Synthesis of optically active 1-(1-phenylethyl)-1H-imidazoles derived from 1-phenylethylamine

Article abstract of DOI:10.1002/hlca.200890028

The three-component reaction of (R)- or (S)-1-phenylethylamine (6), formaldehyde, and an α-(hydroxyimino) ketone 5, i.e., 3-(hydroxyimino) butan-2-one (5a) or 2-(hydroxyimino)-1,2-diphenylethanone (5b), yields the corresponding enantiomerically pure 1-(1-

Full text of DOI:10.1002/hlca.200890028

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Synthesis of Optically Active 1-(1-Phenylethyl)-1H-imidazoles Derived from
1-Phenylethylamine1)
by Grzegorz Mloston´*, Paulina Mucha, Katarzyna Urbaniak, Karolina Broda
´
´
´
´
University of Łodz, Department of Organic and Applied Chemistry, Narutowicza 68, PL-90-136 Łodz
(phone: þ 48426355761; fax: þ 48426355380; e-mail: gmloston@uni.lodz.pl)
and
Heinz Heimgartner*
Organisch-chemisches Institut der Universität Zürich, Winterthurerstrasse 190, CH-8057 Zürich
(phone: þ 41446354282; fax: þ 41446356812; e-mail: heimgart@oci.uzh.ch)
The three-component reaction of (R)- or (S)-1-phenylethylamine (6), formaldehyde, and an a-
(hydroxyimino) ketone 5, i.e., 3-(hydroxyimino)butan-2-one (5a) or 2-(hydroxyimino)-1,2-diphenyl-
ethanone (5b), yields the corresponding enantiomerically pure 1-(1-phenylethyl)-1H-imidazole 3-oxide
7 in high yield (Schemes 2 and 3). The reactions are carried out either in MeOH or in AcOH. Smooth
transformations of the N-oxides into optically active 1-(1-phenylethyl)-1H-imidazoles 10 and 2,3-
dihydro-1-(1-phenylethyl)-1H-imidazole-2-thiones 11 are achieved by treatment of 7 with Raney-Ni and
2,2,4,4-tetramethyl-3-thioxocyclobutanone (12), respectively (Scheme 4).
1. Introduction. – Imidazole derivatives are widely applied as versatile building
blocks for the preparation of more complex molecules [1]. Several compounds
containing the imidazole moiety display biological activities (e.g., [2 – 5]). Recently,
some new methods for the synthesis of differently substituted imidazoles were
described [6 – 8]. Furthermore, in a series of papers, 2-unsubstituted imidazole 3-oxides
were shown to be useful starting materials for the preparation of imidazole derivatives
such as imidazole-2-thiones [9], imidazol-2-ones [10], 2-cyanoimidazoles [10], 2-
(perfluoroethyl)imidazoles [11], 2-(dicyanomethylidene)imidazoles [12], as well as the
parent imidazoles [12][13].
Relatively little is known about optically active imidazole derivatives bearing
substituents with stereogenic centers [14]. In the first paper on optically active
imidazole 3-oxides, a three-component reaction with a-(hydroxyimino) ketones,
formaldehyde, and optically active a-amino acids was reported [15]. By using a
modified procedure, we succeeded in the preparation of some optically active 1H-
imidazole 3-oxides 1 starting from enantiomerically pure b-amino alcohols, e.g., 2 [13]
(Scheme 1). The corresponding formaldimine 3, which is in equilibrium with its trimer
4, reacts with a-(hydroxyimino) ketones 5 in refluxing EtOH to give 1. Analogous
1
´
)
Presented in preliminary form at the 50th Annual Meeting of the Polish Chemical Society, Torun,
Poland, September 2007.
ꢀ 2008 Verlag Helvetica Chimica Acta AG, Zürich

Helvetica Chimica Acta – Vol. 91 (2008)
233
amino components were exploited in a multicomponent reaction with an aldehyde, a
diketone, and NH3 to yield imidazoles with a chiral 2-hydroxyethyl group attached to
N(1) [16]. In a very recent paper, we reported the synthesis of a new type of optically
active bis-imidazoles by using enantiomerically pure trans-1,2-diaminocyclohexane
[17].
Scheme 1
It is well-known that, along with trans-1,2-diaminocyclohexane, the commercially
available and cheap enantiomerically pure 1-phenylethylamine (a-methylbenzyl-
amine) is one of the most frequently used chiral amine in organic synthesis (see, e.g.,
[18]). Here, we report the preparation of new optically active imidazole derivatives
based on 1-phenylethylamine2) as the key reagent used in the reaction with
formaldehyde and a-(hydroxyimino) ketones.
2. Results and Discussion. – The three-component reaction carried out with
equimolar amounts of (þ)-(R)- and (À)-(S)-1-phenylethylamine (6), respectively,
formaldehyde, and 3-(hydroxyimino)butan-2-one (5a) in boiling EtOH gave the
expected 1H-imidazole 3-oxide, albeit in low yield. Therefore, the alternative method
presented in Scheme 1 was applied. Thus, the amine 6 and HCHO reacted in MeOH at
room temperature to yield the corresponding 1,3,5-triazinane of type 4 as an oily
product, which, without purification, was treated with 5a leading to the desired product
7a in good yield (Scheme 2).
1
The spectroscopic data confirm the structure of the product, e.g., the H-NMR
spectrum revealed the typical signal of HÀC(2) at 8.16 ppm. Furthermore, the
presence of the 1-phenylethyl residue was established by the doublet of the Me group
(1.82 ppm, J ¼ 7.2 Hz) and the quadruplet of HÀC(1’) at 5.27 ppm. The product (R)-7a,
2
)
Recently, another strategy for the preparation of imidazole derivatives based on the exploitation of
the racemic a-methylbenzylamine was reported [19].

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Scheme 2
obtained from the reaction with (þ)-(R)-6, showed [a]2D0 ¼ À138.5 (c ¼ 1.00, MeOH).
On the other hand, the enantiomer (S)-7a, which was formed in the reaction with (À)-
(S)-6, displayed the same spectroscopic data and [a]2D0 ¼ þ131.5 (c ¼ 1.02, MeOH).
The 4,5-diphenyl analogues 7b were prepared by using 2-(hydroxyimino)-1,2-
diphenylethanone (5b). In this case, however, the highest yield of the product was
obtained when the reaction of the imine (R)-8 with 5b was carried out in AcOH instead
of MeOH, according to the procedure described earlier [13][17]. After 24 h at room
temperature, the product formed was converted into the corresponding hydrochloride,
which, after crystallization, was neutralized by treatment with solid NaHCO3 to give
the free N-oxide 7b in 75 – 78% yield (Scheme 3).
Scheme 3
The successful preparation of 7a and 7b prompted us to carry out the analogous
reaction with optically active a-cyanobenzylamine (¼2-amino-2-phenylacetonitrile).
However, the experiment with 5a and HCHO under the described conditions failed to
give the desired product of type 7.
The optical purity of (R)-7b and (S)-7b was tested by using (þ)-(R)-(tert-
butyl)(phenyl)thiophosphonic acid ((R)-9) as a chiral solvating agent [20]. Preliminary
1H-NMR experiments with racemic 7b and equimolar amounts of (R)-9 evidenced that,
in CDCl3 at room temperature, two well separated signals of HÀC(2) appeared at 9.25
and 9.10 ppm. Under similar conditions, the optically active (R)-7b and (S)-7b showed
only one single signal at 9.42 and 9.30 ppm, respectively. This result confirms that (R)-
7b and (S)-7b are optically pure according to 1H-NMR accuracy, i.e., the conversion of
6 to the corresponding 1H-imidazole 3-oxides 7b occurred with complete retention of
the configuration of the 1-phenylethylamine fragment.

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Freshly prepared Raney-Ni has been shown to be an excellent deoxygenating agent
for 1H-imidazole 3-oxides [12][13]. Treatment of the (R)- and (S)-enantiomer of 7a
and 7b with this reagent in MeOH at room temperature led to the corresponding 1H-
imidazoles 10 within 30 min (TLC) in almost quantitative yield (Scheme 4).
Scheme 4
The optically active 1H-imidazole-2-thiones of type 11 were easily prepared by
using the S-transfer reaction described in [9]. For example, the color of the red solution
of 2,2,4,4-tetramethyl-3-thioxocyclobutanone (12) and (S)-7a in CHCl3 vanished after
1 h stirring at room temperature. The colorless crystalline product (S)-11a was isolated
in 84% yield (Scheme 4). The mechanism of this conversion via an intermediate 1,4,2-
oxathiazolidine, formed as an unstable [2 þ 3] cycloadduct, was described earlier [9].
3. Conclusions. – The results described show that optically active 1-phenylethyl-
amine can be used for the synthesis of optically active 2-unsubstituted 1H-imidazole 3-
oxides of type 7 via condensation with formaldehyde and a-(hydroxyimino) ketones.
The reaction occurs without loss of optical purity. The enantiomerically pure
thiophosphonic acid (R)-9 is a convenient chiral solvating agent for the determination
of the optical purity of compounds 7. According to the known protocols, 1H-imidazole
3-oxides 7 can easily be converted into the corresponding 1H-imidazoles 10 and 2,3-
dihydro-1H-imidazole-2-thiones 11. All of the described optically active imidazole
derivatives can be considered as attractive ligands in coordination chemistry and
precursors of carbenes derived from imidazole [21].
The authors thank the Polish Ministry for Science and Higher Education for a grant (PBZ KBN 126/
T09/2004) and F. Hoffmann-La Roche AG, Basel, for financial support.
Experimental Part
1. General. M.p.: Melt-Temp. II apparatus (Aldrich); in capillary, uncorrected. IR Spectra (KBr):
NEXUS FT-IR spectrophotometer. 1H- and 13C-NMR spectra: Tesla BS567A (80 and 20 MHz, resp.) or
Bruker AC 300 instrument (300 and 75.5 MHz, resp.); in CDCl3, TMS as an internal standard. The
multiplicity of the 13C signals was deduced from the DEPT spectra. MS (EI or CI): Finnigan MAT-90 or
Finnigan SSQ-700 instruments. Elemental analyses were performed in the Analytical Laboratory of the
University of Zürich.
2. Starting Materials. a-(Hydroxyimino) ketones 5 were obtained according to known protocols: 3-
(hydroxyimino)butan-2-one (5a) by nitrosation of butan-2-one [22a] and 2-(hydroxyimino)-1,2-

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diphenylethanone (5b, ꢁbenzil monooximeꢂ) from dibenzoyl and hydroxylamine hydrochloride [22b].
(þ)-(R)-(tert-Butyl)(phenyl)thiophosphonic acid ((R)-9) was obtained by resolution of the racemic
mixture according to a known protocol [20b].
3. Synthesis of Enantiomerically Pure 1H-Imidazole 3-Oxides. Method A. To a stirred soln. of (R)- or
(S)-1-phenylethylamine ((R)-6 or (S)-6; 242 mg, 2.00 mmol) in MeOH (5 ml), solid HCHO (63.0 g,
2.1 mmol) was added, and stirring was continued overnight. Then, the mixture was concentrated, 5a
(258 mg, 2.56 mmol) was added, and the mixture was heated to reflux for 3 h. The solvent was removed
under reduced pressure, and the resulting solid was washed with acetone to give anal. pure samples.
3.1. (R)-1-(1-Phenylethyl)-4,5-dimethyl-1H-imidazole 3-Oxide ((R)-7a). Yield: 355 mg (82%).
Colorless crystals. M.p. (dec.) 2248. [a]2D0 ¼À 138.5 (c ¼ 1.00, MeOH). IR: 3059m, 2993s, 2939m, 1633m,
1602w, 1490m, 1445m, 1409m, 1346s, 1335vs, 1236m, 1198s, 1047m, 850m, 807m, 752s, 699vs, 595s, 581m.
1H-NMR: 1.82 (d, J ¼ 7.2, MeCH); 2.00, 2.18 (2s, 2 Me); 5.27 (q, J ¼ 7.0, MeCH); 7.08 – 7.40 (m, 5 arom.
H); 8.16 (s, HÀC(2)). 13C-NMR: 7.2, 9.0 (2 Me); 22.0 (MeCH); 55.7 (MeCH); 125.6, 128.4, 129.2 (5
arom. CH); 122.8 (C(2)); 121.3, 127.3, 140.1 (3 Cq). EI-MS: 216 (6, Mþ), 200 (10, [M À 16]þ), 105 (100),
96 (27). CI-MS (NH3): 218 (15), 217 (100, [M þ 1]þ), 201 (19), 105 (9). Anal. calc. for C13H16N2O
(216.29): C 72.19, H 7.46; found: C 72.24, H 7.38.
3.2. (S)-1-(1-Phenylethyl)-4,5-dimethyl-1H-imidazole 3-Oxide ((S)-7a). Yield: 380 mg (88%).
Colorless crystals. M.p. (dec.) 2308. [a]2D0 ¼ þ131.5 (c ¼ 1.02, MeOH). IR: 3060m, 2982s, 2939m,
1633m, 1602w, 1490m, 1445m, 1408m, 1345s, 1334vs, 1236m, 1197s, 1047m, 849m, 807m, 752s, 700vs, 595s,
580m. CI-MS (NH3): 218 (15), 217 (100, [M þ 1]þ), 201 (8), 105 (100).
Method B. To a stirred soln. of (R)-6 or (S)-6 (242 mg, 2.00 mmol) in MeOH (5 ml), solid HCHO
(63.0 g, 2.1 mmol) was added, and stirring was continued overnight. The solvent was evaporated, the
resulting oil and 5b (304 mg, 2.48 mmol) in AcOH (10 ml) was stirred overnight at r.t. Then, HCl gas was
bubbled through the soln. for 1.5 h. The solvent was evaporated, the obtained oil was washed with Et2O,
and the colorless hydrochloride was filtered and dried in vacuo. The crude hydrochloride was dissolved in
MeOH (30 ml), solid NaHCO3 (1.0 g) was added, and stirring was continued for 1 h. The inorg. salts were
filtered off, the solvent was evaporated, and the solid residue washed with CHCl3/MeOH 2 :1 and then
triturated with acetone. The colorless crystals obtained were anal. pure.
3.3. (R)-1-(1-Phenylethyl)-4,5-diphenyl-1H-imidazole 3-Oxide ((R)-7b). Yield: 510 mg (75%).
Colorless crystals. M.p. (dec.) 2178. [a]2D0 ¼ þ30.0 (c ¼ 1.00, MeOH). IR: 3046s, 2990m, 2964m, 2949m,
1636m, 1602m, 1585m, 1497m, 1444m, 1340s, 1237m, 767m, 761m, 703s.
3.4. (S)-1-(1-Phenylethyl)-4,5-diphenyl-1H-imidazole 3-Oxide ((S)-7b). Yield: 530 mg (78%).
Colorless crystals. M.p. (dec.) 2188. [a]2D0 ¼ À27.0 (c ¼ 0.98, MeOH). IR: 3046s, 2990m, 2961m, 2949m,
1636m, 1602m, 1584m, 1497m, 1444m, 1340s, 1236m, 767m, 760m, 703s. 1H-NMR: 1.78 (d, J ¼ 7.1,
MeCH); 5.24 (q, J ¼ 7.1, MeCH); 7.03 – 7.60 (m, 15 arom. H); 8.08 (s, HÀC(2)). 13C-NMR: 21.8 (MeCH);
55.5 (MeCH); 124.1, 125.9, 127.9, 128.5, 129.0, 129.1, 129.5, 129.6, 130.9 (15 arom. CH, C(2)); 126.8, 127.1,
127.6, 128.3, 139.7 (5 Cq). CI-MS (isobutane): 342 (24), 341 (100, [M þ 1]þ), 325 (20). Anal. calc. for
C23H20N2O (340.43): C 81.15, H 5.92, N 8.23; found: C 80.97, H 6.02, N 8.25.
4. Deoxygenation of Enantiomerically Pure 1H-Imidazole 3-Oxides. To a soln. of the corresponding
(R)- or (S)-1H-imidazole 3-oxide 7 (1.0 mmol) in MeOH (5 ml), a suspension of freshly prepared Raney-
Ni in MeOH was added in small portions. When the starting N-oxide 7 was completely reduced (TLC),
the mixture was filtered, and the filtrate was concentrated under reduced pressure. Crude products were
purified by recrystallization from hexane/CH2Cl2.
4.1. (R)-1-(1-Phenylethyl)-4,5-dimethyl-1H-imidazole ((R)-10a). Yield: 153 mg (77%). Colorless
crystals. M.p. (dec.) 1798 (hexane/CH2Cl2). [a]2D0 ¼ À43.0 (c ¼ 1.10, MeOH). IR: 3103m, 3083m, 3062m,
3029m, 2988m, 2980m, 2925m, 2865m, 1641m, 1599m, 1493m, 1482m, 1445m, 1389m, 1344m, 1236s, 755m,
1
699s. H-NMR: 1.83 (d, J ¼ 7.1, MeCH); 1.92, 2.15 (2s, 2 Me); 5.17 (q, J ¼ 7.1, MeCH); 7.00 – 7.38 (m, 5
arom. H); 7.56 (s, HÀC(2)). 13C-NMR: 8.6, 12.6 (2 Me); 22.3 (MeCH); 54.8 (MeCH); 125.5, 127.5, 128.7
(5 arom. CH); 122.4, 134.2, 142.0 (3 Cq); 132.6 (C(2)). CI-MS (NH3): 202 (15), 201 (100, [M þ 1]þ), 200
(10), 105 (8). Anal. calc. for C13H16N2 (200.29): C 77.96, H 8.05, N 13.99; found: C 77.94, H 8.12, N 14.01.
4.2. (S)-1-(1-Phenylethyl)-4,5-dimethyl-1H-imidazole ((S)-10a). Yield: 162 mg (82%). Colorless
crystals. M.p. (dec.) 1788 (hexane/CH2Cl2). [a]2D0 ¼ þ33.3 (c ¼ 1.00, MeOH). IR: 3103m, 3083m, 3062m,

Helvetica Chimica Acta – Vol. 91 (2008)
237
3030m, 2988m, 2980m, 2925m, 2865m, 1646m, 1599m, 1493m, 1482m, 1445m, 1389m, 1344m, 1236s, 755m,
699s. CI-MS (NH3): 202 (15), 201 (100, [M þ 1]þ), 200 (6), 105 (3).
4.3. (R)-1-(1-Phenylethyl)-4,5-diphenyl-1H-imidazole ((R)-10b). Yield: 227 mg (73%). Colorless
crystals. M.p. (dec.) 1808 (hexane/CH2Cl2). [a]2D0 ¼ þ83.0 (c ¼ 1.00, MeOH). IR: 3090m, 3063m, 3049m,
3032m, 2983m, 2945m, 1634s, 1601m, 1505m, 1485m, 1474m, 1454m, 1442m, 1374m, 768m, 695s.
4.4. (S)-1-(1-Phenylethyl)-4,5-diphenyl-1H-imidazole ((S)-10b). Yield: 255 mg (82%). Colorless
crystals. M.p. (dec.) 1768 (hexane/CH2Cl2). [a]2D0 ¼ À80.0 (c ¼ 0.60, MeOH). IR: 3090m, 3063m, 3049m,
3032m, 2984m, 2946m, 1633s, 1601m, 1505m, 1484m, 1473m, 1454m, 1442m, 1375m, 768m, 695s.
1H-NMR: 1.81 (d, J ¼ 7.1, MeCH); 5.11 (q, J ¼ 7.1, MeCH); 6.95 – 7.50 (m, 15 arom. H); 7.76 (s, HÀC(2)).
13C-NMR: 22.4 (MeCH); 54.5 (MeCH); 125.8, 126.2, 126.4, 127.7, 128.1, 128.7, 128.8, 131.1, 134.4 (15
arom. CH, C(2)); 127.3, 128.3, 130.9, 138.1, 141.8 (5 Cq). CI-MS (isobutane): 326 (22), 325 (100, [M þ 1]þ),
.
324 (70, Mþ ). Anal. calc. for C23H20N2 (324.43): C 85.15, H 6.21, N 8.63; found: C 84.95, H 6.17, N 8.54.
5. Transformations of Enantiomerically Pure Imidazole 3-Oxides to 1H-Imidazole-2-thiones. To a
cooled CHCl3 soln. (water bath) of 2,2,4,4-tetramethyl-3-thioxocyclobutanone (12; 1 mmol), the
respective 1H-imidazole 3-oxide 7 (1 mmol) was added in small portions, and the mixture was stirred
for ca. 1 h until the characteristic red color of the soln. vanished. After concentration under reduced
pressure, the mixture was washed with pentane, and the obtained crude solid was recrystallized from
MeOH or from petroleum ether/Et2O.
5.1. (R)-2,3-Dihydro-4,5-dimethyl-1-(1-phenylethyl)-1H-imidazole-2-thione ((R)-11a). Yield:
190 mg (82%). Colorless crystals. M.p. 124 – 1268 (petroleum ether/Et2O). [a]2D0 ¼ þ176.0 (c ¼ 1.00,
CH2Cl2). IR: 3159m, 3086s, 2979m, 2926s, 2718m, 1655m, 1605m, 1496s, 1448s, 1415s, 1374s, 1332m,
1239m, 1028m, 750m, 700s.
5.2. (S)-2,3-Dihydro-4,5-dimethyl-1-(1-phenylethyl)-1H-imidazole-2-thione ((S)-11a). Yield: 194 mg
(84%). Colorless crystals. M.p. 126 – 1288 (petroleum ether/Et2O). [a]2D0 ¼ À170.0 (c ¼ 0.90, CH2Cl2).
IR: 3162m, 3086s, 2978m, 2926s, 2718m, 1656m, 1605m, 1496s, 1448s, 1415s, 1374s, 1332m, 1239m, 1028m,
751m, 700s. 1H-NMR: 1.67, 2.05 (2s, 2 Me); 1.81 (d, J ¼ 7.1, MeCH); 6.61 (q, J ¼ 7.1, MeCH); 7.27 – 7.34
(m, 5 arom. H); 11.69 (br. s, NH). 13C-NMR: 8.7, 9.8 (2 Me); 17.1 (MeCH); 53.3 (MeCH); 121.0, 121.3
(2 MeCq); 126.5, 127.3, 128.5 (5 arom. CH); 139.9 (arom. Cq); 158.5 (C¼S). CI-MS (isobutane): 233 (100,
[M þ 1]þ), 232 (12). Anal. calc. for C13H16N2S (232.35): C 67.20, H 6.94, N 12.06, S 13.80; found: C 67.05,
H 7.05, N 12.17, S 13.55.
5.3. (R)-2,3-Dihydro-4,5-diphenyl-1-(1-phenylethyl)-1H-imidazole-2-thione ((R)-11b). Yield:
275 mg (77%). Colorless crystals. M.p. 282 – 2848 (MeOH). [a]2D0 ¼ þ104.7 (c ¼ 0.57, CH2Cl2). IR:
3088m, 3061m, 2982m, 2936m, 2726m, 1630m, 1603m, 1491s, 1477m, 1446m, 1406m, 1374m, 1345m,
1254m, 761m, 687s. 1H-NMR: 1.61 (d, J ¼ 7.1, MeCH); 7.05 – 7.35 (m, 15 arom. H, MeCH); 12.15 (s, NH).
13C-NMR: 17.4 (MeCH); 54.4 (MeCH); 126.2, 127.9, 128.7, 140.1 (5 Cq); 126.4, 126.9, 127.2, 127.7, 128.1,
128.2, 128.5, 129.0, 132.0 (15 arom. CH); 160.9 (C¼S). CI-MS (isobutane): 358 (24), 357 (100, [M þ 1]þ),
356 (21). Anal. calc. for C23H20N2S (356.49): C 77.49, H 5.65, N 7.86, S 8.99; found: C 77.28, H 5.73, N 7.74,
S 8.78.
5.4. (S)-2,3-Dihydro-4,5-diphenyl-1-(1-phenylethyl)-1H-imidazole-2-thione ((S)-11b). Yield: 268 mg
(75%). Colorless crystals. M.p. 276 – 2788 (MeOH). [a]2D0 ¼ À96.6 (c ¼ 0.57, CH2Cl2). IR: 3089m, 3061m,
2983m, 2938m, 2729m, 1632m, 1603m, 1491s, 1479m, 1446m, 1407m, 1376m, 1344m, 1254m, 759m, 697s.
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Received November 16, 2007