic Data Center as supplementary publication no.
CCDC 241649.
Figure 2. Variation of the arene core and substitution of the
N-methyl group.
Org. Lett., Vol. 6, No. 20, 2004
3479

POH.20 Moreover, concerted ionic 1,2- (see 19)21 and 1,4-
elimination (see 20) of TEMPOH is also feasible. In addition,
SET transfer from the cyclohexadienyl radical to TEMPO
followed by deprotonation cannot be ruled out.
Figure 3. X-ray structure of 13a.
(trans:cis ) 4.2:1).18 For the N-tosyl derivative 6e and the
secondary amide 6g the desired oxindoles were not formed.
Because the TEMPO-phosphonates 6 are highly sterically
hindered, direct HWE olefination on 6 should be very slow
and two-component reactions should be feasible. Indeed, the
heating of a DMF solution of 6a, benzaldehyde, and KOt-
Bu under microwave conditions at 180 °C for 17 min
provided the desired oxindole 8a. However, compared to the
above-described protocol, a lower yield was obtained (32%).
In analogy, 8b was prepared in 30% yield.
Figure 4. Intermediates of the homolytic aromatic substitution.
In conclusion, we have shown that PRE-mediated ho-
molytic aromatic substitutions can be combined with Horner-
type olefinations. These one-pot reactions can efficiently be
performed under microwave conditions. Biologically inter-
esting compounds can be prepared in a short time. It is
obvious that Horner-type alkoxyamines can also be used for
radical carboaminoxylation/olefination reactions. Studies are
currently underway and will be reported in due course.
The mechanistic picture of the nitroxide-mediated ho-
molytic aromatic substitution is currently not clear. C-Radical
addition onto the arene generates the corresponding cyclo-
hexadienyl radical 15 (Figure 4). Trapping of 15 with
TEMPO provides the dienes 16 and 17. The formation of
the tertiary diene 18 is unlikely for steric reasons. Because
the C-O-alkoxyamine bond is very weak,19 TEMPO trap-
ping is reversible. Rearomatization can occur via H-transfer
from the cyclohexadienyl radical 15 to TEMPO to eventually
form the homolytic aromatic substitution product and TEM-
Acknowledgment. We thank the Deutsche Forschungs-
gemeinschaft (STU 280/4-1) and the Fonds der Chemischen
Industrie for support. Kian Molawi, Jason Spruell and
Christoph Knoop are acknowledged for proofreading. LON-
ZA AG is acknowledged for a generous gift of solvents.
Supporting Information Available: Experimental pro-
cedures, analytical data of all new compounds, and crystal-
lographic data in CIF format. This material is available free
of charge via the Internet at http://pubs.acs.org.
(18) In a separate experiment, the reaction was stopped after the
homolytic aromatic substitution. The product was obtained in 68% yield.
Compared to the N-methyl compound 6a the N-benzyl congener affords a
lower yield in the homolytic aromatic substitution. We assume that the
benzylic H-atoms, which are readily abstracted by TEMPO at high
temperature, may be the reason for the decreased yield.
(19) Marque, S.; Le Mercier, C.; Tordo, P.; Fischer, H. Macromolecules
2000, 33, 4403. Marque, S.; Fischer, H.; Baier, E.; Studer, A. J. Org. Chem.
2001, 66, 1146.
OL048759T
(20) Skene, W. G.; Connolly, T. J.; Scaiano, J. C. Tetrahedron Lett. 1999,
40, 7297. Coseri, S.; Ingold, K. U. Org. Lett. 2004, 6, 1641.
(21) Ananchenko, G. S.; Fischer, H. J. Polym. Sci., Part A: Polym. Chem.
2001, 39, 3604.
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