2,2,6,6-Tetramethylpiperidin-1-yloxycarbonyl: A Protecting Group for Primary, Secondary, and Heterocyclic Amines

Article abstract of DOI:10.1021/acs.orglett.8b02874

The 2,2,6,6-tetramethylpiperidin-1-yloxycarbonyl (Tempoc) protecting group is readily introduced by the reaction of amines with a new acyl transfer reagent, 4-nitrophenyl (2,2,6,6-tetramethylpiperidin-1-yl) carbonate (NPTC). Tempoc has a reactivity profile that complements the commonly used t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz) protecting groups. Deprotection can be achieved under mild reductive conditions with in situ generated Cu(I) species or by thermolytic cleavage at 135 °C. Mechanistic studies on the deprotection of Tempoc-indole suggest a combination of ionic and radical fragmentation pathways under thermal conditions.

Full text of DOI:10.1021/acs.orglett.8b02874

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
2,2,6,6-Tetramethylpiperidin-1-yloxycarbonyl: A Protecting Group
for Primary, Secondary, and Heterocyclic Amines
Joseph R. Lizza,† Maximilian Bremerich,‡ Stephanie R. McCabe,† and Peter Wipf*,†
†Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States
‡Institute of Organic Chemistry, RWTH Aachen University, Aachen, Germany
S
* Supporting Information
ABSTRACT: The 2,2,6,6-tetramethylpiperidin-1-yloxycar-
bonyl (Tempoc) protecting group is readily introduced by
the reaction of amines with a new acyl transfer reagent, 4-
nitrophenyl (2,2,6,6-tetramethylpiperidin-1-yl) carbonate
(NPTC). Tempoc has a reactivity profile that complements
the commonly used t-butyloxycarbonyl (Boc) and benzylox-
ycarbonyl (Cbz) protecting groups. Deprotection can be
achieved under mild reductive conditions with in situ
generated Cu(I) species or by thermolytic cleavage at 135 °C. Mechanistic studies on the deprotection of Tempoc-indole
suggest a combination of ionic and radical fragmentation pathways under thermal conditions.
ynthetic efficiency in routes toward complex target
Smolecules, including natural products, strives to minimize
the use of protecting groups; however, basic amines are
frequently incompatible with transition metal catalysis and
oxidative conditions and often require protection during these
transformations.1−3 Furthermore, protecting groups continue
to play a critical role in peptide synthesis4 and carbohydrate
chemistry.5 Therefore, the development of new protecting
groups remains an important goal in organic and biological
chemistry. Orthogonal protecting groups that allow for
selective manipulations in molecules with multiple function-
alities are particularly useful in this context.6−9 Amines are
among the most common functionalities found in both
pharmaceuticals and natural products.10,11 While trifluoroace-
Figure 1. Use of a Tempoc-protected lithium reagent for a selective
1,2-addition.31
tyl,12 tosyl,13 nosyl,14,15 phthaloyl,16 and trityl17 are frequently
used for amine protection, carbamates with t-butoxycarbonyl
(Boc),18 benzyloxycarbonyl (Cbz),18 9-fluorenylmethoxycar-
satisfactory results, and after considerable optimization, we
identified the 2,2,6,6-tetramethylpiperidin-1-yloxycarbonyl
bonyl (Fmoc),19 and allyloxycarbonyl (Aloc or Alloc)20
substituents are among the most common and versatile
amine protecting groups used across all branches of chemistry.
Carbamates offer robustness, ease of introduction and removal,
and opportunities for orthogonal deprotections, and new
variants are continually being developed.21,22 Typical depro-
tection conditions involve acidic (Boc), basic (Fmoc),
hydrogenolytic (Cbz), and transition metal catalyzed (Alloc)
conditions. However, often reagents such as TFA,23 HCl,24
H2/Pd,25 Et3SiH/Pd,26 and Mg/MeOH27 can promote side
reactions such as over-reductions,28 rearrangements,29 and
epimerizations.30
(“Tempoc”) group as a superior protective group for this
transformation.31 We are now presenting studies that illustrate
that Tempoc is of general utility for amine protection.
We first developed a suitable reagent for the introduction of
Tempoc on amines (Scheme 1). Reduction of the stable
nitroxide Tempo (1) with sodium ascorbate (SA)32 and O-
acylation of the intermediate hydroxylamine with p-nitro-
phenyl chloroformate provided the Tempoc transfer reagent 2
(“NPTC”). Under the optimized conditions, treatment of 2-
phenethylamine (3) with 1.2 equiv of NPTC in DMF at room
temperature in the presence of 3 equiv of triethylamine
provided the Tempoc-protected carbamate 4 in 94% yield.
Other suitable solvents and bases include THF, dichloro-
In our recent total synthesis of (−)-cycloclavine,31 a base
stable amine-protecting group was required that should be
resistant to a tin−lithium transmetalation−enone 1,2-addition
sequence and subsequently thermally cleavable during a Diels−
Alder reaction (Figure 1). The Boc group did not provide
Received: September 8, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02874
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Scheme 1. Preparation of p-Nitrophenol Tempo Carbonate
(NPTC) and Protection of 2-Phenethylamine
methane, methanol, pyridine, sodium bicarbonate, and
potassium carbonate, but in this particular case, these reagents
led to slightly reduced yields of 4 (Supporting Information
(SI), Table 1). Several alternatives to NPTC were also
identified (see Supporting Information (SI), reagents S1−S4),
but NPTC consistently provided the highest yields and was
also readily accessible at an ∼100 g scale. Differential scanning
calorimetry (DSC) of NPTC showed an exotherm of 70 cal/g
at an onset temperature of 135 °C, suggesting that, in spite of
the presence of a nitro group and a weak N−O bond, 4 is a
relatively stable compound.33,34 However, we have not yet
pursued shock sensitivity studies that would provide an
additional safety parameter.
Figure 2. Products of Tempoc protection of primary amines (isolated
yields).
Under the optimized conditions (i.e., amine (1 equiv),
NPTC (1.2 equiv), and triethylamine (3 equiv), in DMF (0.5
M, rt, 12 h)), primary amines were converted to the Tempoc
derivatives 5−16 in high yields, with the exception of the
sterically hindered t-butylamine 15 (Figure 2). Branching in
the α-position led to a slight decrease in yields for 6 and 11 to
72% and 75%, respectively, but the sterically less hindered
cyclohexylamine 13 was obtained in 87%.
Interestingly, anilines proved unreactive toward NPTC,
which was used as an advantage for diamine 12, where only
benzyl amine protection was observed in the presence of 1.2
equiv of NPTC. Similarly, no acylation of the indole nitrogen
was found for tryptamine 5 under these conditions. Attempted
preparation of naphthylamine 18 and protection of other
anilines also failed even under more forcing conditions and
with a larger excess of NPTC reagent. Preliminary evidence
suggests that it is necessary to deprotonate anilines in order to
achieve the level of nucleophilicity necessary for acylation with
the carbonate, and we are still exploring suitable bases for this
purpose. In agreement with this finding, we observed that
alcohol functions were well tolerated in the absence of strong
bases, even allowing the use of methanol as a solvent, and
exclusive selectivity for amine carbamoylation was achieved for
amino alcohols 6 and 16. With a 2:1 ratio of hydrazine vs
NPTC, the monoprotected hydrazide reagent 17 was isolated
in 95% yield. Furthermore, the use of 2.6 equiv of NaH as a
base in the presence of 2.4 equiv of NPTC induced double N-
acylation to give phenethylamine 19 in 90% yield.
Figure 3. Products of Tempoc protection of secondary amines
(isolated yields).
obtained in 56% yield. We repeated this reaction several times
but were unable to substantially increase the yield, possibly a
consequence of the subtle decrease in amine nucleophilicity
caused by the steric hindrance of the two flexible propyl chains.
Four equiv of triethylamine were used for the Tempoc
protection of proline methyl ester, providing 24 in 87% yield.
Alcohol groups were still tolerated in the presence of
secondary amines, as shown for 27. Imidazole was also
converted under standard conditions to the Tempoc derivative
29, whereas the use of 1.3 and 1.1 equiv of NaH, respectively,
allowed for the protection of indole and sulfoximine35
nitrogens in 28 and 30. The use of 1.3 equiv of NaH as a
base also allowed for a selective protection of the indole
nitrogen in tryptamine to give 31 in 71% yield (Figure 3).
In the synthesis of (−)-cycloclavine, we had employed a
thermolysis in toluene at 135 °C for 68 h for Tempoc
removal.31 Our current investigations revealed considerable
The protection of secondary amines in 20−27 was also
generally accomplished in excellent yields (Figure 3). Both
linear and cyclic amines behaved uniformly well, with the
exception of dipropylamine derivative 25, which could only be
B
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differences in thermal stabilities depending on the nature of the
protected amine. Microwave heating of a 0.1 M solution of
Tempoc-piperidine 22 in chlorobenzene or pyridine at 165−
175 °C for 1 h only led to trace product (Table 1, entries 1 and
2). In contrast, Tempoc was cleanly removed in propionitrile
in 48% yield after 2 h at 165 °C (Table 1, entry 3). In the more
28 (Scheme 3). We hypothesized that a heterolytic cleavage of
the N−O bond would initially produce carbamic acid anion 35
Scheme 3. Proposed Ionic and Radical Pathways for
Tempoc Deprotection under Thermal Conditions
Table 1. Thermolytic Deprotection of Secondary Amine 22
entry
solvent
temp (°C)
time (h)
yield (%)
1
2
3
4
5
6
PhCl
165
175
165
135
135
135
1
1
2
6
6
8
trace
trace
48
30
73
pyridine
EtCN
TFE
HFIP
HFIP
85
polar, protic solvent trifluoroethanol (TFE), deprotection was
more facile, yielding 30% of 4-phenylpiperidine after 6 h at 135
°C (entry 4). Hexafluoroisopropanol (HFIP), which has
previously been used to cleave carbamates,36,37 further
accelerated Tempoc removal and provided 4-phenylpiperidine
in 73 and 85% yields after 6 and 8 h, respectively (entries 5 and
6).
and iminium ion 36,39 which, after proton exchange and
decarboxylation, would form indole 32 and pyrrolidine
enamine 37. Alternatively, a homolytic N−O bond breakage
would generate radical pair 40 and 41, which would likely
produce indole 28 and piperidine 42 after hydrogen atom
abstractions from solvent. Experimentally, when heated at 150
°C in toluene-d8, 28 was found to generate a 3.6:1 ratio of
pyrrolidine 39 and piperidine 42, in addition to indole 32. This
ratio did not substantially change in the presence of 4 equiv of
H2O, but when the reaction was performed under nitrogen, a
2.3:1:1 ratio of 39, 37, and 42 was observed. Furthermore,
when the temperature was lowered to 135−140 °C, the ratio of
39 to 42 also decreased to 1.8:1. These NMR analyses
suggested that the ionic rearrangement pathway shown in
Scheme 3 was the major source of the desired deprotected
compound but that the homolytic N−O bond cleavage also
participated in the cleavage of the Tempoc group, in particular
under low-temperature conditions. Yet another possibility is a
radical [1,2]-shift of 41 leading to 36 after electron transfer.
N−O bonds are known to undergo facile copper(I)-
catalyzed reduction in the presence of stoichiometric
reductants,40−42 and therefore we also explored a redox
cleavage of the Tempoc group. In the presence of 2.2 equiv
of Cu(I)Cl, a 0.1 M solution of Tempoc-indole 28 in
acetonitrile at room temperature was readily converted to
indole 32 in 83% yield (Table 2, entry 1). Interestingly, under
the same conditions, Cu(I)-iodide did not generate product
(entry 2), and 1.1 equiv of Cu(II)Cl2 only gave 2% of 32
(entry 3). Reducing the amount of Cu(II) salt to 0.2 equiv, but
performing the reaction in the presence of the stoichiometric
reductant sodium ascorbate (SA) or ascorbic acid (Asc) and
water as a cosolvent, increased the yield to a still modest 29%
after 24 h reaction time (entries 4 and 5). A significant increase
in yield to 63% was observed when acetonitrile was changed to
MeOH (entry 6), and a 5:1 mixture of DMF and water
produced 84% of 32 (entry 7). This conversion was
independent of the Cu(II) salt used and was repeated with
CuSO4·5H2O (entry 8), as well as Cu(OAc)2, Cu(ClO4)2, and
Cu(OTf)2 (not shown). Furthermore, Tempoc-protected
piperidine 22 and indole 28 were also deprotected in >90%
Optimized thermolytic conditions were applied to indole 28
and primary amine 8 (Scheme 2). While the indole was
Scheme 2. Thermolytic Tempoc Deprotection of Indole and
Primary Amine
deprotected in 88% yield after 30 min in HFIP at 135 °C,
thermolysis of 8 under analogous conditions generated the
symmetrical urea 33. In the presence of 3 equiv of potassium
trimethylsilanolate (KOTMS) in dioxane at 135 °C,38
however, the desired primary amine 34 was formed in 30
min and 93% yield.
Since the literature information on the thermal breakdown
of O-acyl hydroxylamines is sparse,39 we searched for
intermediates formed in the thermolysis of Tempoc-indole
C
DOI: 10.1021/acs.orglett.8b02874
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In conclusion, our studies demonstrate that the 2,2,6,6-
tetramethylpiperidin-1-yloxycarbonyl (Tempoc) group is an
effective new protecting group for primary, secondary, and
heterocyclic amines, with excellent orthogonality to Boc- and
Cbz-carbamates, including resistance to acidic and hydro-
genolytic conditions. Treatment with the crystalline p-nitro-
phenol Tempo carbonate (NPTC) reagent is a convenient way
to introduce Tempoc in high yield and generally excellent
chemoselectivity. For deprotections, two main reaction
conditions are feasible: thermolysis occurs in HFIP at 135
°C, or alternatively, catalytic Cu(I) conditions release the
amine at room temperature in an organic/aqueous solvent
mixture. Previously, we have already demonstrated that a
Tempoc-protected indole is resistant to strongly basic and
nucleophilic reaction conditions.31 Accordingly, we suggest
that the Tempoc amine protective group is likely to be of
significant utility in the synthesis of functionalized natural and
unnatural target molecules and organic building blocks.
Table 2. Copper-Catalyzed Conversion of Tempoc-indole
28 to Indole 32
reductant
(equiv)
yield
a
entry CuX (equiv)
solvent
(%)
1
2
3
4
5
6
7
8
CuCl (2.2)
CuI (2.2)
−
−
−
MeCN
MeCN
MeCN
MeCN/H2O (2:1)
MeCN/H2O (2:1)
MeOH/H2O (5:1)
DMF/H2O (5:1)
DMF/H2O (5:1)
83
trace
2
29
29
63
84, 82
84
CuCl2 (1.1)
CuCl2 (0.20)
CuCl2 (0.20)
CuCl2 (0.20)
CuCl2 (0.20)
CuSO4
(0.20)
CuCl2 (0.05)
CuCl2 (0.05)
SA (1.1)
Asc (5)
Asc (5)
Asc (5)
Asc (5)
b
c
9
10
Asc (2)
Asc (2)
DMF/H2O (5:1)
MeCN/THF/H2O
(4:1:1)
MeCN/THF/H2O
(4:1:1)
67
c
83
b
11
CuCl2 (0.10)
Asc (2)
84
a
b
c
HPLC yield. Isolated yield after 12 h. Isolated yield after 24 h.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02874.
■
isolated yield under these conditions. Cyclohexyl amine 13
required mild heating at 40 °C for deprotection in 91% yield.
When Cu(II) loading was reduced from 0.20 to 0.05 equiv,
the conversion of 28 to 32 slowed down considerably, and only
67% product was isolated after 24 h in aqueous DMF (Table 2,
entry 9). Switching the solvent to a ternary 4:1:1 mixture of
MeCN, THF, and H2O increased the yield back to 83% (entry
10). At 0.10 equiv of Cu(II) loading, an equivalent yield was
obtained after only 12 h reaction time (entry 11) that could be
further increased to 91% in the presence of 3 equiv of Asc. It is
likely that the cosolvent acetonitrile inhibits the disproportio-
nation of Cu(I) to Cu(II) and Cu(0)43 and thus facilitates the
reduction of the N−O bond and slows the precipitation and
loss of the catalytic metal at low copper loadings.
S
Experimental procedures, compound characterizations,
NMR spectra, and DSC analysis (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: pwipf@pitt.edu
ORCID
Stephanie R. McCabe: 0000-0001-9773-4796
Peter Wipf: 0000-0001-7693-5863
Notes
Finally, we were able to demonstrate that a Tempoc group
has orthogonal deprotection properties compared to two of the
most popular carbamates, the Boc and Cbz groups (Scheme
4). Bis-protected piperazines 26 and 45 were readily converted
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Scheme 4. Orthogonal Deprotections of Tempoc-, Boc-, and
Cbz-Amines
■
This work was supported in part by discretionary funding from
Boehringer−Ingelheim Pharmaceuticals Inc., Ridgefield, CT,
and a Dietrich School of Arts & Sciences Fellowship (JRL).
The authors would also like to thank D. Crocker, T. Maskrey
(University of Pittsburgh) for technical assistance, J. Aube
(University of North Carolina) for stimulating discussions, and
D. K. Achary and B. Godugu (University of Pittsburgh) for
NMR and HRMS analyses, respectively. JRL would also like to
thank L. W. Whaley (Rowan University) for his mentorship,
and MB thanks M. Kerner (University of Pittsburgh) for
insightful discussions.
́
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