Amberlyst-15 catalyzed Cbz protection of amines under solvent-free conditions

Article abstract of DOI:10.1080/00397911.2010.515341

Amberlyst-15 can effectively catalyze Cbz protection of aliphatic and aromatic amines within 10-15 min under solvent-free conditions. The catalyst can be used repeatedly without loss of activity, and the reaction requires no workup and gives excellent yields. Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2010.515341

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Amberlyst-15 Catalyzed Cbz Protection
of Amines Under Solvent-Free Conditions
Pranja P. Bora a , Khiangte Vanlaldinpuia a , Lalthazuala Rokhum a &
Ghanashyam Bez a
a Department of Chemistry, North Eastern Hill University, Shillong,
India
Version of record first published: 29 Jun 2011.
To cite this article: Pranja P. Bora , Khiangte Vanlaldinpuia , Lalthazuala Rokhum & Ghanashyam Bez
(2011): Amberlyst-15 Catalyzed Cbz Protection of Amines Under Solvent-Free Conditions, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
41:18, 2674-2683
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Synthetic Communications1, 41: 2674–2683, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.515341
AMBERLYST-15 CATALYZED Cbz PROTECTION
OF AMINES UNDER SOLVENT-FREE CONDITIONS
Pranja P. Bora, Khiangte Vanlaldinpuia,
Lalthazuala Rokhum, and Ghanashyam Bez
Department of Chemistry, North Eastern Hill University, Shillong, India
GRAPHICAL ABSTRACT
Abstract Amberlyst-15 can effectively catalyze Cbz protection of aliphatic and aromatic
amines within 10–15 min under solvent-free conditions. The catalyst can be used repeatedly
without loss of activity, and the reaction requires no workup and gives excellent yields.
Keywords Amberlyst-15; amine; Cbz; solvent-free
INTRODUCTION
The Cbz group is one of the most widely used functionalities for protection of
amines because it is inert toward most of the basic reaction conditions and aqueous
acidic conditions[1] and removal of the Cbz group upon hydrogenation is easy.
Because of its compatibility for a wide range of pH values, applications of the
Cbz group are important in the field of medicinal chemistry.[2] There are many
efficient methods for preparation of Cbz derivatives of amines, such as lithium
hexamethyldisilazane (LiHMDS) as a base in tetrahydrofuran–hexamethylpho-
sphoramide (THF–HMPA) solvent,[3] cyclodextrine in aqueous media,[4] silica–
sulfuric acid,[5] and La(NO3)3 ꢀ 6H2O under solvent-free conditions,[6] in iodine,[7]
and in miceller media.[8] Recently, we reported an easy method for Cbz protection
of amines in the presence of a catalytic amount of heteropoly acid.[9] Because method
works best when environmentally unfavorable dichloromethane is used as a solvent
and only 50–60% of the catalyst is recovered after methanol wash, we looked for an
alternative where the recovery of the catalyst is very good with excellent reactivity.
Development of resin-bound catalyst for organic transformation is one of the
most important features in organic synthesis because it is reusable and easily sepa-
rated from the reaction system. In recent years, Amberlyst-15 has become one of
Received April 26, 2010.
Address correspondence to Ghanashyam Bez, Department of Chemistry, North Eastern Hill
University, Shillong 793022, India. E-mail: bez@nehu.ac.in
2674

CBz PROTECTION OF AMINES
2675
the most viable alternatives for acid-catalyzed reactions.[10] In contrast to mineral
acid-catalyzed reactions, it has high thermal stability and well-defined acidic proper-
ties. Nevertheless, it has fewer side reactions as compared to mineral acids and is a
very effective heterogeneous reaction medium. Here, we report efficient protection of
both aliphatic and aromatic amines as their Cbz derivatives by reacting with benzyl-
chloroformate in the presence of a catalytic amount of amberlyst-15 under
solvent-free conditions (Scheme 1).
Initially, we tried to carry out the reaction just by mixing the benzylamine and
benzyl chloroformate in equivalent amounts in the absence of any catalyst, keeping
in view that the highly reactive amine may not need a catalyst for this transform-
ation. After stirring for an hour, we observed that the starting benzylamine was
no longer present and a white gel was forming. Thin-layer chromatographic
(TLC) analysis of the crude mixture revealed the formation of a new spot along with
the unreacted benzylchloroformate and a highly polar product at the baseline. Care-
ful scrutiny of the polar product led us to conclude that it was the hydrochloride salt
of benzylamine that gave the white precipitate. Purification of the crude product with
column chromatography gave the Cbz-protected amine in 68% yield. In spite of get-
ting such a result, we decided to test this protocol with other substrates, such as ani-
line and L-proline, with a view that only mixing of the reactants are required to get
the products, at least in an acceptable level with the easily separable hydrochloride
salts in the mix. Ironically, though aniline gave the Cbz-protected amine in 65% yield
after purification, L-proline reached its equilibrium within an hour almost after 50%
conversion of the substrate and the reaction did not proceed further even after 24 h,
leading to only 34% yield of the purified product. These observations led us to con-
clude that use of a catalyst is a must to shift the equilibrium toward the right. A
recent report by Gawande et al.[5] regarding Cbz protection of amine with silica–
sulfuric acid catalyst led us to envisage that the use of polymer-bound sulfonic acid
catalysts such as Amberlyst-15, Dowex-50, and Amberlite IR 120 may also work well
for this conversion and hence may provide us with both increased yield and easy
removal of the catalyst after use, just by filtration. Therefore, a mixture of benzyl
amine (0.107 g, 1.0 mmol) with benzylchloroformate (0.170 g, 1.0 mmol) in CH2Cl2
(1 mL) in the presence of Amberlyst-15 (20 mg=mmol) was stirred at room tempera-
ture. To our pleasure, the reaction showed complete conversion after only 10 min,
leaving no unreacted starting material. Although some white precipitate was formed,
purification of the crude product resulted in improved yield (78%). As halogenated
solvents are not environmentally compatible, we decided to screen out other solvents
such as CH3CN, Et2O, dimethoxyethane (DME), dioxane, and THF for the reac-
tion, but no significant improvement of yield was observed even after half an hour
of reaction time. In ethanol, an environmentally compatible solvent, and also in
water, protection of the amine was not favored even after a prolonged reaction time
(entry 6 and 7, Table 1).
Scheme 1. Cbz-protection of amines.

2676
P. P. BORA ET AL.
Table 1. Effect of solvent on Cbz protection of amine
Entry
Solvent
Time (min)
Yield (%)
1
2
3
4
5
6
7
CH3CN
Et2O
THF
30
30
70
69
30
30
75
72
DME
Dioxane
Ethanol
Water
45
68
20
300
300
No reaction
Given the recent emphasis on reactions under environmentally benign reaction
conditions, we sought to carry out the reaction in the absence of any solvent. The
reaction showed complete conversion of the starting material just after 10 min of stir-
ring with almost similar yield (77%) of the purified product. In an effort to do away
with the hydrochloride salt, which is responsible for lesser yield, we decided to
stir benzylamine with Amberlyst-15 for at least 10 min before the addition of
benzylchloroformate. The protocol worked really well, leading to a much improved
yield (90%) of the Cbz-protected benzylamine.
Inspired by the findings with Amberlyst-15, we decided to carry out Cbz pro-
tection of benzylamine with other resin-bound acid catalysts also. While studying the
catalytic effect of highly acidic resin, Dowex 50, on Cbz protection of benzylamine
following the same reaction protocol, we observed that the starting benzylamine
undergoes complete conversion within 10 min, but the isolated yield of the
Cbz-protected amine was found to be mediocre (62%) as a result of increased forma-
tion of white ammonium salt. Weakly acidic resins Amberlite IRA 120 and Amber-
lite IRP 64 catalyzed the Cbz protection of benzylamine in longer times, yet yields
(entries 2 and 3, Table 2) were better than that with Dowex-50. Given the efficiency
of these resin-bound acid catalysts, we decided to carry out the protection with
Amberlyst-15.
Table 2. Effect of acidic resins on Cbz protection of amine
Entry
Resin
Dowex-50
Time (min)
Yield (%)
1
2
3
10
20
20
62
75
69
Amberlite IRA 120
Amberlite IRP 64

CBz PROTECTION OF AMINES
2677
The catalyst ratio was also studied for benzylamine as the substrate, wherein
use of 20 mg of Amberlyst-15 per mmol of the amine was optimum. Higher catalytic
loading (30 mg=mmol and 40 mg=mmol) did not make any noticeable change in the
reaction time, whereas lower catalytic loading (10 mg=mmol) increased the reaction
time to almost an hour for complete conversion. We studied the reusability of the
recovered catalyst. For that purpose, we thoroughly washed the recovered catalyst
with methanol until no trace of any compound was detected in the filtrate by moni-
toring with TLC. The purified Amberlyst-15 was then kept in the oven at 120 ꢁC
overnight before reuse. Expectedly, we found that the efficiency of the catalyst
was intact even after three recoveries.
Having optimized the reaction protocols involving order of addition, time, and
catalyst ratio, we carried out the reaction on a diverse set of substrates (Table 3) to
explore the general applicability of the method. We initially tried to protect the sim-
ple liquid amines (Table 3), such as morpholine (entry 6), piperidine (entry 7), pyr-
olidine (entry 8), cyclohexylamine (entry 10), and 2-phenethyl amine (entry 12), to
make sure that both the reactants can mix up well in presence of the insoluble
Amberlyst-15. All the substrates formed the desired Cbz derivatives in excellent
yields within a very short reaction time (Table 3). The reaction worked equally well
when benzylamine (entry 5, Table 3), L-proline (entry 13, Table 3), and hexadecyla-
mine (entry 18, Table 3), were subjected to the same reaction protocol with benzyl-
chloroformate (1.2. equiv). It was observed that indole and L-proline melt in
benzylchloroformate to make a homogenous mixture, and completion of the homo-
genization of both the reactants indicates the completion of the reaction, too.
Next, we studied the protection of aromatic amines bearing acid-sensitive func-
tional groups such as -OMe (entry 2, Table 3), -Cl (entry 3, Table 3), 1,3-dioxolanes
(entry 14, Table 3), -OAc (entry 15, Table 3), and -OTHP (entry 17, Table 3), where
they were found to be highly compatible to our reaction conditions and gave very
good yields. When the protection was carried out on TBS-protected 4-aminophenol
(entry 16, Table 3), it was observed that in spite of being sensitive toward p-TsOH,[11]
the catalyst did not have any adverse effect on the reaction yield in our reaction
conditions. The presence of the TBS group in its Cbz-protected derivative is evident
from two singlets at d 0.1 ppm and d 0.78 ppm in 1H NMR spectra, integrating to six
and nine protons respectively. Nevertheless, the presence of a peak at d ꢂ4.33 ppm in
13C NMR spectra also confirmed our contention. The 1,3-dioxolane-protected
3-aminobenzaldehyde (entry 14, Table 3) showed very good result, where the pres-
1
ence of two multiplets in the H NMR spectra at d 3.97 and 4.04 ppm integrating
to two protons each reflected the presence of the 1,3-dioxolane protection. A singlet
at d 5.13 ppm integrating to two protons, a broad singlet at d 6.64 ppm integrating to
one proton, and a multiplet integrating to nine protons at d 7.07–7.41 indicated the
presence of the benzylic ꢂCH2, -NH, and the phenyl protons respectively. The
acetonide-protected highly sterically hindered amine (entry 20, Table 3) derived from
Shi’s ketone could be protected employing the same reaction protocol, which was
1
confirmed from its good yield as well as it H NMR spectra. The presence of four
singlets at d 1.37, 1.38, 1.47, and 1.61 ppm integrating to three protons each
confirmed that both the acetonide groups remained intact, while a double doublet
at d 5.11 ppm and a multiplet at d 7.35 ppm integrating to two and five protons
respectively corresponded to the benzyl of the Cbz group. The presence of a peak

2678
P. P. BORA ET AL.
Table 3. Cbz protection of amines via Scheme 1a
Entry
1
Substrate
Product
Time (min)
15
Yield (%)b
89
2
3
15
15
93
91
4
5
15
10
87
90
6
10
90
7
8
9
10
10
15
92
89
97
10
10
94
11
12
10
10
91
92
13
14
15
15
15
15
79
85
82
(Continued )

CBz PROTECTION OF AMINES
2679
Table 3. Continued
Entry
16
Substrate
Product
Time (min)
10
Yield (%)b
88
17
18
19
10
10
10
83
95
95
20
15
93
aAll the reactions were conducted at room temperature.
bYield of the purified products.
at d 156.49 ppm in the 13C NMR spectra revealed the presence of the carbonyl car-
bon of the Cbz-protected amine. The effect of hydroxyl group was also studied,
wherein it was observed that both the phenolic (entry 4, Table 3) and the alcoholic
-OH (entry 11, Table 3) groups are inert to this reaction condition and gave good
yields of the corresponding Cbz-protected amines to suggest that free hydroxyl
groups are compatible under this reaction condition.
CONCLUSION
In conclusion, we have reported a highly efficient yet simple protocol for Cbz
protection of amines bearing diverse reactive functionalities using Amberlyst-15
under solvent-free conditions. Simple filtration leads to almost pure crude products,
which were purified by column chromatography to get the pure product. The catalyst
can be washed, dried, and used three times with little or no change in the reactivity
profile.
EXPERIMENTAL
The commercially available starting amines were purified by column chroma-
tography before use. Benzylchloroformate and Amberlyst-15 were purchased from
1
Sigma-Aldrich Chemicals and were used without any processing. H NMR and
13C NMR spectra were recorded in CDCl3 in Brucker DRX 400 NMR machines
with tetramethylsilane (TMS) as internal standard, while infrared (IR) spectra

2680
P. P. BORA ET AL.
(Perkin-Elmer) were recorded as thin films unless otherwise stated. Elemental analy-
sis was carried out on automatic analyzer EA 1110 CHNS-O.
Typical Experimental Procedure
A mixture of benzylchloroformate (1.0 equiv) and Amberlyst-15 (20 mg=mmol)
was stirred for 5 min, and amine (1.0 equiv) was added into it. After stirring for the
specified time (Table 1) at rt, the reaction mixture was diluted with ethyl acetate and
filtered through ordinary filter paper. The catalyst was washed thoroughly with ethyl
acetate, and the filtrate was concentrated. The resulting crude was purified by
column chromatography to get the pure N-benzyloxycarbonyl derivative.
Spectral Data for Selected Compounds
N-Cbz-dicyclohexylamine (Entry 9). IR (CHCl3): 3031, 2943, 2860, 1683,
1
1439, 1268, 1237, 1079, 1021 cmꢂ1; H NMR (400 MHz, CDCl3): d 1.29 (m, 4H),
1.60 (m, 8H), 1.77 (m, 8H), 3.52 (m, 2H), 5.16 (s, 2H), 7.30 (m, 5H); 13C NMR
(100 MHz, CDCl3): d 22.70, 26.74, 31.9, 41.12, 66.57, 128.08, 128.13, 128.33,
128.51, 136.66, 156.37. Calculated elemental analysis for C20H29NO2: C, 76.15; H,
9.27; N, 4.44. Found: C, 76.01; H, 9.21; N, 4.59.
N-Cbz-diethanolamine (Entry 11). IR (CHCl3): 3420, 3039, 2940, 2857,
1679, 1441, 1278, 1321, 1105, 917 cmꢂ1 1H NMR (400 MHz, CDCl3): d 3.46
;
(t, J ¼ 5.6 Hz, 4H), 3.77 (dd, J ¼ 8, 3.6 Hz, 4H), 5.10 (s, 2H), 7.32 (m, 5H); 13C
NMR (100 MHz, CDCl3): d 52.04, 52.59, 61.32, 61.66, 67.40, 127.88, 128.36,
136.36, 158.86. Calculated elemental analysis for C12H17NO4: C, 60.24; H, 7.16;
N, 5.85. Found: C, 60.14; H, 7.08; N, 5.91.
N-Cbz-3-(1,3-dioxolan-2-yl)aniline (Entry 14). IR (CHCl3): 3434, 3154,
3019, 2979, 2928, 1734, 1601, 1473, 1383, 1215, 1096, 910 cmꢂ1 1H NMR
;
(400 MHz, CDCl3): d 3.97 (m, 2H), 4.04 (m, 2H), 5.13 (s, 2H), 5.71 (s, 1H), 6.64
(br s, 1H), 7.07–7.41 (m, 9H); 13C NMR (100 MHz, CDCl3): d 65.30, 65.41, 67.05,
103.3, 121.6, 127.00, 127.68, 128.31, 128.39, 128.58, 128.64, 129.20, 135.98, 137.89,
139.05, 158.90. Calculated elemental analysis for C17H17NO4: C, 68.21; H, 5.72;
N, 4.68. Found: C, 68.16; H, 5.63; N, 4.77.
N-Cbz-[4-(tert-butyldimethylsilyloxy)]aniline (Entry 16). IR (CHCl3):
1
3372, 3034, 2925, 2854, 1672, 1608, 1550, 1453, 1291, 1247, 1059, 951 cmꢂ1; H
NMR (400 MHz, CDCl3): d 0.01 (s, 6H), 0.78 (s, 9H), 4.95 (s, 2H), 6.62 (d, J ¼ 7.2
2H), 7.18 (m, 7H), 8.42 (s, 1H); 13C NMR (100 MHz, CDCl3): d ꢂ4.33, 18.76, 26.06,
66.71, 128.79, 128.88, 129.27, 157.82. Calculated elemental analysis for
C20H27NO3Si: C, 67.19; H, 7.61; N, 3.92. Found: C, 67.22; H, 7.52; N, 3.96.
N-Cbz-[3-(tetrahydro-2h-pyran-2-yloxy)methyl]aniline (Entry 17). IR
(CHCl3): 3432, 3155, 2928, 1733, 1601, 1470, 1383, 1095, 902 cmꢂ1 1H NMR
;
(400 MHz, CDCl3): d 1.55–1.88 (m, 6H), 3.54 (dd, J ¼ 11.6, 5.0 Hz, 1H), 3.92 (m,
1H), 4.48 (d, J ¼ 12.0 Hz, 1H), 4.70 (t, J ¼ 3.2 Hz, 1H), 4.76 (d, J ¼ 12.0 Hz, 1H),
5.20 (s, 2H), 5.30 (s, 2H), 6.70 (s, 1H), 7.06–7.42 (m, 8H); 13C NMR (100 MHz,
CDCl3): d 18.30, 24.420, 28.67, 61.10, 65.98, 67.50, 96.76, 116.79, 121.81, 127.28,

CBz PROTECTION OF AMINES
2681
127.34, 127.60, 128.10, 134.99, 136.81, 138.43, 158.20. Calculated elemental analysis
for C20H23NO4: C, 70.36; H, 6.79; N, 4.10. Found: C, 70.24; H, 6.74; N, 4.15.
N-Cbz-hexadecylamine (Entry 18). IR (CHCl3): 3329, 3062, 3034, 2918,
2851, 1693, 1551, 1528, 1470, 1460, 1370, 1267, 1141, 1035 cmꢂ1 1H NMR
;
(400 MHz, CDCl3): d 1.07–1.48 (m, 28H), 3.18 (dd, J ¼ 9.2, 6.8 Hz, 3H), 5.09 (s,
2H), 7.33 (m, 10H), 8.79 (t, J ¼ 7.6 Hz, 2H); 13C NMR (100 MHz, CDCl3): d
14.14, 22.71, 26.75, 29.29, 29.38, 29.56, 29.59, 29.66, 29.67, 29.68, 29.71, 29.96,
31.94, 41.12, 66.56, 128.07, 128.11, 128.50, 136.67, 156.40. Calculated elemental
analysis for C24H41NO2: C, 76.75; H, 11.00; N, 3.73. Found: C, 76.69; H, 10.95;
N, 3.79.
N-Cbz-adamentylamine (Entry 19). IR (CHCl3): 3432, 3018, 2912, 2852,
1720, 1600, 1507, 1420, 1216, 1055 cmꢂ1 1H NMR (400 MHz, CDCl3): d 1.59
;
(m, 8H), 1.86 (m, 6H), 2.01 (m, 3H), 4.95 (s, 2H), 4.56 (s, 1H), 7.24 (m, 5H);
13C NMR (100 MHz, CDCl3): d 29.44, 36.29, 41.83, 50.79, 65.37, 65.94, 126.99,
127.66, 128.01, 128.52, 129.09, 140.90, 158.92. Calculated elemental analysis for
C18H23NO2: C, 75.76; H, 8.12; N, 4.91. Found: C, 75.60; H, 8.03; N, 4.98.
N-Cbz-1,2:4,5-di-O-isopropylidene-3-amino-3-deoxy-b-D-fructopyranose
(Entry 20). IR (CHCl3): 3328, 3100, 2928, 1712, 137, 1456, 1372, 1230, 1088,
1
967 cmꢂ1; H NMR (400 MHz, CDCl3): d 1.37 (s, 3H), 1.38 (s, 3H), 1.47 (s, 3H),
1.61 (s, 3H), 3.89–4.20 (m, 6H), 4.80 (m, 1H), 5.11 (dd, J ¼ 13, 12 Hz, 2H), 7.35
(m, 5H); 13C NMR (100 MHz, CDCl3): d 25.88, 26.38, 26.44, 28.04, 52.86, 60.14,
67.19, 71.67, 72.72, 75.99, 105.09, 109.60, 111.80, 128.06, 128.20, 128.54, 136.14,
156.49. Calculated elemental analysis for C20H27NO7: C, 61.06; H, 6.92; N, 3.56.
Found: C, 61.04; H, 6.91; N, 3.58.
ACKNOWLEDGMENTS
G.B. is grateful to the Council of Scientific and Industrial Research, New Delhi
[Scheme No. 0 1 (1992)=05=EMR-II], and the Department of Science and Tech-
nology, New Delhi (Scheme No. SR=S1=OC-25=2007), for providing the financial
assistance for this work.
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