Dirhodium(II)-catalyzed [3 + 2] cycloaddition of N-arylaminocyclopropane with alkyne derivatives

Article abstract of DOI:10.3762/bjoc.15.48

Dirhodium(II) complex-catalyzed [3 + 2] reactions between N-arylaminocyclopropanes and alkyne derivatives are described. The cycloaddition products proved to be versatile synthetic intermediates. trans-Cyclic β-amino acids and derivatives thereof can be c

Full text of DOI:10.3762/bjoc.15.48

Dirhodium(II)-catalyzed [3 + 2] cycloaddition of
N-arylaminocyclopropane with alkyne derivatives
Wentong Liu1,2, Yi Kuang1,2, Zhifan Wang3, Jin Zhu1 and Yuanhua Wang*3
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2019, 15, 542–550.
1Chengdu Institute of Organic Chemistry, Chinese Academy of
Sciences, Chengdu 610046, China, 2University of Chinese Academy
of Sciences, Beijing 100049, China and 3College of Chemistry,
Sichuan University, Chengdu 610046, China
doi:10.3762/bjoc.15.48
Received: 13 October 2018
Accepted: 13 February 2019
Published: 25 February 2019
Email:
Yuanhua Wang* - yhwang@scu.edu.cn
This article is part of the thematic issue "Cyclopropanes and
cyclopropenes: synthesis and applications".
* Corresponding author
Guest Editor: M. Tortosa
Keywords:
[3 + 2]; alkyne; cycloaddition; cyclopropanes; dirhodium catalysis;
© 2019 Liu et al.; licensee Beilstein-Institut.
License and terms: see end of document.
N-arylaminocyclopropanes
Abstract
Dirhodium(II) complex-catalyzed [3 + 2] reactions between N-arylaminocyclopropanes and alkyne derivatives are described. The
cycloaddition products proved to be versatile synthetic intermediates. trans-Cyclic β-amino acids and derivatives thereof can be
conveniently synthesized using this cycloaddition protocol.
Introduction
N-Arylaminocyclopropanes 1 are important structural motifs for been a challenge [16,17]. Only recently an efficient synthesis
pharmaceuticals and are found especially in marketed fluoro- method by arylation of cyclopropylamine has been developed
quinolone antibiotics [1], such as ciprofloxacin and moxi- and documented by Colacot et al. [16] and Stradiotto et al. [17],
floxacin (Scheme 1), and reverse transcriptase inhibitors [2], which has provided opportunities for further development of
such as nevirapine. Meanwhile, since 1 contains a three-mem- cycloaddition chemistry based on compound 1. Zheng et al. [7]
bered ring with high tension [3-6] and a nitrogen prone to first reported on the [3 + 2] cycloaddition reaction of 1 with an
single-electron oxidation, ring opening readily occurs followed alkene or alkyne mediated by visible light by the aid of the
by N-centered radical formation. The generated distonic radical photocatalyst [Ru(bpz)3](PF6)2. Our group reported the metal
cation can be further trapped by an alkene, alkyne, or triplet catalyst itself, particularly the dinuclear rhodium complex
oxygen to initiate radical cyclization (Scheme 1) [7-15]. Thus, (Rh2(II,II)), that efficiently catalyzes the ring opening of 1 to
as key synthons, this class of molecules may play an important achieve cycloaddition with alkene substrates under an argon at-
role in organic synthesis during construction of a series of mosphere [18]. During the reaction, no metal valence changes
aminocyclic compounds. In fact, the synthesis of 1 has always were observed. We proposed that Rh2(II,II) may coordinate
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Beilstein J. Org. Chem. 2019, 15, 542–550.
Scheme 1: Applications of N-arylaminocyclopropanes.
with the nitrogen in 1 to decrease the bond dissociation energy ciency of the catalysts. Compared to the 1 mol % catalyst
of N–H bonds, which may be beneficial to N-centered radical loading, the yield of 3a dropped to 39 and 44% when Rh2(esp)2
formation. However, due to the characteristics of the radical and [Rh(Cp*)Cl2]2, respectively, were used (Table 1, entries 9,
reaction, the resulting cycloaddition product mixtures have a 10), and kept practically consistent with Rh2(5S, R-MenPY)4
low diastereoisomeric ratio, which increases the difficulty of (Table 1, entry 11). These results indicate that the catalytic effi-
separation and limits applications. In view of this, we applied ciency of Rh2(5S, R-MenPY)4 was the best of all the screened
alkyne derivatives as cycloaddition partners to make the de- catalysts. Further solvent screening studies found the yields of
veloped methodology more applicable, as well as to investigate 3a obtained in non-coordinating solvents, such as DCM,
the possibility of chiral ring construction.
hexane, toluene, and 1,2-dichloroethane (DCE), and weak coor-
dinating solvents, such as 1,2-dimethoxyethane (DME), were
similar (Table 1, entries 11–15). DCE was the best solvent,
Results and Discussion
Initially, phenylcyclopropylamine (1a) and ethyl propiolate (2a) leading to a 67% yield of 3a. Due to axial coordination of
were selected as substrates to study the cycloaddition in dirhodium(II) for a strong coordination solvent, the yield of the
dichloromethane (DCM) with 1 mol % starting catalyst loading resulting cycloaddition product in N,N-dimethylformamide de-
under the previously reported conditions [18]. In the absence of creased to only 33% (Table 1, entry 16). Regrettably, though
a catalyst, no cycloaddition product 3a formed (Table 1, entry Rh2(5S,R-MenPY)4 is a chiral catalyst, the obtained cycloaddi-
1). We then studied the effect of common rhodium catalysts on tion products are racemic.
the reactions. When 1 mol % Rh(I) catalyst [Rh(CH2CH2)2Cl]2
was used (Table 1, entry 2), product 3a was not detected. The According to previous reports [16], after a series of arylcyclo-
commonly used Rh(III) catalyst [Rh(Cp*)Cl2]2 lead to a 72% propylamines 1 with different substituents were synthesized, the
yield of product 3a (Table 1, entry 3). Next, the representative scope of 1 was then explored and the results are shown in
dirhodium(II) carboxylate such as Rh2(OAc)4, Rh2(TFA)4, Table 2. The data suggest that the electronic effect on the aro-
Rh2(esp)2 and dirhodium(II) carboxamidate catalysts such as matic ring of 1 influences the results of the reactions. Com-
Rh2(cap)4, Rh2(5S, R-MenPY)4 were evaluated in the reaction. pound 1 with electron-donating groups, such as methoxy, tert-
Rh2(OAc)4 created 3a with a yield of 45% (Table 1, entry 4) butyl, and methyl groups, all reacted smoothly to produce prod-
and Rh2(TFA)4 improved the yield of 3a to 52% (Table 1, entry ucts with good yields (Table 2, entries 1–3). The cyclization of
5). With the chelating catalyst Rh2(esp)2, the yield further in- substrate 1 containing electron-withdrawing groups at the aro-
creased to 68% (Table 1, entry 6). Although the carboxamidate matic substuituent proceeded slowly, producing considerably
type Rh2(cap)4 resulted in a lower yield (Table 1, entry 7), the lower yields of the corresponding products. For instance,
yield raised to 61% when Rh2(5S, R-MenPY)4 [19,20] was multiple-substituted compound 1 (with a 3,5-disubstitued tri-
applied as the catalyst (Table 1, entry 8). Next, 0.1 mol % cata- fluoromethyl 1f) generated product 3f with a yield of 36% (88%
lytic loading was tested in the reactions to investigate the effi- brsm) after 24 h (Table 2, entry 5), but 3,5-dimethyl compound
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Beilstein J. Org. Chem. 2019, 15, 542–550.
Table 1: Catalyst screening and optimization of reaction conditionsa.
Entry
Conditions
Solvent
Yieldb (%)
1
2
no catalyst
[Rh(CH2CH2)2Cl]2
[Rh(Cp*)Cl2]2
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCE
NR
ND
72
45
52
68
40
61
39
44
58
67
59
59
60
33
3
4
Rh2(OAc)4
5
Rh2(TFA)4
6
Rh2(esp)2
7
Rh2(cap)4
8
Rh2(5S,R-MenPY)4
Rh2(esp)2
9c
10c
11c
12c
13c
14c
15c
16c
[Rh(Cp*)Cl2]2
Rh2(5S,R-MenPY)4
Rh2(5S,R-MenPY)4
Rh2(5S,R-MenPY)4
Rh2(5S,R-MenPY)4
Rh2(5S,R-MenPY)4
Rh2(5S,R-MenPY)4
hexane
toluene
DME
DMF
aReaction conditions: 1a (0.5 mmol, 0.2 M in degassed solvent), 2a (2.5 mmol), catalyst (1 mol %) under argon at room temperature for 24 h unless
otherwise noted. bIsolated yield. c0.1 mol % of catalyst. esp = α,α,α’,α’-tetramethyl-1,3-benzenedipropionate, cap = caprolactamate, 5S,R-MenPY =
(S)-(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl 2-oxopyrrolidine-5-carboxylate, NR = no reaction, ND = not detected.
1d afforded the desired product 3d with an excellent yield of Next, we surveyed the different alkyne substrates 2 for cycload-
91% (Table 2, entry 3). We reasoned the electron-withdrawing dition under optimized reaction conditions. The terminal
groups on the arene increased the nitrogen–hydrogen bond alkynes with electron-withdrawing groups reacted smoothly to
dissociation energy (BDEN–H) of compound 1 [21], decreasing produce the desired products, while alkyl-substituted terminal
the rate of ring opening. Substrates 1i,j containing hindered aldehydes, such as pent-1-yne (2b, Table 3, entry 1), did not
substituents lead to low conversion of the substrates, producing produce the cycloaddition product [22-24]. tert-Butyl-
only poor yields of products 3i,j (Table 2, entries 8 and 9), dimethylsilyl-protected propargyl alcohol 2c had a greatly
which implied that steric hindrance greatly influenced the reac- reduced reactivity (Table 3, entry 2) and the obtained yield was
tions.
less than 10%. For aromatic terminal alkynes, moderate yields
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Beilstein J. Org. Chem. 2019, 15, 542–550.
Table 2: Substrate scope of N-arylaminocyclopropanesa.
Entry
1
Substrate
Product
Yieldb
59%
1b
1c
3b
3c
2
78%
3
4
1d
1e
3d
3e
91%
85%
5
1f
3f
36% (88% brsm)
6
7
1g
1h
3g
3h
67%
24% (52% brsm)
8
1i
3i
20% (67% brsm)
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Beilstein J. Org. Chem. 2019, 15, 542–550.
Table 2: Substrate scope of N-arylaminocyclopropanesa. (continued)
9
1j
3j
37% (65% brsm)
aReaction conditions: 1b–j (1 mmol, 0.2 M in degassed solvent), 2a (5 mmol), catalyst (0.1 mol %) at room temperature for 24 h unless otherwise
noted. bIsolated yield; brsm = based on recovered starting material.
Table 3: Substrate scope of alkyne derivativesa.
Entry
1
Substrate
Product
N.D.
Yieldb(%)
N.R.
2b
2c
4b
4c
2
3
<10
65
2d
2e
4d
4e
4
5
64
65
2f
4f
6
7
2g
2h
4g
4h
64
31
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Beilstein J. Org. Chem. 2019, 15, 542–550.
Table 3: Substrate scope of alkyne derivativesa. (continued)
8c
2i
4id,e
45 (17:83)f
,
9
2j
4j
41 (30:70)f
10
2k
4k
44
40
11c
2l
4ld
aReaction conditions: 1a (1 mmol, 0.2 M in degassed solvent), 2b–l (5 mmol), catalyst (0.1 mol %) at room temperature for 24 h unless otherwise
noted. bIsolated yield. cN-Arylaminocyclopropane 1d was used instead of 1a. dMajor isomer shown. eIsomer ratio 89:11. fDiastereoisomeric ratios
(cis/trans) were determined by 1H NMR spectroscopy of the crude products.
(Table 3, entries 3–6) were obtained regardless of the electron- 44% with the alkyne group being involved in the reaction
donating or electron-withdrawing groups, indicating the elec- (Table 3, entry 10). The reaction with 2l mainly produced 1,3-
tronic effect on the aromatic ring of 2 had little effect on the diene product 4l with a yield of 40% (Table 3, entry 11). In ad-
results of the reactions. Due to the decrease in the activity of the dition, we also examined some alkynes containing heterocycles,
alkyne, the conjugated 2,4-hexadiyne (2h) produced a poor such as 3-ethynylpyridine and 2-ethynylthiophene. Because the
yield of only 31% (Table 3, entry 7). To study the chemical heteroatoms were axially tightly coordinated to the
selectivity of the reaction, we examined conjugated alkyne sub- dirhodium(II) catalyst, coordination of the cyclopropylamine
strates. For 2-methylbut-1-en-3-yne (2i) containing both termi- with the dirhodium(II) catalyst was inhibited, resulting in no
nal alkenes and alkynes, the activity of the olefin was greater cycloaddition reaction occurring.
than that of the alkyne, which favors alkene cycloaddition prod-
ucts with a ratio of 89:11. The observed selectivity of product 4i To explore the synthetic practicality of this transformation,
is similar to that previously reported [11] (Table 3, entry 8), in- racemic compound 3b resulting from 1b and 2a was reduced
dicating the results of this type of reaction are mainly deter- using hydrogen and palladium on carbon (Scheme 2). It is inter-
mined by the stability of the free radical intermediate during the esting to note that only trans-5a was obtained and no cis prod-
reaction. Further investigation revealed cycloaddition preferen- uct formed. After further removal of the para-methoxyphenyl
tially proceeded with the terminal alkene or alkyne. Product 4j (PMP) group using ammonium cerium nitrate (CAN), the cyclic
was obtained with a 41% yield due to cycloaddition with an β-amino acid ester 5b was obtained with a yield of 80%. Cyclic
olefin group in 2j (Table 3, entry 9). When 2k was applied in β-amino acids and derivatives have good bioactivity and are
the reaction, the addition product was obtained with a yield of widely used as key synthetic intermediates in biomedical
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Beilstein J. Org. Chem. 2019, 15, 542–550.
Scheme 2: Synthesis of trans-ethyl 2-aminocyclopentanecarboxylate.
research [25-29]. Thus, based on this cycloaddition protocol, a The mechanism of the [3 + 2] cycloaddition reaction of 1a and
convenient strategy can be established to synthesize trans- 2a is similar to that previously reported [18] (Scheme 3). The
cyclic β-amino acids.
distonic radical cation C resulting from cyclopropane ring
Scheme 3: Proposed mechanism.
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Beilstein J. Org. Chem. 2019, 15, 542–550.
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bar was charged with Rh2(5S,R-MenPY)4 (0.1 mol %), alkyne
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Supporting Information File 1
Experimental procedures, compound characterization, and
NMR spectra.
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-15-48-S1.pdf]
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Acknowledgements
We are grateful for financial support from National Science
Foundation of China (Grant No. 21272162).
ORCID® iDs
Yuanhua Wang - https://orcid.org/0000-0003-0514-6976
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