5090
A.L.Joffe et al./ Tetrahedron Letters 45 (2004) 5087–5090
(c) Shimizu and Sahara recently reported that the TiI4
13. Ishitani, H.; Ueno, M.; Kobayashi, S. J.Am.Chem.Soc.
1997, 119, 7153–7154, Also see Ref. 3b.
14. Satio, S.; Hatanaka, K.; Yamamoto, H. Org.Lett. 2000, 2,
1891–1894.
15. Porter, J. R.; Traverse, J. F.; Hoveyda, A. H.; Snapper, M.
L. J.Am.Chem.Soc. 2001, 123, 10409–10410.
promoted addition of a,a-dialkoxyacetates to premade
imines resulted in the formation of a-oxy-b-amino esters
and in the cases were diastereoselectivity was observed, the
major isomer obtained was that of the anti-configuration
Shimizu, M.; Sahara, T. Chem.Lett. 2002, 888–889.
4. MCC with nonenolizable imines: To a stirred mixture of
ꢀ
crushed 4 A molecular sieves in 6 mL of CH2Cl2 under a
16. Deprotection–reprotection: Methyl 3-N-(acetyl)amino-2-
methoxy-3-(4-chloro)phenylpropanoate. To a stirred solu-
tion of PhI(OAc)2 (364 mg, 1.10 mmol) in methanol (5 mL)
at room temperature was added a solution of the beta-
amino ester 3a (99 mg, 0.30 mmol) in CH2Cl2 (1 mL) and
methanol (1 mL) over 30 min via syringe pump. The
syringe was then rinsed with methanol (2ꢀ0.5 mL) and the
rinses were added to the reaction. After an additional
30 min (60 min total) 1 M HCl (10 mL) was added to the
reaction and a white precipitate immediately formed,
which slowly dissolved with stirring to afford a yellow
solution after 90 min. The organic layer was separated and
the aqueous layer subsequently extracted with 2ꢀ15 mL
portions of CH2Cl2. The combined organic layers were
then back extracted with 10 mL 0.1 M HCl and added to
the previous aqueous layer. To the aqueous layer was
added CH2Cl2 (10 mL). To this biphasic mixture was
added, with vigorous stirring, Ac2O (134 lL, 1.40 mmol)
followed by and Na2CO3 portionwise to afford a pH of
10–11. This mixture was stirred for 90 min with occasional
addition of Na2CO3 to maintain the pH of 10–11. After
separation of the layers, the aqueous layer was extracted
with CH2Cl2 (2ꢀ15 mL). The combined organics were
dried (MgSO4), filtered and concentrated in-vacuo to
afford 67 mg (78%) of 4; mp: 96–98 °C; IR (thin film);
nitrogen atmosphere was added the aldehyde followed by
ortho-anisidine (1:1.05 molar equivalents). The enolate
solution was prepared according to the method used in
Ref. 2. After 30 m the mixture is cooled to )78 °C and the
violet titanium enolate solution (2.0 equiv) was transfered
into the imine solution. After the reaction had gone to
completion, based on TLC analysis, the cold reaction
mixture was suction-filtered directly into a stirring solu-
tion of 1 M HCl and allowed to warm to room temper-
ature. The work-up procedure used in Ref. 2 was followed
from this point.
5. See Supplementary material.
6. Savignac, A.; Bon, M.; Lattes, A. Bull.Soc.Chim.Fr.
1972, 3167–3173.
7. For an extensive list of pKa’s, including that of o-anisidine,
see: Albert, A.; Serjeant, E. P. Ionization Constants of
Acids and Bases; Wiley & Sons: NewYork, 1962 (Chapter
8).
8. Adrian, J. C., Jr.; Snapper, M. L. J.Org.Chem. 2003, 68,
2143–2150, For an additional example of using dimethyl-
zinc as an in situ drying agent, see Ref. 16.
9. MCC with enolizable imines: To a stirred solution of
1 molar equivalent of aldehyde in 6 mL of CH2Cl2 was
added approximately 1.05 molar equivalents of ortho-
methoxyaniline. After 15 min at room temperature,
1.06 molar equivalents of dimethyl zinc (2 M in toluene)
was added. Bubbling commenced immediately indicating
the formation of methane gas. The solution was allowed to
stir for an additional 15 min at room temperature before
being cooled to )78 °C. The procedure used in Ref. 4 was
followed from this point.
10. We did not anticipate significant methyl alkylation since
dimethylzinc is an extremly poor nucleophile, for leading
references see: (a) Inoue, S.; Imanaka, Y. J.Organomet.
Chem. 1972, 35, 1–7; (b) Knochel, P.; Singer, R. Chem.
Rev. 1993, 93, 2117–2188; (c) Boudier, A.; Bromm, L. O.;
3426, 1738, 1651 cmꢁ1 1H NMR (200 MHz, CDCl3): d
;
7.25 (s, 4H), 6.48 (d, 1H, J ¼ 8:0 Hz), 5.42 (dd, 1H,
J ¼ 8:0 Hz, J ¼ 4:0 Hz), 4.13 (d, 1H, J ¼ 4:0 Hz), 3.60 (s,
3H), 3.49 (s, 3H), 2.03 (s, 3H); 13C NMR (50 MHz,
CDCl3): 169.9, 169.3, 135.8, 133.9, 129.0, 128.7, 82.0, 59.3,
53.6, 52.0, 23.4. Anal. Calcd for C13H16ClNO4: C, 54.65;
H, 5.64; N, 4.90. Found: C, 54.89; H, 5.74; N, 4.54. Minor
isomer (syn) is visible in the NMR and the CHOCH3
resonates at d 4.02 (d, 1H, J ¼ 2:0 Hz).
17. The anti:syn ratio was determined by comparative inte-
gration of the H1 NMR of both the starting material and
resulting product.
18. Fox, R. J., Adrian, J. C., Jr. Unpublished results from
these laboratories. The ester adduct, methyl 3-(2-meth-
oxyphenyl)amino-2-methylthio-3-(4-chlorophenyl)propa-
noate, was prepared in a 50% unoptimized yield from a
premade imine according to the procedure in Ref. 2. The
anti:syn ratio was 80:20, additional characterization data
is provided in the supplementary material.
Lotz, M.; Knochel, P. Angew.Chem,. Int.Ed.
4414–4435.
2000, 39,
11. The relative amount of methyl adduct was determined by
comparative integration of the H1 NMR.
12. Adrian, J. C., Jr.; Barkin, J. L.; Hassib, L. Tetrahedron
Lett. 1999, 40, 2457–2460.