Selective cleavage of 3,5-bis-(trifluoromethyl)benzylcarbamate by SmI 2-Et3N-H2O

Article abstract of DOI:10.1039/c3cc41642a

A novel electron poor protection group for amines has been developed. It undergoes rapid cleavage by SmI₂-Et₃N-H₂O and its orthogonality towards the regular benzyl carbamate group (CBz) under reductive or transfer hydrogenolytic conditions is reported.

Full text of DOI:10.1039/c3cc41642a

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Selective cleavage of 3,5-bis-
(trifluoromethyl)benzylcarbamate by SmI2–Et3N–H2O†
Cite this: Chem. Commun., 2013,
49, 6867
Tobias Ankner, Anna Said Stålsmeden and Goran Hilmersson*
¨
Received 4th March 2013,
Accepted 5th June 2013
DOI: 10.1039/c3cc41642a
www.rsc.org/chemcomm
A novel electron poor protection group for amines has been
developed. It undergoes rapid cleavage by SmI2–Et3N–H2O and
its orthogonality towards the regular benzyl carbamate group
(CBz) under reductive or transfer hydrogenolytic conditions is
reported.
Fig. 1 A highly electronegative benzyloxy carbamate (CBTFB) is very efficient as
a protecting group for amines.
Protecting groups are powerful tools for the synthesis of multi-
functional compounds to temporarily mask sites of similar
reactivity in targets such as oligosaccharides and peptides.1
Although it is desirable to minimize their use due to the low
atom economy and increased number of steps, the versatility
offered by this technique is still unprecedented.2 Herein we
present a new protection group for amines that exploits the
exceptionally high reactivity of electron deficient carbamates
towards the powerful reducing agent SmI2–Et3N–H2O (Fig. 1).
Protecting groups should ideally meet several criteria: (i)
easy to introduce and high yielding, (ii) stable under a wide
range of reaction conditions and (iii) use of mild conditions for
its removal allowing for deprotection without interfering with
other functionalities present. If the protecting group in addi-
tion is retained during the removal of alternative protecting
groups it is orthogonal to these, which is a highly desirable
property.3 The amine plays a special role in organic synthesis as
it is a functional group present in almost all compounds
of biological relevance, but its high polarity and basicity
frequently pose problems during multistep synthesis of these
compounds. Therefore, a wide range of protecting groups for
amines have been developed that can be removed under for
instance acidic, reductive and oxidative conditions respectively.
The reductive chemistry of divalent samarium has been the
subject of intense research over the last 30 years, and its
reactivity can be successfully fine-tuned to achieve the desired
transformations.4 We have previously developed highly efficient
protocols for unmasking both allyl protected alcohols5 and tosyl
protected amines and alcohols6 using SmI2–Et3N–H2O. During
our studies of the benzylic deoxygenation using the same reagent
combination,7 we discovered that the trifluoromethyl substi-
tuted benzyl alcohols underwent this reaction very fast. We have
now developed a new variety of the carbonylbenzyloxy (CBz)
group that takes advantage of this accelerating effect, namely
3,5-bis-(trifluoromethyl)-benzyloxycarbonyl (CBTFB). This new
protecting group is resistant towards acids, hydrogenation8
and oxidation, but highly sensitive towards the reductive reagent
SmI2–Et3N–H2O, which indicates that it is also sensitive to single
electron transfer. We believe that protecting groups that are
resistant to such diverse conditions are rare and thus valuable
additions to the available protection strategies that exist for
amines.
The introduction of 3,5-bis-(trifluoromethyl)benzylcarbamate
is achieved in very high yields after a simple two-step sequence
starting from the commercially available 3,5-bis-(trifluoro-
methyl)benzyl alcohol (Scheme 1). The intermediate chlorofor-
mate could also be prepared in larger quantities and stored at
4 1C for weeks with no detection of reduced reactivity. The
formed derivatives are generally very easy to handle and
obtained as solids in all cases. In addition, the high lipophilicity
of the CBTFB group gives desirable solubility properties in
organic solvents.
Department of Chemistry and Molecular Biology, University of Gothenburg,
Gothenburg, Sweden. E-mail: hilmers@chem.gu.se; Fax: +46 772 1394;
Tel: +46 31 786 9022
Scheme 1 Protection of amine with
a CBTFB group. (a) COCl2, THF, rt.
† Electronic supplementary information (ESI) available: NMR data of protected
compounds. See DOI: 10.1039/c3cc41642a
(b) Amine, NaHCO3, acetone–water, rt.
c
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Table
1
Evaluation of the effect of various reducing agents on CBTFB
Table 2 Stability tests performed on 1
protected amine
Entry
Conditionsa
Reaction
1
2
3
4
5
6
7
10% TFA in DCM, rt
CAN–DMF, rt
Piperidine–DMF
Ammonia in MeOH (1.0 M)
K2CO3–MeOH
HBr in HAc
20% KOH in MeOH
Stable 24 h
Stable 24 h
Stable 24 h
Stable 24 h
Stable 24 h
Degraded
Entry
Reagenta
Time
Yield
Degraded
1
2
3
4
5
SmI2
24 h
24 h
5 min
24 h
5 min
n/r
a
See the Experimental section for details regarding the exact reaction
conditions (ESI).
SmI2–H2O (50 equiv.)
SmI2–Et3N–H2O
SmI2–TPPAb
15%
>95%
>95%
>95%
SmI2–TPPA–MeOH
a
(formic acid) was added in portions, and samples were subse-
quently analyzed to monitor the concentration of the amine
over time. This time, a reversal in the selectivity between the
protecting groups was noted. While the CBz protected adamanty-
lamine was fully deprotected, the CBTFB protected adamanty-
lamine was left intact. This also lead to the conclusion that this
protecting group is compatible with isolated double bonds as
SmI2–Et3N–H2O has proven unreactive towards such function-
alities, a feature that frequently restricts the use of transition
metal catalyzed deprotection protocols.
See the Experimental section for details regarding the exact
b
reaction conditions. Tripyrrolidinophosphoric acid triamide (TPPA).
To evaluate the reaction conditions for the deprotection we
chose the adamantyl derivative 1 as a model substance. We
exposed 1 to SmI2 (entry 1, Table 1), but no reaction could be
detected over 24 hours. Addition of common co-solvents however
proved more successful (entries 2–5, Table 1). The additive
combination previously developed by our group (entry 3,
Table 1) outperformed the other reagents in terms of the reaction
rate, ease of work-up and yield. In theory, the cleavage reaction
demands four electrons in total in order to break the two bonds.
Thus addition of 4 equivalents of SmI2 with Et3N (8 equiv.) and
water (12 equiv.) was found to give full conversion of the free
amine (2) in less than 5 min. Addition of less than 4 equivalents
Sm(II) gave incomplete conversion to 2 and 3. Analysis of the post-
reaction mixture using 2 equivalents of Sm(II) revealed no inter-
mediates. The fact that more than 2 equivalents of Sm(II) are
consumed suggests that products from the cleavage reacts faster
with Sm(II) than with the CBTFB-group (Scheme 2).
To gain deeper understanding of the reactivity of the CBTFB
group we performed competitive experiments with the CBz
protected adamantylamine. Thus, a solution containing both 1
and N-CBz adamantylamine in equimolar amounts was added to
an excess of SmI2–Et3N–H2O. After completion of the reaction the
reaction mixture was analyzed and it was found that the CBTFB
protected amine was fully consumed, while the CBz protected
adamantylamine was left intact. Furthermore, we followed the
reaction over time and it could be seen that the decay of 1 was
rapid at room temperature and no carbamate could be detected
after 100 s.
To further evaluate the synthetic potential of this protecting
group, we subjected the model substance to a set of conditions
used for the deprotection of other common protecting groups
for amines and alcohols (Table 2). It was found that 1 was
stable in 10% TFA in DCM (entry 1, Table 2), the reagent of
choice for cleaving t-Boc groups,10 over 24 hours. Neither did
the addition of ceric(IV)ammonium nitrate (entry 2) or piper-
idine (entry 3), reagents used to cleave PMB11 and Fmoc12
groups, respectively, result in a cleavage reaction. Ammonia
in methanol (entry 4) or potassium carbonate (entry 5), fre-
quently used to deprotect trifluoroacetamides,13 also proved
unreactive during 24 h exposure. More forcing conditions, i.e.
strong reductive/hydrolytic conditions (HBr in HAc – known to
cleave tosylamides)14 and strongly alkaline conditions (20%
KOH in MeOH), degraded the carbamate within 10 minutes.
The above results provide evidence that this protecting group
is orthogonal to many of the common groups and yet it is easily
deprotected using SmI2–Et3N–H2O. The resistance towards
hydrogenolysis renders it complementary to the allyloxycarbonyl
(Aloc)15 and trichloroethyloxycarbonyl (Troc)16 groups, which
show similar reactivity (i.e. acid stable and slightly labile towards
bases) but these are not stable towards hydrogenolysis condi-
tions. Altogether, the features of this novel protecting group are
markedly different from common protecting groups for amines
and offer a new ‘‘selectivity window’’ for organic synthesis of
multifunctional substrates previously unavailable.
Intrigued by this, we devised an experiment utilizing
a standard cleavage protocol for the CBz group,9 i.e. hydro-
genolysis with Pd–C and Et3N–formic acid. The hydride donor
In order to explore the scope of the deprotection in the
presence of other protecting groups, we prepared a set of bis-
protected compounds and subjected them to SmI2–Et3N–H2O.
From the result presented in Scheme 3, it can be concluded that
the CBTFB group can be deprotected in excellent isolated yield
in the presence of various commonly used protecting groups
such as TBDMS (4a), t-Boc (5a), and benzyl (6a).
We were also interested in applying the results from the
competing experiments, i.e. having both a CBz and a CBTFB
Scheme 2 A 4-electron reduction of the carbamate bond with SmI2, R3N and
H2O yields bis-CF3–toluene and the free amine.
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groups (Troc, Aloc, Boc, etc.). Although other protective groups
can certainly be removed using SET reagents, they frequently
require very harsh reaction conditions. The electron deficient
benzyl carbamate CBTFB is a promising new protecting group
for amines that exploits the exceptionally high sensitivity of
electron deficient carbamates towards reducing agents and in
particular SmI2–amine–water. The CBTFB protecting group is
easy to introduce and is stable towards most reaction condi-
tions but very sensitive towards reductive conditions, i.e. SmI2–
H2O–amine-mediated, while it is practically inert towards
hydrogenation. We believe that the introduction of this unique
protecting group is important as it is cleaved under very specific
reaction conditions and can potentially be used under many
different reaction conditions. Thus it fulfills all the criteria for
protecting groups outlined above and holds promise as an
important addition to the existing strategies for amine and
thiol protection. We are currently aiming to develop the chem-
istry of this protecting group and to further test the functional
group tolerance associated with its removal as well as its use in
amino glycoside and peptide synthesis.
Scheme 3 Deprotection reactions using 4 equivalents of SmI2 with triethylamine
and water.
Scheme 4 Deprotection reaction of 7a using either 4 equivalents of SmI2 with
triethylamine and water to yield 7b or Pd–C to yield 7c.
Notes and references
group within the same molecule (Scheme 4). To our delight the
CBTFB group was cleanly deprotected leaving the mono CBz
protected amine (7b) in exceptional yields. 7a was also sub-
jected to transfer hydrogenolysis conditions and again we
found very high yield of the mono deprotected amine (7c), this
time with the CBTFB group intact (Scheme 4).
Protection of thiols is another highly important transforma-
tion in for instance protein synthesis.17 However, sulfur is not
easy to protect efficiently and hence new methodologies are
always welcome additions to the available groups. We evaluated
CBTFB as a thiol protecting group and found that the deprotec-
tion was successful using SmI2–Et3N–H2O, and the free thiol
could be isolated in excellent yield. Furthermore, it was stable
under hydrogenolysis conditions (Pd–C with formic acid) but
considerably more sensitive to the corresponding carbamate
base, which was rapidly cleaved by both potassium hydroxide
and potassium carbonate in methanol. It was also sensitive to
piperidine and ammonia yielding the free thiol and the CBTFB
derivative of the amine. It was however stable to 10% TFA and
CAN for long periods of time.
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Other single electron transfer reagents were also assayed in
the reductive cleavage of the carbamate bond. The deprotection
of the carbamate with Mg–MeOH18 was observed to proceed
very slowly and it also gave rise to extensive defluorination of both
the CBTFB group and the resulting 3,5-bis(trifluoromethyl)toluene
that arises from the cleavage reaction.19 Zinc and ammonium
chloride19 were also explored for removal of the electron poor
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19 This is probably because of the fact that the reaction takes place at
been developed that can be selectively cleaved under mild SET
conditions. In this respect, this group has a unique property
the surface of the magnesium metal, lowering the selectivity due to
that is not shared by any of the existing carbamate protecting
transport phenomena.
c
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Chem. Commun., 2013, 49, 6867--6869 6869