Synthesis of pyrazolo[5,1-a]isoquinolines via silver(i)-rhodium(i) cooperative catalysis in the reaction of N′-(2-alkynylbenzylidene) hydrazide with cycloprop-2-ene-1,1-dicarboxylate

Article abstract of DOI:10.1039/c2ob26824h

A tandem reaction between N′-(2-alkynylbenzylidene)hydrazide and cycloprop-2-ene-1,1-dicarboxylate co-catalyzed by silver triflate and tris(triphenylphosphine)rhodium chloride is reported. The reaction proceeds through 6-endo-cyclization, [3 + 2] cycloaddition, cyclopropane opening, and aromatization, leading to pyrazolo[5,1-a]isoquinolines in moderate to good yields.

Full text of DOI:10.1039/c2ob26824h

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Cite this: Org. Biomol. Chem., 2012, 10, 9447
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PAPER
Synthesis of pyrazolo[5,1-a]isoquinolines via silver(I)–rhodium(I) cooperative
catalysis in the reaction of N′-(2-alkynylbenzylidene)hydrazide with
cycloprop-2-ene-1,1-dicarboxylate†
Liangqing Yao,*a Xingxin Yu,b Chen Moa and Jie Wu*b
Received 27th June 2012, Accepted 11th October 2012
DOI: 10.1039/c2ob26824h
A tandem reaction between N′-(2-alkynylbenzylidene)hydrazide and cycloprop-2-ene-1,1-dicarboxylate
co-catalyzed by silver triflate and tris(triphenylphosphine)rhodium chloride is reported. The reaction
proceeds through 6-endo-cyclization, [3 + 2] cycloaddition, cyclopropane opening, and aromatization,
leading to pyrazolo[5,1-a]isoquinolines in moderate to good yields.
been demonstrated to be a versatile synthetic building block due
1. Introduction
to its inherent ring strain,7 and its special reactivity has been dis-
closed.8,9 For instance, an intermolecular N-heterocyclic carbene
Currently, the collection of small molecules embedded with pri-
vileged substructures is of the utmost urgency and importance in
the drug discovery process and for the studies of chemical
biology.1 Therefore, continuous efforts have been dedicated to
the pursuit of practical and efficient approaches for the rapid
access to such molecules.2 As a privileged substructure, the iso-
quinoline core is an attractive moiety which can be found widely
in natural products and biologically active pharmaceuticals.3
Recently, we were involved in the method development for the
construction of pyrazolo[5,1-a]isoquinoline derivatives using
tandem reactions.4 The subsequent biological evaluations
revealed several hits for the inhibition of cervical carcinoma.
Because of these results and of the necessity to find more active
compounds, the generation of diverse pyrazolo[5,1-a]isoquino-
lines is in high demand. Therefore, we initiated a method devel-
opment program for the construction of these polycyclic
isoquinolines and their related libraries.
Although several methods have been reported for the gener-
ation of pyrazolo[5,1-a]isoquinolines,5,6 starting from N′-(2-
alkynylbenzylidene)hydrazides would be a convenient and facile
route. N′-(2-Alkynylbenzylidene)hydrazides could be easily
accessible via condensation of 2-alkynylbenzaldehydes with
hydrazines. In the presence of silver triflate, isoquinolinium-2-yl
amide would be formed in quantitative yield via 6-endo cycliza-
tion of N′-(2-alkynylbenzylidene)hydrazide.6 Cyclopropene has
(NHC) catalyzed hydroacylation of cyclopropenes under mild
conditions could be achieved.9c Additionally, functional cyclo-
propenes could be easily available from simple starting
materials.10 Encouraged by these results, we envisioned that the
tandem reaction of N′-(2-alkynylbenzylidene)hydrazide with
cyclopropene might happen, which would afford the correspond-
ing pyrazolo[5,1-a]isoquinolines.
2. Results and discussion
To construct this interesting molecular framework via a tandem
process, we aimed to search for the optimal conditions first. A
model reaction of N′-(2-alkynylbenzylidene)hydrazide 1a with
dimethyl cycloprop-2-ene-1,1-dicarboxylate 2a was performed
in the presence of 10 mol% of silver triflate (Table 1). No
desired product was detected in THF at 60 °C, and the reaction
stopped at the formation of isoquinolinium-2-yl amide (Table 1,
entry 1). Since the efficiency of cooperative catalysis has been
demonstrated11 and the [3 + 2] cycloaddition of cycloprop-2-
ene-1,1-dicarboxylate could be promoted by a metal catalyst,
different metal catalysts were screened. No reaction occurred
when 5 mol% of nickel perchlorate was added (Table 1, entry 2).
To our delight, pyrazolo[5,1-a]isoquinoline 3a was obtained in
15% yield when copper(II) triflate was used as the additive
(Table 1, entry 3). A higher yield was obtained when RuCl3 was
used as a replacement additive (Table 1, entry 4). These results
were improved dramatically when Fe(acac)3 was added to the
reaction (55% yield, Table 1, entry 5). Interestingly, the corres-
ponding product 3a was isolated and obtained in 61% yield in
the presence of tris(triphenylphosphine)rhodium chloride as the
co-catalyst (Table 1, entry 7). With this promising result in hand,
we screened other solvents. It was found that the reaction
aObstetrics and Gynecology Hospital, Fudan University, 419 Fangxie
Road, Shanghai 200011, China. E-mail: yaoliangqingcn@126.com
bDepartment of Chemistry, Fudan University, 220 Handan Road,
Shanghai 200433, China. E-mail: jie_wu@fudan.edu.cn;
Fax: +86 21 6564 1740; Tel: +86 21 6510 2412
†Electronic supplementary information (ESI) available: Experimental
procedure, characterization data, 1H and 13C NMR spectra of compounds
3. CCDC 901570 (3c). For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c2ob26824h
This journal is © The Royal Society of Chemistry 2012
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Table 1 Initial studies for the tandem reaction of N′-(2-alkynyl-
benzylidene)hydrazide 1a with cycloprop-2-ene-1,1-dicarboxylate 2a
Table 2 Synthesis of pyrazolo[5,1-a]isoquinolines 3 via the
tandem reaction of N′-(2-alkynylbenzylidene)hydrazides 1 with
cycloprop-2-ene-1,1-dicarboxylate 2a
Entry
[M]
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
—
THF
THF
THF
THF
THF
THF
THF
THF
EtOH
DMF
MeCN
DCE
Toluene
1,4-Dioxane
1,4-Dioxane–THF
nr
nr
Ni(ClO4)2
Cu(OTf)2
RuCl3
Fe(acac)3
RhCl3
RhCl(PPh3)3
Co(acac)3
RhCl(PPh3)3
RhCl(PPh3)3
RhCl(PPh3)3
RhCl(PPh3)3
RhCl(PPh3)3
RhCl(PPh3)3
RhCl(PPh3)3
15
27
55
20
61
51
20
28
41
47
52
57
66
9
10
11
12
13
14
15
a Reaction
conditions:
N′-(2-alkynylbenzylidene)hydrazide
1a
(0.5 mmol), dimethyl cycloprop-2-ene-1,1-dicarboxylate 2a (1.2 equiv.),
AgOTf (10 mol%), [M] (10 mol%), solvent (2.0 mL), 60 °C. b Isolated
yield based on N′-(2-alkynylbenzylidene)hydrazide 1a.
performed in 1,4-dioxane provided a similar yield (57%,
Table 1, entry 14). The yield increased to 66% when a mixed
solvent (1,4-dioxane–THF) was used (Table 1, entry 15). No
better yields were observed when the amount of silver triflate or
tris(triphenylphosphine)rhodium chloride was changed (data not
shown in Table 1). The reaction time increased at a lower temp-
erature. The addition of base did not improve the final outcome.
For example, pyrazolo[5,1-a]isoquinoline 3a could not be
detected when DABCO, Et3N, K2CO3, or Cs2CO3 were added in
the reaction. The product was obtained in 28% yield when
potassium acetate was present.
a Isolated yield based on N′-(2-alkynylbenzylidene)hydrazide 1.
Under the above optimized conditions (10 mol% of AgOTf,
10 mol% of RhCl(PPh3)3, 1,4-dioxane–THF, 60 °C), the scope
and generality of this tandem reaction of N′-(2-alkynylbenzyli-
dene)hydrazides 1 with cycloprop-2-ene-1,1-dicarboxylate 2
were then explored. The results are presented in Table 2. We
found that the reaction worked well for a range of N′-(2-alkynyl-
benzylidene)hydrazides 1. Different substituents attached to the
triple bond of N′-(2-alkynylbenzylidene)hydrazides 1 were all
compatible. For instance, compound 3c was afforded in 80%
yield when N′-(2-alkynylbenzylidene)hydrazide 1c with
a
4-methoxyphenyl group attached at the R2 position was used.
The structure of pyrazolo[5,1-a]isoquinoline 3c was confirmed
by X-ray diffraction analysis (Fig. 1). The reaction afforded pyrazolo-
[5,1-a]isoquinoline 3d in 78% yield when a cyclopropyl group
was located at the R2 position. Notably, the reaction worked
efficiently when N′-(2-ethynylbenzylidene)hydrazide was used
as the substrate, leading to the desired product 3e in 60% yield.
Reactions of dimethyl cycloprop-2-ene-1,1-dicarboxylate 2a
Fig. 1 X-ray ORTEP illustration of pyrazolo[5,1-a]isoquinoline 3c
(30% probability ellipsoids).
substituents on the aromatic ring were subsequently investigated.
As expected, all reactions proceeded smoothly to give the
with N′-(2-alkynylbenzylidene)hydrazides
1 with different
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corresponding products. To our surprise, the reaction failed when
substituted cycloprop-2-ene-1,1-dicarboxylate 2b was employed
in the transformation. This might be due to steric hindrance
during the [3 + 2] cycloaddition process (Scheme 1).
3. Conclusion
In conclusion, we have described a novel route for the prep-
aration of pyrazolo[5,1-a]isoquinolines via silver(I)–rhodium(I)
cooperative catalysis in the reaction of N′-(2-alkynylbenzylidene)
hydrazide with cycloprop-2-ene-1,1-dicarboxylate. The tandem
reaction proceeds with the formation of three bonds through
6-endo-cyclization, [3 + 2] cycloaddition, cyclopropane ring
opening, and aromatization. Construction of libraries of such
small molecules and exploration of the reactivity of cycloprop-2-
ene-1,1-dicarboxylates in other transformations are currently
ongoing in our laboratory.
A possible mechanism is presented in Scheme 2. We envi-
sioned that the 6-endo cyclization of N′-(2-alkynylbenzylidene)
hydrazide 1 would occur first in the presence of a catalytic
amount of silver triflate, leading to isoquinolinium-2-yl amide A.
Then a [3 + 2] cycloaddition between isoquinolinium-2-yl amide
A and dimethyl cycloprop-2-ene-1,1-dicarboxylate 2a would
take place under standard conditions,12 giving rise to the poly-
cyclic intermediate B. The subsequent release of the tosyl group
and ring opening of the cyclopropane would afford intermediate
E, which would then undergo aromatization to produce pyrazolo-
[5,1-a]isoquinoline 3.
Experimental section
General procedure for the synthesis of pyrazolo[5,1-a]isoquino-
lines via a tandem reaction of N′-(2-alkynylbenzylidene)hydra-
zides 1 with cycloprop-2-ene-1,1-dicarboxylate 2: a mixture of
N′-(2-alkynylbenzylidene)hydrazide 1 (0.5 mmol) and AgOTf
(7.7 mg, 10 mol%) in 1,4-dioxane (2.0 mL) was heated at 60 °C
with vigorous stirring for 1 h. Then, RhCl(PPh3)3 (27.7 mg,
10 mol%) and dimethyl cycloprop-2-ene-1,1-dicarboxylate 2
(0.36 mmol) and THF (2.0 mL) were added. The reaction
mixture was stirred vigorously at 60 °C overnight until com-
pletion of the reaction. The reaction mixture was diluted with
ethyl acetate (5.0 mL), and quenched with water (5.0 mL). The
organic layer was washed with brine, dried over Na2SO4 and
concentrated under reduced pressure. The residue was purified
by flash column chromatography on silica gel to provide the
desired product 3.
Scheme 1 Reactions of N′-(2-alkynylbenzylidene)hydrazides 1 with
2-phenyl cycloprop-2-ene-1,1-dicarboxylate 2b.
Dimethyl 2-(5-phenylpyrazolo[5,1-a]isoquinolin-1-yl)malonate
3a
White solid; melting point: 118.2–119.9 °C; 1H NMR
(400 MHz, CDCl3): 3.81 (s, 6H), 5.47 (s, 1H), 7.05 (s, 1H),
7.50–7.58 (m, 5H), 7.76 (d, J = 6.9 Hz, 1H), 7.81 (d, J =
6.9 Hz, 2H), 8.11 (s, 1H), 8.22 (d, J = 7.3 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 49.7, 53.2, 106.3, 113.3, 123.0, 124.2,
127.5, 127.7, 128.1, 128.4, 129.4, 129.5, 130.1, 133.7, 135.8,
138.7, 141.6, 168.5; HRMS calcd for C22H19N2O4: (M + H+)
375.1339, found: 375.1342.
Dimethyl 2-(5-(4-fluorophenyl)pyrazolo[5,1-a]isoquinolin-1-yl)-
malonate 3b
White solid; melting point: 135.1–136.4 °C; 1H NMR
(400 MHz, CDCl3): 3.81 (s, 6H), 5.47 (s, 1H), 7.02 (s, 1H), 7.20
(t, J = 8.2 Hz, 2H), 7.57–7.62 (m, 2H), 7.75 (d, J = 7.3 Hz, 1H),
7.81–7.84 (m, 2H), 8.11 (s, 1H), 8.22 (d, J = 7.3 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 49.7, 53.2, 106.4, 113.2, 115.5 (d,
2JCF = 22 Hz), 123.0, 124.2, 127.7, 128.2, 129.7, 130.0, 131.6
3
1
(d, JCF = 9 Hz), 135.8, 137.6, 141.7, 163.4 (d, JCF = 248 Hz),
168.4; HRMS calcd for C22H18FN2O4: (M + H+) 393.1245,
found: 393.1243.
Scheme 2 A possible mechanism for the generation of pyrazolo[5,1-a]-
isoquinoline.
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Dimethyl 2-(5-(4-methoxyphenyl)pyrazolo[5,1-a]isoquinolin-1-
Dimethyl 2-(9-fluoro-5-phenylpyrazolo[5,1-a]isoquinolin-1-yl)-
yl)malonate 3c
malonate 3h
White solid; melting point: 142.6–143.3 °C; 1H NMR
(400 MHz, CDCl3): 3.80 (s, 6H), 3.84 (s, 3H), 5.47 (s, 1H),
6.98–7.02 (m, 3H), 7.49–7.56 (m, 2H), 7.70 (d, J = 6.9 Hz, 1H),
7.76 (d, J = 7.8 Hz, 2H), 8.12 (s, 1H), 8.19 (d, J = 7.3 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 49.7, 53.2, 55.4, 106.2, 112.6,
113.8, 122.9, 123.9, 126.0, 127.3, 127.5, 128.0, 130.2, 130.9,
135.8, 138.4, 141.5, 160.4, 168.5; HRMS calcd for
C23H21N2O5: (M + H+) 405.1445, found: 405.1433.
White solid; melting point: 129.3–130.3 °C; 1H NMR
(400 MHz, CDCl3): 3.83 (s, 6H), 5.38 (s, 1H), 7.02 (s, 1H),
7.29–7.33 (m, 1H), 7.46–7.53 (m, 3H), 7.72–7.81 (m, 3H),
7.89–7.91 (m, 1H), 8.14 (s, 1H); 13C NMR (100 MHz, CDCl3) δ
2
2
49.5, 53.3, 106.8, 108.8 (d, JCF = 24 Hz), 112.6, 116.8 (d, JCF
3
= 24 Hz), 125.2 (d, JCF = 10 Hz), 126.7, 128.5, 129.5, 129.8
3
(d, JCF = 9 Hz), 133.5, 135.1, 135.2, 138.1, 141.8, 161.6 (d,
1JCF = 247 Hz), 168.3; HRMS calcd for C22H18FN2O4:
(M + H+) 393.1245, found: 393.1233.
Dimethyl 2-(5-cyclopropylpyrazolo[5,1-a]isoquinolin-1-yl)-
malonate 3d
Dimethyl 2-(5-cyclopropyl-9-fluoropyrazolo[5,1-a]isoquinolin-1-
yl)malonate 3i
Colourless oil; 1H NMR (400 MHz, CDCl3): 0.87–0.90 (m, 2H),
1.15–1.20 (m, 2H), 2.64–2.69 (m, 1H), 3.80 (s, 6H), 5.46 (s,
1H), 6.68 (s, 1H), 7.50–7.52 (m, 2H), 7.64–7.66 (m, 1H),
8.16–8.18 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 7.0, 11.5,
49.7, 53.1, 106.2, 107.6, 122.8, 123.4, 126.8, 127.0, 127.8,
130.1, 135.3, 140.9, 141.4, 168.5; HRMS calcd for
C19H19N2O4: (M + H+) 339.1339, found: 339.1332.
White solid; melting point: 120.9–122.1 °C; 1H NMR
(400 MHz, CDCl3): 0.86–0.91 (m, 2H), 1.16–1.21 (m, 2H),
2.61–2.68 (m, 1H), 3.82 (s, 6H), 5.36 (s, 1H), 6.67 (s, 1H),
7.24–7.28 (m, 1H), 7.62–7.66 (m, 1H), 7.84–7.86 (m, 1H), 8.20
(s, 1H); 13C NMR (100 MHz, CDCl3) δ 6.9, 11.5, 49.4, 53.2,
2
2
106.6, 107.2, 108.6 (d, JCF = 24 Hz), 116.5 (d, JCF = 23 Hz),
3
3
124.3 (d, JCF = 9 Hz), 126.6, 129.1 (d, JCF = 9 Hz), 134.7,
1
140.3, 141.5, 161.2 (d, JCF = 245 Hz), 168.3; HRMS calcd for
C19H18FN2O4: (M + H+) 357.1245, found: 357.1231.
Dimethyl 2-(pyrazolo[5,1-a]isoquinolin-1-yl)malonate 3e
White solid; melting point: 103.8–105.1 °C; 1H NMR
(400 MHz, CDCl3): 3.81 (s, 6H), 5.42 (s, 1H), 6.99 (d, J =
7.3 Hz, 1H), 7.55–7.61 (m, 2H), 7.72 (d, J = 7.3 Hz, 1H), 8.12
(s, 1H), 8.17–8.23 (m, 2H); 13C NMR (100 MHz, CDCl3) δ
49.6, 53.2, 105.9, 112.7, 123.2, 124.7, 126.7, 127.7, 127.8,
128.0, 129.8, 134.9, 142.0, 168.4; HRMS calcd for
C16H15N2O4: (M + H+) 299.1026, found: 299.1025.
Dimethyl 2-(5-butyl-9-fluoropyrazolo[5,1-a]isoquinolin-1-yl)-
malonate 3j
White solid; melting point: 106.1–107.5 °C; 1H NMR
(400 MHz, CDCl3): 0.98–1.01 (m, 3H), 1.48–1.53 (m, 2H),
1.81–1.87 (m, 2H), 3.13–3.17 (m, 2H), 3.82 (s, 6H), 5.36 (s,
1H), 6.83 (s, 1H), 7.26–7.30 (m, 1H), 7.65–7.69 (m, 1H),
7.83–7.86 (m, 1H), 8.15 (s, 1H); 13C NMR (100 MHz, CDCl3) δ
2
14.0, 22.6, 28.9, 30.7, 49.4, 53.2, 106.5, 108.5 (d, JCF
=
Dimethyl 2-(5-cyclopropyl-8-fluoropyrazolo[5,1-a]isoquinolin-1-
yl)malonate 3f
2
3
24 Hz), 109.6, 116.5 (d, JCF = 23 Hz), 124.6 (d, JCF = 9 Hz),
3
126.6, 129.0 (d, JCF = 9 Hz), 134.7, 139.0, 141.3, 161.1 (d,
1JCF = 245 Hz), 168.3; HRMS calcd for C20H22FN2O4:
1
White solid; melting point: 88.5–89.5 °C; H NMR (400 MHz,
(M + H+) 373.1558, found: 373.1576.
CDCl3): 0.88–0.92 (m, 2H), 1.17–1.22 (m, 2H), 2.65–2.70 (m,
1H), 3.81 (s, 6H), 5.37 (s, 1H), 6.60 (s, 1H), 7.24–7.30 (m, 2H),
8.16–8.18 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 7.2, 11.5,
Dimethyl 2-(9-methyl-5-phenylpyrazolo[5,1-a]isoquinolin-1-yl)-
malonate 3k
2
2
49.6, 53.2, 105.8, 106.8, 111.8 (d, JCF = 21 Hz), 115.3 (d, JCF
= 23 Hz), 120.1, 125.3 (d, 3JCF = 9 Hz), 132.1 (d, JCF = 9 Hz),
3
1
1
135.1, 141.7, 142.2, 161.8 (d, JCF = 247 Hz), 168.4; HRMS
Colorless oil; H NMR (400 MHz, CDCl3): 2.55 (s, 3H), 3.81
calcd for C19H18FN2O4: (M + H+) 357.1245, found: 357.1237.
(s, 6H), 5.49 (s, 1H), 7.00 (s, 1H), 7.38 (d, J = 7.8 Hz, 1H),
7.48–7.50 (m, 3H), 7.63 (d, J = 8.3 Hz, 1H), 7.81 (d, J =
6.9 Hz, 2H), 8.00 (s, 1H), 8.09 (s, 1H); 13C NMR (100 MHz,
CDCl3) δ 22.1, 49.9, 53.1, 106.1, 113.2, 122.8, 124.3, 127.5,
127.9, 128.4, 129.3, 129.5, 129.6, 133.9, 135.6, 137.5, 137.9,
141.5, 168.5; HRMS calcd for C23H21N2O4: (M + H+)
389.1496, found: 389.1490.
Dimethyl 2-(5-butyl-8-fluoropyrazolo[5,1-a]isoquinolin-1-yl)-
malonate 3g
1
White solid; melting point: 69.9–71.3 °C; H NMR (400 MHz,
CDCl3): 0.97–1.01 (m, 3H), 1.48–1.53 (m, 2H), 1.77–1.89 (m,
2H), 3.13–3.17 (m, 2H), 3.81 (s, 6H), 5.37 (s, 1H), 6.78 (s, 1H),
7.23–7.33 (m, 2H), 8.14–8.19 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 13.9, 22.6, 28.9, 30.8, 49.7, 53.2, 105.6, 109.5, 111.7
(d, 2JCF = 22 Hz), 115.2 (d, 2JCF = 23 Hz), 120.3, 125.3 (d, 3JCF
Dimethyl 2-(5-cyclopropyl-9-methylpyrazolo[5,1-a]isoquinolin-1-
yl)malonate 3l
3
= 9 Hz), 132.1 (d, JCF = 9 Hz), 135.1, 140.9, 141.5, 161.8 (d,
White solid; melting point: 125.0–126.6 °C; 1H NMR
(400 MHz, CDCl3): 0.86–0.90 (m, 2H), 1.13–1.19 (m, 2H),
2.60–2.68 (m, 1H), 3.77 (s, 3H), 3.81 (s, 6H), 5.47 (s, 1H), 6.65
1JCF = 247 Hz), 168.4; HRMS calcd for C20H22FN2O4:
(M + H+) 373.1558, found: 373.1545.
9450 | Org. Biomol. Chem., 2012, 10, 9447–9451
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K. Oum and T. Lenzer, Chem.–Eur. J., 2011, 17, 8452; (l) J. Panteleev,
L. Zhang and M. Lautens, Angew. Chem., Int. Ed., 2011, 50, 9089;
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(s, 1H), 7.33 (d, J = 7.8 Hz, 1H), 7.54 (d, J = 7.8 Hz, 1H), 7.95
(s, 1H), 8.16 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 6.8, 11.5,
22.0, 49.8, 53.1, 106.0, 107.6, 122.7, 123.6, 126.9, 127.8,
129.4, 135.2, 136.7, 140.0, 141.2, 168.6; HRMS calcd for
C20H21N2O4: (M + H+) 353.1496, found: 353.1487.
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Acknowledgements
Financial support from the National Natural Science Foundation
of China (Nos. 21032007, 21172038) is gratefully
acknowledged.
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