Click-Connected 2-(Hydroxyimino)aldehydes for the Design of UV-Responsive Functional Molecules

Article abstract of DOI:10.1002/ejoc.202001303

Click chemistry is used to functionalize simple lipophilic and water-soluble molecules, a complex PEGylated phospholipid (DSPE-PEG2000), and two benzylic substrates with the 2-(hydroxyimino)aldehyde (HIA) group. To this end, two terminal alkynes bearing the HIA moiety were synthesized and coupled to different azides through copper(I)-catalyzed azide alkyne cycloaddition (CuAAC). Norrish–Yang photoisomerization (λ= 365 nm, LED source) is successfully obtained, with no interference by the triazole linker, except when the forbidden n-π* carbonyl transition is screened by a remote substituent such as salicylaldehyde. UV-Vis spectrometry suggests a specific interaction of HIAs with Cu(II), whereas no such evidence is found with Cu(I). We thereby show that the CuAAC methodology can be used successfully to obtain HIA-based UV-responsive hydrophilic or lipophilic ligands, phospholipidic components for the construction of liposomes, and macrocycle precursors.

Full text of DOI:10.1002/ejoc.202001303

Communications
doi.org/10.1002/ejoc.202001303
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Click-Connected 2-(Hydroxyimino)aldehydes for the Design
of UV-Responsive Functional Molecules
[a]
[b]
[a, b]
[a, b]
Francesca D’Acunzo,* Linda Carbonaro, Antonella Dalla Cort,
Dario Filippini, Francesca Leonelli, Laura Mancini, and Patrizia Gentili*
Antonio Di Sabato,
[b]
[b]
[b]
[a, b]
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Click chemistry is used to functionalize simple lipophilic and
water-soluble molecules, a complex PEGylated phospholipid
photochemistry is increasing as convenient LED sources
become available across the UV-Vis spectrum, also allowing for
[9–11]
(
(
DSPE-PEG2000), and two benzylic substrates with the 2-
hydroxyimino)aldehyde (HIA) group. To this end, two terminal
flow photochemistry setups.
Therefore, the photoreactions
of oxime and carbonyl compounds have been attracting a
renewed attention in contemporary applications, such as the
alkynes bearing the HIA moiety were synthesized and coupled
to different azides through copper(I)-catalyzed azide alkyne
cycloaddition (CuAAC). Norrish–Yang photoisomerization (λ=
[
12]
manipulation of soft materials properties
and synthetic
[13]
photochemistry and photocatalysis. For instance, we recently
showed that the photochemistry of the HIA group has a
remarkably large impact on the physico-chemical behavior of
aqueous solutions of copolymers of OEGMA and an HIA-
functionalized methacrylate. Applications of the HIA to CBO
photoisomerization can be envisaged in metal ligation and
Furthermore, the cyclobutanol motif is of interest
in organic synthesis as a prochiral unit, it is present in natural
products and has been used as an intermediate in the total
3
65 nm, LED source) is successfully obtained, with no interfer-
ence by the triazole linker, except when the forbidden n-π*
carbonyl transition is screened by a remote substituent such as
salicylaldehyde. UV-Vis spectrometry suggests a specific inter-
action of HIAs with Cu(II), whereas no such evidence is found
with Cu(I). We thereby show that the CuAAC methodology can
be used successfully to obtain HIA-based UV-responsive hydro-
philic or lipophilic ligands, phospholipidic components for the
construction of liposomes, and macrocycle precursors.
[14]
[15,16]
sensors.
[17]
[18]
[19]
synthesis of some sesterpenoids. In a recent report, the Cu-
catalyzed reductive coupling of cyclobutanone oxime ester with
terminal alkynes afforded a route to the direct alkynylation of
3
[20]
The 2-(hydroxyimino)aldehyde (HIA) group exhibits a rich
photochemistry (Figure 1) encompassing E/Z configurational
isomerism of the oxime group and Norrish-Yang rearrangement
remote unfunctionalized sp carbon.
Several examples are
provided in the literature for the metal-catalyzed synthesis of
cyclobutane, cyclubutene and cyclobutanol derivatives through
[1]
[21]
of the carbonyl group. The latter results in the formation of
the cyclobutanol oxime (CBO) structure with the hydroxyl group
and the substituent on the adjacent position on either side of
enantioselective [2+2] cycloaddition reactions or cyclizations
[22–24]
involving γ-activated precursors.
In contrast, the Norrish-
Yang cyclization of carbonyls involves a non-activated, aliphatic
CÀ H bond in γ-position. HIAs have been obtained in good
yields in our group by α-oximation of aliphatic or benzylic
aldehydes. However, aldehyde precursors may be of limited
stability due to spontaneous condensation or oxidation.
Furthermore, the yield of the α-oximation reaction depends on
the bulk and nature of the neighboring group. In fact, in our
previous investigations the yields of different HIAs range from
[2]
the ring. The stereoselectivity of this process is determined by
the stereoelectronic requirements of ring closure and may be
influenced by other factors, such as solvent polarity and
[3]
hydrogen bonding. The Norrish-Yang photochemical reactions
were observed by Cerfontain on a series of 2-oxo-oximes, their
ethers and esters, in a number of papers published between
[4–7]
the late 70’s and early 90’s (see, for instance
et seq). The
[2,25]
photoisomerization aspect of this body of work received limited
attention, whereas the photolysis of oxime esters to iminyl
radicals has been investigated for the initiation of radical
45% to 90%.
The reaction failed altogether when we
attempted it on mPEG300À O(CH ) CHO. Therefore, it may prove
2 5
sensible to graft the pre-formed HIA group onto the desired
platform instead of dealing with the compound-specific out-
come of the α-oximation reaction. The goal is to obtain stimuli-
responsive functional molecules, i.e. structures designed to
serve specific tasks. In this work, we use click chemistry to
functionalize diverse precursors with the HIA group in view of
exploring their potential as UV-responsive moieties in lipophilic
or water-soluble molecules, liposomes and macrocycles (Fig-
ure 2). Since the use of click chemistry brings about the
introduction of a triazole ring as linker between the HIA and the
rest of the molecule, we assess the influence of the linker on
the Norrish-Yang photoisomerization to CBO. In the context of
CuAAC we also look into the interaction of HIAs with Cu(I) and
Cu(II) ions.
[8]
polymerizations. However, the interest in practical aspects of
[
a] Dr. F. D’Acunzo, Prof. A. D. Cort, Dr. A. Di Sabato, Prof. P. Gentili
Istituto per i Sistemi Biologici, Sezione Meccanismi di Reazione,
Consiglio Nazionale delle Ricerche, c/o Dipartimento di Chimica, Sapienza
Università di Roma
P.le A. Moro 5, 00185 Roma, Italy
E-mail: francesca.dacunzo@cnr.it
patrizia.gentili@uniroma1.it
[
b] Dr. L. Carbonaro, Prof. A. D. Cort, Dr. A. Di Sabato, Dr. D. Filippini,
Prof. F. Leonelli, Dr. L. Mancini, Prof. P. Gentili
Dipartimento di Chimica, Sapienza Università di Roma
P.le A. Moro 5, 00185 Roma, Italy
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/ejoc.202001303
Eur. J. Org. Chem. 2020, 1–7
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Figure 1. Main reactions in the photochemistry of HIAs and stereochemistry of CBO formation by cis or trans ring closure.
1
from H-NMR, see Supporting Information), and this may be one
of the factors leading to the low yield of 1b (27%), as this
[25]
reaction is solvent-sensitive. To link 1b and 2b to molecules
of different nature we, then, utilized CuAAC with Cu(I) and no
reductant in a degassed environment (Scheme 1, bottom). The
click reaction worked smoothly in 3–5 h on all azides 3–7 and
no significant differences are observed between alkyne 1b and
2
b, with 80% and 82% yield of products 8 and 10; 70% and
7
8% of 9 and 11, respectively. We thereby conclude that even
though the neighboring HIA may potentially interact with
copper ions, it does not interfere with the CuAAC reaction in
the above conditions. We also tested the popular Cu(II)/
reductant catalyzed CuAAC on azide 3 and 5-hexyn-1-ol
(Supporting Information) and we compared its outcome in the
Figure 2. Prospective uses of the structures obtained in this work.
presence of a stoichiometric amount of 2-(hydroxyimino)-3-
octyltridecanal (HIOTD, Figure 3a), a simple model HIA with no
[2]
other substituents. This way, we were able to check if the HIA
group inhibits the Cu(II)/reductant catalytic system. The reaction
was carried out in DMSO to ensure full solubility of HIOTD. The
reaction is slower compared to the click reactions in Scheme 1
even in the absence of HIOTD. After 48 h, we obtained 70%
yield of the triazole product, whereas the yield dropped to 15%
when Cu(II) was added to the HIOTD- containing mixture. A
somewhat better outcome (30% yield) resulted from adding
pre-mixed copper-ascorbic acid to the reaction mixture, thus
reducing Cu(II) prior to coming into contact with the HIA. To
gain some insight into the interaction between HIA and copper
ions, we looked into the effect of Cu(I) and Cu(II) addition to the
UV-Vis spectrum of HIOTD (Figure 3a, (Figure 3b). We do not
observe any effect of HIOTD on the UV-Vis spectrum up to 1:3
CuI/HIOTD in acetonitrile (Figure 3a). Upon addition of Cu(OAc)2
to HIOTD (Figure 3b), a hyperchromic effect and the suppres-
sion of the typical Cu(II) band at λ=670 nm is observed, along
with the appearance of a new band at λ=413 nm. In the case
of chromatographically purified HIA 11 we observed an
unexpected broad band extending just over 400 nm and no
free Cu(II) band (λ=600-700 nm). As a working hypothesis
based on the HIOTDÀ Cu(II) spectra in Figure 3b, we surmised
that this absorption results from HIA 11-Cu(II) interaction and
we attempted copper removal through treatment with an EDTA
Results and Disussion
We synthesized two HIA-functionalized terminal alkynes for the
standard copper-catalyzed azide-alkyne 1,4-Huisgen cycloaddi-
tion (CuAAC; Scheme 1, top).
The two HIA-alkynes 1b and 2b only differ by the length of
the carbon chain separating the two functional groups. Azides
with alkyl (3), oligo(ethylene glycol) (4), benzyl (5, 6) and
PEGylated phospholipid residues were also synthesized in good
to excellent yields. We used commercial 5-hexyn-1-ol 1, where-
as we chose to obtain 7-octyn-1-ol 2, also available commer-
cially, by base-catalyzed isomerization (“Acetylene zipper”
[26]
reaction)
purification. The two-step synthesis of HIA 2b from
proceeded smoothly to an overall 63% yield after purification
Scheme 1). The 75% yield of the α-oximation step of 2a is in
of 3-octyn-1-ol in very good yield (79%) after
2
(
[2]
keeping with the yields of other unhindered HIAs. Intermedi-
ate 1a, on the other hand, could not be isolated from the
petroleum ether used in the column chromatography purifica-
tion, even after repeated distillation, as already reported by
[27]
other Authors. Therefore, the α-oximation of 1a was con-
ducted in the presence of 27% residual hexanes (estimated
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Scheme 1. Synthesis of CuAAC-ready HIA derivatives and their reaction with different azides. Top: Synthesis of HIAs with a terminal triple bond for CuAAC (1b
and 2b). Bottom: HIAs 1b and 2b are reacted with azides 3–7 through CuAAC. Reaction conditions: (i) SO
then RT 3 h; (ii) p-TsOH (0.2 equiv), pyrrolidine (0.2 equiv), H O (2 equiv), NaNO (1 equiv), FeCl (1 equiv), DMF; (iii) 2,6-lutidine (2 equiv), (i-Pr)
CuI (0.1 equiv), CH CN, RT, 3 h. Given yields are after purification on silica gel column.
3
-Py (3 equiv), Et
3
N (4 equiv), DMSO, CH
2
Cl
2
, 0°C 1 h
2
2
3
2
EtN (2 equiv),
3
solution at pH 7.6–7.7. We avoided higher pH to limit deproto-
nation of the HIA moiety (pK of HIAs range 7.8–9), which may
a
[2]
lead to HIA decomposition. The aqueous EDTA extracts
exhibited a pale blue color confirming extraction of Cu(II)
(Supporting Information), while the HIA 11 spectrum shows the
characteristic wavelength of the HIA n-π* transition, around
[2]
3
20 nm (Figure 3c). In short, these results suggest HIA ligation
of Cu(II) and the observed inhibition of the Cu(II)/ascorbic acid
CuAAC by HIOTD can, therefore be rationalized in terms of
selective ligation of Cu(II) by the HIA group. In principle, the
triazole residue in the HIA 11 may also participate in metal ion
Scheme 2. Cyclobutanol oximes observed in this work by photoisomeriza-
tion of HIAs. LED source assembly is described in the Supporting
Information.
[28]
chelation. These preliminary data elicit a further dedicated
study on HIAs and triazole-HIAs as ligands of different metal
ions.
[2]
We have previously shown that HIAs isomerize to CBOs
Norrish-Yang reaction, Figure 1) when irradiated in a Rayonet
conversion to photoproducts was >95% in 3–5 h only, whereas
[
2]
(
>20 h where necessary with the Rayonet photoreactor. NMR
1
13
photoreactor equipped with high pressure mercury lamps
λmax =350 nm, about 100 nm broad). In the present study, we
evidence (Figure 4 for H NMR; Supporting Information for C,
1
1
(
DEPT135, H- H COSY and HSQC experiments) for the formation
of the Norrish-Yang product CBO is hereby provided, along the
lines of our previous investigation on the photoinduced isomer-
have used a 365 nm LED source (�10 nm width at half height)
to selectively induce the n-π* transition of the aldehyde group
in HIAs 8, 10–14 (Scheme 2).
[2]
ization of a simple aliphatic HIA. The diagnostic signals in the
1
The photo-isomerization was conducted directly in the NMR
H NMR spectrum in DMSO-d for CBOs are >C=NÀ OH (δ~
6
tube with DMSO-d as solvent. Based on the disappearance of
10.5 ppm, i.e. upfield by >2 ppm relative to the HIA oxime),
and >CHÀ OH signals (δ= 5.0–4.5 ppm and 6.0–5.5 ppm,
6
1
the CHO signals of HIAs in the H NMR spectra (Figure 4),
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major sets of NMR signals are present in the NMR spectra,
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instead. The two main >C=NÀ OH signals (A/A’) are detected in
the 10.5–10.25 ppm range. When comparing CBO 8 and 10,
their chemical shift depends on the distance between the
triazole and CBO rings. On the other hand, A/A’ Δδ is only
0
.02 ppm, regardless of the triazole position. A stronger effect is
exerted on the CHÀ OH signals by the distance between the
triazole and cyclobutanol rings. Specifically, in CBOs 10, 11, 12
and 14, in which the triazole and the CBO rings are spaced by
two methylenes, the B/B’ signals are separated by 0.4 ppm vs.
1
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.2 ppm in CBO 8; E/E’ 0.01 ppm vs. 0.15 ppm, and G/G’ by
.15 ppm vs. 0.5 ppm. In short, we observe a large effect of the
vicinity of the triazole ring on the chemical shifts of the CHÀ OH
signals. Thereby, we find it reasonable to assume that the two
main sets of signals correspond to the cis and trans isomers of
the four-membered ring, rather than to the E/Z oxime isomers.
It is worth noting, however, that a further pair of small peaks is
observed in the 10.5–10.2 ppm region, which may account for
the oxime configurational isomerism as well. (Figure 4). As for
the diastereomeric ratio in CBO 8, integration of A/A’, E/E’, G/G’
and B/B’ consistently indicates a slight excess of one ring
closure (diastereomeric ratio, dr= 65:35). In CBOs 10 and 14, dr
is calculated from the intensities of the >CHÀ OH peaks (G, G’),
due to overlap of B’ with other signals. In the spectrum of CBO
[29]
1
1 the G, G’ peaks are, unlike oxime A and A’, too broad to be
observed due to rapid exchange. However, both >CH-OH peaks
B, B’) are clearly detected and the isomeric ratio is thus
(
calculated. Negligible diastereoselection (dr close to 50:50) is
thereby observed with CBOs 10, 11, 12 and 14. This difference
with respect to the dr of CBO 8 can be rationalized in terms of
[
3]
stereoelectronic requirements of the Norrish-Yang cyclization
if we consider the distance between the triazole ring and the
reacting center. In fact, in HIA 8 the triazole group is adjacent to
the reacting CÀ H bond, whereas in HIA 10, 11 and 12 it is
separated by two methylene groups from the reacting γ-
position (Scheme 2). HIA 13 did not yield any significant
photoproduct, unlike HIA 12, which also bears an aromatic R1
group. This is due to the contribution of the salicylaldehyde
moiety, which exhibits a strong absorption band in the 370–
[30,31]
3
00 nm region.
This band, which smothers the forbidden n-
Figure 3. UV-Vis spectra of (a) the model HIA HIOTD in acetonitrile before
and after addition of CuI; (b) HIOTD in acetonitrile with increasing
π* HIA transition, is absent in HIA 12 (Supporting Information).
We did attempt a scale-up of the HIA to CBO isomerization
(60 mg of HIA 10 in 5 mL DMSO) with minor modifications of
the illumination assembly, including the use of a more powerful
LED source (see Supporting Information). HPLC monitoring of
reaction progress showed the formation of one major product
as the substrate was depleted by 90% in 24 h. Upon routine
workup (ethyl acetate/water partitioning and reduced pressure
removal of solvent at room temperature), the product peak was
no longer present in the HPLC trace and two different main
2
concentrations of Cu(OAc) ; (c) HIA 11 in dichloromethane before and after
treatment with EDTA for copper removal. Inset in (b) shows a linear increase
2
+
À 1
À 1
of absorbance at λ=413 nm as [Cu ] is increased (ɛ=3840 M cm ).
respectively). These signals are easily detected in the NMR
1
3
spectrum of photoproducts in Figure 4. The C spectrum in the
1
3
5–0 ppm region is, alone, less informative than H; however,
combined information from DEPT135 and HSQC allowed us to
establish CÀ H connectivity. The formation of two major isomeric
cyclic structures is highlighted by long-range correlations within
1
peaks were detected, along with several impurities. H-NMR
analysis in DMSO-d showed that the triazole linker was still
6
1
1
two sets of analogous signals in the H- H COSY45 experiments.
In principle, up to four CBO diastereomers may be observed by
NMR (Figure 1), resulting from the triazole substituent either cis
or trans with respect to the À OH attached to the cyclobutane
ring and from E/Z isomerism of the oxime >C=NÀ OH. Only two
present, whereas the CBO signals were no longer detected
(Supporting Information). Therefore, so far we have not been
able to isolate and fully characterize the single CBO diaster-
eomers detected by NMR in the small scale reaction. Optimized
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Figure 4. H-NMR signals (DMSO-d
6
, δ: ppm) of CBOs 8, 10, 11, 12 and 14 resulting from the Norrish-Yang photo-isomerization (λ=365 nm) of the
corresponding HIAs (Scheme 2). Left: expansion (11.0–4.0 ppm) of all CBO spectra. Right: Comparison of the full spectrum of CBO 8 with that of the parent
HIA. Two sets of signals are observed with all CBOs due to the formation of a diastereomeric mixture.
LED assembly is obtained by gluing a single LED chip (Nichia
NVSU233 A UV SMD-LED with PCB (10x10 mm), λ=365 nm,
reaction conditions and workup procedures are being sought to
obtain CBOs for synthetic purposes.
1
030 mW radiant flux, 3.75 V forward voltage from LUMITRONIX®
LED-Technik GmbH) on an aluminum heat sink, using Fischer
Elektronik heat-conducting adhesive WLK DK 4. The LED is powered
with a constant current power supply (Meanwell LCM-40 Series,
LUMITRONIX® LED-Technik GmbH). The light intensity delivered to
the sample is determined by chemical actinometry, using o-
Conclusions
CuAAC chemistry can be used successfully to anchor the 2-
hydroxyimino)aldehyde group to aliphatic, benzylic and PEGy-
[32]
nitrobenzaldehyde (NBA) as the substrate.
(
lated structures, including a complex phospholipid. To this end,
we obtained two click chemistry-ready precursors in a two-step
synthesis from commercial products. The HIA moiety retains the
ability to undergo Norrish-Yang photoisomerization to cyclo-
butanol oxime also in the presence of a triazole ring as
substituent. However, as the electronic transition involved in
the Norrish-Yang is associated with a weak absorption, CBO fails
to form when another functional group competes for the same
wavelength, as is the case with the salicylaldehyde substituent.
It should be noted that the Norrish-Yang reaction introduces
two chiral centers in molecules with little or no chiral
information. When the triazole ring is directly attached to the
incipient ciclobutanol, ring closure exhibits some degree of
diastereoselectivity, which fades as the triazole is further
removed from the cyclization site. Reaction scale-up and
isolation of CBOs are the next challenges towards their use in
organic synthesis. Unequivocal identification of the observed
CBO stereoisomers and, possibly, the elaboration of strategies
to control ring closure stereochemistry are in order for synthetic
purposes.
UV-Vis spectrometry of 2-(hydroxyimino)-3-octyltridecanal /
Cu ions
A
solution of 2-(hydroxyimino)-3-octyltridecanal (HIOTD) in
acetonitrile was placed in a 3 mL quarz cuvette. Spectra were
recorded at 25°C after each addition of aliquots of either CuI or Cu
(OAc) in acetonitrile. CuI 8.9 mM, HIOTD 4.5 mM; CuI additions up
2
to HIOTD/CuI=3:1. Cu(OAc)
4.6 mM, HIOTD 7 mM; Cu(OAc)
2 2
additions up to HIOTD/Cu(OAc) =30:1.
2
General procedure for Parikh-Doering oxidation: Compounds 1a
[33]
and 2a. 1.0 mmol of alcohol, 7 mL CH Cl and 0.54 mL (4.0 mmol)
2 2
Et N are introduced in a flame-dried two-necked round bottomed
3
flask equipped with a nitrogen inlet and magnetic stirring. The flask
is chilled in an ice bath, then a solution of 0.48 g (3.0 mmol)
SO ·Pyridine complex in 3 mL DMSO is added. Stirring is continued
3
at 0°C for 1 h, then for 3 h at room temperature. The following
workup procedure is aimed at minimizing product loss and
maximizing removal of DMSO from the reaction crude. The reaction
mixture is diluted with CH Cl or Et O and washed with a 1:1 (v/v)
2
2
2
mixture of NH Cl (sat) and brine. Most of the CH Cl (if used) is
4
2
2
removed by rotary evaporation and the residue is taken up with
Et O. The aqueous phase is extracted with fresh Et O to minimize
2
2
product loss. The combined organic phases are washed again with
the NH Cl/ NaCl (sat), then with brine alone to remove as much
4
DMSO as possible. After drying over anhydrous Na SO , the solvent
2
4
Experimental Section
Chemicals, equipment and detailed syntheses and product charac-
terization are found in the Supporting Information.
is removed and the residue is purified by silica gel chromatography.
General procedure for α-oximation of aldehydes: Compounds 1b
[25]
and 2b. In this order, 4 mL DMF, 36 μL (2.0 mmol) H O, 17 μL
2
(
0.20 mmol) pyrrolidine, 35 mg (0.20 mmol) p-toluenesulfonic acid
Photochemical setup Supporting Information for Figures and
detail. The photoreactor for NMR-scale experiments consists of a
lab-made LED chip assembly equipped with a sample holder. The
and 1.0 mmol of aldehyde are introduced in a two-necked round
bottom flask and magnetic stirring. Then 70 mg (1.0 mmol) of
NaNO are added, followed by 0.162 g (1.0 mmol) of FeCl in small
2
3
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Communications
doi.org/10.1002/ejoc.202001303
portions to avoid excessive heating. The reaction is continued for
h at room temperature, the mixture is diluted with 20 mL EtOAc
[1] C. Chen, Org. Biomol. Chem. 2016, 14, 8641–8647.
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7
[
2] P. Gentili, M. Nardi, I. Antignano, P. Cambise, M. D’Abramo, F. D’Acunzo,
A. Pinna, E. Ussia, Chem. Eur. J. 2018, 24, 7683–7694.
4
and 7 mL of a 1:1 (v/v) mixture of NH Cl (sat) and brine and stirred
4
[3] J. N. Moorthy, P. Mal, Tetrahedron Lett. 2003, 44, 2493–2496.
[4] P. Baas, H. Cerfontain, J. Chem. Soc. Perkin Trans. 2 1979, 156–162.
[5] P. Baas, H. Cerfontain, J. Chem. Soc. Perkin Trans. 2 1979, 151–155.
for 20 minutes at room temperature. The organic layer is set aside
and the aqueous phase is extracted with 5 mL fresh EtOAc to
minimize product loss. The pooled organic solutions are washed
[6] P. Baas, H. Cerfontain, J. Chem. Soc. Perkin Trans. 2 1979, 1653–1660.
[7] T. S. V. Buys, H. Cerfontain, J. A. J. Geenevasen, F. Stunnenberg, Recl. des
Trav. Chim. des Pays-Bas 1986, 105, 188–194.
[8] D. E. Fast, A. Lauer, J. P. Menzel, A.-M. Kelterer, G. Gescheidt, C. Barner-
Kowollik, Macromolecules 2017, 50, 1815–1823.
once more with 7 mL of NH Cl (sat)/brine mixture, then three times
4
with brine. After drying over anhydrous Na SO , EtOAc is removed
2
4
by rotary evaporation. The product is purified by silica gel
chromatography.
[
9] H. E. Bonfield, T. Knauber, F. Lévesque, E. G. Moschetta, F. Susanne, L. J.
Edwards, Nat. Commun. 2020, 11, DOI 10.1038/s41467-019-13988–4.
[34]
General procedure for CuAAC reactions: Compounds 8–14.
.0 mmol of alkyne and 1.0 mmol of azide are dissolved in 4 mL
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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5
5
[
[
[
10] F. Politano, G. Oksdath-Mansilla, Org. Process Res. Dev. 2018, 22, 1045–
1062.
11] F. Secci, S. Porcu, A. Luridiana, A. Frongia, P. C. Ricci, Org. Biomol. Chem.
1
acetonitrile in a schlenk tube equipped with magnetic stirring.
Then, 0.23 mL (0.21 g, 2.0 mmol) of 2,6-lutidine and 0.35 mL (0.26 g,
2.0 mmol) of diisopropylethylamine are added and the solution is
degassed through three freeze-pump-thaw cycles under Argon.
2
020, 18, 3684–3689.
12] M. Nardi, F. D’Acunzo, M. Clemente, G. Proietti, P. Gentili, Polym. Chem.
2017, 8, 4233–4245.
[13] J. A. Dantas, J. T. M. Correia, M. W. Paixão, A. G. Corrêa, ChemPhotoChem
2019, 3, 506–520.
[14] F. D’Acunzo, S. De Santis, G. Masci, M. Nardi, P. Renzi, A. P. Sobolev,
Macromol. Chem. Phys. 2019, 220, DOI 10.1002/macp.201900200.
15] N. Gerasimchuk, Dalton Trans. 2019, 48, 7985–8013.
16] F. Ratsch, W. Schlundt, D. Albat, A. Zimmer, J.-M. Neudörfl, T. Netscher,
H.-G. Schmalz, Chem. Eur. J. 2019, 25, 4941–4945.
[17] J. Hatai, C. Hirschhäuser, J. Niemeyer, C. Schmuck, ACS Appl. Mater.
Interfaces 2020, 12, 2107–2115.
[18] B. Tang, R. S. Paton, Org. Lett. 2019, 21, 1243–1247.
[19] Y. Chen, J. Zhao, S. Li, J. Xu, Nat. Prod. Rep. 2019, 36, 263–288.
[20] Z. Li, R. O. Torres-Ochoa, Q. Wang, J. Zhu, Nat. Commun. 2020, 11, 403.
21] K. Ishihara, K. Nakano, J. Am. Chem. Soc. 2007, 129, 8930–8931.
19 mg of CuI (0.10 mmol) is added under Ar. The reaction was
stirred for 3 h at room temperature. Most of the CH CN is removed
3
by rotary evaporation and the resulting residue is dissolved in
5
0 mL EtOAc. The organic phase is washed three times with 25 mL
4
[
[
NH Cl(sat), then with 25 mL HCl 0.1 M, and finally with 25 mL distilled
water. After drying over anhydrous sodium sulfate, the solvent is
evaporated and the residue is purified by column chromatography
on silica gel. Removal of residual copper ions was achieved by
washing a dichloromethane solution of the product several times
with EDTA 0.1 M, previously adjusted at pH 7.6 (10:1 organic
phase/EDTA solution).
[
[
22] D. Johnston, C. M. McCusker, D. J. Procter, Tetrahedron Lett. 1999, 40,
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2
We thank Prof. Maria Elisa Crestoni of Dipartimento di Chimica e
Tecnologie del Farmaco, Università di Roma “La Sapienza” for
HRMS analyses. We also thank Dr. Carlo Sperilli of Università di
Roma La Sapienza, Dipartimento di Chimica, and Mr. Enrico Rossi
of CNR-ISB, for assembling the photochemical setup. Financial
support by Sapienza Università di Roma, Research grant
RM11816436CD375D 2018
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[
[
[
[
[
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2
Conflict of Interest
[
34] W. S. Horne, C. D. Stout, M. R. Ghadiri, J. Am. Chem. Soc. 2003, 125,
The authors declare no conflict of interest.
9372–9376.
Keywords: Ciclobutanol oxime
·
Click chemistry
·
2-
(Hydroxyimino)aldehyde · Photochemistry · LED
Manuscript received: September 27, 2020
Revised manuscript received: November 16, 2020
Accepted manuscript online: November 18, 2020
Eur. J. Org. Chem. 2020, 1–7
www.eurjoc.org
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© 2020 Wiley-VCH GmbH
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COMMUNICATIONS
The 2-(hydroxyimino)aldehyde (HIA)
group undergoes Norrish–Yang pho-
toisomerization to ciclobutanol
oxime and is under investigation as
metal ions ligand. Herein, click
chemistry was used as a straightfor-
ward procedure to obtain HIA-based
functional molecules, the products
obtained by UV irradiation with a
LED source (λ=365 nm) were charac-
terized and it was shown by UV-Vis
spectrometry that HIAs specifically
interact with Cu(II).
Dr. F. D’Acunzo*, Dr. L. Carbonaro,
Prof. A. D. Cort, Dr. A. Di Sabato, Dr. D.
Filippini, Prof. F. Leonelli, Dr. L.
Mancini, Prof. P. Gentili*
1
– 7
Click-Connected 2-(Hydroxyimino)
aldehydes for the Design of UV-Re-
sponsive Functional Molecules
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