Original synthesis of tetraalkylquinones by poly-S(RN)1 reactions

Article abstract of DOI:10.1016/S0040-4039(00)01069-8

A series of complex and highly branched quinones were obtained by reacting an original tetraalkylating agent, 2,3,5,6-tetrachloromethyl-1,4-benzoquinone with primary or secondary nitroalkanes under S(RN)1 reactions conditions. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01069-8

Tetrahedron Letters 41 (2000) 6383±6385
Original synthesis of tetraalkylquinones by poly-SRN1
reactions
Patrice Vanelle,* Thierry Terme and Michel P. Crozet
   Â
Laboratoire de Chimie Organique, UMR 6517, Universite de la Mediterranee, Faculte de Pharmacie,
27 Bd Jean Moulin, 13385 Marseille Cedex 05, France
Received 16 May 2000; accepted 23 June 2000
Abstract
A series of complex and highly branched quinones were obtained by reacting an original tetraalkylating
agent, 2,3,5,6-tetrachloromethyl-1,4-benzoquinone with primary or secondary nitroalkanes under SRN
reactions conditions. # 2000 Elsevier Science Ltd. All rights reserved.
1
Keywords: quinones; electron transfer; radical reactions.
Signi®cant advances toward the cure of human cancer by chemotherapy have been achieved
primarily with cytotoxic agents directed toward proliferating cells. Among these, quinones, and
particularly anthracyclines or mitomycins, are important antitumor agents.1 Their mode of bio-
logical action involving bioreductive alkylation led us to consider that electron transfer
reactions might provide an ecient access to original quinones. In 1996, Beugelmans has shown,
in aromatic series, the ®rst example of a quadruple SRN1 reaction for macrocycles synthesis.2 In
connection with our program directed toward the development of novel synthetic congeners as
anticancer agents, we report here on the new synthesis of a tetraalkylating agent,3 2,3,5,6-tetra-
chloromethyl-1,4-benzoquinone 2 and the study of its alkylating ability. The tetrachloride 2 was
prepared in two steps by dibromation of 2,3-bis(chloromethyl)-5,6-dimethyl-1,4-benzoquinone
1 in a carbon tetrachloride re¯ux,4 followed by a halogen exchange with lithium chloride in
tetrahydrofuran.
* Corresponding author. Fax: 33 4 91 79 46 77; e-mail: patrice.vanelle@pharmacie.univ-mrs.fr
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01069-8

6384
Two series of products: tetra-C-alkylated benzoquinones 4a±d and tetraalkylanthraquinones
6e±g were obtained by reacting 2 with secondary or primary nitroalkanes. Nitroalkanes were
commercially available or easily obtained in excellent yields from corresponding amines by
oxidation with m-chloroperbenzoic acid in re¯uxing 1,2-dichloroethane.5 The 1,3-dioxane
derivative was prepared from the previously described 2,2-dimethyl-5-hydroxymethyl-5-nitro-1,3-
dioxane.6
Treatment of the tetrachloride 2 (1 equiv.) with the secondary nitroalkanes 3 (8 equiv.) during
2.5 min, under standard SRN1 reaction conditions (inert atmosphere, photostimulation) and
under photostimulated phase transfer conditions (40% tetrabutylammonium hydroxide in water
and dichloromethane) furnished 2,3,5,6-tetranitroalkylmethyl-benzoquinones 4 in good yields
(62±79%).7 Furthermore, the reaction of 2 with the primary nitroalkanes 5 under the same
experimental conditions gave the 2,3,6,7-tetraalkylanthraquinones 6 in 40±46% yields, but over
48 h and by replacing dichloromethane with toluene.8
The reaction of 2 with 2-nitropropane in the presence of classical inhibitors (p-dinitrobenzene
as radical-anion scavenger, 2,2,6,6-tetramethyl-1-piperidinyloxy or TEMPO as radical trap,
bubbling dioxygen) gave e€ective inhibition, indicating the participation of four consecutive
SRN1 processes.9 Moreover, when the reaction was carried out with only 2 equivalents of
2-nitropropane, the tetra-C-alkylated product 4a was isolated but the potential intermediates as
bis- or tris-C-alkylated products were not observed. This pattern of reactivity has identi®ed
precedents in SRN1 reactivity.10,11
As reported previously,12,13 in the case of 6, the tetra-C-alkylation intermediate underwent four
base-promoted nitrous acid elimination, two electrocyclic ring closures and two dehydrogenations
to give the original tetraalkylanthraquinone.
In conclusion, we have demonstrated the ®rst example of poly-SRN1, involving the benzoquinone
system, and described the synthesis of complex and highly branched benzoquinones. Compared to
the classical Diels±Alder reaction,14 the original `one-pot' synthesis of tetraalkylanthraquinones 6
presents the advantages for practical purposes of easy starting material preparations and simple
procedures for similar yields.
Acknowledgements
The support of this work by the Centre National de Recherche Scienti®que is acknowledged. T.
Terme thanks the President of the Universite de la Mediterranee for his appointment as ATER at
Universite de la Mediterranee.

6385
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7. Typical procedure for the formation of 4. Under nitrogen atmosphere, a solution of tetrabutylammonium
hydroxide (40% in water, 4.5 ml, 6.6 mmol) was treated with a nitroalkane (6.6 mmol) for 1 h. A solution of
2,3,5,6-tetrachloromethyl-1,4-benzoquinone 2 (0.25 g, 0.8 mmol) in dichloromethane (20 ml) was added and the
mixture was irradiated with a 300 W sun lamp for 2.5 min under an inert atmosphere. The organic layer was
separated and the aqueous layer was extracted with dichloromethane (3Â10 ml). The combined organic layers
were washed twice with water (20 ml), dried over MgSO4 and removed under reduced pressure. Puri®cation by
chromatography on silica gel eluting with dichloromethane and recrystallization from ethanol gave tetra-C-
alkylated product 4. New derivatives: 4a, Yellow solid, mp 285ꢀC (ethanol), 1H NMR (DMSO-d6) ꢀ 1.39 (s,
24H, CH3); 3.10 (s, 8H, CH2). 13C NMR (DMSO-d6) 27.1 (CH3); 36.1 (CH2); 89.8 (C); 143.2 (C); 185.1 (CO).
Anal. Calcd for C22H32N4O10 (512.52): C, 51.56; H, 6.29; N, 10.93. Found: C, 51.49; H, 6.18; N, 10.90. 4b, Yellow
solid, mp 241ꢀC (ethanol), H NMR (CDCl3) ꢀ 1.23 (m, 8H); 1.57 (m, 24H); 2.35 (m, 8H); 2.97 (s, 8H, CH2). 13C
1
NMR (CDCl3) 22.2 (CH2); 24.4 (CH2); 34.8 (CH2); 36.6 (CH2); 91.4 (C); 142.6 (C); 185 (CO). Anal. Calcd for
C34H48N4O10 (672.77): C, 60.70; H, 7.19; N, 8.33. Found: C, 60.59; H, 7.23; N, 8.31. 4c, Orange solid, mp 110ꢀC
1
(ethanol), H NMR (CDCl3) ꢀ 1.35 (s, 12H, CH3); 1.50 (s, 12H, CH3); 3.26 (s, 8H, CH2); 4.05 (d, JAB=12.7 Hz,
8H, CH2O); 4.28 (d, JAB=12.7 Hz, 8H, CH2O). 13C NMR (CDCl3) 22 (CH3); 24.4 (CH3); 29.5 (CH2); 63.9 (CH2);
84.4 (C); 99.1 (C); 142.8 (C); 185.4 (CO). Anal. Calcd for C34H48N4O18 (800.76): C, 51.00; H, 6.04; N, 7.00.
ꢀ
1
Found: C, 51.05; H, 6.03; N, 7.05. 4d, Yellow solid, mp 101 C (ethanol), H NMR (CDCl3) ꢀ 0.86 (d, J=6.5 Hz,
24H, CH3); 1.18 (m, 8H, CH2); 1.41 (s, 12H, CH3); 1.55 (m, 8H, CH2); 1.75 (m, 4H, CH); 2.02 (m, 8H, CH2); 3.12
(s, 8H, CH2). 13C NMR (CDCl3) 21.7 (CH2); 22 (CH); 22.4 (CH3); 27.6 (CH3); 35.9 (CH2); 38.5 (CH2); 40.7
(CH2); 90 (C); 143.1 (C); 185.5 (CO). Anal. Calcd for C42H72N4O10 (793.04): C, 63.61; H, 9.15; N, 7.06. Found: C,
63.58; H, 9.13; N, 7.05.
8. Typical procedure for the formation of 6. The procedure was similar to that for the formation of 4, except that
dichloromethane was replaced by toluene and the reaction time was 48 h. The same puri®cation gave the 2,3,6,7-
tetraalkylanthraquinone 6. New derivative: 6f, Yellow solid, mp 144ꢀC (ethanol), H NMR (CDCl3) ꢀ 1.31 (t,
1
J=7.5 Hz, 12H, CH3); 2.79 (q, J=7.5 Hz, 8H, CH2); 8.03 (s, 4H). 13C NMR (CDCl3) 14.6 (CH3); 25.8 (CH2);
128.1 (CH); 131.6 (C); 143.6 (C); 183.7 (CO). Anal. Calcd for C22H24O2 (320.42): C, 82.46; H, 7.55. Found: C,
82.42; H, 7.53.
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