Elucidation of a Sequential Iminium Ion Cascade Reaction Triggered by a Silica Gel-Promoted Aza-Peterson Reaction

Article abstract of DOI:10.1021/acs.joc.0c02102

In a recent methodological study investigating the synthesis of N-alkoxyazomethine ylides, an unexpected aminal byproduct was generated during our attempt to isolate O-benzyl-N-((trimethylsilyl)methyl)hydroxylamine. After a strategic investigation, silica

Full text of DOI:10.1021/acs.joc.0c02102

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Elucidation of a Sequential Iminium Ion Cascade Reaction Triggered
by a Silica Gel-Promoted Aza-Peterson Reaction
Elizabeth V. Jones, Doris Chen, Stephen W. Wright, John I. Trujillo, and Stefan France*
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ABSTRACT: In a recent methodological study investigating the synthesis of N-alkoxyazomethine ylides, an unexpected aminal
byproduct was generated during our attempt to isolate O-benzyl-N-((trimethylsilyl)methyl)hydroxylamine. After a strategic
investigation, silica gel was discovered to be the cause of the byproduct formation. Through the mechanistic insight from control and
trapping experiments, we propose the formation of a methaniminium ion via a novel aza-Peterson reaction, which ultimately triggers
a sequential iminium ion cascade sequence. Herein, we discuss the elucidation of this cascade reaction mechanism and the
constraints for the byproduct formation.
reactivity, and identify the factors that lead to its formation.
After strategic troubleshooting guided by various control
experiments, we found that the column stationary phase, silica
gel, caused the generation of 4a from the desired alkylation
product 3a. Herein, we disclose our elucidation of the novel
cascade reaction of O-aryl-N-methylsilyl hydroxylamines and
discuss the constraints of the transformations (Scheme 1).
esearch often leads to unexpected discoveries that were
1,2
Routside the purview of the original experimental design.
These opportunities commonly arise as one troubleshoots
unknown or poor performing reactions,3 elucidates unexpected
reaction byproducts,4 or optimizes chromatographic isola-
tion.5,6 Relevant to this study, chromatography proved to be
the key component in uncovering an interesting cascade
reaction observed during the purification of the reaction
mixture of what was expected to be a simple alkylation. Our
story began with a recent investigation in which we sought to
explore the synthetic accessibility and reactivities of N-
alkoxyazomethine ylides, with the objective of accessing
complex heterocycles.7 One aim of this project probed the
feasibility of N-alkoxyazomethine ylide generation via a
Katritzky-inspired benzotriazole methodology.8,9 The installa-
tion of benzotriazole and trimethylsilyl groups was theorized to
allow for the facile generation of the active ylide upon heating
with a catalytic acid (Figure 1A).
1
The structure of aminal 4a was established using H, 13C,
HSQC, and DEPT-135 NMR spectroscopy. A comparison of
1
the H NMR spectra of aminal 4a to those of secondary
hydroxylamine 3a showed similar chemical shift profiles with
two main differences (Figure 2). For 4a, there is a peak at 3.66
ppm, while the N−H peak for 3a at 5.59 ppm disappeared.11
The comparison of 13C NMR spectra showed an additional
signal at 87.3 ppm for 4a, while the other signals overlapped
(Supporting Information). HSQC analysis revealed that the
carbon signal at 87.3 ppm was correlated to the unique 4a
proton. In addition, DEPT-135 analysis revealed this extra
carbon to be a CH2 unit, allowing us to reassign our
integrations. The combination of NMR analyses led us to
Curiously, during the N-alkylation of O-benzylhydroxyl-
amine 1a with trimethylsilylmethyl triflate 2 to generate O-
benzyl-N-((trimethylsilyl)methyl)hydroxylamine 3a, we ob-
served the formation of a peculiar aminal byproduct 4a (Figure
1B).10 The coelution of 4a with the desired product 3a was
consistently observed when purifying by silica gel column
chromatography despite mobile phase and theoretical plate
modifications. Intrigued by the persistence of aminal 4a, we
launched an investigation to illuminate its origins, probe its
Received: August 31, 2020
Published: November 23, 2020
https://dx.doi.org/10.1021/acs.joc.0c02102
© 2020 American Chemical Society
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Figure 1. Katritzky-inspired ylide formation (A) and byproduct formation (B).
the silica gel-based purification provided aminal 4a as the only
identifiable product isolated in a 39% yield.
Scheme 1. Silica Gel-Mediated Cascade Reaction of O-
Arylmethyl-N-(trimethylsilyl)methyl Hydroxylamines
Intrigued by this conclusive result, we theorized that the
slightly acidic environment at the surface of the silica gel was
definitively the root cause.12 It is known that in the right
environment silica gel can act a weak acid, and it has been
shown to mediate a variety of transformations, including acetal
deprotections,13,14 esterifications,15,16 cyclizations,17,18 and
cycloadditions.19,20 We subsequently ran a short series of
control experiments to probe the nature of the acid required.
The exposure of 3a to trifluoroacetic acid (Brønsted acid) or
AlCl3 (Lewis acid), even in low concentrations, resulted in the
complete degradation of 3a and no observation of 4a.21
However, subjecting 3a to acetic acid at similar concentrations
gave a 57% yield of aminal 4a after 1 h, and the full
consumption of 3a was observed within 24 h via q-NMR
spectroscopy (Scheme 3). In contrast, no aminal formation
and minimal degradation were detected in a stirred solution of
3a in CDCl3 (3 d at 25 °C). These observations collectively
provided further evidence that an external weak Brønsted acid
was required for the transformation.22
Understanding the need for an acid to promote the
transformation, we posited a cascade reaction that proceeds
mechanistically in two different stages. In the first stage, the 2°
hydroxylamine nitrogen is protonated, promoting a rearrange-
ment to reveal the exceptionally reactive methaniminium ion 5
and the transient benzyl trimethylsilyl ether 6 (Figure 3).23
This transformation is akin to Peterson olefination, in which a
β-hydroxysilane undergoes the elimination of Si−OH to form a
CC bond in the presence of acid or base.24−26 In our case,
determine the byproduct identity to be compound 4a with a
plane of symmetry. To attempt to corroborate this structure,
HRMS analysis of 4a was performed; however, the parent m/z
peak was not observed. This is not surprising given the
anticipated labile nature of the N−O bonds and the unknown
stability and reactivity of the aminal. Both 3a and 4a are oils at
ambient temperatures, preventing any X-ray crystallographic
analysis.
Having established its identity, we next sought to understand
the origin of aminal 4a. We hypothesized the alkylation of O-
benzylhydroxylamine was proceeding as planned to form
product 3a, which then underwent a further reaction to form
aminal 4a. The crude 1H NMR spectra of the reaction showed
no aminal formation after aqueous workup nor after solvent
removal under vacuum and mild heat. Thus, we were confident
that silica gel was the culprit. An additional observation that
bolstered this argument was the observed increase in the
isolation of 4a with increasing column length. To test this
theory, two identical reactions were run side-by-side, and the
products were then purified through elongated columns with
different stationary phases, one consisting of alumina and the
other of silica gel (Scheme 2). The alumina-based purification
gave the desired alkylation product 3a in a 69% yield, whereas
1
Figure 2. H NMR spectra of alkylated hydroxylamine 3a (top) and aminal 4a (bottom).
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Scheme 2. Alumina vs Silica Gel Separation
Scheme 3. Reactions Probing the Necessity of Acidity for 4a Formation
Figure 3. Aza-Peterson iminium formation from 3a (A) vs classic Peterson olefination (B).
the O-benzyl-N-(methylsilyl)hydroxylamine presumably
undergoes one of two possible pathways: (a) intramolecular
silyl-oxygen migration with concurrent N−O cleavage and
iminium formation or (b) silica gel-mediated E2-type
elimination to form iminium 5. To the best of our ability,
we found no reported examples of Peterson-type eliminations
to form iminium ions. Thus, we will further refer to this
iminium ion-forming reaction as an aza-Peterson elimination.
In the second stage of the reaction, we propose that the
reactive iminium is immediately trapped by a second molecule
of 2° hydroxylamine 3a to form intermediate 8 (Scheme 4).
Intermediate 8 undergoes proton transfer to form 9, which
eliminates NH3 to generate a new iminium ion 10. Iminium 10
is then trapped by a third molecule of the 2° hydroxylamine 3a.
Finally, the proton loss affords the aminal 4a. Thus, the overall
sequence of reactions can be classified as a sequential iminium
ion cascade triggered by silica gel-mediated aza-Peterson
iminium ion formation, and requires 3 equiv of 2° hydroxyl-
amine to provide the aminal. To date, this is the first reported
example of such a cascade reactivity involving O-substituted-N-
silylmethyl hydroxylamines.
Scheme 4. Second Stage of the Cascade Formation of
Aminal 4a
equiv of the corresponding benzyl silyl ether 6 (Figure 3).23 In
the presence of a high excess of silica gel, the deprotection of
the TMS silyl ether to benzyl alcohol is expected. Anticipating
challenges with the isolation of the benzyl alcohol, we elected
to use an analogous derivative for a proof of concept that
would afford a more easily isolatable alcohol. O-(2-
Naphthylmethyl)-N-(silylmethyl)hydroxylamine 3b was syn-
thesized using a known protocol to access naphthyl hydroxyl-
amine 1b.27 Naphthyl derivative 3b was subjected to treatment
with silica gel, and the anticipated aminal 4b from the aza-
Peterson-triggered iminium ion cascade reaction was formed
If we assume that the aza-Peterson iminium formation
occurs through intramolecular silyl transfer followed by
elimination, the cascade reaction is also expected to yield 1
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Scheme 5. Reactivity of 2-Naphthylmethyl Derivative 3b
Scheme 6. Cascade Crossover Experiment
and isolated in a 64% yield (Scheme 5). Gratifyingly, the
anticipated 2-naphthylmethanol 14 was also isolated in a 66%
yield and matched a commercial sample by 1H NMR, GC-MS,
and melting point data.
whereas in the crude mixture of the crossover experiment a
new aminal proton peak appears neatly between the two
analogous peaks of 4a and 4b (Figure 4C). Attempts at
isolating 4c from the mixture of 4a and 4b were unsuccessful,29
but HSQC analysis of the crude mixture shows the expected
peak correlations in regions consistent with both 4a and 4b. As
additional peak confirmation, known quantities of 4a and 4b
were added to the crude crossover reaction mixture and
appropriately correlated with their assigned peaks (Figure 4C,
blue and red peaks, respectively).
Confident that our proposed mechanism for the formation
of aminals 4 was logically sound, we were still puzzled by the
moderate isolated yields of 4a observed even when 3a was fully
consumed. An NMR time study found a decreased yield of 4a
with an increased reaction time (3 h or more) on silica gel,
suggesting that 4a itself was susceptible to slow degradation.
To probe this notion, a solution of 4a was left on silica gel
overnight, and complete degradation was seen the following
day. This made it evident that, like 3a, 4a was susceptible to
silica gel-promoted reactivity but at a much slower rate. It is
conceivable that 4a could undergo aza-Peterson elimination
reactions as a degradation pathway.
After confirming the conversion of 3b to 4b, we sought
another way to provide evidence of methaniminium 5
formation. We predicted that the direct observation of 5
would be near impossible, as it is likely too reactive to be
directly observed by NMR spectroscopy. Attempts to trap the
imine with traditional nucleophilic sources were unsuccess-
ful,28 so we elected to run a crossover experiment by mixing
the O-benzyl and O-naphthylmethyl hydroxylamines, 3a and
3b, respectively, in the presence of silica gel (Scheme 6). In
this experiment, if methaniminium ion was generated, each of
the homocoupled aminals 4a and 4b would be expected to
form, as well as the mixed aminal 4c. A 1:1 mixture of 3a and
3b in a silica gel slurry was stirred for 1 h, and the resulting
1
crude reaction H NMR spectra show evidence of 4a, 4b, and
heterocoupled aminal 4c formation in a 1.00:1.54:2.15 molar
ratio.
The most structurally distinct peaks for 4a and 4b are the
aminal methylene protons and carbons (Figure 4A and B),
Even with reaction times under 3 h, the yields of aminals
stayed generally between 40 and 66% without recovering
starting material. Crude 1H NMR mixtures showed evidence of
other reaction byproducts between 3.0 and 6.0 ppm, and we
suspected that these were born from methaniminium 5
polymerizing or reacting through other unidentified pathways.
After consulting the literature for known reactivities of
methaniminium, particularly valuable insight was gained from
a reported NMR study of the reaction of formaldehyde with
ammonia to produce hexamethylenetetramine (HMT, 19,
Scheme 7).30 In that study, Nielsen and co-workers proposed
that HMT formation begins when methanimine 5′ is produced
from ammonia and formaldehyde. After the nucleophilic attack
of another ammonia molecule to give methylene diamine 15,
two additional molecules of 5′ are sequentially attacked by
diamine 15 to give triazinane 17 after the loss of ammonia.
Further repetition of this aminal formation process eventually
produces HMT (19).31 A computational analysis by Zeffiro
and co-authors of this proposed mechanism found that the
overall process from methanimine 5′ to intermediate 17 has a
ΔG value of −17.2 kcal mol−1,32 with the transformation from
Figure 4. 1H NMR spectra of aminals 4a (A), 4b (B), and the
crossover reaction mixture for 4c (C).
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Scheme 7. Nielsen’s Proposed Formation of HMT (19) from 5′ and the Supporting Computational Analysis
Scheme 8. Potential Iminium Aza-Peterson Elimination Products
17 to 19 being exothermic as well (−36.6 kcal mol−1 over five
EXPERIMENTAL SECTION
■
steps).33 Zeffiro and co-authors ultimately concluded that
General Information. Chromatographic purification was per-
formed as flash chromatography with either Silicycle silica gel (40−65
μm) or Dynamic Adsorbents Inc. neutral alumina gel (50−200 μm)
and solvents indicated as the eluent with a 0.1−0.5 bar pressure. For
flash chromatography, technical-grade solvents were utilized. Ana-
lytical thin-layer chromatography (TLC) was performed on Sorbent
Technologies Alumina N UV254 (250 μm) TLC glass plates or
Silicycle SiliaPlate TLC silica gel F254 (250 μm) TLC glass plates.
Analytical plate media always matched the media of solid-phase
purification. Visualization was accomplished with UV light. Proton,
carbon, and silicon nuclear magnetic resonance spectra (1H NMR;
13C NMR, 1D and 2D experiments; and 29Si NMR, respectively) were
recorded on a Varian Mercury Vx 300 MHz spectrometer or a Bruker
500 MHz spectrometer with solvent resonances (1H NMR, CDCl3 at
7.26 ppm; 13C NMR, CDCl3 at 77.0 ppm) or Me4Si (29Si NMR, 0
ppm) as the internal standard. MestReNova (ver. 14.0) was used to
analyze NMR spectra. 1H NMR data are reported as follows: chemical
shift (ppm), multiplicity (s = singlet, d = doublet, dd = doublet of
doublets, dt = doublet of triplets, ddd = doublet of doublet of
doublets, t = triplet, m = multiplet, and br = broad), coupling
constants (Hz), and integration. Both 13C NMR and 29Si data were
recorded as proton-decoupled spectra. Infrared (IR) spectra were
obtained on a Thermo Nicolet iS10 FTIR spectrometer and analyzed
using OMNIC software. Mass spectra were obtained with a
MicroMass Autospec M instrument. The accurate mass analyses
were run in the ESI mode at a mass resolution of 10 000 using PFK
(perfluorokerosene) as an internal calibrant. Compounds 1a, 2, 11,
12, 15a, 15b, and 17 were purchased from commercial sources and
used without further purification.
Nielsen’s proposed argument for HMT formation from 5′ was
energetically supported.
This computational work validates our proposal that
methaniminium 5 can react with itself to potentially produce
a handful of amino-carbon intermediates and products.
Attempts at isolating our suspected amino-carbon byproducts
were unsuccessful, and subsequent 2D NMR studies on the
crude mixtures gave little additional insight. As an alternative
method of identification, a commercial sample of HMT was
added to our reaction mixtures to observe the peak correlation.
This NMR study confirmed that HMT itself was not a
component of our crude reaction mixtures despite the
similarity of its NMR profile to our observed byproducts.34
This similarity leaves us suspicious that we are forming either
17 or 18, one of the Nielsen group’s observed precursors to
HMT.35 Without the ability to isolate these reaction mixture
byproducts or observe them by HRMS,36 it is difficult to
conclusively prove their identity and assess their quantity. As
an added complication, once 4a is formed it is also likely
susceptible to aza-Peterson elimination (Scheme 8), albeit
more slowly. This could in theory produce additional iminium
intermediates like 20 and 22 to potentially react with 5, 3a, or
one of the many other intermediates in the reaction mixture.
Any of these reactions, in competition with the 4a formation
pathway, would experimentally result in a reduced yields of 4a
while still having a high consumption of 3a, which is consistent
with our observed reaction outcomes.
In conclusion, the identification of an unexpected reaction
byproduct led to the elucidation of a novel sequential iminium
ion cascade sequence that forms aminals from O-(arylmethyl)-
N-(trimethylsilyl)methyl hydroxylamines. The ensuing inves-
tigation of solid-phase media, in the pursuit of uncovering the
reaction origin and mechanism, serves as a humbling reminder
of silica gel’s potential to play a noninnocent role in reaction
outcomes. Furthermore, the observed reaction pathway
represents a new reactivity for 2° hydroxylamines and
highlights the potential of these hydroxylamines to serve as
an iminium precursor for the development of novel cascade
processes.
General Procedure for the Preparation of O-Aryl-N-
((trimethylsilyl)methyl)hydroxylamine Derivatives (3). O-Ar-
ylhydroxylamine (1) (8.12 mmol, 2.0 equiv) was dissolved in CH2Cl2
(81 mL). To this was added triethylamine (1.13 mL, 8.12 mmol, 2.0
equiv), followed by (trimethylsilyl)methyl trifluoromethanesulfonate
2 (0.813 mL, 4.06 mmol, 1.0 equiv) and stirred at 25 °C for 16 h. The
crude reaction mixture was concentrated and purified via alumina
chromatography.
O-Benzyl-N-((trimethylsilyl)methyl)hydroxylamine (3a). From O-
benzylhydroxylamine (1a); clear oil, 0.585 g, 2.79 mmol, 69% yield
1
(1% EtOAc/hexanes, Rf = 0.53): H NMR (300 MHz, CDCl3) δ
7.40−7.29 (m, 5H), 5.59 (s, 1H), 4.70 (s, 2H), 2.63 (s, 2H), 0.05 (s,
9H); 13C{1H} NMR (75 MHz, CDCl3) δ 138.1, 128.5, 128.3, 127.7,
75.1, 43.7, −2.3; 29Si {1H} NMR (99 MHz, CDCl3) δ −1.91; IR
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(cm−1) 2954 (m), 1248 (s), 1026 (br), 840 (s); HRMS (ESI) m/z
[M + H]+ calcd for C11H19NOSi 210.1309, found 210.1306.
O-(Naphthalen-2-ylmethyl)-N-((trimethylsilyl)methyl)-
hydroxylamine (3b). From O-naphthalen-2-ylmethyl hydroxylamine
(1b); clear oil, 0.864 g, 3.33 mmol, 82% yield (1% EtOAc/hexanes, Rf
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02102.
■
sı
1
1H NMR spectra for known compounds and NMR (1H,
13C, HSQC, and DEPT, where applicable) spectra for all
new compounds (PDF)
= 0.24): H NMR (500 MHz, CDCl3) δ 7.92−7.78 (m, 4H), 7.60−
7.43 (m, 3H), 4.89 (s, 2H), 2.68 (s, 2H), 0.07 (s, 9H); 13C {1H}
NMR (126 MHz, CDCl3) δ 135.7, 133.3, 133.0, 128.02, 127.96,
127.7, 127.3, 126.6, 126.0, 125.9, 75.2, 43.8, −2.3; IR (cm−1) 3055
(w), 2953 (m), 1248 (s), 1037 (w); HRMS (ESI/QTOF) m/z [M +
H]+ calcd for C15H21NOSi 260.1465, found 260.1457.
AUTHOR INFORMATION
Corresponding Author
■
General Procedure for the Preparation of N,N′-
Methylenebis(O-arylmethyl-N-((trimethylsilyl)methyl)-
hydroxylamine) Derivatives (4). O-Arylmethyl-N-
((trimethylsilyl)methyl)hydroxylamine (3, 100 mg) was loaded onto
a preparative TLC plate with minimal CH2Cl2 and left to dry for 20
min. The plate was eluted with 5% EtOAc/hexanes twice, and the
topmost band was removed and extracted with CH2Cl2. The solvent
was removed in vacuo to reveal the product as an oil.
Stefan France − School of Chemistry and Biochemistry and
Petit Institute for Bioengineering and Bioscience, Georgia
Institute of Technology, Atlanta, Georgia 30332, United
States; orcid.org/0000-0001-5998-6167;
Email: stefan.france@chemistry.gatech.edu
Authors
N,N′-Methylenebis(O-benzyl-N-((trimethylsilyl)methyl)-
hydroxylamine) (4a). From O-benzyl-N-((trimethylsilyl)methyl)-
Elizabeth V. Jones − School of Chemistry and Biochemistry,
Georgia Institute of Technology, Atlanta, Georgia 30332,
United States
Doris Chen − School of Chemistry and Biochemistry, Georgia
Institute of Technology, Atlanta, Georgia 30332, United
States
Stephen W. Wright − Medicine Design, Pfizer Worldwide
Research and Development, Groton, Connecticut 06340,
United States; orcid.org/0000-0002-9785-5077
John I. Trujillo − Medicine Design, Pfizer Worldwide Research
and Development, Groton, Connecticut 06340, United States
1
hydroxylamine (3a); clear oil, 25.6 mg, 0.062 mmol, 39% yield: H
NMR (300 MHz, CDCl3) δ 7.39−7.28 (m, 10H), 4.88 (s, 4H), 3.66
(s, 2H), 2.47 (s, 4H), 0.08 (s, 18H); 13C{1H} NMR (75 MHz,
CDCl3) δ 137.8, 128.8, 128.2, 127.6, 87.3, 75.3, 49.4, −1.4; 29Si {1H}
NMR (99 MHz, CDCl3) δ −1.52; IR (cm−1) 3032 (w), 2954 (s),
2900 (m), 1249 (s), 1037 (w), 859 (s); HRMS (ESI) m/z [M + H]+
calcd for C23H38O2N2Si2 430.2472, found 222.1307 and 210.1307
(m/z parent ion not found).
N,N′-Methylenebis(O-(naphthalen-2-ylmethyl)-N-
((trimethylsilyl)methyl)hydroxylamine) (4b). From O-(naphthalen-2-
ylmethyl)-N-((trimethylsilyl)methyl)hydroxylamine (3b); clear oil,
1
65.7 mg, 0.124 mmol, 64% yield; H NMR (500 MHz, CDCl3) δ
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02102
7.84−7.77 (m, 8H), 7.51 (dd, J = 8.2, 1.7 Hz, 2H), 7.47−7.44 (m,
4H), 5.07 (s, 4H), 3.74 (s, 2H), 2.54 (s, 4H), 0.10 (s, 18H); 13C
{1H} NMR (126 MHz, CDCl3) δ 135.4, 133.3, 133.0, 127.9, 127.9,
127.7, 127.4, 126.8, 125.2, 125.8, 87.2, 75.3, 49.4, −1.3; IR (cm−1)
3056 (w), 2953 (m), 2900 (m), 1249 (s), 1046 (w); HRMS (ESI) m/
z [M + Na]+ calcd for C31H42O2N2Si2Na 553.2677, found 553.2663.
2-(Naphthalen-2-ylmethoxy)isoindoline-1,3-dione (13). To a
flask containing N,N-dimethylformamide (45 mL) was added N-
hydroxyphthalimide (12) (3.69 g, 22.6 mmol) and triethylamine
(3.15 mL, 22.6 mmol). The deep red solution was stirred at 25 °C for
10 min. 2-(Bromomethyl)naphthalene (11) (5.00 g, 22.6 mmol) was
added slowly, and mixture was left for 12 h. The resulting suspension
was chilled to 0 °C and filtered, washing repeatedly with water. The
solid was vacuum-dried to give clean 2-(naphthalen-2-ylmethoxy)-
isoindoline-1,3-dione (5.48 g, 18.07 mmol, 80% yield) as a white
solid: 1H NMR (500 MHz, CDCl3) δ 7.98−7.95 (m, 1H), 7.91 (d, J =
8.4 Hz, 1H), 7.87 (d, J = 7.2 Hz, 2H), 7.82 (dd, J = 5.4, 3.1 Hz, 2H),
7.77−7.72 (m, 3H), 7.52 (s, 2H), 5.41 (s, 2H); 13C{1H} NMR (126
MHz, CDCl3) δ 163.6, 134.5, 133.7, 133.0, 131.2, 129.4, 128.9, 128.5,
128.2, 127.8, 127.1, 126.7, 126.3, 123.5, 80.0; HRMS(ESI/QTOF)
m/z [M + H]+ calcd for C19H13NO3 304.0895, found 304.0961.27
O-(Naphthalen-2-ylmethyl)hydroxylamine (1b). To a flask with
ethanol (12 mL) was added 2-(naphthalen-2-ylmethoxy)isoindoline-
1,3-dione (1.09 g, 3.59 mmol). To this hydrazine monohydrate (1.05
mL, 21.56 mmol) was added and stirred at 25 °C for 1 h. The
suspension was filtered, and the crude filtrate was concentrated. The
crude mixture was purified via silica gel chromatography (30%
EtOAc/hexanes, Rf = 0.30) to provide O-(naphthalen-2-ylmethyl)-
hydroxylamine (0.54 g, 3.12 mmol, 87% yield) as a white solid (mp
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors gratefully acknowledge financial and analytical
support from both Georgia Tech and Pfizer. E.V.J. specifically
acknowledges the School of Chemistry and Biochemistry for
Presidential and Bagwell Fellowships.
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1
56−59 °C): H NMR (500 MHz, CDCl3) δ 7.95−7.80 (m, 4H),
7.59−7.44 (m, 3H), 5.46 (s, 2H), 4.88 (s, 2H); 13C{1H} NMR (126
MHz, CDCl3) δ 134.9, 133.3, 133.2, 128.3, 128.0, 127.7, 127.4, 126.2,
126.1, 78.1; IR (cm−1) 3287 (s), 3054 (w), 1582 (m); HRMS (ESI/
QTOF) m/z [M + H]+ calcd for C11H11NO 174.0913, found
174.0910.27
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J. Org. Chem. 2020, 85, 15660−15666

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
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decreased nucleophilicity of the benzyl hydroxyamine as compared to
those of benzyl amines.
(11) The N−H peak at 5.59 ppm was observed only at certain
concentrations and was not a diagnostic peak for the product identity.
(12) Pretreating the silica gel with triethylamine caused a dramatic
decrease of 4a and an increase of isolated 3a, supporting the acidity of
the silica gel surface as the source of the reactivity.
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intermediates earlier in the mechanism, including 5.
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1
(34) The H NMR chemical shift of HMT did match an unknown
reaction peak (4.72 ppm in CDCl3); however, its 13C NMR chemical
shift was distinctly different from any reaction byproduct.
(35) Unfortunately, the only reported NMR data for key
intermediates 16 and 17 were from Nielsen’s NMR study where
materials were reported in D2O. This prevented the direct comparison
of these intermediates to our crude reaction mixture by the chemical
shift.
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(36) These hypothetical intermediates are below the limit of
detection for our available HRMS instrument.
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(21) Conditions for the acetic acid control test are as follows: a 0.08
M solution of 3a with 10 equiv of acetic acid in CDCl3 was left stirring
at room temperature. Analogous reactions with 0.5 equiv of TFA or
20 mol % AlCl3 gave no 4a. Full N−O bond cleavage and degradation
was observed instead. Conversely, an analogous reaction with 4 equiv
of formic acid gave a 54% yield of 4a as additional confirmation of the
necessity of a weakly acidic environment.
(22) The loss of 3a is likely due to slow N−O bond cleavage.
Samples of 3a that were kept neat over a period of several weeks were
not subject to this observed slow degradation.
(23) Reaction monitoring of the conversion of 3a to 4a in the
presence of acetic acid by 29Si NMR shows the presence of new silyl
derivatives, but their identities could not be readily characterized or
confirmed as standards for direct comparison were inaccessible (29Si
spectra can be found in the Supporting Information).
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