Synthesis of 2,3-dialkylquinones by Bis-SRN1 methodology

Article abstract of DOI:10.1081/SCC-100108240

Three series of complex dialkylquinones were prepared by reacting bis(chloromethyl)quinones with simple and more complex nitronate anions under electron transfer reaction conditions.

Full text of DOI:10.1081/SCC-100108240

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SYNTHESIS OF 2,3-DIALKYLQUINONES BY BIS-SRN1
METHODOLOGY
Thierry Terme a , José Maldonado a , Michel P. Crozet a & Patrice Vanelle b
a CNRS-UMR 6517 , Laboratoire de Chimie Organique, Faculté de Pharmacie, 27 Bd Jean
Moulin, Marseille Cx 5, 13385, France
b CNRS-UMR 6517 , Laboratoire de Chimie Organique, Faculté de Pharmacie, 27 Bd Jean
Moulin, Marseille Cx 5, 13385, France
Published online: 09 Nov 2006.
To cite this article: Thierry Terme , José Maldonado , Michel P. Crozet & Patrice Vanelle (2001) SYNTHESIS OF
2,3-DIALKYLQUINONES BY BIS-SRN1 METHODOLOGY, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 31:24, 3877-3883, DOI: 10.1081/SCC-100108240
To link to this article: http://dx.doi.org/10.1081/SCC-100108240
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SYNTHETIC COMMUNICATIONS, 31(24), 3877–3883 (2001)
SYNTHESIS OF 2,3-DIALKYLQUINONES
BY BIS-SRN1 METHODOLOGY
Thierry Terme, Jose Maldonado, Michel P. Crozet,
and Patrice Vanelle*
Laboratoire de Chimie Organique, CNRS-UMR 6517,
Faculte de Pharmacie, 27 Bd Jean Moulin,
13385 Marseille Cx 5, France
ABSTRACT
Three series of complex dialkylquinones were prepared by
reacting bis(chloromethyl)quinones with simple and more
complex nitronate anions under electron transfer reaction
conditions.
Quinones represent a class of organic compounds possessing rich and
fascinating chemistry. Many of them are important therapeutic agents,1,2
quite often they serve as auxiliaries in organic synthesis and in the dye
industry.3,4 Mitomycin C is a representative of the group of bioreductive
bis-alkylating antitumor agents and its reduction has been shown to result in
the formation of reactive species which are able to alkylate DNA.5,6 In the
last few years, the interest in these compounds has been growing and new
trialbioreductive anticancer agents that seem to be more powerfuland with
less undesired effects have been investigated.7,8 In connection with our pro-
gram directed toward the development of novel synthetic quinone congeners
*Corresponding author. E-mail: patrice.vanelle@pharmacie.univ-mrs.fr
3877
Copyright & 2001 by MarcelDekker, Inc.
www.dekker.com

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TERME ET AL.
as anticancer agents,9,10 we reported here the synthesis of three bis(chloro-
methyl)quinones and the study of their reactivity with simple and more
complex nitronate anions leading to original and new dialkylquinones.
2,3-Bis(chloromethyl)-5,6-dimethyl-1,4-benzoquinone 1 was prepared in
three steps from 2,3-dimethyl-1,4-hydroquinone. Whereas, the 2,3-bis(chlo-
romethyl)-1,4-naphtho- 2 and 1,4-anthraquinone 3 were obtained from
respectively 1,4-naphthoquinone and 1,4-anthraquinone according to
Thomson’s procedure,11 by saturating a cooled solution of corresponding
quinone and aqueous formaldehyde in glacial acetic acid with dry hydrogen
chloride for 2 h (Scheme 1).
These bis(chloromethyl)quinones 1–3 reacted with 5 equivalents of
2-nitropropane anion 4a under SRN1 reaction conditions (inert atmo-
sphere, photostimulation) and in a phase-transfer system (40% tetra-
butylammonium hydroxide in water and dichloromethane) to give the
corresponding bis-C-alkylated products 5a–7a in good yields, after 10 min
in benzoquinone series and after 20 min in naphtho- and anthra-
quinone series (Scheme 2). To confirm the nature of these mechanisms,
the reactions of bis-chlorides 1–3 and 4a were studied in presence
of classical inhibitors. Addition of p-dinitrobenzene as radicalanion sca-
venger, TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) as radical trap,
CuCl2 or bubbling dioxygen through the solution in the dark strongly
decreased the yield of corresponding bis-C-alkylated product 5a–7a. These
experimentaldata indicated that these products were formed by a bis-SRN1
mechanism.
Scheme 1.

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3879
Scheme 2.
These bis-SRN1 reactions were extended with various secondary nitro-
nate anions 4b–f (aliphatic, cyclic or heterocyclic) and allowed us to reach at
three series of new highly branched dialkylquinones (Scheme 2).
The nitroalkanes were commercially available or prepared by oxida-
tion of the corresponding amines with m-chloroperbenzoic acid in refluxing
1,2-dichloroethane by Gilbert and Borden procedure.12 The nitroalkanes
were purified by distillation or recrystallization. The 5-nitro-1,3-dioxane
salt was prepared by the method13 described previously from 2-hydroxy-
methyl-2-nitro-propane-1,3-diol, acetone and boron trifluoride diethyl ethe-
rate. Treatment with lithium methoxide split-off formaldehyde to give the
corresponding salt. The extension reaction conditions were determined by
the nitronate anion used. For aliphatic and cyclic nitronate anions 4b–e, we
have utilized, as for 2-nitropropane anion, the classical conditions: phase-
transfer system with 40% of tetrabutylammonium hydroxide in water and
dichloromethane, 5 equivalents of nitronate anion during 10 min in benzo-
quinone series and during 20 min for the other series. Whereas, with the
5-nitro-1,3-dioxane anion 4f, the reactions were carried out in methanol.
In conclusion, we have extended the bis-SRN1 reactions of three
bis(chromethyl)quinones with various nitronate anions. Three series of
highly branched dialkylquinones were synthesized in good yields. Study of
the antitumor activity of related compounds is under active investigation.

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TERME ET AL.
EXPERIMENTAL
Melting points were determined on Buchi B-540 and are uncorrected.
Elemental analyses were performed by the Centre de Microanalyses of the
1
University of Aix-Marseille 3. Both H and 13C NMR spectra were deter-
mined on Bruker ARX 200 spectrometer. The 1H chemicalshifts were
reported as parts per million downfield from tetramethylsilane (Me4Si),
and the 13C chemicalshifts were referenced to the sovlents peaks: CDCl
3
(76.9 ppm) or Me2SO-d6 (39.6 ppm). The following adsorbent was used for
column chromatography: silica gel 60 (Merck, 230–400 mesh). Thin-layer
chromatography was performed with silica gel Merck 60F-254 (0.25 mm
layer thickness).
General procedure for bis-SRN1 reaction with aliphatic and cyclic nitro-
nate anions. Under nitrogen atmosphere, a solution of tetrabutylammonium
hydroxide (1.6 M/water, 6.4 mL, 9.75 mmol) was treated with nitroalkane
(9.75 mmol) for 1 h. A solution of corresponding 2,3-bis(chloromethyl)-1,4-
quinone 1–3 (1.95 mmol) in dichloromethane (20 mL) was added and the
mixture was irradiated with a 300 W sun lamp for 20 min (naphtho- and
anthraquinone series) or 10 min (benzoquinone series) at room temperature
under an inert atmosphere. The organic layer was separated and the aque-
ous layer was extracted with dichloromethane (3 ꢀ 10 mL). The combined
organic layers were washed twice with water (30 mL), dried over MgSO4 and
removed under reduced pressure. Purification by chromatography on silica
gel eluting with dichloromethane and recrystallization from ethanol gave the
corresponding dialkylquinone 5–7.
General procedure for bis-SRN1 reaction with heterocyclic nitronate
anion. 2,2-Dimethyl-5-nitro-1,3-dioxane lithium salt (1.6 g, 9.75 mmol) was
added to a solution of corresponding 2,3-bis(chloromethyl)-1,4-quinone 1–3
(1.95 mmol) in dry methanol (30 mL). The reaction was allowed to proceed
for 20 min (benzo- and naphthoquinone series) or 24 h (anthraquinone
series) at room temperature under nitrogen and in the presence of light
(300 W sun lamp). After reaction, methanol was removed under reduced
pressure and water (50 mL) was added to the residue which was extracted
with dichloromethane (3 ꢀ 50 mL). The combined organic layers were
washed with water (2 ꢀ 30 mL), dried over MgSO4 and removed under
reduced pressure. Purification by chromatography on silica gel eluting
with dichloromethane and recrystallization from ethanol gave the corres-
ponding
5f–7f.
2,3-bis(2,2-dimethyl-5-nitro-1,3-dioxan-5-ylmethyl)-1,4-quinone
2,3-Bis(2-methyl-2-nitropropyl)-5,6-dimethyl-1,4-benzoquinone
(5a).
Yellow solid, mp 156ꢁC (ethanol).1H NMR (CDCl3): d 1.54 (s, 12H), 2.03
(s, 6H), 3.14 (s, 4H). 13C NMR (CDCl3): d 12.6, 26, 36, 87.8, 141.2, 142.1,

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3881
186.4. Anal. Calcd for C16H22N2O6: C, 56.80; H, 6.55; N, 8.28. Found: C,
56.76; H, 6.56; N, 8.23.
2,3-Bis(2-nitrocyclohex-2-ylmethyl)-5,6-dimethyl-1,4-benzoquinone (5c).
Yellow solid, mp 194ꢁC (ethanol). H NMR (CDCl3): d 1.21 (m, 4H), 1.55
1
(m, 12H), 2.02 (s, 6H), 2.33 (m, 4H), 2.96 (s, 4H). 13C NMR (CDCl3): d 12.6,
22.2, 24.2, 34.8, 36.5, 91.8, 141.2, 142.1, 186.1. Anal. Calcd for C22H30N2O6:
C, 63.14; H, 7.23; N, 6.69. Found: C, 63.11; H, 7.28; N, 6.74.
2,3-Bis(2-nitrocyclohept-2-ylmethyl)-5,6-dimethyl-1,4-benzoquinone
(5d). Yellow solid, mp 111ꢁC (ethanol). 1H NMR (CDCl3): d 1.55 (m, 16H),
1.84 (m, 4H), 2.05 (s, 6H), 2.33 (m, 4H), 3.05 (s, 4H). 13C NMR (CDCl3): d
12.6, 22.7, 29.4, 36.5, 37.1, 95.3, 141.2, 142.1, 186.4. Anal. Calcd for
C24H34N2O6: C, 64.55; H, 7.67; N, 6.27. Found: C, 64.61; H, 7.66; N, 6.24.
2,3-Bis(2,2-dimethyl-5-nitro-1,3-dioxan-5-ylmethyl)-5,6-dimethyl-1,4-
benzoquinone (5f ). Brown solid, mp 225ꢁC (ethanol). H NMR (CDCl3): d
1
1.36 (s, 6H), 1.50 (s, 6H), 2.02 (s, 6H), 3.10 (s, 4H), 4.01 (d, J ¼ 12.9 Hz, 4H),
4.27 (d, J ¼ 12.9 Hz, 4H). 13C NMR (CDCl3): d 12.6, 22, 24.4, 29.5, 63.9,
84.3, 99, 141.4, 143.1, 186.9. Anal. Calcd for C22H30N2O10: C, 54.77; H,
6.27; N, 5.81. Found: C, 54.75; H, 6.32; N, 5.77.
2,3-Bis(2-methyl-2-nitropropyl)-1,4-naphthoquinone (6a). Yellow solid,
mp 151ꢁC (ethanol). H NMR (CDCl3): d 1.51 (s, 12H), 3.24 (s, 4H), 7.68
1
(m, 2H), 8.01 (m, 2H). 13C NMR (CDCl3): d 26.5, 36.6, 87.9, 126.8, 131.5,
134.2, 144.9, 184.1. Anal. Calcd for C18H20N2O6: C, 59.99; H, 5.59; N, 7.77.
Found: C, 59.98; H, 5.51; N, 7.68.
2,3-Bis(2-methyl-2-nitropentyl)-1,4-naphthoquinone (6b). Yellow solid,
mp 116ꢁC (ethanol). H NMR (CDCl3): d 0.93 (t, J ¼ 7 Hz, 6H), 1.16–1.45
1
(m, 4H), 1.46 (s, 6H), 1.77 (m, 2H), 2.08 (m, 2H), 3.22 (d, J ¼ 14.3 Hz, 2H),
3.34 (d, J ¼ 14.3 Hz, 2H), 7.74 (m, 2H), 8.08 (m, 2H). 13C NMR (CDCl3):
d 13.9, 17.4, 21.8, 36, 42.3, 91.3, 126.8, 131.6, 134.1, 145, 184.2. Anal. Calcd
for C22H28N2O6: C, 63.45; H, 6.78; N, 6.73. Found: C, 63.40; H, 6.79;
N, 6.66.
2,3-Bis(2-nitrocyclohex-2-ylmethyl)-1,4-naphthoquinone (6c). Yellow
solid, mp 192ꢁC (ethanol). H NMR (CDCl3): d 1.20 (m, 4H), 1.63 (m,
1
12H), 2.38 (m, 4H), 3.13 (s, 4H), 7.74 (m, 2H), 8.08 (m, 2H). 13C NMR
(CDCl3): d 22.2, 24.2, 34.8, 36.7, 91.7, 126.8, 131.5, 134, 144.7, 183.8.
Anal. Calcd for C24H28N2O6: C, 65.44; H, 6.41; N, 6.36. Found: C, 65.45;
H, 6.35; N, 6.33.
2,3-Bis(2-nitrocyclohept-2-ylmethyl)-1,4-naphthoquinone (6d). Yellow
solid, mp 132ꢁC (ethanol). H NMR (CDCl3): d 1.55 (m, 16H), 1.89 (m,
1
4H), 2.36 (m, 4H), 3.21 (s, 4H), 7.75 (m, 2H), 8.07 (m, 2H). 13C NMR
(CDCl3): d 22.7, 29.4, 36.7, 37.1, 95.5, 126.8, 131.6, 134, 144.9, 184.1.
Anal. Calcd for C26H32N2O6: C, 66.65; H, 6.88; N, 5.98. Found: C, 66.60;
H, 6.89; N, 5.94.

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TERME ET AL.
2,3-Bis(2-nitrocyclooct-2-ylmethyl)-1,4-naphthoquinone (6e). Orange
solid, mp 148ꢁC (ethanol). H NMR (CDCl3): d 1.55 (m, 20H), 1.97 (m,
4H), 2.24 (m, 4H), 3.17 (s, 4H), 7.73 (m, 2H), 8.07 (m, 2H). 13C NMR
(CDCl3): d 22.8, 24.8, 27.6, 32.2, 35.4, 95.8, 126.8, 131.6, 134, 145.3, 184.
Anal. Calcd for C28H36N2O6: C, 67.72; H, 7.31; N, 5.64. Found: C, 67.74;
H, 7.28; N, 5.60.
1
2,3-Bis(2,2-dimethyl-5-nitro-1,3-dioxan-5-ylmethyl)-1,4-naphthoquinone
(6f ). Brown solid, mp 234ꢁC (ethanol). H NMR (CDCl3): d 1.37 (s, 6H),
1
1.52 (s, 6H), 3.29 (s, 4H), 4.08 (d, J ¼ 12.8 Hz, 4H), 4.32 (d, J ¼ 12.8 Hz, 4H),
7.76 (m, 2H), 8.08 (m, 2H). 13C NMR (CDCl3): d 22, 24.4, 29.6, 64, 84.4, 99,
126.9, 131.3, 134.4, 143.8, 183.8. Anal. Calcd for C24H28N2O10: C, 57.14; H,
5.59; N, 5.55. Found: C, 57.08; H, 5.62; N, 5.60.
2,3-Bis(2-methyl-2-nitropropyl)-1,4-anthraquinone) (7a). Orange solid,
mp 191ꢁC (ethanol). H NMR (CDCl3): d 1.62 (s, 12H), 3.38 (s, 4H), 7.70
1
(m, 2H), 8.04 (m, 2H), 8.64 (s, 2H). 13C NMR (CDCl3): d 26.5, 36.5, 88,
127.8, 129.4, 129.7, 130.2, 135, 146.4, 183.7. Anal. Calcd for C22H22N2O6:
C, 64.38, H, 5.40; N, 6.83. Found: C, 64.36; H, 5.35; N, 6.74.
2,3-Bis(2-nitrocyclohexan-2-ylmethyl)-1,4-anthraquinone (7c). Orange
solid, mp 197ꢁC (ethanol). H NMR (CDCl3): d 1.20 (m, 4H), 1.66 (m,
1
12H), 2.39 (m, 4H), 3.33 (s, 4H), 7.76 (m, 2H), 8.09 (m, 2H), 8.68 (s, 2H).
13C NMR (CDCl3): d 22.2, 24.2, 34.8, 36.6, 91.8, 127.9, 129.4, 129.6, 130.1,
135, 146.2, 183.5. Anal. Calcd for C28H30N2O6: C, 68.56; H, 6.16; N, 5.71.
Found: C, 68.49; H, 6.15; N, 5.75.
2,3-Bis(2,2-dimethyl-5-nitro-1,3-dioxan-5-ylmethyl)-1,4-anthraquinone
(7f ). Orange solid, mp 237ꢁC (ethanol). H NMR (CDCl3): d 1.38 (s, 6H),
1
1.56 (s, 6H), 3.41 (s, 4H), 4.15 (d, J ¼ 12.8 Hz, 4H), 4.37 (d, J ¼ 12.8 Hz, 4H),
7.78 (m, 2H), 8.09 (m, 2H), 8.69 (s, 2H). 13C NMR (CDCl3): d 22, 24.4, 29.7,
64.1, 84.5, 99, 127.8, 129.6, 129.8, 130, 135.3, 145.8, 183.5. Anal. Calcd for
C28H30N2O10: C, 60.64; H, 5.45; N, 5.05. Found: C, 60.51; H, 5.42; N, 5.15.
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Received in the Netherlands February 12, 2001

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