Preparation and redox properties of N,N,N-1,3,5-trialkylated flavin derivatives and their activity as redox catalysts

Article abstract of DOI:10.1002/chem.200400540

Eight different flavin derivatives have been synthesized and the electronic effects of substituents in various positions on the flavin redox chemistry were investigated. The redox potentials of the flavins, determined by cyclic voltammetry, correlated wit

Full text of DOI:10.1002/chem.200400540

Preparation and Redox Properties of N,N,N-1,3,5-Trialkylated Flavin
Derivatives and Their Activity as Redox Catalysts
[a]
Auri A.LindØn, Nina Hermanns, Sascha Ott, Lars Krüger, and Jan-E.Bäckvall*
Abstract: Eight different flavin derivatives have been synthesized and the elec-
tronic effects of substituents in various positions on the flavin redox chemistry
Keywords: cyclic voltammetry
·
flavins · redox catalysis · redox
chemistry
were investigated. The redox potentials of the flavins, determined by cyclic voltam-
metry, correlated with their efficiency as catalysts in the H2O2 oxidation of methyl
p-tolyl sulfide. Introduction of electron-withdrawing groups increased the stability
of the reduced catalyst precursor.
Introduction
relative to those of percarboxylic acids and other hydroper-
oxides.[10]
Flavins have proven to be efficient mediators in a range of
oxidation reactions. The chemical processes that use flavin
catalysts mimic enzymatic processes mainly performed by
Baeyer–Villiger monooxygenases (BVMOs).[1] In particular
the cyclohexanone monooxygenase,[2] cyclopentanone mono-
oxygenase,[3] and 4-hydroxyacetophenone monooxygenase[4]
catalyze the oxidation of organic sulfides to sulfoxides as
well as Baeyer–Villiger oxidations.[1] Also monoamine oxy-
genases that catalyze oxidative deamination are dependent
on a flavin co-factor.[5]
The first example of the participation of a flavin in stoi-
chiometric amounts in the oxidation of organic substrates
was provided by Mager and co-workers[6] in a reaction of
phenylalanine with dihydroalloxazine in the presence of O2
and H2O2 almost four decades ago. Bruice and co-workers
later reported on the oxidations of aldehydes,[7] sulfides,[8]
and tertiary amines[9] by stoichiometric 4a-hydroperoxy-5-
alkyl-3-methyllumiflavins. The latter group also studied
monooxygen donation to iodide, tertiary amines, and sul-
fides[10] from the 4a-hydroperoxy-5-ethyl-3-methyllumiflavin
and its analogues. In the same article they reported on the
monooxygen donation potentials of 4a-hydroperoxyflavins
The catalytic use of flavins is still quite limited, but exam-
ples of catalytic oxidations of secondary amines to ni-
trones,[11] tertiary amines to N-oxides,[12] and sulfides to sulf-
oxides[13] by hydrogen peroxide as stoichiometric oxidant
have been reported. Flavins have also been employed as cat-
alysts in Baeyer–Villiger oxidations of activated ketones[14]
and in the dihydroxylation of alkenes as part of the biomim-
etic triple catalytic oxidation system.[15] Recently, Murahashi
et al. reported on the flavin-catalyzed oxidation of sulfides
and amines with molecular oxygen as terminal oxidant.[16]
To fully understand the mechanism of flavin-catalyzed ox-
idations and to be able to modify and design efficient flavins
for oxidation reactions, an intimate knowledge of their
chemical and electronic properties is highly desira-
ble.[7,8a,9,10,17] The substituent effect on chemical properties
and redox potentials of a range of flavins has been studied
by a number of groups.[18] Our group has previously studied
the reactivity of different flavins as catalysts in oxidation of
sulfides and tertiary amines.[13a]
A very stable and efficient flavin catalyst 1, alkylated at
the 1-, 3-, and 5-positions, was discovered by our group.[12]
Mager and co-workers had previously reported on the au-
toxidative behavior of a similarly substituted dihydrofla-
vin.[17a] It was found that not only is 1 more robust than any
of the previously reported flavins, it also has superior cata-
lytic activity.
Since then, this catalyst has been successfully applied in
oxidations of tertiary amines to N-oxides[12,13a,15] and sulfides
to sulfoxides (Scheme 1).[13] It has also been successfully in-
corporated into the osmium-catalyzed dihydroxylation of
olefins resulting in an efficient and environmentally friendly,
[a] A. A. LindØn, Dr. N. Hermanns, Dr. S. Ott, Dr. L. Krüger,
Prof. J.-E. Bäckvall
Department of Organic Chemistry
Stockholm University
106 91 Stockholm (Sweden)
Fax : (+46)81-54-908
E-mail: jeb@organ.su.se
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
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DOI: 10.1002/chem.200400540
Chem. Eur. J. 2005, 11, 112 – 119

FULL PAPER
Results and Discussion
Eight different flavin derivatives 1–8 were synthesized and
examined. Three of these (1–3)have previously been stud-
ied as catalysts for the oxidation of sulfides[13] and tertiary
amines[12,13a] in our group.
Dihydroflavins 1–7 were prepared in three steps as depict-
ed in Scheme 2. The first step involves a condensation of the
respective diamine 9a–f with 10, resulting in the tricyclic al-
loxazine ring system 11a–f in good yields. Subsequent N-al-
kylation with methyl or ethyl iodide in the second step gives
the N,N-1,3-dimethyl- or -diethylalloxazine in good yields.
The final step is a reductive alkylation of the N5-position
with acetaldehyde (butanal for 4)and H 2 with Pd on activat-
ed charcoal.
When the 7/8-trifluoromethyl alloxazine 11 f was treated
with ethyl iodide the 1,3-diethyl 7-trifluoromethyl alloxazine
12 f was obtained in 57% yield. Substrates 12d and 12e
were obtained as mixtures of the 7- and 8-regioisomers. In
the final step, in which an ethyl group is introduced at N5,
the methoxy- and butoxy carbonyl dialkyl alloxazines 12d
and 12e reacted somewhat differently. The dihydroflavin 5
was obtained mainly as the 7-isomer with only about 10%
Scheme 1. The proposed catalytic cycle.
triple-catalytic system in which
hydrogen peroxide is employed
as the terminal oxidant.[15]
In previous work by our
group,[13a] we have shown that
electron-withdrawing fluorine
substituents in the 7- and 8-po-
sitions of the flavin result in an
even more stable catalyst pre-
cursor, with the drawback that
a somewhat longer time is re-
quired for activation of the cat-
alyst. The longer induction
period is rationalized by the
need of an initial oxidation of
the catalyst precursor with mo-
lecular oxygen (Scheme 1), and
this step is slower for the elec-
tron deficient 7,8-difluoro ana-
Scheme 2. General pathway to the reduced catalyst precursors 1–7.
logue 2. Once the catalyst has
entered the catalytic cycle as I
contamination of the 8-isomer in 64% combined yield,
whereas dihydroflavin 6 (from 12e)afforded the 7- and 8-
isomers in a 1.7:1 ratio in 29% combined yield. The isomer-
ic mixtures were used as such for the electrochemical meas-
urements, since the products are too air sensitive for column
chromatography or other means of purification after the
final step.
it can transfer its electrophilic oxygen to the substrate via
transition state II forming the hydroxyflavin intermediate
III. The hydroxyl group is then eliminated from III restoring
the aromatic 1,4-diazine form IV. To complete the cycle, IV
reacts with hydrogen peroxide to regenerate the active cata-
lyst species I.
In this paper we report on the preparation and the cata-
lytic and electronic properties of a range of 6,9- and 7- and/
or 8-substituted N,N,N-1,3,5-trialkylated flavin derivatives.
Cyclic voltammetry was used to determine the redox poten-
tials of the novel flavins.
A different approach had to be used for the synthesis of
6,9-dimethylalloxazine 17, since the 2,5-dimethyl-1,2-diami-
nobenzene is not commercially available (Scheme 3). Reac-
tion of 2,5-dimethylaniline hydrochloride 13 with 1,3-di-
methyl-6-aminouracil 15 in 2,5-dimethylaniline 14 at 1608C
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J.-E. Bäckvall et al.
Scheme 3. Synthesis of pre-catalyst 8.
resulted in the formation of the product (16)in 28% yield.
Cyclization with NaNO2 to the tricyclic alloxazine ring struc-
ture yielded product 17 in 70% isolated yield. For the for-
mation of the reduced catalyst precursor the standard reduc-
tive alkylation was applied as described above and the cata-
lyst 8 was obtained in 50% yield.
Kinetics: We have previously observed an induction period
in the oxidation of methyl p-tolyl sulfide with 7,8-difluoro
dihydroflavin 2 as catalyst[13a] (Scheme 4, Figure 1a). This is
thought to arise from the fact that the electron-deficient di-
hydroflavin catalysts are less susceptible towards oxidation
by molecular oxygen.[19]
Scheme 4. The reaction for the kinetic study.
Figure 1. Oxidation of sulfide 18 to sulfoxide 19 by H2O2, a)with flavins
1 and 2 as catalysts, b)with flavin 2 in three consecutive runs.
In order to verify this behavior we conducted the follow-
ing study: after completed oxidation of methyl p-tolyl sul-
fide, we added another equivalent each of sulfide and hydro-
gen peroxide to the reaction mixture. The conversion was
followed by 1H NMR spectroscopy. A total of three runs
were conducted and a remarkable enhancement of the reac-
tion rate was observed in the second run (Figure 1b). This
indeed supports our hypothesis that during the first run
there is an induction period during which the active catalyst
species is slowly generated from 2 by reaction with molecu-
lar oxygen. Once the active species is formed the reaction is
fast and follows the typical first-order rate expression.
The activity of dihydroflavins 3–8 was also studied and
the results are summarized in Table 1. The N5-butyl-substi-
tuted dihydroflavin 4 and 5 showed good catalytic activity.
The results for dihydroflavin 3 have been published before
by our group and are included for comparison. In the case
of 3 the reaction does not proceed further than ~40% due
to oxidative degradation of the catalyst. The dihydroflavin 6
showed very low activity due to that the catalyst fell out of
the reaction mixture.
Redox potentials of flavin derivatives from cyclic voltamme-
try: To gain a better understanding of the electronic proper-
ties of the different flavin catalysts, we measured their half-
wave potentials by cyclic voltammetry. As described above,
the catalyst precursor is oxidized when it enters the catalytic
cycle. Since direct investigation of the oxidation process of
the dihydroflavins as it enters the catalytic cycle is difficult,
we concentrated on the simple one-electron oxidation de-
picted in Scheme 5. The acquired data reflect the thermody-
namics for the activation step of the flavin catalyst precur-
sor. The results are summarized in Table 2.
The oxidations of all flavins presented herein were fully
reversible on the electrochemistry timescale. They are one-
electron processes, evident from a peak split larger than
60 mV and from the bulk electrolysis of dihydroflavin 1,
which gave a charge of approximately 1 F per mole of 1.[20]
The potentials reflect our observation on the catalytic activi-
ty of the flavins studied.
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Chem. Eur. J. 2005, 11, 112 – 119

Flavin Derivatives
FULL PAPER
Table 1. The results for the dihydroflavin activity in oxidation of 18 to
19.[a]
Table 2. Redox potentials of flavins 1–8.[a]
Entry
Flavin
E0 [V]
Dihydroflavin
t
Conversion
[%]
kobs
Rel. rate[b]
[min]
[”10À4 sÀ1
]
1
2
1
60
60
80
34
21
60
60
60
90
60
60
–
96
67
97
100
100
40
99
81
95
15
9.0
1
0.3
1
À0.414
[d]
2[c]
–
–
–
[d]
2[e]
2[f]
3
4
5
1.4
2.4
0.7
1.7
0.4
[d]
21.9
3[g]
4
5
–
[d]
2
À0.305
À0.304
À0.207
À0.182
À0.182
15.2
[d]
–
[d]
6
7
8
6
7
8
–
–
0.07
0.04
–
[d]
10
n.r.[h]
–
3
[a] The reactions were run with substrate 18 (0.223 mmol), catalyst
(1.8 mol%), and H2O2 (1.75 equiv)in CD 3OD (0.6 mL). [b] The relative
rates were obtained from the pseudo-first-order rate constant kobs or esti-
mated from the rate in the early phase of the reaction. [c] First addition.
[d] Cannot be determined due to change of the concentration of the
active catalyst during the reaction. [e] Second addition. [f] Third addition.
[g] Taken from reference [13a]. [h] n. r.=no reaction detected within
20 min.
4
5[b]
6[c]
Scheme 5. Electrochemical oxidation/reduction of flavin 1 to 1’ (model
catalyst).
The catalyst precursor 3 (Table 2, Entry 1), with electron-
donating methyl groups in the 7- and 8-positions is most sus-
ceptible towards oxidation, as evident from the most nega-
tive oxidation potential of the derivatives studied. As previ-
ously observed, this catalyst shows good initial activity in
catalysis, but the reaction slows down remarkably at around
40% due to sensitivity towards autoxidative degradation.[13a]
Upon introduction of an electron-withdrawing group at
the 7-position (flavins 5–7)or at the 7- and 8-positions
(flavin 2), the oxidation potential becomes less negative,
and, hence, the catalyst precursors are more difficult to oxi-
dize. As described above, the 7,8-difluoro derivative is less
susceptible towards oxidation by molecular oxygen and
needs an activation period, which is in agreement with the
higher oxidation potential relative to 1 and 3.
It is important to note that though pre-catalysts 5 and 6
were used as the isomeric mixtures for the measurements,
the observed oxidation potential is for the major isomer.
The signal for the impurity is buried under that of the major
isomer.
The catalyst precursor 7, which has an oxidation potential
between those for 5 and 8, showed poor catalytic activity;
this result is surprising since its oxidation potential is close
to that of 5, and the latter is active in catalysis. The tri-
fluoromethyl group is strongly electron withdrawing and this
7
8
À0.176
À0.162
[a] For conditions see the Experimental Section. [b] Main isomer, 9:1
ratio of 7- and 8-isomers. [c] 1.7:1 ratio of 7- and 8-isomers.
may make the loss of OHÀ from III to IV much less favora-
ble for catalyst 7, rendering the poor activity of the catalyst.
This catalyst also showed poor solubility in the reaction
media. The 6,9-dimethyl-substituted dihydroflavin 8 is oxi-
dized at highest potential. This is consistent with the results
obtained from the catalytic reactions, where 8 also showed
poor catalytic activity (see above). If we compare this with
flavin 3, which also has two methyl substituents, the differ-
ence in oxidation potential is about 0.25 V. Although the
effect of the 6,9-substituent pattern is ambiguous, the high
oxidation potential of 8 cannot be explained solely by the
electronic effect of the substituents, but other factors need
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J.-E. Bäckvall et al.
to be considered. For this particular derivative the effect of
the methyl substituents at the 6- and 9-positions is to a large
extent steric rather than electronic as illustrated in
Scheme 6.
Scheme 6. Illustration of the steric effect of the 6-methyl group.
There is theoretical evidence provided by Vµzquez
et al.[21] on the conformation of flavins in their reduced and
oxidized forms. The reduced form has a significant antiaro-
matic character, which leads to distortion from the plane of
the molecule. This makes the catalyst precursor 8 quite
stable, since the N5-ethyl group is oriented away from the 6-
methyl group. The oxidized form 8’ on the other hand is aro-
matic and planar, bringing the C6 and N5 substituents closer
to one another in space, introducing steric repulsion that re-
sults in an increased free-energy of 8’. In 8’’, the active cata-
lytic species in the oxidation, the 4a-carbon atom is an sp3
hybridized carbon atom and not part of the aromatic
system. However, the double bond between N10 and C10a
together with the electron pair on N5 that is conjugated to
the p-system makes the molecule relatively flat. Rizzo et al.
have reported a similar effect in an analogous system with
methyl groups on the N9 and N10 atoms.[18d]
Figure 2. The Hammett plot of log[Eox/E0ox] against Hammett s values.
tems. They have shown good linear free-energy relationship
correlation between the electronic properties provided by
the substituents on positions 7 and/or 8 and the reduction
potentials for the flavins studied. Rotello et al. showed in
there study that the substituent on C7 has a greater effect
on the reduction of a flavin in a nonaqueous environ-
ment.[18j]
Conclusion
Linear free-energy relationship: To find the correlation be-
tween the oxidation potentials of the dihydroflavins 1–7 and
the electronic effects of their susbstituents, we plotted the
log[Eox/E0ox] against their respective Hammett s values. Eox
is the oxidation potential of the catalyst precursors and E0ox
is the oxidation potential of the unsubstituted dihydroflavin
1, which is set as the standard reaction. Since the proton ab-
straction occurs at N10, we defined the substituent at C8 as
meta and that at C7 as para. This assignment was used for
the calculation of the s values. Since the oxidation poten-
tials reflect the free energy of the reaction for the different
substrates, we can use them directly for the Hammett plot,
presented in Figure 2.
As evident from Figure 2, there is an excellent linear cor-
relation between log[Eox/Eo0x] and s with a deviation R=
0.997. The Hammett 1 value, which reflects the sensitivity of
the substrate to the electronic effect of the substituent in
the reaction, is the slope of the line obtained from the
plot.[22] The negative slope of À0.418 indicates that electron-
donating groups render the electrochemical oxidation of the
dihydroflavin more facile; this result is consistent with the
kinetic studies as well as the direct conclusions drawn from
the oxidation potentials.
The results obtained from the cyclic voltammetry are in
good agreement with our results on the relative catalytic ac-
tivity of the reduced flavin analogues 1–8. We conclude that
electron-donating groups facilitate the oxidation of dihydro-
flavins and that there is a linear free-energy relationship be-
tween the oxidation potentials and the Hammet s values.
The different susceptibility toward oxidation may affect the
catalytic activity in two respects. The electron-rich dihydro-
flavin 3, which is most easily oxidized, enters the catalytic
cycle without any detectable induction period. However, its
performance as catalyst is hampered by autoxidative degra-
dation. The electron-deficient catalyst precursor 2, on the
other hand, needs a long induction period, but once it is ac-
tivated it is a fast and efficient catalyst that is stable toward
autoxidative degradation. This is clearly demonstrated in
the multiple addition experiment, with three consecutive
catalytic runs without adding more catalyst. The reaction
was in fact faster in the second and third run.
Experimental Section
General methods: 1H (300 or 400 MHz)and 13C (75 or 100 MHz)NMR
spectra were recorded on a Varian Mercury spectrometer. Chemical
shifts (d)are reported in ppm, with residual solvent as internal standard
and coupling constants (J)are given in Hz. Merck silica gel 60 (240–
The trend for the substituent effect on the redox poten-
tials found in this study fit well with what has been reported
earlier by Rizzo[18c] and Rotello[18i,j] for analogous flavin sys-
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Flavin Derivatives
FULL PAPER
400 mesh)was used for flash chromatography, and analytical thin-layer
chromatography was performed on Merck pre-coated silica gel 60-F254
plates. Cyclic voltammograms were recorded on an Autolab Potentiostat
(Ecochimie Netherlands), controlled by GPES software (version 4.8). A
glassy carbon disc electrode (diameter 3 mm)was used as the working
electrode and was polished prior to each experiment by using an aqueous
alumina powder slurry. A platinum wire served as a counter electrode
and nonaqueous Ag/Ag+ was used as the reference electrode. All poten-
tials are half-wave potentials and are given versus the Fc+/0 couple.
Cyclic voltammograms were obtained for approximately 1mm solutions
of the analyte in dry acetonitrile, containing 0.1m tetrabutylammonium
hexafluorophosphate as supporting electrolyte. Unless otherwise noted,
all chemicals were obtained from commercial suppliers and used without
further purification.
workup the product was isolated as a mixture of the 7- and 8- isomers,
1.7:1 ratio, in 29% combined yield.
Data for the 7-isomer: 1H NMR (400 MHz, CD2Cl2, 258C): d=7.46–7.48
(d, 3J(H,H)=8 Hz, 1H; Ar-H), 7.43 (s, 1H; Ar-H), 6.62–6.64 (d,
3J(H,H)=8 Hz, 1H; Ar-H), 6.2 (brs, 1H; NH), 4.20–4.27 (m, 2H; CH2),
3
3.44–3.49 (q, J(H,H)=6.8 Hz, 2H; CH2), 3.43 (s, 3H; CH3), 3.28 (s, 3H;
CH3), 1.64–1.72 (m, 2H; CH2), 1.42–1.48 (m, 2H; CH2), 0.95–0.98 ppm (t,
3J(H,H)=7.2 Hz, 3H; CH3).
Data for the 8-isomer: 1H NMR (400 MHz, CD2Cl2, 258C): d=7.50–7.52
(d, 3J(H,H)=8.4 Hz, 1H; Ar-H), 7.14 (s, 1H; Ar-H), 6.70–6.72 (d,
3J(H,H)=8.4 Hz, 1H; Ar-H), 5.97 (brs, 1H; NH), 4.20–4.27 (m, 2H;
CH2), 3.54–3.59 (m, 2H; CH2), 3.42 (s, 3H; CH3), 3.26 (s, 3H; CH3),
1.64–1.72 (m, 2H; CH2), 1.42–1.48 (m, 2H; CH2), 0.95–0 98 ppm (t, J=
7.2 Hz, 3H; CH3); HRMS (FAB): m/z calcd for C19H24N4O4 [M+]:
372.1798; found: 372.1705.
Reductive alkylation of alloxazines 11 and 17—general procedure: All
the steps are performed under strict argon atmosphere, unless otherwise
noted! The 1,3-alkylated alloxazines (0.037m)were mixed in the de-
gassed solvent (1.25:1 volume ratio of EtOH/H2O), together with the Pd/
C catalyst (0.081 mg/22.5 mL solvent), acetaldehyde (32 equiv) and con-
centrated hydrochloric acid (55 equiv), while passing a gentle stream of
argon through the solvent mixture. The mixture was subjected to 30 psi
hydrogen pressure on an autoclave. After the reaction was complete the
mixture was filtered through a 3–4 cm thick Celite layer (flushed with
argon prior)placed in a Schlenk fritt. The liquids were collected in a
proper sized Schlenk flask. The Celite was washed with degassed ethanol
(20–40 mL)while maintaining the argon atmosphere. After the filtration
the Schlenk fritt was removed and concentrated NH4OH (~6 mL to
0.83 mmol starting material)and Na 2S2O4 (~2 g to 0.83 mmol starting ma-
terial)were added. A splash head connected to a glass tube, which in
turn was connected to a solvent trap with a gas outlet cooled by N2(l)
was connected to the Schlenk flask, and the solvents were removed
under vacuum. The remaining solids were suspended in a small amount
of degassed water and filtered through another Schlenk fritt equipped
with a tap, under argon. The solids were washed carefully with small por-
tions (to avoid loss of product due to a slight solubility in water)of de-
gassed water. The product was dried under vacuum and used as such.
1,3,5-Triethyl-7-trifluoromethyl-5,10-dihydro alloxazine (7): This com-
pound was prepared on a 0.68 mmol scale with 1,3-diethyl-7-trifluoro-
methyl alloxazine (0.229 g), acetaldehyde (1.4 mL), hydrochloric acid
(1.4 mL), Pd/C (0.081 g) in ethanol/water (12.5/10 mL) as described in
the general procedure. Reaction time was 47 h. The reaction was worked
up by using the general procedure, after which the product, a mixture of
the desired product together with some nonalkylated product, was isolat-
ed as yellow powder in 54% yield. Spectral data for the desired product
7: 1H NMR (400 MHz, CDCl3, 258C): d=7.08–7.10 (d, 3J(H,H)=8 Hz,
3
1H; Ar-H), 6.77–6.79 (d, J(H,H)=8 Hz, 1H; Ar-H), 6.74 (s, 1H; Ar-H),
3
6.12 (brs, 1H; NH), 3.96–4.02 (q, J(H,H)=7.2 Hz, 4H; 2CH2), 3.52–3.57
3
3
(q, J(H,H)=7.2 Hz, 2H; CH2), 1.32–1.35 (t, J(H,H)=7.2 Hz, 3H; CH3),
1.19–1.23 (t, 3J(H,H)=7.2 Hz, 3H; CH3), 1.18–1.21 ppm (t, 3J(H,H)=
7.2 Hz, 3H; CH3); 13C NMR (100 MHz, CDCl3, 258C): d=157.53, 149.58,
145.46, 140.9, 135.31, 125.06, 124.72 (d, 2J(C, F)=33 Hz), 122.3 (q, 3J=
4 Hz), 120.76, 112.6, 111.58 (q, 3J=3.8 Hz), 100.17, 49.77, 37.41, 37.04,
14.02, 13.26, 12.32 ppm; HRMS (FAB): m/z calcd for C17H19F3N4O2 [M+]:
368.1460; found: 368.1452.
Data for the nonalkylated product: 1H NMR (400 MHz, CDCl3, 258C):
d=6.85–6.87 (d, J=8 Hz, 1H; Ar-H), 6.49 (s, 1H; Ar-H), 6.18–6.20 (d,
J=8 Hz, 1H; Ar-H), 5.58 (brs, 1H; NH), 4.9 (s, 1H; NH) 3.86–3.92 (q,
J=7.2 Hz, 2H; CH2), 3.69–3.75 (q, J=7.2 Hz, 2H; CH2), 1.29–1.33 (t, J=
7.2 Hz, 3H; CH3), 1.23–1.26 ppm (t, J=7.2 Hz, 3H; CH3).
Dihydroflavins 1–3 were prepared using the previously published proce-
dure .[12,13a]
Reductive butylation of 1,3-dimethylalloxazine (12a)—synthesis of 1,3-di-
methyl-5-butyl-5,10-dihydroalloxazine (4): By following the general pro-
tocol, but by employing freshly distilled butanal, compound 4 was ob-
1,3,6,9-Tetramethyl-5-ethyl-5,10-dihydroalloxazine (8): By following the
standard procedure for reductive alkylation of alloxazine compound 17
(100 mg)was converted into compound 8 in 50% yield (55.5 mg). The
product was obtained as a bright yellow powder. 1H NMR (300 MHz,
CDCl3, 258C): d=6.78 (d, 3J(H,H)=7.5 Hz, 1H; Ar-H), 6.71 (d,
3J(H,H)=7.5 Hz, 1H; Ar-H), 5.67 (brs, 1H; NH), 3.50 (s, 3H; CH3), 3.35
(s, 3H; CH3), 3.1 (brs, 2H; CH2), 2.26 (s, 3H; CH3), 2.17 (s, 3H; CH3),
1.04 ppm (t, 3J(H,H)=6.9 Hz, 3H; CH3); 13C NMR (75 MHz, CDCl3,
258C): d=158.42, 150.83, 147.48, 135.62, 133.54, 130.98, 126.68, 126.02,
119.27, 100.70, 49.11, 29.82, 28.29, 17.41, 16.17, 11.16 ppm; HRMS (FAB):
m/z calcd for C16H20N4O2 [M++H]: 300.1665; found: 301.1661.
tained as
a
bright yellow solid in 64% yield (156 mg). 1H NMR
(300 MHz, CDCl3, 258C): d=6.83 (m, 1H; Ar-H), 6.54 (m, 1H; Ar-H),
5.74 (brs, 1H; NH), 3.47 (s, 3H; CH3), 3.41 (t, 3J(H,H)=7.8 Hz, 2H;
CH2), 3.34 (s, 3H; CH3), 1.59 (m, 2H; CH2), 1.25 (m, 2H; CH2),
0.842 ppm (t, 3J(H,H)=7.2 Hz, 3H; CH3). 13C NMR (75 MHz, CDCl3,
258C): d=157.98, 150.51, 146.20, 137.18, 134.81, 125.22, 123.28, 122.11,
114.80, 100.49, 55.76, 29.08, 28.79, 28.46, 20.27, 14.19 ppm.
1,3-Dimethyl-5-ethyl-7-methoxycarbonyl-5,10-dihydroalloxazine (5): This
compound was prepared using the general procedure on a 1.35 mmol
scale, with 12d (0.406 g), acetaldehyde (2.3 mL), hydrochloric acid
(2.3 mL), Pd/C (0.133 g) in ethanol/water (20/16 mL). Reaction time was
44 h. The reaction was worked up by using the general procedure after
which the product, a 9:1 mixture of the 7- and 8-isomers, was isolated as
an orange powder in 64% combined yield. Data for the major isomer (7-
isomer): 1H NMR (300 MHz, CDCl3, 258C): d=7.46–7.49 (dd, 4J(H,H)=
1.8 Hz, 3J(H,H)=8.4 Hz, 1H; Ar-H), 7.44 (apps, 1H; Ar-H), 6.59–6.61
(d, 3J(H,H)=8.4 Hz, 1H; Ar-H), 6.33 (brs, 1H; NH), 3.85 (s, 3H; CH3),
Methyl 3,4-diaminobenzoate (9d): 3,4-Diaminobenzoic acid (2.28 g,
15 mmol)was dissolved in methanol (50 mL.) Sulfuric acid (2 mL)was
added to the solution, which was stirred over night. The reaction was
quenched by addition of 2m NaOH solution (200 mL)and extracted with
CH2Cl2 (3”150 mL). The organic phases were separated and dried over
Na2SO4, evaporated, and dried under vacuum. The product was isolated
without further purification as pale orange solid in 73% yield. 1H NMR
(400 MHz, CDCl3, 258C): d=7.44–7.469 (dd, 4J(H,H)=2 Hz, 3J(H,H)=
8.4 Hz, 1H; Ar-H), 7.39–7.40 (d, 4J(H,H)=2 Hz, 1H; Ar-H), 6.65–6.67
(d, 3J(H,H)=8.4 Hz, 1H; Ar-H), 3.84 (s, 3H; CH3), 3.6 ppm (brs, 4H;
2NH2); 13C NMR (100 MHz, CDCl3, 258C): d=167.47, 140.53, 133.22,
123.36, 121.17, 118.44, 115.0, 51.77 ppm.
3
3.46–3.54 (q, J(H,H)=7.2 Hz, 2H; CH2), 3.48 (s, 3H; CH3), 3.34 (s, 3H;
CH3), 1.15–1.19 ppm (t, 3J(H,H)=7.2 Hz, 3H; CH3). 13C NMR (75 MHz,
CDCl3, 258C): d=166.4, 158.1, 150.4, 145.6, 139,5, 136.7, 127.1, 125,7,
123.1, 114.5, 114.4, 52.2, 50.7, 29.0, 28.5, 11.8 ppm; HRMS (FAB): m/z
calcd for C16H18N4O4: 330.1328; found: 330.1313.
Butyl 3,4-diaminobenzoate (9e): The 3,4-diaminobenzoic acid (2.28 g,
15 mmol)was dissolved in butanol (10 mL)and concentrated sulfuric
acid (2 mL)was added while stirring. The reaction was stirred over night
and worked up as described above. After column chromatography (gradi-
ent CH2Cl2/EtOAc, 400:60, 400:80, 200:60 mL)the product was isolated
as light brown powder in 64% yield. 1H NMR (300 MHz, CDCl3, 258C):
1,3-Dimethyl-5-ethyl-7/8-butoxycarbonyl-5,10-dihydroalloxazine (6): This
compound was prepared by following the general procedure on
a
0.83 mmol scale with 1,3-dimethyl-7/8-butoxycarbonyl alloxazine
(0.283 g), acetaldehyde (1.6 mL), hydrochloric acid (1.6 mL), Pd/C
(0.081 g)in ethanol/water (12.5/10 mL.) Reaction time was 24 h. After
4
3
d=7.45–7.48 (dd, J(H,H)=2.1 Hz, J(H,H)8.1 Hz, 1H; Ar-H), 7.40–7.41
Chem. Eur. J. 2005, 11, 112 – 119
www.chemeurj.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
117

J.-E. Bäckvall et al.
(d, 4J=2.1 Hz, 1H; Ar-H), 6.65–6.67 (d, 3J(H,H)=8.1 Hz, 1H; Ar-H),
4.23–4.27 (t, 3J(H,H)=6.6 Hz, 2H; CH2), 3.6 (brs, 4H; 2NH2), 1.69–1.74
(m, 2H; CH2), 1.41–1.51 (m, 2H; CH2), 0.93–0.98 ppm (t, 3J(H,H)=
7.5 Hz, 3H; CH3); 13C NMR (75 MHz, CDCl3, 258C): d=167.1, 140.4,
133.2, 123.3, 121.6, 118.4, 115.0, 64.4, 64.2, 31.0, 30.3, 19.4, 13.9 ppm.
Data for the 8-trifluoromethyl isomer: 1H NMR (400 MHz, [D6]DMSO,
258C): d=12.1 (brs, 1H; NH), 11.9 (brs, 1H; NH), 8.54 (s, 1H; Ar-H),
8.12–8.15 (dd, 4J(H,H)=1.5 Hz, 3J(H,H)=8.9 Hz, 1H; Ar-H), 8.06–
3
8.09 ppm (d, J(H,H)=8.9 Hz, 1H; Ar-H).
1,3-Dimethyl-7/8-methoxycarbonyl alloxazine (12d): Compound 11d
(0.5 g, 1.8 mmol)was dissolved in dimethylformamide (DMF; 76 mL.)
Potassium carbonate (0.8125 g, 5.88 mmol)and methyl iodide (0.267 g,
2.02 mmol)were added, and the mixture was stirred for 4 h. The inorgan-
ic solids were filtered off and the solvent was evaporated. The remaining
solids were suspended in CH2Cl2 (200 mL)and extracted with diluted
brine (100 mL)and brine (100 mL.) The organic phases were separated
and dried over MgSO4. The product, a yellow powder, was isolated as
54:46 mixture of the 7- and 8-isomers in 76% yield. IR (film): n˜ =3004,
General procedure for the formation of the alloxazine ring structure: A
mixture of alloxane monohydride (10)(1.05 equiv)and boric acid,
H3BO3, (1.12 equiv)in glacial acetic acid was added to a solution of the
diamine in glacial acetic acid. The mixture was stirred for 1–24 h at 508C
or room temperature. For the symmetric diamines, the condensation was
conducted under heating in shorter reaction time, whereas for the unsym-
metric diamines the reaction temperature was decreased to room temper-
ature to avoid a 1:1 regioisomeric mixture of the product. The products
were isolated by filtration, and the filtrate was washed with acetic acid
followed by diethyl ether, water, and again diethyl ether.
2956, 1725, 1681, 1620, 1566 cmÀ1
.
1
Data for the 1,3-dimethyl-7-methoxycarbonyl isomer: H NMR (300 MHz,
CDCl3, 258C): d=8.98 (dd, 5J(H,H)=0.6 Hz, 4J(H,H)=1.8 Hz, 1H; Ar-
H), 8.41–8.44 (dd, 4J(H,H)=1.8 Hz, 3J(H,H)=8.9 Hz, 1H; Ar-H), 8.01–
8.04 (dd, 5J(H,H)=0.6 Hz, 3J(H,H)=8.9 Hz, 1H; Ar-H), 4.0 (s, 3H;
CH3), 3.81 (s, 3H; CH3), 3.58 ppm (s, 3H; CH3); 13C NMR (75 MHz,
CDCl3, 258C): d=165.9 (2), 159.5, 150.8, 146.2, 142.9, 134.8, 133.6, 133.5,
130.8, 128.7, 53.0, 30.0, 29.5 ppm.
7/8-Methoxycarbonyl alloxazine (11d):
A mixture of 10 (0.1204 g,
0.752 mmol)and H 3BO3 (0.0496 g, 0.8018 mmol)in glacial acetic acid
(6 mL)was added to a stirred solution of 9d (0.119 g, 0.716 mmol)in gla-
cial acetic acid (4 mL). The resulting mixture was stirred over night. The
precipitated product was filtered off and washed with acetic acid fol-
lowed by diethyl ether. The washing was continued with water and finally
diethyl ether. After drying under vacuum the product, a yellow powder,
was obtained in 66% yield as a mixture of 7-and 8-regio isomers in 44:56
ratio.
Data for the 7-methoxycarbonyl isomer: 1H NMR (400 MHz, [D6]DMSO,
258C): d=11.9 (brs, 2H; 2NH), 8.61 (dd, 5J(H,H)=0.6 Hz, 4J(H,H)=
2.0 Hz, 1H; Ar-H), 8.28–8.32 (dd, 4J(H,H)=2.0 Hz, 3J(H,H)=8.9 Hz,
1H; Ar-H), 7.94–7.97 (dd, 5J(H,H)=0.6 Hz, 3J(H,H)=8.9 Hz, 1H; Ar-
H), 3.97 ppm (s, 3H; CH3)
1
Data for the 1,3-dimethyl-8-methoxycarbonyl isomer: H NMR (300 MHz,
CDCl3, 258C): d=8.67–8.68 (dd, 5J(H,H)=0.6 Hz, 4J(H,H)=1.8 Hz, 1H;
Ar-H), 8.32–8.35 (dd, 5J(H,H)=0.6 Hz, 3J(H,H)=8.7 Hz, 1H; Ar-H),
8.25–8.29 (dd, 4J(H,H)=1.8 Hz, 3J(H,H)=8.7 Hz, 1H; Ar-H), 4.01 (s,
3H; CH3), 3.81 (s, 3H; CH3), 3.58 ppm (s, 3H; CH3); 13C NMR (75 MHz,
CDCl3, 258C): d=165.9 (2), 159.6, 150.6, 145.5, 141.7, 139.2, 131.4, 131.2,
130.5, 128.3, 53.1, 29.9, 29.6 ppm.
1,3-Dimethyl-7/8-butoxycarbonyl alloxazine (12e): The starting alloxa-
zine 11e (0.4715 g, 1.5 mmol)was dissolved in DMF (70 mL.) First
K2CO3 (0.6634 g, 4.8 mmol)and then methyl iodide (0.449 g, 3.165 mmol)
were added to the solution. The mixture was stirred over night and the
product worked up as described above. Flash column purification (pen-
tane/EtOAc 1:2)yielded the product, a yellow powder, as a 1:1 mixture
of 7- and 8-regioisomers in 96% yield. IR (film): n˜ =3051, 2960, 2936,
Data for the 8-methoxycarbonyl isomer: 1H NMR (400 MHz, [D6]DMSO,
258C): d=11.9 (brs, 2H; 2NH), 8.35 (dd, 5J(H,H)=0.6 Hz, 4J(H,H)=
1.9 Hz, 1H; Ar-H), 8.22–8.25 (dd, 5J(H,H)=0.6 Hz, 3J(H,H)=8.8 Hz,
1H; Ar-H), 8.12–8.16 (dd, 4J(H,H)=1.9, 3J(H,H)=8.8 Hz, 1H; Ar-H),
3.97 ppm (s, 3H; CH3).
7/8-Butoxycarbonyl alloxazine (11e): Compound 9e (0.8316 g, 4 mmol)
was dissolved in glacial acetic acid (70 mL). Compound 10 (0.8415 g,
5.25 mmol)and H 3BO3 (0.344 g, 5.55 mmol)were added and the mixture
was stirred for 7 h. The precipitated product was filtered off, washed as
above and dried under vacuum. A mixture of the 7- and 8-regioisomers
in 45:55 ratio was obtained in 75% combined yield as yellow powder.
1732, 1683, 1621, 1567 cmÀ1
.
Data for the 1,3-dimethyl-7-butoxycarbonyl isomer: 1H NMR (300 MHz,
CDCl3, 258C): d=9.0 (d, 4J(H,H)=1.8 Hz, 1H; Ar-H), 8.41–8.44 (dd,
4J(H,H)=1.8 Hz, 3J(H,H)=9 Hz, 1H; Ar-H), 8.00–8.02 (d, 3J(H,H)=
9 Hz, 1H; Ar-H), 4.36–4.41 (t, 3J(H,H)=6.3 Hz, 2H; overlap with 8-
isomer, CH2), 3.81 (s, 3H; CH3), 3.58 (s, 3H; overlap with 8-isomer,
CH3), 1.74–1.83 (m, 2H; overlap with 7-isomer, CH2), 1.45–1.58 (m, 2H;
overlap, CH2), 0.97–1.02 ppm (t, 3J(H,H)=7.5 Hz, 3H; CH3). 13C NMR
(75 MHz, CDCl3, 258C): d=165.4, 159.4, 150.7, 146.5, 145.4, 139.1, 133.4,
133.3, 131.0, 130.8, 128.1, 65.8, 30.8, 29.9, 29.4, 19.4, 13.9 ppm.
Data for the 7-butoxycarbonyl isomer: 1H NMR (300 MHz, [D6]DMSO,
258C): d=12.07 (brs, 1H; NH), 11.85 (brs, 1H; NH), 8.63 (d, 4J(H,H)=
1.8 Hz, 1H; Ar-H), 8.29–8.33 (dd, 4J(H,H)=1.8 Hz, 3J(H,H)=8.7 Hz,
1H; Ar-H), 7.96–7.99 (d, 3J(H,H)=8.7 Hz, 1H; Ar-H), 4.34–4.38 (t,
3J(H,H)=6.5 Hz, 2H; CH2), 1.71–1.80 (m, 2H; CH2), 1.41–1.53 (m, 2H;
3
CH2), 0.94–0.96 ppm (t, J(H,H)=7.5 Hz, 3H; CH3); 13C NMR (75 MHz,
Data for the 1,3-dimethyl-8-butoxycarbonyl isomer: 1H NMR (300 MHz,
CDCl3, 258C): d=8.66–8.67 (d, 4J(H,H)=1.8 Hz, 1H; Ar-H), 8.33–8.36
(d, 3J(H,H)=8.7 Hz, 1H; Ar-H), 8.26–8.30 (dd, 4J(H,H)=1.8 Hz,
3J(H,H)=8.7 Hz, 1H; Ar-H), 4.39–4.43 (t, 3J(H,H)=6.6 Hz, 2H; overlap
with 7-isomer, CH2), 3.82 (s, 3H; CH3), 3.58 (s, 3H;overlap with 7-
isomer, CH3), 1.74–1.83 (m, 2H; overlap with 7-isomer, CH2), 1.45–1.58
[D6]DMSO, 258C): d=164.9, 160.1, 150.0, 147.6, 144.9, 138.1, 133.7,
133.3, 129.0, 128.5, 126.9, 65.0, 30.2, 18.8, 13.6 ppm.
Data for the 8-butoxycarbonyl isomer: 1H NMR (300 MHz, [D6]DMSO,
258C): d=12.07 (brs, 1H; NH), 11.85 (brs, 1H; NH), 8.36 (d, 4J(H,H)=
1.8 Hz, 1H; Ar-H), 8.24–8.27 (d, 3J(H,H)=8.7 Hz, 1H; Ar-H), 8.14–8.17
(dd, 4J(H,H)=1.8 Hz, 3J(H,H)=8.7 Hz, 1H; Ar-H), 4.36–4.39 (t,
3J(H,H)=6.5 Hz, 2H; CH2), 1.71–1.80 (m, 2H; CH2), 1.41–1.53 (m, 2H;
3
(m, 2H; overlap, CH2), 0.98–1.03 ppm (t, J(H,H)=7.5 Hz, 3H; CH3).
1,3-Diethyl-7-trifluoromethyl alloxazine (12 f): Compound 11 f (0.34 g,
1.20 mmol)was dissolved in DMF (60 mL.) Ethyl iodide and K 2CO3
were added as above and the mixture was stirred for 3 h. After the usual
workup the product was isolated as a single isomer in 57% yield as
yellow powder. IR (film): n˜ =3042, 2973, 2939, 1726, 1674, 1633, 1566,
3
CH2), 0.94–0.96 ppm (t, J(H,H)=7.5 Hz, 3H; CH3); 13C NMR (75 MHz,
[D6]DMSO, 258C): d=164.9, 160.1, 150.0, 148.1, 140.8, 133.3, 131.8,
131.7, 130.8, 127.6, 65.2, 30.1, 18.8, 13.6 ppm.
7/8-Trifluoromethyl alloxazine (11 f): Compound 9 f (0.1321 g, 0.75 mmol)
in hot acetic acid (1.5 mL)was added to a mixture of 10 (0.1265 g,
0.79 mmol)and H 3BO3 (0.0513 g, 0.83 mmol)in hot acetic acid (4.4 mL).
The reaction time was 3 h. After filtration and washing as above the
product, a mixture of 7- and 8-isomers in a ratio of 84:16, was isolated in
53% yield as off white powder (one should be careful with the washing
here because the product is more soluble in diethyl ether).
1505 cmÀ1
;
1H NMR (400 MHz, CDCl3, 258C): d=8.44–8.46 (d,
3J(H,H)=8.8 Hz, 1H; Ar-H), 8.34 (s, 1H; Ar-H), 7.88–7.91 (dd,
4J(H,H)=1.9 Hz, 3J(H,H)=8.8 Hz, 1H; Ar-H), 4.49–4.54 (q, 3J(H,H)=
3
7.0 Hz, 2H; CH2), 4.23–4.28 (q, J(H,H)=7.1 Hz, 2H; CH2), 1.39–1.43 (t,
3J(H,H)=7.0 Hz, 3H; CH3), 1.34–1.38 ppm (t, 3J(H,H)=7.1 Hz, 3H;
CH3); 13C NMR (100 MHz, CDCl3, 258C): d=159.0, 149.6, 145.8, 142.7,
2
Data for the 7-trifluoromethyl isomer: 1H NMR (400 MHz, [D6]DMSO,
258C): d=12.1 (brs, 1H; NH), 11.9 (brs, 1H; NH), 8.34–8.39 (d,
3J(H,H)=8.7 Hz, 1H; Ar-H), 8.22 (s, 1H; Ar-H), 7.97–8.01 ppm (dd,
140.8, 138.8, 134.8 + 135.2 (d, J(C, F)=33 Hz), 132.2, 131.9 + 129.3 (d,
1J(C, F)=260 Hz), 126.0 (q, 3J(C, F)=3 Hz), 124.7 (q, 3J(C, F)=3 Hz),
38.5, 38.2, 13.2, 13.0 ppm. 19F NMR (400 MHz, CDCl3, 258C): d=
À63.6 ppm.
3
4J(H,H)=1.7 Hz, J(H,H)=8.7 Hz, 1H; Ar-H).
118
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2005, 11, 112 – 119

Flavin Derivatives
FULL PAPER
6-(2,5-Dimethylphenylamino)-1,3-dimethyl-1H-pyrimidine-2,4-dione (16):
Compounds 13 (1.0 g, 6.37 mmol)and 15 (987 mg, 6.37 mmol)were sus-
pended in 14 (1.5 mL). The mixture was heated to 1608C for one hour,
while gas evolution was observed. The mixture was allowed to cool to
room temperature and water was added. The mixture was then filtered
and the filtrate extracted with diethyl ether. After drying with MgSO4
the solvent was removed under reduced pressure. Addition of diethyl
ether to the residue resulted in precipitation of the product as a white
solid (470 mg, 28%). When the experiment was repeated, addition of
water to the cool mixture and filtration directly yielded the product as a
white solid. 1H NMR (300 MHz, CDCl3, 258C): d=7.09 (d, 3J(H,H)=
7.5 Hz, 1H; Ar-H), 7.04 (d, 3J(H,H)=7.8 Hz, 1H; Ar-H), 6.93 (s, 1H;
Ar-H), 5.82 (brs, 1H; NH), 4.61 (s, 1H; CH), 3.56 (s, 3H; CH3), 3.29 (s,
3H; CH3), 2.30 (s, 3H; CH3), 2.17 ppm (s, 3H; CH3); 13C NMR (75 MHz,
CDCl3, 258C): d=163.26, 153.10, 152.24, 137.47, 134.89, 131.90, 131.45,
129.05, 128.11, 78.33, 29.32, 28.02, 21.01, 17.33 ppm.
1977, 99, 7064–7067; c)C. Kemal, T. W. Chan, T. C. Bruice, J. Am.
Chem. Soc. 1977, 99, 7272–7286.
[9] a)S. Ball, T. C. Bruice, J. Am. Chem. Soc. 1979, 101, 4017–4019;
b)S. Ball, T. C. Bruice, J. Am. Chem. Soc. 1980, 102, 6498–6503.
[10] T. C. Bruice, J. B. Noar, S. S. Ball, U. V. Venkataram, J. Am. Chem.
Soc. 1983, 105, 2452–2463.
[11] S.-I. Murahashi, T. Oda, Y. Masui, J. Am. Chem. Soc. 1989, 111,
5002–5003.
[12] K. Bergstad, J.-E. Bäckvall, J. Org. Chem. 1998, 63, 6650–6655.
[13] a)A. B. E. Minidis, J.-E. Bäckvall, Chem. Eur. J. 2001, 7, 297–302;
b)A. A. LindØn, L. Krüger, J.-E. Bäckvall, J. Org. Chem. 2003, 68,
5890–5896.
[14] C. Mazzini, J. Lebreton, R. Furstoss, J. Org. Chem. 1996, 61, 8–9.
[15] a)K. Bergstad, S. Y. Jonsson, J.-E. Bäckvall, J. Am. Chem. Soc.
1999, 121, 10424–10425; b)S. Y. Jonsson, H. Adolfsson, J.-E. Bäck-
vall, Org. Lett. 2001, 3, 3463–3466; c)S. Y. Jonsson, K. Färnegårdh,
J.-E. Bäckvall, J. Am. Chem. Soc. 2001, 123, 1365–1371; d)A. Clos-
son, M. Johansson, J.-E. Bäckvall, Chem. Commun. 2004, 1494–
1495.
1,3,6,9-Tetramethylalloxazine (17): Compound 16 (151 mg, 0.6 mmol)was
dissolved in hot glacial acetic acid (1.2 mL). The mixture was then cooled
to À108C. NaNO2 (60 mg, 0.87 mmol)in of water (0.3 mL)was added
dropwise to the reaction mixture over a period of 1 min. The color
changed to brown-red and a precipitate formed. The mixture was stirred
for an additional 15 min at room temperature. After filtration the re-
maining solid was washed with small amounts of water and then dried in
vacuo. Compound 17 was obtained as a yellow solid in 70% yield. IR
[16] Y. Imada, H. Iida, S. Ono, S.-I. Murahashi, J. Am. Chem. Soc. 2003,
125, 2868–2869.
[17] a)H. I. X. Mager, W. Berends, Tetrahedron 1976, 32, 2303–2312;
b)T. C. Bruice, Acc. Chem. Res. 1980, 13, 256–262; c)S. Ball, T. C.
Bruice, J. Am. Chem. Soc. 1981, 103, 5494–5503; d)G. Eberlein,
T. C. Bruice, J. Am. Chem. Soc. 1983, 105, 6679–6684; e)G. Eber-
lein, T. C. Bruice, J. Am. Chem. Soc. 1983, 105, 6685–6697; f)U. V.
Venkataram, T. C. Bruice, J. Am. Chem. Soc. 1984, 106, 5703–5709;
g)S.-R. Keum, D. H. Gregory, T. C. Bruice, J. Am. Chem. Soc. 1990,
112, 2711–2715; h)H. I. X. Mager, S.-C. Tu, Tetrahedron 1994, 50,
5287–5298.
(film): n˜ =3028, 3005, 2954, 2923, 1724, 1679, 1562 cmÀ1
;
1H NMR
(300 MHz, CDCl3, 258C): d=7.54 (d, 3J(H,H)=7.2 Hz, 1H; Ar-H), 7.40
(d, 3J(H,H)=6.8 Hz, 1H; Ar-H), 3.74 (s, 3H; CH3), 3.55 (s, 3H; CH3),
2.78 (s, 3H; CH3), 2.63 ppm (s, 3H; CH3); 13C NMR (75 MHz, CDCl3,
258C): d=160.11, 151.05, 144.12, 142.69, 139.63, 137.26, 133.82, 133.61,
128.74, 127.80, 29.51, 29.23, 17.49, 17.14 ppm.
[18] a)Y. Yano, M. Nakazato, E. Ohya, J. Chem. Soc. Perkin Trans. 2
1985, 77–81; b)S. Shinkai, A. Kawase, T. Yamaguchi, O. Manabe,
Y. Wada, F. Yoneda, Y. Ohta, K. Nishimoto, J. Am. Chem. Soc.
1989, 111, 4928–4935; c)J. J. Hastford, C. J. Rizzo, J. Am. Chem.
Soc. 1998, 120, 2251–2255; d)J. J. Hastford, C. J. Rizzo, Tetrahedron
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Acknowledgement
This research was supported by the Swedish Research Council (VR),
Deutscher Akademischer Austauschdienst (DAAD), the Swedish Energy
Agency, and a Marie Curie Fellowship of the European Community pro-
gram “Improving Human Research Potential and the Socio-Economic
Knowledge” under contract number HPMF-CT-2000-00770.
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Received: May 29, 2004
Published online: November 5, 2004
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