3730
R. A. Singer et al. / Tetrahedron Letters 47 (2006) 3727–3731
S.; McDermott, R. E.; Arpin, P.; Do, N. M. Synthesis
2003, 1727.
methanol and water to afford 8 as a white, crystalline solid
(25.3 g, 94%). Mp 87–88 °C; 1H NMR (CDCl3): d 7.98
(d, J = 7.5 Hz, 4H), 7.59 (t, J = 7.5 Hz, 2H), 7.46
(t, J = 7.5 Hz, 4H), 6.54 (s, 1H); 13C NMR (CDCl3):
d = 189.2, 134.5, 134.0, 129.5, 129.2, 52.9; Anal. Calcd
for C15H11BrO2: C, 59.43; H, 3.66; N, 0.0. Found: C,
59.27; H, 3.33; N, <0.05.
7. X-Phos and related biaryl ligands have been shown to
possess excellent catalytic efficiency in the Pd-catalyzed
amination reaction, see: (a) Huang, X.; Anderson, K. W.;
Zim, D.; Jiang, L.; Klapars, A.; Buchwald, S. L. J. Am.
Chem. Soc. 2003, 125, 6653; (b) Strieter, E. R.; Black-
mond, D. G.; Buchwald, S. L. J. Am. Chem. Soc. 2003,
125, 13978.
8. For directed lithiations on pyrazoles, see: Micetich, R. G.;
Baker, V.; Spevak, P.; Hall, T. W.; Bains, B. K. Hetero-
cycles 1985, 23, 943.
14. Quenching the reaction with 8 still in solution results in
some reduction of 8 to the starting material, which comp-
licates subsequent steps.
15. Note that 9 is isolated as a mixture of keto (major) and
enol (minor) forms. Preparation of 9: Pyrazole (17.1 g, 3
equiv) was added to a solution of 8 (25.3 g, 83.5 mmol, 1
equiv) in NMP (50 mL) at rt. After stirring at rt for 48 h,
the product had crystallized. Water (270 mL) was added to
the reaction mixture over 15 min to completely crystallize
9, and the slurry was stirred for another 6 h. The reaction
mixture was filtered and the filtercake was washed with
water. The product, 9, was isolated as an off-white to pale
yellow solid (23.7 g, 97%) as a >10:1 ratio of keto/enol
forms (NMR data reported for the major keto form). Mp
135–137 °C; 1H NMR (CDCl3): d 7.64 (d, J = 2.1 Hz, 1H),
7.41–7.36 (m, 2H), 7.27–7.23 (m, 9H), 7.18 (d, J = 2.1 Hz,
1H), 6.25 (t, J = 2.1 Hz, 1H); 13C NMR (CDCl3):
d = 187.5, 141.2, 134.7, 134.2, 132.1, 128.5, 128.0, 108.1;
Anal. Calcd for C18H14N2O2: C, 74.47; H, 4.86; N, 9.65.
Found: C, 74.50; H, 4.86; N, 9.60.
16. Preparation of 10: A solution of phenyl hydrazine
(12.0 mL, 1.5 equiv) in methanol (24 mL) was added to
a suspension of 9 (23.8 g, 82.0 mmol, 1 equiv) in methanol
(48 mL) and acetic acid (48 mL). After 24 h the reaction
mixture was diluted with diisopropyl ether (240 mL). The
crystals were stirred for 24 h and then cooled to 0 °C and
stirred an additional hour before filtering. The filtercake
was washed twice with diisopropyl ether, and 10 was
isolated as a white solid (23.6 g, 80%). Mp 168–169 °C; 1H
NMR (CDCl3): d 7.75 (d, J = 2.1 Hz, 1H), 7.44–7.11 (m,
16H), 6.33 (d, J = 2.1 Hz, 1H); 13C NMR (CDCl3):
d = 148.1, 141.2, 141.1, 140.0, 133.1, 131.1, 129.5, 129.3,
129.2, 128.7, 128.6, 128.1, 127.8, 127.0, 125.5, 121.2, 112.5,
107.1; Anal. Calcd for C24H18N4: C, 79.54; H, 5.01; N,
15.46. Found: C, 79.16; H, 4.87; N, 15.30.
17. Preparation of 1: 10 (50.1 g, 138.3 mmol) was dissolved in
THF (400 mL) and cooled to À78 °C. A solution of 2.5 M
n-butyllithium in hexanes (66.0 mL, 166 mmol) was added
and the resulting reaction mixture was stirred at À78 °C
for 1.5 h. At this time, di-tert-butylchlorophosphine
(32 mL, 166 mmol) was added. The reaction mixture was
allowed to gradually warm to room temperature over 1 h
and was stirred at room temperature for an additional
hour. The reaction was quenched with water (300 mL) and
was diluted with tert-butyl methyl ether (600 mL). The
organic layer was separated and washed with brine
(200 mL). The organic layer was then dried over anhydr-
ous sodium sulfate and concentrated in vacuo to a total
volume of about 200 mL. The solution was diluted with
tert-butyl methyl ether (400 mL) and was concentrated to
a volume of about 300 mL. Crystals began to form and the
suspension was cooled to 0 °C to crystallize more material.
After stirring for 2 h, the mixture was diluted with heptane
(600 mL) to induce further crystallization and the slurry
was stirred for 4 h before filtration. The filtercake was
washed with heptane to afford 1 as a white solid (59.0 g,
84%). Mp 191–193 °C; 1H NMR (CDCl3): d 7.93 (d,
J = 1.7 Hz, 1H), 7.48–7.11 (m, 15H), 6.62 (d, J = 1.7 Hz,
1H), 0.69 (d, J = 12.5 Hz, 9H), 0.57 (d, J = 12.5 Hz, 9H);
13C NMR (CDCl3): d = 150.0, 143.5 (d, J = 26 Hz), 141.5,
140.4, 140.1, 132.3, 130.2, 129.0, 128.9, 128.8, 128.7, 128.5,
128.3, 127.8, 127.7, 125.8, 121.1, 113.9 (d, J = 4.5 Hz),
9. Ligand 4 failed to operate effectively with many primary
amines, especially when attempting couplings with elec-
tron rich aryl halides.
10. For rationale on the biaryl design of phosphine ligands,
see (a) Walker, S. D.; Barder, T. E.; Martinelli, J. R.;
Buchwald, S. L. Angew. Chem., Int. Ed. 2004, 43, 1871; (b)
Kocovsky, P. et al. J. Am. Chem. Soc. 1999, 121, 7714.
11. Ligand 7 was prepared in two steps by a cross-coupling
between pyrazole and iodonaphthalene using literature
conditions (Cristau, H.-J.; Cellier, P. P.; Spindler, J.-F.;
Taillefer, M. Eur. J. Org. Chem. 2004, 695), followed by
a directed lithiation. A solution of 2.5 M n-BuLi in hex-
anes (7.6 mL, 1.2 equiv) was added to a solution of
1-pyrazolylnaphthalene (3.08 g, 15.9 mmol, 1 equiv) in
THF (32 mL) at À78 °C. The solution was stirred at
À78 °C for 1.5 h and then di-tert-butylchlorophosphine
(3.6 mL, 1.2 equiv) was added. The reaction mixture was
allowed to warm to rt and stir for an additional hour.
Then the reaction was worked up with MTBE (61 mL)
and water (37 mL). The organic layer was washed with
brine (25 mL), dried over anhydrous MgSO4 and concen-
trated in vacuo to a volume of ꢀ20 mL. Heptane (50 mL)
and diisopropyl ether (24 mL) were added sequentially to
the concentrate. This solution was further concentrated to
a volume of about 20 mL and crystals formed. The
crystals were stirred for 3 h at 0 °C and filtered to isolate 7
as a light tan solid (2.65 g, 50%). Mp 125–126 °C; 1H
NMR (CDCl3): d 7.95 (d, J = 7.9 Hz, 1 H), 7.88 (d,
J = 7.7 Hz, 1H), 7.87 (d, J = 2.1 Hz, 1H), 7.55–7.45 (m,
3H), 7.38 (dt, J = 8.3, 0.83 Hz, 1H), 7.16 (t, J = 8.3 Hz,
1H), 6.88 (t, J = 2.1 Hz, 1H), 1.19 (br s, 9H), 1.06 (br s,
9H); 13C NMR (CDCl3): d = 142.0 (d, J = 26 Hz), 139.8,
137.8, 134.3, 131.6, 129.7, 128.1, 127.1 (d, J = 3.8 Hz),
126.9, 126.6, 124.7, 124.0, 113.2 (d, J = 4.5 Hz), 32.1 (d,
J = 19 Hz), 30.6 (d, J = 14.3 Hz); Anal. Calcd for
C21H27N2P: C, 74.53; H, 8.04; N, 8.28. Found: C, 74.43;
H, 8.11; N, 8.18.
12. Beller and Degussa prepared ligands related to 7 based on
a heterocyclic-biaryl design, see: (a) Zapf, A. et al. Chem.
Commun. 2004, 38; (b) Harkal, S.; Rataboul, F.; Zapf, A.;
Fuhrmann, C.; Riermeier, T.; Monsees, A.; Beller, M.
Adv. Synth. Catal. 2004, 346, 1742; (c) Rataboul, F.; Zapf,
A.; Jackstell, R.; Harkal, S.; Riermeier, T.; Monsees, A.;
Dingerdissen, U.; Beller, M. Chem. Eur. J. 2004, 10, 2983.
13. Preparation of 8: A solution of pyridinium tribromide
(38.2 g, 1.3 equiv) in acetonitrile (80 mL) was added to a
solution of dibenzoylmethane (20.0 g, 89.2 mmol, 1 equiv)
in acetonitrile at 10–15 °C (80 mL) over 15–30 min. The
reaction was allowed to stir for 30 min at 10–15 °C. The
reaction was diluted with methanol (100 mL), followed by
slow addition of water (200 mL) over 15 min at 10–15 °C
to crystallize 8. The reaction mixture was cooled to 0 °C
and stirred for about 1 h. The yellow suspension was then
treated with an aqueous solution of sodium bisulfite (5.0 g
in 40 mL of water) at 0 °C to reduce excess bromine. After
stirring for 15 min at 0 °C, the suspension was filtered and
the filtercake was washed with a cold 1:1 mixture of