Antimycobacterial benzofuro[3,2-f]chromenes from a 5-bromochromen-6-ol

Article abstract of DOI:10.1055/s-2007-966019

In the course of our work on the synthesis of analogues of the specific antimycobacterial 3,3-dimethyl-3H-benzofuro[3,2-f]chromene, we prepared the previously unreported 5-bromo-2,2-dimethyl-2H-chromen-6-ol. We wish to report here an original synthetic sc

Full text of DOI:10.1055/s-2007-966019

1566
PAPER
Antimycobacterial Benzofuro[3,2-f]chromenes from a 5-Bromochromen-6-ol
A
ntimycobact
o
B
enzofu
i
ro[3, 2
z
f
]chromene
i
s
from
c
a
5-Bromochrom
P
en-6-ol rado,a,b,1 Valérie Toum,a Brigitte Saint-Joanis,b Sylvie Michel,c Michel Koch,c Stewart T. Cole,b
François Tillequin,c Yves L. Janin*a
a
Laboratoire de Chimie Organique, URA 2128 CNRS-Institut Pasteur, 28 rue du Dr. Roux, 75724 Paris cedex 15, France
Fax +33(1)45688404; E-mail: yljanin@pasteur.fr
Unité de Génétique Moléculaire Bactérienne, Institut Pasteur, 28 rue du Dr. Roux, 75724 Paris cedex 15, France
Laboratoire de Pharmacognosie, Université René Descartes, UMR/CNRS 8638, Faculté des Sciences Pharmaceutiques et Biologiques,
b
c
4 avenue de l’Observatoire, 75006 Paris, France
Received 7 December 2006; revised 28 February 2007
compounds bearing more hydrophilic substituents. The
Abstract: In the course of our work on the synthesis of analogues
lack of chemical selectivity sometimes encountered5 in
of the specific antimycobacterial 3,3-dimethyl-3H-benzofuro[3,2-
the cyclisation of propargylic ethers into the chromene
f]chromene, we prepared the previously unreported 5-bromo-2,2-
dimethyl-2H-chromen-6-ol. We wish to report here an original syn-
part of some of the analogues was amongst the difficul-
thetic scheme using this compound. The preparation of various 5- ties.4 We have reported an approach addressing this issue,
bromo-2,2-dimethyl-6-(aryloxy)-2H-chromenes was first investi-
gated. This was followed by a palladium-catalysed cyclisation reac-
the synthesis of the chromene ring system by an ytterbium
triflate catalysed reaction between isobutene and various
tion, which takes place only in the presence of air, and leads to 3,3-
salicylaldehydes via the corresponding quinonemethides
dimethyl-3H-benzofuro[3,2-f]chromenes or 3,3-dimethyl-3H-4,7-
formed in situ.6 In the course of this work, we observed
dioxa-10-aza-benzo[c]fluorene. The antimycobacterial properties
that 2,5-dihydroxybenzaldehyde gave the corresponding
chromene in low yield, along with unidentified side prod-
ucts. We also found more recently that, under the same re-
action conditions, the readily available 2-bromo-3,6-
dihydroxybenzaldehyde (3)7 led to the corresponding 5-
bromo-2,2-dimethyl-2H-chromen-6-ol (4) in 65% yield.
This leads us to suggest that the additional bromine pro-
tects the 6-hydroxy moiety from further reactions through
the formation of a stabilising internal hydrogen bond. In
any case, this regioselective access to compound 4 opens
many synthetic possibilities for the preparation of ana-
logues of the antimycobacterial compound 1. Amongst
them, the preparation of various 5-bromo-2,2-dimethyl-6-
(aryloxy)-2H-chromenes would allow subsequent cycli-
sation to give the corresponding tetracyclic analogues fea-
turing a central furan ring in only two steps.
of these analogues have been investigated.
Key words: nucleophilic aromatic substitutions, cyclisations, me-
dicinal chemistry, catalysis, palladium
Tuberculosis figures once again amongst the scourges of
humanity. To combat this threat, the design of new anti-
tuberculosis drugs acting on novel biological targets is a
priority.2 As previously reported,3 the dibenzofuran deriv-
atives 1 and 2 (Figure 1) were found to be remarkably se-
lective in vitro inhibitors of mycobacterial growth. This
has led us to undertake further investigations. One of our
approaches focuses on the synthesis of related com-
pounds, of which it is hoped that this selectivity of action
is retained, but with improved activity in vitro and in vivo.
After a few trials, it became clear that extensive decompo-
sition along with a quite remarkable rearrangement of
compound 4 into its isomer 5 took place under various ba-
sic conditions at high temperature. As illustrated in
Scheme 1, heating compound 4 in dimethylacetamide at
130 °C for 2.5 hours in the presence of potassium carbon-
ate led to a 3:1 mixture of compounds 4 and 5 along with
highly polar material. Further heating, up to 12 hours, led
to a 1:1 ratio and even more polar material. Even worse,
the addition of copper salts under these conditions led to
many other unidentified side reactions. On the other hand,
little or no side reactions took place if potassium carbon-
ate was omitted or if the isomerisation was attempted at
80 °C in N,N-dimethylformamide. Although we could not
O
O
O
1
2
O
Figure 1
The first element of our structure–activity relationship
study was somewhat disappointing, as the ‘easy to make’
analogues of this benzofuro[3,2-f]chromene derivative 1
had lower antimycobacterial activity or were also cytotox-
ic.4 On the other hand, the high CLogP value of 1 (5.5 as
estimated by calculation) or some of the analogues syn-
thesised led us to investigate original synthetic access to
1
separate compounds 4 and 5, H, 13C, and long-distance-
correlation NMR spectroscopic studies demonstrated be-
yond any doubt the presence of 5 in the purified mixture
(see experimental section).
SYNTHESIS 2007, No. 10, pp 1566–1570
Advanced online publication: 18.04.2007
DOI: 10.1055/s-2007-966019; Art ID: T17706SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
7
The reduced chromane 6, selectively prepared under ionic
hydrogenation conditions (Scheme 1),8 was also moni-

PAPER
Antimycobacterial Benzofuro[3,2-f]chromenes from a 5-Bromochromen-6-ol
1567
Br
tored for this isomerisation reaction. Remarkably, under
the conditions described above, this compound does not
isomerise. A literature search found previous reports de-
scribing related bromine migrations in the case of oxygen-
rich aromatic compounds, although only under acidic con-
ditions.9 We have too little experimental data to suggest a
mechanism for this apparent bromine migration. The bro-
mine atom of compound 4 could be displaced sequentially
by successive phenolate ions. Unfortunately, its very
weak ionisation under air-pressure electrospray ionisation
technique precluded conclusive evidence for traces of a
hypothetical dibrominated intermediate in the LC/MS
analysis of the reaction mixture. Since much decomposi-
tion is observed in this reaction, more complex mecha-
nisms cannot be excluded, such as a probably less
plausible chromene ring opening/closure process.
B(OH)2
O
i
+
4
38%
O
7
NO2
Br
Br
NO2
O
F
I
ii
+
+
4
4
8
74%
O
O
O
iii
N
61%
N
9
Scheme 2 Reagents and conditions: (i) Cu(OAc)2, H2O, Et3N,
CH2Cl2, 4-Å MS, air; (ii) NaH, DMF, 25 °C; (iii) NaHCO3, neat,
150 °C.
Br
Br
O
i
1, but also sizable amounts of the linear isomer 104 as well
as traces of the reduced diaryl ether 11 (Scheme 3).4 These
last two unexpected side products were easily identified
by 1H NMR spectroscopy, as we had previously obtained
them by other, unambiguous synthetic routes.4 We veri-
fied that no isomerisation of 7 took place in boiling N,N-
dimethylformamide in the presence of sodium carbonate
and tetrabutylammonium bromide, thus confirming the
importance of the palladium added. Furthermore, in light
of previously reported palladium-promoted dehydrogena-
tive ring closure,27–33 palladium-promoted cyclisation of
pure compound 114 was attempted under the conditions
described above, but resulted in no cyclisation by this
pathway.
65%
O
HO
HO
OH
HO
3
4
ii
O
5
Br
Br
iii
4
O
HO
59%
6
Scheme 1 Reagents and conditions: (i) 1. Yb(OTf)3, HC(OMe)3,
H2C=CMe2, CH2Cl2, r.t., 60 h; 2. H+, 110 °C; (ii) K2CO3, AcNMe2,
130 °C; (iii) TfOH, TESH, CH2Cl2.
Palladium-catalysed cyclisations of ethers 8 and 9 into an-
alogues 12 and 13 were achieved (Scheme 3), albeit in
low yields, probably because of related side reactions. The
The base-induced isomerisation of 4 somehow limited the
possible methods we could use for the synthesis of the
corresponding aryl ethers.10–17 As depicted in Scheme 2,
phenyl ether 7 was prepared in 38% yield by a very mild
copper-catalysed coupling method between 4 and phenyl-
boronic acid.18–20 In another approach, an aromatic nu-
cleophilic substitution reaction took place between 4 and
the reactive 1-fluoro-2-nitrobenzene in N,N-dimethyl-
formamide at room temperature in the presence of sodium
hydride to yield 2-nitrophenyl ether 8 in 74% yield
(Scheme 2). It is remarkable that 4-chloro- or 4-
iodopyridine21 did not undergo etherification to give 4-py-
ridyl ether 9 under these conditions, whereas ether 9 could
be prepared in 60% yield from 4-iodopyridine by a sol-
vent-free approach22 at 150 °C in the presence of sodium
bicarbonate (Scheme 2).
i
O
7
not isolated
O
1
O
O
X
i
+
+
O
O
10
11
8
9
i
21%
17%
i
A fairly simple protocol23,24 involving five mol% of palla-
dium acetate and sodium carbonate was used to attempt
the palladium-catalysed cyclisation of diaryl ethers 7–9
(Scheme 3). Tetrabutylammonium bromine, which likely
acts as a remarkable catalyst stabiliser, was also add-
ed.25,26 Although we did not attempt to purify the reaction
products of this trial, 1H NMR monitoring of the cyclisa-
tion of 7 indicated the formation of the expected product
N
O
O
O2N
O
O
12
13
Scheme 3 Reagents and conditions: (i) Pd(OAc)2, TBAB, DMF,
air, reflux.
Synthesis 2007, No. 10, 1566–1570 © Thieme Stuttgart · New York

1568
S. Prado et al.
PAPER
side products formed could not be properly separated 15 leads us to surmise that there is an initial p-interaction
from the main compounds by chromatography, but recrys- between palladium and the alkene moiety of the
tallisation of these chromatographic fractions allowed the chromenes, which would assist the subsequent palladium
isolation of pure compounds 12 and 13 (in 17 and 21% insertion into the carbon–bromine bond. Again, we have
yield, respectively). A noteworthy feature of this cyclisa- not found a precedent for this putative assisting effect in
tion reaction is that the best yields were obtained only if the literature.
air was allowed into the reaction mixture. Monitoring of
What appears to be less logical is the necessity to run the
reaction trials under an argon atmosphere showed that the
palladium-catalysed cyclisation reaction of compounds
reaction would eventually stall prior to the formation of a
7–9 in the presence of air, an experimental requirement
that has not been reported so far. It is conceivable that a
black precipitate usually characteristic of a palladium de-
posit. A few trials using a more recently reported
more thorough study of the reaction conditions, especially
method34 were also unsuccessful.
the use of modern palladium ligands, would allow the cy-
Along with the isomerisation of 4, these results rather lim- clisation of compounds 14 and 15. However, the antimy-
ited our attempts at the design of a regioselective and ef- cobacterial activity of compounds 12 and 13 described
ficient route to the angular benzofuro[3,2-f]chromene below has not encouraged us to pursue this. Compounds
derivatives. We also investigated an alternative approach 12 and 13 were assayed for their antimycobacterial prop-
aimed at the preparation of chromane-bearing analogues erties according to a previously described procedure.4
of compound 2. We thus prepared ethers 14 and 15, in 61 Probably because of its lack of solubility, compound 12
and 43% yield, respectively, from the more stable chro- was devoid of antimycobacterial activity, whereas the
mane 6 and phenylboronic acid and 4-iodopyridine, re- minimal inhibitory concentration MIC 95 of the much
spectively (Scheme 4). The much improved 61% yield of more soluble compound 13 on Mycobacterium smegmatis
ether 14 was encouraging, as it hinted at chromane 6 being and Mycobacterium tuberculosis was 8 mg/mL and 16 mg/
more stable than chromene 4 giving phenyl ether 7 in only mL, respectively.
38% yield. However, the cyclisation attempts under the
conditions described above in the next step with both
compound 14 and 15 were disappointing, as H NMR
monitoring showed that no reaction took place in the
former case and only slow decomposition occurred in the
latter.
1H and 13C NMR spectra were recorded on a Bruker spectrometer at
400 MHz and 100 MHz, respectively. Chemical shifts (d) are given
in ppm relative to the TMS signal. Column chromatography was
performed on Merck silica gel 60 (0.035–0.070 mm), and a solvent
pump operating at a pressure within 2–7 bar (25–50 mL/min) and
an automated collecting system driven by a UV detector set at 254
nm were used unless it is stated otherwise. Mass spectra were ob-
tained on an Agilent 1100 series LC/MSD system, and an atmo-
spheric electrospray ionisation system and a C18 column were used.
The solvent system consisted of gradients of either H2O and MeCN
containing 0.07% HCO2H or, more often, H2O and MeOH contain-
ing 0.07% ammonium formate. Microanalysis and HRMS were car-
ried at the ICSN, CNRS, Gif sur Yvette, France.
1
Br
B(OH)2
O
i
6
6
+
+
61%
O
14
Br
O
I
5-Bromo-2,2-dimethyl-2H-chromen-6-ol (4)
ii
A previously described procedure was followed:6 In a 300-mL thick
bottle tube fitted with a PTFE-faced screw-cap, 2-bromo-3,6-
dihydroxybenzaldehyde7 (3; 4.00 g, 29.0 mmol) was dissolved in
CH2Cl2 (185 mL). HC(OMe)3 (4.25 mL, 37.7 mmol) and
Yb(OTf)3·xH2O (0.78 g, 1.3 mmol) were then added. The resulting
soln was cooled to 0 °C in an ice bath and 2-methylpropene was
bubbled through the soln. The mass added was monitored by peri-
odic weighing, and 6.2 equiv 2-methylpropene (8.70 g) was thus
added. The bottle was tightly closed and the soln was stirred at r.t.
for 60 h. The resulting soln was cooled to 0 °C before (please note!)
the bottle was opened; the contents were then diluted with CH2Cl2
(150 mL) and washed with 1 M NaHCO3 soln (3 × 50 mL). The or-
N
N
43%
O
15
Scheme 4 Reagents and conditions: (i) Cu(OAc)2, H2O, Et3N,
CH2Cl2, 4-Å MS, air; (ii) NaHCO3, neat, 150 °C.
In summary, we have observed that the electron-rich
chromene 4 is not very stable under basic conditions and
can undergo an unprecedented low-yield rearrangement
into 5. The formation of the isomeric cyclisation product
10 during palladium-catalysed cyclisation of 7 also results
from some kind of palladium-promoted rearrangement. ganic layer was dried (Na2SO4) and concentrated to dryness. The
On the other hand, no base-promoted rearrangement oc-
curred in the case of chromane 6 and the chromane-bear-
ing ethers 14 and 15 did not react under palladium-
residue was dissolved in toluene (185 mL) and TsOH (0.07 g, 0.4
mmol) was added. The mixture was heated to reflux for 1 h while
the MeOH was allowed to distil from the mixture by removal of the
condensate in a Dean-Stark apparatus (four times). After the mix-
promoted conditions to cyclise and form 7. One possible
ture had been concentrated to dryness, the residue was purified by
hypothesis is that because of lower electron density, the
carbon–bromine bond of chromanes 6, 14, and 15 is much
less reactive than the carbon–bromine bond of the corre-
sponding chromenes. This remarkable difference in be-
haviour between biaryl ethers 7–9 and biaryl ethers 14 and
column chromatography (silica gel, cyclohexane–CH2Cl2, 1:1); this
yielded compound 4 as an oil which slowly turned deep purple even
when stored at 0 °C.
Yield: 4.14 g (65%).
Synthesis 2007, No. 10, 1566–1570 © Thieme Stuttgart · New York

PAPER
Antimycobacterial Benzofuro[3,2-f]chromenes from a 5-Bromochromen-6-ol
1569
1H NMR (400 MHz, CDCl3): d = 1.44 (s, 6 H, CH3), 5.18 (s, 1 H,
OH), 5.76 (d, J = 9.9 Hz, 1 H, H-3), 6.60 (d, J = 9.9 Hz, 1 H, H-4),
6.71 (d, J = 8.7 Hz, 1 H, H-7), 6.83 (d, J = 8.7 Hz, 1 H, H-8).
5-Bromo-2,2-dimethyl-6-phenoxy-2H-chromane (14)
By the procedure described above for the preparation of 7, com-
pound 14 was obtained as a white powder.
13C NMR (100 MHz, CDCl3): d = 27.7, 76.0, 109.4, 115.5, 117.0,
Yield: 61%.
121.3, 121.5, 133.5, 146.9, 147.6.
1H NMR (400 MHz, CDCl3): d = 1.37 (s, 6 H, CH3), 1.87 (t, J = 6.8
Hz, 2 H, H-3), 2.82 (t, J = 6.8 Hz, 2 H, H-4), 6.77 (d, J = 8.8 Hz, 1
H, H-7), 6.87 (d, J = 8.8 Hz, 1 H, H-8), 6.93 (m, 2 H, H-Ar), 7.05
(m, 1 H, H-Ar), 7.32 (m, 2 H, H-Ar).
LC/MS (ES): m/z = 253/255 [M – H]–. This compound could not be
properly ionised for HRMS.
7-Bromo-2,2-dimethyl-2H-chromen-6-ol (5)
13C NMR (100 MHz, CDCl3): d = 24.7, 26.9, 33.0, 74.6, 117.1,
Compound 4 (0.1 g, 0.39 mmol), K2CO3 (0.2 g, 1.5 mmol), and
AcNMe2 (20 mL) were heated in a sealed tube for 2.5 h at 130 °C.
The resulting dark soln was concentrated to dryness, diluted with
EtOAc (100 mL) and washed with H2O (3 × 10 mL). After removal
of the solvents, the residue was purified by chromatography (silica
gel, cyclohexane–CH2Cl2, 1:1); this yielded a mixture of com-
pounds and 4 and 5 (3:1) as an oil. (The NMR data for compound 5
given below were obtained by subtracting the NMR signals of 4
from the NMR spectra of this mixture of 4 and 5.)
117.4, 118.9, 120.7, 122.7, 123.0, 129.8, 146.2, 151.8, 158.5.
LC/MS (ES): m/z = 350/352 [M + NH4]+.
Anal. Calcd for C17H17O2Br: C, 61.28; H, 5.14; O, 9.60. Found: C,
61.49; H, 5.35; O, 9.79.
5-Bromo-2,2-dimethyl-6-(2-nitrophenoxy)-2H-chromene (8)
In anhyd DMF (60 mL, dried over 4-Å MS), 4 (0.77 g, 3.0 mmol)
was added followed by 60% NaH in mineral oil (0.13 g, 3.1 mmol).
The mixture was protected from moisture by a CaCl2 guard, and at
the end of the evolution of gas, 1-fluoro-2-nitrobenzene (0.35 mL,
3.3 mmol) was added. The mixture was stirred overnight at r.t. and
then concentrated to dryness. The residue was dissolved in EtOAc
(100 mL) and the organic phase was washed with H2O (5 × 10 mL),
dried (Na2SO4), and concentrated to dryness. The residue was puri-
fied by chromatography (silica gel, cyclohexane–CH2Cl2, 85:15);
this gave compound 8 as a yellow solid.
Yield: 0.03 g (30%).
1H NMR (400 MHz, CDCl3): d = 1.44 (s, 6 H, CH3), 5.09 (s, 1 H,
OH), 5.69 (d, J = 9.9 Hz, 1 H, H-3), 6.26 (d, J = 9.9 Hz, 1 H, H-4),
6.68 (s, 1 H, H-5), 6.92 (s, 1 H, H-8).
13C NMR (100 MHz, CDCl3): d = 28.0, 76.6, 109.1, 113.2, 119.5,
122.0, 122.6, 132.8, 146.7, 147.3.
5-Bromo-2,2-dimethylchroman-6-ol (6)
Yield: 0.84 g (74%).
Compound 4 (0.66 g, 2.6 mmol) was dissolved in CH2Cl2 (100 mL).
TESH (1.65 mL, 10.3 mmol) was added, followed by TfOH (0.91
mL, 10.3 mmol), which was added dropwise. The resulting purple
soln was stirred for 3 h, washed with 1 N NaHCO3 (3 × 10 mL) and
H2O (3 × 10 mL), dried (Na2SO4), and concentrated to dryness. The
residue was purified by chromatography (silica gel, cyclohexane–
CH2Cl2, 1:1); this yielded compound 6 as an oil which also slowly
1H NMR (400 MHz, CDCl3): d = 1.48 (s, 6 H, CH3), 5.79 (d,
J = 10.0 Hz, 1 H, H-3), 6.70 (d, J = 10.0 Hz, 1 H, H-4), 6.81 (m, 2
H, H-7 and H-Ar6), 6.93 (d, J = 8.7 Hz, 1 H, H-8), 7.15 (m, 1 H, H-
Ar4), 7.45 (m, 1 H, H-Ar5), 7.97 (d, J = 8.1 Hz, 1 H, H-Ar3).
13C NMR (100 MHz, CDCl3): d = 28.0, 76.8, 115.4, 116.9, 117.9,
121.3, 121.1, 122.6, 123.0, 126.1, 133.5, 134.3, 140.4, 145.6, 151.5,
151.6.
1
darkened over time. (The H NMR data are closely related to that
reported previously.35)
LC/MS (ES): m/z = 393/395 [M + NH4]+.
Yield: 0.39 g (59%).
Anal. Calcd for C17H14NO4Br: C, 54.28; H, 3.75; N, 3.72. Found: C,
54.45; H, 3.81; N, 3.68.
1H NMR (400 MHz, CDCl3): d = 1.44 (s, 6 H, CH3), 1.83 (t, J = 6.9
Hz, 2 H, CH2-3), 2.74 (t, J = 6.9 Hz, 2 H, CH2-4), 5.32 (s, 1 H, OH),
6.72 (d, J = 8.9 Hz, 1 H, H-7), 6.84 (d, J = 8.9 Hz, 1 H, H-8).
13C NMR (100 MHz, CDCl3): d = 24.7, 26.7, 33.1, 74.0, 112.7,
114.5, 117.7, 121.3, 146.1, 148.7.
4-(5-Bromo-2,2-dimethyl-2H-chromen-6-yloxy)pyridine (9)
In a Kugelrohr distillation apparatus, a mixture of 4 (0.25 g, 1.0
mmol), 4-iodopyridine21 (0.20 g, 1.0 mmol), and NaHCO3 (0.16 g,
2.0 mmol) was heated at 150 °C for 2 h. The residue was purified
by chromatography (silica gel, CH2Cl2–EtOH, 99:1); this gave 9 as
a brown oil. (Note that 9 could be obtained in similar yield from the
commercially available 4-chloropyridine hydrochloride.)
LC/MS (ES): m/z = 256, 257, 258, 259 (weak signals; extensive de-
composition in the source).
5-Bromo-2,2-dimethyl-6-phenoxy-2H-chromene (7)
Yield: 0.2 g (61%).
Compound 4 (0.2 g, 0.78 mmol), PhB(OH)2 (0.19 g, 1.56 mmol),
Cu(OAc)2·xH2O (0.156 g, 0.78 mmol), and Et3N (0.33 mL, 2.34
mmol) were mixed in CH2Cl2 (10 mL). To this suspension was add-
ed 4-Å MS (0.15 g); the mixture was stirred in open air overnight,
and then concentrated to dryness. The residue was purified by chro-
matography (silica gel, cyclohexane–CH2Cl2, 1:1); this yielded
compound 7 as a crystalline solid.
1H NMR (400 MHz, CDCl3): d = 1.49 (s, 6 H, CH3), 5.71 (d, J = 9.9
Hz, 1 H, H-3), 6.60 (d, J = 9.9 Hz, 1 H, H-4), 6.72 (m, 3 H, H-7 and
H-Pyr 3 and 5), 6.83 (d, J = 8.7 Hz, 1 H, H-8), 8.38 (m, 2 H, H-Pyr
2 and 6).
13C NMR (100 MHz, CDCl3): d = 28.1, 76.9, 111.7, 115.9, 117.0,
121.3, 121.7, 123.0, 133.5, 144.7, 151.7, 151.8, 164.9.
LC/MS (ES): m/z = 332/334 [M + H]+.
HRMS (ES): m/z calcd for C16H15NO279Br [M + H]+: 332.0286;
Yield: 0.1 g (38%).
1H NMR (400 MHz, CDCl3): d = 1.47 (s, 6 H, CH3), 5.78 (d, J = 9.9
Hz, 1 H, H-3), 6.74 (d, J = 9.9 Hz, 1 H, H-4), 6.77 (d, J = 8.6 Hz, 1
H, H-7), 6.86 (d, J = 8.6 Hz, 1 H, H-8), 6.93 (m, 2 H, H-Ar), 7.06
(m, 1 H, H-Ar), 7.32 (m, 2 H, H-Ar).
13C NMR (100 MHz, CDCl3): d = 28.0, 76.5, 115.5, 116.7, 117.2,
121.6, 121.8, 122.7, 122.9, 130.0, 133.2, 147.2, 150.7, 158.4.
found: 332.0300.
4-(5-Bromo-2,2-dimethyl-2H-chroman-6-yloxy)pyridine (15)
The procedure described above for the preparation of 9 was used to
prepare 15, which was obtained as an oil.
LC/MS (ES): m/z = 348/350 [M + NH4]+. This compound could not
be properly ionised for HRMS.
Yield: 43%.
1H NMR (400 MHz, CDCl3): d = 1.38 (s, 6 H, CH3), 1.88 (t, J = 6.8
Hz, 2 H, H-3), 2.80 (t, J = 6.8 Hz, 2 H, H-4), 6.81 (m, 2 H, H-Pyr 3
Synthesis 2007, No. 10, 1566–1570 © Thieme Stuttgart · New York

1570
S. Prado et al.
PAPER
and 5), 6.84 (d, J = 8.8 Hz, 1 H, H-7), 6.95 (d, J = 8.8 Hz, 1 H, H-
8), 8.47 (m, 2 H, H-Pyr 2 and 6).
0502 MNHN, Muséum National d’Histoire Naturelle, 57 rue
Cuvier CP54, 75005 Paris, France.
(2) Janin, Y. L. Bioorg. Med. Chem. 2007, 15, 2479.
(3) Prado, S.; Ledeit, H.; Michel, S.; Koch, M.; Darbord, J. C.;
Cole, S. T.; Tillequin, F.; Brodin, P. Bioorg. Med. Chem.
2006, 14, 5423.
(4) Prado, S.; Janin, Y. L.; Saint-Joanis, B.; Brodin, P.; Michel,
S.; Koch, M.; Cole, S. T.; Tillequin, F.; Bost, P. E. Bioorg.
Med. Chem. 2007, 15, 2177.
13C NMR (100 MHz, CDCl3): d = 24.7, 26.9, 32.9, 74.9, 111.9,
117.8, 119.2, 121.5, 123.5, 143.7, 151.2, 153.1, 165.5.
LC/MS (ES): m/z = 334/336 [M + H]+.
HRMS–ES: m/z calcd for C16H17NO279Br [M+H]+: 334.0443;
found: 334.0457.
(5) Pozzo, J. L.; Samat, A.; Guglielmetti, R.; Lokshin, V.;
Minkin, V. Can. J. Chem. 1996, 74, 1649.
(6) Prado, S.; Janin, Y. L.; Bost, P. E. J. Heterocycl. Chem.
2006, 43, 1605.
(7) Li, C.; Johnson, R. P.; Porco, J. A. J. J. Am. Chem. Soc. 2003,
125, 5095.
(8) Bullock, R. M.; Rappoli, B. J. J. Chem. Soc., Chem.
Commun. 1989, 1447.
(9) Pettit, G. A.; Piatak, D. M. J. Org. Chem. 1960, 25, 721.
(10) Hill, A. J.; McGraw, W. J. J. Org. Chem. 1949, 14, 783.
(11) Loupy, A.; Phillipon, N.; Pigeon, P.; Galons, H.
Heterocycles 1991, 32, 1947.
3,3-Dimethyl-8-nitro-3H-benzofuro[3,2-f]chromene (12)
Aryl ether 8 (0.44 g, 1.17 mmol) was dissolved in DMF (30 mL,
dried over 4-Å MS). To this, Pd(OAc)2 (13.0 mg, 0.058 mmol),
TBAB (0.39 g, 1.17 mmol), and K2CO3 (0.4 g, 2.9 mmol) were add-
ed. The suspension was heated to reflux without (important!) an in-
ert atmosphere for 3 h. The solvent was removed under vacuum, the
residue was dissolved in EtOAc (100 mL), and the organic phase
was washed with H2O (5 × 10 mL), dried (Na2SO4), and concentrat-
ed to dryness. The residue was purified by chromatography (silica
gel, cyclohexane–CH2Cl2, 3:1); this gave compound 12, which was
further purified by two successive recrystallisations from cyclohex-
ane.
(12) Yeager, G. W.; Schissel, D. N. Synthesis 1995, 28.
(13) Kunz, K.; Scholz, U.; Ganzer, D. Synlett 2003, 2428.
(14) Cristau, H. J.; Cellier, P. P.; Hamada, S.; Spindler, J. F.;
Taillefer, M. Org. Lett. 2004, 6, 913.
(15) Burgos, C. H.; Barder, T. E.; Huang, X.; Buchwald, S. L.
Angew. Chem. Int. Ed. 2006, 45, 4321.
(16) Frlan, R.; Kikelj, D. Synthesis 2006, 2271.
(17) Voisin, A. S.; Bouillon, A.; Lancelot, J.-C.; Lesnard, A.;
Rault, S. Tetrahedron 2006, 62, 6000.
(18) Chan, D. M. T.; Monaco, K. L.; Wang, R.-P.; Winters, M. P.
Tetrahedron Lett. 1998, 39, 2933.
Yield: 0.06 g (17%); mp 174 °C.
1H NMR (400 MHz, CDCl3): d = 1.53 (s, 6 H, CH3), 5.92 (d, J = 9.8
Hz, 1 H, H-2), 7.05 (m, 2 H, H-1 and H-5), 7.46 (m, 1 H, H-10), 7.50
(d, J = 8.7 Hz, 1 H, H-6), 8.29 (m, 2 H, H-9 and H-11).
13C NMR (100 MHz, CDCl3): d = 27.8, 76.4, 112.3, 116.1, 118.2,
118.25, 118.8 (d), 122.7, 122.9, 128.6, 129.1, 133.5, 134.4, 149.9,
152.1.
LC/MS (ES): m/z = 313 [M + NH4]+.
Anal. Calcd for C17H13NO4: C, 69.15; H, 4.44; N, 4.74. Found: C,
69.37; H, 4.44; N, 4.71.
(19) Evans, A. E.; Katz, J. L.; West, T. R. Tetrahedron Lett. 1998,
39, 2937.
(20) Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Winters,
M. P.; Chan, D. M. T.; Combs, A. Tetrahedron Lett. 1998,
39, 2941.
(21) Wolf, C.; Tumambac, G. E.; Villalobos, C. N. Synlett 2003,
1801.
3,3-Dimethyl-3H-4,7-dioxa-10-aza-benzo[c]fluorene (13)
The procedure described above for the preparation of 12 was used
to prepare 13 from diaryl ether 9; this led to a residue, which was
purified by chromatography (silica gel, CH2Cl2–EtOH, 99:1). This
fraction was purified further by recrystallisation from cyclohexane.
(22) Jerchel, D.; Jakob, L. Chem. Ber. 1959, 52, 724.
(23) Ames, D. E.; Opalko, A. Synthesis 1983, 234.
(24) Ames, D. E.; Opalko, A. Tetrahedron 1984, 40, 1919.
(25) Amatore, C.; Azzabi, M.; Jutand, A. J. Am. Chem. Soc. 1991,
113, 8375.
(26) Jeffrey, T. Tetrahedron 1996, 52, 10113.
(27) Clark, F. R. S.; Norman, R. O. C.; Thomas, C. B.; Willson,
J. S. J. Chem. Soc., Perkin Trans. 1 1974, 1289.
(28) Shiotani, A.; Itatani, H. Angew. Chem., Int. Ed. Engl. 1974,
13, 471.
Yield: 0.14 g (21%); mp 115 °C.
1H NMR (400 MHz, CDCl3): d = 1.53 (s, 6 H, CH3), 5.92 (d, J = 9.8
Hz, 1 H, H-2), 7.01 (d, J = 8.8 Hz, 1 H, H-6), 7.02 (d, J = 9.8 Hz, 1
H, H-1), 7.36 (d, J = 8.8 Hz, 1 H, H-6), 7.52 (d, J = 8.8 Hz, 1 H, H-
7), 8.64 (d, J = 8.8 Hz, 1 H, H-9), 9.30 (s, 1 H, H-11).
13C NMR (100 MHz, CDCl3): d = 27.8, 76.5, 111.7, 116.3, 117.6,
117.9, 119.7, 122.6, 133.4, 144.5, 147.1, 149.8, 151.1, 162.1.
LC/MS (ES): m/z = 251 [M + H]+.
(29) Akermak, B.; Eberson, L.; Jonsson, E.; Petersson, E. J. Org.
Chem. 1975, 40, 1365.
Anal. Calcd for C16H13NO2: C, 76.48; H, 5.21; N, 5.57. Found: C,
76.24; H, 5.17; N, 5.45.
(30) Shiotani, A.; Itatani, H. J. Chem. Soc., Perkin Trans. 1 1976,
1236.
(31) Ljungqvit, A.; Bowers, C. Y.; Folkers, K. Int. J. Pept.
Protein Res. 1993, 41, 427.
(32) Oliveira, A. M.; Raposo, M. M. M.; Oliveira-Campos, A. M.
E.; Griffiths, J.; Machado, A. E. H. Helv. Chim. Acta 2003,
86, 2900.
(33) Fauq, A. H.; Khan, M. A.; Eckman, C. Synth. Commun.
2004, 34, 775.
Acknowledgments
We thank Sanofi-Aventis as well as Pfizer for very generous dona-
tions of scientific equipment. This work received the financial sup-
port of the Institut Pasteur (GPH-5, DVPI) and the European
Community (LHSP-CT-2005-018923).
(34) Campeau, L. C.; Parisien, M.; Jean, A.; Fagnou, K. J. Am.
References
Chem. Soc. 2006, 128, 581.
(1) Current address: Laboratoire de Chimie et Biochimie des
Substances Naturelles, UMR 5154 CNRS/MNHN–USM
(35) Mori, K.; Yamamura, S.; Nishiyama, S. Tetrahedron 2001,
57, 5533.
Synthesis 2007, No. 10, 1566–1570 © Thieme Stuttgart · New York