A Ni–Ir Dual Photocatalytic Liebeskind Coupling of Sulfonium Salts for the Synthesis of 2-Benzylpyrrolidines

Article abstract of DOI:10.1002/ejoc.201900957

A new method has been developed for the synthesis of 2-benzylpyrrolidines utilizing cross-coupling and photoredox catalysis. Using a well-established dual Ni–Ir system, we were able to successfully couple benzylsulfonium salts with proline utilizing radical forming through CO₂ extrusion. This enabled the simple one-step synthesis of 2-benzylpyrrolidines from stable, inexpensive starting materials.

Full text of DOI:10.1002/ejoc.201900957

DOI: 10.1002/ejoc.201900957
Communication
Photoredox Catalysis
A Ni–Ir Dual Photocatalytic Liebeskind Coupling of Sulfonium
Salts for the Synthesis of 2-Benzylpyrrolidines
Bálint Varga,[a] Zsombor Gonda,[a] Balázs L. Tóth,[a] András Kotschy,[b] and Zoltán Novák*[a]
Abstract: A new method has been developed for the synthesis utilizing radical forming through CO2 extrusion. This enabled
of 2-benzylpyrrolidines utilizing cross-coupling and photoredox the simple one-step synthesis of 2-benzylpyrrolidines from sta-
catalysis. Using a well-established dual Ni–Ir system, we were ble, inexpensive starting materials.
able to successfully couple benzylsulfonium salts with proline
Introduction
sulfonium salts in photoredox transformations remains under-
developed.[15] We envisioned that through the combination of
nickel-catalyzed cross-coupling of benzylsulfonium salts and
the decarboxylative photocatalyzed transformation of Boc-pro-
tected prolines a novel synthetic approach could be developed
for the synthesis of 2-benzylpyrrolidines in a one-step dual
photoredox reaction.
2-Benzylpyrrolidines show biological activity as peripheral D-1
and D-2 dopamine agonist which can help the treatment of
hypertension and heart disease.[1] Also, these compounds act
as a dual orexin receptor antagonist, providing a useful strategy
for treating sleep disorders.[2] Furthermore, they can be used as
a calcium receptor antagonist to treat osteoporosis.[3] The typi-
cal preparation of this moiety involves palladium-catalyzed
cyclization,[4,5] use of sensitive organozinc reagent,[6] or a multi-
step process including ene-carbamate generation and its
hydrogenation.[7]
As promising drug candidates, their simple production from
feedstock chemicals can be attractive. For this purpose, we were
inspired by the available photoredox transformations,[8] which
enable the functionalization of sp3 carbon centers of saturated
heterocyclic carboxylic acids.[9] In this scenario, the merge of
photoredox and nickel-catalyzed cross-coupling reactions is a
well-established methodology, which offer novel synthetic tool
to construct C(sp3)–C(sp2) and C(sp3)–C(sp3) bonds.[10]
In our research, we aimed to develop a method for the pho-
tocatalyzed coupling of sulfonium salts and N-protected proline
to reach the desired target benzylpyrrolidines, and demonstrate
the applicability of these onium reagents as coupling partners
in dual photoredox transformations.[11] Sulfonium salts are
widely used versatile reagents in organic chemistry.[12] Among
these compounds, the tetrahydrothiophenium salts are capable
of participating in cross-coupling via oxidative addition reaction
to palladium or nickel center as it was demonstrated by
Liebeskind.[13] Although the usefulness of Umemoto's CF3 rea-
gent is already known,[14] the application of the related alkyl
Results and Discussion
For our study, we prepared several structurally diverse 1-benzyl-
tetrahydro-1H-thiophen-1-ium salts using the known literature
procedures.[13] The reaction of substituted benzyl bromides
with tetrahydrothiophene (THT) in acetone afforded the desired
cyclic sulfonium salts in good yields. In order to get sulfonium
salts with higher stability, we performed the bromide anion ex-
change using NH4PF6 to obtain the hexafluorophosphate salts
(Scheme 1. Method A). For the synthesis of heterocyclic THT
salts 18, 19 we used the appropriate alcohols as substrates for
the nucleophilic replacement of the hydroxy group under acidic
conditions (Scheme 1. Method B).
For the optimization of the dual photocatalytic coupling, we
examined the reaction of N-Boc-proline and benzyltetrahydro-
thiophenium hexafluorophosphate under various reaction con-
ditions.
First, we examined the effect of transition metal-based pho-
tocatalysts on the nickel-catalyzed coupling. We carried out the
coupling in the presence of 10 mol% Ni(glyme)Cl2, 15 mol-%
2,2′-bipyridyl ligand and 1.5 equiv Cs2CO3 base in DMF solvent
under argon atmosphere using LEDs with different wavelength
(Table 1.). In case of Ru(bpy)3PF6 we did not observe the forma-
tion of the desired benzylpyrrolidine (21), only the benzyl ester
of N-Boc-proline (22) was formed, demonstrating the lack of
photocatalytic decarboxylation step and formation of the
heterocyclic radical (Entries 1–2). Based on the redox potentials
and stability, it was expected that the iridium based photocata-
lyst should be more efficient in this transformation. However,
the ligands connected to the metal center had a great impact
on the conversion. Among the tested five different iridium
[a] ELTE “Lendület” Catalysis and Organic Synthesis Research Group,
Institute of Chemistry, Eötvös Loránd University,
Pázmány Péter stny. 1/A, 1117 Budapest, Hungary
E-mail: novakz@elte.hu
https://zng.elte.hu/
[b] Servier Research Institute of Medicinal Chemistry,
Záhony utca 7, 1031 Budapest, Hungary
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201900957.
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Scheme 1. The synthesized sulfonium salts made from benzyl bromides (Method A) and heteroaryl methanol (Method B).
complexes the most successful photocatalyst was the amount (91:1 vs. 36:55, Entries 7 and 13). The results were very
Ir[dF(CF3)ppy]2(dtbbpy)PF6 complex, which led to 91 % conver- promising, and we continued the optimization study with the
sion of 21 after 20 hours reaction time, and the reaction mix- screening of different solvents. While N, N-dimethylformamide
ture contained only 1 % of the benzyl ester side product (22, (DMF) seemed like a good solvent for the reaction, we did not
Entry 7). The other iridium catalysts showed lower photocata- reach full conversion. Among the tested solvents (1,4-dioxane,
lytic activity and provided the desired coupled product in lower 1,2-dimethoxyethane and acetonitrile, entries 14–16) aceto-
efficiency. In parallel, the lower conversion resulted in the for- nitrile proved to the best reaction media. The conversion of
mation of ester 22 in higher amount (entries 3–6). Changing proline in MeCN after 20 hours was 100 % and we did not ob-
royal blue (440–445 nm) LED to the blue (460–470 nm) chip we serve the formation of ester 22. After the workup of the reac-
observed 71 % conversion after 20 hours reaction time (Entry tion mixture 2-benzylpyrrolidine was isolated in 69 % yield (En-
8). Next, we examined the dual photocatalytic nature of the try 16). In order to improve further the efficiency of the reaction
transformation. We found that the reaction did not take place in we studied the effect of the Ni catalyst on the photocatalytic
the absence of photocatalyst, nickel complex or light irradiation coupling. In our comparative study different ligands and nickel
(Entries 9–12). In each case only the appropriate ester formation sources were examined. Among the studied complexes the
occurred, demonstrating the lack of photocatalytic activity and simple unsubstituted bipyridyl-nickel complex provided the
coupling cycle. When the reaction was performed with benzyl highest conversion and yield (Entry 19, 68 % isolated yield). A
bromide instead of the sulfonium salt (2), we observed that the similar reactivity trend was observed when we generated the
esterification of proline is faster and 22 was formed in greater nickel complex in situ from Ni(glyme)Cl2 and the appropriate
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bipyridyl ligand (Entries 20 and 21). In the presence of 2,2′- reactions. Benzylsulfonium salts having alkyl substituents in the
bipyridyl ligand, the Ni–Ir dual system provided the highest aromatic core reacted smoothly with N-Boc-proline under the
yield of the desired product 21 (74 %) in reduced, 1 hour reac- optimized reaction conditions and provided the appropriate
tion time (Entry 22). Finally, we compared the reactivity of the products 23, 24 and 25 in 30 %, 61 %, and 70 % yield respec-
THT salt with benzyl chloride, which was used instead of benzyl tively. The reactivity pattern revealed that steric factors deter-
bromide by MacMillan and co-workers in their Ni–Ir dual photo- mine the efficiency of the reaction, and the ortho-substituted
catalytic alkylation methodology for the suppression of the es- benzyl derivative gave lower yield compared to the other rea-
terification side reaction.[10p] With the application of our photo- gents. Next, halogenated benzylsulfonium salts were used for
reactor, we did not observe the benzyl ester formation, but the the photocatalyzed transformation of N-Boc-proline. The cou-
desired C-alkylated product 21 was formed only in 6 % conver- pling of these substrates could be challenging due to the tend-
sion after 1 hour reaction time when benzyl chloride was used ency of oxidative addition reaction between the aryl halide and
(Entry 23). This finding is in good accordance with the literature the nickel catalyst. We demonstrated that the presence of F, Cl,
data available for different photocatalytic setups (reaction time and Br atoms are compatible with the reaction conditions and
depends on the used photoreactor, 9–48 hours)[10p,10q] How- the desired benzylpyrrolidines (26–33) were isolated in 30–
ever, we were able to isolate 21 only in 20 % yield (84 % conver- 60 % yield when the appropriate sulfonium salts were sub-
sion) after 24 hours irradiation, which is lower than the litera- jected to photocatalyzed transformation.
ture data, supposedly due to the different photochemical set-
ups. This comparative study revealed the enhanced reactivity
of the benzyl-THT salt compared to the corresponding chloride
in the Ni–Ir dual photocatalytic C-benzylation without the for-
mation of the unwanted benzyl ester 22.
The lowest yield (30 %) was observed when the large chlor-
ine atom was in the ortho position of the benzylsulfonium salt.
Some of the halogenated products are ready for further trans-
formation via transition metal-catalyzed cross-coupling reac-
tions. Electron-withdrawing groups such as CF3, CN and COOMe
With the optimized reaction conditions in hand, and after were tolerated, and products 34, 35, 36 were isolated in 51 %,
the first successful isolation of product 21 with 74 % yield, we 28 %, and 60 % yield respectively. In contrast, the presence of
began to explore the scope of the decarboxylative benzylation strong electron-withdrawing NO2 group in the benzyl part com-
Table 1. Optimization of reaction conditions.
Entry
PC[a]
Ni catalyst, Ligand
Solvent
Conversion %, (ratio of 21:22); isolated yield [%][b,c]
1[d]
2[e]
3
4
5
PC 1
PC 1
PC 2
PC 3
PC 4
PC 5
PC 6
PC 6
PC 6
PC 6
–
Ni(glyme)Cl2, bpy
Ni(glyme)Cl2, bpy
Ni(glyme)Cl2, bpy
Ni(glyme)Cl2, bpy
Ni(glyme)Cl2, bpy
Ni(glyme)Cl2, bpy
Ni(glyme)Cl2, bpy
Ni(glyme)Cl2, bpy
Ni(glyme)Cl2, bpy
–
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
Dioxane
DME
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
100 (0:1)
100 (0:1)
28 (11:17)
40 (3:1)
65 (6:1)
72 (7:3)
92 (91:1)
71 (1:0)
100 (0:1)
100 (0:1)
100 (0:1)
100 (0:1)
91 (36:55)
32 (1:1)
86 (85:1)
100 (1:0); [69]
78 (63:15); [36]
57 (41:16); [28]
100 (1:0); [68]
94 (93:1); [50]
76 (68:8); [40]
100 (1:0); [74][h]
6 (1:0);[h] 84 % (1:0) [20]
6
7
8[d]
9[f]
10
11
12
13[d,g]
14
15
16
17
18
19
20
21
22
23[i]
Ni(glyme)Cl2, bpy
–
–
PC 6
PC 6
PC 6
PC 6
PC 6
PC 6
PC 6
PC 6
PC 6
PC 6
PC 6
Ni(glyme)Cl2, bpy
Ni(glyme)Cl2, bpy
Ni(glyme)Cl2, bpy
Ni(glyme)Cl2, bpy
Ni(dtBubpy)Cl2
Ni(dMeObpy)Cl2
Ni(bpy)Cl2
Ni(glyme)Cl2, dtbbpy
Ni(glyme)Cl2, d(MeO)bpy
Ni(glyme)Cl2, bpy
Ni(glyme)Cl2, bpy
[a] PC: photocatalysts: PC 1: Ru(bpy)2PF6, PC 2: Ir(ppy)3, PC 3: Ir[dtbppy]2(dtbbpy)PF6, PC 4: Ir(Fppy)3, PC 5: Ir[dtbbpy](ppy)2PF6, PC 6: Ir[dF(CF3)ppy]2(dtbbpy)PF6.
[b] Conversions determined by GC–MS based on the consumption of proline. [c] Preparative yields are in [] brackets. [d] LED emission maximum: 460–470 nm.
[e] LED emission maximum: 520–525 nm. [f] No LED irradiation. [g] Benzyl bromide was used instead of sulfonium salt 2. [h] 1 hour reaction time instead of
20 hours. [i] Benzyl chloride was used.
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Scheme 2. The scope of the photochemical reaction.
pletely shut down the reaction. Additionally, the couplings with
heteroaryl sulfonium salts were successful, but products 38, 39
were isolated only in 14 % and 24 % yield, probably due to the
sensitivity and instability of the molecules (Scheme 2). It is of
note that the utilization of other protecting groups such as Z,
Fmoc and Ac for the proline nitrogen did not provide the corre-
sponding pyrrolidine derivative. Additionally, the transforma-
tion of other Boc protected amino acids were also unsuccess-
ful.[16]
Regarding the mechanism of the dual photocatalyzed cou-
pling of N-Boc-proline and benzylsulfonium salts, we propose
the following catalytic cycles for the transformation (Scheme 3).
It is established that the photoexcited Ir is a good single-elec-
tron oxidant considering its redox potential (Ir(III) {E1/2red [*Ir(III)/
Ir(II)] = +1.21 V vs. SCE in CH3CN}).[17] It initiates a SET reaction
red
with the deprotonated Boc-proline [(Boc)-Pro-OCs, E1/2
=
+0.95 V vs. SCE in CH3CN][18] producing the 40 radical species
through oxidative quenching and gives Ir(II) in the process. Con-
currently, the sulfonium-salt (2) coordinates to a Ni(0) species
(41)[19] and participates in oxidative addition producing Ni(II)
(42).[20] This complex intercepts the radical (40) generating the
43 Ni(III) organometallic adduct. From this the desired product
Scheme 3. The proposed mechanism of the reaction.
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In summary, we developed a novel dual Ni–Ir photocatalyzed
reaction for the synthesis of benzylpyrrolidine derivatives from
simple N-Boc-proline. We demonstrated for the first time that
benzylsulfonium derivatives are applicable substrates of the
photocatalyzed coupling. This finding could open new syn-
thetic approaches to the construction of C(sp3)–C(sp3) bonds,
and broaden the collection of available photoredox procedures.
The optimized reaction conditions ensured the novel synthesis
of versatile benzylpyrrolidine compounds, which are of high in-
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Experimental Section
A 20 mL glass vial equipped with a magnetic stir bar and N-Boc-
proline (86 mg, 0.40 mmol, 1.00 equiv.), then the Ir[dF(CF3)ppy]2-
(dtbbpy)PF6 (4.5 mg, 0.004 mmol, 1 mol %), Ni(glyme)Cl2 (8.8 mg,
0.04 mmol, 10 mol%), 2,2'-bipyridine (9.4 mg, 0.06 mmol, 15 mol
%), the sulfonium salt (0.40 mmol, 1.00 equiv) and Cs2CO3 (200 mg,
0.60 mmol, 1.50 equiv) was measured in. The vial was sealed, evacu-
ated and backfilled with Ar three times. Then 20 mL of degassed
anh. acetonitrile was added. The reaction vial was put into our pho-
toreactor and stirred at 20 °C (for photoreactor setup see SI). After
1 hour the reaction vessel was removed from the reactor. Ethyl
acetate was added (20 mL) and the mixture was washed with sat.
NaHCO3 solution once then with brine. The organic phase was dried
with anhydrous Na2SO4 then concentrated. The crude product was
purified by column chromatography using silica gel, with a gradient
of hexanes and ethyl acetate.
[10]
Acknowledgments
This research was funded by National Research, Development
and Innovation Office (NN118172 and PD124592); János Bolyai
Research Scholarship of the Hungarian Academy of Sciences
(Z. N.) This work was completed in the ELTE Institutional Excel-
lence Program (1783-3/2018/FEKUTSRAT) supported by the
Hungarian Ministry of Human Capacities. The authors thank the
analytical measurements for László Burai and Tamás Gáti at
Servier Research Institute of Medicinal Chemistry.
[11]
[12]
[13]
Keywords: Sulfonium salts · Cross-coupling · Iridium ·
Nickel · Photoredox catalysis
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Communication
Photoredox Catalysis
B. Varga, Z. Gonda, B. L. Tóth,
A. Kotschy, Z. Novák* ........................ 1–7
A Ni–Ir Dual Photocatalytic Liebes-
kind Coupling of Sulfonium Salts for
the Synthesis of 2-Benzylpyrrol-
idines
A new Ni–Ir dual photochemical cata- reaction partners in the visible light
lyst system was developed for the syn- driven radical coupling reaction for the
thesis of benzylpyrrolidines from benz- construction of new C(sp3)–C(sp3)
ylsulfonium salts. We demonstrated bonds.
that the sulfonium salts are applicable
DOI: 10.1002/ejoc.201900957
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim