Grignard addition to imines derived from isatine: A method for the asymmetric synthesis of quaternary 3-aminooxindoles

Article abstract of DOI:10.1021/jo900623c

(Chemical Equation Presented) Addition of Grignard reagents to chiral imines derived from isatine afforded chiral, optically enriched 3-substituted 3-aminooxindoles in satisfactory yields and diastereoisomeric ratios. A general protocol is described for t

Full text of DOI:10.1021/jo900623c

Grignard Addition to Imines Derived from Isatine: A Method for
the Asymmetric Synthesis of Quaternary 3-Aminooxindoles
Giordano Lesma,† Nicola Landoni,† Tullio Pilati,‡ Alessandro Sacchetti,§ and
Alessandra Silvani*,†
Dipartimento di Chimica Organica e Industriale, UniVersita` degli Studi di Milano, Via G. Venezian 21,
20133 Milano, Italy, Istituto di Scienze e Tecnologie Molecolari - CNR, Via Golgi 19, 20133 Milano, Italy,
and Politecnico di Milano, Dipartimento di Chimica, Materiali ed Ingegneria Chimica “Giulio Natta”, Via
Mancinelli 7, 20131 Milano, Italy
alessandra.silVani@unimi.it
ReceiVed March 26, 2009
Addition of Grignard reagents to chiral imines derived from isatine afforded chiral, optically enriched
3-substituted 3-aminooxindoles in satisfactory yields and diastereoisomeric ratios. A general protocol is
described for the addition of alkyl, alkenyl, and aryl Grignard reagents. In one case, the absolute
configuration at C3 was determined and the selective N-deprotection was described, enabling further
synthetic transformations of the reaction product.
Introduction
Oxindoles constitute a common structural motif in various
natural products and biologically active compounds.1 Among
them, 3-substituted 3-amino-2-oxindoles are a useful class of
compounds found in several drug candidates, including the
potent gastrin/CCK-B receptor antagonist AG-041R (1)2 and
the vasopressin VIb receptor antagonist SSR-149415 (2),3 a drug
now in clinical trials for treatment of anxiety and depression
† Universita` degli Studi di Milano.
‡ Istituto di Scienze e Tecnologie Molecolari.
§ Politecnico di Milano.
(1) (a) Netz, A.; Oost, T.; Geneste, H.; Braje, W. M.; Wernet, W.; Unger,
L.; Hornberger, W.; Lubisch, W. PTC Int. Appl. WO 2008080971, 2008. (b)
Chen, L.; Zhang, J.; Zhang, Z.; Yang, S. PTC Int. Appl. WO2008034736, 2008.
(c) Stevens, F. C.; Bloomquist, W. E.; Borel, A. G.; Cohen, M. L.; Droste, C. A.;
Heima, M. L.; Kriaciunas, A.; Sall, D. J.; Tinsley, F. C.; Jesudason, C. D. Bioorg.
Med. Chem. Lett. 2007, 17, 6270–6273. (d) Shanmugam, P.; Viswambharan,
B.; Madhavan, S. Org. Lett. 2007, 9, 4095–4098. (e) Ghosh, A. K.; Schiltz, G.;
Perali, R. S.; Leshchenko, S.; Kay, S.; Walters, D. E.; Koh, Y.; Maeda, K.;
Mitsuya, H. Bioorg. Med. Chem. Lett. 2006, 16, 1869–1873. (f) Suzuki, H.;
Morita, H.; Shiro, M.; Kobayashi, J. Tetrahedron 2004, 60, 2489–2495. (g)
Somei, M.; Yamada, F. Nat. Prod. Rep. 2003, 20, 216–242. (h) Tang, Y.-Q.;
Sattler, I.; Thiericke, R.; Grabley, S.; Feng, X.-Z. Eur. J. Org. Chem. 2001,
261–267.
FIGURE 1. Selected bioactive quaternary aminooxindoles and a related
natural compound.
(Figure 1). Moreover, several members of the indole alkaloid
family of natural products contain skeleta that could potentially
be accessed synthetically via 3-aminooxindoles, for instance the
3H-indole skeleton of the chartellines (e.g., chartelline C, 3).4
(3) (a) Decaux, G.; Soupart, A.; Vassart, G. Lancet 2008, 371, 1624–1632.
(b) Shimazaki, T.; Iijima, M.; Chaki, S. Eur. J. Pharmacol. 2006, 543, 63–67.
(c) Bernard, K.; Bogliolo, S.; Ehrenfeld, J Br. J. Pharmacol. 2005, 144, 1037.
(2) Ochi, M.; Kawasaki, K.; Kataoka, H.; Uchio, Y. Biochem. Biophys. Res.
Commun. 2001, 283, 1118.
10.1021/jo900623c CCC: $40.75
Published on Web 05/13/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 4537–4541 4537

Lesma et al.
SCHEME 1. Synthesis of N-Protected Isatine-Based Imines
6 and 8 and of Aminal 7
There are a number of reports on the enantioselective
formation of quaternary carbon centers at the 3-position of
oxindoles.5 However, the direct enantioselective formation of
an amine at this position has been elusive until now. Quaternary
3-aminooxindoles have previously been synthesized by few
asymmetric methods, including intramolecular R-arylation of
amides6 and alkylation of 3-aminooxindoles.7 Owing to the
significance of this structural motif, the development of asym-
metric synthetic methods for oxindoles bearing a nitrogen atom
at the C3 stereogenic center is highly valuable. To the best of
our knowledge, there is no example of asymmetric synthesis
of quaternary 3-aminooxindoles, relying on nucleophiles addi-
tion to imines derived from isatine.
We report here the first asymmetric Grignard addition
protocol to achieve this goal. The formation of quaternary carbon
centers via addition of carbon nucleophiles to imine derivatives
still constitutes a major challenge for synthetic chemistry.8 There
are a number of catalytic asymmetric methods employed to this
end.9 However, they still require a relatively large amount of
complex, chiral catalysts, which are often expensive and difficult
to obtain. Moreover, the majority of the literature in this field
addresses the addition of organometallic reagents to aldimines,
but not to ketimines. In fact, an additional challenge to this
approach is that ketimines tend to have poor reactivity toward
nucleophilic addition and are often activated by the addition of
a Lewis acid.
starting substrates were conveniently prepared respectively from
N-p-methoxybenzylisatine 411 and from N-Boc-isatine 512
(Scheme 1). Both PMB and Boc protecting groups are well
suited for selective removal of the auxiliaries, in view of
potential subsequent synthetic transformations of the obtained
addition compounds. In addition, we think that the sterically
demanding Boc could also exert a favorable additional stereo-
directing effect. By reaction with O-TBDMS (R)-phenylglyci-
nol,13 in the presence of TsOH in toluene at reflux, isatine 4
afforded imine 6 quantitatively. Under the same conditions,
starting from the N-Boc-protected isatine 5, we could isolate
only the aminal 7 as a nearly single diastereisomer at C3. We
regard compound 7 as a synthetic equivalent of the desired imine
for the addition reaction. The tert-butanesulfinylimine 8 was
obtained from 4 with (R)-tert-butanesulfinamide in the presence
of 2 equiv of Ti(OEt)4 in THF under reflux. Compounds 6 and
8 have been respectively obtained as 4:1 and 3:2 mixtures of
imine isomers on the NMR time scale.
Results and Discussion
We decided to investigate the arylation, alkylation, and
alkenylation of imines derived from isatin substrates using chiral
auxiliaries at the nitrogen atom, in order to achieve the synthesis
of 3-substituted 3-aminooxindoles. Among the numerous chiral
amines widely used as a nitrogen-linked stereocontrol element
with ketone precursors, we selected commercially available (R)-
phenylglycinol and Ellman’s (R)-tert-butanesulfinamide. Both
auxiliaries are reported10 to perform effectively in Grignard
additions, activating the CdN bond for nucleophilic addition
and exerting a powerful stereodirecting effect. Finally, the
removal of both the auxiliaries is described to occur usually in
high yields under mild conditions.
The addition of Grignard reagents was first investigated
starting from the imine 6 (Table 1). With 1.1 equiv of allylMgBr,
at -40 °C in CH2Cl2, the addition occurred without Lewis acid
(entry 1) to give the amino derivative 9a in 41% yield (68:32
dr), easily separable from the minor diastereoisomer by flash-
chromatography. Compound 9a was crystalline, and its single-
crystal X-ray analysis unequivocally established the relative
configuration, from which the absolute configuration of the
stereocenter at C-3 was deduced as (S).
Since we reasoned that it would be preferable to avoid
interaction with indole N-H in the addition reactions, the
(4) (a) Nielsen, P. H.; Anthoni, U.; Christophersen, C. Acta Chem. Scand.
1988, B42, 489. (b) Anthoni, U.; Chevolot, L.; Larsen, C.; Nielsen, P. H.;
Christophersen, C. J. Org. Chem. 1987, 52, 4709. (c) Chevolot, L.; Chevolot,
A.-M.; Gajhede, M.; Larsen, C.; Anthoni, U.; Christophersen, C. J. Am. Chem.
Soc. 1985, 107, 4542.
(5) (a) Yasui, Y.; Kamisaki, H.; Takemoto, Y. Org. Lett. 2008, 10, 3303–
3306. (b) Tian, X.; Jiang, K.; Peng, J.; Du, W.; Chen, Y.-C. Org. Lett. 2008, 10,
3583–3586. (c) Galliford, C. V.; Scheidt, K. A. Angew. Chem., Int. Ed. 2007,
46, 8748–8758. (d) Gademann, K.; Bonazzi, S. Angew. Chem., Int. Ed. 2007,
46, 5656–5658. (e) Cravotto, G.; Giovenzana, G. B.; Palmisano, G.; Penoni, A.;
Pilati, T. Tetrahedron: Asymmetry 2006, 17, 3070–3074. (f) Marti, C.; Carreira,
E. M. Eur. J. Org. Chem. 2003, 2209–2219. (g) Dounay, A. B.; Hatanaka, K.;
Kodanko, J. J.; Oestreich, M.; Overman, L. E.; Pfeifer, L. A.; Weiss, M. M.
J. Am. Chem. Soc. 2003, 125, 6261–6271.
(6) (a) Jia, Y.-X.; Hillgren, J. M.; Watson, M. L.; Marsden, S. P.; Ku¨ndig,
E. P. Chem. Commun. 2008, 4040–4042. (b) Marsden, S. P.; Watson, M. L.;
Raw, S. A. Org. Lett. 2008, 10, 2905–2908.
(7) Emura, T.; Eseki, T.; Tachibana, K.; Shimizu, M. J. Org. Chem. 2006,
71, 8559.
(8) For revisions of organometallic additions to imines, see: (a) Ding, H.;
Friestad, G. K. Synthesis 2005, 2815–2829, and references cited therein. (b)
Alvaro, G.; Savoia, D. Synlett 2002, 651–673. (c) Bloch, R. Chem. ReV. 1998,
98, 1407–1438.
(9) (a) Vilaivan, T.; Bhanthumnavin, W.; Sritana-Anant, Y. Curr. Org. Chem.
2005, 9, 1315–1392. (b) Kobayashi, S.; Ishitani, H. Chem. ReV. 1999, 99, 1069–
1094.
(10) For (R)-phenylglycinol, see: (a) Fustero, S.; Sa´nchez-Rosello´, M.;
Rodrigo, V.; del Pozo, C.; Sanz-Cervera, J. F.; Simo´n, A. Org. Lett. 2006, 8,
4129–4132. (b) Chaume, G.; Van Severen, M.-C.; Marinkovic, S.; Brigaud, T.
Org. Lett. 2006, 8, 6123–6126. (c) Spero, D. M.; Kapadia, S. R. J. Org. Chem.
1997, 62, 5537–5541. For (R)-tert-butanesulfinamide, see: (d) Rech, J. C.; Yato,
M.; Duckett, D.; Ember, B.; LoGrasso, F. V.; Bergman, R. G.; Ellman, J. A.
J. Am. Chem. Soc. 2007, 129, 490–491. (e) Denolf, B.; Mangelinckx, S.;
To¨rnroos, K. W.; De Kimpe, N. Org. Lett. 2006, 8, 3129–3132. (f) Lanter, J. C.;
Chen, H.; Zhang, X.; Sui, Z. Org. Lett. 2005, 7, 5905–5907. (g) Kuduk, S. D.;
DiPardo, R. M.; Chang, R. K.; Ng, C.; Bock, M. G. Tetrahedron Lett. 2004, 45,
6641–6643. (h) McMahon, J. P.; Ellman, J. A. Org. Lett. 2004, 6, 1645–1647.
(i) Shaw, A. W.; deSolms, S. J. Tetrahedron Lett. 2001, 42, 7173–7176. (j) Davis,
F. A.; McCoull, W. J. Org. Chem. 1999, 64, 3396–3397.
(11) Vine, K. L.; Locke, J. M.; Ranson, M.; Pyne, S. G.; Bremner, J. B.
J. Med. Chem. 2007, 50, 5109–5117.
(12) Wille, G.; Steglich, W. Synthesis 2001, 759–762.
(13) Miller, S. A.; Chamberlin, A. R. J. Org. Chem. 1989, 54, 2502–2504.
4538 J. Org. Chem. Vol. 74, No. 12, 2009

Grignard Addition to Imines DeriVed from Isatine
TABLE 1. Addition of Grignard Reagents across Substrates 6 and 7
entry
substrate
R’MgX
L.A.
product
yield %a
drb
1
2
6
6
6
6
6
6
6
6
6
7
7
7
7
7
allylMgBr
allylMgBr
allylMgBr
allylMgBr
allylMgBr
isopropylMgBr
vinylMgBr
p-Cl-PhMgBr
p-OMe-PhMgBr
allylMgBr
isopropylMgBr
vinylMgBr
9a
9a
9a
9a
9a
9b
9c
9d
41
55
27
43
77
53
0
48
62
48
54
34
53
61
68:32
55:45
59:41
70:30
80:20
80:20
·
BF3 OEt2
3
Yb(OTf)3
MgBr2
MgBr2
MgBr2
MgBr2
MgBr2
MgBr2
MgBr2
MgBr2
MgBr2
MgBr2
MgBr2
4c
5
6
7
8
9
10
11
12
13
14
75:25
70:30
95:5
75:25
80:20
75:25
95:5
9e
10a
10b
10c
10d
10e
p-Cl-PhMgBr
p-OMe-PhMgBr
a Yield of the major diastereoisomer after flash chromatography. b Determined by mass balance after chromatography. c Toluene was used instead of
CH2Cl2.
TABLE 2. Addition of Grignard Reagents across Imine 8
The allylation was more efficiently promoted by 2 equiv of
MgBr2 (entry 5), with CH2Cl2 as solvent of choice, with respect
to as well noncoordinating toluene (entry 4). Lowering or
increasing the temperature of the reaction and, alternatively, the
equivalents of MgBr2, gave a lower range of yields. When the
Lewis acid was changed to BF3 ·Et2O or Yb(OTf)3, a marked
lower diastereoselectivity was obtained (entries 2 and 3), thus
suggesting the best choice of MgBr2 as imine activator and
substrate coordinating agent.
entry
RMgX (equiv)
L.A.
product yield (%)
dr
1
2
3
4
5
6
7
8
9
allylMgBr (2.0)
allylMgBr (2.0)
allylMgBr (2.0)
allylMgBr (2.0)
allylMgBr (2.0)
allylMgBr (5.0)
isopropylMgBr (5.0) MgBr2
vinylMgBr (5.0) MgBr2
p-OMePhMgBr (5.0) MgBr2
11a
11a
11a
11a
11a
11a
11b
11c
11d
32a
30a
35a
25a
38a
46a
52a
0
54:46c
61:39c
65:35c
89:11c
80:20c
85:15c
78:22c
In order to explore the scope of the Grignard addition to imine
6, we substituted allylMgBr with other commonly available
Grignard reagents. All reactions were carried out utilizing the
conditions summarized in Table 1 (entries 6-9). A major
diastereoisomer was always detected and isolated, with yields
up to 62%, except with vinylmagnesium bromide. It should be
noted that imine 6 reacts smoothly with the more reactive
Grignard reagents derived from stabilized carbanions (as allyl-
magnesium bromide). On the other hand, the starting isatine 4
was predominantly recovered, together with N-deprotected
isatine, when more basic reagents, such as vinylmagnesium
bromide (entry 7), were employed.
·
BF3 OEt2
Yb(OTf)3
AlMe3
MgBr2
MgBr2
53b
70:30d
a Yield of the major diastereoisomer after flash chromatography.
b Determined by mass balance of the reaction mixture. c Determined by
mass balance after chromatography. d Determined by 1H NMR
integration of crude reaction products.
It was found that amines 10a-e could be synthesized in
moderate yields (up to 61%) and in good diastereoselectivity
(up to 95:5), starting from aminal 7, under the optimized
conditions (entries 10-14). A Boc protecting group seemed to
be beneficial when vinylmagnesium bromide was used, allowing
the R-vinyl quaternary amine 10c to be isolated (entry 12) in
high dr, albeit in rather low yield.
In all reactions, both on 6 and 7, in addition to the desired
addition product, we could recover consistent amounts of isatine
(4 or 5), deriving from hydrolysis during work up of the
unreacted starting material. All efforts to completely consume
the starting substrate, by increasing the equivalents of Grignard
reagent (up to five), were uneffective.
be necessary. Evaluation of Lewis acid additives for addition
of 2 equiv of allylmagnesium bromide (entries 1-5, Table 2)
revealed that the best results were obtained in the presence of
MgBr2 also in this case. Ellman has used trimethylaluminium
to increase the reaction yield of organomagnesiums with tert-
butanesulfinyl aldimines,14 but in our case, a lowering of yield
was observed, although the diastereoselectivity was slightly
enhanced (entry 4). In this case, the lower isolated yield could
possibly be also attributed to a competitive methyl transfer from
the AlMe3 additive to the imine carbon. Finally, yield of amine
11a further increased (entry 6) when 5 equiv of Grignard reagent
was used. Under these conditions, good results were obtained
also with isopropylmagnesium bromide and with p-methox-
Similar results, in terms of yields and dr, were obtained when
imine 8, containing the (R)-tert-butanesulfinamide chiral aux-
iliary, was used as substrate. With this more sterically demand-
ing auxiliary, a higher excess of Grignard reagent turned out to
(14) Tang, T. P.; Volkman, S. K.; Ellman, J. A. J. Org. Chem. 2001, 66,
8772–8778.
J. Org. Chem. Vol. 74, No. 12, 2009 4539

Lesma et al.
SCHEME 2. Synthesis and Configurational Assignment of
(S)-12 and (R)-12 in Enantiopure Form
FIGURE 2. Explanation of stereochemical outcomes.
the moderate yields for these substrates, it is significant to note
the difficulty in synthesizing these highly substituted and
hindered amines derivatives with current methods.
Application of these protocols to the synthesis of lead
compounds for the medicinal chemistry is in progress and will
be reported in the due course.
Experimental Section
yphenylmagnesium bromide (entries 7 and 9), while also in this
case, no reaction occurred when vinylmagnesium bromide was
employed (entry 8).
(R)-3-(2-(tert-Butyldimethylsilyloxy)-1-phenylethylimino)-1-
(4-methoxybenzyl)indolin-2-one 6. To a solution of 4 (500 mg,
1.87 mmol) in 10 mL of dry CH2Cl2 under nitrogen atmosphere
were added O-TBDMS-(R)-phenylglycinol17 (470 mg, 1.87 mmol)
and MgSO4 (2 g). The reaction was stirred at room temperature
for 24 h. The solution was then filtered through a pad of Celite
and evaporated under reduced pressure to obtain 6 (oil, 917 mg,
98%) as a 4:1 mixture of imine isomers. The compound was used
We then tested the feasibility of the amino group deprotection
both on 9a and 11a. In this way, the configuration of the major
diastereoisomer was assigned for 11a as 3R by correlation of
the derived amine 12 with the corresponding (S)-12, obtained
after desilylation and removal of the (R)-phenylglycinol side
chain from 9a (Scheme 2). To our knowledge, amines (S)-12
and (R)-12 have never been reported before, all the more so in
nonracemic form.
A working model to explain the observed diastereoselectivi-
ties is shown in Figure 2. For both 6 and 8, we postulate an
initial MgBr2-promoted equilibration of the E/Z ketimine
mixtures to the E isomers and simultaneous activation to
nucleophilic attack, through chelation of the oxindole oxigen
and imine nitrogen. On this basis, we propose that the
stereochemical outcome can be explained by 1,3-allylic strain,
which favors the shown conformations. Delivery of the nucleo-
phile would occur from the less hindered faces, that is from the
re face in the case of 6 and from the si face in the case of 8.
According to this interpretation, use of a solvent with a low
coordinating ability such as methylene chloride would maximize
the complexation of the MgBr2 with the substrate.
without further purification: Rf ) 0.35 (hexane/EtOAc 8:1); [R]25
D
1
) -28.1 (c 1, CHCl3); H NMR (400 MHz, CDCl3, δ) 7.88 (d, J
) 7.6 Hz, 0.2H), 7.73 (d, J ) 7.4 Hz, 0.8H), 7.64-7.59 (m, 2H),
7.38 (t, J ) 7.4 Hz, 1.6H), 7.34-7.23 (m, 4.4H), 7.07 (t, J ) 7.4
Hz, 0.8H), 7.01 (t, J ) 7.6 Hz, 0.2H), 6.86 (d, J ) 8.5 Hz, 2H),
6.81 (t, J ) 6.4 Hz, 0.8H), 6.77 (d, J ) 7.9 Hz, 0.2H), 6.71 (d, J
) 7.9 Hz, 0.8H), 5.57 (t, J ) 6.7 Hz, 0.2H), 4.97 (d, J ) 15.5 Hz,
0.2H), 4.90 (br, d, J ) 15.2 Hz, 1H), 4.78 (d, J ) 15.2 Hz, 0.8H),
4.18-4.12 (m, 0.4H), 4.02 (d, J ) 6.4 Hz, 1.6H) 3.80 (s, 3H),
0.82 (s, 7.2H), 0.79 (s, 1.8H), 0.02 (s, 2.4H), -0.02 (s, 2.4H), -0.03
(s, 0.6H), -0.08 (s, 0.6H); 13C NMR (100 MHz, CDCl3, δ) 159.9
and 159.5, 155.0 and 153.7, 147.5 and 145.4, 141.9 and 141.0,
133.5 and 133.1, 129.6-127.7 (9C), 123.5, 123.2 and 122.9, 122.7,
114.9 (2C), 110.7 and 109.8, 70.1 and 69.7, 69.0 and 65.7, 55.9,
44.0 and 44.6, 26.5 (3C), 18.9, -3.7 (2C); HRMS (ESI) calcd for
C30H36N2O3Si 500.2495, found 500.2488.
tert-Butyl 3-((R)-2-(tert-Butyldimethylsilyloxy)-1-phenylethy-
lamino)-3-hydroxy-2-oxoindoline-1-carboxylate 7. To a solution
of 5 (550 mg, 2.22 mmol) in 10 mL of dry CH2Cl2 under nitrogen
atmosphere were added (R)-phenylglycinol (540 mg, 2.22 mmol)
and MgSO4 (2 g). The reaction was stirred at room temperature
for 3 h. The solution was filtered through a pad of Celite and
evaporated under reduced pressure to afford a yellow foamy solid
which was used in the next step without further purification (1.025
The observed selectivity is in accordance with the models
proposed in the case of ketimines containing an R-coordinating
group, such as a nitrogen or a chlorine atom, both in the case
of phenylglycinol15 or tert-butanesulfinamide16 as chiral
auxiliaries.
Conclusions
g, 96%): Rf ) 0.65 (hexane/EtOAc ) 4:1); [R]25 ) +16.0 (c 1,
D
CHCl3); 1H NMR (400 MHz, CDCl3, δ) 8.47 (d, J ) 8.1 Hz, 1H),
8.37 (dd, J ) 8.1, 1.5 Hz, 1H), 7.59 (m, 2H), 7.40-7.29 (m, 5H),
7.04 (t, J ) 8.1 Hz, 1H), 5.14 (dt, J ) 7.8, 4.6 Hz, 1H), 4.03 (dd,
J ) 10.3, 4.4 Hz, 1H), 3.91(dd, J ) 10.3, 4.6 Hz, 1H), 2.30-2.08
(br, s, 1H), 1.57 (s, 9H), 0.89 (s, 9H), 0.00 (s, 3H), -0.02 (s, 3H);
13C NMR (100 MHz, CDCl3, δ) 191.3, 162.5, 152.8, 143.3, 139.2,
136.3, 134.5, 126.5 (2C), 127.7, 128.9 (2C), 121.1, 119.1, 118.2,
81.0, 66.1, 55.0, 28.3 (3C), 25.8 (3C), 18.3, -5.5, -5.6; HRMS
(ESI) calcd for C27H38N2O5Si 498.2550, found 498.2546.
In summary, we have demonstrated the first method for the
asymmetric addition of Grignard reagents to ketimines derived
from isatine, affording chiral, optically enriched 3-substituted-
3-aminooxindoles. The satisfactory stereoselectivity observed
for the addition reactions with two different chiral auxiliaries
is particularly noteworthy since the diastereoselective formation
of quaternary stereocenters has always been a challenge,
especially when ketimines are used as starting materials. Despite
(R)-N-(1-(4-Methoxybenzyl)-2-oxoindolin-3-ylidene)-2-meth-
ylpropane-2-sulfinamide 8. To a solution of 4 (500 mg, 1.87
(15) (a) Steinig, A. G.; Spero, D. M. J. Org. Chem. 1999, 64, 2406–2410.
(b) Spero, D. M.; Kapadia, S. R. J. Org. Chem. 1997, 62, 5537–5541.
(16) (a) Denolf, B.; Mangelinckx, S.; To¨rnroos, K. W.; De Kimpe, N. Org.
Lett. 2007, 9, 187–190. (b) Barrow, J. C.; Ngo, P. L.; Pellicore, J. M.; Selnick,
H. G.; Nantermet, P. G. Tetrahedron Lett. 2001, 42, 2051–2054.
(17) This product was prepared according to the procedure reported in:
Palomo, C.; Aizpurua, J. M.; Balentova´, E.; Jimenez, A.; Oyarbide, J.; Fratila,
R. M.; Miranda, J. I. Org. Lett. 2007, 9, 101–104.
4540 J. Org. Chem. Vol. 74, No. 12, 2009

Grignard Addition to Imines DeriVed from Isatine
mmol) in 5 mL of dry CH2Cl2 under nitrogen atmosphere at room
temperature were added Ti(OEt)4 (1 mL, 3.74 mmol) and (R)-2-
methyl-2-propanesulfinamide (225 mg, 1.87 mmol). The solution
was refluxed until complete disappearance of the starting materials.
The reaction was quenched with 4 mL of saturated aqueous solution
of NaHCO3. The biphasic solution was filtered through a pad of
Celite and the organic phase extracted with water. The organic phase
was dried over Na2SO4 and evaporated under reduced pressure to
afford 8 (oil, 681 mg, 98%) as a 3:2 mixture of imine isomers.
The compound was used without further purification: Rf ) 0.8
(hexane/EtOAc 1:1); [R]25D ) -50.1 (c 1, CHCl3); 1H NMR (400
MHz, CDCl3, δ) 7.61 (dd, J ) 7.4, 1.0 Hz, 0.4H), 7.50 (pseudo td,
J ) 7.8, 1.2 Hz, 0.4H), 7.36 (td, J ) 7.8, 1.0 Hz, 0.6H), 7.32-7.26
(m, 2.6H), 7.10 (td, J ) 7.6, 0.8 Hz, 0.4H), 7.05 (t, J ) 7.7, Hz,
0.6H), 6.90-6.85 (m, 2H), 6.82 (d, J ) 7.8 Hz, 0.4H), 6.76 (d, J
) 7.8 Hz, 0.6H), 4.91 (br,d, J ) 15.6 Hz, 0.6H), 4.88 (s, 0.8H),
4.84 (d, J ) 15.6 Hz, 0.6H), 3.80 (s, 1.2H), 3.79 (s, 1.8H), 1.45 (s,
5.4H), 1.25 (s, 3.6H); 13C NMR (100 MHz, CDCl3, δ) 159.5 and
155.3, 159.4, 150.8 and 148.0, 138.3 and 135.3, 129.7 and 128.2,
128.9 (2C), 126.9 and 126.5, 125.4 and 123.8, 123.5, 117.7 and
113.7, 114.4 (2C), 111.0 and 110.0, 56.0, 55.3, 43.6, 22.3, and 22.1
(3C); HRMS (ESI) calcd for C20H22N2O3S 370.1351, found
370.1359.
General Optimized Procedure for the Grignard Addition
to 6 or 7. A suspension of substrate (6 or 7, 0.20 mmol) and MgBr2
(80 mg, 0.40 mmol) in 6 mL of dry CH2Cl2 under nitrogen
atmosphere was stirred for 20 min at -40 °C. The desired Grignard
reagent (0.22 mmol) was then slowly added. The reaction mixture
was stirred for 1 h at - 40 °C and for 12 h at room temperature.
The reaction was quenched with 5 mL of a saturated aq NH4Cl
solution, and the organic phase was extracted with CH2Cl2, dried
over Na2SO4, and evaporated under reduced pressure. The crude
addition product was purified by flash chromatography.
20 min at -40 °C. The desired Grignard reagent (1.00 mmol) was
then slowly added. The reaction mixture was stirred for 1 h at -40
°C and for 12 h at room temperature. The reaction was quenched
with 5 mL of a saturated aq NH4Cl solution, and the organic phase
was extracted with CH2Cl2, dried over Na2SO4, and evaporated
under reduced pressure. The crude addition product was purified
by flash chromatography.
Spectroscopic data of major diastereoisomers are reported below.
(R)-N-((R)-3-Allyl-1-(4-methoxybenzyl)-2-oxoindolin-3-yl)-2-
methylpropane-2-sulfinamide 11a: Rf ) 0.44 (hexane/EtOAc 1:1);
[R]25D ) -52.4 (c 1, CHCl3); 1H NMR (400 MHz, CDCl3, δ) 7.54
(d, J ) 7.4 Hz, 1H), 7.26-7.15 (m, 3H), 7.11 (t, J ) 7.4 Hz, 1H),
6.84 (d, J ) 8.5 Hz, 2H), 6.77 (d, J ) 7.4 Hz, 1H), 5.53 (ddt, J )
17.1, 9.9, 7.3 Hz, 1H), 5.17 (dd, J ) 17.1, 1.3 Hz, 1H), 5.08 (dd,
J ) 9.9, 1.3 Hz, 1H), 4.89 (d, J ) 15.4 Hz, 1H), 4.81 (d, J ) 15.4
Hz, 1H), 3.79 (s, 3H), 2.90 (dd, J ) 13.3, 6.8, 1H), 2.80 (dd, J )
13.3, 7.8, 1H), 1.71-1.62 (br, s, 1H), 1.18 (s, 9H); 13C NMR (100
MHz, CDCl3, δ) 176.6, 143.2, 131.1, 130.4, 130.2, 129.3 (2C),
129.0, 128.2, 126.4, 123.5, 121.6, 114.8 (2C), 110.1, 64.5, 57.2,
55.9, 44.1, 44.0, 23.1 (3C); HRMS (ESI) calcd for C23H28N2O3S
412.1821, found 412.1817.
(S)-3-Allyl-3-amino-1-(4-methoxybenzyl)indolin-2-one (S)-12.
To a solution of 9a (100 mg, 0.18 mmol) in 1 mL of dry THF
under nitrogen atmosphere at room temperature was added TBAF
(239 µL, 0.24 mmol, 1 M THF solution). The solution was stirred
for 1 h. The reaction was then quenched with 2 mL of NaOH 1 M
and extracted three times with CH2Cl2. The organic layer was
separated, dried over Na2SO4, and evaporated under reduced
pressure to afford the crude product, which was used in the next
step without further purification (75 mg): Rf ) 0.11 (hexane/EtOAc
3:7); [R]25 ) - 45.2 (c 1, CHCl3).
D
To a solution of the obtained alcohol (75 mg, 0.17 mmol) in CH2Cl2/
MeOH (1:1, 2 mL) at 0 °C and under nitrogen atmosphere, Pb(OAc)4
(77 mg, 0.17 mmol, 1 equiv) was added, and the solution was stirred
at 0 °C for one hour. After complete consumption of the starting
material, NH2OH·HCl (182 mg, 2.63 mmol) was added. After 30 min,
the reaction was quenched with aqueous NaHCO3 and the solid residue
was filtered through a pad of Celite; the biphasic solution was diluted
with water and the organic layer was extracted with EtOAc. The
organic phase was dried over Na2SO4 and evaporated under reduced
pressure. The resulting yellow oil was purified by flash chromatography
(EtOAc/hexane 5:1) to afford (S)-12 (48 mg, 87% overall yield): Rf
Spectroscopic data of major diastereoisomers are reported below.
(S)-3-Allyl-3-((R)-2-(tert-butyldimethylsilyloxy)-1-phenylethy-
lamino)-1-(4-methoxybenzyl)indolin-2-one 9a: Rf ) 0.2 (hexane/
1
EtOAc 9:1); [R]25 ) +95.1 (c 1, CHCl3); H NMR (400 MHz,
D
CDCl3, δ) 7.28 (d, J ) 6.8 Hz, 1H), 7.227.16 (m, 4H), 7.08 (t, J
) 7.4, 1H), 6.99-6.94 (m, 4H), 6.76 (d, J ) 8.7 Hz, 2H), 6.53 (d,
J ) 7.7 Hz, 1H), 5.59 (ddt, J ) 17.3, 10.1, 7.5 Hz, 1H), 5.16 (dd,
J ) 17.3, 1.3 Hz, 1H), 5.06 (dd, J ) 10.1, 1.5 Hz, 1H), 4.53 (d, J
) 15.6 Hz,1H), 3.83 (d, J ) 15.6 Hz, 1H), 3.76 (s, 3H), 3.62 (m,
2H), 3.52 (dd, J ) 13.7, 9.0 Hz, 1H), 3.06-2.73 (br, s, 1H), 2.68
(dd, J ) 13.2, 7.5 Hz, 1H), 2.53 (dd, J ) 13.2, 7.5 Hz, 1H), 0.93
(s, 9H), 0,10 (s, 3H), 0.01 (s, 3H); 13C NMR (100 MHz, CDCl3, δ)
177.9, 158.8, 143.0, 139.6, 131.3, 128.9, 128.6-128.4 (6C), 128.1,
127.6 (2C), 127.5, 124.7, 121.8, 113.9 (2C), 109.1, 67.9, 64.5, 60.9,
55.2, 43.5, 42.9, 25.9 (3C), 18.2, -5.45 (2C); HRMS (ESI) calcd
for C33H42N2O3Si 542.2965, found 542.2972.
) 0.27 (EtOAc); [R]25 ) -26.8 (c 1, CHCl3).
D
(R)-3-Allyl-3-amino-1-(4-methoxybenzyl)indolin-2-one (R)-
12. To a solution of 11a (20 mg, 0.05 mmol) in 300 µL of dioxane
was added a HCl saturated dioxane solution (122 µL, 10 equiv) at
room temperature. The reaction mixture was stirred for 15 min.
The reaction was quenched with 4 mL of aqueous NaHCO3, and
the organic phase was extracted with CH2Cl2, dried, and evaporated
under reduced pressure to afford pure (R)-12 (12 mg, 75%), as an
oil: [R]25D ) +24.3 (c 1, CHCl3); 1H NMR (400 MHz, CDCl3, δ)
7.40 (d, J ) 7.5 Hz, 1H), 7.27-7.18 (m, 3H), 7.07 (t, J ) 7.5 Hz,
1H), 6.86 (d, J ) 8.8 Hz, 2H), 6.76 (d, J ) 7.5 Hz, 1H), 5.56 (m,
1H), 5.11 (d, J ) 16.9 Hz, 1H), 5.04 (d, J ) 10.2 Hz, 1H), 4.98
(d, J ) 15.9 Hz, 1H), 4.69 (d, J ) 15.9 Hz, 1H), 3.79 (s, 3H), 2.68
(dd, J ) 13.2, 6.4 Hz, 1H), 2.59 (dd, J ) 13.2, 8.3 Hz, 1H), 2.00
(br, s, 2H); 13C NMR (100 MHz, CDCl3, δ) 180.6, 159.8, 143.1,
132.0, 129.5, 129.4 (2C), 128.5, 124.6, 123.4, 120.4 (2C), 114.8
(2C), 109.9, 61.6, 55.9, 44.2, 44.0; HRMS (ESI) calcd for
C19H20N2O2 308.1525, found 308.1530.
tert-Butyl 3-allyl-3-((R)-2-(tert-butyldimethylsilyloxy)-1-phe-
nylethylamino)-2-oxoindoline-1-carboxylate 10a: Rf ) 0.13 (hex-
ane/EtOAc 9:1); [R]25D ) -7.3 (c 1, CHCl3); 1H NMR (400 MHz,
CDCl3, 1:1 mixture of rotamers, δ) 8.01 (d, J ) 8.2 Hz, 0.5H), 7.88
(d, J ) 8.2 Hz, 0.5H), 7.59 (d, J ) 7.9 Hz, 0.5H), 7.55 (d, J ) 7.9
Hz, 0.5H), 7.39-7.21 (m, 4H), 7.20-7.06 (m, 4H), 5.71 (pseudo sept,
J ) 8.1 Hz, 1H), 5.28 (d, J ) 11.4 Hz, 1H), 5.22 (d, J ) 14.7 Hz,
1H), 4.95 (dt, J ) 7.3, 3.6 Hz, 1H), 3.83 (br, d, J ) 10.2 Hz, 1H),
3.70 (dd, J ) 10.2, 4.3 Hz, 1H), 3.17-3.05 (m, 1H), 2.97 (dd, J )
13.8, 7.1 Hz, 1H), 1.48 (s, 4.5H), 1.45 (s, 4.5H), 0.81 (s, 4.5H), 0.79
(s, 4.5H), -0.1 (s, 3H), -0.14 (s, 1.5H), -0.20 (s, 1.5H); 13C NMR
(100 MHz, CDCl3, 1:1 mixture of rotamers, δ) 174.15, 154.0 and
153.9, 140.3 and 140.2, 138.3 and 138.2, 132.8 and 132.7, 130.6, 129.8,
129.1, 128.9, 128.2, 127.3, 127.15 (2C), 124.7 and 123.8, 124.1 and
124.0, 121.6 and 121.5, 80.4, 78.1, 66.8 and 66.6, 55.4, 43.5 and 43.3,
29.1 (3C), 26.4 (3C), 18.7, -3.6, -3.7; HRMS (ESI) calcd for
C30H42N2O4Si 522.2914, found 522.2908.
Supporting Information Available: Spectroscopic data of
compounds 9b,d,e, 10b-e, and 11b,d; 1H NMR and 13C NMR
spectra of compounds 6-12; crystallographic data of compound
9a. This material is available free of charge via the Internet at
http://pubs.acs.org.
General Procedure for the Grignard Addition to 8. A
suspension of substrate (0.20 mmol) and MgBr2 (80 mg, 0.40 mmol)
in 6 mL of dry CH2Cl2 under nitrogen atmosphere was stirred for
JO900623C
J. Org. Chem. Vol. 74, No. 12, 2009 4541