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Palladium-Catalyzed Regioselective Carbonylative Coupling/Amination of Aryl Iodides with Unactivated Alkenes: Efficient Synthesis of #-Aminoketones Jin-Bao Peng, Fu-Peng Wu, da li, Hui-Qing geng, xinxin qi, jun ying, and Xiao-Feng Wu ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b00774 • Publication Date (Web): 01 Mar 2019 Downloaded from http://pubs.acs.org on March 1, 2019
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Palladium-Catalyzed Regioselective Carbonylative Coupling/Amination of Aryl Iodides with Unactivated Alkenes: Efficient Synthesis of β-Aminoketones Jin-Bao Peng,† Fu-Peng Wu,† Da Li,† Hui-Qing Geng,† Xinxin Qi,† Jun Ying,† and Xiao-Feng Wu*,†,‡ †Department of Chemistry, Zhejiang Sci-Tech University, Hangzhou, Zhejiang 310018, People’s Republic of China ‡Leibniz-Institut für Katalyse e.V. an der Universität Rostock, Albert-Einstein-Straße 29a, Rostock 18059, Germany ABSTRACT: The carbonylative coupling of aryl halides with unactivated alkenes remains a challenge due to the low reactivity of acyl-palladium intermediate to the olefins. In this paper, a palladium-catalyzed carbonylative coupling/amination of aryl iodides with unactivated alkenes for the synthesis of β-aminoketone derivatives has been developed. With the assistance of a directing group (AQ; 8-aminoquinoline), the coordination of the olefin to acylpalladium complex can be enhanced, thereby promoting the acylpalladation across the C-C double bonds. A broad range of β-aminoketone derivatives were prepared in moderate to excellent yields with complete regioselectivity by using 4pentenoic and 2-vinylbenzoic amide derivatives as the starting materials. This methodology involves the formation of two C-C bonds as well as one C-N bond, and provided a method for the carbonylative difunctionalization of unactivated alkenes. KEYWORDS: palladium catalyst, carbonylation, cascade reaction, heterocycles, carbonylative coupling
Introduction Transition metal-catalyzed carbonylation reactions,1 which employ CO as a cheap and abundant C1 synthon, has now emerged as a powerful method for the synthesis of carbonyl-containing compounds with excellent functional group tolerance and wide substrates scope.2 Due to the obvious advantages, carbonylative reactions of aryl halides and related compounds have gained increasing importance both in academic synthesis as well as in large scale industrial processes.3 It is now well accepted that the acyl-palladium complex, which is generated from the oxidative addition of Pd0 to the C-X bond followed by coordination and insertion of CO to the C-Pd bond, serves as a key intermediate in the carbonylation of aryl halides. Various carbonyl-containing compounds such as esters, amides, acids, ketones, and aldehydes can be effectively synthesized based on different nucleophiles (Scheme 1-a). However, compared to the well-established carbonylation reaction with heteroatom nucleophiles (O, N, S, etc.) and the organometallic compounds, the carbonylation of aryl halides with alkenes is rarely reported in the literature.3b One of the main challenges of this type of reaction is the low reactivity of the acyl-palladium complex with olefins. Thus, the initial attempts for the carbonylative coupling of aryl halides with alkenes were performed either intramolecularly4 or with activated olefins.5 The
intermolecular transition metal-catalyzed carbonylative coupling of aryl halides with alkenes was not realized until 2010, when Beller and co-workers developed a palladium-catalyzed carbonylative coupling of aryl triflates with styrenes for the synthesis of pharmaceutical attractive chalcone derivertives.6a Later on, this protocol was extended to aryl iodides and bromides (Scheme 1-b).6 However, a large excess of olefins (≥ 6 equivalents) was necessary to overcome the problem of the sluggish acylpalladation step. Moreover, due to the inherent reactivity of the in-situ generated C(sp3)-Pd(II) species, the alkene substrates were usually limited to styrenes which react with acylpalladium to form electronically stabilized π-benzyl-palladium.6c The carbonylative coupling of aryl halides with unactivated aliphatic alkenes is still unprecedented and remains a great challenge. On the other hand, difunctionalization of unactivated alkenes,7 which install two unique components across the C-C double bonds, is of great interest and has attracted more and more attentions from synthetic chemists. Recently, a number of groups including Engle,8b-k Giri,8a,8l Zhao,8m Bi,8n Loh,8o and others have demonstrated that directing groups connected to the olefins can stabilize the active alkyl-metal species and facilitate the regioselective difunctionalization of olefins. We envisioned that the problem of low reactivity of acyl palladium complex with the olefins could be addressed by utilizing a suitable directing group to promote the coordination of the C-C
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double bond to the palladium center and facilitate the acylpalladation process (Scheme 1-c). Herein, we report the first example of palladium-catalyzed carbonylative coupling/amination of unactivated alkenes for the synthesis of β-aminoketone derivatives. Using easily available aryl iodides and 4-pentenoic amide derivatives as starting material, a broad range of pyrrolidin-2-one derivatives9 were prepared in moderate to excellent yields with complete regioselectivity. Besides, when 2vinylbenzoic amides were used in this reaction, C3substituted isoindolinone structures could be constructed in moderate to excellent yields.
found to be more effective (see details in SI). The yield of 3aa was improved to 63% and 68% when DPPP and DPPF were used as the ligands, respectively (Table 1, entries 4 and 5). However, bidentate phosphine with large bite angle, such as Xantphos, resulted in significant decrease in the yield of 3aa (Table 1, entry 6). These phenomenon were explainable since the steric effect of the bulky ligand would block the coordination of the acyl palladium intermediate A to the amide 1a. Then, various palladium catalysts such as Pd(OAc)2, Pd(TFA)2 and PdCl2 were tested in this reaction. All the catalysts tested were found to be active and produced the desired product 3aa in comparable yields (Table 1, entries 7-9). When Pd(TFA)2 was used as the catalyst, the desired product 3aa was produced in 78% yield (Table 1, entry 8). The reaction temperature also played an important role in this reaction, decreased yields of 3aa were obtained when the reaction were performed at lower temperatures (Table 1, entries 10 and 11). However, overly high reaction temperature led to lower yield (Table 1, entry 12), which might result from the facilitated decarbonylation process of the acyl palladium complex. Screening of the solvent revealed that MeCN is the optimal solvent. When toluene and 1,4-dioxane were used as the solvents, the yields decreased to 63% and 70%, respectively. Notably, the catalyst loading also influenced the reactivity significantly. When the reaction was conducted with lower catalyst loading (1 mol% Pd(TFA)2/DPPF), the desired product 3aa was obtained in 89% yield (Table 1, entry 15). In addition to 8-aminoquinoline (AQ), other nitrogen-based auxiliaries were tested in this reactions under our best reaction conditions (Table 1, entry 15) as well. When N-phenylpent-4-enamide (DG1) or N(pyridin-2-yl)pent-4-enamide (DG2) were subjected to the optimized reaction condition, no desired carbonylative coupling reaction occurred. The alkenes were recovered quantitatively. Bidentate directing groups such as picolinamide (DG3)11 and pyridin-2ylmethanamine (DG4) were also effective to promote this reaction, albeit with lower yields.
Scheme 1. Carbonylative Coupling Reaction of Aryl Halides. a) Palladium-Catalyzed Carbonylation Reactions of Aryl Halides O
X + CO
Pd / L
O PdLnX
HNu
Nu
A HNu = alcohols, amimes, alkynes, organometallic compounds, ...
X = I, Br, OTf
b) Palladium-Catalyzed Carbonylative Heck Reactions O
X + CO +
Pd / L
X = I, Br, OTf c) Palladium-Catalyzed Carbonylative Difunctionalization of Alkenes (This Work) DG O O N I Pd / L DG + CO + N H
O
O Ph A
PdLnX
X DG O Pd N
Ph
O
DG N PdII
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O
O
Ph
Results and Discussion Initially, 4-pentenoic acid derivative bearing 8aminoquinoline (AQ) directing group10 1a and iodobenzene 2a were selected as the model substrates to evaluate the feasibility of the carbonylative coupling reaction. To our delight, by using Pd(acac)2 as the catalyst and PPh3 as the ligand, when a solution of N-(quinolin-8yl)pent-4-enamide 1a and iodobenzene 2a in MeCN was stirred at 100 oC under a CO (2 mmol) atmosphere for 20 h, the desired carbonylative coupling /amination product 3aa was successfully obtained in 28% yield (Table 1, entry 1). Inspired by this exciting result, we examined a range of phosphine ligands for this reaction. Electron-deficient monodentate ligand P(p-FC6H4)3 showed better catalytic activity and provided 3aa in 52% yield (Table 1, entry 2). While bulky electron-rich BuPAd2 decreased the yield to 10% (Table 1, entry 3). Bidentate phosphine ligands were
Table 1. Optimization of the Reaction Conditions.a O N AQ
I + CO +
N H 1a
conditions
O
O N AQ
Ph
2a
3aa
O
DG:
N H DG1 N.R.
N
N
N H DG2 N.R.
N H
DG3 26%
N
N
DG4 10%
N H
DG5 N.R.
Temp.
Yieldb
(oC)
(%)
MeCN
100
28
MeCN
100
52
Entry
[Pd]
Ligand
Solvent
1
Pd(acac)2
PPh3
2
Pd(acac)2
P(p-FC6H4)3
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3
Pd(acac)2
BuPAd2
MeCN
100
10
4
Pd(acac)2
dppp
MeCN
100
63
5
Pd(acac)2
dppf
MeCN
100
68
6
Pd(acac)2
Xantphos
MeCN
100
27
7
Pd(OAc)2
dppf
MeCN
100
74
8
Pd(TFA)2
dppf
MeCN
100
78
9
PdCl2
dppf
MeCN
100
61
10
Pd(TFA)2
dppf
MeCN
90
72
11
Pd(TFA)2
dppf
MeCN
80
67
12
Pd(TFA)2
dppf
MeCN
120
73
13
Pd(TFA)2
dppf
toluene
100
63
14
Pd(TFA)2
dppf
dioxane
100
70
15c
Pd(TFA)2
dppf
MeCN
100
89 (86)d
aReaction
conditions: N-(quinolin-8-yl)pent-4-enamide (0.2 mmol), iodobenzene (0.4 mmol), [Pd] (5 mol%), ligand (10 mol% for monodentate ligands, 5 mol% for bidentate ligands), [CO] (Ac2O+HCO2H, 2 mmol), K2CO3 (0.4 mmol), solvent (1 mL), 20 h. bYields were determined by NMR analysis using 1,3,5-trimethoxybenzene as an internal standard. cPd(TFA)2 (1 mol%), dppf (1 mol%). dIsolated yield. e For different DGs testing, reaction conditions shown in entry 15.
With the optimized reaction conditions in hand (Table 1, entry 15), we first investigated various aryl iodides in this carbonylative coupling reaction of unactivated terminal alkene (1a). As summarized in Table 2, a range of different substituted iodobenzenes were applied to the optimized conditions. The electronic and steric properties of the substituents had a significant impact on reactivity. Iodobenzenes with electron-donating substituent at paraposition showed excellent reactivity, affording the corresponding pyrrolidin-2-one products in excellent yields and complete regioselectivity (Table 2, 3ab-3ae, 3ah-3ai). The electronic effect at the meta- position played a minimal role in the reactivity, the desired carbonylation products bearing both mono- and disubstituents were obtained in moderate yields (Table 2, 3af, 3aj and 3ao). When ortho-OMe substituted iodobenzene was used in this reaction, the corresponding product 3ag was produced in slightly decreased yield (65%) due to the steric hindrance. Iodoarenes substituted with electron-withdrawing groups were also tolerated in this transformation, affording the corresponding product in moderate yields (Table 2, 3am-3ar). Interestingly, iodobenzenes bearing fluorine substituent showed good reactivity and provided the desired products in excellent yields (Table 2, 3ak and 3al). Functional groups such as ketone, cyano and aldehyde group (Table 2, 3ap-3ar) were compatible in this transformation albeit in lower reactivity. However, when strong electron-withdrawing
groups such as CF3 and nitro were attached at paraposition of iodobenzene, ether trace or no desired products could be observed. In addition to substituted iodobenzenes, 1- and 2-iodonaphthalene were also tolerated and the corresponding products were conveniently generated in 33% and 76% yields, respectively (Table 2, 3au and 3av). Moreover, heteroaryl iodides such as 3-iodothiophene and 6-iodoquinoline were tolerated as well (Table 2, 3aw and 3ax). To further explore the substrate scope of this carbonylation reaction, we next evaluated a series of aliphatic alkenes in this reaction with iodobenzene (2a) or 1-(tert-butyl)-4-iodobenzene (2c) as representative electrophiles. Several sterically hindered 4-pentenoic amides with two alkyl or phenyl substitutions at αposition were tested; the corresponding products were successfully prepared in moderate yields (Table 3, 3ba3ec). When α-monosubstituted 4-pentenoic amides were subjected to the optimized reaction condition, the carbonylation reaction took place smoothly and produced the desired products in moderate to excellent yields, albeit with low diastereoselectivity (Table 3, 3fa-3pc). It should be noted that when there are two γ,δ- C-C double bonds on the amide coupling partner, monocarbonylative coupling occurred and produced the corresponding product 3oc in 66% yields. Besides, the carbonylative coupling took place selectively with γ,δ- CC double bond where the more distal alkene was unaffected (Table 3, 3pc). In addition, 4-pentenoic amides with both mono- and disubstitution at β- position were also suitable substrates, affording the corresponding products in moderate yields (Table 3, 3qc-3sc). However, the steric properties of the substituents on the C-C double bonds influenced the carbonylative coupling dramatically. Only low yields of the desired products were obtained when 1,2- and 1,1-disubstituted alkene were used in this transformation (Table 3, 3tc and 3uc). Since substituted 4-pentenoic amides could be prepared from the corresponding acid, this method provides an efficient procedure for the synthesis of pyrrolidin-2-ones from the easily available acids. For example, γ,δunsaturated amide 1v could be easily synthesized from αlinolenic acid via base induced allylation followed by amidation with 8-aminoquinoline. Treatment of 1v with iodobenzene 2a under the standard condition afforded pyrrolidin-2-one derivative 3va in 33% yield (Scheme 2).
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Table 2. Substrate Scope of the Aryl Iodides.a O AQ
N H 1a
O
O
O
N AQ
N AQ
O
O
Cl O
O
N AQ
NO2
3at (0%)
O
N AQ
O
O
Ac
O
O
N AQ
CN
O
O
N AQ
3av (33%)
CHO
3ar (24%) O
O
F
O
O
3aq (30%)
N AQ
3au (76%)
N AQ 3al (93%)
N AQ
3ap (24% (35%)b)
N AQ
O
F O
3ak (90%)
O
3ao (40%)
3af (55%)
N AQ
3aj (59%)
N AQ
Br
OMe
O
O
OMe
N AQ
3ae (98%)
N AQ
O
O
O
CF3
3as (trace)
O
O
O
O
O
3ai (97%)
3an (68%) O
N AQ
Ph
O N AQ
3ad (97%)
N AQ
OMe
N AQ
Cl
3am (68%) O
OMe O
O
O
Bu
O
3ah (97%)
O
t
O
N AQ
3ac (98%)
N AQ
3ag (65%) O
Et O
O
R
O
O
N AQ
3ab (96%) OMe
O
N AQ 3
O
O
N AQ
3aa (86%)
O
O
2 O
O
N AQ
Pd(TFA)2 (1 mol%) dppf (1 mol%) K2CO3 (2 equiv.) CH3CN, 100 °C
I + CO + R
N AQ
S
3aw (49%)
N
3ax (62%)
aReaction
conditions: N-(quinolin-8-yl)pent-4-enamide (0.2 mmol), aryl iodide (0.4 mmol), Pd(TFA)2 (1 mol%), dppf (1 mol%), [CO] (Ac2O+HCO2H, 2 mmol), K2CO3 (0.4 mmol), MeCN (1 mL), 100 oC, 20 h, isolated yields. b110 oC.
Table 3. Substrate Scope of Alkenes.a R2
O AQ
N H
I R4
R1
+
CO
+
R3
1
2
Me Me
Ph O
O
O
N AQ
R1
Pd(TFA)2 (1 mol%) dppf (1 mol%) K2CO3 (2 equiv.) CH3CN (1 mL) 100 °C, 18 h
O
3
O
O
N AQ
t
R3 O
O
O
N AQ
Bu
t
O
N AQ
t
Bu
O
O
N AQ
t
3fa (73%, d.r.=3:2)
N AQ
O t
Bu
3lc (98%, d.r.=3:2) Me Me N AQ 3qc (62%)
O
O
N AQ
t
Me O t
Bu
Bu
O
N AQ
t
Bu
O N AQ
3jc (96%, d.r.=1:1)
3ic (36%, d.r.>99:1)
O
O
N AQ
t
3rc (76%, d.r.=4:1)
O O
N AQ
t
Bu
3mc (99%, d.r.=3:2)
O
t
p-tolyl O
t
Bu
3kc (85%, d.r.=3:2)
Bn
m-tolyl O
O
N AQ
Bu
3hc (87%, d.r.=3:2)
o-tolyl
O
N AQ
Bu
3ec (64%) Ph
O
O
O
N AQ
3da (48%)
3cc (23%)
3gc (56%, d.r.=4:1)
O
R4
Me O
n-Pr
O
N AQ
Ph
3ba (56%)
O
R2
Bu
Bu
O O
N AQ
t
3nc (80%, d.r.=2:1)
3oc (66%, d.r.=2:1)
Ph
O
Bu
O N AQ
t
Bu
3pc (55%, d.r.=2:1) Ph
O
N AQ 3sc (67%, d.r.>99:1)
O t
N AQ
Bu
O
t
3tc (36%, d.r.=2.5:1)
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Bu
O
N AQ t
3uc (
