Catalytic dehydrogenative N-((triisopropylsilyl)oxy)carbonyl (Tsoc) protection of amines using iPr3SiH and CO2

Article abstract of DOI:10.1039/c5cc04594k

A versatile method has been found to catalyze the dehydrogenative N-((triisopropylsilyl)oxy)carbonyl (Tsoc) protection of amines using Pd/C, volatile iPr₃SiH and CO₂ gas without the liberation of any salts. A simple filtration/evaporation process facilitates the easy isolation of the product, thereby enhancing the utility of Tsoc as an amine-protecting group in organic synthesis.

Full text of DOI:10.1039/c5cc04594k

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Catalytic dehydrogenative N-((triisopropylsilyl)oxy)-
carbonyl (Tsoc) protection of amines using iPr3SiH
and CO2†
Cite this:DOI: 10.1039/c5cc04594k
Received 4th June 2015,
Accepted 30th June 2015
S. Tanaka, T. Yamamura, S. Nakane and M. Kitamura*
DOI: 10.1039/c5cc04594k
www.rsc.org/chemcomm
A versatile method has been found to catalyze the dehydrogenative
N-((triisopropylsilyl)oxy)carbonyl (Tsoc) protection of amines using
Pd/C, volatile iPr3SiH and CO2 gas without the liberation of any
salts. A simple filtration/evaporation process facilitates the easy
isolation of the product, thereby enhancing the utility of Tsoc as an
amine-protecting group in organic synthesis.
((Triisopropylsilyl)oxy)carbonyl (Tsoc) group reported by Lipshutz in
19991 is an excellent protecting group for amines. N-Tsoc-protected
amines are stable under the conditions of TFA/CH2Cl2, H2/Pd-C,
and morpholine/DMF used for the removal of Boc, Cbz, and Fmoc
protecting groups, respectively, while Tsoc is easily removed under
the conditions of TBAF/THF.2 The orthogonality of Tsoc toward
Scheme 1 Conventional and new approaches to N-Tsoc-protected
amines.
With a focus on commercially available heterogeneous metal
these protecting groups, as well as its easy detachment process, is catalysts, the reactivity was investigated in the reaction of benzyl
attractive. Furthermore, silyl carbamates can be used both as amine (1a) with iPr3SiH under the standard conditions of 100 mM
intermediates for the synthesis of organic carbamates3,4 and more 1a, 100 mM iPr3SiH, 1 atm CO2, 5 mol% catalyst (metal equivalent),
substituted amines,5 and as linkers in solid-phase combinatorial and DMA at 50 1C for 16 h. Representative results are shown in
chemistry.3 Scheme 1 summarizes the methods reported for Fig. 1.10 The Pd catalysts tested showed more or less reactivity
installing Tsoc on primary and secondary amines 1 to obtain depending on the type or method of support, or the Pd source.
N-Tsoc amines 2, namely, (i) insertion of CO2 into the N–Si bond Among them, 10 wt% Pd on dry matrix carbon (Aldrich 520888)
of silyl amides;6 (ii) silylation of ammonium carbamates;1,7 and showed the highest reactivity in realizing the quantitative
(iii) alkyl/silyl carbamate exchange.8 However, these multistep or conversion of 1a to 2a (red bar). No reactivity was observed
‘‘salt-liberation-type’’ constructions of N-Tsoc amines have low with Fe, RANEYs Ni, Ru/C, Rh/C, Pt/C, or PtO2.
atom- and step-economies, as well as they lack operational
Table 1 summarizes the results of optimization. DMA,
simplicity, which limits their practical utility and generality. CH3CN, and C2H5CN were the solvents of choice (entries 1–3).
Herein, we have focused on a direct and constructive process In DMF, N-formylation of 1a occurred (entry 4). With the
without salt liberation (iv, Scheme 1), in which 1, iPr3SiH, and particular standard substrate tested (1a), N-Tsoc-protected
CO2 are converted to 2 under the influence of a heterogeneous dibenzylamine was produced in 5% yield in CH3CN (entry 2).
catalyst. The only co-product is H2. Simple filtration/evaporation In THF and t-BuOH, the reaction proceeded slowly (entries 5
of the reaction mixture gives 2, which is uncontaminated by and 6), and no reaction occurred in CPME, dioxane, CH2Cl2,
catalyst, unlike in a homogeneous system.9
benzene, or hexane under the standard conditions (entries 7–11).
The reactivity was enhanced by increasing the pressure of CO2
and/or the reaction temperature within the range of 1–10 atm and
25–100 1C, respectively. At 25 1C, the reactivity was slow. At 10 atm
of CO2 and 50 1C, the reaction was completed within 6 h, and the
time was halved at 100 1C (entries 12–14). The catalyst loading
could be reduced to 2 mol% with completion within a tolerable
time range (entry 15). One mol of iPr3SiH was enough to attain a
Graduate School of Pharmaceutical Sciences, Graduate School of Science,
and Research Center for Materials Science, Nagoya University, Chikusa,
Nagoya 464-8601, Japan. E-mail: kitamura@os.rcms.nagoya-u.ac.jp
† Electronic supplementary information (ESI) available: Details of the general
procedure for Tsoc protection, and NMR spectral data of the substrates and
products. See DOI: 10.1039/c5cc04594k
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Table 2 One-step protection of amines by Tsoc using 10 wt% Pd on dry
matrix carbon (Aldrich 520888)a
Yield
(%)
Yield
(%)
Entry Substrate
1b,c,d
Entry Substrate
98
9c,g
10i
95h
495 j
495 j
11k
2b
3e
4e
5f
99
12e
95
93
94
97
95
96
13e,l
14e,l
a
Fig. 1 Screening of heterogeneous metal catalysts.
10 wt% loading,
b
matrix carbon, dry support. 5 wt% loading, matrix carbon powder, wet
support. c 10 wt% loading, matrix activated carbon support. d 5 wt% reduced.
e
Reduced, 5 wt% loading.
Table 1 Dehydrogenative protection of benzylamine (1a) as the N-((tri-
organosilyl)oxy)carbamates using triorganosilane and CO2 in the presence
of 10 wt% Pd on dry matrix carbon (Aldrich 520888)a
6e
7e
8e
1f R = H
1g R = CH3
1h R = C8H5
o1
o1
o1
Time (h) Yieldb (%)
a
Entry Solvent CO2 (atm) Temp. (1C) Silane
The reaction was carried out using 100 mM 1 in DMA on a 0.2 mmol
scale for 16 h, and the yield was determined after isolation unless
1
2
3
4
5
6
7
8
DMA
1
1
1
1
1
1
1
1
1
1
1
10
1
10
1
50
50
50
50
50
50
50
50
50
50
50
50
25
100
50
50
50
50
iPr3SiH
iPr3SiH
iPr3SiH
iPr3SiH
iPr3SiH
iPr3SiH
iPr3SiH
iPr3SiH
iPr3SiH
iPr3SiH
iPr3SiH
iPr3SiH
iPr3SiH
iPr3SiH
iPr3SiH
iPr3SiH
Et3SiH
16
16
16
16
16
16
16
16
16
16
16
6
499
91c
b
otherwise specified. [iPr3SiH] = 100 mM, 5 mol% of Pd/C, 1 atm CO2,
CH3CN
C2H5CN
DMF
c
50 1C. 50 mmol scale. [substrate] = [iPr3SiH] = 500 mM. d A Tedlars bag
87c
was used for supplying 1 atm CO2 gas. e [iPr3SiH] = 250 mM, 10 mol% Pd/C,
86c,d
91
98
o1
o1
o1
o1
o1
499
90
10 atm CO2, 100 1C. f [iPr3SiH] = 250 mM, 10 mol% Pd/C, 1 atm CO2, 50 1C.
THF
g
[iPr3SiH] = 1250 mM, 5 mol% Pd/C, 1 atm CO2, 50 1C. h No racemization.10
t-BuOH
CPME
Dioxane
CH2Cl2
Benzene
Hexane
DMA
i [Et3SiH] = 250 mM, 5 mol% Pd/C, 10 atm CO2, 50 1C. j 1H-NMR yield.
k
l
[Ph2tBuSiH] = 250 mM, 5 mol% Pd/C, 10 atm CO2, 50 1C. 32 h.
9
10
11
12
13
14
using a Tedlars bag to supply 1 atm of CO2 gas afforded 2a in
98% isolated yield, confirming the operational simplicity. The
ICP analysis of the product indicated that contamination with Pd
was o1 ppb.10 The applicability of the new Tsoc installation
method to other amines is provided in Table 2. Primary, secondary,
and tertiary alkyl amines could be used (entries 1–5); however,
aromatic amines could not be used (entries 6–8). Various a-amino
esters protected by Tsoc were quantitatively prepared (entries 9–14).
The isolated yields were very high in all the cases because of
DMA
DMA
16
3
32
6
499
499
499
92c
15e DMA
16f
17f
18f
DMA
CH3CN 10
CH3CN 10
1
16
Ph2tBuSiH 16
95c
a
Conditions: 0.2 mmol scale, [1a] = 100 mM 5 mol% Pd/C (metal equivalent).
b
c
Determined by 1H NMR analysis. N-Tsoc-protected dibenzylamine
was produced in 5%–10% yield. (S)-Phenylalanine methyl ester (1i) was
quantitatively converted to the corresponding silyl carbamate.10 See the simple filtration/evaporation workup. No racemization of
d
e
Table 2. N-Formylbenzylamine was obtained in 9%. 2 mol% of Pd/C.
(S)-phenylalanine methyl ester (Phe-OMe), (1i) was observed
after the Tsoc protection of 1i followed by deprotection (100 mM
CH3CN solution of N-Tsoc-Phe-OMe; 1.0 mol amount TBAF; rt;
f
2.5 mol amt of silane.
quantitative conversion, but 2.5 mol of iPr3SiH shortened the reaction 10 min).‡10
time to 6 h (entry 16). Even with an excess amount of iPr3SiH, the
As shown in Table 2, ester, amide, and indole NH functional
synthetic utility was not reduced because of the high volatility of groups remained intact. Reactivity was maintained even in the
iPr3SiH. Et3SiH and Ph2tBuSiH could also be used to obtain the presence of a sulfide functional group (entry 13). In the
corresponding silyl carbamates in high yield (entries 17 and 18).
presence of 4-phenylbutan-2-one, 3-phenylpropanenitrile, or
The reliability of the new Tsoc installation method was confirmed (3,4-dimethylpent-3-en-1-yl)benzene (100 mM), 1a (100 mM)
using 50 mmol of 1a (entry 1 in Table 2). This large-scale reaction was efficiently converted to 2a under the standard conditions,
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the Young tap, the mixture was vigorously stirred at 50 1C for 16 h, and
then cooled to rt. Filtration through Celite (5 cm f  2 cm) followed by
the evaporation of the filtrate in vacuo gave nearly pure N-Tsoc-(S)-
phenylalanine methyl ester (2i) (20.7 g, 95% yield), which contained less
than 1 ppb of Pd.10
while these competitive substrates remained intact. Ketone, nitrile,
and tetra-substituted alkene functional groups were found to be
tolerated, but a disadvantage was that less-substituted alkenes were
hydrosilylated. This problem could be alleviated by carrying out the
reaction in the presence of sacrificial olefins such as ethene.10
In summary, a new method has been established for the
catalytic dehydrogenative Tsoc protection of amines using iPr3SiH
and CO2 in the presence of a versatile 10 wt% Pd catalyst on dry
matrix carbon (Aldrich 520888). The only coproduct is H2, and
both iPr3SiH and CO2 are easily removed, making the reaction
system clean. The heterogeneous process, which has high atom-
and step-economy, makes product isolation simple and easy.
The high efficiency of the present method should enhance the
utility of the Tsoc protecting group in the multistep synthesis of
natural products and pharmaceuticals.
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2 P. G. M. Wuts, Greene’s Protective Groups in Organic Synthesis, Wiley,
New York, 5th edn, 2014.
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´
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This work was aided by a Grant-in-Aid for Scientific Research
(No. 25E07B212) and (No. 22750088; 24510112; 24106713) from
the Ministry of Education, Culture, Sports, Science and Technology
(Japan), and an Advanced Catalytic Transformation Program for
Carbon Utilization (ACT-C) from Japan Science and Technology
Agency (JST). We thank Miss Yoko Iyoda and Mr Shugo Sakakibara
for their preliminary research.
´
´
´
´
(b) D. Knausz, A. Meszticsky, L. Szakacs, B. Csakvari and K. Ujszaszy,
J. Organomet. Chem., 1983, 256, 11; (c) R. N. Salvatore, F. Chu,
A. S. Nagle, E. A. Kapxhiu, R. M. Cross and K. W. Jung, Tetrahedron,
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8 For other silyl/alkyl exchange, see: (a) D. Amans, V. Bellosta and
J. Cossy, Org. Lett., 2007, 9, 4761; (b) M. Sakaitani, N. Kurokawa and
Y. Ohfune, Tetrahedron Lett., 1986, 27, 3753. See also ref. 4.
¨
9 (a) Handbook of Heterogeneous Catalysis, ed. G. Ertl, H. Knozinger,
F. Schu¨th and J. Weitkamp, Wiley, New York, 2nd edn, 2008,
vol. 8; (b) J. R. H. Ross, Heterogeneous Catalysis, Fundamentals and
Applications, Elsevier, Amsterdam, 2012; (c) Heterogeneous Catalysis:
A Versatile Tool for the Synthesis of Bioactive Heterocycles, ed.
K. L. Ameta and A. Penoni, CRC Press Taylor & Francis Group, Boca
Raton, 2014.
Notes and references
‡ Experimental: a dried and Ar-filled 1-L Young-type Schlenk flask
containing a magnetic stirring bar was charged with (S)-phenylalanine
methyl ester (1i) with an S/R ratio of 499.5 : 0.5 (10.0 g, 56.0 mmol), 10 For details, see ESI†.
iPr3SiH (22.2 g, 140 mmol), and degassed DMA (112 mL). After the 11 The 1H-NMR analysis of 1a (ca. 200 mM) under 1 atm of CO2 in
addition of 10 wt% Pd on dry matrix carbon (Aldrich 520888; 2.80 mmol
in Pd equivalent; 5 mol% for 1i), the inlet pressure of the Schlenk tube
was slightly reduced; 1 atm of CO2 gas was introduced from a cylinder
and the mixture was stirred for 10 min.11 After the tube was sealed with
CD3CN at 25 1C indicated that ca. 20% of 1a was converted to the
carbamate. Decreasing the temperature to 0 1C, 90% of 1a was
consumed, while little formation of the carbamate was observed at
80 1C.
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