N. Zheng et al. / Tetrahedron: Asymmetry 14 (2003) 3435–3446
3445
62°C for 0.75 h. EtOAc (5 L) was added over 50 min.
The slurry was stirred at 60°C for 1 h and then allowed
to cool to 15°C over 8 h. The slurry was heated to 62°C
again and flushed with EtOAc (50 L) at 52–55°C until
nated with 18 mol% n-Bu(OH)2 relative to 13 as
1
detected by H NMR.
References
1
THF was less than 1 mol% as determined by H NMR.
The slurry (12 L) was heated to 60°C and hexane (12 L)
was added over 45 min. The mixture was then refluxed
for 2 h and then allowed to cool to 15°C over 12 h. The
product was collected by filtration, washed with hex-
ane/EtOAc (12 L, 1/1), and then dried in vacuo with a
nitrogen sweep at 18°C for 12 h, giving 2.67 kg of 17
(85% yield, 4 ppm of residual Pd). Mp 136.7–137.8°C;
1H NMR (250 MHz, CDCl3) l 7.45–7.17 (m, 8H), 4.83
(d, J=12.0 Hz, 1H), 4.76–4.68 (m, 2H), 4.52 (d, J=
12.0 Hz, 1H), 4.47 (d, J=4.9 Hz, 1H), 4.28 (d, J=5.7
Hz, 2H), 3.98–3.89 (m, 1H), 3.61–3.53 (m, 1H), 2.64 (d,
J=4.8 Hz, 3H), 1.93–1.25 (m, 6H); 13C NMR (62.9
MHz, CDCl3) l 159.4, 141.0, 140.1, 137.1, 136.8, 130.0,
129.1, 128.0, 127.7, 127.6, 126.9, 98.1, 68.7, 62.3, 42.0,
30.6, 26.7, 25.4, 19.5; IR (Nujol) 3376, 3306, 1652,
1623, 1559, 1457, 1376, 1061, 1033, 1023, 762 cm−1.
Anal. calcd for C21H26N2O3: C, 71.16; H, 7.39; N, 7.90;
found: C, 71.24; H, 7.52; N, 7.87.
1. Smith, R. G.; Cheng, K.; Schoen, W. R.; Pong, S.-S.;
Hickey, G.; Jacks, T.; Butler, B.; Chan, W. W.-S.; Chaung,
L.-Y. P.; Judith, F.; Taylor, J.; Wyvratt, M. J.; Fisher, M.
H. Science 1993, 260, 1640–1643 and references cited
therein.
2. (a) Schoen, W. R.; Wyvratt, M. J.; Smith, R. G. Annual
Reports in Medicinal Chemistry Bristol, J. A., Ed.; Aca-
demic Press: California, 1993; Vol. 28, Chapter 19; (b)
DeVita, R. J.; Wyvratt, M. J. Drugs of the Future 1996, 21,
273–281 and references cited therein.
3. DeVita, R. J.; Bochis, R.; Frontier, A. J.; Kotliar, A.;
Fisher, M. H.; Schoen, W. R.; Wyvratt, M. J.; Cheng, K.;
Chan, W. W.-S.; Butler, B.; Jacks, T. M.; Hickey, G. J.;
Schleim, K. D.; Leung, K.; Chen, Z.; Chiu, S.-H. L.;
Feeney, W. P.; Cunningham, P. K.; Smith, R. G. J. Med.
Chem. 1998, 41, 1716–1728.
4. Armstrong, J. D., III; Eng, K. K.; Keller, J. L.; Purick, R.
M.; Hartner, F. W., Jr.; Choi, W.-B; Askin, D.; Volante,
R. P. Tetrahedron Lett. 1994, 35, 3239–3242.
5. King, A. O.; Anderson, R. K.; Shuman, R. F.; Karady, S.;
Abramson, N. L.; Douglas, A. W. J. Org. Chem. 1993, 58,
3384–3386.
4.12. 3-Iodo-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one 4
To a 50 L round bottom flask were added CH3CN ( 14
L), NaI (1.93 kg, 12.87 mol), and TMSCl (1.63 L, 12.87
mol), whereupon a slurry was formed. After the addi-
tion of TMEDA (3.89 L, 25.74 mol), the mixture was
cooled to −15°C and benzazepin-2-one (1.38 kg, 8.58
mol) was added. 10 min later, I2 (3.27 kg, 12.87 mol)
was added portionwise. The resulting mixture was
allowed to stir between −15 and −10°C for 1 h and then
quenched with 5% aqueous Na2S2O3 (15 L), resulting in
crystallization of 4. The product was collected by filtra-
tion, washed with water (3×4 L), and then dried in
vacuo at 40°C, giving 2.32 kg of 4 (94% yield).
6. Presented at the IBS conference, Peptidomimetics and
Small Molecule Design: Accelerating Drug Discovery and
Development, Philadelphia, PA, March 10–12, 1997. The
edited and updated transcript from this conference was
published by IBC in November, 1997 (IBC Library Series
publication c984, pp. 163–170).
7. Other solvents have been demonstrated on the steroidal
substrates only.
8. King’s procedure for iodination of benzazepin-2-one 5 with
TMSI generated from TMSCl and I2 was unsuccessful.
9. Olah, G. A.; Narang, S. C.; Gupta, B. G. B.; Malhotra,
R. J. Org. Chem. 1979, 44, 1247–1251.
10. Proton and 13C 1D NMR as well as a 2D inverse long range
correlation experiments were used to characterize the
adduct.
4.13. [4-(Hydroxymethyl)phenyl]boronic acid 13
To a solution of dimethyl amine in THF (2 M, 180 mL)
at −70°C was added n-BuLi in hexanes (1.4 M, 190 mL,
266 mmol) slowly. Then a solution of 4-bromobenzyl
alcohol (50.0 g, 267.3 mmol) in THF (100 mL) was
added to the preformed LiN(CH3)2 at −70°C. After
warming up to ambient temperature, the solution was
concentrated to a thick oil, flushed with THF (250 mL),
and then re-dissolved in degassed THF (1 L). After
cooling to −78°C, the solution was treated with n-BuLi
in hexanes (1.4 M, 200 mL, 280.0 mmol) and the
mixture was stirred at −78°C for 1 h. B(Oi-Pr)3 (150.0
mL, 650.0 mmol) was added at −78°C. After stirring at
−78°C for 1 h, the mixture was quenched with NaOH
(1N, 500 mL) and water (500 mL) at −78°C. After
warming up to ambient temperature, the aqueous layer
was separated, back extracted with methyl t-Butyl ether
(800 mL), and then cooled to −40°C. Concentrated HCl
was added until the pH of the solution was 4–5. The
acidified aqueous layer was then extracted with THF
(2×800 mL). The combined THF layers were then
assayed by HPLC giving 31.57 g of the desired boronic
acid 13 (78% assay yield). The product was contami-
11. (a) For the preparation of imidazolidinium salt 6 see:
Peterson, D. J.; Ward, J. F. J. Organomet. Chem. 1974, 66,
209–217; (b) Formation of imidazolidinium salt 6 from
TMEDA and I2 may occur simply by an extension of an
intramolecular Hofmann–Loffler–Freytag reaction.
12. (a) Schoen, W. R.; Pisano, J. M.; Prendergast, K.; Wyvratt,
M. J.; Fisher, M. H.; Cheng, K.; Chan, W. W.-S.; Butler,
B.; Smith, R. G.; Ball, R. G. J. Med. Chem. 1994, 37,
897–906; (b) Breaking of the D-pyroglutamic salt of 2 was
accomplished by partitioning between THF and NaCl
saturated concentrated ammonia. Examination of the THF
extract by Dionex ion chromatography showed only traces
(< 10 ppm) of pyroglutamic acid.
13. (a) Suzuki, A. Pure Appl. Chem. 1985, 57, 1749–1758; (b)
Smith, G. B.; Dezeny, G. C.; Hughes, D. L.; King, A. O.;
Verhoeven, T. R. J. Org. Chem. 1994, 59, 8151–8156.
14. For the preparation of (2-formylphenyl)boronic acid, see:
Wytko, J. A.; Graf, E.; Weiss, J. J. Org. Chem. 1992, 57,
1015–1018.
15. Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.;
Maryanoff, C. A.; Shah, R. D. J. Org. Chem. 1996, 61,
3849–3862.