Aza-oxindole synthesis via base promoted Truce-Smiles rearrangement

Article abstract of DOI:10.1039/c2cc36068c

A novel efficient NaOtBu-mediated protocol for the synthesis of 3,3-disubstituted aza-oxindoles proceeds via a Truce-Smiles rearrangement- cyclisation pathway.

Full text of DOI:10.1039/c2cc36068c

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Aza-oxindole synthesis via base promoted Truce–Smiles rearrangementw
Chandan Dey, Dmitry Katayev, Kai E. O. Ylijoki and E. Peter Ku
¨
ndig*
Received 21st August 2012, Accepted 12th September 2012
DOI: 10.1039/c2cc36068c
A novel efficient NaOtBu-mediated protocol for the synthesis of
3,3-disubstituted aza-oxindoles proceeds via a Truce–Smiles
rearrangement–cyclisation pathway.
largely insensitive to aryl substitution and the identity of the
halide (entry 1 vs. 7). p-Pyridyl substrates (1b–1d) cyclised to
the respective 6-aza-oxindoles (3b–3d) in quantitative yields
(entries 1–3). Spiro-6-aza-oxindoles (3e–3f) were obtained in
almost quantitative yields from the respective p-pyridyl substrates
(1e–1f) (entries 4 and 5). When the amido nitrogen protecting
group was changed from Me to Bn (1g), 6-aza-oxindole 3g was
obtained in lower yield (66%, entry 6). Some sensitivity to the
position of the pyridyl nitrogen is observed, where o-pyridyl
substrates 1i and 1j afford lower yields than p-pyridyl substrates
1b–1h, with the exception of o-pyridyl substrate 1a (entries 8–10).
m-Pyridyl substrate 1k reacted poorly, affording 5-aza-oxindole
3k in 33% yield, the remainder being decomposition products
(entry 11).
The aza-oxindole structural motif is prevalent in compounds
exhibiting interesting biological properties such as oral anti-
inflammatory activity, and potent TrkA kinase and JAK 3
kinase inhibition.1 Several synthetic approaches to this moiety
have been developed, such as oxidation of aza-indoles,2 radical
cyclisation reactions,3 Pauson–Khand type [2+2+1] cyclo-
additions,4 Pd-catalyzed intramolecular a-pyridynation of
amides,5 photocyclisations,6 and cyclisation of aminopyridine-
acetic acids.7 Recently, we have reported a straightforward
and robust protocol for the preparation of aza-oxindoles via
CuCl2-mediated intramolecular Csp2–H/Csp3–H coupling.8
Herein, we report yet another new route to aza-oxindoles via
a Truce–Smiles rearrangement.
Given the utility of this reaction, we undertook a mechanistic
study to better understand the process. Previously, similar
rearrangements have been proposed to involve pyridyne or
aziridine intermediates, or Smiles rearrangements.11 Based on
the above findings, we propose the reaction to involve a base
promoted Truce–Smiles rearrangement,12 followed by subsequent
substitution of the halide (Scheme 2). To probe this hypothesis,
we subjected the halogen-free substrate 4 to the reaction
conditions. This resulted in product 5 in 82% yield (eqn (1))
and establishes the Truce–Smiles rearrangement. We note that
the rate of the rearrangement of 4 was slower than that of the
bromo pyridyl amide 1b (18 h vs. 1 h), due to the higher
electron-density in the aromatic ring.13 The ensuing cyclisation
could proceed via either a pyridyne-type intermediate (Scheme 2,
Path B)14 or a direct addition–elimination SNAr-mechanism
(Path A).
In the course of our ongoing studies on oxindole preparation
via Pd–chiral-NHC catalyzed intramolecular a-arylation9 of
amides, we found that o-pyridyl amide 1a afforded a mixture
of two regioisomeric products: the expected 2 and unexpected 3a
in a 56 : 44 ratio (Scheme 1). It was rapidly clear that 3a, having
undergone a rearrangement of the pyridine N position, must be
formed via a very different mechanism than 2: the Pd–NHC
catalyst plays no role in its formation. 3a was obtained as the
sole product (94% yield) in the reaction with 2.1 equiv. of
NaOtBu (50 1C, 3 h, Scheme 1). While the reaction also
proceeds at rt, complete conversion requires 24 h. Decreasing
the equivalents of base from 2.1 to 1 equiv. resulted in
significantly reduced yield (47%). Solvent screening (DME,
PhMe, CH2Cl2, THF) revealed DME to be most effective.
To explore the generality of the reaction, the optimised
conditions were applied to a series of o-, m-, and p-pyridyl
substrates with varying aryl substitution (Table 1). The requisite
substrates were prepared by reaction of bromo amino pyridine
with acid chloride followed by N-alkylation.10 As shown in
Table 1, product yields are generally good to excellent and are
The reaction of the deuterium labelled 6 afforded 6-aza-
oxindole 7 with complete retention of deuterium in all positions
(eqn (2)). This experiment excludes a pyridyne intermediate while
supporting an SNAr-type mechanism, despite the necessity of
electronically disfavoured m-substitution.15
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, tables of thermodynamic data and coordinate files for
all computationally determined stationary points, figures for select
transition states. See DOI: 10.1039/c2cc36068c
Scheme 1
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 10957–10959 10957

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Table 1 Substrate scope
Time Yieldsa
Entry Substrate
Product
(h)
(%)
Scheme 2
1
1
99
ð1Þ
ð2Þ
2
3
1
1
99
99
To further examine the possibility of a SNAr pathway, we
conducted a DFT computational study (B3LYP16/6-311++G**)
to explore the potential energy surface of the proposed reaction
pathway (Fig. 1). Due to the diastereomeric nature of the
stationary points, two inequivalent yet related routes to the
product exist (shown in black and red). Two transition states
(TS1-2a and TS1-2b) from INT1, leading to two energetically
equivalent b-lactam diastereomers (INT2a and INT2b), are
identified at 17.2 and 19.4 kcal molꢀ1 respectively (Fig. 2). From
INT2, two TSs corresponding to C–N bond breaking (TS2a-3a
4
5
1
1
99
97
and TS2b-3b) are calculated to be 18.0 and 16.8 kcal molꢀ1
.
After C–N bond cleavage, rotation about the C–C bond is
possible, establishing an equilibrium between the INT3a
and INT3b rotamers, allowing crossover between the two
diastereomeric pathways. TS3a-4 and TS3b-4 (18.3 and
17.2 kcal molꢀ1) are the final barriers before formation of
product. All attempts to locate a nucleophilic addition inter-
mediate were unsuccessful, with minimisations from TS3-4
leading directly to the final nucleophilic substitution product.17 All
attempts to locate a cyclisation TS from a pyridyne intermediate
were likewise unsuccessful. Overall, the energetically preferred
pathway passes through TS1-2a, TS2a-3a, and TS3b-4, with
a rate-determining step of 18.0 kcal molꢀ1 corresponding
to C–N bond breaking at TS2a-3a, not the nucleophilic
substitution step. The differences between the various TSs
are small (ca. 0.8 kcal molꢀ1), and may therefore be readily
altered by substituent effects. Most importantly, this study
establishes that the ‘‘disfavoured’’ substitution step is no more
energetically demanding than the experimentally supported
Truce–Smiles rearrangement.
6
7
8
3
66
99
51
1
16
9
3
94
10
11
4
60
33
In conclusion, we have developed a novel, inexpensive
protocol for the synthesis of 3,3-disubstituted aza-oxindoles.
The rate and yield of the reaction are dependent on the
pyridine N atom position. Mechanistic studies suggest that
the reaction proceeds via a Truce–Smiles rearrangement–
nucleophilic substitution pathway.
24
We thank the Swiss National Science Foundation and the
University of Geneva for financial support.
a
Isolated yield.
c
10958 Chem. Commun., 2012, 48, 10957–10959
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Fig. 1 B3LYP/6-311++G** potential energy surface (free energies, kcal molꢀ1).
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c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 10957–10959 10959