University of Groningen
Direct catalytic cross-coupling of organolithium compounds
Giannerini, Massimo; Fananas Mastral, Martin; Feringa, B.L.
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Nature Chemistry
DOI:
10.1038/NCHEM.1678
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Giannerini, M., Fananas Mastral, M., & Feringa, B. L. (2013). Direct catalytic cross-coupling of
organolithium compounds. Nature Chemistry, 5(8), 667-672. DOI: 10.1038/NCHEM.1678
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ARTICLES
PUBLISHED ONLINE: 9 JUNE 2013 | DOI: 10.1038/NCHEM.1678
Direct catalytic cross-coupling of organolithium
compounds
Massimo Giannerini, Martı́n Fañanás-Mastral and Ben L. Feringa*
Catalytic carbon–carbon bond formation based on cross-coupling reactions plays a central role in the production of natural
products, pharmaceuticals, agrochemicals and organic materials. Coupling reactions of a variety of organometallic reagents
and organic halides have changed the face of modern synthetic chemistry. However, the high reactivity and poor selectivity
of common organolithium reagents have largely prohibited their use as a viable partner in direct catalytic cross-coupling.
Here we report that in the presence of a Pd-phosphine catalyst, a wide range of alkyl-, aryl- and heteroaryl-lithium
reagents undergo selective cross-coupling with aryl- and alkenyl-bromides. The process proceeds quickly under mild
conditions (room temperature) and avoids the notorious lithium halogen exchange and homocoupling. The preparation of
key alkyl-, aryl- and heterobiaryl intermediates reported here highlights the potential of these cross-coupling reactions for
medicinal chemistry and material science.
T
ransition metal-catalysed cross-coupling reactions for the
selective formation of C–C bonds enable the facile preparation
of myriad structurally diverse and complex molecules essential
for the development of modern drugs and organic materials1–4.
Typically, Pd or Ni catalysis is used with an organic halide, and
an organometallic or main-group reagent as nucleophilic coupling
partner1,5, although (directing-group based) coupling via C–H activation has recently emerged as a possible alternative6–8. Although
Stille (with organotin as the nucleophile)9,10, Suzuki–Miyaura (organoboron)11,12, Negishi (organozinc)1,13,14, Hiyama–Denmark (organosilicon)15,16 and Kumada (organomagnesium)17,18 couplings are
well established (Fig. 1a), the direct application of organolithium
reagents (among the most reactive and commonly used reagents
in chemical synthesis19) in cross-coupling reactions remains a
formidable challenge. Some of the coupling partners are directly
accessible; for instance, organoboron compounds can be prepared
by hydroboration of unsaturated substrates20 (that is, alkyl and
vinyl boranes) or by borylation of C–H bonds21 (alkyl and aryl
boranes). However, as aryl organoboron and organotin compounds,
in particular, are frequently prepared from the corresponding
lithium reagents, a concise method, taking advantage of the direct
use of organolithium compounds in C–C bond formation, would
eliminate the need for such additional transformations.
Organolithium reagents are cheap and either commercially available
or readily accessible through halogen–metal exchange or direct
metallation. Early studies by Murahashi and co-workers22 on the
use of organolithium reagents for cross-coupling reactions revealed
the limitations of this transformation due to the very high reactivity
of these organometallic compounds and also the high temperatures
required22. One major problem that has precluded the application of
organolithium reagents is the competing formation of homocoupled
products as a result of fast lithium–halogen exchange preceding
Pd-catalysed C–C bond formation. Recently, a Murahashi-type
biaryl coupling was performed using a flow-microreactor23, while
in an alternative approach, a stoichiometric silicon-based transfer
agent was used24. However, the development of an efficient catalytic
protocol for cross-coupling of highly reactive organolithium species
that does not suffer from lithium–halogen exchange and homocoupling has proven elusive until now.
Here, we report a practical method for the fast and highly selective direct cross-coupling of organolithium reagents under mild
conditions, and with broad scope, using Pd catalysis. Catalytic
C–C bond formation readily proceeds with alkyl-, aryl- and heteroaryl-lithium reagents, providing a versatile and mild alternative to
existing protocols (Fig. 1b).
Results and discussions
We anticipated that, to achieve selective cross-coupling of arylbromide and organolithium species, fast lithium–bromide exchange
has to be suppressed by efficient transmetallation and the promotion of fast oxidative addition and subsequent reductive elimination of the organic moieties by the Pd complex. We hypothesized
that competing lithium–bromide exchange might be prevented by
controlling the reactivity and aggregation state of the organolithium
reagent by choosing an appropriate solvent, an approach we recently
took in catalytic asymmetric allylic alkylations25. The high reactivity
of the organolithium species opens the exciting prospect of selective
cross-coupling at room temperature by fine-tuning of the
Pd-catalyst complex.
a
Well established methods:
Transition metal catalyst
R1–X
+
R1–R2
R2–M
X = halide or sulfonate
Stille (M = Sn); Negishi (M = Zn); Suzuki-Miyaura (M = B);
Hiyama-Denmark (M = Si); Kumada (M = Mg).
b
This work: M = Li
Pd catalyst
R1–Br
+
R2–Li
R1 = alkenyl, aryl, heteroaryl
R2 = alkyl, aryl, heteroaryl
1h
Room temperature
R1–R2
Selectivity >95%
High yield
Figure 1 | Catalytic cross-coupling reactions. a, Established methodology
based on organo-tin, -zinc, -boron, -silicon and -magnesium compounds.
b, Cross-coupling using organolithium compounds.
Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 4, 9747 AG, Groningen, The Netherlands. * e-mail: [email protected]
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Table 1 | Cross-coupling of n-BuLi and 4-methoxy-bromobenzene.
Br
Pd complex
Ligand
O
O
O
2a
3
1a
+
Toluene, r.t.
O
n
BuLi
(1.2 equiv.)
O
O
4
Entry
1
2
3
4
5
6
7
Pd complex
Pd2(dba)3 , 2.5 mol%
–
Pd2(dba)3 , 2.5 mol%
Pd2(dba)3 , 2.5 mol%
Pd2(dba)3 , 2.5 mol%
Pd[P(t-Bu)3]2 , 5 mol%
Pd[P(t-Bu)3]2 , 1 mol%
Ligand
XPhos, 10 mol%
–
–
SPhos, 10 mol%
P(t-Bu)3 , 6 mol%
–
–
2x
Reaction time (h)
3
3
3
1
1
1
1
Conversion (%)
Full
25
22
Full
Full
Full
Full
2a:3:4:2x*
80:5:10:5
–:.95:–:–
23:48:29:–
89:5:6:–
90:6:4:–
96:4:–:–
95:4:1:–
*Ratio of products determined by gas chromatography analysis.
Conditions: 1.2 equiv. n-BuLi (1.6 M solution in hexane diluted with toluene to a final concentration of 0.36 M) was added to a solution of 4-methoxy-bromobenzene (3 mmol) in toluene (2 ml).
dba, dibenzylideneacetone; XPhos, 2-dicyclohexylphosphino-2′ ,4′ ,6′ -triisopropylbiphenyl; SPhos, 2-dicyclohexylphosphino-2′ ,6′ -dimethoxybiphenyl.
Pd-catalysed cross-coupling with alkyllithium reagents. For our
initial model reaction (Table 1) we selected 4-methoxybromobenzene, a reluctant arylhalide26 in many coupling
reactions, and n-BuLi, one of the most reactive organometallic
reagents, realizing that successful selective cross-coupling of these
compounds would mean access to an abundance of other
coupling partners. Using, under an inert atmosphere, 1.2 equiv. of
n-BuLi, XPhos (10 mol%)27 as the ligand in combination with
Pd2(dba)3 (2.5 mol%, ratio of Pd to ligand of 1:2), toluene as the
solvent to avoid ethereal compounds capable of enhancing
halogen–metal exchange, with dilution (0.45 M) and slow
addition (3 h) of the lithium reagent to avoid excess
organolithium reagent in solution, the reaction led to the
predominant formation of the desired cross-coupling product
p-methoxybutylbenzene 2a. Although full conversion is reached at
room temperature, the presence of a small but significant amount
(5%) of dehalogenated product 3 (due to Br–Li exchange) and
homocoupled biaryl product 4 (10%), as well as a small amount
(5%) of the isomerized cross-coupling product 2x, illustrates the
manifold competing pathways (Table 1, entry 1). In a few specific
cases, such as the reaction between bromobenzene and n-BuLi in
tetrahydrofuran (THF)28, the coupling product is obtained in the
absence of a metal complex as a result of halogen–metal exchange
and subsequent alkylation of the aryllithium. However, the
reaction with 1a using THF as solvent in the absence of Pd
catalyst gave incomplete conversion, affording a complex mixture
of products (see Supplementary Table S1 for further details).
In toluene, the omission of the Pd catalyst resulted in low
conversion and the exclusive formation of dehalogenated product
3 (Table 1, entry 2). A dramatic drop in selectivity is observed
under phosphine ligand-free conditions (Table 1, entry 3),
implying that the nature of the phosphine ligand is a crucial
parameter27,29,30. Screening in situ prepared Pd catalysts with
different dialkylbiaryl phosphines29 (Supplementary Table S1) we
found that the use of SPhos enhanced the selectivity towards 2,
completely suppressing the isomerization reaction while
simultaneously shortening the addition time to 1 h (entry 4).
However, selectivity higher than 90% could not be achieved using
this type of ligand (Supplementary Table S1). It should be noted
that the coupling reaction is remarkably fast at room temperature
and is finished upon complete addition of the organolithium
reagent. As hindered trialkylphosphines30 are frequently used in
668
cross-coupling reactions to enhance reductive elimination and
avoiding beta-hydrogen elimination (which is yet another
competing pathway to the formation of dehalogenated and
isomerized products)31, the ligand P(tBu)3 was also tested. The use
of the in situ formed complex from Pd2(dba)3 and P(tBu)3 gave
rise to a selectivity comparable with those obtained with
dialkylbiaryl phosphines (Table 1, entry 5). When the
commercially available preformed complex Pd[P(tBu)3]2 (5 mol%)
was used instead of the in situ formed catalyst, cross-coupled
product 2a was obtained in high yield and with excellent
selectivity, with minimal halogen exchange taking place while
completely inhibiting the formation of the homocoupling product
4 (Table 1, entry 6). Remarkably, the reaction also proceeds with
1 mol% of catalyst, with similar selectivity (Table 1, entry 7).
With the optimal conditions for highly selective alkyl–aryl crosscoupling determined, the scope of the reaction of alkyllithium
reagents and arylbromides was examined (Table 2).
The Pd-catalysed coupling of alkyllithium compounds with arylbromides entails substrates bearing halide, alcohol, acetal and ether
functionalities, electron-withdrawing chlorides and electron-donating methoxy and dimethylamine substituents (Table 2). With
p-chloro-bromobenzene, coupling occurs, as expected, exclusively
at the bromine-substituted carbon, but with no detectable chloride
displacement (2c). Polyaromatic compounds such as bromonaphthalene are regioselectively alkylated at position 1 (2d) or 2
(2e–2f ), indicating that benzyne intermediates via 1,2-elimination
are not formed. Remarkably, bromofluorene could be alkylated
(2g,2h) using only 1.2 equiv. of the corresponding organolithium
reagent, despite the acidity of the benzylic protons ( pKa ¼ 22).
The scope of this C(sp 3)–C(sp 2) cross-coupling also includes alkyllithium reagents ranging from the smallest MeLi (2f, 2h) to those
bearing long alkyl chains (2i–2k). The cross-coupling of the functionalized lithium reagent trimethylsilylmethyllithium proceeds with
excellent yields (2l–2o). Facile multiple coupling is illustrated with
the twofold alkylation of 4,4′ -bis-bromobiphenyl, providing 2p in
91% yield. In addition, alkenyl bromides also undergo this crosscoupling with high selectivity, as shown by the coupling between
2-bromovinylbenzene and n-BuLi (2q) and (Z)-1-bromopropene
and n-HexLi (2r). It is important to note that the stereochemical
information is preserved and no olefin isomerization takes place
during the reaction. Using this protocol, acetal-protected aldehydes
were also tolerated (2s) without the interference of n-BuLi-mediated
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Table 2 | Scope of Pd-catalysed cross-coupling of alkyllithium reagents.
Pd[P(tBu)3]2 5 mol%
Ar–Br
+
Ar –R
RLi
Toluene, r.t.
1
N
O
2a, 80%
2
Cl
2b, 88%
2c, 84%
2d, 92%
2e, 87%
15
O
2g, 88%
Cl
2h, 90%
TMS
5
O
TMS
5
N
2i, 88%
TMS
2f, 83%
O
2j, 94%
2k, 95%
2l, 93%
TMS
S
Ph
5
Cl
2m, 97%
2n, 93%
2o, 87%
2p, 91%
2r, 99%*
2q, 89%
OH
CO2Me
O
N
O
2s, 92%
2u, 43%†
2t, 61%
O
2v, 75%
O
2w, 78%
Cl
2x, 89%
2y, 79%
t
Conditions: aryl bromide (0.3 mmol), RLi (0.36 mmol, diluted with toluene to reach 0.36 M concentration and added over 1 h), Pd[P( Bu)3]2 5 mol%, toluene (2 ml) at room temperature. Selectivity .95% in all
cases, unless otherwise noted.
Yield values refer to isolated yields after purification.
*GC yield: product was not isolated due to volatility issues.
†
Reaction carried out with the corresponding aryl iodide, 7.5 mol% Pd[P(tBu)3]2 at 210 8C (see Supplementary Table S3 for details). Added alkyl group is shown in bold in each case.
cleavage of the protecting group. Remarkably, substrate 1t, bearing
an unprotected hydroxyl group, could also be coupled with this
organolithium reagent (2 equiv.) to afford alcohol 2t in a good
yield. Although the use of ketone- or nitrile-containing substrates
proved to be incompatible with this reaction, mainly due to the formation of 1,2-addition side products, compound 1u, bearing an
ester group, could be coupled with MeLi in moderate yield. In
this case, it was necessary to use the corresponding aryl iodide
and a lower temperature (210 8C) to achieve good selectivity (see
Supplementary Table S3 for details).
A recurring challenge in the field of cross-coupling reactions is to
achieve selective C–C bond formation of organometallic reagents
Br
O
3
O
Conditions
1a
Toluene, 1 h
+
O
O
5a
PhLi
1.2 equiv.
O
t
Conditions: Pd[P( Bu)3]2 5 mol%
Pd2(dba)3 2.5 mol%, P(tBu)3 7.5 mol%
4
Conversion
5a:3:4
70%
Full
90:–:10
98:–:2
Figure 2 | Cross-coupling of phenyllithium and 4-methoxy-bromobenzene.
Optimization of the synthesis of biaryl 5a and possible side products arising
from a halogen–lithium exchange (3) and a homocoupling reaction (4).
bearing secondary alkyl moieties32,33, without isomerization of the
alkyl moiety. The ease of coupling secondary alkyllithium reagents
therefore came as a surprise; both i-PrLi and the more challenging
s-BuLi undergo Pd-catalysed coupling with arylbromides with electron-donating and -withdrawing substituents in high yields,
showing no isomerization at all (2v–2y), presumably due to fast
transmetallation–reductive elimination steps being inherent to this
catalytic system.
Pd-catalysed cross-coupling with (hetero)aryllithium reagents.
With an efficient procedure for aryl–alkyl cross-coupling
established, we turned our attention to aryl–aryl cross-coupling
using arylbromides and aryllithium reagents (Fig. 2). Although the
coupling of phenyllithium and 4-methoxybromobenzene 1a
proceeds in toluene at room temperature using Pd[P(tBu)3]2 as
catalyst, full conversion and selectivity was not achieved. Further
optimization of the reaction conditions (Supplementary Table S2)
showed that full conversion was restored by using the in situ
prepared catalyst34 using Pd2(dba)3 and P(tBu)3 as ligand. By
diluting the PhLi reagent in THF the selectivity was further
enhanced, but traces of dehalogenated product appeared. In
accordance with our hypothesis, lowering the amount of THF
eliminated this side reaction, and finally using 2.5 mol% Pd
catalyst with a ligand to Pd ratio of 1.5:1 under optimized
conditions resulted in biaryl formation (in 1 h at room
temperature) with excellent isolated yield and 98% selectivity (Fig. 2).
Studying the scope of biaryl formation via Pd-catalysed cross-coupling of a range of arylbromides and aryllithium reagents showed that at
20 8C in 1 h the corresponding biaryls 5 are obtained in high yields
(Table 3). For example, electron-rich (5a,5b) and electron-poor (5c)
phenylbromides and naphthylbromide (5d) were readily arylated. It
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Table 3 | Scope of Pd-catalysed cross-coupling of aryllithium reagents.
Pd2(dba)3 2.5 mol%
P(tBu)3 7.5 mol%
Ar–Br
+
Ar–Ar'
Ar'Li
Toluene, r.t.
5
1
Organolithium source
Products
Commercial
O
N
Li
N
H
Cl
5a, 84% (93%)*
5b, 80%
5c, 85%
5d, 83%
5e, 89%
S
Li
S
S
S
F3C
O
†
5g, 88%†
5f, 81%
5h, 81%‡
O
Li
R–Li
R
5j, 84%
CF3
Halogen-lithium exchange
Br
5i, 99%†,§
N
O
R
O
5k, 90%
5l, 75%
O
O
5n, 80%
5m, 71%
Directed metallation
DMG
DMG
Li
R–Li
O
O
O
Li
Cl
5o, 84%
OMOM
O
5p, 88%
5q, 86%
OMOM
5r, 82%
Conditions: bromide (0.3 mmol), ArLi (0.45 mmol, diluted with THF to reach 0.60 M concentration and added over 1 h), Pd2(dba)3 2.5 mol%, P(tBu)3 7.5 mol%, toluene (2 ml) at room temperature.
Selectivity .95% in all cases.
Yield values refer to isolated yields after purification.
DMG, directing metallation group. Added aryl group is shown in bold in each case.
*Yield in brackets refers to the 1 g scale reaction using 1 mol% of catalyst.
†
Reaction performed using TMEDA (1.2 equiv.) at 40 8C.
‡
Reaction performed on a 1.5 mmol scale.
§
Gas chromatography yield: single product (see Supplementary Information, page S20 for details).
is important to note that 5a could be obtained in 93% yield with total
selectivity when the reaction was carried out starting with 5.5 mmol
(1.029 g) of 1a using 1 mol% of the catalyst. Remarkably, the presence
of an acidic proton, as in the case of 5-bromo-indole, was tolerated,
providing 5-phenylindole 5e in 89% yield. In this case, 3 equiv. of
PhLi were necessary to reach full conversion.
Heterocyclic lithium compounds are also successful coupling
partners. In the case of thienyllithium the reduced reactivity of
this organometallic reagent required the use of tetramethylethylenediamine (TMEDA) as activating agent and a slightly higher temperature (up to 40 8C, 1 h). Under these conditions, corresponding
products 5f and 5g were obtained in 81% and 88% yield with
electron-poor and electron-rich arylbromides, respectively. The
C(sp 2)–C(sp 2) cross-coupling was also extended to the reaction of
alkenylbromides with aryllithium, providing tetrasubstituted arylalkene 5h and thiophene-substituted Z-olefin 5i in high yields.
Again, 1H-NMR analysis revealed that the olefin geometry was preserved. Moreover, a sterically hindered ortho-substituted arylbromide such as 2,3-dimethyl-bromobenzene could be coupled in
high yield and without loss of selectivity (5j). The versatility and
mild conditions of the cross-coupling prompted us to examine the
compatibility with currently available procedures to access aryllithium species. In Table 3, the various sources of the aryllithium
670
reagents are highlighted; these include commercially available organolithium reagents, those prepared via halogen–metal exchange,
and organolithium compounds synthesized by direct metallation.
The Pd-catalysed coupling reaction of various aryllithium compounds, by exploiting the halogen–lithium exchange reaction starting with arylbromides, showed that a range of substituted
aryllithium compounds can be applied (Table 3, 5k–5n). An intriguing result is that the very hindered bis-ortho-substituted
2,6-dimethyl-phenyllithium undergoes cross-coupling with electron-rich 4-methoxy-bromobenzene to provide biaryl 5k in 90%
yield without the need to increase the temperature, reaction
time or catalyst loading, while the presence of the even more electron-donating 4-N,N-dimethylamino- moiety still provides the
corresponding biaryl 5l in good yield. An illustrative example of
the direct metallation method is the highly selective and fast coupling of furyllithium, obtained by direct lithiation of furan,
which provides p-methoxy- and p-chloro-substituted compounds
5o and 5p in high yields. Having identified extremely mild conditions for heteroaryl–aryl cross-coupling we examined the most
widely used method in synthesis for ortho-functionalization of
arenes, which is based on organolithium reagents obtained
through directed ortho-lithiation35. As shown in Table 3, methoxymethyl (MOM)-protected phenol was converted in the
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a
Reported method
Cl
Cl
Br
O
O
Cl
Cl
Cross-coupling
Cl
M: BF3K (Mw: 106.96)
Pd(dppf)Cl2·CH2Cl2, 5 mol%,
Cs2CO3 (3 equiv.), toluene, 90 oC, 48 h.
85% yield
This work
+
2z
Cl
N
HO
S1P5 selective agonist
M
O
b
M: Li (Aw: 6.94)
Pd[P(tBu)3]2, 5 mol%,
toluene, r.t., 1 h.
86% yield
Reported method
C8H17
Br
C8H17
C8H17
Br
Cross-coupling
C8H17
S
Photo- and redox active polymers
(OLEDs, photovoltaic devices,...)
S
+
This work
M: Li (Aw: 6.94)
Pd2(dba)3, 2.5 mol%, P(tBu)3 7.5 mol%
TMEDA, (1.2 equiv.) toluene, 40 oC, 1 h.
85% yield
5s
S
M: SnBu3 (Mw: 290.06)
Pd(PPh3)4, 3 mol%,
DMF, 90 oC, 24 h.
73% yield
M
Figure 3 | Comparison of established methods and the present cross-coupling protocol with organolithium reagents. a, Synthesis of key intermediates for
an S1P5 receptor agonist compared with the reported procedure using butyl potassium trifluoroborate36. b, Synthesis of optoelectronic polymers, compared
with the reported Stille coupling38,39. These examples illustrate how the use of the corresponding organolithium reagents allows the reactions to proceed
under milder conditions, with shorter reaction times and with a reduction in waste. TMEDA, tetramethylethylenediamine; DMF, N,N-dimethyl formamide.
ortho-lithiated reagent using n-BuLi, and subsequent Pd-catalysed
coupling with p-methoxybenzene provided the corresponding
ortho-para-di-substituted biaryl 5q in 86% yield. A similar selectivity was observed when this ortho-lithiated reagent was coupled with
2-bromonaphthalene (5r).
Applicability of the Pd-catalysed cross-coupling with
organolithium reagents. Finally, we compared the Pd-catalysed
cross-coupling of alkyl- and aryllithium reagents with some
established methods, as shown for representative alkylations and
arylations currently used in the production of building blocks in
pharmaceutical and materials chemistry (Fig. 3). The first example
involves direct aryl–alkylation with organolithium in the
preparation of 3,5-dichlorobutylbenzene, a key intermediate in
the synthesis of an S1P5 receptor agonist, a potential drug for the
treatment of cognitive disorders36. The reaction of 1-bromo-3,5dichlorobenzene with n-BuLi in toluene in the presence of
5 mol% Pd[P(tBu)3]2 provided the cross-coupled product 2z in
86% yield. Although organoboron compounds have proven to be
highly versatile and chemoselective reagents for cross-coupling
reactions37, the lower reactivity of alkyl boron reagents usually
requires more severe coupling conditions. The dramatic difference
in reaction conditions should be noted when comparing the
current procedure, based on the organofluoroborate compound as a
coupling partner, to reach the same yield of target compound and
using the same catalyst loading (48 h at 90 8C versus 1 h at 20 8C).
The versatility of the aryl–aryl cross-coupling is also illustrated in
the synthesis of the bis-thienyl-fluorene derivative 5s, a member of
a family of widely used oligoarene building blocks in the
preparation of optoelectronic organic materials38,39. Pd-catalysed
twofold arylation of representative bis-bromo-dialkylfluorene with
2-thienyllithium provides rapid access to the target compound 5s
in high yield, with both product formation and reaction conditions
again comparing highly favourably with existing synthetic
methodology (40 8C, 1 h, 85% yield when 2-thienyllithium is used
versus 90 8C, 24 h, 73% yield for tributyl(thiophen-2-yl)stannane).
Comparing the direct alkylation and arylation using the lithium
reagents with the organoboron- and stannous-based variants shown
in Fig. 3, the most prominent features are the short reaction times
and very mild reaction temperatures, while still maintaining high
yields. It should be noted that, although used in myriad cross-
couplings and with organoboranes showing high functional group
tolerance, some of the B- or Sn-based methods need an additional
reaction step to prepare the organometallic partner, frequently starting from the corresponding organolithium reagents. Organolithium
reagents are highly reactive, but the fact that they are easy accessible,
among the cheapest of organometallic reagents commercially available, with well-established methodology for safe handling, has contributed to their widespread use in synthetic chemistry. Despite the
tremendous success of cross-coupling, complementary methods
that are concise and selective, avoid toxic waste, and feature
improved step- and atom-economy are highly warranted. The
examples shown in Fig. 3 illustrate how, through the use of organolithium reagents, the need to prepare the Sn or B reagents might be
avoided, the sometimes notorious problems with purification (complete removal of toxic and nonpolar Sn side products) are eliminated, the amount of waste products is drastically reduced
(Fig. 3a; the atom efficiency to prepare 2z is 67% using n-BuLi
versus 17% using potassium n-butyl trifluoroborate) and excess
base (for example, 3 equiv. Cs2CO3) is not required.
Conclusion
In summary, we have developed a fast and highly selective method
for the direct catalytic cross-coupling of alkyl- and (hetero)aryllithium reagents. The reaction takes place under mild conditions
with a broad scope of alkenyl and (hetero)aryl bromides. Several
functional groups, including halides, acetals, ethers, amines and
alcohols, as well as acidic protons, are tolerated. Although this protocol is not compatible with ketones or nitriles, we have shown in a
preliminary study that ester moieties can be used with good selectivity. The results from the present study have demonstrated that
Pd-catalysed cross-coupling of cheap and readily available alkyland aryllithium reagents represents a valuable alternative for the
mild, selective and atom-economic formation of C–C bonds for
the construction of building blocks for biologically active compounds and organic materials.
Methods
General procedure for the Pd-catalysed cross-coupling with alkyllithium
reagents. (Caution! Some organolithium reagents can be pyrophoric.) In a dry
Schlenk flask, Pd[P(t-Bu)3]2 (5 mol%, 0.015 mmol, 7.66 mg) and the substrate
(0.3 mmol) were dissolved in 2 ml of dry toluene under an inert atmosphere. The
corresponding lithium reagent (1.2 equiv.) was diluted with toluene to reach a
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concentration of 0.36 M. This solution was slowly added over 1 h using a syringe
pump. After the addition was completed, a saturated aqueous solution of NH4Cl was
added and the mixture was extracted three times with diethyl ether. The organic
phases were collected, and solvent evaporation under reduced pressure afforded the
crude product, which was then purified by column chromatography.
General procedure for the Pd-catalysed cross-coupling with aryllithium reagents.
In a dry Schlenk flask, Pd2(dba)3 (2.5 mol%, 0.0075 mmol, 6.87 mg) and P(t-Bu)3
(7.5 mol%, 0.0225 mmol, 4.55 mg) were dissolved in toluene and the substrate
(0.3 mmol) was added under an inert atmosphere. The corresponding aryllithium
reagent (1.5 equiv.) was diluted with THF to reach a concentration of 0.6 M (unless
otherwise specified); this solution was slowly added over 1 h using a syringe pump.
After the addition was completed, a saturated solution of aqueous NH4Cl was added
and the mixture was extracted three times with diethyl ether. The organic phases
were collected, and solvent evaporation under reduced pressure afforded the crude
product, which was then purified by column chromatography.
Additional experimental procedures, descriptions of compounds and analytical
methods are given in the Supplementary Information.
Received 14 December 2012; accepted 3 May 2013;
published online 9 June 2013; corrected online 17 June 2013
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Acknowledgements
The authors thank the Netherlands Organization for Scientific Research (NWO-CW), the
National Research School Catalysis (NRSC-C) and the European Research Council (ERC
advanced grant 227897 to B.L.F.) for financial support.
Author contributions
M.G. and M.F.-M. performed the experiments. M.G., M.F.-M. and B.L.F. designed the
experiments, analysed the data and wrote the manuscript. B.L.F. guided the research.
Additional information
Supplementary information and chemical compound information are available in the
online version of the paper. Reprints and permissions information is available online at
www.nature.com/reprints. Correspondence and requests for materials should be addressed
to B.L.F.
Competing financial interests
The authors declare no competing financial interests.
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