Remote activation of the nucleophilicity of isatin

Article abstract of DOI:10.1021/ol500421k

The concept of the remote activation of reactivity was first applied in asymmetric organocatalysis. An isatin 3-phenylimine derivative acts as a donor in the thiourea catalyzed asymmetric addition to unsaturated 1,4-ketoesters, affording aza-Michael adducts in high enantiomeric purity and yield.

Full text of DOI:10.1021/ol500421k

Letter
pubs.acs.org/OrgLett
Remote Activation of the Nucleophilicity of Isatin
†
†
‡
†
,†
̌
Sergei Zari, Marina Kudrjashova, Tonis Pehk, Margus Lopp, and Tonis Kanger*
̃
̃
†Department of Chemistry, Tallinn University of Technology, Akadeemia tee 15, 12618 Tallinn, Estonia
‡National Institute of Chemical Physics and Biophysics, Akadeemia tee 23, 12618 Tallinn, Estonia
S
* Supporting Information
ABSTRACT: The concept of the remote activation of
reactivity was first applied in asymmetric organocatalysis. An
isatin 3-phenylimine derivative acts as a donor in the thiourea
catalyzed asymmetric addition to unsaturated 1,4-ketoesters,
affording aza-Michael adducts in high enantiomeric purity and
yield.
satin 1 is a well-known natural compound.1 Its derivatives
Ihave been widely used as synthetic intermediates for the
synthesis of spirocyclic compounds2 and in multicomponent
reactions.3 Its core structure can be found in various
biologically active compounds possessing, among others, anti-
HIV,4 anticancer,5 antibacterial,6 and antimalarian properties.7
The combination of a phenyl ring, a γ-lactam moiety, and a
carbonyl group in the isatin molecule gives rise to a variety of
chemical transformations. Electrophilic substitution in an
aromatic ring,8 dipolar cycloaddition,9 and especially the
nucleophilic addition to the C3 carbonyl function of isatin
are well-described.10 Much less attention has been paid to the
reactivity of the nucleophilic center at nitrogen. So far, reactions
at the nitrogen atom are scarce11 and have mainly been limited
to alkylation or acylation to prevent side reactions. To the best
of our knowledge, there are only a few references, by the same
authors, where this reactivity has been described in a Michael
reaction.12 However, the conditions of these reactions were
unconventional, using either solvent-free microwave irradiation
or ionic liquids as solvents. No asymmetric version of an aza-
Michael reaction of isatin has been described.13
Herein, we describe a novel reactivity of isatin-derived imine
2 in a thiourea-catalyzed asymmetric organocatalytic aza-
Michael reaction. The key feature of the reaction is the remote
activation of the nucleophilicity of the nitrogen atom by a 3-
phenylimine moiety. Exploiting the nucleophilicity of the
nitrogen atom and using it in reactions with electrophiles
considerably broadens the synthetic utility of isatin and makes
it possible to use it for the synthesis of more complex cyclic
structures. The resulting imine can be easily hydrolyzed with an
aqueous workup affording N-substituted isatins in a one-pot
procedure. In connection with our ongoing studies of 1,4-
unsaturated dicarbonyl compounds14 and organocatalytic
cascade reactions15 we envisioned that the organocatalytic
reaction between an enolizable unsaturated 1,4-dicarbonyl
compound 3 and imine 2 derived from isatin would give a
cascade of Mannich−Michael reactions in the presence of a
thiourea catalyst (Scheme 1). To our surprise, no Mannich
reaction was observed even in the presence of Pihko catalysts I
Scheme 1. Expected and Actual Reactivity of Imine 2
Derived from Isatin 1
and III which are known to be very efficient in promoting
Mannich reactions.16 Instead, aza-Michael product 4 was
formed in good yield and high enantioselectivity. During the
acidic workup the imine was hydrolyzed and isatin derivative 5
was formed.
Based on that result, we decided to investigate the aza-
Michael reaction in detail. The thiourea catalysts used are
presented in Figure 1, and the results of the optimization are in
Table 1.
All four catalysts screened resulted exclusively in aza-Michael
product 4 with excellent enantioselectivity; however, the
reaction rate strongly depended on the catalyst structure.
Both catalysts I and IV showed good results, affording the
product in high yield and selectivity in a reasonable time. It is
worth mentioning that catalyst I, being a dual-activated
analogue of II, was more efficient, while the reaction with IV
proceeded much more smoothly than with its dual-activated
analogue III. Considering the multistep synthesis of catalyst I
together with its lower reactivity, catalyst IV was chosen for
Received: February 10, 2014
Published: March 10, 2014
© 2014 American Chemical Society
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Letter
a
Table 2. Scope of the Reaction
time
(h)
yield
b
ee
cd
,
entry
2 R1
3 R2
3a, Me
5
(%)
(%)
1
2
3
4
5
6
2a, H
2a, H
2a, H
2a, H
2a, H
2a, H
2a, H
2b, Me
5aa
5ab
5ac
5ad
5ae
5af
72
18
16
16
5
80
95
97
95
95
82
73
83
75
91
96
97
94
95
96
93
96
88
90
95
91
95
3b, Ph
3c, pMePh
3d, pMeOPh
3e, pClPh
3f, pBrPh
3g, pNO2Ph
3b, Ph
24
4
e
7
5ag
5bb
5cb
5db
5eb
8
20
96
3.5
2.5
Figure 1. Screened chiral catalysts.
9
2c, MeO 3b, Ph
10
11
2d, Br
3b, Ph
3b, Ph
Table 1. Optimization of Reaction Conditions
2e, NO2
a
b
For experimental conditions, see: Supporting Information. Isolated
c
d
yield. Determined by HPLC with chiral stationary phase. Absolute
configuration (S) was determined by X-ray structure analysis17 of 5ae
e
and presumed to be the same with the other substrates. Ethyl ester
was used.
Next, the role of the imine functional group was studied.
Isatin 1 was much less effective in terms of yield,
enantioselectivity, and reaction time than its imine derivative
2. According to ab initio quantum chemistry calculations there
is no significant difference in the charges of the amide N and H
atoms of compounds 1 and 2a (see Supporting Information).
Therefore, we assumed that the interaction of imine derivative
2 with the catalyst was dependent on the substitution at the N-
atom, and that plays a crucial role in the outcome of the
reaction.
To check this assumption, various Schiff bases with different
substituents (2a, 2f−i) were prepared and tested in the reaction
(Table 3). The results clearly illustrated that the difference in
imine reactivity was based on its substituent. While using N-
phenyl substituted imine 2a resulted in nearly quantitative yield
or product 5 within a reasonable reaction time (Table 3, entry
2), the other substituted imines 2f−i were considerably less
active.
a
b
entry catalyst (mol %)
solvent
time (h) yield (%) ee (%)
1
2
3
4
5
6
7
8
I (20)
toluene
toluene
toluene
toluene
toluene
toluene
DCM
48
96
99
95
51
46
29
95
77
51
95
98
99
97
97
96
96
95
I (10)
I (5)
216
72
II (10)
III (10)
IV (10)
IV (10)
72
c
c
c
72
72
IV (10)
THF
72
a
b
c
Isolated yield. Determined by chiral HPLC. Opposite enantiomer
was in excess.
further investigations. The solvent screening revealed that
toluene was the best solvent for the reaction.
With the optimal conditions in hand (10% of catalyst IV,
toluene, room temperature), the reaction scope was inves-
tigated by using aliphatic or aromatic para-substituted
unsaturated ketoesters 3a−g (2 equiv) and 5-substituted isatin
derivatives 2a−e (Table 2).
Table 3. Effect of the Imine Substituent
In all cases, high or excellent enantioselectivities were
obtained. Aliphatic ketoester 3a was less reactive than aromatic
ones (Table 2, entries 1 and 2−6). Compounds with electron-
withdrawing substituents in the indolinone ring (2d, 2e)
increased the acidity of the N−H proton making deprotonation
easier and the obtained conjugate base a better nucleophile, or
alternatively, shifted the lactam−lactim equilibrium toward a
more nucleophilic lactim. A shorter reaction time was needed
to obtain a high yield for these compounds (Table 2, entries 10,
11). In contrast, isatin derivatives with electron-donating
substituents (2b, 2c) required a longer reaction time (Table
2, entries 8, 9). Michael acceptor 3 was, as expected, activated
by electron-withdrawing groups at the aromatic ring of the
phenyl-substituted ketoester (Table 2, entries 5, 7).
a
b
entry
R3
time (h)
yield (%)
ee (%)
c
1
(isatin 1), O
2a, N-Ph
48
18
59
97
12
30
62
21
62
94
75
88
98
90
2
3
4
5
6
2f, N-H
144
128
72
2g, N-iPr
2h, N-p-MeOPh
2i, N-p-NO2Ph
72
a
b
c
Isolated yield. Determined by HPLC with chiral stationary phase. 3
equiv of ketoester 3b used.
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Letter
Unsubstituted imine 2f afforded the product in the lowest
yield; however, the enantioselectivity of the reaction was higher
than with isatin 1 (Table 3, entries 1, 3). Because 2f was even
less reactive than isatin, we concluded that replacing the
carbonyl group with an unsubstituted imino group did not
activate isatin. N-Alkyl substitution at the N atom (compound
2g) exhibited slightly enhanced reactivity if compared with 2f;
however, the yield was still much lower than that for 2a (Table
3, entries 2 and 4). The substitution at the para position of the
aromatic ring of phenylimines (compounds 2h and 2i) also had
a deleterious effect on the reactivity. Surprisingly, both the
electron-donating methoxy group (compound 2h) and
electron-withdrawing nitro group (compound 2i) had negative
impacts on the reaction (Table 3, entries 5, 6). The low
reactivity of nitro-substituted compound 2i was probably
caused by its poorer solubility if compared with the other
investigated imines.
These experiments revealed the essential role of N-phenyl
substitution at imine in making isatin derivative 2a an active
aza-Michael donor. An extra aromatic ring of imine 2a
(comparing with isatin 1) let us assume that, in addition to
the H-bonding interaction between the catalyst and oxindole
derivative, π−π interactions between aromatic rings could play
some role. We assumed that the remote activation of isatin via
complexation between imine 2 and catalyst IV by π−π
interactions of a quinoline fragment of the catalyst and imine’s
aromatic ring took place, increasing the nucleophilicity of the
heterocyclic nitrogen. Simultaneously, the tertiary amino group
from the quinuclidine fragment of IV could assist the
deprotonation of the N−H proton of lactam and ketoester 3
could be activated by the hydrogen bonds from a thiourea
moiety of the catalyst.
In order to obtain more evidence of the possible π−π
stacking between the catalyst IV and imines, the mixtures of
these compounds were studied by NMR. A comparison of
NMR spectra of imine 2a (E/Z = 95:5) and the mixture of
imine and catalyst IV showed differences in their chemical shifts
(see Supporting Information). In the presence of the catalyst,
the most significant differences occurred in the five-membered
ring of isatin. The difference was biggest for the α-carbon to the
nitrogen (0.5 ppm for 13C). All signals of the protons of the six-
membered ring of 2a were shifted to a higher field pointing to
the association with the aromatic ring(s) of the catalyst. The
same can be concluded from the broadening of doublets of
phenyl ring protons of imine. In the presence of catalyst IV, the
NH signal of phenylimine 2a at 135.0 ppm in 15N NMR spectra
(CDCl3 solution at 296 K) was shifted 2.2 ppm to lower field.
Imine nitrogen of 2a which gave a signal at 356.7 ppm could
not be detected on the addition of the catalyst due to the
exchange broadening of ortho protons of the phenyl ring used
for the detection of the 15N resonance via the HMBC spectrum.
In the case of imine 2g (E/Z = 3:1) methyls of the isopropyl
group became diastereotopic. It is only possible then that imine
is in anisotropic environment, most likely due to binding to an
enantiomerically pure catalyst.
ASSOCIATED CONTENT
* Supporting Information
Experimental details, characterization data for new compounds,
copies of NMR spectra, HPLC chromatograms, X-ray structure,
and computational data. This material is available free of charge
via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: kanger@chemnet.ee.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the Estonian Ministry of Education and
Research (Grant No. IUT 19-32) and EU European Regional
Development Fund (3.2.0101.08-0017) for financial support.
We thank Prof. Toomas Tamm for calculations, Dr. Ivar Jarving
for HRMS, Mrs. Kaja Ilmarinen for X-ray analysis, Dr.
̈
Aleksander-Mati Muurisepp for MS, and Ms. Tiina Aid for IR
̈
̈
from Tallinn University of Technology.
REFERENCES
■
(1) Da Silva, J. F. M.; Garden, S. J.; Pinto, A. C. J. Braz. Chem. Soc.
2001, 12, 273−324.
(2) Singh, G. S.; Desta, Z. Y. Chem. Rev. 2012, 112, 6104−6155.
(3) Liu, Y.; Wang, H.; Wan, J. Asian J. Org. Chem. 2013, 2, 374−386.
(4) (a) Jiang, T.; Kuhen, K. L.; Wolff, K.; Yin, H.; Bieza, K.; Caldwell,
J.; Bursulaya, B.; Wu, T. Y.-H.; He, Y. Bioorg. Med. Chem. Lett. 2006,
16, 2105−2108. (b) Pawar, V. S.; Lokwani, D. K.; Bhandari, S. V.;
Bothara, K. G.; Chitre, T. S.; Devale, T. L.; Modhave, N. S.; Parikh, J.
K. Med. Chem. Res. 2011, 20, 370−380.
(5) (a) Wee, X. K.; Yeo, W. K.; Zhang, B.; Tan, V. B. C.; Lim, K. M.;
Tay, T. E.; Go, M.-L. Bioorg. Med. Chem. 2009, 17, 7562−7571.
(b) Solomon, V. R.; Hu, C.; Lee, H. Bioorg. Med. Chem. 2009, 17,
7585−7592. (c) Matesic, L.; Locke, J. M.; Vine, K. L.; Ranson, M.;
Bremner, J. B.; Skropeta, D. Tetrahedron 2012, 68, 6810−6819.
(d) Romagnoli, R.; Baraldi, P. G.; Cruz-Lopez, O.; Preti, D.; Bermejo,
́
J.; Estevez, F. ChemMedChem 2009, 4, 1668−1676.
(6) Kumari, G.; Singh, R. K. Med. Chem. Res. 2013, 22, 927−933.
(7) Rottmann, M.; McNamara, C.; Yeung, B. K. S.; Lee, M. C. S.;
Zou, B.; Russell, B.; Seitz, P.; Plouffe, D. M.; Dharia, N. V.; Tan, J.;
Cohen, S. B.; Spencer, K. R.; Gonzalez-Paez, G. E.; Lakshminarayana,
S. B.; Suresh, B.; Goh, A.; Suwanarusk, R.; Jelga, T.; Schmitt, E. K.;
Beck, H.-P.; Brun, R.; Nosten, F.; Renia, L.; Dartois, V.; Keller, T. H.;
Fidock, D. A.; Winzeler, E. A.; Diagana, T. T. Science 2010, 329,
1175−1180.
(8) Tingare, Y. S.; Shen, M.-T.; Su, C.; Ho, S.-Y.; Tsai, S.-H.; Chen,
B.-R.; Li, W.-R. Org. Lett. 2013, 15, 4292−4295.
(9) (a) Alimohammadi, K.; Sarrafi, Y.; Tajbakhsh, M.; Yeganegi, S.;
Hamzehloueian, M. Tetrahedron 2011, 67, 1589−1597. (b) Schulz, V.;
Davoust, M.; Lemarie,
́
M.; Lohier, J.-F; Sopkova de Oliveira Santos, J.;
Metzner, P.; Brier
̀
e, J.-F. Org. Lett. 2007, 9, 1745−1748. (c) Lashgari,
N.; Ziarani, G. M. ARKIVOC 2012, 277−320.
(10) Selected examples: (a) Ball-Jones, N. R.; Badillo, J. J.; Franz, A.
K. Org. Biomol. Chem. 2012, 10, 5165−5681. (b) Wang, G.-W.; Zhou,
A.-X.; Wang, J.-J.; Hu, R.-B.; Yang, S.-D. Org. Lett. 2013, 15, 5270−
5273. (c) Liu, H.; Wu, H.; Luo, Z.; Shen, J.; Kang, G.; Liu, B.; Wan, Z.;
Jiang, J. Chem.Eur. J. 2012, 18, 11899−11903.
In conclusion, the first highly enantioselective aza-Michael
addition of isatin is reported. The reaction efficiency was greatly
enhanced by derivatizing the isatin to a Schiff base that can be
easily converted back by hydrolysis with no loss of yield and
enantiomeric excess. This is the first example of remote
activation of nucleophilicity in an organocatalytic reaction. The
described reaction is efficient affording N-substituted isatins in
high enantiomeric purity and high yield.
(11) Zhao, M.-X.; Chen, M.-X.; Tang, W.-H.; Wei, D.-K.; Dai, T.-L.;
Shi, M. Eur. J. Org. Chem. 2012, 3598−3606.
(12) (a) Imanzadeh, G.; Aghaalizadeh, T.; Zamanloo, M.; Mansoori,
Y. J. Chil. Chem. Soc. 2011, 56, 616 −620. (b) Imanzadeh, G. H.;
Mollaei Tavana, M.; Zamanloo, M. R.; Mansoori, Y. Chin. J. Chem.
2009, 27, 389−396. (c) Imanzadeh, G.; Soltanizadeh, Z.; Khodayari,
1742
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Letter
A.; Zamanloo, M.; Mansoori, Y.; Salehzadeh, J. Chin. J. Chem. 2012,
30, 891−899.
(13) For recent reviews of aza-Michael reactions, see: (a) Enders, D.;
Wang, C.; Liebich, J. X. Chem.Eur. J. 2009, 15, 11058−11076.
(b) Wang, J.; Li, P.; Choy, P. Y.; Chan, A. S. C.; Kwong, F. Y.
ChemCatChem 2012, 4, 917−925. (c) Kotke, M.; Schreiner, P. R. In
Hydrogen Bonding in Organic Synthesis, 1st ed.; Pihko, P. M., Ed.;
Wiley-VCH: Weinheim, 2009; pp 141−351.
̌
̈
(14) Zari, S.; Kailas, T.; Kudrjashova, M.; Oeren, M.; Jarving, I.;
̈
Tamm, T.; Lopp, M.; Kanger, T. Beilstein J. Org. Chem. 2012, 8, 1452−
1457.
(15) (a) Noole, A.; Sucman, N. S.; Kabeshov, M. A.; Kanger, T.;
Macaev, F. Z.; Malkov, A. V. Chem.Eur. J. 2012, 18, 14929−14933.
(b) Noole, A.; Jarving, I.; Werner, F.; Lopp, M.; Malkov, A.; Kanger, T.
̈
Org. Lett. 2012, 14, 4922−4925. (c) Noole, A.; Ose
̌
ka, M.; Pehk, T.;
̈
Oeren, M.; Jarving, I.; Elsegood, M. R. J.; Malkov, A. V.; Lopp, M.;
Kanger, T. Adv. Synth. Catal. 2013, 355, 829−835. (d) Noole, A.;
Ilmarinen, K.; Jarving, I.; Lopp, M.; Kanger, T. J. Org. Chem. 2013, 78,
̈
̈
8117−8122.
́
́ ́
(16) Probst, N.; Madarasz, A.; Valkonen, A.; Papai, I.; Rissanen, K.;
Neuvonen, A.; Pihko, P. M. Angew. Chem., Int. Ed. Engl. 2012, 34,
8495−8499. Angew. Chem. 2012, 124, 8623 −8627.
(17) The .cif file of 5ae structure is available free of charge as a part of
the Supporting Information.
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