AgF-mediated dialkylation of activate alkenes: An efficient access to nitrile-containing spirooxindoles

Article abstract of DOI:10.1002/cjoc.201400350

A novel Ag-mediated dialkylation reaction of alkenes was disclosed, in which AgF was essential to activate C－H bond of acetonitrile. This reaction provided an efficient way to nitrile-containing spirooxindoles from readily available (1H-indol-3-yl)methanamine derivatives.

Full text of DOI:10.1002/cjoc.201400350

COMMUNICATION
DOI: 10.1002/cjoc.201400350
AgF-Mediated Dialkylation of Activate Alkenes: An Efficient
Access to Nitrile-Containing Spirooxindoles†
Liang Wu, Pinhong Chen, and Guosheng Liu*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, Shanghai 200032, China
A novel Ag-mediated dialkylation reaction of alkenes was disclosed, in which AgF was essential to activate
C－H bond of acetonitrile. This reaction provided an efficient way to nitrile-containing spirooxindoles from readily
available (1H-indol-3-yl)methanamine derivatives.
Keywords spirooxindoles, activated alkenes, silver fluoride, acetonitrile, C－H bond cleavage
Introduction
alkenes represents an efficient tool for the synthesis of
complex compound, and palladium has been proven to
be one of the best catalysts in the last decades.[6] As part
of our efforts to develop catalytic fluorination of al-
kenes,[7] we reported a palladium-catalyzed intramo-
lecular aminofluorination of alkenes using PhI(OPiv)2/
AgF.[8] With this catalytic system, our group discovered
an unexpected palladium-catalyzed arylalkylation of
α-methyl acrylanilines, rather than arylfluorination, in
which both C－H bonds of aniline and acetonitrile are
cleaved, and AgF plays an important role to activate
acetonitrile (Eq. 1).[9] Importantly, this reaction pro-
ceeds at slightly high temperature, which is not good for
fluorination. In order to achieve arylfluorination of al-
kenes, we envisioned that, if employing active indole
moiety containing substrate, the related transformation
might be conducted under mild reaction condition,
which is helpful to survey the fluorination reaction.
With this consideration, the related investigation was
initiated. Unfortunately, the arylfluorination of alkenes
was still unavailable, and we found an alternative unex-
pected silver-mediated dialkylation of alkenes. Herein,
we reported this study, which presents an efficient ap-
proach to synthesize a range of nitrile-containing spiro-
oxindoles (Eq. 2).
Spirooxindoles have attracted significant attention in
the last decade due to their unique structure and re-
markable biological activities.[1] Many natural spiroox-
indole products are recognized as potent anticancer,
antiinflammatory and antimitotic activities, from sim-
pler class such as horsfiline (A) and coerulescine (B) to
more complex ones such as pteropodine (C) and spiro-
tryprostatin-B (D) (Figure 1).[2] Notably, a valuable col-
lection of fully synthetic spirooxindoles are disclosed as
drug candidates and leading compounds, for example,
MI-888 (E) acted as an efficacious MDM2 Inhibitor.[3]
Generally, these spirooxindole moieties are synthesized
via nucleophilic addition and spirocyclization on isatin
or 3-alkylidine oxindole.[4,5]
From the synthetic viewpoint, difunctionalization of
N
N
R
H
O
O
H
O
N
H
N
H
MeO2C
H
Horsfiline (A), R = OMe
Coerulescine (B), R = H
Pteropodine (C)
H
Cl
N
N
F
O
O
H
OH
O
Results and Discussion
NH
N
Based on above hypothesis, the initial study was fo-
cused on the reaction of 1a. When substrate 1a was
treated by previous fluorination system PhI(OPIv)2/AgF
in the presence of Pd catalyst,[8a] no reaction occurred at
room temperature. When reaction temperature was ele-
vated to 80 ℃, no fluorination reaction was observed.
O
N
N
Cl
H
H
Spirotryprostatin-B (D)
MI-888 (E)
Figure 1 Representative natural and non-natural active spi-
rooxindoles.
*
E-mail: gliu@mail.sioc.ac.cn; Tel.: 0086-021-54925346; Fax: 0086-021-64166128
Received May 29, 2014; accepted June 24, 2014; published online July 20, 2014.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201400350 or from the author.
Dedicated to Professor Chengye Yuan and Professor Li-Xin Dai on the occasion of their 90th birthdays.
†
Chin. J. Chem. 2014, 32, 681—684
© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
681

Wu, Chen & Liu
Table 1 Optimization of reaction conditiona
COMMUNICATION
Previous work:
CN
cat. Pd(OAc)2/L
O
N
O
(1)
(2)
N
O
N
O
PhI(OPiv)2, AgF
CH3CN
N
AgF
CN
O
CH3CN, air, 24 h
This work:
N
N
O
N
1a
N
2a
O
AgF
CN
EntryAgF (equiv.) Additive (equiv)Temp./℃ Yield of 2a/% (dr)b
O
without palladium
and oxidant
N
N
1c AgF (5.0)
－
－
－
－
－
80
80
80
80
80
80
80
80
80
80
80
80
60
110
42 (1.1∶1)
0
2c
3
4
5
6
7
8
9
－
Instead, the reaction afforded spirooxindole product 2a
with CH3CN incorporation in 42% yield and 1.1∶1 dr
ratio (Table 1, Entry 1). Further optimization reaction
conditions showed that the fluorination product was still
not observed. However, we found that both palladium
catalyst and PhI(OPiv)2 were not necessary for this
dialkylation reaction, but stoichiometric amount of AgF
was essential (Entries 2, 3). Furthermore, screening of
silver complex implied that AgF is the only effective
catalyst (see SI). In addition, the amount of silver fluo-
ride is vital to the reaction and 4 equivalent amount of
AgF was the best to give 2a in 62% yield (Entries 3－5).
A series of additives were investigated to improve the
yield. The addition of TEMPO caused slightly drop of
the yield to 41%, which also indicated that the reaction
did not likely undergo radical process (Entry 6). Both
K2CO3 and acetic acid were not beneficial for this reac-
tion (Entries 7 and 8). Water is a good additive for the
reaction, and low yield of 2a (44%) was obtained in
dried acetonitrile (Entries 9 and 10). The reaction was
totally inhibited under oxygen atmosphere. In contrast,
nitrogen atmosphere was helpful for the increasing of
the yield (Entries 11 and 12). Finally, the yield was im-
proved to 72% with elevated temperature at 110 ℃. No
reaction took place when the temperature is lower than
60 ℃ (Entries 12－14).
The substrates scope was next investigated as shown
in Scheme 1. The effect of the protecting group on the
nitrogen atom was firstly screened. For the substrates
bearing alkyl groups on nitrogen of indole, the reactions
proceeded smoothly to provide products 2a－2c in
moderate yields with poor diastereoselectivies (1.1－
1.2∶1). In contrast, the substrates with a simple indole
(R＝H) or bearing an electron-deficient indole (R＝Ac)
did not yield the desired products 2d and 2e. The sub-
strate with t-Bu on the linked nitrogen also gave 2f in
61% yield with 1.1∶1 dr ratio. Substituents on the aro-
matic ring of indole exhibited no significant influence
on the reaction efficiency to afford the desired products
2g－2i. When the methyl group on the alkene moiety
was changed to phenyl, the reaction also gave 2j in 51%,
but the substrate with t-Bu could not provide desired
product 2k. To our delight, substrate with monosubsti-
tuted alkenes was also compatible to the reaction condi-
tion to give product 2l in 62% yield, and the diastereo-
selectivity was improved to 4.1∶1. It should be men-
tioned that the reaction temperature could be lowered to
AgF (4.0)
AgF (3.0)
AgF (2.0)
62 (1.2∶1)
54 (1.2∶1)
13 (1.3∶1)
41 (1.1∶1)
57 (1.2∶1)
44 (1.3∶1)
63 (1.2∶1)
44 (1.3∶1)d
0e
AgF (4.0) TEMPO (0.5)
AgF (4.0)
AgF (4.0)
AgF (4.0)
K2CO3 (1.0)
AcOH (1.0)
H2O (1.0)
10 AgF (4.0)
11 AgF (4.0)
12 AgF (4.0)
13 AgF (4.0)
14 AgF (4.0)
－
－
－
－
－
66 (1.2∶1)f
0f
72 (1.2∶1)f
a Reaction conditions: 1a (0.1 mmol), AgF (0.4 mmol) in CH3CN
(1.0 mL) under air for 24 h; b GC yield with tetradecane as inter-
nal standard and dr ratio was detected by GC; c Pd(OAc)2 (10
mol%) and PhI(OPiv)2 (0.2 mmol) were added; d dried CH3CN;
e under O2 (1 atm); f under N2.
80 ℃ in the presence of K2CO3. Finally, a series of
substrates with monosubstitute alkenes were tested, and
a variety of spirooxindoles 2l－2x were obtained in sat-
isfactory yields and moderate dr ratios (4－5∶1). The
major isomer of 2o was determined with X-ray diffrac-
tion determination (Figure 2).
The detailed mechanism of the dialkylation reaction
is not clear at this moment. As we mentioned, addition
of water is beneficial for this transformation. Thus,
H2O18 was employed as an additive, and we found that
O18 was incorporated into the product 2l (Eq. 3), which
indicated that the oxygen of oxindole should be derived
from nucleophilic addition of H2O. In addition, the ox-
indole substrate 3 was ineffective for this dialkylation
(Eq. 4), which ruled out the initial oxidation of indole
pathway.
Based on above results, the proposed mechanism
pathways were listed in Scheme 2: the reaction was ini-
tiated with nucleophilic attack of indole on AgF coor-
dinated olefin to give alkyl-Ag complex int-I, then cou-
pled with alkyl-Ag complex int-II,[10] which was gener-
ated from C－H bond activation of acetonitrile by two
equivalent of AgF.[9a] The generated intermediate int-III
was attacked by H2O and following oxidized to afford
final produce 2a. Alternatively, the nucleophilic attack
682
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© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2014, 32, 681—684

AgF-Mediated Dialkylation of Activate Alkenes
Scheme 1 AgF-mediated dialkylation of activated alkenesa,b
R3
R3
O
R4
N
O
N
AgF (4 equiv.)
CH3CN, 80 - 110 oC, 24 h
R1
CN
R1
R4
R2
O
N
N
R2
1
2
O
t-Bu
O
N
N
N
O
O
N
O
N
N
N
R
CN
CN
R
O
CN
CN
CN
O
O
O
O
N
N
N
R
R = Me 2l 62% (4.1:1)c
Et 2m 64% (4.0:1)c
Bn 2n 54% (4.7:1)c
R
R = Ph 2j 51% (1.1:1)
t-Bu 2k 0
R = Cl 2g 64% (1.2:1)
Br 2h 65% (1.2:1)
Me 2i 51% (1.1:1)
R = Me 2a 72% (1.1:1)
Et 2b 58% (1.1:1)
Bn 2c 47% (1.2:1)
H 2d 0
2f 61% (1.1:1)
Ac 2e 0
O
N
O
N
O
N
R
O
N
R
CN
CN
CN
O
O
N
O
CN
O
N
N
R
N
R = Me 2q 57% (4.7:1)c
F 2r 45% (4.6:1)c
2x 59% (3.9:1)c
R = Me 2u 64% (3.7:1)c
Cl 2v 51% (4.1:1)c
R = t-Bu 2o 67% (4.9:1)c
Ph 2p 47% (4.3:1)c
Cl 2s 56% (4.3:1)c
Br 2t 61% (4.4:1)c
Br 2w 53% (4.2:1)c
a Reaction conditions: 1 (0.2 mmol), AgF (0.8 mmol) in CH3CN (2 mL) at 110 ℃, N2, 24 h. b Isolated yield, dr in parentheses was determined by GC.
c K2CO3 (0.2 mmol) was added at 80 ℃.
cult to differentiate at this stage.
Conclusions
In conclusion, we have discovered a novel Ag-me-
diated dialkylation of alkenes without additional oxida-
tion, in which AgF activated both alkenes and acetoni-
trile. This reaction provided an efficient way to nitrile-
containing spirooxindoles from readily available (1H-
indol-3-yl)methanamine derivatives with morderate di-
astereoselectivities. Further applications in total synthe-
sis of bioactive spirooxindoles are in progress.
Figure 2 X-ray diffraction of trans-2o.
Experimental
O
AgF (4 equiv.)
K2CO3 (1 equiv.)
H2O18 (3 equiv.)
N
N
N
General procedure for 2a－2j
O
CN
O18
(3)
In a TFE sealed dry glass tube, AgF (102 mg, 0.8
mmol), and alkene 1 (0.2 mmol) were added in CH3CN
(2.0 mL). The mixture was stirred at 110 ℃ for 24 h.
Then ethyl acetate was added and the mixture was fil-
tered through a plug of celite. After removal of the sol-
vent under vacuum, the residue was purified by column
chromatography on silica gel with a gradient eluant of
petroleum ether and ethyl acetate to afford the products
2a－2j.
dried CH3CN, N2, 80 oC, 24 h
N
51% (dr 4.3:1)
1l
2l
O
O
N
N
N
O
AgF (4.0 equiv.)
CH3CN, N2, 110 oC, 24 h
CN
O
(4)
N
3
2a
of H2O possibly occurred with int-I to give alkyl-Ag
complex int-IV, then coupled with int-II to give final
product 2a. These two pathways are possible and diffi-
General procedure for 2l－2x
In a TFE sealed dry glass tube, AgF (102 mg, 0.8
Chin. J. Chem. 2014, 32, 681—684
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683

Wu, Chen & Liu
COMMUNICATION
Scheme 2 Proposed mechanism
O
N
N
CN
H2O
Ag
CN
int-II
int-III
O
O
N
N
N
N
O
AgF
Ag
CN
O
N
N
1a
2a
int-I
O
O
H2O
N
Ag
int-II
CN
Ag
H
H
H
AgF
N
AgF
Ag
CN
int-II
N
int-IV
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mmol) were added in CH3CN (2.0 mL). The mixture
was stirred at 80 ℃ for 24 h. Then ethyl acetate was
added and the mixture was filtered through a plug of
celite. After removal of the solvent under vacuum, the
residue was purified by column chromatography on sil-
ica gel with a gradient eluant of petroleum ether and
ethyl acetate to afford the products 2l－2w.
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