Ytterbium perfluorooctanesulfonate as an efficient and recoverable catalyst for the synthesis of trisubstituted imidazoles

Article abstract of DOI:10.1016/j.jfluchem.2008.03.009

Synthesis of trisubstituted imidazoles was successfully accomplished using rare earth(III) perfluorooctanesulfonates (RE(OPf)₃), RE = Sc, Y, La-Lu as catalysts in fluorous solvents. Ytterbium perfluorooctanesulfonates (Yb(OPf)₃) catalyze the high efficient synthesis of trisubstituted imidazoles in fluorous solvents. By simple separation, fluorous phase containing only catalyst can be reused several times.

Full text of DOI:10.1016/j.jfluchem.2008.03.009

Journal of Fluorine Chemistry 129 (2008) 541–544
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Short communication
Ytterbium perfluorooctanesulfonate as an efficient and recoverable
catalyst for the synthesis of trisubstituted imidazoles
*
Ming-Gui Shen, Chun Cai , Wen-Bin Yi
Chemical Engineering College, Nanjing University of Science & Technology, Nanjing 210094, China
A R T I C L E I N F O
A B S T R A C T
Article history:
Synthesis of trisubstituted imidazoles was successfully accomplished using rare earth(III) perfluor-
ooctanesulfonates (RE(OPf)3), RE = Sc, Y, La–Lu as catalysts in fluorous solvents. Ytterbium perfluor-
ooctanesulfonates (Yb(OPf)3) catalyze the high efficient synthesis of trisubstituted imidazoles in fluorous
solvents. By simple separation, fluorous phase containing only catalyst can be reused several times.
ß 2008 Elsevier B.V. All rights reserved.
Received 8 January 2008
Received in revised form 20 March 2008
Accepted 21 March 2008
Available online 28 March 2008
Keywords:
Trisubstituted imidazoles
Fluorous biphasic catalysis
Rare earth(III) perfluorooctanesulfonates
Perfluorocarbon
1. Introduction
be reused. Wang et al. [14] reported that ytterbium triflate
(Yb(OTf)3) can catalyze the condensation reaction successfully, the
The synthesis, reactions and biological properties of substituted
imidazole constitute a significant part of modern heterocyclic
chemistry. Multi-substituted imidazoles, an important class of
pharmaceutical compounds, exhibit a wide spectrum of biological
activity [1].
catalyst can be recovered conveniently and reused for at least three
reaction cycles without any loss of activity.
There has been rapidly increasing interest in the design and
synthesis of compounds that exhibit high affinities for ‘‘fluorous’’
phases since the technique of ‘‘fluorous biphasic system’’ (FBS) was
´
´
There are numerous classical methods for the synthesis of
multi-substituted imidazoles [2]. In these methods, the one-pot
reaction of diketones, aldehydes and ammonium acetate is a
typical procedure which was widely researched. The typical
procedure is condensed in the presence of H3PO4 [3], H2SO4 [4],
HOAc [5], DMSO [6] as well as organocatalyst in HOAc [7].
However, all of these methods have problems, including drastic
reaction conditions, low yields and severe side-reactions. More-
over, DMF and DMSO lead to complex isolation and recovery
procedure. Several methods comprise the use of MW (microwave)/
silica gel [8], MW/silica gel/H-Y [9], MW/Al2O3 [10], MW/acetic
acid [11], in DMF [12]. These methods promote the condensation
efficiently. But, the use of high temperature, expensive instru-
ments like microwave and corrosive reagents limiting these
methods. Kidwai et al. [13] reported that I2 can catalyze the typical
procedure in good to excellent yield. However, this catalyst cannot
described by Horvath and Rabai [15,16]. The technique of FBS, as a
phase-separation and catalyst immobilization technique, has
become one of the most important methods for facile catalyst
separation from the reaction mixture and recycling of the catalyst
[16]. In this catalytic system, the metal catalyst coordinated by
perfluoroalkylated ligands can dissolve into the fluorous phase
containing the product after the reaction. Recently, novel Lewis
acids
of
lanthanide
tris(perfluorooctanesulfonyl)methide
{Ln[C(SO2Rf8)3]3, Rf8 = (CF2)7CF3, Ln(CPf3)3} [17], lanthanide bis(-
perfluorooctanesulfonyl)amide {Ln[N(SO2Rf8)2]3, Ln(NPf2)3} [18]
and lanthanide perfluorooctanesulfonate [Ln(OSO2Rf8)3, Ln(OPf)3]
[19,20] have been of special interest in that they have character-
istic features such as low hygroscopicity, ease of handling,
robustness for the reuse and high solubility in fluorous solvent.
During our studies to explore the utility of transition metal
perfluorooctanesulfonates catalyzed reactions in fluorous solvents
[20], we found that the one-pot condensation of aldehyde, benzil
and NH4OAc can proceed smoothly in the presence of ytterbium
perfluorooctanesulfonate [Yb(OPf)3] in a FBS composed of HOAc
and perfluorodecalin. Concurrently, we also found that this new
* Corresponding author. Tel.: +86 25 84315514; fax: +86 25 84315030.
E-mail address: c.cai@mail.njust.edu.cn (C. Cai).
0022-1139/$ – see front matter ß 2008 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2008.03.009

542
M.-G. Shen et al. / Journal of Fluorine Chemistry 129 (2008) 541–544
Table 1
process can be carried out successfully with no need of a
stoichiometric amount Lewis base and the robustness of the
catalytic system for reuse can be obtained by simple phase-
separation.
Condensation reaction of benzaldehyde, benzil and NH4OAc in different cosolventsa
Entry
Cosolvent
Yieldb (%)
1
2
3
4
5
6
a
HOAc
97
91
43
90
3
C2H5OH
Toluene
Dioxane
H2O
2. Experimental
2.1. General
CH3COOC2H5
88
The reaction condition: benzaldehyde, 2 mmol; benzil, 1 mmol; NH4OAc,
10 mmol; Yb(OPf)3, 0.004 mmol; solvent, 2 mL; perfluorodecalin (C10F18, cis and
trans-mixture), 1.5 mL; 80 8C; 6 h.
Chemicals used were obtained from commercial suppliers and
used without further purifications. Melting points were deter-
mined on a Shimadzu DSC-50 thermal analyzer. IR spectra were
b
Isolated yields.
recorded on a Bomem MB154S infrared analyzer. 1H NMR and 19
F
NMR spectra were recorded with a Bruker Advance RX500
spectrometer. Mass spectra were recorded on a Saturn 2000GC/
MS instrument or an Agilent 1100LC/MS instrument. Inductively
coupled plasma (ICP) spectra were measured on an Ultima2C
apparatus. Elemental analyses were performed on a Yanagimoto
MT3CHN recorder.
Scheme 2. The condensations of various aldehydes with benzil and NH4OAc.
2.2. Typical procedure for preparation of RE(OPf)3
in 97% yield. Then, the influences of cosolvents on catalytic
property were investigated by using the model condensation of
benzaldehyde, benzil and NH4OAc. The results are shown in
Table 1. It was found that among the solvents tested, HOAc proved
to be the most efficient and was selected to be the reaction solvent
for the subsequent investigation.
We next examined the catalytic activity of 10 RE(OPf)3
complexes in perfluorodecalin. It was found that Yb(OPf)3 was
the most effective catalyst, which produced almost quantitative
yields of imidazole in perfluorodecalin. Table 2 shows the results
we investigated.
RE(OPf)3 was prepared according to the literatures [21]. Method
A: the mixture of PfOH solution (aq) and YbCl3Á6H2O solution (aq)
was stirred at room temperature. Method B: the mixture of PfOH
solution (aq) and Yb2O3 powder was stirred at boiling temperature.
In both methods, the resulting gelatin-like solid was collected,
washed with H2O and dried at 150 8C in vacuum to give a white
solid, which does not have a clear melting point up to 500 8C, but
shrinks around 380 8C and 450 8C. IR (KBr) n 1230 (CF3), 1150 (CF2),
1080 (SO2), 1060 (SO2), 740 (S–O) and 650 (C–S) cmÀ1. ICP: Calcd
for C24O9F51SYb: Yb, 10.30%. Found: Yb, 9.88%. Anal. Calcd for
Then, we decided to use Yb(OPf)3 as a catalyst and perfluor-
odecalin as a fluorous solvent for condensation. The condensations
of various aldehydes with benzil and NH4OAc have been examined
(Scheme 2). The results are summarized in Table 3. Aromatic
aldehydes were efficient reagents and no side-reaction products
were observed (Table 3, entries 1–10). Aromatic aldehydes with
electron-donating groups gave higher yield of the corresponding
imidazoles than those with electron-withdrawing groups. Alipha-
tic aldehydes were not efficient in such protocol, and gave rather
lower yield than aromatic aldehydes (Table 3, entries 11–12).
Steric effects did not influence the yield significantly, for example,
in the reaction of p-chloro (Table 3, entry 6) and o-chloro (Table 3,
entry 7) benzaldehyde, the corresponding condensation products
were obtained in 83% and 80% yields, respectively. When the
reaction was finished, the reaction mixture was filtrated and the
filtrate was cooled to room temperature, the fluorous phase with
RE(OPf)3 can separate from the organic layer and return to the
C
24O9F51S3YbÁH2O: C, 17.21%; H, 0.10%. Found: C, 17.03%; H, 0.18%.
2.3. Typical procedure for preparation of trisubstituted imidazoles in
FBS
A mixture of Yb(OPf)3 (6.7 mg, 0.004 mmol), benzil (0.21 g,
1 mmol), benzaldehyde (0.212 g, 2 mmol) and NH4OAc (0.77 g,
10 mmol) was added to HOAc (2 mL) and perfluorodecalin (C10F18
,
cis and trans-mixture, 1.5 mL). The mixture was stirred at 80 8C for
6 h. After the reaction was finished, the reaction mixture was
filtrated. The filtrate was cooled to room temperature, the fluorous
layer on the bottom was separated for the next condensation, the
solid obtained from the filtration and the combined organic phase
was extracted with ether (10 mL Â 2), washed with NaHCO3
solution aqueous (5% 10 mL), and water (10 mL), and then dried
over Na2SO4. The organic solvent was removed under reduced
pressure and the residue was purified by SiO2 gel column
chromatography using CH2Cl2:MeOH 99:1 as eluent to give a
product 2,4,5-triphenylimidazole (0.287 g, 97%).
Table 2
Effect of the catalysts on the condensationa
3. Results and discussion
Entry
Catalyst
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
a
La(OPf)3
Ce(OPf)3
Nd(OPf)3
Sm(OPf)3
Eu(OPf)3
Tb(OPf)3
Dy(OPf)3
Er(OPf)3
Yb(OPf)3
Lu(OPf)3
80
91
91
90
82
85
88
85
97
80
Firstly, in the condensation, NH4OAc was selected to be the
ammonia source in the model reaction (Scheme 1). In a model
reaction, in the presence of the catalyst, the mixture of
benzaldehyde, benzil and NH4OAc was stirred in HOAc and
perflurodecalin at 80 8C. The corresponding product was obtained
The reaction condition: benzaldehyde, 2 mmol; benzil, 1 mmol; NH4OAc,
10 mmol; RE(OPf)3, 0.004 mmol; HOAc, 2 mL; perfluorodecalin (C10F18, cis and
trans-mixture), 1.5 mL; 80 8C; 6 h.
b
Scheme 1. The model condensation reaction of benzaldehyde, benzil and NH4OAc.
Isolated yields.

M.-G. Shen et al. / Journal of Fluorine Chemistry 129 (2008) 541–544
543
Table 3
Condensation of aldehydes, benzil and NH4OAca
Entry
1
Aldehyde
Product
Time (h)
Yieldb (%)
mp (8C)
6
97
272–273 (lit [14] >260)
2
3
4
5
6
7
8
6
6
6
6
6
6
6
97
90
89
85
83
80
80
227–228 (lit [14] 227–228)
235–237 (lit [22] 233)
209–210 (lit [22] 205)
244–246 (lit [14] 236–237)
261–262 (lit [23] 259–261)
188 (lit [22] 188)
236–237 (lit [14] 241–242)
9
6
6
75
93
>290 (lit [14] >260)
10
227–228 (lit [23] 226–228)
11
12
12
10
31
226–228 (lit [14] 223–224)
256–258 (lit [14] 256–258)
12
a
The reaction condition: aldehyde, 2 mmol; benzil, 1 mmol; NH4OAc, 10 mmol; Yb(OPf)3, 0.004 mmol; HOAc, 2 mL; perfluorodecalin (C10F18, cis and trans-mixture),
1.5 mL; 80 8C.
b
Isolated yields.

544
M.-G. Shen et al. / Journal of Fluorine Chemistry 129 (2008) 541–544
bottom layer. Based on GC-MS and 19F NMR data, the distribution
of Yb(OPf)3 found in organic layer was less than 1% and only trace
of perfluorodecalin leached to organic phase can be detected.
We next sought to probe whether the catalyst could be recycled.
The condensation of benzaldehyde, benzil and NH4OAc under the
conditions described in Table 2 with Yb(OPf)3 as catalysts was run
for five consecutive cycles, furnishing the corresponding imidazole,
with 97%, 96%, 95%, 94%, 94% isolated yields. The robustness of the
catalyst for recycling using may be attributed that these rare-earth
metal perflates are stable in aqueous conditions [24], and the metal
catalyst coordinated by fluorous ponytail ‘‘C8F17’’ can dissolve into
the fluorous phase. The separated fluorous phase containing only
catalyst could be reused for the next condensation without any
treatment, and this workup procedure of recycling was accom-
plished by simple phase-separation.
2H, CH2), 7.50–8.15 (m, 10H, Ar), 13.40 (brs, NH); MS (EI) m/z 248
(M+).
2-Propyl-4,5-diphenylimidazole (12): 31% yield; mp: 256–
258 8C; 1H NMR (500 MHz, CDCl3)
d = 0.96 (t, 3H, CH3), 1.66 (m, 2H,
CH2), 2.55 (t, 2H, CH2), 7.45–8.10 (m, 10H, Ar), 13.40 (brs, NH); MS
(EI) m/z 262 (M+).
References
[1] J.G. Lombardino, E.H. Wiseman, J. Med. Chem. 17 (1974) 1182–1188.
[2] (a) R. Consonni, P.D. Croce, R. Ferraccioli, C.L. Rosa, J. Chem. Res. (S) (1991) 188–
189;
(b) D.A. Evans, K.M. Lundy, J. Am. Chem. Soc. 114 (1992) 1495–1496;
(c) C.F. Claiborne, N.J. Liverton, K.T. Nguyen, Tetrahedron Lett. 39 (1998) 8939–
8942;
(d) J. Tsuji, K. Sakai, H. Nemoto, H. Nagashima, J. Mol. Catal. 18 (1983) 169–
176;
In conclusion, Yb(OPf)3 is demonstrated to be new and highly
effective catalysts for preparation of trisubstituted imidazoles in
fluorous biphasic system. By simple separation of the fluorous
phase containing only catalyst, the reaction can be repeated many
times. Further study on the application of FBS to other reactions,
which can be promoted by such Lewis acids, is under way in this
laboratory.
(e) B. Radziszewski, Ber. Dent. Chem. Ges. (Ber.) 15 (1882) 1493–1496;
(f) H.H. Wasserman, Y.O. Long, R. Zhang, J. Parr, Tetrahedron Lett. 43 (2002)
3351–3353;
(g) Y. Kamitori, J. Heterocyclic Chem. 38 (2001) 773–776;
(h) I. Lantos, W.Y. Zanng, Y. Shiu, D.S. Eggleston, J. Org. Chem. 58 (1993) 7092–
7095;
(i) C.-Z. Zhang, E.J. Moran, T.F. Woiwade, K.M. Short, A.M.M. Mjalli, Tetrahedron
Lett. 37 (1996) 751–754;
(j) C.F. Claiborne, N.J. Liverlon, K.T. Nguyen, Tetrahedron Lett. 39 (1998) 8939–
8942;
2,4,5-Triphenylimidazole (1): 97% yield; mp: 272–273 8C; 1H
(k) K.M. Bleicher, F. Gerber, Y. Wuthrich, A. Alanine, A. Caprella, Tetrahedron Lett.
43 (2002) 7687–7690.
NMR (500 MHz, CDCl3) d = 7.51–7.90 (m, 15H, Ar), 12.60 (brs, NH);
MS (EI) m/z 296 (M+).
[3] F.-J. Liu, J. Chen, J. Zhao, Y. Zhao, L. Li, H. Zhang, Synthesis (2003) 2661–2666.
[4] H. Weinmann, M. Hahhe, K. Koeing, E. Mertin, U. Tilstam, Tetrahedron Lett. 43
(2002) 593–595.
[5] S. Sarshar, D. Siev, A.M.M. Mjalli, Tetrahedron Lett. 37 (1996) 835–838.
[6] N.G. Clark, E. Cawkill, Tetrahedron Lett. (1975) 2717–2720.
[7] E.D. Frantz, L. Morency, A. Soheili, J.A. Murry, E.J.J. Grabowski, R.D. Tillyer, Org.
Lett. 6 (2004) 843–846.
[8] S. Balalaie, M.M. Hashemi, M. Akhbari, Tetrahedron Lett. 44 (2003) 1709–
1711.
[9] S. Balalaie, A. Arabanian, Green Chem. 2 (2000) 274–276.
[10] A.Y. Usyatinsky, Y.L. Khemelnitsky, Tetrahedron Lett. 41 (2000) 5031–5034.
[11] S.E. Wolkenberg, D.D. Wisnoski, W.H. Leister, Y. Wang, Z. Zhao, C.W. Lindsley, Org.
Lett. 6 (2004) 1453–1456.
[12] J.M. Cobb, N. Grimster, N. Khan, T.Y.Q. Lai, H.J. Payne, L.J. Payne, J. Raynham, J.
Taylor, Tetrahedron Lett. 43 (2002) 7557–7560.
[13] M. Kidwai, P. Mothsra, V. Bansal, R.K. Somvanshi, A.S. Ethayathulla, S. Dey, T.P.
Singh, J. Mol. Catal. A: Chem. 265 (2007) 177–182.
[14] L.-M. Wang, Y.-H. Wang, T. He, -Y.F. Yao, J.-H. Shao, B. Liu, J. Fluorine Chem. 127
(2006) 1570–1573.
2-(4-Methoxyphenyl)-4,5-diphenylimidazole (2): 97% yield;
mp: 227–228 8C; 1H NMR (500 MHz, CDCl3)
= 3.85 (s, 3H, OCH3),
d
6.93–6.96 (d, 2H, Ar), 7.25–7.59 (m, 10H, Ar), 8.02–8.05 (d, 2H, Ar),
12.52 (brs, NH); MS (EI) m/z 326 (M+).
2-(4-Hydroxyphenyl)-4,5-diphenylimidazole (3): 90% yield;
mp: 235–237 8C; 1H NMR (500 MHz, CDCl3)
14H, Ar), 9.50 (brs, NH); MS (EI) m/z 312 (M+).
d = 7.00–7.90 (m,
2-(2-Hydroxyphenyl)-4,5-diphenylimidazole (4): 89% yield;
mp: 209–210 8C; 1H NMR (500 MHz, CDCl3)
14H, Ar), 9.50 (brs, NH); MS (EI) m/z 312 (M+).
d = 6.70–7.60 (m,
2-(4-Bromophenyl)-4,5-diphenylimidazole (5): 85% yield; mp:
244–246 8C; 1H NMR (500 MHz, CDCl3)
d = 7.20 (d, 2H, Ar), 7.30–
7.60 (m, 10H, Ar), 7.80 (d, 2H, Ar); MS (EI) m/z 375 (M+).
2-(4-Chlorophenyl)-4,5-diphenylimidazole (6): 83% yield; mp:
261–262 8C; 1H NMR (500 MHz, CDCl3)
d = 7.30 (d, 2H, Ar), 7.40–
[15] I.T. Horva´th, J. Rabai, Science 266 (1994) 72–73.
´
[16] (a) J.A. Gladysz, D.P. Curran, I.T. Horvath, Handbook of Fluorous Chemistry,
7.70 (m, 10H, Ar), 7.90 (d, 2H, Ar), 12.50 (s, NH); MS (EI) m/z 330,
330 + 2 (M+).
2-(2-Chlorophenyl)-4,5-diphenylimidazole (7): 80% yield; mp:
188 8C; 1H NMR (500 MHz, CDCl3)
d = 7.27–7.37 (m, 10H, Ar), 7.45–
Wiley-VCH, Weinheim, 2004;
(b) K. Mikami (Ed.), Green Reaction Media in Organic Synthesis, Blackwell,
Oxford, 2005.
[17] (a) K. Mikami, Y. Mikami, Y. Matsumoto, J. Nishikido, F. Yamamoto, H. Nakajima,
Tetrahedron Lett. 42 (2001) 289–292;
7.49 (dd, 1H, Ar), 7.57–7.59 (d, 2H, Ar), 8.02–8.05 (dd, 1H, Ar), 12.50
(brs, NH); MS (EI) m/z 330, 330 + 2 (M+).
(b) J. Nishikido, M. Kamishima, H. Matsuzawa, K. Mikami, Tetrahedron 58 (2002)
8345–8349.
[18] (a) X.-H. Hao, A. Yoshida, J. Nishikido, J. Fluorine Chem. 127 (2006) 193–199;
(b) X.-H. Hao, A. Yoshida, J. Nishikido, Green Chem. (2004) 566–569.
[19] (a) M. Shi, S.-C. Cui, Y.-H. Liu, Tetrahedron 61 (2005) 4965–4970;
(b) M. Shi, S.-C. Cui, J. Fluorine Chem. 116 (2002) 143–147.
[20] (a) M.-G. Shen, C. Cai, J. Fluorine Chem. 3 (2007) 232–235;
(b) M.-G. Shen, C. Cai, Catal. Commun. 6 (2007) 871–875;
(c) M.-G. Shen, C. Cai, W.-B. Yi, J. Fluorine Chem. 128 (2007) 1421–1424;
(d) W.-B. Yi, C. Cai, X. Wang, J. Fluorine Chem. 128 (2007) 919–924.
[21] T. Hanamoto, Y. Sugimoto, Y.Z. Jin, J. Inanaga, Bull. Chem. Soc. Jpn. 70 (1997)
1421–1426.
[22] A.S. Shapi, C.N. Umesh, S.P. Sanjay, D. Thomas, J.L. Rajgopal, V.S. Kumar, Tetra-
hedron 61 (2005) 3539–3546.
[23] S. Ahmad, R. Abbas, J. Mol. Catal. A: Chem. 249 (2006) 246–248.
[24] (a) M. Shi, S.-C. Cui, Chem. Commun. (2002) 994–995;
(b) S. Kobayashi, M. Sugiura, H. Kitagawa, W.W.-L. Lam, Chem. Rev. 102 (2002)
2227–2302.
2-(4-Nitrophenyl)-4,5-diphenylimidazole (8): 80% yield; mp:
236–237 8C; 1H NMR (500 MHz, CDCl3)
d = 7.35–7.60 (m, 10H, Ar),
8.05–8.30 (m, 4H, Ar); MS (EI) m/z 341 (M+).
2-(3-Nitrophenyl)-4,5-diphenylimidazole (9): 75% yield; mp:
>290 8C; 1H NMR (500 MHz, CDCl3)
d = 7.55–8.95 (m, 14H, Ar),
13.10 (brs, NH); MS (EI) m/z 341 (M+).
2-(4-Methylphenyl)-4,5-diphenylimidazole (10): 93% yield;
mp: 227–228 8C; 1H NMR (500 MHz, CDCl3)
= 2.90 (s, 3H,
d
CH3), 6.80 (d, 2H, Ar), 7.20–7.80 (m, 12H, Ar), 12.60 (brs, NH);
MS (EI) m/z 310 (M+).
2-Ethyl-4,5-diphenylimidazole (11): 10% yield; mp: 226–
228 8C; 1H NMR (500 MHz, CDCl3)
d = 1.24 (t, 3H, CH3), 2.59 (m,