Investigation of a Late-Stage Derivatization Approach to Isatogens: Discovery of New Reaction Pathways

Article abstract of DOI:10.1002/ejoc.201501372

We have developed a new strategy for preparing 2-substituted indolone N-oxides (isatogens) by substitution reactions with aryl- and alkyl-organometallic reagents. This approach allows a range of substituents to be incorporated at a late stage and complements existing methods that necessitate their early stage incorporation during substrate preparation. Further chemistry has been found to take place at the nitrone moiety; intramolecular dipolar cycloaddition provides access to angularly fused tricyclic heterocycles. More unusually however, these compounds are prone to further addition by organozinc reagents leading to 2,2-disubstituted 3-oxindole products.

Full text of DOI:10.1002/ejoc.201501372

DOI: 10.1002/ejoc.201501372
Full Paper
Heterocyclic Chemistry
Investigation of a Late-Stage Derivatization Approach to
Isatogens: Discovery of New Reaction Pathways
Steven J. Edeson,[a] Elvis J. M. Maduli,[a] Stephen Swanson,[b] Panayiotis A. Procopiou,[b] and
Joseph P. A. Harrity*[a]
Abstract: We have developed a new strategy for preparing 2- Further chemistry has been found to take place at the nitrone
substituted indolone N-oxides (isatogens) by substitution reac-
tions with aryl- and alkyl-organometallic reagents. This ap-
proach allows a range of substituents to be incorporated at a
late stage and complements existing methods that necessitate
their early stage incorporation during substrate preparation.
moiety; intramolecular dipolar cycloaddition provides access to
angularly fused tricyclic heterocycles. More unusually however,
these compounds are prone to further addition by organozinc
reagents leading to 2,2-disubstituted 3-oxindole products.
Introduction
Indolone N-oxides (isatogens) were first prepared by
Baeyer[1] and constitute an interesting class of stable dipolar
compounds that have been shown to display a variety of useful
biological properties.[2] These compounds are typically gener-
ated from 2-nitrophenylacetylenes in the presence of acid or
base,[3] or by transition metal catalysis.[4] Recent studies in our
labs sought to develop a new strategy that allowed the
late-stage functionalization of isatogens. Specifically, as shown
in Scheme 1, while traditional approaches have necessitated
the incorporation the C2 substituent by appending this group
at the alkyne, we envisaged that a more divergent approach
to isatogens could comprise the employment of a nucleofuge
bearing alkyne that would offer the potential to incorporate C2-
substituents in the final step by a nucleophilic substitution or
cross-coupling process (Scheme 1). In the event, we were able
to devise a Cu-promoted cyclization of 2-nitrophenyl iodoacet-
ylenes to generate a range of 2-iodoisatogens.[5] Preliminary
studies showed that 2-iodoisatogens could undergo Sonoga-
shira coupling reactions, but the suitability of these compounds
to access more widely utilized 2-aryl/alkyl-isatogens was less
well established. We therefore undertook a more detailed study
into the arylation and alkylation of 2-iodoisatogens and report
our findings herein.
Scheme 1. Late-stage functionalization of isatogens.
Results and Discussion
We began our studies by investigating the Negishi cross-cou-
pling of arylzinc halides to iodoisatogens as a means of access-
ing 2-arylisatogens, and our results are summarized in
Scheme 2. Our preliminary attempts to promote the cross-
coupling with the Pd/SPhos catalyst system delivered the ex-
pected product 2, however, the yields were poor and the reac-
tion mixtures were rather complex. We were aware of the po-
tential of Pd-catalyst to promote conversion of isatogens to
isatins[4c] and so decided to establish whether or not this trans-
formation could proceed smoothly in the absence of the Pd-
ligand system. Pleasingly, the addition of PhZnCl alone resulted
in the formation of 2 in good yield.
[a] Department of Chemistry, University of Sheffield,
Brook Hill, Sheffield S3 7HF, United Kingdom
E-mail: j.harrity@sheffield.ac.uk
https://www.sheffield.ac.uk/chemistry/staff/profiles/
joseph_harrity
[b] GlaxoSmithKline,
Stevenage, Herts SG1 2NY, United Kingdom
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201501372.
Scheme 2. Synthesis of 2-arylisatogens.
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We next decided to examine the scope of this transformation
and our results are summarized in Table 1. Isatogen 1a under-
went smooth substitution with a small selection of 4-substi-
tuted arylzinc reagents in good yield (entries 1–3). The chemis-
try could be extended to 6-halo-substituted substrates, albeit
in more modest yield (entries 4,5). Finally, 7-chloro substituted
isatogen 8 was also generated in modest yield, although the
instability of this product hampered our efforts to isolate this
compound in pure form.
Table 1. Synthesis of 2-arylisatogens.
Entry
R
Ar
Yield
1
2
3
4
5
6
5-MeO; 1a
5-MeO; 1a
5-MeO; 1a
6-F; 1b
6-Br; 1c
7-Cl; 1d
4-ClC6H5
4-MeOC6H5
4-F3CC6H5
Ph
Ph
Ph
3; 65 %
4; 66 %
5; 59 %
6; 40 %
7; 48 %
8; 46 %[a]
Scheme 4. Synthesis of 2-alkylisatogens.
[a] Isatogen 8 was found to decompose after isolation and could not be
generated in analytically pure form. See supporting information for 1H, 13C
spectra.
With simple and practical conditions in hand to generate 2-
arylisatogens, we decided to explore the potential of this trans-
formation to deliver the corresponding 2-alkyl analogs. To our
surprise however, treatment of 1a with freshly prepared EtZnI
returned the expected isatogen in low yield, together with the
N-ethoxy-3-oxindole 10 (Scheme 3).
Scheme 5. Addition of functionalized organometallics.
sult and decided to explore this reaction further. Interestingly,
the utilization of dialkylzinc reagents allowed these compounds
to be isolated in synthetically useful yields. Moreover, the struc-
ture of these unusual compounds was confirmed in the case of
24 which was isolated as a crystalline solid allowing its charac-
terization by X-ray analysis (Scheme 6).[8]
The mechanism of formation of the N-alkoxy-3-oxindoles is
intriguing, and a proposed pathway is outlined in Scheme 7.
The propensity of alkylzinc reagents to generate 2-alkylisato-
gens suggests that the first step involves the displacement of
the iodide. Nucleophilic addition would then provide zinc alkox-
ide 25 which undergoes oxidation to a nitroxyl radical 26. The
oxidation of related zinc alkoxides in the presence of dialkylzinc
reagents has been reported by Maury et al.,[9] moreover, N-
hydroxy 3-indolones are known to readily form the correspond-
ing nitroxyl radicals.[10] Although the nature of the oxidant is
unclear at present, adventitious oxygen and/or the N-alkoxy-3-
oxindole products themselves can all function as electron ac-
ceptors. The final step requires the addition of an alkylzinc rea-
gent to the nitroxyl radical. In this respect, Curran and co-
Scheme 3. Alkylation of 2-iodoisatogen 1a.
The formation of 10 was unexpected and the mechanism of
its formation unclear (vide infra) but in an effort to optimize the
formation of 2-alkylisatogens such as 9 we decided to screen
alternative organometallic reagents. In the event, mixed copper
reagents[6] proved to be most effective, and allowed a range of
alkyl and cycloalkyl groups to be incorporated in modest to
high yield (Scheme 4). Notably, the organocopper reagents did
not preclude formation of the N-alkoxy-3-oxindole by-products,
and minor amounts (typically about 5–10 %) of these were iso-
lated in each case.
The incorporation of more functionalized alkyl groups was
also found to be viable. Isatogen 19 bearing a terminal ester
was prepared in 50 % yield. Interestingly, attempts to prepare
isatogens containing a terminal olefin instead generated angu-
larly fused tricycles 20 and 21, presumably after substitution
and in situ [3 + 2] dipolar cycloaddition (Scheme 5).[7]
Returning to the formation of the N-ethoxy-3-oxindole deriv- worker has shown that various organometallic reagents can
ative 10 (Scheme 3), we were intrigued by this unexpected re- convert TEMPO into the corresponding ethers.[11]
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The proposed mechanistic scheme implied that this chemis-
try should be amenable to the synthesis of unsymmetrical 2,2-
disubstituted oxindoles and so we set out to confirm this. As
shown in Scheme 8, diethylzinc underwent smooth addition to
isatogen 1a to provide the corresponding adducts in good yield
[Equation (1)]. The limited availability of dialkylzinc reagents as
compared to alkylzinc halides prompted us to explore the react-
ivity of the latter reagents. Pleasingly, as shown in Equation (2),
2-phenylisatogen 30 underwent addition of alkylzinc iodides to
give the corresponding products in similar yields. Finally, these
products underwent hydrogenolysis to the corresponding 2,2-
disubstituted 3-oxindoles as exemplified by the synthesis of
compounds 33 and 34.
Conclusions
In conclusion, 2-iodoisatogens function as useful precursors to
a range of new dipolar intermediates through substitution reac-
tions with aryl- and alkyl-organometallic reagents. Further
chemistry has been found to take place at the nitrone moiety;
intramolecular dipolar cycloaddition provides access to angu-
larly fused tricyclic heterocycles. More unusually however, these
compounds are prone to further addition by organozinc rea-
gents leading to 2,2-disubstituted 3-oxindole products.
Scheme 6. Synthesis of N-alkoxy-3-oxindoles.
Experimental Section
General Procedure for the Addition of Cuprates to 2-Iodoisato-
gens. Synthesis of 2-Ethyl-5-methoxy-3-oxo-3H-indole 1-Oxide
(9): A flame dried flask equipped with magnetic stirrer bar was
charged with 2-iodo-5-methoxy-3-oxo-3H-indole 1-oxide (1a)
(0.050 g, 0.165 mmol) in anhydrous THF (5.0 mL) at 20 °C. EtCu(CN)-
ZnI·2LiCl (0.62 mL, 0.281 mmol, 0.45
M THF) was added dropwise
over 5 min. The reaction mixture was stirred at 20 °C for 18 h then
quenched with saturated NH4Cl(aq) (5.0 mL) and brine (10.0 mL)
then extracted with EtOAc (2 × 15.0 mL). The organic extracts were
combined, dried with MgSO4 and concentrated under vacuum to
afford a red amorphous solid which was purified via flash column
chromatography on silica gel (1:18 ethyl acetate/petroleum ether)
providing the title compound as a red crystalline solid (0.025 g,
Scheme 7. Synthesis of N-alkoxy-3-oxindoles.
1
75 %). H NMR (400 MHz, CDCl3): δ = 7.48 (d, J = 8.5 Hz, 1 H), 7.08
(d, J = 2.5 Hz, 1 H), 7.01 (dd, J = 8.5, 2.5 Hz, 1 H), 3.87 (s, 3 H), 2.65
(q, J = 7.5 Hz, 2 H), 1.21 ppm (t, J = 7.5 Hz, 3 H). 13C NMR (100.6 MHz,
CDCl3): δ = 186.6, 162.3, 140.3, 139.6, 125.0, 117.3, 115.0, 108.2, 56.2,
15.0, 9.8 ppm. FTIR (film): 2937 (w), 1704 (s), 1618 (w), 1531 (s), 1486
(s), 1435 (m), 1390 (s), 1356 (s), 1280 (m), 1230 (m), 1097 (m), 821
(m), 801 (w) cm–1. HRMS (TOF MS ES+) m/z calcd. for [C11H12NO3]+:
206.0817 [M + H]+, found 206.0807; M.p. 51–55 °C (CH2Cl2).
General Procedure for the Addition of Diethylzinc to Isatogens.
Synthesis of 1,2-Dihydro-1-ethoxy-2,2-diethyl-3H-indol-3-one
(10): A flame dried flask equipped with magnetic stirrer bar was
charged with 2-iodo-3-oxo-3H-indole 1-oxide (1a) (0.030 g,
0.100 mmol) in anhydrous THF (3.0 mL) at 20 °C. Et2Zn (0.25 mL,
0.150 mmol, 0.6
M hexanes) was added dropwise and the reaction
mixture stirred under nitrogen for 18 h. The reaction mixture was
quenched with H2O (1.8 mL), extracted with ethyl acetate (10.0 mL)
and washed with brine (5.0 mL). The organic layer was dried with
MgSO4 and concentrated under vacuum to give a viscous orange
oil, which was purified by flash column chromatography on silica
Scheme 8. Synthesis of 2,2-disubstituted oxindoles.
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gel (5:95 ethyl acetate/petroleum ether) providing the title com-
pound as a bright yellow oil (0.018 g, 68 %). 1H NMR (400 MHz,
CDCl3): δ = 7.20 (dd, J = 9.0, 2.5 Hz, 1 H), 7.14 (d, J = 9.0 Hz, 1 H),
7.02 (d, J = 2.5 Hz, 1 H), 4.10 (q, J = 7.0 Hz, 2 H), 3.79 (s, 3 H), 1.92
(dq, J = 14.5, 7.0 Hz, 2 H), 1.77 (dq, J = 14.5, 7.0 Hz, 2 H), 1.37 (t,
J = 7.0 Hz, 3 H), 0.70 (t, J = 7.0 Hz, 6 H) ppm. 13C NMR (100.6 MHz,
CDCl3): δ = 201.4, 158.3, 155.3, 126.8, 122.6, 114.8, 103.1, 80.3, 71.7,
55.8, 29.3, 14.4, 8.8 ppm. FTIR (film): 2969 (w), 2929 (w), 1706 (s),
1488 (s), 1439 (m), 1266 (m), 1229 (w), 1145 (w), 1030 (m), 826
(w), 804 (w) cm–1. HRMS (TOF MS ES+) m/z calcd. for [C15H22NO3]+:
264.1600 [M + H]+, found 264.1593.
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Acknowledgments
We are grateful to the Engineering and Physical Sciences Re-
search Council (EPSRC) and GlaxoSmithKline for financial sup-
port.
Keywords: Synthetic methods · Fused-ring systems · Nitrogen
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Received: October 29, 2015
Published Online: November 17, 2015
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