PEG-mediated catalyst-free expeditious synthesis of 2-substituted benzimidazoles and bis-benzimidazoles under solvent-less conditions

Article abstract of DOI:10.1016/j.tetlet.2008.08.041

A wide variety of 2-substituted benzimidazoles and bis-benzimidazoles were synthesized in high yields by PEG-mediated catalyst-free synthesis under solvent-less conditions. The products were directly recrystallized from hot methanol. The reaction occurred giving excellent yields with low as well as high molecular weight PEGs.

Full text of DOI:10.1016/j.tetlet.2008.08.041

Tetrahedron Letters 49 (2008) 6237–6240
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
PEG-mediated catalyst-free expeditious synthesis of 2-substituted
benzimidazoles and bis-benzimidazoles under solvent-less conditions
*
Chhanda Mukhopadhyay , Pradip Kumar Tapaswi
Department of Chemistry, University of Calcutta, 92, APC Road, Kolkata 700009, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A wide variety of 2-substituted benzimidazoles and bis-benzimidazoles were synthesized in high yields
by PEG-mediated catalyst-free synthesis under solvent-less conditions. The products were directly
recrystallized from hot methanol. The reaction occurred giving excellent yields with low as well as high
molecular weight PEGs.
Received 23 June 2008
Revised 7 August 2008
Accepted 11 August 2008
Available online 14 August 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Aldehydes
ortho-Phenylenediamines
Polyethylene glycol
Catalyst-free
Solvent-less conditions
2-Substituted benzimidazoles
Bis-benzimidazoles
1. Introduction
Since organic synthesis in PEG under solvent-less conditions is
an area of very high significance in modern organic synthe-
Over the past few decades, environmentally benign chemical
processes have gained considerable interest both in the academia
and in industry.1 Volatile, toxic and hazardous organic solvents
are continuously being replaced either by the use of solvent-free
techniques,2 or by using ionic liquids,3 water4a or phase-transfer
catalysts.4b The application of PEG as a reaction medium is highly
beneficial as the system remains neutral, which helps in maintain-
ing a wide variety of functional groups unchanged that are either
acid or base susceptible.
sis,4b,14,15 we examined the synthesis of benzimidazoles in PEG
400. PEG is inexpensive, non-toxic, possesses high thermal stabil-
ity, is recyclable and helps in maintaining a neutral reaction
medium.
In order to standardize the reaction, 4-chlorobenzaldehyde
(4 mmol) and 1,2-phenylenediamine (4.5 mmol) were heated in
an oil-bath at 110 °C for 4 h without any catalyst but with PEG
400 (0.1 mL) (Scheme 1, Table 1). On cooling to room temperature
(25 °C), the reaction mixture solidified, and the final product was
recrystallized directly from hot methanol without any need for fur-
ther purification. The results of the study of this standard reaction
for its optimization are summarized in Table 1. We find that the
reaction proceeded best under solvent-less conditions rather than
using solvents. The best result was obtained with 0.1 mL of PEG
400 for 4 mmol of 4-chlorobenzaldehyde under solvent-free condi-
tions (Table 1, entry 4). Using more than 0.1 mL of PEG 400 did not
improve the yield of the product, and at the same time, no reaction
took place in the absence of PEG 400. Thus, the use of PEG is abso-
lutely essential in this reaction. Since only 0.1 mL of PEG 400 is
used it cannot act as a solvent, thus it is the promoter for the reac-
tion without requiring any additional acid catalyst. No formation of
benzimidazole took place under argon atmosphere (the reaction
stopping at the imine stage) indicating that the aerial oxygen is
absolutely necessary for the oxidation step. We investigated our
protocol with various PEGs with molecular weights 200, 400,
4000, 6000 and 9000 (0.01 mol % each) for our model reaction with
2. Results and discussion
In continuation of our efforts in searching for newer synthetic
methodologies for biologically important heterocycles,5,6,7a,b we
chose 2-substituted benzimidazoles as targets. Benzimidazoles
are present in various bioactive compounds possessing antiviral,
antihypertension and anticancer properties.8,9 Compounds pos-
sessing the benzimidazole moiety express significant activity
against several viruses such as HIV,10 Herpes (HSV-1),11 human
cytomegalovirus (HCMV)10 and influenza.12 Bis-benzimidazoles
are DNA-minor grove binding agents possessing anti-tumour
activity.13
* Corresponding author. Tel.: +91 33 23371104; fax: +91 33 23519755.
E-mail addresses: csm@vsnl.net, cmukhop@yahoo.co.in (C. Mukhopadhyay).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.08.041

6238
C. Mukhopadhyay, P. K. Tapaswi / Tetrahedron Letters 49 (2008) 6237–6240
R1
R1
R2
3
N
R2
4
NH2
PEG-400 (0.1 mL)
no catalyst
5
6
2
+
R5-CHO
R5
solvent-free conditions
110 oC
1
N
R3
NH2
R3
7
1
R5 = R4-C6H4 (2)
R5= alkyl (4)
H
R5 = R4-C6H4 (3)
R5= alkyl (5)
(For various R1, R2, R3, R4 and R5 refer to Tables 2A and 2B)
Scheme 1.
Table 1
Table 2A
Synthesis of 2-(40-chlorophenyl)-benzimidazole under various conditions (entry 4
gives the optimum conditions)
Synthesis of 2-aryl-substituted benzimidazoles with PEG 400 (0.1 mL) under solvent-
less conditions in an oil-bath at 110 °C
Entry PEG 400 Solvent (mL)
(mL)
Reaction medium
temperature
Time
(hours)
Yield (%)
(isolated)
Entry
Product 3 (from 2)
Time
(hours)
Yielda
(%)
References
R1
R2
R3
R4
1
2
3
4
5
6
7
8
9
—
—
—
—
—
—
—
—
110 °C
99 °C
20
20
15
4
4
4
20
20
20
20
20
50–55
—
1
2
3
4
5
6
7
8
9
H
H
H
H
H
H
Me
Me
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
4-OH
2-OMe
4-CN
4-Cl
3-OH
H
4-CN
2-OH
3-OMe-4-OH
4-OH
3,4-(OMe)2
2-OMe
3-NO2
4-NMe2
2-Cl
2-OH
4-CN
2,5-(OMe)2
4-CN
2-OMe
2-OH
R4-C6H4@2-furanyl
4-Cl
4-Br
2,5-(OMe)2
3-Br
3,4-(OMe)2
3-NO2
4-Cl
2,5-(OMe)2
4-CN
3,4-(OMe)2
3-OMe-4-OH
R4-C6H4@2-furanyl
6
7
5
8
4
9
6
8
7
7
8
5
6
4
6
8
8
9
4
9
7
7
8
4
3
5
2
5
4
4
5
9
7
8
6
90
92
92
90
95
87
89
93
92
94
88
86
88
91
90
93
92
95
89
86
87
91
93
92
87
88
87
89
90
87
83
82
85
87
93
16
17
18
19
16
20
21
22
23
24
24
24
25
26
24
26
26
25
—
27
—
28
29
—
—
—
—
—
0.05
0.05
0.1
0.2
0.4
0.1
0.1
0.1
0.1
0.1
—
35
50
95
90
80
35
30
42
38
40
—
110 °C
110 °C
110 °C
110 °C
99 °C
Reflux
Reflux
Reflux
Reflux
Reflux
EtOH (5)
DMF (5)
THF (5)
CH3CN (5)
Any above
solvent (5)
—
H
10
11
12
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Cl
13
0.1
Microwave oven
110 °C, 600 W
1
70
H
H
H
4-chlorobenzaldehyde (4 mmol) and 1,2-phenylenediamine
(4.5 mmol). The reaction occurred giving excellent yields of
the product (95–88%) with low as well as high molecular weight
PEGs.
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Cl
Cl
Cl
Cl
Cl
Cl
With the above result in hand, a variety of aldehydes, aliphatic
4, heterocyclic and aromatic 2, possessing both electron-donating
and electron-withdrawing groups were employed for benzimid-
azole formation and in all the cases, the yields were excellent
(Scheme 1, Table 2A and B). Five different ortho-phenylenediam-
ines 1 were employed and all of them reacted smoothly under
the reaction conditions. All the known products were characterized
by comparing their physical and spectral (IR, 1H NMR and 13C
NMR) data with those of the authentic samples reported in the lit-
erature. The data for the selected previously unknown compounds
(Table 2A, entries 19, 21 and 32 and Table 3, entry 6) are reported
in this Letter. The data for all other previously unknown com-
pounds are given in the Supplementary data.
—
—
—
—
—
—
—
Cl
Cl
Cl
Cl
Cl
a
Isolated yields.
The mechanism of the benzimidazole formation is well docu-
mented.26 The initial formation is of the imine normally with trans
stereochemistry.26 The imine 6 obtained from the reaction of 4,5-
dichloro-1,2-phenylenediamine and 4-cyanobenzaldehyde was
isolated, purified and characterized. The imine then cyclizes,
followed by oxidation and dehydration to form the final product
(Table 2A, entry 32).
Encouraged by the above results, we turned our attention to the
synthesis of the bis-benzimidazoles starting from benzene dialde-
hydes. For this purpose, two benzene dialdehydes 1, 4 (7) and 1, 3
(9) were chosen, and applying our methodology at 140 °C in an
oil-bath, the bis-benzimidazoles were synthesized (Scheme 2) in
excellent yields, as summarized in Table 3.
On directly comparing our methodology with some very recent
solvent-free techniques for the benzimidazole formation25,36–39 (i)
this methodology succeeded with a variety of substrates (17 new
compounds were synthesized), (ii) synthesis of benzimidazoles
from 4,5-dichloro-ortho-phenylenediamine produced a number of
previously unknown benzimidazoles (Table 2A, entries 30–35),
(iii) a catalyst is not required and (iv) the methodology is readily
applicable to the synthesis of bis-benzimidazoles.

C. Mukhopadhyay, P. K. Tapaswi / Tetrahedron Letters 49 (2008) 6237–6240
6239
3.1. 1-(40-Cyanophenyliminyl)-4,5-dichloroaniline (6)
Table 2B
Synthesis of 2-alkyl-substituted benzimidazoles with PEG 400 (0.1 mL) under
solvent-less conditions in an oil-bath at 110 °C
Mp 300–302 °C (EtOAc). IR (KBr): 3466, 3370, 2926, 2373, 2222,
Yielda (%)
(isolated)
References
1610, 1477, 1267, 1129, 957 and 831 cmꢀ1
.
1H NMR (300 MHz,
Entry
Product 5 (from 4)
Time
(hours)
R1
R2
R3
R5
0
CDCl3) d: 8.53 (s, 1H, –CH@N), 8.00 (d, J = 8.4 Hz, 2H, C3 –H and
0
0
0
C5 –H), 7.76 (d, J = 8.4 Hz, 2H, C2 –H and C6 –H), 7.24 (s, 1H, C6–
H), 6.87 (s, 1H, C3–H), 4.36 (br s, 2H, –NH2). 13C NMR (75 MHz,
CDCl3) d: 155.71 (–CH@N), 142.39 (C1), 139.57 (C2), 134.92 (C4
1
2
3
4
H
H
H
H
H
Me
Cl
H
Me
Cl
–CH3
–CH3
–CH2CH3
–CH2CH2CH3
5
6
6
6
75
79
77
74
30
31
32
33
Cl
Cl
0
0
0
0
0
and C5), 132.59 (C3 and C5 ), 131.97 (C1 ), 129.06 (C2 and C6 ),
120.96 (CN), 118.33 (C6), 116.37 (C3), 114.62 (C4 ). Anal. Calcd for
a
0
Isolated yields.
C14H9N3Cl2; C: 57.95, H: 3.13, N: 14.48%. Found: C: 58.09, H:
3.03, N: 14.56%.
Table 3
Synthesis of bis-benzimidazoles with PEG 400 (0.1 mL) in an oil-bath at 140 °C
3.2. 2-(20,50-Dimethoxyphenyl)-5-methyl-1H-benzimidazole
(Table 2A, entry 19)
Entry Starting aldehyde Product (8 from 7, Time
Yielda (%) References
(Scheme 2)
10 from 9)
(hours)
R1
R2
R3
Mp 170–172 °C (EtOAc). IR (KBr): 3227, 2932, 1612, 1489, 1433,
1212, 1041, 807 and 736 cmꢀ1
.
1H NMR (300 MHz, CDCl3) d: 10.67
1
2
3
4
5
6
7
7
9
9
9
9
H
H
H
H
H
H
H
Me
H
Me
Me
Cl
H
H
H
Me
H
7
8
8
9
6
8
85
87
83
80
86
68
26
26
34
—
35
—
0
(br s, 1H, –NH), 8.10 (d, J = 1.5 Hz, 1H, C6 –H), 7.78–7.55 (br d, 1H,
C7–H), 7.43–7.28 (br d, 1H, C4–H), 7.09 (d, J = 8.1 Hz, 1H, C6–H),
0
0
0
7.02–6.90 (m, 2H, C3 –H and C4 –H), 4.01 (s, 3H, C2 –OCH3), 3.88
(s, 3H, C5 –OCH3), 2.49 (s, 3H, –CH3). 13C NMR (75 MHz, CDCl3) d:
0
Cl
0
0
154.22 (C2 and C5 ), 151.12 (C2), 149.70 (C3a and C7a), 131.50
a
Isolated yields.
0
0
0
0
(C1 ), 124.10 (C6 ), 118.51 (C5), 117.99 (C3 and C4 ), 113.05 (C4),
0
0
112.98 (C6), 111.10 (C7), 56.41 (C2 -OMe), 55.98 (C5 -OMe), 21.71
(–CH3). Anal. Calcd for C16H16N2O2; C: 71.62, H: 6.01, N: 10.44%.
Found: C: 71.81, H: 6.23, N: 10.25%.
3. General experimental procedure for 2-substituted
benzimidazole formation
A mixture of an aldehyde (4 mmol), substituted ortho-phenyl-
enediamine (4.5 mmol) and PEG 400 (0.1 mL) were taken in a dry
round-bottomed flask (50 mL). The flask was placed in an oil-bath
at a temperature of 110 °C fitted with a condenser. The reaction
mixture was heated for the specified time (Tables 2A and B). The
reaction was monitored by TLC till the disappearance of the start-
ing aldehyde. On cooling to room temperature (25 °C), the reaction
mixture solidified, and product was directly recrystallized from hot
methanol to afford the pure benzimidazoles. The mother liquor
was concentrated further to obtain some more product, and thus
the total yield was calculated. For a 50 mmol-scale reaction with
4-chlorobenzaldehyde and 1,2-phenylenediamine, the mother
liquor after two precipitations was concentrated under vacuum
to obtain the PEG 400, which was washed with water, dried and
used further. In this manner, PEG 400 could be recycled up to 6
cycles.
3.3. 2-(20-Methoxyphenyl)-5,6-dimethyl-1H-benzimidazole
(Table 2A, entry 21)
Mp 214–216 °C (EtOAc). IR (KBr): 3258, 2931, 2371, 1585, 1468,
1443, 1384, 1312, 1243, 1023, 857 and 752 cmꢀ1 1H NMR
.
(300 MHz, CDCl3) d: 10.48 (br s, 1H, –NH), 8.55 (dd, J = 8.1 Hz
0
and 1.7 Hz, 1H, C6 –H), 7.37 (one dd and one d merged together,
0
0
J = 8.6 Hz and 1.8 Hz, 2H, C3 –H and C5 –H), 7.11 (two doublets
merged together as
a
triplet with a small meta coupling,
0
J = 7.5 Hz and 1.8 Hz, 1H, C4 –H), 7.03 and 7.00 (two singlets
merged together to form a doublet, 2H, C4–H and C7–H), 4.02 (s,
3H, OCH3), 2.37 [s, 6H, 2 ꢁ (–CH3)]. 13C NMR (75 MHz, CDCl3) d:
0
0
0
156.58 (C2 ), 149.01 (C2, C3a and C7a), 131.43 (C1 ), 130.72 (C6 ),
0
0
0
129.94 (C4 ), 121.62 (C3 and C5 ), 118.19 (C5 and C6), 111.39 (C4
and C7), 55.85 (OCH3), 20.38 [2 ꢁ (–CH3)]. Anal. Calcd for
C16H16N2O; C: 76.16, H: 6.39, N: 11.10%. Found: C: 76.29, H:
[For the synthesis of the bis-benzimidazoles, the dialdehyde
(4 mmol) was mixed with substituted 1,2-phenylenediamines
(9 mmol) and heated at 140 °C using the same methodology for
the benzimidazoles for the time period as mentioned in Table 3].
All the known compounds were characterized by comparing
their physical and spectral data with those of reported compounds.
The mps, IR, 1H NMR and 13C NMR data of the isolated imine 6 and
the unknown benzimidazoles (Table 2A, entries 19, 21 and 32) and
one bis-benzimidazole (Table 3, entry 6) are given below:
6.23, N: 11.31%.
3.4. 2-(40-Cyanophenyl)-5,6-dichloro-1H-benzimidazole (Table
2A, entry 32)
Mp >320 °C (MeOH). IR (KBr): 3294, 2232, 1610, 1440, 1414,
1291, 1100 and 846 cmꢀ1 1H NMR [300 MHz, (0.4 mL CDCl3 and
.
0.1 mL DMSO-d6)] d: 12.91 (br s, 1H, –NH), 8.30 (d, J = 8.4 Hz, 2H,
0
0
C3 –H and C5 –H), 7.90–7.73 [a br s (for C4–H) and a doublet
0
0
(J = 8.4 Hz for C2 –H and C6 –H) merged together, 3H], 7.61 (br s,
R1
R1
R2
R3
R1
R2
R3
PEG-400 ( 0.1 mL)
N
NH2
NH2
CHO
+
140 oC
R2
R3
1
4
N
1
2
N
H
solvent-free
conditions
4
3
N
H
3
OHC
7 ( 1, 4-di CHO)
9 (1,3-di-CHO)
1
8 (1,4-bis-benzimidazole)
10 (1,3-bis-benzimidazole)
Scheme 2.

6240
C. Mukhopadhyay, P. K. Tapaswi / Tetrahedron Letters 49 (2008) 6237–6240
1H, C7–H). 13C NMR [75 MHz, (0.4 mL CDCl3 and 0.1 mL DMSO-d6]
2. Tanaka, K. Solvent-Free Organic Synthesis; Wiley-VCH, 2003.
3. Green Reaction Media for Organic Synthesis, Wiley-VCH, 2003.
4. (a) Grieco, P. A. Organic Synthesis in Water; Blackie Academic and Professional:
London, 1998; (b) Vasudevan, V. N.; Rajender, S. V. Green Chem. 2001, 3, 146.
5. Banik, B. K.; Reddy, A.; Datta, A.; Mukhopadhyay, C. Tetrahedron Lett. 2007, 48,
7392.
6. Mukhopadhyay, C.; Datta, A. Heterocycles 2007, 71, 181.
7. (a) Mukhopadhyay, C.; Datta, A. Heterocycles 2007, 71, 1837; (b)
Mukhopadhyay, C.; Tapaswi, P. K., unpublished results from this laboratory.
8. Horton, D. A.; Bourne, G. T.; Sinythe, M. L. Chem. Rev. 2003, 103, 893.
9. Alamgir, M.; Black, St. C. D.; Kumar, N. Top. Heterocycl. Chem. 2007, 9, 87.
10. (a) Porcari, A. R.; Devivar, R. V.; Kucera, L. S.; Drach, J. C.; Townsend, L. B. J. Med.
Chem. 1998, 41, 1252; (b) Rath, T.; Morningstar, M. L.; Boyer, P. L.; Hughes, S.
M.; Buckheitjr, R. W.; Michejda, C. J. J. Med. Chem. 1997, 40, 4199.
11. Migawa, M. T.; Girardet, J. L.; Walker, J. A.; Koszalka, G. W.; Chamberlain, S. D.;
Drach, J. C.; Townsend, L. B. J. Med. Chem. 1998, 41, 1242.
12. Tamm, I. Science 1957, 126, 1235.
13. Mann, J.; Baron, A.; Opoku-Boahen, Y.; Johansson, E.; Parkinson, G.; Kelland, L.
R.; Neidle, S. J. Med. Chem. 2001, 44, 138.
14. Kamal, A.; Reddy, D. R.; Rajendar Tetrahedron Lett. 2006, 47, 2261.
15. Wang, X.; Quan, Z.; Wang, F.; Wang, M.; Zhang, Z.; Li, Z. Synth. Commun. 2006,
36, 451.
16. Das, B.; Holla, H.; Srinivas, Y. Tetrahedron Lett. 2007, 48, 61.
17. Chakrabarty, M.; Karmakar, S.; Mukherjee, A.; Arima, S.; Harigaya, Y.
Heterocycles 2006, 68, 967.
0
0
0
d: 150.63 (C2, C3a and C7a), 132.51 (C5, C6 and C1 ), 131.28 (C3 , C5
0
0
0
and C4), 126.15 (C2 , C6 and C7), 117.04 (CN), 111.79 (C4 ). Anal.
Calcd for C14H7N3Cl2; C: 58.36, H: 2.45, N: 14.58%. Found: C:
58.49, H: 2.53, N: 14.66%.
3.5. 5,6-Dichloro-2-[3-(5,6-dichloro-1H-benzimidazol-2 yl)
phenyl]-1H-benzimidazole (Table 3, entry 6)
Mp >320 °C (MeOH). IR (KBr): 3409, 2925, 2856, 2197,1448,
1298, 1098 and 864 cmꢀ1
.
1H NMR (300 MHz, DMSO-d6) d: 13.43
0
[br s, 2H, 2 ꢁ (–NH)], 8.96 (s, 1H, C2 –H), 8.22 (d, J = 7.7 Hz,
0
0
2H, C4 –H and C6 –H), 8.00–7.62 [m, 5H, (2 ꢁ C4–H), (2 ꢁ C7–H)
and C5 –H]. 13C NMR (75 MHz, DMSO-d6) d: 153.16 (two
0
carbons), 143.44 (two carbons), 134.43 (two carbons), 130.20
(two carbons), 129.86, 128.38 (two carbons), 125.25, 125.02 (two
carbons), 124.59 (two carbons), 120.05 (two carbons), 112.99
(two carbons). Anal. Calcd for C20H10N4Cl4; C: 57.18, H: 2.40, N:
6.67%. Found: C: 57.39, H: 2.44, N: 6.45%.
18. Du, L.-H.; Wang, Y.-G. Synthesis 2007, 5, 675.
19. Kerimov, I.; Guelguen, A. K.; Benay, C.-E.; Nurten, A.; Muemtaz, I. J. Enzym.
Inhib. Med. Chem. 2007, 22, 696.
4. Conclusion
20. Adrienn, H.; Zolfan, Z.; Attila, P. Synth. Commun. 2006, 36, 3625.
21. Wang, Y.; Sarris, K.; Sauer, D. R.; Djuric, S. W. Tetrahedron Lett. 2006, 47,
4823.
22. Roth, T.; Morningstar, L. M.; Boyer, P. L.; Hughes, B.; Robert, W., Jr.; Michejeta,
C. J. Med. Chem. 1997, 40, 4199.
23. Wilson, D. M.; Jermin, A. P.; Gonzalez, J. E., III; Zimmermann, N.; Zhang, Y. E.;
Lev, T. D. PCT. Int. Appl. 2005, p 258 (CAN 142: 463725 AN 2005; 409489
CAPLUS).
24. Navarrete-Vazquez, G.; Moreno-Diaz, H.; Estrada-Soto, S.; Torres-Piedra, M.;
Rivera, I. L.; Tlahuext, H.; Muniz, O. M-.; Gomez, H. T. Synth. Commun. 2007, 37,
2815.
Thus PEG 400 has proved to be a very efficient ‘green’ promoter
for the construction of a wide variety of 2-substituted benzimidaz-
oles and particularly bis-benzimidazoles under catalyst-free and
solvent-less conditions at 110 °C (or 140 °C) in excellent yields.
This methodology works equally well with both low and high
molecular weight PEGs and therefore is a very general and environ-
mentally benign eco-friendly procedure, which would prove bene-
ficial to both academia and industry.
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We thank the CAS Instrumentation Facility, University of
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Supplementary data
33. Li, Y.-F.; Wang, G.-F.; He, P.-L.; Huang, W.-G.; Zhu, F.-H.; Gao, H.-Y.; Tang, W.;
Luo, Y.; Feng, C.-L.; Shi, L.-P.; Ren, Y.-D.; Lu, W.; Zuo, J.-P. J. Med. Chem. 2006, 49,
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