Copper-mediated 3-N-arylation of flavins

Article abstract of DOI:10.1055/s-2008-1067045

A generally applicable method for the direct 3-N-arylation of flavins using arylboronic acids and copper acetate was developed. The reaction conditions were optimized considering the lability of flavins in basic conditions and thermal heating. Donor-and acceptor-substituted arylboronic acids were used yielding 3-N-arylflavins in moderate to good yields by C(aryl)-N(imide) bond formation. UV and fluorescence measurements indicate an orthogonal orientation of the additional aromatic substituent to the flavin ring system. The arene substituent is not electronically coupled to the flavin π-system in the ground state, but electron-rich arene substituents in 3-N position significantly reduce the flavin emission intensity.

Full text of DOI:10.1055/s-2008-1067045

PAPER
1767
Copper-Mediated 3-N-Arylation of Flavins
C
opper-Mediated
i
3-N-A
a
rylation of
nFlavins ca Attenberger, Harald Schmaderer, Burkhard König*
Institute of Organic Chemistry, University of Regensburg, Universitätsstr. 31, 93040 Regensburg, Germany
Fax +49(941)9431717; E-mail: burkhard.koenig@chemie.uni-regensburg.de
Received 4 March 2008
the orthogonal orientation of the additional p-system to
the flavin aromatic system. In this work, we present the
first method for direct 3-N-arylation of flavins. The aro-
matic substituent is introduced in the flavin skeleton in a
Abstract: A generally applicable method for the direct 3-N-aryla-
tion of flavins using arylboronic acids and copper acetate was de-
veloped. The reaction conditions were optimized considering the
lability of flavins in basic conditions and thermal heating. Donor-
and acceptor-substituted arylboronic acids were used yielding 3-N- generally applicable copper catalyzed reaction with aryl-
arylflavins in moderate to good yields by C(aryl)–N(imide) bond
boronic acids.
formation. UV and fluorescence measurements indicate an ortho-
gonal orientation of the additional aromatic substituent to the flavin
ring system. The arene substituent is not electronically coupled to Copper-Mediated Flavin 3-N-Arylation
the flavin p-system in the ground state, but electron-rich arene sub-
stituents in 3-N position significantly reduce the flavin emission in-
tensity.
In recent years, several synthetic methods were developed
to directly arylate imides.23 Generally, the yields of this
C(aryl)–N(imide) bond formation are moderate. Initial at-
tempts to react flavin 1a with aryl iodide and glycine un-
der copper(I)-catalysis at 80 °C failed. Other reported
procedures use boronic acids and show a wider scope of
substrates. In most instances, solvents like chloroform and
dichloromethane or methanol gave the best results. Unfor-
tunately, a direct application of these conditions is com-
plicated, because many flavins are not well soluble in such
solvents. In a reaction of flavin 1a with phenylboronic
acid (2-H) moderate yield of flavin 3a-H was obtained in
chloroform. In methanol, however, no product 3a-H was
observed. Dimethylformamide as solvent allowed high
concentrations of starting materials and gave the best re-
sults in 3-N-arylation reactions in our hands. 10-(2-Meth-
oxyethyl)-7,8-dimethylbenzo[g]pteridine-2,4(3H,10H)-
dione (1a)14,24 was used as a standard to optimize the re-
action conditions and explore the scope of the reaction.
Flavins 1 were reacted with various arylboronic acids 2-R
under different conditions (Scheme 1).
Key words: flavin, N-arylation, boronic acid, isoalloxazin, micro-
wave, copper catalysis
Flavins are abundant redox cofactors of key importance
for many biological processes;1,2 typical examples are fla-
vin adenine dinucleotide (FAD) or flavin mononucleotide
(FMN). Their redox properties are tuned for the desired
purpose either by substitution or by specific hydrogen
bonds to the protein they are embedded in.3–8 Many fla-
voenzyme models have been developed to investigate
photo- and redox properties or to utilize flavins in organo-
catalytic reactions.8–14 The synthesis of such flavoenzyme
models or catalysts requires selective modification of the
parent flavin structure.8–11 The nitrogen atom in position 3
is particularly suitable for the introduction of substituents
at a late stage of the flavin synthesis.15 Typically, alkyla-
tions in 3-N position give only moderate yields due to de-
composition of flavins in basic solutions.11d,15–16 So far,
only few examples are known with aryl substitution at the
3-N position.17–22 However, introduction of these aryl sub-
stituents requires additional steps before the flavin ring
system is cyclized. Direct arylation of flavins at this posi-
tion may provide a short cut creating valuable flavin de-
rivatives. Interesting optical properties are expected from
The reaction of flavin 1a (250 mmol, 1 equiv) with arylbo-
ronic acid 2-R (3 equiv), copper acetate (2 equiv), and tri-
ethylamine (3 equiv) was carried out in anhydrous
dimethylformamide by stirring the mixture at room tem-
perature in the dark. To compare the coupling efficiency
of different arylboronic acids, every reaction was termi-
B(OH)2
R'
R'
N
1
Cu(OAc)2
Et3N, DMF
9
10
2
8
7
N
N
O
N
O
+
N
NH
3
N
N
5
4
R
6
O
O
R
1a R' = 2-methoxyethyl
1b R' = tetraacetylribityl
3a-R R' = 2-methoxyethyl
3b-R R' = tetraacetylribityl
2-R
Scheme 1
SYNTHESIS 2008, No. 11, pp 1767–1774
x
x.
x
x
.
2
0
0
8
Advanced online publication: 29.04.2008
DOI: 10.1055/s-2008-1067045; Art ID: Z06108SS
© Georg Thieme Verlag Stuttgart · New York

1768
B. Attenberger et al.
PAPER
Table 1 Results of Flavin 1 3-N-Arylation with Boronic Acids
Entry
Flavin
Boronic acid
Reaction
Recovered
Yield (%) of 3
isolated (corrected)a
By-products
(%)
2-R
Conditions
flavin 1 (%)
1
2
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1a
1a
1a
H
r.t., 48 h
n.d.b
36
56
–
4-Me
4-OMe
4-Br
r.t., 48 h
47 (74)
–
3
r.t., 48 h
23
34 (50)
9 (4)
4
r.t., 48 h
32
29 (43)
–
–
5
3-Br
r.t., 48 h
62
34 (89)
6
4-B(OH)2
r.t., 48 h
5
–
<5 (3a-H) + 9 (5)
c
7
4-B(OH)2
r.t., 48 h
13
–
<5 (7)
8
H
40–50 °C,d 2–3 h
40–50 °C,d 2–3 h
40–50 °C,d 2–3 h
40–50 °C,d 2–3 h
40–50 °C,d 2–3 h
80 °C, 5 h
n.d.b
n.d.b
19
22
–
9
4-Me
25
–
10
11
12
13
14
15
16
17
18
19
20
4-OMe
18 (22)
–
3-Br
n.d.b
28
33
–
4-B(OH)2
–
–
H
H
H
H
H
9
–
<5
42 (6)
0 °C, 24 h
58
40 (95)
–
–
–
–
–
–
–
e
r.t., 96 h, O2
–
68
r.t., 48 h
n.d.b
n.d.b
23
39
40–50 °C,d 2–3 h
r.t., 48 h
16
19 (25)
10
10
r.t., 48 h
n.d.b
n.d.b
–
–
40–50 °C,d 2–3 h
a Yield based on recovered starting material 1a.
b n.d. = not determined.
c 0.5 equiv was used.
d Heating in laboratory microwave oven.
e Addition of molecular sieves (4 Å, 250 mg).
nated after two days. After extraction and chromatogra- Reaction with an excess (3 equiv) of 1,4-phenyldiboronic
phy, purified products and remaining starting material acid [2-4-B(OH)2] (entry 6) was expected to afford a 3-N-
were isolated (Table 1, entries 1–7). Table 1 summarizes arylflavin with a remaining boronic acid function in the
the results of all experiments with reaction conditions, para position for subsequent functionalization. However,
yields of products 3 (corrected by conversion), recovered in that case only small amounts of unsubstituted 3-N-phe-
starting material 1, and observed by-products.
nylflavin 3a-H and its 4-hydroxy derivative 5 were isolat-
ed (Figure 1), resulting from the defunctionalization of
diboronic acid 2-4-B(OH)2 under these conditions. The
reaction with 0.5 equivalents of diboronic acid 2-4-
B(OH)2 (entry 7) yielded aldehyde 7, an oxidation product
of starting material 1a, instead of a phenylene-connected
flavin dimer 8 (Figure 1).
The survey shows moderate to good yields for the C–N
bond formation reaction with bromo, methoxy, methyl,
and unsubstituted monoboronic acids (entries 1–5). In all
cases, the reactions were not completed after two days and
different amounts of unreacted flavin 1a were recovered
after column chromatography. Monitoring by thin layer
chromatography indicated the occurrence of by-products. To explore the possible improvement and acceleration of
In the case of 4-methoxyphenyl (entry 3), product 3a-(4- the reaction at elevated temperatures, a set of experiments
OMe) was oxidized at the C-8-methyl group under the re- was performed in a laboratory microwave oven at 40–
action conditions, yielding additional 9% of the aldehyde 50 °C (entries 8–12). Every 15–30 minutes, the progress
4 (Figure 1).
was monitored by thin layer chromatography. A second
Synthesis 2008, No. 11, 1767–1774 © Thieme Stuttgart · New York

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Copper-Mediated 3-N-Arylation of Flavins
1769
OMe
OMe
N
O
N
N
O
O
N
O
H
N
N
N
N
O
5
4
OMe
OH
OMe
OMe
N
O
O
N
N
O
O
H
N
N
O
H
N
NH
N
6
O
7
MeO
OMe
O
O
N
O
N
N
N
N
O
N
N
N
8
Figure 1 By-products obtained in the 3-N-arylation reaction of flavin 1 with arylboronic acids
portion of boronic acid 2-R (3 equiv), copper acetate (2
equiv), and triethylamine (3 equiv) was added after one
O
O
O
O
hour. After two to three hours, no further reaction
progress was observed and the reaction was worked up as
described before. As expected, the reaction time de-
creased significantly, but more by-products and general
lower yields were observed, making the product purifica-
tion more complicated. Overall, microwave conditions
did not improve the reaction although the conversion of
starting material is significantly accelerated. In another
experiment, flavin 1a and unsubstituted boronic acid 2-H
were allowed to react at 80 °C thermal heating for five
hours (entry 13). Monitoring by thin layer chromatogra-
phy showed fast and complete conversion of all starting
material 1a. After purification, beside little amounts of 3-
N-phenylflavin 3a-H, 42% of aldehyde 6 (Figure 1) was
isolated. Apparently, the desired product 3a-H was further
oxidized at C-8 under these conditions.
B
B
9
10
Figure 2 Phenylboronic esters 9 and 10
ester 10 at room temperature and in the microwave (40–
50 °C) yielded no conversion.
In addition, neither the application of copper acetate in
larger amounts (5–10 equiv), nor the addition of catalytic
amounts of palladium to the mixture could improve the re-
action of flavin 1a with phenylboronic acid (2-H).
As elevated temperatures led to more decomposition of
the starting material and an increased number of by-prod-
ucts, the reaction of flavin 1a with boronic acid 2-H was
carried out at 0 °C in an ice bath (entry 14). Under these
conditions, 40% (95% corrected by recovered starting ma-
terial) of the desired product 3a-H and 58% of flavin 1a
were isolated after one day. The reaction proceeds more
cleanly, facilitating the workup and product isolation. In
another run, the reaction was conducted at room tempera-
ture in the presence of molecular sieves under oxygen at-
mosphere (entry 15). Here, 68% of the product 3a-H was
isolated after extending the reaction time to four days to
complete conversion, representing the highest absolute
yield of all reactions.
To extend the 3-N-arylation reaction to other flavins, tet-
raacetylriboflavin 1b25 was used as the starting material
(entry 16–17). At room temperature, 39% of N-phenylfla-
vin 3b-H was obtained after two days; 16% after two
hours in a microwave reaction. These yields are slightly
lower compared to flavin 1a, because workup of the more
sensitive flavin 3b-H was more complex.
The application of boronic acid esters 9 and 10 (Figure 2),
instead of boronic acids 2-R, gave ambivalent results (en-
tries 18–20). Under standard reaction conditions, with
ethylene ester 9 a yield of 19% of the product (25% cor-
rected by conversion, 23% recovered flavin 1a) was
achieved. A reaction with commercially available pinacol
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B. Attenberger et al.
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Figure 3 UV/Vis spectra of flavins 1a, 3, 4, 5, and 6 in acetonitrile
(2.5 × 10–5 M)
Figure 4 Fluorescence spectra of flavins 1a, 3, 4, 5, and 6 in aceto-
nitrile (2.5 × 10–6 M)
C-8 position on the electronic structure of the flavin as re-
ported previously in the literature.7,8
UV and Fluorescence Spectra of 3-N-Arylflavins
Figure 4 shows the fluorescence spectra of flavins 1a, 3,
4, 5, and 6 in acetonitrile (2.5 × 10–6 M) upon excitation at
440 nm.
The influence of the additional aromatic system in 3-N
position on the electronic properties of the flavin moiety
was examined with optical spectroscopy. UV/Vis spectra
for flavins 1a, 3, 4, 5, and 6 are shown in Figure 3 (aceto-
nitrile, 2.5 × 10–5 M).
As expected from the orthogonal orientation of the p-sys-
tem, UV-spectra of all 3-N-arylated flavins 3 and 5 look
similar and differ only slightly from the parent flavin 1a.
The absorption maxima in the visible and UV region are
slightly shifted and the extinction coefficients are similar
(Table 2). Aldehydes 4 and 6 show different absorption
properties. The absorption maximum in the visible range
is bathochromically shifted by 17–18 nm. This clearly in-
dicates the significant influence of the carbonyl group at
The maximum of emission of flavin 5 is shifted to longer
wavelength (+13 nm) compared to the other 3-N-arylfla-
vins 3a and flavin 1a (Table 3). Fluorescence of 4-meth-
ylphenylflavin 3a-(4-Me) is slightly and of 4-methoxy
and 4-hydroxy derivatives 3a-(4-OMe) and 5 strongly
quenched. This indicates that high electron density in the
3-N aromatic substituent decreases the emission of the fla-
vin. Emission intensities of aldehydes 4 and 6 are also de-
creased. The emission maximum of flavin 6 is shifted by
about 20 nm to longer wavelength.
Figure 5 shows equally concentrated solutions of flavins
3–5 in acetonitrile under a UV lamp with black (top) and
Table 2 UV/Vis Data of Flavins 1a, 3, 4, 5, and 6a
Entry
Flavin
lmax (nm)
l
max (nm)
l
max (nm)
lmax (nm)
(e [L·mol–1·cm–1])
222 (41200)
225 (37650)
225 (39650)
225 (39850)
225 (36750)
225 (37150)
224 (36050)
249 (37750)
–
(e [L·mol–1·cm–1])
267 (35550)
272 (36300)
272 (36200)
272 (36350)
272 (31350)
272 (30450)
272 (31250)
290 (22350)
271 (31750)
292 (23650)
(e [L·mol–1·cm–1])
343 (10200)
340 (9500)
346 (9450)
349 (9000)
348 (8300)
347 (8000)
348 (9600)
338 (13600)
346 (8500)
339 (14250)
(e [L·mol–1·cm–1])
441 (12700)
444 (12950)
444 (12850)
444 (12350)
444 (11250)
444 (10700)
444 (12800)
462 (11900)
444 (11250)
461 (12550)
1
2
1a
3a-H
3
3a-(4-Me)
4
3a-(4-OMe)
5
3a-(4-Br)
6
3a-(3-Br)
7
3b-H
8
4
5
6
9
10
248 (36750)
a In MeCN (2.5 × 10–5 M).
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Copper-Mediated 3-N-Arylation of Flavins
1771
Table 3 Fluorescence Data of Flavins 1a, 3, 4, 5, and 6a
10-(2-Methoxyethyl)-7,8-dimethylbenzo[g]pteridine-2,4(3H,10H)-
dione (1a),14 tetraacetylriboflavin (1b),25 and phenylboronic ester
9
26 were prepared by known methods. All other chemicals were pur-
Entry
Flavin
l
max (nm)
Emission intensity
(a.u.)
chased from commercial suppliers, checked by 1H NMR spectrom-
etry, and then used as received. Before use, solvents were distilled.
Anhydrous DMF was purchased from Fluka. TLC was carried out
on silica gel 60 F254 aluminum sheets (Merck) or on precoated
plastic sheets Polygram SIL G/UV254 (Macherey-Nagel, Düren,
Germany), with detection under 254 nm or 333 nm UV light, or by
direct observation (flavins are intensively yellow-colored). Prepar-
ative TLC was carried out on home-made glass plates (20 × 20 cm)
coated with silica gel 60 GF254 (20 g, Merck). Flash column chro-
matography was carried out on silica gel 0.035–0.070 mm, 60 Å
from Acros. NMR spectra were recorded on a Bruker spectrometer
equipped with a robotic sampler at 300 MHz (1H NMR) or 75 MHz
(13C NMR). TMS was used as the external standard. Electron-im-
pact (EI-MS) and chemical ionization (CI-MS) mass spectra were
recorded on a Finnigan TSQ 710 spectrometer, and electrospray
ionization (ES-MS) mass spectra were recorded on a ThermoQuest
Finnigan TSQ 7000 spectrometer. All methods of high-resolution
mass spectrometry (HRMS) were measured with a ThermoQuest
Finnigan MAT 95 spectrometer. Melting points were measured us-
ing a Büchi SMP-20 apparatus and are uncorrected. UV/Vis spectra
were recorded on a Varian Cary 50 Bio UV/VIS spectrometer
against air. Fluorescence spectra were recorded on a Varian Cary
Eclipse spectrometer. IR spectra were recorded on a Biorad Spec-
trometer Excalibur FTS 3000 spectrometer. Microwave heating was
carried out with Microwave Discover System S-Class from CEM.
1
2
1a
510
508
509
507
510
510
508
510
522
529
198
197
115
26
3a-H
3
3a-(4-Me)
4
3a-(4-OMe)
5
3a-(4-Br)
182
169
190
1
6
3a-(3-Br)
7
3b-H
8
4
5
6
9
11
10
16
a In MeCN (2.5 × 10–6 M) after excitation at 440 nm.
Copper-Mediated 3-N-Arylation of Flavins; General Procedure
Flavin 1a (75 mg, 250 mmol), arylboronic acid (2-R; 3 equiv),
Cu(OAc)2 (100 mg, 500 mmol, 2 equiv) and Et3N (76 mg, 750 mmol,
3 equiv) were stirred in anhyd DMF (3 mL) for 2 d at r.t. in the dark.
Afterwards, the mixture was diluted with CHCl3 (150 mL), and the
CHCl3 layer was washed with H2O (150 mL) and brine (150 mL).
The organic phase was dried (MgSO4) and the solvent was evapo-
rated yielding a dark oil. After purification by flash column chroma-
tography (EtOAc–MeOH, 20:1) and/or preparative TLC (CHCl3–
MeOH, 25:1), the product was obtained as a yellow solid.
Figure 5 Equally concentrated solutions of flavins 3–5 in acetoni-
trile under a UV lamp with black (top) and white (bottom) back-
ground
10-(2-Methoxyethyl)-7,8-dimethyl-3-phenylbenzo[g]pteridine-
2,4(3H,10H)-dione (3a-H)
Prepared from phenylboronic acid (2-H; 91 mg, 750 mmol) accord-
ing to the General Procedure; yield: 53 mg (56%); yellow solid; mp
237 °C; Rf = 0.65 (CHCl3–MeOH, 10:1).
white (bottom) background. The differences in the emis-
sion intensities are clearly visible. More detailed photo-
physical investigations are currently in progress and
results will be disclosed later.
IR (ATR): 1712, 1654, 1577, 1535, 1453, 1400, 1344, 1311, 1273,
1223, 1208, 1157, 1088 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.42 (s, 3 H, ArCH3), 2.53 (s, 3 H,
ArCH3), 3.30 (s, 3 H, OCH3), 3.93 (t, J = 5.21 Hz, 2 H, NCH2), 4.92
(t, J = 5.21 Hz, 2 H, OCH2), 7.28–7.30 (m, 2 H, PhH), 7.41 (t,
J = 7.27 Hz, 1 H, PhH), 7.50 (t, J = 7.55 Hz, 2 H, PhH), 7.68 (s, 1
In summary, we have established a method for the direct
3-N-arylation of flavins using various arylboronic acids in
the presence of copper acetate giving moderate to good
yields of C(aryl)–N(imide) bond formation. The new re- H, ArH), 8.02 (s, 1 H, ArH).
13C NMR (75 MHz, CDCl3): d = 19.5 (C-7¢), 21.7 (C-8¢), 45.5
(NCH2), 59.3 (OCH3), 69.6 (OCH2), 116.8 (C-9), 128.3, 128.6, and
129.4 (CPh), 132.3 (C-9a), 132.4 (C-6), 135.2 (CPh), 135.8 (C-5a),
136.0 (C-4a), 136.8 (C-7), 147.8 (C-8), 149.2 (C-10a), 155.5 (C-2),
160.0 (C-4).
MS (ES): m/z = 377.1 (100%, [M + H]+).
HRMS-EI: m/z calcd for C21H20N4O3 [M]+: 376.1535; found:
action provides a more facile access to a class of flavins
that was difficult to prepare and was therefore not much
investigated. The reaction conditions were optimized con-
sidering the lability of flavins under basic conditions and
heating. Best product yields were achieved at low reaction
temperatures or under oxygen atmosphere with addition
of molecular sieves. The additional orthogonal aromatic
system at 3-N is not electronically coupled to the original 376.1537 (D –0.42 ppm).
flavin p-system as proven by optical spectroscopy. Some
of the new compounds show reduced or quenched emis-
sion intensity.
UV/Vis (MeCN): lmax (e) = 225 (37650), 272 (36300), 340 (9500),
444 nm (12950).
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10-(2-Methoxyethyl)-7,8-dimethyl-3-(4-methylphenyl)ben-
zo[g]pteridine-2,4(3H,10H)-dione [3a-(4-Me)]
(t, J = 5.08 Hz, 2 H, OCH2), 7.19 (d, J = 8.51 Hz, 2 H, PhH), 7.62
(d, J = 8.51 Hz, 2 H, PhH), 7.69 (s, 1 H, ArH), 8.04 (s, 1 H, ArH).
Prepared from 4-methylphenylboronic acid [2-(4-Me); 102 mg, 750
mmol] according to the General Procedure; yield: 46 mg (47%); yel-
low solid; mp 185 °C; Rf = 0.55 (CHCl3–MeOH, 10:1). Recovery of
the unreacted starting material flavin 1a after column chromatogra-
phy: 27 mg (36%).
13C NMR (75 MHz, CDCl3): d = 18.6 (C-7¢), 20.8 (C-8¢), 44.7
(NCH2), 58.4 (OCH3), 68.6 (OCH2), 115.9 (C-9), 121.7 and 129.1
(CPh), 131.4 (C-9a), 131.4 (C-6), 131.7 and 133.8 (CPh), 134.3 (C-
5a), 134.8 (C-4a), 136.1 (C-7), 147.2 (C-8), 148.2 (C-10a), 154.5
(C-2), 158.9 (C-4).
IR (ATR): 3554, 3491, 2919, 2850, 2360, 1708, 1664, 1581, 1542,
1513, 1455, 1401, 1346, 1270, 1241, 1149, 1079, 1066, 1014 cm–1.
MS (ES): m/z = 455.1 (100%, [M + H]+), 911.3 [2 M + H]+.
HRMS-EI: m/z calcd for C21H19BrN4O3 [M]+: 454.0641; found:
454.0636 (D 1.02 ppm).
1H NMR (300 MHz, CDCl3): d = 2.41 (s, 3 H, PhCH3), 2.44 (s, 3 H,
ArCH3), 2.55 (s, 3 H, ArCH3), 3.31 (s, 3 H, OCH3), 3.94 (t, J = 5.08
Hz, 2 H, NCH2), 4.93 (t, J = 5.21 Hz, 2 H, OCH2), 7.19 (d, J = 8.33
Hz, 2 H, PhH), 7.32 (d, J = 7.96 Hz, 2 H, PhH), 7.68 (s, 1 H, ArH),
8.04 (s, 1 H, ArH).
13C NMR (75 MHz, CDCl3): d = 19.6 (C-7¢), 21.4 (PhCH3), 21.7
(C-8¢), 45.5 (NCH2), 59.4 (OCH3), 69.6 (OCH2), 116.8 (C-9), 128.0
and 130.2 (CPh), 132.3 (C-6), 132.4 (C-9a), 133.2 (CPh), 135.1 (C-
5a), 136.0 (C-4a), 136.8 (C-7), 138.6 (CPh), 147.8 (C-8), 149.2 (C-
10a), 155.6 (C-2), 160.1 (C-4).
UV/Vis (MeCN): lmax (e) = 225 (36750), 272 (31350), 348 (8300),
444 nm (11250).
3-(3-Bromophenyl)-10-(2-methoxyethyl)-7,8-dimethylben-
zo[g]pteridine-2,4(3H,10H)-dione [3a-(3-Br)]
Prepared from 3-bromophenylboronic acid [2-(3-Br); 151 mg, 750
mmol] according to General Procedure; yield: 39 mg (34%); yellow
solid; mp 179 °C; Rf = 0.70 (CHCl3–MeOH, 10:1). Recovery of un-
reacted starting material flavin 1a after column chromatography: 46
mg (62%).
MS (ES): m/z = 391.2 (100%, [M + H]+).
HRMS-EI: m/z calcd for C22H22N4O3 [M]+: 390.1692; found:
390.1689 (D 0.74 ppm).
IR (ATR): 2922, 2851, 2360, 1708, 1657, 1581, 1539, 1457, 1400,
1350, 1267, 1225, 1193, 1112, 1065 cm–1.
UV/Vis (MeCN): lmax (e) = 225 (39650), 272 (36200), 346 (9450),
444 nm (12850).
1H NMR (300 MHz, CDCl3): d = 2.45 (s, 3 H, ArCH3), 2.56 (s, 3 H,
ArCH3), 3.30 (s, 3 H, OCH3), 3.94 (t, J = 5.08 Hz, 2 H, NCH2), 4.94
(t, J = 5.21 Hz, 2 H, OCH2), 7.25–7.28 (m, 1 H, PhH), 7.39 (t,
J = 8.10 Hz, 1 H, PhH), 7.48 (t, J = 1.78 Hz, 1 H, PhH), 7.55–7.58
(m, 1 H, PhH), 7.70 (s, 1 H, ArH), 8.05 (s, 1 H, ArH).
10-(2-Methoxyethyl)-3-(4-methoxyphenyl)-7,8-dimethylben-
zo[g]pteridine-2,4(3H,10H)-dione [3a-(4-OMe)]
Prepared from 4-methoxyphenylboronic acid [2-(4-OMe); 114 mg,
750 mmol] according to the General Procedure; yield: 35 mg (34%);
yellow solid; mp 155 °C; Rf = 0.60 (CHCl3–MeOH, 10:1). Recov-
ery of unreacted starting material flavin 1a after column chromatog-
raphy: 17 mg (23%).
13C NMR (75 MHz, CDCl3): d = 19.6 (C-7¢), 21.7 (C-8¢), 45.6
(NCH2), 59.4 (OCH3), 69.6 (OCH2), 116.9 (C-9), 122.6, 127.3,
130.6, 131.7, and 131.9 (CPh), 132.4 (C-6), 132.4 (C-9a), 135.3
(CPh), 136.0 (C-5a), 137.0 (C-4a), 137.1 (C-7), 148.2 (C-8), 149.2
(C-10a), 155.1 (C-2), 159.8 (C-4).
IR (ATR): 2924, 2361, 2343, 1711, 1665, 1577, 1538, 1510, 1449,
1400, 1351, 1301, 1241, 1154, 1111, 1084, 1025 cm–1.
MS (ES): m/z = 455.1 (100%, [M + H]+).
HRMS-EI: m/z [M]+ calcd for C21H19BrN4O3: 454.0641; found:
454.0640 (D 0.14 ppm).
1H NMR (300 MHz, CDCl3): d = 2.43 (s, 3 H, ArCH3), 2.53 (s, 3 H,
ArCH3), 3.30 (s, 3 H, OCH3), 3.83 (s, 3 H, PhOCH3), 3.92 (t,
J = 5.08 Hz, 2 H, NCH2), 4.92 (t, J = 5.08 Hz, 2 H, OCH2), 6.99 (d,
J = 9.06 Hz, 2 H, PhH), 7.21 (d, J = 8.78 Hz, 2 H, PhH), 7.67 (s, 1
H, ArH), 8.02 (s, 1 H, ArH).
13C NMR (75 MHz, CDCl3): d = 19.4 (C-7¢), 21.6 (C-8¢), 45.5
(NCH2), 55.4 (PhOCH3), 59.2 (OCH3), 69.4 (OCH2), 114.7 (CPh),
116.8 (C-9), 128.1 and 129.1 (CPh), 132.1 (C-6), 132.3 (C-9a), 135.2
(C-5a), 135.6 (C-4a), 137.2 (C-7), 148.2 (C-8), 149.0 (C-10a),
156.0 (C-2), 159.5 (CPh), 160.4 (C-4).
UV/Vis (MeCN): lmax (e) = 225 (37650), 272 (36300), 340 (9500),
444 nm (12950).
10-Tetraacetylribityl-7,8-dimethyl-3-phenylbenzo[g]pteridine-
2,4(3H,10H)-dione (3b-H)
Prepared from tetraacetylriboflavin (1b; 155 mg, 250 mmol) and
phenylboronic acid (2-H; 91 mg, 750 mmol) according to the Gen-
eral Procedure; yield: 60 mg (39%); yellow solid; mp 250 °C (dec.);
Rf = 0.65 (EtOAc–MeOH, 20:1).
MS (ES): m/z = 407.2 (100%, [M + H]+).
HRMS-EI: m/z calcd for C22H22N4O4 [M]+: 406.1641; found:
406.1645 (D –0.97 ppm).
IR (ATR): 2361, 1741, 1669, 1584, 1546, 1369, 1203, 1044 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.74 (s, 3 H, COCH3), 2.05 (s, 3
H, COCH3), 2.21 (s, 3 H, COCH3), 2.27 (s, 3 H, COCH3), 2.42 (s, 3
H, ArCH3), 2.55 (s, 3 H, ArCH3), 4.19–4.25 (m, 1 H, ribityl), 4.42
(dd, J = 12.35, 2.47 Hz, 1 H, ribityl), 4.97 (br s, 2 H, ribityl), 5.40
(s, 1 H, ribityl), 5.47 (s, 1 H, ribityl), 5.71 (d, J = 6.86 Hz, 1 H, ribi-
tyl), 7.29 (s, 2 H, PhH), 7.41 (t, J = 7.27 Hz, 1 H, PhH), 7.49 (t,
J = 7.55 Hz, 2 H, PhH), 7.56 (s, 1 H, ArH), 8.01 (s, 1 H, ArH).
UV/Vis (MeCN): lmax (e) = 225 (39850), 272 (36350), 349 (9000),
444 nm (12350).
3-(4-Bromophenyl)-10-(2-methoxyethyl)-7,8-dimethylben-
zo[g]pteridine-2,4(3H,10H)-dione [3a-(4-Br)]
Prepared from 4-bromophenylboronic acid [2-(4-Br); 151 mg, 750
mmol] according to the General Procedure; yield: 33 mg (29%); yel-
low solid; mp 246 °C; Rf = 0.60 (CHCl3–MeOH, 10:1). Recovery of
unreacted starting material flavin 1a after column chromatography:
24 mg (32%).
13C NMR (75 MHz, CDCl3): d = 19.5 (C-7¢), 20.4 (C-8¢), 20.8, 20.9,
21.2 and 21.5 (COCH3), 44.7 (Ca), 61.9 (Ce), 69.0, 69.5 and 70.3
(C-b,c,d), 115.5 (C-9), 128.2, 128.7, and 129.4 (CPh), 131.4 (C-9a),
133.0 (C-6), 134.8 (C-5a), 135.7 (CPh), 136.1 (C-4a), 136.8 (C-7),
147.8 (C-8), 149.6 (C-10a), 154.9 (C-2), 159.7 (C-4), 169.8, 170.0,
170.5 and 170.7 (C=O).
MS (ES): m/z = 621.3 (100%, [M + H]+).
HRMS-EI: m/z calcd for C31H33N4O10 [M + H]+: 621.2197; found:
621.2185 (D 1.88 ppm).
IR (ATR): 2918, 2849, 1707, 1658, 1587, 1539, 1487, 1445, 1400,
1351, 1262, 1228, 1193, 1113, 1066, 1012 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.44 (s, 3 H, ArCH3), 2.55 (s, 3 H,
ArCH3), 3.30 (s, 3 H, OCH3), 3.94 (t, J = 5.08 Hz, 2 H, NCH2), 4.93
Synthesis 2008, No. 11, 1767–1774 © Thieme Stuttgart · New York

PAPER
Copper-Mediated 3-N-Arylation of Flavins
1773
UV/Vis (MeCN): lmax (e) = 224 (36050), 272 (32150), 348 (9600),
444 nm (12800).
OCH2), 7.29–7.32 (m, 2 H, PhH), 7.43–7.56 (m, 3 H, PhH), 8.19 (s,
1 H, ArH), 8.37 (s, 1 H, ArH), 10.48 (s, 1 H, CHO).
13C NMR (75 MHz, CDCl3): d = 18.9 (C-7¢), 45.9 (NCH2), 59.3
(OCH3), 69.5 (OCH2), 120.5 (C-9), 128.2, 128.9, and 129.5 (CPh),
132.3 (C-9a), 135.1 (C-6), 135.3 (CPh), 137.4 (C-8), 137.7 (C-5a),
138.2 (C-4a), 139.6 (C-7), 149.3 (C-10a), 154.9 (C-2), 159.1 (C-4),
191.0 (C=O).
MS (CI): m/z = 391.1 (100%, [M + H]+).
HRMS-EI: m/z calcd for C21H18N4O4 [M]+: 390.1328; found:
390.1328 (D 0.01 ppm).
8-Formyl-10-(2-methoxyethyl)-3-(4-methoxyphenyl)-7-methyl-
benzo[g]pteridine-2,4(3H,10H)-dione (4)
Obtained after chromatographic purification as a by-product from
the reaction of flavin 1a with 4-methoxyphenylboronic acid [2-(4-
OMe); 114 mg, 750 mmol] according to the General Procedure;
yield: 9 mg (9%); orange-red solid; mp 212 °C; Rf = 0.50 (EtOAc–
MeOH, 20:1).
IR (ATR): 2836, 2361, 1701, 1664, 1620, 1581, 1546, 1510, 1451,
1348, 1304, 1253, 1198, 1154, 1112, 1033 cm–1.
UV/Vis (MeCN): lmax (e) = 248 (36750), 292 (23650), 339
(14250), 461 nm (12550).
1H NMR (300 MHz, CDCl3): d = 2.83 (s, 3 H, ArCH3), 3.29 (s, 3 H,
OCH3), 3.86 (s, 3 H, PhOCH3), 3.96 (t, J = 4.94 Hz, 2 H, NCH2),
4.97 (t, J = 4.94 Hz, 2 H, OCH2), 7.03 (d, J = 8.78 Hz, 2 H, PhH),
7.22 (d, J = 9.06 Hz, 2 H, PhH), 8.19 (s, 1 H, ArH), 8.36 (s, 1 H,
ArH), 10.47 (s, 1 H, CHO).
13C NMR (75 MHz, CDCl3): d = 19.0 (C-7¢), 45.9 (NCH2), 55.6
(PhOCH3), 59.4 (OCH3), 69.6 (OCH2), 114.9 (CPh), 120.4 (C-9),
127.9, and 129.2 (CPh), 132.3 (C-9a), 135.2 (C-6), 137.4 (C-8),
137.8 (C-5a), 138.3 (C-4a), 139.7 (C-7), 149.3 (C-10a), 155.2 (C-
2), 159.4 (C-4), 159.7 (CPh), 191.0 (C=O).
Acknowledgment
This research was supported by the DFG Graduate College
GRK640 ‘Sensory Photoreceptors in Natural and Artificial Sys-
tems’. B.A. thanks the Fonds der Chemischen Industrie for a fel-
lowship.
References
MS (CI): m/z = 421.1 (100%, [M + H]+).
HRMS-EI: m/z calcd for C22H20N4O5 [M]+: 420.1434; found:
420.1431 (D 0.64 ppm).
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8-Formyl-10-(2-methoxyethyl)-7-methyl-3-phenylbenzo[g]pte-
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Synthesis 2008, No. 11, 1767–1774 © Thieme Stuttgart · New York

1774
B. Attenberger et al.
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Synthesis 2008, No. 11, 1767–1774 © Thieme Stuttgart · New York