A Hg(ClO4)2 3 3H2O Catalyzed sakurai-hosomi allylation of isatins and isatin ketoimines using allyltrimethylsilane

Article abstract of DOI:10.1021/ol202705g

It is reported that Hg(ClO₄)₂ 3 3H₂O could efficiently activate the cheap but less reactive allyltrimethylsilane for the allylation of isatins or isatin ketoimines, with catalyst loading down to 0.1 mol %. This is the firs

Full text of DOI:10.1021/ol202705g

ORGANIC
LETTERS
2011
Vol. 13, No. 24
6398–6401
A Hg(ClO4)2 3H2O Catalyzed
SakuraiꢀHosomi Allylation of Isatins and
3
Isatin Ketoimines Using Allyltrimethylsilane
Zhong-Yan Cao, Yan Zhang, Cong-Bin Ji, and Jian Zhou*
Shanghai Key Laboratory of Green Chemistry and Chemical Processes, East China
Normal University, 3663 N. Zhongshan Road, Shanghai, 200062, P. R. China
jzhou@chem.ecnu.edu.cn
Received October 9, 2011
ABSTRACT
It is reported that Hg(ClO4)2 3H2O could efficiently activate the cheap but less reactive allyltrimethylsilane for the allylation of isatins or isatin
ketoimines, with catalyst loading down to 0.1 mol %. This is the first example of SakuraiꢀHosomi allylation of ketoimines using
3
allyltrimethylsilane. A rare example of chiral mercury catalysis is also reported.
The exploration of new catalytic properties of cheap and
easily available metal salts such as iron, bismuth, and
copper salts is of current interest in organic synthesis. In
contrast, limited attention was paid to mercury catalysis,
mainly because of the worry about its toxicity.1 This is to
some extent perplexing because mercury is still widely used
for gauges, barometers, high-intensity discharge lamps, elec-
trodes, electrical switches, and extraction of gold.1a In
addition, mercury amalgam is a common tooth filling, and
thimerosal is still used in vaccines in many countries.1a No
convincing proof revealed that mercury-containing vaccines
and mercury amalgams lead to adverse health effects.1
Recent studies have shown that mercury compounds
have interesting properties worthwhile to explore.2 For
example, Barron reported that a stabilized areneꢀmercury
complex could efficiently catalyze H/D exchange of C6D6
with arenes.2a,b Nishizawa had identified Hg(OTf)2 as a
powerful catalyst for a series of transformations,2c,d which
had been applied to natural product synthesis. A recent
example was the synthesis of hippuristanol via Hg(OTf)2-
catalyzed spiroketalization by Deslongchamps.2f
In light of these facts, we believe the discovery of new
catalytic properties of mercury, an “element of mystery”,1a is
still needed. During our efforts in the synthesis of 3,3-
disubstituted oxindoles for biological evaluation,3 we had
developed a highly efficient FriedelꢀCrafts reaction of 3-sub-
stituted 3-hydroxyoxindoles and aromatic compounds cat-
alyzed by Hg(ClO4)2 3H2O.3d Its high efficiency results
3
from aromatic mercuration that produces a strong acid to
facilitate the generation of carbocationic intermediate and
simultaneously forms the more reactive nucleophile aryl
mercural. Here, we wish to report that Hg(ClO4)2 3H2O
could activate allyltrimethylsilane for a highly efficient
allylation of isatins and isatin derived ketoimines.
3
The SakuraiꢀHosomi allylation reaction is very useful
for the synthesis of homoallylic alcohols or amines from
inexpensive and nontoxic allylsilanes.4 Although signifi-
cant achievements have been made in allylation reactions
(1) (a) Clarkson, T. W.; Magos, L. Crit. Rev. Toxicol. 2006, 36, 609.
(b) Doja, A.; Roberts, W. Can. J. Neurol. Sci. 2006, 33, 341.
(2) (a) Borovik, A. S.; Barron, A. R. J. Am. Chem. Soc. 2002, 124, 3743.
(b) Branch, C. S.; Barron, A. R. J. Am. Chem. Soc. 2002, 124, 14156. (c)
Yamamoto, H.; Sasaki, I.; Hirai, Y.; Namba, K.; Imagawa, H.; Nishizawa,
M. Angew. Chem., Int. Ed. 2009, 48, 1244. (d) Namba, K.; Kaihara, Y.;
Yamamoto, H.; Imagawa, H.; Tanino, K.; Williams, R. M.; Nishizawa,
M. Chem.;Eur. J. 2009, 15, 6560. (e) Ravindar, K.; Reddy, M. S.;
Deslongchamps, P. Org. Lett. 2011, 13, 3178. (f) Ravindar, K.; Reddy,
M. S.; Lindqvist, L.; Pelletier, J.; Deslongchamps, P. Org. Lett. 2010, 12,
4420. For a review, see: (g) Nishizawa, M.; Imagawa, H.; Yamamoto, H.
Org. Biomol. Chem. 2010, 8, 511.
(3) (a) Qian, Z.-Q.; Zhou, F.; Du, T.-P.; Wang, B.-L.; Ding, M.;
Zhao, X.-L.; Zhou, J. Chem. Commun. 2009, 6753. (b) Liu, Y.-L; Wang,
B.-L.; Cao, J.-J; Chen, L.; Zhang, Y.-X.; Wang, C.; Zhou, J. J. Am.
Chem. Soc. 2010, 132, 15176. (c) Ding, M.; Zhou, F.; Liu, Y.-L.; Wang,
C.-H.; Zhao, X.-L.; Zhou, J. Chem. Sci. 2011, 2, 2035. (d) Zhou, F.; Cao,
Z.-Y.; Zhang, J.; Yang, H.-B.; Zhou, J. Chem.;Asian J. 2011, in press.
r
10.1021/ol202705g
Published on Web 11/23/2011
2011 American Chemical Society

by Leighton, using strain-release-activated silane reagents,
the activation of less reactive allysilanes for reaction design
is still needed.4k,l In this context, two activation models
have been adopted: one is to activate the electrophile by an
acid to react with allylsilane (eq 1),4b and the other is to
activate allylsilanes by a Lewis base to directly react with
electrophiles4c or to help the formation of reactive allyl
metallic species (eq 2).4hꢀj Despite achievements, efficient
allylation of ketones or ketoimines is very limited, which
often relies on the dual activation of both reaction partners
and using allyltrimethoxysilane or specially designed allyl-
silanes that can be easily activated by Lewis base to form
reactive allylmetallic species.4hꢀj As far as we knew, the
catalytic allylation of ketoimines using cheaper but less
reactive allyltrimethylsilane 1 was not reported yet,4 and
no catalytic asymmetric allylation of ketones using allyl-
trimethylsilane was reported.4
Table 1. Comparing Different Lewis Acids
entrya
cat.
Sc(OTf)3
ꢁ
time (h)
yieldb (%)
1
2
48
48
48
48
1
31
75
10
50
99
95
98
93
71
2
In(ClO4)3 8H2O
2
3
3
Ph3PAuCl þ AgOTf
Bi(OTf)3
2
4
2
5
Hg(OTf)2
2
6
Hg(ClO4)2 3H2O
2
2
3
7
Hg(ClO4)2 3H2O
1
4
3
8c
9d
Hg(ClO4)2 3H2O
0.3
0.1
12
144
3
Hg(ClO4)2 3H2O
3
a On a 0.40 mmol scale. b Isolated yield. c On a 7.0 mmol scale. d On a
20.0 mmol scale, with 23% of 2a recovered.
withsilane1 after several hours (Figure 1). Soft Lewis acids
such as Ph3PAuOTf and AgOTf could interact with 1
slowly. However, borderline Lewis acid Bi(OTf)3 and soft
Lewis acid Hg(ClO4)2 3H2O or Hg(OTf)2 could rapidly
3
interact with silane 1 within 10 min, and the generation of
propylene was observed by NMR analysis. Next, we
examined the performance of these Lewis acids in the
reaction of silane 1 and isatin 2a in CH2Cl2 at 25 °C, with
2 mol % catalyst. Some typical results were shown in Table
1 (for details about NMR studies, screened Lewis acids,
and optimization, see the Supporting Information). Of
To activate the less reactive allyltrimethylsilane 1 for
reaction development, we considered a new approach: the
direct activation of silane 1 by a Lewis acid. It was pos-
tulated that the interaction of a carbophilic Lewis acid with
the double bond of 1 might form an intermediate carbo-
cation, which was stabilized by hyper-conjugative overlap
with the adjacent carbonꢀsilicon bond, followed by the
cleavage of the silyl electrofuge to afford a reactive allylic
metallic species for further transformations (eq 3). To test
this hypothesis, we first analyzed the interaction between
silane 1 and Lewis acids (10 mol %) by NMR analysis
under N2. We found that hard Lewis acids such as Sc-
hard Lewis acids screened, In(ClO4)3 8H2O and Sc(OTf)3,
3
which failed to activate silane1, catalyze this reaction slowly
(Table 1, entries 1 and 2), possibly through the activation
of isatin 2a. Of Lewis acids interacting with silane 1,
Ph3PAuOTf and Bi(OTf)3 catalyze the reaction slowly,
giving product 3a in 10 and 50% yield after 2 days, res-
pectively (Table 1, entries 3 and 4).
(OTf)3 and In(ClO4)3 8H2O have no obvious interaction
3
In contrast, Hg(OTf)2 and Hg(ClO4)2 3H2O enable the
3
completion of reaction within 2 h to afford 3a in 99 and
95% yield, respectively (Table 1, entries 5 and 6). Although
Hg(OTf)2 was more reactive, cheap and easy to handle,
Hg(ClO4)2 3H2O5 was chosen as the optimum. The catalyst
3
loading could be reduced to 0.3 mol % for a 7.0 mmol scale
reaction, which finished within 12 h to give 3a in 93% yield
(4) For reviews, see: (a) Hosomi, A. Acc. Chem. Res. 1988, 21, 200. (b)
Denmark, S. E.; Fu, J. Chem. Rev. 2003, 103, 2763. (c) Denmark, S. E.;
Beutner, G. L. Angew. Chem., Int. Ed. 2008, 47, 1560. (d) Shibasaki, M.;
Kanai, M. Chem. Rev. 2008, 108, 2853. Also see: (e) Hosomi, A.;
Shirahata, A.; Sakurai, H. Tetrahedron Lett. 1978, 33, 3043. (f) Wang,
D.-K.; Zhou, Y.-G.; Tang, Y.; Hou, X.-L.; Dai, L.-X. J. Org. Chem.
1999, 64, 4233. (g) Ishihara, K.; Hiraiwa, Y.; Yamamoto, H. Synlett.
2001, 1851. (h) Yamasaki, S.; Fujii, K.; Wada, R.; Kanai, M.; Shibasaki,
M. J. Am. Chem. Soc. 2002, 124, 6536. (i) Wadamoto, M.; Yamamoto,
H. J. Am. Chem. Soc. 2005, 127, 14556. (j) Kamei, T.; Fujita, K.; Itami,
K.; Yoshida, J.-I. Org. Lett. 2005, 7, 4725. For the use of strained
silacycles, see: (k) Kinnaird, J. W. A.; Ng, P. Y.; Kubota, K.; Wang, X.;
Leighton, J. L. J. Am. Chem. Soc. 2002, 124, 7920. (l) Berger, R.; Rabbat,
P. M. A.; Leighton, J. L. J. Am. Chem. Soc. 2003, 125, 9596.
Figure 1. NMR analysis of the interaction between selected
Lewis acids and silane 1.
(5) For a review about metal perchlorate hydrates, see: Dalpozzo, R.;
Bartoli, G.; Sambri, L.; Melchiorre, P. Chem. Rev. 2010, 110, 3501.
Org. Lett., Vol. 13, No. 24, 2011
6399

Scheme 1. Allylation of Isatins 2 Using Allyltrimethylsilane 1a,b
Scheme 2. Allylation of Isatin Derived Ketoimine 4a,b
a On a 0.40 mmol scale. b Isolated yield.
a On a 0.40 mmol scale. b Isolated yield.
(Table 1, entry 8). Further lowering the catalyst load-
ing to 0.1 mol % for a 20.0 mmol scale reaction, product
3a could still be obtained in 71% yield after 6 days, with 23%
of 2a recovered. As far as we know, this is the lowest cata-
lyst loading for the allylation of ketones using allylsilane.
We further examined the substrate scope by running the
Hg(ClO4)2 3H2O as the catalyst (Scheme 2). It should also be
3
noted that aminooxindoles 5 were very useful building blocks
for a number of bioactive compounds,6a but synthetic
methods to 3-allyl-3-aminooxindoles were very limited.7
In the NMR studies, we observed that Bi(OTf)3 could
interact with allyltrimethylsilane 1 as rapidly as Hg(OTf)2,
but itcatalyzed the allylation of isatin2 veryslowly (entry 4
vs 5, Table 1). During our work, Meshram also reported
reaction in CH2Cl2 with 1 mol % of Hg(ClO4)2 3H2O
3
(THF was used when unprotected isatins dissolved poorly
in CH2Cl2). The nature and the position of the substituents
on isatin had no obvious influence, and all the desired
products 3aꢀl were obtained in high yield (Scheme 1).
These products are very useful.6k For example, product
3a can be used for the synthesis of CPC-1,6b donaxaridine,
and dioxibrassinine,6i and product 3h for convolutamy-
dine A, B, and E.6i In the total synthesis of perophora-
midine,6f Qin used 6.0 equiv of allylmagnesium bromide to
react with 6-bromoisatin to ensure the high yield of product
3d; our method is obviously a good alternative.
that the use of 5 mol % Bi(OTf)3 4H2O was necessary to
catalyze the allylation of isatin 2, with slow addition at
ꢀ78 °C and then warmed to 20 °C.6j Although less reac-
3
tive than Hg(OTf)2, Hg(ClO4)2 3H2O is obviously more
3
efficient than Bi(OTf)3 4H2O for this reaction, and the
catalyst loading could be down to 0.1 mol %.
3
We further compared both catalysts (Scheme 3). First,
Bi(OTf)3 failed to catalyze the allylation of ketoimine 4a
under the same conditions. Although Ollevier reported that
the allylation of compound 6 only gave the desired product
7 in 16% yield with carbamate 8 in 36% yield,8 even using 5
We next tried the Hg(ClO4)2 3H2O catalyzed allylation of
3
isatin derived ketomines 4 using silane 1. As far as we knew,
the use of allyltrimethylsilane 1 for allylation of ketoimines
was unknown, and the limited reports on SakuraiꢀHosomi
allylation of ketomines were based on the more reactive but
expensive allyltrimethoxysilane or special allylsilanes.4h,j
We were pleased to find that different substituted isatin
ketoimine 4worked well in MeOH at 40 °C, using 5 mol % of
mol % of Bi(OTf)3 4H2O and 5.0 equiv of silane 1 in
3
refluxing CH2Cl2, we found that the use of 5 mol % of
Hg(ClO4)2 3H2O and only 2.0 equiv of 1 could afford the
3
desired product 7 in 70% yield at room temperature.
The catalytic asymmetric allylation of isatins is of great
interest because enantioenriched 3-allyl-3-hydroxyoxin-
doles are very useful.6a Although Krische have already
developed a highly enantioselective allylation of N-benzyl
isatins using allylacetate,6d the allylation of unprotected
isatins waited for development,6 and only 42% ee was
obtained when using tetraallylstannane.6b In the Pd-cata-
lyzed asymmetric allylation of unprotected isatin 2a using
allyl alcohol and Et3B, Zhou found the nitrogen of the
(6) For a comprehensive review, see: (a) Zhou, F.; Liu, Y.-L.; Zhou, J.
Adv. Synth. Catal. 2010, 352, 1381. For methods to 3-allyl 3-hydroxy-
oxindoles, see: (b) Kitajima, M.; Mori, I.; Arai, K.; Kogure, N.; Takayama,
H. Tetrahedron Lett. 2006, 47, 3199. (c) Hanhan, N. V.; Sahin, A. H.;
Chang, T. W.; Fettinger, J. C.; Franz, A. K. Angew. Chem., Int. Ed. 2010,
49, 744. (d) Itoh, J.; Han, S. B.; Krische, M. J. Angew. Chem., Int. Ed. 2009,
48, 6313. (e) Qiao, X.-C.; Zhu, S.-F.; Zhou, Q.-L. Tetrahedron: Asymmetry
2009, 20, 1254. (f) Wu, H.; Xue, F.; Xiao, X.; Qin, Y. J. Am. Chem. Soc.
2010, 132, 14052. (g) Nair, V.; Jayan, C. N.; Ros, S. Tetrahedron 2001, 57,
9453. (h) Sano, D.; Nagata, K.; Itoh, T. Org. Lett. 2008, 10, 1593. (i)
Kawasaki, T.; Nagaoka, M.; Satoh, T.; Okamoto, A.; Ukon, R.; Ogawa,
A. Tetrahedron 2004, 60, 3493. (j) Meshram, H. M.; Ramesh, P.; Reddy,
C. B.; Kumar, G. S. Chem. Lett. 2011, 40, 357. (k) Alcaide, B.; Almendros,
P.; Rodriguez-Acebes, R. J. Org. Chem. 2006, 71, 2346. (l) Sano, D.;
Nagata, K.; Itoh, T. Org. Lett. 2008, 10, 1593. (m) Bui, T.; Candeias, N. R.;
Barbas, C. F., III J. Am. Chem. Soc. 2010, 132, 5574. (n) Zheng, K.; Yin,
C.; Liu, X.; Lin, L.; Feng, X. Angew. Chem., Int. Ed. 2011, 50, 2573.
(7) (a) Lesma, G.; Landoni, N.; Pilati, T.; Sacchetti, A.; Silvani, A.
J. Org. Chem. 2009, 74, 4537. (b) Alcaide, B.; Almendros, P.; Aragoncillo,
C. Eur. J. Org. Chem. 2010, 2845. (c) Mouri, S.; Chen, Z.; Mitsunuma, H.;
Furutachi, M.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2010,
132, 1255. For reviews: (d) Kobayashi, S.; Mori, Y.; Fossey, J. S.; Salter,
M. Chem. Rev. 2011, 111, 2626. (e) Shen, K.; Liu, X.; Lin, L.; Feng, X.
Chem. Sci. 2011, 2, No. DOI:10.1039/C1SC00544H.
(8) Ollevier, T.; Li, Z. Adv. Synth. Catal. 2009, 351, 3251.
6400
Org. Lett., Vol. 13, No. 24, 2011

Table 2. Control Experiments
Scheme 3. Comparing Bi(OTf)3 with Hg(ClO4)2 3H2O
3
entry Hg source
additive
time (h) yielda (%) eeb (%)
1
2
3
4
9
no
9
no
48
48
2
trace
trace
91
TMSOTfc
TMSOTfc
TMSOTfc and
(S)-BINAPd
no
product was also masked with an allyl group.6e Although
chiral mercury catalysis was rare,9 we found that at 0 °C in
9
72
84
57
THF, 1.0 mol % of (S)-BINAP/Hg(ClO4)2 3H2O could
3
5
6
7
13
13
13
24
4
trace
90
give the S-enantiomer of product 3 in excellent yield with up
to 63% ee. Although there has much room for improve-
ment, this is the first example of catalytic asymmetric
allylation of ketones using allyltrimethylsilane.4
AgOTfe
AgClO4 H2Oe
4
91
3
a Isolated yield. b By HPLC analysis. c 2.0 mol %. d 1.0 mol %, in
THF at 0 °C. e 1.1 mol %; both silver salts could not catalyze the reaction
(13: allylmercury chloride).
accordance with NMR studies that the in situ generated 11
or 12 could react with silane 1 as quickly as Hg(OTf)2 or
Hg(ClO4)2 3H2O. These results also confirmed that weak-
3
ꢀ
coordinating counteranions such as OTfꢀ and ClO4
were key to ensure the high Lewis acidity of Hg(II) to
activate silane 1. A possible catalytic cycle was then pro-
posed as below (for more details and discussion, please see
the Supporting Information).
To gain more insight into the mechanism, we first tried
NMR studies and observed little interaction between Hg2þ
and N-methylisatin, suggesting Hg(ClO4)2 3H2O might not
3
act as a Lewis acid to activate isatin (see the Supporting
Information). Since diallylmercury 9 could react with alde-
hydes in water,10 we tried the reaction of 9 and 2a, which
worked slowly, and found 1.7 equiv of 9 was need to ensure
90% yield of product 3a after 24 h. We also prepared allyl-
mercury triflate 10 or perchlorate 11, from anion exchange
of allylmercury chloride 13 using AgOTf or AgClO4 H2O,
to react with 2a but found that no reaction took place.
3
In conclusion, we have demonstrated that Hg(OTf)2 and
Hg(ClO4)2 3H2O could activate allyltrimethylsilane for a
3
highly efficient allylation of isatins and isatin ketoimines. The
catalyst loading could be down to 0.1 mol %, the lowest known
for a SakuraiꢀHosomi allylation reaction. Our results further
demonstrated that mercury salts had some interesting catalytic
properties worthwhile to explore.2,11 Efforts to develop a highly
enantioselective version are now in progress in our laboratory.
To probe if diallylmercury 9 was the key intermediate for
allylation of isatin, we tried using different Hg(II) sources to
mediate the reaction of isatin 2a with silane 1. Although the
use of 1 mol % of 9 or 2 mol % of TMSOTf failed to initiate
the reaction (Table 2, entries 1 and 2), the combination of
bothresultedinhighreactivity(Table 2, entry 3). The possible
role of TMSOTf was to cleave the HgꢀO bond of adduct 10
to release O-TMS protected product 15 and allylmercury
triflate 11, which further interact with silane 1 to give
diallylmercury 9. Indeed, the in situ prepared triflate 11 or
perchlorate 12 initiated the reaction well (Table 2, entries 6
and 7), though allylmercury chloride 13 failed to initiate the
reaction (Table 2, entry 5). These results were also in
Acknowledgment. Wethank theNational Natural Science
Foundation of China (20902025, 21172075), Shanghai
Pujiang Program (10PJ1403100), and 973 Program (2011CB-
808600) for the financial support, which is highly appreciated.
Supporting Information Available. Experimental proce-
dures and characterizations, copies of 1HNMRand13CNMR
of new compounds, and HPLC profiles. This material is
available free of charge via the Internet at http://pubs.acs.org.
(9) Only two examples were reported by now: (a) Yamamoto, H.; Ho,
E.; Namba, K.; Imagawa, H.; Nishizawa, M. Chem.;Eur. J. 2010, 16,
11271. (b) Oh, T.; Lopez, P.; Reilly, M. Eur. J. Org. Chem. 2000, 2901.
(10) Hashmi, A. S. K.; Schwarz, L.; Bolte, M. Tetrahedron Lett. 1998,
39, 8969.
(11) As suggested by one reviewer, we checked the Hg contamination
level of product 3a by both CVAFS and ICP-MS analysis, which gave
consistent results that ca. 3.0% of Hg of catalyst remained in product 3a.
For details, please see the Supporting Information.
Org. Lett., Vol. 13, No. 24, 2011
6401