Baylis-Hillman reactions of 2-(trifluoroacetyl)-1,3-azoles

Article abstract of DOI:10.1055/s-0028-1083150

2-(Trifluoroacetyl)-1,3-azoles readily react with methyl acrylate and acrylonitrile under Baylis-Hillman reaction conditions to afford heterocyclic trifluoromethyl-containing allylic alcohols in 36-97% yields. The thus obtained Baylis-Hillman adducts read

Full text of DOI:10.1055/s-0028-1083150

PAPER
3245
Baylis–Hillman Reactions of 2-(Trifluoroacetyl)-1,3-azoles
B
aylis–Hillma
a
nReaction
v
of 2-(Triflu
e
oroacetyl)-
l
1,3-azoles V. Khodakovskiy,a,b Dmitriy M. Volochnyuk,*a,c Alexander Shivanyuk,a,b Oleg V. Shishkin,d
Andrey A. Tolmachevb
a
Enamine Ltd., 23 A. Matrosova st., 01103 Kyiv, Ukraine
Fax +380(44)5373253; E-mail: D.Volochnyuk@enamine.net
National Taras Shevchenko University, 62 Volodymyrska st., 01033 Kyiv-33, Ukraine
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanska 5, 02094 Kyiv-94, Ukraine
Institute for Scintillation Materials, National Academy of Sciences of Ukraine, 60 Lenina Avenue, 61001 Kharkiv, Ukraine
b
c
d
Received 8 May 2008; revised 6 June 2008
A
N
A
N
i
Abstract: 2-(Trifluoroacetyl)-1,3-azoles readily react with methyl
acrylate and acrylonitrile under Baylis–Hillman reaction conditions
to afford heterocyclic trifluoromethyl-containing allylic alcohols in
36–97% yields. The thus obtained Baylis–Hillman adducts readily
undergo Michael addition reactions with various nucleophiles.
CF3
CF3
B
B
EWG
2a,b
+
X
X
HO
O
EWG
1a–f
3aa–bg
EWG = a: CN, b: CO2Me
A, B, X for compounds shown, see Table 1
Key words: Baylis–Hillman reaction, 1,3-azoles, Michael addi-
tions, trifluoromethyl substituted, allylic alcohols
Scheme 1 Reagents and conditions: (i) DABCO (0.05 equiv), THF
or neat, r.t., 30 min to 7 d.
The Baylis–Hillman reaction provides an efficient meth-
odology for the formation of C–C bonds1 through the
base-catalyzed a-oxyalkylation of activated alkenes with,
aldehydes, N-sulfonylimines, and activated ketones (e.g.,
hexafluoroacetone and trifluoropyruvates,2a isatins and
ninhydrin2b). Less electrophilic ketones react under harsh-
er conditions to give the target compounds in moderate or
low yields.3
resulted in 85–90% conversion according to 19F NMR
spectral studies of the reaction mixtures.
The Baylis–Hillman reactions of methyl acrylate (2b)
with ketones 1 gave target compounds 3ba–bg in 36–46%
yield after ten days of stirring in tetrahydrofuran. Several
1
unidentified side products were detected by H NMR
spectroscopic studies of the reaction mixtures. In order to
improve the selectivity, the Baylis–Hillman reactions
were carried out at ambient temperature in a mixture of
neat reagents. Such a simple modification of the synthetic
procedure increased the yield of target compounds to 80–
97% and decreased the reaction time to 1–12 hours
(Table 1).
Recently we synthesized a set of highly electrophilic 2-
(trifluoroacetyl)-1,3-azoles4 that are potential reagents for
the Baylis–Hillman reaction leading to novel polyfunc-
tionalized trifluoromethyl-containing allyl alcohols.
Ketones 1a–f reacted with acrylonitrile (2a) in tetrahydro-
furan at room temperature in the presence of 1,4-diazabi-
cyclo[2.2.2]octane to give products 3aa–af in 55–74%
yield (Scheme 1, Table 1). The reaction took 3–5 days and
Table 1 Synthesis of the Baylis–Hillman Adducts
Entry
Ketone
Alkene
Conditions
Product
Yielda (%)
74
N
N
CF3
CF3
N
HO
Me
N
Me
1a
N
1
2a
THF, r.t., 5 d
O
O
CN
3aa
N
CF3
CF3
N
N
2
2a
THF, r.t., 5 d
62
HO
CN
1b
3ab
SYNTHESIS 2008, No. 20, pp 3245–3252
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x
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Advanced online publication: 25.09.2008
DOI: 10.1055/s-0028-1083150; Art ID: P05508SS
© Georg Thieme Verlag Stuttgart · New York

3246
P. V. Khodakovskiy et al.
PAPER
Table 1 Synthesis of the Baylis–Hillman Adducts (continued)
Entry
3
Ketone
Alkene
Conditions
Product
Yielda (%)
N
N
CF3
CF3
N
N
HO
O
2a
THF, r.t., 5 d
55
CN
3ac
1c
N
N
CF3
CF3
Cl
Cl
N
4
5
2a
2a
THF, r.t., 3 d
neat, r.t., 24 h
56
80
N
HO
O
Me
CN
Me
1d
3ad
N
N
CF3
CF3
N
N
N
N
HO
Me
O
CN
Me
1e
3ae
N
N
CF3
CF3
6
2a
neat, r.t., 24 h
74
S
S
HO
O
CN
1f
3af
N
CF3
N
7
8
1a
2b
2b
THF, r.t., 5 d
neat, r.t., 24 h
46
95
HO
Me
CO2Me
3ba
3ba
1a
1b
N
CF3
N
9
2b
THF, r.t., 5 d
37
HO
CO2Me
3bb
N
CF3
N
10
11
1e
1f
2b
2b
neat, r.t., 0.5 h
neat, r.t., 12 h
N
94
97
HO
Me
CO2Me
3be
N
CF3
S
HO
CO2Me
3bf
N
N
CF3
CF3
12
13
2b
2b
THF, r.t., 10 d
neat, r.t., 2 h
36
80
S
S
HO
O
CO2Me
1g
1g
3bg
3bg
a The yields refer to isolated and purified products.
The use of excess 2b led to the formation of compounds 4 Spontaneous cyclization of imidazole derivatives 3ba fol-
through the Baylis–Hillman reaction of intermediates 3gb lowed by ester hydrolysis afforded zwitterionic com-
with methyl acrylate (Scheme 2).
pound 5 in 39% yield (Scheme 3). Apparently spatial
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Baylis–Hillman Reactions of 2-(Trifluoroacetyl)-1,3-azoles
3247
CF3
N
S
i
3bg
2b
+
CO2Me
CO2Me
HO
excess
4
Scheme 2 Reagents and conditions: (i) DABCO, r.t., 7 d.
O
N+
Figure 1 Molecular structure of compound 5; the hydrogen bond is
shown as a broken line.
i
O–
3ba
N
OH
F3C
Me
O
OMe
5
PhXH
N
i
PhX
6a: X = NH
6b: X = S
Scheme 3 Reagents and conditions: (i) KOH, i-PrOH–H2O, 60 °C,
2 h.
N
HO
CF3
7a: X = NH
7b: X = S
O
OMe
R2
N
N
iii
preorganization of the nucleophilic nitrogen atom of the
imidazole ring and the highly polarized terminal double
bond facilitates this cyclization.
3ba
R1
N
O
OMe
HO
CF3
N
Single crystal X-ray analysis unambiguously revealed the
structure of compound 5 (Figure 1) as well as the forma-
tion of intramolecular hydrogen bond between the hy-
droxy and carboxy groups.
10
1 and R2 see Table 2
MeO
ii
N
HO
R
CF3
8
Scheme 4 Reagents and conditions: (i) MeOH, 60 °C , 4 h; (ii)
KOH, MeOH, 60 °C , 4 h; (iii) MeOH, r.t., 12 h.
Compounds 3 readily reacted with various nucleophiles to
give Michael addition products. The reaction with aniline
6a occurred at 60 °C in methanol whereas thiophenol 6b
required suspended potassium hydroxide as base. In the
case of phenol, a complex mixture of products was ob-
tained which, according to LC-MS, contained ca. 40% of
major compound 8, which was isolated in 39% yield
(Scheme 4). The highest yields of the target compounds
were attained in the case of the most reactive aliphatic
amines 9a–f and imidazole 9g (Table 2).5
Table 2 Products of Michael Addition Reaction of 3aa and 3ba
Entry
Amine
BH adduct
Product
Yielda (%)
CN
N
N
N
1
3aa
95
88
N
H
HO
Me
CF3
9a
9a
10aa
O
OMe
N
2
3
4
3ba
3ba
3ba
N
N
HO
Me
CF3
10ab
O
OMe
N
66
60
N
NH
N
HO
Me
CF3
9b
10bb
O
OMe
O
N
O
N
NH
N
HO
Me
CF3
9c
10cb
Synthesis 2008, No. 20, 3245–3252 © Thieme Stuttgart · New York

3248
P. V. Khodakovskiy et al.
PAPER
Table 2 Products of Michael Addition Reaction of 3aa and 3ba (continued)
Entry
5
Amine
BH adduct
Product
Yielda (%)
Me
N
O
OMe
N
Me
N
N
3ba
67
N
NH
HO
Me
CF3
9d
10db
Ph
N
O
OMe
Ph
N
N
6
7
8
3ba
3ba
3ba
83
N
NH
N
HO
O
Me
9e
CF3
10eb
OMe
Ph
N
N
N
Ph
78
72
NH
N
N
HO
9f
Me
CF3
10fb
O
OMe
N
N
N
N
N
H
N
HO
Me
CF3
9g
10gb
a The yields refer to isolated and purified products.
microanalyses were obtained for all new substances: C 0.33; H
0.45; N 0.25.
The structures of all compounds obtained were confirmed
by IR, 1H, 13C, and 19F NMR, and APCI MS data and ele-
mental analysis.
Baylis–Hillman Adducts 3; General Procedure
In conclusion, a simple method for the preparation of tri-
fluoromethyl-containing allyl alcohols from 2-(trifluoro-
acetyl)-1,3-azoles through the Baylis–Hillman reaction
was elaborated. We have shown that mild reaction condi-
tions resulted in shorter reaction times and considerably
higher yields than the described procedures for the Bay-
lis–Hillman reaction. Compounds 3 readily undergo the
Michael addition reaction to give novel functionally di-
verse druglike heterocycles.
To a stirred mixture of an appropriate ketone 1 (1.0 mmol), alkene
2 (1.0 mmol), and THF (1 mL) or without the solvent was added
DABCO (0.15 mmol) and stirring continued at r.t. for the specified
time. The solvent was removed in vacuo and the residue was
washed with H2O and crystallized (i-PrOH).
2-[2,2,2-Trifluoro-1-hydroxy-1-(1-methyl-1H-imidazol-2-
yl)ethyl]acrylonitrile (3aa)
Colorless crystals; yield: 74%; mp 159–160 °C (dec.).
IR: 3620–3280 (br), 3151, 3132, 2979, 2732, 2233, 1631, 1540,
1485, 1392, 1290, 1240, 1213, 1174, 1157, 1109, 1001, 958, 924,
872, 775, 717, 685, 671 cm–1.
Solvents and other chemicals were used as purchased. Starting ma-
terials were purchased (methyl acrylate, acrylonitrile, amines) or
prepared (a set of 2-trifluoroacetyl-1,3-azoles).3 Melting points
were uncorrected. 1H, 13C, and 19F NMR spectra were recorded on
a Bruker Avance drx 500 instrument at r.t. in DMSO-d6. LC/MS
spectra were recorded using an Agilent 1100 Series HPLC equipped
with diode-matrix and mass-selective detector Agilent LC\MSD
SL. The parameters of chromatography–mass analysis: column,
Zorbax SB-C18, 1.8 mm, 4.6 mm × 15 mm; eluent A: MeCN–H2O
with 0.1% of TFA (95:5); eluent B: H2O with 0.1% of TFA; flow
rate, 3 mL/sec; volume of injected sample: 1 mL; UV-detectors at
215, 254, and 265 nm; ionization method: chemical ionization un-
der atmospheric pressure (APCI); ionization mode: simultaneous
scanning of positive and negative ions in the mass range of 80–1000
m/z. FT-IR spectra were recorded on a Nexus-470 spectrophoto-
meter on samples prepared as KBr discs. Microanalyses were per-
formed in the Microanalytical Laboratory of the Institute of Organic
Chemistry, National Academy of Sciences of Ukraine. Satisfactory
1H NMR (DMSO-d6): d = 3.63 (s, 3 H), 6.23 (s, 1 H), 6.66 (s, 1 H),
6.92 (s, 1 H), 7.27 (s, 1 H), 8.25 (s, 1 H).
13C NMR (DMSO-d6): d = 34.68, 75.17 (q, 2JCF = 29.3 Hz), 116.38,
1
120.60, 124.14 (q, JCF = 288.0 Hz), 125.38, 127.03, 137.80,
140.17.
19F NMR (DMSO-d6): d = –75.51.
MS (APCI): m/z = 232 [M + 1].
2-[1-(1-Allyl-1H-imidazol-2-yl)-2,2,2-trifluoro-1-hydroxyeth-
yl]acrylonitrile (3ab)
Colorless crystals; yield: 62%; mp 127–128 °C.
IR: 3630–3290 (br), 3153, 3116, 2993, 2742, 2642, 2229, 1649,
1620, 1475, 1416, 1402, 1286, 1267, 1201, 1186, 1164, 1142, 1117,
993, 962, 924, 865, 835, 764, 744, 715 cm–1.
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Baylis–Hillman Reactions of 2-(Trifluoroacetyl)-1,3-azoles
3249
1H NMR (DMSO-d6): d = 4.67 (m, 2 H), 5.15 (d, J = 17.0 Hz, 1 H),
5.21 (d, J = 10.5 Hz, 1 H), 5.92 (m, 1 H), 6.28 (s, 1 H), 6.65 (s, 1 H),
6.98 (s, 1 H), 7.25 (s, 1 H), 8.36 (s, 1 H).
1H NMR (DMSO-d6): d = 2.40 (s, 3 H), 6.57 (s, 1 H), 6.70 (s, 1 H),
7.49 (s, 1 H), 8.76 (s, 1 H).
13C NMR (DMSO-d6): d = 17.32, 76.69 (q, 2JCF = 30.2 Hz), 116.41,
13C NMR (DMSO-d6): d = 49.31, 75.24 (q, 2JCF = 29.8 Hz), 116.34,
117.80, 120.67, 123.65 (q, JCF = 288.0 Hz), 137.97, 153.25,
1
1
118.64, 120.85, 123.61, 124.06 (q, JCF = 288.4 Hz), 127.61,
165.00.
133.87, 137.81, 140.03.
19F NMR (DMSO-d6): d = –75.40.
19F NMR (DMSO-d6): d = –81.41.
MS (APCI): m/z = 249 [M + 1].
MS (APCI): m/z = 258 [M + 1].
Methyl 2-[2,2,2-Trifluoro-1-hydroxy-1-(1-methyl-1H-imidazol-
2-yl)ethyl]acrylate (3ba)
Colorless crystals; yield: 95%; mp 106–107 °C.
2-[1-(1-Butyl-1H-imidazol-2-yl)-2,2,2-trifluoro-1-hydroxyeth-
yl]acrylonitrile (3ac)
Colorless crystals; yield: 55%; mp 134–135 °C.
IR: 3560–3300 (br), 3155, 3124, 3020, 2966, 2726, 2663, 2588,
1736, 1631, 1535, 1481, 1446, 1389, 1321, 1269, 1250, 1184, 1171,
1130, 1113, 1103, 1055, 999, 960, 949, 920, 856, 814, 760, 733,
710, 690, 665, 627, 596 cm–1.
IR: 3640–3220 (br), 3156, 3134, 2958, 2933, 2875, 2719, 2675,
2623, 2567, 2231, 1621, 1483, 1458, 1396, 1381, 1294, 1242, 1174,
1105, 1005, 960, 926, 874, 773, 746, 710, 677 cm–1.
1H NMR (DMSO-d6): d = 0.88 (t, J = 7.0 Hz, 3 H), 1.27 (m, 2 H),
1.69 (m, 2 H), 3.96 (m, 2 H), 6.25 (s, 1 H), 6.68 (s, 1 H), 6.94 (s, 1
H), 7.35 (s, 1 H), 8.25 (s, 1 H).
1H NMR (DMSO-d6): d = 3.56 (s, 3 H), 3.58 (s, 3 H), 6.18 (s, 1 H),
6.43 (s, 1 H), 6.81 (s, 1 H), 7.12 (s, 1 H), 7.57 (s, 1 H).
13C NMR (DMSO-d6): d = 34.32, 52.50, 75.14 (q, 2JCF = 28.9 Hz),
13C NMR (DMSO-d6): d = 13.94, 19.85, 32.57, 46.59, 75.28 (q,
124.11, 124.56 (q, JCF = 288.0 Hz), 126.26, 129.34, 137.67,
1
1
2JCF = 28.9 Hz), 116.28, 121.18, 123.36, 124.11 (q, JCF = 288.4
141.99, 165.33.
Hz), 127.44, 137.63, 140.03.
19F NMR (DMSO-d6): d = –75.34.
19F NMR (DMSO-d6): d = –74.88.
MS (APCI): m/z = 265 [M + 1].
MS (APCI): m/z = 274 [M + 1].
Methyl 2-[1-(1-Allyl-1H-imidazol-2-yl)-2,2,2-trifluoro-1-hy-
droxyethyl]acrylate (3bb)
Colorless crystals; yield: 37%; mp 103–104 °C.
MS (IE): m/z (%) = 273 (8) [M]+, 205 (15), 204 (100) [M – CF3]+,
165 (15), 148 (96), 95 (14), 81 (13), 57 (16), 55 (11), 41 (32).
2-[1-(5-Chloro-1-methyl-1H-imidazol-2-yl)-2,2,2-trifluoro-1-
hydroxyethyl]acrylonitrile (3ad)
Colorless crystals; yield: 56%; mp 128–129 °C.
IR: 3600–3200 (br), 3155, 3131, 3028, 2958, 2804–2495 (br), 1741,
1630, 1477, 1444, 1392, 1321, 1267, 1169, 1105, 1001, 958, 920,
812, 760, 671 cm–1.
IR: 3600–2930 (br), 2754, 2708, 2229, 1655, 1525, 1473, 1450,
1400, 1358, 1279, 1205, 1192, 1182, 1134, 1107, 999, 980, 972,
916, 877, 833, 748, 727, 700, 640 cm–1.
1H NMR (DMSO-d6): d = 3.53 (s, 3 H), 4.63 (m, 2 H), 5.13 (m, 2
H), 5.88 (s, 1 H), 6.20 (s, 1 H), 6.45 (s, 1 H), 6.85 (s, 1 H), 7.07 (s,
1 H), 7.64 (s, 1 H).
1H NMR (DMSO-d6): d = 3.57 (s, 3 H), 6.31 (s, 1 H), 6.72 (s, 1 H),
7.11 (s, 1 H), 8.44 (s, 1 H).
13C NMR (DMSO-d6): d = 49.09, 52.42, 75.30 (q, 2JCF = 28.9 Hz),
1
118.07, 122.31, 124.516 (q, JCF = 288.0 Hz), 126.92, 129.66,
134.44, 137.80, 141.81, 165.10.
19F NMR (DMSO-d6): d = –75.19.
MS (APCI): m/z = 291 [M + 1].
13C NMR (DMSO-d6): d = 32.32, 75.29 (q, 2JCF = 29.8 Hz), 116.19,
1
119.90, 120.70, 123.89 (q, JCF = 288.4 Hz), 124.39, 138.57,
140.50.
19F NMR (DMSO-d6): d = –75.39.
Methyl 2-[2,2,2-Trifluoro-1-hydroxy-1-(1-methyl-1H-1,2,4-tri-
azol-5-yl)ethyl]acrylate (3be)
MS (APCI): m/z = 266 [M + 1].
Colorless crystals; yield: 94%; mp 75–76 °C.
2-[2,2,2-Trifluoro-1-hydroxy-1-(1-methyl-1H-1,2,4-triazol-5-
yl)ethyl]acrylonitrile (3ae)
Colorless crystals; yield: 80%; mp 129–130 °C.
IR: 3600–3300 (br), 3140, 3124–2980 (br), 2964, 2777, 1736, 1630,
1506, 1466, 1456, 1443, 1385, 1321, 1271, 1194, 1182, 1161, 1119,
1026, 1001, 962, 931, 899, 858, 816, 787, 715, 671, 588 cm–1.
1H NMR (DMSO-d6): d = 3.56 (s, 3 H), 3.80 (s, 3 H), 6.38 (s, 1 H),
6.58 (s, 1 H), 7.87 (s, 1 H), 8.05 (br s, 1 H).
IR: 3630–3305 (br), 3124, 2924, 2769, 2723, 2237, 1630, 1491,
1458, 1439, 1408, 1389, 1281, 1248, 1190, 1115, 1001, 984, 941,
908, 879, 731, 706, 675 cm–1.
1H NMR (DMSO-d6): d = 3.88 (s, 3 H), 6.40 (s, 1 H), 6.77 (s, 1 H),
8.05 (s, 1 H), 8.74 (s, 1 H).
13C NMR (DMSO-d6): d = 37.35, 52.59, 74.18 (q, 2JCF = 30.2 Hz),
1
124.19 (q, JCF = 288.0 Hz), 130.60, 136.30, 149.51, 150.57,
164.71.
13C NMR (DMSO-d6): d = 37.91, 74.36 (q, 2JCF = 30.2 Hz), 115.90,
119.13, 123.72 (q, 1JCF = 288.0 Hz), 138.93, 148.90, 150.27.
19F NMR (DMSO-d6): d = –75.15.
19F NMR (DMSO-d6): d = –75.74.
MS (APCI): m/z = 231 [M – 1].
MS (APCI): m/z = 266 [M + 1].
Methyl 2-[2,2,2-Trifluoro-1-hydroxy-1-(4-methylthiazol-2-
yl)ethyl]acrylate (3bf)
Colorless oil; yield: 97%.
2-[2,2,2-Trifluoro-1-hydroxy-1-(4-methylthiazol-2-yl)eth-
yl]acrylonitrile (3af)
Yellow oil: yield: 74%.
IR: 3600–3150 (br), 3120, 2958, 2929, 2856, 1733, 1693, 1618,
1529, 1443, 1329, 1265, 1194, 1173, 1136, 980, 962, 885, 818, 744,
619 cm–1.
1H NMR (DMSO-d6): d = 2.31 (s, 3 H), 3.55 (s, 3 H), 6.22 (s, 1 H),
6.48 (s, 1 H), 7.33 (s, 1 H), 8.01 (br s, 1 H).
IR: 3600–3170 (br), 3120, 2931, 2237, 1659, 1527, 1446, 1396,
1273, 1244, 1190, 1174, 1126, 1092, 968, 893, 872, 746 cm–1.
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P. V. Khodakovskiy et al.
PAPER
13C NMR (DMSO-d6): d = 17.29, 52.44, 77.05 (q, 2JCF = 28.9 Hz),
the residue was recrystallized (i-PrOH) to give 7a as colorless crys-
tals; yield: 38%; mp 152–153 °C.
1
116.77, 124.21 (q, JCF = 288.0 Hz), 129.40, 137.48, 152.10,
164.96, 167.73.
19F NMR (DMSO-d6): d = –73.89.
IR: 3367 (br), 3257, 3140, 3118, 3055, 3035, 3010, 2956, 2927,
2872, 1711, 1605, 1539, 1500, 1485, 1470, 1439, 1383, 1356, 1300,
1269, 1238, 1209, 1196, 1173, 1130, 982, 964, 906, 750, 708, 692,
592, 575 cm–1.
MS (APCI): m/z = 282 [M + 1].
Methyl 2-[1-(Benzothiazol-2-yl)-2,2,2-trifluoro-1-hydroxyeth-
yl]acrylate (3bg)
Colorless crystals; yield: 80%; mp 45–46 °C.
1H NMR (DMSO-d6): d = 2.96 (m, 1 H), 3.56 (m, 1 H), 3.60 (s, 3
H), 3.82 (s, 3 H), 4.01 (m, 1 H), 5.73 (m, 1 H), 6.51 (t, J = 7.5 Hz,
1 H), 6.66 (d, J = 7.5 Hz, 2 H), 6.93 (s, 1 H), 6.99 (s, 1 H), 7.03 (dd,
J = 7.5 Hz, 2 H), 7.20 (s, 1 H).
IR: 3250 (br), 3140, 2958, 2926, 2854, 1695, 1616, 1514, 1444,
1417, 1325, 1259, 1186, 1176, 1149, 995, 968, 904, 831, 818, 766,
741, 731, 634 cm–1.
13C NMR (DMSO-d6): d = 35.90, 42.61, 48.88, 52.27, 77.75 (q,
1
2JCF = 28.5 Hz), 112.77, 116.46, 124.97 (q, JCF = 288.0 Hz),
125.64, 127.15, 129.27, 140.78, 148.97, 171.63.
19F NMR (DMSO-d6): d = –76.34.
1H NMR (DMSO-d6): d = 3.54 (s, 3 H), 6.37 (s, 1 H), 6.63 (s, 1 H),
7.47 (dd, J = 8.0, 7.0 Hz, 1 H), 7.52 (dd, J = 8.0, 7.0 Hz, 1 H), 8.02
(d, J = 8.0 Hz, 1 H), 8.13 (d, J = 8.0 Hz, 1 H), 8.32 (s, 1 H).
MS (APCI): m/z = 358 [M + 1].
13C NMR (DMSO-d6): d = 52.52, 77.54 (q, 2JCF = 28.9 Hz), 122.68,
1
123.64, 124.27 (q, JCF = 288.0 Hz), 126.08, 126.66, 130.02,
Methyl 4,4,4-Trifluoro-3-hydroxy-3-(1-methyl-1H-imidazol-2-
yl)-2-[(phenylsulfanyl)methyl]butanoate (7b)
A mixture of PhSH (1.0 mmol), KOH (0.1 mmol), 3ba (1.0 mmol),
and MeOH (1 mL) was stirred at 60 °C for 4 h. CH2Cl2 was added,
the organic phase was washed with H2O and concentrated in vacuo.
Product was purified by flash chromatography to give 7b as a col-
orless oil; yield: 49%.
135.63, 137.13, 152.84, 164.61, 170.92.
19F NMR (DMSO-d6): d = –74.94.
MS (APCI): m/z = 318 [M + 1].
Dimethyl 2-[1-(Benzothiazol-2-yl)-2,2,2-trifluoro-1-hydroxy-
ethyl]-4-methylenepentanedioate (4)
Colorless crystals; yield: 40%; mp 122–123 °C.
IR: 3600–3200 (br), 3114, 3059, 3005, 2954, 1713, 1583, 1524,
1483, 1441, 1352, 1279, 1217, 1165, 1122, 1088, 1054, 1026, 1011,
964, 901, 833, 744, 690, 652 cm–1.
1H NMR (DMSO-d6): d = 2.96 (d, J = 13.5 Hz, 1 H), 3.20 (dd,
J = 13.5, 12.0 Hz, 1 H), 3.62 (s, 3 H), 3.79 (s, 3 H), 3.89 (d, J = 12.0
Hz, 1 H), 6.95 (s, 1 H), 7.16 (s, 1 H), 7.17–7.23 (m, 2 H), 7.28–7.38
(m, 4 H).
IR: 3340 (br), 3078, 3001, 2951, 2855, 1727, 1698, 1635, 1502,
1446, 1438, 1378, 1340, 1317, 1294, 1251, 1236, 1188, 1170, 1141,
1033, 960, 893, 819, 765, 735, 685, 607 cm–1.
1H NMR (DMSO-d6): d = 2.80–2.93 (m, 2 H), 3.25 (s, 3 H), 3.70 (s,
3 H), 3.80 (m, 1 H), 5.62 (s, 1 H), 6.10 (s, 1 H), 7.46 (dd, J = 8.0,
7.0 Hz, 1 H), 7.52 (dd, J = 8.0, 7.0 Hz, 1 H), 8.04 (d, J = 8.0 Hz, 1
H), 8.12 (d, J = 8.0 Hz, 1 H), 8.13 (s, 1 H).
13C NMR (DMSO-d6): d = 31.29, 35.78, 49.99, 52.32, 78.42 (q,
1
2JCF = 28.9 Hz), 124.77 (q, JCF = 288.0 Hz), 125.77, 126.54,
13C NMR (DMSO-d6): d = 29.57, 50.73, 51.84, 52.46, 78.31 (q,
127.20, 128.84, 129.49, 135.39, 140.45, 170.66.
19F NMR (DMSO-d6): d = –76.08.
1
2JCF = 28.1 Hz), 122.74, 123.67, 124.60 (q, JCF = 289.2 Hz),
126.14, 126.86, 128.12, 135.10, 137.00, 153.27, 166.58, 170.11,
170.97.
MS (APCI): m/z = 375 [M + 1].
19F NMR (DMSO-d6): d = –74.84.
Methyl 4,4,4-Trifluoro-3-hydroxy-2-(methoxymethyl)-3-(1-
methyl-1H-imidazol-2-yl)butanoate (8)
MS (APCI): m/z = 404 [M + 1].
A mixture of 3ba (1.0 mmol), KOH (1.0 mmol), and MeOH (1 mL)
was stirred at 60 °C for 4 h. The solvent was removed in vacuo, the
residue was recrystallized (i-PrOH) to give 8 as colorless crystals;
yield: 39%; mp 79–80 °C.
7-Hydroxy-1-methyl-7-(trifluoromethyl)-1,5,6,7-tetrahydro-
pyrrolo[1,2-a]imidazol-4-ium-6-carboxylate (5)
Compound 3ba (3 mmol) was dissolved in i-PrOH (2 mL), a soln of
KOH (0.1 mmol) in H2O (1 mL) was added. The mixture was stirred
at 60 °C for 2 h. The solvent was removed in vacuo, the residue was
recrystallized (i-PrOH) to give 5 as colorless crystals; yield: 39%;
mp 206–207 °C (dec).
IR: 3670–3150 (br), 3138, 3003, 2956, 2918, 1740, 1484, 1439,
1360, 1290, 1242, 1209, 1188, 1163, 1120, 1068, 995, 966, 941,
914, 764, 712, 661 cm–1.
1H NMR (DMSO-d6): d = 3.14 (s, 3 H), 3.27 (dd, J = 9.5, 3.0 Hz, 1
H), 3.63 (s, 3 H), 3.70 (dd, J = 10.5, 9.5 Hz, 1 H), 3.76 (s, 3 H), 3.85
(dd, J = 10.5, 3.0 Hz, 1 H), 6.90 (s, 1 H), 6.97 (s, 1 H), 7.16 (s, 1 H).
IR: 3650–3200 (br), 3109, 3043, 3020, 2980, 1578, 1460, 1441,
1363, 1313, 1250, 1203, 1169, 1149, 1070, 987, 947, 818, 687, 623,
588, 519, 449 cm–1.
1H NMR (DMSO-d6): d = 3.50 (d, J = 8.0 Hz, 1 H), 3.88 (s, 3 H),
4.49 (dd, J = 11.5, 8.0 Hz, 1 H), 4.75 (d, J = 11.5 Hz, 1 H), 7.81 (s,
1 H), 7.82 (s, 1 H), 13.99 (s, 1 H).
13C NMR (DMSO-d6): d = 35.77, 49.77, 52.25, 58.72, 70.76, 77.10
2
1
(q, JCF = 28.9 Hz), 124.81 (q, JCF = 288.4 Hz), 125.45, 127.13,
140.47, 171.20.
19F NMR (DMSO-d6): d = –76.40.
13C NMR (DMSO-d6): d = 34.91, 46.38, 50.89, 77.28 (q, 2JCF = 31.9
Hz), 119.84, 124.85 (q, 1JCF = 285.5 Hz), 129.92, 145.61, 170.44.
MS (APCI): m/z = 297 [M + 1].
19F NMR (DMSO-d6): d = –79.91.
MS (APCI): m/z = 251 [M+1].
Michael Addition of Secondary Amines; General Procedure
A mixture of amine (1.0 mmol), 3 (1.0 mmol), and MeOH (1 mL)
was stirred at r.t. for 12 h. The solvent was removed in vacuo, the
residue was recrystallized (i-PrOH).
Methyl 2-(Anilinomethyl)-4,4,4-trifluoro-3-hydroxy-3-(1-meth-
yl-1H-imidazol-2-yl)butanoate (7a)
A mixture of aniline (1.0 mmol), 3ba (1.0 mmol), and MeOH (1
mL) was stirred at 60 °C for 4 h. The solvent was removed in vacuo,
4,4,4-Trifluoro-3-hydroxy-3-(1-methyl-1H-imidazol-2-yl)-2-
(pyrrolidin-1-ylmethyl)butanenitrile (10aa)
Colorless crystals; yield: 95%; mp 131 °C.
Synthesis 2008, No. 20, 3245–3252 © Thieme Stuttgart · New York

PAPER
Baylis–Hillman Reactions of 2-(Trifluoroacetyl)-1,3-azoles
MS (APCI): m/z = 352 [M + 1].
3251
IR: 3670–3170 (br), 3124, 2941, 2864, 2243, 1473, 1408, 1348,
1254, 1184, 1155, 1136, 1119, 1003, 976, 947, 906, 887, 756, 685,
453 cm–1.
1H NMR (DMSO-d6): d = 1.68 (m, 4 H), 2.39 (m, 2 H), 2.46 (m, 1
H), 2.60 (m, 2 H), 3.09 (m, 1 H), 3.79 (s, 3 H), 4.13 (m, 1 H), 6.91
(s, 1 H), 7.19 (s, 1 H), 8.47 (s, 1 H).
Methyl 4,4,4-Trifluoro-3-hydroxy-3-(1-methyl-1H-imidazol-2-
yl)-2-[(4-methylpiperazin-1-yl)methyl]butanoate (10db)
Colorless crystals; yield: 67%; mp 106–107 °C.
IR: 3670–3150 (br), 3097, 2966, 2953, 2931, 2883, 2848, 2829,
2802, 2775, 1724, 1524, 1479, 1456, 1439, 1356, 1336, 1288, 1252,
1221, 1194, 1174, 1130, 1092, 1012, 985, 962, 928, 901, 870, 812,
785, 679, 621, 567 cm–1.
1H NMR (DMSO-d6): d = 2.05 (s, 3 H), 2.11–2.30 (m, 6 H), 2.42–
2.52 (m, 2 H), 2.84 (dd, J = 11.8 Hz, 1 H), 3.62 (s, 3 H), 3.77 (s, 3
H), 3.86 (m, 1 H), 6.88 (s, 1 H), 6.39 (s, 1 H), 7.13 (s, 1 H).
13C NMR (DMSO-d6): d = 23.71, 35.65, 36.40, 54.14, 54.44, 77.58
2
1
(q, JCF = 28.9 Hz), 118.93, 124.52 (q, JCF = 288.0 Hz), 125.80,
127.19, 140.00.
19F NMR (DMSO-d6): d = –75.52.
MS (APCI): m/z = 303 [M + 1].
13C NMR (DMSO-d6): d = 35.81, 46.08, 47.31, 52.09, 53.26, 55.22,
Methyl 4,4,4-Trifluoro-3-hydroxy-3-(1-methyl-1H-imidazol-2-
yl)-2-(pyrrolidin-1-ylmethyl)butanoate (10ab)
Colorless crystals; yield: 88%; mp 115–116 °C.
2
1
56.48, 77.68 (q, JCF = 28.5 Hz), 124.97 (q, JCF = 288.0 Hz),
125.31, 127.09, 140.74, 171.95.
19F NMR (DMSO-d6): d = –76.36.
IR: 3650–3170 (br), 3154, 3106, 3026, 2968, 2879, 2827, 2783,
2748, 1743, 1730, 1529, 1479, 1444, 1437, 1356, 1284, 1176, 1138,
1117, 1055, 987, 962, 951, 931, 906, 889, 791, 764, 712, 687, 588,
548, 509, 498 cm–1.
1H NMR (DMSO-d6): d = 1.60 (m, 4 H), 2.12 (d, J = 10.5 Hz, 1 H),
2.27 (m, 2 H), 2.46 (m, 2 H), 3.09 (dd, J = 10.5, 9.5 Hz, 1 H), 3.61
(s, 3 H), 3.78 (s, 3 H), 3.84 (d, J = 9.5 Hz, 1 H), 6.88 (s, 1 H), 6.98
(s, 1 H), 7.13 (s, 1 H).
MS (APCI): m/z = 365 [M + 1].
Methyl 4,4,4-Trifluoro-3-hydroxy-3-(1-methyl-1H-imidazol-2-
yl)-2-[(4-phenylpiperazin-1-yl)methyl]butanoate (10eb)
Colorless crystals; yield: 83%; mp 113–114 °C.
IR: 3670–3140 (br), 2960, 2854, 2812, 1724, 1603, 1504, 1481,
1446, 1387, 1354, 1279, 1261, 1238, 1169, 1122, 1011, 984, 953,
931, 764, 692, 675, 517 cm–1.
1H NMR (DMSO-d6): d = 2.21 (m, 1 H), 2.30 (m, 2 H), 2.63 (m, 2
H), 2.93 (dd, J = 12.0 Hz, 1 H), 3.02 (m, 4 H), 3.63 (s, 3 H), 3.78 (s,
3 H), 3.94 (m, 1 H), 6.74 (t, J = 7.0 Hz, 1 H), 6.85–6.95 (m, 4 H),
7.13–7.22 (m, 3 H).
13C NMR (DMSO-d6): d = 23.65, 35.78, 48.74, 52.10, 54.08, 54.68,
2
1
77.86 (q, JCF = 28.9 Hz), 124.97 (q, JCF = 288.0 Hz), 125.23,
127.03, 140.86, 171.99.
19F NMR (DMSO-d6): d = –76.26.
MS (APCI): m/z = 336 [M + 1].
13C NMR (DMSO-d6): d = 35.84, 47.37, 48.78, 52.14, 53.35, 56.56,
2
1
77.67 (q, JCF = 28.5 Hz), 115.79, 119.24, 124.99 (q, JCF = 288.0
Methyl 4,4,4-Trifluoro-3-hydroxy-3-(1-methyl-1H-imidazol-2-
yl)-2-(piperidin-1-ylmethyl)butanoate (10bb)
Colorless crystals; yield: 66%; mp 101–102 °C.
Hz), 125.37, 127.13, 129.30, 140.74, 151.41, 172.00.
19F NMR (DMSO-d6): d = –76.34.
IR: 3630–3150 (br), 2937, 2852, 1743, 1732, 1477, 1437, 1363,
1304, 1284, 1200, 1167, 1130, 1057, 968, 931, 906, 762, 669, 417
cm–1.
1H NMR (DMSO-d6): d = 1.30 (m, 2 H), 1.38 (m, 4 H), 2.09 (m, 2
H), 2.15 (d, J = 11.5 Hz, 1 H), 2.43 (m, 2 H), 2.79 (dd, J = 11.5 Hz,
1 H), 3.61 (s, 3 H), 3.77 (s, 3 H), 3.85 (d, J = 11.5 Hz, 1 H), 6.88 (s,
1 H), 7.05 (s, 1 H), 7.13 (s, 1 H).
MS (APCI): m/z = 427 [M + 1].
Methyl 2-[(4-Benzylpiperazin-1-yl)methyl]-4,4,4-trifluoro-3-
hydroxy-3-(1-methyl-1H-imidazol-2-yl)butanoate (10fb)
Colorless crystals; yield: 78%; mp 117–118 °C.
IR: 3650–3160 (br), 3086, 3032, 2947, 2810, 2767, 1741, 1477,
1456, 1437, 1362, 1294, 1286, 1201, 1165, 1122, 1012, 966, 933,
904, 760, 741, 696 cm–1.
1H NMR (DMSO-d6): d = 2.10–2.39 (m, 7 H), 2.50–2.52 (m, 2 H),
2.84 (dd, J = 12.0 Hz, 1 H), 3.40 (m, 2 H), 3.61 (s, 3 H), 3.77 (s, 3
H), 3.86 (m, 1 H), 6.88 (s, 1 H), 6.94 (s, 1 H), 7.13 (s, 1 H), 7.18–
7.33 (m, 5 H).
13C NMR (DMSO-d6): d = 24.27, 26.14, 35.75, 47.20, 52.03, 54.69,
2
1
57.20, 77.73 (q, JCF = 28.9 Hz), 124.97 (q, JCF = 288.0 Hz),
125.22, 127.01, 140.81, 172.03.
19F NMR (DMSO-d6): d = –76.27.
MS (APCI): m/z = 350 [M + 1].
13C NMR (DMSO-d6): d = 35.78, 47.29, 52.08, 53.13, 53.43, 56.54,
2
1
62.45, 77.68 (q, JCF = 27.7 Hz), 124.97 (q, JCF = 288.0 Hz),
Methyl 4,4,4-Trifluoro-3-hydroxy-3-(1-methyl-1H-imidazol-2-
yl)-2-(morpholin-4-ylmethyl)butanoate (10cb)
Colorless crystals; yield: 60%; mp 118–119 °C.
125.29, 127.05, 127.27, 128.53, 129.18, 138.67, 140.73, 171.94.
19F NMR (DMSO-d6): d = –76.30.
IR: 3670–3190 (br), 3118, 3097, 2999, 2954, 2877, 2852, 2827,
2777, 2688, 1724, 1524, 1485, 1439, 1360, 1338, 1296, 1244, 1211,
1196, 1176, 1142, 1117, 984, 964, 930, 914, 901, 876, 793, 712,
673, 552, 457 cm–1.
1H NMR (DMSO-d6): d = 2.05–2.19 (m, 3 H), 2.40–2.47 (m, 2 H),
2.84 (dd, J = 11.8 Hz, 1 H), 3.37–3.54 (m, 4 H), 3.63 (s, 3 H), 3.77
(s, 3 H), 3.90 (dd, J = 11.0, 3.5 Hz, 1 H), 6.87 (s, 1 H), 6.89 (s, 1 H),
7.14 (s, 1 H).
MS (APCI): m/z = 441 [M + 1].
Methyl 4,4,4-Trifluoro-3-hydroxy-2-(1H-imidazol-1-ylmethyl)-
3-(1-methyl-1H-imidazol-2-yl)butanoate (10gb)
Colorless crystals; yield: 72%; mp 131–132 °C.
IR: 3610, 3500–3300 (br), 3259, 3136, 3116, 2954, 1732, 1514,
1479, 1435, 1360, 1275, 1252, 1219, 1169, 1136, 1107, 1092, 987,
966, 947, 763, 660 cm–1.
13C NMR (DMSO-d6): d = 35.84, 47.14, 52.16, 53.92, 57.05, 66.73,
1H NMR (DMSO-d6): d = 3.54 (s, 3 H), 3.82 (s, 3 H), 3.95 (d,
J = 12.0 Hz, 1 H), 4.09 (d, J = 11.0 Hz, 1 H), 4.41 (dd, J = 12.0,
11.0 Hz, 1 H), 6.87 (s, 1 H), 7.00 (s, 1 H), 7.01 (s, 1 H), 7.24 (s, 1
H), 7.44 (s, 1 H), 7.51 (br s, 1 H).
2
1
77.62 (q, JCF = 28.5 Hz), 124.96 (q, JCF = 288.0 Hz), 125.39,
127.10, 140.69, 171.89.
19F NMR (DMSO-d6): d = –76.36.
Synthesis 2008, No. 20, 3245–3252 © Thieme Stuttgart · New York

3252
P. V. Khodakovskiy et al.
PAPER
13C NMR (DMSO-d6): d = 35.85, 45.77, 51.96, 52.66, 77.60 (q,
References
1
2JCF = 30.2 Hz), 119.50, 124.69 (q, JCF = 288.0 Hz), 125.98,
(1) (a) Basavaiah, D.; Venkateswara Rao, K.; Reddy, R. J.
Chem. Soc. Rev. 2007, 36, 1581. (b) Basavaiah, D.;
Jaganmohan Rao, A.; Satyanarayana, T. Chem. Rev. 2003,
103, 811.
127.44, 129.35, 137.85, 140.24, 170.38.
19F NMR (DMSO-d6): d = –76.01.
MS (APCI): m/z = 333 [M + 1].
(2) (a) CF3 Ketones: Golubev, A. S.; Kolomiets, A. F.; Fokin,
A. V. J. Fluorine Chem. 1991, 54, , 272. (b) Isatins,
ninhydrin: Chung, Y. M.; Im, Y. J.; Kim, J. N. Bull. Korean
Chem. Soc. 2002, 23, 1651.
Single crystal X-ray analysis: Unit cell parameters and intensities of
all sets of reflections were measured using an Xcalibur-3 diffracto-
meter (CCD detector, l(MoKa) irradiation, w-scans) All structures
were solved by direct method using the SHELXTL package.6 The
positions of the hydrogen atoms were located from difference maps
of the electron density and refined as riding atoms. Atomic coordi-
nates and crystallographic parameters were deposited at the Cam-
bridge Crystallographic Data Centre under CCDC 687052.
(3) Common ketones: Hill, J. S.; Isaacs, N. S. Tetrahedron Lett.
1986, 27, 5007..
(4) Khodakovskiy, P. V.; Volochnyuk, D. M.; Panov, D. M.;
Pervak, I. I.; Zarudnitskii, E. V.; Shishkin, O. V.;
Yurchenko, A. A.; Shivanyuk, A.; Tolmachev, A. A.
Synthesis 2008, 948.
(5) For analogous transformation of BH products see: Batra, S.;
Roy, A. K.; Patra, A.; Bhaduri, A. P.; Surin, W. R.;
Raghavan, S. A. V.; Sharma, P.; Kapoor, K.; Dikshit, M.
Bioorg. Med. Chem. 2004, 12, 2059.
Crystal data for 5: C9H9F3N2O3, triclinic, P1, a = 6.619(2) Å,
b = 8.654(5) Å, c = 10.160(3) Å, a = 107.15(4)°, b = 92.01(2)°,
g = 111.11(4)°, V = 512.2(4) Å3, Z = 2,
r
calcd = 1.62 g/cm3,
m = 0.156 mm–1, F(000) = 256, 159 parameters, R1 = 0.0317,
wR2 = 0.0791 (1284 reflections.
F
>
4s), R1 = 0.0451,
wR2 = 0.0842 (1702 unique reflections), S = 0.987, Dr (min/
(6) Sheldrick, G. M. SHELXTL PLUS, PC Version; a system of
computer programs for the determination of crystal structure
from X-ray diffraction data; Rev.5.1, 1998.
max) = –0.202/ 0.191 e Å–3.
Synthesis 2008, No. 20, 3245–3252 © Thieme Stuttgart · New York