Efficient, regioselective access to bicyclic imidazo[1,2-x]- heterocycles via gold- and base-promoted cyclization of 1-alkynylimidazoles

Article abstract of DOI:10.1021/jo902073m

(Chemical Equation Presented) Reactions of 1-alkynylimidazoles involving the formation of their 2-lithio derivatives followed by addition of aldehydes or ketones are presented. The method gives access to 1-alkynyl-2-(hydroxymethyl) imidazoles which underg

Full text of DOI:10.1021/jo902073m

pubs.acs.org/joc
chemotypes.7 Yet, many fused bicyclic imidazole systems
Efficient, Regioselective Access to Bicyclic
Imidazo[1,2-x]- Heterocycles via Gold- and
Base-Promoted Cyclization of 1-Alkynylimidazoles
remain un- or under-explored.6b
One promising approach to the rapid elaboration of a wide
variety of fused bicyclic imidazo[1,2-x] heterocycles, having
a bridgehead imidazole nitrogen atom, focuses on the cycli-
zation reactions of the relatively unexplored 1-alkynylimi-
dazoles.8 We recently reported a coupling reaction between
imidazoles and bromoalkynes mediated by copper com-
plexes allowing access to a wide range of these compounds.9
The further functionalization of those 1-alkynylimidazoles
at the 2 position by formation of their 2-lithio derivatives and
subsequent treatment with various electrophiles has been
studied.10 The cyclization of 1-alkynylimidazoles containing
appropriate nucleophilic groups at their 2 position can
afford two types of bicyclic imidazoles depending upon the
regiochemistry of the cyclization (Figure 1). Of particular
interest is the degree to which the ynamine-like chemistry of
the imidazole-substituted alkyne group plays a role in bias-
ing the regiochemistry of this cyclization as well as the
potential to control the regiochemistry by reagent selection
using transition metals to activate the alkyne π-system.11
In exploring the 2-functionalization of the 1-alkynylimi-
dazole 1a by deprotonation and trapping of the anion with
Christophe Laroche and Sean M. Kerwin*
Division of Medicinal Chemistry, College of Pharmacy and
Department of Chemistry, The University of Texas at Austin,
Austin, Texas 78712
skerwin@mailutexas.edu
Received October 1, 2009
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Sarro, G.; Pannecouque, C.; Witvrouw, M.; Balzarini, J.; De Clercq, E.
Antiviral Chem. Chemother. 2001, 12, 169–174.
Reactions of 1-alkynylimidazoles involving the forma-
tion of their 2-lithio derivatives followed by addition of
aldehydes or ketones are presented. The method gives
access to 1-alkynyl-2-(hydroxymethyl)imidazoles which
undergo 6-endo-dig or 5-exo-dig cyclization under AuCl3-
or base-catalyzed conditions to yield imidazo[1,2-c]-
oxazoles and imidazo[2,1-c][1,4]oxazine heterocycles.
Under transition metal catalysis, the reaction occurs in
a regiospecific manner, leading exclusively to the product
of 6-endo-dig attack, whereas under basic conditions, the
reaction takes place in a regioselective manner giving
preferentially the product from 5-exo-dig attack.
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W. R. S.; Bowman, W. R.; Bridge, E.; Elsegood, M. R. J.; McInally, T.; McKee, V.
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O’Shea, D. F. J. Comb. Chem. 2005, 7, 947–951.
Imidazoles are an extremely important class of com-
pounds with applications across all areas of chemistry,1
biology,2 and material science.3 In particular, fused bicyclic
imidazoles, both naturally occurring and synthetic, display a
wide range of biological activities4 and are found in a number
of clinically important drugs.5 There has been a growing
interest in methods to efficiently access known fused imida-
zole frameworks6 and to explore previously unreported
(1) (a) Grimmett, M. R. Imidazole and Benzimidazole Synthesis; Academic
Press: New York, 1997; pp 1-143. (b) Bellina, F.; Cauteruccio, S.; Rossi, R.
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(2) For review, see: De Luca, L. Curr. Med. Chem. 2006, 13, 1–23.
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V. Y.; Matray, T. J.; Nguyen, C. Chem. Mater. 1993, 5, 1499–1508.
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(8) For cyclizations of 1,2-dialkynylimidazoles to imidazo[1,2-
a]pyridines, see: Nadipuram, A.; Kerwin, S. M. Tetrahedron 2006, 62,
3798–3808.
(9) Laroche, C.; Li, J.; Freyer, M. W.; Kerwin, S. M. J. Org. Chem. 2008,
73, 6462–6465.
(10) Laroche, C.; Kerwin, S. M. Tetrahedron Lett. 2009, 50, 5194–5197.
DOI: 10.1021/jo902073m
r
Published on Web 11/09/2009
J. Org. Chem. 2009, 74, 9229–9232 9229
2009 American Chemical Society

Laroche and Kerwin
JOCNote
TABLE 1. Catalyst Screen for 6-endo-dig Cyclization
entry
catalyst
% conversiona
yieldb
1
2
3
4
5
6
7
AuCl
AuCl3
PdCl2
PtCl2
NiCl2
CuCl2
BiCl3
100
100
70
0
0
100
0
90%
95%
60%
-
FIGURE 1. Regioselective one-pot conversion of 1a to 3a.
-
benzaldehyde, the formation of the 5,7-dihydroimidazo[1,2-
c]oxazole 3a was observed.10,12 The structure of 3a was
confirmed by X-ray crystallography.10 Interestingly, none
of the 6-endo-dig cyclization product 4a was present.14
A number of proposals have been put forth to rationalize
the 5-exo-dig versus 6-endo-dig cyclization modes13 of 4-
ynols under basic conditions, including the double bond
stereochemistry of the 5-exo cyclization products.12,13,15
Recent studies have demonstrated alternative means to
affect the regioselectivity of these cyclizations through metal
catalysis.16 However, it was not clear at the outset how
applicable these precedents would be to the electronically
biased 1-alkynylimidazole system 1a. Thus, in order to
90%
-
aBased on recovered starting material. bIsolated yield after chroma-
tography.
explore the generality of the cyclization to 3a and to develop
a means of accessing the 6-endo-dig cyclization product 4a,
the isolation and characterization of the carbinol derived
from the anion 2a0 were undertaken.
Compound 2a (Table 1) can be isolated in 95% yield from
the reaction of 1-alkynylimidazole 1a under the conditions
shown in Figure 1 when the reaction mixture is quenched
with 1 M HCl solution rather than water. Treatment of
alcohol 2a in the presence of various metal catalysts in
refluxing CH3CN17 was investigated (Table 1). The reaction
proceeded to completion using AuCl3 as catalyst affording
imidazo[2,1-c][1,4]oxazine 4a (Table 1, entry 2) as the only
product in 95% isolated yield.18
(11) (a) Patil, N. T.; Yamamoto, Y. Chem. Rev. 2008, 108, 3395–3442.
(b) Kirsch, S. F. Synthesis 2008, 3183–3204. (c) Hashmi, A. S. K. Chem. Rev.
2007, 107, 3180–3211. (d) Alvarez-Corral, M.; Munoz-Dorado, M.; Rodri-
guez-Garcia, I. Chem. Rev. 2008, 108, 3174–3198. (e) Gorin, D. J.; Toste,
€
F. D. Nature 2007, 446, 395–403. (f) Furstner, A.; Davies, P. W. Angew.
In addition to AuCl3, AuCl (Table 1, entry 1), PdCl2
(Table 1, entry 3), and CuCl2 (Table 1, entry 6) afforded
the cyclized compound 4a, although in lower yield. Interest-
ingly, none of these cases showed any traces of the 5-exo-dig
product 3a.
Chem., Int. Ed. 2007, 46, 3410–3449. (g) Nakamura, I.; Yamamoto, Y. Chem.
Rev. 2004, 104, 2127–2198. (h) Zeni, G.; Larock, R. C. Chem. Rev. 2004, 104,
2285–2309.
(12) For related 5-exo-dig cyclizations, see: (a) Chai, Z.; Xie, Z.-F.; Liu,
X.-Y.; Zhao, G.; Wang, J.-D. J. Org. Chem. 2008, 73, 2947–2950. (b)
Marshall, J. A.; DuBay, W. J. J. Org. Chem. 1994, 59, 1703–1708. (c)
Marshall, J. A.; Bennett, C. E. J. Org. Chem. 1994, 59, 6110–6113.
(13) (a) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734–735. (b)
Johnson, C. D. Acc. Chem. Res. 1993, 26, 476–482. (c) Sheng, Y.; Musaev, D.
G.; Reddy, K. S.; McDonald, F. E.; Morokuma, K. J. Am. Chem. Soc. 2002,
124, 4149–4157.
(14) For reports of analogous, base-promoted 6-endo-dig cyclizations,
see: (a) Hiroya, K.; Jouka, R.; Kameda, M.; Yasuhara, A.; Sakamoto, T.
Tetrahedron 2001, 57, 9697–9710. (b) Brennan, C. M.; Johnson, C. D.;
McDonnell, P. D. J. Chem. Soc., Perkin Trans. 2 1989, 957–961. (c) Garcia,
H.; Iborra, S.; Primo, J. J. Org. Chem. 1986, 51, 4432–4436.
(15) (a) Nakatani, K.; Okamoto, A.; Saito, I. Tetrahedron 1996, 52, 9427–
9446. (b) Houk, K. N.; Strozier, R. W.; Rozeboom, M. D.; Nagase, S. J. Am.
Chem. Soc. 1982, 104, 323–325. (c) Wipf, P.; Graham, T. H. J. Org. Chem.
2003, 68, 8798–8807. (d) Ivanchikova, I. D.; Usubalieva, G. E.; Schastnev, P.
V.; N., E.; Moroz, A. A.; Shvartsberg, M. S. Russ. Chem. Bull. Int. Ed. 1992,
41, 1672–1679. (e) Padwa, A.; Krumpe, K. E.; Weingarten, M. D. J. Org.
Chem. 1995, 60, 5595–5603. (f) Nakatani, K.; Okamoto, A.; Yamanuki, M.;
Saito, I. J. Org. Chem. 1994, 59, 4360–4361. (g) Evans, C. M.; Kirby, A. J.
J. Chem. Soc., Perkin Trans. 2 1984, 1269–1275.
Our interest in the formation of both compounds 3a
and 4a led us to reinvestigate the cyclization reaction of 2a
under basic conditions. Under aqueous conditions (1 equiv
of 1 M NaOH) in THF at room temperature, the desired
compound 3a was obtained in 75% yield. The use of strong
organic bases (n-BuLi or EtMgBr) in THF did not lead to
any conversion at room temperature and led to degradation
under forcing conditions. A catalytic quantity of K3PO4
(5 mol %) in CH3CN at reflux afforded 3a in 80% yield
within an hour. The cyclization was also attempted under
acidic conditions (HCl saturated THF) with no success.19 A
few 5,7-dihydroimidazo[1,2-c]oxazole derivatives have been
reported in the literature for their biological properties
and are generally prepared by condensation reaction
(16) (a) Ramana, C. V.; Mallik, R.; Gonnnade, R. G. Tetrahedron 2008,
64, 219–223. (b) Koo, B.; McDonald, F. E. Org. Lett. 2007, 9, 1737–1740.
(c) Liu, Y H.; Song, F. J.; Song, Z. Q.; Liu, M.; Yan, B. Org. Lett. 2005, 7,
(17) Other solvents screened include CH2Cl2 (5% conversion with 2 mol
% of AuCl3 after 14 h) and THF (100% conversion and 60% yield of 4a with
2 mol % of AuCl3 after 14 h, with the formation of several unidentified side
products).
(18) The imidazo[2,1-c][1,4]oxazine system has been reported previously
only once: (a) Essassi, E. M.; Fifani, J.; Hamamsi, I. Bull. Soc. Chim. Belg.
1994, 103, 83–84. The related 6,8-dihydroimidazo[2,1-c][1,4]oxazines are
also largely unexplored: (b) O’Sullivan, D. G.; Pantic, D.; Wallis, A. K.
Nature 1965, 205, 262–264. (c) Medaer, B. P.; Hoornaert, G. J. Tetrahedron
1999, 55, 3987–4002.
^
5409–5412. (d) Antoniotti, S.; Genin, E.; Michelet, V.; Genet, J.-P. J. Am.
Chem. Soc. 2005, 127, 9976–9977. (e) Genin, E.; Antoniotti, S.; Michelet, V.;
Genet, J.-P. Angew. Chem., Int. Ed. 2005, 44, 4949–4953. (f) Mzhelskaya, M.
A.; Ivanchikova, I. D.; Polyakov, N. E.; Moroz, A. A.; Shvartsberg, M. S.
Russ. Chem. Bull. Int. Ed. 2004, 53, 2798–2804. (g) Gabriele, B.; Salerno, G.;
Fazio, A.; Pittelli, R. Tetrahedron 2003, 59, 6251–6259. (h) Qing, F.-L.; Gao,
W.-Z. Tetrahedron Lett. 2000, 41, 7727–7730. (i) Gabriele, B.; Salerno, G.;
Lauria, E. J. Org. Chem. 1999, 64, 7687–7692. (j) Dalla, V.; Pale, P. New J.
Chem. 1999, 803–805. (k) Gabriele, B.; Salerno, G. Chem. Commun. 1997,
1083–1084. (l) Marshall, J. A.; Sehon, C. A. J. Org. Chem. 1995, 60, 5966–
5968. (m) Seiller, B.; Bruneau, C.; Dixneuf, P. H. Tetrahedron 1995, 51,
13089–13102.
(19) This led to a rapid conversion of 2a into compounds arising from the
addition of HCl across the carbon-carbon triple bond, as has been pre-
viously observed for 1-alkynylimidazoles; see refs 8 and 9.
9230 J. Org. Chem. Vol. 74, No. 23, 2009

Laroche and Kerwin
JOCNote
TABLE 2. Regioselective Cyclizations of 1-Alkynylimidazoles 2a-j
entry
R1
R2
R3
R4
yielda (1 to 2)
yielda (2 to 3)
yielda (2 to 4)
1
2
3
4
5
6
7
8
9
10
H
H
H
Ph
Ph
Ph
Ph
Ph
H
H
Ph
Ph
Ph
H
H
H
H
H
Ph
Et
Et
H
2a (95%)
2b (90%)
2c (86%)
2d (87%)
2e (92%)
2f (92%)
2g (85%)
2h (90%)
2if
3a (80%)
3b (97%)
3c (99%)
3d (96%)
3e (78%)
3f (93%)
3g (85%)
3h (86%)
3i (24%)
3j/4j (93%)g
4a (95%)
4b (99%)
4c (100%)
4d (85%)
4e (95%)
4f (100%)d
4g (85%)e
4h (0%)
Benzb
4-Ph-imc
H
H
H
H
H
H
p-tBu-Ph
p-CF3-Ph
TIPS
Ph
Ph
Ph
Ph
Ph
H
n-Hex
4i (16%)
4j (87%)
2j (87%)
aIsolated yield after chromatography. bBenz refers to the benzimidazole core. c4-Ph-im refers to the (4-Ph)-imidazole core. dYield after 1 h. eYield after
6 days. fYield from 2h (TBAF, THF, -78 °C) is 80%. g3j and 4j were obtained as a 53/47 mixture but can be separated by flash chromatography.
these transformations was evaluated. Toward this end,
compounds 2b-j were synthesized, and their cyclizations
were carried out in presence of AuCl3 or K3PO4 in CH3CN
(Table 2).
Variation of the substituents at the carbinol center (R3,
R4) and at the imidazole core (R1) offered alcohols 2a-e as
well as the corresponding 5-exo-dig 3a-e and 6-endo-dig
4a-e cyclization products from good to excellent yields
FIGURE 2. Iodo-cyclization of 2a into 5a.
(Table 2, entries 1-5). Substrates possessing either an elec-
tron-donating (2f) or an electron-withdrawing (2g) aryl
substituent on the carbon-carbon triple bond both led to
the expected products in high yields (Table 2, entries 6 and 7);
between 2-(hydroxymethyl)imidazole and aldehydes.20
However, 5-methylene-5,7-dihydroimidazo[1,2-c]oxazole
derivatives such as 3a, which possess a cyclic N,O-ketene
acetal poised for further elaboration,21 have not been pre-
viously reported.
however, the rate of the AuCl3-catalyzed cyclization was
dramatically affected. The cyclization of the 4-methoxy
In the same vein, the iodo-cyclization reaction of 2a using
substituent analogue 2f in the presence of AuCl3 is complete
excess of NIS and K3PO4 affords the iodo-imidazo[2,1-c]-
[1,4]oxazine 5a (Figure 2), which provides a chemical handle
for further functionalization of the oxazine ring.22,23
Having optimized the conditions for the cyclization of 2a
in just 1 h, whereas the cyclization of the (4-trifluoro)phenyl
analogue 2g requires 6 days before reaching completion. The
cyclization of the triisopropylsilyl-substituted 1-alkynylimi-
dazole 2h occurred in the presence of K3PO4 to give 3h in
in either the 5-exo-dig or the 6-endo-dig mode, the scope of
86% yield; however, no conversion of 2h into 4h in the
presence of AuCl3 was observed even after extended reaction
times (Table 2, entry 8). Apparently, the steric hindrance of
(20) (a) Katritzky, A. R.; Aslan, D. C.; Leeming, P.; Stell, P. J. Tetra-
hedron: Asymmetry 1997, 8, 1491–1500. (b) Katritzky, A. R.; Aslan, D. C.;
Oniciu, D. C. Tetrahedron: Asymmetry 1998, 9, 2245–2251. (c) Chimirri, A.;
the bulky TIPS substituent prevents approach of the hydro-
xyl group to the terminal sp carbon required for the 6-endo-
dig cyclization. In the case of the 1-ethynylimidazole 2i,
prepared from 2h by protodesilylation (TBAF, THF, -78 °C,
30 min), the corresponding 5-exo-dig 3i and 6-endo-dig 4i
products were obtained in low yields (Table 2, entry 9). In
these cases, the formation of multiple side products was
observed. Finally, reaction of 2j under basic condition is the
sole example where a mixture of compounds has been ob-
tained (Table 2, entry 10). Under gold catalysis, 2j gave
exclusively compound 4j from 6-endo-dig attack. Remark-
ably, with the exceptions of compound 2h, which failed to
ꢀ
Monforte, P.; Zappala, M.; Monforte, A. M.; De Sarro, G.; Pannecouque,
C.; Witvrouw, M.; Balzarini, J.; De Clercq, E. Antiviral Chem. Chemother.
2001, 12, 169–174.
(21) For recent studies of cyclic N,O-ketene acetals, see: Zhou, A.; Cao,
L.; Li, H.; Liu, Z.; Pittman, C. U., Jr. Synlett 2006, 201–206. (b) Zhou, A.;
Njogu, M. N.; Pittman, C. U., Jr. Tetrahedron 2006, 62, 4093–4102. (c)
Huang, Y.-t.; Moeller, K. D. Tetrahedron 2006, 62, 6536–6550. (d) Quast, H.;
Ach, M.; Balthasar, J.; Hergenroether, T.; Regnat, D.; Lehmann, J.; Banert,
K. Helv. Chim. Acta 2005, 88, 1589–1609.
(22) The structure of 5a was confirmed by X-ray diffraction. 5a was
converted into 4a by treating with magnesium followed by H2O quench.
(23) Notably, Liu and co-workers reported compounds arising from a 5-
exo-dig process under similar conditions: Liu, Y.; Song, F.; Cong, L. J. Org.
Chem. 2005, 70, 6999–7002.
J. Org. Chem. Vol. 74, No. 23, 2009 9231

Laroche and Kerwin
JOCNote
afford the 6-endo-dig cyclization product under AuCl3 cata-
lysis, and 2j, which gave a mixture of 3j and 4j under basic
condition, others alcohols 2 examined afforded exclusive
5-exo-dig cyclization in the presence of K3PO4 and exclusive
6-endo-dig cyclization in the presence of AuCl3. We are
unaware of a similar case of such high reagent control of both
5-exo-dig and 6-endo-dig cyclization modes in other
4-ynol cyclizations.
We believe that cycloisomerizations under basic and
π-acid metal conditions are two distinct cases. Under basic
condition, competition should take place between 5-exo-dig
and 6-endo-dig cycloisomerization.15e With 1-alkynylimida-
zole substrates, the nitrogen attached on the carbon-carbon
triple bond should strongly disfavor the formation of the
carbionic species at its R-position (6-endo-dig attack). Under
transition metal catalysis, a complete regioselective process
regardless of the metal or the electronic nature of the
substituents is observed. This indicates that, under transition
metal catalysis, the 5-exo-dig attack is strongly disfavored.13c
We propose that Au catalyzes the cycloisomerization by
activation of the alkyne, for example, through a [(η2-alkyne)-
AuXn] complex as recently described by Behrens.24 This
coordination results in preferential acceleration of the
6-endo-dig cyclization, possibly due to the proximity of the
nucleophile to the alkyne terminal carbon in this proposed
gold η2 complex.
(0-50% EtOAc/hexane) to afford 260 mg (95%) of 2a as a white
crystalline solid: mp 89.8-90.9 °C; 1H NMR (400 MHz, CDCl3)
δ 7.47-7.42 (2H, m), 7.39-7.28 (8H, m), 7.13 (1H, s), 7.00
(1H, s), 6.05 (1H, s), 4.39 (1H, s, OH); 13C NMR (100 MHz,
CDCl3) δ 152.7 (br s), 140.3, 131.6 (2C), 129.0, 128.5 (2C), 128.4
(2C), 128.1, 127.6, 127.1 (2C), 122.3 (br s), 120.9, 77.1, 73.5, 69.5;
IR (KBr) 3127, 2259, 1432, 1248, 1179, 1150, 1054, 758,
695 cm-1; MS (CI) 549 (2M þ 1, 4%), 531 (2M - 17, 8%),
275 (M þ 1, 100%), 257 (M - 17, 23%); HRMS calcd for C18
H15 N2 O (M þ Hþ) 275.1184, found 275.1181.
Typical Procedure for the Synthesis of (Z)-5-Benzylidene-7-
phenyl-5,7-dihydroimidazo[1,2-c]oxazole (3a):. To a solution of
2a (69 mg, 0.25 mmol) in CH3CN (5 mL) was added K3PO4
(3 mg, 0.0125 mmol). The mixture was gently refluxed until
completion. After chilling, the solvent was evaporated under
reduced pressure. The residue was purified by flash chromatog-
raphy (0-20% EtOAc/hexane) to afford 55 mg (80%) of 3a as a
white solid: mp 107.6-109.8 °C; 1H NMR (400 MHz, CDCl3) δ
7.62-7.57 (2H, m), 7.52-7.46 (2H, m), 7.45-7.38 (3H, m),
7.36-7.30 (2H, m), 7.26-7.22 (2H, m), 7.20-7.14 (1H, m), 6.50
(1H, s), 5.50 (1H, s); 13C NMR (100 MHz, CDCl3) δ 150.8,
144.1, 135.9, 135.1, 133.8, 129.4, 128.9 (2C), 128.5 (2C), 127.3
(2C), 126.6 (2C), 125.7, 110.3, 85.4, 80.1; IR (KBr) 3126, 1704,
1536, 1403, 1286, 1155, 1030, 996 cm-1; MS (CI) 549 (2M þ 1,
3%), 275 (M þ 1, 100%), 257 (M - 101, 20%), 157 (M - 117,
40%); HRMS calcd for C18 H15 N2 O (M þ Hþ) 275.1184, found
275.1186.
Typical Procedure for the Synthesis of 6,8-Diphenyl-8H-
imidazo[2,1-c][1,4]oxazine (4a):. To a solution of 2a (69 mg,
0.25 mmol) in CH3CN (5 mL) was added AuCl3 (0.5 mL of a
0.01 M solution in CH3CN, 0.005 mmol). The mixture was
gently refluxed until completion. After chilling, the solvent was
evaporated under reduced pressure. The residue was purified by
flash chromatography (0-30% EtOAc/hexane) to afford 65 mg
In conclusion, we have shown that 1-alkynyl-2-(hydro-
xymethyl)imidazoles can be cyclized in the presence of
K3PO4 or AuCl3 in CH3CN to afford preferentially 5-endo-
dig or exclusively 6-endo-dig cyclization products, respec-
tively. These cyclizations exemplify a powerful new strategy
for the construction of various imidazo-fused heterocycles
from 1-alkynylimidazoles.
1
(95%) of 4a as a white solid: mp 115-117 °C; H NMR (400
MHz, CDCl3) δ 7.63-7.58 (2H, m), 7.46-7.41 (2H, m),
7.41-7.32 (6H, m), 7.16 (1H, d, J = 1.4 Hz), 7.07 (1H, d, J =
1.4 Hz), 7.01 (1H, s), 6.49 (1H, s); 13C NMR (100 MHz, CDCl3)
δ 143.0, 139.6, 136.7, 131.9, 129.2, 128.9, 128.7, 128.5 (2C), 128.4
(2C), 127.1 (2C), 124.4 (2C), 115.6, 102.0, 76.1; IR (KBr) 3112,
1652, 1484, 1449, 1437, 1400, 1337, 1162, 1026, 749 cm-1; MS
(CI) 275 (M þ 1, 100%); HRMS calcd for C18 H15 N2 O (M þ
Hþ) 275.1184, found 275.1185.
Experimental Section
Typical Procedure for the Synthesis of Phenyl-(1-(2-
phenylethynyl)-1H-imidazol-2-yl)methanol (2a): To a solution
of 1-(2-phenylethynyl)-1H-imidazole (1a) (168 mg, 1 mmol)
in THF (10 mL) under argon at -78 °C was added n-BuLi
(0.400 mL of 2.5 M solution in hexane, 1 mmol). The reaction
mixture was stirred for 15 min at -78 °C prior to the addition of
benzaldehyde (0.112 mL, 1.1 mmol). After stirring for 30 min
at -78 °C, the mixture was quenched with 1 M HCl solution
(5 mL) and the temperature was allowed to rise to room
temperature. The reaction mixture was then extracted with
CH2Cl2 (3 ꢀ 50 mL), the combined organic layers were dried
over Na2SO4, and the solvent was evaporated under reduced
pressure. The residue was purified by flash chromatography
Acknowledgment. The Robert Welch Foundation (F-1298)
and the Texas Advanced Research Program (3658-003) are
thanked for financial support of this research.
Supporting Information Available: General experimental
conditions, detailed experimental procedures, X-ray structure of
5a, 1H NMR and 13C NMR spectra for all new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(24) Schulte, P.; Behrens, U. Chem. Commun. 1998, 1633.
9232 J. Org. Chem. Vol. 74, No. 23, 2009