Pd/C mediated synthesis of 2-substituted benzo[b]furans/nitrobenzo[b] furans in water

Article abstract of DOI:10.1016/j.tetlet.2003.09.080

An efficient synthesis of 2-alkyl/aryl substituted benzo[b]furans/nitrobenzo[b]furans in water has been accomplished via Pd/C catalyzed reaction of o-iodophenols with terminal alkynes in the presence of PPh₃, CuI and prolinol. This method can t

Full text of DOI:10.1016/j.tetlet.2003.09.080

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8221–8225
Pd/C mediated synthesis of 2-substituted
benzo[b]furans/nitrobenzo[b]furans in waterꢀ
Manojit Pal,* Venkataraman Subramanian and Koteswar Rao Yeleswarapu*
Chemistry-Discovery Research, Dr. Reddy’s Laboratories Ltd., Bollaram Road, Miyapur, Hyderabad 500050, India
Received 6 August 2003; revised 3 September 2003; accepted 11 September 2003
Abstract—An efficient synthesis of 2-alkyl/aryl substituted benzo[b]furans/nitrobenzo[b]furans in water has been accomplished via
Pd/C catalyzed reaction of o-iodophenols with terminal alkynes in the presence of PPh3, CuI and prolinol. This method can
tolerate a variety of functional groups present in the alkynes as well as base labile nitro group in the o-iodophenols. The protocol
does not require the use of a phase transfer catalyst or water-soluble phosphine ligands and is free from the use of any organic
co-solvent.
© 2003 Elsevier Ltd. All rights reserved.
Benzo[b]furans are of considerable interest due to their
occurrence in nature as well as their biological activi-
ties,1,2 especially as anti-tumor agents,3a as calcium
entry blockers3b or as potent inhibitors of protein
tyrosine phosphatase 1B3c for the treatment of type 2
diabetes. They are also known to be useful inhibitors of
5-lipoxygenase (5-LO)4a and cyclooxygenase-2 (COX-
2)4b for the treatment of inflammation and pain.
Nitrobenzofurans also display interesting pharmacolog-
ical properties.4c–d
In most of these cases the synthesis of the benzo-
[b]furans is accomplished through a tandem Sono-
gashira coupling/5-endo-dig cyclization starting from
either o-alkynylphenols or o-iodophenols. Typically
these reactions are carried out using a palladium cata-
lyst and a copper salt10 as co-catalyst in the presence of
an amine base in an organic solvent. These one-pot
palladium mediated protocols have advantages over the
multi-step traditional methods in terms of functional
group tolerability and yields. However, this single step
coupling-cyclization was found to be less efficient when
the starting o-iodophenols contain additional
substitutents11 especially base-labile nitro groups.11a In
a few cases, formation of 1,3-diynes was observed to
predominate over the normal coupling product.11d
In continuation of our research in a new drug discovery
program, we have recently reported the synthesis of
3,4-diarylfuranones,5 3,4-diarylmaleic anhydrides,6a 1,5-
diarylpyrazoles6b along with other heterocycles.6c–d In
further pursuance of our research on the development
of general methods for the synthesis of various oxygen
containing heterocycles we became interested in the
synthesis of benzofurans.7 Various methods are known
for the synthesis of benzo[b]furan and its derivatives of
which the intramolecular cyclization of a suitably sub-
stituted benzene is the most commonly employed.1,8
However, benzo[b]furans are the focus of many recent
reports on transition metal-mediated heteroannulation
especially alkyne-based palladium catalyzed reactions.9
Palladium catalyzed reactions in aqueous media have
attracted much attention12 recently because water based
synthetic processes are inherently safer as well as inex-
pensive. Therefore, the use of water-soluble catalysts12g
and water-soluble phosphine ligands, e.g. sulfonated
phosphines12f have been explored successfully. The use
of Pd/C-CuI-PPh3 as catalyst system for efficient Sono-
gashira coupling of aryl halides with terminal alkynes
has also been reported.12e When compared to the most
frequently used expensive palladium catalysts [e.g.
Pd(PPh3)4, (PPh3)2PdCl2 etc.], Pd/C-based methods
have an economic advantage and hence remain attrac-
tive in large or industrial scale preparations. Neverthe-
less, all these Pd-catalyzed reactions are usually carried
out in an aqueous-organic media and a co-solvent such
as acetonitrile12f or DME12e is often required for these
coupling reactions.
Keywords: benzo[b]furans; Sonogashira coupling/5-endo-dig cycliza-
tion; palladium catalyst; water.
ꢀ DRL publication number 319.
* Corresponding authors. Fax: 91-40-23045438/23045007; e-mail:
manojitpal@drreddys.com; koteswarraoy@drreddys.com
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.09.080

8222
M. Pal et al. / Tetrahedron Letters 44 (2003) 8221–8225
While the use of prolinol in the transition metal cata-
lyzed Michael reaction in organic/aqueous media has
been investigated,13 its use in palladium catalyzed reac-
tions is not common. Our continuing interest in palla-
dium catalyzed reactions14 prompted us to develop a
mild and efficient method for the synthesis of 2-substi-
tutedbenzo[b]furans via Pd/C catalyzed C–C bond for-
mation reaction in water9r in the presence of prolinol.
nitrobenzo[b]furans (previous synthesis of which often
required a separation of regio-isomers or multi-step
procedures)16 were prepared in aqueous media. Thus,
when o-iodophenol I17a,b was treated with 2–3 equiva-
lents of terminal alkyne (II, R=alkyl, hydroxyalkyl
etc.)17c in water in the presence of 10% Pd/C (0.03
equiv.), PPh3 (0.12 equiv.), CuI (0.06 equiv.) and (S)-
prolinol (3 equiv.) under nitrogen, benzofurans III were
obtained as desired products.17d The results are summa-
rized in Table 2.
Very recently we have developed an efficient method
for the Sonogashira coupling of 3-iodoflavone with
terminal alkynes in aqueous–dimethylformamide (H2O–
DMF) using prolinol as a base.14e To extend the scope
and generality of this protocol we examined the reac-
tion of o-iodophenol Ia with 2-methyl-3-butyn-2-ol IIa
under various reaction conditions in the presence of
(S)-prolinol (Table 1) in water. As can be seen, the
o-ethynyl phenol derivative9b,h IIIaa was isolated as the
major product15 when the reaction was carried out in
the presence of a Pd(0) complex and CuI for 3 h at
25°C (entry 1, Table 1). The cyclized product IIIa was
isolated when the reaction temperature was increased to
80°C (entry 2, Table 1). The best result for the synthesis
of IIIa, however, was achieved by using 10% Pd/C,
PPh3 along with CuI as a catalyst system (entry 5,
Table 1) in a ratio of 1:4:2. Any change in this ratio
resulted in inferior yields. Interestingly, unlike Pd(0)
compounds the Pd/C mediated method required a
higher temperature to afford IIIaa (entry 1 versus 4,
Table 1) and no reaction was observed at 25°C (entry 3,
Table 1). This clearly indicates that a new Pd(0) species
generated in situ from Pd/C–PPh3 at higher tempera-
ture is responsible for the coupling reactions.
While the yields were not optimized, the heteroannula-
tion of acetylenic compounds in a single synthetic oper-
ation afforded the desired benzofurans III in good to
excellent yields. By the use of this palladium catalyzed
reaction a variety of terminal acetylenes were reacted
with o-iodophenol (Table 2). Various substituents
(including alkyl, hydroxyl, phenyl etc.) present in
acetylenic compounds II were well tolerated during the
course of the reaction and yields were generally high
irrespective of the nature of the substituents present in
the acetylenic component (entries 1–6, Table 2). Yields
were also found to be good irrespective of the presence
of nitro group in the starting o-iodophenol (Table 2
versus Table 3). This is in sharp contrast to an earlier
report where the synthesis of nitrobenzofurans via a
single step coupling-cyclization method using
(PPh3)2PdCl2–CuI as catalyst system afforded only low
Table 2. Pd/C catalyzed synthesis of 2-substituted benzo-
[b]furans in aqueous mediaa
Using the optimized protocol as detailed above (entry
5, Table 1), several 2-substituted benzo[b]furans and
Table 1. Effect of base on the palladium catalyzed coup-
ling reaction of o-iodophenol with 2-methyl-3-butyn-2-ol
in aqueous mediaa
Entry
Pd-catalyst
Temp.(°C);
Yield (%)c
time (h)
IIIaab
IIIab
1
2
Pd(PPh3)4
Pd(PPh3)4
10% Pd/C-PPh3
10% Pd/C-PPh3
10% Pd/C-PPh3
25; 3
80; 3
25; 18
50; 18
80; 3
50
21
70
n.d.
17
85
n.d.
n.d.
46
3d
4d
5d
n.d.
a Reaction conditions: Ia (1.0 equiv), II (3.0 equiv), Pd-catalyst (0.05
equiv), CuI (0.10 equiv), (S)-prolinol (3 equiv) in water under N2.
b Identified by 1H NMR, 13C NMR, IR, MS.
c Isolated yields.
d The reaction was carried out using 1:4:2 ratio of Pd/C:PPh3:CuI.
n.d.=not detected.

M. Pal et al. / Tetrahedron Letters 44 (2003) 8221–8225
8223
Table 3. Pd/C catalyzed synthesis of 2-substituted
Table 4. Pd/C catalyzed synthesis of 2-substituted-7-
alkynylbenzo[b]furans in aqueous mediaa
nitrobenzo[b]furans in aqueous mediaa
amine bases18b–c especially in the large-scale
preparation.
to moderate yields of the desired products.11a Further-
more we successfully coupled terminal alkynes with
4-nitro-2,6-diiodophenol to give the expected 7-alkynyl
benzofurans as the only products in good yields (Table
4).
Mechanistically, the reaction may proceed9h via in situ
generation of a prolinol-stabilized Pd(0)-complex which
perhaps facilitates the reaction in aqueous media due to
its interaction with the water molecules (via the
hydroxyl group of prolinol). Further study is in pro-
gress to confirm the nature of the actual catalytic
species involved in this coupling reaction.
The coupling reactions were usually carried out using
10%Pd/C–PPh3 as catalyst and CuI as a co-catalyst in
water. Apart from the low cost and stability, the use of
Pd/C has advantages of ease of use and facilitation of
reaction mixture work-up. It is noteworthy that the use
of an organic co-solvent12c is not required in the present
case and this eliminates recyclability (waste handling)
problems. Moreover, neither a phase transfer catalyst18a
nor water soluble phosphine ligands12b,f are required for
the successful single step coupling–cyclization reaction.
In summary, we have described the first palladium on
carbon mediated synthesis of 2-alkyl/aryl substituted
benzo[b]furans/nitrobenzo[b]furans in water in the pres-
ence of prolinol. Since the water based syntheses are
safer and inexpensive, the described methodology holds
promise in modern organic synthesis. Some of the
benzofurans synthesized were converted to compounds
of potential biological interest.19
While prolinol was used as a base in the present cases,
the use of triethylamine was also investigated. Prolinol
possesses better miscibility with water and therefore
facilitated the coupling reaction affording better yields
of products. Moreover, due to its lower volatility
(thereby avoiding internal pressure development as well
as ensuring its maximum recovery) in comparison to
triethylamine, prolinol has advantages over the other
Acknowledgements
The authors thank Dr. A. Venkateswarlu, Dr. R. Rajago-
palan and Professor J. Iqbal for their encouragement and
the analytical group for spectroscopic support.

8224
M. Pal et al. / Tetrahedron Letters 44 (2003) 8221–8225
Lett. 1998, 39, 5101–5104; (l) Lu¨tjens, H.; Scammells, P.
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M. Pal et al. / Tetrahedron Letters 44 (2003) 8221–8225
8225
13.39 min. Elemental analysis found C, 59.49; H, 5.05;
C11H11NO4 requires C, 59.73; H, 5.01%.
IVb: light brown solid; yield 75%; mp 56–58°C; H NMR
(200 MHz, CDCl3) 8.42 (d, J=2.1 Hz, 1H), 8.17 (dd,
J=9.1, 2.1 Hz, 1H), 7.50 (d, J=9.1 Hz, 1H), 6.67 (s, 1H),
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Chem. 1990, 33, 749–754. For alternative access to
nitrobenzo[b]furans via intramolecular condensation of
suitably substituted nitrobenzenes, including intramolecu-
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Guitto, A. Synthesis 1998, 309–313; (c) Kaminsky, D.;
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1
4.04 (t, J=6.2 Hz, 2H, CH6 2OH), 3.09 (t, J=6.2 Hz, 2H,
CH2), 1.65 (bs, D2O exchangeable, OH); IR (neat, cm−1
)
3115.0 (bs, OH), 1511.1; m/z (CI) 208 (M+1, 100); 13C
NMR (CDCl3, 50 MHz) 159.9, 157.5, 143.8, 129.1, 119.3,
116.7, 110.9, 104.2, 59.9 (C6 H2OH), 31.8 (CH2); UV
(MeOH, nm) 286.5, 244; HPLC: 99%. INERTSIL ODS
3V, 0.01M KH2PO4/CH3CN, 1mL/min, 243 nm, reten-
tion time 11.86 min. Elemental analysis found C, 57.88;
H, 4.40; C10H9NO4 requires C, 57.97; H, 4.38%.
17. o-Iodophenols were prepared according to the known
procedure, see: (a) Kometani, T.; Watt, D. S.; Ji, T.
Tetrahedron Lett. 1985, 26, 2043–2046; (b) Edgar, K. J.;
Falling, S. N. J. Org. Chem. 1990, 55, 5287–5291; (c) All
the terminal alkynes used are commercially available. (d)
General procedure for the preparation of 2-substituted
benzo[b]furans (III, IV, V): A mixture of I (1 mmol), 10%
Pd/C (32 mg, 0.03 mmol), PPh3 (32 mg, 0.12 mmol), CuI
(12 mg, 0.06 mmol) and (S)-prolinol (3.0 mmol) in H2O
(3 mL) was stirred at 25°C for 1 h under nitrogen. The
acetylenic compound II (2–3 mmol) was added slowly to
the mixture with stirring. The reaction mixture was then
stirred at 80°C for 3 h. The mixture was cooled to room
temperature, diluted with EtOAc (100 mL) and filtered
through celite. The filtrate was collected, washed with
cold water (2×50 mL), dried over Na2SO4, filtered and
concentrated under vacuum. The residue thus obtained
was purified by column chromatography (petroleum
ether-EtOAc) to afford the desired product.
Va: light yellow solid; yield 75%; DSC: 137.80°C; 1H
NMR (200 MHz, CDCl3) 8.38 (d, J=1.9 Hz, 1H), 8.24
(d, J=1.9 Hz), 6.74 (s, 1H), 2.30 (bs, D2O exchangeable,
OH), 1.72 (s, 6H, 2CH3), 1.70 (s, 6H, 2CH3); IR (neat,
cm−1) 3353.6 (bs, OH), 1531.3; m/z (CI) 304 (M+1, 80),
286 (M+–OH, 100); 13C NMR (CDCl3, 50 MHz) 166.9,
157.0, 143.8, 128.6, 128.4, 123.0, 117.2, 107.8, 101.5, 74.7,
69.3 (C6 (OH)Me2), 65.7 (C6 (OH)Me2), 31.3 (2C, Me), 28.7
(2C, Me); UV (MeOH, nm) 260.5, 226.5, 221.5; HPLC:
99%, INERTSIL ODS 3V, 0.01M KH2PO4/CH3CN, 1
mL/min, 260 nm, retention time=13.54 min. Elemental
analysis found C, 63.38; H, 5.55; C16H17NO5 requires C,
63.36; H, 5.65%.
18. (a) Carpita, A.; Lessi, A.; Rossi, R. Synthesis 1984,
571–572. Use of other amine bases e.g. DBU, DBACO,
DBN etc. in Sonogashira-type reactions has been previ-
ously reported: (b) Bodwell, G. J.; Miller, D. O.; Vermeij,
R. J. Org. Lett. 2001, 3, 2093–2096. (c) Mio, M. J.;
Kopel, L. C.; Braun, J. B.; Gadzikwa, T. L.; Hull, K. L.;
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Lett. 2002, 4, 3199–3202.
19. Compound IIIb has been converted to a benzofuro[3,2-
c]pyridine as a potential antidepressant. See: Kennis, L.
E. J.; Bischoff, F. P.; Mertens, C. J.; Love, C. J.; Van den
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Spectral and analytical data for IVa: yellow solid; yield
1
79%; mp 60–62°C; H NMR (200 MHz, CDCl3) 8.46 (d,
J=1.9 Hz, 1H), 8.20 (dd, J=8.9, 2.0 Hz, 1H), 7.53 (d,
J=8.9 Hz, 1H), 6.73 (s, 1H), 2.18 (bs, D2O exchangeable,
OH), 1.70 (s, 6H, 2CH3); 13C NMR (CDCl3, 50 MHz)
166.7, 157.5, 144.1, 128.7, 119.9, 117.4, 111.4, 101.2, 69.3
(C6
(OH)Me2), 28.7 (2C, CH3); IR (neat, cm−1) 3394.4 (bs,
OH), 1522.7; m/z (CI) 222 (M+1, 100); UV (MeOH, nm)
285, 243.5; HPLC: 99%, INERTSIL ODS 3V, 0.01M
KH2PO4/CH3CN, 1 mL/min, 243 nm, retention time