Inman and Moody
JOCNote
SCHEME 2
dithionite followed by reduction of the ester with lithium
aluminum hydride and reoxidation of the hydroquinone to
the quinone 7 with iron(III) chloride (Scheme 1). Compar-
ison of the 13C NMR spectrum of the alcohol thus derived
with an authentic sample confirmed conclusively that the
regiochemistry was as shown in Scheme 1.
In order to investigate the generality of this method, a
number of bromoquinones were reacted with a wide range of
enamines, readily available in excellent yield by condensa-
tion of primary amines with β-keto esters or by 1,4-addition
of primary amines to electron-deficient alkynes, to give
indolequinones 6 and 8-20 bearing various functional
groups (Table 2). A wide range of functionalities was toler-
ated, including TBS, allyl and PMB ethers, Boc-protected
amines, and methyl, ethyl, and tert-butyl esters. The N-
substituent could be varied to include alkyl and aryl func-
tionalities, but attempts to synthesize 1-unsubstituted
derivatives using methyl 3-aminocrotonate proved unsuc-
cessful. Reaction of 2,6-dibromo-1,4-benzoquinone with 2
equiv of the enamine component allowed access to the
symmetrical pyrroloindolequinone 13 in moderate yield
(Table 2, entry 7).
The inferior reactivity of 2-bromo-5-methoxybenzoqui-
none, compared with the 6-methoxy isomer, is noteworthy
but is consistent with the results reported by Murphy and co-
workers20 and with the proposed mechanism which begins
with 1,4-addition of the enamine through carbon to the
3-position of the bromoquinone and reoxidation (Scheme 2).
Premature termination of the reaction afforded the inter-
mediate uncyclized enaminoquinone 21, observed in all
reactions as a red component which eventually converted
to the product under the reaction conditions.
NAD(P)H:quinone oxidoreductase 1 (NQO1),12-17 we re-
quired a scalable and general route to the heterocyclic frame-
work. We report here an efficient, convergent, and general
procedure for the synthesis of indolequinone-3-carboxylate
esters that can be readily converted into a range of biologi-
cally active derivatives.
In their approach to the synthesis of mitosenes related to
MMC, Luly and Rapoport reported the reaction of 2,3-
dibromo-1,4-benzoquinones with enamine derivatives to give
the indolequinone core structure.18 Subsequently, in their
synthesis of EO9 and related mitosenes, Murphy et al. reported
a synthesis of indolequinone esters by oxidative annulation of
monobromoquinones with enamines, using catalytic amounts
of copper(II) bromide and utilizing air as the terminal
oxidant.19,20 Although this appears to be an attractive route,
the procedure proved extremely sensitive to structural changes
in the substrates and generally gave unsatisfactory yields in our
hands. Therefore, we initiated a series of optimization experi-
ments using the reaction of 2-bromo-6-methoxy-1,4-benzoqui-
none 4 and methyl N-methylamino-crotonate 5 (to give the
indolequinone 6) under a range of conditions employing
copper(II) salts (Table 1). The results suggest that copper(II)
acetate is superior to the bromide in mediating the reaction,
with the optimum conditions (89% yield of indolequinone 6)
employing 1.5 equiv of copper(II) acetate monohydrate with
K2CO3 in boiling acetonitrile. When the reaction was carried
out under argon, the yield was reduced to 62%. The reaction
still proceeds with catalytic amounts of copper, suggesting that
either air or the copper(II) salt can act as the terminal oxidant.
Under the optimized conditions, the reaction could be
repeated on a large scale, and the product could also be
isolated by recrystallization from methanol, with a slight
reduction in yield to 65%. The regiochemistry of the reaction
was confirmed by conversion of the product 6 into the known
3-hydroxymethylindolequinone 716 via a three-step proce-
dure, starting with reduction of the quinone with sodium
In summary, we present an efficient, regioselective, and
versatile method for the construction of indolequinones
from various bromoquinones and enamines. The indolequi-
nones serve as precursors to a range of derivatives with
anticancer properties.
Experimental Section
Bromoquinones. 2-Bromo[1,4]naphthoquinone is commercially
available; 2-bromo-6-methoxy[1,4]benzoquinone,21 2-bromo-5-
methoxy[1,4]benzoquinone,21 and 2,6-dibromo[1,4]benzoquinone22
were prepared by literature methods.
Preparation of Enamines: Typical Procedure. (Z)-tert-Butyl
3-(Methylamino)but-2-enoate. A solution of methylamine (25%
w/v in water; 3.72 mL, 30 mmol) was added in a single portion to
a stirred suspension of silica gel (0.3 g) and tert-butyl acetoace-
tate (3.95 g, 25 mmol) at room temperature, and the resulting
mixture was stirred at room temperature for 15 h. The mixture
was extracted with dichloromethane (3 ꢀ 15 mL), and the
combined organic phases were dried (MgSO4), filtered, and
concentrated in vacuo to give the title compound as a pale
yellow oil (4.15 g, 97%): found M þ Hþ, 172.1342, C9H18NO2
requires 172.1332; IR νmax (CHCl3)/cm-1 3306, 3005, 2980,
2931, 1595, 1293; NMR δH (400 MHz; CDCl3) 8.45 (1H, br s,
NH), 4.41 (1H, s, CH), 2.89 (3H, d, J = 4.8 Hz, NMe), 1.89 (3H,
s, Me), 1.47 (9H, s, tBu); δC (75 MHz; CDCl3) 170.9, 162.2, 83.5
(CH), 77.7, 29.5 (Me), 28.6 (Me), 19.0 (Me); HRMS m/z (EI) 365
(2M þ Naþ, 100), 172 (M þ Hþ, 79).
(14) Winski, S. L.; Faig, M.; Bianchet, M. A.; Siegel, D.; Swann, E.; Fung,
K.; Duncan, M. W.; Moody, C. J.; Amzel, M.; Ross, D. Biochemistry 2001,
40, 15135–15142.
(15) Reigan, P.; Colucci, M. A.; Siegel, D.; Chilloux, A.; Moody, C. J.;
Ross, D. Biochemistry 2007, 46, 5941–5950.
(16) Colucci, M. A.; Reigan, P.; Siegel, D.; Chilloux, A.; Ross, D.;
Moody, C. J. J. Med. Chem. 2007, 50, 5780–5789.
(17) Colucci, M. A.; Couch, G. D.; Moody, C. J. Org. Biomol. Chem.
2008, 6, 637–656.
(18) Luly, J. R.; Rapoport, H. J. Am. Chem. Soc. 1983, 105, 2859–2866.
(19) Murphy, W. S.; O’Sullivan, P. J. Tetrahedron Lett. 1992, 33, 531–534.
(20) Comer, E.; Murphy, W. S. ARKIVOC 2003, 286–296.
(21) Saa, J. M.; Morey, J.; Costa, A. Tetrahedron Lett. 1986, 27, 5125–
5128.
(22) Perumal, P. T.; Bhatt, M. V. Synthesis 1979, 205–206.
J. Org. Chem. Vol. 75, No. 17, 2010 6025