Organic & Biomolecular Chemistry
Paper
the presence of water, acid catalysed hydrolysis can occur.).
Therefore, when handled under the proposed dry and solvent-
free conditions, the presence of these protecting groups and
functionalities becomes inconsequential. However, we did
observe that epoxides, activated olefins and the N-Cbz group
were not stable under these conditions and reacted with HCl.
Finally, this procedure is easily scalable by simply using a
larger two-chamber reactor. This was illustrated by de-
protection of N-Boc benzylamine on a 5 mmol scale and Boc-L-
pyroglutamic acid methyl ester on a 5 gram scale resulting in
quantitative isolated yields of 1 and 18 (Scheme 3b).41 This
procedure was shown to be scalable on a laboratory scale and
can be used as an enabling framework towards kilogram scale
gas-solid N-Boc deprotections.27
2 A. Isidro-Llobet, M. Álvarez and F. Albericio, Chem. Rev.,
2009, 109, 2455–2504.
3 P. G. M. Wuts and T. W. Greene, Greene’s Protective Groups
in Organic Synthesis, 2006, pp. 1–15, DOI: 10.1002/
9780470053485.ch1.
4 S. D. Roughley and A. M. Jordan, J. Med. Chem., 2011, 54,
3451–3479.
5 P. J. Kocieński, Protecting Groups, Georg Thieme Verlag,
Stuttgart, New York, 3rd edn, 2005.
6 E. Langille, C. S. Bottaro and A. Drouin, J. Flow Chem.,
2020, 10, 377–387.
7 J. Wu, C. Zheng, B. Li, J. M. Hawkins and S. L. Scott, React.
Chem. Eng., 2021, 6, 279–288.
8 G. Wang, C. Li, J. Li and X. Jia, Tetrahedron Lett., 2009, 50,
1438–1440.
9 J. Wang, Y.-L. Liang and J. Qu, Chem. Commun., 2009,
5144–5146, DOI: 10.1039/B910239F.
Conclusions
10 A. R. Bogdan, M. Charaschanya, A. W. Dombrowski,
Y. Wang and S. W. Djuric, Org. Lett., 2016, 18, 1732–1735.
11 B. Li, R. Li, P. Dorff, J. C. McWilliams, R. M. Guinn,
S. M. Guinness, L. Han, K. Wang and S. Yu, J. Org. Chem.,
2019, 84, 4846–4855.
12 S. S. Bhawal, R. A. Patil and D. W. Armstrong, RSC Adv.,
2015, 5, 95854–95856.
13 S. Majumdar, J. De, A. Chakraborty, D. Roy and D. K. Maiti,
RSC Adv., 2015, 5, 3200–3205.
14 D. J. C. Constable, C. Jimenez-Gonzalez and
R. K. Henderson, Org. Process Res. Dev., 2007, 11, 133–137.
15 D. Margetić and M. Đud, Int. J. Org. Chem., 2017, 7, 140–
144.
16 G. Pavan Kumar, D. Rambabu, M. V. Basaveswara Rao and
M. Pal, J. Chem., 2013, 2013, 5.
17 D. Shonnard, A. Lindner, N. Nguyen, P. A. Ramachandran,
D. Fichana, R. Hesketh, C. S. Slater and R. Engler, in Kent
and Riegel’s Handbook of Industrial Chemistry and
Biotechnology, ed. J. A. Kent, Springer US, Boston, MA,
2007, pp. 210–270, DOI: 10.1007/978-0-387-27843-8_6.
18 C. J. Mallia and I. R. Baxendale, Org. Process Res. Dev.,
2016, 20, 327–360.
In summary, a procedure has been developed for the clean
removal of N-Boc protecting groups and isolation of products
in quantitative yields without the need for purification or
work-up. The reaction proceeds under solvent-free conditions
at room temperature, using down to near-stoichiometric
amounts of ex situ generated HCl gas. We devised an opera-
tionally simple two-chamber reactor with
a detachable
chamber allowing transfer-free product isolation and follow-up
reactions. Besides being a labor-, waste- and cost-effective
N-Boc deprotection method, it displays a broad scope with
respect to the N-Boc groups that can be deprotected and func-
tional groups that are tolerated. The high tolerance towards
otherwise acid sensitive functional groups and expanded func-
tional group orthogonality will likely render it a useful tool in
protecting group strategies for complex organic syntheses.
Moreover, this solvent-free procedure and new reactor design
are promising for further sustainable synthetic purposes.
Conflicts of interest
There are no conflicts of interest to declare.
19 S. D. Friis, A. T. Lindhardt and T. Skrydstrup, Acc. Chem.
Res., 2016, 49, 594–605.
20 J. Demaerel, C. Veryser and W. M. De Borggraeve, React.
Chem. Eng., 2020, 5, 615–631.
Acknowledgements
21 G. Kaupp and A. Kuse, Mol. Cryst. Liq. Cryst. Sci. Technol.,
Sect. A, 1998, 313, 361–366.
22 G. Kaupp, Organic Solid-State Reactions with 100% Yield,
in Organic Solid State Reactions, ed. F. Toda, Springer Berlin
Heidelberg, Berlin, Heidelberg, 2005, DOI: 10.1007/
b100997, pp. 95–183.
We are grateful to Bart Van Huffel (KU Leuven) for the assistance
with NMR measurements and performing the elemental ana-
lyses and Wouter Stuyck (cMACS – KU Leuven) for performing
the chiral HPLC analyses. R. H. V. and P. G. thank the Research
Foundation – Flanders (FWO) for support received through fel-
lowships 11D6220N and 1S09017N. R. H. V. would like to thank
Elien J. Van der Gucht for the unconditional support.
23 V. Declerck, P. Nun, J. Martinez and F. Lamaty, Angew.
Chem., Int. Ed., 2009, 48, 9318–9321.
24 O. Maurin, P. Verdié, G. Subra, F. Lamaty, J. Martinez and
T.-X. Métro, Beilstein J. Org. Chem., 2017, 13, 2087–2093.
25 Y. Yeboue, B. Gallard, N. Le Moigne, M. Jean, F. Lamaty,
J. Martinez and T.-X. Métro, ACS Sustainable Chem. Eng.,
2018, 6, 16001–16004.
Notes and references
1 M. Schelhaas and H. Waldmann, Angew. Chem., Int. Ed.
Engl., 1996, 35, 2056–2083.
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