Nonsolvent application of ionic liquids: Organo-catalysis by 1-alkyl-3-methylimidazolium cation based room-temperature ionic liquids for chemoselective N-tert-butyloxycarbonylation of amines and the influence of the C-2 hydrogen on catalytic efficiency

Article abstract of DOI:10.1021/jo201102q

1-Alkyl-3-methylimidazolium cation based ionic liquids efficiently catalyze N-tert-butyloxycarbonylation of amines with excellent chemoselectivity. The catalytic role of the ionic liquid is envisaged as "electrophilic activation" of di-tert-butyl dicarbonate (Boc₂O) through bifurcated hydrogen bond formation with the C-2 hydrogen of the 1-alkyl-3-methylimidazolium cation and has been supported by a downfield shift of the imidazolium C-2 hydrogen of 1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide ([bmim][NTf₂]) from δ 8.39 to 8.66 in the presence of Boc₂O in the ¹H NMR and a drastic reduction of the catalytic efficiency with 1-butyl-2,3-dimethylimidazolium ionic liquids that are devoid of the C-2 hydrogen. The differential time required for reaction with aromatic and aliphatic amines has offered means for selective N-t-Boc formation during inter and intramolecular competitions. Preferential N-t-Boc formation with secondary aliphatic amine has been achieved in the presence of primary aliphatic amine. Comparison of the catalytic efficiency for N-t-Boc formation with a common substrate revealed that [bmim][NTf₂] is superior to the reported Lewis acid catalysts.

Full text of DOI:10.1021/jo201102q

ARTICLE
pubs.acs.org/joc
Nonsolvent Application of Ionic Liquids: Organo-Catalysis by
1-Alkyl-3-methylimidazolium Cation Based Room-Temperature Ionic
Liquids for Chemoselective N-tert-Butyloxycarbonylation of Amines
and the Influence of the C-2 Hydrogen on Catalytic Efficiency
Anirban Sarkar, Sudipta Raha Roy, Naisargee Parikh, and Asit K. Chakraborti*
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67,
S.A.S. Nagar 160 062, Punjab, India
S Supporting Information
b
ABSTRACT: 1-Alkyl-3-methylimidazolium cation based ionic liquids efficiently
catalyze N-tert-butyloxycarbonylation of amines with excellent chemoselectivity.
The catalytic role of the ionic liquid is envisaged as “electrophilic activation” of
di-tert-butyl dicarbonate (Boc2O) through bifurcated hydrogen bond formation with the C-2 hydrogen of the 1-alkyl-3-methylimi-
dazolium cation and has been supported by a downfield shift of the imidazolium C-2 hydrogen of 1-butyl-3-methylimidazolium
1
bis(trifluoromethylsulfonyl)imide ([bmim][NTf2]) from δ 8.39 to 8.66 in the presence of Boc2O in the H NMR and a drastic
reduction of the catalytic efficiency with 1-butyl-2,3-dimethylimidazolium ionic liquids that are devoid of the C-2 hydrogen. The
differential time required for reaction with aromatic and aliphatic amines has offered means for selective N-t-Boc formation during inter
and intramolecular competitions. Preferential N-t-Boc formation with secondary aliphatic amine has been achieved in the presence
of primary aliphatic amine. Comparison of the catalytic efficiency for N-t-Boc formation with a common substrate revealed that
[bmim][NTf2] is superior to the reported Lewis acid catalysts.
’ INTRODUCTION
efficiency of the bmim cation-based ILs is influenced by the C-2
hydrogen of the bmim cation.
Modulating the reactivity of amine functionality is a requisite
exercise with 39% frequency in the preparation of drug molecules.1
Protection of amine through acylation2 is an easy approach but
requires harsh reaction conditions,3 which are not compatible
with a multifunctional substrate, to regenerate the amine. An
alternative and preferred strategy is N-tert-butoxycarbonylation4
due to the stability of tert-butylcarbamates (N-t-Boc) toward a
variety of routinely adopted experimental conditions and ease of
regeneration of the parent amines under mild acidic conditions.
Thus, the development of more effective methodologies for N-t-
Boc formation has a long-standing interest in organic synthesis.5
The increasing influence of green chemistry on chemical
research6 urges for greener reaction conditions. The prime
attention toward this direction is on the use of an alternative
reaction medium, and ionic liquids (ILs) are hailed as green
solvents of the future.7 However, ILs do not always exhibit
innocuous behavior,8 which puts their green image under
scrutiny9 on several issues such as combustibility,10 toxicity,11
and biodegradability.12 These are deterrents for the enthusiasm
for the use of ILs as reaction media. Therefore, to benefit from
the spectacular ability of ILs to accelerate organic reactions and
modulate selectivity, the “non-solvent” application of ILs is
gaining momentum.13
’ RESULTS AND DISCUSSION
For catalyst selection 3-chloro-4-fluoroaniline (1) and 2,4,6-
trimethylaniline (2) were chosen as model substrates as repre-
sentatives of electron-deficient and sterically hindered aromatic
amines, respectively, for N-t-Boc formation by reaction with di-
tert-butyl dicarbonate (Boc2O) in the presence of various 1-alkyl-
3-methylimidazolium RTILs (Scheme 1), and the results are
summarized in Table 1.
The 1-alkyl-3-methylimidazolium-derived RTILs exhibited very
good to excellent catalytic activity (entries 1ꢀ14, Table 1).
However, the catalytic efficiency of the protic IL [Hmim][BF4]
was found to be significantly inferior to that of the bmim cation
containing ILs (entry 15, Table 1). Poor yields were obtained
in carrying out the reactions in the absence of any IL (entries
16ꢀ18, Table 1) and highlighted the necessity of the catalytic
assistance of the ILs for N-t-Boc formation. For reactions that
afforded lesser/poor yields of the N-t-Boc derivatives, the corres-
ponding unreacted starting amine remained unchanged and
could be recovered.
To demonstrate the general usability of the ILs as organo-
catalysts for N-t-Boc formation, we chose 1-butyl-3-methylimi-
dazolium bis(trifluoromethylsulfonyl)imide [bmim][NTf2]
because of its advantageous physicochemical properties such as
In the pursuit of exploring catalytic uses of ILs,14 we report
herein that the 1-alkyl-3-methylimidazolium (bmim: alkyl = n-
butyl; emim: alkyl = ethyl) cation based room-temperature ionic
liquids (RTILs) are efficient organo-catalysts for chemoselective
N-tert-butyloxycarbonylation of amines and that the catalytic
Received: May 28, 2011
Published: July 21, 2011
r
2011 American Chemical Society
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|

The Journal of Organic Chemistry
ARTICLE
Scheme 1. Ionic Liquid Catalyzed Reaction of 1 and 2 with
Boc2O
Table 2. [bmim][NTf2]-Catalyzed N-t-Boc Formation of
Aminesa
Table 1. N-t-Boc Formation from 1 and 2 Catalyzed by
RTILsa
entry
IL
yield (%)b from 1
yield (%)c from 2
1
2
[emim][Cl]
[emim][PF6]
[bmim][Br]
[bmim][BF4]
[bmim][PF6]
[bmim][NTf2]
[bmim][MeSO3]
[bmim][MeSO4]
[bmim][HSO4]
[bmim][N(CN)2]
[bmim][OAc]
[bmim][ClO4]
[bmim][N3]
[bmim][HCO2]
[Hmim][BF4]f
none
93
93
93
92
91
95d,e
93
92
89
91
86
84
84
85
20
20g
nilh
15i
85
86
82
82
75
86
82
75
75
82
74
76
75
80
50
35g
15h
17i
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
none
none
a The amine (2.5 mmol) was treated with (Boc)2O (2.5 mmol, 1 equiv)
in the presence of the IL (2.5 mol %) under neat conditions at rt. b Yield
of the purified N-t-Boc derivative of 1 obtained after 15 min reaction.
c Yield of the purified N-t-Boc derivative of 2 obtained after 45 min
reaction. d The use of 1 mol % of the IL afforded 70% yield of the N-t-Boc
amine after 15 min. e The use of 5 mol % of the IL afforded the N-t-Boc
amine in 82 and 96% yields after 10 and 15 min, respectively. f Hmim =
N-methylimidazolium. g The reaction was performed under neat condi-
tion in the absence of any IL. h The reaction was performed in dioxane
i
(2.5 mL) in the absence of any IL. The reaction was performed in
dioxaneꢀwater (1:1) (2.5 mL) in the absence of any IL.
lower melting point, lower viscosity, and increased hydrophobicity
that would be beneficial in the ease of handling and recovery of
the IL for reuse.15 The optimal catalyst amount was found to be
2.5 mol %. The use of lesser amounts (e.g., 1 mol %) of the IL
afforded inferior product yield (Table 1, entry 6, footnote d). On
the otherhand, the use of higher quantities (e.g., 5 mol %) oftheIL
did not provide any significant advantage in terms of reducing the
reaction time (Table 1, entry 6, footnote e).
Therefore, various aromatic, heteroaromatic, aryl alkyl, het-
eroaryl alkyl, and alkyl amines were treated with Boc2O under the
catalytic influence of [bmim][NTf2] (Table 2). The correspond-
ing N-t-Boc derivatives were formed in excellent yields in a short
time (1ꢀ45 min) without competitive formation of isocyanate,16
urea,16c and N,N-di-Boc16c,17 (IR, GCMS). No O/S-t-Boc for-
mation (IR) took place with substrates having an OH/SH group
a The amine (2.5 mmol) was treated with Boc2O (2.5 mmol, 1 equiv) in
the presence of [bmim][NTf2] (2.5 mol %) at rt (∼30ꢀ35 °C). b Yield
of the N-t-Boc compound. c The products were characterized by IR,
NMR, and MS. d The N-t-Boc product was formed in 55 and 28% yields
after 2 h in dioxane and dioxaneꢀwater (1:1), respectively, in the
absence of the IL. e The product was formed in 65 and 35% yields after
6 h in dioxane and dioxaneꢀwater (1:1), respectively, in the absence of
formed. h The N-t-Boc product was formed in 18 and 15% yields in
dioxane and dioxaneꢀwater (1:1), respectively, in the absence of the IL.
i The N-t-Boc product was formed in 32 and 25% yields in dioxane and
dioxaneꢀwater (1:1), respectively, in the absence of the IL. j The N-t-
Boc product was formed in 12 and 10% yields in dioxane and dioxaneꢀ
water (1:1), respectively, in the absence of the IL. k The N-t-Boc product
was formed in 45 and 36% yields in dioxane and dioxaneꢀwater (1:1),
respectively, in the absence of the IL.
f
the IL. No O-t-Boc product was formed. g No S-t-Boc product was
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Table 3. [bmim][NTf2]-Catalyzed N-t-Boc Formation of
Chiral Amines, Esters of R-Amino Acids, and Amino Alcohola
Table 4. Reusability of [bmim][NTf2] during the N-t-Boc
Formation of 1a
scalec
amt usedd
(g)
amt rece
(g)
recf
yieldg
(%)
useb
(mmol)
(%)
first (fresh)
first recycle
second recycle
third recycle
fourth recycle
fifth recycle
25
25
25
25
25
25
0.261
0.251
0.238
0.222
0.200
0.172
0.251
0.238
0.222
0.200
0.172
0.143
96
95
93
90
86
83
95
95
92
90
87
85
a The amine 1 (3.63 g, 25 mmol) and (Boc)2O (5.74 mL, 25 mmol,
1 equiv) in a 25 mL round bottomed flask, [bmim] [NTf2] (0.26 g,
2.5 mol %) at rt (30ꢀ35 °C) for 15 min. b Refers to the status of the
c
IL use. Amount of 1 used for the reaction. d Amount of the IL used.
e Amount of the IL recovered. f Refers to the recovered IL. g Refers to the
yield of the N-t-Boc derivative of 1 after purification.
Scheme 2. Role of the IL in Catalyzing N-t-Boc Formation
a The substrate (2.5 mmol) was treated with Boc2O (2.5 mmol, 1 equiv)
in the presence of [bmim][NTf2] (2.5 mol %) at rt (∼30ꢀ35 °C).
b Yield of the N-t-Boc compound. c The products were characterized by
IR, NMR and MS. d The enantiomeric amine afforded 95% yield. e The
N-t-Boc was formed in 18, 25, and 12% yields in dioxane, water, and
dioxaneꢀwater (1:1), respectively, for 20 min in the absence of the IL.
f No O-t-Boc product was formed. g The N-t-Boc was formed in 43 and
39% yields after 20 min in dioxane and dioxaneꢀwater (1:1), respec-
tively, in the absence of the IL. h No O-t-Boc or oxazolidinone formation
(1:1) in the absence of the IL, and in each case, poor yields of the
N-t-Boc derivatives were obtained compared to the IL-catalyzed
reactions highlighting the catalytic assistance provided by the IL.
We next planned to assess the feasibility of recovery and reuse
of the IL and observed that based on the solubility of the N-t-Boc
product and the IL [bmim][NTf2] an appropriate solvent could
be chosen to separate the IL from the product. In case of the
reaction with 1 we observed that the N-t-Boc product is soluble in
Et2O but [bmim][NTf2] is insoluble in Et2O. The differential
solubility of the product and the catalyst/IL enable us to extract
the product by extraction of the reaction mixture with a minimal
amount of Et2O whereupon the catalyst was retained in the
reaction flask and could be reused after activation under vacuum
at 80 °C for 0.5 h. Thus, the IL was recovered and reused for five
subsequent fresh batches of reaction without significant decrease
in the catalytic activity. The recovery efficiency was 96ꢀ83% with
95ꢀ85% yields of the N-t-Boc compound (Table 4). The large-
scale (25 mmol) preparation of the N-t-Boc compound demon-
strated the potential for scale-up operation.
i
was observed. The N-t-Boc was formed in 49 and 43% yields after
10 min in dioxane and dioxaneꢀwater (1:1), respectively, in the absence
of the IL.
(entries 12ꢀ16).14b,18 In case of 2-aminophenols (entries 14ꢀ
16) oxazolidinone,16c,19 formation was not observed. Aminoa-
cetaldehyde dimethyl acetal, an acid-sensitive substrate, under-
went clean conversion to the N-t-Boc derivative (entry 24).
The mildness of the procedure was next demonstrated
(Table 3) with chiral amines (entry 1), esters of R-amino acids
(entries 2ꢀ7), and amino alcohol that gave optically pure N-t-
Boc derivatives (determined by optical rotation).20 The amino
alcohol (entry 8) did not produce any side product due to com-
petitive O-t-Boc or oxazolidinone formation.
As aliphatic amines are more nucleophilic than aromatic
amines it was anticipated that with such substrates the use of the
IL may not offer any distinct advantage. Therefore, a few repre-
sentative amines (Table 2, entries 23ꢀ26; Table 3, entries 2, 4,
and 8) were treated with Boc2O in dioxane and dioxaneꢀwater
The role of the ILs is depicted in Scheme 2. The C-2 hydrogen
of imidazolium ion exhibits acidic character21 and possesses
hydrogen bond donor (HBD) ability.22 The hydrogen bond
(HꢀB) formation ability of the C-2 H in 1-butyl-3-methylimi-
dazlium (bmim) based ionic liquids (ILs) plays a crucial role in
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Table 5. Influence of the C-2 Hydrogen on the Catalytic
Efficiency of ILs for N-t-Boc Formation of 1 and 2a
entry
IL
yieldb (%) from 1
yieldc (%) from 2
1
2
none
20
21
25
20
20
21
24
27
20
24
35
41
40
40
39
45
37
37
35
38
[bdmim][BF4]
3
[bdmim][PF6]
4
[bdmim][NTf2]
[bdmim][MeSO4]
[bdmim][N(CN)2]
[bdmim][OAc]
[bdmim][ClO4]
[bdmim][N3]
5
6
7
8
9
10
[bdmim][HCO2]
a The amine (2.5 mmol) was treated with (Boc)2O (2.5 mmol, 1 equiv)
in the presence of the IL (2.5 mol %) under neat conditions at room
temperature. b Yield of the purified N-Boc derivative of 1 obtained after
c
15 min reaction. Yield of the purified N-Boc derivative of 2 obtained
after 45 min reaction.
their catalytic activity.14 The IL acts as an inducer of “electro-
philic activation” of Boc2O through bifurcated hydrogen bond23
formation between the C-2 hydrogen of the bmim moiety and
the carbonyl oxygen atoms of (Boc)2O (TS I). The anions of
bmim-based ILs are hydrogen bond acceptors.24 The counter-
anion (Xꢀ) of the IL may also play an important role in modu-
lating the reactivity/selectivity of the amine through the inter-
mediate A wherein the anion forms HꢀB with one of the NH2
hydrogens and exerts nucleophilic activation effect.25 The HꢀB
formation between the anion and the hydrogen of the NH2
group brings the amino nitrogen in close proximity to the
electrophilically activated carbonyl group of Boc2O to facilitate
the nucleophilic attack and ease of formation of the N-t-Boc
product. Therefore, the overall catalytic influence of the IL may be
realized as “electrophileꢀnucleophile dual activation”26 through a
cooperative hydrogen-bonded network.5g,14,27 An alternative path-
way involving 2-carbo-tert-butoxyimidazolininium intermediate,
presumed to be formed by the reaction of a nucleophilic hetero-
cyclic carbene (NHC) with Boc2O, does not seem to be operative
on the following grounds: (i) the formation of NHCs normally
requires the use of a strong base28 and (ii) the IL is recovered and
found to be identical (spectral data) with the unused IL.29,30
To demonstrate the influence of the C-2 hydrogen on the
overall catalytic efficiency of the ILs, the reactions of 1 and 2 with
Boc2O were performed in the presence of several 1-butyl-2,3-
dimethylimidazolium (bdmim)-based ILs that are devoid of the
C-2 hydrogen (Table 5). A drastic decrease in the catalytic power
was observed in these bdmim-derived ILs compared to that of the
corresponding bmim-based ILs (compare the results of entries
2ꢀ10 in Table 5 with those of entries 4ꢀ6, 8, and 10ꢀ14 of
Table 1). These signified the important role of the C-2 hydrogen
of the bmim cation in imparting catalytic activity to the ILs.
However, the lack of appreciable catalytic activity of [Hmim]-
[BF4] can be rationalized by the inferior ability of the C-2
hydrogen of Hmim cation to form HꢀB as compared to that
of the 1,3-dialkylimidazolium cation because of its lower acidic
property.31
Figure 1. Shift of the C-2 H of the bmim moiety of [bmim][NTf2] in
the presence of Boc2O in the NMR reflecting HꢀB formation between
the C-2 H and Boc2O.
To further demonstrate the importance/role of the imidazo-
lium C-2 hydrogen in electrophilc activation of Boc2O through
its involvement in the HꢀB formation with the carbonyl
oxygen atoms of Boc2O in the intermediate I (Scheme 2) we
designed/performed 1H NMR experiments.29 The 1H NMR spec-
tra of samples containing equimolar mixture of [bmim][NTf2] and
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Scheme 3. [bmim][NTf2]-Catalyzed Selective N-t-Boc Formation during Competition of Aromatic and Aliphatic Amines
Scheme 4. [bmim][NTf2]-Catalyzed Selective N-t-Boc Formation during Competition of Primary and Secondary Aliphatic
Amines
(Boc)2O were recorded (using D2O as an external lock) at different
time intervals (0, 5, 10 min) to observe any shift of C-2 the proton of
the bmim moiety of the IL (catalyst). In the 1H NMR the sample of
the catalyst/IL [bmim][NTf2] alone, the bmim C-2 proton signal
appears at δ 8.38. However, the signal shifted to δ 8.41 when the
spectra of the equimolar mixture of the IL and (Boc)2O were
recorded immediately after mixing (0 min). The absorption of the
C-2 proton further shifted to δ 8.65 when the spectra of equimolar
mixture of the IL and (Boc)2O were recorded after 5 and 15 min
after mixing. The downfield shift of the C-2 proton signal from
δ 8.38 to 8.65 (Figure 1) is indicative of the fact that the C-2
hydrogen of the IL is involved in hydrogen bond formation with
Boc2O to form I (Scheme 2).
The selective formation of N-t-Boc over O-t-Boc with sub-
strates bearing NH2 and OH groups is due to the better nucleo-
philicity of the NH2 group. Because of the better nucleophilicity
of aliphatic amines compared to aromatic amines, the N-t-Boc
formation takes place over shorter time periods in the case of
aliphatic amines. On a similar note, the reaction of the secondary
aliphatic amine occurs at a faster rate than that of the aliphatic
primary amine. The rate of N-t-Boc formation is also sensitive to
the steric factors surrounding the amine moiety (compare entry 1
with entries 6, 10, 18, and 20; Table 2). However, the overall
course/progress of the reaction may not be solely governed by the
substrate nucleophilicity. The anion (Xꢀ) is likely to undergo
HꢀB formation with the N-H hydrogen to induce nucleophilic
activation as well as to bring the amino nitrogen atom in close
proximity to the carbonyl carbon of Boc2O and facilitate N-t-Boc
formation. The weakHꢀB formation ability of theSꢀH hydrogen
in intermediate A (Scheme 1) may account for the lack of S-t-Boc
formation with amino thiol (entry 13, Table 2). The influence of
such an HꢀB effect of the anion may account for the longer
reaction time with more nucleophilic anilines (entries 2ꢀ4, 6,
12ꢀ16; Table 2) compared to aniline (entry 1, Table 2), as the
amino hydrogen atoms of these aniline derivatives are inferior
HBDs compared to those of aniline.32
aromatic amine with an aliphatic amine (Scheme 3). The reaction
of aniline (1 mmol) and benzylamine (1 mmol) with (Boc)2O
(1 mmol) afforded exclusive formation of the N-t-Boc derivative
of benzyl amine. For intramolecular competition between an
aromatic and an aliphatic amino group we considered 4-amino-
benzylamine as the model substrate. However, we realized that
the treatment of 4-aminobenzylamine with (Boc)2O may lead to
the formation of three products: the (4-aminobenzyl)carbamic
acid tert-butyl ester and the (4-aminomethylphenyl)carbamic
acid tert-butyl ester as the mono-N-t-Boc compounds and the
di-N,N0-t-Boc of 4-aminobenzylamine. The treatment of 4-ami-
nomethylaniline (1 mmol) with (Boc)2O (1 mmol) under the
catalytic influence of [bmim][NTf2] resulted in selective N-t-Boc
formation at the alkyl amino group affording (4-aminobenzyl)-
carbamic acid tert-butyl ester as the sole product. The corre-
sponding product has been reported to be formed in 69ꢀ75%
yields by treatment of the diamine with 1 equiv of (Boc)2O in
the presence of stoichiometric quantities of N,N-diisopropyl-
ethylamine at 0 °C for 4 h followed by 12 h at rt.33 However,
when the reaction of 4-aminomethylaniline (1 mmol) with
(Boc)2O (1 mmol) following this reported procedure was
performed, the product mixture obtained after the usual work-
up on subjection to 1H NMR analysis was found to be a 85:15
mixture of the mono- and the di-Boc derivatives29 on compar-
ison with the 1H NMR of an authentic sample of the di-N,N0-t-
Boc of 4-aminobenzylamine prepared following an unambig-
uous route [the [bmim][NTf2]-catalyzed reaction of 4-amino-
benzylamine with 2 molar equiv of (Boc)2O] different from
that of the reported procedure.34 These results clearly high-
light the advantage of the catalytic use of [bmim][NTf2] in
terms of selectivity, shortening of the reaction time, and
increasing the product yield.
We next performed intermolecular competitive study to
observe any selectivity in N-t-Boc formation between a second-
ary and a primary aliphatic amine (Scheme 4) as secondary
amines generally take lesser reaction time due to better nucleo-
philicity. The treatment of piperidine (1 mmol) and 2-piperidi-
noethylamine (1 mmol) with (Boc)2O (1 mmol) afforded 63:37
selectivity in favor of the secondary amine.
The varying electronic environment between aromatic and
aliphatic amines encouraged us to study the selective N-t-Boc
formation during inter- and intramolecular competition of an
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ARTICLE
Table 6. Comparison of the Catalytic Efficiency of [bmim]-
[NTf2] with That of Reported Lewis Acid Catalysts for
N-t-Boc Formation from 1a
compared to that of aniline although these aniline derivatives are
more nucleophilic than aniline. The IL [bmim][NTf2] proved to
be superior in its catalytic action for N-t-Boc formation from a
reference/common amine substrates than some of the reported
Lewis acid catalysts. The organo-catalytic procedure for the
N-t-Boc formation described in the present work has distinct
advantages such as the (i) catalyst reuse and nonhazardous
reaction conditions, (ii) operation at rt, (ii) short reaction time,
(iii) high yields, and (iv) excellent chemoselectivity that fulfill the
triple bottom line philosophy of green chemistry.35
entry
catalyst
mol %b solvent yieldc,d (%)
lit refe
1
2
3
4
1
2
5
8
9
Zn(ClO4)2 6H2O
5
5
neat
25
10
30
22
28
15
56
15
17
25
40
95
82
75
20
10
10
5a
3
Zn(ClO4)2 6H2O
DCM
neat
5a
3
ZrCl4
10
10
20
20
1
5b
ZrCl4
MeCN
neat
5b
LiClO4
LiClO4
Cu(BF4)2•XH2O
InBr3
5c
DCM
neat
5c
’ EXPERIMENTAL SECTION
5d
General Methods. The 1H and 13C NMR spectra were recorded
on a 300 MHz or a 400 MHz NMR spectrometer in CDCl3 with residual
undeuterated solvent (CDCl3: 7.26/77.0) using Me4Si as an internal
standard. The chemical shifts (δ) values are given in ppm and J values in
Hz. The IR spectra were recorded either as KBr pellets (for solids) or
neat or in CCl4 (for liquids) on a FTIR spectrometer. The mass spectra
were recorded under EI. Melting points were measured using a melting
point apparatus and were uncorrected. Open column chromatography
and thin-layer chromatography (TLC) were performed on silica gel
[60ꢀ120 mesh, F254 and commercially available silica gel, respectively].
Evaporation of solvents was performed at reduced pressure using a
rotary vacuum evaporator. All chemicals were purchased and used as
received.
Typical Procedure for N-t-Boc Formation Catalyzed by
[bmim][NTf2]. To the mixture of 2 (0.33 g, 2.5 mmol) and Boc2O
(0.54 g, 2.5mmol, 1 equiv) was added [bmim][NTf2] (0.03 g, 2.5 mol %),
and the reaction mixture was stirred magnetically at rt (30ꢀ35 °C). After
complete consumption of 2 (TLC, 45 min), the reaction mixture was
extracted with Et2O (3 ꢁ 5 mL), and the combined Et2O extracts were
concentrated under vacuum rotary evaporation. The residue was passed
through a bed of silica gel (10 g; 60ꢀ120 mesh) and eluted with 10%
EtOAc in hexane (300 mL) to afford the (2,4,6-trimethylphenyl)carba-
mic acid tert-butyl ester as a white or off-white solid (0.50 g, 86%),
identical (spectral data) with an authentic sample.5d
Typical Large-Scale Procedure for N-t-Boc Formation and
Catalyst Recovery. To a magnetically stirred mixture of 1 (3.63 g,
25 mmol) and (Boc)2O (5.74 mL, 25 mmol, 1 equiv) in a 25 mL round-
bottom flask was added [bmim] [NTf2] (0.26 g, 2.5 mol %), and the
mixture was stirred at rt (30ꢀ35 °C) until completion of the reaction
(15 min, TLC). The reaction mixture was extracted with Et2O (3 ꢁ
5 mL). The combined ethereal extracts were concentrated to crystallize
out the tert-butyl carbamate of 3-chloro-4-fluoroaniline as a solid (5.8 g,
95%), identical (mp and spectral data) with an authentic sample.5d The
IL (catalyst) that remained in the reaction flask ([bmim] [NTf2] is
insoluble in Et2O) was activated under vacuum at 80 °C for 0.5 h and
reused for further reactions.
1
neat
5e
InCl3
1
neat
5e
10 HClO4ꢀSiO2
11 Montmorillonite K 10
12 [bmim][NTf2]
13 [bmim][NTf2]
14 [bmim][NTf2]
15 none
1
neat
5f
10
neat
5h
2.5
neat
this work
this work
this work
this work
this work
this work
2.5
2.5
DCM
MeCN
neat
16 none
DCM
MeCN
17 none
a The amine 1 (2.5 mmol) was treated with (Boc)2O (2.5 mmol,
1 equiv) in the presence of the catalyst (2.5 mol %) under neat condi-
tions (except for entries) at room temperature for 15 min. b Amount
of the catalyst used with respect to 1. c Yield of the purified N-Boc
derivative of 1. d The unreacted starting amine remained unchanged
wherever the yield of the N-t-Boc derivative was poor. e The correspond-
ing literature wherein this catalyst has been reported for the use in
N-t-Boc formation.
Finally, to demonstrate the superior catalytic activity of
[bmim][NTf2] for N-t-Boc formation compared to the Lewis
acid catalysts we performed the reaction of 1 with Boc2O in the
presence of a few selective reported Lewis acid catalysts and com-
pared the results with those obtained during the [bmim][NTf2]-
catalyzed reactions. The results (Table 6) clearly established that
[bmim][NTf2] is more efficient in N-t-Boc formation from
amines than these Lewis acid catalysts.
’ CONCLUSIONS
In conclusion, we have described herein nonsolvent applica-
tion of 1-alkyl-3-methylimidazolium cation based RTILs for
chemoselective N-tert-butyloxycarbonylation of amines. The IL
[bmim][NTf2] has been used in catalytic quantities (2.5 mol %)
for chemoselective N-t-Boc formation of various functionalized
amines. Chiral amines, amino alcohol, and esters of R-amino
acids afforded the corresponding optically pure N-t-Boc com-
pounds. The IL can be recovered and reused for consecutive
batches of reactions without significant loss of the catalytic
property. The IL acts as an “electrophilic activation” agent
through HꢀB formation of the C-2 hydrogen of the bmim
cation with Boc2O as evidenced by the lack of appreciable
catalytic efficiency of bmim-based ILs that are devoid of the
C-2 hydrogen in the imidazolium moiety and a dwonfield shift of
the C-2 hydrogen in [bmim][NTf2] in the presence of Boc2O in
Reusability of [bmim][NTf2] Recovered from the Reaction
of 1 with Boc2O. After complete consumption of 1 during the N-t-Boc
formation catalyzed by [bmim][NTf2], the catalyst (IL) was recovered
and reused in the following way:
(i) The N-t-Boc product was isolated by extracting the reaction
mixture with ether (3 ꢁ 5 mL) followed by concentrating the
combined ethereal extracts to crystallize out the product.
(ii) The IL ([bmim][NTf2]) remained in the reaction flask
([bmim][NTf2] is insoluble in Et2O) and was activated under
vacuum at 80 °C for 30 min. The amount of the recovered
catalyst was estimated by subtracting the weight of the empty
reaction flask from the combined weight of the flask and the
recovered IL (0.25 g; 96% recovery).
1
the H NMR. The counteranion also plays significant role in
“nucleophilic activation” by HꢀB formation with the amine
hydrogen and may account for the longer reaction times for
substitued anilines with higher pKa values of the NH2 hydrogens
(iii) The reaction flask containing the activated catalyst/IL was
charged with a fresh batch of 1 (3.63 g, 25 mmol) and
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The Journal of Organic Chemistry
ARTICLE
(Boc)2O (5.74 mL, 25 mmol, 1 equiv) to afford the N-t-Boc
derivative (5.8 g, 95%).
9 H), 2.21 (s, 6 H), 2.25 (s, 3 H), 5.80 (bs, 1 H), 6.86 (s, 2 H). MS (EI):
m/z 235 (M+).5d
(iv) Following the above sequence of procedures the catalyst was
recovered and reused five consecutive times without any sig-
nificant loss of catalytic activity
(4-Fluorophenyl)carbamic Acid tert-Butyl Ester (Table 2, Entry 7). IR
(KBr) ν: 1694 cmꢀ1. 1H NMR (CDCl3, 300 MHz) δ: 1.51 (s, 9 H), 6.44
(bs, 1 H), 6.93ꢀ7.01 (m, 2 H), 7.26ꢀ7.32 (m, 2 H). MS (EI): m/z 211
(M+).5d
Synthesis of an Authentic Sample of (4-Aminobenzyl)-
carbamic Acid tert-Butyl Ester Following the Reported Pro-
cedure33a. To a solution of 4-aminobenzylamine (0.244 g; 2 mmol)
in THF (4 mL) were added (Boc)2O (0.436 g, 2 mmol) and N,N-
diisopropylethylamine (0.28 g, 2.24 mmol, 0.39 mL). The reaction
mixture was stirred for 4 h at 0 °C and then warmed to rt, and the stirring
was continued for 12 h. The resultant reaction mixture was filtered, and
the filtrate was concentrated under rotary vacuum evaporation. The
residue was dissolved in toluene (15 mL), washed successively with
brine (3 ꢁ 5 mL), 0.1 N KOH (3 ꢁ 5 mL), and brine again (5 mL), dried
(anhyd MgSO4), and concentrated under reduced pressure to afford the
crude product (0.4 g) which was subjected to 1H NMR and was found to
be an 85:15 mixture of the mono-N-t-Boc (with respect to the aliphatic
amine) and di-N-t-Boc on the basis of the integration of the benzylic
protons. Recrystallization (CHCl3ꢀhexane) of the crude product
afforded the mono-N-t-Boc (4-aminobenzyl)carbamic acid tert-butyl
(4-Chlorophenyl)carbamic Acid tert-Butyl Ester (Table 2, Entry 8). IR
(KBr) ν: 1689 cmꢀ1. 1H NMR (CDCl3, 300 MHz) δ: 1.51 (s, 9 H), 6.50
(bs, 1 H), 7.22ꢀ7.32 (m, 4 H). MS (EI): m/z 227 (M+).5q
(4-Bromophenyl)carbamic acid tert-Butyl Ester (Table 2, Entry 9). IR
(KBr) ν: 1694 cmꢀ1. 1H NMR (CDCl3, 300 MHz) δ: 1.51 (s, 9 H), 6.49
(bs, 1 H), 7.25 (d, J = 8.5 Hz, 2 H), 7.38 (d, J = 8.6 Hz, 2 H). MS (EI):
m/z 272 (M+).5d
(4-Bromo-2-methylphenyl)carbamic Acid tert-Butyl Ester (Table 2,
Entry 10). IR (KBr) ν: 1698 cmꢀ1. 1H NMR (CDCl3, 300 MHz) δ: 1.50
(s, 9 H), 2.21 (s, 3 H),6.23 (bs, 1 H), 7.27ꢀ7.30 (m, 2 H), 7.70ꢀ7.73
(m, 1 H). MS (EI): m/z 286 (M+).5d
(3-Chloro-4-fluorophenyl)carbamic Acid tert-Butyl Ester (Table 2,
Entry 11). IR (KBr) ν: 1689 cmꢀ1. 1H NMR (CDCl3, 300 MHz) δ: 1.51
(s, 9 H), 6.49 (bs, 1 H), 7.03ꢀ7.10 (m, 2 H), 7.56ꢀ7.57 (m, 1 H). MS
(EI): m/z 245 (M+).5d
(4-Hydroxyphenyl)carbamic Acid tert-Butyl Ester (Table 2, Entry 12).
IR (KBr) ν: 1697 cmꢀ1. 1H NMR (CDCl3, 300 MHz) δ: 1.50 (s, 9 H),
5.48 (bs, 1 H), 6.35 (bs, 1 H), 6.71ꢀ6.74 (m, 2 H), 7.15 (d, J = 8.654, 2
H). MS (EI): m/z 109 (M+).5d
(4-Mercaptophenyl)carbamic Acid tert-Butyl Ester (Table 2, Entry
13). IR (KBr) ν: 1698 cmꢀ1. 1H NMR (CDCl3, 300 MHz) δ: 1.50 (s, 9
H), 3.38 (s, 1 H), 6.46 (bs, 1 H), 7.24 (m, 4 H). MS (EI): m/z 109 (M+).
13C NMR (CDCl3, 75 MHz) δ: 28.9, 81.2, 119.9, 123.9, 131.6, 137.3,
153.2. MS (EI): m/z 225 (M+).5d
(2-Hydroxyphenyl)carbamic Acid tert-Butyl Ester (Table 2, Entry 14).
IR (KBr) ν: 1690 cmꢀ1. 1H NMR (CDCl3, 300 MHz) δ: 1.51 (s, 9 H),
6.68 (bs, 1 H), 6.82ꢀ6.88 (m, 1 H), 6.94ꢀ7.10 (m, 3 H), 8.16 (bs, 1 H).
MS (EI): m/z 109 (M+).5d
(2-Hydroxy-4-methylphenyl)carbamic Acid tert-Butyl Ester (Table 2,
Entry15). Dark yellow solid. Mp: 88ꢀ89 °C. IR(KBr) ν: 3432, 3286, 1688,
1154 cmꢀ1. 1H NMR (CDCl3, 300 MHz) δ: 1.52 (bs, 9 H), 2.26 (s, 3 H),
6.56 (bs, 1 H), 6.65 (d, J = 7.9 Hz, 2 H), 6.79 (s, 1 H), 6.88 (d, J = 8.2 Hz, 2
H), 8.17 (s, 1 H). 13C NMR (CDCl3, 75 MHz) δ: 21.3, 28.8, 82.5, 119.9,
121.9, 123.4, 136.3, 147.9, 155.7. MS (EI): m/z 166 (M+ꢀ 57). Anal.
Calcd for C12H17NO3: C, 64.55; H, 7.67; N, 6.27. Found C, 64.50; H, 7.70;
N, 6.26.
ester (0.32 g, 71%). IR (KBr) ν: 1689 cmꢀ1 1H NMR (CDCl3,
.
400 MHz) δ: 1.45 (bs, 9 H), 3.64 (bs, 2 H), 4.18 (d, J = 5.4, 2 H),
4.70 (bs, 1 H), 6.62ꢀ6.65 (m, 2 H), 7.07 (d, J = 8.20 Hz, 2 H). MS (EI):
m/z 222 (M+).
Synthesis of an Authentic Sample of Di-N,N0-t-Boc of
4-Aminobenzylamine. The di-N,N0-t-Boc of 4-aminobenzylamine
was prepared following an unambiguous route different from that of the
reported34 procedure. To the mixture of 4-aminobenzylamine (0.122 g,
1 mmol) and (Boc)2O (0.218 g, 2 mmol, 2.0 equiv) was added [bmim]-
[NTf2] (0.010 g, 2.5 mol %), and the reaction mixture was stirred
magnetically at rt (∼30ꢀ35 °C). After 50 min, the mixture was diluted
with EtOAc (5 mL), washed with water (2 ꢁ 5 mL), dried (anh
MgSO4), and concentrated under reduced pressure to afford the di-N,
N0-t-Boc of 4-aminobenzylamine as a white solid (293 mg, 91%). IR
1
(KBr) ν: 1630, 1685 cmꢀ1. H NMR (CDCl3, 400 MHz) δ: 1.45 (s,
9 H), 1.51 (s, 9H), 4.25 (d, J = 5.4 Hz, 2 H), 4.77 (bs, 1 H), 6.45 (bs,
1 H), 7.20 (d, J = 8.40 Hz, 2 H), 7.31 (d, J = 8.36 Hz, 2 H). MS (EI): m/z
322(M+).
Characterization of the Compounds. Phenylcarbamic Acid
1
tert-Butyl Ester (Table 2, Entry 1). IR (KBr) ν: 1689 cmꢀ1. H NMR
(CDCl3, 300 MHz) δ: 1.51 (s, 9 H), 6.48 (bs, 1 H), 7.02ꢀ7.05 (m,1 H),
(2-Hydroxy-5-methylphenyl)carbamic Acid tert-Butyl Ester (Table 2,
Entry 16). White solid. Mp: 98ꢀ99 °C. IR (KBr) ν: 3427, 3308, 1689,
1153 cmꢀ1. 1H NMR (CDCl3, 300 MHz) δ: 1.51 (bs, 9 H), 2.23 (s, 3 H),
6.65 (bs, 1 H), 6.79ꢀ6.85 (m, 2 H), 6.95 (s, 1 H), 7.78 (bs, 1 H). 13C
NMR (CDCl3, 75 MHz) δ: 21.1, 28.8, 82.4, 118.7, 122.1, 126.3, 130.8,
145.3, 155.4. MS (EI): m/z 166 (M+ꢀ 57). Anal. Calcd. for C12H17NO3:
C, 64.55; H, 7.67; N, 6.27. Found: C, 64.49; H, 7.72; N, 6.28.
(4-Acetylaminophenyl)carbamic Acid tert-Butyl Ester (Table 2,
7.25ꢀ7.36 (m, 4 H). MS (EI): m/z 193 (M+).5g
(3,4,5-Trimethoxyphenyl)carbamic Acid tert-Butyl Ester (Table 2,
Entry 2). IR (KBr) ν: 1694 cmꢀ1. 1H NMR (CDCl3, 400 MHz) δ: 1.51
(s, 9 H), 3.79 (s, 3 H), 3.83 (s, 6 H), 6.47 (bs, 1 H), 6.65 (s, 2 H). 13C
NMR (CDCl3, 100 MHz) δ: 28.3, 56.1, 60.7, 80.5, 96.1, 133.7, 134.5,
152.7, 153.4; MS (EI): m/z 283 (M+). Anal. Calcd for C14H21NO5: C,
59.36; H, 7.42; N, 4.94. Found: C, 59.30; H, 7.38; N, 4.96.
(4-Methoxyphenyl)carbamic Acid tert-Butyl Ester (Table 2, Entry 3).
IR (KBr) ν: 1689 cmꢀ1. 1H NMR (CDCl3, 300 MHz) δ: 1.50 (s, 9 H),
3.77 (s, 3 H), 6.35 (bs, 1 H), 6.80ꢀ6.85 (m, 2 H), 7.24ꢀ7.27(m, 2 H).
MS (EI): m/z 223 (M+).5d
(4-Methylphenyl)carbamic Acid tert-Butyl Ester (Table 2, Entry 4).
IR (KBr) ν: 1701 cmꢀ1. 1H NMR (CDCl3, 300 MHz) δ: 1.50 (s, 9 H),
2.28 (s, 3 H), 6.41 (bs, 1 H), 7.07 (d, J = 8.2 Hz, 2 H), 7.23 (d, J = 8.2 Hz,
2 H). MS (EI): m/z 207 (M+).5d
1
Entry 17). IR (KBr) ν: 1693 cmꢀ1. H NMR (CDCl3, 300 MHz) δ:
1.51 (s, 9 H), 2.15 (s, 3 H), 6.45 (bs, 1 H), 7.16 (bs, 1 H), 7.29 (d, J = 9
Hz, 2 H), 7.40 (d, J = 9 Hz, 2 H). 13C NMR (CDCl3, 75 MHz) δ: 24.9,
28.9, 30.2, 81.1, 119.9, 121.5, 133.8, 135.22, 153.5, 169.0. MS (EI): m/z
250 (M+).36
Naphthalen-1-yl-carbamic Acid tert-Butyl Ester (Table 2, Entry 18).
IR (KBr) ν: 1697 cmꢀ1. 1H NMR (CDCl3, 300 MHz) δ: 1.55 (s, 9 H),
6.85 (bs, 1 H), 7.74 (m, 3 H), 7.62 (d, J = 6 Hz, 2 H), 7.87 (m, 3 H). MS
(EI): m/z 243 (M+).5i
(4-Benzoyloxyphenyl)carbamic Acid tert-Butyl Ester (Table 2, Entry
5). IR (KBr) ν: 1700 cmꢀ1. 1H NMR (CDCl3, 300 MHz) δ: 1.50 (s, 9
H), 5.02 (s, 2 H), 6.36 (bs, 1 H), 6.87ꢀ6.92 (m, 2 H), 7.23ꢀ7.30 (m, 2
H), 7.31ꢀ7.42 (m, 5 H). MS (EI): m/z 299 (M+).5d
Pyridin-4-yl-carbamic Acid tert-Butyl Ester (Table 2, Entry 19). IR
(KBr) ν: 1728, 1606 cmꢀ1. 1H NMR (CDCl3, 300 MHz) δ: 1.52 (s, 9 H),
7.32 (t, J = 3 Hz, 2 H), 8.43 (t, J = 3 Hz, 2 H). MS (EI): m/z 194 (M+).5g
(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)carba-
(2,4,6-Trimethylphenyl)carbamic Acid tert-Butyl Ester (Table 2, En-
try 6). IR (KBr) ν: 1711 cmꢀ1. 1H NMR (CDCl3, 300 MHz) δ: 1.49 (bs,
mic Acid tert-Butyl Ester (Table 2, Entry 20). IR (KBr) ν: 1715 cmꢀ1
.
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The Journal of Organic Chemistry
ARTICLE
1H NMR (CDCl3, 300 MHz) δ: 1.48 (s, 9 H), 2.26 (s, 3 H), 3.03 (s,
3 H), 5.98 (bs, 1 H), 7.26ꢀ7.31 (m, 1 H), 7.38ꢀ7.51 (m, 4 H). MS (EI):
m/z 303 (M+).5d
300 MHz) δ: 0.94 (d, J = 6 Hz, 6 H), 1.27 (t, J = 6 Hz, 3 H), 1.44 (m,
12 H), 4.21 (m, 3 H), 4.97 (d, J = 6 Hz, 1 H). 13C NMR (CDCl3,
100 MHz) δ: 14.2, 21.9, 22.8, 24.8, 28.3, 29.7, 41.9, 52.1, 61.1, 79.8,
155.4, 173.6. Optical rotation: [R]20D ꢀ25.7 (c = 0.95, MeOH). Anal.
Calcd for C13H25NO4: C, 60.12; H, 9.71; N, 5.40. Found: C, 60.10;
H, 9.73; N, 5.39.
(1H-Benzoimidazol-2-yl)carbamic Acid tert-Butyl Ester (Table 2,
Entry 21). IR (KBr) ν: 1734, 1633 cmꢀ1. 1H NMR (CDCl3, 300 MHz)
δ: 1.71 (m, 9 H), 7.02ꢀ7.07 (bs, 2 H), 7.19 (t, J = 6 Hz, 1 H), 7.33 (d,
J = 6 Hz, 1 H), 7.61 (d, J = 6 Hz, 1 H). MS (EI): m/z 233 (M+).5g
(9-Ethyl-9H-carbazol-3-yl)carbamic Acid tert-Butyl Ester (Table 2,
Entry 22). IR (KBr) ν: 1692 cmꢀ1. 1H NMR (CDCl3, 300 MHz) δ: 1.25
(t, J = 9 Hz, 3 H), 1.58 (s, 9 H), 4.20ꢀ4.36 (m, 2 H), 6.55 (bs, 1 H),
7.16ꢀ7.46 (m, 5 H), 8.04ꢀ8.07 (m, 1 H), 8.18 (s, 1 H). MS (EI): m/z
310 (M+).5g
(S)-1-Hydroxymethyl-2-phenylethyl)carbamic Acid tert-Butyl Ester
(Table 3, Entry 8). IR (KBr) ν: 1685 cmꢀ1. 1H NMR (CDCl3, 300 MHz)
δ: 1.41 (bs, 9 H), 2.45 (bs, 1 H), 2.84 (d, J = 7.01 Hz, 2 H), 3.55ꢀ3.56
(m, 1 H), 3.66ꢀ3.68 (m, 1 H), 3.87 (bs, 1 H), 4.76 (d, J = 6.77 Hz, 1 H),
7.20ꢀ7.32 (m, 5 H). Optical rotation reported: [R]25 ꢀ27.0 (c = 1,
D
CHCl3), found [R]20D ꢀ26.7.0 (c = 1, CHCl3).5d
Furan-2-ylmethylcarbamic Acid tert-Butyl Ester (Table 2, Entry 23).
IR (KBr) ν: 1701 cmꢀ1. 1H NMR (CDCl3, 300 MHz) δ: 1.45 (m, 9 H),
4.28 (d, J = 6 Hz, 2 H) 4.80 (bs, 1 H), 6.19 (s, 1 H), 6.28ꢀ6.30 (m, 1 H),
7.32ꢀ7.33 (m, 1 H). MS (EI): m/z 197 (M+).5g
(4-Aminobenzyl)carbamic Acid tert-Butyl Ester (Scheme 3). IR
(KBr) ν: 1689 cmꢀ1. 1H NMR (CDCl3, 300 MHz) δ: 1.45 (bs, 9 H),
3.65 (bs, 2 H), 4.17 (d, J = 5.25, 2 H), 4.75 (bs, 1 H), 6.63 (d, J = 8.22 Hz,
2 H), 7.06 (d, J = 8.00 Hz, 2 H). MS (EI): m/z 222 (M+).33a
(2,2-Dimethoxyethyl)carbamic Acid tert-Butyl Ester (Table 2, Entry
24). IR (CCl4) ν: 1686 cmꢀ1. 1H NMR (CDCl3, 300 MHz) δ: 1.44 (s,
9 H), 3.25ꢀ3.38 (m, 8 H) 4.37 (t, J = 6 Hz, 1 H), 4.86 (bs, 1 H). MS
(EI): m/z 205 (M+).5g
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental design of NMR
b
4-Methyl-piperazine-1-carboxylic Acid tert-Butyl Ester (Table 2,
1
study and scanned spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
Entry 25). IR (CCl4) ν: 1696 cmꢀ1. H NMR (CDCl3, 300 MHz) δ:
1.45 (s, 9 H), 2.29 (s, 3 H), 2.29ꢀ2.35 (m, 4 H), 3.42ꢀ3.45 (m, 4 H).
MS (EI): m/z 200 (M+).5g
’ AUTHOR INFORMATION
Cyclohexylcarbamic Acid tert-Butyl Ester (Table 2, Entry 26). IR
(KBr) ν: 1681 cmꢀ1. 1H NMR (CDCl3, 300 MHz) δ: 1.03ꢀ1.15 (m,
3 H), 1.26ꢀ1.34 (m, 2 H) 1.43 (s, 9 H), 1.57ꢀ1.71 (m, 3 H), 1.90ꢀ1.93
(m, 2 H), 3.43 (bs, 1 H), 4.44 (bs, 1 H). MS (EI): m/z 199 (M+).5g
(R)-(1-Phenylethyl)carbamic Acid tert-Butyl Ester (Table 3, Entry 1).
IR (KBr) ν: 1687 cmꢀ1. 1H NMR (CDCl3, 300 MHz) δ: 1.42 (bs, 12
H), 4.8 (bs, 2 H), 7.24ꢀ7.35 (m, 5 H). MS (EI): m/z 164 (M+ꢀ 57).5d
(S)-2-tert-Butoxycarbonylaminophenylacetic Acid Methyl Ester
Corresponding Author
*Tel: 91-(0)-172 2214683. Fax: 91-(0)-172 2214692. E-mail:
akchakraborti@niper.ac.in.
’ ACKNOWLEDGMENT
Financial support received from CSIR (SRF to A.S. and
S.R.R.) and DST (SR/S1/OC-33/2008), New Delhi, India.
1
(Table 3, Entry 2). IR (KBr) ν: 1684 cmꢀ1. H NMR (CDCl3, 300
MHz) δ: 1.43 (s, 9 H), 3.71 (s, 3 H), 5.32 (d, J = 7.17 Hz, 1 H), 5.54 (bs,
1 H), 7.34 (m, 5 H). Optical rotation: reported [R]20D +135.7 (c = 0.08,
CHCl3), found [R]20D ꢀ135.2 (c = 0.08, CHCl3).36
’ REFERENCES
(1) Carey, J. S.; Laffan, D.; Thomson, C.; Williams, M. T. Org.
Biomol. Chem. 2006, 4, 2337.
(S)-2-tert-Butoxycarbonylamino-3-phenylpropionic Acid Methyl
1
Ester (Table 3, Entry 3). IR (KBr) ν: 1683 cmꢀ1. H NMR (CDCl3,
(2) (a) Chakraborti, A. K.; Gulhane, R. Tetrahedron Lett. 2003,
44, 3521. (b) Chakraborti, A. K.; Gulhane, R. J. Chem. Soc., Chem.
Commun. 2003, 44, 1896. (c) Chakraborti, A. K.; Gulhane, R. Tetra-
hedron 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. (h) Shivani; Gulhane, R.; Chakraborti, A. K. J. Mol. Catal. A:
Chem. 2007, 264, 208–213.
300 MHz) δ: 1.41 (bs, 9 H), 3.08ꢀ3.10 (m, 2H), 3.7 (s, 3 H), 4.59 (s,
1 H), 5.02 (s, 1 H), 7.12 (m, 2 H), 7.26 (m, 3 H). Optical rotation:
reported [R]20D ꢀ4.0 (c = 2.0, MeOH), found [R]20D ꢀ4.2 (c = 2.0,
MeOH).5d
(S)-2-tert-Butoxycarbonylamino-3-(4-hydroxyphenyl)propionic
Acid Methyl Ester (Table 3, Entry 4). IR (KBr) ν: 1687 cmꢀ1. 1H NMR
(CDCl3, 300 MHz) δ: 1.42 (bs, 9 H), 3.00 (t, J = 6 Hz, 2 H), 3.71 (s,
1 H), 4.54 (d, J = 6 Hz, 1 H), 4.98 (d, J = 6 Hz, 1 H), 5.25 (bs, 1 H), 6.73
(d, J = 9 Hz, 2 H), 6.97 (d, J = 9 Hz, 2 H). Optical rotation: reported
[R]22D +51.0 (c = 1.0, CHCl3), found [R]25D 51.4 (c = 1.0, CHCl3).5g
(S)-2-tert-Butoxycarbonylamino-3-(4-hydroxyphenyl)propionic
Acid Ethyl Ester (Table 3, Entry 5). IR (KBr) ν: 1685 cmꢀ1. 1H NMR
(CDCl3, 300 MHz) δ: 1.24 (t, J = 6 Hz, 3 H), 1.42 (bs, 9 H), 2.99 (t, J =
6 Hz, 2 H), 4.16 (q, J = 6.9 Hz, 2 H), 4.51 (d, J = 6 Hz, 1 H), 5.00 (d, J =
9 Hz, 1 H), 5.50 (bs, 1 H), 6.72 (d, J = 9 Hz, 2 H), 6.97 (d, J = 9 Hz, 2 H).
13C NMR (CDCl3, 100 MHz) δ: 14.1, 28.3, 37.6, 54.7, 61.5, 80.2, 115.5,
127.6, 130.4, 155.1, 155.3, 172.2. Optical rotation: [R]20D +1.05 (c = 0.5,
MeOH). Anal. Calcd for C16H23NO5 C, 62.12; H, 7.49; N, 4.53. Found:
C, 62.10; H, 7.51; N, 4.52.
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(S)-2-tert-Butoxycarbonylamino-3-methylbutyric Acid Methyl Ester
(Table 3, Entry 6). IR (KBr) ν: 1684 cmꢀ1. 1H NMR (CDCl3, 300 MHz)
δ: 0.92 (dd, J = 6 Hz, 18 Hz, 6 H), 1.44 (s, 1 H), 2.10 (m, 1 H), 3.73 (s, 3
H), 4.15 (m, 1 H), 5.00 (bs, 1 H). Optical rotation reported: [R]20D ꢀ
22.0 (c = 1, MeOH), found [R]20D ꢀ22.2 (c = 1, MeOH).37
(S)-2-tert-Butoxycarbonylamino-4-methylpentanoic Acid Ethyl
1
Ester (Table 3, Entry 7). IR (KBr) ν: 1687 cmꢀ1. H NMR (CDCl3,
7139
dx.doi.org/10.1021/jo201102q |J. Org. Chem. 2011, 76, 7132–7140

The Journal of Organic Chemistry
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dx.doi.org/10.1021/jo201102q |J. Org. Chem. 2011, 76, 7132–7140