Synthesis and redox potentials of methylated vitamin K derivatives

Article abstract of DOI:10.1039/a900190e

We report the synthesis of derivatives of vitamin K₃ as well as of vitamins K₁ and K₂ containing a different number of methyl groups in various positions in order to reduce their redox potentials and to change systematically their steric features. The long aliphatic chain of vitamins K₁ and K₂ is simulated by an undecyl chain or a methyl group, respectively. The redox potentials of the first reduction step were measured by cyclic voltammetry in DMF. These compounds are relevant for studies of the structure-function relationship of vitamin K dependent enzymes and the investigation of electron transfer reactions in photosynthetic reaction centers.

Full text of DOI:10.1039/a900190e

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Synthesis and redox potentials of methylated vitamin K derivatives
Ralf Schmid, Friederike Goebel, André Warnecke and Andreas Labahn*
Institut für Physikalische Chemie, Albert-Ludwigs-Universität Freiburg, Albertstr. 23A,
D-79104 Freiburg, Germany
Received (in Cambridge) 6th January 1999, Accepted 23rd March 1999
We report the synthesis of derivatives of vitamin K3 as well as of vitamins K1 and K2 containing a different number
of methyl groups in various positions in order to reduce their redox potentials and to change systematically their
steric features. The long aliphatic chain of vitamins K1 and K2 is simulated by an undecyl chain or a methyl group,
respectively. The redox potentials of the first reduction step were measured by cyclic voltammetry in DMF. These
compounds are relevant for studies of the structure–function relationship of vitamin K dependent enzymes and the
investigation of electron transfer reactions in photosynthetic reaction centers.
Introduction
Results and discussion
Among the naturally occurring naphthoquinones, which
are widely distributed in microorganisms, plants and mammals,
the most important compounds are vitamins of the K group.
The basic structure of vitamin K is vitamin K3 (2-methyl-
naphtho-1,4-quinone, menadione). In vitamin K1 (2-methyl-
3-phytylnaphtho-1,4-quinone, phylloquinone) and vitamin K2
(2-methyl-3-(isoprenyl)(7–9)naphtho-1,4-quinone, menaquinone)
the hydrogen in position 3 is replaced by an aliphatic side
chain.
Vitamin K serves as an essential cofactor for the carboxylase
that activates the proteins of the blood-clotting cascade.1
Several artificial vitamin K derivatives have been used for
studying the vitamin K dependent carboxylase.2,3
Furthermore, the vitamins of the K group are involved as
cofactors in various electron transfer reactions. Vitamin K2 was
identified as the primary electron acceptor in reaction centers
in a number of photosynthetic bacteria4–7 and vitamin K1 was
found to be the electron acceptor A1 in the photosystem I
of green plants.8–10 Electron transfer reactions in biological
systems depend strongly on the energetics of the involved
cofactors. Hence, the systematic variation of the redox poten-
tials of vitamin K derivatives is of major importance for the
investigation of electron transfer reactions in photosynthetic
reaction centers.11–14
Synthesis
Depending on the position of the methyl groups in the quinone
ring system we chose three ways for the preparation of the
naphthoquinone derivatives.
2,3-Dimethylnaphtho-1,4-quinone 3a, 2,5-dimethylnaphtho-
1,4-quinone
1a,
2,6-dimethylnaphtho-1,4-quinone
1b,
R4
O
R4
O
R3
R3
R2
R2
n-C11H23
R1
O
O
R1
Vit K3 R1 = R2 = R3 = R4 = H
1a R1 = Me, R2 = R3 = R4 = H
1b R2 = Me, R1 = R3 = R4 = H
1c R3 = Me, R1 = R2 = R4 = H
1d R4 = Me, R1 = R2 = R3 = H
1e R1 = R4 = Me, R2 = R3 = H
1f R2 = R3 = Me, R1 = R4 = H
1g R1 = R2 = R3 = R4 = Me
2a R1 = Me, R2 = R3 = R4 = H
2b R2 = Me, R1 = R3 = R4 = H
2c R3 = Me, R1 = R2 = R4 = H
2d R4 = Me, R1 = R2 = R3 = H
2e R1 = R4 = Me, R2 = R3 = H
2f R2 = R3 = Me, R1 = R4 = H
2g R1 = R2 = R3 = R4 = Me
2h R1 = R2 = R3 = R4 = H
The primary reaction in the bacterial reaction center
protein from Rhodobacter sphaeroides is the absorption of light
by the primary electron donor, D, and the subsequent rapid
electron transfer via several intermediate acceptors, a bacterio-
pheophytin, ΦA, a primary ubiquinone, QA, to the secondary
ubiquinone, QB, forming the final charge separated state
DϩQAQBϪ. Recently, 2,3,5-trimethylnaphtho-1,4-quinone and
2,3,6,7-tetramethylnaphtho-1,4-quinone have been used to
increase the energy level of DϩQAϪQB relative to the ground
state while retaining the native ubiquinone at the QB site.15–17 To
increase the free energy gap between the states DϩQAϪQB and
2,7-dimethylnaphtho-1,4-quinone 1c, 2,8-dimethylnaphtho-
1,4-quinone 1d and 2,3,5-trimethylnaphtho-1,4-quinone 3b
were synthesized from the corresponding naphthalenes (i.e.
2,3-dimethylnaphthalene, 1,6-dimethylnaphthalene, 2,6-di-
methylnaphthalene, 2,7-dimethylnaphthalene, 1,7-dimethyl-
naphthalene and 1,6,7-trimethylnaphthalene, respectively),
using the chromium trioxide oxidation procedure.19 2,3,6-
Trimethylnaphtho-1,4-quinone 3c, 2,5,8-trimethylnaphtho-1,4-
quinone 1e, 2,6,7-trimethylnaphtho-1,4-quinone 1f, 2,3,5,8-
tetramethylnaphtho-1,4-quinone 3d and 2,3,6,7-tetramethyl-
naphtho-1,4-quinone 3e were prepared via Diels–Alder
additions using 2,3-dimethylbuta-1,3-diene, isoprene or hexa-
2,4-diene as the diene and 2-methylbenzo-1,4-quinone or 2,3-
dimethylbenzo-1,4-quinone as the dieneophile, followed by
dehydrogenation of the adducts with activated MnO2.20 For the
synthesis of naphthoquinones containing four methyl groups in
positions 5,6,7 and 8 (1g, 2g, 3f), 2,3,4,5-tetramethylthiophene
dioxide was prepared to act as the diene reagent.
Ϫ
DϩQAQB we synthesized various derivatives of vitamin K3 as
well as of vitamins K1 and K2. Their reduction potentials are
varied by introducing methyl groups into the ring system. A
long aliphatic chain substituent in position 3 is expected to
drastically improve the binding affinity of these quinones to the
QA site as has been found for ubiquinones.18
We have determined the redox potentials for the first reduc-
tion step of the quinones by cyclic voltammetry in DMF and
discuss the influence of electron donating substituents on the
in vitro redox properties.
During the TLC of the Diels–Alder adduct of 2,3,4,5-tetra-
methylthiophene dioxide and the benzoquinone, a change in the
colour of the TLC spot from brown to yellow was observed,
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Table 1 Reduction potentials of vitamin K3 derivatives vs. ferrocene/
ferrocinium
Table 2 Reduction potentials of vitamin K1,2 derivatives containing a
long alkyl chain in position 3 vs. ferrocene/ferrocinium
Quinone
E/mV
E/mV (calc.)
Ϫ1140
Ϫ1220
Ϫ1180
Ϫ1180
Ϫ1220
Ϫ1300
Ϫ1220
Ϫ1380
Quinone
E/mV
E/mV (calc.)
Ϫ1215
Vitamin K3
Ϫ1146
Ϫ1218
Ϫ1173
Ϫ1179
Ϫ1224
Ϫ1300
Ϫ1209
Ϫ1391
2h
Ϫ1206
Ϫ1219
Ϫ1197
Ϫ1288
Ϫ1261
Ϫ1255
Ϫ1295
Ϫ1366
Ϫ1294
Ϫ1477
1a
1b
1c
1d
1e
1f
Vitamin K2
Ϫ1215
Ϫ1215
Ϫ1295
Ϫ1255
Ϫ1255
Ϫ1295
Ϫ1375
Ϫ1295
Ϫ1455
Vitamin K1
2a
2b
2c
2d
2e
2f
1g
Ubiquinone
Ϫ1103
—
2g
Ubiquinone
Ϫ1103
—
R4
O
R3
Table 3 Reduction potentials of vitamin K1,2 derivatives containing a
methyl group in position 3 vs. ferrocene/ferrocinium
R2
Quinone
E/mV
E/mV (calc.)
Ϫ1225
Ϫ1305
Ϫ1265
Ϫ1385
Ϫ1305
Ϫ1465
O
R1
3a
3b
3c
3d
3e
3f
Ϫ1227
Ϫ1297
Ϫ1279
Ϫ1386
Ϫ1280
Ϫ1487
3a R1 = R2 = R3 = R4 = H
3b R1 = Me, R2 = R3 = R4 = H
3c R2 = Me, R1 = R3 = R4 = H
3d R1 = R4 = Me, R2 = R3 = H
3e R2 = R3 = Me, R1 = R4 = H
3f R1 = R2 = R3 = R4 = Me
Ubiquinone
Ϫ1103
—
indicating the formation of a naphthoquinone. Based on this
finding, the Diels–Alder adducts were treated with silica to
catalyse the loss of SO2 and the air oxidation to 2,5,6,7,8-
pentamethylnaphtho-1,4-quinone 1g and 2,3,5,6,7,8-hexa-
methylnaphtho-1,4-quinone 3f, respectively. For the synthesis
of the vitamin K1,2 derivatives (2a–2h) containing an undecyl
chain in position 3, we used the radical alkylation of the corre-
sponding vitamin K3 derivatives with lauric acid (dodecanoic
acid) in the presence of (NH4)2S2O8 and AgNO3.21
lating the intensity of the delayed fluorescence emitted during
Ϫ
the life time of the state DϩQA to the reduction potentials
measured in DMF as described previously.22
In this work we have reported the synthesis of several vitamin
K derivatives covering a wide range of reduction potentials
(Ϫ43 to Ϫ384 mV relative to ubiquinone). Their functional
reconstitution to the QA site under conditions where ubiqui-
none is present at QB provides a powerful tool to study the
coupling between proton transfer and electron transfer reac-
tions in bacterial reaction centers. In addition, this pool of
vitamin K derivatives with its systematic variation of the substi-
tution pattern is useful for the investigation of steric properties
on the structure–function relationships of vitamin K dependent
enzymes.
Redox potentials
The redox potentials of methyl substituted vitamin K deriv-
atives were measured by cyclic voltammetry (Tables 1–3). The
redox potentials of vitamin K1, vitamin K2, 2,3-dimethyl-
naphtho-1,4-quinone 3a and 2-methyl-3-undecylnaphtho-1,4-
quinone 2h agree within the accuracy of the method ( 15 mV)
indicating that the effect of either an alkyl or isoprenyl sub-
stituent in position 3 on the reduction potential is very similar.
An increasing number of methyl substituents results in a
decrease in the reduction potential due to the electron donating
effect (ϩI effect) of alkyl substituents. The reduction potential
of the vitamin K1,2 derivatives is, in the case of the undecyl
substituent, ≈75 mV (see Tables 1 and 2), and in the case of a
methyl substituent, ≈85 mV (see Tables 1 and 3) smaller than
was found for the corresponding vitamin K3 analogues since an
additional alkyl substituent is present in position 3. For methyl
substituents in the aryl ring increments of ≈Ϫ80 mV for the
positions 5 and 8 (1a, 1d, 1e, 1g, 2a, 2d, 2e, 2g, 3b, 3d, 3f) and
≈Ϫ40 mV for the positions 6 and 7 (1b, 1c, 1f, 1g, 2b, 2c, 2f, 2g,
3c, 3e, 3f) were determined. These increments are additive and
allow predictions of the reduction potentials of other alkyl
substituted naphthoquinones. Column 3 of Tables 1, 2 and 3
refers to the calculated redox potentials using the increments
mentioned above and a value of Ϫ1140 mV for vitamin K3.
The in vitro reduction potentials cannot be related quanti-
tatively to the in situ reduction potentials of the quinone bound
at the QA site in the bacterial reaction center because these
depend subtly on the interactions with the protein environment
and the nature of the solvent. However, the effect of methyl
substituents is expected to be comparable. Work is in progress
to determine the actual in situ reduction potentials by corre-
Experimental
Cyclic voltammetry
Cyclic voltammetry was performed at a platinum working elec-
trode with a platinum counter electrode and silver reference
electrode using a potentiostat of local design (T = 293 K). The
voltammograms were recorded in DMF with 50 mM tetra-n-
butylammonium tetrafluoroborate as supporting electrolyte at
a voltage sweep rate of 20–100 mV sϪ1. Reduction potentials
for the redox couple Q/QϪ were reported against ferrocene
as internal standard. Under these conditions ferrocene has a
half-reduction potential of ϩ524 mV relative to the saturated
calomel electrode.23
General methods
Melting points were uncorrected. 1H NMR spectra were
recorded on a Bruker WM 250 spectrometer in CDCl3 solution
with tetramethylsilane as internal standard. Elemental analyses
were performed by the Analytische Abteilung des Chem.
Laboratoriums of the Albert-Ludwigs-Universität Freiburg.
Synthesis
Naphthalene oxidation (general procedure).19 These reactions
were performed with slight modifications of the method
1200
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described in the literature. CrO3 (3.0 g, 30 mmol) dissolved in
acetic acid (8 ml; 50%) was added dropwise at 10 ЊC over 1 h
to a solution of the naphthalene (6.4 mmol) in acetic acid (25
ml, 90%). The mixture was heated to 50 ЊC and stirred at this
temperature for 45 min. The reaction mixture was diluted with
ice–water (25 ml) to precipitate the quinone. The raw product
was filtered over a Büchner funnel, washed with 25 ml water,
dried in vacuo and recrystallized from methanol.
needles (6.8 g, 56%), mp 101–102 ЊC, (lit.,27 103 ЊC); δH (250
MHz, CDCl3) 2.09 (s, 6 H), 2.43 (s, 3 H), 7.47 (d, 1 H), 7.81
(s, 1 H), 7.92 (d, 1 H).
2,5,8-Trimethylnaphtho-1,4-quinone 1e. The naphthoquinone
1e was synthesized from hexa-2,4-diene and 2-methylbenzo-1,4-
quinone. Quinone 1e formed as yellow needles (2.9 g, 24%), mp
104–105 ЊC (C13H12O2 requires: C, 77.98; H, 6.04. Found: C,
77.92; H, 6.14%); δH (250 MHz, CDCl3) 2.08 (s, 3 H), 2.62
(s, 6 H), 6.65 (s, 1 H), 7.31 (s, 2 H).
2,3-Dimethylnaphtho-1,4-quinone 3a. Quinone 3a was syn-
thesized starting from 2,3-dimethylnaphthalene (1.00 g, 6.4
mmol) and gave yellow needles (1.00 g, 84%), mp 88 ЊC, (lit.,24
88–90 ЊC); δH (250 MHz, CDCl3) 2.12 (s, 6 H), 7.58–7.66 (m,
2 H), 7.95–8.08 (m, 2 H).
2,6,7-Trimethylnaphtho-1,4-quinone 1f. Product 1f was pre-
pared from 2,3-dimethylbuta-1,3-diene and 2-methylbenzo-1,4-
quinone and gave yellow needles (6.2 g, 51%), mp 105–106 ЊC,
(lit.,28 108 ЊC); δH (250 MHz, CDCl3) 2.12 (s, 3 H), 2.35 (s, 6 H),
6.70 (s, 1 H), 7.76 (s, 1 H), 7.80 (s, 1 H).
2,5-Dimethylnaphtho-1,4-quinone 1a. The quinone 1a was
prepared from 1,6-dimethylnaphthalene (1.00 g, 6.4 mmol) as
starting material. In this case the general procedure had to be
modified as follows. The reaction mixture was extracted three
times with diethyl ether, neutralized with saturated NaHCO3
solution and the collected organics were dried over MgSO4.
After evaporation of the solvent the remainder was purified by
column chromatography with cyclohexane–ethyl acetate (10:1)
as eluant. Crystallization from methanol gave 1a (0.25 g, 21%)
as yellow needles, mp 93 ЊC (lit.,25 95 ЊC); δH (250 MHz, CDCl3)
2.10 (s, 3 H), 2.68 (s, 3 H), 6.70 (s, 1 H), 7.40–7.55 (m, 2 H), 7.96
(d, 1 H).
2,3,5,8-Tetramethylnaphtho-1,4-quinone 3d. Quinone 3d was
synthesized from hexa-2,4-diene and 2,3-dimethylbenzo-1,4-
quinone and formed yellow needles (5.0 g, 39%), mp 122–
123 ЊC (C14H14O2 requires: C, 78.48; H, 6.57. Found: C, 78.34;
H, 6.73%); δH (250 MHz, CDCl3) 2.05 (s, 6 H), 2.61 (s, 6 H),
7.29 (s, 2 H).
2,3,6,7-Tetramethylnaphtho-1,4-quinone 3e. Oxidation of the
Diels–Alder adduct of 2,3-dimethylbuta-1,3-diene and 2,3-
dimethylbenzo-1,4-quinone yielded 3e as yellow needles (7.0 g,
54%), mp 169–170 ЊC, (lit.,29 170 ЊC); δH (250 MHz, CDCl3)
2.09 (s, 6 H), 2.33 (s, 6 H), 7.75 (s, 2 H).
2,6-Dimethylnaphtho-1,4-quinone 1b. The starting material
for 1b was 2,6-dimethylnaphthalene (1.00 g, 6.4 mmol).
Quinone 1b formed as yellow needles (0.94 g, 79%), mp 135–
136 ЊC, (lit.,25 136–137 ЊC); δH (250 MHz, CDCl3) 2.19 (s, 3 H),
2.49 (s, 3 H), 6.81 (s, 1 H), 7.52 (d, 1 H), 7.85 (s, 1 H), 7.99
(d, 1 H).
3,4-Bis(chloromethyl)-2,5-dimethylthiophene 4. Refluxing of
2,5-dimethylthiophene (30.0 g, 267 mmol) with trioxane (72.0 g,
801 mmol) in the presence of conc. HCl (100 ml) gave 4 (50.1 g,
90%), mp 73 ЊC , (lit.,30 73 ЊC); δH (250 MHz, CDCl3) 2.41 (s,
6 H), 4.62 (s, 4 H).31
2,7-Dimethylnaphtho-1,4-quinone 1c. The quinone 1c was
prepared from 2,7-dimethylnaphthalene (1.00 g, 6.4 mmol) and
formed as yellow needles (0.80 g, 67%), mp 111–112 ЊC (lit.,25
114 ЊC); δH (250 MHz, CDCl3) 2.14 (s, 3 H), 2.46 (s, 3 H), 6.75
(s, 1 H), 7.49 (d, 1 H), 7.84 (s, 1 H), 7.91 (d, 1 H).
2,3,4,5-Tetramethylthiophene 5. The intermediate product 4
(46.0 g, 220 mmol) was subsequently reduced with LiAH (25 g,
660 mmol) in absolute diethyl ether (600 ml) to give 5 (17.3 g,
56%), bp 73–74 ЊC/33 mbar (lit.,30 74–79 ЊC/20 mbar); δH (250
MHz, CDCl3) 1.93 (s, 6 H), 2.20 (s, 6 H).31
2,8-Dimethylnaphtho-1,4-quinone 1d. Starting from 1,7-
dimethylnaphthalene (1.00 g, 6.4 mmol) 1d was obtained as
yellow needles (0.38 g, 32%), mp 132 ЊC (lit.,26 135 ЊC); δH (250
MHz, CDCl3) 2.10 (s, 3 H), 2.69 (s, 3 H), 6.73 (s, 1 H), 7.40–7.57
(m, 2 H), 7.95 (d, 1 H).
2,3,4,5-Tetramethylthiophene dioxide 6. Compound 5 (16.3 g,
116 mmol), dissolved in CH2Cl2 (35 ml), was added dropwise
over an hour at 0 ЊC to a solution of MCPBA (60.0 g, 348
mmol) in CH2Cl2 (450 ml). Stirring was continued for 6 hours at
room temperature. The reaction mixture was cooled to Ϫ70 ЊC
and filtered off. The filtrate was washed twice with saturated
NaHCO3 solution and the solvent was evaporated off. The resi-
due was recrystallized from diethyl ether and gave colourless
needles (8.4 g, 42%), mp 116 ЊC, (lit.,32 116–117.5 ЊC); δH (250
MHz, CDCl3) 1.92 (s, 6 H), 2.02 (s, 6 H).
2,3,5-Trimethylnaphtho-1,4-quinone 3b. Quinone 3b was pre-
pared from 1,6,7-trimethylnaphthalene (0.50 g, 2.9 mmol).
Quinone 3b formed as yellow needles (0.31 g, 54%), mp 126 ЊC
(lit.,19 128 ЊC); δH (250 MHz, CDCl3) 2.15 (s, 6 H), 2.74 (s, 3 H),
7.44–7.58 (m, 2 H), 8.01 (d, 1 H).
2,5,6,7,8-Pentamethylnaphtho-1,4-quinone 1g. 2-Methyl-
benzo-1,4-quinone (0.73 g, 6.0 mmol) and 6 (1.03 g, 6.0 mmol)
were dissolved in chloroform (30 ml) and refluxed for 24 h. The
solvent was removed in vacuo and the black precipitate redis-
solved in diethyl ether. Silica was added and the suspension was
allowed to stand at room temperature overnight. The silica
adsorbed product was extracted twice with diethyl ether (2 × 50
ml). The collected extracts were washed with H2O and the
solvent was evaporated off. The crude product was purified
by column chromatography (silica, cyclohexane–ethyl acetate
10:1) and recrystallized from ethanol. Quinone 1g formed as
yellow needles (0.63 g, 46%), mp 107–108 ЊC (C15H16O2
requires: C, 78.92; H, 7.06. Found: C, 78.72; H, 6.88%); δH (250
MHz, CDCl3) 2.04 (s, 3 H), 2.27 (s, 6 H), 2.54 (s, 6 H), 6.56
(s, 1 H).
General procedure for Diels–Alder reactions and subsequent
oxidation
The freshly distilled diene (isoprene, hexa-2,4-diene or 2,3-
dimethylbuta-1,3-diene; 61 mmol) and the dieneophile (2-
methylbenzo-1,4-quinone or 2,3-dimethylbenzo-1,4-quinone;
61 mmol) were dissolved in ethanol (25 ml) and refluxed over
night. After cooling with ice the brown precipitate was
recrystallized from cyclohexane. The adduct was suspended
together with activated MnO2 (5.0 g, 57 mmol per 1.0 g of the
adduct) in petrol ether 60–70 ЊC (100 ml per 1.0 g of the adduct)
and refluxed. After 7 h the hot suspension was filtered off
and the remainder washed twice with petrol ether 60–70 ЊC. The
organics were collected and the solvent was evaporated off
in vacuo. The raw product was recrystallized from ethanol.
2,3,6-Trimethylnaphtho-1,4-quinone 3c. Starting from 2,3-
dimethylbenzo-1,4-quinone and isoprene, 3c formed as yellow
2,3,5,6,7,8-Hexamethylnaphtho-1,4-quinone 3f. The naphtho-
quinone 3f was prepared from 2,3-dimethylbenzo-1,4-quinone
J. Chem. Soc., Perkin Trans. 2, 1999, 1199–1202
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(0.82 g, 6.0 mmol) and 6 (1.03 g, 6.0 mmol) as described for 1g.
Quinone 3f gave yellow needles (0.78 g, 54%), mp 135–136 ЊC
(C16H18O2 requires: C, 79.31; H, 7.49. Found: C, 79.15; H,
7.56%); δH (250 MHz, CDCl3) 2.03 (s, 6 H), 2.28 (s, 6 H) 2.52
(s, 6 H).
81.31; H, 9.67. Found: C, 81.11; H, 9.87%); δH (250 MHz,
CDCl3) 0.81 (t, 3 H), 1.11–1.58 (m, 18 H), 2.10 (s, 3 H), 2.28
(s, 6 H), 2.53 (t, 2 H), 7.76 (s, 2 H).
2,5,6,7,8-Pentamethyl-3-undecylnaphtho-1,4-quinone 2g. The
alkylation of 1g (228 mg, 1.0 mmol) yielded 2g (140 mg, 38%)
as yellow needles, mp 72–73 ЊC (C26H38O2 requires: C, 81.62; H,
10.01. Found: C, 81.31; H, 10.42%); δH (250 MHz, CDCl3) 0.82
(t, 3 H), 1.10–1.51 (m, 18 H), 2.02 (s, 3 H), 2.25 (s, 6 H), 2.48
(t, 2 H) 2.50 (s, 6 H).
Alkylation of 1a–1g (general procedure)
The alkylation was performed with some modifications of a
literature method.33,24 A solution of (NH4)S2O8 (2.1 g, 9.1
mmol) in H2O (20 ml) was added dropwise using a perfusor (5
ml hϪ1) to a vigorously stirred solution of vitamin K3 or 1a–1g
(3.0 mmol), dodecanoic acid (840 mg, 4.2 mmol) and AgNO3
(720 mg, 4.2 mmol) in a mixture of acetonitrile (60 ml) and
water (30 ml). After a further 30 minutes of stirring the reaction
was allowed to cool to room temperature. The suspension was
extracted three times with diethyl ether. The extract was washed
with a saturated solution of NaHCO3 and dried over MgSO4.
After evaporation of the solvent the product was recrystallized
twice from methanol and if necessary further purified with
PTLC using a mixture of cyclohexane and ethyl acetate (5:1)
as eluant.
Acknowledgements
We would like to thank P. Gräber for support and encourage-
ment and R. Grèzes for helpful discussions. Our work was sup-
ported by a grant from the Deutsche Forschungsgemeinschaft
(La 816/3-1). R. S. gratefully acknowledges a Ph.D. scholarship
from the Graduiertenkolleg ‘Ungepaarte Elektronen’ of the
Deutsche Forschungsgemeinschaft.
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(s, 3 H), 2.65 (t, 2 H), 7.66–7.72 (m, 2 H), 8.04–8.12 (m,
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2,5-Dimethyl-3-undecylnaphtho-1,4-quinone 2a. The alkyl-
ation of 1a (186 mg, 1.0 mmol) yields 2a (129 mg, 38%) as
yellow needles, mp 62–63 ЊC (C23H32O2 requires: C, 81.13; H,
9.47. Found: C, 80.99; H, 9.53%); δH (250 MHz, CDCl3) 0.81
(t, 3 H), 1.13–1.55 (m, 18 H), 2.09 (s, 3 H), 2.55 (t, 2 H), 2.68
(s, 3 H), 7.37–7.50 (m, 2 H), 7.94 (d, 1 H).
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27 O. Kruber, Chem. Ber., 1939, 72, 1972.
2,6-Dimethyl-3-undecylnaphtho-1,4-quinone 2b. The synthesis
of 2b started with 1b (559 mg, 3.0 mmol). Quinone 2b (582 mg,
57%) was obtained as yellow needles, mp 77–78 ЊC (C23H32O2
requires: C, 81.13; H, 9.47. Found: C, 80.96; H, 9.54%); δH (250
MHz, CDCl3) 0.85 (t, 3 H), 1.14–1.45 (m, 18 H) 2.16 (s, 3 H),
2.45 (s, 3 H), 2.58 (t, 2 H), 7.48 (d, 1 H), 7.83 (s, 1 H), 7.95
(d, 1 H).
2,7-Dimethyl-3-undecylnaphtho-1,4-quinone 2c. The starting
material for 2c was 1c (559 mg, 3.0 mmol). Quinone 2c (623 mg,
61%) formed as yellow needles, mp 52–53 ЊC (C23H32O2
requires: C, 81.13; H, 9.47. Found: C 80.65; H, 9.36%); δH (250
MHz, CDCl3) 0.85 (t, 3 H), 1.13–1.49 (m, 18 H), 2.14 (s, 3 H),
2.44 (s, 3 H), 2.58 (t, 2 H), 7.48 (d, 1 H), 7.85 (s, 1 H), 7.96
(d, 1 H).
2,8-Dimethyl-3-undecylnaphtho-1,4-quinone 2d. The quinone
2d (204 mg, 41%) resulted from 1d (279 mg, 1.5 mmol) as yellow
needles, mp 72 ЊC (C23H32O2 requires: C, 81.13; H, 9.47. Found:
C 81.06; H, 9.54%); δH (250 MHz, CDCl3) 0.82 (t, 3 H), 1.12–
1.52 (m, 18 H), 2.10 (s, 3 H), 2.55 (t, 2 H), 2.67 (s, 3 H), 7.38–
7.55 (m, 2 H), 7.95 (d, 1 H).
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2,5,8-Trimethyl-3-undecylnaphtho-1,4-quinone 2e. Derivative
2e was synthesized from 1e (601 mg, 3.0 mmol). Quinone 2e
(425 mg, 40%) crystallized as yellow plates, mp 49–50 ЊC
(C24H34O2 requires: C, 81.31; H, 9.67. Found: C, 80.86;
H, 9.79%); δH (250 MHz, CDCl3) 0.82 (t, 3 H), 1.12–1.51 (m,
18 H), 2.08 (s, 3 H), 2.53 (t, 2 H), 2.61 (s, 6 H), 7.28 (s, 2 H).
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99.
2,6,7-Trimethyl-3-undecylnaphtho-1,4-quinone 2f. The quin-
one 2f (457 mg, 43%) was prepared from 1f (601 mg, 3.0 mmol)
and formed as yellow needles, mp 92 ЊC (C24H34O2 requires: C,
Paper 9/00190E
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J. Chem. Soc., Perkin Trans. 2, 1999, 1199–1202