Investigation of benzoyloximes as benzoylating reagents: Benzoyl-Oxyma as a selective benzoylating reagent

Article abstract of DOI:10.1039/c5ob02092a

Hydroxybenzotriazole (HOBt) and HOBt-derived reagents have been classified as Class I explosives, with restrictions on their transportation and storage. We explored a range of benzoylated oxime-based reagents as alternatives to benzoyloxybenzotriazole (BBTZ) for the selective benzoylation of carbohydrate polyols. Benzoylated oximes derived from 2-hydroximino-malononitrile, ethyl 2-hydroximino-2-cyanoacetate (Oxyma), and tert-butyl 2-hydroximino-2-cyanoacetate were most effective for benzoylation of a simple primary alcohol, with yields approaching that obtained for BBTZ. When applied to carbohydrate diols, the most effective reagent was identified as benzoyl-Oxyma. Benzoyl-Oxyma is a highly crystalline, readily prepared alternative to BBTZ, useful in the selective benzoylation of carbohydrate polyols.

Full text of DOI:10.1039/c5ob02092a

View Article Online
View Journal
Organic &
Biomolecular
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: S. Burugupalli, S.
Shah, P. L. van der Peet, S. Arora, J. M. White and S. J. Williams, Org. Biomol. Chem., 2015, DOI:
10.1039/C5OB02092A.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/obc

Page 1 of 24
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C5OB02092A
Investigation of benzoyloximes as benzoylating reagents: BenzoylꢀOxyma as a selective
benzoylating reagent
Satvika Burugupalli, Sayali Shah, Phillip L. van der Peet, Seep Arora, Jonathan M. White,
Spencer J. Williams*
School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of
Melbourne, Parkville, Victoria, Australia 3010
sjwill@unimelb.edu.au
Keywords: carbohydrates; benzoylation; safety; chemoselective; regioselective
1

Organic & Biomolecular Chemistry
Page 2 of 24
View Article Online
DOI: 10.1039/C5OB02092A
Abstract
Hydroxybenzotriazole (HOBt) and HOBtꢀderived reagents have been classified as Class I
explosives, with restrictions on their transportation and storage. We explored a range of
benzoylated oximeꢀbased reagents as alternatives to benzoyloxybenzotriazole (BBTZ) for the
selective benzoylation of carbohydrate polyols. Benzoylated oximes derived from 2ꢀ
hydroximinoꢀmalononitrile, ethyl 2ꢀhydroximinoꢀ2ꢀcyanoacetate (Oxyma), and tertꢀbutyl 2ꢀ
hydroximinoꢀ2ꢀcyanoacetate were most effective for benzoylation of a simple primary
alcohol, with yields approaching that obtained for BBTZ. When applied to carbohydrate
diols, the most effective reagent was identified as BenzoylꢀOxyma. BenzoylꢀOxyma is a
highly crystalline, readily prepared alternative to BBTZ, useful in the selective benzoylation
of carbohydrate polyols.
2

Page 3 of 24
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C5OB02092A
Introduction
Benzoic acid esters are a widely used hydroxyl protecting group for polyhydroxylated
substrates such as nucleosides, sugars, and inositols owing to their ease of introduction and
removal, and their stability to a wide range of reaction conditions.1, 2 In the context of
carbohydrate chemistry, benzoates can be used to alter stereoselectivity of glycosylations by
providing anchimeric assistance,3 and to attenuate reactivity according to the armed/disarmed
principle.4 The selective benzoylation of a polyol5 can be achieved by careful control of
reaction conditions6 and through use of a range of selective benzoylating reagents including
8
10, 12
benzoyl cyanide,7,
Nꢀbenzoyltetrazole,9ꢀ11 Nꢀbenzoylimidazole,9,
Mitsunobu
conditions,13 benzoyl chloride/collidine,14 and BzCl in combination with organotin reagents.15
However, depending on the substrate or reagent, various problems emerge including poor
solubility for many polyol substrates at the low temperatures sometimes required, high
toxicity, poor reactivity, and/or poor regioselectivity. Among the most reliable and widelyꢀ
used selective benzoylating reagent is the hydroxybenzotriazole (HOBt; 1) derived
benzoyloxybenzotriazole (BBTZ, 2), first introduced for this purpose by Kim and coꢀworkers
(Figure 1).16 BBTZ reacts under mild conditions with outstanding regioꢀ and
chemoselectivity that surpasses that of most other benzoylating reagents.17 The intrinsically
high regioselectivity of benzoylation with BBTZ has been harnessed in the use of BzOH with
the HOBtꢀderived ammonium salt TBTU (3),18 which ostensibly proceeds through a BBTZ
intermediate.
3

Organic & Biomolecular Chemistry
Page 4 of 24
View Article Online
DOI: 10.1039/C5OB02092A
N
N
O
O
N
N
N
N
OH
PF6
N
N
N
N
O
N
TBTU (3)
benzoyloxybenzotriazole
HOBt (1)
2
)
(BBTZ;
O
O
O
N
N
N
N
N
OH
O
N
N
N
N
O
PF6
PF6
N
X
N
O
O
O
HDMA (4): X = N
HDMB (5): X = CH
Oxyma (6)
COMU (7)
Figure 1. Benzotriazoleꢀ and Oxymaꢀbased reagents.
In recent years, the safety of HOBt has been called into question. HOBt and its
monohydrate are classified as Class 1 explosives, with significant limitations on their
transport and storage.19 Safety concerns extend to HOBtꢀderivatives such as TBTU (3),19
HDMA (4)20 and HDMB (5) (Figure 1).20 Against this backdrop, various oximeꢀbased
alternatives have emerged as viable alternatives to HOBt as nucleophilic catalysts in peptide
couplings. In particular ethyl 2ꢀhydroximinoꢀ2ꢀcyanoacetate (Oxyma, OxymaPure, 6) has
been identified as a viable alternative to HOBt,21 and has been elaborated to the uroniumꢀtype
22
coupling reagent COMU (7),20,
which is effective for both peptide couplings20 and
esterifications.18, 23 Both Oxyma and COMU show a better safety profile than HOBt and
HOBtꢀbased reagents, including a lower heatflow associated with smaller increases in
temperature and lower released pressures, equating to a lower risk of runaway thermal
explosions.20, 21 In this work we report the synthesis of a range of benzoylated oximes and
investigation of their ability to act as selective benzoylating reagents. BenzoylꢀOxyma is
identified as a readily synthesized, highly crystalline and storable alternative for BBTZ in the
regioꢀ and chemoselective acylation of carbohydrate alcohols.
4

Page 5 of 24
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C5OB02092A
Results and Discussion
1. Design and synthesis of oximeꢀbased benzoylating reagents
Initially we sought to explore a range of benzoylated oximeꢀbased reagents varying in the
nature of the electronꢀwithdrawing groups adjacent to the oxime. It has been found that
Oxyma (6) can undergo sideꢀreactions at the ethoxylcarbonyl group.21, 24 Therefore we also
studied the tertꢀbutyl ester 8 (derived from tertꢀbutyl cyanoacetate)25 and the bisꢀnitrile 9
(derived from malonitrile) (Table 1).26 In order to complete the series we included the bisꢀ
ethoxycarbonyl derivative 10 (derived from diethyl malonate).27 Several analogues of COMU
have been reported to provide improved peptide couplings, most notably based on oximes 11
(derived from Meldrum's acid)28 and 12 (derived from dimethylbarbituric acid),29 which were
also included in our studies. Oximes 6, 10ꢀ12 or the corresponding silver salts of 8 and 9,
were converted to benzoylated derivatives 13, 14, 15,26 16,30 17 and 18 by treatment with
benzoic anhydride (Bz2O) in ether, or using BzCl and pyridine or Et3N. Among these
examples, we highlight the exceptionally simple preparation of BenzoylꢀOxyma (13):
addition of Bz2O to a 0.3 M solution of Oxyma in Et2O resulted in the formation of a
precipitate within 1 min. Filtration and drying provided the pure reagent. This result stands in
contrast with the preparation of BBTZ (2): commercial HOBt containing 20% water can
either be dried under vacuum (caution: explosion risk) or alternatively stirred with activated
molecular sieves, prior to reaction with BzCl and Et3N.16 Following aqueous workup, the
reagent may, with some difficulty, be crystallized from EtOAc/petrol, with the crystallization
likely complicated by the known interconversion of Oꢀ and Nꢀacyl isomers.31 In the case of
the esters 13 and 14 derived from unsymmetrical oximes, the stereochemistry about the
oxime double bond was defined as Z by single crystal Xꢀray diffraction analysis (Figure 2).
Table 1. Oximes and their benzylated derivatives. pKa values and preparation.
5

Organic & Biomolecular Chemistry
Page 6 of 24
View Article Online
DOI: 10.1039/C5OB02092A
Oxime
pKa value
Benzoylꢀoxime
Methoda
Yield (%)
4.32
A
90
4.39
C
65
4.0932
C
D
64
78
4.32
3.96
4.46
D
B
80
83
a Method A: Bz2O, Et3N, Et2O; Method B: Bz2O, Et3N, CH2Cl2; Method C: BzCl, pyr,
CH2Cl2; Method D: BzCl, Et3N, CH2Cl2.
6

Page 7 of 24
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C5OB02092A
Figure 2. ORTEP representations of the molecular structures of benzoylated oximes a) 13
and b) 14, determined by singleꢀcrystal Xꢀray crystallography. Ellipsoids are at the 50%
probability level.
While simple oximes possess pKa values of 8.3ꢀ11.8,33 Oxyma (6) is characterized by
the presence of strongly electronꢀwithdrawing cyano and ethoxycarbonyl groups. The pKa
value of Oxyma is reported to be 4.6,34 matching that reported for HOBt (1).35 In order to
understand the leaving group ability of various oximes we initially sought to extract pKa data
from the literature; however, owing to the range of different solvents used for these studies
we were unable to directly compare the various oximes. Consequently, we measured the pKa
values for the series of compounds by spectrophotometric titration of the oximes in a solution
in 95% MeCN in water.32 As revealed in Table 1, the pKa values for the series of oximes fell
within the range 3.96ꢀ4.39, and under these conditions the pKa value of HOBt was
determined to be 4.25; based on their pKa values, the series of oximes possess similar
intrinsic leaving group ability.
2. Investigation of the benzoylation of a simple primary alcohol
The effectiveness of the benzoylated oximes as benzoylating agents was investigated by
studying their reaction with a simple alcohol, 4ꢀphenylbenzyl alcohol 19 (Table 2). This
substrate was chosen as it is crystalline, easily dried and readily detected owing to the
7

Organic & Biomolecular Chemistry
Page 8 of 24
View Article Online
DOI: 10.1039/C5OB02092A
presence of a chromaphore. Treatment of 19 with 1.1 equiv. of BBTZ (2) and Et3N at 0 °C
and warming to room temperature overnight afforded the benzoate 20 in quantitative yield
(entry 1), highlighting the impressive benzoylating ability of this reagent. Treatment with 1.1
equiv. of the nitrileꢀcontaining reagents 13ꢀ15 gave yields of 95ꢀ98% (entries 2ꢀ4).
Significantly, we found that for optimal yields using BenzoylꢀOxyma 13, use of dry Et3N was
critical, as using undried Et3N only afforded an 80% yield. This sensitivity to trace moisture
appears to be unique to the Oxymaꢀderived reagent as close to quantitative yields were
obtained with the tꢀbutyl ester 14, dicyanooxime 15 and BBTZ using undried Et3N, results
that suggest that the carbonyl group of the Oxymaꢀderived 13 may be a site of unwanted
reactivity. On the other hand the malonateꢀderived reagents 10ꢀ12 gave much poorer yields.
The diethyl malonate derivative 10 provided just 50% after 5 d, with tlc evidence of both
unreacted 10 and 19 (entry 5); the Meldrum's acid derivative 11 delivering only 2% (entry 6),
accompanied by degradation of the reagent to materials that could not be identified; and the
barbiturate 12 providing only a 15% yield (entry 7). In the last case, the major byꢀproduct
was tentatively assigned as the addition product 21. Overall, these results reveal that despite
similarity in the pKa value of the conjugate acid of the leaving group, significant differences
in reactivity occur across the series.
Table 2. Comparison of benzoylation of 4ꢀphenylbenzyl alcohol (19) by BBTZ and various
benzoyl oximes.
entry
reagent
yield (%)a
100
1
2
BBTZ (2)
80 (95)b
BenzoylꢀOxyma (13)
8

Page 9 of 24
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C5OB02092A
3
4
5
6
7
98
95
50c
2
14
15
16
17
18
15
a Reactions performed using Et3N as received.
b Reaction using Et3N dried by distillation over CaH2.
c Yield after 5 days. At this time the reaction still contained unreacted 4 and 19.
Securing exclusive nucleophilic attack at the carbonyl of the oximeꢀester for these
reagents, which contain multiple electrophilic sites at the oxime imino group and the adjacent
nitrile/ester positions, is critical for highꢀyielding benzoylation. The isolation of the adduct 21
provides an indication of one of the alternative modes of reactivity. Despite considerable
effort, we were unable to convincingly identify any byꢀproducts derived from reaction at the
ethoxycarbonyl group of 13. ElꢀFahem, Albericio and coworkers demonstrated that Oxyma
undergoes reaction at the imino and ethoxycarbonyl groups when used as an additive in
peptide coupling .21 In the case of the Meldrum’s acid derived 17, tlc analysis revealed rapid
consumption of the reagent yet little product formation, and it appears likely that nucleophilic
attack at the dioxanedione carbonyl groups results in fragmentation of the reagent. The poor
reactivity of 16 is at odds with the pKa value of the conjugate acid of the leaving group;
however, we highlight that this reagent is the only nonꢀcrystalline compound of the series and
9

Organic & Biomolecular Chemistry
Page 10 of 24
View Article Online
DOI: 10.1039/C5OB02092A
we speculate that the two ethoxycarbonyl groups
α
system, affecting its conjugation and attenuating its reactivity.
3. Selective benzoylation of carbohydrate alcohols
to the oxime cause steric distortion of the
Having identified the nitrileꢀcontaining oximes 13ꢀ15 as the most effective benzoylating
reagents for a simple alcohol, we next turned our attention to the selective acylation of
carbohydrate diols. Typically, good acylation selectivity is observed for diols when one
hydroxyl group has a cisꢀdisposed vicinal oxygen, which is believed to result from the
presence of an intramolecular hydrogen bond that enhances the reactivity of the hydroxyl
group. Using the optimum protocol identified from Table 2, the benzoylation of galactoside
22 was studied (Table 3). Consistent with literature yields36 treatment of galactoside 22 with
BBTZ provided a quantitative yield of the 3ꢀbenzoate 23 (entry 1). Among the three nitrileꢀ
based reagents, the best yield of 23 was obtained for the Oxymaꢀderived reagent 13 (90%,
entry 2), which could be improved to a quantitative yield by using 1.4 equivalents of the
reagent. We next explored acylation of the glucoside 24. BBTZ afforded 25 in an 87% yield
(entry 5). The three nitrileꢀcontaining oximes 13ꢀ15 gave marginally lower yields, with the
best result obtained for the Oxymaꢀderived reagent (83%, entry 6). Increasing the amount of
the Oxymaꢀderived reagent to 1.4 equivalents provided 25 in an 89% yield, commensurate
with that obtained using 1.1 equivalents of BBTZ. We therefore conclude that the nitrileꢀ
based reagents are effective for selective acylation of diols, with the Oxymaꢀderived reagent
13 the most promising. Although these reagents are slightly less effective than BBTZ, use of
1.4 equiv. of 13 provides similar yields to that obtained using 1.1 equiv. BBTZ.
Table 3. Comparison of benzoylation of galactoside 22 (to the 3ꢀbenzoate 23) and glucoside
24 (to the 2ꢀbenzoate 25) by BBTZ and benzoyl oximes 13ꢀ15.
10

Page 11 of 24
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C5OB02092A
entry
substrate
reagent
yield (%)a
1
2
3
4
5
6
7
8
100
BBTZ
22
22
22
22
24
90 (100)b
90 (100)b
72 (90)b
87
BenzoylꢀOxyma (13)
14
15
BBTZ (1)
83 (89)b
75 (93)b
80 (93)b
24
24
BenzoylꢀOxyma (13)
14
15
24
a Reactions were performed using 1.1 equivalent of reagent, 1.2 equiv. dry Et3N in dry
CH2Cl2, 0 °C to rt overnight.
b Yield for reaction performed using 1.4 equiv of BenzoylꢀOxyma.
In view of the importance of selective hydroxyl functionalization in carbohydrate
chemistry, we explored several additional examples using BenzoylꢀOxyma (13) (Table 4).
Selectivity for a primary versus a secondary alcohol was demonstrated through the
benzoylation of the 4,6ꢀdiol 26 to afford the 6ꢀbenzoate 27 in 86% yield (entry 1), the 2,6ꢀ
diol 28 to afford the 6ꢀbenzoate 29 in 50% yield (entry 2), and the 2,4,6ꢀtriol 30 to afford the
6ꢀbenzoate 31 in 93% yield (entry 3), in each case using 1.4 equiv of 13. Two additional
transformations are noteworthy. Treatment of 2,4,6ꢀtriol 30 with 2.8 equivalents of 13
afforded 2,6ꢀdibenzoate 31 in 41%, with the greater reactivity of the 2ꢀposition relative to the
4ꢀposition a result of the cisꢀrelationship with the anomeric oxygen. Finally, treatment of
tetraol 33 with 2.2 equiv. of 13 directly provided the 3,6ꢀdibenzoate 34 in 55% yield.
11

Organic & Biomolecular Chemistry
Page 12 of 24
View Article Online
DOI: 10.1039/C5OB02092A
Table 4. Selective benzoylation of carbohydrate alcohols using BenzoylꢀOxyma (13).
entry
substrate
product
equivalents
of Benzoylꢀ
Oxyma
yield (%)a
OH
O
OBz
O
HO
BnO
HO
BnO
1
2
1.4
1.4
86
50
BnO
BnO
OMe
OMe
26
27
MeO
HO
OH
O
MeO
BzO
OH
O
O
O
O
O
OMe
STol
OMe
STol
28
OH
29
OBz
O
O
HO
HO
BnO
3
1.4
93
BnO
HO
HO
OMe
OMe
30
31
OH
O
OBz
HO
O
HO
BnO
4
5
2.8
2.2
41
55
BnO
HO
BzO
OMe
OMe
30
32
OH
O
OBz
O
HO
HO
HO
BzO
OPh
OPh
HO
HO
34
33
a Reactions were performed using the indicated equivalent of reagent, 1.2ꢀfold of dry Et3N in
dry CH2Cl2, 0 °C to rt overnight.
Conclusions
The classification of HOBt and related reagents as Class I explosives has provided an
impetus for the development of new reagents that allow similar transformations with a lower
risk of explosion. Oximeꢀbased reagents, particularly those based on Oxyma, have emerged
12

Page 13 of 24
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C5OB02092A
as effective alternatives for HOBt and have formed the basis of the development of COMU as
a replacement for HBTU and HDMB. In this work we have explored a range of oximeꢀbased
alternatives to the selective acylating reagent BBTZ, leading to the identification of the
nitrileꢀbased benzoates 13ꢀ15 as the most promising representatives. In particular, Benzoylꢀ
Oxyma (13) can be considered a viable alternative to BBTZ, featuring a facile preparation,
yields that approach those of BBTZ in various model reactions and a broad utility in the
selective benzoylation of various carbohydrates.
Acknowledgements
We thank the Australian Research Council (ARC) for financial support. SJW is an ARCꢀ
funded Future Fellow.
Experimental
General
Proton nuclear magnetic resonance spectra (1H NMR) and proton decoupled carbon nuclear
magnetic resonance spectra (13C NMR) were obtained in deuterated chloroform, methanolꢀd4
(CD3OD) and DMSOꢀd6 with residual protonated solvent as internal standard. Abbreviations
for multiplicity are s, singlet; d, doublet; t, triplet; q, quartet; p, pentet. Flash chromatography
was carried out on silica gel 60 according to the procedure of Still et al.37 IR spectra were
obtained as thin films or solids on a Fourierꢀtransform attenuated total reflectance infrared
spectrophotometer equipped with a diamondꢀcoated zinc selenide sample accessory.
Analytical thin layer chromatography (t.l.c.) was conducted on aluminiumꢀbacked 2 mm
thick silica gel 60 GF254 and chromatograms were visualized with ceric ammonium
molybdate (Hanessian's stain) or orcinol/FeCl3 (Bial’s reagent). High resolution mass spectra
(HRMS) were obtained by ionizing samples using electroꢀspray ionization (ESI) and a timeꢀ
13

Organic & Biomolecular Chemistry
Page 14 of 24
View Article Online
DOI: 10.1039/C5OB02092A
ofꢀflight mass analyzer. Dry DMF was obtained by drying over 4 Å molecular sieves.
Hexanes refers to petroleum ether, boiling range 40ꢀ60 °C. CH2Cl2 and THF were dried over
alumina according to the method of Pangborn et al.38 Oxyma (ethyl hydroximino
cyanoacetate, 6) was purchased from SigmaꢀAldrich. The synthesis of various oximes and
oxime benzoates has been reported previously: 8,25 9,26 10,27 11,28 12,29 15,26 and 16.30
Ethyl benzoyloximino cyanoacetate (BenzoylꢀOxyma, 13)
A mixture of benzoic anhydride (2.21 g, 8.44 mmol) and Oxyma (6) (1.00 g, 7.04 mmol) in
dry diethyl ether (25 mL) was stirred at room temperature for 1 min. The resulting precipitate
was filtered and washed with cold petroleum ether to afford 13 as a white crystalline powder
(1.50 g, 90%), m.p 99.3 °C (lit.39 100 °C); 1H NMR (CDCl3, 400 MHz) δ 1.43 (3 H, t, J 7.1
Hz, CH3), 4.50 (2 H, q, J 7.1 Hz, CH2), 7.54–8.21 (5 H, m, Ph); 13C NMR (CDCl3, 100 MHz)
14.1 (CH3), 64.6 (CH2), 107.1 (C=N), 125.8 (C≡N), 129.2, 130.6, 131.7, 135.2 (Ph), 157.0
(C=O), 160.7 (C=O); IR
ν 2988.1, 2200.2, 1776.1, 1752.3, 1599.1, 1583.7, 1451.9, 1368.7,
1297.3, 1233.3, 1179.0, 1146.7, 1110.4, 1077.1, 1031.0, 996.2, 904.4, 837.5, 801.6, 764.9,
709.2, 666.5 cmꢀ1; HRMS [M+Na]+ calcd for C12H10N2O4Na m/z 269.0533, found 269.0532.
tꢀButyl benzoyloximino cyanoacetate (14)
A solution of sodium nitrite (2.93 g, 42.5 mmol) in water (13 mL) was added to a solution of
tꢀbutyl cyanoacetate (2.00 g, 14.1 mmol) in acetic acid (6 mL) and water (6 mL) at 0 °C. The
solution was stirred at room temperature for 12 h in the dark. A solution of AgNO3 (2.40 g,
14.1 mmol) in water (13 mL) was added and stirred for 30 min. The resulting yellow
precipitate was collected by filtration, washed with cold petroleum ether, and dried under
vacuum (3.57 g, 70%). BzCl (0.554 g, 3.94 mmol) was added to a stirred solution of the
yellow precipitate (1.00 g, 3.58 mmol) in toluene (7.5 mL). A drop of pyridine was added to
14

Page 15 of 24
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C5OB02092A
the solution resulting in the rapid formation of a white precipitate. Stirring was continued for
another 30 min and then the precipitate was collected by filtration. The filtrate was
concentrated and the residue recrystallized to afford 14 as a white crystalline solid (0.62 g,
65%), m.p. 72.5–73.5 °C (ether/petroleum ether); 1H NMR (CDCl3, 400 MHz) δ 1.63 (9 H,
s), 7.55–8.21 (5 H, m, Ph); 13C NMR (CDCl3, 100 MHz) 27.0, 87.4, 107.4, 125.7, 128.9,
130.3, 132.6, 134.8, 155.2, 160.6; IR
ν 3679.5, 2984.8, 2938.9, 2844.3, 2238.0, 1978.2,
1928.0, 1841.7, 1778.1, 1730.8, 1598.1, 1449.1, 1347.5, 1259.5, 1224.9, 1175.7, 1141.2,
1028.8, 989.8, 901.6, 843.0, 701.9, 665.7 cmꢀ1; HRMS [M+Na]+ calcd for C14H14N2O4Na m/z
297.0846, found 297.0847.
Benzoate ester of isonitroso Meldrum's acid (17)
Isonitroso Meldrum's acid 1128 (0.500 g, 2.89 mmol) was dissolved in CH2Cl2 (7 mL) and
Et3N (0.44 mL, 3.16 mmol) was added, followed by addition of BzCl (0.34 mL, 2.9 mmol).
The solution was stirred for 1 h, then diluted with CH2Cl2 (35 mL) and stirred for another 5
min. The solution was washed with water (2
× 20 mL), dried (MgSO4), filtered and
concentrated under reduced pressure. Flash chromatography (5ꢀ10% EtOAc/petroleum ether)
afforded 17 as a brown solid (1.50 g, 70%), m.p. 108.5–109 °C; 1H NMR (CDCl3, 400 MHz)
δ 1.87 (6 H, s, CH3), 7.55–8.27 (5 H, m, Ph); 13C NMR (CDCl3, 100 MHz) 28.4, 46.0, 106.8,
126.2, 129.0, 129.2, 130.7, 131.0, 134.6, 135.1, 139.2, 150.9, 155.7, 161.3, 162.5; IR
ν
3750.7, 2943.4, 1778.5, 1749.4, 1589.9, 1556.2, 1493.8, 1453.1, 1396.4, 1384.2, 1293.3,
1264.7, 1230.0, 1198.3, 1181.8, 1159.3, 1055.4, 1032.0, 1011.9, 982.3, 969.9, 949.0, 930.9,
891.0, 864.9, 798.8, 739.0, 701.8, 677.7, 667.1 cmꢀ1; HRMS [M+Na]+ calcd for
C13H11NO6Na m/z 300.0479, found 297.0478.
Benzoate ester of isonitroso dimethylbarbituric acid (18)
15

Organic & Biomolecular Chemistry
Page 16 of 24
View Article Online
DOI: 10.1039/C5OB02092A
Benzoic anhydride (0.70 g, 2.97 mmol) was added to a solution of isonitroso
dimethylbarbituric acid 1229 (0.500 g, 2.70 mmol) in dry Et2O (12.5 mL) and the solution was
stirred overnight at room temperature. The resulting precipitate was filtered and washed with
cold petroleum ether. The product was obtained as a green solid (0.65 g, 83%), m.p. 218.5–
219 °C; 1H NMR (CDCl3, 400 MHz) δ 3.45 (3 H, s, CH3), 3.47 (3 H, s, CH3), 7.54–8.33 (5 H,
m, Ph); 13C NMR (CDCl3, 100 MHz) 29.0, 29.5, 31.0, 126.5, 129.1, 130.9, 134.9, 161.7; IR
3000.1, 1949.2, 1773.7, 1686.0, 1447.8, 1367.7, 1283.3, 1234.9, 1070.9, 1014.7, 994.2,
970.3, 924.2, 866.2, 793.4, 746.3, 716.5 cmꢀ1; HRMS [M+Na]+ calcd for C13H11N3O5Na m/z
312.0591, found 312.0595.
ν
Protocol for benzoylation of 4ꢀphenylbenzyl alcohol (19)
A mixture of 4ꢀphenylbenzyl alcohol (19) (0.100 g, 0.542 mmol), 1.1 equivalents of the
benzoylating reagent and Et3N (0.091 mL, 0.650 mmol) in dry CH2Cl2 (3.0 mL) at 0 °C was
stirred overnight. The solution was diluted with CH2Cl2, washed with water (2 × 20 mL),
dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by
flash chromatography (10–15% EtOAc/petroleum ether) to afford 4ꢀphenylbenzyl benzoate
1
20 as a white solid, m.p. 62–63 °C (lit.40 61.5–62.5 °C); H NMR (CDCl3, 400 MHz) δ 5.42
(2 H, s, CH2), 7.34–8.12 (15 H, m, Ph); 13C NMR (CDCl3, 100 MHz) 66.6 (CH2), 127.2,
127.5, 127.6, 128.5, 128.9, 129.8, 130.2, 133.2, 135.1, 140.8, 141.3 (Ph), 166.6 (C=O);
HRMS [M+Na]+ calcd for C20H16O2Na m/z 311.1043, found 311.1042.
Characterization data for adduct of benzoate ester of isonitroso dimethylbarbituric acid
and 4ꢀphenylbenzyl alcohol, compound (21)
1H NMR (CDCl3, 400 MHz) δ 3.01 (3 H, s, Me), 3.05 (3 H, s, Me), 5.29 (1 H, d, J 12 Hz,
CH2), 5.41 (1 H, d, J 12 Hz, CH2), 7.42–7.85 (14 H, m, 2
×
Ph, C6H4); 13C NMR (CDCl3, 100
16

Page 17 of 24
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C5OB02092A
MHz) δ 25.54, 26.15, 69.32, 82.3, 126.4, 127.2, 127.3, 127.4, 127.6, 127.7, 128.5, 128.8,
128.9, 129.0, 129.4, 129.2, 129.4, 132.8, 134.1, 140.4, 142.2, 155.9, 162.3, 164.8, 166.3;
HRMS [M+H]+ calcd for C26H23N3O6 m/z 474.1620, found 474.1659
Methyl 3ꢀ
O
ꢀbenzoyl 4,6ꢀ
O
ꢀbenzylideneꢀβꢀ
D
ꢀgalactopyranoside (23)
A mixture of methyl 4,6ꢀOꢀbenzylideneꢀβꢀ
Dꢀgalactopyranoside (22) (0.100 g, 0.354 mmol),
benzoylating reagent (1.1 equivalent), and Et3N (0.060 mL, 0.42 mmol) in dry CH2Cl2 (3.0
mL) at 0 °C was stirred overnight. The solution was diluted with CH2Cl2, washed with water
(2 × 20 mL), dried (MgSO4), filtered and concentrated under reduced pressure. Flash
chromatography (75–85 % EtOAc/petroleum ether) of the residue afforded the 3ꢀbenzoate 23
as a white solid, m.p. 163–164 °C (lit.36 m.p. 166–167 °C); [α]D +94 (c 1.0, CHCl3; lit.36 [α]D
1
+95); H NMR (CDCl3, 400 MHz) δ 2.34 (1 H, d, J 2.4 Hz, OH), 3.60ꢀ3.62 (4 H, m,
H5,CH3), 4.11 (1 H, dd, J 12.5, 1.7 Hz, H6), 4.18 (1 H, ddd, J 10.1, 7.8, 2.5 Hz, H2), 4.41–
4.36 (2 H, m, H1,6), 4.51 (1 H, d, J 3.6 Hz, H4), 5.15 (1 H, dd, J 10.1, 3.7 Hz, H3), 5.53 (1
H, s, PhCH), 7.29–8.12 (10 H, m, Ph) 13C NMR (CDCl3, 100 MHz) 57.4 (CH3), 66.7, 68.9,
69.1, 73.7, 74.3, 100.9, 104.2 (C1), 126.2, 128.1, 128.5, 128.9, 129.8, 130.0, 133.4, 137.7
(Ph), 166.6 (C=O); HRMS [M+H]+ calcd for C21H22O7Na m/z 409.1254, found 409.1254.
Methyl 2ꢀ
O
ꢀbenzoyl 4,6ꢀ
O
ꢀbenzylideneꢀαꢀ
D
ꢀglucopyranoside (25)
A mixture of methyl 4,6ꢀOꢀbenzylideneꢀαꢀ
D
ꢀglucopyranoside (24) (0.100 g, 0.354 mmol), 1.4
equivalents of the benzoylating reagent and Et3N (0.060 mL, 0.415 mmol) in dry CH2Cl2 (3.0
mL) at 0 °C was stirred overnight. The solution was diluted with CH2Cl2, washed with water
(2 × 20 mL), dried (MgSO4), filtered and concentrated under reduced pressure. Flash
chromatography (25–35 % EtOAc/petroleum ether) of the residue afforded the 2ꢀbenzoate 25
as a white solid, m.p.169–170 °C (169–170 °C); [α]D +108 (c 1.0, CHCl3; lit.16 [α]D +107);
17

Organic & Biomolecular Chemistry
Page 18 of 24
View Article Online
DOI: 10.1039/C5OB02092A
1H NMR (CDCl3, 400 MHz) δ 2.57 (1 H, s, OH), 3.40 (3 H, s, CH3), 3.63 (1 H, t, J 9.4 Hz,
H6), 3.80 (1 H, t, J 10.3 Hz, H6), 3.91 (1 H, ddd, J 9.8, 9.8, 4.7 Hz, H5), 4.34 (2 H, m, H3,4),
5.04 (1 H, dd, J 9.5, 3.8 Hz, H2), 5.08 (1 H, d, J 3.8 Hz, H1), 5.58 (1 H, s, PhCH), 7.36–8.13
(10 H, m, Ph); 13C NMR (CDCl3, 100 MHz) 55.7 (CH3), 62.2, 69.0, 69.1, 74.2, 81.6, 97.9,
102.2 (C1), 126.4, 128.5, 128.6, 129.4, 130.1, 133.5, 137.1 (Ph), 166.3 (C=O); HRMS
[M+H]+ calcd for C21H22O7Na m/z 409.1257, found 409.1260
Methyl 2,3ꢀdiꢀ
Oꢀbenzylꢀ6ꢀOꢀbenzoylꢀαꢀDꢀglucopyranoside (27)
A mixture of BenzoylꢀOxyma 13 (0.092 g, 0.374 mmol), methyl 2,3ꢀdiꢀOꢀbenzylꢀαꢀ
Dꢀ
glucopyranoside 2641 (0.100 g, 0.267 mmol) and Et3N (0.050 mL, 0.32 mmol) in dry CH2Cl2
(3.0 mL) at 0 °C was stirred overnight. The solution was diluted with CH2Cl2, washed with
water (2 × 20 mL), dried over (MgSO4), filtered and concentrated under reduced pressure.
Flash chromatography (30–40% EtOAc/petroleum ether) of the residue afforded 27 (0.11 g,
1
86%), m.p 77–79 °C (lit.42 75–77 °C); [α]D +35 (c 0.25, CHCl3; lit.42 [α]D +25); H NMR
(CDCl3, 400 MHz) δ 2.53 (1 H, d, J 2.9 Hz, OH), 3.40 (3 H, s, CH3), 3.53 (2 H, m, H4,5),
3.87 (2 H, m, H2,3), 4.51 (1 H, dd, J 12.1, 2.1 Hz, H6), 4.59–4.68 (3 H, m, H1,6,CH2), 4.77
(2 H, dd, J 11.6, 10.3 Hz, CH2Ph), 5.01 (1 H, d, J 11.3, CH2Ph), 7.28–8.02 (15 H, m, Ph); 13C
NMR (CDCl3, 100 MHz) 55.3, 63.8, 69.5, 70.2, 73.3, 75.7, 79.7, 81.3, 98.2 (C1), 128.0,
128.1, 128.2, 128.4, 128.6, 128.7, 129.8, 133.2, 138.0, 138.7 (Ph), 166.8 (C=O); HRMS
[M+Na]+ calcd for C28H30O7Na m/z 501.1884, found 501.1886
4ꢀMethylphenyl
3,4ꢀOꢀ(2',3'ꢀdimethoxybutanꢀ2',3'ꢀdiyl)ꢀ6ꢀOꢀbenzoylꢀ1ꢀthioꢀαꢀDꢀ
mannopyranoside (29)
A mixture of BenzoylꢀOxyma 13 (0.036 g, 0.146 mmol), 3,4ꢀdiꢀOꢀ(2,3ꢀdimethoxybutaneꢀ2,3ꢀ
diyl)ꢀαꢀ
D
ꢀmannopyranoside 2843 (0.042 g, 0.105 mmol), and Et3N (0.020 mL, 0.126 mmol) in
18

Page 19 of 24
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C5OB02092A
dry CH2Cl2 (3.0 mL) at 0 °C was stirred overnight. The solution was diluted with CH2Cl2,
washed with water (2 × 20 mL), dried over (MgSO4), filtered and concentrated under reduced
pressure. Flash chromatography (50–70% EtOAc/petroleum ether) of the residue afforded 29
as a syrup (0.030 g, 50%), [α]D +167.8 (c 0.25, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 1.30
(3 H, s, CH3), 1.34 (3 H, s, CH3), 2.27 (3 H, s, CH3Ar), 3.17 (3 H, s, OCH3), 3.32 (3 H, s,
OCH3), 4.07 (1 H, dd, J 9.1, 3.0 Hz, H2), 4.18–4.22 (2 H, m, H3,6), 4.49 (1 H, ddd, J 11.9,
6.1 Hz, H6), 4.55–4.65 (2 H, m, H4,5), 5.52 (1 H, s, H1), 6.98–8.01 (10 H, m, Ph); 13C NMR
(CDCl3, 100 MHz) 14.1 (CH3), 17.7 (CH3), 17.8, 21.2, 29.8, 48.1, 48.3, 63.0, 64.1, 64.7,
67.1, 69.7, 72.7, 87.1, 100.2, 100.5, 107.1, 125.8, 128.4, 128.54, 129.2, 129.7, 129.8, 130.0,
130.0, 130.7, 132.7, 133.1, 133.3, 135.3, 138.2, 157.1 (Ph), 160.7, 165.9, 166.4 (C=O);
HRMS [M+H]+ calcd for C26H32O8SNa m/z 527.1701 found 527.1705.
Methyl 3ꢀOꢀbenzyl 6ꢀOꢀbenzoylꢀαꢀDꢀglucopyranoside (31)
A mixture of BenzoylꢀOxyma 13 (0.121 g, 0.491 mmol), methyl 3ꢀOꢀbenzylꢀαꢀ
D
ꢀ
glucopyranoside 3044 (0.100 g, 0.351 mmol) and Et3N (0.060 mL, 0.421 mmol) in dry
CH2Cl2 (3.0 mL) at 0 °C was stirred overnight. The solution was diluted with CH2Cl2 washed
with water (2 × 20 mL), dried over (MgSO4), filtered and concentrated under reduced
pressure. Flash chromatography (40–50% EtOAc/petroleum ether) of the residue afforded 31
1
as a white solid (0.13 g, 55%), m.p 70–71 °C; [α]D +88.0 (c 1.0, CHCl3); H NMR (CDCl3,
400 MHz) δ 2.27 (1 H, d, J 8.3 Hz, OH), 2.83 (1 H, d, J 3.2 Hz, OH), 3.45 (3 H, s, CH3), 3.54
(1 H, ddd, J 9.1, 9.1, 2.3 Hz, H4), 3.63 (1 H, dd, J 8.4, 8.4 Hz, H3), 3.69 (1 H, ddd, J 9.1, 3.8
Hz, H2), 3.87 (1 H, ddd, J 9.8, 4.7, 2.2 Hz, H5), 4.52 (1 H, dd, J 12.1, 2.2 Hz, H6), 4.67 (1 H,
dd, J 12.1, 4.7 Hz, H6), 4.77–4.83 (2 H, m, H1, CH2), 4.98 (1 H, d, J 11.4, CH2), 7.29–8.08
(10 H, m, Ph); 13C NMR (CDCl3, 100 MHz) 55.4 (CH3), 63.7, 69.9, 69.9, 72.7, 75.3, 82.5,
19

Organic & Biomolecular Chemistry
Page 20 of 24
View Article Online
DOI: 10.1039/C5OB02092A
99.6 (C1), 120.3, 128.1, 128.5, 128.7, 129.8, 129.8, 133.3, 138.5 (Ph), 167.0 (C=O); HRMS
[M+H]+ calcd for C21H24O7 Na m/z 411.1414, found 411.1412.
Methyl 3ꢀOꢀbenzylꢀ2,6ꢀdiꢀOꢀbenzoylꢀαꢀDꢀglucopyranoside (32)
A mixture of BenzoylꢀOxyma 13 (0.194 g, 0.787 mmol), of methyl 3ꢀOꢀbenzylꢀαꢀ
Dꢀ
glucopyranoside 3044 (0.080 g, 0.281 mmol) and Et3N (0.05 mL, 0.337 mmol) in dry CH2Cl2
(3.0 mL) at 0 °C was stirred overnight. The solution was diluted with CH2Cl2, washed with
water (2 × 20 mL), dried over (MgSO4), filtered and concentrated under reduced pressure.
Flash chromatography (30–40% EtOAc/petroleum ether) of the residue afforded 32 as a
syrup (0.0600 g, 41%), [α]D +100.4 (c 0.5, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 3.42 (3 H,
s, CH3), 3.72 (1 H, t, J 9.1 Hz, H4), 3.98 (1 H, ddd, J 10.1, 4.4, 2.2 Hz, H5), 4.08 (1 H, t, J
9.0 Hz, H3), 4.56 (1 H, dd, J 12.1, 2.2 Hz, H6), 4.73–4.79 (2 H, m, H2,6), 4.88 (1 H, d, J 11.3
Hz, CH2Ph), 5.07–5.12 (2 H, m, H1,CH2Ph), 7.48–8.12 (10 H, m, Ph); 13C NMR (CDCl3,
100 MHz) 55.4 (CH3), 63.6, 69.7,70.4, 73.9, 75.5, 79.6, 82.5, 97.5, 99.6 (C1), 128.0, 128.1,
128.5, 128.6, 128.7, 129.7, 129.8, 129.9, 129.9, 130.2, 133.3, 133.4, 133.5, 138.1 (Ph), 160.0,
167.1 (C=O); HRMS [M+H]+ calcd for C28H28O8Na m/z 515.1676 found 515.1668.
Phenyl 3,6ꢀdiꢀOꢀbenzoylꢀβꢀDꢀglucopyranoside (34)
A mixture of BenzoylꢀOxyma 13 (0.210 g, 0.853 mmol), phenyl βꢀ
D
ꢀglucopyranoside 33
(0.100 g, 0.390 mmol) and Et3N (0.060 mL, 0.468 mmol) in dry CH2Cl2 (3.0 mL) at 0 °C was
stirred overnight. The solution was diluted with CH2Cl2, washed with water (2 × 20 mL),
dried (MgSO4), filtered and concentrated under reduced pressure. Flash chromatography (2–5
% acetone/CH2Cl2) of the residue afforded 34 as a white solid (0.11 g, 55%), m.p 144 °C;
[α]D +2.7 (c 0.5, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 2.81 (1 H, s, OH), 3.49 (1 H, s, OH),
3.83 (1 H, t, J 9.3 Hz, H4), 3.90 (1 H, ddd, J 9.7, 6.1, 2.3 Hz, H5), 4.00 (1 H, dd, J 9.1, 8.0
20

Page 21 of 24
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C5OB02092A
Hz, H2), 4.63 (1 H, dd, J 12.0, 6.1 Hz, H6), 4.74 (1 H, dd, J 12.0, 2.3 Hz, H6), 5.07 (1 H, d, J
7.7 Hz, H1), 5.33 (1 H, t, J 9.1 Hz, H3), 7.07–8.08 (15 H, m, Ph); 13C NMR (CDCl3, 100
MHz) 63.0, 69.7, 72.2, 74.6, 78.6 (C2,3,4,5), 101.0 (C1), 117.0, 123.2, 128.5, 128.6, 129.3,
129.6, 129.7, 129.9, 130.1, 133.4, 133.7, 157.0 (Ph), 166.9, 167.6 (C=O); HRMS [M+H]+
calcd for C26H24O8Na m/z 487.1363, found 487.1361.
Xꢀray crystallography
Crystals of 13 and 14 were mounted in low temperature oil then flash cooled using an Oxford
low temperature device. Intensity data were collected at 130 K on an Oxford SuperNova Xꢀ
ray diffractometer with CCD detector using CuꢀKα (α = 1.54184 Å) radiation. Data were
reduced and corrected for absorption. The structures were solved by direct methods and
difference Fourier synthesis using the SHELX suite of programs45 as implemented within the
WINGX software.46 Thermal ellipsoid plots were generated using the program ORTEPꢀ3.
Crystal data for 13: C12H10N2O4 M = 246.22, T = 130.0(1) K, λ = 1.54184, monoclinic,
space group P21/n, a = 11.8867(1), b = 8.0556(1), c = 12.3853(1) Å, β = 99.064(1), V =
1171.14(2) Å3, Z = 4, Dc = 1.396 g cmꢀ3, µ(CuꢀKα) 0.904 mmꢀ1, F(000) = 512, crystal size
0.49
× 0.44 × 0.32 mm. 8000 reflections measured, 2434 independent reflections (Rint =
0.0170), the final R was 0.0342 [I > 2 σ (I) 2347 data] and wR(F2) (all data) was 0.0966.
CCDC deposition: 1406156.
Crystal data for 14: C14H14N2O4 M = 274.27, T = 130.0(1) K, λ = 1.54184 Å, monoclinic,
space group P21/n, a = 5.9020(1), b = 21.5230(3), c = 11.2041(2) Å, β = 102.073(2)°, V =
1391.76(4) Å3, Z = 4, Dc = 1.309 g cmꢀ3, µ(CuꢀKα) 0.813 mmꢀ1, F(000) = 576, crystal size
0.50
× 0.15 × 0.06 mm. 9619 reflections measured, 2897 independent reflections (Rint =
0.0299), the final R was 0.0392 [I > 2 σ (I) 2605 data] and wR(F2) (all data) was 0.1018.
CCDC deposition: 1406157.
21

Organic & Biomolecular Chemistry
Page 22 of 24
View Article Online
DOI: 10.1039/C5OB02092A
Spectrophotometric titrations
Dissociation constants (pKa values) of the oximes or HOBt were measured
spectrophotometrically using a Caryꢀ50 Bio UV/Vis spectrophotometer in 95% (v/v) MeCNꢀ
water at wavelengths of 220ꢀ315 nm. Buffer solutions across the pH range of 2ꢀ10 were
prepared by adding 0.2 M NaOH to a mixture of 0.04 M phosphoric acid, acetic acid, and
boric acid. HOBt or oximes at 0.1 mM concentration were prepared in the buffer solutions
and the absorbance measured. Each cuvette contained 50 µl of 1 mM stock solution of oxime
or HOBt in MeCN, 100 µl of 40 mM buffer, and 1.85 mL of MeCN were used to obtain a
final concentration of 0.025 mM of the reagent. Absorbances were measured at the
wavelength where the maximum difference between the absorbance of the oxime or HOBt,
and its conjugate base. Titration curves are provided in the Supporting Information.
22

Page 23 of 24
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C5OB02092A
References
1.
2.
P. Wuts, Greene's Protective Groups in Organic Synthesis, John Wiley & Sons, New
York, 5th edn., 2014.
R. V. Stick and S. J. Williams, Carbohydrates: The Essential Molecules of Life,
Elsevier, Oxford: United Kingdom, 2009.
3.
4.
D. Crich, Z. Dai and S. Gastaldi, J. Org. Chem., 1999, 64, 5224ꢀ5229.
D. R. Mootoo, Konradsson, P., Udodong, U., and FraserꢀReid, B., J. Am. Chem. Soc.,
1988, 110, 5583ꢀ5584.
5.
A. H. Haines, in Adv. Carbohydr. Chem. Biochem., eds. R. S. Tipson and H. Derek,
Academic Press, 1976, vol. Volume 33, pp. 11ꢀ109.
6.
7.
8.
9.
10.
11.
J. M. Williams and A. C. Richardson, Tetrahedron, 1967, 23, 1369ꢀ1378.
A. Holý and M. Souček, Tetrahedron Lett., 1971, 12, 185ꢀ188.
S. A. Abbas and A. H. Haines, Carbohydr. Res., 1975, 39, 358ꢀ363.
F. A. Carey and K. O. Hodgson, Carbohydr. Res., 1970, 12, 463ꢀ465.
G. J. F. Chittenden, Carbohydr. Res., 1971, 16, 495ꢀ496.
J. Stawinski, T. Hozumi and S. A. Narang, J. Chem. Soc. Chem. Commun., 1976,
DOI: 10.1039/C39760000243, 243ꢀ244.
12.
13.
N. L. Holder and B. FraserꢀReid, Synthesis, 1972, 83.
O. Mitsunobu, J. Kimura, K.ꢀi. Iiizumi and N. Yanagida, Bull. Chem. Soc. Jpn., 1976,
49, 510ꢀ513.
14.
15.
16.
17.
18.
19.
20.
K. Ishihara, H. Kurihara and H. Yamamoto, J. Org. Chem., 1993, 58, 3791ꢀ3793.
S. David and S. Hanessian, Tetrahedron, 1985, 41, 643ꢀ663.
S. Kim, H. Chang and W. J. Kim, J. Org. Chem., 1985, 50, 1751ꢀ1752.
B. L. Wilkinson, Aust. J. Chem., 2013, 66, 910ꢀ912.
J. D. Twibanire and T. B. Grindley, Org. Lett., 2011, 13, 2988ꢀ2991.
K. D. Wehrstedt, P. A. Wandrey and D. Heitkamp, J. Hazard. Mater., 2005, 126, 1ꢀ7.
A. ElꢀFaham, R. S. Funosas, R. Prohens and F. Albericio, Chem. Eur. J., 2009, 15,
9404ꢀ9416.
21.
22.
23.
R. SubirosꢀFunosas, R. Prohens, R. Barbas, A. ElꢀFaham and F. Albericio, Chem.
Eur. J., 2009, 15, 9394ꢀ9403.
R. SubirósꢀFunosas, S. N. Khattab, L. NietoꢀRodríguez, A. ElꢀFaham and F.
Albericio, Aldrichimica Acta, 2013, 46.
B. Cao, X. Chen, Y. YamaryoꢀBotte, M. B. Richardson, K. L. Martin, G. N.
Khairallah, T. W. Rupasinghe, R. M. O'Flaherty, R. A. O'Hair, J. E. Ralton, P. K.
Crellin, R. L. Coppel, M. J. McConville and S. J. Williams, J. Org. Chem., 2013, 78,
2175ꢀ2190.
24.
25.
D. Dev, N. B. Palakurthy, N. Kumar and B. Mandal, Tetrahedron Lett., 2013, 54,
4397ꢀ4400.
G. Duguay, J.ꢀP. Guémas, J.ꢀC. Meslin, J.ꢀP. Pradère, F. Reliquet, A. Reliquet, C.
TeaꢀGokou, H. Quiniou and C. Rabiller, J. Heterocylic Chem., 1980, 17, 767ꢀ770.
J. Perrocheau, R. Carrié and J.ꢀP. Fleury, Can. J. Chem., 1994, 72, 2458ꢀ2467.
D. A. May and T. D. Lash, J. Org. Chem., 1992, 57, 4820ꢀ4828.
A. ElꢀFaham, R. SubirósꢀFunosas and F. Albericio, Eur. J. Org. Chem., 2010, 2010,
3641ꢀ3649.
26.
27.
28.
29.
30.
Y. E. Jad, S. N. Khattab, B. G. de la Torre, T. Govender, H. G. Kruger, A. ElꢀFaham
and F. Albericio, Org. Biomol. Chem., 2014, 12, 8379ꢀ8385.
A. I. Mishchenko, A. V. Prosyanik, P. N. Belov, V. A. Romanchenko, E. G. Belova
and V. I. Markov, Chem. Heterocyclic Compounds, 1984, 20, 270ꢀ274.
23

Organic & Biomolecular Chemistry
Page 24 of 24
View Article Online
DOI: 10.1039/C5OB02092A
31.
B. D. Brink, J. R. DeFrancisco, J. A. Hillner and B. R. Linton, J. Org. Chem., 2011,
76, 5258ꢀ5263.
32.
33.
M. F. Fathallah and S. N. Khattab, J. Chem. Soc. Pak., 2011, 33, 324ꢀ332.
M. Charton, in The Chemistry of Hydroxylamines, Oximes and Hydroxamic Acids,
eds. Z. Rappoport and J. F. Liebman, John Wiley & Sons, Ltd, 2008, DOI:
10.1002/9780470741962.ch12, pp. 553ꢀ608.
34.
35.
36.
M. Itoh, Bull. Chem. Soc. Jpn., 1973, 46, 2219ꢀ2222.
I. E. Pop, B. P. Deprez and A. L. Tartar, J. Org. Chem., 1997, 62, 2594ꢀ2603.
I. F. Pelyvás, T. K. Lindhorst, H. Streicher and J. Thiem, Synthesis, 1991, 1991, 1015ꢀ
1018.
37.
38.
W. C. Still, M. Kahn and A. M. Mitra, J. Org. Chem., 1978, 43, 2923ꢀ2925.
A. B. Pangborn, M. A. Giardello, R. H. Grubbs, R. K. Rosen and F. J. Timmers,
Organometallics, 1996, 15, 1518ꢀ1520.
39.
J.ꢀM. Biehler, J.ꢀP. Fleury, J. Perchais and A. Regent, Tetrahedron Lett., 1968, 9,
4227ꢀ4230.
40.
41.
42.
43.
M. Sawada, Y. Tsuno and Y. Yukawa, Bull. Chem. Soc. Jpn., 1972, 45, 1206ꢀ1209.
D. J. Bell and J. Lorber, J. Chem. Soc., 1940, DOI: 10.1039/JR9400000453, 453ꢀ455.
H. C. Jarrell and W. A. Szarek, Can. J. Chem., 1978, 56, 144ꢀ146.
Y. Zhang, C. Meng, L. Jin, X. Chen, F. Wang and H. Cao, Chem. Commun., 2015, 51,
11654ꢀ11657.
44.
45.
46.
J. M. Küster and I. Dyong, Liebigs Ann. Chem., 1975, 1975, 2179ꢀ2189.
G. Sheldrick, Acta Crystallogr. A, 2008, 64, 112ꢀ122.
L. J. Farrugia, J. Appl. Cryst., 1999, 32, 837ꢀ838.
24