Copper-catalyzed alkylation of benzoxazoles with secondary alkyl halides

Article abstract of DOI:10.1021/ol300348w

Copper-catalyzed direct alkylation of benzoxazoles using nonactivated secondary alkyl halides has been developed. The best catalyst is a new copper(I) complex (1), and the reactions are promoted by bis[2-(N,N-dimethylamino)ethyl] ether.

Full text of DOI:10.1021/ol300348w

ORGANIC
LETTERS
2012
Vol. 14, No. 7
1748–1751
Copper-Catalyzed Alkylation of
Benzoxazoles with Secondary
Alkyl Halides
Peng Ren, Isuf Salihu, Rosario Scopelliti, and Xile Hu*
Laboratory of Inorganic Synthesis and Catalysis, Institute of Chemical Sciences and
ꢀ ꢀ
Engineering, Ecole Polytechnique Federale de Lausanne (EPFL), SB-ISIC-LSCI,
BCH 3305, Lausanne 1015, Switzerland
xile.hu@epfl.ch
Received February 13, 2012
ABSTRACT
Copper-catalyzed direct alkylation of benzoxazoles using nonactivated secondary alkyl halides has been developed. The best catalyst is a new
copper(I) complex (1), and the reactions are promoted by bis[2-(N,N-dimethylamino)ethyl] ether.
Aromatic heterocycles are important organic molecules
because they often exhibit interesting biological, pharma-
ceutical, and material functions.1 In recent years, direct
CꢀH functionalization has emerged as one of the most
straightforward and efficient methods for the deriva-
tization of aromatic heterocycles. Significant progress
has been made in direct arylation, alkenylation, and
alkynylation.2,3 Direct alkylation, however, proves to be
more challenging, especially if the alkyl groups contain β-
hydrogens.4 This islikelydue tothe tendencyof metal alkyl
intermediates to undergo unproductive β-H elimination.5
Several approaches are now available for direct alkylation
of aromatic heterocycles, including FriedelꢀCrafts,6 radical
alkylation,7 insertion of CꢀH bonds into olefins,8,9 cou-
pling of heterocycles with tosylhydrozones,10,11 and cou-
pling of heterocycles with alkyl electrophiles.12ꢀ14 Most
reported methods only introduce a primary alkyl group.
Metal-catalyzed hydroarylation of olefins is in principle an
effective way to incorporate a secondary alkyl group onto
heterocycles, yet current success is largely limited to the
introduction of activated alkyl (e.g., benzyl and allyl)
groups.8 Wang et al. pioneered Cu-catalyzed direct benzyla-
tion and allylation of azoles with N-tosylhydrozones.10
(1) (a) Eicher, T.; Hauptmann, S. The Chemistry of Heterocycles;
Wiley-VCH: Weinheim, 2003. (b) Carey, J. S.; Laffan, D.; Thomson, C.;
Williams, M. T. Org. Biomol. Chem. 2006, 4, 2337–2347. (c) Kraft, A.;
Grimsdale, A. C.; Holmes, A. B. Angew. Chem., Int. Ed. 1998, 37, 402–
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2008, 130, 8172–8174. (c) Cho, S. H.; Kim, J. Y.; Kwak, J.; Chang, S.
Chem. Soc. Rev. 2011, 40, 5068–5083. (d) Ackermann, L.; Althammer,
A.; Fenner, S. Angew. Chem., Int. Ed. 2009, 48, 201–204. (e) Join, B.;
Yamamoto, T.; Itami, K. Angew. Chem., Int. Ed. 2009, 48, 3644–3647. (f)
Besselievre, F.; Piguel, S. Angew. Chem., Int. Ed. 2009, 48, 9553–9556. (g)
Brand, J. P.; Charpentier, J.; Waser, J. Angew. Chem., Int. Ed. 2009, 48,
9346–9349. (h) Turner, G. L.; Morris, J. A.; Greaney, M. F. Angew.
Chem., Int. Ed. 2007, 46, 7996–8000. (i) Matsuyama, N.; Hirano, K.;
Satoh, T.; Miura, M. Org. Lett. 2009, 11, 4156–4159. (j) Hachiya, H.;
Hirano, K.; Satoh, T.; Miura, M. Angew. Chem., Int. Ed. 2010, 49, 2202–
2205. (k) Kitahara, M.; Hirano, K.; Tsurugi, H.; Satoh, T.; Miura, M.
Chem.;Eur. J. 2010, 16, 1772–1775. (l) Messaoudi, S.; Brion, J. D.;
Alami, M. Eur. J. Org. Cherm. 2010, 6495–6516. (m) Li, H.; Sun, C. L.;
Yu, M. A.; Yu, D. G.; Li, B. J.; Shi, Z. J. Chem.;Eur. J. 2011, 17, 3593–
3597.
(4) For representative examples of direct alkylation of nonhetero-
cyclic substrates, see: (a) Ackermann, L.; Novak, P.; Vicente, R.;
Hofmann, N. Angew. Chem., Int. Ed. 2009, 48, 6045–6048. (b) Ackermann,
L.; Hofmann, N.; Vicente, R. Org. Lett. 2011, 13, 1875–1877. (c) Zhang,
Y. H.; Shi, B. F.; Yu, J. Q. Angew. Chem., Int. Ed. 2009, 48, 6097–6100.
(d) Shabashov, D.; Daugulis, O. J. Am. Chem. Soc. 2010, 132, 3965–3972.
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r
10.1021/ol300348w
Published on Web 03/09/2012
2012 American Chemical Society

˚
(amide) distance (1.9406(16) A) is significantly shorter
Miura et al. reported Ni- and Co-catalyzed alkylation of
azoles with N-tosylhydrozones, which was the first general
method to couple nonactivated secondary alkyl groups with
azoles.11 We and others recently developed metal-catalyzed
direct alkylation of azoles and thiazoles using nonactivated
alkyl halides.10,13,14 Unfortunately, only primary alkyl ha-
lides could be used. Herein we describe Cu-catalyzed alkyla-
tion of benzoxazoles with secondary alkyl halides. An
important additive is also identified.
˚
than the CuꢀN (amine) distance (2.1339(16) A).
Earlier work from our group showed that a Ni pincer
complex, [(MeN2N)NiCl],15,16 was an active (pre)catalyst for
cross coupling of nonactivated alkyl halides17,18 and direct
CꢀH alkylation.13,19 We then became interested in the
chemistry of analogous Cu complexes. The anionic bis-
(amino)amide ligand N2N alone was not sufficient to
stabilize the Cu(I) ion, as the reactions of [(MeN2N)Li]2
15
with a Cu(I) precursor (e.g., CuI, CuCl, [Cu(CH3CN)4]PF6)
led to the formation of copper mirror and protonated ligand
HMeN2N. Triphenylphosphine, however, could be used as a
coligand to form a stable Cu(I) complex. Thus, reaction of
[(MeN2N)Li]2 with[Cu(PPh3)Cl]4 yielded [(MeN2N)Cu(PPh3)] -
(1).20 The solid-state molecular structure of 1 was estab-
lished by X-ray crystallography (Figure 1). The Cu ion is in
a distorted trigonal planar ligand environment. The N2N
ligand is bidentate, with one of the amine donors being
Figure 1. (Left) Structural formula for complex 1. (Right) X-ray
structure of 1. The thermal ellipsoids are displayed in 50% probability.
˚
Selected bond lengths (A) and angles (deg): Cu1ꢀN1, 2.1339(16);
Cu1ꢀN2, 1.9406(16); Cu1ꢀP1, 2.1492(6); N1ꢀCu1ꢀN2, 85.00(6);
N2ꢀCu1ꢀP1, 143.42(5); P1ꢀCu1ꢀN1, 131.34(5).
Complex 1 turned out to be a good catalyst for direct
alkylation. The coupling of benzoxazole with cyclopentyl
iodide was used as the test reaction (Table 1). The Ni/Cu
based method, which was efficient for direct coupling of
azoles with primary alkyl halides,13 was inefficient for this
reaction. After modification, it gave a maximum yield of
4% (entry 1, Table 1). Replacing [(MeN2N)NiCl] with 1
improved the yield to 32% (entry 2, Table 1). Increasing
the loading of 1 to 10 mol % further increased the yield to
50% (entry 3, Table 1). The yields were similar when the
reactions were run at 80 or 100 °C. tBuONa and toluene were
the best base and solvent combination. Other combinations
˚
noncoordinating (N3ꢀCu1 = 3.290(2) A). The CuꢀN
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(g) Mukai, T.; Hirano, K.; Satoh, T.; Miura, M. J. Org. Chem. 2009, 74,
6410–6413.
t
t
such as BuOLi þ dioxane, BuOLi þ DMF, Cs2CO3 þ
toluene gave no or inferior yields. Interestingly, without CuI
as cocatalyst, the yield was only 11% (entry 4, Table 1). CuI
alone did not catalyze the reaction (entry 5, Table 1).
In our previous studies of Ni-catalyzed Kumada-type
coupling reactions, we found that bis[(2-(N,N-dimethyl-
aminoethyl)]ether (BDMAEE, previously abbreviated as
O-TMEDA) often promoted the catalysis.18 Out of curi-
osity, we tested the effect of BDMAEE for direct alkyla-
tion. To our delight, addition of 5 mol % or 0.2 equiv of
BDMAEEledtoacouplingyieldof77%(entry6, Table1).
Slightly lower yields were obtained when the loadings of
BDMAEE were between 1 and 5 equiv. Lowering the
temperature from 100 to 80 °C further increased the yield
to 87% (entry 7, Table 1). CuI was no longer necessary
under these conditions, and when 1 was replaced by CuI
(15 mol %) the yield decreased to 62%. When another
soluble Cu(I) complex, [Cu(Phen)(PPh3)2]NO3 (phen =
phenanthroline) or Cu(S(CH3)2)Br or [Cu(PPh3)Cl]4, was
used as precatalyst, the yield was about 60% (entry 9,
Table 1). These results indicate a superior catalytic activity
for complex 1. On the other hand, [(MeN2N)NiCl] was still
a poor catalyst even with BDMAEE as additive (compare
entries 1 and 10, Table 1). A control experiment showed
(9) Lewis, J. C.; Bergman, R. G.; Ellman, J. A. Acc. Chem. Res. 2008,
41, 1013–1025.
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C.; Kapdi, A. R. Org. Lett. 2011, 13, 3082–3085.
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2010, 49, 3061–3064.
(14) (a) Yao, T.; Hirano, K.; Satoh, T.; Miura, M. Chem.;Eur. J.
2010, 16, 12307–12311. (b) Ackermann, L.; Punji, B.; Song, W. F. Adv.
Synth. Catal. 2011, 353, 3325–3329.
(15) Csok, Z.; Vechorkin, O.; Harkins, S. B.; Scopelliti, R.; Hu, X. L.
J. Am. Chem. Soc. 2008, 130, 8156–8157.
(16) Vechorkin, O.; Csok, Z.; Scopelliti, R.; Hu, X. L. Chem.;Eur. J.
2009, 15, 3889–3899.
(17) Vechorkin, O.; Hu, X. L. Angew. Chem., Int. Ed. 2009, 48, 2937–
2940.
(18) (a) Vechorkin, O.; Proust, V.; Hu, X. L. J. Am. Chem. Soc. 2009,
131, 9756–9766. (b) Vechorkin, O.; Scopelliti, R.; Hu, X. L. Angew.
Chem., Int. Ed. 2011, 50, 11777–11781.
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(20) See the Supporting Information.
Org. Lett., Vol. 14, No. 7, 2012
1749

Table 1. Optimization of Conditions for the Coupling of Benzoxazole with Cyclopentyl-Ia
entry
catalysts
conditions
yieldb (%)
1
2
3
4
5
6
5 mol % of [(MeN2N)NiCl] and 5 mol % of CuI
5 mol % of 1 and 5 mol % of CuI
10 mol % of 1 and 5 mol % of CuI
10 mol % of 1
1.4 equiv of tBuONa, 140 °C
4
1 equiv of tBuONa, 100 °C
32
50
11
0
1.2 equiv of tBuONa, 80 or 100 °C
1.2 equiv of tBuONa, 80 °C
5 mol % of CuI
1.2 equiv of tBuONa, 80 °C
10 mol % of 1 and 5 mol % of CuI
5 mol % or 0.2 equiv of BDMAEE,
77
1.2 equiv of tBuONa, 100 °C
7
8
9
10 mol % of 1
0.2 equiv of BDMAEE, 1.2 equiv of tBuONa, 80 °C
0.2 equiv of BDMAEE, 1.2 equiv of tBuONa, 80 °C
0.2 equiv of BDMAEE, 1.2 equiv of tBuONa, 80 °C
87/80c
62
15 mol % of CuI
10 mol % of [Cu(Phen)(PPh3)2]NO3,
Cu(S(CH3)2)Br, or [Cu(PPh3)Cl]4
10 mol % of [(MeN2N)NiCl] and 5 mol % of CuI
none
57ꢀ61
10
11
12
13
14
15
0.2 equiv of BDMAEE, 1.2 equiv of tBuONa, 80 °C
0.2 equiv of BDMAEE, 1.2 equiv of tBuONa, 80 °C
0.2 equiv of BDMAEE, 1.2 equiv of tBuONa, 80 °C
0.2 equiv of TMEDA, 1.2 equiv of tBuONa, 80 °C
0.2 equiv of TMEDA, 1.2 equiv tBuONa, 80 °C
1.2 equiv of tBuONa, 80 °C
10
0
6.5 mol % of [(BDMAEE)Cu2I2]
10 mol % of 1
61
44
0
15 mol % of CuI
10 mol % of [(TMEDA)CuI]
0
a See the Supporting Information for experimental details. b GC yield relative to benzoxazole. c Isolated yield.
that without a Cu catalyst, BDMAEE did not catalyze the
coupling (entry 11, Table 1). Finally, apreparative reaction
under the optimized conditions (entry 7, Table 1) gave the
alkylated product in an isolated yield of 80%.
The scope of the Cu-catalyzed alkylation was then ex-
plored (Table 2). Cycloheptyl- and cyclooctyl-I were
coupled to benzoxazole in high yields (entries 1ꢀ2, Table 2).
Acyclic secondary alkyl iodides were also suitable sub-
strates, and the reactions were insensitive to the length of
the alkyl chains (entries 3ꢀ7, Table 2). Secondary alkyl
bromides could be coupled (entries 8ꢀ10, Table 2). Addition
of a catalytic amount of CuI increased the yield substantially,
probably because CuI mediated an I/Br exchange reaction.21
Other iodide sources were not as effective. Unfortunately
secondary alkyl chlorides did not react even in the presence
As BDMAEE was essential for achieving high yields in
the Cu-catalyzed direct alkylation, its roles were investi-
gated. Obviously BDMAEE is a potential ligand. When CuI
or Cu(S(CH3)2)Br was used as precatalyst (entries 8 and 9,
Table 1), the real catalyst most likely was a CuꢀBDMAEE
complex. Reaction of CuI with BDMAEE produced a
copper complex that appeared to be [(BDMAEE)Cu2I2]
according to NMR and elemental analysis.20 Using this
complex as catalyst, the coupling of benzoxazole with
cyclopentyl iodide had a yield of 61%, similar to those
obtained using CuI or Cu(S(CH3)2)Br in conjunction with
BDMAEE. However, BDMAEE was not a ligand when
complex 1 was used as catalyst, as no reaction occurred
between 1 and BDMAEE. Furthermore, using 1 as
catalyst, the yield was significantly higher (87%) than using
[(BDMAEE)Cu2I2] as catalyst. Under these conditions,
BDMAEE must have another important role. It is possible
that BDMAEE partially solubilizes the inorganic base and
promotes the deprotonation of azole. It is also possible that
BDMAEE facilitates the transmetalation of azole anions to
the Cu center in 1. These roles might be replaced by CuI,
albeit with a lower efficiency. In fact, the combination of 1
and CuI gave a coupling yield of about 50% (entry 3,
Table 1), much higher than that of 11% using 1 alone
(entry 4, Table 1). TMEDA (tetramethylethylenediamine)
was another poor substitute for BDMAEE, resulting in a
yield of 40% (entry 13, Table 1). The combination of CuI
and TMEDA alone was not catalytically active (entries 14
and 15, Table 1).
n
of Bu4NI. Cl/I exchange must be difficult for secondary
alkyl chlorides under these conditions. Substituted benzox-
azoles could also be alkylated in high yields (entries 11ꢀ16,
Table 2). Both electron-donating Me and MeO groups and
electron withdrawing Cl and Br groups were tolerated. The
aryl-Cl and aryl-Br moieties in the products (entries 14 and
15, Table 2) leave room for further functionalization by
traditional cross coupling methods. Interestingly, for some
unknown reasons, the coupling of primary alkyl halides was
not efficient (Table S1, Supporting Information). Fortu-
nately, such coupling could be achieved using previously
reported Ni-catalysis.10,13,14 Oxazoles other than benzoxa-
zoles could not be coupled with high efficiency either.
The catalytic cycle of the Cu-catalyzed alkylation reaction
might be similar to those proposed for Cu-catalyzed direct
arylation and alkynylation of aromatic heterocycles.2c,3 The
azoles are deprotonated and transmetalated to Cu, and the
resulting organometallic Cu species react with alkyl halides
to give the coupling products. We showed earlier by a Hg-test
(21) In the coupling reactions of alkyl bromides, trace amounts of
alkyl iodides could be observed by GC in the product mixture.
1750
Org. Lett., Vol. 14, No. 7, 2012

Hg. The yield was 74%, close to the value obtained in the
absence of Hg. This result suggests, albeit does not prove, that
homogeneous Cu complexes are the active species.
Table 2. Scope of Cu-Catalyzed Alkylation of Benzoxazolesa
A few experiments were carried out to probe the activation
process of alkyl halides. Coupling of benzoxazole with tert-
butyl-I gave 3 in a yield of 23% (eq 1, Scheme 1). While the
yield is too low to be synthetically useful, the result rules out
the possibility of a SN2 process for the alkylation. The
reaction of benzoxazole with 6-iodohept-1-ene gave the
ring-closed product 4 in a yield of 62% (eq 2, Scheme 1).
This result indicates that the activation of secondary alkyl
halides occurs via a radical process. Furthermore, the re-
combination of the resulting secondary carbon radical with
the catalyst is slower than the ring-closing rearrangement of
the hept-6-en-2-radical, which has a first-order rate constant
of about 105 sꢀ1 22 When the coupling of benzoxazole with
.
cyclopentyl-I was conducted in the presence of 1 equiv of a
radical inhibitor, TEMPO, the yield was zero. This result is
consistent with a radical mechanism for the alkylation.
Scheme 1. Alkylation Reactions Using Mechanistic Probes
(Isolated Yields Are Reported)
In conclusion, we have developed a Cu-catalyzed direct
alkylation of benzoxazoles. While the scope is limited and
remains to be improved, to the best of our knowledge, this
is the first time nonactivated secondary alkyl halides have
been used as electrophiles. The well-defined Cu complex 1
is the best catalyst. The higher efficiency of 1 relative to
other copper catalysts might result from a hemilabile
property of the pincer ligand, which is subject to further
elucidation and exploitation. The alkylation is promoted
by a catalytic amount of BDMAEE. A similar promotion
might be found for other CꢀH functionalization reactions.
a 80 °C for alkyl-I and 100 °C for alkyl-Br. See the Support-
ing Information for experimental details. b Isolated yield.
c 10 mol % of 1 þ 20 mol % of CuI þ 40 mol % of BDMAEE were
used.
Acknowledgment. This work is supported by the Swiss
National Science Foundation (ProjectNo. 20021_126498).
experiment that Ni particles were the active species for Ni-
catalyzed direct alkylation.13 A similar Hg-test was conducted
for the Cu catalysis. Thus, the coupling of benzoxazole with
cyclopentyl-I was conducted in the presence of 10 equiv of
Supporting Information Available. Experimental de-
tails, additional entries, and characterization data. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(22) Fossey, J. S.; Lefort, D.; Sorba, J. Free Radicals in Organic
Chemistry; Wiley: New York, 1995.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 7, 2012
1751