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Synlett 2022; 33(12): 1194-1198
DOI: 10.1055/a-1665-9220
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Organic Photoredox Catalysis in Synthesis – Honoring Prof. Shunichi Fukuzumi’s 70th Birthday

Red-Light-Induced N,N′-Dipropyl-1,13-dimethoxyquinacridinium-Catalyzed [3+2] Cycloaddition of Cyclopropylamines with Alkenes or Alkynes

Savannah M. Stull
a   Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ 85721, USA
,
Liangyong Mei
b   Department of Chemistry, Colgate University, 13 Oak Dr, Hamilton, NY 13346, USA
,
Thomas L. Gianetti  ∗
a   Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ 85721, USA
› Author Affiliations

We are grateful to the University of Arizona and the ACS Petroleum Research Fund (grant no. 59631-DNI3) for financially supporting this work. All NMR data were collected in the NMR facility of the Department of Chemistry and Biochemistry at the University of Arizona, and we thank Dr. Jixun Dai for his help. The purchase of the Bruker NEO 500 MHz spectrometer was supported by the National Science Foundation (Grant No. 1920234) and by the University of Arizona.
› Further Information
 
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Abstract

A red-light-mediated [3+2] annulation of cyclopropylamines with akenes or alkynes in the presence of N,N′-dipropyl-1,13-dimethoxyquinacridinium is reported. An array of cyclopentane or cyclopentene derivatives with diverse functional groups have been obtained in moderate to excellent yields under mild conditions.


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Key words

photoredox catalysis - [3+2] cycloaddition - cyclopropylamines - alkenes - alkynes - dipropyldimethoxyquinacridinium

Cyclopentyl functional group motifs are prevalent in a wide range of bioactive pharmaceuticals and natural products such as peramivir,[1] aristeromycin,[2] prostaglandin F2α,[3] and vibralactone[4] (Figure [1]). As a consequence, various strategies for their synthesis have been developed.[5] [6] [7] [8] [9] Representative examples include the Pauson–Khand reaction,[5] Nazarov cyclization,[6] [3+2] cycloaddition,[7] ring-closing metathesis,[8] and the intramolecular Henry reaction.[9] In particular, the visible-light-mediated [3+2] cycloaddition of cyclopropylamines caught our attention, because it not only represents an atom-economical process, but also takes advantage of readily available and environmentally friendly visible light.[10] During the reaction, cyclopropylamine serves as a three-carbon-atom precursor by generating a crucial distonic radical cation intermediate through a radical mechanism.[10]

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Figure 1 Selected examples of pharmaceuticals and natural products bearing a cyclopentane/cyclopentene core

Cha and co-workers pioneered this work by introducing a photomediated intramolecular [3+2] annulation of olefin-tethered cyclopropylamines,[10a] which built the foundation for future developments (Scheme [1a]). Nevertheless, its requirements for UV light and stoichiometric amounts of photosensitizer have rendered his protocol less than practical. Over the past decade, the renaissance of modern visible-light-induced photoredox catalysis has brought new life to this reaction because its milder conditions can address the previously noted drawbacks.[11] As a result, the Zheng group has reported several exquisite examples of visible-light-mediated intermolecular [3+2] annulations of cyclopropylamines with olefins, alkynes, enynes, or diynes in the presence of tris(2.2′-bipyrazyl)ruthenium(II) [Ru(bpz)3 2+] (Scheme [1b]).[10`] [d] [e] Afterwards, the Waser group presented a synthesis of bicyclo[3.1.0]hexanes through a 1,3-dicyano-2,4,5,6-tetrakis(diphenylamino)benzene (4DPAIPN)-catalyzed [3+2] cycloaddition of cyclopropenes with aminocyclopropanes under blue-light irradiation (Scheme [1c]).[10f] Later, the Jiang group disclosed an asymmetric version of Zheng’s original protocol by employing cooperative photoredox and chiral Brønsted acid catalysis in the presence of blue LEDs (Scheme [1d]).[10g] More recently, Aggarwal et al. introduced a diastereoselective blue-light-mediated 1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene (4CzIPN)-catalyzed [3+2] cycloaddition of N‑sulfonyl cyclopropylamines with electron-deficient olefins, which further expanded the substrate scope of this reaction (Scheme [1e]).[10h] Despite the impressive progress to date, all the current protocols employ relatively high-energy blue or white light. In contrast, red light features a lower energy, greater penetration depth, fewer health risks, fewer side reactions, and more abundance from sunlight.[12] Therefore, developing a red-light-induced [3+2] cycloaddition of cyclopropylamine for the synthesis cyclopentane and cyclopentene derivatives is still highly desirable.

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Scheme 1 (a–e) Previous work on visible-light-mediated [3+2] cycloaddition of cyclopropylamines, and (f) this work

Recently, we demonstrated that the helicenium ion N,N′-dipropyl-1,13-dimethoxyquinacridinium (nPr-DMQA+) is an efficient organic photocatalyst for red-light-mediated reactions.[13] This photocatalyst has successful catalyzed a series of well-studied photocatalyzed reactions, as well as a novel red-right-mediated cascade trifluoromethylation/dearomatization of indole derivatives with Umemoto’s reagent for the synthesis of trifluoromethylated spirocyclic indolines.[13] [14] In the above-mentioned visible-light-mediated Ru(bpz)3 2+-catalyzed [3+2] cycloadditions,[10c–e] Ru(bpz)3 2+ {E1/2 [Ru(I)/Ru(II*)] = +1.45 V vs. the saturated calomel electrode (SCE)}[15] acted as a photooxidant by oxidizing cyclopropylamine to the corresponding nitrogen radical cation (ArRNH/ArRNH∙+ ≈ +1.0 V vs. SCE[16]) through reductive quenching. With E1/2(C+*/C∙) = +1.15 V and E1/2(C+/C∙) = –0.78 V vs. SCE[13] for nPr-DMQA+, along with E1/2 [Ru(I)/Ru(II)] = –0.80 V vs. SCE[15] for Ru(bpz)3 2+), nPr-DMQA+ should be competent to catalyze such transformation. We present an nPr-DMQA+-catalyzed [3+2] annulation of cyclopropylamines with olefins or alkynes in the presence of red light that provides a simple and more sustainable approach for the construction of functionalized cyclopentanes or cyclopentenes under mild conditions (Scheme [1f]).

For our initial examinations, we used N-cyclopropylaniline (1a) and styrene (2a) as model substrates in the presence of nPr-DMQA+ under red-light irradiation to screen the optimal conditions, and the results of these experiments are summarized in Table [1]. Delightfully, the desired product N-(2-phenylcyclopentyl)aniline (3a) was obtained in 95% NMR yield and a 1.1:1 (trans/cis) dr in nitromethane (MeNO­2) when the reaction was run with 3.0 mol% of nPr-DMQ­A+ at r.t. for 18 hours (Table [1], entry 1). The use of MeNO­2 as the solvent is consistent with other literature reports.[10] Solvents other than MeNO2, such as acetonitrile (MeCN) (entry 10), resulted in a lower yield. By decreasing the catalyst loading, we observed that 1.0 mol% of PC gave the best performance, furnishing 3a in 95% NMR yield and 1:1.1 dr (entry 2). An investigation of the reaction time revealed that six hours was sufficient to complete the reaction, giving 3a in 95% NMR yield and 1:1.1 dr in the presence of 1.0 mol% of nPr-DMQA+ (entries 4–6). Thus, MeNO2 as the solvent, 1.0 mol % of nPr-DMQA+ as the catalyst loading, and a reaction time of six hours are the optimal reaction conditions (entry 5). Furthermore, in the absence of red light or nPr-DMQA+, none of the desired product 3a was detected, with mainly the starting materials 1a and 2a being recovered, which suggested that both red light and nPr-DMQA+ are essential (entries 7 and 8). Running the reaction under air lowered the reaction yield significantly, which is consistent with Zheng’s work[10c] (entry 9).

Table 1 Optimization of Red-Light-Mediated nPr-DMQA+-Catalyzed [3+2] Cycloaddition

Entrya

Catalyst loading (mol%)

Time (h)

Yield (%)b

d.r.c

 1

3.0

18

95

1:1.1

 2

1.0

18

95

1:1.1

 3

0.5

18

71

1:1.1

 4

1.0

 8

95

1:1.1

 5

1.0

 6

95

1:1.1

 6

1.0

 4

73

1:1.1

 7

1.0

20

nde

–

 8

–

20

nde

–

 9f

1.0

20

65

1:1.1

10g

3.0

36

66

1:1.4

a Reaction conditions: 1a (0.2 mmol), 2a (1.0 mmol), nPr-DMQA+, MeNO2 (1 mL).

b Yield by 1H NMR with 1,3,5-trimethoxybenzene as the internal standard.

c Determined by 1H NMR of the crude product.

d In darkness.

e nd = not detected.

f In the presence of air.

g In MeCN (1.0 mL)

With the optimal conditions in hand, we next sought to explore the substrate scope of this red-light-induced [3+2] cycloaddition (Scheme [2]). By using styrene (2a) as a model substrate, cyclopropylamines 1a–f with various aromatic groups were tested. The electronic properties or substitution patterns on the phenyl ring of 1 had little effect on the reaction outcome, and the corresponding cyclopentane derivatives 3a–f were obtained in yields of 60–93%. For example, substrate 1b with a phenyl group in the ortho-position gave the desired product 3b smoothly in 68% yield. Product 3c was isolated in 60% yield when styrene derivative 1c with a trifluoromethyl group at the meta-position reacted with 2a. In addition, 1d and 1e with methyl and chloro groups, respectively, in their para-positions provided the five-membered carbocycles 3d and 3e in moderate yields. Alkene 1f with a 3-pyridyl group was also suitable for this [3+2] annulation, furnishing 3f in 80% yield. Then, a wide range of alkenes 2b–i with diverse useful functional groups such as cyano (2b), ketone (2c), ester (2d), or halo (2e and 2f) were examined, and all reacted smoothly with N-cyclopropylaniline (1a). In detail, olefins 2b–d with strong electron-withdrawing groups afforded products 3g–i in yields of 61–95%. Products 3j–n were also obtained in yields of 62–91% when styrene derivatives 2e–i reacted with 1a. Although the reaction showed relatively poor diastereoselectivity, most pairs of trans- and cis-diastereomers were fully isolated by flash column chromatography, except for 3b, 3c, 3j, and 3m.

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Scheme 2 Substrate scope of red-light-mediated nPr-DMQA+-catalyzed [3+2] cycloaddition of cyclopropylamine with alkenes. Reagents and conditions: 1 (0.2 mmol), 2 (1.0 mmol), nPr-DMQA+ (0.002 mmol), MeNO2 (1.0 mL), red LEDs (λmax = 640 nm), under N2. The dr values were determined by 1H NMR of the crude products. a Reaction time: 6 h. b Reaction time: 24 h.

Notably, under the optimal reaction conditions, the [3+2] addition of cyclopropylamine with alkynes could also be achieved with a broad range of substrates (Scheme [3]). The corresponding cyclopentene products 5a–d were obtained in yields of 71–81% when electron-neutral, electron-deficient, or electron-rich terminal alkynes 4a–d reacted with 1a. Moreover, the dialkyne substrate 4e was also compatible under the standard reaction conditions, affording the desired product 5e in 65% yield. When internal alkynes 4f and 4g were tested, the desired products 5f and 5g were smoothly obtained, albeit in somewhat lower yields, possibly due to steric effects. It is also noteworthy that 5e was obtained in a much higher yield compared with that reported in the literature,[10d] presumably due to the relatively milder condition with red light in this protocol.

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Scheme 3 Substrate scope of red-light-mediated nPr-DMQA+-catalyzed [3+2] cycloaddition of cyclopropylamine with alkynes. Reagents and conditions: 1 (0.2 mmol), 2 (1.0 mmol), nPr-DMQA+ (0.002 mmol), MeNO2 (1.0 mL), red LEDs (λmax = 640 nm), under N2.

On the basis of previous work,[10] [13] [14] we propose the reaction mechanism for these transformations that is shown in Scheme [4]. First, nPr-DMQA+*, formed by irradiation with red light, undergoes a single-electron-transfer process with the cyclopropylamine 1a to generate the nitrogen radical cation intermediate A. Due to the inherent torsional and angular strain of the cyclopropane ring, A undergoes β-scission of this ring to form the β-carbon radical iminium ion B, which attacks styrene (2a) to produce another stabilized distonic radical cation species C. Intramolecular addition of the in situ-formed radical to the iminium ion in intermediate C furnishes another nitrogen radical cation species D. Lastly, D is reduced by the nPr-DMQA∙ to form the final product 3a, together with ground-state nPr-DMQA+, completing the catalytic cycle.

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Scheme 4 Plausible reaction mechanism

In conclusion, we have developed an nPr-DMQA+-catalyzed [3+2] cycloaddition of cyclopropylamines with alkenes or alkynes in the presence of red light that provides a facile and efficient route for the construction of functionalized five-membered carbocycles. A mechanism involving reductive quenching of a critical distonic radical cation species is proposed. The employment of low-energy red light permits this approach to serve as a complementary option to the current white- or blue-light-mediated protocols. Further investigations of this red-light-mediated [3+2] annulation of cyclopropylamines with other interesting substrates are underway in our laboratory.


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Conflict of Interest

The authors declare no conflict of interest.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-1665-9220. Included are general information, substrate synthesis and characterization, mechanistic investigation, experimental procedures, as well as NMR spectroscopy data.
  • Supporting Information

Corresponding Author

Thomas L. Gianetti
Department of Chemistry and Biochemistry, University of Arizona
Tucson, AZ 85721
USA   

Publication History

Received: 26 August 2021

Accepted after revision: 10 October 2021

Accepted Manuscript online:
10 October 2021

Article published online:
12 November 2021

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   Permissions and Reprints All articles of this category
Zoom Image
Figure 1 Selected examples of pharmaceuticals and natural products bearing a cyclopentane/cyclopentene core
Zoom Image
Scheme 1 (a–e) Previous work on visible-light-mediated [3+2] cycloaddition of cyclopropylamines, and (f) this work
Zoom Image
Scheme 2 Substrate scope of red-light-mediated nPr-DMQA+-catalyzed [3+2] cycloaddition of cyclopropylamine with alkenes. Reagents and conditions: 1 (0.2 mmol), 2 (1.0 mmol), nPr-DMQA+ (0.002 mmol), MeNO2 (1.0 mL), red LEDs (λmax = 640 nm), under N2. The dr values were determined by 1H NMR of the crude products. a Reaction time: 6 h. b Reaction time: 24 h.
Zoom Image
Scheme 3 Substrate scope of red-light-mediated nPr-DMQA+-catalyzed [3+2] cycloaddition of cyclopropylamine with alkynes. Reagents and conditions: 1 (0.2 mmol), 2 (1.0 mmol), nPr-DMQA+ (0.002 mmol), MeNO2 (1.0 mL), red LEDs (λmax = 640 nm), under N2.
Zoom Image
Scheme 4 Plausible reaction mechanism