Synthesis of Spirooxindoles via the tert-Amino Effect

Article abstract of DOI:10.1021/acs.orglett.7b01752

A new method is developed for the synthesis of spirooxindoles from amines and isatins via C-H functionalization. The reaction leverages the tert-amino effect to form an enolate-iminium intermediate via [1,5]-hydride shift followed by cyclization. Interest

Full text of DOI:10.1021/acs.orglett.7b01752

Letter
pubs.acs.org/OrgLett
Synthesis of Spirooxindoles via the tert-Amino Effect
Kinthada Ramakumar, Tapan Maji, James J. Partridge, and Jon A. Tunge*
Department of Chemistry, The University of Kansas, 2010 Malott Hall, 1251 Wescoe Hall Drive, Lawrence, Kansas 66045, United
States
The KU Chemical Methodologies and Library Development Center of Excellence, The University of Kansas, 2034 Becker Drive,
Lawrence, Kansas 66047, United States
*
S Supporting Information
ABSTRACT: A new method is developed for the synthesis of
spirooxindoles from amines and isatins via C−H functionaliza-
tion. The reaction leverages the tert-amino effect to form an
enolate−iminium intermediate via [1,5]-hydride shift followed
by cyclization. Interestingly the hydride migrates to the N
atom of a CN, which is atypical for hydride additions to
imines.
ynthesis of biologically active compounds through
S
functionalization of relatively unreactive C−H bonds is
3
an area of intense interest. For example, C(sp )−H bond
activation has attracted considerable attention because of its
potential to rapidly generate molecular complexity and expedite1
the synthesis of natural products and drug intermediates.
Likewise, the tert-amino effect provides an interesting
mechanism for complexity generation via C−H functionaliza-
2
,3
Figure 1. Biologically active spirooxindoles.
tion. These reactions commonly proceed by an internal redox
isomerization involving a hydride migration from the α-carbon
2c
of amines (Scheme 1). For example, Seidel and others have
spirooxindoles could be accessed via exploiting the tert-amino
effect in cyclocondensations with α-dicarbonyl compounds
Scheme 1. tert-Amino Effect: Hydride Migrations
(
Scheme 2). In such a case, condensation of a diamine with the
α-dicarbonyl compound should generate an imine that is
5
predisposed for [1,5]-hydride migration to nitrogen. Cycliza-
Scheme 2. Hypothetical Mechanisms for Cyclocondensation
shown the [1,5]-hydride shift from amines to alkenes that are
2
j−q
activated by a Lewis acid, followed by cyclization.
hydride shifts can occur from amines to the carbon atom of
appropriately activated imines.
Similarly,
2d−i,3
Herein we report a related
synthesis that proceeds via formal hydride shift to the nitrogen
atom of an imine, giving rise to spirooxindoles.
Spirooxindoles are of significant interest due to their
presence in bioactive natural products such as the spirotry-
prostatins, horsfiline, gelsemine, gelseverine, rhynchophylline,
Received: June 9, 2017
4
and elacomine (Figure 1). We hypothesized that unique
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01752
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
tion of the resulting enolate by reaction with the iminium
electrophile would form spirooxindoles. Indeed, a thorough
search of the literature revealed one example of this overall
eomers since they were inseparable; thus, it is not clear whether
the observed diastereoselectivities arise from a kinetic or
thermodynamic selectivity or a combination of both.
3
transformation, although a yield was not reported.
Importantly, attempts to increase the yield of redox
cyclization by increasing the quantity of isatin from 1 to 2
equiv led to much lower yields (entry 18). The decrease in
yield may be explained by preferential binding of the catalyst to
isatin instead of intermediate 3, slowing the activation. Thus,
the best conditions for the spirocyclization involve reaction of
isatin with 1.2 equiv of amine at 80 °C in DCE with 30 mol %
While hydride migration to the carbon of imines is preferred
under conditions where the imine has its standard polarization,
it was expected that Lewis acids could activate the α-imino
amide 3 and stabilize the intermediate enolate, which would
2r,5
facilitate hydride shift to nitrogen. Intermediate 4 may also
be accessible through hydride shift to carbon followed by
3
b,6
rearrangement.
In either case, subsequent cyclization would
of FeCl as a promoter.
3
7
give rise to potentially valuable spirooxindoles 5. A screen of
potential catalysts showed that the reaction of diamine 2 with
With the optimized reaction conditions in hand, we further
explored the substrate scope of this reaction using diamine 2
and functionalized isatins (Scheme 3). A series of isatins
isatin and a catalytic amount of MgCl furnished a 2:1 ratio of
2
diastereomeric spirooxindoles in 15% yield after reaction for 20
h in dichloroethane at 80 °C (Table 1). Screening a variety of
Scheme 3. Spirooxindole Formation Using Different
Isatins
, ,
a b c
a
Table 1. Optimization of Spirooxindole Formation
b
c
entry
promoter
solvent (0.5 M) time (h)
dr
yield (%)
1
2
3
4
5
6
7
8
MgCl2
Gd(OTf)3
AuCl3
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
toluene
THF
DMSO
CHCl3
EtOH
DCE
DCE
20
5
2.0:1
1.0:1
4.3:1
1.6:1
1.3:1
2.5:1
1.7:1
2.7:1
1.0:1
2.0:1
−
15
15
20
25
30
31
36
37
45
68
−
2
Cu(OTf)2
ln(OTf)3
Zn(OTf)2
Sc(OTf)3
TfOH
FeCl3
2
3
4
21
2
d
9
21
2.5
24
24
2
d
10
11
12
13
14
15
16
1
1
FeCl3
−
FeCl3
−
−
FeCl3
1.5:1
1.3:1
2.6:1
1.1:1
2.1:1
1.6:1
48
50
50
54
58
30
FeCl3
2
FeCl3
2
FeCl3
2
e
7
8
FeCl3
2
f
FeCl3
2
a
Reactions of o-pyrrolidinyl aniline (0.5 mmol), isatin (0.5 mmol), and
b
1
promoter (0.15 mmol) in 1 mL of solvent. Determined by H NMR
of the crude reaction mixture. Isolated yield 0.6 mmol of o-
pyrrolidinyl aniline was used. 1.0 mmol of o-pyrrolidinyl aniline was
used. 1.0 mmol of isatin was used.
c
d
e
f
other Lewis acids showed that, while AuCl provided the
3
highest diastereoselectivity for spirocyclization (entry 3, Table
1), FeCl3 produced the product in highest overall yield.
a
o-Pyrrolidinyl aniline (0.6 mmol), isatin (0.5 mmol) and FeCl (0.15
3
Interestingly, the FeCl -promoted reaction gives higher yields
b
1
3
mmol) in 1 mL of DCE. Determined by H NMR of the crude
c d
at shorter reaction times, and decomposition has been observed
at longer reaction times (entries 9 and 10, Table 1).
Importantly, no product formation was observed in the absence
of promoter in DCE solvent after 24 h (entry 11). Finally, a
screen of other solvents revealed that the reaction proceeds well
in THF, DMSO, and EtOH, but failed in toluene. However,
none of the solvents evaluated produced higher yields of 5a
than were achieved in DCE, nor did they provide substantially
higher diastereoselectivity in the cyclization. Unfortunately, we
were unable to definitively observe equilibration of diaster-
reaction mixture. Isolated yield. 1 mmol of o-pyrrolidinyl aniline was
used; 18 h reaction time.
containing different functional groups were treated with amine
and 30 mol % of FeCl3 at 80 °C in DCE to furnish
spirooxindoles with moderate to good yields as shown in
Scheme 3.
Isatins that are substituted at the 5-position with either
electron-donating (i-Pr, OMe) or electron-withdrawing (OCF3,
B
DOI: 10.1021/acs.orglett.7b01752
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
NO , Cl) groups were compatible with the cyclization
conditions, providing yields ranging from 60% to 80% (Scheme
To conclude, we have developed a method for the synthesis
of spirooxindoles through intermolecular reaction between
diamines and isatins. This cyclocondensation process leverages
the inherent reducing power of a tertiary amine donor and is
2
3
). Moreover, halogen substitution at the 7- (5g) or 4,6-
positions (5h) led to spirooxindoles in 72% and 55% yield,
respectively. Importantly, related halogenated spirooxindoles
facilitated by a Lewis acid promoter (FeCl ). Ultimately, the
3
4f
have proven useful as antimalarial agents and as intermediates
in the parallel synthesis and screening of cross-coupled
formal hydride migration from carbon to nitrogen provides
rapid access to biologically and medicinally relevant spiroox-
indoles.
4
b
derivatives. While unprotected isatins with free N−H groups
were effective substrates for the reaction, the isatin nitrogen can
also be alkylated with methyl (5i), aromatic (5j), or benzyl
groups (5k, 5l). In fact, the N-substituted isatins gave
somewhat higher yields than the analogous unprotected isatin.
Next, the ability of various substituted ortho-amino anilines
to form spirooxindoles was evaluated (Scheme 4). For example,
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01752.
Experimental procedures and complete compound
characterization data (PDF)
Scheme 4. Spirooxindole Formation from Different
Amines
, ,
a b c
AUTHOR INFORMATION
Corresponding Author
■
*
E-mail: tunge@ku.edu.
ORCID
Jon A. Tunge: 0000-0002-5849-0888
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Science Foundation (CHE-1465172),
Kansas Bioscience Authority Rising Star program, and National
Institutes of Health KU Chemical Methodologies and Library
Development Center of Excellence (P50 GM069663) for
financial support.
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Org. Lett. XXXX, XXX, XXX−XXX