A mild and efficient synthesis of spiroquinolinones via an unexpected rearrangement

Article abstract of DOI:10.1016/j.tetlet.2015.09.054

A mild and efficient synthesis of spiroquinolinones 6 via condensation of chlorooxoindolines 5 and benzene-1,2-diamines 3 is reported. Instead of expected spirooxindole product 4′, spiroquinolinones 6 were isolated in up to 95% yield. A plausible mechanism involving an interesting ring rearrangement to form spiroquinolinones is proposed.

Full text of DOI:10.1016/j.tetlet.2015.09.054

Accepted Manuscript
A mild and efficient synthesis of spiroquinolinones via an unexpected rear-
rangement
Bin Zou, Seh Yong Leong, Mei Ding, Paul W. Smith
PII:
S0040-4039(15)30096-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.09.054
TETL 46726
Reference:
Tetrahedron Letters
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31 July 2015
15 September 2015
Please cite this article as: Zou, B., Leong, S.Y., Ding, M., Smith, P.W., A mild and efficient synthesis of
spiroquinolinones via an unexpected rearrangement, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/
j.tetlet.2015.09.054
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1
Tetrahedron Letters
A mild and efficient synthesis of spiroquinolinones via an unexpected rearrangement
Bin Zou, Seh Yong Leong, Mei Ding and Paul W. Smith
Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos, 138670, Singapore
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A mild and efficient synthesis of spiroquinolinones 6 via condensation of chlorooxoindolines 5
and benzene-1,2-diamines 3 is reported. Instead of expected spirooxindole product 4',
spiroquinolinones 6 were isolated in up to 95% yield. A plausible mechanism involving an
interesting ring rearrangement to form spiroquinolinones is proposed.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
spiroquinolinones
condensation reaction
chlorooxoindolines
diamines
mechanism
The spirooxindole motif is a unique architecture found in
many natural products and synthetic drugs.1 After the discovery
of NITD609 as a new chemotype with a novel mechanism of
action for the treatment of malaria (Figure 1),2 we recently
identified another spirooxindole 1 with promising anti-dengue
activity.3 These interesting findings further enhanced our
confidence and interest in the design and synthesis of further
novel spirooxindole scaffolds as potential drug lead candidates.4
Scheme 1. Synthesis of unexpected spiroquinolinone 6a.
Figure 1. Spriooxindoles identified as possessing antimalarial and antiviral
activity.
Previously, we reported a new approach for the synthesis of
spriooxindole 4 by condensation of chloroxoindoline 2 with
benzene-1,2-diamines 3a under mild conditions (Scheme 1).4b
Following a similar approach, we attempted to use compound 5a
with an extended methylene as the substrate for this reaction.
However, to our surprise under similar reaction conditions,
spiroquinolinone 6a was formed with excellent yield (84%)
instead of the expected spirooxindole 4' (Scheme 1). The
structure of compound 6a was unambiguously confirmed by
single crystal X-ray analysis (Figure 1).5
Figure 1. The X-ray crystal structure of compound 6a.
Following this interesting observation, herein, we report the
synthesis of a series of novel spiroquinolinones. We initially
———
 Corresponding author. Tel.: +65-67222921; fax: +65-67222918; e-mail: bin.zou@novartis.com

2
investigated the reaction conditions to study the effect of
diamines (3d-f), the electronic and steric effect of the substituents
differentiates the nucleophilicity of the two amino groups,
impacting the regioselectivity of the observed products.4b Both
3d (3-tBu) and 3e (4-OMe) afforded single regioisomers 6n and
6o, respectively (Table 2, entries 14-15). However, in 3f, the 4-Cl
had less impact on the nucleophilicity of the two amino groups,
leading to an inseparable 1:1 mixture of 6p and 6q (determined
by 1H NMR analysis, entry 16).
changing solvent and base (Table 1). When organic bases, Et3N
and DABCO were utilized, the yield of product 6a was
significantly reduced (Entries 2 and 3). Product 6a was isolated
with similar yield to the original experiment (86%) when Cs2CO3
was utilized as the base (Entry 4). Further screening of inorganic
bases revealed that basicity was critical for the yield (Entries 4-
6). For example, only a trace amount of product was isolated
when the less reactive base Li2CO3 was used (Entry 6).
Chlorinated solvents, such as 1,2-dichloroethane, gave a similar
yield of 6a (85%, Entry 7). However, polar solvents, such as
THF and DMF, produced relatively low yields (56% and 54%,
respectively) of the desired product (Entries 8 and 9).
Table 2 Synthesis of spiroquinolinones 6a-m. a
Table 1 Optimization of the reaction conditions.
Entry
Conditionsa
CsF, CH2Cl2,
Yield (%)b
1
2
3
4
5
6
7
8
9
84
11
Et3N, CH2Cl2,
Entry Compound
R1
6-Cl
R2
Yield (%)b
DABCO,c CH2Cl2
Cs2CO3, CH2Cl2
Na2CO3, CH2Cl2
Li2CO3, CH2Cl2
Cs2CO3, ClCH2CH2Cl
Cs2CO3, THF
0
1
2
6a
6b
6c
6d
6e
6f
H
86
85
61
81
88
79
70
31
62
65
62
95
86
61
5-Cl
H
trace
85
3
7-Cl
H
4
8-Cl
H
56
Cs2CO3, DMF
54
5
6-OMe
6-OCF3
6-F
H
aMolar ratio of 5a/3a 0.20/0.40 mmol, base (1 mmol), rt, 16 h; bIsolated
6
H
yield; c1,4-diazabicyclo[2.2.2]octane
7
6g
6h
6i
H
In order to examine the substrates scope for this reaction, a series
of substituted 3-chlorooxoindolines 5a-k were synthesized via
condensation of substituted isatins 7a-k with mono-ethyl
malonate 8 followed by chlorination with thionyl chloride
(Scheme 2).6,7
8
6-NO2
H
H
9
H
10
11
12
6j
6-Me
6-tBu
6-Cl
H
H
6k
6l
6',7'-di-F
13
6m
6-Cl
6',7'-OCH2CH2O
78
14
15
6n
6o
6-Cl
6-Cl
5'-tBu
64
78
6'-OMe
Scheme 2 Synthesis of 3-chlorooxoindolines 5a-k.
6p
6q
6-Cl
6-Cl
6'-Cl
7'-Cl
16
77c
With a diverse set of 3-chlorooxoindolines 5 in hand, the
condensation with diamines 3a-f was investigated (Table 2).8 In
general, good to excellent yields were observed. For instance,
substrates 5a-d with Cl-substitution at different positions gave
compounds 6a-d in good yields (Table 2, entries 1-4), although
the yield of 6c was somehow lower (61%). As a trend,
compounds with electron-donating groups at the 6-position
appear more favorable compared to electron-withdrawing groups
(Table 2, entries 5-8). For example, product 6e with 6-OMe
substitution was isolated in 88% yield, while compound 6h with
6-NO2 substitution was obtained in only 31% yield. A steric
effect at the 6-position was not apparent since products 6i-k were
isolated in similar yields (62-65%, Table 2, entries 9-11). These
findings were not surprising since 5-substitution of 3-
chlorooxoindolines 5i-k should have only a marginal steric effect
on reactivity. 4,5-Di-substiuted diamines 3b-c gave the
corresponding products 6l and 6m in 95% and 78% yields,
respectively (entries 12-13). In the case of mono-substituted
aReaction conditions: Molar ratio of 5:3 0.20/0.40 mmol, Cs2CO3 (1
mmol), CH2Cl2, rt, 16 h; bIsolated yield; cTotal yield of 6p and 6q.
A plausible mechanism for this condensation to form the
spiroquinolinones is proposed (Scheme 3). Elimination of
chloroxoindoline 5a in the presence of base affords indolone
intermediate A, which undergoes nucleophilic attack by benzene-
1,2-diamine 3a to give intermediate B. The primary amine of
intermediate B attacks the carbonyl of the oxindoline to give
aniline intermediate C, which is further transformed to the spiro-
6,6-ring system product 6a by intramolecular lactamization.9 To
the best of our knowledge, this is the first case reported involving
an oxindoline rearrangement to form a spiroquinolinone.10

3
corresponding 3-hydroxyloxindolines as dark red solids. To the
solution of above residue in THF (25 mL) was added pyridine (15 mmol)
and SOCl2 (25 mmol) at 0 °C. After reaction completion as indicated by
TLC, the reaction mixture was concentrated in vacuo. The residue was
dissolved in ethyl acetate (30 mL) and washed with aqueous sat.
NaHCO3 (20 mL), brine (20 mL), dried over Na2SO4 and concentrated.
The crude product was purified by column chromatography (0%-50%
ethyl acetate in cyclohexane) to give compounds 5a-k.
8. General procedure for synthesis of spiroquinolinones: A mixture of
diamines 3 (0.70 mmol) and Cs2CO3 (1.75 mmol) in CH2Cl2 (1.5 mL)
were stirred at rt for 10 min before a solution of 3-chlorooxindolines 5
(0.35 mmol) in CH2Cl2 (1.5 mL) was added dropwise. The resultant
mixture was stirred at room temperature for 16 h. The reaction mixture
was concentrated in vacuo and the residue purified by column
chromatography (0%-50% ethyl acetate in cyclohexane) to give
compounds 6 as solids.
9. For an example of oxidative spriooxindole ring expansion, see: Bergman,
J.; Arewang, C-J.; Svensson, P. H. J. Org. Chem. 2014, 79, 9065-9073.
10. For similar examples involving oxindoline ring opening rearrangements,
see: a) Rajesh, R.; Raghunathanm R. Eur. J. Org. Chem. 2013, 2597-
2607; b) Bertamino, A.; Aquino, C.; Sala, M.; de Simone, N.; Mattia, C.
A.; Erra, L.; Musella, S.; Iannelli, P.; Carotenuto, A.; Grieco, P.;
Novellino, E.; Campiglia, P.; Gomez-Monterrey, I. Bioorg. Med. Chem.
2010, 18, 4328-4337.
Scheme 3. Proposed mechanism of the reaction.
In summary, a mild and efficient synthesis of a novel class of
spiroquinolinone compounds via a two component condensation
reaction has been developed. Evaluation of the biological
activities for this new class of spiro-compounds will be reported
in due course.
Acknowledgments
We thank all the chemists at Novartis Institute for Tropical
Diseases for providing support performing this research. We
thank Dr. Trixie Wagner and Dr. Ina Dix for collecting the X-ray
data.
Supplementary Material
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References and notes
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B. K. S.; Zou, B.; Rottmann, M.; Lakshminarayana, S. B.; Ang, S. H.;
Leong, S. Y.; Tan, J.; Wong, J.; Keller-Maerki, S.; Fischli, C.; Goh, A.;
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7. General procedure for the synthesis of 3-chlorooxindolines 5a-k: To the
mixture of isatins 7 (5 mmol) in ethanol/pyridine/acetic acid (33 mL,
7.5:2.5:1) was added acid 8 (5.5 mmol) and the resulting mixture was
heated at reflux for 16 h. After cooling to rt, the reaction mixture was
concentrated in vacuo. The residue was dissolved in ethyl acetate (50
mL) and the resulting solution washed with aqueous NaHCO3 (30 mL),
brine (30 mL), dried over Na2SO4 and concentrated to give the

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Bin Zou*, Seh Yong Leong, Mei Ding and Paul W. Smith