The first palladium-catalyzed Sonogashira coupling of unactivated secondary alkyl bromides

Article abstract of DOI:10.1016/j.tetlet.2006.02.111

A palladium-carbene catalyzed Sonogashira coupling of unactivated alkyl bromides with alkyl substituted alkynes is reported. For the first time, unactivated secondary alkyl halides were successfully employed in Sonogashira reactions.

Full text of DOI:10.1016/j.tetlet.2006.02.111

Tetrahedron Letters 47 (2006) 2925–2928
The first palladium-catalyzed Sonogashira coupling of
unactivated secondary alkyl bromides
Gereon Altenhoff,a Sebastian Wurtzb and Frank Gloriusb,*
¨
aBASF AG, GCB/K-M311, 67056 Ludwigshafen, Germany
bPhilipps-Universita¨t, Fachbereich Chemie, Hans-Meerwein-Straße, 35032 Marburg, Germany
Received 20 January 2006; revised 14 February 2006; accepted 17 February 2006
Available online 7 March 2006
Abstract—A palladium-carbene catalyzed Sonogashira coupling of unactivated alkyl bromides with alkyl substituted alkynes is
reported. For the first time, unactivated secondary alkyl halides were successfully employed in Sonogashira reactions.
Ó 2006 Elsevier Ltd. All rights reserved.
R1
Cross-coupling reactions of aryl halides have become
important transformations, significantly altering the
way organic molecules are made.1 For a long time, the
corresponding application of non-activated alkyl halides
remained elusive, due to a generally more difficult oxida-
tive addition step and possible side reactions like b-
hydride elimination. In this respect, secondary and ter-
tiary alkyl halides are especially demanding substrates.2
Recently, catalyst systems have been developed that can
oxidatively add to alkyl halides and suppress side reac-
tions and thereby allow the cross-coupling of these sub-
strates.3,4 In a pioneering effort, Fu et al. developed the
first examples of cross-coupling reactions of unactivated
secondary alkyl halides in 2003.4a Later on, other nickel-
catalyzed Suzuki, Hiyama and Negishi reactions4 and an
iron-catalyzed Kumada coupling of unactivated second-
ary alkyl halides were reported.5
2 mol% [IBiox7PdCl2]2
8 mol% CuI, Cs2CO3
R2
R2
+
R1
Br
R3 DMF/DME, 60 C
R3
˚
Scheme 1. Sonogashira reaction of secondary alkyl halides.
primary or activated alkyl halides. On the contrary, the
corresponding uncatalyzed coupling of secondary unacti-
vated alkyl halides is troublesome and very low yielding.9
Therefore, the successful application of more sterically
hindered substrates like secondary and tertiary alkyl
halides in the Sonogashira reaction would be highly
desirable.
Herein we report the first Sonogashira coupling of alky-
nes with secondary alkyl bromides, enabled by the use of
palladium-N-heterocyclic carbene complexes (Scheme
1). To the best of our knowledge, this represents the first
palladium-catalyzed cross-coupling of unactivated sec-
ondary alkyl halides.
The Sonogashira coupling6 of alkynes with organic
halides is an efficient method for the synthesis of differ-
ently substituted alkynes, versatile synthetic intermedi-
ates and also important motifs of biologically active
compounds.7 Traditionally, aromatic halides have been
used as the alkyne coupling partner. Fu was the first to
efficiently employ unactivated primary alkyl bromides
and iodides in the Sonogashira reaction using a palla-
dium-carbene catalyst (Scheme 1).8 However, similar
products can be obtained by the prevalent uncatalyzed
coupling of deprotonated alkynes with unactivated
Our investigation began with the Sonogashira coupling
of 1-octyne with cycloheptyl bromide (Table 1). First,
using in situ prepared palladium–NHC complexes and
the reaction conditions developed by Fu8 for the cou-
pling of primary alkyl halides, only low amounts of
the desired coupling products were formed. A systematic
screening of the reaction conditions revealed that in-
creased solvent polarity and elevated temperatures are
crucial for the success of this coupling reaction. Cs2CO3
was found to be the optimal base. In addition, a variety
of NHC ligands were tested under optimized conditions
Keywords: Sonogashira coupling; Cross-coupling; Secondary alkyl
halide; Palladium; N-heterocyclic carbene.
*
Corresponding author. E-mail: glorius@chemie.uni-marburg.de
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.02.111

2926
G. Altenhoff et al. / Tetrahedron Letters 47 (2006) 2925–2928
Table 1. Effect of ligand structure on the Sonogashira coupling of
IBiox ligands in this study. IBiox6 and IBiox7 were the
best ligands resulting in yields of above 60% and the for-
mation of significantly less side products (entries 5 and
6).12 The use of the preformed complex [IBiox7PdCl2]2
led to an additionally increased yield of 70%. Phosphine
ligands were not suitable as ligands in this reaction under
the conditions employed (entries 10 and 11).
cycloheptyl bromidea
2.5% [(π-allyl)PdCl]2
5% ligand, 10% CuI
Br
1.4 equiv Cs2CO3
+
DMF/DME (3:2)
Hex
60 C, 16 h
˚
1
Hex
A variety of differently substituted alkyl and cycloalkyl
bromides can be successfully coupled with 1-octyne using
this new catalyst system. Interestingly, the additional use
of catalytic amounts of 1,2-diaminocyclohexane was
found to be beneficial in some cases (Table 2). Under
standard conditions, the coupling of 1-octyne with a
cis/trans-mixture of 4-methylcyclohexyl bromide gave
only a low yield of the desired coupling products. The
addition of 1,2-diaminocyclohexane led to an improved
yield and the formation of less side products (entries 1
and 2). The Sonogashira coupling of the acyclic bromide
3 also benefited from this additive (entries 3 and 4).
However, in other cases the additive did not effect the
yield or had a deleterious effect. In the case of cycloheptyl
bromide, only a minor improvement was observed
(entries 5–7). Interestingly, related amine additives like
n-hexyl amine gave comparable results.13
Entry
Ligand
Yield (%)
1
2
3
4
5
6
7
8
IMesÆHCl
IAdÆHCl
IBioxMe4ÆHOTf
IBioxPent4ÆHOTf
IBiox6ÆHOTf
IBiox7ÆHOTf
51
41
57
55
62
61
70c
60
55
<5
15
b
[IBiox7PdCl2]2
IBiox8ÆHOTf
IBiox12ÆHOTf
PPh3
9
10
11
PCy3
a Average yield of two experiments, determined by GC (internal
standard).
b This preformed Pd complex was used.
c Isolated yield.
Table 3 summarizes the results of the Sonogashira cou-
pling of secondary alkyl bromides.14,15 Cyclopentyl,
-hexyl, -heptyl and -octyl bromide were successfully cou-
pled under these conditions. The use of the correspond-
ing iodide often gave a significantly reduced yield
(entries 2 and 5). The more challenging secondary acy-
clic alkyl bromides can also be coupled. Since the reac-
tion conditions are rather mild, a variety of functional
groups is tolerated on the alkyl bromide chain. Acetyl
giving distinctly different results (Table 1). IMes resulted
in the formation of a competent catalyst (entry 1). On
the other hand, a lower yield was obtained with IAd,
the best ligand in Fu’s study (entry 2).8 In both cases,
a significant amount of side products like alkyne dimer-
ization products and reductive dimerization products
was produced.
Recently, we have reported on the synthesis and applica-
tion of a new family of bioxazoline-derived NHC (IBiox)
(Scheme 2).10 These electron-rich donor ligands are steri-
cally demanding but exhibit a certain degree of flexibil-
ity.11 In addition, this family of ligands has very similar
electronic properties but different steric demand render-
ing the IBiox ligands well suited for the systematic opti-
mization of a metal–NHC complex catalyzed reaction.
This was showcased by employing a series of different
Table 2. Additive effect of 1,2-diaminocyclohexane on the Sonogashira
coupling of different substratesa
R1
R1
R2
Br
[IBiox7PdCl2]2, CuI
R2
+
Cs2CO3, DMF/DME, 60
1,2-diaminocyclohexane
C
˚
Hex
Br
Hex
+
+
N
N
N
N
Mes
Mes
Ad
Ad
Br
_
_
Br
Cl
IMes HCl
Cl
IAd HCl
2
3
4
Entry Bromide 1,2-Diamino-cyclohexane Product Yield
O
O
[mol%]
[%]
IBioxMe4 HOTf, R = Me
IBioxPent4 HOTf, R = Pent
+
N
N
1
2
3
4
5
6
7
2
2
3
3
4
4
4
0
20
0
20
0
5
5
6
6
1
1
1
24
56
33
62
70
76
71
R
R
R
_
R
OTf
IBiox5 HOTf, n = 1
IBiox6 HOTf, n = 2
IBiox7 HOTf, n = 3
IBiox8 HOTf, n = 4
IBiox12 HOTf, n = 8
O
O
8
20
+
N
N
_
( )n
a Reaction conditions: [IBiox7PdCl2]2 (2 mol %), CuI (8 mol %),
Cs2CO3 (1.45 equiv), alkyne (1.45 equiv), DMF/DME (3:2), 60 °C,
16–18 h, isolated yield.
( )n
OTf
Scheme 2. NHC ligand precursor.

G. Altenhoff et al. / Tetrahedron Letters 47 (2006) 2925–2928
2927
Table 3. Sonogashira coupling of secondary alkyl halides with 1-
Oct
ee = 99%
octynea
Br
1.4 equiv Cs2CO3
1.5 mol% [IBiox7PdCl2]2
7.5 mol% CuI
Entry
Alkyl halide
Product
Yield [%]
65
+
1
7
DMF/DME (3:2)
Br
I
60 C, 16 h
˚
18
Oct
2b
7
8
45
71
76
49
71
77
54
56
77
62
67
39
63
76
57
65%, rac
Scheme 3. Sonogashira coupling of an enantiomerically pure second-
ary alkyl bromide.
3
4c
Br
1
Table 4. Sonogashira coupling of primary alkyl bromides with 1-
Br
I
octyne
Entry
Alkyl halide
Product
19
Yield [%]
5b
1
1
2
H3C
77
66
Br
Br
7
6d
9
20
Ph
Br
Br
3
21
61
Br
Br
4
7e
10
11
5
4
5
22
23
60
78
Cl
2
EtO2C
Br
Br
8
2
Br
6
24
62
4
O
9b
Br
An interesting aspect of this coupling reaction is the pos-
sible creation of a stereocenter. In order to investigate
the stereochemical nature of this process, we submitted
an enantiomerically pure substrate, (R)-2-bromo octane,
to the Sonogashira reaction conditions (Scheme 3).
Interestingly, this reaction resulted in a complete loss
of the stereochemical information and in the formation
of racemic product.
10b
11b
12
13b
14
15
16
12
6
Br
Br
13
14
15
16
17
Br
4
In addition to secondary alkyl bromides, primary alkyl
bromides are also suitable substrates for the Sonogash-
ira coupling under the conditions developed in this study
(Table 4). Once again, multiple functional groups like
chloride, ester or epoxide groups are well tolerated.
The yields obtained for these primary substrates are
comparable to the results obtained by Fu.8
Br
AcO
Br
EtO2C
Br
In conclusion, a palladium-IBiox-based catalyst system
allows the Sonogashira coupling of some alkynes with
primary and secondary alkyl bromides, tolerating many
functional groups in the alkyl bromide component.
Br
O
a Reaction conditions: [IBiox7PdCl2]2 (2 mol %), CuI (8 mol %),
Cs2CO3 (1.4 equiv), alkyne (1.45 equiv), DMF/DME (3:2), 60 °C, 16–
18 h, isolated yield.
b 20 mol % 1,2-diaminocyclohexane used as an additive.
c 8 mol % 1,2-diaminocyclohexane used as an additive.
d 1-decyne was used instead of 1-octyne.
Acknowledgements
e 1-dodecyne was used instead of 1-octyne.
Generous financial support by the Fonds der Chemis-
chen Industrie (FCI), Deutsche Forschungsgemeins-
chaft (DFG), Lilly Germany and BASF AG as well as
the donation of chemicals by Heraeus is gratefully
acknowledged.
protected alcohols, ester groups, epoxides, olefines and
aromatics are well tolerated. In addition, the chain
length of the alkyne can be varied (entries 6 and 7).
However, it has to be noted that the alkyne substrate
scope is rather limited. We have been surprised that a
variety of other alkynes like phenylacetylene or propar-
gyl alcohol failed to give the desired products in this
coupling reaction.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tet-

2928
G. Altenhoff et al. / Tetrahedron Letters 47 (2006) 2925–2928
9. The uncatalyzed coupling of deprotonated alkynes with
secondary alkyl halides is described in the following
references, resulting in yields of up to 6%, 11% or 4%,
respectively: (a) Chong, J. M.; Wong, S. Tetrahedron Lett.
1986, 27, 5445; (b) Holmes, A. B.; Jones, G. E. Tetrahe-
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10. (a) Altenhoff, G.; Goddard, R.; Lehmann, C. W.; Glorius,
F. Angew. Chem., Int. Ed. 2003, 42, 3690; (b) Altenhoff,
G.; Goddard, R.; Lehmann, C. W.; Glorius, F. J. Am.
Chem. Soc. 2004, 126, 15195; For excellent reviews on the
use of NHC ligands in catalysis, see: (c) Herrmann, W. A.
Angew. Chem., Int. Ed. 2002, 41, 1291; (d) Herrmann, W.
let.2006.02.111. It contains experimental procedures for
the synthesis of [(IBiox7)PdCl2]2 and for the Sonogash-
ira reactions as well as characterization data for all
coupling products.
References and notes
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15. General procedure for the Sonogashira reaction using
alkyl halides: [IBiox7PdCl2]2 (10 mg, 0.01 mmol), Cs2CO3
(228 mg, 0.7 mmol) and CuI (8 mg, 0.04 mmol) were
stirred with dry DMF (1.2 mL) and dry DME (0.8 mL)
at room temperature for 20 min. After addition of the
alkyl bromide (0.5 mmol, 1.0 eq), alkyne (0.73 mmol,
1.45 equiv) and amine-additive the reaction mixture was
stirred at 60 °C for 16–18 h. The reaction mixture was
allowed to cool to room temperature and was quenched by
either filtering through a short silica column (eluent:
hexane or dichloromethane) or by extraction with pentane
or diethyl ether (3–4 times, 15 mL) and water (15 mL, with
a few drops of TMEDA). The organic phase was washed
with brine (20 mL), dried over Na2SO4 (20 mL) and
concentrated under reduced pressure. After purification by
flash chromatography (eluent: hexane or pentane/diethyl-
ether) the products were obtained as pale-yellow liquids.
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