Molecular iodine-catalyzed facile procedure for N-Boc protection of amines

Article abstract of DOI:10.1021/jo0612473

An efficient and practical protocol for the protection of various structurally and electronically divergent aryl and aliphatic amines using (Boc)₂O in the presence of a catalytic amount of molecular iodine (10 mol%) under solvent-free conditions at ambient temperature is presented.

Full text of DOI:10.1021/jo0612473

Due to the very attractive nature of the N-Boc group, apart
from the classical base-induced procedures, only a few Lewis
acids or reagents employing Zn(ClO4)2‚6H2O, yttria-zirconia,
LiClO4, â-cyclodextrin, and ZrCl4 have been implemented so
far to effect the transformation.6 However, some of these
methods are associated with drawbacks such as use of costly
reagents and limited substrate scope. To overcome the problems
associated with protection of poorly reactive 1° or 2° arylamines
and various side reactions such as biscarboamoylation/formation
of isocyanates as well as urea,7 there is further need for
developing improved synthetic strategies for the synthesis of
N-Boc amines which can be applied to a number of substrates
in a catalytic process.
Molecular Iodine-Catalyzed Facile Procedure for
N-Boc Protection of Amines
Ravi Varala, Sreelatha Nuvula, and Srinivas R. Adapa*
Indian Institute of Chemical Technology,
Hyderabad-500 007, India
rVarala_iict@yahoo.co.in
ReceiVed June 17, 2006
In this context, molecular iodine has drawn considerable
attention lately as an inexpensive, nontoxic, nonmetallic, and
readily available catalyst for effecting various organic trans-
formations.8 Another promising approach to environmentally
friendly chemistry is to minimize or completely eliminate the
use of harmful organic solvents in organic syntheses. This is
because organic reactions run under solvent-free conditions are
advantageous because of their enhanced selectivity, efficiency,
ease of manipulation, and cleaner product formation as well as
toxic or often volatile solvents are avoided.9
Thus, a paradigm shift from using solvents toward solvent-
free reactions not only simplifies organic synthesis but also
improves process conditions for large-scale synthesis. (Note:
Exothermicity of the reaction while carrying out the reaction
on a large-scale operation should be controlled by maintaining
the temperature and using the appropriate solVent depending
on substrate reactiVity and solubility, if necessary.)
An efficient and practical protocol for the protection of
various structurally and electronically divergent aryl and
aliphatic amines using (Boc)2O in the presence of a catalytic
amount of molecular iodine (10 mol %) under solvent-free
conditions at ambient temperature is presented.
The choice of the protection and deprotection strategy in a
synthetic sequence is inevitable owing to chemoselective
transformations in the presence of various functional groups.1
Due to the desire to develop a mild, selective, and efficient
protecting group, especially for amines, Boc protection has
become one of the most useful steps due to its stability toward
catalytic hydrogenation and extreme resistance toward basic and
nucleophilic reactions.2 Furthermore, removal of the Boc
protecting group could be easily carried out with TFA within
5-10 min at room temperature on a bench scale and 3 M HCl
in EtOAc or 10% H2SO4 in dioxane in large-scale operations.
Although there are a variety of base-mediated reaction condi-
tions available for Boc protection in the literature,3 use of Lewis
acid (LA)-catalyzed Boc protection of amines is limited because
of the strong affinity of several LA’s for amino groups which
do not allow regeneration of the Lewis acids (LAs) in the
reaction,4 and moreover, they are decomposed or deactivated
by the amines/their derivatives with the use of more than
stoichiometric amounts.5
In a continuation of our efforts to develop new synthetic
routes for carbon-carbon and carbon-heteroatom bond forma-
tion and heterocycles,10herein we disclose the first example of
an efficient synthetic protocol for the selective tert-butoxycar-
bonylation of amines using iodine as LA under solvent-free
conditions (Scheme 1).
Initially, we screened several mild Lewis acids such as silica
gel, InCl3, FeCl3, CAN, Yb(OTf)3, and molecular iodine (I2)
(6) (a) Bartoli, G.; Bosco, M.; Locatelli, M.; Marcantoni, E.; Massaccesi,
M. Synlett 2004, 1794. (b) Pandey, R. K.; Ragade, S. P.; Upadhyay, R. K.;
Dongare, M. K.; Kumar, P. ARKIVOC 2002, 28. (c) Heydari, A.; Hosseini,
S. E. AdV. Synth. Catal. 2005, 347, 1929. (d) Reddy, M. S.; Narender, M.;
Nageswar, Y. V. D.; Rama Rao, K. Synlett 2006, 1110. (e) Sharma, G. V.
M.; Reddy, J. J.; Lakshmi, P. S.; Radha Krishna, P. Tetrahedron Lett. 2004,
45, 6963.
(7) (a) Darnbrough, S.; Mervic, M.; Condon, S. M.; Burns, C. J. Synth.
Commun. 2001, 31, 3273. (b). Kelly, T. A.; McNeil, D. W. Tetrahedron
Lett. 1994, 35, 9003. (c) Basel, Y.; Hassner, A. J. Org. Chem. 2000, 65,
6368. (d) Knoelker, H.-J.; Braxmeier, T.; Schlechtingen, G. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 2497. (e) Knoelker, H.-J.; Braxmeier, T.;
Schlechtingen, G. Synlett 1996, 502.
* To whom correspondence should be addressed. Phone: (+91)-40-27193169.
Fax: (+91)-40-27160921.
(1) Kocienski, P. J. Protecting Groups; Georg Thieme Verlag: New
York, 2000.
(2) (a) Wuensch, E. In Houben-Weyl, Methods of Organic Chemistry,
4th ed.; Muller, E., Bayer, O., Meerwein, H., Ziegler, K., Eds.; Georg
Thieme Verlag: Stuttgart, 1974; Vol. 15/1, p 46. (b) Xiuo, X. Yi.; Ngu,
K.; Choa, C.; Patel, D. V. J. Org. Chem. 1997, 62, 6968.
(3) For examples, see: (a) Grehn, L.; Ragnarsson, U. Angew. Chem.,
Int. Ed. Engl. 1985, 24, 510. (b) Knoelker, H. J.; Braxmeier, T. Tetrahedron
Lett. 1996, 37, 5861. (c) Lutz, C.; Lutz, V.; Knochel, P. Tetrahedron 1998,
54, 6385. (d) Bailey, S. W.; Chandrasekaran, R. Y.; Ayling, J. E. J. Org.
Chem. 1992, 57, 4470.
(4) Niimi, L.; Serita, K.-i.; Hiraoka, S.; Yokozawa, T. Tetrahedron Lett.
2000, 41, 7075.
(5) (a) Kobayashi, S.; Araki, M.; Yasuda, M. Tetrahedron Lett. 1995,
36, 5773. (b) Kobayashi, S.; Akiyama, R.; Kawamura, M.; Ashitani, H.
Chem. Lett. 1997, 1039.
(8) For a review, see: Wang, H. S.; Miao, J. Y.; Zhao, L. F. Chin. J.
Org. Chem. 2005, 25, 615. For recent references, see: (a) Wu, J.; Xia, H.
G.; Gao, K. Org. BioMol. Chem. 2006, 4, 126 and references therein. (b)
Lin, C.; Hsu, J. C.; Sastry, M. N. V.; Fang, H.; Tu, Z. J.; Liu, J. T.; Yao,
C. F. Tetrahedron 2005, 61, 11751. (c) Banik, B. K.; Chapa, M.; Marquez,
J.; Cardona, M. Tetrahedron Lett. 2005, 46, 2341.
(9) For reviews on solvent-free organic synthesis, see: (a) Cave, G. W.
V.; Raston. L.; Scott, J. L. Chem. Commun. 2001, 2159. (b) Tanaka, K.;
Toda, F. Chem. ReV. 2000, 100, 1025.
(10) (a) Varala, R.; Ramu, E.; Sreelatha, N.; Adapa, S. R. Tetrahedron
Lett. 2006, 47, 877. (b) Varala, R.; Ramu, E.; Sreelatha, N.; Adapa, S. R.
Synlett 2006, 7, 1009. (c) Varala, R.; Adapa, S. R. Org. Proc. Res. DeV.
2005, 9, 853. (d) Varala, R.; Sreelatha, N.; Adapa, S. R. Synlett 2006, 10,
1549 and references therein.
10.1021/jo0612473 CCC: $33.50 © 2006 American Chemical Society
Published on Web 09/09/2006
J. Org. Chem. 2006, 71, 8283-8286
8283

TABLE 1. Comparison of the Effect of Catalysts in N-Boc Protection of Aniline with (Boc)2O at Room Temperature (10 mol % as standard)
entry
catalyst
catalyst load (mol %)
time
solvent
isolated yield (%)
1
2
3
4
5
6
7
8
silica gel
InCl3
FeCl3
CAN
50 mg/1 mmol
18 h
30 min
1 h
30 min
30 min
30 min
14 h
3 min
12 h
neat
neat
neat
neat
neat
neat
CH3CN
CH3CN
CH2Cl2
H2O
69
90
89
74
89
95a
90
95
92
75
60
10
10
10
10
10
20
10
5
Yb(OTf)3
I2
yttria-zirconia6b
6e
ZrCl4
9
10
11
Zn(ClO4)2‚6H2O6a
â-cyclodextrin6d
uncatalyzed
10
2.5 h
48 h
a Conditions: Solvent-free (95%); MeOH (=95%); acetone (85%); dichloromethane (55%); dichloroethane (60%); DMSO (=78%); THF (90%); CH3CN
(=90%).
TABLE 2. Iodine-Catalyzed Boc Protection of Functionalized
Amines
SCHEME 1. Iodine-Catalyzed N-Boc Protection of Amines
for this reaction. We deliberately chose these reagents because
they are compatible with the capacity to retain their activity
even in the presence of nitrogen-containing compounds. These
catalysts are then screened for the model reaction between
aniline (1 mmol) and (Boc)2O (1 mmol) at room temperature
under solvent-free conditions,7c and the results are summarized
in Table 1. The model reaction could also be carried out in
different organic solvents such as MeOH (=95%), acetone
(85%), dichloromethane (55%), dichloroethane (60%), DMSO
(=78%), THF (90%), and CH3CN (=90%) for the specified
time. It is clear from Table 1, most prominently, that I2 was
found to be the best catalyst in terms of reaction times and yields
(95%, 30 min, entry 6, Table 1), although good results are
obtained with other catalysts screened (entries 1-5, Table 1)
and compared with the reported results using other LA’s or
additives (entries 7-10, Table 1), while conversion of aniline
to the corresponding N-Boc derivative appears to be sluggish
at room temperature without catalyst (entry 11, Table 1).
An optimum catalytic amount of 10 mol % of I2 is sufficient
to afford the desired product in excellent yield. To test the role
of iodine for N-Boc protection, initially a mixture of Boc2O
and aniline were vigorously stirred under solvent-free conditions
for 30 min without catalyst. There is no commencement of
effervescence. Typically, shortly after introduction of a catalytic
amount of I2 into the reaction mixture there is evolution of heat
and quick effervescence took place with concomitant formation
of the corresponding N-Boc derivative (as confirmed by TLC).
With the optimized reaction conditions in hand, we then
evaluated the scope of the reaction using a variety of structurally
divergent sec-alicyclic amines and (Boc)2O (Table 2). All
substrates smoothly reacted to give the corresponding N-Boc
adducts in 30-140 min in excellent yields. All products were
a Yields refer to pure isolated products. b 2.2 equiv of Boc2O is
used.
mixture could be continuously stirred for the specified time by
adding methanol (1 mL/1 mmol substrate).
Alkylamines (entries 1-9, Table 3) reacted faster and gave
the monoprotected derivatives in good yields. In contrast,
analogous reactions of primary and secondary arylamines
(entries 10-15, Table 3) proceed in a sluggish manner. These
results are not surprising because alkylamines are more nucleo-
philic than arylamines. It is important to note that in the case
of primary amines any side reaction, such as formation of
isocyanates or ureas, there were never any bis-Boc derivatives
observed, as confirmed by 1H NMR analysis of the crude
products. In general, aromatic amines with electron-withdrawing
substituents reacted slower than those with electron-donating
substituents (see entries 11-14 and 21-23, Table 3). The
present iodine-catalyzed N-Boc protection protocol is highly
chemoselective: the amine group is exclusively protected in
comparatively good yields even in the presence of alcohol (entry
1
characterized by instrumental techniques such as IR, H/13C
NMR, and mass spectrometry.
The reaction conditions employed also enable use of various
aliphatic, aromatic, and heterocyclic amines as well, and the
results are summarized in Table 3. The protection methodology
was carried out under neat conditions for almost all substrates.
In particular, for substrates (entries 24-26 and 29, Table 3)
which solidify during the course of the reaction, the reaction
8284 J. Org. Chem., Vol. 71, No. 21, 2006

TABLE 3. Iodine-Catalyzed Boc Protection of Amines
a Yields refer to pure isolated products. b Reaction carried out without catalyst. c 1 mL/1 mmol MeOH was added.
5, Table 3) or phenolic -OH (entry 17, Table 3), thiophenol
(entry 18, Table 3) groups. For entries 16-18, Table 3, the
mono-N-Boc-protected products were obtained in good yields,
and interestingly, the reaction times were also lower compared
to those reported earlier using other catalysts.6a,7a However,
2-aminobenzoic acid did not furnish the corresponding product
even after stirring for 24 h under the standardized conditions.
On the other hand, 3- and 4-aminobenzoic acids gave the
corresponding N-Boc-protected derivatives with acceptable
results considering their low reactivities (entry 19, Table 3).6a,7a
It is worth mentioning that heteroaromatic amines were also
possible for the present reaction to give products in moderate
to good yields (entries 20 and 24-27, Table 3).
On the basis of the reactivity differences of the amine group
under various electronic and steric environments, few competi-
tive experiments were conducted to study the efficacy of iodine-
catalyzed selective N-Boc protection. Reaction of benzylamine
(1 mmol) and p-methoxy aniline (1 mmol) with Boc2O (1 mmol)
afforded the corresponding N-Boc derivatives in 78% and 22%
yields, respectively, after 30 min. Likewise, reaction of piperi-
dine (1 mmol) and p-nitro aniline (1 mmol) with Boc2O (1
mmol) afforded the corresponding piperidine N-Boc derivative
exclusively in 90% yield after 10 min.
Moreover, chiral amine (entry 28, Table 3) gave optically
pure N-Boc derivative.11c We then decided to test the utility of
our protocol in reactions with hydrazines and sulfonamides
(entries 29-33, Table 3). The corresponding mono-N-Boc
products were obtained in reasonably good yields, although
reaction times are slightly longer. Reaction of cyclic carbamate
with Boc2O afforded the corresponding N-Boc derivative in 76%
yield after 1.5 h (entry 34, Table 3).
We further studied the iodine-catalyzed N-Boc protection
protocol using a variety of amino acid esters and alcohols, and
the results are summarized in Table 4. Free amino acids did
not react under optimized conditions, maybe due to the presence
of zwitterionic species, although trace amounts of products were
observed after prolonged hours.
In the case of the corresponding amino acid alcohols (R-amino
alcohols) esters (R-amino acid esters) were efficiently converted
to their corresponding optically pure N-Boc products as
determined by optical rotation and comparison with literature
(11) (a) Padron, J. M.; Kokotos, G.; Martyn, T.; Markidis, T.; Gibbons,
W. A.; Martyn, V. S. Tetrahedron: Asymmetry 1998, 9, 3381. (b) Dondoni,
A.; Perrone, D.; Semola, T. Synthesis 1995, 181. (c) Aldrich Handbook of
Fine Chemicals and Laboratory Equipments; Aldrich: India, 2003-2004;
pp 336 and 1215.
J. Org. Chem, Vol. 71, No. 21, 2006 8285

TABLE 4. Iodine-Catalyzed Boc Protection of Amino Acid
Derivatives
SCHEME 2. Proposed Mechanism for Iodine-Catalyzed
N-Boc Protection of Amines
a Yields refer to pure isolated products.
advantages: (i) it is mild and operationally simple; (ii) it is
inexpensive, has lower catalyst loading, and is a readily available
and environmentally benign catalyst under solvent-free condi-
tions; (iii) it has high chemoselectivity; (iv) it has wide substrate
scope and tolerability of labile functionalities; (v) it has no side
reactions.
values under similar conditions (entries 1-4, Table 4).6b,e,11 It
is noteworthy that the reaction is chemoselective in the case
with L-phenyl alaninol and L-tert-leucinol as the amines; N-Boc-
protected products were solely obtained (not O-Boc derivatives)
as, in general, alcohols are known to react with Boc2O in the
presence of DMAP to give O-Boc derivatives.12
We believe that our protocol will be a valuable addition for
the N-Boc protection of amines both in academia and industries.
To explore the mechanism of the iodine-catalyzed N-Boc
protection of amines (see Supporting Information), the IR
spectrum of a mixture of 1 equiv of I2 and 1 equiv of (Boc)2O
was recorded. Two frequency bands of the CdO stretching
vibration of carbonyl oxygen atoms were observed in the region
of 1807.33 and 1761.20 cm-1. Comparing the frequency of free
carbonyl oxygen atoms of (Boc)2O at 1808.87 and 1761.91 cm-1
(a doublet due to Fermi resonance), the shift of Vibration
frequency implicated the possible coordination of I2 with
Experimental Section
General Procedure. To a magnetically stirred mixture of amine
(1 mmol) and (Boc)2O (1 mmol) a catalytic amount of iodine (10
mol %) was added under solvent-free conditions at room temper-
ature. After stirring the reaction mixture for the specified time
(Tables 2-4), diethyl ether (10 mL) was added. The reaction
mixture was washed with Na2S2O3 (5%, 5 mL) and saturated
NaHCO3 and dried over Na2SO4, the solvent was rotavaped under
reduced pressure, and the residue was purified by silica gel column
chromatography (60-120, 5-15% EtOAc in hexane) to afford the
corresponding pure product.
1
(Boc)2O. The H NMR spectrum of a mixture of 1 equiv of I2
and 1 equiv of (Boc)2O in CDCl3 showed that the chemical
shift of the proton attached to the methyl protons of the tert-
butyl group was 1.524. The chemical shift of the same proton
in methyl protons of free (Boc)2O was 1.531.
Representative Examples. Entry 20, Table 3: IR (neat) δ 3364,
2975, 2930, 1725, 1699, 1502, 1308, 1165, 1070, 1015 cm-1; H
1
NMR (300 MHz, CDCl3) δ 1.63 (s, 9H), 7.02 (s, 1H), 7.33 (s,
1H), 8.04 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 27.6, 85.6,
117.2, 130.3, 137.2, 147.4; EI-MS 168 (M+); Anal. Calcd for
C8H12N2O2: C, 57.13; H, 7.19; N, 16.66. Found: C, 57.11; H, 7.12;
N, 16.69.
Entry 4, Table 4: IR (neat) ν 3436, 3025, 2965, 2981, 1732,
1714, 1682, 1657, 1503, 1369, 1168, 1068, 754, 629 cm-1; 1H NMR
(300 MHz, CDCl3) δ 1.43 (s, 9H), 1.85-2.00 (m, 1H), 2.10-2.25
(m, 1H), 2.34-2.45 (t, 2H), 3.62-3.78 (s, 3H), 3.80-3.98 (s, 3H),
4.27 (dd, 1H, CH), 5.17 (br s, 1H, NH); 13C NMR (75 MHz, CDCl3)
δ 27.7, 28.2, 30.0, 51.7, 52.3, 52.8, 79.9, 155.3, 172.6, 173.1; FAB-
MS: 276 (M+ + H). Anal. Calcd for C12H21NO6: C, 52.35; H,
7.69; N, 5.09. Found: C, 52.26; H, 7.81; N, 5.05. [R]25D: +12.5
(c) 2, CHCl3). Optical purity: 96.89%. HPLC retention time (Rt)
4.683 min (purity (area %) 95.80 at 230 nm).11a
The change of chemical shift also suggested possible coor-
dination of I2 with (Boc)2O. As already mentioned, formation
of N-Boc-protected amine 3 (IR frequency of CdO of 3 1688.33
1
cm-1a nd H NMR value of 3 1.514) occurs by addition of a
catalytic amount of I2 with exothermicity and commencement
of effervescence (evolution of CO2 is observed-Lime water test
) +Ve).
Thus, the following mechanism can be proposed for the
reaction. Both carbonyl oxygen atoms of (Boc)2O are activated
by iodine (TS I, 2) initially, making the carbonyl group more
susceptible to nucleophilic attack by amine 1 in one pot. This
facilitates extrusion of tert-butanol and carbon dioxide as leaving
entities, eventually leading to formation of N-Boc-protected
amine 3 (Scheme 2).
In conclusion, molecular iodine shows promising results for
the monoprotection of various electronically and structurally
divergent open chain, cyclic aliphatic, aromatic amines, 1,2-
diamines, heteroaromatic amines, hydrazides, sulfonamides,
cyclic carbamates, amino alcohols, and amino acid esters as
N-Boc derivatives in moderate to excellent isolated yields. In
contrast to the existing methods using many Lewis acid catalysts/
additives,6,7 this new method offers the following competitive
Acknowledgment. Ravi Varala thanks DIICT, Dr. J. S.
Yadav, and the Council of Scientific Industrial Research (CSIR,
India) for financial support and also the referees for their
valuable suggestions.
Supporting Information Available: Experimental Section and
IR, 1H NMR, 13C NMR, and mass spectral data for all compounds
with representative copies of 1H NMR spectra for selected
compounds and proof of evidence for I2-catalyzed N-Boc-protected
amines. This material is available free of charge via the Internet at
http://pubs.acs.org.
(12) (a) Pozdnev, V. F. Int. J. Pept. Protein Res. 1992, 40, 407.
8286 J. Org. Chem., Vol. 71, No. 21, 2006
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