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Letter
Iron-Catalyzed Directed Alkylation of Carboxamides with Olefins via a Carbometalation Pathway Laurean Ilies, Yi Zhou, Haotian Yang, Tatsuaki Matsubara, Rui Shang, and Eiichi Nakamura ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b03967 • Publication Date (Web): 02 Nov 2018 Downloaded from http://pubs.acs.org on November 3, 2018
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ACS Catalysis
Iron-Catalyzed Directed Alkylation of Carboxamides with Olefins via a Carbometalation Pathway †
‡
‡
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Laurean Ilies,*, Yi Zhou, Haotian Yang, Tatsuaki Matsubara, Rui Shang, Eiichi Nakamura*, † ‡
RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198
Department of Chemistry, School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033
ABSTRACT: A catalytic amount of an iron salt and bipyridine ligand in the presence of an organozinc base activates the ortho C– H bond of a carboxamide, and the following reaction with and alkene such as ethylene gas (1 atm), styrene derivatives, and vinylsilane or vinylboron derivatives via carbometalation gives a putative alkylzinc intermediate. This intermediate can be further reacted with electrophiles such as deuterium oxide or allyl bromide. When monosubstituted alkenes are used as a substrate, the linear alkyl product is selectively obtained. The monoalkylated product is exclusively obtained, and dialkylation does not proceed. KEYWORDS: iron catalysis, C–H activation, alkylation, carbometalation, amide
Transition-metal-catalyzed directed C–H bond activation1 followed by reaction with an alkene has matured into an established methodology for the synthesis of alkylarenes. Typically, these Murai-type reactions2,3 proceed through C–H activation followed by the reaction of the metal intermediate with an alkene via hydrometalation,4,5 to give an alkylated product containing the hydrogen atom of the substrate (Figure 1b). We demonstrate here an alternative reaction mode, 6 where the metal intermediate reacts with an alkene via carbometalation7,8 to install a 2-metalloalkyl chain at the ortho position of an aromatic or heteroaromatic carboxamide, which is synthetically useful for further elaboration (Figure 1a). In order to achieve this scenario, the reaction uses a stoichiometric amount of PhZnX as a base to remove an ortho proton from N(8-quinolyl)-3-toluamide (1) 9 in the presence of catalytic amount of Fe(acac)310 and 2,2'-bipyridine (bpy), and then the resulting intermediate A carbometalates an olefin11 at 50 °C in THF. While previously reported reactions6 that proceed through carbometalation gave an unstable metal intermediate prone to demetalation or reaction with the directing group, the merit of the strategy reported here is the formation of a stable alkylzinc intermediate B, which can be deuterated to obtain deuterated product 2-D, or it can be electrophilically trapped by allyl bromide to produce 3. The reaction reported here is mechanistically and synthetically distinct from our previously reported 12 oxidative alkylation with alkylzinc (Figure 1c), where after C–H activation the iron intermediate undergoes reductive elimination to give the alkylated product. Carbometalation of an alkene is intrinsically more difficult than the reaction of an alkyne, which is more electrophilic.8 Thus, the conditions we developed for alkyne carbometalation13 with iron intermediate A generated via C–H activation of N-(quinol-8-yl)toluamide (1)10 gave only a trace of the desired product. Reoptimization of the reaction conditions indicated that the olefin carbometalation reaction prefers 2,2’bipyridine (bpy) as the ligand of choice. Thus, 1 (0.20 mmol) was reacted with ethylene (1 atm, balloon) in the presence of
Fe(acac)3 (10 mol%) and 2,2’-bipyridine (bpy, 11 mol%), and of an organometallic base formed in situ from ZnCl2 (1.2 equiv) and PhMgBr (2.6 equiv, 1.0 equiv used for deprotonation of NH in 1) in THF at 50 °C for 18 h, followed by trapping with DCl to give 2-D in 82% yield (86% D incorporation), or with allyl bromide to give 3 in 50% yield, after isolation by GPC (Figure 1a). We also observed the formation of a 2-phenylated byproduct14 (2%, formed via A bearing a Ph group on Fe), and biphenyl (5%)15; in the reaction with allyl bromide, ethylated product 2, formed through protonation of unreacted zinc intermediate B, was also obtained in 32%. (a)
R
O NHQ H 1 Q = 8-quinolyl
PhFeLn
–PhH
R
1)
O
2) PhZn(II)
N Fe
N
N
–Ph[Fe]
Zn
Ln
(b)
NHQ R
E+
ZnCl2 (1.2 equiv) E PhMgBr (2.6 equiv) THF, 50 °C E+ = DCl 2-D 82% (86% D) allyl bromide 3 50% R = H (1 atm) E+
O
A
O
Fe(acac)3 (10 mol %) bpy (11 mol %)
B R
DG H
R
DG R
DG
cat. M
N
H
M
H
R (c)
O
O
O NHQ
ACS Paragon Plus Environment
Alkyl-ZnX
oxidant
N
cat. Fe(III)/ diphosphine
Fe
Alkyl
N Ln
NHQ
Alkyl
ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Figure 1. (a) Iron-catalyzed ortho alkylation of toluamide (1) with an alkene via carbometalation, followed by reaction with an electrophile. (b) Classical Murai-type reaction that proceeds via hydrometalation. (c) Iron-catalyzed oxidative alkylation with alkylzinc. The key reaction parameters for the iron-catalyzed reaction of toluamide 1 with styrene are shown in Table 1. Under the “standard” conditions in Figure 1a (entry 1), the desired alkylated product 4 was obtained in 81% yield (GC), together with the ortho-phenylated byproduct 5 (5%), and recovery of 1 (10%). The ligand has a strong influence on the reaction outcome: changing 2,2’-bipyridine (bpy) to the more rigid phenanthroline decreased the yield to 31% (entry 2). By contrast, a diphosphine ligand bearing a saturated backbone (1,2bis(diphenylphosphino)ethylene, dppe) gave the desired 4 in 69% yield (entry 4). When we changed the backbone of the diphosphine to a more rigid ethene (cis-1,2bis(diphenylphosphino)ethene, dppen), the alkylation reaction was completely shut down (entry 3). Increasing the electron density on the catalytic iron species by using an electron-rich 4,4’-dimethoxy-2,2’-bipyridine (MeO-bpy) largely retarded the reaction (entry 5). We also found that fine tuning of the organometallic reagent is necessary to achieve optimal results: thus, a small excess of PhMgBr with respect to ZnCl2 (please note that 1 equiv of PhMgBr deprotonates the amide’s nitrogen) gave the best result (entries 6–8). This result suggests the reduction of the Fe(III) precursor to a putative Fe(II) active species16 by the excess Grignard reagent.17 In agreement with this hypothesis, we observed the formation of biphenyl in ca. 5%. Also, the use of an Fe(II) salt with 1.2 equiv ZnCl2 and 2.2 equiv of PhMgBr gave a higher yield as compared with Fe(III) (entry 9 vs entry 6), and an excess of Grignard reagent (2.6 equiv) improved the yield to 81% (entry 10). Table 1. Study of the key reaction parameters for the ironcatalyzed alkylation of N-(quinol-8-yl)toluamide (1) with styrene to give 4a
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We next investigated the substrate scope of this reaction (Tables 2 and 3). Table 2 describes the reaction of several carboxamides with monosubstituted alkenes. In all cases, the linear alkylated product was obtained selectively and we could not detect any branched alkyl product in the reaction mixture. A variety of electron-rich and electron-deficient styrenes (entries 1–5) reacted well with toluamide. A sterically demanding styrene also reacted well (entry 6), suggesting that the carbometalation step is not sensitive to steric bias. Highly electrondeficient pentafluorostyrene also reacted well to give a polyfluorinated product (entry 7). Notably, a vinylsilane (entry 8) and a vinylboron derivative (entry 9) also took part in this reaction to afford the corresponding linear alkylsilane and alkylboron compounds, amenable to further functionalization. The tolerance of functional groups such as halide, including bromide (entry 4), ester (entry 5), silane (entry 8), or boron (entry 9) emphasize the synthetic advantage of using an alkene as the alkylating reagent as compared with an organometallic reagent.12 An ester group on the benzamide was tolerated (entry 10). A 3,5-disubstituted benzamide (entry 11) reacted well to give a densely functionalized product, indicating that the iron active species is insensitive to the steric environment of the C–H bond. Table 2. Iron-catalyzed alkylation of various carboxamides with substituted alkenesa entry
amide
1
O
yield (%)b
product
alkene O
74
R = Ph R = 4-FC6H4
45 (84)
R = 4-ClC6H4
68
4
R = 4-BrC6H4
52
5
R = 4-AcOC6H4
43 (64)
6
R = 2-MeOC6H4
48 (78)
2
NHQ
R
NHQ
3
R
O 7
NHQ
C6F5
65
C6F5
entry
conditions
4 (%)b
1 (%)b
5 (%)b
1
“standard” (Figure 1a)
82
10
3
2
phen as a ligand
31
60
7
3
dppen as a ligand
