A new entry to benzo[4,5]furo[3,2-b]pyridines via N-(benzofuran-3-yl) iminophosphorane

Article abstract of DOI:10.1055/s-0029-1218551

Mild thermal reaction of enones with N-(benzofuran-3yl)iminophosphorane, newly prepared by Staudinger reaction of 3azidobenzofuran with triphenylphosphine, provides a synthetic entry to virtually unknown benzo[4,5]furo[3,2-b]pyridines via a tandem aza-Wittig-electrocyclization process. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1218551

LETTER
77
A New Entry to Benzo[4,5]furo[3,2-b]pyridines via
N-(Benzofuran-3-yl)iminophosphorane
New
E
ntry to Benzo[4
a
,5]furo[3,2-
r
b
]pyridin
i
es a Funicello,*a Valeria Laboragine,a Rocco Pandolfo,a Piero Spagnolob
a
Dipartimento di Chimica, Università della Basilicata, Via N. Sauro 85, 85100 Potenza, Italy
Fax +39(0971)202223; E-mail: maria.funicello@unibas.it
b
Dipartimento di Chimica Organica ‘A. Mangini’, Università di Bologna, Viale Risorgimento 4, 40136 Bologna, Italy
E-mail: spagnolo@ms.fci.unibo.it
Received 3 October 2009
Dedicated to the memory of Professor Antonio Mario Tamburro.
ing phenyl azides with triphenylphosphine, have become
a powerful tool in synthetic methods for the construction
of nitrogen-containing heterocycles.8a
Abstract: Mild thermal reaction of enones with N-(benzofuran-3-
yl)iminophosphorane, newly prepared by Staudinger reaction of 3-
azidobenzofuran with triphenylphosphine, provides a synthetic en-
try to virtually unknown benzo[4,5]furo[3,2-b]pyridines via a tan-
dem aza-Wittig–electrocyclization process.
Ph3Bi(OAc)2
N
Cl
N
Cl
Cu(OPv)2
Key words: iminophosphoranes, azides, aza-Wittig, electrocy-
clization, benzofuropyridines
CH2Cl2
O
OH
1
2 (74%)
Pd(OAc)2, K2CO3
Bu4NCl, DMF, reflux
Small heterocyclic molecules play an important role in
modern pharmaceutical and medicinal chemistry.1 In par-
ticular, benzo[4,5]furopyridines, isosteric of both carbo-
lines and dibenzofuran, often display important biological
and pharmacological activities.2,3
N
O
3a (64%)
Scheme 1 Synthesis of parent benzo[4,5]furo[3,2-b]pyridine
Benzo[4,5]furo[c]pyridines and their tetrahydro deriva-
tives are long-known compounds available through vari-
ous reported methods.4 In contrast, the benzo-
[4,5]furo[b]pyridine congeners remain little known. In-
deed, only scant examples of benzo[4,5]furo[2,3-b]py-
ridines were present in the literature4b,5c,d until two very
recent papers described the preparation of a variety of
those tricyclic compounds through the unusual use of in
situ generated 2-aminobenzofuran as the crucial interme-
diate.5a,b,6
In particular, the aza-Wittig reaction of suitable imino-
phosphoranes with a,b-unsaturated carbonyl compounds,
followed by 6p-electrocyclization of the resultant aza-
hexatrienes, has found extensive application in the synthe-
sis of simple and c-fused pyridines8a–c,9 as well as, but to a
much lesser extent, of the b-fused ones.8d
Our long interest in the chemistry of nitrogen-containing
heteroaromatic systems recently led us to discover that
iminophosphoranes arising from 2-azido- and 3-azido-
benzothiophene are conveniently employed in the aza-
Wittig-electrocyclization strategy for the synthesis of
benzothieno[3,2-b]pyridines and benzothieno[2,3-b]py-
ridines.10 More recently, we also found that such a strate-
gy can successfully be extended to iminophosphoranes
prepared from 2-azido-1-methylindole for the construc-
tion of a variety of pyrido[2,3-b]indoles (a-carbolines).11
As for the possible benzo[4,5]furo[3,2-b]pyridine family,
surprisingly the parent compound 3a seems to represent
the only documented member. In fact, the parent benzofu-
ropyridine 3a was recently produced in fairly good yield
through ‘intramolecular Heck cyclization’ of chlorophe-
noxypyridine 2 achieved by not trivial phenylation of
commercially available chloropyridinol 1 with triphenyl-
bismuth(V) diacetate and Cu(II) pivaloate (Scheme 1).4b,7
Unfortunately, this interesting, though rather expensive,
organometallic method would be poorly practicable for
attaining desired substitution of the pyridine moiety ow-
ing to often (very) difficult access to 2-chloro-3-pyridinol
bearing further substituent(s) on the heteroaromatic ring.
In this paper we report our preliminary results from at-
tempted use of analogous methodology for the prepara-
tion of parent benzofuro[3,2-b]pyridine 3a and additional
mono- and disubstituted congeners 3b–f shown in
Scheme 4.
In the past thirty years iminophosphoranes, first prepared
at the beginning of the last century by Staudinger by react-
The appealing use of N-(benzofuranyl)iminophospho-
ranes in the synthesis of benzofuro[b]pyridines is unprec-
edented. Indeed, iminophosphoranes derived from 3-
azido- or 2-azido-benzofuran remain to date totally un-
known, despite the fact that straightforward methods af-
fording both azido precursors have long been
available.12,13 Particularly, 3-azidobenzofuran (4) was
SYNLETT 2010, No. 1, pp 0077–0080
x
x.
x
x.
2
0
0
9
Advanced online publication: 10.12.2009
DOI: 10.1055/s-0029-1218551; Art ID: G31109ST
© Georg Thieme Verlag Stuttgart · New York

78
M. Funicello et al.
LETTER
newly prepared in very good yield as early as 1978 After suitably prolonged reaction time (18–24 h) every
through a peculiar method entailing smooth addition of io- crude mixture was evaporated under reduced pressure and
dine azide to benzofuran, followed by treatment of result- then directly subjected to chromatographic purification.
ing cis/trans-2,3-diazido-2,3-dihydrobenzofuran adducts
with ethanolic potassium hydroxide.13
R2
Since (parent) 2- and 3-azides, including 2-azidobenzofu-
N
PhMe, 90 °C
ran,12 arising from electron-rich five-membered het-
+ R1CH=CHCOR2
5
18–24 h
6a–f
eroarenes are usually prepared by means of ‘azido-group
R1
O
transfer’ reaction of tosyl azide with the lithiated het-
eroarene,8d,14 at the outset of the present work we became
interested in proving that the azido-transfer method could
conceivably be applied to the additional synthesis of azide
4. It was actually found that standard lithiation of 3-bro-
mobenzofuran with BuLi at –70 °C, followed by usual
reaction with tosyl azide and final hydrolysis with aque-
ous sodium pyrophosphate, led to rewarding isolation of 4
in 66% yield after chromatographic purification on Flori-
sil column (Scheme 2). The obtained azide 4 was an oily
compound whose physical and IR and NMR spectral data
were consistent with those previously reported.13,15 In or-
der to avoid dangerous use of explosive iodine azide we
presently chose to adopt the azido-transfer method even
though the original protocol was found to afford a still bet-
ter yield of 4.
R2
N
– 2 H
R1
O
3a–f
a R1 = R2 = H
b R1 = Me, R2 = H
d R1 = H, R2 = Me
c R1 = Ph, R2 = H
e R1 = COOMe, R2 = Me f R1 = COOMe, R2 = 4-MeC6H4
Scheme 4 Synthesis of benzofuro[3,2-b]pyridines
Table 1 Benzofuropyridines 3a–f17 Prepared from Iminophospho-
rane 5 and Enones 6a–f
Entry
Enone 6
Yield of benzofuropyridine 3 (%)
N3
Br
1) BuLi (1.6 M), Et2O,
–70 °C,1 h
1
2
3
4
5
6
6a R1 = R2 = H
6b R1 = Me, R2 = H
6c R1 = Ph, R2 = H
6d R1 = H, R2 = Me
3a 34
3b 20
3c 21
3d 28
2) TsN3, –70 °C, 5 h
3) Na4P2O7⋅10H2O
O
O
4 (66%)
Scheme 2 Synthesis of 3-azidobenzofuran
6e R1 = COOMe, R2 = Me
3e 80
3f 85
Staudinger reaction of azide 4 with triphenylphosphine in
diethyl ether at 0 °C furnished an excellent yield of the de-
sired iminotriphenylphosphorane 5 which was isolated as
a stable, yellow, oily compound (Scheme 3).16
6f R1 = COOMe,R2 = 4-MeC6H4
As can be seen from Table 1 (entries 1–3) and Scheme 4,
with the aldehydes 6a–c iminophosphorane 5 actually fur-
nished the corresponding unsubstituted benzofuropyri-
dine 3a as well as the 4-Me- and 4-Ph-substituted ones
3b,c but only in modest, though still practicable, yields
(20–34%). These rather disappointing findings were
somewhat unexpected since previous reactions of our
benzothienyl and indolyl iminophosphoranes with the
same aldehydes were generally found to afford markedly
better yields of b-fused pyridine products.10,11 However,
with the 4-oxo-2-pentenoate 6e and 4-oxo-2-butenoate 6f
very good yields of the desired 2,4-disubstituted pyridines
3e–f could be fortunately achieved (Table 1, entries 5, 6,
and Scheme 4). Such observations strictly supported orig-
inal chemical evidence that tandem aza-Wittig electro-
cyclization reactions of heteroaryl iminophosphoranes are
significantly encouraged by the use of enones bearing
electron-withdrawing methoxycarbonyl substituent on the
b-ethylenic carbon.10,11 Interestingly, simple but-2-enone
6d also gave a useful yield of the respective 2-methyl-
pyridine 3d (Table 1, entry 4, and Scheme 4). This fact is
noteworthy in light of the relative inertness previously
N3
N=PPh3
Ph3P
Et2O, 0 °C, 3 h
O
O
4
5 (95%)
Scheme 3 Synthesis of (benzofuran-3-yl)iminotriphenylphospho-
rane
The new iminophosphorane 5 was then reacted in toluene
solution at 90 °C with equimolar amounts of various a,b-
unsaturated aldehydes and ketones, including acrylalde-
hyde (6a), trans-crotonaldehyde (6b), trans-cinnamalde-
hyde (6c), but-2-enone (6d), methyl trans-4-oxo-2-
pentenoate (6e), and methyl trans-4-(4-methylphenyl)-4-
oxo-2-butenoate (6f). The enones 6a–e were commercial
compounds, whereas the oxobutenoate 6f was produced
by conventional esterification of the commercially avail-
able acid (Scheme 4).
Synlett 2010, No. 1, 77–80 © Thieme Stuttgart · New York

LETTER
New Entry to Benzo[4,5]furo[3,2-b]pyridines
79
Clarke, K.; Dumadag, L.; Younger, J.; Ivy, P.; Winer, E. P.
Invest. New Drugs 2007, 25, 161. (c) Brachwitz, K.;
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(f) Klioze, S. S. EP 100046 A1, 1984; Chem. Abstr. 1984,
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(5) (a) Iaroshenko, V. O.; Wang, Y.; Zhang, B.; Volochnyuk,
D.; Sosnovskikh, V. Y. Synthesis 2009, 2393.
displayed by that ketone with both 2- and 3-(benzothie-
nyl)iminotriphenylphosphoranes.10a,b
It is worth noting that with the enones 6b–f the outcoming
benzofuropyridines 3b–f were always produced as single
regioisomeric compounds.10a Evidently, the iminophos-
phorane 5 could initially form formal aza-Wittig aza-
hexa-1,3,5-triene intermediates. These intermediates then
underwent thermal electrocyclization eventually leading
to the isolated pyridines 3 after further dehydrogenation of
the cyclized dihydropyridines (Scheme 4). In this respect,
the (benzofuran-3-yl)iminotriphenylphosphorane (5) was
consistent with the benzothienyl and indolyl counterparts
which similarly furnished only aza-Wittig electrocycliza-
tion pyridines in their reactions with enones.10a,11,18
However, the rather peculiar outcome of the iminophos-
phorane 5 reactions with aldehydes 6a–c remains unclear
at this stage. It is possible that in such cases ensuing
hexatriene intermediates were notably prevented from un-
dergoing usual electrocyclization reaction owing to spe-
cial occurrence of inappropriate geometrical isomers.
(b) Iaroshenko, V. O.; Groth, U.; Kryvokhyzha, N. V.;
Obeid, S.; Tolmachev, A. A.; Wesh, T. Synlett 2008, 343.
(c) Degl’Innocenti, A.; Funicello, M.; Scafato, P.; Spagnolo,
P. Tetrahedron Lett. 1997, 38, 2171. (d) Stolle, W. A. W.;
Marcelis, A. T. M.; Koetsier, A.; van der Plas, H. C.
Tetrahedron 1989, 45, 6511.
In conclusion, we have shown that the fairly mild thermal
reaction of simple enones with N-(benzofuran-3-yl)im-
inotriphenylphosphorane (5) can offer a synthetic entry to
virtually unknown benzo[4,5]furo[3,2-b]pyridines, which
should be especially rewarding when using enones ‘acti-
vated’ by a suitable carbonyl substituent attached to the b-
ethylenic carbon.
(6) The 2- and 3-amines derived from electron-rich, five-
membered heteroaromatic compounds usually are highly
unstable compounds, unless electron-withdrawing
substituents are present, and therefore find uncommon
use in synthetic annulation processes.
(7) Tricycle 3a was originally reported in low yield via a
troublesome six-step sequence from an N-(aryloxy)-
pyridinium salt, see: Abramovitch, R. A.; Inbasekaran,
M. N.; Kato, S.; Radzikowska, T. A.; Tomask, P. J. Org.
Chem. 1983, 48, 690.
(8) For leading reviews on the chemistry of iminophosphoranes
and their use in aza-Wittig electrocyclization reactions, see:
(a) Wamhoff, H.; Richard, G.; Stolben, S. Adv. Heterocycl.
Chem. 1995, 64, 159. (b) Molina, P.; Vilaplana, M. J.
Synthesis 1994, 1197. (c) Fresneda, P.; Molina, P. Synlett
2004, 1. (d) Funicello, M.; Spagnolo, P. In Targets in
Heterocyclic Systems, Vol. 8; Attanasi, O. A.; Spinelli, D.,
Eds.; Società Chimica Italiana: Roma, 2004, 274.
(9) Selected examples: (a) Molina, P.; Pastor, A.; Vilaplana,
M. J. J. Org. Chem. 1996, 61, 8094. (b) Kobayashi, T.;
Nitta, M. Chem. Lett. 1981, 1459. (c) Iino, Y.; Nitta, M.
Bull. Chem. Soc. Jpn. 1988, 61, 2235. (d) Molina, P.;
Pastor, A.; Vilaplana, M. J. Tetrahedron Lett. 1993, 34,
3773. (e) Molina, P.; Pastor, A.; Vilaplana, M. J.; Foces-
Foces, C. Tetrahedron 1995, 51, 1265.
Even though pyridine products should predictably arise to
an extent highly dependent upon structural and electronic
features of the starting enones, the present protocol could,
however, find wide synthetic interest owing to prompt
availability of iminophosphorane and enone precursors,
fair flexibility for substituent introduction, and very sim-
ple practical use.
Studies are in progress to fully discover the actual syn-
thetic potential of our protocol through the use of other
(benzofuran-3-yl)iminophosphoranes P-phenyl/methyl-
substituted.19
Acknowledgment
The authors gratefully acknowledge financial support from the Uni-
versity of Basilicata.
(10) (a) Degl’Innocenti, A.; Funicello, M.; Scafato, P.; Spagnolo,
P.; Zanirato, P. J. Chem. Soc., Perkin Trans. 1 1996, 2561.
(b) Bonini, C.; Chiummiento, L.; Funicello, M.; Spagnolo,
P. Tetrahedron 2000, 56, 1517. (c) Bonini, C.; D’Auria, M.;
Funicello, M.; Romaniello, G. Tetrahedron 2002, 58, 3507.
(d) Bonini, C.; Funicello, M.; Scialpi, R.; Spagnolo, P.
Tetrahedron 2003, 59, 7515.
(11) Bonini, C.; Funicello, M.; Spagnolo, P. Synlett 2006, 1574.
(12) Foresti, E.; Spagnolo, P.; Zanirato, P. J. Chem. Soc., Perkin
Trans. 1 1989, 1354.
(13) Tamura, Y.; Chun, M. W.; Kwon, S.; Bayomi, S. M.; Okada,
T.; Ikeda, M. Chem. Pharm. Bull. 1978, 26, 3515.
(14) (a) Unlike aryl azides, the (electron-rich) five-membered
heteroaryl counterparts are usually hardly available from
corresponding amines via diazonium salts. (b) For the first
report of azido-group-transfer reaction with thiophenes and
References and Notes
(1) (a) Kovtunenko, V. O. In Drug Methods Acting on the
Central Nervous System; Perun: Kiev, 1997, 373.
(b) Silvermann, R. B. In The Organic Chemistry of Drug
Design and Drug Action, 2nd ed; Elsevier Academic Press:
New York, 2004, 617.
(2) Wakelin, L. P. G.; Waring, M. J. In Comprehensive
Medicinal Chemistry; Sammes, P. G., Ed.; Pergamon Press:
Oxford, 1990, 703.
(3) (a) Venkat, R. G.; Qi, L.; Pierce, M.; Robbins, P. B.;
Sahasrabudhe, S. R.; Selliah, R. WO 2007076085, 2007;
Chem. Abstr. 2007, 147, 143456. (b) Burstein, H. J.;
Overmoyer, B.; Gelman, R.; Silverman, P.; Savoie, J.;
Synlett 2010, No. 1, 77–80 © Thieme Stuttgart · New York

80
M. Funicello et al.
LETTER
benzothiophenes, see: Spagnolo, P.; Zanirato, P. J. Org.
Chem. 1978, 43, 3539. (c) For original general information
on the synthesis of five-membered heteroaromatic azides,
see: Funicello, M.; Spagnolo, P.; Zanirato, P. Acta Chem.
Scand. 1993, 47, 231.
NMR (125 MHz, CDCl3): d = 132.78, 132.71, 132.59,
132.51, 131.99, 131.75, 128.77, 128.67, 128.53, 128.44,
123.57, 121.18, 120.05, 119.84, 110.88, 110.67.
(17) Synthesis of Benzofuropyridines 3a–f: Typical
Procedure
(15) Synthesis of 3-Azidobenzofuran (4) via Azido-Group-
A mixture of iminotriphenylphosphorane 5 (1 mmol) and
methyl trans-4-oxo-2-pentenoate (6e, 1 mmol) in dry
toluene (5 mL) was stirred at 90 °C for ca. 20 h under a
stream of nitrogen. After cooling, the solvent was removed
in vacuo, and the resultant crude was purified on a silica gel
column by progressive elution with PE–EtOAc mixtures to
give the benzofuropyridine 3e in 80% yield as a dark-yellow
thick oil. 1H NMR (500 MHz, CDCl3): d = 8.27 (d, J = 7.0
Hz, 1 H), 7.76 (s, 1 H), 7.72 (d, J = 8.0 Hz, 1 H), 7.62 (t,
J = 7.0 Hz, 1 H), 7.47 (t, J = 8.0 Hz, 1 H), 4.10 (s, 3 H), 2.81
(s, 3 H). 13C NMR (125 MHz, CDCl3): d = 165.7, 164.3,
156.2, 153.6, 133.5, 130.2, 126.2, 124.2, 121.7, 118.6,
114.1, 113.2, 52.7, 29.7. MS (EI): m/z = 241 [M]. The parent
benzofuropyridine 3a had spectral data consistent with those
previously reported.4b The hitherto unknown benzofuro-
pyridines 3b–d,f were identified on the basis of 1H NMR,
13C NMR, and MS spectral data.
Transfer Reaction
To a solution of 3-bromobenzofuran (1.07 mmol) in dry
Et2O (6 mL) n-BuLi (1.6 M in hexane, 1.07 mmol) was
added at –70 °C under a stream of nitrogen. After 1 h, tosyl
azide (1.07 mmol in 4 mL of dry Et2O) was added dropwise,
and the mixture was stirred for 5 h at –70 °C. The resulting
yellow mixture was slowly led to r.t. and then treated with an
aq solution of sodium pyrophosphate (5 mL, 1.07 mmol).
After stirring for 30 min, the eventual reaction mixture was
extracted with Et2O and then with EtOAc; the collected
organic layers were dried over Na2SO4 and finally evapo-
rated in vacuo. Column chromatography of the crude on a
Florisil column using PE as eluant isolated the title azide
(0.71 mmol, 66%) as yellow thick oil. Physical and IR and
NMR spectral data were fully consistent with those
originally reported.
(16) Synthesis of Triphenyliminophosphorane 5
3-Azidobenzofuran (4, 1 mmol) in dry Et2O (3 mL) was
slowly added to a solution of Ph3P (1 mmol) in dry Et2O (3
mL) at 0 °C under a stream of nitrogen. The mixture was
stirred at 0 °C for 3 h and then at r.t. for an additional 1 h.
Removal of the solvent in vacuo afforded the title imino-
phosphorane as yellow thick oil in 95% yield. 1H NMR (500
MHz, CDCl3): d = 7.23–7.70 (m, 16 H), 7.20 (t, J = 10.5 Hz,
(18) Reactions of enones with (benzothien-3-yl)iminophos-
phoranes bearing methyl substituent(s) on phosphorus were
shown to form b-fused pyridines due to aza-Wittig
electrocyclization along with those due to opposite
regiochemistry, see ref. 10b,c.
(19) Replacement of phenyl with electron-donating methyl
group(s) on phosphorus could enhance the reactivity of
previous (benzothien-2-yl)- and, especially, (benzothien-3-
yl)imino-phosphoranes with enones, see ref. 10b,c.
2 H), 7.03 (d, J = 9.0 Hz, 1 H), 6.94 (d, J = 8.0 Hz, 1 H). 13
C
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