Palladium- and nickel-catalyzed direct alkylation of azoles with unactivated alkyl bromides and chlorides

Article abstract of DOI:10.1002/chem.201001631

Long-ing alkyl chain: The catalytic direct C-H alkylation of azoles with unactivated alkyl bromides and chlorides is described. A palladium catalyst enables the alkylation of oxazoles, whereas a nickel one shows unique activity for thiazole. The catalyses allow a straightforward access to azole motifs bearing long, functional alkyl side chains.

Full text of DOI:10.1002/chem.201001631

COMMUNICATION
DOI: 10.1002/chem.201001631
Palladium- and Nickel-Catalyzed Direct Alkylation of Azoles with
Unactivated Alkyl Bromides and Chlorides
Tomoyuki Yao, Koji Hirano,* Tetsuya Satoh, and Masahiro Miura*[a]
À
Metal-mediated direct C C bond-forming reactions in-
Based on the literature for the successful cross-coupling
reaction with alkyl electrophiles,[13] we began our study with
a Pd/bulky phosphine catalyst system. Indeed, treatment of
benzoxazole (1a, 0.50 mmol) with 1-bromohexane (2a,
À
volving C H bond cleavage are commonly of great interest
in modern organic chemistry, because of their potential for
providing an alternative to the conventional cross-coupling
strategy with a stoichiometric amount of organometallic re-
0.60 mmol) in the presence of PdACTHNUTRGEN(UNG OAc)2 (5 mol%), PCy3
À
agents and transformation of ubiquitous C H bonds into di-
(Cy=cyclohexyl; 10 mol%), and LiO-tBu (1.5 mmol) in di-
glyme (3.0 mL) at 1208C for 2 h provided the desired 2-hex-
ylbenzoxazole (3aa) albeit in 34% yield (GC; Table 1,
entry 1). With this interesting preliminary result in hand, we
screened various monodentate bulky ligands involving
verse functions in a single synthetic operation.[1] In particu-
lar, various catalytic systems for the direct arylation,[2] alke-
nylation,[3] and alkynylation[4] of arenes and heteroarenes
with the corresponding organic halides and pseudohalides
have been widely explored. On the other hand, the direct al-
kylation reaction with alkyl halides has received less atten-
tion, probably due to its substantial difficulty in controlling
undesired b-H elimination. Although recent efforts have en-
abled the use of activated alkylating reagents, such as ben-
zylic electrophiles,[5] the reaction with unactivated alkyl hal-
ides, especially those possessing the b-hydrogen atoms,[6]
thus, remains largely elusive.[7] Hoarau,[5c] Yu,[8] Wang,[9] and
Daugulis[10] independently reported palladium-catalyzed al-
kylation processes, whereas Ackermann[11] also succeeded in
a similar alkylation by using a ruthenium catalyst. However,
most of them are restricted in substrate scope to arenes con-
taining directing groups, and the alkyl donors are still limit-
ed to relatively reactive alkyl iodides and bromides. Here,
we report effective palladium- and nickel-based catalysts for
the direct alkylation of azole compounds. The present cata-
lytic systems are composed of common catalyst precursors,
and especially, the palladium-based system allows unactivat-
ed alkyl chlorides as well as bromides to serve as the prom-
ising alkyl sources.[12]
À
Table 1. Optimization studies for palladium-catalyzed direct C H alkyla-
tion of benzoxazole (1a) with 1-bromohexane (2a).[a]
Entry
Pd
Ligand
Yield of 3aa [%][b]
1
2
3
4
5
6
7
8
9
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
N
PCy3
PPhCy2
PPh2Cy
34
18
43
0
18
trace
0
14
30
43
48
55 (44)
34
20
66
P
N
PPh3
SPhos[c]
RuPhos[d]
IMes·HCl[e]
PPh2Cy
PPh2Cy
PPh2Cy
PPh2Cy
PdCl2
[Pd2A
(dba)3][i]
[{PdCl
(h3-C3H5)}2]
[{PdCl
(h3-C3H5)}2]
[{PdCl
(h3-C3H5)}2]
[{PdCl
(h3-C3H5)}2]
[{PdCl
(h3-C3H5)}2]
[{PdCl
(h3-C3H5)}2]
[{PdCl
(h3-C3H5)}2]
10
11
12[f]
13[f]
14[f]
15[f]
16[f]
17[f,h]
T
E
N
G
R
R
[g]
E
E
PCyp3
E
N
P
P
U
G
G
R
G
PMe3
(nBu)3
16
77 (64)
A
A
P
A
[a] T. Yao, Dr. K. Hirano, Prof. Dr. T. Satoh, Prof. Dr. M. Miura
Department of Applied Chemistry
Faculty of Engineering, Osaka University
Suita, Osaka 565-0871 (Japan)
[a] A mixture of Pd (0.025 mmol), ligand (0.050 mmol), LiO-tBu
(1.5 mmol), 1a (0.50 mmol), and 2a (0.60 mmol) in diglyme (3.0 mL) was
heated at 120 8C for 2 h under N2. [b] Yield determined by GC methods.
Yield of isolated product is in parentheses. [c] 2-Dicyclohexylphosphino-
2’,6’-dimethoxybiphenyl. [d] 2-Dicyclohexylphosphino-2’,6’-diisopropoxy-
biphenyl. [e] 1,3-Bis(2,4,6-trimethylphenyl)imidazolium chloride. [f] Used
Fax : (+81)6-6879-7362
E-mail: k_hirano@chem.eng.osaka-u.ac.jp
miura@chem.eng.osaka-u.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201001631.
1.0 mmol of 2a. [g] Cyp=cyclopentyl. [h] 20 mol% of PACTHGUNETRNNU(G nBu)3. [i] dba=
dibenzylideneacetone.
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12307

Buchwaldꢁs biaryl phosphines and NHC (entries 2–8) and
found the good activity of PPh2Cy (entry 3). Among other
palladium salts tested (entries 9–11), a combination of
With the prolonged reaction periods (12 h), under the other-
À
wise identical conditions, the direct C H alkylation proceed-
ed smoothly (entries 7–9). Notably, an acetal protection was
compatible toward the reaction (entry 9). However, 1-iodo-
hexane (2a’) and the secondary alkyl halide, bromocyclo-
hexane (2j) reacted with 1a sluggishly, probably due to the
rapid decomposition under the basic conditions and the
steric factors in the oxidative addition step (vide infra), re-
spectively (entries 10 and 11).
[{PdClACHTUNGTRENNUNG
(h3-C3H5)}2] and PPh2Cy gave better result (entry 11).
While an increase in the amount of 2a to two equivalents
slightly improved the reaction efficiency (entry 12), any
changes of other reaction parameters such as base, solvent,
and temperature gave no positive effect on yield. Thus, the
additional ligand investigation was carried out (entries 13–
16). To our surprise, a smaller P
which runs counter to the reported trends[13] (entry 15).
With 20 mol% of P(nBu)3 as the ligand, 3aa was obtained
in 64% isolated yield (entry 17).
With the [{PdCl
(h3-C3H5)}2]/P
G
Subsequently, we investigated the scope of azoles in the
palladium-catalyzed direct coupling (Scheme 1). 5-Substitut-
ed benzoxazoles coupled with alkyl bromides and chlorides
ACHTUNGTRENUNG
without any difficulties (3bi, 3cb, and 3db). It should be
3
À
G
noted that the sp C halide bond activation in preference to
2
À
formed the direct alkylation of 1a with an array of alkyl
bromides 2 (Table 2). In general, 7.5 mol% (based on Pd)
that of sp C halide bond was observed, which may enjoy
further manipulation (3db). In addition to benzoxazoles, 5-
À
Table 2. Palladium-catalyzed direct C H alkylation of benzoxazole (1a)
with various alkyl halides 2.[a]
Entry
1
2
Yield of 3 [%][b]
3ab, 71
2
3ac, 48
3
4
3ad, 65
3ae, 59
5
3af, 51
6
3ag, 33
7[c]
8[c]
3ah, 63
3ae, 65
9[c]
3ai, 75
10[d]
11[d]
3aa, 20[e]
3aj, trace
[a] A mixture of [{PdClACHTUNGTRENNUNG ACHUTNGTREN(NUGN nBu)3
(h3-C3H5)}2] (0.019 mmol, 7.5 mol% Pd), P
(0.15 mmol), LiO-tBu (1.5 mmol), 1a (0.50 mmol), and 2 (1.0 mmol) in
diglyme (3.0 mL) was heated at 120 8C for 4 h under N2. [b] Yield of iso-
lated product. [c] The reaction time was 12 h. [d] Under the conditions of
entry 17 in Table 1. [e] Yield determined by GC methods.
catalyst loading gave the good reproducibility. Phenylpropyl
(2b) and citronellyl bromide (2c) as well as simple 2a par-
ticipated in the reaction (entries 1 and 2). Benzyl ether, silyl
ether, and pivaloyl ester functionalities were tolerant, and
the corresponding alkylated benzoxazoles 3ad–f were
formed in moderate to good yields (entries 3–5), whereas
the imide moiety caused in the drop of the yield (entry 6). It
is worth noting that not only alkyl bromides, but also unacti-
vated alkyl chlorides worked well as the alkylating reagents.
Scheme 1. Products of the palladium-catalyzed direct coupling of azoles 1
À
with alkyl halides 2. The forming C C bond is illustrated with a bold
line. The leaving group (Br or Cl) on alkyl halides is in parenthesis. Reac-
tion conditions: A mixture of [{PdCl
Pd), P(nBu)3 (0.15 mmol), LiO-tBu (1.5 mmol), 1a (0.50 mmol), and 2
(h3-C3H5)}2] (0.019 mmol, 7.5 mol%
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
(1.0 mmol) in diglyme (3.0 mL) was heated at 120 8C for 4 h (Br) or 12 h
(Cl) under N2. [a] Used 1.5 mmol of 2 and 2.0 mmol of LiO-tBu.
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Chem. Eur. J. 2010, 16, 12307 – 12311

À
C H Functionalization
COMMUNICATION
aryloxazoles bearing the electronically and sterically diverse
functions such as trifluoromethyl, cyano, methoxy, and naph-
thyl groups underwent the alkylation. Moreover, the func-
tional group tolerance on alkyl halide was also generally
good.
In sharp contrast to the above success with oxazoles, no
product was detected when benzothiazole (1j) was em-
ployed under the standard reaction conditions using palladi-
um. Thus, we turned our attention to a nickel catalyst.[14,15]
It was found that a NiBr2·diglyme/terpyridine[16] catalyst cat-
mechanisms: the palladium catalysis would involve i) SN2-
type oxidative addition of alkyl halide to Pd0,[19] ii) subse-
quent transmetalation between the resultant [PdII
ACHTUNGTRENNUNG(alkyl)X]
(X=halide) and heteroaryllithium generated in situ from
azole and LiO-tBu,[20] and iii) productive reductive elimina-
tion from the [PdII
ACHTNUGETRNNU(G alkyl)(heteroaryl)] complex (Scheme 3).
alyzed the alkylation of 1j with alkyl bromides
2
(Scheme 2). While the yields were moderate, our prelimina-
ry studies showed the intrinsic potential of nickel in the
[12,17]
À
direct C H alkylation.
Scheme 2. Nickel-catalyzed direct alkylation of benzothiazole (1j) with
alkyl bromides 2a,b.
Scheme 3. Plausible mechanism for the palladium catalysis.
To obtain an insight into the mechanism, we implemented
the following reactions [Eqs. (1)–(3)]. The palladium-cata-
lyzed coupling of benzoxazole (1a) with alkyl bromide 2k
bearing the pendant olefin moiety exclusively afforded the
usual alkylated product 3ak [Eq. (1)].
On the other hand we propose that the nickel-catalyzed re-
action proceeds through i) formation of an alkyl radical trig-
gered by a single-electron transfer from an electron-rich het-
eroarylnickelate complex to the alkyl halide,[15,16,21] ii) re-
combination of the formed radical with the heteroarylnickel,
and iii) reductive elimination (Scheme 4). Further elucida-
tion of the detailed mechanism including the reason for the
suppression of the conceivable b-H elimination from the al-
kylmetal intermediate[22] is ongoing.
Even with 2l,[18] the corresponding 3al was produced with
the C=C double bond left intact. In contrast, the nickel cata-
lyst led to the formation of 5-exo-cyclized 3jk, and no linear
coupling product was observed [Eq. (2)]. In addition, the
radical clock 2m was transformed to the ring-opened 3jm as
the sole detectable product [Eq. (3)]. The results were
highly suggestive of the existence of a radical intermediate
arising from the alkyl halide under nickel catalysis. On the
basis of these outcomes, we propose the following reaction
Scheme 4. Plausible mechanism for the nickel catalysis.
In summary, we have demonstrated the effective palladi-
um and nickel catalyst systems for the direct C H alkylation
of electron-deficient arenes, azoles with unactivated alkyl
bromides and chlorides, and the striking mechanistic de-
À
Chem. Eur. J. 2010, 16, 12307 – 12311
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www.chemeurj.org
12309

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[8–12]
À
ment the known direct C H alkylation methodologies
as
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alkyl side chain to heteroarenes, which is known to generally
enhance their lipophilicity and solubility and to tune the ar-
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polymers.
Experimental Section
À
Palladium-catalyzed direct C H alkylation of benzoxazole (1a) with 1-
bromohexane (2a) (Table 1, entry 17): [{PdCl
A
0.013 mmol) and LiO-tBu (120 mg, 1.5 mmol) were placed in a 20 mL
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standard Schlenk technique. Diglyme (2.0 mL) and PACTHNUGTRENUNG(nBu)3 (0.5m in tol-
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solution was stirred for 10 min at room temperature. Finally, a solution of
benzoxazole (1a, 60 mg, 0.50 mmol), 1-bromohexane (2a, 165 mg,
1.0 mmol), and 1-methylnaphthalene (ca. 50 mg, internal standard) in di-
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yield.
Acknowledgements
This work was partly supported by Grants-in-Aid from the Ministry of
Education, Culture, Sports, Science, and Technology, Japan.
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À
Keywords: alkylation · azoles · C H activation · nickel ·
palladium
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À
C H Functionalization
COMMUNICATION
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À
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À
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À
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Received: June 10, 2010
Published online: September 17, 2010
Chem. Eur. J. 2010, 16, 12307 – 12311
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
12311