Alkoxyamine-cyanoborane adducts: Efficient cyanoborane transfer agents

Article abstract of DOI:10.1039/c1cc11345c

We report the synthesis of the hitherto unknown zwitterionic alkoxyamino cyanoboranes by reduction of O-alkyloximes with sodium cyanoborohydride; unprecedented cyanoboronated N-alkoxyformamidines were also isolated as by-products. Boronated alkoxyamines were found to be efficient cyanoborane transfer agents towards more basic amines, including aminosugars; they were also successfully transformed into neoglycoconjugates by the neoglycorandomization reaction with reducing sugars.

Full text of DOI:10.1039/c1cc11345c

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COMMUNICATION
Alkoxyamine-cyanoborane adducts: efficient cyanoborane transfer
agentsw
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Jose M. Marquez, Elisa Martınez-Castro, Serena Gabrielli, Oscar Lopez, Ines Maya,
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Manuel Angulo, Eleuterio Alvarez and Jose G. Fernandez-Bolanos*
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Received 8th March 2011, Accepted 25th March 2011
DOI: 10.1039/c1cc11345c
We report the synthesis of the hitherto unknown zwitterionic
alkoxyamino cyanoboranes by reduction of O-alkyloximes with
sodium cyanoborohydride; unprecedented cyanoboronated
N-alkoxyformamidines were also isolated as by-products.
Boronated alkoxyamines were found to be efficient cyanoborane
transfer agents towards more basic amines, including amino-
sugars; they were also successfully transformed into neoglyco-
conjugates by the neoglycorandomization reaction with reducing
sugars.
comparable to conventional radiotherapy. Therefore, new
effective methods to prepare boron-containing amino derivatives
are of relevance in synthetic, bioinorganic, and pharmaceutical
chemistry.
Herein we report the synthesis of the first examples of
N-alkoxyamine-cyanoboranes by an experimentally-simple
procedure and their use as cyanoborane transfer agents
towards aliphatic amines.
O-Alkyloximes 1 and 2 were prepared by condensation of
chloroacetaldehyde diethylacetal with N-alkyl(methyl, benzyl)-
oxyamine hydrochlorides in water medium (Scheme 1). For the
oxime 3, the N-benzyloxyamine hydrochloride was previously
transformed into the N-benzyloxyamine sulfate in order to
avoid mixtures of 2 and 3, in situ produced by nucleophilic
displacement of Br by chloride when reacting bromo-
acetaldehyde diethylacetal with N-benzyloxyamine hydrochloride.
The liquid oximes 1–3 were obtained in high yields (81, 84,
74%, respectively) as mixtures of the E/Z isomers in roughly
2 : 1 ratios, as deduced from the NMR spectra.
Much effort has been devoted to the preparation of organo-
boron compounds; such derivatives exhibit unique structural
and chemical profiles which make them valuable intermediates
and catalysts in organic synthesis,1 including asymmetric
processes. Boron-containing compounds are widely used in
hydroborations,2 reductions,3 cross-coupling reactions (e.g.
Suzuki–Miyaura reaction),4 or cycloadditions,5 among others.
Organoboron derivatives are also of great interest from a
biological and pharmacological point of view.6 In this context,
a-aminoboronic acids, considered as isoelectronic analogues
of amino acids, have been reported as inhibitors of proteases;7
aminocarboxyboranes, and their precursors amine-cyanoboranes8
have shown antifungal, antibacterial, antiarthritic, and anti-
inflammatory properties.9 Some cyanoboronated nucleosides
have been reported to act as potent antitumor agents in
mammalian cell lines, and to possess antiinflammatory and
hypolipidemic activities.10
We have accomplished the reduction of O-alkyl oximes
1–3 with sodium cyanoborohydride in glacial acetic acid,
Furthermore, numerous organoboron derivatives have been
assayed in imaging studies11 and radiotherapy, as boron
carriers to tumor cells for the boron neutron capture therapy
(BNCT),12 which has been demonstrated to be a successful
treatment against some tumoral malignancies, with efficiency
a
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Departamento de Quımica Organica, Facultad de Quımica,
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Universidad de Sevilla, c/Profesor Garcıa Gonzalez 1, E-41012,
Seville, Spain. E-mail: bolanos@us.es; Fax: +34 954624960;
Tel: +34 954550996
b Servicio de RMN, Universidad de Sevilla, Apartado 1152, E-41071,
Seville, Spain
Instituto de Investigaciones Quımicas ‘‘Isla de la Cartuja’’,
c
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CSIC-USE, Americo Vespucio 49, 41092, Seville, Spain
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w Electronic supplementary information (ESI) available: Experimental
details, NMR spectra, X-ray structures showing unit cells of
compounds 6–8. CCDC 816969–816971. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c1cc11345c
Scheme 1
c
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Chem. Commun., 2011, 47, 5617–5619 5617

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Fig. 1 ORTEP drawing of 6.
Scheme 3
conditions commonly used for reducing oximes. Surprisingly,
the expected N-alkyloxy-N-(2-haloethyl)amines
4 and 5
The presence of a haloalkyl moiety in compounds 6–8
makes them suitable for being transformed into a variety
of derivatives; compound 7 was subjected to nucleophilic
displacement of the chlorine atom with sodium azide in
DMF to give a separable mixture of cyanoboronated derivative
12 (53%) and benzyloxyamine 11 (22%), obtained by a partial
deboronation reaction.
were obtained as minor compounds after chromatographic
purification (the volatile methoxy derivative was not isolated).
The hitherto unknown zwitterionic N-cyanoboronated-N-
alkoxyamines 6–8 were isolated as the major compounds
(29–62%), obtained as crystalline derivatives stable to air
and silica purification. To our knowledge, no boronated
derivatives have been previously reported in the reduction of
O-alkyloximes with boron-containing reducing agents.
Boronated derivatives 6–8 were characterized by NMR
spectroscopy, including 11B-NMR, MS, and single crystal
X-ray crystallographyz (Fig. 1 depicts ORTEP drawing of 6
showing thermal ellipsoids at the 50% probability level).
1H-NMR spectra of compounds 6–8 showed a broad signal
located at roughly 2 ppm, and associated to the BH2CN
protons; furthermore, the benzylic protons of 7 and 8
appeared as diastereotopic signals, due to the chiral nitrogen.
11B-NMR spectra of 7 exhibited a broad triplet at ꢀ21 ppm,
with a coupling constant of 90 Hz, which agrees with the
proposed structure. X-Ray diffraction structures of 6–8
confirmed that they crystallize as racemic compounds.
Remarkably, cyanoboronated N-benzyloxy-N-(2-haloethyl)-
formamidines 9 and 10 were also isolated in modest yields
(8% and 6%, respectively) upon reduction of 2 and 3
(Scheme 1). The high coupling constants between the protons
of the amidino group (16.2 and 15.9 Hz, respectively) indicate
a trans arrangement of such protons. No previous reports on
cyanoboronated amidines can be found in the literature.
We postulate that the formation of formamidine derivatives
can take place by reaction of the cyanoborohydride anion with
cyanoborane (Scheme 2) to afford adduct 13; further reaction
with acetic acid can lead to the intermediate 16, which can be
trapped by N-alkoxyamines 4 and 5 to furnish formamidines 9
and 10.
We have also explored the ability of cyanoboronated
N-alkoxyamines to behave as new boron transfer agents
towards amines; for that purpose we chose as model compounds
cyanoboronated benzyloxyamines
7 and 8, which were
subjected to reaction with benzylamine and tetra-O-acetyl-b-
D-glucosamine under mild conditions to give 18 and 19 in a
57–93% yield (Scheme 3). Alkoxyamine cyanoborane 7 was
regenerated (63% yield) by treatment of 4 with sodium
cyanoborohydride in acetic acid. The number of amino-
boranes derived from carbohydrates is scarce, limited to
oxazaborolidine13 and cyanoborane-nucleoside adducts.10
These results suggest that cyanoboronated N-alkoxyamines
act as effective cyanoborane transfer agents probably due to
the lower basicity of alkoxyamines compared to amines. The
reaction can be performed at rt, in contrast with reported
procedures involving the use of other transfer agents in
refluxing diethyl ether or dimethoxyethane.14
We have also accomplished the preparation of neoglyco-
conjugates 20–25 from cyanoboronated N-benzyloxyamines 7,
8 and 12 by an N-glycosylation reaction with D-glucose,
D-xylose and D-galactose in methanolic acetic acid (Scheme 4).
The distribution of isomeric N-glycosides was found to be
dependent on the nature of the carbohydrate.
Such a chemoselective reaction, originally developed by
Peri and co-workers15 and currently known as neoglyco-
randomization,16 is a very robust glycosylation methodology
Scheme 2
Scheme 4
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5618 Chem. Commun., 2011, 47, 5617–5619
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which involves treatment of an alkoxyamine with a non-
activated reducing sugar. We have simplified the original
conditions used by Peri, by replacing DMF and the acetic/
acetate buffer by greener MeOH and catalytic amounts of
glacial acetic acid to furnish the corresponding b-glycopyranosides
20–23 in a totally stereoselective fashion in short reaction
times and from good to almost quantitative yields (55–94%),
starting from D-glucose or D-xylose and cyanoboronated
N-alkoxyamines 7, 8 and 12 (Scheme 4).
In conclusion, we have developed a novel procedure for the
preparation of the hitherto unknown cyanoboronated
N-alkoxyamines by reduction of O-alkyloximes with sodium
cyanoborohydride in acetic acid. Title compounds were
efficiently used as cyanoborane transfer agents towards
aliphatic amines, including aminosugars under mild conditions.
The novel and efficient preparation of N-glycosides from
cyanoboronated N-alkoxyamines under glycorandomization
conditions is also reported.
Similarly, by coupling D-galactose with 7, a separable
mixture of b-D-galactopyranoside 24 (52%) and b-D-galacto-
furanoside 25 (9%) was obtained (Scheme 4); remarkably, no
equilibration was observed in solution.
We thank the Direccio
(CTQ2008 02813 and Integrated Action HI-2006-0131) and
Junta de Andalucı (FQM 134) for financial support.
n General de Investigacion of Spain
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J.M.M. and E.M.-C. thank MICINN for grants.
The syntheses of N-glycosides 20–25 constitute the first
examples of cyanoboronated N-alkoxyamines being transformed
into N-glycosides via the neoglycorandomization reaction; the
outcome of the reaction proved to be compatible with alkoxy-
amines bearing a cyanoborane moiety and a variety of
functional groups such as halides and azido.
Notes and references
z Crystal data for 6: C4H10BClN2O,
M
6.5034(6) A,
=
c
148.40, triclinic,
= 9.6048(9) A,
a
=
6.2785(6) A,
b
=
a = 83.088(3)1, b = 87.368(4)1, g = 78.440(3)1, V = 381.34(6) A3,
T = 173(2) K, space group P1, Z = 2, m(MoKa) = 0.424 mmꢀ1, 6575
ꢀ
reflections measured, 2301 independent reflections (Rint = 0.0335).
The final R1 values were 0.0405 (I > 2s(I)). The final wR(F2) values
were 0.0956 (I > 2s(I)). The final R1 values were 0.0566 (all data). The
final wR(F2) values were 0.1140 (all data). The goodness of fit on F2
was 1.095. Crystal data for 7: C10H14BClN2O, M = 224.49, mono-
clinic, a = 9.5051(4) A, b = 12.3772(5) A, c = 9.9685(4) A,
a = 90.001, b = 92.1500(10)1, g = 90.001, V = 1171.93(8) A3, T =
The same kind of reaction was assayed on non-boronated
alkoxyamine 4 (Scheme 4), obtained either by reduction of 2,
as indicated in Scheme 1, or by removal of the cyanoborane
moiety of 7 by refluxing in aqueous THF. For D-mannose, a
non-separable mixture of a- and b-D-mannopyranosides 26, 27
and a-D-mannofuranoside 28 were obtained in a 2 : 2 : 1 ratio
and in a 76% yield after chromatographic purification.
The same ratio was obtained starting from alkoxyamine
cyanoborane 7.
173(2) K, space group P2(1)/c, Z = 4, m(MoKa) = 0.300 mmꢀ1
,
=
33074 reflections measured, 3579 independent reflections (Rint
0.0320). The final R1 values were 0.0317 (I > 2s(I)). The final
wR(F2) values were 0.0851 (I > 2s(I)). The final R1 values were
0.0412 (all data). The final wR(F2) values were 0.0893 (all data). The
goodness of fit on F2 was 1.047. Crystal data for 8: C10H14BBrN2O,
M = 268.95, monoclinic, a = 9.6308(3) A, b = 12.4411(4) A,
c = 9.9555(4) A, a = 90.001, b = 92.716(2)1, g = 90.001, V =
1191.51(7) A3, T = 173(2) K, space group P2(1)/c, Z = 4, m(MoKa) =
We have also extended the previous reactions to carbo-
hydrate-derived alkoxyamines. In this context, reaction
of partially-protected xylo-configured aldehyde 29 with
BnONH2ꢁHCl afforded the corresponding oxime 30
(Scheme 5) as a stereoisomeric 2 : 1 E/Z mixture (87% yield).
NaBH3CN-mediated reduction of 30 using the same conditions
as indicated in Scheme 1 furnished a separable mixture of
alkoxyamine 31 and alkoxyamine cyanoborane 32 (5 : 1
diastereoisomeric ratio) in almost quantitative overall yield
(68% and 22%, respectively). No formamidine was detected.
Coupling of 31 with reducing sugars (D-glucose, D-xylose
and D-galactose) under glycosylation conditions led to the
3.425 mmꢀ1
reflections (Rint
,
15111 reflections measured, 3094 independent
=
0.0399). The final R1 values were 0.0369
(I > 2s(I)). The final wR(F2) values were 0.0736 (I > 2s(I)). The
final R1 values were 0.0632 (all data). The final wR(F2) values were
0.0829 (all data). The goodness of fit on F2 was 1.025.
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Scheme 5
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 5617–5619 5619