Palladium-catalyzed domino process to spirooxindoles: Ligand effect on aminopalladation versus carbopalladation

Article abstract of DOI:10.1002/chem.201000312

(Figure Presented) Double intra, from linear to spiro: A Pd-catalyzed domino sequence involving an intramolecular aminopalladation followed by arylation that convert linear anilides 1 into the functionalized spiropyrrolidine-3,3′-oxindoles 2 in good to excellent yields is presented. The use of 2-di-tert-butylphosphino-2′methylbiphenyl as a ligand determines the success of the domino process. A trans-aminopalladation mechanism seems to account for the observed diastereoselectivity.

Full text of DOI:10.1002/chem.201000312

COMMUNICATION
DOI: 10.1002/chem.201000312
Palladium-Catalyzed Domino Process to Spirooxindoles: Ligand Effect on
Aminopalladation versus Carbopalladation
Stꢀphanie Jaegli,[a] William Erb,[a] Pascal Retailleau,[a] Jean-Pierre Vors,[b]
Luc Neuville,*[a] and Jieping Zhu*[a]
The spiropyrrolidine-3,3’-oxindole skeleton is present in a
number of bioactive natural products[1] and is a sought after
structural motif for the development of pharmaceuticals and
agrochemicals.[2] This class of compounds can be as simple
as elacomine (1)[3] or present additional structural complexi-
ty as seen in spirotryprostatine (2)[4]. The synthesis of such
heterocycles has received considerable attention in recent
ladium complex.[8] Starting from appropriately functional-
ized dienes, Overman[6b] and Takemoto[6c] reported the syn-
thesis of spiro[indoline-3,3’-pyrrolidine] by a Pd-catalyzed
À
Heck/allylic-substitution sequence. Although C N bonds
are formed in these transformations, they do not involve the
capture of a s-alkylpalladium complex by a nucleophilic ni-
trogen. Indeed such a capture would require a reductive
elimination between an sp3 carbon atom and a heteroatom,
which has little precedent.[9] On the other hand, palladium-
catalyzed, intramolecular carboamination of alkenes has re-
cently emerged as an attractive method for the construction
of heterocycles.[10,11] Whereas this process has been well
studied for intra/intermolecular sequences, little is known
about the related intra/intramolecular one.[12]
We recently reported a facile method for accessing func-
tionalized 3-alkyl-3-cyanomethyl-2-oxindoles by a palladi-
um-catalyzed, domino intramolecular-Heck/cyanation pro-
cess and applied it to the total syntheses of both physostig-
mine and horsfiline (3).[13] In connection with our previous
years.[5] However, most of these approaches rely upon the
stepwise construction of two rings and examples of the si-
multaneous formation of the spirocycle and the quaternary
carbon remain rare.[6]
Palladium-catalyzed double addition across an alkene is a
well-documented reaction.[7] Heck/anionic-capture sequen-
ces have been extensively developed and a variety of nucle-
ophiles have been used to trap the intermediate s-alkylpal-
work on palladium-catalyzed domino reactions involving
[14]
À
À
À
either multiple C C bond formation
or C C and C N
bond formation,[15] we became interested in developing a
one-step synthesis of spiropyrrolidine-3,3’-oxindoles 5.
Herein, we report an efficient palladium-catalyzed spirocyc-
lization of linear anilides 4 that leads to the formation of
compounds 5 in good to excellent yields (Scheme 1). Pre-
liminary results indicated that the domino process[16] was ini-
tiated by aminopalladation instead of by an intramolecular
Heck reaction.
[a] Dr. S. Jaegli, W. Erb, Dr. P. Retailleau, Dr. L. Neuville, Dr. J. Zhu
Centre de Recherche de Gif
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
neuville@icsn.cnrs-gif.fr
[b] Dr. J.-P. Vors
Bayer CropScience SA
14-20 Rue Pierre Baizet, 69009 Lyon (France)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201000312.
Scheme 1. Synthesis of spirooxindole 5 by a palladium-catalyzed spirocyc-
lization of anilide 4.
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The cyclization of 4 under the influence of palladium is
challenging, since a number of competitive reactions could
occur: a) b-Hydride elimination a to the amine; b) intra- or
intermolecular N-arylation of the amine; or c) intramolec-
ular Michael addition leading to pyrrolidine formation.
Other challenges arise because of the interplay between car-
bopalladation (the Heck reaction) and aminopalladation
and, even if the desired sequence occurs, the transformation
poses interesting questions regarding regio- and stereoselec-
tivity.
quinone or Cu
observed if PhIAHCTUNGTRENNUNG
ACHTUNGTRENNUNG
From these preliminary results, we concluded that: 1) the
use of either polar or apolar solvents combined with a
strong base should be avoided in order to suppress the for-
mation of pyrrolidine 6; 2) the Heck pathway is a viable
route but was unproductive due to the high stability of pal-
ladacycle 7. Therefore, we hypothesized that, to achieve the
desired spirocyclization, the Heck manifold has to be avoid-
ed and conditions that favor carboamination were sought.
First, the effect of the ligand structure was examined.[22]
Using tri-tert-butylphosphane as a supporting ligand allowed
us to isolate spirooxindole 5a in 5% yield, thus demonstrat-
ing the feasibility of the spirocyclization (for details see the
Supporting Information). Bidentate ligands (BINAP, Xant-
phos,[23] and dppf)[20] were inefficient for the reaction. Fur-
ther screening of biaryl-type phosphanes[24] showed that the
use of sterically encumbered, electron-rich phosphanes con-
taining the di-tert-butylphosphinyl group was necessary to
allow the spirocyclization. Among them, tBuMePhos gave
spirocycle 5a in the highest yield (19%).
We selected N-tosyl derivative 4a (R1 =SEM, R2 =H,
R3 =Ts)[20] as a probe for a survey of reaction conditions. In
our initial studies, various bases and solvents were screened
by using [PdACHTUNGTRENNUNG(PPh3)4] (10 mol%) as the catalyst. Performing
the reaction in solvents such as toluene, dioxane, or acetoni-
trile in the presence of a weak base (K2CO3) resulted in low
conversion (<30%) and none of the desired product was
formed. In DMF, in the presence of K2CO3 or a stronger
base (K3PO4 or PhONa), high conversion (>90%) was ob-
served, but led to the formation of pyrrolidine 6 as the main
product instead of the desired spiro compound (Scheme 2).
With the optimum ligand in hand, we set out to further
optimize the conditions by varying the palladium source, the
base, and the solvent. Although PdCl2 was ineffective, both
[PdACTHNUGRTNENUG ACHUTNGTRENNUGN
(tfa)2][20] and [Pd(dba)2][20] displayed catalytic activity,
with the latter providing slightly better results. The base also
considerably affected the reaction outcome. Whereas strong
bases (tBuOK, NaHMDS,[20] NaOH) and tertiary amines
(DIPEA)[20] were clearly inefficient, carbonated bases gener-
ally gave superior results, with Na2CO3 showing the best ac-
tivity. Under otherwise identical conditions, reactions per-
formed in toluene or dioxane provided much better results
than those performed in polar solvents, such as CH3CN,
DMSO and NMP. Overall, the optimum reaction conditions
Scheme 2. Preliminary observations.
Further experiments indicated that 6 was formed, even in an
apolar solvent, if a strong base (K3PO4 or PhONa) was
used. The formation of pyrrolidine 6 can be explained by an
intramolecular Michael addition through 5-endo-trig cycliza-
tion. A related cyclization has recently been reported, al-
though such a process is disfavored according to Baldwinꢁs
rules.[17] Furthermore, a control experiment showed that pal-
ladium is not involved in the formation of 6 as K2CO3 alone,
in DMF, promoted the cyclization of 4a to afford pyrroli-
dine 6 in 80% yield.
In these preliminary experiments, we consistently isolated
another product, in addition to 6, in about 10% yield. Based
on the spectroscopic data (see the Supporting Information),
we assigned the structure of this product to be palladacycle
7 (Scheme 2). A control experiment, performed with a stoi-
chiometric amount of tetrakis(triphenylphosphane)palladi-
um(0), in toluene, at reflux, afforded, after flash column
chromatography, palladacycle 7 in 78% yield. Such s-alkyl
palladium complexes, resulting from Heck reactions, have
been documented in the literature.[18] The reactivity of com-
were found to be as follows: 10 mol% [PdACTHNURTGNENG(U dba)2], 20 mol%
tBuMePhos, and 2.5 equivalents of Na2CO3 in toluene or di-
oxane, at 1108C, C 0.20m. Under these conditions, spiropyr-
rolidine-3,3’-oxindole 5a was isolated in 45% yield (67%
based on conversion).[25]
The scope of this novel spirocyclization was then exam-
ined by using the established conditions. A variety of spiro-
pyrrolidine-3,3’-oxindoles, containing an electron-donating
(OMe, Me) or -withdrawing group (CN, NO2, halogen) on
the aniline, were readily synthesized in good to excellent
yields (Table 1, entries 2–9). The presence of a substituent at
the ortho-, meta-, or para-position of the aniline was well
tolerated. Extraneous halogens, such as chlorine or fluorine,
were unaffected by the reaction (Table 1, entries 4 and 5),
providing the potential for further functionalization of the
skeleton.[26] The effect of the protecting group on the pri-
mary amine was next examined (Table 1, entries 10–13). It is
interesting to note that, under these optimized conditions,
the N-Boc[20] and N-Cbz[20] derivatives (4j and k, Table 1,
entries 10 and 11) underwent the desired spirocyclization, al-
though less efficiently than their N-tosyl counterpart. Other
para-substituted benzenesulfonyl groups (NO2 and OMe,
Table 1, entries 12 and 13) can also be used and give the spi-
plex 7 was examined next, in an attempt to induce the for-
[19]
À
mation of the C N bond. Heating the complex at 1108C
for a prolonged period of time (15 h) both in the presence
or absence of additional ligands (PPh3, tBuMePhos)[20] led
to full recovery of the starting complex; this was also the
case if the reaction was performed in the presence of benzo-
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Spiropyrrolidine-3,3’-oxindoles
COMMUNICATION
Table 1. Spirocyclization of substituted anilides.
were investigated (Table 2). Unfortunately, low conversion
(<20%) was observed when compound 4n (R=iPr) was
submitted to the standard reaction conditions. Fortunately,
Table 2. Spirocyclization of a-substituted tosylamines.
Anilide 4
Product 5
Yield
[%][a]
Anilides 4
Products 5
R=iPr
R=H
R=CH3
R=tBu
R=CH2OBn
R=Ph
Yield [%][a]
1
2
3
4
5
R=iPr
R=H
R=CH3
R=tBu
R=CH2OBn
R=Ph
4n
4o
4p
4q
4r
5n
5o
5p
5q
5r
90
1
2
3
4
5
R=H
4a R=H
4b R=OMe
5a 45 (67)[b]
5b 57 (75)[b]
57[b]
58
R=OMe
R=CN
R=Cl
R=F
4c
R=CN
5c
72
80
48
54
4d R=Cl
4e R=F
5d 76
5e 73
6
4s
5s
7
8
9
10
R=p-MeOC6H4
R=p-ClC6H4
R=p-Ph-C6H4
R=CO2tBu
4t
R=p-MeOC6H4
R=p-ClC6H4
R=p-Ph-C6H4
R=CO2tBu
5t
58
58
4u
4v
4w
5u
5v
5w
63
40[c]
[a] Refers to chromatographically pure product. [b] Na2CO3 was used as
the base. [c] 1/1 mixture of diastereoisomers.
6
7
4 f
5 f
67 (85)[b]
simply changing the base from Na2CO3 to Cs2CO3 allowed
the reaction to reach full conversion and led to spirooxin-
dole 5n, as a single diastereomer, in 90% isolated yield
(Table 2, entry 1). Therefore, we applied this new protocol
to other substrates. As can be seen in Table 2, substrates
bearing an alkyl side chain were successfully converted to
spirooxindoles (Table 2, entries 1–5). Steric hindrance was,
to a certain extent, beneficial as seen for the isopropyl and
tert-butyl derivatives (4n and q, Table 2, entries 1 and 4),
which afforded the spirocyclic product in higher yields than
4o and p (R=H and Me, respectively, Table 2, entries 2 and
3). Aromatic ring substituents with various electronic prop-
erties were also tolerated at the 4-position of the 4-(N-tos-
4g
5g 64 (80)[b]
8
9
R=Me
R=NO2
4h R=Me
4i
5h 81
5i
52 (75)[b]
R=NO2
AHCTUNGTREGyNNNU l)aminobutanamides (Table 2, entries 6–9). It should be
noted that, in most cases, the diastereoselectivity was excel-
lent as only one stereoisomer could be detected in the
1H NMR spectra of the crude products. Of these types of
compound we only observed the presence of a second dia-
stereoisomer for compound 5t (R=4-MeOPh, major/
minor=15:1). In contrast, cyclization of compound 4w, con-
taining an ester functionality, afforded two diastereoisomers
in a 1:1 ratio (Table 2, entry 10). A control experiment per-
formed by separately resubmitting each diastereoisomer of
5w to the reaction conditions revealed that complete epime-
rization a to the ester function occurs in this compound.
The relative stereochemistry of the substituted spiropyrroli-
dine-3,3’-oxindoles was found to be cis, based on detailed
NOE correlations for compound 5q and confirmed by X-ray
crystallographic analysis of compound 5v.[28]
10 R2 =Boc
11 R2 =Cbz
4j
4k R2 =Cbz
4l
R2 =Boc
5j
5k 19 (45)[b]
5l
32 (55)[b]
32 (45)[b]
12 R2 =p-NO2C6H4SO2
R2 =p-NO2C6H4 SO2
13 R2 =p-OMeC6H4 SO2 4m R2 =p-OMe-C6H4SO2 5m 42 (62)[b]
[a] Refers to chromatographically pure product. [b] Isolated yield based
on conversion appears in parentheses.
rooxindole in reduced or comparable yields. However, the
N-benzylated derivative is incompatible with the proposed
reaction sequence.[27] Substitution of the amide was also ex-
amined and, as expected, N-Me amides cyclized efficiently
to give the corresponding spirooxindoles in good to excel-
lent yields (see Table 2).
To further extend the scope of this spirocyclization, sub-
strates containing a substituent a to the terminal tosylamine
Several possible reaction pathways could explain the for-
mation of these spirooxindoles. In principle, pyrrolidines 6
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www.chemeurj.org
5865

J. Zhu, L. Neuville et al.
could be converted to spirooxindoles by palladium-catalyzed
a-arylation of the amide group[29] and, indeed, this process
has been used for the preparation of spiropiperidine-3,3’-ox-
indoles.[30] However, this pathway was ruled out in our
system, since resubmitting pyrrolidine 6 to the reaction con-
ditions only led to recovery of the starting materials. The
second pathway to be considered is one that is initiated by
the Heck reaction. Isolation of palladacycle 7 supports the
which would result from b-Hydride elimination of B, were
not observed under our reaction conditions.
In summary, we have developed a novel palladium-cata-
lyzed, domino spirocyclization process for the formation of
biologically relevant spiropyrrolidine-3,3’-oxindoles. Experi-
mental results indicate that both Heck and aminopalladation
processes were viable pathways from amide 4 and the route
that occurs is dependent upon the ligand chosen. However,
only the latter process is conducive to the spirocyclization
and the use of tBuMePhos as the ligand is required for the
success of this palladium-catalyzed process. Excellent dia-
3
À
feasibility of this pathway. However, the fact that C
N
bond-forming reductive elimination did not take place from
this complex allows us to infer that this pathway is not con-
ducive to product formation. A third mechanism, which
most probably accounts for the formation of spirooxindoles,
involves aminopalladation of the double bond as the initial
step (Scheme 3). Thus, after oxidative addition of the arylha-
AHCTUNGTREGsNNUN tereoselectivity was obtained for cases in which a-substitut-
ed terminal sulfonamides are used, which can be accounted
for by a trans-aminopalladation process.
Experimental Section
Typical procedure: Anilide 4a (50.0 mg, 0.083 mmol, 1.0 equiv) and tBu-
MePhos (5.2 mg, 0.017 mmol, 0.20 equiv) were added to a stirred suspen-
sion of [PdACHTNUTRGNE(UNG dba)2] (4.8 mg, 0.0083 mmol, 0.10 equiv) in dioxane (0.40 mL)
under argon. This was followed by the addition of the base (Na2CO3;
28.8 mg, 0.208 mmol, 2.5 equiv). The reaction mixture was then heated to
reflux and stirred overnight. The reaction mixture was cooled to room
temperature, diluted with water and extracted with EtOAc. The com-
bined organic layers were washed with brine, dried over sodium sulfate
and concentrated under reduced pressure. Purification by flash column
chromatography (SiO2, heptane/EtOAc, 2:1) afforded 5a as a white solid
(17.8 mg, 45%, 67% based on conversion); m.p. 73–748C; 1H NMR
(CDCl3, 500 MHz): d=7.76 (d, J=8.2 Hz, 2H), 7.36 (d, J=8.2 Hz, 2H),
7.28 (dt, J=7.7, 1.0 Hz, 1H), 7.11 (dd, J=7.7, 0.9 Hz, 1H), 7.05–7.02 (m,
2H), 5.12 (d, J=10.9 Hz, 1H), 5.08 (d, J=10.9 Hz, 1H), 3.78–3.73 (m,
1H), 3.57 (d, J=9.7 Hz, 1H), 3.55–3.49 (m, 3H), 3.44 (d, J=9.7 Hz, 1H),
2.47 (s, 3H), 2.32–2.25 (m, 1H), 2.07–2.02 (m, 1H), 0.89 (t, J=8.7 Hz,
2H), À0.04 ppm (s, 9H); 13C NMR (CDCl3, 75 MHz): d=177.3, 143.9,
141.0, 133.4, 131.9, 129.8, 128.6, 127.7, 123.6, 122.9, 109.8, 69.5, 66.1, 56.3,
52.7, 47.3, 36.6, 21.6, 17.7, À1.5 ppm; IR (CHCl3): n˜ =3056, 2950, 2890,
1721, 1613, 1487, 1467, 1348, 1246, 1228, 1163, 1081 cmÀ1; HRMS (ES+):
m/z calcd for C24H32N2O4NaSSi: 495.1750; found: 495.1762.
Scheme 3. Possible mechanism and rationale for the stereoselectivity;
X=halide.
lide to Pd0, aminopalladation via the coordinated intermedi-
ate A leads to palladacycle B; reductive elimination of this
complex then provides the spirooxindoles. Both trans- and
cis-aminopalladation are known to occur.[31,32] In our case,
cis-aminopalladation would involve the unfavorable forma-
tion of a nine-membered chelate; nevertheless, the entropic
penalty could, in part, be compensated for by the additional
alkene coordination in this intermediate (Scheme 3). How-
ever, if cis-aminopalladation operates, transition state A1, in
which the R1 substituent adopts a pseudo axial position
would be preferred, since this avoids unfavorable allylic-1,2
strain with the tosyl group;[33] this would provide a dia-
Acknowledgements
Financial support from the CNRS, the Bayer CropScience (Doctoral fel-
lowship to S.J.) and the “Ministꢂre de l’Enseignement Supꢃrieur et de la
Recherche” (Doctoral fellowship to W.E.) is gratefully acknowledged.
Keywords: aminopalladation · carbopalladation · domino
reactions · oxindoles · palladium · spiro compounds
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Spiropyrrolidine-3,3’-oxindoles
COMMUNICATION
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À
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Received: February 4, 2010
Published online: April 13, 2010
Chem. Eur. J. 2010, 16, 5863 – 5867
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5867