An efficient catalytic asymmetric route to 1-aryl-2-imidazol-1-yl-ethanols

Article abstract of DOI:10.1021/op049838n

The asymmetric hydrogenation of 1-aryl-2-imidazol-1-yl-ethanones offers a concise route to homochiral 1-aryl-2-imidazol-1-yl-ethanols. Catalytic asymmetric transfer hydrogenation with formic acid using [(R,R)-TsDPEN] Ru(Cymene)Cl as precatalyst was shown to be effective in this transformation. Preliminary process development showed that the hydrogenation could be carried out under mild conditions at a molar substrate-to-catalyst (S/C) ratio of 1000-2000.

Full text of DOI:10.1021/op049838n

Organic Process Research & Development 2005, 9, 110−112
An Efficient Catalytic Asymmetric Route to 1-Aryl-2-imidazol-1-yl-ethanols
Ian C. Lennon and James A. Ramsden*
Dowpharma, Chirotech Technology Ltd., A subsidiary of The Dow Chemical Company, Unit 321,
Cambridge Science Park, Milton Road, Cambridge CB4 0WG, United Kingdom
Abstract:
The asymmetric hydrogenation of 1-aryl-2-imidazol-1-yl-etha-
nones offers a concise route to homochiral 1-aryl-2-imidazol-
1-yl-ethanols. Catalytic asymmetric transfer hydrogenation with
formic acid using [(R,R)-TsDPEN]Ru(Cymene)Cl as precatalyst
was shown to be effective in this transformation. Preliminary
process development showed that the hydrogenation could be
carried out under mild conditions at a molar substrate-to-
catalyst (S/C) ratio of 1000-2000.
Figure 1. 1-Aryl-2-imidazol-1-yl-ethanol 1 and azole antifungal
agents 2.
Chiral alcohols are fundamentally important building
blocks in the pharmaceutical and fine chemical industry.
There is a constant need to discover and develop new
methods capable of supplying such building blocks contain-
ing an increasingly diverse range of structural features.
The authors recently became interested in developing a
route to 1-phenylethanols bearing an imidazolyl substituent
R- to the alcohol 1. Racemic alcohols of this type have found
widespread use in topical fungicides such as econazole 2a
and miconazole 2b (Figure 1).1
While the use of racemic chiral alcohols is suitable for
some of the existing topical applications, the trend within
the pharmaceutical industry is to utilise single isomer chiral
material;2 therefore, a route to such chiral alcohols in high
enantiomeric excess is desirable.3 Although the resolution
of some 2-(imidazol-1-yl)-1-(aryl)ethanols via the formation
of diastereomeric salts has been demonstrated,4 an asym-
metric synthesis offers a potentially more general and
efficient route to compounds such as 1. While there are many
synthetic approaches that furnish chiral alcohols in high
enantiomeric excess, catalytic asymmetric hydrogenation
offers several advantages as it can easily be applied to a wide
range of substrates, the utilisation of material is high, and
waste and byproducts can be drastically reduced. Two
outstanding catalytic asymmetric hydrogenation technologies
have been developed in recent years for the enantioselective
reduction of ketones. First, bisphosphino ruthenium diamine
complexes have been shown to be very efficient catalysts
for the hydrogenation of simple prochiral ketones with
gaseous hydrogen, furnishing the desired alcohols with very
high enantioselectivity.5 Second, monosulfonated diamino
Figure 2. 1-Phenyl-2-imidazol-1-yl-ethanone 3 and 1-(2,4-
dichloro-phenyl)-2-imidazol-1-yl-ethanone 4.
ruthenium arene complexes, which utilise hydrogen donors
such as propan-2-ol and formic acid as hydrogen sources,
have been used to reduce ketones with similarly high
enantioselectivities.6
Two imidazolyl acetophenone substrates were chosen to
gain an understanding of the hydrogenation reaction of this
type of substrate; 1-phenyl-2-imidazol-1-yl-ethanone 3 was
synthesised from 2-bromoacetophenone and imidazole. 1-(2,4-
Dichloro-phenyl)-2-imidazol-1-yl-ethanone 4 was made in
a similar fashion from 2,2′,4′-trichloroacetophenone and
imidazole.
Bisphosphino ruthenium diamine complexes have been
shown to give extremely high catalyst efficiency demon-
strated in the hydrogenation of simple acetophenone deriva-
tives.5 In light of these results this class of catalyst was
examined in the first instance. Using the standard literature
conditions no hydrogenation was observed using [((S)-
XylylPhanePhos)Ru((R,R)-DPEN)Cl2].7 The use of triiso-
propyl borate as an additive has been shown to be effective
in promoting the hydrogenation of acetylpyridines.8 It is
(5) Noyori, R.; Ohkuma, T. Angew. Chem., Int. Ed. 2001, 40, 40 and references
therein.
(6) Noyori, R.; Hashiguchi, S. Acc. Chem. Res. 1997, 30, 97. Palmer, M. J.;
Wills, M. Tetrahedron: Asymmetry 1999, 10, 2045. Hamada, T.; Torii,
T.; Izawa, K.; Noyori, R.; Ikariya, T. Org. Lett. 2002, 4, 4373. Yamada,
Y.; Noyori, R. Org. Lett. 2000, 2, 3425. Watanabe, M.; Murata, K.; Ikariya,
T. J. Org. Chem. 2002, 67, 1712. Sˇterck, D.; Stephan, M. S.; Mohar, B.
Tetrahedron Lett. 2004, 45, 535. Marshall, J. A.; Bourbeau, M. P. Org.
Lett. 2003, 5, 3197. Bøgevig, A.; Pastor, I. M.; Adolfson, H. Chem.sEur.
J. 2004, 10, 294.
(7) Burk, M. J.; Hems, W.; Herzberg, D.; Malan, C.; Zanotti-Gerosa, A. Org.
Lett. 2000, 2, 4173. Chaplin, D.; Harrison, P.; Henschke, J. P.; Lennon, I.
C.; Meek, G.; Moran, P.; Pilkington, C. J.; Ramsden, J. A.; Watkins, S.;
Zanotti-Gerosa, A.; Org. Process Res. DeV. 2003, 7, 89.
* To whom correspondence should be addressed. E-mail: jramsden@dow.com.
(1) Miconazole, Merck Index 12th ed.; 6266; Econazole, Merck Index 12th
ed.; 3550.
(2) De Camp, W. H. Chirality 1989, 1, 2.
(3) Nelson, R. A.; Thomas N. W.; Matcham, G. W.; Lin, S. L.; Zhang, M.;
Lewis, C. International Patent Application WO 00/38521. Foguet, R.;
Ramentol, J.; Guglietta, A.; Palacin, C.; Anglada, L. International Patent
Application WO 03/068770 A1.
(4) Lis, R.; Morgan, T. K., Jr.; DeVita, R. J.; Davey, D. D.; Lumma, W. C.,
Jr; Wohl, R. A.; Diamond, J.; Wong, S. S.; Sullivan, M. E. J. Med. Chem.
1987, 30, 696.
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10.1021/op049838n CCC: $30.25 © 2005 American Chemical Society
Published on Web 11/20/2004

Scheme 1. Preliminary results for the catalytic asymmetric
transfer hydrogenation of 1-aryl-2-imidazol-1-yl-ethanones
Table 1. Effect of temperature on conversion and selectivity
for the catalytic asymmetric transfer hydrogenation of
1-(2,4-dichloro-phenyl)-2-imidazol-1-yl-ethanone 4
conversion %
2 h 20 h
ee %
temp
°C
entry
2 h
20 h
1
2
3
4
25
40
55
70
84
100
100
100
100
100
100
100
86
84
82
83
85
85
84
83
believed that the borate catalytically removes the â-amino
alcohol from a postulated ruthenium adduct which lacks
activity. However, for the hydrogenation of these substrates
the addition of a borate ester did not promote the reaction.
When standard conditions for catalytic asymmetric trans-
fer hydrogenation using [(R,R)TsDPEN]Ru(cymene)Cl as the
catalyst precursor were applied, both ketones were reduced
to the corresponding 1-aryl-2-imidazol-1-yl-ethanols. The
hydrogenation of 1-phenyl-2-imidazol-1-yl-ethanone 3 pro-
ceeded to completion yielding (S)-2-imidazol-1-yl-1-phenyl-
ethanol 5 with a 99% ee.9 Under very similar conditions the
hydrogenation of 1-(2,4-dichloro-phenyl)-2-imidazol-1-yl-
ethanone proceeded to 85% conversion and 88% ee (Scheme
1). Bearing in mind the incomplete reaction and the high
catalyst loading used, there was obviously considerable scope
for optimising the reaction conditions for the formation of
6.
Table 2. Effect of temperature on conversion and selectivity
for the catalytic asymmetric transfer hydrogenation of
1-(2,4-dichloro-phenyl)-2-imidazol-1-yl-ethanone 4 at reduced
catalyst loading
conversion %
molar
S/C
temp
°C
entry
2 h
20 h
ee %
1
2
3
4
5
6
7
100
200
300
400
600
1000
2000
25
25
25
25
25
40
40
89
59
47
35
24
50
36
100
100
100
100
100
100
100
85
81
86
87
86
81
81
To improve catalyst utilisation the reaction for substrate
4 was repeated at higher temperatures (Table 1). As can be
seen from these results, the reaction will tolerate a range of
temperatures and the alcohol is stable to the reaction
conditions even when held at 70 °C for 20 h. The selectivity
appears to fall slightly as temperature is increased; however,
these variations are similar in magnitude to the variability
of the analytical method. It is more significant that at the
higher temperatures unidentified impurities become apparent
one of the best selectivities and nearly complete conversion
within 20 h at S/C ) 1000 (entry 3).
By increasing the overall reaction concentration, the
amount of formic acid and triethylamine could be reduced
to 5 equiv while still obtaining complete conversion at a
reasonable catalyst loading within a practical reaction time
frame. These conditions (S/C 1000, 40 °C, CH2Cl2) were
reproduced on a 16 g input of 1-(2,4-dichloro-phenyl)-2-
imidazol-1-yl-ethanone, the rate and selectivity observed in
the smaller scale reaction was maintained for the larger scale
reaction with complete conversion achieved in 26 h and the
product obtained in 91% ee. The optimised conditions were
also applied at a higher catalyst loading (S/C ) 200) to the
asymmetric transfer hydrogenation of 1-phenyl-2-imidazol-
1-yl-ethanone which gave (S)-1-phenyl-2-imidazol-1-yl-
ethanol in 97% ee.
1
in the H NMR spectra of the crude reaction products. At
40 °C complete conversion could be achieved for overnight
reactions at significantly lower catalyst loadings (Table 2,
entries 6 and 7).
The choice of solvent in which the reaction is run had a
dramatic effect on selectivity, catalyst utility, and rate (Table
3). Acetonitrile gave the highest reactivity but with modest
selectivity (entry 7). Although DMF gave rise to a high initial
conversion (37% in 2 h), the reaction slowed considerably
and after 20 h had only reached 76% conversion (entry 4).
Dichloromethane emerged as the pre-eminent solvent giving
(8) Ohkuma, T.; Koizumi, M.; Yoshida, M.; Noyori, R. Org. Lett. 2000, 2,
1749.
(9) Stereochemistry is assigned on the basis of the rotation compared to
literature data for the (R)-enantiomer: Kotsuki, H.; Wakao, M.; Hayakawa,
H.; Shimanouchi, T.; Shiro, M. J. Org. Chem. 1996, 61, 8915.
In conclusion, we have demonstrated the application of
catalytic asymmetric transfer hydrogenation to the synthesis
of an interesting and challenging class of substrates, where
Vol. 9, No. 1, 2005 / Organic Process Research & Development
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111

Table 3. Effect of solvent on conversion and selectivity for
the catalytic asymmetric transfer hydrogenation of
1-(2,4-dichloro-phenyl)-2-imidazol-1-yl-ethanone 4
(dd, J ) 8 and 14 Hz, 1H), 4.19 (dd, J ) 2 and 14 Hz, 1H),
5.21 (dd, J ) 2 and 8 Hz, 1H), 6.81 (br, 1H), 6.89 (br, 1H),
7.30 (dd, J ) 2 and 8 Hz, 1H), 7.36 (br, 1H), 7.39 (d, J )
2 Hz, 1H), 7.60 (d, J ) 8 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 58.4, 69.7, 120.4, 128.0, 129.1, 129.3, 132.3, 134.4,
137.9. [R]25 ) +83.8 (c ) 0.998, MeOH, 91% ee), lit.10
D
+88 (c ) 1.06, MeOH, 98.8% ee); Chiral analytical assay:
Chiralpak AS-H 250 × 4.6 mm × 5 µm, mobile phase
heptane/ethanol 90/10, flow rate 1 mL/min, temp ambient,
detector 220 nm, retention times 6.77 min (S)-(+) and 8.70
min (R)-(-), starting material 19.6 min.
conversion %
1-Phenyl-2-imidazol-1-yl-ethanone 3: 2-Bromoaceto-
phenone (11.89 g, 59.7 mmol) was added in portions to a
solution of imidazole (8.63 g, 127 mmol) in dichloromethane
(100 mL) (exothermic). After stirring at room temperature
for 3 h, the reaction was quenched with water (100 mL).
The organic layer was washed with brine during which time
a white solid formed which was removed by filtration.
Solvent was removed under vacuum, the residue was
dissolved in ethyl acetate and (150 mL) filtered, and the
solvent was removed again to give a light brown solid (7.54
g, 68%, yield). 1H NMR (400 MHz, CDCl3) δ 5.41, (s, 2H),
6.96 (br, 1H), 7.15 (br, 1H), 7.51-7.57 (m, 3H), 7.64-7.70
(m, 1H), 7.96-8.00 (m, 2H).
entry
solvent
2 h
20 h
90 h
ee %
1
2
3
4
5
6
7
MTBE
toluene
CH2Cl2
DMF
13
11
30
37
7
15
50
75
59
98
76
33
74
>98
97
97
92
92
93
87
93
89
81
iPrOH
EtOAc
CH3CN
30
99
the bisphosphino ruthenium diamine complexes were found
to be ineffective. During the preliminary process develop-
ment, conditions were discovered that allowed for efficient
utilisation of catalyst and reagents and thus furnish a
practicable synthetic route.
(S)-1-Phenyl-2-imidazol-1-yl-ethanol 5: A solution of
[(R,R)-TsDPEN]Ru(Cymene)Cl11 (3.5 mg, 5.5 µmol) in
dichloromethane (5.5 mL) was prepared in a Schlenk tube
under nitrogen. A 1 mL aliquot (1 µmol) was taken for the
hydrogenation reaction. A solution of 1-phenyl-2-imidazol-
1-yl-ethanone (0.186 g, 1 mmol) in dichloromethane (2 mL)
was prepared under nitrogen, and triethylamine (1.4 mL, 9
mmol) and catalyst solution (1 mL) were added followed
by formic acid (0.4 mL, 9 mol). The mixture was stirred at
40 °C for 22 h. Sodium bicarbonate solution (saturated, 10
mL) was added, and the product was extracted into dichlo-
romethane. The organic layer was washed with water (10
mL) and dried (MgSO4); the removal of solvent gave the
Experimental Section
1-(2,4-Dichlorophenyl)-2-imidazol-1-yl-ethanone 4: A
solution of 2,2′,4′-trichloroacetophenone (36.9 g, 0.12 mol)
in dichloromethane (50 mL) was added dropwise over 30
min to a suspension of imidazole (24.5 g, 0.36 mol) in
dichloromethane (100 mL). The mixture was heated to 40
°C for 2 h and then overnight at room temperature. The
reaction mixture was washed with water (2 × 100 mL) and
brine (100 mL) and dried (MgSO4), and solvent was removed
under vacuum to give a red oil. The oil was recrystallised
twice from hot methanol (120 mL) to give the product as a
1
product as a white solid 97% ee. H NMR (400 MHz, d6-
DMSO) δ 4.08 (dd, J ) 8 and 14 Hz, 1H), 4.18 (dd, J ) 4
and 14 Hz, 1H), 4.83-4.89 (m, 1H) [4.08, 4.18 and 4.86
signals ABX system], 6.88 (br, 1H), 7.16 (br, 1H), 7.29-
7.34 (m, 1H), 7.34-7.42 (m, 4H), 7.54 (br, 1H); 13C NMR
(100 MHz, d6-DMSO) δ 53.9, 72.4, 120.4, 126.4, 127.7,
128.1, 128.4, 138.1, 143.0. [R]25D ) +46.1 (c ) 0.98, EtOH,
97% ee, lit.9 -47.6 for (R)-enantiomer); Chiral analytical
assay: Chiracel OD-H 250 × 4.6 mm × 5 µm, mobile phase
heptane/ethanol 92/8, flow rate 1 mL/min, temp ambient,
detector 210 nm, retention times 21.8 min (S)-(+) and 24.3
min (R)-(-).
1
white powder (17.73 g, 58% yield). H NMR (400 MHz,
CDCl3) δ 5.34 (s, 2H), 6.93-6.95 (m, 1H), 7.13 (br, 1H),
7.38 (dd, J ) 8 and 2 Hz, 1H), 7.51 (d, J ) 2 Hz, 2H), 7.57
(d, J ) 8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 55.5,
120.0, 127.9, 129.8, 130.8, 131.1, 132.5, 134.1, 138.1, 139.2,
193.7.
(S)-1-(2,4-Dichlorophenyl)-2-imidazol-1-yl-ethanol 6: A
flask was charged with 1-(2,4-dichlorophenyl)-2-imidazol-
1-yl-ethanone (16.3 g, 63.9 mmol) and [(R,R)-TsDPEN Ru-
(Cymene)Cl (40 mg, 63 µmol). A nitrogen atmosphere was
established, and dichloromethane (50 mL) and triethylamine
(44 mL, 0.32 mol) were added. Formic acid (12.5 mL, 0.32
mol) was added over a period of an hour via syringe pump.
During the addition, the temp rose slowly to 30 °C. The
mixture was heated at 40 °C for 26 h. NaHCO3 (saturated
solution, 100 mL) was cautiously added, and the organic
layer was separated and washed with water (100 mL),
NaHCO3 (100 mL), water (100 mL), and brine (100 mL)
and dried (MgSO4). Solvent was removed to give a red glassy
mass which crystallised on standing to give the product (16.1
g, 98% yield, 91% ee). 1H NMR (400 MHz, CDCl3) δ 3.84
Acknowledgment
We thank Paul Harrison, Catherine Hill, and Brendan
Mullen for their invaluable work in sample analysis.
Received for review August 27, 2004.
OP049838N
(10) La¨mmerhofer. M.; Lindner, W. Chirality 1994, 6, 261.
(11) Haack, K.-J.; Hashiguichi, S.; Fujii, A.; Ikariya, T.; Noyori, R. Angew
Chem., Int. Ed. Engl. 1997, 36, 285.
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