Deprotection of N-tert-Butoxycarbonyl (Boc) Protected Functionalized Heteroarenes via Addition–Elimination with 3-Methoxypropylamine

Article abstract of DOI:10.1002/ejoc.201901811

Continued pursuit of functionalized soft-N-donor complexant scaffolds with favorable solubility and kinetics profiles applicable for the separation of the trivalent minor actinides from the lanthanides has attracted significant interest over the last three decades. Recent work from this laboratory resulted in the production of various N-Boc protected [1,2,4]triazinyl-pyridin-2-yl indole Lewis basic procomplexants which necessitated the removal of the indole N-Boc protecting group prior to evaluation of complexant efficacy in separations assays. Traditional deprotection strategies involving trifluoroacetic and other protic and Lewis acids proved unsuccessful in removal of the recalcitrant indole-N-Boc protecting group necessitating the development of a new strategy for deprotection of this complexant class. A serendipitous result facilitated utilization of 3-methoxypropylamine as a mild deprotecting agent for various N-Boc protected heteroarenes via a proposed addition–elimination mechanism. Method development, application to various heteroarenes including indoles, 1,2-indazoles, 1,2-pyrazoles, and related derivatives, a ten-fold scale-up reaction, and experimental evaluation of a preliminary mechanistic hypothesis are reported herein.

Full text of DOI:10.1002/ejoc.201901811

DOI: 10.1002/ejoc.201901811
Full Paper
N-Boc Deprotection
Deprotection of N-tert-Butoxycarbonyl (Boc) Protected
Functionalized Heteroarenes via Addition–Elimination with
3-Methoxypropylamine
Zachary Z. Gulledge[a] and Jesse D. Carrick*[a]
Abstract: Continued pursuit of functionalized soft-N-donor the recalcitrant indole-N-Boc protecting group necessitating the
complexant scaffolds with favorable solubility and kinetics pro- development of a new strategy for deprotection of this com-
files applicable for the separation of the trivalent minor actin- plexant class. A serendipitous result facilitated utilization of 3-
ides from the lanthanides has attracted significant interest over methoxypropylamine as a mild deprotecting agent for various
the last three decades. Recent work from this laboratory re- N-Boc protected heteroarenes via a proposed addition–elimina-
sulted in the production of various N-Boc protected [1,2,4]- tion mechanism. Method development, application to various
triazinyl-pyridin-2-yl indole Lewis basic procomplexants which heteroarenes including indoles, 1,2-indazoles, 1,2-pyrazoles, and
necessitated the removal of the indole N-Boc protecting group related derivatives, a ten-fold scale-up reaction, and experimen-
prior to evaluation of complexant efficacy in separations assays. tal evaluation of a preliminary mechanistic hypothesis are re-
Traditional deprotection strategies involving trifluoroacetic and ported herein.
other protic and Lewis acids proved unsuccessful in removal of
Introduction
Functionalized heteroarenes with protected N-functionality are
ubiquitous in alkaloid natural products,[1] pharmaceuticals,[2]
materials,[3] and related compounds.[4] The tert-butyloxycarb-
onyl (Boc) and related carbamate protecting groups are com-
monly employed to diminish the nucleophilicity of sp2-hybrid-
ized nitrogen atoms of indoles,[5] 1,2-indazoles,[6] pyrroles,[7]
and related structures. As the pursuit of more complex, func-
tionaly diverse structures continues to expand the need to de-
velop differential protecting group installation and deprotec-
tion strategies concomitantly must evolve.
Scheme 1. Discovery of indole N-Boc deprotection method.
While completing a recent project[8] aimed at the formation
of the pyridin-2-yl-indole C–C bond to afford procomplexants
for potential employment in liquid–liquid separations[9] of mi-
lack of formation of the desired N–C bond via Pd-catalyzed
nor actinides from lanthanides in simulated spent nuclear fuel,
a series of functional group interconversions of 1 towards po-
tentially improving solubility properties of prepared complex-
ant scaffolds were undertaken (Scheme 1).
amination, discovery of this transformation was a significant
blessing given our previous inability to this point in the project
to successfully deprotect the N-Boc group from the indole N-
atom.
Pursuant to the aforementioned, the attempted Pd-catalyzed
amination[10] of 1 failed to afford the desired indole amination
product, but serendipitously yielded the Boc-deprotection
product 2 via the proposed addition/elimination intermediate.
Adjustment of reaction conditions, including additional equiva-
lents of 3-methoxypropylamine, failed to afford the initially de-
sired amination product. While initially disappointed with the
While electronic properties of the residual functionality of
bonded N-Boc groups are important, recently reported results
have postulated that ease of bond heterolysis in the case of
conformationally strained amides can be attributed to ground
state destabilization of the N–C=O bond via twisting, thus pro-
moting cleavage.[11] The aforementioned phenomena can be
readily exploited for downstream functional group interconver-
sion of the amide bond via traditional addition–elimination
with nucleophilic, primary amines[12] via tetrahedral intermedi-
ates.[13]
[a] Department of Chemistry, Tennessee Technological University,
55 University Drive, Cookeville, TN 38505-0001, USA
E-mail: jcarrick@tntech.edu
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201901811.
Further exploration and optimization of 3-methoxypropyl-
amine as a mild, competent reagent for the N-Boc deprotection
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of various functionalized heteroarenes including tridentate
[1,2,4]triazinyl-pyridin-2-yl indoles, 1,2-indazoles, 1,2-pyrazoles
and related structures resulted in applicability to 25 diverse
substrates. Method development, pyridinyl indole and Boc-pro-
tected heteroarene scope, as well as a scale-up experiment, and
initial mechanistic interpretation of the transformation are re-
ported herein.
Table 1. Indole N-Boc deprotection method development.
Entry
Reagent[a]
TFA
Equiv Solvent
360 Tol
Temp Time
Result[b]
[%]
[°C]
[h]
Results and Discussion
1
50–90
40
6
3
3
2
1
M
HNO3
0.1
Tol
2
The discovery of 3-methoxypropylamine as an effective reagent
for the deprotection of 1 was a welcomed result as many previ-
ous attempts at deprotection of 3 under standard conditions
proved futile.[14] Table 1 highlights selected experiments to-
wards the deprotection of the N-Boc of 3 which were concur-
rently underway with the chemistry described in Scheme 1. Tra-
ditionally stalwart conditions for reliable N-Boc deprotection of
sp3, sp2, and aromatic N atoms with trifluoroacetic acid,[15] nitric
acid,[16] water,[17] and sodium methoxide[18] (entries 1–4) proved
unproductive for the transformation of interest. Attempted re-
duction with lithium borohydride (entry 5) resulted in decom-
position of 3 without substantive N-Boc deprotection. Reaction
conditions employing trimethylsilyltrifluoromethane sulfonate
in concert with 2,6-lutidine[19] afforded 90 % conversion of 3 to
4. However, subsequent attempts to optimize this transforma-
tion towards reliable production and chromatographic isolation
of 4 proved elusive. Further experimentation was attempted by
3
4
5
6
7
8
9
10
11
H2O
NaOCH3
LiBH4
TMSOTf, 2,6-Lut.
SiO2
CuI
555 CPME
100
25
0–25
25
12
16
2
12
–
16
16
16
4.5
3
0.2
1.1
6.0
–
0.5
0.5
0.5
CH3OH
THF
DCM
MeOH
THF
3
3[c]
4 (90 %)
3
23
0–50
0–50
0–50
50
3
3
LiCl
AlCl3
THF
THF
4 (99 %)[c]
4 (99 %)
3-methoxypropyl- 1.05 Tol
amine
2-methoxypropyl- 1.05 Tol
amine
ethanolamine
octylamine
4-tert-butylbenzyl- 1.05 Tol
amine
N,N-diisopropyl-
amine
N,N-diisopropyl-
ethylamine
3-methoxypropyl- 1.05 CH3CN
amine
3-methoxypropyl- 1.05 DMF
amine
3-methoxypropyl- 1.05 THF
amine
12
50
48
4 (68 %)
13
14
15
1.05 Tol
1.05 Tol
50
50
50
24
18
24
4 (45 %)
4 (99 %)
4 (5 %)
16
17
18
19
20
1.05 Tol
1.05 Tol
50
50
50
50
50
24
24
18
48
3
3
3
4 (99 %)
4 (80 %)
4 (99 %)
employing standard Lewis acids including SiO2,[20] CuI,[21] and
LiCl[22] (entries 7–9) without success. AlCl3
affected conver-
[23]
sion of 3 to 4, but with significant decomposition. Thermolytic
degradation of the N-Boc group,[24] in addition to discrete treat-
ment of 3 with trifluoroethanol,[25] were also unsuccessful.
Realizing the result in Scheme 1 was commensurate with inves-
tigating the preliminary conditions described, a refocused ap-
proach to N-Boc deprotection of 3 via an addition–elimination
strategy.
Reaction conditions: In an 8 mL reaction vial with magnetic stirring bar at
ambient temperarture was charged: 3 (0.110 mmol), in solvent indicated
(0.25 M), followed by reagent indicated, for temperature and time indicated.
[a] Percent listed describes the ratio of 3 to 4, in cases where 4 was afforded
as determined by integration of selected aryl resonances in the crude 1H
NMR spectrum without internal standard. [b] Significant product decomposi-
tion was observed.
Pursuant to the aforementioned, an experiment was con-
ceived which employed 3-methoxypropylamine (1.2 equiv.) in
toluene at 50 °C to test the original hypothesis which afforded
4 in high conversion and good isolated yield after a modest
4.5 h reaction time. An amine screen was subsequently con-
ducted to evaluate if alternatives existed to improve the desired
transformation. In the case of 2-methoxypropylamine (entry 12)
much slower conversion to 4 was observed relative to entry 11.
Ethanolamine behaved similarly to entry 12 with lower conver-
sion and extended reaction time. The discrete electronic envi-
ronment in the case of 3-methoxypropylamine resulted in
superior performance. Aliphatic and aromatic amines including
octylamine (entry 14) and 4-tert-butylbenzene (entry 15), af-
forded slower conversion in the case of the former, and poorer
conversion in the case of the latter. Hindered aliphatic amines,
Huenig's base and the conjugate acid of LDA (entries 16–17)
were attempted, and as expected, resulted in inadequate per-
formance presumably due to steric hindrance of addition to the
A solvent screen was conducted in various polar aprotic sol-
vents with diverse dielectric constants (entries 18–20) with THF
affording the cleanest conversion and minimized impurity pro-
file of 3 to 4 while simultaneously resulting in the highest iso-
lated yield. Temperature and concentration optimization at-
tempts of the transformation did not improve upon previously
defined conditions. Control experiments were also performed
and underscored the necessity of both 3-methoxypropylamine
and mild heating to afford 4. With a seemingly viable method
for indole N-Boc deprotection realized, efforts transitioned to
the application to of this strategy to tridentate [1,2,4]triazinyl-
pyridin-2-yl indole Lewis basic procomplexants delineated in
Table 2.
Table 2 highlights the N-Boc-[1,2,4]triazinyl-pyridin-2-yl de-
N-Boc carbonyl. With a preliminary set of reaction conditions protection scope of the transformation. Synthetic access to the
defined for the transformation, focus shifted to the optimization starting materials for this investigation have been previously
of the N-Boc deprotection.
reported.[8] A total of eleven examples in this area were evalu-
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Table 2. Tridentate procomplexant N-Boc deprotection.
indole and resulted in achievement of the desired products 9
and 10 in good yield. The 3,3′-dimethoxy substituted 1,2,4-tria-
zinyl moiety has afforded useful results in separations experi-
ments of the minor actinides from lanthanides in simulated
spent nuclear fuel.[26] This functionality in entries 10 and 11
also proved competent, affording 12 and 13 in similar yield. A
consistent theme which emerged in the context of the diverse
examples explored to this point in the project, which was fur-
ther underscored as a function of additional examples below in
Table 3 and Table 4, was that the main prerequisite for success-
ful N-Boc deprotection of the indole moiety via addition–elimi-
nation with 3-methoxypropylamine was centralized on induc-
tive-electron withdrawing groups situated in close proximity to
the indole N-atom. With definition of a coherent strategy for
deprotection of the procomplexants in Table 2 our attention
turned to evaluating the N-Boc deprotection scope with other
functionalized indoles (Table 3).
Table 3. Pyridinyl indole N-Boc deprotection scope.
[a] Reaction Conditions: Isolated, purified, and unoptimized yield. [b] Yield
over two steps. [c] Percent listed describes the ratio of the starting material
as determined by integration of selected aryl resonances in the crude 1H
NMR spectrum without internal standard. [d] Mixture of E/Z diastereomers.
ated for N-Boc deprotection with the optimized conditions de-
scribed in Table 1. Phenyl substituents on the 1,2,4-triazine moi-
ety, in concert with varied resonance and electron-donating
functionality at the 4, 5, and 6 positions (entries 1–5),[8] afforded
consistent performance with respect to deprotection with the
exception of 2 where the lower isolated yield was a direct con-
sequence of purification challenges. Examples which varied the
functionality of the aryl substituents on the 1,2,4-triazine were
evaluated subsequent. As such, inductively electron-withdraw-
ing substituents in the 4,4′-positions of the 1,2,4-triazine (en-
tries 6 and 9) afforded the desired products 8 and 11 in 76 %
and 71 % yields, respectively. Fidelity of the tert-butyldimethyl-
silyl protecting group in the case of 11 was maintained. Entries
7 and 8 evaluated an aliphatic substituted 1,2,4-triazine with an
electron-donating and electron-withdrawing substituent on the
[a] Reaction Conditions: Isolated, purified, and unoptimized yield. [b] Yield
over two steps. [c] Percent conversion after 48 hours from integration of
selected resonances in the 1H NMR spectrum without internal standard. [d]
Mixture of E/Z diastereomers.
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Table 4. Heterocycle N-Boc deprotection scope.
products painstakingly slow. A double N-Boc deprotection at-
tempted in entry 7 resulted in 20[8] in 46 % over two synthetic
steps from the bis-protected starting material. Quinoline deriva-
tive 21 performed commensurate to previous 2-pyridinyl exam-
ples in Table 3. Deprotected pyridinyl oxime 22 was afforded in
86 % isolated yield over two steps including Suzuki–Miyaura
cross-coupling and subsequent N-Boc deprotection as a mix-
ture of greater than 95:5 E/Z diastereomers without observing
the transimination product. Unfortunately, the described
method was not successful with sp3-hybridized N-Boc deprotec-
tions of several examples including l-N-Boc tryptophan, as well
as l-bis-N-Boc tryptophan with unreacted starting material ob-
served in both of the aforementioned cases. Having evaluated
the impact of positional substituents on functionalized indoles
we shifted application of the method to various heteroarenes
of relevant interest which included an N-Boc protected moiety
(Table 4).
Table 4 delineates examples focused on variation of the N-
Boc protected heteroarene in the context of structures similar
to the examples successful in Table 2 and Table 3 above. Fo-
cused on evaluating examples for which inductive-electron
withdrawing functionality could facilitate a smooth transforma-
tion a series of 1,2-indazole derivatives (entries 1–3) were ex-
plored resulting in the desired products 23–25 in 48–73 % iso-
lated yield. Further support for the necessity of activating the
N-Boc group for deprotection with inductive-electron with-
drawing functionality[29] is exemplified in entry 4 which is the
indole analogue to successful 1,2-indazole 24. In this example,
sequestration of the additional N-atom proved deleterious to
the formation of 26 with 0 % conversion observed after 48
hours. Other heteroarenes were evaluated including deprotec-
tion of N-Boc protected tautomeric 1,2-pyrazoles 27 and 28[30]
which were afforded in modest yields over two steps[31] via
protection and deprotection. Deprotection of N-Boc protected
imidazole was also successful under the reaction conditions af-
fording 29 in 55 % isolated yield. It should be noted that the
lower yields in this series of experiments can be attributed more
to difficulty of isolation of pure compound via chromatography
than poor performance of the transformation.
[a] Reaction Conditions: Isolated, unoptimized, purified yield. [b] Percent con-
version after 72 h as determined from integration of selected resonances in
the 1H NMR. [c] Isolated yield for N-Boc protection and N-Boc deprotection
of tautomers.
Examples in Table 3 sought to expand the method scope
beyond the procomplexants delineated in Table 2 with various
functionalized indoles.[27] Positional arrangement of an induc-
tive electron-withdrawing functionality was critical to success
in these cases. Pursuant to the aforementioned, entries 1 and 2
with pyridinyl connections to the indole moiety at the 2-posi-
tion resulted in smooth N-Boc deprotection although the pres-
ence of an additional electron withdrawing group at C-4 on 15
afforded an improved yield. When a 6-methoxy substituent was
present on the pyridine ring product 17 was afforded in 45 %
yield. Carboxylic acid derivatives including the methyl ester and
Weinreb amide[28] afforded the same product 17 in 92 % yield
for the methyl ester over two steps via N-Boc deprotection and
subsequent transamidation. Observing reaction progress for
A tenfold scale up experiment (Scheme 2) was executed to
ascertain the feasibility of material throughput via deprotection
beyond the development scale transformation (Table 2). Con-
version of 3 to 4 was realized in slightly lower yield than the
development scale reaction.
1
this discrete example via TLC, which was benchmarked by H
NMR, substantiated that the addition–elimination with 3-meth-
oxypropyl-amine occurred first followed by subsequent N-Boc
deprotection to afford 17. Interestingly, in the case of the Wein-
reb amide starting material the product was afforded even
though superficially a strong thermodynamic preference for the
Scheme 2. Tenfold scale-up experiment.
A preliminary mechanistic hypothesis for the N-Boc depro-
transamidated product would appear minimal. Entries 5–6 tection of functionalized heteroarenes is described below in
buttressed the positional arguments in entries 3–4 by evaluat- Figure 1 based on initially acquired experimental spectroscopic
ing substituted 3-indole pyridines. In these cases with intem- data. Pursuant to the aforementioned, 3-methoxypropylamine
perate disposition, the pyridinyl-N-atom relocated by one posi- is postulated to add to the N-Boc carbonyl resulting in tetrahe-
tion made conversion to the desired N-Boc deprotected dral intermediate 32 which eliminates carbamate 34 and the
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compounds and corrected for residual solvent, if applicable, from
1H NMR spectroscopy unless otherwise indicated. Infrared spectro-
scopic data was acquired using attenuated total reflectance (ATR)
from the (form) listed. All 1H and 13C NMR data was acquired from a
500 MHz multinuclear spectrometer with broad-band probe unless
stated otherwise. *13C NMR spectra acquired on a 500 MHz spec-
trometer with broadband N2-cryoprobe were corrected for ring-
down using linear back prediction via a vendor provided algorithm
to improve baseline aesthetics. Chemical shifts are reported using
the δ scale and are referenced to the residual solvent signal: CDCl3
(δ = 7.26), (CD3)2C=O (δ = 2.05), (CD3)OD (δ = 3.31), and
weakly basic product (33) post proton transfer. Thermal degra-
dation of the carbamate under the reaction conditions liberates
CO2 and affords tert-butanol and 3-methoxypropylamine.
1
(CD3)2S=O (δ = 2.50) for H NMR and CDCl3 (δ = 77.16), (CD3)2C=O
(δ = 29.84), (CD3)OD (δ = 49.00), and (CD3)2S=O (δ = 39.52) for 13C
NMR.[32] Splittings are reported as follows: (s) = singlet, (d) = dou-
blet, (t) = triplet, (dd) = doublet of doublets, (dt) = doublet of trip-
lets, (br) = broad, (br-d) = broad doublet, (br-m) = broad multiplet,
(br-s) = broad singlet, and (m) = multiplet. High resolution mass
spectrometry (HRMS) data was obtained utilizing electron impact
ionization (EI) with a magnetic sector (EBE trisector), double focus-
ing-geometry mass analyzer.
Figure 1. Proposed N-Boc deprotection mechanism.
As mentioned previously, when sub-stoichiometric amounts
of 3-methoxypropylamine were added, incomplete conversion
occurred, underscoring that the reaction is not perfectly cata-
lytic with respect to the 3-methoxypropylamine. Observation of
tert-butanol in crude reaction products post concentration un-
der reduced pressure was observed, whereas 32 and 3-me-
thoxypropylamine were not, suggesting azeotropic removal of
the amine. Further, tert-butyl-3-methoxypropylamine also was
Supporting Information (see footnote on the first page of this
1
article): Further detailed experimental procedures and copies of H
and 13C NMR spectra as well as automated flash purification chro-
matograms are disseminated are available as supporting informa-
tion.
1
not observed via H NMR of crude reaction mixtures.
Conflict of Interest
The authors declare no conflict of interest.
Conclusion
In summary, the authors have disclosed a mild N-Boc deprotec-
tion of various heteroarenes via an addition–elimination strat-
egy with 3-methoxypropylamine leading to the production of
25 discretely successful examples, a ten-fold scale-up experi-
ment, in addition to laying the groundwork for a preliminary
mechanistic hypothesis. During the course of method develop-
ment, the important role of inductive electron-withdrawing
functionality proximal to the N-Boc group of interest was dis-
covered to be critical to successful deprotection. The functional
group scope of the transformation can be applied to a variety
of N-heterocycles and the specificity of the developed method
for activated, sp2-hybridized heteroaryl N-atoms provides strate-
gic opportunities for subsequent employment in complex mol-
ecule synthesis in which chemoselective N-Boc deprotection
strategies are required. The tridentate complexants afforded
from the method as described in Table 2 are currently being
evaluated for efficacy in minor actinide separations and per-
formance results will be disseminated in due course.
Acknowledgments
Financial support for this work was provided by an award from
the U.S. Department of Energy, Basic Energy Sciences, Separa-
tions Program Award: DE-SC0018033. An award from the Na-
tional Science Foundation (NSF) Major Research Instrumenta-
tion Program (1531870) is gratefully acknowledged for the
acquisition of the University's 500 MHz multinuclear NMR spec-
trometer with broad-band N2 cryoprobe. The authors would like
to thank Dr. Giri Babu Veerakanellore (TN Tech) for the prepara-
tion of synthons towards 29 and 30, Kyle R. Lyons (TN Tech)
for preliminary experiments, Dr. Qiaoli Liang (The University of
Alabama), for acquisition of HRMS data, and Dr. Markus W.
Voehler (Vanderbilt University) for acquisition of the 13C NMR
of 2, 5, and 12, supported in part by grants for NMR instrumen-
tation from the NSF (0922862), National Institutes of Health
(S10 RR025677) and Vanderbilt University matching funds.
Keywords: Deprotection · Aminolysis · Addition ·
Elimination · Heteroarenes
Experimental Section
General Considerations: All reagents were purchased from U.S.
chemical suppliers, stored according to published protocols, and
used as received unless indicated otherwise. All experiments were
performed in oven- or flame-dried glassware. Reaction progress was
monitored using thin-layer chromatography on glass-backed silica
gel plates and/or 1H NMR analysis of crude reaction mixtures. Rf
values for compounds that resulted in a concentrically observed
spot on basic alumina TLC plates are reported using the conditions
listed. Melting point data listed is for a single, uncorrected experi-
ment unless noted otherwise. All reported yields listed are for pure
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Received: December 6, 2019
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© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
N-Boc Deprotection
Z. Z. Gulledge, J. D. Carrick* ........... 1–7
Deprotection
of
N-tert-Butoxy-
carbonyl (Boc) Protected Functional-
ized Heteroarenes via Addition–
Elimination with 3-Methoxypropyl-
amine
The utilization of 3-methoxypropyl- heteroarenes including indoles, 1,2-
amine as a mild deprotecting agent for indazoles, 1,2-pyrazoles, and related
various N-Boc protected heteroarenes derivatives, a ten-fold scale-up reac-
via a proposed addition/elimination tion, and experimental evaluation of a
mechanism is described. Method de- preliminary mechanistic hypothesis
velopment, application to various are reported herein.
DOI: 10.1002/ejoc.201901811
Eur. J. Org. Chem. 0000, 0–0
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7
© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim