Direct C-H alkylation of naphthoquinones with amino acids through a revisited Kochi-Anderson radical decarboxylation: Trends in reactivity and applications

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DOI: 10.1002/ejoc.201200722

Direct C–H Alkylation of Naphthoquinones with Amino Acids Through a

Revisited Kochi–Anderson Radical Decarboxylation: Trends in Reactivity and

Applications

Guillaume Naturale,^[a]Marc Lamblin,^[a]Claude Commandeur,^[a]François-Xavier Felpin,^[b]

and Jean Dessolin*^[a]

Keywords: Medicinal chemistry / Antitumor agents / Quinones / Amino acids / Radical reactions / Alkylation

In our ongoing research program into the discovery of new

anticancer drugs , we were interested in the preparation of

naphthoquinone scaffolds bearing aminoalkyl side-chains.

Following this aim, we revisited the Kochi–Anderson radical

decarboxylation of amino acids in order to set up a versatile

route to the direct functionalization of naphthoquinones. The

best reaction conditions were applied to a selected series of

compounds in a systematic methodological study which al-

lowed us to establish important trends in reactivity. We found

that α-substituted β-amino acids were the most suitable sub-

strates for the radical addition. In contrast, α-amino acids

gave modest results. The influence of the amine protecting

groups on the reaction outcome has also been studied. This

practical procedure allows the introduction of various unsym-

metrical moieties, including orthogonally protected linear

aminoalkyl chains or chiral dipeptidic chains, and opens the

door to a wide scope of easily accessible chemical diversity.

Introduction

Quinones are an important class of naturally occurring

and synthetic compounds with a great variety of functions.

The naphthoquinone moiety is a structure of choice for me-

dicinal chemists, since it exhibits a wide spectrum of impor-

tant biological activities including, among others, antitu-

mor,^[1]antibiotic,^[2]antiviral,^[3]antidiabetic,^[4]antimalar-

ial,^[5]and antineurodegenerative^[6]activities. This privileged

class of compounds is also found in many natural products

including juglone (1), plumbagin (2), β-lapachone (3), dau-

norubicin (4), and doxorubicin (5),^[7]one of the most com-

monly used drugs in the treatment of a wide range of can-

cers (Figure 1). It has also a key role in living systems. For

instance, vitamin K1 (6),^[8]a naphthoquinone-derived com-

pound, is required for blood coagulation, where it partici-

pates in the carboxylation of glutamate.

Figure 1. Representative examples of natural and biologically active

naphthoquinones.

In the course of our ongoing research program devoted

to the discovery of novel anticancer drugs, we were inter-

ested in the synthesis of simple naphthoquinone derivatives

substituted with aminoalkyl side-chains that would allow

further functionalization. Having considered several pro-

teins that are overexpressed into cancer cells and their de-

scribed potential inhibitors, it is obvious that this type of

scaffold is commonly observed. For instance, the quinoline-

dione derivative NSC 663284 (7), a 1,4-naphthoquinone-

like compound with a functionalized aminated side-chain

was shown to be an effective and highly specific inhibitor

of Cdc25B phosphatase.^[9]

According to the literature, the functionalization of qui-

nones with alkyl chains is usually achieved through radical

additions. The formation of radicals from 1,3-dicarbonyl

compounds could efficiently be initiated by Mn^IIIor Ce^IV

metal ions.^[10]Very recently, Baran and co-workers reported

[a] Université de Bordeaux, CNRS UMR 5248, CBMN, IECB,

2 rue Robert Escarpit, 33607 Pessac, France

Fax: +33-5-40002200

E-mail: j.dessolin@iecb.u-bordeaux.fr

Homepage: www.cbmn.u-bordeaux.fr

[b] Université de Nantes, UFR des Sciences et des Techniques,

CNRS UMR 6230, CEISAM,

2 rue de la Houssinière, 44322 Nantes Cedex 3, France

Supporting information for this article is available on the

WWW under http://dx.doi.org/10.1002/ejoc.201200722.

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the radical alkylation of benzoquinone with unfunction-

alized alkyl boronic acids.^[11]However, the Barton pro-

cedure involving the conversion of a carboxylic acid into a

thiohydroxamate ester, followed by homolytic cleavage to

give the corresponding free radical, is the most common

method.^[12]Unfortunately, it suffers from severe limitations

under oxidative conditions, where the alkyl and pyridylthio

disubstituted adduct is obtained as the major product. Un-

fortunately with naphthoquinones as substrates, desulfur-

ization under reductive conditions is often impossible due

to the concomitant reduction into 1,4-dihydroxynaphth-

alene derivatives.^[13]Recent examples of electrochemical

radical decarboxylation can also be found in the context of

the synthesis of natural product analogs.^[14]

Some of us previously highlighted the benefits of the al-

most unexplored Kochi–Anderson radical decarboxyl-

ation^[15]for the functionalization of naphthoquinone moie-

ties.^[16]This reaction, also known as the Minisci reaction

when performed on heteroaromatic bases,^[17]involves radi-

cal generation by an Ag^II-assisted oxidative decarboxyl-

ation (Scheme 1). Subsequent nucleophilic addition to the

electron-deficient naphthoquinone (i.e., I) allows carbon

alkylation and affords the desired product (i.e., IV) after

rearomatization of a semiquinone radical II and oxidation

of the tautomer III.

Scheme 2. Scope of the methodological study.

Results and Discussion

We started our studies with the reaction of menadione

(8) with the amino acid Boc-β-Ala-OH (Boc = tert-butoxy-

carbonyl) under the reaction conditions previously devel-

oped in our laboratory.^[16]The decarboxylation was carried

out at 65 °C with addition of ammonium persulfate over

two hours. The mixture was then allowed to stir at the same

temperature for an additional hour. Under these conditions,

we obtained less than 60% conversion and only a 37% iso-

lated yield of naphthoquinone 10. This disappointing result

encouraged us to reconsider the reaction conditions. We

reasoned that three parameters would be critical for the suc-

cess of the C–H alkylation. Hence, we studied the influence

of the temperature, the addition time of the ammonium per-

sulfate, and the concentration. A selection of representative

results is reported in Table 1. As a general remark, we ob-

served that the temperature was the most important param-

eter for obtaining the highest yields. Indeed, addition of

ammonium persulfate at 100 °C significantly improved the

reaction yield (Table 1, entry 3 vs. 5). At 65 °C, we also de-

termined that dilute conditions were detrimental to the suc-

cess of the reaction (Table 1, entry 1 vs. 2). Surprisingly, this

behavior was not observed at higher temperature (100 °C),

where a concentrated solution slightly decreased the yield

(Table 1, entry 4 vs. 5). This result suggests that the concen-

tration of radical species is higher at higher temperature

(100 vs. 65 °C), , and thus that dilute conditions limit the

formation of by-products. From these optimization studies,

we showed that the alkylation of menadione could be

achieved by a free radical decarboxylation reaction that

Scheme 1. Kochi–Anderson addition to naphthoquinones by oxi-

dative decarboxylation.

This process proved to be very efficient for creating

chemically diverse quinones, as it is compatible with a vari-

ety of substrates including N-protected amino acids,^[16]lin-

ear or branched carboxylic acids,^[16]vinylic acids,^[18]and α-

keto acids,^[19]and it can also occur in an intramolecular

manner.^[20]In this paper, we report a methodological study

into the Kochi–Anderson decarboxylation reaction that ex-

pands the scope of the radical alkylation of naphthoquin-

ones with amino acids (Scheme 2). Considering linear and

chiral amino acids with different alkyl chain lengths, we ex-

pected to get information on the influence of the structure

of the amino acids for the efficiency of the alkylation reac-

tion. Moreover, a comparison of results obtained with me-

nadione (8) and 1,4-naphthoquinone (9) would give us im-

portant information on the effect of steric hindrance and

semiquinone radical stability on the reaction outcome.

Table 1. Optimization studies.

Entry

Temperature

[°C]

Addition Concentration

time [min.]

Yield

[%]^[a]

[M]

1

2

3

4

5

65

100

120

30

0.3

0.06

0.3

0.06

0.3

37

12

7

58

51

[a] Isolated yields.

2

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Alkylation of Naphthoquinones with Amino Acids

could be conveniently conducted at 100 °C with a short ad- alanines 14a–d (Table 2, entry 4) and phenylalanines 15a–d

dition time of the ammonium persulfate under rather dilute (Table 2, entry 5) than with glycines 11a–d (Table 2, en-

conditions.

try 1). The use of an electron-withdrawing protecting group

Having optimized the reaction conditions, we screened a (Troc = 2,2,2-trichloroethoxycarbonyl, or TFA = trifluo-

variety of amino acids for the C–H alkylation of menadione roacetyl) limited the oxidation side-reaction, and conse-

(8) (Table 2). As a general remark, it is important to men- quentially, allowed the formation of the corresponding al-

tion that the efficiency of the reaction was dramatically im- kylated products, albeit in rather modest yields. Although

proved in the new procedure, as indicated by comparison for many substrates the protecting group had a low influ-

with the lower yields obtained for some substrates using the ence on the reaction yield, we observed that Troc was the

previous procedure (reported in parentheses).^[16]We also most reliable.

observed that primary and secondary free radicals reacted

Having obtained these promising results, we went on to

with similar efficiencies (Table 2, entry 2 vs. 6). However, study the free radical C–H alkylation of naphthoquinone 9

this trend was only true when the free alkyl radical gener- (Table 3). Although a similar result could concievably be

ated by decarboxylation was not contiguous to a nitrogen expected, it should be noted that naphthoquinone 9 has two

atom. Indeed, with substituted α-amino acids (Table 2, en- reactive positions, which could result in a mixture of mono-

tries 4 and 5), the generated secondary free radical was and dialkylated products. The optimized procedure fre-

highly unstable and could easily be oxidized into the corre- quently resulted in reaction yields higher than those ob-

sponding iminium species, which was subsequently hy- tained with our previous procedure, but in some cases, the

drolyzed under the reaction conditions. It appeared that proportion of the unwanted dialkylated compounds also in-

secondary radicals were more easily oxidized that primary creased (see compounds 18b–18bb and 18d–18dd). As al-

ones, which accounts for the lower yields obtained with ready observed with menadione (8) as starting material, the

C–H alkylation of naphthoquinone (9) was not very sensi-

tive to the nature of the protecting group. However, with

Table 2. Screening of amino acids with menadione.

most α- and β-amino acids, the use of Troc as a protecting

group enhanced the reactivity of the radical. However, this

high reactivity was detrimental to the selectivity, since the

ratio of mono- to dialkylation also decreased. The dialky-

ation process could not be suppressed with the GABA

amino acids, whatever the nature of the protecting group

(Table 3, entry 3). With primary radicals generated from α-

and β-amino acids, it was possible to selectively produce

the mono-alkylated naphthoquinone by a fine-tuning of the

protecting group (Table 3, entries 1–2). Unfortunately, there

is no general rule for the selection of the ideal protecting

group, and a short screening seems to be required for any

new coupling. Comparison of the results obtained with the

GABA amino acids (Table 3, entry 3), with those obtained

with α- and β-amino acids (Table 3, entries 1–2) suggested

that a correlation exists between the mono-/dialkylation ra-

tio and the distance between the nitrogen and the radical-

bearing carbon. In other words, in the absence of the elec-

tronic and steric influence of a nitrogen atom, selective

monoalkylation seems impossible.

The ease of functionalizing the two reactive positions of

naphthoquinone (9) with primary alkyl radicals suggested

that the sequential introduction of two different chains with

orthogonal N-protecting groups would be feasible. This

would allow us to access unsymmetrical dialkylated

naphthoquinone derivatives. To this end, naphthoquinones

18a and 19a were treated with Troc-β-Ala-OH and TFA-β-

Ala-OH amino acids, following the procedure optimized in

this study (Scheme 3). We were pleased to find that this

strategy allowed the formation of the target naphtho-

quinones 23a–b and 24a–b in synthetically useful yields.

Encouraged by these results, we were interested in intro-

ducing more chemical complexity, with the introduction of

dipeptidic side-chains onto menadione (8) (Table 4). We ini-

tially opted for a linear strategy in which the first amino

[a] Isolated yields. [b] Yields in parentheses were obtained with the

procedure described in reference.^[16]

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Table 3. Screening of amino acids with naphthoquinone.

from Boc-Gly-OH or Boc-β-Ala-OH (Table 4, entries 1–2),

we were surprised to find that the introduction of Boc-

GABA-OH and Boc-Me-β-Ala-OH was incompatible with

the second peptidic coupling (Table 4, entries 3–4). Indeed,

when removing the Boc protecting group, instead we iso-

lated cyclized compounds 27 and 28, shown in Figure 2,

with unreproducible results.

Table 4. Linear introduction of a dipeptidic chain.

Entry Boc-AA₁-OH

Product,

% yield^[a]

Boc-AA₂-OH Product,

% yield^[a]

1

2

3

4

Boc-Gly-OH

Boc-β-Ala-OH

Boc-GABA-OH

11a, 40

12a, 58

13a, 61

Boc-Ala-OH 25, 40

Boc-Ala-OH 26, 53

Boc-Ala-OH See text

Boc-Phe-OH See text

Boc-Me-β-Ala-OH 16a, 50

[a] Isolated yields.

Figure 2. Structures of compounds 27 and 28.

[a] Isolated yields. [b] Yields in parentheses were obtained with the

procedure described in reference.^[16]

These contrasting results forced us to explore a more ef-

ficient and convergent strategy. To this end, we reasoned

that the direct introduction of a dipeptidic chain by radical

decarboxylation would be an interesting alternative

(Table 5). The dipeptidic side-chains were prepared follow-

ing standard chemistry as described in the Supporting In-

formation. The radical alkylation of menadione (8) and

naphthoquinone (9) with three different dipeptides, under

the optimized conditions developed in this study, gave the

expected compounds with modest to synthetically useful

yields (18–51%). It was assumed that this convergent route

was synthetically more interesting than the three-step se-

quence described in Table 4, since the critical decarboxyl-

ation step was moved to the end of the process. This strat-

Scheme 3. Synthesis of unsymmetrical dialkylated naphthoquin-

ones.

acid was introduced by our free radical procedure. The sub- egy also allowed the preparation of structures previously

sequent protecting group cleavage under acidic conditions, inaccessible by the linear route. Interestingly, the steric hin-

followed by a standard peptidic coupling, would install the drance of the dipeptidic chain prevented the formation of

desired dipeptidic side-chain onto menadione (8). While the disubstituted adduct when starting from naphtho-

this strategy gave interesting overall results when starting quinone (9) (Table 5, entry 4). However, the two-step dialk-

4

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Alkylation of Naphthoquinones with Amino Acids

Scientific Ltd, Alfa Aesar, or TCI Europe. Amino acids were of l

configuration unless otherwise stated. Silica gel (40–63 μm) used

in flash column chromatography was obtained from Merck. TLC

analysis was performed on aluminium-backed plates (Merck)

coated with 0.2 mm silica with UV indicator 60_F254, visualized with

a Spectroline UV₂₅₄lamp, and stained with a basic solution of

KMnO₄or ninhydrin. Solvent systems associated with R_fvalues

and flash column chromatography are reported as percentage by

volume values. Mass spectra were performed by the CESAMO

(Bordeaux, France) with a QStar Elite mass spectrometer (Applied

Biosystems). The instrument was equipped with an ESI source, and

spectra were recorded in the positive mode. The electrospray needle

was maintained at 5000 V and operated at room temperature. Sam-

ples were introduced by injection through a 20 μL sample loop into

a 4.5 mL/min flow of methanol from the LC pump. ¹H and ¹³C

NMR spectra were recorded at 300 and 75 MHz, respectively, with

a Bruker Advance 300 spectrometer. Proton chemical shifts were

internally referenced to the residual proton resonance in CDCl₃(δ

= 7.26 ppm), CD₃OD (δ = 3.31 ppm), [D₆]acetone (δ = 2.05 ppm),

or DMSO (δ = 2.54 ppm). Carbon chemical shifts were internally

referenced to the deuterated solvent signals in CDCl₃(δ =

77.2 ppm), CD₃OD (δ = 49.0 ppm), [D₆]acetone (δ = 206.3,

29.8 ppm), or DMSO (δ = 40.45 ppm). FTIR spectra were recorded

with a Bruker FTIR IFS55 spectrometer with samples loaded as

neat films on ZnSe plates. Melting points (m.p.) were determined

with a melting point apparatus with a temperature gradient of 1 °C/

min and are not corrected.

ylation of naphthoquinone (9) was still possible with a di-

peptide, as illustrated in Scheme 4, and provided naphtho-

quinones with a high degree of molecular complexity.

Table 5. Convergent introduction of a dipeptidic chain.

Entry

Substrate Boc-AA₂–AA₁–OH

Product

% Yield^[a]

1

2

3

4

8

9

Boc-Ala-Gly-OH

29

30

31

32

18

51

36

37

Boc-Phe-GABA-OH

Boc-Phe-β-Ala-OH

[a] Isolated yields.

General Procedure A for the Radical Decarboxylation at 100 °C:

The carboxylic acid (3.2 equiv.) and silver nitrate (0.55 equiv.) were

added to a solution of quinone (1 equiv., 0.016 m) in CH₃CN/H₂O

(4:3). The mixture was warmed to 100 °C. A homogeneous solution

of ammonium persulfate (1.63 equiv., 0.06 m) in CH₃CN/H₂O (4:3)

was added dropwise over 30 min. At the end of the addition, the

reaction mixture was allowed to stir at 100 °C for an additional

30 min, and then it was cooled down to room temperature and

extracted with CH₂Cl₂. The combined organic extracts were

washed with water and brine, then dried with MgSO₄and filtered

through Celite. The solvent was removed under reduced pressure.

Purification was performed by silica gel chromatography to yield

chromatographically and spectroscopically pure product.

Scheme 4. Synthesis of unsymmetrical dialkylated naphthoquin-

ones.

Conclusions

The functionalization of naphthoquinones by a radical

addition of decarboxylated α, β and γ N-protected amino

acids has been described. A large methodological study has

considered a wide variety of substrates, which were selected

for their structure. This has allowed us to underline trends

in reactivity. Even if no general rules could be derived, we

were able to better understand the influence of various reac-

tion parameters. The outcome of the decarboxylation reac-

tion depends on a close mix of steric, electronic, and sta-

bility issues. We also highlighted that the N-protecting

group had a moderate influence on the reaction outcome,

tert-Butyl 2-(3-Methyl-1,4-dioxo-1,4-dihydronaphthalen-2-yl)ethyl-

carbamate (10): This compound was prepared according to general

procedure A starting from menadione (8) (51 mg, 0.3 mmol) and

Boc-β-alanine (182 mg, 0.96 mmol), and was purified by flash

chromatography on silica gel (5 to 20% ethyl acetate/hexanes). Un-

reacted menadione (8) was collected (2 mg, 0.012 mmol, 96% con-

version). Pure 10 (53 mg, 0.17 mmol, 58%) was obtained as a yel-

although electronic effects can be considered to play a role, low solid, m.p. 107–108 °C. R_f= 0.30 (20% ethyl acetate/hexanes).

¹H NMR (300 MHz, CDCl₃): δ = 8.06–7.99 (m, 2 H), 7.71–7.62

especially with substituted α-amino acids. All in all, we have

described in this paper a direct and versatile route that op-

ens an easy access to new functionalized naphthoquinones.

The application of our methodology to the one-step intro-

duction of chiral peptides or orthogonally N-protected side-

chains has been described. Further work to explore the

preparation of compounds of biological interest is currently

in progress.

(m, 2 H), 4.92 (br. s, 1 H), 3.31 (q, J = 6.5 Hz, 2 H), 2.86 (t, J =

6.8 Hz, 2 H), 2.22 (s, 3 H), 1.37 (s, 9 H) ppm. ¹³C NMR (75 MHz,

CDCl₃): δ = 185.1, 184.9, 156.0, 145.2, 144.0, 133.5, 133.4, 132.1,

132.0, 126.3, 126.2, 79.4, 39.5, 28.3, 27.9, 13.0 ppm. IR (ZnSe): ν

˜

= 3400, 2978, 1710, 1659, 1596, 1511, 1296, 1251, 1169, 973, 787,

711 cm^–1. HRMS (ESI-TOF): calcd. for C₁₈H₂₁NO₄Na 338.1362;

found 338.1361.

tert-Butyl (3-Methyl-1,4-dioxo-1,4-dihydronaphthalen-2-yl)methyl-

carbamate (11a): This compound was prepared according to gene-

ral procedure A starting from menadione (8) (51 mg, 0.3 mmol)

and Boc-glycine (162 mg, 0.92 mmol), and was purified by flash

chromatography on silica gel (5 to 20% ethyl acetate/hexanes). Un-

reacted menadione (8) was collected (13 mg, 0.08 mmol, 74% con-

Experimental Section

General Remarks: All commercially acquired solvents and reagents

were used as received from the Aldrich Chemical Company, Fischer

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version). Pure 11a (35 mg, 0.12 mmol, 40%) was obtained as a yel-

low solid, m.p. 105–106 °C. R_f= 0.32 (20% ethyl acetate/hexanes).

1

anes). H NMR (300 MHz, CDCl₃): δ = 8.03–7.95 (m, 2 H), 7.66–

7.59 (m, 2 H), 5.71 (t, J = 6.0 Hz, 1 H), 4.66 (s, 2 H), 3.43 (q, J =

¹H NMR (300 MHz, CDCl₃): δ = 8.17–7.98 (m, 2 H), 7.79–7.66 6.8 Hz, 2 H), 2.89 (t, J = 6.9 Hz, 2 H), 2.19 (s, 3 H) ppm. ¹³C

(m, 2 H), 5.26 (m, 1 H), 4.32 (d, J = 6.5 Hz, 2 H), 2.37 (s, 3 H),

NMR (75 MHz, CDCl₃): δ = 184.8, 184.7, 154.7, 145.3, 143.4,

1.43 (s, 9 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 185.6, 185.5, 133.6, 133.5, 131.9, 131.8, 126.3, 126.2, 95.5, 74.4, 40.1, 27.6,

155.7, 145.1, 142.0, 133.8, 133.7, 132.2, 131.9, 126.6, 126.2, 79.7,

12.9 ppm. IR (ZnSe): ν = 3377, 2951, 2922, 1736, 1658, 1595, 1509,

˜

37.2, 28.4, 12.7 ppm. IR (ZnSe): ν = 3394, 2976, 2930, 1712, 1661,

1331, 1296, 1243, 1146, 711 cm^–1. HRMS (ESI-TOF): calcd. for

C₁₆H₁₄Cl₃NO₄Na 411.9880; found 411.9884.

˜

1595, 1504, 1366, 1294, 1249, 1168, 715 cm^–1. HRMS (ESI-TOF):

calcd. for C₁₇H₁₉NO₄Na 324.1206; found 324.1206.

N-[2-(3-Methyl-1,4-dioxo-1,4-dihydronaphthalen-2-yl)ethyl]acet-

2,2,2-Trichloroethyl (3-Methyl-1,4-dioxo-1,4-dihydronaphthalen-2- amide (12c): This compound was prepared according to general

yl)methylcarbamate (11b): This compound was prepared according

to general procedure A starting from menadione (8) (172 mg,

1 mmol) and Troc-glycine (801 mg, 3.2 mmol), and was purified by

flash chromatography on silica gel (10 to 20% ethyl acetate/hex-

anes). Unreacted menadione (8) was collected (17 mg, 0.1 mmol,

89% conversion). Pure 11b (219 mg, 0.58 mmol, 58%) was ob-

tained as a yellow solid, m.p. 153–154 °C. R_f= 0.37 (20% ethyl

procedure A starting from menadione (8) (51 mg, 0.3 mmol) and

N-acetyl-β-alanine (126 mg, 0.96 mmol), and was purified by flash

chromatography on silica gel (80 to 100% ethyl acetate/hexanes).

Unreacted menadione (8) was collected (22 mg, 0.13 mmol, 57%

conversion). Pure 12c (10 mg, 0.04 mmol, 13%) was obtained as a

brown solid, m.p. 163–164 °C. R_f= 0.33 (80% ethyl acetate/hex-

1

anes). H NMR (300 MHz, CDCl₃): δ = 8.09–8.01 (m, 2 H), 7.74–

7.66 (m, 2 H), 6.18 (br. s, 1 H), 3.42 (ddd, J = 6.7, 6.8, 6.8 Hz, 2

1

acetate/hexanes). H NMR (300 MHz, CDCl₃): δ = 8.11–8.02 (m,

2 H), 7.76 –7.68 (m, 2 H), 5.81 (br. s, 1 H), 4.69 (s, 2 H), 4.41 (d, H), 2.88 (t, J = 6.9 Hz, 2 H), 2.24 (s, 3 H), 1.94 (s, 3 H) ppm. ¹³C

J = 6.3 Hz, 2 H), 2.36 (s, 3 H) ppm. ¹³C NMR (75 MHz, CDCl₃):

δ = 185.3, 185.1, 154.6, 145.6, 141.0, 133.9, 133.8, 132.1, 131.7,

NMR (75 MHz, CDCl₃): δ = 185.3, 184.9, 145.2, 143.8, 133.6,

133.5, 132.1, 131.9, 126.3, 126.2, 38.6, 27.1, 23.1, 12.9 ppm. IR

126.6, 126.2, 95.4, 74.7, 37.8, 12.7 ppm. IR (ZnSe): ν = 3365, 2953, (ZnSe): ν = 3383, 3286, 1655, 1595, 1577, 1559, 1457, 1437, 1376,

˜

1736, 1661, 1595, 1517, 1458, 1295, 1233, 1148, 720 cm^–1. HRMS

(ESI-TOF): calcd. for C₁₅H₁₂Cl₃NO₄Na 397.9724; found 397.9729.

716 cm^–1. HRMS (ESI-TOF): calcd. for C₁₅H₁₅NO₃Na 280.0955;

found 280.0956.

N-[(3-Methyl-1,4-dioxo-1,4-dihydronaphthalen-2-yl)methyl]acet-

amide (11c): This compound was prepared according to general

procedure A starting from menadione (8) (51 mg, 0.3 mmol) and

N-acetyl-glycine (112 mg, 0.96 mmol), and was purified by flash

chromatography on silica gel (50 to 70% ethyl acetate/hexanes).

Unreacted menadione (8) was collected (1 mg, 0.01 mmol, 98 %

conversion). Pure 11c (36 mg, 0.15 mmol, 49%) was obtained as a

pale orange solid, m.p. 162–164 °C. R_f= 0.52 (ethyl acetate). ¹H

NMR (300 MHz, CDCl₃): δ = 8.10–8.02 (m, 2 H), 7.75–7.67 (m, 2

2,2,2-Trifluoro-N-[2-(3-methyl-1,4-dioxo-1,4-dihydronaphthalen-2-

yl)ethyl]acetamide (12d): This compound was prepared according

to general procedure A starting from menadione (8) (172 mg,

1 mmol) and TFA-β-alanine (592 mg, 3.2 mmol), and was purified

by flash chromatography on silica gel (10 to 20% ethyl acetate/

hexanes). No unreacted menadione (8) was collected (100% conver-

sion). Pure 12d (158 mg, 0.51 mmol, 51%) was obtained as a yellow

1

solid, m.p. 110–112 °C. R_f= 0.38 (20% ethyl acetate/hexanes). H

NMR (300 MHz, CDCl₃): δ = 8.09–7.99 (m, 2 H), 7.78–7.69 (m, 2

H), 6.27 (br. s, 1 H), 4.42 (d, J = 6.3 Hz, 2 H), 2.38 (s, 3 H), 1.96 H), 7.19 (br. s, 1 H), 3.57 (q, J = 6.5 Hz, 2 H), 2.96 (t, J = 6.8 Hz,

(s, 3 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 185.7, 185.2, 169.8,

145.5, 141.4, 133.9, 132.1, 131.7, 126.6, 126.1, 36.3, 23.1, 12.7 ppm.

2 H), 2.24 (s, 3 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 185.6,

184.7, 158.3/157.8/157.3/156.8, 145.8, 142.8, 133.9, 133.7, 132.0,

131.7, 126.5, 126.4, 121.5/117.6/113.8/110.0, 38.8, 26.4, 12.9 ppm.

IR (ZnSe): ν = 3391, 3292, 3067, 1651, 1594, 1542, 1376, 1332,

˜

1294, 1014, 721 cm^–1. HRMS (ESI-TOF): calcd. for C₁₄H₁₃NO₃Na

266.0787; found 266.0798.

IR (ZnSe): ν = 3339, 1708, 1660, 1595, 1553, 1329, 1296, 1208,

˜

1180, 713 cm^–1. HRMS (ESI-TOF): calcd. for C₁₅H₁₂F₃NO₃Na

334.0661; found 334.0663.

2,2,2-Trifluoro-N-[(3-methyl-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-

methyl]acetamide (11d): This compound was prepared according to

general procedure A starting from menadione (8) (51 mg,

0.3 mmol) and TFA-glycine (164 mg, 0.96 mmol), and was purified

by flash chromatography on silica gel (10 to 20% ethyl acetate/

hexanes). No unreacted menadione (8) was collected (100% conver-

tert-Butyl 3-(3-Methyl-1,4-dioxo-1,4-dihydronaphthalen-2-yl)propyl-

carbamate (13a): This compound was prepared according to gene-

ral procedure A starting from menadione (8) (51 mg, 0.3 mmol)

and Boc-γ-aminobutyric acid (195 g, 0.96 mmol), and was purified

by flash chromatography on silica gel (20 to 30% ethyl acetate/

sion). Pure 11d (37 mg, 0.12 mmol, 42%) was obtained as a yellow hexanes). Unreacted menadione (8) was collected (6 mg,

1

solid, m.p. 133–135 °C. R_f= 0.27 (10% ethyl acetate/hexanes). H

NMR (300 MHz, CDCl₃): δ = 8.14–8.03 (m, 2 H), 7.79–7.71 (m, 2

H), 7.19 (br. s, 1 H), 4.55 (d, J = 6.4 Hz, 2 H), 2.39 (s, 3 H) ppm.

¹³C NMR (75 MHz, CDCl₃): δ = 185.4, 184.7, 158.2/157.7/157.2/

0.04 mmol, 88% conversion). Pure 13a (60 mg, 0.18 mmol, 61%)

was obtained as an orange semi-solid. R_f= 0.40 (30% ethyl acetate/

hexanes). ¹H NMR (300 MHz, CDCl₃): δ = 8.10–8.00 (m, 2 H),

7.73–7.64 (m, 2 H), 4.89 (br. s, 1 H), 3.17 (dd, J = 12.7, 6.3 Hz, 2

156.8, 146.5, 136.4, 134.2, 133.9, 132.1, 131.5, 126.8, 126.3, 121.6/ H), 2.69–2.65 (m, 2 H), 2.18 (s, 3 H), 1.71–1.67 (m, 2 H), 1.43 (s,

117.7/113.9/110.1, 36.7, 12.8 ppm. IR (ZnSe): ν = 3342, 2358, 2340, 9 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 185.1, 184.8, 156.0,

˜

1716, 1662, 1595, 1552, 1333, 1296, 1211, 1179, 693 cm^–1. HRMS

(ESI-TOF): calcd. for C₁₄H₁₀F₃NO₃Na 320.0504; found 320.0517.

146.4, 143.8, 133.4, 133.3, 132.1, 132.0, 126.3, 126.2, 79.1, 40.2,

28.8, 28.4, 24.1, 12.6 ppm. IR (ZnSe): ν = 3366, 2924, 2855, 1693,

˜

1658, 1515, 1293, 1215, 1169, 716 cm^–1. HRMS (ESI-TOF): calcd.

for C₁₉H₂₃NO₄Na 352.1519; found 352.1514.

2,2,2-Trichloroethyl 2-(3-Methyl-1,4-dioxo-1,4-dihydronaphthalen-2-

yl)ethylcarbamate (12b): This compound was prepared according

to general procedure A starting from menadione (8) (172 mg,

1 mmol) and Troc-β-alanine (846 mg, 3.2 mmol), and was purified

by flash chromatography on silica gel (10 to 20% ethyl acetate/

hexanes). No unreacted menadione (8) was collected (100% conver-

sion). Pure 12b (164 mg, 0.42 mmol, 42%) was obtained as a dark

2,2,2-Trichloroethyl 3-(3-Methyl-1,4-dioxo-1,4-dihydronaphthalen-2-

yl)propylcarbamate (13b): This compound was prepared according

to general procedure A starting from menadione (8) (51 mg,

0.3 mmol) and Troc-γ-aminobutyric acid (267 mg, 0.96 mmol), and

was purified by flash chromatography on silica gel (20 to 30% ethyl

yellow solid, m.p. 136–138 °C. R_f= 0.41 (20% ethyl acetate/hex- acetate/hexanes). Unreacted menadione (8) was collected (7 mg,

6

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Alkylation of Naphthoquinones with Amino Acids

0.04 mmol, 86% conversion). Pure 13b (72 mg, 0.18 mmol, 60%) procedure A starting from menadione (8) (51 mg, 0.3 mmol) and

was obtained as a yellow oil. R_f= 0.34 (30% ethyl acetate/hexanes).

N-acetyl-d,l-alanine (126 mg, 0.96 mmol), and was purified by

¹H NMR (300 MHz, CDCl₃): δ = 8.10–8.01 (m, 2 H), 7.73–7.66 flash chromatography on silica gel (40 to 60% ethyl acetate/hex-

(m, 2 H), 5.51 (t, J = 5.4 Hz, 1 H), 4.73 (s, 2 H), 3.30 (q, J = anes). Unreacted menadione (8) was collected (36 mg, 0.21 mmol,

6.6 Hz, 2 H), 2.72–2.68 (m, 2 H), 2.19 (s, 3 H), 1.79–1.76 (m, 2 H)

ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 185.0, 184.9, 154.7, 146.1,

144.0, 133.5, 133.4, 132.1, 131.9, 126.4, 126.3, 95.7, 74.4, 40.8, 28.5,

29% conversion). Pure 14c (12 mg, 0.05 mmol, 16%) was obtained

as a brown solid, m.p. 156–158 °C. R_f= 0.28 (50% ethyl acetate/

hexanes). ¹H NMR (300 MHz, CDCl₃): δ = 8.13–8.01 (m, 2 H),

7.78–7.69 (m, 2 H), 6.83 (d, J = 8.9 Hz, 1 H), 5.45 (dq, J = 9.4,

7.1 Hz, 1 H), 2.34 (s, 3 H), 1.98 (s, 3 H), 1.50 (d, J = 7.1 Hz, 3 H)

ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 185.8, 185.1, 169.3, 144.8,

143.9, 133.9, 133.7, 132.2, 131.9, 126.5, 126.1, 29.7, 23.5, 20.2,

23.9, 12.7 ppm. IR (ZnSe): ν = 3381, 3353, 2939, 1734, 1657, 1595,

˜

1524, 1296, 1240, 1144, 717 cm^–1. HRMS (ESI-TOF): calcd. for

C₁₇H₁₆Cl₃NO₄Na 426.0037; found 426.0036.

N-[3-(3-Methyl-1,4-dioxo-1,4-dihydronaphthalen-2-yl)propyl]acet-

amide (13c): This compound was prepared according to general

procedure A starting from menadione (8) (51 mg, 0.3 mmol) and

N-acetyl-γ-aminobutyric acid (139 mg, 0.96 mmol), and was puri-

fied by flash chromatography on silica gel (0 to 5% methanol/ethyl

acetate). Unreacted menadione (8) was collected (13 mg,

0.08 mmol, 75% conversion). Pure 13c (44 mg, 0.16 mmol, 54%)

was obtained as a yellow solid, m.p. 129–132 °C. R_f= 0.38 (ethyl

acetate). ¹H NMR (300 MHz, CDCl₃): δ = 8.09–8.00 (m, 2 H), 7.68

(dd, J = 5.7, 3.4 Hz, 2 H), 6.23 (br. s, 1 H), 3.27 (q, J = 6.6 Hz, 2

H), 2.69–2.63 (m, 2 H), 2.17 (s, 3 H), 2.01 (s, 3 H), 1.72–1.68 (m,

2 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 185.1, 185.0, 170.3,

146.2, 144.1, 133.6, 133.4, 132.1, 131.9, 126.3, 126.2, 39.0, 28.3,

12.2 ppm. IR (ZnSe): ν = 3397, 3288, 2924, 2851, 1658, 1372, 1330,

˜

1293, 720 cm^–1. HRMS (ESI-TOF): calcd. for C₁₅H₁₅NO₃Na

280.0944; found 280.0956.

2,2,2-Trifluoro-N-[1-(3-methyl-1,4-dioxo-1,4-dihydronaphthalen-2-

yl)ethyl]acetamide (14d): This compound was prepared according

to general procedure A starting from menadione (8) (128 mg,

0.75 mmol) and TFA-d,l-alanine (440 mg, 2.4 mmol), and was

purified by flash chromatography on silica gel (0 to 20% ethyl acet-

ate/CH₂Cl₂). Unreacted menadione (8) was collected (10 mg,

0.06 mmol, 92% conversion). Pure 14d (62 mg, 0.20 mmol, 27%)

was obtained as a yellow solid, m.p. 211–214 °C. R_f= 0.34 (10%

ethyl acetate/CH₂Cl₂). ¹H NMR (300 MHz, [D₆]DMSO): δ = =

9.85 (d, J = 5.6 Hz, 1 H), 8.07–7.99 (m, 2 H), 7.90–7.82 (m, 2 H),

5.19 (p, J = 6.9 Hz, 1 H), 2.22 (s, 3 H), 1.53 (d, J = 7.2 Hz, 3 H)

ppm. ¹³C NMR (75 MHz, [D₆]DMSO): δ = 185.1, 183.7, 156.8/

156.3/155.8/155.3, 144.7, 143.7, 134.6, 134.5, 132.0, 131.8, 126.4,

24.0, 23.3, 12.7 ppm. IR (ZnSe): ν = 3296, 3084, 2933, 1657, 1595,

˜

1555, 1439, 1376, 1295, 693 cm^–1. HRMS (ESI-TOF): calcd. for

C₁₆H₁₇NO₃Na 294.1100; found 294.1109.

2,2,2-Trifluoro-N-[3-(3-methyl-1,4-dioxo-1,4-dihydronaphthalen-2-

yl)propyl]acetamide (13d): This compound was prepared according

to general procedure A starting from menadione (8) (51 mg,

0.3 mmol) and TFA-γ-aminobutyric acid (191 mg, 0.96 mmol), and

was purified by flash chromatography on silica gel (20 to 30% ethyl

acetate/hexanes). Unreacted menadione (8) was collected (1 mg,

0.01 mmol, 98% conversion). Pure 13d (52 mg, 0.16 mmol, 53%)

was obtained as a yellow solid, m.p. 115–116 °C. R_f= 0.43 (30%

ethyl acetate). ¹H NMR (300 MHz, CDCl₃): δ = 8.12–8.03 (m, 2

H), 7.75–7.68 (m, 2 H), 7.36 (br. s, 1 H), 3.39 (q, J = 6.4 Hz, 2 H),

2.71 (t, J = 7.4 Hz, 2 H), 2.20 (s, 3 H), 1.85–1.81 (m, 2 H) ppm.

¹³C NMR (75 MHz, CDCl₃): δ = 185.5, 184.8, 158.1/157.6/157.1/

156.7, 145.4, 144.7, 133.8, 133.6, 132.1, 131.8, 126.4, 126.3, 121.7/

126.3, 121.9/118.1/114.3/110.5, 45.3, 18.1, 12.3 ppm. IR (ZnSe): ν

˜

= 3356, 3068, 2985, 2945, 1719, 1658, 1590, 1543, 1294, 1203, 1156,

720, 624 cm^–1. HRMS (ESI-TOF): calcd. for C₁₅H₁₂F₃NO₃Na

334.0661; found 334.0666.

2,2,2-Trichloroethyl 1-(3-Methyl-1,4-dioxo-1,4-dihydronaphthalen-2-

yl)ethylcarbamate (15b): This compound was prepared according

to general procedure A starting from menadione (8) (172 mg,

1 mmol) and Troc-d,l-phenylalanine (1.09 g, 3.2 mmol), and was

purified by flash chromatography on silica gel (0 to 10% ethyl acet-

ate/hexanes). Unreacted menadione (8) was collected (92 mg,

0.5 mmol, 42% conversion). Pure 15b (159 mg, 0.34 mmol, 34%)

was obtained as a yellow solid, m.p. 128–131 °C. R_f= 0.48 (5%

ethyl acetate/hexanes). ¹H NMR (300 MHz, CDCl₃): δ = 8.18–8.09

(m, 1 H), 8.09–7.98 (m, 1 H), 7.85–7.66 (m, 2 H), 7.33–7.09 (m, 5

H), 6.42 (d, J = 9.9 Hz, 1 H), 5.35–5.18 (m, 1 H), 4.79 (d, J =

12.0 Hz, 1 H), 4.56 (d, J = 12.0 Hz, 1 H), 3.40–3.09 (m, 2 H), 1.97

(s, 3 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 185.7, 184.6, 154.2,

145.5, 136.9, 134.0, 133.8, 132.0, 131.8, 129.3, 128.6, 127.0, 126.6,

117.8/114.0/110.2, 38.9, 27.4, 23.4, 12.7 ppm. IR (ZnSe): ν = 3317,

˜

3098, 2925, 1710, 1659, 1595, 1558, 1459, 1296, 1211, 1181,

717 cm^–1. HRMS (ESI-TOF): calcd. for C₁₆H₁₄F₃NO₃Na

348.0817; found 348.0801.

2,2,2-Trichloroethyl 1-(3-Methyl-1,4-dioxo-1,4-dihydronaphthalen-2-

yl)ethylcarbamate (14b): This compound was prepared according

to general procedure A starting from menadione (8) (172 mg,

1 mmol) and Troc-d,l-alanine (846 mg, 3.2 mmol), and was puri-

fied by flash chromatography on silica gel (5 to 10% ethyl acetate/

hexanes). Unreacted menadione (8) was collected (103 mg,

0.6 mmol, 35 % conversion). Pure 14b (72 mg, 0.18 mmol, 18 %)

was obtained as a yellow solid, m.p. 149–151 °C. R_f= 0.47 (20%

ethyl acetate/hexanes). ¹H NMR (300 MHz, CDCl₃): δ = 8.13–8.02

(m, 2 H), 7.75–7.68 (m, 2 H), 6.35 (d, J = 9.6 Hz, 1 H), 5.16 (dq,

J = 9.6, 7.1 Hz, 1 H), 4.79 (d, J = 12.0 Hz, 1 H), 4.60 (d, J =

12.0 Hz, 1 H), 2.32 (s, 3 H), 1.56 (d, J = 7.1 Hz, 3 H) ppm. ¹³C

NMR (75 MHz, CDCl₃): δ = 185.3, 184.9, 154.1, 144.4, 143.6,

133.8, 133.7, 132.2, 131.8, 126.4, 126.2, 95.4, 74.6, 47.1, 20.4,

126.3, 95.4, 74.6, 53.1, 41.0, 12.1 ppm. IR (ZnSe): ν = 3422, 2952,

˜

1735, 1655, 1593, 1498, 1452, 1375, 1294, 1226, 1134, 1090, 1038,

9 5 4 , 8 1 9 , 7 1 9 c m ^{– 1}. H R M S ( E S I - T O F ) : c a l c d . f o r

C₂₂H₁₈Cl₃NO₄Na 488.0193; found 488.0187.

N-[1-(3-Methyl-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-2-phenyleth-

yl]acetamide (15c): This compound was prepared according to ge-

neral procedure A starting from menadione (8) (51 mg, 0.3 mmol)

and N-acetyl-d,l-phenylalanine (199 mg, 0.96 mmol), and was

purified by flash chromatography on silica gel (50% ethyl acetate/

hexanes). Unreacted menadione (8) was collected (39 mg,

0.23 mmol, 24% conversion). Pure 15c (24 mg, 0.07 mmol, 24%)

was obtained as a yellow solid, m.p. 122–124 °C. R_f= 0.35 (50%

ethyl acetate/hexanes). ¹H NMR (300 MHz, CDCl₃): δ = 8.13–8.02

(m, 2 H), 7.78–7.71 (m, 2 H), 7.27–7.08 (m, 5 H), 6.87 (d, J =

9.4 Hz, 1 H), 5.57 (td, J = 9.1, 7.1 Hz, 1 H), 3.23–3.17 (m, 2 H),

1.97 (s, 3 H), 1.95 (s, 3 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ =

186.1, 184.6, 169.4, 145.9, 142.7, 137.1, 133.9, 133.7, 132.1, 131.9,

12.1 ppm. IR (ZnSe): ν = 3428, 3375, 2926, 1735, 1657, 1594, 1501,

˜

1451, 1331, 1293, 1221, 1119, 1086, 791 cm^–1. HRMS (ESI-TOF):

calcd. for C₁₆H₁₄Cl₃NO₄Na 411.9880; found 411.9880.

N-[1-(3-Methyl-1,4-dioxo-1,4-dihydronaphthalen-2-yl)ethyl]acet-

amide (14c): This compound was prepared according to general

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J. Dessolin et al.

FULL PAPER

129.2, 128.5, 126.9, 126.6, 126.2, 50.5, 40.9, 23.4, 12.2 ppm. IR

was obtained as a brown solid, m.p. 142–144 °C. R_f= 0.29 (30%

ethyl acetate/hexanes). ¹H NMR (300 MHz, CDCl₃): δ = 8.05–7.93

(m, 2 H), 7.71–7.62 (m, 2 H), 6.23 (br. s, 1 H), 3.64–3.57 (m, 2 H),

3.41–3.35 (m, 1 H), 2.18 (s, 3 H), 1.90 (s, 3 H), 1.30 (d, J = 7.0 Hz,

3 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 185.3, 185.1, 170.5,

147.9, 145.4, 133.5, 133.4, 132.5, 131.7, 126.2, 126.1, 43.9, 35.4,

(ZnSe): ν = 2927, 1657, 1504, 1372, 1292, 720 cm^–1. HRMS (ESI-

˜

TOF): calcd. for C₂₁H₁₉NO₃Na 356.1257; found 356.1262.

2,2,2-Trifluoro-N-[1-(3-methyl-1,4-dioxo-1,4-dihydronaphthalen-2-

yl)-2-phenylethyl]acetamide (15d): This compound was prepared ac-

cording to general procedure A starting from menadione (8)

(172 mg, 1 mmol) and TFA-phenylalanine (784 mg, 3.2 mmol), and

was purified by flash chromatography on silica gel (0 to 10% ethyl

acetate/hexanes). Unreacted menadione (8) was collected (62 mg,

0.36 mmol, 64% conversion). Pure 15d (118 mg, 0.30 mmol, 29%)

was obtained as a yellow solid, m.p. 156–157 °C. R_f= 0.35 (10%

ethyl acetate/hexanes). ¹H NMR (300 MHz, CDCl₃): δ = 8.19–8.11

23.1, 16.5, 12.4 ppm. IR (ZnSe): ν = 3297, 3077, 2931, 1657, 1593,

˜

1554, 1440, 1374, 1292, 693 cm^–1. HRMS (ESI-TOF): calcd. for

C₁₆H₁₇NO₃Na 294.1111; found 294.1108.

2,2,2-Trifluoro-N-[2-(3-methyl-1,4-dioxo-1,4-dihydronaphthalen-2

-yl)propyl]acetamide (16d): This compound was prepared according

to general procedure A starting from menadione (8) (51 mg,

(m, 1 H), 8.11–8.04 (m, 1 H), 7.98 (br. d, J = 9.3 Hz, 1 H), 7.84– 0.3 mmol) and TFA-d,l-3-aminoisobutyric acid (191 mg,

7.73 (m, 2 H), 7.35–7.08 (m, 5 H), 5.54 (dd, J = 16.3, 8.9 Hz, 1 H),

3.36–3.17 (m, 2 H), 1.96 (s, 3 H) ppm. ¹³C NMR (75 MHz, CDCl₃):

δ = 186.0, 184.1, 157.3/156.8/156.3/155.8, 146.6, 140.9, 136.0, 134.3,

134.0, 131.8, 131.7, 129.2, 128.8, 127.3, 126.8, 126.5, 121.5/117.7/

0.96 mmol), and was purified by flash chromatography on silica gel

(10 to 20% ethyl acetate/hexanes). No unreacted menadione (8)

was collected (100% conversion). Pure 16d (38 mg, 0.12 mmol,

39%) was obtained as a yellow solid, m.p. 97–100 °C. R_f= 0.36

(20% ethyl acetate/hexanes). ¹H NMR (300 MHz, CDCl₃): δ =

113.9/110.1, 51.2, 40.7, 12.3 ppm. IR (ZnSe): ν = 3355, 3029, 1702,

˜

1663, 1592, 1566, 1455, 1294, 1272, 1209, 1188, 965, 784, 705 cm^–1. 8.08–7.97 (m, 2 H), 7.76–7.65 (m, 2 H), 7.20 (br. s, 1 H), 3.92–3.84

HRMS (ESI-TOF): calcd. for C₂₁H₁₆F₃NO₃Na 410.0974; found (m, 1 H), 3.70–3.65 (m, 1 H), 3.49–3.45 (m, 1 H), 2.21 (s, 3 H),

410.0967.

1.37 (d, J = 6.2 Hz, 3 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ

= 185.6, 184.7, 158.4/157.9/157.4/156.9, 146.8, 145.8, 133.7, 132.3,

131.7, 126.3, 126.2, 121.6/117.7/113.9/110.1, 43.7, 34.7, 16.3,

tert-Butyl 2-(3-Methyl-1,4-dioxo-1,4-dihydronaphthalen-2-yl)propyl-

carbamate (16a): This compound was prepared according to gene-

ral procedure A starting from menadione (8) (51 mg, 0.3 mmol)

and Boc-d,l-3-aminoisobutyric acid (195 mg, 0.96 mmol), and was

purified by flash chromatography on silica gel (10 to 20% ethyl

acetate/hexanes). No unreacted menadione (8) was collected (100%

conversion). Pure 16a (49 mg, 0.15 mmol, 50%) was obtained as a

12.4 ppm. IR (ZnSe): ν = 3340, 2933, 1709, 1660, 1594, 1555, 1330,

˜

1294, 1210, 1182, 1162, 717 cm^–1. HRMS (ESI-TOF): calcd. for

C₁₆H₁₄F₃NO₃Na 348.0817; found 348.0820.

tert-Butyl (1,4-Dioxo-1,4-dihydronaphthalen-2-yl)methylcarbamate

(17a): This compound was prepared according to general pro-

yellow solid, m.p. 106–107 °C. R_f= 0.32 (20% ethyl acetate/hex- cedure A starting from naphthoquinone 9 (47 mg, 0.3 mmol) and

1

anes). H NMR (300 MHz, CDCl₃): δ = 8.06–7.99 (m, 2 H), 7.71– Boc-glycine (168 mg, 0.96 mmol), and was purified by flash

7.63 (m, 2 H), 4.83 (br. s, 1 H), 3.60–3.56 (m, 2 H), 3.46–3.40 (m,

chromatography on silica gel (10 to 20% ethyl acetate/hexanes).

1 H), 2.22 (s, 3 H), 1.37 (s, 9 H), 1.31 (d, J = 6.8 Hz, 3 H) ppm.

Pure 17a (32 mg, 0.11 mmol, 37%) was obtained as a yellow solid,

1

¹³C NMR (75 MHz, CDCl₃): δ = 185.2, 185.1, 156.0, 148.0, 145.5, m.p. 98–100 °C. R_f= 0.48 (20% ethyl acetate/hexanes). H NMR

133.4, 133.3, 132.6, 131.8, 126.1 (ϫ2), 79.2, 44.9, 36.0, 28.3, 16.5, (300 MHz, CDCl₃): δ = 8.14–8.06 (m, 2 H), 7.80–7.72 (m, 2 H),

12.4 ppm. IR (ZnSe): ν = 3384, 2971, 2930, 1707, 1656, 1509, 1293,

6.91 (s, 1 H), 5.04 (br. s, 1 H), 4.30 (d, J = 6.0 Hz, 2 H), 1.48 (s, 9

H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 185.2, 185.0, 155.7,

147.3, 134.1, 134.0, 133.8, 132.1, 132.0, 126.4, 126.3, 80.2, 39.6,

˜

1169, 717 cm^–1. HRMS (ESI-TOF): calcd. for C₁₉H₂₃NO₄Na

352.1519; found 352.1517.

28.4 ppm. IR (ZnSe): ν = 3347, 2975, 2932, 1697, 1664, 1594, 1514,

˜

2,2,2-Trichloroethyl 2-(3-methyl-1,4-dioxo-1,4-dihydronaphthalen-2-

yl)propylcarbamate (16b): This compound was prepared according

to general procedure A starting from menadione (8) (51 mg,

0.3 mmol) and Troc-d,l-3-aminoisobutyric acid (267 mg,

0.96 mmol), and was purified by flash chromatography on silica gel

(5 to 15% ethyl acetate/hexanes). No unreacted menadione (8) was

collected (100% conversion). Pure 16b (66 mg, 0.16 mmol, 55%)

was obtained as a yellow solid, m.p. 131–133 °C. R_f= 0.31 (10%

ethyl acetate/hexanes). ¹H NMR (300 MHz, CDCl₃): δ = 8.08–7.99

1300, 1247, 1166, 776 cm^–1. HRMS (ESI-TOF): calcd. for

C₁₆H₁₇NO₄Na 310.1049; found 310.1058.

Di-tert-Butyl (1,4-Dioxo-1,4-dihydronaphthalene-2,3-diyl)bis(meth-

ylene)dicarbamate (17aa): This compound was obtained along with

17a as described above, as a yellow solid (22 mg, 0.05 mmol, 18%),

m.p. 94–97 °C. R_f= 0.34 (20% ethyl acetate/hexanes). ¹H NMR

(300 MHz, CDCl₃): δ = 8.17–8.05 (m, 2 H), 7.83–7.76 (m, 2 H),

5.62 (br. s, 2 H), 4.50 (d, J = 6.3 Hz, 4 H), 1.44 (s, 18 H) ppm. ¹³C

(m, 2 H), 7.72–7.65 (m, 2 H), 5.44 (t, J = 6.0 Hz, 1 H), 4.72 (d, J NMR (75 MHz, CDCl₃): δ = 185.6, 155.7, 142.8, 134.0, 131.9,

= 12.1 Hz, 1 H), 4.65 (d, J = 12.1 Hz, 1 H), 3.75–3.71 (m, 1 H), 126.5, 79.8, 36.4, 28.4 ppm. IR (ZnSe): ν = 3400, 2979, 2932, 1708,

˜

3.62–3.58 (m, 1 H), 3.45–3.41 (m, 1 H), 2.22 (s, 3 H), 1.35 (d, J =

7.0 Hz, 3 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 185.2, 185.0,

154.7, 147.4, 145.6, 133.5, 133.4, 132.5, 131.7, 126.3, 126.2, 95.6,

1663, 1594, 1507, 1366, 1294, 1250, 1168 cm^–1. HRMS (ESI-TOF):

calcd. for C₂₂H₂₉N₂O₆Na 439.1839; found 439.1853.

2,2,2-Trichloroethyl (1,4-Dioxo-1,4-dihydronaphthalen-2-yl)methyl-

carbamate (17b): This compound was prepared according to gene-

ral procedure A starting from naphthoquinone 9 (47 mg, 0.3 mmol)

and Troc-glycine (240 mg, 0.96 mmol), and was purified by flash

chromatography on silica gel (10 to 30% ethyl acetate/hexanes).

Pure 17b (12 mg, 0.04 mmol, 11%) was obtained as a brown semi-

74.4, 45.3, 35.8, 16.5, 12.5 ppm. IR (ZnSe): ν = 3373, 2963, 2938,

˜

1737, 1657, 1593, 1524, 1449, 1330, 1294, 1238, 1147, 770,

719 cm^–1. HRMS (ESI-TOF): calcd. for C₁₇H₁₆Cl₃NO₄Na

426.0037; found 426.0045.

N-[2-(3-Methyl-1,4-dioxo-1,4-dihydronaphthalen-2-yl)propyl]acet-

amide (16c): This compound was prepared according to general

procedure A starting from menadione (8) (45 mg, 0.26 mmol) and

N-acetyl-d,l-3-aminoisobutyric acid (120 mg, 0.83 mmol), and was

purified by flash chromatography on silica gel (50 to 80% ethyl

acetate/hexanes). Unreacted menadione (8) was collected (3 mg,

0.02 mmol, 93% conversion). Pure 16c (44 mg, 0.16 mmol, 57%)

1

solid. R_f= 0.41 (20% ethyl acetate/hexanes). H NMR (300 MHz,

CDCl₃): δ = 8.17–8.09 (m, 2 H), 7.87–7.75 (m, 2 H), 6.96 (s, 1 H),

5.53 (br. s, 1 H), 4.79 (s, 2 H), 4.42 (dd, J = 6.4, 1.4 Hz, 2 H) ppm.

¹³C NMR (75 MHz, CDCl₃): δ = 185.1, 184.8, 155.1, 144.5, 134.6,

134.2, 134.0, 132.0, 131.9, 126.5, 126.4, 95.8, 74.8, 40.3 ppm. IR

(ZnSe): ν = 3354, 2958, 2924, 1734, 1664, 1594, 1532, 1336, 1301,

˜

8

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Alkylation of Naphthoquinones with Amino Acids

1241, 1161, 1138, 818, 775, 724 cm^–1. HRMS (ESI-TOF): calcd.

for C₁₄H₁₀Cl₃NO₄Na 383.9567; found 383.9563.

126.1, 79.4, 39.2, 31.1, 28.3 ppm. IR (ZnSe): ν = 3382, 2977, 2934,

˜

1698, 1663, 1595, 1523, 1366, 1302, 1267, 1168, 780 cm^–1. HRMS

(ESI-TOF): calcd. for C₁₇H₁₉NO₄Na 324.1206; found 324.1196.

Bis(2,2,2-trichloroethyl) (1,4-Dioxo-1,4-dihydronaphthalene-2,3-diyl)-

bis(methylene)dicarbamate (17bb): This compound was obtained

along with 17b according to general procedure A as described

above, as a brown semi-solid (49 mg, 0.09 mmol, 29%). R_f= 0.36

(20% ethyl acetate/hexanes). ¹H NMR (300 MHz, CDCl₃): δ =

8.18–8.09 (m, 2 H), 7.84–7.77 (m, 2 H), 5.97 (br. t, J = 6.3 Hz, 2

2,2,2-Trichloroethyl 2-(1,4-Dioxo-1,4-dihydronaphthalen-2-yl)ethyl-

carbamate (18b): This compound was prepared according to gene-

ral procedure A starting from naphthoquinone 9 (47 mg, 0.3 mmol)

and Troc-β-alanine (254 mg, 0.96 mmol), and was purified by flash

chromatography on silica gel (10 to 30% ethyl acetate/hexanes).

H), 4.72 (s, 4 H), 4.63 (d, J = 6.5 Hz, 4 H) ppm. ¹³C NMR Pure 18b (56 mg, 0.15 mmol, 50%) was obtained as a brown solid,

(75 MHz, CDCl₃): δ = 185.3, 154.7, 142.3, 134.3, 131.8, 126.6, 95.3,

1

m.p. 110–112 °C. R_f= 0.46 (20% ethyl acetate/hexanes). H NMR

(300 MHz, CDCl₃): δ = 8.13–8.06 (m, 1 H), 8.06–7.98 (m, 1 H),

7.78–7.69 (m, 2 H), 6.83 (s, 1 H), 5.41 (br. s, 1 H), 4.69 (s, 2 H),

3.54 (q, J = 6.5 Hz, 2 H), 2.82 (t, J = 6.4 Hz, 2 H) ppm. ¹³C NMR

(75 MHz, CDCl₃): δ = 185.1, 184.7, 154.7, 148.0, 136.4, 133.9,

133.8, 132.1, 132.0, 126.7, 126.2, 95.4, 74.4, 39.9, 30.7 ppm. IR

74.7, 37.2 ppm. IR (ZnSe): ν = 3374, 2956, 2925, 1732, 1662, 1594,

˜

1518, 1294, 1237, 1148, 823, 724, 568 cm^–1. HRMS (ESI-TOF):

calcd. for C₁₈H₁₄Cl₆N₂O₆Na 586.8875; found 588.8840.

N-[(1,4-Dioxo-1,4-dihydronaphthalen-2-yl)methyl]acetamide (17c):

This compound was prepared according to general procedure A

starting from naphthoquinone 9 (47 mg, 0.3 mmol) and N-acetyl-

glycine (112 mg, 0.96 mmol), and was purified by flash chromatog-

raphy on silica gel (50 to 100% ethyl acetate/hexanes). Pure 17c

(16 mg, 0.07 mmol, 23%) was obtained as a brown solid, m.p. 151–

(ZnSe): ν = 3355, 2957, 1733, 1662, 1594, 1524, 1329, 1303, 1268,

˜

1243, 1144, 821, 777, 721 cm^–1. HRMS (ESI-TOF): calcd. for

C₁₅H₁₂Cl₃NO₄Na 397.9724; found 397.9727.

Bis(2,2,2-trichloroethyl) (1,4-Dioxo-1,4-dihydronaphthalene-2,3-diyl)-

153 °C. R_f

=

0.27 (80% ethyl acetate/hexanes). ¹H NMR bis(methylene)dicarbamate (18bb): This compound was obtained

(300 MHz, CDCl₃): δ = 8.16–8.04 (m, 2 H), 7.82–7.71 (m, 2 H), along with 18b from general procedure A as described above, as a

6.90 (t, J = 1.4 Hz, 1 H), 6.16 (br. s, 1 H), 4.40 (dd, J = 6.3, 1.4 Hz, brown solid (23 mg, 0.04 mmol, 13%), m.p. 107–109 °C. R_f= 0.34

2 H), 2.09 (s, 3 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 185.2,

184.9, 170.4, 146.2, 134.6, 134.1, 133.9, 132.0, 131.9, 126.4, 126.3,

(20 % ethyl acetate/hexanes). ¹H NMR (300 MHz, CDCl₃): δ =

8.14–8.05 (m, 2 H), 7.78–7.70 (m, 2 H), 5.71 (br. t, J = 6.0 Hz, 2

H), 4.68 (s, 4 H), 3.60–3.46 (m, 4 H), 2.97 (t, J = 7.0 Hz, 4 H) ppm.

¹³C NMR (75 MHz, CDCl₃): δ = 184.8, 154.9, 145.2, 133.8, 131.9,

38.6, 23.2 ppm. IR (ZnSe): ν = 3302, 3070, 1661, 1594, 1542, 1371,

˜

1335, 1299, 1250, 1029, 777, 667 cm^–1. HRMS (ESI-TOF): calcd.

for C₁₃H₁₁NO₃Na 252.0631; found 252.0634.

126.5, 95.5, 74.5, 40.6, 28.1 ppm. IR (ZnSe): ν = 3352, 2954, 2927,

˜

1720, 1660, 1595, 1527, 1329, 1295, 1246, 1147, 817, 722 cm^–1

.

N,NЈ-(1,4-Dioxo-1,4-dihydronaphthalene-2,3-diyl)bis(methylene)di-

acetamide (17cc): This compound was obtained along with 17c ac-

cording to the procedure described in reference^[16]as a brown solid

(104 mg, 0.35 mmol, 3%). R_f= 0.17 (50% ethyl acetate/hexanes).

HRMS (ESI-TOF): calcd. for C₂₀H₁₈Cl₆N₂O₆Na 616.9146; found

614.9188.

N-[2-(1,4-Dioxo-1,4-dihydronaphthalen-2-yl)ethyl]acetamide (18c):

¹H NMR (300 MHz, CDCl₃): δ = 8.05–7.95 (m, 2 H), 7.72–7.64 This compound was prepared according to general procedure A

(m, 2 H), 7.15 (br. s, 2 H), 4.47 (d, J = 5.7 Hz, 4 H), 1.94 (s, 6 H)

ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 184.8, 170.7, 142.6, 134.0,

131.7, 126.4, 35.4, 23.0 ppm. HRMS (ESI-TOF): calcd. for

C₁₆H₁₆N₂O₄Na 323.1008; found 323.0997.

starting from naphthoquinone 9 (47 mg, 0.3 mmol) and N-acetyl-

β-alanine (126 mg, 0.96 mmol), and was purified by flash

chromatography on silica gel (80 to 100% ethyl acetate/hexanes).

Pure 18c (19 mg, 0.08 mmol, 26%) was obtained as a brown solid,

m.p. 136–138 °C. R_f= 0.29 (ethyl acetate). ¹H NMR (300 MHz,

CDCl₃): δ = 8.14–7.98 (m, 2 H), 7.80–7.66 (m, 2 H), 6.82 (s, 1 H),

6.17 (br. s, 1 H), 3.51 (q, J = 6.4 Hz, 2 H), 2.78 (td, J = 6.7, 0.7 Hz,

2 H), 1.96 (s, 3 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 185.2,

184.8, 170.6, 148.5, 136.1, 133.9, 133.8, 132.1, 132.0, 126.6, 126.1,

N-[(1,4-Dioxo-1,4-dihydronaphthalen-2-yl)methyl]-2,2,2-trifluoro-

acetamide (17d): This compound was prepared according to general

procedure A starting from naphthoquinone 9 (47 mg, 0.3 mmol)

and TFA-glycine (164 mg, 0.96 mmol), and was purified by flash

chromatography on silica gel (10 to 30% ethyl acetate/hexanes).

Pure 17d (32 mg, 0.11 mmol, 38%) was obtained as an orange so-

lid, m.p. 146–148 °C. R_f= 0.42 (20% ethyl acetate/hexanes). ¹H

NMR (300 MHz, CDCl₃): δ = 8.17–8.09 (m, 2 H), 7.85–7.78 (m, 2

38.4, 30.2, 23.1 ppm. IR (ZnSe): ν = 3295, 3080, 2925, 2854, 1659,

˜

1593, 1548, 1373, 1330, 1302, 1265, 778, 719, 666 cm^–1. HRMS

(ESI-TOF): calcd. for C₁₄H₁₃NO₃Na 266.0787; found 266.0777.

H), 7.11 (br. s, 1 H), 6.96 (t, J = 1.3 Hz, 1 H), 4.51 (dd, J = 6.3, N-[2-(1,4-Dioxo-1,4-dihydronaphthalen-2-yl)ethyl]-2,2,2-trifluoro-

0.4 Hz, 2 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 185.1, 184.4,

158.2/157.7/157.2/156.7, 143.8, 135.8, 134.5, 134.1, 132.0, 131.7,

acetamide (18d): This compound was prepared according to general

procedure A starting from naphthoquinone 9 (47 mg, 0.3 mmol)

and TFA-β-alanine (178 mg, 0.96 mmol), and was purified by flash

chromatography on silica gel (2 to 20% ethyl acetate/CH₂Cl₂). Pure

18d (38 mg, 0.13 mmol, 43%) was obtained as a brown solid, m.p.

186–188 °C. R_f= 0.43 (5 % ethyl acetate/CH₂Cl₂). ¹H NMR

(300 MHz, [D₆]acetone): δ = 8.17–8.10 (m, 1 H), 8.08–8.03 (m, 1

H), 7.85–7.79 (m, 2 H), 6.83 (t, J = 1.0 Hz, 1 H), 3.58 (t, J =

6.6 Hz, 2 H), 2.87–2.79 (m, 2 H) ppm. ¹³C NMR (75 MHz, [D₆]-

acetone): δ = 184.6, 184.4, 157.7/157.2/156.7/156.2, 148.0, 136.1,

133.8, 133.7, 132.4, 132.2, 126.2, 125.6, 121.9/118.1/114.3/110.5,

126.6, 126.5, 121.4/117.6/113.8/110.0, 39.1 ppm. IR (ZnSe): ν =

˜

3321, 1715, 1665, 1594, 1555, 1336, 1301, 1214, 1184, 1159, 1004,

776 cm^–1. HRMS (ESI-TOF): calcd. for C₁₃H₈F₃NO₃Na 306.0348;

found 306.0355.

tert-Butyl 2-(1,4-Dioxo-1,4-dihydronaphthalen-2-yl)ethylcarbamate

(18a): This compound was prepared according to general pro-

cedure A starting from naphthoquinone 9 (47 mg, 0.3 mmol) and

Boc-β-alanine (182 mg, 0.96 mmol), and was purified by flash

chromatography on silica gel (10 to 20% ethyl acetate/hexanes).

Pure 18a (42 mg, 0.14 mmol, 46%) was obtained as an orange semi-

38.1, 29.6 ppm. IR (ZnSe): ν = 2957, 2924, 2855, 1714, 1664, 1591,

˜

1557, 1543, 1304, 1267, 1214, 1158, 775 cm^–1. HRMS (ESI-TOF):

calcd. for C₁₄H₁₀F₃NO₃Na 320.0504; found 320.0517.

1

solid. R_f= 0.45 (20% ethyl acetate/hexanes). H NMR (300 MHz,

CDCl₃): δ = 8.14–8.05 (m, 2 H), 7.79–7.71 (m, 2 H), 6.85 (t, J =

1.0 Hz, 1 H), 4.75 (br. s, 1 H), 3.43 (q, J = 6.3 Hz, 2 H), 2.79 (t, J

= 6.5 Hz, 2 H), 1.40 (s, 9 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ

= 185.1, 182.1, 156.2, 141.6, 136.1, 133.7, 133.6, 132.2, 132.1, 126.7,

N,NЈ-[2,2Ј-(1,4-Dioxo-1,4-dihydronaphthalene-2,3-diyl)bis(ethane-

2,1-diyl)]bis(2,2,2-trifluoroacetamide) (18dd): This compound was

obtained along with 18d from general procedure A as described

Eur. J. Org. Chem. 0000, 0–0

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J. Dessolin et al.

9 4 2 , 8 1 4 , 7 2 2 c m ^{– 1}. H R M S ( E S I - T O F ) : c a l c d . f o r

FULL PAPER

above, as a brown solid (12 mg, 0.03 mmol, 9%), m.p. 195–197 °C.

R_f= 0.31 (5 % ethyl acetate/CH₂Cl₂). ¹H NMR (300 MHz, C₂₂H₂₂Cl₆N₂O₆Na 642.9501; found 642.9494.

CD₃OD): δ = 8.14–8.06 (m, 2 H), 7.84–7.76 (m, 2 H), 3.53 (t, J =

N-[3-(1,4-Dioxo-1,4-dihydronaphthalen-2-yl)propyl]acetamide (19c):

6.8 Hz, 4 H), 2.97 (t, J = 6.9 Hz, 4 H) ppm. ¹³C NMR (75 MHz,

[D₆]acetone): δ = 185.0, 157.7/157.2/156.7/156.2, 147.1, 133.7,

This compound was prepared according to general procedure A

starting from naphthoquinone 9 (47 mg, 0.3 mmol) and N-acetyl-γ-

aminobutyric acid (139 mg, 0.96 mmol), and was purified by flash

chromatography on silica gel (0 to 10% methanol/ethyl acetate).

Pure 19c (28 mg, 0.11 mmol, 36%) was obtained as a brown semi-

solid. R_f= 0.43 (10% methanol/ethyl acetate). ¹H NMR (300 MHz,

CDCl₃): δ = 8.13–7.99 (m, 2 H), 7.78–7.65 (m, 2 H), 6.82 (s, 1 H),

6.10 (br. s, 1 H), 3.40–3.28 (m, 2 H), 2.65–2.56 (m, 2 H), 2.01 (s, 3

H), 1.87–1.76 (m, 2 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ =

185.3, 184.9, 170.4, 150.8, 135.3, 133.8, 133.7, 132.1, 132.0, 126.6,

132.0, 125.7, 121.8/118.0/114.2/110.5, 38.3, 30.1 ppm. IR (ZnSe): ν

˜

= 3319, 2956, 2923, 2853, 1708, 1661, 1595, 1558, 1458, 1295, 1210,

1180, 718 cm^–1. HRMS (ESI-TOF): calcd. for C₁₈H₁₄F₆N₂O₄Na

459.0749; found 459.0741.

tert-Butyl 3-(1,4-Dioxo-1,4-dihydronaphthalen-2-yl)propylcarbamate

(19a): This compound was prepared according to general pro-

cedure A starting from naphthoquinone 9 (47 mg, 0.3 mmol) and

Boc-γ-aminobutyric acid (195 mg, 0.96 mmol), and was purified by

flash chromatography on silica gel (20 to 30% ethyl acetate/hex-

anes). Pure 19a (40 mg, 0.13 mmol, 42%) was obtained as a brown

solid, m.p. 71–74 °C. R_f= 0.42 (30% ethyl acetate/hexanes). ¹H

NMR (300 MHz, CDCl₃): δ = 8.13–8.03 (m, 2 H), 7.77–7.70 (m, 2

H), 6.82 (t, J = 1.2 Hz, 1 H), 4.74 (br. s, 1 H), 3.22 (dd, J = 13.0,

6.5 Hz, 2 H), 2.66–2.56 (m, 2 H), 1.79 (dt, J = 14.4, 7.0 Hz, 2 H),

1.44 (s, 9 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 185.2, 185.0,

156.0, 151.0, 135.1, 133.7, 133.6, 132.2, 132.1, 126.6, 126.1, 79.3,

126.1, 39.0, 28.2, 26.9, 23.3 ppm. IR (ZnSe): ν = 3274, 2925, 2854,

˜

1660, 1593, 1556, 1440, 1370, 1330, 1301, 1263, 780, 718 cm^–1

.

HRMS (ESI-TOF): calcd. for C₁₅H₁₅NO₃Na 280.0944; found

280.0954.

N,NЈ-[3,3Ј-(1,4-Dioxo-1,4-dihydronaphthalene-2,3-diyl)bis(propane-

3,1-diyl)]diacetamide (19cc): This compound was obtained along

with 19c from general procedure A as described above, as a brown

semi-solid (19 mg, 0.05 mmol, 18%). R_f= 0.30 (10% methanol/

ethyl acetate). ¹H NMR (300 MHz, CDCl₃): δ = 8.12–8.02 (m, 2

H), 7.76–7.67 (m, 2 H), 6.52 (br. s, 2 H), 3.35 (q, J = 6.5 Hz, 4 H),

2.73–2.62 (m, 4 H), 2.05 (s, 6 H), 1.80–1.67 (m, 4 H) ppm. ¹³C

NMR (75 MHz, CDCl₃): δ = 185.0, 170.8, 146.8, 133.6, 132.0,

40.0, 28.6, 28.4, 26.9 ppm. IR (ZnSe): ν = 3367, 2924, 2854, 1694,

˜

1663, 1594, 1517, 1455, 1366, 1302, 1263, 1166, 780 cm^–1. HRMS

(ESI-TOF): calcd. for C₁₈H₂₁NO₄Na 338.1362; found 338.1378.

Di-tert-Butyl 3,3Ј-(1,4-Dioxo-1,4-dihydronaphthalene-2,3-diyl)bis-

(propane-3,1-diyl)dicarbamate (19aa): This compound was obtained

along with 19a from general procedure A as described above, as a

brown solid (29 mg, 0.06 mmol, 20%), m.p. 134–136 °C. R_f= 0.24

(30 % ethyl acetate/hexanes). ¹H NMR (300 MHz, CDCl₃): δ =

8.11–8.03 (m, 2 H), 7.74–7.66 (m, 2 H), 4.99 (br. s, 2 H), 3.20 (dd,

J = 12.4, 6.1 Hz, 4 H), 2.70–2.58 (m, 4 H), 1.78–1.63 (m, 4 H), 1.45

(s, 18 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 185.0, 156.0,

146.8, 133.5, 132.1, 126.3, 79.2, 40.4, 29.8, 28.4, 24.0 ppm. IR

126.3, 39.5, 29.4, 24.3, 23.2 ppm. IR (ZnSe): ν = 3293, 3080, 2943,

˜

1657, 1595, 1551, 1441, 1364, 1294, 722 cm^–1. HRMS (ESI-TOF):

calcd. for C₂₀H₂₄N₂O₄Na 379.1628; found 379.1621.

N-[3-(1,4-Dioxo-1,4-dihydronaphthalen-2-yl)propyl]-2,2,2-trifluoro-

acetamide (19d): This compound was prepared according to general

procedure A starting from naphthoquinone 9 (47 mg, 0.3 mmol)

and TFA-γ-aminobutyric acid (191 mg, 0.96 mmol), and was puri-

fied by flash chromatography on silica gel (20 to 30% ethyl acetate/

hexanes). Pure 19d (36 mg, 0.12 mmol, 39%) was obtained as a

brown solid, m.p. 126–128 °C. R_f= 0.41 (30% ethyl acetate/hex-

(ZnSe): ν = 3356, 2965, 2924, 2854, 1692, 1660, 1523, 1513, 1366,

˜

1286, 1251, 1169, 772 cm^–1. HRMS (ESI-TOF): calcd. for

C₂₆H₃₆N₂O₆Na 495.2465; found 495.2459.

1

anes). H NMR (300 MHz, [D₆]acetone): δ = 8.11–8.04 (m, 1 H),

8.04–7.98 (m, 1 H), 7.89–7.81 (m, 2 H), 6.92 (t, J = 1.3 Hz, 1 H),

3.52–3.45 (m, 2 H), 2.73–2.58 (m, 2 H), 2.02–1.87 (m, 2 H) ppm.

¹³C NMR (75 MHz, [D₆]acetone): δ = 184.7, 184.5, 157.9/157.8/

157.4/157.3, 150.5, 134.9, 133.8, 133.7, 132.3, 132.1, 126.1, 125.6,

2,2,2-Trichloroethyl 3-(1,4-Dioxo-1,4-dihydronaphthalen-2-yl)prop-

ylcarbamate (19b): This compound was prepared according to ge-

neral procedure A starting from naphthoquinone 9 (47 mg,

0.3 mmol) and Troc-γ-aminobutyric acid (267 mg, 0.96 mmol), and

was purified by flash chromatography on silica gel (20 to 30% ethyl

acetate/hexanes). Pure 19b (47 mg, 0.12 mmol, 40%) was obtained

as a brown solid, m.p. 103–105 °C. R_f= 0.39 (30% ethyl acetate/

hexanes). ¹H NMR (300 MHz, CDCl₃): δ = 8.13–8.02 (m, 2 H),

7.81–7.69 (m, 2 H), 6.84 (s, 1 H), 5.33 (br. s, 1 H), 4.73 (s, 2 H),

3.34 (q, J = 6.8 Hz, 2 H), 2.64 (td, J = 7.8, 1.1 Hz, 2 H), 1.96–1.78

(m, 2 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 185.2, 184.9,

154.7, 150.6, 135.3, 133.9, 133.7, 132.1, 132.0, 126.7, 126.1, 95.6,

122.0/118.2/114.3/110.5, 38.9, 27.0, 26.5 ppm. IR (ZnSe): ν = 3293,

˜

2925, 1705, 1662, 1594, 1461, 1304, 1209, 1182, 779, 722, 663 cm^–1.

HRMS (ESI-TOF): calcd. for C₁₅H₁₂F₃NO₃Na 334.0661; found

334.0668.

N,NЈ-[3,3Ј-(1,4-Dioxo-1,4-dihydronaphthalene-2,3-diyl)bis(propane-

3,1-diyl)]bis(2,2,2-trifluoroacetamide) (19dd): This compound was

obtained along with 19d from general procedure A as described

above, as a brown solid (27 mg, 0.06 mmol, 19%), m.p. 143–145 °C.

1

74.5, 40.7, 28.4, 26.8 ppm. IR (ZnSe): ν = 3341, 2925, 1726, 1661,

˜

R_f= 0.26 (30% ethyl acetate/hexanes). H NMR (300 MHz, [D₆]-

1594, 1527, 1448, 1303, 1264, 1241, 1144, 945, 814, 775, 723 cm^–1.

HRMS (ESI-TOF): calcd. for C₁₆H₁₄Cl₃NO₄Na 411.9880; found

411.9878.

acetone): δ = 8.56 (br. s, 2 H), 8.12–8.01 (m, 2 H), 7.86–7.79 (m, 2

H), 3.48 (dd, J = 13.3, 6.8 Hz, 4 H), 2.82–2.67 (m, 4 H), 1.91–1.77

(m, 4 H) ppm. ¹³C NMR (75 MHz, [D₆]acetone): δ = 184.5, 157.5/

157.0/156.5/156.0, 146.3, 133.6, 132.2, 125.9, 122.0/118.2/114.4/

Bis(2,2,2-trichloroethyl) 3,3Ј-(1,4-Dioxo-1,4-dihydronaphthalene-

2,3-diyl)bis(propane-3,1-diyl)dicarbamate (19bb): This compound

was obtained along with 19b from general procedure A as de-

scribed above, as a brown oil (42 mg, 0.07 mmol, 22%). R_f= 0.27

(30 % ethyl acetate/hexanes). ¹H NMR (300 MHz, CDCl₃): δ =

8.12–8.02 (m, 2 H), 7.76–7.69 (m, 2 H), 5.58 (br. t, J = 5.4 Hz, 2

H), 4.75 (s, 4 H), 3.40–3.29 (m, 4 H), 2.73–2.62 (m, 4 H), 1.85–1.73

110.6, 39.5, 28.4, 24.0 ppm. IR (ZnSe): ν = 3317, 3104, 2924, 2854,

˜

1707, 1658, 1595, 1559, 1457, 1293, 1211, 1182, 1159, 722 cm^–1.

HRMS (ESI-TOF): calcd. for C₂₀H₁₈F₆N₂O₄Na 487.1062; found

487.1044.

tert-Butyl 1-(1,4-Dioxo-1,4-dihydronaphthalen-2-yl)ethylcarbamate

(20a): This compound was prepared according to general pro-

(m, 4 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 185.0, 156.0, cedure A starting from naphthoquinone 9 (235 mg, 1.5 mmol) and

146.8, 133.5, 132.1, 126.3, 79.2, 40.4, 29.8, 28.4, 24.0 ppm. IR Boc-d,l-alanine (840 mg, 4.8 mmol), and was purified by flash

(ZnSe): ν = 3346, 2951, 1719, 1658, 1594, 1454, 1286, 1241, 1145,

chromatography on silica gel (10 to 20% ethyl acetate/hexanes).

˜

10

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Alkylation of Naphthoquinones with Amino Acids

Pure 20a (50 mg, 0.16 mmol, 11%) was obtained as a yellow solid,

m.p. 140–142 °C. R_f= 0.45 (20% ethyl acetate/hexanes). H NMR

156.2/155.7, 145.6, 134.4, 132.0, 126.6, 121.5, 117.6, 113.8, 110.0,

47.6, 20.9 ppm. IR (ZnSe): ν = 3330, 2957, 1719, 1663, 1594, 1532,

˜

1

(300 MHz, CDCl₃): δ = 8.14–8.07 (m, 2 H), 7.81–7.74 (m, 2 H), 1459, 1291, 1210, 1170, 722 cm^–1. HRMS (ESI-TOF): calcd. for

6.89 (s, 1 H), 5.12 (br. s, 1 H), 4.93–4.87 (m, 1 H), 1.47 (br. d, J = C₁₈H₁₄F₆N₂O₄Na 459,0749; found 459,0748.

6.9 Hz, 3 H), 1.45 (s, 9 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ =

tert-Butyl 1-(1,4-Dioxo-1,4-dihydronaphthalen-2-yl)-2-phenylethyl-

185.4, 184.8, 154.7, 151.7, 133.9, 133.8, 133.2, 132.4, 131.9, 126.6,

carbamate (21a): This compound was prepared according to gene-

126.1, 80.0, 46.9, 28.2, 21.1 ppm. IR (ZnSe): ν = 3340, 2979, 2925,

˜

ral procedure A starting from naphthoquinone 9 (47 mg, 0.3 mmol)

and Boc-d,l-phenylalanine (255 mg, 0.96 mmol), and was purified

by flash chromatography on silica gel (0 to 20% ethyl acetate/hex-

anes). Pure 21a (26 mg, 0.07 mmol, 23%) was obtained as a dark

yellow solid, m.p. 175–177 °C. R_f= 0.43 (20% ethyl acetate/hex-

1700, 1664, 1594, 1509, 1332, 1301, 1247, 783, 719 cm^–1. HRMS

(ESI-TOF): calcd. for C₁₇H₁₉NO₄Na 324.1206; found 324.1205.

2,2,2-Trichloroethyl 1-(1,4-Dioxo-1,4-dihydronaphthalen-2-yl)ethyl-

carbamate (20b): This compound was prepared according to gene-

ral procedure A starting from naphthoquinone 9 (47 mg, 0.3 mmol)

and Troc-d,l-alanine (254 mg, 0.96 mmol), and was purified by

flash chromatography on silica gel (10 to 30% ethyl acetate/hex-

anes). Pure 20b (35 mg, 0.09 mmol, 31%) was obtained as a brown

1

anes). H NMR (300 MHz, CDCl₃): δ = 8.22–8.13 (m, 1 H), 8.12–

8.01 (m, 1 H), 7.88–7.72 (m, 2 H), 7.48–7.09 (m, 5 H), 6.65 (s, 1

H), 5.23 (br. d, J = 7.9 Hz, 1 H), 5.05 (dd, J = 14.7, 7.3 Hz, 1 H),

3.21 (dd, J = 13.7, 6.6 Hz, 1 H), 3.02 (dd, J = 13.7, 7.6 Hz, 1 H),

1.39 (s, 9 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 185.1, 184.9,

154.9, 149.2, 136.7, 134.9, 134.0, 133.9, 132.3, 131.9, 129.2, 128.7,

1

solid, m.p. 134–136 °C. R_f= 0.51 (20% ethyl acetate/CH₂Cl₂). H

NMR (300 MHz, CDCl₃): δ = 8.16–8.01 (m, 2 H), 7.82–7.71 (m, 2

H), 6.90 (s, 1 H), 5.71 (br. d, J = 7.8 Hz, 1 H), 5.00–4.89 (m, 1 H), 127.0, 126.6, 126.2, 80.1, 52.9, 40.8, 28.3 ppm. IR (ZnSe): ν = 3356,

˜

4.80–4.65 (m, 2 H), 1.55 (d, J = 7.0 Hz, 3 H) ppm. ¹³C NMR

(75 MHz, CDCl₃): δ = 185.1, 184.8, 153.6, 150.1, 134.1, 134.0, 1249, 1169, 780, 702 cm^–1. HRMS (ESI-TOF): calcd. for

2977, 2925, 1714, 1687, 1663, 1594, 1522, 1495, 1367, 1333, 1303,

133.7, 132.3, 131.9, 126.7, 126.2, 95.4, 74.7, 48.1, 21.0 ppm. IR

C₂₃H₂₃NO₄Na 400.1519; found 400.1536.

(ZnSe): ν = 3349, 2958, 1739, 1665, 1595, 1525, 1333, 1302, 1237,

˜

2,2,2-Trichloroethyl 1-(1,4-Dioxo-1,4-dihydronaphthalen-2-yl)-2-

phenylethylcarbamate (21b): This compound was prepared accord-

ing to general procedure A starting from naphthoquinone 9 (47 mg,

0.3 mmol) and Troc-d,l-phenylalanine (327 mg, 0.96 mmol), and

was purified by flash chromatography on silica gel (5 to 20% ethyl

acetate/hexanes). Pure 21b (62 mg, 0.14 mmol, 46%) was obtained

1117, 822, 781, 720 cm^–1. HRMS (ESI-TOF): calcd. for

C₁₅H₁₂Cl₃NO₄Na 397.9724; found 397.9723.

N-[1-(1,4-Dioxo-1,4-dihydronaphthalen-2-yl)ethyl]acetamide (20c):

This compound was prepared according to general procedure A

starting from naphthoquinone 9 (47 mg, 0.3 mmol) and N-acetyl-

d,l-alanine (126 mg, 0.96 mmol), and was purified by flash

chromatography on silica gel (60 to 80% ethyl acetate/hexanes).

Pure 20c (14 mg, 0.06 mmol, 19%) was obtained as a brown solid,

1

as a brown semi-solid. R_f= 0.35 (20% ethyl acetate/hexanes). H

NMR (300 MHz, CDCl₃): δ = 8.19–8.11 (m, 1 H), 8.10–7.99 (m, 1

H), 7.84–7.70 (m, 2 H), 7.38–7.08 (m, 5 H), 6.71 (s, 1 H), 5.87 (br.

d, J = 8.7 Hz, 1 H), 5.19–5.02 (m, 1 H), 4.78–4.60 (m, 2 H), 3.25

1

m.p. 185–187 °C. R_f= 0.43 (80% ethyl acetate/hexanes). H NMR

(300 MHz, CDCl₃): δ = 8.21–8.04 (m, 2 H), 7.86–7.73 (m, 2 H), (dd, J = 13.8, 6.5 Hz, 1 H), 3.08 (dd, J = 13.8, 8.2 Hz, 1 H) ppm.

6.88 (s, 1 H), 6.21 (d, J = 6.5 Hz, 1 H), 5.14 (p, J = 7.0 Hz, 1 H),

2.05 (s, 3 H), 1.52 (d, J = 7.0 Hz, 3 H) ppm. ¹³C NMR (75 MHz,

CDCl₃): δ = 185.2, 185.1, 169.3, 150.2, 134.1, 134.0, 133.9, 132.4,

¹³C NMR (75 MHz, CDCl₃): δ = 185.1, 184.7, 153.8, 148.0, 136.3,

135.2, 134.2, 134.0, 132.2, 131.8, 129.2, 128.8, 127.2, 126.7, 126.3,

95.3, 74.6, 54.1, 40.7 ppm. IR (ZnSe): ν = 3355, 1722, 1664, 1594,

˜

131.9, 126.6, 126.2, 46.6, 23.4, 21.0 ppm. IR (ZnSe): ν = 3286,

1536, 1392, 1333, 1303, 1137, 1109, 1042, 820, 779, 722, 703 cm^–1.

HRMS (ESI-TOF): calcd. for C₂₁H₁₆Cl₃NO₄Na 474.0042; found

474.0033.

˜

3065, 2921, 2850, 1663, 1594, 1540, 1372, 1332, 1300, 1250, 781,

720 cm^–1. HRMS (ESI-TOF): calcd. for C₁₄H₁₃NO₃Na 266.0787;

found 266.0784.

N-[1-(1,4-Dioxo-1,4-dihydronaphthalen-2-yl)-2-phenylethyl]acet-

amide (21c): This compound was prepared according to general

procedure A starting from naphthoquinone 9 (47 mg, 0.3 mmol)

and N-acetyl-d,l-phenylalanine (199 mg, 0.96 mmol), and was

purified by flash chromatography on silica gel (0 to 10% ethyl acet-

N-[1-(1,4-Dioxo-1,4-dihydronaphthalen-2-yl)ethyl]-2,2,2-trifluoro-

acetamide (20d): This compound was prepared according to general

procedure A starting from naphthoquinone 9 (47 mg, 0.3 mmol)

and TFA-d,l-alanine (178 mg, 0.96 mmol), and was purified by

flash chromatography on silica gel (10 to 30% ethyl acetate/hex- ate/CH₂Cl₂). Pure 21c (31 mg, 0.1 mmol, 32%) was obtained as a

anes). Pure 20d (30 mg, 0.1 mmol, 34%) was obtained as an orange

solid, m.p. 156–158 °C. R_f= 0.36 (20% ethyl acetate/hexanes). H

brown solid, m.p. 219–221 °C. R_f= 0.48 (50% ethyl acetate/hex-

anes). H NMR (300 MHz, CDCl₃): δ = 8.21–8.12 (m, 1 H), 8.11–

1

NMR (300 MHz, CDCl₃): δ = 8.18–8.07 (m, 2 H), 7.87–7.77 (m, 2

8.01 (m, 1 H), 7.88–7.71 (m, 2 H), 7.40–7.07 (m, 5 H), 6.62 (d, J

H), 7.36 (br. d, J = 6.8 Hz, 1 H), 6.91 (d, J = 0.6 Hz, 1 H), 5.24– = 0.7 Hz, 1 H), 6.28 (d, J = 8.4 Hz, 1 H), 5.40–5.19 (m, 1 H), 3.22

5.06 (m, 1 H), 1.63 (d, J = 7.1 Hz, 3 H) ppm. ¹³C NMR (75 MHz,

(dd, J = 13.7, 7.5 Hz, 2 H), 3.10 (dd, J = 13.7, 7.5 Hz, 1 H), 1.99

CDCl₃): δ = 185.1, 184.7, 157.2/156.7/156.2/155.7, 147.8, 135.0, (s, 3 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 185.5, 184.7, 169.4,

134.5, 134.2, 132.1, 131.7, 126.8, 126.4, 121.5/117.6/113.8/110.0, 147.9, 136.6, 135.6, 134.2, 133.9, 132.3, 131.8, 129.1, 128.8, 127.2,

47.7, 20.8 ppm. IR (ZnSe): ν = 3318, 3077, 1708, 1665, 1594, 1552,

126.6, 126.3, 52.3, 40.6, 23.4 ppm. IR (ZnSe): ν = 3313, 3066, 2923,

˜

1332, 1303, 1254, 1212, 1184, 781, 717 cm^–1. HRMS (ESI-TOF):

calcd. for C₁₄H₁₀F₃NO₃Na 320,0504; found 320,0504.

2853, 1660, 1643, 1594, 1539, 1454, 1372, 1334, 1303, 1271, 1254,

1234, 781, 709 cm^–1. HRMS (ESI-TOF): calcd. for C₂₀H₁₇NO₃Na

342.1100; found 342.1112.

N,NЈ-[1,1Ј-(1,4-Dioxo-1,4-dihydronaphthalene-2,3-diyl)bis(ethane-

1,1-diyl)]bis(2,2,2-trifluoroacetamide) (20dd): This compound was N-[1-(1,4-Dioxo-1,4-dihydronaphthalen-2-yl)-2-phenylethyl]-2,2,2-tri-

obtained along with 20d from general procedure A as described

above, as a yellow solid (11 mg, 0.03 mmol, 8%), m.p. 160–162 °C.

R_f= 0.39 (20 % ethyl acetate/hexanes). ¹H NMR (300 MHz,

CDCl₃): δ = 8.17–8.02 (m, 2 H), 7.90–7.76 (m, 2 H), 7.60 (br. d, J

= 8.5 Hz, 2 H), 5.56 (dq, J = 14.4, 7.1 Hz, 1 H), 1.74 (d, J = 7.1 Hz,

fluoroacetamide (21d): This compound was prepared according to

general procedure A starting from naphthoquinone 9 (237 mg,

1.5 mmol) and TFA-d,l-phenylalanine (1.25 mg, 4.8 mmol), and

was purified by flash chromatography on silica gel (10 to 60% ethyl

CH₂Cl₂/hexanes). Pure 21d (124 mg, 0.33 mmol, 22 %) was ob-

6 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 185.0, 157.2/156.7/ tained as a brown solid, m.p. 171–173 °C. R_f= 0.30 (60% CH₂Cl₂/

Eur. J. Org. Chem. 0000, 0–0

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J. Dessolin et al.

FULL PAPER

hexanes). ¹H NMR (300 MHz, CDCl₃): δ = 8.20–8.13 (m, 1 H), CDCl₃): δ = 185.0, 184.8, 154.8, 152.5, 134.6, 133.8, 132.3, 131.8,

8.10–8.02 (m, 1 H), 7.86–7.76 (m, 2 H), 7.43 (br. d, J = 8.6 Hz, 1 126.8, 126.1, 95.4, 74.4, 45.7, 33.5, 16.6 ppm. IR (ZnSe): ν = 3354,

H), 7.37–7.11 (m, 5 H), 6.60 (d, J = 0.5 Hz, 1 H), 5.21 (q, J = 2965, 2933, 1730, 1663, 1594, 1533, 1332, 1305, 1248, 1149, 813,

7.8 Hz, 1 H), 3.22 (d, J = 7.6 Hz, 2 H) ppm. ¹³C NMR (75 MHz, 781, 722 cm^–1. HRMS (ESI-TOF): calcd. for C₁₆H₁₄Cl₃NO₄Na

˜

CDCl₃): δ = 185.4, 184.4, 157.3/156.8/156.3/155.8, 145.5, 136.4, 411.9886; found 411.9875.

135.5, 134.6, 134.1, 132.0, 131.7, 129.1, 129.0, 127.6, 126.8, 126.4,

N-[2-(1,4-Dioxo-1,4-dihydronaphthalen-2-yl)propyl]acetamide (22c):

121.2/117.4/113.7/109.8, 53.5, 40.5 ppm. IR (ZnSe): ν = 3300, 3031,

˜

This compound was prepared according to general procedure A

starting from naphthoquinone 9 (41 mg, 0.26 mmol) and N-acetyl-

d,l-3-aminoisobutyric acid (120 mg, 0.83 mmol), and was purified

by flash chromatography on silica gel (70 to 90% ethyl acetate/

hexanes). Pure 22c (34 mg, 0.13 mmol, 51%) was obtained as a

brown solid, m.p. 130–132 °C. R_f= 0.31 (80% ethyl acetate/hex-

1702, 1661, 1593, 1560, 1333, 1304, 1272, 1209, 1183, 965, 915,

781, 706 cm^–1. HRMS (ESI-TOF): calcd. for C₂₀H₁₄F₃NO₃Na

396.0817; found 396.0828.

N,NЈ-[1,1Ј-(1,4-Dioxo-1,4-dihydronaphthalene-2,3-diyl)bis(2-phenyl-

ethane-1,1-diyl)]bis(2,2,2-trifluoroacetamide) (21dd): This com-

pound was obtained along with 21d from general procedure A as

described above, as a yellow solid (15 mg, 0.03 mmol, 2%), m.p.

1

anes). H NMR (300 MHz, CDCl₃): δ = 8.12–8.03 (m, 1 H), 8.04–

7.94 (m, 1 H), 7.76–7.66 (m, 2 H), 6.75 (s, 1 H), 6.14 (br. s, 1 H),

195–197 °C. R_f= 0.50 (60 % CH₂Cl₂/hexanes). ¹H NMR 3.54–3.43 (m, 1 H), 3.43–3.23 (m, 2 H), 1.90 (s, 3 H), 1.22 (d, J =

(300 MHz, CDCl₃): δ = 8.22–8.07 (m, 2 H), 7.94–7.80 (m, 2 H), 6.8 Hz, 3 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 185.0, 184.9,

7.55 (br. d, J = 9.2 Hz, 2 H), 7.37–7.17 (m, 10 H), 5.80–5.64 (m, 2

170.4, 153.1, 134.2, 133.8 (ϫ2), 132.3, 131.7, 126.7, 126.0, 44.1,

H), 3.37–3.15 (m, 4 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 33.2, 23.1, 16.9 ppm. IR (ZnSe): ν = 3290, 2926, 2854, 1660, 1593,

˜

185.5, 157.4/156.9/156.4/155.9, 143.6, 135.7, 134.9, 131.7, 129.3,

128.9, 127.4, 126.9, 121.3/117.5/113.8/109.9, 50.6, 40.5 ppm. IR (ESI-TOF): calcd. for C₁₅H₁₅NO₃Na 280.0944; found 280.0950.

1548, 1441, 1374, 1332, 1303, 1258, 927, 780, 718 cm^–1. HRMS

(ZnSe): ν = 3356, 3065, 3031, 1719, 1656, 1592, 1529, 1455, 1294,

˜

N-[2-(1,4-Dioxo-1,4-dihydronaphthalen-2-yl)propyl]-2,2,2-trifluoro-

acetamide (22d): This compound was prepared according to general

procedure A starting from naphthoquinone 9 (47 mg, 0.3 mmol)

and TFA-d,l-3-aminoisobutyric acid (191 mg, 0.96 mmol), and

was purified by flash chromatography on silica gel (0 to 3% ethyl

acetate/CH₂Cl₂). Pure 22d (53 mg, 0.17 mmol, 57%) was obtained

as a brown solid, m.p. 127–129 °C. R_f= 0.44 (3% ethyl acetate/

CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃): δ = 8.12–8.05 (m, 1 H),

8.05–7.95 (m, 1 H), 7.79–7.64 (m, 2 H), 7.09 (br. s, 1 H), 6.80 (d,

J = 0.7 Hz, 1 H), 3.71–3.47 (m, 2 H), 3.47–3.33 (m, 1 H), 1.29 (d,

1218, 1168, 722, 700, 603, 523 cm^–1. HRMS (ESI-TOF): calcd. for

C₃₀H₂₂F₆N₂O₄Na 611.1367; found 611.1375.

tert-Butyl 2-(1,4-Dioxo-1,4-dihydronaphthalen-2-yl)propylcarbamate

(22a): This compound was prepared according to general pro-

cedure A starting from naphthoquinone 9 (47 mg, 0.3 mmol) and

Boc-d,l-3-aminoisobutyric acid (195 mg, 0.96 mmol), and was

purified by flash chromatography on silica gel (10 to 30% ethyl

acetate/hexanes). Pure 22a (60 mg, 0.19 mmol, 63%) was obtained

as a brown solid, m.p. 87–90 °C. R_f= 0.39 (20% ethyl acetate/

hexanes). ¹H NMR (300 MHz, CDCl₃): δ = 8.08–8.04 (m, 1 H), J = 7.0 Hz, 3 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 184.9

8.02–7.98 (m, 1 H), 7.75–7.67 (m, 2 H), 6.75 (s, 1 H), 4.77 (br. s, 1 (ϫ2), 157.9/157.8/157.4/157.3, 152.1, 134.8, 134.1, 134.0, 132.1,

H), 3.53–3.49 (m, 1 H), 3.32–3.29 (m, 2 H), 1.33 (s, 9 H), 1.21 (d, 131.7, 126.8, 126.1, 121.5/117.7/113.9/110.1, 44.3, 32.9, 16.6 ppm.

J = 6.9 Hz, 3 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 185.1,

184.7, 155.9, 153.1, 134.2, 133.7, 133.6, 132.4, 131.8, 126.8, 125.9,

IR (ZnSe): ν = 3315, 3103, 2927, 1713, 1664, 1594, 1557, 1332,

˜

1305, 1210, 1183, 1160, 924, 781, 719 cm^–1. HRMS (ESI-TOF):

calcd. for C₁₅H₁₂F₃NO₃Na 334.0661; found 334.0660.

79.4, 44.9, 33.7, 28.2, 16.5 ppm. IR (ZnSe): ν = 3381, 2976, 2931,

˜

1707, 1664, 1595, 1519, 1304, 1331, 1304, 1252, 1171, 990, 929,

861, 781, 721 cm^–1. HRMS (ESI-TOF): calcd. for C₁₈H₂₁NO₄Na

338.1362; found 338.1367.

N,NЈ-[1,1Ј-(1,4-Dioxo-1,4-dihydronaphthalene-2,3-diyl)bis(ethane-

1,1-diyl)]bis(2,2,2-trifluoroacetamide) (22dd): This compound was

obtained along with 22d from general procedure A as described

above, as a brown semi-solid (20 mg, 0.04 mmol, 14%). R_f= 0.25

(3% ethyl acetate/CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃): δ = 8.11–

8.03 (m, 2 H), 7.84–7.75 (m, 2 H), 3.82–3.63 (m, 4 H), 3.55–3.41

(m, 2 H), 1.41 (d, J = 7.0 Hz, 6 H) ppm. ¹³C NMR (75 MHz,

CDCl₃): δ = 184.9, 158.6/158.1/157.6/157.1, 149.0, 133.4, 132.3,

Di-tert-butyl 2,2Ј-(1,4-Dioxo-1,4-dihydronaphthalene-2,3-diyl)bis-

(propane-2,1-diyl)dicarbamate (22aa): This compound was obtained

along with 22a from general procedure A as described above, as a

brown solid (16 mg, 0.03 mmol, 11%), m.p. 154–156 °C. R_f= 0.34

(20 % ethyl acetate/hexanes). ¹H NMR (300 MHz, CDCl₃): δ =

8.08–8.00 (m, 2 H), 7.74–7.66 (m, 2 H), 4.77 (br. s, 2 H), 3.68–3.64 125.6, 121.8/118.0/114.2/110.4, 43.7, 34.6, 16.2 ppm. IR (ZnSe): ν

˜

(m, 2 H), 3.47–3.43 (m, 4 H), 1.38–1.35 (m, 18 H), 1.23 (d, J = = 3315, 3102, 2967, 1707, 1661, 1594, 1556, 1329, 1291, 1211, 1182,

6.9 Hz, 6 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 185.0, 154.8,

1162, 723 cm^–1. HRMS (ESI-TOF): calcd. for C₂₀H₁₈F₆N₂O₄Na

153.0, 133.9, 132.0, 126.0, 79.6, 44.8, 32.9, 28.1, 15.9 ppm. IR 487.1062; found 487.1060.

(ZnSe): ν = 3384, 2977, 2932, 1704, 1659, 1594, 1520, 1366, 1290,

˜

tert-Butyl 2-{1,4-Dioxo-3-[2-(2,2,2-trifluoroacetamido)ethyl]-1,4-di-

hydronaphthalen-2-yl}ethylcarbamate (23a): This compound was

prepared according to general procedure A starting from quinone

1250, 1170, 986, 724 cm^–1. HRMS (ESI-TOF): calcd. for

C₂₆H₃₆N₂O₆Na 439.1839; found 439.1853.

2,2,2-Trichloroethyl 2-(1,4-Dioxo-1,4-dihydronaphthalen-2-yl)prop- 18a (90 mg, 0.3 mmol) and TFA-β-alanine (178 mg, 0.96 mmol),

ylcarbamate (22b): This compound was prepared according to ge-

neral procedure A starting from naphthoquinone 9 (35 mg,

0.22 mmol) and Troc-d,l-3-aminoisobutyric acid (200 mg,

0.72 mmol), and was purified by flash chromatography on silica gel

(10 to 30% ethyl acetate/hexanes). Pure 22b (63 mg, 0.16 mmol,

and was purified by flash chromatography on silica gel (10 to 30%

ethyl acetate/CH₂Cl₂). Pure 23a (78 mg, 0.18 mmol, 59%) was ob-

tained as a brown solid, m.p. 162–164 °C. R_f= 0.27 (10% ethyl

acetate/CH₂Cl₂). H NMR (300 MHz, CDCl₃): δ = 8.11–7.96 (m,

2 H), 7.85 (br. s, 1 H), 7.76–7.65 (m, 2 H), 5.12 (br. s, 1 H), 3.63

1

73%) was obtained as a brown oil. R_f= 0.35 (20% ethyl acetate/ (d, J = 6.0 Hz, 2 H), 3.31 (d, J = 6.5 Hz, 2 H), 3.00 (t, J = 6.6 Hz,

hexanes). ¹H NMR (300 MHz, CDCl₃): δ = 8.15–8.07 (m, 1 H), 2 H), 2.89 (t, J = 7.1 Hz, 2 H), 1.35 (s, 9 H) ppm. ¹³C NMR

8.07–7.96 (m, 1 H), 7.85–7.65 (m, 2 H), 6.80 (s, 1 H), 5.31 (br. t, J (75 MHz, CDCl₃): δ = 185.2, 184.7, 158.3/157.8/157.3/156.8, 156.3,

= 5.4 Hz, 1 H), 4.66 (d, J = 3.0 Hz, 2 H), 3.59–3.44 (m, 2 H), 3.43–

145.9, 144.6, 133.8, 133.7, 131.9, 131.8, 126.4, 126.3, 121.5/117.6/

3.32 (m, 1 H), 1.27 (d, J = 6.6 Hz, 3 H) ppm. ¹³C NMR (75 MHz,

113.8/110.0, 79.9, 40.1, 39.3, 28.2 (ϫ2), 26.8 ppm. IR (ZnSe): ν =

˜

12

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Alkylation of Naphthoquinones with Amino Acids

3379, 2966, 2929, 1703, 1663, 1593, 1561, 1539, 1303, 1267, 1215,

1.3 equiv.) and DIEA (diisopropylethylamine, 5.4 equiv.) were

1165, 777 cm^–1. HRMS (ESI-TOF): calcd. for C₂₁H₂₃F₃N₂O₅Na added to a solution of the amino acid (1.2 equiv., 0.12 m) in

463.1457; found 463.1464.

CH₂Cl₂were added. The reaction mixture quickly became clear, and

it was stirred for 45 min under a nitrogen atmosphere before am-

monium trifluoroacetate (1 equiv.) was added. The reaction mix-

ture was stirred at room temperature for 3 h, then concentrated

under reduced pressure. The residue was dissolved in ethyl acetate,

washed with water, dried with MgSO₄, and filtered through Celite.

The organic phase was then concentrated under reduced pressure.

Purification was performed by silica gel chromatography to yield

the pure product.

Compound 23b: This compound was prepared according to general

procedure A starting from quinone 18a (90 mg, 0.3 mmol) and

Troc-β-alanine (254 mg, 0.96 mmol), and was purified by flash

chromatography on silica gel (0 to 20% ethyl acetate/CH₂Cl₂). Pure

23b (85 mg, 0.16 mmol, 55%) was obtained as a brown solid, m.p.

135–137 °C. R_f= 0.35 (5% ethyl acetate/CH₂Cl₂). ¹H NMR

(300 MHz, CDCl₃): δ = 8.10–7.98 (m, 2 H), 7.72–7.63 (m, 2 H),

6.07 (br. s, 1 H), 5.09 (br. s, 1 H), 4.64 (s, 2 H), 3.55–3.43 (m, 2 H),

3.40–3.30 (m, 2 H), 2.95 (t, J = 6.7 Hz, 2 H), 2.89 (t, J = 7.0 Hz,

2 H), 1.34 (s, 9 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 184.9

(ϫ2), 156.2, 154.8, 145.8, 145.0, 133.6 (ϫ2), 132.0 (ϫ2), 126.3,

(S)-tert-Butyl 1-[(3-Methyl-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-

methylamino]-1-oxopropan-2-ylcarbamate (25): This compound was

prepared according to general procedure B starting from quinone

11a (301 mg, 1 mmol), Boc-alanine (227 mg, 1.2 mmol), HBtU

(607 mg, 1.6 mmol), HOBt (176 mg, 1.3 mmol), and DIEA

(940 μL, 5.4 mmol), and was purified by flash chromatography on

silica gel (40 to 60% ethyl acetate/hexanes). Pure 25 (149 mg,

0.40 mmol, 40%) was obtained as an orange solid, m.p. 140–

95.6, 79.5, 74.4, 40.4 (ϫ2), 28.3, 27.9 (ϫ2) ppm. IR (ZnSe): ν =

˜

3381, 3356, 2964, 2930, 1735, 1665, 1594, 1524, 1369, 1330, 1303,

1267, 1244, 1155, 822, 779, 715 cm^–1. HRMS (ESI-TOF): calcd.

for C₂₂H₂₅Cl₃N₂O₆Na 541.0676; found 541.0679.

tert-Butyl 3-{1,4-Dioxo-3-[2-(2,2,2-trifluoroacetamido)ethyl]-1,4-di-

hydronaphthalen-2-yl}propylcarbamate (24a): This compound was

prepared according to general procedure A starting from quinone

19a (95 mg, 0.3 mmol) and TFA-β-alanine (178 mg, 0.96 mmol),

and was purified by flash chromatography on silica gel (5 to 20%

ethyl acetate/CH₂Cl₂). Pure 24a (61 mg, 0.13 mmol, 45%) was ob-

tained as a brown solid, m.p. 150–152 °C. R_f= 0.37 (10% ethyl

143 °C. R_f

=

0.30 (40% ethyl acetate/hexanes). ¹H NMR

(300 MHz, CDCl₃): δ = 8.09 (m, 2 H), 7.73 (m, 2 H), 6.80 (br. s, 1

H), 4.94 (br. s, 1 H), 4.45 (d, J = 6.3 Hz, 2 H), 4.13 (m, 1 H), 2.39

(s, 3 H), 1.39 (s, 9 H), 1.34 (d, J = 7.1 Hz, 3 H) ppm. ¹³C NMR

(75 MHz, CDCl₃): δ = 185.3, 185.2, 172.5, 155.3, 145.6, 141.2,

133.8, 133.6, 126.5, 126.2, 132.1, 131.7, 80.2, 50.1, 36.2, 28.2, 18.2,

1

12.7 ppm. IR (ZnSe): ν = 3361, 3294, 3046, 2971, 2930, 1633, 1538,

˜

acetate/CH₂Cl₂). H NMR (300 MHz, CDCl₃): δ = 8.14–8.01 (m,

1294, 1180, 1073, 1021, 725 cm^–1. HRMS (ESI-TOF): calcd. for

C₂₀H₂₄N₂O₅Na 395.1577; found 395.1567.

2 H), 7.77–7.69 (m, 2 H), 7.39 (br. s, 1 H), 4.96 (br. s, 1 H), 3.57

(q, J = 6.3 Hz, 2 H), 3.23 (q, J = 6.0 Hz, 2 H), 2.95 (t, J = 7.0 Hz,

2 H), 2.79–2.65 (t, J = 7.1 Hz, 2 H), 1.81–1.69 (m, 2 H), 1.43 (s, 9

H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 185.6, 184.6, 158.3/

157.8/157.3/156.8, 156.2, 148.8, 143.1, 133.9, 133.7, 132.0, 131.8,

126.5, 126.4, 121.5/117.6/113.8/110.0, 79.3, 40.4, 39.4, 29.7, 28.3,

(S)-tert-Butyl 1-[(3-Methyl-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-

methylamino]-1-oxopropan-2-ylcarbamate (26): This compound was

prepared according to general procedure B starting from quinone

12a (315 mg, 1 mmol), Boc-alanine (227 mg, 1.2 mmol), HBtU

(607 mg, 1.6 mmol), HOBt (176 mg, 1.3 mmol), and DIEA

(940 μL, 5.4 mmol), and was purified by flash chromatography on

silica gel (40 to 60% ethyl acetate/hexanes). Pure 26 (205 mg,

0.53 mmol, 53%) was obtained as a yellow solid, m.p. 164–166 °C.

R_f= 0.38 (50% ethyl acetate/hexanes). ¹H NMR (300 MHz,

CDCl₃): δ = 8.11 (m, 2 H), 7.75 (m, 2 H), 6.83 (br. s, 1 H), 4.93

(br. s, 1 H), 4.13 (m, 1 H), 3.79 (q, J = 6.5 Hz, 2 H), 2.75 (t, J =

6.8 Hz, 2 H), 2.40 (s, 3 H), 1.39 (s, 9 H), 1.33 (d, J = 7.1 Hz, 3 H)

ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 185.3, 185.2, 172.4, 155.4,

145.5, 141.1, 133.8, 133.6, 126.4, 126.2, 132.1, 131.8, 80.4, 50.3,

39.4, 28.3, 27.8, 18.2, 12.6 ppm.

26.5, 24.2 ppm. IR (ZnSe): ν = 3356, 3316, 3103, 2979, 2938, 1698,

˜

1657, 1594, 1541, 1454, 1298, 1276, 1196, 1179, 722 cm^–1. HRMS

(ESI-TOF): calcd. for C₂₂H₂₅F₃N₂O₅Na 477.1607; found 477.1616.

Compound 24b: This compound was prepared according to general

procedure A starting from quinone 19a (95 mg, 0.3 mmol) and

Troc-β-alanine (254 mg, 0.96 mmol), and was purified by flash

chromatography on silica gel (5 to 20% ethyl acetate/CH₂Cl₂). Pure

24b (87 mg, 0.16 mmol, 54%) was obtained as a brown solid, m.p.

121–122 °C. R_f= 0.42 (10% ethyl acetate/CH₂Cl₂). ¹H NMR

(300 MHz, CDCl₃): δ = 8.09–7.99 (m, 2 H), 7.73–7.65 (m, 2 H),

5.76 (br. s, 1 H), 5.09 (br. s, 1 H), 4.68 (s, 2 H), 3.43 (d, J = 6.8 Hz,

2 H), 3.22 (q, J = 5.8 Hz, 2 H), 2.90 (t, J = 7.2 Hz, 2 H), 2.75–2.66

(t, J = 5.9 Hz, 2 H), 1.80–1.66 (m, 2 H), 1.44 (s, 9 H) ppm. ¹³C

NMR (75 MHz, CDCl₃): δ = 185.1, 184.7, 156.2, 154.8, 148.5,

143.5, 133.6, 132.0, 131.9, 126.4, 126.3, 95.5, 79.2, 74.4, 40.6, 29.7,

5-Methyl-3,4-dihydrobenzo[h]quinolin-6(2H)-one (27): This com-

pound was prepared according to general procedure B starting

from quinone 13a (203 mg, 1 mmol), Boc-alanine (227 mg,

1.2 mmol), HBtU (607 mg, 1.6 mmol), HOBt (176 mg, 1.3 mmol),

and DIEA (940 μL, 5.4 mmol), and was purified by flash

chromatography on silica gel (CH₂Cl₂). The unexpected pure cy-

clized compound (i.e., 27) was obtained as a brown solid. R_f= 0.50

(CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃): δ = 8.25 (d, J = 7.6 Hz, 1

H), 8.11 (dd, J = 7.6, 1.2 Hz, 1 H), 7.60 (dt, J = 7.6, 1.2 Hz, 1 H),

7.54 (dt, J = 7.6, 1.2 Hz, 1 H), 4.08 (t, J = 5.6 Hz, 2 H), 2.70 (t, J

= 6.4 Hz, 2 H), 2.07 (s, 3 H), 1.88 (quint, J = 6.4 Hz, 2 H) ppm.

¹³C NMR (75 MHz, CDCl₃): δ = 185.0, 155.8, 135.6, 135.3, 132.4,

130.9, 130.8, 130.1, 125.8, 124.0, 50.9, 25.9, 21.7, 11.2 ppm. IR

28.4, 28.3, 27.8, 24.3 ppm. IR (ZnSe): ν = 3366, 2959, 2925, 1735,

˜

1694, 1663, 1594, 1522, 1456, 1325, 1302, 1263, 1243, 1155, 823,

780 cm^–1. HRMS (ESI-TOF): calcd. for C₂₃H₂₇Cl₃N₂O₆Na

555.0832; found 555.0821.

General Procedure B, Peptidic Coupling of Amino Acids with N-Boc-

Protected Aminoalkyl Naphthoquinones. Preparation of Compounds

25, 26, 27, and 28: A solution of N-Boc-protected aminoalkyl naph-

thoquinone (1 equiv., 0.1 m) in CH₂Cl₂/trifluoroacetic acid (1:1)

was stirred at 0 °C for 5 min before it was concentrated under re-

duced pressure. The residue was dissolved in toluene and then con-

centrated again. This co-evaporation was repeated three times in

order to remove the excess of trifluoroacetic acid. The crude am-

monium trifluoroacetate was used without further purification.

(ZnSe): ν = 3391, 2975, 2932, 1693, 1656, 1514, 1293, 1250, 1166,

˜

715 cm^–1. HRMS (ESI-TOF): calcd. for C₁₄H₁₁NONa (oxidation

during analysis) 209.0841; found 209.0841.

3-Methyl-2,3-dihydrobenzo[g]indol-5-one (28): This compound was

HBtU [O-(benzotriazol-1-yl)-N,N,NЈ,NЈ-tetramethyluronium hexa- prepared according to general procedure B starting from quinone

fluorophosphate; 1.6 equiv.], HOBt (hydroxybenzatriazole; 16a (16 mg, 0.05 mmol), Boc-phenylalanine (16 mg, 0.06 mmol),

Eur. J. Org. Chem. 0000, 0–0

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J. Dessolin et al.

HBtU (30 mg, 0.08 mmol), HOBt (9 mg, 0.07 mmol), and DIEA 172.7, 155.9, 145.1, 144.3, 138.9, 134.6, 134.5, 132.6, 132.5, 129.9,

FULL PAPER

(47 μL, 0.27 mmol), and was purified by flash chromatography on

silica gel (20 to 40% ethyl acetate/hexanes). The unexpected pure

cyclized compound (i.e., 28; 9 mg, 0.04 mmol, 82%) was obtained

as a brown solid. When this reaction was reconducted, the com-

pound yields were different, we reported our best result, m.p. 83–

85 °C. R_f= 0.51 (40% ethyl acetate/hexanes). ¹H NMR (300 MHz,

CDCl₃): δ = 8.32–8.25 (m, 1 H), 8.22–8.16 (m, 1 H), 7.75–7.60 (m,

2 H), 4.55 (dd, J = 19.0, 6.0 Hz, 1 H), 4.03 (d, J = 19.0 Hz, 1 H),

3.37–3.22 (m, 1 H), 2.17 (s, 3 H), 1.31 (d, J = 7.3 Hz, 3 H) ppm.

¹³C NMR (75 MHz, CDCl₃): δ = 185.3, 163.4, 154.9, 133.4, 132.3,

131.9, 130.8, 130.2, 126.8, 124.7, 69.5, 36.0, 19.2, 11.1 ppm. IR

128.7, 127.0, 126.7, 126.6, 78.7, 56.6, 38.3, 37.0, 29.0, 28.3,

13.6 ppm. IR (ZnSe): ν = 3325, 2981, 2475, 1686, 1647, 1294, 1168,

˜

1047, 1027, 714 cm^–1. HRMS (ESI-TOF): calcd. for

C₂₇H₃₀N₂O₅Na 485.2046; found 485.2056.

(S)-tert-Butyl

1-[2-(1,4-Dioxo-1,4-dihydronaphthalen-2-yl)ethyl-

amino]-1-oxo-3-phenylpropan-2-ylcarbamate (32): This compound

was prepared according to general procedure A starting from

naphthoquinone 9 (21 mg, 0.14 mmol) and Boc-Phe-β-Ala-OH

(145 mg, 0.43 mmol), and was purified by flash chromatography

on silica gel (40 to 60% ethyl acetate/hexanes). Pure 32 (22 mg,

0.05 mmol, 37%) was obtained as a yellow solid, m.p. 96–99 °C. R_f

(ZnSe): ν = 3375, 3320, 2963, 2925, 1702, 1644, 1600, 1439, 1378,

˜

1

= 0.41 (50% ethyl acetate/hexanes). H NMR (300 MHz, CDCl₃):

1332, 1299, 1261, 1161, 977, 780, 696 cm^–1. HRMS (ESI-TOF):

calcd. for C₁₄H₁₃NONa 212.1069; found 212.1076.

δ = 8.07 (m, 2 H), 7.75 (m, 2 H), 7.18 (m, 5 H), 6.73 (s, 1 H), 6.20

(br. s, 1 H), 5.05 (br. s, 1 H), 4.29 (q, J = 7.1 Hz, 1 H), 3.45 (q, J

= 6.5 Hz, 2 H), 3.02 (d, J = 6.9 Hz, 2 H), 2.66 (dd, J = 13.0, 6.6 Hz,

2 H), 1.40 (s, 9 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 185.2,

184.7, 171.5, 155.4, 148.2, 136.7, 136.1, 133.9, 133.7, 132.1, 132.0,

129.2, 128.6, 126.9, 126.6, 126.1, 80.2, 56.1, 38.6, 38.1, 30.1,

(S)-tert-Butyl 1-[(3-Methyl-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-

methylamino]-1-oxopropan-2-ylcarbamate (29): This compound was

prepared according to general procedure A starting from me-

nadione (8) (40 mg, 0.23 mmol) and Boc-Ala-Gly-OH (258 mg,

0.74 mmol), and was purified by flash chromatography on silica gel

(20 to 40% ethyl acetate/hexanes). Pure 29 (16 mg, 0.043 mmol,

18%) was obtained as an orange solid, m.p. 140–143 °C. R_f= 0.30

(40% ethyl acetate/hexanes). ¹H NMR (300 MHz, CDCl₃): δ = 8.09

(m, 2 H), 7.73 (m, 2 H), 6.80 (br. s, 1 H), 4.94 (br. s, 1 H), 4.45 (d,

J = 6.3 Hz, 2 H), 4.13 (m, 1 H), 2.39 (s, 3 H), 1.39 (s, 9 H), 1.34

(d, J = 7.1 Hz, 3 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 185.3,

185.2, 172.5, 155.3, 145.6, 141.2, 133.8, 133.6, 126.5, 126.2, 132.1,

28.2 ppm. IR (ZnSe): ν = 3338, 2977, 2931, 1663, 1521, 1302, 1267,

˜

1168, 1048, 702 cm^–1. HRMS (ESI-TOF): calcd. for

C₂₆H₂₈N₂O₅Na 471.1890; found 471.1905.

Naphthoquinone 33: This compound was prepared according to ge-

neral procedure A starting from quinone 18a (40 mg, 0.14 mmol)

and Boc-Phe-β-Ala-OH (145 mg, 0.43 mmol), and was purified by

flash chromatography on silica gel (10 to 40% ethyl acetate/hex-

anes). Pure 33 (28 mg, 0.05 mmol, 35%) was obtained as a brown

solid, m.p. 98–100 °C. R_f= 0.23 (50% ethyl acetate/hexanes). ¹H

NMR (300 MHz, CDCl₃): δ = 8.16–7.98 (m, 2 H), 7.81–7.59 (m, 2

H), 7.34–7.07 (m, 5 H), 6.56 (br. s, 1 H), 5.13 (br. s, 1 H), 4.38–

4.22 (m, 1 H), 3.58–3.43 (m, 1 H), 3.35 (m, 3 H), 3.10–2.94 (m, 2

H), 2.86 (t, J = 7.2 Hz, 2 H), 2.80 (t, J = 6.9 Hz, 2 H), 1.38 (s, 9

H), 1.33 (s, 9 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 185.2,

184.7, 171.7, 156.1, 136.7, 133.6, 133.5, 132.1, 132.0, 129.3, 128.5,

126.8, 126.4, 126.3, 79.4, 55.8, 45.5, 39.0, 28.3, 27.5, 23.9 ppm. IR

131.7, 80.2, 50.1, 36.2, 28.2, 18.2, 12.7 ppm. IR (ZnSe): ν = 3361,

˜

3294, 3046, 2971, 2930, 1633, 1538, 1294, 1180, 1073, 1021,

725 cm^–1. HRMS (ESI-TOF): calcd. for C₂₀H₂₄N₂O₅Na 395.1577;

found 395.1567.

(S)-tert-Butyl 1-[3-(3-Methyl-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-

propylamino]-1-oxo-3-phenylpropan-2-ylcarbamate (30): This com-

pound was prepared according to general procedure A starting

from menadione (8) (42 mg, 0.25 mmol) and Boc-Phe-GABA-OH

(276 mg, 0.79 mmol), and was purified by flash chromatography

on silica gel (30 to 50% ethyl acetate/hexanes). Pure 30 (61 mg,

0.13 mmol, 51%) was obtained as a yellow solid, m.p. 152–154 °C.

(ZnSe): ν = 3380, 339, 2877, 2932, 1698, 1663, 1595, 1522, 1369,

˜

1302, 1267, 1168, 1049, 780, 701 cm^–1. HRMS (ESI-TOF): calcd.

for C₃₃H₄₁N₃O₇Na 614.2842; found 614.2849.

1

R_f= 0.39 (50% ethyl acetate/hexanes). H NMR (300 MHz, [D₆]-

Naphthoquinone 34: This compound was prepared according to ge-

neral procedure A starting from quinone 18a (40 mg, 0.14 mmol)

and Boc-Phe-GABA-OH (150 mg, 0.43 mmol), and was purified

by flash chromatography on silica gel (10 to 40% ethyl acetate/

hexanes). Pure 34 (29 mg, 0.05 mmol, 36%) was obtained as a

brown solid, m.p. 92–94 °C. R_f= 0.30 (30% ethyl acetate/hexanes).

¹H NMR (300 MHz, CDCl₃): δ = 8.14–8.01 (m, 2 H), 7.81–7.64

(m, 2 H), 7.35–7.13 (m, 5 H), 6.52 (br. s, 1 H), 5.33 (br. s, 1 H),

5.04 (br. s, 1 H), 4.41 (m, 1 H), 3.42–2.99 (m, 6 H), 2.82 (t, J =

6.7 Hz, 2 H), 2.66–2.44 (m, 2 H), 1.78–1.57 (m, 2 H), 1.41 (s, 9 H),

1.39 (s, 9 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 185.0, 171.5,

156.1, 148.0, 144.2, 137.0, 133.6, 133.5, 132.1, 129.4, 128.6, 126.8,

126.3, 79.4, 55.8, 40.1, 39.0, 38.7, 28.7, 28.4, 28.3, 28.1, 24.0 ppm.

DMSO): δ = 7.99 (m, 2 H), 7.83 (m, 2 H), 7.25 (s, 4 H), 7.18 (m,

1 H), 6.90 (d, J = 8.6 Hz, 1 H), 4.12 (td, J = 9.6, 4.7 Hz, 1 H), 3.13

(m, 2 H), 2.94 (dd, J = 13.7, 4.7 Hz, 1 H), 2.74 (dd, J = 13.5,

10.1 Hz, 1 H), 2.56 (m, 2 H), 2.11 (s, 1 H), 1.54 (m, 2 H), 1.30 (s,

9 H) ppm. ¹³C NMR (75 MHz, [D₆]DMSO): δ = 185.0, 184.4,

172.0, 155.7, 146.5, 143.6, 138.7, 134.3, 132.1, 132.0, 129.6, 128.4,

126.7, 126.6, 126.3, 126.2, 78.4, 56.3, 39.0, 38.2, 28.6, 28.5, 24.5,

12.9 ppm. IR (ZnSe): ν = 3338, 2970, 2930, 1681, 1657, 1523, 1298,

˜

1169, 1026, 716 cm^–1. HRMS (ESI-TOF): calcd. for

C₂₈H₃₂N₂O₅Na 499.2203; found 499.2206.

(S)-tert-Butyl 1-[2-(3-Methyl-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-

ethylamino]-1-oxo-3-phenylpropan-2-ylcarbamate (31): This com-

pound was prepared according to general procedure A starting

from menadione (8) (34 mg, 0.22 mmol) and Boc-Phe-β-Ala-OH

(234 mg, 0.70 mmol), and was purified by flash chromatography

on silica gel (30 to 50% ethyl acetate/hexanes). Pure 31 (37 mg,

0.08 mmol, 36%) was obtained as a yellow solid, m.p. 156–159 °C.

IR (ZnSe): ν = 3381, 3322, 2977, 2933, 1702, 1663, 1594, 1523,

˜

1366, 1302, 1266, 1167, 1049, 780, 703 cm^–1. HRMS (ESI-TOF):

calcd. for C₃₄H₄₃N₃O₇Na 628.2999; found 628.2987.

Naphthoquinone 35: This compound was prepared according to ge-

neral procedure A starting from quinone 19a (43 mg, 0.14 mmol)

and Boc-Phe-β-Ala-OH (145 mg, 0.43 mmol), and was purified by

flash chromatography on silica gel (10 to 50% ethyl acetate/hex-

anes). Pure 35 (30 mg, 0.05 mmol, 37%) was obtained as a brown

1

R_f= 0.37 (50% ethyl acetate/hexanes). H NMR (300 MHz, [D₆]-

DMSO): δ = 8.01 (dd, J = 5.8, 3.2 Hz, 2 H), 7.84 (dd, J = 5.4,

3.6 Hz, 2 H), 7.21 (m, 5 H), 6.85 (d, J = 17.1 Hz, 1 H), 4.04 (m, 1

H), 3.26 (m, 2 H), 2.85 (dd, J = 13.7, 4.1 Hz, 1 H), 2.73 (t, J =

1

solid, m.p. 115–117 °C. R_f= 0.38 (50% ethyl acetate/hexanes). H

6.5 Hz, 2 H), 2.65 (dd, J = 13.7, 4.1 Hz, 1 H), 2.13 (s, 3 H), 1.27 NMR (300 MHz, CDCl₃): δ = 8.12–8.01 (m, 2 H), 7.76–7.67 (m, 2

(s, 9 H) ppm. ¹³C NMR (75 MHz, [D₆]DMSO): δ = 185.4, 184.8,

H), 7.34–7.09 (m, 5 H), 6.39 (br. s, 1 H), 5.37 (br. s, 1 H), 5.16 (br.

14

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Job/Unit: O20722

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Date: 23-08-12 19:02:31

Pages: 16

Alkylation of Naphthoquinones with Amino Acids

S. W. Luckman, D. M. Roll, G. T. Carter, J. Antibiot. 2002, 55,

s, 1 H), 4.34 (m, 1 H), 3.41–3.14 (m, 4 H), 3.06 (d, J = 6.8 Hz, 2

H), 2.87–2.61 (m, 4 H), 1.84–1.65 (m, 2 H), 1.46 (s, 9 H), 1.41 (s,

9 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 185.2, 184.7, 171.7,

156.3, 148.5, 143.6, 136.7, 133.6, 133.5, 132.1, 131.9, 129.3, 128.6,

126.9, 126.4, 126.3, 79.2, 55.8, 39.2, 38.7, 34.3, 29.7, 28.5, 28.3,

1072–1075.

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27.1, 24.4 ppm. IR (ZnSe): ν = 3368, 3338, 2978, 2928, 1695, 1663,

˜

1594, 1519, 1458, 1302, 1265, 1167, 1049, 777, 701 cm^–1. HRMS

(ESI-TOF): calcd. for C₃₄H₄₃N₃O₇Na 628.2999; found 628.3004.

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Naphthoquinone 36: This compound was prepared according to ge-

neral procedure A starting from quinone 19a (43 mg, 0.14 mmol)

and Boc-Phe-GABA-OH (150 mg, 0.43 mmol), and was purified

by flash chromatography on silica gel (10 to 40% ethyl acetate/

hexanes). Pure 36 (32 mg, 0.05 mmol, 38%) was obtained as a

brown solid, m.p. 123–125 °C. R_f= 0.33 (50% ethyl acetate/hex-

[6] P. Bermejo-Bescós, S. Martín-Aragón, K. L. Jiménez-Aliaga,

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1

anes). H NMR (300 MHz, CDCl₃): δ = 8.14–8.04 (m, 2 H), 7.75–

7.66 (m, 2 H), 7.38–7.10 (m, 5 H), 6.38 (br. s, 1 H), 5.35 (br. s, 1

H), 5.22 (br. s, 1 H), 4.37 (m, 1 H), 3.39–3.16 (m, 4 H), 3.08 (d, J

= 6.9 Hz, 2 H), 2.90–2.67 (m, 4 H), 2.62–2.39 (m, 2 H), 1.85–1.65

(m, 2 H), 1.45 (s, 9 H), 1.39 (s, 9 H) ppm. ¹³C NMR (75 MHz,

CDCl₃): δ = 185.3, 184.8, 171.9, 156.2, 148.7, 143.5, 136.6, 133.6,

133.5, 132.1, 131.9, 129.3, 128.6, 126.7, 126.2, 126.1, 79.1, 55.8,

39.2, 38.7, 34.2, 29.9, 28.5, 28.2, 27.1, 24.3 ppm. IR (ZnSe): ν =

˜

3367, 3323, 2927, 1694, 1663, 1594, 1524, 1456, 1366, 1302, 1252,

1166, 780 cm^–1. HRMS (ESI-TOF): calcd. for C₃₅H₄₅N₃O₇Na

642.3155; found 642.3169.

Supporting Information (see footnote on the first page of this arti-

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wish to thank the Ligue Contre le Cancer (Comité de la Dordogne,

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Received: May 30, 2012

Published Online: ᭿

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15

Job/Unit: O20722

/KAP1

Date: 23-08-12 19:02:31

Pages: 16

J. Dessolin et al.

FULL PAPER

Radical Alkylation

The Kochi–Anderson radical decarb-

oxylation was revisited for the preparation

of highly functionalized naphthoquinones.

An extensive study has been carried out in

order to highlight the power of this strat-

egy.

G. Naturale, M. Lamblin, C. Commandeur,

F.-X. Felpin, J. Dessolin* ................ 1–16

Direct C–H Alkylation of Naphthoquin-

ones with Amino Acids Through a Re-

visited Kochi–Anderson Radical Decarb-

oxylation: Trends in Reactivity and Appli-

cations

Keywords: Medicinal chemistry

/ Anti-

tumor agents / Quinones / Amino acids /

Radical reactions / Alkylation

16

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Eur. J. Org. Chem. 0000, 0–0

Article Doi

Direct C-H alkylation of naphthoquinones with amino acids through a revisited Kochi-Anderson radical decarboxylation: Trends in reactivity and applications

DOI: 10.1002/ejoc.201200722

Source and publish data:

Authors:

Article abstract of DOI:10.1002/ejoc.201200722

Full text of DOI:10.1002/ejoc.201200722

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