Copper bromide-catalyzed c-alkylation of 2-amino-1,4-naphthoquinone: New synthesis of 1-azaanthraquinones

Article abstract of DOI:10.1080/00397910902963421

Copper(I) bromide catalyzes the regioselective Michael addition reaction of 2-amino-1,4-naphthoquinone (5) with methyl vinyl ketone and 2-propenal to provide easy access to C-alkylated quinone derivatives, useful precursors of 1-azaanthraquinones.

Full text of DOI:10.1080/00397910902963421

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Copper Bromide–Catalyzed C-Alkylation
of 2-Amino-1,4-Naphthoquinone: New
Synthesis of 1-Azaanthraquinones
Ricardo A. Tapia a , Juan Venegas a & Lorena B. Cantuarias a
a Facultad de Química, Pontificia Universidad Católica de Chile ,
Santiago , Chile
Published online: 09 Dec 2009.
To cite this article: Ricardo A. Tapia , Juan Venegas & Lorena B. Cantuarias (2009) Copper
Bromide–Catalyzed C-Alkylation of 2-Amino-1,4-Naphthoquinone: New Synthesis of 1-
Azaanthraquinones, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 40:1, 151-156, DOI: 10.1080/00397910902963421
To link to this article: http://dx.doi.org/10.1080/00397910902963421
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Synthetic Communications1, 40: 151–156, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910902963421
COPPER BROMIDE–CATALYZED C-ALKYLATION OF
2-AMINO-1,4-NAPHTHOQUINONE: NEW SYNTHESIS
OF 1-AZAANTHRAQUINONES
Ricardo A. Tapia, Juan Venegas, and Lorena B. Cantuarias
´
Facultad de Quımica, Pontificia Universidad Catolica de Chile, Santiago, Chile
ꢀ
Copper(I) bromide catalyzes the regioselective Michael addition reaction of 2-amino-1,
4-naphthoquinone (5) with methyl vinyl ketone and 2-propenal to provide easy access to
C-alkylated quinone derivatives, useful precursors of 1-azaanthraquinones.
Keywords: 2-Amino-1,4-naphthoquinone; 1-azaantraquinones; catalysts; CuBr; Michael addition
INTRODUCTION
The azaanthraquinone framework occurs in natural alkaloids such as cleisto-
pholine (1),[1] dielsiquinone (2),[2] and the fungal metabolite phomazarin (3).[3] The
synthesis of 1 was successfully performed by Bracher[4] through a [4 þ 2] cycloaddi-
tion between 2-bromonaphthoquinone and crotonaldehyde N,N-dimethylhydra-
zone. The Diels–Alder strategy was also used to obtain some substituted
derivatives of 1.[5,6]
The total synthesis of 3 has been recently described by Boger and coworkers
using a selective nucleophilic addition of an aryllithium reagent to a pyridine
anhydride followed by intramolecular Friedel–Craft acylation.[7]
Considering that Michael adducts of hydroxyquinones are useful intermediates
for the synthesis of pyranonaphthoquinones,[8] we wanted to extend this
methodology to the synthesis of aza-analogs 4 through the reaction of 2-amino-1,
4-naphthoquinone (5) with methyl vinyl ketone (6).
Despite the poor nucleophilicity of the amino group in quinone 5, this quinone
reacts with b-ketoesters or similar electrophiles to give N-alkylated products, which
under cyclization afford azaanthraquinon-2-ones.[9,10] Taking into account that
copper bromide catalyzes the conjugated additions of enaminones to quinones,[11,12]
we decided to study the reaction of 2-amino-1,4-naphthoquinone (5) with ketone 6
in the presence of copper halides.
Received January 27, 2009.
Address correspondence to Ricardo A. Tapia, Facultad de Quımica, Pontificia Universidad
´
Catolica de Chile, Casilla 306, Santiago 6094411, Chile. E-mail: rtapia@uc.cl
ꢀ
151

152
R. A. TAPIA, J. VENEGAS, AND L. B. CANTUARIAS
RESULTS AND DISCUSSION
Treatment of 2-amino-1,4-naphthoquinone (5) with methyl vinyl ketone (6) in
a pyridine-t-butanol (10:1) mixture under reflux resulted in recovery of starting
material. However, the acid-catalyzed reaction of compound 5 with ketone 6 in
1
refluxing toluene for 5 h gave the N-alkylated compound 7 in 50% yield. The H
NMR spectrum of 7 shows one quinone proton signal at d 5.76, together with signals
for CH3CO (d 2.21), COCH2 (d 2.83), CH2NH (d 3.49), and NH (d 6.18), confirming
the structure of N-alkylated product 7.
Then, the reaction of aminonaphthoquinone 5 with methyl vinyl ketone (6) in
the presence of copper halides was examined. Copper(II) halides were less suitable
catalysts than copper(I) halides, and copper(I) bromide gave cleaner and faster
reactions. Thus, reaction of 5 with methyl vinyl ketone (6) in acetonitrile at room
temperature for 5 days in the presence of 10 mol% of copper(I) bromide afforded
1
C-alkylated product 8 (78%). The H NMR spectrum suggests that 8 exists in the
cyclic form 9 in solution, showing singlet peaks for methyl (d 1.60 ppm), hydroxy
(d 3.03 ppm), and amino protons (d 6.10 ppm), respectively. Treatment of compound
9 with silica gel and tetrachloro-1,4-benzoquinone (p-chloranil) gave azaanthraqui-
none 10 in 69% yield (Scheme 1).
We also examined the copper(I) bromide–catalyzed reaction of 5 with methyl
vinyl ketone (6) in acetonitrile under reflux, giving a mixture of the N-alkylated
product 7 and aza-anthraquinone 10 in 14% and 35% yields, respectively.
The regioselective C-alkylation procedure was next studied with 2-propenal.
Thus, reaction of 2-amino-1,4-naphthoquinone (5) with 2-propenal in acetonitrile
at room temperature for 3 days in the presence of 10 mol% copper(I) bromide
afforded C-alkylated product 11 in 63% yield. As in the case of compound 8, the
Scheme 1. Reagents and conditions: a) toluene, HOAc, 6, reflux, 5 h; b) CH3CN, K2CO3, CuBr, 6; and c)
silica gel, p-chloranil, CH2Cl2, reflux, 1 h.

C-ALKYLATION OF AMINO NAPHTHOQUINONE
153
Scheme 2. a) CH3CN, K2CO3, CuBr, 2-propenal; and b) silica gel, p-chloranil, CH2Cl2, reflux, 1 h.
C-alkylated product 12 also exists as its cyclic isomer 13. Then, treatment of
compound 12 with silica gel and p-chloranil led to azaanthraquinone 14 in 64% yield
(Scheme 2).
In conclusion, copper(I) bromide–catalyzed C-alkylation of 2-amino-
1,4-naphthoquinone provides another useful methodology to reach the azaanthra-
quinone system.
EXPERIMENTAL
Melting points were determined with a Kofler hot-stage apparatus and were
not corrected. Infrared (IR) spectra were obtained on a Bruker model Vector 22
1
spectrophotometer. H and 13C NMR spectra were recorded on a Bruker AM-200
spectrometer, using tetramethylsilane (TMS) as internal reference. Column chroma-
tography was performed on Merck silica gel 60 (70–230 mesh). Elemental analyses
were performed on a Fisons EA 1108 CHNS-O analyzer.
N-(3-Oxobutyl)-2-amino-1,4-naphthoquinone (7)
A mixture of 2-amino-1,4-naphthoquinone 5[13] (200 mg, 1.16 mmol), five
drops acetic acid, and ketone 6 (0.5 mL, 6.2 mmol) in toluene (5.0 mL) was heated
to reflux for 5 h. The reaction mixture was evaporated under vacuum, and the
residue was purified by column chromatography using chloroform–ethyl acetate
(1:1) as eluent to give compound 7 (140 mg, 50%), mp 175–177ꢀC; IR (KBr):
3260, 1710, 1670 cmꢁ1
;
1H NMR d: 2.21 (s, 3H, CH3), 2.83 (t, 2H, J ¼ 6.1 Hz,
CH2CO), 3.49 (c, 2H, J ¼ 6.1 Hz, CH2NH), 5.76 (s, 1H, 3-H), 6.18 (br. s, 1H,
NH), 7.61 (ddd, 1H, J ¼ 7.5, 7.5, and 1.5 Hz, 7-H), 7.73 (ddd, 1H, J ¼ 7.5, 7.5,
and 1.5 Hz, 6-H), 8.01 (dd, 1H, J ¼ 7.3 and 1.4 Hz, 5-H), 8.07 (dd, 1H, J ¼ 7.4
and 1.4 Hz, 8-H); 13C NMR d: 30.1 (CH3), 41.2 (CH2), 100.7 (CH), 126.1
(CH), 126.3 (CH), 130.5 (C), 132.0 (CH), 133.5 (C), 134.7 (CH), 147.6 (C),
181.6 (C), 182.9 (C), 206.1 (C). Anal. calcd. for C14H13NO3: C, 69.12; H, 5.39;
N, 5.76. Found: C, 69.08; H, 5.42; N, 5.71.

154
R. A. TAPIA, J. VENEGAS, AND L. B. CANTUARIAS
2-Amino-3-(3-oxobutyl)-1,4-naphthoquinone (8)
A mixture of 2-amino-1,4-naphthoquinone 5 (200 mg, 1.16 mmol), ketone 6
(190 mL, 2.32 mmol), potassium carbonate (700 mg, 5.04 mmol), and copper(I)
bromide (16.6 mg, 0.116 mmol) in acetonitrile (20 mL) was stirred at room tempera-
ture for 5 days under nitrogen. The reaction mixture was filtered, the filtrate was
evaporated under vacuum, and the residue was recrystallized from benzene to give
1
compound 8 (190 mg, 78%), mp 95ꢀC (d); IR (nmax): 3420, 3320, 1660 cmꢁ1; H
NMR d: 1.42–1.69 (m, 4H, 3-H and CH3), 2.05–2.14 (m, 1H, 3-H), 2.52 (ddd, 1H,
J ¼ 18.2, 13.0 and 5.8 Hz, 4-H), 2.90 (ddd, 1H, J ¼ 18.2, 13.0, and 2.6 Hz, 4-H),
3.03 (br. s, 1H, OH), 6.07 (s, 1H, NH), 7.55 (dt, 1H, J ¼ 7.5 and 1.5 Hz, 7-H or
8-H), 7.66 (dt, 1H, J ¼ 7.5 and 1.5 Hz, 8-H or 7-H), 7.85 (d, 1H, J ¼ 7.4 Hz, 6-H
or 9-H), 7.99 (d, 1H, J ¼ 7.4 Hz, 9-H or 6-H); 13C NMR d: 16.4 (CH2), 28.9
(CH3), 32.6 (CH2), 78.1 (C), 113.1 (C), 125.8 (CH), 126.1 (CH), 130.3 (C), 132.1
(CH), 132.9 (C), 134.5 (CH), 142.2 (C), 180.4 (C), 181.7 (C). Anal. calcd. for
C14H13NO3: C, 69.12; H, 5.39; N, 5.76. Found: C, 68.34; H, 4.97; N, 5.89.
2-Methybenzo[g]quinoline-5,10-dione (10)
A suspension of compound 8 (270 mg, 1.11 mmol), silica gel (1.0 g), and
p-chloranil (273 mg, 1.11 mmol) in dichloromethane (DCM) (50 mL) was heated to
reflux for 1 h. After filtration and evaporation, the residue was purified by column
chromatography using DCM as eluent to afford 10 (170 mg, 69%); mp 181–183ꢀC.
1
IR (nmax): 1680, 1660 cmꢁ1; H NMR d: 2.83 (s, 3H, CH3), 7.59 (d, 1H, J ¼ 8.1 Hz,
Hz, 3-H), 7.82–7.86 (m, 2H, 7-H and 8-H), 8.33–9.27 (m, 2H, 6-H and 9-H), 8.53 (d,
1H, J ¼ 8.1 Hz, 4H); 13C NMR d: 25.4 (CH3), 127.1 (CH), 127.9 (CH), 128.0 (CH),
128.5 (C), 132.7 (C), 133.5 (C), 134.4 (CH), 134.6 (CH), 135.6 (CH), 148.4 (C), 165.4
(C), 181.8 (C), 182.6 (C). Anal. calcd. for C14H9NO2: C, 75.33; H, 4.06; N, 6.27.
Found: C, 75.50; H, 3.98; N, 6.33.
2-Amino-3-(2-formylethyl)-1,4-naphthoquinone (12)
A mixture of 2-amino-1,4-naphthoquinone 5 (200 mg, 1.16 mmol), 2-propenal
(155 mL, 2.32 mmol), potassium carbonate (560 mg, 5.04 mmol), and copper(I) bro-
mide (16.6 mg, 0.116 mmol) in acetonitrile (15 mL) was stirred at room temperature
for 3 days under nitrogen. The reaction mixture was filtered, the filtrate was evapo-
Figure 1. Cleistopholine, dielsiquinone, and phomazarin.

C-ALKYLATION OF AMINO NAPHTHOQUINONE
155
Figure 2. Retrosynthetic analysis.
rated under vacuum, and the residue was purified by column chromatography on
neutral alumina using methylene chloride–ethyl acetate–methanol 85:15:5. Evapor-
ation of the solvent gave compound 12 (167 mg, 63%), mp 115ꢀC (d); IR (nmax):
3340, 1660 cmꢁ1 1H NMR d: 1.60–180 (m, 1H, 3-H), 2.05–2.20 (m, 1H, 3-H),
;
2.49 (ddd, 1H, J ¼ 18.0, 13.4 and 5.7 Hz, 4-H), 2.69 (br. s, 1H, OH), 2.90 (ddd,
1H, J ¼ 18.0, 5.5, and 2.2 Hz, 4-H), 5.23 (m, 1H, 2-H), 6.36 (br. s, 1H, NH), 7.59
(dt, 1H, J ¼ 7.5 and 1.5 Hz, 7-H or 8-H), 7.69 (dt, 1H, J ¼ 7.5 and 1.5 Hz, 8-H or
7-H), 7.94 (dd, 1H, J ¼ 7.5 and 1.5 Hz, 6-H or 9-H), 8.06 (dd, 1H, J ¼ 7.5 and
1.5 Hz, 9-H or 6-H); 13C NMR d: 15.5 (CH2), 27.6 (CH2), 73.2 (CH), 114.1 (C),
126.6 (CH), 128.6 (CH), 132.0 (C), 133.1 (CH), 134.6 (C), 135.5 (CH), 143.9 (C),
181.9 (C), 182.1 (C). Anal. calcd. for C13H11NO3: C, 68.11; H, 4.84; N, 6.11. Found:
C, 68.34; H, 4.97; N, 5.89.
Benzo[g]quinoline-5,10-dione (14)
A suspension of compound 12 (100 mg, 0.44 mmol), silica gel (0.5 g), and
p-chloranil (108.2 mg, 0.44 mmol) in DCM (25 mL) was heated to reflux for 1 h.
After filtration and evaporation, the residue was purified by column chromato-
graphy using DCM as eluent to afford 14 (59 mg, 65%); mp 274–275ꢀC (lit.[14] mp
275–276ꢀC).
ACKNOWLEDGMENTS
ꢀ
We are grateful to Fondo Nacional de Desarrollo Cientıfico y Tecnologico
(FONDECYT, Research Grant 1060592) and Comision Nacional de Investigacion
´
ꢀ
ꢀ
ꢀ
´
Cientıfica y Tecnologica (CONICYT, fellowship to L. C. and Research Grant
AT24080019).
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