Microwave assisted mild, rapid, solvent-less, and catalyst-free chemoselective N-tert-butyloxycarbonylation of amines

Article abstract of DOI:10.1016/j.tetlet.2012.08.089

Microwave assisted simple, rapid, solventless, and catalyst-free chemoselective method for the protection of amino group in aromatic, aliphatic, heterocyclic, aralkyl amines, phenyl hydrazine, and amino acid esters in good to excellent isolated yield (83-98%) in short reaction time (2-12 min) has been reported.

Full text of DOI:10.1016/j.tetlet.2012.08.089

Tetrahedron Letters 53 (2012) 5803–5806
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Microwave assisted mild, rapid, solvent-less, and catalyst-free chemoselective
N-tert-butyloxycarbonylation of amines
⇑
Satish N. Dighe, Hemant R. Jadhav
Department of Pharmacy, Birla Institute of Technology and Sciences Pilani, Pilani Campus, Vidya Vihar, Pilani 333 031, (RJ), India
a r t i c l e i n f o
a b s t r a c t
Article history:
Microwave assisted simple, rapid, solventless, and catalyst-free chemoselective method for the protec-
tion of amino group in aromatic, aliphatic, heterocyclic, aralkyl amines, phenyl hydrazine, and amino acid
esters in good to excellent isolated yield (83–98%) in short reaction time (2–12 min) has been reported.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 22 June 2012
Revised 21 August 2012
Accepted 23 August 2012
Available online 31 August 2012
Keywords:
Amines
Boc anhydride
Boc protection
MWI
Solventless
In organic synthesis, protection and deprotection of amino
groups play an important role.1 For choice of protecting group,
simplicity, yield, ease of handling, and cost of the process are gen-
erally considered. Amine functionality is present in a wide range of
biologically active compounds and hence the protection of amines
is frequently needed in synthetic, organic, and medicinal chemis-
reagents are explosive and most Lewis acids are deactivated by
amines, more than stoichiometric amounts are needed and hence
1
7,18
14
not suitable.
Recently, HClO
4
/SiO
2
,
Montmorillonite K10 or
1
9
20
21
22a
23
24
KSF,
I2,
H
3
5
PW12
O
40
,
thiourea,
HFIP,
sulfamic acid,
2
26
Amberlyst 15, and H
2
O
have been used. Most of these methods
have limitations like high costs, toxicity, corrosiveness, limited
2
3
27
try. The most easy method is acylation. However, it requires
applications, deprotection of other protecting groups, difficulties
4
harsh reaction conditions to regenerate the amine from the acyl-
in the isolation of products, lack of generality especially with deac-
tivated (electron-deficient) amines, etc. Khaksar et al . have re-
ported that thiourea, thioglycoluril, and guanidine hydrochloride
can also catalyze N-Boc protection of various activated amines.2
Microwave assisted organic synthesis has been widely used in
ated derivative and hence is not suitable for multifunctional sub-
strates. Therefore, a protecting group that can be cleaved under
mild reaction conditions is required. One of the most useful pro-
2b,c
5
tecting groups is the tert-butoxycarbonyl (Boc) group introduced
6
28
29
30
using commercially available (Boc)
2
O.
organic synthesis. Introduced in 1986 by Gedye and Giguere,
3
1
N-tert-Butoxycarbonyl group is preferred due to its stability
it has advantages like reduction of reaction times, enhancement
of product yields, elimination of unwanted side products,28 ability
to precisely control the temperature, and pressure profiles of reac-
toward basic and nucleophilic attacks and the ease of removal by
7
acid. Conventionally, for Boc protection, amines are reacted with
3
2
di-tert-butyl dicarbonate [(Boc)
2
O] in the presence of 4-(N,N-
tions, reproducibility, etc.
dimethylamino)pyridine (DMAP) or inorganic bases.9 However,
8
In this Letter, we report the use of microwave for selective
tert- butoxycarbonylation of various amines. It is a green chemistry
approach for the synthesis of Boc-protected amines wherein the
use of solvents and catalysts is avoided.
the reagents are toxic and the reaction takes a long time to com-
1
0
plete. In base-catalyzed reactions, the formation of isocyanates,
8
11
ureas, and N,N-di-Boc derivatives is also reported. Methods
12
13
14
using Lewis acids such as ZrCl
4
,
LiClO
are reported. However, these have
limited applications and have drawbacks. ZrCl is highly moisture
sensitive and liberates hydrochloric acid fumes, perchlorate
4
,
4
HClO ,
Zn(ClO
4
)
2
Á
For model reaction, we reacted 1 mmol of aniline with 1.1 mmol
1
5
16
6
H
2
O, and La(NO
3
)
3
2
Á6H O
2
di-tert-butyl dicarbonate [(Boc) O] in the absence of any catalyst
4
O
O
MWI, 300W
R
NH2
R NHBoc
O
O
O
Neat
⇑
Corresponding author. Tel.: +91 94146 48696; fax: +91 1596 244183.
E-mail addresses: hemantrj@bits-pilani.ac.in, hemantrj@gmail.com
H.R. Jadhav).
Amine
Boc protected amine
Boc anhydride
(
Scheme 1.
0
040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.08.089

5
804
S. N. Dighe, H. R. Jadhav / Tetrahedron Letters 53 (2012) 5803–5806
Table 1
N-tert-Butyloxycarbonylation of amines under microwave irradiation (MWI)
Table 1 (continued)
Entry
14
Amine
Time (min)
Yielda (%)
Entry
Amine
Time (min)
Yielda (%)
NH2
1
2
98
N
5
93
NH2
S
NH2
NH2
NH2
CH3
2
3
4
5
97
97
15
10
85
COCH3
NH2
CH3
NH2
16
12
86
94
4
5
5
4
98
95
COOH
NH2
CH3
NH2
17
5
N
N
1
1
8
9
5
2
94
88
OCH3
NH
2
NH2
HN
NH
6
7
8
4
4
5
92
90
96
HN
N
OCH3
20
2
2
89
89
NH2
HN
21
N
Cl
NH2
NH2
2
2
2
3
5
2
96
96
NH
Cl
NH2
O
2
2
4
5
2
2
95
94
9
5
5
4
95
90
91
NH
HO
NH2
Br
NHNH2
C H
2
5
2
2
6
7
N
2
2
92
91
H N
C H
2
2
5
1
1
0
1
NH2
NH2
F
NH2
OEt
2
2
8
9
10
8
84
83
O
F
O
OEt
NH2
NH2
1
1
2
3
4
8
87
89
a
Isolated yield.
H CO
3
NH
H CO
3

S. N. Dighe, H. R. Jadhav / Tetrahedron Letters 53 (2012) 5803–5806
5805
O
O
OH
O
O
MWI
Ar
O
O
O
O
O
O
NH
O
HN
ArNH2
Ar
CO2
t-BuOH
Scheme 2.
with methanol as a solvent under microwave irradiation. The reac-
tion was completed in just 2 min. We performed the reaction with-
out methanol and got the same yield. Also, the time required for
completion of the reaction was also the same (Scheme 1). Thus
we concluded that the solvent does not have any role in this reac-
tion and that microwave irradiation plays an important role.
To increase the scope of this reaction, we used substituted ani-
lines, aliphatic amines, heterocyclic anilines, aralkyl amine, phenyl
hydrazine, and also amino acid esters.33 Results are shown in
Table 1. In all cases, we obtained the product with excellent yield.
We also used anilines having electron donating and electron with-
drawing groups and all the products were isolated in good to excel-
lent yield.
5. Greene, T. W.; Wuts, P. G. M. In Protective Group in Organic Synthesis, 2nd ed.;
Wiley: New York, 1999. pp 503–550, and references cited therein.
6
7
.
.
Pope, B. M.; Yamamoto, X.; Tarbell, D. S. Org. Synth. Coll. 1988, VI, 418.
(a) Nicolaou, K. C.; Mitchell, H. J. Angew. Chem., Int. Ed. 2001, 40, 1576; (b) Zhu,
X.; Schmidt, R. R. Angew. Chem., Int. Ed. 2009, 48, 1900. and references cited
therein.
8
9
.
.
Basel, Y.; Hassner, A. J. Org. Chem. 2000, 65, 6368.
Aqueous NaOH: (a) Lutz, C.; Lutz, V.; Knochel, P. Tetrahedron 1998, 54, 6385;
K
2
CO
Tetrahedron Lett. 2004, 45, 5057; Me
Subasinghe, N. L.; Johnson, R. L. Tetrahedron Lett. 1996, 37, 3441; NaHCO
3
–Bu
4
NI in DMF: (b) Handy, S. T.; Sabatini, J. J.; Zhang, Y.; Vulfora, I.
NOHÁ5H O in MeCN: (c) Khalil, E. M.;
in
4
2
3
MeOH under sonication: (d) Eunhorn, J.; Einhorn, C.; Luche, J.-L. Synlett 1991,
37; NaHMDS in THF: (e) Kelly, T. A.; McNeil, D. W. Tetrahedron Lett. 1994, 35,
9003.
1
1
0. Knoelker, H.-J.; Braxmeier, T. Tetrahedron Lett. 1996, 37, 5861.
1. Darnbrough, S.; Mervic, M.; Condon, S. M.; Burns, C. J. Synth. Commun. 2001, 31,
3273.
12. Sharma, G. V. S.; Reddy, J. J.; Lakshmi, P. S.; Krishna, P. R. Tetrahedron Lett. 2004,
The following mechanism can be proposed for this reaction.
Microwave irradiation not only quickly heats the system to very
high temperature facilitating the reaction but also activates the
4
5, 6963.
13. Heydari, A.; Hosseini, S. E. Adv. Synth. Catal. 1929, 2005, 347.
14. Chakraborti, A. K.; Chankeshwara, S. V. Org. Biomol. Chem. 2006, 4, 2769.
15. Bartoli, G.; Bosco, M.; Locatelli, M.; Marcantoni, E.; Massaccesi, M.; Melchiorre,
P.; Sambri, L. Synlett 2004, 1794.
2
carbonyl oxygen atom of (Boc) O making the carbonyl group more
susceptible to nucleophilic attack by the amine which forms the
intermediate. This facilitates the removal of tert-butanol and car-
bon dioxide from the intermediate, eventually leading to the for-
mation of N-Boc-protected amine (Scheme 2).
To summarize, we report the microwave assisted, efficient, and
green method for N-tert-butoxycarbonylation of various structur-
ally diverse amines in good-to-excellent isolated yields. In contrast
to some existing methods using potentially hazardous catalysts/
additives, this new method offers advantages like short reaction
times, no use of catalyst, no use of solvent, ease of product isola-
tion, no side reactions, and simple processing and handling.
16. Suryakiran, N.; Prabhakar, P.; Reddy, S. T.; Rajesh, K.; Venkateswarlu, Y.
Tetrahedron Lett. 2006, 47, 8039.
17. Niimi, K.-J.; Serita, S.; Hiraoka, T.; Yokozawa, T. Tetrahedron Lett. 2000, 41, 7075.
1
8. (a) Kobayashi, S.; Araki, M.; Yasuda, M. Tetrahedron Lett. 1995, 36, 5773; (b)
Kobayashi, S.; Akiyama, R.; Kawamura, H.; Ashitani, H. Chem. Lett. 1977, 1039.
9. Chankeshwara, S. V.; Chakraborti, A. K. J. Mol. Catal. A 2006, 253, 198.
1
20. Varala, R.; Nuvula, S.; Adapa, S. R. J. Org. Chem. 2006, 71, 8283.
21. Heydari, A.; Kazem Shiroodi, R.; Hamadi, H.; Esfandyari, M.; Pourayoubi, M.
Tetrahedron Lett. 2007, 48, 5865.
2
2. (a) Khaksar, S.; Heydari, A.; Tajbakhsh, M.; Vahdat, S. M. Tetrahedron Lett. 2008,
49, 3527; (b) Khaksar, S.; Vahdat, S. M.; Tajbakhsh, M.; Jahani, F.; Heydari, A.
Tetrahedron Lett. 2010, 51, 6388; (c) Jahani, F.; Tajbakhsh, M.; Golchoubian, H.;
Khaksar, S. Tetrahedron Lett. 2011, 52, 1260.
2
2
3. Heydari, A.; Khaksar, S.; Tajbakhsh, M. Synthesis 2008, 3126.
4. Upadhyaya, D. J.; Barge, A.; Stefania, R.; Cravotto, G. Tetrahedron Lett. 2007, 48,
8
318.
Acknowledgment
2
2
2
2
2
5. Kumar, K. S.; Iqbal, J.; Pal, M. Tetrahedron Lett. 2009, 48, 8318.
6. Chankeshwara, S. V.; Chakraborti, A. K. Org. Lett. 2006, 8, 3259.
7. Sartori, G.; Maggi, R. Chem. Rev. 2004, 104, 199.
8. Colombo, M.; Peretto, I. Drug Discovery Today 2008, 13, 677.
9. Gedye, R.; Smith, F.; Westaway, K.; Ali, H.; Baldisera, L.; Laberge, L.; Rousell, J.
Tetrahedron Lett. 1986, 27, 279.
This work has been carried out as a part of the Department of
Science and Technology (DST) sponsored research project (SR/FT/
CS-100/2009). We are thankful to DST, India for the financial
support.
30. Giguere, R. J.; Bray, T. L.; Duncan, S. M.; Majetich, G. Tetrahedron Lett. 1986, 27,
945.
4
3
3
3
1. Kappe, C. O.; Dallinger, D. Nat. Rev. Drug Disc. 2006, 5, 51.
2. Zhang, S.; Arvidsson, P. I. Int. J. Pept. Res. Ther. 2008, 14, 219.
3. (General procedure for the N-tert-butoxycarbonylation of amines: Amine
Supplementary data
(
1 mmol) and di-tert-butyl dicarbonate [(Boc)
microwave reaction vial. The LG microwave oven MG 555f was programmed to
00 W at 100 °C. The reaction was monitored using TLC. After the reaction, ice
2
O] (1.1 mmol) were placed in a
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.08.
3
water was added to the reaction mixture which resulted in the precipitation of
the product. The solid product was merely filtered off and washed with excess
cold water. The product was pure enough for all practical purposes. For
characterization purpose, it was further purified by column chromatography
(
(
Spectroscopic data for few products are given below.
(
NMR (CDCl
0
89.
References and notes
Neutral Alumina as adsorbent, solvent system: Hexane: Ethyl acetate
7.5:2.5)).
1
.
(a) Greene, T. W.; Wuts, P. G. M. In Protecting Group in Organic Synthesis; John
Wiley and Sons: New York, 1999; (b) Kocienski, P. J. In Protecting Groups; Georg
Thieme: New York, 2000.
: 1685 cmÀ1. 1
3
, 300 MHz) d: 1.54 (s, 9 H), 6.51 (bs, 1 H), 7.02–7.05 (m,1 H), 7.28–
1) Phenyl-carbamic acid tert-butyl ester (entry 1). IR (KBr)
m
H
2
.
.
(a) Theodoridis, G. Tetrahedron 2000, 56, 2339; (b) Sartori, G.; Ballini, R.; Bigi, F.;
Bosica, G.; Maggi, R.; Righi, P. Chem. Rev. 2004, 104, 199.
+
7
(
.39 (m, 4 H). MS (EI): m/z 193 (M ).
2) o-Tolyl-carbamic acid tert-butyl ester (entry 2) IR (KBr)
NMR (CDCl3, 300 MHz) d : 1.54 (s,9H), 2.27 (s,3 H), 6.26 (bs, 1H), 7.01 (s, 1H),
: 1693 cmÀ1; 1
m H
3
(a) Chakraborti, A. K.; Gulhane, R. Tetrahedron Lett. 2003, 44, 3521; (b)
Chakraborti, A. K.; Gulhane, R. J. Chem. Soc., Chem. Commun. 1896, 2003, 44; (c)
Chakraborti, A. K.; Gulhane, R. Tetrahedron Lett. 2003, 44, 6749; (d) Chakraborti,
A. K.; Sharma, L.; Gulhane, R.; Shivani Tetrahedron 2003, 59, 7661; (e)
Chakraborti, A. K.; Gulhane, R.; Shivani Synlett 2003, 1805; (f) Chakraborti, A.
K.; Gulhane, R.; Shivani Synthesis 2004, 111; (g) Chakraborti, A. K.; Gulhane, R.
Synlett 2004, 627.
+
7
.15–7.28 (m, 2H), 7.78 (d, Hz,1H). MS (EI): m/z 207 (M ).
3) m-Tolyl-carbamic acid tert-butyl ester (entry 3) IR (KBr)
NMR (CDCl3, 300 MHz) d: 1.54 (s, 9H), 2.34 (s, 3H), 6.48 (bs, 1H), 7.09 (s, 1H),
: 1694 cmÀ1; 1
m H
(
+
7
(
.16 (m, 3H); MS (EI): m/z 207 (M ).
4) p-Tolyl-carbamic acid tert-butyl ester (entry 4) IR (KBr)
NMR (CDCl3, 300 MHz) d: 1.53 (s, 9H), 2.31 (s, 3H), 6.44 (bs, 1H), 7.09 (d, 2H),
: 1690 cmÀ1; 1
m H
4
.
Dilbeck, G. A.; Field, L.; Gallo, A. A.; Gargiulo, R. J. J. Org. Chem. 1978, 43, 4593.
+
7
.24 (d, 2H); MS (EI): m/z 207 (M ).

5
806
S. N. Dighe, H. R. Jadhav / Tetrahedron Letters 53 (2012) 5803–5806
5) (4-Methoxy-phenyl)-carbamic acid tert-butyl ester (entry 6) IR (KBr) (10) 4-Benzyl-piperazine-1-carboxylic acid tert-butyl ester (entry 21) IR (KBr)
(
1
1
m:
À1
1
À1
1
698 cm
;
H NMR (CDCl3, 300 MHz) d: 1.52 (s, 9H), 3.05 (s, 3H), 6.35 (bs,
m: 1698 cm ; H NMR (CDCl3, 300 MHz) d: 1.45 (s, 9H), 2.37–2.40 (t, 4H),
+
+
H), 6.84–6.87 (d, 2H), 7.26–7.28 (d, 2H); MS (EI): m/z 223 (M ).
3.38–3.42 (t, 4H), 7.24–7.32 (s, 5H); MS (EI): m/z 276 (M ).
(
1
1
6) (3-Chloro-phenyl)-carbamic acid tert-butyl ester (entry 7) IR (KBr)
m
:
(11) Pyrrolidine-1-carboxylic acid tert-butyl ester (entry 23) IR (KBr) m:
À1
1
À1
1
701 cm
;
H NMR (CDCl3, 300 MHz) d: 1.53 (s, 9H), 6.53 (bs, 1H), 7.00 (d,
1695 cm ; H NMR (CDCl3, 300 MHz) d: 1.46 (s, 9H), 1.83–1.84 (s, 4H),
+
+
H), 7.15–7.28 (m, 2H), 7.53 (s, 1H); MS (EI): m/z 227 (M ).
3.28–3.33 (s, 4H), MS (EI): m/z 171 (M ).
(
1
7) Naphthalen-1-yl-carbamic acid tert-butyl ester (entry 12). IR (KBr)
m
:
(12) Morpholine-4-carboxylic acid tert-butyl ester (entry 24): Colorless oil, IR
À1
1
À1 1
701 cm
.
H NMR (CDCl
3
, 300 MHz) d: 1.58 (s, 9 H), 6.89 (bs, 1 H), 7.45 (m, 3
(Neat) m: 1695 cm . H NMR (CDCl , 300 MHz) d : 1.46 (s, 9H), 3.39–3.42 (m,
3
+
+
H), 7.64 (d, 1 H), 7.86 (m, 3 H). MS (EI): m/z 243 (M ).
4H), 3.62–3.65 (m, 4H). MS (EI): m/z 187 (M ).
(
1
8) Pyridin-4-yl-carbamic acid tert-butyl ester (entry 17). IR (KBr)
m
:
(13) 2-tert-Butoxycarbonylamino-3-phenyl-propionic acid ethyl ester (entry
À1
1
3
28). IR (KBr) m , 300 MHz) d: 1.24 (t, 3 H), 1.42 (bs,
: 1685 cmÀ1. 1H NMR (CDCl
721 cm
.
H NMR (CDCl
3
, 300 MHz) d: 1.52 (s, 9 H), 7.32 (t, 2 H), 8.43 (t, 2
+
H). MS (EI): m/z 194 (M ).
9 H), 2.99 (t, 2 H), 4.16 (q, 2 H), 4.51 (d, 1 H), 5.00 (d, 1 H), 5.50 (bs, 1 H), 6.72 (d,
+
(
9) 4-Phenyl-piperazine-1-carboxylic acid tert-butyl ester (entry 20) IR (KBr)
m:
2 H), 6.97 (d, 2 H), MS (EI): 293 (M ).
À1
1
1
685 cm
; H NMR (CDCl3, 300 MHz) d: 1.54 (s, 9H), 3.13–3.16 (t, 4H), 3.58–
3
.61 (t, 4H), 3.51 (s, 2H), 6.88–6.93 (m, 3H), 7.27–7.32 (t, 2H); MS (EI): m/z 262
+
(
M ).