Regioselective synthesis of 1-aklyl-4-(3-pyridyl)-substituted imidazole

Article abstract of DOI:10.1021/op0498767

A practical and regioselective synthesis of 1-alkyl-4-(3-pyridyl) imidazole via a Suzuki coupling reaction employing 3-pyridyl-boronates has been investigated. The use of sec-butyllithium in place of n-butyllithium for complete selectivity in removing bromines on tribromoimidazole to provide a key bromoimidazole coupling unit is described. For effective Suzuki coupling reaction, the nature of pyridylboronates and the conditions employed are discussed. The factors affecting the outcome of the Suzuki coupling reaction are presented.

Full text of DOI:10.1021/op0498767

Organic Process Research & Development 2004, 8, 955−957
Regioselective Synthesis of 1-Aklyl-4-(3-pyridyl)-Substituted Imidazole
Hengxu Wei,* Ravinder Sudini, and Hao Yin
Synthetic Chemistry, GlaxoSmithKline Pharmaceutical, 709 Swedeland Road,
King of Prussia, PennsylVania 19406, U.S.A.
Abstract:
A practical and regioselective synthesis of 1-alkyl-4-(3-pyridyl)
imidazole via a Suzuki coupling reaction employing 3-pyridyl-
boronates has been investigated. The use of sec-butyllithium
in place of n-butyllithium for complete selectivity in removing
bromines on tribromoimidazole to provide a key bromoimida-
zole coupling unit is described. For effective Suzuki coupling
reaction, the nature of pyridylboronates and the conditions
employed are discussed. The factors affecting the outcome of
the Suzuki coupling reaction are presented.
Figure 1.
Scheme 1
The modified erythromycin macrolides and ketolides are
major new classes of semisynthetic compounds which exhibit
antibacterial activity against erythromycin-resistant bacteria.1
Among them, the substances possessing a 4-(3-pyridyl)-
substituted imidazole side chain (Figure 1) are of particular
interest to various pharmaceutical companies2 due to their
Scheme 2
promising biological activities. Generally these compounds
are synthesized from a core macrolide unit and a 1-alkyl-
4-(3-pyridyl)imidazole side chain.
Early literature examples of the synthesis of 1-alkyl-4-
(3-pyridyl) imidazoles were achieved by alkylation2a of and
Michael addition2b to 3-pyridylimidazoles. However both of
these approaches suffered from poor yield and regioselec-
tivity. Additionally, the chemistry reported for the synthesis
of 4-(3-pyridyl) imidazoles is tedious and expensive.2b,3
Therefore, it was deemed impractical to rely on existing
synthetic methods for any large-scale delivery.
To support our macrolide antibacterial program, we
needed to provide a large amount of [4-(3-pyridyl)-1H-
imidazol-1-yl]acetaldehyde (1) for the preparation of mac-
rolide derivatives for further preclinical studies. Work was
initiated on discovering and developing a new and more
practical synthetic route for 3-{1-[2,2-bis(ethyloxy)ethyl]-
1H-imidazol-4-yl}pyridine 2, a precursor to [4-(3-pyridinyl)-
1H-imidazol-1-yl]acetaldehyde 1 (Scheme 1).
Initial attempts made to improve the regioselectivity of
the alkylation of pyridylimidazole with 2-bromo-1,1-bis-
(ethyloxy)ethane under various reaction conditions (e.g.,
solvents, bases, temperature) resulted in poor selectivity and
low yields. To circumvent regioselectivity problems, we
employed a different strategy, we envisioned that 3-pyridyl-
boron 3 and 1-alkyl-4-bromoimidazole 4 could be coupled
employing transition-metal-catalyzed Suzuki type reaction
conditions (Scheme 2).
The palladium-catalyzed Suzuki cross-coupling of aryl
halides with organoboron reagents has become one of the
most versatile synthetic methods for C-C bond formation4
and plays a very important role in the preparation of aryl-
substituted heterocycles.5 The Suzuki coupling reaction
generally employs organoboronic acids or borates due to their
high reactivity,6 good stability, and commercial availability.
Organoboranes are rarely employed. For our studies, the
* To whom correspondence should be addressed. E-mail: hengxu.2.wei@
gsk.com.
(1) (a) Agouridas, C.; Denis, A.; Auger, J.-M.; Benedetti, Y.; Bonnefoy, A.;
Bretin, F.; Chantot, J.-F.; Dussarat, A.; Fromentin, C.; Gouin D’Ambrie`res,
S.; Lachaud, S.; Laurin, P.; Le Martret, O.; Loyau, V.; Tessot, N. J. Med.
Chem. 1998, 41, 4080-4100. (b) Denis, A.; Bretin, F.; Fromentin, C.;
Bonnet, A.; Piltan, G.; Bonnefoy, A.; Agouridas, C. Bioorg. Med. Chem.
Lett. 2000, 10, 2019-2022.
(2) (a) Denis, A.; Agouridas, C.; Auger, J. M.; Benedetti, Y.; Bonnefoy, A.;
Bretin, F.; Chantot, J. F.; Dussarat, A.; Fromentin, C.; D’Ambrieres, S.
G.; Lachaud, S.; Laurin, P.; Martret, O. L.; Loyau, V.; Tessot, N.; Pejac,
J. M.; Perron, S. Bioorg. Med. Chem. Lett. 1999, 9, 3075-3080. (b) Ripin,
D. H. B.; Vanderplas, B. C.; Kaneko, T.; McMillen, W. T.; McLaughlin,
R. W. (Pfizer Inc) U.S. Patent 6,403,776, 2002. (c) Chu, D.; Burger, M.;
Lin, X.; Georgia Law, C.; Plattner, J.; Rico, A. (Chiron Corp.) WO
2003004509. (d) Dominique, L.; Gilles, D. R.; Franck, H.; Didier, B.;
Thomas, R. (Aventis Pharma S.A.) WO 2004022544. (e) Suleman, A.;
Andrea, B.; Francesca, C.; Antun, H.; Gorjana, L.; Sergio, L.; Zorica, M.
I.; Stjepan, M.; Alfonso, P.; Marko, D. (GlaxoSmithKline Plc) WO
2002032917.
(4) (a) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457-2483. (b) Suzuki,
A. J. Organomet. Chem. 1999, 576, 147-168. (c) Stanforth, S. P.
Tetrahedron 1998, 54, 263-303. Kotha, S.; Lahiri, K.; Kashinath, D.
Tetrahedron 2002, 58, 9633-9695.
(3) Kirchhoff, E. W.; Anderson, D. R.; Zhang, S.; Cassidy, C. S.; Flavin, M.
T. Org. Process Res. DeV. 2001, 5, 50-53.
(5) Li, J. J.; Gribble, G. W. Palladium in Heterocyclic Chemistry; Pergamon:
Oxford, 2000.
10.1021/op0498767 CCC: $27.50 © 2004 American Chemical Society
Published on Web 09/17/2004
Vol. 8, No. 6, 2004 / Organic Process Research & Development
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955

Scheme 3
Table 1. Suzuki coupling reaction between organoboron
reagents 3 and bromoimidazole 4
organoboron ratio of 2/8 time
entry catalyst
ligand
reagent
(HPLC area%) (h)
1
2
3
4
5
Pd(OAc)2 P(Cycl)3
Pd(OAc)2 P(Cycl)3
Pd(OAc)2 P(Cycl)3
Pd(OAc)2 P(O-tolyl)3
Pd(OAc)2 P(t-Bu)3
3a
3b
3c
3c
3c
0/100
40/60
96/4
83/17
96/4
10
7
2
96
2
Scheme 5
Scheme 4
organoboron reagents 3 (3a, R ) OH; 3b, R ) OC(CH3)2C-
(CH3)2O; 3c, R ) C2H5) are commercially available. The
coupling partner 4 was easily synthesized from the readily
available tribromoimidazole as a starting material (Scheme
3).
2/8 with a 40/60 ratio (Scheme 5). Interestingly, a higher
yield of cross coupled product was obtained when pyridyl
borane 3c was used under identical conditions (entry 3). It
should be noted that 3c has recently been employed in a
large-scale Suzuki reaction.8
Alkylation of commercially available tribromoimidazole
5 with diethoxy bromoacetaldehyde acetal in the presence
of potassium carbonate in DMSO at 145 °C afforded 6 in
96% yield. The selective removal of bromine at the 2 and 5
positions of compound 6 to afford 4 could be achieved using
n-butyllithium according to literature precedent.7 However,
when compound 6 was exposed to n-butyllithium, only 95%
of desired product 4 was obtained. This was accompanied
by 5% butyl-substituted imidazole 7 as shown in Scheme 3.
Compound 7 formed presumably from the reaction of the
lithiated imidazole ring with byproduct butylbromide gener-
ated from lithium-bromine exchange. Interestingly, when
sec-butyllithium was used in place of n-butyllithium, com-
plete regioselectivity was observed and no alkylation product
was detected. One explanation for no formation of alkylated
compound is the sterics involved in reacting the lithiated
imidazole ring with sec-BuBr. Thus treating compound 6
with sec-butyllithium provided 4 in quantitative yield as
shown in Scheme 4.
With the bromoimidazole 4 in hand, we investigated the
Suzuki coupling reaction conditions for 3 and 4. A number
of organoboron reagents and catalysts were screened, and
the results were summarized in Table 1.
No desired coupled product formed when pyridyl boronic
acid 3a was reacted with 4 in the presence of palladium
acetate as shown; instead the self-coupled bipyridine 8
product was exclusively observed (entry 1). Substituting
borate 3b in place of acid 3a afforded a mixture of products
The outcome of Suzuki coupling reactions depends
heavily on the reaction conditions employed. Among the
reaction parameters, palladium catalyst and phosphine ligands
are found to be the most important factors for the success
of this reaction. Tetrakis(triphenylphosphine)palladium, fre-
quently used for such types of reactions, was too labile under
the reaction conditions and failed to deliver any of the desired
product in all cases. The combination of Pd(OAc)2 and tri-
o-tolylphosphine only gave low yields (50%) of cross
coupled product even after prolonged reaction time. When
more electron rich ligands such as tricyclohexylphosphine
and tri-tert-butylphosphine were employed, a clean conver-
sion to 2 was observed (entry 3, 5) and the product 2 was
isolated as HCl salt 9 in a yield of 81% with a purity >99%.
The use of electron rich phosphines in Suzuki reactions has
been well documented.9 They may not only stabilize the
active Pd(0)L2 species but also promote reductive elimina-
tion. The stability of oraganoborons is believed to play an
important role in the cross coupling reactions. The observed
low yield of coupled product in our reactions with 3a and
3b may be partly due to a facile protodeboronation10 or partial
decomposition under the strong basic conditions employed
to promote the coupling reaction.
(8) Lipton, M. F.; Mauragis, M. A.; Maloney, M. T.; Veley, M. F.; VanderBor,
D. W.; Newby, J. J.; Appell, R. B.; Daugs, E. D. Org. Process Res. DeV.
2003, 7, 385-392.
(9) (a) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 1998, 37, 3387-3388.
(b) Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122, 4020-
4028. (c) Zapf, A.; Ehrentraut, A.; Beller, M. Angew. Chem., Int. Ed. 2000,
39, 4153-4155.
(6) Miyaura, N.; Yamada, K.; Suginome, H.; Suzuki, A. J. Am. Chem. Soc.
1985, 107, 972-980.
(7) Iddon, B.; Khan, N. J. Chem. Soc., Perkin Trans. 1 1987, 1453-1455.
(10) Fischer, F. C.; Havinga, E. Recl. TraV. Chim. Pays-Bas 1974, 93, 21-24.
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Scheme 6
room temperature. TBME (30 mL) and water (4.0 mL) were
added. The aqueous layer was extracted with TBME (20
mL). The combined organic layers were washed with brine
(10 mL) and then dried with Na2SO4 (anhydrous). After
evaporation of solvents, an oil (4.95 g, 99%) was obtained;
1H NMR (300 MHz, CDCl3) δ 7.46 (d, J ) 1.5 Hz, 1 H),
6.95 (d, J ) 1.5 Hz, 1 H), 4.56 (t, J ) 5.1 Hz, 1 H), 3.98 (d,
J ) 5.1 Hz, 2 H), 3.70 (m, 2 H), 3.47 (m, 2 H), 1.18 (t, J )
7.1 Hz, 6 H); 13C NMR (75 MHz, CDCl3) δ 137.5, 119.1,
114.7, 101.1, 63.7, 50.5 (2C), 15.2 (2C).
Oxygen is known in the literature to promote the self-
coupling of arylborons.11 We observed that the impurity level
of 3,3-bipyridine 8 generated in the reaction was related to
the oxygen level in the reaction mixture. Pre-exclusion of
oxygen at the beginning of reaction was critical to maintain
low levels of 8. Introduction of trace amounts of oxygen
when taking samples to monitor the reaction consumed active
Pd (0), requiring more pyridylborane 3c to regenerate the
active catalyst and consequently producing more 3,3-bipy-
ridine 8 (Scheme 6).
3-{1-[2,2-Bis(ethyloxy)ethyl]-1H-imidazol-4-yl}pyri-
dine Hydrochloride Salt 9: Tetrabutylammonium iodide
(2.45 g, 6.65 mmol, 0.05 equiv), 1,1-diethoxy-2-(4-bro-
moimidazolyl)ethane 4 (35 g, 133 mmol, 1.0 equiv), DMF
(166 mL), and Pd(OAc)2 (0.9 g, 4.0 mmol, 0.03 equiv) were
added to a round-bottom flask (500 mL) at room temperature.
Then a solution of K3PO4 in water (2.0 M, 133 mL, 266
mmol, 2.0 equiv) was added. The mixture was degassed by
house vacuum (1.0 min) at ambient temperature and then
filled with argon (three times). Tricyclohexylphosphine (2.2
g, 8.0 mmol, 0.06 equiv) and diethyl-(3-pyridyl)borane (20.6
g, 140 mmol, 1.05 equiv) were added into a reaction flask
at room temperature. The mixture was degassed as described
above once again. The reaction mixture was stirred and
heated at 100 °C for 3-5 h. The reaction was deemed
complete when less than 0.5% of the starting bromide
material remained. The reaction contents were cooled to 70
°C and distilled under house vacuum until 175 mL of residue
was left. The residue was cooled to room temperature. Water
(17.5 mL) and methylene chloride (350 mL) were added.
Two layers were separated, and the aqueous layer was
extracted with methylene chloride (350 mL). The combined
organic layers were filtered through a pad of Celite (20 g).
The solvent was distilled until 70 mL of solution remained,
and TBME (210 mL) was added followed by addition of a
solution of HCl in ethanol (4.4 N, 62 mL, 273 mmol, 2.05
equiv). The slurry was stirred for another 30 min. The solid
product was filtered and washed with TBME (70 mL). The
wet cake was then dried under house vacuum at 50 °C for 2
h to give 2 (32 g, 81%); 1H NMR (300 MHz, DMSO-d6) δ
9.16 (d, J ) 1.5 Hz, 1 H), 8.69 (m, 1 H), 8.67 (dd, J ) 5.4,
1.5 Hz, 1 H), 8.54 (dt, J ) 8.1, 1.5 Hz, 1 H), 8.23 (d, J )
1.5 Hz, 1 H), 7.77 (dd, J ) 7.8, 5.4 Hz, 1 H), 4.83 (t, J )
5.1 Hz, 1 H), 4.26 (d, J ) 5.1 Hz, 2 H), 3.66 (m, 2 H), 3.51
(m, 2 H), 1.10 (t, J ) 7.2 Hz, 6 H); 13C NMR (75 MHz,
DMSO-d6) δ145.6, 142.9, 138.7, 136.0, 131.9, 127.9, 125.8,
120.5, 100.0, 63.0, 50.6 (2C), 15.5 (2C).
In conclusion an efficient and practical process for the
production of 1-alkyl-4-pyridyl-imidazole was developed.
Suzuki coupling between pyridylborane and imidazolylbro-
mide under the conditions above-described in this com-
munication would be suitable for large-scale preparation of
pyridylimidazole derivatives.
Experimental Section
1-[2,2-Bis(ethyloxy)ethyl]-2,4,5-tribromo-1H-imida-
zole 6: A mixture of tribromoimidazole (6.1 g, 20 mmol,
1.0 equiv), bromoacetaldehyde diethyl acetal (4.73 g, 24
mmol, 1.2 equiv), and potassium carbonate (4.14 g, 30 mmol,
1.5 equiv) in DMSO (6.5 mL) was heated to 145 °C for 2 to
4 h. The reaction mixture was cooled to room temperature
before addition of water (40 mL) and tert-butyl methyl ether
(TBME) (40 mL). The aqueous layer was extracted with
TBME (40 mL). The combined organic layers were washed
with water (20 mL) and brine (10 mL) and then dried with
Na2SO4 (anhydrous). After evaporation of solvents, an oil
(7.96 g, 96%) was obtained; 1H NMR (300 MHz, CDCl3) δ
4.68 (t, J ) 5.5 Hz, 1H), 4.09 (d, J ) 5.5 Hz, 2 H), 3.73 (m,
2 H), 3.43 (m, 2 H), 1.15 (t, J ) 7.1 Hz, 6 H); 13C NMR (75
MHz, CDCl3) δ 119.1, 116.7, 105.8, 100.4, 64.3, 50.6 (2C),
15.2 (2C).
1-[2,2-Bis(ethyloxy)ethyl]-4-bromo-1H-imidazole 4:
Crude product from the previous step (7.96 g, 18.9 mmol,
1.0 equiv) was dissolved in THF (40 mL). The resulting
solution was cooled to -75 °C. sec-Butyllithium (1.3 M in
cyclohexane, 36.3 mL, 47.3 mmol, 2.5 equiv) was added at
a rate to maintain the reaction temperature below -55 °C.
After 30 min water (6.0 mL) was added to quench the
reaction at -75 °C and then the mixture was warmed to
(11) (a) Parrish, J. P.; Floyd, R. J.; Jung, K. W. Abstracts of Papers, 223rd
ACS National Meeting, Orlando, FL, United States, April 7-11, 2002. (b)
Smith, K. A.; Campi, E. M.; Jackson, W. R.; Marcuccio, S.; Naeslund, C.
G. M.; Deacon, G. B. Synlett 1997, 131-132.
Received for review June 21, 2004.
OP0498767
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