A rate enhancement of tert-butoxycarbonylation of aromatic amines with Boc2O in alcoholic solvents

Article abstract of DOI:10.1016/j.tetlet.2006.07.097

A rate enhancement of tert-butoxycarbonylation of aromatic amines by Boc₂O in alcohols compared to aprotic solvents was demonstrated. Kinetic analysis by NMR suggested that the reaction in CD₃OD was faster than in CDCl₃ by a factor of 70. Reactions between Boc₂O and various aliphatic and aromatic amines in ethanol provided the N-Boc derivatives in good to excellent yields in short reaction times.

Full text of DOI:10.1016/j.tetlet.2006.07.097

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
Tetrahedron Letters 47 (2006) 6739–6742
A rate enhancement of tert-butoxycarbonylation of aromatic
amines with Boc2O in alcoholic solvents
Tirayut Vilaivan*
Organic Synthesis Research Unit, Department of Chemistry, Faculty of Science, Chulalongkorn University,
Phayathai Road, Patumwan, Bangkok 10330, Thailand
Received 8 May 2006; revised 13 July 2006; accepted 20 July 2006
Available online 8 August 2006
Abstract—A rate enhancement of tert-butoxycarbonylation of aromatic amines by Boc2O in alcohols compared to aprotic solvents
was demonstrated. Kinetic analysis by NMR suggested that the reaction in CD3OD was faster than in CDCl3 by a factor of 70.
Reactions between Boc2O and various aliphatic and aromatic amines in ethanol provided the N-Boc derivatives in good to excellent
yields in short reaction times.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Protection of amines is a frequently employed strategy
for decreasing the nucleophilicity of the amino group
in order to perform other transformations in molecules.
Among various amine protecting groups, the tert-butoxy-
carbonyl (Boc) group is perhaps one of the most widely
used due to its exceptional stability towards a variety of
reagents and reaction conditions, yet it can be readily
removed under moderately strong acidic conditions.1
The Boc group has also been used as a directing group
for ortho-metallation of aromatic amines.2 Di-tert-butyl
dicarbonate (Boc2O, 1)3 is usually the reagent of choice
for introduction of Boc groups due to its high reactivity
and reasonable stability.4 However, Boc-protection of
poorly nucleophilic aromatic amines is generally not as
efficient as that of aliphatic amines. N-Deprotonation
of the aromatic amine using a strong base such as
NaHMDS has been employed to increase the reactivity.5
Other solutions to overcome the low reactivity of aro-
matic amines exist. These include the use of a high tem-
perature, a nucleophilic catalyst such as DMAP6 or
NH2OH,7 and, more recently, Lewis acid catalysts such
as Yttria-Zirconia,8 ZrCl49 and Zn(ClO4)2.10 These pro-
cedures, although effective, have certain drawbacks
including the formation of side-products such as isocya-
nates11 and poly-acylated products,6a the requirement of
unusual, highly reactive or environmentally harmful cat-
alysts, and the necessity for chromatographic, or extrac-
tive work-up to isolate the product from the catalyst.
Although the unique role of water to mediate many
organic reactions is currently attracting much interest,12
the ability of alcohols to mediate or accelerate several
reactions via general acid catalysis has not been widely
appreciated. We have previously reported an interesting
rate enhancement on the addition of organoindium
reagents to imines in alcoholic solvents.13 In this letter,
a rate enhancement on the tert-butoxycarbonylation of
aromatic amines in alcohols is reported. Boc protections
of amines have been typically carried out in aprotic sol-
vents such as dichloromethane or THF, often in the
presence of a base such as triethylamine. Although the
use of alcohols or aqueous alcohols as solvents for
Boc protection of polar compounds such as amino acids
is well known,1,4 there has been no specific mention of
rate enhancement. A model reaction between p-toluidine
2a and Boc2O (1, 1.5 equiv) was carried out in a variety
of solvents (Table 1) without addition of base. TLC
monitoring suggested that the reactions in methanol
and ethanol were essentially complete within 0.5 h at
30 ꢁC (entries 1 and 2). The same reactions in aprotic
solvents were slower (4–6 h) (entries 3–5). Addition of
triethylamine did not result in any rate improvement
(entry 6). The same trend was observed with electron
deficient p-chloroaniline 2b as the substrate (entries
7–8). While the reaction in ethanol required 6 h to
complete, the reaction in CH2Cl2 was only 50%
complete after the same period of time.
From Table 1, it is clear that the alcoholic solvent exerts
a beneficial rate acceleration on the tert-butoxycarbonyl-
ation of aromatic amines. In order to obtain a more
Keywords: Amine; Boc2O; Protecting group.
*
Fax: +66 2 2187598; e-mail: vtirayut@chula.ac.th
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.07.097

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
6740
T. Vilaivan / Tetrahedron Letters 47 (2006) 6739–6742
Table 1. Comparison of reaction time for tert-butoxycarbonylation of aromatic amines in various solventsa
O
O
solvent
R
NHBoc
R
NH2
+
O
O
O
2a R = Me
2b R = Cl
3a R = Me
3b R = Cl
Boc2O, 1
Substrate
Entry
Solvent
Time (h)
Product (% yield)b
1
2
3
4
5
6
7
8
2a
2a
2a
2a
2a
2a
2b
2b
MeOH
EtOH
MeCN
THF
CH2Cl2
CH2Cl2 + Et3N
EtOH
0.5
0.5
4
6
6
6
6
3a (93)
3a (96)
Not determined
Not determined
Not determined
Not determined
3b (96)
CH2Cl2
<50% at 6 h
Not determined
a Reaction conditions: 0.75 mmol of 1, 0.5 mmol of 2a or 2b, 1 mL of solvent, 30 ꢁC, progress monitored by TLC.
b Isolated yield.
quantitative picture, reactions between p-toluidine 2a
and 1 were studied by H NMR spectroscopy. While
yields and high purities after evaporation of the solvent
without the requirement for chromatographic purifica-
tion and/or acid–base extraction. Unhindered primary
and secondary aliphatic amines usually reacted instanta-
neously to give the products in almost quantitative
yields (Table 2, entries 1–5). The sterically hindered di-
cyclohexylamine gave a somewhat poorer yield (Table
2, entry 6). Electron-rich or moderately electron-defi-
cient aromatic amines (Table 1, entries 1, 2, 7 and Table
2, entries 7–9) reacted within 6 h at room temperature.
Sterically hindered and secondary aromatic amines (en-
tries 10–14) reacted somewhat more slowly (up to 48 h).
Electron deficient aromatic amines required stronger
conditions (50 ꢁC, 3–5 equiv of Boc2O, a few days)
and gave poorer yields (entries 16–18). The presence of
phenolic and alcoholic hydroxyl groups was well toler-
ated. Both amino alcohols and amino phenols chemose-
lectively provided the N-Boc products even when 1 was
added in excess (entries 3, 4, 8 and 11). Highly deacti-
vated aromatic amines including diphenylamine and 4-
chloro-2-aminobenzonitrile failed to react under these
conditions. Interestingly, the reaction of 2-aminopyri-
dine with Boc2O in EtOH provided the ethyl carbamate
instead of the expected Boc-derivative. This is most
likely due to attack of the solvent on the isocyanate
formed in situ.11 Changing the solvent to tert-butanol
gave Boc derivative 3u in 72% yield (Table 2, entry
19). This behavior is unique to 2-aminopyridine since
1
the reaction was essentially complete after 1 h in
CD3OD, the same reaction in CDCl3 only proceeded
to 50% extent after 12 h at 20 ꢁC. Kinetic analysis sug-
gested that in both cases the reactions follow a second-
order rate law. From the calculated second-order rate
constants of 1.3 · 10À2 and 1.8 · 10À4 l molÀ1 sÀ1 in
CD3OD and CDCl3, respectively, it was estimated that
the rate in CD3OD was enhanced relative to that in
CDCl3 by a factor of 70. This remarkable rate enhance-
ment could be attributed to activation of the electro-
philic C@O group in 1 by hydrogen-bonding with the
hydroxyl group of the alcohol (Scheme 1). Furthermore,
stabilization of the polar transition state of the initial
tetrahedral intermediate resulting from attack of the
nucleophile on the carbonyl group of 1 may also play
a significant role. Interestingly, the rate in the more
acidic alcohol, 2,2,2-trifluoroethanol, was comparable
to that in acetonitrile. This is probably because of the
diminished nucleophilicity of the amine as a result of
acid–base interaction with the acidic solvent.
In order to study the generality and scope of the alcohol-
assisted tert-butoxycarbonylation of amines, a number
of aliphatic and aromatic amines (2c–2u) were employed
as substrates (Table 2).14 With few exceptions, the
desired products were obtained in good to excellent
OR
H
O
OH
O
O
O
Ar
N
H
O
O
O
O
O
O
O
+
HN
Ar
CO2
+
ArNH2
OR
H
O
δ-
O
tBuOH
O
via
O
O
H2N
δ+
Ar
Scheme 1.

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
T. Vilaivan / Tetrahedron Letters 47 (2006) 6739–6742
6741
Table 2. Yield of N-Boc products obtained from the tert-butoxycarbonylation of various aliphatic and aromatic amines in ethanol as solvent
H
N
Boc
N
EtOH
tBuOH
R1
R2
CO2
+
+
Boc2O
+
R1
R2
3
1
2
Entry
Amine
Product
R1
Bn
R2
Time
Yielda (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
2c
2d
2e
2f
3c
3d
3e
3f
H
H
H
<1 min
<1 min
<1 min
<1 min
<1 min
2 h
0.5 h
2 h
2 h
12 h
24 h
48 h
48 h
24 h
12 h
72 hc
72 hc
72 hc
24 hd
92
98
98
>99
95
76
94
86
>99b
86
>99
>99
97
99
94
38
96
88
72
(S)-PhCH(Me)
HOCH2CH2CH2
D-Phenylalaninol
N-Phenylpiperazine
2g
2h
2i
3g
3h
3i
cHex
4-MeOC6H4
2-HOC6H4
cHex
H
2j
3j
H
2k
2l
3k
3l
o-Phenylenediamine
Me
C6H5
C6H5
2m
2n
2o
2p
2q
2r
2s
2t
3m
3n
3o
3p
3q
3r
3s
3t
HOCH2CH2
2,6-Me2C6H3
2,6-iPr2C6H3
1-Naphthyl
3-MeO2CC6H4
4-O2NC6H4
4-Cl-3-O2NC6H3
2-HO2CC6H4
2-Pyridyl
H
H
H
H
H
H
H
H
2u
3u
a Isolated yield.
b Bis-Boc derivative.
c The reaction was carried out at 50 ꢁC with excess of 1 (3.5 equiv) added.
d The reaction was performed in tert-butanol.
no ethyl carbamate formation was observed with other
substrates. It should be noted that the alcoholic solution
of 1 is fairly stable, no significant decomposition (<2%)
terms of yield and reaction rate compared to Lewis acid
mediated protocols.16,17 The reaction conditions and
isolation of the products are simple and involve a readily
available and environmentally benign solvent. By-prod-
ucts from the reactions are volatile and relatively non-
toxic. These features should make the reaction attractive
for both laboratory and process chemists.
1
of 1 was observed in CD3OD by H NMR after 8 h at
30 ꢁC. However, significant decomposition was ob-
served at higher temperature, therefore a large excess
of 1 was required for the poorly reactive substrates
which required heating. When 1 was used in excess,
chromatographic purification or treatment of the reac-
tion mixture with 3-morpholinopropylamine to form
an acid-soluble by-product, which could be removed
by simple extraction, was necessary.15
Acknowledgements
Financial support from Rachadapisek Sompoj Endow-
ment from Chulalongkorn University to Organic Syn-
thesis Research Unit, and technical assistance by Miss
Wanna Bannarukkul is acknowledged.
To explore further the scope of this reaction with other
urethane-type amine protecting groups such as Z and
Fmoc, it was observed that p-anisidine 2i reacted
smoothly with benzyl N-succinimidyl carbonate (ZOSu)
and 9-fluorenylmethyl N-succinimidyl carbonate (Fmoc-
OSu) in ethanol as a solvent to afford the Z- and Fmoc-
protected p-anisidine derivatives (3v and 3w) in 93% and
94% yields, respectively, after aqueous work-up (Scheme
2).
Supplementary data
Spectroscopic data of compounds 3a–3w and details of
the second-order rate constant calculations are avail-
able. Supplementary data associated with this article
can be found, in the online version, at doi:10.1016/
j.tetlet.2006.07.097.
The present procedure for Boc as well as Z and Fmoc
protection offers several practical advantages. The reac-
tion provides improved or at least comparable results in
References and notes
PG-OSu
MeO
NH2
MeO
NHPG
1. Greene, T. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis, 3rd ed.; John Wiley and Sons: New
York, 1999.
2. (a) Davies, A. J.; Brands, K. M. J.; Cowden, C. J.;
Dolling, U.-H.; Lieberman, D. R. Tetrahedron Lett. 2004,
EtOH, rt, O/N
PG = Z
93%
2i
PG =Fmoc 94%
Scheme 2.

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
6742
T. Vilaivan / Tetrahedron Letters 47 (2006) 6739–6742
45, 1721–1724; (b) Stanetty, P.; Koller, H.; Mihovilovic,
M. J. Org. Chem. 1992, 57, 6833–6837; (c) Muchowski,
J. M.; Venuti, M. C. J. Org. Chem. 1980, 45, 4798–
4801.
Kno¨lker, H.-J.; Braxmeier, T. Tetrahedron Lett. 1996, 37,
5861–5864.
12. (a) Grieco, P. A. In Organic Synthesis in Water; Thomson
Science: London, 1988; (b) Li, C. J.; Chen, L. Chem. Soc.
Rev. 2006, 35, 68–82; (c) Lubineau, A.; Auge, J. Tops.
Curr. Chem. 1999, 206, 1–39.
3. Tarbell, D. S.; Yamamoto, Y.; Pope, B. M. Proc. Natl.
Acad. Sci. USA 1972, 69, 730–732.
4. For a review see: Wakselman, M. In Di-t-butyl Dicarbon-
ate; Paquette, L. A., Ed.; Handbook of Reagents for
Organic Synthesis: Activating Agents and Protecting
Groups; John Wiley and Sons: New York, 1999; pp
123–130.
13. (a) Vilaivan, T.; Winotapan, C.; Shinada, T.; Ohfune, Y.
Tetrahedron Lett. 2001, 42, 9073–9076; (b) Vilaivan, T.;
Winotapan, C.; Banphavichit, V.; Shinada, T.; Ohfune, Y.
J. Org. Chem. 2005, 70, 3464–3471.
14. Typical procedure for Boc-protection: To a solution of the
amine (0.5 mmol) in EtOH (1 mL) was added Boc2O
(0.55 mmol). The reaction was stirred at 30 ꢁC until the
reaction was complete as indicated by TLC. The solvent
was removed to provide practically pure product, which
may be further purified by extraction or chromatography
if desired.
5. Kelly, T. A.; McNeil, D. W. Tetrahedron Lett. 1994, 35,
9003–9006.
6. (a) Darnbrough, S.; Mervic, M.; Condon, S. M.; Burns, C.
J. Synth. Commun. 2001, 31, 3723–3780; (b) Ragnarsson,
U.; Grehn, L. Acc. Chem. Res. 1998, 31, 494–501; (c)
Basel, Y.; Hassner, A. J. Org. Chem. 2000, 65, 6368–6380,
and references cited therein.
15. For a related method to remove excess Boc2O, see: Basel,
Y.; Hassner, A. Synthesis 2001, 550–552.
7. Harris, R. B.; Wilson, I. B. Tetrahedron Lett. 1983, 24,
231–232.
16. Boc protections of aniline and 2,4,6-trimethylaniline in
MeCN at room temperature required 48 h and 168 h,
respectively, to complete (Ref. 6c). In the presence of
Zn(ClO4)2, the reaction time for 2,4,6-trimethylaniline
decreased to 48 h (Ref. 10). In all cases, the products were
isolated in >90% yields.
17. After submission of this manuscript, a related tert-
butoxycarbonylation of amines in water is reported:
Chankeshwara, S. V.; Chakraborti, A. K. Org. Lett.
2006, 8, 3259–3262.
8. Pandey, R. K.; Ragade, S. P.; Upadhyay, R. K.; Dongare,
M. K.; Kumar, P. Arkivoc 2002, VII, 28–33.
9. Sharma, G. V. M.; Reddy, J. J.; Lakshmi, P. S.; Krishna,
P. R. Tetrahedron Lett. 2004, 45, 6963–6965.
10. Bartoli, G.; Bosco, M.; Locatelli, M.; Marcantoni, E.;
Massaccesi, M.; Melchiorre, P.; Sambri, L. Synlett 2004,
1794–1798.
11. (a) Kno¨lker, H.-J.; Braxmeier, T.; Schlechtingen, G.
Angew. Chem., Int. Ed. Engl. 1995, 34, 2497–2500; (b)