Ylide mediated carbonyl homologations for the preparation of isatin derivatives

Article abstract of DOI:10.1039/c3ob42024h

An exceptionally mild method for the preparation of isatin derivatives has been developed using a sulfur ylide mediated carbonyl homologation sequence starting from anthranilic acid precursors. This method proceeds at ambient temperature via a sulfur ylide intermediate without the need for protection of the amine or chromatographic isolation of the intermediate ylide. Gentle oxidation of the sulfur ylides provides isatin derivatives with N-H, N-alkyl, N-aryl substitution, electron-rich and electron-poor aromatic rings, and heterocyclic aromatic systems. We anticipate that this method will greatly expand the accessibility of complex isatin derivatives.

Full text of DOI:10.1039/c3ob42024h

Organic &
Biomolecular Chemistry
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Ylide mediated carbonyl homologations for the
preparation of isatin derivatives†
Cite this: Org. Biomol. Chem., 2014,
12, 406
Christina T. Lollar,a Katherine M. Krenek,a Kevin J. Bruemmera and
Received 10th October 2013,
Accepted 8th November 2013
Alexander R. Lippert*a,b
DOI: 10.1039/c3ob42024h
www.rsc.org/obc
An exceptionally mild method for the preparation of isatin deriva- selenium-mediated oxidations,30 indole oxidations,31 aryne-
tives has been developed using a sulfur ylide mediated carbonyl based methods,32 Sandmeyer modifications,33 and molecular
homologation sequence starting from anthranilic acid precursors. elaboration of simple isatin synthons.34 Many of these
This method proceeds at ambient temperature via a sulfur ylide methods, however, still display limited substrate scope or
intermediate without the need for protection of the amine or chro- harsh reaction conditions. As such, there is a pressing need
matographic isolation of the intermediate ylide. Gentle oxi- for safe, mild, and versatile strategies to prepare isatin
dation of the sulfur ylides provides isatin derivatives with N–H, derivatives.
N-alkyl, N-aryl substitution, electron-rich and electron-poor aro-
Sulfur ylides have received increasing attention due to their
matic rings, and heterocyclic aromatic systems. We anticipate that unique modes of reactivity, including epoxidations,35 aziridi-
this method will greatly expand the accessibility of complex isatin nations,36 cyclopropanations,37 and rearrangements.38 Reson-
derivatives.
ance stabilized sulfur ylides can be readily acylated using a
variety of coupling reagents, and oxidation of the carbon–
sulfur bond leads to dicarbonyl derivatives,39,40 most notably
α-ketoacids used in α-ketoacid-hydroxylamine peptide ligation
reactions.41 We envisioned that the mild conditions used in
sulfur ylide mediated carbonyl homologations of this type
could provide ready access to isatin derivatives from anthrani-
lic acid precursors. Herein, we report an efficient and mild
preparation of the isatin moiety that utilizes an ylide acylation/
oxidation sequence to affect an overall carbonyl homologation
with concomitant amide bond formation (Scheme 1). This pro-
cedure offers significant advantages over classical methods
including ambient temperature, mild reagents, and perfect
regiochemical control.
Isatin (1H-indol-2,3-dione) is an oxidized indole derivative that
is endogenously present in mammalian blood, urine, and
tissue.1–3 Isatin and its derivatives display rich biological
activity,4,5 having been shown to inhibit monoamine oxidase
enzymes,6 attenuate natriuretic peptide-stimulated7 and nitric
oxide-stimulated cyclic guanosine monophosphate release,8
and act as sedatives,9 anti-inflammatory,10 antiviral,11 and
anticancer,12–15 agents. In addition, isatin is endowed with ver-
satile reactivity, and is often employed as a synthetic inter-
mediate.16,17 The great potential of this important
pharmacophore and synthetic building block is ultimately
limited by the harsh conditions needed for its preparation.
Classical methods for the synthesis of isatin and its deriva-
tives, including the Sandmeyer,18–20 Stollé,21–23 Martinet,24,25
and the Gassman26 procedures, typically require harsh
reagents, elevated temperatures, and non-ideal solvents.
Additionally, most of these methods do not allow for easy
control of regiochemistry, limiting the substrate scope of the
reaction. Recently, several improved protocols have been put
forth including copper-catalyzed C–H oxidations,27–29
aDepartment of Chemistry, Southern Methodist University, Dallas, TX 75275-0314,
USA. E-mail: alippert@smu.edu; Fax: +1-214-768-4089; Tel: +1-214-768-2482
bCenter for Drug Discovery, Design, and Delivery (CD4), Southern Methodist
University, Dallas, TX 75275-0314, USA. E-mail: alippert@smu.edu;
Fax: +1-214-768-4089; Tel: +1-214-768-2482
†Electronic supplementary information (ESI) available: Experimental pro-
cedures, 1H NMR, 13C NMR, and HRMS data. See DOI: 10.1039/c3ob42024h
Scheme 1 Mild sulfur ylide mediated preparation of isatin derivatives.
406 | Org. Biomol. Chem., 2014, 12, 406–409
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entry 2). The ylide coupling reaction was found to be optimal
in CH2Cl2, but also tolerated DMF, THF, and CH3CN (Table 1,
entries 3–5), albeit with reduced yields at the measured time
points. We next explored the conditions of the oxidation reac-
ð1Þ
We began by exploring the conversion of anthranilic acid tion using the sulfur ylide 2a formed in CH2Cl2. The oxidation
into the α-keto-cyanosulfur ylide 2a (Table 1). Our strategy was reaction proceeded best in H2O and an organic co-solvent such
to form a cyanosulfur ylide in situ from the corresponding as THF, DMF, or acetone, which effectively solubilized the
sulfonium bromide salt 1. This salt is easily prepared from the Oxone salts and the ylide (Table 1, entries 1, 6–8). Even in the
neat reaction of dimethyl sulfide and bromoacetonitrile absence of added H2O, Oxone could still affect ylide oxidation
(eqn (1)). Stirring overnight at ambient temperature yields a in DMF, providing the isolated isatin in 61% (Table 1, entry 9).
pure white solid that is easily handled and stable for months It is important to note that the pH of the reaction under these
when stored under nitrogen at 4 °C. Our initial concern was conditions is in the range of 2–3, due to the acidity of the
that the unprotected amine of the anthranilic acid would Oxone salt mixture. Attempts to buffer to pH 7 resulted in a
compete with the cyanosulfur ylide formed in situ from 1 in significant drop in yield (Table 1, entry 10).
the acylation reaction. Indeed, we found that using 1.2 equiva-
Having found optimal conditions, we next explored the
lents of the sulfonium bromide salt 1 lead to an unoptimized scope of the reaction across a panel of anthranilic acid deriva-
60% yield of isatin due to formation of a dimerized side tives. The reaction proceeded efficiently with N–H, N-methyl,
product (Table 1, entry 1). Fortunately, simply using three and N-phenyl substituents, providing the corresponding
equivalents of 1 effectively suppressed this side reaction, pro- isatins in 85%, 60%, and 76% yields, respectively (Table 2,
viding the coupled α-keto-cyanosulfur ylide product 2a in an entries 1–3). Electron-poor aromatic rings, including 5-Br-,
efficient manner (Table 1, entry 2). Using the appropriate 4-Cl-, 4-F-, and 2-CF3- substituted anthranilic acids, were good
work-up, the coupled ylide product 2a could be obtained substrates for this reaction sequence, cleanly affording the
essentially pure except for the presence of 2 equivalents of the halogenated isatin products (Table 2, entries 4–7). Electron
unreacted cyanosulfur ylide derived from the sulfonium rich aromatic systems, including 6-Me- and 4-MeO- substituted
bromide salt 1.
anthranilic acids also yielded the corresponding isatins
We found that, unlike other resonance-stabilized α-keto- (Table 2, entries 8 and 10). We found, however, that 3-Me-
cyanosulfur ylides,36,37 these α-keto-γ-amino-cyanosulfur ylides anthranilic acid produced isatin 3i in a reduced yield, indicat-
spontaneously oxidized on silica gel forming a mixture of ing that steric hindrance at the 6-position attenuates the reac-
isatins and other fluorescent oxidation products. Hence, the tion efficiency, most likely during the ylide formation step
ylides were directly oxidized without further chromatographic (Table 2, entry 9). Finally, we utilized our ylide acylation/oxi-
purification. Treatment with 1.5 equivalents of Oxone (2KOOSO3· dation sequence on an amino nicotinic acid substrate (Table 2,
KHSO4·K2SO4)42 for 10 minutes in 2 : 1 THF–H2O provided the entry 11) and were pleased to find that aza-isatin derivatives
isatin 3a in 85% yield over the two step protocol (Table 1, could be readily prepared using this method. In all cases, the
two-step sequence proceeded without chromatographic purifi-
cation of the ylides 2a–k, and most of the ylides were obtained
in good purity after a simple aqueous work-up, with the most
Table 1 Reaction optimization of sulfur ylide mediated carbonyl homo-
logation of anthranilic acid to isatin 3aa
significant impurity being the unreacted cyanosulfur ylide
derived from 1. However, some of the ylides, including the
3-Me- and 4-MeO- sulfur ylides 2i and 2j, provided mixtures
after the sulfur ylide coupling step, indicating that activated
carboxylates of anthranilic acids with steric congestion or
electron rich aromatic systems are less efficacious as ylide
acylating agents.
In summary, we have developed a new, mild, and efficient
preparation of isatin derivatives using a sulfur ylide mediated
carbonyl homologation sequence. The sulfonium bromide 1 is
readily prepared, easily handled, and the ylide formed in situ
can be rapidly and efficiently coupled to anthranilic acid
derivatives using mild reagents without the need for protection
of the amino group. The sulfur ylides 2a–k can be directly oxi-
dized without chromatographic purification. Treatment with
Oxone for 10 minutes at room temperature provides the isatins
3a–k, highlighting a wide substrate scope for this easy and ver-
satile isatin-forming process. We expect that this streamlined
procedure will allow access to isatin derivatives that would be
difficult to prepare using classical methods.
Entry
Solvent A
Solvent B
Yieldb
1c
2
3
4
5
6
7
8
9
CH2Cl2
CH2Cl2
DMF
2 : 1 THF–H2O
2 : 1 THF–H2O
2 : 1 THF–H2O
2 : 1 THF–H2O
2 : 1 THF–H2O
2 : 1 acetone–H2O
4 : 1 H2O–DMF
9 : 1 H2O–DMF
DMF
60%
85%
59%
75%
40%
68%
75%
81%
61%
26%
THF
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
10
9 : 1 500 mM PBS pH 7–DMF
a Reactions were performed with anthranilic acid (1 mmol),
1
(3 mmol), HBTU (1.2 mmol), and DIPEA (3 mmol) in solvent A
(10 mL), then Oxone (1.5 mmol) in solvent B (20 mL). b Isolated yields.
c Reaction was performed with 1.2 mmol 1.
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Table 2 Substrate scope of sulfur ylide mediated carbonyl homologa-
tion of anthranilic acids to isatins 3a–3ka
Acknowledgements
We gratefully acknowledge Southern Methodist University
(start-up funds to A.R.L.) for providing financial support for
this project. We thank the Engaged Learning program at
Southern Methodist University (research funds to C.T.L.) for
providing additional funding. C.T.L. and K.J.B. are supported
by a Hamilton Undergraduate Research Scholarship. We thank
Maciej Kukula of the Shimadzu Center for Advanced Analytical
Chemistry at the University of Texas at Arlington for acquiring
high-resolution mass spectrometry data. Sara Merrikhihaghi
provided experimental assistance for the characterization of
compounds.
Entry
1
Yield
Isatin
Yieldb,c
85%
2
3
4
5
6
7
60%
76%
69%
60%
81%
91%
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