Difunctionalisation of arenes and heteroarenes by directed metallation and sulfoxide-magnesium exchange

Article abstract of DOI:10.1002/chem.201003657

The aryl sulfoxide moiety allows an expedient two-step difunctionalisation of readily available diaryl sulfoxides. Highly functionalised 1,2,4-trisubstituted arenes and difunctionalised heteroarenes (furans, thiophenes, benzofurans and pyridines) were prepared in a two-step sequence, triggered by an aryl sulfoxide group. In the first step, the sulfoxide moiety acts as a metallation-directing group, allowing smooth ortho-magnesiation with TMPMgCl.LiCl (TMP=tetramethylpiperidine). After a quenching reaction with an electrophile, the resulting sulfoxide is converted into a second magnesium reagent with iPrMgCl.LiCl (sulfoxide-magnesium exchange), which can be trapped with various electrophiles. Highly chemoselective TMPMgCl.LiCl and iPrMgCl.LiCl are compatible with a broad range of functional groups (e.g., F, Cl, CF ₃, CN, CO₂tBu, alkynyl, ethers, thioethers). Large-scale reactions (25-40 mmol) and the preparation of fully functionalised furans and thiophenes are also reported. Successful exchange: Highly functionalised 1,2,4-trisubstituted arenes and difunctionalised heteroarenes were prepared in a two-step sequence, triggered by an aryl sulfoxide group. The chemoselective reagents used, TMPMgCl.LiCl (TMP=tetramethylpiperidine) and iPrMgCl.LiCl, are compatible with a broad range of functional groups (see scheme; E=electrophile.)

Full text of DOI:10.1002/chem.201003657

DOI: 10.1002/chem.201003657
Difunctionalisation of Arenes and Heteroarenes by Directed Metallation and
Sulfoxide–Magnesium Exchange
Laurin Melzig, Christian B. Rauhut, Nikolaus Naredi-Rainer, and Paul Knochel*[a]
Dedicated to Professor Alfredo Ricci on the occasion of his 72th birthday
Abstract: The aryl sulfoxide moiety
allows an expedient two-step difunc-
tionalisation of readily available diaryl
sulfoxides. Highly functionalised 1,2,4-
trisubstituted arenes and difunctional-
ised heteroarenes (furans, thiophenes,
benzofurans and pyridines) were pre-
pared in a two-step sequence, triggered
by an aryl sulfoxide group. In the first
step, the sulfoxide moiety acts as a
metallation-directing group, allowing
smooth
ortho-magnesiation
with
(sulfoxide–magnesium
which can be trapped with various elec-
trophiles. Highly chemoselective
exchange),
TMPMgCl·LiCl (TMP=tetramethylpi-
peridine). After a quenching reaction
with an electrophile, the resulting sulf-
oxide is converted into a second mag-
nesium reagent with iPrMgCl·LiCl
TMPMgCl·LiCl and iPrMgCl·LiCl are
compatible with a broad range of func-
tional groups (e.g., F, Cl, CF3, CN,
CO2tBu, alkynyl, ethers, thioethers).
Large-scale reactions (25–40 mmol)
and the preparation of fully functional-
ised furans and thiophenes are also re-
ported.
Keywords: arenes · heterocycles ·
magnesium · metalation · sulfoxide–
magnesium exchange
Introduction
Results and Discussion
The functionalisation of arenes and heteroarenes via organ-
ometallic intermediates is of central importance for the
preparation of polyfunctional aromatics.[1] Whereas organo-
magnesium compounds are readily prepared by a directed
ortho-metallation,[2] a magnesium insertion[3] or a halogen–
magnesium exchange,[4] the use of diaryl sulfoxides for the
synthesis of functionalised aryl- or hetarylmagnesium deriv-
atives by a sulfoxide–magnesium exchange have barely been
reported.[5] This is surprising because the sulfoxide group
also has an exceptional directing-metallation ability[6] and
would therefore allow access to unusual substitution pat-
terns of aromatic scaffolds. Furthermore, the sulfoxide
moiety is a versatile functionality, which has found numer-
ous applications in organic synthesis.[7] Recently, we have
shown that the sulfoxide group undergoes smooth sulfox-
ide–magnesium exchange on a variety of aromatic and het-
eroaromatic substrates, providing that a para-methoxyphen-
yl or para-dimethylaminophenyl group was attached to the
sulfur centre.[8] Herein, we report the full scope of these aro-
matic difunctionalisation reactions using the sulfoxide
moiety in a two-step sequence.
We have envisaged that aromatic sulfoxides of type 1, with
various functional groups (FG=F, Cl, CN, CO2tBu, CF3, al-
kynyl) can be magnesiated in the ortho-position by using
2,[9] leading, after quenching with an electrophile (E1), to
arenes of type 3 (Scheme 1). A subsequent sulfoxide–mag-
Scheme 1. Metallation of sulfoxides, followed by a sulfoxide–magnesium
exchange reaction, leading to 1,2,4-trifunctionalised arenes.
nesium exchange with iPrMgCl·LiCl provides an intermedi-
ate magnesium reagent 4. After reaction with a second elec-
trophile (E2), meta- and para-difunctionalised aromatics of
type 5 can be obtained. This type of substitution pattern is
difficult to achieve by standard methods.[10] Thus, the start-
ing diaryl sulfoxides 1a–f can be considered as synthetic
equivalents of the bis-carbanionic synthon 6 (Scheme 1). To
successfully perform this sequence, sulfoxides 1a–f should
[a] Dr. L. Melzig, Dr. C. B. Rauhut, Dipl.-Chem. N. Naredi-Rainer,
Prof. Dr. P. Knochel
Department Chemie, Ludwig-Maximilians-Universitꢀt Mꢁnchen
Butenandtstr 5-13, Haus F, 81377 Mꢁnchen (Germany)
Fax : (+49)89-2180-77680
E-mail: paul.knochel@cup.uni-muenchen.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201003657.
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FULL PAPER
undergo a regioselective deprotonation on the aromatic ring
containing FG, as well as a regioselective sulfoxide–magnesi-
um exchange reaction producing the organomagnesium re-
agent 4 (and not the alternative exchange product: ArMgCl;
Scheme 1). After extensive experimentation, we have solved
both of these problems by introducing donor substituents at
the para-position of the Ar group of 1.[11]
Two types of diaryl sulfoxides proved to be excellent
starting materials: the 4-N,N-dimethylaminophenyl sulfoxide
derivatives (1a and 1b) and the 4-methoxyphenyl sulfoxide
compounds (1c–f). These sulfoxides were obtained by two
convergent and practical synthetic routes (Scheme 2). Thus,
yield, respectively (Table 1, entries 1 and 2). Quenching the
magnesiated derivative of 1a with iodine, followed by a Ne-
gishi cross-coupling with 2-phenylethynylzinc chloride or 2-
(trimethylsilyl)ethynylzinc chloride, gave products 3c and
3d in 91 and 88% yield, respectively (Table 1, entries 3 and
4).[16] Similarly, sulfoxide 1b (FG=F) was metallated with 2
in THF at À308C within 20 min. After transmetallating to
the organozinc species, a palladium-catalysed cross-coupling
with 4-iodobenzonitrile, 4-iodoanisole or 4-bromo-N,N-di-
methylaniline led to the corresponding sulfoxides 3e–g in
84-95% yield (Table 1, entries 5–7). The organomagnesium
species of 1b could also be quenched with iodine and cross-
coupled with 2-phenylethynylzinc chloride or 1-pentynylzinc
chloride to give sulfoxides 3h and 3i in 94 and 74% yield,
respectively (Table 1, entries 8 and 9). Likewise, tosyl (Tos)
cyanide or (S)-(4-chlorophenyl)benzene thiosulfonate[17]
were used to quench the magnesiated derivative of 1b to
give nitrile 3j and thioether 3k in 79 and 82% yield, respec-
tively (Table 1, entries 10 and 11). Using similar procedures,
we were able to functionalise the diaryl sulfoxides 1c (FG=
CO2tBu), 1d (FG=CN), 1e (FG=CF3) and 1 f (FG=trime-
thylsilyl (TMS)-acetylene) in 61–91% yield (Table 1, en-
tries 12–18).
Preparation of 1,2,4-trisubstituted arenes (5a–l) by a sulfox-
ide–magnesium exchange using iPrMgCl·LiCl: The second
step of the synthetic sequence (Scheme 1), that is, the sulf-
oxide–magnesium exchange, was >95% regioselective and
provided only the desired magnesium reagent 4 (and not the
alternative cleavage product ArMgCl). Thus, the reaction of
3a with iPrMgCl·LiCl (1.1 equiv) in 2-methyltetrahydrofur-
an (2-Me-THF)[18] at À508C was complete within 1 h, and
after transmetallation with ZnCl2 was followed by a cross-
coupling with 4-iodobenzonitrile to give terphenyl 5a in
93% yield (Table 2, entry 1). Similarly, the arylmagnesium
reagent obtained from the reaction of 3a with iPrMgCl·LiCl
could be cross-coupled with ethyl 4-iodobenzoate to give
compound 5b in 89% yield (Table 2, entry 2). The sulfox-
ide–magnesium exchange was also performed on sulfoxide
3b (À508C, 1 h, 2-Me-THF) and quenching the intermediate
arylmagnesium derivative with DMF led to benzaldehyde
5c in 74% yield (Table 2, entry 3). A copper-catalysed ally-
lation reaction with ethyl 2-(bromomethyl)acrylate[19] gave
biphenyl 5d in 48% yield, whereas a Pd-catalysed cross-cou-
pling with 5e in 90% yield (Table 2, entries 4 and 5, respec-
tively). In the case of alkynyl-substituted sulfoxide 3c, the
sulfoxide–magnesium exchange took place in only 5 min
(À508C, 2-Me-THF) and the functionalised benzaldehyde
5 f could be obtained in 93% yield after trapping with DMF
(Table 2, entry 6). A range of polyfunctional compounds
5g–l were prepared in 59–89% yield by applying the same
procedure to sulfoxides 3c and 3d (Table 2, entries 7–12).
Scheme 2. Preparation of sulfoxides 1a–g. mCPBA=meta-chloroperben-
zoic acid.
the N,N-dimethylamino-substituted sulfoxides 1a and 1b
were prepared in 64–69% yield by the reaction of function-
alised organomagnesium reagents (7)[4] with 4-(dimethylami-
no)phenyl thiocyanate (8),[12] followed by mCPBA oxidation
(1.1 equiv, CH2Cl2, À208C).[13] On the other hand, the reac-
tion of functionalised arylmagnesium reagents of type 7[4]
with 4-methoxybenzenesulfinyl chloride (9)[14] afforded the
desired 4-methoxy-substituted sulfoxides 1c–f in 70–91%
yield.[15] Having prepared the required diaryl sulfoxides 1a–
f, we performed the directed-metallation step (step 1 of
Scheme 1).
Preparation of functionalised sulfoxides 3a–s by direct met-
allation using 2: Thus, sulfoxide 1a (FG=Cl) was deproton-
ated with 2 (1.1 equiv) in THF at À308C within 20 min.
After transmetallation to the corresponding zinc reagent
Preparation of 1,2,4-trisubstituted arenes (5m–z) by a sulf-
oxide–magnesium exchange using iPrMgCl·LiCl: The 2,4-
disubstitued arylsulfoxide derivatives of 1b (FG=F) reacted
equally well in the sulfoxide–magnesium exchange reaction
(using ZnCl2 in THF), a Pd-catalysed (2% [PdACTHNUGTRNEUNG(PPh3)4])
cross-coupling[16] with iodobenzene or 4-iodobenzonitrile
gave the expected sulfoxides 3a and 3b in 97 and 92%
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P. Knochel et al.
Table 1. ortho-Magnesiation of functionalised sulfoxides 1a–f followed by reaction with an electrophile.
Entry Sulfoxide
Electrophile
Product
Yield [%][a] Entry Sulfoxide
Electrophile
Product
Yield [%][a]
79
1
1a
PhI
97[b]
10
1b
TosCN
3a
3j
2
1a
92[b]
11
1b
82
3b
3k
1) I2
12
13
1c
1c
1) I2
61
68
3
1a
91
2)
3c
3d
2)
3l
1) I2
1) I2
4
5
1a
1b
88
2)
2)
3m
94[b]
14
15
16
1d
1e
1e
88[b]
91[b]
79
3e
3 f
3g
3n
3o
3p
6
7
1b
93[b]
1b
84[b]
1) I2
2)
1) I2
17
18
1 f
73[b]
8
9
1b
94
74
2)
3h
3q
1) I2
1 f
1) I2
72
1b
2)
3i
2)
3r
[a] Yield of isolated, analytically pure product. [b] After transmetallation to zinc using 1m zinc chloride in THF. [c] Ar1 =p-NMe2-C6H4; Ar2 =p-OMe-
C6H4.
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Difunctionalisation of Arenes and Heteroarenes
FULL PAPER
Table 2. Sulfoxide–magnesium exchange of functionalised sulfoxides 3a–d followed by reaction with an electrophile.
Entry Sulfoxide
Electrophile Product
Yield
[%][a]
Entry Sulfoxide
Electrophile Product
Yield
[%][a]
1
93[b]
7
8
3c
3c
73[b]
3a
5a
5g
5h
2
3
3a
89[b]
72[b]
5b
DMF
74
48
9
3c
59[b]
3b
3b
5c
5i
4
10
DMF
89
5d
3d
3d
5j
5
6
3b
90[b]
11
12
87
5e
5k
DMF
93
3d
84[b]
3c
5 f
5l
[a] Yield of isolated, analytically pure product with respect to 0.8 equiv of electrophile. [b] After transmetallation to zinc using 1m zinc chloride in THF.
[c] Ar1 =p-NMe2-C6H4.
for the second step of the two-step sequence (Scheme 1).
Thus, sulfoxide 3e could be exchanged with iPrMgCl·LiCl
(À508C, 1 h, 2-Me-THF) and quenching of the intermediate
Grignard reagent with DMF gave the functionalised benzal-
dehyde 5m in 76% yield (Table 3, entry 1). Alternatively,
the magnesium species resulting from the exchange reaction
could be transmetallated into an organozinc reagent and
used in a Negishi-type cross-coupling reaction with 4-iodo-
benzonitrile or ethyl 4-iodobenzoate, leading to terphenyls
5n and 5o in 76 and 75% yield, respectively (Table 3, en-
tries 2 and 3). The sulfoxide–magnesium exchange was also
performed on electron-rich substituted sulfoxides 3 f and 3g
(08C, 1 h, 2-Me-THF) and by performing cross-coupling re-
actions or directly reacting the magnesiumorganyl com-
pound with DMF, we obtained trisubstituted arenes 5p–r in
72–86% yield (Table 3, entries 4–6). With the 2-alkynyl-sub-
stituted bis-aryl sulfoxides 3h and 3i, the iPrMgCl·LiCl-trig-
gered exchange step took place within 5 min (À508C, 2-Me-
THF). Trapping with DMF or ethyl chloroformate and by
performing a cross-coupling reaction (after transmetallation
with ZnCl2 in THF) with aryl iodides or an allylation reac-
tion led to the polyfunctionalised arylacetylenes 5s–w in 67–
94% yield (Table 3, entries 7–11). Sulfoxide 3j, with a nitrile
ortho to the sulfoxide, was treated with iPrMgCl·LiCl
(À508C, 5 min, 2-Me-THF), transmetallated and used in
cross-coupling reactions with ethyl 4-iodobenzoate or ethyl
5-bromofuran-2-carboxylate. The resulting disubstituted
benzonitrile derivatives 5x and 5y were obtained in 78 and
72% yield, respectively (Table 3, entries 12 and 13). In the
same manner, sulfoxide 3k underwent the exchange reac-
tion (À508C, 3 h, 2-Me-THF) and was submitted to an ami-
noalkylation. The biologically active sulfide 5z, which is a
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P. Knochel et al.
Table 3. Sulfoxide–magnesium exchange of functionalised sulfoxides 3e–k followed by reaction with an electrophile.
Entry Sulfoxide
Electrophile Product
Yield
[%][a]
Entry Sulfoxide
Electrophile Product
Yield
[%][a]
1
DMF
76
8
3h
3h
3h
ClCO2Et
67[b]
84[b]
83[b]
71
3e
5m
5t
2
3
4
5
3e
76[b]
75[b]
86[b]
79
9
5n
5u
5v
5w
5x
5y
3e
10
11
12
5o
3 f
5p
3i
DMF
78
3g
3g
5q
3j
6
7
72[b]
13
14
72
82
5r
3j
+
H2C=NMe2
DMF
94
À
CF3CO2
3h
5s
3k
5z
[a] Yield of isolated, analytically pure product with respect to 0.8 equiv of electrophile. [b] After transmetallation to zinc using 1m zinc chloride in THF.
[c] Ar1 =p-NMe2-C6H4.
serotonin reuptake inhibitor,[20] was obtained in 82% yield
(Table 3, entry 14).
iPrMgCl·LiCl (À508C, 5 min, 2-Me-THF), and quenching
with DMF gave aldehyde 5aa in 71% yield (Table 4,
entry 1). The intermediate arylmagnesium compound de-
rived from 3l could also be trapped with 3,4-dichlorobenzal-
dehyde, leading to the secondary alcohol 5ab in 84% yield
(Table 4, entry 2). Similarly, sulfoxide 3m underwent the ex-
change reaction (À508C, 5 min, 2-Me-THF) and could be
functionalised by using 3,4-dichlorobenzaldehyde or 4-iodo-
benzonitrile, which led to the trisubstituted arenes 5ac and
Preparation of 1,2,4-trisubstituted arenes (5aa–aj) by a sulf-
oxide–magnesium exchange using iPrMgCl·LiCl: The sulf-
oxide–magnesium exchange protocol is compatible with a
variety of other functional groups, such as an ester, a tri-
fluoromethyl or a nitrile. Thus, bis-aryl sulfoxide 3l (FG=
CO2tBu) underwent
a smooth exchange reaction with
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Difunctionalisation of Arenes and Heteroarenes
FULL PAPER
Table 4. Sulfoxide–magnesium exchange of functionalised sulfoxides 3l–r followed by the reaction with an electrophile.
Entry Sulfoxide
Electrophile Product
Yield
[%][a]
Entry Sulfoxide
Electrophile Product
Yield
[%][a]
1
DMF
71
5
64[b]
3l
5aa
3n
5ae
2
3
3l
84
82
6
79[b]
5ab
5ac
3o
5af
7
87[b]
3m
3m
3p
5ag
4
77[b]
8
DMF
68
5ad
5ae
5af
3q
5ah
5
6
64[b]
9
3q
68[b]
3n
5ai
79[b]
10
72
3o
3r
5aj
[a] Yield of isolated, analytically pure product with respect to 0.8 equiv of electrophile. [b] After transmetallation to zinc using 1m zinc chloride in THF.
[c] Ar2 =p-OMe-C6H4; R1 =TMS-acetylene.
5ad in 82 and 77% yield, respectively (Table 4, entries 3 and
4). Sulfoxide 3n, with two nitrile groups, could readily be
exchanged with iPrMgCl·LiCl (À508C, 5 min, 2-Me-THF),
transmetallated with ZnCl2 and cross-coupled with 4-iodo-
benzonitrile, yielding the tricyanoterphenyl 5ae in 64%
yield (Table 4, entry 5). Diaryl sulfoxides 3o–r (FG=CF3,
TMS-acetylene) could be metallated and functionalised in
the same fashion to give 1,2,4-trisubstituted arenes 5af–aj in
68–87% yield (Table 4, entries 6–10).
change using iPrMgCl·LiCl) could also be applied to large-
scale reactions. Thus, sulfoxide 1g (FG=F) was magnesiat-
ed with 2 (À308C, 20 min, 40 mmol scale, THF) and trapped
with iodine. The resulting aryliodide then underwent a
smooth Negishi cross-coupling reaction with TMS-acetylene-
zinc chloride using a Pd catalyst to give sulfoxide 3s in 86%
yield (Scheme 3). Treating 3s with iPrMgCl·LiCl (À508C,
5 min, 34 mmol scale, 2-Me-THF) and subsequent transme-
tallation (ZnCl2 in THF) and cross-coupling with ethyl 4-io-
dobenzoate gave trisubstituted benzene 5ak in 86% yield.
Alternatively, sulfoxide 1g could be deprotonated by using
the same conditions as those described above and the mag-
nesiated species was trapped with (S)-(4-chlorophenyl)ben-
zene thiosulfonate to give diaryl thioether 3k in 87% yield
Large-scale preparation of 1,2,4-trisubstituted arenes (5ak–
am) using the two-step protocol: The two-step protocol
(step 1 being the metallation using 2 directed by the sulfox-
ide group, and step 2 being the sulfoxide–magnesium ex-
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P. Knochel et al.
Therefore, 2-furyl sulfoxide
(1h) was selectively metallated
with 2 (20 min, À308C, THF) in
position 3. The resulting hetero-
cyclic magnesium reagent was
transmetallated (using ZnCl2 in
THF) and cross-coupled with
ethyl 4-iodobenzoate using Pd
catalysis, leading to furan deriv-
ative 10a in 77% yield
(Table 5, entry 1). By using
iPrMgCl·LiCl, the sulfoxide
moiety was exchanged (À508C,
2 h, 2-Me-THF) and the organ-
ometallic species was quenched
with TosCN to give the 1,2-dis-
ubstituted furanyl derivate 11a
in 63% yield. Alternatively,
after exchanging the sulfoxide
group of 10a and transmetalla-
tion to the zinc species, a Ne-
gishi cross-coupling with 4-iodo
Scheme 3. Large-scale preparation of 1,2,4-trisubstituted arenes (5ak–am).
chlorobenzene was performed
(Scheme 3). By treating 3k with the exchange reagent
iPrMgCl·LiCl (À508C, 15 min, 33 mmol scale, 2-Me-THF)
and quenching with 3,4-dichlorobenzaldehyde, we isolated
benzylic alcohol 5al in 49% yield. Sulfoxide 1e underwent
smooth magnesiation (2, À308C, 20 min, 35 mmol scale,
THF) and gave biphenyl 3o in 75% yield after a Pd-cata-
lysed cross-coupling reaction with 4-iodochlorobenzene
(Scheme 3). Finally, by treating 3o with iPrMgCl·LiCl
(À508C, 30 min, 2-Me-THF) on a 25 mmol scale and trap-
ping the intermediate with DMF, the trisubstituted benzal-
dehyde 5am was provided in 83% yield.
to yield heterocycle 11b in 68% yield (Table 5, entry 2). By
deprotonating 1h with 2 and trapping with iodine, the 3-
iodo-furanyl derivative was obtained. This underwent a
straightforward cross-coupling with 2-phenylethynylzinc
chloride to give compound 10b in 69% yield (Table 5,
entry 3). After exchanging the sulfoxide group of 10b
(iPrMgCl·LiCl, À788C, 15 min, 2-Me-THF) a second cross-
coupling was performed to afford the disubstituted furanyl
derivate 11c in 68% yield. 2-Thiophenyl and 2-benzofuryl
sulfoxides were also suitable for our reaction conditions, and
therefore, we prepared the 1,2-difunctionalised 5-membered
heterocycles 11d–i in 77–97% yield (Table 5, entries 4–9).
Preparation of 1,2-disubstituted heteroarenes (11) by using
the two-step protocol: The two-step difunctionalisation syn-
thesis was used for five-membered heterocyclic sulfoxides in
a similar manner (Scheme 4). The required sulfoxides 1h–j
were prepared according to method 1 in Scheme 2 starting
from the corresponding 2-heteroaryl organolithiums.
Preparation of fully functionalised five-membered heteroar-
enes: These 2,3-difunctionalised heterocycles were readily
converted into tetra-substituted heterocycles in a straightfor-
ward manner. Thus, the 2-silylated furan 11b was converted
to the corresponding 2-iodofuran (ICl, 1.5 equiv, 08C, 1 h,
79%).[21] A subsequent I–Mg exchange with iPrMgCl·LiCl[4b]
(1.1 equiv, À408C, 20 min) gave the expected organomagne-
sium intermediate, which was treated with ethyl cyanofor-
mate, leading to the furan 12 in 86% yield (Scheme 5). Fur-
ther metallation at position
4
of this furan with
TMP2Mg·2LiCl[2b] (TMP=tetramethylpiperidine; 1.35 equiv,
À408C, 25 min) and consecutive copper(I)-mediated acyla-
tion with 3,3-dimethylbutyryl chloride led to the tetra-substi-
tuted furan 13 in 93% yield. This full functionalisation of
the furan ring was realised in 5 steps and 42% overall yield
(Scheme 5). The thiophene scaffold could be tetra-function-
alised in a similar manner. First, the trimethylsilyl group of
11g was converted with ICl (1.5 equiv, 08C, 1 h) to the cor-
responding 2-iodothiophene, which was used in the next
step without further purification. Then, cross-coupling with
Scheme 4. Metallation of 2-heteroaryl sulfoxides (1h–j), followed by a
sulfoxide–magnesium exchange reaction, leading to 1,2-difunctionalised
5-membered heterocycles.
trimethylsilylethynylzinc chloride (2% [PdACHTNUTRGNE(UNG PPh3)4], 258C,
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Difunctionalisation of Arenes and Heteroarenes
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Table 5. Directed ortho-metallation and sulfoxide–magnesium exchange of functionalised sulfoxides 1h–j fol-
lowed by reaction with an electrophile.
À208C, 12 h) and submitted to
a Negishi cross-coupling (2%
Entry E1
Sulfoxide 10
Yield E2
[%][a]
Product 11
Yield
[%][b]
[PdACHTNURTGNE(UNG PPh3)4], 258C, 3 h) with (4-
iodophenoxy)triisopropylsi-
lane[22] to give the fully func-
tionalised thiophene 15 in 75%
yield. The tetra-substitution of
the thiophene was therefore
carried out in 4 steps and 49%
overall yield (Scheme 5).
1
4-IC6H4CO2Et
77[c]
TosCN
63
10a
10a
11a
11b
Preparation of 3,4-disubstituted
pyridines (17) by using the two-
step protocol: The developed
method was also suitable for
2
3
4-IC6H4Cl
68[c]
pyridinyl
sulfoxides,
which
a)
I2,
69
78
4-IC6H4CO2Et
68[c]
could be prepared similarly to
method 1 in Scheme 2 with 3-
or 4-pyridinyl Grignard re-
agents (Scheme 6).
b)
10b
11c
11d
Therefore, 4-[(4-methoxyphe-
nyl)sulfinyl]pyridine (1k) un-
derwent a smooth magnesiation
reaction with 2 (À308C, 30 min,
THF) in the first step of the re-
action sequence and was
trapped with iodine. This pyri-
dinyliodide was used for a Ne-
gishi-type cross-coupling reac-
tion with trimethylsilylethynyl-
zinc chloride and sulfoxide 16a
was obtained in 69% yield
(Table 6, entry 1). Compound
16a reacted with iPrMgCl·LiCl
(À508C, 5 min, 2-Me-THF) in
the sulfoxide–magnesium ex-
change (the second step of the
synthesis) and after trapping
with DMF the 3,4-disubstituted
pyridine 17a was isolated in
58% yield (Table 6, entry 1). In
another reaction sequence, the
exchange of the sulfoxide
moiety was performed on sulf-
oxide 16a, the organomagnesi-
um reagent was transmetallated
to zinc and used in a cross-cou-
pling with ethyl 4-iodobenzoate
to give 17b in 63% yield
(Table 6, entry 2). Similarly,
sulfoxide 1l was used in the re-
action protocol and led to di-
functionalised pyridines 17c
and 17d in 50 and 67% yield,
respectively (Table 6, entries 3
4
5
PhSO2SC6H4Cl
DMF
97
10c
10c
4-IC6H4CO2Et
88[c]
11e
11 f
11g
6
7
4-IC6H4CN
89[c]
PhSO2SC6H4Br
94
10d
10e
3-IC6H4OMe
87[c]
4-IC6H4CN
85[c]
8
9
PhSO2SC6H4Cl
88
43
3-ClC6H4CHO
4-IC6H4CO2Et
77
10 f
10g
11h
11i
TosCN
87[c]
[a] Yield of isolated, analytically pure product. [b] Yield of isolated, analytically pure product with respect to
0.8 equiv of electrophile. [c] After transmetallation to zinc using 1m zinc chloride in THF. [d] Ar2 =p-OMe-
C6H4.
1 h) led to the tri-substituted product 14 in 88% yield. Final-
ly, thiophene 14 was treated with TMP2Mg·2LiCl (1.5 equiv,
and 4). Finally, sulfoxide 1m was also a suitable starting ma-
terial for the difunctionalisation method. Hence, tetra-sub-
Chem. Eur. J. 2011, 17, 5362 – 5372
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5369

P. Knochel et al.
above, transmetallated (ZnCl2
in THF) and submitted to a Ne-
gishi cross-coupling with 4-io-
dobenzonitrile to give pyridine
22 in 63% yield. To accomplish
the final step of the synthesis,
the ligand-exchange reaction,
we treated sulfoxide 22 with
iPrMgCl·LiCl (À508C, 5 min,
THF) and obtained the cyclo-
oxygenase-2 inhibitor[24] 23 in
83% yield. The total synthesis
was therefore carried out in 3
steps and 32% overall yield
(Scheme 8).
Scheme 5. Synthesis of fully functionalised furan 13 and thiophene 15. TIPS=triisopropylsilyl.
Scheme 7. Ligand-exchange reaction of 2-pyridinyl sulfoxides.
Scheme 6. Metallation of 3- and 4-pyridinyl sulfoxides 1k–m, followed by
a sulfoxide–magnesium exchange reaction, leading to 3,4-difunctionalised
pyridines 17.
stituted pyridines 17e and 17 f were obtained after directed
ortho-metallation and sulfoxide–magnesium exchange in 61
and 82% yield, respectively (Table 6, entries 5 and 6).
Preparation of a cyclooxygenase-2 inhibitor by directed met-
allation with 2 and ligand exchange with iPrMgCl·LiCl: A
remarkable characteristic of 2-pyridinyl sulfoxides 18 was re-
ported by Oae et al.[23] When treated with a Grignard re-
agent, instead of sulfoxide–magnesium exchange creating a
new organomagnesium reagent, these compounds undergo a
so-called ligand-exchange reaction by directly connecting
the two aromatic groups attached to the sulfoxide moiety to
generate 2-substituted pyridines 19 (Scheme 7).
Scheme 8. Synthesis of the cyclooxygenase-2 inhibitor 23. DBA=diben-
zylideneacetone, TFP=tris-2-furylphosphine.
We have used this interesting behaviour by applying this
very clean and fast reaction to a short total synthesis.
Hence, we performed a bromine–magnesium exchange on 2-
bromopyridine (20) using iPrMgCl·LiCl (08C, 2 h, THF) and
trapped the 2-pyridinylmagnesium chloride with 4-methoxy-
benzenesulfinyl chloride (9). The expected 2-[(4-methoxy-
phenyl)sulfinyl]pyridine (21) was isolated in 61% yield
(Scheme 8). This sulfoxide was treated with 2 (À308C,
30 min, THF) according to the methodology described
Conclusion
We have developed an efficient two-step sequence that
allows meta-, para-difunctionalisation of substituted aromat-
ics using the chameleon chemical behaviour of the sulfoxide
moiety. This versatile functional group acts as a metallation-
directing group in the presence of 2 and as a leaving group
in the presence of iPrMgCl·LiCl, generating a new Grignard
reagent. The protocol is suitable for multi-gram synthesis.
5370
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Chem. Eur. J. 2011, 17, 5362 – 5372

Difunctionalisation of Arenes and Heteroarenes
FULL PAPER
Table 6. Directed ortho-metallation and sulfoxide–magnesium exchange of functionalised sulfoxides 1k–m fol-
lowed by reaction with an electrophile.
Experimental Section
Entry E1
Sulfoxide 16
Yield
[%][a]
E2
Product 17
Yield
[%][b]
For experimental procedures, analyti-
cal data, and NMR spectra, see the
Supporting Information.
a)
I2,
1
69
DMF
58
Typical procedure for the directed
metallation reaction and subsequent
cross-coupling with an electrophile
(step 1)
b)
16a
16a
17a
17b
Representative preparation of 16e: A
dry and argon-flushed Schlenk flask,
equipped with a magnetic stirrer and a
septum, was charged with 1m
(5.0 mmol, 1.51 g) in THF (10 mL).
The reaction mixture was cooled to
2
4-IC6H4CO2Et
63[c]
À308C and
2 (5.5 mmol, 4.58 mL,
1.20m in THF) was added dropwise.
After 20 min of stirring at À308C, zinc
chloride (5.5 mmol, 5.5 mL, 1.0m in
THF) was added and the solution was
stirred for 30 min at À308C. Then 4-io-
doanisole (6.0 mmol, 1.40 g) and [Pd-
3
4
4-IC6H4CN
38[c]
4-IC6H4CO2Et
50[c]
AHCTNUTGREGN(NNU PPh3)4] (0.01 mmol, 110 mg) were
16b
17c
added and the solution was stirred at
508C for 2 h. The reaction mixture
was quenched with a saturated aque-
ous solution of NH4Cl (25 mL) and ex-
tracted three times with ethyl acetate
(50 mL). The combined organic layers
were dried (MgSO4) and, after filtra-
tion, the solvent was removed under
reduced pressure. Flash chromato-
graphic purification (pentane/diethyl
ether 1:1, silica gel) gave 16e as a col-
ourless solid (1.38 g, 68%). M.p. 113–
1148C; 1H NMR (CDCl3, 600 MHz):
d=8.12 (s, 1H), 7.22 (dd, J=8.58,
1.91 Hz, 1H), 7.01 (dd, J=8.58,
2.86 Hz, 1H), 6.89–6.87 (m, 2H), 6.74–
6.71 (m, 3H), 6.43 ppm (dd, J=8.58,
1.91 Hz, 1H); 13C NMR (CDCl3,
150 MHz): d=162.6, 160.8, 160.3,
150.2, 132.8, 131.9 (CH), 131.5, 131.4,
130.6 (CH), 128.4 (CH), 123.9, 117.6
(CH), 114.7 (CH), 114.6 (CH), 113.5
(CH), 55.5 (CH3), 55.3 ppm (CH3); IR
(ATR): n˜ =3000 (vw), 2838 (w), 1610
(w), 1592 (m), 1576 (m), 1558 (m),
1510 (m), 1496 (m), 1404 (m), 1306
(m), 1258 (s), 1246 (vs), 1178 (s), 1152
(m), 1096 (m), 1084 (m), 1050 (s),
1034 (s), 1028 (s), 994 (m), 880 (w),
828 (s), 812 (m), 792 cmÀ1 (s); MS (EI,
70 eV): m/z (%): 409 (28), 408 (9), 407 (41) [M+], 391 (9), 261 (20), 156
(13), 155 (100), 139 (9), 124 (15), 43 (10); HRMS (EI): m/z calcd for
C19H1535L2NO332S: 407.0150; found: 407.0142.
4-IC6H4Cl
53[c]
PhSO2SC6H4Cl
67
16c
17d
5
4-IC6H4Cl
74[c]
4-IC6H4NO2
61[c]
16d
17e
6
4-IC6H4OMe
68[c]
PhSO2SC6H4Cl
82[c]
16e
17 f
[a] Yield of isolated, analytically pure product. [b] Yield of isolated, analytically pure product with respect to
0.8 equiv of electrophile. [c] After transmetallation to zinc using 1m zinc chloride in THF. [d] Ar2 =p-OMe-
C6H4.
Furthermore, we used this method to prepare 1,2-disubsti-
tuted furans, thiophenes and benzofurans. A further use of
iPrMgCl·LiCl and TMP2Mg·2LiCl allows the full functional-
isation of the two remaining positions of these heterocycles.
Moreover, the preparation of 3,4-disubstituted pyridines and
the total synthesis of a cyclooxygenase-2 inhibitor, further-
more exploiting the properties of the sulfoxide group, have
been shown. Further extensions of the use of the sulfoxide
group for generating polyfunctional Grignard reagents are
currently being studied in our laboratories.
Typical procedure for the sulfoxide–magnesium exchange reaction and
subsequent cross-coupling with an electrophile (step 2)
Representative preparation of 17 f: A dry and argon-flushed Schlenk
flask, equipped with a magnetic stirrer and a septum, was charged with a
solution of 16e (1.0 mmol, 402 mg) in 2-Me-THF (2 mL). The reaction
mixture was cooled to À508C and iPrMgCl·LiCl (1.1 mmol, 0.92 mL,
1.20m in THF) was added dropwise. After stirring at À508C for 5 min,
zinc chloride (1.1 mmol, 1.1 mL, 1.0m in THF) was added and the solu-
tion was stirred for 30 min at À508C. Then ethyl 5-bromonicotinate
(0.8 mmol, 184 mg) and [PdACHTNUTRGNEUNG(PPh3)4] (0.02 mmol, 22 mg) were added and
the solution was stirred at 508C for 5 h. The reaction mixture was
quenched with a saturated aqueous solution of NH4Cl (5 mL) and ex-
Chem. Eur. J. 2011, 17, 5362 – 5372
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5371

P. Knochel et al.
tracted three times with ethyl acetate (10 mL). The combined organic
layers were dried (MgSO4) and, after filtration, the solvent was removed
under reduced pressure. Flash chromatographic purification (pentane/di-
ethyl ether 7:3, silica gel) gave 17 f as a colourless solid (265 mg, 82%).
M.p. 120–1218C; 1H NMR (CDCl3, 300 MHz): d=9.07 (d, J=1.73 Hz,
1H), 8.41 (d, J=2.23 Hz, 1H), 8.02 (dd, J=2.23, 1.73 Hz, 1H), 7.36 (s,
1H), 7.02–6.97 (m, 2H), 6.83–6.78 (m, 2H), 4.37 (q, J=7.18 Hz, 2H),
3.76 (s, 3H), 1.37 ppm (t, J=7.18 Hz, 3H); 13C NMR (CDCl3, 75 MHz):
d=164.4, 159.6, 152.7 (CH), 151.2, 150.3 (CH), 149.6, 149.1, 137.1 (CH),
134.2, 133.1, 131.5 (CH), 126.0, 125.8, 123.6 (CH), 114.1 (CH), 61.7
(CH2), 55.2 (CH3), 14.2 ppm (CH3); IR (ATR): n˜ =2936 (vw), 1716 (s),
1608 (w), 1564 (m), 1528 (m), 1430 (m), 1370 (w), 1336 (m), 1306 (m),
1292 (s), 1272 (s), 1254 (vs), 1226 (m), 1178 (m), 1162 (m), 1136 (m),
1114 (m), 1088 (m), 1028 (m), 1016 (m), 882 (w), 858 (w), 840 (s), 820
(m), 794 (m), 764 (m), 706 (m), 698 cmÀ1 (m); MS (EI, 70 eV): m/z (%):
406 (14), 405 (18), 404 (73), 403 (48), 402 (100) [M+], 401 (34), 375 (21),
373 (30), 357 (11), 44 (55); HRMS (EI): m/z calcd for C20H16Cl2N2O3:
402.0538; found: 402.0533.
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We thank the European Research Council (ERC) for financial support.
We also thank Chemetall GmbH (Frankfurt) and BASF SE (Ludwigsha-
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Received: December 19, 2010
Published online: April 1, 2011
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Chem. Eur. J. 2011, 17, 5362 – 5372