Thiourea-enhanced flavin photooxidation of benzyl alcohol

Article abstract of DOI:10.1002/chem.200701319

Upon irradiation, flavin oxidises 4-methoxybenzyl alcohol to the corresponding aldehyde using aerial O₂ as the terminal oxidant. We have observed that this reaction is significantly accelerated by the presence of thiourea. A series of thiourea-functionalised flavins has been prepared from flavin isothiocyanates and their photocatalytic efficiencies have been monitored by NMR. The alcohol photooxidation proceeds rapidly and cleanly with high turnover numbers of up to 580, exceeding previously reported performances. A likely mechanistic rationale for the more than 30-fold acceleration of the photo-redox reaction by thiourea has been derived from spectroscopic, electrochemical, and kinetic studies. Thus, thiourea acts as an electron-transfer mediator for the initial photooxidation of 4-methoxybenzyl alcohol by the excited flavins. This mechanism has similarities to electron-relay mechanisms in flavoenzymes, for which cysteine sulfenic acid intermediates are proposed. The observation that thiourea mediates flavin photo-redox processes is valuable for the design of more sophisticated photocatalysts based on Nature's best redox chromophore.

Full text of DOI:10.1002/chem.200701319

DOI: 10.1002/chem.200701319
Thiourea-Enhanced Flavin Photooxidation of Benzyl Alcohol
Jirˇí Svoboda, Harald Schmaderer, and Burkhard Kçnig*[a]
Abstract: Upon irradiation, flavin oxi-
dises 4-methoxybenzyl alcohol to the
corresponding aldehyde using aerial O2
as the terminal oxidant. We have ob-
served that this reaction is significantly
accelerated by the presence of thio-
with high turnover numbers of up to
580, exceeding previously reported per-
formances. A likely mechanistic ration-
ale for the more than 30-fold accelera-
tion of the photo–redox reaction by
thiourea has been derived from spec-
troscopic, electrochemical, and kinetic
studies. Thus, thiourea acts as an elec-
tron-transfer mediator for the initial
photooxidation of 4-methoxybenzyl al-
cohol by the excited flavins. This mech-
anism has similarities to electron-relay
mechanisms in flavoenzymes, for which
cysteine sulfenic acid intermediates are
proposed. The observation that thiour-
ea mediates flavin photo–redox pro-
cesses is valuable for the design of
ACHTREUNGurea. A series of thiourea-functional-
ised flavins has been prepared from
flavin isothiocyanates and their photo-
catalytic efficiencies have been moni-
tored by NMR. The alcohol photooxi-
dation proceeds rapidly and cleanly
more
sophisticated
photocatalysts
Keywords: flavins · photooxidation ·
redox chemistry · thiourea
based on Natureꢀs best redox chromo-
phore.
Introduction
In this work, we report flavin molecules functionalised
with a thiourea group,[40–42] which, it was envisaged, would
reversibly bind substrates of photooxidation reactions to
keep them in the vicinity of the excited chromophore. The
aim was to increase the electron-transfer efficiency by
making the process intramolecular rather than diffusion-
controlled.[33,34,43] To investigate possible effects of thiourea
functionalisation, the activity of the newflavin molecules in
the photooxidation of 4-methoxybenzyl alcohol in air has
been studied.[44]
Flavins are Natureꢀs beloved redox co-factors.[1,2] They occur
in a number of enzymes which are responsible for some of
the most essential biochemical processes, mostly in the form
of flavin adenine dinucleotide (FAD) or flavin mononucleo-
tide (FMN) co-factors. Their redox properties, reactivity,
and selectivity for the desired process are fine-tuned by sub-
stitution, non-covalent interactions, and the presence of the
surrounding protein, and their function can therefore be
tailored to the required task. Their reactivity increases fur-
ther upon irradiation, making them strong oxidising
agents.[3–6]
Results and Discussion
A large number of flavoenzyme models, usually designed
to simulate a particular feature of the protein in a minimised
system, have been studied.[7–29] Most studies of this type
have been focussed on changes of the flavin chromophore
redox potentials caused by non-covalent interactions. How-
ever, examples in which the modification of flavin reactivity
has been applied to chemical catalysis are less common.[30–39]
The newcompounds were synthesised according to the
Kuhn protocol.[45] The preparation of 4,5-dimethyl-1,2-dini-
trobenzene (1) was optimised to obtain the starting material
in sufficient quantities (see the Supporting Information).
Heating the dinitro compound 1 with 3-oxabut-1-yl amine,
2-(tert-butyloxycarbonylamino)ethyl amine, or symmetrical
3,6-dioxaoctyl-1,8-diyl diamine led to N-substituted 2-nitro-
AHCTREaUNG nilines 2–4 (Scheme 1). The glycol chains increase the solu-
[a] Dr. J. Svoboda, Dipl.-Chem. H. Schmaderer, Prof. Dr. B. Kçnig
Institute of Organic Chemistry, Universität Regensburg
93040 Regensburg (Germany)
bility of the target molecules in polar solvents, and the
amino groups could be converted into thiourea moieties at a
later stage. Although 3,6-dioxaoct-1,8-diyl diamine was not
mono-protected, two-fold substitution was not observed.
However, the side chain amino group disturbs the course of
the cyclocondensation reaction of the phenylene–diamine
Fax : (+49)941-943-1717
E-mail: burkhard.koenig@chemie.uni-regensburg.de
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
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FULL PAPER
Scheme 1. ipso-Substitution of dinitro compound 1 with amines and pro-
tection of the side chain amino group. i) 3-Oxabut-1-yl amine (neat),
808C, 6 h, 99%; ii) pyridine, 24 h, 908C, 46%; iii) ethanol, reflux, 62 h,
51%; iv) Cbz-Cl, TEA, dichloromethane, RT, 30 min, 64%; v) Ethyl tri-
fluoroacetate (ETFA), TEA, methanol, RT, 24 h, 83%.
Scheme 2. Completion of flavin synthesis. i) 1) H2 (g), 10% palladium on
activated charcoal, acetic acid (compounds 2, 3, and 4-TFA), or tin(II)
chloride, ethanol, reflux, 72 h (compound 4-Cbz); 2) alloxane hydrate,
boric acid, acetic acid, RT, 50% (5), 47% (6-Boc), 71% (7-Cbz), 48%
(7-TFA); ii) dimethyl sulfate, caesium carbonate, DMF (dry), RT, over-
night, 53%; iii) HCl, diethyl ether, chloroform, RT, overnight, 83%;
iv) HCl, diethyl ether, chloroform, RT, overnight, 100%; v) aqueous HCl
(6m), 90–958C, 90 min, 100%.
intermediate with alloxane hydrate, and so had to be pro-
tected to enable completion of the flavin synthesis. The
flavin skeleton is sensitive to bases,[46,47] hence protective
groups that require removal by base were unsuitable. Suita-
ble protection was ensured by benzyloxycarbonyl and tri-
fluoroacetyl groups.
The synthesis of the flavin skeleton was completed by re-
duction of the remaining nitro group and cyclocondensation
of the resulting phenylene–diamine intermediates with allox-
ane hydrate in the presence of boric acid. In this way, flavins
5, 6-Boc, 7-Cbz, and 7-TFA were obtained (Scheme 2).
Flavin 6-Boc was N-methylated with dimethyl sulfate to
give the corresponding analogue 8-Boc. tert-Butyl carba-
mates 6-Boc and 8-Boc were cleaved with hydrogen chloride
to afford 10-(2’-aminoethyl) flavins 6·HCl and 8·HCl. Un-
fortunately, the benzyloxycarbonyl protective group of
flavin 7-Cbz could not be removed by any of the usual
methods.[48,49] Cleavage of the trifluoroacetamide 7-TFA in a
strongly acidic environment[50] led to the quantitative forma-
tion of aminoglycol flavin 7·HCl.
Scheme 3. Synthesis of 3-(2’-aminoeth-1’-yl) flavin (9). i) 2-(tert-Butyloxy-
carbonylamino)eth-1-yl bromide, K2CO3, NaI, DMF (dry), RT, 3 d, 54%;
ii) HCl, diethyl ether, RT, 95%.
ty, and the corresponding thioureas were obtained in excel-
lent yields.
Passing gaseous ammonia through solutions of the respec-
tive isothiocyanates led to the mono-substituted thioureas
14–17 (Scheme 5), which were less soluble than the starting
Flavin 5 was N-alkylated with 2-(tert-butyloxycarbonyl-
amino)ethyl bromide (Scheme 3). Cleavage of tert-butyl car-
bamate 9-Boc with hydrogen
chloride yielded the corre-
sponding 3-(2’-aminoeth-1’-yl)
flavin 9·HCl. Amines 6–9 were
then converted into the corre-
sponding isothiocyanates 10–13
by reaction with thiophosgene
in a two-phase solvent mixture
(Scheme 4). The reactions were
clean and rapid, and very good
yields of the isothiocyanates
were obtained.
The reaction of isothiocya-
nates with amines leads to the
formation of substituted thio-
ACHTREUNG
ureas.[40,51] Flavin isothiocya-
nates 10–13 showhigh reactivi-
Scheme 4. Synthesis of isothiocyanates 10–13. Thiophosgene, dichloromethane, calcium carbonate, water, RT,
87% (10), 79% (11), 97% (12), 89% (13).
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1855

B. Kçnig et al.
Scheme 6. Synthesis of flavin–bis-thioureas 25 and 26. i) 2-(tert-Butyloxy-
carbonylamino)eth-1-yl bromide, K2CO3, NaI, DMF (dry), 3 d, 52%;
ii) HCl, diethyl ether, methanol, RT, overnight, 100%; iii) thiophosgene,
dichloromethane, calcium carbonate, water, overnight, 81%; iv) NH3 (g),
methanol, chloroform, 100%, RT, 1 h; v) perfluorooctylethyl amine,
TEA, chloroform, reflux, 51%.
amine yielded compound 26 containing two N,N’-substituted
thiourea groups.
The reaction of isothiocyanate 12 with aminoglycol flavin
7 (Scheme 7) and two-fold reaction of isothiocyanate 12
Scheme 5. Synthesis of thioureas 14–21 from isothiocyanates 10–13.
i) NH3 (g), methanol, RT, 3 h, 76%; ii) perfluorooctylethyl amine, TEA,
chloroform, reflux, overnight, 68%; iii) NH3 (g), chloroform, RT, 2 h,
68%; iv) perfluorooctylethyl amine, TEA, chloroform, reflux, overnight,
79%; v) NH3 (g), chloroform, RT, 3 h, 44%; vi) 3-oxabut-1-yl amine,
chloroform, reflux, 2.5 h, 100%; vii) NH3 (g), chloroform, RT, 3 h, 100%;
viii) perfluorooctylethyl ammonium chloride, TEA, reflux, 18 h, 67%.
materials and could be isolated in yields of 44–100% by fil-
tration or trituration. Reactions with primary amines led to
N,N’-substituted thioureas 18–21. A hydrophilic chain (thio-
urea 18) or fluorophilic chain (thioureas 19–21) was intro-
duced to increase the solubility of the molecules in hydro-
philic or fluorophilic solvents, respectively.
Flavins containing two thiourea groups were prepared
starting from flavin 6-Boc, which was alkylated with 2-(tert-
butyloxycarbonylamino)ethyl bromide to afford flavin 22
(Scheme 6). Removal of both Boc protective groups led to
bis(2’-aminoethyl) flavin dihydrochloride 23·2HCl in quanti-
tative yield. Two-fold reaction with thiophosgene under the
conditions mentioned above led to bis(isothiocyanatoethyl)
flavin 24. Reaction of both isothiocyanate groups with am-
monia gave compound 25 containing two mono-substituted
thiourea groups, and reaction with perfluorooctylethyl
Scheme 7. Synthesis of bis-flavin 27. TEA, chloroform, reflux, 22 h,
100%.
with 3,6-dioxaoct-1,8-diyl diamine (Scheme 8) yielded bis-
flavins 27 and 28, respectively, containing one and two thio-
urea groups and a glycol linker of varying length, both in
high yields.[21,26,37]
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Thiourea-Enhanced Flavin Photooxidation
FULL PAPER
Figure 1. Stack plot of the aromatic region of the 1H NMR spectra re-
corded during the irradiation of 4-methoxybenzyl alcohol in the presence
of 10-thioureidoglycol flavin 16. Perspective viewof the spectra is used
*
(no change of the chemical shift of the signals). : 4-methoxybenzyl alco-
*
hol aromatic signals; : 4-methoxybenzaldehyde aromatic signals. Reso-
nance signals in the baseline noise belong to flavin. Initial concentration
of 4-methoxybenzyl alcohol 2”10À3 m; concentration of flavin 2”10À4 m.
Recorded on a Bruker spectrometer at working frequency 400 MHz
using 64 transitions.
in a very clean conversion. At the concentrations used
(flavin 2”10À4 m, 4-methoxybenzyl alcohol 2”10À3 m), the
resonance signals of the photocatalysts are observed only as
minor peaks in the baseline noise. Hydrogen peroxide was
not detected by NMR, presumably due to fast deuterium ex-
change with the solvent.[56]
Scheme 8. Synthesis of bis-flavin 28. Chloroform, reflux, 8 h, 93%.
Flavin-mediated photooxidation of 4-methoxybenzyl alco-
hol to the corresponding aldehyde using aerial oxygen as
terminal oxidant was chosen as the model reaction to study
the catalytic activity of the newflavin–thiourea compounds.
Other photocatalysts, such as titanium dioxide, can also me-
diate this oxidation, but they require intense UV irradia-
tion.[52] The catalytic flavin cycle starts with the oxidised
form of flavin, which is irradiated with visible light (l=
440 nm; the absorption maximum of flavin is in the visible
region). The excited chromophore is a strong oxidising
agent,[3–6] and accepts electrons and protons in a stepwise
manner from the benzyl alcohol substrate. The aldehyde is
formed, along with the reduced flavin, which rapidly reacts
with oxygen dissolved in the reaction mixture to yield the
hydroperoxide intermediate. The hydroperoxide intermedi-
ate then instantaneously releases hydrogen peroxide and re-
generates the oxidised flavin, thus completing the catalytic
cycle.[53,54] The oxidation of benzyl alcohol to benzaldehyde
by oxygen is an exothermic process, but it does not proceed
in the absence of flavin or light. The efficiency of the flavin
photooxidation increases if substrate-binding sites are pres-
ent in the vicinity of the chromophore,[23,33,34] and the experi-
ments described herein were performed with the aim of clar-
ifying the effect of thiourea substituents on the photooxida-
tion process.
In the absence of flavin, light, or oxygen, or in the pres-
ence of thiourea alone, the reaction did not proceed
(Table 1, entries 17–20).[57] Using simple flavins 5, 30, and 31
(Scheme 9), which do not contain a thiourea group, some
amount of the product was formed, but the conversion re-
mained very low(entries 11, 12, and 16). Bis-flavins 27 and
28 (entries 13 and 14) were not very efficient either, presum-
ably due to steric factors or unproductive excimer forma-
tion.[25] Thiourea groups attached at the 3- or 10-position led
to similar rate enhancements: 3-(2’-thioureidoethyl) flavin
17 oxidised 64% of the alcohol within 60 min, while 10-(2’-
thioureidoethyl) flavin 14 oxidised 47% of the alcohol in
this time (cf. entries 2 and 4). The distance of the thiourea
group from the chromophore was found to play a significant
role.[58] With the thiourea group located at the end of the di-
oxaoctyl chain (catalyst 16) the conversion reached 92%,
while with a short ethylene spacer (catalyst 14) only 47%
conversion was observed (cf. entries 1 and 4).
The flavin–thiourea photocatalysts remained active for
several subsequent cycles (Figure 2). At hourly intervals, the
conversion of 4-methoxybenzyl alcohol to the aldehyde was
1
determined by H NMR, and an aliquot of concentrated al-
The reactions were monitored in
a
mixture of
cohol stock solution was added to restore the initial alcohol-
to-sensitiser ratio. While high conversion within 1 h was ob-
served in the first cycles, the activity of the photocatalyst
subsequently decayed due to photodecomposition of the
flavin chromophore.
[D3]acetonitrile and [D6]dimethyl sulfoxide (98:2 v/v) by
1H NMR.[55] Upon irradiation, the intensity of the resonance
signals corresponding to the benzyl alcohol decreased, while
benzaldehyde resonance signals appeared (Figure 1, Table 1)
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B. Kçnig et al.
Table 1. Results of flavin-mediated photooxidations of 4-methoxybenzyl alcohol to 4-methoxybenzaldehyde.
catalysts 19 and 20 and bis-thio-
urea catalysts 25 and 26 (en-
tries 3, 8, 10, and 15) were not
sufficiently soluble to test their
efficiencies at 2”10À4 m. How-
ever, they were highly active
even at lower concentrations,
especially compound 19, which
oxidised 64% of the substrate
while present at 1.5 mol%, thus
achieving a turnover frequency
(TOF) of 45 hÀ1.
Surprisingly, the covalent
linkage between the flavin
chromophore and the thiourea
group was not decisive for the
catalytic activity. Mixtures of
related flavin molecules not
bearing a covalently-linked thi-
ourea group with stoichiometric
amounts of thiourea worked
comparably well (Table 1, en-
tries 24–26). This made us
revise the hypothesis of reversi-
ble non-covalent binding of the
substrate to the thiourea group.
Indeed, addition of 4-methoxy-
benzyl alcohol to the most
active catalyst, 16, did not cause
any quenching of the flavin
fluorescence and induced no
changes in the UV/Vis spec-
trum, suggesting no direct bind-
ing between the substrate and
the thiourea group. This as-
sumption was supported by
19F NMR titration of 2-fluoro-
benzyl alcohol with flavin–thio-
urea 16. Upon addition of the
Entry
Flavin
4-Me-
thoxy-
benzyl
alcohol
Substrate/
catalyst
ratio
Irradiation
time [h]
Conversion
[%]
TON TOF
[hÀ1
Quantum
yield
F (”100)
photocatalyst
]
[mol LÀ1
]
A
]
flavin-catalysed photooxidations
1
2
3
4
5
6
7
8
16 (2”10À4
17 (2”10À4
19 (3”10À5
14 (2”10À4
18 (2”10À4
15 (2”10À4
21 (2”10À4
25 (5”10À5
29 (2”10À4
20 (2”10À5
)
)
)
)
)
)
)
)
)
)
2”10À3
2”10À3
2”10À3
2”10À3
2”10À3
2”10À3
2”10À3
2”10À3
2”10À3
2”10À3
2”10À3
2”10À3
2”10À3
2”10À3
2”10À3
2”10À3
10:1
10:1
70:1
10:1
10:1
10:1
10:1
40:1
10:1
100:1
10:1
10:1
10:1
10:1
200:1
10:1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
92
64
64
47
41
40
39
27
25
20
9
9.2 9.2
6.4 6.4
0.93
0.65
0.65
0.48
0.42
0.41
0.40
0.27
0.25
0.20
0.09
0.07
0.06
0.06
0.03
0.02
45
45
4.7 4.7
4.1 4.1
4.0 4.0
3.9 3.9
11
11
9
2.5 2.5
10
11
12
13
14
15
16
20
20
5 (2”10À4
31 (2”10À4
27 (2”10À4
28 (2”10À4
26 (1”10À5
30 (2”10À4
)
0.9 0.9
0.7 0.7
0.6 0.6
0.6 0.6
)
)
)
)
)
7
6
6
3
6
6
2
0.2 0.2
experiments without light, oxygen, or flavin
17
18
19
20
16 (2”10À4
16 (2”10À4
None
)
)
2”10À3
2”10À3
2”10À3
2”10À3
10:1
10:1
1[a]
1[b]
1
5
0
0
0
0.5 0.5
0.05
–
–
–
–
–
–
–
–
–
N/A
N/A
None[c]
1
experiments with lower catalyst loading
21
22
23
16 (2”10À4
16 (2”10À5
16 (2”10À4
)
)
)
2”10À2
2”10À3
2”10À1
100:1
100:1
16
156
96
84[d]
61
87
61
580
5.4
0.4
6.0
0.55
0.004
0.006
1000:1
50[e]
stoichiometric mixtures of flavin and thiourea and miscellaneous experiments
[c]
24
25
26
27
28
5 (2”10À4
)
2”10À3
2”10À3
2”10À3
2”10À3
2”10À3
10:1
10:1
10:1
10:1
10:1
1
1
0.5
1
91
95
89
99
3
9.1 9.1
9.5 9.5
8.9 18
9.9 9.9
0.3 0.3
0.92
0.97
1.81
1.01
0.03
[c]
[c]
[f]
30
A
)
)
)
31 (2”10À4
30 (2”10À4
[g]
5 (2”10À4
)
1
[a] The reaction mixture was thoroughly purged with argon prior to irradiation. [b] Instead of irradiation, the
reaction mixture was left to stand in the dark. [c] Thiourea (2”10À4 m) was added to the reaction mixture.
[d] Mixture of 4-methoxybenzaldehyde (81%) and p-anisic acid (3%). [e] Mixture of 4-methoxybenzaldehyde
(42%) and p-anisic acid (8%). [f] N,N,N’,N’-Tetramethylthiourea (2”10À4 m) was added to the reaction mix-
ture. [g] Urea (2”10À4 m) was added to the reaction mixture.
To further probe the activity of the most efficient com-
pound 16, experiments with higher substrate-to-photocata-
lyst ratios were carried out (Table 1, entries 21–23). Regard-
less of whether the concentration of the substrate was in-
creased or the concentration of the flavin sensitiser was low-
ered to reach the higher ratio, the reaction was significantly
slower and longer irradiation times were therefore required.
Nevertheless, unprecedented turnovers were observed:
using a mere 0.1 mol% of the flavin photocatalyst, a total
conversion of 50% after 4 d of irradiation was observed. 4-
Methoxybenzaldehyde (42%) was in this case accompanied
by p-anisic acid (8%), the product of a subsequent oxida-
tion, which was not observed in the experiments employing
10 mol% of flavin sensitiser, even after prolonged irradia-
tion of the fully converted reaction mixtures or of mixtures
with authentic 4-methoxybenzaldehyde. This result corre-
sponds to a TON of 580, significantly exceeding the highest
turnover hitherto reported for this reaction.[33] Fluorophilic
flavin–thiourea, no change in the chemical shift of the fluo-
rine nucleus was observed, again indicating no direct inter-
action.
To assess whether the presence of thiourea influences the
redox potential of the flavin through hydrogen binding, as
observed in natural flavoenzymes and models there-
of,[15,16,20,21,24,59–65] the reduction potentials of 10-thioureido-
glycol flavin 16 and 10-(3’,6’-dioxahept-1’-yl) flavin 30 were
determined by cyclic voltammetry (see the Supporting Infor-
mation). These measurements revealed a shift of the reduc-
tion potential by +90 mV for flavin–thiourea 16 as com-
pared to 30. This shift is not as pronounced as those for re-
lated flavin molecules that catalyse the oxidation of 4-me-
thoxybenzyl alcohol less efficiently (e.g., the reduction po-
tential of compound 29 is shifted by +200 mV compared to
that of compound 30),[33] and so cannot be cited to justify
the high activity in the oxidation reactions. To disprove a hy-
drogen-bond-mediated change in the redox potential of the
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Thiourea-Enhanced Flavin Photooxidation
FULL PAPER
Scheme 10. Proposed catalytic cycle for the thiourea-mediated photooxi-
dation of 4-methoxybenzyl alcohol.
ties participating in the system is thermodynamically feasi-
ble, the relevant redox potentials were determined by cyclic
voltammetry and DG values for the electron-transfer reac-
tions were calculated using the Rehm–Weller equation (Sup-
porting Information).[68,69] It was found that the excited
flavin can indeed oxidise either the alcohol (DG=
À29 kJmolÀ1) or thiourea (DG=À100 kJmolÀ1). The re-
duced form of the flavin may also reduce thiourea (DG=
À55 kJmolÀ1) or be re-oxidised by oxygen (DG=
À35 kJmolÀ1); however, the rate-determining step is the oxi-
dation of the substrate, not the re-oxidation of the reduced
form of the flavin, as only the oxidised form can be ob-
served in UV spectra recorded during the reaction. Thiourea
must therefore exert its positive effect on the oxidation of
the substrate. The ability of thiourea to enhance the reactivi-
ty of flavin may stem from its propensity to be oxidised to
highly reactive (radical) intermediates.[70–72] Accordingly,
urea, which cannot tautomerise to the isourea form[73] that is
necessary to enable oxidation,[74] does not increase the effi-
ciency of the flavin photocatalyst (Table 1, entry 28). The sit-
uation may be analogous to that in certain oxidases, which
contain a stabilised sulfenic acid based on the cysteine side
chain in the vicinity of the flavin-dependent active site.[75–80]
The effect of thiourea on the reaction rate is a diffusion-
controlled process rather than a photochemical reaction
within a non-covalent assembly. When an excess of thiourea
with respect to the flavin is used, the oxidation proceeds sig-
nificantly more rapidly than in the case of a stoichiometric
mixture of flavin and thiourea. In addition, the difference in
photocatalyst efficiency between covalently tethered thio-
Scheme 9. Flavin molecules that do not contain a thiourea group, used
for comparison.
Figure 2. Repeated oxidation of 4-methoxybenzyl alcohol. Conditions:
flavin–thiourea 16 2”10À4 m, 4-methoxybenzyl alcohol 2”10À3 m before
every cycle (1 h). Products accumulated in the reaction mixture.
flavin as the origin of the increased reactivity in alcohol
photooxidation, experiments were carried out using mix-
tures of 10-(3’,6’-dioxahept-1’-yl) flavin 30 with either thio-
ACHTREUNGurea or N,N,N’,N’-tetramethylthiourea, and these gave com-
parable results (Table 1, cf. entries 25 and 27).
Another potential effect of thiourea, which is a mild or-
ganic base, is deprotonation of the alcohol, making it more
electron-rich and facilitating its oxidation. However, al-
though thiourea is more basic than alcohols in aqueous envi-
ronments, the situation changes in organic media due to less
effective solvation of the alcoholate anion, making deproto-
nation by thiourea virtually impossible.[66,67]
AHCTREUNG
Conclusion
Having disproved the hypotheses described above, we
turned our attention to the possibility that thiourea func-
tions as an electron mediator between the substrate and the
flavin moiety, and assists the chromophore in bringing the
oxidation about (Scheme 10). To assess whether electron
transfer between the flavin unit and thiourea and other enti-
Flavin–thioureas 14–21 and 25–28 have been prepared by
the Kuhn synthesis and the application of isothiocyanate
chemistry. The photocatalysts have been successfully applied
to the oxidation of 4-methoxybenzyl alcohol to 4-methoxy-
benzaldehyde using aerial oxygen as the terminal oxidising
Chem. Eur. J. 2008, 14, 1854 – 1865
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1859

B. Kçnig et al.
methylsilyl peak of the TSP internal standard. The quantum yield was es-
timated by standard ferrioxalate actinometry.[85]
agent. The activities of some of the catalysts exceeded those
of known systems and high TONs of up to 580 were ob-
served. The presence of thiourea, either covalently bound to
a flavin derivative or added stoichiometrically, led to a 30-
fold increase in the quantum yield of the reaction in some
cases. Our investigations have revealed that thiourea pre-
sumably acts as an efficient electron mediator between the
photoactive flavin chromophore and the substrate.
Cyclic voltammetry: Cyclic voltammograms were recorded on an Autolab
potentiostat, using a glassy carbon working electrode, a platinum auxili-
ary electrode, and a saturated calomel reference electrode (SCE). The
auxiliary electrolyte was 0.1m tetrabutylammonium tetrafluoroborate, the
solvent was a mixture of acetonitrile and dimethyl sulfoxide (98:2, v/v),
and the analytes were present at a concentration of 1 mm. Solutions were
degassed with a stream of argon prior to the measurements and were
maintained under a gentle stream of argon during acquisition of the vol-
tammograms; a step potential of 0.1 VsÀ1 was used.
N-(3’-Oxabut-1’-yl)-4,5-dimethyl-2-nitroaniline (2): Dinitrobenzene
1
(2.94 g, 15 mmol) was dissolved in 3-oxabut-1-yl amine (25 mL) and the
reaction mixture was heated to 808C for 6 h. It was then diluted with di-
chloromethane (100 mL) and washed with water (2”100 mL) and brine
(100 mL); the organic phase was dried over magnesium sulfate and con-
centrated to dryness in vacuo. The product (brown oil) partially solidified
upon drying (3.35 g, 99%); 1H NMR (CDCl3): d=2.14 (s, 3H; CH3-4),
2.23 (s, 3H; CH3-5), 3.40 (s, 3H; CH3-4’), 3.42–3.47 (m, 2H; CH2-1’), 3.65
(m, 2H; CH2-2’), 6.60 (s, 1H; H-6), 7.87 (s, 1H; H-3), 8.07 ppm (brs, 1H;
NH); 13C NMR (CDCl3): d=18.4, 20.6 (2”CH3), 42.6 (CH2), 58.9 (CH3),
70.4 (2”CH2), 114.0 (CH), 124.4 (quaternary C), 126.3 (CH), 129.8,
143.9, 147.1 ppm (3”quaternary C); CI-MS: m/z (%): 225.1 (100)
[M+H]+, 195.2 (60) [M+HÀNO]+.
Experimental Section
General: 10-(3’-Oxabut-1’-yl) flavin 5,[81] 10-[2’-(tert-butyloxycarbonylami-
no)eth-1’-yl] flavin 6-Boc,[17] 10-(2’-aminoeth-1’-yl) flavin 6,[17] 2-
perfluoroACHTREUNG
octylethyl amine,[82] 2-(tert-butyloxycarbonylamino)ethyl bro-
mide,[83] and (3’,6’-dioxahept-1’-yl) flavin 30[33] were prepared by known
methods. Flavin–zinc(II)–cyclene 29 was a gift from Dr. Radek Cibulka.
All other chemicals were purchased from commercial suppliers, checked
by 1H NMR spectrometry, and then used as received. Solvents were dis-
tilled before use and dried by standard methods if required by the experi-
mental procedure. Dry N,N-dimethylformamide was purchased from
Fluka. Thin-layer chromatography (TLC) was carried out on silica gel 60
F254 coated aluminium sheets (Merck) or on pre-coated Polygram SIL G/
UV254 plastic sheets (Macherey-Nagel, Düren, Germany), with detection
under 254 nm or 333 nm UV light, by the naked eye (flavins are intensely
yellow-coloured), or by staining with ninhydrin solution. Preparative
thin-layer chromatography (PTLC) was carried out on home-made glass
plates (20”20 cm) coated with silica gel 60 GF254 (20 g, Merck). Column
chromatography was carried out on silica gel Geduran 60 (Merck) or
silica gel 60M (Macherey-Nagel). Flash chromatography was carried out
on silica gel 60A, 0.035–0.070 mm, from Acros. Nuclear magnetic reso-
nance spectra were recorded on a Bruker spectrometer equipped with a
robotic sampler at 300 MHz (1H NMR) or 75 MHz (13C NMR), unless
otherwise indicated. Tetramethylsilane (TMS) was used as an external
standard. Electron-impact (EI-MS) and chemical ionisation (CI-MS)
mass spectra were measured on a Finnigan TSQ 710 spectrometer, and
electrospray ionisation (ES-MS) mass spectra were measured on a Ther-
moQuest Finnigan TSQ 7000 spectrometer. All determinations by high-
resolution mass spectrometry (HR-MS) were performed on a Thermo-
Quest Finnigan MAT 95 spectrometer. Elemental compositions (C, H, N,
S) of the newcompounds were determined either by HR-MS or by com-
bustion elemental analysis. Melting points were measured with a Büchi
SMP-20 melting point apparatus using a glass capillary tube immersed in
heated silicon oil, and are uncorrected. UV/Vis spectra were recorded on
a Varian Cary 50 Bio UV/Vis spectrometer with reference to air. Fluores-
cence spectra were recorded on a Varian Cary Eclipse fluorescence spec-
trophotometer.
N-(8’-Amino-3’,6’-dioxaoct-1’-yl)-4,5-dimethyl-2-nitroaniline (4): The pro-
cedure used was analogous to that described by Sawhney et al.[86] Thus,
dinitro compound 1 (6.0 g, 30 mmol) was dissolved in ethanol (3 L). 1,8-
Diamino-3,6-dioxaoctane (23.8 g, 160 mmol, 5.3 equiv) was added and
the reaction mixture was heated to reflux for 62 h. It was then concen-
trated in vacuo, and the residue was redissolved in dichloromethane. This
solution was extracted with dilute hydrochloric acid, and the aqueous
phase was separated and neutralised with dilute sodium hydroxide solu-
tion. The resulting solution was extracted with dichloromethane, the or-
ganic phase was separated and concentrated, and the residue was co-
evaporated with toluene and dried to obtain a red oil (4.6 g, 51%). Rf =
0.17 (CH2Cl2/MeOH/TEA 50:2:1); 1H NMR (CDCl3): d=2.15 (s, 3H;
CH3-4), 2.24 (s, 3H; CH3-5), 2.86, 3.52, 3.66, 3.77 (4”m, 12H in total; 6”
CH2 glycol), 6.61 (s, 1H; H-6), 7.90 (s, 1H; H-3), 8.13 ppm (brs, 1H; Ar-
NH-); 13C NMR (CDCl3): d=18.6, 20.7 (2”CH3), 41.1, 42.7, 69.1, 70.3,
70.6, 71.7 (6”CH2), 114.2 (CH), 117.8, 124.6 (2”quaternary C), 126.5
(CH), 144.1, 147.3 (2”quaternary C); ES-MS: m/z (%): 298.2 (100)
[M+H]+; HR-MS (EI-MS): m/z: calcd for C14H23N3O4 [M]+ : 297.1689;
C
found: 297.1689 (delta 0.00 ppm).
N-[8’-(Benzyloxycarbonylamino)-3’,6’-dioxaoct-1’-yl]-4,5-dimethyl-2-ni-
troaniline (4-Cbz): The procedure used was analogous to that described
by Nicola et al.[87] Thus, free amine 4 (650 mg, 2.2 mmol) was dissolved in
dry dichloromethane (100 mL).
A solution of benzyl chloroformate
(380 mg, 2.2 mmol, 1 equiv) in dry dichloromethane (50 mL) was added
dropwise. Triethylamine (0.75 mL) was added to the reaction mixture
and the reaction was monitored by TLC (mobile phase CH2Cl2/MeOH/
TEA 50:2:1; staining with ninhydrin). After 30 min, the spot due to the
starting material (Rf =0.17) was no longer visible. The reaction mixture
was concentrated in vacuo, the residue was dissolved in the minimum
volume of methanol, and this solution was applied to four PTLC plates.
The mixture was separated using the aforementioned eluent system, and
the appropriate zone (Rf =0.58) was thoroughly extracted with chloro-
form. The extract was concentrated in vacuo and the residue was dried to
yield a red oil (610 mg, 64%). Rf =0.58 (CHCl2/MeOH/TEA 50:2:1);
1H NMR (CDCl3): d=2.13 (s, 3H; CH3-4), 2.22 (s, 3H; CH3-5), 3.41,
3.55, 3.63, 3.77 (4”m, 12H in total; 6”CH2 glycol), 5.05 (s, 2H; CH2Ph),
5.44 (brs, 1H; H-8’), 6.57 (s, 1H; H-6), 7.30 (m, 5H; Ph), 7.86 (s, 1H; H-
3), 8.13 ppm (s, 1H; NH aniline); 13C NMR (CDCl3): d=18.6, 20.7 (2”
CH3), 42.7 (CH2Ph), 65.1, 66.6, 69.1, 70.2, 70.3, 70.5 (6”CH2 glycol),
114.2 (CH aniline), 124.5 (quaternary C), 126.4 (CH aniline), 126.8 (qua-
ternary C), 128.0, 128.5, 130.0 (3”CH phenyl), 137.7, 144.0, 147.3 (4”
quaternary C), 156.5 ppm (C=O); EI-MS (70 eV): m/z (%): 91.1 (100)
Kinetic experiments: Kinetic experiments were carried out in a mixture
of [D3]acetonitrile and [D6]dimethyl sulfoxide (98:2, v/v). The latter was
required to improve the solubility of the flavin–thiourea photocatalysts.
A typical reaction mixture, prepared in an NMR tube,[84] contained the
flavin derivative (2”10À3 m) and 4-methoxybenzyl alcohol (2”10À4 m) and
had a total volume of 1 mL. The reaction mixture was prepared under
aerobic conditions, but the solution was not additionally saturated with
oxygen. The reaction mixture was irradiated by means of a light-emitting
diode with an emission wavelength of 440 nm and an electric power of
6 W. The NMR tube was placed vertically above the aperture of the
LED. The optical path using this set-up was about 73 mm. The reaction
mixture was irradiated for the desired time, and then the 1H NMR spec-
trum of the mixture was recorded using a Bruker spectrometer with a
working frequency of 400 or 300 MHz using 64 transitions to achieve a
better signal-to-noise ratio and hence more accurate integration. Sodium
3-(trimethylsilyl)-2,2,3,3-tetradeuteropropionate (TSP, 2”10À3 m)
used as an internal standard. The concentrations of the substrate and
product were derived from the areas under the peaks of the aromatic
doublets (see Figure 1) by comparison with the integral value of the tri-
w
as
[C7H7]+, 179.1 (62) [ArNH=CH2]+, 431.2 (5) [M]+ ; elemental analysis
C
1860
www.chemeurj.org
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 1854 – 1865

Thiourea-Enhanced Flavin Photooxidation
FULL PAPER
calcd (%) for C22H29N3O6: C 61.24, H 6.77, N 9.74; found: C 61.44, H
6.91, N 9.65.
Rf =0.65 (CHCl3/MeOH/AcOH 77.5:15:7.5); m.p. 2158C (decomp);
1H NMR ([D6]DMSO): d=2.40 (s, 3H; CH3-7), 2.50 (s, 3H; CH3-8),
3.25–3.46 (m, 8H; 4”CH2 glycol), 3.81 (t, J=5.9 Hz, 2H; CH2-2’), 4.78
(t, J=5.9 Hz, 2H; CH2-1’), 7.85 (s, 1H; H-9), 7.88 (s, 1H; H-6), 9.47,
11.33 ppm (2”brs, 2”1H; 2”NH); a 13C NMR spectrum could not be
recorded due to the very lowsolubility of the title compound in organic
solvents; ES-MS: m/z (%): 470.3 (100) [M+H]+; elemental analysis calcd
(%) for C20H22F3N5O5: C 51.17, H 4.72, F 12.14, N 14.92; found: C 51.34,
H 4.87, N 14.83.
N-[8’-(Trifluoroacetamido)-3’,6’-dioxaoct-1’-yl]-4,5-dimethyl-2-nitroani-
line (4-TFA): Free amine 4 (5.8 g, 20 mmol) was dissolved in methanol
(200 mL), and ethyl trifluoroacetate (13 g, 92 mmol, 4.6 equiv) and tri-
ACHTREUNGethylamine (11 g, 0.11 mol, 5.4 equiv) were added to the solution. The
mixture was stirred at ambient temperature and the progress of the reac-
tion was monitored by TLC (mobile phase CH2Cl2/MeOH/TEA 50:2:1).
After 24 h, the spot due to the starting material (Rf =0.17) was no longer
visible. The reaction mixture was concentrated in vacuo, the residue was
redissolved in dichloromethane (100 mL), and this solution was washed
with water (3”100 mL). The organic phase was separated, concentrated
in vacuo, and the residue was dried to yield a red oil (6.5 g, 83%). Rf =
0.46 (CHCl2/MeOH/TEA 50:2:1); 1H NMR (CDCl3): d=2.10 (s, 3H;
CH3-4), 2.20 (s, 3H; CH3-5), 3.43, 3.53, 3.60, 3.63, 3.72 (5”m, 12H in
total; 6”CH2 glycol), 6.57 (s, 1H; H-6), 7.42 (brs, 1H; -NH-CO-), 7.81
(s, 1H; H-3), 8.15 ppm (br, 1H; Ar-NH-); 19F NMR (CDCl3): d=
10-[2’-(tert-Butyloxycarbonylamino)eth-1’-yl]-3,7,8-trimethylbenzo[g]-
pteridine-2,4-dione (8-Boc): Flavin 6-Boc (0.8 g, 2.1 mmol) was dissolved
in dry DMF (80 mL). Caesium carbonate (0.9 g, 2.8 mmol, 1.3 equiv) and
dimethyl sulfate (2.7 g, 2 mL, 21 mmol, 10 equiv) were added, and the
mixture was stirred overnight at ambient temperature in the dark. The
suspension was then diluted with chloroform (250 mL) and washed se-
quentially with water (3”100 mL), 5% aqueous NH3 solution (100 mL),
and further water (100 mL). The organic phase was separated, dried over
magnesium sulfate, and concentrated in vacuo. The crude product was
purified by column chromatography (CHCl3/MeOH 20:1) to yield an
orange solid (0.44 g, 53%). Rf =0.38 (CHCl3/MeOH 20:1); m.p. 2328C
(decomp); 1H NMR ([D6]DMSO): d=1.21 (s, 9H; Boc), 2.41 (s, 3H;
CH3-7), 2.51 (s, 3H; CH3-8), 3.28 (s, 3H; CH3-3), 3.41 (m, 2H; CH2-1’),
4.67 (t, J=5.8 Hz, 2H; CH2-2’), 6.99 (t, J=5.8 Hz, 1H; NH), 7.87 (s, 1H;
H-9), 7.95 ppm (s, 1H; H-6); 13C NMR ([D6]DMSO): d=18.8, 20.9, 28.0,
28.2 (4”CH3), 37.0, 44.1 (2”CH2), 77.9 (quaternary C), 116.2, 131.0
(CH), 131.5, 134.2, 135.8, 135.9, 146.5, 148.9, 155.1, 155.8, 159.7 ppm (9”
quaternary C); ES-MS: m/z (%): 300.1 (55) [M+HÀBoc]+, 344.1 (65)
[M+HÀC4H8]+, 400.2 (100) [M+H]+, 422.2 (20) [M+NH4]+, 438.2 (15)
[M+K]+.
À76.4 ppm; ES-MS: m/z (%): 394.2 (100) [M+H]+; EI-MS: m/z (%):
+
393.3 (100) [M]+ ; HR-MS: m/z: calcd for C16H22F3N3O5 [M] : 393.1512;
C
C
found: 393.1509 (delta À0.76 ppm).
10-[8’-(Benzyloxycarbonylamino)-3’,6’-dioxaoct-1’-yl]-7,8-dimethylben-
zo[g]pteridine-2,4-dione (7-Cbz): The reduction procedure used was anal-
ogous to one reported in the literature.[88,89] Thus, o-nitroaniline 4-Cbz
(430 mg, 1 mmol) was dissolved in ethanol (100 mL), and tin(II) chloride
dihydrate (1.7 g, 7.5 mmol, 7.5 equiv) was added. The mixture was heated
to reflux and the progress of the reaction was monitored by TLC
(CH2Cl2/MeOH/TEA 50:2:1). After 72 h, the spot due to the starting ma-
terial (Rf =0.58) was no longer visible. The reaction mixture was concen-
trated in vacuo and the residue was redissolved in ethyl acetate. This so-
lution was washed with 2m sodium hydroxide solution; the organic phase
was separated, dried over magnesium sulfate, and concentrated in vacuo,
and the residue was dried. The crude reduction product was dissolved in
acetic acid (25 mL), and alloxane hydrate (1.1 g, 6.9 mmol, 6.9 equiv) and
boric acid (1 g, 16 mmol, 16 equiv) were added. The flask was wrapped in
aluminium foil and the mixture was stirred at ambient temperature for
22 h. It was then diluted with water (25 mL) and extracted with dichloro-
methane (50 mL). The organic phase was concentrated in vacuo and the
residue was co-evaporated with toluene to remove traces of water and
acetic acid. The crude product was dissolved in the minimum volume of
methanol and separated on four PTLC plates (CH2Cl2/MeOH/TEA
50:2:1, eluting twice). The appropriate zone (Rf =0.43) was extracted
with methanol, the extract was concentrated in vacuo, and the residue
was dried. Yield: 360 mg (71%) of an orange solid; Rf =0.43 (CH2Cl2/
MeOH/TEA 50:2:1, eluted twice); m.p. 2328C (decomp); 1H NMR
(CDCl3): d=2.41 (s, 3H; CH3-7), 2.50 (s, 3H; CH3-8), 3.31, 3.47, 3.55,
3.97 (4”m, 8H in total; 4”CH2 glycol), 4.86 (br, 2H; CH2-2’), 5.06 (s,
2H; PhCH2), 5.30 (br, 2H; CH2-1’), 7.15–7.38 (m, 5H; Ph), 7.66 (s, 1H;
H-9), 7.97 ppm (s, 1H; H-6); a 13C NMR spectrum could not be recorded
due to the very lowsolubility of the title compound in organic solvents;
10-(2’-Aminoeth-1’-yl)-3,7,8-trimethylbenzo[g]pteridine-2,4-dione (8):
Flavin 8-Boc (100 mg, 0.25 mmol) was dissolved in chloroform (25 mL),
and HCl in diethyl ether (3 mL) was added dropwise. The reaction mix-
ture was stirred overnight at ambient temperature, and was then concen-
trated in vacuo to leave a yellowsolid to yield the hydrochloride salt of
the title compound (84 mg, 100%). Rf =0.00 (CHCl3/MeOH 20:1); m.p.
1
2578C (decomp); H NMR ([D6]DMSO): d=2.42 (s, 3H; CH3-7), 2.54 (s,
3H; CH3-8), 3.19–3.21 (m, 2H; CH2-2’), 3.29 (s, 3H; CH3-3), 4.92 (t, J=
6.5 Hz, 2H; CH2-1’), 7.99 (s, 1H; H-9), 8.06 (s, 1H; H-6), 8.18 ppm (brs,
3H; NH3+); a 13C NMR spectrum could not be measured due to the ex-
tremely lowsolubility of the title compound; ES-MS: m/z (%): 300.1
(100) [M+H]+.
10-(8’-Amino-3’,6’-dioxaoct-1’-yl)-7,8-dimethylbenzo[g]pteridine-2,4-
dione (7): Trifluoroacetamide 7-TFA (1.1 g, 2.3 mmol) was dissolved in a
6m aqueous solution of HCl (200 mL, ca. 1.2 mol, ca. 520 equiv), and the
reaction mixture was heated to 90–958C with monitoring by TLC
(CHCl3/MeOH/AcOH 77.5:15:7.5). After 90 min, the spot due to the
starting material (Rf =0.65) was no longer visible. The reaction mixture
was then concentrated in vacuo and the residue was dried (dark-brown
oil) to yield 7·HCl (940 mg, 100%). Rf =0.04 (CHCl3/MeOH/AcOH
77.5:15:7.5); 1H NMR (CD3OD): d=2.46 (s, 3H; CH3-7), 2.58 (s, 3H;
CH3-8), 3.06 (t, J=4.9 Hz, 2H; CH2-8’), 3.60–3.68 (m, 6H; 3”CH2
glycol), 4.00 (t, J=5.6 Hz, 2H; CH2-2’), 5.00 (t, J=5.6 Hz, 2H; CH2-1’),
7.86 (s, 1H; H-9), 7.91 ppm (s, 1H; H-6); 13C NMR (CD3OD): d=19.5,
21.4 (2”CH3), 40.7, 46.3, 68.0, 68.7, 71.3, 71.8 (6”CH2), 118.1 (CH),
132.5, 133.3, 138.9, 139.0, 141.3, 149.7, 151.7, 158.4 (8”quaternary C),
172.8 ppm (CH); ES-MS: m/z (%): 374.3 (100) [M+H]+; HR-MS (EI-
MS): m/z: calcd for C18H23N5O4 [M+H]+: 374.1828; found: 374.1834
(delta 1.69 ppm).
+
[90]
EI-MS: m/z (%): 242.0 (100) [MÀside chain]+ , 507.2 (5) [M]
;
ele-
C
C
mental analysis calcd (%) for C26H29N5O6: C 61.53, H 5.76, N 13.80;
found: C 61.33, H 5.84, N 13.85.
7,8-Dimethyl-10-[8’-(trifluoroacetamido)-3’,6’-dioxaoct-1’-yl]benzo[g]p-
teridine-2,4-dione (7-TFA): Trifluoroacetamide 4-TFA (2 g, 5 mmol) was
dissolved in acetic acid (60 mL), and palladium on activated charcoal
(10% Pd/C, 1 spatula load) was added. The reaction mixture was placed
in an autoclave, which was flushed three times with hydrogen and then
filled to 50 bar. The reaction mixture was stirred at ambient temperature
for 16 h. It was then filtered through Celite to remove the catalyst, and
the filtrate was transferred to a round-bottomed flask. Alloxane hydrate
(2.1 g, 13 mmol, 2.6 equiv) and boric acid (7 g, 0.11 mol, 22 equiv) were
added to the filtrate. The flask was wrapped in aluminium foil and the re-
action mixture was stirred at ambient temperature for 6 d. It was then
concentrated in vacuo, the residue was dissolved in water (300 mL), and
this solution was extracted with dichloromethane (2”250 mL). The sepa-
rated organic phases were combined, dried over anhydrous magnesium
sulfate, and concentrated in vacuo, and the residue was dried to yield
orange crystals (1.13 g, 48%). Rf =0.27 (CH2Cl2/MeOH/TEA 50:2:1),
3-[2’-(tert-Butyloxycarbonylamino)eth-1’-yl]-7,8-dimethyl-10-(3’’-oxabut-
1’’-yl)benzo[g]pteridine-2,4-dione (9-Boc): Flavin
5 (1.2 g, 4 mmol,
1 equiv) was dissolved in dry DMF (150 mL) at 808C. After cooling the
solution to ambient temperature, potassium carbonate (2.8 g, 20 mmol,
5 equiv) was added and the mixture was stirred for 30 min. A solution of
2-(tert-butyloxycarbonylamino)ethyl bromide (2.3 g, 10 mmol, 2.5 equiv)
in DMF (5 mL) was added dropwise, followed by sodium iodide (0.9 g,
6 mmol, 1.5 equiv). The reaction mixture was stirred at ambient tempera-
ture for 1 d. Another portion of the bromide (2.3 g, 10 mmol, 2.5 equiv)
was then added, and the reaction mixture was stirred for a further 2 d at
Chem. Eur. J. 2008, 14, 1854 – 1865
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1861

B. Kçnig et al.
ambient temperature. It was then concentrated in vacuo, the residue was
redissolved in dichloromethane (400 mL), and this solution was washed
with aqueous sodium hydrogen carbonate solution (250 mL), water
(250 mL), and brine (250 mL). The organic phase was separated, dried
over magnesium sulfate, and concentrated in vacuo. The remaining dark
oil was purified by column chromatography (AcOEt/MeOH 20:1), giving
the title product as a yellowsolid (950 mg, 54%). Rf =0.42 (AcOEt/
MeOH 10:1); m.p. 1768C (decomp); 1H NMR ([D6]DMSO): d=1.32 (s,
9H; Boc), 2.40 (s, 3H; CH3-7), 2.51 (s, 3H; CH3-8), 3.19–3.21 (m, 2H;
CH2-2’), 3.24 (s, 3H; CH3-4’’), 3.76 (t, J=5.6 Hz, 2H; CH2-1’’), 3.96 (t,
J=5.9 Hz, 2H; CH2-1’), 4.83 (t, J=5.6 Hz, 2H; CH2-2’’), 6.82 (t, J=
5.9 Hz, 1H; NH), 7.89 (s, 1H; H-9), 7.95 ppm (s, 1H; H-6); 13C NMR
([D6]DMSO): d=18.8, 20.7, 28.2 (3”CH3), 37.7, 40.9, 43.8 (3”CH2), 58.5
(CH3), 68.4 (CH2), 77.6 (quaternary C), 116.8, 130.8 (2”CH), 131.4,
133.9, 136.0, 136.4, 146.5, 148.8, 154.8, 155.7, 159.7 ppm (9”quaternary
C); ES-MS: m/z (%): 388.1 (65) [M+HÀC4H8]+, 444.2 (100) [M+H]+.
3-(2’-Aminoeth-1’-yl)-7,8-dimethyl-10-(3’’-oxabut-1’’-yl)benzo[g]pteri-
dine-2,4-dione (9): Flavin 9-Boc (0.85 g, 1.9 mmol) was dissolved in di-
chloromethane (150 mL), and HCl in diethyl ether (10 mL) was added
dropwise. The reaction mixture was stirred for 15 h at ambient tempera-
ture. The brown precipitate that formed was collected by filtration and
dried to yield 9·HCl (0.69 mg, 95%). Rf =0.00 (AcOEt/MeOH 10:1);
m.p. 1508C (decomp); 1H NMR ([D6]DMSO): d=2.41 (s, 3H; CH3-7),
2.51 (s, 3H; CH3-8), 3.07–3.09 (m, 2H; CH2-2’), 3.24 (s, 3H; CH3-4’’),
3.79 (t, J=5.5 Hz, 2H; CH2-1’’), 4.16 (t, J=5.9 Hz, 2H; CH2-1’), 4.87 (t,
J=5.8 Hz, 2H; CH2-2’’), 7.94 (s, 1H; H-9), 7.94–7.96 (br, 3H; NH3+),
7.96 ppm (s, 1H; H-6); 13C NMR ([D6]DMSO): d=18.8, 20.7 (2”CH3),
37.3, 39.9, 44.0 (3”CH2), 58.5 (CH3), 68.4 (CH2), 117.0, 130.8 (CH),
131.4, 133.9, 136.3, 136.4, 146.8, 148.9, 154.9, 160.2 ppm (8”quaternary
C); ES-MS: m/z (%): 344.1 (100) [M+H]+.
(C-9a), 132.4 (C-6), 133.0 (NCS), 135.0 (C-5a), 136.0 (C-4a), 137.1, 148.1
(C-7, -8), 150.4 (C-10a), 155.1, 159.6 (C-2, -4), 166.8 ppm (C-9); EI-MS:
+
m/z (%): 91.2 (100) [C7H7]+, 242.2 (98) [MÀside chain]+ , 415.3 (5) [M]
C
[90]
;
ES-MS: m/z (%): 416.1 (100) [M+H]+; HR-MS (EI-MS): m/z: calcd
C
for C19H21N5O4S [M]+ : 415.1314; found: 415.1320 (delta À1.39 ppm).
C
3-(2’-Isothiocyanatoeth-1’-yl)-7,8-dimethyl-10-(3’’-oxabut-1’’-yl)benzo[g]-
pteridine-2,4-dione (13): Preparation according to GP 1 starting from
9·HCl (0.6 g) yielded 13 as
a yellowsolid (0.54 g, 89%). Rf =0.33
(AcOEt); m.p. 190–1938C; 1H NMR ([D6]DMSO): d=2.41 (s, 3H; CH3-
7), 2.51 (s, 3H; CH3-8), 3.24 (s, 3H; CH3-4’’), 3.77 (t, J=5.8 Hz, 2H;
CH2-1’’), 3.95 (t, J=5.9 Hz, 2H; CH2-1’), 4.20 (t, J=5.8 Hz, 2H; CH2-2’),
4.84 (t, J=5.6 Hz, 2H; CH2-2’’), 7.91 (s, 1H; H-9), 7.96 ppm (s, 1H; H-
6); 13C NMR ([D6]DMSO): d=18.8, 20.7 (2”CH3), 40.0, 42.8, 44.0 (3”
CH2), 58.5 (CH3), 68.3 (CH2), 116.9, 130.8 (2”CH), 131.5, 134.1, 136.0,
136.2, 146.8, 149.0, 154.4, 159.6 ppm (8”quaternary C); the signal of the
isothiocyanate group was not observed, presumably due to a long relaxa-
tion time; EI-MS: m/z (%): 242.2 (100) [MÀCH2OCH2CH2ÀCH2CH2-
+
+ [90]
C
C
.
A
General Procedure 2 for the preparation of flavin photocatalysts bearing
a primary thiourea group (14–17 and 25): The flavin was dissolved in
chloroform and gaseous NH3 was passed through the solution for 3 h.
The precipitate was collected by filtration and purified by trituration or
chromatography as required.
7,8-Dimethyl-10-(2’-thioureidoeth-1’-yl)benzo[g]pteridine-2,4-dione (14):
Preparation according to GP 2 starting from 10 (60 mg) yielded 14 as a
yellowsolid (48 mg, 76%). M.p. 178 8C (decomp); 1H NMR
([D6]DMSO): d=2.40 (s, 3H; CH3-7), 2.48 (s, 3H; CH3-8), 3.78 (m, 2H;
CH2-2’), 4.71 (m, 2H; CH2-1’), 7.16 (brs, 2H; NH2), 7.72 (m, 1H; NH),
7.87 (s, 1H; H-9), 8.14 (s, 1H; H-6), 11.27 ppm (s, 1H; H-3); 13C NMR
([D6]DMSO): d=18.8, 20.6 (2”CH3), 39.5, 43.6 (2”CH2), 116.5, 130.8
(2”CH), 131.5, 133.7, 135.8, 136.8, 146.5, 150.3, 155.6, 159.9, 183.8 ppm
(9”quaternary C); ES-MS: m/z (%): 345.0 (100) [M+H]+; elemental
analysis calcd (%) for C15H16N6O2S: C 52.31, H 4.68, N 24.40, S 9.31;
found: C 52.55, H 4.53, N 24.51, S 9.20.
General Procedure 1 for the preparation of isothiocyanates 10–13 and
24: The flavin was dissolved in water and calcium carbonate (2.5 equiv)
was added. The solution was then added to a rapidly stirred solution of
thiophosgene (2 equiv) in dichloromethane, prepared by diluting a 0.1m
stock solution in dichloromethane, at 08C. The reaction mixture was
stirred overnight at ambient temperature. It was then diluted with di-
chloromethane, and the organic phase was separated, washed with water,
dried over magnesium sulfate, and concentrated in vacuo. If required, the
crude product was purified by chromatography.
3,7,8-Trimethyl-10-(2’-thioureidoeth-1’-yl)benzo[g]pteridine-2,4-dione
(15): Preparation according to GP 2 starting from 11 (50 mg) yielded 15
as a yellowsolid (36 mg, 68%). Rf =0.70 (CHCl3/MeOH 7:1); m.p. 2528C
(decomp); 1H NMR ([D6]DMSO): d=2.38 (s, 3H; CH3-7), 2.47 (s, 3H;
CH3-8), 3.29 (s, 3H; CH3-3), 3.77 (m, 2H; CH2-2’), 4.70 (m, 2H; CH2-1’),
7.18 (m, 2H; NH2), 7.75 (m, 1H; NH), 7.87 (s, 1H; H-9), 8.14 ppm (s,
1H; H-6); 13C NMR ([D6]DMSO): d=18.8, 20.7, 28.0 (3”CH3), 39.5,
43.6 (2”CH2), 116.5, 130.8 (2”CH), 131.5, 133.7, 135.8, 136.8, 146.5,
150.3, 155.6, 159.9, 183.8 ppm (9”quaternary C); ES-MS: m/z (%): 357.1
(100) [MÀH+]À, 417.2 (65) [M+AcO]À, 471.1 (55) [M+TFA]À; HR-MS
10-(2’-Isothiocyanatoeth-1’-yl)-7,8-dimethylbenzo[g]pteridine-2,4-dione
(10): Preparation according to GP 1 starting from 6·HCl (150 mg) yielded
10 as an orange solid (130 mg, 87%). Rf =0.39 (AcOEt/MeOH 10:1);
m.p. 1828C (decomp); 1H NMR ([D6]DMSO): d=2.41 (s, 3H; CH3-7),
2.50 (s, 3H; CH3-8), 4.14 (t, J=5.8 Hz, 2H; CH2-2’), 4.95 (t, J=5.8 Hz,
2H; CH2-1’), 7.92 (s, 1H; H-9), 8.00 (s, 1H; H-6), 11.37 ppm (s, 1H;
NH); ES-MS: m/z (%): 328 (100) [M+H]+.
(EI-MS): calcd for C16H19N6O2S [M]+ : 359.1290; found: 359.1297 (delta
C
À1.89 ppm).
10-(2’-Isothiocyanatoeth-1’-yl)-3,7,8-trimethylbenzo[g]pteridine-2,4-dione
(11): Preparation according to GP 1 starting from 8·HCl (109 mg) yielded
11 as an orange solid (88 mg, 79%). Rf =0.35 (CHCl3/MeOH 20:1); m.p.
7,8-Dimethyl-10-(3’,6’-dioxa-8’-thioureidooct-1’-yl)benzo[g]pteridine-2,4-
dione (16): Preparation according to GP 2 starting from 12 (0.5 g) yielded
16 as a brown solid (230 mg, 44%). Rf =0.60 (CHCl3/MeOH/AcOH
77.5:15:7.5); m.p. 1708C (decomp); 1H NMR ([D6]DMSO): d=2.40 (s,
3H; CH3-7), 2.50 (s, 3H; CH3-8), 3.35–3.56 (m, 8H; CH2-4’, -5’, -7’, -8’),
3.81 (t, J=5.9 Hz, 2H; CH2-2’, 4.80 (t, J=5.5 Hz, 2H; CH2-1’), 7.01 (brs,
2H; NH2), 7.54 (brs, 1H; NH-C(S)NH2), 7.88 (s, 2H; CH-6, -9),
11.33 ppm (s, 1H; H-3); 13C NMR (150 MHz, [D6]DMSO): d=18.8, 20.6
(2”CH3), 43.8 (CH2), 44.0 (CH2-1’), 66.7 (CH2-2’), 69.0, 69.5, 70.1 (3”
CH2), 116.8, 130.7 (2”CH), 131.4 (C-9a), 133.7 (C-5a), 135.8, 136.0,
137.1, 146.2, 155.6, 159.9 (6”quaternary C), 182.9 ppm (C=S); ES-MS:
m/z (%): 433.1 (100) [M+H]+; ES-MS: m/z (%): 431.1 (100) [MÀH]+,
467.1 (50) [M+Cl]À, 491.3 (24) [M+AcO]À; HR-MS (EI-MS): m/z: calcd
1
1958C (decomp); H NMR (CDCl3): d=2.46 (s, 3H; CH3-7), 2.59 (s, 3H;
CH3-8), 3.52 (s, 3H; CH3-3), 4.17 (t, J=5.8 Hz, 2H; CH2-2’), 4.97 (t, J=
5.6 Hz, 2H; CH2-1’), 7.55 (s, 1H; H-9), 8.09 ppm (s, 1H; H-6); 13C NMR
([D6]DMSO): d=18.8, 20.6, 30.0 (3”CH3), 41.9, 42.8 (2”CH2), 116.3
(CH), 130.8 (quaternary C), 131.1 (CH), 133.9, 136.0, 136.3, 146.9, 148.9,
155.0, 159.6 (7”quaternary C). The signal of the isothiocyanate group
was not observed, presumably due to a long relaxation time; ES-MS: m/z
(%): 342.1 (100) [M+H]+.
10-(8’-Isothiocyanato-3’,6’-dioxaoct-1’-yl)-7,8-dimethylbenzo[g]pteridine-
2,4-dione (12): Preparation according to GP 1 starting from 7·HCl
(100 mg) yielded 12 as an orange solid (98 mg, 97%). Rf =0.84 (CHCl3/
MeOH/AcOH 77.5:15:7.5); m.p. 1788C (decomp); NMR signals could be
completely assigned with the help of 2D experiments (NOESY, HMBC,
HSQC) and reported data for analogous compounds;[91] 1H NMR
(600 MHz, CDCl3): d=2.45 (s, 3H; CH3-7), 2.56 (s, 3H; CH3-8), 3.57–
3.62 (m, 8H; CH2-4’, -5’, -7’, -8’), 4.04 (t, J=5.5 Hz, 2H; CH2-2’), 4.95 (t,
J=5.5 Hz, 2H; CH2-1’), 7.73 (s, 1H; H-9), 8.03 (s, 1H; H-6), 8.58 ppm (s,
1H; H-3); 13C NMR (150 MHz, CDCl3): d=19.5 (CH3-7), 21.5 (CH3-8),
45.3 (C-4’), 45.6 (C-1’), 67.9 (C-2’), 69.2, 70.6, 70.8 (C-5’, -7’, -8’), 132.1
for C19H24N6O4S [M]+ : 432.1580; found: 432.1575 (delta 1.10 ppm).
C
3-(2’-Thioureidoeth-1’-yl)-10-(3’’-oxabut-1’’-yl) flavin (17): Preparation ac-
cording to GP 2 starting from 13 (100 mg) yielded 104 mg (100%) of 17
as an orange solid; Rf =0.30 (AcOEt/MeOH 10:1); m.p. 1718C
(decomp); 1H NMR ([D6]DMSO): d=2.39 (s, 3H; CH3-7), 2.49 (s, 3H;
CH3-8), 3.24 (s, 3H; CH3-4’’), 3.66 (br, 2H; CH2-1’), 3.76 (t, J=5.6 Hz,
2H; CH2-1’’), 4.03 (br, 2H; CH2-2’), 4.82 (t, J=5.5 Hz, 2H; CH2-2’’),
6.98, 7.62 (2”s, 3H in total; NH), 7.88 (s, 1H; H-9), 7.90 ppm (s, 1H; H-
6); 13C NMR ([D6]DMSO): d=18.8, 20.7 (2”CH3), 39.5, 42.1, 43.9 (3”
1862
www.chemeurj.org
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 1854 – 1865

Thiourea-Enhanced Flavin Photooxidation
FULL PAPER
CH2), 58.5 (CH3), 68.3 (CH2), 116.8, 130.8 (2”CH), 131.4, 133.9, 136.1,
136.2, 146.6, 148.8, 154.9, 159.7, 183.5 ppm (9”quaternary C); ES-MS:
m/z (%): 403.1 (100) [M+H]+; HR-MS (EI-MS): calcd for C18H22N6O3S
calcd for C28H25F17N6O6S [M]+
À0.07 ppm).
: 848.1437; found: 848.1438 (delta
C
3,10-BisCAHTRE[UGN 2’-(tert-butyloxycarbonylamino)eth-1’-yl]-7,8-dimethylbenzo[g]-
[M]+ : 402.1474; found: 402.1479 (delta À1.22 ppm).
C
pteridine-2,4-dione (22): Flavin 6-Boc (300 mg, 0.78 mmol, 1 equiv) was
dissolved in dry DMF (40 mL) at 808C. The solution was allowed to cool
to ambient temperature, whereupon potassium carbonate (540 mg,
3.9 mmol, 5 equiv) was added and the mixture was stirred for 30 min. 2-
(tert-Butyloxycarbonylamino)ethyl bromide (520 mg, 2.3 mmol, 3 equiv)
and sodium iodide (180 mg, 1.2 mmol, 1.5 equiv) were then added, and
the reaction mixture was stirred at ambient temperature. After stirring
for 1 d and then again after 2 d, further portions of the bromide (520 mg,
2.3 mmol, 3 equiv each) were added. After 3 d, the reaction mixture was
diluted with chloroform (300 mL), washed with aqueous sodium hydro-
gen carbonate solution (100 mL), water (3”100 mL), and brine
(100 mL), and the organic phase was concentrated in vacuo. Compound
22 was isolated by flash chromatography (CHCl3/MeOH 15:1) to yield an
orange solid (210 mg, 52%). Rf =0.34 (CHCl3/MeOH 15:1); m.p. 1368C
(decomp); 1H NMR ([D6]DMSO): d=1.24 (s, 9H; tBu), 1.34 (s, 9H;
tBu), 2.41 (s, 3H; CH3-7), 2.50 (s, 3H; CH3-8), 3.19 (d, J=6.0 Hz, 2H;
CH2-2’), 3.40 (d, J=5.8 Hz, 2H; CH2-2’), 3.96 (t, J=6.0 Hz, 2H; CH2-1’),
4.66 (t, J=5.6 Hz, 2H; CH2-1’), 6.83 (t, J=5.8 Hz, 1H; NH), 7.03 (t, J=
5.8 Hz, 1H; NH), 7.89 (s, 1H; H-9), 7.95 ppm (s, 1H; H-6); 13C NMR
([D6]DMSO): d=18.8, 20.8, 27.9, 28.1 (4”CH3), 36.9, 37.8, 40.8, 43.9 (4”
CH2), 77.5, 77.8 (2”quaternary C), 116.1, 130.9 (2”CH), 131.3, 134.0,
135.7, 135.8, 146.5, 148.7, 154.7, 155.6, 155.8, 159.6 ppm (10”quaternary
C); ES-MS: m/z (%): 429.2 (25) [M+HÀBoc]+, 473.3 (35) [M+HÀBu]+,
529.3 (100) [M+H]+, 551.4 (40) [M+Na]+.
General Procedure 3 for the preparation of N,N’-substituted flavin–thio-
urea compounds 18–21 and 26–28: The flavin isothiocyanate was dis-
solved in chloroform, and the appropriate amine (2.5 equiv) and TEA
(2 equiv) were added. The reaction mixture was heated to reflux under
TLC control until complete conversion was indicated. The mixture was
then concentrated in vacuo and the crude product was purified by chro-
matography if required.
10-(9’,11’-Diaza-3’,6’,14’-trioxa-10’-thioxopentadec-1’-yl)-7,8-dimethylben-
zo[g]pteridine-2,4-dione (18): Preparation according to GP 3 starting
from 12 (20 mg) yielded 18 as an orange solid (24 mg, 100%). Rf =0.69
(CHCl3/MeOH/AcOH 77.5:15:7.5); m.p. 1788C (decomp); NMR signals
were assigned in analogy to those of the isothiocyanate 12 and with the
help of HMBC and HSQC experiments; 1H NMR (CDCl3): d=2.43 (s,
3H; CH3-7), 2.54 (s, 3H; CH3-8), 3.14–3.72 (m, 15H; CH2-4’, -5’, -7’, -8’,
-12’, -13’), 4.05 (br, 2H; CH2-2’), 4.99 (br, 2H; CH2-1’), 7.59 (s, 1H; H-9),
8.01 ppm (s, 1H; H-6); 13C NMR (100 MHz, CDCl3): d=19.5 (CH3-7),
21.6 (CH3-8), 44.3 (C-4’), 44.9 (C-1’), 58.5 (C-15’), 70.1, 70.3, 70.6, 70.9,
71.5, 71.5 (C-2’, -5’, -7’, -8’, -12’, -13’), 116.0 (C-9), 131.5 (C-9a), 132.6 (C-
6), 135.1 (C-5a), 136.0 (C-4a), 137.3, 148.3 (C-7, -8), 150.5 (C-10a), 156.5,
159.7 (C-2, -4), 183.1 ppm (C=S); ES-MS: m/z (%): 491.3 (100) [M+H]+;
HR-MS (LSI-MS): m/z: calcd for C22H31N6O5S [M+H]+: 491.2077;
found: 491.2086 (delta À1.90 ppm).
10-(3’,5’-Diaza-8’,8’,9’,9’,10’,10’,11’,11’,12’,12’,13’,13’,14’,14’,15’,15’,15’-hep-
tadecafluoro-4’-thioxopentadec-1’-yl)-7,8-dimethylbenzo[g]pteridine-2,4-
dione (19): Preparation according to GP 3 starting from isothiocyanate
10 (50 mg) yielded 19 as a yellowsolid (82 mg, 68%). M.p. 237 8C
(decomp); 1H NMR ([D6]DMSO): d=2.38 (s, 3H; CH3-7), 2.46 (br, 5H;
CH3-8, CH2), 3.50–4.00 (m, 4H; 2”CH2), 4.72 (m, 2H; CH2), 7.78 (t, J=
5.4 Hz, 1H; NH), 7.88 (s, 1H; H-9), 8.03 (s, 1H; H-6), 11.37 ppm (s, 1H;
H-3); a 13C NMR spectrum could not be measured to the extremely low
solubility of the title compound; 19F NMR ([D6]DMSO): d=À125.2 (m,
2F), À122.6 (m, 2F), À121.9 (m, 2F), À121.2 (m, 6F), À112.7 (m, 2F),
À79.7 ppm (t, J=9.5 Hz, 3F; CF3); ES-MS: m/z (%): 791.2 (100)
[M+H]+; HR-MS (LSI-MS): m/z: calcd for C25H20F17N6O2S [M+H]+:
791.1097; found: 791.1102 (delta 0.64 ppm).
3,10-Bis(2’-aminoeth-1’-yl)-7,8-dimethylbenzo[g]pteridine-2,4-dione (23):
Flavin 22 (150 mg, 0.29 mmol) was dissolved in methanol (30 mL), and
HCl in diethyl ether (3 mL) was added dropwise. The reaction mixture
was stirred overnight at ambient temperature. It was then concentrated
in vacuo and the yellow-brownish residue was dried to yield 23·2HCl
(114 mg, 100%). Rf =0.00 (CHCl3/MeOH 15:1); m.p. 2688C (decomp);
1H NMR ([D6]DMSO): d=2.42 (s, 3H; CH3-7), 2.55 (s, 3H; CH3-8), 3.07
(d, J=5.5 Hz, 2H; CH2-2’), 3.18 (d, J=5.2 Hz, 2H; CH2-2’), 4.18 (t, J=
5.9 Hz, 2H; CH2-1’), 4.97 (t, J=6.6 Hz, 2H; CH2-1’), 7.97 (s, 1H; H-9),
8.13 (brs, 3H; NH3), 8.30 (s, 1H; H-6), 8.57 ppm (brs, 3H; NH3);
13C NMR ([D6]DMSO): d=18.8, 20.5 (2”CH3), 35.8, 37.1, 38.5, 41.2 (4”
CH2), 116.3 (CH), 130.5 (quaternary C), 131.2 (CH), 134.2, 136.4, 136.5,
147.6, 149.4, 154.9, 160.0 ppm (7”quaternary C); ES-MS: m/z (%): 329.1
(100) [M+H]+.
10-(3’,5’-Diaza-8’,8’,9’,9’,10’,10’,11’,11’,12’,12’,13’,13’,14’,14’,15’,15’,15’-hep-
tadecafluoro-4’-thioxopentadec-1’-yl)-3,7,8-trimethylbenzo[g]pteridine-
2,4-dione (20): Preparation according to GP 3 starting from isothiocya-
nate 11 (15 mg) yielded 28 mg (79%) of 20 as an orange solid; m.p.
2088C (decomp); 1H NMR ([D6]DMSO): d=2.37 (s, 3H; CH3-7), 2.45
(br, 5H; CH3-8, CH2), 3.30 (s, 3H; CH3-3), 3.52–3.98 (m, 4H; 2”CH2),
4.69 (m, 2H; CH2), 7.79 (t, J=5.4 Hz, 1H; NH), 7.89 (s, 1H; H-9), 8.05
(s, 1H; H-6); a 13C NMR spectrum could not be measured due to the ex-
tremely lowsolubility of the title compound; 19F NMR (CDCl3): d=
À126.6 (m, 2F), À123.9 (m, 2F), À123.2 (m, 2F), À122.4 (m, 2F), À122.1
(m, 2F), À114.2 (m, 2F), À81.2 (t, J=9.8 Hz, 3F); ES-MS: m/z (%):
805.2 (100) [M+H]+; HR-MS (LSI-MS): m/z: calcd for C26H22F17N6O2S
[M+H]+: 805.1253; found: 805.1281 (delta À3.42 ppm).
3,10-Bis(2’-isothiocyanatoeth-1’-yl)-7,8-dimethylbenzo[g]pteridine-2,4-
dione (24): Preparation according to GP 1 starting from 23·2HCl
(114 mg) yielded 24 as a yellowsolid (95 mg, 81%). Rf =0.35 (CHCl3/
MeOH 25:1); m.p. 1408C (decomp); 1H NMR (CDCl3): d=2.47 (s, 3H;
CH3-7), 2.60 (s, 3H; CH3-8), 3.91 (t, J=6.3 Hz, 2H; CH2-2’), 4.19 (t, J=
5.6 Hz, 2H; CH2-2’), 4.43 (t, J=6.3 Hz, 2H; CH2-1’), 4.99 (t, J=5.9 Hz,
2H; CH2-1’), 7.57 (s, 1H; H-9), 8.10 ppm (s, 1H; H-6); 13C NMR
(CDCl3): d=18.8, 20.9 (2”CH3), 40.4, 42.0, 42.3, 43.8 (4”CH2), 115.6
(CH), 131.1 (quaternary C), 132.0 (CH), 134.6, 135.0, 137.6, 148.6, 149.4,
155.4, 159.9 ppm (7”quaternary C); the signals of the isothiocyanate
groups were not observed, presumably due to a long relaxation time; ES-
MS: m/z (%): 413.1 (100) [M+H]+.
3-(3’,5’-Diaza-8’,8’,9’,9’,10’,10’,11’,11’,12’,12’,13’,13’,14’,14’,15’,15’,15’-hepta-
decafluoro-4’-thioxopentadec-1’-yl)-7,8-dimethyl-10-(3’’-oxabut-1’’-yl)ben-
zo[g]pteridine-2,4-dione (21): Preparation according to GP 3 starting
from isothiocyanate 13 (40 mg) yielded 21 as an orange solid (59 mg,
67%). Rf =0.63 (CH2Cl2/MeOH 10:1); m.p. 1868C (decomp); 1H NMR
(CDCl3): d=2.45 (s, 3H; CH3-7), 2.55 (m, 5H; CH3-8 and CH2-6’), 3.27
(s, 3H; CH3-4’’), 3.65 (m, 2H; CH2-2’), 3.91 (t, J=5.1 Hz, 2H; CH2-1’’),
3.99 (m, 2H; CH2-7’), 4.30 (t, J=6.2 Hz, 2H; CH2-1’), 4.91 (t, J=5.1 Hz,
2H; CH2-2’’), 7.71 (s, 1H; H-9), 8.04 ppm (s, 1H; H-6); 13C NMR
(CDCl3): d=19.6, 21.8 (2”CH3), 30.6, 40.6, 40.7, 45.6, 45.7 (5”CH2), 59.3
(CH3), 69.5 (CH2), 117.0, 132.1 (2”CH), 132.2, 134.9, 135.4, 137.6, 137.6,
148.6, 148.8, 156.5, 160.5 ppm (9”quaternary C); 19F NMR (CDCl3): d=
À126.7 (m, 2F), À124.0 (m, 2F), À123.3 (m, 2F), À122.5 (m, 4F), À122.2
(m, 2F), À114.3 (t, J=13.5 Hz, 2F; CF2-8’), À81.3 ppm (t, J=9.8 Hz, 3F;
CF3-16’); ES-MS: m/z (%): 849.3 (100) [M+H]+; HR-MS (EI-MS): m/z:
7,8-Dimethyl-3,10-bis(2’-thioureidoeth-1’-yl)benzo[g]pteridine-2,4-dione
(25): Preparation according to GP 2 starting from isothiocyanate 24
(60 mg) yielded 65 mg (100%) of 25 as an orange-red solid; Rf =0.30
1
(CHCl3/MeOH 10:1); m.p. 2358C (decomp); H NMR ([D6]DMSO): 2.42
(s, 3H; CH3-7), 2.50 (s, 3H; CH3-8), 3.67–3.69 (m, 4H; 2”CH2), 4.06 (m,
2H; CH2-2’), 4.76 (m, 2H; CH2-1’), 6.98–7.77 (m, 6H; NH and NH2
groups), 7.95 (s, 1H; H-9), 8.21 ppm (s, 1H; H-6); a 13C NMR spectrum
could not be measured due to the extremely lowsolubility of the title
compound; ES-MS: m/z (%): 447.2 (100) [M+H]+; HR-MS (LSI-MS):
m/z: calcd for C18H23N8O2S2 [M+H]+: 447.1385; found: 447.1372 (delta
À3.00 ppm).
3,10-BisACTHRE[UNG 2’-(3’,5’-diaza-8’,8’,9’,9’,10’,10’,11’,11’,12’,12’,13’,13’,14’,14’,15’,15’,
15’-heptadecafluoro-4’-thioxopentadec-1’-yl)eth-1’-yl]-7,8-dimethylben-
zo[g]pteridine-2,4-dione (26): Preparation according to GP 3 starting
from isothiocyanate 24 (60 mg) yielded a red solid (99 mg, 51%). Rf =
Chem. Eur. J. 2008, 14, 1854 – 1865
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B. Kçnig et al.
0.50 (CHCl3/MeOH 10:1); m.p. 2118C (decomp); 1H and 13C NMR spec-
tra could not be measured due to the extremely lowsolubility of the title
compound; 19F NMR ([D6]DMSO): d=À125.4 (m, 4F), À122.6 (m, 4F),
À122.0 (m, 4F), À121.2 (m, 12F), À112.8 (m, 4F), À79.7 (m, 6F); ES-
MS: m/z (%): 1339.2 (100) [M+H]+, 1361.2 (15) [M+Na]+; elemental
analysis calcd (%) for C38H28F34N8O2S2: C 34.09, H 2.11, F 48.25, N 8.37,
S 4.79; found: C 34.31, H 1.95, N 8.24, S 4.91.
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Bis-flavin 27: Preparation according to GP 3 starting from isothiocyanate
12 (40 mg) and amine 7·HCl (80 mg) yielded 27 as an orange solid
(76 mg, 100%). Rf =0.62 (CHCl3/MeOH/AcOH 77.5:15:7.5); m.p. 1658C
(decomp); 1H NMR (CDCl3): d=2.44 (s, 6H; CH3-7), 2.56 (s, 6H; CH3-
8), 3.59–3.72 (m, 16H; CH2-4’, -5’, -7’, -8’, -12’, -13’, -15’, -16’), 4.05 (t, J=
5.1 Hz, 4H; CH2-2’, -18’), 4.11 (t, J=5.1 Hz, 4H; CH2-1’, -19’), 7.02 (brs,
2H; H-9’, -11’), 7.64 (s, 2H; H-9), 7.99 (s, 2H; H-6), 9.38 ppm (brs, 2H;
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,
414.3 (21) [M+H+K]2+, 798.4 (100) [M+H]+, 811.4 (47) [M+Na]+, 827.3
(4) [M+K]+; elemental analysis calcd (%) for C37H44N10O8S: C 56.33, H
5.62, N 17.75, S 4.06; found: C 56.47, H 5.42, N 17.91, S 4.05.
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1
1178C (decomp); H NMR (CDCl3): d=2.42 (s, 6H; CH3-7), 2.55 (s, 6H;
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Acknowledgements
This research was supported by the DFG Graduate College GK640 “Sen-
sory Photoreceptors in Natural and Artificial Systems” and the DFG Pri-
ority Programme SPP1118 “Use of Secondary Interaction for Directed
Functionalization of Less Reactive Substrates”. J.S. thanks Prof. Vladimir
Mirsky and Nataliya Roznyatovskaya for their help with cyclic voltam-
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Received: August 24, 2007
Published online: November 30, 2007
Chem. Eur. J. 2008, 14, 1854 – 1865
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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