Catalytic direct cross-coupling of organolithium compounds with aryl chlorides

Article abstract of DOI:10.1021/ol402408v

Palladium-catalyzed direct cross-coupling of aryl chlorides with a wide range of (hetero)aryl lithium compounds is reported. The use of Pd-PEPPSI-IPent or Pd₂(dba)₃/XPhos as the catalyst allows for the preparation of biaryl and heterobiaryl compounds in high yields under mild conditions (room temperature to 40 C) with short reaction times.

Full text of DOI:10.1021/ol402408v

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
Catalytic Direct Cross-Coupling of
Organolithium Compounds with Aryl
Chlorides
000–000
Valent ´ı n Hornillos, Massimo Giannerini, Carlos Vila, Mart ´ı n Fa ~n an ꢀa s-Mastral,* and
Ben L. Feringa*
Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 4,
9
747 AG Groningen, The Netherlands
b.l.feringa@rug.nl; m.fananas.mastral@rug.nl
Received September 4, 2013
ABSTRACT
Palladium-catalyzed direct cross-coupling of aryl chlorides with a wide range of (hetero)aryl lithium compounds is reported. The use of Pd-
PEPPSI-IPent or Pd (dba) /XPhos as the catalyst allows for the preparation of biaryl and heterobiaryl compounds in high yields under mild
2
3
conditions (room temperature to 40 °C) with short reaction times.
5
The development of new catalytic methodologies for
CÀC bond formation continues to be a major challenge
HiyamaÀDenmark (organosilicon), or Kumada (organ-
6
omagnesium) reactions are widely employed for this
1
in organic synthesis. Cross-coupling reactions, in parti-
transformation with numerous applications in disciplines
varying from material science to natural products synth-
1,7
esis, asymmetric catalysis, and medicinal chemistry.
Organolithium compounds areamongthe mostversatile
8
and widely used reagents in organic synthesis. Their use is
also well documented for the preparation of softer orga-
9
nometallic nucleophiles including Sn, Si, or B reagents.
However, their direct use in catalytic cross-couplings,
which would eliminate this additional transformation,
has been largely prohibited due to the high reactivity
cular Pd-catalyzed processes, are among the most im-
1
e
portant current methods for CÀC bond formation. The
2
well-established Stille (with organotin as the nucleophile),
3
4
SuzukiÀMiyaura (organoboron), Negishi (organozinc),
(
1) (a) Negishi, E. Angew. Chem., Int. Ed. 2011, 50, 6738. (b)
Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed.
005, 44, 4442. (c) Corbet, J.; Mignani, G. Chem. Rev. 2006, 106, 2651.
d) Dunetz, J. R. Chem. Rev. 2011, 111, 2177. (e) Johansson Seechurn,
2
(
C. C. C.; Kitching, M. O.; Colacot, T. J.; Snieckus, V. Angew. Chem., Int.
Ed. 2012, 51, 5062.
(
2) (a) Stille, J. K. Angew. Chem., Int. Ed. 1986, 25, 508. (b) Espinet,
P.; Echavarren, A. M. Angew. Chem., Int. Ed. 2004, 43, 4704.
3) (a) Suzuki, A. Angew. Chem., Int. Ed. 2011, 50, 6723. (b) Miyaura,
(6) (a) Tamao, K.; Sumitani, K.; Kumada, M. J. Am. Chem. Soc.
1972, 94, 4374. (b) Knappe, C. E. I.; von Wangelin, A. J. Chem. Soc. Rev.
2011, 40, 4948. (c) Corriu, R. J. P.; Masse, J. P. Chem. Commun. 1972,
144.
(7) Bringmann, G.; Price Mortimer, A. J.; Keller, P. A.; Gresser,
M. J.; Garner, J.; Breuning, M. Angew. Chem., Int. Ed. 2005, 44, 5384.
(8) Rappoport, Z.; Marek, I. The Chemistry of Organolithium Com-
pounds; Wiley-VCH: Chichester, 2004.
(9) Anctil, E. J. Snieckus, V. In Metal Catalyzed Cross-Coupling
Reactions, Vol. 1; de Meijere, A., Diederich, F., Eds.; Wiley-VCH:
Weinheim, 2004; pp 761À813.
(
N. In Metal Catalyzed Cross-Coupling Reactions; De Meijere, A., Diederich,
F., Eds.; Wiley-VCH: New York, 2004; Vol. 1, pp 41À123.
(4) (a) Negishi, E.; King, A. O.; Okukado, N. J. Org. Chem. 1977, 42,
1
821. (b) King, A. O.; Okukado, N.; Negishi, E. J. Chem. Soc., Chem.
Commun. 1977, 683. (c) Knochel, P.; Singer, R. D. Chem. Rev. 1993, 93,
117. (d) Phapale, V. B.; C ꢀa rdenas, D. J. Chem. Soc. Rev. 2009, 38, 1598.
5) (a) Hiyama, T.; Nakao, Y. Chem. Soc. Rev. 2011, 40, 4893. (b)
Denmark, S. E.; Regens, C. S. Acc. Chem. Res. 2008, 41, 1486.
2
(
1
0.1021/ol402408v r XXXX American Chemical Society

1
0
usually accompanied by the lack of selectivity. Our group
has recently described the direct use of organolithium
reagents in the Pd-catalyzed cross-coupling of a wide
drastically reduce the amount of byproducts, the light and
nontoxic LiCl being the onlystoichiometricreaction waste.
Herein, we report that the use of the commercially avail-
able Pd-PEPPSI-IPent or Pd (dba) /XPhos catalysts al-
lows the selective cross-coupling of (hetero)aryllithium
compounds with aryl chlorides in high yields under mild
conditions (rt to 40 °C) and short reaction times (40 min
to 4 h).
1
1
variety of aryl and alkenyl bromides. By the use of
t
toluene as a solvent and P( Bu) as ligand and by fine-
2
3
3
tuning of the reaction conditions, the high reactivity of the
organolithium reagents was controlled, efficient transme-
talation was achieved, and high selectivity and good yields
were obtained, avoiding the notorious lithium halogen
exchange and homocoupling side reactions. Nonetheless,
the coupling of organolithium reagents with the corre-
sponding aryl chlorides remains challenging. Aryl chlor-
ides are generally more desirable substrates than their
corresponding bromide and iodide counterparts taking
We started this study with the reaction between phenyl-
lithium and 2-chloronaphthalene 1a. Under the optimized
conditions for the cross-coupling of organolithium re-
t
11
agents with aryl bromides (Pd (dba) /P( Bu) ), the de-
2
3
3
sired product 2a was obtained in the presence of a large
amount of homocoupling side product 4 (Table 1, entry 1).
1
2
advantage of low cost and availability. However, their
low reactivity has traditionally made these substrates
reluctant coupling partners in these reactions, usually
Table 1. Screening of Different Ligands (see also Supporting
Information, Table S1)
1
3
requiring high temperatures and long reaction times.
Major efforts have been made in the past decade toward
the development of highly active Pd catalysts for the cross-
coupling of aryl chlorides and organometallic reagents
1
4
under mild reaction conditions. In general, sterically
hindered dialkylbiaryl phosphines and N-heterocyclic car-
benes (NHCs) have proved to be useful in effecting these
transformations with organoboron, organozinc, organo-
1
5
tin, or organomagnesium reagents.
We surmised that the development of new cross-
coupling methodology which combines both, cheap and
easy accessible organolithium reagents and aryl chlo-
rides is highly desirable. The anticipated process would
conv
a
b
entry
[Pd]
ligand
(%)
2a:3:4:5
c
(
10) (a) Murahashi, S.; Yamamura, M.; Yanagisawa, K.; Mita, N.;
1
2
3
4
Pd
Pd
Pd
(dba)
L1, P(tBu)
78
46:3:26:2
49:2:20:19
99:<1:<1:0
94:3:2:0
2
2
2
3
3
3
3
c
Kondo, K. J. Org. Chem. 1979, 44, 2408. (b) For an alternative approach
using a flow microreactor: Nagaki, A.; Kenmoku, A.; Moriwaki, Y.;
Hayashi, A.; Yoshida, J. Angew. Chem., Int. Ed. 2010, 49, 7543. For the
use of a silicon-based transfer agent, see: (c) Smith, A. B., III; Hoye,
A. T.; Martinez-Solorio, D.; Kim, W.; Tong, R. J. Am. Chem. Soc. 2012,
(dba)
(dba)
L2, P(Cy)
L3, XPhos
3
90
full
full
full
Pd-PEPPSI-IPent
Pd-PEPPSI-IPent
d
5
97:3:<1:0
1
34, 4533. (d) Nguyen, M. H.; Smith, A. B., III. Org. Lett. 2013, 15, 4268.
11) Giannerini, M.; Fa n~ an ꢀa s-Mastral, M.; Feringa, B. L. Nat.
Chem. 2013, 5, 667.
12) (a) Grushin, V. V.; Alper, H. Chem. Rev. 1994, 94, 1047. (b)
a
(
Conditions: PhLi (0.45 mmol, 1.8 M solution in dibutyl ether diluted
with THF to a final concentration of 0.6 M) was added (1 mL/h) to a
solution of 2-chloronaphthalene (0.3 mmol) in toluene (2 mL unless
(
b
c
Grushin, V. V.; Alper, H. In Activation of Unactive Bonds and Organic
Synthesis; Murai, S., Ed.; Springer: Berlin, 1999; p 203.
otherwise noted). 2a:3:4:5 ratios determined by GC analysis. 7.5 mol %
was used. In 1 mL of toluene. dba = dibenzylideneacetone.
d
(13) (a) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 1998, 37, 3387.
(
b) Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122, 4020. (c)
The use of PCy was detrimental for the selectivity and
3
Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 2719. (d) Littke, A. F.;
Schwarz, L.; Fu, G. C. J. Am. Chem. Soc. 2002, 124, 6343. (e) Littke,
A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176. (f) Wolfe, J. P.;
Buchwald, S. L. Angew. Chem., Int. Ed. 1999, 38, 2413. (g) Old, D. W.;
Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1998, 120, 9722. (h)
Buchwald, S. L.; Surrey, D. L. Angew. Chem., Int. Ed. 2008, 47, 6338. (i)
Kataoka, N.; Shelby, Q.; Stambuli, J. P.; Hartwig, J. F. J. Org. Chem.
1-phenylnaphthalene 5 was also formed indicating the
formation of a benzyne intermediate via 1,2-elimination
1
6
promoted by the organolithium reagent (entry 2). To our
delight, when XPhos (L3) was used in combination with
Pd (dba) (2.5 mol %) the cross-coupled product 2a was
2
002, 67, 5553. (j) Herrmann, W. A. Angew. Chem., Int. Ed. 2002, 41,
2
3
1
290. (k) Altenhoff, G.; Goddard, R.; Lehman, C. W.; Glorius, F. J. Am.
obtained with excellent selectivity (>99%), avoiding de-
halogenation (<1%) and inhibiting the formation of the
homocoupling orisomerized side products (<1%, entry 3).
The use of other sterically hindered phosphines resulted in
lower selectivity with incomplete conversion (see Support-
ing Information (SI), Table S1). We also evaluated cata-
lysts based on NHC ligands and observed that the air
Chem. Soc. 2004, 126, 15195.
14) (a) Fu, G. C. Acc. Chem. Res. 2008, 41, 1555. (b) Martin, R.;
Buchwald, S. L. Acc. Chem. Res. 2008, 41, 1461. (c) Nasielski, J.; Hadei,
N.; Achonduh, G. E.; Kantchev, A. B.; O’Brien, C. J.; Lough, A.; Organ,
M. G. Chem.;Eur. J. 2010, 16, 10844. (d) Valente, C.; Calimsiz, S.; Hoi,
K. H.; Mallik, D.; Sayah, M.; Organ, M. G. Angew. Chem., Int. Ed. 2012,
(
5
1, 3314.
(
15) (a) Navarro, O.; Kelly, R. A.; Nolan, S. P. J. Am. Chem. Soc.
2
003, 125, 16194. (b) Marion, N.; Navarro, O.; Mei, J.; Stevens, E. D.;
1
5e
Scott, N. M.; Nolan, S. P. J. Am. Chem. Soc. 2006, 128, 4101. (c) Diebolt,
O.; Braunstein, P.; Nolan, S. P.; Cazin, C. S. J. Chem. Commun. 2008,
3
stable Pd-PEPPSI-IPent, introduced by Organ, also
displayed high reactivity and selectivity (entry 4). In this
190. (d) Han, C.; Buchwald, S. L. J. Am. Chem. Soc. 2009, 131, 7532. (e)
Organ, M. G.; C- alimsiz, S.; Sayah, M.; Hoi, K. H.; Lough, A. J. Angew.
Chem., Int. Ed. 2009, 48, 2383. (f) Sau, S. C.; Santra, S.; Sen, T. K.;
Mandal, S. K.; Koley, D. Chem. Commun. 2012, 48, 555.
(16) Kaye, S.; Fox, J. M.; Hicks, F. A.; Buchwald, S. L. Adv. Synth.
Catal. 2001, 343, 789.
B
Org. Lett., Vol. XX, No. XX, XXXX

case, slower addition of PhLi (0.5 mL/h) and a higher
concentration were found to be beneficial for an increase
of the selectivity (entry 5). It should be noted that, for both
catalytic systems, the reaction proceeds at rt and is finished
once the addition of the lithium reagent is completed (40 min
to 1 h) providing 2a in 88% and 93% yield, respectively.
Having in hand these two optimized catalytic systems
gratifying were the results observed with sterically hin-
dered ortho-substituted organolithium reagents as in the
preparation of compounds 2g, 2h, 2i, and 2j where in all
cases the cross-coupling reaction proceeded at rt, in high
yield and without loss of selectivity. It should be empha-
sized that this new methodology is compatible with cur-
rently available procedures to access organolithium
species. For example, aryl lithium reagents used in the
preparation of biaryls 2gÀ2i were prepared via halogenÀ
metal exchange, and the one used in the synthesis of 2j
(
A based on Pd-PEPPSI-IPent and B using Pd (dba) /
2 3
XPhos), we examined the cross-coupling between different
organolithium reagents and aryl chlorides (Scheme 1).
9
was prepared by direct metalation of methoxymethyl
(MOM)-protected phenol (see SI for details). In addition,
direct lithiation of furan led to furyllithium which was used
for the reaction with chlorides 1k,l to give the correspond-
ing cross-coupling products in good yields and high
selectivity.
Scheme 1. Pd-Catalyzed Cross-Coupling of Aryl Lithium
Reagents with Activated Aryl Chlorides
a
To explore the effectiveness of this cross-coupling with
respect to the reactivity of the aryl chloride, we examined
a more electron-rich aryl chloride such as 1-butyl-4-
chlorobenzene 1m (Table 2).
Table 2. Optimization of the Cross-Coupling of PhLi with
Electron-Rich Aryl Chloride 1m (see also SI, Table S2)
a
Aryl chloride (0.3 mmol), ArLi (0.45 mmol, diluted with THF to
t
reaction
time
conv
(%)
a
b
reach 0.60 M concentration, unless otherwise noted). Catalytic system
A: Pd-PEPPSI-IPent (5 mol %). Toluene (1 mL), flow rate = 0.5 mL/h.
Catalytic system B: Pd (dba) (2.5 mol %)/XPhos (10 mol %). Toluene
entry
[Pd]
(°C)
2m:6:7
c
d
1
Pd
2
(dba)
3
/L3
rt
rt
40 min
<1
61
<1:0:0
57:4:0
2
3
b
d
(
2
2 mL), flow rate = 1.0 mL/h. 10 mmol (1.63 g) scale reaction using
2
Pd-PEPPSI-
IPent
40 min
c
mol % of catalyst. TMEDA (1.2 equiv) was added to a thienyllithium
solution (0.45 mmol, diluted with toluene to reach 0.60 M concentra-
tion), and the reaction was performed at 40 °C. Selectivity >95% in all
cases. Yield values refer to isolated yields after purification. EWG =
electron withdrawing group.
e
3
4
Pd
2
(dba)
3
/L3
40
35
3.5 h
full
full
93:1:6
92:4:4
e
Pd-PEPPSI-
IPent
3.5 h
a
Conditions: PhLi (1.8 M solution in dibutyl ether diluted with THF
to a final concentration of 0.6 M) was added to a solution of 1-butyl-4-
chlorobenzene (0.3 mmol) in toluene (1 mL unless otherwise noted).
2m:6:7 ratios determined by GC analysis. In 2 mL of toluene. Flow
e
rate = 1 mL/h. Flow rate = 0.2 mL/h. dba: dibenzylideneacetone.
1
-Chloronaphthalene (1b) was selectively coupled with
phenyllithium in high yield (91À98%), with no formation
of the regioisomer 2a. Notably, when this reaction is
performed on gram scale (10 mmol, 1.63 g) employing
b
c
d
2
mol % of catalyst B, product 2b is still obtained, after 6 h
No conversion was found when Pd (dba) /Xphos was
2
3
at rt, with similar selectivity and yield. The electron defi-
cient 1-chloro-4-(trifluoromethyl)benzene 1c also under-
went clean coupling with phenyllithium giving high iso-
lated yields (catalyst A: 89% and catalyst B: 95%) of the
trifluoromethylated biaryl scaffold 2c. Heteroaryl lithium
compounds were also successful coupling partners. Thus,
commercially available thienyllithium was shown to allow
the cross-coupling with 1d, 1e, 1f giving rise to compounds
used as a catalyst, and incomplete conversion was ob-
served in the case of Pd-PEPPSI-IPent at rt (Table 2,
entries 1 and 2). Further optimization of the reaction
conditions (entries 3 and 4, and SI, Table S2) showed that
slightly higher temperatures (35 or 40 °C) and longer
addition times (3 h) of the organolithium reagent were
key factors to reach full conversion with high selectivity.
Interestingly, as electron-rich aryl chlorides do not react at
rt in the presence of the Pd (dba) /Xphos catalytic sys-
2d, 2e, and 2f with high yields and excellent selectivity
Scheme 1). In this case, the use of tetramethylethylene-
2
3
(
diamine (TMEDA) as an activating agent and a slightly
tem (B) while electron-poor aryl chlorides are coupled
higher temperature (40 °C) was necessary due to the
reduced reactivity of this organometallic reagent. Highly
(17) For illustrative examples on the substrate scope limitations, see
Supporting Information, Scheme S1.
11
Org. Lett., Vol. XX, No. XX, XXXX
C

efficiently at this temperature, the difference could be ex-
ploited for selective cross-coupling with different chlorides
present in the same molecule.
Scheme 3. Selective Consecutive Cross-Coupling of 1-Bromo-4-
chlorobenzene with Different Aryl Lithium Reagents
A range of deactivated aryl chlorides could be coupled
with different organolithium reagents using these opti-
1
7
mized conditions (Scheme 2).
Scheme 2. Pd-Catalyzed Cross-Coupling of Aryl Lithium
Reagents with Deactivated Aryl Chlorides
a
and optoelectronic materials (e.g., organic light emitting
1
9
diodes, OLED). A remarkable result is that the very
hindered bis-ortho-substituted biaryl 2r was readily for-
med under mild conditions and high yield by reaction
between aryl chloride 1r and 2-methoxyphenyllithium,
employing catalytic system A. Finally, highly selective
and fastcouplingwas alsoobtainedinthe reactionbetween
furyllithium and 4-methoxy-chlorobenzene using the same
catalytic system.
In our previous work, we described that the cross-
coupling of 1-bromo-4-chlorobenzene 8 with PhLi using
the Pd (dba) /P(tBu) catalyst system proceeds selectively,
2
3
3
1
1
leaving the chloride untouched. To demonstrate the
complementarity of our new methodology, we further
converted chloride 9, in a subsequent cross-coupling, into
heterotriaryl 10 in high yield by reaction with 2-furyl-
lithium in the presence of the Pd-PEPPSI-IPent catalyst
(Scheme 3).
a
Aryl chloride (0.3 mmol), ArLi (0.45 mmol, diluted with THF to
reach 0.60 M concentration and added at 0.2 mL/h flow rate). Toluene
In summary, we have shown the direct cross-coupling of
aryl-lithium reagents with aryl chlorides in high yields and
excellent selectivity. The methodology is based on the use
of commercially available catalytic systems, Pd (dba) /
b
(
1 mL) at 40 °C. Selectivity >95% unless otherwise noted. Reaction
performed at 35 °C. PhLi (0.9 mmol). Selectivity >90%. Selectivity
85%. Yield values refer to isolated yields after purification. EDG =
electron donating group.
c
d
e
>
2
3
XPhos or air stable Pd-PEPPSI-IPent. The reactions take
place under mild conditions and feature short reaction
times. The low cost and availability of both aryllithium
reagents and aryl chlorides, together with the selectivity of
this new methodology, make it a valuable alternative for
well-established cross-coupling procedures.
Sterically hindered ortho-substituded aryl chloride 1n
reacted in high selectivity with phenyllithium providing
biaryl 2n in good yield using both optimized catalytic
systems. The cross-coupling of PhLi with 4-methoxychlor-
1
8
obenzene 1o, a reluctant chloride coupling partner, using
Pd (dba) /XPhos gave rise to a large amount of homo-
2
3
Acknowledgment. The Netherlands Organization for
Scientific Research (NWO-CW), National Research
School Catalysis (NRSC-C), European Research Council
coupling side product. Nonetheless, we could reduce
the formation of this side product to <2% by the use
of Pd-PEPPSI-IPent as a catalyst which afforded product
(ERC Advanced Grant 227897 to B.L.F.), Royal Nether-
2
o in excellent yield (94%). Similarly 1-chloro-3-methox-
land Academy of Arts and Sciences (KNAW), and Min-
istry of Education Culture and Science (Gravity program
ybenzene 1p was readily arylated in good yield employing
catalytic system A. Twofold arylation of 1,4-dichloro-2,5-
dimethylbenzene, to form 2q, was achieved in high selec-
tivity and good yield exemplifying the applications of this
catalytic system in multiple couplings. Triaryl compound
024.601035) are acknowledged for financial support. C.V.
was supported by an Intra-European Marie Curie fellow-
ship (FP7-PEOPLE-2011-IEF) (Contract No. 300826).
2q is a precursor for a variety of indenofluorene derivates
with application in electronic (e.g., thin film transistor)
Supporting Information Available. Optimization tables,
experimental procedures, and characterization data. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(
18) Denmark, S. E.; Smith, R. C.; Tau, W. T.; Muhuhi, J. M. J. Am.
Chem. Soc. 2009, 131, 3104.
19) (a) Merlet, S.; Birau, M.; Wang, Z. Y. Org. Lett. 2002, 4, 2157.
b) Lin, T.-C.; Hsu, C.-S.; Hu, C.-L.; Chen, Y.-F.; Huang, W.-J.
(
(
Tetrahedron Lett. 2009, 50, 182.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX