Palladium-catalyzed enantioselective domino heck-cyanation sequence: Development and application to the total synthesis of esermethole and physostigmine

Article abstract of DOI:10.1002/chem.200601016

An efficient synthesis of functionalized 3-alkyl-3-cyanomethyl-2-oxindole 1 by a palladium-catalyzed domino Heck-cyanation reaction has been developed. Reaction of ortho-iodoanilide 5 with potassium ferro(II)cyanide, K ₄[Fe(CN)₆], dissolved in DMF in the presence of palladium acetate and sodium carbonate afforded oxindole 1 in good to excellent yields. An enantioselective domino Heck-cyanation process has been developed for the first time using (S)-DIFLUORPHOS as a chiral supporting ligand, and an enantioselectivity of up to 79% ee in the enantiomerically enriched oxindole was obtained under optimized conditions. A concise total synthesis of esermethole and physostigmine, powerful inhibitors of acetyl- and butyryl-cholinesterase, is documented.

Full text of DOI:10.1002/chem.200601016

FULL PAPER
DOI: 10.1002/chem.200601016
Palladium-Catalyzed Enantioselective Domino Heck–Cyanation Sequence:
Development and Application to the Total Synthesis of Esermethole and
Physostigmine
Artur Pinto, Yanxing Jia, Luc Neuville, and Jieping Zhu*[a]
Abstract: An efficient synthesis of
functionalized 3-alkyl-3-cyanomethyl-2-
oxindole 1 by a palladium-catalyzed
domino Heck–cyanation reaction has
been developed. Reaction of ortho-io-
doanilide 5 with potassium ferro(ii)cya-
nide, K4[Fe(CN)6], dissolved in DMF
in the presence of palladium acetate
and sodium carbonate afforded oxin-
dole 1 in good to excellent yields. An
enantioselective domino Heck–cyana-
tion process has been developed for
the first time using (S)-DIFLUOR-
PHOS as a chiral supporting ligand,
and an enantioselectivity of up to
79% ee in the enantiomerically en-
riched oxindole was obtained under
optimized conditions. A concise total
synthesis of esermethole and physostig-
mine, powerful inhibitors of acetyl- and
butyryl-cholinesterase, is documented.
Keywords: alkaloids · asymmetric
synthesis
· cyanation · domino
reactions · oxindoles
Introduction
ty of nucleophiles including organoboronic acids, organotin
derivatives, enolates, and p nucleophiles have been utilized
to trap the stable s-alkylpalladium complex; while alkynes,
allenes, and carbon monoxide have served as relays to prop-
agate the reaction sequence before the terminating step.[7]
On the other hand, cyanide has rarely been used as a termi-
nating agent, aside from two examples reported indepen-
dently by the groups of Torii and Grigg.[8] We report herein,
The development of catalytic processes allowing the forma-
tion of multiple chemical bonds in a single synthetic opera-
tion represents an attractive and very active research field
of synthetic organic chemistry.[1] The high bond-forming effi-
ciency of such domino processes is ideally suited for gener-
ating molecular complexity and for reducing waste produc-
tion.[2] The importance and reliability of transition-metal-
catalyzed transformations has made them ideal starting
points for the elaboration of such domino processes, and
indeed, significant progress has been achieved in this
regard.[3] Among them, palladium-catalyzed carbopallada-
tion, especially the Heck reaction,[4] has played a prominent
role in developing some of the most powerful domino pro-
the development of an efficient synthesis of 3,3-disubstituted
A
2-oxindole 1 by a domino intramolecular Heck–cyanation
sequence using potassium ferro(ii)cyanide (4)[9] as a cyanide
donor. An enantioselective version of this process is also
documented for the first time, and its utility is illustrated by
the development of an efficient synthesis of esermethole (2)
and physostigmine (3), which is a powerful inhibitor of
acetyl- and butyrylcholinesterase, isolated from the seeds of
physostigma venenosum.[10]
cesses. In particular, the oligocyclization of a halogenated
polyene[5] and sequences of intramolecular Heck reaction–
anion capture[6] have met with great success in the synthesis
of structurally diverse heterocycles and spirocycles. A varie-
[a] A. Pinto, Dr. Y. Jia, Dr. L. Neuville, Dr. J. Zhu
Institut de Chimie des Substances Naturelles
CNRS, 91198 Gif-sur-Yvette Cedex (France)
Fax : (+33)1-6907-7247
E-mail: zhu@icsn.cnrs-gif.fr
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author. It contains copies
Results and Discussion
1
of H and 13C NMR spectra of compounds 1a–1k, esermethole (2)
Heck–cyanation process: Metal-catalyzed cyanation of aryl
halides, including the classic Rosenmund–von Braun reac-
and physostigmine (3), and chiral HPLC diagrams of racemic and
enantiomerically enriched oxindole 1k.
Chem. Eur. J. 2007, 13, 961 – 967
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961

tion and its palladium-catalyzed version, is a common and
useful transformation as a result of the versatility of the
cyano group in synthesis and its prevalence in pharmaceuti-
cal agents.[11] It has long been known that the palladium-cat-
alyzed cyanation reaction is very sensitive to the reaction
conditions, and in particular, the cyanide source. Indeed, it
has been proposed that the presence of two or more equiva-
lents of cyanide relative to palladium, in solution, can inter-
rupt the catalytic cycle by forming a stable palladium cyan-
ate complex.[12] To prevent catalyst deactivation, a variety of
cyanide sources, such as alkali cyanide, zinc cyanide, acetone
cyanohydrine, and trimethylsilyl cyanide, in combination
with different solvents, have been proposed to fine-tune the
cyanide concentration.[13] Recently Beller et al.,[14] and sub-
sequently Weissman et al.[15] have demonstrated that potassi-
um ferro(ii)cyanide (4) is an excellent cyanide source for the
palladium-catalyzed cyanation of aryl halides. Following
these observations, an intramolecular Heck–cyanation se-
quence involving a palladium catalyst was investigated by
using o-iodoanilide 5a as the test substrate with 4 as the ter-
minating agent. The results are summarized in Table 1.
The possible reaction path is depicted in Scheme 1. Oxi-
dative addition of an aryl iodide to a Pd0 species generated
in situ gives intermediate A, which undergoes 5-exo-trig cy-
Scheme 1. Domino Heck–cyanation sequence, a plausible reaction path.
A
Table 1. Palladium-catalyzed domino Heck–cyanation sequence: a survey
of reaction conditions.[a]
placement of the iodide by cyanide would afford palladium
complex C, which upon reductive elimination, would pro-
duce desired oxindole 1 with the concurrent regeneration of
the Pd0 species.
To probe the scope and limitation of this new protocol,
cyclic cyanation of a range of substituted o-iodoanilides[16]
were examined and the results are shown in Table 2. The
outcome of this domino process is not sensitive to the elec-
tronic properties of the aryl halide, and a variety of oxin-
doles substituted at C-4, C-5, C-6, and C-7 by an electron-
donating or an electron-withdrawing group can be prepared
in good to excellent yields. Even the electron-rich and steri-
cally encumbered 2,6-disubstituted aryl iodide 5b participat-
ed in the reaction to provide the desired oxindole 1b in
78% yield (entry 1). A chlorine atom was also tolerated
(entry 4), which provides the potential for further function-
alization. N-Benzyl anilide 5i underwent cyclic cyanation,
albeit with a slightly decreased yield (entry 8). As an N-
benzyl group is readily removed, it constituted a route to N-
unsubstituted oxindole. Lastly, tert-butyldimethylsilyl
(TBDMS)-functionalized 3-hydroxymethyl-3-cyanomethyl
oxindole 1j was synthesized from 5j without any problems.
Partial cleavage of the TBDMS ether under the basic reac-
tion conditions may account for the reduced yield of 1j
(entry 9).
Entry Catalyst
Solvent Base
(OAc)2 DMF Na2CO3
Pd(OAc)2 DMA
(OAc)2 NMP
[Pd(dba)2] DMF
Pd(OAc)2 DMF
Pd(OAc)2 DMF
Pd(OAc)2 DMF
Time [h] Conv. [%] Yield [%]
1
Pd
A
3
>99
59
>99
78
>99
34
83
55
82
68
47
65
0
2
A
Na2CO3 24
Na2CO3 24
Na2CO3 27
K2CO3 20
CaCO3 20
3Pd
4
A
ACHTREUNG
5
A
6
ACHTREUNG
7
A
Ag3PO4
–
0
[a] All reactions were carried out under an argon atmosphere using
1.0 equiv of 5a, 0.015 equiv of Pd catalyst, 0.22 equiv of 4, 1.0 equiv of
base, and solvent (0.2m) at 1208C.
Under the ligandless conditions employed by Weissman
et al., the reaction outcome was both solvent and base de-
pendent. Sodium carbonate (entry 1) was a superior base to
potassium carbonate (entry 5), calcium carbonate (entry 6),
and silver phosphate (entry 7) when palladium acetate was
used as a palladium source. Results also indicate that DMF
or N-methylpyrrolidinone (NMP) (entries 1 and 3) were
better reaction media than N,N-dimethylacetamide (DMA)
o-Bromoanilide 5l participated in the domino process
leading to the formation of 1a in 63% yield at a higher cata-
(entry 2). Bis(dibenzylideneacetone)palladium, [Pd
can also catalyze the domino sequence, albeit less efficiently
(entry 4). Under optimized conditions (Pd(OAc)2 (1.5
(dba)2],
AHCTREUNG
mol%), K4[Fe(CN)6] (0.22 equiv), Na2CO3, (1.0 equiv),
DMF, 0.2m, 1208C), cyclic cyanation of 5a afforded the de-
sired 3-methyl-3-cyanomethyl-2-oxindole (1a) in an isolated
yield of 83%. As in the case of cyanation of aryl halides, all
six cyanide anions bound to iron are transferable.
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Enantioselective Total Synthesis
FULL PAPER
Table 2. Scope of the palladium-catalyzed Heck–cyanation reaction of
o-iodoanilides 5b–5j.[a]
Entry
Substrate
Product
Yield [%][b]
1
78
2
3
4
5
78
70
72
90
Scheme 2. Total synthesis of physostigmine. Reagents and conditions:
a) Et3N, CH2Cl2, 76%; b) NaH, MeI, THF, 93%; c) Pd(OAc)2 (1.5
A
mol%), K4[Fe(CN)6] (0.22 eqiv), Na2CO3 (1.0 eqiv), DMF, 80%;
d) LAH, THF, 85%; e) HCHO, NaBH4, Et3N, MeOH, 70%; f) HBr
(48% aqueous solution), reflux; g) NaH, THF, 11, 44% for two steps.
6
7
8
71
80
61
oxindole 1k in 80% yield. Reductive cyclization of oxindole
1k using conditions optimized by Brossi and Yu provided
hexahydropyrroloindole 9 in 85% yield.[18] N-Methylation
under reductive amination conditions afforded esermethole
2 in 70% yield. Cleavage of the methyl ether group under
acidic conditions (aqueous HBr) afforded the corresponding
phenol 10. Previously, methyl isocyanate has been used to
provide the urea functionality. However, we found that reac-
tion of sodium phenoxide with N-succinimidyl-N-methylcar-
bamate (11) provided the desired (Æ)-physostigmine in
comparable yield (44% yield over two steps compared with
31% reported by Overman et al.[17a]). Potentially, this modi-
fication could be useful for large-scale synthesis because 11
is much cheaper and easier to handle than methyl isocya-
nate.[19]
9
51
[a] All reactions were carried out under an argon atmosphere using
0.015 equiv of Pd catalyst, 0.22 equiv of 4, 1.0 equiv of Na2CO3 dissolved
in DMF (0.2m) at 1208C. [b] Isolated yield after flash column chromatog-
raphy.
Enantioselective Heck–cyanation process: A number of pal-
ladium-catalyzed enantioselective Heck cyclizations and
oligocyclizations have been developed since the seminal
G
lyst loading (Pd
A
contributions of the groups of Shibasaki[20] and Overman, re-
spectively.[21] Whereas examples of enantioselective Heck
cyclization–anion capture of resulting p-allyl–PdII complexes
are known,[22] to the best of our knowledge, the correspond-
ing enantioselective Heck cyclization–anion capture of the
resulting s-alkyl–PdII complex is unknown. Initial investiga-
tions into reaction conditions using (R)-BINAP (see
Figure 1, below), a highly efficient ligand in oxindole synthe-
sis,[23] are summarized in Table 3. The domino sequence of
5k proceeded efficiently in the presence of (R)-BINAP to
provide 1k in 90% yield although the enantioselectivities
achieved remained low (entry 1). Addition of silver phos-
phate (Ag3PO4) (entry 2) did not disrupt the reaction (cf.
Table 1, entry 7); however, no enantioselectivity was ob-
fluorosulfonyl anilide 5m under standard conditions afford-
ed 1a in a low yield (22%) owing to competitive hydrolysis
of the triflate (OTf) function. On the other hand, the
secondary amide 5n failed to produce the desired compound
A
probably as a result of an unfavorable conformational pref-
erence.
Total synthesis of physostigmine: The utility of this domino
process is illustrated by the total synthesis of physostigmine
(3) (Scheme 2).[17] Acylation of 2-iodo-4-methoxyaniline (6)
with methacryloyl chloride (7) afforded anilide 8, which was
N-methylated to give 5k in 93% yield. Treatment of 5k
under established palladium-catalysis conditions provided
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963

J. Zhu et al.
Table 3. Palladium-catalyzed enantioselective Heck–cyanation reaction
of 5k using (R)-BINAP as ligand.[a]
Entry
Catalyst
Additive
Solvent
Time
[h]
Yield
[%]
ee
[%][b]
1
2
3[Pd
4
5
6
Pd
Pd(OAc)2
(dba)2]
[Pd(dba)2]
[Pd(dba)2]
[Pd(dba)2]
C
–
DMF
DMF
DMF
DMA
NMP
DMA
390
365
5
5
356
354
7
0
89
76
22
0
Ag3PO4
Ag3PO4
Ag3PO4
Ag3PO4
PMP[c]
13
24
[a] Pd catalyst (5 mol%) was treated with (R)-BINAP (12 mol%) and
Ag3PO4 (2.0 equiv) at RT for 40 min before the addition of Na2CO3
(1.0 equiv), 4 (0.22 equiv), and 7c. The reaction was then maintained at
1208C. [b] Determined by chiral HPLC. [c] PMP=1,2,2,6,6-pentamethyl-
piperidine (5 equiv).
served under these conditions. The palladium source can
also influence the reaction outcome, and in general, better
enantioselectivities were obtained when using [Pd
A
relative to Pd(OAc)2 (entry 2 vs. entries 3–5). Using
ACHTREUNG
1,2,2,6,6-pentamethylpiperidine (PMP) as an additive led to
a racemic compound (entry 6), which indicates that the
cation mechanism might be es-
Figure 1. Structure of chiral bidentate ligands screened for the enantiose-
lective palladium-catalyzed Heck–cyanation sequence.
sential for enantioselectivity.
Table 4. Enantioselective Heck–cyanation reaction of 5k: effect of ligand structure.[a]
The low enantioselectivity
observed (24%, entry 4) is in
sharp contrast to the high ee
value obtained by Overman in
his synthesis of oxindole by
means of an intramolecular
Heck reaction.[24] It is reason-
Entry
Ligand
Base
Time [h]
Yield [%]
Config.[b]
ee [%]
1
2
3
4
5
6
7
8
(R)-Tol-BINAP
(R)-SYNPHOS
(S)-phosphino oxazoline
(R)-DIOP
(R)-SYNPHOS
(S)-DIFLUORPHOS
(S)-Cl-MeO-BIPHEP
(R)-C13-TUNEPHOS
(S)-DIFLUORPHOS[d]
(S)-DIFLUORPHOS[e]
(S)-DIFLUORPHOS[f]
(S)-DIFLUORPHOS[g]
(S)-PHANEPHOS[f]
R)-(S)-JOSIPHOS[f]
Na2CO3
Na2CO3
Na2CO3
Na2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO53
K2CO3
K2CO3
K2CO3
K2CO3
320
384
24
R
R
R
–
R
S
S
R
S
S
S
S
R
R
6
33
26
rac
46
66
52
48
53
37
72
72
16
3
A
12[c]
20
ence of cyanide may modify the
coordination sphere of palladi-
24
369
357
346
6
24
33
378
344
6
À
um prior to the key C C bond-
forming step. To raise the ee to
a synthetically useful level, a
screening of bidentate ligands
(Figure 1) was performed and
the results are summarized in
Table 4. The enantioselectivity
of the present domino process
is very sensitive to the ligand
structure. Thus, a simple switch
from BINAP to Tol-BINAP
(entry 1) decreased the enantio-
selectivity and the yield of 1k
significantly. Similarly, (S)-
63
9
25[c]
10
10
11
12
13(
41
28
22
[a] [Pd(dba)2] (5 mol%) was treated with a ligand (12 mol%) and Ag3PO4 (2.0 equiv) at RT for 40 min before
the addition of a base (1 equiv), 4 (0.22 equiv), and 5k. The reaction was then maintained at 1208C. [b] Ab-
solute configuration. [c] Anilide 5k was not fully consumed. [d] The reaction was maintained at 908C.
[e] Same as conditions [a] with 5 mol% Pd2
as conditions [a] with 10 mol% of [Pd(dba)2].
G
A
AHCTREUNG
phosphinooxazoline (entry 3), (R)-DIOP (entry 4), (S)-
PHANEPHOS (entry 12), and (R,S)-JOSIPHOS (entry 13)
were found to be less efficient as ligands than BINAP for
this transformation. Alternatively, chiral biaryl-based ligands
such as (R)-SYNPHOS, (S)-Cl-MeO-BIPHEP, (R)-TUNE-
PHOS, and (S)-DIFLUORPHOS gave superior results to
BINAP in terms of enantioselectivity. Among them, (S)-DI-
FLUORPHOS[25] proved to be the most effective ligand.
Under optimized conditions, cyclic cyanation of 5k in the
presence of (S)-DIFLUORPHOS afforded (S)-1k in 78%
yield and with 72% ee (entry 10).
Applying these enantioselective domino Heck–cyanation
conditions to anilides 5a and 5h led to the formation of the
corresponding oxindoles 1a and 1h with 61 and 79% ee, re-
spectively (Scheme 3).
The absolute configuration of 1k was determined by com-
parison of the optical rotation value with that reported in
the literature.[26] As a result of converting (S)-1k into
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Enantioselective Total Synthesis
FULL PAPER
156.1, 144.3, 130.4, 116.2, 106.1, 102.0, 55.4, 46.0, 26.7, 24.0, 21.0 ppm; IR
(CHCl3): n˜ =1708, 1606, 1474, 1260, 1067 cmÀ1; HRMS: m/z calcd for
C13H14N2NaO2 [M++Na]: 253.0953; found: 253.0944.
(6-Methoxy-1,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-3-yl)acetonitrile
(1c): Colorless oil; yield 78%; 1H NMR (300 MHz, CDCl3): d=7.36 (d,
J=8.2 Hz, 1H), 6.62 (dd, J=8.2, 2.3Hz, 1H), 6.47 (d, J=2.3Hz, 1H),
3.84 (s, 3H), 3.21 (s, 3H), 2.65 (AB, J=16.6 Hz, DnAB =86.3Hz, 2H),
1.50 ppm (s, 3H); 13C NMR (75 MHz, CDCl3): d=178.1, 161.0, 155.6,
144.0, 123.8, 122.9, 116.7, 106.8, 96.8, 55.6, 44.5, 26.6, 26.5, 22.4 ppm; IR
(CHCl3): n˜ =1713, 1625, 1380, 1096, 729, 702 cmÀ1; HRMS: m/z calcd for
C13H14N2NaO2 [M++Na]: 253.0953; found: 253.0962.
(7-Methoxy-1,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-3-yl)acetonitrile
(1d): Colorless oil; yield 70%; 1H NMR (300 MHz, CDCl3): d=7.05 (m,
2H), 6.90 (dd, J=8.1, 2.2 Hz, 1H), 3.87 (s, 3H), 3.21 (s, 3H), 2.70 (AB,
J=16.4 Hz, DnAB =78.2 Hz, 2H), 1.42 ppm (s, 3H); 13C NMR (75 MHz,
CDCl3): d=177.7, 153.2, 145.7, 132.6, 123.9, 116.6, 115.6, 112.9, 56.0, 44.9,
29.8, 26.5, 22.4 ppm; IR (CHCl3): n˜ =2251, 1702, 1252, 734 cmÀ1; HRMS:
m/z calcd for C13H14N2NaO2 [M++Na]: 253.0953; found: 253.0928.
Scheme 3. Palladium-catalyzed enantioselective Heck–cyanation reaction.
Reagents and conditions: a) [Pd(dba)2] (5 mol%), (S)-DIFLUORPHOS
A
(12 mol%), Ag3PO4 (2 equiv), K2CO3 (1 equiv), K4[Fe(CN)6]
(0.22 equiv), 1208C.
(6-Chloro-1,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-3-yl)acetonitrile (1e):
Colorless oil; yield 72%; 1H NMR (300 MHz, CDCl3): d=7.33 (d, J=
8.0 Hz, 1H), 7.04 (dd, J=8.0, 1.8 Hz, 1H), 6.84 (d, J=1.8 Hz, 1H), 3.16
(s, 3H), 2.64 (AB, J=16.6 Hz, DnAB =85.0 Hz, 2H), 1.45 ppm (s, 3H);
13C NMR (75 MHz, CDCl3): d=177.4, 143.9, 135.2, 129.2, 124.1, 123.1,
116.4, 109.5, 44.6, 26.6, 26.2, 22.1 ppm; IR (CHCl3): n˜ =1718, 1610, 1495,
1370 cmÀ1; HRMS: m/z calcd for C12H11ClN2NaO [M++Na]: 257.0458;
found: 257.0453.
(À)-physostigmine, the present work represents a formal
synthesis of this natural product.
Conclusion
(1,3-Dimethyl-5-nitro-2-oxo-2,3-dihydro-1H-indol-3-yl)acetonitrile (1 f):
1
Yellow solid; yield 90%; m.p. 94–968C; H NMR (300 MHz, CDCl3): d=
We have developed an efficient synthesis of 3-substituted-3-
cyanomethyl-2-oxindoles by using a palladium-catalyzed
domino intramolecular Heck–cyanation sequence employing
potassium ferro(ii)cyanide, K4[Fe(CN)6], as a trapping agent
for the s-alkylpalladium intermediate.[27] The reaction is ap-
plicable to a wide range of substrates with different elec-
tronic properties. In addition, a concise synthesis of physo-
8.28 (dd, J=8.6, 2.2 Hz, 1H), 8.24 (d, J=2.2 Hz, 1H), 6.94 (d, J=8.6 Hz,
1H), 3.26 (s, 3H), 2.76 (AB, J=16.7 Hz, DnAB =46.2 Hz), 1.51 ppm (s,
3H); 13C NMR (75 MHz, CDCl3): d=177.5, 148.5, 143.9, 131.6, 126.5,
119.1, 115.6, 108.5, 45.2, 27.0, 26.1, 22.3ppm; IR (CHCl 3): n˜ =1656, 1521,
1343 cmÀ1; HRMS: m/z calcd for C12H11N3NaO3 [M++Na]: 268.0698;
found: 268.0673.
(1,3-Dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-3-yl)acetonitrile (1g):
Yellow oil; yield 71%; 1H NMR (300 MHz, CDCl3): d=8.06 (dd, J=8.2,
2.1 Hz, 1H), 7.74 (d, J=2.1 Hz, 1H), 7.64 (d, J=8.2 Hz, 1H), 3.33 (s,
3H), 2.79 (AB, J=16.7 Hz, DnAB =84.1 Hz, 2H), 1.57 ppm (s, 3H);
13C NMR (75 MHz, CDCl3): d=176.8, 149.1, 144.1, 137.6, 123.7, 118.8,
115.9, 103.8, 45.1, 26.9, 25.9, 22.0 ppm; IR (CHCl3): n˜ =1722, 1528,
1348 cmÀ1; HRMS: m/z calcd for C12H11N3NaO3 [M++Na]: 268.0698;
found: 268.0689.
A
tion of the core framework has been accomplished. An
enantioselective version of this domino process has also
been developed by using (S)-DIFLUORPHOS as a chiral
ligand and represents, to the best of our knowledge, the first
such example of this type of domino process.
(1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzo[f]indol-3-yl)acetonitrile (1h):
Colorless oil; yield 80%; 1H NMR (300 MHz, CDCl3): d=7.92 (s, 1H),
7.85 (d, J=8.1 Hz, 1H), 7.80 (d, J=8.1 Hz, 1H), 7.51 (ddd, J=8.2, 6.9,
1.4 Hz, 1H), 7.42 (ddd, J=8.2, 7.0, 1.4 Hz, 1H), 7.18 (s, 1H), 3.35 (s,
3H), 2.80 (AB, J=16.6 Hz, DnAB =89.2 Hz, 2H), 1.62 ppm (s, 3H);
13C NMR (75 MHz, CDCl3): d=177.0, 140.7, 134.0, 131.6, 130.4, 128.4,
127.14, 127.12, 124.8, 122.9, 116.6, 104.5, 44.4, 26.8, 26.7, 22.7 ppm; IR
(CHCl3): n˜ =1715, 1645, 1470, 1381, 1050, 750 cmÀ1; HRMS: m/z calcd
for C16H14N2NaO [M++Na]: 273.1004; found: 273.0985.
Experimental Section
Typical procedure for palladium-catalyzed domino Heck–cyanation se-
quence: Potassium ferrocyanide (0.22 equiv), Na2CO3 (1.0 equiv), and Pd-
(OAc)2 (1.5 mol%) were added to a degassed 0.2m solution of iodoani-
lide 5 dissolved in DMF. After being stirred at 1208C under an argon at-
mosphere for 3h, the reaction mixture was quenched with water and ex-
tracted with EtOAc. The combined organic layers were washed with
brine, dried (Na2SO4), and concentrated. The residue was purified by
using flash chromatography to give the corresponding oxindole 1.
N
(1-Benzyl-3-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl)acetonitrile
(1i):
Colorless oil; yield 61%; 1H NMR (300 MHz, CDCl3): d=7.41 (d, J=
7.4 Hz, 1H), 7.25–7.13(m, 6H), 7.02 (dt, J=7.6, 0.8 Hz, 1H), 6.71 (d, J=
7.8 Hz, 1H), 4.86 (s, 2H), 2.72 (AB, J=16.6 Hz, DnAB =80.5 Hz, 2H),
1.51 ppm (s, 3H); 13C NMR (75 MHz, CDCl3): d=177.7, 141.8, 135.3,
131.0, 129.1, 128.9, 127.8, 127.2, 123.3, 123.2, 109.8, 44.9, 44.0, 26.4,
22.5 ppm; IR (CHCl3): n˜ =2248, 1712, 1612, 1488, 1380, 1362, 1178,
(1,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-3-yl)acetonitrile (1a): Color-
less oil; 1H NMR (300 MHz, CDCl3): d=7.53(dd, J=7.5, 1.5 Hz, 1H),
7.42 (dt , J=7.5, 1.5 Hz, 1H), 7.19 (dt, J=7.5, 1.1 Hz, 1H), 6.93(dd, J=
7.5, 1.1 Hz, 1H), 3.25 (s, 3H), 2.98 (AB, J=16.6 Hz, DnAB =87.3Hz, 2H),
1.55 ppm (s, 3H); 13C NMR (75 MHz, CDCl3) d=177.5, 142.7, 131.0,
129.2, 123.3, 123.1, 116.6, 108.7, 44.8, 26.5, 26.3, 22.2 ppm; IR (CHCl3):
753cm À1 HRMS: m/z calcd for C18H16N2NaO [M++Na]: 299.1160;
;
found: 299.1125.
{3-[(tert-Butyldimethylsilyloxy)methyl]-1-methyl-2-oxo-2,3-dihydro-1H-
n˜ =2255, 1715 cmÀ1
.
1
indol-3-yl}acetonitrile (1j): Colorless oil; yield 51%; H NMR (300 MHz,
CDCl3): d=7.52 (dd, J=7.4, 0.7 Hz, 1H), 7.41 (dt, J=7.8, 1.2 Hz, 1H),
7.17 (dt, J=7.6, 0.9 Hz, 1H), 6.94 (d, J=7.8 Hz, 1H), 3.91 (AB, J=
(4-Methoxy-1,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-3-yl)acetonitrile
(1b): Colorless oil; yield 78%; H NMR (300 MHz, CDCl3): d=7.30 (dd,
1
9.5 Hz, DnAB =54.1 Hz, 2H), 3.29 (s, 3H), 2.93 (AB, J=16.7 Hz, DnAB
=
J=8.4, 7.9 Hz, 1H), 6.65 (dd, J=8.4, 0.4 Hz, 1H), 6.56 (dd, J=7.9,
0.4 Hz, 1H), 3.90 (s, 3H), 3.20 (s, 3H), 2.98 (AB, J=16.3Hz, DnAB
=
77.3Hz, 2H), 0.79 (s, 9H), À0.02 (s, 3H), À0.06 ppm (s, 3H); 13C NMR
53.2 Hz, 2H), 1.50 ppm (s, 3H); 13C NMR (75 MHz, CDCl3): d=177.8,
(75 MHz, CDCl3): d=175.3, 143.7, 129.3, 128.5, 124.1, 122.9, 116.4, 108.4,
Chem. Eur. J. 2007, 13, 961 – 967
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
965

J. Zhu et al.
66.5, 51.0, 29.7, 26.4, 25.6, 21.5, 18.0, À5.7, À5.8 ppm; IR (CHCl3): n˜ =
1718, 1614, 1471, 1121, 839 cmÀ1; HRMS: m/z calcd for C18H26N2NaO2Si
[M++Na]: 353.1661; found: 353.1635.
1H NMR (300 MHz, CDCl3): d=6.58 (m, 2H), 6.31 (d, J=8.2 Hz, 1H),
4.08 (s, 1H), 3.68 (s, 3H), 2.84 (s, 3H), 2.74 (ddd, J=9.8, 6.1, 4.4 Hz,
1H), 2.55 (m, 1H), 2.48 (s, 3H), 1.92 (m, 2H), 1.38 ppm (s, 3H);
13C NMR (75 MHz, CDCl3): d=153.2, 146.3, 138.0, 112.4, 109.8, 107.7,
98.0, 56.0, 53.1, 52.9, 40.5, 38.1, 37.6, 27.3 ppm; IR (CHCl3): n˜ =1496,
N-(2-Iodo-4-methoxyphenyl)-2-methylacrylamide
(3.16 mL, 22.3 mmol) was added to a stirred solution of 2-iodo-4-meth-
oxyaniline (6) (4.28 g, 17.2 mmol) dissolved in CH2Cl2 (15 mL) at RT,
(8):
Triethylamine
1279, 1220, 1032 cmÀ1
.
A
ACHTREUNG
Physostigmine (3): Esermethole (2) (92 mg, 0.40 mmol) was dissolved in
an aqueous solution of HBr (48%, 1 mL) and stirred at reflux for 19 h.
The mixture was then cooled and poured into cold water. The acidic solu-
tion was basified by using a solution of NaOH (10%), then extracted
with EtOAc, dried (Na2SO4), and evaporated to dryness. The crude prod-
uct was used directly in the next step of the reaction without purification.
A mixture of the resulting phenol 10 (53.0 mg, 0.24 mmol), NaH (60%,
22 mg, 0.54 mmol), and THF (2 mL) was stirred at 08C for 5 min before
N-succinimidyl-N-methylcarbamate (11) was added at this temperature.
The resulting mixture was stirred at RT for 1 h, quenched with water,
and extracted with EtOAc. The organic layers were then combined,
washed with brine, dried (Na2SO4), and concentrated. The residue was
purified by using flash column chromatography (heptanes/EtOAc 9:1) to
give 3 as a colorless oil (48 mg, 44%). 1H NMR (300 MHz, CDCl3): d=
6.86 (dd, J=8.5, 2.3Hz, 1H), 6.79 (d, J=2.3Hz, 1H), 6.40 (d, J=8.5 Hz,
1H), 4.92 (brs, 1H), 4.37 (s, 1H), 2.98 (s, 3H), 2.89 (d, J=4.8 Hz, 3H),
2.65 (m, 2H), 2.60 (s, 3H), 2.07 (m, 2H), 1.47 ppm (s, 3H); 13C NMR
(75 MHz, CDCl3): d=156.2, 149.5, 143.2, 137.4, 120.5, 116.2, 106.6, 97.9,
53.1, 52.6, 40.7, 38.2, 37.1, 27.7, 27.2 ppm; IR (CHCl3): n˜ =1730, 1496,
and 2-methylacryloyl chloride (7) (2.16 mL, 22.3mmol) was added drop-
wise at 08C. The resulting solution was stirred at RT for 2 h. After addi-
tion of water, the mixture was extracted with CH2Cl2. The organic layers
were then combined, washed with brine, dried (Na2SO4), and concentrat-
ed. The residue was purified by using flash column chromatography (hep-
tanes/EtOAc 9:1) to give 8 as a colorless solid (4.12 g, 76%). M.p. 74–
758C ; 1H NMR (300 MHz, CDCl3): d=8.06 (d, J=9.0 Hz, 1H), 7.66
(brs, 1H), 7.26 (d, J=2.8 Hz, 1H), 6.85 (dd, J=9.0, 2.8 Hz), 5.87 (s, 1H),
5.43 (s, 1H), 3.71 (s, 3H), 2.04 ppm (s, 3H); 13C NMR (75 MHz, CDCl3):
d=166.0, 156.7, 140.3, 131.7, 123.8, 122.8, 120.7, 114.7, 90.9, 55.7,
18.7 ppm; IR (CHCl3): n˜ =3279, 2922, 2851, 1655, 1620, 1531 cmÀ1
;
HRMS: m/z calcd for C11H12INNaO2 [M++Na]: 339.9811; found:
339.9796.
N-(2-Iodo-4-methoxyphenyl)-N,2-dimethylacrylamide (5k): A solution of
8 (4.09 g, 12.9 mmol) in THF (20 mL) was added dropwise at 08C to a
stirring suspension of NaH (60%, 774 mg, 19.3mmol) and THF (14 mL).
The resulting mixture was stirred at 08C for 40 min, and then MeI (2 mL,
32.25 mmol) was added. The resulting mixture was maintained at RT for
3h, quenched with water, and extracted with EtOAc. The organic layers
were then combined, washed with brine, dried (Na2SO4), and concentrat-
ed. The residue was purified by using flash column chromatography (hep-
tanes/EtOAc 4:1) to give 5k as a colorless solid (3.97 g, 93%). M.p. 82–
848C; 1H NMR (300 MHz, CDCl3): d=7.38 (d, J=2.8 Hz, 1H), 7.01 (d,
J=8.7 Hz, 1H), 6.88 (dd, J=8.7, 2.7 Hz, 1H), 5.08 (s, 1H), 5.00 (s, 1H),
3.81 (s, 3H), 3.22 (s, 3H), 1.83 ppm (s, 3H); 13C NMR (75 MHz, CDCl3):
d=172.0, 158.9, 140.4, 139.8, 129.4, 124.7, 115.1, 99.4, 55.7, 37.0,
1256, 1202 cmÀ1
.
Typical procedure for enantioselective palladium-catalyzed domino
Heck–cyanation sequence—Synthesis of (5-methoxy-1,3-dimethyl-2-oxo-
2,3-dihydro-1H-indol-3-yl)acetonitrile (1k): Potassium ferrocyanide
(14 mg, 0.03mmol), K 2CO3 (16 mg, 0.15 mmol), silver phosphate
(126 mg, 0.3mmol), [Pd (dba)2] (4.34 mg, 0.008 mmol), and (S)-DI-
G
FLUORPHOS (12.3mg, 0.033mmol) were added to a degassed solution
of 5k (50 mg, 0.15 mmol) in DMA (1 mL). After being stirred at 1208C
under an argon atmosphere for 3h, the reaction mixture was quenched
with water and extracted with EtOAc. The combined organic layers were
washed with brine, dried (Na2SO4), and concentrated. The residue was
purified by using flash chromatography (silica gel, heptanes/EtOAc 3:1)
to give 1k as a colorless oil (26.8 mg, 78%). The ee of 1k was determined
to be 72% by chiral column HPLC analysis (AD column; flow rate:
20.6 ppm; IR (CHCl3): n˜ =1652, 1625, 1491, 1285, 1224, 1030 cmÀ1
;
HRMS: m/z calcd for C12H14INNaO2 [M++Na]: 353.9967; found:
330.9941.
(5-Methoxy-1,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-3-yl)acetonitrile
(1k): By following the general procedure, 5k was converted to 1k in
1
80% yield as a colorless oil. H NMR (300 MHz, CDCl3): d=7.09 (d, J=
2.0 Hz, 1H), 6.86 (dd, J=8.6, 2.0 Hz, 1H), 6.81 (d, J=8.6 Hz, 1H), 3.82
(s, 3H), 3.22 (s, 3H), 2.84 (AB, J=16.5 Hz, DnAB =85.6 Hz, 2H),
2.55 ppm (s, 3H); 13C NMR (75 MHz, CDCl3): d=178.2, 157.6, 136.9,
133.0, 116.1, 113.9, 111.0, 109.4, 57.6, 45.2, 26.9, 26.4, 22.5 ppm; IR
(CHCl3): n˜ =1710, 1655, 1504, 1363, 1292, 668 cmÀ1; HRMS: m/z for
C13H14N2NaO2 [M++Na]: calcd 253.0953; found: 253.0937.
1 mLminÀ1; eluent: hexane/EtOH 4:1;
18.82 min; cf. the Supporting Information).
tR(minor) =8.21 min, tR(major) =
5-Methoxy-8-methyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole (9): Ox-
A
Acknowledgements
indole 1k (187 mg, 0.81 mmol) was dissolved in THF (16 mL), and
LiAlH4 (142 mg, 3.74 mmol) was added. The reaction mixture was stirred
under an Ar atmosphere for 1 h and then heated to reflux. After heating
at reflux for 10 min, the mixture was quenched at 08C with water and ex-
tracted with EtOAc. The organic layers were then combined, washed
with brine, dried (Na2SO4), and concentrated. The residue was purified
by using flash column chromatography (CH2Cl2/MeOH 9:1) to give 9 as
a yellow oil (150 mg, 85%). 1H NMR (300 MHz, CDCl3): d=6.67 (d, J=
2.5 Hz, 1H), 6.35 (dd, J=8.3, 2.5 Hz, 1H), 6.27 (d, J=8.3Hz, 1H), 5.0
(brs, 1H), 4.44 (s, 1H), 3.75 (s, 3H), 3.06 (ddd, J=10.4, 7.2, 3.0 Hz, 1H),
2.84–2.78 (m, 4H), 2.01 (ddd, J=9.3, 6.3, 3.0 Hz, 1H), 1.79 (ddd, J=12.2,
9.7, 7.1 Hz, 1H), 1.42 ppm (s, 3H); 13C NMR (75 MHz, CDCl3): d=152.5,
145.5, 137.3, 111.9, 110.4, 105.6, 93.2, 56.0, 52.2, 46.1, 42.2, 33.1, 26.1 ppm;
Financial supports from CNRS and the Institut de Chimie des Substances
Naturelles are gratefully acknowledged. A.P. thanks Minist›re de lꢁEn-
seignement SupØrieur et de la Recherche for a doctoral fellowship.
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1 mLminÀ1; eluent: hexane/EtOH 4:1; tR(minor) =8.21 min, tR(major)
=
18.82 min, ee=72%. [a]2D0 =+57.5 (c=0.5 in CHCl3), see: Q.-S. Yu,
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For the synthesis of optically enriched 1k by enantioselective alkyla-
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Received: July 16, 2006
Published online: September 29, 2006
Chem. Eur. J. 2007, 13, 961 – 967
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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