Functionalizations of Mixtures of Regioisomeric Aryllithium Compounds by Selective Trapping with Dichlorozirconocene

Article abstract of DOI:10.1002/anie.201508719

The reaction of mixtures of aryllithium regioisomers obtained either by directed lithiation or by Br/Li exchange with substoichiometric amounts of Cp₂ZrCl₂ proceeds with high regioselectivity. The least sterically hindered regioisome

Full text of DOI:10.1002/anie.201508719

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International Edition: DOI: 10.1002/anie.201508719
German Edition: DOI: 10.1002/ange.201508719
Transmetalation
Functionalizations of Mixtures of Regioisomeric Aryllithium
Compounds by Selective Trapping with Dichlorozirconocene
Alicia Castelló-Micó, Simon A. Herbert, Thierry León, Thomas Bein, and Paul Knochel*
Abstract: The reaction of mixtures of aryllithium regioisomers
obtained either by directed lithiation or by Br/Li exchange with
substoichiometric amounts of Cp2ZrCl2 proceeds with high
regioselectivity. The least sterically hindered regioisomeric
aryllithium is selectively transmetalated to the corresponding
arylzirconium species leaving the more hindered aryllithium
ready for various reactions with electrophiles. As an applica-
tion, these regioselective transmetalations from Li to Zr were
used to prepare all three lithiated regioisomers of 1,3-bis(tri-
fluoromethyl)benzene.
Scheme 1. Nonselective metalation of unsymmetrical arenes followed
O
rganolithium compounds are important organometallic
intermediates in organic synthesis.[1] The most convenient
preparation of aryllithiums involves halogen–lithium
by selective transmetalation.
a
exchange or a directed metalation.[2] The presence of
a directing group usually ensures lithiation at the ortho-
position; however, in cases where unsymmetrical substrates of
type 1 are used, a mixture of regioisomeric aryllithiums 2 and
3 may be produced.[3] The formation of such mixtures
hampers synthetic applications. This lack of regioselectivity
could potentially be solved by a preferential transmetalation
of one of two regioisomers 2 and 3. Therefore, we envisioned
that a selective transmetalation of the less sterically hindered
aryllithium 3 with an appropriate metal salt (M-X) may
selectively produce the new metalated arene 4 leaving the
more sterically hindered aryllithium (2) untouched and
therefore available for a reaction with an electrophile (E1+)
leading to the 1,2,3-trisubstituted arenes of type 5. On the
other hand, in the organometallic species (4), produced after
the transmetalation step, the carbon–metal bond should be
significantly less reactive than the carbon–lithium bond in 2
and may thus be trapped by a second and different electro-
phile (E2+) producing the regioisomeric 1,3,6-trisubstituted
arene of type 6 (Scheme 1).
Scheme 2. Chemoselective transmetalation using Cp2ZrCl2.
thylphenyllithium 8 leaving 7 untouched and ready for
a selective reaction with an electrophile (Scheme 2). Only
the less sterically hindered aryllithium 8 reacts with Cp2ZrCl2
leading to a less reactive diarylzirconium species (A). These
encouraging results led us to examine the lithiation of various
substrates of type 1. Since oxazolines are important directing
groups for ortho-lithiations, we first examined the lithiation of
the 3-thiomethylaryloxazoline (9).[5] Thus, the lithiation of 9
with nBuLi–TMEDA (1.1 equiv, À808C, 3 h) produces a 4:1
mixture of the regioisomeric 2- and 6-lithio derivatives as
shown by iodolysis. Addition of Cp2ZrCl2 (0.2 equiv, À808C,
1 h) achieved a completely selective transmetalation of the
sterically less hindered 6-lithio derivative of 9, providing the
zirconium species (11) and leaving the lithiated arene (10a)
untouched. Thus, treatment of a mixture of 10a and 11 with
MeSSMe (0.8 equiv, À808C, 1 h) produces only the trisub-
stituted arene (12a) in 84% yield.[6,7] Similarly, the addition of
PhCHO (0.8 equiv, À808C, 1 h) affords alcohol (12b) in 88%
yield and quenching with 4-chlorobenzoyl chloride provides
ketone 12c in 68% yield (Scheme 3).
Herein, we report a successful method for solving the
regioselectivity problem in such arene lithiations. Preliminary
experiments for identifying an appropriate metal salt (M-X)
to perform selective transmetalations were performed on 1:1
mixtures of 2,6-dimethylphenyllithium (7) and 3,5-dimethyl-
phenyllithium (8) and showed that reactions with various Zn,
Mg, Cu, Ti, and Sn salts gave no selective transmetalation.
[4]
However, Cp2ZrCl2 reacted preferentially with 3,5-dime-
We then extended our study to unsymmetrical arenes 13–
16 (Table 1). Thus, the methoxy-substituted oxazoline 13
produces after lithiation with nBuLi–TMEDA (1.1 equiv,
À808C, 3 h) a 93:7 mixture. 1,3-Dicyanobenzene (14) affords,
after metalation with TMPLi (TMP = 2,2,6,6-tetramethylpi-
peridyl; 1.05 equiv, À808C, 0.5 h), an 85:15 mixture; the
reaction of benzonitrile 15 with TMPLi (1.0 equiv, À808C,
20 min) gives a 60:40 mixture. Alkynylbenzene 16 also
[*] M. Sc. A. Castelló-Micó, Dr. S. A. Herbert, Dr. T. León,
Prof. Dr. T. Bein, Prof. Dr. P. Knochel
Department Chemie, Ludwig-Maximilians-Universität München
Butenandtstrasse 5–13, Haus F, 81377 München (Germany)
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/anie.201508719.
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401

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furnishes an 80:20 mixture after lithiation with TMPLi (1.0–
1.1 equiv, À808C, 0.5 h). Treatment of these aryllithium
mixtures with the appropriate amount of Cp2ZrCl2 allows
selective transmetalation of the less sterically hindered
aryllithium providing a less reactive arylzirconium species
and leaving the major aryllithium reagent ready to react with
various electrophiles producing > 97% regioisomerically pure
products of type 17–20. In a typical experiment, the lithiated
aryloxazolines derived from 13 were treated with Cp2ZrCl2
(0.1 equiv, À808C, 1 h) followed by the addition of ethyl
chloroformate (0.9 equiv, À808C, 1 h) providing the 2-carbo-
methoxy arene (17a) in 85% yield free of any regioisomeric
by-product. Similarly addition of BuSSBu led to the produc-
tion of thioether 17b in 83% yield. The 85:15 mixture of
lithiated 14 was similarly treated with Cp2ZrCl2 (0.15 equiv,
À808C, 0.5 h) followed by various electrophiles ((pTolS)2,
(BrCCl2)2, TMSCl), furnishing regioisomerically pure 1,2,3-
trisubstituted dinitriles 18a–c in 66–75% yield (entries 3–5).
The same strategy was applied to arene 15. After the addition
of Cp2ZrCl2 (0.35–0.4 equiv, À808C, 0.5 h), the more sterically
hindered 3-lithio isomer reacted with various electrophiles
(furfural, (ICH2)2, or cyclopropanecarbonyl chloride in the
presence of 10% Sc(OTf)3[8]) producing the regioisomerically
pure products (crude ratio 97:3) 19a–c in 61–78% yield
(entries 6–8). Also, the unselective lithiation of 16 leads, after
the addition of Cp2ZrCl2 (0.25 equiv, À808C, 0.5 h) and
various electrophiles (cyclohexyl isocyanate, iPrOBpin, 4-
chlorobenzaldehyde, furfural, (ICH2)2, (BrCCl2)2, MeSSMe,
2,4-dichlorobenzoyl chloride), to isomerically pure products
(20a–h) in 72–95% yield (entries 9–16).
Scheme 3. Regioselective functionalization of oxazoline (9). Condi-
tions: nBuLi (1.1 equiv), TMEDA (1.1 equiv); 2) Cp2ZrCl2 (0.2 equiv);
3) E1 (0.8 equiv); 4) H2O.
Table 1: Regioselective functionalization of unsymmetric arenes.
Entry Substrate Electrophile
Product[a]
1
2
13
13
ClCO2Et
BuSSBu
17a: E1 =CO2Et, 85%
17b: E1 =SBu, 83%
This methodology was also successfully applied to regioi-
someric mixtures of aryllithiums obtained by Br/Li exchange
(Scheme 4). Indeed, dibromobiphenyl 21 undergoes a non-
3
4
5
14
14
14
(pTolS)2
(BrCCl2)2
TMSCl
18a: E1 =SpTol, 73%
18b: E1 =Br, 75%
18c: E1 =TMS, 66%
6
15
19a: E1 =CH(OH)2-furyl, 75%
7
8
15
15
(ICH2)2
19b: E1 =I, 78%
19c: E1 =COcPr, 61%[b]
Scheme 4. Regioselective functionalization of dibromobiphenyl (21).
Conditions: i) nBuLi (1.05 equiv), ii) Cp2ZrCl2 (0.15 equiv), iii) E1 (0.70–
0.75 equiv), iv) Br2 (excess). All products obtained in >97:3 regioiso-
meric ratio.
9
10
11
16
16
16
cHexNCO
iPrOBpin
20a: E1 =CONHcHex, 85%
20b: E1 =Bpin, 90%
4-ClC6H4CHO 20c: E1 =CH(OH)4-ClC6H4, 79%
20d: E1 =CH(OH)2-furyl, 95%
12
16
regioselective Br/Li exchange with nBuLi (THF, 1.05 equiv,
À808C, 0.5 h) producing a 70:30 mixture of isomers 22a and
22b. The addition of Cp2ZrCl2 (0.15 equiv, À808C, 1.5–2 h)
led to a selective transmetalation (> 97:3) of the less sterically
hindered aryllithium (22b), providing the bis-aryl zircono-
cene (23) and unreacted 22a. Functionalization of 22a with
a range of electrophiles (4-methoxybenzaldehyde, 4-chloro-
benzoyl chloride, phenyl isocyanate, ethyl cyanoformate)
produces the corresponding products (24a–d) in 68–83%
13
14
15
16
16
16
(ICH2)2
(BrCCl2)2
MeSSMe
20e: E1 =I, 74%
20 f: E1 =Br, 72%
20g: E1 =SMe, 87%
16
16
20h: 77%
[a] Yield of analytically pure product (>99%). [b] Sc(OTf)3 was added.
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yield. The remaining diarylzirconocene (23) was converted
back to the starting dibromide 21 in 60–75% yield by adding
bromine.[9]
Interestingly, the related 2,5-dibromotoluene (25) also
undergoes an unselective Br/Li exchange with nBuLi (THF,
1 equiv, À808C, 0.5 h) producing a 30:70 mixture of the two
regioisomeric lithium species 26a and 26b (Scheme 5). The
major regioisomer (26b) is converted into the corresponding
Scheme 6. Unselective 2-, 4-, or 5-lithiation of 1,3-bis(trifluoromethyl)-
benzene (30).
Scheme 5. Regioselective functionalization of 2,5-dibromotoluene (25).
Conditions: i) nBuLi (1.0 equiv), ii) Cp2ZrCl2 (0.3 equiv), iii) (BrCH2)2 or
ArCHO (0.40–0.45 equiv), iv) E2 (0.45–0.55 equiv). All products
obtained in >97:3 regioisomeric ratio.
diarylzirconocene (27) upon addition of Cp2ZrCl2 (0.3 equiv,
À808C, 1.5 h). Quenching of the aryllithium 26a with
(BrCH2)2 or 4-MeOC6H4CHO (0.4–0.45 equiv, À808C, 0.5–
1 h) generates the starting material (25) or the corresponding
alcohol 28, leaving the zirconocene species 27 untouched.
Further allylation, acylation, 1,4-addition, and cross-coupling
allows functionalization of the zirconocene 27 providing the
expected products (29a–d) in 73–79% yield.
CF3-substituted aromatics are very important pharma-
ceutical targets and much recent work on the selective
preparation of CF3-substituted molecules has been
reported.[10] The lithiation of 1,3-bis(trifluoromethyl)benzene
(30) proceeds without any appreciable regiocontrol.[11] Thus,
metalation with nBuLi in THF produces a 40:60 mixture of
the 2- and 4-lithio derivatives 31a and 31b. Alternatively, the
use of tBuLi in ether leads to a 40:60 mixture of the 4- and 5-
lithio derivatives 31b and 31c (Scheme 6). The production of
regioisomeric mixtures makes these lithiations preparatively
useless. However, using the zirconium transmetalation, it was
possible to regioselectively functionalize the three positions
of 30. Selective lithiation at position 2 is reached by treating
30 with nBuLi (THF, 1 equiv, À408C, 1 h), followed by
subsequent addition of Cp2ZrCl2 (0.7 equiv, À808C, 1.5 h);
31b is converted into the corresponding zirconium species
leaving 31a as the sole remaining lithiated reagent. Its
reaction with different electrophiles (4-MeOC6H4CHO, and
(ICH2)2) furnishes the corresponding products 32a and 32b in
81 and 50% yield, respectively (Scheme 7). The selective
functionalization at position 4 is possible using tBuLi (Et2O,
1 equiv, À408C, 18 h) followed by the addition of Cp2ZrCl2
(0.3 equiv, À808C, 1–1.5 h) to the 40:60 mixture of 31b and
31c. In this case, 31c is transmetalated into the corresponding
Scheme 7. Selective 2-, 4-, or 5-functionalization of 1,3-bis(trifluoro-
methyl)benzene (30).
zirconium species and the lithium reagent (31b) is quenched
with various electrophiles: (2-PyrS)2, 3-bromobenzoyl chlo-
ride leading to 33a and 33b with 68 and 69% yield,
respectively. On the other hand, lithiation with tBuLi in
ether has been also used to functionalize the position 5, but in
this case the mixture of 31b and 31c was treated with
Cp2ZrCl2 (0.3 equiv, À808C, 1.5 h) followed by the addition of
4-MeOC6H4CHO (0.5 equiv, À808C, 1 h), which reacted
exclusively with the lithio species (31b). The zirconium
species reacted with subsequently introduced electrophiles
(4-chlorobenzoyl chloride, ethyl 4-iodobenzoate) to produce
the products 34a and 34b in 92 and 79% yield, respectively.
In conclusion, we have demonstrated that the regioselec-
tive transmetalation of isomeric mixtures of various aryllithi-
ums can be readily achieved using a substoichiometric
amount of Cp2ZrCl2 as the transmetalating agent. This
selectivity is best explained by steric considerations. This
method allows the selective differentiation of a mixture of
regioisomeric aryllithiums.
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Acknowledgements
We thank the SFB 749 for financial support. We also thank
Rockwood Lithium GmbH for the generous gift of chemicals.
The research leading to these results has received funding
from the European Research Council under the European
Unionꢀs Seventh Framework Programme (FP7/2007-2013)/
ERC Grant Agreement no. 321339.
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Keywords: lithium · metalation · regioselectivity ·
transmetalation · zirconium
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Received: September 17, 2015
Published online: November 20, 2015
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