Noncatalytic Electrophilic Oxyalkylation of Some Five-Membered Heterocycles with 2-(Trifluoroacetyl)-1,3-azoles

Abstract

A set of electrophilic 2-(trifluoroacetyl)-1,3-azoles demonstrated­ excellent activity in the C-oxyalkylation of pyrrole, furan, thiophene, 1,3-thiazole, and 1,2-oxazole derivatives. The reaction conditions and the yields of the corresponding trifluoromethyl-substituted alcohols depend strongly on both the electronic and steric nature of the 1,3-azole unit.

The substitution of fluorine for hydrogen is widely used to improve the pharmacological characteristics of organic compounds. [¹] Moreover, many commercially available pharmaceuticals are fluorine-containing, although fluorine scarcely occurs in organic matter. [²] The trifluoromethyl group, in particular, is one of the most attractive functional groups in organic chemistry, and incorporation of this group into organic compounds is still a topic of growing interest. [³] The commercially available trifluoro­methyl ketones hexafluoroacetone (1) and trifluoropyruvate (2) are highly valuable building blocks commonly used to prepare trifluoromethyl-containing compounds. [4] However, despite the great potential of both 1 and 2, the chemistry of other trifluoroacetyl ketones has received much less attention so far. [5]

Recently, we started a project aimed at the synthesis and application of various trifluoromethyl hetaryl ketones 3 (some representative examples are given in Scheme  [¹] ). [6] We have already shown that indole smoothly reacts with 3 to form the corresponding trifluoromethyl-substituted alcohols (Scheme  [¹] , reaction d). [6d] We report here on the extension of this strategy to other electron-rich heterocycles, namely pyrroles 4-8, furans 9 and 10, thiophenes 11-13, 1,3-thiazoles 14-18, and 1,2-oxazole 19 (Figure  [¹] ).

Among the many available representatives of 3 [6a] (Scheme  [¹] ), we chose highly reactive 2-(trifluoroacetyl)-1,3-benzothiazole (3a) as a model compound to test the potential of 4-19 in C-oxyalkylation reactions (Scheme 2).

As shown in Table  [¹] , all compounds 4-19 smoothly react with 3a under heating in toluene to provide the corresponding tertiary alcohols 4a-19a in moderate to excellent yields. The reaction conditions and the yields of the products depend strongly on both the electronic and steric nature of the starting heterocycles 4-19.

For example, the reaction of pyrrole derivative 4 with 3a was already completed after 30 minutes of heating in toluene at 60 ˚C (Table  [¹] ). However, pyrroles 5 and 6 bearing electron-accepting substituents and pyrroles 7 and 8 substituted at the α-positions required harsher conditions (100-120 ˚C, 2-4 h) (Table  [¹] ). Interestingly, the addition of 3a to thiazole 15 occurred more easily than the addition to thiazole 14 (Table  [¹] ). The presence of the methyl group adjacent to the reaction center in 14 hampers the reaction and deactivates the substrate. The reactions of 15-18 with 3a also illustrate the importance of steric effects. The yields of the alkylamino-substituted thiazoles 16a and 17a (99% and 76%, respectively) are significantly higher than those of amino-substituted product 15a (64%) and dialkyl­amino-substituted product 18a (52%) (Table  [¹] ). Obviously, incorporation of an electron-donating alkyl group instead of a hydrogen atom increases the reactivity of thiazoles 16 and 17 compared to 15. However, incorporation of a second bulky alkyl group already reduces the reactivity of 18 compared to 16 and 17.

Incorporation of the 3a moiety into 4-19 follows the general pattern of aromatic electrophilic substitution in the abovementioned heterocyclic systems. In pyrroles 4-6, furans 9 and 10, and thiophenes 11 and 12 the substitution occurs at the 2-position. However, if the 2-position is blocked (7,8,13), the substitution proceeds at the 3-position. The substitution in 15-18 occurs at the 5-position.

To demonstrate the applicability of this reaction to a wide variety of 2-(trifluoroacetyl)-1,3-azoles 3, we performed several syntheses with diverse ketones 3b-j (Figure  [²] ) with the electron-rich heterocycles 16 and 19 (Table  [²] ). The reaction was just as efficient as in the case of 3a (Table  [¹] ), and the corresponding products were obtained in 53-85% yield.

In summary, we have developed a very simple and efficient one-step procedure to prepare novel trifluoromethyl-substituted tertiary alcohols from various 2-(trifluoroacetyl)-1,3-azoles and derivatives of pyrrole, furan, thiophene, 1,3-thiazole, and 1,2-oxazole.

Table 1 Reaction Conditions for the Synthesis of Trifluoromethyl-Substituted Alcohols 4a-19a (continued)

Azole	Conditions	Product	Yield (%)
4	3a, toluene, 60 ˚C, 0.5 h		61
5	3a, toluene, 100 ˚C, 2 h		64
6	3a, toluene, 100 ˚C, 2 h		84
7	3a, toluene, 120 ˚C, 4 h		95
8	3a, toluene, 120 ˚C, 4 h		85
9	3a, toluene, 60 ˚C, 2 h		64
10	3a, toluene, 60 ˚C, 0.5 h		34
11	3a, toluene, 100 ˚C, 4 h		71
12	3a, toluene, 100 ˚C, 4 h		80
13	3a, toluene, 100 ˚C, 4 h		83
14	3a, toluene, 100 ˚C, 4 h		49
15	3a, toluene, 100 ˚C, 1 h		64
16	3a, toluene, 100 ˚C, 0.5 h		99
17	3a, toluene, 100 ˚C, 0.5 h		76
18	3a, toluene, 100 ˚C, 4 h		52
19	3a, toluene, 60 ˚C, 0.5 h		89

Table 2 Reaction Conditions for the Synthesis of Trifluoromethyl-Substituted Alcohols 16b,c and 19d-f,j

Azole	Conditions	Product	Yield (%)
16	3b, toluene, 100 ˚C, 0.5 h		76
16	3c, toluene, 100 ˚C, 0.5 h		85
19	3d, toluene, 60 ˚C, 0.5 h		74
19	3e, toluene, 60 ˚C, 0.5 h		81
19	3f, toluene, 60 ˚C, 0.5 h		53
19	3j, toluene, 60 ˚C, 0.5 h		72

2-(Trifluoroacetyl)-1,3-azoles 3 were prepared as described previously. [6a] ^¹H, ^¹³C, and ^¹9F NMR spectra were recorded on a Bruker Avance 500 spectrometer (at 499.9 MHz, 124.9 and 470.3 MHz, respectively). Chemical shifts are reported in ppm downfield from TMS (^¹H, ^¹³C) or CFCl₃ (^¹9F) as internal standards. Mass spectra (CI) were recorded on an Agilent 1100 LCMSD SL instrument.

Alcohols 4a-19a, 16b,c, and 19d-f,j; General Procedure

A mixture of the appropriate trifluoromethyl ketone 3 (1 mmol), the appropriate heterocycle 4-19 (1 mmol), and toluene (2 mL) was stirred under the corresponding conditions given in Table  [¹] or 2. The reaction mixture was cooled to r.t., and the crystalline solid that had formed was collected by filtration. The product was washed with CCl₄ on the filter, and recrystallized from i-PrOH.

1-(1,3-Benzothiazol-2-yl)-2,2,2-trifluoro-1-(1-methyl-1 H -pyrrol-2-yl)ethanol (4a)

Yield: 61%; colorless solid; mp 133 ˚C.

^¹H NMR (500 MHz, DMSO-d ₆): δ = 3.28 (s, 3 H), 6.02 (s, 1 H), 6.33 (s, 1 H), 6.79 (s, 1 H), 7.42 (dd, J = 8.0, 7.0 Hz, 1 H), 7.52 (dd, J = 7.5, 7.0 Hz, 1 H), 8.02 (d, J = 8.0 Hz, 1 H), 8.15 (d, J = 7.5 Hz, 1 H), 8.40 (s, 1 H).

^¹³C NMR (125 MHz, DMSO-d ₆): δ = 35.74, 76.53 (q, ^² J _CF = 30.2 Hz), 106.64, 110.65, 122.43, 123.87, 124.55 (q, ^¹ J _CF = 288.0 Hz), 126.21, 126.32, 126.44, 126.88, 135.72, 153.18, 170.75.

^¹9F NMR (470 MHz, DMSO-d ₆): δ = -74.58.

MS (CI): m/z = 313 [M + 1].

1-{5-[1-(1,3-Benzothiazol-2-yl)-2,2,2-trifluoro-1-hydroxyethyl]-2,4-dimethyl-1 H -pyrrol-3-yl}ethanone (5a)

Yield: 64%; colorless solid; mp 194-195 ˚C.

^¹H NMR (500 MHz, DMSO-d ₆): δ = 1.81 (s, 3 H), 2.29 (s, 3 H), 2.49 (s, 3 H), 7.52 (dd, J = 8.0, 7.5 Hz, 1 H), 7.58 (dd, J = 8.0, 7.5 Hz, 1 H), 8.11-8.17 (m, 2 H), 8.50 (s, 1 H), 11.18 (s, 1 H).

^¹³C NMR (125 MHz, DMSO-d ₆): δ = 12.18, 14.83, 31.54, 75.79 (q, ^² J _CF = 30.2 Hz), 120.08, 121.68, 122.25, 122.81, 124.11, 124.91 (q, ^¹ J _CF = 288.0 Hz), 126.60, 126.95, 135.45, 135.63, 152.31, 170.77, 194.58.

^¹9F NMR (470 MHz, DMSO-d ₆): δ = -75.13.

MS (CI): m/z = 369 [M + 1].

Ethyl 5-[1-(1,3-Benzothiazol-2-yl)-2,2,2-trifluoro-1-hydroxyethyl]-2,4-dimethyl-1 H -pyrrole-3-carboxylate (6a)

Yield: 84%; colorless solid; mp 168-169 ˚C.

^¹H NMR (500 MHz, DMSO-d ₆): δ = 1.21 (t, J = 7.0 Hz, 3 H), 1.80 (s, 3 H), 2.43 (s, 3 H), 4.11 (q, J = 7.0 Hz, 2 H), 7.52 (dd, J = 7.5 Hz, 1 H), 7.58 (dd, J = 7.5 Hz, 1 H), 8.10-8.17 (m, 2 H), 8.48 (s, 1 H), 11.19 (s, 1 H).

^¹³C NMR (125 MHz, DMSO-d ₆): δ = 11.50, 13.85, 14.80, 58.97, 75.55 (q, ^² J _CF = 30.6 Hz), 111.73, 120.43, 121.55, 122.80, 124.10, 124.89 (q, ^¹ J _CF = 288.0 Hz), 126.57, 126.93, 135.61, 135.98, 152.35, 165.46, 170.82.

^¹9F NMR (470 MHz, DMSO-d ₆): δ = -75.22.

MS (CI): m/z = 399 [M + 1].

1-(1,3-Benzothiazol-2-yl)-1-(1-cyclohexyl-2,5-dimethyl-1 H -pyrrol-3-yl)-2,2,2-trifluoroethanol (7a)

Yield: 95%; colorless solid; mp 148-149 ˚C.

^¹H NMR (500 MHz, DMSO-d ₆): δ = 1.16 (m, 1 H), 1.35 (m, 2 H), 1.63 (m, 1 H), 1.71 (m, 2 H), 1.79 (m, 2 H), 1.87 (m, 2 H), 2.06 (s, 3 H), 2.25 (s, 3 H), 3.91 (m, 1 H), 5.87 (s, 1 H), 7.47 (dd, J = 8.0, 7.5 Hz, 1 H), 7.52 (dd, J = 7.5 Hz, 1 H), 7.73 (s, 1 H), 8.02 (d, J = 7.5 Hz, 1 H), 8.12 (d, J = 8.0 Hz, 1 H).

^¹³C NMR (125 MHz, DMSO-d ₆): δ = 12.66, 14.76, 25.45, 26.46, 32.24, 56.08, 77.00 (q, ^² J _CF = 28.9 Hz), 107.57, 114.88, 122.65, 123.65, 125.28 (q, ^¹ J _CF = 288.0 Hz), 125.93, 126.62, 127.53, 135.38, 153.37, 173.51.

^¹9F NMR (470 MHz, DMSO-d ₆): δ = -74.79.

MS (CI): m/z = 409 [M + 1].

1-(1,3-Benzothiazol-2-yl)-1-[2,5-dimethyl-1-(4-tolyl)-1 H -pyrrol-3-yl]-2,2,2-trifluoroethanol (8a)

Yield: 85%; colorless solid; mp 148-149 ˚C.

^¹H NMR (500 MHz, DMSO-d ₆): δ = 1.77 (s, 3 H), 1.91 (s, 3 H), 2.34 (s, 3 H), 6.06 (s, 1 H), 7.06 (d, J = 7.5 Hz, 2 H), 7.28 (d, J = 7.5 Hz, 2 H), 7.46 (dd, J = 8.0, 7.0 Hz, 1 H), 7.52 (dd, J = 8.0, 7.0 Hz, 1 H), 7.85 (s, 1 H), 8.04 (d, J = 8.0 Hz, 1 H), 8.11 (d, J = 8.0 Hz, 1 H).

^¹³C NMR (125 MHz, DMSO-d ₆): δ = 12.44, 12.99, 21.09, 77.01 (q, ^² J _CF = 28.9 Hz), 106.58, 115.48, 122.67, 123.71, 125.34 (q, ^¹ J _CF = 288.0 Hz), 125.97, 126.67, 127.08, 128.03, 128.34, 130.37, 135.30, 135.37, 138.11, 153.44, 173.32.

^¹9F NMR (470 MHz, DMSO-d ₆): δ = -76.15.

MS (CI): m/z = 417 [M + 1].

1-(1,3-Benzothiazol-2-yl)-2,2,2-trifluoro-1-(5-methyl-2-furyl)ethanol (9a)

Yield: 64%; yellowish oil.

^¹H NMR (500 MHz, DMSO-d ₆): δ = 2.23 (s, 3 H), 6.14 (d, J = 2.4 Hz, 1 H), 6.49 (d, J = 2.4 Hz, 1 H), 7.50 (t, J = 7.6 Hz, 1 H), 7.55 (7, J = 7.6 Hz, 1 H), 8.06 (d, J = 7.6 Hz, 1 H), 8.17 (d, J = 7.6 Hz, 1 H), 8.61 (s, 1 H).

^¹³C NMR (125 MHz, DMSO-d ₆): δ = 13.77, 75.55 (q, ^² J _CF = 30.2 Hz), 107.38, 112.10, 122.81, 123.87, 124.05 (q, ^¹ J _CF = 288.0 Hz), 126.29, 126.93, 135.25, 147.09, 153.44, 153.67, 169.81.

^¹9F NMR (470 MHz, DMSO-d ₆): δ = -76.66.

MS (CI): m/z = 314 [M + 1].

5-[1-(1,3-Benzothiazol-2-yl)-2,2,2-trifluoro-1-hydroxyethyl]furan-2-carbaldehyde Dimethylhydrazone (10a)

Yield: 34%; colorless solid; mp 87-88 ˚C.

^¹H NMR (500 MHz, DMSO-d ₆): δ = 2.86 (s, 6 H), 6.46 (d, J = 3.2 Hz, 1 H), 6.64 (d, J = 3.2 Hz, 1 H), 7.09 (s, 1 H), 7.50 (dd, J = 7.6, 7.2 Hz, 1 H), 7.55 (dd, J = 7.6, 7.6 Hz, 1 H), 8.06 (d, J = 7.6 Hz, 1 H), 8.17 (d, J = 7.2 Hz, 1 H), 8.72 (s, 1 H).

^¹³C NMR (125 MHz, DMSO-d ₆): δ = 42.74, 42.75, 75.77 (q, ^² J _CF = 30.2 Hz), 106.76, 113.05, 122.03, 122.80, 123.89, 124.01 (q, ^¹ J _CF = 288.0 Hz), 126.34, 126.95, 135.34, 147.40, 153.40, 154.18, 169.64.

^¹9F NMR (470 MHz, DMSO-d ₆): δ = -76.30.

MS (CI): m/z = 370 [M + 1].

2-Amino-5-[1-(1,3-benzothiazol-2-yl)-2,2,2-trifluoro-1-hydroxyethyl]thiophene-3-carboxamide (11a)

Yield: 71%; colorless solid; mp 173-174 ˚C.

^¹H NMR (500 MHz, DMSO-d ₆): δ = 6.65-6.85 (br, 1 H), 7.10-7.60 (br, 3 H), 7.30 (s, 1 H), 7.49 (dd, J = 8.0, 7.0 Hz, 1 H), 7.56 (dd, J = 8.5, 7.0 Hz, 1 H), 8.07 (d, J = 8.5 Hz, 1 H), 8.15 (d, J = 8.0 Hz, 1 H), 8.57 (s, 1 H).

^¹³C NMR (125 MHz, DMSO-d ₆): δ = 77.03 (q, ^² J _CF = 30.2 Hz), 107.03, 117.57, 122.82, 123.87, 124.36 (q, ^¹ J _CF = 288.0 Hz), 126.30, 126.38, 126.94, 135.23, 153.38, 163.42, 167.87, 171.44.

^¹9F NMR (470 MHz, DMSO-d ₆): δ = -76.14.

MS (CI): m/z = 374 [M + 1].

Ethyl 2-Amino-5-[1-(1,3-benzothiazol-2-yl)-2,2,2-trifluoro-1-hydroxyethyl]thiophene-3-carboxylate (12a)

Yield: 80%; colorless solid; mp 161-162 ˚C.

^¹H NMR (500 MHz, DMSO-d ₆): δ = 1.23 (t, J = 7.0 Hz, 3 H), 4.16 (q, J = 7.0 Hz, 3 H), 7.09 (s, 1 H), 7.40 (br, 2 H), 7.51 (dd, J = 7.6, 7.2 Hz, 1 H), 7.57 (dd, J = 8.0, 7.2 Hz, 1 H), 8.09 (d, J = 8.0 Hz, 1 H), 8.17 (d, J = 7.6 Hz, 1 H), 8.71 (s, 1 H).

^¹³C NMR (125 MHz, DMSO-d ₆): δ = 14.90, 59.64, 76.90 (q, ^² J _CF = 30.2 Hz), 103.80, 118.12, 122.91, 123.80, 124.20 (q, ^¹ J _CF = 288.0 Hz), 126.36, 126.40, 127.08, 135.03, 153.34, 164.60, 165.43, 171.17.

^¹9F NMR (470 MHz, DMSO-d ₆): δ = -76.65.

MS (CI): m/z = 403 [M + 1].

Ethyl 5-Amino-4-[1-(1,3-benzothiazol-2-yl)-2,2,2-trifluoro-1-hydroxyethyl]-3-methylthiophene-2-carboxylate (13a)

Yield: 83%; colorless solid; mp >250 ˚C.

^¹H NMR (500 MHz, DMSO-d ₆): δ = 1.17 (m, 3 H), 1.73 (s, 3 H), 4.08 (m, 2 H), 6.96 (br, 2 H), 7.51 (m, 1 H), 7.57 (m, 1 H), 8.13 (m, 2 H), 8.64 (s, 1 H).

^¹³C NMR (125 MHz, DMSO-d ₆): δ = 14.80, 14.82, 59.96, 78.96 (q, ^² J _CF = 29.8 Hz), 106.62, 110.33, 122.92, 124.22, 125.75 (q, ^¹ J _CF = 288.0 Hz), 126.81, 127.06, 135.73, 146.99, 151.49, 161.27, 162.38, 170.90.

^¹9F NMR (470 MHz, DMSO-d ₆): δ = -75.43.

MS (CI): m/z = 417 [M + 1].

1-(2-Amino-4-methyl-1,3-thiazol-5-yl)-1-(1,3-benzothiazol-2-yl)-2,2,2-trifluoroethanol (14a)

Yield: 49%; colorless solid; mp 189-190 ˚C.

^¹H NMR (500 MHz, DMSO-d ₆): δ = 1.95 (s, 3 H), 6.98 (s, 2 H), 7.51 (m, 1 H), 7.57 (m, 1 H), 8.09 (m, 1 H), 8.16 (m, 1 H), 8.50 (s, 1 H).

^¹³C NMR (125 MHz, DMSO-d ₆): δ = 17.23, 76.54 (q, ^² J _CF = 30.6 Hz), 112.81, 122.86, 123.89, 124.89 (q, ^¹ J _CF = 288.0 Hz), 126.47, 127.00, 135.40, 148.74, 152.85, 167.97, 172.15.

^¹9F NMR (470 MHz, DMSO-d ₆): δ = -75.95.

MS (CI): m/z = 346 [M + 1].

1-(2-Amino-1,3-thiazol-5-yl)-1-(1,3-benzothiazol-2-yl)-2,2,2-trifluoroethanol (15a)

Yield: 64%; colorless solid; mp 168-169 ˚C.

^¹H NMR (500 MHz, DMSO-d ₆): δ = 7.10 (s, 1 H), 7.16 (s, 2 H), 7.51 (dd, J = 8.5, 6.5 Hz, 1 H), 7.57 (dd, J = 8.0, 6.5 Hz, 1 H), 8.08 (d, J = 8.5 Hz, 1 H), 8.17 (d, J = 8.0 Hz, 1 H), 8.65 (s, 1 H).

^¹³C NMR (125 MHz, DMSO-d ₆): δ = 76.37 (q, ^² J _CF = 31.0 Hz), 120.11, 122.89, 123.79, 124.27 (q, ^¹ J _CF = 288.0 Hz), 126.35, 127.02, 135.09, 139.60, 153.35, 171.13, 171.43.

^¹9F NMR (470 MHz, DMSO-d ₆): δ = -76.75.

MS (CI): m/z = 332 [M + 1].

1-(1,3-Benzothiazol-2-yl)-2,2,2-trifluoro-1-[2-(methylamino)-1,3-thiazol-5-yl]ethanol (16a)

Yield: 99%; colorless solid; mp 139-140 ˚C.

^¹H NMR (500 MHz, DMSO-d ₆): δ = 2.79 (d, J = 4.5 Hz, 3 H), 7.20 (s, 1 H), 7.51 (dd, J = 8.0, 7.0 Hz, 1 H), 7.57 (dd, J = 8.0, 7.0 Hz, 1 H), 7.69 (q, J = 4.5 Hz, 1 H), 8.09 (d, J = 8.0 Hz, 1 H), 8.17 (d, J = 8.0 Hz, 1 H), 8.69 (s, 1 H).

^¹³C NMR (125 MHz, DMSO-d ₆): δ = 31.22, 76.38 (q, ^² J _CF = 31.4 Hz), 119.69, 122.87, 123.82, 124.26 (q, ^¹ J _CF = 288.0 Hz), 126.36, 127.02, 135.09, 139.88, 153.34, 171.35, 171.89.

^¹9F NMR (470 MHz, DMSO-d ₆): δ = -76.73.

MS (CI): m/z = 346 [M + 1].

1-(1,3-Benzothiazol-2-yl)-1-[2-(cyclohexylamino)-1,3-thiazol-5-yl]-2,2,2-trifluoroethanol (17a)

Yield: 76%; colorless solid; mp 193-194 ˚C.

^¹H NMR (500 MHz, DMSO-d ₆): δ = 2.79 (d, J = 1.0 Hz, 3 H), 3.81 (s, 3 H), 6.80 (s, 1 H), 7.70 (q, J = 1.0 Hz, 1 H), 7.99 (s, 1 H), 8.21 (s, 1 H).

^¹³C NMR (125 MHz, DMSO-d ₆): δ = 31.16, 37.93, 73.66 (q, ^² J _CF = 31.0 Hz), 118.96, 124.29 (q, ^¹ J _CF = 288.0 Hz), 139.66, 149.79, 151.11, 171.90.

^¹9F NMR (470 MHz, DMSO-d ₆): δ = -77.29.

MS (CI): m/z = 294 [M + 1].

1-(1,3-Benzothiazol-2-yl)-1-[2-(diethylamino)-1,3-thiazol-5-yl]-2,2,2-trifluoroethanol (18a)

Yield: 52%; colorless solid; mp 128-129 ˚C.

^¹H NMR (500 MHz, DMSO-d ₆): δ = 1.11 (m, 6 H), 3.40 (m, 4 H), 7.27 (s, 1 H), 7.50 (m, 1 H), 7.56 (m, 1 H), 8.09 (d, J = 7.5 Hz, 1 H), 8.16 (d, J = 7.5 Hz, 1 H), 8.67 (s, 1 H).

^¹³C NMR (125 MHz, DMSO-d ₆): δ = 12.79, 45.40, 76.35 (q, ^² J _CF = 31.0 Hz), 119.70, 122.89, 123.87, 124.27 (q, ^¹ J _CF = 288.0 Hz), 126.38, 127.04, 135.09, 140.48, 153.36, 170.63, 171.32.

^¹9F NMR (470 MHz, DMSO-d ₆): δ = -76.79.

MS (CI): m/z = 388 [M + 1].

1-(5-Amino-3-methylisoxazol-4-yl)-1-(1,3-benzothiazol-2-yl)-2,2,2-trifluoroethanol (19a)

Yield: 89%; colorless solid; mp 227-228 ˚C.

^¹H NMR (500 MHz, DMSO-d ₆): δ = 1.68 (s, 3 H), 6.75 (s, 2 H), 7.48-7.66 (m, 2 H), 8.08-8.27 (m, 2 H), 8.50 (s, 1 H).

^¹³C NMR (125 MHz, DMSO-d ₆): δ = 11.83, 75.35 (q, ^² J _CF = 30.6 Hz), 86.11, 122.94, 124.04, 125.43 (q, ^¹ J _CF = 288.0 Hz), 126.74, 127.13, 135.25, 152.08, 159.11, 168.36, 171.24.

^¹9F NMR (470 MHz, DMSO-d ₆): δ = -76.69.

MS (CI): m/z = 330 [M + 1].

2,2,2-Trifluoro-1-[2-(methylamino)-1,3-thiazol-5-yl]-1-(1-methyl-1 H -1,2,4-triazol-5-yl)ethanol (16b)

Yield: 76%; colorless solid; mp 193-194 ˚C.

^¹H NMR (500 MHz, DMSO-d ₆): δ = 2.79 (d, J = 1.0 Hz, 3 H), 3.81 (s, 3 H), 6.80 (s, 1 H), 7.70 (q, J = 1.0 Hz, 1 H), 7.99 (s, 1 H), 8.21 (s, 1 H).

^¹³C NMR (125 MHz, DMSO-d ₆): δ = 31.16, 37.93, 73.66 (q, ^² J _CF = 31.0 Hz), 118.96, 124.29 (q, ^¹ J _CF = 288.0 Hz), 139.66, 149.79, 151.11, 171.90.

^¹9F NMR (470 MHz, DMSO-d ₆): δ = -77.29.

MS (CI): m/z = 294 [M + 1].

2,2,2-Trifluoro-1-[2-(methylamino)-1,3-thiazol-5-yl]-1-(5-phenyl-1,3-oxazol-2-yl)ethanol (16c)

Yield: 85%; colorless solid; mp 165-166 ˚C.

^¹H NMR (500 MHz, DMSO-d ₆): δ = 2.82 (s, 3 H), 7.10 (s, 1 H), 7.40 (t, J = 7.5 Hz, 1 H), 7.49 (dd, J = 7.5 Hz, 2 H), 7.68-7.78 (m, 3 H), 7.82 (s, 1 H), 8.15 (s, 1 H).

^¹³C NMR (125 MHz, DMSO-d ₆): δ = 31.21, 73.91 (q, ^² J _CF = 31.4 Hz), 119.10, 123.24, 124.04 (q, ^¹ J _CF = 288.0 Hz), 124.70, 127.34, 129.55, 129.65, 139.75, 152.26, 158.70, 171.71.

^¹9F NMR (470 MHz, DMSO-d ₆): δ = -77.72.

MS (CI): m/z = 356 [M + 1].

1-(5-Amino-3-methylisoxazol-4-yl)-2,2,2-trifluoro-1-(1-methyl-1 H -imidazol-2-yl)ethanol (19d)

Yield: 74%; colorless solid; mp 230-230 ˚C.

^¹H NMR (500 MHz, DMSO-d ₆): δ = 1.29 (s, 3 H), 3.45 (s, 3 H), 6.34 (s, 2 H), 6.88 (s, 1 H), 7.23 (s, 1 H), 7.74 (s, 1 H).

^¹³C NMR (125 MHz, DMSO-d ₆): δ = 10.03, 33.97, 72.24 (q, ^² J _CF = 30.6 Hz), 85.53, 124.35, 125.85 (q, ^¹ J _CF = 286.7 Hz), 126.07, 142.90, 158.81, 168.47.

^¹9F NMR (470 MHz, DMSO-d ₆): δ = -77.12.

MS (CI): m/z = 277 [M + 1].

1-(5-Amino-3-methylisoxazol-4-yl)-2,2,2-trifluoro-1-(1-vinyl-1 H -imidazol-2-yl)ethanol (19e)

Yield: 81%; colorless solid; mp 215-225 ˚C (sublimation).

^¹H NMR (500 MHz, DMSO-d ₆): δ = 1.25 (s, 3 H), 4.81 (d, J = 9.0 Hz, 1 H), 5.41 (d, J = 16.0 Hz, 1 H), 6.44 (s, 2 H), 7.03 (s, 1 H), 7.08 (dd, J = 16.0, 9.0 Hz, 1 H), 7.80 (s, 1 H), 8.04 (s, 1 H).

^¹³C NMR (125 MHz, DMSO-d ₆): δ = 9.83, 72.25 (q, ^² J _CF = 30.2 Hz), 85.99, 102.74, 118.62, 125.65 (q, ^¹ J _CF = 288.0 Hz), 127.62, 129.36, 142.62, 158.61, 168.26.

^¹9F NMR (470 MHz, DMSO-d ₆): δ = -77.10.

MS (CI): m/z = 289 [M + 1].

1-(5-Amino-3-methylisoxazol-4-yl)-1-[4-(1 H -benzimidazol-2-yl)-1,3-thiazol-2-yl]-2,2,2-trifluoroethanol (19f)

Yield: 53%; colorless solid; mp >250 ˚C.

^¹H NMR (500 MHz, DMSO-d ₆): δ = 1.84 (s, 3 H), 6.85 (br, 2 H), 7.32 (m, 2 H), 7.69 (m, 2 H), 8.50 (br, 1 H), 8.68 (s, 1 H).

^¹³C NMR (125 MHz, DMSO-d ₆): δ = 12.28, 75.09 (q, ^² J _CF = 31.4 Hz), 86.03, 115.62, 123.82, 123.96, 125.34 (q, ^¹ J _CF = 288.0 Hz), 137.77, 144.24, 146.00, 159.43, 168.17, 171.96.

^¹9F NMR (470 MHz, DMSO-d ₆): δ = -76.80.

MS (CI): m/z = 396 [M + 1].

1-(5-Amino-3-methylisoxazol-4-yl)-2,2,2-trifluoro-1-(4-methyl-5-phenyl-4 H -1,2,4-triazol-3-yl)ethanol (19j)

Yield: 72%; colorless solid; mp 201-202 ˚C.

^¹H NMR (500 MHz, DMSO-d ₆): δ = 1.43 (s, 3 H), 3.50 (s, 3 H), 6.58 (s, 2 H), 7.58 (m, 3 H), 7.69 (m, 2 H), 8.15 (s, 1 H).

^¹³C NMR (125 MHz, DMSO-d ₆): δ = 10.36, 32.58, 71.57 (q, ^² J _CF = 31.4 Hz), 83.69, 125.46 (q, ^¹ J _CF = 288.0 Hz), 126.98, 129.36, 129.45, 130.71, 151.13, 156.26, 158.21, 168.94.

^¹9F NMR (470 MHz, DMSO-d ₆): δ = -77.16.

MS (CI): m/z = 354 [M + 1].

References

• 1a O’Hagan D. Rzepa HS. Chem. Commun.  1997,  645 
• 1b Kirsch P. In Modern Fluoroorganic Chemistry   Wiley-VCH; Weinheim: 2004. 
• 1c Smits R. Damiano Cadicamo C. Burger K. Koksch B. Chem. Soc. Rev.  2008,  37:  1727 
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• 1d Qiu X.-L. Meng W.-D. Qing F.-L. Tetrahedron  2004,  60:  6711 
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• 1e Dave R. Badet B. Meffre P. Amino Acids  2004,  24:  245 
  Search in Google Scholar
• 1f Kukhar VP. Soloshonok VA. Fluorine-Containing Amino Acids   John Wiley and Sons; New York: 1995. 
• 2a Harper DB. O’Hagan D. Nat. Prod. Rep.  1994,  123 
• 2b Murphy CD. Schaffrath C. O’Hagan D. Chemosphere  2003,  455 
• 3a Singh RP. Shreeve JM. Tetrahedron  2000,  56:  7613 
  Search in Google Scholar
• 3b Prakash GKS. Yudin AK. Chem. Rev.  1997,  97:  757 
  Search in Google Scholar
• 3c Umemoto T. Chem. Rev.  1996,  96:  1757 
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• 3d Burton DJ. Yang Z.-Y. Tetrahedron  1992,  48:  189 
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• 3e McClinton MA. McClinton DA. Tetrahedron  1992,  48:  6555 
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• 4a Lin P. Jiang J. Tetrahedron  2000,  56:  3635 
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• 4b Nenaidenko VG. Sanin AV. Balenkova ES. Russ. Chem. Rev.  1999,  437 
• 4c Bégué J.-P. Bonnet-Delpon D. Tetrahedron  1991,  47:  3207 
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• 4d Dolenský B. Kvíčala J. Paleček J. Paleta O. J. Fluorine Chem.  2002,  115:  67 
  Search in Google Scholar
• 4e Friezer RW. Ducharme Y. Ball RG. Blouin M. Boulet L. Côté B. Frenette R. Girard M. Guay D. Huang Z. Jones TR. Laliberté F. Lynch JJ. Mancini J. Martins E. Masson P. Muise E. Pon DJ. Siegl PKS. Styhler A. Tsou NN. Turner MJ. Young RN. Girard Y. J. Med. Chem.  2003,  46:  2413 
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• 4f Middleton L. J. Am. Chem. Soc.  1964,  86:  4948 
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• 4g Palecek J. Paleta O. Synthesis  2004,  521 
• 4h Braun RA. J. Org. Chem.  1966,  31:  3828 
  Search in Google Scholar
• 4i Ohkura H. Berbasov DO. Soloshonok VA. Tetrahedron  2003,  59:  1647 
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• 5a Regel E. Buechel KH. Liebigs Ann. Chem.  1977,  145 
• 5b Kawase M. Sakagami H. Kusama K. Motohashi N. Saito S. Bioorg. Med. Chem. Lett.  1999,  9:  3113 
  Search in Google Scholar
• 5c Fujii S. Maki Y. Kimoto H. J. Fluorine Chem.  1987,  35:  437 
  Search in Google Scholar
• 5d Salvador RL. Saucier M. Tetrahedron  1971,  27:  1221 
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• 6a Khodakovskiy PV. Volochnyuk DM. Panov DM. Pervak II. Zarudnitskii EV. Shishkin OV. Yurchenko AA. Shivanyuk A. Tolmachev AA. Synthesis  2008,  948 
• 6b Khodakovskiy PV. Volochnyuk DM. Tolmachev AA. Synthesis  2009,  1099 
• 6c Khodakovskiy PV. Volochnyuk V. Shivanyuk A. Shishkin OV. Tolmachev AA. Synthesis  2008,  3245 
• 6d Khodakovskiy PV. Mykhailiuk PK. Volochnyuk DM. Tolmachev AA. Synthesis  2010, DOI: 10.1055/s-0029-1219219

References

• 1a O’Hagan D. Rzepa HS. Chem. Commun.  1997,  645 
• 1b Kirsch P. In Modern Fluoroorganic Chemistry   Wiley-VCH; Weinheim: 2004. 
• 1c Smits R. Damiano Cadicamo C. Burger K. Koksch B. Chem. Soc. Rev.  2008,  37:  1727 
  Search in Google Scholar
• 1d Qiu X.-L. Meng W.-D. Qing F.-L. Tetrahedron  2004,  60:  6711 
  Search in Google Scholar
• 1e Dave R. Badet B. Meffre P. Amino Acids  2004,  24:  245 
  Search in Google Scholar
• 1f Kukhar VP. Soloshonok VA. Fluorine-Containing Amino Acids   John Wiley and Sons; New York: 1995. 
• 2a Harper DB. O’Hagan D. Nat. Prod. Rep.  1994,  123 
• 2b Murphy CD. Schaffrath C. O’Hagan D. Chemosphere  2003,  455 
• 3a Singh RP. Shreeve JM. Tetrahedron  2000,  56:  7613 
  Search in Google Scholar
• 3b Prakash GKS. Yudin AK. Chem. Rev.  1997,  97:  757 
  Search in Google Scholar
• 3c Umemoto T. Chem. Rev.  1996,  96:  1757 
  Search in Google Scholar
• 3d Burton DJ. Yang Z.-Y. Tetrahedron  1992,  48:  189 
  Search in Google Scholar
• 3e McClinton MA. McClinton DA. Tetrahedron  1992,  48:  6555 
  Search in Google Scholar
• 4a Lin P. Jiang J. Tetrahedron  2000,  56:  3635 
  Search in Google Scholar
• 4b Nenaidenko VG. Sanin AV. Balenkova ES. Russ. Chem. Rev.  1999,  437 
• 4c Bégué J.-P. Bonnet-Delpon D. Tetrahedron  1991,  47:  3207 
  Search in Google Scholar
• 4d Dolenský B. Kvíčala J. Paleček J. Paleta O. J. Fluorine Chem.  2002,  115:  67 
  Search in Google Scholar
• 4e Friezer RW. Ducharme Y. Ball RG. Blouin M. Boulet L. Côté B. Frenette R. Girard M. Guay D. Huang Z. Jones TR. Laliberté F. Lynch JJ. Mancini J. Martins E. Masson P. Muise E. Pon DJ. Siegl PKS. Styhler A. Tsou NN. Turner MJ. Young RN. Girard Y. J. Med. Chem.  2003,  46:  2413 
  Search in Google Scholar
• 4f Middleton L. J. Am. Chem. Soc.  1964,  86:  4948 
  Search in Google Scholar
• 4g Palecek J. Paleta O. Synthesis  2004,  521 
• 4h Braun RA. J. Org. Chem.  1966,  31:  3828 
  Search in Google Scholar
• 4i Ohkura H. Berbasov DO. Soloshonok VA. Tetrahedron  2003,  59:  1647 
  Search in Google Scholar
• 5a Regel E. Buechel KH. Liebigs Ann. Chem.  1977,  145 
• 5b Kawase M. Sakagami H. Kusama K. Motohashi N. Saito S. Bioorg. Med. Chem. Lett.  1999,  9:  3113 
  Search in Google Scholar
• 5c Fujii S. Maki Y. Kimoto H. J. Fluorine Chem.  1987,  35:  437 
  Search in Google Scholar
• 5d Salvador RL. Saucier M. Tetrahedron  1971,  27:  1221 
  Search in Google Scholar
• 6a Khodakovskiy PV. Volochnyuk DM. Panov DM. Pervak II. Zarudnitskii EV. Shishkin OV. Yurchenko AA. Shivanyuk A. Tolmachev AA. Synthesis  2008,  948 
• 6b Khodakovskiy PV. Volochnyuk DM. Tolmachev AA. Synthesis  2009,  1099 
• 6c Khodakovskiy PV. Volochnyuk V. Shivanyuk A. Shishkin OV. Tolmachev AA. Synthesis  2008,  3245 
• 6d Khodakovskiy PV. Mykhailiuk PK. Volochnyuk DM. Tolmachev AA. Synthesis  2010, DOI: 10.1055/s-0029-1219219