New imidazole-based tripodal ligands as CuB site mimics of cytochrome c oxidase

Full text of DOI:10.1021/jo010737m

8252
J . Org. Chem. 2001, 66, 8252-8256
New Im id a zole-Ba sed Tr ip od a l Liga n d s a s
Cu B Site Mim ics of Cytoch r om e c Oxid a se
J ames P. Collman,* Min Zhong, Simona Costanzo, and
Chi Zhang
Department of Chemistry, Stanford University, Stanford,
California 94305-5080
jpc@stanford.edu
Received J uly 23, 2001
In tr od u ction
Cytochrome c oxidase (CcO) is the terminal enzyme of
the respiratory chains of mitochondria and aerobic
bacteria.1 Recent high-resolution X-ray diffraction analy-
ses2 have disclosed that the active site of CcO is composed
of a five-coordinate myoglobin-type iron center (heme a3)
with an imidazole ligand from a histidine residue on the
proximal side of the heme and a copper atom (CuB)
coordinated to three histidine imidazoles on the distal
side. Moreover, one of the CuB ligands, His240, is cross-
linked through a C-N bond to the phenol residue from
Tyr244, which has been postulated to serve as a hydrogen
atom donor during the 4H+, 4e- reduction of O2 to H2O.3
In the course of our long-term program on biomimetic
studies of CcO, a series of active-site model compounds
based on the R3â-5,10,15,20-tetra(2′-aminophenyl)por-
phyrin (R3â-TAPP) template have been designed and
synthesized.4 For example, model 1 bears a covalently
linked TACN-type tridentate ligand on the distal side
(Figure 1).4c To make these models structurally closer to
the active site in CcO, our recent effort has been devoted
to the preparation of new superstructures such as
compound 2 (Figure 1)4g containing three individual
distal imidazole ligands. However, our preliminary elec-
trochemical studies on catalytic O2 reduction have shown
F igu r e 1.
that these compounds can lose copper after a few cycles
on a graphite electrode, making the analyses of their
electrochemical properties more difficult. Recently, mod-
els 3 and 4 (Figure 1) were reported by Naruta et al.5
and our group.6 Although the imidazole-based tripod in
each model binds copper tightly,7 this tripodal complex
is linked to the porphyrin through a single amide bond.
This single-point attachment allows free rotation of the
tripod on the distal side, interfering with the formation
of stable binuclear heme(Fe)/trisimidazole(Cu) oxygen
adducts. Therefore, we set forth to prepare several novel
model compounds containing two or three links between
tripodal ligands and customized porphyrins such as R3â-
TAPP and RâRâ-TAPP employing Michael acceptor,4a-e,h
chloroacetamido,4d or isocyanate groups8 as links.
Although the preparation of specialized porphyrins4
based on the R3â-TAPP and RâRâ-TAPP templates and
simple imidazole-based tripods9 has been well developed,
the chemistry for synthesizing trisimidazoles containing
two or three functional groups is still not satisfactory.
To the best of our knowledge, the -OH free precursor of
compound 5 (Figure 2) synthesized from 1-methyl-1H-
4-histamine (9) by Potvin et al.9d is the only example of
this class to date. Herein, we present a practical synthesis
of several new imidazole-based tridentates 6, 7, and 8
(Figure 2) containing -OH or -NHCH3 groups as im-
portant intermediates for model studies of CcO.
* To whom correspondence should be addressed. Phone: (650) 725-
0283. Fax: (650) 725-0259.
(1) Ferguson-Miller, S.; Babcock, G. T. Chem. Rev. 1996, 96, 2889-
2907 and references therein.
(2) (a) Ostermeier, C.; Harrenga, A.; Ermler, U.; Michel, H. Proc.
Natl. Acad. Sci. U.S.A. 1997, 94, 10547-10553. (b) Yoshikawa, S.;
Shinzawa-Itoh, K.; Nakashima, R.; Yaono, R.; Yamashita, E.; Inoue,
N.; Yao, M.; Fei, M. J .; Libeu, C. P.; Mizushima, T.; Yamaguchi, H.;
Tomizaki, T.; Tsukihara, T. Science 1998, 280, 1723-1729.
(3) (a) Gennis, R. B. Biochim. Biophys. Acta 1998, 1365, 241-248.
(b) Sucheta, A.; Szundi, I.; Einarsdottir, O. Biochemistry 1998, 37,
17905-17914. (c) Proshlyakov, D. A.; Pressler M. A.; Babcock G. T.
Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 8020-8025. (d) MacMillan, F.;
Kannt, A.; Behr, J .; Prisner, T.; Michel, H. Biochemistry 1999, 38,
9179-9184. (e) Proshlyakov, D. A.; Pressler, M. A.; DeMaso, C.;
Leykam, J . F.; DeWitt, D. L.; Babcock, G. T. Science 2000, 290, 1588-
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(4) (a) Collman, J . P.; Herrmann, P. C.; Boitrel, B.; Zhang, X.;
Eberspacher, T. A.; Fu, L. J . Am. Chem. Soc. 1994, 116, 9783-9784.
(b) Collman, J . P.; Zhang, X.; Herrmann, P. C.; Uffelman, E. S.; Boitrel,
B.; Straumanis, A.; Brauman, J . I. J . Am. Chem. Soc. 1994, 116, 2681-
2682. (c) Collman, J . P.; Fu, L.; Herrmann, P. C.; Zhang, X. M. Science
1997, 275, 949-951. (d) Collman, J . P.; Boitrel, B.; Fu, L.; Galanter,
J .; Straumanis, A.; Rapta, M. J . Org. Chem. 1997, 62, 2308-2309. (e)
Collman, J . P.; Bro¨ring, M.; Fu, L.; Rapta, M.; Schwenninger, R.;
Straumanis, A. J . Org. Chem. 1998, 63, 8082-8083. (f) Collman, J .
P.; Bro¨ring, M.; Fu, L.; Rapta, M.; Schwenninger, R. J . Org. Chem.
1998, 63, 8084-8085. (g) Collman, J . P.; Rapta, M.; Bro¨ring, M.;
Raptova, L.; Schwenninger, R.; Boitrel, B.; Fu, L.; L’Her, M. J . Am.
Chem. Soc. 1999, 121, 1387-1388. (h) Collman, J . P.; Schwenninger,
R.; Rapta, M.; Bro¨ring, M.; Fu, L. Chem. Commun. 1999, 137-138.
(5) Tani, F.; Matsumoto, Y.; Tachi, Y.; Sasaki, T.; Naruta, Y. Chem.
Commun. 1998, 1731-1732.
(6) Collman, J . P.; Zhong, M.; Wang, Z.; Rapta, M.; Rose, E. Org.
Lett. 1999, 1, 2121-2124.
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(8) (a) J agessar, R. C.; Burns, D. H. Chem. Commun. 1997, 1685-
1686. (b) Collman, J . P.; Wang, Z.; Straumanis, A. J . Org. Chem. 1998,
63, 2424-2425.
(9) Representative examples for the synthesis of imidazole-based
tripodal ligands: (a) Tang, C. C.; Davalian, D.; Huang, P.; Breslow, R.
J . Am. Chem. Soc. 1978, 100, 3918-3922. (b) Brown, R. S.; Huguet, J .
Can. J . Chem. 1980, 58, 889-901. (c) Breslow, R.; Hunt, J . T.; Smiley,
R.; Tarnowski, T. J . Am. Chem. Soc. 1983, 105, 5337-5342. (d) Potvin,
P. G.; Wong, M. H. Chem. Commun. 1987, 672-674. (e) Manoharan,
T. S.; Brown, R. S. J . Org. Chem. 1989, 1439-1442. (f) Collman, J . P.;
Zhong, M.; Wang, Z. Org. Lett. 1999, 1, 949-951. (g) Collman, J . P.;
Zhong, M.; Boulatov, R. J . Chem. Res., Synop. 2000, 230-231.
10.1021/jo010737m CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/31/2001

Notes
J . Org. Chem., Vol. 66, No. 24, 2001 8253
Sch em e 2a
F igu r e 2.
Sch em e 1a
a
Reagents and conditions: (a) KSCN, CH3NH2, acetic acid,
n-butanol, 3 days, 62%; (b) HNO3, catalytic NaNO2, 75%; (c) NaH,
CH3I, DMF, 60% (for 16) or NaH, p-methoxybenzylic bromide,
DMF, 61% (for 17); (d) n-BuLi, methyl chloroformate, THF, -78
f room temperature, 24 h, 92% (from 16 to 18) and 77% (from 17
to 19); (e) NaH, CH3I, THF, 73%; (f) CAN, 9/1 (v/ v) CH2Cl2/H2O,
room temperature, overnight, 62%.
Sch em e 3a
a
Reagents and conditions: (a) acetonylacetone, AcOH, benzene,
reflux, overnight, 81%; (b) n-BuLi, I2, -78 f 0 °C, 51%; (c) n-BuLi,
(EtO)2CO, -78 f room temperature, overnight, 68%.
Resu lts a n d Discu ssion
Initially, we planned to use Potvin’s procedure9d to
prepare compound 5 and then condense it with R3â-TAPP
through urea-type links. 1-Methyl-1H-4-histamine (9) can
be selectively prepared from histamine in high yield
following a modified procedure;10 however, it was re-
ported that the silylation of the amino group in compound
9 with Me3SiCl gives a low yield (37%) of the correspond-
ing protected intermediate.9d Moreover, this trimethyl-
silyl protective group is very labile in hydroxylic media11
and the corresponding intermediate is hard to purify by
ordinary chromatography. Hence, after some trials using
the trimethylsilyl group, we focused our effort on finding
other suitable protective groups for the free -NH2 in
compound 9.
a
Reagents and conditions: (a) MnO2, CHCl3, reflux, 48 h, 71%.
(b) 40% aqueous CH3NH2, CH3OH, room temperature, overnight;
NaBH4, reflux, overnight, 93%. (c) (Boc)2O, NaHCO3, 2/1 (v/v)
CHCl3/H2O, 72% (for 23); triphenylmethyl bromide, Et3N, DMF,
75% (for 24); allyl bromide, Cs2CO3, DMF, 82% (for 25). (d) n-BuLi,
(EtO)2CO, -78 f room temperature, 24 h, 35% (from 25 to 26).
(e) NaH, CH3I, THF, 51%. (f) Catalytic Pd(PPh3)4, p-tolylsulfinic
acid, CH2Cl2, 85%.
As shown in Scheme 1, the -NH2 group in compound
9 is readily converted to its 2,5-dimethyl pyrrole11 deriva-
tive (10), which is stable and can be easily obtained in a
much higher yield (81%) compared with the trimethyl-
silyl-protected form of compound 9. However, treatment
of compound 10 with n-BuLi, followed by the addition of
methyl chloroformate, only generates the bidentate ligand
12. None of the desired tripodal ligand is formed by
treating compound 12 with either the 2-imidazolyl anion
of compound 10 or the Grignard reagent of compound 11
or by treating the latter with diethyl carbonate, presum-
ably due to the steric hindrance of the two 2,5-dimethyl
pyrrole moieties.
ligand. When compound 16 is treated with n-BuLi,
followed by the addition of methyl chloroformate, the
tripodal ligand 18 is formed in 92% yield. Encouraged
by this result, we then transformed compound 15 to its
corresponding p-methoxybenzyl (PMB) ether in order to
differentiate the three primary alcohols from the tertiary
alcohol in the following steps. When 3 equiv of the
2-imidazolyl anion of compound 17 react with 1 equiv of
methyl chloroformate, a 77% yield of tripod 19 is formed.
The tridentate 6 is produced in 45% yield by methylation
of compound 19 and oxidative deprotection of the PMB
groups in compound 20 with ammonium cerium nitrate
(CAN).13
The tridentate ligand 6 having one carbon less in the
side chains compared to compound 5 was then prepared.
As shown in Scheme 2, the imidazole alcohol 15 is
prepared in 46% yield in two steps from 1,3-dihydroxy-
acetone (13) following Rapoport’s procedure12 with some
modifications. Compound 15 was then converted to its
corresponding methyl ether 16 in order to test the
feasibility of the condensation for preparing a tripodal
Subsequently, -NHCH3-functionalized tridentates 7
and 8 were also prepared. As shown in Scheme 3,
aldehyde 21, obtained by oxidizing compound 15 with
activated MnO2, is readily converted to the secondary
amine 22 by condensation with methylamine and reduc-
tion of the corresponding imine intermediate with NaBH4.
Whereas tert-butoxylcarbonyl (Boc)- or trityl (Tr)-pro-
tected intermediates 23 and 24 cannot generate the
corresponding tripod by treatment with n-BuLi and
diethyl carbonate, the intermediate 25, filled with the
(10) Collman, J . P.; Zhong, M.; Costanzo, S. J . Chem. Res., Synop.
2001, 195-197 and references therein.
(11) Bruekelman, S. P.; Leach, S. E.; Meakins, G. D.; Tirel, M. D.
J . Chem. Soc., Perkin Trans. 1 1984, 2801-2807.
(12) Dener, J . M.; Zhang, L.-H.; Rapoport, H. J . Org. Chem. 1993,
58, 1159-1166.
(13) (a) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett.
1982, 23, 885-888. (b) J ohansson, R.; Samuelsson, B. J . Chem. Soc.,
Perkin Trans. 1 1984, 2371-2374.

8254 J . Org. Chem., Vol. 66, No. 24, 2001
Notes
Sch em e 4a
spectra were measured by the Mass Spectrometry Facility at
the University of California, San Francisco.
4-[2′-(2′′,5′′-Dim e t h yl-1′′-p yr r olyl)e t h yl]-1-m e t h yl-1H -
im id a zole (10). A mixture of 1-methyl-1H-4-histamine (9) (2.00
g, 16.0 mmol), acetonylacetone (1.86 g, 16.3 mmol), and acetic
acid (0.40 g, 6.7 mmol) in benzene (40 mL) was refluxed
overnight. The reaction mixture was cooled to room temperature
and then stirred with K2CO3 for 30 min, and the solid was
filtered off. The filtrate was concentrated, and the residue was
purified by preparative silica gel thin-layer chromatography
using 1/3 (v/ v) CHCl3/hexanes (saturated with NH3 gas) as the
eluent to give 2.63 g of compound 10 as a pale yellow liquid in
81% yield. 1H NMR (400 MHz, CDCl3): δ 7.37 (s, 1H), 6.54 (s,
1H), 5.76 (s, 2H), 4.02 (t, J ) 7.9 Hz, 2H), 3.63 (s, 3H), 2.83 (t,
J ) 7.9 Hz, 2H), 2.19 (s, 6H). 13C NMR (100 MHz, CDCl3): δ
139.40, 137.33, 127.48, 117.19, 104.88, 43.69, 33.23, 29.92, 12.36.
MS (m/z): 203(M+), 188, 108(100), 95, 83, 67. HRMS: calcd for
a
Reagents and conditions: (a) n-BuLi, (EtO)2CO, -78 f room
temperature, 24 h, 55%. (b) n-BuLi, 1-(2′-methoxyphenyl)-1H-
imidazole, THF, -78 °C, 1 h; 28, THF, -78 f room temperature,
24 h, 55%. (c) NaH, CH3I, THF, 51%. (d) Catalytic Pd(PPh3)4,
p-tolylsulfinic acid, CH2Cl2, 83%.
C
12H17N3 (M+), 203.142; found, 203.142.
4-[2′-(2′′,5′′-Dim eth yl-1′′-p yr r olyl)eth yl]-2-iod o-1-m eth yl-
1H-im id a zole (11). To a solution of compound 10 (814 mg, 4.0
mmol) in dry THF (80 mL) was added n-BuLi (1.6 mL, 2.5 M in
hexanes, 4.0 mmol) at -78 °C under an atmosphere of N2, and
the solution was stirred at this temperature for 30 min. Then,
a solution of I2 (1.07 g, 4.2 mmol) in dry THF (10 mL) was added
and the resulting mixture was allowed to warm to 0 °C and
stirred for 30 min. The reaction was quenched by adding several
drops of a saturated aqueous solution of NH4Cl. The solvent was
removed, and the residue was purified by preparative silica gel
thin-layer chromatography using 1/3 (v/ v) CHCl3/hexanes (satu-
rated with NH3 gas) as the eluent to give 671 mg of compound
11 as a pale yellow liquid in 51% yield. 1H NMR (400 MHz,
CDCl3): δ 6.66 (s, 1H), 5.74 (s, 2H), 3.99 (t, J ) 7.7 Hz, 2H),
3.55 (s, 3H), 2.81 (t, J ) 7.7 Hz, 2H), 2.17 (s, 6H). 13C NMR (100
MHz, CDCl3): δ 142.52, 127.50, 121.49, 104.98, 43.49, 36.56,
30.04, 12.41. MS (FAB, m/z): 342 (M+ + Na), 331 (M+ + 2), 330
(M+ + 1, 100), 328 (M+ - 1), 235, 202.
Bis{4-[2′-(2′′,5′′-d im eth yl-1′′-p yr r olyl)eth yl]-1-m eth yl-1H-
2-im id a zolyl}k eton e (12). To a solution of compound 10 (370
mg, 1.82 mmol) in dry THF (20 mL) was added n-BuLi (0.76
mL, 2.5 M in hexanes, 1.91 mmol) at -78 °C, and the solution
was stirred at this temperature for 30 min. Then, (EtO)2CO (65
mg, 0.55 mmol) was added to the solution and the resulting
mixture was allowed to warm to room temperature and stirred
at room temperature for 24 h. The reaction was quenched by
the addition of several drops of a saturated aqueous solution of
NH4Cl. The solvent was removed, and the residue was purified
by preparative silica gel thin-layer chromatography using 1/3
(v/ v) CHCl3/hexanes (saturated with NH3 gas) as the eluent to
give 162 mg of compound 12 as a pale yellow liquid in 68% yield
based on the amount of the carbonyl substrate. 1H NMR (400
MHz, CDCl3): δ 6.61 (s, 2H), 5.76 (s, 4H), 4.06 (t, J ) 7.8 Hz,
4H), 3.93 (s, 6H), 2.96 (t, J ) 7.8 Hz, 4H), 2.17 (s, 12H). 13C
NMR (100 MHz, CDCl3): δ 173.94, 142.52, 139.98, 127.53,
124.72, 105.09, 43.16, 35.68, 29.97, 12.49. MS (m/z): 432(M+),
338, 243, 203, 149, 108(100), 71, 57. HRMS: calcd for C25H32N6O
(M+), 432.264; found, 432.264.
less sterically hindered allylic protective group, gives a
35% yield of tripod 26. No improved yield of the tripodal
ligand 26 was obtained either by increasing the ratio of
25/carbonyl substrate, by changing the reaction temper-
ature, by adding N,N,N′,N′-tetramethylethylenediamine
(TMEDA), or by replacing n-BuLi with a milder lithiation
reagent such as lithium N,N-di-iso-propylamine (LDA).
Presumably, the interaction of the two sp3 N atoms in
compound 25 with lithium ion in the presence of n-BuLi
or LDA reduces the reactivity of the corresponding
substrate, resulting in a lower yield of the tripodal ligand
26 compared to that of compounds 18 and 19. Methyla-
tion of compound 26 gives compound 27 in 51% yield.
Only a 20% yield of tripod 7 is generated when a Pd2-
(dba)3/dppb/o-thiolbenzoic acid/THF system14a is used to
remove all of the allylic groups in compound 27, but the
yield increases to 85% when a Pd(PPh3)4/p-tolylsulfinic
acid/CH2Cl2 system is employed.14b
When 2 equiv of the 2-imidazolyl anion of compound
25 react with 1 equiv of diethyl carbonate, a 55% yield
of bidentate 28 is formed (Scheme 4). The treatment of
compound 28 with 1 equiv of 1-(2′-methoxyphenyl)-1H-
2-imidazolyl anion generates the tripodal ligand 29 in
55% yield. Methylation of compound 29 and the subse-
quent deprotection of the allylic groups in compound 30
yield the tripodal ligand 8, which contains a functional-
ized phenol moiety as a projected Tyr244 mimic.
In summary, we have prepared three new functional-
ized tripodal ligands 6, 7, and 8 as CuB site mimics of
CcO using the readily available imidazole alcohol 15 as
a starting material. It should be noted that all these
tripodal ligands could serve as active-site mimics of other
metalloenzymes such as zinc enzymes.9a-c The condensa-
tion of these ligands with specialized porphyrins as well
as the metalation, coordination, and electrochemical
properties of the model compounds is currently being
investigated, and the results will be reported in due
course.
5-Hydr oxym eth yl-2-m er capto-1-m eth yl-1H-im idazole (14).
This compound was prepared following Rapoport’s procedure12
with some modifications. A mixture of 1,3-dihydroxyacetone
dimer (72.0 g, 0.8 mol), KSCN (116.6 g, 1.2 mol), and methyl-
amine hydrochloride (67.5 g, 1.0 mol) in acetic acid (90 mL) and
n-butanol (600 mL) was mechanically stirred in an ultrasonic
bath for 3 days. The resulting suspension was diluted with water
and washed with CHCl3 several times in a separatory funnel.
The aqueous layer was filtered, and the solid was washed with
CHCl3 and dried over P2O5 in vacuo to give 72 g of compound
1
14 as a pale yellow solid in 62% yield. Mp: 200-202 °C dec. H
NMR (400 MHz, d6-DMSO): δ 11.99 (s, 1H), 6.80 (s, 1H), 5.19
(s, 1H), 4.31 (s, 2H), 3.43 (s, 3H).
Exp er im en ta l Section
All reagents were used as supplied commercially without
further purification unless otherwise noted. Melting points are
uncorrected. 1H NMR spectra were recorded at 400 and 500
MHz; 13C NMR spectra were recorded at 100 and 125 MHz. Mass
5-Hyd r oxym eth yl-1-m eth yl-1H-im id a zole (15). This com-
pound was prepared following Rapoport’s procedure12 with some
modifications. To a vigorously stirred solution of NaNO2 (100
mg, 1.45 mmol) in aqueous nitric acid (30 mL, 2.4 M in water)
was added compound 14 (5.1 g, 35.4 mmol) in small portions
over a 2 h period at 0 °C. After the addition was complete, the
yellow solution was stirred at room temperature overnight. The
reaction mixture was adjusted to pH 9.0 by adding solid NaHCO3
(14) (a) Lemaire-Audoire, S.; Savignac, M.; Geneˆt, J . P.; Bernard,
J .-M. Tetrahedron Lett. 1995, 36, 1267-1270. (b) Honda, M.; Morita,
H.; Nagakura, I. J . Org. Chem. 1997, 62, 8932-8936.

Notes
J . Org. Chem., Vol. 66, No. 24, 2001 8255
and evaporated to dryness in vacuo. The residue was extracted
with hot CHCl3, and the extract was dried over Na2SO4. The
solvent was removed, and the residue was dried over P2O5 in
vacuo to give 3.0 g of compound 15 as a pale yellow solid in 75%
preparative silica gel thin-layer chromatography using 3/1 (v/
v) CHCl3/hexanes (saturated with NH3 gas) as the eluent to give
130 mg of compound 20 as a yellow liquid in 73% yield. 1H NMR
(400 MHz, CDCl3): δ 7.21 (d, J ) 8.6 Hz, 6H), 6.98 (s, 3H), 6.84
(d, J ) 8.6 Hz, 6H), 4.43 (s, 6H), 4.38 (s, 6H), 3.78 (s, 9H), 3.48
(s, 3H), 3.41 (s, 9H). 13C NMR (125 MHz, CDCl3): δ 159.23,
145.36, 130.40, 129.62, 129.54, 127.71, 113.75, 78.79, 71.00,
60.81, 55.17, 54.54, 31.80. MS (ESI, m/z): 737 (M+ + 1), 736
(M+, 100), 704, 567, 505, 233, 120.
1
yield. Mp: 108-110 °C. H NMR (400 MHz, CDCl3): δ 7.31 (s,
1
1H), 6.77 (s, 1H), 4.56 (s, 2H), 3.66 (s, 3H). H NMR (400 MHz,
d6-DMSO): δ 7.53 (s, 1H), 6.77 (s, 1H), 4.42 (s, 2H), 3.60 (s, 3H).
13C NMR (100 MHz, CDCl3): δ 138.42, 131.71, 127.52, 53.50,
31.51. 13C NMR (100 MHz, d6-DMSO): δ 138.55, 131.97, 127.13,
52.54, 31.00.
Tr is(5-h yd r oxym eth yl-1-m eth yl-1H-2-im id a zolyl)m eth -
yl Meth yl Eth er (6). A solution of compound 20 (130 mg, 0.18
mmol) and ammonium cerium nitrate (580 mg, 1.06 mmol) in
CH2Cl2 (4.5 mL) and water (0.5 mL) was stirred at room
temperature overnight. The solvent was removed, and the
residue was diluted with water (10 mL). The aqueous solution
was extracted several times with ether, and then the pH was
adjusted to 9.0 by adding solid NaHCO3. The solvent was
removed, and the residue was extracted with a small amount of
methanol. Subsequently, the organic portion was concentrated
and the residue was purified by preparative silica gel thin-layer
chromatography using 9/1 (v/ v) CHCl3/CH3OH (saturated with
NH3 gas) as the eluent to give 41 mg of compound 6 as a white
5-Meth oxym eth yl-1-m eth yl-1H-im id a zole (16). To a solu-
tion of compound 15 (1.0 g, 8.9 mmol) in dry DMF (25 mL) was
added NaH (392 mg, 9.8 mmol, 60% in paraoil), and the resulting
mixture was stirred at room temperature for 1 h. Subsequently,
CH3I (0.61 mL, 9.8 mmol) was added to the solution and the
mixture was stirred at room temperature overnight. The solvent
was removed, and the residue was purified by silica gel column
chromatography using 1/1 (v/ v) CHCl3/hexanes (saturated with
NH3) as the eluent to give 675 mg of compound 16 as a yellow
1
liquid in 60% yield. H NMR (400 MHz, CDCl3): δ 7.44 (s, 1H),
7.01 (s, 1H), 4.41 (s, 2H), 3.65 (s, 3H), 3.30 (s, 3H). 13C NMR
(100 MHz, CDCl3): δ 139.19, 130.03, 127.78, 63.34, 57.11, 31.36.
MS (m/z): 126 (M+), 111, 95 (100), 83, 77, 57. HRMS: calcd for
C6H10N2O (M+), 126.079; found, 126.079.
1
semisolid in 62% yield. H NMR (400 MHz, CD3OD): δ 6.83 (s,
1
3H), 4.45 (s, 6H), 3.32 (s, 9H), 3.22 (s, 3H). H NMR (400 MHz,
5-[(4′-Meth oxyph en yl)m eth oxym eth yl]-1-m eth yl-1H-im id-
a zole (17). This compound was obtained as a yellow liquid in
61% yield following the procedure for preparing compound 16
using p-methoxybenzylic bromide15 instead of CH3I as the
electrophile. 1H NMR (400 MHz, CDCl3): δ 7.44 (s, 1H), 7.23
(d, J ) 8.6 Hz, 2H), 7.00 (s, 1H), 6.88 (d, J ) 8.6 Hz, 2H), 6.17
(s, 1H), 4.47 (s, 2H), 4.41 (s, 2H), 3.80 (s, 3H), 3.63 (s, 3H). 13C
NMR (125 MHz, CDCl3): δ 159.46, 139.38, 130.21, 129.84,
129.77, 128.14, 114.00, 71.14, 60.72, 55.42, 31.69. MS (m/z): 232
(M+), 202, 138, 121 (100), 109, 95, 82, 77. HRMS: calcd for
C13H16N2O2 (M+), 232.121; found, 232.122.
d5-pyridine): δ 7.17 (s, 3H), 4.80 (s, 6H), 3.80 (s, 3H), 3.76 (s,
9H). 13C NMR (100 MHz, CD3OD): δ 145.83, 136.28, 126.42,
79.92, 55.26, 54.45, 32.46. MS (m/z): 376 (M+), 375 (M+ - 1),
374 (M+ - 2), 359, 266, 161, 130 (100), 83. HRMS: calcd for
C17H22N6O4 (M+ - 2), 374.1702; found, 374.1712.
1-Meth yl-1H-im id a zole-5-ca r boxa ld eh yd e (21). This com-
pound was prepared following Rapoport’s procedure12 with some
modifications. A mixture of compound 15 (24.7 g, 0.22 mol) and
activated MnO2 (95.6 g, 1.1 mol) in CHCl3 was refluxed for 48
h. The reaction mixture was cooled to room temperature and
filtered through a Celite 545 column. The filter cake was washed
with 5% CH3OH in CHCl3, and the filtrate was concentrated.
The residue was purified by silica gel column chromatography
using 1/19 (v/ v) CH3OH/CHCl3 as the eluent to give 17.4 g of
compound 21 as a pale yellow solid in 71% yield. Mp 52-54 °C.
1H NMR (400 MHz, CDCl3): δ 9.75 (s, 1H), 7.77 (s, 1H), 7.60 (s,
1H), 3.93 (s, 3H).
Tr is(5-m eth oxym eth yl-1-m eth yl-1H-2-im id a zolyl)m eth -
yl Alcoh ol (18). To a solution of compound 16 (180 mg, 1.4
mmol) in dry THF (7 mL) was added n-BuLi (0.57 mL, 1.4 mmol,
2.5 M in hexanes) at -78 °C under an atmosphere of N2, and
the solution was warmed to -40 °C and stirred for 1 h. The
solution was cooled to -78 °C again, and methyl chloroformate
(34 mg, 0.35 mmol) was added. The mixture was allowed to
warm to room temperature and stirred for 24 h. The reaction
was quenched by adding several drops of a saturated aqueous
solution of NH4Cl; the solvent was removed, and the residue was
purified by preparative silica gel thin-layer chromatography
using 4/1 (v/ v) CHCl3/hexanes (saturated with NH3 gas) as the
eluent to give 131 mg of compound 18 as a white semisolid in
92% yield based on the amount of the carbonyl substrate. 1H
NMR (400 MHz, CDCl3): δ 6.95 (s, 3H), 4.40 (s, 6H), 3.38 (s,
9H), 3.30 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 147.40, 130.35,
127.23, 71.99, 63.73, 57.19, 31.35. MS (m/z): 404 (M+), 279, 231,
N-Meth yl-5-a m in om eth yl-1-m eth yl-1H-im id a zole (22). A
solution of compound 21 (15.4 g, 0.14 mol) in CH3NH2 (36.0 mL,
0.42 mol, 40% in water) and CH3OH (270 mL) was stirred at
room temperature overnight, and then NaBH4 (15.9 g, 0.42 mol)
was cautiously added to the solution. The resulting mixture was
stirred at room temperature for several hours and then refluxed
overnight. The reaction mixture was cooled to room temperature
and evaporated to dryness in vacuo. The resulting solid was
extracted with hot CHCl3, and the extract was dried over
anhydrous Na2SO4. The solvent was removed, and the residue
was purified by silica gel column chromatography using 1/19 (v/
v) CH3OH/CHCl3 (saturated with NH3 gas) as the eluent to give
153, 126, 95 (100), 83, 57. HRMS: calcd for C19H29N6O4 (M+
1), 405.225; found, 405.225.
+
1
16.3 g of compound 22 as a pale yellow liquid in 93% yield. H
Tr is{5-[(4′-m et h oxyp h en yl)m et h oxym et h yl]-1-m et h yl-
1H-2-im id a zolyl}m et h yl Alcoh ol (19). This compound was
obtained as a white semisolid in 77% yield following the
procedure for preparing compound 18 using compound 17
instead of compound 16 as the substrate. 1H NMR (400 MHz,
CDCl3): δ 7.23 (d, J ) 8.6 Hz, 6H), 6.90 (s, 3H), 6.86 (d, J ) 8.6
Hz, 6H), 6.09 (s, 1H), 4.44 (s, 6H), 4.39 (s, 6H), 3.78 (s, 9H), 3.40
(s, 9H). 13C NMR (125 MHz, CDCl3): δ 159.50, 147.60, 130.82,
129.88, 129.85, 127.65, 114.04, 72.14, 71.20, 61.07, 55.45, 31.77.
MS (ESI, m/z): 723 (M+ + 1), 705, 490 (100), 353, 258, 224.
Tr is{5-[(4′-m et h oxyp h en yl)m et h oxym et h yl]-1-m et h yl-
1H-2-im id a zolyl}m eth yl Meth yl Eth er (20). To a solution of
compound 19 (175 mg, 0.24 mmol) in dry THF (5 mL) was added
NaH (11 mg, 0.27 mmol, 60% in paraoil), and the resulting
mixture was stirred at room temperature for 1 h. Subsequently,
CH3I (38 mg, 0.27 mml) was added and the mixture was stirred
at room temperature overnight. The reaction was quenched by
adding several drops of a saturated aqueous solution of NH4Cl.
The solvent was removed, and the residue was purified by
NMR (400 MHz, CDCl3): δ 7.37 (s, 1H), 6.88 (s, 1H), 3.67 (s,
2H), 3.63 (s, 3H), 2.40 (s, 3H). 13C NMR (100 MHz, CDCl3): δ
138.01, 129.63, 127.70, 44.63, 35.56, 30.98. MS (m/z): 125 (M+),
95 (100), 83, 68. HRMS: calcd for C6H11N3 (M+), 125.095; found,
125.095.
N -(t er t -Bu t oxyca r b on yl)-N -m e t h yl-5-a m in om e t h yl-1-
m eth yl-1H-im id a zole (23). To a mixture of compound 22 (2.0
g, 16 mmol) and NaHCO3 (1.4 g, 16 mmol) in a biphasic solvent
CHCl3/H2O (30 mL/15 mL) was added (Boc)2O (3.5 g, 16 mmol),
and the resulting mixture was stirred at room temperature for
2 h and then refluxed for another 1 h. The reaction mixture was
cooled to room temperature and extracted with CHCl3. The
extract was washed with brine and dried over anhydrous Na2-
SO4. The solvent was removed, and the residue was purified by
preparative silica gel thin-layer chromatography using 3/1 (v/
v) CHCl3/hexanes (saturated with NH3 gas) as the eluent to give
2.6 g of compound 23 as a yellow oil in 72% yield. 1H NMR (400
MHz, CDCl3): δ 7.43 (s, 1H), 6.95 (s, 1H), 4.43 (s, 2H), 3.59 (s,
3H), 2.71 (s, 3H), 1.46 (s, 9H). 13C NMR (100 MHz, CDCl3): δ
155.50, 138.99, 129.59, 127.49, 79.90, 40.73, 32.47, 31.54, 28.31.
MS (m/z): 225 (M+), 169, 124, 110, 95 (100), 83, 58. HRMS: calcd
for C11H19N3O2 (M+), 225.1477; found, 225.1478.
(15) Burke, S. D.; Hong, J .; Lennox, J . R.; Mongin, A. P. J . Org.
Chem. 1998, 63, 6952-6967.

8256 J . Org. Chem., Vol. 66, No. 24, 2001
Notes
N-Tr it yl-N-m et h yl-5-a m in om et h yl-1-m et h yl-1H -im id -
a zole (24). To a solution of compound 22 (350 mg, 2.8 mmol) in
dry DMF (10 mL) were added, respectively, dry Et3N (425 mg,
4.2 mmol) and triphenylmethyl bromide (970 mg, 3.0 mmol). The
resulting mixture was stirred at room temperature overnight.
The solvent was removed in vacuo, and the residue was purified
by preparative silica gel thin-layer chromatography using 1/19
(v/ v) CH3OH/EtOAc as the eluent to give 770 mg of compound
thin-layer chromatography using 1/1 (v/ v) CHCl3/hexanes (satu-
rated with NH3 gas) as the eluent to give 313 mg of compound
28 as a yellow semisolid in 55% yield. 1H NMR (500 MHz,
CDCl3): δ 7.18 (s, 2H), 5.84 (m, 2H), 5.19 (m, 4H), 3.98 (s, 6H),
3.49 (s, 4H), 3.02 (d, J ) 6.6 Hz, 4H), 2.19 (s, 6H). 13C NMR
(125 MHz, CDCl3): δ 174.56, 144.56, 135.36, 134.89, 131.40,
118.38, 60.66, 50.81, 42.28, 33.15. MS (ESI, m/z): 357 (M+ + 1,
100), 334, 317, 302, 286, 215, 202, 179, 143.
1
24 as a yellow liquid in 75% yield. H NMR (400 MHz, CDCl3):
Bis(N-a llyl-N-m et h yl-5′-a m in om et h yl-1′-m et h yl-1′H -2′-
im idazolyl)[1′′-(2′′′-m eth oxyph en yl)-1′H-2′-im idazolyl] Meth -
yl Alcoh ol (29). To a solution of 1-(2′-methoxyphenyl)-1H-
imidazole (278 mg, 1.6 mmol) in dry THF (16 mL) was slowly
added n-BuLi (0.64 mL, 1.6 mmol, 2.5 M in hexanes) at -78 °C
under an atmosphere of N2, and the resulting mixture was
warmed to -40 °C and stirred for 1 h. The mixture was cooled
to -78 °C again, and compound 28 (517 mg, 1.45 mmol) in dry
THF (4 mL) was added. Subsequently, it was warmed to room
temperature and stirred at room temperature for 24 h. The
reaction was quenched by adding several drops of a saturated
aqueous solution of NH4Cl. The solvent was removed, and the
residue was purified by preparative silica gel thin-layer chro-
matography using 2/1 (v/ v) CHCl3/hexanes (saturated with NH3
gas) as the eluent to give 420 mg of compound 29 as a yellow oil
δ 7.55 (d, J ) 7.5 Hz, 6H), 7.36 (s, 1H), 7.24-7.28 (m, 6H), 7.22
(s, 1H), 7.16 (t, J ) 7.5 Hz, 3H), 3.47 (s, 3H), 3.30 (s, 2H), 2.03
(s, 3H). MS (m/z): 367 (M+), 243 (100), 165, 95. HRMS: calcd
for C25H25N3 (M+), 367.2048; found, 367.2050.
N -Allyl-N -m e t h yl-5-a m in om e t h yl-1-m e t h yl-1H -im id -
a zole (25). A mixture of compound 22 (6.25 g, 50.0 mmol), allyl
bromide (6.65 g, 55.0 mmol), and Cs2CO3 (19.5 g, 60.0 mmol) in
dry DMF (120 mL) was stirred at room temperature overnight.
The solvent was removed, and the residue was dissolved in
CHCl3. The mixture was passed through a Celite 545 column,
and the filter cake was washed with CHCl3. The filtrate was
concentrated, and the residue was purified by silica gel column
chromatography using 1/1 (v/ v) CHCl3/hexanes (flushed with
NH3 gas) as the eluent to give 6.77 g of compound 25 as a yellow
1
1
liquid in 82% yield. H NMR (400 MHz, CDCl3): δ 7.37 (s, 1H),
in 55% yield. H NMR (400 MHz, CDCl3): δ 7.23 (t, J ) 8.0 Hz,
6.85 (s, 1H), 5.80 (m, 1H), 5.14 (m, 2H), 3.62 (s, 3H), 3.38 (s,
2H), 2.96 (d, J ) 6.4 Hz, 2H), 2.11 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ 138.29, 135.21, 128.96, 128.50, 117.48, 59.96, 50.12,
41.50, 31.31. MS (m/z): 165 (M+), 122, 95 (100), 84. HRMS: calcd
for C9H15N3 (M+), 165.1266; found, 165.1261.
1H), 7.10 (d, J ) 1.2 Hz, 1H), 7.04 (br, 1H), 6.94 (d, J ) 1.2 Hz,
1H), 6.79 (d, J ) 8.0 Hz, 1H), 6.75 (t, J ) 8.0 Hz, 1H), 6.66 (s,
2H), 5.84 (m, 2H), 5.60 (s, 1H), 5.16 (m, 4H), 3.69 (s, 3H), 3.44
(s, 6H), 3.43 (m, 2H), 3.31 (m, 2H), 3.01 (m, 4H), 2.16 (s, 6H).
13C NMR (100 MHz, CDCl3): δ 154.36, 147.18, 146.37, 135.36,
130.66, 129.83, 129.21, 126.63, 126.39, 126.13, 124.58, 119.71,
117.88, 110.90, 71.66, 60.34, 55.49, 50.61, 41.85, 31.62. MS (m/
z): 530 (M+), 461, 366, 295, 287 (100), 201, 174, 146, 95.
HRMS: calcd for C29H38N8O2 (M+), 530.3118; found, 530.3114.
Bis(N-a llyl-N-m et h yl-5′-a m in om et h yl-1′-m et h yl-1′H -2′-
im idazolyl)[1′′-(2′′′-m eth oxyph en yl)-1′H-2′-im idazolyl] Meth -
yl Meth yl Eth er (30). This compound was obtained as a yellow
oil in 51% yield following the procedure for preparing compound
20 using compound 29 instead of compound 19 as the substrate.
1H NMR (500 MHz, CDCl3): δ 7.22 (br, 1H), 7.14 (t, J ) 8.0 Hz,
1H), 7.10 (d, J ) 1.2 Hz, 1H), 6.85 (d, J ) 1.2 Hz, 1H), 6.71 (t,
J ) 8.0 Hz, 1H), 6.63 (d, J ) 8.5 Hz, 1H), 6.60 (br, 2H), 5.79 (m,
2H), 5.10 (m, 4H), 3.56 (s, 3H), 3.40 (s, 6H), 3.37 (s, 3H), 3.32
(m, 4H), 2.94 (m, 4H), 2.10 (s, 6H). 13C NMR (125 MHz, CDCl3):
δ 153.63, 145.62, 144.50, 135.13, 130.01, 129.61, 129.26, 126.76,
126.08, 125.77, 124.10, 119.44, 117.41, 110.14, 78.07, 59.97,
54.98, 54.19, 50.37, 41.57, 31.34. MS (m/z): 544 (M+), 529, 475
(100), 444, 373, 279, 187, 84. HRMS: calcd for C30H40N8O2 (M+),
544.3274; found, 544.3268.
Bis(5-m eth yla m in om eth yl-1-m eth yl-1H-2-im id a zolyl)[1′-
(2′′-m eth oxyph en yl)-1′H-2′-im idazolyl] Meth yl Meth yl Eth er
(8). This compound was obtained as a yellow oil in 83% yield
following the procedure for preparing compound 7 using com-
pound 30 instead of compound 27 as the substrate. 1H NMR
(500 MHz, CDCl3): δ 7.27 (d, J ) 7.5 Hz, 1H), 7.16 (t, J ) 7.5
Hz, 1H), 7.10 (d, J ) 1.0 Hz, 1H), 6.86 (d, J ) 1.2 Hz, 1H), 6.76
(t, J ) 7.5 Hz, 1H), 6.64 (d, J ) 7.5 Hz, 3H), 3.61 (s, 3H), 3.55
(s, 3H), 3.42 (s, 6H), 3.39 (s, 4H), 2.41 (s, 6H). 13C NMR (125
MHz, CDCl3): δ 153.90, 145.75, 144.57, 131.63, 130.17, 129.66,
126.35, 125.87, 125.60, 124.59, 119.75, 110.39, 78.30, 55.29,
54.56, 45.40, 36.01, 31.57. MS (m/z): 464 (M+), 449 (100), 434,
418, 281, 187, 138, 57. HRMS: calcd for C24H32N8O2 (M+),
464.2648; found, 464.2634.
Tr is(N-a llyl-N-m et h yl-5-a m in om et h yl-1-m et h yl-1H -2-
im id a zolyl)m eth yl Alcoh ol (26). This compound was obtained
as a white semisolid in 35% yield following the procedure for
preparing compound 18 using compound 25 instead of compound
16 as the substrate. 1H NMR (500 MHz, CDCl3): δ 6.77 (s, 3H),
6.29 (s, 1H), 5.76 (m, 3H), 5.09 (m, 6H), 3.36 (s, 6H), 3.32 (s,
9H), 2.93 (d, J ) 6.5 Hz, 3H), 2.10 (s, 9H). 13C NMR (125 MHz,
CDCl3): δ 147.04, 135.47, 126.81, 117.68, 71.80, 60.12, 50.81,
41.74, 31.34. MS (m/z): 521 (M+), 452, 357, 315, 287 (100), 84.
HRMS: calcd for C29H43N9O (M+), 521.3590; found, 521.3593.
Tr is(N-a llyl-N-m et h yl-5-a m in om et h yl-1-m et h yl-1H -2-
im id a zolyl)m eth yl Meth yl Eth er (27). This compound was
obtained as a yellow semisolid in 51% yield following the
procedure for preparing compound 20 using compound 26
instead of compound 19 as the substrate. 1H NMR (500 MHz,
CDCl3): δ 6.82 (s, 3H), 5.76 (m, 3H), 5.09 (m, 6H), 3.49 (s, 3H),
3.36(s, 6H), 3.34 (s, 9H), 2.92 (d, J ) 6.5 Hz, 3H), 2.09 (s, 9H).
13C NMR (125 MHz, CDCl3): δ 145.15, 135.41, 130.95, 127.11,
117.69, 78.76, 60.14, 54.63, 50.73, 41.72, 31.54. MS (ESI, m/z):
536 (M+ + 1, 100), 504, 465, 433, 311, 197, 163.
Tr is(5-m eth yla m in om eth yl-1-m eth yl-1H-2-im id a zolyl)-
m eth yl Meth yl Eth er (7). A mixture of compound 27 (391 mg,
0.73 mmol), Pd(PPh3)4 (169 mg, 0.15 mmol), and p-tolylsulfinic
acid (342 mg, 2.4 mmol) in dry CH2Cl2 (30 mL) was stirred at
room temperature for 24 h under an atmosphere of N2. To the
solution was added Na2CO3 (500 mg, 4.7 mmol), and the mixture
was stirred at room temperature for 1 h. The solid was filtered
off, and the filtrate was concentrated. The residue was purified
by preparative silica gel thin-layer chromatography using 1/19
(v/ v) CH3OH/CHCl3 (saturated with NH3 gas) as the eluent to
give 257 mg of compound 7 as a white semisolid in 85% yield.
1H NMR (400 MHz, CDCl3): δ 6.87 (s, 3H), 3.65 (s, 6H), 3.45(s,
3H), 3.39 (s, 9H), 2.41 (s, 9H). 13C NMR (100 MHz, CDCl3): δ
144.65, 132.22, 125.57, 78.78, 54.31, 45.49, 35.93, 31.45. MS
(ESI, m/z): 416 (M+ + 1, 100), 401, 384, 369, 352, 316, 311, 177.
Bis(N -a llyl-N -m e t h yl-5-a m in om e t h yl-1-m e t h yl-1H -2-
im id a zolyl)k eton e (28). To a solution of compound 25 (529
mg, 3.2 mmol) in dry THF (15 mL) was added n-BuLi (1.3 mL,
3.2 mmol, 2.5 M in hexanes) at -78 °C under an atmosphere of
N2, and the resulting solution was warmed to -40 °C and stirred
for 1 h. The solution was cooled to -78 °C again, and diethyl
carbonate (189 mg, 1.6 mmol) was added. Subsequently, the
mixture was allowed to warm to room temperature and stirred
for 24 h. The reaction was quenched by adding several drops of
a saturated aqueous solution of NH4Cl. The solvent was re-
moved, and the residue was purified by preparative silica gel
Ack n ow led gm en t. We thank the National Insti-
tutes of Health (NIH) (Grant GM17880) for financial
support. We also thank the Mass Spectrometry Facility
at the University of California, San Francisco, supported
by the NIH (Grants RR 04112 and RR 01614).
Su p p or tin g In for m a tion Ava ila ble: Copies of the 1H and
13C NMR spectra for new compounds 6-8, 16-20, and 25-
30. This material is available free of charge via the Internet
at http://pubs.acs.org.
J O010737M