Synthesis of O- tert-Butyl- N,N-disubstituted Hydroxylamines by N-O Bond Formation

Article abstract of DOI:10.1021/acs.orglett.1c02215

The reaction of magnesium amides with tert-butyl 2,6-dimethyl perbenzoate in tetrahydrofuran at 0 °C provides a method for the synthesis O-tert-butyl-N,N-disubstituted hydroxylamines by direct N-O bond formation with a broad functional group tolerance. Less sterically hindered magnesium amides require ortho,ortho-disubstitution on the perester electrophile component, whereas sterically encumbered magnesium amides perform comparably with either tert-butyl perbenzoate or tert-butyl 2,6-dimethyl perbenzoate. A reaction mechanism is presented to account for the observed reactivity.

Full text of DOI:10.1021/acs.orglett.1c02215

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Letter
Synthesis of O-tert-Butyl-N,N-disubstituted Hydroxylamines by N−O
Bond Formation
Jarvis Hill and David Crich*
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ABSTRACT: The reaction of magnesium amides with tert-butyl
2,6-dimethyl perbenzoate in tetrahydrofuran at 0 °C provides a
method for the synthesis O-tert-butyl-N,N-disubstituted hydroxyl-
amines by direct N−O bond formation with a broad functional
group tolerance. Less sterically hindered magnesium amides
require ortho,ortho-disubstitution on the perester electrophile
component, whereas sterically encumbered magnesium amides
perform comparably with either tert-butyl perbenzoate or tert-butyl
2,6-dimethyl perbenzoate. A reaction mechanism is presented to
account for the observed reactivity.
e have identified the N,N,O-trialkylhydroxylamine unit
as an under-represented functional group in medicinal
chemistry that is suitable for the bioisosteric replacement of
ether and branched alkyl units in natural products (Figure
1).1−6 This concept was first applied to the synthesis of a
chemistry. Adapting earlier methods for ether synthesis,9,10 we
reported11 a novel method for the construction of N,N,O-
trisubstituted hydroxylamines whereby magnesium amides
react with methyltetrahydro-2H-pyran (MTHP) monoperox-
yacetals to afford N,N,O-trisubstituted hydroxylamines with
broad functional group tolerance. This method was applicable
to primary and secondary alcohol-derived N,N,O-trisubstituted
hydroxylamines but failed under the standard conditions when
applied to the tert-butanol-derived MTHP (Figure 2).11
In view of the importance of the tert-butyl group in
medicinal chemistry and agrochemistry (Figure 3)12−15 and
W
Figure 1. Hydroxalog concept applied to a β-(1 → 3)-glucan and a
marine natural product.
hydroxalog (hydroxylamine analog) of the β-(1 → 3)-glucan
laminaritriose, which showed an improved biological activity
compared to that of the parent trisaccharide.3 More recently,
we applied the hydroxalog concept to the synthesis of a potent
anticancer derivative 10-aza-9-oxakalkitoxin (IC50 = 2.4 ng/
mL), a kalkitoxin analog with an activity comparable to that of
the parent compound (IC50 = 3.2 ng/mL) against the human
hepatocarcinoma cell line HepG2.1,7,8
Figure 2. Reaction of MTHP peroxides with magnesium amides.
Received: July 1, 2021
Encouraged by these results, we focused on developing a
method for the preparation of N,N,O-trisubstituted hydroxyl-
amines by direct N−O bond formation, thereby facilitating
access to the hydroxalog moiety for use as a tool in medicinal
https://doi.org/10.1021/acs.orglett.1c02215
© XXXX American Chemical Society
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Figure 3. Examples of the tert-butyl group in medicinal chemistry and
agrochemistry.
the recent advances16−21 in bioisosteric replacements of tert-
butyl groups, we have devised and report here a method to
access a broad range of O-tert-butyl-N,N-disubstituted
hydroxylamines. Effectively, we sought a simple protocol to
overcome the inherent limitations of our earlier method,11
enabling further investigation of the hydroxalog1,3 concept.
While the preparation of O-tert-alkyl-N,N-disubstituted
hydroxylamines can be achieved through [2,3]-Meisenheimer
rearrangements of allylic N-oxides, this method is limited to
the synthesis of allylic substrates and is not extendable to the
desired O-tert-butyl derivatives.22 The literature synthesis of O-
tert-butyl-N,N-disubstituted hydroxylamines is mainly limited
to the solvolysis of tert-butanol with N-hydroxyphthalimide,
which is adequate for the installation of the tert-butoxy moiety
but requires multiple functionalization steps for the completion
of the amino portion.23,24 Alternatively, O-tert-butyl-N,N-
disubstituted hydroxylamines can be prepared under the
Whitesides procedure, or related processes, through the
reaction of stable nitroxyl radicals with tert-butyl lithium;
however, the amino portion of this protocol is limited to
sterically encumbered amines such as 2,2,6,6-tetramethylpiper-
idine (TMP).25,26 We sought a general method for the direct
construction of a wide array of O-tert-butyl-N,N-disubstituted
hydroxylamines by direct N−O bond formation employing an
easily accessible “RO+” reagent. As before, we drew on parallels
with ether forming reactions and were drawn to a report27 by
Lawesson and Yang where the reaction of Grignard and
alkyllithium reagents with tert-butyl perbenzoate (TBPB)
afforded O-tert-butyl ethers in good yields (Figure 4a). The
extrapolation of this method to hydroxylamine formation was
attractive considering that TBPB is commercially available and
employed in oxidations.28 Moreover, derivatives can be easily
accessed by standard acylation chemistry.28
Figure 4. Previously reported nucleophilic displacements of tert-butyl
perbenzoates and the current work.
extended to the synthesis of N-alkoxyaminyl radicals by
Miura,32−34 when as in the study by Benn and Meesters31
yields were modest at best and extremely sensitive to the steric
nature of the nucleophile. We now report that the reaction of
magnesium dialkylamides with an appropriately substituted
TBPB derivative, tert-butyl 2,6-dimethyl perbenzoate, offers a
practical method to access a wide array of O-tert-butyl-N,N-
disubstituted hydroxylamines in a direct fashion by N−O bond
formation without the inherent scope limitations previously
observed31−34 (Figure 4c). We also report that the well-
documented29−31 bias of amines to react selectively with
peresters in a 1,2-fashion can be overcome by a modification of
the perester electrophile.
We began our investigation by evaluating the reaction of
commercially available TBPB with the magnesium salt of
dibenzylamine using conditions resembling those of our
previously reported11 hydroxylamine forming reaction (Figure
2; Table 1), where the O-tert-butyl-N,N-disubstituted hydrox-
ylamine (4a) was formed in a 67% isolated yield along with 6%
of the corresponding benzamide (5a). Swapping the
magnesium salt for the lithium salt of dibenzylamine yielded
only trace amounts of the intended product (4a) at −78 °C,
with the major product isolated being the benzamide (5a)
a
Table 1. Optimization of Reaction Conditions
Nucleophilic addition to perester electrophiles can occur
through two different pathways: (i) 1,2-addition at the
carbonyl group and (ii) 1,4-addition to the peroxy oxygen.28
Previous studies on the nucleophilic addition of amines to
TBPB demonstrated that the C-attack (1,2-addition) predom-
inates over the corresponding O-attack (1,4-addition). For
example, Bhanage reported29 a mild benzoylation procedure
wherein amines react chemoselectively with TBPB to afford
benzamides in high yields. Similarly, Zhang and Gong
reported30 that under basic conditions formamides decarbon-
ylate and react selectively with TBPB, affording benzamides in
good to excellent yields. In contrast, an early report by Benn
and Meesters showed that sterically encumbered primary tert-
alkyl lithium amides react with TBPB to afford O-tert-butyl-N-
monosubstituted hydroxylamines by direct N−O bond
formation in modest yields (Figure 4b).31 This strategy was
entry
variation of the standard condition
4a yield (%) 5a yield (%)
1
2
3
4
5
6
7
none
69 (67)
trace
10
6
n-BuLi instead of EtMgBr (−78 °C)
n-BuLi instead of EtMgBr (0 °C)
Et2O instead of THF
toluene instead of THF
no EtMgBr
68 (62)
5
8
7
63
59
b
b
n.r.
n.r.
b
b
MgBr2 instead of EtMgBr
n.r.
n.r.
a
All reactions were run on the 0.3 mmol scale. NMR yields were
determined with 1,3,5-trimethoxybenzene as the internal standard
b
(isolated yield in parentheses). The reaction was run for 24 h and
monitored by TLC and MS. Crude NMR spectra were taken after 24
h to confirm no reaction.
B
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(62%). Treating the lithium salt of dibenzylamine with TBPB
at 0 °C resulted in significantly lower yields of both products.
A slight decrease in the yield was observed by switching the
solvent from THF to ether or toluene, with the intended
product (4a) formed in 63 and 59% yields, respectively, and
the corresponding benzamide (5a) formed in comparable
yields as with THF (8 and 7%, respectively). Under neutral or
Lewis acidic conditions, no reaction was observed, with only
the unreacted perester detected by NMR spectroscopy of the
crude reaction mixture.
amine nucleophiles bearing a wide range of functional groups
(Figure 5). With an emphasis on heterocycles commonly
Working with the magnesium amides, we explored the initial
scope of the amine nucleophiles (Table 2). Surprisingly, upon
Table 2. Investigation of Steric Effects on the
a
Regioselectivity
entry
R
R′
4a−4c yield (%)
5a−5c yield (%)
1
2
3
4
5
6
Bn
Bn
Me
Me
iPr
iPr
H
Me
H
Me
H
69 (67)
62
21
60 (55)
31
6
<5
66 (63)
<5
trace
trace
Me
35 (29)
a
All reactions were run on the 0.3 mmol scale. NMR yields were
determined with 1,3,5-trimethoxybenzene as an nternal standard
(isolated yield in parentheses).
treatment of the magnesium salt of N-methylbenzylamine with
TBPB, only 21% of the desired product (4b) was observed,
with the major product being the benzamide (5b) (63%).
Considering the major steric dependence noted by Benn31 in
the reaction of lithium amides with TBPB, we resorted to the
time-honored strategy of employing ortho,ortho-disubstitution
to impede 1,2-addition to the carbonyls.35−38 Accordingly, we
prepared tert-butyl 2,6-dimethyl perbenzoate by standard
acylation chemistry28 for further investigation (see the
Supporting Information for more details).
Upon the reaction of the magnesium salt of N-methylbenzyl-
amine with tert-butyl 2,6-dimethyl perbenzoate, an improved
isolated yield of 55% was obtained for the desired product
(4b), and only a minor amount (<5%) of the benzamide (5b)
was observed, thus demonstrating that steric interactions
contribute to the chemoselectivity of reactions of peresters
with metal amides. Additionally, the reaction of magnesium
dibenzylamide with tert-butyl 2,6-dimethyl perbenzoate
afforded the intended product (4a) in a 62% yield, which is
comparable to that obtained using TBPB. Finally, we also
performed the reaction of the magnesium salt derived from N-
isopropylbenzylamine with both electrophiles whereby the
intended product (4c) was formed in comparably reduced
yields (31 and 35%) with either electrophile, likely reflecting
the highly hindered nature of the intended product (4c).
Effectively, the less hindered amide nucleophile is best paired
with the ortho,ortho-disubstituted electrophile, while the more
hindered nucleophiles function comparably with either
electrophile.
Figure 5. Synthesis of O-tert-butyl-N,N-disubstituted hydroxylamines.
aReactions were performed on a 0.4 mmol scale. All reported yields
b
are after isolation unless otherwise stated. Reaction was run on the
0.3 mmol scale. NMR yield was determined with 1,3,5-trimethox-
ybenzene as an internal standard (isolated yield in parentheses). ctert-
d
Butyl perbenzoate (TBPB) was used as the electrophile. Reaction
was run on the 1.57 mmol scale.
encountered in drug motifs,39 we began with tetrahydro- and
perhydro-isoquinoline-derived magnesium salts, which af-
forded products 4d−4e in good yields (67−80%) upon
reaction with the sterically matched electrophile. Substituted
piperidine derivatives were also well-tolerated in the reaction,
with 4-benzylpiperidine-, 4-benzylidenepiperidine-, and 4-
morpholinopiperidine-derived magnesium salts affording the
corresponding products (4f−4h) in 66, 65, and 70% yields,
respectively, upon reaction with the sterically matched
electrophile. The 4-benzylpiperidine-derived magnesium salt
was also reacted on the 500 mg scale to afford the product (4f)
in a comparable 58% yield. N-Aryl-piperazines were also
competent nucleophiles in the reaction, with 1-(2-methox-
yphenyl)-piperazine-, 1-(4-trifluoromethylphenyl)-piperazine-,
and 1-(2-pyridyl)-piperazine-derived magnesium salts affording
products 4i−4k in 67, 69 and 76% yields, respectively, upon
reaction with the sterically matched electrophile. Additionally,
the 1-(2-methoxyphenyl)-piperazine-derived magnesium salt
was also reacted on the 500 mg scale, with the intended
product (4i) formed in a 60% yield. Frameworks encountered
in pharmaceutical agents were then used to further
With the reaction optimized to favor 1,4-addition to the
peroxy oxygen, we investigated the tolerance of a variety of
C
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demonstrate the methodology. All such fragments tested
afforded products 4l−4o in fair to good yields (60−74%), with
even a thiazole (4n) moiety being well-tolerated when paired
with the sterically matched electrophile. We then turned to the
scale-up of the reaction, employing a selection of the
pharmaceuticals and pharmaceutical fragments. We began
with the potent histamine H1 receptor antagonist deslorata-
dine,40 which upon reaction with the sterically matched
electrophile on the 1 g scale afforded the intended product
(4m) in a 62% yield. Moreover, 1-(2,3-dichlorophenyl)-
piperazine, a fragment of the widely used41 antipsychotic
aripiprazole, was reacted on the 850 mg scale to afford the
intended product (4o) in a 66% yield when paired with the
sterically matched electrophile. The structure of 4o was also
confirmed by X-ray crystallography. Finally, we note that
excess amine can be recovered either as the hydrochloride salt
or the free base, as was performed with products 4f and 4i (see
the Supporting Information for more details).
ranging alternative to existing methods23−26,31 for the
preparation of O-tert-butyl-N,N-disubstituted hydroxylamines.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c02215.
Detailed experimental procedures, spectroscopic charac-
terizations of all new compounds, and crystallographic
data of 4o (PDF)
Accession Codes
CCDC 2093160 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Mechanistically, the observed reactivity can be rationalized
by the occurrence of an irreversible attack on the peroxy
oxygen bond in competition with a reversible carbonyl
addition (Figure 6), the latter as previously observed by
AUTHOR INFORMATION
Corresponding Author
■
David Crich − Department of Pharmaceutical and Biomedical
Sciences, University of Georgia, Athens, Georgia 30602,
United States; Department of Chemistry, University of
Georgia, Athens, Georgia 30602, United States; Complex
Carbohydrate Research Center, University of Georgia, Athens,
Georgia 30602, United States; orcid.org/0000-0003-
2400-0083; Email: David.crich@uga.edu
Author
Jarvis Hill − Department of Pharmaceutical and Biomedical
Sciences, University of Georgia, Athens, Georgia 30602,
United States; Department of Chemistry, University of
Georgia, Athens, Georgia 30602, United States;
orcid.org/0000-0003-2251-5569
Figure 6. Proposed reaction pathway.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c02215
Cline and Hanna for the aminolysis of N-hydroxysuccinimide
esters.42 For unsubstituted TBPB, k1 > k3 and is followed by
the irreversible collapse (k2) of the tetrahedral intermediate to
afford both the benzamides observed in this study and those
seen by Benn.31 Switching to the sterically matched tert-butyl
2,6-dimethyl perbenzoate results in a retardation of 1,2-
addition to the carbonyl, in parallel to observations on the
hydrolysis35 of ortho,ortho-disubstituted benzoyl choline esters
such that k3 > k1. Thus, irreversible 1,4-peroxy oxygen addition
(k3) by N−O bond formation predominates, and the intended
O-tert-butyl-N,N-disubstituted hydroxylamines are formed in
high yields. Finally, the insensitivity of the more sterically
encumbered nucleophiles to ortho-substitution is best
accounted for by reversible 1,2-addition, with the collapse of
the tetrahedral intermediate to the amide (k2) being hampered
both by the increased steric interactions of the product amide
in the corresponding transition state.
Overall, O-tert-butyl-N,N-disubstituted hydroxylamines can
be obtained in high yields upon the reaction of magnesium
amides with tert-butyl-derived peresters by exploiting the steric
environment of the electrophile. A feature of this chemistry is
that the less hindered magnesium amide nucleophiles require
an ortho,ortho-disubstituted electrophile to favor 1,4-addition
to the peroxy oxygen, whereas sterically encumbered
magnesium amides function well with either electrophile.
The described transformation offers a versatile and broad-
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. Pingrong Wei (University of Georgia) for the X-
ray crystallography of 4o. We thank Dr. Michael G. Pirrone
(University of Georgia) for his assistance with NMR
experiments.
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