Decarboxylative aldol-type reaction of 2-(trifluoroacetyl)-1,3-diazoles with activated acetic acids

Article abstract of DOI:10.1055/s-0028-1087985

The highly electrophilic ketones 2-(trifluoroacetyl)-1,3-diazoles easily undergo a decarboxylative aldol-type reaction with activated acetic acids to afford heterocyclic trifluoromethyl-substituted alcohols bearing various functionalities. Georg Thieme Ve

Full text of DOI:10.1055/s-0028-1087985

PAPER
1099
Decarboxylative Aldol-Type Reaction of 2-(Trifluoroacetyl)-1,3-diazoles with
Activated Acetic Acids
R
eactionof 2-
a
(Trifluoroa
v
e
zoles
w
ith
l
Acetic
A
cidsV. Khodakovskiy,a,b Dmitriy M. Volochnyuk,*a,c Andrey A. Tolmachevb
a
Enamine Ltd., 23 Alexandra Matrosova st., 01103 Kyiv, Ukraine
Fax +380(44)5373253; E-mail: D.Volochnyuk@enamine.net
b
c
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
Received 15 October 2008; revised 24 November 2008
methyl and ethyl trifluoropyruvates5 in reaction with ma-
lonic and cyanoacetic acids in pyridine. The reactions pro-
ceeded similarly, and aldols 3 were the only products.
Abstract: The highly electrophilic ketones 2-(trifluoroacetyl)-1,3-
diazoles easily undergo a decarboxylative aldol-type reaction with
activated acetic acids to afford heterocyclic trifluoromethyl-substi-
tuted alcohols bearing various functionalities.
The reactions of ketones 1a–c with 1.5 equivalents of ma-
Key words: heterocycles, 1,3-diazoles, aldol reactions, trifluoro- lonic acid (2a) or cyanoacetic acid (2b) in pyridine at
methyl compounds, alcohols
70 °C gave the corresponding products in good yields
(67–87%; Table 1, entries 1–5). The reaction took 8–12
hours and resulted in 90–95% conversion of 1, as shown
by 19F NMR spectroscopy of the reaction mixtures. Since
The trifluoromethyl group is one of the most attractive
the hydrates of 1 easily eliminated the water under the re-
action conditions3 with no decrease in reactivity, it was
possible to use the more convenient hydrates. The out-
come of the reactions of 1 with more complex methylene
substrates such as aryl- and hetarylacetic acids depended
on the electron-withdrawing properties of the heterocycle.
The imidazole derivatives 1a and 1b were less reactive
than benzothiazole 1c and, particularly, benzoxazole de-
rivative 1d.
functional groups in organic chemistry, since trifluoro-
methyl-containing molecules often possess valuable
physical and biological properties. Therefore, efficient in-
troduction of a trifluoromethyl group is a topic of growing
interest in fluoroorganic chemistry and many approaches
to such compounds have been described recently.1 The
most popular a-trifluoromethylated ketones have found
wide application in the synthesis of trifluoromethyl-con-
taining derivatives.2
Only azolylacetic acids 2c and 2d reacted with 1a to form
3ac and 3ad in satisfactory yields (Table 1, entries 6 and
7). The reactions of the rest of the substrates 2e–k with 1a
gave complex mixtures with only traces of the desired
products. Prolonged reaction times or harsher reaction
conditions did not improve the results, since the processes
were complicated by decarboxylation of 2 to a larger ex-
tent, according to LC-MS studies of the reaction mixtures.
We have recently synthesized a set of highly electrophilic
2-(trifluoroacetyl)-1,3-diazoles 1 (Scheme 1) that demon-
strated excellent activity toward different nucleophiles.3
Here we describe the decarboxylative addition of carbox-
ylic acid derivatives 2a–k to (trifluoroacetyl)hetarenes
1a–d in pyridine solution under mild conditions to pro-
vide simple polyfunctionalized alcohols 3aa–dk
(Scheme 1, Table 1).
Much more reactive 1c gave good results with all hetaryl-
acetic acids 2c–i (Table 1, entries 8–14). The reaction of
1c with 9H-fluorene-9-carboxylic acid (2j) also proceed-
ed smoothly under these conditions to form 3cj in 77%
yield (Table 1, entry 15), but analogous diphenylacetic
acid and 9H-xanthene-9-carboxylic acid gave only traces
of the corresponding products on refluxing in pyridine for
24 hours, probably because of steric hindrance of the re-
action centers.
R1
R1
R1
R1
N
N
a
CF3
R2
+
HO2C
R2
– CO2
X
X
HO
O
CF3
1a–d
2a–k
3aa–dk
X = NR3, O, S
1 = H, R1–R1 = (CH=CH)2
R2 = CO2H, CN, aryl, hetaryl
R
Scheme 1 Reagents and conditions: (a) py, 60–90 °C, 1–12 h.
Arylacetic acids showed poor reactivity toward 1 under
these conditions. Of the acids tried, namely phenylacetic,
(4-chlorophenyl)acetic, [4-(trifluoromethyl)phenyl]ace-
tic, and (4-nitrophenyl)acetic acid (2k), only acid 2k re-
acted with 1c on prolonged heating at 90 °C to give a
satisfactory yield of 33% (Table 1, entry 16). In contrast,
the reaction of 2k with the more reactive ketone 1d took
place much more easily at 60 °C, giving 3dk in an excel-
lent yield (78%; entry 17).
The ketones 1 behaved similarly to some other a-poly-
fluorocarbonyls such as trifluoroacetaldehyde, trifluoro-
acetone, triflouroacetophenone,4 hexafluoroacetone, and
SYNTHESIS 2009, No. 7, pp 1099–1104
x
x
.
x
x
.2
0
0
9
Advanced online publication: 02.03.2009
DOI: 10.1055/s-0028-1087985; Art ID: P11708SS
© Georg Thieme Verlag Stuttgart · New York

1100
P. V. Khodakovskiy et al.
PAPER
Table 1 Decarboxylative Addition of Carboxylic Acid Derivatives to (Trifluoroacetyl)hetarenes
Entry Ketone 1a
Acetic acid 2
Conditions
70 °C, 12 h
Product
Yieldb
(%)
N
N
N
COCF3
CO2H
1
1a
2a
3aa
67
HO2C
CO2H
N
HO
CF3
Me
Me
N
N
COCF3
CO2H
2
3
4
5
6
1b
1c
1a
1c
1a
2a
2a
2b
2b
2c
70 °C, 12 h
70 °C, 8 h
70 °C, 12 h
70 °C, 8 h
80 °C, 12 h
3ba
72
75
70
87
29
N
N
HO
CF3
n-Bu
n-Bu
N
CO2H
N
3ca
3ab
3cb
3ac
COCF3
S
HO
S
CF3
N
CN
NC
CO2H
N
HO
CF3
N
Me
CN
S
HO
CF3
N
N
N
N
CO2H
N
N
N
N
H
N
H
N
HO
CF3
Me
N
N
N
7
8
1a
1c
2d
2c
80 °C, 12 h
70 °C, 8 h
3ad
3cc
73
99
CO2H
N
S
HO
S
CF3
N
Me
N
N
N
S
S
N
H
N
HO
N
CF3
9
10
11
1c
1c
1c
2d
2e
2f
70 °C, 8 h
80 °C, 8 h
90 °C, 12 h
3cd
3ce
3cf
75
82
44
S
HO
CF3
N
CO2H
N
N
S
HO CF3
N
N
O
CO2H
S
HO
CF3
N
O
O
H
O
N
CO2H
N
12
13
1c
1c
2g
2h
90 °C, 8 h
3cg
3ch
72
80
NH
HN
NH
S
HO CF3
O
O
H
N
N
N
90 °C, 12 h
O
CO2H
S
HO CF3
N
O
N
H
Synthesis 2009, No. 7, 1099–1104 © Thieme Stuttgart · New York

PAPER
Reaction of 2-(Trifluoroacetyl)-1,3-diazoles with Acetic Acids
1101
Table 1 Decarboxylative Addition of Carboxylic Acid Derivatives to (Trifluoroacetyl)hetarenes (continued)
Entry Ketone 1a
Acetic acid 2
Conditions
90 °C, 12 h
Product
Yieldb
(%)
Me
N
N
N
CO2H
14
15
1c
1c
2i
3ci
53
77
O
N
S
HO
CF3
O
N
Me
CO2H
2j
80 °C, 12 h
3cj
N
S
HO
N
CF3
CO2H
16
17
1c
2k
2k
90 °C, 24 h
60 °C, 8 h
3ck
3dk
33
78
NO2
NO2
S
O2N
HO
CF3
CF3
N
N
O
1d
COCF3
O
HO
a Ketones 1c and 1d were used in hydrated form.
b Yields of isolated and purified products.
1 mL; UV detectors, l = 215, 254 and 265 nm; chemical ionization
under atmospheric pressure (APCI) used; ionization mode: simulta-
neous scanning of positive and negative ions for m/z = 80–1000].
Microanalyses were performed in the Microanalytical Laboratory
of the Institute of Organic Chemistry, National Academy of
Sciences of Ukraine. Satisfactory microanalyses were obtained for
all new substances (C 0.33; H 0.45; N 0.25).
Dicarboxylic acid 4 demonstrated special behavior in the
reactions with both 1a and 1c. The carboxylic group in the
ortho position facilitates the aldol condensation by hold-
ing 1 near the reaction center, followed by intramolecular
cyclization on the hydroxy group (Scheme 2).
CF3
Ar
a
CO2H
CO2H
Decarboxylative Addition; General Procedure
+
1a,c
– CO2
– H2O
O
A mixture of ketone 1 (1.0 mmol), activated acetic acid 2 or 4 (1.2
mmol), and pyridine (2.0 mL) was stirred under the conditions spec-
ified in Schemes 1 and 2 and Table 1. The solvent was removed in
vacuo, the residue was treated with H2O and 2% aq NaHCO3 (ex-
cept 3aa, 3ba, 3ca), and crystallized from EtOH.
O
4
5a: Ar = 1-methyl-1H-imidazol-2-yl
5c: Ar = benzothiazolyl
Scheme 2 Reagents and conditions: (a) py, 90 °C, 8 h.
4,4,4-Trifluoro-3-hydroxy-3-(1-methyl-1H-imidazol-2-yl)bu-
tanoic Acid (3aa)
In summary, we have demonstrated that 2-(trifluoro- Yield: 67%; colorless crystals; mp 187–188 °C (dec).
1H NMR (500 MHz, DMSO-d6): d = 2.94 (d, J = 16.3 Hz, 1 H), 3.38
acetyl)-1,3-diazoles enter into aldol-type reactions with
activated acetic acids on heating in pyridine, similarly to
the reports on a-polyfluorinated carbonyl compounds.
The reactivity of the ketones and the scope of the applica-
bility of this reaction depend on the electron-acceptor na-
ture of the azole.
(d, J = 16.3 Hz, 1 H), 3.80 (s, 3 H), 6.86 (s, 1 H), 7.13 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 35.48, 39.50, 74.63 (q,
1
2JCF = 28.9 Hz), 125.11, 125.27 (q, JCF = 287.1 Hz), 126.47,
142.12, 170.51.
19F NMR (470 MHz, DMSO-d6): d = –78.94.
MS (APCI): m/z = 239 [M + 1].
Solvents and other chemicals were obtained from commercial
sources (Aldrich, Fluka, Enamine Ltd.) and used without further pu-
rification. A set of 2-(trifluoroacetyl)-1,3-diazoles was prepared ac-
cording to our previously reported method.3 Melting points are
uncorrected. 1H NMR, 13C NMR, and 19F NMR spectra of samples
in DMSO-d6 were recorded on a Bruker Avance DRX 500 instru-
ment at ambient temperature. LC-MS spectra were obtained with a
chromatography/MS system consisting of an HPLC Agilent 1100
Series chromatograph equipped with diode-matrix and mass-selec-
tive Agilent LC/MSD SL detector [Zorbax SB-C18 column, 1.8 mm,
4.6 mm × 15 mm; eluent A: MeCN–H2O, 95:5 with 0.1% TFA; B:
H2O with 0.1% TFA; flow rate, 3 mL/s; volume of injected sample,
3-(1-Butyl-1H-imidazol-2-yl)-4,4,4-trifluoro-3-hydroxybutano-
ic Acid (3ba)
Yield: 72%; colorless crystals; mp 55–56 °C.
1H NMR (500 MHz, DMSO-d6): d = 0.88 (t, J = 7.3 Hz, 3 H), 1.23–
1.33 (m, 2 H), 1.62–1.83 (m, 2 H), 2.93 (d, J = 16.3 Hz, 1 H), 3.40
(d, J = 16.3 Hz, 1 H), 4.05–4.15 (m, 1 H), 4.26–4.36 (m, 1 H), 6.87
(s, 1 H), 7.19 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 14.03, 19.84, 33.50, 39.82,
2
1
47.49, 74.89 (q, JCF = 29.3 Hz), 123.28, 125.15 (q, JCF = 288.0
Hz), 126.79, 141.80, 170.48.
Synthesis 2009, No. 7, 1099–1104 © Thieme Stuttgart · New York

1102
P. V. Khodakovskiy et al.
PAPER
19F NMR (470 MHz, DMSO-d6): d = –78.75.
MS (APCI): m/z = 281 [M + 1].
13C NMR (125 MHz, DMSO-d6): d = 16.96, 35.52, 38.56, 76.63 (q,
1
2JCF = 28.9 Hz), 115.52, 125.50 (q, JCF = 288.0 Hz), 125.61,
126.99, 140.90, 150.89, 163.09.
3-(1,3-Benzothiazol-2-yl)-4,4,4-trifluoro-3-hydroxybutanoic
Acid (3ca)
Yield: 75%; white powder; mp 147–148 °C.
19F NMR (470 MHz, DMSO-d6): d = –78.46.
MS (APCI): m/z = 292 [M + 1].
1H NMR (500 MHz, DMSO-d6): d = 3.09 (d, J = 16.2 Hz, 1 H), 3.51
(d, J = 16.2 Hz, 1 H), 7.47 (dd, J = 8.0 Hz, 1 H), 7.53 (dd, J = 8.0
Hz, 1 H), 8.00 (br s, 1 H), 8.03 (d, J = 8.0 Hz, 1 H), 8.13 (d, J = 8.0
Hz, 1 H), 12.50 (br s, 1 H).
2-(1,3-Benzothiazol-2-yl)-1,1,1-trifluoro-3-(1H-tetrazol-5-
yl)propan-2-ol (3cc)
Yield: 99%; beige powder; mp 98–100 °C.
1H NMR (500 MHz, DMSO-d6): d = 3.81 (d, J = 14.8 Hz, 1 H), 4.04
(d, J = 14.8 Hz, 1 H), 7.46 (dd, J = 7.5 Hz, 1 H), 7.53 (dd, J = 7.5
Hz, 1 H), 8.08 (m, 2 H), 8.17–8.67 (br, 1 H).
2
13C NMR (125 MHz, DMSO-d6): d = 39.02, 75.32 (q, JCF = 28.5
1
Hz), 122.27, 123.03, 124.16 (q, JCF = 288.0 Hz), 125.43, 126.17,
135.29, 152.74, 168.80, 170.97.
19F NMR (470 MHz, DMSO-d6): d = –79.07.
2
13C NMR (125 MHz, DMSO-d6): d = 30.49, 76.71 (q, JCF = 28.8
1
Hz), 122.76, 123.77, 124.69 (q, JCF = 288.0 Hz), 126.12, 126.80,
135.53, 151.12, 153.32, 169.79.
19F NMR (470 MHz, DMSO-d6): d = –77.79.
MS (APCI): m/z = 292 [M + 1].
4,4,4-Trifluoro-3-hydroxy-3-(1-methyl-1H-imidazol-2-yl)bu-
tanenitrile (3ab)
MS (APCI): m/z = 316 [M + 1].
Yield: 70%; colorless crystals; mp 130–150 °C (sublimed).
2-(1,3-Benzothiazol-2-yl)-1,1,1-trifluoro-3-(4-methyl-1,3-thia-
zol-2-yl)propan-2-ol (3cd)
Yield: 75%; yellow powder; mp 91–92 °C.
1H NMR (500 MHz, DMSO-d6): d = 2.22 (s, 3 H), 3.80 (d, J = 14.8
Hz, 1 H), 4.12 (d, J = 14.8 Hz, 1 H), 7.00 (s, 1 H), 7.48 (dd, J = 7.2
Hz, 1 H), 7.55 (dd, J = 7.6 Hz, 1 H), 8.10 (m, 2 H), 8.30 (br s, 1 H).
1H NMR (500 MHz, DMSO-d6): d = 3.28 (d, J = 16.5 Hz, 1 H), 3.64
(d, J = 16.5 Hz, 1 H), 3.79 (s, 3 H), 6.92 (s, 1 H), 7.23 (s, 1 H), 7.97
(s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 26.25, 35.35, 74.31 (q,
1
2JCF = 29.8 Hz), 117.05, 124.83 (q, JCF = 288.0 Hz), 125.99,
127.32, 140.35.
19F NMR (470 MHz, DMSO-d6): d = –78.76.
13C NMR (125 MHz, DMSO-d6): d = 16.83, 38.65, 77.54 (q,
1
2JCF = 28.5 Hz), 115.82, 122.77, 123.72, 124.77 (q, JCF = 288.4
Hz), 126.14, 126.86, 135.71, 151.21, 153.22, 161.33, 169.93.
19F NMR (470 MHz, DMSO-d6): d = –77.88.
MS (APCI): m/z = 345 [M + 1].
MS (APCI): m/z = 220 [M + 1].
3-(1,3-Benzothiazol-2-yl)-4,4,4-trifluoro-3-hydroxybutaneni-
trile (3cb)
Yield: 87%; yellow powder; mp 136–137 °C.
2-(1,3-Benzothiazol-2-yl)-1,1,1-trifluoro-3-(4-pyridyl)propan-
2-ol (3ce)
Yield: 82%; yellow powder; mp 191–192 °C.
1H NMR (500 MHz, DMSO-d6): d = 3.44 (d, J = 14.0 Hz, 1 H), 3.69
(d, J = 14.0 Hz, 1 H), 7.11 (m, 2 H), 7.45 (dd, J = 8.0, 6.5 Hz, 1 H),
7.55 (dd, J = 8.0, 6.5 Hz, 1 H), 8.04 (d, J = 8.0 Hz, 1 H), 8.07 (s, 1
H), 8.10 (d, J = 8.0 Hz, 1 H), 8.29 (m, 2 H).
1H NMR (500 MHz, DMSO-d6): d = 3.41 (d, J = 16.4 Hz, 1 H), 3.62
(d, J = 16.4 Hz, 1 H), 7.48 (dd, J = 7.6 Hz, 1 H), 7.54 (dd, J = 7.6
Hz, 1 H), 8.05 (d, J = 7.6 Hz, 1 H), 8.07 (d, J = 7.6 Hz, 1 H), 8.52
(br s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 25.57, 74.95 (q, JCF = 29.5
2
1
Hz), 115.73, 122.61, 123.39, 123.58 (q, JCF = 288.0 Hz), 126.16,
126.74, 135.09, 152.58, 168.29.
19F NMR (470 MHz, DMSO-d6): d = –78.26.
2
13C NMR (125 MHz, DMSO-d6): d = 39.58, 78.03 (q, JCF = 28.1
1
Hz), 122.78, 123.64, 125.07 (q, JCF = 288.4 Hz), 126.09, 126.34,
126.89, 135.23, 143.18, 149.41, 153.23, 169.96.
19F NMR (470 MHz, DMSO-d6): d = –79.76.
MS (APCI): m/z = 325 [M + 1].
MS (APCI): m/z = 273 [M + 1].
1,1,1-Trifluoro-2-(1-methyl-1H-imidazol-2-yl)-3-(1H-tetrazol-
5-yl)propan-2-ol (3ac)
Yield: 29%; colorless crystals; mp 187–188 °C.
3-(1,2-Benzisoxazol-3-yl)-2-(1,3-benzothiazol-2-yl)-1,1,1-tri-
fluoropropan-2-ol (3cf)
Yield: 44%; yellow powder; mp 138–139 °C.
1H NMR (500 MHz, DMSO-d6): d = 3.88 (d, J = 15.0 Hz, 1 H), 4.12
(d, J = 15.0 Hz, 1 H), 7.19 (dd, J = 8.0, 7.0 Hz, 1 H), 7.43 (dd,
J = 8.5, 7.0 Hz, 1 H), 7.47–7.55 (m, 2 H), 7.59 (d, J = 8.5 Hz, 1 H),
7.74 (d, J = 8.0 Hz, 1 H), 8.02 (d, J = 8.5 Hz, 1 H), 8.09 (d, J = 8.0
Hz, 1 H), 8.33 (s, 1 H).
1H NMR (500 MHz, DMSO-d6): d = 3.69 (d, J = 15.0 Hz, 1 H), 3.74
(s, 3 H), 4.02 (d, J = 15.0 Hz, 1 H), 6.84 (s, 1 H), 7.13 (s, 1 H), 7.55
(br s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 30.02, 35.45, 75.37 (q,
1
2JCF = 28.9 Hz), 125.35 (q, JCF = 288.0 Hz), 125.48, 126.96,
140.95, 151.44.
19F NMR (470 MHz, DMSO-d6): d = –78.11.
2
13C NMR (125 MHz, DMSO-d6): d = 31.84, 77.28 (q, JCF = 28.9
MS (APCI): m/z = 263 [M + 1].
Hz), 109.86, 122.14, 122.77, 123.17, 123.64, 123.80, 124.93 (q,
1JCF = 288.4 Hz), 126.11, 126.89, 130.54, 135.41, 153.28, 153.32,
162.58, 170.12.
1,1,1-Trifluoro-2-(1-methyl-1H-imidazol-2-yl)-3-(4-methyl-1,3-
thiazol-2-yl)propan-2-ol (3ad)
Yield: 73%; colorless crystals; mp 109–110 °C.
19F NMR (470 MHz, DMSO-d6): d = –77.37.
1H NMR (500 MHz, DMSO-d6): d = 2.29 (s, 3 H), 3.61 (d, J = 14.6
Hz, 1 H), 3.73 (s, 3 H), 4.14 (d, J = 14.6 Hz, 1 H), 6.90 (s, 1 H), 7.03
(s, 1 H), 7.16 (s, 1 H), 7.39 (s, 1 H).
MS (APCI): m/z = 365 [M + 1].
Synthesis 2009, No. 7, 1099–1104 © Thieme Stuttgart · New York

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Reaction of 2-(Trifluoroacetyl)-1,3-diazoles with Acetic Acids
1103
6-[2-(1,3-Benzothiazol-2-yl)-3,3,3-trifluoro-2-hydroxypro-
pyl]pyrimidine-2,4(1H,3H)-dione (3cg)
Yield: 72%; white powder; mp >220 °C.
1H NMR (500 MHz, DMSO-d6): d = 3.57 (d, J = 13.5 Hz, 1 H), 3.82
(d, J = 13.5 Hz, 1 H), 7.42 (m, 3 H), 7.54 (m, 1 H), 7.92–8.07 (m, 3
H), 8.10 (m, 2 H).
2
1H NMR (500 MHz, DMSO-d6): d = 3.18 (d, J = 14.8 Hz, 1 H), 3.52
(d, J = 14.8 Hz, 1 H), 5.09 (s, 1 H), 7.45 (dd, J = 7.2 Hz, 1 H), 7.52
(dd, J = 7.6 Hz, 1 H), 7.56–7.76 (br s, 1 H), 8.00–8.10 (m, 2 H),
10.15–10.40 (br s, 1 H), 10.65–10.80 (br s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 39.99, 78.19 (q, JCF = 28.5
1
Hz), 122.76, 123.12, 123.65, 125.05 (q, JCF = 288.4 Hz), 126.07,
126.87, 132.39, 135.23, 142.36, 146.98, 153.25, 169.92.
19F NMR (470 MHz, DMSO-d6): d = –77.48.
MS (APCI): m/z = 367 [M – 1].
2
13C NMR (125 MHz, DMSO-d6): d = 36.16, 76.72 (q, JCF = 28.5
1
Hz), 100.87, 122.53, 123.25, 124.11 (q, JCF = 287.6 Hz), 125.91,
126.60, 134.93, 149.01, 151.02, 152.66, 163.60, 168.99.
19F NMR (470 MHz, DMSO-d6): d = –78.36.
MS (APCI): m/z = 358 [M + 1].
2-(1,3-Benzoxazol-2-yl)-1,1,1-trifluoro-3-(4-nitrophenyl)pro-
pan-2-ol (3dk)
Yield: 78%; colorless crystals; mp 143–144 °C.
1H NMR (500 MHz, DMSO-d6): d = 3.56 (d, J = 14.0 Hz, 1 H), 3.73
(d, J = 14.0 Hz, 1 H), 7.35–7.51 (m, 4 H), 7.76 (d, J = 7.5 Hz, 1 H),
7.81 (d, J = 7.0 Hz, 1 H), 7.93 (s, 1 H), 8.04 (d, J = 9.0 Hz, 2 H).
4-[2-(1,3-Benzothiazol-2-yl)-3,3,3-trifluoro-2-hydroxypro-
pyl]phthalazin-1(2H)-one (3ch)
Yield: 80%; white powder; mp >220 °C.
2
13C NMR (125 MHz, DMSO-d6): d = 39.53, 76.06 (q, JCF = 28.5
1H NMR (500 MHz, DMSO-d6): d = 3.83 (d, J = 15.6 Hz, 1 H), 4.00
(d, J = 15.6 Hz, 1 H), 7.43 (dd, J = 6.8 Hz, 1 H), 7.50 (dd, J = 7.6
Hz, 1 H), 7.71–7.82 (m, 2 H), 7.81 (s, 1 H), 7.95–8.01 (m, 2 H), 8.05
(d, J = 6.8 Hz, 1 H), 8.15 (d, J = 7.6 Hz, 1 H), 12.43 (s, 1 H).
Hz), 111.71, 120.82, 123.22, 124.73 (q, JCF = 288.4 Hz), 125.61,
126.75, 132.36, 140.29, 142.24, 147.18, 150.69, 161.28.
19F NMR (470 MHz, DMSO-d6): d = –77.57.
MS (APCI): m/z = 353 [M + 1].
13C NMR (125 MHz, DMSO-d6): d = 36.03, 77.25 (q, JCF = 27.8
2
1
Hz), 122.21, 123.07, 124.59 (q, JCF = 288.0 Hz), 125.45, 125.53,
3-(1-Methyl-1H-imidazol-2-yl)-3-(trifluoromethyl)-3,4-dihy-
dro-1H-isochromen-1-one (5a)
125.85, 126.23, 127.35, 130.03, 131.23, 132.90, 134.98, 140.20,
152.81, 159.13, 170.86.
19F NMR (470 MHz, DMSO-d6): d = –77.38.
Yield: 40%; white powder; mp 158–160 °C (sublimed).
1H NMR (500 MHz, DMSO-d6): d = 3.74 (d, J = 16.0 Hz, 1 H), 3.79
(s, 3 H), 4.24 (d, J = 16.0 Hz, 1 H), 6.80 (s, 1 H), 7.17 (s, 1 H), 7.38
(dd, J = 8.0, 7.0 Hz, 1 H), 7.53 (d, J = 7.0 Hz, 1 H), 7.65 (dd,
J = 8.0, 7.0 Hz, 1 H), 7.86 (d, J = 8.0 Hz, 1 H).
MS (APCI): m/z = 392 [M + 1].
4-[2-(1,3-Benzothiazol-2-yl)-3,3,3-trifluoro-2-hydroxypropyl]-
2-methylphthalazin-1(2H)-one (3ci)
Yield: 53%; white powder; mp 216–217 °C.
1H NMR (500 MHz, DMSO-d6): d = 3.32 (s, 3 H), 3.86 (d, J = 15.4
Hz, 1 H), 4.02 (d, J = 15.4 Hz, 1 H), 7.44 (dd, J = 7.6 Hz, 1 H), 7.51
(dd, J = 7.8 Hz, 1 H), 7.74–7.84 (m, 2 H), 7.84 (s, 1 H), 7.98–8.04
(m, 2 H), 8.08 (d, J = 8.0 Hz, 1 H), 8.19 (d, J = 7.2 Hz, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 30.32, 35.27, 82.04 (q,
2JCF = 31.4 Hz), 122.66, 123.54 (q, JCF = 284.2 Hz), 126.86,
1
127.93, 128.33, 129.36, 129.94, 135.70, 137.64, 138.11, 161.33.
19F NMR (470 MHz, DMSO-d6): d = –78.04.
MS (APCI): m/z = 297 [M + 1].
13C NMR (125 MHz, DMSO-d6): d = 36.27, 38.93, 77.56 (q,
3-(1,3-Benzothiazol-2-yl)-3-(trifluoromethyl)-3,4-dihydro-1H-
isochromen-1-one (5b)
Yield: 79%; white powder; mp 144–145 °C.
1H NMR (500 MHz, DMSO-d6): d = 4.06 (d, J = 16.0 Hz, 1 H), 4.20
(d, J = 16.0 Hz, 1 H), 7.38 (dd, J = 7.5 Hz, 1 H), 7.47 (dd, J = 7.5
Hz, 1 H), 7.52 (dd, J = 7.5 Hz, 1 H), 7.55 (d, J = 7.5 Hz, 1 H), 7.62
(dd, J = 7.5 Hz, 1 H), 7.90 (d, J = 7.5 Hz, 1 H), 8.02 (d, J = 7.5 Hz,
1 H), 8.11 (d, J = 7.5 Hz, 1 H).
1
2JCF = 28.9 Hz), 122.62, 123.44, 125.00 (q, JCF = 288.0 Hz),
125.88, 126.05, 126.28, 126.68, 127.22, 129.92, 132.01, 133.28,
135.34, 139.92, 153.27, 158.50, 171.67.
19F NMR (470 MHz, DMSO-d6): d = –78.48.
MS (APCI): m/z = 406 [M + 1].
1-(1,3-Benzothiazol-2-yl)-1-(9H-fluoren-9-yl)-2,2,2-trifluoro-
ethanol (3cj)
Yield: 77%; colorless crystals; mp 163–164 °C.
1H NMR (500 MHz, DMSO-d6): d = 5.07 (s, 1 H), 6.80 (d, J = 8.0
Hz, 1 H), 7.10 (dd, J = 7.5 Hz, 1 H), 7.22 (dd, J = 7.5, 7.0 Hz, 1 H),
7.35 (dd, J = 7.5 Hz, 2 H), 7.46–7.50 (m, 2 H), 7.54 (dd, J = 7.5 Hz,
1 H), 7.80 (d, J = 7.5 Hz, 1 H), 7.82 (d, J = 7.5 Hz, 1 H), 7.87 (s, 1
H), 8.03 (d, J = 8.0 Hz, 1 H), 8.12 (d, J = 7.5 Hz, 1 H).
2
13C NMR (125 MHz, DMSO-d6): d = 30.88, 83.41 (q, JCF = 31.0
1
Hz), 122.70 (q, JCF = 285.5 Hz), 123.16, 123.28, 123.95, 127.00,
127.55, 128.90, 129.22, 130.04, 135.37, 135.82, 135.82, 152.59,
160.97, 165.00.
19F NMR (470 MHz, DMSO-d6): d = –77.86.
MS (APCI): m/z = 350 [M + 1].
2
13C NMR (125 MHz, DMSO-d6): d = 53.68, 80.18 (q, JCF = 27.7
1
Hz), 120.25, 120.28, 122.87, 123.80, 125.10 (q, JCF = 289.2 Hz),
References
126.32, 126.42, 126.95, 127.00, 127.41, 127.42, 128.46, 128.60,
135.35, 140.49, 141.23, 142.48, 142.68, 152.66, 170.89.
(1) (a) Singh, R. P.; Shreeve, J. M. Tetrahedron 2000, 56, 7613.
(b) Prakash, G. K. S.; Yudin, A. K. Chem. Rev. 1997, 97,
757. (c) Umemoto, T. Chem. Rev. 1996, 96, 1757.
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Chem. Rev. 1999, 437. (c) Bégué, J.-P.; Bonnet-Delpon, D.
Tetrahedron 1991, 47, 3207.
19F NMR (470 MHz, DMSO-d6): d = –71.81.
MS (APCI): m/z = 398 [M + 1].
2-(1,3-Benzothiazol-2-yl)-1,1,1-trifluoro-3-(4-nitrophenyl)pro-
pan-2-ol (3ck)
Yield: 33%; yellow powder; mp 123–124 °C.
Synthesis 2009, No. 7, 1099–1104 © Thieme Stuttgart · New York

1104
P. V. Khodakovskiy et al.
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Synthesis 2009, No. 7, 1099–1104 © Thieme Stuttgart · New York