Addition of TMSCN to chiral ketimines derived from isatin. Synthesis of an oxindole-based peptidomimetic and a bioactive spirohydantoin

Article abstract of DOI:10.1039/c1ob05532a

We investigated the Strecker-type reaction of isatin derived chiral ketimines with TMSCN in the presence of a Lewis acid. The desired α-amino nitriles have been obtained in good yields with moderate diastereoselectivity. Further elaboration of the cyanide

Full text of DOI:10.1039/c1ob05532a

View Article Online / Journal Homepage / Table of Contents for this issue
Organic &
Biomolecular
Chemistry
Dynamic Article Links
Cite this: Org. Biomol. Chem., 2011, 9, 5515
www.rsc.org/obc
PAPER
Addition of TMSCN to chiral ketimines derived from isatin. Synthesis of an
oxindole-based peptidomimetic and a bioactive spirohydantoin†
Alessandro Sacchetti,*a Alessandra Silvani,*b Francesco G. Gatti,a Giordano Lesma,b Tullio Pilatic and
Beatrice Trucchib
Received 5th April 2011, Accepted 5th May 2011
DOI: 10.1039/c1ob05532a
We investigated the Strecker-type reaction of isatin derived chiral ketimines with TMSCN in the
presence of a Lewis acid. The desired a-amino nitriles have been obtained in good yields with moderate
diastereoselectivity. Further elaboration of the cyanide group allowed the preparation of a new
oxindole-based peptidomimetic and a pharmaceutically relevant spirohydantoin.
spiro-oxindole alkaloids (-)-horsfiline13 and spirotryprostatin.14
Some important synthetic therapeutic agents also contain a 3-
Introduction
The addition of cyanide ions to imines to give a-amino nitriles is
a useful tool in synthetic organic chemistry. The a-amino nitrile
products are versatile intermediates for the synthesis of a number
of interesting molecules.1 The cyano group2 can be transformed
into a primary amine3 or aldehyde4 (by reduction), ketone (by
organometallic addition) or carboxylic acid (by hydrolysis). The
latter transformation is involved in a classicala-amino acid synthe-
sis, the Strecker5 reaction, and has found important applications
in the preparation of both natural and unnatural amino acids.6
Moreover, the recognized value of enantiopure amino acids has
stimulated a lot of efforts in designing asymmetric versions of
the Strecker reaction.7 Besides enantioselective catalytic methods,
the use of chiral auxiliaries has generally been distinguished
as a powerful tool in stereoselective synthesis. The utility of
amines as chiral auxiliaries is of particular significance since
many enantiopure amines are easily available from the chiral pool.
Accordingly, chiral aldimines8 and ketimines9 have been exploited
as substrates for the addition of cyanide ions.
substituted-3-aminooxindole core, as the potent gastrin/CCK-B
receptor antagonist AG-041R (1),15 the vasopressin/V1b receptor
antagonist SSR-149415 (2)16 and the spirohydantoin (3) developed
by AstraZeneca for potential use in the treatment of pain (Fig. 1).17
In the course of our studies on new methodologies to access
pharmaceutically relevant heterocyclic scaffolds,10 we recently
became interested in the asymmetric synthesis of quaternary 3-
aminooxindoles.11 The important oxindole moiety is found in
many natural compounds having several biological activities,
as evidenced in the cyclic peptide Celogentin K12 and the
Fig. 1 Some important therapeutic agents containing a 3-substitut-
ed-3-aminooxindole core.
aPolitecnico di Milano, Dipartimento di Chimica, Materiali ed Ingegneria
Chimica ‘Giulio Natta’, via Mancinelli 7, 20131, Milano, Italy. E-mail:
alessandro.sacchetti@polimi.it; Tel: +39 223993017
Despite the relevance of the quaternary 3-amino oxindole nu-
cleus, the synthesis of 3-amino-3-cyano oxindole has received little
attention.18 Only very recently work from Zhou19 described the use
ofa Cinchonabasedcatalystintheenantioselectiveorganocatalytic
addition of TMSCN to ketimines derived from isatin, however
with moderate yields and enantioselectivities. In light of this,
we decided to report here our auxiliary-based approach to the
cyanide ion addition to chiral ketimines, obtained from isatin and
chiral primary amines. As a preliminary demonstration of the
versatility of 3-amino-3-cyano oxindoles, we also accomplished
bDipartimento di Chimica Organica e Industriale, Universita` degli Studi di
Milano, via G. Venezian 21, 20133, Milano, Italy
cIstituto di Scienze e Tecnologie Molecolari – CNR, Via Golgi 19, 20133,
Milano, Italy
† Electronic supplementary information (ESI) available: General methods,
1
copies of H NMR and 13C NMR spectra for compounds 4–6, 7a, 8a,b,
9a,b, 10a, 10b, 12, 14, 15a, 16a, 16b, 17, 19, 20a,b, 21a,b, 3. Crystallographic
data for compound 10a. CCDC reference numbers 816608. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c1ob05532a
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 5515–5522 | 5515
©

View Article Online
Table 1 Addition of TMSCN to imines 4–6
Entry
Imine
LA
TMSCN (eq)
Time (h)
Yield (%)
dr
Product
1
4
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
6
6
MgBr2
MgBr2
MgBr2
MgBr2
MgBr2
BF3·Et2O
Yb(OTf)3
Ti(iPrO)4
ZnCl2
TMSOTf
SnCl4
MgBr2
SnCl4
1.5
3
3
3
5
3
3
3
3
22
5
22
22
20
4
22
45
28
4
21
22
24
24
24
22
24
22
49
78
68
65 : 35
67 : 33
65 : 35
66 : 34
74 : 26
55 : 45
57 : 43
57 : 43
—
56 : 44
74 : 26
55 : 45
68 : 32
62 : 38
—
7a,b
7a,b
7a,b
7a,b
7a,b
7a,b
7a,b
7a,b
2
3a
4b
5
51
quant.
6
7
55
43
26
—
81
40
61
88
32
—
71
80
8c
9c
10
11
12
13
14
15
16
17
18
3
3
7a,b
7a,b
8a,b
8a,b
8a,b
1.5
1.5
1.5
1.5
1.5
3
BF3·Et2O
ZnCl2
—
MgBr2
SnCl4
53 : 47
46 : 54
61 : 39
8a,b
9a,b
9a,b
3
68
a T = -30◦ C. b T = -40 ◦C. c T = -20 ◦C to rt.
the synthesis of a new oxindole-based quaternary amino acid and
of the spirohydantoin 3.
The results of this study are outlined in Table 1. The addition
products 7–9 were obtained in moderate to good yields and in
moderate diastereoisomeric ratios. The best performing Lewis acid
was SnCl4 which afforded a 74 : 26 dr (determined by 1H NMR) on
substrate 4 (entry 11) and 68 : 32 dr on 5 (entry 13). Quantitative
yield and similar dr were obtained on 4 using MgBr2 and a 5
fold excess of TMSCN (entry 5). Furthermore, imine 5 efficiently
adds TMSCN even in the absence of a Lewis acid but with
poor diastereoselectivity, revealing the importance of the metal
coordination for the stereochemical outcome of the process. To
our disappointment, the two diastereoisomers a and b of products
7–9 were not separable by standard column chromatography.
This prompted us to explore at once the reactivity of the cyano
group, versatile precursor of other functionalities. We first studied
its hydrolysis to the primary amide group. After testing different
conditions, the amino nitriles 7a,b (from entry 4) were conveniently
converted into the desired diastereoisomeric amino amides 10a,b
by reaction with 30% H2O2 in acetone–1 N aq. Na2CO3 (2 : 1)21
(Scheme 1, vide infra for determination of the shown configuration
at the C3 stereocenter).
After facile separation by flash chromatography, the major
amino amide diastereoisomer was crystallized from an i-Pr2O–
MeOH 9 : 1 mixture.
The X-ray diffraction of the obtained crystal established the
absolute configuration at the quaternary stereocenter C3 corre-
sponding to the product 10a, which was attributed as 3R as the
configuration on the phenylglycinol residue was known to be R.
(Fig. 3).
The chiral auxiliary of 10a was then removed by a standard
two step procedure, consisting of the cleavage of the TBDMS
protective group (4% HCl in ethanol) and the subsequent treat-
ment of the resulting amino alcohol with Pb(OAc)4, followed by
Results and discussion
We selected the chiral imines 4–6, which were easily pre-
pared by treating isatin with the proper enantiopure amine in
dichloromethane with MgSO4 as dehydrating agent (Fig. 2).
Fig. 2 Substrates for the addition of TMSCN.
Commercially available (S)-1-phenylethylamine and (S)-1-
(1-naphthyl)ethylamine were used, while O-TBDMS (R)-
phenylglycinol was prepared according to the literature.20 As
expected, the products 4–6 were isolated as 1 : 1 E/Z mixtures
at the C N bond. The ketimines 4–6 were then reacted with
TMSCN in the presence of different Lewis acids. We assumed
that the Lewis acid could act both by blocking the E geometry
of the imine, through the concurrent coordination of the imine
nitrogen and the oxindole oxygen, and by activating the C
N
bond to the nucleophilic addition of the cyanide ion. The
reactions were carried out using 1.5 eq. of Lewis acid (MgBr2,
BF3·Et2O, Yb(OTf)3, Ti(iPrO)4, ZnCl2, TMSOTf and SnCl4 were
screened) and with different amounts of TMSCN. To improve the
diastereoselectivity, the temperature was maintained at -20 ◦C.
5516 | Org. Biomol. Chem., 2011, 9, 5515–5522
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
Scheme 2 Proposed mechanism for the addition of TMSCN to imines 4
and 5.
atom is ruled by the steric hindrance with the aromatic H4 of
oxindole (see structures 13a and 13b). In both cases, this results
in a favored attack on the re face of the ketimine double bond,
affording preferentially amino nitriles 7a or 8a.
The cyano group was also successfully converted into the
corresponding methyl ester to address the synthesis of a,a-
disubstituted amino esters, which are potentially useful as pre-
cursors of constrained quaternary amino acids. Thus treatment of
7a,b and 8a,b with saturated HCl–methanol afforded the desired
methyl esters, as products 15a,b and 16a,b. Also in this case, the two
diastereoisomers could easily be separated by chromatography.
After removal of the chiral auxiliary as previously described from
major diastereoisomers 15a and 16a, the amino ester 14 could be
readily obtained.
Scheme 1 Elaboration of the cyanide group.
To verify the reactivity of the sterically hindered quaternary
amino group of 14, coupling with N-Boc-L-alanine using BopCl
as a condensation agent was performed (Scheme 3). Orthogonally
protected dipeptide mimetic 17 could be obtained in satisfactory
yield.
Scheme 3 Synthesis of dipeptide 17.
As a further demonstration of the high versatility of oxindole-
based amino nitriles, we also investigated the conversion of 12 into
a spirohydantoin derivative by reaction with different reagents
(CDI, phosgene, triphosgene), but, to our disappointment, no
useful results were obtained. We then changed our strategy to use
hydantoin-based compounds and we focused our attention on the
synthesis of 3. This compound is presently synthesized as a racemic
mixture by reaction of isatin 18 with ammonium carbonate
and KCN (Bucherer–Bergs reaction) followed by resolution of
enantiomers by means of chiral Simulated Moving Bed (SMB)
chromatography.22 At the present time, no stereoselective synthesis
of 3 has been reported in the literature. The isatin derivative 18,
prepared according to the literature,23 was converted into imine
19 (Scheme 4). Following our previous results, in order to obtain
the correct stereochemistry of the final product 3, this time (R)-1-
phenylethylamine was used as the chiral auxiliary. Imine 19 was
reacted with TMSCN to afford 20a,b in a 71 : 29 diastereoisomeric
ratio, again as an inseparable mixture.
Fig. 3 Plot of the structure of compound 10a as determined by X-ray
crystallography. Atomic displacement parameters at 50% probability level.
addition of a 3 M HCl–dioxane solution, to cleanly afford com-
pound 12.
In the same way, amino nitriles 8a,b were converted into the
corresponding amino amides 11a,b which could also be isolated
separately. In this case, the cleavage of the chiral auxiliary from
the major diastereoisomer was achieved by simple hydrogenation
over Pd(OH)2/C, obtaining 12 as the same (-) enantiomer
already obtained from 10a. Absolute configuration of the major
diastereoisomer 11a was consequently ascertained again as 3R.
These data allowed us to propose a possible mechanism for
the addition of TMSCN to both ketimines 4 and 5, according
to Scheme 2. In our hypothesis, the coordination with the metal
of the Lewis acid, stabilizes the E geometry of the imine, and
the spatial arrangement of the chiral residue on the nitrogen
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 5515–5522 | 5517
©

View Article Online
1
EtOAc, 7 : 3). [a]2D0= -8.2 (c 0.65, CHCl3). H NMR (400 MHz,
CDCl3, 1 : 1 mixture of isomers) d 9.71 (br s, 0.5H) and 8.86 (br s,
0.5H), 7.86 (d, J = 7.7 Hz, 0.5H), 7.71 (d, J = 7.3 Hz, 0.5H), 7.63–
7.20 (m, 6H), 7.10–7.00 (m, 1H), 6.97–6.93 (m, 0.5H), 6.83 (d, J =
7.8 Hz, 0.5H), 6.73–6.67 (m, 0.5H) and 5.55 (t, J = 6.7 Hz, 0.5H),
4.14 (d, J = 6.6 Hz, 1H) and 4.03–3.98 (m, 1H), 0.82 (s, 4.5H),
0.79 (s, 4.5H), 0.02 (s, 1.5H), -0.01 (s, 1.5H), -0.05 (s, 1.5H), -0.08
(s, 1.5H). 13C NMR (100 MHz, CDCl3) d 165.6 and 160.8, 155.0
and 153.3, 145.2 and 142.9, 141.1 and 140.2, 134.1 and 133.4,
129.6–127.2 (5C), 126.1 and 124.3, 123.9 and 123.7, 117.3, 113.4
and 112.0, 69.3 and 68.9, 68.4 and 64.8, 25.8 (3C), 18.3 and 18.2,
-5.3 and -5 (2C). IR (CHCl3) nmax 3431, 1741, 1620 (cm-1). HRMS
(ESI) calcd for C22H28N2O2Si 380.1920, found 380.1919.
3-[(S)-1-Phenyl-ethylimino]-1,3-dihydro-indol-2-one 5. To a so-
lution of isatin (500 mg, 3.40 mmol) in dry CH2Cl2 (15 ml) at room
temperature, MgSO4 (3.3 g, 27.20 mmol, 8 equiv) and a solution
of (S)-1-phenyl-ethylamine (520 mg, 3.40 mmol, 1 equiv) in dry
CH2Cl2 (3 ml) were subsequently added. The reaction mixture was
stirred at room temperature for five days. The solution was filtered
through a pad of Celite and the solvent evaporated under reduced
pressure affording the mixture of imine isomers 5 (833.5 mg, 98%
yield). The product was used in the next reaction without any
further purification. Mixture of stereoisomers (ª 1 : 1). Rf = 0.57
Scheme 4 Synthesis of spirohydantoin 3.
1
(hexane–EtOAc, 1 : 1). [a]2D0 = -58.9 (c 0.25, CHCl3). H NMR
Reaction of 20a,b with chlorosulfonyl isocyanate (CSI) in
CH2Cl2, followed by refluxing in aqueous 1 M HCl, gave the
spirohydantoin products 21a,b. The pure major diastereoisomer
21a could be obtained by recrystallization from hexane–EtOAc or,
alternatively, by careful chromatographic separation with toluene–
EtOAc 95 : 5 as eluent. In order to preserve the olefin functional
group, the removal of the chiral auxiliary was performed by reflux-
ing 21a in toluene in the presence of MeOH.24 The spirohydantoin
3 was obtained in quantitative yield. By comparison of its optical
rotatory power with literature,22 a 97% ee was determined and the
S configuration at the quaternary stereocenter was assessed, thus
confirming again our proposal on the mechanism of the TMSCN
addition.
In conclusion, we have investigated the addition of TMSCN
to chiral imines derived from isatin. The addition reactions
proceeded with good yields and moderate diastereoselectivity. The
versatility of the amino nitrile products has been demonstrated
by synthesizing the new quaternary amino ester 14, potentially
useful in peptidomimetic chemistry, and by accomplishing the
first stereoselective synthesis of the bioactive spirohydantoin 3.
(400 MHz, CDCl3) d 9.71–9.31 (br s, 0.5H), 8.53 (br s, 0.5H), 7.72
(d, J = 7.6 Hz, 0.5H), 7.68 (d, J = 7.0 Hz, 0.5H), 7.56 (d, J = 7.0 Hz,
1H), 7.51 (d, J = 7.3 Hz, 1H), 7.39–7.21 (m, 4H), 7.07–7.01 (m,
1H), 6.96 (d, J = 7.6 Hz, 0.5H), 6.80 (d, J = 7.8 Hz, 0.5H), 6.59 (q,
J = 6.6 Hz, 0.5H), 5.54 (q, J = 6.6 Hz, 0.5H), 1.75 (d, J = 6.4 Hz,
1.5H), 1.61 (d, J = 6.7 Hz, 1.5H). 13C NMR (101 MHz, CDCl3)
d = 166.2 and 160.9, 153.8 and 151.9, 145.7, 144.3 and 143.4, 133.7
and 132.9, 128.8–128.6 (3C), 127.4–126.8 (4C), 123.1 and 122.7,
122.8 and 116.9, 112.3 and 110.8, 61.8 and 58.5, 24.9 and 24.5.
IR (CHCl3) nmax 3437, 1728, 1620 (cm-1). HRMS (ESI) calcd for
C16H14N2O 250.1106, found 250.1103.
3-[(R)-1-Naphthalen-2-yl-ethylimino]-1,3-dihydro-indol-2-one 6.
To a solution of isatin (500 mg, 3.40 mmol) in anhydrous CH2Cl2
(14 ml) at room temperature, MgSO4 (3.3 g, 27.20 mmol, 8
equiv) and a solution of (R)-1-naphthalen-2-yl-ethylamine (546 ml,
3.40 mmol, 1 equiv) in anhydrous CH2Cl2 (3 ml) were subsequently
added. The reaction mixture was stirred at room temperature for
six days. The solution was filtered through a pad of Celite and the
solvent removed in vacuo providing the mixture of imine isomers
6 (928 mg, 91% yield). The product was used in the next reaction
without any further purification. Mixture of diastereoisomers
(ª 1 : 1) Rf = 0.40 (hexane–EtOAc, 7 : 3). [a]2D0 = -238.1 (c 0.62,
CHCl3). 1H NMR (400 MHz, CDCl3) d 10.11 (br s, 0.5 H), 9.10
(br s, 0.5 H), 8.31 (d, J = 9.1 Hz, 0.5 H), 8.15 (d, J = 9.1 Hz, 0.5 H),
8.01 (d, J = 9.0 Hz, 0.5 H), 7.85 (t, J = 8.7 Hz, 0.5 H),7.80–7.75 (m,
2 H), 7.72–7.26 (m, 6 H), 7.15–6.96 (m, 1,5 H), 6.90–6.72 (m, 1.5
H), 6.21 (q, J = 6.5 Hz, 0.5H), 5.42 (q, J = 6.5 Hz, 0.5H),1.93 (d,
J = 6.5 Hz, 1.5H), 1.77 (d, J = 6.5 Hz, 1.5H). 13C NMR (101 MHz,
CDCl3) d 166.3 and 161.8, 155.2 and 152.3, 147.2 and 143.8, 142.7
and 140.6, 138.2, 134.7, 134.2, 132.8 and 131.7 and 131.0, 128.8
and 128.2, 127.3 and 127.2, 126.9 and 126.7, 126.2 and 125.8,
123.9 and 123.7, 123.3 and 122.7,118.3 and 117.2, 113.3 and 112.4,
111.2, 58.8 and 55.5, 25.2 and 24.6. IR (CHCl3) nmax 3437, 1738,
Experimental section
3-[(R)-2-(tert-Butyl-dimethyl-silanyloxy)-1-phenyl-ethylimino]-
1,3-dihydro-indol-2-one 4. To a solution of isatin (643 mg, 4.37
mmol) in anhydrous CH2Cl2 (20 ml) at room temperature, MgSO4
(4.2 g, 34.96 mmol, 8 equiv) and a solution of (R)-OTBDMS-
phenylglycinol (1.1 g, 4.37 mmol, 1 equiv) in anhydrous CH2Cl2
(4 ml) were subsequently added. The reaction mixture was stirred
at room temperature for five days. The solution was filtered
through a pad of Celite and the solvent evaporated under reduced
pressure affording the mixture of imine isomers (1.63 g, 98% yield).
The product was used in the next reaction without any further
purification. Mixture of stereoisomers (ª 1 : 1) Rf = 0.37 (hexane–
5518 | Org. Biomol. Chem., 2011, 9, 5515–5522
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
1618 (cm-1). HRMS (ESI) calcd for C20H16N2O 300.1263, found
300.1267.
(m, 0.5 H), 7.76–7.86 (m, 1 H), 7.61–7.71 (m, 1 H), 7.53 (d, J =
6.7 Hz, 0.5 H), 7.34–7.48 (m, 2 H), 7.26–7.32 (m, 2 H), 7.18 (td, J =
7.7, 1.2 Hz, 0.5 H), 7.04–7.12 (m, 1 H), 6.90 (d, J = 7.6 Hz, 0.5 H),
6.68–6.79 (m, 1.5 H), 5.17 (q, J = 6.7 Hz, 0.5 H), 4.83 (q, J = 6.5 Hz,
0.5 H), 2.52–3.34 (br s, 1 H), 1.65 (d, J = 6.7 Hz, 1.5 H), 1.61 (d, J =
6.7 Hz, 1.5 H). 13C NMR (101 MHz, CDCl3) d 172.3 and 171.8,
141.1 and 140.6, 139.2, 134.5, 131.4, 131.1 and 130.9, 129.5, 128.3,
126.7 (2C), 126.4 and 126.1, 125.9 (2C), 125.0 and 124.7, 123.9,
123.3 and 123.0, 117.1 and 116.9, 111.4 and 111.3, 60.6 and 60.3,
51.6 and 51.3, 25.7 and 25.5. IR (CHCl3) nmax 3428, 3215, 2242,
1732 (cm-1). HRMS (ESI) calcd for C21H17N3O 327.1372 found
327.1373.
Representative procedure for the addition of TMSCN to the
imines 4–6. To a solution of the imine (0.26 mmol) in dry CH2Cl2
(2.5 ml) at -20 ◦C, was first added the Lewis acid (0.39 mmol, 1.5
equiv) and then, dropwise, TMSCN (50 ml, 42 mmol, 1.5 equiv).
The reaction mixture was stirred at -20 ◦C for 22 h. The solution
was then poured into a saturated aqueous solution of NaHCO3
(8 ml). The aqueous layer was extracted with CH2Cl2 (3 ¥ 4
ml) and the combined organic extracts were washed with water
(15 ml), dried over Na2SO4, filtered and evaporated under reduced
pressure. The mixture of isomers was recovered as a yellow oil, and
could be used in the next reaction without any further purification.
3-[(R)-2-(tert-Butyl-dimethyl-silanyloxy)-1-phenyl-ethylamino]-
2-oxo-2,3-dihydro-1H-indole-3-carboxylic acid amide (10a,b). To
a stirring solution of 7a,b (827.39 mg, 2.03 mmol) in acetone
(16.2 ml) was added a 1 N aqueous solution of Na2CO3 (6.9 ml,
3.45 mmol, 3.4 equiv) and dropwise 30% H2O2 (6.9 ml, 60.9 mmol,
30 equiv). The reaction mixture was stirred for 3 days at room
temperature. The solvent was removed in vacuo and the resulting
aqueous mixture was extracted with CH2Cl2 (3 ¥ 20 ml). The
organic layer was dried over Na2SO4, filtered and concentrated
under reduced pressure. Purification by flash chromatography
(hexane–EtOAc, 3 : 7) provided compound 10a (381.7 mg) and
compound 10b (282.2 mg) (77% overall yield). Crystals of 10a
suitable for X-ray analysis were obtained by slow evaporation at
room temperature of a solution of 10a in iPr2O/MeOH, 9 : 1. 10a.
3-[(R)-2-(tert-Butyl-dimethyl-silanyloxy)-1-phenyl-ethylamino]-
2-oxo-2,3-dihydro-1H-indole-3-carbonitrile (7a,b). Mixture of di-
1
astereoisomers 7a,b Rf = 0.32 (hexane–EtOAc, 7 : 3). H NMR
(300 MHz, CDCl3) d 8.62 (br s, 0.5H) and 8.48 (br s, 0.5H), 7.26–
7.17 (m, 6H), 7.05 (d, J = 7.5 Hz, 0.5H) and 6.92 (d, J = 7.9 Hz,
0.5H), 6.83–6.70 (m, 1.5H), 6.58 (d, J = 7.2 Hz, 0.5H), 4.31 (dd,
J = 9.2, 4.2 Hz, 0.5H) and 3.84 (dd, J = 8.7, 4.4 Hz, 0.5H), 3.73
(dd, J = 10.3, 4.3 Hz, 0.5H), 3.60 (dd, J = 10.3, 4.4 Hz, 0.5H),
3.57–3.45 (m, 1H), 2.21–2.02 (br s, 1H),0.96 (s, 4.5H) and 0.92 (s,
4.5H), 0.26 (s, 1.5H) and 0.09 (s, 1.5H), 0.07 (s, 1.5H) and 0.03
(s, 1.5H). 13C NMR (75 MHz, CDCl3) d 172.4 and 172.1, 140.5,
139.6, 130.9 and 130.7, 126.3 and 126.0, 123.3 and 123.0, 111.5
and 111.1, 128.2–127.3 (5C, Ph), 124.9, 116.5 and 115.7, 67.6 and
67.3, 61.8 and 61.1, 60.3, 25.9 (3C), 18.2, -5.3 (2C). IR (CHCl3)
nmax 3431, 3288, 2249, 1743 (cm-1). An analytical sample of the
major diastereoisomer could be obtained by chromatographic
separation. Major diastereoisomer 7a Rf = 0.44 (hexane–EtOAc,
◦
Rf = 0.16 (hexane–EtOAc, 3 : 7). Mp 173–175 C. [a]2D0 = -167.0
(c 1, CHCl3). 1H NMR (400 MHz, CDCl3) d 7.82 (br s, 1H), 7.35
(d, J = 7.4 Hz, 1H), 7.27 (t, J = 7.2 Hz, 1H), 7.23–7.11 (m, 3H),
7.08 (t, J = 7.6 Hz, 1H), 6.98–6.92 (m, 2H), 6.73 (d, J = 7.7 Hz,
1H), 5.96 (br s, 2H), 3.84 (t, 3J = 5.7 Hz, 1H), 3.75–3.69 (m, 2H),
1.26 (s, 1H), 0.90 (s, 9H), 0.02 (s, 3H), -0.01 (s, 3H). 13C NMR
(100 MHz, CDCl3) d 177.4, 171.9, 142.4, 140.4, 130.5, 128.8–
128.3 (5C), 127.3, 126.1, 123.1, 111.0, 70.7, 68.3, 61.0, 26.5 (3C),
18.9, -4.9 (2C). IR (CHCl3) nmax 3498, 3433, 1734, 1691 (cm-1).
HRMS (ESI) calcd for C23H31N3O3SiNa (MNa+) 448.2027, found
448.2028. 10b. Rf = 0.28 (hexane–EtOAc, 3 : 7). [a]2D0 = -9.2 (c 1,
CHCl3). 1H NMR (400 MHz, CDCl3) d 9.02 (br s, 1H), 7.13–7.08
(m, 3H), 7.07–6.99 (m, 3H), 6.76 (d, J = 7.8 Hz, 1H), 6.73–6.62 (m,
1H), 6.54 (t, J = 7.5 Hz, 1H), 6.31 (br s, 2H), 3.73–3.64 (m, 1H),
3.63–3.54 (m, 2H), 2.22 (s, 1H), 0.95 (s, 9H), 0.07 (s, 3H), 0.06 (s,
3H). 13C NMR (100 MHz, CDCl3) d 177.3, 172.2, 142.3, 130.1,
128.5–127.8 (6H), 127.1, 126.6, 122.7, 110.9, 72.0, 68.1, 61.9, 26.6
(3C), 19.0, -4.7, -4.9.
1
7 : 3). [a]2D0 = -40.2 (c 1, CHCl3). H NMR (400 MHz, CDCl3)
d 8.27 (br s, 1H), 7.29–7.19 (m, 6H), 6.84 (d, J = 7.8 Hz, 1H),
6.75 (dt, J = 7.7, 1.0 Hz, 1H), 6.59 (d, J = 7.6 Hz, 1H), 4.40 (dd,
J = 9.2, 4.3 Hz, 1H), 3.79 (dd, J = 10.3, 4.3 Hz, 1H), 3.57 (dd,
J = 10.3, 9.3 Hz, 1H), 2.47–2.33 (br s, 1H), 0.97 (s, 9H), 0.14 (s,
3H), 0.11 (s, 3H). 13C NMR (100 MHz, CDCl3) d 171.7, 140.4,
139.6, 130.6, 128.3–128.0 (5C),126.5, 125.0, 123.0, 110.9, 115.6,
67.6, 62.0, 60.2, 25.9 (3C), 18.2, -5.3, -5.5. HRMS (ESI) calcd for
C23H29N3O2SiNa (MNa+) 430.1921, found 430.1919.
2-Oxo-3-((S)-1-phenylethylamino)indoline-3-carbonitrile.
Mixture of diastereoisomers 8a,b (ª 3 : 2) Rf = 0.56 (hexane–
1
EtOAc, 1 : 1) H NMR (400 MHz, CDCl3) d 8.00 (br. s., 0.5 H),
7.80 (br. s., 0.5 H), 7.11–7.30 (m, 7 H), 6.96–7.01 (m, 0.5 H),
6.88–6.95 (m, 0.5 H), 6.85 (d, J = 7.8 Hz, 0.5 H), 6.81 (d, J =
8.1 Hz, 0.5 H), 4.24 (m, J = 6.3, 4.3 Hz, 0.5 H), 3.97 (m, J = 6.4,
3.1 Hz, 0.5 H), 2.54 (br s, 0.5 H), 2.50 (br s, 0.5 H), 1.45 (d, J =
6.7 Hz, 1.5 H), 1.42 (d, J = 6.7 Hz, 1.5 H). 13C NMR (101 MHz,
CDCl3) d 172.3 and 172.1, 144.8 and 144.1, 140.7 and 140.5,
130.9, 128.3 (3C), 127.4 and 127.1, 126.9, 126.3 and 125.9, 124.7
and 124.4, 123.4 and 123.3, 116.4 and 116.2, 111.1, 60.0 and 59.7,
55.0 and 54.5, 25.2 and 25.0. IR (CHCl3) nmax 3437, 3208, 2249,
1730 (cm-1). HRMS (ESI) calcd for C17H15N3O 277.1215 found
277.1219.
2-Oxo-3-((S)-1-phenyl-ethylamino)-2,3-dihydro-1H-indole-3-
carboxylic acid amide (11a,b). To a stirring solution of 8a,b
(2.04 g, 7.36 mmol) in acetone (59 ml) was added an 1 N aqueous
solution of Na2CO3 (25 ml, 12.51 mmol, 3.4 equiv) and dropwise
30% H2O2 (21.5 ml, 220.8 mmol, 30 equiv). The reaction mixture
was stirred at room temperature for 3 days. The solvent was
removed in vacuo and the resulting aqueous mixture was extracted
with CH2Cl2 (3 ¥ 30 ml). The organic layer was dried over Na2SO4,
filtered and concentrated under reduced pressure. Purification by
flash chromatography (hexane–EtOAc, 1 : 9) afforded compound
11a (783 mg) and compound 11b (417 mg), (1.2 g, 55% overall
yield). 11a. Rf = 0.21 (hexane–EtOAc, 1 : 9). [a]2D0 = -274.6 (c 1,
3-((R)-1-Naphthalen-2-yl-ethylamino)-2-oxo-2,3-dihydro-1H-
indole-3-carbonitrile (9a,b). Mixture of diastereoisomers Rf
0.17 (hexane–EtOAc, 7 : 3). H NMR (400 MHz, CDCl3) d 8.27
(br s, 0.5 H), 8.10 (br s, 0.5 H), 8.06 (d, J = 9.1 Hz, 0.5 H), 7.96–8.01
=
1
1
CH3OH). H NMR (400 MHz, CD3OD. Exchangeable protons
were not detected) d 7.39 (d, J = 7.4 Hz, 1H), 7.30 (t, J = 7.6 Hz,
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 5515–5522 | 5519
©

View Article Online
3
1H), 7.17–7.04 (m, 4H), 6.81 (d, J = 6.8 Hz, 2H), 6.73 (d, J =
(S)-3-Amino-2-oxo-2,3-dihydro-1H-indole-3-carboxylic acid
7.7 Hz, 1H), 3.77 (q, J = 6.6 Hz, 1H), 1.34 (d, J = 6.7 Hz, 3H).
13C NMR (100 MHz, CD3OD) d 178.6, 173.5, 143.9, 143.5, 129.6,
127.5 (2C), 127.2, 126.7 (3C), 124.6, 121.8, 110.3, 71.0, 54.3, 23.6.
IR (CHCl3) nmax 3500, 3431, 1734, 1689 (cm-1). 11b. Rf = 0.27
(hexane–EtOAc, 1 : 9). [a]2D0 = -31.6 (c 1, CH3OH). 1H NMR
(400 MHz, CD3OD. Exchangeable protons were not detected) d
7.11–7.00 (m, 6H), 6.82 (d, J = 7.8 Hz, 1H), 6.72 (d, J = 7.4 Hz,
1H), 6.60 (t, J = 7.6 Hz, 1H), 3.52 (q, J = 6.7 Hz, 1H), 1.31 (d, J =
6.7 Hz, 3H). 13C NMR (100 MHz, CD3OD) d 173.4 (2C), 146.9,
143.1, 129.7, 128.2 (2C), 127.7, 126.8 (3C), 125.8, 122.4, 110.5,
72.6, 55.1, 24.8. HRMS (ESI) calcd for C17H17N3O2 295.1321,
found 295.1320.
methyl ester 14
Synthesis of 14 from 15a. To a solution of 15a (98 mg,
0.31 mmol) in 3.1 ml of CH2Cl2–MeOH 1 : 1, at 0 ◦C, was added
Pb(OAc)4 (137.4 mg, 0.31 mmol, 1 equiv). The mixture was stirred
at room temperature for 17 h. A 3 M solution of HCl in dioxane
was added (2 ml) and the mixture was stirred at room temperature
for 3 days. The solution was then basified to pH 8–9 by the addition
of solid Na2CO3. The aqueous layer was extracted with AcOEt
(3 ¥ 7 ml). The organic layer was dried over Na2SO4, filtered
and concentrated under reduced pressure. The crude product was
purified by flash chromatography (hexane–EtOAc, 1.5 : 8.5) giving
14 (38.4 mg, 60% yield).
Synthesis of 14 from 16a. To a solution of 16a (164.8 mg,
0.53 mmol) in dry MeOH (5.3 ml), 20% Pd(OH)2/C (35 mg) was
added and the reaction mixture was stirred at room temperature
under hydrogen atmosphere for 6 days. The suspension was then
filtered through a pad of Celite and the residue washed with EtOAc
(3 ¥ 6 ml). The solvent was evaporated in vacuo providing 14
(107 mg, 98% yield).
(R)-3-Amino-2-oxo-2,3-dihydro-1H-indole-3-carboxylic acid
amide 12
Synthesis of 12 from 10a. 10a (80 mg, 0.19 mmol) was dissolved
in a 4% solution of HCl in EtOH (2.7 ml). The reaction mixture
was allowed to stir at room temperature for 3 h. The solution was
neutralized with a saturated aqueous solution of NaHCO3 and
then the solvent was removed in vacuo. The aqueous layer was
extracted with AcOEt (2 ¥ 5 ml). The combined organic layers
were dried over Na2SO4, filtered and concentrated under reduced
pressure providing the alcohol intermediate (41.2 mg, 70% yield).
Rf = 0.22 (EtOAc–MeOH, 9.5 : 0.5). [a]2D0 = -257.1 (c 1, CH3OH).
1H NMR (400 MHz, CD3OD. Exchangeable protons were not
detected) d 7.39 (dd, J = 7.5, 0.6 Hz, 1H), 7.31 (dt, J = 7.7, 1.3 Hz,
1H), 7.21–7.08 (m, H, 3H), 6.83 (dd, J = 8.0, 1.4 Hz, 2H), 6.75 (d,
J = 7.6 Hz, 1H), 3.73–3.65 (m, 2H), 3.47 (dd, J = 15.3, 8.7 Hz,
1H). 13C NMR (100 MHz, CD3OD) d 178.7 (2C), 143.4, 139.8,
129.6, 125.0, 121.8, 110.3, 127.5–127.2 (5C), 126.9, 70.7, 66.2, 60.9.
To a solution of the alcohol intermediate (26.5 mg, 0.09 mmol)
14. Rf = 0.25 (hexane–EtOAc, 3 : 7). [a]2D0 = -113.8 (c 0.7,
1
CH3OH). H NMR (400 MHz, CD3OD. Exchangeable protons
were not detected) d 7.33–7.25 (m, 2H), 7.02 (t, J = 7.6 Hz,
1H), 6.93 (d, J = 7.6 Hz, 1H), 3.66 (s, 3H). 13C NMR
(100 MHz, CD3OD) d 178.5, 172.0, 144.2, 131.5, 130.1, 125.1,
124.2, 111.8, 61.3, 53.9. IR (CHCl3) nmax 3433, 3211, 1747,
1620 (cm-1). HRMS (ESI) calcd for C10H10N2O3 206.0691, found
206.0690.
3-((R)-2-Hydroxy-1-phenyl-ethylamino)-2-oxo-2,3-dihydro-1H-
indole-3-carboxylic acid methyl ester (15a,b). 7a,b (112 mg, 0.27
m◦mol) was dissolved in dry MeOH (3.5 ml) and cooled to
0 C. HCl gas was then slowly bubbled through the solution for
15 min. The resulting dark red solution was then left to stir at
room temperature for 22 h. Excess HCl was removed bubbling N2
into the solution. After dilution with water (3.5 ml), the solution
was neutralized by the addition of a saturated aqueous solution
of NaHCO3 and then the solvent removed in vacuo. The aqueous
layer was extracted with CH2Cl2 (3 ¥ 3.5 ml) and the organic layer
obtained was dried over Na2SO4, filtered and concentrated under
reduced pressure. Purification by flash chromatography (hexane–
EtOAc, 6 : 4) yielded compound 15a (35.1 mg) and compound
15b (24.8 mg) (68% overall yield). 15a. Rf = 0.27 (hexane–EtOAc,
◦
in 0.9 ml of CH2Cl2–MeOH, 1 : 1, at 0 C, was added Pb(OAc)4
(39.9 mg, 0.09 mmol, 1 equiv). The mixture was stirred at room
temperature for 1 h. A 3 M solution of HCl in dioxane (0.6 ml)
was added and the mixture was stirred at room temperature for
16 h. The solution was then basified to pH 8–9 by the addition
of solid Na2CO3. The aqueous layer was extracted with EtOAc
(3 ¥ 2 ml). The organic layer was dried over Na2SO4, filtered and
concentrated under reduced pressure yielding 12 (11.9 mg, 69%
yield).
Synthesis of 12 from 11a. To a solution of 11a (223.6 mg,
0.76 mmol) in dry MeOH (7.6 ml), 20% Pd(OH)2/C (45 mg) was
added and the reaction mixture was stirred at room temperature
under hydrogen atmosphere for 3 days. The suspension was then
filtered through a pad of Celite and the residue washed with MeOH
(3 ¥ 8 ml). The solvent was evaporated in vacuo to obtain 12
(145.0 mg, 98%).
1
3 : 7). [a]2D0 = -136.7 (c 1, CHCl3). H NMR (400 MHz, CDCl3)
d 8.31 (br s, 1 H), 7.39–7.30 (m, 2H), 7.21–7.16 (m, 3H), 7.12
(m, 1H), 7.14–7.08 (m, 2H), 6.83 (d, J = 7.6 Hz, 1H), 3.79–
3.74 (m, 1H), 3.72–3.63 (m, 1H), 3.65 (s, 3H), 3.58–3.52 (m,
1H), 2.67–2.51 (br s 2H). 13C NMR (100 MHz, CDCl3) d 175.7,
169.3, 141.9, 139.1, 130.3, 125.0, 123.0, 110.7, 128.1–128.0 (5C),
125.8, 70.8, 66.5, 60.1, 53.5. IR (CHCl3) nmax 3433, 3330, 1747,
1620 (cm-1). HRMS (ESI) calcd for C18H18N2O4 326.1267 found
326.1263.
15b. Rf = 0.32 (hexane–EtOAc, 3 : 7).1H NMR (300 MHz,
CDCl3) d 8.08 (br s, 1 H), 7.42–7.27 (m, 3H), 7.26–7.19 (m, 2H),
7.15 (dt, J = 7.6, 1.5 Hz, 1H), 6.87 (dd, J = 7.6, 1.4 Hz, 1H),
6.77–6.65 (m, 2H), 3.74–3.57 (m, 3H). 3.64 (s, 3H), 2.78–2.59 (br s
2H).
12. Rf = 0.46 (EtOAc/MeOH, 9.5 : 0.5). [a]2D0 = -72.4 (c 0.5,
1
CH3OH). H NMR (400 MHz, CD3OD. Exchangeable protons
were not detected) d 7.35 (d, J = 7.5 Hz, 1H), 7.30 (dt, J = 7.7,
1.2 Hz, 1H), 7.06 (dt, J = 7.6, 0.8 Hz, 1H), 6.95 (d, J = 7.8 Hz, 1H).
13C NMR (100 MHz, CD3OD) d 174.1 (2C), 143.3, 131.2, 130.2,
124.0, 123.0, 110.8, 70.8. IR (CHCl3) nmax 3435, 3338, 3226, 1724,
1616 (cm-1). HRMS (ESI) calcd for C9H9N3O2 191.0695, found
191.0695.
5520 | Org. Biomol. Chem., 2011, 9, 5515–5522
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
2-Oxo-3-((S)-1-phenyl-ethylamino)-2,3-dihydro-1H-indole-3-
carboxylic acid methyl ester (16a,b)
MgSO4 (5.8 g, 48.16 mmol, 8 equiv) and then a solution of (S)-
phenyl-ethylamine (922.5 mg, 6.02 mmol, 1 equiv) in dry THF
(20 ml). The reaction mixture was stirred at room temperature
overnight. The reaction mixture was filtered through a pad of
Celite and the solvent removed in vacuo affording the mixture of
imine isomers 19 (2.57 g, 98% yield). Mixture of diastereoisomers
(ª 3 : 1) [a]2D5 = -142.0 (c 1.5, CHCl3) 1H NMR (400 MHz, CDCl3)
d 7.68 (d, J = 7.7 Hz, 0.25H), 7.64 (d, J = 7.7 Hz, 0.75H), 7.51
(d,3J = 7.7 Hz, 1.5H), 7.46 (d, J = 7.7 Hz, 0.5H), 7.34–7.22 (m,
5H), 7.20–7.14 (m, 1H), 7.09–6.95 (m, 2H), 6.81 (d, J = 7.7 Hz,
0.25H), 6.72 (d, J = 7.7 Hz, 0.75H), 6.57 (q, J = 6.2 Hz, 0.75H),
6.43 (d, J = 16.1 Hz, 1H), 6.12 (dt, J = 16.1, 6.2 Hz, 1H), 5.49 (q,
J = 6.2 Hz, 0.25H), 4.47 (d, J = 6.2 Hz, 0.5), 4.41 (J = 6.2 Hz, 1.5H),
1.69 (d, J = 6.2 Hz, 0.75H), 1.55 (d, J = 6.2 Hz, 2.25H). 13C NMR
(101 MHz, CDCl3) d 158.2 and 158.1, 151.0 and 150.9, 145.7 and
145.4, 144.5 and 144.4, 136.3 and 136.1, 133.1 and 132.7, 132.5,
131.6, 130.8 and 130.4, 128.3 and 128.2 (3C), 126.9 and 126.5
(4C), 125.5, 124.6, 123.1 and 122.9, 122.4, 121.9, 109.8 and 108.8,
61.5 and 58.5, 41.6 and 41.2, 24.8 and 24.6. IR (CHCl3) nmax 3419,
1733, 1624 (cm-1). HRMS (ESI) calcd for C25H20Cl2N2O 434.0953,
found 434.0951.
8a,b (1.08 g, 3.89 mmol) was dissolved in dry MeOH (30 ml) and
cooled to 0 ◦C. HCl gas was then slowly bubbled through the
solution for 45 min. The resulting dark red solution was then left
to stir at room temperature for 16 h. Excess HCl was removed by
bubbling N2 into the solution. After dilution with water (30 ml), the
solution was neutralized by the addition of solid Na2CO3 and then
the solvent removed in vacuo. The aqueous layer was extracted with
CH2Cl2 (3 ¥ 30 ml) and the organic layer was dried over Na2SO4,
filtered and concentrated under reduced pressure. Purification by
flash chromatography (hexane–EtOAc, 6.5 : 3.5) allowed a partial
separation of compound 16a (332.2 mg) and compound 16b (319.5
mg) as a light yellow solid (651.7 mg, 54% overall yield). 16a.
Rf = 0.39 (hexane–EtOAc, 1 : 1). [a]2D0 = -150.3 (c 1.3, CH3OH).
1H NMR (400 MHz, CD3OD. Exchangeable protons were not
detected) d 7.35–7.27 (m, 2H), 7.19–7.04 (m, 4H), 6.92 (dd, J =
7.7, 1.3 Hz, 2H), 6.76 (d, J = 7.9 Hz, 1H), 3.75 (q, J = 6.6 Hz,
1H), 3.62 (s, 3H), 1.27 (d, J = 6.7 Hz, 3H). 13C NMR (100 MHz,
CD3OD) d 176.2, 169.7, 143.5, 143.1, 129.8, 127.5–126.9 (5C),
126.3, 124.4, 121.9, 110.3, 70.5, 54.0, 52.3, 23.6. IR (CHCl3) nmax
3433, 3338, 1747, 1618 (cm-1). HRMS (ESI) calcd for C18H18N2O3
310.1317 found 310.1319.
1-[(E)-3-(3,4-Dichloro-phenyl)-allyl]-2-oxo-3-((S)-1-phenyl-
ethylamino)-2,3-dihydro-1H-indole-3-carbonitrile (20a,b). To a
solution of 19 (1 g, 2.30 mmol) in anhydrous CH2Cl2 (25 ml), at
-20 ◦C, was first added SnCl4 (633 ml, 3.45 mmol, 1.5 equiv) and
then dropwise TMSCN (863 ml, 6.90 mmol, 3 equiv). The reaction
mixture was stirred at -20 ◦C for 24 h. The solution was then
poured into a saturated aqueous solution of NaHCO3 (25 ml).
The aqueous layer was extracted with CH2Cl2 (3 ¥ 50 ml), and
the combined organic extracts were washed with water, dried over
Na2SO4, filtered and evaporated under reduced pressure delivering
16b. Rf = 0.43 (hexane–EtOAc, 1 : 1). [a]2D0 = -63.8 (c 1.2,
1
CH3OH). H NMR (400 MHz, CD3OD. Exchangeable protons
were not detected) d7.12–6.96 (m, 6H), 6.81 (dd, J = 7.5, 0.7 Hz,
1H), 6.76 (d, J = 7.7 Hz, 1H), 6.69 (dt, J = 7.6,1.0 Hz, 1H), 3.64 (s,
3H), 3.64 (q, J = 6.6 Hz, 1H), 1.31 (d, J = 6.6 Hz, 3H). 13C NMR
(100 MHz, CD3OD) d 176.5, 169.3, 145.3, 142.1, 129.2, 124.8,
122.0, 109.9, 127.5–126.3 (5C), 126.8, 71.4, 54.2, 52.3, 23.9.
1
(S)-3-(R)-2-tert-Butoxycarbonylamino-propionylamino)-2-oxo-
2,3-dihydro-1H-indole-3-carboxylic acid methyl ester 17. 14a
(68.4 mg, 0.33 mmol) was dissolved in dry CH2Cl2 (2 ml) at
0 ◦C. Dry Et3N (51 ml, 0.37 mmol, 1.1 equiv) and BopCl (127.3 mg,
0.50 mmol, 1.5 equiv) were added and the reaction mixture was
stirred at 0 ◦C for 40 min. Keeping the mixture at 0 ◦C, a
solution of Boc-Ala-OH (62.4 mg, 0.33 mmol, 1 equiv) in dry
CH2Cl2 (2 ml) and dry Et3N (51 ml, 0.37 mmol, 1.1 equiv) was
slowly added. The reaction mixture was allowed to warm to room
temperature and stirred for 22 h. The reaction was quenched with
H2O (4 ml) and the organic layer was washed with 1 M HCl (2
¥ 4 ml), saturated aqueous solution of NaHCO3 (2 ¥ 4 ml) and
water (4 ml), dried over Na2SO4, filtered and the solvent removed
in vacuo. Purification by flash chromatography (hexane–EtOAc,
1 : 1) afforded compound 17 (66 mg, 53% yield). Rf = 0.48 (hexane–
EtOAc, 3 : 7). [a]2D9 = -31.0 (c 0.72, CH3OH). 1H NMR (400 MHz,
CD3OD. Exchangeable protons were not detected) d 7.30 (dt, J =
8.0, J = 1.3 Hz, 1H), 7.13 (d, J = 7.3 Hz, 1H), 7.01 (dt, J = 7.6,
0.9 Hz, 1H), 6.93 (d, J = 7.8 Hz, 1H), 4.13 (q, J = 7.2 Hz, 1H), 3.73
(s, 3H), 1.51 (s, 9H), 1.29 (d, J = 7.2 Hz, 3H). 13C NMR (100 MHz,
CD3OD) d 173.1 (2C), 167.3, 157.2, 143.1, 129.7, 126.9, 122.4 (2C),
110.1, 79.6, 66.0, 53.0, 50.0, 27.3 (3C), 16.4. IR (CHCl3) nmax 3525,
3348, 1748, 1718, 1604 (cm-1). HRMS (ESI) calcd for C18H23N3O6
377.1587, found 377.1589.
20 (936 mg, 88% yield). Mixture of diastereoisomers (65 : 35) H
NMR (400 MHz, CDCl3) d 7.46–7.03 (m, 10H), 7.03–6.93 (m,
1H), 6.84 (d, J = 12.4 Hz, 0.4H), 6.78 (d, J = 12.4 Hz, 0.6H),
6.60–6.39 (m, 1H), 6.18 (dt, J = 16.7, 9.2 Hz, 0.4H), 6.01 (dt, J =
16.7, 9.2 Hz, 0.6H), 4.50 (dd, J = 9.2, 2.7 Hz, 1.2H), 4.36–3.97
(m, 1.8H), 2.64 (d, J = 3.9 Hz, 0.6H), 2.59 (d, J = 3.9 Hz, 0.4H),
1.46 (d, J = 11.0 Hz, 1.8H), 1.43 (d, J = 11.0 Hz, 1.2H). 13C NMR
(101 MHz, CDCl3) d 169.6 and 169.5, 144.3 and 143.5, 142.2 and
141.9, 135.8 and 135.7, 132.5 and 132.4, 131.5 and 131.4, 131.0
and 130.8, 130.7 and 130.6, 130.3 and 130.2, 128.2 and 128.1,
128.0, 127.9 and 127.8, 127.2 and 127.0, 126.7 and 126.6, 126.2,
125.8 and 125.6, 125.5 and 125.4, 123.8 and 123.6, 123.4 and 123.2,
123.3, 116.3 and 116.2, 109.6 and 109.5, 59.1 and 58.8, 54.7 and
54.2, 42.0, 25.1 and 24.9. IR (CHCl3) nmax 3425, 2246, 1736 (cm-1).
HRMS (ESI) calcd for C26H21Cl2N3O 461.1062, found 461.1066.
1¢-[(2E)-3-(3,4-dichlorophenyl)prop-2-en-1-yl]-1H,3-[(S)-1-
phenyl-ethyl]spiro[imidazolidine-4,3¢-indole]-2,2¢,5(1¢H )-trione
(21a,b). To a solution of 20a,b (900 mg, 1.95 mmol) in dry
CH2Cl2 (23 ml) was added CSI(276 mg, 1.95 mmol, 1 equiv).
The reaction mixture was stirred at room temperature for 15 min,
then concentrated in vacuo. After addition of 18 ml of 1 N
HCl, the suspension was stirred for 15 min at room temperature,
followed by heating to reflux for 2 h. Once the mixture cooled
to room temperature, the solid was filtered, washed with water
and dried affording product 21a,b in 93% yield. Crystallization
(hexane–EtOAc, 95 : 5) and purification by flash chromatography
(toluene–EtOAc, 95 : 5) allowed a partial separation of the major
1-[(E)-3-(3,4-Dichloro-phenyl)-allyl]-3-[(S)-1-phenyl-ethyl-
imino]-1,3-dihydro-indol-2-one 19. To a solution of 18 (2 g, 6.02
mmol) in dry THF (20 ml) was first added at room temperature
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 5515–5522 | 5521
©

View Article Online
diastereoisomer 21a. Mixture of diastereoisomers (ª 3 : 1) 1H NMR
(400 MHz, CDCl3) d 9.40 (br s, 1H), 7.51–7.02 (m, 10H), 6.95–6.73
(m, 2H), 6.62 (d, J = 16.3 Hz, 0.75H), 6.49 (d, J = 16.3 Hz, 0.25H),
6.20 (dt, J = 16.3, 4.7 Hz, 0.75H), 6.45 (dt, J = 16.3, 4.7 Hz, 0.25H),
5.40 (q, J = 6.2 Hz, 0.75H), 5.15 (q, J = 6.2 Hz, 0.25H), 4.63 (dd,
J = 15.5, 4.7 Hz, 0.75H), 4.39 (dd, J = 15.5, 4.7 Hz, 0.75H), 4.34
(dd, J = 15.5, 4.7 Hz, 0.25H), 3.88 (dd, J = 15.5, 4.7 Hz, 0.25H),
1.71 (d, J = 6.2 Hz, 0.75H), 1.66 (d, J = 6.2 Hz, 2.25H). 13C NMR
(101 MHz, CDCl3) d 169.9, 168.4 and 168.3, 156.4 and 156.3,
143.0, 139.3, 136.9, 136.1, 132.7, 131.7, 131.0, 130.7, 130.5, 129.2,
128.2 (2C), 128.0 (2C), 127.9, 127.7, 125.8 and 124.9, 123.4 and
123.3, 122.5, 109.6, 60.4, 54.0 and 52.7, 42.2 and 42.0, 17.8 and
14.1. IR (CHCl3) nmax 3442, 1729, 1633 (cm-1). HRMS (ESI) calcd
for C27H21Cl2N3O3 505.0960, found 505.0962.
627–630; (d) O. G. Backeberg and B. Staskun, J. Chem. Soc., 1962,
2961–2963; (e) R. C. Larock, Comprehensive Organic Transformations
(2nd edn), Wiley-VCH, 1999, 1271–1272.
5 A. Strecker, Justus Liebigs Ann. Chem., 1850, 75, 27–45.
6 (a) S. J. Connon, Angew. Chem., Int. Ed., 2008, 47, 1176–1178; (b) C.
Spino, Angew. Chem., Int. Ed., 2004, 43, 1764–1766; (c) H. Gro¨ger,
Chem. Rev., 2003, 103, 2795–2827; (d) L. Yet, Angew. Chem., Int. Ed.,
2001, 40, 875–877.
7 (a) S. J. Connon, Angew. Chem., Int. Ed., 2008, 47, 1176–1178;
(b) H. Groeger, Chem. Rev., 2003, 103, 2795–2827; (c) J. Martens,
ChemCatChem, 2010, 2, 379–381; (d) M. Shibasaki, M. Kanai and T.
Mita, Org. React., 2008, 70, 1–119; (e) L. Yet, Angew. Chem., Int. Ed.,
2001, 40(5), 875–877.
8 (a) S. P. Vincent, A. Schleyer and C. Wong, J. Org. Chem., 2000, 65,
4440–4443; (b) T. K. Chakraborty, K. Azhar Hussain and G. Venkat
Reddy, Tetrahedron, 1995, 51, 9179–9190.
9 (a) A. A. Cordi, J.-M. Lacoste, F. L. Borgne, Y. Herve, L. Vaysse-
Ludot, J.-J. Descombes, C. Courchay, M. Laubie and T. J. Verbeuren,
J. Med. Chem., 1997, 40, 2931–2935; (b) Y. Ohfune, S.-H. Moon and
M. Horikawa, Pure Appl. Chem., 1996, 68, 645–648; (c) D. Ma, H.
Tian and G. Zou, J. Org. Chem., 1999, 64, 120–125; (d) R. Warmuth,
T. E. Munsch, R. A. Stalker, B. Li and A. Beatty, Tetrahedron, 2001,
57, 6383–6397; (e) R. Badorrey, C. Cativiela, M. D. D´ıaz-de-Villegas,
R. D´ıez, F. Galbiati and J. A. Ga´lvez, J. Org. Chem., 2005, 70, 10102–
10105; (f) F. Huguenot and T. Brigaud, J. Org. Chem., 2006, 71, 7075–
7078.
10 (a) G. Lesma, N. Landoni, T. Pilati, A. Sacchetti and A. Silvani, J. Org.
Chem., 2009, 74, 8098–8105; (b) G. Lesma, N. Landoni, A. Sacchetti
and A. Silvani, J. Org. Chem., 2007, 72, 9765–9768; (c) G. Lesma, E.
Meschini, T. Recca, A. Sacchetti and A. Silvani, Tetrahedron, 2007, 63,
5567–5578.
11 (a) G. Lesma, N. Landoni, T. Pilati, A. Sacchetti and A. Silvani, J. Org.
Chem., 2009, 74, 4537–4541; (b) G. Lesma, N. Landoni, A. Sacchetti
and A. Silvani, Tetrahedron, 2010, 66, 4474–4478; (c) M. Baroni, G.
Lesma, L. Puleio, A. Sacchetti, A. Silvani and M. Zanchet, Synthesis,
2010, 23, 4075–4081.
12 H. Suzuki, H. Morita, M. Shiro and J. Kobayashi, Tetrahedron, 2004,
60, 2489–2495.
1¢-[(2E)-3-(3,4-Dichlorophenyl)prop-2-en-1-yl]-2H,5H-spiro-
[imidazolidine-4,3¢-indole]-2,2¢,5(1¢H)-trione (3). To a solution of
21a (120 mg, 0.24 mmol) in dry toluene (3 ml) was added MsOH
(31 ml, 0.48 mmol, 2 equiv). The mixture was refluxed for 24 h. The
reaction mixture was then cooled to room temperature, washed
with a saturated aqueous solution of NaHCO3 (2 ¥ 5 ml) and with
water (5 ml), dried over Na2SO4, filtered and evaporated under
reduced pressure yielding 3 (90 mg, 93% yield). [a]2D5 = +16.2 (c
0.5, CH3OH, lit +16.8, see ref. 22). 1H NMR (400 MHz, DMSO-
d6) d 11.50 (br s, 1H), 8.70 (br s, 1H), 7.68–7.63 (m, 1H), 7.56
(d, J = 7.7 Hz, 1H), 7.47–7.36 (m, 3H), 7.19–7.10 (m, 2H), 6.53
(d, J = 15.8 Hz, 1H), 6.44 (dt, J = 15.8, 3.8 Hz, 1H), 4.54 (d, J =
4.1 Hz, 2H) 13C NMR (101 MHz, DMSO-d6) d 170.8, 170.6, 157.6,
143.4, 136.8, 131.5, 130.8 (2C), 130.0, 128.8, 128.1, 126.4, 125.4,
124.8, 124.2, 123.5, 110.1, 69.2, 41.5. IR (CHCl3) nmax 3440, 3330,
1797, 1734, 1702 (cm-1). HRMS (ESI) calcd for C19H13Cl2N3O3
401.0334, found 401.0333.
13 A. Jossang, P. Jossang, H. A. Hadi, T. Sevenet and B. Bodo, J. Org.
Chem., 1991, 56, 6527–6530.
14 C. B. Cui, H. Kakeya, G. Okada, R. Onose, M. Ubukata, I. Takahashi,
K. Isono and H. Osada, J. Antibiot., 1995, 48, 1382–1384.
15 M. Ochi, K. Kawasaki, H. Kataoka and Y. Uchio, Biochem. Biophys.
Res.
Acknowledgements
16 C. S.-L. Gal, J. Wagnon, J. Simiand, G. Griebel, C. Lacour, G. Guillon,
C. Barberis, G. Brossard, P. Soubrie´, D. Nisato, M. Pascal, R. Pruss,
B. Scatton, J.-P. Maffrand and G. R. Le Fur, J. Pharmacol. Exp. Ther.,
2002, 300, 1122–1130.
We are grateful for the generous financial support from the
E.U. INTENANT project.
17 D. R. Brittain and R. Wood, Eur. Pat. Appl. EP28906, 1981 (Chem.
Abstr., 1981, 95, 150660).
18 (a) H. Otomatsu, K. Natori and H. Takahashi, Chemi. Pharm. Bull.,
1975, 23, 1431–1435; (b) S. Bodforss, Justus Liebigs Ann. Chem., 1971,
745, 99–108; (c) M. G. Moloney and M. Yaqoob, Synlett, 2004, 1631–
1633.
Notes and references
1 D. Enders and J. P. Shilvock, Chem. Soc. Rev., 2000, 29, 359–373.
2 For a review, see Rabinovitz in The chemistry of the cyano group,
Z. Rappoport, Ed; Wiley, New York, 1970, 307–340.
3 (a) B. M. Trost, I. Fleming Comprehensive Organic Synthesis, Perg-
amon, Oxford, 1991; Vol. 8, 251–254; (b) J. Seyden-Penne Reduction
by Alumino- and Borohydrides in Organic Synthesis (2nd edn), Wiley-
VCH, 1997, 149–154; (c) D. Addis, S. Enthaler, K. Junge, B. Wendt
and M. Beller, Tetrahedron Lett., 2009, 50, 3654–3656; (d) N. Umino,
T. Iwakuma and N. Itoh, Tetrahedron Lett., 1976, 17, 2875–2876; (e) S.
Satoh and S. Suzuki, Tetrahedron Lett., 1969, 10, 4555–4558.
4 (a) H. Stephen, J. Chem. Soc., 1925, 127, 1874–1877; (b) H. C. Brown
and C. P. Grag, J. Am. Chem. Soc., 1964, 86, 1085–1089; (c) A. E. G.
Miller, J. W. Biss and L. H. Schwartzaman, J. Org. Chem., 1959, 24,
19 Y.-L. Liu, F. Zhou, J.-J. Cao, C.-B. Ji, M. Ding and J. Zhou, Org. Biomol.
Chem., 2010, 8, 3847–3850.
20 S. A. Miller and A. R. Chamberlin, J. Org. Chem., 1989, 54, 2502–2504.
21 S. Fioravanti, D. Massari, A. Morreale, L. Pellacani and P. A. Tardella,
Tetrahedron, 2008, 64, 3204–3211.
22 C. Leugn, M. Tomaszewski and S. Woo, U.S. Pat. Appl. Publ.
US2007185179, 2007(Chem. Abstr., 2007, 147, 257771).
23 L. Horoszok, C. Leung, M. Tomaszewski and C. Walpole, PCT Int.
Appl. WO2007091946, 2007 (Chem. Abstr., 2007, 147, 277602).
24 S. Paik and J. Y. Lee, Tetrahedron Lett., 2006, 47, 1813–1815.
5522 | Org. Biomol. Chem., 2011, 9, 5515–5522
This journal is
The Royal Society of Chemistry 2011
©