Lithium perchlorate-catalyzed Boc protection of amines and amine derivatives

Article abstract of DOI:10.1002/adsc.200505218

A new mild and chemoselective method for mono-N-protection of amines and amine derivatives as tert-butoxycarbonyl derivatives is reported. The reaction proceeds with lithium perchlorate (20 mol %) and pyrocarbonates, and shows general applicability. The catalytic action of LiClO₄ is specific for the activation of Boc₂O, thus acid-sensitive functionalities of the starting materials remain unchanged in the protection process. This procedure works well for sterically hindered primary amine as well as electron-deficient primary arylamines, primary and secondary amino alcohols, α-amino acid esters, hydroxylamines, hydrazines and sulfonamides.

Full text of DOI:10.1002/adsc.200505218

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DOI: 10.1002/adsc.200505218
Lithium Perchlorate-Catalyzed Boc Protection of Amines and
Amine Derivatives
Akbar Heydari,* Seyed Esmaeil Hosseini
Chemistry Department, Tarbiat Modarres University, P. O. Box 14155-4838, Tehran, Iran
Fax: (þ98)-21-8800-6544, e-mail: Akbar.heydari@gmx.de
Received: May 26, 2005; Accepted: August 10, 2005
Dedicated to Professor Abdoljalil Mostashari on the occasion of his 66th birthday.
Abstract: A new mild and chemoselective method
for mono-N-protection of amines and amine deriva-
tives as tert-butoxycarbonyl derivatives is reported.
The reaction proceeds with lithium perchlorate
(20 mol %) and pyrocarbonates, and shows general
applicability. The catalytic action of LiClO4 is specif-
ic for the activation of Boc2O, thus acid-sensitive
functionalities of the starting materials remain un-
changed in the protection process. This procedure
works well for sterically hindered primary amine as
well as electron-deficient primary arylamines, pri-
mary and secondary amino alcohols, a-amino acid
esters, hydroxylamines, hydrazines and sulfonamides.
ondary arylamines proceed sluggishly.[4] Moreover,
when a primary arylamine is able to react, various side
reactions such as biscarbamoylation or the formation
of isocyanates as well as urea can also occur.[5] Due to
the very attractive nature of the N-Boc group, there
have been many attempts to find alternative methodol-
ogies for this reaction which do not suffer the severe
drawbacks of the classical procedures, most of which
are carried out in the presence of a base.[6] The use of
Lewis acid catalysts to effect the above type of transfor-
mation is rare.[7] It is difficult to extend the Lewis acid-
catalyzed Boc protection of amines, because the strong
affinity of many Lewis acids for amino groups does not
allow regeneration of the Lewis acids in the reaction.[8]
Moreover, it should be noted that most Lewis acids can-
not used in this reaction since they are decomposed or
deactivated by the amines and amine derivatives. Even
when the desired reactions proceed, because the acids
are trapped by nitrogen, more than the stoichiometric
amounts of Lewis acids are needed.[9]
Keywords: amine protection; Boc derivatives; di-tert-
butyl pyrocarbonate, lithium perchlorate
The development of mild and selective methods for the
In the past few years, lithium perchlorate has been
protection of amine groups is important for organic syn- widely exploited as a Lewis acid promoter in various or-
thesis.[1]. Due to its stability towards catalytic hydrogen- ganic transformations.[10] Furthermore, lithium perchlo-
olysis and extreme resistance towards basic and nucleo- rate is found to retain its activity even in the presence of
philic reactions, the tert-butoxycarbonyl (abbreviated nitrogen-containing compounds.[11] This prompted us to
Boc or t-Boc) group is one of the most useful functions use this catalyst for the synthesis of N-Boc protected
for the protection of amines.[2] Removal of the Boc pro- amines. Herein we report that LiClO4 serves as an excel-
tecting group is conveniently and easily carried out with lent catalyst for the selective tert-butoxycarbonylation
CF3COOH within 5–10 min at room temperature. of amines.
Cheaper acids such as 3 M HCl in EtOAc or 10%
The substrates examined in our studies and the results
H2SO4 in dioxane might be considered for large-scale obtained are summarized in Scheme 1. Thus, the present
deprotection. The stability of the Boc group makes it procedure to introduce the N-Boc protecting group is
an ideal orthogonal partner for benzyl esters and carb- quite general as a wide range of structurally varied
amates which are used in peptide synthesis. The com- amines such as open chain, cyclic, aromatic, heteroaro-
mercially available di-tert-butyl pyrocarbonate (Boc2O) matic amines as well as a-amino alcohols and a-amino
is an efficient reagent for the clean and rapid intro- acid esters underwent reaction smoothly with Boc2O.
duction of the Boc-protecting group at the amine func- The method can be applied for the conversion of low re-
tionality.[3] Although alkylamines are well known to active amine, such as 4-nitroaniline, as well as the steri-
give the mono-protected derivatives by the action of cally hindered tert-butylamine, to the corresponding N-
Boc2O, without the assistance of any catalyst, the analo- Boc derivatives. Similarly, with 1,2-phenylenediamine
gous reactions of some poorly reactive primary and sec- the mono-N-Boc protected product was obtained in a
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Akbar Heydari, Seyed Esmaeil Hosseini
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In a further study, an amino acid ester was converted
to the corresponding N-Boc ester under similar reaction
conditions. It is noteworthy that the reaction is chemose-
lective in the case of 2-phenylglycinol and ephedrine as
the amine, where the N-Boc protected products were
obtained as the sole products and neither O-Boc nor ox-
azolidinone derivatives were observed (by NMR). Al-
though alcohols are known to react with Boc2O in the
presence of DMAP to give O-Boc derivatives together
with symmetrical carbonates,[12] in the above cases no
O-Boc or oxazolidinone derivatives were observed (by
NMR). Another notable feature of the reaction is that
even a secondary amine reacted smoothly to afford the
product in high isolated yield.
To extend the synthetic potential this novel method of
chemoselective protection of amines, we also examined
its efficiency in reactions with hydroxylamines, hydra-
zines and sulfonamides. As shown in Scheme 2, the cor-
responding mono-N-Boc compounds were obtained in
good isolated yields.
In summary, a new, simple and efficient method for
the monoprotection of primary aliphatic and aromatic
amines, secondary amines, 1, 2-diamines, as well as het-
eroaromatic amines, amino alcohols, a-amino acid es-
ters, hydroxylamines, hydrazines and sulfonamides as
N-Boc derivatives has been developed. The noteworthy
feature of this methodology is that substrates with labile
functionalities, such as esters, are compatible with the
reaction conditions. The protection reaction is chemose-
lective: the amine is exclusively protected in the pres-
ence of an alcohol group. It is important to highlight
that, in the case of primary amines or amine derivatives,
any side reaction, such as formation of bis-Boc deriva-
tives, isocyanates or ureas, were never observed, as veri-
1
fied by H-NMR spectroscopy of the crude products.
Scheme 1. LiClO4 (20 mol %)-catalyzed protection of amines.
reasonably good yield. However, reaction of 2-amino-
aniline with Boc2O (1.5 equivs.) in MeCN at room tem-
perature afforded the N,N’-di-Boc product in 95% yield
after 24 h.[7a] The use of Boc2O in the presence of 0.5
equivs. of 4-(dimethylamino)pyridine and 2-aminoani-
line afforded 1,3-di-Boc-benzimidazolidinone in 50%
yield and 50% of starting amine was recovered.[5a]
Scheme 2. LiClO4 (20 mol %)-catalyzed protection of amine
derivatives.
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Adv. Synth. Catal. 2005, 347, 1929 – 1932

Boc Protection of Amines and Amine Derivatives
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d¼1.35 (bs, 1H, NH), 1.47 (bs, 1H, OH), 1.5 (s, 9H), 3.8 (d,
2H), 4.7 (t, 1H), 7.2–7.6 (m, 5H); 13C NMR (22.5 MHz,
CDCl3): d¼27.9 (CH3), 56.8 (C), 66.6 (CH), 79.9 (CH2),
126.7 (CH), 127.8 (CH), 128.8 (CH), 139.8 (C), 156.5 (CO).
3i: IR (neat): n¼3430, 3060, 2945, 2925, 1798, 1741, 1660,
1H NMR (90 MHz, CDCl3): d¼1.3 (d, 3H), 1.7 (s, 9H), 2.6 (s,
3H), 3.2 (bs, 1H), 4.1 (q, 1H), 4.7 (d, 1H, CH), 7.1–7.5 (m,
5H); 13C NMR (22.5 MHz): d¼12.7 (CH3), 27.1 (CH3), 28.0
(CH3), 30.8 (CH), 57.4 (CH), 79.6 (C), 126.5 (CH), 127.6
(CH), 128.2 (CH), 142.5 (C), 156.5 (CO).
Moreover, this protocol appears to be competitive and
in some cases superior to previously reported proce-
dures that work under basic conditions. For example,
in the case of N-Boc-4-nitroaniline (3e, Table 1) we ob-
tained a good yield in 5 hours at room temperature,
while other procedure failed or required long times or
very harsh reaction condition (14 h, 50%).[7b]
1469, 1437, 1398, 1368, 1331, 1249, 1148, 1044, 754, 693 cmꢀ1
;
Experimental Section
5a: IR (neat): n¼3305, 2970, 1700, 1451, 1398, 1366, 1277,
1
1247 cmꢀ1; H NMR (90 MHz, CDCl3): d¼0.13 (s, 9H), 1.5
General Procedure for Preparation of N-Boc-Amines
and Amine Derivatives
(s, 9H), 7.1 (bs, 1H); 13C NMR (22.5 MHz, CDCl3): d¼3.25
(CH3), 29.6 (CH3), 83.4 (C), 160 (CO).
5b: IR (neat): n¼3245, 2970, 2850,1706, 1505, 1441, 1364,
1242, 1180, 1094 cmꢀ1; 1H NMR (90 MHz, CDCl3): d¼1.5 (s,
9H), 2.7 (s, 6H), 5.5 (bs, 1H); 13C-NMR (22.5 MHz, CDCl3):
d¼28.0 (CH3), 47.5 (CH3), 80.2 (C), 154.7 (CO).
To a mixture of Boc2O (437 mg, 2 mmol) and LiClO4 (43 mg,
20 mol %) in 4 mL of CH2Cl2 was added 2 mmol of amine or
amine derivative. After stirring for 5 h at room temperature,
the resulting suspension was filtered and the filtrate concen-
trated on a rotary evaporatur to afford the crude product.
The product was purified by flash chromatography (hexane-
5c: IR (neat): n¼3360, 3340, 3125, 2990, 2980, 1799, 1755,
1
1452, 1371, 1302, 1208, 1151, 1116, 1066, 767, 661 cmꢀ1; H
NMR (90 MHz, CDCl3): d¼1.5 (s, 9H), 2.2 (s, 3H), 5.2 (bs,
1H), 7.3 (d, 2H), 7.8 (d, 2H); 13C NMR (22.5 MHz, CDCl3):
d¼21.5 (CH3), 27.4 (CH3), 85.1 (C), 126.4 (CH), 129.4 (CH),
139.2 (C), 143.5 (C), 146.7 (CO).
1
ethyl acetate). H-NMR, 13C-NMR, IR spectra were entirely
consistent with the assigned structures. Spectroscopic data
for selected examples are given below.
3a: IR (neat): n¼3420, 2950, 1799, 1762, 1680, 1451,
1
13671207, 1113, 1066 cmꢀ1; H NMR (90 MHz, CDCl3): d¼
1.6 (s, 9H), 2.2 (s, 9H), 3.5 (bs, 1H); 13C NMR (22.5 MHz):
d¼27.4 (CH3), 29.9 (CH3), 50.1 (C), 85.1 (C), 147.1 (CO).
3b: IR (neat): n¼2920, 1685, 1445, 1403, 1230, 1161, 1112,
872 cmꢀ1; 1H NMR (90 MHz, CDCl3): d¼1.5 (s, 9H), 4.5 (bs,
4H), 7.7–7.3 (m, 10H); 13C NMR (22.5 MHz): d¼28.1 (CH3),
48.9 (C), 80 (CH2), 127.4 (CH), 127.9 (CH), 128.7 (CH),
138.2 (C), 156.3 (CO).
Acknowledgements
We would like to express our sincere thanks to Professor Mo-
hamed Yalpani for his helpful discussion. Research supported
by the National Research Council ofI. R. Iran as a National Re-
search project under the number 984.
3c: IR (neat): n¼2995, 1683, 1448, 1413, 1360, 1277, 1246,
1166, 1123, 1083, 860 cmꢀ1; H NMR (90 MHz, CDCl3): d¼
1
1.5 (s, 9H), 3.37 (t, 4H), 3.52 (t, 4H); 13C NMR (22.5 MHz,
CDCl3): d¼28.1 (CH3), 43.7 (C), 66.6 (CH2), 79.9 (CH2), 155
(CO).
References and Notes
[1] a) P. J. Kociensky, in: Protecting Groups; Georg Thieme
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[2] a) E. Wuensch, in: Houben-Weyl, Methods ofOrganic
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[3] a) L. Moroder, A.Hallett, E. Wuensch, O. Keller, G.
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McNeil, Tetrahedron Lett. 1994, 35, 9003.
3d: IR (neat): n¼3385, 3030, 1679, 1507, 1441, 1390, 1365,
1
1307, 1244, 1167, 1070, 749, 688 cmꢀ1; H NMR (500 MHz,
CDCl3 ): d¼1.42 (s, 9H), 1.41 (d, 3H), 4.8 (bs, 2H , NH and
CH), 7.22–7.34 (m, 5H); 13C NMR (122 MHz, CDCl3): d¼
22.6 (CH3), 28.1 (CH3), 50.2 (C), 79.4 (CH), 125.8 (CH), 12.7
(CH), 128.5 (CH), 144.0 (C), 155.1 (CO).
3e: IR (neat): n¼3380, 2990, 2965, 1718, 1588, 1522, 1492,
1
1461, 1365, 1305, 1281, 1220, 1106, 840 cmꢀ1; H NMR (90
MHZ, CDCl3): d¼1.5 (s, 9H), 4.5 (bs, 1H), 6.7 (d, 2H), 8.1
(d, 2H); 13C NMR (22.5 MHz, CDCl3): d¼29.1 (CH3), 51.5
(C), 113.0 (CH), 125.3 (CH), 126.3 (C), 137.6 (C), 152.7 (CO).
3f: IR (neat): n¼3445, 3350, 3300, 3120, 2975, 1677, 1622,
1587, 1513, 1484, 1444, 1365, 1294, 1248, 1159, 1049, 740 cmꢀ1
;
1H NMR (90 MHz, CDCl3); d¼1.5 (s, 9H), 3.8 (bs, 2H), 6.4
(bs, 1H), 6.7–7.4 (m, 4H); 13C NMR (22.5 MHz, CDCl3): d¼
28 (CH3), 80.4 (C), 117.8 (CH), 119.8 (CH), 124.9 (CH),
125.0 (CH), 126.0 (C), 139.7 (C), 154.2 (CO).
3g: IR (neat): n¼3125, 2975, 1747, 1464, 1379, 1315, 1291,
1241, 1150, 1089, 995, 833, 765, 644 cmꢀ1; 1H-NMR (90 MHz,
CDCl3): d¼1.5 (s, 9H), 7.2 (s, 1H), 7.37 (s, 1H), 8.1 (s, 1H);
13C NMR (22.5 MHz, CDCl3): d¼27.6 (CH3), 85.6 (C), 117.2
(CH), 130.3 (CH), 137.2 (CH), 147.4 (CO).
[5] a) Y. Basel, A. Hassner, J. Org. Chem. 2000, 65, 6368;
b) H.-J. Knoelker, T. Braxmeier, G. Schlechtingen, An-
gew. Chem. Int. Ed. Engl. 1995, 34, 2497; c) H.-J. Knoelk-
er, T. Braxmeier, G. Schlechtingen, Synlett 1996, 502.
3h: IR (neat): n¼3345, 3305, 2895, 1663, 1541, 1363, 1285,
1
1176, 1049, 1023, 753, 694 cmꢀ1; H NMR (90 MHz, CDCl3):
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Akbar Heydari, Seyed Esmaeil Hosseini
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[6] For examples, see: a) L. Grehn, U. Gagnarsson, Angew.
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Lutz, V. Lutz, P. Knochel, Tetrahedron 1998, 54, 6385;
d) S. W. Bailey, R. Y. Chandrasekaran, J. E. Ayling, J.
Org. Chem. 1992, 57, 4470; for highly sterically hindered
substrates as well as electron deficient arylamines these
methods often give poor yields and are generally not sat-
isfactory.
[7] a) F. Porta, S. Cenini, M. Pizzotti, C. Crotti, Gazz. Chim.
Ital. 1985, 115, 275; b) G. Bartoli, M. Bosco, M. Locatelli,
E. Marcantoni, M. Massaccesi, Synlett 2004, 10, 1794;
c) R. K. Pandey, S. P. Ragade, R. K. Upadhyay, M. K.
Dongare, P. Kumar, Arkivoc 2002, 28.
[8] L. Niimi, K.-J. Serita, S. Hiraoka, T. Yokozawa, Tetrahe-
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[9] a) S. Kobayashi, M. Araki, M. Yasuda, Tetrahedron Lett.
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mura, H. Ashitani, Chem. Lett. 1997, 1039.
[10] For a review, see: A. Heydari, Tetrahedron, 2002, 58,
6777, and references cited therein.
[11] a) J. S. Yadav, B. V. S. Reddy, Ch. V. S. R. Murthy, J. M.
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[12] V. F. Pozdnev, Int. J. Pept Protein Res. 1992, 40, 407.
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