Rutheniumkatalysierte regioselektive direkte Alkylierungen von Arenen mit nichtaktivierten Alkylhalogeniden unter C-H-Bindungsspaltung

Full text of DOI:10.1002/anie.200902458

Angewandte
Chemie
DOI: 10.1002/anie.200902458
À
C H Bond Functionalization
Ruthenium-Catalyzed Regioselective Direct Alkylation of Arenes with
À
Unactivated Alkyl Halides through C H Bond Cleavage**
Lutz Ackermann,* Petr Novꢀk, Rubꢁn Vicente, and Nora Hofmann
À
Direct arylation of arenes by C H bond cleavage, which is
attractive because of its ecologically and economically benign
nature, is an increasingly viable alternative to conventional
cross-coupling reactions with stoichiometric amounts of
organometallic reagents.[1,2] However, while the development
of stabilizing ligands allowed for the use of unactivated alkyl
halides in traditional cross-coupling chemistry,[3–5] generally
applicable methodologies for intermolecular[6] regioselective
Table 1: Optimization of ruthenium-catalyzed direct alkylation.[a]
Entry
L
Solvent
T [8C]
Yield [%]
direct alkylations of arenes[7] with alkyl halides[8] by C H
bond cleavage have proven elusive.
À
[b]
1
2
3
4
5
6
7
8
–
–
PPh3
PCy3
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
toluene
NMP
NMP
NMP
NMP
NMP
NMP
120
120
120
120
120
120
120
120
120
120
120
100
80
–
13
21
23
33
45
53
61
69
51
49[c]
68
68
73
17
–
Recently, we reported on the beneficial effect of carbox-
ylic acids[9] as additives in ruthenium-catalyzed direct aryla-
tion[10,11] with aryl bromides, chlorides, or tosylates.[12] Given
the significantly improved activity of the in situ generated
catalytic system, we became interested in exploring its use for
unprecedented ruthenium-catalyzed direct alkylations[13] with
unactivated alkyl halides[14,15] as electrophiles. Herein, we
MesCO2H
MeCO2H
nPrCO2H
iPrCO2H
1-AdCO2H
1-AdCO2H
1-AdCO2H
1-AdCO2H
1-AdCO2H
1-AdCO2H
1-AdCO2H
1-AdCO2(nHex)
9
10
11
12
13
14
15
16
À
report our findings on the development of such C H bond
functionalization reactions, which allowed for the efficient
conversion of primary and secondary alkyl halides and proved
applicable to neopentyl-substituted electrophiles.
60
23
100
At the outset of our studies, we probed various additives
in the ruthenium-catalyzed direct alkylation of 2-pyridyl
benzene (1a), employing unactivated alkyl bromide 2a in
NMP as solvent (Table 1). Different phosphines did not
significantly affect the outcome of the envisioned reaction
(Table 1, entries 1–4). On the contrary, more promising
results were obtained when catalytic amounts of carboxylic
acids were used as additives (Table 1, entries 5–9). The alkyl-
substituted, sterically hindered acid 1-AdCO2H gave the best
results (Table 1, entry 9).
[a] Reaction conditions: 1a (1.0 mmol), 2a (3.0 mmol), [{RuCl2(p-
cymene)}2] (2.5 mol%), (30 mol%), K2CO3 (2.0 mmol), solvent
L
(4.0 mL), 20 h, yield of isolated product. NMP=N-methylpyrrolidinone;
Ad=adamantyl. [b] In the absence of [{RuCl2(p-cymene)}2].
[c] RuCl3·nH2O (5.0 mol%) instead of [{RuCl2(p-cymene)}2].
performed at reaction temperatures as low as 608C with
comparable efficiencies (Table 1, entries 13–15). Finally, the
use of independently prepared carboxylic ester 1-AdCO2-
(nHex) clearly indicated that its formation was not relevant to
the generation of the catalytically active ruthenium species
(Table 1, entry 16).
We then explored the scope of the optimized catalytic
system in the direct alkylation of pyridine derivatives 1
(Table 2). A variety of unactivated alkyl bromides bearing b-
hydrogen atoms enabled regioselective direct alkylations
(Table 2, entries 1–8). While an alkyl iodide also led to an
acceptable yield of product 3a (Table 2, entry 9), the corre-
sponding alkyl chloride turned out to be a more challenging
substrate (Table 2, entry 10). Notably, our in situ generated
catalytic system was not limited to the use of primary alkyl
halides but also enabled the conversion of sterically more
congested secondary alkyl halides, albeit with lower yield
(Table 2, entry 11). Importantly, neopentyl bromide also
served as starting material for a direct alkylation (Table 2,
entry 12), which indicated that mechanisms relying on either a
Reactions performed in toluene[16] as solvent proceeded
less efficiently (Table 1, entry 10), and other solvents, such as
THF, 1,4-dioxane, DMSO, or N,N-dimethylacetamide, gave
considerably lower yields of desired product 3a. As an
economically attractive alternative, RuCl3·nH2O[17] could be
employed as catalyst precursor (Table 1, entry 11).[18] Impor-
tantly, direct alkylation of pyridine derivative 1a could be
[*] Prof. Dr. L. Ackermann, P. Novꢀk, R. Vicente, N. Hofmann
Institut fꢁr Organische und Biomolekulare Chemie
Georg-August-Universitꢂt
Tammannstrasse 2, 37077 Gꢃttingen (Germany)
Fax: (+49)551-39-6777
E-mail: lutz.ackermann@chemie.uni-goettingen.de
Homepage: http://www.org.chemie.uni-goettingen.de/ackermann/
[**] Support by the DFG and the Alexander-von-Humboldt foundation
(fellowship to R.V.) is gratefully acknowledged.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200902458.
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Table 2: Ruthenium-catalyzed direct alkylation of pyridine derivatives 1.[a]
Table 3: Ruthenium-catalyzed direct alkylation of pyrazole derivatives
5.[a]
À
Entry
Ralkyl
X
T [8C]
3
R1
Yield [%]
À
Entry
Ralkyl Br
6
R1
Yield [%]
À
1
2
3
4
5
6
7
8
9
10
nBu Br
100
60
60
100
60
100
100
100
100
100
3b
3c
3d
3e
3 f
3g
3h
3i
H
H
H
H
H
H
4-Me
4-MeO
H
74
69
80
81
78
80
52
53
61
31[b]
À
1
2
3
4
5
nPent Br
6a
6b
6c
6d
6e
H
H
H
H
H
89
87
87
92
91
À
nPent Br
À
nDec Br
À
nOct Br
À
nUndec Br
À
nDec Br
À
nDodec Br
nTetradec Br
À
nDodec Br
À
À
nTetradec Br
À
nHex Br
6
6 f
H
75
À
nHex Br
À
nHex I
3a
3a
7
8
9
6g
H
58
56
43
À
nHex Cl
H
6h
6i
5-Me
H
11
12
100
100
3j
H
H
51
57
3k
[a] Reaction conditions:
cymene)}2] (2.5 mol%), 1-AdCO2H (30 mol%), K2CO3 (2.0–3.2 mmol),
meta-xylene (4.0 mL), 20 h, yield of isolated product.
5
(1.0 mmol), 2 (3.0 mmol), [{RuCl2(p-
[a] Reaction conditions:
cymene)}2] (2.5 mol%), 1-AdCO2H (30 mol%), K2CO3 (2.0–3.2 mmol),
NMP (4.0 mL), 20 h, yield of isolated product. [b] GC analysis.
1 (1.0 mmol), 2 (3.0 mmol), [{RuCl2(p-
simple nucleophilic substitution or electrophilic aromatic
substitution (Friedel–Crafts reaction) are not operative.
Furthermore, a mechanism involving initial b-elimination
of HX from the alkyl halide, along with a subsequent
ruthenium-catalyzed hydroarylation,[14] could be ruled out,
as alkene 4 yielded only trace amounts of pyridine derivative
3a under otherwise identical reaction conditions
(Scheme 1).[19]
Scheme 2. Ruthenium-catalyzed direct alkylation of ketimine 7a.
Finally, we became interested in probing the nature of the
catalytically active species. Under the optimized reaction
À
conditions of catalytic C H bond functionalization, ruthe-
nium(II) carboxylate complex 9 was formed quantitatively,
even at ambient temperature.[19] Importantly, well-defined
complex 9 displayed a catalytic activity comparable to that
observed when using the in situ generated system (Scheme 3
vs. Table 1, entry 12).
Scheme 1. Attempted alkylation with alkene 4.
The catalytic system was not restricted to pyridine
derivatives as pronucleophilic substrates. Indeed, efficient
alkylation of pyrazole derivatives was also viable (Table 3).
Interestingly, initial optimization studies showed that aro-
matic solvent meta-xylene[16] enabled more efficient and
À
selective C H bond functionalization. Thus, various primary
(Table 3, entries 1–8) and secondary (Table 3, entry 9) alkyl
bromides could be converted, including one functionalized
derivative (Table 3, entry 6) and neopentyl bromide (Table 3,
entries 7 and 8). Moreover, direct alkylation with a meta-
substituted arene proceeded with high regioselectivity at the
sterically less hindered ortho-position, thereby yielding pyr-
azole derivative 6h as the sole product (Table 3, entry 8).
Remarkably, a comparable reactivity profile was observed
when using ketimine 7a as substrate. Thus, chemo- and
regioselective alkylations occurred, and subsequent reduction
yielded secondary amines 8a and 8b (Scheme 2).[20]
Scheme 3. Synthesis of ruthenium complex 9 and its use in catalytic
direct alkylation.
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121, 2694 – 2708; Angew. Chem. Int. Ed. 2009, 48, 2656 – 2670;
In summary, we report the development of the first
ruthenium-catalyzed direct alkylation of arenes with unac-
tivated alkyl halides bearing b-hydrogen atoms. A catalytic
system derived from carboxylic acid 1-AdCO2H enabled
regioselective intermolecular alkylation of pyridine, pyrazole,
or ketimine derivatives with primary as well as secondary
alkyl halides, and the method proved amenable to the use of
neopentyl bromide as electrophile. Additionally, a ruthen-
ium(II) carboxylate complex was identified as being catalyti-
cally competent.
c) J. Terao, N. Kambe, Acc. Chem. Res. 2008, 41, 1545 – 1554;
d) B. D. Sherry, A. Fꢁrstner, Acc. Chem. Res. 2008, 41, 1500 –
1511; e) A. C. Frisch, M. Beller, Angew. Chem. 2005, 117, 680 –
695; Angew. Chem. Int. Ed. 2005, 44, 674 – 688; f) M. R. Nether-
ton, G. C. Fu, Adv. Synth. Catal. 2004, 346, 1525 – 1532.
[6] For palladium-catalyzed intramolecular alkylations with acti-
vated alkyl halides, see: a-chloroacetanilides: a) E. J. Hennessy,
S. L. Buchwald, J. Am. Chem. Soc. 2003, 125, 12084 – 12085;
benzyl halides: b) S. J. Hwang, S. H. Cho, S. Chang, J. Am. Chem.
Soc. 2008, 130, 16158 – 16159.
[7] For reviews on palladium-catalyzed sequential reactions involv-
ing alkylations using norbornene, see: a) M. Catellani, E. Motti,
N. Della Ca, Acc. Chem. Res. 2008, 41, 1512 – 1522; b) Ref. [2f];
c) M. Catellani, Synlett 2003, 298 – 313; d) for a recent example
of palladium-catalyzed alkylations of one heteroarene with two
alkyl halides, see: C. Verrier, C. Hoarau, F. Marsais, Org.
Biomol. Chem. 2009, 7, 647 – 650.
[8] For palladium-catalyzed direct alkylations with stoichiometric
amounts of organometallic reagents, see: X. Chen, J.-J. Li, X.-S.
Hao, C. E. Goodhue, J.-Q. Yu, J. Am. Chem. Soc. 2006, 128, 78 –
79.
Experimental Section
Representative procedure for ruthenium-catalyzed direct alkylation:
3a (Table 1, entry 12):
A suspension of [{RuCl2(p-cymene)}2]
(15.4 mg, 0.025 mmol, 2.5 mol%), 1-AdCO2H (54.1 mg, 0.30 mmol,
30 mol%), K2CO3 (276 mg, 2.00 mmol), 1a (155 mg, 1.00 mmol), and
1-bromo-n-hexane (495mg, 3.00mmol) in NMP (4mL) was stirred for
20h at 1008C under N2. EtOAc (50 mL) and H2O (50 mL) were added
to the cold reaction mixture. The aqueous phase was extracted with
EtOAc (2 ꢀ 50 mL). The combined organic layers were washed with
H2O (50 mL) and brine (50 mL), dried over Na2SO4, and concen-
trated in vacuo. The remaining residue was purified by column
chromatography on silica gel (n-hexane/EtOAc 15:1) to yield 3a
(163 mg, 68%) as a colorless oil.
[9] Pivalic acid was used in palladium-catalyzed direct arylations:
a) M. Lafrance, K. Fagnou, J. Am. Chem. Soc. 2006, 128, 16496 –
16497; b) M. Lafrance, S. I. Gorelsky, K. Fagnou, J. Am. Chem.
Soc. 2007, 129, 14570 – 14571; examples from our laboratories:
c) L. Ackermann, R. Vicente, R. Born, Adv. Synth. Catal. 2008,
350, 741 – 748; d) L. Ackermann, A. Althammer, S. Fenner,
Angew. Chem. 2009, 121, 207 – 210; Angew. Chem. Int. Ed. 2009,
48, 201 – 204; reviews: e) M. Miura, T. Sato, in Modern Arylation
Methods (Ed.: L. Ackermann), Wiley-VCH, Weinheim, 2009,
pp. 335 – 361; f) P. de Mendoza, A. M. Echavarren in Modern
Arylation Methods (Ed.: L. Ackermann), Wiley-VCH, Wein-
heim, 2009, pp. 363 – 400.
[10] L. Ackermann, R. Vicente in Modern Arylation Methods (Ed.:
L. Ackermann), Wiley-VCH, Weinheim, 2009, pp. 311 – 399.
[11] For selected examples of ruthenium-catalyzed direct arylations,
see: a) L. Ackermann, M. Mulzer, Org. Lett. 2008, 10, 5043 –
5045; b) I. ꢂzdemir, S. Demir, B. Cetinkaya, C. Gourlaouen, F.
Maseras, C. Bruneau, P. H. Dixneuf, J. Am. Chem. Soc. 2008, 130,
1156 – 1157; c) S. Oi, R. Funayama, T. Hattori, Y. Inoue,
Tetrahedron 2008, 64, 6051 – 6059; d) L. Ackermann, R. Born,
P. ꢃlvarez-Bercedo, Angew. Chem. 2007, 119, 6482 – 6485;
Angew. Chem. Int. Ed. 2007, 46, 6364 – 6367; e) L. Ackermann,
A. Althammer, R. Born, Angew. Chem. 2006, 118, 2681 – 2685;
Angew. Chem. Int. Ed. 2006, 45, 2619 – 2622; f) L. Ackermann,
Org. Lett. 2005, 7, 3123 – 3125; g) F. Kakiuchi, Y. Matsuura, S.
Kan, N. Chatani, J. Am. Chem. Soc. 2005, 127, 5936 – 5945; h) S.
Oi, E. Aizawa, Y. Ogino, Y. Inoue, J. Org. Chem. 2005, 70, 3113 –
3119, and references therein.
Received: May 8, 2009
Published online: July 11, 2009
Keywords: alkyl halides · alkylation · arenes ·
.
À
C H bond functionalization · ruthenium
[1] L. Ackermann, Modern Arylation Methods, Wiley-VCH, Wein-
heim, 2009.
[2] Recent reviews: a) F. Kakiuchi, T. Kochi, Synthesis 2008, 3013 –
3039; b) B.-J. Li, S.-D. Yang, Z.-J. Shi, Synlett 2008, 949 – 957;
c) J. C. Lewis, R. G. Bergman, J. A. Ellman, Acc. Chem. Res.
2008, 41, 1013 – 1025; d) T. Satoh, M. Miura, Top. Organomet.
Chem. 2007, 24, 61 – 84; e) L. Ackermann, Top. Organomet.
Chem. 2007, 24, 35 – 60; f) D. Alberico, M. E. Scott, M. Lautens,
Chem. Rev. 2007, 107, 174 – 238; g) I. V. Seregin, V. Gevorgyan,
Chem. Soc. Rev. 2007, 36, 1173 – 1193; h) S. Pascual, P. de Men-
doza, A. M. Echavarren, Org. Biomol. Chem. 2007, 5, 2727 –
2734; i) L.-C. Campeau, D. R. Stuart, K. Fagnou, Aldrichimica
Acta 2007, 40, 35 – 41; j) L. Ackermann, Synlett 2007, 507 – 526;
k) O. Daugulis, V. G. Zaitsev, D. Shabashov, Q. N. Pham, A.
Lazareva, Synlett 2006, 3382 – 3388; l) J.-Q. Yu, R. Giri, X. Chen,
Org. Biomol. Chem. 2006, 4, 4041 – 4047.
[12] L. Ackermann, R. Vicente, A. Althammer, Org. Lett. 2008, 10,
2299 – 2302.
[3] For early examples, see: a) T. Ishiyama, S. Abe, N. Miyaura, A.
Suzuki, Chem. Lett. 1992, 691 – 694; b) A. Devasagayaraj, T.
Stuedemann, P. Knochel, Angew. Chem. 1995, 107, 2952 – 2954;
Angew. Chem. Int. Ed. Engl. 1995, 34, 2723 – 2725.
[13] Recently, ruthenium-catalyzed amino- and alkoxycarbonyla-
tions were reported: T. Kochi, S. Urano, H. Seki, E. Mizushima,
M. Sato, F. Kakiuchi, J. Am. Chem. Soc. 2009, 131, 2792 – 2793.
[14] For reviews on elegantly developed ruthenium-catalyzed hydro-
arylations of alkenes, see: a) F. Kakiuchi, S. Murai, Acc. Chem.
Res. 2002, 35, 826 – 834; b) F. Kakiuchi, N. Chatani in Ruthenium
Catalysts and Fine Chemistry (Ed.: C. Bruneau, P. H. Dixneuf),
Springer, Berlin, 2004, pp. 45 – 79; c) F. Kakiuchi, N. Chatani in
Ruthenium in Organic Synthesis (Ed.: S.-I. Murahashi), Wiley-
VCH, Weinheim, 2004, pp. 219 – 255.
[4] For representative examples, see: a) S. W. Smith, G. C. Fu,
Angew. Chem. 2008, 120, 9474 – 9476; Angew. Chem. Int. Ed.
2008, 47, 9334 – 9336; b) J. Terao, H. Todo, S. A. Begum, H.
Kuniyasu, N. Kambe, Angew. Chem. 2007, 119, 2132 – 2135;
Angew. Chem. Int. Ed. 2007, 46, 2086 – 2089; c) R. B. Bedford,
M. Betham, D. W. Bruce, S. A. Davis, R. M. Frost, M. Hird,
Chem. Commun. 2006, 1398 – 1400; d) A. C. Frisch, N. Shaikh,
A. Zapf, M. Beller, Angew. Chem. 2002, 114, 4218 – 4221; Angew.
Chem. Int. Ed. 2002, 41, 4056 – 4059, and references therein.
[5] For reviews, see: a) M. Nakamura, S. Ito in Modern Arylation
Methods (Ed.: L. Ackermann), Wiley-VCH, Weinheim, 2009,
pp. 155 – 181; b) A. Rudolph, M. Lautens, Angew. Chem. 2009,
[15] For oxidative alkylations with cycloalkanes using four equiva-
lents of peroxides, see: G. Deng, L. Zhao, C.-J. Li, Angew. Chem.
2008, 120, 6374 – 6378; Angew. Chem. Int. Ed. 2008, 47, 6278 –
6282.
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[16] Products originating from nondirected alkylations of aromatic
[19] A potential reaction mechanism could involve cyclometalation,
along with subsequent oxidative addition of the alkyl halide to a
ruthenacycle.
[20] N,N-Dimethylbenzylamine yielded no products of direct alkyla-
tion.
solvents were not detected.
[17] a) L. Ackermann, A. Althammer, R. Born, Tetrahedron 2008, 64,
6115 – 6124; b) L. Ackermann, A. Althammer, R. Born, Synlett
2007, 2833 – 2836.
[21] The molecular structure of the corresponding ruthenium(II)
carboxylate complex derived from carboxylic acid MesCO2H
was established by X-ray diffraction analysis: L. Ackermann, R.
Vicente, C. Schulzke, unpublished results.
[18] Anhydrous RuCl3 and [RuCl2(PPh3)3] yielded 12% and 16% of
product 3a, respectively, under otherwise identical reaction
conditions.
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