Please do not adjust margins
Organic & Biomolecular Chemistry
Page 4 of 4
COMMUNICATION
Journal Name
Scheme 3 Gram‐scale synthesis of 2,5‐disubstituted tetrazole 4aa.
Henan Province (19HASTIT036), and the 111 Project (No.
DOI: 10.1039/C8OB02089B
D17007).
Notes and references
1
(a) R. J. Herr, Bioorg. Med. Chem., 2002, 10, 3379; (b) J. Roh,
K. Vávrová and A. Hrabálek, Eur. J. Org. Chem., 2012, 6101.
D. J. Carini, J. V. Duncia, P. E. Aldrich, A. T. Chiu, A. L. Johnson,
M. E. Pierce, W. A. Price, J. B. Santella III, G. J. Wells, R. R.
Wexler, P. C. Wong, S.‐E. Yoo and P. B. M. W. M.
Timmermans, J. Med. Chem., 1991, 34, 2525.
and TBSOTf 3a proceeded well at RT for 2 h, giving the desired
2,5‐disubstituted tetrazole hemiaminal silyl ether 4aa in 2.96 g
without any loss of yield and regioselectivity.
2
3
4
E. J. Lewis , L. G. Hunsicker , W. R. Clarke , T. Berl , M. A. Pohl ,
J. B. Lewis , E. Ritz , R. C. Atkins , R. Rohde and I. Raz, N. Engl.
J. Med., 2001, 345, 851.
(a) W. R. Schoen, J. M. Pisano, K. Prendergast, M. J. Wyvratt,
M. H. Fisher, K. Cheng, W. W.‐S. Chan, B. Butler, R. G. Smith
and R. G. Ball, J. Med. Chem., 1994, 37, 897; (b) Y. Uchiyama,
J. S. Dolphin, R. L. Harlow, W. J. Marshall and A. J. Arduengo,
III, Aust. J. Chem., 2014, 67, 405.
Scheme 4 The release of 5‐phenyl tetrazole 1a from 2,5‐disubstituted
tetrazole hemiaminal silyl ether 4aa
.
5
(a) D. E. Ryono, J. Lloyd, M. A. Poss, J. E. Bird, J. Buote, S.
Chong, T. Dejneka, K. E. J. Dickinson, Z. Gu, P. Mathers, S.
Moreland, R. A. Morrison, E. W. Petrillo, J. R. Powell, T.
Schaeffer, E. R. Spitzmiller and R. E. White, Bioorg. Med.
Considering that silyl ether prodrugs are acid labile and
release the corresponding drugs under acid conditions, the
release experiment of 5‐substituted tetrazole from 2,5‐
disubstituted tetrazole hemiaminal silyl ether was performed
(Scheme 4). In the presence of 5 mol% of HCl solution in
CH3OH for 2 h, the 2,5‐disubstituted tetrazole hemiaminal silyl
ether 4aa was consumed completely, affording 5‐phenyl
tetrazole 1a in 99% yield.
Chem. Lett., 1994, 4, 201; (b) M. T. Obermeier, S. Chong, S. A.
Dando, A. M. Marino, D. E. Ryono, A. Starrett‐Arroyo, G. C.
DiDonato, B. M. Warrack, R. E. White and R. A. Morrison, J.
Pharm. Sci., 1996, 85, 828.
K. M. Huttunen, H. Raunio and J. Rautio, Pharmacol. Rev.,
2011, 63, 750.
K. S. Chu, M. C. Finniss, A. N. Schorzman, J. L. Kuijer, J. C. Luft,
C. J. Bowerman, M. E. Napier, Z. A. Haroon, W. C. Zamboni
and J. M. DeSimone, Nano Lett., 2014, 14, 1472.
M. C. Parrott, M. Finniss, J. C. Luft, A. Pandya, A. Gullapalli, M.
6
7
Conclusions
8
9
We have reported an efficient route to construct 2,5‐
disubstituted tetrazole hemiaminal silyl ethers via one‐pot
three‐component hemiaminal silylation reaction of 5‐
substituted tetrazoles, aldehydes, and silyl triflates. With
iPr2EtN as the base, a variety of 2,5‐disubstituted tetrazole
hemiaminal silyl ethers were afforded in moderate to good
yields and 37:62‐>99:1 regioisomeric ratios. The
regioselectivities of this three‐component hemiaminal
silylation were significantly affected by the steric hindrance
and conjugation effects of substitutions on the 5‐position of
tetrazoles. Furthermore, the three‐component hemiaminal
silylation reaction could be performed on a gram‐scale,
delivering the desired disubstituted tetrazole in excellent
results. In addition, the 5‐phenyl tetrazole could be released
totally under acid atmosphere from the 2,5‐disubstituted
tetrazole hemiaminal silyl ether.
E. Napier and J. M. DeSimone, J. Am. Chem. Soc., 2012, 134
,
7978.
(a) R. N. Butler and V. C. Garvin, J. Chem. Soc., Perkin Trans. 1,
1981, 390; (b) R. N. Butler, D. P. Shelly and V. C. Garvin, J.
Chem. Soc., Perkin Trans. 1, 1984, 1589.
10 (a) G. I. Koldobskii and R. B. Kharbash, Russ. J. Org. Chem.,
2003, 39, 453; (b) G. Ortar, M. G. Cascio, A. Schiano Moriello,
M. Camalli, E. Morera, M. Nalli and V. Di Marzo, Eur. J. Med.
Chem., 2008, 43, 62; (c) G. Ortar, A. Schiano Moriello, M. G.
Cascio, L. De Petrocellis, A. Ligresti, E. Morera, M. Nalli and V.
Di Marzo, Bioorg. Med. Chem. Lett., 2008, 18, 2820; (d) Y. A.
Efimova, T. V. Artamonova and G. I. Koldobskii, Russ. J. Org.
Chem., 2009, 45, 725; (e) S. Harusawa, H. Yoneyama, D.
Fujisue, M. Nishiura, M. Fujitake, Y. Usami, Z.‐y. Zhao, S. A.
McPhee, T. J. Wilson and D. M. J. Lilley, Tetrahedron Lett.,
2012, 53, 5891.
11 (a) L. Wang, K. Zhu, Q. Chen and M. He, J. Org. Chem., 2014,
79, 11780; (b) K.‐q. Zhu, L. Wang, Q. Chen and M.‐y. He,
Tetrahedron Lett, 2015, 56, 4943; (c) I. Melnikova, J. Roh, J.
Kuneš, T. Artamonova, Y. Zevatskii and L. Myznikov,
Tetrahedron Lett., 2017, 58, 3842.
12 (a) D. W. Piotrowski, A. S. Kamlet, A.‐M. R. Dechert‐Schmitt, J.
Yan, T. A. Brandt, J. Xiao, L. Wei and M. T. Barrila, J. Am.
Chem. Soc., 2016, 138, 4818; (b) A. Kinens, M. Sejejs, A. S.
Kamlet, D. W. Piotrowski, E. Vedejs and E. Suna, J. Org.
Chem., 2017, 82, 869; (c) A. Akin, M. T. Barrila, T. A. Brandt,
A.‐M. R. Dechert‐Schmitt, P. Dube, D. D. Ford, A. S. Kamlet, C.
Limberakis, A. Pearsall, D. W. Piotrowski, B. Quinn, S.
Rothstein, J. Salan, L. Wei and J. Xiao, Org. Process Res. Dev.,
2017, 21, 1990.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
We are grateful for financial support from the National Natural
Science Foundation of China (Nos. U1604283, 21472037, and
21778014), China Postdoctoral Science Foundation funded
project (2016M592293 and 2018T110726), the Program for
13 M.‐S. Xie, Y.‐G. Chen, X.‐X. Wu, G.‐R. Qu and H.‐M. Guo, Org.
Lett., 2018, 20, 1212.
4 | J. Name., 2012, 00, 1‐3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins