A novel one-pot three-component synthesis of 3-halofurans and sequential Suzuki coupling

Article abstract of DOI:10.1039/b502324f

A novel sequence of Sonogashira coupling and electrophilic addition to an ynone, with concomitant deprotection and cyclocondensation, opens a new one-pot synthesis of 3-halofurans; the method can be readily elaborated to a new sequential Sonogashira-addit

Full text of DOI:10.1039/b502324f

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
A novel one-pot three-component synthesis of 3-halofurans and
sequential Suzuki coupling{
Alexei S. Karpov, Eugen Merkul, Thomas Oeser and Thomas J. J. M u¨ ller*
Received (in Cambridge, UK) 16th February 2005, Accepted 21st March 2005
First published as an Advance Article on the web 6th April 2005
DOI: 10.1039/b502324f
A novel sequence of Sonogashira coupling and electrophilic
addition to an ynone, with concomitant deprotection and
According to these optimal conditions, with the extension to
using sodium iodide as a halide source, various acid chlorides 1
and tetrahydropyranyl propargyl ethers 2 can be successfully
transformed into 3-halofurans 3 in a one-pot coupling–addition–
cyclocondensation, opens
a new one-pot synthesis of
3-halofurans; the method can be readily elaborated to a new
14
cyclocondensation sequence (Scheme 2, Table 1).
sequential
Sonogashira–addition–cyclocondensation–Suzuki
The structure of the 3-halofurans 3 is unambiguously supported
by an X-ray structure analysis for 3i (Fig. 1).{
reaction to furnish 2,3,5-trisubstituted furans in a one-pot
fashion.
Methodologically, this new one-pot three-component synthesis
of 3-halofurans proceeds efficiently under mild conditions with a
wide variety of electronically diverse acid chlorides. Applying NaI
as a halide source leads to even milder reaction conditions and
shorter reaction times, now giving extremely valuable 3-iodofur-
ans. Therefore, due to the acid sensitivity of iodofurans, this
methodology has significant advantages over existing protocols
using HI as an acid.
Furans are ubiquitous structural units in numerous natural
1
products, in pharmaceuticals, and even in photonic chromo-
2
3
4
phores. Among various syntheses of furans, the two major
5
approaches are either based upon the construction of the furan
6
ring starting from acyclic precursors or substitution reactions on
the furan core. In particular, by regiospecific substitutions,
halofurans are ideal starting materials, either as electrophiles in
7
cross-coupling reactions or, via halogen–metal exchange, as
Finally, as a showcase for the highly topical field of sequential
15
catalysis we probed a sequential Sonogashira–addition–cyclo-
8
nucleophiles for subsequent electrophilic trapping. However,
efficient and concise syntheses of 3-substituted halofurans are still
condensation–Suzuki reaction where the same catalyst system
should be applied for two consecutive, significantly different, cross-
coupling reactions in the same reaction vessel. Therefore, upon
consecutive reactions of acid chlorides 1 and tetrahydropyranyl
propargyl ethers 2, NaI and PTSA, and addition of 1.05 equiv. of
9,10
a methodological challenge. As part of our program directed to
develop new one-pot multi-component heterocycle syntheses
1
1
initiated by transition metal catalyzed alkyne coupling, here,
we communicate a novel one-pot three-component synthesis of
3
-halofurans and sequential cross-coupling, still in a one-pot
fashion.
Recently, we have developed a modification of the Sonogashira
coupling of acid chlorides and terminal alkynes to give
11
alkynones, where only one stoichiometric equivalent of triethyl-
amine, necessary as hydrochloric acid scavenging base, is applied.
Therefore, the reaction medium becomes essentially base free, now
setting the stage for acid catalyzed consecutive steps. Ynones
possess an enormous potential as key intermediates in heterocycle
1
2
synthesis. Hence, we reacted benzoyl chloride (1a) and the
tetrahydropyranyl propargyl ether (2a) under modified
Sonogashira conditions, followed by the addition of NaCl and
p-tolylsulfonic acid (PTSA) in methanol, to give, through the
1
3
Scheme 1 Coupling–addition–cyclocondensation sequence to 4-chloro-
furan 3a.
intermediacy of an c-hydroxy alkynone, 4-chloro-2-phenylfuran
3a) in 63% yield (Scheme 1).
(
This novel sequence can be rationalized as a cross-coupling
furnishing a THP-protected 3-hydroxy alkynone that is solvolyzed
under acid catalysis to give rise to the c-hydroxy alkynone.
Acid-assisted Michael addition of HCl and subsequent cyclocon-
densation conclude the three-component sequence to give the
4-chlorofuran 3a.
{ Electronic supplementary information (ESI) available: experimental
procedures and characterization for compounds 3 and 5. See http://
www.rsc.org/suppdata/cc/b5/b502324f/
*Thomas_J.J.Mueller@urz.uni-heidelberg.de
Scheme 2 Coupling–addition–cyclocondensation synthesis of 3-halofur-
ans 3.
This journal is ß The Royal Society of Chemistry 2005
Chem. Commun., 2005, 2581–2583 | 2581

View Article Online
Table 1 One-pot three-component synthesis of 3-halofurans 3
Entry
Acid chloride 1
Alkyne 2
3-Halofuran 3 (yield)
a
1
R 5 Ph (1a)
2
R 5 H (2a)
1
3a (R 5 Ph , R 5 H, Hal 5 Cl, 63%)
2
1
a
1
R 5 p-MeOC
1
2
2
6
H
4
(1b)
2a
R 5 Et (2b)
3b (R 5 p-MeOC
6
H
4
, R 5 H, Hal 5 Cl, 71%)
a
2
1
2
3c (R 5 Ph, R 5 Et, Hal 5 Cl, 70%)
3
1a
R 5 2-thienyl (1c)
a
1
1
2
4
2b
2b
2a
2a
2a
2a
2b
3d (R 5 2-thienyl, R 5 Et, Hal 5 Cl, 59%)
1 2
a
1
5
R 5 PhCHLCH (1d)
R 5 1-cyclohexenyl (1e)
3e (R 5 PhCHLCH, R 5 Et, Hal 5 Cl, 73%)
a
1
1
2
6
3f (R 5 1-cyclohexenyl, R 5 H, Hal 5 Cl, 64%)
1 2
3g (R 5 Ph, R 5 H, Hal 5 I, 63%)
b
7
1a
1b
b
1
2
8
3h (R 5 p-MeOC
6
H
4
, R 5 H, Hal 5 I, 63%)
b
1
1
3i (R 5 p-NO
2
, R 5 H, Hal 5 I, 40%)
9
R 5 p-NO
1a
2
C
6
H
4
(1f)
2
2
C
3j (R 5 Ph, R 5 Et, Hal 5 I, 72%)
6
H
4
b
1
1
0
a
b
2
.0 equiv. of NaCl, 60 uC, 20 h. 5 equiv. of NaI, r.t., 2 h.
The authors gratefully acknowledge DFG (Graduiertenkolleg
850), MORPHOCHEM AG, Fonds der Chemischen Industrie,
and Dr Otto-R o¨ hm Ged a¨ chtnisstiftung, and cordially thank Ms
Michaela Schmitt for experimental assistance.
Alexei S. Karpov, Eugen Merkul, Thomas Oeser and
Thomas J. J. M u¨ ller*
Organisch-Chemisches Institut der Ruprecht-Karls-Universit a¨ t
Heidelberg, Im Neuenheimer Feld 270, D-69120 Heidelberg, Germany.
E-mail: Thomas_J.J.Mueller@urz.uni-heidelberg.de;
Fax: +49(0)6221546579; Tel: +49(0)6221546207
1
2
2 6 4
Fig. 1 Molecular structure of 3i (R 5 p-NO C H , R 5 H, Hal 5 I).
Notes and references
Only 1 of 4 independent molecules is shown. The enumeration is adjusted.
¯
, M 5 315.1, triclinic, space group P1,
{
Crystal data for 3i: C10
H
6
INO
3
˚
a 5 8.2679(1), b 5 11.0675(1), c 5 22.2477(2) A, a 5 84.927(1)u,
3
˚
b 5 83.749(1)u, c 5 88.385(1)u, V 5 2015.39(4) A , T 5 200(2) K, Z 5 8,
r 5 2.077 g cm , crystal dimensions 0.50 6 0.34 6 0.30 mm , Mo K
23
3
a
2
1
˚
radiation, m 5 3.162 mm , l 5 0.71073 A. There are four independent
molecules in the asymmetric unit. Data were collected on a Bruker Smart
APEX diffractometer and a total of 9160 of the 20833 reflections were
2
unique [R(int) 5 0.0201]. Refinement on F , wR
2
5 0.049 (observed
1
reflections), R 5 0.021 for [I . 2s(I)]. CCDC 260725. See http://
www.rsc.org/suppdata/cc/b5/b502324f/ for crystallographic data in CIF or
other electronic format.
1
2
B. A. Keay and P. W. Dibble, in Comprehensive Heterocyclic Chemistry
II, ed. A. R. Katritzky, C. W. Rees and E. F. V. Scriven, Elsevier,
Oxford, 1997, vol. 2, pp. 395.
For pharmaceuticals, see e.g.: D. S. Mortensen, A. L. Rodrigues,
K. E. Karlson, J. Sun, B. S. Katzenellenbogen and
J. A. Katzenellenbogen, J. Med. Chem., 2001, 44, 3838.
C. Liu and T. Luh, Org. Lett., 2002, 4, 4305.
3
4
Scheme 3 Sequential Sonogashira–addition–cyclocondensation–Suzuki
synthesis of substituted 3-arylfurans 5.
For reviews, see e.g.: R. C. D. Brown, Angew. Chem. Int. Ed., 2005, 44,
8
50; G. Zeni and R. C. Larock, Chem. Rev., 2004, 104, 2285.
For recent reviews, see e.g.: T. L. Gilchrist, J. Chem. Soc., Perkin Trans.
, 1999, 2849; X. L. Hou, H. Y. Cheung, T. Y. Hon, P. L. Kwan,
T. H. Lo, S. Y. Tong and H. N. C. Wong, Tetrahedron, 1998, 54,
955.
5
1
boronic acids 4 and sodium carbonate, the substituted 3-arylfurans
1
6
5
were obtained in decent yields (Scheme 3).
The new one-pot Sonogashira–addition–cyclocondensation–
1
6 For Pd-catalyzed transformations of acyclic precursors to furans, see
e.g.: A. Jeevanandam, A. Ghule and Y.-C. Ling, Curr. Org. Chem.,
2002, 6, 841; D. K. Barma, A. Kundu, R. Baati, C. Mioskowski and
J. R. Falck, Org. Lett., 2002, 4, 1387.
For investigations on cross-coupling of halofurans, see e.g.:
M. W. Hooper and J. F. Hartwig, Organometallics, 2003, 22, 3394.
For the preparation of 3-lithiofuran, see e.g.: C. C. Bond and
M. Hooper, Synthesis, 1974, 443.
For the recent synthesis of 3-substituted 4-chlorofurans, see e.g.:
R. N. Ram and I. Charles, Chem. Commun., 2003, 2267.
Suzuki synthesis of substituted 3-arylfurans 5 proceeds in reason-
able yields that are almost comparable (one-pot sequence to 5a:
50%) with a stepwise procedure (overall yield of 5a: 45%).
7
8
9
In conclusion, we have developed a novel consecutive three-
component coupling–addition–cyclocondensation synthesis of
3-halofurans, highly versatile building blocks in organic synthesis.
In addition, a new sequential Sonogashira–addition–cycloconden-
sation–Suzuki multi-component furan synthesis was readily
10 For the recent synthesis and further transformations of b-iodofurans,
see e.g.: G. M. M. El-Taeb, A. B. Evans, S. Jones and D. W.
Knight, Tetrahedron Lett., 2001, 42, 5945; C. Schultz-Fademrecht,
M. Zimmermann, R. Fr o¨ hlich and D. Hoppe, Synlett, 2003,
elaborated as
a new diversity-oriented consecutive multi-
component access to substituted 3-arylfurans. Studies addressing
the scope of this sequence to enhance molecular diversity are
currently under investigation.
1969; S. P. Bew and D. W. Knight, Chem. Commun., 1996,
1007.
2
582 | Chem. Commun., 2005, 2581–2583
This journal is ß The Royal Society of Chemistry 2005

View Article Online
1
1 A. S. Karpov, T. Oeser and T. J. J. M u¨ ller, Chem. Commun., 2004, 1502;
A. S. Karpov and T. J. J. M u¨ ller, Synthesis, 2003, 2815; A. S. Karpov
and T. J. J. M u¨ ller, Org. Lett., 2003, 5, 3451.
15 For excellent recent reviews, see e.g.: A. Ajamian and J. L. Gleason,
Angew. Chem. Int. Ed., 2004, 43, 3754; J. M. Lee, Y. Na, H. Han and
S. Chang, Chem. Soc. Rev., 2004, 33, 302.
1
2 For heterocycle synthesis from ynones, see e.g.: M. C. Bagley,
D. D. Hughes and P. H. Taylor, Synlett, 2003, 259; C. G. Savarin,
J. A. Murry and P. G. Dormer, Org. Lett., 2002, 4, 2071.
3 2 2
16 Typical procedure (compound 5a): 35 mg (0.05 mmol) of Pd(PPh ) Cl
and 7 mg (0.04 mmol) of CuI were dissolved in 5 mL of degassed THF.
Then 171 mg (1.00 mmol) of 1b, 141 mg (1.00 mmol) of 2a, and 0.14 mL
(1.00 mmol) of triethylamine were successively added to the solution and
the mixture was stirred for 2 h at room temperature. Then 750 mg
(5.00 mmol) of sodium iodide, 209 mg (1.10 mmol) of p-tolylsulfonic
acid monohydrate and 3 mL of methanol were added and stirring at
room temperature was continued for 2 h. Then 4 mL (8 mmol) of a 2 M
solution of aqueous sodium carbonate and 128 mg (1.05 mmol) of
boronic acid 4a were added and the mixture was heated at 90 uC for
28 h. After aqueous work up and chromatography on silica gel, 115 mg
(50%) of the analytically pure 2-substituted 3-phenylfuran 5a were
13 The successful conversion of c-hydroxy alkynones into halofurans has
been reported by: D. Obrecht, Helv. Chim. Acta, 1989, 72, 447.
3 2 2
14 Typical procedure (compound 3j): 14 mg (0.02 mmol) of Pd(PPh ) Cl
and 7 mg (0.04 mmol) of CuI were dissolved in 5 mL of degassed THF.
Then 141 mg (1.0 mmol) of 1a, 168 mg (1.0 mmol) of 2b, and 0.14 mL
(
1.00 mmol) of triethylamine were successively added to the solution and
the mixture was stirred for 2 h at room temperature. Then 750 mg
5.00 mmol) of sodium iodide, 209 mg (1.10 mmol) of p-tolylsulfonic
(
acid monohydrate and 3 mL of methanol were added and stirring at
room temperature was continued for 2 h. After aqueous work up with a
saturated solution of NaHCO and Na SO and chromatography on
obtained as a colorless solid. R
f
5 0.42 (hexane–ethyl acetate 9:1). Mp
, 300 MHz): d 3.84 (s, 3 H), 7.02 (d, J 5
1
3
2
3
129 uC. H NMR (acetone-d
6
neutral aluminium oxide (hexane–ethyl acetate 9:1–20:1), 215 mg (72%)
8.8 Hz, 2 H), 7.16 (d, J 5 0.7 Hz, 1 H), 7.24–7.31 (m, 1 H), 7.36–7.44
(m, 2 H), 7.63–7.68 (m, 2 H), 7.72 (d, J 5 8.8 Hz, 2 H), 8.02 (d, J 5
1
6
of pure 3j were obtained as a light yellow oil. H NMR (acetone-d ,
1
3
3
00 MHz): d 1.26 (t, J 5 7.7 Hz, 3 H), 2.76 (q, J 5 7.7 Hz, 2 H), 6.89 (s,
6 3
0.7 Hz, 1H). C NMR (acetone-d , 75 MHz): d 55.6 (CH ), 103.3 (CH),
13
1
H), 7.26–7.32 (m, 1 H), 7.38–7.45 (m, 2 H), 7.66–7.71 (m, 2 H).
, 75 MHz): d 12.8 (CH ), 21.6 (CH ), 63.9 (Cquat),
13.6 (CH), 124.2 (CH), 128.5 (CH), 129.7 (CH), 131.0 (Cquat), 154.4
C
115.1 (CH), 124.5 (Cquat), 126.1 (CH), 126.5 (CH), 127.8 (CH), 129.3
(Cquat), 129.6 (CH), 133.4 (Cquat), 138.6 (CH), 155.8 (Cquat), 160.4
NMR (acetone-d
6
3
2
+
+
+
1
(Cquat). EI MS [m/z (%)]: 250 (M , 100), 235 (M 2 CH
3
, 14), 221 (M 2
(
2
C
quat), 158.1 (Cquat). Calc. HRMS for C12
H11IO: 297.9855. Found:
CHO, 15). Anal calc. for C17H O (250.30): C 81.58, H 5.64. Found:
14 2
C 81.20, H 5.63.
97.9861.
This journal is ß The Royal Society of Chemistry 2005
Chem. Commun., 2005, 2581–2583 | 2583