Synthesis of Six-Membered Spiro Azacyclic Oxindole Derivatives via a One-Pot Process of Umpolung Allylation/Aza-Prins Cyclization

Article abstract of DOI:10.1021/acs.orglett.1c00292

An unprecedented synthetic approach involving umpolung allylation/aza-Prins cyclization of N-2,2,2-trifluoroethylisatin ketimines is described. The reactions proceed smoothly with allyl bromide in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene, H2O, and trimethylsilyl bromide; this one-pot protocol allows access to six-membered spiro azacyclic oxindole derivatives in good to excellent yields. Notably, while the general aza-Prins cyclization involves amines and aldehydes, the present synthetic strategy represents the first aza-Prins cyclization that utilizes the umpolung property of N-2,2,2-trifluoroethylisatin ketimines.

Full text of DOI:10.1021/acs.orglett.1c00292

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Letter
Synthesis of Six-Membered Spiro Azacyclic Oxindole Derivatives via
a One-Pot Process of Umpolung Allylation/Aza-Prins Cyclization
Woo Cheol Jang,§ Myeongjin Jung,§ and Haye Min Ko*
Cite This: Org. Lett. 2021, 23, 1510−1515
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ABSTRACT: An unprecedented synthetic approach involving
umpolung allylation/aza-Prins cyclization of N-2,2,2-trifluoroethy-
lisatin ketimines is described. The reactions proceed smoothly with
allyl bromide in the presence of 1,8-diazabicyclo[5.4.0]undec-7-
ene, H2O, and trimethylsilyl bromide; this one-pot protocol allows
access to six-membered spiro azacyclic oxindole derivatives in good
to excellent yields. Notably, while the general aza-Prins cyclization
involves amines and aldehydes, the present synthetic strategy
represents the first aza-Prins cyclization that utilizes the umpolung property of N-2,2,2-trifluoroethylisatin ketimines.
pirooxindoles, which are prevalent in natural products,1 are
Scheme 1. Synthetic Strategies for Spirooxindole Derivatives:
(a) General Aza-Prins Reaction; (b) One-Pot Umpolung
Allylation/Aza-Prins Reaction
Sattractive target motifs owing to their diverse biological
activities.2 Among these molecules, spiro N-heterocyclic
oxindoles exhibit important pharmacological activities such as
IRAP inhibitory, SIRT1 inhibitory, antibreast cancer, antitumor,
and antimalarial activities (Figure 1).3 In addition, the
trifluoromethyl group has been known to improve the metabolic
stability, bioavailability, and lipophilicity of bioactive mole-
cules.4 Despite their importance, only a few synthetic methods
that use N-2,2,2-trifluoroethylisatin ketimines have been
developed for the construction of spiro N-heterocyclic oxindoles
featuring CF3 groups.5
Zhao and co-workers have accomplished the [3 + 3]
cycloaddition of N-2,2,2-trifluoroethylisatin ketimines and
N,N′-dialkyloxyureas in the presence of NaH and PhI(OH)-
(OTs) for the synthesis of spiro-1,3,5-triazinan-2-one oxin-
allyl cations generated in situ in moderate yields. To the best of
our knowledge, this is the only reported example of [3 + 3]
doles.6 Azomethine ylides reacted with N,N′-dialkyloxy diaza-
cycloaddition of N-2,2,2-trifluoroethylisatin ketimines thus far.
Consequently, a practical and efficient synthetic methodology
for six-membered spiro azacyclic oxindole backbones remains.
The well-established aza-Prins cyclization7,8 is a stereo-
selective strategy for the synthesis of piperidines. Generally,
the aza-Prins cyclization involves the condensation of
homoallylic amines with aldehydes in the presence of a Lewis
acid to generate iminium ions, which cyclize spontaneously
through intramolecular nucleophilic attack from the olefin
(Scheme 1a). Inspired by the aza-Prins cyclization, we
Received: January 26, 2021
Published: February 9, 2021
Figure 1. Representative examples of bioactive molecules containing
the spirooxindole motif
https://dx.doi.org/10.1021/acs.orglett.1c00292
© 2021 American Chemical Society
Org. Lett. 2021, 23, 1510−1515
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a,e
a
Table 1. Optimization of Reaction Conditions
Scheme 2. Substrate Scope of Ketimines
b
entry
variation from standard conditions
3a (%)
1
2
3
CHCl3, DCM, or CH3CN/-10 °C/40 °C
−10 °C/40 °C
−10 °C
89, 88, 82
92
92
c
4
5
none
rt
92
80
c
6
7
without H2O/−10 °C/40 °C, 48 h
DCM/2.0 equiv TMSBr, 40 °C, 18 h
59
70
d
8
9
2.0 equiv 2a
tBuOK
88
trace
10
11
12
13
14
15
16
17
18
Cs2CO3
BF3 OEt2
TMSI, TMSOAc, or InCl3
TMSCl
TMSOTf
TESOTf
TiCl4
FeCl3
Cu(OTf)2
no reaction
75
N.D.
11/7 (3a′)
36/11 (3a″)
15/31 (3a″)
14/32 (3a′)
5/4 (3a′)
0/4 (3a″)
.
a
Reaction conditions: 1a (0.1 mmol), 2a (3.0 equiv), and DBU (1.0
equiv) in DCE (1.0 M), 0 °C, 30 min; then H2O (1.0 equiv), TMSBr
b
c
(3.0 equiv), rt, 10 min. Isolated yield. Temperature of the allylation
d
e
step. Temperature and time of the cyclization step. The ellipsoids
are drawn at the 50% probability level.
envisioned that N-2,2,2-trifluoroethylisatin ketimine is a suitable
substrate for the synthesis of six-membered spiro azacyclic
oxindoles via an umpolung allylation/aza-Prins reaction
(Scheme 1b). Unlike previous aza-Prins reactions, this synthetic
method would take advantage of the umpolung property of N-
2,2,2-trifluoroethylisatin ketimine.9 Thus, we decided to
investigate the umpolung allylation/aza-Prins reaction of N-
2,2,2-trifluoroethylisatin ketimines in a one-pot process for the
preparation of spiro[indoline-3,2′-piperidin]-2-ones. Herein, we
report the first efficient and facile synthetic methodology that
uses the umpolung allylation/aza-Prins reaction of N-2,2,2-
trifluoroethylisatin ketimines to produce useful spiro[indoline-
3,2′-piperidin]-2-ones and 5′,6′-dihydro-1′H-spiro[indoline-
3,2′-pyridin]-2-ones.
a
Reaction conditions: 1a (0.1 mmol), 2a (3.0 equiv), and DBU (1.0
equiv) in DCE (1.0 M), 0 °C, 30 min; then H2O (1.0 equiv), TMSBr
b
c
(3.0 equiv), rt, 10 min. 30 min for the cyclization step. −10 °C, 30
min for the allylation step and 40 °C, 12 h for the cyclization step.
was confirmed by single-crystal X-ray diffraction analysis
(CCDC 2053124). When the temperature of the cyclization
step was lowered from 40 °C to room temperature or that of the
allylation step was raised from −10 to 0 °C, the reaction afforded
3a in very high yields (entries 3 and 4). In contrast, when the
reaction was attempted with an allylation step at room
temperature or without H2O in the cyclization step, lower
yields of 3a were observed (entries 5 and 6). Interestingly, 1.0
equiv of H2O critically affected the yield of the product.
Furthermore, when 2.0 equiv of 2a or TMSBr was utilized, 3a
was generated in yields of 88% and 70%, respectively (entries 7
and 8). Next, the use of various bases was examined; however, 3a
was not produced (entries 9 and 10). Additionally, various
reagents that trigger aza-Prins cyclization other than TMSBr
were investigated (entries 11−18). In the presence of BF3·OEt2,
3a was provided in yield of 75%, while no desired products were
formed in the presence of TMSI, TMSOAc, or InCl3. The
expected allylation/aza-Prins reaction occurred when TMSCl,
Initially, we used ketimine 1a6,10−14 as the standard substrate
to screen various sets of reaction conditions with allyl bromide
2a, and the results are summarized in Table 1. In the presence of
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 1.0 equiv), 1a and
2a (3.0 equiv) were reacted in CHCl3 at −10 °C for 30 min; then
H2O (1.0 equiv) and trimethylsilyl bromide (TMSBr, 3.0 equiv)
were added, and the reaction continued at 40 °C for 10 min.
Gratifyingly, desired product 3a was isolated in 89% yield; it was
also obtained in 88%, 82%, and 92% yields when dichloro-
methane (DCM), CH3CN, and dichloroethane (DCE),
respectively, were used (entries 1 and 2). The structure of 3a
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a
Scheme 3. Substrate Scope of Dihydro-1′H-spiro[indoline-3,2′-pyridin]-2-one Synthesis
a
Reaction conditions: 1a (0.1 mmol), 2a (1.5 equiv), and DBU (1.0 equiv) in DCE (1.0 M), 0 °C, 30 min; then H2O (1.0 equiv), TMSBr (3.0
b
c
d
equiv), 100 °C, 1 h. CH3CN was used instead of DCE. 2a (3.0 equiv) was used; 12 h for the cyclization step. Allyl tosylate was used instead of
allyl bromide; rt for the cyclization step. rt for the cyclization step.
e
Scheme 4. Proposed Reaction Mechanism
9%, respectively. Similarly, when 3.0 equiv of TMSOTf or
triethylsilyl triflate (TESOTf) was used, mixtures of 3a and 3a″,
which were isolated by column chromatography, were obtained
in combined yields of 47% and 46%, respectively. Finally, the
reaction was attempted using Cu(OTf)2, and a trace amount of
3a″ was observed.
With the optimal reaction conditions in hand, we explored the
ketimine substrate scope, and the results are shown in Scheme 2.
The reactions with N-protected ketimines featuring a benzyl,
allyl, or trityl group gave excellent yields of 99%, 98%, and 99%,
respectively (3aa−3ac). Unprotected ketimine 1ad6,10,12
reacted smoothly to generate 3ad in a yield of 51%, while a
mixture of 3ae and 3ad was obtained from N-tert-butyldime-
thylsilyl (TBS)-protected ketimine 1ae12 in a combined yield of
61%. 5-Halogen-substituted ketimines produced the corre-
sponding products 3b, 3c, 3d, and 3e in 91%, 73%, 83%, and
77% yields, respectively. Similarly, the expected products 3f, 3g,
and 3h were furnished in good yields of 86%, 89%, and 82%,
respectively, from 6-bromo-, 6-chloro-, and 7-fluoro-N-2,2,2-
trifluoroethylisatin ketimines. The reactions of 5-methyl and 5-
trifluoromethoxy ketimines 1i6,10−13 and 1j12 gave products 3i
and 3j in 98% and 80% yields, respectively. In the case of N-
2,2,2-trifluoroethylisatin ketimines with a methoxy group at the
C5 or C6 position, the targeted products 3k and 3l were
produced in good yields of 76% and 66%, respectively. The
TiCl4, or FeCl3 was used, affording mixtures of 3a and 3a′, which
were separated completely, in combined yields of 18%, 46%, and
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reaction with 5-electron-withdrawing group substituted keti-
mines 1m,10−12 1p, and 1q led to the formation of the desired
products 3m, 3p, and 3q in 63%, 57%, and 83% yields,
respectively. With disubstituted ketimines 1n12 and 1o,12 the
corresponding products 3n and 3o were synthesized in excellent
yields of 85% and 94%, respectively.
such as (R)-BINAP, affect the desymmetrization of 1a with
promising levels of enantioselectivity (Scheme 4b, 19%
enantiomeric excess (ee)). This result suggests that umpolung
allylation/aza-Prins cyclization is amenable to an asymmetric
catalysis system, and this research is underway.
In conclusion, we have demonstrated the first umpolung
allylation/aza-Prins cyclization of N-2,2,2-trifluoroethylisatin
ketimines for the syntheses of spiro[indoline-3,2′-piperidin]-2-
ones and 5′,6′-dihydro-1′H-spiro[indoline-3,2′-pyridin]-2-ones
in a one-pot process. The six-membered spiro azacyclic oxindole
framework, which is found often in natural products and
pharmaceuticals, is considered as an important structure that
requires facile synthetic routes toward the development of new
drug candidates because of the bioactivity of compounds
possessing this motif. The developed protocol, which grants
access to this crucial scaffold, features a single-step process with
broad functional group tolerance under transition-metal free
conditions. Moreover, a new [3 + 3] cycloaddition strategy
involving aza-Prins cyclization and utilizing the umpolung
reactivity of ketimines was established, enabling the con-
struction of six-membered spiro azacyclic oxindoles. This aza-
Prins cyclization differs clearly from the general version, which
involves an amine, aldehyde, and acid. Further investigations for
controlling the enantioselectivity are ongoing.
Next, encouraged by these results, we focused our attention
on the scope of the allyl bromides as coupling partners (Scheme
3). When the reaction of methyl-substituted allyl bromide 2b
was conducted, a mixture of at least four compounds was
detected. It was attributed to the formation of a mixture of
diastereomers due to a quaternary center at the C4 and C2
positions of the piperidine backbone and to a trace amount of
tetrahydropyridine triggered by DBU. To avoid the difficult
separation of the mixture and complicacy, reaction temperatures
ranging from 60 to 100 °C were examined for the aza-Prins
cyclization step. At 100 °C, spiro N-heterocyclic oxindoles 4b
and 4b′, which were isolated using column chromatography,
with carbon−carbon double bonds in the six-membered rings
were generated in yields of 56% and 26%, respectively. Using the
optimal reaction conditions, the reaction of ketimine 1a with 2a
was attempted, affording 4a and 3a in yields of 12%, and 69%,
respectively. Cyclopentyl-substituted allyl tosylate 2c15 was
converted to the products 4c and 4c′ in 14% and 15% yields,
respectively. The expected products 4d and 4d′ were obtained in
a combined yield of 93% from phenyl-substituted allyl bromide.
In contrast to the alkyl groups, the phenyl group enhanced the
reaction, and this was attributed to the construction of a fully
conjugated styrene moiety in the structure of the product. When
1a was treated with 2e16,17 or 2f,16−19 mixtures of regioisomers
4e and 4e′ and regioisomers 4f and 4f′ were formed in combined
yields of 92% and 81%, respectively. p-Chlorophenyl- and p-
fluorophenyl-substituted allyl bromides 2g16−19 and 2h17−19
were tolerated, and they yielded the adducts 4g and 4g′ and
adducts 4h and 4h′ in combined yields of 89% and 82%,
respectively. In the case of polyaromatic substituted allyl
bromide 2i,16,19 the corresponding products 4i and 4i′ were
prepared in yields of 64% and 15%, respectively. The reaction
with 2j20 led to give the products 4j and 4j′ in a combined yield
of 53%. Allyl bromides with a variety of substituents at the C1
position could not be converted to the anticipated products
owing to steric hindrance.
Based on the experimental results, a possible reaction
mechanism, depicted in Scheme 4, was proposed for the
synthesis of 3a from ketimine 1a via umpolung allylation/aza-
Prins cyclization. Hydrogen on the carbon atom adjacent to the
CF3 group in ketimine 1a is abstracted by DBU to generate an 2-
azaallyl anion, which reacts with allyl bromide (Scheme 4a).
Interestingly, the 2-azaallyl anion furnishes intermediates I and
I′ in a ratio of 1:0.2, according to 1H NMR spectroscopy. This
result showed well-known umpolung reactivity9a,b,21 of ketimine
1a, which acts as a nucleophile through the imine carbon on
either the Re- or Si-face. In addition, some 2-azaallyl anions
spontaneously undergo aza-Cope rearrangement to produce I′
or allylation occurs at the nucleophilic carbon adjacent to the
CF3 group. Finally, the intermediates I and I′ transform into the
desired products II and II′ through aza-Prins cyclization in the
presence of H2O and TMSBr. Remarkably, water does not react
with intermediates I and I′ as a nucleophile; thus, we assume that
water either solubilizes the iminium bromide generated from
DBU to prevent whatever hampers the reaction22 or activates
TMSBr to accelerate aza-Prins cyclization.23 Furthermore,
preliminary studies have shown that chiral phosphine ligands,
ASSOCIATED CONTENT
* Supporting Information
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00292.
Experimental procedures, characterization data, and
1
copies of all H and 13C NMR spectra for all isolated
compounds (PDF)
Accession Codes
CCDC 2053124 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Haye Min Ko − Department of Chemistry and Wonkwang
Institute of Materials Science and Technology, Wonkwang
University, Iksan, Jeonbuk 54538, Republic of Korea;
orcid.org/0000-0003-2807-9980; Email: hayeminko@
wku.ac.kr
Authors
Woo Cheol Jang − Department of Chemistry, Wonkwang
University, Iksan, Jeonbuk 54538, Republic of Korea
Myeongjin Jung − Department of Chemistry, Wonkwang
University, Iksan, Jeonbuk 54538, Republic of Korea
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00292
Author Contributions
§W.C.J. and M.J. contributed equally.
Notes
The authors declare no competing financial interest.
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(5) Gui, H.-Z.; Wei, Y.; Shi, M. Recent Advances in the Construction
of Trifluoromethyl-Containing Spirooxindoles through Cycloaddition
Reactions. Chem. - Asian J. 2020, 15, 1225−1233.
ACKNOWLEDGMENTS
■
This research was supported by the Basic Science Research
Program through the National Research Foundation of Korea
(NRF), funded by the Ministry of Science, ICT & Future
Planning (NRF-2018R1D1A1B07042179, NRF-
2020R1A4A3079595).
(6) Zhao, H.-W.; Guo, J.-M.; Wang, L.-R.; Ding, W.-Q.; Tang, Z.;
Song, X.-Q.; Wu, H.-H.; Fan, X.-Z.; Bi, X.-F. Diastereoselective formal
[3 + 3] cycloaddition of isatin-based α-(trifluoromethyl)imines with
N,N′-dialkyloxyureas. Org. Chem. Front. 2019, 6, 3891−3895.
(7) For reviews, see: (a) Olier, C.; Kaafarani, M.; Gastaldi, S.;
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2010, 66, 413−445. (b) Pastor, I. M.; Yus, M. Focused Update on the
Prins Reaction and the Prins Cyclization. Curr. Org. Chem. 2012, 16,
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