Study of radical decarboxylation toward functionalization of naphthoquinones

Article abstract of DOI:10.1002/ejoc.200700135

In order to obtain functionalized naphthoquinones, a systematic study of the Kochi-Anderson procedure for the alkylation of quinones is presented. While linear amino acids of different lengths were good substrates for this decarboxylation procedure, chira

Full text of DOI:10.1002/ejoc.200700135

FULL PAPER
DOI: 10.1002/ejoc.200700135
Study of Radical Decarboxylation Toward Functionalization of
Naphthoquinones
Claude Commandeur,[a] Céline Chalumeau,[a] Jean Dessolin,*[a] and Michel Laguerre[a]
Dedicated to the memory of Anne Chobelet
Keywords: Naphthoquinones / Radical decarboxylation / Kochi–Anderson procedure / Amino acids / Radical reactions
In order to obtain functionalized naphthoquinones, a system-
atic study of the Kochi–Anderson procedure for the alky-
lation of quinones is presented. While linear amino acids of
different lengths were good substrates for this decarboxyl-
ation procedure, chiral α-amino acids were unsuccessful sub-
strates. The best reaction conditions were evaluated with β-
alanine and then applied to a series of carboxylic acids to
obtain chemical diversity on the naphthoquinones. We ob-
served that the substitution of the acids is critical for the alky-
lation, and that it was possible to realize a double alkylation
with 1,4-naphthoquinone, even with different reactants. The
Barton procedure was attempted on some substrates to com-
pare with our results, but no reaction was observed, no mat-
ter which radical trap was used.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
method with AgI and ammonium persulfate as a radical
initiator because of its reported ease of handling and its
efficiency in synthesizing amine-functionalized quinones.
This little-known procedure resembles earlier work by Ko-
chi and Anderson,[10] which involved an excess of a suitable
carboxylic acid mixed with a quinone in a homogeneous
H2O/CH3CN mixture. Such a procedure, with variations in
the quinone/acid ratio was shown to be successful in the
preparation of natural products[11] and was sometimes re-
ported as the Minisci reaction when performed in a two-
phase solvent mixture.[12]
Introduction
Quinones are present in many natural products and have
been widely used in medicinal chemistry due to their broad
spectrum of biological activity including antimicrobial, an-
tibiotic, antiviral, antimalarial, and anticancer activities.[1,2]
In the course of our ongoing research in the field of anti-
cancer drugs, we are interested in synthesizing simple naph-
thoquinone derivatives incorporating a chemical group that
would allow further functionalization.
Examples of radical addition to quinones in the literature
are numerous, either with organotellurium compounds[3] or
mediated by metal ions like MnIII or CeIV as a way to initi-
ate a carbon radical.[4,5] To date, the most common pro-
cedure is the Barton method that uses esters as radical pre-
cursors.[6] While the alkylation of a variety of quinones gave
good yields with this reaction,[7,8] it still suffers from serious
drawbacks. The sensitive thiohydroxamic ester has to be
prepared prior to the addition, which usually leads to a Scheme 1. Barton procedure adducts.
mixture of two quinone adducts (Scheme 1) under oxidative
conditions (most commonly obtained by a quinone excess).
Moreover, in the case of naphthoquinones, desulfurization Results and Discussion
of the major product proved to be difficult if not imposs-
ible.[7] Previous work in the field of naphthoquinone func-
tionalization[7,9] led us to consider a radical decarboxylation
Preliminary Amino Acid Addition
Our first aim was to obtain a naphthoquinone moiety
bearing a lateral chain terminated by an amine. Menadione
(2-methyl-1,4-naphthoquinone, M) was chosen since only
the carbon atom at position 3 could react. Boc-glycine was
first allowed to react with M to lead to the corresponding
functionalized quinone in a moderate yield under pre-
viously reported conditions. The homologous linear amino
[a] UMR 5248 CBMN, CNRS – Université Bordeaux 1 – ENITAB,
IECB,
2 rue Robert Escarpit, 33607 Pessac, France
Fax: +33-5-40002215
E-mail: j.dessolin@iecb.u-bordeaux.fr
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2007, 3045–3052
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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C. Commandeur, C. Chalumeau, J. Dessolin, M. Laguerre
FULL PAPER
acids with 2–4 methylene groups, namely Boc-β-alanine, alkyl side-chain in Boc-glycine, while explaining its de-
Boc-aminobutyric, and Boc-aminopentanoic acid, were creased inclination to oxidation and reactivity (Scheme 2)
also added under the same conditions in order to compare does not substantiate the stability of the amine protecting
our results with the initial report (Scheme 2).[9] Our results group. Another possibility could be that the alkyl substitu-
differed slightly from the original study. The best compro- ent in a chiral α-amino acid could change the course of
mise between reaction yield and M recycling was obtained the reaction to favor a one-electron transfer to the quinone
with one methylene unit (1), while three methylene units led instead of a radical addition.[16]
to the best alkylation yield (3). One might consider these
yields as poor, but they correspond to the purified adducts
and do not take into account the low conversion rate of the
quinone, which was easily recovered by chromatography
and recycled (yields based on conversions for 1 and 3 were
82% and 80%, respectively).
Scheme 3. Radical addition of α-amino acids to M.
Assessment of the Reaction Parameters
The mechanism of the reaction involves the generation
of the carbon radical through an AgII-assisted oxidative de-
carboxylation of the carboxylic acid. Nucleophilic addition
of the radical to an electron-deficient naphthoquinone, fol-
lowed by rearomatization can allow carbon alkylation
(Scheme 5). To determine the validity of the procedure, we
Scheme 2. Radical addition of linear carboxylic acids.
varied the parameters of the reaction of readily available
We then attempted to introduce chiral substituents into Boc-β-alanine with M. The experimental procedure was re-
the naphthoquinone ring. This might be achieved by the alized in a homogeneous solvent mixture, which insured sol-
same method, with a protected α-amino acid (Scheme 3). ubility of all reaction components (see Experimental Sec-
Surprisingly, neither Boc-alanine nor Boc-valine led to the tion). In the case of the Minisci reaction, either a two-phase
desired adducts, while a substantial quantity of menadione mixture[12,17] or a strong acidic medium has been used.[15]
was recycled after purification. No trace of the α-amino While the latter conditions were unsuitable with a tert-butyl
acids, neither decarboxylated nor unreacted, was recovered, carbamate protecting group and led to unpredictable results
which led us to suppose that rearranged substrates were re- in the case of α-amino acids, they also gave an unexpected
moved during workup. These unsuccessful attempts could (and in our case undesired) regioselectivity when M was
be the result of a lack of reactivity of the carbon radical used.[12] In all reports related to the Minisci procedure, the
bearing both an alkyl group and a carbamate-protected ammonium persulfate was initially present or quickly added
amino group. Indeed, the mild electron-donor effect of the to the reaction mixture. In our hands, the radical initiator
menadione methyl group can decrease the reactivity of the had to be slowly added to the medium to ensure a correct
intermediate radical, leading to side reactions or degrada- balance between conversion of the quinone and addition
tion.[13] Among the expected degradation pathways, the oxi- yield (Table 1, Entries 1, 5, and 6). Changing the amount of
dation of the amidoalkyl radical has been reported for its carboxylic acid also diminished the reaction yield (Table 1,
synthetic usefulness, and should lead to a tert-butyl carba- Entries 1–4). Concentration of the medium in order to in-
mate (Scheme 4).[14] However, this amine was not detected, crease the primary radical reactivity also led to a less satis-
and we suppose the carbamate protecting group was un- factory result (Table 1, Entry 7). Moreover, it appeared that
stable under the reaction conditions.[15] The absence of an these modifications were also accompanied by a decreased
Scheme 4. Behavior of carbon radicals derived from carboxylic acids.
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Radical Decarboxylation Toward Functionalization of Naphthoquinones
FULL PAPER
recycling of the naphthoquinone (Table 1, Entries 3–7), tyric acid and NQ led to M or 11 as expected but also
whereas carboxylic acid recovery after workup was deceiv- yielded the double-addition compounds 9 (Table 2, Entry 4)
ing. Unexpectedly, the initial reaction conditions were the and 12 (Table 2, Entry 5). This double addition was not ob-
most suitable to functionalize the quinone. To the best of served with more highly substituted acids (Table 2, En-
our knowledge, no previous study had considered the prob- try 6), confirming the importance of steric hindrance on the
lem.
reaction outcome.
Table 2. Addition of various carboxylic acids to M or NQ.
Scheme 5. Kochi–Anderson addition to naphthoquinones.
Entry Quinone
Carboxylic acid
Compound,
Yield [%]
Table 1. Influence of addition parameters on Boc-β-alanine ad-
dition.
1
2
M
M
CH3–COOH
iPr–COOH
(CH3)3C–COOH
CH3–COOH
9, 38
10, 32
Entry
Acid
[equiv.]
Addition Yield of product Yield of M Yield of acid
3
M
no addition
M, 36
[%][a]
[%][a]
4[a]
NQ
time [h]
[%]
9, 23
1
2
3
4
5
3
1.3
2
6
3
2
2
2
2
0.5
5
43
17
31
33
7
51
67
24
7
39
19
40
12
15
24
22
1
5[a]
NQ
iPr–COOH
11, 42
12, 9
6
7
8
9
10
NQ
M
(CH3)3C–COOH
BrCH2–COOH
MeO–CH2–COOH
13, 25
no addition
no addition
no addition
7, 10
M
6
7[b]
3
3
25
25
12
15
M
MeOOC–CH2–COOH
HO2C–CH(CH3)–CH2–CO2H
2
M
[a] After workup and purification. [b] More concentrated than in
Entry 1.
8, 3
11
12
M
MeOOC–(CH2)2–COOH
MeOOC–(CH2)2–COOH
Boc–β-Ala–OH
14, 58
NQ
NQ
NQ
15, 28
13[b]
14[c]
16, 27
Boc–β-Ala–OH
16, 26
17, 12
Reaction of Different Substrates with Naphthoquinones
15
16
NQ
18
16
NQ
Boc–NH–CH2–CO2H
Boc–β-Ala–OH
Boc–NH–CH2–CO2H
Boc–NH–CH2–CO2H and
Boc–β-Ala–OH
18, 47
19, 76
Considering these results, we thought it could be impor-
tant to determine the behavior of differently functionalized
substrates toward the Kochi–Anderson procedure. Either a
primary, secondary, or tertiary carbon-radical-containing
acid was first allowed to react with M and 1,4-naphthoqui-
none (NQ, Table 2, Entries 1–6). Interestingly, reactions
with acetic and isobutyric acids yielded the alkylated qui-
nones, while pivaloic acid gave no conversion in the case of
M. These results need to be compared with those obtained
from a previous study in which no addition occurred when
thiocarbonyl derivatives leading to the three types of radi-
17
19, 45
18[d]
18, 37
20, 19
[a] Yields were calculated from NMR spectra (see Experimental
Section). [b] 3 equiv. of carboxylic acid, 1.3 equiv. of (NH4)2S2O8,
and 0.3 equiv. of AgNO3. [c] 6 equiv. of carboxylic acid, 2.6 equiv.
of (NH4)2S2O8, and 0.6 equiv. of AgNO3. [d] 3 equiv. of each car-
boxylic acid, 2.6 equiv. of (NH4)2S2O8, and 0.6 equiv. of AgNO3.
Reactions of three carboxylic acids bearing electron-
cals were used with M according to the Barton methodol- donating or electron-withdrawing groups only resulted in
ogy.[8c] On the contrary, reaction of pivaloic acid with NQ the recycling of the starting quinone (Table 2, Entries 7–9).
led to the desired adduct (Table 2, Entry 6), which might be Introduction of a second methylene unit in the starting ma-
explained by a lack of steric hindrance from the methyl terial was more successful, as demonstrated by Table 2, En-
group present in M. The reaction between acetic or isobu- tries 10–13.
Eur. J. Org. Chem. 2007, 3045–3052
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C. Commandeur, C. Chalumeau, J. Dessolin, M. Laguerre
FULL PAPER
As expected, the reaction of M with racemic 2-methyl- The Barton Procedure
succinic acid led to a regioisomeric mixture, albeit with a
poor yield (Table 2, Entry 10), the major product 7 resulting
The Barton decarboxylation procedure was then applied
to some carboxylic acids in order to allow comparison with
our results. Preparation of the thiopyridone derivatives of
monoethyl malonate or monomethyl succinate led to un-
stable compounds (Figure 2, 21 and 22). No purification
was possible with either thiohydroxamic ester since a color
shift was observed when silica filtration was attempted, and
a complex decomposition mixture was eluted. Direct ad-
dition of the crude esters 21 and 22 to M under UV light
led only to recovered quinone. Boc-alanine ester 23 proved
more stable, but no reaction occurred under irradiation.
Even when the well-known radical trap phenyl vinyl sul-
fone[18] was subjected to the same conditions, it was reco-
vered unreacted. Neither addition products nor amino acid
derivatives were detected after purification. The Boc-β-ala-
nine ester 24 was also directly treated with M and led to
a complex mixture, which probably contained the desired
addition compound as a trace among unknown species.[19]
from the formation of the secondary radical (Figure 1).
Figure 1. Products of 2-methylsuccinic acid addition to M.
Monomethylsuccinic acid led to a much better yield with
M than with NQ (Table 2, Entries 11–12). This is fully in
accordance with a greater stability of the intermediate semi-
quinone radical obtained in the case of the 2-methyl-substi-
tuted aromatic ring (Scheme 5). The reaction between Boc-
β-alanine and NQ (Table 2, Entry 13) gave only monoalkyl-
ated adduct 16 but in a lower yield than that obtained with
M, which confirms the previous observation. We surmised
that a double addition on NQ might be possible if the
amount of carboxylic acid was increased. By reaction of
6 equiv. of Boc-β-alanine, we obtained both mono- and di-
substituted NQ in a 2:1 ratio (Table 2, Entry 14). In that
case, the yield of isolated 16 (26%) was similar to that ob-
tained when performing the reaction under the usual condi-
tions (27%, Table 2, Entry 13), despite the excess of carbox-
ylic acid. However, the yield obtained for the dialkylated
adduct 17 (12%) was not consistent with a higher stability
of the substituted quinone, which would then allow a sec-
ond radical addition.
Figure 2. Thiohydroxamic esters used in the Barton procedure.
From these experiments, with the better known decar-
boxylation procedure, we observed either a lack of stability
and reactivity toward the desired compounds or the forma-
tion of complex mixtures, which were difficult to purify.
This latter experiment suggested the possibility of intro-
ducing some diversity on the NQ structure by successively
treating different carboxylic acids. In order to test this hy-
pothesis, Boc-glycine was added to NQ to yield the desired
substrate 18 in a better yield (47%) than that obtained with
Conclusions
We have described the reactivity of versatile carboxylic
M (37%, Scheme 2). A second substituent was then added acids toward NQ and M, with the rarely reported Kochi–
(Table 2, Entry 16) by a reaction between Boc-β-alanine Anderson decarboxylation procedure. We have first as-
and 18 to yield the expected dialkylated adduct 19 in good sessed the best reaction conditions with an N-Boc-protected
yield. Reversing the order of the double addition by treating linear β-amino acid. While the addition of a chiral α-amino
the protected glycine with 16 (Table 2, Entry 17) led to the acid proved impossible with this method, we had no more
desired doubly substituted naphthoquinone 19 but in a success with the Barton procedure. Nevertheless, we were
much lower yield. Finally, the simultaneous addition of able to easily prepare new functionalized naphthoquinone
3 equiv. of Boc-glycine and 3 equiv. of Boc-β-alanine was derivatives in reasonable yields. Monosubstituted com-
attempted with NQ (Table 2, Entry 18) to yield only the pounds resulted from the reaction of M, and both mono-
mono- and dialkylated adducts of the former carboxylic and disubstituted analogs resulted from the reaction of NQ.
acid. In this case, no addition of Boc-β-alanine was ob- Introduction of different moieties in the latter case was pos-
served, which confirmed the better reactivity of the carbon sible and opened the door to structural diversity. All new
radical formed from Boc-glycine.
compounds reported herein allow for further variation
The results presented in Table 2 demonstrate the dra- through the introduced chemical functionality. We have
matic influence of the substitution on the carbon atom noted the importance of the quinone substitution (M com-
bearing the carboxylic acid group. It was quite surprising pared to NQ), as well as the carbon-radical stability on the
to observe no reaction with Boc-protected α-amino acids reaction outcome (Table 2). So far, we believe that both pa-
(Scheme 3), while Boc-glycine led to the desired compound. rameters are equally important to alkylation with the
Moreover, Table 2, Entries 7–9 suggest that a functionalized Kochi–Anderson procedure. Further work is currently in
single methylene group was unsuitable for this reaction, progress to determine whether replacement of the N-Boc
Table 2, Entries 10–12 seem to confirm this hypothesis.
group could lead to the addition of chiral α-amino acids.
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Radical Decarboxylation Toward Functionalization of Naphthoquinones
FULL PAPER
CCH2 and C(O)CCH3], 155.9 (NHCO), 145.1 (=CCH3), 143.9
(=CCH2), 133.4 and 133.3 [2ϫCHCC(O)], 132.1 and 132.0
[2ϫCHCC(O)], 126.3 and 126.2 [2ϫCHCHCC(O)], 79.3
[C(CH3)3], 39.4 (CH2NH), 28.3 [C(CH3)3], 27.8 (CH2CH2NH),
Experimental Section
General Techniques: All reagents were commercially obtained (Ald-
rich, Acros) at the highest commercial quality and used without
further purification. Yields refer to spectroscopically (1H NMR)
homogeneous materials. Reactions were monitored by thin-layer
12.9 (=CCH ) ppm. IR (ATR): ν = 3378, 2971, 1686, 1659, 1594,
˜
3
1520, 1336, 1251, 1162, 767, 683, 662 cm–1. HRMS: calcd. for
chromatography carried out on 0.25 mm E. Merck silica gel plates
(60F-254) with UV light for detection and p-anisaldehyde or ninhy-
drin solution and heat as developing agents. E. Merck silica gel (60,
particle size 0.040–0.063 mm) was used for flash chromatography.
NMR spectra were recorded with Bruker 300 MHz or 400 MHz
instruments and calibrated with residual non-deuterated solvent as
an internal reference. Chemical shifts are reported in ppm down-
field from the internal reference. The following abbreviations are
used for the multiplicities: s = singlet, d = doublet, t = triplet, q =
quartet, m = multiplet, br. = broad. IR spectra were recorded with
a Bruker Tensor 27 spectrophotometer with ATR (Attenuated To-
tal Reflection). Absorbance frequencies are given at the maximum
of intensity in cm–1. High resolution mass spectra (HRMS) were
recorded with a WATERS ESI-TOF LCT Premier spectrometer
under electrospray (ESI) conditions.
C18H21NNaO4 324.1368; found 338.1335; ∆ = 3.9 ppm.
tert-Butyl [3-(3-Methyl-1,4-dioxo-1,4-dihydronaphthalen-2-yl)pro-
pyl]carbamate (3):[9] This compound was prepared according to the
general procedure starting from M (1.050 mg, 6.10 mmol) and was
purified by flash chromatography on silica gel with CH2Cl2 as the
eluent to furnish the desired product as an orange solid (1.04 g,
1
3.16 mmol, 52% yield). H NMR (300 MHz, CDCl3): δ = 8.07 [m,
2 H, CHCC(O)], 7.69 [m, 2 H, CHCHCC(O)], 4.81 (br. s, 1 H,
NH), 3.17 (m, 2 H, CH2N), 2.68 (m, 2 H, CH2CAr), 2.19 [s, 3 H,
C(O)CCH3], 1.68 (m, 2 H, CH2CH2N), 1.44 [s, 9 H, OC(CH3)3]
ppm. 13C NMR (100 MHz, CDCl3): δ = 184.9 [C(O)CCH2], 184.6
[C(O)CCH3], 155.9 (NHCO), 146.3 (=CCH3), 143.6 (=CCH2),
133.3 and 133.2 [2ϫCHCC(O)], 131.9 and 131.8 [2ϫCHCC(O)],
126.1 and 126.0 [2ϫCHCHCC(O)], 78.9 [C(CH3)3], 40.1
(CH2NH), 28.7 (CH2CH2N), 28.3 [C(CH3)3], 24.0 (CH2CAr), 12.5
Synthetic Procedures
(=CCH ) ppm. IR (ATR): ν = 3388, 2976, 1694, 1657, 1595, 1516,
˜
3
1294, 1251, 1168, 787, 716 cm–1. HRMS: calcd. for C19H23NNaO4
General Procedure for Radical Decarboxylation: To a solution of
quinone (1 equiv., 0.1 ) in CH3CN/H2O (2:1), the carboxylic acid
(3 equiv.) was added, and the mixture was warmed to 65 °C. Silver
nitrate (0.3 equiv.) was added to the stirred mixture. A homogen-
eous solution of ammonium persulfate (1.3 equiv., 0.3 ) in
CH3CN/H2O (2:1) was added dropwise over 2 h. At the end of the
addition, the reaction mixture was continually stirred at 65 °C for
1 h. The mixture was then cooled to room temperature, extracted
with CH2Cl2, and washed with brine. The organic layer was dried
with MgSO4, filtered through Celite, and concentrated under re-
duced pressure. The crude product was purified by flash
chromatography on silica gel.
352.1525; found 352.1544; ∆ = 5.5 ppm.
tert-Butyl [4-(3-Methyl-1,4-dioxo-1,4-dihydronaphthalen-2-yl)butyl]-
carbamate (4):[9] This compound was prepared according to the
general procedure starting from M (450 mg, 2.61 mmol), and its
purification on silica gel with C6H12/AcOEt (7:3) led to the desired
1
compound as an orange solid (262 mg, 0.76 mmol, 29% yield). H
NMR (300 MHz, CDCl3): δ = 8.04 [dd, J = 5.4 and 3.3 Hz, 2 H,
CHCC(O)], 7.67 [dd, J = 5.4 and 3.3 Hz, 2 H, CHCHCC(O)], 4.83
(br. s, 1 H, NH), 3.17 (m, 2 H, CH2NH), 2.64 (t, J = 7.5 Hz, 2 H,
CH2CAr), 2.18 [s,
CH2CH2CH2N), 1.44 [s,
3
H, C(O)CCH3], 1.64–1.48 (m,
4 H,
9
H, OC(CH3)3] ppm. 13C NMR
(75 MHz, CDCl3): δ = 185.0 and 184.4 [C(O)CCH2 and C(O)-
CCH3], 155.9 (NHCO), 146.7 (=CCH3), 143.2 (=CCH2), 133.15
and 133.14 [2ϫCHCC(O)], 131.92 and 131.91 [2ϫCHCC(O)],
126.1 and 126.0 [2ϫCHCHCC(O)], 78.8 [C(CH3)3], 40.0
(CH2NH), 30.1 (CH2CH2N), 28.2 [C(CH3)3], 26.4 and 25.6
(CH2CH2CH2CH2NH), 12.4 (=CCH3) ppm. HRMS: calcd. for
C20H25NNaO4 366.1681; found 366.1699; ∆ = 4.8 ppm.
tert-Butyl
(3-Methyl-1,4-dioxo-1,4-dihydroaphthalen-2-ylmethyl)-
carbamate (1): This compound was prepared according to the gene-
ral procedure starting from M (1000 mg, 5.80 mmol) and was puri-
fied by flash chromatography on silica gel with CH2Cl2 as the elu-
ent. The pure compound was obtained as an orange solid (651 mg,
2.16 mmol, 37% yield). 1H NMR (400 MHz, CDCl3): δ = 8.08 [dd,
J = 5.6 and 3.2 Hz, 2 H, CHCC(O)], 7.72 [dd, J = 5.6 and 3.2 Hz,
2 H, CHCHCC(O)], 5.18 (br. s, 1 H, NH), 4.31 (d, J = 6.4 Hz, 2
H, CH2NH), 2.36 [s, 3 H, C(O)CCH3], 1.41 [s, 9 H, OC(CH3)3]
ppm. 13C NMR (75 MHz, CDCl3): δ = 185.5 and 185.4 [C(O)-
CCH2 and C(O)CCH3], 155.6 (NHCO), 145.1 (=CCH3), 142.0
(=CCH2), 133.7 and 133.6 [2ϫCHCC(O)], 132.1 and 131.8
[2ϫCHCC(O)], 126.5 and 126.1 [2ϫCHCHCC(O)], 79.6
[C(CH3)3], 37.1 (CH2NH), 28.3 [C(CH3)3], 12.6 (=CCH3) ppm. IR
3-Methyl-3-(3-methyl-1,4-dioxo-1,4-dihydronaphthalen-2-yl)butyric
Acid (7) and 2-Methyl-3-(3-methyl-1,4-dioxo-1,4-dihydronaphthalen-
2-yl)propionic Acid (8): These compounds were prepared according
to the general procedure starting from M (300 mg, 1.74 mmol), and
flash chromatography on silica gel with C6H12/AcOEt (1:1) as the
eluent led to an inseparable 3:1 mixture (orange solid) of the two
regioisomers 7 and 8 (60 mg, 0.23 mmol, 13% yield). 1H NMR
(300 MHz, CDCl3): δ = 8.03 [m, 4 H, CHCC(O)], 7.67 [m, 4 H,
CHCHCC(O)], 3.50 [m, 1 H, CHCH3 (7)], 3.06 [m, 2 H, parts of
CH2 (7) and CH2 (8)], 2.82 [m, 3 H, parts of CH2 (7) and CH2 (8),
CHCH3 (8)], 2.23 [s, 3 H, C(O)CCH3 (7)], 2.19 [s, 3 H, C(O)CCH3
(8)], 1.36 [d, J = 6.9 Hz, 3 H, CHCH3 (7)], 1.22 [d, J = 6.3 Hz, 3
H, CHCH3 (8)] ppm. 13C NMR (75 MHz, CDCl3) of 7: δ = 185.3
and 184.8 [C(O)CCH2 and C(O)CCH3], 178.6 (COOH), 148.2
(=CCH3), 144.2 (=CCH2), 133.5 and 133.3 [2ϫCHCC(O)], 132.5
and 131.8 [2ϫCHCC(O)], 126.21 and 126.19 [2ϫCHCHCC(O)],
38.9 (CH2COOH), 31.6 (CHCH3), 19.1 (CHCH3), 12.4 (=CCH3)
ppm. 13C NMR (75 MHz, CDCl3) of 8: δ = 185.1 and 184.7 [C(O)-
CCH2 and C(O)CCH3], 181.6 (COOH), 145.1 (=CCH3), 144.1
(=CCH2), 133.53 and 133.51 [2ϫCHCC(O)], 132.1 and 132.0
[2ϫCHCC(O)], 126.4 and 126.3 [2ϫCHCHCC(O)], 38.8
(ATR): ν = 3385, 2924, 1691, 1650, 1592, 1520, 1281, 1248, 1155,
˜
783, 715, 690, 613 cm–1. HRMS: calcd. for C17H19NNaO4
324.1212; found 324.1211; ∆ = 0.2 ppm.
tert-Butyl [2-(3-Methyl-1,4-dioxo-1,4-dihydro-naphthalen-2-yl)ethyl]-
carbamate (2):[9] This compound was prepared according to the
general procedure starting from M (260 mg, 1.51 mmol) and was
purified by flash chromatography on silica gel with C6H12/AcOEt
(9:1) as the eluent. The pure compound was obtained as an orange
solid (205 mg, 0.65 mmol, 43% yield). 1H NMR (300 MHz,
CDCl3): δ = 8.04 [dd, J = 5.7 and 3.6 Hz, 2 H, CHCC(O)], 7.67
[dd, J = 5.7 and 3.6 Hz, 2 H, CHCHCC(O)], 4.81 (br. s, 1 H, NH),
3.29 (pseudo q, J = 6.6 Hz, 2 H, CH2NH), 2.86 (t, J = 6.6 Hz, 2
H, CH2CH2N), 2.22 [s, 3 H, C(O)CCH3], 1.37 [s, 9 H, OC(CH3)3]
ppm. 13C NMR (75 MHz, CDCl3): δ = 185.0 and 184.8 [C(O)-
Eur. J. Org. Chem. 2007, 3045–3052
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3049

C. Commandeur, C. Chalumeau, J. Dessolin, M. Laguerre
(CHCH3), 30.8 [CH2CH(CH3)], 17.0 (CHCH3), 13.2 (=CCH3) 1330, 1306, 1248, 1201, 1125, 892, 785, 719, 670, 626 cm–1. We were
FULL PAPER
ppm. IR (ATR): ν = 2924, 1702, 1651, 1591, 1292, 1234, 922, 863,
unable to detect the molecular ion peak by HRMS, as was the case
for 9 and 10.
˜
716, 688 cm–1. HRMS: calcd. for C15H14NaO4 281.0766; found
281.0774; ∆ = 5.6 ppm. HRMS: calcd. for C15H13Na2O4 303.0609;
found 303.0611; ∆ = 0.6 ppm.
Methyl
3-(3-Methyl-1,4-dioxo-1,4-dihydronaphthalen-2-yl)propi-
onate (14): This compound was prepared according to the general
procedure starting from M (1 g, 5.81 mmol), and its purification
on silica gel with CH2Cl2 as the eluent gave the pure compound as
2,3-Dimethyl-1,4-naphthoquinone (9).[20] Method A: This compound
was prepared according to the general procedure starting from M
(400 mg, 2.32 mmol) and was purified by flash chromatography on
silica gel with C6H12/AcOEt (95:5) as the eluent. The pure com-
pound was obtained as a yellow solid (165 mg, 0.89 mmol, 38%
yield). Method B: This compound was prepared according to the
general procedure starting from NQ (316 mg, 2.00 mmol) and was
purified by flash chromatography on silica gel with C6H12/AcOEt
(95:5) as the eluent. A mixture of NQ, M, and 9 was obtained as
a yellow solid (240 mg) with M/9 = 9:5 (see Supporting Infor-
a
yellow solid (875 mg, 3.39 mmol, 58% yield) 1H NMR
(400 MHz, CDCl3): δ = 8.07 [m, 2 H, CHCC(O)], 7.69 [m, 2 H,
CHCHCC(O)], 3.68 (s, 3 H, CO2CH3), 2.97 (t, J = 8.0 Hz, 2 H,
=CCH2), 2.55 (t, J = 8.0 Hz, 2 H, CH2CO2Me), 2.22 (s, 3 H,
=CCH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 185.0 [C(O)-
CCH2], 184.4 [C(O)CCH3], 172.8 (CO2CH3), 145.1 (=CCH3), 144.3
(=CCH2), 133.45 and 133.44 [2ϫCHCC(O)], 132.10 and 132.06
[2ϫCHCC(O)], 126.30 and 126.28 [2ϫCHCHCC(O)], 51.8
(CO2CH3), 32.6 (CH2CO2CH3), 22.8 (CH2CH2CO2CH3), 12.7
1
mation). H NMR (400 MHz, CDCl3): δ = 8.08 [dd, J = 5.6 and
3.2 Hz, 2 H, CHCC(O)], 7.68 [dd, J = 5.6 and 3.2 Hz, 2 H,
(=CCH ) ppm. IR (ATR): ν = 2923, 1733, 1656, 1594, 1437, 1377,
˜
3
CHCHCC(O)], 2.18 [s, 6 H, C(O)CCH3] ppm. 13C NMR (75 MHz,
1330, 1291, 1171, 790, 715 cm–1. HRMS: calcd. for C15H14NaO4
CDCl3):
δ = 184.7 (2ϫC=O), 143.3 (2ϫ=CCH3), 133.2
281.0790; found 281.0781; ∆ = 3.1 ppm.
[2ϫCHCC(O)], 132.0 [2ϫCHCC(O)], 126.1 [2ϫCHCHCC(O)],
Methyl 3-(1,4-Dioxo-1,4-dihydronaphthalen-2-yl)propionate (15):[22]
This compound was prepared according to the general procedure
starting from NQ (97 mg, 0.61 mmol), and its purification on silica
gel with C6H12/AcOEt (9:1) as the eluent gave the pure compound
as a yellow solid (40 mg, 0.17 mmol, 28% yield). 1H NMR
(400 MHz, CDCl3): δ = 8.08 [m, 2 H, CHCC(O)], 7.73 [m, 2 H,
CHCHCC(O)], 6.82 (s, 1 H, CH=CCH2), 3.69 (s, 3 H, CO2CH3),
2.91 (t, J = 7.2 Hz, 2 H, =CCH2), 2.66 (t, J = 7.2 Hz, 2 H,
CH2CO2Me) ppm. 13C NMR (75 MHz, CDCl3): δ = 184.86 and
184.84 [2ϫC(O)], 172.5 (CO2CH3), 149.6 (=CCH2), 135.3
(CH=CCH2), 133.8 and 133.7 [2ϫCHCC(O)], 132.1 and 132.0
[2ϫCHCC(O)], 126.6 and 126.1 [2ϫCHCHCC(O)], 51.8
(CO2CH3), 32.0 (CH2CO2CH3), 25.1 (CH2CH2CO2CH3) ppm. IR
12.8 (2ϫ=CCH ) ppm. IR (ATR): ν = 2924, 1656, 1620, 1592,
˜
3
1458, 1371, 1334, 1293, 790, 695 cm–1. HRMS: calcd. for C12H11O2
181.0759; found 181.0756; ∆ = 1.6 ppm (the molecular ion peak is
very weak).
2-Isopropyl-3-methyl-1,4-naphthoquinone (10):[3] This compound
was prepared according to the general procedure starting from M
(150 mg, 0.87 mmol) and was purified by flash chromatography on
silica gel with C6H12/AcOEt (95:5) as the eluent. The pure com-
pound was obtained as a yellow solid (60 mg, 0.28 mmol, 32%
yield). 1H NMR (400 MHz, CDCl3): δ = 8.04 [dd, J = 5.6 and
3.2 Hz, 2 H, CHCC(O)], 7.66 [dd, J = 5.6 and 3.2 Hz, 2 H,
CHCHCC(O)], 3.25 [sept, J = 6.8 Hz, 1 H, CH(CH3)2], 2.21 [s, 3 H,
C(O)CCH3] 1.35 [d, J = 6.8 Hz, 6 H, CH(CH3)2] ppm. 13C NMR
(ATR): ν = 2923, 2852, 1726, 1658, 1590, 1435, 1422, 1328, 1302,
˜
(75 MHz, CDCl3):
[=CCH(CH3)2], 142.7 (=CCH3), 133.3 and 133.0 [2ϫCHCC(O)],
132.8 and 131.8 [2ϫCHCC(O)], 126.1 and 126.0
δ = 185.6 and 184.8 (2ϫC=O), 151.4
1266, 1208, 1173, 1163, 893, 846, 785, 721, 708 cm–1. HRMS: calcd.
for C14H13O4 245.0814; found 245.0805; ∆ = 3.6 ppm.
tert-Butyl [2-(1,4-Dioxo-1,4-dihydronaphthalen-2-yl)ethyl]carbamate
(16). Method A: This compound was prepared according to the
general procedure starting from NQ (300 mg, 1.90 mmol) and was
purified by flash chromatography on silica gel with C6H12/AcOEt
(90:10) as the eluent. The pure compound was obtained as an
orange solid (154 mg, 0.51 mmol, 27% yield). Method B: To a solu-
tion of NQ (300 mg, 1.90 mmol, 0.1 ) in CH3CN/H2O (2:1,
12 mL) was added Boc-β-alanine (2.14 g, 11.38 mmol, 6 equiv.),
and the mixture was warmed to 65 °C. Silver nitrate (194 mg,
1.14 mmol, 0.6 equiv.) was added to the stirred mixture. A homo-
geneous solution of ammonium persulfate (1.13 g, 4.94 mmol,
2.6 equiv., 0.3 ) in CH3CN/H2O (2:1, 9 mL) was added dropwise
over 2 h. At the end of the addition, the reaction mixture was
stirred at 65 °C for 1 h. The mixture was then cooled to room tem-
perature, extracted with CH2Cl2, and washed with brine. The or-
ganic layer was dried with MgSO4, filtered through Celite, and con-
centrated under reduced pressure. Purification by flash chromatog-
raphy on silica gel with C6H12/AcOEt (8:2) as the eluent led to the
desired product as an orange solid (146 mg, 0.49 mmol, 26% yield).
1H NMR (300 MHz, CDCl3): δ = 8.08 [m, 2 H, CHCC(O)], 7.73
[m, 2 H, CHCHCC(O)], 6.82 (s, 1 H, CH=CCH2), 4.69 (br. s, 1 H,
[2ϫCHCHCC(O)], 29.3 [CH(CH3)2], 20.4 [CH(CH3)2], 12.3
(=CCH3) ppm. HRMS: calcd. for C14H15O2 215.1072; found
215.1072; ∆ = 0.0 ppm (the molecular ion peak is very weak).
2-Isopropyl-1,4-naphthoquinone (11) and 2,3-Diisopropyl-1,4-naph-
thoquinone (12): These compounds were prepared according to the
general procedure starting from NQ (316 mg, 2.00 mmol) and were
purified by flash chromatography on silica gel with C6H12/AcOEt
(95:5) as the eluent to lead to an inseparable 9:2 mixture (213 mg,
orange solid) of 11 and 12 (see Supporting Information). 1H NMR
(300 MHz, CDCl3): δ = 7.98 [m, 4 H, CHCC(O) (11 and 12)], 7.62
[m, 4 H, CHCHCC(O) (11 and 12)], 6.71 [s, 1 H, iPrCCH (11)],
3.35 [sept, J = 6.9 Hz, 1 H, CH(CH3)2 (12)], 3.19 [sept, J = 6.9 Hz,
1 H, CH(CH3)2 (11)], 1.30 [d, J = 6.9 Hz, 12 H, CH(CH3)2 (12)],
1.15 [d, J = 6.9 Hz, 6 H, CH(CH3)2 (11)] ppm.
2-tert-Butyl-1,4-naphthoquinone (13):[21] This compound was pre-
pared according to the general procedure starting from NQ
(475 mg, 3.00 mmol) and was purified by flash chromatography on
silica gel with CH2Cl2/CH3OH (10:0 to 95:5) as the eluent. The
pure compound was obtained as
a
yellow solid (165 mg,
0.77 mmol, 25%). H NMR (400 MHz, CDCl3): δ = 8.02 [m, 2 H,
CHCC(O)], 7.68 [m, 2 H, CHCHCC(O)], 6.82 [s, 1 H, C(O)CH], NH), 3.41 (pseudo q, J = 6.3 Hz, 2 H, CH2NH), 2.76 (t, J = 6.3 Hz,
1.35 (s, 9 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 185.8 and 2 H, CH2CAr), 1.37 [s, 9 H, OC(CH3)3] ppm. 13C NMR (75 MHz,
184.8 (2ϫC=O), 158.3 [=CC(CH3)3], 133.8 and 133.6 CDCl3): δ = 185.0 and 184.8 [C(O)CCH2 and C(O)CCH3], 155.8
1
[2ϫCHCC(O)], 133.5 and 131.5 [2ϫCHCC(O)], 133.2 (=CH),
126.8 and 125.5 [2ϫCHCHCC(O)], 35.7 [C(CH3)3], 29.3
(NHCO), 148.5 (CH=CCH2), 136.0 (=CCH2), 133.66 and 133.61
[2ϫCHCC(O)], 132.1 and 132.0 [2ϫCHCC(O)], 126.6 and 126.0
[2ϫCHCHCC(O)], 79.4 [C(CH3)3], 39.1 (CH2NH), 31.0 [C-
[C(CH ) ] ppm. IR (ATR): ν = 2958, 1654, 1593, 1483, 1459, 1361,
˜
3 3
3050
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 3045–3052

Radical Decarboxylation Toward Functionalization of Naphthoquinones
(CH3)3], 28.2 (CH2CAr) ppm. IR (ATR): ν = 3392, 2966, 2932,
FULL PAPER
added dropwise over 2 h. At the end of the addition, the reaction
˜
1704, 1656, 1591, 1514, 1304, 1269, 1250, 1158, 981, 966, 854, 777, mixture was stirred at 65 °C for 1 h. The mixture was cooled to
735, 702 cm–1. HRMS: calcd. for C17H19NNaO4 324.1212; found
324.1202; ∆ = 3.0 ppm.
room temperature, extracted with CH2Cl2, and washed with brine.
The organic layer was dried with MgSO4, filtered through Celite,
and concentrated under reduced pressure. Purification by flash
chromatography on silica gel with C6H12/AcOEt (10:0 to 9:1 and
finally 7:3) as the eluent led to the desired product as an orange
solid (240 mg, 0.58 mmol, 19% yield). 1H NMR (300 MHz,
CDCl3): δ = 8.07 [dd, J = 5.7 and 3.3 Hz, 2 H, CHCC(O)], 7.72
[dd, J = 5.7 and 3.3 Hz, 2 H, CHCHCC(O)], 5.61 (br. s, 2 H, NH),
4.45 (d, J = 6.3 Hz, 4 H, CH2NH), 1.40 [s, 18 H, OC(CH3)3] ppm.
13C NMR (75 MHz, CDCl3): δ = 185.5 [C(O)], 155.7 (NHCO),
142.8 (CArCH2), 133.9 [C(O)CAr], 131.8 [CHCC(O)], 126.4
[CHCHCC(O)], 79.7 [C(CH3)3], 36.3 (CH2NH), 28.3 [C(CH3)3]
tert-Butyl {2-[3-(2-tert-Butoxycarbonylaminoethyl)-1,4-dioxo-1,4-di-
hydronaphthalen-2-yl]ethyl}carbamate (17): This compound was ob-
tained along with 16 (method B described above) as an orange solid
(101 mg, 0.23 mmol, 12% yield). 1H NMR (300 MHz, CDCl3): δ
= 8.08 [dd, J = 5.7 and 3.3 Hz, 2 H, CHCC(O)], 7.70 [dd, J = 5.7
and 3.3 Hz, 2 H, CHCHCC(O)], 5.01 (br. s, 2 H, NH), 3.35 (t, J =
6.6 Hz, 4 H, CH2NH), 2.90 (t, J = 6.6 Hz, 4 H, CH2CAr), 1.35 [s,
18 H, OC(CH3)3] ppm. 13C NMR (75 MHz, CDCl3): δ = 184.9
[2ϫC(O)], 156.0 (2ϫNHCO), 145.5 (2ϫ=CCH2), 133.4
[2ϫCHCC(O)], 132.1 [2ϫCHCC(O)], 126.3 [2ϫCHCHCC(O)],
79.3 [2ϫC(CH3)3], 50.7 (2ϫCH2CH2NH), 39.9 (2ϫCH2NH),
ppm. IR (ATR): ν = 3354, 2975, 2927, 1690, 1661, 1594, 1507,
˜
1366, 1248, 1155, 938, 857, 762, 719 cm–1. HRMS: calcd. for
28.2 [2ϫC(CH ) ] ppm. IR (ATR): ν = 3365, 2925, 2852, 1689,
˜
3 3
C22H28N2NaO6 439.1845; found 439.1844; ∆ = 0.2 ppm.
1657, 1594, 1510, 1450, 1391, 1284, 1248, 1161, 971, 857, 780,
717 cm–1. HRMS: calcd. for C24H32N2NaO6 467.2158; found
467.2151; ∆ = 1.5 ppm.
2-Thioxo-2H-pyridin-1-yl 2-(tert-Butoxycarbonylamino)propionate
(23): Boc--alanine (446 mg, 2.36 mmol, 1 equiv.) and 2-mercap-
topyridine N-oxide (300 mg, 2.36 mmol, 1 equiv.) in CH2Cl2 (4 mL)
were added to a flask, which was protected from light by aluminum
foil at 0 °C in an ice bath. N-[3-(Dimethylamino)propyl]-NЈ-ethyl-
carbodiimide hydrochloride (452 mg, 2.36 mmol, 1 equiv.) was then
added, and the mixture was stirred at room temperature for 10 h.
After completion of the reaction, the organic phase was washed
twice with saturated aqueous NaHCO3 (10 mL) and then with
brine (10 mL). The aqueous phases, still protected from light, were
extracted CH2Cl2 (2ϫ10 mL), and the organic layers were dried
with MgSO4, filtered, and concentrated under reduced pressure.
The residue was quickly filtered through a small pad of silica gel
and washed with C6H12/AcOEt (1:1). The crude product was ob-
tained as a yellow oil (703 mg, 2.36 mmol, quantitative yield) and
used without further purification due to its instability. 1H NMR
(300 MHz, CDCl3): δ = 7.71 (m, 1 H, CHCHC=S), 7.25 (m, 2 H,
CHCHNO and CHC=S), 6.65 (m, 1 H, CHNO), 5.18 (br. s, 1 H,
NH), 4.63 (q, J = 6.7 Hz, 1 H, CHCH3), 1.73 (d, J = 6.7 Hz, 3 H,
CHCH3), 1.50 [s, 9 H, OC(CH3)3] ppm. 13C NMR (75 MHz,
CDCl3): δ = 174.9 (C=S), 169.4 (NOC=O), 155.2 (NHCOO), 137.7
(CHCHC=S), 137.0 (CHC=S), 133.4 (CHNO), 113.0 (CHCHNO),
80.4 [OC(CH3)3], 48.6 (CHCH3), 28.1 [C(CH3)3], 17.7 [CH(CH3)]
ppm.
tert-Butyl (1,4-Dioxo-1,4-dihydronaphthalen-2-ylmethyl)carbamate
(18): This compound was prepared according to the general pro-
cedure starting from NQ (950 mg, 6.00 mmol) and was purified by
flash chromatography on silica gel with CH2Cl2/CH3OH (10:0 to
95:5) as the eluent. The pure compound was obtained as an orange
solid (812 mg, 2.83 mmol, 47% yield). 1H NMR (300 MHz,
CDCl3): δ = 8.03 [dd, J = 5.1 and 3.3 Hz, 2 H, CHCC(O)], 7.71
[dd, J = 5.1 and 3.3 Hz, 2 H, CHCHCC(O)], 5.06 (br. s, 1 H, NH),
4.24 (d, J = 5.7 Hz, 2 H, CH2NH), 1.43 [s, 9 H, OC(CH3)3] ppm.
13C NMR (75 MHz, CDCl3): δ = 185.1 and 184.9 [C(O)CCH2 and
C(O)CCH3], 155.6 (NHCO), 147.2 (CH=CCH2), 133.98, 133.96
and 133.94 [=CCH2 and 2ϫCHCC(O)], 133.75 and 133.74
[2ϫCHCC(O)], 126.3 and 126.2 [2ϫCHCHCC(O)], 80.1
[C(CH ) ], 39.5 (CH NH), 28.3 [C(CH ) ] ppm. IR (ATR): ν =
˜
3 3
2
3 3
3378, 2971, 1686, 1658, 1634, 1520, 1363, 1336, 1251, 1162, 1050,
890, 859, 767, 683, 662 cm–1. HRMS: calcd. for C16H17NNaO4
310.1055; found 310.1069; ∆ = 4.4 ppm.
tert-Butyl {2-[3-(tert-Butoxycarbonylaminomethyl)-1,4-dioxo-1,4-di-
hydronaphthalen-2-yl]ethyl}carbamate (19): This compound was
prepared according to the general procedure starting from 18
(290 mg, 1.01 mmol) and was purified on silica gel with C6H12/
AcOEt (9:1 to 7:3) to yield the desired compound as an orange
solid (330 mg, 0.77 mmol, 76% yield). 1H NMR (300 MHz,
CDCl3): δ = 8.05 [m, 2 H, CHCC(O)], 7.70 [t, J = 3.3 Hz, 2 H,
CHCHCC(O)], 5.38 (br. s, 1 H, NH), 5.03 (br. s, 1 H, NH), 4.30
(d, J = 6.6 Hz, 2 H, =CCH2NH), 3.37 (m, 2 H, CH2CH2NH), 3.06
(m, 2 H, CH2CH2NH), 1.41 [s, 9 H, OC(CH3)3], 1.23 [s, 9 H,
OC(CH3)3] ppm. 13C NMR (75 MHz, CDCl3): δ = 185.7 and 185.0
[2ϫC(O)], 156.1 and 156.0 (2ϫNHCO), 145.8 [=C(CH2)], 142.7
[=C(CH2)2], 133.8 and 133.7 [2ϫC(O)CAr], 132.2 and 131.8
[2ϫCHCC(O)], 126.6 and 126.0 [2ϫCHCHCC(O)], 79.8 and 79.1
[2ϫC(CH3)3], 43.4 (CH2CH2NH), 31.5 and 30.1 (2ϫCH2NH),
2-Thioxo-2H-pyridin-1-yl 3-(tert-Butoxycarbonylamino)propionate
(24): This compound was prepared according to the procedure de-
scribed for 23 starting from 2-mercaptopyridine N-oxide (150 mg,
1.18 mmol) and was obtained as a yellow oil (350 mg, 1.18 mmol,
quantitative yield). 1H NMR (300 MHz, CDCl3): δ = 7.71 (m, 1
H, CHCHC=S), 7.25 (m, 2 H, CHCHNO and CHC=S), 6.67 (m,
1 H, CHNO), 5.52 (br. s, 1 H, NH), 3.64 (m, 2 H, CH2NH), 2.91
(m, 2 H, CH2CO), 1.47 [s, 9 H, OC(CH3)3] ppm. 13C NMR
(75 MHz, CDCl3): δ = 175.4 (C=S), 167.4 (NOC=O), 155.8
(NHCOO), 137.7 (CHCHC=S), 136.9 (CHC=S), 133.8 (CHNO),
112.7 (CHCHNO), 79.4 [OC(CH3)3], 36.0 (CH2N), 33.1
(CHCH2N), 28.2 [C(CH3)3] ppm.
28.3 and 28.1 [2ϫC(CH ) ] ppm. IR (ATR): ν = 3381, 2977, 2930,
˜
3 3
1702, 1664, 1595, 1512, 1367, 1294, 1251, 1164, 859 cm–1. HRMS:
Supporting Information (see footnote on the first page of this arti-
cle): NMR spectra of all synthesized compounds are available.
calcd. for C23H30N2NaO6 453.2002; found 453.2019; ∆ = 3.8 ppm.
tert-Butyl [3-(tert-Butoxycarbonylaminomethyl)-1,4-dioxo-1,4-dihy-
dronaphthalen-2-ylmethyl]carbamate (20): To a solution of NQ
(475 mg, 3.00 mmol, 0.1 ) in CH3CN/H2O (2:1, 30 mL) was added
Boc-glycine (1.58 g, 9 mmol, 3 equiv.) and Boc-β-alanine (1.7 g,
9 mmol, 3 equiv.), and the mixture was warmed to 65 °C. Silver
nitrate (153 mg, 0.9 mmol, 0.6 equiv.) was added to the stirred mix-
ture. A homogeneous solution of ammonium persulfate (890 mg,
Acknowledgments
CNRS, Université de Bordeaux I, Ligue Nationale Contre le Can-
cer (Comité de la Dordogne), Association pour la Recherche sur le
Cancer, (postdoctoral grant to Cl. C.) and Fluofarma are gratefully
3.9 mmol, 2.6 equiv., 0.3 ) in CH3CN/H2O (2:1, 15 mL) was acknowledged for financial support. The authors warmly thank
Eur. J. Org. Chem. 2007, 3045–3052
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3051

C. Commandeur, C. Chalumeau, J. Dessolin, M. Laguerre
FULL PAPER
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Received: February 14, 2007
Published Online: April 30, 2007
3052
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Eur. J. Org. Chem. 2007, 3045–3052