Synthesis of tri- and tetrasubstituted imidazoles

Article abstract of DOI:10.1016/j.tetlet.2008.08.036

A reliable sequence that allows for regiospecific incorporation of four alkyl substituents on an imidazole ring has been developed. This procedure involves the addition of a substituted amino alcohol to a thioamide and subsequent oxidation with PDC. Unlike many imidazole syntheses, acid-sensitive functionality is tolerated given the mild conditions.

Full text of DOI:10.1016/j.tetlet.2008.08.036

Tetrahedron Letters 49 (2008) 6155–6159
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Tetrahedron Letters
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Synthesis of tri- and tetrasubstituted imidazoles
a
Daniel V. Paone a, , Anthony W. Shaw
*
a Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, West Point, PA 19486, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A reliable sequence that allows for regiospecific incorporation of four alkyl substituents on an imidazole
ring has been developed. This procedure involves the addition of a substituted amino alcohol to a thio-
amide and subsequent oxidation with PDC. Unlike many imidazole syntheses, acid-sensitive functionality
is tolerated given the mild conditions.
Received 14 July 2008
Revised 4 August 2008
Accepted 8 August 2008
Available online 14 August 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Imidazole
Thioamide
Amino alcohol
Intramolecular cyclization
R2
N
Imidazoles are commonly utilized substructures within the
pharmaceutical industry, as these heterocycles impart unique
physical and biological properties to compounds of interest.1 With-
in the context of a recent medicinal chemistry program, we identi-
fied a promising 1,2-dialkyl imidazole template, which prompted
us to more fully investigate structure–activity relationships in this
new lead series. This required preparation of analogs with various
substituents at the 4- and 5-positions, resulting in tri- and tetra-
substituted imidazoles.
To enable higher throughput of target compounds, it was neces-
sary to carry out the imidazole ring formation in the presence of an
N-Boc group—a commonly employed amine protective group that
is easily removed under acidic conditions. Additionally, we found
that only alkyl substitution of the imidazole was tolerated, and this
presented further challenges toward the synthesis of these
compounds.2
R2
R1
R3
O
R1
+
R3 NH2
+
R4
NH2
HO
N
OH
R4
Scheme 1. Imidazole retrosynthesis.
ceeded cleanly and without loss of the N-Boc group. We proceeded
to explore the generality of this approach and envisioned tetrasub-
stituted imidazoles arising from three fragments (Scheme 1).
Amide bond formation would allow incorporation of the first two
substituents (R3 and R4), and the remaining two substituents (R1
and R2) could be introduced via an amino alcohol to yield tetrasub-
stituted imidazoles after oxidation and cyclization.
The sequence begins with EDC coupling of 3-phenylpropan-1-
amine (1) and 3-(4-fluorophenyl)propanoic acid (2) to give the
amide in high yield (Scheme 2).5 Treatment with Lawesson’s
reagent6 furnishes corresponding thioamide 3, which upon
condensation with a substituted vicinal amino alcohol (4) with
mercury(II) chloride assistance gives rapid formation of the inter-
mediate amidine (5), typically within 10 min at ambient tempera-
ture. Filtration of this mixture followed by addition of pyridinium
dichromate (PDC) directly to the filtrate and heating at 60 °C for 2 h
affords cyclized imidazole products (6) in good yields after aque-
ous workup7 and purification by silica gel chromatography.8 Of
note is the absence of either an aqueous workup or purification
of the amidine intermediate. Though generally useful as a means
of preparing tri- and tetraalkyl-substituted imidazoles, this proto-
col is particularly efficient when investigating variations of R1 and/
or R2, as analogs can be prepared in two steps from thioamide
starting material with a single workup and purification.
There are several known methods for the preparation of poly-
substituted imidazoles. Two of the more common approaches in-
clude introduction of
a substituted amine to a dicarbonyl
substructure,3 and acid-catalyzed cyclization of a masked aldehyde
or ketone onto an amidine.4 Use of these conditions requires protic
or Lewis acid conditions to effect deprotection of the carbonyl
group, which is not compatible with acid-sensitive functionality.
Further, the amino acetal or ketal subunits themselves often
require several synthetic steps to prepare.
We developed an efficient and mild sequence toward tri- and
tetraalkyl-substituted imidazoles, which could be performed on
late-stage intermediates. Importantly, imidazole formation pro-
* Corresponding author. Tel.: +1 215 993 2269; fax: +1 215 652 7310.
E-mail address: daniel_paone@merck.com (D. V. Paone).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.08.036

6156
D. V. Paone, A. W. Shaw / Tetrahedron Letters 49 (2008) 6155–6159
O
HO
1.
2
F
S
EDC, HOBT, Et3N, CH2Cl2 (97%)
NH2
N
H
2. Lawesson's reagent
F
3
1
toluene, 90 °C (99%)
R2
R2
N
R1
R1
R2
N
R1
NH2
N
PDC
OH
4
HO
N
HgCl2, CH3CN, 10 min
filter
60 ˚C, 2 h
6
H
(~ 60-80%)
F
5
F
Scheme 2. Synthesis of substituted imidazoles.
Substituted amino alcohols (4), where R1 = H (Scheme 2), are
readily available from reduction of the corresponding amino acids,
and several derivatives are also commercially available. For the less
common trisubstituted isomer, where R2 = H, we utilize a one-pot,
two-step protocol starting with aliphatic aldehydes (Table 1).9
Treatment with trimethylsilyl cyanide affords the silyl-protected
cyanohydrins, which are then reduced with lithium aluminum hy-
dride. The amino alcohols obtained after filtration are of sufficient
purity for subsequent transformations.
Table 1
Synthesis of substituted amino alcohols
a) TMSCN, cat. ZnI2, CH2Cl2, 16 h
R
H
R
NH2
O
OH
b) 1M LAH in Et2O, 0 °C to rt, 1 h
Entry
1
R
Yield (%)
81
Isolated yields of several analogs of substituted imidazole 6 are
shown in Table 2.10 1,2,5-Trialkyl-substituted derivatives (entries
1–7) were synthesized from amino alcohols prepared using the se-
quence described in Table 1. Branched, fluorinated, and oxygen-
ated alkyl substituents are tolerated (entries 1–6),11 as is the
acid-sensitive acetal functional group (entry 7). This methodology
is compatible with aryl substituted amino alcohols as well, giving
the 5-aryl-substituted imidazole (entry 8). Generation of the
1,2,4-trialkyl-substituted isomers proceeds in a similar manner
(entries 9–11) though yields are generally lower. Again aryl substi-
tution is tolerated (entry 12).
F3C
2
3
87
91
O
4
5
92
75
O
O
Table 2
Formation of differentially substituted imidazoles: variation of R1 and R2
R2
R2
R1
R1
N
N
NH2
S
a)
OH
, HgCl2, CH3CN
4
N
H
b) filter, then PDC, 60 °C
6
F
3
F
Entry
1
Amino alcohol
Imidazole product
Yieldb (%)
68
Me
Me
NH2
N
N
OH
OH
2
72
NH2
N
N

D. V. Paone, A. W. Shaw / Tetrahedron Letters 49 (2008) 6155–6159
6157
Table 2 (continued)
Entry
Amino alcohol
Imidazole product
Yieldb (%)
63
F3C
F3C
OH
NH2
3a
N
N
F3C
F3C
NH2
4
5
69
71
N
N
OH
NH2
N
N
OH
O
O
6
72
NH2
N
N
O
OH
O
7
8
64
75
O
O
NH2
N
N
OH
NH2
N
N
OH
Me
Me
9
10
11
60
66
60
N
N
NH2
N
N
OH
NH2
OH
Cl
Cl
N
N
N
N
NH2
OH
OH
12
50
NH2
13
14
68
N
NH2
N
N
OH
OH
Me
N
Me
87
NH2
(continued on next page)

6158
D. V. Paone, A. W. Shaw / Tetrahedron Letters 49 (2008) 6155–6159
Table 2 (continued)
Entry
Amino alcohol
Imidazole product
Yieldb (%)
68
15
16
NH2
OH
N
N
Me
Me
NH2
70
62
N
N
OH
O
O
O
N
O
N
17
NH2
N
N
OH
a
HCl salt of the amino alcohol was used with equimolar amounts of triethylamine.
Isolated yield after column chromatography.
b
Gelens, E.; DeKanter, F. J. J.; Schmitz, R. F.; Sliedregt, L. A. J. M.; Van Steen, B. J.;
Kruse, C. G.; Leurs, R.; Groen, M. B.; Orru, R. V. A. Mol. Div. 2006, 10, 17–22; (h)
Bleicher, K. H.; Gerber, F.; Wuthrich, Y.; Alanine, A.; Capretta, A. Tetrahedron
Lett. 2002, 43, 7687–7690.
1,2,4,5-Tetrasubstituted imidazoles containing either one or
two aryl substituents (entries 13–14) were prepared in good yield.
The cyclohexane-fused analog in entry 15 represents an interesting
approach to partially saturated benzimidazoles,12 and the utility of
this methodology is highlighted by the successful preparation of
differentially substituted tetraalkyl imidazoles (entries 16–17).
The cyclohexyl analog in entry 16 was synthesized from the corre-
sponding disubstituted amino alcohol13 in 70% yield from thioam-
ide 3. Further, tolerance of the N-Boc-protected piperidine moiety
in entry 17 demonstrates the mildness of this protocol.
In summary, we have optimized a two-step procedure for the
synthesis of tri- and tetraalkyl-substituted imidazoles starting
from readily available thioamides. This sequence proceeds under
mild conditions enabling preparation of compounds containing
acid-sensitive functionality. Additionally, aryl substitution at both
the 4- and 5-positions is tolerated. Finally, facile preparation of the
required substituted amino alcohols for use in preparation of 1,2,5-
trisubstituted imidazoles was described.
4. (a) Frutos, R. P.; Gallou, I.; Reeves, D.; Xu, Y.; Krishnamurthy, D.; Senanayake, C.
H. Tetrahedron Lett. 2005, 46, 8369–8372; (b) Gall, M.; Kamdar, B. V. J. Org.
Chem. 1981, 46, 1575–1585; (c) Bock, M. G.; DiPardo, R. M.; Evans, B. E.; Rittle,
K. E.; Veber, D. F.; Freidinger, R. M.; Chang, R. S. L.; Lotti, V. J. J. Med. Chem. 1988,
31, 176–181; (d) Bock, M. G.; DiPardo, R. M.; Newton, R. C.; Bergman, F. M.;
Veber, D. F.; Freedman, S. B.; Smith, A. J.; Chapman, K. L.; Patel, S.; Kemp, J. A.;
Marshall, G. R.; Freidinger, R. M. Bioorg. Med. Chem. 1994, 2, 987–998; (e)
Thurkauf, A.; Chen, X.; Zhang, S.; Gao, Y.; Kieltyka, A.; Wasley, J. W. F.;
Brodbeck, R.; Greenlee, W.; Ganguly, A.; Zhao, H. Bioorg. Med. Chem. Lett. 2003,
13, 2921–2924; (f) Liu, C.-H.; Wang, B.; Li, W.-Z.; Yun, L.-H.; Liu, Y.; Su, J. L.; Liu,
H. Bioorg. Med. Chem. 2004, 12, 4701–4707; (g) Pacofsky, G. J.; Stafford, J. A.;
Cox, R. F.; Cowan, J. R.; Dorsey, G. F.; Gonzales, S. S.; Kaldor, I.; Koszalka, G. W.;
Lovell, G. G.; McIntyre, M. S.; Tidwell, J. H.; Todd, D.; Whitesell, G.; Wiard, R. P.;
Feldman, P. L. Bioorg. Med. Chem. Lett. 2002, 12, 3219–3222.
5. The differentiated alkyl-tethered aryl chain 1- and 2-substituents were chosen
for ease of UV detection and purification.
6. Scheibye, S.; Pederson, B. S.; Lawesson, S. O. Bull. Soc. Chim. Belg. 1978, 87, 229.
7. The aqueous workup of the PDC reaction is greatly facilitated by first
quenching with a reducing agent such as sodium sulfite, then adjusting the
mixture to mildly acidic pH (ꢀ5). This allows for complete dissolution of
chromium salts and separation of two homogeneous layers.
8. Major byproducts of the sequence include reversion back to the amide
precursor of 3 and oxazoline formation resulting from nucleophilic attack of
the hydroxyl group prior to oxidation.
Acknowledgments
The authors thank Drs. Christopher S. Burgey and Shaun R.
Stauffer for reviewing this Letter, and Hongbo Qi for the prepara-
tion of the amino alcohol in entry 17 of Table 2.
9. Typical procedure for the synthesis of substituted aminomethyl alcohols (Table 1,
entry 3): Trimethylsilyl cyanide (920 mg, 9.28 mmol) was added dropwise to a
solution of 2,2-dimethylpropanal (400 mg, 4.64 mmol) and zinc iodide (15 mg,
0.046 mmol) in dichloromethane (10 mL) at 0 °C, and the solution was allowed
to warm to ambient temperature. After 16 h the solution was recooled to 0 °C,
lithium aluminum hydride (1.0 M in ether; 11.6 mL, 11.6 mmol) was added,
and the solution was allowed to warm to ambient temperature. After 1 h the
mixture was cooled to 0 °C and treated successively with water (0.44 mL), 15%
aqueous sodium hydroxide (0.44 mL), and water (1.32 mL). After stirring for
30 min, the mixture was filtered and washed with dichloromethane. The
filtrate was dried with sodium sulfate, filtered, and concentrated to give 1-
amino-3,3-dimethyl-butan-2-ol (496 mg, 91% yield). 1H NMR (500 MHz, CDCl3)
References and notes
1. For some examples of imidazole-containing drug lead series: (a) Bunnage, M.
E.; Owen, D. R. Curr. Opin. Drug Discovery Dev. 2008, 11, 480–486; (b) Laufer, S.
A.; Wagner, G. K.; Kotschenreuther, D. A.; Albrecht, W. J. Med. Chem. 2003, 46,
3230–3244; (c) Ganellin, C. R.; Fkyerat, A.; Bang-Anderson, B.; Athmani, S.;
Tertiuk, W.; Garbarg, M.; Ligneau, X.; Schwartz, J.-C. J. Med. Chem. 1996, 39,
3806–3813. For reviews of imidazole-containing natural products: (d)
Weinreb, S. M. Nat. Prod. Rep. 2007, 24, 931–948; (e) Jin, Z. Nat. Prod. Rep.
2006, 23, 464–498.
2. With certain methods, the presence of enolizable hydrogens in carbonyl
precursors can often preclude imidazole formation altogether, thus requiring
the use of aryl substituents at specific positions; see Refs. 2 and 3.
3. (a) Sadeghi, B.; Mirjalili, B. B. F.; Hashemi, M. M. Tetrahedron Lett. 2008, 49,
2575–2577; (b) Claiborne, C. F.; Liverton, N. J.; Nguyen, K. T. Tetrahedron Lett.
1998, 39, 8939–8942; (c) Frantz, D. E.; Morency, L.; Soheili, A.; Murry, J. A.;
Grabowski, E. J. J.; Tillyer, R. D. Org. Lett. 2004, 6, 843–846; (d) Davies, J. R.;
Kane, P. D.; Moody, C. J. Tetrahedron 2004, 60, 3967–3977; (e) Haberhauer, G.;
Rominger, F. Tetrahedron Lett. 2002, 43, 6335–6338. For specifically tetraalkyl
substituted: (f) Lee, H. B.; Balasubramanian, S. Org. Lett. 2000, 2, 323–326; (g)
d
3.14 (dd, J = 10.3, 2.9 Hz, 1H), 2.92 (dd, J = 12.2, 2.7 Hz, 1H), 2.47 (dd,
J = 12.2 Hz, 10.3 Hz, 1H), 0.91 (s, 9H).
10. Typical procedure for the synthesis of substituted imidazoles (Table 2, entry 5):
To
a solution of 3-(4-fluorophenyl)-N-(3-phenylpropyl)propanethioamide
(50.0 mg, 0.17 mmol) and 1-amino-3,3-dimethyl-butan-2-ol (38.9 mg,
0.33 mmol) in acetonitrile (1.7 mL) was added mercury(II) chloride (90.1 mg,
0.33 mmol). After 10 min the mixture was filtered and washed with a total of
6 mL acetonitrile. Pyridinium dichromate (312 mg, 0.83 mmol) was added to
the filtrate and the mixture was heated to 60 °C. After 2 h the mixture was
allowed to cool to ambient temperature and quenched with saturated aqueous
sodium sulfite (4 mL) and water (4 mL). The mixture was adjusted to pH 5 with
concentrated hydrochloric acid (1 mL), extracted with ethyl acetate, washed
with brine, dried with magnesium sulfate, filtered and concentrated.

D. V. Paone, A. W. Shaw / Tetrahedron Letters 49 (2008) 6155–6159
6159
Purification by silica gel chromatography (dichloromethane?4% methanol/
dichloromethane with 1% ammonium hydroxide) gave 5-(1,1-dimethylethyl)-
2-[2-(4-fluorophenyl)ethyl]-1-(3-phenylpropyl)-1 H-imidazole (43.0 mg, 71%
yield). 1H NMR (500 MHz, CDCl3) d 7.31–7.28 (m, 2H), 7.24–7.21 (m, 1H), 7.16–
7.14 (m, 2H), 7.00–6.98 (m, 2H), 6.95–6.90 (m, 2H), 6.67 (s, 1H), 3.69–3.66 (m,
2H), 3.03 (t, J = 8.6 Hz, 2H), 2.74–2.71 (m, 2H), 2.65 (t, J = 7.1 Hz, 2H), 1.95–1.89
(m, 2H), 1.26 (s, 9H). HPLC Rt = 2.56 min (100% purity). HRMS calcd for
11. For the trifluoroethyl analog in entry 3 of Table 2, the HCl salt of the amino
alcohol was used along with equimolar triethylamine, and the yields were
comparable to those when the free base was used.
12. The corresponding cyclopentane-fused imidazole was not obtained under the
standard conditions, presumably due to increased ring strain versus the 6,5-
fused system.
13. The amino alcohol in entry 16 was obtained from hydrogenation of the
commercially available aryl derivative.
C24H29N2F [M+H]: 365.2388; found 365.2390.