Convenient synthesis of 3-alkoxy-3-aryloxindoles by intramolecular arylation of mandelic amides

Article abstract of DOI:10.1021/jo8010842

(Chemical Equation Presented) Medicinally important 3-alkoxy-3- aryloxindoles are conveniently prepared by the rapid microwave-promoted palladium-catalyzed intramolecular enolate arylation of mandelate-derived anilides.

Full text of DOI:10.1021/jo8010842

lation of 3-aryloxindoles,10 and SNAr reactions of 2-fluoroni-
troarenes on dioxolanone templates.11 Asymmetric variants of
many of these approaches are known.7a,b,10a,11
Convenient Synthesis of 3-Alkoxy-3-aryloxindoles
by Intramolecular Arylation of Mandelic Amides
The synthesis of 3,3-disubstituted oxindoles by palladium-
catalyzed intramolecular arylation of anilide enolates developed
by Hartwig12 has received some attention from other workers.13,14
Asymmetric variants of the reaction have been developed,14 with
recent developments using chiral N-heterocyclic carbene ligands
giving usable (>90% ee) levels of enantioselectivity.14d To date,
however, there has been only a single example of the arylation
of an alkoxy-substituted enolate, specifically, the synthesis of
a spirocyclic oxindole by arylation of a 2-carboxytetrahydrofuran
derivative.12b Given our interest in the construction of quaternary
centers by functionalization of oxygen-substituted enolates,15
we wished to investigate the extension of enolate arylation
chemistry to the synthesis of the valuable 3-alkoxy-3-arylox-
indoles. Provided that the presence of the aryl substituent did
not detrimentally affect the arylation process (for example by
competing direct arylation), this would be an attractive con-
vergent route to the target molecules, given the ready com-
mercial availability of both substituted mandelic acid derivatives
and o-haloanilines as building blocks. The potential for the
development of asymmetric variants downstream was a further
attraction. In this paper, we outline optimized conditions for
the key transformation and report the scope and limitations of
the process in terms of O- and N-substitution.
J. Mikael Hillgren and Stephen P. Marsden*
School of Chemistry, UniVersity of Leeds, Leeds LS2 9JT,
United Kingdom
s.p.marsden@leeds.ac.uk
ReceiVed May 19, 2008
Medicinally important 3-alkoxy-3-aryloxindoles are conve-
niently prepared by the rapid microwave-promoted pal-
ladium-catalyzed intramolecular enolate arylation of mandelate-
derived anilides.
Initial screening studies on substrate 4a identified that a 1:1
mixture of palladium(II) acetate and tricyclohexylphosphine
(conveniently added as the air-stable phosphonium salt) was
the most effective precatalyst combination. The reaction was
further optimized in terms of base, solvent and temperature,
and the results are summarized in Table 1.
In dioxane, the optimum base was found to be sodium tert-
butoxide (entries 1-3). While the reaction could be carried out
effectively under simple thermal heating (entry 4), we found that
the reactions were more conveniently run under microwave
irradiation, giving full conversion in only 10 min at a fixed
3-Hydroxy- and 3-alkoxyoxindoles are found as core struc-
tures in a wide range of biologically active natural products1
and pharmaceutical candidates. The 3-aryl-3-hydroxyoxindole
skeleton in particular is found in several drug candidates,
including the growth hormone secretagogue SM-130686 (1)2
and the potassium channel opener 2,3 an early candidate in the
program that led to the development of MaxiPost.4 Hypogly-
cemic agents related to the antidepressant ciclazindol (3) can
be accessed via 3-aryl-3-hydroxyoxindoles.5
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The most commonly employed methods for the synthesis of
this motif are the addition of aryl nucleophiles to isatins
(Grignard reagents6 and boronic acids7), inter-8 and intramo-
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10.1021/jo8010842 CCC: $40.75
Published on Web 07/11/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 6459–6461 6459

TABLE 1. Optimisation of Intramolecular Arylation of 4a
TABLE 2. Scope of Intramolecular Arylation Approach to
3-Alkoxy-3-aryloxindoles
a
entry
X
solvent
base
t (°C) time conversion
yield (%)
1
2
3
4
5
6
7
8
Br dioxane NaOtBu
70
Br dioxane LiHMDS 70
22 h
26 h
23 h
1 h
100
100
0
70
56
n/a
73
77
77
58
73
45
53
n/a
91
Br dioxane LiTMP
70
85
Br dioxane NaOtBu
100
100
100
100
100
100
100
10
Br dioxane NaOtBu 100b 10 min
Br toluene NaOtBu 100b 10 min
Br toluene LiHMDS 100b 10 min
Br toluene LiOtBu
100b 10 min
9
Br THF
LiHMDS 100b 10 min
10
11
12
Br TBME LiHMDS 100b 10 min
Cl toluene NaOtBu 100b 10 min
I
toluene NaOtBu 100b 10 min
100
a From crude 1H NMR spectrum. b Carried out in microwave reactor
(fixed temperature, variable power).
temperature of 100 °C (entry 5). Toluene was found to be a
convenient solvent (entry 6) and was used thereafter since it is
less harmful than dioxane. Sodium tert-butoxide was also found
to be the best base in toluene (entries 6-8). Finally, we assessed
the effect of changing the halide. While the aryl chloride gave very
low conversion under the reaction conditions (entry 11), the
corresponding iodide gave the best isolated yield at 91% (entry
12). However, since substituted 2-bromoanilines are both cheaper
and more widely available than their iodo counterparts, we elected
to conduct all future work on the bromoanilides.
In many of the above reactions, a small amount (ca. 5-10%)
of a side product was isolated, which was identified as the
diarylmethane 6. This is presumed to arise by conversion of
the oxindole product to the acyclic carboxylic acid, followed
by decarboxylation. The carboxylic acid may be formed either
by hydrolysis by adventitious water or ring opening by tert-
butoxide followed by thermal cleavage of the tert-butyl ester.
presence of electron-withdrawing sulfonyl and Cbz substituents
was not. Although no identifiable products were isolated from
these reactions, we suspect that this is due to the enhanced pKa
(and hence leaving group ability) of the protected anilide leading
to substrate cleavage, either by acyl substitution or R-elimination
of the corresponding enolate.
Finally, since many of the bioactive targets have free C3-
hydroxyl groups, the arylation was attempted on the unprotected
substrate 4m. The resulting reaction was extremely messy,
however, and no identifiable products could be found. We
therefore examined the performance of two potentially readily
deprotected substrates 4n and 4o (entries 13 and 14). These
returned good yields of oxindoles 5n and 5o, which could be
deprotected under standard (and unoptimised) conditions to yield
the desired free hydroxyoxindole 5m (eq 1).
With a robust general procedure established, we next tested the
substrate scope of the reaction. The requisite starting materials 4
were readily prepared by acylation of the (substituted) 2-bromoa-
niline with a hydroxyl-protected mandelic acid using triph-
enylphosphonium dichloride,16 followed by protection (normally
by N-methylation) of the resulting anilide.12b Fourteen further
substrates were examined in the arylation using the optimized
conditions and the results are summarized in Table 2.
The reaction tolerates a range of substituents (electron-
withdrawing and -releasing) in the mandelate-derived aryl ring
(entries 1-3). The presence of a chlorine substituent is not
problematic (entry 1), which is significant both in terms of the
presence of chloroarenes in the bioactive targets 1-3 and also
as a potential handle for further functionalization of the products.
Similarly, good yields of products were obtained with diverse
substituents on the anilide ring (entries 4-6) or both aryl rings
(entries 7 and 8).
Alternative nitrogen substituents were investigated (entries
9-11). While the N-benzyl substituent was well tolerated, the
6460 J. Org. Chem. Vol. 73, No. 16, 2008

1,5-Dimethyl-3-methoxy-3-(4-trifluoromethylphenyl)-oxin-
dole 5i. Yield 50 mg (75%), colorless solid, mp 97.6-97.8 °C
(hexane). 1H NMR (300 MHz, CDCl3) δ 7.56 (2 H, d, J ) 8.4 Hz),
7.48 (2 H, d, J ) 8.4 Hz), 7.22 (1 H, dd, J ) 7.9, 0.9 Hz), 7.03 (1 H,
s), 6.84 (1 H, d, J ) 7.9 Hz), 3.24 (3 H, s), 3.23 (3 H, s), 2.35 (3 H,
s); 13C NMR (75 MHz, CDCl3) δ 174.5, 142.9, 142.1, 133.3, 130.8,
130.4 (q, J ) 32.2 Hz), 127.4, 126.7, 126.2, 125.3 (q, J ) 3.7 Hz),
124.0 (q, J ) 272.0 Hz), 108.5, 83.8, 53.1, 26.5, 21.1; IR (film) ν2935,
2829, 1728, 1500, 1326, 1124, 1103; HRMS m/z (EI+) found [M +
Na]+ 358.1016, C18H16F3NO2Na requires 358.1025.
In summary, the intramolecular arylation of o-haloanilides
has been extended to the novel synthesis of medicinally relevant
3-alkoxy-3-aryloxindoles. In particular, the results highlight the
tolerance of the arylation protocol toward heteroatom substit-
uents upon the enolate, of which there has only been a single
prior example. The convergent nature of the synthesis (starting
from readily available 2-bromoanilines and mandelic acid
derivatives) coupled with the potential for asymmetric variants
makes this an attractively convenient approach to this important
class of molecules.
1-Benzyl-3-methoxy-3-phenyloxindole 5j. Yield 57 mg (86%),
1
pale yellow oil. H NMR (300 MHz, CDCl3) δ 7.42-7.23 (12 H,
Experimental Section
m), 7.10 (1 H, td, J ) 7.5, 0.9 Hz), 6.80 (1 H, dd, J ) 8.4, 1.0
Hz), 4.93 (2 H, apparent d, J ) 3.0 Hz), 3.28 (3 H, s); 13C NMR
(75 MHz, CDCl3) δ 175.3, 143.6, 138.8, 135.6, 130.0, 128.8,
128.43, 128.38, 128.1, 127.7, 127.3, 126.3, 125.8, 123.3, 109.6,
83.9, 53.2, 44.0; IR (film) ν 3054, 3027, 2930, 2824, 1725, 1611,
1466; HRMS m/z (EI+) found [M + H]+ 330.1491, C22H20NO2
requires 330.1489.
General Procedure for Enolate Arylation. Pd(OAc)2 (4.5 mg,
0.020 mmol) and HPCy3BF4 (7.4 mg, 0.020 mmol) were combined
with sodium tert-butoxide (58 mg, 0.60 mmol) in a flame-dried
5-mL microwave tube. The tube was sealed with a septum and
flushed with nitrogen, followed by the addition of degassed toluene
(2 mL). The resulting solution was stirred at room temperature for
10 min, followed by the addition of the appropriate substrate 4
(0.20 mmol) dissolved in degassed toluene (2 mL). The mixture
was subjected to microwave irradiation (fixed temperature of 100
°C, variable power) for 10 min. After cooling, the reaction mixture
was filtered through a pad of Celite, washing with dichloromethane
(50 mL), the filtrate was concentrated, and the residue was purified
by silica gel chromatography.
Acknowledgment. We thank the EPSRC (grant EP/D002818/
1) for funding.
Supporting Information Available: Experimental details,
compound characterization data, and copies of the 1H/13C NMR
spectra for all substrates and products. This material is available
free of charge via the Internet at http://pubs.acs.org.
(16) Azumaya, I.; Okamoto, T.; Imabeppu, F.; Takayanagi, H. Tetrahedron
2003, 59, 2325.
JO8010842
J. Org. Chem. Vol. 73, No. 16, 2008 6461