Checked by Hiroshi Nakagawa and Jonathan A. Ellman.
1. Procedure
2. Notes
1.
Sodium hydride (dispersion, 60% in oil) was purchased from the Aldrich Chemical Company, Inc. and was used as received. When using 60% dispersions, the submitters have found the need to add 1.2 equiv. Consequently for the chemistry of Step A the submitters have found that the reaction proceeds to completion more reliably with a total of 2.4 equiv of NaH.
2.
Hexanes (HPLC Grade) was purchased from EMD and was used as received.
3.
Drisolv®
THF (99.9%) was purchased from EMD and was used as received.
4.
3'-Bromo-acetophenone (99%) was purchased from the Aldrich Chemical Company, Inc. and was used as received.
5.
2-Chloro-5-(trifluoromethyl)pyridine was purchased from the Aldrich Chemical Company, Inc. and was used as received.
6.
Aqueous saturated brine solution was added dropwise to minimize the exotherm.
7.
Submitters made proton and carbon assignments using 2D NMR and found product
1 exists as an approximate 7:3 keto/enol tautomeric mixture: mp 85-86 °C; IR (film) cm
-1 1603, 1547, 1477, 1323, 1259, 1161, 1116, 1075, 1058; TLC: R
f = 0.52 (silica gel, 4:1 hexanes:ethyl acetate);
1H NMR
pdf (400 MHz, DMSO-
d6) δ: 4.71 (s, 0.5 H), 6.58 (s, 0.75 H), 7.39 (m, 1.5 H), 7.49(t, 0.25 H,
J = 8.0 Hz), 7.62 (m, 1 H), 7.82 (m, 1 H), 7.98 (m, 1 H), 8.07 (d, 0.75 H,
J = 8.0 Hz), 8.14 (m, 0.5 H), 8.74 (br s, 0.75 H), 8.85 (br s, 0.25 H), 14.97 (br s, 0.75 H);
13C NMR
pdf (100 MHz, DMSO-
d6) δ: 47.8, 94.9, 120.0 (q), 122.5, 122.6, 122.7, 122.9, 123.6, 124.0, 124.9, 125.4, 127.8, 128.1, 128.5, 131.1, 131.2, 131.4, 133.2, 134.2 (q), 134.9 (q), 136.5, 138.2, 138.7, 142.3 (q), 146.1 (q), 160.6, 164.9, 195.9;
19F NMR
pdf (376 MHz, DMSO-
d6) δ: -60.03, -60.06; LRMS (ESI)
m/z (%): 344 (100), 345 (17), 346 (100), 347 (17); HRMS (FAB)
m/z M
+ calcd for C
14H
9BrF
3NO: 342.9820. Found: 342.9825. Anal. Calcd for C
14H
9BrF
3NO: C, 48.86; H, 2.64; N, 4.07. Found: C, 48.82; H, 2.69; N, 4.07.
8.
Methanol was purchased from EMD and was used as received.
9.
Sodium hydroxide (2.50 ± 0.02 M) was purchased from VWR and was used as received.
10.
Hydroxylamine hydrochloride (98%) was purchased from the Aldrich Chemical Company, Inc. and was used as received.
11.
The submitters found that extended reaction time is required when less than 5 equiv of hydroxylamine hydrochloride is used. For example, 3 equiv of hydroxylamine hydrochloride required 24 h at 70 °C to reach completion. In addition, test reactions demonstrated that the use of at least 2.5 equiv of hydroxylamine hydrochloride was necessary for the reaction to reach completion.
12.
The submitters obtained a white flocculent solid (12.0 g, 76%) out of the reaction solution, which was used without purification in the next step.
13.
The oxime (
2) exhibits the following characteristics: mp 123-125 °C; IR (film) cm
-1 3002, 2835, 1610, 1324, 1176, 1164, 1127, 1081, 1059, 1028; TLC: R
f = 0.33 (silica gel, 4:1 hexanes:ethyl acetate);
1H NMR
pdf (400 MHz, DMSO-
d6) δ: 4.35 (s, 2 H), 7.30 (t, 1 H,
J = 8.0 Hz), 7.52 (m, 2 H), 7.68 (d, 1 H,
J = 8.0 Hz), 7.87 (s, 1 H), 8.08 (d, 1 H,
J = 8.0 Hz), 8.83 (br s, 1 H), 11.75 (br s, 1 H);
13C NMR
pdf (100 MHz, DMSO-
d6) δ: 34.3, 122.2, 123.8, 125.5, 128.9, 131.0, 131.9, 134.5 (q), 138.7, 146.2 (q), 152.6, 162.5;
19F NMR
pdf (376 MHz, DMSO-
d6) δ: -59.99; LRMS (ESI)
m/z (%): 359 (100), 360 (17), 361 (100), 362 (17); HRMS (FAB)
m/z [M+H]
+ calcd for C
14H
11BrF
3N
2O: 359.0005 found: 359.0006. Anal. Calcd for C
14H
10BrF
3N
2O: C, 46.82; H, 2.82; N, 7.80. Found: C, 46.55; H, 2.68; N, 7.67.
14.
The submitters reported yields that ranged from 65-81% for this step, with decreasing returns as the reaction scale was increased. The submitters also reported that the oxime (
2) could be efficiently converted back to ketone (
1) by treatment with 1:1 water:acetone and a few drops of 4M HCl at 50°C for 24 h.
15.
Dry dichloromethane (99.8%) was purchased from the Aldrich Chemical Company, Inc. and was used as received.
16.
Triethylamine was purchased from the Aldrich Chemical Company, Inc. and was used as received.
17.
Trifluoroacetic anhydride was purchased from the Aldrich Chemical Company, Inc. and was used as received.
18.
Trifluoroacetic anhydride is volatile under these conditions; the addition should be made slowly and carefully.
19.
The azirine (
3) exhibits the following characteristics: IR (film)
cm
-1 1736, 1604, 1323, 1162, 1123, 1077; TLC: R
f = 0.30 (silica gel, 9:1 hexanes:ethyl acetate);
1H NMR
pdf (400 MHz, DMSO-
d6) δ: 3.63 (s, 1 H), 7.57 (t, 1 H,
J = 8.0 Hz), 7.59 (d, 1 H,
J = 8 Hz), 7.87 (d, 1 H,
J = 8.0 Hz), 7.91 (d, 1 H,
J = 8.0 Hz, 1 H), 8.07 (m, 1 H), 8.09 (dm 1 H,
J = 8.0 Hz), 8.76 (s, 1 H);
13C NMR
pdf (100 MHz, DMSO-
d6) δ: 35.3, 122.2, 122.9, 123.0, 123.9 (q), 125.5, 129.2, 132.1, 132.6, 134.2 (q), 136.8, 146.2 (q), 160.4, 164.4;
19F NMR
pdf (376 MHz, DMSO-
d6) δ: -60.04; LRMS (ESI)
m/z (%): 341 (100), 342 (17), 343 (100), 344 (17); HRMS (FAB)
m/z [M+H]
+ calcd for C
14H
9BrF
3N
2: 340.9901 found: 340.9895. Anal. Calcd for C
14H
8BrF
3N
2: C, 49.29; H, 2.36; N, 8.21. Found: C, 49.37; H, 2.38; N, 7.96. The submitters observed that the product solidified over time: mp 123-125 °C;
20.
1,2-Dichloroethane (99.8%) was purchased from the Aldrich Chemical Company, Inc. and was used as received.
21.
Safety precautions should always be taken with any "sealed flask" reaction. The microwave reactor has a built-in "blast shield" and an automatic shut-off when a pressure is over the instrument maximum setting. Solvent choice can be a very important factor in microwave chemistry as the vapor pressure buildup must be taken into consideration as the reaction is heated. 1,2-Dichloroethane was used in Step D because it can be heated high enough to facilitate the desired transformation while maintaining a safe vapor pressure.
22.
The submitters reported that 1,2,4-trichlorobenzene was a suitable solvent under conventional refluxing conditions and that diglyme and 1,2,4-trichlorobenzene proved to be suitable alternatives under microwave conditions. The detailed procedure described herein provided the highest conversion and yield of the desired product. Because the microwave reactor has a maximum volume of 20 mL, the checkers ran three identical reactions of 2.2 g, and the submitters ran two identical reactions of 3.3 g. The submitters also reported that the transformation of azirine (
3) to pyrazolo[1,5-a]pyridine (
4) is much cleaner when the microwave is used for 1 h instead of conventional heating for longer times.
23.
The pyrazolo[1,5-a]pyridine (
4) exhibits the following characteristics: mp 59-60 °C; IR (film) cm
-1 1647, 1460, 1334, 1321, 1157, 1112, 1076, 1052; TLC: R
f = 0.38 (silica gel, 4:1 hexanes:ethyl acetate);
1H NMR
pdf (400 MHz, DMSO-
d6) δ: 7.24 (s, 1 H), 7.35 (d, 1 H,
J = 9.2 Hz), 7.39 (t, 1 H,
J = 8.0 Hz), 7.54 (d, 1 H,
J = 8.0 Hz), 7.81 (d, 1 H,
J = 9.2 Hz), 7.95 (d, 1 H,
J = 8.0 Hz), 8.12 (m, 1 H), 9.26 (s, 1 H);
13C NMR
pdf (100 MHz, DMSO-
d6) δ: 96.3, 115.3 (q), 119.7, 122.7, 122.7, 125.4, 125.6, 128.5 (q), 129.1, 131.4, 132.1, 134.7, 142.1, 153.6;
19F NMR
pdf (376 MHz, DMSO-
d6) δ: -59.73; LRMS (ESI)
m/z (%): 341 (100), 342 (25), 343 (83), 344 (17); HRMS (FAB)
m/z M
+ calcd for C
14H
8BrF
3N
2: 339.9823 found: 339.9827. Anal. Calc for C
14H
8BrF
3N
2: C, 49.29; H, 2.36; N, 8.21. Found: C, 49.26; H, 2.33; N, 8.11.
24.
The submitters made proton and carbon assignments based on correlations in the TOCSY, gCOSY, NOESY, gHSQC, and gHMBC experiments that fully support the structure (2D NMR data not shown).
The procedures in this article are intended for use only by persons with prior training in experimental organic chemistry. All hazardous materials should be handled using the standard procedures for work with chemicals described in references such as "Prudent Practices in the Laboratory" (The National Academies Press, Washington, D.C., 2011 www.nap.edu). All chemical waste should be disposed of in accordance with local regulations. For general guidelines for the management of chemical waste, see Chapter 8 of Prudent Practices.
These procedures must be conducted at one's own risk. Organic Syntheses, Inc., its Editors, and its Board of Directors do not warrant or guarantee the safety of individuals using these procedures and hereby disclaim any liability for any injuries or damages claimed to have resulted from or related in any way to the procedures herein.
3. Discussion
Azirine intermediates in the synthesis of the complex pyrazolo[1,5-a]pyridine heterocycle are utilized because the method is facile and the intramolecular nature allows control of substituent regiochemistry on the resulting bicycle (the CF3 group in 4, for example). Thermal reactions of azirines involve regioselective ring opening to form highly reactive nitrene intermediates. With appropriately substituted pyridyl azirines, the electrophilic nitrene can be intercepted by the pyridyl nitrogen to give the bicyclic pyrazolo[1,5-a]pyridine with predictable substitution patterns based on the original pyridyl substitution. The most common side products derive from nitrene dimerization. The product resulting from formal C-H insertion is rarely seen in appreciable quantity.
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