A new synthetic access to furo[3,2-f]chromene analogues of an antimycobacterial

Article abstract of DOI:10.1016/j.bmc.2008.06.057

From the structure of 3,3-dimethyl-3H-benzofuro[3,2-f][1]-benzopyran, a selective in vitro inhibitor of mycobacterial growth, we have undertaken a structure-activity relationship investigation. We wish to report here our results on the use of [2+3] cycloadditions between 2-formylbenzoquinone and various enol derivatives to give various 4-formyl-5-hydroxy benzofurans. In the next step, an ytterbium triflate-catalysed reaction with 2-methylpropene allowed the preparation of various original furo[3,2-f]chromenes derivatives. Their biological evaluation on the growth of Mycobacterium smegmatis as well as Mycobacterium tuberculosis pointed out that some analogues were four times more active than the initial hit.

Full text of DOI:10.1016/j.bmc.2008.06.057

Bioorganic & Medicinal Chemistry 16 (2008) 8264–8272
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
A new synthetic access to furo[3,2-f]chromene analogues
of an antimycobacterial
Luke Alvey a, Soizic Prado b, Valérie Huteau a, Brigitte Saint-Joanis c, Sylvie Michel d,
Michel Koch d, Stewart T. Cole c, François Tillequin d, Yves L. Janin a,
*
a Laboratoire de Chimie Organique, URA 2128 CNRS-Institut Pasteur, 25-28 rue du Docteur Roux, 75724 Paris Cedex 15, France
b Laboratoire de Chimie et Biochimie des Substances Naturelles, UMR 5154 CNRS/MNHN, Muséum National d’Histoire Naturelle, 57 rue Cuvier, CP54, 75005 Paris, France
c Unité de Génétique Moléculaire Bactérienne, Institut Pasteur, 28 rue du Docteur Roux, 75724 Paris Cedex 15, France
d Laboratoire de Pharmacognosie de l’Université Paris Descartes, UMR/CNRS 8638, Faculté des Sciences Pharmaceutiques et Biologiques, 4 avenue de l’Observatoire, 75006 Paris, France
a r t i c l e i n f o
a b s t r a c t
Article history:
From the structure of 3,3-dimethyl-3H-benzofuro[3,2-f][1]-benzopyran, a selective in vitro inhibitor of
mycobacterial growth, we have undertaken a structure–activity relationship investigation. We wish to
report here our results on the use of [2+3] cycloadditions between 2-formylbenzoquinone and various
enol derivatives to give various 4-formyl-5-hydroxy benzofurans. In the next step, an ytterbium tri-
flate-catalysed reaction with 2-methylpropene allowed the preparation of various original furo[3,2-
f]chromenes derivatives. Their biological evaluation on the growth of Mycobacterium smegmatis as well
as Mycobacterium tuberculosis pointed out that some analogues were four times more active than the ini-
tial hit.
Received 14 April 2008
Revised 15 June 2008
Accepted 20 June 2008
Available online 3 August 2008
Keywords:
Antimycobacterial
Benzofuro[3,2-f][1]-benzopyran
2-Formylbenzoquinone
[2+3] Cycloaddition
Furo[3,2-f]chromene
Mycobacterium tuberculosis
[2+4] Cycloadditions
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
As we previously reported, the dibenzofurans 1 and 2 were
found out to be remarkably selective in vitro inhibitors of myco-
bacterial growth1 (Fig. 1).
O
O
The first elements of structure–activity relationship were
somewhat disappointing as the structural analogues made, bear-
ing a benzofuro[3,2-f][1]-benzopyran ring system, had lower anti-
mycobacterial activity or were also cytotoxic.2 An attempt was
also made to alleviate the high lipophilicity of compounds 1 and
2 by the preparation of an aza analogue, which met with some rel-
ative success.3 In the course of preliminary work on the synthesis
of tricyclic furo[3,2-f]chromenes analogues of 1, we undertook the
preparation of 2-aryl-6-hydroxybenzofuranes 5a,b from the addi-
tion of the corresponding enamines 3a,b on benzoquinone (4).
However, if the preparation of 5a was achieved by adapting a
method previously reported4 our attempt to extend this to the
4-pyridyl analogue 5b met with some success although in a much
lower 3.9% yield. This was followed by their alkylation with dim-
ethylpropargylchloride to provide ethers 6a,b which again pro-
O
1
2
O
Figure 1.
ceeded in a low yield in the case of compound 6b. These ethers
were then thermally cyclized5–7 to give the 2-phenyl and the 2-
pyridyl analogues 7a and 7b. As described in the biological part
of this manuscript, the level of antimycobacterial activity of the
4-pyridyl analogue 7b, along with the very poor overall yield of
this synthesis, drove us not only to study in depth this reaction
but also to design better synthetic accesses to this compound
and its analogues. From our work on the reaction of enamines with
benzoquinone, we found out that the use of sodium metabisulfite
was crucial as, in its absence, only minute amounts of 5b were ob-
tained along with quite intractable over-oxidized reaction prod-
ucts. Moreover, when using the more hindered enamine of 4-
propionyl pyridine 3c,8 a far better 13.2% yield of the 2-pyridyl
product 5c was obtained. A very recent report describing the
unprecedented addition of dihydrofurane on benzoquinone9 catal-
* Corresponding author. Tel.: +33 (0) 6 85 42 49 47; fax: +33 (0) 1 45 68 84 04.
E-mail address: yljanin@pasteur.fr (Y.L. Janin).
0968-0896/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2008.06.057

L. Alvey et al. / Bioorg. Med. Chem. 16 (2008) 8264–8272
8265
ysed by a remarkable boron-containing Lewis acid10 would proba-
bly be of interest for further improvement of this particular reac-
tion. Again, in the next step, the preparation of the propargylic
ether only led to 45% of compound 6c, which then provided the
3-methylated analogue 7c in a 62% yield. In any case, the difficul-
ties encountered in this study encouraged us even more to find
alternative accesses to analogues of compounds 7a–c.
As depicted in the Scheme 2, a different synthetic access was
designed via a two-stage process. First, we investigated a [2+3]
cycloaddition reaction between 2-formylbenzoquinone (8) and
various enol ethers. This actually stemmed from the association
of a report describing the reaction between many enolethers and
2-acetylbenzoquinone11 along with more recent work illustrating
the synthetic usefulness of 2-formylquinone.12–14 From the ortho
formylphenol-bearing cycloadducts arising from this reaction, we
then made good use of our ytterbiumtriflate-catalysed addition
of isobutene to ortho-quinonemethides.15 This strategy allowed
us to prepare many analogues of 7a,b. Some of the scope of this
reaction, along with the biological assays of the analogues pre-
pared, are described in this paper.
hydrogens of carbons 4a and 9a is 6.1 Hz. This value is only com-
patible with a cis conformation, with a dihedral angle close to zero,
which can result from a [2+3] cycloaddition.10 Many trials were
made to improve the reaction yield, and the following comments
can be made from them. An excess of dihydropyran is important
as only a 16% yield of 11 was obtained if only one equivalent
was used. Trials in acetonitrile instead of ethyl acetate led to a sim-
ilar yield of compound 11. In this particular case, mixing DDQ and
compound 8 followed by the immediate addition of dihydropyran
(10) led to the same reaction yield. A small yield increase (56%)
was achieved if the reaction was run under an inert atmosphere
and if the cycloaddition step was allowed to run overnight. In
any case, we then built the pyran ring of compound 12 in a 75%
yield, using our ytterbiumtriflate-catalysed addition of isobutene
on ortho-quinonemethides (Scheme 3).15
The same route was investigated using other enol ethers. Exten-
sive decomposition was the only result of the reaction between
vinylethylether and formylbenzoquinone (8) generated in situ.
This was unexpected as a cycloaddition between this ether and
acetylbenzoquinone has been reported previously.11 From tertbu-
tylvinyl ether, traces of the expected compound were detected.
From the more hindered 1-propenylethyl ether (13), an overall
yield of 18% of the diastereoisomeric cycloadducts 14a and 14b
was obtained. These diastereoisomers could actually be separated
In order to prepare the 2-formylquinone (8), we used the re-
ported DDQ oxidation of various 2,5-dihydrobenzaldehyde such
as compound (9).12,16 However, as the formylquinone 8 is not
really stable,17 we then directly added dihydropyran (10) in the
reaction mixture. This procedure led to a 42% yield of the ortho
formylphenol 11. The study of the 1H NMR spectra of compound
3
and their relative conformations could be assigned by their JHH
coupling constants between the hydrogens of carbons 3 and 2. A
small dihedral angle is reflected by the 6.1 Hz value for the cis iso-
mer (14a) whereas a dihedral angle close to 90° leads to the 0.9 Hz
value for the trans isomer (14b). In the next step, using the mixture
of 14a and 1b, an unoptimised 11% yield of compound 15 was only
obtained along with a diastereoisomeric mixture of compound 16
(27%) and the adduct 17 (11%). On the other hand, from 2-
methoxypropene (18), the cycloaddition gave the cycloadduct 19
in a 46% yield, and the corresponding chromene-bearing analogue
20 was obtained in a 56% yield. When starting from diethoxyketen-
e 21, the crude cycloadduct 22 was obtained in a 78% yield (a pure
sample could be obtained only after a recrystallisation with much
loss). However, an extensive decomposition of this electron-rich
benzofuran was the only thing observed at the next stage. Since
the furan ring of 22 is far more reactive than isobutene, we suggest
that an intermolecular addition on the intermediate quinonemet-
hide takes place and leads to fairly complex polymeric material
(Scheme 4).
3
11 shows that the value of JHH coupling constant between the
R
O
N
+
i
O
X
O
3a-c
4
OR'
R
O
5a-c: R' = H
6a-c: R' = C(CH3)2CCH
ii
X
X
iii
R
From a twofold excess of 1-(trimethylsiloxy)cyclohexene (23), a
far better 37% overall yield of the previously2 prepared compound
25 was obtained via the not so stable cycloadduct 24, which was
only partially purified before the next synthetic step. The use of
the same procedure from the commercially available trimethyl(1-
phenylvinyloxy)silane (26) led, again via the not fully purified cyc-
a : X = CH, R = H
b : X = N, R = H
c : X = N, R = Me
O
7a-c
O
Scheme 1. Reagents and conditions: (i) a—EtOH; b—H2O, Na2S2O5; c—AcOH, reflux;
(ii) ClC(Me)2CCH, DBU, MeCN, CuCl2; (iii) 1,3-dichlorobenzene, reflux.
O
O
O
O
R
O
R2
i
R2
O
OH
O
OH
+
i
+
RO
R1
R1
O
O
O
HO
O
O
9
8
10
8
O
O
4a
O
OH
O
ii
ii
OH
O
O
O
9a
O
O
R
R
R
11
12
Scheme 3. Reagents and conditions: (i) DDQ, AcOEt, 25 °C, 1 h, then 10 overnight;
(ii) 2-methylpropene, Yb(OTf)3, HC(OMe)3, dichloromethane, 25 °C, 60 h, then TSA,
toluene, reflux, 1 h.
Scheme 2. Reagents and conditions: (i) see text below; (ii) 2-methylpropene,
Yb(OTf)3, HC(OMe)3, dichloromethane, 25 °C, 60 h, then TSA, toluene, reflux, 1 h.

8266
L. Alvey et al. / Bioorg. Med. Chem. 16 (2008) 8264–8272
O
O
O
O
N
Si
O
3
OH
ii
OH
i
O
O
O
R
O
N
i
2
O
O
O
O
O
27a: R = H
28b: R = Cl
29
Cl
13
15
14a,b
Si
OH
O
O
i
O
Br
Br
N
N
+
+
30
31
Br
O
O
O
16
17
OH
O
Si
O
OH
ii
O
N
i
O
O
O
i
O
O
Br
32
33
N
18
19
20
O
Scheme 6. Reagents and conditions: (i) a—compound 9, DDQ, MeCN, 1 h; b—enols.
i
OH
22
O
O
O
21
Unexpectedly, the construction of the pyran ring failed in the
case of compound 29. It appears that the highly insoluble property
of this compound is at the source of this result. In fact, the NMR
measurements of compound 29 had to be made in deuterated pyr-
idine as it was only weakly soluble in DMSO. On the other hand,
from the more soluble compounds 31, the chromene-bearing ana-
logue 34 was obtained in 55% yield. In the case of the compound
33, the corresponding reaction product 35 was obtained in a 30%
yield along with 44% of unreacted starting material. The reduction
of compound 35 and 36 allowed us to obtain compounds 37 and
38, the chromane-bearing isomers of compound 7b (Scheme 7).
Further transformations were made. For instance, the bromine
atom of compounds 34 or 35 could be displaced by amines to give
compound such as the diaminated side-chain bearing analogue 38
and 39. Moreover, the pyran ring of compound 12 could be opened
thus providing an access to the tricyclic ester 40 and the corre-
sponding alcohol 41 (Scheme 8).
O
Scheme 4. Reagents and conditions: (i) a—compound 9, DDQ, AcOEt, 2 h; b—enols;
(ii) 2-methylpropene, Yb(OTf)3, HC(OMe)3, dichloromethane, 25 °C, 60 h, then TSA,
toluene, reflux, 1 h.
O
OH
i
O
O
Si O
Si
24
23
O
ii
25
O
O
Si
O
OH
i
ii
2. Biological results and discussion
7a
O
26
27
The antimycobacterial activity was screened on the fast grow-
ing saprophyte Mycobacterium smegmatis mc2155 and on the viru-
lent strain Mycobacterium tuberculosis H37Rv for all synthesised
compounds, using the new Microdilution resazurin assay
Scheme 5. Reagents and conditions: (i) a—compound 9, DDQ, AcOEt, 2 h; b—enols;
(ii) 2-methylpropene, Yb(OTf)3, HC(OMe)3, dichloromethane, 25 °C, 60 h; then TSA,
toluene, reflux, 1 h.
loadduct 27, to the 2-aryl analogue 7a in a 18% overall yield. This
last unoptimized yield is actually identical with the one obtained
using the synthetic path described in Schemes 1 and 5.
31
33
i
i
O
Br
O
O
From this last result, we set out to prepare the silylenolether of
4-acetylpyridine which we obtained by altering a reported proce-
dure.18 Unexpectedly, from the resulting 4-pyridylsilylenolether
(28a) or the enamine 3b, despite repeated attempts, no cycloaddi-
tion reaction could be detected in the reaction mixture. On the
other hand, we prepared the 2-chlorinated enolether (28b) and ob-
tained the corresponding cycloaddition product 29 in a modest 8%
yield. In view of this, we suggest that the nucleophilic nature of the
pyridine ring may hamper the cycloaddition of 28a via the occur-
rence of a Michael adduct,19 which would block any other pro-
cesses. This nucleophile nature would actually be lowered in the
case of the 2-chlorine-bearing enolether 28b. Moreover, from the
more hindered bromine-bearing silylenolethers 30 and 32, the
cycloaddition reaction turned out to proceed much better, and
the compounds 31 and 33 were obtained in 55% and 44% yield,
respectively (Scheme 6).
O
O
N
N
34
35
Br
ii
ii
O
O
O
N
N
36
37
Scheme 7. Reagents and conditions: (i) 2-methylpropene, Yb(OTf)3, HC(OMe)3,
dichloromethane, 25 °C, 60 h, then TSA, toluene, reflux, 1 h; (ii) HCOOH, NH3, Pd/C
ethanol reflux.

L. Alvey et al. / Bioorg. Med. Chem. 16 (2008) 8264–8272
8267
ious enol ethers and formylbenzoquinone 8 allowed the position-
ing of a formyl moiety on the reaction products 11, 14, 19, 24,
27, 31 and 33 perfectly set to ensure the regioselectivity of another
(formal) [2+4] cycloaddition reaction with isobutene to build the
pyran ring. However, this original synthetic access to furo[3,2-
f]chromenes has inherent limits. This method requires mixing an
oxidant (benzoquinone 8) and enol ethers which are, as the initial
reaction products, potential oxidation substrates. This aspect very
likely explains the rather low yield we observed in the case of
the compounds that are less inherently stable as compound 11.
The lack of solubility of some of the synthetic intermediates 29
pointed out a serious limitation of the second cycloaddition step
used to build the pyran ring system. For these reasons, we then fo-
cused on the design of easier diversity-oriented synthesis of
furo[3,2-f]chromenes-bearing analogues, which will be described
in a forthcoming paper.
i
O
34 or 35
O
or
N
O
N
38
HN(CH2)3NMe2
O
Me2N(CH2)3HN
39
RO
O
ii
40: R = Ac
41: R = H
12
iii
O
Scheme 8. Reagents and conditions: (i) H2N(CH2)3NMe2, 120 °C; (ii) AcOH, HCl,
reflux; (iii) MeONa, MeOH.
3. Experimental
1H NMR and 13C NMR spectra were recorded on a Bruker spec-
trometer at 400 and 100 MHz, respectively. Shifts (d) are given in
ppm with respect to the TMS signal and coupling constants (J)
are given in Hertz. Column chromatography are performed over
Merck silica gel 60 (0.035–0.070 mm), using a solvent pump oper-
ating at pressure between 2 and 7 bar (25–50 mL/mn), and an
automated collecting system driven by a UV detector set to
254 nm unless stated otherwise (i.e., if ethylacetate was used then
it would be set to 280 nm). Mass spectra were obtained on an Agi-
lent 1100 serie LC/MSD system using an atmospheric electrospray
ionisation system. High resolution mass spectroscopy (HRMS) was
performed using a water Micromass Q-Tof with an electrospray ion
source.
Table 1
In vitro biological assays
Compound
MIC95
(lg/mL) M. smegmatis
MIC95 (lg/mL) M. tuberculosis
Isoniazid
1
2
5a
5b
5c
6b
7a
7b
7c
11
12
20
25
34
35
36
37
38
39
40
41
12
10
10
8
>50
>50
25
>500
3
0.1
10
10
125
>10
>10
16
32
2.5
3
125
250
>500
120
>10
>10
10
6.2
>125
125
>500
>500
>50
>50
25
Biology
MIC determinations
MICs were determined using the new Microdilution Resazurin
Assay (MRA).20 Resazurin salt powder (Sigma) was prepared at
0.01% (wt/vol) in distilled water, sterilized by filtration through a
6.2
10
10
10
>500
125
12.5
12.5
>500
62
0.22 lm membrane and stored at 4 °C for a week. Drug stock solu-
tions were prepared in dimethylsulfoxide (DMSO) at concentration
of 50 mg/mL and frozen until used. The inocula were prepared
from M. tuberculosis H37Rv and M. smegmatis mc2155 strains
grown in Dubos medium supplemented with 10% ADC enrichment
(Difco). One microliter of twofold serial dilutions of each drug was
ND, not determined.
(MRA).20 The minimal inhibitory concentration (MIC95) is defined
as the amount of compound required for >95% inhibition of bacte-
rial growth (Table 1).
prepared in 100
concentrations from 500 to 0.9
DMSO and isoniazid (from 1 g/mL to 1 ng/mL) were also included.
The plates were covered, sealed and incubated at 37 °C. After 48 h
for M. smegmatis or 6 days for M. tuberculosis, 30 L of resazurin
lL of Dubos medium directly in 96-well plates at
lg/mL. Growth controls containing
l
In conclusion, the design of an original synthetic access to
furo[3,2-f]chromenes allowed easier preparations of compounds
related to the 4-pyridyl derivative 7b, which still displays the best
antimycobacterial activity we have found so far.1–3 Simple ana-
logues featuring the core 7H-furo[3,2-f]chromen ring system, with
substituents on carbon 2 or 3, have little or no activity. On the
other hand, pyridyl-bearing compounds 36–39 have equal antimy-
cobacterial activity although they are of a lesser interest or equal to
the initial 2-pyridyl-bearing analogue 7b. The bromopyridyl-bear-
ing analogues 34 and 35 were of no interest although it is difficult
to say whether it is due to their lack of solubility or their inherent
lack of biological effect on mycobacteria. Aside from this, the
replacement of this pyridyl by a phenyl (compound 7a) or a methyl
(compound 19) as well as the introduction of an aliphatic side-
chain on carbon 3 (compounds 40 and 41) are disappointing. In
conclusion, this work proved that it is possible to escape the most
used propargylic ethers cyclization strategy to build chromene-
bearing compounds. The use of a [2+3] cycloaddition between var-
l
solution was added to each well and plates were allowed to incu-
bate at 37 °C for an additional 24 h. A change from blue to pink
indicates reduction of resazurin and therefore bacterial growth.
The MIC was defined as the lowest drug concentration that pre-
vented this colour change.
2-Phenyl-benzofuran-5-ol (5a). To a solution of benzoquinone
(4) (1.08 g, 10 mmol) in ethanol (15 mL, dried over 4 Å molecular
sieves) enamine 3a (1.89 g, 10 mmol), dissolved in ethanol
(15 mL, dried over 4 Å molecular sieves), was added drop-wise.
The reaction mixture was stirred at room temperature for
45 min. This was followed by the addition of water (50 mL) and
then sodium metabisulfite (3 g, 15.8 mmol), the suspension was
protected from air and stirred at room temperature overnight.
The mixture was diluted with water and extracted with ethyl ace-
tate (three times). The organic layer was dried over anhydrous so-

8268
L. Alvey et al. / Bioorg. Med. Chem. 16 (2008) 8264–8272
dium sulfate, filtered and evaporated to dryness. It was then dis-
persed in acetic acid (30 mL), and the suspension was heated at re-
flux for 1 h. The mixture was evaporated to dryness. Purification by
chromatography of the residue over silica gel (dichloromethane)
gave compound 5a as an amorphous solid (0.58 g, 27.6%).
Mp = 191 °C (lit.4 = 189 °C). HRMS (ES) calcd for C14H10O2:
211.0759, found: 211.0724. 1H (DMSO): 6.76 (dd, 1H, J = 8.8 and
2.4), 6.95 (d, 1H, J = 2.4), 7.29 (s, 1H), 7.40 (m, 2H), 7.49 (m, 2H),
7.88 (m, 2H),9.24 (s, 1H). 13C (DMSO-d6): 102.8, 106.2, 112.2,
114.2, 125.3, 129.5, 129.8, 130.4, 130.8, 149.3, 154.3, 156.4.
robutyne (0.45 mL, 4.06 mmol) was added. After stirring for 5 h, the
mixture was concentrated at reduced pressure, and the residue was
partitioned between water and toluene. The organic fraction was
washed with hydrochloric acid 1 N, sodium hydroxide 1 N, sodium
hydrogenocarbonate 1 N and brine and dried over anhydrous so-
dium sulfate. Following a concentration to dryness, compound 6a
was obtained as a yellow amorphous solid (0.57 g, 77%) after purifi-
cation by a chromatography over silica gel (cyclohexane/dichloro-
methane 1:1). Mp = 90 °C. LC/MS (ES) m/z = 277 [M+H]+. 1H
(DMSO-d6): 1.59 (s, 6H), 3.65 (s, 1H), 7.90 (dd, 2H, J = 0.9 and 8.5),
7.09 (dd, 1H, J = 2.4 and 8.8), 7.52 (m, 3H), 7.41 (m, 3H). 13C
(DMSO-d6): 30.2, 73.6, 77.6, 87.0, 103.1, 111.8, 114.4, 120.6, 125.5,
129.7, 129.9, 130.0, 130.6, 151.5, 151.9, 156.9.
2-(Pyridin-4-yl)benzofuran-5-ol(5b). To a solution of benzo-
quinone (4) (2.26 g, 20.9 mmol) in ethanol (30 mL, dried over 4 Å
molecular sieves) enamine 3b21 (4 g, 20.2 mmol), dissolved in
ethanol (30 mL, dried over 4 Å molecular sieves), was added
drop-wise. The reaction was protected from air and stirred at room
temperature for 45 min. This was followed by the addition of water
(50 mL) and then sodium metabisulfite (4 g, 21.0 mmol). The sus-
pension was protected from air and stirred at room temperature
overnight before diluting in water and extracting it with ethyl ace-
tate (three times). The organic layer was dried over anhydrous so-
dium sulfate, filtered and evaporated to dryness. It was then
dispersed in acetic acid (100 mL) and the suspension was heated
at reflux for 2.5 h. The mixture was evaporated to dryness. Purifi-
cation by chromatography of the residue over silica gel (dichloro-
methane/ethanol, from 1% to 5%) gave the fluorescent compound
5b as an amorphous solid (0.17 g, 3.9%). Mp >250 °C. HRMS (ES)
calcd for C13H9NO2: 212.0712, found: 212.0685. 1H (DMSO-d6):
6.85 (dd, 1H, J = 2.3 and 8.8), 7.00 (d, 1H, J = 2.3), 7.47 (d, 1H,
J = 8.8), 7.61 (d, 1H, J = 0.8), 7.80 (dd, 2H, J = 1.6 and 4.6), 8.66
(dd, 2H, J = 1.6 and 4.6), 9.36 (s, 1H). 13C (DMSO-d6): 106.5,
106.6, 112.6, 115.8, 119.2, 129.9, 137.5, 149.8, 151.2, 153.7, 154.6.
4-(5-(2-Methylbut-3-yn-2-yloxy)benzofuran-2-yl)pyridine
(6b). This compound was obtained by following the procedure
described for compound 6a from compound 5b. The resulting
crude extract was purified by a chromatography over silica gel
(dichloromethane/ethanol 100:0 then 98:2) to yield compound
6b as a wax (33%). HRMS (ES) calcd for C18H16NO2: 278.1181,
found: 278.1154. 1H (DMSO-d6): 1.60 (s, 6H), 3.66 (s, 1H), 7.17
(dd, 1H, J = 2.4 and 8.9), 7.50 (d, 1H, J = 2.4), 7.61 (d, 1H, J = 8.9),
7.73 (s, 1H), 7.84 (dd, 2H, J = 1.6 and 4.5), 8.69 (dd, 2H, J = 1.6
and 4.5). 13C (DMSO-d6): 32.3, 75.8, 79.9, 89.0, 109.1, 114.5,
117.0, 121.5, 124.1, 131.5, 139.5, 153.4, 154.0, 154.2, 156.3.
4-(3-Methyl-5-(2-methylbut-3-yn-2-yloxy)benzofuran-2-yl)pyr-
idine (6c). This compound was obtained by following the proce-
dure described for compound 6a from compound 5c. The resulting
crude extract was purified by a chromatography over silica gel
(dichloromethane/ethanol 98:2 then 95:5) to yield compound 6c
as a wax (45%). HRMS (ES) calcd for C14H12NO2: 226.0608, found:
226.0899. 1H (DMSO-d6): 1.60 (s, 6H), 2.48 (s, 3H), 3.63 (s, 1H),
7.31 (dd, 1H, J = 2.4 and 8.8), 7.46 (d, 1H, J = 2.4), 7.53 (d, 1H,
J = 8.8), 7.76 (m (l), 2H), 8.71 (m (l), 2H). Note: upon heating, the
1H pyridyl signals became much sharper. 13C (DMSO-d6): 10.1,
30.2, 73.8, 77.7, 87.0, 112.0, 113.7, 116.6, 121.1 (l), 122.1, 131.4,
138.0 (l), 148.9, 150.7, 151.0 (l), 151.9.
2-(Pyridin-4-yl)benzofuran-5-ol (5c). Note: the following pro-
cedure can also be used with success for the synthesis of com-
pound 5b. To a solution of benzoquinone (4) (1.05 g, 9.7 mmol)
in ethanol (30 mL, dried over 4 Å molecular sieves) enamine 3c8
(2 g, 9.7 mmol), dissolved in ethanol (20 mL, dried over 4 Å molec-
ular sieves), was added. The reaction mixture was protected from
air and stirred at room temperature for 1 h. Concentrated hydro-
chloric acid (1.37 mL, 14.55 mmol) was then added followed by
water (15 mL). This was stirred for 10 min and neutralised with so-
lid potassium carbonate (1.05 g, 7.6 mmol). More water (80 mL)
was added along with sodium metabisulfite (3.72 g, 19.4 mmol).
The suspension was protected from air and stirred at room temper-
ature overnight before concentrating the ethanol under vacuum.
The residue was diluted in water and extracted with ethyl acetate
(three times). The organic layer was dried over anhydrous sodium
sulfate, filtered and evaporated to dryness. The resulting residue
was then dispersed in acetic acid (100 mL), and the suspension
was heated at reflux for 2.5 h. The mixture was evaporated to dry-
ness. Purification by chromatography of the residue over silica gel
(cyclohexane/ethyl acetate 2:3) gave the fluorescent compound 5b
as an amorphous solid, which was further purified by a recrystalli-
sation in aqueous ethanol (0.29 g, 13.2%). Mp 229 °C. LC/MS (ES) m/
z = 226 [M+H]+. 1H (DMSO-d6): 2.46 (s, 3H), 6.91 (dd, 1H, J = 2.5 and
7,7-Dimethyl-2-phenyl-7H-furo[3,2-f]chromene
(7a). Com-
pound 6a (0.53 g, 1.9 mmol) was heated to reflux in 1,2-dichloro-
benzene (40 mL) for 12 h under an inert atmosphere. Purification
of the residue, obtained after concentration to dryness, was made
by a chromatography over silica gel (cyclohexane/dichloromethane
85:15) to give compound 7a as a yellow amorphous solid (0.47 g,
89%). Mp = 82 °C. HRMS (ES) calcd for C19H16O2: 277.1229, found:
277.1112. 1H (DMSO-d6): 1.39 (s, 6H), 5.85 (d, 1H, J = 9.8), 6.75 (dd,
2H, J = 16 and 9.8), 7.34 (dd, 1H, J = 0.6 and 8.7), 7.40 (m, 1H), 7.49
(m, 2H), 7.58 (d, 1H, J = 0.8), 7.89 (dd, 2H, J = 1.3 and 3.3). 13C
(DMSO-d6): 28.1, 76.6, 101.1, 111.5, 113.6, 114.2, 119.9, 125.4,
126.7, 128.9, 129.7, 129.9, 130.7, 132.0, 150.2, 157.0.
4-(7,7-Dimethyl-7H-furo[3,2-f]chromen-2-yl)pyridine (7b). The
same protocol used for compound 7a was used with compound 6b,
and after a purification by chromatography over silica gel (dichloro-
methane/ethanol 95:5) compound 7b was obtained as a wax (74%).
HRMS (ES) calcd for C18H16NO2: 278.1181, found: 278.1238. 1H
(CDCl3): 1.49 (s, 6H), 5.74 (d, 1H, J = 9.8), 6.65 (dd, 1H, J = 0.3 and
9.8), 6.84 (d, 1H, J = 9.1), 7.24 (d, 1H, J = 0.9), 7.28 (m, 1H), 7.49 (m,
2H), 7.69 (m, 2H), 8.69 (m, 2H). 13C (CDCl3): 27.9, 76.5, 103.0, 111.3,
113.7, 115.7, 119.0, 119.4, 125.8, 131.6, 137.8, 149.1, 150.8, 150.9,
154.2.
8.7), 7.42 (d, 1H, J = 8.7), 7.72 (m, 2H), 8.68 (m, 2H), 9.30 (s, 1H). 13
C
(DMSO-d6): 10.1, 105.1, 112.3, 115.9, 116.3, 120.6, 131.8, 138.4,
148.3, 149.5, 151.1, 154.4.
5-(2-Methylbut-3-yn-2-yloxy)-2-phenylbenzofuran
(6a). 2-
Phenyl-benzofuran-5-ol (5a) (0.57 g, 2.71 mmol) was dissolved in
anhydrous acetonitrile (25 mL for 5.5 mmol; dried over 4A molecu-
lar sieves) under argon and cooled using an ice bath. To this solution
were added DBU (0.63 mL, 4.2 mmol) and copper chloride dihydrate
(4.6 mg, 0.027 mmol). Thesolutionwas maintainedat0 °C, andchlo-
4-(1,7,7-Trimethyl-7H-furo[3,2-f]chromen-2-yl)pyridine (7c). The
same protocol used for compound 7a was used with compound
6c, and after a purification by chromatography over silica gel

L. Alvey et al. / Bioorg. Med. Chem. 16 (2008) 8264–8272
8269
(cyclohexane/ethyl acetate 3:1) compound 7c was obtained as a
14a: 1H (CDCl3): 1.30 (d, 3H, J = 7.0), 1.43 (d, 3H, J = 7.2), 2.77 (m, 2H),
4.02 (m, 1H), 5.74 (d, 1H, J = 6.6), 6.78 (d, 1H, J = 8.8), 7.01 (d, 1H,
J = 8.8), 10.17 (s, 1H), 10.85 (s, 1H). Compound 14b: 1H (CDCl3):
1.24 (d, 3H, J = 7.1), 1.38 (d, 3H, J = 7.3), 3.65 (m, 2H), 3.92 (m, 1H),
5.34 (d, 1H, J = 0.9), 6.80 (d, 1H, J = 8.8), 7.04 (d, 1H, J = 8.8), 10.08
(s, 1H), 10.71 (s, 1H).
solid (62%). Mp = 72 °C). HRMS (ES) calcd for
C19H18NO2:
292.1338, found: 292.1325. 1H (CDCl3): 1.48 (s, 6H), 2.63 (s, 3H),
5.72 (d, 1H, J = 9.9), 6.84 (d, 1H, J = 8.7), 6.96 (d, 1H, J = 8.7), 7.23
(d, 1H, J = 9.9), 7.63 (m, 2H), 8.70 (m, 2H). 13C (CDCl3): 12.3, 27.6,
75.6, 111.3, 115.1, 115.9, 116.1, 119.2, 121.3, 126.0, 131.4, 138.8,
149.1, 149.4, 150.1, 150.4.
Preparation of compounds 15–17
6-Hydroxy-3,4,4a,9a-tetrahydro-2H-benzofuro[2,3-b]pyran-5-
carbaldehyde (11). 2,5-Dihydroxybenzaldehyde (9) (0.5 g,
3.62 mmol) was dissolved in ethyl acetate (50 mL) and 2,3-di-
chloro-5,6-dicyano-1,4-benzoquinone (0.82 g, 3.62 mmol) was
added. The solution was protected from air and stirred for 4 h before
theadditionofdihydropyran (1.98 mL, 21.7 mmol). Themixturewas
stirred overnight, concentrated to dryness and the residue was puri-
fied by a chromatography over silica gel (dichloromethane/cyclo-
hexane 1:1) to yield compound 11 (0.34 g, 42.7%) which was
recrystallised in cyclohexane for analytical purposes. Mp = 134 °C).
HRMS (ES) calcd for C12H15O4: 221.0814, found: 221.0870. 1H
(DMSO): 1.22 (m, 1H), 1.51 (m, 2H), 2.12 (m, 1H), 3.49 (m, 1H),
3.71 (m, 1H), 5.81 (d, 1H, J = 6.1), 6.77 (d, 1H, J = 8.7), 7.01 (d, 1H,
J = 8.7), 10.3 (s, 1H), 10.7 (s, 1H). 13C (DMSO): 21.7, 25.3, 37.9, 62.0,
105.8, 116.9, 118.4, 119.8, 113.0, 150.0, 156.3, 191.8.
The mixture of compounds 14a,b was treated as described for
the synthesis of compound 12. Following a purification of the res-
idue by a chromatography over silica (cyclohexane/dichlorometh-
ane, from 7:3 to 1:1), compounds 15, 17 and 16 were obtained in
that order of elution as described below.
1,7,7-Trimethyl-7H-furo[3,2-f]chromene (15). 11% as an oil.
HRMS (ES) calcd for C14H15O2: 215.1072, found: 215.1097. 1H
(CDCl3): 1.47 (s, 6H), 2.37 (s, 3H), 5.69 (d, 1H, J = 9.9), 6.77 (d,
1H, J = 8.7), 6.89 (d, 1H, J = 9.9), 7.19 (d, 1H, J = 8.7), 7.35 (s, 1H).
13C (CDCl3): 10.0, 27.7, 75.7, 111.4, 114.1, 114.7, 116.2, 119.5,
124.6, 131.0, 143.2, 148.7, 151.3.
2,20,7,7,70,70-Hexamethyl-80,90-dihydro-7H,70H-1,90-bifuro[3,2-f]-
chromene (17). 11% as an oil. HRMS (ES) calcd for C28H29O4:
429.2066, found: 429.2072. Extensive two dimensional NMR studies
were undertaken to determine the structure of this compound. 1H
(CDCl3): 1.38 (s, 6H), 1.42 (s, 3H), 1.44 (s, 3H), 1.71 (s, 3H), 1.89 (s,
3H), 2.13 (dd, 1H, J = 8.5 and 13.7), 2.31 (dd, 1H, J = 7.5 and 13.7),
4.79 (m, 1H), 5.62 (d, 1H, J = 9.9), 6.68 (d, 1H, J = 8.7), 6.81 (d, 1H,
J = 9.9), 6.85 (d, 1H, J = 8.8), 7.08 (d, 1H, J = 8.7), 7.22 (s, 1H), 7.31 (d,
1H, J = 8.8). 13C (CDCl3): 9.9, 10.3, 25.4, 27.6, 27.9, 28.5, 32.0, 41.2,
73.9, 75.6, 110.6, 110.9, 112.1, 112.8, 113.3, 114.3, 115.9, 116.9,
119.4 126.3, 127.6, 130.6, 143.0, 148.8, 149.1, 150.2, 151.1, 157.6.
3,3-Dimethyl-9,10,11,11a-tetrahydro-3H,7aH-4,7,8-trioxa-benzo
[c]fluorene (12). In a 60 mL round-bottomed thick glass tube fit-
ted with a PTFE-faced screw-cap, compound 11 (0.15 g, 0.68 mmol)
was dissolved in dichloromethane (40 mL). Trimethylorthoformate
(0.111 mL, 1.02 mmol) and ytterbium triflate hydrate (0.021 g,
0.034 mmol) were then added. The resulting solution was cooled to
0 °C using an ice bath and 2-methylpropene was bubbled through
the solution. The mass added was monitored by periodic weighting,
thus 2-methylpropene (0.8 g, 14 mmol) was added. The glass tube
was tightly closed and the solution was stirred at room temperature
for60 h. Theresultingsolutionwascooledat0 °Candthiswasdiluted
in dichloromethane and washed three times with a 1 N sodium
hydrogen carbonate solution. The organic layer was dried over so-
dium sulfate and concentrated to dryness. The residue was dissolved
in toluene (60 mL) and p-toluenesulfonic acid (0.002 g, 0.01 mmol)
wasadded. This was heated toreflux for1 h while allowingthemeth-
anol to distil from the reaction mixture by removing the water con-
denser four times (we suggest the much safer use of a distillation
or a Dean-Stark apparatus for larger reaction scale). After concentra-
tion to dryness, the residue was purified by a chromatography over
silica gel (dichloromethane/cyclohexane 7:3) to yield the compound
12(0.17 g, 75%). Mp = 78 °C. HRMS (ES) calcdforC16H19O3: 259.1334,
found: 259.1299. 1H (CDCl3): 1.43 (s, 6H), 1.63 (m, 3H), 2.09 (m, 1H),
3.23 (m, 1H), 3.88 (m, 2H), 5.71 (d, 1H, J = 9.8), 5.88 (d, 1H, J = 6.4),
6.32 (d, 1H, J = 9.8), 6.60 (m, 2H). 13C (CDCl3): 21.1, 25.1, 27.8, 27.9,
37.4, 61.5, 75.7, 105.0, 109.7, 115.8, 118.4, 119.2, 126.9, 133.0,
147.2, 151.5.
2-Ethoxy-1,7,7-trimethyl-2,7-dihydro-1H-furo[3,2-f]chro-
mene (16). 27% as an oil; mixture of diastereoisomers. LC/MS
(ES) m/z = 261 [M+H]+ (no proper ionisation in HRMS). 1H (CDCl3):
1.24 (t, 3H, J = 7.1), 1.28 (t, 3H, J = 7.3), 1.40 (s, 6H), 3.27 (m, 1H),
3.63 (m, 1H), 3.93 (m, 1H), 5.16 (d, 0.2H, J = 1.1), 5.26 (d, 0.8H,
J = 1.1), 5.66 (m, 1H), 6.34 (d, 1H, J = 9.8), 6.59 (m, 2H). 13C (CDCl3):
15.5, 18.6, 27.9, 27.95, 42.8, 64.3, 75.7, 109.6, 113.0, 115.8, 118.2,
119.3, 127.2, 132.7, 147.5, 152.0.
5-Hydroxy-2-methoxy-2-methyl-2,3-dihydrobenzofuran-4-
carbaldehyde (19). 2,5-dihydroxybenzaldehyde (9) (0.25 g,
1.81 mmol) was dissolved in ethyl acetate (50 mL) and DDQ
(0.41 g, 1.81 mmol) was added. The solution was protected from
air and stirred for 90 min before the addition of 2-methoxypropene
(18) (1 mL, 10.4 mmol). The mixture was stirred overnight, concen-
trated to dryness and the residue was purified by a chromatogra-
phy over silica gel (dichloromethane/cyclohexane 4:6) to yield
compound 19 (0.26 g, 68%) as an oil. LC/MS (ES): extensive decom-
position. 1H (CDCl3): 1.74 (s, 3H), 3.36 (s, 3H), 3.37 (m, 1H), 3.52
(m, 1H), 6.80 (d, 1H, J = 8.8), 7.03 (d, 1H, J = 8.8), 10.00 (s, 1H),
10.66 (s, 1H). 13C (CDCl3): 23.9, 39.9, 50.3, 112.6, 117.0, 117.3,
119.4, 128.5, 151.9, 157.7, 194.1.
2-Ethoxy-5-hydroxy-3-methyl-2,3-dihydrobenzofuran-4-carbal-
dehyde (14a,b). 2,5-Dihydroxybenzaldehyde (9) (1 g, 7.2 mmol)
was dissolved in ethyl acetate (100 mL) and 2,3-dichloro-5,6-dicy-
ano-1,4-benzoquinone (1.64 g, 7.2 mmol) was added. The solution
was protected from air and stirred for 2 h before the addition of
ethyl-1-propenyl ether (4.78 mL, 43.2 mmol). The mixture was stir-
red overnight, concentrated to dryness and the residue was purified
by a chromatography over silica gel (dichloromethane) to yield com-
pounds 14a,b (0.28 g, 17.5%) as a crude mixture of diastereoisomers.
This was usually used directly in the next step leading to compounds
15–17. In one instance we proceeded in their separation by a chro-
matography over silica gel (cyclohexane/dichloromethane 1:1),
which led to pure compound 14a (cis conformation) and compound
14b(transconformation)stillcontainingabout5%of14a. Compound
2,7,7-Trimethyl-7H-furo[3,2-f]chromene (20). The protocol
described for compound 12 was used starting from 19 (0.24 g,
1.15 mmol), and the resulting residue was purified by a chroma-
tography over silica gel (dichloromethane/cyclohexane 4:1) to
yield compound 20 (0.14 g, 56%) as an oil %). HRMS (ES) calcd for
C
14H14O2: 215.1072, found: 215.1089. 1H (CDCl3): 1.50 (s, 6H),
2.49 (s, 3H), 5.71 (d, 1H, J = 9.6), 6.41 (m, 1H), 6.59 (d, 1H,
J = 9.6), 6.71 (d, 1H, J = 8.6), 7.17 (d, 1H, J = 8.6). 13C (CDCl3): 14.5,
27.9, 76.1, 100.8, 110.6, 112.5, 112.8, 120.0, 126.4, 130.8, 148.6,
150.3, 156.8.

8270
L. Alvey et al. / Bioorg. Med. Chem. 16 (2008) 8264–8272
2-Ethoxy-5-hydroxybenzofuran-4-carbaldehyde
(22). 2,5-
ano-1,4-benzoquinone (1.23 g, 5.4 mmol) in dry acetonitrile
(25 mL). After 15 min, compound 28b (1.23 g, 5.4 mmol) was
added. After 5 h, volatiles were removed via rotary evaporation.
Acetic acid (20 mL) was added to the residue, and the mixture
was refluxed for 2 h. After cooling, volatiles were removed via ro-
tary evaporation. Toluene (20 mL) was added, and again volatiles
were removed via rotary evaporation. The residue was purified
Dihydroxybenzaldehyde (9) (2 g, 14.5 mmol) was dissolved in
ethyl acetate (100 mL) and DDQ (3.28 g, 14.5 mmol) was added.
The solution was protected from air and stirred for 60 min before
the addition of diethoxyketene (5.7 mL, 43.5 mmol). The mixture
was stirred for 2 h, concentrated to dryness and the residue was
purified by
a chromatography (dichloromethane/cyclohexane
2:1) to yield compound 22 (2.35 g) as a crude solid which could
be recrystallised in cyclohexane for analytical purposes.
Mp = 89 °C. LC/MS (ES) m/z = 207 [M+H]+ (no proper ionisation in
HRMS). 1H (CDCl3): 1.54 (m, 3H), 4.33 (d, 2H, J = 7.2), 5.88 (s,
1H), 6.66 (d, 1H, J = 8.8), 7.72 (d, 1H, J = 8.8), 10.22 (s, 1H), 11.24
(s, 1H). 13C (CDCl3): 14.8, 67.8, 74.9, 110.1, 111.5, 119.3, 133.2,
142.6, 159.6, 166.2, 193.0.
by a chromatography on silica gel (dichloromethane/ethanol
98:2). The resulting fraction was triturated in dichloromethane
(20 mL) and filtered to give 29 as a bright yellow powder (0.12 g,
8% yield). Mp = 271 °C (decomp.). HRMS (ES) calcd for
C
14H935ClNO3: 274.0271, found: 274.0251. 1H (pyridine-d5): 8.69
(d, 1H, J = 8.9), 9.17 (d, 1H, J = 5.2), 9.27 (d, 1H, J = 8.9), 9.40 (s,
1H), 9.85 (s, 1H), 10.01 (d, 1H, J = 5.2), 12.52 (s, 1H), 14.31 (s,
1H). 13C (pyridine-d5): one carbon signal probably occulted by
the solvent signals, 108.8, 117.0, 118.4, 119.9, 121.2, 121.3,
129.9, 141.9, 152.5, 154.3, 156.3, 162.4, 192.5.
3,3-Dimethyl-8,9,10,11-tetrahydro-3H-benzofuro[3,2-f]chro-
mene (25). 2,5-Dihydroxybenzaldehyde (9) (0.1 g, 0.72 mmol)
was dissolved in ethyl acetate (30 mL) and 2,3-dichloro-5,6-dicy-
ano-1,4-benzoquinone (0.16 g, 0.72 mmol) was added. The solu-
tion was protected from air and stirred for 45 min before the
addition of 1-(trimethylsiloxy)cyclohexene (0.27 mL, 1.45 mmol).
The mixture was stirred for two days, concentrated to dryness
and the residue was purified by a chromatography over silica gel
eluting with a dichloromethane and then dichloromethane/ethanol
98:2 to yield a mixture of compounds containing 24 and the prod-
uct of the trimethylsilanol elimination (0.2 g). This chromato-
graphic fraction was used without further purification following
the protocol described for compound 12. The resulting residue
was purified by a chromatography over silica gel (dichlorometh-
ane/cyclohexane 15:85) to yield compound 25 (0.07 g, 37%) as a
white solid with analytical data similar to the one we previously
described2 Note: by following the same protocol, 7,7-dimethyl-2-
phenyl-7H-furo[3,2-f]chromene (7a) described above was obtained
in a 18% overall yield via the partially purified compound 27.
2-(6-Bromopyridin-2-yl)-5-hydroxybenzofuran-4-carbaldehyde
(31). A round-bottomed flask (250 mL) was charged with 2,5-
dihydroxybenzaldehyde (2.90 g, 20.1 mmol) and dry acetonitrile
(75 mL), and to this was added a solution of 2,3-dichloro-5,6-dicy-
ano-1,4-benzoquinone (4.76 g, 21.0 mmol) in dry acetonitrile
(75 mL). After 15 min, compound 30 (5.71 g, 21.0 mmol) was added.
After 12 h, volatiles were removed via rotary evaporation. Acetic
acid (50 mL) was added to the residue, and the mixture was refluxed
for 2 h. After cooling, volatiles were removed via rotary evaporation.
Toluene (50 mL) was added, and again volatiles were removed via
rotary evaporation. The residue was purified by a chromatography
on silica gel (dichloromethane) to give 31 as a bright yellow powder
(3.67 g, 55% yield). Mp = 179 °C. HRMS (ES) calcd for C14H979BrNO3:
317.9766, found: 317.9779. 1H (DMSO-d6): 7.02 (d, 1H, J = 9.0), 7.62
(d, 1H, J = 7.7), 7.83 (d, 1H, J = 9.0), 7.86 (t, 1H, J = 7.7), 7.92 (d, 1H,
J = 9.0), 7.94 (s, 1H), 10.50 (s, 1H), 10.81 (br s, 1H). 13C (DMSO-d6):
106.7, 114.8, 116.5, 120.0, 120.3, 127.8, 128.7, 141.3, 142.4, 149.5,
149.8, 156.7, 160.0, 191.0.
2-Chloro-4-(1-(trimethylsilyloxy)vinyl)pyridine (28b). A reac-
tion tube (60 mL) was charged with 1-(2-chloropyridin-4-yl)etha-
none22 (3.1 g, 20.3 mmol), triethylamine (3.00 mL, 21.5 mmol) and
dry toluene (30 mL) and sealed with a septum. To this was added
drop-wise trimethylsilyl trifluoromethanesulfonate (4.0 mL,
22 mmol) via syringe. The mixture was heated at 80 °C for 5 h. After
cooling, the upper toluene phase was isolated and volatiles were re-
moved via rotary evaporation. The residue was distilled on a Kugel-
rohr apparatus under oil pump vacuum at 160 °C to give 28b as a
colourless liquid (3.79 g, 82% yield). 1H (CDCl3): 0.29 (s, 9H), 4.63
(d, 1H, J = 2.4), 5.10 (d, 1H, J = 2.4), 7.36 (d, 1H, J = 5.3), 7.47 (s, 1H),
8.33 (d, 1H, J = 5.3).
2-(6-Bromopyridin-3-yl)-5-hydroxybenzofuran-4-carbaldehyde
(33). A round-bottomed flask (500 mL) was charged with 2,5-
dihydroxybenzaldehyde (3.27 g, 23.7 mmol) and dry acetonitrile
(75 mL), and to this was added a solution of 2,3-dichloro-5,6-dicy-
ano-1,4-benzoquinone (5.38 g, 23.7 mmol) in dry acetonitrile
(75 mL). After 15 min, compound 32 (6.44 g, 23.6 mmol) was
added. After 12 h, volatiles were removed via rotary evaporation.
Acetic acid (50 mL) was added to the residue, and the mixture
was refluxed for 1 h. After cooling, volatiles were removed via ro-
tary evaporation. Toluene (50 mL) was added, and again volatiles
were removed via rotary evaporation. The residue was purified
2-Bromo-6-(1-(trimethylsilyloxy)vinyl)pyridine
(30). This
by a chromatography on silica gel (dichloromethane/ethanol
compound was obtained from 1-(6-bromopyridin-2-yl)ethanone
by following the procedure described for the preparation of com-
pound 28, to give 30 as a colourless liquid (92% yield). 1H (CDCl3):
0.30 (s, 9H), 4.62 (d, 1H, J = 1.1), 5.72 (d, 1H, J = 1.1), 7.37 (dd, 1H,
J = 5.6, 3.1), 7.54 (d, 1H, J = 5.6), 7.55 (d, 1H, J = 3.1).
98:2). The resulting fraction was triturated in dichloromethane
(20 mL) and filtered to give 33 as a bright yellow powder (3.29 g,
44% yield). Mp = 218 °C (decomp.). HRMS (ES) calcd for
C
14H979BrNO3: 317.9766, found: 317.9793. 1H (DMSO-d6): 7.00
(d, 1 H, J = 8.9), 7.77 (d, 1H, J = 8.4), 7.82 (d, 1H, J = 8.9), 8.04 (s,
1H), 8.26 (d, 1H, J = 8.4), 8.96 (s, 1H), 10.51 (s, 1H), 10.74 (s, 1H).
13C (DMSO-d6): 105.3, 114.8, 115.8, 120.0, 126.1, 128.0, 129.3,
136.1, 142.2, 147.5, 149.5, 155.3, 160.0, 190.6.
2-Bromo-5-(1-(trimethylsilyloxy)vinyl)pyridine
(32). This
compound was obtained from 1-(6-bromopyridin-3-yl)ethanone
by following the procedure described for the preparation of com-
pound 28, to give 32 as a colourless liquid (6.44 g, 93% yield). 1H
(CDCl3): 0.29 (s, 9H), 4.53 (d, 1H, J = 2.3), 4.95 (d, 1H, J = 2.3),
7.44 (d, 1H, J = 8.3), 7.71 (dd, 1H, J = 2.5, 8.3), 8.58 (d, 1H, J = 2.5).
2-Bromo-6-(7,7-dimethyl-7H-furo[3,2-f]chromen-2-yl)pyridine
(34). A round-bottomed flask (250 mL) was charged with 33
(3.44 g, 10.8 mmol), trimethylorthoformate (6.00 mL, 54.8 mmol),
ytterbium triflate hydrate (0.30 g, 0.48 mmol) and dry dichloro-
methane (150 mL, dried over 4 Å molecular sieves). After 30 min,
the flask was cooled in an ice bath, and isobutylene (8.57 g,
153 mmol) was added to the solution. The flask was sealed with
a rubber septum, and then the cold bath was removed. After
2-(2-Chloropyridin-4-yl)-5-hydroxybenzofuran-4-carbaldehyde
(29). A round-bottomed flask (100 mL) was charged with 2,5-
dihydroxybenzaldehyde (0.75 g, 5.4 mmol) and dry acetonitrile
(25 mL), and to this was added a solution of 2,3-dichloro-5,6-dicy-

L. Alvey et al. / Bioorg. Med. Chem. 16 (2008) 8264–8272
8271
60 h, the solution was washed with sodium hydrogenocarbonate
(150 mL, 1 M) and brine (150 mL) and dried over magnesium sul-
fate. After filtration, volatiles were removed via rotary evaporation.
The residue was combined with dry toluene (30 mL) and p-toluene
sulfonic acid (0.11 g) in a round-bottomed flask (100 mL), and
heated at 115 °C for 1 h. After cooling, diethylether (100 mL) was
added, and the mixture was washed with sodium hydrogenocar-
bonate (50 mL, 1 M) and brine (100 mL) and dried over magnesium
sulfate. This was concentrated to dryness and the residue was puri-
fied by a chromatography on silica gel (dichloromethane/cyclohex-
ane 1:1) to give compound 34 (1.98 g, 51% yield) as a colourless
amorphous solid. Mp = 155–156 °C. HRMS (ES) calcd for
3-(7,7-Dimethyl-8,9-dihydro-7H-furo[3,2-f]chromen-2-yl)pyri-
dine (37). A round-bottomed flask (50 mL) was charged with 35
(0.076 g, 0.21 mmol), ammonium formate (0.048 g, 0.76 mmol),
10% palladium over charcoal (0.0220 g, 0.0207 mmol) and ethanol
(10 mL), and the mixture was refluxed for 4 h. Upon cooling, the
mixture was filtered on a plug of Celite on a fritted funnel, and
washed with dichloromethane (20 mL). The filtrate was concen-
trated to dryness and the residue purified by a chromatography
on silica gel (ethylacetate/cyclohexane 1:1, UV monitoring at
280 nm) to give compound 37 (0.0436 g, 73% yield) as a colourless
amorphous solid. Mp = 129–130 °C. HRMS (ES) calcd for
C
18H18NO2: 280.1338, found: 280.1356. 1H (CDCl3): 1.39 (s, 6H),
C
18H1579BrNO2: 356.0286, found: 356.0273. 1H (CDCl3): 1.43 (s,
1.92 (t, 2H, J = 6.8), 2.94 (t, 2H, J = 6.8), 6.81 (d, 1H, J = 8.8), 7.06
(s, 1H), 7.28 (d, 1H, J = 8.8), 7.38 (dd, 1H, J = 4.0, 8.0), 8.12 (d, 1H,
J = 8.0), 8.57 (d, 1H, J = 4.0), 9.11 (s, 1H). 13C (CDCl3): 20.4, 27.0,
32.7, 74.3, 101.5, 110.3, 112.6, 116.0, 124.0, 127.4, 128.6, 132.2,
146.5, 149.1, 149.8, 150.1, 153.4.
6H), 5.67 (d, 1H, J = 9.8), 6.60 (d, 1H, J = 9.8), 6.77 (d, 1H, J = 8.8),
7.21 (d, 1H, J = 8.8), 7.35 (d, 1H, J = 7.8), 7.48 (s, 1H), 7.56 (t, 1H,
J = 7.8), 7.76 (d, 1H, J = 7.8). 13C (CDCl3): 28.0, 76.4, 104.5, 111.3,
114.0, 115.6, 118.4, 119.5, 126.0, 127.3, 131.4, 139.3, 142.6,
149.1, 150.6, 151.1, 154.8.
N1-(6-(7,7-Dimethyl-7H-furo[3,2-f]chromen-2-yl)pyridin-2-yl)-
N3,N3-dimethylpropane-1,3-diamine (38). A round-bottomed
flask (5 mL) was charged with compound 34 (0.050 g, 0.14 mmol)
and N1,N1-dimethylpropane-1,3-diamine (0.30 mL, 2.4 mmol) and
was heated at 120 °C for 60 h. After cooling, the residue was puri-
fied by a chromatography on a column of neutral alumina (1.2%
wt/wt water, eluting with a dichloromethane/2 N ammonia in
ethanol 95:5 mixture) to give compound 38 (0.051 g, 95% yield)
as a wax. calcd HRMS (ES) calcd for C23H28N3O2: 378.2182,
found: 378.2200. 1H (CDCl3): 1.47 (s, 6H), 1.84 (quintet, 2H,
J = 6.9), 2.27 (s, 6H), 2.44 (t, 2H, J = 7.0), 3.41 (t, 2H, J = 6.7),
5.70 (d, 1H, J = 9.7), 6.37 (d, 1H, J = 8.3), 6.66 (d, 1H, J = 9.8),
6.77 (d, 1H, J = 8.8), 7.18 (d, 1H, J = 7.3), 7.25 (d, 1H, J = 8.7),
7.33 (d, 1H, J = 0.7), 7.49 (dd, 1H, J = 7.5, 8.1). 13C (CDCl3): 27.5,
27.9, 41.2, 45.8, 58.1, 76.3, 102.2, 107.0, 109.3, 111.2, 113.7,
114.4, 119.9, 126.2, 131.0, 138.2, 147.7, 148.8, 150.7, 157.4,
159.1.
2-Bromo-5-(7,7-dimethyl-7H-furo[3,2-f]chromen-2-yl)pyridine
(35). A round-bottomed flask (500 mL) was charged with com-
pound 33 (3.29 g, 10.3 mmol), trimethylorthoformate (6.00 mL,
54.8 mmol), ytterbium triflate hydrate (0.35 g, 0.57 mmol) and
dry dichloromethane (300 mL, dried over 4 Å molecular sieves).
After 30 min, the flask was cooled with an ice bath, and isobutyl-
ene (6.56 g, 117 mmol) was added to the solution. The flask was
sealed with a rubber septum, and then the cold bath was removed.
After 60 h, the mixture was filtered on a fritted funnel to recover
some unreacted starting material (0.35 g). The filtrate was washed
with sodium hydrogenocarbonate (200 mL, 1 M) and brine
(200 mL) and dried over magnesium sulfate. After concentration
to dryness, the residue was combined with dry toluene (40 mL)
and p-toluene sulfonic acid (0.12 g) in a round-bottomed flask
(250 mL), and heated at 115 °C for 1 h. After cooling, diethylether
(100 mL) was added, and the mixture was washed with sodium
hydrogenocarbonate (50 mL, 1 M) and brine (100 mL) and dried
over magnesium sulfate. After a concentration to dryness, the res-
idue was purified by a chromatography on silica gel (dichloro-
methane/ethanol from 100:0 to 98:2) to give, in order of elution,
compound 35 (1.09 g, 30% yield) as a colourless amorphous solid,
described below and more unreacted starting material (1.12 g).
Mp = 159–160 °C. HRMS (ES) calcd for C18H1579BrNO2: 356.0286,
found: 356.0286. 1H NMR (CDCl3): 1.48 (s, 6H), 5.73 (d, 1H,
J = 9.8), 6.60 (d, 1H, J = 9.8), 6.81 (d, 1H, J = 8.8), 7.08 (s, 1H), 7.24
(d, 1H, J = 8.8), 7.54 (d, 1H, J = 8.3), 7.91 (dd, 1H, J = 2.1, 8.3), 8.80
(d, 1H, J = 2.1). 13C NMR (CDCl3): 27.9, 76.4, 101.5, 111.2, 113.6,
115.1, 119.4, 125.8, 126.3, 128.5, 131.5, 134.4, 141.7, 146.7,
149.2, 150.7, 152.9.
N1-(5-(7,7-Dimethyl-7H-furo[3,2-f]chromen-2-yl)pyridin-2-yl)-
N3,N3-dimethylpropane-1,3-diamine (39). A round-bottomed
flask (5 mL) was charged with 35 (0.083 g, 0.233 mmol) and
N1,N1-dimethylpropane-1,3-diamine (1 mL, 8 mmol) and was
heated at 120 °C for 60 h. After cooling, the residue was purified
by a chromatography on a column of neutral alumina (1.2% wt/
wt water, eluting with a dichloromethane/2 N ammonia in ethanol
95:5 mixture) to give compound 39 (0.025 g, 28% yield) as a col-
ourless amorphous solid. Mp >240 °C (decomp.) HRMS (ES) calcd
for C23H28N3O2: 378.2182, found: 378.2167. 1H NMR (CDCl3):
1.47 (s, 6H), 1.84 (quintet, 2H, J = 6.6), 2.31 (s, 6H), 2.48 (t, 2H,
J = 6.6), 3.43 (m, 2H), 5.69 (d, 1H, J = 9.7), 5.69 (m br, 1H), 6.46 (d,
1H, J = 8.7), 6.62 (d, 1H, J = 9.7), 6.71 (d, 1H, J = 8.6), 6.80 (s, 1H),
7.21 (d, 1H, J = 8.6), 7.83 (dd, 1H, J = 2.3, 8.7), 8.59 (d, 1H, J = 2.3).
13C (CDCl3): 26.9, 27.9, 41.5, 45.7, 58.3, 76.2, 96.8, 107.0, 110.7,
112.97, 113.02, 116.4, 119.9, 126.7, 130.8, 134.3, 145.9, 148.8,
150.1, 156.2, 159.0.
2-(7,7-Dimethyl-8,9-dihydro-7H-furo[3,2-f]chromen-2-yl)pyri-
dine (36). A round-bottomed flask (25 mL) was charged with
compound 34 (0.10 g, 0.29 mmol), ammonium formate (0.18 g,
2.8 mmol), 10% palladium over charcoal (0.0336 g, 0.0316 mmol)
and ethanol (6 mL), and the mixture was refluxed for 4 h. Upon
cooling, the mixture was filtered on a plug of Celite on a fritted fun-
nel, and washed with dichloromethane (20 mL). The filtrate was
concentrated to dryness and the residue purified by a chromatog-
raphy on silica gel (ethylacetate/cyclohexane 1:3, UV monitoring at
280 nm) to give compound 36 (0.0422 g, 51% yield) as a colourless
amorphous solid. Mp = 116–117 °C. HRMS (ES) calcd for
3-(7,7-Dimethyl-7H-furo[3,2-f]chromen-1-yl)propyl
acetate
(40). Compound 24 (0.3 g, 1.16 mmol) was dissolved in acetic
acid (30 mL). Concentrated hydrochloric acid (1 mL) was added
and this was heated to reflux for 1 h. The solution was concentred
to dryness, and the residue was purified by a chromatography over
silica gel (ethylacetate/cyclohexane 1:6, UV monitoring at 280 nm)
to yield the compound 40 (0.32 g, 92%). Mp = 80 °C. LC/MS (ES) m/
z = 318 [M+NH4]+. 1H (CDCl3): 1.47 (s, 6H), 2.04 (m, 2H), 2.10 (s,
3H), 2.85 (s, 3H), 2.85 (m, 2H), 4.20 (t, 2H, J = 6.3), 5.71 (d, 1H,
J = 9.9), 6.70 (m, 2H), 7.20 (d, 1H, J = 8.7), 7.38 (s, 1H). 13C (CDCl3):
21.4, 22.3, 27.7, 28.7, 64.2, 75.7, 111.6, 114.3, 114.4, 119.5, 120.2,
123.7, 131.3, 142.9, 148.8, 151.4, 171.5.
C
18H18NO2: 280.1338, found: 280.1348. 1H (CDCl3): 1.39 (s, 6H),
1.90 (t, 2H, J = 6.8), 2.95 (t, 2H, J = 6.8), 6.82 (d, 1H, J = 8.8), 7.23
(m, 1H), 7.30 (d, 1H, J = 8.8), 7.43 (s, 1H), 7.77 (td, 1H, J = 1.7,
7.9), 7.89 (d, 1H, J = 7.9), 8.67 (d, 1H, J = 4.6). 13C (CDCl3): 20.4,
27.0, 32.7, 74.3, 103.7, 110.4, 113.0, 116.4, 120.0, 123.0, 128.7,
137.2, 149.8, 150.0, 150.1, 155.6 (one signal doubled).

8272
L. Alvey et al. / Bioorg. Med. Chem. 16 (2008) 8264–8272
2. 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.
3. Prado, S.; Toum, V.; Saint-Joanis, B.; Michel, S.; Koch, M.; Cole, S. T.; Tillequin,
F.; Janin, Y. L. Synthesis 2007, 1566.
4. Domschke, G. J. Prakt. Chem. 1966, 32, 144.
5. Iwai, I.; Ide, J. Chem. Pharm. Bull. 1963, 10, 926.
6. Iwai, I.; Ide, J. Chem. Pharm. Bull. 1963, 11, 1042.
7. Hlubucek, J.; Ritchie, E.; Taylor, W. C. Aust. J. Chem. 1971, 24, 2347.
8. Stradi, R.; Pocar, D.; Cassio, C. J. Chem. Soc., Perkin Trans. 1 1974, 2671.
9. Kedrowski, S. M. A.; Bower, K. S.; Dougherty, D. A. Org. Lett. 2007, 9,
3205.
10. Zhou, G.; Corey, E. J. J. Am. Chem. Soc. 2006, 127, 11958.
11. von Kuser, P.; Frauenfelder, E. F.; Eugster, C. H. Helv. Chim. Acta 1971, 54,
969.
12. Kraus, G. A.; Hoover, K.; Zhang, N. Tetrahedron Lett. 2002, 43, 5319.
13. Valderrama, J. A.; Pessoa-Mahana, D.; Tapia, R. A.; Rojas de Arias, A.;
Nakayama, H.; Torres, S.; Miret, J.; Ferreira, M. E. Tetrahedron 2001, 57,
8653.
3-(7,7-Dimethyl-7H-furo[3,2-f]chromen-1-yl)propan-1-ol(41).
Compound 40 (0.15 g, 0.5 mmol) was dissolved in a 1 N solution of
sodiummethanolateinmethanol (10 mL). Thiswas stirredat 0 °C for
1 h and neutralized with a saturated solution of ammonium chloride
and diluted in water. The aqueous phase was extracted with
dichloromethane, the organic phase was washed with water, dried
over sodium sulfate and concentrated to dryness to yield pure
compound 41 (0.09 g, 70%) as an oil. LC/MS (ES). HRMS (ES) calcd for
C
16H19O3: 259.1334, found: 259.1352. 1H (CDCl3): 1.47 (s, 6H), 2.00
(m, 2H), 2.88 (m, 2H), 3.80 (t, 2H, J = 6.2), 5.70 (d, 1H, J = 9.8), 6.78 (d,
1H, J = 8.7), 6.84 (d, 1H, J = 9.8), 7.20 (d, 1H, J = 8.7), 7.38 (s, 1H). 13
C
(CDCl3): 22.0, 27.7, 32.5, 62.6, 75.7, 111.5, 114.3, 114.4, 119.6, 120.7,
123.9, 131.2, 142.8, 148.8, 151.4.
14. Valderrama, J. A.; Benites, J.; Cortes, M.; Pessoa-Mahana, D.; Prina, E.; Fournet,
A. Tetrahedron 2002, 58, 881.
Acknowledgments
15. Prado, S.; Janin, Y. L.; Bost, P. E. J. Heterocycl. Chem. 2006, 43, 1605.
16. Noland, W. E.; Kedrowski, B. L. Org. Lett. 2000, 2, 2109.
17. Bruce, J. M.; Heatley, F.; Ryles, R. G.; Scrivens, J. H. J. Chem. Soc., Perkin Trans. 2
1980, 860.
18. Mahboobi, S.; Wiegrebe, W. Arch. Pharm. 1988, 321, 175.
19. Schmidt, A.; Mordhorst, T.; Fleischhauer, H.; Jeschke, G. ARKIVOC 2005,
150.
We thank Sanofi-Aventis as well as Pfizer for very generous
donations of scientific equipment. This work received the financial
support of the Institut Pasteur (GPH-5, DVPI) and the European
Community (LHSP-CT-2005-018923).
References
20. Palomino, J.-C.; Martin, A.; Camacho, M.; Guerra, H.; Swings, J.; Portaels, F.
Antimicrob. Agents Chemother. 2002, 46, 2720.
21. Noyori, R.; Yokoyama, K.; Hayakawa, Y. Org. Synth. Coll. 1988, VI, 520.
22. LaMattina, J. L. J. Heterocycl. Chem. 1983, 20, 533.
1. Prado, S.; Ledeit, H.; Michel, S.; Koch, M.; Darbord, J. C.; Cole, S. T.; Tillequin, F.;
Brodin, P. Bioorg. Med. Chem. 2006, 14, 5423.