Expeditious synthesis of N0-substituted N-mesitylimidazolium salts as NHC precursors

Article abstract of DOI:10.1016/j.tetlet.2010.07.097

In contrast to time-consuming, conventional thermal approaches, microwave irradiation provides rapid and convenient access to unsymmetrical N0-substituted N-mesitylimidazolium salts, which are important precursors for NHC ligands used in the construction

Full text of DOI:10.1016/j.tetlet.2010.07.097

Tetrahedron Letters 51 (2010) 5041–5043
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Tetrahedron Letters
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Expeditious synthesis of N0-substituted N-mesitylimidazolium salts
as NHC precursors
*
Byron J. Truscott, Rosalyn Klein, Perry T. Kaye
Department of Chemistry, Rhodes University, Grahamstown 6140, South Africa
a r t i c l e i n f o
a b s t r a c t
Article history:
In contrast to time-consuming, conventional thermal approaches, microwave irradiation provides rapid
and convenient access to unsymmetrical N0-substituted N-mesitylimidazolium salts, which are important
precursors for NHC ligands used in the construction of metal–NHC complexes.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 7 May 2010
Revised 30 June 2010
Accepted 16 July 2010
Available online 22 July 2010
N-Heterocyclic carbenes (NHCs) have attracted considerable
attention as electron-donating ligands for transition metals in vari-
ous oxidation states.1,2 The isolation of stable NHC–carbenes was
first described by Arduengo et al.3 in 1991, and reports of analogues
containing simple alkyl, aryl or even highly functionalised substitu-
alkylation, first reported by Arduengo et al.3 then typically leads to
the corresponding N-substituted imidazolium salt—a well docu-
mented and versatile route to NHC proligands. However, the final
alkylation step tends to be very slow using conventional methods,
with the reaction mixtures requiring stirring at room temperature
or under reflux for as long as seven days.6,13–25 In the methodology
reported herein, N-mesitylimidazole (4) was reacted in toluene, un-
der microwave-assisted conditions, with a series of eight different
alkyl halides to afford the corresponding N-substituted mesitylimi-
dazolium salts 8–15 in 30–120 min (Table 1), with the desired salt
typically precipitating out of the reaction mixture in high purity.
As is evident from the data in Table 1, the N0-substituted
N-mesitylimidazolium salts 9–13 and 15 were isolated in moder-
ate to good yields. Unfortunately, the malonate ester derivative
8, required for our research on the development of novel tridentate
ligands, was obtained in very low yield. N-Mesitylimidazole (4)24
and diethyl (3-chloropropyl)malonate (7)31,32 were prepared
ents have followed.4–6 NHCs are generally much stronger
and weaker
r
-donors
p-acceptors than phosphine ligands. These properties
permit the formation of strong metal–NHC bonds4,5,7,8—advantages
exploited in the development of the widely used Grubbs II catalyst.9
The catalytic activity and efficiency of NHC–metal complexes can be
customized by changing the electronic, steric and even stereochem-
ical features of the ring substituents.9–12 N0-Substituted N-mesity-
limidazolium salts provide stable precursors for NHC–metal
complexes and are generally obtained via a two-step sequence,
involving the preparation of N-mesitylimidazole6 and subsequent
alkylation at the second nitrogen.6,13–25 Our interest in imidazolium
salts arises from an ongoing programme directed at the develop-
ment of novel metathesis catalysts.26 The practical difficulties
encountered in the preparation and isolation of the critical imidazo-
lium salts as carbene precursors prompted us to explore a micro-
wave-assisted approach. Applications of microwave-assisted
organic synthesis (MAOS), first reported in the mid-eighties,27,28
have advanced significantly, with sophisticated laboratory equip-
ment replacing domestic microwave ovens.29,30 While improve-
ments in selectivity, reaction time and efficiency using
conventional protocols30 have been reported,12,29,30 the dramatic
advantages offered by a microwave-assisted approach in the rate
of formation and ease of isolation of strategically important N-mesi-
tylimidazolium salts may well facilitate research into the develop-
ment of novel analogues of the Grubbs type II ruthenium-based
metathesis catalysts.
Table 1
N0-Substituted N-mesitylimidazolium salts obtained under microwave-assisted con-
ditionsa via Scheme 1
Entry Reactant
Product Time
(min)
Isolated yield
(%)
1
Diethyl (3-
8
120
7
chloropropyl)malonate (7)
3-Chloropropanol (16)
Allyl iodide (17)
Benzyl bromide (18)
Ethyl 2-bromopropionate (19)
1-Bromodecane (20)
2-(Bromomethyl)-
2
3
4
5
6
7
9
10
11
60
30
30
30
30
30
74c
69d
80e
77
61
39
12
13
14b
pyridineꢀHBr (21)
The key precursor, N-mesitylimidazole (4) was prepared in excel-
lent yield (98%) by reacting 2,4,6-trimethylanilinium chloride (1)
with glyoxal (2) and formaldehyde (3) (Scheme 1).6 The subsequent
8
1-Bromo-3-chloropropane (6)
15
30
70
a
b
c
Reactions conducted in toluene at 150 W, 85 °C.
Reaction conducted in EtOH at 150 W, 85 °C.
Previously isolated in 69% yield after conventional heating for 15 h (see Ref. 14).
Previously isolated in 70% yield after conventional heating overnight (see Ref. 15).
Previously isolated in 100% yield after conventional heating for 16 h (see Ref. 13).
d
e
* Corresponding author. Tel.: +27 46 6037030; fax: +27 46 6225109.
E-mail address: P.Kaye@ru.ac.za (P.T. Kaye).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.097

5042
B. J. Truscott et al. / Tetrahedron Letters 51 (2010) 5041–5043
Scheme 1. Preparation of N0-substituted N-mesitylimidazolium salts under microwave-assisted conditions. Reagents and reaction conditions: (i) NH4Cl, H2O, 1,4-dioxane,
100 °C, then NaOH, 0 °C; (ii) NaH, THF, reflux; (iii) MW, 150 W, 85 °C, alkyl halide (6,7, 16–21, Table 1), toluene or EtOH.
following the literature methods, the N0-substituted N-mesitylimi-
21. Peng, H. M.; Webster, R. D.; Li, X. Organometallics 2008, 27, 4484–4493.
22. Maes, B. U. W.; Loones, K. T. J.; Hostyn, S.; Diels, G.; Rombouts, G. Tetrahedron
2004, 60, 11559–11564.
23. Peng, H. M.; Song, G.; Li, Y.; Li, X. Inorg. Chem. 2008, 47, 8031.
dazolium salts 8–15 using a general procedure, and all new com-
pounds were fully characterized.34
24. Alcalde, E.; Dinarès, I.; Rodríguez, S.; de Miguel, C. D. Eur. J. Org. Chem. 2005, 8,
1637–1643.
Acknowledgements
25. Occhipinti, G.; Bjorsvik, H.; Tornroos, K. W.; Furstner, A.; Jensen, V. R.
Organometallics 2007, 26, 4383–4385.
26. Sabbagh, I. T. Ph.D. Thesis, Rhodes University, 2005.
27. Giguere, R. J.; Bray, T. L.; Duncan, S. M.; Majetich, G. Tetrahedron Lett. 1986, 27,
4945–4948.
28. Gedye, R.; Smith, F.; Westaway, K.; Ali, H.; Baldisera, L.; Laberge, L.; Rousell, J.
Tetrahedron Lett. 1986, 26, 279–282.
The authors thank Sasol Technologies for a bursary (to B.J.T.)
and Sasol Technologies and Rhodes University for the generous
financial support.
29. Loones, K. T. J.; Maes, B. U. W.; Rombouts, G.; Hostyn, S.; Diels, G. Tetrahedron
2005, 61, 10338–10348.
References and notes
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31. Hu, W.; Wang, J. C. N. Patent 1422847, 2003; Chem. Abstr. 2003, 143, 172688.
32. Novotny, J.; Dalecky, V.; Zavodna, I.; Kiss, F.; Mikuskova, A.; Jonas, P.; Macka,
M.; Marcikova, L.; Kozisek, R. CS Patent 277196, 1992; Chem. Abstr. 1992, 120,
322819.
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10. Nguyen, S. T.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1993, 115, 9858–9859.
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114, 3974–3975.
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34. General procedure for the alkylation of N-mesitylimidazole (4). A solution of N-
mesitylimidazole (4) and an equimolar equivalent of the alkyl halide in toluene
or EtOH (1 mL) was heated at 85 °C, 150 W with stirring in a CEM Discover
single-mode microwave apparatus, producing controlled irradiation at
2450 MHz, using a standard 10 mL silicon–septum sealed glass pressure vial.
The reactions were optimized using the temperature–time mode of operation
and the temperature was monitored by means of an IR sensor directed at the
outside wall of the reaction vial. The reaction times (Table 1) refer to hold
times at the indicated temperature and not total irradiation times. Upon
completion, the reaction mixture was cooled to below 50 °C via propelled air
flow, and the precipitate was washed with toluene and, in some cases, with
acetone or Et2O to give the desired N0-substituted N-mesitylimidazolium salts
8–15. Alkylations were typically repeated using 100–250 mg of the starting
material. The largest quantity of starting material used in a reaction was
500 mg and the reaction proceeded as normal.
1-[4,4-Bis(ethoxycarbonyl)butyl]-3-mesitylimidazol-2-ium chloride 8 (15 mg, 7%)
as a brown oil (found: M+ 387.2273. C22H31N2O4 requires M, 387.2284); mmax
/
cmꢁ1 1722 (C@O), and 1546 (C@N); dH (400 MHz; CDCl3) 1.25 (6H, t, J 7.1,
2 ꢂ CH2CH3), 1.94 (2H, m, CH2CH), 2.07 (6H, s, 2 ꢂ o-CH3), 2.08 (2H, m,
CH2CH2CH2), 2.33 (3H, s, p-CH3), 3.42 (1H, t, J 7.0, CH), 4.17 (4H, m, 2 ꢂ OCH2),
4.80 (2H, t, J 6.9, NCH2), 6.98 (2H, s, 2 ꢂ ArH), 7.14 and 7.71 (2H, 2 ꢂ s, 4- and 5-
H) and 10.64 (1H, s, NCHN); dC (100 MHz; CDCl3) 14.0 (q, 2 ꢂ CH2CH3), 17.5 (q,
19. Perry, M. C.; Cui, X.; Powell, M. T.; Hou, D.; Reibenspies, J. H.; Burgess, K. J. Am.
Chem. Soc. 2003, 125, 113–123.
20. Pruhs, S.; Lehmann, C. W.; Furstner, A. Organometallics 2004, 23, 280–287.

B. J. Truscott et al. / Tetrahedron Letters 51 (2010) 5041–5043
5043
2 ꢂ o-CH3), 21.0 (q, p-CH3), 25.0 (t, CH2CH), 27.9 (t, CH2CH2CH2), 49.8 (t, NCH2),
50.9 (d, CH), 61.6 (t, 2 ꢂ OCH2), 122.4 and 123.0 (2 ꢂ d, C-4 and C-5), 129.8 (d,
2 ꢂ ArCH), 130.8 (s, ArC), 134.2 (s, 2 ꢂ ArC), 139.2 (d, NCHN), 141.3 (s, ArC) and
168.9 (s, 2 ꢂ C@O).
CH2CH3), 17.7 (q, 2 ꢂ o-CH3), 21.1 (q, p-CH3), 22.6, 26.1, 29.0, 29.2, 29.3, 29.4,
30.6 and 31.8 (8 ꢂ t, 8 ꢂ CH2), 50.6 (t, NCH2), 122.4 (d, NCH), 123.0 (d, NCH),
129.9 (d, 2 ꢂ ArCH), 130.7 (s, ArC), 134.2 (s, 2 ꢂ ArC), 138.6 (d, NCHN) and
141.4 (s, ArC).
1-(3-Hydroxypropyl)-3-mesitylimidazol-2-ium chloride 9 (560 mg, 74%), white
solid, mp 180–182 °C (from MeOH) (lit.,14,20 no mp reported).
1-(Prop-2-enyl)-3-mesitylimidazol-2-ium iodide 1015,35 (68.4 mg, 69%) brown
solid, mp 166–167 °C (from CH2Cl2–Et2O).
1-[(Pyridin-2-yl)methyl]-3-mesitylimidazol-2-ium bromide 14 (120 mg, 39%) as a
light brown solid, mp 128–130 °C (from MeOH) [lit.,33 210 °C (decomp.)].
1,3-Bis-(3-mesitylimidazolium-2-yl)propane dihydrogen halide salt 1535 (52 mg,
70%), white solid; mp 148–149 °C; m
/cmꢁ1 1549 (C@N); (found: M-1 413.2706.
1-Benzyl-3-mesitylimidazol-2-ium bromide 11 (78 mg, 80%), white solid; mp
C27H33N4 requires, M-1 413.2705); dH (400 MHz; CDCl3) 2.07 (12H, s, 4 ꢂ o-
CH3), 2.35 (6H, s, 2 ꢂ p-CH3), 3.22 (2H, m, 2-H2), 4.99 (4H, t, J 7.7, 2 ꢂ NCH2),
7.01 (4H, s, 4 ꢂ ArH), 7.09 (2H, s, 2 ꢂ 40-H), 8.51 (2H, s, 2 ꢂ 50-H) and 9.98 (2H,
s, 2 ꢂ 20-H); dC (100 MHz; CDCl3) 17.5 (q, 4 ꢂ o-CH3), 20.9 (q, 2 ꢂ p-CH3), 32.0
(t, C-2), 47.0 (t, 2 ꢂ NCH2), 122.9 (d, 2 ꢂ C-40), 124.8 (d, 2 ꢂ C-50), 129.7 (d,
4 ꢂ ArCH), 130.6 (s, 2 ꢂ ArC), 134.1 (s, 4 ꢂ ArC), 137.1 (d, 2 ꢂ C-20) and 141.2
(s, 2 ꢂ ArC).
249–251 °C (from CH2Cl2–Et2O) (lit.,15 237–238 °C).
1-[(1-Ethoxycarbonyl)ethyl]-3-mesitylimidazol-2-ium bromide 1218 (69 mg, 77%),
yellow oil.
1-Decyl-3-mesitylimidazol-2-ium bromide 13 (67 mg, 61%), grey solid; mp 105–
106 °C (found: M+ 327.2788. C22H35N2 requires M, 327.2800); max/cmꢁ1 1541
m
(C@N); dH (400 MHz; CDCl3) 0.87 (3H, t, J 6.8, CH2CH3), 1.24 (10H, br s,
5 ꢂ CH2), 1.35 (4H, m, 2 ꢂ CH2), 1.98 (2H, m, CH2), 2.08 (6H, s, 2 ꢂ o-CH3), 2.33
(3H, s, p-CH3), 4.74 (2H, t, J 7.2, NCH2), 6.99 (2H, s, 2 ꢂ ArH), 7.15 (1H, s, NCH),
7.63 (1H, s, NCH) and 10.50 (1H, s, NCHN); dC (100 MHz; CDCl3) 14.0 (q,
35. Song, L.; Luo, X.; Wang, Y.; Gai, B.; Hu, Q. J. Organomet. Chem. 2009, 694, 103–
112. Compound 15 was reported as the dibromide salt.