Mild approach to the deprotection of Troc from protected amines using mischmetal and TMSCl

Article abstract of DOI:10.1080/00397910903419910

The 2,2,2-trichloroethoxycarbonyl (Troc) protecting group was efficiently removed from Troc-protected aliphatic and aromatic amines and also some Troc, Tos- and Troc, Ac-protected amines using activated mischmetal (MM). All reactions were performed by ref

Full text of DOI:10.1080/00397910903419910

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Mild Approach to the Deprotection
of Troc from Protected Amines Using
Mischmetal and TMSCl
Eerold Vellemäe a , Vladimir Stepanov a & Uno Mäeorg a
a Institute of Chemistry , University of Tartu , Tartu, Estonia
Published online: 15 Oct 2010.
To cite this article: Eerold Vellemäe , Vladimir Stepanov & Uno Mäeorg (2010) Mild Approach to the
Deprotection of Troc from Protected Amines Using Mischmetal and TMSCl, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 40:22, 3397-3404,
DOI: 10.1080/00397910903419910
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Synthetic Communications1, 40: 3397–3404, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903419910
MILD APPROACH TO THE DEPROTECTION OF TROC
FROM PROTECTED AMINES USING MISCHMETAL
AND TMSCl
¨
Eerold Vellemae, Vladimir Stepanov, and Uno Maeorg
Institute of Chemistry, University of Tartu, Tartu, Estonia
¨
The 2,2,2-trichloroethoxycarbonyl (Troc) protecting group was efficiently removed
from Troc-protected aliphatic and aromatic amines and also some Troc, Tos- and Troc,
Ac-protected amines using activated mischmetal (MM). All reactions were performed by
refluxing in dry tetrahydrofuran under an argon atmosphere and gave moderate to
excellent yields. Several new compounds were synthesized, and new data about reactivity
of Troc group were obtained.
Keywords: Amines; deprotection; mischmetal; TMSCl; Troc
Protection strategies have been exceedingly useful in the synthesis of many biologi-
cally active compounds such as apratoxin A,[1] Isotaxe,[2] and aminoacridines[3] for
the masking of the hydroxy- and amino groups in intermediate products. Therefore,
when a reaction is to be conducted at specific site in a polyfunctional substrate, it is
first necessary to block all other reactive sites by employing protecting groups that
can be easily removed after the desired chemical transformation. One option is to
utilize the Troc protecting group. Troc is a stable protecting group and has a rela-
tively simple introduction method when employed for the protection of the hydroxy-
and amino groups.[4] Therefore, it has been an extensively used protecting group in
organic synthesis. It also allows selective stepwise cleavage[5] in the presence of an
orthogonal protective group that adds to its usefulness in organic synthesis. Accord-
ing to the originally published Troc cleavage method,[6] which is still being actively
used today, the removal is carried out via a reductive elimination process using
Zn dust in 90% aqueous AcOH. Thus, the classical deprotection conditions do not
allow easily reducible or acid-sensitive groups to be retained in substrates.[7] Because
of this particular problem, numerous attempts to modify this method were made,
where Zn has been substituted by metal pairs, such as Zn-Cu, Zn-Pb, and Cd-Pb,[8]
or a less active metal than Zn.[8] However, these methods still need acidic reaction
media to cleave the Troc group. In recent years, a few methods were published in
which the Troc group was removed in pH-neutral conditions, for example, using
Received August 5, 2009.
Address correspondence to Uno Ma¨eorg, Institute of Chemistry, University of Tartu, Jakobi 2,
51014 Tartu, Estonia. E-mail: uno.maeorg@ut.ee
3397

¨ ¨
E. VELLEMAE, V. STEPANOV, AND U. MAEORG
3398
In=NH4Cl in EtOH-H2O[7] mixture or using Zn-N-methylimidazole in ethyl acetate
or acetone.[9] Also, numerous papers have been published in recent years describing
lanthanoids and corresponding salts used for this purpose, including a method where
SmI2 in tetrahydrofuran (THF) has been applied to remove the Troc group.[4]
Regardless of good yields, some of these previously mentioned methods and the
reagents used for this purpose are expensive (In, SmI2). Also, those procedures were
applied exclusively in the absence of other well-known protecting groups such as
Cbz(Z), Boc, Tos, and Ac.
However, our previous work has shown that a trimethylsilylchloride (TMSCl)
and mischmetal (MM) (50% Ce, 25% La, 16% Nd, 6% Pr)[10] system works relatively
fast and very selectively when applied to cleavage of the Troc protective group from
hydrazines and aromatic amines without decomposition of hydrazines or Boc and
Cbz groups present in the starting substrates. The aim of this research was therefore
to explore those mild conditions in the presence of other well-known protecting and
functional groups such as Tos, Ac, CN, and COOEt in detail (Scheme 1). Herein we
report the results of our work where we utilize MM for this purpose.
Using already optimized deprotection conditions[10] for various Troc-protected
starting compounds such as aliphatic and aromatic amines and amino acids, we have
applied the method to Troc,Tos- and Troc,Ac-protected amines.[11] The results of the
cleavage of the Troc group from several starting compounds under optimized reac-
tion conditions are outlined in Table 1. It shows that the reaction proceeds smoothly,
yielding the corresponding deprotected products. In the course of these studies, we
have confirmed that activated mischmetal in THF is capable of removing the Troc
protecting group from esters and aliphatic and aromatic amines in the presence of
other well-known protecting groups such as Ac and Tos or the presence of other
well-known functional groups such as CN and COOEt. The cleavage of the Troc
group was very selective under very mild conditions that left the ester group as well
as other protecting groups in place. The behavior of MM in these conditions is inter-
esting, because it allows the selective cleavage of the Troc group from Troc(Tos)N or
Troc(Ac)N in substituted amines while the Ac and Tos groups remain unaffected.
This is a very good example of the orthogonality of this new method.
During this investigation it was found that the TMSCl=MM system in THF
cleaves the Troc group from p-MeO-C6H4-NH-Troc considerably faster than in
the published method[7] where the Troc group was cleaved with In=NH4Cl in
EtOH–H2O. The reaction times were 3 and 4 h, respectively. Also, when we com-
pared reaction speeds of p-MeO-C6H4-(CH2)2-NH-Troc and of p-Br-C6H4-(CH2)2-
NH-Troc from the same work,[7] we also found that TMSCl=MM system cleaves
the Troc group considerably faster than the system In=NH4Cl. The reaction times
for cleavage of the Troc group from those compounds were 2 and 3 h, respectively.
Scheme 1. R1 ¼ H, PhCH2, p-HOOC-C6H4, EtOOCH2, p-CN-Ph, p-MeO-C6H4CH2CH2, R2 ¼ H, Tos,
Ac; MM ¼ mischmetal.

DEPROTECTION OF TROC WITH TMSCl/MM
3399
Table 1. Deprotection of Troc group with MM=TMSCl in THF
Entry
1a
Compound (A)
Product (B)
Reaction time (h)
3
Yield (%)
Ph-CH2-NH-Troc
Ph-CH2-NH2
62e
2
4
88
3b,c
24
No reaction
4c
5
3
2
54e
92
Ph-NH-Troc
Ph-NH2
6
2
3
87
80
7c
8
8
3
3
60e
65d
81
9c
10
11c
1,5
52d,e
aThe identity of products (B 1, 5, 6) were confirmed by GC, and IR spectroscopy and the rest of the
products were confirmed by 1H NMR and=or 13C NMR spectroscopy.
bIn the reaction of number 3, 4 mmol of MM and 6.2 mmol of TMSCl were used instead of optimized
conditions.
cNew compounds (A 3, 4, 7, 9, 11) were identified by HR mass spectrometry.
dThe yields of the products 9B and 11B were determined after purification of the crude product by col-
umn chromatography.
eBrine was used for washing the extract instead of distilled H2O.
During this investigation, it was also discovered that the rate of cleavage of the
Troc group from aliphatic or aromatic amines can be influenced by the adjacent pro-
tective group. Remarkable acceleration was observed (see Table 1, entries 8–11) if
the Ac group was residing at the same nitrogen as the Troc group. It was expected

¨ ¨
E. VELLEMAE, V. STEPANOV, AND U. MAEORG
3400
that the Tos group would also bring an acceleration effect similar to one observed in
the case of the Ac protective group. Unexpectedly, instead of acceleration, deceler-
ation actually was observed in the case of the Tos group occupying the same adjacent
position (see Table 1, entries 4–7), but this discrepancy can be explained by steric
hindrance of the bulky Tos group.
However, other authors[12,13] have demonstrated this acceleration effect only in
the case of a Boc group, but to the best of our knowledge the impact of other pro-
tecting groups, like Ac (or Boc in our previous work[10]) on the Troc group reactivity
was not reported. Usually the cleavage of the Troc group with the TMSCl=MM sys-
tem took about 2 to 3 h refluxing in THF, with some significant exceptions. Thus, the
cleavage of the Troc group from Troc-protected p-aminobenzoic acid in the system
TMSCl=MM was not successful. Because of the possibility that substituted benzoic
acid could react with MM, it therefore is not a suitable compound for those con-
ditions. To avoid the reaction between p-aminobenzoic acid and MM, the
p-aminobenzoic acid was converted into corresponding silyl esters with TMSCl in
situ (using for that purpuse the known procedures[14,15]) and then proceeded to
the cleavage reaction. However, even so, no desired reaction occurred after refluxing
the reaction mixture with MM in dry THF for 24 h.
Another phenomenon was observed in the case of the cleavage of the Troc
group from compound 9a (see Table 1), and the reaction was ended within 3 h.
We suppose that this considerable acceleration can be explained by the following fac-
tors: Ac is a strong deactivating group, and therefore it activates a corresponding
nitrogen atom and brings the acceleration. Also, it is important that the Ac group
has low steric hindrance, which does not hinder the interaction between TMSCl=
MM and the reaction center. Indeed, it was demonstrated in our previous work[10]
that a Boc group also brings the acceleration, but because of the much larger sterical
hindrance of the bulky Boc group compared to the Ac group, the acceleration effect
was smaller.
However, when we tried to cleave the Troc group from 8a, which is very similar
to compound 9a, the reaction proceeded in a very different way. During this parti-
cular reaction, the TMSCl=MM system did not cleave the Troc group but instead
transformed the CCl3CH2O group into CH3CH2O. This unusual result could be
explained by the fact that compound 8a includes a cyano group in the conjugating
p-position of the aromatic ring, which would reduce the reactivity of nitrogen. Also,
it is important to consider the fact that all lanthanoids in MM are very active metals
and in this particular case the reaction time was very long. Thus, all these factors
(low activity of nitrogen, presence of active metals, and long reaction time at elevated
temperatures) could be the reasons why this kind of transformation takes place.
Thus, as we mentioned before, the role of an adjacent protecting group could be very
important not only for the speed of the cleavage reaction but also it could signifi-
cantly change the path of reaction.
In summary, we have described a new mild and cheap deprotection method for
cleavage of the Troc group from various substrates using a TMSCl=MM system in
dry THF. The reactions in these conditions are relatively fast and generally provide
excellent yields. We also demonstrated that this deprotection method could be suc-
cessfully utilized in the presence of Tos, Ac, and COOEt groups. Thus, an extremely
simple, mild, cheap, and reproducible protocol is reported.

DEPROTECTION OF TROC WITH TMSCl/MM
3401
EXPERIMENTAL
All reactions were conducted under an argon atmosphere, and all the starting
compounds were confirmed by 1H NMR and 13C NMR spectroscopy. Column
chromatography was performed using MN Kieselgel 60 (70–230 mesh).
1H and 13C NMR spectra were determined on a Bruker Avance II 200
instrument operating at 200 and 50 MHz respectively, and tetramethylsilane
(TMS) was used as reference.
Gas chromatography (GC) analyses were performed on an HP 5890A
instrument with FID detector, using helium as carrier gas and fused silica capillary
column Elite PE-5, 30 m ꢀ 0.25 mm.
High-resolution (HR) mass spectra were measured with a Thermo Electron
LTQ Orbitrap ESI mass spectrometer.
Infrared (IR) spectra were measured on a Spectrum BXII (Perkin-Elmer)
Fourier transform (FT)–IR spectrometer with ATR device (Zn-Se), using the KBr
pellet technique.
MM was purchased from Redel-de Haen (50% Ce, 25% La, 16% Nd, 6% Pr).
General Procedure
Freshly, manually filed MM powder (380 mg, 2.7 mmol; grain size 0.1–0.3 mm)
was added to 10 ml of dry THF and activated with 0.52 ml (4.1 mmol) of TMSCl by
refluxing for 30 min under an argon atmosphere. Then, 0.44 mmol of Troc-protected
starting compound was added, and the obtained mixture was refluxed again. The
progress of the deprotection reaction was monitored using thin-layer chromato-
graphy (TLC; EtOAc–hexane, usually 4:1 or 2:1). Before TLC, the sample was
quenched with saturated Na2CO3. When the reaction was complete, the MM powder
was filtered, and the resulting filtrate was neutralized with 30 ml of saturated aqueous
solution of Na2CO3 (or ꢁ10% NaOH), stirred for 5 min, and then extracted with
dichloromethane (5 ꢀ 15 ml) and with EtOAc (3 ꢀ 15 ml). The combined organic
layers were washed with 0.2 M citric acid aqueous solution, twice with distilled water
(or brine), and then dried over anhydrous MgSO4. The mixture was filtered and
concentrated by rotary evaporation. If purification was needed, the crude product
was purified by column chromatography.
Preparation of Compound 9a
Compound 8a (520 mg, 1.77 mmol) and DIPEA (N,N-diisopropylethylamine;
1.3 ml, 7.4 mmol) were added to 30 ml of acetonitrile. Then 0.5 ml (6.6 mmol) of AcCl
was added, and the obtained mixture was refluxed overnight under an Ar atmos-
phere. The progress of the reaction was monitored using TLC (EtOAc–hexane,
2:1). When the reaction was complete, the solvent was removed on a rotary evapor-
ator and the crude product was purified twice by column chromatography (EtOAc–
hexane 1:2 and EtOAc–hexane 2:1). The collected fractions were combined and
concentrated by rotary evaporation, and 250 mg of compound 9a was obtained.
1
The structure of the new compound was confirmed by H NMR and 13C NMR
spectroscopy and HR mass spectrometry.

¨ ¨
E. VELLEMAE, V. STEPANOV, AND U. MAEORG
3402
Preparation of Compound 11a
The compound 11a was prepared essentially the same way as 9a, except that
instead of DIPEA, DMAP (4-dimethylaminopyridine) was used. The yield after
purification was 25%.
Spectral Data of the Starting Compounds
Compound 1A. 1H NMR (CDCl3): d ¼ 4.41=4.44 (d, 2H, Ph-CH2), 4.76 (s,
2H, CH2, Troc), 5.33 (s, 1H, NH, Bn-NH), 7.31–7.33 (m, 5H, Ph). 13C NMR
(CDCl3): d ¼ 45.6 (Ph-CH2), 74.9 (CH2, Troc), 95.7 (CCl3, Troc), 127.6, 127.8,
=
128.9, 137.9 (Ar), 154.7 (C O, Troc).
Compound 2A. 1H NMR (CDCl3): d ¼ 1.26=1.30=1.34 (t, 3H, EtO),
4.00–4.29 (m, 2H, CH2 EtO), 4.75 (s, 2H, CH2, Troc), 5.77 (s, 1H, NH). 13C
NMR (CDCl3): d ¼ 13.9 (Me, EtO), 43.1 (CH2, EtO), 61.5 (CH2-N), 75.0 (CH2,
=
=
Troc), 95.4 (CCl3, Troc), 154.1 (C O, Troc), 169.2 (C O, COOEt).
Compound 3A. 1H NMR (CDCl3 þ d6-DMSO): d ¼ 4.86 (s, 2H, CH2, Troc),
7.47 (s, 1H, NH), 7.61=7.65 (d, 2H, Ar), 7.95=7.99 (d, 2H, Ar), 9.79 (s, 1H, COOH).
13C NMR (CDCl3 þ d6-DMSO): d ¼ 74.5 (CH2, Troc), 95.7 (CCl3, Troc), 118.3,
125.8, 130.8, 142.5 (Ar), 151.9 (C O, Troc) 167.9 (C O, COOH). FTIR n (cmꢂ1):
=
=
=
=
3300–2500 (COOH), 1530 NH (NH-Troc), 1716 (C O, COOH), 1674 (C O, Troc),
1222 (C-O-C), 718 (C-Cl). Mp ¼ 226–228 ꢃC. C10H8Cl3NO4 Mþ þ H calc. 313.95622;
Mþ þ H found 313.95697.
Compound 4A. 1H NMR (CDCl3): d ¼ 2.47 (s, 3H, Me, Tos), 4.65 (s, 2H,
CH2, Troc), 7.27–7.47 (m, 7H, Ar), 7.92=7.97 (d, 2H, Ar). 13C NMR (CDCl3):
d ¼ 21.6 (Me, Tos), 75.7 (CH2, Troc), 94.1 (CCl3, Troc), 12ꢂ91.2, 129.6, 129.7, 135.6,
=
=
136.0, 145.3, 150.9 (Ar), 153.2 (C O, Troc). FTIR n (cm ): 1734 (C O, Troc),
1383, 1170 (SO2, Tos), 1289 (C-O-C), 713 (C-Cl). Mp ¼ 110–112 ꢃC. C16H14Cl3NO4S
Mþ þ H calc. 421.97819, Mþ þ H found 421.97812.
Compound 5A. 1H NMR (CDCl3): d ¼ 4.83 (s, 2H, CH2, Troc), 6.94 (s, 1H,
NH), 7.11–7.41 (m, 7H, Ar). 13C NMR (CDCl3): d ¼ 74.6 (CH2, Troc), 95.3 (CCl3,
=
Troc), 119.1, 124.2, 129.2, 137.0 (Ar), 155.1 (Ar-N), 155.4 (C O, Troc).
Compound 6A. 1H NMR (CDCl3): d ¼ 2.74–2.81 (m, 2H, Ph-CH2),
3.39–3.49 (m, 2H, CH2-NH), 3.79 (s, 3H, CH3O), 4.71 (s, 2H, CH2, Troc), 5.19 (s,
1H, NH), 6.82–7.13 (m, 4H, Ar). 13C NMR (CDCl3): d ¼ 35.3 (Ph-CH2), 42.9
(CH2-NH), 55.4 (CH3O), 74.8 (CH2, Troc), 95.8 (CCl3, Troc), 114.5, 1þ29.8, 130.6,
ꢃ
=
154.7 (Ar), 158.3 (C O, Troc). Mp ¼ 89–91 C. C19H20Cl3NO5S M þ H calc.
482.01710; Mþ þ H found 482.01743.
Compound 7A. 1H NMR (CDCl3): d ¼ 2.43 (s, 3H, Me, Tos), 3.02=3.06=3.10
(t, 2H, Ph-CH2), 3.79 (s, 3H, CH3O), 4.02–4.10 (m, 2H, CH2-NH), 4.70 (s, 2H, CH2,
Troc), 6.83–6.87 (m, 4H, Ar), 7.17–7.32 (m, 4H, Ar), 7.82–7.86 (m, 4H, Ar). 13C
NMR (CDCl3): d ¼ 21.5 (Me, Tos), 35.8 (Ph-CH2), 49.3 (CH2-NH), 55.4 (CH3O),
76.1 (CH2, Troc), 94.5 (CCl3, Troc), 114.5, 128.6, 129.5, 130.1, 136.8, 144.9, 151.2,

DEPROTECTION OF TROC WITH TMSCl/MM
3403
ꢂ1
=
=
(Ar), 159.0 (C O, Troc). FTIR n (cm ): 1750 (C O, Troc), 1250 (C-O-C), 1358,
1165 (SO2, Tos), 714 (Cl). Oil.
Compound 8A. 1H NMR (CDCl3): d ¼ 4.84 (s, 2H, CH2, Troc), 7.36 (s, 1H,
NH), 7.59–7.62 (m, 4H, Ar). 13C NMR (CDCl3): 75.0 (CH2, Troc), 95.0 (CCl3,
=
Troc), 107.6 (CN), 118.5, 118.9, 133.5, 141.4 (Ar), 151.1 (C O, Troc).
Compound 9A. 1H NMR (CDCl3): d ¼ 2.71 (s, 3H, CH3, Ac), 4.74 (s, 2H,
CH2, Troc), 7.28=7.32 (d, 2H, Ar), 7.72=7.76 (d, 2H, Ar). 13C NMR (CDCl3): 26.3
(CH3, Ac), 75.6 (CH2, Troc), 94.1 (CCl3, Troc), 112.0 (CN), 117.9, 129.7, 133.0,
141.2 (Ar), 151.1 (C O, Troc), 172.0 (C O, Ac). FTIR n (cmꢂ1): 2234 (CN),
=
=
ꢃ
=
=
1752 (C O, Troc), 1716 (C O), 1238 (C-O), 714 (C-Cl). Mp ¼ 58–60 C.
C12H9Cl3N2O3 Mþ þ H calc. 334.97515: Mþ þ H found 334.97495.
Compound 10A. 1H NMR (CDCl3): d ¼ 3.79 (s, 3H, CH3O), 4.81 (s, 2H,
CH2, Troc), 6.84–6.89 (m, 2H, Ar), 7.26 (s, 1H, NH), 7.30=7.34 (d, 2H, Ar). 13C
NMR (CDCl3): 55.5 (CH3O), 74.6 (CH2, Troc), 95.4 (CCl3, Troc), 114.5, 121.1,
=
130.1, 152.0 (Ar), 156.6 (C O, Troc).
Compound 11A. 1H NMR (CDCl3): d ¼ 2.63 (s, 3H, CH3, Ac), 3.82 (s, 3H,
CH3O) 4.74 (s, 2H, CH2, Troc), 6.91=6.95 (d, 2H, Ar), .05=7.09 (d, 2H, Ar). 13C
NMR (CDCl3): 26.4 (CH3, Ac), 55.5 (CH3O), 75.4 (CH2, Troc), 94.5 (CCl3, Troc),
114.5, 129.4, 129.9, 152.8 (Ar), 159.4 (C O, Troc), 172.6 (C O, Ac). FTIR n (cmꢂꢃ1):
=
=
=
1742 (Troc), 1719 (C O, Ac), 1246 (C-O-C), 721 (C-Cl). Mp ¼ 51–52 C.
C12H12Cl3NO4 Mþ þ H calc. 339.99047, Mþ þ H found 339.99033.
1H and 13C NMR spectral data of 1A,[16]2A,[17] 5A,[18] 6A,[19] 8A,[7] and 10A[7]
were identical to previously published publications.
ACKNOWLEDGMENT
We thank the Estonian Science Foundation for financial support (Grant Nos.
6706 and 8031).
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