S. R. Kotturi et al. / Tetrahedron Letters 50 (2009) 5267–5269
5269
Table 3 (continued)
R. M.; Stoltz, B. M. J. Am. Chem. Soc. 2006, 128, 7738; (f) Heim, R.; Wiedemann,
S.; Williams, C. M.; Bernhardt, P. V. Org. Lett. 2005, 7, 1327.
2. (a) Hoffmann, R. W. Synthesis 2006, 21, 3531–3541; (b) Schelhaas, M.;
Waldmann, H. Angew. Chem., Int. Ed. 1996, 35, 2056.
3. Choice of NAP-protection versus benzyl ethers: Inoue, M.; Uehara, H.;
Maruyama, M.; Hirama, M. Org. Lett. 2002, 4, 4551.
4. (a) Wuts, P. G. M.; Greene, T. W. Protective Groups in Organic Synthesis, 4th ed.;
Wiley and Sons: New York, 2006; (b) Kocienski, P. J. Protecting Groups, 3rd ed.;
Thieme: Stuttgart, 2005.
5. (a) Sartori, G.; Ballini, R.; Bigi, F.; Bosica, G.; Maggi, R.; Righi, P. Chem. Rev. 2004,
104, 199; (b) Sharma, G. V. M.; Mahalingam, A. K. J. Org. Chem. 1999, 64, 8943.
6. (a) Wright, J. A.; Yu, J. Q.; Spencer, J. B. Tetrahedron Lett. 2001, 42, 4033; (b)
Plante, O. J.; Buchwald, S. L.; Seeberger, P. H. J. Am. Chem. Soc. 2000, 122, 7148.
7. Yan, L.; Kahne, D. Synlett 1995, 523.
8. (a) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett. 1982, 23, 885; (b)
Marco, J. L.; Huesorodriguez, J. A. Tetrahedron Lett. 1988, 29, 2459; (c) Nakajima,
N.; Horita, K.; Abe, R.; Yonemitsu, O. Tetrahedron Lett. 1988, 29, 4139.
9. (a) Lopez, S. S.; Dudley, G. B. Beilstein J. Org. Chem. 2008, 4. doi:10.3762/
bjoc.4.44; (b) Nwoye, E. O.; Dudley, G. B. Chem. Commun. 2007, 1436; (c) Poon,
K. W. C.; Dudley, G. B. J. Org. Chem. 2006, 71, 3923.
Entrya
ROPMB
Yieldb (%)
O
PMBO
HO
O
13
14
80
O
O
OAllyl
O
O
Cl
Cl
O
O
O
55
56
PMBO
O
OAllyl
O
15
MeO
OPMB
10. Hanessian, S.; Huynh, H. K. Tetrahedron Lett. 1999, 40, 671.
11. Marcune, B. F.; Karady, S.; Dolling, U. H.; Novak, T. J. J. Org. Chem. 1999, 64,
2446.
a
Activator added at 0 °C, then reaction mixture was allowed to warm to rt over
4–12 h. Reagents are relative to 1 equiv of the alcohol.
Isolated yields. Although yields were not optimized for each case, all unreacted
alcohols were fully recovered.
12. Lear, M. J.; Yoshimura, F.; Hirama, M. Angew. Chem., Int. Ed. 2001, 40, 946.
13. Ren, F.; Hogan, P. C.; Anderson, A. J.; Myers, A. G. J. Am. Chem. Soc. 2007, 129,
5381.
b
14. In our hands, PMB-TOPCAT was found to be unstable and decarboxylated to 2-
pyridyl thioethers akin to PMB-ST (1), which were found unreactive to mild
activation methods such as AgOTf/DTBMP.
gave the mono p-methoxybenzylated products at the 3- and
6-positions, respectively. Although this selectivity is similar to
methods that employ dibutyltin oxide, the PMB-ST system is less
toxic.22 Lastly, PMB-ST 1 shows advantages over PMB-TOPCAT10
in terms of its stability and leaving group potential, typically giving
maximum yields within 24 h.
In summary, we report the synthesis and utility of 5-(p-meth-
oxybenzylthio)-1-phenyl-1H-tetrazole (PMB-ST, 1) as a new re-
agent for PMB etherification. The functional group tolerance of
the reagent system was studied over a range of alcohols. Even sen-
sitive substrates and functionality survived the PMB-ST/AgOTf/
DTBMP conditions, thereby allowing full recovery of precious start-
ing material. We thus envisage this reagent system to find utility in
the PMB protection of advanced, multifunctional substrates.
Improvements and application to other protecting modalities, such
as to the NAP, MOM, benzyl and allyl ethers and carbonates, are
ongoing.
15. (a) Lee, J. I.; Park, H. Bull. Korean Chem. Soc. 2001, 22, 421; (b) Takeda, K.;
Tsuboyama, K.; Takayanagi, H.; Shirokami, R.; Takeura, M.; Ogura, H. Chem.
Pharm. Bull. 1989, 37, 2334; (c) (c) One-pot preparation of 5-(p-
methoxybenzylthio)-1-phenyl-1H-tetrazole (1): Trichloromethyl chloroformate
(0.6 ml, 5.00 mmol) was added dropwise to a solution of 1-phenyl-1H-tetrazole-
5-thiol (3.6 g, 20.00 mmol) and triethylamine (3.1 ml, 22.50 mmol) in freshly
distilled dichloromethane (40 ml) at 0 °C. The reaction mixture was allowed to
warm up to room temperature slowly and left to stir overnight. The reaction
mixture was cooled to 0 °C and p-methoxybenzyl alcohol (0.9 ml, 7.50 mmol) and
triethylamine (3.1 ml, 22.50 mmol) were added. The reaction mixture was
allowed to warm up slowly to room temperature and left to stir overnight. The
reaction mixture was evaporated to dryness in vacuo, followed by precipitation
from ethyl acetate. The suspension obtained was filtered through Celite and the
filtrate was evaporated to dryness in vacuo. The crude product was purified by
silica gel column chromatography using n-hexane/EtOAc (16:1) as eluent to give
5-(p-methoxybenzylthio)-1-phenyl-1H-tetrazole (2.2 g, 99%). Rf = 0.30 (hexane/
EtOAc 4:1); 1H NMR (300 MHz, CDCl3): d 7.52 (5H, m), 7.34 (2H, d, J = 8.7 Hz), 6.84
(2H, d, J = 8.8 Hz), 4.59 (2H, s), 3.79 (3H, s); 13C NMR (75 MHz, CDCl3): d 159.48,
153.97, 133.64, 130.50, 129.70, 127.07, 123.77, 114.20, 55.27, 37.30; MS-EI [M+]
calcd for C15H14N4OS: 298.0888, found 298.0893.
16. PMB-ST 1 can also prepared by reacting 1-phenyl-1H-tetrazole-5-thiol under
Mitsunobu conditions (with PMB-OH) or by halide displacement (with PMB-
Cl); see Supplementary data.
Acknowledgements
17. For a proposed mechanism of decarboxylation, see: Tsuboyama, K.; Takeda, K.;
Torii, K.; Ebihara, M.; Shimizu, J.; Suzuki, A.; Sato, N.; Furuhata, K.; Ogura, H.
Chem. Pharm. Bull. 1990, 38, 636.
Financial support from the NUS Academic Research Fund (AcRF
Tier-1: R-143-000-304-112) and a PhD scholarship (to S.R.K.) is
greatly appreciated.
18. The dual action of both ‘soft’ Lewis acids or ‘p-acids’ and ‘hard’ Brønsted bases
are gaining importance: (a) Duschek, A.; Kirsch, S. F. Angew. Chem., Int. Ed.
2008, 47, 5703; (b) Hashmi, A. S. K. Chem. Rev. 2007, 107, 3180; (c) Yamamoto,
Y. J. Org. Chem. 2007, 72, 7817.
19. Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A. Synlett 1998, 26.
20. General protocol for the p-methoxybenzylation of alcohols: A solution of 5-(p-
methoxybenzylthio)-1-phenyl-1H-tetrazole (PMB-ST, 0.095 g, 0.32 mmol,
1.60 equiv) and DTBMP (0.05 g, 0.25 mmol, 1.25 equiv) in freshly distilled
anhydrous dichloromethane (1.5 ml) was added to the alcohol (0.20 mmol,
Supplementary data
Supplementary data (experimental procedures, characteriza-
tion data and NMR spectra of selected compounds) associated with
this article can be found, in the online version, at doi:10.1016/
1.0 equiv). The reaction mixture was cooled to 0 °C and transferred to
a
solution of silver triflate (0.08 g, 0.32 mmol, 1.60 equiv) in freshly distilled
anhydrous dichloromethane (0.5 ml). The mixture was allowed to warm up to
room temperature slowly and left to stir overnight. Ethyl acetate was added to
the reaction mixture and the suspension obtained was filtered through Celite.
The filtrate was evaporated to dryness in vacuo. The crude product was
purified by silica gel column chromatography to provide the isolated O-PMB
product.
References and notes
1. (a) Young, I. S.; Baran, P. S. Nat. Chem. 2009, 1, 193; (b) Gudmundsdottir, A. V.;
Nitz, M. Org. Lett. 2008, 10, 3461; (c) Lainchbury, M. D.; Medley, M. I.; Taylor, P.
M.; Hirst, P.; Dohle, W.; Booker-Milburn, K. I. J. Org. Chem. 2008, 73, 6497; (d)
Baran, P. S.; Maimone, T. J.; Richter, J. M. Nature 2007, 446, 404; (e) McFadden,
21. Ager, D. J. Org. React. 1990, 38, 1.
22. Wong, C. H.; Ye, X. S.; Zhang, Z. Y. J. Am. Chem. Soc. 1998, 120, 7137.