Cobalt-catalyzed C-4 selective alkylation of quinolines

Article abstract of DOI:10.1002/adsc.201300991

The cobalt-catalyzed direct C-4 selective alkylation of quinolines is described. The reaction conditions used previously for pyridines were fully modified to achieve C-4 selectivity in quinoline alkylation. Cobalt(II) acetate [Co(OAc)2] (2- 4 mol%) in com

Full text of DOI:10.1002/adsc.201300991

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DOI: 10.1002/adsc.201300991
Cobalt-Catalyzed C-4 Selective Alkylation of Quinolines
Shohei Yamamoto,a Yutaka Saga,a Takashi Andou,a Shigeki Matsunaga,a,b,*
and Motomu Kanaia,*
a
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Fax : (+81)-3-5684-5206; phone: (+81)-3-5841-4830; e-mail: kanai@mol.f.u-tokyo.ac.jp
ACT-C, JST, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
b
Fax : (+81)-3-5684-5206; phone: (+81)-3-5841-4836; e-mail: smatsuna@mol.f.u-tokyo.ac.jp
Received: November 7, 2013; Revised: January 9, 2014; Published online: February 2, 2014
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300991.
Abstract: The cobalt-catalyzed direct C-4 selective
alkylation of quinolines is described. The reaction
conditions used previously for pyridines were fully
modified to achieve C-4 selectivity in quinoline al-
Nakao/Hiyama et al.[10] and Ong et al.[11] independent-
ly reported the first C-4 selective direct alkylation
and alkenylation under cooperative Ni(0) and Lewis
acid catalysis, wherein the C H functionalization was
realized through an oxidative addition/insertion/re-
ductive elimination sequence. As a part of our ongo-
À
kylation. Cobalt(II) acetate [Co
N
4 mol%) in combination with butyllithium (BuLi)
and pyridine was best, and C-4 alkylation proceed-
ed in 54–95% yield with C-4/C-2= >20:1–2.5:1 and
branched/linear= >20:1 selectivity.
À
ing studies on first-row transition metal-catalyzed C
H functionalization,[16–19] we also succeeded in C-4 se-
lective alkylation of pyridines under cobalt hydride
catalysis generated from CoBr2 and LiBEt3H.[17]
Mechanistic studies suggested that the reaction pro-
ceeded via hydrometalation/C-4 selective nucleophilic
addition/re-aromatization,[20] giving C-4 alkylated pyr-
idines without the need for a stoichiometric oxidant
(Scheme 1).[21,22] Here, we describe our efforts to
À
À
Keywords: catalysis; C C bond formation; C H
functionalization; cobalt; heterocycles
Nitrogen-containing heteroarenes, such as pyridines
and quinolines, are important structural cores found
in many biologically active natural products, drug can-
didates, and clinically used drugs.[1] The regioselective
functionalization of pyridines and quinolines has been
intensively investigated, focusing mainly on C-2 func-
tionalization, such as C-2 selective nucleophilic addi-
tion of organometallic reagents and C-2 selective de-
protonation with a strong base followed by reactions
with electrophiles.[2]
À
Transition metal-catalyzed regioselective direct C
H bond functionalization[3] of heteroarenes has re-
cently attracted attention for providing atom-[4] and
step-economical[5] access to various functionalized
heteroarenes.[6] In many reports, a Lewis basic sp2 ni-
trogen atom in the heteroarenes was utilized as the
À
Scheme 1. C-4 selective catalytic C H functionalization via
nucleophilic addition/re-aromatization strategy.
À
directing group to achieve C-2 selective C H bond
functionalization of pyridines and quinolines.[7] In
striking contrast, other regioselective reactions, such expand the scope of the heteroarenes to include qui-
as C-3,[8,9] C-4,[10–12] or C-8[13] selective catalytic C H nolines. The previously optimized conditions for pyri-
À
bond functionalization of pyridines and/or quinolines dines were not at all effective for quinolines, and thus
without an additional directing group, are rather lim- the reaction conditions were fully modified to realize
ited.[14,15] With regard to the C-4 selective catalytic C
H bond functionalization of pyridines and quinolines, enes.
the C-4 selective alkylation of quinolines with styr-
À
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Shohei Yamamoto et al.
Table 1. Optimization studies.
Entry
Cat.
[HÀ]
x
Solvent
Yield [%][a]
Ratio (C-4/C-2/double)[b]
1[c]
2[c,d]
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
CoBr2
CoBr2
CoBr2
CoBr2
CoBr2
CoBr2
CoBr2
CoBr2
CoI2
LiBEt3H
LiBEt3H
LiBEt3H
LiAlH4
NaBH4
KBEt3H
BuLi
BuLi
BuLi
BuLi
BuLi
BuLi
BuLi
BuLi
BuLi
BuLi
BuLi
0
0
0
0
0
0
0.4
1.4
1.4
1.4
1.4
1.4
1.4
1.4
1.4
1.4
1.4
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene/1,4-dioxane
toluene/THF
54
42
>95
0
0
0
29
42
35
11
42
<5
<5
<5
<5
24
94
1:1.7:0
1:3.1:0
1:6.0:10
ND
ND
ND
1.8:1:0
1.8:1:0
3.1:1:0
ND
3.2:1:0
ND
ND
ND
ND
4.9:1:0
>20:1:0
CoF2
Co
Cu
U
CuOAc
Mn(OAc)2
Fe(OAc)2
E
E
Co
Co
U
[a]
1
Combined yield of alkylated products (C-4, C-2, and C-4/C-2 double) based on quinoline 1a. Determined by H NMR
analysis of the crude mixture using 1,2-dibromoethane as an internal standard.
Product ratio (C-4/C-2/double) was determined by H NMR analysis of the crude mixture.
1 equiv. of 2a was used.
0.4 equiv. of Et3B were added.
[b]
[c]
[d]
1
The reaction of 6-methoxyquinoline 1a with styrene 4/C-2=3.2:1 selectivity (entry 11).[23] Other metal ace-
2a under the previously optimized conditions for the tates were also investigated, but resulted in poor reac-
C-4 selective alkylation of pyridines, CoBr2/LiBEt3H, tivity (entries 12–15). Coordinating ether solvents
gave product 3aa in 54% yield with an unexpected C- drastically affected the present reaction, and both the
2 preference (entry 1, C-4:C-2=1.0:1.7; Table 1). The reactivity and C-4 selectivity were best in tolue-
addition of Et3B, which improved C-4 selectivity in ne:THF=1:2, giving the product in 95% yield and C-
the pyridine alkylation,[17] was not effective (entry 2). 4:C-2= >20:1 (entry 17). The branched/linear ratio
Increasing the amount of styrene 2a improved the was also good and the branched adduct was predomi-
combined yield of alkylated products, but the C-2 nantly obtained (>20:1).
adduct and C-4/C-2 doubly alkylated adduct were ob-
The optimized procedure for cobalt-catalyzed C-4
tained as the major products. Hydride sources to gen- selective alkylation of quinolines is summarized in
erate a postulated cobalt hydride active species in situ Scheme 2. Pyridine (0.4 equiv.) was first reacted with
affected not only the catalytic activity, but also the C- BuLi (0.4 equiv.) in toluene, and CoACHTNUTGRNEUNG(OAc)2 (2 mol%)
4/C-2 selectivity. While LiAlH4, NaBH4, and KBEt3H was added to the mixture to generate the postulated
did not promote the desired reaction (entries 4–6), cobalt amide. We speculated that an active cobalt hy-
À
40 mol% of pyridine mixed with 40 mol% of BuLi dride species [Co H] would be generated via b-hy-
was effective, and alkylated products were obtained dride elimination.[24] When different lithium amides
in 29% yield in a ratio of C-4:C-2=1.8:1 (entry 7). were used instead of that derived from pyridine and
The observed C-4 preference in entry 7 led us to fur- BuLi, much less satisfactory results were obtained
ther optimize the reaction conditions. Changing the (lithium diisopropylamide: 0% yield, lithium piperi-
ratio of pyridine and BuLi improved the product dide: 35% yield, C-4:C-2= >20:1), suggesting that
yield (entry 8, 42%), but did not change the C-4/C-2 a re-aromatization process was the key for efficiently
selectivity. Among the cobalt salts screened, 2 mol% producing the cobalt hydride species. The presumed
of CoACHTUNGTRENNUNG(OAc)2 gave the products in 42% yield with C- cobalt hydride was then utilized for the reaction of
402
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Cobalt-Catalyzed C-4 Selective Alkylation of Quinolines
observed (branched/linear= >20:1). C-4/C-2 selectivi-
ty, however, was significantly affected by subtle
changes in the substrates. ortho- and meta-substituted
styrene derivatives 2b, 2c, 2e, and 2f gave products
with high C-4/C-2 selectivity (entries 2,3, 5,6, C-4/C-
2= >20:1), while para-substituted styrene derivative
2d gave 3ad with unexpectedly low C-4/C-2 selectivity
(entry 4, C-4/C-2=3.0:1). Because the reactivity of 2d
and 2e was much lower than that of other styrene de-
rivatives, the reaction conditions were modified as de-
scribed in the footnotes of entries 4 and 5. Alkyl-
AHCTUNGTREGaNNUN lkenes, such as 1-dodecene, were not applicable in
Scheme 2. Optimized procedure for cobalt-catalyzed C-4 se-
lective alkylation of quinolines.
the present reaction conditions, and the desired alky-
lated product was not obtained. The reaction of other
quinolines 1b–1g with styrene 2a also proceeded, but
quinolines and styrenes in THF in the presence of ad- the C-4/C-2 selectivity changed depending on the sub-
ditional pyridine (1.0 equiv.). In the quinoline alkyla- stitution patterns (entries 7–12, C-4/C-2=6.5:1 to
tion, THF and pyridine played key roles to realize C- 2.5:1). Differences in C-4 selectivity depending on
4 selectivity. We assume that THF (excess) and pyri- substrates might be caused by the subtle change in
dine (1.4 equiv.) coordinated to cobalt, thereby sup- the coordination ability of the sp2 nitrogen atom in
pressing the undesired C-2 selective nucleophilic addi- quinolines. The reaction with 2-methylquinoline 1h
tion pathway directed by the sp2 nitrogen atom in qui- proceeded without difficulty (entry 13), thus support-
nolines.
ing our assumption that coordination of the sp2 nitro-
The substrate scope of the reaction is summarized gen atom in quinolines to cobalt is less important.
in Table 2. In all entries, only branched adducts were
Table 2. Cobalt-catalyzed C-4 selective alkylation of quinolines.[a]
Entry
X, 1
Y, 2
Yield [%][b]
3
Ratio branched/linear[c]
Product ratio (C-4/C-2/double)[d]
1
2
3
6-MeO, 1a
6-MeO, 1a
6-MeO, 1a
6-MeO, 1a
6-MeO, 1a
6-MeO, 1a
6-Me, 1b
6-i-Pr, 1c
6-t-Bu, 1d
8-Me, 1e
7-Me, 1f
H, 2a
95
85
95
66
54
90
93
80
74
66
61
60
70
3aa
3ab
3ac
3ad
3ae
3af
3ba
3ca
3da
3ea
3fa
3ga
3ha
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1:0
>20:1:0
>20:1:0
3.0:1:0
>20:1:0
>20:1:0
5.6:1:0.4
6.5:1:0
4.1:1:0
4.3:1:0
4.1:1:0
2.5:1:0
2-Me, 2b
3-Me, 2c
4-Me, 2d
2-MeO, 2e
3-MeO, 2f
H, 2a
H, 2a
H, 2a
H, 2a
H, 2a
4[e]
5[f]
6
7
8
9
10[g]
11
12
13
H, 1g
2-Me, 1h
H, 2a
H, 2a
C-4 only
[a]
The reaction was run using 1 (0.60 mmol), 2 (5 equiv.), Co
ACHTUNGRTEN(NNUG OAc)2 (2 mol%), BuLi (0.4 equiv.), and pyridine (1.4 equiv.) in
toluene/THF=1:2 (0.2M) at 608C, unless otherwise noted.
Combined yield of alkylated products based on 1 after purification by silica gel column chromatography.
[b]
[c]
[d]
[e]
[f]
Only branched adducts were observed.
Product ratio (C-4/C-2/double) was determined by H NMR analysis of the crude mixture.
1
Excess 2d (15 equiv.) was used. 4 mol% of Cy3P was added to the standard catalyst system.
CoACHTUNGTRENNUNG
[g]
Adv. Synth. Catal. 2014, 356, 401 – 405
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Shohei Yamamoto et al.
(Eds.: J.-Q. Yu, Z.-J. Shi), Springer, Berlin. Heidelberg,
2010.
In summary, we successfully achieved the C-4 selec-
tive alkylation of quinoline with styrenes. The reac-
tion conditions were modified to achieve moderate to
[4] B. M. Trost, Science 1991, 254, 1471.
[5] P. A. Wender, B. L. Miller, Nature 2009, 460, 197.
good C-4 selectivity with quinolines. CoACTHNUGTRENUNG(OAc)2 (2–
À
[6] Review on C H functionalization of pyridines, see: Y.
4 mol%) in combination with BuLi and pyridine was
best, giving products in 54–95% yield with C-4/C-2=
>20:1–2.5:1 and branched/linear= >20:1 selectivity.
Further studies to improve the C-4 selectivity and
expand the scope of the alkenes, especially focusing
on the design of cobalt complexes, are ongoing in our
group.
Nakao, Synthesis 2011, 3209.
[7] For selected examples of C-2 selective catalytic direct
alkylation of pyridines and quinolines without prior ac-
tivation, see: a) R. F. Jordan, D. F. Taylor, J. Am.
Chem. Soc. 1989, 111, 778; b) J. C. Lewis, R. G. Berg-
man, J. A. Ellman, J. Am. Chem. Soc. 2007, 129, 5332;
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d) B.-T. Guan, Z. Hou, J. Am. Chem. Soc. 2011, 133,
18086, and references cited therein. For other C-2 se-
lective functionalizations of pyridines, quinolines, and
Experimental Section
À
their N-oxides via C H activation, see reviews in
refs.[1,5]
Preparation of a Co-Catalyst Solution
À
[8] For C-3 selective catalytic C C bond formation of pyri-
To a solution of pyridine (19 mL, 0.24 mmol) in toluene
(1.0 mL) under argon was added a solution of BuLi (2.69M
in hexane, 89 mL, 0.24 mmol) at room temperature. After
5 min, CoACHTUNGTRENNUNG(OAc)2 (2.1 mg, 12 mmol, 2.0 mol%) was added to
the solution, and the mixture was used immediately for the
alkylation reaction.
dines, see: a) M. Ye, G.-L. Gao, A. J. F. Edmunds, P. A.
Worthington, J. A. Morris, J.-Q. Yu, J. Am. Chem. Soc.
2011, 133, 19090; b) M. Ye, G.-L. Gao, J.-Q. Yu, J. Am.
Chem. Soc. 2011, 133, 6964.
À
[9] The C-3 selective catalytic C C bond formation of pyr-
idines was also achieved under Ir catalysis, see: a) B.-J.
Li, Z.-J. Shi, Chem. Sci. 2011, 2, 488. For the Ir-cata-
lyzed regioselective borylation, see a review: b) J. F.
Hartwig, Chem. Soc. Rev. 2011, 40, 1992.
Co-Catalyzed C-4 Selective Alkylation
To a solution of quinoline derivative 1 (0.60 mmol), pyridine
(48 mL, 0.60 mmol) and styrene derivative 2 (3.0 mmol) in
THF (2.0 mL) was added a Co-catalyst solution in toluene
(1.0 mL). The reaction mixture was heated at 608C under
argon. After 20 h, the resulting mixture was quenched by
adding saturated aqueous NH4Cl, and was extracted with
ethyl acetate (ꢁ3). Combined organic layers were washed
with brine, dried over Na2SO4, and filtered. After evapora-
tion of the solvent, the regioselectivity was determined by
1H NMR analysis of the crude mixture. The crude residue
was purified by flash silica gel column chromatography
(hexane/ethyl acetate as eluent) to afford product 3.
[10] For C-4 selective catalytic alkylation of pyridines and
quinolines, see: Y. Nakao, Y. Yamada, N. Kashihara, T.
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[11] For C-4 selective catalytic alkenylation of pyridines and
quinolines, see: C.-C. Tsai, W.-C. Shih, C.-H. Fang, C.-
Y. Li, T.-G. Ong, G. P. A. Yap, J. Am. Chem. Soc. 2010,
132, 11887.
[12] For C-4 selective catalytic silaboration/rearomatization
of pyridines, see: K. Oshima, T. Ohmura, M. Suginome,
J. Am. Chem. Soc. 2011, 133, 7324.
[13] For C-8 selective catalytic arylation of quinolines, see:
J. Kwak, M. Kim, S. Chang, J. Am. Chem. Soc. 2011,
133, 3780.
[14] For directing group-assisted C-3 or C-4 selective cata-
lytic functionalization of pyridine derivatives, see:
a) M. Wasa, B. T. Worrell, J.-Q. Yu, Angew. Chem.
2010, 122, 1297; Angew. Chem. Int. Ed. 2010, 49, 1275;
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[15] For C-4 selective catalytic arylation of pyridines with
electron-deficient substituents at the C-3 position, see:
P. Guo, J. M. Joo, S. Rakshit, D. Sames, J. Am. Chem.
Soc. 2011, 133, 16338.
Acknowledgements
We thank Mr. H. Komai for his contribution at the initial
stage of this project. This work was supported in part by
ACT-C from JST and Grant-in-Aid for Scientific Research
on Innovative Areas “Molecular Activation Directed toward
Straightforward Synthesis” from MEXT. T.A. thanks JSPS
for postdoctoral fellowships.
[16] For reviews on the first-row transition metal-catalyzed
À
À
C H bond activation/C C bond formation, see:
a) A. A. Kulkarni, O. Daugulis, Synthesis 2009, 4087;
b) N. Yoshikai, Synlett 2011, 1047.
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À
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À
[24] A similar protocol for in situ [Co H] generation was
utilized as a part of mechanistic studies in our previous
report.[17] To support our assumption that the proper-
ties of an active species in this manuscript are similar
to those in our previous report for C-4 selective pyri-
dine alkylation, we performed an H/D scrambling ex-
periment with pyridine-d5 under the present conditions,
and the profile of H/D scrambling was similar to our
previous report. See the Supporting Information.
Adv. Synth. Catal. 2014, 356, 401 – 405
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