Aza-Henry Reaction of Isatin Ketimines with Methyl 4-Nitrobutyrate en Route to Spiro[piperidine-3,3′-oxindoles]

Article abstract of DOI:10.1002/adsc.201500716

A new enantioselective route to spiro[piperidine-3,3′-oxindoles] from isatin ketimines is described. The aza-Henry reaction of N-Boc-isatin ketimines with methyl 4-nitrobutyrate in the presence of a Ph₂BOX-CuBr₂ complex provided the corresponding nitro amino esters with good diastereoselectivity and excellent enantioselectivity (up to >99% ee). The aza-Henry adducts were transformed into spiro[piperidine-3,3′-oxindoles] after reduction of the nitro group to oxime, and cleavage of the N-Boc group and lactamisation.

Full text of DOI:10.1002/adsc.201500716

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DOI: 10.1002/adsc.201500716
Aza-Henry Reaction of Isatin Ketimines with Methyl 4-Nitrobuty-
rate en Route to Spiro[piperidine-3,3’-oxindoles]
Melireth Holmquist,a Gonzalo Blay ,a,* M. Carmen MuÇoz,b and JosØ R. Pedroa,*
a
Departament de Química Orgànica, Facultat de Química, Universitat de Val›ncia, C/Dr. Moliner 50, E-46100 Burjassot
(Val›ncia), Spain
Fax: (+34)-96-354-4328, phone: (+34)-96-354-4329; e-mail: gonzalo.blay@uv.es or jose.r.pedro@uv.es
Departament de Física Aplicada, Universitat Polit›cnica de Val›ncia, E-46071 Val›ncia, Spain
b
Received: July 28, 2015; Revised: September 8, 2015; Published online: December 4, 2015
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500716.
Abstract: A new enantioselective route to spiro[pi-
peridine-3,3’-oxindoles] from isatin ketimines is de-
scribed. The aza-Henry reaction of N-Boc-isatin ke-
timines with methyl 4-nitrobutyrate in the presence
of a Ph2BOX-CuBr2 complex provided the corre-
sponding nitro amino esters with good diastereose-
lectivity and excellent enantioselectivity (up to
>99% ee). The aza-Henry adducts were trans-
formed into spiro[piperidine-3,3’-oxindoles] after
reduction of the nitro group to oxime, and cleavage
of the N-Boc group and lactamisation.
The molecular and stereochemical complexity that
characterises this class of compounds represents a sig-
nificant synthetic challenge;[13] in particular, the con-
struction of a highly hindered, strained spirocyclic
quaternary chiral centre is not trivial, especially in an
enantioselective manner.[14] Therefore, only a limited
number of synthetic approaches to these kinds of spi-
rooxindoles in enantioselective manner are available.
For instance, tetrahydro-b-carboline spirooxindoles
have been prepared by means of the Pictet–Spengler
reaction between tryptamines and isatins in either
a non-enantioselective[15] or an enantioselective fash-
ion,[16] and via cyclization of alkynylanilines in race-
mic form.[17] On the other hand, quinoline spirooxin-
doles have been obtained via a Povarov reaction from
isatin ketimines.[10,18] Alternatively, formation of the
spiranic ring can be accomplished from 3-substituted-
3-aminooxindoles via cyclization procedures[19] such
Keywords: asymmetric catalysis; copper; lactams;
nitrogen heterocycles; nucleophilic addition
3,3’-Spirocyclic oxindoles are attractive targets in or- as lactamisation.[20] However, the synthesis of enan-
ganic synthesis due to the presence of this structural tioenriched spirooxindoles by using this strategy re-
motif in numerous naturally occurring alkaloids and quires procedures for the highly stereoselective for-
pharmaceutically active compounds,[1,2] exhibiting an- mation of the amino-substituted quaternary stereo-
titumour,[3] antibacterial,[4] analgesic[5] or antitubercu- centre at the position 3 of the oxindole, and the intro-
losis[6] activities, among others. Many 3,3’-spirocyclic duction of a properly functionalised chain at this posi-
oxindoles feature a heterocyclic spiranic ring with a ni- tion.
trogen atom at the 2 position of the oxindole nu-
Recently, the aza-Henry reaction with ketimines
cleus.[7] Among these, oxindoles bearing a spiranic pi- has experienced considerable progress,[21] and several
peridine ring, either alone, or fused with an aromatic
or heteroaromatic system have attracted great interest
on account of their biological profile. Examples
(Figure 1) include tetrahydro-b-carboline spirooxin-
doles (spiroindolinones) with anticonvulsive activity,[8]
the experimental drug NITD609, which has recently
been identified as a potential treatment for malaria,[9]
or (iso)quinoline spirooxindoles with potential antitu-
mour activity.[10] Some simple spiro[piperidine-3,3’-ox-
indoles] have shown analgesic properties[11] while
others are being investigated as peptide isosteres
which are able to mimetise a type II b-turn in the
Figure 1. Some examples of bioactive 3-aminospiro[piperi-
dine-3,3’-oxindoles].
search for new enzyme inhibitors.[12]
Adv. Synth. Catal. 2015, 357, 3857 – 3862
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Melireth Holmquist et al.
groups[22] including ours[23] have developed efficient
procedures for the enantioselective aza-Henry reac-
tion with isatin ketimines leading to 3-aminooxindoles
bearing a quaternary stereogenic centre. These studies
with isatins have been limited to unfunctionalised ni-
troalkanes. We envisioned that the addition of alkyl
nitrobutyrates to isatin ketimines[24,25] would provide
chiral 3-aminooxindoles with an ester-functionalised
chain at the 3 position of the oxindole which would
make possible the access to highly enantioenriched
spiro[piperidine-3,3’-oxindoles] after lactamisation
(Scheme 1).[26]
In our previous work[23] we performed the enantio-
selective addition of nitromethane to N-Boc-isatin ke-
timines using a copper(II)-Ph2BOX (L1) catalyst with
excellent enantiomeric excesses. Election of the
copper salt was crucial for the success of this reaction
Scheme 1. Enantioselective approach to spiro[piperidine-
3,3’-oxindoles] based on the aza-Henry reaction with methyl
4-nitrobutyrate.
as the use of copper(II) triflate caused the hydrolysis This undesired reaction could be avoided by using
of the N-Boc-imine, being detrimental to the yield. other copper salts, the best results in terms of yield
Table 1. BOX-Cu(II)-catalysed aza-Henry reaction of methyl-4-nitrobutyrate with N-Boc–isatin ketimines.[a]
Entry
1
R1
R2
3
t [h]
Yield [%]
dr[b]
ee[c] [%]
1[d]
2
3
4
5
6
7
8
9
10
11
12
13
14
15[f]
16[g]
1a
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1a
1a
H
H
Me
Bn
MOM
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
3a
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3a
3a
19
19
14
15
14
16
15
16
14
21
15
16
14
16
19
19
58
84
84
90
96
98
87
88
89
97
87
94
90
94
84
86
93:07
90:10
60:40
83:17
84:16
91:09
91:09
82:18
85:15
69:31
90:10
83:17
86:14
90:10
76:24
76:24
99/99
99/98[e]
99/99
91/99[e]
99/99[e]
99/96
H
5-Me
5-MeO
5-Br
5-Cl
6-Cl
7-Me
7-Cl
7-F
98/96
98/90
97/93[e]
96/96[e]
98/96
99/98[e]
99/99[e]
99/98
5,7-Me2
H
H
76/73[h]
2/2
[a]
CuBr2 (10 mol%), L1 (10 mol%), DIPEA (14 mol%), methyl 4-nitrobutyrate (5 equiv.), room temperature.
[b]
[c]
[d]
[e]
Determined by 1H NMR.
Determined by HPLC.
Cu(BF4)2 was used instead of CuBr2.
The ee values may experience some minor deviations (1–2% ee) due to experimental error caused by partial overlapping
of peaks in HPLC traces.
L2 was used instead of L1.
L3 was used instead of L1.
The enantiomer with the opposite configuration at the quaternary stereogenic centre was obtained.
[f]
[g]
[h]
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Aza-Henry Reaction of Isatin Ketimines with Methyl 4-Nitrobutyrate
and enantioselectivity being obtained with copper(II) or at different positions of the homoaromatic ring
tetrafluoroborate hydrate. However, when these con- (Table 1, entries 3–14). The aza-Henry products 3b–
ditions were applied to the addition of methyl 4-nitro- 3m were obtained in high yields and remarkable dia-
butyrate (2) to isatin ketimine 1a (Table 1, entry 1), stereoselectivities (dr>80:20) for most of the exam-
the expected nitroamine was obtained with excellent ples tested. Although protection of the N-1 is not re-
enantioselectivity although in low yield (58%), to- quired, isatin ketimines substituted at this position re-
gether with products arising from the hydrolysis of acted also with good yields, diastereoselectivity and
the ketimine. It seemed that addition of the bulkier enantioselectivity (Table 1, entries 3–5), the diastereo-
methyl 4-nitrobutyrate does not take place at a suffi- selectivity was low only in the case of the imine 1b
cient rate to avoid completely the hydrolysis of the derived from 1-methylisatin (Table 1, entry 3). The re-
imine as in the case of the more reactive nitrome- action also allowed the presence of electron-donating
thane. Fortunately, the use of copper(II) bromide (entries 6, 7, 11 and 14) or electron-withdrawing (en-
(Table 1, entry 2) instead of copper(II) tetrafluorobo- tries 8–10, 12 and 13) groups on the homoaromatic
rate hydrate allowed us to obtain the aza-Henry prod- ring, providing the expected products with good
uct 3a with high yield (84%), good diastereoselectiv- yields and diastereoselectivities. Remarkably, both
ity (90:10) and excellent enantiomeric excesses for diastereomers were obtained with high enantioselec-
both diastereomers (99% and 98%, respectively). Al- tivity. Thus the major diastereomer was obtained with
though in the view of these results further optimisa- enantiomeric excesses above 91% and the minor dia-
tion was not considered necessary, we also assessed stereomer was obtained with enantiomeric excesses
two more commercially available BOX ligands L2 above 90% for all the ketimines tested.
and L3 in this reaction (Table 1, entries 15 and 16).
Next we studied the formation of the spiranic ring
The reaction in the presence of L2-CuBr2 provided via lactamisation. To avoid any retro-Henry reaction
compound 3a with good yield and fair diastereo- and while keeping a functional group on the side chain,
enantioselectivity, while the use of ligand L3 delivered the nitro group was first converted into an oxime via
the diastereomeric mixture of compound 3a in almost a reductive Nef-type reaction with SnCl2/thiophe-
racemic form.
nol.[27] The corresponding oximes 4 were obtained
The optimised conditions for the aza-Henry reac- predominantly with the E geometry in fair to good
tion with methyl 4-nitrobutyrate were applied to yields without detrimental effects on the enantiomeric
a number of isatin N-Boc-ketimines 1b–1m substitut- excesses (Table 2). After that we attempted the de-
ed at either the N-1 atom of the heteroaromatic ring protection of the N-Boc group and lactamisation. Al-
Table 2. Transformation of aza-Henry adducts 3 into spiro[piperidine-3,3’-oxindoles].[a,b]
Entry
3
R1
R2
4
Yield of 4 [%]
ee of 4 [%][c]
5
Yield of 5 [%]
ee of 5 [%][c]
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
3g
3h
3i
H
H
H
H
H
5-Me
5-MeO
5-Br
5-Cl
6-Cl
7-Me
7-Cl
7-F
4a
4b
4c
4d
4e
4f
4g
4h
4i
82
68
76
59
92
86
97
88
78
67
80
88
81
97
97
99
98
99
98
99
97
96
99
97
99
99
5a
5b
–
82
68
–
99
99
–
Me
Bn
MOM
H
H
H
H
H
H
H
–
–
–
5e
5f
5g
5h
5i
5j
5k
5l
92
86
97
88
78
67
80
88
81
92
95
99
97
99
99
99
99
99
9
10
11
12
13
3j
3k
3l
4j
4k
4l
H
H
3m
5,7-Me2
4m
5m
[a]
3 (1 equiv.), SnCl2 (2 equiv.), PhSH (6 equiv.), Et3N (6 equiv.), EtOH, 20 min.
4 (1 equiv.), TFA (2 equiv.), toluene, 908C.
Determined by HPLC.
[b]
[c]
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though cyclisation to d-lactams from amino esters
usually takes place readily,[26] in our case the lactami-
sation reaction was difficult due to the strain associat-
ed with the formation of the spiranic ring and re-
quired treatment of compounds 4 with trifluoroacetic
acid in toluene at 908C. Under these conditions the
N-Boc group was removed and the resulting free NH2
group underwent intramolecular amidation to give
the expected spiro[piperidine-3,3’-oxindoles] 5. Com-
pounds 5 were insoluble in toluene and precipitated
from the reaction mixture upon cooling, making their
purification easy. Compounds 5 were obtained with
fair to good yields and with excellent enantiomeric
excesses, except for compound 5c, which decomposed
Figure 3. Stereochemical model for the aza-Henry reaction.
during this treatment, and compound 5d having an phenyl groups of the ligand. The nitronate is posi-
acid sensitive group attached to N-1. Remarkably, no tioned in one of the apical positions of the Cu(II)
products resulting from oxime hydrolysis or Beck- centre being activated as a nucleophile, so that nucle-
mann rearrangement were observed.
ophilic attack takes place from the si face of the
X-ray analysis of compound 5k (Figure 2) con- imine, to give the corresponding nitroamide with the
firmed the formation of the spiranic system and al- S configuration at the newly formed quaternary ste-
lowed determination of the configuration of the qua- reogenic centre.
ternary stereogenic centre, as well as the geometry of
In summary, a highly catalytic enantioselective aza-
the C=N double bond in the oxime.[28] For the rest of Henry reaction of methyl 4-nitrobutyrate with keti-
products the absolute stereochemistry was assigned mines is reported. The addition of methyl 4-nitrobuty-
upon the assumption of a uniform stereochemical rate[30] to N-Boc-isatin ketimines in the presence of
mechanism.
a Ph2BOX-CuBr2 complex provided the correspond-
The observed S configuration in the quaternary ste- ing nitro amino esters with good diastereoselectivity
reogenic centre is in good agreement with the model and excellent enantioselectivity (up to 99% ee). The
proposed in Figure 3.
selection of the copper salt was essential to obtain
In this model,[29] we propose that the isatin keti- good yields. The aza-Henry adducts were transformed
mine coordinates the catalyst Cu(II) centre in a biden- into highly enantioenriched spiro[piperidine-3,3’-oxin-
tate fashion giving a distorted square planar complex doles] after reduction of the nitro group to oxime,
with both the oxygen atom of the amide carbonyl and cleavage of the N-Boc group and lactamisation.
group and the imine nitrogen occupying the most
acidic equatorial positions for the maximum electro-
philic activation. In this disposition access to the re
À
face of the C N imine is hampered by one of the
Experimental Section
General Procedure for the Enantioselective Addition
of Methyl 4-Nitrobutyrate to Isatin Ketimines
Copper(II) bromide (8.4 mg, 0.038 mmol) contained in
a Schlenk tube was dried under vacuum and the tube was
filled with nitrogen. A solution of ligand Ph2BOX (L1,
12.5 mg, 0.038 mmol) and methyl 4-nitrobutyrate (2, 276 mg,
240 mL, 1.9 mmol) in THF (0.38 mL) was added via syringe.
After stirring for 1 h, a solution of ketimine 1 (0.38 mmol)
and N,N-diisopropylethylamine (9.1 mL, 0.053 mmol) in
THF (0.57 mL) was added. The reaction mixture was stirred
at room temperature until completion (monitored by TLC).
The reaction mixture was diluted with EtOAc (30 mL),
washed with 0.5M aqueous HCl (1 mL), brine (2”1 mL),
dried over MgSO4 and concentrated under reduced pressure.
The residue was chromatographed on silica gel eluting with
hexane/EtOAc mixtures to give compounds 3. Racemic
Figure 2. ORTEP plot for the X-ray structure of compound
5k. The thermal ellipsoids are drawn at the 50% probability
level.
compounds 3 for comparative purposes were prepared fol-
lowing the same procedure by using 2,2’-bipyridine as sub-
stitutive for Ph2BOX.
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Aza-Henry Reaction of Isatin Ketimines with Methyl 4-Nitrobutyrate
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General Procedure for the Synthesis of Oximes 4
Compound 3 (0.28 mmol) was added to a solution of
SnCl2·2H2O (126.4 mg, 0.56 mmol), thiophenol (185.1 mg,
173 mL, 1.68 mmol) and triethylamine (170.0 mg, 234 mL,
1.68 mmol) in absolute EtOH (1.4 mL) at room tempera-
ture. After 20 min, the reaction mixture was poured into 1M
aqueous HCl (2 mL) and CH2Cl2 (4 mL) at 08C. The layers
were separated and the aqueous layer was extracted with
CH2Cl2 (2”50 mL). The combined organic layer was washed
with saturated aqueous NaHCO3 (4 mL), brine (3 mL) and
dried over MgSO4. After removal of the solvent, the residue
was chromatographed through a short plug of silica gel elut-
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to a solution of compound 4 (0.16 mmol) in dry toluene
(1.6 mL) at room temperature under a nitrogen atmosphere.
The mixture was heated at 908C for 3–4 h, and allowed to
cool down to room temperature. The supernatant liquid was
removed and the solid washed with DCM/toluene mixtures
to give compounds 5. Alternatively, after the reaction time,
the mixture was concentrated under reduced pressure and
the residue washed with DCM/toluene mixtures to give
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Acknowledgements
Financial support from the Ministerio de Economía y Com-
petitividad (Gobierno de EspaÇa) and FEDER (EU)
(CTQ2013-47949-P) and from Generalitat Valenciana (ISIC
2012/001) is acknowledged. MH thanks the GV for a pre-
doctoral grant (Santiago Grisolía Program). Access to NMR
and MS facilities from the Servei Central de Suport a la In-
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aza-Henry reaction of compound 1a with 4-nitrobutyl
methanesulfonate. Under our reaction conditions, we
observed the formation of isatin, from the hydrolysis of
imine 1a, as the main product. This result may be due
to the reaction of the catalytic amount of triethylamine
with the mesylate. In the absence of the base, the aza-
Henry reaction would become disfavoured with respect
to the competitive hydrolysis of the imine promoted by
the copper(II) Lewis acid. For an organocatalysed aza-
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3862
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