Continuous flow-ultrasonic synergy in click reactions for the synthesis of novel 1,2,3-triazolyl appended 4,5-unsaturated l-ascorbic acid derivatives

Article abstract of DOI:10.1039/c6ra25244c

A combination of flow chemistry and batch-based synthetic procedures has been successfully applied to the assembly of novel 4,5-unsaturated l-ascorbic acid series 6a-6n with diverse C-6-substituted 1,2,3-triazole moiety. We report herein the first Cu(i)-catalyzed 1,3-dipolar cycloaddition of azido functionalized l-ascorbic acid derivative and selected alkynes to provide target 1,2,3-triazolyl appended 4,5-didehydro-5,6-dideoxy-l-ascorbic acid library 6a-6n under both micro-flow and batch conditions. Implementation of ultrasound with flow chemistry accelerated hour-scale reaction conditions in batch to the minute range in micro-flow device and considerably improved the yields for the flow syntheses of 6a-6n. Moreover, the synergistic use of microreactor technology and ultrasonic irradiation highlights the sustainable eco-friendly aspect of utilized method.

Full text of DOI:10.1039/c6ra25244c

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Continuous flow-ultrasonic synergy in click
reactions for the synthesis of novel 1,2,3-triazolyl
appended 4,5-unsaturated L-ascorbic acid
derivatives†
Cite this: RSC Adv., 2017, 7, 791
Andrijana Mescic,a Anita Sˇalic,b Tomislav Gregoric,a Bruno Zelicb and Silvana Raic-
ˇˇ ´
´
´
´
´
a
*
Malic
´
A combination of flow chemistry and batch-based synthetic procedures has been successfully applied to
the assembly of novel 4,5-unsaturated L-ascorbic acid series 6a–6n with diverse C-6-substituted 1,2,3-
triazole moiety. We report herein the first Cu(I)-catalyzed 1,3-dipolar cycloaddition of azido
functionalized L-ascorbic acid derivative and selected alkynes to provide target 1,2,3-triazolyl appended
4,5-didehydro-5,6-dideoxy-L-ascorbic acid library 6a–6n under both micro-flow and batch conditions.
Implementation of ultrasound with flow chemistry accelerated hour-scale reaction conditions in batch
to the minute range in micro-flow device and considerably improved the yields for the flow syntheses of
6a–6n. Moreover, the synergistic use of microreactor technology and ultrasonic irradiation highlights the
sustainable eco-friendly aspect of utilized method.
Received 14th October 2016
Accepted 7th November 2016
DOI: 10.1039/c6ra25244c
www.rsc.org/advances
butenolides exhibited most potent activity against breast cancer
cells and preliminary due to reactive oxygen species (ROS)
Introduction
generation, subsequent activation of p38, leading to apoptosis
and inhibition of cancer cells.7 Furthermore, several preclinical
and clinical trials on vitamin C have also supported its prom-
ising efficacy against a number of cancer types and low toxicity
of high-dose vitamin C, that has been demonstrated in anti-
cancer therapy.8
L-Ascorbic acid (AA) or vitamin C is known as a ubiquitous
carbohydrate of vital importance in the living beings. Since the
discovery of vitamin C, the number of its known biological
functions is continually expanding.1 Thus, it plays an important
role in a number of cellular processes, including collagen
synthesis, cellular oxidation, and as a cofactor in several
important hydroxylation reactions.2 AA is one of the most
important biomolecules, which protects cellular components
against oxidative damage caused by free radicals and oxidants
that are involved in the development of a multitude of chronic
diseases. Furthermore, some L-ascorbic acid derivatives showed
to be effective antitumoral agents,3 immunostimulants4 and
protecting agents against peroxidation of lipids of the bio-
membranes.5 In previous study we demonstrated that some
pyrimidine and purine derivatives of 4,5-didehydro-5,6-dideoxy-
and 6-deoxy-L-ascorbic acid exhibited selective and efficient
cytostatic activities and displayed antiviral activities against
varicella zoster virus (TK+VZV and TKꢀVZV) and cytomegalo-
virus (CMV).6 Structurally related g-(triazolyl ethylidene)
On the other hand, 1,2,3-triazoles have been the nuclei of
choice in recent years because of their excellent pharmaco-
kinetic characteristics, favourable safety prole, latent ability
for the formation of hydrogen bonds, moderate dipole char-
acter, rigidity and stability under in vivo conditions.9 There-
fore, triazole chemistry has recently received signicant
impulse from the pioneering work of Sharpless and Meldal on
Cu(I)-catalyzed alkyne–azide cycloaddition (CuAAC).10 The
CuAAC reaction has become the cream of the crop for click
chemistry and has been broadly used in many areas of
modern chemistry, such as polymer and materials sciences,11
supramolecular chemistry,12 bioconjugation,13 and combina-
torial chemistry.14 This reaction is also signicant from the
viewpoint of drug discovery,15 because 1,2,3-triazoles possess
a wide range of biological properties, such as anticancer,16
antiviral,17 antibacterial18 and antifungal activities.19 There-
fore, the 1,2,3-triazole moiety is extensively used in medicinal
chemistry as a pharmacophore to modify known bioactive
molecules and to potentiate their biological activities.9a,20
A growing effort has been devoted to the employment of
click chemistry for the synthesis of functionally diverse
aUniversity of Zagreb, Faculty of Chemical Engineering and Technology, Department of
´
Organic Chemistry, Marulicev trg 20, HR-10000 Zagreb, Croatia. E-mail: sraic@it.
hr; Fax: +385-1-4597260; Tel: +385-1-4597213
bUniversity of Zagreb, Faculty of Chemical Engineering and Technology, Department of
Reaction Engineering and Catalysis, Savska cesta 16, HR-10000 Zagreb, Croatia
† Electronic supplementary information (ESI) available: 1H and 13C NMR spectra
of 6a–6n, and 2D NMR spectra of 6a and 6n, HPLC chromatograms for micro-ow
reactions of 6a–6n. See DOI: 10.1039/c6ra25244c
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carbohydrate derivatives as bioactive compounds and uo-
rescent glycoprobes.21
Although click reactions are traditionally conducted in batch
process, the progress toward increased sustainability that
requires novel approaches with reduced environmental impact
opened up in recent years continuous-ow as a novel alternative
to conventional batch-based synthesis.22 Flow chemistry tech-
nique performs a chemical reaction in a continuously owing
stream in a network of interconnecting tubes. The reagents
coming from different tubes are mixed together in the reactor to
start the chemical reaction. Due to its many advantages over
batch reaction processes, ow chemistry has become an
emerging eld in organic synthesis, and has recently been
employed to enhance the selectivity, safety, and efficiency of
chemical syntheses, including the rapid synthesis of natural
products and pharmaceuticals.23 Microreactor technology has
the potential to revolutionize the pharmaceutical industry
because the number of potential drug candidates that can be
prepared and screened can be considerably increased, hence
the likelihood of developing new drugs is considerably
enhanced.24 Besides being more economical and environmen-
Fig. 1 Synthesis of C-6-substituted 1,2,3-triazolyl 4,5-unsaturated L-
ascorbic acid derivatives 6a–6n utilizing ultrasonic (US)-assisted
continuous flow in click reactions.
and investigate both continuous ow-ultrasound and batch
approach for CuAAC reaction.
Results and discussion
Synthesis of the 1,2,3-triazolyl appended 4,5-unsaturated
L-ascorbic acid library under batch conditions
tally friendly, microreactor technology (MRT) is even more In order to synthesize C-6-substituted 1,2,3-triazolyl 4,5-didehy-
advantageous than the macroscopic batch reactor method, dro-5,6-dideoxy-L-ascorbic acid derivatives, synthetic trans-
mainly due to the high surface/volume ratio, reduced utilization formations of L-ascorbic acid that included selective protection
of reagents, and also better control over mass as well as heat and deprotection of 2,3- and 5,6-dihydroxyl groups were per-
transfer.25 Many previously challenging or hazardous reactions formed as described in the literature.31 Thus, 5,6-O,O-iso-
can now be safely and efficiently conducted in ow.26 In addi- propylidene-L-ascorbic acid (1) was synthesized via reaction of L-
tion, ow chemical synthesis can be performed under non- ascorbic acid with acetyl chloride, while the remaining C-2 and C-
classical reaction conditions, such as applying ultrasound and 3 hydroxyl groups of the lactone ring were protected by reaction
microwave irradiation, to signicantly improve efficiency of of compound 1 with benzyl chloride in the presence of potassium
reactions.27 It was demonstrated that the use of ultrasound, an carbonate to afford compound 2. To apply molecular hybridiza-
alternative green source of energy, to promote chemical reac- tion by coupling of L-ascorbic acid derivative with 1,2,3-triazole
tions allowed a decrease in the reaction time and side reactions. ring, we used the strategy that involved the functionalization of L-
On the other hand, with a well-dened inner micro-structure, ascorbic acid with an azide substituent at the C-6 (Scheme 1).
a microreactor provides an ideal environment to investigate Therefore, isopropylidene protection in 2 was removed in acidic
and control the acoustic cavitation process, which is the main condition to give compound 3 with free C-5 and C-6 hydroxyl
mechanism causing sonochemical effects.28 Although the functionalities, which were subsequently converted to tosylate, as
advantages of the continuous ow reactor technology for the a good leaving group, using p-toluenesulfonyl chloride (p-TsCl) in
synthesis of 1,4-disubstituted 1,2,3-triazoles over their batch pyridine. The 5,6-O,O-ditosyl derivative of L-ascorbic acid (4) was
reaction counterparts have been demonstrated recently29 used as the parent compound for the preparation of the C-6 azido
further improvement in this direction is still mandatory. derivative of 4,5-unsaturated L-ascorbic acid 5. Compound 5 was
Despite the increasingly importance of ow chemistry in successfully synthesized from compound (4) through elimination
discovery of biologically active molecules, to our knowledge no to an exocyclic allylic tosylate which through a subsequent SN2
studies are hitherto performed on the use of continuous ow to reaction with sodium azide (NaN3) directly afforded azide 5 in
provide L-ascorbic acid and its derivatives, as molecules with a moderate yield of 51%. 1,2,3-Triazolyl appended 4,5-unsatu-
unique biological properties. Realizing the benets of ow rated L-ascorbic acid derivatives 6a–6n with various substituents
chemistry and in continuation of our study towards the at C-8 of the triazole ring were obtained through the copper
synthesis of 1,2,3-triazole-containing heterocycle pharmaco- mediated 1,3-dipolar cycloaddition of C-6 azido L-ascorbic acid
phores,15b,30 our aim was to improve the practical applicability of derivative 5 and terminal alkynes (Scheme 1). In order to assess
Cu(I)-catalyzed azide–alkyne 1,3-dipolar cycloaddition (CuAAC) the inuence of structural modications at C-8 of the triazole on
to provide diverse C-6-substituted 1,2,3-triazolyl 4,5-unsatu- activity, selected alkynes a–n were used in click reaction with the
rated L-ascorbic acid derivatives 6a–6n using innovative azide 5. The synthesis of 6a–6n was performed using Cu(OAc)2,
enabling ultrasound (US) and continuous ow hybrid system which enabled the reduction of Cu(II) to Cu(I) ions through
(Fig. 1).
reaction with methanol.32 (Z)-Conguration around the C-4]C-5
Herein we report classical multistep synthesis to afford azido double bond was veried by the ROESY spectra which displayed
functionalized L-ascorbic acid for clicking with terminal alkynes the cross peak between the O-methylene at C-3 and methine C-5
protones. In the hypothetical (E)-conguration, where the spatial
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Scheme 1 Synthesis of novel 1,4-disubstituted-1,2,3-triazole L-ascorbic acid derivatives by conventional batch and flow-ultrasound conditions.
Reagents and conditions: (a) acetyl chloride, acetone; (b) benzyl chloride, K2CO3; (c) 50% acetic acid, CH3OH; (d) p-TsCl, CH2Cl2, pyridine, 0 ꢁC;
(e) NaN3, acetonitrile, 80 ꢁC; (f) CH3OH.
distance between C-3 and C-5 protons is too large, mentioned same time safe and efficient, by directly immersing the micro-
interactions would not be expected. These ndings are in reactor in the ultrasonic bath.
agreement with the determined (Z)-conguration of closely
related pyrimidine and purine derivatives of L-ascorbic acids.33
For the optimization of reaction parameters, click chemistry
of azido derivative of L-ascorbic acid and 3,5-di(tri-
5
uoromethyl)phenylacetylene and 3-butyne-1-ol were chosen as
test reactions to obtain 1,4-disubstituted 1,2,3-triazoles 6a and
6l, respectively, with the highest yield (Scheme 1 and Table 1,
entries 1–4). The highest conversion of azide 5 to 1,2,3-triazole
products was observed under ultrasound-assisted micro-ow
using the 0.1 M solution of the starting azide and alkyne, ow
rate of 0.5 mL minꢀ1 and a slightly elevated temperature of 50 ꢁC
(Table 1, entry 3). The residence time for the compounds
prepared under these reaction conditions amounted 9 min.
Higher reaction temperatures typically resulted in the forma-
tion of unidentied side-products.
Synthesis of the 1,2,3-triazolyl appended 4,5-unsaturated L-
ascorbic acid library under continuous ow process
In order to investigate the advantages of ow chemistry over
batch methods, the Cu(I)-catalyzed click reactions of azido
functionalized L-ascorbic acid derivative 5 and alkynes were
performed in a microreactor system. Two enabling technolo-
gies, micro-ow chemistry and ultrasound irradiation (US) have
been combined and compared to batch mode synthesis. To
combine ultrasound irradiation and microuidic system, we
applied a simple and inexpensive technique, which was at the
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Table 1 The effect of the flow rate and ultrasound irradiation on the
reactions between azido derivative of L-ascorbic acid 5 and corre-
sponding alkynes in a flow microreactora
to decrease the residence time by increasing the ow rate to 1 mL
minꢀ1 the yields of 6a and 6l decreased.
As we can observe from Table 2, the yields of both ow-
ultrasound and batch-based reactions were dependent on the
C-8 substituents at 1,2,3-triazole scaffold. Interestingly, the
effects of C-8 substituents in continuous micro-ow and batch
syntheses were similar. Notably, all tested reactions using
combination of micro-ow and ultrasound method were more
successful than those under classical synthetic conditions.
Among the aromatic alkynes, type of the substituents and their
position on the phenyl ring were nicely tolerated in click reac-
tions. In general, electron-donating groups gave target 1,2,3-
triazolyl appended L-ascorbic acid derivatives (6e–6h) under
micro-ow in excellent yields. Only exception was the click
reaction with alkyne containing p-methylphenyl moiety, that
afforded 4-tolyl-1,2,3-triazolyl appended L-ascorbic acid (6d)
using both micro-ow and batch conditions in the lowest yields
Yieldb [%]
Entry
Conditions
Compd 6a
Compd 6l
1
2
3
4
1 mL minꢀ1
35
50
99
Clogging
51
72
83
Clogging
0.5 mL minꢀ1
0.5 mL minꢀ1, US
0.2 mL minꢀ1
a
0.1 M solution of substrate, 1 equiv. alkyne and temperature of 50 ꢁC.
Yields were determined by HPLC chromatography.
b
Higher concentration of the starting compounds and lower
ow rate (0.2 mL minꢀ1) led to the precipitation of the triazole
product in the ow microreactor. However, when we attempted
Table 2 A comparison of continuous micro-flow and batch approaches for the synthesis of 1,2,3-triazolyl appended 4,5-unsaturated L-ascorbic
acid library 6a–6n
Yield [%]
Batcha
Yield [%]
Batcha
Entry
1
Compd
R6
Flowb
99
Entry
8
Compd
R6
Flowb
99
6a
81
62
6h
79
70
2
6b
89
9
6i
76
3
4
5
6
6c
6d
6e
6f
49
20
46
49
63
45
88
98
10
11
12
13
6j
64
83
61
36
74
98
83
86
6k
6l
6m
7
6g
82
94
14
6n
26
62
a
Yield was determined by HPLC chromatograms of the reaction mixture. b Yields were determined by isolation of the product.
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of 45% and 20%, respectively. While the position of the account the potential synergy of biological activity of 1,2,3-tri-
electron-donating substituents did not affect the CuAAC reac- azole and L-ascorbic acid, we anticipate that L-ascorbic acid and
tion in ow method, o- and m-substituted electron-donating 1,2,3-triazole pharmacophores if linked together would
group signicantly improved the reactions (6g and 6h) in generate novel molecular entities which are likely to exhibit
comparison to p-substituted phenyl (6e and 6f) using classical promising biological properties. Therefore, further antitumoral
synthetic approach. From the halogen and triuoromethyl, as evaluations of described compounds are envisaged and will be
electron-withdrawing substituents on the phenyl ring in reported on in due course.
selected alkynes, we can note that p-bromo substituent caused
the moderate yield in the synthesis of the desired 4-(p-
bromophenyl)-1,2,3-triazole appended L-ascorbic acid (6c). In
contrast to that, 1,3-dipolar reaction with dipolarophile con-
Experimental part
General
taining stronger electron-withdrawing uorine and tri- Melting points (uncorrected) were determined with a Koer
uoromethyl substituents at 3 and 5 position of the phenyl micro hot-stage (Reichert, Wien, Austria). Precoated Merck
moiety proceeded under micro-ow with excellent yields (6a (Darmstadt, Germany) silica gel 60F-254 plates were used for
and 6b). From the aliphatic alkynes, we found that unbranched thin layer chromatography and the spots were detected under
alkynes afforded 1,2,3-triazolyl appended L-ascorbic acid (6j– UV light (254 nm). Column chromatography was performed
6m) with side chains at C-8 of triazole in higher yields than using Fluka (Buchs, Switzerland) silica gel (0.063–0.2 mm); glass
branched alkyne (6n). Thus, long-chain dodecyne was success- columns were slurry-packed under gravity. Compounds 6a–6n
fully applied, as a dipolarophile in CuAAC reaction, affording where additionally ltered through a short column of Merck
the 4-decyl-1,2,3-triazole appended L-ascorbic acid (6k) in the (Darmstadt, Germany) aluminium oxide (Al2O3, 0.063–0.2 mm)
highest yields of 98% and 83% under micro-ow and batch in order to scavenge the copper residues from the click
conditions, respectively. Overall, it was demonstrated that the reactions.
ultrasonic-assisted ow method applied in click reactions to
All continuous ow reaction were performed using tubular
provide target 1,2,3-triazolyl appended 4,5-unsaturated L- glass microreactor (length: width: depth ¼ 330 mm: 250 mm: 50
ascorbic acid derivatives gave improved yields and considerably mm with the internal volume of 6 mL). Two syringe pumps (PHD
shortened the reaction time of click reactions. Thereby, the 4400 Syringe Pump Series, Harvard Apparatus, USA) equipped
applied methodology demonstrated to be a more efficient and with high pressure stainless steel syringes (8 cm3, Harvard
sustainable approach than the batch-based synthesis.
Apparatus, USA) were used to feed substrates to the inlet
streams of microreactor. Total ow velocity (F ¼ 0.2–2 mL
minꢀ1) was altered and the inuence on the reaction yield was
monitored. When the reaction was performed in a microreactor
Conclusions
We have performed the multistep synthesis of the 6-azido in combination with ultrasound, microreactor was completely
derivative of L-ascorbic acid 5 as a precursor for Cu(I)-catalyzed emerged in to an ultrasonic bath (Bandelin Sonorex, Germany)
1,3-dipolar cycloaddition (CuAAC) with alkynes. Click reactions under the continuous frequency of 35 kHz and temperature of
ꢁ
of the azide 5 and selected terminal alkynes were subsequently 50 C. The samples were analyzed by high performance liquid
carried out in the presence of Cu(OAc)2, that was employed as chromatography on a Prominence HPLC system (Shimadzu,
a catalyst to generate the required Cu(I)-ions in situ, to provide Germany) equipped with a LC-20AT pump, CBM-20A system
the novel C-6-substituted 1,2,3-triazolyl 4,5-didehydro-5,6- controller, DGU-20A5 degasser, SPD-M20A photodiode array
dideoxy-L-ascorbic acid series 6a–6n. (Z)-Conguration across detector using an Agilent Eclipse XDB-C18 reverse-phase
the C-4]C-5 double bond in 6a–6n was deduced from analytical column (4.6 ꢂ 150 mm). UV absorption was moni-
connectivities in ROESY spectra. To evaluate the potential tored at 254 nm wavelength. Water (A: 99.9% H2O, 0.1% formic
benets of continuous micro-ow on CuAAC reactions, the acid) and acetonitrile (B: 475 mL acetonitrile, 50 mL H20, 0.5 mL
batch conditions of click chemistry were successfully translated formic acid) were used for elution at a ow rate of 1 mL minꢀ1
.
into a ow regime. Moreover, for the environmentally benign For the analysis of the reaction mixtures 6a–6n, a gradient
synthesis of 6a–6n two enabling technologies, ultrasound irra- method starting with 40% B within 20 min, increasing to 60% B
diation and ow microreactors, have been combined and within next 25 min and then to 90% B within 25 min (total run
compared to batch mode synthesis. The CuAAC reactions time 70 min) and a gradient method starting with 40% B within
leading to triazole–L-ascorbic acid hybrids 6a–6n were greatly 28 min, increasing to 60% B within next 32 min and then to 90%
facilitated through the benecial features of continuous micro- B within 5 min (total run time 65 min) were used. Elemental
ow and ultrasound. Namely, reduced reaction time from hour- analyses were performed in the Central Analytic Service, RuCer
ˇ
´
scale reaction to minute range and signicantly improved yields Boskovic Institute, Zagreb. All elemental compositions were
in ow click reactions demonstrated the excellent synthetic within the 0.4% of the calculated values.
capabilities of the applied method. Finally, we may conclude
1H and 13C NMR spectra were acquired on a Bruker 300 and
that translating batch click chemistry to ultrasound-assisted 600 MHz NMR spectrometer (Bruker Biospin, Rheinstetten,
micro-ow processes in the present study highlights the Germany). All data were recorded in DMSO-d6 at 298 K. Chem-
successful advancement of click chemistry to generate new ical shis were referenced to the residual solvent signal of
hybrids with L-ascorbic acid and 1,2,3-triazole units. Taking into DMSO at d 2.50 ppm for 1H and d 39.50 ppm for 13C. Individual
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resonances were assigned on the basis of their chemical shis,
signal intensities, multiplicity of resonances and H–H coupling
constants.
Preparation of (Z)-2,3-O,O-dibenzyl-4,5-didehydro-5,6-dideoxy-
6-[4-(3,5-diuorophenyl)-1,2,3-triazole-1-yl]-L-ascorbic acid (6b).
Compound 6b was synthesized according to the general proce-
dure using compound 5 (300 mg, 0.826 mmol), Cu(OAc)2
(7.50 mg, 0.041 mmol) and 3,5-diuorophenylacetylene (0.12 mL,
0.991 mmol) in CH3OH (16.5 mL). Compound 6b (257 mg, 62%,
mp 74–76 C) was isolated as white powder. H-NMR (300 MHz,
DMSO) d 8.75 (s, 1H, H-7), 7.58–7.18 (m, 13H, OCH2 Ph , Ph-20, Ph-
40, Ph-60), 5.69 (t, J ¼ 7.2 Hz, 1H, H-5), 5.34 (s, 2H, OCH2Ph), 5.29
(d, J ¼ 7.8 Hz, 2H, H-6), 5.18 (s, 2H, OCH2Ph) ppm. 13C-NMR (75
Synthetic procedures
5,6-O,O-Isopropylidene-L-ascorbic acid (1), 2,3-O,O-dibenzyl-5,6-
O,O-isopropylidene-L-ascorbic acid (2), 2,3-O,O-dibenzyl-L-
ascorbic acid (3), 2,3-O,O-dibenzyl-4,5-didehydro-5,6-O,O-dito-
syl-L-ascorbic acid (4) were synthesized in accordance with
procedures given in the literature.29
1
ꢁ
MHz, DMSO) d 163.5 (C-1), 165.0; 164.6; 161.3; 161.1 (dd, JCF
¼
Preparation of (Z)-C-6-azido-2,3-O,O-dibenzyl-4,5-didehydro-
5,6-dideoxy-L-ascorbic acid (5).7 Ditosylated L-ascorbic acid
derivative 4 (2.03 g, 3.056 mmol) was reuxed in acetonitrile (55
246.3, 13.6 Hz, Ph-30, Ph-50), 147.9 (C-3), 144.6 (C-8), 143.6 (C-4),
135.7 (Ph-q), 135.3 (Ph-q), 134.3; 134.1; 133.9 (t, JCF ¼ 11.0 Hz,
Ph-10), 128.8–127.9 (OCH2 Ph ), 123.4 (C-2), 123.0 (C-7), 108.3;
108.1; 108.0; 107.9 (dd, JCF ¼ 17.9, 8.6 Hz, Ph-20, Ph-60), 103.5;
103.1; 102.8 (t, JCF ¼ 26.0 Hz, Ph-40), 102.8 (C-5), 74.0(OCH2Ph),
73.1 (OCH2Ph), 44.4 (C-6) ppm. Anal. calcd for C28H21F2N3O4: C,
67.06; H, 4.22; N, 8.38. Found: C, 67.12; H, 4.21; N, 8.40.
ꢁ
mL) together with NaN3 (1.19 g, 18.34 mmol) at 80 C for 4 h.
The reaction mixture was then allowed to stir overnight at room
temperature. Aer purication with column chromatography
on silica gel (CH2Cl2) compound 5 was isolated as yellow oil
(569 mg, 51%).
Preparation of (Z)-2,3-O,O-dibenzyl-6-[4-(4-bromophenyl)-
1H NMR (300 MHz, DMSO) d 7.65–7.04 (m, 10H, OCH2 Ph ),
5.53 (t, J ¼ 7.7 Hz, 1H, H-5), 5.34 (s, 2H, OCH2Ph), 5.15 (s, 2H,
OCH2Ph), 4.09 (d, J ¼ 7.7 Hz, 2H, H-6) ppm. 13C NMR (151 MHz,
DMSO) d 163.6 (C-1), 147.9 (C-3), 143.6 (C-4), 135.7 (Ph-q), 135.5
(Ph-q), 128.9–127.9 (OCH2 Ph ), 123.3 (C-2), 102.2 (C-5), 74.0
(OCH2Ph), 73.0 (OCH2Ph), 44.5 (C-6) ppm.
1,2,3-triazole-1-yl]-4,5-didehydro-5,6-dideoxy-L-ascorbic
acid
(6c). Compound 6c was synthesized according to the general
procedure using compound 5 (300 mg, 0.826 mmol), Cu(OAc)2
(7.50 mg, 0.041 mmol) and 4-bromophenylacetylene (179 mg,
0.991 mmol) in CH3OH (16.5 mL). Compound 6c (220 mg, 49%,
1
ꢁ
mp ¼ 126–131 C) was isolated as white powder. H NMR (300
MHz, DMSO) d 8.66 (s, 1H, H-7), 7.80 (d, J ¼ 8.5 Hz, 2H, Ph-20,
Ph-60), 7.64 (d, J ¼ 8.6 Hz, 2H, Ph-30, Ph-50), 7.51–7.27 (m, 10H,
OCH2 Ph ), 5.69 (t, J ¼ 7.5 Hz, 1H, H-5), 5.33 (s, 2H, OCH2Ph),
5.27 (d, J ¼ 7.5 Hz, 2H, H-6), 5.17 (s, 2H, OCH2Ph) ppm. 13C
NMR (151 MHz, DMSO) d 163.5 (C-1), 147.9 (C-3), 145.4 (C-8),
143.4 (C-4), 135.7 (Ph-q), 135.3 (Ph-q), 131.8 (Ph), 129.9 (Ph-
10), 128.8–127.1 (OCH2 Ph , Ph0), 123.4 (C-2), 121.9 (C-7), 120.8
(Ph-40), 101.7 (C-5), 74.0 (OCH2Ph), 73.0 (OCH2Ph), 44.3 (C-
6) ppm. Anal. calcd for C28H22BrN3O4: C, 61.77; H, 4.07; N, 7.72.
Found: C, 61.83; H, 4.08; N, 7.74.
General procedure for the preparation of 1,2,3-triazole-L-
ascorbic acid derivatives (6a–6n) under batch conditions
The C-6 azido L-ascorbic acid derivative 5 (200–350 mg) and
Cu(OAc)2 (0.05 equiv.) were dissolved in CH3OH. The corre-
sponding alkyne (1.2 equiv.) was then added and the reaction
ꢁ
mixture was heated for 5 h at 55 C. The reaction mixture was
stirred overnight at room temperature and the solvent was
evaporated in vacuo. The product was puried with column
chromatography on silica gel (CH2Cl2 : CH3OH ¼ 200 : 1–40 : 1)
and Al2O3. The oily product was triturated with n-hexane in
order to obtain compounds 6a–6i.
Preparation
dideoxy-6-(4-tolyl-1,2,3-triazole-1-yl)-L-ascorbic
of
(Z)-2,3-O,O-dibenzyl-4,5-didehydro-5,6-
acid
(6d).7
Preparation
of
(Z)-2,3-O,O-dibenzyl-4,5-didehydro-5,6-
Compound 6d was synthesized according to the general
procedure using compound 5 (345 mg, 0.950 mmol), Cu(OAc)2
(8.62 mg, 0.047 mmol) and 4-tolylacetylene (0.15 mL, 1.140
mmol) in CH3OH (19 mL). Compound 6d (91 mg, 20%, mp ¼
108–111 ꢁC, in literature colorless oil) was isolated as white
powder. 1H NMR (300 MHz, DMSO) d 8.54 (s, 1H, H-7), 7.72 (d, J
¼ 8.1 Hz, 2H, Ph-20, Ph-60), 7.46–7.20 (m, 12H, OCH2 Ph , Ph-30,
Ph-50), 5.69 (t, J ¼ 7.5 Hz, 1H, H-5), 5.33 (s, 2H, OCH2Ph), 5.26 (d,
J ¼ 7.5 Hz, 2H, H-6), 5.17 (s, 2H, OCH2Ph), 2.32 (s, 3H,
CH03) ppm. 13C NMR (151 MHz, DMSO) d 163.6 (C-1), 148.0 (C-3),
146.6 (C-8), 143.3 (C-4), 137.2 (Ph-40), 135.7 (Ph-q), 135.4 (Ph-q),
129.5–127.9 (OCH2 Ph , Ph0), 127.9 (Ph-10), 125.1 (Ph0), 123.4 (C-
2), 121.2 (C-7), 102.0 (C-5), 74.1 (OCH2Ph), 73.1 (OCH2Ph), 44.2
dideoxy-6-[4-(3,5-di(triuoromethyl)phenyl)-1,2,3-triazole-1-yl]-
L-ascorbic acid (6a). Compound 6a was synthesized according to
the general procedure using compound 5 (300 mg, 0.826 mmol),
Cu(OAc)2 (7.50 mg, 0.041 mmol) and 3,5-di(triuoromethyl)
phenylacetylene (0.18 mL, 0.991 mmol) in CH3OH (16.5 mL).
Compound 6a (401 mg, 81%, mp 89–90 ꢁC) was isolated as
white powder.
1H-NMR (300 MHz, DMSO) d 9.00 (s, 1H, H-7), 8.51 (s, 2H, Ph-
20, Ph-60), 8.07 (s, 1H, Ph-40), 7.44–7.32 (m, 10H, OCH2 Ph ), 5.72
(t, J ¼ 7.7 Hz, 1H, H-5), 5.34 (2H, s, OCH2Ph), 5.34 (d, J ¼ 7.6 Hz,
2H, H-6), 5.18 (s, 2H, OCH2Ph) ppm. 13C NMR (151 MHz,
DMSO) d 163.5 (C-1), 147.9 (C-3), 143.9 (C-8), 143.7 (C-4), 135.6
(Ph-q), 135.3 (Ph-q), 133.2 (Ph-10), 131.3; 131.1; 130.9; 130.7 (q,
JCF ¼ 33.1 Hz, Ph-30, Ph-50), 128.8–127.9 (OCH2 Ph ), 125.3; 125.3
(C-6), 20.8 (CH0 ) ppm. Anal. calcd for C29H25N3O4: C, 72.64; H,
3
5.25; N, 8.76. Found: C, 72.74; H, 5.26; N, 8.77.
(d, JCF ¼ 3.6 Hz, Ph-20, Ph-60), 125.9; 124.1; 122.3; 120.5 (q, JCF
¼
Preparation
of
(Z)-2,3-O,O-dibenzyl-4,5-didehydro-5,6-
272.7 Hz, CF), 123.5 (C-2), 123.4 (C-7), 121.2–121.0 (m, Ph-40),
101.4 (C-5), 74.0 (OCH2Ph), 73.1 (OCH2Ph), 44.5 (C-6) ppm.
Anal. calcd for C30H21F6N3O4: C, 59.90; H, 3.52; N, 6.99.
Found: C, 59.98; H, 3.51; N, 6.99.
dideoxy-6-[4-(4-pentylphenyl)-1,2,3-triazole-1-yl]-L-ascorbic acid
(6e). Compound 6e was synthesized according to the general
procedure using compound 5 (300 mg, 0.826 mmol), Cu(OAc)2
796 | RSC Adv., 2017, 7, 791–800
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(7.50 mg, 0.041 mmol) and 4-pentylphenylacetylene (0.20 mL, OCH2 Ph , Ph0), 6.74–6.71 (m, 1H, Ph-40), 5.70 (t, J ¼ 7.5 Hz, 1H, H-
0.991 mmol) in CH3OH (16.5 mL). Compound 6e (202 mg, 46%, 5), 5.33 (s, 2H, OCH2Ph), 5.26 (d, J ¼ 7.5 Hz, 2H, H-6), 5.17 (s, 2H,
mp ¼ 97–99 ꢁC) was isolated as white powder. 1H NMR (300 OCH2Ph) ppm. 13C NMR (151 MHz, DMSO) d 163.7 (C-1), 157.8
MHz, DMSO) d 8.54 (s, 1H, H-7), 7.73 (d, J ¼ 8.1 Hz, 2H, Ph-20, (Ph-30), 148.1 (C-3), 146.7 (C-8), 143.4 (C-4), 135.7 (Ph-q), 135.4 (Ph-
Ph-60), 7.53–7.14 (m, 12H, OCH2 Ph , Ph-30, Ph-50), 5.69 (t, J ¼ q), 131.9 (Ph-10), 130.0–128.0 (OCH2 Ph , Ph0), 123.4 (C-2), 121.6
7.5 Hz, 1H, H-5), 5.33 (s, 2H, OCH2Ph), 5.26 (d, J ¼ 7.5 Hz, 2H, (C-7), 116.1 (Ph0), 115.0 (Ph0), 111.9 (Ph0), 102.1 (C-5), 74.1
H-6), 5.17 (s, 2H, OCH2Ph), 2.58 (t, 2H, H-10), 1.66–1.44 (m, 2H, (OCH2Ph), 73.1 (OCH2Ph), 44.3 (C-5) ppm. Anal. calcd for
H-20), 1.32–1.15 (m, 4H, H-30, H-40), 0.86 (t, J ¼ 6.8 Hz, 3H, C28H23N3O5: C, 69.84; H, 4.81; N, 8.73. Found: C, 69.70; H, 4.81; N,
CH03) ppm. 13C NMR (151 MHz, DMSO) d 163.5 (C-1), 147.9 (C-3), 8.73.
146.6 (C-8), 143.3 (C-4), 142.1 (Ph-40), 135.7 (Ph-q), 135.3 (Ph-q),
Preparation of (Z)-2,3-O,O-dibenzyl-6-[4-cyclopropyl-1,2,3-
128.8–128.1 (OCH2 Ph , Ph0), 127.8 (Ph-10), 125.1 (Ph0), 123.4 (C- triazole-1-yl]-4,5-didehydro-5,6-dideoxy-L-ascorbic acid (6i).7
2), 121.1 (C-7), 101.9 (C-5), 74.0 (OCH2Ph), 73.0 (OCH2Ph), 44.2 Compound 6i was synthesized according to the general proce-
(C-6), 34.8 (C-10), 30.8 (CH20 ), 30.4 (CH20 ), 21.9 (C-40), 13.8 dure using compound 5 (330 mg, 0.908 mmol), Cu(OAc)2
(CH0 ) ppm. Anal. calcd for C33H33N3O4: C, 74.00; H, 6.21; N, (8.25 mg, 0.045 mmol) and cyclopropylacetylene (0.1 mL, 1.090
3
7.84. Found: C, 74.16; H, 6.20; N, 7.83.
mmol) in CH3OH (18 mL). Compound 6i (273 mg, 70%, mp ¼
Preparation of (Z)-2,3-O,O-dibenzyl-4,5-didehydro-5,6-dideoxy- 65–67 ꢁC, in literature colorless oil) was isolated as white
1
6-[4-(4-methoxyphenyl)-1,2,3-triazole-1-yl]-L-ascorbic acid (6f). powder. H-NMR (300 MHz, DMSO) d 7.85 (s, 1H, H-7), 7.44–
Compound 6f was synthesized according to the general procedure 7.30 (m, 10H, OCH2 Ph ), 5.60 (t, J ¼ 7.5 Hz, 1H, H-5), 5.32 (s, 2H,
using compound 5 (291 mg, 0.801 mmol), Cu(OAc)2 (7.27 mg, OCH2Ph), 5.14 (s, 2H, OCH2Ph), 5.12 (s, 2H, H-6), 1.96–1.87 (m,
0.048 mmol) and 4-methoxyphenylacetylene (0.13 mL, 0.961 1H, H-10), 0.91–0.84 (m, 2H, CH02), 0.71–0.66 (m, 2H, CH20 ) ppm.
mmol) in CH3OH (16 mL). Compound 6f (193 mg, 49%, mp ¼ 13C-NMR (151 MHz, DMSO) d 163.5 (C-1), 149.2 (C-8), 147.9 (C-
1
ꢁ
131–134 C) was isolated as white powder. H NMR (300 MHz, 3), 143.1 (C-4), 135.7 (Ph-q), 135.3 (Ph-q), 128.8–127.9
DMSO) d 8.49 (s, 1H, H-7), 7.76 (d, J ¼ 8.7 Hz, 2H, Ph-20, Ph-60), (OCH2 Ph ), 123.3 (C-2), 120.8 (C-7), 102.2 (C-5), 74.0 (OCH2Ph),
7.54–7.24 (m, 10H, OCH2 Ph ), 7.00 (d, J ¼ 8.8 Hz, 2H, Ph-30, Ph- 73.0 (OCH2Ph), 43.9 (C-6), 7.5 (C-20, C-30), 6.5 (C-10) ppm. Anal.
50), 5.69 (t, J ¼ 7.5 Hz, 1H, H-5), 5.33 (s, 1H, OCH2Ph), 5.25 (d, J ¼ calcd for C25H23N3O4: C, 69.92; H, 5.40; N, 9.78. Found: C, 70.04;
7.5 Hz, 1H, H-6), 5.17 (s, 1H, OCH2Ph), 3.78 (s, 3H, OCH0 ) ppm. H, 5.41; N, 9.77.
3
13C NMR (75 MHz, DMSO) d 163.6 (C-1), 159.0 (Ph-40), 148.0 (C-3),
Preparation of (Z)-2,3-O,O-dibenzyl-6-(4-butyl-1,2,3-triazole-
146.5 (C-8), 143.3 (C-4), 135.7 (Ph-q), 135.4 (Ph-q), 128.8–126.5 1-yl)-4,5-didehydro-5,6-dideoxy-L-ascorbic acid (6j).7 Compound
(OCH2 Ph , Ph-20, Ph-60), 123.4 (C-2), 123.2 (Ph-10), 120.6 (C-7), 6j was synthesized according to the general procedure using
114.3 (Ph-30, Ph-50), 102.0 (C-5), 74.1 (OCH2Ph), 73.1 (OCH2Ph), compound 5 (300 mg, 0.826 mmol), Cu(OAc)2 (7.50 mg, 0.041
55.1 (OCH3), 44.2 (C-6) ppm. Anal. calcd for C29H25N3O5: C, 70.29; mmol) and 1-hexyne (0.12 mL, 0.991 mmol) in CH3OH (16.5
H, 5.09; N, 8.48. Found: C, 70.31; H, 5.08; N, 8.47.
mL). Compound 6j (236 mg, 64%, mp ¼ 64–67 ꢁC, in literature
Preparation of (Z)-2,3-O,O-dibenzyl-4,5-didehydro-5,6-dideoxy- colorless oil) was isolated as white powder. 1H NMR (300 MHz,
6-[4-(2-methoxyphenyl)-1,2,3-triazole-1-yl]-L-ascorbic acid (6g). DMSO) d 7.87 (s, 1H, H-7), 7.63–7.14 (m, 10H, OCH2 Ph ), 5.61 (t,
Compound 6g was synthesized according to the general proce- J ¼ 7.5 Hz, 1H, H-5), 5.32 (s, 2H, OCH2Ph), 5.22–5.03 (m, 4H,
dure using compound 5 (350 mg, 0.963 mmol), Cu(OAc)2 OCH2Ph, H-6), 2.59 (t, J ¼ 7.5 Hz, 2H, H-10), 1.63–1.50 (m, 2H, H-
(8.75 mg, 0.048 mmol) and 2-methoxyphenylacetylene (0.15 mL, 20), 1.41–1.14 (m, 2H, H-30), 0.88 (t, J ¼ 7.3 Hz, 3H, CH30 ) ppm.
1.156 mmol) in CH3OH (19 mL). Compound 6g (392 mg, 82%) 13C NMR (75 MHz, DMSO) d 163.6 (C-1), 148.0 (C-3), 147.1 (C-8),
was isolated as yellow oil. 1H NMR (300 MHz, DMSO) d 8.45 (s, 1H, 143.0 (C-4), 135.7 (Ph-q), 135.4 (Ph-q), 128.8–127.9 (OCH2 Ph ),
H-7), 8.12 (dd, J ¼ 7.7 Hz, 1.6 Hz, 1H, Ph-60), 7.52–7.24 (m, 11H, 123.3 (C-2), 121.9 (C-7), 102.3 (C-5), 74.0 (OCH2Ph), 73.0
OCH2 Ph , Ph-40), 7.13 (d, J ¼ 8.8 Hz, 1H, Ph0), 7.08–7.01 (m, 1H, (OCH2Ph), 43.9 (C-6), 31.0 (C-10), 24.6 (CH20 ), 21.6, (CH20 ), 13.7
Ph0), 5.69 (t, J ¼ 7.5 Hz, 1H), 5.33 (s, 2H, OCH2Ph), 5.25 (d, J ¼ (CH0 ) ppm. Anal. calcd for C26H27N3O4: C, 70.09; H, 6.11; N,
3
7.5 Hz, 2H, H-6), 5.17 (s, 2H, OCH2Ph), 3.78 (s, 3H, OCH3) ppm. 9.43. Found: C, 69.99; H, 6.08; N, 9.40.
13C NMR (151 MHz, DMSO) d 163.6 (C-1), 155.3 (Ph-20), 148.0 (C-
Preparation of (Z)-2,3-O,O-dibenzyl-6-[4-decyl-1,2,3-triazole-
3), 143.0 (C-4), 141.9 (C-8), 135.7 (Ph-q), 135.4 (Ph-q), 128.9–126.5 1-yl]-4,5-didehydro-5,6-dideoxy-L-ascorbic acid (6k). Compound
(OCH2 Ph , Ph0), 124.1 (C-7), 123.3 (C-2), 120.6 (Ph-50), 119.0 (Ph- 6k was synthesized according to the general procedure using
10), 111.5 (Ph-30), 102.4 (C-5), 74.0 (OCH2Ph), 73.0 (OCH2Ph), 55.4 compound 5 (351 mg, 0.966 mmol), Cu(OAc)2 (8.77 mg, 0.048
(OCH3), 44.1 (C-6) ppm. Anal. calcd for C29H25N3O5: C, 70.29; H, mmol) and 1-dodecyne (0.25 mL, 1.159 mmol) in CH3OH (19
5.09; N, 8.48. Found: C, 70.36; H, 5.10; N, 8.50.
Preparation of (Z)-2,3-O,O-dibenzyl-4,5-didehydro-5,6-dideoxy- white powder.
mL). Compound 6k (425 mg, 83%, mp 88–70 ꢁC) was isolated as
6-[4-(3-hydroxyphenyl)-1,2,3-triazole-1-yl]-L-ascorbic acid (6h).
1H-NMR (300 MHz, DMSO) d 7.87 (s, 1H, H-7), 7.44–7.31 (m,
Compound 6h was synthesized according to the general proce- 10H, OCH2 Ph ), 5.61 (t, J ¼ 7.2 Hz, 1H, H-5), 5.32 (s, 2H,
dure using compound 5 (300 mg, 0.826 mmol), Cu(OAc)2 OCH2Ph), 5.19–5.15 (m, 4H, OCH2Ph, H-6), 2.57 (t, J ¼ 7.5 Hz,
(7.50 mg, 0.041 mmol) and 3-hydroxyphenylacetylene (0.11 mL, 2H, H-10), 1.60–1.51 (m, 2H, H-20), 1.23 (s, 14H, CH20 ꢂ 7), 0.84 (t,
0.991 mmol) in CH3OH (16.5 mL). Compound 6h (314 mg, 79%, J ¼ 6.9 Hz, 3H, CH03) ppm. 13C-NMR (151 MHz, DMSO) d 163.5
mp 160–161 ꢁC) was isolated as white powder. 1H-NMR (300 MHz, (C-1), 147.9 (C-3), 147.2 (C-8), 143.0 (C-3), 135.7 (Ph-q), 135.4
DMSO) d 9.53 (s, 1H, OH), 8.6 (s, 1H, H-7), 7.54–7.11 (m, 13H, (Ph-q), 128.8–127.9 (OCH2 Ph ), 123.3 (C-2), 121.8 (C-7), 102.2 (C-
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5), 74.0 (OCH2Ph), 73.0 (OCH2Ph), 43.8 (C-6), 31.2 (C-10), 28.9
(CH02), 28.9 (CH20 ), 28.9 (CH20 ), 28.7 (CH20 ), 28.6 (CH20 ), 28.5 (CH02),
24.9 (CH02), 22.1 (CH20 ), 13.9 (CH03) ppm. Anal. calcd for
General ow procedure for the synthesis of 1,2,3-triazolyl L-
ascorbic acid derivatives 6a–6n in a microreactor
Solution 1: C-6 azido L-ascorbic acid derivative (5) (0.1 M) and
terminal alkyne (1 equiv.) were diluted in CH3OH.
Solution 2: Cu(OAc)2 was diluted in CH3OH (0.005 M) and
homogenized by sonication.
C
32H39N3O4: C, 72.56; H, 7.42; N, 7.93. Found: C, 72.69; H, 7.43;
N, 7.95.
Preparation
of
(Z)-2,3-O,O-dibenzyl-4,5-didehydro-5,6-
dideoxy-6-[4-(2-hydroxyethyl)-1,2,3-triazole-1-yl]-L-ascorbic acid
(6l). Compound 6l was synthesized according to the general
procedure using compound 5 (300 mg, 0.826 mmol), Cu(OAc)2
(7.50 mg, 0.041 mmol) and 3-butyne-1-ol (0.08 mL, 0.991
mmol) in CH3OH (16.5 mL). Compound 6l (218 mg, 61%, mp
¼ 59–60 ꢁC) was isolated as white powder. 1H NMR (300 MHz,
DMSO) d 7.89 (s, 1H, H-7), 7.56–7.17 (m, 10H, OCH2 Ph ), 5.61
(t, J ¼ 7.5 Hz, 1H, H-5), 5.32 (s, 2H, OCH2Ph), 5.24–5.09 (m, 4H,
OCH2Ph, H-6), 4.67 (t, J ¼ 5.0 Hz, 1H, OH), 3.61 (dd, J ¼ 11.6,
6.7 Hz, 2H, H-20), 2.75 (t, J ¼ 6.9 Hz, 1H, H-10) ppm. 13C NMR
(151 MHz, DMSO) d 163.5 (C-1), 147.9 (C-3), 144.7 (C-8), 143.1
(C-4), 135.7 (Ph-q), 135.4 (Ph-q), 128.8–127.9 (OCH2 Ph ), 123.3
(C-2), 122.5 (C-7), 102.2 (C-5), 74.0 (OCH2Ph), 73.0 (OCH2Ph),
60.3 (C-20), 43.8 (C-6), 29.1 (C-10) ppm. Anal. calcd for
Solution 1 and 2 were loaded into an injection loop and
injected into the micro-ow reactor set at 50 C at a rate of 0.5
ꢁ
mL minꢀ1 (9 min residence time). The microreactor was posi-
tioned into an ultrasound bath. Outows from the micro-
reactors were collected in vials placed on ice and lled with
QuadraPure BZA copper-scavenger resin (polymer supported
benzylamine) to stop the reaction. Reaction mixture was ltered
via cotton. Prior to the HPLC analysis the sample (10 mL) was
diluted in H2O (300 mL) and acetonitrile (400 mL). Conversion of
compound 5 in ow reactions was determined using a prepared
calibration curve of compound 5.
Acknowledgements
C
24H23N3O5: C, 66.50; H, 5.35; N, 9.69. Found: C, 66.74; H,
We greatly appreciate the nancial support of the Croatian
Science Foundation (project No. IP-2013-11-5596).
5.36; N, 9.69.
Preparation of (Z)-2,3-O,O-dibenzyl-6-(4-chloropropyl-1,2,3-
triazole-1-yl)-4,5-didehydro-5,6-dideoxy-L-ascorbic acid (6m).
Compound 6m was synthesized according to the general
procedure using compound 5 (347 mg, 0.955 mmol), Cu(OAc)2
(8.67 mg, 0.048 mmol) and 5-chloro-1-pentyne (0.12 mL, 1.146
mmol) in CH3OH (19 mL). Compound 6m (158 mg, 36%) was
isolated as white powder.
Notes and references
¨
1 (a) J. L. Svirbely and A. Szent-Gyorgyi, Biochem. J., 1933, 27,
279–285; (b) J. Dua, J. J. Cullena and G. R. Buettner,
Biochim. Biophys. Acta, 2012, 1826, 443–457.
1H NMR (300 MHz, DMSO) d 7.94 (s, 1H, H-7), 7.54–7.17 (m,
10H, OCH2 Ph ), 5.62 (t, J ¼ 7.5 Hz, 1H, H-5), 5.32 (s, 2H,
OCH2Ph), 5.25–5.06 (m, 4H, OCH2Ph, H-6), 3.67 (t, J ¼ 6.5 Hz,
2H, H-30), 2.74 (t, J ¼ 7.4 Hz, 2H, H-10), 2.14–1.88 (m, 2H, H-
20) ppm. 13C NMR (151 MHz, DMSO) d 163.5 (C-1), 147.9 (C-3),
145.7 (C-8), 143.1 (C-3), 135.7 (Ph-q), 135.3 (Ph-q), 128.8–127.9
(OCH2 Ph ), 123.3 (C-2), 122.2 (C-7), 102.1 (C-5), 74.0 (OCH2Ph),
73.0 (OCH2Ph), 44.6 (C-30), 43.9 (C-6), 31.7 (C-10), 22.2 (C-
20) ppm. Anal. calcd for C25H24ClN3O4: C, 64.44; H, 5.19; N, 9.02.
Found: C, 64.58; H, 5.20; N, 9.04.
2 G. Grosso, R. Bei, A. Mistretta, S. Marventano, G. Calabrese,
L. Masuelli, M. G. Giganti, A. Modesti, F. Galvano and
D. Gazzol, Front. Biosci., Landmark Ed., 2013, 18, 1017–1029.
3 (a) J. Yun, E. Mullarky, C. Lu, K. N. Bosch, A. Kavalier,
K. Rivera, J. Roper, I. I. Chio, E. G. Giannopoulou,
C. Rago, A. Muley, J. M. Asara, J. Paik, O. Elemento,
Z. Chen, D. J. Pappin, L. E. Dow, N. Papadopoulos,
S. S. Gross and L. C. Cantley, Science, 2015, 350, 1391–
1396; (b) K. Blaschke, K. T. Ebata, M. M. Karimi,
´
J. A. Zepeda-Martınez, P. Goyal, S. Mahapatra, A. Tam,
Preparation of (Z)-2,3-O,O-dibenzyl-6-(4-tert-butyl-1,2,3-tri-
D. J. Laird, M. Hirst, A. Rao, M. C. Lorincz and
M. Ramalho-Santos, Nature, 2013, 500, 222–226; (c)
H. E. Sauberlich, Annu. Rev. Nutr., 1994, 14, 371–385; (d)
M. Osmak, I. Kovacek, I. Ljubenkov, R. Spaventi and
M. Eckert-Maksic, Neoplasma, 1997, 44, 101–107; (e)
H. Sakagami, M. Takeda, A. Utsumi, S. Fujinaga,
A. Tsunoda, N. Yasuda, M. Shibusawa, T. Koike, H. Ota,
K. Kazama, D. Shiokawa, S. Tanuma and M. Kochi,
Anticancer Res., 1996, 13, 65–71.
4 (a) H. Sakagami, M. Takeda, A. Utsumi, S. Fujinaga,
A. Tsunoda, N. Yasuda, M. Shibusawa, T. Koike, H. Ota,
K. Kazama, D. Shiokawa, S. Tanuma and M. Kochi,
Anticancer Res., 1996, 13, 65–71; (b) P. E. Maxim and
R. W. Veltri, FASEB J., 1988, 2, A370.
azole-1-yl)-4,5-didehydro-5,6-dideoxy-L-ascorbic
acid
(6n).
Compound 6n was synthesized according to the general
procedure using compound 5 (300 mg, 0.826 mmol), Cu(OAc)2
(7.50 mg, 0.041 mmol) and 3,3-dimethyl-1-butyne (0.12 mL,
0.991 mmol) in CH3OH (16.5 mL). Compound 6n (96 mg,
26%) was isolated as a transparent oil. 1H NMR (300 MHz,
DMSO) d 7.89 (s, 1H, H-7), 7.61–7.18 (m, 10H, OCH2 Ph ), 5.62
(t, J ¼ 7.5 Hz, 1H, H-5), 5.33 (s, 2H, OCH2Ph), 5.23–5.09 (m,
4H, OCH2Ph, H-6), 1.25 (s, 9H, 3 ꢂ CH03) ppm. 13C NMR (151
MHz, DMSO) d 163.5 (C-1), 156.4 (C-8), 147.9 (C-3), 143.0 (C-4),
135.7 (Ph-q), 135.3 (Ph-q), 128.8–127.9 (OCH2 Ph ), 123.3 (C-2),
119.9 (C-7), 102.3 (C-5), 74.0 (OCH2Ph), 73.0 (OCH2Ph), 43.9
(C-6), 30.5 (C-10), 30.2 (C H30 ) ppm. Anal. calcd for C26H27N3O4:
C, 70.09; H, 6.11; N, 9.43. Found: C, 69.97; H, 6.11; N, 9.44.
5 (a) Y. Nihro, H. Miyataka, T. Sudo, H. Matsumoto and
T. Satoh, J. Med. Chem., 1991, 34, 2152–2157; (b)
R. P. Tripathi, B. Singh, S. S. Bisht and J. Pandey, Curr.
Org. Chem., 2009, 13, 99–122.
798 | RSC Adv., 2017, 7, 791–800
This journal is © The Royal Society of Chemistry 2017

View Article Online
Paper
6 (a) S. Raic-Malic, A. Hergold-Brundic, A. Nagl, M. Grdisa,
RSC Advances
´
´
´
ˇ
J. Zeidler, Antiviral Chem. Chemother., 2014, 23, 161–171;
(b) Y. W. He, C. Z. Dong, J. Y. Zhao, L. L. Ma, Y. H. Li and
H. A. Aisa, Eur. J. Med. Chem., 2014, 76, 245–255; (c)
H. Cheng, J. Wan, M. I. Lin, Y. Liu, X. Lu, J. Liu, Y. Xu,
J. Chen, Z. Tu, Y. S. Cheng and K. Ding, J. Med. Chem.,
2012, 55, 2144–2153.
´
K. Pavelic, E. De Clercq and M. Mintas, J. Med. Chem.,
´
´
´
1999, 42, 2673–2678; (b) S. Raic-Malic, D. Svedruzic,
´
´
T. Gazivoda, A. Marunovic, A. Hergold-Brundic, A. Nagl,
J. Balzarini, E. De Clercq and M. Mintas, J. Med. Chem.,
ˇ
ˇ
´
2000, 43, 4806–4811; (c) T. Gazivoda, M. Sokcevic, M. Kralj,
ˇ
´
L. Suman, K. Pavelic, E. De Clercq, G. Andrei, R. Snoeck, 18 (a) H. Behbehani, H. M. Ibrahim, S. Makhseed and
´
´
J. Balzarini, M. Mintas and S. Raic-Malic, J. Med. Chem.,
2007, 50, 4105–4112.
H. Mahmoud, Eur. J. Med. Chem., 2011, 46, 1813–1820; (b)
N. S. Vatmurge, B. G. Hazra, V. S. Pore, F. Shirazi,
M. V. Deshpande, S. Kadreppa, S. Chattopadhyay and
R. G. Gonnade, Org. Biomol. Chem., 2008, 6, 3823–3830.
19 (a) X. L. Wang, K. Wan and C. H. Zhou, Eur. J. Med. Chem.,
2010, 45, 4631–4639; (b) P. M. Chaudhary, S. R. Chavan,
F. Shirazi, M. Razdan, P. Nimkar, S. P. Maybhate,
A. P. Likhite, R. Gonnade, B. G. Hazara, M. V. Deshpande
and S. R. Deshpande, Bioorg. Med. Chem., 2009, 17, 2433–
2440.
7 N. Devender, K. K. G. Ramakrishna, Hamidullah,
S. K. Shukla, R. Konwar and R. P. Tripathi, Eur. J. Med.
Chem., 2014, 82, 106–119.
8 (a) J. J. Casciari, N. H. Riordan, T. L. Schmidt, X. L. Meng,
J. A. Jackson and H. D. Riordan, Br. J. Cancer, 2001, 84,
1544–1550; (b) S. W. Hong, D. H. Jin, E. S. Hahm,
S. H. Yim, J. S. Lim, K. I. Kim, Y. Yang, S. S. Lee, J. S. Kang,
W. J. Lee, K. W. Lee and M. S. Lee, Oncol. Rep., 2007, 18,
¨
¨
´
¨
¨
811–815; (c) P. Chen, J. Yu, B. Chalmers, J. Drisko, J. Yang, 20 S. B. Otvos, I. M. Mandity, L. Kiss and F. Fulop, Chem.–Asian
B. Li and Q. Chen, Anti-Cancer Drugs, 2012, 23, 437–444; (d) J., 2013, 8, 800–808.
H. Fritz, G. Flower, L. Weeks, K. Cooley, M. Callachan, 21 (a) X. P. He, Y. Zang, T. D. James, J. Li, G. R. Chen and J. Xie,
J. McGowan, B. Skidmore, L. Kirchner and D. Seely, Integr.
Cancer Ther., 2014, 13, 280–300; (e) C. Vollbracht,
B. Schneider, V. Leendert, G. Weiss, L. Auerbach and
J. Beuth, In Vivo, 2011, 25, 983–990.
Chem. Commun., 2017, 53, 82–90; (b) X. P. He, Y. L. Zeng,
Y. Zang, J. Li, R. A. Field and G. R. Chen, Carbohydr. Res.,
2016, 429, 1–22.
22 (a) A. R. Bogdan and K. James, Chem.–Eur. J., 2010, 16,
14506–14512; (b) A. R. Bogdan and K. James, Org. Lett.,
2011, 13, 4060–4063; (c) A. R. Bogdan, S. V. Jerome,
K. N. Houk and K. James, J. Am. Chem. Soc., 2012, 134,
2127–2138; (d) L. Vaccaro, D. Lanari, A. Marrocchi and
G. Strappaveccia, Green Chem., 2014, 16, 3680–3704.
9 (a) J. Hou, X. Liu, J. Shen, G. Zhao and P. G. Wang, Expert
Opin. Drug Discovery, 2012, 7, 489–501; (b) N. V. Sokolova
and V. G. Nenajdenko, RSC Adv., 2013, 3, 16212–16242.
10 (a) H. C. Kolb, M. G. Finn and K. B. Sharpless, Angew. Chem.,
Int. Ed. Engl., 2001, 40, 2004–2021; (b) V. V. Rostovtsev,
L. G. Green, V. V. Fokin and K. B. Sharpless, Angew. 23 (a) J. Wegner, S. Ceylan and A. Kirschning, Adv. Synth. Catal.,
Chem., Int. Ed., 2002, 41, 2596–2599.
2012, 354, 17–57; (b) J. Bao and G. K. Tranmer, Chem.
Commun., 2015, 51, 3037–3044; (c) T. Rodrigues,
P. Schneider and G. Schneider, Angew. Chem., Int. Ed.,
2014, 53, 5750–5758; (d) I. R. Baxendale, J. Deeley,
11 (a) K. Kempe, A. Krieg, C. R. Becer and U. S. Schubert, Chem.
Soc. Rev., 2012, 41, 176–197; (b) R. K. Iha, K. L. Wooley,
A. M. Nystrom, D. J. Burke, M. J. Kade and C. J. Hawker,
Chem. Rev., 2009, 109, 5620–5686.
C.
M. Griffiths-Jones, S.
V. Ley, S. Saaby and
12 (a) Y. Hua and A. H. Flood, Chem. Soc. Rev., 2010, 39, 1262–
1271; (b) A. C. Fahrenbach and J. F. Stoddart, Chem.–Asian J.,
2011, 6, 2660–2669.
13 A. H. El-Sagheer and T. Brown, Chem. Soc. Rev., 2010, 39,
1388–1405.
14 (a) K. A. Kalesh, P. Y. Yang, R. Srinivasan and S. Q. Yao, QSAR
Comb. Sci., 2007, 26, 1135–1144; (b) C. M. Salisbury and
B. F. Cravatt, QSAR Comb. Sci., 2007, 26, 1229–1238.
15 (a) J. L. Hou, X. F. Liu, J. Shen, G. L. Zhao and P. G. Wang,
G. K. Tranmer, Chem. Commun., 2006, 24, 2566–2568; (e)
J. C. Pastre, D. L. Browne and S. V. Ley, Chem. Soc. Rev.,
2013, 42, 8849–8869; (f) C. Wiles and P. Watts, Future Med.
Chem., 2009, 1, 1593–1612; (g) L. Matel-Sanz and
F. Susanne, J. Med. Chem., 2012, 55, 4062–4098; (h)
R. L. Hartman and K. F. Jensen, Lab Chip, 2009, 9, 2495–
2507.
24 (a) P. Watts and S. J. Haswell, Drug Discovery Today, 2003, 8,
586–593; (b) D. M. Roberage, L. Ducry, N. Bieler, P. Cretton
and B. Zimmermann, Chem. Eng. Technol., 2005, 28, 318–
322.
´
Expert Opin. Drug Discovery, 2012, 7, 489–501; (b) S. Raic-
´
ˇˇ ´
Malic and A. Mescic, Curr. Med. Chem., 2015, 22, 1462–1499.
16 (a) P. S. Rao, C. Kurumurthy, B. Veeraswamy, G. S. Kumar, 25 (a) P. Watts and C. Wiles, Org. Biomol. Chem., 2007, 5, 727–
Y. Poornachandra, G. C. Kumar, S. B. Vasamsetti,
S. Kotamraju and B. Narsaiah, Eur. J. Med. Chem., 2014, 80,
184–191; (b) Y. C. Duan, Y. C. Zheng, X. C. Li,
M. M. Wang, X. W. Ye, Y. Y. Guan, G. Z. Liu, J. X. Zheng
and H. M. Liu, Eur. J. Med. Chem., 2013, 64, 99–110; (c)
H. Elamari, R. Slimi, G. G. Chabot, L. Quentin,
D. Scherman and C. Girard, Eur. J. Med. Chem., 2013, 60,
360–364.
732; (b) C. Wiles and P. Watts, Chem. Commun., 2011, 47,
¨
6512–6535; (c) W. Ehrfeld, V. Hessel and H. Lowe,
Microreactors: New technology for modern chemistry, Wiley-
VCH, Weinheim, 2000, pp. 1–12; (d) G. N. Doku,
D. N. Verboom, D. N. Reinhoudt and A. van den Berg,
ˇ
´
´
Tetrahedron, 2005, 61, 2733–2742; (e) A. Salic and B. Zelic,
RSC Adv., 2014, 4, 41714–41721.
26 (a) D. H. DeWitt, Curr. Opin. Chem. Biol., 1999, 3, 350–356; (b)
Y. Zhang, T. F. Jamison, S. Patel and N. Mainol, Org. Lett.,
2011, 13, 280–283.
17 (a) A. Krajczyk, K. Kulinska, T. Kulinski, B. L. Hurst,
C. W. Day, D. F. Smee, T. Ostrowski, P. Januszczyk and
This journal is © The Royal Society of Chemistry 2017
RSC Adv., 2017, 7, 791–800 | 799

View Article Online
RSC Advances
Paper
27 (a) Z. Dong, C. Yao, X. Zhang, J. Xu, G. Chen, Y. Zhao and 29 (a) C. O. Kappe and E. Van der Eycken, Chem. Soc. Rev., 2010,
¨
¨
¨
¨
¨
Q. Yuan, Lab Chip, 2015, 15, 1145–1152; (b) S. Hubner,
39, 1280–1290; (b) S. B. Otvos and F. Fulop, Catal. Sci.
S. Kressirer, D. Kralisch, C. Bludszuweit-Philipp, K. Lukow,
Technol., 2015, 5, 4926–4941.
ˇ
¨
ˇ ´
´
ˇ ´
I. Janich, A. Schilling, H. Hieronymus, C. Liebner and 30 (a) S. Maracic, T. Gazivoda Kraljevic, H. Cipcic Paljetak,
¨
´
ˇ ´
´
K. Jahnisch, ChemSusChem, 2012, 5, 279–288; (c)
M. Peric, M. Matijasic, D. Verbanac, M. Cetina and S. Raic-
´
Malic, Bioorg. Med. Chem., 2015, 23, 7448–7463; (b)
G. Cravotto and P. Cintas, Chem. Soc. Rev., 2006, 35, 180–
196; (d) D. F. Rivas, P. Cintas and H. J. G. E. Gardeniers,
Chem. Commun., 2012, 48, 10935–10947.
´
´
´
T. Gazivoda Kraljevic, A. Harej, M. Sedic, S. Kraljevic
´
´
ˇ
´
Pavelic, V. Stepanic, D. Drenjancevic, J. Talapko and
´ ´
S. Raic-Malic, Eur. J. Med. Chem., 2016, 124, 794–808.
28 (a) D. F. Rivas, M. Ashokkumar, T. Leong, K. Yasui,
T. Tuziuti, S. Kentish, D. Lohse and H. J. G. E. Gardeniers, 31 (a) F. Von Dallacker and J. Sanders, Chem.-Ztg., 1985, 109,
´
197–202; (b) T. Gazivoda, K. Wittine, I. Lovric, D. Makuc,
Ultrason. Sonochem., 2012, 19, 1252–1259; (b) T. Tandiono,
S. W. Ohl, D. S. W. Ow, E. Klaseboer, V. V. Wong,
R. Dumkec and C. D. Ohl, Proc. Natl. Acad. Sci. U. S. A.,
ˇ
ˇ
J. Plavec, M. Cetina, D. Mrvos-Sermek, L. Suman, M. Kralj,
´
´
´
K. Pavelic, M. Mintas and S. Raic-Malic, Carbohydr. Res.,
2011, 108, 5996–5998; (c) T. Tandiono, S.
W. Ohl,
2006, 4, 433–442.
D. S. W. Ow, E. Klaseboer, V. V. Wong, A. Camattari and 32 G. C. Kuang, P. M. Guha, W. S. Brotherton, J. T. Simmons,
C. D. Ohl, Lab Chip, 2010, 10, 1848–1855; (d) J. Rooze,
E. V. Rebrov, J. C. Schouten and J. T. F. Keurentjes,
Ultrason. Sonochem., 2013, 20, 1–11.
L. A. Stankee, B. T. Nguyen, R. J. Clark and L. Zhu, J. Am.
Chem. Soc., 2011, 133, 13984–14001.
´
33 T. Gazivoda, M. Plevnik, J. Plavec, S. Kraljevic, M. Kralj,
´
K. Pavelic, J. Balzarini, E. De Clercq, M. Mintas and
´
´
S. Raic-Malic, Bioorg. Med. Chem., 2005, 13, 131–139.
800 | RSC Adv., 2017, 7, 791–800
This journal is © The Royal Society of Chemistry 2017