2,3-Functionalization of furans, benzofurans and thiophenes via magnesiation and sulfoxide-magnesium exchange

Article abstract of DOI:10.1039/b907330b

The use of TMPMgCl·LiCl and iPrMgCl·LiCl allows a sequential 2,3-difunctionalization of various 2-arylsulfinyl furans, thiophenes and benzofurans. Subsequent use of the same reagents permits a selective full functionalization of all 4 positions of the fur

Full text of DOI:10.1039/b907330b

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2,3-Functionalization of furans, benzofurans and thiophenes via
magnesiation and sulfoxide–magnesium exchangew
Laurin Melzig, Christian B. Rauhut and Paul Knochel*
Received (in Cambridge, UK) 9th April 2009, Accepted 13th May 2009
First published as an Advance Article on the web 20th May 2009
DOI: 10.1039/b907330b
The use of TMPMgClÁLiCl and iPrMgClÁLiCl allows a
sequential 2,3-difunctionalization of various 2-arylsulfinyl furans,
thiophenes and benzofurans. Subsequent use of the same reagents
permits a selective full functionalization of all 4 positions of the
furan and thiophene scaffolds.
furnished the 2,3-difunctionalized furan 3a in 68% yield
(Table 1, entry 1). In another two step sequence, the sulfoxide
(1a) was ortho-metalated and trapped with I2. The resulting
3-iodofuran derivative then underwent a Negishi12 cross-
coupling with phenylethynylzinc chloride leading to the
product 2b in 69% yield.13 A sulfoxide–magnesium exchange
at À50 1C for 15 min, followed by a transmetalation using
ZnCl2 in THF and a Pd-catalyzed cross-coupling (Pd(PPh3)4,
2 mol%, 25 1C, 1 h) with ethyl 4-iodobenzoate gave the desired
product 3b in 68% yield (entry 2).
Substituted furans, benzofurans and thiophenes are important
heterocycles that are found in a wide variety of natural
compounds and pharmaceutical molecules.1 They are also
building blocks for the elaboration of organic materials.2
Derivatization of such heterocycles in position 2 by metalation
is well established.3 However, the functionalization of position
3 by directed metalation is much less explored. Recently, we
have shown that the sulfoxide group, which has excellent
The thiophene 1b undergoes the same two step reaction
sequence allowing to prepare 2,3-disubstituted thiophenes.
Thus, deprotonation of 1b and trapping with S(4-chlorophenyl)-
benzene thiosulfonate14 led to the thioether 2c in 78% yield.
This thiophene 2c underwent smooth exchange reaction with
iPrMgClÁLiCl (1.1 equiv., À50 1C, 1 h), furnishing the pyridine
derivative 3c in 67% yield after transmetalation with ZnCl2
and Pd-catalyzed cross-coupling with 5-bromonicotinic acid
ethyl ester (entry 3). In another reaction sequence, thiophene
1b was ortho-metalated with TMPMgClÁLiCl, transmetalated
with ZnCl2 and reacted with 4-iodobenzonitrile and 3-iodo-
anisole (Pd(PPh3)4, 2 mol%, 25 1C, 1 h), yielding thienyl
sulfoxides 2d and 2e in 87–89% yield. The two thiophenes
2d and 2e were submitted to a sulfoxide–magnesium exchange,
which gave the desired secondary alcohol 3d and the aryl-
disubstituted thiophene 3e by respective quenching of the
intermediate magnesium compound with 3,4-dichloro-
benzaldehyde, or cross-coupling with 4-iodobenzonitrile
((i) ZnCl2; (ii) Pd(PPh3)4, 2 mol%, 25 1C, 1 h) in 83–85%
yield (entries 4 and 5).
metalation-directing abilities,4 undergoes also
a smooth
sulfoxide–magnesium exchange on a variety of aromatic
substrates, providing that a para-methoxyphenyl group was
attached to the sulfur center.5 Therefore, sulfoxides such as
ArSOC6H4OMe, when treated with iPrMgClÁLiCl afford only
the magnesium reagent ArMgCl and p-MeOC6H4SOiPr.5
Herein, we report an efficient functionalization of positions
2 and 3 of various 5-membered heterocycles using a sulfoxide–
magnesium exchange. Thus, the magnesiation of heteroaryl
sulfoxides such as 1a–c with TMPMgClÁLiCl6 gave after
quenching with an electrophile (E1) products of type 2. A
sulfoxide–magnesium exchange triggered by iPrMgClÁLiCl7
affords an intermediate magnesium reagent, which after
quenching with a second electrophile (E2), yields 2,3-disubstituted
heterocycles of type 3 (Scheme 1).
The required starting 2-arylsulfinyl-heterocycles (1a–c) are
readily available by the lithiation of benzofuran, 5-TMS-
substituted thiophene and furan8 with BuLi (0 1C, 2 h)
followed by the addition of p-MeOC6H4SOCl9 (1.3 equiv.,
À78 1C to rt, 1 h) in 47–85% yield.
Also, benzofuran underwent ortho-magnesiation with
TMPMgClÁLiCl (1.1 equiv., À50 1C, 45 min) and led after
quenching with S(4-chlorophenyl)benzene thiosulfonate or
after a Negishi cross-coupling with 1-fluoro-4-iodobenzene
(Pd(PPh3)4, 2 mol%, 25 1C, 1 h) to the benzofurans 2f and
2g in 80–88% yield. Again, a sulfoxide–magnesium exchange
with iPrMgClÁLiCl (1.1 equiv., À50 1C, 5 min) and coupling
Thus, the sulfoxide (1a) was deprotonated at position 3 with
TMPMgClÁLiCl (1.1 equiv.) at À40 1C within 20 min. After
transmetalation to the corresponding zinc reagent (using
ZnCl2 in THF) a Pd-catalyzed cross-coupling10 (Pd(PPh3)4,
2
mol%) with ethyl 4-iodobenzoate gave the expected
sulfoxide (2a) in 77% yield. The subsequent reaction of 2a
with iPrMgClÁLiCl (1.1 equiv.) in 2-methyltetrahydrofuran11
at À50 1C for 2 h, followed by a Negishi cross-coupling
(Pd(PPh3)4, 2 mol%, 25 1C, 1 h) with 4-chloro-iodobenzene,
Ludwig-Maximilians-Universitat, Butenandtstr. 5-13, Munich,
¨
Germany. E-mail: Paul.Knochel@cup.uni-muenchen.de;
Fax: +49-89-2180-77680; Tel: +49-89-2180-77681
w Electronic supplementary information (ESI) available: Experimental
procedures and analytical data. See DOI: 10.1039/b907330b
Scheme 1 2,3-Difunctionalization of 5-membered heterocycles.
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Table 1 2,3-Difunctionalized furans, thiophenes and benzofurans
Entry
Electrophiles E1, E2
Product of type 2 (step 1)
Yield [%]a
Product of type 3 (step 2)
Yield [%]a
1
p-EtO2C-C6H4I, p-Cl-C6H4I
2
(i) I2 (ii) C6H5CCZnCl, p-EtO2C-C6H4I
3
p-Cl-C6H4S-SO2C6H5, 5-bromonicotinic acid ethyl ester
4
p-NC-C6H4I, 3,4-di-Cl-C6H3CHO
5
m-MeO-C6H4I, p-NC-C6H4I
6
p-Cl-C6H4S-SO2C6H5, p-NC-C6H4I
7
p-F-C6H4I, DMF
a
b
Yield of analytically pure product. A transmetalation using zinc chloride (1.0 M in THF) was performed; Ar = C6H4-pOMe.
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system was therefore carried out in 4 steps and 49% overall
yield (Scheme 2).
In summary, we have developed an efficient two-step
sequence allowing a 2,3-difunctionalization of 5-membered
heterocycles using the chameleon chemical behavior of the
sulfoxide moiety (ArSO).5 This versatile functional group
acts as a metalation directing group in the presence of
TMPMgClÁLiCl, but also as a leaving group after the reaction
with iPrMgClÁLiCl, generating a new Grignard reagent.
A further use of iPrMgClÁLiCl and TMP2MgÁ2LiCl allows
the full substitution of the two remaining positions of these
heterocycles. Further extensions of the sulfoxide group for
preparing relevant polyfunctional heterocyclic scaffolds are
currently being studied in our laboratories.
We thank the Fonds der Chemischen Industrie and the
DFG for financial support and Chemetall GmbH (Frankfurt),
BASF AG (Ludwigshafen) and Heraeus GmbH (Hanau) for
generous gifts of chemicals.
Notes and references
1 X. L. Hou, Z. Yang and H. N. C. Wong, in Progress in Hetero-
cyclic Chemistry, ed. G. W. Gribble and T. L. Gilchrist, Pergamon,
Oxford, 2003, vol. 15, p. 167; B. A. Keay and P. W. Dibble, in
Comprehensive Heterocyclic Chemistry II, ed. A. R. Katritzky,
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2 H. N. C. Wong, P. Yu and C.-Y. Yick, Pure Appl. Chem., 1999, 71,
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and H. N. C. Wong, Pure Appl. Chem., 2005, 77, 139.
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Scheme 2 Synthesis of fully functionalized furan 6 and thiophene 8.
with 4-iodobenzonitrile (Pd(PPh3)4, 2 mol%, 25 1C, 1 h) or a
trapping with DMF afforded the 2,3-disubstituted benzo-
furans 3f and 3g in 84–91% yield (entries 6 and 7).
4 C. Quesnelle, T. Iihama, T. Aubert, H. Terrier and V. Snieckus,
Tetrahedron Lett., 1992, 33, 2625; A. Abramovitch and I. Marek,
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These 2,3-difunctionalized heterocycles could readily be
converted into tetra-substituted systems in a straightforward
manner. Thus, the 2-silylated furan (3a) was converted to the
corresponding 2-iodofuran (ICl, 1.5 equiv., 0 1C, 1 h, 79%).15
A subsequent I–Mg exchange with iPrMgClÁLiCl7 (1.1 equiv.,
À40 1C, 20 min) gave the expected organomagnesium inter-
mediate which was reacted with ethyl cyanoformate leading to
the furan (5) in 86% yield. A further metalation at position
4 of this furan with TMP2MgÁ2LiCl16 (1.35 equiv., À40 1C,
25 min) and consecutive copper(I)-mediated acylation with
3,3-dimethylbutyryl chloride led to the tetra-substituted furan
(6) in 93% yield. This full functionalization of the furan ring
was realized in 5 steps and 42% overall yield (Scheme 2).
The thiophene scaffold could be tetra-functionalized in a
similar manner. First, the trimethylsilyl group of 3e was
converted with ICl (1.5 equiv., 0 1C, 1 h) to the corresponding
2-iodothiophene which was used in the next step without
further purification. Then, cross-coupling with trimethyl-
silylethynylzinc chloride (Pd(PPh3)4, 2 mol%, 25 1C, 1 h),
led to the tri-substituted product (7) in 88% yield. Finally,
thiophene (7) was treated with TMP2MgÁ2LiCl (1.5 equiv.,
À20 1C, 12 h) and submitted to a Negishi cross-coupling
(Pd(PPh3)4, 2 mol%, 25 1C, 3 h) with (4-iodo-phenoxy)-
triisopropylsilane,17 furnishing the fully functionalized thio-
phene (8) in 75% yield. The tetra-substitution of the thiophene
6 TMP
=
2,2,6,6-tetramethylpiperidyl, see: A. Krasovskiy,
V. Krasovskaya and P. Knochel, Angew. Chem., Int. Ed., 2006,
45, 2958.
7 A. Krasovskiy and P. Knochel, Angew. Chem., Int. Ed., 2004, 43,
3333.
8 Without protecting position 5 of furan 1a and thiophene 1b a
mixture of 3- and 5-metalated species was obtained when treating
these 2-arylsulfinyl-heterocycles with TMPMgClÁLiCl at À78 1C.
9 M. Peyronneau, N. Roques, S. Mazieres and C. Le Roux, Synlett,
2003, 631.
10 E. Negishi, L. F. Valente and M. Kobayashi, J. Am. Chem. Soc.,
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E. Negishi, M. Quian, F. Zeng, L. Anastasia and D. Babinski,
Org. Lett., 2003, 5, 1597; X. Zeng, M. Quian, Q. Hu and
E. Negishi, Angew. Chem., Int. Ed., 2004, 43, 2259.
11 Performing the sulfoxide–magnesium exchange reaction in THF
led to 10–35% of protonated Grignard reagent. However we have
found that the use of 2-methyltetrahydrofuran considerably
reduces this protonation side reaction.
12 E. Negishi, M. Qian, F. Zeng, L. Anastasia and D. Babinski, Org.
Lett., 2003, 5, 1597.
13 A direct metal-catalyzed coupling reaction with metalated 1a gave
less satisfactory yields.
14 K. Fujiki, N. Tanifuji, Y. Sasaki and T. Yokoyama, Synthesis,
2002, 343.
15 G. Felix, J. Dunogues and R. Calas, Angew. Chem., Int. Ed. Engl.,
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16 G. Clososki, C. J. Rohbogner and P. Knochel, Angew. Chem., Int.
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17 M. Rottlander, N. Palmer and P. Knochel, Synlett, 1996, 573.
¨
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This journal is The Royal Society of Chemistry 2009
3538 | Chem. Commun., 2009, 3536–3538