Rapid assembly of tetrahydrodibenzofurans and tetrahydrocarbazoles from benzene and o-iodophenols and o-iodoanilines: Reductive radical arylation of benzene in action

Article abstract of DOI:10.1016/S0040-4020(02)00288-0

In the presence of catalytic benzeneselenol, generated in situ from diphenyl diselenide, tributyltin hydride brings about the radical addition of ortho-functionalized aryl iodides to benzene giving aryl cyclohexadienes. These may then be cyclized by means of standard electrophilic reagents. The use of o-methoxycarbamoyliodobenzene leads to a tetrahydrocarbazole, whereas o-iodobenzoic acid provides a tetrahydrodibenzopyranone. o-Iodophenols lead, overall, to tetrahydrodibenzofurans.

Full text of DOI:10.1016/S0040-4020(02)00288-0

TETRAHEDRON
Pergamon
Tetrahedron 58 32002) 3319±3322
Rapid assembly of tetrahydrodibenzofurans and
tetrahydrocarbazoles from benzene and o-iodophenols and
o-iodoanilines: reductive radical arylation of benzene in action
David Crichp and Mousumi Sannigrahi
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, IL 60607-7061, USA
Received 12 February 2002; accepted 11 March 2002
AbstractÐIn the presence of catalytic benzeneselenol, generated in situ from diphenyl diselenide, tributyltin hydride brings about the
radicaladdition of ortho-functionalized aryl iodides to benzene giving aryl cyclohexadienes. These may then be cyclized by means of
standard electrophilic reagents. The use of o-methoxycarbamoyliodobenzene leads to a tetrahydrocarbazole, whereas o-iodobenzoic acid
provides a tetrahydrodibenzopyranone. o-Iodophenols lead, overall, to tetrahydrodibenzofurans. q 2002 Elsevier Science Ltd. All rights
reserved.
1. Introduction
rence of reduced dibenzofurans and carbazoles the overall
sequence meshes nicely with a recurring theme of contem-
porary organic chemistry; the rapid, convergent assembly of
pharmacophore-like molecular scaffolds7 with a maximum
of atom ef®ciency8±10 from readily available feedstocks.
One of the most important reactions in preparative organic
chemistry is the Birch reduction enabling the facile con-
version of accessible, stable aromatic nuclei into versatile,
reactive cyclohexadienes.1±3 The usefulness of this reaction
is enhanced when the intermediate radicalanions, or anions,
can be trapped with suitable electrophiles leading to con-
comitant arene reduction and carbon±carbon bond forma-
tion.1±4 The value of the overall transformation is
emphasized by the recent introduction of alternative
methods, anionic and metal-catalyzed, for the reductive
functionalization of arenes.5,6 Here we describe a direct
entry into tetrahydrodibenzofurans and tetrahydrocarba-
zoles, by dearomatizing addition of readily available
o-functionalized aryl radicals onto benzene itself, followed
by a simple electrophile mediated cyclization onto the
cyclohexadiene 3Scheme 1). Given the widespread occur-
Arylradicasl add rapidyl to arenes to give substituted
s
cyclohexadienyl radicals 3kˆ4.5£105 M21 21
at 258C).11
Unfortunately, the adduct radical does not propagate chains
by hydrogen abstraction from stannanes. Consequently most
tin hydride mediated additions of arylhaildes to arenes,
intra- or intermolecular, are inef®cient, require large
amounts of initiator, and give rise to the fully aromatized
products as a consequence of disproportionation or oxi-
dation of the intermediate cyclohexadienyl radicals. While
the usefulness of oxidative radical cyclizations in synthesis
cannot be denied,12 we contend that the inability to trap the
cyclohexadienyl radical and so take advantage of the more
highly functionalized, cyclohexadiene product represents a
missed opportunity in preparative free radicalchemistry.
Recently, we described how a catalytic amount of benzene-
selenol, conveniently introduced as diphenyl diselenide,
serves to trap the cyclohexadienyl radicals, thereby enabling
isolation of aryl substituted cyclohexadienes in moderate to
good yield.13 The present purpose is to illustrate how,
through the use of o-functionalized aryl iodides, this
reductive CC bond forming sequence may be exploited.
Scheme 1. Dearomatizing radial addition to benzene followed by electro-
philic cyclization.
2. Results and discussion
Keywords: radicals and radical reactions; dienes; cyclisation; selenium and
compounds.
Corresponding author. Tel.: 11-312-996-5189; fax: 11-312-996-2183;
e-mail: dcrich@uic.edu
In a ®rst example 3Table 1), a benzene solution of tributyltin
hydride and AIBN was added dropwise to a re¯uxing solu-
tion of o-iodophenol3 1) and 20 mol% diphenyl diselenide
p
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020302)00288-0

3320
D. Crich, M. Sannigrahi / Tetrahedron 58 +2002) 3319±3322
Table 1. Addition of functionalized aryl radicals to benzene
Entry
Substrate
Cyclohexadiene
3skipped/conjugated)
Aromatized adduct
Deiodination
1
2
3
Not isolated
Not isolated
Not isolated
4
5
Not isolated
Not isolated
in benzene at re¯ux over a period of 12 h. After removalof
the volatiles, silica gel chromatography enabled the iso-
lation of the desired adduct 2 in 48% yield together with
5% of the rearomatized product 3 and 16% of phenol. The
substrate 31) was completely consumed under these con-
ditions whereas in the absence of diphenyldiselnide
large amounts of 1 were recovered and the major products
were phenol, the result of simple deiodination, and the
aromatized adduct 33). The presence of benzeneselenol,
3Table 1) illustrates the further functional group compati-
bility typical of free radical chain reactions and demon-
strates application to more complex substrates. Finally, the
last example of Table 1 con®rms the applicability of the
process to o-iodoanilines, provided that they are protected
in the form of carbamates. In this last example analysis of
the crude reaction mixture, before passage over silica gel, by
1H NMR revealed the non-conjugated diene to be formed in
a ratio of .10:1. The ratio of 3:2 reported in Table 1 is
therefore the result of partial equilibration occurring on
chromatographic puri®cation.16
14
derived by in situ reduction of the diphenyldiseelnide,
is clearly important for the smooth operation of these
reactions: it functions by trapping of the intermediate cyclo-
hexadienylradica,l thereby ensuring chain propagation.
13
Although the isolated yields in the above additions are
typically only 40±50%, we believe that they represent
synthetically useful processes given that the products are
derived from very readily available starting materials,
namely benzene and an o-functionalized iodoarene, and
because of the considerable increase in complexity obtained
in a single reaction step. The functionality present in the
adducts is most readily exploited by cyclization reactions
as illustrated by the selenium bromide mediated ring
closures of Table 2.
The ratio of non-conjugated to conjugated diene product
resembles that seen in the earlier examples,13 and re¯ects
on the preferentialkinetic trapping of the cycol hexadienyl
radicalat the internalsite. The predominant formation of the
non-conjugated diene in this example argues against intra-
molecular quenching of the intermediate cyclohexadienyl
15
radicalby the pheno.l
In a second example 3Table 1) the o-cyclohexadienyl
benzoic acid 5 was isolated in 54% yield from the selenol
catalyzed addition of 4 to benzene. The third example
3Table 1) takes advantage of the greater reactivity of
aryl±iodine bonds over aryl±bromine bonds and provides
7, poised for further functionalization perhaps by organo-
metallic means. The use of o-iodovanillin 38) as substrate
In conclusion, we have provided methodology for the
addition of o-functionalized aryl radicals to benzene under
reductive conditions that enables the isolation of arylated
cyclohexadienes in moderate yield. These functionalized
cyclohexadienes are ideally set up for cyclization reactions

D. Crich, M. Sannigrahi / Tetrahedron 58 +2002) 3319±3322
3321
Table 2. Selenium bromide medicated cyclizations
3.1.1. 2-&Cyclohexadienyl)phenol &2). Ratio 10:1. HRMS
Calcd for C12H12O [M]1z: 172.0888, found: 172.0878.
Major isomer: H NMR 3CDCl3) d 2.78±2.85 3m, 2H),
Entry
Substrate
Product, % yield
1
4.15±4.21 3m, 2H), 5.60 3br s, 1H), 5.79±5.86 3m, 2H),
5.92±6.00 3m, 2H), 6.81 3d, Jˆ7.5 Hz, 1H), 6.91 3t, Jˆ
7.5 Hz, 1H), 7.3±7.4 3m, 2H); 13C NMR 3CDCl3) d 25.8,
38.6, 115.9, 120.7, 125.3, 127.4, 128.8, 130.4, 138.4, 154.8.
The minor isomer was distinguished in the 1H NMR
spectrum by signals at d 2.30±2.42 3m, 1H), 2.50±2.62
3m, 1H), 3.80±3.96 3m, 1H).
1a
2a
3.1.2. 2-&Cyclohexadienyl)benzoic acid &5). Ratio 7:1.
HRMS Calcd for C13H112O2 [M]1z: 200.0837, found:
200.0818. Major isomer: H NMR 3CDCl3) d 2.77 3m,
2H), 5.05 3m, 1H), 5.71±5.84 3m, 4H), 7.30 3d, Jˆ7.8 Hz,
1H), 7.47 3t, Jˆ7.8 Hz, 1H), 7.52 3t, Jˆ7.8 Hz, 1H), 8.00 3d,
Jˆ7.8 Hz, 1H); 13C NMR 3CDCl3) d 25.9, 38.0, 124.1,
126.3, 127.8, 128.6, 130.6, 131.2, 133.3, 147.3, 172.5.
The minor isomer was distinguished in the 1H NMR
spectrum by signals at d 2.35 3m, 1H), 4.58±4.70 3m, 1H).
3b
3.1.3. 4-Bromophenylcyclohexadiene &7). Ratio 4:1.
HRMS Calcd for C12H111 [M2Br]1: 155.0861, found:
155.0861. Major isomer: H NMR 3CDCl3) d 2.71±2.80
3m, 2H), 3.82±3.90 3m, 1H), 5.62±5.71 3m, 2H), 5.78±
5.82 3m, 2H), 7.11 3d, Jˆ8.4 Hz, 2H), 7.42 3d, Jˆ8.4 Hz,
2H); 13C NMR 3CDCl3) d 26.0, 41.7, 124.3, 128.1, 128.7,
131.6, 131.7, 136.7. The minor isomer was distinguished in
the H NMR spectrum by signals at 3 2.22±2.32 3m, 1H),
2.41±2.60 3m, 1H), 3.51±3.61 3m, 1H), 5.92±6.11 3m, 2H),
7.15 3d, Jˆ8.4 Hz, 2H).
4c
a
Reaction performed with the inseparable 10/1 mixture of non-conjugated/
conjugated diene.
b
c
Reaction performed with the inseparable 10/1 mixture of non-conjugated/
conjugated diene. The product was a ,8:1 inseparable mixture of 1,2-
and 2,3-alkene arising from cyclization of the mixture.
Reaction performed with a pure sample of non-conjugated diene.
1
3.1.4. 5-&Cyclohexadienyl)vanillin &9). Ratio 4:1. HRMS
leading to the formation of tetrahydrodibenzofurans and
tetrahydrocarbazoles, thereby providing a very rapid
means of entry into these nuclei from commodity chemicals.
Finally, we note that in the ultimate cyclized products
3Table 2) three adjacent sites of the original benzene ring
are directly functionalized, while the remaining three are set
up for immediate exploitation.
Calcd for C14H14O3 [M]1z: 230.0942, found: 230.0945. Mp
112±1148C. Major isomer: H NMR 3CDCl3) d 2.73±2.76
1
3m, 1H), 3.96 3s, 3H), 4.45±4.52 3m, 1H), 5.70±5.98 3m,
4H), 6.41 3s, 1H), 7.26 3d, Jˆ1.8 Hz, 1H), 7.51 3d,
Jˆ1.8 Hz, 1H), 9.82 3s, 1H); 13C NMR 3CDCl3) d 25.9,
34.4, 56.4, 106.7, 124.1, 124.9, 125.5, 126.9, 127.6, 148.8,
172.2, 191.4. The minor isomer was distinguished in the 1H
NMR spectrum by signals at: d 2.31±2.48 3m, 1H), 2.52±
2.68 3m, 1H), 3.99±4.08 3m, 1H), 5.99±6.01 3m, 2H), 6.20±
6.25 3m, 2H), 6.41 3s, 1H), 7.25 3d, 1H, Jˆ1.8 Hz, 1H), 7.40
3d, Jˆ1.8 Hz, 1H), 9.83 3s, 1H).
3. Experimental
3.1. Typical protocol for radical addition to benzene
3.1.5. Cyclohexadienyl-2-methoxycarbamoylbenzene &11).
Ratio 3:2. MS Calcd for C14H16N02 [MH]1z: 130.1, found
130.1. Major isomer: H NMR 3CDCl3) d 2.80±2.85 3m,
A ¯ask ®tted with a condensor is charged with 3PhSe)2
30.2 mmol), the aryl iodide 31 mmol) and benzene
320 mL) is ¯ushed thoroughly with argon by sparging for
30 min. The solution is brought to re¯ux, then a solution of
AIBN 30.1 mmol) and Bu3SnH 31.2 mmol) in degassed
benzene 310.0 mL) is added via a syringe pump over 12 h
with care being taken that the needle tip is not placed in
the hot re¯uxing vapors. After completion of addition, the
reaction mixture is re¯uxed for an additionalhour, then
cooled down to room temperature and the volatiles are
removed under vacuum. The crude reaction mixture is
redissolved in acetonitrile 330.0 mL) and washed with
hexane 33£7 mL). The acetonitrile layer is concentrated
and the residue puri®ed by chromatography on silica gel
using a mixture of ethylacetate±hexane as eluent. Mixtures
of regioisomers were not separated but were characterized
as such.
1
2H), 3.79 3m, 3H), 4.08±4.18 3m, 1H), 5.62±5.75 3m,
2H), 5.82±5.98 3m, 2H), 7.00±7.31 3m, 4H), 7.80 3br s,
1H); 13C NMR 3CDCl3) d 25.7, 41.3, 52.4, 125.0, 125.2,
127.2, 127.9, 128.5, 129.0, 130.0, 136.8, 154.6. The minor
isomer was distinguished in the 1H NMR spectrum by
signals at d 2.22±2.58 3m, 2H), 3.78 3m, 1H), 3.79 3s,
3H), 5.70 3m, 1H), 5.81 3m, 1H), 5.95 3m, 1H), 6.12 3m,
1H), 6.71 3br s, 1H), 7.15 3t, Jˆ7.8 Hz, 1H), 7.22±7.35 3m,
2H), 7.38±7.40 3m, 1H).
3.2. Typical protocol for selenocyclization
To a cooled 32788C) solution of the cyclohexadiene
30.4 mmol) in CH2Cl2 32.0 mL) is added a solution of
PhSeBr 31.1 mmol). The reaction mixture is stirred under

3322
D. Crich, M. Sannigrahi / Tetrahedron 58 +2002) 3319±3322
argon for 5 h, then warmed to 08C and quenched with
saturated aqueous NaHCO3. The organic layer is dried
3Na2SO4), concentrated and puri®ed by column chroma-
tography over silica gel using ethyl acetate±hexane as an
eluent.
4.20 3m, 1H), 4.81 3t, Jˆ9 Hz, 1H), 5.75±5.82 3m, 1H),
5.91±6.08 3m, 1H), 7.02 3t, Jˆ7.8 Hz, 1H,), 7.15±7.18 3d,
Jˆ7.5 Hz, 1H), 7.19±7.23 3m, 4H), 7.50±7.58 3m, 2H); 13C
NMR 3CDCl3) d 25.7, 26.8, 29.3, 40.7, 52.4, 122.4, 124.4,
125.1, 127.2, 127.6, 127.9, 128.1, 128.6, 129.4, 130.1,
130.3, 136.8, 154.6. ESI-HRMS Calcd for C20H19NNaO2Se
[M1Na]1: 408.0479, found: 408.0494.
3.2.1.
4Sp,4aSp,9bRp-4-Phenylseleno-3,4,4a,9b-tetra-
1
hydrodibenzofuran &13). H NMR 3CDCl3) d 2.35±2.42
3m, 1H), 2.62±2.78 3m, 1H), 3.68±3.77 3m, 1H), 4.08 3m,
1H), 5.01 3t, Jˆ7.1 Hz, 1H), 5.75±5.82 3m, 2H), 6.75 3d,
Jˆ8.1 Hz, 1H), 6.86 3t, Jˆ7.2 Hz, 1H), 7.10±7.25 3m, 5H),
7.58±7.62 3m, 2H); 13C NMR 3CDCl3) d 27.4, 39.9, 40.8,
84.0, 110.2, 121.0, 124.5, 125.4, 126.9, 127.8, 127.9, 128.4,
129.3, 131.1, 134.8, 158.7. HRMS Calcd for C18H16OSe
[M]1z: 328.0366, found: 328.0350.
Acknowledgements
We thank the NSF 3CHE 9986200) for support of this work
and Dr Jae-Taeg Hwang and Mr Peng He for preliminary
experiments.
References
3.2.2. 4Sp,4aSp,10bRp-4-Phenylseleno-3,4,4a,10b-tetra-
hydrobenzo[b,d]pyran-6-one &14). H NMR 3CDCl3) d
1
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2.40±2.46 3m, 1H), 3.08±3.15 3m, 1H), 3.92 3t, Jˆ4.5 Hz,
1H), 4.11±4.15 3m, 1H), 4.81 3t, Jˆ3.9 Hz, 1H), 5.49 3d,
Jˆ10.2 Hz, 1H), 5.72±5.81 3m, 1H), 7.21±7.25 3m, 2H),
7.30±7.45 3m, 4H), 7.57±7.62 3m, 2H), 8.10 3d, Jˆ
7.8 Hz, 1H); 13C NMR 3CDCl3) d 26.9, 34.9, 38.9, 72.4,
124.1, 125.1, 125.3, 127.6, 128.2, 128.8, 129.8, 130.6,
134.5, 134.7, 141.9, 164.9. Calcd for C19H16O2SeNa
[M1Na]1: 379.0213, found: 379.0230.
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9b-tetrahydrodibenzofuran-8-carboxaldehyde
&15).
Ratio 8:1. HRMS Calcd for C20H18O3Se [M]1z: 386.0421,
found 386.0430. Major isomer: H NMR 3CDCl3) 2.40±
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1
2.45 3m, 1H), 2.80±2.87 3m, 1H), 3.80±3.85 3m, 1H), 3.95
3s, 3H), 4.18 3m, 1H), 5.17 3dd, Jˆ6.0, 7.05 Hz, 1H), 5.71±
5.80 3m, 2H), 7.21±7.48 3m, 5H), 7.52±7.61 3m, 2H), 9.75
3s, 1H); 13C NMR 3CDCl3) d 26.3, 40.0, 42.2, 56.2, 86.2,
111.6, 121.0, 125.6, 125.7, 126.4, 128.1, 129.4, 132.0,
132.1, 133.8, 134.5, 145.3, 190.6. The minor isomer was
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1
distinguished in the H NMR spectrum by signals at d
1.90 3m, 1H), 2.40 3m, 1H), 3.98 3s, 3H), 4.68±4.70 3m,
1H), 5.30 3m, 1H), 6.18±6.22 3m, 1H), 6.30±6.33 3m,
1H), 9.76 3s, 1H).
16. It is interesting to note that the isomerization gives the
2,4-conjugated diene and not the 1,3-diene in conjugation
with the aromatic ring.
3.2.4. 1Sp,9aSp,4aRp-9-Methoxycarbonyl-1-phenylseleno-
1,2,4a,9a-tetrahydrocarbazole &16). H NMR 3CDCl3) d
2.38±2.42 3m, 2H), 3.72±3.80 3m, 1H), 3.80 3s, 3H), 4.11±
1