Pd-Catalyzed R-Arylation of N-Boc-Pyrrolidine
Impurities Generated in the Coupling Reaction (Chart 1). A
portion of the mother liquors from the crystallization of compound
5 (see above) was concentrated and separated by flash chromatog-
raphy on silica gel (hexane/EtOAc 4:1 to neat EtOAc) followed
by mass-directed reverse phase preparative HPLC in the case of
18, 19, and 20 to provide the following compounds: 2,3-dihydro-
stirred for 1 h. The brown suspension was filtered, and the filter
cake was washed with 2:1 H2O:i-PrOH (7 L). The cake was dried
under a stream of nitrogen overnight and in a 35 °C vacuum oven
at 65 mmHg with nitrogen flow for an additional night. Mother
liquor loss: 8.3%. The product was obtained as 2.45 kg of a light
brown dusty solid (87%); 99.1 wt %; 99.7% LCAP; 99.3% ee
(Chiralpak AD-H; 250 × 4.6 mm; 1.5 mL/min; 210 nm; isocratic
30% MeOH/ 70% CO2; major (R)-21: 3.6 min; minor (S)-21: 5.4
min); 63 ppm Pd: mp 140-142 °C; [R]20D +97.6 (c 1.48, MeOH);
IR (film) 2054.5, 2894.3, 1688.9, 1528.0, 1400.3, 1265.6, 1166.4,
1
pyrrole-1-carboxylic acid tert-butyl ester (17): H NMR spectrum
matched the reported data.19 3-(4-Amino-2-fluorophenyl)pyrroli-
dine-1-carboxylic acid tert-butyl ester (18), a viscous oil: 1H NMR
(400 MHz, CDCl3) δ 6.99 (br t, J ) 8.1 Hz, 1H), 6.43 (br d, J )
8.1 Hz, 1H) 6.39 (dd, J ) 12.2, 2.3 Hz, 1H), 3.85-3.19 (m, 7 H),
2.25-2.13 (m, 1H), 2.04-1.92 (m, 1H), 1.50 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 161.8 (d, J ) 244 Hz), 154.6, 146.9, 146.8,
128.3, 117.3, 110.77, 110.75, 102.4, 102.1, 79.1, 51.4, 50.7, 45.7,
45.4, 37.1, 36.3, 32.2, 31.2, 28.6; 19F NMR (377 MHz, CDCl3) δ
-117.1, -117.3; the compound exhibited two amide rotamers in
the NMR spectra; the structure of 18 was further confirmed by
HMBC and NOE experiments (see Supporting Information); HRMS
1
743.1, 704.8 cm-1; H NMR (400 MHz, CDCl3) δ 10.03 (br s,
1H), 8.60 (d, 1H, J ) 4.3 Hz), 8.27 (d, 1H, J ) 7.8 Hz), 7.90 (t,
1H, J ) 7.4 Hz), 7.80 - 7.62 (m, 1H), 7.48 (m, 1H), 7.33 (d, 1H,
J ) 7.8 Hz), 7.19 (m, 1H), 5.15 (br s, 0.3H), 5.03 (br s, 0.7H),
3.70-3.50 (m, 2H), 2.30 (br s, 1H), 1.88 (br s, 3H), 1.46 (br s,
3H), 1.22 (br s, 6H); 13C NMR (100 MHz, CDCl3) δ 162.2, 162.1,
159.8 (d, J ) 244.5 Hz), 159.7 (d, J ) 244.3 Hz), 154.6, 154.5,
149.3, 149.2, 148.1, 148.1, 138.0, 138.0, 137.6 (d, J ) 11.0 Hz),
137.4 (d, J ) 11.2 Hz), 127.5 (d, J ) 13.9 Hz), 127.2 (d, J ) 5.9
Hz), 127.0, 126.9, 126.8 (d, J ) 5.9 Hz), 126.6 (d, J ) 14.0 Hz),
122.5, 122.5, 114.9 (d, J ) 2.8 Hz), 114.7 (d, J ) 2.7 Hz), 107.4
(d, J ) 26.5 Hz), 106.8 (d, J ) 27.1 Hz), 79.7, 79.6, 55.3, 55.0,
47.2, 46.9, 34.5, 33.4, 28.6, 28.3, 27.1, 23.6, 23.4; 19F NMR (377
MHz, CDCl3) δ -116.90, -117.96; the compound exhibited two
amide rotamers in the NMR spectra. Anal. Calcd for C21H24FN3O3:
C, 65.44; H, 6.28; N, 10.90. Found: C, 65.33; H, 6.10; N, 10.84.
+
(ESI+) [MNa]+ calcd for C15H21FNaN2O2 303.14793; found
1
303.1488. 4-sec-Butyl-3-fluoroaniline (19), an oil: H NMR (400
MHz, CDCl3) δ 7.00 (t, J ) 8.3 Hz, 1H), 6.46 (dd, J ) 8.3, 2.4
Hz, 1H), 6.39 (dd, J ) 12.1, 2.4 Hz, 1H), 3.65 (br s, 2H), 2.91
(sextet, J ) 7.0 Hz, 1H), 1.62 (pent, J ) 7.4 Hz, 2H), 1.26 (d, J )
6.8 Hz, 3H), 0.88 (t, J ) 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 161.5 (d, J ) 242 Hz), 145.6 (d, J ) 12 Hz), 128.5 (d, J ) 7
Hz), 123.7 (d, J ) 16 Hz), 110.9 (d, J ) 2 Hz), 102.3 (d, J ) 26
Hz), 33.7, 30.16, 20.78, 12.15; 19F NMR (377 MHz, CDCl3) δ
-118.8; HRMS (ESI+) [MH]+ calcd for C10H15FN+ 168.11830;
Pyridine-2-carboxylic acid [4-((R)-1-acetylpyrrolidin-2-yl)-3-
fluorophenyl]amide. A 75 L four-neck round-bottom flask equipped
with a thermocouple, mechanical stirrer, and nitrogen inlet was
charged with 5 M aq HCl (12.4 L, 61.9 mol) and cooled to 0 °C.
Compound 21 (2.39 kg, 6.19 mol) was added in portions over 25
min while maintaining the internal temperature at 0 °C. The reaction
was stirred for 2 h at an internal temperature range of 5-10 °C
and then at 20 °C for 2 h. Upon completion of the reaction (HPLC),
the reaction was cooled again to 0 °C. CH2Cl2 (12 L) was added,
and the pH was raised to 14 with 10 M NaOH (6.31, 63.1 mol)
solution while maintaining the temperature at 0 °C. All suspended
solids dissolved at this point. Acetic anhydride (717 mL, 7.43 mol)
was added over 10 min, and the pH was adjusted to 14 with
additional 10 M NaOH solution (1 L). The reaction was allowed
to warm to room temperature and was stirred overnight. The
reaction mixture was pumped into a 100 L extractor, and the
reaction flask was washed with H2O (16 L) and CH2Cl2 (4 L). The
layers were allowed to separate, and the organic phase was removed.
The aq phase was extracted with CH2Cl2 (12 + 12 L). Total aqueous
losses were <0.01%. The organic phase was transferred into a 75
L four-neck round-bottom flask and concentrated to a volume of 6
L (2 mL/g) using a batch concentrator at a vacuum of 14 in Hg
and an internal temperature of 25 °C. The resulting solution was
used directly in the next step. For analytical purposes, the compound
could be isolated by flash chromatography as a white amorphous
1
found 168.1189. 4-n-Butyl-3-fluoroaniline (20), an oil: H NMR
(400 MHz, CDCl3) δ 6.94 (t, J ) 8.3 Hz, 1H), 6.42-6.35 (m, 2H),
3.65 (br s, 2H), 2.53 (t, J ) 7.8 Hz, 2H), 1.60-1.52 (m, 2H),
1.42-1.33 (m, 2H), 0.94 (t, J ) 7.3 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 161.8 (d, J ) 243 Hz), 145.9 (d, J ) 11 Hz), 131.1 (d,
J ) 7 Hz), 119.3 (d, J ) 17 Hz), 110.7 (d, J ) 3 Hz), 102.3 (d, J
) 26 Hz), 32.7, 28.0, 22.4, 14.0; 19F NMR (377 MHz, CDCl3) δ
-119.1; HRMS (ESI+) [MH]+ calcd for C10H15FN+ 168.11830;
found 168.1188.
(R)-2-{2-Fluoro-4-[(pyridine-2-carbonyl)amino]phenyl}pyrrolidine-
1-carboxylic acid tert-butyl ester (21). A 75 L round-bottom flask
equipped with a thermocouple, mechanical stirrer, and nitrogen inlet
was charged with CH3CN (20 L) and picolinic acid (1.28 kg, 10.28
mol). Thionyl chloride (750 mL, 10.28 mol) was added to the
suspension while maintaining the internal temperature at 20 °C over
30 min. The resulting thick suspension was stirred at 20 °C for 1 h
during which time it turned from white to pale green to light yellow,
and SO2 gas evolved. The reaction was cooled to 0 °C by adding
dry ice to the acetone bath. NEt3 (4.12 L, 29.38 mol) was added
over 45 min while maintaining the internal temperature at 0 °C.
Immediately upon completion of the NEt3 charge, addition of aniline
5 was started in portions over 20 min while maintaining the internal
temperature between 10 and 16 °C. The thick, brown suspension
was stirred for an additional 90 min at 15 °C after which time HPLC
analysis showed complete conversion of 5. The reaction was
quenched by careful addition of 2 M aq NH4Cl (8 L) and dilution
with MTBE (8 L). The organic layer turned dark red in color and
all suspended solids dissolved. The biphasic mixture was pumped
into a 100 L cylindrical extractor, and the flask was rinsed with an
additional 2 M NH4Cl (8 L) and MTBE (8 L). The layers were
separated, and the organic phase was washed with water (2 × 14
L). Combined aqueous losses: 1.3%, assay yield: 98%. The organic
phase was transferred into a 75 L flask. A total of 33 L of i-PrOH
was used to remove the residual MTBE as determined by 1H NMR,
and the batch was concentrated to a volume of 17 L at a vacuum
of 28 in Hg and an internal temperature of 28 °C. To this was
added water (22 L) over 80 min at 27 °C. Ice/H2O was added to
the bath to cool the suspension to 20 °C after which time it was
solid: [R]20 +100.4 (c 1.30, MeOH); IR (film) 3054.2, 2986.6,
D
1422.0, 1265.8, 747.0, 705.4 cm-1; 1H NMR (400 MHz, CDCl3) δ
9.95 (br s, 0.7H), 9.88 (br s, 0.3H), 8.45 (m, 1H), 8.12 (m, 1H),
7.76 (td, 1H, J ) 7.8, 1.7 Hz), 7.72 (dd, 0.7H, J ) 12.3, 2.0 Hz),
7.56 (dd, 0.3H, J ) 12.4, 2.0 Hz), 7.34 (m, 1H), 7.15 (td, 1H, J )
8.6, 1.9 Hz), 6.93 (t, 0.7H, J ) 8.4 Hz), 6.84 (t, 0.3H, J ) 8.4 Hz),
5.20 (m, 0.3H), 5.00 (d, 0.7H, J ) 6.5 Hz), 3.65-3.40 (m, 2H),
2.30-2.08 (m, 2H), 1.98 (s, 1H), 1.85-1.65 (m, 3H), 1.72 (s, 2H);
13C NMR (100 MHz, CDCl3) δ 169.9, 168.9, 162.0, 161.8, 159.7
(d, J ) 245.0 Hz), 159.4 (d, J ) 244.9 Hz), 169.3, 149.1, 147.9,
147.8, 138.4 (d, J ) 11.2 Hz), 137.6, 137.6 (d, J ) 11.2 Hz), 137.5,
127.0 (d, J ) 6.4 Hz), 126.8 (d, J ) 5.6 Hz), 126.6, 126.4, 125.5
(d, J ) 13.7 Hz), 125.5 (d, J ) 13.7 Hz), 122.3, 122.3, 115.1 (d,
J ) 3.2 Hz), 114.6 (d, J ) 3.2 Hz), 107.4 (d, J ) 26.5 Hz), 107.3
(d, J ) 26.5 Hz), 56.1 (d, J ) 2.3 Hz), 55.2 (d, J ) 2.3 Hz), 48.2,
46.6, 34.6, 32.7, 23.8, 22.6, 22.2, 21.9; 19F NMR (377 MHz, CDCl3)
δ -116.19, -116.78; the compound exhibited two amide rotamers
(19) Oliveira, D. F.; Miranda, P. C. M. L.; Correia, C. R. D. J. Org. Chem.
1999, 64, 6646.
J. Org. Chem. Vol. 73, No. 13, 2008 4991