J. Brown et al. / Tetrahedron Letters 49 (2008) 4968–4971
4971
F
F
HO
Ph
HO
H2, Pd/C
9
+
N
N
H
Ph
9
9
10
Silica 3 :
eluted with
Not retained
MeOH
Retained
5% Et3N/MeOH
-
Silica 2 :
eluted with
Retained
5% Et3N/MeOH
Retained
~1% NH3/MeOH
-
Scheme 4.
Ph
N
O
P
OH
OH
NH2
NH2
Cl
PhCHO (xs), PhB(OH)2 (xs
)
2
Caught
PdCl2(PPh3)2
0.7 M NH3
in MeOH
Released
N
N
N
Na2CO3, toluene
11
12
Washed off
impurities
60% yield
98% purity
Scheme 5.
3. Liu, Y-S.; Zhao, C.; Bergbreiter, D. E.; Romo, D. J. Org. Chem. 1998, 63, 3471.
4. Ghassemi, S.; Fuchs, K. Mol. Divers. 2005, 9, 295.
5. Karimi, B.; Zareyee, D. Tetrahedron Lett. 2005, 46, 4661.
6. Das, B.; Venkateswarlu, K.; Krishnaiah, M.; Holla, H. Tetrahedron Lett. 2006, 47,
7551.
7. Humphries, P. S.; Finefield, J. M. Tetrahedron Lett. 2006, 47, 2443.
8. Siegel, M. G.; Hahn, P. J.; Dressman, B. A.; Fritz, J. E.; Grunwell, J. R.; Kaldor, S. W.
Tetrahedron Lett. 1997, 38, 3357; Wang, Y.; Sarris, K.; Sauer, D. R.; Djuric, S. W.
Tetrahedron Lett. 2007, 48, 5181.
9. Galaffu, N.; Man, S.; Wilkes, R. D.; Wilson, J. R. H. Org. Process Res. Dev. 2007, 11,
406.
10. Al-Hashimi, M.; Fisset, E.; Sullivan, A. C.; Wilson, J. R. H. Tetrahedron Lett. 2006,
47, 8017 and references cited therein; Al-Hashimi, M.; Sullivan, A. C.; Wilson, J.
R. H. J. Mol. Catal. A: Chem. 2007, 273, 298; Al-Hashimi, M.; Qazi, A.; Sullivan, A.
C.; Wilson, J. R. H. J. Mol. Catal. A: Chem. 2007, 278, 160.
was achieved by extractive aqueous work-up, involving initial
imine 11 cleavage with aqueous hydrochloric acid, followed in
some cases by a crystallisation step. We have found that this inten-
sive work-up protocol can be replaced by simply loading the crude
Suzuki reaction product onto 2, as shown in Scheme 5, resulting in
the imine 11 being retained, purified, deprotected and finally
released as the desired 1° aminopyridine reaction product 12 using
ammonia in methanol solution as eluant. The product was isolated
in a promising, unoptimised yield of 60% and in high purity, with
no additional purification steps required.
A typical protocol for reaction purification using these function-
alised cation exchange silicas is provided.15
11. Bugrayev, A.; Al-Haq, N.; Okopie, R. A.; Qazi, A.; Suggate, M.; Sullivan, A. C.;
Wilson, J. R. H. J. Mol. Catal. A: Chem. 2008, 280, 96.
In conclusion, we have shown the potential of functionalised
silicas with modified acidities,16 in comparison to the tradition-
ally-employed sulfonic acid materials, for catch and release SPE
purifications. These materials allow acid-sensitive functionalities
such as Boc, TBDMS and OtBu to be retained during the purification
of basic compounds. Use of the materials for the separation of basic
products such as 2° and 3° amines and saturated and unsaturated
nitrogen heterocycles has also been demonstrated, and further
elaboration of this work is ongoing.
12. Commercially available 7 N ammonia in methanol solution (Aldrich) was
diluted ꢁ10 with methanol (ꢀ1% v/v solution).
13. Triethylamine (5 mL) was added to methanol (95 mL) to give a 5% v/v solution
(ꢀ0.35 M).
14. Caron, S.; Massett, S. S.; Bogle, D. E.; Castaldi, M. J.; Braish, T. F. Org. Process Res.
Dev. 2001, 5, 254.
15. Typical purification procedure using functionalised silicas for cation exchange: The
appropriate SPE cartridge containing 1 g of functionalised silica was
conditioned by passing 10 mL of MeOH through it, either under gravity or
with positive pressure or under controlled vacuum. The reaction mixture was
next loaded onto the top of the cartridge in the solvent of choice (ꢀ1–2 mL
solvent/0.050 g product). Loading onto the cartridge should typically be 5% by
weight (reaction mixture: functionalised silica), though higher loadings are
sometimes possible. Once the reaction mixture has been eluted through, a
further 5 mL of methanol was passed through the cartridge. This ‘load’ fraction
may contain unretained reaction components. The cartridge was washed with
2 ꢁ 10 mL of MeOH and fractions were collected. These ‘wash’ fractions should
contain any further traces of unretained reaction components. Basic product
elution is dependent on the functionalised silica used. The cartridge was eluted
with either triethylamine in MeOH solution13 (5% v/v; ꢀ0.35 M, 10 mL) or
ammonia in MeOH solution12 (ꢀ1.2% v/v; ꢀ0.7 M, 10 mL), or both, and the
fractions collected. Fractions from these elution steps should contain any
retained reaction components. The cartridge was finally rinsed using 10 mL of
MeOH, which was also collected. Fractions were analysed to confirm that the
desired purification had been achieved. The desired fractions were
concentrated in vacuo to afford the purified product(s). In some cases,
solvent quantities and wash steps may be reduced as the user deems most
suitable for their particular purification process.
Supplementary data
Example HPLC traces for the separations of the basic mixtures
described are available. Supplementary data associated with this
article can be found, in the online version, at doi:10.1016/
References and notes
1. Cork, D.; Hird, N. Drug Discovery Today 2002, 7, 56; Ripka, W. C.; Barker, G.;
Krakover, J. Drug Discovery Today 2001, 6, 471; Weinbrenner, S.; Tzschucke, C.
C. In Combinatorial Chemistry; Bannwarth, W., Hinzen, B., Eds.; Wiley-VCH:
Weinheim, 2006; Chapter 1; pp 1–30.
2. Salimi, H.; Rahimi, A.; Pourjavadi, A. Monatsh. Chem. 2007, 138, 363 and
references cited therein.
16. PhosphonicSTM cation exchange SPE materials POH1d
2 and STMAd 3 are
available loose as well as in easy-to-use, pre-packed polypropylene 1 g or 10 g
cartridges. Cartridges are also available for metal SPE purifications and organic