Synthesis of Benzophenone Nucleosides and Their Photocatalytic Evaluation for [2+2] Cycloaddition in Aqueous Media

Article abstract of DOI:10.1002/ejoc.201500885

Four benzophenone nucleosides that are para-substituted (-NH₂, -NMe₂, -OMe, and -Me) in relation to the carbonyl group were synthesized and characterized by their optical properties. The electron-donating character of the substituent

Full text of DOI:10.1002/ejoc.201500885

FULL PAPER
DOI: 10.1002/ejoc.201500885
Synthesis of Benzophenone Nucleosides and Their Photocatalytic Evaluation
for [2+2] Cycloaddition in Aqueous Media
Nadine Gaß[a] and Hans-Achim Wagenknecht*[a]
Keywords: Photochemistry / Photocatalysis / UV/Vis spectroscopy / Cycloaddition / C–C coupling / Nucleosides
Four benzophenone nucleosides that are para-substituted
(–NH2, –NMe2, –OMe, and –Me) in relation to the carbonyl
group were synthesized and characterized by their optical
properties. The electron-donating character of the substitu-
ents influenced the optical properties of these nucleosides,
especially the bathochromic shift of the charge-transfer band
in their UV/Vis absorption spectra. The solubility of the syn-
ture with 365 nm light-emitting diode (LED) lamps. The
MeO- and Me-substituted benzophenone nucleosides were
subjected to these reaction conditions in substoichiometric
amounts. After prolonged irradiation times, substrate conver-
sions competed with product decomposition. On the basis of
our results, we determined that the Me-substituted benzo-
phenone nucleoside has potential applications in the devel-
thetic nucleosides in aqueous solution allowed for a photo- opment of photocatalytically active DNAzymes for both in
catalytic intramolecular [2+2] cycloaddition of a quinolone vivo applications in chemical biology and enantioselective
substrate to take place in H2O/MeCN by irradiating the mix- photocatalysis in aqueous solutions.
itiators for interstrand crosslinks.[9] We recently synthesized
Introduction
a C-nucleoside that contains a conventional unmodified
benzophenone, and the dinucleotides thereof have one of
the natural nucleotides (A, C, T and G).[10] These dinucleo-
tides represent both interesting biologically relevant systems
with respect to DNA damage and the starting point for
future applications in chemical biology and photocatalysis.
The exploration of the benzophenone dinucleotides by
time-resolved transient absorption spectroscopy and theo-
retical methods, including molecular dynamics, revealed
charge-transfer processes predominantly with guanosine as
the second component.[11] It became clear that the solvent,
H2O or MeOH, controls the conformational distribution
and thereby actually gates the charge-transfer process as a
result of differences in the distance and degree of stacking
between benzophenone and the second component of the
dinucleotide. Our results gave a full understanding of the
photophysical properties of the singlet and triplet state of
the BP chromophore in the context of each of the four dif-
ferent DNA bases.[11] Moreover, these studies clearly re-
vealed that nucleotides that contain conventional benzo-
phenone as the artificial DNA base are not suited to serve
as a photochemically inert architecture for benzophenone-
mediated photocatalysis. However, dinucleotides and oligo-
nucleotides with less reactive but still photocatalytically
active benzophenone might be considered for the design of
stable DNA photocatalysts. On the basis of substituted
quinolone 2 as the substrate for a photocatalyzed reaction
(see below), a triplet energy of at least ET = 2.86 eV[12] is
required to provide the triplet-triplet energy transfer as sen-
sitization. Conventional benzophenone has a triplet energy
of ET = 2.98 eV, which clearly fulfills this requirement.[13]
For decades, benzophenones (BP) have played a substan-
tial and central role in photochemistry.[1–3] The major ad-
vantages of benzophenones are: (i) their chemical and
photochemical stability, (ii) their nearly quantitative yield
of intersystem crossing and formation of the triplet state,
(iii) the relatively long-lived nature of the triplet state, and
(iv) their UV-A absorption properties, which allow for the
use of 365 nm light-emitting diodes (LEDs) for excitation.
Benzophenones are also important chromophores for enan-
tioselective photocatalysis.[2,3]
Both template-assisted triplet-triplet energy transfer[4]
and photoinduced triplet electron transfer[5] have been used
for enantioselective [2+2] cycloadditions and cyclizations,
which are synthetically valuable C–C bond forming reac-
tions.[2,3] To bring this photocatalysis to aqueous media and
thereby to potential biological applications, it seemed rea-
sonable to design new C-nucleosides that have a benzo-
phenone moiety as an artificial DNA base. A backbone
that consists of sugar and phosphodiester units can enhance
the solubility of benzophenone in water and might serve as
a template. Because benzophenone is known to sensitize
DNA damage,[6] there are few published examples of benzo-
phenone-modified nucleoside analogues as models for ribo-
nucleotide reductases,[7] as photoreactive dyads,[8] and as in-
[a] Institute of Organic Chemistry, Karlsruhe Institute of
Technology (KIT),
Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany
E-mail: Wagenknecht@kit.edu
www.ioc.kit.edu/wagenknecht/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500885.
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Moreover, modified benzophenones with slightly lower sin- substituted benzophenone 8a was synthesized in 59% yield
glet and triplet states would also allow the driving force ΔG by the acylation of bromobenzene with 4-nitrobenzoyl
to be tuned for electron transfer to more positive values chloride followed by reduction of the nitro group with con-
and thereby energetically inhibit a reductive excited state centrated hydrochloric acid in the presence of iron. The
quenching, as observed with conventional benzophen- other functionalized benzophenones 8b–8d that were used
ones.[11] An electron-donating group bonded to one of the as precursors to the glycosidic coupling were synthesized
phenyl groups and para to the carbonyl group should by Friedel–Crafts-type acylations between 4-bromobenzoyl
render singlet and triplet energy states of benzophenones chloride and the corresponding aryl components. The yields
into the desired direction. For instance, 4-aminobenzo- varied as reported in Table 1. Glycal 5 was obtained in a
phenone 1a provides a singlet state of ES = 3.03 eV,[13] yield of 57% by tert-butyldimethylsilyl (TBDMS) protec-
which corresponds to 410 nm, and thereby allows a selective tion of thymidine 3 at the 3Ј- and 5Ј-positions and subse-
excitation outside the absorption range of substrate 2. The quent elimination of thymine as described by Hammer et al.
triplet state of 4-aminobenzophenone 1a is ET = 2.91 eV in and Engels et al.[17,18] For the central Heck-type coupling
benzene,[14] which is still sufficient to sensitize substrate 2. between the brominated benzophenones 8a–8d and the
The major drawback, however, for the substitution of 4- glycal 5, several palladium catalysts were screened and
aminobenzophenone 1a is that the quantum yield of in- Pd(dppf)Cl2 [dppf = 1,1Ј-bis(diphenylphosphino)ferrocene]
tersystem crossing is reduced to ΦT = 0.82 in nonpolar sol- was determined to be the catalyst of choice. After deprotec-
vents.[15] Herein, we follow this approach and present the tion of the glycosides 9a–9d at their 3Ј- and 5Ј-positions
synthesis of C-nucleosides that contain 4-aminobenzo- and reduction of the intermediate 3Ј-keto derivatives by
phenone (i.e., 1a), 4-(dimethylamino)benzophenone (i.e., treatment with NaBH(OAc)3 as described by Hocek et
1b), 4-methoxybenzophenone (i.e., 1c), and 4-methylbenzo- al.,[19] C-nucleosides 1a–1d were obtained.
phenone (i.e., 1d) as aglycons. The optical and electrochemi-
cal properties of 1a–1d and an evaluation of them as photo-
sensitizers for substrate 2, especially in aqueous media, are
also presented.
Table 1. Benzophenone nucleosides yields.
Friedel–Crafts
Heck-type
Deprotection and
reduction [% yield]
acylation [% yield]
coupling [% yield]
1a
1b
1c
1d
27[a]
38
96
52
28
46
55
65
75
65
66
76
Results and Discussion
[a] Friedel–Crafts reaction with 4-bromo-4Ј-nitrobenzophenone
was then followed by reduction of the nitro group.
C-Nucleosides 1a–1d that contain 4-aminobenzophen-
one, 4-(dimethylamino)benzophenone, 4-methoxybenzo-
phenone, and 4-methylbenzophenone moieties, respectively,
It is important to point out that both steps: (i) the palla-
were synthesized in four steps by using a Heck-type cou- dium-catalyzed coupling reaction and (ii) the final re-
pling reaction as the central step (Scheme 1).[16] Amino- duction are highly stereoselective. The stereoselectivity re-
Scheme 1. Synthesis of benzophenone nucleosides 1a–1d and structure of the benzophenones 10a–10d. Reagents and conditions: (a) imid-
azole, TBDMS-Cl, N,N-dimethylformamide (DMF), room temp., 16 h, 99%; (b) hexamethyldisilazane (HMDS), (NH4)SO4, 120 °C, 4 h,
58%; (c) AlCl3, reflux, 16 h; (d) 5, Pd(dppf)Cl2, Et3N, MeCN, 75 °C, 48 h; (e) (1) Et3N·3HF, tetrahydrofuran (THF), 0 °C, 12 h; (2) NaB-
H(OAc)3, MeCN/AcOH, 1:1, 0 °C, 8 h.
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Benzophenone Nucleosides and Their Photocatalytic Evaluation
sults are a consequence of substrate control because: (i) the whereas in nonpolar solvents, such as cyclohexane, the CT
lower face of glycal 5 is effectively shielded by the sterically band is above it.[21] Hence, we can assume that the triplet-
demanding TBDMS group in the 3Ј-position to give only triplet energy transfer that is required for the photocatalytic
the desired β-anomers[16] and (ii) the free 5Ј-hydroxy group conversion of substrate 2 in aqueous solution primarily
binds to the boron atom of NaBH(OAc)3 thereby leading originates from the CT states of nucleosides 1a–1d as pho-
to a hydride attack of the C=O bond from the top to re- tocatalysts.[23] Hence, the observed CT state as the lowest
cover the 2Ј-deoxyribofuranoside configuration.[20]
triplet state probably plays a major role in the later photo-
The influence of substituent R on the optical properties catalytic experiments that take place in aqueous solutions.
of the nucleosides is tremendous as shown by the UV/Vis Typically, in different polar solvent mixtures, the absorption
absorption spectra of benzophenone-C-nucleosides 1a–1d of the nucleoside with the strongest electron-donating
(Figure 1) and also compared to those of non-nucleosidic group (i.e., 1b) demonstrates solvatochromic behavior that
chromophores 10a–10d (see Supporting Information). All supports the assignment of the CT state (Figure 2), as the
optical measurements were performed in H2O/MeCN (4:1), bathochromic shift tracks well with the polarity of the sol-
which is the aqueous solvent of the later photocatalytic ex- vents according to the ET(30) values of Reichardt.[24] The
periments (in which all ingredients are soluble). The typical strongest bathochromic shift is observed in H2O and has a
absorption of an unsubstituted benzophenone can be at- maximum at 370 nm. This corresponds to an excited state
tributed to the π–π* and n–π* transitions of the carbonyl with an energy of 3.3 V that – despite the fact that the trip-
group. With an electron-donating substituent, the absorp- let state might by slightly lower than this value – should be
tion of the benzophenone is extended because of an ad- sufficiently high for photocatalysis to occur with substrate
ditional charge-transfer (CT) state.[21] This is clearly seen in 2.
the absorptions of synthesized nucleosides 1a–1d. 4-(Di-
methylamino)benzophenone-C-nucleoside 1b displays an
absorption maximum at 370 nm, whereas the maxima of 1a
and 1c are found at 335 and 293 nm, respectively. Nucleo-
side 1d with the methyl substituent has an absorption maxi-
mum at 270 nm, which is very similar to that of unsubsti-
tuted benzophenone (260 nm). The unsymmetric shape of
that absorption band and the broad shoulder at approxi-
mately 290 nm indicates the occurrence of a CT band in
this nucleoside. As the electron-donating ability of the sub-
stituent increases, the bathochromic shift of the CT band
of the corresponding nucleoside also increases. This tracks
well with the oxidation potentials of the benzophenones,
which are 1.15 V for 10b, which has a dimethylamino sub-
stituent, 1.26 V for 10a, 2.20 V for 10c, and 2.60 V for
methyl-substituted 10d (vs. Ag/AgCl).[22] Unsubstituted
Figure 2. UV/Vis absorption spectra of 1b in different solvent mix-
benzophenone has the highest oxidation potential of
tures (buffer: 10 mm Na2HPO4/NaH2PO4, pH = 8.55).
2.85 V.[22]
For the photocatalytic experiments, we investigated the
commonly used substrate 2 that can undergo an intramolec-
ular [2+2] cycloaddition reaction to afford the two products
11 and 12.[25] In principle, enantiomeric pairs of both prod-
ucts resulted, but a templated photocatalytic process by
Bach et al. achieved this conversion enantioselectivity.[26]
Two 365 nm LED lamps were used as a light source, and
although the corresponding extinction coefficients of nu-
cleosides 1a–1d are rather low (Table 2), this excitation
wavelength is required to avoid direct excitation of substrate
Table 2. Optical and electrochemical parameters of nucleosides 1a–
1d.
Nucleoside
λmax
λmax
ελ
ε365 nm
max
[nm][a]
[nm][b] [mM–1 cm–1][b] [mM–1 cm–1][b]
Figure 1. UV/Vis absorption spectra of 1a–1d and substrate 2 in
H2O/MeCN (4:1, 20 μm).
1a
1b
1c
1d
335
370
293
270
321
345
285
262
13.0
14.3
15.4
22.4
1.5
9.1
0.7
0.3
Suppan et al. showed that the energy of the CT band
of benzophenone 10a in polar solvents, such as isopropyl
alcohol, is located energetically below the nπ* band, [a] Solvent: H2O. [b] Solvent: MeCN.
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N. Gaß, H.-A. Wagenknecht
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Scheme 2. Intramolecular [2+2] cycloaddition of substrate 2.
2. A 20% solution of MeCN in water was required to guar- Careful HPLC analysis, however, revealed that the yield of
antee sufficient solubility of substrate 2 along with the the products 11 and 12 did not track with conversion at
photocatalysts nucleosides 1a–1d. The conversions of 2 and irradiation times longer than 15–25 min. The loss of yield
the yields of 11 and 12 were determined by HPLC analysis. was especially observed between 15 and 30 min of irradia-
Among the four nucleosides 1a–1d, the amino-substi- tion time with nucleoside 1d, as indicated by decomposition
tuted nucleosides, especially 1b, have the best match to the of the products 11 and 12 upon their formation. When nu-
365 nm LED, as their extinction coefficients are highest at cleoside 1c was used as the photocatalyst in a stoichiometric
this excitation wavelength. However, all experimental amount (100 μm), the optimum results of 79% conversion
attempts to employ nucleosides 1a and 1b as photocatalysts and 48% yield were reached within 25 min of irradiation
failed, although the CT states of these nucleosides should time (Table 3, Entry 1). However, a substoichiometric ap-
provide sufficient energy for an efficient triplet-triplet en- proach (25 μm) resulted in 85% conversion and 51% yield
ergy transfer to substrate 2, as reported[14,21,23] and indi- after 120 min of irradiation time (Table 3, Entry 3). Nucleo-
cated by the UV/Vis absorption spectra described above. side 1d was more efficient, and 88% conversion along with
Control experiments in pure (i.e., nonaqueous) MeCN re- 77% yield of the product was obtained after 15 min of irra-
vealed the successful conversion of substrate 2 in the pres- diation time by using a stoichiometric amount of the photo-
ence of nucleosides 1a and 1b. Hence, the excited state pro- catalyst (Table 3, Entry 2). A substoichiometric amount of
ton transfer by the protic solvent interferes with the energy catalyst 1d gave 88% conversion and 53% yield after 60 min
transfer in the corresponding photocatalytic experiments. of irradiation time. The photochemical decomposition of
We assume that this proton transfer occurs to the carbonyl products 11 and 12 was faster in the presence of nucleoside
group, which is conjugated to the para-amino group of 1a 1c than in experiments with nucleoside 1d (Figure 3).
and 1b, respectively.
In contrast, the photocatalytic experiments with nucleo-
sides 1c and 1d clearly show conversion of substrate 2 in
H2O/MeCN (4:1; Scheme 2, Table 3). According to their
absorption properties described above, the CT states of
both nucleosides provide enough energy to be transferred
to the substrate. Additionally, the absence of a nitrogen
atom in the substituents of these two benzophenone deriva-
tives lowers the basicity significantly, which reduces the in-
terference from a proton transfer. All of these experiments
afforded the regioisomeric mixture 11/12 in a 2.2:1 ratio.
Table 3. Photocatalytic reactions with 1c and 1d [25 μm (substoichi-
ometric) or 100 μm (stoichiometric)] and substrate 2 (100 μm).
Figure 3. Time-dependent conversion of 2 and yield of 11 and 12
during irradiation in the presence of 1c and 1d. Reagents and con-
Entry Photocatalyst
Time
Conv. Yield Time Conv.
Yield
[%][b]
[min][a]
[%]
[%]
[min]
[%]
ditions: 1d or 1c (100 μm), 2 (100 μm), H2O/MeCN (4:1), Na2HPO4/
NaH2PO4 (10 mm), pH = 8.55, 365 nm (LED), 10 °C.
1
2
3
4
1c[c]
1d[c]
1c[d]
1d[d]
25
15
120
60
79
88
85
88
48
77
51
53
30
30
30
30
85
89
33
66
47
64
14
46
Conclusions
[a] Irradiation time for maximum yield. [b] All experiments gave
the regioisomeric mixture 11/12 (2.2:1). No enantioselectivity was
observed. [c] Reagents and conditions: 1c or 1d (100 μm), 2 (100
μm), H2O/MeCN (4:1), Na2HPO4/NaH2PO4 (10 mm), pH = 8.55,
365 nm, 10 °C. Reaction was monitored by HPLC analysis. [d] Rea-
gents and conditions: 1c or 1d (25 μm), 2 (100 μm), H2O/MeCN
(4:1), Na2HPO4/NaH2PO4 (10 mm), pH = 8.55, 365 nm, 10 °C. Re-
action was monitored by HPLC analysis.
In summary, we have presented the synthesis of four C-
nucleosides that contain several benzophenones with elec-
tron-donating substituents as aglycons to develop photocat-
alysts for [2+2] cycloaddition reactions in aqueous media.
The optical properties of nucleosides 1a–1d reveal CT states
with triplet energies that depend on the electron-donating
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Benzophenone Nucleosides and Their Photocatalytic Evaluation
H), 3.97–3.82 (m, 1 H, 2Ј-H), 3.76 (dd, J = 11.4, 2.4 Hz, 1 H), 2.25
(ddd, J = 13.1, 5.8, 2.6 Hz, 1 H), 2.00 (ddd, J = 13.1, 8.0, 6.0 Hz,
1 H), 1.92 (d, J = 1.2 Hz, 3 H), 0.93 (s, 9 H), 0.89 (s, 9 H), 0.11 (d, J
= 0.8 Hz, 6 H), 0.08 (d, J = 2.1 Hz, 6 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = –5.3, –5.2, –4.7, –4.5, 12.7, 18.1, 18.5, 25.9, 26.0, 41.5,
63.1, 72.4, 85.0, 88.2, 111.0, 135.6, 150.5, 164.1 ppm. MS (FAB):
calcd. for C22H43N2O5Si2 [M + H]+ 471.3; found 471.4.
character of the benzophenone chromophore and solvent
polarity. Quinolone 2 was employed as typical substrate to
evaluate the benzophenone nucleosides as photosensitizers
in aqueous media. Although the CT bands of the amino-
substituted benzophenone nucleosides 1a and 1b had the
best match to the 365 nm LED as a light source, the conver-
sion of 2 was not detectable in aqueous solvents. Overall,
benzophenone nucleoside 1d was the most powerful catalyst
for this type of [2+2] cycloaddition in aqueous media, as
the conversion of substrate 2 tracked well with the yield
within 15 min of irradiation time. Nucleoside 1d can be em-
ployed in the development of photocatalytically active
DNAzymes for both in vivo applications in chemical bio-
logy and enantioselective photocatalysis in aqueous solu-
tions.
3,5-Bis-O-(tert-butyldimethylsilyl)-1,2-dideoxy-2,2-didehydro-D--
ribofuranose (5): A mixture of 4 (3.00 g, 6.40 mmol) and ammo-
nium sulfate (337 mg, 2.55 mmol) was dissolved in hexamethyldisil-
azane (11.7 g, 72.5 mmol) in a dry flask, and the resulting mixture
was heated at reflux for 4 h. After the solvents were removed under
vacuum, the residue was dissolved in CH2Cl2. The solution was
washed with saturated NaHCO3 solution, water, and brine, dried
with Na2SO4, and concentrated under vacuum. The crude product
was purified by silica gel column chromatography (hexane/Et2O,
19:1) to give 4 (1.27 g, 58%) as a yellow oil; Rf = 0.70 (hexane/
Et2O, 19:1). 1H NMR (300 MHz, CDCl3): δ = 6.4 (dd, J = 2.7,
1.0 Hz, 1 H), 5.01 (t, J = 2.6 Hz, 1 H), 4.86 (td, J = 2.7, 1.1 Hz, 1
H), 4.29 (td, J = 6.0, 2.7 Hz, 1 H), 3.69 (dd, J = 10.7, 5.7 Hz, 1
H), 3.51 (dd, J = 10.7, 6.4 Hz, 1 H), 0.89 (d, J = 2.0 Hz, 18 H),
0.07 (d, J = 2.8 Hz, 12 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
–5.2, –5.1, –4.3, –4.1, 18.3, 18.4, 26.0, 26.0, 63.0, 76.1, 89.1, 103.6,
149.1 ppm.
Experimental Section
General Methods: All reagents were purchased from Aldrich, Alfa
Aesar, ABCR, Fluka, and TCI and used without further purifica-
tion. The NMR spectroscopic data were recorded with a 75, 101,
and 300 MHz instrument. The chemical shifts in the 1H and 13C
NMR spectra are reported in parts per million (ppm) relative to
tetramethylsilane as an internal standard. Coupling constants (J)
are given in Hertz (Hz), and the multiplicity of signals are reported
as follows: s (singlet), d (doublet), t (triplet), q (quadruplet), quint
(quintet), sext (sextet), m (multiplet), br. s (broad singlet), dt (doub-
let of triplets), and td (triplet of doublets). Mass spectrometry was
performed on a Finnigan Modell MAT 95 with FAB and EI as
ionization methods. Thin layer chromatography was performed on
Fluka silica gel 60 F254 coated aluminium foil. Flash chromatog-
raphy was carried out on silica gel 60 from Aldrich (43–60 μm).
Chiral HPLC analyses were recorded on a Varian ProStar appara-
tus with a Chiralpak IB column (250 mm ϫ 4.6 mm, 5 μm). The
UV/Vis absorption measurements were recorded on a Perkin–
Elmer Lambda 750 spectrometer. Irradiation experiments were per-
formed with two Nichia UV-LEDs (NCSU033B) at 365 nm.
(4-Aminophenyl)(4-bromophenyl)methanone (8a): A solution of 4-
nitrobenzoyl chloride (2.00 g, 10.7 mmol) and bromobenzene
(1.69 g, 10.7 mmol) in anhydrous CH2Cl2 (60 mL) was cooled to
0 °C. AlCl3 (2.85 g, 21.4 mmol) was added, and the reaction was
stirred for 1 h. After the mixture was stirred for 14 h at room tem-
perature, it was poured into ice water (300 mL). The aqueous solu-
tion was extracted with EtOAc, and the combined organic layers
were dried with Na2SO4 and concentrated under vacuum. The
crude product was purified by silica gel column chromatography
(hexane/EtOAc, 40:1) to give (4-bromophenyl)(4-nitrophenyl)meth-
anone (0.873 g, 27%) as a yellow solid; Rf = 0.41 (hexane/EtOAc,
1
40:1). H NMR (300 MHz, [D6]DMSO): δ = 8.40–8.34 (m, 2 H),
7.99–7.93 (m, 2 H), 7.84–7.78 (m, 2 H), 7.74–7.68 (m, 2 H) ppm.
13C NMR (75 MHz, [D6]DMSO): δ = 193.7, 149.5, 142.1, 135.0,
131.9, 130.8, 127.7, 123.7 ppm. MS (EI): calcd. for C13H9BrNO3
[M + H]+ 307.1; found 307.1. A mixture that contained (4-bromo-
phenyl)(4-nitrophenyl)methanone (0.203 g, 0.660 mmol), iron pow-
der (0.174 g, 3.12 mmol), concentrated HCl (0.0700 g, 1.92 mmol),
and EtOH (80% in water) was placed in an ultrasonic bath at 85 °C
for 14 h. The remaining iron was removed by filtration, and the
solvents were removed under vacuum. The residue was dissolved
in EtOAc, and the resulting solution was washed with Na2CO3
solution (10% in water), dried with Na2SO4, and concentrated un-
der vacuum. The crude product was purified by silica gel column
chromatography (hexane/EtOAc, 5:1) to give 8a (0.106 g, 59%) as
an orange solid; Rf = 0.20 (hexane/EtOAc, 5:1). 1H NMR
(300 MHz, [D6]DMSO): δ = 7.73–7.68 (m, 2 H), 7.57–7.48 (m, 4
H), 6.63–6.56 (m, 2 H), 6.23 (s, 2 H) ppm. 13C NMR (75 MHz,
[D6]DMSO): δ = 192.2, 154.0, 138.1, 132.7, 131.1, 130.8, 124.7,
123.2, 112.5 ppm. MS (EI): calcd. for C13H11BrNO [M + H]+
276.0; found 276.0.
Photocatalytic Reactions: Catalyst 1a–1d (25 or 100 μm) and sub-
strate 2 (100 μm) in H2O/MeCN (4:1, 4 mL) that contained
Na2HPO4/NaH2PO4 buffer (10 mm, pH = 8.55) were degassed in a
4 mL cuvette by bubbling argon through the solution for 10 min.
The reaction mixture was irradiated with two LEDs (365 nm) at
10 °C. During the irradiation, samples (250 μL) were taken for
HPLC analysis. The samples were concentrated under vacuum and
dissolved in the HPLC eluent (50 μL). HPLC analyses were re-
corded at 242 nm by using heptane/isopropyl alcohol (9:1) as an
isocratic eluent.
4-(ω-Butenyloxy)quinolin-2(1H)-one (2): By starting with commer-
cially available 4-nitroquinoline-N-oxide, substrate 2 was synthe-
sized as described in the literature.[27,28]
3Ј,5Ј-Bis-O-(tert-butyldimethylsilyl)thymidine (4): A mixture of 2Ј-
deoxythymidine (10.0 g, 41.3 mmol) and imidazole (11.8 g,
173 mmol) in anhydrous DMF was stirred at room temperature for
5 min. Then tert-butyldimethylsilyl chloride (13.1 g, 86.7 mmol) (4-Bromophenyl)[4-(dimethylamino)phenyl]methanone (8b): After
was added, and the mixture was stirred for another 12 h. After
adding water (100 mL), the reaction mixture was extracted with
hexane, dried with Na2SO4 and concentrated under vacuum to give
4 (19.3 g, 99%) as a white solid; Rf = 0.81 (CH2Cl2/MeOH, 19:1).
1H NMR (300 MHz, CDCl3): δ = 8.30 (s, 1 H), 7.47 (d, J = 1.3 Hz,
cooling 4-bromobenzoyl chloride (5.00 g, 22.8 mmol) and N,N-di-
methylaniline (4.31 g, 34.2 mmol) in anhydrous Et2O (100 mL) to
0 °C, AlCl3 (8.81 g, 66.1 mmol) was added. The mixture was stirred
at 0 °C for 1 h and then heated at reflux for 12 h. The reaction was
poured into a mixture of ice water (500 mL) and concentrated HCl
1 H), 6.33 (dd, J = 7.9, 5.8 Hz, 1 H), 4.40 (dt, J = 5.5, 2.6 Hz, 1 (45 mL). The aqueous layer was extracted with CHCl3. The com-
Eur. J. Org. Chem. 2015, 6661–6668
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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6665

N. Gaß, H.-A. Wagenknecht
FULL PAPER
bined organic layers were washed with 1 n HCl, water, and brine,
dried with Na2SO4, and concentrated under vacuum. The crude
product was purified by silica gel column chromatography (hexane/
(9b): A mixture of 8b (0.250 g, 0.821 mmol), 5 (0.283 g,
0.821 mmol), and Et3N (0.178 g, 1.77 mmol) was dissolved in
MeCN (20 mL) in a dry vial, and the resulting mixture was de-
EtOAc, 10:1) to give 8b (2.62 g, 38%) as a yellow solid; Rf = 0.24 gassed by a pump–freeze–thaw method. [1,1Ј-Bis(diphenylphos-
1
(hexane/EtOAc, 10:1). H NMR (300 MHz, CDCl3): δ = 7.71 (s, 2
H), 7.57 (d, J = 8.0 Hz, 2 H), 7.46 (d, J = 7.5 Hz, 1 H), 7.28 (s, 1
phino)ferrocene]dichloropalladium(II) (0.101 g, 0.123 mmol) was
added, and the mixture was heated at 60 °C for 20 h. The reaction
H), 3.07 (s, 1 H), 3.01–2.84 (m, 4 H), 2.28 (quint, J = 8.0 Hz, 2 H), was concentrated under vacuum, and the crude product was puri-
2.02 (s, 6 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 146.8, 139.2, fied by silica gel column chromatography (hexane/EtOAc, 40:1 +
137.2, 136.9, 126.9, 126.4, 125.1, 123.3, 122.0, 118.1, 117.6, 76.5,
0.1% Et3N) to give 9b (0.335 g, 28%) as a yellow oil; Rf = 0.14
37.8, 29.9, 24.1, 15.2 ppm. MS (EI): calcd. for C15H14BrNO [M]+ (hexane/EtOAc, 20:1). 1H NMR (300 MHz, [D6]DMSO): δ = 7.71–
303.0; found 303.0.
7.52 (m, 6 H), 6.76 (d, J = 8.7 Hz, 2 H), 5.73 (d, J = 2.7 Hz, 1 H),
5.03 (s, 1 H), 4.54 (s, 1 H), 3.86–3.61 (m, 2 H), 3.03 (s, 6 H), 0.92
(s, 9 H), 0.85 (s, 9 H), 0.23 (s, 3 H), 0.20 (s, 3 H), 0.01 (s, 6 H) ppm.
13C NMR (101 MHz, [D6]DMSO): δ = 193.3, 153.2, 150.2, 146.5,
138.1, 132.1, 128.7, 126.8, 123.6, 110.7, 102.1, 83.4, 63.5, 59.8, 39.6,
25.8, 18.2, 17.7, –5.2, –5.4 ppm. MS (FAB): calcd. for
C32H50NO4Si2 [M + H]+ 568.3; found 568.4.
(4-Bromophenyl)(4-methoxyphenyl)methanone (8c): After cooling 4-
bromobenzoyl chloride (5.00 g, 22.8 mmol) in anhydrous nitroben-
zene (25 mL) to 0 °C, AlCl3 (3.34 g, 25.1 mmol) was added. The
mixture was stirred for 10 min, and anisole (7.50 g, 34.2 mmol) was
added slowly through a dropping funnel. The mixture was stirred
at 0 °C for 30 min and then at room temperature for 12 h. The
reaction mixture was then poured into ice water (200 mL). The
aqueous layer was extracted with CH2Cl2. The combined organic
layers were washed with 1 n HCl, dried with Na2SO4, and concen-
trated under vacuum. The crude product was purified by silica gel
column chromatography (hexane/EtOAc, 20:1) to give 8c (6.39 g,
1β-{[4-(Methoxy)phenyl](phenyl)methanone}-3,5-bis-O-(tert-butyldi-
methylsilyl)-1,2-dideoxy-2,3-didehydro-D-ribofuranose (9c): A mix-
ture of 8c (0.500 g, 1.71 mmol), 5 (0.591 g, 1.171 mmol), and Et3N
(0.373 g, 3.69 mmol) was dissolved in MeCN (15 mL) in a dry vial,
and the resulting mixture was degassed by a pump–freeze–thaw
method. [1,1Ј-Bis(diphenylphosphino)ferrocene]dichloropalladi-
um(II) (0.210 g, 0.258 mmol) was added, and the mixture was
heated at 75 °C for 60 h. The reaction was concentrated under vac-
uum, and the crude product was purified by silica gel column
chromatography (hexane/EtOAc, 20:1 + 0.1 % Et3N) to give 9c
1
96%) as a white solid; Rf = 0.22 (hexane/EtOAc, 20:1). H NMR
(300 MHz, CDCl3): δ = 7.79 (dd, J = 8.9, 1.2 Hz, 2 H), 7.62 (t, J
= 1.0 Hz, 4 H), 7.03–6.89 (m, 2 H), 3.89 (s, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 194.5, 163.6, 137.2, 132.6, 131.6, 131.4,
129.9, 127.0, 113.8, 55.7 ppm. MS (EI): calcd. for C14H12BrO2 [M
+ H]+ 291.0; found 291.0.
1
(0.435 g, 46%) as a yellow oil; Rf = 0.20 (hexane/EtOAc, 20:1). H
(4-Bromophenyl)(4-tolyl)methanone (8d): A mixture of 4-bromo-
benzoyl chloride (3.00 g, 13.7 mmol) and AlCl3 (2.73 g, 20.5 mmol)
in anhydrous toluene (30 mL) was heated at reflux for 2 h. The
reaction was then poured into a mixture of ice water (100 mL) and
concentrated HCl (9 mL). The aqueous layer was extracted with
EtOAc. The combined organic layers were washed with 1 n HCl,
water, and brine, dried with MgSO4, and concentrated under vac-
uum. The crude product was purified by recrystallization (hexane)
to give 8d (2.84 g, 76%) as a light pink solid; Rf = 0.46 (hexane/
EtOAc, 20:1). 1H NMR (300 MHz, CDCl3): δ = 7.67–7.53 (m, 6
H), 7.26–7.19 (m, 2 H), 2.39 (s, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 195.5, 143.7, 136.8, 134.6, 131.6, 130.3, 129.2, 127.3,
21.8 ppm. MS (EI): calcd. for C14H11BrO [M]+ 274.0; found 274.0.
NMR (300 MHz, [D6]DMSO): δ = 7.77–7.68 (m, 2 H), 7.62 (s, 4
H), 7.08 (d, J = 8.8 Hz, 2 H), 5.78–5.69 (m, 1 H), 5.02 (d, J =
1.9 Hz, 1 H), 4.57–4.48 (m, 1 H), 3.80 (d, J = 2.0 Hz, 1 H), 3.72
(dd, J = 11.4, 3.6 Hz, 1 H), 0.92 (s, 9 H), 0.84 (s, 9 H), 0.21 (d, J
= 10.1 Hz, 6 H), 0.01 (s, 6 H) ppm. 13C NMR (101 MHz, [D6]-
DMSO): δ = 162.9, 150.2, 147.4, 136.9, 132.1, 129.4, 129.1, 126.9,
113.9, 83.3, 63.5, 55.6, 25.7, 25.4, 22.1, 18.1, 17.7, –5.4 ppm. MS
(FAB): calcd. for C31H47O5Si2 [M + H]+ 555.3; found 555.3.
1β-{[4-(Methyl)phenyl](phenyl)methanone}-3,5-bis-O-(tert-butyldi-
methylsilyl)-1,2-dideoxy-2,3-didehydro-D-ribofuranose (9d): A mix-
ture of 8d (0.500 g, 1.80 mmol), 5 (0.626 g, 1.180 mmol), and Et3N
(0.395 g, 3.90 mmol) was dissolved in MeCN (15 mL) in a dry vial,
and the resulting mixture was degassed by bubbling argon through
the solution as it was placed in an ultrasonic bath for 5 min. [1,1Ј-
Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.233 g,
0.300 mmol) was added, and the mixture was heated at 75 °C for
48 h. The reaction was concentrated under vacuum, and the crude
product was purified by silica gel column chromatography (hexane/
EtOAc, 20:1 + 0.1% Et3N) to give 9d (0.538 g, 55%) as a yellow
oil; Rf = 0.17 (hexane/EtOAc, 20:1). 1H NMR (300 MHz, [D6]-
DMSO): δ = 7.71–7.60 (m, 6 H), 7.39–7.31 (m, 3 H), 5.76–5.71 (m,
1 H), 4.55–4.50 (m, 1 H), 3.85–3.78 (m, 1 H), 3.74–3.70 (m, 1 H),
2.41 (s, 3 H), 0.92 (s, 9 H), 0.84 (s, 9 H), 0.20 (d, J = 7.4 Hz, 6 H),
–0.01 (d, J = 5.1 Hz, 6 H) ppm. 13C NMR (75 MHz, [D6]DMSO):
δ = 195.1, 150.2, 147.7, 143.1, 136.5, 134.4, 129.8, 129.2, 128.5,
126.9, 101.9, 83.2, 25.8, 25.4, 21.2, 18.1, 17.7, –5.2, –5.5 ppm. MS
(FAB): calcd. for C31H46O4Si2 [M]+ 538.3; found 538.3.
1β-{[4-(Amino)phenyl](phenyl)methanone}-3,5-bis-O-(tert-butyldi-
methylsilyl)-1,2-dideoxy-2,3-didehydro-D-ribofuranose (9a): A mix-
ture of 8a (0.321 g, 0.917 mmol), 5 (0.252 g, 0.917 mmol), and tri-
ethylamine (0.197 g, 1.95 mmol) was dissolved in acetonitrile
(20 mL) in a dry vial, and the resulting mixture was degassed by a
pump–freeze–thaw method. [1,1Ј-Bis(diphenylphosphino)ferro-
cene]dichloropalladium(II) (0.111 g, 0.154 mmol) was added, and
the mixture was heated at 60 °C for 20 h. The reaction was concen-
trated under vacuum, and the crude product was purified by silica
gel column chromatography (hexane/EtOAc, 5:1 + 0.1% Et3N) to
give 9a (0.251 g, 52%) as a yellow oil; Rf = 0.54 (hexane/EtOAc,
5:1). 1H NMR (300 MHz, [D6]DMSO): δ = 7.61–7.44 (m, 6 H),
6.77 (d, J = 8.3 Hz, 1 H), 6.60 (d, J = 8.3 Hz, 1 H), 6.16 (d, J =
5.2 Hz, 2 H), 5.11 (dd, J = 10.8, 5.3 Hz, 1 H), 4.34 (d, J = 5.0 Hz,
1 H), 3.85 (d, J = 5.3 Hz, 1 H), 3.68 (dd, J = 10.7, 4.5 Hz, 1 H),
3.54 (dd, J = 10.7, 6.8 Hz, 1 H), 0.14, 0.11 (d, J = 0.8 Hz, J =
0.9 Hz, 18 H), 0.06, 0.01 (d, J = 0.8 Hz, J = 0.8 Hz, 12 H) ppm.
13C NMR (101 MHz, [D6]DMSO): δ = 193.1, 153.7, 145.5, 138.0,
132.6, 128.8, 125.7, 123.8, 112.5, 88.1, 79.1, 73.9, 43.5, 1.8, 0.2,
–0.5 ppm.
(4-Aminophenyl){4-[(4S,5R)-4-hydroxy-5-(hydroxymethyl)-tetra-
hydrofuran-2-yl]phenyl}methanone (1a): Under argon, 9a (0.123 g,
0.230 mmol) was dissolved in anhydrous THF (6 mL), and the
solution was cooled to 0 °C. NEt3·3HF (0.309 g, 1.92 mmol) was
added, and the reaction mixture was stirred at 0 °C for 15 min and
then at 30 °C for 12 h. The reaction mixture was eluted with acet-
one through a short silica gel column (1 cm), and the eluate was
1β-{[4-(N,N-Dimethylamino)phenyl](phenyl)methanone}-3,5-bis-O-
(tert-butyldimethylsilyl)-1,2-dideoxy-2,3-didehydro-
D-ribofuranose
6666
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 6661–6668

Benzophenone Nucleosides and Their Photocatalytic Evaluation
concentrated under vacuum. Without further purification, the resi-
due was dissolved in AcOH/MeCN (1:1, 8 mL), and the solution
was cooled to 0 °C. NaBH(OAc)3 (0.109 g, 0.510 mmol) was added,
and the reaction mixture was stirred at room temperature for 2 h
and then neutralized with EtOH/water (1:1, 5 mL). The resulting
mixture was concentrated under vacuum, and the crude product
was purified by silica gel chromatography (CH2Cl2/MeOH, 20:1 +
0.1% Et3N) to give 1a (46.1 mg, 65%) as an orange solid; Rf =
0.13 (CH2Cl2/MeOH, 20:1). 1H NMR (300 MHz, [D6]DMSO): δ =
7.70–7.39 (m, 6 H), 6.60 (d, J = 8.40 Hz, 2 H), 6.15 (s, 2 H), 5.09
(dd, J = 10.3, 5.4 Hz, 1 H), 4.22 (d, J = 5.3 Hz, 1 H), 3.83 (s, 1 H),
3.48 (dd, J = 11.9, 5.2 Hz, 1 H), 3.48 (dd, J = 11.9, 5.2 Hz, 1 H),
2.14 (dd, J = 12.1, 5.4 Hz, 1 H), 1.90–1.76 (m, 2 H) ppm. 13C NMR
(75 MHz, [D6]DMSO): δ = 193.2, 153.7, 146.0, 137.9, 132.6, 128.9,
125.7, 123.8, 112.5, 90.0, 78.9, 72.5, 62.5, 43.6 ppm. HRMS (FAB):
calcd. for C18H20NO4 [M + H]+ 314.1387; found 314.1386.
72.43, 62.41, 55.57 ppm. HRMS (FAB): calcd. for C19H21O5 [M +
H]+ 329.1384; found 329.1382.
(4-Methylphenyl){4-[(4S,5R)-4-hydroxy-5-(hydroxymethyl)-tetra-
hydrofuran-2-yl]phenyl}methanone (1d): Under argon, 9d (1.06 g,
1.97 mmol) was dissolved in anhydrous THF (30 mL), and the
solution was cooled to 0 °C. NEt3·3HF (0.890 g, 5.50 mmol) was
added, and the reaction mixture was stirred at 0 °C for 15 min and
at 30 °C for 12 h. The reaction mixture was then eluted with acet-
one through a short silica gel column (1 cm), and the eluate was
concentrated under vacuum. Without further purification, the resi-
due was dissolved in AcOH/MeCN (1:1, 40 mL), and the resulting
mixture was cooled to 0 °C. NaBH(OAc)3 (1.01 g, 4.81 mmol) was
added, and the reaction mixture was stirred at room temperature
for 40 min and then neutralized with EtOH/water (1:1, 40 mL). The
reaction mixture was concentrated under vacuum, and the crude
product was purified by silica gel chromatography (CH2Cl2/MeOH,
20:1) to give 1d (406 mg, 66%) as a yellow oil; Rf = 0.15 (CH2Cl2/
(4-N,N-Dimethylaminophenyl){4-[(4S,5R)-4-hydroxy-5-(hydroxy-
methyl)-tetrahydrofuran-2-yl]phenyl}methanone (1b): Under argon,
9b (0.740 g, 0.130 mmol) was dissolved in anhydrous THF
(5 mL), and the solution was cooled to 0 °C. NEt3·3HF (59.0 mg,
0.360 mmol) was added, and the reaction mixture was stirred at
0 °C for 15 min and then at room temperature for 12 h. The mix-
ture was eluted with acetone through a short silica gel column
(1 cm), and the eluate was concentrated under vacuum. Without
further purification, the residue was dissolved in AcOH/MeCN
(1:1, 8 mL), and the resulting solution was cooled to 0 °C. NaB-
H(OAc)3 (42.0 mg, 0.200 mmol) was added, and the reaction mix-
ture was stirred at room temperature for 20 min and then neutral-
ized with EtOH/water (1:1, 2 mL). The reaction mixture was con-
centrated under vacuum, and the crude product was purified by
silica gel column chromatography (CH2Cl2/MeOH, 40:1 + 0.1%
Et3N) to give 1b (33.0 mg, 75%) as a yellow oil; Rf = 0.12 (CH2Cl2/
MeOH, 20:1). 1H NMR (300 MHz, [D6]DMSO): δ = 7.70–7.54 (m,
4 H), 7.50 (d, J = 7.9 Hz, 2 H), 6.76 (d, J = 8.8 Hz, 2 H), 5.10 (dd,
J = 10.3, 5.4 Hz, 1 H), 4.82 (br. s, 1 H), 4.22 (d, J = 5.2 Hz, 1 H),
3.88–3.76 (m, 1 H), 3.58–3.26 (m, 3 H), 3.03 (s, 6 H), 2.21–2.09 (m,
1 H), 1.88–1.72 (m, 1 H) ppm. 13C NMR (101 MHz, [D6]DMSO):
δ = 193.3, 153.2, 146.2, 137.7, 132.1, 128.9, 125.7, 123.7, 110.7,
87.8, 78.8, 72.4, 64.4, 43.6, 39.6 ppm. HRMS (FAB): calcd. for
C20H24NO4 [M + H]+ 342.1700; found 342.1703.
1
MeOH, 20:1). H NMR (300 MHz, [D6]DMSO): δ = 7.65 (t, J =
8.7 Hz, 4 H), 7.52 (d, J = 8.0 Hz, 2 H), 7.35 (d, J = 7.8 Hz, 2 H),
5.11 (t, J = 5.5 Hz, 2 H), 4.79 (t, J = 5.5 Hz, 1 H), 4.20 (d, J =
4.9 Hz, 1 H), 3.87–3.76 (m, 1 H), 3.46 (m, J = 17.2, 6.0 Hz, 2 H),
2.39 (s, 3 H), 2.15 (dd, J = 12.8, 5.5 Hz, 1 H), 1.79 (td, J = 12.1,
5.4 Hz, 1 H) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 195.1,
147.6, 143.0, 136.2, 134.4, 129.8, 129.6, 129.1, 125.9, 88.0, 78.8,
72.5, 62.4, 43.6, 21.1 ppm. HRMS (FAB): calcd. for C19H21O4 [M
+ H]+ 313.1434; found 313.1436.
Acknowledgments
Financial support by the Deutsche Forschungsgemeinschaft
(DFG) (Wa 1386/16-1 and GRK 1626) and the Karlsruhe Institute
of Technology (KIT) is gratefully acknowledged.
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(4-Methoxyphenyl){4-[(4S,5R)-4-hydroxy-5-(hydroxymethyl)-tetra-
hydrofuran-2-yl]phenyl}methanone (1c): Under argon, 9c (0.435 g,
0.780 mmol) was dissolved in anhydrous THF (15 mL), and the
solution was cooled to 0 °C. NEt3·3HF (59.0 mg, 0.360 mmol) was
added, and the reaction mixture was stirred at 0 °C for 15 min and
at 30 °C for 12 h. The mixture was then eluted with acetone
through a short silica gel column (1 cm), and the eluate was con-
centrated under vacuum. Without further purification, the residue
was dissolved in AcOH/MeCN (1:1, 8 mL) and cooled to 0 °C.
NaBH(OAc)3 (533 mg, 2.51 mmol) was added, and the reaction
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tralized with EtOH/water (1:1, 20 mL). The mixture was concen-
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gel chromatography (CH2Cl2/MeOH, 40:1) to give 1c (166.0 mg,
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779.
(300 MHz, [D6]DMSO): δ = 7.74 (d, J = 8.8 Hz, 2 H), 7.65 (d, J
= 8.2 Hz, 2 H), 7.53 (d, J = 8.2 Hz, 2 H), 7.09 (d, J = 8.8 Hz, 2
H), 5.11 (q, J = 5.8 Hz, 2 H), 4.79 (t, J = 5.3 Hz, 1 H), 4.22 (s, 1
H), 3.86 (d, J = 1.8 Hz, 3 H), 3.83 (dd, J = 5.5, 2.2 Hz, 1 H), 3.56–
3.39 (m, 2 H), 2.16 (ddd, J = 12.6, 5.5, 1.6 Hz, 1 H), 1.80 (ddd, J
= 12.8, 10.5, 5.5 Hz, 1 H) ppm. 13C NMR (101 MHz, [D6]DMSO):
δ = 162.88, 147.20, 132.13, 129.43, 125.85, 113.88, 88.00, 78.81,
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Eur. J. Org. Chem. 2015, 6661–6668
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6667

N. Gaß, H.-A. Wagenknecht
FULL PAPER
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Received: July 6, 2015
Published Online: September 9, 2015
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