User-friendly [(diglyme)NiBr2]-catalyzed direct alkylations of heteroarenes with unactivated alkyl halides through C-H bond cleavages

Article abstract of DOI:10.1002/adsc.201100487

A nitrogen and phosphorus ligand-free catalytic system derived from inexpensive [(diglyme)NiBr₂] allowed for efficient direct C-H bond alkylations of heteroarenes with unactivated β-hydrogen-containing alkyl halides under basic reaction conditi

Full text of DOI:10.1002/adsc.201100487

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DOI: 10.1002/adsc.201100487
User-Friendly [(Diglyme)NiBr2]-Catalyzed Direct Alkylations of
ꢀ
Heteroarenes with Unactivated Alkyl Halides through C H Bond
Cleavages
Lutz Ackermann,a,* Benudhar Punji,a and Weifeng Songa
a
Institut fꢀr Organische und Biomolekulare Chemie, Georg-August-Universitꢁt, Tammannstrasse 2, 37077 Gçttingen,
Germany
Fax : (+49)-551-39-6777; e-mail: Lutz.Ackermann@chemie.uni-goettingen.de
Received: June 23, 2011; Revised: July 25, 2011; Published online: December 8, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201100487.
Abstract: A nitrogen and phosphorus ligand-free
catalytic system derived from inexpensive [(di-
limit its broader applications.[13] Moreover, four direct
alkylations of benzothiazole were recently achieved
with a nickel complex derived from the tridentate ni-
trogen ligand terpyridine.[8g] Within our research pro-
gram directed towards the development of user-
ꢀ
G
alkylations of heteroarenes with unactivated b-hy-
drogen-containing alkyl halides under basic reaction
conditions.
ꢀ
friendly and sustainable C H bond functionaliza-
tions,[14] we developed a cost-effective nitrogen- and
phosphorus ligand-free[15] free nickel catalyst for
direct alkylations of heteroarenes, on which we wish
to report herein.
ꢀ
Keywords: alkylation; azoles; C H activation; het-
erocycles; mechanism; nickel
At the outset of our studies, we tested a diverse
array of commercially available nickel precursors for
ꢀ
the direct C H bond functionalization of benzoxazole
Substituted heteroarenes are indispensable substruc- (1a) with alkyl iodide 2a as the electrophile, 2,2’-bi-
tures of, among others, biologically active compounds pyridine (bpy, 4) as the ligand, and CuI[10] as cocata-
and functional materials.[1–3] In particular, strategies lyst (Table 1). Among different nickel sources, [(di-
ꢀ
relying on direct C H bond functionalizations argua-
bly constitute the most ecologically benign and eco-
nomically attractive methods for their preparation.[4]
In recent years, various transition metal catalysts
were devised for versatile direct arylations, alkenyla-
ꢀ
Table 1. Nickel precursors for the direct C H bond alkyla-
AHCTUNGTRENNUNG
tion.[a]
tions or alkynylations of heteroarenes by cleavages of
[5]
ꢀ
unreactive C H bonds. In contrast, direct alkyla-
tions of (hetero)arenes with unactivated alkyl halides
under basic reaction conditions continue to be diffi-
cult, predominantly because these challenging electro-
philes lead to undesired b-eliminations.[6] Remarkable
recent progress was represented by efficient rutheni-
um[7] and palladium catalyzed[8] direct alkylations of
(hetero)arenes.[6] On the contrary, direct alkylations
with less expensive nickel catalysts[9] are scarce, and
were thus far solely achieved with nickel complexes
derived from tridentate nitrogen ligands.[8g,10–12] Thus,
Hu and co-workers elegantly devised the nickel com-
plex [(MeNN2)NiCl] bearing a tridentate pincer N2N-
ligand for direct functionalizations of heteroarenes
with alkyl halides.[10] Unfortunately, the synthesis of
this catalyst involves several reaction steps, which can
Entry
[Ni]
3aa
1
2
3
4
5
A
36%
35%
48%
64%
61%
Ni(acac)2
[(DME)NiCl2]
Ni(COD)2
[(diglyme)NiBr2]
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
[a]
Reaction conditions: 1a (1.0 mmol), 2a (1.5 mmol), [Ni]
(5.0 mol%), CuI (7.5 mol%), 4 (6.0 mol%), t-BuOLi
(2.0 mmol), 1,4-dioxane (3.0 mL), 1408C, 16 h; isolated
yields.
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Lutz Ackermann et al.
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Table 2. Ligand effect on the nickel-catalyzed direct alkyla-
A
Table 3. Optimization of the nickel-catalyzed direct alkyla-
tion.[a]
tion.[a]
Entry
Base
Solvent
3aa
Entry
L
3aa
1
2
3
4
5
6
7
8
9
t-BuONa
t-BuOK
K2CO3
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
DME
NMP
toluene
diglyme
1,4-dioxane
1,4-dioxane
28%
1
2
3
4
5
6
7
8
dppe
dppf
ACHTUNGTRENNUNG(rac)-BINAP
1,10-phenanthroline
4,4’-di-tert-butylbipyridine
37%
31%
28%
55%
42%
62%
61%
65%
20%
<2%[b]
65%
37%
23%
52%
bpy (4)
–
diglyme[b]
22%
43%[c]
<3%[b,d]
[a]
Reaction conditions: 1a (1.0 mmol), 2a (1.5 mmol), [(di-
glyme)NiBr2] (5.0 mol%), CuI (7.5 mol%),
(6.0 mol%), t-BuOLi (2.0 mmol), 1,4-dioxane (3.0 mL),
1408C, 16 h; isolated yields.
Diglyme (15 mol%).
10
L
[a]
Reaction conditions: 1a (1.0 mmol), 2a (1.5 mmol), [(di-
glyme)NiBr2] (5.0 mol%), diglyme (15 mol%), CuI
(7.5 mol%), base (2.0 mmol), solvent (3.0 mL), 1408C,
16 h; isolated yields.
GC conversion.
NiBr2 (5.0 mol%).
[b]
[b]
[c]
[d]
ACHTUNGTRENNUNG
Without [(diglyme)NiBr2].
AHCTUNGTRENNUNG
Thereafter, we explored a set of representative ni- out to be beneficial, when less expensive alkyl bro-
trogen as well as phosphorus ligands in the direct al- mides or chlorides 2 served as the electrophiles.
kylation of heteroarene 1a, and observed that the Thereby, alkyl halides 2 with various chain lengths
former ligands delivered the desired product 3aa in furnished the desired products 3 in satisfactory yields.
more satisfactory yields, with 2,2’-bipyridine (4) fur- Importantly, the inexpensive nickel catalyst displayed
nishing optimal results (Table 2, entries 1–6). Unex- a valuable chemoselectivity, and thus tolerated among
pectedly, the simple nickel(II) complex [(diglyme)- others methoxy or chloro substituents, the latter of
NiBr2] provided a comparably high yield in the ab- which can be exploited for further metal-catalyzed de-
sence of an additional ligand (Table 2, entry 7). Nota- rivatization reactions. On the contrary, the secondary
bly, the catalytic activity could slightly be improved alkyl bromide 2-bromohexane only led to an unsatis-
through the addition of co-catalytic amounts of di- factory low conversion to the desired product.
glyme (entry 8).
Furthermore, benzothiazole (5) turned out to be a
Subsequently, we probed a variety of bases and sol- viable substrate as well, which set the stage for its
vents for the desired direct alkylation of substrate 1a site-selective functionalization with unactivated alkyl
under nitrogen and phosphine ligand-free reaction bromides and chlorides 2 (Scheme 2).
conditions (Table 3). As a result, most effective trans-
Given the user-friendly nature of our inexpensive
formations were accomplished with t-BuOLi as the catalytic system, we became interested in probing its
base (entries 1–4) in 1,4-dioxane or toluene as the sol- mode of action.[8g,10] Hence, the direct alkylation of
ꢀ
vent (entries 4–7). On the contrary, C H bond func- substrate 1a with 5-bromo-1-pentene (2f) delivered
tionalizations occurred with significantly reduced effi- the expected n-alkylated product 3af [Scheme 3 (a)].
ꢀ
cacy when employing diglyme as the solvent (entry 8). In contrast, the C H bond functionalization with elec-
It is noteworthy that the direct alkylation proceeded trophile 2g gave rise to the 5-exo-cyclized product
also with simple NiBr2 as the catalyst (entries 9), yet 3ag, hence indicating a radical mechanism [Scheme 3
not in the absence of a nickel complex (entry 10).
(b)]. Moreover, the reaction with cyclopropylmethyl
With an optimized catalytic system in hand, we bromide (2h) provided additional support for the for-
ꢀ
probed its scope in the C H bond functionalization mation of a radical intermediate [Scheme 3 (c)].
of diversely substituted azoles 1 employing unactivat-
Based on these experimental mechanistic studies as
ed b-hydrogen-containing alkyl halides 2 (Scheme 1). well as insights into conventional nickel-catalyzed
Remarkably, co-catalytic amounts of NaI[10] turned cross-coupling reactions[12,16] we propose a working
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Adv. Synth. Catal. 2011, 353, 3325 – 3329

User-Friendly [(Diglyme)NiBr2]-Catalyzed Direct Alkylations of Heteroarenes
Scheme 1. Scope of the nickel-catalyzed direct alkylation of azoles 1.
Scheme 2. Nickel-catalyzed alkylation of benzothiazole (5).
mode for our nickel-catalyzed direct alkylations, Experimental Section
which involves odd-electron transfer (Scheme 4).
In summary, we have developed an unprecedented General Remarks
nitrogen and phosphorus ligand-free nickel catalyst
Catalytic reactions were carried out under a N2 atmosphere
for user-friendly direct alkylations of heteroarenes
with ample scope. The inexpensive nickel catalyst dis-
played an excellent chemo- and site-selectivity, which
using pre-dried glassware. 1,4-Dioxane was dried over
sodium. 5-Substituted benzoxazoles 1 were synthesized ac-
cording to previously described procedures.[17] Other sub-
strates were obtained from commercial sources, and were
used without further purification. Yields refer to isolated
compounds, estimated to be >95% pure as determined by
ꢀ
enabled direct C H bond functionalizations of vari-
ous azoles with unactivated b-hydrogen-containing
alkyl iodides, bromides and chlorides.
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Lutz Ackermann et al.
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Scheme 3. Mechanistic studies on the nickel-catalyzed direct alkylations.
Representative Procedure: Nickel-Catalyzed Direct
Alkylation of Benzoxazoles 1 (Table 2, entry 8)
A
solution of [(diglyme)NiBr2] (18 mg, 0.05 mmol,
5.0 mol%), diglyme (20 mg, 0.15 mmol, 15 mol%), CuI
(14 mg, 0.07 mmol, 7.5 mol%), t-BuOLi (160 mg,
2.00 mmol), benzoxazole (1a) (119 mg, 1.00 mmol) and n-
octyl iodide (2a) (360 mg, 1.50 mmol) in 1,4-dioxane
(3.0 mL) was stirred at 1408C for 16 h under N2. At ambient
temperature, H2O (15 mL) and aqueous HCl (0.5 mL, 2N)
were added and the reaction mixture was extracted with
MTBE (3ꢄ20 mL). The combined organic layers were dried
over Na2SO4 and the solvent was removed under vacuum.
The remaining residue was purified by column chromatogra-
phy on silica gel (n-hexane/EtOAc: 100/1 ! 50/1) to afford
3aa as
a
yellow oil; yield: 150 mg (65%). 1H NMR
(300 MHz, CDCl3): d=7.67–7.61 (m, 1H), 7.47–7.41 (m,
1H), 7.29–7.23 (m, 2H), 2.90 (t, J=7.5 Hz, 2H), 1.91–1.81
(m, 2H), 1.42–1.20 (m, 10H), 0.85 (t, J=6.0 Hz, 3H);
13C NMR (75 MHz, CDCl3): d=167.7 (Cq), 151.1 (Cq), 141.7
(Cq), 124.7 (CH), 124.3 (CH), 119.8 (CH), 110.5 (CH), 32.1
(CH2), 29.5 (2CH2), 29.4 (CH2), 28.9 (CH2), 27.1 (CH2), 22.9
(CH2), 14.4 (CH3); IR (neat): n=2925, 2854, 1615, 1572,
1455, 1241, 1146, 1104, 1002, 925 cmꢀ1; MS (EI): m/z (rela-
tive intensity)=231 (8) [M+], 202 (6), 188 (17), 175 (21), 160
(8), 146 (62), 133 (100), 104 (9), 41 (24). HR-MS (EI): m/z=
231.1621, calcd. for C15H21NO+ [M+]: 231.1623. The analyti-
cal data were in accordance with those reported in the liter-
ature.[10]
Scheme 4. Possible pathway for the nickel-catalyzed direct
alkylations.
1H NMR and GC. TLC: Macherey–Nagel, TLC plates Alu-
gramꢃ Sil G/UV254, detection under UV light at 254 nm.
Chromatographic separations were carried out on Merck
Silica 60 (0.063–0.200 mm, 70–230 mesh ASTM). All IR
spectra were recorded on a Bruker FT-IR Alpha device.
MS: EI-MS: Finnigan MAT 95, 70 eV; ESI-MS: Finnigan
LCQ. High resolution mass spectrometry (HR-MS): APEX
IV 7T FTICR, Bruker Daltonic. Melting points (mp): Bꢀchi
540 capillary melting point apparatus, values are uncorrect-
ed. NMR (1H and 13C) spectra were recorded at 300 (1H)
and 75 MHz [13C, APT (attached proton test)], respectively,
on Varian Unity-300 and AMX 300 instruments in CDCl3
solutions, if not otherwise specified, chemical shifts (d) are
provided in ppm.
Acknowledgements
Support by the Alexander von Humboldt foundation (fellow-
ship to B.P.) and the Chinese Scholarship Council (fellowship
to W.S.) is gratefully acknowledged.
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User-Friendly [(Diglyme)NiBr2]-Catalyzed Direct Alkylations of Heteroarenes
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