C. D. Gutierrez et al. / Tetrahedron Letters 46 (2005) 3595–3597
3597
isopropoxide ligands with a chlorine atom would in-
crease the Lewis acidity of the reagent and facilitate
Referencesand notes
the condensation of the amine with the aldehyde. In-
deed, use of TiCl(O Pr) and subsequent treatment with
NaBH(OAc) gave higher yields and excellent purity
3
1. Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.;
Maryanoff, C. A.; Shah, S. D. J. Org. Chem. 1996, 61,
i
3
3
849–3862.
2. Bae, J. W.; Lee, H. L.; Cho, Y. J.; Yoon, C. M. J. Chem.
Soc., Perkin Trans. 1 2000, 145–146.
3. Bomann, M. D.; Guch, I. C.; DiMare, M. J. Org. Chem.
(
Table 1, entry 4).
Encouraged by these preliminary results on solid phase,
a closer investigation of TiCl(O Pr) in solution was
1
995, 60, 5995–5996.
4. White, W. A.; Weingarten, H. J. Org. Chem. 1967, 32,
13–214.
i
3
undertaken. Using 3-amino-5-tert-butylisoxazole as the
amine component and 2,4-dimethoxybenzaldehyde, as
a model for linker 1, imine formation was monitored
2
5. Mattson, R. J.; Pham, K. M.; Leuck, D. J.; Cowen, K. A.
J. Org. Chem. 1990, 55, 2552–2554.
6. Breitenbucher, J. G.; Hui, H. C. Tetrahedron Lett. 1998,
1
by H NMR spectroscopy following the disappearance
of the CHO signal at d = 10.2. When 1 equiv of aldehyde
and 1.1 equiv of the amine were shaken with 1.1 equiv of
38, 8207–8210.
. Neidigh, K. A.; Avery, M. A.; Williamson, J. S.;
Bhattacharyya, S. J. Chem. Soc., Perkin Trans. 1 1998,
7
i
TiCl(O Pr) in CDCl for 5 min the intensity of the alde-
3
3
2
. Green, J. J. Org. Chem. 1995, 60, 4287–4290.
527–2531.
hyde signal was reduced by ca. 50%, and a new singlet
appeared at d = 9.1 corresponding to the expected imine.
Prolonged shaking at room temperature for up to 24 h
did not significantly change the ratio of aldehyde to
8
9
. Devraj, R.; Cushman, M. J. Org. Chem. 1996, 61, 9368–
9
373.
1
0. Gordon, D. W.; Steele, J. Bioorg. Med. Chem. Lett. 1995,
5, 47–50.
11. Atrash, B.; Bradley, M.; Kobylecki, R.; Cowell, D.;
imine, but addition of 1.1 extra equivalents of
TiCl(O Pr) caused the compete disappearance of the
i
3
1
aldehyde peak in the H NMR spectra within 5 min.
Reader, J. Angew. Chem., Int. Ed. 2001, 40, 938–941.
2. Makara, G. M.; Ma, Y. Tetrahedron Lett. 2001, 42, 4123–
125.
1
Addition of NaBH(OAc) then effected complete reduc-
3
tion of the imine.
4
1
1
3. Swayze, E. E. Tetrahedron Lett. 1997, 38, 8465–8468.
4. Fivush, A. M.; Willson, T. M. Tetrahedron Lett. 1997, 41,
The scope for performing reductive amination in situ
was then explored using 2.2 equiv of TiCl(O Pr) ,
7
5. Bui, C. T.; Bray, A. M.; Pham, Y.; Campbell, R.; Ercole,
151–7154.
i
3
1
NaBH(OAc) and 1.1 equivalent of amine. Under these
3
F.; Rasoul, F. A.; Maeji, N. J. Mol. Divers. 1998, 4, 155–
1
conditions it was possible to reductively aminate elec-
tron rich aldehydes with deactivated heterocyclic
amines, such as 2-aminopyridine and 2-amino-5-bromo-
pyridine (Table 2, entries 1 and 2). Likewise, the reac-
tion proceeded in good yields with sterically hindered
63.
16. Representative procedure: Synthesis of (2,4-dimethoxy-
benzyl)-thiazol-2-yl-amine (Table 2, entry 3): To a stirred
solution of 2-aminothiazole (0.110 g, 1.1 mmol, 1.1 equiv)
and 2,4-dimethoxybenzaldehyde (0.166 g, 1.0 mmol,
1
TiCl(O Pr) (0.524 mL, 2.2 mmol, 2.2 equiv) in one por-
equiv) in anhydrous CH
Cl
2 2
(3 mL) was added
2
4
-aminotoluene (Table 2, entry 4) or with deactivated
-nitroaniline (Table 2, entry 5). Both ester and amide
i
3
tion under argon. The solution was stirred for 5 min
before the portionwise addition of freshly ground
NaBH(OAc) (1.05 g, 5 mmol, 5 equiv) (caution: exother-
3
mic reaction and evolves gas) and three drops of AcOH.
The reaction mixture was stirred for an additional 6 h,
then poured into saturated aqueous NaHCO3 solution
functionalities were tolerated under the reaction condi-
tions (Table 2, entries 6–8). Yields of 50–89% were
achieved.
i
In conclusion, we have found that TiCl(O Pr) in combi-
3
nation with NaBH(OAc) is a useful system for the
3
(30mL) and extracted with CH
combined extracts were washed with brine (30mL), dried
MgSO ), and concentrated in vacuo. The residue was
purified by column chromatography on silica (Et O–
CH Cl ; v/v 1:1) to give 181 mg (79%) of the title
2
Cl
2
(4 · 10mL). The
reductive amination of aldehydes with a variety of elec-
tron-deficient amines. These reaction conditions are
currently being evaluated on the solid phase and will
be reported in future communications.
(
4
2
2
2
compound as a white solid; mp: 115–117 ꢁC; mmax (thin
À1
1
film)/cm 3390(NH), 1155 (OMe); H NMR (CDCl
50MHz): d 3.80(s, 3H, OC H ), 3.83 (s, 3H, OCH ), 4.38
s, 2H, CH ), 6.46 (m, 3H, thiazole, Ph H-3, and Ph H-5),
3
,
2
(
3
3
2
Acknowledgements
7
.10(d, J = 3.6 Hz, 1H, thiazole), 7.22 (d, J = 8.0Hz, 1H,
1
3
Ph H-6); C NMR (CDCl
8.7, 103.8, 106.3, 118.3, 130.2, 139.0, 158.6, 160.7, 170.5;
Found C, 57.29; H, 5.65; N, 10.84; C H N O S requires
3
, 63 MHz): d 45.6, 55.4, 55.4,
Financial support from The Institute of Cancer Re-
search and Cancer Research UK (V.B.) is gratefully
acknowledged.
9
1
2
14
2
2
C, 57.58; H, 5.64; N, 11.19.