Aza-oxindole synthesis by oxidative coupling of Csp 2-H and Csp3-H centers

Article abstract of DOI:10.1039/c2cc17871k

A Cu(ii) mediated oxidative C_sp²-H and C _sp³-H coupling protocol gives access to aza-oxindoles in good to excellent yield in the presence of NaOtBu as base and toluene as solvent. The Royal Society of Chemistry

Full text of DOI:10.1039/c2cc17871k

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COMMUNICATION
Aza-oxindole synthesis by oxidative coupling of Csp
centersw
2–H and Csp3–H
Chandan Dey and E. Peter Kundig*
¨
Received 16th December 2011, Accepted 27th January 2012
DOI: 10.1039/c2cc17871k
A Cu(II) mediated oxidative Csp2–H and Csp3–H coupling
protocol gives access to aza-oxindoles in good to excellent yield
in the presence of NaOtBu as base and toluene as solvent.
Table 1 Optimization of reaction conditions for the intramolecular
radical addition/oxidation of 1aa
Compounds containing the aza-oxindole structural motif exhibit
biological activities such as oral anti-inflammatory activity, and
potent TrkA kinase and JAK 3 kinase inhibition.1 Literature
protocols for the synthesis of aza-oxindoles2 include the oxida-
tion of azaindoles,2a radical cyclization reactions,2b Pauson–
Khand type [2+2+1] cycloadditions,2c Pd-catalyzed intra-
molecular a-pyridination of amides,2d photo cyclizations,2e and
cyclization of aminopyridineacetic acids.2f All the afore-
mentioned methods require a specifically functionalized precursor;
for instance an ortho pyridyl halogen, an a-xanthate group or an
a-hydroxy group, or a preexisting bicyclic ring system.
Oxidative inter- and intramolecular radical coupling
protocols are powerful tools for the construction of C–C
bonds.3 We here communicate a simple, robust protocol for
the preparation of aza-oxindoles. It involves an oxidative
Csp2–H/Csp3–H coupling using cheap CuCl2 as oxidant.
We discovered this reaction sequence while working on Pd
catalyzed asymmetric intramolecular arylations of aryl amides
to give highly enantiomerically enriched 3,3-disubstituted
oxindoles.4 Attempting to couple the reaction with an ortho-
palladation step under oxidative conditions led to the finding
that Pd is not involved and that oxindoles are formed via a
radical process under these conditions.5 Shortly following our
publication, Taylor and coworkers published similar findings
leading to oxindoles with ester, nitrile and phosphonate func-
tions in the 3-position.6 The key step of this transformation is
an intramolecular radical cyclization reaction.
Entry
Solvent
Temp/1C
Time/h
Yieldb (%)
1
DMF
DMF
PhMe
Xylene
nBu2O
Mesitylene
PhMe
Xylene
Diglyme
PhMe
PhMe
Mesitylene
110
180
110
110
110
110
140
140
140
110
110
165
3
0.15
2.5
2.5
2.5
2.5
2
2
2
2.5
2.5
20
50
51
68
64
58
64
67
61
62
40
59
Trace
2c
3
4
5
6
7
8
9
10d
11e
12f
a
b
0.2 mmol scale in 4.0 mL solvent. Isolated yield. Microwave
c
d
irradiation. 2.2 equiv. Cu(OAc)2 was used. 5.0 equiv. KOtBu was
used. 5 mol% Cu(OAc)2ÁH2O was used, no base added.6
e
f
N-Methyl-2-phenyl-N-(pyridin-2-yl)propanamide (1a) was
prepared by reaction of 2-amino pyridine with 2-phenyl
propanoyl chloride followed by N-methylation. Reaction with
2.2 equiv. of CuCl2 and 5 equiv. of NaOtBu in DMF at 110 1C
for 3 h afforded aza-oxindole 2a in 50% yield (Table 1, entry 1).10
Microwave heating cuts the reaction time to 10 min but did
not improve the yield (entry 2). Solvent screening revealed
toluene to be the best choice (entries 3–6). Higher reaction
temperatures did not improve the yield (entries 7–9).
Radical addition to pyridines is known as the Minisci reaction.7,8
Literature shows that it works best when the reaction is carried
out in acidic media. Recently, intramolecular variants of the
Minisci reaction have come to the fore.9 To the best of our
knowledge, there is no literature precedent for the synthesis of
aza-oxindoles via the oxidative coupling method described here.
Different oxidants and bases were probed but CuCl2 and
NaOtBu proved to be the best combination (entry 3 vs. entries
10 and 11). This has precedence in the synthesis of oxindoles.5
The use of catalytic quantities of Cu(II) in refluxing mesitylene
for 20 h6 returned mainly starting material 1a (Table 1, entry 12).
In all other reactions, 1a was consumed completely, the mass
balance being made up of intractable materials.
Department of Organic Chemistry, University of Geneva,
30 Quai Ernest Ansermet, 1211 Geneva 4, Switzerland.
E-mail: peter.kundig@unige.ch; Web: http://www.unige.ch/sciences/
chiorg/kundig/; Fax: +41 22-379-3215; Tel: +41 22-379-6093
w Electronic supplementary information (ESI) available: Experimental
details, spectral characterisation and analytical data of reported
compounds. See DOI: 10.1039/c2cc17871k
Using the optimized conditions found for 2a, the reaction
was extended to other ortho-, meta-, and para-pyridyl substrates
and to precursors with substituted aryl groups (Table 2). Reac-
tion with substrate 1e, containing a p-trifluoromethyl required a
c
3064 Chem. Commun., 2012, 48, 3064–3066
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Table 2 Scope of aza-oxindole synthesis via intramolecular oxidative couplinga
a
b
0.4 mmol scale for 1b–e, g–j, m–p in toluene (8.0 mL), 0.8 mmol scale for 1a,f,k. Yields given are those of the isolated pure products. 2e was
obtained together with an inseparable, unidentified impurity (B15%).
longer reaction time. Yields with para-pyridyl substrates 1f–h
were considerably higher than with ortho-pyridyl substrates. A
similar increase in efficiency was reported by Harrowven and
coworkers for intramolecular addition of phenyl radicals to
pyridines.11 The origin may simply be one of statistics given
that for the para-pyridyl substrates there are two positions
for cyclization whereas for ortho-pyridyl substrates there is
only one. The reaction times for the synthesis of 7- and of
5-aza-oxindoles were shorter than the synthesis of oxindoles
(2.5–3 h cf. 5 h5) due to the faster addition of the amidyl
radical to pyridine over that to a phenyl ring.
enhanced electrophilicity at the o-position due to pyridyl-N-
coordination to Cu(II).12
In summary, we have developed a simple, cheap and
efficient method for the synthesis of 3,3-disubstituted aza-
oxindoles by the direct intramolecular oxidative coupling of
pyridyl Csp2–H and Csp3–H centers. This method has been
applied to a range of substrates. The rate and yield of the
reaction depend on the position of the nitrogen atom in the
pyridine ring and on the aryl substituents.
We thank the Swiss National Science Foundation and the
University of Geneva for financial support.
The data in Table 2 show the product yields to be usually
good to excellent. The reactions worked well with both
electron-rich and electron-poor aryl rings but the latter require
longer reaction times. N-Benzyl protected substrates afforded
aza-oxindoles 2d, 2j, and 2m in 64, 79 and 71% yields
respectively. As expected, the oxidative coupling reaction of
3-pyridyl amide substrates 1k–1p, affords two regioisomeric
products with the one resulting from addition ortho to the
pyridyl N being largely favoured or (for 2m–o), the exclusive
product. A similar trend of regioselectivity of radical addition
to a 3-pyridyl substrate under Lewis acidic conditions was also
reported by Harrowven and co-workers and may be linked to
Notes and references
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