Formal radical closure onto aromatic rings-a general route to carbocycles

Article abstract of DOI:10.1039/b803308k

A general method is described for indirectly effecting radical carbocyclization of an alkyl chain onto an aromatic ring. Birch reductive-alkylation of aromatic tert-butyl esters with α,ω- dibromides, chromium(vi)-mediated oxidation of the resulting 1,4-dienes and Finkelstein displacement of Br^- with NaI gives cross-conjugated ketones that undergo radical cyclization. The products are easily aromatized to phenols by silylation, Saegusa oxidation and treatment with BiCl ₃.H₂O. A special feature of the route is that it allows attachment of a substituent to the original aromatic ring in place of the phenolic oxygen of the normal product.

Full text of DOI:10.1039/b803308k

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Formal radical closure onto aromatic rings—a general route to carbocycles†
Derrick L. J. Clive,* Rajesh Sunasee and Zhenhua Chen
Received 26th February 2008, Accepted 2nd April 2008
First published as an Advance Article on the web 8th May 2008
DOI: 10.1039/b803308k
A general method is described for indirectly effecting radical carbocyclization of an alkyl chain onto an
aromatic ring. Birch reductive-alkylation of aromatic tert-butyl esters with a,x-dibromides,
chromium(VI)-mediated oxidation of the resulting 1,4-dienes and Finkelstein displacement of Br− with
NaI gives cross-conjugated ketones that undergo radical cyclization. The products are easily aromatized
to phenols by silylation, Saegusa oxidation and treatment with BiCl3.H2O. A special feature of the route
is that it allows attachment of a substituent to the original aromatic ring in place of the phenolic oxygen
of the normal product.
such examples as we have found in the literature confirm this
Introduction
assessment.3 The approaches we tried include use of PhI(OAc)2
Previous publications1 from this laboratory have described an
indirect method for effecting radical cyclization onto a benzene
ring, along the lines summarized in Scheme 1 (X = O, N). The
essential steps of the method involve converting a phenol into a
cross-conjugated ketone (1→2), which then undergoes stannane-
mediated radical cyclization under standard conditions (2→3).
Finally, exposure to TsOH causes rearomatization (3→4). In cases
where X = O, the cross-conjugated ketone can be generated as
shown, by oxidation in MeOH; alternatively, if the original ben-
zene ring carries a MeO group para to the phenolic OH, then the
oxidation must be done in the presence of an a,x-iodoalcohol in
order to generate the ketones 2. When X = N, a route similar to that
of Scheme 1 is followed,1b,c but with an additional step in which the
nitrogen is protected as a carbamate before introduction of iodine
and oxidation to the cross-conjugated ketone. Such cyclizations
of alkyl radicals onto a benzene nucleus are generally difficult,
but can be achieved in special cases, which we have summarized
in other publications.1 Application of the process summarized in
Scheme 1 to an all-carbon case (1, X = C) could be a useful
extension of the methodology.2 However, we find that when X = C,
oxidation in the sense 1→2 proceeds in poor yield. A few examples
of such oxidation of para alkyl phenols have been reported to
proceed efficiently, but these almost always involve para methyl
substitution.3 When the alkyl chain is longer than one carbon,
our experiments show that the oxidation is usually inefficient, and
in water–MeOH;3 PhI(OCOCF3)2 in water–MeCN or in MeOH;4
t-BuOOH, RuCl2(PPh3)3;5 t-Ph(Me2)COOH, RuCl2(PPh3)3.
Results and discussion
Our inability to extend the process of Scheme 1 directly to the
all-carbon case caused us to consider alternatives to a MeO
group that would still allow rearomatization, and the use of
a tert-butyl ester, as in 5 (Scheme 2) appeared to be worthy
of consideration. Such esters ought to be readily available by
Birch reductive alkylation,6 since preparation of the corresponding
methyl esters had already been reported, together with studies on
their radical cyclization.7 We had anticipated that after radical
cyclization (5→6), removal of the tert-butyl group (6→7) and
oxidative decarboxylation8 would give the desired rearomatized
product (7→8). In the event, these speculations could not be
fully implemented, as rearomatization along the intended lines was
problematic; however, a modified version of the plan allowed us
to effect the desired rearomatization.9 We also investigated minor
changes to the sequence, so as to expand the range of final products
from phenols 8 to compounds of type 9 in which the phenolic OH
of 8 is replaced by H, or an alkyl, allyl, propargyl, alkynyl, aryl or
heteroaryl group.
Scheme 2 Cyclization of alkyl chains onto aromatic rings.
Scheme 1 General approach to radical closure onto aromatic rings. X =
O, N.
Chemistry Department, University of Alberta, Edmonton, Alberta, T6G 2G2,
Canada. E-mail: derrick.clive@ualberta.ca
† Electronic supplementary information (ESI) available: Experimental
procedures. See DOI: 10.1039/b803308k
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Table 1 Formation of cross-conjugated ketones. Reductive alkylations
were done by the general method given in the Experimental section.
General method A was used for oxidations, except for entries 2 and 3,
where method B was used, and entry 6, in which PDC-t-BuOOH was used
Birch reductive alkylation of a number of aromatic tert-butyl
esters (Table 1) with 1,3-dibromopropane, 1,4-dibromobutane or
o-iodobenzyl bromide proceeded smoothly, giving in most cases
yields of at least 80%. The second stage of the process requires
oxidation of the resulting 1,4-diene system to a cross-conjugated
ketone, and this was best achieved with CrO3 in AcOH-Ac2O.10
In a few cases, better results were obtained under basic conditions
with 3,5-dimethylpyrazole and CrO3.7,11 In one example (Table 1,
entry 6), PDC-t-BuOOH was the best oxidant.12 Formation of
the cross-conjugated ketones is successful with benzenoid and
naphthalenoid systems, and substituents such as methyl and
methoxy groups can be present.
The bromides were converted into the corresponding iodides
by Finkelstein reaction and in all cases the radical cyclization
step (Table 2) was easily carried out by the standard method of
slow addition (5 h) of a benzene solution of Bu3SnH containing a
catalytic amount of AIBN to a refluxing solution of the substrate
in PhH.7 At the end of the addition the mixtures were refluxed
for an arbitrary period of 3–12 h. Attempts to use bromide
16b, instead of the iodide, as a radical precursor gave a poor
yield, presumably because bromides react with tributylstannyl
radicals about 100 times more slowly than iodides.7,13 Five- and
six-membered rings are formed in 65–96% yield, but our attempts
to generate a 7-membered ring (Table 2, entry 3) were unsuccessful.
7-Exo-trig cyclizations are not common, but a number are known14
and it is not clear why the process is unsuccessful in the present
case. We tried very slow addition of the stannane (over 10 h) in
refluxing PhH or PhMe, or reactions at room temperature with
◦
Et3B/air as initiator (in EtOAc), or at −78 C with Et3B/air (in
PhMe), but always observed simple reduction (replacement of I
by H) as by far the major product.
The next step of our planned sequence—the critical
rearomatization—was initially troublesome and several ap-
proaches had to be tried. With 10d as a test substrate (Scheme 3),
we first removed the tert-butyl group in the standard way by
treatment with CF3CO2H. Exposure of acid 10f to the action
of Pb(OAc)4 in the presence of Cu(OAc)2—conditions that had
served us well in the past for the conversion of 18 into 19
(Scheme 4),8 during a natural product synthesis—did not proceed
as expected, but gave instead a compound tentatively identified
as the acetate 10g, which was itself resistant to elimination of
AcOH under the influence of DBU in refluxing PhMe. When
we used PhI(OAc)2 for the attempted oxidative decarboxylation
of 10f, a complex mixture was obtained. Treatment of 10f
with DDQ in refluxing dioxane slowly produced the required
aromatized product 10h, but in poor yield (33%). These initial
experiments prompted us to introduce a second double bond
before attempting the decarboxylation. To this end, compound
10d was subjected to Saegusa oxidation15 by conversion into
the corresponding silyl enol ether, followed by treatment with
Scheme 3 Decarboxylation and rearomatization.
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Table 2 Radical cyclization and reoxidation. Radical cyclization was
done by the general method given in the Experimental section and Saegusa
oxidation was used for desaturation of the ketones, except for entry 6, in
which selenation and selenoxide fragmentation were used
Scheme 4 Oxidative decarboxylation.
Pd(OAc)2 (Table 2, entry 1, 10d→10e). This method of oxidation
was applied to several other enones (Table 2) and in all but one
case (entry 6) gave yields a little above 60%. In the case of 15d,
the silylation step, using either Me3SiOSO2CF3 and 2,6-lutidine,
or LDA and Me3SiCl was unsuccessful, but these procedures were
not examined exhaustively, since we found that phenylselenation
(LDA, PhSeCl) and oxidation (H2O2) generated the required
double bond, although only in modest yield (56%), presumably
because just one of the two intermediate phenyl selenides had the
appropriate stereochemistry for syn elimination.
The cross-conjugated ketone 10e was treated with CF3CO2H
to remove the tert-butyl group and, as expected, the resulting
acid underwent spontaneous decarboxylation16 to afford (55%)
indanol 10h (shown in Table 3) together with an unidentified
byproduct. Addition of anisole to suppress formation of this
byproduct was ineffective. We therefore turned our attention to
the use of BiCl3.H2O which had recently been reported to effect
smooth removal of
N-Boc groups from protected amino acids and peptides.17 In
these deprotections,17 prolonged reaction times had to be avoided
if the substrate also contained an ordinary tert-butyl ester, as
cleavage of the latter then started to occur during reaction times
longer than 1.5–2 h.17 With our substrate 10e, exposure to
BiCl3.H2O in aqueous MeCN at 65 ◦C resulted in efficient removal
of the tert-butyl group as well as decarboxylation to give directly
the desired aromatized product 10h (90%, Table 3, entry 1). We
did not establish if the decarboxylation occurred spontaneously
or whether the bismuth reagent is involved. The removal of the
tert-butyl group and decarboxylative aromatization are general
and overall yields with our dienones were in the range 79–95%
(Table 3). In no case did we notice the type of byproduct observed
with 10e when it was treated with CF3CO2H.
The intermediate ketones in our sequence can be modified by
hydride reduction to the alcohol level or they can be converted
into tertiary alcohols by reaction with a Grignard reagent or
organolithium (Table 4). Decarboxylation and aromatization then
gives the expected non-phenolic products. Simple alkyl and aryl
groups can be introduced, as well as allylic, propargylic, acetylenic
and heteroaromatic units (Table 4). When the intermediate ketone
is modified in this way, either by hydride reduction or by carbanion
addition, the rearomatization in the presence of BiCl3.H2O still
occurs efficiently but requires stoichiometric amounts of the
reagent. In contrast, the cross-conjugated ketones themselves
(Table 3) usually needed only 0.5 equivalents of BiCl3.H2O. Among
all 23 examples we studied, using BiCl3.H2O, only that of Table 4,
entry 14 took an unexpected course, giving the vinyl chloride 16n.
Conclusions
In summary, we have examined an indirect method for effecting
radical cyclization of an all-carbon chain onto an aromatic ring
and have shown that the process can be modified easily so that
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Table 3 Formation of phenols. In all cases 0.5 equiv BiCl3.H2O was used
to effect rearomatization, except for entries 6 and 7, where 1 equiv was
used
Table 4 Formation of alkylated aromatics. NaBH4-CeCl3.7H2O, or ap-
propriate Grignard reagent or organolithium were used to generate the
secondary or tertiary alcohols. Rearomatization was effected with 1 equiv
of BiCl3.H2O. Yields for rearomatization refer to two steps from the ketone
instead of the normal phenolic product one obtains compounds
with H, alkyl, aryl, allyl, propargyl, alkynyl or heteroaryl groups
in place of the phenolic OH. A key step in the sequence is
the use of BiCl3.H2O to deprotect the intermediate tert-butyl
esters; the reagent is compatible with the presence of double
and triple bonds as well as a furanyl unit. While many of
our final products are expected to be available by transition
metal catalyzed coupling processes, the present route avoids the
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sometimes awkward synthesis of haloaromatics that would be
required in order to apply such procedures.
extracts were washed with brine, dried (MgSO4) and evaporated.
Flash chromatography of the residue over silica gel gave the cross-
conjugated ketone as an oil.
Experimental
General procedure for Finkelstein displacement
Experimental procedures not described below or in the Electronic
Supplementary Information† are given in the supporting informa-
tion for the preliminary communication.9
˚
Acetone (distilled from KMnO4 and dried over 4 A molecular
sieves) was added to a mixture of the bromide and anhydrous
NaI. The mixture was stirred and refluxed for 16–20 h, cooled
and partitioned between Et2O and water. The combined organic
extracts were washed with brine, dried (MgSO4) and evaporated.
Flash chromatography of the residue over silica gel gave the iodide
as an oil.
General procedure for reductive alkylation7
The apparatus consists of a three-necked round-bottomed flask
fitted with a cold finger condenser fused onto one of the necks
and containing a magnetic stirring bar. The exit of the condenser
carried a drying tube filled CaSO4. An external mark on the
flask indicated the level corresponding to the desired volume
of liquid ammonia. The central neck was closed by a septum
carrying a nitrogen inlet. The flask was cooled in a dry ice-acetone
bath and the cold finger condenser was charged with dry ice-
acetone. Another round-bottomed flask was half-filled with liquid
ammonia and several small pieces of Na were added, so as to
form a permanently blue solution. This flask was connected via
bent adaptors and dry Tygon tubing to the third neck of the other
flask. A solution of the starting aromatic ester in a mixture of dry
THF and t-BuOH (1–1.1 mole per mole ester) was injected into the
three-necked flask, and liquid ammonia was condensed into the
flask. Small pieces of Li wire (2–2.5 g-atom per mole ester) were
added rapidly to the vigorously stirred solution, and stirring at
−78 ◦C was continued for 10–15 min, to ensure that the dark blue
color persisted. A solution of the alkyl halide in THF was then
added dropwise from a syringe over ca. 2 min, and the resulting
General procedure A for radical cyclization
A solution of Bu3SnH and AIBN in dry PhH ◦was added over 5 h
by syringe pump to a stirred and heated (85 C) solution of the
iodide in PhH. Heating was continued for several hours after the
addition. Evaporation of the solvent and flash chromatography
of the residue over KF-flash chromatography silica gel (10%w/w
KF) afforded the cyclized product as an oil.
General procedure B for radical cyclization
Method A was followed, except that THF was used as the solvent.
General procedure for Saegusa oxidation15
2,6-Lutidine was added to a stirred and cooled (0 ◦C) solution
of the enone in dry CH2Cl2. Neat Me3SiOSO2CF3 was then
added dropwise over 1 h. After the addition, stirring at 0 ◦C was
continued for 1 h and then the mixture was quenched by addition
of saturated aqueous NaHCO3. The mixture was diluted with
CH2Cl2 and the organic phase was dried (MgSO4) and evaporated,
first under waterpump vacuum and then under oilpump vacuum
until all lutidine had been removed. The resulting enol silane
was used directly without purification. Dry MeCN was added,
followed by Pd(OAc)2, and the mixture was stirred overnight
(Ar atmosphere) and then filtered through a pad of Celite, using
CH2Cl2. Evaporation of the filtrate and flash chromatography of
the residue over silica gel gave the dienone.
◦
yellow solution was stirred for 1 h at −78 C. Then the cooling
bath was removed and the NH3 was evaporated under a stream of
N2 (2–3 h). Water was added and the mixture was extracted with
Et2O (4 times). The combined organic extracts were washed with
brine, dried (MgSO4) and evaporated. Flash chromatography of
the residue over silica gel gave the product.
General procedure A for oxidation10
A stirred solution of CrO3 and Ac2O in AcOH was cooled to 7 ◦C
and diluted with dry PhH. A solution of the reductive alkylation
product in PhH was added dropwise and stirring was continued
for 1–3 h (TLC control) at 7 ◦C. The mixture was diluted with
EtOAc and quenched carefully with saturated aqueous NaHCO3,
washed with water and brine, dried (MgSO4) and evaporated.
Flash chromatography of the residue over silica gel gave the cross-
conjugated ketone as an oil.
General procedure A for rearomatization
BiCl3.H2O17 was added to a solution of the dienone in a mixture
of MeCN and water, and the mixture was stirred at 65–70 ◦C. An
additional equal portion of BiCl3.H2O was added after 1 h, and
stirring at 65–70 ◦C was continued until the reaction was complete
(TLC control). Solid NaHCO3 was added and mixture was stirred
at room temperature for 10 min, and then filtered through a pad
of Celite, using CH2Cl2 as a rinse. The filtrate was washed with
brine, dried (MgSO4) and evaporated. Flash chromatography of
the residue over silica gel gave the aromatized product.
General procedure B for oxidation7,11
3,5-Dimethylpyrazole was added in one portion to a stirred and
cooled (−20 ◦C) suspension of dry CrO3 in CH2Cl2. Stirring at
−20 ◦C was continued for 10–20 min, and a solution of the
reductive alkylation product in CH2Cl2 was then added at a fast
dropwise rate. Stirring at −20 ◦C was continued for 30 min (TLC
control). The mixture was transferred to an ice bath and aqueous
General procedure B for rearomatization
◦
NaOH (5 M) was added. Stirring at 0 C was continued for 1 h,
Method A was followed, except that 1 equiv of BiCl3.H2O was
added at the beginning of the reaction, and no further additions
were made.
and the mixture was then partitioned between Et2O and water. The
aqueous phase was extracted with Et2O and the combined organic
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6-Hydroxy-6-phenyl-1,2,3,6-tetrahydroindene-3a-carboxylic acid
tert-butyl ester (10o). PhMgCl (2 M in THF, 0.22 mL,
0.44mmol)wasaddedatafastdropwiseratetoastirredandcooled
(−78 ◦C) solution of 10e (51 mg, 0.22 mmol) in Et2O (5 mL). The
cold bath was removed and stirring was continued for 1 h. The
mixture was cooled to 0 ◦C, quenched by dropwise addition of
saturated aqueous NH4Cl, and extracted with Et2O. The combined
organic extracts were washed with brine, dried (MgSO4) and
evaporated. The crude product (10o) was used directly in the next
step.
overnight reaction period. Flash chromatography of the crude
product over silica gel, using hexane, gave 16l (20 mg, 60%) as an
1
oil: H NMR (CDCl3, 400 MHz) d 2.25 (apparent quintet, J =
7.4 Hz, 2 H), 3.11 (t, J = 7.6 Hz, 2 H), 3.27 (t, J = 7.6 Hz, 2 H),
3.84 (d, J = 6.4 Hz, 2 H), 5.10 (t, J = 1.6 Hz, 1 H), 5.12–5.15 (m,
1 H), 6.09–6.19 (m, 1 H), 7.30 (s, 1 H), 7.44–8.05 (m, 4 H); 13C
NMR (CDCl3, 100 MHz) d 24.5 (t), 31.2 (t), 33.9 (t), 37.5 (t), 115.9
(t), 123.8 (d), 124.6 (d), 124.7 (d), 125.0 (d), 125.5 (d), 130.8 (s),
130.9 (s), 134.7 (s), 137.4 (d), 138.1 (s), 140.7 (s); mmax (microscope,
CDCl3 cast; cm−1) 3074, 2950, 2844, 1638, 1439; exact mass m/z
calcd for C16H16 208.12520, found 208.12512.
5-Phenylindan (10p)18. General procedure B for rearomatiza-
tion was followed, using BiCl3.H2O (73 mg, 0.218 mmol), 10o
(total product from the previous step) in MeCN (5 mL) and water
(0.1 mL), and an overnight reaction period. Flash chromatography
of the crude product over silica gel, using hexane, gave 10p (36 mg,
5-Furan-2-yl-5-hydroxy-1,2,3,5-tetrahydrocyclopenta[a]naph-
thalene-9b-carboxylic acid tert-butyl ester (16o). n-BuLi (1.6 M
in hexane, 3.125 mL, 5 mmol) was added dropwise to a stirred
◦
and cooled (−78 C) solution of furan (0.363 mL, 5 mmol) and
1
85%) as an oil: H NMR (CDCl3, 400 MHz) d 2.16 (apparent
TMEDA (0.748 mL, 5 mmol) in Et2O (1.8 mL). The cooling
bath was replaced by an ice bath and stirring was continued
for 45 min. The resulting furanyllithium (0.46 mL) was taken
up into a syringe and added at a fast dropwise rate to a stirred
and cooled (−78 ◦C) solution of 16e (65 mg, 0.23 mmol) in Et2O
(5 mL). The cold bath was replaced by an ice bath and stirring was
quintet, J = 7.4 Hz, 2 H), 2.89 (two overlapping apparent q, J =
7.6 Hz, 4 H), 7.34–7.63 (m, 8 H); 13C NMR (CDCl3, 100 MHz)
d 25.6 (t), 32.6 (t), 32.9 (t), 123.2 (d), 124.6 (d), 125.2 (d), 126.8
(d), 127.2 (d), 128.7 (d), 139.5 (s), 141.8 (d), 143.4 (s), 144.9 (s);
mmax (microscope, CDCl3 cast; cm−1) 3058, 3030, 2950, 2842, 1599,
1480; exact mass m/z calcd for C15H14 194.10956, found 194.10907.
◦
continued overnight. The mixture was cooled to 0 C, quenched
by dropwise addition of saturated aqueous NH4Cl, and extracted
with Et2O. The combined organic extracts were washed with brine,
dried (MgSO4) and evaporated. The crude product (16o) was used
directly in the next step.
7-Hydroxy-7-methyl-1,3,4,7-tetrahydro-2H-naphthalene-4a-car-
boxylic acid tert-butyl ester (11g). MeMgBr (3 M in THF,
0.20 mL, 0.60 mmol) was added at a fast dropwise rate to a stirred
and cooled (−78 ◦C) solution of 11e (100 mg, 0.40 mmol) in Et2O
(5 mL). The cold bath was removed and stirring was continued
for 2 h. The mixture was cooled to 0 ◦C, quenched slowly with
water, and extracted with Et2O. The combined organic extracts
were washed with brine, dried (MgSO4) and evaporated. The
crude product (11g) was used directly in the next step.
2-(2,3-Dihydro-1H-cyclopenta[a]naphthalen-5-yl)furan (16p).
General procedure B for rearomatization was followed, using
BiCl3.H2O (77 mg, 0.23 mmol), 16o (total product from previous
step) in MeCN (5 mL) and water (0.1 mL), and an overnight
reaction period. Flash chromatography of the crude product over
silica gel, using hexane, gave 16p (37 mg, 69%) as an oil: 1H NMR
(CDCl3, 300 MHz) d 2.29 (apparent quintet, J = 7.5 Hz, 2 H),
3.15 (t, J = 7.8 Hz, 2 H), 3.30 (t, J = 7.8 Hz, 2 H), 6.57–6.59 (m,
1 H), 6.66–6.67 (m, 1 H), 7.47–8.38 (m, 6 H); 13C NMR (CDCl3,
100 MHz) d 24.4 (t), 31.3 (t), 33.7 (t), 108.6 (d), 111.1 (d), 123.6
(d), 124.7 (d), 125.2 (d), 125.8 (d), 126.1 (d), 127.3 (s), 129.6 (s),
130.7 (s), 140.2(s), 140.4 (s), 142.0 (s), 153.4 (s); mmax (microscope,
CDCl3 cast; cm−1) 3063, 2952, 2844, 1579, 1514, 1498, 1457; exact
mass m/z calcd for C17H14O 234.10446, found 234.10441.
6-Methyl-1,2,3,4-tetrahydronaphthalene (11h)19. General pro-
cedure B for rearomatization was followed, using BiCl3.H2O
(116.8 mg, 0.35 mmol), 11g (total product from the previous step)
in MeCN (5 mL) and water (0.1 mL), and a reaction time of 9 h.
Flash chromatography of the crude product over silica gel (1.5 ×
15 cm), using hexane, gave 11h (38 mg, 74%) as an oil: 1H NMR
(CDCl3, 300 MHz) d 1.78–1.83 (m, 4 H), 2.30 (s, 3 H), 2.73–2.77
(m, 4 H), 6.91 (s, 1 H), 6.94–6.97 (m, 2 H); 13C NMR (CDCl3,
100 MHz) d 20.8 (q), 23.2 (t), 23.3 (t), 28.9 (t), 29.3 (t), 126.1
(d), 128.9 (d), 129.6 (d), 133.9 (s), 134.7 (s), 136.8 (s); mmax (CHCl3
cast; cm−1) 3000, 2925, 2857, 1505, 1449.
1-(4-Bromobutyl)-1,4-dihydronaphthalene-1-carboxylic
acid
tert-butyl ester (17). The general procedure for reductive
alkylation was followed, using 16 (1.79 g, 7.85 mmol) in dry THF
(20 mL), t-BuOH (0.83 mL, 8.70 mmol), liquid NH3 (70 mL),
Li (0.12 g, 16.60 mmol), and 1,4-dibromobutane (2.40 mL,
19.80 mmol) in THF (20 mL). Flash chromatography of the crude
product over silica gel (4 × 38 cm), using first hexane and then
5-Allyl-5-hydroxy-1,2,3,5-tetrahydrocyclopenta[a]naphthalene-
9b-carboxylic acid tert-butyl ester (16k). Allylmagnesium bro-
mide (1 M in Et2O, 0.24 mL, 0.24 mmol) was added at a fast
dropwise rate to a stirred and cooled (−78 ◦C) solution of 16e
(46 mg, 0.16 mmol) in Et2O (5 mL). The cold bath was removed
and stirring was continued overnight. The mixture was cooled
to 0 ◦C, quenched by dropwise addition of saturated aqueous
NH4Cl, and extracted with Et2O. The combined organic extracts
were washed with brine, dried (MgSO4) and evaporated. The crude
product (16k) was used directly in the next step.
1
1 : 9 EtOAc-hexane, gave 17 (2.56 g, 90%) as an oil: H NMR
(CDCl3, 400 MHz) d 0.97–1.02 (m, 1 H), 1.31–1.33 (m, 1 H), 1.36
(s, 9 H), 1.75–1.83 (m, 2 H), 1.90–1.96 (m, 1 H), 2.09–2.16 (m,
1 H), 3.28–3.33 (m, 2 H), 3.40–3.44 (m, 2 H), 5.70 (ddd, J = 10.1,
2.2, 2.2 Hz, 1 H), 6.10 (ddd, J = 10.1, 3.7, 3.7 Hz, 1 H), 7.14–7.17
(m, 3 H), 7.20–7.32 (m, 1 H); 13C NMR (CDCl3, 100 MHz) d 23.0
(t), 27.7 (q), 29.7 (t), 33.0 (t), 33.3 (t), 38.1 (t), 51.6 (s), 80.7 (s),
125.7 (d), 126.1 (d), 126.3 (d), 126.4 (d), 128.2 (d), 128.4 (d), 134.1
(s), 135.5 (s), 173.7 (s); mmax (CH2Cl2 cast; cm−1) 2977, 2933, 1722,
5-Allyl-2,3-dihydro-1H-cyclopenta[a]naphthalene (16l). Gen-
eral procedure B for rearomatization was followed, using
BiCl3.H2O (53 mg, 0.16 mmol), 16k (total product from the
previous step) in MeCN (5 mL) and water (0.1 mL), and an
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1454, 1367, 1246; exact mass m/z calcd for C19H2579BrNaO2 (M +
Na) 387.09301, found 387.09299.
(705 mg, 2.35 mmol), CH2Cl2 (15 mL), Me3SiOSO2CF3 (1.3 mL,
7.05 mmol), Pd(OAc)2 (522 mg, 2.33 mmol) and MeCN (10 mL).
Flash chromatography of the crude product over silica gel (2.5 ×
25 cm), using 10% EtOAc-hexane, gave 17d (434 mg, 60%) as
1-(4-Bromobutyl)-4-oxo-1,4-dihydronaphthalene-1-carboxylic
acid tert-butyl ester (17a). General procedure A for oxidation
was followed, using CrO3 (3.48 g, 34.80 mmol), Ac2O (6.10 mL),
AcOH (10.0 mL), PhH (10 mL), 17 (2.54 g, 6.96 mmol) in PhH
(30 mL), and a reaction time of 3 h. Flash chromatography of the
crude product over silica gel (4 × 36 cm), using first hexane and
then EtOAc-hexane mixtures up to 3 : 7 EtOAc-hexane, gave 17a
(1.98 mg, 75%) as an oil: 1H NMR (CDCl3, 300 MHz) d 0.82–0.88
(m, 1 H), 1.22–1.25 (m, 1 H), 1.30 (s, 9 H), 1.68–1.70 (m, 2 H),
2.15 (ddd, J = 13.6, 12.2, 4.6 Hz, 1 H), 2.30 (ddd, J = 13.6, 12.3,
4.9 Hz, 1 H), 3.20–3.28 (m, 2 H), 6.56 (d, J = 10.3 Hz, 1 H), 6.92
(d, J = 10.3 Hz, 1 H), 7.41–7.46 (m, 1 H), 7.51–7.60 (m, 2 H), 8.16
(ddd, J = 7.9, 1.5, 0.6 Hz, 1 H); 13C NMR (CDCl3, 100 MHz) d
22.6 (t), 27.7 (q), 32.6 (t), 32.8 (t), 37.7 (t), 53.5 (s), 82.5 (s), 126.2
(d), 126.7 (d), 127.7 (d), 129.6 (d), 131.8 (s), 132.6 (d), 141.7 (s),
148.2 (d), 170.2 (s), 184.4 (s); mmax (CH2Cl2 cast; cm−1) 2977, 2933,
1729, 1667, 1456, 1244; exact mass m/z calcd for C19H2379BrNaO3
(M + Na) 401.07228, found 401.07211.
1
an oil: H NMR (CDCl3, 400 MHz) d 1.28 (s, 9 H), 1.37–1.42
(m, 2 H), 1.81–1.86 (m, 2 H), 2.00–2.60 (m, 1 H), 2.28–2.29 (m,
1 H), 2.60–2.71 (m, 1 H), 2.92–2.97 (m, 1 H), 6.42 (s, 1 H), 7.43–
7.59 (m, 1 H), 7.54–7.59 (m, 2 H), 8.21–8.23 (m, 1 H); 13C NMR
(CDCl3, 100 MHz) d 23.4 (t), 27.4 (q), 27.7 (t), 35.3 (t), 39.6 (t),
53.9 (s), 81.9 (s), 124.9 (d), 125.5 (d), 126.5 (d), 127.6 (d), 130.3
(s), 132.3 (d), 143.8 (s), 161.8 (s), 169.8 (s), 184.9 (s); mmax (CH2Cl2
cast; cm−1) 2935, 2861, 1727, 1663, 1560, 1254; exact mass m/z
calcd for C19H22NaO3 (M + Na) 321.14612, found 321.14608.
1,2,3,4-Tetrahydrophenanthren-9-ol (17e)20. General proce-
dure B for rearomatization was followed, using BiCl3.H2O (386 mg,
1.16 mmol), 17d (345 mg, 1.16 mmol) in MeCN (5 mL) and water
(0.1 mL), and a reaction time of 12 h. Flash chromatography of
the crude product over silica gel (1.5 × 15 cm), using 10% EtOAc-
1
hexane, gave 17e (188 mg, 82%) as an oil: H NMR (CDCl3,
400 MHz) d 1.87–1.90 (m, 2 H), 1.97–1.99 (m, 2 H), 2.83 (t, J =
6.1 Hz, 2 H), 3.06 (t, J = 6.3 Hz, 2 H), 5.40 (s, 1 H), 6.52 (s, 1 H),
7.46–7.51 (m, 1 H), 7.52–7.60 (m, 1 H), 7.97 (d, J = 8.4 Hz, 1 H),
8.23 (t, J = 8.3 Hz, 1 H); 13C NMR (CDCl3, 100 MHz) d 22.9 (t),
23.3 (t), 25.2 (t), 30.4 (t), 110.5 (d), 121.8 (d), 122.8 (s), 123.4 (s),
124.1 (d), 125.1 (s), 126.3 (d), 133.6 (s), 134.4 (s), 149.0 (s); mmax
(CDCl3 cast; cm−1) 3408, 2929, 2859, 1626, 1599; exact mass m/z
calcd for C14H14O 198.10446, found 198.10438.
1-(4-Iodobutyl)-4-oxo-1,4-dihydronaphthalene-1-carboxylic acid
tert-butyl ester (17b). The general procedure for Finkelstein
displacement was followed, using acetone (25 mL), 17a (1.81 g,
4.75 mmol), anhydrous NaI (2.49 g, 16.6 mmol), and a reaction
time of 17 h. Flash chromatography of the crude product over
silica gel (2 × 20 cm), using 10% EtOAc-hexane, gave 17b (1.86 g,
92%) as an oil: 1H NMR (CDCl3, 400 MHz) d 0.81–0.83 (m, 1 H),
1.15–1.20 (m, 1 H), 1.31 (s, 9 H), 1.70–1.75 (m, 2 H), 2.14–2.18 (m,
1 H), 2.25–2.30 (m, 1 H), 3.00–3.05 (m, 2 H), 6.57 (d, J = 11.3 Hz,
1 H), 6.94 (d, J = 11.3 Hz, 1 H), 7.42–7.47 (m, 1 H), 7.52–7.60 (m,
2 H), 8.19 (d, J = 7.8 Hz, 1 H); 13C NMR (CDCl3, 100 MHz) d 5.6
(t), 24.7 (t), 27.5 (q), 33.2 (t), 37.3 (t), 53.4 (s), 82.4 (s), 126.3 (d),
126.7 (d), 127.7 (d), 129.6 (d), 131.8 (s), 132.7 (d), 141.7 (s), 148.2
(d), 170.2 (s), 184.4 (s); mmax (CH2Cl2 cast; cm−1) 2925, 2853, 1727,
1665, 1600, 1242; exact mass m/z calcd for C19H23INaO3 (M +
Na) 449.05842, found 449.05835.
Acknowledgements
We thank the Natural Sciences and Engineering Research Council
of Canada for financial support.
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Org. Biomol. Chem., 2008, 6, 2434–2441 | 2441
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