Planar chiral flavinium salts: Synthesis and evaluation of the effect of substituents on the catalytic efficiency in enantioselective sulfoxidation reactions

FULL PAPER

DOI: 10.1002/ejoc.201300847

Planar Chiral Flavinium Salts: Synthesis and Evaluation of the Effect of

Substituents on the Catalytic Efficiency in Enantioselective Sulfoxidation

Reactions

[a]

[b]

[c]

ˇ

Radek Jurok, Jana Hodacová, Václav Eigner, Hana Dvoráková,

[d]

[a]

ˇ

Vladimír Setnicka, and Radek Cibulka*

Keywords: Organocatalysis / Asymmetric catalysis / Sulfoxidation / Nitrogen heterocycles / Peroxides

A series of substituted planar chiral flavinium salts with a

phenyl “cap” have been prepared as potential catalysts for

enantioselective sulfoxidation reactions with hydrogen per-

oxide by using an approach based on the synthesis of (aryl-

amino)uracils and their condensation with substituted

nitrosobenzenes. The effect of substituents at various posi-

tions on the ability of the catalyst to promote enantioselective

sulfoxidation recations was investigated. Introduction of the

tyrosine group into the side-chain of the flavinium species

or substitution of the nitrogen N-3 of the flavin unit by o-

isopropylphenyl has a remarkably positive effect on the

enantioselectivity of the sulfoxidation reactions of aromatic

and aliphatic substrates, respectively. On the other hand,

substitution of the phenyl “cap” led to a substantial decrease

in the efficiency of the catalyst. In summary, optimisation of

the structures of the planar chiral flavinium catalysts led to

enantioselectivities of up to 61% ee for aromatic sulfides and

of up to 65% ee for tert-butyl methyl sulfide.

on the basis of the high enantioselectivities (above 90% ee)

achieved in stoichiometric sulfoxidation reactions with chi-

ral oxaziridines and oxaziridinium salts.^[5,6]However, even

if a stoichiometric amount of imine or iminium precursor

is used, the enantioselectivities of the sulfoxidations are

substantially lower than those with chiral oxaziridines pre-

pared in advance.^[4a,4b]By using truly catalytic amounts of

imines or iminium salts, maximal enantioselectivities of

only 42% ee have been observed.^[4c]Another approach in-

volves the activation of hydrogen peroxide through hydro-

gen bonding with a chiral Brønsted acid.^[7]Imidodiphos-

phoric acid (2 mol-%) with two BINOL moieties allows the

oxidation of aromatic and aliphatic sulfides with hydrogen

peroxide, achieving ee values greater than 90%.^[7b]

The activation and desymmetrisation of hydrogen perox-

ide through covalent bonding has been exploited in cata-

lysed reactions with flavinium salts, which are some of the

most promising organocatalysts for sulfoxidation reactions

(Scheme 1).^[1a,1b,8,9]Flavinium salts reversibly bind hydro-

gen peroxide with the formation of flavin-4a-hydroperoxide,

which then oxidises the substrate. Subsequently, hydroxy-

flavin is formed and the flavinium catalyst is regenerated by

the elimination of water (see Scheme 2 for illustration).^[8]

The presence of a stereodiscriminating element on the

flavinium species can lead to the diastereoselective forma-

tion of flavin-4a-hydroperoxide, which can then stereoselec-

tively oxidise a prochiral substrate. Through this approach,

chiral flavinium salts with a cyclophane moiety catalyse the

H₂O₂sulfoxidation of aromatic sulfides with up to 65% ee

for aryl methyl sulfide and 72% ee for naphthyl methyl sulf-

Introduction

The organocatalytic enantioselective oxidation of sulfides

to sulfoxides with hydrogen peroxide as a stoichiometric ox-

idant performed as an alternative to sulfoxidation reactions

catalysed by metal complexes is the subject of intense re-

search.^[1–3]The principle of organocatalytic H₂O₂sulfoxid-

ation is based on the in situ activation of hydrogen peroxide

by covalent or non-covalent interactions with an organic

catalyst.^[1]The oxygenation species thus formed is substan-

tially more reactive than hydrogen peroxide towards nucleo-

philic sulfides and, if the catalyst is chiral, it allows stereose-

lective transfer of oxygen to the sulfur atom and the subse-

quent preferential formation of one sulfoxide stereoisomer.

One class of organocatalytic systems for sulfoxidation is

based on the in situ generation of chiral oxaziridines or ox-

aziridinium salts from chiral imines or iminium salts by re-

action with peroxide.^[4]These systems have been developed

[a] Department of Organic Chemistry, Institute of Chemical

Technology,

Prague, Technická 5, 166 28 Prague, Czech Republic

E-mail: cibulkar@vscht.cz

http://ww w .vscht.cz

[b] Department of Solid State Chemistry, Institute of Chemical

Technology,

Prague, Czech Republic

[c] Central Laboratories, Institute of Chemical Technology,

Prague, Czech Republic

[d] Department of Analytical Chemistry, Institute of Chemical

Technology,

Prague, Czech Republic

Supporting information for this article is available on the

WWW under http://dx.doi.org/10.1002/ejoc.201300847.

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Eur. J. Org. Chem. 2013, 7724–7738

Planar Chiral Flavinium Salts

ide.^[10]Nevertheless, high loading of the catalyst (up to dation of para-substituted thioanisoles with enantiomeric

12 mol-% relative to the substrate) is necessary to achieve excesses of 34–44%. The highest enantioselectivity (54% ee)

such stereoselectivities. Catalysed asymmetric sulfoxidation was observed for the oxidation of methyl naphthyl sulfide.

with the use of an active polymer containing tetra-O-acetyl-

riboflavin units has also been described. In this case, the

enantioselectivity is controlled by π–π interactions between

an aromatic substrate and the flavin unit bound to the poly-

meric helical structure.^[11]Flavin–cyclodextrin conjugates,

in which the flavinium moiety is covalently attached to

cyclodextrin, allow the sulfoxidation with H₂O₂with

enantioselectivities of up to 91% ee for tert-butyl methyl

sulfide and 80% ee for aromatic substrates. The enantio-

selectivities achieved by using these supramolecular cata-

lysts are based on the interaction of the prochiral sulfide

with the chiral cavity of cyclodextrin.^[12]The only other ex-

ample of an enantioselective oxidation catalysed by a chiral

flavinium salt is the Baeyer–Villiger oxidation of para-sub-

stituted 3-phenylcyclobutanones to the corresponding lac-

tones with ee values ranging from 61 to 74%.^[13]

Scheme 1. Formation of flavin-4a-hydroperoxide. Substituents R^x

are labeled in accord with the numbering of the flavin skeleton.

In our previous communication,^[14]we reported the

planar chiral flavinium salt 1a (Scheme 2) as a new catalyst

for enantioselective sulfoxidations of aromatic sulfides. This

flavinium salt possesses a covalently bound phenyl “cap”

that covers one side of the isoalloxazinium skeleton, thus

Figure 1. Chiral flavinium catalysts employed in this study. The

allowing the access of hydrogen peroxide and the substrate

planar chiral skeleton is drawn uniformly irrespective of the actual

configuration of the catalysts tested for enantioselective sulfoxid-

from only the uncovered face of the flavin moiety. Salt 1a

in the enantiomerically pure form catalyses the H₂O₂oxi- ation reactions.

Scheme 2. Catalytic cycle for the H₂O₂sulfoxidation of aromatic sulfides mediated by planar chiral flavinium salt 1a.

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FULL PAPER

Comparison of the enantioselectivities of the oxidation of

thioanisole and cyclohexyl methyl sulfide showed that π–π

interactions between the catalyst and substrate are neces-

sary to achieve high stereoselectivity.

With the aim of improving the catalytic efficiency of 1a,

we have extended our investigation to derivatives 2 and 3

with an additional stereodiscriminating element provided

by a chiral amino acid attached through a carboxylic group

on the benzene ring and substitution with ortho-substituted

phenyl at the 3-position of the flavin unit, respectively (Fig-

ure 1). Moreover, we studied the effect of substitution of

the phenyl cap with bulky tert-butyl groups (catalyst 4) and

the effect of extension of the flavin π-electron system (cata-

lyst 5). The influence of benzene ring substitution on the

catalytic activity of the flavinium unit has also been investi-

gated through a series of catalysts 6 (Figure 1). We have

extended our research to other substrates (non-aromatic

sulfides with bulky groups) by using tert-butyl methyl sulf-

ide as an example. To gain an insight into the enantioselec-

tive oxidations achieved by using planar chiral flavinium

catalysts 1–6, their absolute configurations were also deter-

mined.

Scheme 3. Retrosynthetic analysis of the flavinium catalysts. Sub-

stituents R^xare labeled in accord with the numbering of the flavin

skeleton.

starting from bromonaphthylamine with protection of the

amino function.

At first, the main components, 8-phenylnaphthalen-1-

amines 7, chlorouracils 8 and substituted nitrosobenzenes 9

were prepared according to known procedures (for details,

see the Supporting Information). The flavin skeleton was

constructed starting by the condensation of 7 with 8 to

Results and Discussion

Synthesis of Substituted Flavinium Salts

For the synthesis of substituted planar chiral flavinium form 6-(arylamino)uracils 10 (Scheme 4). This reaction pro-

salts 2–6, we had planned to use an approach analogous to ceeded almost quantitatively, and the isolated yields (90–

that used for the synthesis of the simple non-substituted 98%) did not depend on the substitution of the uracil (sub-

salt 1a, as described in our previous paper.^[14]However, the stituents may be alkyls, aryls and benzyl) or phenyl in 7 (for

versatility of this procedure had to be determined. The ret- details, see the Supporting Information).

rosynthetic analysis (Scheme 3) clearly indicates that sub-

In contrast, the yields of the reactions between 6-(aryl-

stituents on the benzene ring of the flavin species (R⁶, R⁷amino)uracils 10 and substituted nitrosobenzenes 9 were

and R⁸) should be introduced with nitrosobenzene func- strongly dependent upon the character and position of the

tionalised at a suitable position relative to the nitroso group. substituents (Table 1). Although the condensation of

The aryl (or alkyl) group at the 3-position of the flavin sub- nitrosobenzene 9f with the electron-donating methoxy

unit (R³) should come from chlorouracil, which can be pre- group produced a high yield, the reactions of nitrosobenz-

pared by the formation of the uracil subunit from the corre- enes 9b–e with electron-withdrawing substituents took place

sponding urea. The phenyl “cap” possessing R^Cgroups may with more difficulty (cf., entries 6–11). The condensation of

be a part of the naphthylamine available by Suzuki coupling 3-aryl-6-(arylamino)uracils 10c and 10d with nitrosobenz-

Scheme 4. General scheme for the synthesis of planar chiral flavinium salts. Reagents and conditions: i) 180 °C; ii) AcOH, reflux;

iii) 1. CH₃CHO, 10% Pd/C, H₂, AcOH; 2. NaNO₂, HClO₄, MeOH, H₂O, NaClO₄; iv) HPLC on a chiral stationary phase, for details,

see the Exp. Sect.

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Planar Chiral Flavinium Salts

Table 1. Effect of substitution on yields of flavins 11 prepared by the condensation of nitrosobenzenes 9 with 6-(arylamino)uracils 10.

Entry Nitroso-benzene

6-(Aryl-

amino)uracil

Flavin

R^C

R³

R⁶

R⁷

R⁸

Yield [%]

1

2

3

4

5

6

7

8

9a

9b

9c

9d

9e

9f

10a

10b

10c

10d

10e

10b

10a

10b

11a

11b

11c

11d

11e

11f

11g

11h

11i

H

tBu

H

CH₃

Bn

o-iPrPh

o-tBuPh

Bn

CH₃

Bn

H

65^[a]

69^[a]

38^[b]

12^[c]

25

H

COOCH₃

18

H

COOCH₃

39^[d]

47

9

10

11

H

COOCH₃

CF₃

CH₃O

14

27

82

11j

11k

H

Bn

[a] Ref.^[14][b] anti/syn 1:1. [c] anti/syn 7:5. [d] 4% of the 9 isomer 11l was isolated as a byproduct.

ene 9a yielded flavins in substantially lower yields than rangement of rings (Scheme 6). Surprisingly, despite the

those produced by the condensation of the 3-methyl (10a) protection, the condensation of 9g with 6-(arylamino)uracil

and 3-benzyl (10b) derivatives, probably because of steric 10b yielded only one isomer 11m.

hindrance (cf. entries 1–4). Analogously, the yield of flavin

11e with the di-tert-butylphenyl “cap” was relatively low

(entry 5). Condensation with meta-substituted nitrosobenz-

ene could theoretically lead to two isomeric flavins substi-

tuted at the 7- or 9-position. Nevertheless, we observed rela-

tively good regioselectivity in the condensation of methyl 3-

nitrosobenzenecarboxylate (9c) with 3-benzyl-6-arylamino-

uracil 10b, the formation of 7-(methoxycarbonyl)flavin 11g

favoured over its 9-isomer 11l due to the steric effect of the

adjacent phenylnaphthyl group (entry 7). We did not ob-

serve the formation of the 9-isomer even during the reaction

of 9c with 3-methyl-6-arylaminouracil 10a, which selectively

led to 7-(methoxycarbonyl)flavin 11h (entry 8).

Two diastereoisomers differing in the position of the sub-

stituent on the 3-phenyl ring relative to the phenyl “cap”

were formed in a ratio of almost 1:1 in the cases of 11c

and 11d (Scheme 5). These stereoisomers were separated by

column chromatography on silica gel and found to be con-

figurationally relatively stable; isomerisation of 11c and 11d

took place at temperatures above 70 and 150 °C, respec-

tively. Thermally induced isomerisation was utilised to in-

crease the yield of the anti isomer of 11d to levels suitable

to prepare a catalyst. The unwanted syn isomer was heated

in N-methylpyrrolidone at 190 °C to obtain an approximate

1:1 mixture of syn and anti isomers separable by column

chromatography.

Scheme 6. Synthesis of flavin rac-11m with an extended aromatic

system.

Our strategy for the synthesis of enantiomerically pure

substituted planar chiral flavinium salts was analogous to

that used for the synthesis of non-substituted derivative

1a:^[14]separation of enantiomers of neutral flavins 11 by

HPLC on a chiral stationary phase followed by their trans-

formation into the final, optically pure flavinium salts

(Scheme 4). This approach was possible because of the ri-

gidity of planar chiral flavins precluding racemisation dur-

ing the final step of the synthesis.^[14]At first, the transfor-

mation of flavins into the corresponding flavinium salts in

racemic form was investigated. By applying the usual pro-

cedure for reductive alkylation of the flavin followed by oxi-

dation of the thus obtained 5-ethyl-1,5-dihydro derivative

(not isolated) with sodium nitrite in dilute perchloric acid,

flavins 11h, 11j, 11k, 11e, anti-11c, and anti-11d gave the

corresponding flavinium salts in high yields (85–87%). On

the other hand, despite many attempts, the 6- and 8-meth-

Scheme 5. Diastereoisomers of 11c (R = iPr) and 11d (R = tBu).

To synthesise a flavin with an extended aromatic system, oxycarbonyl derivatives 11f and 11i did not form flavinium

2-nitrosonaphthalene 9g with a protected 1-position was salts. The decreased reactivity of the nitrogen at the 5-posi-

prepared. The 1-position was protected in keeping with our tion in 6-substituted flavin 11f is probably caused by steric

original plan to prepare extended flavins with a linear ar- hindrance.

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FULL PAPER

With the exception of methoxy derivative 11k, enantio- corresponding chloride and finally the amide 12a by reac-

mers of all the prepared racemic planar chiral flavins were tion with the methyl ester of the (S)-amino acid. The ob-

separated by HPLC on a chiral stationary phase (see the tained mixture of diastereoisomers was separated by col-

Exp. Sect. for details). Subsequently, the selected enantio- umn chromatography on silica gel, which allowed synthesis

mers were transformed into the final enantiopure flavinium on a multigram scale. In the same manner, isomeric flavin

salts by the procedure used for racemic flavins described conjugate 12c, substituted at the 6-position, was prepared

above (Scheme 4).

for single crystal analysis (see below). Diastereoisomeric

amides (S_p,S)-12a and (R_p,S)-12a were also used as a source

of the enantiomerically pure acids (S_p)-11n and (R_p)-11n,

which were used as the starting materials for the prepara-

tion of (S_p,S)-12b and (R_p,S)-12b, respectively, bearing the

(S)-O-methyltyrosine methyl ester (Scheme 7). All the

stereoisomers of flavins 12a and 12b were finally trans-

formed into flavinium salts 2a and 2b in good yields (79–

85%) by using the standard procedure. Despite much effort,

we were unable to record clear NMR spectra of 2a and 2b

because of peak broadening, which is probably a result of

the presence of radical species.^[12c,15]The expected struc-

tures of the flavinium conjugates are supported by high-

resolution mass spectra.

Synthesis of Conjugates with Esters of Amino Acids

Racemic 7-(methoxycarbonyl)flavin 11h was used as the

starting material for the introduction of the next chiral sub-

unit into the structure of the flavin catalyst (Scheme 7). The

6- and 8-methoxycarbonyl derivatives were excluded be-

cause such substitution makes transformation into the fla-

vinium salt unfeasible. Ester 11h was hydrolysed to the race-

mic carboxylic acid 11n, which was transformed into the

Configurations of the Flavinium Catalysts

Usually, flavinium salts are isolated as amorphous mate-

rials. Consistent with this characteristic, we failed to pre-

pare crystals suitable for X-ray analysis of any flavinium

salt. Bearing in mind the configurational stability of planar

chiral flavins, we decided to determine the configuration of

a neutral flavin with a chiral centre in the side-chain. Fortu-

nately, derivative 12c, which has (S)-valine methyl ester

bound by an amide bond to carbonyl at the 6-position of

the flavin moiety, crystallised well. This allowed single-crys-

tal analysis (Figure 2), which showed the S_pconfiguration

of the planar chiral subunit.

Figure 2. Crystal structure of 12c showing the S_pconfiguration.

For the ORTEP drawing, see the Supporting Information.

Hydrolysis of (S_p,S)-12c followed by decarboxylation of

the obtained acid (Scheme 8) yielded (S_p)-11b with an op-

tical rotation of –879°, which shows that enantiomers of

the basic flavin (–)-11b and (+)-11b have the S_pand R_p

Scheme 7. Synthesis of flavin conjugates 12. Reagents and condi-

tions: i) HCl; ii) 1. oxalyl chloride, DMF; 2. (S)-H₂NCH(R)CO-

OCH₃; iii) HCl, CH₃COOH.

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Planar Chiral Flavinium Salts

configurations, respectively. Thus, the configurations of the with hydrogen peroxide is not influenced by the presence of

flavinium salts (S_p)-(–)-1a and (R_p)-(+)-1a, prepared from the phenyl “cap”. This finding is based on a comparison

(S_p)-(–)-11b and (R_p)-(+)-11b, respectively, could be as- of the kinetics of sulfoxidation reactions performed in the

signed. The configurations of the other substituted flavins presence of the salt 1a and the simple “uncovered” 5-ethyl-

11 were assigned by comparison of their ECD spectra with 3,10-dimethylflavinium perchlorate. To evaluate the effect

that of the flavin (S_p)-11b (Figure 3). This assignment could of other structural changes in the planar chiral flavinium

be used because of the similarity of the derivatives and the salts on their catalytic activity, we compared the course of

high intensity of the Cotton effect, which originates from oxidation of thioanisole (model substrate) under the usual

the planar chirality.

conditions,^[9,14,16]that is, with a small excess of hydrogen

peroxide in the presence of 1.5 mol-% of the catalyst (rela-

tive to the substrate) at room temperature (for details, see

the Exp. Sect.). It was found that substitution by an alkoxy-

carbonyl group at the 8-position (catalyst 6a), the presence

of a trifluoromethyl group at the 7-position (catalyst 6b)

and extension of the benzene ring (catalyst 5) did not influ-

ence the reactivity of the basic flavinium unit in 1a (see the

Supporting Information for details). On the other hand, the

electron-donating methoxy group (catalyst 6c) decreases the

activity of the flavinium salt, as shown in Figure 4. Interest-

ing results were obtained with 3-aryl derivatives 3a and 3b.

Although only a small rate reduction was observed with the

catalyst 3a with o-isopropylphenyl as substituent, the rate

of catalytic oxidation was significantly decreased in the

presence of the tert-butylphenyl group (catalyst 3b) in the

flavinium catalyst (Figure 4). Significant inhibition of the

activity of the flavinium salt was also observed when the

phenyl cap was substituted with the tert-butyl group (cata-

lyst 4). Here, formation of the anti-hydroperoxyflavin anti-

4-OOH with a butterfly conformation^[17]might be impeded

because of the steric hindrance by the two bulky tert-butyl

groups.

Scheme 8. Transformation of the flavin derivative 12c into flavin

11b. Reagents and conditions: i) 1. HCl, CH₃CO₂H, H₂O;

2. Ag₂CO₃, AcOH, DMSO.

Figure 3. ECD spectra of flavins 11. Spectra of enantiomers used

for the preparation of flavinium catalysts are shown. a) ECD spec-

tra of (S_p)-11b (black), (R_p)-anti-11c (red), (R_p)-anti-11d (brown),

(S_p)-11e (green), (S_p)-11j (violet), (S_p)-11o (light blue); (b) ECD

spectra of (S_p)-11b (black) and (S_p)-11m (blue).

Figure 4. Comparison of the course of the sulfoxidation of thio-

anisole with H₂O₂catalysed by substituted flavinium salts 3a (᭢),

3b (᭡), 4 (ᮀ) and 6c (star) relative to oxidation catalysed by 1a

(᭿). Non-catalysed reaction: (᭺).

Catalytic Activity of Flavinium Salts in H₂O₂Sulfoxidation

Reactions

Enantioselective Sulfoxidation Reactions Catalysed by 1

As we reported previously,^[14]the efficiency of the

With the knowledge of the absolute configuration of the

flavinium subunit in the catalysis of sulfoxidation reactions catalyst and of the major isomer of the sulfoxide (Table 2),

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R. Cibulka et al.

Config.^[d]

FULL PAPER

Table 2. Enantioselective H₂O₂sulfoxidations of sulfides catalysed by the enantiomerically pure flavinium salts 1.

Entry

Substrate

Catalyst^[a]

Time [h]

Yield [%]^[b]

ee [%]^[c]

1

2

3

4

5

6

7

8

9

10

PhSMe

p-MePhSMe

2-naphthyl-SMe

tBuSMe

cyclohexyl-SMe

PhSMe

tBuSMe

PhSMe

(S_P)-1a

(R_P)-1a

(S_P)-1a

(S_P)-1b

(S_P)-1a^[f]

(S_P)-1a^[g]

72

96

72

168

48

55

54

61

65

35

42

55

34

52

54

34^[e]

42^[e]

54^[e]

43

(S)

(R)

(S)

(R)

(S)

(R)

(S)

4^[e]

35

42

33

34

[a] 5 mol-% relative to substrate unless otherwise indicated. [b] Preparative yields; conversions were higher than 80% in all cases. [c] The

enantiomeric ratios were determined by HPLC on a chiral stationary phase (Chiralcel OD or Phenomenex^®Lux Cellulose-4 columns).

[d] The absolute configurations were assigned by comparing optical rotations and HPLC elution orders with known literature data.^[18]

[e] Ref.^[14][f] 2 mol-%. [g] 10 mol-%.

we initially attempted to elucidate the mode of action of the

The situation is completely different for aliphatic tert-

basic planar chiral flavinium salt 1a in the enantioselective butyl methyl sulfide with one small and one bulky alkyl

sulfoxidation reactions. Oxidation of aromatic sulfides cata- group (Table 2, entry 5). In this case, an unusually high

lysed by the enantiomers (S_p)-1a and (R_p)-1a preferentially enantioselectivity was observed, but with the major

produce the (S) and (R) enantiomers of the corresponding enantiomer of the product being opposite to that of the

sulfoxide, respectively (Table 2, entries 1–4). This observa- aromatic substrates: (R)-tert-butyl methyl sulfoxide pre-

tion is consistent with our original proposal for the stereo- dominated when (S_p)-1a was used as the catalyst. Most

chemical model (Scheme 9, a).^[14]The aryl ring of the sub- probably, for aliphatic sulfides, the stereoselectivity is con-

strate interacts with flavin hydroperoxide through a π–π in- trolled by steric effects based on the orientation of the bulky

teraction and the alkyl group moves away from the catalytic tert-butyl group away from the oxidant (Scheme 9, b). The

centre. This hypothetical position of the alkyl group is sup- oxidation of the non-aromatic cyclohexyl methyl sulfide

ported by the independence of the enantioselectivity of the (Table 2; entry 6) shows similar stereodiscrimination, but

steric demand of the alkyl group, that is, the enantio- the effect is significantly less because of the smaller steric

selectivity is the same with methyl, isopropyl and tert-butyl demand of the cyclohexyl group.

sulfoxides.^[14]

We sought to determine whether the 3-benzyl substituent

in 1a plays a role in stereoinduction. Therefore derivative

1b with a non-aromatic octyl group at the 3-position was

prepared and analysed for comparison. The nearly identical

enantioselectivities observed in the oxidations of both aro-

matic and aliphatic sulfides catalysed by 1a and 1b (cf. en-

tries 1 and 5 vs. 7 and 8, Table 2) show that benzyl probably

does not interact with the substrate. Catalyst loading influ-

ences only the rate and not the enantioselectivity of the sulf-

oxidation, as is evident by comparison of the experiments

performed with 2, 5 and 10 mol-% of the catalyst 1a (cf.

entries 1, 9 and 10). It also reflects a very slow non-cata-

lysed reaction under the conditions (–20 °C) used for enan-

tioselective oxidation (only 3% conversion after 72 h was

observed for the oxidation with H₂O₂without the

catalyst). Thus, the non-catalysed (non-stereoselective) pro-

cess cannot compete with the reaction promoted by a chiral

catalyst even if it is slower due to decreased catalyst load-

ing.

To exclude the effect of the diastereoselectivity of flavin

hydroperoxide 1-OOH formation on chiral induction in sul-

foxidation reactions (see Scheme 2), we studied the stereo-

chemistry of the model reaction of (S_p)-1a with water. The

¹H NMR spectra show only one set of signals for the ad-

duct (S_p)-1a-OH, which indicates that one diastereoisomer

was preferentially formed. Accordingly, high diastereoselec-

tivity can also be expected for 1-OOH formation.

Scheme 9. Proposed mode of action of planar chiral flavinium salts

1 in the enantioselective oxidation of a) aryl methyl sulfides and

b) tert-butyl methyl sulfide.

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Planar Chiral Flavinium Salts

Table 3. Enantioselective H₂O₂sulfoxidation of sulfides catalysed by the substituted flavinium salts 2–6.

Entry Substrate

ee [%]^[a]/configuration^[b]

(S_p,S)-2a

(R_p,S)-2a

(S_p,S)-2b

(R_p,S)-2b

(R_p)-3a

(R_p)-3b

(S_p)-4

(S_p)-5

(S_p)-6b

1

2

3

4

5

PhSMe

38/(S)

43/(S)

55/(S)

34/(R)

2/(R)

34/(R)

38/(R)

53/(R)

33/(S)

3/(S)

39/(S)

47/(S)

59/(S)

36/(R)

2/(R)

41/(R)

49/(R)

61/(R)

40/(S)

3/(S)

25/(R)

27/(R)

38/(R)

65/(S)

7/(S)

19/(R)

20/(R)

30/(R)

19/(S)

0/(S)

7/(S)

9/(S)

25/(S)

29/(S)

42/(S)

15/(R)

0/(R)

36/(S)

37/(S)

55/(S)

41/(R)

0/(R)

p-MePhSMe

2-naphthyl-SMe

tBuSMe

n.d.^[c]

cyclohexyl-SMe

[a] The enantiomer ratios were determined by HPLC on a chiral stationary phase (Chiralcel OD or Phenomenex^®Lux Cellulose-4

columns). [b] The absolute configurations were assigned by comparing the optical rotations and HPLC elution orders with known

literature data.^[18][c] n.d.: not determined.

Enantioselective Sulfoxidation Reactions Catalysed by

Substituted Flavinium Salts 2–6

second benzene ring in 5 may not be optimal. Unfortu-

nately, this is the only isomer that can be prepared by our

synthetic method. The trifluoromethyl group does not in-

fluence the enantioselectivity of the oxidation reactions at

all (see the results for 6b in Table 3).

The optimised conditions^[14][methanol/water, 2:1,

–20 °C, c(substrate) = 0.01 molL^–1, 5 mol-% of the catalyst

relative to the substrate] were used to investigate the

enantioselectivity of the oxidation of selected sulfides in the

presence of the substituted planar chiral flavinium catalysts.

The results are summarised in Table 3. In almost all cases,

the observed enantioselectivities are moderate for all sub-

strates excluding cyclohexyl methyl sulfide. Of the catalysts,

4 proved to be an exception, showing not only poor cata-

lytic activity (Figure 4), but also low enantioselectivity. As

expected, the configuration of the major enantiomer of the

sulfoxide formed by oxidation is determined by the configu-

ration of the planar chiral subunit of the catalyst, that is,

the catalyst with the S_pconfiguration gives predominantly

aromatic sulfoxides with the S configuration and tert-butyl

methyl sulfoxide with the R configuration, and vice versa.

The effect of additional substituents or stereodiscriminating

groups on the enantioselectivity is less significant but never-

theless remarkable; in some cases, the effect is positive. The

presence of an additional chiral centre in the side-chain

plays a positive role in the oxidation of aromatic substrates.

Better results were obtained with the catalyst containing

tyrosine in the side-chain, which is known to interact with

aromatic substrates in flavin-dependent enzymes.^[19]The ee

values for (R_p,S)-2b are higher by 7% compared with that

for the non-substituted derivative 1a. On the other hand,

flavinium salts 2 were less efficient in the oxidation of tert-

butyl methyl sulfide (cf. entry 4 in Table 3, columns 1–4

with entry 5 in Table 2).

Conclusions

We have developed a methodology for the synthesis of

planar chiral flavinium salts. This procedure involves the

preparation of arylaminouracils and their condensation

with substituted nitrosobenzenes. Such a procedure allows

the synthesis of various derivatives possessing substituents

on the flavin benzene ring, on nitrogen N-3 of the pyrimid-

ine ring of the flavin and on the phenyl “cap”. These results,

together with those previously reported,^[14,20]clearly show

that the construction of the flavin skeleton by using

nitrosobenzenes is suitable for sterically hindered flavins.

We have shown that the introduction of substituents on

to the basic planar chiral flavin skeleton (in 1a) influences

its catalytic efficiency in the enantioselective oxidation of

sulfides to sulfoxides with hydrogen peroxide. The most ef-

fective salt, (R_p,S)-2b, which has O-methyltyrosine in the

side-chain, allows the oxidation of aryl methyl sulfides with

enantioselectivities of up to 61% ee. The origin of this

enantioselectivity is the weak π–π interactions of the sub-

strate with the chiral oxidant, flavin hydroperoxide, which

is formed in the catalytic cycle. Interestingly, the planar chi-

ral salts also promote the enantioselective oxidation of non-

aromatic tert-butyl methyl sulfide. For this aliphatic sub-

strate, the enantioselectivity of the oxidation probably arises

from the steric hindrance between the catalyst and the

bulky tert-butyl group. For the enantioselectivity of tert-bu-

tyl methyl sulfide oxidation, derivatisation of the basic

planar chiral skeleton of flavinium catalyst 1 seems to be

important. Although 43% enantioselectivity was observed

with the basic salt 1a, 65% enantioselectivity was achieved

with 3a. An investigation of the activity of planar chiral

flavinium salts in other types of oxidation reactions is un-

derway in our laboratory.

For the oxidation of tert-butyl methyl sulfide, catalyst 3a

seems to be the most suitable from the tested series, achiev-

ing an enantioselectivity of 65% ee (Table 3). Thus, intro-

duction of a phenyl with an o-isopropyl group appears to

be a good way to optimise the enantioselectivity of the oxi-

dation of the substrate, which is controlled by steric effects

only. However, there is an optimum size of the phenyl ring

substituent because the introduction of the larger tert-butyl

group leads not only to decreased reactivity (Figure 4, b),

but also to lower stereoselectivity (Table 3). Surprisingly, a

negative effect was observed on the oxidation of aromatic

substrates catalysed by flavinium catalyst 5 with an ex-

tended aromatic system that can better interact with aro-

Experimental Section

General: NMR spectra were recorded with Varian Mercury Plus

matic substrates. On the other hand, the position of the 300 (299.97 MHz for H and 75.44 MHz for ¹³C), Bruker Avance

1

Eur. J. Org. Chem. 2013, 7724–7738

www.eurjoc.org

7731

R. Cibulka et al.

FULL PAPER

DRX 500 (500.13 MHz for ¹H and 125.77 MHz for ¹³C) and

(br. s, 1 H), 8.45 (d, J = 8.2 Hz, 1 H) ppm. ¹³C NMR (CD₃CN,

75 MHz): δ = 14.6, 23.2, 23.4, 28.4, 121.1, 122.6, 125.8, 127.0,

127.2, 127.4, 127.58, 127.63, 128.5, 129.1, 129.4, 130.4, 130.6,

131.3, 132.4, 132.8, 133.7, 136.5, 139.3, 140.5, 141.5, 146.8, 151.7,

152.0, 155.3 ppm. C₃₇H₃₁ClN₄O₆(663.12): calcd. C 67.02, H 4.71,

N 8.45; found C 66.91, H 4.87, N 8.36.

Bruker 600 Avance III spectrometers (600.13 MHz for ¹H and

1

150.92 MHz for ¹³C). The H and ¹³C chemical shifts are reported

in ppm relative to tetramethylsilane as internal standard. Optical

rotations were measured with a Perkin–Elmer M-241 digital polari-

meter. All reagents were purchased from commercial sources and

used as received unless indicated otherwise. TLC analyses were car-

ried out on DC Alufolien Kieselgel 60H F254 (Merck). Preparative

column chromatography was performed on silica gel Kieselgel 60

(0.040–0.063 mm, Merck). Elemental analyses were performed on

a Perkin–Elmer 240 analyser. Preparative HPLC was carried out

with an Agilent 1100 Series instrument.

(R_p)-3a: Starting from (R_p)-anti-11c (17 mg, 31 μmol), (R_p)-3a

(16 mg, 75%) was obtained as a dark-violet solid, [α]_D= +764 (c

= 0.1, CH₃CN).

rac-3b: Starting from rac-11d (55 mg, 0.1 mmol), rac-3b (59 mg,

87%) was obtained as dark-violet crystals; m.p. 172–175 °C. ¹H

NMR (CD₃CN, 300 MHz): δ = 1.25 (s, 9 H), 1.81 (br. s, 3 H),

4.60–6.10 (br. s, 2 H), 6.45 (br. s, 1 H), 6.68 (t, J = 7.3 Hz, 1 H),

7.17 (dd, J = 7.3, 1.8 Hz, 1 H), 7.22–7.33 (m, 4 H), 7.36 (d, J =

7.3 Hz, 1 H), 7.43–7.58 (m, 3 H), 7.68–7.79 (m, 2 H), 7.88–8.00 (m,

2 H), 8.06 (br. s, 1 H), 8.28 (d, J = 8.2 Hz, 1 H), 8.40 (br. s, 1 H),

8.45 (d, J = 8.2 Hz, 1 H) ppm. ¹³C NMR (CD₃CN, 75 MHz): δ =

15.3, 31.8, 36.5, 126.2, 127.4, 127.7, 127.9, 128.2, 128.7, 129.5,

130.0, 130.4, 130.8, 130.9, 131.6, 132.9, 133.7, 134.2, 136.9, 140.1,

141.9, 147.6, 152.2, 153.1 ppm. C₃₈H₃₃ClN₄O₆(677.14): calcd. C

67.40, H 4.91, N 8.27; found C 67.29, H 5.01, N 8.18.

General Procedure for the Synthesis of Flavinium Perchlorates 2–6:

Palladium on charcoal (10%; 25 mg) and acetaldehyde (0.25 mL)

were added to a solution of isoalloxazine (0.1 mmol) in a mixture

of acetic acid (10 mL) and water (1 mL). The resulting mixture was

stirred for 48 h in an autoclave under H₂(0.4 MPa) at room tem-

perature. Then the catalyst was filtered off, acetic acid was evapo-

rated under reduced pressure and the remaining solid was dried in

vacuo. Perchloric acid (2 m, 1 mL) was added to the residue, fol-

lowed by the minimum amount of methanol necessary to dissolve

the solid material. Sodium nitrite (55 mg) was added in several por-

tions to the stirred mixture at 10 °C during 30 min and then sodium

perchlorate (250 mg). After stirring for an additional 45 min at the

same temperature, most of the methanol was evaporated under re-

duced pressure at room temp., the precipitate was filtered off,

washed with water and dried in vacuo. The crude product was dis-

solved in acetonitrile, precipitated by the addition of diethyl ether

and dried in vacuo at room temperature.

(R_p)-3b: Starting from (R_p)-anti-11d (50 mg, 92 μmol), (R_p)-3b

(53 mg, 85%) was obtained as a dark-violet solid, [α]_D= +815 (c

= 0.1, CH₃CN).

rac-4: Starting from rac-11e (62 mg, 0.1 mmol), rac-4 (62 mg, 83%)

was obtained as a dark-violet solid; m.p. 185–188 °C. ¹H NMR

(CD₃CN, 300 MHz): δ = 0.84 [s, 9 H, (CH₃)₃], 1.03 [s, 9 H,

(CH₃)₃], 1.82 (br. s, 3 H, N⁺CH₂CH₃), 4.75–5.25 (br. s, 1 H,

2

N⁺CHHCH₃), 5.09 (d, J = 14.2 Hz, 1 H, PhCHH), 5.24 (d, J =

14.2 Hz, 1 H, PhCHH), 5.40–5.90 (br. s, 1 H, N⁺CHHCH₃), 6.27

(m, 1 H), 6.78 (s, 1 H), 7.05 (m, 1 H), 7.19 (d, J = 8.2 Hz, 1 H),

7.25 (d, J = 7.0 Hz, 1 H), 7.35 (d, J = 7.2 Hz, 1 H), 7.40 (t, J =

7.2 Hz, 2 H), 7.41–7.50 (m, 3 H), 7.69 (t, J = 7.5 Hz, 1 H), 7.85 (t,

J = 7.8 Hz, 1 H), 7.88 (t, J = 7.8 Hz, 1 H), 7.99 (t, J = 7.7 Hz, 1

H), 8.22 (d, J = 8.5 Hz, 1 H), 8.35 (d, J = 7.9 Hz, 1 H), 8.40 (d, J

= 8.5 Hz, 1 H) ppm. ¹³C NMR (CD₃CN, 75 MHz): δ = 15.0, 31.4,

34.4, 47.0, 121.3, 122.7, 126.1, 127.1, 127.3, 127.4, 127.7, 127.8,

128.9, 129.1, 129.3, 129.4, 129.5, 129.6, 129.7, 130.7, 131.4, 131.7,

132.7, 134.0, 136.5, 136.6, 136.7, 136.74, 139.5, 140.6, 141.6, 151.3,

152.6, 155.3 ppm. C₄₃H₄₃ClN₄O₆(747.28): calcd. C 69.11, H 5.80,

N 7.50; found C 68.98, H 5.94, N 7.42.

(S_p,S)-2a: Starting from (S_p,S)-12a (100 mg, 0.17 mmol), (S_p,S)-2a

(96 mg, 79%) was obtained as a dark-violet solid; m.p. 184–186 °C,

[α]_D

C₃₆H₃₄N₅O₅

=

–592 (CH₃CN,

c

=

0.1). HRMS (ESI): calcd. for

+

[M

–

ClO₄]⁺616.25545; found 616.25541.

C₃₆H₃₄ClN₅O₉(716.14): calcd. C 60.38, H 4.79, N 9.78; found C

60.08, H 4.58, N 9.77.

(R_p,S)-2a: Starting from (R_p,S)-12a (70 mg, 0.12 mmol), (R_p,S)-2a

(69 mg, 81%) was obtained as a dark-violet solid; m.p. 178–181 °C,

[α]_D

C₃₆H₃₄N₅O₅

=

+581 (CH₃CN,

c

=

0.1). HRMS (ESI): calcd. for

+

[M

–

ClO₄]⁺616.25545; found 616.25552.

C₃₆H₃₄ClN₅O₉(716.14): calcd. C 60.38, H 4.79, N 9.78; found C

60.09, H 4.89, N 9.65.

(S_p)-4: Starting from (S_p)-11e (32 mg, 52 μmol), (S_p)-4 (31 mg,

80%) was obtained as a dark-violet solid.

(S_p,S)-2b: Starting from (S_p,S)-12b (80 mg, 0.12 mmol), (S_p,S)-2a

(81 mg, 85%) was obtained as a dark-violet solid; m.p. 178–180 °C,

rac-5: From rac-11m (62 mg, 0.1 mmol), rac-5 (62 mg, 83%) was

obtained as a dark-violet solid; m.p. 225–228 °C. ¹H NMR

(CD₃CN, 300 MHz): δ = 1.82 (br. s, 3 H), 4.65–5.20 (br. s, 1 H),

[α]_D

C₄₁H₃₆N₅O₆

=

–523 (CH₃CN,

c

=

0.1). HRMS (ESI): calcd. for

+

[M

–

ClO₄]⁺694.26601; found 694.26612.

C₄₁H₃₆ClN₅O₁₀(794.21): calcd. C 62.00, H 4.57, N 8.82; found C

61.71, H 4.71, N 8.69.

2

5.25 (d, J = 13.9 Hz, 1 H), 5.31 (d, J = 13.9 Hz, 1 H), 5.29–5.82

(br. s, 1 H), 6.28 (br. s, 1 H), 6.43 (t, J = 7.4 Hz, 1 H), 6.59 (t, J =

7.4 Hz, 1 H), 6.86 (br. s, 1 H), 6.85 (t, J = 7.5 Hz, 1 H), 7.00–6.95

(m, 1 H), 7.01 (d, J = 7.6 Hz, 1 H), 7.18 (d, J = 6.6 Hz, 1 H), 7.25

(d, J = 6.9 Hz, 1 H), 7.31 (t, J = 7.3 Hz, 1 H), 7.36 (t, J = 7.5 Hz,

2 H), 7.55 (t, J = 7.4 Hz, 1 H), 7.60 (t, J = 7.6 Hz, 1 H), 7.66 (t, J

= 7.8 Hz, 1 H), 7.70 (d, J = 7.4 Hz, 2 H), 7.88 (d, J = 8.8 Hz, 1

H), 7.91 (d, J = 7.9 Hz, 1 H), 8.22 (d, J = 8.8 Hz, 1 H), 8.35 (br.

s, 1 H), 8.41 (d, J = 8.1 Hz, 1 H) ppm. ¹³C NMR (CD₃CN,

75 MHz): δ = 44.9, 122.7, 126.0, 126.5, 126.6, 126.7, 126.9, 127.1,

127.8, 127.9, 128.4, 128.5, 128.9, 129.7, 129.8, 129.9, 130.1, 131.9,

132.6, 132.9, 135.99, 136.02, 137.4, 137.5, 137.6, 140.7, 151.4,

155.2, 159.3 ppm. C₃₉H₂₉ClN₄O₆(685.12): calcd. C 68.37, H 4.27,

N 8.18; found C 68.23, H 4.39, N 8.05.

(R_p,S)-2b: Starting from (R_p,S)-12b (70 mg, 0.10 mmol), (R_p,S)-2a

(67 mg, 80%) was obtained as a dark-violet solid; m.p. 172–175 °C,

[α]_D

C₄₁H₃₆N₅O₆

=

+592 (CH₃CN,

c

=

0.1). HRMS (ESI): calcd. for

+

[M

–

ClO₄]⁺694.26601; found 694.26597.

C₄₁H₃₆ClN₅O₁₀(794.21): calcd. C 62.00, H 4.57, N 8.82; found C

61.78, H 4.69, N 8.71.

rac-3a: Starting from rac-anti-11c (54 mg, 0.1 mmol), rac-3a

(56 mg, 85%) was obtained as a dark-violet solid; m.p. 187–191 °C.

¹H NMR (CD₃CN, 300 MHz): δ = 1.09 (d, J = 6.7 Hz, 3 H), 1.14

(d, J = 6.7 Hz, 3 H), 1.80 (br. s, 3 H, N⁺CH₂CH₃), 2.77 (br. s, 1

H), 4.70–5.30 (br. s, 1 H), 5.38–6.10 (br. s, 1 H), 6.46 (br. s, 1 H),

6.68 (t, J = 7.3 Hz, 1 H), 7.22–7.33 (m, 5 H), 7.36 (d, J = 7.0 Hz,

1 H), 7.44 (m, 1 H), 7.51–7.59 (m, 3 H), 7.75 (t, J = 7.3 Hz, 1 H), (S_p)-5: Starting from (S_p)-11m (45 mg, 81 μmol), (S_p)-5 (44 mg,

7.88–7.98 (m, 2 H), 8.04 (br. s, 1 H), 8.28 (d, J = 8.2 Hz, 1 H), 8.41 80%) was obtained as a dark-violet solid.

7732

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Eur. J. Org. Chem. 2013, 7724–7738

Planar Chiral Flavinium Salts

1

rac-6a: Starting from rac-11g (56 mg, 0.1 mmol), rac-6a (59 mg, syn-11c: M.p. 341–343 °C. H NMR (CDCl₃, 300 MHz): δ = 1.31

85%) was obtained as dark-violet crystals; m.p. 221–224 °C. ¹H

(d, J = 7.0 Hz, 3 H), 1.38 (d, J = 7.0 Hz, 3 H), 3.02 (m, 1 H), 6.26

(d, J = 7.6 Hz, 1 H), 6.52 (td, J = 7.6, 1.8 Hz, 1 H), 6.62 (dd, J =

NMR (CD₃CN, 300 MHz): δ = 1.81 (br. s, 3 H, CH₂CH₃), 3.98 (s,

3 H, OCH₃), 4.65–6.00 (br. s, 2 H, CH₂CH₃), 5.11 (d, ²J = 14.2 Hz, 8.2, 1.5 Hz, 1 H), 6.98–7.09 (m, 3 H), 7.19 (dd, J = 7.0, 1.2 Hz, 1

2

1 H, PhCHH), 5.27 (d, J = 14.2 Hz, 1 H, PhCHH), 6.11 (br. s, 1

H), 7.27–7.33 (m, 2 H), 7.38 (dd, J = 7.6, 1.2 Hz, 1 H), 7.44 (dd,

H), 6.19 (br. s, 1 H), 6.45 (d, J = 7.6 Hz, 1 H), 6.60 (d, J = 9.1 Hz, J = 7.0, 1.5 Hz, 1 H), 7.49 (dd, J = 7.9, 1.8 Hz, 2 H), 7.51–7.61

1 H), 6.86 (br. s, 1 H), 6.94 (d, J = 7.6 Hz, 1 H), 7.13 (d, J = 7.0 Hz, (m, 2 H), 7.72 (t, J = 7.3 Hz, 1 H), 8.06 (dd, J = 7.6, 0.8 Hz, 1 H),

1 H), 7.28–7.38 (m, 4 H), 7.55 (t, J = 7.3 Hz, 1 H), 7.65 (d, J =

6.4 Hz, 2 H), 7.70 (t, J = 7.6 Hz, 1 H), 8.04 (d, J = 8.56 Hz, 1 H),

8.13 (dd, J = 7.9, 1.5 Hz, 1 H), 8.19 (dd, J = 7.6, 0.8 Hz, 1 H) ppm.

¹³C NMR (CDCl₃, 75 MHz): δ = 23.9, 24.1, 28.9, 117.8, 126.3,

8.12 (d, J = 9.1 Hz, 1 H), 8.20 (d, J = 7.0 Hz, 1 H), 8.77 (d, J = 126.4, 126.5, 126.7, 126.8, 127.0, 127.2, 127.6, 128.1, 128.3, 128.8,

2.0 Hz, 1 H) ppm. ¹³C NMR (CD₃CN, 75 MHz): δ = 14.4, 45.4,

53.1, 124.2, 125.5, 125.6, 126.2, 126.5, 126.7, 127.8, 127.9, 128.2,

128.4, 128.6, 128.9, 129.0, 129.5, 130.3, 131.6, 132.2, 132.7, 132.9,

135.1, 135.6, 136.1, 136.3, 137.2, 137.4, 137.8, 141.5, 150.7,

155.0,158.7, 166.4 ppm. C₃₇H₂₉ClN₄O₈(693.10): calcd. C 64.12, H

4.22, N 8.08; found C 63.92, H 4.31, N 7.95.

128.9, 129.6, 129.7, 131.7, 131.9, 132.4, 132.6, 133.5, 135.2, 136.0,

136.2, 137.2, 138.1, 140.8, 146.0, 150.9, 155.3, 159.3 ppm.

(R_p)-anti-11c and (S_p)-anti-11c: Enantiomers of isoalloxazine anti-

11c were separated on a Eurocel 01 column (250ϫ 20 mm; heptane/

isopropyl alcohol, 60:40; 10 mL/min) with retention times of 15.4

and 25.3 min for R_pand S_p, respectively. (R_p)-anti-11c: [α]_D= +780

(c = 0.3, CHCl₃); (S_p)-anti-11c: [α]_D= –772 (c = 0.3, CHCl₃).

rac-6b: Starting from rac-11j (57 mg, 0.1 mmol), rac-6b (60 mg,

86%) was obtained as a dark-violet solid; m.p. 198–201 °C. ¹H

NMR (CD₃CN, 300 MHz): δ = 1.83 (br. s, 3 H), 4.70–6.05 (br. s,

3-(2-tert-Butylphenyl)-10-(8-phenylnaphthalene-1-yl)isoalloxazine

(11d): Isoalloxazine 10d was prepared from aminouracil 10d

(4.50 g, 9.8 mmol), nitrosobenzene 9a (3.15 g, 29.2 mmol) and ace-

tic acid (120 mL). Chromatography (chloroform/ethyl acetate, 7:1)

afforded crude anti-11d and syn-11d, which were purified sepa-

rately. The anti-11d was purified twice by chromatography (first:

toluene/ethyl acetate, 2:1; second: (dichloromethane/methanol,

100:1) and crystallised from dichloromethane/hexane to afford

270 mg (5 %) of anti-11d; m.p. 275–276 °C. ¹H NMR (CDCl₃,

600 MHz): δ = 1.30 (s, 9 H), 6.23 (d, J = 7.6 Hz, 1 H), 6.57 (t, J =

7.6 Hz, 1 H), 6.64 (d, J = 7.9 Hz, 1 H), 7.11 (dd, J = 7.6, 1.2 Hz,

1 H), 7.15 (t, J = 7.7 Hz, 1 H), 7.20 (t, J = 7.6 Hz, 1 H), 7.23 (d,

J = 7.6 Hz, 1 H), 7.36 (d, J = 7.6 Hz, 1 H), 7.38–7.44 (m, 2 H),

7.46 (d, J = 7.6 Hz, 1 H), 7.55 (t, J = 7.6 Hz, 1 H), 7.57–7.64 (m,

3 H), 7.76 (t, J = 7.6 Hz, 1 H), 8.08 (d, J = 7.3 Hz, 1 H), 8.21 (d,

J = 7.8 Hz, 1 H), 8.23 (d, J = 7.6 Hz, 1 H) ppm. ¹³C NMR (CDCl₃,

150 MHz): δ = 31.9, 36.3, 117.6, 126.3, 126.4, 126.8, 126.9, 127.4,

127.6, 128.4, 129.0, 129.2, 129.4, 129.5, 129.7, 130.9, 131.6, 131.9,

132.4, 132.6, 133.9, 135.1, 135.2, 136.1, 136.2, 137.2, 137.9, 140.8,

146.9, 150.6, 155.9, 159.9 ppm. C₃₆H₂₈N₄O₂(548.63): calcd. C

78.81, H 5.14, N 10.21; found C 79.02, H 4.98, N 10.09.

2

2 H), 5.11 (d, J = 13.7 Hz, 1 H, PhCHH), 5.28 (d, J = 13.7 Hz,

1 H, PhCHH), 6.43–6.58 (m, 2 H), 6.63 (dd, J = 7.3 Hz, 1 H), 6.95

(d, J = 6.4 Hz, 1 H), 7.07 (br. s, 1 H), 7.31 (d, J = 7.0 Hz, 1 H),

7.35–7.58 (m, 7 H), 7.75 (t, J = 7.3 Hz, 1 H), 7.89 (t, J = 7.9 Hz,

1 H), 8.11 (d, J = 8.2 Hz, 1 H), 8.28 (d, J = 8.2 Hz, 1 H), 8.46 (d, J

= 7.9 Hz, 1 H), 8.57 (d, J = 8.8 Hz, 1 H) ppm. ¹³C NMR (CD₃CN,

75 MHz): δ = 14.3, 45.7, 124.1, 124.4, 126.0, 126.8, 127.0, 127.2,

127.6, 128.3, 128.5, 128.9, 129.1, 129.6, 130.3, 132.3, 133.9, 135.8,

136.0, 136.3, 138.6, 141.3, 150.6, 151.7, 154.3 ppm.

C₃₆H₂₆ClF₃N₄O₆(703.06): calcd. C 61.50, H 3.73, N 7.97; found

C 61.34, H 3.91, N 7.82.

(S_p)-6b: Starting from (S_p)-11j (35 mg, 61 μmol), (S_p)-6b (35 mg,

82%) was obtained as a dark-violet solid.

rac-6c: Starting from rac-11k (54 mg, 0.1 mmol), rac-6c (58 mg,

88%) was obtained as a dark-violet solid; m.p. 212–214 °C. HRMS

+

(ESI): calcd. for C₃₆H₂₉N₄O₃[M – ClO₄]⁺565.22342; found

565.22335. C₃₆H₂₉ClN₄O₇(665.09): calcd. C 65.01, H 4.39, N 8.42;

found C 64.85, H 4.51, N 8.35.

General Procedure for the Synthesis of Flavins 11: A mixture of

(arylamino)uracil 10 (1 equiv.) and the appropriate nitrosobenzene

9 (3 equiv.) in acetic acid was stirred at reflux for 45 min. Then the

solvent was evaporated and the residue was purified by column

chromatography and crystallisation.

The crude syn-11d was washed several times with toluene and was

then purified twice by chromatography (first: toluene/ethyl acetate,

2:1; second: dichloromethane/methanol, 100:1) and crystallised

from chloroform/diethyl ether to afford syn-11d (375 mg, 7%); m.p.

1

330–333 °C. H NMR (CDCl₃, 300 MHz): δ = 1.47 (s, 9 H), 6.35

3-(2-Isopropylphenyl)-10-(8-phenylnaphthalen-1-yl)isoalloxazine

(11c): Isoalloxazine 11c was prepared from aminouracil 10c (4.00 g,

18.2 mmol), nitrosobenzene 9a (1.70 g, 15.9 mmol) and acetic acid

(39 mL). Chromatography (chloroform/ethyl acetate, 5:1) afforded

crude anti-11c and syn-11c, which were crystallised from chloro-

form/diethyl ether repeatedly to afford anti-11c (550 mg, 19%) and

syn-11c (540 mg, 19%) as yellow crystals.

(d, J = 7.9 Hz, 1 H), 6.50 (t, J = 7.6 Hz, 1 H), 6.68 (d, J = 8.5 Hz,

1 H), 6.89–7.05 (m, 3 H), 7.19 (d, J = 7.0 Hz, 1 H), 7.29 (m, 2 H),

7.36–7.64 (m, 6 H), 7.72 (t, J = 7.6 Hz, 1 H), 8.06 (m, 2 H), 8.20

(d, J = 8.2 Hz, 1 H) ppm. ¹³C NMR (CDCl₃, 75 MHz): δ = 32.0,

36.2, 118.3, 126.2, 126.3, 126.4, 126.6, 127.0, 127.2, 127.7, 127.8,

128.0,129.0, 129.1, 129.3, 129.7, 130.7, 131.5, 132.0, 132.5, 132.6,

134.3,134.9, 135.2, 135.9, 136.2, 137.1, 137.9, 140.7, 146.9, 151.3,

156.2, 160.4 ppm.

1

anti-11c: M.p. 199–210 °C. H NMR (CDCl₃, 600 MHz): δ = 1.18

(d, J = 6.9 Hz, 3 H), 1.20 (d, J = 6.9 Hz, 3 H), 2.75 (m, 1 H), 6.24

(d, J = 7.6 Hz, 1 H), 6.58 (td, J = 7.6, 1.2 Hz, 1 H), 6.67 (dd, J =

8.1, 1.6 Hz, 1 H), 7.14 (t, J = 7.6, Hz, 1 H), 7.19–7.25 (m, 3 H),

7.34 (d, J = 7.6 Hz, 1 H), 7.39 (m, 1 H), 7.43–7.50 (m, 3 H), 7.55

(t, J = 7.5 Hz, 1 H), 7.58–7.63 (m, 2 H), 7.75 (t, J = 7.6 Hz, 1 H),

8.09 (dd, J = 7.6, 0.9 Hz, 1 H), 8.20 (dd, J = 7.6, 2.0 Hz, 1 H), 8.23

(R_p)-anti-11d and (S_p)-anti-11d: Enantiomers of isoalloxazine anti-

11c were separated on a Eurocel 01 column (250ϫ 20 mm; heptane/

isopropyl alcohol, 60:40; 10 mL/min) with retention times of 14.8

and 26.7 min for R_pand S_p, respectively. (R_p)-anti-11d: [α]_D= +870

(c = 0.5, CHCl₃); (S_p)-anti-11d: [α]_D= –860 (c = 0.5, CHCl₃).

(dd, J = 7.2, 0.9 Hz, 1 H) ppm. ¹³C NMR (CDCl₃, 150 MHz): δ = 3-Benzyl-10-[8-(3,5-di-tert-butylphenyl)naphthalen-1-yl]isoallox-

23.9, 24.0, 117.6, 126.3, 126.5, 126.8, 126.9, 127.0, 127.1, 127.4,

128.2, 128.3, 129.0, 129.4, 129.6, 129.7, 131.6, 131.9, 132.4, 132.6,

133.5, 135.1, 135.2, 136.0, 136.2, 137.2, 137.9, 140.8, 146.3, 150.7,

155.2, 159.1 ppm. C₃₅H₂₆N₄O₂(534.61): calcd. C 78.63, H 4.90, N

10.48; found C 78.80, H 4.64, N 10.32.

azine (11e): Isoalloxazine 11e was prepared from aminouracil 10e

(0.70 g, 1.3 mmol), nitrosobenzene 9a (0.42 g, 4.0 mmol) and acetic

acid (10 mL). Chromatography (chloroform/ethyl acetate, 8:1) and

crystallisation from chloroform/hexane afforded 0.20 g (25%) of

1

11e as bright-yellow crystals; m.p. 324–326 °C. H NMR (CDCl₃,

Eur. J. Org. Chem. 2013, 7724–7738

www.eurjoc.org

7733

R. Cibulka et al.

FULL PAPER

300 MHz): δ = 0.84 (s, 9 H), 1.03 (s, 9 H), 5.14 (d, J = 13.2 Hz, 1

2

124.2, 125.5, 125.6, 126.2, 126.5, 126.7, 127.8, 127.9, 128.2, 128.4,

H), 5.20 (d, ²J = 13.2 Hz, 1 H), 6.21 (t, J = 1.5 Hz, 1 H), 6.67 (dd, 128.6, 128.9, 129.0, 129.5, 130.3, 131.6, 132.2, 132.7, 132.9, 135.1,

J = 8.4, 1.2 Hz, 1 H), 6.98 (t, J = 1.5 Hz, 1 H), 7.05 (t, J = 1.5 Hz,

1 H), 7.13 (dd, J = 7.3, 1.0 Hz, 1 H), 7.17 (d, J = 7.3 Hz, 1 H),

7.20–7.28 (m, 3 H), 7.42–7.61 (m, 5 H), 7.64 (t, J = 7.9 Hz, 1 H),

8.04 (dd, J = 8.2, 1.2 Hz, 1 H), 8.08 (dd, J = 7.9, 1.5 Hz, 1 H), 8.17

(d, J = 8.2 Hz, 1 H) ppm. ¹³C NMR (CDCl₃, 75 MHz): δ = 31.4,

34.4, 45.3, 118.1, 121.4, 122.5, 123.2, 126.2, 126.4, 127.4, 127.9,

128.5, 128.7, 129.2, 130.4, 132.2, 132.3, 132.8, 133.1, 135.0, 135.2,

135.6, 136.0, 136.7, 137.5, 138.7, 140.5, 149.2, 149.5, 150.5, 155.4,

159.3 ppm. C₄₁H₃₈N₄O₂(618.77): calcd. C 79.58, H 6.19, N 9.05;

found C 79.42, H 6.39, N 8.94.

135.6, 136.1, 136.3, 137.2, 137.4, 137.8, 141.5, 150.7, 155.0,158.7,

166.4 ppm.

Methyl 3-Methyl-10-(8-phenylnaphthalen-1-yl)isoalloxazine-7-carb-

oxylate (11h): A mixture of aminouracil 10a (2.15 g, 6.26 mmol)

and nitrosobenzene 9c^[21](3.10 g, 18.77 mmol) in acetic acid

(50 mL) and acetic anhydride (8 mL) was stirred at reflux for 1 h.

The solvent was evaporated and ethanol (20 mL) was added to the

residue to form a fine suspension. Product was removed by fil-

tration, washed with ethanol (2ϫ 15 mL) and crystallised from

chloroform (with 10 % methanol)/diethyl ether to afford 11h

1

(R_p)-11e and (S_p)-11e: Enantiomers of isoalloxazine 11e were sepa-

rated on a Chiralpak IA column (250ϫ 4.6 mm; heptane/isopropyl

alcohol, 65:35; 0.5 mL/min) with retention times of 9.2 and

11.8 min for R_pand S_p, respectively. (R_p)-11e: [α]_D= +734 (c =

0.32, CHCl₃); (S_p)-11e: [α]_D= –732 (c = 0.32, CHCl₃).

(1.42 g, 49%) as yellow crystals; m.p. Ͼ 350 °C. H NMR (CDCl₃

+ 5% CD₃OD, 300 MHz): δ = 3.43 (s, 3 H), 3.94 (s, 3 H), 6.13 (d,

J = 7.3 Hz, 1 H), 6.46 (t, J = 7.6 Hz, 1 H), 6.61 (d, J = 9.1 Hz, 1

H), 6.86 (t, J = 7.0 Hz, 1 H), 6.98 (t, J = 7.3 Hz, 1 H), 7.04 (d, J

= 7.6 Hz, 1 H), 7.13 (d, J = 7.0 Hz, 1 H), 7.28 (d, J = 7.3 Hz, 1

H), 7.53 (t, J = 7.9 Hz, 1 H), 7.67 (t, J = 7.3 Hz, 1 H), 8.02 (d, J

= 8.2 Hz, 1 H), 8.11 (dd, J = 9.1, 2.0 Hz, 1 H), 8.17 (d, J = 7.9 Hz,

1 H), 8.74 (d, J = 2.0 Hz, 1 H) ppm. ¹³C NMR (CDCl₃+ 5%

CD₃OD, 75 MHz): δ = 28.8, 52.4, 117.8, 124.3, 125.5, 125.8,

126.37, 126.42, 126.5, 127.7, 127.9, 128.5, 128.9, 129.1, 129.5,

132.2, 132.5, 133.0, 135.0, 135.6, 136.28, 136.34, 137.2, 141.6,

155.7, 159.2, 166.4 ppm. C₂₉H₂₀N₄O₄(488.49): calcd. C 71.30, H

4.13, N 11.47; found C 71.12, H 4.22, N 11.35.

Methyl 3-Benzyl-10-(8-phenylnaphthalen-1-yl)isoalloxazine-6-carb-

oxylate (11f): Isoalloxazine 11f was prepared from aminouracil 10b

(1.68 g, 4 mmol), nitrosobenzene 9b (2.00 g, 12 mmol) and acetic

acid (25 mL). Chromatography (chloroform/ethyl acetate, 4:1) and

crystallisation from methanol afforded 11f (408 mg, 18%) as yellow

1

crystals; m.p. 260–262 °C. H NMR (CDCl₃, 300 MHz): δ = 4.07

2

(s, 3 H), 5.20 (d, J = 14.0 Hz, 1 H), 5.25 (d, J = 14.0 Hz, 1 H),

6.09 (d, J = 7.6 Hz, 1 H), 6.17 (t, J = 7.9 Hz, 1 H), 6.48 (t, J =

7.6 Hz, 1 H), 6.66 (d, J = 8.5 Hz, 1 H), 6.87 (t, J = 7.6 Hz, 1 H),

6.93 (d, J = 7.9 Hz, 1 H), 7.13 (d, J = 7.0 Hz, 1 H), 7.27–7.37 (m,

4 H), 7.51–7.59 (m, 2 H), 7.65 (d, J = 8.5 Hz), 7.69 (t, J = 7.3 Hz,

1 H), 7.73 (dd, J = 7.3, 1.2 Hz, 1 H), 8.04 (d, J = 8.5 Hz, 1 H),

8.18 (d, J = 8.2 Hz, 1 H) ppm. ¹³C NMR (CDCl₃, 75 MHz): δ =

45.2, 53.5, 120.1, 126.3, 126.4, 126.5, 126.6, 126.7, 126.8, 127.0,

128.1, 128.4, 128.6, 128.9, 129.1, 129.6, 130.1, 131.3, 131.8, 132.5,

133.2, 133.9, 134.8, 135.0, 136.2, 137.1, 137.3, 138.1, 140.3, 149.8,

155.4, 158.3, 166.4 ppm. C₃₅H₂₄N₄O₄(564.59): calcd. C 74.46, H

4.28, N 9.92; found C 74.39, H 4.37, N 9.82.

Methyl 3-Benzyl-10-(8-phenylnaphthalene-1-yl)isoalloxazine-8-carb-

oxylate (11i): Isoalloxazine 11i was prepared from aminouracil 10b

(1.20 g, 2.9 mmol), nitrosobenzene 9d (1.42 g, 8.6 mmol) and acetic

acid (21 mL). Chromatography (chloroform/ethyl acetate, 7:1) and

crystallisation from chloroform/diethyl ether afforded 11i (0.23 g,

14 %) as yellow crystals; m.p. 318–320 °C. ¹H NMR (CDCl₃,

2

500 MHz): δ = 3.83 (s, 3 H), 5.21 (d, J = 13.5 Hz, 1 H), 5.25 (d,

²J = 13.5 Hz, 1 H), 6.08 (d, J = 7.4 Hz, 1 H), 6.17 (t, J = 7.4 Hz,

1 H), 6.39 (t, J = 7.4 Hz, 1 H), 6.84 (t, J = 7.4 Hz, 1 H), 6.93 (d,

J = 7.4 Hz, 1 H), 7.11 (d, J = 6.7 Hz, 1 H), 7.24–7.35 (m, 5 H),

7.54 (t, J = 7.4 Hz, 1 H), 7.63 (d, J = 7.2 Hz, 2 H), 7.69 (t, J =

7.9 Hz, 1 H), 8.04 (d, J = 8.2 Hz, 1 H), 8.07 (d, J = 8.6 Hz, 1 H),

8.16 (d, J = 8.5 Hz, 1 H), 8.20 (d, J = 8.1 Hz, 1 H) ppm. ¹³C NMR

(CDCl₃, 125 MHz): δ = 44.9, 52.9, 118.6, 125.9, 126.1, 126.2, 126.3,

126.4, 127.3, 127.8, 127.9, 128.4, 128.6, 128.7, 129.5, 129.9, 130.7,

131.7, 132.2, 132.5, 134.6, 135.0, 136.1, 136.7, 137.0, 137.5, 139.0,

140.4, 149.9, 154.8, 158.3, 165.0 ppm. C₃₅H₂₄N₄O₄(564.59): calcd.

C 74.46, H 4.28, N 9.92; found C 74.38, H 4.22, N 9.87.

Methyl 3-Benzyl-10-(8-phenylnaphthalen-1-yl)isoalloxazine-7-carb-

oxylate (11g): Isoalloxazine 11g was prepared from aminouracil

10b (1.00 g, 2.4 mmol), nitrosobenzene 9c (1.18 g, 7.2 mmol) and

acetic acid (25 mL). Chromatography (dichloromethane/ethyl acet-

ate, 10:1) afforded crude 11g and 11l (byproduct), which were crys-

tallised from chloroform/diethyl ether repeatedly to afford 11g

(520 mg, 39%) and 11l (56 mg, 4%) as yellow crystals.

1

11g: M.p. 295–297 °C. H NMR (CDCl₃, 300 MHz): δ = 3.98 (s, 3

H), 5.25 (s, 2 H), 6.11 (d, J = 7.6 Hz, 1 H), 6.19 (t, J = 7.0 Hz, 1

H), 6.45 (t, J = 7.6 Hz, 1 H), 6.60 (d, J = 9.1 Hz, 1 H), 6.86 (t, J

= 7.3 Hz, 1 H), 6.94 (d, J = 7.6 Hz, 1 H), 7.13 (d, J = 7.0 Hz, 1

H), 7.28–7.38 (m, 4 H), 7.55 (t, J = 7.3 Hz, 1 H), 7.65 (d, J =

6.4 Hz, 2 H), 7.70 (t, J = 7.6 Hz, 1 H), 8.04 (d, J = 8.56 Hz, 1 H),

8.12 (dd, J = 9.1, 2.0 Hz, 1 H), 8.20 (d, J = 7.0 Hz, 1 H), 8.77 (d,

J = 2.0 Hz, 1 H) ppm. ¹³C NMR (CDCl₃, 75 MHz): δ = 45.4, 53.1,

124.2, 125.5, 125.6, 126.2, 126.5, 126.7, 127.8, 127.9, 128.2, 128.4,

128.6, 128.9, 129.0, 129.5, 130.3, 131.6, 132.2, 132.7, 132.9, 135.1,

135.6, 136.1, 136.3, 137.2, 137.4, 137.8, 141.5, 150.7, 155.0,158.7,

166.4 ppm. C₃₅H₂₄N₄O₄(564.59): calcd. C 74.46, H 4.28, N 9.92;

found C 74.55, H 4.19, N 9.95.

3-Benzyl-10-(8-phenylnaphthalen-1-yl)-8-(trifluoromethyl)isoallox-

azine (11j): Isoalloxazine 11j was prepared from aminouracil 10b

(1.20 g, 2.9 mmol), nitrosobenzene 9e (1.50 g, 8.6 mmol) and acetic

acid (21 mL). Chromatography (chloroform/ethyl acetate, 8:1) and

crystallisation from chloroform/diethyl ether afforded 11j (0.45 g,

27 %) as yellow crystals; m.p. 263–264 °C. ¹H NMR (CDCl₃,

300 MHz): δ = 5.24 (m, 2 H), 6.09 (d, J = 7.6 Hz, 1 H), 6.21 (t, J

= 7.6 Hz, 1 H), 6.44 (t, J = 7.6 Hz, 1 H), 6.82 (s, 1 H), 6.86 (t, J =

7.6 Hz, 1 H), 6.94 (d, J = 7.6 Hz, 1 H), 7.14 (d, J = 7.0 Hz, 1 H),

7.29–7.38 (m, 4 H), 7.57 (t, J = 7.6 Hz, 1 H), 7.64 (d, J = 7.3 Hz,

2 H), 7.69 (dd, J = 8.5, 1.4 Hz, 1 H), 7.71 (t, J = 7.6 Hz, 1 H), 8.06

(d, J = 8.2 Hz, 1 H), 8.21 (d, J = 8.5 Hz, 2 H) ppm. ¹³C NMR

(CDCl₃, 75 MHz): δ = 45.2, 114.7 (q, J = 3.9 Hz), 122.4 (q, J =

3.3 Hz), 122.9 (q, J = 272.1 Hz), 126.2, 126.5, 126.59, 126.62,

126.65, 127.3, 128.2, 128.24, 128.6, 128.8, 129.0, 129.8, 130.2,

130.6, 132.0, 133.0, 133.3, 134.9, 135.7 (q, J = 33.0 Hz), 136.3,

1

11l: M.p. 288–290 °C. H NMR (CDCl₃, 300 MHz): δ = 2.88 (s, 3

H), 5.16 (d, J = 13.3 Hz, 1 H), 5.22 (d, J = 13.3 Hz, 1 H), 6.14 (t,

J = 7.3 Hz, 1 H), 6.41 (t, J = 7.3 Hz, 1 H), 6.82–6.92 (m, 3 H),

7.20 (dd, J = 7.0, 0.9 Hz, 1 H), 7.23 (dd, J = 7.3, 0.9 Hz, 1 H),

7.29–7.38 (m, 3 H), 7.50–7.60 (m, 4 H), 7.65 (d, J = 7.6 Hz, 2 H), 136.8, 136.9, 137.1, 139.7, 140.6, 150.2, 154.9, 158.4 ppm.

7.99 (d, J = 8.2 Hz, 1 H), 8.11 (d, J = 8.2 Hz, 1 H), 8.20 (dd, J =

C₃₄H₂₁F₃N₄O₂(574.55): calcd. C 71.08, H 3.68, N 9.75; found C

71.23, H 3.54, N 9.84.

8.2, 1.8 Hz, 1 H) ppm. ¹³C NMR (CDCl₃, 75 MHz): δ = 45.1, 52.4,

7734

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Eur. J. Org. Chem. 2013, 7724–7738

Planar Chiral Flavinium Salts

(S_p)-11j and (R_p)-11j: Enantiomers of isoalloxazine 11j were sepa-

rated on a Whelk-O1 column (250 ϫ 10 mm; dichloromethane;

4.0 mL/min) with retention times of 14.9 and 22.5 min for S_pand

R_p, respectively. (S_p)-11j: [α]_D= –794 (c = 0.3, CHCl₃); (R_p)-11j:

[α]_D= +789 (c = 0.3, CHCl₃), m.p. 259–261 °C.

131.4, 132.0, 132.2, 134.3, 134.7, 135.5, 136.5, 137.0, 138.3, 140.1,

150.3, 154.7, 158.4, 155.9 ppm. C₂₈H₁₈N₄O₄: calcd. C 70.88, H

3.82, N 11.81; found C 70.59, H 4.09, N 11.65.

(S_p)-11n: Amide (S_p)-12a (250 mg, 425 μmol) was hydrolysed in a

mixture of hydrochloric acid (6 mL) and acetic acid (3 mL) by heat-

ing at 120 °C for 10 h. After cooling, the mixture was diluted with

water (35 mL) and the resulting solid was filtered off. The solid was

dissolved in a solution of NaHCO₃(35 mL, 5%), extracted with

chloroform (3ϫ 10 mL) and acidified with hydrochloric acid. The

resulting solid was filtered off, washed with water and dried to

afford the acid (S_p)-11n (192 mg, 95%); m.p. Ͼ 350 °C, [α]_D= –775

(c = 0.5, DMSO).

3-Benzyl-10-(8-phenylnaphthalen-1-yl)-8-methoxyisoalloxazine

(11k): Isoalloxazine 11k was prepared from aminouracil 10b

(0.45 g, 1.1 mmol), nitrosobenzene 9f (0.50 g, 3.6 mmol) and acetic

acid (9 mL). Chromatography (dichloromethane/ethyl acetate, 15:2)

and crystallisation from dichloromethane/diethyl ether afforded

11k (0.47 g, 82%) as yellow crystals; m.p. 308–310 °C. ¹H NMR

(CDCl₃, 300 MHz): δ = 3.63 (s, 3 H), 5.25 (s, 2 H), 5.87 (d, J =

2.6 Hz, 1 H), 6.19 (t, J = 7.6 Hz, 1 H), 6.22 (d, J = 7.7 Hz, 1 H),

6.48 (t, J = 7.6 Hz, 1 H), 6.85 (t, J = 7.3 Hz, 1 H), 6.96 (d, J =

7.6 Hz, 1 H), 7.08 (dd, J = 9.1, 2.6 Hz, 1 H), 7.12 (d, J = 7.0 Hz,

1 H), 7.26–7.36 (m, 4 H), 7.54 (t, J = 7.3 Hz, 1 H), 7.67 (m, 3 H),

8.02 (d, J = 9.1 Hz, 2 H), 8.16 (d, J = 8.5 Hz, 1 H) ppm. ¹³C NMR

(CDCl₃, 75 MHz): δ = 44.9, 56.2, 100.0, 115.7, 126.3, 126.4,

126.5,126.7, 128.0, 128.1, 128.5, 128.7, 129.2, 129.6, 130.2, 131.6,

131.7, 132.0, 132.4, 134.1, 134.3, 136.2, 137.2, 137.3, 137.7, 140.4,

150.3, 155.6, 159.6, 165.6 ppm. C₃₄H₂₄N₄O₃(536.58): calcd. C

76.11, H 4.51, N 10.44; found C 76.25, H 4.47, N 10.12.

(R_p)-11n: Acid (R_p)-11n was prepared according to the procedure

used for (S_p)-11n from (R_p)-12a (250 mg, 425 μmol), yield 185 mg,

93%. (+)-(R_p)-11n: [α]_D= +782 (c = 0.5, DMSO), m.p. Ͼ 350 °C.

3-Benzyl-10-(8-phenylnaphthalen-1-yl)isoalloxazine-6-carboxylic

Acid (11o): Flavin 11f (300 mg, 0.53 mmol) was hydrolysed analo-

gously to flavin 11m to afford 11o as a red solid (277 mg, 95%);

m.p. Ͼ 350 °C. ¹H NMR (CDCl₃, 300 MHz): δ = 5.22 (d, ²J =

2

13.5 Hz, 1 H), 5.27 (d, J = 13.5 Hz, 1 H), 6.08 (d, J = 7.6 Hz, 1

H), 6.25 (t, J = 7.6 Hz, 1 H), 6.48 (t, J = 7.6 Hz, 1 H), 6.83 (d, J

= 8.8 Hz, 1 H), 6.90 (t, J = 7.6 Hz, 1 H), 6.96 (d, J = 7.6 Hz, 1 H),

7.14 (d, J = 5.9 Hz, 1 H), 7.30–7.40 (m, 4 H), 7.58 (t, J = 8.2 Hz,

1 H), 7.63 (d, J = 8.2 Hz, 2 H), 7.70 (t, J = 7.6 Hz, 1 H), 7.73 (t,

J = 8.2 Hz, 1 H), 8.07 (dd, J = 8.2, 1.2 Hz, 1 H), 8.23 (dd, J = 8.5,

1.4 Hz, 1 H), 8.47 (dd, J = 8.5, 1.4 Hz, 1 H) ppm. ¹³C NMR ([D₆]

DMSO, 75 MHz): δ = 44.8, 120.0, 125.8, 126.5, 126.6, 126.7, 126.9,

127.1, 127.9, 128.0, 128.1, 128.4, 128.6, 129.0, 129.6, 130.2, 131.9,

132.1, 132.5, 132.6, 135.0, 135.6, 135.7, 136.1, 137.1, 137.9, 138.1,

140.7, 150.6, 155.1, 158.7, 167.8 ppm. C₃₄H₂₂N₄O₄·H₂O: calcd. C

71.82, H 4.25, N 9.85; found C 71.63, H 4.32, N 9.75.

3-Benzyl-10-(8-phenylnaphthalen-1-yl)benzo[j]isoalloxazine (11m):

Isoalloxazine 11m was prepared from aminouracil 10b (1.35 g,

3.2 mmol), nitrosonaphthalene 9g (2.07 g, 9.7 mmol) and acetic

acid (23 mL). Chromatography (chloroform/ethyl acetate, 5:1) and

crystallisation from chloroform/diethyl ether afforded 11m (0.25 g,

14 %) as red crystals; m.p. 324–326 °C. ¹H NMR (CDCl₃,

2

600 MHz): δ = 5.25 (d, J = 13.5 Hz, 1 H), 5.31 (d, J = 13.5 Hz, 1

H), 6.17 (d, J = 7.5 Hz, 1 H), 6.24 (t, J = 7.4 Hz, 1 H), 6.29 (t, J

= 7.4 Hz, 1 H), 6.71 (d, J = 9.1 Hz, 1 H), 6.85 (t, J = 7.5 Hz, 1 H),

7.00–6.95 (m, 1 H), 7.01 (d, J = 7.6 Hz, 1 H), 7.18 (d, J = 6.6 Hz,

1 H), 7.25 (d, J = 6.9 Hz, 1 H), 7.31 (t, J = 7.3 Hz, 1 H), 7.36 (t,

J = 7.5 Hz, 2 H), 7.55 (t, J = 7.4 Hz, 1 H), 7.60 (t, J = 7.6 Hz, 1

H), 7.66 (t, J = 7.8 Hz, 1 H), 7.70 (d, J = 7.4 Hz, 2 H), 7.88 (d, J

= 8.8 Hz, 1 H), 7.91 (d, J = 7.9 Hz, 1 H), 8.02 (d, J = 8.8 Hz, 1

H), 8.11 (d, J = 8.1 Hz, 1 H), 8.27 (d, J = 8.1 Hz, 1 H) ppm. ¹³C

NMR (CDCl₃, 150 MHz): δ = 44.9, 122.7, 126.0, 126.5, 126.6,

126.7, 126.9, 127.1, 127.2, 127.8, 127.9, 128.0, 128.4, 128.5, 128.8,

128.9, 129.7, 129.8, 129.9, 130.1, 131.9, 132.6, 132.9, 135.7, 135.99,

136.02, 136.2, 137.4, 137.5, 137.6, 140.7, 151.4, 155.2, 159.3 ppm.

C₃₇H₂₄N₄O₂(556.61.54): calcd. C 79.84, H 4.35, N 10.07; found C

79.63, H 4.47, N 9.95.

(S_p,S)-N-(1-Isopropyl-2-methoxy-2-oxoethyl)-3-methyl-10-(8-

phenylnaphthalen-1-yl)isoalloxazine-7-carboxamide [(S_p,S)-12a] and

(R_p,S)-N-(1-Isopropyl-2-methoxy-2-oxoethyl)-3-methyl-10-(8-phen-

ylnaphthalen-1-yl)isoalloxazine-7-carboxamide [(R_p,S)-12a]: Oxalyl

chloride (1.03 g, 0.71 mL, 8.1 mmol) and 2 drops of DMF were

added to a suspension of rac-11n (1.30 g, 2.7 mmol) in dichloro-

methane (80 mL) . The mixture was stirred for 4 h and the solvents

evaporated. Dichloromethane (60 mL) and (S)-valine methyl ester

hydrochloride (0.50 g, 3.00 mmol) were added to the residue fol-

lowed by the dropwise addition of triethylamine (0.88 mL,

6.3 mmol) in dichloromethane (8 mL). Then the mixture was

washed with diluted hydrochloric acid (60 mL), a saturated solu-

tion of NaHCO₃(60 mL), water (60 mL) and dried with MgSO₄.

The crude product was purified by filtration through a short plug

of silica gel (chloroform/methanol, 100:2) to afford a mixture of

amides (S_p,S)-12a and (R_p,S)-12a (1.51 g). The mixture was sepa-

rated by column chromatography (chloroform/ethyl acetate, 5:1)

followed by crystallisation from ethyl acetate to afford (S_p,S)-12a

(0.64 g, 40%) as bright-yellow crystals and (R_p,S)-12a (0.57 g, 36%)

as an orange solid.

(S_p)-11m and (R_p)-11m: Enantiomers of isoalloxazine 11m were

separated on a Whelk-O1 column (250ϫ 10 mm; dichloromethane;

5.0 mL/min) with retention times of 7.8 and 13.3 min for S_pand

R_p, respectively. (S_p)-11m: [α]_D= –1398 (c = 0.3, CHCl₃); (R_p)-11m:

[α]_D= +1385 (c = 0.3, CHCl₃), m.p. 146–148 °C.

3-Methyl-10-(8-phenylnaphthalen-1-yl)isoalloxazine-7-carboxylic

Acid (11n): Isoalloxazine 11h (1.40 g, 2.8 mmol) was dissolved in

hydrochloric acid (70 mL, 35%) and heated at 90 °C for 3 h. After

cooling, the mixture was diluted with water (150 mL) and the re-

sulting solid was filtered off, washed with water and dried in vacuo

to afford 11n as a yellow solid (1.32 g, 97%); m.p. Ͼ 350 °C. ¹H

(S_p,S)-12a: M.p. 238–239 °C, [α]_D= –619 (c = 1.0, CHCl₃). ¹H

NMR (CDCl₃, 300 MHz): δ = 1.01 (dd, J = 6.7, 1.8 Hz, 6 H), 2.30

(m, 1 H), 3.50 (s, 3 H), 3.82 (s, 3 H), 4.77 (m, 1 H), 6.21 (d, J =

NMR ([D₆]DMSO, 300 MHz): δ = 3.28 (s, 3 H), 6.25 (dd, J = 7.6, 7.6 Hz, 1 H), 6.56 (t, J = 7.6 Hz, 1 H), 6.64 (d, J = 8.8 Hz, 1 H),

1.5 Hz, 1 H), 6.46 (m, 1 H), 6.76 (d, J = 9.1 Hz, 1 H), 6.89–6.98

(m, 3 H), 7.19 (dd, J = 7.3, 1.2 Hz, 1 H), 7.56 (dd, J = 7.3, 1.2 Hz,

6.80 (d, J = 8.2 Hz, 1 H), 6.92 (t, J = 7.3 Hz, 1 H), 7.05 (t, J =

7.3 Hz, 1 H), 7.13 (d, J = 7.6 Hz, 1 H), 7.20 (d, J = 7.0 Hz, 1 H),

1 H), 7.67 (t, J = 7.0 Hz, 1 H), 7.86 (t, J = 7.6 Hz, 1 H), 8.17 (dd, 7.30 (d, J = 7.3 Hz, 1 H), 7.58 (t, J = 7.0 Hz, 1 H), 7.70 (t, J =

J = 9.1, 2.0 Hz, 1 H), 8.27 (dd, J = 8.2, 1.2 Hz, 1 H), 8.40 (dd, J

= 8.2, 1.2 Hz, 1 H), 8.43 (d, J = 2.0 Hz, 1 H), 13.48 (br. s, 1

7.6 Hz, 1 H), 8.03–8.12 (m, 2 H), 8.20 (d, J = 8.2 Hz, 1 H), 8.51

(d, J = 1.8 Hz, 1 H) ppm. ¹³C NMR (CDCl₃, 75 MHz): δ = 18.0,

H) ppm. ¹³C NMR ([D₆]DMSO, 75 MHz): δ = 28.1, 117.9, 125.9, 19.1, 28.9, 31.7, 52.7, 57.8, 118.0, 126.1, 126.2, 126.5, 126.6, 126.8,

126.0, 126.2, 126.5, 127.3, 127.5, 127.9, 128.2, 128.9, 129.5, 131.2,

127.3, 128.2, 128.7, 129.3, 129.7, 129.8, 131.0, 131.7, 131.8, 132.8,

Eur. J. Org. Chem. 2013, 7724–7738

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7735

R. Cibulka et al.

FULL PAPER

134.2, 134.8, 136.2, 136.8, 136.9, 138.3, 140.5, 150.3, 155.5, 159.0,

ture of diastereoisomers of 12c was prepared analogously to 12a

164.8, 172.4 ppm. C₃₄H₂₉N₅O₅: calcd. C 69.49, H 4.97, N 11.92; from rac-11o (170 mg, 0.3 mmol), oxalyl chloride (80 μL,

found C 69.32, H 5.08, N 11.85.

0.9 mmol), (S)-valine methyl ester hydrochloride (70 mg, 0.4 mmol)

and triethylamine (140 μL, 1.0 mmol). The crude mixture was first

purified by filtration through silica gel (chloroform/methanol,

100:2) to afford a mixture of diastereoisomers of 12c (193 mg). The

diastereomers were separated by column chromatography (chloro-

form/ethyl acetate, 5:1) to afford (S_p,S)-12c (91 mg, 44%); m.p.

235–237 °C, [α]_D= –770 (c = 1.0, CHCl₃). ¹H NMR (CDCl₃,

300 MHz): δ = 1.21 [dd, J = 14.3, 6.7 Hz, 6 H, CH(CH₃)₂], 2.49

[m, 1 H, CH(CH₃)₂], 3.86 (s, 3 H, OCH₃), 4.73 (dd, J = 7.3, 5.3 Hz,

1 H, NHCH), 5.19–5.30 (m, 2 H, PhCH₂), 5.99 (d, J = 7.6 Hz, 1

H), 6.26 (dd, J = 7.4 Hz, 1 H), 6.58 (dd, J = 7.6 Hz, 1 H), 6.68 (d,

J = 8.5 Hz, 1 H), 6.92 (m, 2 H), 7.10 (d, J = 7.3 Hz, 1 H), 7.26–

7.37 (m, 4 H), 7.54 (dd, J = 8.2 Hz, 1 H), 7.58–7.65 (m, 3 H), 7.71

(dd, J = 7.6 Hz, 1 H), 8.03 (d, J = 8.2 Hz, 1 H), 8.19 (d, J = 8.2 Hz,

1 H), 8.51 (d, J = 7.6 Hz, 1 H), 10.14 (d, J = 7.3 Hz, 1 H, NH) ppm.

¹³C NMR (CDCl₃, 75 MHz): δ = 18.3, 19.8, 31.2, 45.1, 52.3, 59.4,

120.7, 126.3, 126.4, 126.5, 126.6, 126.7, 127.3, 127.8, 128.1, 128.6,

128.9, 129.3, 129.7, 129.9, 130.1, 131.1, 131.2, 132.0, 132.6, 133.0,

134.7, 135.4, 136.3, 136.7, 136.8, 137.3, 140.6, 149.6, 155.3, 157.8,

163.8, 172.5 ppm. C₄₀H₃₃N₅O₅·CHCl₃: calcd. C 62.88, H 4.38, N

8.94; found C 63.02, H 4.20, N 9.03.

(R_p,S)-12a: M.p. 210–212 °C, [α]_D= +605 (CHCl₃, c = 0.5). ¹H

NMR (CDCl₃, 300 MHz): δ = 1.05 (dd, J = 7.0 Hz, 6 H), 2.33 (m,

1 H), 3.49 (s, 3 H), 3.78 (s, 3 H), 4.76 (m, 1 H), 6.21 (d, J = 7.6 Hz,

1 H), 6.53 (dd, J = 7.6 Hz, 1 H), 6.64 (d, J = 8.8 Hz, 1 H), 6.78 (d,

J = 8.2 Hz, 1 H), 6.92 (t, J = 7.3 Hz, 1 H), 7.04 (t, J = 7.3 Hz, 1

H), 7.13 (d, J = 7.6 Hz, 1 H), 7.19 (d, J = 7.0 Hz, 1 H), 7.30 (d, J

= 7.3 Hz, 1 H), 7.57 (t, J = 7.0 Hz, 1 H), 7.70 (t, J = 7.6 Hz, 1 H),

8.05 (dd, J = 8.2, 1.2 Hz, 1 H), 8.07 (dd, J = 9.1, 2.1 Hz, 1 H), 8.20

(d, J = 8.2 Hz, 1 H), 8.52 (d, J = 2.1 Hz, 1 H) ppm. ¹³C NMR

(CDCl₃, 75 MHz): δ = 18.1, 19.1, 28.8, 31.7, 52.7, 57.8, 118.0,

126.1, 126.2, 126.5, 126.6, 126.8, 127.3, 128.2, 128.7, 129.3, 129.7,

129.8, 131.0, 131.7, 131.8, 132.7, 134.2, 134.8, 136.1, 136.8, 136.9,

138.3, 140.5, 150.3, 155.5, 159.1, 165.0, 172.4 ppm. C₃₄H₂₉N₅O₅:

calcd. C 69.49, H 4.97, N 11.92; found C 69.18, H 5.04, N 11.76.

(S_p,S)-N-[1-(4-Methoxybenzyl)-2-methoxy-2-oxoethyl]-3-methyl-

10-(8-phenylnaphthalen-1-yl)isoalloxazine-7-carboxamide [(S_p,S)-

12b]: Amide (S_p,S)-12b was prepared analogously to (S_p,S)-12a

from (S_p)-11n (70 mg, 150 μmol), oxalyl chloride (100 μL,

1.1 mmol), (S)-O-methyltyrosine methyl ester hydrochloride

(50 mg, 200 μmol) and triethylamine (56 μL, 400 μmol). Column

chromatography (chloroform/methanol, 100:2) afforded (S_p,S)-12b

Crystallisation of (S_p,S)-12c from chloroform provided crystals

suitable for X-ray analysis.

1

(92 mg, 93%); m.p. 162–164 °C, [α]_D= –541 (CHCl₃, c = 0.6). H

NMR (CDCl₃, 300 MHz): δ = 3.13–3.27 (m, 2 H), 3.49 (s, 3 H),

3.81 (s, 3 H), 5.05 (m, 1 H), 6.18 (d, J = 7.6 Hz, 1 H), 6.52 (t, J =

7.6 Hz, 1 H), 6.63 (d, J = 8.8 Hz, 1 H), 6.78 (t, J = 7.6 Hz, 1 H),

6.80 (d, J = 8.2 Hz, 2 H), 6.91 (t, J = 7.6 Hz, 1 H), 6.98–7.06 (m,

1 H), 7.02 (d, J = 8.2 Hz, 2 H), 7.11 (d, J = 7.3 Hz, 1 H), 7.18 (d,

J = 7.0 Hz, 1 H), 7.30 (d, J = 7.3 Hz, 1 H), 7.57 (t, J = 7.3 Hz, 1

H), 7.70 (t, J = 7.6 Hz, 1 H), 8.03–8.08 (m, 2 H), 8.20 (d, J =

7.6 Hz, 1 H), 8.41 (d, J = 2.0 Hz, 1 H) ppm. ¹³C NMR (CDCl₃,

75 MHz): δ = 28.7, 37.7, 52.2, 53.6, 55.3, 114.1, 118.0, 126.1, 126.2,

126.5, 126.6, 126.8, 127.3, 128.2, 128.7, 129.0, 129.3, 129.7, 129.8,

129.9, 131.0, 131.7, 131.8, 132.7, 134.2, 134.8, 136.1, 136.8, 136.9,

Hydrolysis of (S_p,S)-12c Followed by Decarboxylation:^[22]Amide

(S_p,S)-12c (80 mg, 120 μmol) was hydrolysed in a mixture of hydro-

chloric acid (4 mL) and acetic acid (3 mL) by heating at 120 °C for

10 h. After cooling, the mixture was diluted with water (20 mL)

and the resulting solid was filtered off. The solid was dissolved in

a solution of NaHCO₃(10 mL, 5%), extracted with chloroform

(3ϫ 3 mL) and acidified with hydrochloric acid. The resulting solid

was filtered off, washed with water and dried to afford acid (S_p)-

11o (60 mg, 91%); m.p. Ͼ 350 °C, [α]_D= –816 (c = 0.5, DMSO).

A mixture of (S_p)-11o (35 mg, 53 μmol), Ag₂CO₃(4 mg, 16 μmol)

138.3, 140.5, 150.3, 155.5, 158.9, 159.0, 164.8, 172.0 ppm. and acetic acid (0.4 μL, 8 μmol) in dry DMSO (400 μL) was stirred

C₃₉H₃₁N₅O₆: calcd. C 70.37, H 4.69, N 10.52; found C 70.42, H

4.58, N 10.45.

under nitrogen at 120 °C for 16 h. After cooling, the mixture was

diluted with water (12 mL) and extracted with chloroform. After

evaporation, the crude product was purified by column chromatog-

raphy (chloroform/ethyl acetate, 5:1) to afford (S_p)-11b (24 mg,

89%). [α]_D= –857 (c = 0.4, CHCl₃) {the [α]_Dof pure (S_p)-11b is

–879 (c = 0.5, CHCl₃)^[14]}.

(R_p,S)-N-[1-(4-Methoxybenzyl)-2-methoxy-2-oxoethyl]-3-methyl-10-

(8-phenylnaphthalen-1-yl)isoalloxazine-7-carboxamide [(R_p,S)-12b]:

Amide (R_p,S)-12b was prepared analogously to (S_p,S)-12a from

(R_p)-11n (70 mg, 150 μmol), oxalyl chloride (100 μL, 1.1 mmol),

(S)-O-methyltyrosine methyl ester hydrochloride (50 mg, 200 μmol)

and triethylamine (56 μL, 400 μmol). Column chromatography

(chloroform/acetone, 10:1Ǟ8:1) afforded the product (R_p,S)-12b

Crystallographic Data for (S_p,S)-12c·CHCl₃(C₄₀H₃₃N₅O₅·CHCl₃):

M = 783.11 gmol^–1, orthorhombic system, space group P2₁2₁2₁, a

= 13.1934(4), b = 15.6146(5), c = 17.3883(6) Å, Z = 4, V =

3582.16 (19) Å³, D_c= 1.452 gcm^–3, μ(Cu-K_α) = 2.77 mm^–1, crystal

dimensions 0.47ϫ0.35ϫ0.30 mm. Data were collected at 150(2) K

with an Xcalbur Onyx CCD diffractometer with graphite-mono-

chromated Cu-K_αradiation. The structure was solved by direct

methods^[23]using the CRYSTALS suite of programs^[24]and aniso-

tropically refined by full-matrix least-squares method on F²

squared to give the final R = 0.081 and R_w= 0.219 by using 7430

independent reflections (Θ_max= 77.7°), 488 parameters and 0 re-

straints. The hydrogen atoms were placed in calculated positions

and determined by using a riding model.

1

(84 mg, 85%); m.p. 158–160 °C, [α]_D= +626 (CHCl₃, c = 0.7). H

NMR (CDCl₃, 300 MHz): δ = 3.13–3.28 (m, 2 H), 3.48 (s, 3 H),

3.78 (s, 3 H), 5.02 (m, 1 H), 6.17 (d, J = 7.6 Hz, 1 H), 6.48 (t, J =

7.6 Hz, 1 H), 6.60 (d, J = 8.8 Hz, 1 H), 6.77 (d, J = 7.6 Hz, 1 H),

6.83 (d, J = 8.2 Hz, 2 H), 6.90 (t, J = 7.6 Hz, 1 H), 6.98–7.08 (m,

3 H), 7.11 (d, J = 7.6 Hz, 1 H), 7.16 (d, J = 7.0 Hz, 1 H), 7.30 (d,

J = 7.3 Hz, 1 H), 7.56 (t, J = 7.3 Hz, 1 H), 7.68 (t, J = 7.6 Hz, 1

H), 8.00 (dd, J = 8.8, 2.0 Hz, 1 H), 8.04 (d, J = 7.6 Hz, 1 H), 8.19

(d, J = 7.6 Hz, 1 H), 8.40 (d, J = 2.0 Hz, 1 H) ppm. ¹³C NMR

(CDCl₃, 75 MHz): δ = 28.7, 37.6, 52.3, 53.8, 55.3, 114.2, 118.1,

126.1, 126.2, 126.5, 126.6, 126.8, 127.3, 128.2, 128.7, 129.0, 129.3,

129.7, 129.8, 129.9, 131.0, 131.7, 131.8, 132.7, 134.2, 134.8, 136.1,

136.8, 136.9, 138.4, 140.6, 150.3, 155.5, 158.9, 159.1, 164.9,

172.1 ppm. C₃₉H₃₁N₅O₆: calcd. C 70.37, H 4.69, N 10.52; found C

70.25, H 4.54, N 10.46.

CCDC-923930 contains the supplementary crystallographic data

for this paper. These data can be obtained free of charge from The

Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/

data_request/cif.

(S_p,S)-N-(1-Isopropyl-2-methoxy-2-oxoethyl)-3-benzyl-10-(8-phenyl-

naphthalen-1-yl)isoalloxazine-6-carboxamide [(S_p,S)-12c]: A mix-

ECD Spectra: The ECD spectra were recorded at room tempera-

ture on a Jasco J-815 spectropolarimeter (Japan). Samples at a con-

7736

www.eurjoc.org

Eur. J. Org. Chem. 2013, 7724–7738

Planar Chiral Flavinium Salts

centration of 0.0002 molL^–1in chloroform as the solvent were ana-

lysed in a 2 mm quartz cell in the range 315–550 nm: 1 nm band-

width, 2 s response and 50 nmmin^–1scan rate. Six scans were re-

corded, averaged, and, by using a spectrum of the solvent obtained

under the same experimental conditions, baseline-subtracted.

Clare, E. J. Corey, J. Am. Chem. Soc. 2012, 134, 17354–17357;

e) J. Fujisaki, K. Matsumoto, T. Katsuki, J. Am. Chem. Soc.

2011, 133, 56–61; f) H. Tanaka, H. Nishikawa, T. Uchida, T.

Katsuki, J. Am. Chem. Soc. 2010, 132, 12034–12041; g) I. Lip-

pold, J. Becher, D. Klemm, W. Plass, J. Mol. Catal. A 2009,

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Fujisaki, B. Saito, T. Katsuki, Chem. Asian J. 2008, 3, 351–358;

j) K. P. Bryliakov, E. P. Talsi, Eur. J. Org. Chem. 2008, 3369–

3376; k) A. Pordea, M. Creus, J. Panek, C. Duboc, D. Mathis,

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8088; l) K. Matsumoto, T. Yamaguchi, T. Katsuki, Chem. Com-

mun. 2008, 1704–1704; m) E. Kiromichi, T. Katsuki, Synlett

2008, 10, 1543–1546.

Kinetic Measurements: Flavinium salt (3.8 μmol), thioanisole

(0.255 mmol) and CD₃OD (600 μL) were charged into an NMR

tube. The mixture was homogenised by sonication and tempered

for 15 min at 25 °C. The reaction was started by the addition of

30% aqueous hydrogen peroxide (40 μL, 0.392 mmol) and the con-

versions calculated from the integrals of the corresponding signals

1

in the H NMR spectra.

[4]

General Procedure for the Asymmetric Sulfoxidation Reactions: The

flavinium salt (5 μmol) and a substrate (0.1 mmol) were dissolved

in methanol/water (2:1, 10 mL). The mixture was homogenised by

sonication and tempered for 30 min at –20 °C. 30% Aqueous hy-

drogen peroxide (10.5 μL, 0.1 mmol) was added and the reaction

mixture stirred at –20 °C. The reaction was monitored by HPLC.

When 70% conversion was reached, the reaction was quenched by

5% aqueous sodium bisulfite (5 mL). Methanol was carefully evap-

orated and the remaining aqueous solution was extracted with

dichloromethane. After the evaporation of the solvents, the residue

was purified by column chromatography (ethyl acetate/hexane, 1:1).

The ratio of enantiomers was determined by HPLC analysis on a

Chiralcel OD or Phenomenex^®Lux Cellulose-4 column (hexane/2-

PrOH, 9:1).^[18]

a) P. C. B. Page, J. P. Heer, D. Bethell, B. A. Lund, Phosphorus

Sulfur Silicon Relat. Elem. 1999, 153–154, 247–258; b) D. Beth-

ell, P. C. B. Page, H. Vahedi, J. Org. Chem. 2000, 65, 6756–

6760; c) A. Głuszyn´ska, I. Mackowska, M. D. Rozwadowska,

W. Sienniak, Tetrahedron: Asymmetry 2004, 15, 2499–2505.

a) F. A. Davis, R. T. Reddy, W. Han, R. E. Reddy, Pure Appl.

Chem. 1993, 65, 633–640; b) F. A. Davis, R. T. Reddy, W. Han,

P. J. Carroll, J. Am. Chem. Soc. 1992, 114, 1428–1437; c) F. A.

Davis, R. B. C. Chen, Chem. Rev. 1992, 92, 919–934.

a) L. Bohé, M. Lusinchi, X. Lusinchi, Tetrahedron 1999, 55,

155–166; b) S. Schoumacker, O. Hamelin, S. Téti, J. Pécaut, M.

Fontecave, J. Org. Chem. 2005, 70, 301–308; c) R. E. del Rio,

B. Wang, S. Achab, L. Bohé, Org. Lett. 2007, 9, 2265–2268; d)

A. Akhatou, M. Rahimi, K. Cheboub, L. Ghosez, G. Hanquet,

Tetrahedron 2007, 63, 6232–6240.

[5]

[6]

[7]

[8]

[9]

a) Z.-M. Liu, H. Zhao, M.-Q. Li, Y.-B. Lan, Q.-B. Yao, J.-C.

Supporting Information (see footnote on the first page of this arti-

cle): Experimental details for the synthesis of compounds 1b and

Tao, X.-W. Wang, Adv. Synth. Catal. 2012, 354, 1012–1022; b)

ˇ

S. Liao, I. Coric´, Q. Wang, B. List, J. Am. Chem. Soc. 2012,

1

7–10, H and ¹³C NMR spectra of flavinium salts 3–6 and flavins

134, 10765–10768.

11 and 12, ORTEP drawing of 12c and analysis with time of the

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Applications of flavinium salts in catalysis are reviewed in: a)

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Received: June 10, 2013

Published Online: October 9, 2013

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Article Doi

Planar chiral flavinium salts: Synthesis and evaluation of the effect of substituents on the catalytic efficiency in enantioselective sulfoxidation reactions

DOI: 10.1002/ejoc.201300847

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