Hydrogen bond catalyzed chemoselective N-tert-butoxycarbonylation of amines

Article abstract of DOI:10.1016/j.tetlet.2008.03.138

A novel, chemoselective mono-N-Boc protection of various structurally diverse amines with di-tert-butoxypyrocarbonate (Boc)₂O is described that relies on selective carbonyl activation by hydrogen bond formation. This mild, acid- and metal-free process requires only catalytic amounts of thiourea as hydrogen bond donor.

Full text of DOI:10.1016/j.tetlet.2008.03.138

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 3527–3529
Hydrogen bond catalyzed chemoselective
N-tert-butoxycarbonylation of amines
a,
b
c
a
*
Samad Khaksar , Akbar Heydari , Mahmood Tajbakhsh , Seyed Mohammad Vahdat
a Chemistry Department, Islamic Azad University, Ayatollah Amoli Branch, PO Box 678, Amol, Iran
b Chemistry Department, Tarbiat Modares University, PO Box 14115-175, Tehran, Iran
c Department of Chemistry, Mazandaran University, Babolsar 47415, Iran
Received 27 January 2008; revised 4 March 2008; accepted 27 March 2008
Available online 29 March 2008
Abstract
A novel, chemoselective mono-N-Boc protection of various structurally diverse amines with di-tert-butoxypyrocarbonate (Boc)2O is
described that relies on selective carbonyl activation by hydrogen bond formation. This mild, acid- and metal-free process requires only
catalytic amounts of thiourea as hydrogen bond donor.
Ó 2008 Published by Elsevier Ltd.
Keywords: Amines; (Boc)2O; Chemoselective; Thiourea; Hydrogen bonding
In recent years, increasing attention has been paid to
organocatalysts owing to their environmentally benign nat-
ure and other notable advantages (reactions catalyzed by
organocatalysts often proceed under an aerobic atmo-
sphere even in wet solvents; the organocatalysts are usually
inexpensive and are commercially available).1,2 In addition,
and in contrast to metallic Lewis acids, these organocata-
lysts can be recovered and reused for a second reaction.
Recently, Menche et al. demonstrated that thiourea effi-
ciently activates imines.3 Bearing in mind the usefulness
and efficiency of organocatalysts, we decided to explore
thiourea as a catalyst for the N-Boc-protection of amines.
Among carbonic acid derivatives used as protecting
groups, tert-butyl carbonates (O-Boc alcohols) and carb-
amates (N-Boc amines) are of great importance in organic
chemistry. Boc-protected aryl amines are important inter-
mediates in organic synthesis and have been used for the
directed lithiation of aromatic rings and the preparation
of unsymmetrical ureas amongst others.4,5 However, vari-
ous reagents and methodologies developed over the years
to introduce this group using (Boc)2O have been carried
out either in the presence of a base (DMAP,6 aq NaOH,7
NaHMDS8) or Lewis acid catalysts such as Zr(ClO4)2Á
6H2O,9 ZrCl4,10 I2,11 H3PW12O40,12 sulfamic acid,13
LiClO4 and indium(III) halides.15 These reports have
14
demonstrated that the reaction of Boc2O requires acidic
or basic catalysts, extended reaction times,16 elevated tem-
peratures,17 tedious work-up and anhydrous organic sol-
vents. Despite improvements in performing N-tert-
butoxycarbonylations, new and milder conditions are still
required.
Herein, we report an efficient method for the chemo-
selective N-tert-butyloxycarbonylation of amines which relies
exclusively on hydrogen bonding for carbonyl activation.
This completely acid-free reaction is mediated by catalytic
amounts of thiourea as a simple and readily modifiable
organocatalyst and uses (Boc)2O as the reagent for the pro-
tection of amines. The general applicability of the method
for the synthesis of a wide variety of diverse N-Boc-amines
is demonstrated and the mechanistic background is
studied.
In the presence of 10 mol % of thiourea, the reaction of
aniline 1a with (Boc)2O proceeded smoothly in toluene at
60 °C to afford the corresponding N-Boc aniline 3a in an
*
Corresponding author. Tel.: +98 91 26996316; fax: +98 21 88006544.
E-mail address: s_khaksar@modares.ac.ir (S. Khaksar).
0040-4039/$ - see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2008.03.138

3528
S. Khaksar et al. / Tetrahedron Letters 49 (2008) 3527–3529
Table 1
Table 1 (continued)
Entry Substrate
Time Product
(min)
Yield
3 (%)
S
R1
R1
N
H2N
NH2
Boc
O
N
N
p
q
H
15
30
94
92
N
H
N
H
N
Boc2O
+
R2
R2
Boc
Toluene, 60 - 70 ºC
H
1
2
3
Boc
O
H
HO
N
H
HO
N
H
Entry
Substrate
Time
(min)
Product
Yield
3 (%)
H
N
H
N
HO
HO
OH
Boc
HO
HO
OH
r
35
90
a
H
40
30
Boc
95
94
N
H
NH2
H
N
H
NH2
NH2
N
b
s
t
20
15
97
97
H
H
Boc
Boc
NH2
Boc
NH
N
H
N
Boc
N
N
N
H
N
H
c
30
35
92
95
Boc
O
H
H
N
H
Cl
Cl
N
Boc
Boc
H
H
u
20
94
O
d
N
H
N
H
OMe
OMe
e
20
97
N
H
N
H
excellent isolated yield of 95% (Table 1). (Note: The reac-
tion of amines with (Boc)2O cannot be performed in a closed
glass or vial as CO2 (g) is liberated during the reaction.)
Various amines and amine derivatives 1a–u were treated
with (Boc)2O at 60 °C in toluene. No competitive forma-
tion of isocyanate, urea or N,N-di-Boc derivatives was
observed (by NMR). Amines having an OH group afforded
the corresponding N-Boc derivatives without O-Boc
formation (by NMR). The chemoselectivity was further
demonstrated in the cases of 2-aminoalcohols, which did
not form oxazolidinones. The method can be applied for
the conversion of sterically hindered tert-butylamine 1f,
to the corresponding N-Boc derivative. Similarly, 1,2-di-
amine 1s was mono N-Boc-protected at the primary amine
in excellent yield. In a further study, hydrazine 1p and
amino acid ester 1u were converted to the corresponding
N-Boc derivatives under similar reaction conditions in
20 min and in good yields. In all the cases, a remarkable
rate acceleration effect was observed as demonstrated by
the short reaction times and excellent yields of the corres-
ponding N-Boc products. TLC was used to monitor the
progress of reactions. The reactions could also be followed
visually. In the case of secondary amines, an exothermic
reaction took place immediately after the addition of
(Boc)2O to the amine with vigorous effervescence. For
primary amines, commencement of slow effervescence took
place with concomitant formation of the N-Boc deriva-
tives.18 However, aromatic amines with strong electron-
withdrawing groups such as p-CN and p-NO2 did not
afford any significant amount of N-Boc derivatives as these
groups decreased the nucleophilicity of the nitrogen atom
of the amine group.
Boc
f
20
10
96
93
N
H
NH2
N
Ph
N
Ph
Ph
Ph
g
H
Boc
h
i
5
5
95
99
Boc
N H
N H
N
Boc
O
O
N
N
j
10
30
94
95
N
H
Boc
H
N
NH2
OH
k
Boc
OH
NH2
NH Boc
OH
l
20
95
OH
OH
H
N
OH
N
m
n
30
10
25
92
93
92
Boc
OH
OH
N
N
H
Boc
OH
OH
o
N
NH2
H
Boc

S. Khaksar et al. / Tetrahedron Letters 49 (2008) 3527–3529
3529
147.75 (C), 155.4 (C@O); compound: 3n 1H NMR
(500 MHz, CDCl3): d = 1.51 (s, 9H), 2.18 (br s, 1H, OH),
3.44 (m, 2H), 3.74 (m, 2H), 4.50 (s, 2H), 7.27–7.32 (m,
3H), 7.37 (m, 2H); 13C NMR (125 MHz, CDCl3):
d = 28.8 (CH3), 50.12 (CH2), 52.40 (CH2), 62.2 (CH2),
80.94 (C), 128.0 (CH), 128.9 (CH), 138.68 (CH), 147.19
(C) 157.64 (C@O); compound: 3q 1H NMR (500 MHz,
CDCl3): d = 1.37 (s, 9H), 3.24 (m, 2H), 3.47 (t,
J = 5.5 Hz, 2H), 3.49 (t, J = 4 Hz, 2H), 3.65 (t, J = 5 Hz,
2H), 5.25 (br s, 1H, OH), 5.44 (br s, 1H, NH); 13C NMR
(125 MHz, CDCl3): d = 28.73 (CH3), 40.70 (CH2), 61.71
(CH2), 70.58 (CH2), 72.67 (CH2), 79.56 (C), 156.64 (C@O).
S
H
H
O
N
H
N
H
S
H
H
N
H
N
H
O
O
O
O
O
O
O
O
O
H
N
R
R
S
CO2
H
H
N
H
N
O
H
+
O
R
H
H
O
O
N
R
O
N
O
+
R
O
S
R
References and notes
O
H
H
N
H
N
H
1. Peter, P. I. D.; Moisan, L. Angew. Chem., Int. Ed. 2001, 40, 3726–
3748.
Scheme 1. Proposed mechanism of the hydrogen bond catalyzed chemo-
selective N-tert-butoxycarbonylation of amines.
2. (a) List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc. 2000,
122, 2395–2396; (b) Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F.,
III. J. Am. Chem. Soc. 2001, 123, 5260–5261; (c) Cordova, A.; Notz,
W.; Zhong, G.; Betancort, J. M.; Barbas, C. F., III. J. Am. Chem. Soc.
2002, 124, 1842–1843; (d) Cordova, A.; Watanabe, S.; Tanaka, F.;
Notz, W.; Barbas, C. F., III. J. Am. Chem. Soc. 2002, 124, 1866–1867;
(e) Ooi, T.; Kameda, M.; Tannai, H.; Maruoka, K. Tetrahedron Lett.
2000, 41, 8339–8342; (f) Ooi, T.; Takeuchi, M.; Kameda, M.;
Maruoka, K. J. Am.Chem. Soc. 2000, 122, 5228–5229; (g) Ooi, T.;
Doda, K.; Maruoka, K. Org. Lett. 2001, 3, 1273–1276; (h) Iwabuchi,
Y.; Nakatani, M.; Yokoyama, N.; Hatakeyama, S. J. Am. Chem. Soc.
1999, 121, 10219–10220; (i) Enders, D.; Kallfass, U. Angew. Chem.,
Int. Ed. 2002, 41, 1743–1745; (j) Kerr, M. S.; Read de Alaniz, J.;
Rovis, T. J. Am. Chem. Soc. 2002, 124, 10298–10299.
The role of thiourea may be explained by Scheme 1.3
Hydrogen bond formation between thiourea and the
carbonyl oxygen atoms of (Boc)2O leads to ‘electrophilic
activation’ (TS1) making the carbonyl group more suscep-
tible to nucleophilic attack. The nitrogen atom of thiourea
in turn forms a hydrogen bond with the hydrogen atom of
the amine and increases the electron density at the nitrogen
atom (nucleophilic activation). Electrostatic attraction
between the carbonyl group and the nitrogen atom leads
to TS2. Intramolecular nucleophilic attack by the nitrogen
atom on the carbonyl carbon followed by the elimination
of CO2, t-BuOH and urea forms the carbamate.
¨
3. (a) Menche, D.; BOhm, S.; Li, J.; Zander, W.; Rudolph, S.
Tetrahedron Lett. 2007, 48, 365–369; (b) Menche, D.; Arikan, F.
Synlett 2006, 841; (c) Menche, D.; Hassfeld, J.; Li, J.; Menche, G.;
Ritter, A.; Rudolph, S. Org. Lett. 2006, 8, 741–744.
4. Snieckus, V. Chem. Rev. 1990, 90, 879–933.
5. Lamothe, M.; Perez, M.; Colovray-Gotteland, V.; Halazy, S. Synlett
1996, 507–508.
6. (a) Basel, Y.; Hashers, A. J. Org. Chem. 2000, 65, 6368–6380; (b)
Grehn, L.; Ragnarsson, U. Angew. Chem., Int. Ed. Engl. 1985, 510–
511; (c) Knolker, T.; Braxmeier, H.-J. Tetrahedron Lett. 1996, 37,
5861–5864.
7. For examples, see: (a) Lutz, C.; Lutz, V.; Knochel, P. Tetrahedron
1998, 54, 6385–6402; (b) Bailey, S. W.; Chandrasekaran, R. Y.;
Ayling, J. E. J. Org. Chem. 1992, 57, 4470–4477.
8. Kelly, T. A.; McNeil, D. W. Tetrahedron Lett. 1994, 35, 9003–9006.
9. Boger, D. L.; McKie, J. A. J. Org. Chem. 1995, 60, 1271–1275.
10. Muchowski, J. M.; Venuti, M. C. J. Org. Chem. 1980, 45, 4798–4801.
11. Varala, R.; Nuvula, S.; Adapa, S. R. J. Org. Chem. 2006, 71, 8283–
8286.
12. Heydari, A.; Kazem Shiroodi, R.; Hamadi, H.; Esfandyari, M.;
Pourayoubi, M. Tetrahedron Lett. 2007, 48, 5865–5867.
13. Upadhyaya, D. J.; Barge, A.; Stefania, R.; Cravotto, G. Tetrahedron
Lett. 2007, 48, 8318–8322.
14. Heydari, A.; Hosseini, S. E. Adv. Synth. Catal. 2005, 347, 1929–1931.
15. Chankeshwara, S. V.; Chakraborti, A. K. Synthesis 2006, 16, 2784–
2788.
16. Bartoli, G.; Bosco, M.; Locatelli, M.; Marcantoni, E.; Massaccesi,
M.; Melchiorre, P.; Sambri, L. Synlett 2004, 1794–1798.
17. Sharma, G. V. M.; Reddy, J. J.; Lakshmi, P. S.; Krishna, P. R.
Tetrahedron Lett. 2004, 45, 6963–6965.
In summary, we have developed the first hydrogen bond
catalyzed chemoselective N-tert-butoxycarbonylation of
amines, which allows the efficient synthesis of diverse N-
Boc amines. The mild and nonacidic conditions together
with the high chemoselectivity of this protocol should
enable applications to complex or acid-sensitive substrates.
General procedure: N-tert-butoxycarbonylation of
amines: A solution of the amine (1.00 mmol) and (Boc)2O
(1 mmol) in toluene (5 mL) was treated with thiourea
(0.100 mmol) and the mixture was stirred until complete
conversion (5–40 min). After filtration, the solvent was
evaporated and the residue purified by column chromato-
graphy (silica gel) eluting with hexane–EtOAc (1:1) followed
by evaporation of the solvent. The physical data (mp, IR,
NMR) of the known compounds were found to be identical
with those reported in the literature.16 Spectroscopic data
for selected examples follows: Compound 3j: 1H NMR
(500 MHz, CDCl3): d = 1.54 (s, 9H), 2.18 (quin,
J = 6.5 Hz, 2H), 3.94 (t, J = 5.0 Hz, 4H); 13C NMR
(125 MHz, CDCl3): d = 15.7 (CH2), 28.7 (CH3), 44.1
1
(CH2), 79.4 (C), 156.6 (C@O); compound: 3k H NMR
(500 MHz, CDCl3): d = 1.57 (s, 9H), 6.69 (br s, 1H, OH),
6.89 (t, J = 7.5 Hz, 1H), 7.01 (d, J = 9.5 Hz, 1H), 7.06–
7.11 (m, 2H), 8.17 (br s, 1H, NH); 13C NMR (125 MHz,
CDCl3): d = 28.69 (CH3), 82.43 (C), 119.06 (CH),
121.176 (CH), 121.71 (C), 125.87 (CH), 126.1 (CH),
18. For a review on recent advances in solventless organic reactions, see:
Cave, G. W. V.; Raston, G. L.; Scott, J. L. Chem. Commun. 2001,
2159–2169; Rothenberg, G.; Downie, A. P. K.; Toda, F. Chem. Rev.
2000, 100, 1025–1074.