Palladium-catalysed direct cross-coupling of secondary alkyllithium reagents

Article abstract of DOI:10.1039/c3sc53047g

Palladium-catalysed cross-coupling of secondary C(sp³) organometallic reagents has been a long-standing challenge in organic synthesis, due to the problems associated with undesired isomerisation or the formation of reduction products. Based on our recently developed catalytic C-C bond formation with organolithium reagents, herein we present a Pd-catalysed cross-coupling of secondary alkyllithium reagents with aryl and alkenyl bromides. The reaction proceeds at room temperature and on short timescales with high selectivity and yields. This methodology is also applicable to hindered aryl bromides, which are a major challenge in the field of metal catalysed cross-coupling reactions.

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Palladium-catalysed direct cross-coupling of secondary alkyllithium
reagents
Carlos Vila, Massimo Giannerini, Valentín Hornillos, Martín Fañanás-Mastral* and Ben L. Feringa*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
Palladiumꢀcatalysed crossꢀcoupling of secondary C(sp3) organometallic reagents has been a longꢀstanding
challenge in organic synthesis, due to the problems associated with undesired isomerization or the
formation of reduction products. Based on our recently developed catalytic CꢀC bond formation with
organolithium reagents, herein, we present a Pdꢀcatalysed crossꢀcoupling of secondary alkyllithium
10 reagents with aryl and alkenyl bromides. The reaction proceeds at room temperature and in short times
with high selectivity and yields. This methodology is also applicable to hindered aryl bromides and
comprises a major challenge in the field of metal catalysed crossꢀcoupling reactions.
the secondary organometallic reagent affords the corresponding
intermediate B. This intermediate can form the desired branched
iPrꢀAr product (b) and regenerate the palladium catalyst via
35 reductive elimination. As a competing reaction, B can undergo βꢀ
hydride elimination resulting in the formation of olefinꢀ
coordinated metal hydride C, which can afford D by migratory
insertion leading to the undesired linear product (l) after reductive
elimination. Also, the dissociation of the intermediate C can give
40 rise to the corresponding olefin and formation of arene (ArꢀH)
upon reductive elimination. To suppress the isomerisation
products, the rate of reductive elimination, relative to βꢀhydride
elimination should be enhanced as much as possible. Successful
examples of the use of palladium,4ꢀ16 nickel17 and other metal
45 complexes18 as catalysts for the crossꢀcoupling of secondary
organometallic reagents have been described. For example, in the
pioneering work of Hayashi,4 PdCl2(dppf) was shown to catalyse
efficiently the reaction between secꢀbutylmagnesium chloride
with some aryl and alkenyl halides. Suzuki5 reported in 1989 the
50 crossꢀcoupling of secondary alkylboron compounds with
iodobenzene in moderate yields. Crudden6 in 2009 reported a
palladiumꢀcatalysed crossꢀcoupling of benzylic boronic esters and
aryl iodides with retention of configuration. Molander7 and van
den Hoogenband,8 disclosed a SuzukiꢀMiyaura reaction with
55 secondary alkyl trifluoroborates. In the case of Negishi crossꢀ
coupling, Knochel9 reported a stereoselective reaction between
secondary diorganozinc reagents and (E)ꢀ1ꢀiodohexene.
Subsequently, several groups focused on secondary organozinc
reagents. In order to avoid aryl iodides, Buchwald10 described an
60 efficient catalytic system based on the bulky biarylphosphine
ligand CPhos for the reaction of secondary alkylzinc reagents
with common aryl bromides and chlorides. In 2010, Knochel11
described a highly diastereoselective Negishi coupling with
substituted fiveꢀ and sixꢀmembered cycloalkylzinc reagents.
65 Finally, Organ12 disclosed a very effective system using secꢀ
alkylZnBr reagents and PdꢀPEPPSIꢀIPentCl while Hiyama13
Introduction
Transition metal catalysed crossꢀcoupling reactions, and in
15 particular palladium mediated couplings, have been extensively
used for CꢀC bond formation in synthetic chemistry during the
past three decades.1 Among all these transformations, the
coupling between C(sp2) and secondary C(sp3) partners is a
challenging reaction. In this context, the coupling of secondary
20 alkyl halides and C(sp2) nucleophiles2 has been studied to a larger
extent than the reverse crossꢀcoupling of secondary C(sp3)
organometallic nucleophiles with aryl halides.3 The use of
secondary organometallic reagents in palladium catalysed crossꢀ
coupling presents an additional problem as these organometallics
25 moieties show propensity to isomerise the alkyl chain as
illustrated in the mechanism depicted in Scheme 1.1a
Scheme 1 Proposed catalytic cycle for the Pdꢀcatalysed crossꢀcoupling of
iPrM with an aryl bromide.1a
30
The oxidative addition of the aryl bromide to the Pd(0)
complex generates Pd(II) species A, which by transmetallation of
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reported a crossꢀcoupling with secondary alkylsilanes with very
good selectivities. Recently, Biscoe14 described a successful Stille
were alkylated regioselectively at the position of the bromoꢀ
substituted carbon (2lꢀq), showing that the formation of benzyne
reaction between aryl halides and secondary alkyl 55 intermediate via 1,2ꢀelimination did not take place.
azastannatranes.
R1
R2
R1
R2
Pd(PtBu3)2 (5 mol%)
Toluene, rt
5
Despite the great progress in crossꢀcoupling of secondary alkyl
organometallics, the toxicity, availability or preparation of these
reagents represent a limitation in a number of cases. The design
of alternative mild and selective catalytic procedures based on
readily available reagents continues therefore to be a highly
Ar
Ar Br
+
Li
2
1
10 desirable goal.
Organolithium reagents are commonly used reagents in
chemical synthesis.19 Pioneering studies by Murahashi20a of biaryl
coupling using organolithium reagents revealed also the major
limitations associated with the high reactivity of these
15 organometallic compounds. As a consequence, the use of
organolithium reagents has largely been neglected in the field of
crossꢀcoupling reactions.20 In particular, secondary organolithium
reagents represent a formidable challenge owing to their even
higher reactivity and basicity. Very recently, our group described
20 a direct catalytic crossꢀcoupling of organolithium compounds
with high selectivity and broad scope.21 The process proceeds
quickly at room temperature and avoids the notorious lithium
halogen exchange and homocoupling while the waste is simply
LiBr.
MeO
MeO
MeO
2e, 55%
OMe
OMe
2a, 85%
2b, 73%, 77%a
2c, 85%
2d, 76%
F3C
NMe2
2i, 75%
Cl
CH2OH
2j, 61%
Cl
2h, >98% convb.
2f, >98% conv.b
2g, 78%
25 Building on our recent findings, herein, we present a highly
efficient and selective catalytic crossꢀcoupling of secondary
alkyllithium reagents with aryl and alkenyl bromides which
proceeds quickly (1ꢀ1.5 h) at ambient temperature (Scheme 2).
We also performed the reaction with hindered aryl bromides that
30 have been rarely studied previously.3
2m, 90%,e
95:5 b:ld
2l, 87%c
98:2 b:ld
2k, 83%
2n, 96%
2q, 97%, 99:1 b:ld
2r, 94%
2o, 93%
2p, 80%
Scheme 2 Palladium catalysed direct crossꢀcoupling of secondary alkyl
organolithium reagents.
MeO
2t, 94%
Cl
Cl
2v, 87%
Cl
2s, 95%
2u, 89%
Results and discussion
Ph
35 In order to establish a mild and general methodology for the
coupling of secondary lithium reagents, a wide range of aromatic
bromides were reacted with these lithium reagents, at room
S
temperature in the presence of a catalytic amount of Pd(PtBu3)2
22
MeO
2y, 95%f 2z, 86%f
(Scheme 3). As shown in our previous work,21 the use of a nonꢀ
40 polar solvent such as toluene and the slow addition of the
organolithium reagent were key factors in order to avoid the
lithiumꢀhalogen exchange.23 Thus, the corresponding C(sp2)ꢀ
C(sp3) crossꢀcoupling products were obtained in high yields and
OMe
2w, 93%
2x, 79%
Scheme 3 Substrate scope for the palladium catalyse crossꢀcoupling of
secondary alkyllithium reagents and aryl bromides. Reaction conditions:
60 RLi (0.36 mmol, diluted in toluene to reach 0.36 M) was added dropwise
over 1 h to a stirred solution of ArBr (0.3 mmol) and Pd(PtBu3)2 (0.015
mmol) in 2 mL of dry toluene at room temperature. Yield values refer to
isolated yields after column chromatography. Branched:linear ratio >99:1
by 1H NMR analysis unless otherwise noted.a 5.5 mmol (1.03 g) scale
i
with excellent selectivities. The reaction with PrLi or secꢀBuLi
45 proceeds smoothly, independently of the electronic nature of the
substituents in the aromatic ring (2a-h). For example, in the
reaction with pꢀchloroꢀbromobenzene (2f and 2g), only the
substitution of the bromide was observed, proving the high
selectivity of this palladiumꢀcatalysed crossꢀcoupling. In addition,
50 (4ꢀbromophenyl)methanol 1j, bearing a free hydroxyl group,
could be coupled with iPrLi (2.4 equiv) in good yield.
Polyaromatic compounds such as 1ꢀ and 2ꢀbromonaphthalene
b
65 reaction using 2 mol% of catalyst. GC conversion, the product was not
isolated due to volatility issues. 4% dehalogenation (ArꢀH) determined
c
1
d
by GC and H NMR analysis. b:l refers to the branched:linear ratio of
the product determined by 1H NMR analysis. e 5% dehalogenation (ArꢀH)
determined by GC and 1H NMR analysis. RLi (0.4 mmol) was added
f
70 dropwise over 2 h at 40 °C.
2
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Interestingly, 2ꢀbromofluorene could be alkylated (2r and 2s)
with only 1.2 equivalents of the corresponding organolithium
reagent, despite the acidity of the benzylic protons (pKa=22).
Cyclopropyllithium could also be coupled successfully and the
corresponding products 2e and 2p were obtained in good yields.
Additionally, to test the synthetic utility of the present
methodology, 2b was prepared on a gram scale (1.03 g, 5.5
mmol) with similar yield and selectivity using only 2 mol% of
Pd(PtBu3)2 in this case.
5
10
Taking into consideration the acidity of the benzylic protons of
fluorene,24 we decided to investigate the coupling of the
corresponding fluorenyllithium reagent generated directly and
n
easily by deprotonation of fluorene with BuLi.25,26 The resulting
products would be of special synthetic interest as fluorene is an
15 essential core structure in numerous material science applications.
For example, polyfluorenes are widely used in organic
optoelectronic devices, such as organic lightꢀemitting diodes or
organic photovoltaic cells.27 The palladiumꢀcatalysed crossꢀ
coupling of fluorenyllithium reagent with different substituted
20 aryl bromides proceeded smoothly, and the corresponding
products (2tꢀx) were isolated in excellent yields. Notably, the
presence of MeO or Cl substituents in products 2t-x allows for
further functionalization of the aromatic ring. Finally, 2ꢀbromoꢀ5ꢀ
phenylthiophene was successfully coupled with fluorenyllithium
25 affording the corresponding product 2x in 79% yield.
Indenyllithium, prepared easily by deprotonation of indene with
tBuLi, was also examined as a lithium reagent. Due to the lower
reactivity of this lithium reagent, the reaction had to be carried
out at 40 °C to reach full conversion. The corresponding products
30 2y and 2z were isolated with excellent yields. Note that complete
isomerization of the double bond to the more substituted position
was observed.
55
Scheme 4 Threeꢀcomponent coupling involving olefin carbolithiation and
alkylꢀaryl cross coupling Reaction conditions: RLi (0.36 mmol) was
added dropwise over 1ꢀ1.5h to a stirred solution of aryl bromide (0.3
mmol) and Pd(PtBu3)2 (0.015 mmol) in 2 mL of dry toluene at room
60 temperature.
Having established this new coupling reaction with different
aryl bromides, we turned our attention to the palladiumꢀcatalysed
crossꢀcoupling of secondary alkyllithium reagents with alkenyl
bromides. This reaction would imply a selective synthesis of
65 olefins branched at the alpha position which represents a
cornerstone in organic chemistry. However, examples of
palladiumꢀcatalysed crossꢀcoupling of secondary alkyl
organometallic reagents with alkenyl bromides are scarce.
Following the early report of Hayashi,4 where the crossꢀcoupling
70 reaction of secꢀBuMgCl with (E)ꢀβꢀbromostyrene and 2ꢀ
bromopropene was described for the first time, only Knochel9 had
shown the reaction between secondary diorganozinc reagents and
(E)ꢀ1ꢀiodohexene catalysed by palladium. Therefore, the
development of new crossꢀcouplings of alkenyl bromides is
75 highly desirable. To our delight, βꢀbromostyrene (commercially
available as 84/16 trans/cis mixture) reacted under the above
mentioned conditions (1 h, rt) with isopropyl, secꢀbutyl,
cyclopropyl, and 9ꢀfluorenyllithium reagents, affording the
corresponding products (5aꢀd) in high yields (Scheme 5). In
A particular interesting method to generate secondary alkyl
organolithium reagents involves the direct alkene carbolithiation.
35 This is an efficient and versatile procedure, that occurs with
complete atom economy.28 Consequently, we examined our
palladiumꢀcatalysed crossꢀcoupling methodology with the
corresponding secondary alkyl organolithium reagents generated
in situ from the carbolithiation of styrene and 2ꢀvinylnaphthalene
i
40 with commercially available alkyllithium reagents such as PrLi,
t
nBuLi, secꢀBuLi or BuLi (Scheme 4). Once we generated the
corresponding benzylic organolithium reagents, the reaction with
aryl bromides was tested under the optimised conditions and the
corresponding 1,1ꢀdiarylalkane products 3a-f could be isolated in
45 moderate yields.29 It is important to note that the 1,1ꢀdiarylalkane
core is present in many natural products and is a prominent
structure in numerous pharmaceutical intermediates.30 The
present methodology represents a straightforward transformation
to access these moieties. In addition, these results showed that a
50 three component addition/crossꢀcoupling is feasible. It should be
noted that this carbometalation for the generation of secondary
alkyl reagents in palladium catalysed crossꢀcoupling has, to the
best of our knowledge, not been previously described.
80 addition,
2ꢀbromoꢀ3ꢀmethylbutene
and
(bromomethylene)cyclohexane, also underwent this palladiumꢀ
catalysed crossꢀcoupling affording the corresponding olefins with
very good conversions (5eꢀg and 5hꢀi). It should be emphasized
that the stereochemical integrity of the alkenyl bromide is
85 preserved and no olefin isomerisation occurs in the course of the
reaction. Thus, (Z)ꢀ1ꢀbromopropene and 9ꢀfluorenyllithium were
successfully coupled, providing the product 5j as pure Z isomer.
Finally, the coupling of secꢀbutyl, cyclopropyl, and 9ꢀ
fluorenyllithium reagents with 1ꢀ(1ꢀbromovinyl)ꢀ4ꢀchlorobenzene
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occurred exclusively at the Brꢀsubstituted carbon, and the
corresponding olefins (5kꢀm) were selectively obtained in high
and the rate of the βꢀhydride elimination and migratory insertion
sequence is of a similar order as the rate of the reductive
yields, showing no dechlorination or coupling at the aromatic 30 elimination (see Scheme 1). Other bulky phosphines were
ring.
evaluated (Table 1) in order to increase the reductive elimination
rate relative to the rate of βꢀhydride elimination. Biaryl based
ligands31 L1, L2 and L3 gave unsatisfactory results, and the
major reaction product was the reduced arene32 (anthracene, 9)
35 (entries 2ꢀ4). PdꢀPEPPSIꢀIPent12 (entry 5) gave an improvement
reducing the isomerisation to afford a 2:1 b:l ratio, but showing
far from satisfactory selectivity. Finally, when Hartwig’s Qphos33
(L4, entry 6), a very hindered ligand, was used full conversion
was achieved with 96% isolated yield of the desired product 7a,
40 with an excellent 97:3 b:l ratio. Therefore, when QPhos is used as
a ligand, probably, a fast transmetallationꢀreductive elimination
occurs, that avoids the other competitive pathways leading to 7a
as the major product. Remarkably, the catalyst loading could be
decreased to 2.5 mol% without erosion in the reactivity or
45 selectivity providing 7a in 97% isolated yield (entry 7).
Furthermore, 0.63 mol% of Pd2(dba)3 and 2.5 mol% of Qphos
could be used (entry 8), still with a high branched:linear ratio
although a slight decrease in yield was observed and some
reduction product (arene) was detected in this case.
5
50
Table 1 Optimization of the reaction between hindered aryl bromide 6a
and iPrLi.a
Scheme 5 Substrate scope for the palladium catalysed crossꢀcoupling of
secondary alkyllithium reagents and alkenyl bromides. Reaction
Entry Pd complex (mol%) Ligand (mol%) Conv.b(yield)c 7a:8:9d
10 conditions: RLi (0.36 mmol, diluted in toluene to reach 0.36 M) was
added dropwise over 1 h to a stirred solution of alkenyl bromide (0.3
mmol) and Pd(PtBu3)2 (0.015 mmol) in 2 mL of dry toluene at room
temperature. Yield values refer to isolated yields after column
chromatography. Branched:linear ratio >99:1 by 1H NMR analysis unless
1
2
3
4
5
Pd(PtBu3)2 (5)
Pd2(dba)3 (2.5)
Pd2(dba)3 (2.5)
Pd2(dba)3 (2.5)
PdꢀPEPPSIꢀIPent (5)
Pd2(dba)3(2.5)
-
Full (96)
Full
Full
Full
Full
Full (95)
Full (97)
Full (97)
48:52:0
13:16:71
5:5:90
0:0:>95
57:28:15
97:3:0e
97:3:0e
88:3:9
L1 (10)
L2 (10)
L3 (10)
-
L4 (10)
L4 (5)
L4 (2.5)
a
15 otherwise noted. Conversion determined by GC analysis; the product
was not isolated due to volatility issues. b b:l refers to the branched:linear
ratio determined by 1H NMR analysis.
6
7f
8g
Pd2(dba)3(1.25)
Pd2(dba)3(0.63)
The crossꢀcoupling of secondary alkyllithium reagents was
also studied with hindered aryl bromides, such as 9ꢀ
20 bromoanthracene (6a) (Table 1). This type of coupling has been
rarely described, presumably due to reactivity, isomerisation or
elimination issues. First we tried the optimised conditions of the
palladium crossꢀcoupling shown above for the reaction between
i
a Reaction conditions: PrLi (0.36 mmol, diluted in toluene to reach 0.36
M) was added dropwise over 1 h to a stirred solution of 6a (0.3 mmol)
55 and catalyst (5 mol%) in 2 mL of dry toluene at room temperature.
bConversions were determined by GC analysis. Isolated yields after
c
column chromatography. d Determined by GC analysis. e Determined by
1H NMR analysis. 2.5 mol% of catalyst was used. 1.25 mol% of
f
g
catalyst was used.
i
6a and PrLi (Table1, entry 1). The reaction proceeded with very
60
25 high conversion, but unfortunately the ratio between branched
and linear product was 1:1. This finding could be explained
because the reductive elimination is presumably not fast enough
With an efficient catalyst for the Pdꢀcatalysed coupling of
hindered aryl bromides established (entry 7, Table 1), the scope
4
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was studied using different secondary alkyllithium reagents and
Conclusions
hindered aryl bromides (Scheme 6). SecꢀBuLi was reacted with
6a, and the corresponding alkylated product 7b was obtained
after 1 h in 88% yield with a branched:linear ratio of 91:9. 9ꢀ
cyclopropylanthracene (7c) was also synthesised using the
optimal conditions in very good yield (87%). Fluorenyllithium
could be coupled, using in this case Pd(PtBu3)2, resulting in the
corresponding alkylated product in 57% yield. In addition, other
hindered aryl bromides were reacted with iPrLi under the
10 optimised conditions, and the corresponding products (7e-i) were
obtained with excellent yields with almost no isomerisation (b:l=
96:4 to 99:1). One limitation of this crossꢀcoupling is the use of
1ꢀbromoꢀ2ꢀmethoxybenzene as a coupling partner. In this case,
the major product was the homocoupled biaryl (2,2'ꢀdimethoxyꢀ
15 1,1'ꢀbiphenyl) resulting, most probably, from a LiꢀBr exchange
and subsequent coupling. Probably, precomplexation of the
organolithium with the Lewis basic ether moiety might facilitate
the metalꢀhalogen exchange as the high stabilisation by the
methoxy group in the ortho position makes the corresponding
20 lithium reagents the most stable lithium species. On the contrary
both alkyl and aryl substituents are tolerated in the ortho position
of the aryl bromide (7eꢀh).
35 In conclusion, we have developed a highly efficient and selective
catalytic system for the palladiumꢀcatalysed crossꢀcoupling of
secondary alkyllithium reagents with a wide range of aryl and
alkenyl bromides. The reaction takes place under mild conditions
and the products are obtained with good to excellent yields, with
40 the undesired βꢀhydride elimination and isomerization pathways
being effectively suppressed in nearly all the cases. In addition,
different benzylic lithium reagents were prepared from direct
carbolithiation of styrene or 2ꢀvinylnaphthalene, and successfully
coupled to provide different 1,1ꢀdiarylmethine compounds with
45 moderate yields. This tandem carbometalation/crossꢀcoupling
involving secondary alkyl organometallic reagents has, as far as
we know, not been reported for palladiumꢀcatalysed crossꢀ
coupling. Furthermore, a crossꢀcoupling with hindered aryl
bromides is described using Pd2(dba)3ꢀQphos as the catalyst
50 providing the corresponding alkylated products in high yields and
excellent selectivity. This new methodology shows the
possibilities of using inexpensive and readily available secondary
lithium reagents as complementary coupling partners. Moreover,
the crossꢀcoupling of the indenyl and fluorenyl moieties as a
55 nucleophilic partner is described showing excellent selectivity
and reactivity, and opens new possibilities for the
functionalization of the fluorene skeleton for optoelectronic
materials. The results demonstrate that secondary alkyllithium
reagents represent a valuable alternative for a mild and selective
60 CꢀC bond formation in an atomꢀeconomic way.
5
Acknowledgements
Financial support from The Netherlands Organization for
Scientific Research (NWOꢀCW), National Research School
Catalysis (NRSCꢀCatalysis), the European Research Council
65 (ERC advanced grant 227897), the Royal Netherland Academy of
Arts and Sciences (KNAW) and the Ministry of Education
Culture and Science (Gravity program 024.601035) is gratefully
acknowledged. C.V. was supported by IntraꢀEuropean Marie
Curie fellowship (FP7ꢀPEOPLEꢀ2011ꢀIEF) (Contract number:
70 300826). We thank T. D. TiemersmaꢀWegman for the HRMS
analysis.
Notes and references
Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 4,
9747 AG Groningen, The Netherlands. Fax: +31 50 363 4278; Tel: +31
75 50 3634296; E-mail: b.l.feringa@rug.nl, m.fananas.mastral@rug.nl
† Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/b000000x/
1
(a) A. de Meijere and F. Diederich, in Metal-Catalyzed Cross-
Coupling Reactions, WileyꢀVCH, Weinheim, 2nd edn, 2004; (b) M.
Beller and C. Bolm, in Transition Metals for Organic Synthesis,
WileyꢀVCH Verlag GmbH, Weinheim, 2nd edn, 2004; (c) Handbook
of Organopalladium Chemistry for Organic Synthesis, ed. E;ꢀi.
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and G. C. Fu, in Topics in Organometallic Chemistry: Palladium in
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80
85
90
Scheme 6 Substrate scope for the palladium catalyse crossꢀcoupling of
25 secondary alkyllithium reagents and hindered aryl bromides. Reaction
conditions: RLi (0.36 mmol, diluted in toluene to reach 0.36 M) was
added dropwise over 1h to a stirred solution of ArBr (0.3 mmol),
Pd2(dba)3 (0.00375 mmol, 1.25 mol%) and QPhos (0.015 mmol, 5 mol%)
in 2 mL of dry toluene at room temperature. Isolated yield after column
30 chromatography. Branched:linear ratios determined by 1HꢀNMR analysis.
a
3% dehalogenation. b Pd(PtBu3)2 (0.015 mmol) was used as a catalyst. c
d
e
f
8% dehalogenation. 25% dehalogenation. 3% homocoupling. 4%
homocoupling.
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