Unexpected reactivity in naphthoquinone series

Article abstract of DOI:10.1016/S0040-4039(00)01998-5

An unexpected reactivity of 2-chloromethyl-3-methyl-1,4-naphthoquinone 1 with primary nitroalkanes in classical S_RN1 reaction conditions gives two series of new quinones: dialkyl anthraquinones and C-alkylated naphthoquinones.

Full text of DOI:10.1016/S0040-4039(00)01998-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 391–393
Unexpected reactivity in naphthoquinone series
Patrice Vanelle,* Thierry Terme, Luc Giraud and Michel P. Crozet
Laboratoire de Chimie Organique, UMR 6517, Universit e´ de la M e´ diterran e´ e, Facult e´ de Pharmacie, 27 Bd Jean Moulin,
3385 Marseille Cedex 05, France
1
Received 17 October 2000; accepted 30 October 2000
Abstract—An unexpected reactivity of 2-chloromethyl-3-methyl-1,4-naphthoquinone 1 with primary nitroalkanes in classical
SRN1 reaction conditions gives two series of new quinones: dialkyl anthraquinones and C-alkylated naphthoquinones. © 2001
Elsevier Science Ltd. All rights reserved.
1
The discovery of new drugs for the treatment and
chemosuppression of malaria has become a priority in
view of the continuing emergence and spread of multi-
resistant strains of Plasmodium falciparum. Atovaquone
is a novel hydroxynaphthoquinone which is the result
of intensive synthetic efforts aimed at producing a
metabolically stable compound with optimum activity
against Plasmodium falciparum in vitro. Although first
identified for its antimalarial activity, atovaquone was
subsequently found to possess broad spectrum antipro-
tozoal activity and is now licensed for the treatment of
opportunistic infections in patient with acquired im-
munodeficiency syndrome. We have recently shown
that 2-chloromethyl-3-methyl-1,4-naphthoquinone
(easily prepared from menadione according to Thom-
son’s procedure ) reacts with 2-nitropropane anion 2 to
give the C-alkylation product 3.
1
2
3
As a part of our program directed toward the study of
electron transfer reactions to synthesize new biologi-
cally active naphthoquinones, we investigated the reac-
tivity of 1 with nitroethane anion 4 and we obtained the
required C-alkylation product 5a and the unexpected
anthraquinone 6a (Table 1).
*
0
Corresponding author. Fax: 33 4 91 79 46 77; e-mail: patrice.vanelle@pharmacie.univ-mrs.fr
040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01998-5

3
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P. Vanelle et al. / Tetrahedron Letters 42 (2001) 391–393
Table 1. Influence of experimental conditions in the reac-
a
tion of 1 and 4
Entry
Mol. equiv.
Conditionsb
Yield %
of 4
5a
6a
1
2
3
4
5
6
7
8
9
1.0 equiv.
2.0 equiv.
3.0 equiv.
4.0 equiv.
1.0 equiv.
1.0 equiv.
2.0 equiv.
3.0 equiv.
4.0 equiv.
4.0 equiv.
CH Cl /H O, 20 min
45
34
22
16
59
85
45
55
45
0
0
0
16
19
0
0
7
7
9
2
2
2
CH Cl /H O, 20 min
2
2
2
CH Cl /H O, 20 min
2
2
2
Moreover, for these reactions, a similar yield was ob-
served in the presence of classical inhibitors (p-dini-
trobenzene, TEMPO) indicating the absence of SET
reaction for the transformation of 5a into 6a or 8. All
these experimental data led us to propose an original
ionic mechanism for the formation of 6a or 8 from 5a.
This mechanism was based on the participation of an
anionic intermediate able to easily give a Michael ac-
ceptor which in the presence of an anion excess gives
the bis-C-alkylated anion. As reported previously for
CH Cl /H O, 20 min
2
2
2
C H CH /H O, 20 min
6
5
3
2
C H CH /H O, 10 min
6
5
3
2
C H CH /H O, 20 min
6
5
3
2
C H CH /H O, 20 min
6
5
3
2
C H CH /H O, 20 min
6
5
3
2
1
0
C H CH /H O, 48 h
39
6
5
3
2
a
All the reactions are performed at room temperature under argon
and irradiated by fluorescent lamps (2×60 W).
b
Phase-transfer conditions with NBu OH 40% in water.
4
5
annulation reactions in naphtho and anthraquinone
6
series, after oxidation, nitrous acid elimination, elec-
The reaction of 1 with nitroethane anion 4, in the
conditions of entry 6, in presence of classical inhibitors
trocyclization and dehydrogenation, the corresponding
anthraquinone (6a or 8) was obtained.
(
p-dinitrobenzene as radical-anion scavenger, 2,2,6,6-
tetramethyl-1-piperidinyloxy or TEMPO as radical
trap) gave effective inhibition, indicating a classical
SRN1 mechanism for the formation of 5a.
After these original results, we generalized these reac-
tions to various primary nitroalkanes and we prepared
7
new series of C-alkylated products 5a–c and dialkyl-
8
anthraquinones 6a–c.
For explaining the formation of the unexpected an-
thraquinone 6a, we studied the reactivity of 5a with an
excess (3.0 equiv.) of primary nitronate anion in phase-
transfer conditions with toluene as solvent during 24 h.
We obtained the 2,3-dimethylanthraquinone 6a from
In conclusion, we showed an unexpected reactivity of a
2-methylnaphthoquinone derivative and we proposed
an original mechanism to explain this reactivity. More-
over, a series of new C-alkylated naphthoquinones was
prepared from primary nitroalkanes according to a
classical SRN1 mechanism.
nitroethane anion (R=CH ) and the 2-ethyl-3-methyl-
3
9
,10-anthraquinone 8 from 1-nitropropane anion 7
4
(
R=CH CH ).
3 2

P. Vanelle et al. / Tetrahedron Letters 42 (2001) 391–393
393
Acknowledgements
lamp for 10 min under an inert atmosphere. The organic
layers were washed twice with water, dried over MgSO4
and removed under reduced pressure. Purification by chro-
matography on silica gel eluting with dichloromethane and
recrystallization from isopropyl alcohol gave C-alkylated
This work was supported by the Centre National de la
Recherche Scientifique. T. Terme thanks the President
of the Universit e´ de la M e´ diterran e´ e for his appoint-
ment as ATER at Universit e´ de la M e´ diterran e´ e.
1
product 5. New derivatives: 5a, Yellow solid, mp 84°C, H
NMR (CDCl ) l 1.6 (d, J=6.7 Hz, 3H); 2.15 (s, 3H);
3
3
.1–3.3 (m, 2H); 4.97 (m, 1H); 7.78 (m, 2H); 8.01 (m, 2H).
1
3
C NMR (CDCl ) l 12.9 (CH ); 19.3 (CH ); 33.1 (CH );
3
3
3
2
References
81.8 (CH); 126.2 (CH); 126.4 (CH); 131.5 (C); 131.8 (C);
33.6 (CH); 133.7 (CH); 140.5 (C); 146.4 (C); 183.4 (CꢀO);
1
1
. Looareesuwan, S.; Viravan, C.; Webster, H. K.; Kyle, D.
E.; Hutchinson, D. B.; Canfield, C. J. Am. J. Trop. Med.
Hyg. 1996, 54, 62–66.
183.5 (CꢀO). Anal. calcd for C H NO (259.26): C,
14
13
4
64.86; H, 5.05; N, 5.40. Found: C, 64.78; H, 5.07; N, 5.29.
1
5b, orange solid, mp 61°C, H NMR (CDCl ) l 0.96 (t,
3
2
3
. Thomson, R. H. J. Chem. Soc. 1953, 1196–1199.
. Vanelle, P.; Terme, T.; Giraud, L.; Crozet, M. P. Recent
J=7.3 Hz, 3H); 1.88–2.08 (m, 2H); 2.11 (s, 3H); 3.10–
3.22 (m, 2H); 4.79 (m, 1H); 7.64 (m, 2H); 7.98 (m, 2H).
13
Res. Devel. Org. Chem. 2000, 4, 1–28.
. New product 8: orange solid, mp 144°C (ethanol),
C NMR (CDCl ) l 14.2 (CH ); 16.4 (CH ); 19.4 (CH );
3 3 3 2
1
4
H
21.1 (CH ); 81.7 (CH); 126.6 (CH); 126.9 (CH); 131.5 (C);
2
NMR (CDCl ) l 1.28 (t, J=7.6 Hz, 3H); 2.44 (s, 3H);
131.6 (C); 134.2 (CH); 134.4 (CH); 142.1 (C); 144.3 (C);
3
2
1
.74 (q, J=7.6 Hz, 2H); 7.75 (m, 2H); 8.01 (s, 1H); 8.04 (s,
181.6 (CꢀO); 184.5 (CꢀO). Anal. calcd for C H NO
1
5
15
4
13
H); 8.26 (m, 2H). C NMR (CDCl ) l 14.6 (CH ); 20.1
(273.28): C, 65.92; H, 5.53; N, 5.13. Found: C, 65.91; H,
3
3
1
(
CH ); 25.8 (CH ); 126.8 (CH); 126.9 (CH); 127 (CH);
5.63; N, 5.17. 5c, orange solid, mp 51°C, H NMR
3
2
1
1
1
27.1 (CH); 131.4 (C); 131.5 (C); 133.6 (CH); 133.7 (CH);
33.8 (C); 133.9 (C); 149.1 (C); 149.2 (C); 183.3 (CꢀO);
83.4 (CꢀO). Anal. calcd for C H O (250.29): C, 81.58;
(CDCl ) l 0.97 (t, J=7.3 Hz, 3H); 1.32–1.5 (m, 2H);
3
1.75–1.90 (m, 2H); 2.17 (s, 3H); 3.10–3.22 (m, 2H); 4.81
13
(m, 1H); 7.63 (m, 2H); 8.07 (m, 2H). C NMR (CDCl ) l
17
14
2
3
H, 5.64. Found: C, 81.53; H, 5.61.
13.1 (CH ); 16.3 (CH ); 19.9 (CH ); 23.2 (CH ); 24.1
3
3
2
2
5
6
7
. Vanelle, P.; Terme, T.; Maldonado, J.; Crozet, M. P.;
Giraud, L. Synlett 1998, 1067–1068.
. Terme, T.; Crozet, M. P.; Giraud, L.; Vanelle, P. Tetra-
hedron 2000, 56, 1097–1101.
. Typical procedure for 5a–c. Under argon atmosphere, a
solution of tetrabutylammonium hydroxide (40% in water,
(CH ); 81.7 (CH); 126.6 (CH); 126.9 (CH); 131.5 (C);
131.6 (C); 134.2 (CH); 134.4 (CH); 142.1 (C); 144.3 (C);
2
181.6 (CꢀO); 184.5 (CꢀO). Anal. calcd for C H NO
16
17
4
(287.31): C, 66.89; H, 5.96; N, 4.88. Found: C, 66.85; H,
5.95; N, 4.82.
8. Typical procedure for 6a–c. The procedure was similar to
that for the formation of 5a–c, except that the reaction
time was 48 h and 4 equivalents of nitronate anion were
used. The same purification gave the 2,3-dialkylan-
thraquinone 6a–c.
2.6 ml, 4 mmol) was treated with a nitroalkane (4 mmol)
for 1 h. A solution of 2-chloromethyl-3-methyl-1,4-naph-
thoquinone 1 (0.88 g, 4 mmol) in toluene (30 ml) was
added and the mixture was irradiated with 300 W sun
.
.