Acta Chim. Slov. 2000, 47, 1-18.
1
HALOGENATED (ACYLAMINO)IMIDAZOLES AND BENZIMIDAZOLES
FOR DIRECTED HALOGEN-METAL EXCHANGE-BASED
FUNCTIONALIZATION
Michael P. Groziak* and Hong Ding
Pharmaceutical Discovery Division, SRI International
333 Ravenswood Avenue, Menlo Park, CA, 94025-3493, USA
Phone: (650)-859-6299
Fax: (650)-859-3153
e-mail: michael.groziak@sri.com
Received 13.7.1999
Abstract
Regioselective syntheses of 4- and 5-(acylamino)-1-alkylimidazoles bearing an ortho-halogen atom have been developed. Suitable for use in ortho-directed halogen-metal exchange-mediated ring functionalizations, these compounds are valuable precursors to ortho-functionalized versions of biologically active 4- and 5-aminoimidazoles. To widen the scope of this approach to cover similarly-substituted benzimidazoles and their potentially bioactive nucleosides, the synthesis of halogenated 5- and 6-(acylamino)-benzimidazoles and their ribosides was also explored.
Introduction
Imidazoles and their benzo derivatives are key components in a great many bio-active compounds of both natural and synthetic origin. In the imidazole class, nucleo-sides of amino derivatives are well known for their biological activity. Examples include 5-aminoimidazole ribonucleotide, a key intermediate on the de novo purine biosynthetic pathway [1] and 5-(formylamino)imidazole ribonucleoside, a competitive inhibitor of adenosine deaminase we have recently studied [2]. In the benzimidazole class, it is the nucleosides of halogeno derivatives that are becoming well known as bioactive compounds. For example, some of the (poly)halogenated benzimidazole nucleosides are potent antiviral agents [3-6], while others have been found to inhibit casein kinase [7]. One part of our program to develop new bioactive imidazole- and benzimidazole-based heterocycles   and   nucleosides   focuses   on   4(5)-aminoimidazoles   and   5(6)-amino-
M. P. Groziak, H. Ding: Halogenated (Acylamino)imidazoles and benzimidazoles for Directed…
2
Acta Chim. Slov. 2000, 47, 1-18.
benzimidazoles equipped with a variable substituent ortho to the amino group. Although methodologies related to the preparation of the former [8-11] and the latter [12-15] do exist, we found there is clearly a need for wider regioselective access to both. To this end, ortho-halogenated 4- and 5-(acylamino)imidazoles and 5- and 6-(acylamino)benzimidazoles would be extremely useful, since these heterocycles could be used to prepare ortho-substituted aminoimidazoles and aminobenzimidazoles along a route like that developed by Sharp for the C-functionalization of aromatic tosyl-hydrazones [16]. In this approach, an amidate anion is generated (e.g., with MeLi) and is used to direct a halogen-metal exchange (e.g., with BuLi or EtMgBr), and then an ortho functionalization is effected by reacting the resulting dianion with an electrophile. By carefully controlling the reaction conditions, all of this can be accomplished even while the (benz)imidazole C2 position remains unprotected [17-20]. Simple deacylation would afford the desired ortho-substituted amino(benz)imidazoles. Herein, we report the synthesis of ortho-halogenated 4- and 5-(acylamino)imidazoles and 5- and 6-(acylamino)benzimidazoles suitable for use in just such a synthetic strategy.
Results and Discussion
The regioselective synthesis of ortho-halogenated 4- and 5-(acylamino)imidazoles is shown in Scheme 1. 1-Methyl-5-nitroimidazole (1) was prepared from 4(5)-nitro-imidazole by a new regioselective route we developed using a AgBF4-assisted methyl-ation of 4-nitro-1-(trimethylsilyl)imidazole. This two-step, one-pot route gave 1 in a 68% overall yield—higher than other methods reported to date. We then used Ramsden's procedure [9] to reduce 1 to the air(oxidation)-sensitive amine 2 (97%). Attempts at N-acylating the enamine 2 did not proceed smoothly, and so instead we accessed the 5-(formylamino)- and 5-(benzoylamino)imidazoles 3a,b directly from 1 via catalytic hydrogenation in the presence of the acylating agents HCO2H and Bz2O, respectively. Benzamide 3b was then subjected to electrophilic iodination, which proceeded regioselectively to give the iodo-benzamide 4.
M. P. Groziak, H. Ding: Halogenated (Acylamino)imidazoles and benzimidazoles for Directed…
Acta Chim. Slov. 2000, 47, 1-18.
3
Scheme 1 N

1. HMDS, Me3SiCl
H
i        NO2   2. Mel, AgBF4

H 2, Pd/C
Me
NO2
 Mel, AgNOß or I Me2S04, aq. NaOH Y     or Mel, K2CO3
<J
1
Me
<x
NH2
H2, Pd/C and HCO2H or Bz2O
N
Me
5
H2, Pd/C and
HCO2H, Ac2O,
or Bz2O

'2
Me
NHCOR
K2CO3
N N
IH2, Pd/C
N Me7    6
3a, R = H b, R = Ph
Me
NHCOPh
N-
N
NHCOR
'2
Me
7a, R = H
b, R = Me
c, R = Ph
K2CO3
ISk/
» OC
3            /^
Me
,NHCOPh
For the isomeric acylaminoimidazole, three methods for preparing the known 1-methyl-4-nitroimidazole (5) were examined. The first one employed the same silver 4(5)nitroimidazolide [21] that was reported to give a 1.6:1 mixture of 1-alkyl-5-nitro-and 1-alkyl-4-nitroimidazoles when condensed with 2,3,5-tri-O-acetylribofuranosyl bromide [22]. Using iodomethane in this procedure, we obtained 5 in a 41% yield. An alternative alkylation approach employing Me2SO4 and aq. NaOH [23] also gave predominantly 5, in surprising contrast to a published report [24]. Finally, methylation with iodomethane using K2CO3 in dry DMF proceeded well, and gave 5 in a 70% yield. Catalytic hydrogenation of 5 gave the corresponding amine 6, which like 2 could not be directly N-acylated in an efficient manner. Therefore, the formamide, acetamide, and benzamide derivatives 7a-c were prepared by catalytic hydrogenation of 5 in the presence of the appropriate acylating agent (HCO2H, Ac2O, and Bz2O, respectively). As with 3a, electrophilic iodination proceeded regioselectively, giving iodo-benzamide 8. The ortho-halogeno 4- and 5-(acylamino)imidazoles like 4 and 8 and their variants are ready for use in directed halogen-metal exchange-based functionalizations.
Similar regioselective access to ortho-halogeno 5- and 6-(acylamino)benzimidazoles is complicated by the fact that there is more than one ortho position activated for
2
4
M. P. Groziak, H. Ding: Halogenated (Acylamino)imidazoles and benzimidazoles for Directed…
4
Acta Chim. Slov. 2000, 47, 1-18.
electrophilic halogenation. Benzimidazoles are commonly synthesized from substituted benzenes by imidazole ring annelation. For instance, they can be prepared by oxidative cyclization of N-arylamidines [12,13] or from diaminobenzenes [15]. These routes, though, are not readily adapted to the preparation of acylamino-equipped compounds. Although 5(6)-formylamino-substituted benzimidazoles have been prepared by an annelation route [14,25-27] and some have even been converted to their corresponding nucleosides [28], none are suitable for halogen-metal exchange reactions because they are fluorinated.
We explored access to ortho-halogeno 5- and 6-(acylamino)benzimidazoles involving the manipulation of functional groups on preformed benzimidazoles. As shown in Scheme 2, 5(6)-nitrobenzimidazole was acetylated to a mixture of isomers 9a,b, which was directly hydrogenated in HCO2H to give 5(6)-(formylamino)benzimidazole (10, 70%). Formamide 10 underwent smooth regioselective electrophilic bromination to give 4(7)-bromo-5(6)-(formylamino)benzimidazole (11, 75%). After protection of the imidazole ring with, for instance, a trityl group, heterocycle 11 will be suitable for directed halogen-metal exchange-based functionalization.
Scheme 2
H2, Pd/C                           Br2, NaOAc,
N—/^        HCO2H    J/>T^i            Ac0H      -
J'Y^l          Ac2°         /(Y^S       HCO2H   J^Y^I           Ac0H    P "îT^i
Y   ^^^R   (R = NO2)         N^^^N02                (^"^^^NHCHO             [^">^^NHCHO
9a,b                                      10                                           Br   11
(R = H) \^ aq. Br2                                                                                  \u   Ac?0
Ac
^Br               N     "Y^^NHCHO              {^     ^V^^NHCHO
ll                                                      l_l              I                                                      1                                              Ap             _
Il                                                                II                                                                                   I                                                        a/
H                                        H          R 2                                     Ac                               Ač
15,  R 1 = N02 , R 2 = H       12a, R = H —Im^Aa^I— 12b' R = H
16,  R! = H, R2 = N02       13a, R = Br -«-' ^77               ' R = Br
Non-regioselective ortho-activation by the formylamino group was encountered next when we subjected 10 to acetylation. This gave a mixture of 1,4-diacetyl-5- and 1,5-diacetyl-6-(formylamino)benzimidazoles (12a,b). Even though benzimidazole itself is
M. P. Groziak, H. Ding: Halogenated (Acylamino)imidazoles and benzimidazoles for Directed…
Acta Chim. Slov. 2000, 47, 1-18.
5
known to undergo facile dinitration [29], the ease with which diacetylation occurred was somewhat surprising. Electrophilic bromination of the 12a,b mixture in
Scheme 3

N H
1. HMDS, (NH^SC^
------------------------------>
N02   2- SnCI4, CICH2CH2CI, 2,3,5-tri-O-benzoyl-ribofliranosyl acetate
R3O
O,
N     v^^
R-l R2
R30         0R3
17,  R-i = N02; R2 = H; R3 = Bz
18,  Ri = H, R2 = NO^ R3 = Bz
19,  R-l = N02; R2 = R3 = H
20, R-i = R3 :
N^v/^/     2    1. BSA, CICH2CH2CI
N H
*Br
(15)
2. TMSOTf, CICH2CH2CI, 2,3,5-tri-O-benzoyl-ribofliranosyl acetate
R3O
O,
H; R2 = NC^ -
<xX /     R2
abs. MeOH, cat. KCN
19 20
R3O         OR3
21,  R-i = N02; R2 = Br; R3 = Bz
22,  R-i = Br; R2 = N02; R3 = Bz H2, Pd/C,          23, R-i = N02; R2 = Br; R3 = H -
HC02H    j      24, R-i = Br; R2 = N02; R3 = H - ^25, R-i = NHCHO; R2 = R3 = H ^"26, R-i = R3 = H; R2 = NHCHO
abs. MeOH, cat. KCN
buffered AcOH gave the isomeric 6-bromo-1,4-diacetyl-5- and 7-bromo-1,5-diacetyl-6-(formylamino)benzimidazoles (13a,b), but the presence of the acetyl groups in these likely precludes their use in directed halogen-metal exchange reactions. Bromination of benzimidazole (60%) followed by nitration afforded a readily separated mixture of 5-bromo-6-nitro- and 5-bromo-4-nitrobenzimidazole (15 and 16, respectively). Since the former had an attractive substitution pattern, we chose it to for an exploration of nucleoside syntheses (Scheme 3).
In an initial effort, 5(6)-nitrobenzimidazole was silylated with HMDS and (NH4)2SO4 and then was condensed with 2,3,5-tri-O-benzoylribofuranosyl acetate to give the protected nucleosides 17 and 18. These were easily separated and deprotected (CH3OH, cat. KCN) [30] to the corresponding ribosides 19 and 20. Next, under slightly different conditions [6], BSA was used to trimethylsilylate 15 for condensation with the same ribofuranosyl acetate, this time in the presence of TMSOTf.    The mixture of
M. P. Groziak, H. Ding: Halogenated (Acylamino)imidazoles and benzimidazoles for Directed…
6
Acta Chim. Slov. 2000, 47, 1-18.
isomers 21 and 22 obtained was not easily separated, and so it was deblocked to give a mixture of the ribosides 23 and 24. Catalytic hydrogenation of these in formic acid gave only the halogen-less formamides 25 and 26, also obtained from nucleosides 19 and 20 using the same procedure. Interestingly, the halogen atom in both 5-bromo-1-ethyl-6-nitrobenzimidazole and its 6-bromo-1-ethyl-5-nitro isomer is reportedly inert to metalation with BuLi or K metal [31]. As evidenced by the conversions of 23/24 to 25/26, though, this type of halogen does not survive catalytic hydrogenation. Still, other non-Pd-based conditions for nitro group reductive-acylation can be applied to the task of converting 23/24 to their ortho-bromo (acylamino)-substituted counterparts, and then appropriate aglycon-protected versions of these can be used in the halogen-metal exchange-based ring functionalizations of interest.
Experimental
Melting points were determined on a Thomas-Hoover UniMelt capillary apparatus and are uncorrected. Preparative (flash) column chromatography was performed using Merck silica gel-60 (200-430 ASTM), and radial preparative-layer chromatography was performed on a Chromatotron instrument (Harrison Research, Inc., Palo Alto, CA) using Merck silica gel-60 PF254 as adsorbent. Thin-layer chromatography (TLC) employed 250 micron silica gel-GF Analtech Uniplates illuminated by short-wave (254 nm) UV light. 1H and 13C NMR spectra were recorded on a Varian VXR-300 or VXR-500 spectrometer using (CH3)4Si (d = 0.0 for 1H), CDCl3 (d = 7.26 for 13C), or (CD3)2SO (d = 39.5 for 13C) as internal references. Moisture-sensitive reactions were conducted in flame-dried, argon-purged glassware. 5(6)-Nitrobenzimidazole, benzimidazole, N,O-bis(trimethylsilyl)acetamide (BSA), Bz2O, SnCl4, BH3 in THF, trimethylsilyltriflate (TMSOTf), AgBF4, and 10% Pd/C were purchased from Aldrich. Royer palladium catalyst beads (1% Pd on polyethyleneimine/SiO2) were obtained from GFS Chemicals. 4(5)-Nitroimidazole was purchased from Acros, and 2,3,5-tri-O-benzoyl-1-O-acetyl-D-ribose was purchased from Pfanstiehl Laboratories. 1,4-Dioxane, Et2O, and THF were each dried by distillation from Na(s) under argon using benzophenone ketyl as indicator. 1,2-Dichloroethane, CH2Cl2, and 1,1,1,3,3,3-hexamethyldisilazane (HMDS) were each
M. P. Groziak, H. Ding: Halogenated (Acylamino)imidazoles and benzimidazoles for Directed…
Acta Chim. Slov. 2000, 47, 1-18.
7
dried by distillation from CaH2 under argon. CH3OH was dried by distillation from Mg(OCH3)2 under argon, and both CH3I and Ac2O were freshly distilled from P2O5 under argon immediately before use. Anhydrous AcOH was prepared by distilling glacial AcOH from tetraacetoxydiborate prepared by heating B(OH)3 in Ac2O. Anhydrous HCO2H was prepared by distilling 97% HCO2H from B2O3. Some compounds were characterized solely on the basis of their NMR or mass spectral characteristics. Like the 5-(formylamino)imidazole ribonucleoside we studied earlier [2], many of the acylamino compounds reported herein were slowly interconverting E and Z amide rotamers in solution, determined by NMR.
l-Methyl-5-nitroimidazole (1). A suspension of 4(5)-nitroimidazole (1.13 g, 10 mmol) in 100 mL of HMDS containing 1 mL of (CH3)3SiCl was heated at reflux under argon overnight. The volatiles were removed in vacuo to give 4-nitro-1-(trimethylsilyl)imidazole as a hygroscopic white solid: 1H NMR (CDCl3) 8 7.78 (s, 1H, H2), 7.49 (s, 1H, H4), 0.57 (s, 9H, Si(CH3)3). 13C NMR (CDCl3) 8 139.4 (C2), 121.4 (C4), 0.02 (Si(CH3)3). This was dissolved directly in 15 mL of anhyd. CH3I, and AgBF4 (1.95 g, 10 mmol) was added all at once to the solution. Although the reaction was likely complete earlier, the mixture was stirred at 23 °C for 10 h. The volatiles were removed by rotary evaporation, and the product was extracted from the residue with CH2Cl2. The extracts were combined and rotary evaporated to a yellow solid which was purified by column chromatography (15% CH3OH/CH2Cl2 as eluent) to give 852 mg (68%) of 1 as yellow crystals: mp 48-53 °C (lit. [9,11] 53-55 °C). 1H NMR (CDCl3) 8 7.92 (s, 1H, H2), 7.49 (s, 1H, H4), 3.94 (s, 3H, CH3). 13C NMR (CDCl3) 8 141.5 (C2), 133.0 (C4), 35.1 (CH3). Anal. Calcd. for C4H5N3O2•1/3H2O: C, 36.09; H, 4.29; N, 31.57. Found: C, 36.19; H, 4.15; N, 31.53.
5-Amino-l-methylimidazole (2). [9,11] A solution of 1 (264 mg, 2 mmol) in 25 mL of anhyd. 1,4-dioxane was treated with 150 mg of 10% Pd/C and was stirred under 1 atm of H2 for 6 h. The mixture was filtered through Celite and the filtrate was rotary evaporated to dryness to give 190 mg (97%) of 2 as a hygroscopic, air-sensitive grey powder with NMR spectral properties closely matching literature values:    1H NMR
M. P. Groziak, H. Ding: Halogenated (Acylamino)imidazoles and benzimidazoles for Directed...
8
Acta Chim. Slov. 2000, 47, 1-18.
((CD3)2SO) d 7.04 (s, 1H, H2), 6.01 (s, 1H, H4), 4.43 (bs, exchanges upon addition of D2O, 2H, NH2), 3.34 (s, 3H, CH3). 13C NMR ((CD3)2SO) d 138.3 (C2), 136.7 (C5), 110.4 (C4), 29.8 (CH3).
5-(Formylamino)-1-methylimidazole (3a). A solution of 1 (700 mg, 5.51 mmol) in 25 mL of anhyd. HCO2H was treated with 100 mg of 10% Pd/C and the mixture was stirred under 1 atm of H2 overnight. The catalyst was removed by suction filtration and the solution was rotary evaporated to dryness under vacuum. The dark brown oil obtained was purified by column chromatography (10% CH3OH/CH2Cl2 as eluent) to give 500 mg (70%) of 3a, found to exist as a mixture of E and Z amide rotamers in (CD3)2SO solution: 1H NMR ((CD3)2SO) d 10.00 (bs, exchanges upon addition of D2O, 1H, NH major), 9.65 (d, J = 10 Hz, exchanges upon addition of D2O, 1H, NH minor), 8.24 (s, 1H, CHO major), 8.08 (d, J = 10 Hz, 1H, CHO minor), 7.45 (s, 1H, H2 major), 7.53 (s, 1H, H2 minor), 6.81 (s, 1H, H4 major), 6.79 (s, 1H, H4 minor), 3.46 (s, 3H, CH3 major), 3.32 (s, 3H, CH3 minor).
5-(Benzoylamino)-1-methylimidazole (3b). This was prepared from 1 by the procedure used to prepare 7c from 5: 1H NMR ((CD3)2SO) d 10.05 (bs, exchanges upon addition of D2O, 1H, NH), 7.97 (d, J = 8 Hz, 2H, o-PhH), 7.61-7.47 (m, 4H, m-PhH, p-PhH, and H2), 7.00 (s, 1H, H4), 3.62 (s, 3H, CH3). Low-resolution DCI mass spectrum, m/z 201 (MH+), 219 (MNH4+).
5-(Benzoylamino)-4-iodo-1-methylimidazole (4). This was prepared from 3b by the procedure used to prepare 8 from 7c: 1H NMR ((CD3)2SO) d 10.0 (bs, exchanges upon addition of D2O, 1H, NH), 7.97 (d, J = 8 Hz, 2H, o-PhH), 7.71 (s, 1H, H2), 7.58 (pseudo-q, 1H, p-PhH), 7.50 (pseudo-t, 2H, m-PhH), 3.62 (s, 3H, CH3).
1-Methyl-4-nitroimidazole (5). Using AgNO3 and CH3I. In a modification of literature procedures [21,22], a stirred solution of 3.0 g (26.5 mmol) of 4(5)-nitroimid-azole in a mixture of 40 mL of concd. aq. NH4OH and 21 mL of EtOH was treated with a warm solution of 5.4 g (31.8 mmol, 1.2 equiv) of AgNO3 in 75 mL of EtOH. After 15 min, the precipitated silver nitroimidazolide was collected by suction filtration and was washed with EtOH and dried overnight in vacuo.  A suspension of this salt in 50 mL of
M. P. Groziak, H. Ding: Halogenated (Acylamino)imidazoles and benzimidazoles for Directed…
Acta Chim. Slov. 2000, 47, 1-18.
9
dry benzene was treated with 2 mL of freshly distilled CH3I and the mixture was heated at reflux for 24 h, during which time two additional 2 mL portions of CH3I were added at 8 h intervals. The benzene and the unreacted CH3I were removed by distillation, and the residue was extracted with 200 mL of hot water. The aqueous solution was rotary evaporated to a solid, which was recrystallized from water and then purified by column chromatography (5% CH3OH/CH2Cl2 as eluent) to afford 1.38 g (41%) of 5 as a yellow solid: mp 130-132 °C (lit. [21] 133-134 °C). 1H NMR ((CD3)2SO) 8 8.40 (s, 1H, H2), 7.80 (s, 1H, H5), 3.79 (s, 3H, CH3).
Using Me2SC>4 and aq. NaOH. In a modification of another literature procedure [23,24], a solution of 4(5)-nitroimidazole (6.0 g, 53 mmol) and 60 mL of 10% aq. NaOH at 5 °C was treated dropwise with 0.56 mL (1.5 equiv.) of Me2SO4 and the mixture was stirred at 23 °C for 2 h. The pH of the solution was adjusted to 7 by the addition of cold dilute aq. HCl, and the solution was reduced to a small volume by rotary evaporation. The precipitate was collected by filtration and then purified by column chromatography (5% CH3OH/CH2Cl2 as eluent) to give a 9:1 mixture of 5 and 1, by 1H NMR. This ratio is the exact opposite of that reported by Benjes and Grimmett [24].
Using Mel and K2CO3. A solution of dry 4(5)-nitroimidazole (5.23 g, 46.2 mmol) in 120 mL of dry DMF was treated with 65 g of powdered K2CO3 and then was stirred vigorously while 3.39 mL (54 mmol) of iodomethane was added dropwise via syringe. After 22 h of continued stirring at 23 °C, the mixture was suction filtered through 0.5 g of Celite and the filter cake was washed with additional dry DMF. The DMF solutions were combined and rotary evaporated in vacuo at 40 °C to a yellow-white solid which was purified by column chromatography (20% CH3OH/CH2Cl2 as eluent to give a 4:1 mixture of 5 and 1 in a 92% yield. The latter was removed from the mixture by trituration with water, giving 5 in a 70% yield: mp 133-135 °C.
4-Amino-l-methylimidazole (6). The 9:1 mixture of 5/1 from above was reduced with 1 atm of H2 overnight using 10% Pd/C in 1,4-dioxane to give 6 in a 60% yield. 1H NMR ((CD3)2SO) 8 7.09 (s,  1H, H2), 6.10 (s,  1H, H5), 4.41 (bs, exchanges upon
M. P. Groziak, H. Ding: Halogenated (Acylamino)imidazoles and benzimidazoles for Directed...
10
Acta Chim. Slov. 2000, 47, 1-18.
addition of D2O, 2H, NH2), 3.49 (s, 3H, CH3).    13C NMR ((CD3)2SO) 8 147.2 (C4), 133.3 (C2), 100.1 (C5), 32.9 (CH3).
4-(Formylamino)-l-methylimidazole (7a). A solution of 5 (500 mg, 3.9 mmol) in 20 mL of 97% HCO2H (20 mL) was treated with 250 mg of Pd/C and was stirred under 1 atm of H2 overnight. The solution was rotary evaporated in vacuo to give 7a as a dark brown oil, found to exist as a mixture of E and Z amide rotamers in (CD3)2SO solution. 1H NMR ((CD3)2SO) 8 10.38 (s, exchanges with D2O, 1H, NH major), 9.88 (s, exchanges with D2O, 1H, NH minor), 8.50 (d, 1H, CHO minor), 8.09 (s, 1H, CHO major), 7.41 (s, 1H, H2 minor), 7.38 (s, 1H, H2 major), 7.19 (s, 1H, H5 major), 6.79 (s, 1H, H5 minor), 3.59 (s, 3H, CH3 major), 3.40 (s, 3H, CH3 minor).
4-(Acetylamino)-l-methylimidazole (7b). A solution of 5 (890 mg, 7.0 mmol) in 35 mL of Ac2O was treated with 372 mg of 10% Pd/C and two drops of AcOH and was stirred under 1 atm of H2 overnight. The catalyst was removed by filtration, washed with Ac2O, and the filtrate and washing were combined and were rotary evaporated to give 7b, found to exist as a mixture of E and Z amide rotamers in (CD3)2SO solution. 1H NMR ((CD3)2SO) 8 10.2 (s, exchanges with D2O, 1H, NH major), 9.66 (s, exchanges with D2O, 1H, NH minor), 7.34 (s, 3H, H2 major, H2 minor, and H5 minor), 7.14 (s, 1H, H5 major), 3.59 (s, 3H, NCH3 major), 3.40 (s, 3H, NCH3 minor), 1.96 (s, 3H, COCH3 minor), 1.89 (s, 3H, COCH3 major). 13C NMR ((CD3)2SO) 8 172.2 (C=O), 168.0 (C=O), 167.1, 166.4, 138.1, 133.6, 129.8, 122.3, 107.4 (C5), 33.1 (CH3), 30.4 (CH3), 21.3 (CH3), 20.3 (CH3).
4-(Benzoylamino)-l-methylimidazole (7c). A solution of 5 (2.0 g, 15.7 mmol) in 90 mL of dry 1,4-dioxane was treated with Bz2O (5 g, 22.1 mmol) and 1.2 g 10% Pd/C, and the mixture was stirred under 1 atm of H2 at 23 °C for 48 h. The catalyst was removed by suction filtration and the filtrate was rotary evaporated to a brown oil. A solution of this oil in CH2Cl2 was washed with satd. aq. NaHCO3, and the organic soluble fraction was purified by column chromatography (4% CH3OH/CH2Cl2 as eluent) to give 1.9 g (60%) of 7c: mp 169-171 °C (EtOH). 1H NMR (CDCl3) 8 11.34 (bs, exchanges upon addition of D2O, 1H, NH), 7.98-7.95 (m, 2H, m-PhH), 7.55-7.43 (m, 4H, o-PhH,
M. P. Groziak, H. Ding: Halogenated (Acylamino)imidazoles and benzimidazoles for Directed...
Acta Chim. Slov. 2000, 47, 1-18.
11
p-PhH, and H5), 6.78 (s, 1H, H2), 3.61 (s, 3H, CH3); ((CD3)2SO) 8 10.71 (bs, exchanges upon addition of D2O, 1H, NH), 8.01 (dd, J = 8.1, 1.8 Hz, 2H, o-PhH), 7.56-7.44 (m, 4H, m-PhH, p-PhH, and H2), 7.39 (s, 1H, H5), 3.66 (s, 3H, CH3). 13C NMR (CDCl3) 8 165.2 (C=O), 138.8 (C2), 135.0 (ipso-PhC), 133.3 (C2), 131.2 (p-PhC), 128.2 (o-PhC), 127.7 (m-PhC), 108.7 (C5), 33.7 (CH3). Anal. Calcd. for C11H11N3O: C, 65.66; H, 5.51; N, 20.88. Found: C, 65.53; H, 5.52; N, 20.79.
4-(Benzoylamino)-5-iodo-l-methylimidazole (8). A solution of 7c (503 mg, 2.5 mmol) in 25 mL of CH2Cl2 was treated with 3.5 g of K2CO3 and stirred vigorously at 23 °C while one equivalent of I2 dissolved in Et2O was added dropwise. The reaction mixture was stirred at 23 °C for 2 h, and then it was passed through a short pad of SiO2 using 10% CH3OH/CH2Cl2 as eluent. The solution collected was rotary evaporated to a dark brown oil that was separated by column chromatography to give 8 and of 7c (200 mg). Recrystallization of the former from CH2Cl2 gave 245 mg (30%, 50% based upon unrecovered 7c) of 8: mp 176-177 °C. 1H NMR ((CD3) 2SO) 8 9.96 (bs, exchanges upon addition of D2O, 1H, NH), 7.95-7.97 (m, 2H, m-PhH), 7.86 (s, 1H, H2), 7.50-7.56 (m, 3H, o-PhH, p-PhH), 3.59 (s, 3H, CH3). 13C NMR ((CD3) 2SO) 8 165.0 (C=O), 140.5 (C4), 138.0 (C2), 131.6 (p-PhC), 128.3 (o-PhC), 127.6 (m-PhC), 98.0 (C5), 35.2 (CH3). Low-resolution DCI (direct chemical ionization) mass spectrum, m/z 328 (MH+). Anal. Calcd. for C11H10IN3O: C, 40.39; H, 3.08; N, 12.85. Found: C, 39.71; H, 3.00; N, 12.46.
l-Acetyl-5- and 6-nitrobenzimidazoles (9a,b). A solution of 5(6)-nitroben-zimidazole (16.3 g, 0.1 mol) in 200 mL of Ac 2O was stirred at 23 °C for 48 h. The white precipitate produced (10.8 g) and the pale yellow powder obtained by rotary evaporation of the filtrate (9.1 g) both proved to be a mixture of 9a,b (97% combined) by TLC (5% CH3OH/CH2Cl2) and NMR. 9a: 1H NMR ((CD3)2SO) 8 9.13 (s, 1H, H2), 8.54 (d, J = 1.2 Hz, 1H, H4), 8.22-8.29 (m, 1H, H6), 7.95 (d, J = 8.8 Hz, 1H, H7), 2.80 (s, 3H, CH3). 9b: 1H NMR ((CD3)2SO) 8 9.20 (s, 1H, H2), 8.88 (d, J = 2.2 Hz, 1H, H7), 8.22-8.29 (m, 2H, H4, H5), 2.80 (s, 3H, CH3).
M. P. Groziak, H. Ding: Halogenated (Acylamino)imidazoles and benzimidazoles for Directed...
12
Acta Chim. Slov. 2000, 47, 1-18.
5(6)-(Formylamino)-benzimidazole (10). A solution of the isomeric mixture of 9a,b (19 g) in 200 mL of anhyd. HCO2H was treated with 1.0 g of 10% Pd/C and the mixture was stirred under 1 atm of H2 overnight. The catalyst was removed by suction filtration and the filtrate was rotary evaporated to a brown oil that was purified by a short column chromatography (15-20% CH3OH/CH2Cl2 as eluent) to afford 10 g (70%) of pure 10, found to exist as a mixture of E and Z amide rotamers in (CD3)2SO solution. 1H NMR ((CD3)2SO) d 10.25 (bs, exchanges upon addition of D2O, 1H, NH major), 10.15 (d, J = 10 Hz, exchanges upon addition of D2O, 1H, NH minor), 8.78 (d, J = 11 Hz, 1H, CHO minor), 8.25 (s, 1H, CHO major), 8.19 (s, 1H, H2), 8.11 (d, J = 1.8 Hz, H4 major), 7.58 (d, J = 8.7 Hz, H7), 7.45 (d, J = 1.8 Hz, H4 minor), 7.30 (dd, J = 8.6, 2.0 Hz, H6 major), 7.09 (dd, J = 8.6, 2.0 Hz, H6 minor). Low-resolution DCI mass spectrum, m/z 162 (MH+).
4-Bromo-5-(formylamino)-benzimidazole (11). A solution of 10 (1.57 g, 10 mmol) and NaOAc (3 g, 36 mmol) in 20 mL of anhyd. AcOH was treated dropwise with Br2 (0.51 mL, 10 mmol). The brown precipitate produced was collected by filtration and was dried in vacuo to afford 1.78 g (75%) of 11, found to exist as a mixture of E and Z amide rotamers in (CD3)2SO solution: 1H NMR ((CD3)2SO) d 10.73 (bs, exchanges upon addition of D2O, 1H, NH major), 10.22 (d, J = 11 Hz, exchanges upon addition of D2O, 1H, NH minor), 9.57 (s, 1H, CHO major), 8.90 (d, J = 11 Hz, 1H, CHO minor), 8.39 (s, 1H, H2), 7.85 (d, J = 9 Hz, 1 H, H7), 7.60 (d, J = 8.9 Hz, 1H, H6).
1,4-Diacetyl-5- and 1,5-Diacetyl-6-(formylamino)-benzimidazoles (12a,b). A solution of 10 (3.2 g, 20 mmol) in 15 mL of Ac2O was heated at reflux for 2 h, at which time 10 had been consumed, by TLC. The volatiles were removed by rotary evaporation to leave a mixture of 12a,b as a brown solid. 12a: 1H NMR ((CD3)2SO) d 9.45 (s, 1H, CHO), 8.97 (s, 1H, H2), 8.22 (d, J = 8.4 Hz, 1H, H7), 7.70 (s, 1H, H4), 7.28 (m, 2 H, H6), 2.26 (s, 3H, CH3); 12b: 1H NMR ((CD3)2SO) d 9.41 (s, 1H, CHO), 8.97 (s, 1H, H2), 8.05 (s, 1H, H4), 7.83 (d, J = 8.4 Hz, 1H, H7), 7.28 (m, 2 H, H6), 2.20 (s, 3H, CH3). Low-resolution DCI mass spectrum, m/z 246 (MH+).
M. P. Groziak, H. Ding: Halogenated (Acylamino)imidazoles and benzimidazoles for Directed…
Acta Chim. Slov. 2000, 47, 1-18.
13
6-Bromo-1,4-diacetyl-5- and 7-Bromo-1,5-diacetyl-6-(formylamino)-benz-imidazoles (13a,b). A solution of 12a,b (320 mg, 1.6 mmol) and NaOAc (394 mg, 4.8 mmol) in 3 mL of anhyd. AcOH was treated dropwise with Br2 (82 mL, 1.6 mmol). The reaction mixture was stirred at 23 °C for 2 h. The volatiles were removed under vacuum, and the brown solid residue was purified by column chromatography (5-10% CH3OH/CH2Cl2 as eluent) to afford 13a,b: 1H NMR ((CD3)2SO) d 9.95 (s, 1H, CHO minor), 9.48 (s, 1H, CHO major), 8.36 (s, 2H, H2 major), 8.18 (s, 1H), 8.10 (s, 1H, H2 minor), 7.65 (d, 1H), 7.54 (d, 1H), 7.25 (dd, 1H), 7.05 (dd, 1H), 2.25-2.20 (four s, each 3H, each CH3).
5(6)-Bromobenzimidazole (14). [25] A solution of Br2 (260 mL) in 60 mL of water was added dropwise to a suspension of benzimidazole (600 mg, 5 mmol) in a solution of 2 g of KOAc in 50 mL of H2O. The resulting white suspension was stirred at 23 °C overnight, and then was extracted with CH2Cl2. The combined organic layers were washed with satd. aq. NaCl and then were dried (MgSO4). Rotary evaporation afforded 590 mg (60%) of 14 as a foam. 1H NMR ((CD3)2SO) d 8.28 (s, 1H, H2), 7.80 (s, 1H, H4), 7.55 (d, J = 8.6 Hz, 1H, H6), 7.31 (d, J = 8.5 Hz, 1H, H7). Low-resolution DCI mass spectrum, m/z 197 (MH+).
5-Bromo-6-nitro- and 5-bromo-4-nitrobenzimidazole (15 and 16). [15] A solution of 14 (590 mg, 3 mmol) in 1 mL of 98% H2SO4 at 0 °C was treated dropwise with a solution of 0.1 mL of conc. HNO3 in 1 mL of 98% H2SO4 [32]. The reaction mixture was stirred at 0-5 °C for 2 h, and then it was poured into an ice/water mixture. The pH of the mixture was adjusted to 8 by the addition of conc. NH4OH, and the precipitate which formed was collected by suction filtration and the filtrate was extracted with CH2Cl2. The organic layer was washed with satd. aq. NaCl and was dried (MgSO4). The residue obtained by rotary evaporation of this was combined with the original precipitate, and the crude product mixture was purified by column chromatography (5-10% CH3OH/CH2Cl2 as eluent) to afford 15 and 16 separately. 15: 1H NMR ((CD3)2SO) d 8.53 (s, 1H, H2), 8.35 (s, 1H, H4), 8.06 (s, 1H, H7). Low-resolu tion DCI mass spectrum, m/z 242/244 (MH+); 16: 1H NMR ((CD3)2SO) d 8.47 (s, 1H, H2), 7.82
M. P. Groziak, H. Ding: Halogenated (Acylamino)imidazoles and benzimidazoles for Directed…
14
Acta Chim. Slov. 2000, 47, 1-18.
(d, J = 8.4 Hz, 1H, H6), 7.62 (d, J = 8.4 Hz, 1H, H7).   Low-resolution DCI mass spectrum, m/z 242/244 (MH+).
5- and 6-Nitro-l-(2,3,5-tri-0-benzoyl-/3-D-ribofuranosyl)-benzimidazoles (17
and 18). 5(6)-Nitrobenzimidazole (3.26 g, 20 mmol) was suspended in 60 mL of HMDS, 60 mg of (NH4)2SO4 was added, and the reaction mixture was heated at reflux overnight, at which time most of the starting material had dissolved. The HMDS was removed by distillation, and white solid residue was dissolved in 100 mL of freshly distilled dichloroethane. This was treated with 1-acetyl-2,3,5-tribenzoylribofuranose (10.08 g, 20 mmol) and SnCl4 (3-4 mL), and the reaction mixture was stirred at 23 °C overnight. The reaction mixture was treated with 250 mL of CHCl3 and the organic phase was washed with satd. aq. NaHCO3 solution thrice, and then with satd. aq. NaCl solution twice. The organic layer was dried (Na2SO4) and rotary evaporated in vacuo to a yellow foam. Column chromatography (0.5-0.75% CH3OH/CH2Cl2) gave a mixture of 17 and 18, which were separated by radial chromatography (1:1 EtOAc/hexanes as eluent). 17: mp 88-93 °C. 1H NMR ((CD3)2SO) 8 8.91 (s, 1H, H2), 8.59 (s, 1H, H4), 8.04-7.42 (m, 17H, H6, H7, and three Ph), 6.82 (d, 1H, H1'), 6.15 (m, 1H, H2'), 6.05 (m, 1H, H3'), 4.95 (m, 1H, H4'), 4.85 (m, 2H, 5'CH2). Anal. Calcd. for C33H25N3O9: C, 65.24; H, 4.15; N, 6.92. Found: C, 65.05; H, 4.19; N, 6.66. 18: mp 91-95 °C. 1H NMR ((CD3)2SO) 8 9.00 (s, 1H, H2), 8.88 (s, 1H, H4), 8.20-7.46 (m, 17H, H6, H7, and three Ph), 6.95 (d, 1H, H1'), 6.20 (m, 1H, H2'), 6.05 (m, 1H, H3'), 4.95 (m, 1H, H4'), 4.83 (m, 2H, 5'CH2). Anal. Calcd. for C33H25N3O9: C, 65.24; H, 4.15; N, 6.92. Found: C, 65.48; H, 4.19; N, 5.94.
5-Nitro-l-(/3-D-ribofuranosyl)-benzimidazole (19). A suspension of 15 (300 mg) in 10 mL of CH3OH was treated with KCN (18 mg) [30] and the reaction mixture was stirred at 23 °C for 6 h, at which time no starting material remained, by TLC. The volatiles were removed by rotary evaporation, and the residue was purified by a column chromatography (15% CH3OH/CH2Cl2 as eluent) to afford 138 mg (95%) of 19: mp 191-192 °C. 1H NMR ((CD3)2SO) 8 8.78 (s, 1H, H2), 8.55 (d, 1H, H4), 8.17 (dd, 1H, H7), 7.96 (d, 1H, H6), 5.98 (d, 1H, H1'), 5.55 (m, exchanges upon addition of D2O, 1H,
M. P. Groziak, H. Ding: Halogenated (Acylamino)imidazoles and benzimidazoles for Directed...
Acta Chim. Slov. 2000, 47, 1-18.
15
OH), 5.27 (m, exchanges upon addition of D2O, 1H, OH), 5.18 (m, exchanges upon addition of D2O, 1H, OH), 4.37 (m, 1H, H2'), 4.14 (m, 1H, H3'), 4.02 (m, 1H, H4'), 3.66 (m, 2H, 5'CH2). Low-resolution DCI mass spectrum, m/z 296 (MH+). Anal. Calcd. for C12H13N3O6: C, 48.82; H, 4.44; N, 14.23. Found: C, 48.23; H, 4.45; N, 13.88.
6-Nitro-l-(/3-D-ribofuranosyl)-benzimidazole (20). This nucleoside was prepared from 18 by the method described above: mp 168-170 °C. 1H NMR ((CD3)2SO) 8 8.85 (s, 1H, H2), 8.83 (d, 1H, H7), 8.15 (dd, 1H, H5), 7.86 (d, 1H, H7),
6.04  (d, 1H, H1'), 5.60 (m, exchanges upon addition of D2O, 1H, OH), 5.26 (m, exchanges upon addition of D2O, 2H, two OH), 4.40 (m, 1H, H2'), 4.15 (m, 1H, H3'),
4.05  (m, 1H, H4'), 3.70 (m, 2H, 5'CH2). Low-resolution DCI mass spectrum, m/z 296 (MH+). Anal. Calcd. for C12H13N3O6: C, 48.82; H, 4.44; N, 14.23. Found: C, 48.69; H, 4.36; N, 14.00.
6-Bromo-5-nitro- and 5-Bromo-6-nitro-l-(2,3,5-tri-0-benzoyl-/3-D-ribo-furanosyl)-benzimidazoles (21 and 22). Adapting a published procedure [6], a suspension of 15 (1.93 g, 8 mmol) in 40 mL of dichloroethane was treated dropwise with 2 mL of BSA, and the resulting yellow suspension was heated at 70-80 °C for 20 min, giving a clear solution. The reaction mixture was allowed to cool to 23 °C, and then was treated with 1-acetyl-2,3,5-tribenzoylribofuranose (4.43 g, 8.8 mmol) and TMSOTf (1.86 mL, 10.5 mmol). The reaction mixture was stirred at 23 °C overnight, at which point no starting material remained, by TLC. The reaction mixture was diluted with 100 mL of CHCl3 and the organic solution was washed 3 times with satd. aq. NaHCO3, 2 times with satd. aq. NaCl, and then was dried (Na2SO4). Rotary evaporation gave a yellow foam which was purified by column chromatography (1:1 EtOAc/hexanes as eluent) to give 1.4 g (26%) of a mixture of 21 and 22. 21: 1H NMR ((CD3)2SO) 8 8.92 (s, 1H, H2), 8.46 (s, 1H, H4), 8.43 (s, 1H, H7), 8.00-7.51 (m, 15H, three Ph), 6.82 (d, 1H, H1'), 6.16 (m, 1H, H2'), 6.05 (m, 1H, H3'), 4.92 (m, 1H, H4'), 4.80 (m, 2H, 5'CH2). 22: 1H NMR ((CD3)2SO) 8 8.99 (s, 1H, H2), 8.69 (s, 1H, H7), 8.23 (s, 1H, H4), 8.00-7.51 (m, 15H, three Ph), 6.82 (d, 1H, H1'), 6.16 (m H, H2'), 6.05 (m, 1H, H3'), 4.92 (m, 1H, H4'), 4.80 (m, 2H, 5'CH2).
M. P. Groziak, H. Ding: Halogenated (Acylamino)imidazoles and benzimidazoles for Directed...
16
Acta Chim. Slov. 2000, 47, 1-18.
6-Bromo-5-nitro- and 5-Bromo-6-nitro-l-(/3-D-ribofuranosyl)-benzimidazoles (23 and 24). The mixture of 21 and 22 from above (1.4 g, 2 mmol) was suspended in 20 mL of CH3OH and 65 mg of KCN was added. The reaction mixture was stirred at 23 °C for 6 h, at which time the deprotection was complete, by TLC. The volatiles were removed in vacuo, and the residue purified by column chromatography (15% CH3OH/CH2Cl2 as eluent) to give 700 mg (95%) of a mixture of 23 and 24. 23: 1H NMR ((CD3)2SO) 8 8.80 (s, 1H, H2), 8.46 (s, 1H, H4), 8.43 (s, 1H, H7), 6.00 (d, 1H, H1'), 5.60 (m, exchanges upon addition of D2O, 1H, OH), 5.26 (m, exchanges upon addition of D2O, 2H, two OH), 4.35 (m, 1H, H2'), 4.15 (m, 1H, H3'), 4.05 (m, 1H, H4'), 3.70 (m, 2H, 5'CH2). 24: 1H NMR ((CD3)2SO) 8 8.76 (s, 1H, H2), 8.71 (s, 1H, H7), 8.21 (s, 1H, H4), 5.98 (d, 1H, H1'), 5.60 (m, exchanges upon addition of D2O, 1H, OH), 5.26 (m, exchanges upon addition of D2O, 2H, two OH), 4.35, 1H, H2'), 4.15 (m, 1H, H3'), 4.05 (m, 1H, H4'), 3.70 (m, 2H, 5'CH2).
5- and 6-(Formylamino)-l-(/3-D-ribofuranosyl)-benzimidazoles (25 and 26).
[28] A solution of the above mixture of 23 and 24 (300 mg, 0.8 mmol) in 5 mL of anhyd. HCO2H was treated with 50 mg of 10% Pd/C and then was stirred under 1 atm of H2 at 23 °C overnight. The volatiles were removed in vacuo, and the residue was purified by radial chromatography to afford a mixture of 25 and 26, each of which were found to exist as a mixture of E and Z amide rotamers in (CD3)2SO solution: 25: 1H NMR ((CD3)2SO) 8 10.43 (bs, exchanges upon addition of D2O, 1H, NH major), 10.12 (d, J = 11 Hz, exchanges upon addition of D2O, 1H, NH minor), 8.75 ( d, 1H, CHO minor), 8.40 (s, 1H, CHO major), 8.28 (s, 1H, H2), 8.10 (s, 1H, H7), 7.60 (d, 1H, H4), 7.32 (dd, 1H, H6), 5.78 (d, 1H, H1'), 5.48 (m, exchanges upon addition of D2O, 1H, OH), 5.26-5.00 (m, exchanges upon addition of D2O, 2H, two OH), 4.35 (m, 1H, H2'), 4.10 (m, 1H, H3'), 3.97 (m, 1H, H4'), 3.58 (m, 2H, 5'CH2). 26: 1H NMR ((CD3)2SO) 8 10.32 (bs, exchanges upon addition of D2O, 1H, NH major), 10.08 (d, J = 11 Hz, exchanges upon addition of D2O, 1H, NH minor), 8.71 (d, 1H, CHO minor), 8.41 (s, 1H, CHO major), 8.26 (s, 1H, H2), 8.06 (s, 1H, H4), 7.67 (d, 1H, H4), 7.38 (dd, 1H, H6), 5.82 (d, 1H, H1'), 5.48 (m, exchanges upon addition of D2O, 1H, OH), 5.26-5.00 (m, exchanges upon addition of D2O, 2H, two OH), 4.35 (m, 1H, H2'), 4.10 (m, 1H, H3'), 3.97 (m, 1H, H4'),
M. P. Groziak, H. Ding: Halogenated (Acylamino)imidazoles and benzimidazoles for Directed...
Acta Chim. Slov. 2000, 47, 1-18.
17
3.58 (m, 2H, 5'CH2). Low-resolution DCI mass spectrum, m/z 294 (MH+). Nucleosides 19 and 20 also gave 25 and 26 when subjected to these conditions.
Acknowledgments
This work was supported by grant GM44819 from the National Institutes of Health and has appeared in preliminary form: Groziak, M. P; Ding, H. 16th International Congress of Heterocyclic Chemistry, 1997, Bozeman, MT, Abstr. POI-73. We thank Anusree Ganguly for help with 5, 6, and 7a,b, and Liya Chen for help with 5 and 7c.
References
[I]          F. J. Schendel, Y. S. Cheng, J. D. Otvos, S. Wehrli, J. Stubbe, Biochemistry 1988, 27, 2614– 2623.
[2]         M. P. Groziak, Z.-W. Huan, H. Ding, Z. Meng, W. C. Stevens, P. D. Robinson, J. Med. Chem.
1997, 40, 3336–3345.
[3]         R. V. Devivar, E. Kawashima, G. R. Revankar, J. M. Breitenbach, E. D. Kreske, J. C. Drach, L.
B. Townsend, J. Med. Chem. 1994, 37, 2942–2949.
[4]         L. B. Townsend, R. V. Devivar, S. R. Turk, M. R. Nassiri, J. C. Drach, J. Med. Chem. 1995, 38,
4098–4105.
[5]         S. Saluja, R. Zou, J. C. Drach, L. B. Townsend, J. Med. Chem. 1996, 39, 881–891.
[6]         R. Zou, K. R. Ayres, J. C. Drach, L. B. Townsend, J. Med. Chem. 1996, 39, 3477–3482.
[7]         R. Szyszka, N. Grankowski, K. Felczak, D. Shugar, Biochem. Biophys. Res. Commun. 1995,
208, 418–424.
[8]         Y. F. Shealy, J. Pharm. Sci. 1970, 59, 1533–1558.
[9]         A. H. Al-Shaar, D. W. Gilmour, D. J. Lythgoe, I. McClenaghan, C. A. Ramsden, J. Chem. Soc.,
Chem. Commun. 1989, 551–552.
[10]       A.H.M. Al-Shaar, R. K. Chambers, D. W. Gilmour, D. J. Lythgoe, I. McClenaghan, C. A. Ramsden, J. Chem. Soc., Perkin Trans. 1 1992, 2789–2811.
[II]        A.H.M. Al-Shaar, D. W. Gilmour, D. J. Lythgoe, I. McClenaghan, C. A. Ramsden, J. Chem. Soc., Perkin Trans. 1 1992, 2779–2788.
[12]       V. J. Grenda, R. E. Jones, G. Gal, M. Sletzinger, J. Org. Chem. 1965, 30, 259–261.
[13]       M. Miocque, C. Fauran, A. Y. Le Cloarec, Ann. Chim. 1972, 7, 89–102.
[14]       M.-J. Camarasa, P. L. Coe, A. S. Jones, R. T. Walker, J. Chem. Soc., Perkin Trans. 1 1987, 2317–2320.
[15]       W. Tian, S. Grivas, Synthesis 1992, 1283–1286.
[16]       J. T. Sharp, C.E.D. Skinner, Tetrahedron Lett. 1986, 27, 869–872.
[17]       M. P. Groziak, L. Wei, J. Org. Chem. 1991, 56, 4296–4300.
[18]       R. M. Turner, S. D. Lindell, S. V. Ley, J. Org. Chem. 1991, 56, 5739–5740.
[19]       R. M. Turner, S. V. Ley, S. D. Lindell, SYNLETT 1993, 748–750.
[20]       D. S. Carver, S. D. Lindell, E. A. Saville-Stones, Tetrahedron 1997, 53, 14481–14496.
[21]       W. E. Allsebrook, J. M. Gulland, L. F. Story, J. Chem. Soc. 1942, 232–236.
M. P. Groziak, H. Ding: Halogenated (Acylamino)imidazoles and benzimidazoles for Directed…
18
Acta Chim. Slov. 2000, 47, 1-18.
[22]       M. J. Humphries, C. A. Ramsden, SYNLETT 1995, 203-204.
[23]       C. E. Hazeldine, F. L. Pyman, J. Winchester, J. Chem. Soc. 1924, 1431-1441.
[24]       P. Benjes, R. Grimmett, Heterocycles 1994, 37, 735-738.
[25]       Z. Kazimierczuk, L. Dudycz, R. Stolarski, D. Shugar, Z. Naturforsch. 1980, 35c, 30-35.
[26]       Z. Kazimierczuk, R. Stolarski, L. Dudycz, D. Shugar, Z. Naturforsch. 1981, 36c, 126-134.
[27]       Z. Kazimierczuk, R. Stolarski, D. Shugar, Z Naturforsch. 1985, 40c, 715-720.
[28]       M.-J. Camarasa, R. T. Walker, A. S. Jones, Nucleosides Nucleotides 1988, 7, 181-193.
[29]       Z. Kazimierczuk, D. Shugar, Nucleosides Nucleotides 1989, 8, 1379-1385.
[30]       J. Herzig, A. Nudelman, H. E. Gottlieb, B. Fischer, J. Org. Chem. 1986, 51, 727-730.
[31]       Y. P. Andreichikov, A. M. Simonov, Khim. Geterotsikl. Soedin. 1970, 6, 679-680.
[32]       Belg. patent 611895, 1962, to Farbwerke Hoechst A.-G.; Chem. Ab str., 1962, 57, 13765g.
Povzetek
Razvili smo regioselektivno sintezo 4- in 5-(acilamino)-1-alkilimidazolov s halogenom na orto mestu. Pripravljene spojine so primerni intermediati za pripravo derivatov bioaktivnih 4- in 5-aminoimidazolov z orto usmerjeno izmenjavo halogen-kovina in sledečo funkcio nalizacijo. Pristop smo razširili tudi na derivate benzimidazola in njegove potencialno biološko aktivne nukleozide. Raziskali smo sinteze halogeniranih 5- in 6-(acilamino)-benzimidazolov.
M. P. Groziak, H. Ding: Halogenated (Acylamino)imidazoles and benzimidazoles for Directed…