Two-directional synthesis of 2,6-Dimethylpyrrolo-[2,3-f]indole-4,8-dione by double Claisen rearrangement and nitrene cyclization

Article abstract of DOI:10.3987/COM-13-S(S)25

Double Claisen rearrangement of the bis-allyl ether of 2,5-dichloro-1,4-hydroquinone, followed by alkene isomerization, oxidation and double chloride displacement with azide gives 2,5-diazido-3,6-dipropenyl-1,4-benzoquinone. Upon heating, a double nitrene cyclization occurs completing a high yielding, two-directional route to the pyrrolo[2,3-f]indole-4,8-dione ring system.

Full text of DOI:10.3987/COM-13-S(S)25

HETEROCYCLES, Vol. 88, No. 1, 2014
705
HETEROCYCLES, Vol. 88, No. 1, 2014, pp. 705 - 710. © 2014 The Japan Institute of Heterocyclic Chemistry
Received, 4th June, 2013, Accepted, 1st July, 2013, Published online, 8th July, 2013
DOI: 10.3987/COM-13-S(S)25
TWO-DIRECTIONAL SYNTHESIS OF 2,6-DIMETHYLPYRROLO-
[2,3-f]INDOLE-4,8-DIONE BY DOUBLE CLAISEN REARRANGEMENT
AND NITRENE CYCLIZATION †
Andrea Visconti and Christopher J. Moody*
School of Chemistry, University of Nottingham, University Park, Nottingham,
NG7 2RD, U.K. Email: c.j.moody@nottingham.ac.uk
Abstract – Double Claisen rearrangement of the bis-allyl ether of
2,5-dichloro-1,4-hydroquinone, followed by alkene isomerization, oxidation and
double chloride displacement with azide gives 2,5-diazido-3,6-dipropenyl-
1,4-benzoquinone. Upon heating, a double nitrene cyclization occurs completing a
high yielding, two-directional route to the pyrrolo[2,3-f]indole-4,8-dione ring
system.
The indole heterocycle is ubiquitous among biologically active compounds, both naturally occurring
indole alkaloids and synthetic medicinal compounds. One interesting subset of indoles are the
pyrroloindoles (benzodipyrroles), particularly the symmetrical pyrrolo[2,3-f]indoles (Figure 1). Interest in
this class of indoles has been heightened by the structure of terreusinone, a UV-protective natural product
isolated from the marine fungus Aspergillus terreus.1,2 In keeping with their structure, the synthesis of
pyrrolo[2,3-f]indoles is best approached through a strategy that takes advantage of the symmetry, and a
number of such approaches have been developed. These include oxidative cyclization of
2,5-di(2-aminoethyl)-1,4-hydroquinones,3 a double Leimgruber-Batcho synthesis starting from
2,5-dinitro-p-xylene,4 and
a
Rh(I) catalyzed intramolecular hydroamination reaction of
2,5-diethynyl-p-phenylenediamine.5 A related Au(I) catalyzed double intramolecular hydroamination has
recently been reported for the two-directional synthesis of terreusinone itself.6 We now report a
complementary, new two-directional approach to pyrrolo[2,3-f]indoles based on a double Claisen
rearrangement and nitrene cyclization. Routes to symmetrical pyrrolo[2,3-f]indole-4,8-diones are also
known, for example from 2,5-diamino-3,6-dibromobenzoquinones.7
† Dedicated with respect and affection to Professor Victor Snieckus, Queen’s University, Canada

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HETEROCYCLES, Vol. 88, No. 1, 2014
O
H
N
Me
H
Me
OH
Me
N
N
H
N
H
HO
Me
O
pyrrolo[2,3-f]indole
terreusinone
Figure 1. The pyrrolo[2,3-f]indole ring system, and the natural product terreusinone
The starting point for the synthesis was 2,5-dichloro-1,4-hydroquinone that was converted into its diallyl
ether (1) in excellent yield by reaction with allyl bromide and sodium hydride in DMF. On heating to
220 °C under microwave irradiation in 1,2-dichlorobenzene a double Claisen rearrangement ensued to
give bis-allyl hydroquinone (2) in good yield (Scheme 1). Rearrangement under microwave conditions
was generally superior to conventional heating, although the reaction could be carried out at room
temperature albeit in lower yield (35%) by treatment with diethylaluminium chloride Lewis acid.
Although the aromatic Claisen rearrangement is well known,8 there are relatively few examples involving
a double (or tandem) rearrangement of bis(allyloxy)arenes.9-11 Hydroquinone (2) was treated with
palladium(II) chloride bis(acetonitrile) in catalytic amount to give the isomerized hydroquinone (3) in
excellent yield. Oxidation with cerium(IV) ammonium nitrate gave dichloroquinone (4) in good yield,
which was treated with sodium azide to give diazidoquinone (5) in excellent yield. Finally, heating in
toluene at 85 °C gave dipyrrolobenzoquinone (6) in quantitative yield (Scheme 1). The structure of
pyrrolo[2,3-f]indole (6) was confirmed both by NMR spectroscopy and mass spectrometry. The
appearance of a broad singlet at 12.18 ppm for the NH groups, a singlet at 6.14 ppm for the CH groups
1
and a singlet at 2.20 ppm for the methyl groups in the H-NMR spectrum were in agreement with the
symmetrical structure of (6).
O
HO
OH
OH
OH
H2C=CHCH2Br
NaH, DMF
MW (300W)
220 °C, 0.5 h
PdCl2(MeCN)2
reflux, CH2Cl2
Cl
Cl
Cl
Cl
Me
97%
97%
1,2-Cl2C6H4
71%
Cl
Cl
Cl
Cl
Me
O
OH
OH
1
2
3
CAN
aq THF
rt
75%
O
O
O
H
N
NaN3
0 °C, aq acetone
85 °C
toluene
N3
Cl
Me
Me
Me
Me
N
H
99%
95%
N3
Cl
Me
Me
O
O
O
6
4
5
Scheme 1. Double Claisen rearrangement and nitrene cyclization

HETEROCYCLES, Vol. 88, No. 1, 2014
707
The proposed mechanism for the cyclization involves the thermolysis of the azide group with loss of
nitrogen and formation of a nitrene intermediate; a six-electron electrocyclic ring closure followed by
[1,5]-sigmatropic hydrogen shift, gives the fused pyrrole (Scheme 2). This mechanism is preferred over a
direct nitrene insertion into the alkene C-H bond.12,13 It is not known whether the two nitrene cyclizations
occur simultaneously or sequentially, but in combination with the double Claisen rearrangement it
constitutes a very convenient, high yielding two-directional route to the pyrrolo[2,3-f]indole core
structure.
Me
Me
heat
-N2
electrocyclic
[1,5]-sigmatropic
H shift
Me
H
Me
N
N
H
N3
N:
..
Scheme 2. Proposed mechanism of nitrene cyclization
EXPERIMENTAL
Commercially available reagents were used throughout without purification unless otherwise stated. All
anhydrous solvents were used as supplied, except dichloromethane that was freshly distilled according to
standard procedures. Reactions were routinely carried out under an argon atmosphere unless otherwise
stated, and all glassware was flame-dried before use. Light petroleum refers to the fraction with bp 40-60
ºC.
Analytical thin layer chromatography was carried out on aluminium backed plates coated with silica gel,
and visualized under UV light at 254 and/or 360 nm and/or by chemical staining. Flash chromatography
was carried out using silica gel, with the eluent specified.
Infrared spectra were recorded using an FT-IR spectrometer over the range 4000-600 cm-1. NMR spectra
were recorded at 400 MHz (1H frequency, 100 MHz C frequency). Chemical shifts are quoted in parts
13
per million (ppm), and are referenced to residual H in the deuterated solvent as the internal standard.
13
Coupling constants, J, are quoted in Hz. In the C NMR spectra, signals corresponding to CH, CH2, or
CH3 groups are assigned from DEPT. Mass spectra were recorded on a time-of-flight mass spectrometer
using electrospray ionization (ESI).
1,4-Diallyloxy-2,5-dichlorobenzene 1
A stirred suspension of anhydrous, oil-free sodium hydride (60% in mineral oil; 2.23 g, 55.9 mmol) in
DMF (56 mL) was treated dropwise with a solution of 2,5-dichloro-1,4-hydroquinone (5.00 g, 27.9
mmol) in DMF (56 mL) and allyl bromide (6.76 g, 55.9 mmol). The resulting reaction mixture was stirred
at room temperature for 16 h, diluted with EtOAc (200 mL), washed with water (3 ! 100 mL) and

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HETEROCYCLES, Vol. 88, No. 1, 2014
saturated aqueous sodium chloride (100 mL), dried (MgSO4), filtered and the filtrate evaporated in vacuo.
Flash chromatography of the residue on silica, eluting with EtOAc-light petroleum (1:9), gave the title
compound (7.02 g, 97%) as a colourless solid; mp 62-64 °C; Anal. Calcd for C12H12Cl2O2: C, 55.62; H,
4.67. Found: C, 55.44; H, 4.64; C12H1235Cl2O2 + Na+ requires 281.0107; Found: M+Na+, 281.0107. "max
(CHCl3)/cm-1 3088, 2991, 2872, 1649, 1498, 1083, 997; #H (400 MHz; CDCl3) 6.99 (2 H, s, ArH),
6.10-6.00 (2 H, m, ArOCH2CH=CH2), 5.48-5.43 (2 H, m, ArOCH2CH=CHH), 5.34-5.30 (2 H, m,
ArOCH2CH=CHH), 4.57-4.54 (4 H, m, ArOCH2CH=CH2); #C (100 MHz; CDCl3) 148.5 (C), 132.4 (CH),
121.7 (C), 118.2 (CH2), 116.4 (CH), 70.7 (CH2); m/z (ESI) 285/283/281 (M+Na+, 9/61/100%).
2,5-Diallyl-3,6-dichlorobenzene-1,4-hydroquinone 2
A solution of 1,4-diallyloxy-2,5-dichlorobenzene (0.200 g, 0.771 mmol) in 1,2-dichlorobenzene (2 mL) in
a sealed tube was heated at 220 °C for 30 min in a microwave reactor (300 W). The solvent was removed
under reduced pressure, and purification of the residue by flash chromatography on silica, eluting with
CH2Cl2-light petroleum (2:8), gave the title compound (0.141 g, 71%) as a colourless solid; mp
120-122 °C; C12H1235Cl2O2 + Na+ requires 281.0107; Found: M+Na+, 281.0097. "max (CHCl3)/cm-1 3541,
3083, 2984, 2927, 1639, 1425, 1319, 1172; #H (400 MHz; CDCl3) 5.98-5.88 (2 H, m, ArCH2CH=CH2),
5.42 (2 H, s, OH), 5.10-5.05 (4 H, m, ArCH2CH=CH2), 3.59-3.57 (4 H, m, ArCH2CH=CH2); #C (100
MHz; CDCl3) 143.6 (C), 134.0 (CH), 122.9 (C), 119.8 (C), 115.9 (CH2), 32.2 (CH2); m/z (ESI)
285/283/281 (M+Na+, 10/62/100%).
2,5-Dichloro-3,6-di(prop-1-enyl)-1,4-hydroquinone 3
A solution of 2,5-diallyl-3,6-dichlorobenzene-1,4-hydroquinone (1.00 g, 3.86 mmol) and palladium(II)
chloride bis(acetonitrile) (0.100 g, 0.386 mmol) in CH2Cl2 (100 mL) was heated under reflux for 3 h,
filtered through Celite® and the filtrate evaporated in vacuo to give the title compound (0.974 g, 97%) as a
colourless solid; mp 190-192 °C; C12H1235Cl2O2 + Na+ requires 281.0107; Found: M+Na+, 281.0096. "max
(CHCl3)/cm-1 3527, 2916, 1602, 1430, 1415, 1318, 1253, 1176, 969; #H (400 MHz; DMSO-d6) 8.78 (2 H,
s, OH), 6.49-6.42 (4 H, m, CH=CHCH3), 1.88 (6 H, d, J 5.3, CHCH3); #C (100 MHz; DMSO-d6) 144.2 (C),
133.1 (CH), 123.8 (CH), 123.3 (C), 120.1 (C), 19.4 (Me); m/z (ESI) 285/283/281 (M+Na+, 10/64/100%).
2,5-Dichloro-3,6-di(prop-1-enyl)-1,4-benzoquinone 4
A solution of cerium(IV) ammonium nitrate (2.60 g, 4.75 mmol) in water (50 mL) was added dropwise to
a stirred solution of 2,5-dichloro-3,6-di(prop-1-enyl)-1,4-hydroquinone (0.492 g, 1.90 mmol) in THF (50
mL). The resulting reaction mixture was stirred at room temperature for 2 h, concentrated, and extracted
with EtOAc (3 ! 20 mL). The organic layer was dried (MgSO4) and evaporated in vacuo. The residue was

HETEROCYCLES, Vol. 88, No. 1, 2014
709
purified by flash chromatography on silica eluting with CH2Cl2-light petroleum (2:8) to give the title
compound (0.367 g, 75%) as a bright red solid; mp 130-132 °C; Anal. Calcd for C12H10Cl2O2: C, 56.06; H,
3.92%. Found: C, 55.71; H, 3.90. C12H1035Cl2O2 + Na+ requires 278.9950; Found: M+Na+, 278.9940. $max
(MeCN)/nm 255 (log % 4.31), 340 (log % 3.99); "max (CHCl3)/cm-1 2914, 1673, 1627, 1189, 1168, 966,
851; #H (400 MHz; CDCl3) 7.19-7.10 (2 H, dq, J 15.9, 6.9, CH=CHCH3), 6.55-6.50 (2 H, dq, J 15.9, 1.7,
CH=CHCH3), 2.01-1.99 (6 H, dd, J 6.9, 1.8, CHCH3); #C (100 MHz; CDCl3) 177.8 (C), 144.3 (CH), 137.2
(C), 137.1 (C), 122.2 (CH), 20.7 (Me); m/z (ESI) 283/281/279 (M+Na+, 10/63/100%).
2,5-Diazido-3,6-di(prop-1-enyl)-1,4-benzoquinone 5
A solution of 2,5-dichloro-3,6-di(prop-1-enyl)-1,4-benzoquinone (0.154 g, 0.599 mmol) in acetone (20
mL) was stirred at 0 °C while sodium azide (0.082 g, 1.26 mmol) in water (1 mL) was added dropwise.
After 10 min, the solution was diluted with water (20 mL) and extracted with CH2Cl2 (3 x 20 mL). The
organic layer was dried (MgSO4), filtered and the filtrate and evaporated in vacuo to give the title
compound (0.154 g, 95%) as a dark red solid; mp >300 °C; C12H10N6O2 + Na+ requires 293.0757; Found:
M+Na+, 293.0753. $max (MeCN)/nm 280 (log % 4.60), 369 (log % 4.24); "max (CHCl3)/cm-1 3012, 2115,
1658, 1626, 1550, 1362, 1316, 1249; #H (400 MHz; CDCl3) 7.08-6.99 (2 H, dq, J 16.0, 6.9, CH=CHCH3),
6.41-6.36 (2 H, dq, J 15.9, 1.8, CH=CHCH3), 1.96-1.93 (6 H, dd, J 6.9, 1.8, CHCH3); #C (100 MHz;
CDCl3) 181.0 (C), 139.6 (CH), 137.4 (C), 123.2 (C), 120.3 (CH), 20.4 (Me).
2,6-Dimethylpyrrolo[2,3-f]indole-4,8(1H,5H)-dione 6
A stirred solution of 2,5-diazido-3,6-di(prop-1-enyl)-1,4-benzoquinone (0.460 g, 1.702 mmol) in toluene
(100 mL) was heated at 85 °C for 1 h and then evaporated in vacuo. The solid obtained was washed with
EtOH and the solvent was filtered off to give the title compound (0.364 g, 99%) as a dark red solid; mp
>300 °C; C12H10N2O2 + Na+ requires 237.0634; Found: M+Na+, 237.0633. $max (MeCN)/nm 243 (log %
3.77); "max (CHCl3)/cm-1 3207, 1725, 1602, 1240; #H (400 MHz; DMSO-d6) 12.18 (2 H, s, NH), 6.14 (2 H,
s, CH), 2.20 (6 H, s, Me); #C (100 MHz; DMSO-d6) 173.7 (C), 135.5 (C), 131.5 (C), 126.3 (C), 105.7
(CH), 12.5 (Me).
ACKNOWLEDGEMENTS
We thank the University of Nottingham for support.

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