A highly diastereo- and enantioselective Hg(II)-catalyzed cyclopropanation of diazooxindoles and alkenes

Article abstract of DOI:10.1021/ol302998m

It is reported for the first time that Hg(II) can catalyze the cyclopropanation of diazo reagents and alkenes, which contributes to the unprecedented highly diastereo- and enantioselective synthesis of spirocyclopropyloxindoles.

Full text of DOI:10.1021/ol302998m

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
A Highly Diastereo- and Enantioselective
Hg(II)-Catalyzed Cyclopropanation of
Diazooxindoles and Alkenes
Zhong-Yan Cao, Feng Zhou, Yi-Hua Yu,† and Jian Zhou*
Shanghai Key Laboratory of Green Chemistry and Chemical Processes, East China
Normal University, Shanghai, 200062, P. R. China, and Shanghai Key Laboratory of
Magnetic Resonance, Department of Physics, Shanghai 200062, P. R. China
jzhou@chem.ecnu.edu.cn
Received October 31, 2012
ABSTRACT
It is reported for the first time that Hg(II) can catalyze the cyclopropanation of diazo reagents and alkenes, which contributes to the unprecedented
highly diastereo- and enantioselective synthesis of spirocyclopropyloxindoles.
The metal-catalyzed cyclopropanation between diazo
compounds and alkenes is a powerful strategy for the
synthesis of cyclopropane derivatives.1 Despite that, the
search for stereoselective catalysts has a long and continu-
ing history,2ꢀ6 and there is still much work to to be done to
enable diazo compounds with low reactivity and poor
stereocontrollability for catalytic asymmetric reactions.
For example, catalytic asymmetric synthesis of spiro-
cyclic compounds using cyclic diazoamides such as
diazooxindoles 1 is unprecedented, although spirocyclo-
propyl oxindoles 3 are very vaulable, which are known to
have inotropic and herbicidal properties.7 Furthermore,
Carreira et al. have demonstrated that oxindole 3 is a
(3) For selected Rh-catalyzed reactions, see: (a) Doyle, M. P.;
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€
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133, 8972. (l) Qin, C.-M.; Boyarskikh, V.; Hansen, J. H.; Hardcastle,
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† Shanghai Key Laboratory of Magnetic Resonance.
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Chem. Rev. 1994, 94, 1091. (d) Doyle, M. P.; Forbes, D. C. Chem. Rev.
1998, 98, 911. (e) Lebel, H.; Marcoux, J.-F.; Molinaro, C.; Charette,
A. B. Chem. Rev. 2003, 103, 977. (f) Zhang, Z.-H.; Wang, J.-B. Tetra-
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r
10.1021/ol302998m
XXXX American Chemical Society

versatile synthon for the synthesis of spiro[pyrrolidin-
3,30-oxindoles] via the ring-expansion reaction with
imines.8 Recently, the need for privileged scaffolds in
drug discovery gives an impetus for the catalytic asym-
metric synthesis of 3,3-disubstituted oxindoles, which are
widely present in natural products and drugs.9,10 With
our interest in this field,11 we tried to apply diazooxin-
doles 1 for catalytic asymmetric reactions and found that
although catalysts 4ꢀ83a,3c,12,2c,2e had proven to be ex-
cellent for the decomposition of diazo compounds for
reaction design, they were unable to achieve high ee in the
reaction of diazoamide 1a and styrene 2a under their
reported conditions, respectively (Scheme 1, for details,
see the Supporting Information). These results showed
the necessity to develop new chiral catalysts for this valuable
reaction. Here, we report a Hg(II)-catalyzed highly enan-
tioselective reaction of diazooxindoles 1 and alkenes 2.
Scheme 1. Exploratory Studies
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We have reported that Hg(II) could highly effici-
ently activate allyltrimethylsilane for allylation of isatins
and activate electron-rich aromatics for the arylation of
3-hydroxyoxindoles.13 Considering the excellence of Hg(II)
as a soft Lewis acid to activate soft bases, we speculated
that it would be possible to use Hg(II) to decompose diazo
compounds, a kind of soft bases,14 for cyclopropanation
reactions. With this in mind, we tried using 5.0 mol % of
Hg(OTf)2 to catalyze the reaction of 1a and 2a in CH2Cl2
at 0 °C and found to our delight that the reaction could be
complete within 4 h to give product 3a in 60% yield with
excellent dr (entry 1, Table 1). We further compared
Hg(OTf)2 with other widely used metal catalysts in this reac-
tion, and Hg(OTf)2 turned out to be more efficient (entries
2ꢀ10). Rh2(OAc)4 failed to catalyze the reaction at 0 °C
but worked well at 25 °C to give product 3a in 91% yield
after 48 h, with lower dr (entry 2). Even at 25 °C, Ru(II),
Cu(I), and Cu(II) catalyzed the reaction very slowly (entries
3ꢀ5). At 0 °C, Pd(OTf)2 catalyzed the reaction at a much
lower rate than Hg(OTf)2 (entry 6 vs 1). Other triflates
derived from Ag(I), Co(II), Fe(III), and Fe(II) all failed to
catalyze this reaction, either at 0 or 25 °C (entries 7ꢀ10).
These results were in accordance with Wang’s observation
that the reactivity of diazooxindole 1 was low.7d
The high efficiency that Hg(OTf)2 demonstrated in this
reaction was very impressive, which encouraged us to
develop an asymmetric protocol. Diphosphine ligands could
effectively modulate the catalyst properties of Hg(OTf)2,
(11) (a) 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. (b) Ding, M.;
Zhou, F.; Liu, Y.-L.; Wang, C.-H.; Zhao, X.-L.; Zhou, J. Chem. Sci.
2011, 2, 2035. (c) Qian, Z.-Q.; Zhou, F.; Du, T.-P.; Wang, B.-L.; Ding,
M.; Zhao, X.-L.; Zhou, J. Chem. Commun. 2009, 6753. (d) Liu, Y.-L.;
Zhou, J. Chem. Commun. 201210.1039/c2cc36665g. (e) Liu, Y.-L.; Zhou, J.
Chem. Commun. 2012, 48, 1919. (f) Zhou, F.; Ding, M.; Liu, Y.-L.;
Zhou, J. Adv. Synth. Catal. 2011, 353, 2945.
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11916.
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6398. (b) Zhu, F.; Zhou, F.; Cao, Z.-Y.; Wang, C.; Zhang, Y.-X.; Wang,
C.-H.; Zhou, J. Synthesis 2012, 3129. (c) Zhou, F.; Cao, Z.-Y.; Zhang, J.;
Yang, H.-B.; Zhou, J. Chem.;Asian J. 2012, 7, 233.
(14) Ho, T.-L. Chem. Rev. 1975, 75, 1.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Comparing Different Metal Saltsa
Table 3. Substrate Scopea
temp
time
(h)
yieldb
(%)
entry
cat.
Hg(OTf)2
(°C)
drc
>20:1
1
2
0
4
60
temp
yieldb eec
0 (25) 24 (48) nrg (91) ndg (13:1)
entry
1
2
X
(°C)
3
(%)
(%)
d
Rh2(OAc)4
(Ph3P)3Ru(OTf)2 0 (25) 24 (48) nr (30)
3
nd (10:1)
1
2
3
4
5
6
7
8
9
1a: R = H, R1 = H
2a
2a
2a
2a
2a
5
5
5
5
5
5
5
2
2
2
2
2
2
2
5
5
0
0
3a
3b
3c
3d
3e
3f
93
82
58
89
78
97
92
84
87
90
97
90
93
99
57
48
90
94
91
87
93
90
91
99
90
87
83
90
92
92
86
86
4
CuOTf 1/2C6H6
0 (25) 24 (48) nr (30)e nd (20:1)
0 (25) 24 (48) nr (31)e nd (20:1)
1b: R = H, R1 = Me
1c: R = H, R1 = Bn
1d: R = 5-Me, R1 = H
1e: R = 7-Me, R1 = H
3
5
Cu(OTf)2
0
39e
>20:1
nd
f
6
Pd(OTf)2
0
24
0
7
AgOTf
0 (25) 24 (48) nr
0 (25) 24 (48) nr
0 (25) 24 (48) nr
0 (25) 24 (48) nr
0
f
8
Co(OTf)2
nd
1f: R = 5,7-Me2, R1 = H 2a
1g: R = 6,7-Me2, R1 = H 2a
1h: R = 4,6-Me2, R1 = H 2a
0
9
Fe(OTf)3
Fe(OTf)2
nd
0
3g
3h
3i
10
nd
25
25
25
25
25
25
25
0
1i: R = 5-F, R1 = Me
2a
2a
2a
2a
a On a 0.20 mmol scale. b Isolated yield. c Determined by 1H NMR
analysis of the crude mixture. d 2.5 mol %. e NMR yield using 1,3,5-
Me3C6H3 as the internal standard. f By anion exchange of PdCl2 or
CoCl2 with AgOTf. g nr = no reaction. nd = not determined.
10 1j: R = 5-Cl, R1 = Me
11 1k: R = 5-Br, R1 = H
12 1l: R = 5-I, R1 = Me
3j
3k
3l
13 1m: R = 7-Cl, R1 = Me 2a
3m
3n
3o
3p
14 1b: R = H, R1 = Me
15d 1a: R = H, R1 = H
16 1a: R = H, R1 = H
2b
2c
2d
and the electron-deficient ligand (R)-915 proved to be the
best, which afforded product 3a in 62% yield and 61% ee
(Table 2, entries 1ꢀ4). Further screening revealed that toluene
was the optimal reaction solvent (entry 5). When the reaction
was run at 0 °C, using 5 mol % of chiral catalyst 9/Hg(OTf)2
and 10.0 equivs of styrene 2a, up to 90% ee and 93% yield for
product 3a was achieved (entry 6). For the full studies of
condition optimization, see the Supporting Information.
0
a On a 0.20 mmol scale. b Isolated yield. c Determined by chiral
HPLC analysis. d 13:1 dr.
had no big influence on the enantiofacial control, and di-
azooxindoles 1aꢀm afforded the desired products 3aꢀm
in high to excellent ee (entries 1ꢀ13). Other aromatic sub-
stituted alkenes 2bꢀd also worked well to give the desired
products 3nꢀp in reasonable yield with high ee (entries
14ꢀ16). The absolute configuration of product 3n was
determined by X-ray analysis (Figure 1), and those of
others were tentatively assigned by analogy.
Table 2. Condition Optimizationa
entry
L
solvent temp (°C) time (h) yieldb (%) ee (%)
1
9
CH2Cl2
25
25
25
25
25
0
1
2
62
52c
49c
71
61
45c
51c
49
2
10 CH2Cl2
11 CH2Cl2
12 CH2Cl2
3
24
4
Figure 1. X-ray structure of product 3n.
4
5
6d
9
9
toluene
toluene
5
64
87
The less reactive disubstituted alkenes were also viable
substrates for this reaction, if the counteranion was changed
from OTfꢀ to PF6ꢀ. Accordingly, when 5.0 mol % of in situ
generated catalyst 9/Hg(PF6)2 was used, R-methylstyrene 2e
provided product 3q, with two adjacent quaternary stereo-
genic carbon centers, in excellent dr and 83% ee. While a
trans double bond is generally deemed to be too sterically
12
93
90
a On a 0.20 mmol scale. b Isolated yield. c Opposite enantiomer.
d 5.5 mol % of 9, 5.0 mol % of Hg(OTf)2, and 10.0 equiv of 2a used.
The substrate scope with respect to different diazooxin-
doles 1and alkenes 2was then examined (Table 3). Generally,
the nature and position of substituent on the diazooxindoles
(15) Jeulin, S.; Paule, S. D.; Ratovlomanana-Vidal, V.; Genet, J.-P.;
Champion, N.; Dellis, P. Angew. Chem., Int. Ed. 2004, 43, 320.
(16) Davies, H. M. L.; Coleman, M. G.; Ventura, D. L. Org. Lett.
2007, 9, 4971.
Org. Lett., Vol. XX, No. XX, XXXX
C

crowded for cyclopropanation,16 the trans-anethole 2f could
give the desired product 3r in 50% yield, excellent dr, and
60% ee under these improved conditions. The diazooxindole
1b could react with indene 2g to give strained spirocyclo-
propanooxindole 3s in excellent dr, 65% yield, and 64% ee.
Table 4. Ligand Acceleration Studiesa
entry
X
time (h)
yieldb (%)
eec (%)
1
2
3
4
5
6
0
18
5
7
74
77
82
83
89
nd
83
83
86
87
87
0.1
0.2
0.4
0.5
1.1
5
5
5
5
a On a 0.20 mmol scale. b Isolated yield. c Determined by chiral
HPLC analysis.
The synthetic utility of the spirocyclopropyl oxindoles 3
was shown by an unprecedented [3 þ 2] cycloaddition of
spirocyclopropyl oxindoles 3 with aldehyde. After protec-
tion, the resulting N-acetyloxindole 13 could react with
benzaldehyde, in the presence of 10 mol % of Cu(OTf)2, to
furnish spiro[furan-3,30-indolin]-2-one 14 in 45% overall
yield for three steps, 3:1 dr and 87% ee. This transforma-
tion might have potential application in the synthesis of
spirocyclic oxindoles of current interest.9,10
by Davies,3d for cyclopropanation involving donor/accep-
tor carbenoids. The alkene approached the carbenoid
intermediate side-on over the lactam group, with the Ar
group of the alkene favoring an orientation away from the
bulky metal (Figure 2), which finally led to the formation
of trans isomer as the major product.
While Corma recently mentioned that “there is not a
single example of a ligand-modulated Hg(II) catalyst”,17
the results shown above clearly demonstrated that the
catalyst properties of Hg(II) could be readily modulated
by variation of ligands and counteranions. Furthermore,
this cyclopropanation reaction turned out to be ligand-
accelerated. Without ligand 9, the reaction proceeded very
slowly in toluene at 25 °C, and only 7% of 3a was obtained
after 18 h (entry 1, Table 4). In sharp contrast, the use of
only0.1equivof ligand 9 relativetoHg(OTf)2 dramatically
improved the reactivity, and product 3a was obtained in
74% yield with 83% ee (entry 2). This result confirmed that
the property of Hg(II) could be modulated by using diphos-
phine ligands, which offers the promise to develop more
powerful chiral mercury catalysts. Currently, the reaction
mechanism is under investigation.
Figure 2
In conclusion, we have discovered that Hg(II) could
catalyze the cyclopropanation of diazo reagents and al-
kenes, which rebounds to the first highly diastereo- and
enantioselective synthesis of spirocyclopropyl oxindoles
from diazooxindoles and alkenes. We also proved that
the catalytic properties of Hg(II) could be readily modu-
lated by variation of ligands and counteranions. Consider-
ing the high efficiency that Hg(II) exhibited in this useful
reaction, we believe that mercury compounds might find
more applications in asymmetric catalysis.18,19
Acknowledgment. We acknowledge financial support
from the NSFC (21172075, 21222204), 973 program
(2011CB808600), and Innovation Program of SMEC
(12ZZ046).
Although the chiral catalytic species was under investi-
gation, the high dr observed in this Hg(II)-catalyzed reac-
tion could be rationalized by the general model, proposed
Supporting Information Available. Experimental pro-
1
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(17) Leyva-Perez, A.; Corma, A. Angew. Chem., Int. Ed. 2012, 51, 614.
cedures and characterizations, copies of H NMR and
(18) For recent examples on mercury catalysis, see: (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) Andrews, L.; Wang, X. F.; Gong, Y.;
13C NMR of new compounds, and HPLC profiles. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(19) Caution: Special care should be taken when using mercury salts
and disposing of the waste containing mercury due to the toxicity of
mercury salts.
€
Schloder, T.; Riedel, S.; Franger, M. J. Angew. Chem., Int. Ed. 2012, 51,
8235. (g) Namba, K.; Kanaki, M.; Suto, H.; Nishizawa, M.; Tanino, K.
Org. Lett. 2012, 14, 1222. For a review, see: (h) Nishizawa, M.; Imagawa,
H.; Yamamoto, H. Org. Biomol. Chem. 2010, 8, 511.
The authors declare no competing financial interest.
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