Nickel-catalyzed cross-coupling reactions of aryltitanium(IV) alkoxides with aryl halides

Article abstract of DOI:10.1055/s-2007-984906

A nickel-catalyzed cross-coupling reaction between aryltitanium(IV) alkoxides and various functionalized aryl halides is described. The reaction requires Ni(acac)₂ (0.5 mol%), a phosphine or an N-heterocyclic carbene ligand (NHC ligand; 0.5-1.0 mol%) and proceeds at 25°C within 1-24 hours. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-984906

LETTER
2077
Nickel-Catalyzed Cross-Coupling Reactions of Aryltitanium(IV) Alkoxides
with Aryl Halides
C
ross-Coupling of
e
Aryltitaniu
o
m(IV
)
A
lkox
r
ide
s
g Manolikakes, Navid Dastbaravardeh, Paul Knochel*
Department Chemie und Biochemie, Ludwig-Maximilians-Universität München, Butenandtstr. 5–13, Haus F, 81377 München, Germany
Fax +49(89)218077680; E-mail: Paul.Knochel@cup.uni-muenchen.de
Received 15 May 2007
mol%; Figure 1) turned out to be the best (Scheme 2). In-
Abstract: A nickel-catalyzed cross-coupling reaction between
terestingly, tris(2,4,5-trimethoxyphenyl)phosphine7 (5;
1.0 mol%; Figure 1) gave better results for the cross-cou-
aryltitanium(IV) alkoxides and various functionalized aryl halides
is described. The reaction requires Ni(acac)2 (0.5 mol%), a phos-
pling reaction with electron-rich aryl halides (Scheme 2).
However, for other aryl halides, the phosphine 5 led to
slow reactions and poor yields. Other tested N-hetero-
cyclic carbenes, phosphines, diphosphines and phosphites
were less effective.8
phine or an N-heterocyclic carbene ligand (NHC ligand; 0.5–1.0
mol%) and proceeds at 25 °C within 1–24 hours.
Key words: organotitanium reagents, cross-coupling, nickel
Palladium- or nickel-catalyzed cross-coupling reactions
between aryl organometallics and aryl or heteroaryl
electrophiles are important methods for the preparation of
biaryls in modern organic chemistry.1 Transition-metal-
catalyzed reactions of organomagnesium, -boron, -sili-
con, -zinc and -tin compounds have been extensively
studied.1 On the other hand, aryltitanium(IV) alkoxides of
type 1 have been mainly used for performing addition re-
actions to carbonyl groups2 and carbotitanation reactions.3
Although the required organotitanium compounds can be
easily prepared by transmetalation from the correspond-
ing lithium or magnesium organometallics,4 they have
received less attention for the performance of cross-cou-
pling reactions.5 Herein, we wish to report the cross-cou-
pling between aryltitanium compounds of type 1 and aryl
and heteroaryl chlorides or bromides 2, which proceeds
readily at room temperature in THF, using small amounts
of Ni(acac)2 (0.5 mol%) (Scheme 1).
OMe
N
N+
MeO
P
OMe
Cl–
3
4
5
Figure 1 Ligands for the cross-coupling reaction
The optimized reaction conditions allow performing a
broad range of cross-coupling reactions at room tempera-
ture within 1–24 hours (Table 1). The used aryltitanium
reagents tolerate functionalized aryl halides not com-
patible with the corresponding lithium or magnesium
reagents. Thus phenyltitanium triethoxide (1a, 1.5 equiv)
obtained from PhMgCl9 by transmetalation with Ti(OEt)4,
reacted with ethyl 4-bromobenzoate (2a) in the presence
of Ni(acac)2 (0.5 mol%) and ligand 4 (0.5 mol%) at 25 °C,
leading to the cross-coupling product 3a (3 h, 95% yield,
entry 1 of Table 1). By using ethyl 4-chlorobenzoate the
same cross-coupling reaction required 24 hours and gave
3a in 73% yield (entry 1). Cross-coupling of the indole de-
rivative 2b with 1a provided the product 3b in 78% yield
(entry 2). For most cases, aryl chlorides were suitable
electrophiles. Cross-coupling of the protected aldehyde
2d with p-tolyltitanium triethoxide (1b) afforded the bi-
phenyl 3d in 73% yield (25 °C, 17 h, entry 4). Similarly,
the reaction of 1b with the sulfonamide 2e furnished
the desired cross-coupling product 3e in 75% yield (25 °C,
17 h, entry 5). By using ligand 5, p-tolyltitanium triethox-
ide (1b) reacted with the sterically hindered 2-chloro-1,4-
dimethoxybenzene (2f) only at 65 °C (3 h), giving the
coupling product 3f in 60% yield (entry 6). Heterocyclic
chlorides like 2-chloropyridine (2h) reacted with 1-naph-
thyltitanium triethoxide (1c) within six hours at 25 °C,
leading to the pyridine 3h in 98% yield (entry 8). The
same reaction with 1-naphthyltitanium triisopropoxide af-
forded only 35% of 3h after six hours (entry 8). By using
Ti(OEt)3
+
X
Ni(acac)2 (0.5 mol%)
ligand (0.5–1.0 mol%)
R2
R1
R2
R1
THF, 25 °C, 1–24 h
3
54–98%
2
1
X = Cl, Br
Scheme 1 Nickel-catalyzed cross-coupling reaction of aryltitanium
alkoxides with aryl halides
The required titanium(IV) reagents of type 1 were ob-
tained by the transmetalation of an aryllithium or aryl-
magnesium halide with Ti(OEt)4 and provided higher
yields and shorter reaction times than a transmetalation
with TiCl4, TiF4 or other titanium alkoxides, e.g. Ti(Oi-
Pr)4 (Table 1, entry 8). A broad number of ligands were
tested and N-heterocyclic carbene ligand precursor 46 (0.5
SYNLETT 2007, No. 13, pp 2077–2080
1
3
.0
8
.2
0
0
7
Advanced online publication: 17.07.2007
DOI: 10.1055/s-2007-984906; Art ID: G14607ST
© Georg Thieme Verlag Stuttgart · New York

2078
G. Manolikakes et al.
LETTER
3-chloropyridine (2i) the cross-coupling reaction with 1c with phenyltitanium triethoxide (1a) within six hours at
required 14 hours and gave the expected product 3i in –10 °C leading selectively to the desired cross-coupling
61% yield (entry 9). Electron-poor aryltitanium reagents product 3c (60% yield, entry 3). Similarly, the reaction of
reacted well only with aryl bromides. Thus, the cross-cou- 1e with 4-bromovalerophenone (2c) afforded within six
pling of ethyl 4-bromobenzoate (2a) with the titanium hours at –10 °C the biphenyl 3k in 57% yield (entry 11).
reagent 1d, bearing a trifluoromethyl group, provided bi- The cross-coupling reaction of 4-bromoacetophenone
phenyl 3j in 70% yield (25 °C, 16 h, entry 10). The reac- (2g) with 1b required lower temperatures of –20 °C in or-
tion of 1b with the less reactive aryl chloride afforded the der to avoid an addition on the keto function and furnished
product 3j in only 49% yield after 28 hours of reaction the expected product 3g in 54% yield (entry 7).
time (entry 10). Reaction of 2-chloroquinoline (2j) with
Finally we have compared the reactivity of organotitani-
the aryltitanium triethoxide 1e afforded dubamin (3l), a
um compounds with the corresponding arylzinc halides,
haplophyllum alkaloid,10 in 90% yield (25 °C, 18 h, entry
which are widely used in Negishi cross-couplings.13 The
12). The coupling of titanated heterocycles requires ele-
vated temperatures. Thus, 2-chloroquinoline (2j) reacted
reaction of PhTi(OEt)3 (1a) with N,N-dimethyl-4-bro-
moaniline (2k) afforded the biphenyl 3o in 92% yield
after 16 hours at 25 °C (Scheme 2). The same reaction
with the arylzinc halide 6, gave only 17% of 3o at 25 °C
with 2-titanated N-methylpyrrole (1f), obtained from the
corresponding lithium compound,11 within 24 hours at 65
°C, leading to the quinoline 3m in 98% yield (entry 13).
after 24 hours in the presence of a polar co-solvent like
In the case of titanated benzofurane 1g, prepared by trans-
NMP.14 The same behavior was observed with 4-bro-
metalation from the lithium reagent,12 the cross-coupling
moanisole (2l) as electrophile.
with 2-chloroquinoline (2j) afforded the heterocycle 3n in
73% yield after 24 hours at 65 °C (entry 14). Aryl
bromides may bear a keto function, but require lower
temperatures. Thus, 4-bromovalerophenone (2c) reacted
Table 1 Cross-Coupling Reactions of Aryltitanium Reagents with Functionalized Aryl Halides
Entry Aryltitanium 1
Aryl halide 2
Product 3
Ligand Reaction Yield
time (h)a (%)b
1
4
3
95 (73)c
CO2Et
Ti(OEt)3
Br
2a
Br
CO2Et
1a
3a15
Ph
2
3
4
18
78
N
N
Boc
Boc
1a
1a
2b
3b
3c
O
O
4
6d
60
Br
Bu
Bu
2c
O
O
O
O
4
5
4
4
17
17
73
75
Me
Me
Ti(OEt)3
Cl
1b
2d
3d
Cl
SO2 N
Me
SO2 N
1b
1b
2e
3e
MeO
MeO
6
5
3e
60
Cl
Me
OMe
OMe
2f
3f
Synlett 2007, No. 13, 2077–2080 © Thieme Stuttgart · New York

LETTER
Cross-Coupling of Aryltitanium(IV) Alkoxides
2079
Table 1 Cross-Coupling Reactions of Aryltitanium Reagents with Functionalized Aryl Halides (continued)
Entry Aryltitanium 1
Aryl halide 2
Product 3
Ligand Reaction Yield
time (h)a (%)b
O
O
7
4
6f
54
Me
Br
Me
Me
1b
2g
3g
Ti(OEt)3
N
8
4
6
98 (35)g
Cl
N
1c
2h
3h
N
9
4
14
61
Cl
N
1c
2i
3i
Ti(OEt)3
CO2Et
10
11
4
4
16
70 (49)c
Br
CO2Et
F3C
F3C
1d
2a
3j
O
O
6d
57
Ti(OEt)3
O
O
Br
n-Bu
n-Bu
O
O
1e
1e
2c
3k
12
13
4
4
18
90
98
O
N
Cl
N
O
2j
3l
24e
Ti(OEt)3
N
N
N
Me
Me
1f
2j
2j
3m
14
4
24e
73
N
Ti(OEt)3
O
O
1g
3n
a Reaction time at 25 °C.
b Yield of analytically pure product.
c Yield of analytically pure product obtained with the corresponding aryl chloride.
d Reaction performed at –10 °C.
e Reaction performed at 65 °C.
f Reaction performed at –20 °C.
g GC yield determined with n-teradecane as internal standard by using Ti(Oi-Pr)4 for transmetalation.
Synlett 2007, No. 13, 2077–2080 © Thieme Stuttgart · New York

2080
G. Manolikakes et al.
LETTER
(4) (a) Weidmann, B.; Widler, L.; Olivero, A.; Maycock, C.;
Met
Br
Ni(acac)2 (0.5 mol%)
Seebach, D. Helv. Chim. Acta 1981, 64, 357. (b) Reetz, M.
Top. Curr. Chem. 1982, 106, 1.
ligand 5 (1.0 mol%)
+
X
(5) (a) Tsuji, T.; Ishii, T. J. Organomet. Chem. 1992, 425, 41.
(b) Fleming, S.; Kabara, K.; Nickisch, K.; Neh, H.;
Westermann, J. Tetrahedron Lett. 1994, 35, 6075. (c) Arai,
M.; Lipshutz, B.; Nakamura, E. Tetrahedron 1992, 48,
5709. (d) Bumagin, N.; Ponomaryov, A.; Beletskaya, I. J.
Organomet. Chem. 1985, 291, 129. (e) Han, J.; Tokunaga,
N.; Hayashi, T. Synlett 2002, 871. (f) Obora, Y.; Moriya,
H.; Tokunaga, M.; Tsuji, Y. Chem. Commun. 2003, 2820.
(6) (a) Arduengo, A.; Krafczyk, R.; Schmutzler, R.; Craig, H.;
Goerlich, J.; Marshall, W.; Unverzagt, M. Tetrahedron
1999, 55, 14523. (b) Scott, N.; Nolan, S. Eur. J. Inorg.
Chem. 2005, 1815. (c) Marion, N.; Navarro, O.; Mei, J.;
Stevens, E.; Scott, N.; Nolan, S. J. Am. Chem. Soc. 2006,
128, 4101. (d) Organ, M.; Avola, S.; Dubovyk, I.; Hadei, N.;
Kantchev, E.; O’Brien, C.; Valente, C. Chem. Eur. J. 2006,
12, 4749. (e) The NHC ligand itself is generated by
deprotonation with the organometallic reagent. See also
references above.
THF
25 °C
X
2k: X = NMe2
2l: X = OMe
3o: X = NMe2; 92% after 16 ha
3p: X = OMe; 83% after 1 ha
1a: Met = Ti(OEt)3
3o: X = NMe2; 14% after 24 hb
with ligand 4 <5% after 24 hb
3p: X = OMe; 17% after 24 hb
6: Met = ZnBrc
Scheme 2 Comparison of aryltitanium and -zinc reagents. a Yield
of analytically pure product. b Yield determined by GC analysis with
n-tetradecane as an internal standard. c Solvent: THF–NMP (8:1).
In summary, we have developed an efficient Ni-catalyzed
cross-coupling reaction of aryltitanium reagents with aryl
chlorides and bromides. The reaction scope is broad and
most of the cross-couplings proceed at room temperature
or even at lower temperatures.
(7) Wada, M.; Higashizaki, S. Chem. Commun. 1984, 482.
(8) Polar solvents such as NMP, NEP (N-ethyl-2-pyrroli-
dinone), DMPU or DME were not effective as co-solvents,
as it is known in other cross-coupling reactions. See also:
Gavryushin, A.; Kofink, C.; Manolikakes, G.; Knochel, P.
Org. Lett. 2005, 7, 4871.
Acknowledgment
(9) Krasovskiy, A.; Knochel, P. Angew. Chem. Int. Ed. 2004, 43,
3333.
(10) Yunusov, S.; Sidakin, G. Zh. Obshch. Khim. 1955, 25, 2009.
(11) Brittain, J.; Jones, R.; Arques, J.; Saliente, T. Synth.
Commun. 1982, 12, 231.
We thank the Fonds der Chemischen Industrie and the DFG for
financial support and Saltigo (Leverkusen), Degussa (Hanau),
Chemetall (Frankfurt) and BASF (Ludwigshafen) for the generous
gift of chemicals.
(12) Nguyen, T.; Negishi, E. Tetrahedron Lett. 1991, 32, 5903.
(13) (a) Negishi, E.; Valente, L.; Kobayashi, M. J. Am. Chem.
Soc. 1980, 102, 3298. (b) Negishi, E. Acc. Chem. Res. 1982,
15, 340. (c) Zeng, X.; Quian, M.; Hu, Q.; Negishi, E. Angew.
Chem. Int. Ed. 2004, 43, 2259. (d) Quian, M.; Huang, Z.;
Negishi, E. Org. Lett. 2004, 6, 1531.
References and Notes
(1) (a) Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.; de
Meijere, A.; Diederich, F., Eds.; Wiley-VCH: Weinheim,
2004. (b) Tsuji, J. Transition Metal Reagents and Catalysts:
Innovations in Organic Synthesis; Wiley: Chichester, 1995.
(c) Cross-Coupling Reactions: A Practical Guide, In Top.
Curr. Chem., Vol. 219; Miyaura, N., Ed.; Springer-Verlag:
Berlin-Heidelberg, 2002.
(2) (a) Duthaler, R.; Hafner, A. In Transition Metals for Organic
Synthesis; Beller, M.; Bolm, C., Eds.; Wiley-VCH:
Weinheim, 1998, 447. (b) Reetz, M. Organotitanium
Reagents in Organic Synthesis; Springer Verlag: Berlin,
1986. (c) Weidmann, B.; Seebach, D. Helv. Chim. Acta
1980, 63, 2451.
(14) Not using NMP leads to heterogeneous reactions and lower
yields.
(15) Typical Procedure for the Cross-Coupling Reaction;
Preparation of Biphenyl-4-carboxylic Acid Ethyl Ester
(3a): A flame-dried flask equipped with a magnetic stirring
bar, an argon inlet, and a septum was charged with a
Ti(OEt)4 solution (1.0 mL, 1.5 M in THF). First phenyl-
magnesium chloride (0.84 mL, 1.79 M in THF) was added
dropwise at 0 °C, then Ni(acac)2 (1.3 mg, 0.005 mmol),
ligand 4 (2.1 mg, 0.005 mmol) and 4-bromobenzoic acid
ethyl ester (2a; 229 mg, 1.00 mmol) were added. The
reaction mixture was stirred for 3 h at r.t. Then the mixture
was quenched with a sat. NH4Cl solution and extracted with
Et2O. Column chromatography (pentane–Et2O, 9:1) of the
crude residue yielded 3a as colorless solid (215 mg, 95%).
(3) (a) Sato, F.; Urabe, H.; Okamoto, S. Chem. Rev. 2000, 100,
2835. (b) Sato, F.; Urabe, H. In Titanium and Zirconium in
Organic Synthesis; Marek, I., Ed.; Wiley-VCH: Weinheim,
2002, 319. (c) Kulinkovich, O.; de Meijere, A. Chem. Rev.
2002, 100, 2789.
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