Simple and efficient method for n-boc protection of amines using PEG-400 as a reaction medium under mild conditions

Article abstract of DOI:10.1080/00397911.2010.520831

Simple and efficient method for N-Boc protection of amines using PEG-400 as an ecofriendly reaction medium at room temperature is described. Various aromatic, heteroaromatic, and aliphatic amines were converted to the corresponding N-tert-butyl-carbamates in good to excellent yields in short times.

Full text of DOI:10.1080/00397911.2010.520831

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Simple and Efficient Method for N-Boc
Protection of Amines Using PEG-400 as a
Reaction Medium Under Mild Conditions
Hongyao Zeng a , Yongjia Li b & Huawu Shao a
a Natural Products Research Center, Chengdu Institute of Biology,
Chinese Academy of Sciences, Chengdu, ChinaGraduate School of
Chinese Academy of Sciences, China
b College of Chemistry, Sichuan University, Chengdu, China
Accepted author version posted online: 30 Jun 2011. Version of
record first published: 14 Sep 2011
To cite this article: Hongyao Zeng, Yongjia Li & Huawu Shao (2012): Simple and Efficient Method for
N-Boc Protection of Amines Using PEG-400 as a Reaction Medium Under Mild Conditions, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
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Synthetic Communications1, 42: 25–32, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.520831
SIMPLE AND EFFICIENT METHOD FOR N-BOC
PROTECTION OF AMINES USING PEG-400 AS A
REACTION MEDIUM UNDER MILD CONDITIONS
Hongyao Zeng,1 Yongjia Li,2 and Huawu Shao1
1Natural Products Research Center, Chengdu Institute of Biology,
Chinese Academy of Sciences, Chengdu, China, and
Graduate School of Chinese Academy of Sciences, China
2College of Chemistry, Sichuan University, Chengdu, China
GRAPHICAL ABSTRACT
Abstract Simple and efficient method for N-Boc protection of amines using PEG-400 as an
ecofriendly reaction medium at room temperature is described. Various aromatic, heteroaro-
matic, and aliphatic amines were converted to the corresponding N-tert-butyl-carbamates in
good to excellent yields in short times.
Keywords Di-tert-butyl dicarbonate; N-tert-butoxycarbonylation; PEG-400; protection
of amines
INTRODUCTION
The protection of amines plays an essential role in synthetic organic chemistry
and medicinal chemistry, especially peptide synthesis.[1] Out of the vast array of
available amine protecting groups, the tert-butoxycarbonyl (Boc) group has emerged
as the most commonly and widely used strategy because of ease of protection and
deprotection.[2] Various conventional base-mediated methods for the N-Boc protec-
tion of amines have been developed, for example, dimethylaminopyridine (DMAP),[3]
NaHMDS,[4] K2CO3,[5] NaOH,[6] and Et3N.[7] However, the base-catalyzed reactions
often lead to the formation of side products such as isocyanate, urea, and N,N-di-Boc
derivatives.[3b,8] Additionally, the unpleasant smell, high toxicity, requirement for
large excess, and nonrecyclability of these catalysts makes the method objectionable,
especially from the standpoint of green chemistry.
Lately several Lewis acids and heterogeneous catalysts such as ZrCl4,[9]
LiClO4,[10] Cu(BF4)2,[11] Zn(ClO4)2 ꢀ 6H2O,[12] La(NO3)3,[13] H3PW12O40,[14] I2,[15]
Received December 17, 2009.
Address correspondence to Huawu Shao, Chengdu Institute of Biology, Chinese Academy of
Sciences, Chengdu 610041, China. E-mail: shaohw@cib.ac.cn
25

26
H. ZENG, Y. LI, AND H. SHAO
and Montmorillonite K10[16] have been extensively investigated to achieve such
transformations. Although these methods circumvented the problem associated with
formation of the side products, many of Lewis acids are corrosive, moisture sensi-
tive, and nonrecoverable reagents, and the synthesis of heterogeneous catalysts often
involves long and tedious procedures. Moreover, most of these methodologies suffer
from use of volatile organic solvents, long reaction time, elevated temperature, and=
or substrate limitations. Therefore, new and mild methods for N-Boc protection are
in demand. In recent years, polyethylene glycols (PEGs) have attracted great interest
as powerful ecofriendly reaction media for various organic transformations[17]
because they are relatively inexpensive, thermally stable, readily recyclable, and
biodegradable.[18]
In continuation of our work on the utilization of PEG,[19] we report here a
simple and efficient method for the N-Boc protection of amines using PEG-400 as
an ecofriendly reaction medium at room temperature (Scheme 1).
The reaction of aniline (2.0 mmol) with (Boc)2O (1.2 equiv) using PEG-400
(2.0 mL) as a reaction medium at room temperature gave the corresponding N-Boc
aniline in 95% yield (Table 1, entry 7). This result encouraged us to extend the gener-
ality of the reaction. Various structurally diverse primary and secondary aliphatic,
aromatic, alicyclic, heterocyclic, and glycosyl amines with di-tert-butyl dicarbonate
gave the corresponding N-tert-butylcarbamates in good to excellent yields (Table 1).
No competitive side reactions leading to formation of isocyanate, urea or N,N-di-Boc
derivatives were detected by thin-layer chromatography (TLC), mass spectrometry
(MS), and 1H NMR analyses of the crude product. In general, alkylamines
(Table 1, entries 1–5) reacted completely in very short times. In contrast, arylamines
(Table 1, entries 7–14) proceeded in a sluggish manner. These results are not surpris-
ing because alkylamines are more nucleophilic than arylamines. Additionally, more
sluggish reactions were also observed with arylamines containing electron-deficient
or bulky groups (Table 1, entries 11–14). It is important to note that N-Boc protection
in PEG-400 is highly chemoselective: the amino group is protected exclusively in
presence of phenolic -OH (Table 1, entries 13 and 14), alcoholic -OH (Table 1, entries
23 and 24), or -Ac, -Ms, -Ts, and -Cbz groups (Table 1, entries 18–21, respectively).
However, in our study, it was observed that when the diamines were subjected
to N-tert-butoxycarbonylation, mono-N-Boc-protected products were difficult to
control even by using <1.0 equiv of (Boc)2O and short time, but di-N-Boc-protected
products were easy to form with 2.2 equiv of (Boc)2O in a very short time (Table 1,
entries 16 and 17), which is different from previous reports. Moreover, amino acid
derivatives, such as a-amino alcohols and a-amino acid ester, were also converted
into the corresponding N-Boc ester under similar reaction conditions (Table 1,
entries 23–25). N-Boc-protected products were solely obtained and no O-Boc or
oxazolidinone derivatives were observed.
Scheme 1. N-Boc protection form amines in PEG-400.

N-BOC PROTECTION OF AMINES
27
Table 1. N-Boc protection of amines in PEG-400a
Entry
1
Amine
Product
Time
Yieldb,c (%)
86
20 min
2
3
15 min
20 min
90
95
4
5
20 min
30 min
98
97
6
7
8
1.5 h
2 h
90
95, 92,d 88e
96
1.5 h
9
2 h
2 h
88
93
92
10
11
2.5 h
12
13
2.5 h
2.5 h
87
85
(Continued )

28
H. ZENG, Y. LI, AND H. SHAO
Table 1. Continued
Entry
14
Amine
Product
Time
3 h
Yieldb,c (%)
81
15
16
2.5 h
87
<5 min
98f
17
18
<5 min
98f
86
2 h
19
20
21
2 h
2 h
87
87
85
2.5 h
22
23
10 min
30 min
96
95
24
25
15 min
40 min
98
91
aThe amines (2.0 mmol) were treated with (Boc)2O (1.2 equiv) in PEG-400 (2.0 mL) at room temperature
under neat conditions.
bIsolated yield of the corresponding N-Boc derivative.
cThe products were characterized by IR, 1H NMR, and MS analyses.
dThe second run.
eThe third run.
fThe reaction was carried out with 2.4 equiv of (Boc)2O.

N-BOC PROTECTION OF AMINES
29
In summary, we have developed an environmentally friendly method for N-Boc
protection of variously amines. PEG-400 has been found to be an efficient and
recyclable reaction medium for the chemoselective transformation of amines to
N-(tert-butoxycarbonyl) amines. Compared to the previously reported methods,
this protocol offers several advantages including exceedingly mild conditions, oper-
ational simplicity, short reaction time, and good yield.
EXPERIMENTAL
Reactions were monitored by TLC using silica-gel HSGF254 plates. Flash
1
chromatography was performed using silica gel HG=T2354-92. H NMR and 13C
1
NMR (600 and 150 MHz, respectively) spectra were recorded in CDCl3. H NMR
chemical shifts are reported in ppm (d) relative to tetramethylsilane (TMS) with
the solvent resonance employed as the internal standard (CDCl3, d 7.26 ppm). Data
are reported as follows: chemical shift, multiplicity (s ¼ singlet, d ¼ doublet,
t ¼ triplet, m ¼ multiplet), coupling constants (Hz), and integration. 13C NMR
chemical shifts are reported in ppm from TMS with the solvent resonance as the
internal standard (CDCl3, d 77.0 ppm). Melting points were determined with an
X-6 (Beijing Fukai Co., Ltd.) melting-point apparatus and are uncorrected. Electro-
spray ioinization–high-resolution mass spectrographic (ESI-HRMS) spectra were
recorded on a BioTOF Q.
N-tert-Butoxycarbonylation of Amines
A mixture of amine (2.0 mmol) and (BOC)2O (2.4 mmol) in PEG-400 (2.0 mL)
was vigorously stirred at room temperature for the appropriate time (Table 1) until
TLC indicated total disappearance of the amine. After completion, the reaction
mixture was poured into water and extracted into dry ether. The combined organic
layer was dried over anhydrous sodium sulfate and concentrated under reduced
pressure to give a crude product, which was purified by silica-gel column chromato-
graphy to afford the corresponding N-tert-butyl-carbamate. The PEG-400 was
recovered from the aqueous layer and reused without loss of activity. The physical
data (mp, IR, NMR) of the known compounds were found to be identical with those
reported in the literature. Products 3r, 3 s, 3 t, and 3 u are new compounds. Spectral
data for selected new compounds are as follows:
6-Deoxy-6-[(tert-butoxycarbonyl)amino]-1,2:3,4-bis-O-
(1-methylethylidene)-a-D-galactopyranose (3v)
1
White solid, mp 116–117 ꢁC (lit.[20] 122–123 ꢁC). H NMR (600 MHz, CDCl3):
dH 1.32 (s, 3H), 1.33 (s, 3H), 1.43 (s, 9H), 1.44 (s, 3H), 1.50 (s, 3H), 3.16 (distorted br s,
1H), 3.44 (distorted br s, 1H), 3.91 (distorted br s, 1H), 4.19 (dd, J ¼ 1.4 Hz,
J ¼ 7.9 Hz, 1H), 4.30 (dd, J ¼ 2.2 Hz, J ¼ 4.8 Hz, 1H), 4.59 (dd, J ¼ 2.1 Hz, J ¼ 7.9 Hz,
Hz, 1H), 4.89 (br s, 1H), 5.51 (d, J ¼ 4.9 Hz, 1 H); 13C NMR (150 MHz, CDCl3): dC
24.4, 25.0, 25.9, 26.0, 28.3, 41.2, 66.7, 70.6, 70.8, 71.7, 79.2, 96.3, 108.7, 109.4, 156.1;
IR (KBr, cmꢂ1): v 3396, 2979, 2932, 1708, 1520, 1382, 1366, 1249, 1209, 1174, 1111,
1065, 1010.

30
H. ZENG, Y. LI, AND H. SHAO
tert-Butyl-4-acetamidophenylcarbamate (3r)
White solid, mp 182–183 ꢁC. 1H NMR (600 MHz, CDCl3): dH 1.51 (s, 9H), 2.15
(s, 3H), 6.43 (s, 1H), 7.10 (s, 1H), 7.30 (d, J ¼ 8.3 Hz, 2H), 7.41 (d, J ¼ 8.8 Hz, 2H);
13C NMR (150 MHz, CDCl3): dC 24.5, 28.3, 80.5, 119.2, 120.7, 133.2, 134.8, 152.8,
168.1; IR (KBr, cmꢂ1): v 3331, 2971, 2928, 1696, 1679, 1662, 1560, 1518, 1451, 1402,
1370, 1310, 1245, 1154, 1048, 1017, 901, 839, 774; ESI-HRMS Anal. calcd. for
C13H18N2O3Na [M þ Na]þ 273.1210; found: 273.1213.
tert-Butyl-4-(methylsulfonamido)phenylcarbamate (3s)
Light gray solid, mp 194–195 ꢁC. 1H NMR (600 MHz, CDCl3): dH 1.52 (s, 9H),
2.96 (s, 3H), 6.21 (s, 1H), 6.47 (s, 1H), 7.17 (d, J ¼ 8.8 Hz, 2H), 7.36 (d, J ¼ 8.4 Hz,
2H); 13C NMR (150 MHz, CDCl3): dC 28.6, 79.4, 119.5, 122.3, 132.8, 136.8, 153.3;
IR (KBr, cmꢂ1): v 3333, 3193, 2970, 2927, 1702, 1602, 1532, 1400, 1368, 1326,
1311, 1249, 1219, 1150, 1059, 980, 910, 814, 777. ESI-HRMS anal. calcd. for
C12H18N2O4SNa [M þ Na]þ 309.0879; found: 309.0865.
tert-Butyl-4-(4-methylphenylsulfonamido)phenylcarbamate (3t)
White solid, mp 170–171 ꢁC. 1H NMR (600 MHz, CDCl3): dH1.49 (s, 9H), 2.38
(s, 3H), 6.44 (s, 2H), 6.97 (d, J ¼ 8.8 Hz, 2H), 7.20 (d, J ¼ 8.2 Hz, 2H), 7.23 (d,
J ¼ 8.6 Hz, 2H), 7.59 (d, J ¼ 8.2 Hz, 2H); 13C NMR (150 MHz, CDCl3): dC 21.5,
28.3, 80.8, 119.2, 123.9, 127.3, 129.6, 131.1, 136.0, 136.4, 143.8, 152.6; IR (KBr,
cmꢂ1): v 3346, 3256, 2925, 1702, 1601, 1520, 1445, 1392, 1367, 1338, 1309, 1241,
1218, 1090, 1057, 912, 815, 714. ESI-HRMS anal. calcd. for C18H22N2O4SNa
[M þ Na]þ 385.1192; found: 385.1200.
tert-Butyl-4-(benzoyloxycarbonylamido)phenylcarbamate (3u)
White solid, mp 182–184 ꢁC. 1H NMR (600 MHz, CDCl3): dH 1.51 (s, 9H), 5.19
(s, 2H), 6.39 (s, 1H), 6.57 (s, 1H), 7.30 (s, 4H), 7.34 (t, 1H), 7.36–7.40 (overlap, 4H);
13C NMR (150 MHz, CDCl3): dC 28.3, 67.0, 119.4, 128.2, 128.3, 128.6, 136.1; IR
(KBr, cmꢂ1): v 3359, 2983, 2927, 1702, 1606, 1544, 1527, 1499, 1311, 1242, 1219,
1167, 1065, 829, 744. ESI-HRMS anal. calcd. for C19H22N2O4Na [M þ Na]þ
365.1472; found: 365.1462.
ACKNOWLEDGMENT
We are grateful for financial support from the Chinese Academy of Sciences
(Hundreds of Talents Program).
REFERENCES
1. Greene, T. W.; Wuts, P. G. M. In Protecting Group in Organic Synthesis; John Wiley and
Sons: New York, 1999.

N-BOC PROTECTION OF AMINES
31
2. (a) Wuensch, E. In Houben-Weyl Methods of Organic Chemistry, 4th ed.; E. Muller, O.
Bayer, H. Meerwein, K. Ziegler (Eds.); Georg Thieme: Stuttgart, 1974; vol. 15=1, p. 46;
(b) Agami, C.; Couty, F. The reactivity of the N-Boc protecting group: An underrated
feature. Tetrahedron 2002, 58, 2701–2724.
3. (a) Burk, M. J.; Allen, J. G. A mild amide to carbamate transformation. J. Org. Chem. 1997,
62, 7054–7057; (b) Basel, Y.; Hassner, A. Di-tert-butyl dicarbonate and 4-(dimethylamino)-
pyridine revisited: Their reactions with amines and alcohols. J. Org. Chem. 2000, 65,
6368–6380.
4. Kelly, T. A.; McNeil, D. W. A. simple method for the protection of aryl amines as their
t-butylcarbamoyl (Boc) derivatives. Tetrahedron Lett. 1994, 35, 9003–9006.
5. Barcelo, G.; Senet, J.-P.; Sennyey, G. Alkyl 1-chloroalkyl carbonates: Reagents for the
synthesis of carbamates and protection of amino groups. Synthesis 1986, 627–632.
6. For examples, see (a) Lutz, C.; Lutz, V.; Knochel, P. Enantioselective synthesis of 1,2-, 1,3-,
and 1,4-aminoalcohols by the addition of dialkylzincs to 1,2-, 1,3-, and 1,4-aminoaldehydes.
Tetrahedron 1998, 54, 6385–6402; (b) Bailey, S. W.; Chandrasekaran, R. Y.; Ayling, J. E.
Synthesis of tetrahydropteridine C6-stereoisomers, including N5-formyl-(6S)-
tetrahydrofolic acid. J. Org. Chem. 1992, 57, 4470–4477.
7. Itoh, M.; Hagiwara, D.; Kamiya, T. A new tert-butyloxycarbonylating reagent, 2-tert-
butyloxycarbonyloxyimino-2-phenylacetonitrile. Tetrahedron Lett. 1975, 4393–4394.
8. (a) Darnbrough, S.; Mervic, M.; Condon, S. M.; Burns, C. J. An improved synthesis of
N-Boc-protected aryl amines. Synth. Commun. 2001, 31, 3273–3280 (b) Knolker, H. J.;
Braxmeier, T.; Schlechtingen, G. Isocyanates—part 2: Synthesis of symmetrical and
unsymmetrical ureas by DMAP-catalyzed reaction of alkyl- and arylamines with
di-tert-butyldicarbonate. Synlett 1996, 502–504; (c) Knoelker, H.-J.; Braxmeier, T.
Isocyanates—part 3: Synthesis of carbamates by DMAP-catalyzed reaction of amines
with di-tert-butyldicarbonate and alcohols. Tetrahedron Lett. 1996, 37, 5861–5864; (d)
Knolker, H. J.; Braxmeier, T.; Schlechtingen, G. A novel method for the synthesis of
isocyanates under mild conditions. Angew. Chem., Int. Ed. Engl. 1995, 34, 2497–2500.
9. Sharma, G. V. S.; Reddy, J. J.; Lakshmi, P. S.; Krishna, P. R. Rapid and facile Lewis
acid–catalysed Boc protection of amines. Tetrahedron Lett. 2004, 45, 6963–6965.
10. Heydari, A.; Hosseini, S. E. Lithium perchlorate-catalyzed Boc protection of amines and
amine derivatives. Adv. Synth. Catal. 2005, 347, 1929–1932.
11. Chakraborti, A. K.; Chankeshwara, S. V. Copper(II) tetrafluoroborate as a novel and
highly efficient catalyst for N-tert-butoxycarbonylation of amines under solvent-free
conditions at room temperature. Tetrahedron Lett. 2006, 47, 1087–1091.
12. Bartoli, G.; Bosco, M.; Locatelli, M.; Marcantoni, E.; Massaccesi, M.; Melchiorre, P.;
Sambri, L. A Lewis acid–mediated protocol for the protection of aryl amines as their
Boc-derivatives. Synlett 2004, 1794–1798.
13. Suryakiran, N.; Prabhakar, P.; Reddy, S. T.; Rajesh, K.; Venkateswarlu, Y. Facile N-tert-
butoxycarbonylation of amines using La(NO3)3ꢀ6H2O as a mild and efficient catalyst
under solvent-free conditions. Tetrahedron Lett. 2006, 47, 8039–8042.
14. Heydari, A.; Kazem Shiroodi, R.; Hamadi, H.; Esfandyari, M.; Pourayoubi, M. N-tert-
Butoxycarbonylation of amines using H3PW12O40 as an efficient heterogeneous and
recyclable catalyst. Tetrahedron Lett. 2007, 48, 5865–5867.
15. Varala, R.; Nuvula, S.; Adapa, S. R. Molecular iodine–catalyzed facile procedure for
N-Boc protection of amines. J. Org. Chem. 2006, 71, 8283–8286.
16. Chankeshwara, S. V.; Chakraborti, A. K. Montmorillonite K 10 and montmorillonite
KSF as new and reusable catalysts for conversion of amines to N-tert-butylcarbamates.
J. Mol. Catal. A 2006, 253, 198–202.
17. For recent some examples of the use of PEG in organic synthesis, see (a) Rupesh, K.;
Preeti, C.; Surendra, N.; Ramesh, C. Polyethylene glycol as a non-ionic liquid solvent

32
H. ZENG, Y. LI, AND H. SHAO
for Michael addition reaction of amines to conjugated alkenes. Green Chem. 2006, 8,
356–358; (b) Das, B.; Krishnaiah, M.; Balasubramanyam, P. Veeranjaneyulu, P.; Kumar,
D. N. A remarkably simple N-formylation of anilines using polyethylene glycol.
Tetrahedron Lett. 2008, 49, 2225–2227; (c) Kumar, D.; Patel, G.; Mishra, B. G.; Varma,
R. S. Eco-friendly polyethylene glycol–promoted Michael addition reactions of
a,b-unsaturated carbonyl compounds. Tetrahedron Lett. 2008, 49, 6974–6976; (d) Zhu,
D. J.; Chen, J. X.; Xiao, H. L.; Liu, M. C.; Ding, J. C.; Wu, H. Y. Efficient and
expeditious synthesis of di- and trisubstituted thiazoles in PEG under catalyst-free con-
ditions. Synth. Commun. 2009, 39, 2895–2906; (e) Liang, J.; Lv, J.; Fan, J. C.; Shang,
Z. C. Polyethylene glycol as a nonionic liquid solvent for the synthesis of N-alkyl and
N-arylimides. Synth. Commun. 2009, 39, 2822–2828.
18. (a) Sheldon, R. A. Green solvents for sustainable organic synthesis: State of the art. Green
Chem. 2005, 7, 267–278; (b) Chen, J.; Spear, S. K.; Huddleston, J. G.; Rogers, R. D.
Polyethylene glycol and solutions of polyethylene glycol as green reaction media. Green
Chem. 2005, 7, 64–82.
19. Zhao, J.; Wei, S.; Ma, X.; Shao, H. A mild and environmentally benign method for the
synthesis of glycals in PEG-600=H2O. Green Chem. 2009, 11, 1124–1127.
20. Kotsuki, H.; Ohishi, T.; Araki, T. A new facile method for the chemoselective reductive
transformation of azides to N-(tert-butoxycarbonyl) amines. Tetrahedron Lett. 1997, 38,
2129–2132.