Rhodium-Catalysed [4+2] Annulation of Aromatic Oximes with Terminal Alkenes by C?H/N?O Functionalization towards 3,4-Dihydroisoquinolines

Article abstract of DOI:10.1002/adsc.201900922

Rhodium (Rh)-catalysed [4+2] annulation of aromatic oximes with common terminal alkenes for the synthesis of 3,4-dihydroisoquinolines is presented. Through the cooperation of a Rh(III) catalyst and a catalytic amount of K₂HPO₄ base, the reaction enables the formation of two new bonds, a C(sp²)?C(sp³) bond and a C(sp³)?N bond, in a single reaction via functionalization of both the C?H and N?O bonds and provides a practical method to produce 3,4-dihydroisoquinolines with exquisite selectivity and excellent compatibility of functional groups. (Figure presented.).

Full text of DOI:10.1002/adsc.201900922

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DOI: 10.1002/adsc.201900922
Rhodium-Catalysed [4+2] Annulation of Aromatic Oximes with
Terminal Alkenes by CÀ H/NÀ O Functionalization towards 3,4-
Dihydroisoquinolines
Xu Zhang,a, b Xuan-Hui Ouyang,b Yang Li,b Bo Chen,a,* and Jin-Heng Lia, b, c,
*
a
Key Laboratory of Chemical Biology & Traditional Chinese Medicine Research (Ministry of Education), Hunan Normal
University, Changsha 410081, People’s Republic of China
phone: +86731-8871-3642
fax: +86731-8871-3642
E-mail: dr-chenpo@vip.sina.com; jhli@hnu.edu.cn
Key Laboratory of Jiangxi Province for Persistent Pollutants Control and Resources Recycle, Nanchang Hangkong University,
Nanchang 330063, People’s Republic of China
b
c
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, People’s Republic of China
Manuscript received: July 25, 2019; Revised manuscript received: September 5, 2019;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.201900922
hydrocarbons (e.g., alkynes, allenes, alkenes, ketenes)
have proved to be promising platforms for the
Abstract: Rhodium (Rh)-catalysed [4+2] annula-
tion of aromatic oximes with common terminal
preparation of nitrogen-containing heterocycles,
alkenes for the synthesis of 3,4-dihydroisoquino-
wherein the NÀ O bond in aromatic oximes serves as
lines is presented. Through the cooperation of a Rh
the internal oxidative chelation group to selectively
(III) catalyst and a catalytic amount of K2HPO4
achieve ortho-C(sp2)À H functionalization.[3–6] While
base, the reaction enables the formation of two new
bonds, a C(sp2)À C(sp3) bond and a C(sp3)À N bond,
the annulation of aromatic oximes with internal
alkynes has been thoroughly investigated for the
preparation of 3,4-disubstituted isoquinolines (Sche-
in a single reaction via functionalization of both the
CÀ H and NÀ O bonds and provides a practical
method to produce 3,4-dihydroisoquinolines with
exquisite selectivity and excellent compatibility of
functional groups.
me 1a–i),[3,5] similar versions with alkenes are rare.[6]
Moreover, these transformations focus on special
alkenes, including vinyl acetates,[6a] 1,3-dienes[6b] and
electron-poor alkenes,[6c] which serve as convenient
acetylene equivalents for the synthesis of 3-substituted
isoquinolines. Examples that utilize common terminal
alkenes as reaction partners towards 3,4-dihydroisoqui-
nolines have not been reported. In 2015, the group of
Yu/Cheng[6a] reported the first rhodium-catalysed se-
Keywords: alkenes; oximes; rhodium; annulation;
dihydroisoquinolines
Isoquinolines are structural motifs present in many quential oxidative CÀ H activation/annulation of aro-
biologically active natural products, pharmaceuticals, matic oxime esters with vinyl acetates leading to 3-
and functional materials.[1] Accordingly, considerable substituted or non-C3-substituted isoquinolines (Sche-
effort has been devoted to developing increasingly me 1a–ii). The group of Glorius[6b] has developed a
efficient methods for the construction of such isoquino- PivOH-promoted Rh(III)-catalysed redox-neutral CÀ H
line molecular scaffolds, especially through intramo- activation/cyclization/isomerization
strategy
for
lecular cyclization or intermolecular annulation achieving [4+2] annulation of aromatic oxime esters
reactions.[2,3] Despite substantial progress in the field, and diverse 1,3-dienes towards 3-alkyl-substituted
the development of highly atom-economic, sustainable isoquinolines (Scheme 1a–iii). Cui and co-workers[6c]
routes that can achieve CÀ H functionalization under have expanded the PivOH-promoted Rh(III)-catalysed
external-oxidizing-reagent-free conditions that release redox-neutral CÀ H activation strategy to include
nontoxic waste products (e.g., H2O) remains a annulation of aromatic oximes with electron-poor
challenging area.[4] In recent years, transition-metal- alkenes, such as vinyl aldehydes, ketones, esters and
catalysed intermolecular annulation of aromatic oximes amides (Scheme 1a–iv). Thus, it would be desirable to
and their derivatives (often esters) with unsaturated develop general routes for direct annulation of
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Scheme 1. [4+2] Annulation of Aromatic Oximes.
Table 1. Optimization of the Reaction Conditions[a].
aromatic oximes with common olefins for targeting
diverse isoquinolines and the construction of their
derivatives.
Herein, we report a rhodium(III)-catalysed oxida-
tive [4+2] annulation of aromatic oximes with
terminal alkenes using an internal oxidative strategy
for producing 3,4-dihydroisoquinolines, in which both
the CÀ H and NÀ O bonds are functionalized in a single
reaction to form two new bonds, a C(sp2)À C(sp3) bond
and a C(sp3)À N bond (Scheme 1b). This method
represents the first example of directly utilizing
aromatic oximes and common terminal alkenes to
achieve [4+2] annulation and assembly of 3,4-
dihydroisoquinoline frameworks.
Experimentation started by investigating the opti-
mal reaction conditions for the annulation between 1-
(p-tolyl)ethan-1-one oxime (1a) and 1-methoxy-4-
vinylbenzene (2a) by means of [Cp*RhCl2]2 catalyst
(Table 1). Treatment of oxime 1a with alkene 2a using
optimized parameters (3 mol% of [Cp*RhCl2]2 and
50 mol% of K2HPO4 in MeCN under argon atmosphere
Entry Variation from the standard conditions Yield [%][b]
1
2
3
4
5
6
7
8
none
70/65[c]
0
without [Cp*RhCl2]2
[Cp*RhCl2]2 (5 mol%)
without K2HPO4
71
trace
39
49
67
27
56
45
5
16
7
62
37
37
K2HPO4 (20 mol%)
K2HPO4 (100 mol%)
K3PO4 instead of K2HPO4
CsF instead of K2HPO4
K2CO3 instead of K2HPO4
Ag2CO3 instead of K2HPO4
AgSbF6 instead of K2HPO4
1,4-dioxane instead of MeCN
MeOH instead of MeCN
9
10
11
12
13
14
15
16[d]
°
at 60 C
at 100 C
air instead of argon
°
[a] Reaction conditions: 1a (0.1 mmol), 2a (0.15 mmol),
°
at 80 C for 12 h) resulted in the desired product 3aa
with a 70% yield (entry 1). The reaction is scalable,
[Cp*RhCl2]2 (3 mol%), K2HPO4 (50 mol%), MeCN (2 mL),
with a 65% yield at the 1 mmol scale of 1a (entry 1).
°
argon, 80 C and 12 h.
These results show that both [Cp*RhCl2]2 and a base [b] Isolated yield.
[c] 1a (1 mmol), MeCN (4 mL) and 36 h.
(e.g., K2HPO4) are crucial because omission of each
results in no reaction occurring (entries 2 and 4). A
higher loading (5 mol%) of [Cp*RhCl2]2 had no
obvious improvement on the yield (entry 3). The
[d] Oxime 1a was recovered in 53% yield.
°
amount of K2HPO4 base was examined, and the 80 C gave the best results (entry 1 versus entries 12–
experiments reveal 50 mol% of K2HPO4 as the best 15). However, replacement of argon by air had a
option (entries 1, 5 and 6). Several other bases, deleterious effect (entry 16).
including K3PO4, CsF, K2CO3, Ag2CO3 and AgSbF6,
Under the optimal reaction conditions, the [4+2]
exhibited reactivity (entries 7–11), but they were all annulation of various aromatic oximes 1 with terminal
inferior to K2HPO4. Brief screening of the effect of alkenes 2 is performed efficiently in moderate to good
solvents (e.g., 1,4-dioxane, MeOH) and reaction yields (Table 2). The optimal conditions were also
temperatures indicated that the reaction in MeCN at found to be compatible with a wide array of aromatic
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Table 2. Variations of the aromatic oximes (1) and alkenes (2)[a].
[a]
°
Reaction conditions: 1 (0.1 mmol), 2 (0.15 mmol), [Cp*RhCl2]2 (3 mol%), K2HPO4 (50 mol%), MeCN (2 mL), argon, 80 C, and
12 h.
[b] The reaction was performed by directly using three components, including 1-methoxy-4-vinylbenzene 1a, (E)-1-(4-
hydroxyphenyl)ethan-1-one oxime, adamantane-1-carboxylic acid because 4-(1-(hydroxyimino)ethyl)phenyl-adamantane-1-
carboxylate is not stable.
[c] Ratio of the regioselective isomers is given in the parentheses.
oximes 1b–m. Using 1-phenylethan-1-one oxime 1b ring were tolerated by the reaction system (3ca–ha),
reacted with alkene 2a, [Cp*RhCl2]2 and K2HPO4 and the steric properties of each aromatic oxime
afforded 3ba with a 50% yield. A variety of aromatic affected the reactivity. While the bulky p-adamantane-
oximes 1c–h, possessing an adamantane-1-carboxy- 1-carboxylate-containing aromatic oxime 1c was con-
late, a Br, a F, a NO2 or a Me group, on the aromatic verted to 3ca in a lower yield, oximes 1d–f bearing a
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weak (Br, F) or a strong (NO2) electron-withdrawing
group produce 3da–fa in good yields. Using o-Me-
substituted oxime 1g delivered 3ga with lower yields.
For the m-Me-substituted oxime 1h, the annulation
occurred regiospecifically at the lower steric effect
position, giving 3-(4-methoxyphenyl)-1,7-dimethyl-3,4
dihydroiso-quinoline 3ha with a 65% yield, with
>20:1 regioselectivity. The annulation protocol was
applicable to the heteroaromatic oxime 1-(thiophen-2-
yl)ethan-1-one, oxime 1i, resulting in a product
containing two different heteroatoms, 3ia. 1-(Naphtha-
len-2-yl)ethan-1-one, oxime 1j, was a suitable sub-
strate for accessing a mixture of two regioselective
isomers 3ja/3ja’. Several functionalized oximes, 1-
phenylbutan-1-one (oxime 1k), 1-phenylpentan-1-one
(oxime 1m), cyclobutyl(phenyl)methanone (oxime 1n)
and diphenylmethanone (oxime 1o), successfully
performed the annulation reaction (3ka–oa). Oxime
ethers and esters, such as 1-(p-tolyl)ethan-1-one O-
methyl oxime and 1-(p-tolyl)ethan-1-one O-acetyl
oxime, were tested under the optimal conditions, and
the results showed that they had no reactivity.
Scheme 2. Kinetic Experiment.
Furthermore, a wide range of aromatic and aliphatic
terminal alkenes 2b–n are amenable to the annulation
protocol (3ab–an). Using styrene (2b) enabled the
formation of 3ab with a moderate yield. Several aryl
t
alkenes bearing a substituent, such as Bu, Cl, F, CN
and NO2, on the aryl ring were consistent with the
optimal conditions, giving 3ac–ag in moderate to good
yields. It is notable that 1,2,3,4,5-pentafluoro-6-vinyl-
benzene (2h) is viable for accomplishing the annula-
tion reaction (3ah). Both 2-vinylnaphthalene (2i) and
allylbenzene (2j) also underwent the reaction smoothly
to give the corresponding products 3ai–aj in moderate
yields. Unfortunately, other alkenes, including 1,1-
diphenylethene (2k), 1,2-diphenylethene (2l), alkyl
olefin 2m and acrylate 2n, were inert (3ak–an).
Scheme 3. Possible pathways.
To elucidate the mechanism, control experiments
were carried out (Scheme 2). Competition experiments
and the line Hammett analysis plot support the reactive
order of electron-withdrawing styrene>electron-rich results support that C(sp2)À H bond cleavage is the rate-
styrene (see the Supporting Information). Furthermore, determining step.
significant H/D exchanges could be detected in the
Consequently, the following mechanism for the Rh
reactions of 1k/CD3OD without 2a [eq (1) in (III)-catalysed [4+2] annulation protocol is proposed
Scheme 2]. We also conducted the reaction of [D5]-1k on the basis of our current results and the results of
with 2a under standard reaction conditions, the previously reported studies (Scheme 3).[2,4–7] Initially,
existence of 44% H/D exchange in product 3ka/[D4]- activation of the [Cp*RhCl2]2 species with the aid of a
3ka [eq (2) in Scheme 2] was observed. In addition, base forms the active [Cp*Rh(III)] species,[5–7] which
react 1k/CD3OD with 2a under standard reaction subsequently undergoes insertion at the C(sp2)À H bond
conditions; the existence of 14% H/D exchange in in aromatic oxime 1a to generate the Cp*RhIII complex
product 3ka/[D1]-3ka [eq (3) in Scheme 2] was A. Coordination of the Cp*RhIII complex A with alkene
observed. These observations were, hence, indicative 2 followed by insertion across the C=C bond to
of a reversible CÀ H bond metalation step by an produce the seven-membered rhodacycle C. The
alkene-coordinated ruthenium complex, likely proceed- intermediate C possibly undergoes reductive elimina-
ing through base assistance. A kinetic isotope effect tion to give the intermediate D[5a,7] and a RhI
(KIE) experiment was carried out [eq (4) in Scheme 2], species.[5a,7] Finally, the cleavage of the NÀ O bond of
which provided a large primary KIE value (4.6). The the intermediate D by the Rh(I) species releases
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Liu, J.-G. Zeng, Curr. Org. Chem. 2017, 21, 1920; c) Z.-
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In summary, we have reported the first acid-free,
Rh(III)-catalysed, redox-neutral [4+2] annulation of
aromatic oximes using common terminal alkenes for
producing 3,4-dihydroisoquinolines. By cooperative
Rh catalysis of a catalytic amount of K2HPO4 base,
this two-component reaction enables annulation of
various functionalized aromatic oximes with readily
available common alkenes in moderate to good yields
with excellent selectivity. The valuable 3,4-dihydroiso-
quinolines assembled using this method represents
examples of the potential for simple bases to activate
the Rh catalyst and allow the practical functionaliza-
tion of oximes and alkenes.
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Experimental Section
General Considerations
1
The H and 13C NMR spectra were recorded in CDCl3 solvents
on an NMR spectrometer using TMS as the internal standard.
LRMS was performed on a GC-MS instrument. HRMS was
measured on an electrospray ionization (ESI) apparatus using
time-of-flight (TOF) mass spectrometry.
Typical Experimental Procedures
Typical Experimental Procedure for the Rh(III)-catalyzed
redox-neutral [4+2] annulation of aromatic oximes (2) with
common terminal alkenes (2): To a Schlenk tube were added
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kin, Chem. Rev. 2017, 117, 13039.
oxmines
1 (0.1 mmol), aromatic alkenes 2 (0.15 mmol),
[Cp*RhCl2]2 (3 mol%), K2HPO4 (50 mol%), and MeCN (2 mL).
°
Then the mixture was stirred under argon at 80 C (oil bath
temperature) for 12 h until consumption of starting material as
monitored by TLC and/or GC-MS analysis. After the reaction
was finished, the reaction extracted with ethyl acetate (3×
10 mL). The organic layer was washed with saturated NaCl
solution (3×5 mL), dried over anhydrous MgSO4, filtered, and
concentrated in vacuo. The resulting residue was purified by
silica gel column chromatography (hexane/ethyl acetate=20:1)
to afford the desired products 3.
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Acknowledgements
We thank the National Natural Science Foundation of China
(Nos. 21625203, 21871126, 21575040 and 21775040), and the
Opening Fund of Key Laboratory of Chemical Biology and
Traditional Chinese Medicine Research, Ministry of Education
(No. KLCBTCMR18-02) for financial support.
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Rhodium-Catalysed [4+2] Annulation of Aromatic Oximes
with Terminal Alkenes by CÀ H/NÀ O Functionalization
towards 3,4-Dihydroisoquinolines
Adv. Synth. Catal. 2019, 361, 1–7
X. Zhang, X.-H. Ouyang, Y. Li, B. Chen*, J.-H. Li*