Rapid synthesis of alkoxyamine hydrochloride derivatives from alkyl bromide and N,N′-Di-tert-butoxycarbonylhydroxylamine [(Boc)2NOH]

Article abstract of DOI:10.1080/00397911.2014.895014

The conventional route to alkoxyamine hydrochloride derivatives is by reaction of alkyl bromides with N-hydroxyphthalimide or N-hydroxysuccinimide followed by addition of hydrazine and HCl. Transformation of an alkyl bromide to the corresponding alkoxyamine hydrochloride can be accomplished more rapidly in good yields without using hazardous hydrazine by reaction of (Boc) ₂NOH (N,N′-di-tert-butoxycarbonylhydroxylamine) and alkyl bromide followed by addition of HCl. Alkoxyamine hydrochlorides are powerful reagents in organic synthesis that can be used to synthesize alkoxyimino derivatives after condensation with a ketone or aldehyde. Copyright

Full text of DOI:10.1080/00397911.2014.895014

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Synthetic Communications: An
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Rapid Synthesis of Alkoxyamine
Hydrochloride Derivatives from
Alkyl Bromide and N,N′-Di-tert-
butoxycarbonylhydroxylamine
[(Boc)2NOH]
P. Suresh Jayasekara a & Kenneth A. Jacobson a
a Molecular Recognition Section, Laboratory of Bioorganic Chemistry,
National Institute of Diabetes and Digestive and Kidney Diseases,
National Institutes of Health , Bethesda , Maryland , USA
Accepted author version posted online: 22 Apr 2014.Published
online: 13 Jun 2014.
To cite this article: P. Suresh Jayasekara & Kenneth A. Jacobson (2014) Rapid Synthesis
of Alkoxyamine Hydrochloride Derivatives from Alkyl Bromide and N,N′-Di-tert-
butoxycarbonylhydroxylamine [(Boc)2NOH], Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 44:16, 2344-2347, DOI:
10.1080/00397911.2014.895014
To link to this article: http://dx.doi.org/10.1080/00397911.2014.895014
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Synthetic Communications1, 44: 2344–2347, 2014
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2014.895014
RAPID SYNTHESIS OF ALKOXYAMINE
HYDROCHLORIDE DERIVATIVES FROM
ALKYL BROMIDE AND N,N’-DI-TERT-
BUTOXYCARBONYLHYDROXYLAMINE [(Boc)2NOH]
P. Suresh Jayasekara and Kenneth A. Jacobson
Molecular Recognition Section, Laboratory of Bioorganic Chemistry,
National Institute of Diabetes and Digestive and Kidney Diseases,
National Institutes of Health, Bethesda, Maryland, USA
GRAPHICAL ABSTRACT
Abstract The conventional route to alkoxyamine hydrochloride derivatives is by reaction of
alkyl bromides with N-hydroxyphthalimide or N-hydroxysuccinimide followed by addition
of hydrazine and HCl. Transformation of an alkyl bromide to the corresponding alkoxya-
mine hydrochloride can be accomplished more rapidly in good yields without using hazard-
ous hydrazine by reaction of (Boc)2NOH (N,N0-di-tert-butoxycarbonylhydroxylamine)
and alkyl bromide followed by addition of HCl. Alkoxyamine hydrochlorides are powerful
reagents in organic synthesis that can be used to synthesize alkoxyimino derivatives after
condensation with a ketone or aldehyde.
Keywords Alkoxyamine; alkyl bromide; O-alkylation
INTRODUCTION
Synthesis of alkoxyimino derivatives through condensation of an alkoxyamine
hydrochloride with a ketone or aldehyde with is a very powerful tool to introduce a
heteroatom (i.e., nitrogen) in organic synthesis.[1] There are two current approaches
to the synthesis of R-ONH2 (alkoxyamino derivatives). One approach involves
conversion of an alcohol to R-ONH2 using (a) displacement of an alcohol using
Received January 22, 2014.
This article is not subject to U.S. copyright laws.
Address correspondence to K. A. Jacobson, Molecular Recognition Section, Bldg. 8A, Rm.
B1A-19, NIH, NIDDK, LBC, Bethesda, MD 20892-0810. E-mail: kajacobs@helix.nih.gov
2344

RAPID SYNTHESIS OF ALKOXYAMINES
2345
N-hydroxyphthalimide under Mitsunobu conditions and subsequent treatment with
hydrazine[2] or (b) by direct amination through reaction of an alcohol and a
substituted oxaziridine.[3] Another approach consists of substitution of R-Br=I with
N-hydroxyphthalimide (Gabriel synthesis), N-hydroxysuccinimide, or another
N-protected hydroxylamine.[4] It appears that new methods for this conversion are
needed, and here we have developed a method through which R-ONH2 can be
synthesized rapidly and in good yield from R-Br by reaction with (Boc)2NOH.
RESULTS
N,N0-Di-tert-butoxycarbonylhydroxylamine [(Boc)2NOH] 1 was synthesized
from BzONH2 ꢀ HCl as a white solid in good yield.[5] Reaction of (Boc)2NOH
and R-Br with Hunig’s base (DIPEA) or 1,8-diazabicyclo[5.4.0]undec-7-ene
¨
(DBU) in dimethylformamide (DMF) at room temperature is slow and normally
requires 12–24 h for reaction completion. The reaction rate can be accelerated by
heating at 50 ꢁC in DMF to achieve completion, typically in 1 to 2 h. Unlike the
synthesis of R-ONH2 using R-Br and N-hydroxyphthalimide or N-hydroxysuccini-
mide, by this method hydrazine is not needed to convert the acylated N-hydroxy
adduct to R-ONH2, and the Boc protecting groups can be removed easily in acidic
conditions. Normally, the intermediate R-ON(Boc)2 is dissolved in CH2Cl2 and
treated with 4 M HCl (16 eq) in dioxane at room temperature, and the mixture
is stirred for 6–12 h. The resulting R-ONH2 ꢀ HCl can be isolated as a precipitate
by filtration.
Thus, we have demonstrated a practical and efficient synthetic route to
R-ONH2 ꢀ HCl from R-Br in two steps. The product R-NH2 ꢀ HCl can be easily iso-
lated in good yield mainly by precipitation. The starting (Boc)2NOH is very stable
for several months at room temperature and for more than 1 year at 4 ꢁC. Although
Table 1. Results of reaction of R-Br and (Boc)2NOH, varying group R
R-Br
Product
Yield (%) (2 steps)
85
76a
79a
75
87
aProduct was isolated from 4 M aqueous HCl.

2346
P. S. JAYASEKARA AND K. A. JACOBSON
Scheme 1. Intended biological application of alkoxyamine hydrochloride 5b and related derivatives for the
study of P2Y nucleotide receptor agonists, such as 9 (MRS4062).
several methods for the synthesis of R-NH2 ꢀ HCl from R-Br are available, improved
methods to obtain R-ONH2 are needed to overcome some of the existing drawbacks,
most notably use of toxic and hard-to-remove hydrazine in the Gabriel synthesis.
One important biological application of R-ONH2 ꢀ HCl (e.g., 5b) is in the synthesis
of N4-alkoxy modified cytidine derivatives (Scheme 1), which after phosphorylation
have proven to be potent and selective ligands of P2Y nucleotide receptors.[1d,1e] The
target O-substituted hydroxylamine compounds are also useful for the orthogonal
labeling of proteins and surfaces of cells and biomaterials.[1a,1b,5]
Chemical Synthesis
N,N’-Di-tert-butoxycarbonylhydroxylamine (1). Compound
1
was
obtained by a modification of two literature procedures (see the supporting
information).[6,7] The product 1 was isolated as a homogeneous, white crystalline
solid. 1H NMR (400 MHz, CDCl3): 1.50. 13C NMR (100 MHz, CDCl3): 150.9,
84.5, 28.0. Melting point (ꢁC): 87.4 ꢂ 0.5. HRMS EI m=z (M – H); found:
232.1186; calc. for C10H18O5N: 232.1190.
The alkoxyamine hydrochloride derivatives (2b–6b) were prepared using the
synthetic routes shown in Scheme 2. A typical reaction procedure to obtain
R-ONH2 is as follows:
DBU (0.42 mmol, 60 mL, 1.2 eq) was added to a magnetically stirred mixture
of 6a (0.36 mmol, 83 mg, 1 eq) and 1 (0.34 mmol, 79 mg, 0.95 eq) in 0.5 mL of DMF
at room temperature under N2. Then, the mixture was heated to 50 ꢁC and stirred
for 2 h. The reaction was monitored using thin-layer chromatography (TLC). After
completion, the solvent was removed and the mixture was dissolved in EtOAc
(50 mL) and washed with water and brine. The organic phase was dried (Na2SO4),
Scheme 2. General reaction conditions for O-alkylation of hydroxylamine in two steps.

RAPID SYNTHESIS OF ALKOXYAMINES
2347
redissolved in CH2Cl2 (1 mL) in a round-bottom flask, treated with 4 M HCl in
dioxane (5.7 mmol, 1.4 mL, 16 eq), and stirred overnight. The resulting white precipi-
tate was filtered, washed with 1 mL of CH2Cl2, and dried to obtain 6b (0.30 mmol,
65 mg, 87%).
O-(3-(4-Methoxyphenyl)propyl)hydroxylamine Hydrochloride (6b). 1H
NMR (400 MHz, MeOD): 7.06 (d, J1 ¼ 8.52 Hz, 2H), 6.80 (d, J1 ¼ 8.50 Hz, 2H),
3.97 (t, J1 ¼ 6.44 Hz, 2H), 3.72 (s, 3H), 2.62 (t, J1 ¼ 7.44 Hz, 2H), 1.94 (m, 2H).
13C NMR (100 MHz, MeOD): 158.2, 132.5, 128.9, 113.5, 74.1, 54.2, 30.2, 29.2.
HRMS ESI m=z (M þ H) found: 182.1183; calc. for C10H16NO2: 182.1181.
FUNDING
Support from the Intramural Research Program of NIDDK, National Insti-
tutes of Health, is acknowledged.
SUPPORTING INFORMATION
Supplemental data for this article can be accessed on the publisher’s website.
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